PMID- 29693462 TI - The current prevalence of asthma, allergic rhinitis, and eczema related symptoms in school-aged children in Costa Rica. AB - OBJECTIVE: Asthma prevalence in Costa Rica is among the highest worldwide. We aimed to determine the prevalence of asthma among school-age children in the Central Highland Area of Costa Rica. METHODS: Cross-sectional study using the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire was performed. Parents or guardians of children aged 6-13 years completed written questionnaires. RESULTS: Total of 2817 school-aged children returned these questionnaires (74.1% return rate). The prevalence of asthma, rhinitis, and eczema was 21.9%, 42.6%, and 19.2%, respectively. The co-existence of the 3 diseases was seen in 22.6% of children with asthma. Boys had a slightly higher prevalence of these conditions, and younger children had higher prevalence of asthma and eczema, but lower prevalence of rhinitis than older children. The use of acetaminophen and antibiotics in the first 12 months of life showed a significant association with the prevalence of asthma, rhinitis, and eczema. Wheezing with exercise, dry cough at night, and ever rhinitis was highly associated with asthma symptoms in the last 12 months. In contrast, no association was found between children exposed to smoking at home. Frequent traffic next to the house was reported more frequently by the parents of children with asthma, although no significant association was found. CONCLUSION: The prevalence of asthma showed a significant decrease compared to previous studies. However, there was an unexpected high prevalence of rhinitis. Exposure to acetaminophen and antibiotic during the first year of life was highly associated with asthma symptoms. PMID- 29693463 TI - Living with limb loss: everyday experiences of "good" and "bad" days in people with lower limb amputation. AB - PURPOSE: To provide an understanding of the everyday experiences of individuals with a limb amputation. METHODS: Twenty-two participants (14 female, 8 male) with a mean-age of 42 years (SD = 10 years) were recruited to take part in two focus groups. The participants reported a range of lower-limb amputations (i.e., congenital, acquired, transfemoral, trantibial, unilateral, and bilateral) and on an average were 5 years post-surgery (SD = 7 years). Each focus group comprised of 11 participants and was moderated by either the first or second author. The moderator asked participants to discuss their everyday experiences of life with an amputation using Charmaz's good day/bad day approach. Focus groups were transcribed verbatim and analyzed using an inductive thematic analysis. RESULTS: Four themes were identified: pain, organization and planning, the embodied experience after amputation, and interactions with others. CONCLUSIONS: These themes provide a key resource for understanding daily fluctuations in physical, social, and psychological functioning. Implications for Rehabilitation Lower limb amputation can result in daily fluctuations in physical, social, and psychological functioning. These fluctuations can be illustrated through experiences of pain, planning and organization, embodied experiences, and interactions with others. At a policy level, evaluations of daily living after an amputation should be based on a longitudinal assessment. PMID- 29693464 TI - Motivation in rehabilitation and acquired brain injury: can theory help us understand it? AB - BACKGROUND: In acquired brain injury (ABI) populations, low motivation to engage in rehabilitation is associated with poor rehabilitation outcomes. Motivation in ABI is thought to be influenced by internal and external factors. This is consistent with Self-determination Theory, which posits that motivation is intrinsic and extrinsic. This paper discusses the benefit of using Self determination Theory to guide measurement of motivation in ABI. METHODS: Using a narrative review of the Self-determination Theory literature and clinical rehabilitation research, this paper discusses the unique role intrinsic and extrinsic motivation has in healthcare settings and the importance of understanding both when providing rehabilitation in ABI. RESULTS: Based on the extant literature, it is possible that two independently developed measures of motivation for ABI populations, the Brain Injury Rehabilitation Trust Motivation Questionnaire-Self and the Motivation for Traumatic Brain Injury Rehabilitation Questionnaire, may assess intrinsic and extrinsic motivation, respectively. CONCLUSION: Intrinsic and extrinsic motivation in ABI may be two equally important but independent factors that could provide a comprehensive understanding of motivation in individuals with ABI. This increased understanding could help facilitate behavioural approaches in rehabilitation. Implications for Rehabilitation Conceptualization of motivation in ABI would benefit from drawing upon Self-determination Theory. External factors of motivation such as the therapeutic environment or social support should be carefully considered in rehabilitation in order to increase engagement. Assessing motivation as a dual rather than a global construct may provide more precise information about the extent to which a patient is motivated. PMID- 29693465 TI - The influence of prenatal mental health service use on the incidence of childhood asthma: a population-based cohort study. AB - OBJECTIVES: We aimed to determine whether maternal mental health service use during pregnancy, a potential proxy measure of prenatal maternal stress, is associated with the development of asthma in a large population-based sample of children. We hypothesized that children born to mothers with mental health service use during pregnancy would have a higher incidence of childhood asthma. STUDY DESIGN: Health administrative data from Ontario, Canada (population >13 million) was used to identify pairs of mothers linked with their children born between April 1, 2001 to March 31, 2002. Descriptive statistics were used to compare the cumulative incidence of asthma by age 12 years in children whose mothers did or did not have prenatal mental health service use. Multivariable logistic regression was used to estimate the association between prenatal maternal mental health service use and childhood asthma incidence, after adjusting for the child's sex, residency (rural vs. urban), socioeconomic status, comorbid health conditions, low birthweight, and maternal history of asthma. RESULTS: In a population-based sample of 122,333 children, those born to mothers with mental health service use during pregnancy had increased odds of developing asthma (odds ratio: 1.16, 95% confidence intervals: 1.12, 1.20, p < 0.001). CONCLUSIONS: Prenatal maternal mental health service use is an independent risk factor for the development of asthma in childhood. This supports growing evidence for the importance of in utero exposure to maternal stress factors in asthma pathogenesis. This study highlights a potential strategy for the primary prevention of childhood asthma, namely improved recognition and management of mental health issues and stress in pregnant mothers. PMID- 29693466 TI - Isoprostane in systemic sclerosis: A systematic review and meta-analysis. AB - OBJECTIVES: To further the knowledge of oxidative stress in systemic sclerosis (SSc), we performed a systematic review and meta-analysis on studies measuring isoprostane, a vasoactive agent deriving from arachidonic acid and implicated in the vasculopathy of SSc. METHODS: Systematic search following the PRISMA guidelines in PubMed and EMBASE between January-1990/December-2017 using the terms: oxidative stress, isoprostane, systemic sclerosis and scleroderma. RESULTS: After the screening process, 8 studies including 240 SSc patients and 192 controls were included in the systematic review and meta-analysis, 6 investigating urinary and 2 serum isoprostane: random effect meta-analysis revealed isoprostane overgeneration in SSc (p < .001) with wide heterogeneity (I2 = 75%). Subgroup analysis on urinary isoprostane favoured excess excretion in SSc (p = .009) with slightly lower heterogeneity (I2 = 67%); further subgroup analysis according to unit of measurement revealed no increased isoprostane excretion when expressed as pg/mg creatinine but increased when expressed as pmol/mmol creatinine (p = .05) with medium heterogeneity (I2 = 32%). Subgroup analysis on serum isoprostane favoured overproduction in SSc (p < .0001) with no heterogeneity. CONCLUSION: There is some evidence for isoprostane overgeneration in SSc that confirms the occurrence of oxidative stress in this setting: further prospective studies with specified outcomes are needed to evaluate the prognostic value of this functional biomarker. PMID- 29693468 TI - Penetrating head injury due to angle grinder: an occupational hazard. AB - Penetrating head injury is a life threatening condition. In the workplace, these are mostly non missile type, low velocity civilian injuries caused by sharp objects. Angle grinders are used to cut stones, metal etc, and cause penetrating head injuries due to shattered rotating discs from the grinder at home and workplaces. We report a series of three cases of penetrating head injuries due to unsafe use of angle grinders. The relevant literature is reviewed and management of such cases is discussed. PMID- 29693467 TI - The RFK catalytic cycle of the pathogen Streptococcus pneumoniae shows species specific features in prokaryotic FMN synthesis. AB - Emergence of multidrug-resistant bacteria forces us to explore new therapeutic strategies, and proteins involved in key metabolic pathways are promising anti bacterial targets. Bifunctional flavin-adenine dinucleotide (FAD) synthetases (FADS) are prokaryotic enzymes that synthesise the flavin mononucleotide (FMN) and FAD cofactors. The FADS from the human pathogen Streptococcus pneumoniae (SpnFADS)-causative agent of pneumonia in humans - shows relevant catalytic dissimilarities compared to other FADSs. Here, by integrating thermodynamic and kinetic data, we present a global description of the riboflavin kinase activity of SpnFADS, as well as of the inhibition mechanisms regulating this activity. Our data shed light on biophysical determinants that modulate species-specific conformational changes leading to catalytically competent conformations, as well as binding rates and affinities of substrates versus products. This knowledge paves the way for the development of tools - that taking advantage of the regulatory dissimilarities during FMN biosynthesis in different species - might be used in the discovery of specific anti-pneumococcal drugs. PMID- 29693469 TI - Implementation of inclusive education for children with intellectual and developmental disabilities in African countries: a scoping review. AB - PURPOSE: To advance understanding of practices that support inclusion of children with intellectual and developmental disabilities in inclusive education classrooms in Africa by conducting a review of the extant literature. METHODS: Five academic databases were searched supplemented by a hand search of key journals and references of included studies. Two authors independently screened studies via a reference manager (Covidence) which allowed for blinding. A third author was consulted in cases of conflict. RESULTS: Thirty articles that provided empirical evidence of inclusive education implementation were included. Eight articles highlighted practices that support inclusion of children with intellectual and developmental disabilities. Using Bronfenbrenner's bioecological framework, findings revealed that inclusive education implementation is influenced by factors on the bio level, micro level, meso level, and macro level. Recommendations for promoting inclusive education implementation are provided. CONCLUSIONS: Inclusion goes beyond teachers and requires strong commitment of other stakeholders such as families and governments. To guarantee the smooth inclusion of children with special education needs and particularly with intellectual and developmental disabilities, a set of practices validated through rigorous research as supportive and unique and that can be universal to Africa is wise. Implications for rehabilitation A number of strategies were identified that can improve the classroom inclusion of children with intellectual and developmental disabilities. Development of policies that support such strategies could improve implementation. Inclusion goes beyond teachers. Rehabilitation professionals (i.e. occupational therapists) and educational professionals should partner to identify practical solutions to the challenges of creating inclusive environments for children with special education needs. Committing more resources and time towards the development and implementation of special education policies can advance the successful inclusion of children with special education needs. PMID- 29693470 TI - Chryseobacterium bacteraemia: a single-centre case series. PMID- 29693471 TI - Hidden Blood Loss in Spine Surgery for A1-A3 thoracolumbar Fractures. Comparison Between Three Approaches. PMID- 29693472 TI - Single piece fronto-temporo-orbito-zygomatic craniotomy: a personal experience and review of surgical technique. AB - BACKGROUND: Fronto-Temporo-Orbito-Zygomatic (FTOZ) craniotomy has progressed from its humble beginnings. Numerous variations including one piece, two piece and even three piece FTOZ craniotomies have been described. The ideal technique still remains elusive and its use remains restricted to a few specialised centres even when benefits far outweigh the surgical difficulties. OBJECTIVE: To analyse 11 cases in which single piece FTOZ craniotomy was used and to review the steps of surgery along with its advantages. METHODS: A total of 11 cases of skull base lesions were operated over a period of 30 months and followed up for a minimum period of 6 months. They were analysed for intraoperative benefits, requirement of cerebral retraction, surgical difficulties, post op recovery, complications faced and post-op cosmetic appearance. RESULT: A total of nine cases had tumours of skull base including Spheno-Petro-Clival meningiomas, Trigeminal schwannomas, Solitary fibrous histiocytoma and two had giant aneurysms of P1 segment. Intraoperative cerebral retraction was significantly less. There were two post-op deaths. Three patients had temporary and 1 patient had permanent third nerve deficit. There was no injury to periorbital fat and post op cosmetic appearance was good. CONCLUSION: Single piece FTOZ craniotomy is no more difficult than two or three piece craniotomy, rather it facilitates a rapid craniotomy closure with excellent handling of single piece of bone. It provides a wide, multidirectional access to skull base. Lesions become shallow and their access easier. Benefits far outweigh the difficulties if any, and its use should be encouraged even at centres outside of the specialised units. PMID- 29693473 TI - Getting inTOUCH: outcomes of a knowledge translation intervention for tactile assessment knowledge, barriers, and practice in paediatric therapists working with children with cerebral palsy. AB - BACKGROUND: Tactile impairments are common in children with cerebral palsy (CP), however assessment is not routinely carried out by therapists. We investigated a multi-faceted Knowledge Translation intervention to improve Knowledge, remove Barriers and enhance Practice of tactile assessments by paediatric therapists. METHOD: Twelve therapists from a state-wide service for children with CP (seven physiotherapists, five occupational therapists; 12 female) received: written information, demonstration videos, a face-to-face workshop, equipment provision, and on-call mentoring. Therapists completed pre-post-intervention questionnaires reporting their perceived tactile assessment Knowledge, current Practices and implementation Barriers. RESULTS: Following intervention, therapists improved Knowledge of correct (1) tactile impairment prevalence in children with CP (pre 3/12; post 9/12), (2) tactile assessment items (e.g. Registration - pre 1/12; post 9/12; Localisation - pre 2/12; post 10/12), and (3) equipment choice (e.g. Monofilaments - pre 1/12; post 10/12). Tactile assessment Practice improved slightly. All major clinician-level implementation Barriers were resolved and less obvious organisational-level Barriers were identified for follow-up. CONCLUSION: A 12-month multi-faceted Knowledge Translation intervention can improve tactile assessment Knowledge, resolve major clinician-level implementation Barriers, and identify less obvious organisational-level Barriers to be addressed to achieve maximum Practice improvement. Ongoing multi-faceted knowledge translation processes are essential for high-performing organisations. Implications for rehabilitation A multi-faceted knowledge translation intervention significantly improved paediatric therapists' knowledge of the items and equipment necessary for tactile assessment. A 12-month intervention can address clinician-level barriers of knowledge, confidence, and access to equipment and assist in the identification of less obvious organisational-level barriers. Consideration of motivational readiness for change, intervention timelines, monitoring of emergent barriers, and fitting tactile assessment into a broader assessment framework are critical for improving uptake of tactile assessment in practice. PMID- 29693474 TI - Acute Kidney Injury in Critically Ill Patients with Sepsis: Clinical Characteristics and Outcomes. AB - OBJECTIVE: The objectives of this study were to examine the clinical profile of critically ill patients with septic acute kidney injury (AKI) and to investigate clinical characteristics associated with the outcome of patients. METHODS: Data from 582 critically ill patients were collected and retrospectively reviewed. Patients were divided into two groups: without AKI development and with AKI development. Baseline characteristics, laboratory, and other clinical data were compared between these two groups, and correlations between the characteristics and AKI development were examined. Patients with AKI development were further divided into two groups according to the survival outcome, and variables associated with the outcome were determined. RESULTS: AKI was developed in 54.12% (n = 315) of patients, and these patients had blood pressure, SOFA score, APACHE II score, GCS, and various blood chemistry and hematology characteristics significantly different from the patients without AKI. Demographic characteristics (e.g. age and weight) were comparable between the two groups of patients. Among the 315 patients with AKI, 136 of them died during the study period. Multivariate logistic regression analysis revealed that the outcome of patients was associated with lung infection, coagulation system dysfunction, staphylococcus aureus infection, and use of various treatments (epinephrine, norepinephrine, and the use of mechanical ventilation) after AKI development. CONCLUSION: AKI occurred in approximately half of the critically ill patients admitted to ICU. The site and type of infections, as well as the use of vasopressor agents, were associated with the outcome. PMID- 29693475 TI - Transcranial doppler ultrasonography cerebral blood flow dynamics study of neurosurgical patients in peri-agonal period with fixed dilated or non-reacting pupils. AB - INTRODUCTION: Fixed dilated and unreactive pupils are a harbinger of imminent death in neurosurgical patients, signifying that the brainstem is not functioning. Transcranial Doppler (TCD) ultrasonography is a noninvasive, bedside method of determining the flow velocities in the basal cerebral arteries, used extensively in various neurosurgical conditions. AIMS AND OBJECTIVES: To study the cerebral blood flow dynamics of neurosurgical patients in peri-agonal period with fixed dilated or non reacting pupils using TCD. MATERIALS AND METHODS: Repeated TCD studies were done in patients with fixed dilated or unreactive pupils in a tertiary care, neurosurgical hospital over a year, recording the various waveforms and indices as Pulsatility Index (PI), Resistivity Index, Peak systolic flow velocity (PSV), End diastolic flow velocity (EDV), Mean cerebral blood flow velocity (MCBFV) of their middle cerebral artery in their peri-agonal period. The subsequent change in the indices as the patients died or improved was analyzed. RESULTS: A total of 104 TCD studies were done on 57 patients. Mean initial PI and MCBFV in the patients that died were 1.52 +/- 0.76 and 28.55 +/- 14.92 cm/sec respectively; and in the patients that showed neurosurgical recovery was 1.11 +/- 0.28 and 36.52 +/- 8.56 cm/sec respectively. Four out of 57 patients showed neurosurgical recovery and all of them had an initial PI less than 1.4 and they showed decrement in PI and increment in MCBFV on subsequent TCD study. The specificity and positive predictive value of the TCD waveform in predicting death was 100%, however, it had low sensitivity (47.17%) and negative predictive value (12.5%). CONCLUSION: The various indices and waveforms of TCD can be useful in assessing the cerebral blood flow dynamics in patients with various traumatic and non-traumatic ailments in the peri-agonal period; and hence help in their management as well as in the confirmation of brainstem death. PMID- 29693476 TI - Effects of gut microbiota manipulation on ex vivo lipolysis in human abdominal subcutaneous adipocytes. AB - The intestinal microbiota may contribute to the development of obesity by affecting host lipid metabolism and insulin sensitivity. To investigate the effects of microbiota manipulation on ex vivo basal and beta-adrenergically stimulated lipolysis in human adipocytes, 36 obese men were randomized to amoxicillin (broad-spectrum antibiotic), vancomycin (narrow-spectrum antibiotic) or placebo treatment (7 d, 1500 mg/d). Before and after treatment, ex vivo adipose tissue lipolysis was assessed under basal conditions and during stimulation with the non-selective beta-agonist isoprenaline using freshly isolated mature adipocytes. Gene (targeted microarray) and protein expression were analyzed to investigate underlying pathways. Antibiotics treatment did not significantly affect basal and maximal isoprenaline-mediated glycerol release from adipocytes. Adipose tissue beta-adrenoceptor expression or post-receptor signalling was also not different between groups. In conclusion, 7 d oral antibiotics treatment has no effect on ex vivo lipolysis in mature adipocytes derived from adipose tissue of obese insulin resistant men. PMID- 29693477 TI - Family Forward: a social work clinical trial promoting family adaptation following paediatric acquired brain injury. AB - OBJECTIVE: To test the efficacy of a family intervention Family Forward in promoting early adaptation following a child's acquired brain injury (ABI). RESEARCH DESIGN: Prospective, sequential comparison group design. METHODS AND PROCEDURES: Families of children (n = 47) diagnosed with ABI received Family Forward (n = 25): two family counselling sessions plus optional multi-family group session per week or Usual Care (n = 22) during their child's inpatient rehabilitation admission. Family adaptation outcomes were measured using Family Assessment Device (FAD-GF) and Family Management Measure (FAMM). Relationships between family psychosocial risk, social work interventions, and family adaptation outcomes were explored. MAIN OUTCOMES AND RESULTS: The Family Forward group endured longer hospital admissions (FF M = 56.4 days SD 46.1; p = 0.029), rehabilitation admissions (FF M = 33.3 days SD 29.0; p = 0.019) and reported poorer functioning pre-intervention FAD-GF (FF M = 1.626 SD = 0.391; UC M = 1.491 SD 0.394) than the Usual Care group. No significant difference in family adaptation outcomes (FAD-GF) were detected; this suggests that the Family Forward intervention played a protective role in preventing deterioration in family functioning. The Family Forward group achieved superior outcomes in managing their child's care at home (FAMM Child Management Ability scale p = 0.029) and greater parental satisfaction in focusing on their child's care (FAMM Parent Mutuality scale p = 0.04) post-intervention. CONCLUSION: The Family Forward intervention moderated for poorer initial family functioning to achieve positive family adaptation outcomes. PMID- 29693478 TI - Psychoeducation against depression, anxiety, alexithymia and fibromyalgia: a pilot study in primary care for patients on sick leave. AB - OBJECTIVES: Feasibility testing of a psychoeducational method -The Affect School and Script Analyses (ASSA) - in a Swedish primary care setting. Exploring associations between psychological, and medically unexplained physical symptoms (MUPS). DESIGN: Pilot study. SETTING: Three Swedish primary care centers serving 20,000 people. INTERVENTION: 8 weekly 2-hour sessions with a 5-7 participant group led by two instructors - followed by 10 individual hour-long sessions. SUBJECTS: Thirty-six patients, 29 women (81%), on sick-leave due to depression, anxiety, or fibromyalgia. OUTCOME MEASURES: Feasibility in terms of participation rates and expected improvements of psychological symptoms and MUPS, assessed by self-report instruments pre-, one-week post-, and 18 months post-intervention. Regression coefficients between psychological symptoms and MUPS. RESULTS: The entire 26-hour psychoeducational intervention was completed by 30 patients (83%), and 33 patients (92%) completed the 16-hour Affect School. One-week post intervention median test score changes were significantly favorable for 27 respondents, with p < .05 after correction for multiple testing for 9 of 11 measures (depression, anxiety, alexithymia, MUPS, general health, self affirmation, self-love, self-blame, and self-hate); 18 months post intervention the results remained significantly favorable for 15 respondents for 7 of 11 measures (depression, alexithymia, MUPS, general health, self-affirmation, self love, and self-hate). CONCLUSIONS: A psychoeducational method previously untested in primary care for mostly women patients on sick-leave due to depression, anxiety, or fibromyalgia had >80% participation rates, and clear improvements of self-assessed psychological symptoms and MUPS. The ASSA intervention thus showed adequate feasibility in a Swedish primary care setting. Key Points A pilot study of a psychoeducational intervention - The Affect School and Script Analyses (ASSA) - was performed in primary care * The intervention showed feasibility for patients on sick-leave due to depression, anxiety, or fibromyalgia * 92% completed the 8 weeks/16 hours Affect School and 83% completed the entire 26-hour ASSA intervention * 9 of 11 self-reported measures improved significantly one week post intervention * 7 of 11 self-reported measures improved significantly 18 months post-intervention. PMID- 29693479 TI - Creation of a restrictive atrial communication in pulmonary arterial hypertension (PAH): effective palliation of syncope and end-stage heart failure. AB - Atrial septostomy (AS) is recommended for pulmonary arterial hypertension (PAH) associated right ventricular (RV) failure, recurrent syncope, or pulmonary hypertensive crisis (PHC). We aimed to evaluate the feasibility and efficacy of AS to manage PAH from infancy to adulthood. From June 2009 to December 2016, transcatheter atrial communications were created in 11 PAH patients (4 girls/women; median age = 4.3 years; range = 33 days-26 years; median body weight = 14 kg; range = 3-71 kg; NYHA-/Ross class IV; n = 11). PAH was classified as idiopathic (n = 6) or secondary (n = 5). History of syncope was dominant (n = 6); two with patent foramen ovale (PFO) admitted with recurrent PHC, three patients required resuscitation before AS. Three patients had PAH-associated low cardiac output. The average pulmonary arterial pressures (PAP systolic/diastolic) were 101/50 (+/-34/23); the corresponding systemic arterial pressures (SAP) were 99/54 (+/-23/11); and the mean ratio of PAPd / SAPd was 0.97 (+/-0.4). Percutaneous trans-septal puncture was uneventfully performed in nine patients; a PFO was dilated in two patients. There was no procedure-related mortality. The median balloon size was 10 mm (range = 6-14 mm); the mean catheter time was 174.6 +/- 48 min; fluoroscopy time was 19.8 (+/-11) min. Syncope and PHC were successfully treated in all patients. The mean arterial oxygen saturation decreased from 97 +/ 2 to 89 +/- 11.7. One patient died awaiting lung transplantation, one continues to be listed; two patients received a reverse Potts-shunt, one patient died during follow-up; seven patients are stable with PAH-specific treatment. Percutaneous AS is an effective method palliating PAH-associated syncope, PHCs or right (bi-) ventricular heart failure. PMID- 29693480 TI - Change in R wave in lead V1 predicts survival of patients with pulmonary arterial hypertension. AB - Clinical guidelines for pulmonary hypertension recommend evaluating treatment response through various methods; however, electrocardiography (ECG) is not included as one of the methods of choice. We aimed to identify ECG parameters that correlated with prognosis in patients with pulmonary arterial hypertension (PAH). A total of 112 consecutive patients with PAH were enrolled in this study. Among them, 83 with treatment escalation were studied for further analysis. Survival analyses were conducted using the Kaplan-Meier method with the log-rank test. Cox proportional hazards regression modeling was used to identify predictors of survival. Receiver operating characteristic analysis was used to determine cut-off values for selected variables. ECG parameters were changed from baseline to three months after treatment. Patients in whom the R wave amplitude in lead V1 decreased by >=1 mm (0.1 mV) within three months demonstrated significantly better survival ( P = 0.017). Our results suggest that evaluation of ECG parameters can contribute to assessments of survival in patients with PAH. PMID- 29693481 TI - Streamlining cardiopulmonary exercise testing for use as a screening and tracking tool in primary care. AB - Cardiopulmonary exercise testing (CPET) using a spectrum of different approaches demonstrates usefulness for objectively assessing patient disease severity in clinical and research settings. Still, an absence of trained specialists and/or improper data interpretation techniques can pose major limitations to the effective use of CPET for the clinical classification of patients. This study aimed to test an automated disease likelihood scoring algorithm system based on cardiopulmonary responses during a simplified step-test protocol. For patients with heart failure (HF), pulmonary hypertension (PAH), obstructive lung disease (OLD), or restrictive lung disease (RLD), we compared patient scores stratified into one of four "silos" generated from our novel algorithm system against patient evaluations provided by expert clinicians. Patients with HF (n = 12), PAH (n = 9), OLD (n = 16), or RLD (n = 10) performed baseline pulmonary function testing followed by submaximal step-testing. Breath-by-breath measures of ventilation and gas exchange, in addition to oxygen saturation and heart rate were collected continuously throughout testing. The algorithm demonstrated close alignment with patient assessments provided by clinical specialists: HF (r = 0.89, P < 0.01); PAH (r = 0.88, P < 0.01); OLD (r = 0.70, P < 0.01); and RLD (r = 0.88, P < 0.01). Furthermore, the algorithm was capable of differentiating major disease from other disease pathologies. Thus, in a clinically relevant manner, these data suggest this simplified automated disease algorithm scoring system used during step-testing to identify the likelihood that patients have HF, PAH, OLD, or RLD closely correlates with patient assessments conducted by trained clinicians. PMID- 29693482 TI - Inferior vena cava filters (IVCFs): a review of uses and application to international guidelines at a single Australian center; implications of venous thromboembolism associated with malignancy. AB - Venous thromboembolism (VTE) is a potentially lethal event. Anticoagulation is the cornerstone of treatment. Inferior vena cava filters (IVCFs) may be used in circumstances when anticoagulation is contraindicated or as an adjunct to anticoagulation. IVCF use is not without controversy due to concerns over their safety profile, differences in guidelines from international societies, and a limited randomized control trial evidence. We retrospectively undertook a review of IVCF use over a three-year period (2014-2016) at our center, which has a large oncology service but no trauma unit. There were 44 patients with successful IVCF insertion and one patient with an unsuccessful attempt. Indications for insertion included: a contraindication to anticoagulation (n = 28); recurrent VTE on anticoagulation (n = 10); and extensive VTE (n = 7). There were 13 retrieval attempts, of which ten were successful. There were five documented IVCF complications (tilting: n = 2, IVC thrombus: n = 3) with one episode of IVCF failure and two episodes of deep vein thrombosis during the follow-up period. Of the patients, 71% had an active malignancy (of whom 71% had metastatic disease). Seventeen patients died due to progressive malignancy during the study period. There were no life-threatening VTEs or IVCF-associated mortalities. Adherence with published international guidelines was variable. Patients with malignancy were less likely to undergo IVCF retrieval and had a reduced rate of retrieval success. None of the international guidelines comment on the use of IVCFs in patients with malignancy despite being commonly used. IVCF use may be an underappreciated tool in this group. PMID- 29693483 TI - Rehabilitation for improved cognition in patients with stress-related exhaustion disorder: RECO - a randomized clinical trial. AB - Stress-related exhaustion has been associated with selective and enduring cognitive impairments. However, little is known about how to address cognitive deficits in stress rehabilitation and how this influences stress recovery over time. The aim of this open-label, parallel randomized controlled trial (ClinicalTrials.gov: NCT03073772) was to investigate the long-term effects of 12 weeks cognitive or aerobic training on cognitive function, psychological health, and work ability for patients diagnosed with exhaustion disorder (ED). One hundred-and-thirty-two patients (111 women) participating in multimodal stress rehabilitation were randomized to receive additional cognitive training (n = 44), additional aerobic training (n = 47), or no additional training (n = 41). Treatment effects were assessed before, immediately after and one-year post intervention. The primary outcome was global cognitive function. Secondary outcomes included domain-specific cognition, self-reported burnout, depression, anxiety, fatigue and work ability, aerobic capacity, and sick-leave levels. Intention-to-treat analysis revealed a small but lasting improvement in global cognitive functioning for the cognitive training group, paralleled by a large improvement on a trained updating task. The aerobic training group showed improvements in aerobic capacity and episodic memory immediately after training, but no long-term benefits. General improvements in psychological health and work ability were observed, with no difference between interventional groups. Our findings suggest that cognitive training may be a viable method to address cognitive impairments for patients with ED, whereas the effects of aerobic exercise on cognition may be more limited when performed during a restricted time period. The implications for clinical practice in supporting patients with ED to adhere to treatment are discussed. PMID- 29693485 TI - Toward adaptive deep brain stimulation in Parkinson's disease: a review. AB - Clinical deep brain stimulation (DBS) is now regarded as the therapeutic intervention of choice at the advanced stages of Parkinson's disease. However, some major challenges of DBS are stimulation induced side effects and limited pacemaker battery life. Side effects and shortening of pacemaker battery life are mainly as a result of continuous stimulation and poor stimulation focus. These drawbacks can be mitigated using adaptive DBS (aDBS) schemes. Side effects resulting from continuous stimulation can be reduced through adaptive control using closed-loop feedback, while those due to poor stimulation focus can be mitigated through spatial adaptation. Other advantages of aDBS include automatic, rather than manual, initial adjustment and programming, and long-term adjustments to maintain stimulation parameters with changes in patient's condition. Both result in improved efficacy. This review focuses on the major areas that are essential in driving technological advances for the various aDBS schemes. Their challenges, prospects and progress so far are analyzed. In addition, important advances and milestones in state-of-the-art aDBS schemes are highlighted - both for closed-loop adaption and spatial adaption. With perspectives and future potentials of DBS provided at the end. PMID- 29693484 TI - The dilemma of repeat weak opioid prescriptions - experiences from swedish GPs. AB - OBJECTIVE: To explore general practitioners' (GP) experiences of dealing with requests for the renewal of weak opioid prescriptions for chronic non-cancer pain conditions. DESIGN: Qualitative focus group interviews. Systematic text condensation analysis. SETTING AND SUBJECTS: 15 GPs, 4 GP residents and 2 interns at two rural and two urban health centres in central Sweden. MAIN OUTCOME MEASURES: Strategies for handling the dilemma of prescribing weak opioids without seeing the patient. RESULTS: After analysing four focus group interviews we found that requests for prescription renewals for weak opioids provoked adverse feelings in the GP regarding the patient, colleagues or the GP's inner self and were experienced as a dilemma. To deal with this, the GP could use passive as well as active strategies. Active strategies, like discussing the dilemma with colleagues and creating common routines regarding the renewal of weak opioids, may improve prescription habits and support physicians who want to do what is medically correct. CONCLUSION: Many GPs feel umcomfortable when prescribing weak opioids without seeing the patient. This qualitative study has identified strategic approaches to deal with that issue. Key points Opioid prescription for chronic non-cancer pain is known to cause discomfort, feelings of guilt and conflicts for the prescribing doctor. From focus group interviews with GPs we found that to deal with this: * Doctors can use active strategies, such as confronting the patient or creating common routines together with their colleagues, or... * They can use passive coping strategies such as accepting the situation, handing over the responsibility to the patient or choosing not to see that there is a problem. * Opportunities for doctors to discuss prescription routines may be the best way to influence prescription habits. PMID- 29693487 TI - The potential impact of monitoring disease activity biomarkers on rheumatoid arthritis outcomes and costs. AB - Rheumatoid arthritis (RA) management requires monitoring of disease activity to determine course of treatment. Global assessments are used in clinical practice to determine RA disease activity. Monitoring disease activity via biomarkers may also help providers optimize biologic and nonbiologic drug use while decreasing overall drug spend by delaying use of expensive biologic therapies. By testing multiple biologic domains at the same time, a multibiomarker disease activity test may have utility in RA patient management, through improved intra- and inter rater reliability. This report provides a comprehensive review of studies of objective measures, single biomarkers and multibiomarker disease activity tests as disease activity measures to decrease uncertainty in treatment decisions, and of biomarkers' potential impact on economic and clinical outcomes of treatment choices. PMID- 29693486 TI - Serum Galectin 7 is Not Useful to Predict Abortion in the First Trimester. AB - OBJECTIVE: Galectins are animal lectins that bind to surface glycoproteins expressed at the fetal-maternal interface. The aim of this prospective case control study was to investigate the possible relationship between levels of maternal serum galectin-7 and threatened abortion (TA) and to determine whether serum galectin-7 had any prognostic value. METHODS: This prospective study was conducted between August 2014 and February 2015. Included in the study were 31 consecutive pregnant women who were hospitalized for TA between 6 and 14 weeks of gestation and 33 healthy gestational age matched pregnant women without any symptoms of miscarriage. Serum galectin-7 levels were measured via ELISA. RESULTS: The mean serum galectin-7 levels of the two groups were not significantly different (31 TA patients: 2.84 +/- 0.43 pg/mL, 33 controls: 2.785 +/- 0.32 pg/mL, p = 0.543). Six pregnancies in the TA group resulted in abortion (19.4%). CONCLUSION: Serum galectin-7 was not useful for predicting prognosis in TA. PMID- 29693489 TI - New perspectives on the roles of pyrimidines in the central nervous system. AB - Since 1956, when exogenous uridine and cytidine were found to be necessary for the maintenance of perfused rat brain function, the co-existence of de novo synthesis, salvage pathways and removal of pyrimidine bases in the CNS has been a controversial subject. Here, we review studies on metabolites and enzymes of pyrimidine metabolism through more than 60 years. In view of known and newly described inherited pyrimidine and purine disorders - some with complex clinical profiles of neurological impairments - we underline the necessity to investigate how the different pathways work together in the developing brain and then sustain plasticity, regeneration and neuro-transmission in the adult CNS. Experimentally, early incorporation studies in animal brain slices and homogenates with radio labelled nucleosides or precursors demonstrated salvage activity or de novo synthesis. Later, the nucleoside transporters and organic anionic transporters underlying uptake of metabolites and anti-pyrimidine drugs in the CNS were identified. Recently, the expression of de novo enzymes in glial cells and neurons was verified using (immuno) histochemical and in-situ-hybridization techniques. Adult brain was shown to take up or produce all pyrimidine (deoxy) ribonucleosides or, after uptake and phosphorolysis of nucleosides, to make use of ribose for different purposes, including energy. More recently, non-canonical pyrimidine bases (5mC, 5hmC) have been found most notably in brain, pointing to considerable postreplicative DNA metabolism, with the need for pyrimidine specific enzymes. Even more perspectives are emerging, with advances in genome analysis and in the manipulation of expression from the gene. PMID- 29693488 TI - Elevated TGF beta2 serum levels in Emery-Dreifuss Muscular Dystrophy: Implications for myocyte and tenocyte differentiation and fibrogenic processes. AB - Among rare diseases caused by mutations in LMNA gene, Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B are characterized by muscle weakness and wasting, joint contractures, cardiomyopathy with conduction system disorders. Circulating biomarkers for these pathologies have not been identified. Here, we analyzed the secretome of a cohort of patients affected by these muscular laminopathies in the attempt to identify a common signature. Multiplex cytokine assay showed that transforming growth factor beta 2 (TGF beta2) and interleukin 17 serum levels are consistently elevated in the vast majority of examined patients, while interleukin 6 and basic fibroblast growth factor are altered in subgroups of patients. Levels of TGF beta2 are also increased in fibroblast and myoblast cultures established from patient biopsies as well as in serum from mice bearing the H222P Lmna mutation causing Emery Dreifuss Muscular Dystrophy in humans. Both patient serum and fibroblast conditioned media activated a TGF beta2-dependent fibrogenic program in normal human myoblasts and tenocytes and inhibited myoblast differentiation. Consistent with these results, a TGF beta2 neutralizing antibody avoided fibrogenic marker activation and myogenesis impairment. Cell intrinsic TGF beta2-dependent mechanisms were also determined in laminopathic cells, where TGF beta2 activated AKT/mTOR phosphorylation. These data show that TGF beta2 contributes to the pathogenesis of Emery-Dreifuss Muscular Dystrophy type 2 and Limb-Girdle muscular Dystrophy 1B and can be considered a potential biomarker of those diseases. Further, the evidence of TGF beta2 pathogenetic effects in tenocytes provides the first mechanistic insight into occurrence of joint contractures in muscular laminopathies. PMID- 29693490 TI - Fatal Wounding Pattern and Causes of Potentially Preventable Death Following the Pulse Night Club Shooting Event. AB - BACKGROUND: Mortality following shooting is related to time to provision of initial and definitive care. An understanding of the wounding pattern, opportunities for rescue, and incidence of possibly preventable death is needed to achieve the goal of zero preventable deaths following trauma. METHODS: A retrospective study of autopsy reports for all victims involved in the Pulse Nightclub Shooting was performed. The site of injury, probable site of fatal injury, and presence of potentially survivable injury (defined as survival if prehospital care is provided within 10 minutes and trauma center care within 60 minutes of injury) was determined independently by each author. Wounds were considered fatal if they involved penetration of the heart, injury to any non extremity major blood vessel, or bihemispheric, mid-brain, or brainstem injury. RESULTS: There were an average of 6.9 wounds per patient. Ninety percent had a gunshot to an extremity, 78% to the chest, 47% to the abdomen/pelvis, and 39% to the head. Sixteen patients (32%) had potentially survivable wounds, 9 (56%) of whom had torso injuries. Four patients had extremity injuries, 2 involved femoral vessels and 2 involved the axilla. No patients had documented tourniquets or wound packing prior to arrival to the hospital. One patient had an isolated C6 injury and 2 victims had unihemispheric gunshots to the head. CONCLUSIONS: A comprehensive strategy starting with civilian providers to provide care at the point of wounding along with a coordinated public safety approach to rapidly evacuate the wounded may increase survival in future events. PMID- 29693491 TI - Breast cancer patients' search for meaning. AB - The aim of this study was to analyze the search for meaning in women with breast cancer and its relationship with the emotional well-being. One hundred thirty-one breast cancer survivors were assessed using a mixed method. Results showed that the meaning of suffering cancer can be explained by nine categories; and the utility of the suffering experienced was divided in seven categories. Moreover, the results showed a significant correlation between the meaning and the utility of suffering cancer, and the emotional well-being. The search for meaning in breast cancer women affects the emotional well-being, so it is necessary to attend it. PMID- 29693492 TI - Interpersonal gargalesthesia. AB - When someone touches, say, your upper arm, mirror neurons in your brain's area S2 fire. These neurons also fire when you merely watch another person being touched. However, you do not literally feel the touch from his arm on your own skin. Consistent with this view, we find when someone's arm is removed, he does start experiencing another's sensations [Ramachandran, V. S., & Brang, D. (2009)]. A congenital variant of this syndrome also exists, as in our subject TC. TC experienced referred touch, referred tickle in her axilla, and was able to tickle herself. PMID- 29693493 TI - Targeted next-generation sequencing reveals that a compound heterozygous mutation in phosphodiesterase 6a gene leads to retinitis pigmentosa in a Chinese family. AB - PURPOSE: Retinitis pigmentosa (RP) is a genetically heterogeneous disease with over 70 causative genes identified to date. However, approximately 40% of RP cases remain genetically unsolved, suggesting that many novel disease-causing mutations are yet to be identified. The purpose of this study is to identify the causative mutations of a Chinese RP family. METHODS: Targeted next-generation sequencing (NGS) for a total of 163 genes which involved in inherited retinal disorders were used to screen the possible causative mutations. Sanger sequencing was used to verify the mutations. RESULTS: As results, we identified two heterozygous mutations: a splicing site mutation c.1407 + 1G>C and a nonsense mutation c. 1957C>T (p.R653X) in phosphodiesterase 6A (PDE6A) gene in the RP patient. These two mutations are inherited from his father and mother, respectively. Furthermore, these mutations are unique in our in-house database and are rare in human genome databases, implicating that these two mutations are pathological. CONCLUSION: By using targeted NGS method, we identified a compound heterozygous mutation in PDE6A gene that is associated with RP in a Chinese family. PMID- 29693494 TI - Ongoing recruitment crisis In Norwegian general practice. PMID- 29693496 TI - OPQRST(U): Integrating substance use disorders or "Use" into the medical history. AB - Substance use disorders (SUDs) are pervasive in the United States, with 20.1 million cases in 2016, of which only 19% receive treatment. SUDs permeate all medical specialties and should be considered in the differential diagnosis of every chief complaint. Acknowledging the salience of SUDs provides a unique opportunity for early identification and intervention. Thus, SUDs should be reflected prominently in the history of the present illness rather than in the social history. To this effect, we propose the inclusion of Use (U) in the history of present illness and incorporating "U" into the pedagogical mnemonic of OPQRST that is commonly used in medical training. Obtaining this history will help determine if and which abused substances may be contributing to the chief complaint. We also suggest the incorporation of an additional acronym, SORTED, to account for the various domains of Use, including Street (illicit drugs), OTCs (over-the-counter medications), Rx (prescriptions, including nonmedicinal use of pharmaceutical drugs), Tobacco (including e-cigarettes), EtOH (alcohol), and Dietary (caffeine, vitamins, and herbal supplements) agents. We discuss how utilizing OPQRSTU will help reshape the way medical students think about SUDs and will facilitate detection and diagnosis of all domains of SUDs. PMID- 29693495 TI - A Randomized Clinical Trial of Nicotine Preloading for Smoking Cessation in People with Posttraumatic Stress Disorder. AB - OBJECTIVE: The aim of this research was to determine whether augmenting standard smoking cessation treatment by wearing an active nicotine patch before the smoking quit date improves rates of smoking cessation in individuals with posttraumatic stress disorder (PTSD) and to explore mechanisms of treatment response such as decreased cigarette craving and symptom relief from smoking. METHODS: This was a double-blind parallel randomized controlled trial in 81 people with PTSD who smoked cigarettes. Participants were recruited from Veterans Affairs outpatient clinics and flyers in the community. Participants provided ecological momentary assessments (EMAs) of PTSD symptoms, smoking withdrawal symptoms, and cravings before and after smoking a cigarette during one week of ad lib smoking and then three weeks of either a nicotine patch (n = 37) or placebo patch (n = 44) preceding the quit date. All participants received standard pharmacotherapy and behavioral treatment for smoking cessation after the quit date. To test the efficacy of nicotine patch preloading for engaging proposed treatment targets during the pre-quit phases, we used multilevel models to compare post-smoking changes in symptoms and cravings during the preloading phases to post-smoking changes reported during the ad lib smoking phase. RESULTS: There was no significant difference in quit rates across the two conditions on the primary outcome of seven-day point prevalence smoking abstinence bioverified with breath carbon monoxide at six weeks post-quit date. In a multivariable multilevel model pre- to post-cigarette changes in PTSD symptom clusters, smoking withdrawal symptoms, and cravings, there was a significant interaction between treatment phase and condition. Relative to participants in the placebo condition, participants in the nicotine patch condition experienced diminished relief from PTSD reexperiencing symptoms, smoking withdrawal symptoms, and cigarette craving after smoking a cigarette. CONCLUSIONS: Relative to placebo patch preloading, nicotine patch preloading diminished the reinforcing effects of smoking cigarettes. However, the low quit rates in both conditions suggest that nicotine patch preloading is not a sufficiently intensive treatment for achieving smoking cessation in people with PTSD. TRIAL REGISTRATION: clinicaltrials.gov: NCT00625131. PMID- 29693498 TI - Erratum to: The blocking effect in associative learning involves learned biases in rapid attentional capture. AB - Luque, D., Vadillo, M, A., Gutierrez-Cobo, M, J., Le Pelley, M, E. (2018). The blocking effect in associative learning involves learned biases in rapid attentional capture. Quarterly Journal of Experimental Psychology, 71, 522-544. doi: 10.1080/17470218.2016.1262435. The above article is part of the Special Issue on Associative Learning (in honour of Nick Mackintosh) and was inadvertently published in the February 2018 issue of Quarterly Journal of Experimental Psychology. After publication of the Special Issue, an online collection on Associative Learning will be created on SAGE Journals and this paper will be included in that collection. The Publisher apologises for this error. PMID- 29693497 TI - Ocular Neuromyotonia: Case Reports and Literature Review. AB - Ocular neuromyotonia (ONM) is a rare eye movement disorder, presenting as a paroxysmal involuntary spasm of one or more extra-ocular muscles, that can persist for a few seconds up to several minutes. The phenomenon is caused by the contraction of an extra-ocular muscle, excited by a damaged nerve, which leads to delayed muscle relaxation. We present eight patients with this rare condition together with an overview of the literature on all published ONM cases. One of the presented cases is possibly secondary to hypovitaminosis D. This association has not been reported previously in the literature. A possible underlying mechanism is given. PMID- 29693499 TI - Adsorption of mercury by activated carbon prepared from dried sewage sludge in simulated flue gas. AB - : Conversion of sewage sludge to activated carbon is attractive as an alternative method to ocean dumping for the disposal of sewage sludge. Injection of activated carbon upstream of particulate matter control devices has been suggested as a method to remove elemental mercury from flue gas. Activated carbon was prepared using various activation temperatures and times and was tested for their mercury adsorption efficiency using lab-scale systems. To understand the effect of the physical property of the activated carbon, its mercury adsorption efficiency was investigated as a function of its Brunauer-Emmett-Teller (BET) surface area. Two simulated flue gas conditions, (1) without hydrogen chloride (HCl) and (2) with 20 ppm HCl, were used to investigate the effect of flue gas composition on the mercury adsorption capacity of activated carbon. Despite very low BET surface area of the prepared sewage sludge activated carbons, their mercury adsorption efficiencies were comparable under both simulated flue gas conditions to those of pinewood and coal activated carbons. After injecting HCl into the simulated flue gas, all sewage sludge activated carbons demonstrated high adsorption efficiencies, that is, more than 87%, regardless of their BET surface area. IMPLICATIONS: We tested activated carbons prepared from dried sewage sludge to investigate the effect of their physical properties on their mercury adsorption efficiency. Using two simulated flue gas conditions, we conducted mercury speciation for the outlet gas. We found that the sewage sludge activated carbon had mercury adsorption efficiency comparable to pinewood and coal activated carbons, and the presence of HCl minimized the effect of physical property of the activated carbon on its mercury adsorption efficiency. PMID- 29693500 TI - Impact of intranasal application of nerve growth factor on the olfactory epithelium in rats with chemically induced diabetes. AB - Recent studies suggest that nerve growth factor (NGF) protects olfactory cells and axons from injury in vitro. Eighteen Wistar-Albino rats randomly divided into three groups: control group, diabetic group without NGF, and diabetic with NGF. Intranasal NGF (6 ug/day) was administered over a 5-day period. At the end of 30 days, the olfactory epithelium (OE) of NGF-applied diabetic rats regenerated, the epithelium thickness was significantly higher, and caspase-3 expression was not significantly different from the control. The current results demonstrate that intranasally administered NGF significantly reversed OE morphological changes in diabetes by decreasing diabetes-related cell death and inflammation. PMID- 29693501 TI - Improving Research in Radiation Oncology through Interdisciplinary Collaboration. AB - The contribution of radiation oncology to the future of cancer treatment depends significantly on our continued clinical progress and future research advancements. Such progress relies on multidisciplinary collaboration among radiation oncologists, medical physicists and radiobiologists. Cultivating collaborative educational and research opportunities among these three disciplines and further investing in the infrastructure used to train both clinicians and researchers will therefore help us improve the future of cancer care. This article evaluates the success of a short-term educational environment to foster multidisciplinary collaboration. The NIH-funded educational course developed at Wayne State University, called "Integration of Biology and Physics into Radiation Oncology" (IBPRO), was designed to facilitate the engagement of radiation oncologists, medical physicists and radiobiologists in activities that enhance collaborative investigation. Having now been delivered to nearly 200 participants over the past four years, the relative success of IBPRO in fostering productive interdisciplinary collaboration and producing tangible research outcomes can be evaluated. The 140 IBPRO participants from the first three years were surveyed to quantify the effectiveness of the course. In total, 62 respondents reported developing 23 institutional protocols, submitting more than 25 research grants (nine of which have been funded thus far), and publishing more than 30 research manuscripts attributable to participation in IBPRO. Nearly one half (45%) of respondents reported generating at least one of these research metrics attributable to participation in IBPRO and these participants reported an average of over four such quantitative research metrics per respondent. This represents a very substantial contribution to radiation oncology research by a relatively small number of researchers within a relatively short time. Nearly one half of respondents reported ongoing collaborative working relationships generated by IBPRO. In addition, approximately one-half of respondents stated that specific information presented at IBPRO changed the way they practice, and over 80% of respondents practicing in a clinical setting stated that, since participation in IBPRO, they have approached clinical dilemmas more collaboratively. We believe that educational opportunities such as IBPRO can have a significant impact on interdisciplinary collaborative research. In addition, such interventions have the ability to effect significant clinical change. Both of these should have a positive impact on future advancements in radiation oncology and affect the future contribution of radiation oncology to the treatment of cancer. PMID- 29693502 TI - New Radiation Dosimetry Estimates for [18F]FLT based on Voxelized Phantoms. AB - 3'-Deoxy-3-[18F]fluorothymidine, or [18F]FLT, is a positron emission tomography (PET) tracer used in clinical studies for noninvasive assessment of proliferation activity in several types of cancer. Although the use of this PET tracer is expanding, to date, few studies concerning its dosimetry have been published. In this work, new [18F]FLT dosimetry estimates are determined for human and mice using Monte Carlo simulations. Modern voxelized male and female phantoms and [18F]FLT biokinetic data, both published by the ICRP, were used for simulations of human cases. For most human organs/tissues the absorbed doses were higher than those reported in ICRP Publication 128. An effective dose of 1.70E-02 mSv/MBq to the whole body was determined, which is 13.5% higher than the ICRP reference value. These new human dosimetry estimates obtained using more realistic human phantoms represent an advance in the knowledge of [18F]FLT dosimetry. In addition, mice biokinetic data were obtained experimentally. These data and a previously developed voxelized mouse phantom were used for simulations of animal cases. Concerning animal dosimetry, absorbed doses for organs/tissues ranged from 4.47 +/- 0.75 to 155.74 +/- 59.36 mGy/MBq. The obtained set of organ/tissue radiation doses for healthy Swiss mice is a useful tool for application in animal experiment design. PMID- 29693503 TI - Men and maternal health: The dilemma of short-lived male involvement strategies in Uganda. AB - This article has been written to call for further attention to the importance of involving males in efforts to reduce maternal mortality. Since the 1995 International Conference on Population and Development [ICPD], institutional and community arrangements have been implemented in developing countries to engage males in maternal and child health promotions. The government of Uganda - in partnership with other health promotion institutions such as the United Nations agencies - has in the past decade formulated and implemented national and local strategies for male involvement in Sexual and Reproductive Health and Rights (SRHR). Nevertheless, strategies are such as Male Action Groups (MAGs) have been short-lived because the strategies within cannot by themselves work without 'genuine' acceptance at community levels where implementation takes place. Even acceptance alone is also not enough. Majority of males have more interest in economic than social endeavors. They have less interest to engage in maternal health promotion initiatives. Cultural based perceptions and behaviors associated with patriarchal tendencies remain the greatest challenge. Therefore, relevancy, functionality, adaptability, and sustainability in relation to the effectiveness of male involvement initiatives must be assessed before these interventions are initiated in such culturally diverse communities with different informal institutional arrangements. The individual, interpersonal and institutional contexts in which interventions operate matters. The article identifies relevant stakeholders and suggests, though not discussed in detail, strategies for improving stakeholders' interests to respond to male involvement as a core issue in maternal health. PMID- 29693504 TI - Cylindrospermopsin toxicity in mice following a 90-d oral exposure. AB - Cylindrospermopsin (CYN) is a toxin associated with numerous species of freshwater cyanobacteria throughout the world. It is postulated to have caused an episode of serious illnesses in Australia through treated drinking water, as well as lethal effects in livestock exposed to water from farm ponds. Toxicity included effects indicative of both hepatic and renal dysfunction. In humans, symptoms progressed from initial hepatomegaly, vomiting, and malaise to acidosis and hypokalemia, bloody diarrhea, and hyperemia in mucous membranes. Laboratory animal studies predominantly involved the intraperitoneal (i.p.) route of administration and confirmed this pattern of toxicity with changes in liver enzyme activities and histopathology consistent with hepatic injury and adverse renal effects. The aim of this study was designed to assess subchronic oral exposure (90 d) of purified CYN from 75 to 300 ug/kg/d in mouse. At the end of the dosing period, examinations of animals noted (1) elevated organ to body weight ratios of liver and kidney at all dose levels, (2) treatment-related increases in serum alanine aminotransferase (ALT) activity, (3) decreased blood urea nitrogen (BUN) and cholesterol concentrations in males, and (4) elevated monocyte counts in both genders. Histopathological alterations included hepatocellular hypertrophy and cord disruption in the liver, as well as renal cellular hypertrophy, tubule dilation, and cortical tubule lesions that were more prominent in males. A series of genes were differentially expressed including Bax (apoptosis), Rpl6 (tissue regeneration), Fabp4 (fatty acid metabolism), and Proc (blood coagulation). Males were more sensitive to many renal end points suggestive of toxicity. At the end of exposure, toxicity was noted at all dose levels, and the 75 ug/kg group exhibited significant effects in liver and kidney/body weight ratios, reduced BUN, increased serum monocytes, and multiple signs of histopathology indicating that a no-observed-adverse-effect level could not be determined for any dose level. PMID- 29693505 TI - Age-related differences in the rate and diagnosis of 30-day readmission after hospitalization for acute ischemic stroke. AB - Background Little is known about the association between age and readmission within 30 days after hospitalization for acute ischemic stroke. Aim To examine the age-related differences in rate and principal reason of 30-day readmissions in patients hospitalized for acute ischemic stroke. Methods In this retrospective, population-based cohort study using State Inpatient Databases from eight US states, we identified all adults hospitalized for acute ischemic stroke. We grouped the patients into four age categories: < 65, 65-74, 75-84, and >=85 years. Outcomes were any-cause readmission within 30 days of discharge from the index hospitalization for acute ischemic stroke and the principal diagnosis of 30 day readmission. Results We identified 620,788 hospitalizations for acute ischemic stroke. The overall 30-day readmission rate was 16.6% with an increase with advanced age. Compared to patients aged <65 years, the readmission rate was significantly higher in age 65-74 years (OR 1.19; 95% CI 1.16-1.21), in age 75-84 years (OR 1.29; 95% CI 1.27-1.31), and in >= 85 years (OR 1.24; 95% CI 1.22-1.27; all P<0.001). There was heterogeneity in the age-readmission rate association between men and women (Pinteraction < 0.001). Overall, 45.8% of readmissions were assigned stroke-related conditions or rehabilitation care. Compared to younger adults, older adults were more likely to present with non-stroke-related conditions (46.1% in < 65 years, 50.6% in 65-74 years, 57.1% in 75-84 years, and 62.9% in >= 85 years; P<0.001). Conclusions Advanced age was associated with a higher 30-day readmission rate after acute ischemic stroke. Compared with younger adults, older adults were more likely to be readmitted for non-stroke-related conditions. PMID- 29693506 TI - Arguments about Abortion: Personhood, Morality, and Law. PMID- 29693507 TI - Status of postpartum depression in Turkey: A meta-analysis. AB - We determined the prevalence of postpartum depression (PPD) and related risk factors in Turkey based on relevant research. This study is a systematic review and meta-analysis and was conducted by performing a scan of the Turkish and English literature over the period of January-February 2016. Most of the research included in this systematic compilation made use of the Edinburgh Postpartum Depression Scale. The scans executed indicated that 4,740 women out of 18,780 were at risk for PPD. In the computations made based on these data, it was found that the consolidated prevalence of PPD was 24% (21%-27% at a confidence interval of 95%) and that this rate varied between 9% and 51%. The study revealed 54 risk factors related to PPD. Those most commonly reported were mental problems/depression prior to pregnancy, unplanned/unwanted pregnancy, low income/socioeconomic level, bad marital relationship/problems with spouse/dissatisfaction with married life, and being a housewife. In this study, we showed that the prevalence rate of PPD is significantly high, that it varies within a wide range, that the prevalence of depression decreased with the increase of the time passed after childbirth, and that it is related to numerous and different factors. PMID- 29693509 TI - Is It More Feeling or Thinking? The Influence of Affective and Cognitive Attitude on Adolescents' Intention to Engage in Binge Drinking. AB - Previous work has revealed that interventions aiming to reduce adolescent binge drinking commonly focus on cognitive attitudes, but are insufficiently effective in changing binge-drinking intentions. The focus on these cognitive attitudes might be the reason for this insufficient success. That is, other work has revealed that affective attitudes have a stronger influence on binge-drinking intention than cognitive attitudes. However, this relation has so far only been found among traditional college students and pre-vocational school students, therewith neglecting another important population at risk, namely vocational community college students. This study examines whether affective attitudes are also significantly stronger influencers of binge-drinking intentions among vocational community college students. Using a sample of 298 vocational community college students (Mage = 17.63), the current study shows that affective attitudes were more strongly related to vocational community college students' intention to engage in binge drinking than cognitive attitudes. This finding indicates that the effectiveness of interventions targeting adolescent binge drinking can be improved by incorporating content elements concerning affective attitudes. PMID- 29693508 TI - To report or not to report: Exploring healthy volunteers' rationales for disclosing adverse events in Phase I drug trials. AB - BACKGROUND: Phase I trials test the safety and tolerability of investigational drugs and often use healthy volunteers as research participants. Adverse events (AEs) are collected in part through participants' self-reports of any symptoms they experience during the trial. In some cases, experiencing AEs can result in trial participation being terminated. Because of the economic incentives underlying their motivation to participate, there is concern that healthy volunteers routinely fail to report AEs and thereby jeopardize the validity of the trial results. METHODS: We interviewed 131 U.S. healthy volunteers about their experiences with AEs, including their rationales for reporting or failing to report symptoms. RESULTS: We found that participants have three primary rationales for their AE reporting behavior: economic, health-oriented, and data integrity. Participants often make decisions about whether to report AEs on a case-by-case basis, evaluating what effects reporting or not reporting might have on the compensation they receive from the trial, the risk to their health, and the results of the particular clinical trial. Participants' interpretations of clinic policies, staff behaviors, and personal or vicarious experiences with reporting AEs also shape reporting decisions. CONCLUSIONS: Our findings demonstrate that participants' reporting behavior is more complex than previous portraits of healthy volunteers have suggested. Rather than finding participants who were so focused on the financial compensation that they were willing to subvert trial results, our study indicates that participants are willing in most cases to forgo their full compensation if they believe not reporting their symptoms jeopardizes their own safety or the validity of the research. PMID- 29693510 TI - Airway and systemic inflammatory responses to ultrafine carbon black particles and ozone in older healthy subjects. AB - Increased adverse health effects in older subjects due to exposure to ambient air pollutants may be related to the inflammatory response induced by these contaminants. The aim of this study was to assess airway and systemic inflammatory responses in older healthy subjects to a controlled experimental exposure with spark-generated elemental carbon black ultrafine particles (cbUFPs) and ozone (O3). Twenty healthy subjects, age 52-75 years, were exposed on three occasions separated by at least 8 weeks. The exposures to filtered air (FA), to cbUFP (50 MUg/m3), or to cbUFP in combination with 250 ppb ozone (cbUFP + O3) for 3 h with intermittent exercise were performed double blind, and in random order. Sputum and blood samples were collected 3.5 h after each exposure. Exposure to cbUFP + O3 significantly increased plasma club cell protein 16 (CC16), the number of sputum cells, the number and percent of sputum neutrophils, and sputum interleukin 6 and matrix metalloproteinase 9. Exposure to cbUFP alone exerted no marked effect, except for an elevation in sputum neutrophils in a subgroup of 13 subjects that displayed less than 65% sputum neutrophils after FA exposure. None of the inflammatory markers was correlated with age, and serum cardiovascular risk markers were not markedly affected by cbUFP or cbUFP + O3. Exposure to cbUFP+O3 induced a significant airway and systemic inflammatory response in older healthy volunteer subjects. The effects induced by cbUFP alone suggest that the inflammation was predominantly mediated by O3, although one cannot rule out that the interaction of cbUFP and O3 played a role. PMID- 29693511 TI - What a Journey! What a Contribution!-An Interview With Dr. Kenneth H. Cooper, the 'Father of Aerobics'. PMID- 29693512 TI - Effects of dog-assisted intervention on quality of life in nursing home residents with dementia. AB - BACKGROUND: People with dementia often have a poor quality of life. Therefore, methods that can improve their life situation must be identified. One promising method is dog-assisted intervention. AIM: This study aimed to investigate the effects of dog-assisted intervention on quality of life in nursing home residents with dementia. MATERIALS AND METHODS: A one-group, pretest post-test study design was used. Quality of life was measured using the QUALID in 59 nursing home residents prior to and after a dog-assisted intervention. Non-parametric tests were used to analyze the data, and effect sizes were calculated. RESULTS: The participants' total scores improved significantly between baseline and post-test 1 (p = < 0.001) and worsened significantly at post-test 2 (p = 0.025). The largest effect size was found for the item 'Verbalization suggests discomfort' (p = 0.001). CONCLUSION: The results indicate that dog-assisted interventions can have positive effects on quality of life in nursing home residents with moderate to severe dementia. SIGNIFICANCE: The results contribute to a growing knowledge base about non-pharmacological methods that can be used in dementia care. Occupational therapists should consider dog-assisted interventions when planning activities that can reduce the illness burden and improve the quality of life for people with dementia. PMID- 29693513 TI - Validation of the Short Form of the Academic Procrastination Scale. AB - The factor structure, internal consistency reliability, and convergent validity of the five-item Academic Procrastination Scale-Short Form was investigated on an ethnically diverse sample of college students. The results provided support for the Academic Procrastination Scale-Short Form as a unidimensional measure of academic procrastination, which possessed good internal consistency reliability in this sample of 282 students. The scale also demonstrated good convergent validity, with moderate to large correlations with both the Procrastination Assessment Scale-Students and the Tuckman Procrastination Scale. Implications of the results are discussed and recommendations for future work provided. PMID- 29693514 TI - Boosting Performance on an Evaluative Math Test: Goal Activation vs Self Affirmation. AB - This study compared the effectiveness of goal activation versus self-affirmation and a control condition as interventions for increasing performance on an evaluative task (a difficult math test; N = 78; M age = 20.3 yr., SD = 1.9). Although there has been much recent literature on the effects of activating goals, the existing literature does not examine possible spillover effects of activating goals on performance tasks. Results indicated that goal activation resulted in significant performance enhancements over both the self-affirmation and control conditions, while self-affirmation did not improve performance significantly relative to the control condition. Additionally, interest in the task, as a cue for self-regulatory resources, mediated the effect of goal activation on increased performance. PMID- 29693515 TI - Psychological Type of Person-Centered Counselors. AB - There are various models and approaches to counseling and psychotherapy. Important characteristics of therapists include psychological type. This study aimed to investigate the psychological type profile of person-centered counselors. The psychological type of 85 counselors (63 women, 22 men) was measured with the Francis Psychological Type Scales (FPTS). Results indicate that the FPTS can reliably measure psychological type among counselors, and the most common psychological type was introvert, intuitive, feeling, and judging (INFJ). The relation of these psychological types with a person-centered approach is further discussed. PMID- 29693516 TI - Rational Thinking and Belief in Psychic Abilities: It Depends on Level of Involvement. AB - Previous research has shown that lay believers in psychic abilities are more prone to intuitive thinking, less inclined to rational thinking, and have an external locus of control, compared to non-believers. Psychic practitioners, however, may have different characteristics. Psychic practitioners ( n = 31; M age = 42.7 yr., SD = 13.1), lay believers ( n = 33; M age = 33.0 yr., SD = 10.3), and non-believers ( n = 31; M age = 34.4 yr., SD = 15.4) completed questionnaires measuring thinking styles, locus of control, and psychic belief. Comparisons of lay believers with non-believers confirmed previous observations: believers had a higher propensity for intuitive thinking, lower propensity for rational thinking, and more external locus of control. In contrast, practitioners were equivalent to non-believers in rational thinking and had the highest internal locus of control. This highlights the importance of considering level of involvement with psychic practice in understanding the thinking styles of believers. Results suggested that practitioners may have rationalized their beliefs and constructed a coherent model of psychic phenomena that satisfies a propensity for rational thinking within a community of belief. PMID- 29693517 TI - An Episodic Plot and an Unhappy Ending: What Emotional Sound Patterns Reveal About the Structure of Coleridge's Rime of the Ancyent Marinere. AB - Pleasant sounds (phonemes) within Coleridge's 1798 Rime of the Ancyent Marinere were employed to study the poem's structure in terms of the Aristotelean concepts of fortune (many pleasant emotions/phonemes) and misfortune (few) and to address questions as to how the poem doubled in length shortly before publication. The distribution of emotionally pleasant phonemes such as long e (i), l, v, and th (theta) indicated the presence of a (likely original) poem with a pleasant ending where the albatross drops from the mariner's neck. Three episodes of threat and escape were probably added to the albatross episode later, along with an unhappy ending. Significant differences in the proportion of pleasant phonemes employed in various sections support these conclusions. PMID- 29693518 TI - Self-Rated ADHD Symptoms Among Biological Mothers or Fathers of Children with Confirmed ADHD in a French Population. AB - Parents of children with ADHD are more likely to present the disorder, which can affect quality of life and parenting strategies. Few studies have examined parental ADHD to date, none in France. Prevalence of self-rated ADHD symptoms in adulthood and childhood was estimated among 60 biological mothers or fathers of children with confirmed ADHD in France. Cutoffs were total score >=46 on the Wender Utah Rating Scale and >=4 on the Adult ADHD Self-Report Scale Screener. Results indicated possible child and adult ADHD in 12.5% of mothers and 10.0% of fathers. As these percentages exceed reported prevalence rates for the French population, a greater effort must be made to diagnose the disorder in parents. PMID- 29693519 TI - Understanding The Mediating Role of Quality of Work Life on the Relationship between Emotional Intelligence and Organizational Citizenship Behaviors. AB - Organizational citizenship behaviors are not directly rewarded by organizations. However, they seem to contribute to excellent performance at work. The aim of this study is to test quality of working life's (QoWL) mediating role in the relationship between emotional intelligence (EI) and organizational citizenship behaviors (OCB). 203 French adults working regularly in teams completed validated self-report measures corresponding to each construct. The collected data showed that in the studied sample, a high quality of working life was associated with Sportsmanship behaviors. However, mediation was not observed for the other OCB subscales: Altruism, Helping, or Civic virtues. These behaviors tend to occur in individuals with high emotional intelligence scores, unrelated to their quality of working life. Theoretical background, practical implications, and limitations of the study are discussed. PMID- 29693520 TI - Relationships Among Valued Action, Behavioral Activation, Avoidance, and Reinforcement in a Sample of College Students. AB - Behavioral activation is a validated intervention for depression, which helps depressed people re-engage overt behaviors to facilitate contacts with reinforcing environmental contingencies and subsequent reductions in depression. Moreover, behavioral activation deals with values that are based on acceptance and commitment therapy. However, there is no empirical study that examines the role of behavior in line with values in behavioral activation. This study examined the role of behavior in line with values in behavioral activation by examining the association between behavior in line with values and variables of behavioral activation intervention targets, as well as the mediating effect of behavioral commitment. Japanese versions of the Personal Values Questionnaire II, the Behavioral Activation for Depression Scale, the Environmental Reward Observation Scale, and the Center for Epidemiological Studies Depression were completed by 292 Japanese undergraduate students ( M age = 19.2 yr., SD = 1.7; 65 men, 226 women, 1 unknown). Results indicated that behavior in line with values was associated with focused, goal-directed activation and completion of scheduled activities, which were mediated by behavioral commitment to values. PMID- 29693521 TI - Construct Validity of the Children's Coping Strategies Scale (CCSS): A Bifactor Model Approach. AB - There has been debate regarding the factor structure of the Children's Coping Strategies Scale (CCSS); in most previous studies there were different subscales, representing coping strategies. However, according to the theoretically multidimensional construct of coping, coping consists of an adaptive process and uses the lowest possible level of coping strategy. Accordingly, this study applies a new method of multidimensional item response theory (MIRT) to testing the latent structure of teenagers' coping strategies and to improve the construct validity of the CCSS. The participants were 1,138 16-year-old high school students (48.2% female, 51.8% male) studying arts and science. This study compares three different model types: a unidimensional model, a simple multidimensional construct model, and a bifactor model. The results indicate that the latent structure of CCSS is not only described by specific coping strategies (e.g., rumination) but also by a general adaptation process, which is consistent with theoretical understandings of coping. Furthermore, the five-factor model, which contains a "reflection" dimension, is more suitable for Chinese teenagers. PMID- 29693522 TI - Individual Differences in Preventive Jealousy Determine Men's Jealousy after Subliminal Exposure to Rivals Wearing High- or Low-Status Clothes. AB - This study investigated sex differences in jealousy after subliminal exposure to rivals wearing high-status or low-status clothes. It was expected that individual differences in preventive jealousy would moderate the relationship between a rival's characteristics and jealousy. Participants (Men: n = 54, M age = 21.6 yr., SD = 3.5; women: n = 71, M age = 20.7 yr., SD = 1.9) completed a parafoveal subliminal priming paradigm as well as questionnaires about jealousy and preventive jealousy. As predicted, women were not affected by their rival's status, but women high in preventive jealousy reported more jealousy than women low in preventive jealousy. However, whereas men low in preventive jealousy reported equal amounts of jealousy after exposure to a high-status and a low status rival, surprisingly, and contrary to the expectations, men high in preventive jealousy reported most jealousy after exposure to a low-status rival. To explain these unexpected results, threats to self-esteem were discussed. PMID- 29693523 TI - Do Suicides From the Golden Gate Bridge Cluster? AB - Suicides from popular venues (known as "hotspots") are often publicized and may result in imitation by subsequent suicides that may lead to clustering of the suicides over time. In order to examine whether the suicides from the Golden Gate Bridge showed clustering, data from the 224 suicides during 1999-2009 were analyzed using the Anderson-Darling Test was run on the data against a null hypothesis of a negative exponential distribution (as would be generated by a homogenous Poisson process). It was found that the data were almost a perfect fit for the Poisson distribution and so showed no evidence of clustering beyond that expected to occur by chance alone. This indicates that there was no imitation or contagion in the suicides from the Golden Gate Bridge. PMID- 29693524 TI - The Effect of Overconfidence on Persistent Behavior: The Mediation Effect of "I Think I Can Do It" Rather Than "I'm Attracted To It". AB - The present study explored the effects of state overconfidence on persistent behavior with consideration of feasibility and desirability as mediators. The persistent behaviors of 61 participants (35 women, 26 men; M age = 20.9 yr, SD = 1.9), placed in overconfidence and under-confidence groups based on random positive or negative bogus feedback, were measured. Results showed that participants with overconfidence were more persistent in solving problems than were those with under-confidence. Further mediation analyses revealed that the rating of the feasibility rather than the desirability of the task mediated the influence of state overconfidence on persistent behaviors. These findings provided future support for the self-justification hypothesis, and addressed arguments regarding the origins of overconfidence. PMID- 29693525 TI - Emotional Intelligence Partially Mediates the Association between Anxiety Sensitivity and Anxiety Symptoms1,2. AB - Anxiety Sensitivity (AS), the propensity to fear the somatic, mental, and social consequences of anxiety, is associated with an elevated risk of developing anxiety disorders. It was hypothesized that Emotional Intelligence (EI) might serve as a mediating variable between AS and anxiety symptom expression. Sixty one healthy adults (30 men, 31 women; M age = 30.4 yr., SD = 8.0), recruited through posted advertisements, completed the Anxiety Sensitivity Index (ASI) and the ANX subscale of the Personality Assessment Inventory (PAI), as well as three assessments of EI, including two indices of the Ability model of EI (MSCEIT; SREIS), and one index of the Trait model of EI (i.e., Bar-On EQ-i). Partial mediation between AS and ANX was found for the EQ-i but not for the MSCEIT or SREIS, as determined by the bootstrap method of mediation analysis. The association between AS and anxiety symptoms was partly explained through its effects on the intervening variable of Trait EI, and points to the possibility that interventions improving Trait EI may be useful in reducing the expression of anxiety symptoms in people with high AS. PMID- 29693526 TI - Relationship Between Sport Website Quality and Consumption Intentions: Application of a Bifactor Model. AB - This study investigated the cognitive structure of sport website quality constructs by comparing a bifactor model (a.k.a., a general-specific model) to a second-order model. The models are two alternative approaches for representing general constructs consisting of several highly related but distinct domains. In addition, the link between sport website quality and the revisitation and media consumption intentions was empirically tested. Data ( N = 272) were collected through an online survey, and the majority of respondents were men (66.3%) between 21 and 30 years old (63.0%). The bifactor and second-order models of sport website quality were also assessed and compared, and a simultaneous equation modeling analysis was used. The bifactor model fit the data significantly better than the second-order model, indicating that the five sub constructs revealed both the specific dimensions of sport website quality and the holistic nature of sport website quality. Results from the simultaneous equation model indicated that sport website quality explained 70.2% of the variance in revisitation and 58.7% of intention to consume sports media. PMID- 29693527 TI - Animal-Assisted Interventions for Children with Attention Deficit/Hyperactivity Disorder: A Theoretical Review and Consideration of Future Research Directions. AB - Attention Deficit Hyperactivity Disorder (ADHD) is one of the most prevalent neurodevelopmental disorders and is characterized by core symptoms of inattention, impulsivity, and hyperactivity. Given the limitations of the existing treatment strategies, it seems necessary to consider the further exploration of alternative treatment approaches. In this review, the application and complementary use of animal-assisted interventions to the treatment of ADHD were discussed. Several mechanisms including calming, socializing, motivating, and cognitive effects of animal-assisted interventions were explored. Since studies directly investigating these effects on ADHD are scarce, so each of them were examined in terms of how it could benefit the treatment of ADHD. These effects can have a positive effect on several core symptoms of ADHD. PMID- 29693528 TI - Psychometric Properties of the Revised and Abbreviated form of the Turkish Version of the Dysfunctional Attitude Scale. AB - Dysfunctional attitudes are considered to be important risk factors in the onset and maintenance of depression. Thus, a psychometrically reliable and valid measure is necessary for understanding depression. The Dysfunctional Attitude Scale (DAS) is widely used and has good psychometric properties, but there is no consensus about its factor structure. To examine its psychometric properties and factor structure, a total of 885 individuals consisting of patients with depression and healthy controls were evaluated. After the sample was randomly divided into two subsets, exploratory and confirmatory factor analyses were performed. Then the DAS was abbreviated according to the factor profiles and theoretical background. Analyses indicated two factors, named Perfectionism/Achievement and Need for Approval/Dependency for the revised DAS . Reliability analyses revealed a good internal consistency, and the concurrent validity indicated significant correlations with the Beck Depression Inventory and the Automatic Thoughts Questionnaire. PMID- 29693529 TI - The Precision of Effect Size Estimation From Published Psychological Research: Surveying Confidence Intervals. AB - Confidence interval ( CI) widths were calculated for reported Cohen's d standardized effect sizes and examined in two automated surveys of published psychological literature. The first survey reviewed 1,902 articles from Psychological Science. The second survey reviewed a total of 5,169 articles from across the following four APA journals: Journal of Abnormal Psychology, Journal of Applied Psychology, Journal of Experimental Psychology: Human Perception and Performance, and Developmental Psychology. The median CI width for d was greater than 1 in both surveys. Hence, CI widths were, as Cohen (1994) speculated, embarrassingly large. Additional exploratory analyses revealed that CI widths varied across psychological research areas and that CI widths were not discernably decreasing over time. The theoretical implications of these findings are discussed along with ways of reducing the CI widths and thus improving precision of effect size estimation. PMID- 29693530 TI - Nostalgia and Perceptions of Artwork. AB - A total of 179 participants completed the Nostalgia Proneness Scale, a measure of historical nostalgia, and the Nostalgia Inventory, a measure of personal nostalgia. Participants were also asked to indicate how much they "liked" four different artworks and to indicate how much the artworks "made them think." The results indicated that respondents with higher historical nostalgia reported liking artwork that included human figures more than artwork with no such inclusion; and that they found these artworks more thought-provoking. These findings are consistent with previous research suggesting that nostalgia involves some component of social connectedness. PMID- 29693531 TI - Satisfaction with Life, Meaning in Life, Sad Childhood Experiences, and Psychological Symptoms among Turkish Students. AB - The aim of the current study was to investigate the contributions of sad childhood experiences, depression, anxiety, and stress, existence of a sense of meaning, and pursuit of meaning in explaining life satisfaction of young adults in Turkey. The sample comprised 400 undergraduate students ( M age = 20.2 yr.) selected via random cluster sampling. There were no statistically significant differences between men and women in terms of their scores on depression, existence of meaning, pursuit of meaning, and life satisfaction scores. However, there were statistically significant differences between men and women on the sad childhood experiences, anxiety and stress. In heirarchical regression analysis, the model as a whole was significant. Depression and existence of meaning in life made unique significant contributions to the variance in satisfaction in life. Students with lower depression and with a sense of meaning in life tended to be more satisfied with life. PMID- 29693532 TI - Self-Serving Bias in the Implicit and Explicit Evaluation of Partners and Exes as Parents: A Pilot Study. AB - The quality of partners' relationship can be influenced by the reciprocal respect of the other's parenting role, especially when the couple breaks up. This study is aimed at investigating the implicit versus explicit self-serving biases in the evaluation of partners and exes as parents (or potential parents), exploring sex differences and possible relationships with dyadic cohesion. Two Implicit Association Tests and two semantic differentials, comparing each respondent with current partners and last significant exes, and also a scale measuring dyadic cohesion were administered to 108 participants (40 men; M age = 28.1 yr., SD = 8.7). As expected, participants assessed themselves as better than others on both IAT and self-report evaluations, with larger effects toward exes than toward partners and on implicit than explicit measures. Women devalued exes, but not partners, more than men. Dyadic cohesion scores were negatively correlated with the explicit evaluations of partners but not with implicit ones. Theoretical interpretations in terms of self-serving bias were discussed. PMID- 29693533 TI - Development and evaluation of a scale assessing therapist fidelity to guidelines for delivering therapist-assisted Internet-delivered cognitive behaviour therapy. AB - Internet-delivered cognitive behaviour therapy (ICBT) is often accompanied by therapist emails, but there is limited research on the quality of this therapist assistance. In this study, an ICBT Therapist Rating Scale (ICBT-TRS) was developed and evaluated to assess whether therapist emails showed fidelity to specific therapist behaviours. Using data from a previous ICBT trial for depression and anxiety, the ICBT-TRS was used to rate 706 emails sent by 39 therapists to 91 randomly selected patients. Emails were rated for adherence (absent/present) and quality (inadequate/competent) on the following behaviours: Builds Rapport, Seeks Feedback, Provides Symptom Feedback, Provides Psychoeducation, Facilitates Understanding, Praises Effort, Encourages Practice, Clarifies Administrative Procedures, and Communicates Effectively. Inter-rater reliability was high. Most behaviours were identified as present in 72-100% of emails, with the exception of Provides Symptom Feedback and Facilitating Understanding which were only present in 54 and 61% of emails. The majority of emails were rated as high quality (88-98% of messages). While not related to symptom improvement, ICBT-TRS ratings were higher when patients were more engaged in ICBT (e.g. log-ins) and among therapists who specialized in ICBT or had a background in Psychology. The ICBT-TRS has potential to facilitate ICBT research and clinical training. PMID- 29693534 TI - Special Section on Older Immigrants and Refugees. PMID- 29693537 TI - Detail, dynamics and depth: useful correctives for some current research trends. AB - SummarySeveral research trends in contemporary psychiatry would benefit from greater emphasis on detailed assessment, modelling dynamic change, and micro level analysis. This may assist with clarifying nosological and pathoaetiological issues. We make this case by referring to three areas: psychopathology and nosology; prediction research; and 'big N' data sets.Declaration of interestNone. PMID- 29693535 TI - Neurodevelopmental risk copy number variants in adults with intellectual disabilities and comorbid psychiatric disorders. AB - BACKGROUND: Copy number variants (CNVs) are established risk factors for neurodevelopmental disorders. To date the study of CNVs in psychiatric illness has focused on single disorder populations. The role of CNVs in individuals with intellectual disabilities and psychiatric comorbidities are less well characterised.AimsTo determine the type and frequency of CNVs in adults with intellectual disabilities and comorbid psychiatric disorders. METHOD: A chromosomal microarray analysis of 599 adults recruited from intellectual disabilities psychiatry services at three European sites. RESULTS: The yield of pathogenic CNVs was high - 13%. Focusing on established neurodevelopmental disorder risk loci we find a significantly higher frequency in individuals with intellectual disabilities and comorbid psychiatric disorder (10%) compared with healthy controls (1.2%, P<0.0001), schizophrenia (3.1%, P<0.0001) and intellectual disability/autism spectrum disorder (6.5%, P < 0.00084) populations. CONCLUSIONS: In the largest sample of adults with intellectual disabilities and comorbid psychiatric disorders to date, we find a high rate of pathogenic CNVs. This has clinical implications for the use of genetic investigations in intellectual disability psychiatry.Declaration of interestNone. PMID- 29693538 TI - 'We've had enough of experts': the enduring charm of quackery. AB - Broadcaster and journalist. FRCP (hon). PMID- 29693539 TI - We all know what we mean by treatment-resistant depression - don't we? AB - SummaryAlthough in common use, treatment-resistant depression is unhelpful both conceptually and practically. In this issue a new term, multiple-therapy resistant major depressive disorder, is proposed; although it may be useful in guiding treatment options for patients with persisting depression, it should not be an automatic trigger for further, more invasive treatments.Declaration of interestsI.M.A. has been a consultant for pharmaceutical companies developing and marketing antidepressants and has been an author on publications that have used the term treatment-resistant depression. PMID- 29693540 TI - Don't forget to connect with patient experience: conversations on trust, ties and surprise. PMID- 29693541 TI - Phylogenetic comparison of enteroinvasive Escherichia coli isolated from cases of diarrhoeal disease in England, 2005-2016. AB - We compared the genomes of 60 isolates of enteroinvasive Escherichia coli (EIEC) in order to better understand the step-wise evolutionary process from non pathogenic to host-adapted pathogenic E. coli. All isolates belonged to either sequence type (ST) 6, ST99 or ST270. Each ST was located on different branches of the E. coli phylogeny and had invasion plasmids (pINVs) belonging to FII-21 (ST99, ST270), FII-27 (ST270) or FII-28 (ST6, ST270) incompatibility groups. A higher number of insertion sequence (IS) elements were identified in ST6 and ST270 than in ST99, and appeared to be driving the loss of functional genes. Comparison of the pINV from each ST revealed different degrees of gene loss, with pINV from ST270 being most similar to that found in Shigella species. We captured three EIEC STs at different stages of patho-adaptation, with ST270 being the most 'shigella-like' and the most divergent from non-pathogenic E. coli, and ST99 being the least divergent. PMID- 29693542 TI - Hymenobacter aquatilis sp. nov., isolated from a mesotrophic artificial lake. AB - A novel strain, designated HMF3095T, isolated from freshwater of a mesotrophic artificial lake in the Republic of Korea, was characterized by polyphasic taxonomy. The cells were Gram-stain-negative, aerobic, non-motile, straight rods and formed reddish colonies. Phylogenetic analysis based on its 16S rRNA gene sequence revealed that strain HMF3095T fell within the cluster of the genus Hymenobacterand was most closely related to Hymenobacter seoulensis 16F7GT and Hymenobacter tenuis POB6T (96.7 % sequence similarity). Sequence similarities to all other type strains were 96.3 % or less. The major fatty acids were iso-C15 : 0, C16 : 1omega5c, summed feature 4 (iso-C17 : 1 I and/or anteiso-C17 : 1 B), summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and anteiso-C15 : 0. The major isoprenoid quinone was menaquinone 7. The major polar lipids were phosphatidylethanolamine, three unidentified aminophospholipids and one unidentified phospholipid. The DNA G+C content was 58.9 mol%. On the basis of the evidence presented in this study, strain HMF3095T represents a novel species of the genus Hymenobacter, for which the name Hymenobacter aquatilis sp. nov. is proposed. The type strain is HMF3095T (=KCTC 52398T=NBRC 112669T). PMID- 29693543 TI - Urinary tract infection by Acinetobacter baumannii and Pseudomonas aeruginosa: evolution of antimicrobial resistance and therapeutic alternatives. AB - PURPOSE: Acinetobacter baumannii and Pseudomonas aeruginosa are responsible for numerous nosocomial infections. The objective of this study was to determine the development of their susceptibility to ten antibiotics and the antibiotic consumption of patients with suspicion of urinary tract infection (UTI). METHODOLOGY: A retrospective study was conducted on the susceptibility profiles of A. baumannii and P. aeruginosa isolates from 749 urine samples gathered between January 2013 and December 2016, and on the consumption of imipenem, meropenem and piperacillin-tazobactam between 2014 and 2016. RESULTS: Hospital patients were the source of 82 (91.1 %) of the 90 A. baumannii isolates detected and 555 (84.2 %) of the 659 P. aeruginosa isolates. Globally, the lowest percentage susceptibility values were found for fosfomycin, aztreonam and ciprofloxacin, while colistin continued to be the most active antibiotic in vitro. In 2016, the susceptibility of A. baumannii to carbapenem and piperacillin tazobactam decreased to very low values, while the susceptibility of P. aeruginosa to carbapenem remained stable but its susceptibility to piperacillin tazobactam decreased. There was a marked increase in the consumption of piperacillin-tazobactam. CONCLUSION: In our setting, it is no longer possible to use carbapenems and piperacillin-tazobactam for empirical treatment of UTI due to A. baumannii or to use piperacillin-tazobactam for empirical treatment of UTI due to P. aeruginosa. Colistin was found to be the most active antibiotic in vitro. There was a marked increase in the consumption of piperacillin-tazobactam. PMID- 29693544 TI - Pannonibacter carbonis sp. nov., isolated from coal mine water. AB - Two bacterial strains were isolated from coal mine water in China. Isolates were facultatively anaerobic, Gram-stain-negative, rod-shaped, motile by means of a single polar flagellum, and they did not produce bacteriochlorophyll alpha. Cells grew in tryptic soy broth with 0-5.5 % (w/v) NaCl, at 4-55 degrees C and pH 3.5 10.5. Isolates were positive for catalase, oxidase, urease, Voges-Proskauer test, gelatin hydrolysis and H2S production. Analysis of 16S rRNA gene sequences indicated that the closest relatives of strains Q4.6T and Q2.11 were the type strains Labrenzia suaedae DSM 22153T (97.4 %), Pannonibacter phragmitetus DSM 14782T (96.9 and 97.0 %) and Pannonibacter indicus DSM 23407T (96.8 %). The genomic average nucleotide identity (ANI) value for Q4.6T and Q2.11 was 100 %; however, this value was less than 77.7 % for the type strains P. phragmitetus and P. indicus, and less than 74.0 % for the type strain L. suaedae. The cellular fatty acid profile of strains Q4.6T and Q2.11 consisted primarily of C18 : 1omega7c. The principal quinone of the isolates was Q-10. The polar lipid profile consisted of diphosphatidyl glycerol, phosphatidyl glycerol, phosphatidyl ethanolamine and phosphatidyl choline. On the basis of phylogenetic analysis, genomic ANI analysis, DNA-DNA hybridization results, as well as phenotypic and chemotaxonomic data, strains Q4.6T and Q2.11 are assigned as a novel species within the genus Pannonibacter. The type strain is Pannonibacter carbonis Q4.6T (=CGMCC 1.15703T=KCTC 52466T). PMID- 29693545 TI - Joys and challenges of relationships in Scotland and New Zealand rural midwifery: A multicentre study. AB - BACKGROUND: Globally there are challenges meeting the recruitment and retention needs for rural midwifery. Rural practice is not usually recognised as important and feelings of marginalisation amongst this workforce are apparent. Relationships are interwoven throughout midwifery and are particularly evident in rural settings. However, how these relationships are developed and sustained in rural areas is unclear. AIM: To study the significance of relationships in rural midwifery and provide insights to inform midwifery education. METHODS/DESIGN: Multi-centre study using online surveys and discussion groups across New Zealand and Scotland. Descriptive and template analysis were used to organise, examine and analyse the qualitative data. FINDINGS: Rural midwives highlighted how relationships with health organisations, each other and women and their families were both a joy and a challenge. Social capital was a principal theme. Subthemes were (a) working relationships, (b) respectful communication, (c) partnerships, (d) interface tensions, (e) gift of time facilitates relationships. CONCLUSIONS: To meet the challenges of rural practice the importance of relationship needs acknowledging. Relationships are created, built and sustained at a distance with others who have little appreciation of the rural context. Social capital for rural midwives is thus characterised by social trust, community solidarity, shared values and working together for mutual benefit. Rural communities generally exhibit high levels of social capital and this is key to sustainable rural midwifery practice. IMPLICATIONS: Midwives, educationalists and researchers need to address the skills required for building social capital in rural midwifery practice. These skills are important in midwifery pre- and post registration curricula. PMID- 29693546 TI - Self-management of gestational diabetes among Chinese migrants: A qualitative study. AB - BACKGROUND: Gestational diabetes mellitus is one of the most common complications of pregnancy. Women with Gestational diabetes are at increased risk of serious health outcomes, such as pre-eclampsia, obstructed labor, and the development of Type 2 diabetes later in life. Chinese migrants, the third largest cultural group in Australia, are more likely to develop Gestational diabetes than Australian born women. However, to date, Gestational diabetes self-management has not been investigated in this population. AIM: To explore the understanding and self management experiences of Gestational diabetes among Chinese migrants. METHODS: Data were collected through individual semi-structured face-to-face interviews. Participants were recruited from the antenatal clinic at the Royal Prince Alfred Hospital. Interviews were audio-recorded, transcribed verbatim and thematically analyzed. FINDINGS: Although the majority of participants demonstrated a good understanding of Gestational diabetes, some did not understand the principles behind healthcare advice and faced challenges in self-management. Confusion about self-monitoring of blood glucose and fear of insulin were also evident. Participants relied on both formal and informal sources of information. Some had difficulty obtaining adequate support. Cultural influences on self-management included meeting family needs, Chinese diet and use of Chinese medicines. CONCLUSION: To assist Chinese women with Gestational diabetes to better self manage their condition, there is a need for clinicians to: (1) provide more effective diabetes education to ensure clear understanding of self-management principles; (2) actively elicit and respond to women's confusion and concerns; (3) provide women with adequate practical support; and (4) develop greater cultural awareness. PMID- 29693547 TI - The role of clinical factors in the association of gestational diabetes amongst women aged 15-49 years residing in Yazd-Iran. AB - BACKGROUND: Gestational diabetes mellitus (GDM) has occurred in Fourteen percent of all pregnancies in the world. Epidemiological evidences about risk factors of GDM may be different from region to region and are unknown, exactly. This study examines the role of clinical factors in the association of gestational diabetes in Yazd, Iran. METHODS: This study was carried out on 168 women with gestational diabetes and 168 women as controls after matching for age and place of residence. Each participant was interviewed about her pregnancy history and tobacco consumption. Information including BMI, weight before pregnancy and background of underlying diseases were recorded from information system in Health Centers. Finally, data were analyzed by using chi-square test, logistic regression and multiple correspondence analyze(MCA). RESULTS: History of gestational diabetes in past pregnancy OR = 3.2[95%CI:1.1, 9.7], a family history of gestational diabetes OR = 3.7 [95%CI:1.1, 11.5], a history of hookah smoking OR = 3.6 [95%CI:1.06, 12.3], being obese before pregnancy OR = 1.9[95%CI:1.01, 3.5], and weight gain during pregnancy OR = 0.5[95%CI:0.2, 0.9], were the most important determinants of gestational diabetes. There were not significant relation between GDM and underlying diseases, history of stillbirth, abortion, twinning, cigarette smoking, alcohol and drug abuse. CONCLUSIONS: In this research modifiable risk factors for gestational diabetes were high BMI before pregnancy, weight gain during pregnancy and history of hookah consumption. We advise that appropriate education, avoiding sedentary lifestyle, diet improvement and advertising which focus on tobacco consumption is playing as an important role in developing the chronic diseases, including GDM. PMID- 29693548 TI - Prevalence and association of clinical characteristics and biochemical factors with complications of diabetes mellitus in Palestinians treated in primary healthcare practice. AB - AIMS: The current study was carried out to examine prevalence of complications related to diabetes mellitus (DM) and to investigate association between clinical variables and biochemical factors with complications of DM in patients treated in primary healthcare settings in the West Bank of Palestine. MATERIALS AND METHODS: Sociodemographic, clinical, and biochemical variables were collected from 385 patients visiting 17 primary healthcare settings in the West Bank. Patients provided blood and urine samples, responded to a questionnaire interview, and were subjected to ophthalmic examination. RESULTS: HbA1c levels were predicted by duration of DM (p < 0.001), HDL (p = 0.011), alkaline phosphatase (p = 0.001), blood urea (p = 0.006), and LDL (p = 0.008). Triglycerides levels were predicted by blood urea (p = 0.002), HDL (p < 0.001), and total cholesterol (p < 0.001). GOT levels were predicted by LDL (p = 0.002) and GPT (p < 0.001). GPT levels were predicted by HDL (p = 0.003) and blood urea (p = 0.025). Urine albumin were predicted by total cholesterol (p = 0.001), LDL (p = 0.005), and blood urea (p = 0.036). CD ratio was predicted by the IOP and the IOP was predicted by the CD ratio (p = 0.001). CONCLUSIONS: Prevalence of complications related to DM was high among patients with DM treated in primary healthcare practice. These complications and risk factors were predicted by certain clinical characteristics and biochemical factors. Policies and programs are needed to manage these modifiable risk factors. PMID- 29693549 TI - Lack of impact of dietary inclusion of dried Artemisia annua leaves for cattle on infestation by Rhipicephalus (Boophilus) microplus ticks. AB - The present study evaluated whether a natural dietary additive, dried Artemisia annua leaves, may be useful to control Rhipicephalus (Boophilus) microplus on naturally infested cattle. Twenty heifers of the Canchim breed, weighing around 250 kg, were divided into two equally sized experimental groups: 1) control animals and 2) animals receiving 200 g/day of dried A. annua leaves for two months. Before treatment began, the animals were homogeneously distributed in control and treatment groups based on their pre-treatment weight and tick infestation level. Counts of engorged female ticks then occurred weekly during the two-month experimental period. We also monitored cattle weight gain and packed cell volume (PCV). Artemisinin (0.96%) was quantified in the plant material by high-performance liquid chromatography with refractive index detector (HPLC-IR). No statistical differences between the control and treatment groups were observed for engorged female counts (log averages of 1.3 ticks and 1.4 ticks per animal, respectively), daily cattle weight gain (0.910 kg and 0.888 kg, respectively) or PCV (33.5% and 33.0%, respectively). We conclude that the oral supplementation of cattle feed with dried A. annuna leaves did not control natural infestation of R. (B.) microplus. The hypothesis of artemisinin's action on cattle ticks by ingestion through the animals' blood was not confirmed at the evaluated dose. PMID- 29693550 TI - Serological and molecular detection of Theileria equi and Babesia caballi in Philippine horses. AB - Theileria equi and Babesia caballi are tick-borne protozoan parasites that can cause anemia in horses. In the Philippines, serological detection of these parasites has only been reported in the Northern area (Luzon). In this study, 105 horses from Cebu and Bohol, Philippines were tested using peripheral blood smear examination (PBSE), immunochromatographic test (ICT) strips, and PCR. Clinical history, presenting clinical signs and complete blood count were obtained. Results revealed that although all horses were negative using PBSE, 23 (21.9%) were positive (12 for T. equi, and 11 for B. caballi) using ICT. PCR revealed 26 and 2 horses positive for T. equi and B. caballi, respectively. All positive horses showed no clinical signs. Partial DNA sequences of representative amplicons were found 100% identical to GenBank registered T. equi and B. caballi sequences. Statistical analyses revealed that location was found associated with T. equi PCR positivity and B. caballi seropositivity. This study documents the first serological detection of T. equi and B. caballi in horses in the southern area of the Philippines, and their first molecular detection and characterization in the country. PMID- 29693551 TI - Infestation of Rhipicephalus sanguineus sensu lato on cats in Malta. AB - Studies on cats as hosts of Rhipicephalus sanguineus sensu lato (s.l.) are scarce. Cats are regarded as infrequent hosts of this species complex, and usually only when dogs are also present. In order to compare the occurrence of developmental stages and mitochondrial DNA haplotypes of R. sanguineus s.l. on cats and other domestic or synanthropic mammalian species, 540 ticks were collected from cats, dogs, hedgehogs and one goat. Collections were made from April to September in 2016 and 2017, from 20 locations in Malta in southern Europe. The sampling sites included six cat colonies, where no dogs were present. Compared to adults, significantly more immatures of R. sanguineus s.l. were found on cats (123 larvae and nymphs versus 10 adults) than on dogs (190 larvae and nymphs versus 173 adults). Furthermore, compared to nymphs, significantly more larvae of R. sanguineus s.l. were found on cats (50 larvae versus 73 nymphs) than on dogs (11 larvae versus 179 nymphs). Adult ticks predominated on male dogs (42 adults versus 28 larvae or nymphs), whereas immatures were significantly more abundant compared to adult ticks on female dogs (142 larvae or nymphs versus 80 adults). Similarly, immature as compared with adult ticks were significantly more likely to occur on female cats (72 immature ticks versus 1 adult) in comparison with male cats (46 immature ticks versus 8 adults). Moreover, R. sanguineus s.l. larvae were found significantly more frequently as compared with nymphs on female cats (38 larvae versus 34 nymphs) than on male cats (12 larvae versus 34 nymphs). To confirm morphological identification and to compare mitochondrial markers (cytochrome c oxidase subunit 1 [cox1] and 16S rRNA genes) of ticks across hosts, 57 ticks were analysed. The amplified parts of the cox1 and 16S rRNA genes of R. sanguineus s.l. collected from various hosts showed 100% sequence identity with each other and with those in GenBank from the middle to western Mediterranean Basin. In conclusion, the present study highlights that cats can be important hosts of the immature life stages of R. sanguineus s.l., even in the absence of dogs. This finding has veterinary-medical significance, because stray cats and free-roaming cats may transport immature stages of R. sanguineus s.l. into gardens, i.e. near dogs and humans. PMID- 29693552 TI - Bio-resin for high resolution lithography-based biofabrication of complex cell laden constructs. AB - Lithography-based three-dimensional (3D) printing technologies allow high spatial resolution that exceeds that of typical extrusion-based bioprinting approaches, allowing to better mimic the complex architecture of biological tissues. Additionally, lithographic printing via digital light processing (DLP) enables fabrication of free-form lattice and patterned structures which cannot be easily produced with other 3D printing approaches. While significant progress has been dedicated to the development of cell-laden bioinks for extrusion-based bioprinting, less attention has been directed towards the development of cyto compatible bio-resins and their application in lithography-based biofabrication, limiting the advancement of this promising technology. In this study, we developed a new bio-resin based on methacrylated poly(vinyl alcohol) (PVA-MA), gelatin-methacryloyl (Gel-MA) and a transition metal-based visible light photoinitiator. The utilization of a visible light photo-initiating system displaying high molar absorptivity allowed the bioprinting of constructs with high resolution features, in the range of 25-50 MUm. Biofunctionalization of the resin with 1 wt% Gel-MA allowed long term survival (>90%) of encapsulated cells up to 21 d, and enabled attachment and spreading of endothelial cells seeded on the printed hydrogels. Cell-laden hydrogel constructs of high resolution with complex and ordered architecture were successfully bioprinted, where the encapsulated cells remained viable, homogenously distributed and functional. Bone and cartilage tissue synthesis was confirmed by encapsulated stem cells, underlining the potential of these DLP-bioprinted hydrogels for tissue engineering and biofabrication. Overall, the PVA-MA/Gel-MA bio-resin is a promising material for biofabrication and provides important cues for the further development of lithography-based bioprinting of complex, free-form living tissue analogues. PMID- 29693553 TI - Highly efficient and stable blue-emitting CsPbBr3@SiO2 nanospheres through low temperature synthesis for nanoprinting and WLED. AB - Inorganic perovskite quantum dots (QDs) have attracted wide attention in display and solid-state lighting because of their easily tunable band-gaps and high photoluminescence quantum yields (PLQY) of green light emission. However, some drawbacks limit their practical applications, including the low PLQY of blue light emission and the instability in the moisture environment. In this work, efficient blue-light emitting CsPbBr3 perovskite QDs with PLQY of 72% were developed through a bandgap engineering approach. The achieved blue-light emitting PLQY is much higher than the values acquired in the inorganic perovskite QDs in the literature. And the emission color of the as-prepared QDs can be facially tuned by only adjusting the reaction temperature. Further, the mono dispersed perovskite QDs@SiO2 composites were constructed benefiting from the low temperature synthesis. The optical performance of the QDs could be well persisted even in the moisture environment. Finally, the as-prepared QDs@SiO2 composite was fabricated as the QD ink on the anti-counterfeit printing technology, from which the obtained pattern would emit varied color under UV lamp. And the as-prepared composites was also applied for fabricating WLED, with Commission Internationale de l'Eclairage (CIE) color coordinates of (0.33, 0.38) and power efficiency of 32.5 lm W-1, demonstrating their promising potentials in solid-state lighting. PMID- 29693554 TI - Increase in random component of heart rate variability coinciding with developmental and degenerative stages of life. AB - OBJECTIVE: To adapt to a new environment or situation, biological systems explore the most convenient state while moving between attractors by the force of random fluctuation. From this concept, the random component in physiological signals is assumed to increase during developmental and degenerative stages of life. To examine this hypothesis, we measured the age-dependent changes in the random component of heart rate variability (HRV) in 24-h electrocardiography (ECG) big data and in patients with a developmental disorder (DD). APPROACH: We measured separately regulated and random components of HRV with autoregressive (AR) model fitting, by which the ratio of random component as the fractional variance of AR residual time series. From the ALLSTAR database of about 304 000 ambulatory 24-h ECGs, we randomly extracted the data of 1930 men and 1987 women uniformly for all ages from 0 to 100 years old (100 cases per 5-year strata for each sex). Data were also obtained from male pediatric patients with DD (age 10-15 years). MAIN RESULTS: While the variance of the regulated component of HRV increased from age 0 to 20, decreased with age until 40, and reached a plateau in both sexes, the ratio of the random component was high at birth, decreased with age until 35 in men and 30 in women, and increased again after 75 in men and 85 in women (P < 0.0001 for all). In patients with a DD, the ratio of the random component was significantly lower than that in age-and-sex matched subjects in the database. SIGNIFICANCE: We found that the ratio of the random component of HRV is increased during developmental and degenerative stages of life and that it may be reduced in DD patients during their development. PMID- 29693556 TI - Prediction of Fatigue Crack Growth in Gas Turbine Engine Blades Using Acoustic Emission. AB - Fatigue failure is the main type of failure that occurs in gas turbine engine blades and an online monitoring method for detecting fatigue cracks in blades is urgently needed. Therefore, in this present study, we propose the use of acoustic emission (AE) monitoring for the online identification of the blade status. Experiments on fatigue crack propagation based on the AE monitoring of gas turbine engine blades and TC11 titanium alloy plates were conducted. The relationship between the cumulative AE hits and the fatigue crack length was established, before a method of using the AE parameters to determine the crack propagation stage was proposed. A method for predicting the degree of crack propagation and residual fatigue life based on the AE energy was obtained. The results provide a new method for the online monitoring of cracks in the gas turbine engine blade. PMID- 29693555 TI - Co-Localization of Crotamine with Internal Membranes and Accentuated Accumulation in Tumor Cells. AB - Crotamine is a highly cationic; cysteine rich, cross-linked, low molecular mass cell penetrating peptide (CPP) from the venom of the South American rattlesnake. Potential application of crotamine in biomedicine may require its large-scale purification. To overcome difficulties related with the purification of natural crotamine (nCrot) we aimed in the present study to synthesize and characterize a crotamine analog (sCrot) as well investigate its CPP activity. Mass spectrometry analysis demonstrates that sCrot and nCrot have equal molecular mass and biological function—the capacity to induce spastic paralysis in the hind limbs in mice. sCrot CPP activity was evaluated in a wide range of tumor and non tumor cell tests performed at different time points. We demonstrate that sCrot Cy3 showed distinct co-localization patterns with intracellular membranes inside the tumor and non-tumor cells. Time-lapse microscopy and quantification of sCrot Cy3 fluorescence signalss in living tumor versus non-tumor cells revealed a significant statistical difference in the fluorescence intensity observed in tumor cells. These data suggest a possible use of sCrot as a molecular probe for tumor cells, as well as, for the selective delivery of anticancer molecules into these tumors. PMID- 29693557 TI - Continuous Glucose Monitoring in Resource-Constrained Settings for Hypoglycaemia Detection: Looking at the Problem from the Other Side of the Coin. AB - The appearance, over a decade ago, of continuous glucose monitoring (CGM) devices has triggered a patient-centred revolution in the control and management of diabetes mellitus and other metabolic conditions, improving the patient’s glycaemic control and quality of life. Such devices, the use of which remains typically restricted to high-income countries on account of their elevated costs, at present show very limited implantation in resource-constrained settings, where many other urgent health priorities beyond diabetes prevention and management still need to be resolved. In this commentary, we argue that such devices could have an additional utility in low-income settings, whereby they could be selectively used among severely ill children admitted to hospital for closer monitoring of paediatric hypoglycaemia, a life-threatening condition often complicating severe cases of malaria, malnutrition, and other common paediatric conditions. PMID- 29693558 TI - S1P4 Regulates Passive Systemic Anaphylaxis in Mice but Is Dispensable for Canonical IgE-Mediated Responses in Mast Cells. AB - Mast cells are key players in the development of inflammatory allergic reactions. Cross-linking of the high-affinity receptor for IgE (FcεRI) on mast cells leads to the generation and secretion of the sphingolipid mediator, sphingosine-1 phosphate (S1P) which is able, in turn, to transactivate its receptors on mast cells. Previous reports have identified the expression of two of the five receptors for S1P on mast cells, S1P1 and S1P2, with functions in FcεRI mediated chemotaxis and degranulation, respectively. Here, we show that cultured mouse mast cells also express abundant message for S1P4. Genetic deletion of S1pr4 did not affect the differentiation of bone marrow progenitors into mast cells or the proliferation of mast cells in culture. A comprehensive characterization of IgE-mediated responses in S1P4-deficient bone marrow-derived and peritoneal mouse mast cells indicated that this receptor is dispensable for mast cell degranulation, cytokine/chemokine production and FcεRI-mediated chemotaxis in vitro. However, interleukin-33 (IL-33)-mediated enhancement of IgE induced degranulation was reduced in S1P4-deficient peritoneal mast cells, revealing a potential negative regulatory role for S1P4 in an IL-33-rich environment. Surprisingly, genetic deletion of S1pr4 resulted in exacerbation of passive systemic anaphylaxis to IgE/anti-IgE in mice, a phenotype likely related to mast cell-extrinsic influences, such as the high circulating levels of IgE in these mice which increases FcεRI expression and consequently the extent of the response to FcεRI engagement. Thus, we provide evidence that S1P4 modulates anaphylaxis in an unexpected manner that does not involve regulation of mast cell responsiveness to IgE stimulation. PMID- 29693559 TI - A Novel Approach to the Identification of Compromised Pulmonary Systems in Smokers by Exploiting Tidal Breathing Patterns. AB - Smoking causes unalterable physiological abnormalities in the pulmonary system. This is emerging as a serious threat worldwide. Unlike spirometry, tidal breathing does not require subjects to undergo forceful breathing maneuvers and is progressing as a new direction towards pulmonary health assessment. The aim of the paper is to evaluate whether tidal breathing signatures can indicate deteriorating adult lung condition in an otherwise healthy person. If successful, such a system can be used as a pre-screening tool for all people before some of them need to undergo a thorough clinical checkup. This work presents a novel systematic approach to identify compromised pulmonary systems in smokers from acquired tidal breathing patterns. Tidal breathing patterns are acquired during restful breathing of adult participants. Thereafter, physiological attributes are extracted from the acquired tidal breathing signals. Finally, a unique classification approach of locally weighted learning with ridge regression (LWL ridge) is implemented, which handles the subjective variations in tidal breathing data without performing feature normalization. The LWL-ridge classifier recognized compromised pulmonary systems in smokers with an average classification accuracy of 86.17% along with a sensitivity of 80% and a specificity of 92%. The implemented approach outperformed other variants of LWL as well as other standard classifiers and generated comparable results when applied on an external cohort. This end-to-end automated system is suitable for pre-screening people routinely for early detection of lung ailments as a preventive measure in an infrastructure-agnostic way. PMID- 29693560 TI - Self-Catalyzed CdTe Wires. AB - CdTe wires have been fabricated via a catalyst free method using the industrially scalable physical vapor deposition technique close space sublimation. Wire growth was shown to be highly dependent on surface roughness and deposition pressure, with only low roughness surfaces being capable of producing wires. Growth of wires is highly (111) oriented and is inferred to occur via a vapor-solid-solid growth mechanism, wherein a CdTe seed particle acts to template the growth. Such seed particles are visible as wire caps and have been characterized via energy dispersive X-ray analysis to establish they are single phase CdTe, hence validating the self-catalysation route. Cathodoluminescence analysis demonstrates that CdTe wires exhibited a much lower level of recombination when compared to a planar CdTe film, which is highly beneficial for semiconductor applications. PMID- 29693562 TI - beta-Hemolysis May Not Be a Reliable Indicator of Leukotoxicity of Mannheimia haemolytica Isolates. AB - Mannheimia (Pasteurella) haemolytica causes bronchopneumonia in domestic and wild ruminants. Leukotoxin is the critical virulence factor of M. haemolytica. Since β-hemolysis is caused by a large number of leukotoxin-positive M. haemolytica isolates, all β-hemolytic M. haemolytica isolates are considered to be leukotoxic as well. However, conflicting reports exist in literature as to the leukotoxic and hemolytic properties of M. haemolytica. One group of researchers reported their leukotoxin-deletion mutants to be hemolytic while another reported their mutants to be non-hemolytic. The objective of this study was to determine whether β-hemolysis is a reliable indicator of leukotoxicity of M. haemolytica isolates. Ninety-five isolates of M. haemolytica were first confirmed for presence of leukotoxin gene (lktA) by a leukotoxin specific PCR assay. Culture supernatant fluids from these isolates were then tested for presence of leukotoxin protein by an ELISA, and for leukotoxic activity by a cytotoxicity assay. All isolates were tested for β-hemolysis by culture on blood agar plates. Sixty-two isolates (65%) produced leukotoxin protein while 33 isolates (35%) did not. Surprisingly, 18 of the 33 isolates (55%), that did not produce leukotoxin protein, were hemolytic. Of the 62 isolates that produced leukotoxin, 55 (89%) were leukotoxic while 7 (11%) were not. All except one of the 55 leukotoxic isolates (98%) were also hemolytic. All seven isolates that were not leukotoxic were hemolytic. Taken together, these results suggest that β-hemolysis may not be a reliable indicator of leukotoxicity of M. haemolytica isolates. Furthermore, all M. haemolytica isolates that possess lktA gene may not secrete active leukotoxin. PMID- 29693561 TI - Framing the Future with Bacteriophages in Agriculture. AB - The ability of agriculture to continually provide food to a growing world population is of crucial importance. Bacterial diseases of plants and animals have continually reduced production since the advent of crop cultivation and animal husbandry practices. Antibiotics have been used extensively to mitigate these losses. The rise of antimicrobial resistant (AMR) bacteria, however, together with consumers’ calls for antibiotic-free products, presents problems that threaten sustainable agriculture. Bacteriophages (phages) are proposed as bacterial population control alternatives to antibiotics. Their unique properties make them highly promising but challenging antimicrobials. The use of phages in agriculture also presents a number of unique challenges. This mini-review summarizes recent development and perspectives of phages used as antimicrobial agents in plant and animal agriculture at the farm level. The main pathogens and their adjoining phage therapies are discussed. PMID- 29693563 TI - Rationalism, Empiricism, and Evidence-Based Medicine: A Call for a New Galenic Synthesis. AB - Thirty years after the rise of the evidence-based medicine (EBM) movement, formal training in philosophy remains poorly represented among medical students and their educators. In this paper, I argue that EBM’s reception in this context has resulted in a privileging of empiricism over rationalism in clinical reasoning with unintended consequences for medical practice. After a limited review of the history of medical epistemology, I argue that a solution to this problem can be found in the method of the 2nd-century Roman physician Galen, who brought empiricism and rationalism together in a synthesis anticipating the scientific method. Next, I review several of the problems that have been identified as resulting from a staunch commitment to empiricism in medical practice. Finally, I conclude that greater epistemological awareness in the medical community would precipitate a Galenic shift toward a more epistemically balanced, scientific approach to clinical research. PMID- 29693565 TI - Rupture Predictions of Notched Ti-6Al-4V Using Local Approaches. AB - Ti-6Al-4V has been extensively used in structural applications in various engineering fields, from naval to automotive and from aerospace to biomedical. Structural applications are characterized by geometrical discontinuities such as notches, which are widely known to harmfully affect their tensile strength. In recent years, many attempts have been done to define solid criteria with which to reliably predict the tensile strength of materials. Among these criteria, two local approaches are worth mentioning due to the accuracy of their predictions, i.e., the strain energy density (SED) approach and the theory of critical distance (TCD) method. In this manuscript, the robustness of these two methods in predicting the tensile behavior of notched Ti-6Al-4V specimens has been compared. To this aim, two very dissimilar notch geometries have been tested, i.e., semi circular and blunt V-notch with a notch root radius equal to 1 mm, and the experimental results have been compared with those predicted by the two models. The experimental values have been estimated with low discrepancies by either the SED approach and the TCD method, but the former results in better predictions. The deviations for the SED are in fact lower than 1.3%, while the TCD provides predictions with errors almost up to 8.5%. Finally, the weaknesses and the strengths of the two models have been reported. PMID- 29693564 TI - Cerebral Blood Flow Measurements in Adults: A Review on the Effects of Dietary Factors and Exercise. AB - Improving cerebrovascular function may be a key mechanism whereby a healthy lifestyle, of which a healthy diet combined with increased physical activity levels is a cornerstone, protects against cognitive impairments. In this respect, effects on cerebral blood flow (CBF)—a sensitive physiological marker of cerebrovascular function—are of major interest. This review summarizes the impact of specific dietary determinants and physical exercise on CBF in adults and discusses the relation between these effects with potential changes in cognitive function. A limited number of randomized controlled trials have already demonstrated the beneficial effects of an acute intake of nitrate and polyphenols on CBF, but evidence for a relationship between these effects as well as improvements in cognitive functioning is limited. Moreover, long-term trans resveratrol supplementation has been shown to increase CBF in populations at increased risk of accelerated cognitive decline. Long-term supplementation of n-3 long-chain polyunsaturated fatty acids may also increase CBF, but related effects on cognitive performance have not yet been found. Significant decreases in cerebral perfusion were observed by commonly consumed amounts of caffeine, while alcohol intake was shown to increase CBF in a dose-dependent way. However, the long-term effects are not clear. Finally, long-term exercise training may be a promising approach to improve CBF, as increases in perfusion may contribute to the beneficial effects on cognitive functioning observed following increased physical activity levels. PMID- 29693566 TI - Specificity of Induction of Glycopeptide Antibiotic Resistance in the Producing Actinomycetes. AB - Glycopeptide antibiotics are drugs of last resort for treating severe infections caused by Gram-positive pathogens. It is widely believed that glycopeptide resistance determinants (van genes) are ultimately derived from the producing actinomycetes. We hereby investigated the relationship between the antimicrobial activity of vancomycin and teicoplanins and their differential ability to induce van gene expression in Actinoplanes teichomyceticus—the producer of teicoplanin—and Nonomuraea gerenzanensis—the producer of the teicoplanin-like A40926. As a control, we used the well-characterized resistance model Streptomyces coelicolor. The enzyme activities of a cytoplasmic-soluble d,d dipeptidase and of a membrane-associated d,d-carboxypeptidase (corresponding to VanX and VanY respectively) involved in resistant cell wall remodeling were measured in the actinomycetes grown in the presence or absence of subinhibitory concentrations of vancomycin, teicoplanin, and A40926. Results indicated that actinomycetes possess diverse self-resistance mechanisms, and that each of them responds differently to glycopeptide induction. Gene swapping among teicoplanins producing actinomycetes indicated that cross-talking is possible and provides useful information for predicting the evolution of future resistance gene combinations emerging in pathogens. PMID- 29693567 TI - Optical and Acoustic Sensor-Based 3D Ball Motion Estimation for Ball Sport Simulators ?. AB - Estimation of the motion of ball-shaped objects is essential for the operation of ball sport simulators. In this paper, we propose an estimation system for 3D ball motion, including speed and angle of projection, by using acoustic vector and infrared (IR) scanning sensors. Our system is comprised of three steps to estimate a ball motion: sound-based ball firing detection, sound source localization, and IR scanning for motion analysis. First, an impulsive sound classification based on the mel-frequency cepstrum and feed-forward neural network is introduced to detect the ball launch sound. An impulsive sound source localization using a 2D microelectromechanical system (MEMS) microphones and delay-and-sum beamforming is presented to estimate the firing position. The time and position of a ball in 3D space is determined from a high-speed infrared scanning method. Our experimental results demonstrate that the estimation of ball motion based on sound allows a wider activity area than similar camera-based methods. Thus, it can be practically applied to various simulations in sports such as soccer and baseball. PMID- 29693568 TI - Theoretical Design of a Two-Photon Fluorescent Probe for Nitric Oxide with Enhanced Emission Induced by Photoninduced Electron Transfer. AB - In the present work, we systematically investigate the sensing abilities of two recently literature-reported two-photon fluorescent NO probes, i.e., the o phenylenediamine derivative of Nile Red and the p-phenylenediamine derivative of coumarin. The recognition mechanisms of these probes are studied by using the molecular orbital classifying method, which demonstrates the photoinduced electron transfer process. In addition, we have designed two new probes by swapping receptor units present on fluorophores, i.e., the p-phenylenediamine derivative of Nile Red and the o-phenylenediamine derivative of coumarin. However, it illustrates that only the latter has ability to function as off-on typed fluorescent probe for NO. More importantly, calculations on the two-photon absorption properties of the probes demonstrate that both receptor derivatives of coumarin possess larger TPA cross-sections than Nile Red derivatives, which makes a better two photon fluorescent probe. Our theoretical investigations reveal that the underlying mechanism satisfactorily explain the experimental results, providing a theoretical basis on the structure-property relationships which is beneficial to developing new two-photon fluorescent probes for NO. PMID- 29693569 TI - Integration of a Copper-Containing Biohybrid (CuHARS) with Cellulose for Subsequent Degradation and Biomedical Control. AB - We previously described the novel synthesis of a copper high-aspect ratio structure (CuHARS) biohybrid material using cystine. While extremely stable in water, CuHARS is completely (but slowly) degradable in cellular media. Here, integration of the CuHARS into cellulose matrices was carried out to provide added control for CuHARS degradation. Synthesized CuHARS was concentrated by centrifugation and then dried. The weighed mass was re-suspended in water. CuHARS was stable in water for months without degradation. In contrast, 25 μg/mL of the CuHARS in complete cell culture media was completely degraded (slowly) in 18 days under physiological conditions. Stable integration of CuHARS into cellulose matrices was achieved through assembly by mixing cellulose micro- and nano-fibers and CuHARS in an aqueous (pulp mixture) phase, followed by drying. Additional materials were integrated to make the hybrids magnetically susceptible. The cellulose-CuHARS composite films could be transferred, weighed, and cut into usable pieces; they maintained their form after rehydration in water for at least 7 days and were compatible with cell culture studies using brain tumor (glioma) cells. These studies demonstrate utility of a CuHARS-cellulose biohybrid for applied applications including: (1) a platform for biomedical tracking and (2) integration into a 2D/3D matrix using natural products (cellulose). PMID- 29693570 TI - Pharmacists' Attitudes and Practices Regarding Tetanus, Diphtheria and Pertussis (Tdap) Vaccination in Pregnancy and Surrounding Newborns. AB - BACKGROUND: Bordetella pertussis or whooping cough is a serious and vaccine preventable illness. Despite widespread vaccination in the pediatric population, pertussis still infects approximately 100,000 infants each year in the United States. The purpose of this study was to determine gaps in pharmacists’ understanding, attitudes, practices, and barriers surrounding the tetanus, diphtheria, and pertussis (Tdap) vaccination recommendation for patients who are pregnant or planning to come in close contact with infants. METHODS: This study was a descriptive, exploratory electronic survey. The survey assessed three major areas; the role of the pharmacist in Tdap vaccination, perceived barriers to vaccination, and understanding the recommendations. RESULTS: A total of 225 pharmacists responded to the survey. Pharmacists who responded to this survey agreed that pharmacists should have a role vaccinating the public and individuals expecting to come into contact with a newborn, (88.5% and 86.9%) respectively, but fewer agreed that pharmacists should have a role vaccinating pregnant women against tetanus, diphtheria, and pertussis (77%, p < 0.001). Based on the responses to case scenarios, only 22.5% and 30.6% of respondents understood the recommendations. Numerous barriers to vaccinating pregnant women were identified. CONCLUSION: While most pharmacists surveyed felt they should have a role in vaccinating pregnant women and those expecting to come in contact with a newborn, there are barriers to implementing this practice. Future efforts should focus on further evaluating identified gaps and developing programs for pharmacists that emphasize the significance of vaccinating these patients to reduce the burden of pertussis in infants. PMID- 29693571 TI - Influence of Latitude on the Prevalence of Kawasaki Disease: A Retrospective Cohort Study from the Taiwan National Health Insurance Database and Review of the Literature. AB - Background: Countries at higher latitudes have higher incidence rates of Kawasaki disease (KD) than do countries at lower latitudes in the Asian and West Pacific area. However, the precise influence of latitude on KD incidence rates requires further clarification. Methods: We searched the Longitudinal Health Insurance Database 2005 to retrieve patients’ medical records from 1996 to 2009. The patients with KD were categorized as living in northern, middle, and southern Taiwan; the period prevalence of KD for each area was determined. Climate variables, including temperature, sunshine duration, precipitation, and relative humidity, were collected from the Taiwan Central Weather Bureau. The effect of latitude on the period KD prevalence and the correlation between climate variables and KD prevalence were calculated. Results: After patients without complete data excluded, a total of 61,830 children up to 10 years old were retrieved, from which 404 patients with KD were recognized. The period prevalence of KD increased significantly with latitude (p = 0.0004). Climate variables associated with high temperature demonstrated a connection with KD prevalence; however, this correlation was not statistically significant. Conclusions: Our study demonstrated that higher latitude is associated with a higher KD prevalence in Taiwan. PMID- 29693572 TI - Sialidosis: A Review of Morphology and Molecular Biology of a Rare Pediatric Disorder. AB - Sialidosis (MIM 256550) is a rare, autosomal recessive inherited disorder, caused by α-N-acetyl neuraminidase deficiency resulting from a mutation in the neuraminidase gene (NEU1), located on 6p21.33. This genetic alteration leads to abnormal intracellular accumulation as well as urinary excretion of sialyloligosaccharides. A definitive diagnosis is made after the identification of a mutation in the NEU1 gene. So far, 40 mutations of NEU1 have been reported. An association exists between the impact of the individual mutations and the severity of clinical presentation of sialidosis. According to the clinical symptoms, sialidosis has been divided into two subtypes with different ages of onset and severity, including sialidosis type I (normomorphic or mild form) and sialidosis type II (dysmorphic or severe form). Sialidosis II is further subdivided into (i) congenital; (ii) infantile; and (iii) juvenile. Despite being uncommon, sialidosis has enormous clinical relevance due to its debilitating character. A complete understanding of the underlying pathology remains a challenge, which in turn limits the development of effective therapeutic strategies. Furthermore, in the last few years, some atypical cases of sialidosis have been reported as well. We herein attempt to combine and discuss the underlying molecular biology, the clinical features, and the morphological patterns of sialidosis type I and II. PMID- 29693573 TI - Correction: Lee, Y.-H., et al. Beverage Intake, Smoking Behavior, and Alcohol Consumption in Contemporary China-A Cross-Sectional Analysis from the 2011 China Health and Nutrition Survey. Int. J. Environ. Res. Public Health 2017, 14, 493. PMID- 29693574 TI - Liver Transplantation and Gut Microbiota Profiling in a Child Colonized by a Multi-Drug Resistant Klebsiella pneumoniae: A New Approach to Move from Antibiotic to "Eubiotic" Control of Microbial Resistance. AB - The increase of microorganisms multi-drug resistant (MDR) to antibiotics (ATBs) is becoming a global emergency, especially in frail subjects. In chronic liver disease (LD) with indications for liver transplantation (LT), MDR colonization can significantly affect the LT outcome. However, no clear guidelines for microbial management are available. A novel approach toward MDR-colonized patients undergoing LT was developed at our Center refraining from ATBs use during the transplant waiting list, and use of an intensive perioperative prophylaxis cycle. This study aimed to couple clinical evaluation with monitoring of gut microbiota in a pediatric LD patient colonized with MDR Klebsiella pneumoniae (KP) who underwent LT. No peri-transplant complications were reported, and a decontamination from the MDR bacteria occurred during follow-up. Significant changes in gut microbiota, especially during ATB treatment, were reported by microbiota profiling. Patterns of Klebsiella predominance and microbiota diversity revealed opposite temporal trends, with Klebsiella ecological microbiota niches linked to ATB-driven selection. Our infection control program appeared to control complications following LT in an MDR-KP colonized patient. The perioperative ATB regimen, acting as LT prophylaxis, triggered MDR-KP overgrowth and gut dysbiosis, but buffered infectious processes. Mechanisms modulating the gut ecosystem should be taken into account in MDR colonization clinical management. PMID- 29693575 TI - Maternal Vaccination as an Essential Component of Life-Course Immunization and Its Contribution to Preventive Neonatology. AB - Maternal immunisation schedules are increasingly coming under the spotlight as part of the development of lifetime immunisation programmes for the role that they play in improving maternal, foetal, and neonatal health. Maternally-acquired antibodies are critical in protecting infants during the first months of their lives. Maternal immunisation was previously overlooked owing to concerns regarding vaccinations in this untested and high-risk population but is now acknowledged for its potential impact on the outcomes in many domains of foetal and neonatal health, aside from its maternal benefits. This article highlights the role that maternal immunisation may play in reducing infections in preterm and term infants. It explores the barriers to antenatal vaccinations and the optimisation of the immunisation uptake. This review also probes the part that maternal immunisation may hold in the reduction of perinatal antimicrobial resistance and the prevention of non-infectious diseases. Both healthcare providers and expectant mothers should continue to be educated on the importance and safety of the appropriate immunizations during pregnancy. Maternal vaccination merits its deserved priority in a life-course immunization approach and it is perhaps the only immunization whereby two generations benefit directly from a single input. We outline the current recommendations for antenatal vaccinations and highlight the potential advances in the field contributing to “preventive neonatology”. PMID- 29693576 TI - Suicidal Ideation and Healthy Immigrant Effect in the Canadian Population: A Cross-Sectional Population Based Study. AB - Understanding suicidal ideation is crucial for preventing suicide. Although “healthy immigrant effect” is a phenomenon that has been well documented across a multitude of epidemiological and social studies—where immigrants are, on average, healthier than the native-born, little research has examined the presence of such effect on suicidal ideation. The objective of this study is to investigate if there is a differential effect of immigration identity on suicidal ideation and how the effect varies by socio-demographic characteristics in the Canadian population. Data from the Canadian Community Health Survey in year 2014 were used. Multivariate logistic regression was employed. Our findings indicated that recent immigrants (lived in Canada for 9 or less years) were significantly less likely to report suicidal ideation compared with non-immigrants. However, for established immigrants (10 years and above of living in Canada), the risk of suicidal ideation converged to Canadian-born population. Moreover, male immigrants were at significantly lower risk of having suicidal ideation than Canadian-born counterparts; whereas, female immigrants did not benefit from the “healthy immigrant effect”. Our findings suggest the need for targeted intervention strategies on suicidal ideation among established immigrants and female immigrants. PMID- 29693577 TI - Multi-Frequency Signal Detection Based on Frequency Exchange and Re-Scaling Stochastic Resonance and Its Application to Weak Fault Diagnosis. AB - Mechanical fault diagnosis usually requires not only identification of the fault characteristic frequency, but also detection of its second and/or higher harmonics. However, it is difficult to detect a multi-frequency fault signal through the existing Stochastic Resonance (SR) methods, because the characteristic frequency of the fault signal as well as its second and higher harmonics frequencies tend to be large parameters. To solve the problem, this paper proposes a multi-frequency signal detection method based on Frequency Exchange and Re-scaling Stochastic Resonance (FERSR). In the method, frequency exchange is implemented using filtering technique and Single SideBand (SSB) modulation. This new method can overcome the limitation of "sampling ratio" which is the ratio of the sampling frequency to the frequency of target signal. It also ensures that the multi-frequency target signals can be processed to meet the small-parameter conditions. Simulation results demonstrate that the method shows good performance for detecting a multi-frequency signal with low sampling ratio. Two practical cases are employed to further validate the effectiveness and applicability of this method. PMID- 29693579 TI - Influence of Surface Features for Increased Heat Dissipation on Tool Wear. AB - The critical problems faced during the machining process of heat resistant superalloys, (HRSA), is the concentration of heat in the cutting zone and the difficulty in dissipating it. The concentrated heat in the cutting zone has a negative influence on the tool life and surface quality of the machined surface, which in turn, contributes to higher manufacturing costs. This paper investigates improved heat dissipation from the cutting zone on the tool wear through surface features on the cutting tools. Firstly, the objective was to increase the available surface area in high temperature regions of the cutting tool. Secondly, multiple surface features were fabricated for the purpose of acting as channels in the rake face to create better access for the coolant to the proximity of the cutting edge. The purpose was thereby to improve the cooling of the cutting edge itself, which exhibits the highest temperature during machining. These modified inserts were experimentally investigated in face turning of Alloy 718 with high pressure coolant. Overall results exhibited that surface featured inserts decreased flank wear, abrasion of the flank face, cutting edge deterioration and crater wear probably due to better heat dissipation from the cutting zone. PMID- 29693578 TI - A Metabolism-Based Synergy for Total Coumarin Extract of Radix Angelicae Dahuricae and Ligustrazine on Migraine Treatment in Rats. AB - Radix Angelicae dahuricae, containing coumarins, which might affect cytochrome P450 enzyme (CYP450) activity, has been co-administered with ligustrazine, a substrate of CYP450s, for the clinical treatment of migraine. However, whether a pharmacokinetic-based synergy exists between Radix Angelicae dahuricae and ligustrazine is still unknown. In this study, the total coumarin extract (TCE) of Radix Angelicae dahuricae (50 mg/kg, orally) reinforced the anti-migraine activity of ligustrazine by declining head scratching, plasma calcitonin gene related peptide, and serum nitric oxide, as well as increasing plasma endothelin levels in rats (p < 0.05). Moreover, the pharmacokinetic study reflected that TCE potentiated the area under the concentration-time curve of ligustrazine and prolonged its mean retention time in rats (p < 0.05). Besides, the IC50 for TCE, imperatorin and isoimperatorin inhibiting ligustrazine metabolism were 5.0 ± 1.02, 1.35 ± 0.46, 4.81 ± 1.14 µg/mL in human liver microsomes, and 13.69 ± 1.11, 1.19 ± 1.09, 1.69 ± 1.17 µg/mL in rat liver microsomes, respectively. Moreover, imperatorin and isoimperatorin were CYP450s inhibitors with IC50 < 10 µM for CYP1A2, 2C9, 2D6, and 3A4. Therefore, this study concluded that Radix Angelicae dahuricae could increase ligustrazine plasma concentration and then reinforce its pharmacological effect by inhibiting its metabolism through interference with CYP450s. This could be one mechanism for the synergy between Radix Angelicae dahuricae and ligustrazine on migraine treatment. PMID- 29693581 TI - A Low-Ambiguity Signal Waveform for Pseudolite Positioning Systems Based on Chirp. AB - Signal modulation is an essential design factor of a positioning system, which directly impacts the system’s potential performance. Chirp compressions have been widely applied in the fields of communication, radar, and indoor positioning owing to their high compression gain and good resistance to narrowband interferences and multipath fading. Based on linear chirp, we present a modulation method named chirped pseudo-noise (ChPN). The mathematical model of the ChPN signal is provided with its auto-correlation function (ACF) and the power spectrum density (PSD) derived. The ChPN with orthogonal chirps is also discussed, which has better resistance to near-far effect. Then the generation and detection methods as well as the performances of ChPN are discussed by theoretical analysis and simulation. The results show that, for ChPN signals with the same main-lobe bandwidth (MLB), generally, the signal with a larger sweep bandwidth has better tracking precision and multipath resistance. ChPN yields slighter ACF peaks ambiguity due to its lower ACF side-peaks, although its tracking precision is a little worse than that of a binary offset carrier (BOC) with the same MLB. Moreover, ChPN provides better overall anti-multipath performance than BOC. For the ChPN signals with the same code rate, a signal with a larger sweep bandwidth has better performance in most aspects. In engineering practice, a ChPN receiver can be implemented by minor modifications of a BOC receiver. Thus, ChPN modulation shows promise for future positioning applications. PMID- 29693580 TI - The Effect of PUFA-Rich Plant Oils and Bioactive Compounds Supplementation in Pig Diet on Color Parameters and Myoglobin Status in Long-Frozen Pork Meat. AB - The study evaluated the effect of pig diet supplementation with rapeseed or linseed oil, and vitamin E or selenium, or both vitamin E and selenium on color parameters and myoglobin content of pork Semimembranosus muscle after long-term freezing storage during nine months. The influence of the type of the bioactive compounds added to pig diet on the content of myoglobin or oxymyoglobin, metmyoglobin and deoksymyoglobin in Semimembranosus m. was also assessed. The results indicate that the presence of oils rich in polyunsaturated fatty acids (PUFA) in pig diet improves the color of pork meat. Supplementation of dietary plant oils or dietary oils with antioxidants tended to increase significantly the concentration of oxymyoglobin and decrease the concentration of metmyoglobin in meat compared to the control group. The highest content of oxymyoglobin was observed in meat obtained from pigs fed diets with linseed oil. The best color scores (highest a* parameter) was noted for rapeseed oil group (with no addition of antioxidants). In conclusion, the addition of antioxidants to pigs’ forage supplemented with PUFA-rich oils is not recommended in order to improve color of long-term frozen pork. PMID- 29693582 TI - Ultrasound Pulse-Echo Coupled with a Tracking Technique for Simultaneous Measurement of Multiple Bubbles. AB - Bubbly flows are commonly used in various applications and their measurement is an important research topic. The ultrasound pulse-echo technique allows for the detection of each bubble and the measurement of the position of its surface. However, so far it has been used only to measure single bubbles. This paper investigates whether the pulse-echo technique can be applied for measuring multiple bubbles concurrently. The ultrasonic transducer wavelength and diameter were selected based on expected bubble diameters so that each bubble produced a strong reflection. The pulse-echo was implemented to obtain good accuracy without sacrificing the signal processing speed. A tracking technique was developed for the purpose of connecting detected reflections to trajectories. The technique was tested experimentally by measuring the horizontal position of rising air bubbles in a water tank. The results show that the pulse-echo technique can detect multiple bubbles concurrently. The pulse-echo technique detected almost the same number of bubbles as a high-speed video. For average void fractions up to around 1 % (and instantaneous void fraction reaching 5.3 % ), the rate of bubbles missed by the pulse-echo and the rate of noise trajectories both stayed less than 5%. The error rate increased with the void fraction, limiting the technique’s application range. PMID- 29693584 TI - Understanding the Thermal Properties of Precursor-Ionomers to Optimize Fabrication Processes for Ionic Polymer-Metal Composites (IPMCs). AB - Ionic polymer-metal composites (IPMCs) are one of many smart materials and have ionomer bases with a noble metal plated on the surface. The ionomer is usually Nafion, but recently Aquivion has been shown to be a promising alternative. Ionomers are available in the form of precursor pellets. This is an un-activated form that is able to melt, unlike the activated form. However, there is little study on the thermal characteristics of these precursor ionomers. This lack of knowledge causes issues when trying to fabricate ionomer shapes using methods such as extrusion, hot-pressing, and more recently, injection molding and 3D printing. To understand the two precursor-ionomers, a set of tests were conducted to measure the thermal degradation temperature, viscosity, melting temperature, and glass transition. The results have shown that the precursor Aquivion has a higher melting temperature (240 °C) than precursor Nafion (200 °C) and a larger glass transition range (32-65°C compared with 21-45 °C). The two have the same thermal degradation temperature (~400 °C). Precursor Aquivion is more viscous than precursor Nafion as temperature increases. Based on the results gathered, it seems that the precursor Aquivion is more stable as temperature increases, facilitating the manufacturing processes. This paper presents the data collected to assist researchers in thermal-based fabrication processes. PMID- 29693583 TI - Adenylate Cyclases of Trypanosoma brucei, Environmental Sensors and Controllers of Host Innate Immune Response. AB - Trypanosoma brucei, etiological agent of Sleeping Sickness in Africa, is the prototype of African trypanosomes, protozoan extracellular flagellate parasites transmitted by saliva (Salivaria). In these parasites the molecular controls of the cell cycle and environmental sensing are elaborate and concentrated at the flagellum. Genomic analyses suggest that these parasites appear to differ considerably from the host in signaling mechanisms, with the exception of receptor-type adenylate cyclases (AC) that are topologically similar to receptor type guanylate cyclase (GC) of higher eukaryotes but control a new class of cAMP targets of unknown function, the cAMP response proteins (CARPs), rather than the classical protein kinase A cAMP effector (PKA). T. brucei possesses a large polymorphic family of ACs, mainly associated with the flagellar membrane, and these are involved in inhibition of the innate immune response of the host prior to the massive release of immunomodulatory factors at the first peak of parasitemia. Recent evidence suggests that in T. brucei several insect-specific AC isoforms are involved in social motility, whereas only a few AC isoforms are involved in cytokinesis control of bloodstream forms, attesting that a complex signaling pathway is required for environmental sensing. In this review, after a general update on cAMP signaling pathway and the multiple roles of cAMP, I summarize the existing knowledge of the mechanisms by which pathogenic microorganisms modulate cAMP levels to escape immune defense. PMID- 29693585 TI - On-Board, Real-Time Preprocessing System for Optical Remote-Sensing Imagery. AB - With the development of remote-sensing technology, optical remote-sensing imagery processing has played an important role in many application fields, such as geological exploration and natural disaster prevention. However, relative radiation correction and geometric correction are key steps in preprocessing because raw image data without preprocessing will cause poor performance during application. Traditionally, remote-sensing data are downlinked to the ground station, preprocessed, and distributed to users. This process generates long delays, which is a major bottleneck in real-time applications for remote-sensing data. Therefore, on-board, real-time image preprocessing is greatly desired. In this paper, a real-time processing architecture for on-board imagery preprocessing is proposed. First, a hierarchical optimization and mapping method is proposed to realize the preprocessing algorithm in a hardware structure, which can effectively reduce the computation burden of on-board processing. Second, a co-processing system using a field-programmable gate array (FPGA) and a digital signal processor (DSP; altogether, FPGA-DSP) based on optimization is designed to realize real-time preprocessing. The experimental results demonstrate the potential application of our system to an on-board processor, for which resources and power consumption are limited. PMID- 29693586 TI - Ellagic Acid Alleviates Hepatic Oxidative Stress and Insulin Resistance in Diabetic Female Rats. AB - Non-alcoholic fatty liver disease (NAFLD) affects more than 70% of patients with type 2 diabetes mellitus (T2DM) and has become one of the most common metabolic liver diseases worldwide. To date, treatments specifically targeting NAFLD do not exist. Oxidative stress and insulin resistance have been implicated in the pathogenesis of NAFLD in diabetes. Accordingly, the goal of this present study was to determine whether Ellagic acid (EA), a natural antioxidant polyphenol found in berries and nuts, mitigates hepatic oxidative stress and insulin resistance in T2DM rats, and thus alleviates NAFLD. Using adult female Goto Kakizaki (GK) rats, a non-obese and spontaneous model of T2DM, we found that EA treatment significantly lowered fasting blood glucose and reduced insulin resistance, as shown by a 21.8% reduction in the homeostasis model assessment index of insulin resistance (HOMA-IR), while triglyceride and total cholesterol levels remained unchanged. Increased hepatic lipid accumulation and oxidative stress present in diabetic GK rats was markedly reduced with EA treatment. This effect was associated with a downregulation of the NADPH oxidase subunit, p47 phox, and overexpression of NF-E2-related factor-2 (NRF2). Moreover, EA was able to decrease the hepatic expression of hypoxia-inducible factor (HIF-α), a transcription factor linked to hypoxia and hepatic steatosis. We further showed that EA treatment activated an insulin signaling pathway in the liver, as evidenced by increased levels of phosphorylated Akt (Ser 473). In conclusion, our results demonstrate that EA diminishes blood glucose levels and potently suppress NAFLD in diabetic rats via mechanisms that involve reductions in p47-phox and HIF α, upregulation of NRF2 and enhancement of the Akt signaling pathway in the liver. Together, these results reveal that EA improves hepatic insulin sensitivity and lipid metabolism as a result of its antioxidant effects. This implies an anti-diabetic effect of EA with beneficial effects for the treatment of hepatic complications in T2DM. PMID- 29693588 TI - Relative Contribution of Cellular Complement Inhibitors CD59, CD46, and CD55 to Parainfluenza Virus 5 Inhibition of Complement-Mediated Neutralization. AB - The complement system is a part of the innate immune system that viruses need to face during infections. Many viruses incorporate cellular regulators of complement activation (RCA) to block complement pathways and our prior work has shown that Parainfluenza virus 5 (PIV5) incorporates CD55 and CD46 to delay complement-mediated neutralization. In this paper, we tested the role of a third individual RCA inhibitor CD59 in PIV5 interactions with complement pathways. Using a cell line engineered to express CD59, we show that small levels of functional CD59 are associated with progeny PIV5, which is capable of blocking assembly of the C5b-C9 membrane attack complex (MAC). PIV5 containing CD59 (PIV5 CD59) showed increased resistance to complement-mediated neutralization in vitro comparing to PIV5 lacking regulators. Infection of A549 cells with PIV5 and RSV upregulated CD59 expression. TGF-beta treatment of PIV5-infected cells also increased cell surface CD59 expression and progeny virions were more resistant to complement-mediated neutralization. A comparison of individual viruses containing only CD55, CD46, or CD59 showed a potency of inhibiting complement-mediated neutralization, which followed a pattern of CD55 > CD46 > CD59. PMID- 29693587 TI - Chromosome Synapsis and Recombination in Male-Sterile and Female-Fertile Interspecies Hybrids of the Dwarf Hamsters (Phodopus, Cricetidae). AB - Hybrid sterility is an important step in the speciation process. Hybrids between dwarf hamsters Phodopus sungorus and P.campbelli provide a good model for studies in cytological and genetic mechanisms of hybrid sterility. Previous studies in hybrids detected multiple abnormalities of spermatogenesis and a high frequency of dissociation between the X and Y chromosomes at the meiotic prophase. In this study, we found that the autosomes of the hybrid males and females underwent paring and recombination as normally as their parental forms did. The male hybrids showed a significantly higher frequency of asynapsis and recombination failure between the heterochromatic arms of the X and Y chromosomes than the males of the parental species. Female hybrids as well as the females of the parental species demonstrated a high incidence of centromere misalignment at the XX bivalent and partial asynapsis of the ends of its heterochromatic arms. In all three karyotypes, recombination was completely suppressed in the heterochromatic arm of the X chromosome, where the pseudoautosomal region is located. We propose that this recombination pattern speeds up divergence of the X- and Y-linked pseudoautosomal regions between the parental species and results in their incompatibility in the male hybrids. PMID- 29693589 TI - Ethylene Responsive Factor MeERF72 Negatively Regulates Sucrose synthase 1 Gene in Cassava. AB - Cassava, an important food and industrial crop globally, is characterized by its powerful starch accumulation in its storage root. However, the underlying molecular mechanism for this feature remains unclear. Sucrose synthase initializes the conversion of sucrose to starch, and, to a certain extent, its enzyme activity can represent sink strength. To understand the modulation of MeSus gene family, the relatively high expressed member in storage root, MeSus1, its promoter was used as bait to screen cassava storage root full-length cDNA library through a yeast one-hybrid system. An ethylene responsive factor cDNA, designated as MeERF72 according to its homolog in Arabidopsis, was screened out. The transcript level of MeERF72 was induced by ethylene, drought, and salt treatments and repressed by abscisic acid, Auxin, gibberellin, salicylic acid, and low and high temperatures. The MeERF72 protein has a conserved APETALA2 domain in its N-terminus and an activated domain of 30 amino acids in its C terminus, can bind to MeSus1 promoter in vitro and in vivo, and represses the promoter activity of MeSus1. MeERF72 is a transcription factor that can negatively regulate the expression level of MeSus1 in cassava. PMID- 29693590 TI - Textile Retrieval Based on Image Content from CDC and Webcam Cameras in Indoor Environments. AB - Textile based image retrieval for indoor environments can be used to retrieve images that contain the same textile, which may indicate that scenes are related. This makes up a useful approach for law enforcement agencies who want to find evidence based on matching between textiles. In this paper, we propose a novel pipeline that allows searching and retrieving textiles that appear in pictures of real scenes. Our approach is based on first obtaining regions containing textiles by using MSER on high pass filtered images of the RGB, HSV and Hue channels of the original photo. To describe the textile regions, we demonstrated that the combination of HOG and HCLOSIB is the best option for our proposal when using the correlation distance to match the query textile patch with the candidate regions. Furthermore, we introduce a new dataset, TextilTube, which comprises a total of 1913 textile regions labelled within 67 classes. We yielded 84.94% of success in the 40 nearest coincidences and 37.44% of precision taking into account just the first coincidence, which outperforms the current deep learning methods evaluated. Experimental results show that this pipeline can be used to set up an effective textile based image retrieval system in indoor environments. PMID- 29693591 TI - Effect of Inoculant Alloy Selection and Particle Size on Efficiency of Isomorphic Inoculation of Ti-Al. AB - The process of isomorphic inoculation relies on precise selection of inoculant alloys for a given system. Three alloys, Ti-10Al-25Nb, Ti-25Al-10Ta, and Ti-47Ta (at %) were selected as potential isomorphic inoculants for a Ti-46Al alloy. The binary Ti-Ta alloy selected was found to be ineffective as an inoculant due to its large density difference with the melt, causing the particles to settle. Both ternary alloys were successfully implemented as isomorphic inoculants that decreased the equiaxed grain size and increased the equiaxed fraction in their ingots. The degree of grain refinement obtained was found to be dependent on the number of particles introduced to the melt. Also, more new grains were formed than particles added to the melt. The grains/particle efficiency varied from greater than one to nearly twenty as the size of the particle increased. This is attributed to the breaking up of particles into smaller particles by dissolution in the melt. For a given particle size, Ti-Al-Ta and Ti-Al-Nb particles were found to have a roughly similar grain/particle efficiency. PMID- 29693592 TI - Ethnic Variations in Psychosocial and Health Correlates of Eating Disorders. AB - The aim of this study is to explore ethnic variations in psychosocial and health correlates of eating disorders in the United States, Specifically, we compared associations between gender, socioeconomic status (SES), body mass index (BMI), physical and mental self-rated health (SRH), and major depressive disorder (MDD) with eating disorders (EDs) across 10 different ethnic groups in the United States. Data was obtained from the Collaborative Psychiatric Epidemiology Surveys (CPES), a national household probability sample collected in 2001-2003. Data for this study included a sample of 17,729 individuals with the following ethnic profile: 520 Vietnamese, 508 Filipino, 600 Chinese, 656 Other Asian, 577 Cuban, 495 Puerto Rican, 1442 Mexican, 1106 Other Hispanic, 4746 African American, and 7587 Non-Latino Whites. Gender, SES (education and income), BMI, SRH, MDD, and presence of EDs were measured across different ethnic groups. Logistic regression analysis was conducted for each ethnic group with lifetime EDs as the main outcome. Ethnic group varied in psychosocial and health correlates of EDs. In most ethnic groups, gender and SES were not associated with EDs. In almost all ethnic groups, EDs were associated with MDD and BMI. EDs were found to be associated with SRH in half of the ethnic groups studied. The associations between gender, SES, BMI, SRH, MDD, and EDs vary across different ethnic groups. These differences must be considered in further studies and in clinical practice in order to improve our approach towards diagnosis and treatment of EDs. PMID- 29693593 TI - Botulinum Neurotoxin Injection for the Treatment of Recurrent Temporomandibular Joint Dislocation with and without Neurogenic Muscular Hyperactivity. AB - The aim of this study was to compare treatment outcomes following intramuscular injection of botulinum neurotoxin (BoNT) in patients with recurrent temporomandibular joint dislocation, with and without muscle hyperactivity due to neurological diseases. Thirty-two patients (19 women and 13 men, mean age: 62.3 years) with recurrent temporomandibular joint dislocation were divided into two groups: neurogenic (8 women and 12 men) and habitual (11 women and 1 man). The neurogenic group included patients having neurological disorders, such as Parkinson’s disease or oromandibular dystonia, that are accompanied by muscle hyperactivity. BoNT was administered via intraoral injection to the inferior head of the lateral pterygoid muscle. In total, BoNT injection was administered 102 times (mean 3.2 times/patient). The mean follow-up duration was 29.5 months. The neurogenic group was significantly (p < 0.001) younger (47.3 years) than the habitual group (84.8 years) and required significantly (p < 0.01) more injections (4.1 versus 1.7 times) to achieve a positive outcome. No significant immediate or delayed complications occurred. Thus, intramuscular injection of BoNT into the lateral pterygoid muscle is an effective and safe treatment for habitual temporomandibular joint dislocation. More injections are required in cases of neurogenic temporomandibular joint dislocation than in those of habitual dislocation without muscle hyperactivity. PMID- 29693594 TI - Functional Analysis of the Arabidopsis thaliana CDPK-Related Kinase Family: AtCRK1 Regulates Responses to Continuous Light. AB - The Calcium-Dependent Protein Kinase (CDPK)-Related Kinase family (CRKs) consists of eight members in Arabidopsis. Recently, AtCRK5 was shown to play a direct role in the regulation of root gravitropic response involving polar auxin transport (PAT). However, limited information is available about the function of the other AtCRK genes. Here, we report a comparative analysis of the Arabidopsis CRK genes, including transcription regulation, intracellular localization, and biological function. AtCRK transcripts were detectable in all organs tested and a considerable variation in transcript levels was detected among them. Most AtCRK proteins localized at the plasma membrane as revealed by microscopic analysis of 35S::cCRK-GFP (Green Fluorescence Protein) expressing plants or protoplasts. Interestingly, 35S::cCRK1-GFP and 35S::cCRK7-GFP had a dual localization pattern which was associated with plasma membrane and endomembrane structures, as well. Analysis of T-DNA insertion mutants revealed that AtCRK genes are important for root growth and control of gravitropic responses in roots and hypocotyls. While Atcrk mutants were indistinguishable from wild type plants in short days, Atcrk1 1 mutant had serious growth defects under continuous illumination. Semi-dwarf phenotype of Atcrk1-1 was accompanied with chlorophyll depletion, disturbed photosynthesis, accumulation of singlet oxygen, and enhanced cell death in photosynthetic tissues. AtCRK1 is therefore important to maintain cellular homeostasis during continuous illumination. PMID- 29693596 TI - Measurement of Pesticide Residues from Chemical Control of the Invasive Spodoptera frugiperda (Lepidoptera: Noctuidae) in a Maize Experimental Field in Mokwa, Nigeria. AB - The management of the fall armyworm Spodoptera frugiperda in maize field necessitates the use a big quantities of insecticides and sometimes the use of multiple types and formulations of chemicals. The use of insecticides in crops is associated with environmental risks and health hazards to both producers and consumers. This study was designed to evaluate the residue of 11 insecticides that were used to control high population of the fall armyworm in maize field in Mokwa, Nigeria. Maize and soil samples were collected from an experimental field to investigate the residue level using high performance liquid chromatography (HPLC, Agilent Technologies, Santa Clara, CA, USA) analysis techniques. Results revealed the presence of five insecticide compounds (Cypermethrin, Deltamethrin, Lambda-Cyhalothrin, Permethrin, and Chorpyrifos) in soil samples with possible adverse effects on soil born organisms and other non-targeted species. In contrast, no residue was found in maize stems and seeds. From these results, we conclude that the treated maize remains safe for consumption and the producers may not get any serious risk of contamination from the chemical control of the fall armyworm. PMID- 29693595 TI - The Costimulatory Pathways and T Regulatory Cells in Ischemia-Reperfusion Injury: A Strong Arm in the Inflammatory Response? AB - Costimulatory molecules have been identified as crucial regulators in the inflammatory response in various immunologic disease models. These molecules are classified into four different families depending on their structure. Here, we will focus on various ischemia studies that use costimulatory molecules as a target to reduce the inherent inflammatory status. Furthermore, we will discuss the relevant role of T regulatory cells in these inflammatory mechanisms and the costimulatory pathways in which they are involved. PMID- 29693597 TI - University Students' Willingness to Assist Fellow Students Who Experience Alcohol Related Facial Flushing to Reduce Their Drinking. AB - This study explored bystanders’ willingness to help a friend who flushes when drinking to reduce his/her drinking. Alcohol-related facial flushing is an indicator of an inherited variant enzyme, aldehyde dehydrogenase (ALDH), that impairs alcohol metabolism and increases drinkers’ lifetime risk of certain aerodigestive cancers. Individuals who flush should reduce their alcohol exposure, but they may continue to drink if social pressures and rules of etiquette make not drinking socially risky. The analysis used data from 2912 undergraduate students from 13 universities in southwestern, central and northeastern China from a survey asking how they respond to someone’s flushing in various scenarios. Latent class analysis grouped students by similar responses to flushing. A multinomial logistic regression explored how class membership was associated with knowledge, drinking status, and reactions to one’s own flushing. Five classes were derived from the latent class analysis, ranging from always intervene to mostly hesitate to help; in between were classes of students who were willing to help in some scenarios and hesitant in other scenarios. Only 11.6% students knew the connection between facial flushing and impaired alcohol metabolism, and knowledgeable students were somewhat more likely to assist when they saw someone flushing. In the absence of knowledge, other factors—such as drinking status, the gender of the bystander, the gender of the person who flushed, and degree of friendship with the person who flushed—determined how willing a person was to help someone reduce or stop drinking. Class membership was predicted by knowledge, gender, drinking status, and reactions to one’s own flushing. Of these 4 factors, knowledge and reactions to one’s own flushing could be influenced through alcohol education programs. It will take some time for alcohol education to catch up to and change social and cultural patterns of drinking. Meanwhile, motivational strategies should be developed to increase the willingness of bystanders to assist friends and to create a social expectation that flushers should stop or reduce their drinking. PMID- 29693598 TI - Inulin Improves Postprandial Hypertriglyceridemia by Modulating Gene Expression in the Small Intestine. AB - Postprandial hyperlipidemia is an important risk factor for cardiovascular diseases in the context of obesity. Inulin is a non-digestible carbohydrate, known for its beneficial properties in metabolic disorders. We investigated the impact of inulin on postprandial hypertriglyceridemia and on lipid metabolism in a mouse model of diet-induced obesity. Mice received a control or a western diet for 4 weeks and were further supplemented or not with inulin for 2 weeks (0.2 g/day per mouse). We performed a lipid tolerance test, measured mRNA expression of genes involved in postprandial lipid metabolism, assessed post-heparin plasma and muscle lipoprotein lipase activity and measured lipid accumulation in the enterocytes and fecal lipid excretion. Inulin supplementation in western diet-fed mice decreases postprandial serum triglycerides concentration, decreases the mRNA expression levels of Cd36 (fatty acid receptor involved in lipid uptake and sensing) and apolipoprotein C3 (Apoc3, inhibitor of lipoprotein lipase) in the jejunum and increases fecal lipid excretion. In conclusion, inulin improves postprandial hypertriglyceridemia by targeting intestinal lipid metabolism. This work confirms the interest of using inulin supplementation in the management of dyslipidemia linked to obesity and cardiometabolic risk. PMID- 29693599 TI - Dietary Supplementation with Oleum Cinnamomi Improves Intestinal Functions in Piglets. AB - The present study was to determine the efficacy of dietary supplementation with oleum cinnamomi (OCM) on growth performance and intestinal functions in piglets. Sixteen piglets (24-day-old) were randomly assigned to the control or OCM groups. Piglets in the control group were fed a basal diet, whereas piglets in the OCM group were fed the basal diet supplemented with 50 mg/kg OCM. On day 20 of the trial, blood samples and intestinal tissues were obtained from piglets. Compared with the control group, dietary OCM supplementation increased (p < 0.05) average daily feed intake, plasma insulin levels, villus width and villous surface area in the duodenum and jejunum, DNA levels and RNA/DNA ratios in the ileum, the abundance of Enterococcus genus and Lactobacillus genus in caecum digesta, mRNA levels for epithelial growth factor receptor (EGFR), Ras, extracellular signal regulated kinase 1/2 (Erk1/2), b-cell lymphoma-extra large (Bcl-xL), villin, junctional adhesion molecule A (JAM-A), myxovirus resistance (MX) 1, MX2 and regenerating islet-derived protein 3 gamma (REG3G), and protein abundances of Ras and claudin-1, but decreased (p < 0.05) diarrhoea incidence; the abundances of Enterobacteriaceae family, Enterococcus genus, Lactobacillus genus, Bifidobacterium genus, and Clostrium coccoides in the colon digesta, and AMP activated protein kinase (AMPK) mRNA levels and caspase-3 protein abundance in the jejunal mucosa of piglets. Taken together, these data indicate that dietary OCM supplementation modulates intestinal microbiota and improves intestinal function in weanling pigs. OCM is an effective feed additive and alternative to feed antibiotics for improving intestinal health in swine. PMID- 29693600 TI - Exploiting Botulinum Neurotoxins for the Study of Brain Physiology and Pathology. AB - Botulinum neurotoxins are metalloproteases that specifically cleave N ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in synaptic terminals, resulting in a potent inhibition of vesicle fusion and transmitter release. The family comprises different serotypes (BoNT/A to BoNT/G). The natural target of these toxins is represented by the neuromuscular junction, where BoNTs block acetylcholine release. In this review, we describe the actions of botulinum toxins after direct delivery to the central nervous system (CNS), where BoNTs block exocytosis of several transmitters, with near-complete silencing of neural networks. The use of clostridial neurotoxins in the CNS has allowed us to investigate specifically the role of synaptic activity in different physiological and pathological processes. The silencing properties of BoNTs can be exploited for therapeutic purposes, for example to counteract pathological hyperactivity and seizures in epileptogenic brain foci, or to investigate the role of activity in degenerative diseases like prion disease. Altogether, clostridial neurotoxins and their derivatives hold promise as powerful tools for both the basic understanding of brain function and the dissection and treatment of activity-dependent pathogenic pathways. PMID- 29693601 TI - Rapid, High Affinity Binding by a Fluorescein Templated Copolymer Combining Covalent, Hydrophobic, and Acid-Base Noncovalent Crosslinks. AB - A new type of biomimetic templated copolymer has been prepared by reverse addition fragmentation chain transfer polymerization (RAFT) in dioxane. The initial formulation includes the template fluorescein, N-isopropylacrylamide (NIPAM, 84 mol %), methacrylic acid (MAA, 5-mol %), 4-vinylpyridine (4-VP, 9 mmol %), and N,N′-methylenebis(acrylamide) (MBA, 2 mol %). PolyNIPAM is a thermosensitive polymer that comes out of aqueous solution above its lower critical solution temperature forming hydrophobic ‘crosslinks’. MAA and 4-VP interact in dioxane forming acid-base crosslinks. The excess 4-VP serves as a recognition monomer organizing around the template fluorescein to form a binding site that is held in place by the noncovalent and covalent crosslinks. The MBA is a covalent crosslinker. The RAFT agent in the resulting copolylmer was reduced to a thiol and attached to gold nanoparticles. The gold nanoparticle bound copolymer binds fluorescein completely in less than two seconds with an affinity constant greater than 108 M−1. A reference copolymer prepared with the same monomers by the same procedure binds fluorescein much more weakly. PMID- 29693602 TI - A New Approach to Assessing HSV-1 Recombination during Intercellular Spread. AB - The neuroinvasive Herpes simplex virus type 1 (HSV-1) utilizes intergenomic recombination in order to diversify viral populations. Research efforts to assess HSV-1 recombination are often complicated by the use of attenuating mutations, which differentiate viral progeny but unduly influence the replication and spread. In this work, we generated viruses with markers that allowed for classification of viral progeny with limited attenuation of viral replication. We isolated viruses, harboring either a cyan (C) or yellow (Y) fluorescent protein (FP) expression cassette inserted in two different locations within the viral genome, in order to visually quantify the recombinant progeny based on plaque fluorescence. We found that the FP marked genomes had a limited negative affect on the viral replication and production of progeny virions. A co-infection of the two viruses resulted in recombinant progeny that was dependent on the multiplicity of infection and independent of the time post infection, at a rate that was similar to previous reports. The sequential passage of mixed viral populations revealed a limited change in the distribution of the parental and recombinant progeny. Interestingly, the neuroinvasive spread within neuronal cultures and an in vivo mouse model, revealed large, random shifts in the parental and recombinant distributions in viral populations. In conclusion, our approach highlights the utility of FP expressing viruses in order to provide new insights into mechanisms of HSV-1 recombination. PMID- 29693603 TI - Comparison of Staphylococcus Phage K with Close Phage Relatives Commonly Employed in Phage Therapeutics. AB - The increase in antibiotic resistance in pathogenic bacteria is a public health danger requiring alternative treatment options, and this has led to renewed interest in phage therapy. In this respect, we describe the distinct host ranges of Staphylococcus phage K, and two other K-like phages against 23 isolates, including 21 methicillin-resistant S. aureus (MRSA) representative sequence types representing the Irish National MRSA Reference Laboratory collection. The two K like phages were isolated from the Fersisi therapeutic phage mix from the Tbilisi Eliava Institute, and were designated B1 (vB_SauM_B1) and JA1 (vB_SauM_JA1). The sequence relatedness of B1 and JA1 to phage K was observed to be 95% and 94% respectively. In terms of host range on the 23 Staphylococcus isolates, B1 and JA1 infected 73.9% and 78.2% respectively, whereas K infected only 43.5%. Eleven open reading frames (ORFs) present in both phages B1 and JA1 but absent in phage K were identified by comparative genomic analysis. These ORFs were also found to be present in the genomes of phages (Team 1, vB_SauM-fRuSau02, Sb_1 and ISP) that are components of several commercial phage mixtures with reported wide host ranges. This is the first comparative study of therapeutic staphylococcal phages within the recently described genus Kayvirus. PMID- 29693604 TI - Adult Stem Cells Spheroids to Optimize Cell Colonization in Scaffolds for Cartilage and Bone Tissue Engineering. AB - Top-down tissue engineering aims to produce functional tissues using biomaterials as scaffolds, thus providing cues for cell proliferation and differentiation. Conversely, the bottom-up approach aims to precondition cells to form modular tissues units (building-blocks) represented by spheroids. In spheroid culture, adult stem cells are responsible for their extracellular matrix synthesis, re creating structures at the tissue level. Spheroids from adult stem cells can be considered as organoids, since stem cells recapitulate differentiation pathways and also represent a promising approach for identifying new molecular targets (biomarkers) for diagnosis and therapy. Currently, spheroids can be used for scaffold-free (developmental engineering) or scaffold-based approaches. The scaffold promotes better spatial organization of individual spheroids and provides a defined geometry for their 3D assembly in larger and complex tissues. Furthermore, spheroids exhibit potent angiogenic and vasculogenic capacity and serve as efficient vascularization units in porous scaffolds for bone tissue engineering. An automated combinatorial approach that integrates spheroids into scaffolds is starting to be investigated for macro-scale tissue biofabrication. PMID- 29693605 TI - Impact of a Translated Disease Self-Management Program on Employee Health and Productivity: Six-Month Findings from a Randomized Controlled Trial. AB - Disease management is gaining importance in workplace health promotion given the aging workforce and rising chronic disease prevalence. The Chronic Disease Self Management Program (CDSMP) is an effective intervention widely offered in diverse community settings; however, adoption remains low in workplace settings. As part of a larger NIH-funded randomized controlled trial, this study examines the effectiveness of a worksite-tailored version of CDSMP (wCDSMP [n = 72]) relative to CDSMP (‘Usual Care’ [n = 109]) to improve health and work performance among employees with one or more chronic conditions. Multiple-group latent-difference score models with sandwich estimators were fitted to identify changes from baseline to 6-month follow-up. Overall, participants were primarily female (87%), non-Hispanic white (62%), and obese (73%). On average, participants were age 48 (range: 23-72) and self-reported 3.25 chronic conditions (range: 1 16). The most commonly reported conditions were high cholesterol (45%), high blood pressure (45%), anxiety/emotional/mental health condition (26%), and diabetes (25%). Among wCDSMP participants, significant improvements were observed for physically unhealthy days (uΔ = −2.07, p = 0.018), fatigue (uΔ = −2.88, p = 0.002), sedentary behavior (uΔ = −4.49, p = 0.018), soda/sugar beverage consumption (uΔ = −0.78, p = 0.028), and fast food intake (uΔ = −0.76, p = 0.009) from baseline to follow up. Significant improvements in patient-provider communication (uΔ = 0.46, p = 0.031) and mental work limitations (uΔ = −8.89, p = 0.010) were also observed from baseline to follow-up. Relative to Usual Care, wCDSMP participants reported significantly larger improvements in fatigue, physical activity, soda/sugar beverage consumption, and mental work limitations (p < 0.05). The translation of Usual Care (content and format) has potential to improve health among employees with chronic conditions and increase uptake in workplace settings. PMID- 29693606 TI - Feasibility of Optical Coherence Tomography (OCT) for Intra-Operative Detection of Blood Flow during Gastric Tube Reconstruction. AB - In this study; an OCT-based intra-operative imaging method for blood flow detection during esophagectomy with gastric tube reconstruction is investigated. Change in perfusion of the gastric tube tissue can lead to ischemia; with a high morbidity and mortality as a result. Anastomotic leakage (incidence 5-20%) is one of the most severe complications after esophagectomy with gastric tube reconstruction. Optical imaging techniques provide for minimal-invasive and real time visualization tools that can be used in intraoperative settings. By implementing an optical technique for blood flow detection during surgery; perfusion can be imaged and quantified and; if needed; perfusion can be improved by either a surgical intervention or the administration of medication. The feasibility of imaging gastric microcirculation in vivo using optical coherence tomography (OCT) during surgery of patients with esophageal cancer by visualizing blood flow based on the speckle contrast from M-mode OCT images is studied. The percentage of pixels exhibiting a speckle contrast value indicative of flow was quantified to serve as an objective parameter to assess blood flow at 4 locations on the reconstructed gastric tube. Here; it was shown that OCT can be used for direct blood flow imaging during surgery and may therefore aid in improving surgical outcomes for patients. PMID- 29693608 TI - Magnesium and Nitrogen Co-Doped Mesoporous Carbon with Enhanced Microporosity for CO2 Adsorption. AB - Mesoporous carbons (MC) have attracted a tremendous amount of interest due to their efficient molecular transport properties. However, the limited number of active sites and low microporosity generally impede their use for practical applications. Herein, we have fabricated Mg and N co-doped mesoporous carbon (Mg NMC) with high microporosity via one-pot synthetic route followed by further steam activation. In comparison with the parent N-doped mesoporous carbon, Mg-NMC shows partially ordered mesostructure and improved CO2 adsorption capacity attributed to the introduction of basic site after Mg doping. Upon further steam activation, the microporosity is enhanced to 37.3%, while the CO2 adsorption capacity is also increased by 70.4% at 273 K and 1.0 bar. PMID- 29693609 TI - Synthesis and Fluorescence Properties of Structurally Characterized Heterobimetalic Cu(II)-Na(I) Bis(salamo)-Based Complex Bearing Square Planar, Square Pyramid and Triangular Prism Geometries of Metal Centers. AB - A novel heterotrinuclear complex [Cu2(L)Na(µ-NO3)]?CH3OH?CHCl3 derived from a symmetric bis(salamo)-type tetraoxime H4L having a naphthalenediol unit, was prepared and structurally characterized via means of elemental analyses, UV-Vis, FT-IR, fluorescent spectra and single-crystal X-ray diffraction. The heterobimetallic Cu(II)-Na(I) complex was acquired via the reaction of H4L with 2 equivalents of Cu(NO3)2·2H2O and 1 equivalent of NaOAc. Clearly, the heterotrinuclear Cu(II)-Na(I) complex has a 1:2:1 ligand-to-metal (Cu(II) and Na(I)) ratio. X-ray diffraction results exhibited the different geometric behaviors of the Na(I) and Cu(II) atoms in the heterotrinuclear complex; the both Cu(II) atoms are sited in the N2O2 coordination environments of fully deprotonated (L)4− unit. One Cu(II) atom (Cu1) is five-coordinated and possesses a geometry of slightly distorted square pyramid, while another Cu(II) atom (Cu2) is four-coordination possessing a square planar coordination geometry. Moreover, the Na(I) atom is in the O6 cavity and adopts seven-coordination with a geometry of slightly distorted single triangular prism. In addition, there are abundant supramolecular interactions in the Cu(II)-Na(I) complex. The fluorescence spectra showed the Cu(II)-Na(I) complex possesses a significant fluorescent quenching and exhibited a hypsochromic-shift compared with the ligand H4L. PMID- 29693610 TI - The Application of an Ultrasound Tomography Algorithm in a Novel Ring 3D Ultrasound Imaging System. AB - Currently, breast cancer is one of the most common cancers in women all over the world. A novel 3D breast ultrasound imaging ring system using the linear array transducer is proposed to decrease costs, reduce processing difficulties, and improve patient comfort as compared to modern day breast screening systems. The 1 × 128 Piezoelectric Micromachined Ultrasonic Transducer (PMUT) linear array is placed 90 degrees cross-vertically. The transducer surrounds the mammary gland, which allows for non-contact detection. Once the experimental platform is built, the breast model is placed through the electric rotary table opening and into a water tank that is at a constant temperature of 32 °C. The electric rotary table performs a 360° scan either automatically or mechanically. Pulse echo signals are captured through a circular scanning method at discrete angles. Subsequently, an ultrasonic tomography algorithm is designed, and a horizontal slice imaging is realized. The experimental results indicate that the preliminary detection of mass is realized by using this ring system. Circular scanning imaging is obtained by using a rotatable linear array instead of a cylindrical array, which allows the size and location of the mass to be recognized. The resolution of breast imaging is improved through the adjustment of the angle interval (>0.05°) and multiple slices are gained through different transducer array elements (1 × 128). These results validate the feasibility of the system design as well as the algorithm, and encourage us to implement our concept with a clinical study in the future. PMID- 29693607 TI - Harnessing the Power of Microbiome Assessment Tools as Part of Neuroprotective Nutrition and Lifestyle Medicine Interventions. AB - An extensive body of evidence documents the importance of the gut microbiome both in health and in a variety of human diseases. Cell and animal studies describing this relationship abound, whilst clinical studies exploring the associations between changes in gut microbiota and the corresponding metabolites with neurodegeneration in the human brain have only begun to emerge more recently. Further, the findings of such studies are often difficult to translate into simple clinical applications that result in measurable health outcomes. The purpose of this paper is to appraise the literature on a select set of faecal biomarkers from a clinician’s perspective. This practical review aims to examine key physiological processes that influence both gastrointestinal, as well as brain health, and to discuss how tools such as the characterisation of commensal bacteria, the identification of potential opportunistic, pathogenic and parasitic organisms and the quantification of gut microbiome biomarkers and metabolites can help inform clinical decisions of nutrition and lifestyle medicine practitioners. PMID- 29693611 TI - Smart System for Bicarbonate Control in Irrigation for Hydroponic Precision Farming. AB - Improving the sustainability in agriculture is nowadays an important challenge. The automation of irrigation processes via low-cost sensors can to spread technological advances in a sector very influenced by economical costs. This article presents an auto-calibrated pH sensor able to detect and adjust the imbalances in the pH levels of the nutrient solution used in hydroponic agriculture. The sensor is composed by a pH probe and a set of micropumps that sequentially pour the different liquid solutions to maintain the sensor calibration and the water samples from the channels that contain the nutrient solution. To implement our architecture, we use an auto-calibrated pH sensor connected to a wireless node. Several nodes compose our wireless sensor networks (WSN) to control our greenhouse. The sensors periodically measure the pH level of each hydroponic support and send the information to a data base (DB) which stores and analyzes the data to warn farmers about the measures. The data can then be accessed through a user-friendly, web-based interface that can be accessed through the Internet by using desktop or mobile devices. This paper also shows the design and test bench for both the auto-calibrated pH sensor and the wireless network to check their correct operation. PMID- 29693612 TI - Effect of the Channel Length on the Transport Characteristics of Transistors Based on Boron-Doped Graphene Ribbons. AB - Substitutional boron doping of devices based on graphene ribbons gives rise to a unipolar behavior, a mobility gap, and an increase of the I O N / I O F F ratio of the transistor. Here we study how this effect depends on the length of the doped channel. By means of self-consistent simulations based on a tight-binding description and a non-equilibrium Green’s function approach, we demonstrate a promising increase of the I O N / I O F F ratio with the length of the channel, as a consequence of the different transport regimes in the ON and OFF states. Therefore, the adoption of doped ribbons with longer aspect ratios could represent a significant step toward graphene-based transistors with an improved switching behavior. PMID- 29693614 TI - Poly(urethane-norbornene) Aerogels via Ring Opening Metathesis Polymerization of Dendritic Urethane-Norbornene Monomers: Structure-Property Relationships as a Function of an Aliphatic Versus an Aromatic Core and the Number of Peripheral Norbornene Moieties. AB - We report the synthesis and characterization of synthetic polymer aerogels based on dendritic-type urethane-norbornene monomers. The core of those monomers is based either on an aromatic/rigid (TIPM/Desmodur RE), or an aliphatic/flexible (Desmodur N3300) triisocyanate. The terminal norbornene groups (three at the tip of each of the three branches) were polymerized via ROMP using the inexpensive 1st generation Grubbs catalyst. The polymerization/gelation conditions were optimized by varying the amount of the catalyst. The resulting wet-gels were dried either from pentane under ambient pressure at 50 °C, or from t-butanol via freeze-drying, or by using supercritical fluid (SCF) CO2. Monomers were characterized with high resolution mass spectrometry (HRMS), 1H- and solid-state 13C-NMR. Aerogels were characterized with ATR-FTIR and solid-state 13C-NMR. The porous network was probed with N2-sorption and SEM. The thermal stability of monomers and aerogels was studied with TGA, which also provides evidence for the number of norbornene groups that reacted via ROMP. At low densities (<0.1 g cm−3) all aerogels were highly porous (porosity > 90%), mostly macroporous materials; aerogels based on the aliphatic/flexible core were fragile, whereas aerogels containing the aromatic/rigid core were plastic, and at even lower densities (0.03 g cm−3) foamy. At higher densities (0.2-0.7 g cm−3) all materials were stiff, strong, and hard. At low monomer concentrations all aerogels consisted of discrete primary particles that formed spherical secondary aggregates. At higher monomer concentrations the structure consisted of fused particles with the size of the previous secondary aggregates, due to the low solubility of the developing polymer, which phase-separated and formed a primary particle network. Same-size fused aggregates were observed for both aliphatic and aromatic triisocyanate-derived aerogels, leading to the conclusion that it is not the aliphatic or aromatic core that determines phase separation, but rather the solubility of the polymeric backbone (polynorbornene) that is in both cases the same. The material properties were compared to those of analogous aerogels bearing only one norbornene moiety at the tip of each branch deriving from the same cores. PMID- 29693613 TI - Gender and Body-Fat Status as Predictors of Parental Feeding Styles and Children's Nutritional Knowledge, Eating Habits and Behaviours. AB - The home food environment is critically important for the development of children’s health-related practices. By managing dietary restrictions, providing nutritional knowledge and demonstrating eating behaviours, parents contribute to children’s food preferences and eating patterns. The present study examined nutritional knowledge, eating habits and appetite traits among 387 Polish five-year-old healthy and overfat boys and girls in the context of parental feeding styles and body-fat status. We observed that girls presented healthier eating habits than boys; however, overfat boys had better nutritional knowledge. Children’s body-fat percentage (%BF) was found to be linked with eating behaviours such as low satiety responsiveness and increased food responsiveness in girls as well as low emotional undereating and increased emotional overeating in boys. Our results revealed that overfat mothers, who were more prone to use the encouragement feeding style, rarely had daughters with increased %BF. Parents of overfat girls, however, were less likely to apply encouragement and instrumental feeding styles. Contrary to popular belief and previous studies, overfat women do not necessarily transmit unhealthy eating patterns to their children. Parents’ greater emphasis on managing the weight and eating habits of daughters (rather than sons) probably results from their awareness of standards of female physical attractiveness. PMID- 29693615 TI - Observance of Sterilization Protocol Guideline Procedures of Critical Instruments for Preventing Iatrogenic Transmission of Creutzfeldt-Jakob Disease in Dental Practice in France, 2017. AB - Effective sterilization of reusable instruments contaminated by Creutzfeldt-Jakob disease in dental care is a crucial issue for public health. The present cross sectional study investigated how the recommended procedures for sterilization were implemented by French dental practices in real-world settings. A sample of dental practices was selected in the French Rhône-Alpes region. Data were collected by a self-questionnaire in 2016. Sterilization procedures (n = 33) were classified into 4 groups: (1) Pre-sterilization cleaning of reusable instruments; (2) Biological verification of sterilization cycles—Monitoring steam sterilization procedures; (3) Autoclave performance and practitioner knowledge of autoclave use; (4) Monitoring and documentation of sterilization procedures—Tracking and tracing the instrumentation. Answers were provided per procedure, along with the global implementation of procedures within a group (over 80% correctly performed). Then it was verified how adherence to procedure groups varied with the size of the dental practice and the proportion of dental assistants within the team. Among the 179 questionnaires available for the analyses, adherence to the recommended procedures of sterilization noticeably varied between practices, from 20.7% to 82.6%. The median percentages of procedures correctly implemented per practice were 58.1%, 50.9%, 69.2% and 58.2%, in Groups 1, 2, 3 and 4, respectively (corresponding percentages for performing over 80% of the procedures in the group: 23.4%, 6.6%, 46.6% and 38.6%). Dental practices ≥ 3 dental units performed significantly better (>80%) procedures of Groups 2 and 4 (p = 0.01 and p = 0.002, respectively), while no other significant associations emerged. As a rule, practices complied poorly with the recommended procedures, despite partially improved results in bigger practices. Specific training regarding sterilization procedures and a better understanding of the reasons leading to their non-compliance are needed. PMID- 29693616 TI - Association between Sleep Duration and Overweight/Obesity at Age 7-18 in Shenyang, China in 2010 and 2014. AB - This study was designed to examine the association between sleep duration and being overweight/obese in primary, middle, and high school students. This was a multiple cross-sectional study using data from the 2010 and 2014 National Survey on Students’ Constitution and Health (CNSSCH). A total of 23,602 students aged 7-18 years were enrolled in this study. The prevalence of being overweight and obese—stratified by age, gender, and sleep duration—in 2010 and 2014 were compared. Sleep duration was categorized as <7 h, ≥7 to 8 h, ≥8 to 9 h, and ≥9 h. Overweight and obesity were defined according to the cut point criteria in China. Multivariable logistic regression results in 2010 and 2014 revealed that students sleeping <7 h and aged 7-12 years had an increased risk of becoming overweight/obese. In 2010, the adjusted prevalence ratios of overweight for 7-12-year-old students sleeping <9 h was 1.196 (95%CI: 1.004 1.424) and 13-15-year-old students sleeping <8 h was 1.265 (95%CI: 1.023-1.565). In 2014, the adjusted prevalence ratios of overweight and obesity for 7-12-year old students sleeping <9 h were 1.295 (95%CI: 1.091-1.537) and 1.231 (95%CI: 1.045-1.449); 16-18-year-old students sleeping <7 h were 1.530 (95%CI: 1.239 1.888) and 1.585 (95%CI: 1.270-2.081). Our study revealed that different levels of sleep curtailment increased the risk of becoming overweight/obesity in different age groups of students. PMID- 29693617 TI - Complete Chloroplast Genome of Cercis chuniana (Fabaceae) with Structural and Genetic Comparison to Six Species in Caesalpinioideae. AB - The subfamily Caesalpinioideae of the Fabaceae has long been recognized as non monophyletic due to its controversial phylogenetic relationships. Cercis chuniana, endemic to China, is a representative species of Cercis L. placed within Caesalpinioideae in the older sense. Here, we report the whole chloroplast (cp) genome of C. chuniana and compare it to six other species from the Caesalpinioideae. Comparative analyses of gene synteny and simple sequence repeats (SSRs), as well as estimation of nucleotide diversity, the relative ratios of synonymous and nonsynonymous substitutions (dn/ds), and Kimura 2 parameter (K2P) interspecific genetic distances, were all conducted. The whole cp genome of C. chuniana was found to be 158,433 bp long with a total of 114 genes, 81 of which code for proteins. Nucleotide substitutions and length variation are present, particularly at the boundaries among large single copy (LSC), inverted repeat (IR) and small single copy (SSC) regions. Nucleotide diversity among all species was estimated to be 0.03, the average dn/ds ratio 0.3177, and the average K2P value 0.0372. Ninety-one SSRs were identified in C. chuniana, with the highest proportion in the LSC region. Ninety-seven species from the old Caesalpinioideae were selected for phylogenetic reconstruction, the analysis of which strongly supports the monophyly of Cercidoideae based on the new classification of the Fabaceae. Our study provides genomic information for further phylogenetic reconstruction and biogeographic inference of Cercis and other legume species. PMID- 29693618 TI - Quantification of 6-Mercaptopurine and Its Metabolites in Patients with Acute Lympoblastic Leukemia Using Dried Blood Spots and UPLC-MS/MS. AB - This research aimed to quantitatively bioanalyze 6-mercaptopurine (6-MP), 6 methylmercaptopurine (6-MMP), and 6-thioguanosine-5′-monophosphate (6-TGMP) in dried blood spots (DBS) prepared from a small volume of acute lymphoblastic leukemia (ALL) patients. Analytes on the DBS card were extracted using 90% methanol with 5-fluorouracil (5-FU) as an internal standard. Analytical separation was performed on a Waters Acquity® UPLC BEH AMIDA column of 1.7 μm (2.1 × 100 mm) with a mobile phase mixture of 0.2% formic acid in water and 0.1% formic acid in acetonitrile-methanol, with gradient elution and a flow rate of 0.2 mL/min. Mass detection of 6-MP, 6-MMP, 6-TGMP, and 5-FU showed m/z values of 153.09 > 119.09, 167.17 > 126.03, 380.16 > 168.00, and 129.09 > 42.05, respectively. This DBS method had a run time of 5 min and yielded a linear calibration curve over a range of 25.5-1020 ng/mL for 6-MP, 6-MMP, and 6-TGMP. Analyte analysis in 22 of 24 ALL patients showed that the measured value of 6 TGMP as an active metabolite was in the range of 29-429 pmol/8 × 108 erythrocytes. Five of 22 patients had concentrations in a therapeutic range, which indicates that the treatment is effective, while 17 of 24 patients had concentrations below the therapeutic range, which indicates that a treatment dose adjustment is needed. The measured value of 6-MMP, an inactive metabolite, was in the range of 28-499 pmol/8 × 108 erythrocytes, which includes concentrations below the hepatotoxic range. The method employed here can thus be effectively utilized to support therapeutic drug monitoring. PMID- 29693619 TI - Ecological Vulnerability Assessment Based on Fuzzy Analytical Method and Analytic Hierarchy Process in Yellow River Delta. AB - The Yellow River Delta (YRD), located in Yellow River estuary, is characterized by rich ecological system types, and provides habitats or migration stations for wild birds, all of which makes the delta an ecological barrier or ecotone for inland areas. Nevertheless, the abundant natural resources of YRD have brought huge challenges to the area, and frequent human activities and natural disasters have damaged the ecological systems seriously, and certain ecological functions have been threatened. Therefore, it is necessary to determine the status of the ecological environment based on scientific methods, which can provide scientifically robust data for the managers or stakeholders to adopt timely ecological protection measures. The aim of this study was to obtain the spatial distribution of the ecological vulnerability (EV) in YRD based on 21 indicators selected from underwater status, soil condition, land use, landform, vegetation cover, meteorological conditions, ocean influence, and social economy. In addition, the fuzzy analytic hierarchy process (FAHP) method was used to obtain the weights of the selected indicators, and a fuzzy logic model was constructed to obtain the result. The result showed that the spatial distribution of the EV grades was regular, while the fuzzy membership of EV decreased gradually from the coastline to inland area, especially around the river crossing, where it had the lowest EV. Along the coastline, the dikes had an obviously protective effect for the inner area, while the EV was higher in the area where no dikes were built. This result also showed that the soil condition and groundwater status were highly related to the EV spatially, with the correlation coefficients −0.55 and −0.74 respectively, and human activities had exerted considerable pressure on the ecological environment. PMID- 29693620 TI - Plasma Tryptophan/Large Neutral Amino Acids Ratio in Domestic Dogs Is Affected by a Single Meal with High Carbohydrates Level. AB - Aim of this study was to evaluate the plasma ratio between l-tryptophan (TRP) and five large neutral amino acids (isoleucine + leucine + phenylalanine + tyrosine + valine) (5LNAAs) after a single meal with high carbohydrates level. Five female Labrador Retrievers were involved. Each dog was fed three different meals: M1 (a mix of puffed rice, minced meat and olive oil), M2 (puffed rice and olive oil) and M3 (commercial dry food usually consumed) once in the morning per day for 30 days. Blood was collected right before the first meal (t0) and after 2, 4, 6, 8, 10 and 24 h. Plasma amino acids’ concentrations were measured using an HPLC (High-performance liquid chromatography) method with fluorimetric detection. Plasmatic TRP concentrations showed no significant difference between M1, M2 and M3 samples at any sampling time. M2 led to a decrease in 5LNAAs levels and consequently led to a significant higher TRP/5LNAAs ratios in the 6 h period after the provision of carbohydrates, compared to both M1 and M3. In addition, the mean TRP/5LNAAs ratio was significantly higher in M2 than in M3 at t8 and t10. These results indicate that meal composition affects TRP/5LNAAs ratio and possibly, TRP bioavailability. PMID- 29693621 TI - The Combined Influence of Hydrostatic Pressure and Temperature on Nonlinear Optical Properties of GaAs/Ga0.7Al0.3As Morse Quantum Well in the Presence of an Applied Magnetic Field. AB - Studies aimed at understanding the nonlinear optical (NLO) properties of GaAs/Ga0.7Al0.3As morse quantum well (QW) have focused on the intersubband optical absorption coefficients (OACs) and refractive index changes (RICs). These studies have taken two complimentary approaches: (1) The compact-density-matrix approach and iterative method have been used to obtain the expressions of OACs and RICs in morse QW. (2) Finite difference techniques have been used to obtain energy eigenvalues and their corresponding eigenfunctions of GaAs/Ga0.7Al0.3As morse QW under an applied magnetic field, hydrostatic pressure, and temperature. Our results show that the hydrostatic pressure and magnetic field have a significant influence on the position and the magnitude of the resonant peaks of the nonlinear OACs and RICs. Simultaneously, a saturation case is observed on the total absorption spectrum, which is modulated by the hydrostatic pressure and magnetic field. Physical reasons have been analyzed in depth. PMID- 29693623 TI - Impact of the Introduction of the Electronic Health Insurance Card on the Use of Medical Services by Asylum Seekers in Germany. AB - Objectives: Asylum seekers in Germany represent a highly vulnerable group from a health perspective. Furthermore, their access to healthcare is restricted. While the introduction of the Electronic Health Insurance Card (EHIC) for asylum seekers instead of healthcare-vouchers is discussed controversially using politico-economic reasons, there is hardly any empirical evidence regarding its actual impact on the use of medical services. The aim of the study is to examine this impact on the use of medical services by asylum seekers as measured by their consultation rate of ambulant physicians (CR). Study Design: For this purpose, a standardized survey was conducted with 260 asylum seekers in different municipalities, some of which have introduced the EHIC for asylum seekers, while others have not. Methods: The period prevalence was compared between the groups “with EHIC” and “without EHIC” using a two-sided t-test. Multivariate analysis was done using a linear OLS regression model. Results: Asylum seekers in possession of the EHIC are significantly more likely to seek ambulant medical care than those receiving healthcare-vouchers. Conclusions: The results of this study suggest that having to ask for healthcare-vouchers at the social security office could be a relevant barrier for asylum seekers. PMID- 29693624 TI - Gait Shear and Plantar Pressure Monitoring: A Non-Invasive OFS Based Solution for e-Health Architectures. AB - In an era of unprecedented progress in sensing technology and communication, health services are now able to closely monitor patients and elderly citizens without jeopardizing their daily routines through health applications on their mobile devices in what is known as e-Health. Within this field, we propose an optical fiber sensor (OFS) based system for the simultaneous monitoring of shear and plantar pressure during gait movement. These parameters are considered to be two key factors in gait analysis that can help in the early diagnosis of multiple anomalies, such as diabetic foot ulcerations or in physical rehabilitation scenarios. The proposed solution is a biaxial OFS based on two in-line fiber Bragg gratings (FBGs), which were inscribed in the same optical fiber and placed individually in two adjacent cavities, forming a small sensing cell. Such design presents a more compact and resilient solution with higher accuracy when compared to the existing electronic systems. The implementation of the proposed elements into an insole is also described, showcasing the compactness of the sensing cells, which can easily be integrated into a non-invasive mobile e-Health solution for continuous remote gait monitoring of patients and elder citizens. The reported results show that the proposed system outperforms existing solutions, in the sense that it is able to dynamically discriminate shear and plantar pressure during gait. PMID- 29693622 TI - Targeting Splicing in Prostate Cancer. AB - Over 95% of human genes are alternatively spliced, expressing splice isoforms that often exhibit antagonistic functions. We describe genes whose alternative splicing has been linked to prostate cancer; namely VEGFA, KLF6, BCL2L2, ERG, and AR. We discuss opportunities to develop novel therapies that target specific splice isoforms, or that target the machinery of splicing. Therapeutic approaches include the development of small molecule inhibitors of splice factor kinases, splice isoform specific siRNAs, and splice switching oligonucleotides. PMID- 29693625 TI - Experiences of Pharmacy Trainees from an Interprofessional Immersion Training. AB - Interprofessional education is essential in that it helps healthcare disciplines better utilize each other and provide team-based collaboration that improves patient care. Many pharmacy training programs struggle to implement interprofessional education. This purpose of the study was to examine the effect of a 30-h interprofessional training that included pharmacy students to determine if the training helped these students build valuable knowledge and skills while working alongside other health care professions. The interprofessional training included graduate-level trainees from pharmacy, behavioral health, nursing, and family medicine programs where the trainees worked within teams to build interprofessional education competencies based on the Interprofessional Education Collaborative core competencies. Sixteen pharmacy trainees participated in the training and completed pre- and post-test measures. Data were collected over a two-year period with participants completing the Team Skills Scale and the Interprofessional Attitudes Scale. Paired sample t-tests indicated that, after this training, pharmacy trainees showed significant increases in feeling better able to work in healthcare teams and valuing interprofessional practice. PMID- 29693626 TI - Enhanced Strength of a Mechanical Alloyed NbMoTaWVTi Refractory High Entropy Alloy. AB - A NbMoTaWVTi refractory high entropy alloy (HEA) has been successfully synthesized by mechanical alloying (MA) and spark plasma sintering (SPS). The microstructure and mechanical properties of this alloy are investigated. It is observed that only two types of body-centered cubic (BCC) solid solutions are formed in the powders after ball milling for 40 h. However, a new face-centered cubic (FCC) precipitated phase is observed in the BCC matrix of bulk material consolidated by SPS. The FCC precipitated phase is identified as TiO, due to the introduction of O during the preparing process of HEA. The compressive yield strength, fracture strength, and total fracture strain of the consolidated bulk HEA are 2709 MPa, 3115 MPa, and 11.4%, respectively. The excellent mechanical properties can be attributed to solid solution strengthening and grain boundary strengthening of the fine-grained BCC matrix, as well as the precipitation strengthening owing to the formation of TiO particles. PMID- 29693627 TI - Effect of Silver Nitrate and Sodium Fluoride with Tri-Calcium Phosphate on Streptococcus mutans and Demineralised Dentine. AB - This study investigated the effect of 25% silver nitrate (AgNO3) and 5% sodium fluoride (NaF) varnish with functionalized tri-calcium phosphate (fTCP) on a Streptococcus mutans (S. mutans) biofilm and dentine caries lesion. Demineralised dentine specimens were treated with 25% AgNO3 and 5% NaF + fTCP (Group 1), 25% AgNO3 and 5% NaF (Group 2), 25% AgNO3 (Group 3), or water (Group 4). The specimens were subjected to a S. mutans biofilm challenge after treatment. The biofilm was then studied via scanning electron microscopy (SEM), confocal laser scanning microscopy (CLSM), and colony forming units (CFU). The specimens were assessed by micro-computed tomography, X-ray diffraction (XRD), and Fourier transform infrared spectroscopy (FTIR). SEM and CLSM revealed less biofilm in Groups 1 to 3. The log10 CFU of Groups 1 to 4 were 4.5 ± 0.7, 4.4 ± 0.9, 4.4 ± 0.9, and 6.7 ± 1.0, respectively (Groups 1, 2, 3 < 4, p < 0.001). The lesion depths of Groups 1 to 4 were 212.6 ± 20.1 µm, 280.8 ± 51.6 µm, 402.5 ± 61.7 µm, and 497.4 ± 67.2 µm, respectively (Groups 1 < 2 < 3 < 4, p < 0.001). XRD demonstrated silver chloride formation in Groups 1, 2, and 3. FTIR found the amide I: HPO42− values of the four groups were 0.22 ± 0.05, 0.25 ± 0.05, 0.41 ± 0.12, and 0.64 ± 0.14, respectively (Groups 1, 2 < 3 < 4; p < 0.001). In conclusion, this study revealed that AgNO3 and NaF + fTCP reduced the damage of dentine caries by cariogenic biofilm. PMID- 29693629 TI - A Proteomic View of Salmonella Typhimurium in Response to Phosphate Limitation. AB - Salmonella enterica serovar Typhimurium (S. Typhimurium), an important foodborne pathogen, often encounters phosphate (Pi) shortage both in the environment and inside host cells. To gain a global view on its physiological responses to Pi starvation, we performed proteomic profiling of S. Typhimurium upon the shift from Pi-rich to Pi-low conditions. In addition to the Pho regulon, many metabolic processes were up-regulated, such as glycolysis, pentose phosphate pathway, pyrimidine degradation, glycogen, and trehalose metabolism, allowing us to chart an overview of S. Typhimurium carbon metabolism under Pi starvation. Furthermore, proteomic analysis of a mutant lacking phoB (that encodes a key regulator of Pi shortage response) suggested that only a small subset of the altered proteins upon Pi limitation was PhoB-dependent. Importantly, we present evidence that S. Typhimurium N-acetylglucosamine catabolism was induced under Pi-limiting conditions in a PhoB-dependent manner. Immunoblotting and β-galactosidase assays demonstrated that PhoB was required for the full activation of NagB, a key enzyme of this pathway, in response to low Pi. Thus, our study reveals that N acetylglucosamine catabolism may represent an additional PhoB-regulated pathway to tackle bacterial Pi shortage. PMID- 29693628 TI - Influence of Mechanical Unloading on Articular Chondrocyte Dedifferentiation. AB - Due to the limited self-repair capacity of articular cartilage, the surgical restoration of defective cartilage remains a major clinical challenge. The cell based approach, which is known as autologous chondrocyte transplantation (ACT), has limited success, presumably because the chondrocytes acquire a fibroblast like phenotype in monolayer culture. This unwanted dedifferentiation process is typically addressed by using three-dimensional scaffolds, pellet culture, and/or the application of exogenous factors. Alternative mechanical unloading approaches are suggested to be beneficial in preserving the chondrocyte phenotype. In this study, we examined if the random positioning machine (RPM) could be used to expand chondrocytes in vitro such that they maintain their phenotype. Bovine chondrocytes were exposed to (a) eight days in static monolayer culture; (b) two days in static monolayer culture, followed by six days of RPM exposure; and, (c) eight days of RPM exposure. Furthermore, the experiment was also conducted with the application of 20 mM gadolinium, which is a nonspecific ion-channel blocker. The results revealed that the chondrocyte phenotype is preserved when chondrocytes go into suspension and aggregate to cell clusters. Exposure to RPM rotation alone does not preserve the chondrocyte phenotype. Interestingly, the gene expression (mRNA) of the mechanosensitive ion channel TRPV4 decreased with progressing dedifferentiation. In contrast, the gene expression (mRNA) of the mechanosensitive ion channel TRPC1 was reduced around fivefold to 10-fold in all of the conditions. The application of gadolinium had only a minor influence on the results. This and previous studies suggest that the chondrocyte phenotype is preserved if cells maintain a round morphology and that the ion channel TRPV4 could play a key role in the dedifferentiation process. PMID- 29693630 TI - Enhanced Photocatalytic Activity of {110}-Faceted TiO2 Rutile Nanorods in the Photodegradation of Hazardous Pharmaceuticals. AB - Rutile TiO2 with highly active facets has attracted much attention owing to its enhanced activity during the photocatalytic degradation of pollutants such as pharmaceuticals in wastewater. However, it is difficult to obtain by controlling the synthetic conditions. This paper reports a simple hydrothermal synthesis of rutile TiO2 nanorods with highly exposed {110} facets. The obtained rutile was characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), high-resolution transmission electron microscopy (HR-TEM), and Raman spectroscopy. The main contribution to the photocatalytic activity comes from rutile nanorods with highly dominant active {110} facets, which were studied in the photodegradation of reactive cinnamic acid and more recalcitrant ibuprofen. The contribution of active species was also investigated. The present work further confirmed the hydrothermal synthesis route for controlling the preparation of highly crystalline and active rutile nanocrystals. PMID- 29693631 TI - Vitamin D Requirements for the Future-Lessons Learned and Charting a Path Forward. AB - Estimates of dietary requirements for vitamin D or Dietary Reference Values (DRV) are crucial from a public health perspective in providing a framework for prevention of vitamin D deficiency and optimizing vitamin D status of individuals. While these important public health policy instruments were developed with the evidence-base and data available at the time, there are some issues that need to be clarified or considered in future iterations of DRV for vitamin D. This is important as it will allow for more fine-tuned and truer estimates of the dietary requirements for vitamin D and thus provide for more population protection. The present review will overview some of the confusion that has arisen in relation to the application and/or interpretation of the definitions of the Estimated Average Requirement (EAR) and Recommended Dietary Allowance (RDA). It will also highlight some of the clarifications needed and, in particular, how utilization of a new approach in terms of using individual participant-level data (IPD), over and beyond aggregated data, from randomised controlled trials with vitamin D may have a key role in generating these more fine-tuned and truer estimates, which is of importance as we move towards the next iteration of vitamin D DRVs. PMID- 29693632 TI - Fruit and Vegetable By-Products to Fortify Spreadable Cheese. AB - In this work, spreadable cheese was enriched with flours from by-products (red and white grape pomace, tomato peel, broccoli, corn bran, and artichokes) as sources of fibres and antioxidant compounds. The physicochemical and the sensory properties of all the cheese samples were analysed. Results revealed that total phenolic content, flavonoids, and antioxidant activity of samples containing grape pomace significantly increased, followed by broccoli, artichoke, corn bran, and tomato peel by-products, compared to the control cheese. Specifically, cheeses containing white and red grape pomace recorded high phenolic content (2.74 ± 0.04 and 2.34 ± 0.15 mg GAEs/g dw, respectively) compared to the control (0.66 mg GAEs/g dw). PMID- 29693633 TI - Grains Contribute Shortfall Nutrients and Nutrient Density to Older US Adults: Data from the National Health and Nutrition Examination Survey, 2011-2014. AB - Previous data demonstrate grain foods contribute shortfall nutrients to the diet of U.S. adults. The 2015-2020 Dietary Guidelines for Americans have identified several shortfall nutrients in the U.S. population, including fiber, folate, and iron (women only). Intake of some shortfall nutrients can be even lower in older adults. The present analyses determined the contribution of grain foods for energy and nutrients in older U.S. adults and ranked to all other food sources in the American diet. Analyses of grain food sources were conducted using a 24-hour recall in adults (≥51 years old; n = 4522) using data from the National Health and Nutrition Examination Survey, 2011-2014. All grains provided 278 kcal/day or 14% of all energy in the total diet, ranking as the 4th largest contributor of energy compared to 15 main food groups. All grain foods ranked 1st for thiamin (33%) and niacin (23%) intake relative to 15 main food groups. The grain foods category ranked 2nd highest of 15 main food groups for daily dietary fiber (23%), iron (38%), folate (40%), and magnesium (15%) and was the 3rd largest food group contributor for daily calcium intake (13%). When considering nutrients to limit as outlined by dietary guidance, main group of grains contributed 6% total fat, 5% saturated fat, 14% sodium and 9% added sugar. Breads, rolls and tortillas provided 150 kcal/day or 8% of all energy in the total diet, ranking as the 2nd largest contributor of energy compared to 46 food subcategories. Breads, rolls and tortillas ranked 1st of 46 foods for daily thiamin (16%) and niacin (10%) intake and 2nd for dietary fiber (12%), iron (12%), folate (13%), and magnesium (7%). Breads, rolls and tortillas ranked 3rd largest food group contributor for daily calcium (5%) intake. Ready-to-eat cereals provided 47 kcal/day or 2% of all energy in the total diet, ranking as the 20th largest contributor of energy compared to 46 food subcategories. All ready-to-eat cereals ranked 1st for daily iron (19%), 1st for folate (21%), 5th for dietary fiber (7%), 3rd for niacin (9%), 8th for magnesium (4%), and 13th for calcium (2%) intake. Given all grain foods and specific subcategories of grain foods provided a greater percentage of several underconsumed nutrients than calories (including dietary fiber, iron, and folate), grain foods provide nutrient density in the American diet of the older adult. PMID- 29693634 TI - Within-Host Recombination in the Foot-and-Mouth Disease Virus Genome. AB - Recombination is one of the determinants of genetic diversity in the foot-and mouth disease virus (FMDV). FMDV sequences have a mosaic structure caused by extensive intra- and inter-serotype recombination, with the exception of the capsid-encoding region. While these genome-wide patterns of broad-scale recombination are well studied, not much is known about the patterns of recombination that may exist within infected hosts. In addition, detection of recombination among viruses evolving at the within-host level is challenging due to the similarity of the sequences and the limitations in differentiating recombination from point mutations. Here, we present the first analysis of recombination events between closely related FMDV sequences occurring within buffalo hosts. The detection of these events was made possible by the occurrence of co-infection of two viral swarms with about 1% nucleotide divergence. We found more than 15 recombination events, unequally distributed across eight samples from different animals. The distribution of these events along the FMDV genome was neither uniform nor related to the phylogenetic distribution of recombination breakpoints, suggesting a mismatch between within-host evolutionary pressures and long-term selection for infectivity and transmissibility. PMID- 29693635 TI - Commensal Staphylococcus aureus Provokes Immunity to Protect against Skin Infection of Methicillin-Resistant Staphylococcus aureus. AB - Unlike USA300, a strain of community-acquired methicillin-resistant Staphylococcus aureus (MRSA), commensal Staphylococcus aureus (S. aureus) bacteria isolated from human skin demonstrated the ability to mediate the glycerol fermentation to produce short-chain fatty acids (SCFAs). Quantitative proteomic analysis of enzymes involved in glycerol fermentation demonstrated that the expression levels of six enzymes, including glycerol-3-phosphate dehydrogenase (GPDH) and phosphoglycerate mutase (PGM), in commensal S. aureus are more than three-fold higher than those in USA300. Western blotting validated the low expression levels of GPDH in USA300, MRSA252 (a strain of hospital acquired MRSA), and invasive methicillin-susceptible S. aureus (MSSA). In the presence of glycerol, commensal S. aureus effectively suppressed the growth of USA300 in vitro and in vivo. Active immunization of mice with lysates or recombinant α-hemolysin of commensal S. aureus or passive immunization with neutralizing sera provided immune protection against the skin infection of USA300. Our data illustrate for the first time that commensal S. aureus elicits both innate and adaptive immunity via glycerol fermentation and systemic antibody production, respectively, to fight off the skin infection of pathogenic MRSA. PMID- 29693636 TI - Spore Acquisition and Survival of Ambrosia Beetles Associated with the Laurel Wilt Pathogen in Avocados after Exposure to Entomopathogenic Fungi. AB - Laurel wilt is a disease threatening the avocado industry in Florida. The causative agent of the disease is a fungus vectored by ambrosia beetles that bore into the trees. Until recently, management strategies for the vectors of the laurel wilt fungus relied solely on chemical control and sanitation practices. Beneficial entomopathogenic fungi (EPF) are the most common and prevalent natural enemies of pathogen vectors. Laboratory experiments demonstrated that commercial strains of EPF can increase the mortality of the primary vector, Xyleborus glabratus, and potential alternative vectors, Xylosandrus crassiusculus, Xyleborus volvulus and Xyleborus bispinatus (Coleoptera: Curculionidae: Scolytinae). Our study provides baseline data for three formulated commercially available entomopathogenic fungi used as potential biocontrol agents against X. crassiusculus, X. volvulus and X. bispinatus. The specific objectives were to determine: (1) the mean number of viable spores acquired per beetle species adult after being exposed to formulated fungal products containing different strains of EPF (Isaria fumosorosea, Metarhizium brunneum and Beauveria bassiana); and (2) the median and mean survival times using paper disk bioassays. Prior to being used in experiments, all fungal suspensions were adjusted to 2.4 × 106 viable spores/mL. The number of spores acquired by X. crassiusculus was significantly higher after exposure to B. bassiana, compared to the other fungal treatments. For X. volvulus, the numbers of spores acquired per beetle were significantly different amongst the different fungal treatments, and the sequence of spore acquisition rates on X. volvulus from highest to lowest was I. fumosorosea > M. brunneum > B. bassiana. After X. bispinatus beetles were exposed to the different suspensions, the rates of acquisition of spores per beetle amongst the different fungal treatments were similar. Survival estimates (data pooled across two tests) indicated an impact for each entomopathogenic fungus per beetle species after exposure to a filter paper disk treated at the same fungal suspension concentration. Kaplan-Meier analysis (censored at day 7) revealed that each beetle species survived significantly shorter in bioassays containing disks treated with EPF compared to water only. This study demonstrated that ambrosia beetles associated with the laurel wilt pathogen in avocados are susceptible to infection by EPF under laboratory conditions. However, the EPF needs to be tested under field conditions to confirm their efficacy against the beetles. PMID- 29693637 TI - PALTEM: What Parameters Should Be Collected in Disaster Settings to Assess the Long-Term Outcomes of Famine? AB - Evidence suggests that nutritional status during fetal development and early life leaves an imprint on the genome, which leads to health outcomes not only on a person as an adult but also on his offspring. The purpose of this study is to bring forth an overview of the relevant parameters that need to be collected to assess the long-term and transgenerational health outcomes of famine. A literature search was conducted for the most pertinent articles on the epigenetic effects of famine. The results were compiled, synthesized and discussed with an expert in genetics for critical input and validation. Prenatal and early life exposure to famine was associated with metabolic, cardiovascular, respiratory, reproductive, neuropsychiatric and oncologic diseases. We propose a set of parameters to be collected in disaster settings to assess the long-term outcomes of famine: PALTEM (parameters to assess long-term effects of malnutrition). PMID- 29693638 TI - The Preschool-Aged and School-Aged Children Present Different Odds of Mortality than Adults in Southern Taiwan: A Cross-Sectional Retrospective Analysis. AB - Background: This study aimed to profile the epidemiology of injury among preschool-aged and school-aged children in comparison to those in adults. Methods: According to the Trauma Registry System of a level I trauma center, the medical data were retrieved from 938 preschool-aged children (aged less than seven years), 670 school-aged children (aged 7-12 years), and 16,800 adults (aged 20-64 years) between 1 January 2009 and 31 December 2016. Two-sided Pearson’s, chi-squared, and Fisher’s exact tests were used to compare categorical data. A one-way analysis of variance (ANOVA) with the Games-Howell post-hoc test was used to assess the differences in continuous variables among different groups of patients. The mortality outcomes of different subgroups were assessed by a multivariable regression model under the adjustment of sex, injury mechanisms, and injury severity. Results: InFsupppjury mechanisms in preschool aged and school-aged children were remarkably different from that in adults; in preschool-aged children, burns were the most common cause of injury requiring hospitalization (37.4%), followed by falls (35.1%) and being struck by/against objects (11.6%). In school-aged children, injuries were most commonly sustained from falls (47.8%), followed by bicycle accidents (14%) and being struck by/against objects (12.5%). Compared to adults, there was no significant difference of the adjusted mortality of the preschool-aged children (AOR = 0.9; 95% CI 0.38-2.12; p = 0.792) but there were lower adjusted odds of mortality of the school-aged children (AOR = 0.4; 95% CI 0.10-0.85; p = 0.039). The school aged children had lower odds of mortality than adults (OR, 0.2; 95% CI, 0.06 0.74; p = 0.012), but such lower odds of risk of mortality were not found in preschool-aged children (OR, 0.7; 95% CI, 0.29-1.81; p = 0.646). Conclusions: This study suggests that specific types of injuries from different injury mechanisms are predominant among preschool-aged and school-aged children. The school-aged children had lower odds of mortality than adults; nonetheless there was no difference in mortality rates of preschool-aged children than adults, with or without controlling for sex, injury mechanisms and ISS. These results highlight the importance of injury prevention, particularly for preschool-aged children in Southern Taiwan. PMID- 29693639 TI - Synthesis, Characterization, and Photocatalytic Properties of Bamboo Charcoal/TiO2 Composites Using Four Sizes Powder. AB - Visible-light-active bamboo biochar/TiO2 composites were fabricated by the calcination method using C16H36O4Ti as the titanium source and bamboo powder with different sizes as the carbon source. The TiO2 nanoparticles were observed to disperse onto the surface of bamboo biochar fiber. The sizes of the bamboo powder played an important role in the microstructures and the properties of bamboo biochar/TiO2 composites. The bamboo biochar/TiO2 composites displayed the photocatalytic activities both under visible light irradiation and UV irradiation. The adsorption isotherms better fitted Freundlich isotherm models and the photodegradation reactions followed pseudo-first-order kinetics. Bamboo charcoal/TiO2 composites exhibited high stability after up to four cycles. This research could pave the way for high-value applications of biomass in the environmental field. PMID- 29693641 TI - Effects of Internet and Smartphone Addictions on Depression and Anxiety Based on Propensity Score Matching Analysis. AB - The associations of Internet addiction (IA) and smartphone addiction (SA) with mental health problems have been widely studied. We investigated the effects of IA and SA on depression and anxiety while adjusting for sociodemographic variables. In this study, 4854 participants completed a cross-sectional web-based survey including socio-demographic items, the Korean Scale for Internet Addiction, the Smartphone Addiction Proneness Scale, and the subscales of the Symptom Checklist 90 Items-Revised. The participants were classified into IA, SA, and normal use (NU) groups. To reduce sampling bias, we applied the propensity score matching method based on genetics matching. The IA group showed an increased risk of depression (relative risk 1.207; p < 0.001) and anxiety (relative risk 1.264; p < 0.001) compared to NUs. The SA group also showed an increased risk of depression (relative risk 1.337; p < 0.001) and anxiety (relative risk 1.402; p < 0.001) compared to NCs. These findings show that both, IA and SA, exerted significant effects on depression and anxiety. Moreover, our findings showed that SA has a stronger relationship with depression and anxiety, stronger than IA, and emphasized the need for prevention and management policy of the excessive smartphone use. PMID- 29693640 TI - Nanotechnological Strategies for Protein Delivery. AB - The use of therapeutic proteins plays a fundamental role in the treatment of numerous diseases. The low physico-chemical stability of proteins in physiological conditions put their function at risk in the human body until they reach their target. Moreover, several proteins are unable to cross the cell membrane. All these facts strongly hinder their therapeutic effect. Nanomedicine has emerged as a powerful tool which can provide solutions to solve these limitations and improve the efficacy of treatments based on protein administration. This review discusses the advantages and limitations of different types of strategies employed for protein delivery, such as PEGylation, transport within liposomes or inorganic nanoparticles or their in situ encapsulation. PMID- 29693642 TI - Antibiotic Prescribing for Oro-Facial Infections in the Paediatric Outpatient: A Review. AB - There are many reports on the complications associated with antibiotics abuse during the treatment of paediatric patients, particularly those related to antimicrobial resistance. The dental profession is no exception; there is growing evidence that dental practitioners are misusing antibiotics in the treatment of their paediatric patients. This review is directed to dental practitioners who provide oral healthcare to children. It is also directed to medical practitioners, particularly those working in emergency departments and encountering children with acute orofacial infections. A systematic search of literature was conducted to explore the clinical indications and recommended antibiotic regimens for orofacial infections in paediatric outpatients. The main indications included cellulitis, aggressive periodontitis, necrotizing ulcerative gingivitis, and pericoronitis. Amoxicillin was found to be the most commonly recommended antibiotic for short durations of 3-5 days, with metronidazole or azithromycin being the alternative antibiotics in penicillin-sensitive patients. PMID- 29693644 TI - Exploring on the Sensitivity Changes of the LC Resonance Magnetic Sensors Affected by Superposed Ringing Signals. AB - LC resonance magnetic sensors are widely used in low-field nuclear magnetic resonance (LF-NMR) and surface nuclear magnetic resonance (SNMR) due to their high sensitivity, low cost and simple design. In magnetically shielded rooms, LC resonance magnetic sensors can exhibit sensitivities at the fT/√Hz level in the kHz range. However, since the equivalent magnetic field noise of this type of sensor is greatly affected by the environment, weak signals are often submerged in practical applications, resulting in relatively low signal-to-noise ratios (SNRs). To determine why noise increases in unshielded environments, we analysed the noise levels of an LC resonance magnetic sensor (L ≠ 0) and a Hall sensor (L ≈ 0) in different environments. The experiments and simulations indicated that the superposed ringing of the LC resonance magnetic sensors led to the observed increase in white noise level caused by environmental interference. Nevertheless, ringing is an inherent characteristic of LC resonance magnetic sensors. It cannot be eliminated when environmental interference exists. In response to this problem, we proposed a method that uses matching resistors with various values to adjust the quality factor Q of the LC resonance magnetic sensor in different measurement environments to obtain the best sensitivity. The LF-NMR experiment in the laboratory showed that the SNR is improved significantly when the LC resonance magnetic sensor with the best sensitivity is selected for signal acquisition in the light of the test environment. (When the matching resistance is 10 kΩ, the SNR is 3.46 times that of 510 Ω). This study improves LC resonance magnetic sensors for nuclear magnetic resonance (NMR) detection in a variety of environments. PMID- 29693643 TI - Common microRNA-mRNA Interactions in Different Newcastle Disease Virus-Infected Chicken Embryonic Visceral Tissues. AB - To investigate the roles and explore the altered expression of microRNAs (miRNAs) and mRNAs in chicken embryos in response to Newcastle disease virus (NDV) infection, deep sequencing was performed. Then, a conjoint analysis of small RNA seq and mRNA-seq was performed to screen interactional miRNA-mRNA pairs during NDV infection. In total, 15 and 17 up- and downregulated miRNAs were identified that potentially targeted 4279 and 6080 mRNAs in NDV-infected chicken embryonic tissues, respectively; in addition, 595 upregulated and 480 downregulated mRNAs were identified. The conjoint analysis of the obtained data identified 1069 miRNA mRNA pairs. Among these pairs, 130 pairs were related to immune or inflammatory responses. The relationship between gga-miR-203a and its target transglutaminase 2 (TGM2) was confirmed using a dual-luciferase reporter system and a real time quantitative polymerase chain reaction (RT-qPCR) assay. Overall, the discovery of miRNAs, mRNAs, and their potential pairing relationships, which may be involved in the regulation of NDV infection, will facilitate our understanding of the complex regulatory relationship between the host and the virus. PMID- 29693645 TI - Wide Angle of Incidence-Insensitive Polarization-Independent THz Metamaterial Absorber for Both TE and TM Mode Based on Plasmon Hybridizations. AB - An ultra-wide-angle THz metamaterial absorber (MA) utilizing sixteen-circular sector (SCR) resonator for both transverse electric (TE) and transverse magnetic (TM) mode is designed and investigated numerically. At normal incidence, the absorptivity of the proposed MA is higher than 93.7% at 9.05 THz for different polarization angles, due to the rotational symmetry structure of the unit cell. Under oblique incidence, the absorptivity can still exceed 90%, even when the incident angle is up to 70 degrees for both TE and TM mode. Especially, the frequency variation in TE mode is less than 0.25% for different incident angles from 0 degrees to 70 degrees . The electric field (Ez) distributions are used to explain the absorption mechanism. Numerical simulation results show that the high absorption with wide-angle independence stems from fundamental dipole resonance and gap surface plasmons. The broadband deep-infrared MA is also obtained by stacking three metal-dielectric layers. The designed MA has great potential in bolometric pixel elements, biomedical sensors, THz imaging, and solar cells. PMID- 29693646 TI - Effects of C5/C6 Intervertebral Space Distraction Height on Pressure on the Adjacent Intervertebral Disks and Articular Processes and Cervical Vertebrae Range of Motion. AB - BACKGROUND This study aimed to investigate the association between range of motion of the cervical vertebrae and various C5/C6 intervertebral space distraction heights. MATERIAL AND METHODS The cervical vertebrae from 6 fresh adult human cadavers were used to prepare the models. Changes in C4/C5 and C6/C7 intervertebral disk pressures, articular process pressure, and range of motion of the cervical vertebrae before and after the distraction of the C5/C6 intervertebral space at benchmark heights of 100%, 120%, 140%, and 160% were tested under different exercise loads. RESULTS The pressure on the adjacent intervertebral disks was highest with the standing upright position before distraction, varied with different positions of the specimens and distraction heights after distraction, and was closest to that before distraction at a distraction height of 120% (P<0.05). The pressure of the adjacent articular processes was highest with left and right rotations before distraction, varied with different positions of the specimens and distraction heights after distraction, and was lowest under the same exercise load with different positions at a distraction height of 120% (P<0.05). The ranges of motion of the cervical vertebrae and intervertebral disks were largest without distraction and at a distraction height of 120% after distraction, respectively (P<0.05). CONCLUSIONS When removing the C5/C6 intervertebral disk and implanting an intervertebral bone graft, a benchmark height of 120% had little influence on the pressure of the adjacent intervertebral disks and articular processes and range of motion of the cervical vertebrae and is therefore an appropriate intervertebral space distraction height. PMID- 29693648 TI - Urbanorum Spp: First Report in Brazil. AB - BACKGROUND The first scientific case related to Urbanorum spp protozoan infection was identified in Peru in 1994. Considering there are few cases catalogued, the aim of this study was to register the first case of Urbanorum spp infection in Brazil. CASE REPORT A thin 41-year-old female patient with dark skin, weighing 55 to 60 kg attended the Buriti Municipal Central Laboratory, in Maranhao, Brazil to undergo routine exams. Among the exams requested was a parasitological exam of feces, which was processed according to the protocol of Hoffman, Pons, and Janer (HPJ) or Lutz, an easy, simple, and low-cost parasitological technique. This method consists in spontaneous sedimentation of a filtered homogenate of feces sample and water. The sample was stained with Lugol and examined under light microscopy at 10* and 40*. We detected a light-yellow structure with rounded shape and several filaments similar to pseudopods. The microscopic analysis raised doubts about the identity and pathogenicity of this microorganism. CONCLUSIONS This study reports the first case of Urbanorum spp infection in Brazil, where the current environmental conditions have contributed to new parasitological cases. Therefore, further studies are recommended to identify unknown cases of Urbanorum spp infection in other regions of the country to create a national registry related to this new protozoan. PMID- 29693647 TI - Anti-Interferon Alpha Antibodies in Patients with High-Risk BCR/ABL-Negative Myeloproliferative Neoplasms Treated with Recombinant Human Interferon-alpha. AB - BACKGROUND The objective of this study was to characterize the incidence and impact of immunogenicity to interferon-a (IFN-alpha-2a, IFN-alpha-2b, and Peg-IFN alpha-2a) over a period of 12 months in patients with BCR/ABL-negative myeloproliferative neoplasms (MPNs). MATERIAL AND METHODS A total of 131 patients from an observational prospective cohort were selected. Antidrug antibodies, in serial serum samples obtained monthly after initiation of therapy, were measured by ELISA and WISH/VSV CPE assays. The association between antidrug antibodies and treatment response and adverse effects was evaluated. RESULTS Among patients who completed 12 months of follow-up, binding antibodies (BAbs) were detected in 53% of those receiving IFN-alpha (69 of 131) and neutralizing antibodies (NAbs) were detected in 19% (25 of 131). NAbs-positivity was correlated with poorer clinical response, and Bab-positivity was associated with more adverse events. Almost all BAbs and NAbs appeared within 8 months after treatment began (>=95%). Complete remission (CR) rate was 62% for patients who were BAbs-positive and 69% for patients who were BAbs-negative; however, the CR rate of patients with NAbs(+) (24%) was obviously lower than in patients with NAbs(-) (75%). Patients with BAbs(+) had more immune adverse effects (including fever, myalgia, skin reaction, and stomatitis) than BAbs(-) patients, and NAbs to IFN-alpha had no obvious influence on the adverse effects rate. CONCLUSIONS The development of BAbs and NAbs can adversely affect IFN-a treatment in patients with MPN. PMID- 29693650 TI - A randomized trial to study the comparative efficacy of phenylbutyrate and benzoate on nitrogen excretion and ureagenesis in healthy volunteers. AB - PURPOSE: Benzoate and phenylbutyrate are widely used in the treatment of urea cycle disorders, but detailed studies on pharmacokinetics and comparative efficacy on nitrogen excretion are lacking. METHODS: We conducted a randomized, three-arm, crossover trial in healthy volunteers to study pharmacokinetics and comparative efficacy of phenylbutyrate (NaPB; 7.15 g*m-2BSA*day-1), benzoate (NaBz; 5.5 g*m-2BSA*day-1), and a combination of two medications (MIX arm; 3.575 g NaPB and 2.75 g NaBz*m-2BSA*day-1) on nitrogen excretion. Stable isotopes were used to study effects on urea production and dietary nitrogen disposal. RESULTS: The conjugation efficacy for both phenylbutyrate and benzoate was 65%; conjugation was superior at the lower dose used in the MIX arm. Whereas NaPB and MIX treatments were more effective at excreting nitrogen than NaBz, nitrogen excretion as a drug conjugate was similar between phenylbutyrate and MIX arms. Nitrogen excreted per USD was higher with combination therapy compared with NaPB. CONCLUSION: Phenylbutyrate was more effective than benzoate at disposing nitrogen. Increasing phenylbutyrate dose may not result in higher nitrogen excretion due to decreased conjugation efficiency at higher doses. Combinatorial therapy with phenylbutyrate and benzoate has the potential to significantly decrease treatment cost without compromising the nitrogen disposal efficacy. PMID- 29693651 TI - Biallelic PADI6 variants linking infertility, miscarriages, and hydatidiform moles. AB - Recurrent hydatidiform moles (RHM) are aberrant human pregnancies characterized by absence of, or abnormal, embryonic development, hydropic degeneration of chorionic villi, and hyperproliferation of the trophoblast. Biallelic mutations in two maternal-effect genes, NLRP7 and KHDC3L, underlie the causation of RHM in 60% of patients. We performed exome sequencing on a patient with six pregnancy losses, two miscarriages and four HM, and found no variants that affect the functions of the known genes. We found biallelic missense variants that affect conserved amino acids in PADI6 and segregate with the disease phenotype in the family. PADI6 is another maternal-effect gene and a member of the subcortical maternal complex that has been shown to have recessive variants that affect the gene function in four unrelated women with infertility who also experienced early embryonic arrest during preimplantation development after IVF. We demonstrated that PADI6 co-localizes with NLRP7 in human oocytes and preimplantation embryos and reviewed the morphology and genotypes of four products of conception from our patient. Our data expand the involvement of PADI6 to other forms of reproductive loss and highlight the commonality between infertility, miscarriages, and molar pregnancies, in some cases. PMID- 29693653 TI - Publisher Correction: Normal-to-mildly increased albuminuria predicts the risk for diabetic retinopathy in patients with type 2 diabetes. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29693652 TI - Precisely printable and biocompatible silk fibroin bioink for digital light processing 3D printing. AB - Although three-dimensional (3D) bioprinting technology has gained much attention in the field of tissue engineering, there are still several significant engineering challenges to overcome, including lack of bioink with biocompatibility and printability. Here, we show a bioink created from silk fibroin (SF) for digital light processing (DLP) 3D bioprinting in tissue engineering applications. The SF-based bioink (Sil-MA) was produced by a methacrylation process using glycidyl methacrylate (GMA) during the fabrication of SF solution. The mechanical and rheological properties of Sil-MA hydrogel proved to be outstanding in experimental testing and can be modulated by varying the Sil-MA contents. This Sil-MA bioink allowed us to build highly complex organ structures, including the heart, vessel, brain, trachea and ear with excellent structural stability and reliable biocompatibility. Sil-MA bioink is well-suited for use in DLP printing process and could be applied to tissue and organ engineering depending on the specific biological requirements. PMID- 29693654 TI - Publisher Correction: Human single chain-transbodies that bound to domain-I of non-structural protein 5A (NS5A) of hepatitis C virus. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29693655 TI - New activities for old antibiotics. PMID- 29693656 TI - Revising Leishmania's life cycle. PMID- 29693657 TI - Staphylococcus aureus blocks insulin function. PMID- 29693658 TI - Richness and ecosystem development across faecal snapshots of the gut microbiota. PMID- 29693660 TI - Make scientific conferences count. PMID- 29693659 TI - A high-frequency phenotypic switch links bacterial virulence and environmental survival in Acinetobacter baumannii. AB - Antibiotic-resistant infections lead to 700,000 deaths per year worldwide 1 . The roles of phenotypically diverse subpopulations of clonal bacteria in the progression of diseases are unclear. We found that the increasingly pathogenic and antibiotic-resistant pathogen Acinetobacter baumannii harbours a highly virulent subpopulation of cells responsible for disease. This virulent subpopulation possesses a thicker capsule and is resistant to host antimicrobials, which drive its enrichment during infection. Importantly, bacteria harvested from the bloodstream of human patients belong exclusively to this virulent subpopulation. Furthermore, the virulent form exhibits increased resistance to hospital disinfectants and desiccation, indicating a role in environmental persistence and the epidemic spread of disease. We identified a transcriptional 'master regulator' of the switch between avirulent and virulent cells, the overexpression of which abrogates virulence. Furthermore, the overexpression strain is capable of vaccinating mice against lethal challenge. This work highlights a phenotypic subpopulation of bacteria that drastically alters the outcome of infection, and illustrates how knowledge of the regulatory mechanisms controlling such phenotypic switches can be harnessed to attenuate bacteria and develop translational interventions. PMID- 29693661 TI - Microrheology and microstructure of water-in-water emulsions containing sodium caseinate and locust bean gum. AB - The mechanical response on the microscale of phase-separated water-in-water emulsions containing sodium caseinate (SCN) and locust bean gum (LBG) has been monitored by confocal laser scanning microscopy and particle tracking microrheology. Mixed biopolymer systems exhibiting phase-separated micro-regions were enriched in either protein or polysaccharide in the continuous or dispersed phase, depending on the weight ratio of the two biopolymers. Measurements of the tracking of charged probe particles revealed that the local rheological properties of protein-rich regions were considerably lower than that of LBG-rich domains for all the biopolymer ratios examined. At pH 7 in the absence of added salt, the viscosity of the protein-rich regions was little affected by an increase in overall LBG concentration, which is consistent with the phase separation mechanism in the mixed solution of charged (SCN) and uncharged (LBG) biopolymers being dominated by the relative entropy of the counter-ions associated with the charged protein molecules. Addition of salt was found to produce an enhancement in the level of thermodynamic incompatibility, leading to faster and more pronounced phase separation, and altering the micro-viscosity of protein-rich regions. At high ionic strength, it was also noted that there was a pronounced accumulation of incorporated probe particles at the liquid-liquid interface. The microrheological properties of the SCN-rich regions were found to be substantially pH-dependent in the range 7 > pH > 5.4. By adjusting the acidification conditions and the biopolymer ratio, discrete protein-based microspheres were generated with potential applications as a functional food ingredient. PMID- 29693662 TI - In vitro diagnosis of DNA methylation biomarkers with digital PCR in breast tumors. AB - Liquid biopsy of cancers using DNA methylation biomarkers has received significant interest, where the quantification of multiple biomarkers is generally needed for improving the sensitivity and specificity of cancer diagnosis. However, the inefficiency of the traditional quantitative polymerase chain reaction (qPCR)-based MethyLight assay for detecting the extremely low concentration of methylated DNA fragments in body fluids limits its clinical applications. Here, we developed an ultrasensitive microwell chip digital polymerase chain reaction (dPCR)-based MethyLight assay. Using the synthesized samples, the developed MethyLight assay can achieve 103-104-fold lower limit of detection and 1-16-fold lower limit of quantification than the traditional MethyLight assay. Four hypermethylated alleles (RARbeta2, BRCA1, GSTP1 and RASSF1A) related to breast cancer in twenty-three clinical samples were tested using the microwell chip dPCR-based MethyLight assay. The results showed that the dPCR assay achieves ~2 times enhancement in the cancer detection rate over the traditional quantitative PCR. Furthermore, the dPCR can detect the healthy and benign samples, which are undetectable using the traditional MethyLight assay. In multiple gene analysis, we achieved the highest detection rate of 93.3% (in the "OR" format of RARbeta2 and GSTP1). Lastly, the estimated cut-off values in the dPCR assay were: <1, ~1 to 100 and >100 (copies per MUL) referring to the healthy, benign and malignant breast cancers, respectively. Therefore, the developed microwell chip dPCR-based MethyLight assay could provide a powerful tool for cancer biopsy diagnosis and disease monitoring. PMID- 29693663 TI - Thermal glass transition beyond kinetics of a non-crystallizable glass-former. AB - A long-debated problem related to glass formation in amorphous materials is the interplay of thermodynamic, kinetic and alpha-relaxation processes. For the first time, low-frequency dynamics, as well as kinetic or quasi-static thermal expansion coefficients of a non-crystallizable glass-former are simultaneously measured. Based on the feedback between low-frequency dynamics and morphology, the study supports the viewpoint that glass formation can be observed in internal equilibrium, i.e. beyond kinetics, and might stem from spontaneous local-scale morphological changes. PMID- 29693664 TI - Self-assembled two-dimensional gold nanoparticle film for sensitive nontargeted analysis of food additives with surface-enhanced Raman spectroscopy. AB - The use of different food additives and their active metabolites has been found to cause serious problems to human health. Thus, considering the potential effects on human health, developing a sensitive and credible analytical method for different foods is important. Herein, the application of solvent-driven self assembled Au nanoparticles (Au NPs) for the rapid and sensitive detection of food additives in different commercial products is reported. The assembled substrates are highly sensitive and exhibit excellent uniformity and reproducibility because of uniformly distributed and high-density hot spots. The sensitive analyses of ciprofloxacin (CF), diethylhexyl phthalate (DEHP), tartrazine and azodicarbonamide at the 0.1 ppm level using this surface-enhanced Raman spectroscopy (SERS) substrate are given, and the results show that Au NP arrays can serve as efficient SERS substrates for the detection of food additives. More importantly, SERS spectra of several commercial liquors and sweet drinks are obtained to evaluate the addition of illegal additives. This SERS active platform can be used as an effective strategy in the detection of prohibited additives in food. PMID- 29693665 TI - Bond energy, site preferential occupancy and Eu2+/3+ co-doping system induced by Eu3+ self-reduction in Ca10M(PO4)7 (M = Li, Na, K) crystals. AB - Ca10M(PO4)7:Eu (M = Li, Na, K) phosphors have been synthesized via a solid-state reaction process, their phase purity was examined using XRD patterns, and Rietveld refinement confirmed that the Ca10Li(PO4)7, Ca10Na(PO4)7 and Ca10K(PO4)7 are pure phases. The photoluminescence properties of the Ca10M(PO4)7:Eu (M = Li, Na, K) phosphors showed that the self-reduction of Eu3+ to Eu2+ can occur in an air atmosphere. Eu3+ ions can be reduced to Eu2+ ions when doped in Ca10Li(PO4)7, Ca10Na(PO4)7 and Ca10K(PO4)7 crystals, which was detected using photoluminescence spectra. In this work, the bond energy method was used to determine and explain the mechanism of site occupation of Eu entering the host matrix. According to the calculated value of the deviation of bond energy for Eu3+-doped Ca10M(PO4)7 (M = Li, Na, K) crystals, the similar value between and , and , and and can provide the conditions for the self-reduction of Eu3+ in the Ca10M(PO4)7 (M = Li, Na, K) system. Meanwhile, the smaller deviation values of , , and in Ca10Li(PO4)7, Ca10Na(PO4)7, and Ca10K(PO4)7 crystals and in Ca10K(PO4)7 crystals indicated that the preferential sites of Eu ion occupancy in the Ca10M(PO4)7 (M = Li, Na, K) lattices are Li, Na, K and Ca sites. The conclusions obtained from the calculated results of the bond energy method are consistent with the Rietveld refinement and the photoluminescence spectra of Ca10M(PO4)7 (M = Li, Na, K). PMID- 29693666 TI - Schiff-base -ate derivatives with main group metals: generation of a tripodal aluminate metalloligand. AB - New heterobimetallic aluminates with well-defined structures bearing bidentate Schiff bases as ligands have been prepared. The ligands studied are PhO-CH[double bond, length as m-dash]N-Ar (Ar = C6H5 (La) and 2,6-iPr-C6H3 (Lb)), with and without donor substituents in the ortho position of the arene ring bonded to the iminic nitrogen. To prepare the heterometallic species, the HL proligands were treated with the appropriate alkali metal precursor and then AlMe3 was added. In these reactions the alkali metal size has a substantial influence on the outcome. For lithium, the formation of [LiAlMe3(L)]21(a-b) compounds was straightforward and their nuclearity in the solid state was confirmed by X-ray studies. When moving to sodium, the analogous species [NaAlMe3(L)]n initially formed, quickly evolved to [NaAlMe2(L)2]n3(a-b) in solution. As well, for potassium, the initial derivatives formed [KAlMe3L] progressed very rapidly to the generation of [KAlMe2L2] as evidenced from the isolation of [KAlMe2(Lb)2] 4b as a crystalline product. Furthermore, for potassium the unique species [KAlMe(Lb)3] 5b was isolated which shows, as a striking feature, the presence of an unusual tripodal metalloligand. PMID- 29693667 TI - Tracking the energy flow in the hydrogen exchange reaction OH + H2O -> H2O + OH. AB - The prototypical hydrogen exchange reaction OH + H2O -> H2O + OH has attracted considerable interest due to its importance in a wide range of chemically active environments. In this work, an accurate global potential energy surface (PES) for the ground electronic state was developed based on ~44 000 ab initio points at the level of UCCSD(T)-F12a/aug-cc-pVTZ. The PES was fitted using the fundamental invariant-neural network method with a root mean squared error of 4.37 meV. The mode specific dynamics was then studied by the quasi-classical trajectory method on the PES. Furthermore, the normal mode analysis approach was employed to calculate the final vibrational state distribution of the product H2O, in which a new scheme to acquire the Cartesian coordinates and momenta of each atom in the product molecule from the trajectories was proposed. It was found that, on one hand, excitation of either the symmetric stretching mode or the asymmetric stretching mode of the reactant H2O promotes the reaction more than the translational energy, which can be rationalized by the sudden vector projection model. On the other hand, the relatively higher efficacy of exciting the symmetric stretching mode than that of the asymmetric stretching mode is caused by the prevalence of the indirect mechanism at low collision energies and the stripping mechanism at high collision energies. In addition, the initial collision energy turns ineffectively into the vibrational energy of the products H2O and OH while a fraction of the energy transforms into the rotational energy of the product H2O. Fundamental excitation of the stretching modes of H2O results in the product H2O having the highest population in the fundamental state of the asymmetric stretching mode, followed by the ground state and the fundamental state of the symmetric stretching mode. PMID- 29693669 TI - Push and pull: the potential role of boron in N2 activation. AB - Recent developments in main group chemistry towards the activation and conversion of N2 have lead to the revelation that boron can greatly affect these processes. Boron is capable of acting both as a borane Lewis acid to activate metal-N2 complexes and as an ambiphilic borylene able to activate free N2. The latter example is capable of both accepting and donating electron density in a manner reminiscent of transition metal systems containing both filled and empty d orbitals. PMID- 29693671 TI - Self-assembled polymeric micelles for combined delivery of anti-inflammatory gene and drug to the lungs by inhalation. AB - Acute lung injury (ALI) is a lung inflammatory disease for which pulmonary delivery of drug and gene could be a useful strategy. In this study, cholesterol conjugated polyamidoamine (PAM-Chol) was synthesized and characterized as a carrier for combined delivery of anti-inflammatory gene and drug into the lungs by inhalation. The PAM-Chol formed self-assembled micelles in an aqueous solution with a critical micelle concentration of 0.22 mg ml-1. An in vitro transfection assay to L2 lung epithelial cells showed that the PAM-Chol micelle had higher transfection efficiency than lipofectamine and polyethylenimine (25 kDa, PEI25k). As the anti-inflammatory drug, resveratrol was loaded into the cores of the PAM Chol micelles using the oil-in-water emulsion/solvent evaporation method. In lipopolysaccharide (LPS)-activated macrophage cells, resveratrol-loaded PAM-Chol (PAM-Chol/Res) reduced pro-inflammatory cytokines, confirming the anti inflammatory effects of resveratrol. In in vitro transfection assays to L2 cells, the PAM-Chol/Res micelles had transfection efficiency similar to that of PAM Chol. The delivery of resveratrol or the heme oxygenase-1 gene (pHO-1) by inhalation was evaluated in an ALI animal model. Resveratrol delivery using the PAM-Chol/Res micelles inhibited the nuclear translocation of nuclear factor kappaB (NF-kappaB) and reduced pro-inflammatory cytokines in the lungs. pHO-1 delivery using PAM-Chol induced HO-1 expression and reduced pro-inflammatory cytokines. However, the highest anti-inflammatory effects were obtained with combined delivery of pHO-1 and resveratrol using the pHO-1/PAM-Chol/Res complex, as demonstrated in cytokine assays and immunohistochemical studies. Therefore, the PAM-Chol micelle is an efficient carrier of resveratrol and pHO-1 into the lungs and could be useful for the treatment of ALI by inhalation. PMID- 29693673 TI - Non-Dirac Chern insulators with large band gaps and spin-polarized edge states. AB - Based on first-principles calculations and k.p models, we demonstrate that PbC/MnSe heterostructures are a non-Dirac type of Chern insulator with very large band gaps (244 meV) and exotically half-metallic edge states, providing the possibilities of realizing very robust, completely spin polarized, and dissipationless spintronic devices from the heterostructures. The achieved extraordinarily large nontrivial band gap can be ascribed to the contribution of the non-Dirac type electrons (composed of px and py) and the very strong atomic spin-orbit coupling (SOC) interaction of the heavy Pb element in the system. Surprisingly, the band structures are found to be sensitive to the different exchange and correlation functionals adopted in the first-principles calculations. Chern insulators with various mechanisms are acquired from them. These discoveries show that the predicted nontrivial topology in PbC/MnSe heterostructures is robust and can be observed in experiments at high temperatures. The system has great potential to have attractive applications in future spintronics. PMID- 29693672 TI - "Dip-and-read" paper-based analytical devices using distance-based detection with color screening. AB - An improved paper-based analytical device (PAD) using color screening to enhance device performance is described. Current detection methods for PADs relying on the distance-based signalling motif can be slow due to the assay time being limited by capillary flow rates that wick fluid through the detection zone. For traditional distance-based detection motifs, analysis can take up to 45 min for a channel length of 5 cm. By using a color screening method, quantification with a distance-based PAD can be achieved in minutes through a "dip-and-read" approach. A colorimetric indicator line deposited onto a paper substrate using inkjet printing undergoes a concentration-dependent colorimetric response for a given analyte. This color intensity-based response has been converted to a distance based signal by overlaying a color filter with a continuous color intensity gradient matching the color of the developed indicator line. As a proof-of concept, Ni quantification in welding fume was performed as a model assay. The results of multiple independent user testing gave mean absolute percentage error and average relative standard deviations of 10.5% and 11.2% respectively, which were an improvement over analysis based on simple visual color comparison with a read guide (12.2%, 14.9%). In addition to the analytical performance comparison, an interference study and a shelf life investigation were performed to further demonstrate practical utility. The developed system demonstrates an alternative detection approach for distance-based PADs enabling fast (~10 min), quantitative, and straightforward assays. PMID- 29693674 TI - Role of the puckered anisotropic surface in the surface and adsorption properties of black phosphorus. AB - Nanomaterials have a high surface-to-mass ratio and their surface properties significantly affect their features and application potential. Phosphorene, a single layer of black phosphorus (BP), was the first homoatomic two-dimensional material to be prepared after the discovery of graphene. The structure of phosphorene resembles the honeycomb arrangement of graphene, but its layers are buckled and highly anisotropic. We studied how this difference affects the surface properties of BP, namely the free surface energy and adsorption affinity of various organic molecules. Using inverse gas chromatography, we measured the total surface free energy of BP powder to be 90 mJ m-2 and showed that it was dominantly determined by dispersion forces, but, unlike on graphene, with a notable contribution from specific acid-base interactions. We further measured adsorption enthalpies of volatile organic compounds on BP and rationalized them using density functional theory calculations. Polar molecules showed an increased affinity due to a significant contribution of dipole-dipole interactions to the molecule-surface bonding, because the buckled surface of BP causes higher diffusion barriers than those on graphene, hinders molecular in-plane motion and supports mutual orientation of molecular dipoles over longer distances, in contrast to graphene. PMID- 29693677 TI - Water oxidation by Ni(1,4,8,11-tetraazacyclotetradecane)2+ in the presence of carbonate: new findings and an alternative mechanism. AB - Herein, the water-oxidation reaction by Ni(1,4,8,11-tetraazacyclotetradecane)2+ in the presence of carbonate was reinvestigated by scanning electron microscopy, energy dispersive spectrometry, electrochemistry, and high-resolution spectroelectrochemical and hydrogen nuclear magnetic resonance spectroscopy methods. These methods showed that the complex was not stable under water oxidation conditions. The role of nanosized particles or Ni ions on the surface of the electrode for water oxidation was studied and it is proposed that Ni ions or Ni oxides on the surface of the electrode are at least one of the candidates contributing to the observed catalysis. PMID- 29693678 TI - Formation and selection of the macrocycle [{(tBuN[double bond, length as m dash])P(MU-NtBu)}2(MU-Se)2{P(MU-NtBu)}2]3. AB - Main group inorganic macrocycles, based on p-block element backbones other than carbon, are a challenging synthetic target that has been largely overlooked. In this study, we show that a simple strategy based on the combination of electrophilic and nucleophilic phosphazane building blocks can be extended to readily accessible [E(tBuN)P(MU-NtBu)]22- nucleophilic components, as exemplified by the Se-bridge PIII/PV phosphazane macrocycle [{(tBuN[double bond, length as m dash])PV(MU-NtBu)}2(MU-Se)2{PIII(MU-NtBu)}2]3. PMID- 29693681 TI - Outstanding Reviewers for Chemical Society Reviews in 2017. PMID- 29693683 TI - Recent progress in heavy atom-free organic compounds showing unexpected intersystem crossing (ISC) ability. AB - In this review, recent progress in heavy atom-free triplet photosensitizers was summarized. The general approaches include attaining S1/Tn states sharing similar energy levels or proper molecular geometry to satisfy the angular momentum reservation in intersystem crossing (ISC). ISC via the higher singlet excited state (Sn, n > 1) -> Tm (m > 1), which is a rarely reported phenomenon, was also discussed. The ISC of some Bodipy dimers was proposed to be via the 'doubly excited state', but recent studies show that the ISC mechanism of these Bodipy dimers is charge separation/recombination. These new findings in the study of triplet photosensitizers are useful for photovoltaics, photodynamic therapy and photocatalysis, as well as in fundamental photochemistry studies. PMID- 29693684 TI - Rab35-dependent extracellular nanovesicles are required for induction of tumour supporting stroma. AB - Communication between diseased cells and the microenvironment is a complex yet crucial element in progression of varied pathological processes. Recent studies in cancer highlight an important role for small extracellular nanovesicles secreted by cancer cells as modulators of cancer-associated stroma, leading to enhanced angiogenesis and metastatic priming. The intrinsic factors regulating extracellular nanovesicle biogenesis and secretion are therefore relevant in studies of nano-communication in the cancer milieu. We generated prostate cancer cells bearing stable knockdown of several candidate vesicle regulating factors and examined the impact on cell health, vesicle secretion and on communication with fibroblastic stromal cells. We highlight that RAB11B and RAB35 regulate phenotypically distinct nanovesicle populations, each accounting for only around 20% of the total. Depleting RAB35, but not RAB11B leaves a remaining population of vesicles whose phenotype is insufficient for driving fibroblast to myofibroblast differentiation, leading to attenuated motile behaviours in 3D in vitro models. Co-implantation of tumour cells with stromal fibroblasts in xenografts similarly showed that RAB11B knockdown had little effect on growth rates in vivo. In contrast, significant attenuation in growth, and attenuation of myofibroblasts at the tumour site was evident when using RAB35-knockdown cells. The study concludes that a RAB35 regulated nanovesicle sub-population is particularly important for communication between cancer and stromal cells, and is required for generating a tumour-supportive microenvironment. PMID- 29693686 TI - Trithiazolyl-1,3,5-triazines bearing decyloxybenzene moieties: synthesis, photophysical and electrochemical properties, and self-assembly behavior. AB - We report the synthesis, photophysical properties, redox characteristics, and self-assembly behavior of disk-shaped trithiazolyl-1,3,5-triazines that bear decyloxybenzene moieties. These compounds were synthesized by a Migita-Kosugi Stille coupling reaction of 1,3,5-trichlorotriazine with three different tributyltin(thiazoles) as the key step. The structure-property relationships, namely the effects of the incorporation of thiazole units into the triazine unit, the conjugation connectivity between the thiazole and triazine units, and the insertion of ethynylene spacers between the thiazole and decyloxybenzene moieties on the properties of the trithiazolyl-1,3,5-triazines were comprehensively investigated. Binding of the triazine core at the 5-position of the thiazole moieties effectively extended the pi-conjugation and afforded high fluorescence quantum yields. The ethynylene spacers substantially lowered the LUMO level relative to the HOMO level. The prepared trithiazolyl-1,3,5-triazines self assembled in solution, and the introduction of thiazole units at the 5-position enhanced this behavior. Detailed thermodynamic studies on the self-association behavior were conducted, and the formation of self-assembled 1D clusters is disclosed. PMID- 29693687 TI - Electrolyte solutions at heterogeneously charged substrates. AB - The influence of a chemically or electrically heterogeneous distribution of interaction sites at a planar substrate on the number density of an adjacent fluid is studied by means of classical density functional theory (DFT). In the case of electrolyte solutions the effect of this heterogeneity is particularly long ranged, because the corresponding relevant length scale is set by the Debye length which is large compared to molecular sizes. The DFT used here takes the solvent particles explicitly into account and thus captures phenomena, inter alia, due to ion-solvent coupling. The present approach provides closed analytic expressions describing the influence of chemically and electrically nonuniform walls. The analysis of isolated delta-like interactions, isolated interaction patches, and hexagonal periodic distributions of interaction sites reveals a sensitive dependence of the fluid density profiles on the type of the interaction, as well as on the size and the lateral distribution of the interaction sites. PMID- 29693688 TI - Facile synthesis of substituted diaryl sulfones via a [3 + 3] benzannulation strategy. AB - A base-mediated [3 + 3] benzannulation strategy for the conversion of 1,3 bis(sulfonyl)propenes and beta,gamma-unsaturated alpha-ketoesters to diaryl sulfones has been developed. This method provides facile, metal-free and efficient access to highly substituted diaryl sulfones in good to excellent yields. In addition, the sulfonyl group could be easily removed or converted to other functional groups via an organostannane intermediate. PMID- 29693693 TI - Synthesis of the [7-5-5] tricyclic core of Daphniphyllum alkaloids. AB - The [7-5-5] tricyclic core of the Daphniphyllum alkaloids was constructed, featuring a Claisen-Ireland rearrangement to install the two contiguous stereogenic centers, E1cB elimination to form the tetrasubstituted C-C double bond, and a 2,3-Wittig rearrangement to construct the quaternary carbon. Ring closing metathesis and an intramolecular carbonyl ene reaction were employed for construction of the requisite ring system. PMID- 29693690 TI - Glycosyl nitrates in synthesis: streamlined access to glucopyranose building blocks differentiated at C-2. AB - In an attempt to refine a CAN-mediated synthesis of 1,3,4,6-tetra-O-acetyl-alpha d-glucopyranose (2-OH glucose) we unexpectedly discovered that this reaction proceeds via the intermediacy of glycosyl nitrates. Improved mechanistic understanding of this reaction led to the development of a more versatile synthesis of 2-OH glucose from a variety of precursors. Also demonstrated is the conversion of 2-OH glucose into a variety of building blocks differentially protected at C-2, a position that is generally hard to protect regioselectively in the glucopyranose series. PMID- 29693694 TI - Flocking transitions in confluent tissues. AB - Collective cell migration in dense tissues underlies important biological processes, such as embryonic development, wound healing and cancer invasion. While many aspects of single cell movements are now well established, the mechanisms leading to displacements of cohesive cell groups are still poorly understood. To elucidate the emergence of collective migration in mechanosensitive cells, we examine a self-propelled Voronoi (SPV) model of confluent tissues with an orientational feedback that aligns a cell's polarization with its local migration velocity. While shape and motility are known to regulate a density-independent liquid-solid transition in tissues, we find that aligning interactions facilitate collective motion and promote solidification, with transitions that can be predicted by extending statistical physics tools such as effective temperature to this far-from-equilibrium system. In addition to accounting for recent experimental observations obtained with epithelial monolayers, our model predicts structural and dynamical signatures of flocking, which may serve as gateway to a more quantitative characterization of collective motility. PMID- 29693695 TI - Rheological behavior and mechanism of pH-responsive wormlike micelle variations induced by isomers of phthalic acid. AB - Responsive wormlike micelles (WLMs) constructed by different carboxylic acids are fascinating. However, it is unknown how the position of the carboxylic groups alters the stimuli-response of wormlike micellar systems. Herein, three pH responsive WLMs based on Gemini-like surfactants (named o-EAPA, m-EAPA, and p EAPA) were formed and studied through the complexation of N-erucamidopropyl-N,N dimethylamine (UC22AMPM) and o-phthalic acid (o-PA), m-phthalic acid (m-PA), or p phthalic acid (p-PA) at the molar ratio of 2 : 1. The viscoelasticity, phase behavior and aggregate microstructure were separately explored by rheological, appearance observation and cryo-TEM methods. The results show that all phthalic acids can protonate UC22AMPM, thereby forming WLMs. However, with the shorter spacer distance between two carboxyl groups in phthalic acid, o-EAPA exhibits the longer length scale of aggregates and a more efficient thickening ability compared to the other two systems. Similar results in the N,N-dimethyl oleoaminde propylamine (DOAPA) and o-PA, m-PA, and p-PA systems further verify the applicability of this mechanism. Furthermore, the phthalic acid based WLMs are found to exhibit intriguing reversible pH-responsive behaviors, which include promptly switching between a high elastic system and a low viscosity fluid by pH control. The o-EAPA system possesses a larger viscosity maximum, which produces more precipitous viscosity changes as the pH varies. This study is beneficial for the formation of pH-responsive WLMs and to determine their advantages for applications. PMID- 29693696 TI - Aggressive Rare T-cell Lymphomas with Manifestation in the Skin: A Monocentric Cross-sectional Case Study. AB - Rare T- or NK-cell lymphomas with cutaneous manifestation may display a highly aggressive clinical course and major diagnostic/therapeutic challenges. This report describes our experiences with different lymphomas of this rare category and the therapeutic options used. This retrospective, descriptive, monocentric, cross-sectional case study, identified 4 rare aggressive T-/NK-cell lymphomas with manifestation in the skin, which were diagnosed in a tertiary care centre over a period of 4 years. Two patients had an Epstein-Barr virus-associated extranodal NK/T-cell lymphoma and 2 patients had a primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma. Concomitant extracutaneous involvement was observed in 2 of all 4 patients. Two patients had fulminant disease progression and resistance to chemotherapy. Two patients underwent allogeneic haematopoietic stem cell transplantation, which resulted in one complete remission and one partial remission. This report emphasizes the importance of an early diagnostic work-up and a prompt aggressive therapeutic approach. PMID- 29693697 TI - Identification of Antibacterial Components in Human Hair Shafts. PMID- 29693698 TI - Eosinophils are a Major Source of Interleukin-31 in Bullous Pemphigoid. AB - Bullous pemphigoid (BP) is characterized by substantial skin and blood eosinophilia as well as intensive pruritus. Since the pruritogenic cytokine interleukin (IL)-31 is increased in inflammatory skin diseases the aim of this study was to determine whether IL-31 plays a role in BP. Using immunofluorescence, IL-31 expression was analysed in eosinophils derived from blister fluids and skin from patients with BP and IL-31 levels in blister fluids, serum and culture supernatants were determined by enzyme-linked immunoassay (ELISA). High levels of IL-31 expression were observed in BP blister fluids, but they were only marginally elevated in BP serum compared with healthy controls. Eosinophils from either BP blister fluids or skin biopsies showed strong expression of IL-31. Furthermore, peripheral blood eosinophils from patients with BP, but not healthy controls, released high levels of IL-31, reflecting those in blister fluids. In conclusion, eosinophils are a major source of IL-31 in BP and this cytokine may contribute to itch in patients with BP. PMID- 29693699 TI - Oxidative and cytotoxic stress induced by inorganic granular and fibrous particles. AB - The hazards of granular and fibrous particles have been associated with the generation of reactive oxygen species (ROS), which in turn is often associated with physicochemical properties exhibited by these particles. In the present study, the ability of various types of fibrous and granular dusts to generate oxidative stress, and their cytotoxicity, was investigated. Biopersistent granular dusts employed in the present study included micro- and nanosized titanium dioxide with rutile or anatase crystal structure modifications. Additionally, glass fibres, chrysotile and crocidolite asbestos representative of fibrous dust were selected. Detailed characterisation of particles was performed using scanning electron microscopy, and the effect of exposure to these particles on cell viability and intracellular ROS generation was assessed by PrestoBlue and 2',7'-dichlorofluorescein assays, respectively. A549 human lung epithelial adenocarcinoma cells were exposed to increasing concentrations (0.1-10 ug/cm2) of particles and fibres for 24 h. Subsequently, the gene expression of X-linked inhibitor of apoptosis (XIAP), superoxide dismutase (SOD)1 and SOD2 were analysed by reverse transcription-quantitative polymerase chain reaction. All investigated granular particles induce ROS production in A549 lung carcinoma cells within 24 h. Hematite increased ROS production in a dose-dependent manner. A concentration of >1 ug/cm2 TiO2 na with its disordered surface, demonstrated the greatest ability to generate ROS. Therefore, the crystalline surface structure of the particle may be considered as a determinant of the extent of ROS induction by the particle. Fibrous particle compared with granular particles were associated with a lower ability to generate ROS. Glass fibres did not significantly increase ROS production in A549 cells, but elevated gene expression of SOD2 was observed. The results demonstrated that in general, the ability of particles to generate ROS depends on their number and crystal phase. Therefore, the present study helps to understand the cause of particle toxicity. PMID- 29693700 TI - Silencing activating transcription factor 2 promotes the anticancer activity of sorafenib in hepatocellular carcinoma cells. AB - The present study aimed to investigate the anticancer effect of sorafenib combined with silencing of activating transcription factor 2 (ATF2) in hepatocellular carcinoma (HCC) cells and to assess the underlying molecular mechanisms. Huh-7 HCC cell line was selected for the present study. Small interfering RNA (siRNA)-ATF2 sequence was constructed to silence ATF2 expression. The experiment was divided into 6 groups: i) Control; ii) vector; iii) sorafenib (6.8 uM); iv) vector+sorafenib; v) siRNA-ATF2; and vi) siRNA-ATF2+sorafenib groups. Cell proliferation, apoptosis, migration and invasion were detected following treatments with sorafenib and/or ATF2 silencing. Additionally, expression of tumor necrosis factor (TNF)-alpha and c-Jun N-terminal kinase 3 (JNK3) was detected using reverse transcription-quantitative polymerase chain reaction and western blotting. The current findings revealed that siRNA-ATF2 significantly reduced ATF2 expression. Cell proliferation, migration and invasion abilities in the sorafenib and siRNA-ATF2 groups were significantly reduced compared with the control group (P<0.05). Apoptotic rate in the sorafenib and siRNA-ATF2 groups was significantly increased compared with the control group (P<0.05). The mRNA and protein expression levels of ATF2 in the sorafenib or siRNA-ATF2 groups was significantly reduced when compared with control group. The phosphorylation of ATF2 was also reduced following sorafenib treatment or ATF2 silence. Although JNK3 mRNA expression level was not affected, the phosphorylation level of JNK3 was significantly promoted following sorafenib treatment or ATF2 silencing. Additionally, TNF-alpha mRNA and protein expression levels were increased following sorafenib treatment or ATF2 silencing. It is of note that siRNA-ATF2 treatment promoted the anticancer activity of sorafenib in Huh-7 cells. Additionally, siRNA-ATF2+sorafenib treatment combined additionally promoted TNF-alpha expression and phosphorylation of JNK3. Combined siRNA-ATF2 and sorafenib treatment had a greater anticancer effect compared with sorafenib or ATF2 silencing alone. The possible mechanism involved in the anticancer effect of sorafenib and ATF2 silencing may be associated with the activation of the TNF alpha/JNK3 signaling pathway. PMID- 29693701 TI - Cell-specific and roasting-dependent regulation of the Keap1/Nrf2 pathway by coffee extracts. AB - Coffee is a popular beverage that contains various bioactive compounds. However, its molecular mechanism of action is not fully elucidated. In this context, two previously characterized coffee extracts, a lightly roasted and the corresponding green one, were investigated for their effect on nuclear factor erythroid 2 related factor 2 (Nrf2) target gene expression in myoblasts and endothelial cells using quantitative PCR. The tested concentrations were non-cytotoxic and led to improved redox cell status, as was evident by increased reduced glutathione (GSH) levels. In both cell lines, the roasted extract upregulated gene expression more readily than its green counterpart leading to increased NAD(P)H quinone dehydrogenase 1 and gamma-glutamyl cysteine ligase catalytic subunit, among others. The green extract had a mixed effect on the endothelial cells, while, as regards the myoblasts it caused the downregulation of some Nrf-target genes. Therefore, a potential dose- and roasting-dependent mechanism is proposed in the current study, accounting for coffee's antioxidant activity. PMID- 29693702 TI - Glycine and succinic acid are effective indicators of the suppression of epithelial-mesenchymal transition by fucoxanthinol in colorectal cancer stem-like cells. AB - Fucoxanthinol (FxOH) is a strong anticancer metabolite of fucoxanthin that accumulates in abundance in edible brown algae and promises human health benefits. FxOH has been shown to suppress tumorigenicity and sphere formation in human colorectal cancer stem cell (CCSC)-like spheroids (colonospheres, Csps). In the present study, we aimed to clarify the inhibitory activity of FxOH on epithelial-mesenchymal transition (EMT), which is essential for cancer recurrence and distant metastasis, and to identify intracellular low-molecular-weight metabolites that may be useful for evaluating the cellular effects of FxOH on CCSCs. FxOH significantly suppressed sphere-forming activity, migration and invasion in a dose-dependent manner. In addition, treatment with 50 umol/l FxOH suppressed N-cadherin and vimentin expression and the activation of integrin signaling linked to EMT suppression by western blot analysis. MAPK signaling and STAT signaling related to cell growth and apoptosis in Csps derived from human CRC HT-29 and HCT116 cells were also altered. According to our metabolite profiling by GC-MS analysis, reduced glycine and succinic acid levels were correlated with EMT suppression and apoptosis induction in Csps. Our data indicate that simple amino acids such as glycine and succinic acid may be good prognostic indicators of physiological changes to CCSCs induced by FxOH treatment. PMID- 29693703 TI - The role of VEGF in the diagnosis and treatment of malignant pleural effusion in patients with non-small cell lung cancer (Review). AB - Malignant pleural effusion (MPE) is a severe medical condition, which can result in breathlessness, pain, cachexia and reduced physical activity. It can occur in almost all types of malignant tumors; however, lung cancer is the most common cause of MPE, accounting for ~1/3 of clinical cases. Although there are numerous therapeutic approaches currently available for the treatment of MPE, none are fully effective and the majority can only alleviate the symptoms of the patients. Vascular endothelial growth factor (VEGF) has now been recognized as one of the most important regulatory factors in tumor angiogenesis, which participates in the entire process of tumor growth through its function to stimulate tumor angiogenesis, activate host vascular endothelial cells and promote malignant proliferation. Novel drugs targeting VEGF, including endostar and bevacizumab, have been developed and approved for the treatment of various tumors. Data from recent clinical studies have demonstrated that drugs targeting VEGF are effective and safe for the clinical management of MPE. Therefore, VEGF-targeting represents a promising novel strategy for the diagnosis and treatment of MPE. The present review summarized recent advances in the role of VEGF in the pathogenesis, diagnosis and clinical management of MPE in patients with non-small cell lung cancer. PMID- 29693704 TI - LncSOX4 serves an oncogenic role in the tumorigenesis of epithelial ovarian cancer by promoting cell proliferation and inhibiting apoptosis. AB - Epithelial ovarian cancer is one of the primary causes of gynecological cancer mortality. Increasing evidence has suggested that long non-coding RNAs (lncRNAs) may serve a pivotal role in cancer development. To determine whether Lnc SRY-box 4 (SOX4), an lncRNA, promotes the self-renewal of liver tumor cells and contributes to the development of epithelial ovarian cancer, the present study investigated the expression of LncSOX4 in clinical epithelial ovarian cancer tissues and non-cancer controls by reverse transcription-quantitative polymerase chain reaction analysis. In addition, siRNA targeting LncSOX4 was designed and transfected into epithelial ovarian cancer cells to further assess the effect of knocking out LncSOX4 on cellular apoptosis, cell viability, proliferation and the cell cycle. The results demonstrated that the LncSOX4 expression level was significantly upregulated in epithelial ovarian cancer tissues (3.98 vs. 1.71, P<0.001). Silencing LncSOX4 in the SKOV3 and OVCAR3 cell lines significantly impaired cell proliferation (P<0.001). Cell cycle assays revealed that the proportion of cells in the G0/G1 phase increased significantly, whereas those in the S phase and G2/M phase decreased. Apoptosis rate additionally increased following knockdown of LncSOX4 in the two cell lines. Furthermore, it was observed that an increased LncSOX4 expression level was positively associated with larger tumor sizes, more advanced tumor grade and more distant metastases. PMID- 29693705 TI - Effect of treadmill exercise on spatial navigation impairment associated with cerebellar Purkinje cell loss following chronic cerebral hypoperfusion. AB - In addition to roles in motor coordination, the cerebellum is also associated with cognitive function. The aim of the present study was to investigate the effect of treadmill exercise on spatial navigation deficit induced by chronic cerebral hypoperfusion (CCH). Furthermore, whether decreased loss of Purkinje cells, which contain the calcium-binding protein in the posterior lobe of the cerebellum, attenuates the spatial navigation deficit induced by CCH was also investigated. Wistar rats were randomly divided into three groups: Sham group, bilateral common carotid arteries occlusion (BCCAO) group and a BCCAO + exercise (Ex) group. The rats in the BCCAO + Ex group ran on a treadmill for 30 min once a day for 8 weeks, starting at 4 weeks post-birth. CCH was induced by performing BCCAO at 12 weeks post-birth. The Morris water maze test was performed to determine the spatial navigation function of the rats. To investigate the histological features of the cerebellum in all of the experimental groups post treatment, terminal deoxynucleotidyl transferase dUTP nick end labeling staining, as well as immunohistochemical analysis revealing the expression of calbindin, parvalbumin, glial fibrillary acidic protein, ionized calcium-binding adaptor molecule 1 and caspase-3, was performed. The results of the present study revealed that treadmill exercise improved spatial navigation, decreased the expression of reactive astrocytes and microglial cells, and decreased apoptotic rates in the cerebellar vermis post-CCH. Treadmill exercise also attenuated the loss of Purkinje cells following CCH. The number of Purkinje cells was revealed to be negatively correlated with spatial navigation performance. These results indicate that treadmill exercise may attenuate spatial navigation impairment via inhibition of Purkinje cell loss in the posterior lobe of the cerebellum following CCH. Therefore, treadmill exercise may represent a therapeutic strategy for the treatment of patients with spatial navigation impairment following CCH. PMID- 29693706 TI - Effects of triptolide on the expression of MHC II in microglia in kainic acid induced epilepsy. AB - The purpose of the present study was to determine whether triptolide (T10) had any effect on major histocompatibility complex class II (MHC II) expression in kainic acid (KA)-activated microglia, and to investigate the underlying molecular mechanism. BV-2 microglia were pretreated with T10 prior to activation with KA. The expression level of MHC II and class II transactivator (CIITA) mRNA was determined via reverse transcription-polymerase chain reaction. The expression of MHC II, CIITA and the phosphorylation level of c-Jun and proto-oncogene c-Fos (c Fos) was determined by western blotting. The protein expression level of MHC II was determined by immunocytochemistry. It was observed that the mRNA and protein levels of MHC II and CIITA were increased in KA-activated BV-2 microglia, and that this increase was almost completely eliminated by T10. AP-1 is a family of homodimers or heterodimers, composed of Jun family and Fos family proteins. Sequence analysis revealed an AP-1 DNA binding site in the promoter of CIITA. The phosphorylation of c-Jun and c-Fos was increased in KA-activated microglia, while T10 was able to suppress the phosphorylation of c-Jun and c-Fos in KA-activated microglia. These data suggested that T10 may exert suppressive effects on MHC II expression in KA-activated microglia, and that the mechanism may involve the regulation of AP-1 activity. PMID- 29693707 TI - c-Jun suppresses the expression of WNT inhibitory factor 1 through transcriptional regulation and interaction with DNA methyltransferase 1 in gallbladder cancer. AB - WNT inhibitory factor 1 (WIF-1) is involved in the tumorigenicity and progression of several types of tumor, which has been attributed to aberrant hypermethylation of its promoter. However, the role of WIF-1 in the pathogenesis of gallbladder cancer (GBC) remains to be fully elucidated, and the data available are insufficient to identify the upstream molecular mechanisms involved. In the present study, the methylation status of the WIF-1 promoter was investigated using methylation-specific polymerase chain reaction (PCR) and bisulfate sequencing PCR in GBC cells. Immunohistochemistry, reverse transcription quantitative PCR and western blotting were used to analyze the expression of WIF 1 and c-Jun. In addition, a co-immunoprecipitation assay was designed to determine the DNA methyltransferase that was implicated in WIF-1 methylation. The results revealed that the expression of WIF-1 was low in GBC, and that this was caused by aberrant DNA hypermethylation. However, there were no significant correlations between the expression of WIF-1 and certain key clinicopathological characteristics of GCB. Subsequently, a negative correlation was found between the protein expression of c-Jun and WIF-1 in 50 GBC specimens using immunohistochemistry. The demethylation and re-expression of WIF-1 was observed when the expression of c-Jun was silenced. Finally, it was found that the knockdown of c-Jun downregulated the expression of DNA methyltransferase 1 (DNMT1) and that c-Jun interacted with DNMT1. Taken together, the present study suggested that c-Jun suppressed the expression of WIF-1 through transcriptional regulation and interaction with DNMT1 in GBC. These findings provide an alternative pathogenesis of GBC, which may be promising as a novel reference for early diagnosis or future treatment. PMID- 29693708 TI - Diazoxide inhibits of ER stress-mediated apoptosis during oxygen-glucose deprivation in vitro and cerebral ischemia-reperfusion in vivo. AB - Neuroprotective strategies using diazoxide (DZX) have been demonstrated to limit ischemia/reperfusion (I/R)-induced injury and cell apoptosis. In type 2 diabetes mellitus, DZX has been reported to improve beta-cell function and reduce their apoptosis, through suppressing endoplasmic reticulum (ER) stress. However, the effects of DZX on ER stress during I/R-induced neuronal apoptosis in the hippocampus remains to be elucidated. In the present study, pretreatment of hippocampal neurons with DZX was revealed to inhibit oxygen-glucose deprivation (OGD)-stimulated apoptosis in vitro and to alleviate I/R-induced hippocampal injury and behavioral deficits in rats in vivo. Furthermore, OGD and I/R were demonstrated to induce ER stress via upregulating the expression of ER stress associated proteins, including C/EBP homologous protein, 78 kDa glucose-regulated protein and caspase-12, whereas the exogenous administration of DZX effectively downregulated ER stress-associated protein expression following OGD and I/R. In addition, DZX was revealed to significantly increase the protein expression of B cell lymphoma (Bcl)-2 and suppress the expression of caspase-3 and Bcl-2 associated X protein. These findings suggested that DZX may protect cells against apoptosis via regulating the expression of ER stress-associated proteins in vitro and in vivo, thus enhancing the survival of hippocampal cells. The present results suggested a novel mechanism that may underlie the protective effect of DZX administration in the central nervous system. PMID- 29693709 TI - Identification of differential expression lncRNAs in gastric cancer using transcriptome sequencing and bioinformatics analyses. AB - The current study aimed to identify novel long non-coding RNAs (lncRNAs) associated with gastric cancer (GC). Transcriptome sequencing of the lncRNAs and mRNAs from GC tissues and normal adjacent tissues was performed. The data were analyzed using bioinformatics analysis, specifically analysis of differentially expressed lncRNAs and mRNA, target gene prediction and functional enrichment analysis. A total of 1,181 differentially expressed mRNA and 390 differentially expressed lncRNAs were identified. The targets of upregulated lncRNAs were significantly enriched in functions associated with collagen fibril organization, whereas the downregulated lncRNA were significantly associated with ion transmembrane transport and regulation of membrane potential. A total of 7 lncRNAs were verified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Following RT-qPCR validation, AC016735.2, AP001626.1, RP11 400N13.3 and RP11-243M5.2 were considered to be consistent with the prediction of the bioinformatics analysis. Transcriptome sequencing and RT-qPCR experiments identified 4 lncRNAs, including AC016735.2, AP001626.1, RP11-400N13.3 and RP11 243M5.2 to have an important role in the carcinogenesis of GC. PMID- 29693710 TI - A review on heme oxygenase-1 induction: is it a necessary evil. AB - Heme oxygenase-1 (HO-1) is considered to be the main protein in diseases arising as a result of oxidative and inflammatory insults. Tremendous research has been carried out on HO-1 since years, pertaining its cytoprotective effect against oxidative injury and other cellular stresses. HO-1, by regulating intracellular levels of pro-oxidant heme, or by other benefits of its by-products such as carbon monoxide (CO) and biliverdin (BV) had become an important candidate protein to be up-regulated to combat diverse stressful events. Although the beneficial effects of HO-1 induction have been reported in a number of cells and tissues, a growing body of evidence indicates that this increased HO-1 expression may lead to the progression of several diseases such as neurodegeneration, carcinogenesis. But it is not clear, what accounts for the increased expression of HO-1 in cells and tissues. The observed friendly role of HO-1 in a wide range of stress conditions since times is now doubtful. Therefore, more studies are needed to elucidate the exact role of HO-1 in various stressful events. Being more concise, elucidating the effect of HO-1 up-regulation on critical genes involved in particular diseases such as cancer will help to a larger extent to comprehend the exact role of HO-1. This review will assist in understanding the dual role (protective and detrimental) of HO-1 and the signaling pathway involved and will help in unraveling the doubtful role of HO-1 induction. PMID- 29693711 TI - Telocytes in skeletal, cardiac and smooth muscle interstitium: morphological and functional aspects. AB - Telocytes (TCs) represent a new distinct type of cells found in the stromal compartment of many organs, including the skeletal, cardiac and smooth muscles. TCs are morphologically defined as interstitial cells with a small cellular body from which arise very long (up to hundreds of micrometers) and thin moniliform processes (named telopodes) featuring the alternation of slender segments (called podomers) and small dilated portions (called podoms) accommodating some organelles. Although these stromal cells are mainly characterized by their ultrastructural traits, in the last few years TCs have been increasingly studied for their immunophenotypes, microRNA profiles, and gene expression and proteomic signatures. By their long-distance spreading telopodes, TCs build a three dimensional network throughout the whole stromal space and communicate with each other and neighboring cells through homocellular and heterocellular junctions, respectively. Moreover, increasing evidence suggests that TCs may exert paracrine functions being able to transfer genetic information and signaling molecules to other cells via the release of different types of extracellular vesicles. A close relationship between TCs and stem/progenitor cell niches has also been described in several organs. However, the specific functions of TCs located in the muscle interstitium remain to be unraveled. Here, we review the morphological and possible functional aspects of TCs in skeletal, cardiac and smooth muscle tissues. The potential involvement of TCs in muscle tissue pathological changes and future possibilities for targeting TCs as a novel promising therapeutic strategy to foster muscle tissue regeneration and repair are also discussed. PMID- 29693712 TI - Effects of Rolapitant Administered Intravenously on the Pharmacokinetics of a Modified Cooperstown Cocktail (Midazolam, Omeprazole, Warfarin, Caffeine, and Dextromethorphan) in Healthy Subjects. AB - Rolapitant is a selective, long-acting neurokinin-1 receptor antagonist, approved in the United States and Europe for prevention of delayed chemotherapy-induced nausea and vomiting in adults. This open-label study evaluated the effects of a new intravenous formulation of rolapitant on cytochrome P450 (CYP) enzyme (CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2D6) activity. On days 1 and 14, 36 healthy volunteers received a modified Cooperstown cocktail (midazolam 3 mg [CYP3A substrate], caffeine 200 mg [CYP1A2 substrate], S-warfarin 10 mg [CYP2C9 substrate] + vitamin K 10 mg, omeprazole 40 mg [CYP2C19 substrate], and dextromethorphan 30 mg [CYP2D6 substrate]). On day 7, subjects received the modified Cooperstown cocktail after 166.5-mg rolapitant infusion. On days 21, 28, and 35, subjects received oral dextromethorphan. Maximum plasma concentration (Cmax ) and area under the plasma concentration-time curve (AUC0-last ) of probe drugs post- vs pre-rolapitant administration were assessed using geometric least squares mean ratios (GMRs) with 90%CIs. The 90%CIs of the GMRs were within the 0.80-1.25 no-effect limits for caffeine and S-warfarin Cmax and AUC0-last . For midazolam Cmax and AUC0-last and omeprazole Cmax , the 90%CIs of the GMRs were marginally outside these limits. Intravenous rolapitant coadministration increased dextromethorphan exposure, peaking 14 days post-rolapitant administration (GMRs: Cmax , 2.74, 90%CI 2.21-3.40; AUC0-last , 3.36, 90%CI 2.74 4.13). Intravenous rolapitant 166.5 mg and probe drugs were well tolerated when coadministered. These data suggest that intravenous rolapitant is not an inhibitor of CYP3A, CYP2C9, CYP2C19, or CYP1A2 but is a moderate inhibitor of CYP2D6. PMID- 29693713 TI - Low NR3C2 levels correlate with aggressive features and poor prognosis in non distant metastatic clear-cell renal cell carcinoma. AB - NR3C2 has previously been described as a tumor suppressor gene in several cancers; however the prognostic significance and biological function of NR3C2 in patients with non-metastatic clear cell renal cell carcinoma (ccRCC) remain largely unclear. The prognostic value of NR3C2 expression was evaluated using data from The Cancer Genome Atlas (TCGA) and 181 patients with non-metastatic ccRCC undergoing nephrectomy in our center. Predictive nomograms were generated and identified independent prognosticators to assess ccRCC patient overall survival (OS) and progression free survival (PFS) at 1, 5, and 8 years. The functional involvement of NR3C2 in RCC was examined in both in vitro and in vivo models upon overexpression of NR3C2. NR3C2 was found to be downregulated in tumor tissues and was correlated with several clinicopathological parameters, including the T status (p <0.001) and histological Fuhrman grade (p = 0.002). Both Cox regression analysis and Kaplan-Meier survival curves showed that low NR3C2 expression correlated with poor OS (HR = 2.21, p = 0.014) and PFS (HR = 1.71, p = 0.051). The incorporation of NR3C2 status into the T stage, UISS, or SSIGN scores helps to refine individual risk stratification. The newly built nomograms involving NR3C2 expression could better predict OS and PFS. Overexpression of NR3C2 inhibited RCC cell proliferation, colony formation, invasion, migration, and vasculogenic mimicry in vitro and reduced the growth of RCC xenografts in vivo. Together, these results suggest that NR3C2 may serve as a potential prognostic factor in non-metastatic ccRCC patients after nephrectomy and is involved in RCC oncogenesis. PMID- 29693714 TI - Optimization of the method of the content-containing interaction evaluation for cosmetic products by gas chromatography-mass spectrometry. AB - In July 2013, the European Regulation (EC) No 1223/2009 came into effect in order to secure cosmetic products. The content-containing interaction between the packaging and the product must be considered for the safety assessment. Indeed, some compounds are able to migrate from the packaging to the product and may be harmful to the consumer health. This is why a first test was established by EXPERTOX laboratory in 2012 to deal with this new regulation. A new analytical method was developed and validated for the quantification of 23 substances able to migrate from the packaging to the product. It was applied on a plastic packaging with the five simulants of migration. To evaluate the content containing interaction, a gas chromatography-mass spectrometry method was developed and validated. Liquid-liquid extraction was used to extract contaminants (thirteen phthalates and ten substances of very high concern) from migration simulants. Calibration curves showed good linearity regression from 2 to 50 MUg mL-1 for nineteen molecules and from 5 to 45 MUg mL-1 for the others. The limits of quantification were respectively 2 and 5 MUg mL-1 . The accuracy, precision, repeatability of the analytical method and extraction yields were acceptable. No molecule was found in simulants of migration, so the potential contaminants present in the packaging did not migrate. A gas chromatography-mass spectrometry method and liquid-liquid extraction were validated for 23 molecules and can be used for the evaluation of the content-containing interaction of cosmetic products. Both quantification and extraction procedures are more robust and faster than previous method. PMID- 29693715 TI - Pharmacokinetics, Safety, and Tolerability of Oral Semaglutide in Subjects With Hepatic Impairment. AB - Semaglutide is a human glucagon-like peptide-1 analog that has been co-formulated with the absorption enhancer, sodium N-(8-[2-hydroxybenzoyl] amino) caprylate, for oral administration. This trial (NCT02016911) investigated whether hepatic impairment affects the pharmacokinetics, safety, and tolerability of oral semaglutide. Subjects were classified into groups: normal hepatic function (n = 24), and mild (n = 12), moderate (n = 12), or severe (n = 8) hepatic impairment according to Child-Pugh criteria, and received once-daily oral semaglutide (5 mg for 5 days followed by 10 mg for 5 days). Semaglutide plasma concentrations were measured during dosing and for up to 21 days post-last dose. Area under the semaglutide plasma concentration-time curve from 0-24 hours after the 10th dose (primary end point) and maximum semaglutide concentration after the 10th dose appeared similar across hepatic function groups. Similarly, there was no apparent effect of hepatic impairment on time to maximum semaglutide concentration (median range 1.0-1.5 hours) or half-life (geometric mean range 142-156 hours). No safety concerns were identified in subjects with hepatic impairment receiving semaglutide. Reported adverse events were in line with those observed for other glucagon-like peptide-1 receptor agonists. There was no apparent effect of hepatic impairment on the pharmacokinetics, safety, and tolerability of oral semaglutide. The results of this trial suggest that dose adjustment of oral semaglutide is not warranted in subjects with hepatic impairment. PMID- 29693716 TI - Parental Divorce and Family History of Alcohol Disorder: Associations with Young Adults' Alcohol Problems, Marijuana Use, and Interpersonal Relations. AB - BACKGROUND: This study used prospective data from 706 young adults to evaluate the impact of parental divorce and family history of alcoholism (FH+) on the outcomes of offspring alcohol problems, marijuana use, and interpersonal relationships with parents. METHODS: Assessments of parental divorce were based on parent reports, and young adult outcomes were collected from an offspring cohort (n = 706; X age = 33.25 years; females = 53%) via computer-based individual interviews (CAPI and ACASI). Family history of alcohol disorders for parents was based on assessments by mothers, fathers, and young adults. RESULTS: Parental divorce significantly predicted marijuana use but not alcohol problems. Maternal, but not paternal, alcoholism also significantly predicted marijuana use. Two-way interactions indicated that sex moderated several of the relationships. For example, among those with divorced parents, daughters reported higher levels of conflict with fathers than sons, and sons reported lower levels of maternal support than daughters. Paternal alcoholism was also associated with higher levels of alcohol problems among sons relative to daughters. There was also a significant 2-way interaction between divorce status and maternal alcoholism indicating that young adults who experienced both maternal alcoholism and parental divorce had the highest levels of marijuana use. CONCLUSIONS: These findings highlight the role that parental divorce and FH+ have on alcohol problems, marijuana use, and interpersonal relationships in young adulthood, and how sex may moderate some of these more nuanced relationships. PMID- 29693717 TI - Left ventricular end-diastolic volume predicts exercise capacity in patients with a normal ejection fraction. AB - BACKGROUND: Exercise capacity is a powerful predictor of all-cause mortality. The duration of exercise with treadmill stress testing is an important prognostic marker in both healthy subjects and patients with cardiovascular disease. Left ventricular (LV) structure is known to adapt to sustained changes in level of physical activity. HYPOTHESIS: Poor exercise capacity in patients with a preserved LV ejection fraction (LVEF) should be reflected in smaller LV dimensions, and a normal exercise capacity should be associated with larger LV dimensions, irrespective of comorbidities. METHODS: This hypothesis was first tested in a cross-sectional analysis of 201 patients with normal chamber dimensions and preserved LVEF who underwent a clinically indicated treadmill stress echocardiogram using the Bruce protocol (derivation cohort). The best LV dimensional predictor of exercise capacity was then tested in 1285 patients who had a Bruce-protocol treadmill exercise stress test and a separate transthoracic echocardiogram (validation cohort). RESULTS: In the derivation cohort, there was a strong positive relationship between exercise duration and LV end-diastolic volume deciles (r 2 = 0.85; P < 0.001). Regression analyses of several LV dimensional parameters revealed that the body surface area-based LV end-diastolic volume index was best suited to predict exercise capacity (P < 0.0001). In a large validation cohort, LV end-diastolic volume was confirmed to predict exercise capacity (P < 0.0001). CONCLUSIONS: Among patients referred for outpatient stress echocardiography who have a preserved LVEF and no evidence of myocardial ischemia, we found a strong positive association between LV volume and exercise capacity. PMID- 29693718 TI - Comparison of transabdominal and transvaginal sonography in the diagnosis of placenta previa. AB - PURPOSE: To compare the accuracies of transabdominal sonography (TAS) and transvaginal sonography (TVS) in the diagnosis of placenta previa. METHODS: A prospective, cross-sectional study was conducted at a university hospital. Both TAS and TVS were performed on 81 pregnant women with a suspicion of placenta previa in the third trimester. The final diagnosis was confirmed at delivery. The agreement between the two ultrasound methods and the parameters of each method were calculated. RESULTS: Fifty-eight percent of the women had a placenta previa. The sensitivities of TAS and TVS were 86% (95% CI 78-94%) and 95% (95% CI 91 100%), respectively (p= 0.2). The specificity of both methods was 93% (95 CI 88 99%), and the overall accuracies of TAS and TVS were 89% (95% CI 82-96%) and 94% (95% CI 89-100%), respectively. When TAS was followed by TVS, 23% of the previous diagnoses were changed. The agreement between both methods was good (Kappa value = 0.7, 95%CI 0.55-0.86). CONCLUSIONS: For the diagnosis of placenta previa, TAS showed a high sensitivity and specificity, which were comparable to those of TVS. PMID- 29693719 TI - Smectite for acute infectious diarrhoea in children. AB - BACKGROUND: As mortality secondary to acute infectious diarrhoea has decreased worldwide, the focus shifts to adjuvant therapies to lessen the burden of disease. Smectite, a medicinal clay, could offer a complementary intervention to reduce the duration of diarrhoea. OBJECTIVES: To assess the effects of smectite for treating acute infectious diarrhoea in children. SEARCH METHODS: We searched the Cochrane Infectious Diseases Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Pubmed), Embase (Ovid), LILACS, reference lists from studies and previous reviews, and conference abstracts, up to 27 June 2017. SELECTION CRITERIA: Randomized and quasi-randomized trials comparing smectite to a control group in children aged one month to 18 years old with acute infectious diarrhoea. DATA COLLECTION AND ANALYSIS: Two review authors independently screened abstracts and the full texts for inclusion, extracted data, and assessed risk of bias. Our primary outcomes were duration of diarrhoea and clinical resolution at day 3. We summarized continuous outcomes using mean differences (MD) and dichotomous outcomes using risk ratios (RR), with 95% confidence intervals (CI). Where appropriate, we pooled data in meta-analyses and assessed heterogeneity. We explored publication bias using a funnel plot. MAIN RESULTS: Eighteen trials with 2616 children met our inclusion criteria. Studies were conducted in both ambulatory and in-hospital settings, and in both high income and low- or middle-income countries. Most studies included children with rotavirus infections, and half included breastfed children.Smectite may reduce the duration of diarrhoea by approximately a day (MD -24.38 hours, 95% CI -30.91 to -17.85; 14 studies; 2209 children; low-certainty evidence); may increase clinical resolution at day 3 (risk ratio (RR) 2.10, 95% CI 1.30 to 3.39; 5 trials; 312 children; low-certainty evidence); and may reduce stool output (MD 11.37, 95% CI -21.94 to -0.79; 3 studies; 634 children; low-certainty evidence).We are uncertain whether smectite reduces stool frequency, measured as depositions per day (MD -1.33, 95% CI -2.28 to -0.38; 3 studies; 954 children; very low-certainty evidence). There was no evidence of an effect on need for hospitalization (RR 0.93, 95% CI 0.75 to 1.15; 2 studies; 885 children; low certainty evidence) and need for intravenous rehydration (RR 0.77, 95% CI 0.54 to 1.11; 1 study; 81 children; moderate-certainty evidence). The most frequently reported side effect was constipation, which did not differ between groups (RR 4.71, 95% CI 0.56 to 39.19; 2 studies; 128 children; low-certainty evidence). No deaths or serious adverse effects were reported. AUTHORS' CONCLUSIONS: Based on low-certainty evidence, smectite used as an adjuvant to rehydration therapy may reduce the duration of diarrhoea in children with acute infectious diarrhoea by a day; may increase cure rate by day 3; and may reduce stool output, but has no effect on hospitalization rates or need for intravenous therapy. PMID- 29693720 TI - Inflammatory residual risk: An emerging target to reduce cardiovascular disease? PMID- 29693721 TI - H19 promotes non-small-cell lung cancer (NSCLC) development through STAT3 signaling via sponging miR-17. AB - LncRNAs can exhibit crucial roles in the development of multiple cancers, including non-small cell lung cancer (NSCLC). Currently, we investigated the role of lncRNA H19 in NSCLC. In our study, it was found that H19 was upregulated in A549 and H1299 cells compared to normal lung epithelial BEAS-2B cells. Meanwhile, we observed that miR-17 was downregulated in NSCLC cell lines. Inhibited H19 can suppress the growth, migration, and invasion of NSCLC cells and bioinformatics search was performed to predict the correlation between H19 and miR-17. Overexpression of miR-17 was able to inhibit the progression of NSCLC cells while reversely miR-17 inhibitors reversed this process. In addition, signal transducers and activators of transcription (STAT3), as an mRNA target of miR-17, was presented in our research. Moreover, we discovered that H19 demonstrated its biological functions via regulating miR-17 and STAT3 in vitro. Silencing H19 greatly increased STAT3 expression by sponging miR-19 in vitro. It was hypothesized that H19 may serve as a competing endogenous RNA (ceRNA) to modulate STAT3 by attaching miR-17 in lung cancer. In summary, our findings indicated that H19/miR-17/STAT3 axis participated in NSCLC development. H19 could be regarded as a significant prognostic biomarker in NSCLC progression. PMID- 29693722 TI - A fungal avirulence factor encoded in a highly plastic genomic region triggers partial resistance to septoria tritici blotch. AB - Cultivar-strain specificity in the wheat-Zymoseptoria tritici pathosystem determines the infection outcome and is controlled by resistance genes on the host side, many of which have been identified. On the pathogen side, however, the molecular determinants of specificity remain largely unknown. We used genetic mapping, targeted gene disruption and allele swapping to characterise the recognition of the new avirulence factor Avr3D1. We then combined population genetic and comparative genomic analyses to characterise the evolutionary trajectory of Avr3D1. Avr3D1 is specifically recognised by wheat cultivars harbouring the Stb7 resistance gene, triggering a strong defence response without preventing pathogen infection and reproduction. Avr3D1 resides in a cluster of putative effector genes located in a genome region populated by independent transposable element insertions. The gene was present in all 132 investigated strains and is highly polymorphic, with 30 different protein variants identified. We demonstrated that specific amino acid substitutions in Avr3D1 led to evasion of recognition. These results demonstrate that quantitative resistance and gene for-gene interactions are not mutually exclusive. Localising avirulence genes in highly plastic genomic regions probably facilitates accelerated evolution that enables escape from recognition by resistance proteins. PMID- 29693723 TI - Aqueous and Ethanol Extracts of Daylily Flower (Hemerocallis fulva L.) Protect HUVE Cells Against High Glucose. AB - The content of several phenolic acids and flavonoids in aqueous extract (AE) and ethanol extract (EE) of daylily flower (Hemerocallis fulva L.) was analyzed. The effects of AE or EE at 0.5%, 1%, or 2% in HUVE cells against high glucose-induced cell death, oxidative, and inflammatory damage were examined. Results showed that seven phenolic acids and seven flavonoids could be detected in AE or EE, in the range of 29 to 205 and 41 to 273 mg/100 g, respectively. Compared with the control groups, high glucose raised the activity of caspase-3 and caspase-8; suppressed Bcl-2 mRNA expression and increased Bax mRNA expression; and induced HUVE cells apoptosis. The pretreatments from AE or EE at 1% or 2% reduced caspase 3 activity and Bax mRNA expression, and enhanced cell viability. High glucose decreased glutathione content; stimulated the production of reactive oxygen species, interleukin-6, tumor necrosis factor-alpha, and prostaglandin E2 ; raised the activity of cyclooxygenase-2 and nuclear factor kappa B p50/65 binding; and reduced the activity of glutathione peroxidase, glutathione reductase, and catalase in HUVE cells. AE pretreatments at 1% and 2% reversed these changes. These novel findings suggested that daylily flower was rich in phytochemicals, and could be viewed as a potent functional food against diabetes. PMID- 29693724 TI - Response to "Fish Oil-Containing Lipid Emulsions in Adult Parenteral Nutrition: A Review of the Evidence". PMID- 29693726 TI - Uterotonic agents for preventing postpartum haemorrhage: a network meta-analysis. AB - BACKGROUND: Postpartum haemorrhage (PPH) is the leading cause of maternal mortality worldwide. Prophylactic uterotonic drugs can prevent PPH, and are routinely recommended. There are several uterotonic drugs for preventing PPH but it is still debatable which drug is best. OBJECTIVES: To identify the most effective uterotonic drug(s) to prevent PPH, and generate a ranking according to their effectiveness and side-effect profile. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (1 June 2015), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) for unpublished trial reports (30 June 2015) and reference lists of retrieved studies. SELECTION CRITERIA: All randomised controlled comparisons or cluster trials of effectiveness or side-effects of uterotonic drugs for preventing PPH.Quasi-randomised trials and cross-over trials are not eligible for inclusion in this review. DATA COLLECTION AND ANALYSIS: At least three review authors independently assessed trials for inclusion and risk of bias, extracted data and checked them for accuracy. We estimated the relative effects and rankings for preventing PPH >= 500 mL and PPH >= 1000 mL as primary outcomes. We performed pairwise meta-analyses and network meta-analysis to determine the relative effects and rankings of all available drugs. We stratified our primary outcomes according to mode of birth, prior risk of PPH, healthcare setting, dosage, regimen and route of drug administration, to detect subgroup effects.The absolute risks in the oxytocin are based on meta-analyses of proportions from the studies included in this review and the risks in the intervention groups were based on the assumed risk in the oxytocin group and the relative effects of the interventions. MAIN RESULTS: This network meta-analysis included 140 randomised trials with data from 88,947 women. There are two large ongoing studies. The trials were mostly carried out in hospital settings and recruited women who were predominantly more than 37 weeks of gestation having a vaginal birth. The majority of trials were assessed to have uncertain risk of bias due to poor reporting of study design. This primarily impacted on our confidence in comparisons involving carbetocin trials more than other uterotonics.The three most effective drugs for prevention of PPH >= 500 mL were ergometrine plus oxytocin combination, carbetocin, and misoprostol plus oxytocin combination. These three options were more effective at preventing PPH >= 500 mL compared with oxytocin, the drug currently recommended by the WHO (ergometrine plus oxytocin risk ratio (RR) 0.69 (95% confidence interval (CI) 0.57 to 0.83), moderate quality evidence; carbetocin RR 0.72 (95% CI 0.52 to 1.00), very low-quality evidence; misoprostol plus oxytocin RR 0.73 (95% CI 0.60 to 0.90), moderate quality evidence). Based on these results, about 10.5% women given oxytocin would experience a PPH of >= 500 mL compared with 7.2% given ergometrine plus oxytocin combination, 7.6% given carbetocin, and 7.7% given misoprostol plus oxytocin. Oxytocin was ranked fourth with close to 0% cumulative probability of being ranked in the top three for PPH >= 500 mL.The outcomes and rankings for the outcome of PPH >= 1000 mL were similar to those of PPH >= 500 mL. with the evidence for ergometrine plus oxytocin combination being more effective than oxytocin (RR 0.77 (95% CI 0.61 to 0.95), high-quality evidence) being more certain than that for carbetocin (RR 0.70 (95% CI 0.38 to 1.28), low-quality evidence), or misoprostol plus oxytocin combination (RR 0.90 (95% CI 0.72 to 1.14), moderate-quality evidence)There were no meaningful differences between all drugs for maternal deaths or severe morbidity as these outcomes were so rare in the included randomised trials.Two combination regimens had the poorest rankings for side-effects. Specifically, the ergometrine plus oxytocin combination had the higher risk for vomiting (RR 3.10 (95% CI 2.11 to 4.56), high-quality evidence; 1.9% versus 0.6%) and hypertension [RR 1.77 (95% CI 0.55 to 5.66), low-quality evidence; 1.2% versus 0.7%), while the misoprostol plus oxytocin combination had the higher risk for fever (RR 3.18 (95% CI 2.22 to 4.55), moderate-quality evidence; 11.4% versus 3.6%) when compared with oxytocin. Carbetocin had similar risk for side-effects compared with oxytocin although the quality evidence was very low for vomiting and for fever, and was low for hypertension. AUTHORS' CONCLUSIONS: Ergometrine plus oxytocin combination, carbetocin, and misoprostol plus oxytocin combination were more effective for preventing PPH >= 500 mL than the current standard oxytocin. Ergometrine plus oxytocin combination was more effective for preventing PPH >= 1000 mL than oxytocin. Misoprostol plus oxytocin combination evidence is less consistent and may relate to different routes and doses of misoprostol used in the studies. Carbetocin had the most favourable side effect profile amongst the top three options; however, most carbetocin trials were small and at high risk of bias.Amongst the 11 ongoing studies listed in this review there are two key studies that will inform a future update of this review. The first is a WHO-led multi-centre study comparing the effectiveness of a room temperature stable carbetocin versus oxytocin (administered intramuscularly) for preventing PPH in women having a vaginal birth. The trial includes around 30,000 women from 10 countries. The other is a UK-based trial recruiting more than 6000 women to a three-arm trial comparing carbetocin, oxytocin and ergometrine plus oxytocin combination. Both trials are expected to report in 2018.Consultation with our consumer group demonstrated the need for more research into PPH outcomes identified as priorities for women and their families, such as women's views regarding the drugs used, clinical signs of excessive blood loss, neonatal unit admissions and breastfeeding at discharge. To date, trials have rarely investigated these outcomes. Consumers also considered the side-effects of uterotonic drugs to be important but these were often not reported. A forthcoming set of core outcomes relating to PPH will identify outcomes to prioritise in trial reporting and will inform futures updates of this review. We urge all trialists to consider measuring these outcomes for each drug in all future randomised trials. Lastly, future evidence synthesis research could compare the effects of different dosages and routes of administration for the most effective drugs. PMID- 29693727 TI - Plastic breeding system response to day length in the California wildflower Mimulus douglasii. AB - PREMISE OF THE STUDY: Angiosperms have evolved multiple breeding systems that allow reproductive success under varied conditions. Striking among these are cleistogamous breeding systems, where individuals can produce alternative flower types specialized for distinct mating strategies. Cleistogamy is thought to be environmentally-dependent, but little is known about environmental triggers. If production of alternate flowers is environmentally induced, populations may evolve locally adapted responses. Mimulus douglasii, exhibits a cleistogamous breeding system, and ranges across temperature and day-length gradients, providing an ideal system to investigate environmental parameters that control cleistogamy. METHODS: We compared flowering responses across Mimulus douglasii population accessions that produce distinct outcrossing and self-pollinating flower morphs. Under controlled conditions, we determined time to flower, and number and type of flowers produced under different temperatures and day lengths. KEY RESULTS: Temperature and day length both affect onset of flowering. Long days shift flower type from predominantly chasmogamous to cleistogamous. The strength of the response to day length varies across accessions whether temperature varies or is held constant. CONCLUSIONS: Cleistogamy is an environmentally sensitive polyphenism in Mimulus douglasii, allowing transition from one mating strategy to another. Longer days induce flowering and production of cleistogamous flowers. Shorter days induce chasmogamous flowers. Population origin has a small effect on response to environmental cues. PMID- 29693725 TI - Tctex-1, a novel interaction partner of Kidney Injury Molecule-1, is required for efferocytosis. AB - Kidney injury molecule-1 (KIM-1) is a phosphatidylserine receptor that is specifically upregulated on proximal tubular epithelial cells (PTECs) during acute kidney injury and mitigates tissue damage by mediating efferocytosis (the phagocytic clearance of apoptotic cells). The signaling molecules that regulate efferocytosis in TECs are not well understood. Using a yeast two-hybrid screen, we identified the dynein light chain protein, Tctex-1, as a novel KIM-1 interacting protein. Immunoprecipitation and confocal imaging studies suggested that Tctex-1 associates with KIM-1 in cells at baseline, but, dissociates from KIM-1 within 90 min of initiation of efferocytosis. Interfering with actin or microtubule polymerization interestingly prevented the dissociation of KIM-1 from Tctex-1. Moreover, the subcellular localization of Tctex-1 changed from being microtubule-associated to mainly cytosolic upon expression of KIM-1. Short hairpin RNA-mediated silencing of endogenous Tctex-1 in cells significantly inhibited efferocytosis to levels comparable to that of knock down of KIM-1 in the same cells. Importantly, Tctex-1 was not involved in the delivery of KIM-1 to the cell-surface. On the other hand, KIM-1 expression significantly inhibited the phosphorylation of Tctex-1 at threonine 94 (T94), a post-translational modification which is known to disrupt the binding of Tctex-1 to dynein on microtubules. In keeping with this, we found that KIM-1 bound less efficiently to the phosphomimic (T94E) mutant of Tctex-1 compared to wild type Tctex-1. Surprisingly, expression of Tctex-1 T94E did not influence KIM-1-mediated efferocytosis. Our studies uncover a previously unknown role for Tctex-1 in KIM-1 dependent efferocytosis in epithelial cells. PMID- 29693728 TI - Evolution at the tips: Asclepias phylogenomics and new perspectives on leaf surfaces. AB - PREMISE OF THE STUDY: Leaf surface traits, such as trichome density and wax production, mediate important ecological processes such as anti-herbivory defense and water-use efficiency. We present a phylogenetic analysis of Asclepias plastomes as a framework for analyzing the evolution of trichome density and presence of epicuticular waxes. METHODS: We produced a maximum-likelihood phylogeny using plastomes of 103 species of Asclepias. We reconstructed ancestral states and used model comparisons in a likelihood framework to analyze character evolution across Asclepias. KEY RESULTS: We resolved the backbone of Asclepias, placing the Sonoran Desert clade and Incarnatae clade as successive sisters to the remaining species. We present novel findings about leaf surface evolution of Asclepias-the ancestor is reconstructed as waxless and sparsely hairy, a macroevolutionary optimal trichome density is supported, and the rate of evolution of trichome density has accelerated. CONCLUSIONS: Increased sampling and selection of best-fitting models of evolution provide more resolved and robust estimates of phylogeny and character evolution than obtained in previous studies. Evolutionary inferences are more sensitive to character coding than model selection. PMID- 29693730 TI - Culture of the human pilosebaceous unit, hair follicle and sebaceous gland. AB - Terence Kealey first pioneered the isolation and organ maintenance of human eccrine and sebaceous glands in the early to mid-1980. This led to subsequent methods describing the isolation and culture of human hair follicles, the human pilosebaceous unit as well as the sebaceous duct. The importance of these models in the study of the biology of human skin glands and appendages has been demonstrated in numerous publications and their importance as models for animal replacement, refinement and reduction (3Rs) is increasingly important. In particular, in vitro (ex vivo) hair follicle culture has played a significant part in helping elucidate the role of signalling molecules in regulating hair growth and hair fibre formation and has been especially useful in understanding metabolic aspects of hair growth. However, obtaining sufficient numbers of hair follicles is becoming increasingly difficult as plastic surgery becomes less invasive and smaller skin samples provided. There is therefore an urgent requirement for the next generation of in vitro models using cell lines and tissue engineering, and this has led to the development of immortalised cell lines as well as attempts to model hair follicle embryogenesis in vitro and development of skin on a chip. PMID- 29693732 TI - DNA sequencing to clarify the taxonomical conundrum of the clinical coelomycetes. AB - The taxonomy of the fungi that produce human infections and that develop asexual fruiting bodies in culture has become very complex. Recent molecular studies have produced dramatic changes in their classification. Currently, the coelomycetes traditionally included in Sphaeropsidales and Melanconiales are in fact distributed across at least three different classes of the Phylum Ascomycota. Approximately 1000 genera and 7000 species have been grouped in the classes Dothideomycetes, Leotiomycetes and Sordariomycetes and their proper identification can only be made by analysing their DNA sequences and comparing them with those corresponding to type strains available in the adequate databases. To facilitate this task for scientists and clinicians involved in the study of these complex, and every day more numerous taxa, we have updated the knowledge about the taxonomy of the commonest coelomycetes of clinical interest with the aim of improving their identification and antifungal treatment. PMID- 29693729 TI - Inflammatory bowel disease and immunonutrition: novel therapeutic approaches through modulation of diet and the gut microbiome. AB - Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract, thought to at least in part reflect an aberrant immune response to gut bacteria. IBD is increasing in incidence, particularly in populations that have recently immigrated to western countries. This suggests that environmental factors are involved in its pathogenesis. We hypothesize that the increase in IBD rates might reflect the consumption of an unhealthy Western diet, containing excess calories and lacking in key nutritional factors, such as fibre and vitamin D. Several recent studies have determined that dietary factors can dramatically influence the activation of immune cells and the mediators they release through a process called immunonutrition. Moreover, dietary changes can profoundly affect the balance of beneficial versus pathogenic bacteria in the gut. This microbial imbalance can alter levels of microbiota-derived metabolites that in turn can influence innate and adaptive intestinal immune responses. If the diet-gut microbiome disease axis does indeed underpin much of the 'western' influence on the onset and progression of IBD, then tremendous opportunity exists for therapeutic changes in lifestyle, to modulate the gut microbiome and to correct immune imbalances in individuals with IBD. This review highlights four such therapeutic strategies - probiotics, prebiotics, vitamin D and caloric restriction - that have the potential to improve and add to current IBD treatment regimens. PMID- 29693731 TI - Genetic and Epigenetic Defects at the GNAS Locus Lead to Distinct Patterns of Skeletal Growth but Similar Early-Onset Obesity. AB - Pseudohypoparathyroidism type 1A (PHP1A), pseudoPHP (PPHP), and PHP type 1B (PHP1B) are caused by maternal and paternal GNAS mutations and abnormal methylation at maternal GNAS promoter(s), respectively. Adult PHP1A patients are reportedly obese and short, whereas most PPHP patients are born small. In addition to parathyroid hormone (PTH) resistance, PHP1A and PHP1B patients may display early-onset obesity. Because early-onset and severe obesity and short stature are daily burdens for PHP1A patients, we aimed at improving knowledge on the contribution of the GNAS transcripts to fetal and postnatal growth and fat storage. Through an international collaboration, we collected growth and weight data from birth until adulthood for 306 PHP1A/PPHP and 220 PHP1B patients. PHP1A/PPHP patients were smaller at birth than healthy controls, especially PPHP (length Z-score: PHP1A -1.1 +/- 1.8; PPHP -3.0 +/- 1.5). Short stature is observed in 64% and 59% of adult PHP1A and PPHP patients. PHP1B patients displayed early postnatal overgrowth (height Z-score at 1 year: 2.2 +/- 1.3 and 1.3 +/- 1.5 in autosomal dominant and sporadic PHP1B) followed by a gradual decrease in growth velocity resulting in normal adult height (Z-score for both: 0.4 +/- 1.1). Early-onset obesity characterizes GNAS alterations and is associated with significant overweight and obesity in adults (bodey mass index [BMI] Z-score: 1.4 +/- 2.6, 2.1 +/- 2.0, and 1.4 +/- 1.9 in PPHP, PHP1A, and PHP1B, respectively), indicating that reduced Gsalpha expression is a contributing factor. The growth impairment in PHP1A/PPHP may be due to Gsalpha haploinsufficiency in the growth plates; the paternal XLalphas transcript likely contributes to prenatal growth; for all disease variants, a reduced pubertal growth spurt may be due to accelerated growth plate closure. Consequently, early diagnosis and close follow-up is needed in patients with GNAS defects to screen and intervene in case of early-onset obesity and decreased growth velocity. (c) 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research (ASBMR). PMID- 29693733 TI - Tunable Molecular-Scale Materials for Catalyzing the Low-Overpotential Electrochemical Conversion of CO2. AB - Electrochemical CO2 reduction provides a clean and viable alternative for mitigating the environmental aspects of global greenhouse gas emissions. To date, the simultaneous goals of CO2 reduction at high selectivity and activity have yet to be achieved. Here, the importance of engineering both sides of the electrode electrolyte interface as a rational strategy for achieving this milestone is highlighted. An emphasis is placed on researchers contributing to the design of solid electrodes based on metal-organic frameworks (MOFs) and electrolytes based on room-temperature ionic liquids (RTILs). Future research geared toward optimizing the electrode-electrolyte interface for efficient and selective CO2 reduction can be achieved by understanding the structure of newly designed RTILs at the electrified interface, as well as structure-activity relationships in highly tunable MOF platforms. PMID- 29693734 TI - Metastable MoS2 : Crystal Structure, Electronic Band Structure, Synthetic Approach and Intriguing Physical Properties. AB - The 2H molybdenum disulfide (MoS2 ), as a stable hexagonal phase, has been one of the most studied transition metal dichalcogenides over the past decades. In the last five years, the metastable phases of MoS2 (1T, 1T', 1T'', and 1T''') have seen a revival of interests. Different from the edge-sharing [MoS6 ] trigonal prisms in the 2H MoS2 phase, these metastable phases are composed of the edge sharing [MoS6 ] octahedra, in which the neighboring Mo-Mo distances differ. Due to the various crystal structures and different electronic configurations of the building [MoS6 ] motifs, these metastable polytypes are endowed with intriguing physical properties and potential applications in diverse fields. In this Review, the recent research progress on metastable MoS2 is summarized, especially with an emphasis on the diverse synthetic approaches and the newly uncovered physical properties. The phase structures and electronic band structures are also outlined. In the end, a perspective of the future investigation on metastable MoS2 is discussed. PMID- 29693735 TI - Weight suppression and weight elevation are associated with eating disorder symptomatology in women age 50 and older: Results of the gender and body image study. AB - OBJECTIVE: Weight suppression (WS), the difference between highest past non pregnancy weight and current weight, predicts negative outcomes in eating disorders, but the impact of WS and related weight constructs are understudied in nonclinical, midlife populations. We examined WS (current weight < highest weight) and weight elevation (WE), the opposite of WS (current weight > lowest weight) and their associations with eating psychopathology in women aged 50+. METHOD: Participants were a community-based sample (N = 1,776, Mage = 59) who completed demographic and eating psychopathology questions via online survey. WS, WE, and WS * WE were tested as predictors of outcome variables; BMI and medical conditions that affect weight were controlled for. RESULTS: Individuals that were higher on WS and WE were most likely to engage in current weight loss attempts, dieting in the past 5 years, and extreme lifetime restriction. Individuals with higher WS were more likely to experience binge eating, greater frequency of weight checking, overvaluation of shape and weight, and lifetime fasting. Individuals with higher WE were more likely to report negative life impacts of eating and dieting. Higher WS and WE each predicted higher levels of skipping meals over the lifetime. DISCUSSION: This novel study investigated WS in midlife women and introduced a new conceptualization of weight change (WE) that may be more relevant for aging populations given that women tend to gain weight with age. The findings implicate the utility of investigating both WS and WE as factors associated with eating psychopathology in midlife women. PMID- 29693736 TI - Influence of a Metal Substrate on Small-Molecule Activation Mediated by a Surface Adsorbed Complex. AB - Activating small molecules with transition metal complexes adsorbed on metal surfaces is a novel approach combining aspects of homogeneous and heterogeneous catalysis. In order to study the influence of an Au(111) substrate on the activation of the small-molecule ligand carbon monoxide, a molybdenum tricarbonyl complex containing a PN3 P pincer ligand was synthesized and investigated in the bulk, in solution, and adsorbed on an Au(111) surface. By means of a platform approach, a perpendicular orientation of the molybdenum complex was achieved and confirmed by IRRAS and NEXAFS. By using vibrational spectroscopy (IR, Raman, IRRAS) coupled to DFT calculations, the influence of the metal substrate on the activation of the CO ligands bound to the molybdenum complex was determined. The electron-withdrawing behavior of gold causes an overall shift of the CO stretching vibrations to higher frequencies, which is partly compensated by dynamic charge transfer from the substrate to the molybdenum center, which increases its (dynamic) polarizability. PMID- 29693737 TI - How to prophylax against invasive fungal infections in adult ALL? An unmet need. AB - Although the benefit for any type of antifungal prophylaxis in patients with acute myelogenous leukaemia is well accepted, less is known about the risk for invasive fungal infections (IFIs) and the optimal prophylaxis strategies in patients with acute lymphocytic leukaemia (ALL). Based on recent studies, ALL is a disease that appears to be associated with significant risk for IFIs. The pharmacokinetic interactions between azoles and vincristine, an antineoplastic agent that is part of modern combination chemotherapies in ALL, results in clinically significant neurotoxicity that makes the use of azoles problematic. However, a number of questions regarding azole-vincristine interactions remain unanswered. In this viewpoint, we call for a renewed interest in antifungal prophylaxis studies in ALL in view of the availability of several non-azole novel antifungal agents that are under preclinical and/or clinical development. This is clearly a major unmet need in modern clinical mycology. PMID- 29693739 TI - Substituent effects on chiral resolutions of derivatized 1-phenylalkylamines by heptakis(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl)-beta-cyclodextrin GC stationary phase. AB - Chiral resolutions of trifluoroacetyl-derivatized 1-phenylalkylamines with different type and position of substituent were investigated by capillary gas chromatography by using heptakis(2,3-di-O-methyl-6-O-tert-butyldimethylsilyl) beta-cyclodextrin diluted in OV-1701 as a chiral stationary phase. The influence of column temperature on retention and enantioselectivity was examined. All enantiomers of meta-substituted analytes as well as fluoro-substituted analytes could be resolved. Temperature had a favorable influence on enantioselectivity for small amines with substituents at the ortho-position. The type of substituent at the stereogenic center of amines also had a crucial effect as the ethyl group led to poor enantioseparation. Among all analytes studied, trifluoroacetyl derivatized 1-(2'-fluorophenyl)ethylamine exhibited baseline resolution with the shortest analysis time. PMID- 29693738 TI - Growth of children in Greenland exceeds the World Health Organization growth charts. AB - AIM: Previous studies have found high rates of stunted linear growth in Greenlandic children. We measured growth patterns in Greenland and compared them with international growth charts. METHODS: The study cohort comprised 279 healthy children aged 6-10 years in 2012. They participated in two pregnancy and birth cohorts in Greenland and longitudinal growth data as birth was extracted from their medical records. Growth reference ranges were estimated with the lambda-mu sigma (LMS) method and compared with growth charts from Denmark and the World Health Organization (WHO). RESULTS: The children's mean length, weight and head circumference were significantly larger than the WHO growth charts (p < 0.001). We found that 21-28% of the children aged zero to one years exceeded the WHO growth chart for length by more than two standard deviations. For weight and head circumference, 9-16% of the children aged 0-10 years and 9-11% of the children from zero to two years exceeded the WHO charts by more than two standard deviations. The Danish references were exceeded to a lesser degree. CONCLUSION: This study showed that the growth of Greenlandic children up to 10 years was no longer stunted. Major determining factors suggested are genetic admixture, maternal overweight, changes in nutrition and improved health. PMID- 29693740 TI - Enantioselective separation of (+/-)-beta-hydroxy-1,2,3-triazoles by supercritical fluid chromatography and high-performance liquid chromatography. AB - This paper reports the enantioseparation of beta-hydroxy-1,2,3-triazole derivatives, which present a broad range of biological properties, by supercritical fluid chromatography (SFC) and high-performance liquid chromatography techniques (HPLC). Polysaccharide-based chiral columns (cellulose and amylose) were used to evaluate the separation in SFC and HPLC. Time of analyses, consumption of solvent, and parameter optimization were reduced using SFC technique. The columns based on cellulose chiral stationary phase using 2 propanol and ethanol as modifiers showed the best results for the enantioresolution of the (+/-)-beta-hydroxy-1,2,3-triazoles by SFC analyses. These techniques were applied to evaluate the selectivity of biocatalytic reduction of beta-keto-1,2,3-triazoles by marine-derived fungus Penicillium citrinum CBMAI 1186 to obtain the (+/-)-beta-hydroxy-1,2,3-triazoles. PMID- 29693741 TI - PAI-1, CAIX, and VEGFA expressions as prognosis markers in oral squamous cell carcinoma. AB - BACKGROUND: In oral squamous cell carcinoma (OSCC), the HIF-1 complex promotes the expression of genes involved in specific mechanisms of cell survival under hypoxic conditions, such as plasminogen activator inhibitor-1 (PAI-1), carbonic anhydrase 9 (CAIX), and vascular endothelial growth factor A (VEGFA). The study aimed to investigate the presence and prognostic value of PAI-1, CAIX, and VEGFA in OSCC. MATERIALS AND METHODS: Immunohistochemistry was used to analyze the expressions of these proteins in 52 tumoral tissue samples of patients with OSCC, surgically treated and followed by a minimum of 24 months after surgery. The correlations between protein expressions and clinicopathological parameters and prognosis were analyzed. RESULTS: Positive PAI-1 membrane expression was significantly associated with local disease relapse (P = .027). Multivariate analysis revealed that the positive PAI-1 membrane expression is an independent marker for local disease relapse, with approximately 14-fold increased risk when compared to negative expression (OR = 14.49; CI = 1.40-150.01, P = .025). Strong PAI-1 cytoplasmic expression was significantly associated with the less differentiation grade (P = .027). Strong CAIX membrane expression was significantly associated with local disease-free survival (P = .038). Positive CAIX cytoplasmic expression was significantly associated with lymph node affected (P = .025) and with disease-specific survival (P = .022). Multivariate analysis revealed that the positive CAIX cytoplasmic expression is an independent risk factor for disease-related death, increasing their risk approximately 3-fold when compared to negative expression (HR = 2.84; CI = 1.02-7.87, P = .045). Positive VEGFA cytoplasmic expression was significantly associated with less differentiation grade (P = .035). CONCLUSION: Our results suggest a potential role for these expressions profiles as tumor prognostic markers in OSCC patients. PMID- 29693742 TI - Evaluation of 4-bp insertion/deletion polymorphism within the 3'UTR of SGSM3 in bladder cancer using mismatch PCR-RFLP method: A preliminary report. AB - The small G protein signaling modulator 3 (SGSM3) has been shown to be associated with small G-protein-coupled receptor signaling. There is little data regarding the impact of SGSM3 polymorphisms on cancer risk. In the present study, we aimed to evaluate the impact of 4-bp insertion/deletion (rs56228771) polymorphism in the 3'UTR of SGSM3 and susceptibility to bladder cancer in a sample of the Iranian population. This case-control study included 143 pathologically confirmed bladder cancer patients and 144 healthy subjects. The SGSM3 4-bp ins/del (rs56228771) variant was determined by mismatch PCR-RFLP. The findings showed that ins/del genotype and ins allele of SGSM3 4-bp ins/del polymorphism significantly increased the risk of bladder cancer (OR = 3.11, 95%CI = 1.70-5.71, P < 0.0001 and OR = 2.11, 95%CI = 1.27-3.52, P = 0.004, respectively). Our findings support an association between 4-bp ins/del polymorphism in the 3'UTR of SGSM3 and the risk of bladder cancer in an Iranian population. Additional studies with larger sample sizes and diverse ethnicities are warranted to establish if such an association exists in general. PMID- 29693743 TI - Invisible megafauna. PMID- 29693744 TI - On-resonance and off-resonance continuous wave constant amplitude spin-lock and T1rho quantification in the presence of B1 and B0 inhomogeneities. AB - Spin-lock MRI is a valuable diagnostic imaging technology, as it can be used to probe the macromolecule environment of tissues. Quantitative T1rho imaging is one application of spin-lock MRI that is reported to be promising for a number of clinical applications. Spin-lock is often performed with a continuous RF wave at a constant RF amplitude either on resonance or off resonance. However, both on- and off-resonance spin-lock approaches are susceptible to B1 and B0 inhomogeneities, which results in image artifacts and quantification errors. In this work, we report a continuous wave constant amplitude spin-lock approach that can achieve negligible image artifacts in the presence of B1 and B0 inhomogeneities for both on- and off-resonance spin-lock. Under the adiabatic condition, by setting the maximum B1 amplitude of the adiabatic pulses equal to the B1 amplitude of spin-lock RF pulse, the spins are ensured to align along the effective field throughout the spin-lock process. We show that this results in simultaneous compensation of B1 and B0 inhomogeneities for both on- and off resonance spin-lock. The relaxation effect during the entire adiabatic half passage (AHP) and reverse AHP, and the stationary solution of the Bloch-McConnell equation present at off-resonance frequency offset, are considered in the revised relaxation model. We demonstrate that these factors create a direct current component to the conventional relaxation model. In contrast to the previously reported dual-acquisition method, the revised relaxation model just requires one acquisition to perform quantification. The simulation, phantom, and in vivo experiments demonstrate that the proposed approach achieves superior image quality compared with the existing methods, and the revised relaxation model can perform T1rho quantification with one acquisition instead of two. PMID- 29693745 TI - Human APOBEC3B interacts with the heterogenous nuclear ribonucleoprotein A3 in cancer cells. AB - Human APOBEC3B (A3B), like other APOBEC3 members, is a cytosine deaminase which causes hypermutation of single stranded genome. Recent studies have shown that A3B is predominantly elevated in multiple cancer tissues and cell lines such as the bladder, cervix, lung, head and neck, and breast. Upregulation and activation of A3B in developing tumors can cause an unexpected cluster of mutations which promote cancer development and progression. The cellular proteins which facilitate A3B function through direct or indirect interactions remain largely unknown. In this study, we performed LC-MS-based proteomics to identify cellular proteins which coimmunoprecipitated with A3B. Our results indicated a specific interaction of A3B with hnRNP A3 (heterogeneous nuclear ribonucleoprotein). This interaction was verified by co-immunoprecipitation and was found to be RNA dependent. Furthermore, A3B and hnRNP A3 colocalized as evident from immunofluorescence analysis. PMID- 29693746 TI - Group 13 Complexes of Chelating N2 O2n- Ligands as Hybrid Molecular Materials. AB - Recent synthetic advances have afforded opportunities for the creation of a wide range of potentially tetradentate N2 O2n- ligands. When combined with group 13 elements, robust functional molecular materials can be realized. This concept article describes advances surrounding group 13 complexes of selected families of N2 O2n- ligands, including examples with unique chirality, sensing/detection capabilities, utility in organic electronics, and redox properties. It also highlights the bridge between fundamental main group chemistry and useful application that is being established within this research field. PMID- 29693747 TI - Core psychopathology in anorexia nervosa and bulimia nervosa: A network analysis. AB - OBJECTIVE: The cognitive-behavioral theory of eating disorders (EDs) proposes that shape and weight overvaluation are the core ED psychopathology. Core symptoms can be statistically identified using network analysis. Existing ED network studies support that shape and weight overvaluation are the core ED psychopathology, yet no studies have estimated AN core psychopathology and concerns exist about the replicability of network analysis findings. The current study estimated ED symptom networks among people with anorexia nervosa (AN) and bulimia nervosa (BN) and among a combined group of people with AN and BN. METHOD: Participants were girls and women with AN (n = 604) and BN (n = 477) seeking residential ED treatment. ED symptoms were assessed with the Eating Disorder Examination-Questionnaire (EDE-Q); 27 of the EDE-Q items were included as nodes in symptom networks. Core symptoms were determined by expected influence and strength values. RESULTS: In all networks, desiring weight loss, restraint, shape and weight preoccupation, and shape overvaluation emerged as the most important symptoms. In addition, in the AN and combined networks, fearing weight gain emerged as an important symptom. In the BN network, weight overvaluation emerged as another important symptom. DISCUSSION: Findings support the cognitive behavioral premise that shape and weight overvaluation are at the core of AN psychopathology. Our BN and combined network findings provide a high degree of replication of previous findings. Clinically, findings highlight the importance of considering shape and weight overvaluation as a severity specifier and primary treatment target for people with EDs. PMID- 29693748 TI - MicroRNA-9 suppresses cancer proliferation and cell cycle progression in acute lymphoblastic leukemia with inverse association of neuropilin-1. AB - Acute lymphoblastic leukemia (ALL) is one of the most common and most malign childhood cancers. In this work, we investigated the expression and function of human mature microRNA-9 (miR-9) in ALL. In ALL in vitro cell lines and in situ clinical specimens, gene expression of miR-9 was tested by qRT-PCR. MiR-9 was overexpressed in CEM/C1 and Molt-3 cells to investigate its possible anti-cancer effects on ALL in vitro proliferation, cell-cycle progression, and in vivo explant growth. The possible downstream target of miR-9, neuropilin-1 (NRP1), was examined by dual-luciferase activity assay, qRT-PCR, and Western blot. NRP1was upregulated in miR-9-overexpressed CEM/C1 and Molt-3 cells to investigate the functional involvement of NRP1 in miR-9-mediated regulation on ALL in vitro proliferation and cell-cycle progression. MiR-9 was downregulated in ALL cell lines and leukemic T-cells of ALL patients. Lentivirus-mediated miR-9 overexpression inhibited ALL in vitro proliferation, cell-cycle progression, and in vivo explant growth. NRP1 was confirmed be the downstream target of miR-9, and inversely modulated by miR-9 in ALL. NRP1 upregulation reversed the anti-cancer regulations of miR-9 on ALL in vitro proliferation and cell-cycle progression. MiR-9 is downregulated in ALL. Overexpressing miR-9 may inhibit ALL development, possible through its downstream target of NRP1. PMID- 29693749 TI - Randomized controlled psychotherapy trials in eating disorders: Improving their conduct, interpretation and usefulness. AB - BACKGROUND: While randomized controlled trials (RCTs) inform the efficacy and effectiveness of treatments, we need to understand that even RCTs can be associated with sub-optimal execution. This is of special pertinence to eating disorders given the majority of treatment studies involving cognitive behaviour therapy are of poor quality with respect to managing risk of bias adequately. METHODS: The current paper outlines the components of a good RCT for psychotherapy, and examines ways to improve the conduct, interpretation, and usefulness of RCTs. RESULTS: This includes managing reporting bias, recognizing the limits of randomization, applicability, and ethical considerations. CONCLUSIONS: We highlight a number of strategies for future research, including issues related to utilizing a variety of designs to examine treatment outcomes, integrity, openness and reproducibility. PMID- 29693750 TI - Protein phosphatase 2A mediates JS-K-induced apoptosis by affecting Bcl-2 family proteins in human hepatocellular carcinoma HepG2 cells. AB - Protein phosphatase 2A (PP2A) is an important enzyme within various signal transduction pathways. The present study was investigated PP2A mediates JS-K induced apoptosis by affecting Bcl-2 family protein. JS-K showed diverse inhibitory effects in five HCC cell lines, especially HepG2 cells. JS-K caused a dose- and time-dependent reduction in cell viability and increased in levels of LDH release. Meanwhile, JS-K- induced apoptosis was characterized by mitochondrial membrane potential reduction, Hoechst 33342+ /PI+ dual staining, release of cytochrome c (Cyt c), and activation of cleaved caspase-9/3. Moreover, JS-K-treatment could lead to the activation of protein phosphatase 2A-C (PP2A-C), decrease of anti-apoptotic Bcl-2 family-protein expression including p-Bcl-2 (Ser70), Bcl-2, Bcl-xL, and Mcl-1 as well as the increase of pro-apoptosis Bcl-2 family-protein including Bim, Bad, Bax, and Bak. Furthermore, JS-K caused a marked increase of intracellular NO levels while pre-treatment with Carboxy-PTIO (a NO scavenger) reduced the cytotoxicity effects and the apoptosis rate. Meanwhile, pre-treatment with Carboxy-PTIO attenuated the JS-K-induced up regulation of PP2A, Cyt c, and cleaved-caspase-9/3 activation. The silencing PP2A C by siRNA could abolish the activation of PP2A-C, down-regulation of anti apoptotic Bcl-2 family-protein (p-Bcl-2, Bcl-2, Bcl-xL, and Mcl-1), increase of pro-apoptosis Bcl-2 family-protein (Bim, Bad, Bax, and Bak) and apoptotic-related protein (Cyt c, cleaved caspase-9/3) that were caused by JS-K in HepG2 cells. In addition, pre-treatment with OA (a PP2A inhibitor) also attenuated the above effects induced by JS-K. In summary, NO release from JS-K induces apoptosis through PP2A activation, which contributed to the regulation of Bcl-2 family proteins. PMID- 29693751 TI - The anti-inflammatory effect of microRNA-383-3p interacting with IL1R2 against homocysteine-induced endothelial injury in rat coronary arteries. AB - MicroRNAs (miRs) are widely reported to be novel biomarkers involved in the process of coronary atherosclerosis (CAS). Hence, this study aims to explore the function of miR-383-3p targeting IL1R2 on inflammatory injury of coronary artery endothelial cells (CAECs) in CAS. The underlying regulatory mechanisms of miR-383 3p were analyzed in concert with the treatment of miR-383-3p mimics, miR-383-3p inhibitors, and the combination of miR-383-3p inhibitors and siRNA against IL1R2 in homocysteine (HCY)-induced CAECs. MTT, Hoechst 33258 staining, and tube formation assay were employed in order to measure cell viability, apoptosis, and tube formation, respectively. The levels of IL-1beta, IL-6, IL-10, and IL-18 were determined by ELISA. IL1R2 was verified as the target gene of miR-383-3p by dual luciferase reporter gene assay. MiR-383-3p was down-regulated in myocardial tissues of AS rats while IL1R2 was the reciprocal. The up-regulation of miR-383 3p decreased the levels of IL1R2, caspase-1, IL-1beta, IL-6, and IL-18 expressions, as well as cell apoptosis rate in the HCY-induced CAECs, while IL-10 expression, cell viability, and tube formation ability were increased. These results were contraindicated in the HCY-induced CAECs treated by miR-383-3p inhibitors. In conclusion, miR-383-3p mediating IL1R2 prevents HCY-induced apoptosis and inflammation injury in CAECs through the inhibition of the activation of inflammasome signaling pathway. These findings highly indicate that miR-383-3p may be beneficial in the prevention of CAS and other cardiovascular diseases. PMID- 29693752 TI - A DNA Nanotube-Peptide Biocomplex for mRNA Detection and Its Application in Cancer Diagnosis and Targeted Therapy. AB - A biocomplex of DNA nanotube-peptide, consisting of six concatenated DNA strands, three locked DNA strands, and a cell-penetrating peptide, is reported. The barrel structured DNA nanotube-peptide was successfully applied as a codrug-delivery system for targeting cancer therapy. The mucin 1 protein (MUC-1) aptamer is part of a DNA nanotube that can specifically recognize MUC-1 protein on the surface of MCF-7 cells. Cyclo (Arg-Gly-Asp-d-Phe-Lys; cRGD), as a cell-penetrating peptide, facilitates recruitment and uptake of targeting drugs by binding to integrin receptors (alphav beta3 ) of the cytomembrane surface. Anticancer drugs doxorubicin (DOX) and paclitaxel (PTX) were loaded into the capsulated DNA nanotube-peptide (CDNP), which was used as codrug cargo models. The as-prepared biocomplex can be utilized not only to deliver drugs, but also to achieve anticancer effects in vivo. Experimental results suggested that the treatment efficacy of the codrug delivery platform (CDNP/DOX/PTX) was better than that of a single-drug delivery platform (CDNP/DOX or CDNP/PTX). This system, which is composed of DNA strands and peptide, has good biocompatibility and biodegradability. Furthermore, the system can readily detect target mRNA in MCF-7 cells in vitro. The detection limits of mRNA are 9.7*10-8 and 1.8*10-8 m with CDNP/DOX and CDNP/PTX-FITC (FITC=fluorescein isothiocyanate), respectively, as probes. PMID- 29693753 TI - Bridging beta-Cyclodextrin Prevents Self-Inclusion, Promotes Supramolecular Polymerization, and Promotes Cooperative Interaction with Nucleic Acids. AB - A bridge to assemble: Cyclodextrins bridged with an ammonium linker bearing a hydrophobic substituent can efficiently form supramolecular polymers and avoid the competing self-inclusion and head-to-head processes. Furthermore, the self assembling cyclodextrin derivative interacts in a highly cooperative manner with DNA, as demonstrated by compaction experiments. It also interacts cooperatively with siRNA and allows its transfection. PMID- 29693754 TI - A Bis(MU-oxido)dinickel(III) Complex with a Triplet Ground State. AB - A bis(MU-oxido)dinickel(III) complex was synthesized and characterized by single crystal X-ray diffraction, resonance Raman, and ESI-mass measurements. Magnetic susceptibility measurements by SQUID and EPR spectroscopy reveal that the complex has a triplet ground state, which is unprecedented for high-valent metal (M) complexes with [M2 (MU-O)2 ] diamond core. DFT studies indicate ferromagnetic coupling of the nickel(III) centers. The complex exhibits hydrogen abstraction reactivity and oxygenation reactivity toward external substrates. PMID- 29693755 TI - Psychosocial factors and mortality in patients with heart failure. PMID- 29693756 TI - Enantioselective Hydroamidation of Enals by Trapping of a Transient Acyl Species. AB - An enantioselective synthesis of beta-chiral amides through asymmetric and redox neutral hydroamidation of enals is reported. In this reaction, a chiral N heterocyclic carbene (NHC) catalyst reacts with enals to generate the homoenolate intermediate. Upon highly enantioselective beta-protonation through proton shuttle catalysis, the resulting azolium intermediate reacts with imidazole to yield the key beta-chiral acyl species. This transient intermediate provides access to diversified beta-chiral carbonyl derivatives, such as amides, hydrazides, acids, esters, and thioesters. In particular, beta-chiral amides can be prepared in excellent yield and ee (40 chiral amides, up to 95 % yield and 99 % ee). This modular strategy overcomes the challenge of disruption of the highly selective proton-shuttling process by basic amines. PMID- 29693757 TI - Adjunctive probiotic microorganisms to prevent rehospitalization in patients with acute mania: A randomized controlled trial. AB - OBJECTIVE: Immunological abnormalities play a role in the pathophysiology of mania and have been associated with relapse. Probiotic organisms such as Lactobacilli and Bifidobacteria modulate inflammation in humans and animal models. The trial examined whether the administration of probiotic organisms prevents psychiatric rehospitalizations in patients recently discharged following hospitalization for mania. METHODS: Patients hospitalized for mania (N = 66) were randomized after discharge to receive 24 weeks of adjunctive probiotics (Lactobacillus rhamnosus strain GG and Bifidobacterium animalis subsp. lactis strain Bb12) or adjunctive placebo in a parallel two-group design format. The effect of treatment group on the risk of rehospitalization was calculated using Cox regression models. The modulating effect of systemic inflammation was measured employing an inflammation score based on immunoglobulin levels directed at previously defined antigens. RESULTS: During the 24-week observation period there were a total of 24 rehospitalizations in the 33 individuals who received placebo and eight rehospitalizations in the 33 individuals who received the probiotics (z = 2.63, P = .009). Hazard functions indicated that the administration of the probiotics was associated with a significant advantage in time to all psychiatric rehospitalizations (hazard ratio [HR] = 0.26, 95% confidence interval [CI] 0.10, .69; P = .007). Probiotic treatment also resulted in fewer days rehospitalized (mean 8.3 vs 2.8 days for placebo and probiotic treatment, respectively; chi2 = 5.17, P = .017). The effect of the probiotic treatment on the prevention of rehospitalization was increased in individuals with elevated levels of systemic inflammation at baseline. CONCLUSION: Probiotic supplementation is associated with a lower rate of rehospitalization in patients who have been recently discharged following hospitalization for mania. PMID- 29693758 TI - Performance of serum (1,3)-beta-d-glucan screening for the diagnosis of invasive aspergillosis in neutropenic patients with haematological malignancies. AB - We report our experience with the use of (1,3)-beta-d-glucan (BDG) screening for the diagnosis of invasive aspergillosis (IA) in neutropenic patients with haematological malignancies. The performance of BDG screening was assessed retrospectively in per patient and per sample analyses. Overall, 20 among 167 patients developed IA (12%). In the per patient analysis, BDG showed 60% sensitivity and 78% specificity when the criterion for positivity was the presence of at least one BDG value >=80 pg/mL. For 2 consecutive positive results, sensitivity decreased to 40%, while specificity increased to 93% and was similar to that of a positive galactomannan (GM; 90%). The highest specificity (97%) was observed for combined positivity of at least one BDG and at least one GM. In the per sample analysis, the specificity of BDG was 100% in the best scenario, 96% in the median scenario and 89% in the worst scenario. BDG became positive before GM in 33% of IA patients with both markers positive (n = 12). Despite good specificity for 2 consecutive positive results, the BDG test offered unsatisfactory performance for the diagnosis of IA due to low sensitivity. The combination of BDG and GM showed the potential for increasing specificity. PMID- 29693759 TI - A Hybrid Co Quaterpyridine Complex/Carbon Nanotube Catalytic Material for CO2 Reduction in Water. AB - Associating a metal-based catalyst to a carbon-based nanomaterial is a promising approach for the production of solar fuels from CO2 . Upon appending a CoII quaterpyridine complex [Co(qpy)]2+ at the surface of multi-walled carbon nanotubes, CO2 conversion into CO was realized in water at pH 7.3 with 100 % catalytic selectivity and 100 % Faradaic efficiency, at low catalyst loading and reduced overpotential. A current density of 0.94 mA cm-2 was reached at -0.35 V vs. RHE (240 mV overpotential), and 9.3 mA cm-2 could be sustained for hours at only 340 mV overpotential with excellent catalyst stability (89 095 catalytic cycles in 4.5 h), while 19.9 mA cm-2 was met at 440 mV overpotential. Such a hybrid material combines the high selectivity of a homogeneous molecular catalyst to the robustness of a heterogeneous material. Catalytic performances compare well with those of noble-metal-based nano-electrocatalysts and atomically dispersed metal atoms in carbon matrices. PMID- 29693760 TI - High-throughput screening of a collection of known pharmacologically active small compounds for inhibitors of Salmonella invasion and intracellular replication. AB - AIMS: The aim of this study was to screen a chemical library consisting of over 1200 pharmacologically active, already approved off-patent compounds, to determine whether any of the compounds reduced or eliminated the invasion or intracellular replication phenotypes of Salmonella enterica serovar Typhimurium (S. Typhimurium). METHODS AND RESULTS: LacZ reporter and tissue culture-based infection assays were used to screen for compounds that significantly reduced expression of key virulence genes, and were required for the invasion or intracellular replication phenotypes of S. Typhimurium in host cells. The search lead to the discovery of four compounds that reduced invasion by between 90-100%, and two compounds that reduced intracellular replication by between 65-93% at concentrations of either 2, 10 or 50 MUg ml-1 , relative to an untreated control strain. CONCLUSIONS: We identified six compounds that significantly reduced expression of S. Typhimurium virulence genes resulting in decreased in vitro virulence. SIGNIFICANCE AND IMPACT OF THE STUDY: The emergence of multidrug resistant strains of Salmonella poses a considerable and growing worldwide threat to human and animal health. The screening of off-patent chemical libraries represents a potential discovery route for novel antimicrobials. PMID- 29693761 TI - Modeling the Evolution of Crosslinked and Extractable Material in an Oil-Based Paint Model System. AB - The construction of mechanistic models for the autoxidation of fatty acid or ester substrates found in oil paint binders is a challenging undertaking due to the complexity of the large crosslinked species that form, and the small molecules that volatilize. Building models that capture this product diversity are made possible by automating the process of network generation. This work presents a microkinetic model for the autoxidation of ethyl linoleate catalyzed by cobalt(II) 2-ethyl hexanoate. The mechanism size was controlled by using a rate-based criterion to include the most kinetically relevant reactions from among the millions of possible reactions generated. The resulting model was solved and compared to experimental metrics. Quantities such as hexanal production and the consumption of unsaturated moieties were in good agreement with experiment. Finally, the model was used to explore the effect of the catalyst concentration and temperature on key measurables. PMID- 29693762 TI - Growth, body composition, and bone density following pediatric liver transplantation. AB - Patients transplanted for cholestatic liver disease are often significantly fat soluble vitamin deficient and malnourished pretransplant, with significant corticosteroid exposure post-transplant, with increasing evidence of obesity and metabolic syndrome post-LT. Our study aimed to assess growth, body composition, and BMD in patients post-pediatric LT. Body composition and bone densitometry scans were performed on 21 patients. Pre- and post-transplant anthropometric data were analyzed. Bone health was assessed using serum ALP, calcium, phosphate, and procollagen-1-N-peptide levels. Median ages at transplant and at this assessment were 2.7 and 10.6 years, respectively. Physiological markers of bone health, median z-scores for total body, and lumbar spine aBMD were normal. Bone area was normal for height and BMAD at L3 was normal for age, indicating, respectively, normal cortical and trabecular bone accrual. Median z-scores for weight, height, and BMI were 0.6, -0.9, 1.8 and 0.6, 0.1, 0.8 pre- and post-transplant, respectively. Total body fat percentages measured on 21 body composition scans revealed 2 underweight, 7 normal, 6 overweight, and 6 obese. Bone mass is preserved following pediatric LT with good catch-up height. About 52% of patients were either overweight/obese post-transplant, potentially placing them at an increased risk of metabolic syndrome and its sequelae in later life. BMI alone is a poor indicator of nutritional status post-transplant. PMID- 29693763 TI - Facile Stabilization of the Sodium Metal Anode with Additives: Unexpected Key Role of Sodium Polysulfide and Adverse Effect of Sodium Nitrate. AB - Sodium metal is an attractive anode for next-generation energy storage systems owing to its high specific capacity, low cost, and high abundance. Nevertheless, uncontrolled Na dendrite growth caused by the formation of unstable solid electrolyte interphase (SEI) leads to poor cycling performance and severe safety concerns. Sodium polysulfide (Na2 S6 ) alone is revealed to serve as a positive additive or pre-passivation agent in ether electrolyte to improve the long-term stability and reversibility of the Na anode, while Na2 S6 -NaNO3 as co-additive has an adverse effect, contrary to the prior findings in the lithium anode system. A superior cycling behavior of Na anode is first demonstrated at a current density up to 10 mA cm-2 and a capacity up to 5 mAh cm-2 over 100 cycles. As a proof of concept, a high-capacity Na-S battery was prepared by pre passivating the Na anode with Na2 S6 . This study gives insights into understanding the differences between Li and Na systems. PMID- 29693764 TI - Visible-Light-Accelerated Copper(II)-Catalyzed Regio- and Chemoselective Oxo Azidation of Vinyl Arenes. AB - The visible-light-accelerated oxo-azidation of vinyl arenes with trimethylsilylazide and molecular oxygen as stoichiometric oxidant was achieved. In contrast to photocatalysts based on iridium, ruthenium, or organic dyes, [Cu(dap)2 ]Cl or [Cu(dap)Cl2 ] were found to be unique for this transformation, which is attributed to their ability to interact with the substrates through ligand exchange and rebound mechanisms. CuII is proposed as the catalytically active species, which upon coordinating azide will undergo light-accelerated homolysis to form CuI and azide radicals. This activation principle (CuII -X->CuI +X. ) opens up new avenues for copper-based photocatalysis. PMID- 29693766 TI - Tuning PEDOT:Tos Thermoelectric Properties Through Nanoparticle Inclusion. AB - Thermoelectric application of conjugated polymers has recently become a subject of scientific interest. This is due to the peculiar features of these organic materials, such as low cost, safety, abundance of atomic components, and easy processing, which make them an interesting alternative to inorganic materials commonly used for this application in the room temperature range, i.e., tellurides derivatives, such as Bi2Te3 and Sb2Te3. Two are the main drawbacks of organic materials employment: the first is their poor thermoelectrical performance, which is still low in comparison with inorganic benchmark, the second is the scarcity of stable and easy-to-dope n-type polymers. In order to address the first issue, we tried to obtain a further and crucial efficiency improvement, developing a nanocomposite embedding inorganic nanoparticles in a matrix of conjugated polymer. A hybrid film of poly(3,4 ethylenedioxithiophene):Tosylate (PEDOT:Tos) and Mn3O4 nanoparticles have been achieved through a novel strategy, involving nanoparticle functionalization and in situ polymerization. The purpose is to enable energy filtering thanks to the presence of the NPs so as to extend this beneficial effect already been observed in inorganic semiconductor to polymers. Our study indicates a new path to obtain PEDOT-based nanocomposite and enlightens the peculiar behaviour of this hybrid material. PMID- 29693765 TI - Integrating dynamic contrast-enhanced magnetic resonance imaging and diffusion kurtosis imaging for neoadjuvant chemotherapy assessment of nasopharyngeal carcinoma. AB - BACKGROUND: Since neoadjuvant chemotherapy (NAC) has proven a benefit for locally advanced nasopharyngeal carcinoma (NPC), early response evaluation after chemotherapy is important to implement individualized therapy for NPC in the era of precision medicine. PURPOSE: To determine the combined and independent contribution between dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) and diffusion kurtosis imaging (DKI) in the early monitoring of NAC response for NPC. STUDY TYPE: Prospective. POPULATION: Fifty-three locally advanced NPC patients. FIELD STRENGTH/SEQUENCE: Four examinations before and at 4, 20, and 40 days after NAC initiation were performed at 3T MRI including DCE-MRI and DKI (b values = 0, 500, 1000, 1500 s/mm2 ). ASSESSMENT: DCE-MRI parameters (Ktrans [the volume transfer constant of Gd-DTPA], kep [rate constant], nue [the extracellular volume fraction of the imaged tissue], and nup [the blood volume fraction]) and DKI parameters (Dapp [apparent diffusion for non-Gaussian distribution] and Kapp [apparent kurtosis coefficient]) were analyzed using dedicated software. STATISTICAL TESTS: MRI parameters and their corresponding changes were compared between responders and nonresponders after one or two NAC cycles treatment using independent-samples Student's t-test or Mann-Whitney U-test depending on the normality contribution test and then followed by logistic regression and receiver operating characteristic curve (ROC) analyses. RESULTS: The responder group (RG) patients presented significantly higher mean Ktrans and Dapp values at baseline and larger DATA CONCLUSION: Combined DCE-MRI and DKI models had higher diagnostic accuracy for NAC assessment compared with either model used independently. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1208-1216. PMID- 29693767 TI - 7-Ketocholesterol impairs phagocytosis and efferocytosis via dysregulation of phosphatidylinositol 4,5-bisphosphate. AB - The plasma membrane is inhomogeneously organized containing both highly ordered and disordered nanodomains. 7-Ketocholesterol (7KC), an oxysterol formed from the nonenzymatic oxidation of cholesterol, is a potent disruptor of membrane order. Importantly, 7KC is a component of oxidized low-density lipoprotein and accumulates in macrophage and foam cells found in arterial plaques. Using a murine macrophage cell line, J774, we report that both IgG-mediated and phosphatidylserine-mediated phagocytic pathways are inhibited by the accumulation of 7KC. Examination of the well-studied Fcgamma receptor pathway revealed that the cell surface receptor abundance and ligand binding are unaltered while downstream signaling and activation of spleen tyrosine kinase is not affected. However, while the recruitment of phospholipase Cgamma1 was unaffected its apparent enzymatic activity was compromised resulting in sustained phosphatidylinositol 4,5-bisphosphate [PtdIns(4,5)P2 ] levels and polymerized actin at the base of the phagocytic cup. Additionally, we found that 7KC prevented the activation of PLCbeta downstream of the P2Y6 G-protein coupled receptor and that 7KC impaired PLCgamma activity in response to a direct elevation of cytosolic calcium induced by ionomycin. Finally, we demonstrate that 7KC partly attenuates the activity of rapamycin recruitable constitutively active PLCbeta3. Together, our results demonstrate that the accumulation of 7KC impairs macrophage function by altering PtdIns(4,5)P2 catabolism and, thus, impairing actin depolymerization required for the completion of phagocytosis. PMID- 29693768 TI - Simultaneous kissing stents to treat unprotected left main stem coronary artery bifurcation disease; stent expansion, vessel injury, hemodynamics, tissue healing, restenosis, and repeat revascularization. AB - OBJECTIVES: To perform detailed analysis of stent expansion, vessel wall stress, hemodynamics, re-endothelialization, restenosis, and repeat PCI in the simultaneous kissing stents (SKS) technique of bifurcation left main stem (LMS) stenting. BACKGROUND: The SKS technique is useful to treat patients with true bifurcation disease of the LMS but remains controversial. METHODS AND RESULTS: Computational structural analysis of SKS expansion demonstrated undistorted and evenly expanded stents. Computational fluid dynamics modelling revealed largely undisturbed blood flow. 239 PCI procedures were performed on 217 patients with unprotected bifurcation LMS disease with SKS using DES (2004-2017). We electively studied 13 stable patients from baseline to 10 years post-SKS with repeat angiography and optical coherence tomography, and demonstrated tissue coverage of the stent struts at the carina, with no evidence of lacunae behind the stents. We studied all patients with symptomatic recurrence. Target lesion revascularization rate was 3.2% at 1 year and 4.6% at 2 years. Of all 20 patients with restenosis, the site was the LMS-Cx stent in 7, the LMS-LAD stent in 2 and both in 11. Two year recurrence rate was 7/32 (5.3%) for first, and 4/108 (3.7%) for second generation DES. Treatment with repeat kissing techniques was undertaken in 19/20, with sustained clinical results with re-SKS. CONCLUSION: The SKS technique for treating unprotected LMS bifurcation disease does not distort the stents, is associated with favorable hemodynamics, tissue coverage of the exposed struts, and a low restenosis rate when performed with contemporary stents. Re-PCI with repeat SKS appears feasible, safe, and durable. PMID- 29693769 TI - Identification and comparative analysis of the ovary and testis microRNAome of mud crab Scylla paramamosain. AB - The role of microRNA (miRNA) in reproductive regulation is attracting increasingly more attention. In this study, we obtained 9,643,114 and 15,498,999 raw reads from the ovary and testis library of important farmed mud crab Scylla paramamosain, respectively. After data mining, a total of 4,096,464 and 11,737,973 mappable small RNA sequences remained for analysis. By mapping to the reference genome and expressed sequence tag (EST) of Daphnia pulex and other crabs, a total of 1,417 miRNAs were identified. On the basis of 1,417 miRNAs, 514 (36.3%) unique miRNAs coexpressed in the gonad of female and male libraries, and 336 (23.7%) and 567 (40%) expressed preferentially in female and male libraries, respectively. Analysis of library sequencing data resulted in the identification of 108 miRNAs (out of 1,417; 7.6%) that showed significant differential expression between the two samples. Of these, 13 miRNAs were expressed only in the testis, two miRNAs were expressed only in the ovary, and 93 miRNAs were coexpressed: 57 (61.3%) were upregulated (ovary/testis) and 36 (38.7%) were downregulated (ovary/testis). To confirm the expression patterns of the predicted miRNAs, we randomly selected 14 candidate miRNAs from 108 differentially expressed miRNAs and performed stem-loop real time quantitative PCR (RT-qPCR) assays in five ovary developing stages. Five miRNAs showed similar expression patterns in almost every stage as those revealed by identification of differentially expressed genes (IDEG6) analysis. The above five miRNAs were predicted to match the 3'-untranslated region of the published S. paramamosain gene. Four out of five miRNA had a regulation effect on many genes, especially the genes related to gonadal development. PMID- 29693770 TI - Histone deacetylase inhibitor treatment restores memory-related gene expression and learning ability in neonicotinoid-treated Apis mellifera. AB - Apis mellifera plays crucial roles in maintaining the balance of global ecosystems and stability of agricultural systems by helping pollination of flowering plants, including many crops. In recent years, this balance has been disrupted greatly by some pesticides, which results in great losses of honeybees worldwide. Previous studies have found that pesticide-caused memory loss might be one of the major reasons for colony loss. Histone deacetylase inhibitors (HDACis) are chemical compounds that inhibit the activity of histone deacetylases and are known to cause hyperacetylation of histone cores and influence gene expression. In our study, the HDACi sodium butyrate was applied to honeybees as a dietary supplement. The effect of sodium butyrate on the expression profiles of memory related genes was analysed by quantitative reverse transcription PCR. The results revealed that this HDACi had up-regulation effects on most of the memory-related genes in bees, even in bees treated with imidacloprid. In addition, using the proboscis extension reflex to evaluate olfactory learning in bees, we found that this HDACi boosted the memory formation of bees after impairment owing to imidacloprid exposure. This study investigated the association between gene expression and memory formation from an epigenetic perspective. Additionally, we further demonstrate the possibility of enhancing bee learning using HDACis and provide initial data for future research. PMID- 29693771 TI - A Simple Glycolipid Mimic of the Phosphatidylinositol Mannoside Core from Mycobacterium tuberculosis Inhibits Macrophage Cytokine Production. AB - Glycolipids from Mycobacterium tuberculosis have a profound impact on the innate immune response of the host. Macrophage-inducible C-type lectin (Mincle) is a pattern-recognition receptor that has been shown to bind trehalose dimycolate (TDM) from the mycobacterium and instigate intracellular signalling in the immune cell. There are structural similarities between the structures of TDM and phosphatidyl inositol mannoside (PIM). We thus hypothesized that these latter structures might also modulate an immune response in a similar manner. To test this, we synthesized a series of new mannose derivatives modified with fatty esters at the 6-position and assessed the release of inflammatory cytokines in human U937 macrophages under the induction of lipopolysaccharides (LPS) after glycolipid treatment. The results showed that the amount of two major cytokines tumour necrosis factor (TNF)-alpha and interleukin (IL)-6-released from LPS stimulated U937 cells decreased significantly when compared to a control upon treatment with the prepared glycolipids, thus indicating a reduction in cytokine production by the macrophages. PMID- 29693772 TI - Expression of granulosa cell microRNAs, AVEN and ATRX are associated with human blastocyst development. AB - A greater understanding of the key molecules associated with embryo development during human-assisted reproduction is imperative for the development of advanced diagnostics. Previous studies have shown that follicular microRNAs (miRNAs) are reliable markers of the polycystic ovarian syndrome (PCOS). Leveraging the utility of miRNAs in PCOS, the aim of this study was to identify miRNAs in human granulosa cells that may be indicative of blastocyst development. Granulosa cells and oocytes were collected from the first follicle aspirated from patients undergoing oocyte retrieval for in vitro fertilization or intracytoplasmic sperm injection. The development of isolated oocytes was recorded, and granulosa cell samples in this study were separated as follows. Group 1-BLAST: granulosa cells from follicles containing an oocyte that fertilized and developed into a blastocyst, and Group 2-FERT: granulosa cells from oocytes that fertilized but failed to reach blastocyst. A panel of 84 miRNAs, related to development and cellular differentiation, was assessed between the two groups using a miScript PCR array. Fourteen miRNAs and one snoRNA were differentially expressed between the groups. In addition, two downstream candidate protein biomarkers, ATRX and AVEN, were also found to be differentially expressed between the groups. The findings of this pilot study reveal follicular abnormalities on a molecular level, which may affect oocyte competence and its potential to develop successfully as an embryo. We encourage additional studies to confirm and expand on our findings and to determine the usefulness of granulosa-borne miRNAs, ATRX, and AVEN as biomarkers. PMID- 29693773 TI - Regulation of the sperm-to-oocyte transition in Caenorhabditis briggsae hermaphrodites by the Cbr-met-2 and Cbr-fem-3 genes. AB - In Caenorhabditis briggsae hermaphrodites, spermatogenesis begins in the L4 larval stage and persists into early adulthood. Oogenesis begins after spermatogenesis; the sperm-to-oocyte transition is irreversible. The timing of this transition is believed to have evolved in response to selection to maximize the intrinsic growth rate. Sperm-to-oocyte transitions occurred early in Cbr-met 2 and Cbr-fem-3 mutants. These early transitions resulted in reduced brood sizes, but had little or no impact on the intrinsic growth rate. In Cbr-met-2; Cbr-fem-3 doubly mutant hermaphrodites, the transition to oogenesis occurred even earlier and brood size was further reduced, indicating that Cbr-met-2 and Cbr-fem-3 regulate the sperm-to-oocyte transition through separate pathways. Mutations in Cbr-met-2 also resulted in an increase in the frequency of males in mutant populations. These increased male frequencies were not caused by increased rates of X nondisjunction during oogenesis in mutant hermaphrodites. Rather, increases in the rates of outcrossing in mutant populations likely were an indirect effect of reduced brood sizes derived from self-fertilization. Based on these observations, it is possible that the timing of the sperm-to-oocyte transition in C. briggsae evolved in response to sexual selection on hermaphrodites to limit rates of outcrossing. Mutations in the orthologous Caenorhabditis elegans gene, Cel-met-2, did not impact the timing of the sperm-to-oocyte transition, consistent with the independent evolution of hermaphroditic reproduction in these species. Although brood sizes were reduced in Cel-met-2 mutant strains, increased male frequencies were not observed. Cbr- and Cel-met-2 mutations also differed in terms of germline mortality, observed in C. elegans, but not in C. briggsae. PMID- 29693774 TI - Selective deletion of WLS in peritubular myoid cells does not affect spermatogenesis or fertility in mice. PMID- 29693775 TI - The Caenorhabditis elegans spe-49 gene is required for fertilization and encodes a sperm-specific transmembrane protein homologous to SPE-42. AB - Fertilization, the fusion of sperm and oocyte to form a zygote, is the first and arguably the most important cell-cell interaction event in an organism's life. Forward and reverse genetic approaches in the nematode Caenorhabditis elegans have identified many genes that are required for gametogenesis and fertilization and thus are beginning to elucidate the molecular pathways that underlie these processes. We identified an allele of the spe-49 gene in a second filial generation (F2 ) mutagenesis screen for spermatogenesis-defective (spe) mutants. Mutant worms for spe-49 produce sperm that have normal morphology, activate to form ameboid spermatozoa, and can migrate to and maintain their position in the hermaphrodite reproductive tract but fail to fertilize oocytes. This phenotype puts spe-49 in the spe-9 class of late-acting genes that function in sperm at the time of fertilization. We cloned the spe-49 gene through a combination of deficiency mapping, transgenic rescue, and genomic sequencing. spe-49 messenger RNA (mRNA) is enriched in male germ cells, and the complementary DNA (cDNA) encodes a predicted 772-amino-acid six-pass transmembrane protein that is homologous to SPE-42. Indeed, SPE-49 and SPE-42 have identical predicted membrane topology and domain structure, including a large extracellular domain with six conserved cysteine residues, a DC-STAMP domain, and a C-terminal cytoplasmic domain containing a C4-C4 RING finger motif. The presence of two SPE-42 homologs in animal genomes from worms to humans suggests that these proteins are highly conserved components of the molecular apparatus required for the sperm-oocyte recognition, binding, and fusion. PMID- 29693776 TI - Contributions of nonmaternal caregivers to infant feeding in a low-income African American sample. AB - Infant feeding is a well-established topic of interest in obesity research, yet few studies have focused on contributions of nonmaternal caregivers (NMCs)-such as fathers, grandparents, and daycare providers-to infant feeding. Data from the Infant Care, Feeding and Risk of Obesity Project in North Carolina were used to investigate (a) which factors were associated with NMC feeding styles and (b) how NMCs' and mothers' feeding styles compared. Multivariate regression models utilizing random effects were used to analyse data from 108 NMCs who were identified by mothers as being heavily involved in infant feeding. Feeding styles were measured using the Infant Feeding Style Questionnaire. Several individual characteristics were important. Higher laissez faire-attention scores were reported by men and NMCs who lived in the same household as infant. Men reported higher indulgent-coax and indulgent-pamper scores. Perceptions of fussier infants, older infant age, and higher infant weight-for-length z-scores were also important. Mothers' and NMCs' feeding styles differed. Compared with mothers, grandparents reported lower laissez faire and indulgent-permissive scores. Fathers reported higher pressure-soothe and indulgent scores. Daycare providers reported higher restriction-diet quality and responsive satiety. Feeding styles were also predicted to change over time for all caregiver types. These findings highlight the importance of helping all caregivers develop skills that will promote optimal infant feeding outcomes. Given the paucity of research in this area, it is important to improve our understanding of what influences caregivers' feeding styles, especially among diverse populations, and how exposure to different feeding styles may shape children's obesity risk. PMID- 29693778 TI - Identification of Potentially Potent Heme Oxygenase 1 Inhibitors through 3D-QSAR Coupled to Scaffold-Hopping Analysis. AB - A 3D quantitative structure-activity relationship (3D-QSAR) model for predicting the activity of heme oxygenase 1 (HO-1) inhibitors was constructed with the aim of providing a useful tool for the identification, design, and optimization of novel HO-1 inhibitors. The model was built using a set of 222 HO-1 inhibitors recovered from the Heme Oxygenase Database (HemeOxDB) and developed with the software Forge. The present model showed high statistical quality, as confirmed by its robust predictive potential and satisfactory descriptive capability. The drawn-up 3D map enables prompt visual comprehension of the electrostatic, hydrophobic, and shaping features underlying the interactions with HO-1 inhibitors. A theoretical approach for the generation of new lead compounds was performed by means of scaffold-hopping analysis. For the first time, a 3D-QSAR model is reported for this target, and was built with a number of chemically diverse HO-1 inhibitors; the model also accounts well for individual ligand affinities. The new model contains all of the inhibitors published to date with high potency toward the selected target and contains a complete pharmacophore description of the binding cavity of HO-1. These features will ensure application in accelerating the identification of new potent and selective HO-1 inhibitors. PMID- 29693779 TI - High-dose chemotherapy with autologous stem cell transplantation spares re irradiation for recurrent intracranial germinoma. AB - The clinical outcome of high-dose chemotherapy (HDC) with autologous stem cell transplantation was retrospectively analyzed in six patients with recurrent intracranial germinoma. Prior to HDC, all patients achieved complete remission after platinum and ifosfamide-based chemotherapy. A melphalan-based conditioning regimen was administered in either a single cycle or multiple sequential cycles. Five of the six patients are alive and free from disease, with a median survival of 65 months, among which four patients avoided re-irradiation. In a significant proportion of patients, recurrent intracranial germinoma is curable by HDC without re-irradiation, provided that the disease remains sensitive to salvage chemotherapy. PMID- 29693780 TI - Autologous stem cell transplantation for refractory opsoclonus myoclonus ataxia syndrome. AB - Opsoclonus, myoclonus, ataxia syndrome (OMA) is a severe neurologic disorder often associated with neuroblastoma. It is challenging to treat and can have long term neurologic sequelae. Current recommended therapies include intravenous immunoglobulin, corticosteroids, rituximab, and chemotherapy (cyclophosphamide). We present two cases who were refractory to conventional therapy and underwent autologous stem cell transplantation (ASCT). One patient had complete resolution of symptoms following ASCT and the other patient had minimal change in symptoms with this therapy. These findings support consideration of ASCT as a therapeutic option for patients with refractory OMA after failure of known effective therapies. PMID- 29693777 TI - Milk feeding and first complementary foods during the first year of life in the TEDDY study. AB - The aim was to describe milk feeding patterns and first weaning foods during the first year of life in a large prospective birth cohort of infants with increased genetic risk for Type 1 diabetes (T1D) recruited in 4 different countries: the United States, Finland, Germany, and Sweden. All enrolled children with dietary information (n = 8,673) were included in the analyses; 1,307 (15%) children who dropped out before the first birthday were excluded from some analyses. Supplementary milk feeding in the first 3 days of life was common in all the four countries, although the type of the supplementary milk differed by country and by maternal T1D. Donated human milk was commonly used only in Finland. In all the countries, the most common first supplementary food was cow's milk-based infant formula, especially among offspring of mothers with T1D. The use of specific types of infant formulas differed notably by country: Extensively hydrolysed formulas were most used in Finland, partially hydrolysed ones in the United States and in Germany, and soy formulas only in the United States. Infant formulas commonly included probiotics, prebiotics, and starches. During the first year of life, most of the infants received conventional cow's milk. Overall, milk feeding during the first 3 days of life and thereafter until the first birthday differed markedly by maternal T1D status and across countries. These descriptive data may be useful in understanding early infant feeding practices and in planning potential interventions, which affect infant feeding. PMID- 29693781 TI - The effect of physical activity interventions on youth with autism spectrum disorder: A meta-analysis. AB - : The purpose of this meta-analysis was to examine the effect of physical activity interventions on youth diagnosed with autism spectrum disorder. Standard meta-analytical procedures determining inclusion criteria, literature searches in electronic databases, coding procedures, and statistical methods were used to identify and synthesize articles retained for analysis. Hedge's g (1988) was utilized to interpret effect sizes and quantify research findings. Moderator and outcome variables were assessed using coding procedures. A total of 29 studies with 30 independent samples (N = 1009) were utilized in this analysis. Results from meta-analyses indicated an overall moderate effect (g = 0.62). Several outcomes indicated moderate-to-large effects (g >= 0.5); specifically, moderate to large positive effects were revealed for participants exposed to interventions targeting the development of manipulative skills, locomotor skills, skill-related fitness, social functioning, and muscular strength and endurance. Moderator analyses were conducted to explain variance between groups; environment was the only subgrouping variable (intervention characteristics) to produce a significant difference (QB = 5.67, P < 0.05) between moderators. While no significant differences were found between other moderators, several trends were apparent within groups in which experimental groups outperformed control groups. Autism Res 2018, 11: 818-833. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Results of the meta-analysis-a method for synthesizing research-showed physical activity interventions to have a moderate or large effect on a variety of outcomes, including for the development of manipulative skills, locomotor skills, skill-related fitness, social functioning, and muscular strength and endurance. The authors conclude that physical activity's standing as an evidence-based strategy for youth with ASD is reinforced. PMID- 29693782 TI - Access to hematopoietic stem cell transplant for patients with sickle cell anemia. AB - Hematopoietic stem cell transplantation (HSCT) is a curative therapy for patients with phenotypically severe sickle cell anemia, and survival rates following matched-sibling HSCT are very high. However, despite cure rates much higher than HSCT for malignant diseases, the field has been slow to adopt this treatment modality for sickle cell anemia. This article explores some of the social forces that may contribute to this dichotomy. PMID- 29693783 TI - Electron-Catalyzed Cross-Coupling of Arylboron Compounds with Aryl Iodides. AB - Arylboroxines in combination with zinc chloride and potassium tert-butoxide were found to undergo the electron-catalyzed cross-coupling with aryl iodides to give the corresponding biaryls without the aid of transition-metal catalysis. PMID- 29693784 TI - Meta-analysis of the incidence and patterns of second neoplasms after photon craniospinal irradiation in children with medulloblastoma. AB - BACKGROUND: Second neoplasms (SNs) are a well-established long-term adverse effect of radiation therapy (RT), but there are limited data regarding their incidence and location relative to the radiation field, specific to medulloblastoma (MB) survivors after craniospinal irradiation (CSI). METHODS: A systematic literature review, per Preferred Reporting Items for Systematic Reviews and Meta-Analyses, identified six studies reporting the incidence and locations of SNs for 1,114 patients with MB, after CSI, with a median follow-up of ~9 years (7.6-15.4 years). The study-specific cumulative incidence (CI) of SNs, second benign neoplasms (SBNs), and second malignant neoplasms (SMNs) were standardized to a 10-year time frame. Meta-analysis was performed using random effects models, with pooled data from selected studies and an institutional cohort of 55 patients. RESULTS: The 10-year CI was 6.1% for all SNs (excluding skin cancer and leukemia), 3.1% for SBNs, and 3.7% for SMNs. Fifty-eight percent of SNs were malignant; high-grade glioma was the most common SMN (15/33; 45%) and meningioma, the most common SBN (16/24; 67%). Forty percent of SNs occurred outside the target central nervous system (CNS) field, with a majority in areas of exit RT dose. Seventy-four percent of extra-CNS tumors (17/23) were malignant, most commonly thyroid carcinoma (7/17; 41%) and bone and soft-tissue tumors (6/17, 35%). CONCLUSIONS: Survivors of MB are at risk of SNs both within and outside the CNS. A significant proportion of SNs occur in areas of exit RT dose. Studies are needed to determine whether the use of proton therapy, which has no exit RT dose, is associated with a lower incidence of SNs. PMID- 29693785 TI - Clinical spectrum of KIAA2022 pathogenic variants in males: Case report of two boys with KIAA2022 pathogenic variants and review of the literature. AB - KIAA2022 is an X-linked intellectual disability (XLID) syndrome affecting males more severely than females. Few males with KIAA2022 variants and XLID have been reported. We present a clinical report of two unrelated males, with two nonsense KIAA2022 pathogenic variants, with profound intellectual disabilities, limited language development, strikingly similar autistic behavior, delay in motor milestones, and postnatal growth restriction. Patient 1, 19-years-old, has long ears, deeply set eyes with keratoconus, strabismus, a narrow forehead, anteverted nares, cafe-au-lait spots, macroglossia, thick vermilion of the upper and lower lips, and prognathism. He has gastroesophageal reflux, constipation with delayed rectosigmoid colonic transit time, difficulty regulating temperature, several musculoskeletal issues, and a history of one grand mal seizure. Patient 2, 10 years-old, has mild dysmorphic features, therapy resistant vomiting with diminished motility of the stomach, mild constipation, cortical visual impairment with intermittent strabismus, axial hypotonia, difficulty regulating temperature, and cutaneous mastocytosis. Genetic testing identified KIAA2022 variant c.652C > T(p.Arg218*) in Patient 1, and a novel nonsense de novo variant c.2707G > T(p.Glu903*) in Patient 2. We also summarized features of all reported males with KIAA2022 variants to date. This report not only adds knowledge of a novel pathogenic variant to the KIAA2022 variant database, but also likely extends the spectrum by describing novel dysmorphic features and medical conditions including macroglossia, cafe-au-lait spots, keratoconus, severe cutaneous mastocytosis, and motility problems of the GI tract, which may help physicians involved in the care of patients with this syndrome. Lastly, we describe the power of social media in bringing families with rare medical conditions together. PMID- 29693786 TI - Reply to: Comment on: Comparison of hypersensitivity rates to intravenous and intramuscular PEG-asparaginase in children with acute lymphoblastic leukemia: A meta-analysis and systematic review. PMID- 29693787 TI - Integrated strategy based on high-resolution mass spectrometry coupled with multiple data mining techniques for the metabolic profiling of Xanthoceras sorbifolia Bunge husks in rat plasma, urine, and feces. AB - An integrated strategy based on high-resolution mass spectrometry coupled with multiple data mining techniques was developed to screen the metabolites in rat biological fluids after the oral administration of Xanthoceras sorbifolia Bunge husks. Mass defect filtering, product ion filtering, and neutral loss filtering were applied to detect metabolites from the complex matrix. As a result, 55 metabolites were tentatively identified, among which 45 barrigenol-type triterpenoid metabolites were detected in the feces, and six flavonoids and four coumarins metabolites were in the urine. Moreover, eight prototype constituents in plasma, 36 in urine and 23 in feces were also discovered. Due to the poor bioavailability of barrigenol type triterpenoids, most of them were metabolized by intestinal flora. Phase I metabolic reactions such as deglycosylation, oxidation, demethylation, dehydrogenation, and internal hydrolysis were supposed to be their principal metabolic pathways. Coumarins were found in all the biosamples, whereas flavonoids were mainly in the urine. Unlike the saponins, they were mainly metabolized through phase II metabolic reactions like glucuronidation and sulfonation, which made them eliminated more easily by urine. This work suggested the metabolic profile of X. sorbifolia husks for the first time, which will be very valuable for its further development. PMID- 29693788 TI - 'What the hell is water?' How to use deliberate clinical inertia in common emergency department situations. AB - Appropriate deliberate clinical inertia refers to the art of doing nothing as a positive clinical response. It includes shared decision-making to improve patient care with the use of clinical judgement. We discuss common clinical scenarios where the use of deliberate clinical inertia can occur. The insertion of peripheral intravenous cannulae, investigating patients with suspected renal colic and the investigation of low risk chest pain are all opportunities for the thoughtful clinician to 'stand there' and use effective patient communication to avoid low value tests and procedures. Awareness is key to identifying these opportunities to practice deliberate clinical inertia, as many of the situations may be so much a part of our environment that they are hidden in plain view. PMID- 29693789 TI - Protein Science best paper awards to Minfei Su and Chang-Ting Lin. PMID- 29693791 TI - Feasibility and results of an intraarterial chemotherapy program for the conservative treatment of retinoblastoma in Argentina. AB - BACKGROUND: The feasibility and results of intraarterial chemotherapy, also termed ophthalmic artery chemosurgery (OAC), for retinoblastoma in less developed countries have seldom been reported. PROCEDURE: A retrospective evaluation of a program of OAC in Argentina from 2010 to 2015. RESULTS: Ninety-seven eyes from 81 patients (61 bilateral) were analyzed. In 35 eyes, OAC was given as primary therapy and in 62 it was used for the treatment of tumors with partial response or those relapsing after systemic chemoreduction with focal therapy or external beam radiotherapy. Twenty-two primarily treated eyes had group D and 13 groups B/C. A total of 400 procedures were carried out. Chemotherapy used included combinations of melphalan, carboplatin, and topotecan. There was no mortality associated with OAC. Toxicity included fever and neutropenia in five (1.25%), hypotension and bradycardia during anesthesia in two and femoral thrombosis in one, eyelid edema in nine, and neutropenia or thrombocytopenia in 28 cycles. With a median follow-up of 48.7 months (range 12-79), the 3-year probability of event free survival (pEFS) (enucleation and/or radiotherapy were considered events) was comparable for patients who received first-line therapy and those treated at relapse (0.65 vs. 0.63, P = 0.5). In the former, the pEFS was 0.91 and 0.43 for groups B/C and D, respectively (P = 0.01). Two patients died of extraocular dissemination after refusal of enucleation. CONCLUSIONS: OAC was feasible with low toxicity. pEFS improved in all groups compared to the previous experience with systemic chemotherapy reducing the use of radiotherapy. The overall mortality associated with OAC is comparable to our previous experience with systemic chemoreduction. PMID- 29693793 TI - Does leisure-time physical activity attenuate or eliminate the positive association between obesity and high blood pressure? AB - We examine the joint association of weight status and leisure-time physical activity on high blood pressure in a nationally representative sample of adults and older adults in Brazil. This was a national cross-sectional survey conducted in Brazil in 2013 (Brazilian Health Survey). The sample consisted of 59 402 participants (56% women, aged 18 to 100 years). Outcome was objectively assessed blood pressure. Body mass index (BMI) was objectively measured, while self reported information on leisure-time physical activity, TV viewing, chronological age, race, educational status, tobacco smoking, sodium consumption, and hypertension medication was obtained using questionnaires. Logistic regression analysis with adjusted odds ratio was conducted to test the joint association of BMI and leisure-time physical activity categories on high blood pressure. Overall, compared to normal weight (NW) and physically active group, the NW/inactive (OR = 1.28; 1.04 to 1.58), overweight/active (OR = 1.38; 1.08 to 1.78), overweight/inactive (OR = 1.89; 1.53 to 2.33), obese/active (OR = 2.19; 1.59 to 3.01) and obese/inactive (OR = 2.54; 2.05 to 3.15) groups were 28% to 254% more likely to have high blood pressure. The attenuation and high blood pressure was greater for women and adults than for men and older adults. Thus, leisure-time physical inactivity and being overweight and obesity were associated with high blood pressure in Brazilian population. Engaging in sufficient level of physical activity during leisure could attenuate, but not eliminate, the negative influence of obesity on high blood pressure in Brazilian adults and older adults. PMID- 29693792 TI - Comparative proteomic analyses of human adipose extracellular matrices decellularized using alternative procedures. AB - Decellularized human adipose tissue has potential clinical utility as a processed biological scaffold for soft tissue cosmesis, grafting, and reconstruction. Adipose tissue decellularization has been accomplished using enzymatic-, detergent-, and/or solvent-based methods. To examine the hypothesis that distinct decellularization processes may yield scaffolds with differing compositions, the current study employed mass spectrometry to compare the proteomes of human adipose-derived matrices generated through three independent methods combining enzymatic-, detergent-, and/or solvent-based steps. In addition to protein content, bioscaffolds were evaluated for deoxyribose nucleic acid depletion, extracellular matrix composition, and physical structure using optical density, histochemical staining, and scanning electron microscopy. Mass spectrometry based proteomic analyses identified 25 proteins (having at least two peptide sequences detected) in the scaffolds generated with an enzymatic approach, 143 with the detergent approach, and 102 with the solvent approach, as compared to 155 detected in unprocessed native human fat. Immunohistochemical detection confirmed the presence of the structural proteins actin, collagen type VI, fibrillin, laminin, and vimentin. Subsequent in vivo analysis of the predominantly enzymatic and detergent-based decellularized scaffolds following subcutaneous implantation in GFP+ transgenic mice demonstrated that the matrices generated with both approaches supported the ingrowth of host-derived adipocyte progenitors and vasculature in a time dependent manner. Together, these results determine that decellularization methods influence the protein composition of adipose tissue derived bioscaffolds. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2481-2493, 2018. PMID- 29693794 TI - Butanol production from sweet sorghum bagasse with high solids content: Part I comparison of liquid hot water pretreatment with dilute sulfuric acid. AB - In these studies, we pretreated sweet sorghum bagasse (SSB) using liquid hot water (LHW) or dilute H2 SO4 (2 g L-1 ) at 190 degrees C for zero min (as soon as temperature reached 190 degrees C, cooling was started) to reduce generation of sugar degradation fermentation inhibiting products such as furfural and hydroxymethyl furfural (HMF). The solids loading were 250-300 g L-1 . This was followed by enzymatic hydrolysis. After hydrolysis, 89.0 g L-1 sugars, 7.60 g L-1 acetic acid, 0.33 g L-1 furfural, and 0.07 g L-1 HMF were released. This pretreatment and hydrolysis resulted in the release of 57.9% sugars. This was followed by second hydrolysis of the fibrous biomass which resulted in the release of 43.64 g L-1 additional sugars, 2.40 g L-1 acetic acid, zero g L-1 furfural, and zero g L-1 HMF. In both the hydrolyzates, 86.3% sugars present in SSB were released. Fermentation of the hydrolyzate I resulted in poor acetone butanol-ethanol (ABE) fermentation. However, fermentation of the hydrolyzate II was successful and produced 13.43 g L-1 ABE of which butanol was the main product. Use of 2 g L-1 H2 SO4 as a pretreatment medium followed by enzymatic hydrolysis resulted in the release of 100.6-93.8% (w/w) sugars from 250 to 300 g L-1 SSB, respectively. LHW or dilute H2 SO4 were used to economize production of cellulosic sugars from SSB. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:960-966, 2018. PMID- 29693795 TI - Reply to comment on: Effectiveness of antibacterial prophylaxis during induction chemotherapy in children with acute lymphoblastic leukemia. PMID- 29693796 TI - A phase 1 study of cabozantinib in children and adolescents with recurrent or refractory solid tumors, including CNS tumors: Trial ADVL1211, a report from the Children's Oncology Group. AB - BACKGROUND: We conducted a phase 1 trial to determine the maximum tolerated dose (MTD), toxicity profile, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary activity of cabozantinib in children with refractory or relapsed solid tumors. METHODS: Patients received cabozantinib tablets on a continuous dosing schedule in a rolling-six escalating phase 1 trial design. PK and PD studies were performed. RESULTS: Forty-one patients, median (range) age 13 (4-18) years, received cabozantinib to achieve a weekly cumulative dose equivalent to 30 (n = 6), 40 (n = 23). or 55 (n = 12) mg/m2 /day. At 40 mg/m2 /d, dose-limiting toxicities (DLTs) were palmar-plantar erythrodysesthesia syndrome, mucositis, and elevated alanine aminotransferase, lipase, and bilirubin. At 55 mg/m2 /d, hypertension, reversible posterior leukoencephalopathy syndrome, headache, fatigue, and proteinuria were DLTs. Frequent non-DLTs included diarrhea, hypothyroidism, fatigue, nausea, vomiting, elevated hepatic transaminases, and proteinuria. In subsequent cycles, DLTs occurred at all dose levels. Across all dose levels, the steady-state exposure and peak cabozantinib concentrations were similar. Four patients experienced a confirmed partial response: medullary thyroid cancer (MTC; n = 2), Wilms tumor, and clear cell sarcoma. Stable disease (>6 cycles) was seen in seven patients (MTC [n = 2], Ewing sarcoma, synovial sarcoma, alveolar soft part sarcoma, paraganglioma, and ependymoma). CONCLUSIONS: A protocol-defined MTD was not reached; DLTs and dose reductions for toxicity occurred in the first and subsequent cycles at all dose levels. Based on the toxicity profile, pharmacokinetics, and responses, the recommended dose of cabozantinib in pediatric patients with refractory solid tumors is 40 mg/m2 /day. A phase 2 study of cabozantinib is being conducted. PMID- 29693797 TI - Mobile health intervention for youth with sickle cell disease: Impact on adherence, disease knowledge, and quality of life. AB - BACKGROUND: Adherence to illness self-management among youth with sickle cell disease (SCD) positively impacts health outcomes and decreases overall healthcare costs. Despite this, children with SCD face several barriers to adherence, with adherence rates that remain moderate to low. The current feasibility study examined the Intensive Training Program (ITP), a mobile health (mHealth) intervention for youth with SCD designed to promote disease knowledge, adherence, and patient-provider communication. PROCEDURE: Youth with SCD prescribed hydroxyurea between ages 7-18 completed baseline disease knowledge and psychosocial assessments and then were provided with the ITP app. Youth participated in the 90-day ITP, during which they completed three education modules, tracked adherence through daily self-recorded videos on the app, and received video messages from providers. Participants completed poststudy knowledge, psychosocial, and feasibility questionnaires. Medication possession ratio (MPR) was obtained via pharmacy-refill rates. RESULTS: Thirty-two youths (mean age = 13.0 years) participated, with an average adherence tracking rate of 0.6 (standard deviation = 0.34). All participants demonstrated increased MPR (0.57-0.74, P < 0.001, d = 0.75) and disease knowledge (59.6-88.6%, P < 0.001). There was variable engagement in the ITP; completers demonstrated significantly better SCD-related functioning (P < 0.05), higher parent-reported treatment functioning (P < 0.05), and lower pain impact than noncompleters of the ITP (P < 0.05). CONCLUSIONS: Results support the ITP can feasibly be implemented to promote adherence among youth with SCD. All participants demonstrated increased adherence and disease knowledge. However, there was variable engagement and only intervention completers showed improvements in psychosocial outcomes. Further research is needed to evaluate long-term outcomes and ways to promote engagement in mHealth interventions among the youth. PMID- 29693798 TI - Treating Langerhans cell histiocytosis, globally. PMID- 29693799 TI - Evaluation of boost irradiation in patients with intermediate-risk stage III Wilms tumour with positive lymph nodes only: Results from the SIOP-WT-2001 Registry. AB - OBJECTIVE: To evaluate the value of radiotherapy boost omission in patients with intermediate-risk, stage III Wilms tumours (WT) with positive lymph nodes (LN). METHODS AND MATERIALS: All patients with intermediate-risk, stage III (LN positive) WT consecutively registered in the SIOP-WT-2001 study were included in this analysis. Endpoints were 5-year event-free survival (EFS), loco-regional control (LRC) and overall survival (OS). RESULTS: Between June 2001 and May 2015, 2,569 patients with stage I to III WT after preoperative chemotherapy were registered in the SIOP-WT-2001 study. Five hundred and twenty-three (20%) had stage III disease, of which 113 patients had stage III due to positive LN only. Of those, 101 (89%) received radiotherapy, 36 of which (36%) received, apart from flank irradiation, a boost dose to the LN positive area. Four patients (4%) did not receive any adjuvant radiotherapy. In eight patients information on radiotherapy was not available. With a median follow-up of 71 months, no difference in 5-year EFS (84% vs. 83%, P = 0.77) and LRC (96% vs. 97%, P = 0.91) was observed between patients receiving a radiotherapy boost and those without boost, respectively. Five-year OS, including salvage therapy, was excellent (boost vs. no boost: 97% vs. 95%, P = 0.58). CONCLUSIONS: Outcome data demonstrate that omission of the radiotherapy boost to the loco-regional positive lymph nodes in patients with intermediate-risk, stage III WT who receive preoperative chemotherapy and postoperative flank irradiation (14.4 Gy) can be considered a safe approach for future SIOP protocols. PMID- 29693800 TI - Pharmacokinetics and Pharmacodynamics of Luseogliflozin, a Selective SGLT2 Inhibitor, in Japanese Patients With Type 2 Diabetes With Mild to Severe Renal Impairment. AB - This open-label, parallel-group, multicenter study aimed to assess the effects of renal impairment on the pharmacokinetics, pharmacodynamics, and safety of luseogliflozin. A single 5-mg dose of luseogliflozin was administered to Japanese patients with type 2 diabetes mellitus in the following groups: G1, normal renal function; G2, mild renal impairment; G3a, mild to moderate impairment; G3b, moderate to severe impairment; G4, severe impairment, based on estimated glomerular filtration rate (eGFR; >=90, 60-89, 45-59, 30-44, 15-29 mL/min/1.73 m2 , respectively). While luseogliflozin pharmacokinetics were similar for patients across all renal function groups, the increase in plasma concentration was slightly slower and maximum concentration was slightly reduced in the lower eGFR groups compared with the other groups. However, luseogliflozin pharmacodynamics were affected by the severity of renal impairment. Urinary glucose excretion (UGE) increased in all groups relative to baseline levels, but the degree of UGE increase was smaller in the lower eGFR groups. Moreover, plasma glucose AUC changes from baseline tended to be smaller in the lower eGFR groups. No clear trends were observed between eGFR and incidence, type, or severity of adverse events. Thus, luseogliflozin administration should be carefully considered, as patients with renal impairment may show an insufficient response to treatment. PMID- 29693801 TI - Visit-to-visit variability in blood pressure and Alzheimer's disease. AB - Alzheimer's disease is the most common type of dementia and one of the leading sources of disability and dependency in the elderly. Given the limited treatment options, understanding the role of modifiable risk factors implied in the disease pathogenesis is a worthwhile endeavor to limit its global burden. Recently, the variability of blood pressure has been suggested to be a significant determinant of brain alterations and a potential therapeutic target. The aim of this article is to review the clinical evidence on the association between visit-to-visit blood pressure variability and Alzheimer's disease, highlight the underlying mechanisms, and suggest future implications. PMID- 29693802 TI - Effect of nanoparticle on cellular growth and lipid production in Chlorella vulgaris culture. AB - Magnetic cobalt ferrite/silica nanoparticles (MSNs) and methyl functionalized MSNs (methyl-MSNs) were used to enhance lipid production in Chlorella vulgaris culture through enhancement of gas-water mass transfer and increased dissolved concentration of CO2 . Methyl-MSNs enhanced CO2 -water mass transfer rate better than MSNs, and 0.3 wt% methyl-MSNs are more effective than 0.1 wt% MSNs. In the cultivation experiment, 0.3 wt% methyl-MSNs yielded the highest dry cell weight and subsequently, the highest mass transfer rate. However, enhancement of mass transfer rate did not increase lipid content. The volumetric lipid productivity in C. vulgaris culture depends not only on intracellular lipid content but also on the cell mass concentration. Consequently, 0.1 wt% methyl-MSNs yielded the highest volumetric lipid productivity in C. vulgaris cultivation. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:929-933, 2018. PMID- 29693803 TI - Experience with host cell protein impurities in biopharmaceuticals. AB - In the 40-year history of biopharmaceuticals, there have been a few cases where the final products contained residual host cell protein (HCP) impurities at levels high enough to be of concern. This article summarizes the industry experience in these cases where HCP impurities have been presented in public forums and/or published. Regulatory guidance on HCP impurities is limited to advising that products be as pure as practical, with no specified numerical limit because the risk associated with HCP exposure often depends on the clinical setting (route of administration, dose, indication, patient population) and the particular impurity. While the overall safety and purity track record of the industry is excellent, these examples illustrate several important lessons learned about the kinds of HCPs that co-purify with products (e.g., product homologs, and HCPs that react with product), and the kinds of clinical consequences of HCP impurities (e.g., direct biological activity, immunogenicity, adjuvant). The literature on industry experience with HCP impurities is scattered, and this review draws in to one reference documented examples where the data have been presented in meetings, patents, product inserts, or press releases, in addition to peer-reviewed journal articles. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:828-837, 2018. PMID- 29693805 TI - Adapting Traditional Ideas for a New Reality: Cosmographers and Physicians Updating Astrology to Encompass the New World. AB - This paper aims to demonstrate that astrology was one of the disciplines that most strongly experienced the process that led European natural philosophers, once they were confronted with the nature of the New World, to recognise that previous knowledge was not as complete or absolute as previously assumed, and that the content of several disciplines had to be renewed, both epistemologically and methodologically. This paper focuses on the work by the cosmographer Henrico Martinez, Repertorio de los tiempos (1606), in which he established the astrological influences specific to Mexico, and the work Sitio, naturatezay propiedades de la Ciudad de Mexico (1618) by the physician Diego Cisneros, who refuted Martinez's astrology for Mexico and created his own instructions for the use of astrology in the practice of medicine in New Spain. PMID- 29693804 TI - Synergistic Growth Inhibitory Effects of Chrysin and Metformin Combination on Breast Cancer Cells through hTERT and Cyclin D1 Suppression AB - Objective: To explore the possibility of a novel chemopreventive strategy for improving breast cancer treatment,the anticancer effects of a combination two natural compounds, Chrysin and Metformin, against T47D breast cancercells were investigated. Materials and Methods: After treatment of T47D cells with Metformin, Chrysin and the twodrugs in combination, toxicity to cancer cells was evaluated by MTT assay. Real time PCR was then used to determinethe expression levels of hTERT and cyclin D1 genes. Results: The MTT test findings showed that the combination ofmetformin and chrysin had high synergistic effects in killing cancer cells. In addition PCR demonstrated a significantdecrease in cyclin D1 and hTERT gene expression in the T47D breast cancer cell line. Conclusion: The conmbinationof metformin and chrysin suppressing hTERT and cyclin D1 gene expression might offer an appropriate approach forbreast cancer therapy. PMID- 29693806 TI - Natural History Illustration between Bologna and Valencia: The Aldrovandi-Pomar Case. AB - The manuscript Atlas de Historia Natural, known as the Pomar Codex, in the University Library of Valencia contains more than a hundred images that are practically identical to those found in the Tavole acquerellate in the collection of Ulisse Aldrovandi in the University Library of Bologna. I will argue that the overwhelming presence of images belonging to Ulisse Aldrovandi's collection in the Pomar Codex indicates that future research on this text should be based on trying to understand possible methods of exchange between Italy and the Iberian Peninsula. This case study will enable us to better understand the mechanisms of communication and exchange among early modem members of the Republic of Letters. PMID- 29693807 TI - A Powerful Antidote, a Strange Camel and Turkish Pepper: Iberian Science, the Discovery of the New World and the Early Modem Czech Lands. AB - This article analyses the reception of knowledge about new world nature, and, more specifically, the reception of Iberian scientific knowledge of nature in the Americas, in the early modem Czech lands. It shows how the process of the reception of information about nature in the new world differed among the urban classes, intellectuals and the nobility; particular attention is paid to herbals, cosmographical works and travel reports. On the one hand, the study reveals that the efforts of Central European intellectuals to interpret new world nature were limited by the lack of necessary data and experience, which led to some misinterpretations and simplifications. On the other hand, it shows these Central European scholars to be fully-fledged members of an information network, whose works share many of the same characteristics as Iberian and, in general, early modem European science. PMID- 29693808 TI - A Behind-the-Scenes Glimpse into the Princeps Edition of Coloquios dos simples (Goa, 1563). AB - Considered by many to be the most learned Portuguese physician who lived in Goa during the sixteenth century, Garcia de Orta (c. 1500-1568) was the author of CoIoquios dos Simples, e Dro gas he cousas medicinais da India [Colloquies on the Simples and Drugs of India] (Goa, 1563). Devoted entirely to the description of Asian natural resour ces, very little is known about how this treatise came into existence. Publish ed at the edges of the Portuguese empire, and a hostage to technical, structural and human constraints, the princeps edition had a limited circulation. The diffusion around Europe of the novelties described in Col6quios dos Simples owed in part to the efforts of Clusius (1526-1609), one of the leading botanists of the time. This scholar promptly published Aromatum et Simplicium (Antwerp, 1567), a Latin epitome of Coloquios dos Simples. This complete reframing of Orta's treatise guaranteed the wide dissemination of the new knowledge about Asian plants, fruits and drugs validated by the Portuguese physician on the periphery of the empire. In this essay I analyse the background to the publication of the Portuguese treatise and demonstrate that, especially due to structural constraints, the princeps edition had a limited circulation. I show that the wide diffusion of the novelties about the natural resources of the Indies was dependent on the technical equipment, artistic skills and editorial criteria dictated and managed by European academics, artists and printers. I propose that the appropriation of local knowledge collected and validated in the Iberian Empires by imperial agents challenged European academics and typographers to create innovative treatises about the Indies' natural resources that assured the widespread circulation of an entirely new natural knowledge. PMID- 29693809 TI - Visiting Old Libraries: Scientific Books in the Religious Institutions of Early Modem Portugal. AB - Knowledge of libraries and book collecting is a preliminary task for the characterisation of scientific culture and practice. In the case of Iberia, and especially Portugal, this is still a desideratum. This paper provides a first global look at this issue. In early modem Portugal religious institutions organised impressive collections of books, by far the largest in the country These libraries not only served the religious institutions themselves, but also supplied books to lesser libraries, such as the University Library of Coimbra and the Royal Library. The Portuguese book market mirrored the purchase and selection of books made by religious congregations. This was also true for the circulation of scientific books, which depended above all on the interests, choices and cultural relations of these most peculiar book collectors. PMID- 29693810 TI - Venereal diseases: an international health problem in 1900. AB - During the second half of the XIX century a powerful international health movement appeared as the expression of the political and economic importance of the health-disease relationship. From 1850 a long series of international health conferences on epidemics, hygiene, charity, tuberculosis, mother-baby health and rural health brought together doctors, diplomats and governors from many countries to look for political solutions to the social impact of disease. An international health diplomacy arose from this as a channel for debate and solution to the main health problems. According to official statistics, the elevated prevalence of syphilitics at the beginning of the XX century set off the alarm regarding the problems of preventing and treating the disease. Two international conferences on syphilis were convened. This article analyses the contributions and debates among the international experts, the medico-sanitary, moral and social arguments, and the political reactions, national regulations for prostitution as well as international initiatives and recommendations. The main sources used are national regulations, and the lectures, reports and debates that occurred during the two International Conferences on Syphilis, held in Paris and Brussels between 1998 and 1902. PMID- 29693811 TI - [Ramon de la Sota y Lastra (1832-1913): an approach to his social and professional biography.] AB - This article aims to be a contribution to a better understanding of the physician, Ram6n de la Sota y Lastra. Exhaustive heuristic work has permitted the gathering of a group of sources that has modified, both in quantity and quality, the information that was available on him. His role in the constitution of the speciality of otorhino-laryngology in our country has been recognised, but without entering in detail. This role, as well as his academic career, his professional activity or the internationalization of his written works, is addressed in this work. PMID- 29693812 TI - STEMI in Pregnancy. PMID- 29693813 TI - Crystal Induced Acute Kidney Injury. PMID- 29693814 TI - PROJECT REFRESH: Phase II of EP Review Project. PMID- 29693815 TI - APPROVED: Revisions to Advanced Certification Requirements for Inpatient Diabetes Care. PMID- 29693816 TI - Consistent Interpretation. Joint Commission Surveyors' Observations on EC.02.05.01, EP 15. PMID- 29693818 TI - A Sad State of Affairs. PMID- 29693817 TI - Community-I nitiated Pilot Program "My Baby's Breath" to Reduce Prenatal Alcohol Use. AB - Prenatal alcohol use puts mothers and their children at risk for complications during pregnancy, birth, and the neonatal periods. This paper describes a currently implemented community-based pilot program to reduce drinking among pregnant mothers. The program has worked in collaboration with case managers from Crow Wing County Social Services. Participants were required to provide daily breath samples with monetary incentives on alcohol-negative sample submissions. The program has treated four pregnant mothers so far, with an average of 94 percent compliance rate and no alcohol-positive breath samples. Future planned adjustments include using a remotely reloadlable debit card to reinforce daily sample submission, switching to completely random monitoring schedules to avoid falsenegative results, and expanding the program service in other counties. The community-based program using mobile technology has promise to increase opportunities to reinforce healthy lifestyle during pregnancy. PMID- 29693820 TI - Apples & Oranges - How to Compare Job Offers. PMID- 29693819 TI - Not All Chest Pains Are Made Equal: A Case of Apica Hypertrophic Cardiomyopathy. PMID- 29693821 TI - [Evaluation of occupationally conditioned and non-occupational risks of health disorders in truck drivers]. AB - The authors present analysis of changes in genera! morbidity related to age and length of service for truck drivers (chronic diseases of cardiovascular system, respiratory and digestive organs, urinary system, spine, locomotory system and connective tissue) exposed to complex combination of occupational hazards (unusual work schedule, night shifts, air pollution with automobile transport exhaust gases). Morbid "ity parameters were calculated according to deep medical investigation results in periodic examinations of drivers and their appealability to medical office. General hygienic evaluation of work conditions was performed according to increment in risk of diseases for length of service years (annual risk increase). Difference of disease risk increase rates related to age and length of service was applied to determine occupational and non-occupational fractions of general morbidity in drivers working in hazardous conditions. PMID- 29693822 TI - [Occupational health risks in transport workers of mi ning chemical enterprise in Kolsk Transpolar area]. AB - The study covered features of work conditions, occupational risks and health state in 574 workers of automobile and railway transport, engaged into transportation of lobe rock in Kolsk Transpolar area. Findings are higher risk of occupationally conditioned (onychomycosis, obesit arterial hypertension and peptic ulcer of duodenum/stomach) and occupational diseases (neurosensory deafness, radiculopathy, vibration disease) in rock handler drivers. Conclusion was made on necessity to improve prophylaxis and treatment of health disorders in these workers. PMID- 29693823 TI - [Levels of exposure to metals in population of Pechenga district of Murmansk region]. AB - Serum levels of zincum, lead, nickel and mercury decrease in a row <>; average levels of manganese, cobalt, copper and arsenic are higher among females; in pregnant women serum levels of most metals are the lowest. If compared to the WHO. reference, levels of metals in whole blood demonstrated no excess in cobalt and cadmium, nearly absent - in arsenic, increased percentage of excess (but insignificant values) in copper and zincum, extremely high percentage of excess (and significant values) in manganese and nickel. Maximal manganese concentrations in blood reach 300 micrograms/I, those of nickel - 100 micrograms/I. Average blood concentrations of mercury in the examinees do not reach the most severe <> (S micrograms/1), and shares of men and women with blood concentrations of mercury over this limit are relatively small. Average blood concentrations of lead in the examinees do not reach lower allowable level (50 micrograms/1). PMID- 29693824 TI - [Alternative investigation methods in toxicologic hygienic evaluation of industrial and environmental objects]. AB - North-West Public Health Research Center, 4, 2-ya Sovetskaya str, S.-Petersburg, Russia, 191036 The authors reviewed toxicologic alternative investigation methods used in Russia for evaluation of occupational and natural environment. PMID- 29693825 TI - [Justifying standards of workup in patients with occupational polyneuropathy caused by physical overload]. AB - The authors examined algorithm of investigations in occupational pathology centers for suspected occupational polyneuropathy due to physical overload. Suggestions included a procedure to investigate the patients, including medical specialists consultations, set of laboratory and instrumental studies divided into obligatory and by special indications. PMID- 29693826 TI - [Health state and morbidity of underground mines in mining chemical enterprise in Arctic area of Russian Federation]. AB - The study covered health state of mine workers of "Apatit" enterprise according to periodic medical examination data in 2014. Medical workup covered 1360 miners of main, auxiliary occupations, with assessment of standardized intensive morbidity parameters. The analysis defined the most unfavorable health state of main occupations workers, with leading pathology of locomotory diseases, nervous system (polyneuritis) and ear disorders. These diseases could be caused by specific work conditions characterized by exposure to vibration, noise, intense physical exertion, cooling. PMID- 29693827 TI - Comparative evaluation of X-ray contrast myography and ultrasound study in diagnosis of occupational myofibrosis]. AB - The article presents results proving significant advantage of ultrasound examination vs. X-ray contrast myography in diagnosis of occupational myofibrosis early stages. The authors recommend implementation of thi s method into medical examination practice for better diagnosis of occuptional myofibrosis to objectify decision on linking the disease with occupation. PMID- 29693828 TI - [Regional model of integrating occupational control over work condition into social hygienic monitoring system]. AB - Existing practice implementing data obtained by occupational control and special evaluation of work conditions fails to evaluate hazardous effects caused in workers' health state by wide spectrum of risk factors such as social, ecologic, climate, etc. Widening possibilities for deeper health risk analysis can be provided by integration of laboratory and instrumental data on evaluation of hazardous and dangerous occupational factors into present systems of social hygienic monitoring. According to results of joint project within disciplinary program, Leningrad regional division of Federal Agency on sanitary epidemiologic supervision specified and implemented a regional model of integrated data base in informational funds of social hygienic monitoring. Consequently, quality and validity of management decisions in health risk factors control have significantly improved.i. PMID- 29693829 TI - [Results of sanitary epidemiologic examination of sanitary protective zone projects (discussion). AB - The authors defined main transgressions of law in sanitary epidemiologic well being of population during sanitary epidemiologic examination of project materials for sanitary protective zones for enterprises, constructions and other objects, and during determination of their final dimensions. PMID- 29693830 TI - [Contemporary approach to evaluation of sensory disorders in polyneuropathy due to vibration]. AB - Recently, the studies search possibilities to visualize and objectify sensory disorders in polyneuropathy caused by vibration. Special attention is paid on studies of injuried structures responsible for temperature and pain sensitivity. Examination covered 92 patients with vibration disease, aged 34 to 73 years. Methods used are: pallesthesiometry, quantitative sensory tests, questionnaires and s 'cales of pain (visual analog scale (VAS) of pain, Pain-Detect, MPQ DN-, HADS). Correlation was found between.temperature, pain thresholds and VAS and pallesthesiometry parameters. The obtained results analysis indicates formation distal polyneuropathy syndrome of upper limbs with concomitant pain during vibration disease. PMID- 29693832 TI - [[Medical practice in the virtual space: Long distance relationships between Juan Munoz y Peralta (1665-1746) and his patients].] AB - In the eighteenth century, it was a common practice to send consultation letters to physicians, particularly to renowned ones. Accessing the virtual space of correspondence was for the patients in many cases the final stage of a long therapeutic itinerary or the attempt to overcome the geographical distance that arouse out of different motives between the practitioner and the sick. From early modern Spain, very few patient letters have survived to the present days. A great exception are the letters addressed to the physician Juan Munoz y Peralta (1665 1746). As a royal physician and the first president of the "Royal Society of Medicine and other Sciences of Seville", Spain's first scientific academy, Munoz y Peralta was an outstanding figure of the Spanish "Novator" movement, promoting the modern medicine. Today, the National Historic Archive preserves a collection of 67 letters, written between 1709 and 1721 by men and women to the physician Peralta. The aim of this paper is to analyse these letters in order to reconstruct from the very perspective of the patient why and how they initiated a correspondence with Peralta as well as their attitudes towards the different therapeutic offers that ranged between the traditional and the modern. Crucially, it wvill examine the physician-patient relationship that came into being in a very particular setting: the virtual space correspondence. PMID- 29693831 TI - [Medical and sanitary conditions of life activities of sea craft crew (review of literature)]. AB - The article characterizes sea work conditions under which crew-members carry occupational activitie's during the sail. Negative factors influencing health of crew members are listed. Among these factors, the major influence is caused by physical (noise, vibration, mechanical impacts, ionizing radiation varying in frequency), chemical, climate and.geographic, social an psychologic factors. Conclusion is that extreme work conditions of sailing staffers cause overstrain of adaptation systems, disorders of regulation fuctions, worsen health state and induce disablement. Within a system of medical care.for water transport workers, necessity is to have complex accounting of occupational hazards for more qualitative and safe work conditions. PMID- 29693833 TI - [Eugenics and Falange through the journal Ser (1942-1957)]. AB - Biopolitics has played an important role in fascist totalitarianism and the Francoist regime was no exception. From the and with ultimate goal or regulating the population, measures were implemented to increase, care for and indoctrinate the population. This present study analyses the selection and promotion measures of some populations and the marginalisation of others proposed the Spanish Falangist Movement's official publication in the field of medicine, the journal Ser, Revista Medico-Social by the National Delegation of Health of the Traditionalist Spanish Phalanx of the Committees of the National Syndicalist Offensivie (F.E.T y de las J. O. N. S. 1942-1957). In this respect, the analysis of eugenic ideas and practice defended therein become especially interesting, claiming that, through indoctrination and health development, the race would be improved both physically and mentally. From the systematic analysis of the journals's contenets it has been demonstrated that this was one of the instruments used by the dictatorial regime to reconfigure eugenics in accordance with Catholic morals and national syndicalist politics. PMID- 29693834 TI - Practice Transitions. PMID- 29693835 TI - How to move the conversation when chairside chatter turns to politics. PMID- 29693836 TI - Failure to follow protocol is difficult to swallow. PMID- 29693837 TI - Wrigley grants at work in our communities. PMID- 29693838 TI - A rose by any other name. PMID- 29693839 TI - CYTOLOGICAL ANALYSIS OF THYROGLOSSAL DUCT CYSTS. AB - INTRODUCTION: Thyroglossal duct cysts are regarded as congenital anomalies. They arise from the residual segments of thyroglossal duct. A cancer with the incidence rate from 1% to 1.5% may develop in thyroglossal duct cysts. Approximately 30% of patients asked to be examined due to inflammatory cysts. This Study was aimed at determining the cytological characteristics of thyroglossal duct cyst smear, Such as cell specificity, cellularity and the content of the extracellular matrix. MATERIAL AND METHODS: Thyroglossal duct cyst smears were analyzed in 28 adult patients who had undergone the fine-needle aspiration cytology in the period from 2004 to 2014. Three patients underwent the Surgery following the Sistrunk procedure. The rest of the patients are in the process of monitoring. The monitoring process lasts from I to 10 years. RESULTS: As many as 27 Out of 28 smears contained macrophages, 9 contained stratified squamious.epithelial cells and only 4 smears contained follicular cells. Granulocytes were present in 4 smears. Two smears had scarce cellularity, 21 had moderate and 5 high cellularity. Malignant cells were not observed. In 19 smears, extracellular matrix consisted of cholesterol crystals. CONCLUSION: Thyroglossal duct cysts have no specific cytological featres. Macrophages are the dominant cell population. Cholesterol crystals and stratified squamous epithelial cells enable differentiation of thyroglossal duct cysts from thyroid gland Cystic nodules. Fine-needle aspiration cytology is necessary when assessing the cellular composition of thyroglossal duct cysts in order to promptly detect the possible presence of malignant cells and to conduct a surgical treatment. PMID- 29693840 TI - PLASMA ENDOTHELIN-1 LEVELS AND ALBUMINURIA IN PATIENTS WITH TYPE 2 DIABETES MELLITUS. AB - INTRODUCTION: Microalbuminuria is a very important independent risk factor for the progression of renal diseases as well as diseases of the cardiovascular system. Pathophysiological mechanisms that lead to the development ofmicroalbuminuria in patients with diabetes are complex and they are a result of numerous factors. In the past decade, endothelin-1, the most potent vasoconstrictor peptide, was identified as animportant factor that significantly contributes to the functional and structural renal changes. The objective of this study was to investigate the relationship between plasma concentration of endothelin-1 and urinary albumin excretion in patients with type 2 diabetes mnellitus. MATERIAL AND METHODS: There were 76 patients with type 2 diabetes who were divided into those having normoalbuminuria (n-33), microalbuminuria (n=29) and macroalbuinuria (n=14), and 30 healthy controls. Plasma levels of endothelin 1 were measured by enzyme-linked immunosorbent assay. RESULTS: There were significant differences in plasma concentration of endothelin-1 among groups (P<0.01). The correlation between endothelin-1. albuminuria. proteinuria and glomercular filtration rate was significant. In multiple regression analyses the plasma concentration of endothelin-l was independently and significantly associated with albuminuria (beta=0.01, p=0.009), proteinuria =.02, p<0.001) and glon.erular filtration rate (P3=0betal. pO-.P=)6).0Conclu- sion. Higher plasma concentrations of endothelin-1 are independently associated with the levels of urinary, excretion of albumin Whicw May morroborate tlse hpothesis of apotenstial role of this peptide inl th de- vepment of microalbUminuriauin diabetic necphrpathy. PMID- 29693841 TI - PROGNOSTIC FACTORS FOR POSTOPERATIVE VISUAL OUTCOME IN SURGICALLY TREATED SUPRASELLAR MENINGIOMAS. AB - INTRODUCTION: The prognosis of postoperative visual acuity in patients with surgically treated suprasellar meningiomas is influenced not only by the size and precise localization of meningiomas in the optochiasmatic region and their compressive effect, but also by certain parameters, such as the age of patient, duration of symptoms, and preoperative visual acuity. The purpose of this study was to analyze the influence of these factors on postoperative visual acuity in the patients with surgically treated optochiasmatic meningioma as well as to determine their prognostic value in the recovery of visual function after surgery. MATERIAL AND METHODS: The study sample consisted of 43 pati- ents operated for suprasellar meningioma. All tumors were dia- gnosed by computed tomography or nuclear magnetic resonance scans. Visual acuity was analyzed both before surgery and six months after surgery. The effects of age, preoperative Visual loss, duration of visual symptoms and tumor size on visual outcome were analyzed. RESULTS: Postoperative improvement of visual acuity was observed in 50% of eyes (68.4% of patients). Visual outcome was better in the younger patients. The patients with better preoperative visual acuity had better postoperative visual acuity outcome. Chances of achieving better postoperative visual function and favorable tumor resection outcome were inversely proportional to the increased length of history of disease and tumor size. CONCLUSION: Postoperative visual acuity prognosis in suprasellar meningioma surgery was favorably affected by the mean duration of symptoms of less than 24 months, tumor size less than 30 mm. and preoperative visual acuity loss below 0.1. PMID- 29693842 TI - THE IMPACT OF COMBINED MENISCUS TEAR ON QUALITY OF LIFE AFTER ANTERIOR CRUCIATE LIGAMENT RECONSTRUCTION. AB - INTRODUCTION: An anterior cruciate ligament injury represents a significant epidemiological problem worldwide, especially due to involving young, sporty and active working-age population. This study has been conducted in order to compare the quality of life of patients who had isolated anterior cruciate ligament tear and of those who suffered from anassociated meniscal injury. MATERIAL AND METHODS: This study included 185 patients who had undergone reconstruction of the anterior cruciate ligament at the Department of Orthopedic Surgery and Traumatology in Novi Sad from January lst, 2012 to December 31st 2012. The patients vere divided into 2 groups: group AZ consisted of patients who had anterior cruciate ligament reconstruction only, and group B consisted of patients who had partial meniscectomy in addition to the anterior cruciate ligament reconstruction. The follow-up period was 12 months. RESULTS: Distribution of patients by gendei was significantly in favor of men. In our study, 146 patients ~vere male and 39 patients ~vere female. The average age of patients was 26.1 years overall (16-55 years), being 26.9 years tbr men, and 23.3 years for female patients. Out of 185 patients, 110 had an isolated anterior cruciate ligament injury, while 75 suffered both meniscus, internal or external, and anterior cruciate ligament injury. CONCLUSION: The comparison of the quality of life of patients in both groups showed no statistically significant difference. Therefore, we were not able to prove the hypothesis about the superior quality of life of those patients who had suffered from a runnired anterior cruciate linament only. PMID- 29693843 TI - THE RELATIONSHIP BETWEEN THE RANGE OF MOTON OF THE HIP JOINT WITH RUPTURED ANTERIOR CRUCIATE LIGAMENT. AB - INTRODUCTION: A knee injury, especially anterior cruciate ligament. has recently become more common significantly affecting the life standard. There are many factors that cause an injury of the anterior eruciate ligament, ~nd one of them is limited range of motion in the hip joint. This studyhas been aimed at finding a relationship between the range of motion in the hip joint and the anterior eriiciate ligament injury. Matcrial and Methods. Of88 male athletes included in the study sample in 2014, 60 (68%) had ruptured knee anterior cruciate ligament and 28 (32%) were without an injury. There was no sianificant difference in sex, height, weight, age and time of injury between the two groups. RESULTS: Significant differences were found in the range ofmotion between the lefi and right leg in both groups. The athletes with a ruptured anterior cruciate ligament had an abduction limit of the hip joint (p0.007) and a wider rang of motion of the knee joint (p0.O02) than thc athletes without the inj Liry. CONCLUSION: Data obtained in this study suggest a possible relationship between a limited hip abduction of range of motion in athletes and an increased risk of anterior cruciate ligament injury. PMID- 29693844 TI - AN INCIDENTAL FINDING OF THYMIC CARCINOMA DURING ELECTIVE CORONARY ARTERY BYPASS GRAFTING. AB - INTRODUCTION: Thymoma is a rare malignant tumor of the anterior mediastinum. Thymic squamous cell carcinoma has been recognized as an aggressive form of thymoma with different behavior. It is associated with paraneoplastic syndromes, variety of clinical presentations, different way of treatment and complex prognosis. Improved imaging techniques show that an early diagnosis of thymoma is possible, which makes thymoma a potentially dangerous but preventable disease. CASE REPORT: In this report. we describe the clinical and histological findings of a patient with incidental finding of squamouscell thymic carcinoma presented during elcc tive coronary artery bypass grafting surgery. PMID- 29693845 TI - CRITICAL REVIEW OF AVAILABLE TREATMENT OPTIONS FOR TREATMENT REFRACTORY DEPRESSION AND ANXIETY - CLINICAL AND ETHICAL DILEMMAS. AB - Treatment-resistant mood and anxiety disorders require an intensive therapeutic approach, and it should balance benefits and adverse effects or other potential detrimental effects of medications. The goal of treatment is to provide consistent and lasting improvement in symptoms of depression and anxiety. Beozodiazepines are effective for anxiety symptoms, but with no sustained treatment effects. Other medication treatment options for anxiety disorders are outlined. Ketamine is usually very effective in treating maior depressive disorder but without sustained benefits. Loog-term use may pose a signiticant risk of developing tolerance and dependence. Stimulant medication augmentation for treatment-resistant depression is effective for residual symptoms of depression, but effects are usually short-lasting and it sounds mor as an artificial way of improving energy, alertness and cognitive functioning. Synthetic cannabinoids and medical marijuana are increasingly prescribed for various medical conditions. but more recently also for patients with mood and anxiety disorders. All of these treatments may raise ethical dilemmas about appropriateness of prescribing these medications and a number of questions regarding the optimal treatment for patients with treatment-resistant depression and treatment refractory anxiety disorders. PMID- 29693846 TI - ALTERNATIVES OF MENOPAUSAL HORMONE THERAPY. AB - INTRODUCTION: It has been generally accepted that the benefits of menopausal hormone therapy outweigh the risks. but there are still some concerns about the administration of menopausal hormone therapy, which has introduced alternative treatments. Pharmacological Alternatives. Central alpha-2 agonist clonidine is only marginally more effective than placebo, and significantly less effective than estrogen. Antiepileptic drug gabapentin reduces hot flashes; however, it is less effective than estrogen. Selective serotonin reuptake inhibitors (paroxetine and fluoxetine) and selective noradrenaline reuptake inhibitors (venlafaxine) reduce vasomotor symptoms and improve depression, anxiety and sleep. Results of studies about dehydroepiandrosterone effects on menopausal symptoms are inconsistent and additional investigations are needed. Non-Pharmacological Alternatives. Stellatum ganglion blockade is a successful treatment for reducing vasomotor symptoms in patients with contraindications for menopausal hormone therapy. Efficacy of acupuncture, homeopathy and reflexology Should be proved by adequate studies. Phytoestrogens could reduce vasomotortymptoms but to a lesser extent than conventional menopausal hormone therapy. However, they have not been proved yet to pro-ide cardiovascular protection and prevention of osteoporosis. nor they could be recommended instead of traditional menopausal hor-one therapy. There is a concern about their undesirable effects. Adequate diet, unchanging body weight Nwthin ideal values and adequate physical activities have beneficial long-term effects, first of all onlpreservation of bone density Alternatives for Atrophic Changes of Vaginal Epithelium. Menopausal symptoms resulting from vaginal atrophy could be resolved by use of hydrophilic prep- arations, lubricants and topical lidocaine creamn r 4% lidocaine water solution for dyspareunia. CONCLUSION: If there are contrain-ications to menopausal hormone therapy or patients are unwilling to take hormone therapy, alternative treatments, which canlalso solve menopausal symptoms, should be considered. PMID- 29693847 TI - HEALTH EFFECTS OF SLEEP DEPRIVATION ON NURSES WORKING SHIFTS. AB - INTRODUCTION: Atypical work schedules cause reduced sleep, leading to drowsiness, fatigue, decline of cognitive performance and health problems among the members of the nursing staff. The study was aimed at reviewing current knowledge and attitudes concerning the impact of sleep disorders on health and cognitive functions among the members of the nursing staff. Sleep and Interpersonal Relations in Modern Society. The modern 24-hour society involves more and more employees (health services, police departments, public transport) in non-standard forms of work. In European Union countries, over 50% of the nursing staff work night shifts, while in the United States of America 55% of nursing staff work more than 40 hours a week, and 30-70% of nurses sleep less than six hours before their shift. Cognitive Effects of Sleep Deprivation. Sleep deprivation impairs the performance of tasks that require intensive and prolonged attention which increases the number of errors in patients care, and nurses are subject to incre- ased risk of traffic accidents. Sleep Deprivation and Health Disorders. Sleep deprived members of the nursing staff are at risk of obesity, diabetes, gastrointestinal disorders and cardiovascular disease. The risk factors for breast cancer are increased by 1.79 times. and there is a significantly higher risk for colorectal carcinoma. CONCLUSION: Too long or repeated shifts reduce the opportunity for sleep, shorten recovery time in nurses, thus endangering their safety and health as well as the quality of care and patients' safety. Bearing in mind the significance of the problerm it is necessary to conduct the surveys of sleep quality and health of nurses in the Republic of Serbia as well in order to tackle this issue which is insufficiently recognized. PMID- 29693848 TI - ANTHROPOMETRIC CHARACTERISTICS AND FUNCTIONAL CAPACITY OF ELITE ROWERS AND HANDBALL PLAYERS. AB - INTRODUCTION: Anthropometric and anaerobic profile of elite athletes are fundamental for the assessment of their respective performance. The present study was designed to evaluate the anthro- pornetric parameters, body composition and anaerobic characteristics of elite male handball players and rowers, and to compare them in relation to specific sport demands. MATERIAL AND METHODS: The study group consisted of 41 elite national level athletes: 20 handball players (aged 23.7+/-3.72) and 21 rowers (aged 19.7+/-2.84). Anthropometric characteristics (body mass, body height, skinfold thickness, body circumferences), and body fat mass were evaluated, and Wingate anaerobic test for anaerobic power assessment Iwas applied. RESULTS: The significant differences were noted in chest-upper arm, waist and hip circumferences, and supraspinal and calf skinfolds between the two investigated groups. Rowers showed higher values of fat body mass (13.2+/-3.76 vs. 10.7+/-3.76%), but lower body mass index (22.0+/-1,92 vs. 25.7?2.31 kg/in12) compared to handball players. When analyzing the Wingate test parameters, significantly higher values of absolute anaerobic power (786+/-127 vs. 691+/-140 W), absolute explosive power in the handball players compared to the rowers were recorded ( 18+/-26.3 vs. 105+/-27.8 W/s), whi le rowers achieved higher relative anaerobic capacity (192+/-3 1.2 vs. 177+/ E20.8 J/ kg). CONCLUSION: Specific body composition and anthropometri- cal assessment as a part of morphological analysis should complement physiological profile of elite athletes. The analysis of the anaerobic performance shows that the handball players have greater alactic anaerobic and explosive power component, compared to the rowers in whom the anaerobic endurance and specific training have the greatest effect on the consumption of dominant metabolic substrate during the race. PMID- 29693849 TI - COMPARISON OF DIET IN WOMEN OF REPRODUCTIVE AGE WITH AND WITHOUT DIAGNOSED POLYCYSTIC OVARY SYNDROME - PILOT STUDY. AB - INTRODUCTION: This study was aimed at comparing diets, dietary patterns and lifestyle habits of women with polycystic ovary syndrome and controls in Croatia. MATERIAL AND METHODS: In this pilot, matched pair study, the participants were women of reproductive age: 12 with Polycystic Ovary Syndrome and 16 healthy (between the ages of 18 and 41 years). The following data sets were collected and a,nalysed:.nutrient intake, dietary habits and physical activity, polycystic ovary syndrome symptoms, anthropometry and biochemical records. RESULTS: The analyses of dietary habits showed a significantly (p=0.030) higher score for the controls (92.4?8.7 points) compared to the women with polycystic ovary syndrome (83.3?12.2 points). There was a significant correlation between the age and intake of total carbohydrates, and intake of plant protein in the women with polycystic ovary syndrome. A significant correlation was found between the age and total fats intake, as well as intake of different types of fats, and energy intake in the controls. The free time activity index showed a significant difference (t-test: p=0.043, ANOVA: p=.004) in favour of the control group of women who were more active. CONCLUSIONS: This study has shown that Croatian women with polycystic ovary syndrome compared to the controls have significantly poorer dietary habits characterised by high Glycaemic Index diets, they are less physically active during free time. and have positive significant correlation between the age and carbohydrate intake whereas the controls have positive significant correlation between the age and fat intake. PMID- 29693850 TI - SUN PROTECTION BEHAVIOR AMONG ADOLESCENTS - A COMPARATIVE STUDY CONDUCTED IN 2008 AND 2012. AB - INTRODUCTION: Adolescents should limit their exposure to sun and apply sun protection measures. The purpose of this study was to establish changes in adolescents behavior regarding sun protection beetwen years 2008 and 2012, as well as to assess the impact of sex and skin photo-type on behavior in order to suggest positive sun protection behavior practised in other countries and to improve educational program. MATERIAL AND METHODS: An original, tailormade questionnaire (about the skin types, exposure to sun and the use of sunbed) was distributed among 16 and 17-year-old students in high school in Belgrade, Serbia to be fulfilled within the framework of the educational project in. 2008 and 2012. Data were analyzed by the Pearson's chi square test and logistic regression analyses. RESULTS: The total number of questionnaires completed in 2008 and in 2012 was 1138 and 583, respectively. In 2012, the students spent less time outdoors. According to the 2008 survey, the girls used more sun protection measures, but reported more sunburns and the use of sunbed than the boys. In 2012 more sunburns were reported by the boys as well as the increased use of the sunglasses, wearing a hat/cap and staying in the shade. CONCLUSION: There were statistically significant changes in behavior of adolescents regarding exposure to sun between 2008 and 2012, and between male and female gender. It is recommended to organize regular educational interventions at schools which should emphasize the following: the importance of sun protection measures, limited sunbathing and outdoor physical activities as well. PMID- 29693851 TI - RELATIONSHIP BETWEEN HEAD POSTURE AND PARAMETERS OF SAGITTAL POSITION AND LENGTH OF JAWS. AB - INTRODUCTION: Head posture in relation to the cervical spine is correlated with the morphology of the face and jaw, the position and the mutual relationship of the maxilla and mandible, their length and inclination. The aim of this study is to examine the relationship between the head posture and parameters of the sagittal position and length of the jaws. MATERIAL AND METHODS: The study included 90 subjects (30 for I, II and II skeletal class each) between the ages of 8 and 14 years, who were examined at the Department of Dentistry of Vojvodina inNovi Sad. Each subject had the lateral cephalogram made, and the analysis was performed by means of the computer program "Onyx Ceph." The following parameters were analyzed: craniocervical angle, angle of maxillary prognathism, angle of mandibulary prognathism, the difference angles of maxillary and mandibulary prognathism, length of maxillae, and length of mandible. RESULTS: The angle of maxillary prognathism was in positive correlation with the craniocervical angle in the patients with class I and II, and they were negatively correlated in the patients with class III. The angle of mandibulary prognathism was in positive correlation with the craniocervical angle in the patients with class I and III, but they were negatively correlated in the patients with class II. The patients wi th class II had a statistically significant positive correlation between the craniocervical angle and length of the maxilla, and a significant, but negative correlation between the craniocervical angle and length of the mandible. CONCLUSION: Increased extension of the head in relation to the cervical spine can be a contributing factor to the formation of class II malocclusion. PMID- 29693852 TI - ANAESTHESIA FOR AWAKE BRAIN TUMOUR SURGERY: CASE REPORT. AB - INTRODUCTION: There is an increasing trend towards performing awake craniotomy procedures. The method is indicated for surgical treatment of brain changes located in functional regions. This technique poses a unique challenge for the anaesthesiologist in view of providing adequate sedation, analgesia, hemodynamic and respiratory stability yet to keep the patient awake and cooperative during the procedure' Case Report. After the adequate preoperative preparation of the patient, the surgical procedure on tumorous change in the left frontoparietal area (Broca's area) was performed. Due to the tumour localization, the surgical treatment was performed in awake condition under intraoperative neurophysiological monitoring of the patient. Analgosedation (Ramsay score 2-3) was provided via continuous infusion. of propofol and reminfentanil. Local infiltration anaesthesia (scalp block) was preformed with levobupivacaine. The surgical procedure proceeded without any major incidents and complications. CONCLUSION: A propofol/remiWentanil combination provided safe and effective analgosedation of the patient. PMID- 29693853 TI - THE LIGATION OF THE INTERSPHINETRIC TRACT PROCEDURE OF THE PERIANAL FISTULA: CASE REPORT. AB - INTRODUCTION: Perianal fistula is usually of cryptoglandular origin, namely it results from inflammation of the anal glands. The main challenge in its management is how to resolve a fistula but avoid its recurrence as well as incontinence, which is even a bigger problem. Several treatment methods have been described and they all focus on cutting the anal sphincter and "opening" the fistula, placing the seton, plug technique, creating a mucosal advancement flap, injecting medical occlusive agents or using a combination of methods. In 2007 a method of managing a fistula by ligation of the intersphincteric fistula tract was described. The procedure is still getting a wider application. CASE REPORT: A 60-year old male patient had had a fistula for 30 years. He underwent incision of perianal abscess on multiple occasions resulting in multiple scars in the gluteus area. The diagnosis revealed a high transsphincteric fistula. The inner ostium was diagnosed by injecting hydrogen-peroxide and by probing. The patient's general condition was satisfactory. For the first time the ligation of intersphincteric fistula tract procedure was applied in our regional hospital. Under general anesthesia, in a lithotomy position, the ligation of intersphincteric fistula tract procedure was successfully performed in approximately 30 minutes. The external opening of the fistula and the scars were widely excised. The postoperative course was uneventful. After 6 months there was no recurrence. CONCLUSION: The ligation of intersphincteric fistula tract procedure for transsphincteric fistulae can be a treatment of choice in all hospitals treating colorectal patients because the incontinence risk is low, and the disease is curable at a high percentage. PMID- 29693854 TI - INTERMITTENT EXOTROPIA COURSE IN FRONTONASAL DYSPLASIA AND SEVERE ORBITAL HYPERTELORISM: CASE REPORT. AB - INTRODUCTION: Frontonasal dysplasia is a rare condition of congenital structure malformations of the midface. Ophthalmologic abnormalities have been estimated to occur in 87% of cases of frontonasal dysplasia. CASE REPORT: We report a case of type I frontonsal dysplasia in a 15-year old boy after the correction of severe hypertelorism, median nasal cleft w~ith a broad nasal root and associated decompensated intermittent exotropia with overaction. of the inferior oblique muscles and V pattern. He underwent bilateral lateral rectus recessions of 6.0 mm for intermittent exotropia when he was six years old. The correction of hypertelorism was performed with orbital rotation surgery when he was thirteen years old. For some time after strabismus surgery, the ocular alignment improved, but it deteriorated gradually. The ocular alignment improved after the hipertelorismus correction; however, intermittent exotropia deteriorated gradually again six to seven months later. On the last ophthalmologic examination, he had the ocular alignment on the level of small angle exotropia and associated hypertropia and occasionally even.small angle esotropiaat near. There was bilateral overelevation in addiction and V pattern, which remained unchanged after extensive facial bones surgical procedures. CONCLUSION: The high incidence of ocular abnormalities, particularly exodeviations, indicates that the early assessment by an ophthalmologist should be a part of the initial evaluation of patients with frontonasal dysplasia to detect treatable visual or ocular problems. PMID- 29693855 TI - SPECIFIC FEATURES OF ANESTHESIA IN PATIENTS WITH MYASTHENIA GRAVIS. AB - INTRODUCTION: Myasthenia gravis is an autoimmune disease caused by antibodies leading to the destruction of nicotinic acetylcholine receptors on the neuromuscular junction. It is characterized by muscle weakness that gets aggravated with physical activity and improves at rest. Myasthenia Gravis Foundation of America made the clinical classification of Myasthenia gravis which is still in use today. "Tensilon test" is still the gold standard for the diagnosis of Myasthenia gravis. In addition to this test repeated muscular stimulation can be used as well as the analysis of specific autoantibodies. Treatment of Myasthenia Gravis. In conservative treatment of Mysthenia gravis anticholinesterases, immunosuppressants and plasmapheresis can be used. If conservative treatment does not lead to the desired remission, surgical treatment is indicated. The most accepted indication for thymectomy is the presence of thymoma with generalized form of Myasthenia gravis in adults. How to Distinguish Myasthenic From Cholinergic Crisis.'The following is important to make a difference between these two crises: knowledge of the events that preceded the crisis, the size of pupils as well as the presence of muscarinic signs and tensilon test. Specific Features of Anesthesia in Patients with Myasthienia Gravis. Mechanism of the disease development is the reason'for the increased sensitivity or resistance of these patients to certain types of drugs used in anesthesia. Protocol of Perioperative Anesthesia in Patients with Myasthenia Gravis. Based on 35 years of experience in the surgical treatment of patients with Myasthenia gravis anesthesiologists at the Department of Thoracic Surgery, Institute for Pulmonary Diseases of Vojvodina. made the protocol of anesthesia and perioperative treatment for these patients. CONCLUSION: Anesthesiologists may have to deal with a patient with myasthenia gravis in different types of surgical interventions. The protocol for anesthesia and perioperative management of these patients herewith presented may greatly help them in their clinical practice. PMID- 29693856 TI - NIKOLA TESLA AND MEDICINE: 160TH ANNIVERSARY OF THE BIRTH OF THE GENIUS WHO GAVE LIGHT TO THE WORLD - PART I. AB - INTRODUCTION: The interest in Nikola Tesla, a scientist, physicist, engineer and inventor, is constantly growing. In the millennialong history of human civilization, it is almost impossible to find another person whose life and work has been under so much scrutiny of such a wide range of researchers, medical professionals included. Although Tesla was not primarily dedicated to biomedical research, his work significantly contributed to the development of radiology, and high frequency electrotherapy. This paper deals with the impact of Tesla's work on the development of a new medical branch - radiology. Nikola Tesla and the Discovery of X-ray radiation. Tesla pioneered the use of X-rays for medical purposes, practically laying the foundations of radiology. Namely, since 1887, Tesla periodically experimented with X-rays, at that time still unknown and unnamed, which he called "shadowgraphs". Moreover, at the end of 1894, lie conducted extensive research focusing on X-rays, but unfortunately it was inlerrupted after the fire burning down his laboratory in 1895. In 1896 and 1897, Tesla published ten papers on the biologic effects of X-ray radiation. All his studies on X-rays were experimental. During 1896 and 1897, Tesla continued improving X-ray devices. Apart from this, Tesla was the first to point out the harmful effects of exposure to X-ray radiation on human body. CONCLUSION: Nikola Tesla was a visionary genius of the future. Tesla's pioneer steps, made more than a century ago in the domain of radiology, are still being used today. PMID- 29693857 TI - 120 YEARS SINCE THE DISCOVERY OF X-RAYS. AB - This paper is intended to celebrate the 120th anniversary of the discovery of X rays. X-rays (Roentgen-rays) were discovered on the 8th ofNovember, 1895 by the German physicist Wilhelm Conrad Roentgen. Fifty days after the discovery of X ray, on December 28, 1895. Wilhelm Conrad Roentgen published a paper about the discovery of X-rays - "On a new kind of rays" (Wilhelm Conrad Roentgen: Ober eine neue Art von Strahlen. In: Sitzungsberichte der Wurzburger Physik.-Medic.- Gesellschaft. 1895.). Therefore, the date of 28th ofDecember, 1895 was taken as the date of X-rays discovery. This paper describes the work of Wilhelm Conrad Roentgen, Nikola Tesla, Mihajlo Pupin and Maria Sklodowska-Curie about the nature of X-rays . The fantastic four - Wilhelm Conrad Roentgen, NikolaTesla, Mihajlo ldvorski Pupin and Maria Sklodowska-Curie set the foundation of radiology with their discovery and study of X-rays. Five years after the discovery of X-rays, in 1900, Dr Avram Vinaver had the first X-ray machine installed in abac, in Serbia at the time when many developed countries did not have an X-ray machine and thus set the foundation of radiology in Serbia. PMID- 29693858 TI - THE VOICE OF HEALTH: FINDING A CURE FOR THE CLIMATE CHANGE MALADY. PMID- 29693859 TI - SEMIOLOGY OF PATHOLOGICAL CONDITIONS IN PATIENTS INDICATED FOR STEREOTACTIC BIOPSY. AB - INTRODUCTION: Brain tumors produce symptoms and signs which are often non specific, and therefore they may occur for more than a few months prior to diagnosis. The aim of this study was to determine the frequency of referent signs and symptoms among patients referred for stereotactic brain biopsy. MATERIAL AND METHODS: In this study, we retrospectively analyzed medical history of 65 patients (67.7% males and 32.3% females) between the ages of 16 and 81 years. The following symptoms and signs were included in the analysis: organic brain syndrome, lateralization of crossed pyramidal tract, cranial nerve dysfunction, speech disorders, cerebellar-vestibular syndrome, nausea, vomiting, headache, the occurrence of at least one epileptic seizure and respondents' physical weakness. RESULTS: Physical weakness was the most frequent symptom to be recogized (76.9%), whereas pyramidal neurological lateralization was the most commonly recognized sign (58.5%). There was a significant correlation between the course of disease and physical weakness (rho = -0.34, p = 0.005), as well as the course of disease and lateralization of the pyramidal tract (rho =0.65, p = 0.00). No significant correlation was found between other clinical signs and symptoms. CONCLUSION: An accurate diagniosis and early recognition of signs and symptoms may be useful in determining indications for stereotactic brain biopsy. PMID- 29693860 TI - COMPLETENESS OF CIRCLE OF WILLIS IN ASYMPTOMATIC AND SYMPTOMATIC EXTRACRANIAL CAROTID DISEASE. AB - INTRODUCTION: This research has been aimed at determining whether incomplete Circle of Willis in patients with significant extracranial carotid stenosis is associated with a higher incidence of neurological symptomatology and/or ischemnic cerebral lesions. MATERIAL AND METHODS: The research was conducted as a prospective study which comprised 211 patients who underwent surgical treatment of extracranial carotid disease at the Department of Vascular Surgery in Novi Sad and 102 patients in the control group. Each patient underwent preoperative magnetic resonance imaging and magnetic resonance angiography with visualization of cerebral parenchyma. extracranial and intracranial cerebral circulation. Assessment of Circle of Willis morphology was performed by 3D time-of-fight magnetic resonance angiogram sequence analysis. The patients were divided into two groups: group I - the patients with'complete Circle of Willis and group II - the patients with incomplete Circle of Willis i.e. with the disruption of anterior and/ or ipsilateral posterior circulation - regarding the side of signif icant carotid stenosis. RESULTS: Out of 211 patients who -were operated during a two-year period, 133 had the complete Circle of Willis. while 78 patients had the incomplete Circle of Willis. Out of 111 patients with symptomatic carotid disease or silent cerebral infarction, 52.5% (58) had the complete Circle of' Willis and 47.5% (53) had the incomplete Circle of Willis. It was shown to be statistically different (P = 0.0146) in relation with the asymptomatic group of patients (100), where the frequency of the complete Circle of Willis was 75% (75) while the insufficiency of anterior or ipsilateral posterior collateral ization was found in 25% (25). In the control group there were significantly fewer cases of developed collateral flow and the complete Circle of Willis (41%) compared to the operated patients with extracranial carotid stenosis (63%) (P= 0.0003). CONCLUSION: Incompleteness of Circle of Willis is associated with more frequent occurrence of neurological symptomatology or ischemic lesions of brain parenchyma in operated patients with significant extracranial carotid stenosis. The control group without extracranial carotid stenosis had less developed collaterals of Circle of Willis compared to extracranial carotid patients. PMID- 29693861 TI - THE PREVALENCE OF STRESS AND BURNOUT SYNDROME IN HOSPITAL DOCTORS AND FAMILY PHYSICIANS. AB - : Introducti on. Burnout syndrome is the result of chronic emotional stress. It is characterized by high levels of emotional exhaustion and depersonalization, and reduced level of personal accomplishment. The aim of this study was to determine the level of stress and risk ror burnout syndrome in doctors employed in health centers and hospitals, and to investigate the impact of socio derrdgraphic characteristics on the level of stress and the o ccurrence of burnout syndrome. MATERIAL AND METHODS: A cross-sectional study was conducted in the period from October I to December 31, 2015 in three health centers and in the University Clinical Center of the Republic of Srpska. The survey was anonymous. A socio-demographic questionnaire and a questionnaire for self-assessment of the level of stress and Maslach Burnout Inventory were used as research instruments. Out of 151 doctors included in the study, 49% were family physicians, and 51% were hospital doctors. RESULTS: The analysis of responses to questionnaires for self-assessment of stress level revealed that 51.7% of participants had high levels of stress (52.7% of family physicians, 50.6% of doctors working in hospital). A high degree of emotional exhaustion was found in 27.2% of participants (29.7% of fam ily physicians, 24.6% of doctors working in hospital), high depersonalization was found in 23.8% of participants (25.7% of family physicians, 22. 1% of doctors working in hospital), a low level of personal accomplishment was found in 39.7% of participants (37.8% of family physicians. 41.6% of doctors working in hospital). No statistically significant difference regarding stress degree, emotional exhaustion and depersonalizaion and personal accomplishment was found between hospital doctors and family physicians. The physicians aged over 45 years had a significantly (p = 0.030) higher level of emotional exhaustion than their younger colleagues. CONCLUSION: This study found that there was a high risk of burnout syndrome in physicians in the Republic of Srpska. Although the exposure to professional stress was higher in family physicians than in hospital doctors, the obtained difference was not statistically significant. PMID- 29693862 TI - CONTEMPORARY PRINCIPLES OF SUICIDE PREVENTION. AB - INTRODUCTION: Suicide remains a significant public health problem worldwide. This study is aimed at analyzing and presenting contemporary methods in suicide prevention in the world as well as at identifying specific risk groups and risk factors in order to explain their importance. in suicide prevention. MATERIAL AND METHODS: The literature search covered electronic databases PubMed, Web of Science and Scopus. In order to select the relevant articles, the authors searched for the combination of key-words which included the following medical subject heading terms (suicide or suicide ideation or attempted) and (prevention or risk factors) and (man or elders or mental disorders). Data analysis covered meta-analyses, systematic reviews and original scientific papers with different characteristics of suicide preventions, risk factors and risk groups. RESULTS: Worldwide evidence-based interventions for suicide prevention are divided in universal, selective and indicated interventions. Restricted approach to various methods of committing suicide as well as pharmacotherapy contributes to a lower suicide rate. Suicide risk factors can be categorized as proximal and distal. The following groups are at highest risk of committing suicide: males. older persons and persons with registered psychiatric disorders. CONCLUSION: There is a lot of evidence that suicide is preventable. It is known that only 28 coun tries in the world have national suicide prevention strategies and Serbia is not one of them. PMID- 29693863 TI - DYKE-DAVIDOFF-MASSON SYNDROME - TYPICAL IMAGING FEATURES. AB - INTRODUCTION: Dyke-Davidoff-Masson syndrome is an uncommon neurological disorder clinically presented with seizures, various degrees of mental retardation, motor weakness and sometimes body asymmetry. Typical neuroimaging features include cerebral hemiatrophy with ipsilateral hyper pneumatization of paranasal sinuses. The purpose of this report was to present a rare cause of seizures revealed by Magnetic resonance imaging. CASE REPORT: We report a case of a 17-year-old boy admitted to hospital due to a severe headache. He had been treated because of partial epileptic seizures for six years. Neuropsychological examination revealed mild mental retardation, mild speech and reading difficulties and discrete right sided hemiparesis. Typical magnetic resonance imaging features confirmed clinical suspicion of Dyke-Davidoff-Masson syndrome. revealing left frontal lobe atrophy, with consecutive widening of the left lateral ventricle frontal horn, thickening of the nearby frontal squama and hypertrophy of left frontal sinus. CONCLUSION: Magnetic resonance imaging is the key imaging modality that confirms clinical suspicion of Dyke-Davidoff-Masson syndrome based on a proper physical and neurological examination. PMID- 29693864 TI - THE CASE OF T-CELL LARGE GRANULAR LYPHOCYTE LEUKEMIA PRESENTED AS TRANSFUSION DEPENDENT ANEMIA WITH SUSTAINED RESPONSE TO CYC- LOSPORINE A THERAPY: CASE REPORT. AB - CASE REPORT: A 41-year-old man presented with anemia, lymphocytosis and splenoniegaly. T-cell large granular lymphocyte leukemia was diagnosed based on lymphocytosis of T-cell large granular lymphocytes, characteristic inimunophenotype (CD)3+ CD8+, CD16+, CD57+) of the lymphocytes and clonally rearranged T-cell receptor genes. Therapy indication was transfusion-dependent anemia. Initial cyclosporine therapy and low-dose oral methotrexate failed to control anemia and lymphocytosis. Yet, a complete clinical and hematological. response (without molecuIlar remission) was achieved and sustained when cyclosporine was reintroduced into the therapy. CONCLUSION: Our case confirms that cyclosporine therapy is effective in treating T-celI large granular lymphocyte leukemia and suggests that indefinite treatment may not be needed to maintain the response. PMID- 29693865 TI - EFFICIENCY OF SILDANEFIL MONOTHERAPY IN BENIGN PROSTATIC HYPERPLASIA. AB - INTRODUCTION: High incidences of benign prostatic hyperplasia and lower urinary tract symptoms have a high socioeconomic importance. There are several published studies which have proved the efficiency of phosphodiesterase type 5 inhibitors in treatment of benign prostatic hyperplasia and lower urinary tract symptoms. However, more studies are needed to make this therapy the standard option for treating benign prostatic hyperplasia and lower urinary tract symptoms. This study was aimed at exploring changes in International Prostate Symptom Score, post voiding residuum and maximal urine flow in benign prostatic hyperplasia and lower urinary tract symptoms patients treated by sildenafil for benign prostatic hyperplasia and lower urinary tract symptoms. Matcrial and Methods. This study, which was conducted as a prospective:controlled, opened, randomized study, included 30 patients with benign prostatic hyperplasia and lower urinary tract symptoms. Research was conducted at the Department of Urology, Clinical Center of Vojvodina (November 2011 till November 2012). The inclusion criteria were as following: >45 years of age, International Prostate Symptom Score >3, prostatic specific antigen < l0, normal urinalysis. The patients were periodically tested for International Prostate Symptom Score, maximal urine flow, and post voiding residuum. RESULTS: Statistically significant changes were found in all pprameters: mean International Prostate Symptom Score value improved from 12.8 to 8.6 (32.8% change), mean post voiding residuum value decreased from 49.4 ml to 40.2 ml (186% change), mean maximal urine flow value increased from 11.8 mI/s to 12.8 mI/s (8.5% change). CONCLUSION: Treatment of benign prostatic hyperplasia and lower urinary tract symptoms with a continuous low dose of sildenatil seems to be a good treatment choice for the patients with mild to moderate benign prostatic hyperplasia and lower urinary tract symptoms, especially in the patients with concomitant erectile dysfunction. The authors are aware that their study is limited by a small number of patients. Since there are not too many studies on this topic, they believe that their study will contribute to the determination of place and role of this treatment approach. PMID- 29693866 TI - THE REGULATION ROLE OF CAROTID BODY PERIPHERAL CHEMORECEPTORS IN PHYSIOLOGICAL AND PATHOPHYSIOLOGICAL CONDITIONS. AB - INTRODUCTION: The major oxygen sensors in the human body are peripheral chemoreceptors. also known as interoreceptors- as connected with internal organs, located in the aortic arch and in the body of the common carotid artery. Chemoreceptor function under physiological conditions. Stimulation of peripheral chemoreceptors during enviromental hypoxia causes a reflex-mediated increased ventilation, followed by the increase of the muscle sympatic activity, aiming to maintain tissue oxygen homeostatis, as well as glucosae, homeostatis. Besides that, peripheral chemoreceptors interact with central chemoreceptors. responsible for carbon dioxide changes . and they are able to modulate each other. Chemoreceptor function in pathophysiological conditions. Investigations of respiratory function in many pathological processes, such as hypertension, obstructive sleep apnea, congestive heart failure and many other diseases that are presented with enhanced peripheral chemosensitivity and impaired functional sy mpatholysis ultimately determine the peripheral chemorcceptor role and significance of peripheral chemoreceptors in the process of those pathological conditions development. Considering this, the presumed influence of peripheral chemoreceptors is important in patients having the above mentioned pathology. CONCLUSION: The importance and the role of peripheral chemoreceptors in the course of the breathing control is still controversial, despite many scientific attempts to solve this problem. The main objective of this review is to give the latest data on the peripheral chemoreceptor role and to highlight the importance of peripheral chemoreceptors for maintaining of oxygen homeostasis in pateints with hypoxia caused by either physiological or pathological conditions. PMID- 29693867 TI - NIKOLA TESLA AND MEDICINE: 160TH ANNIVERSARY OF THE BIRTH OF THE GENIUS WHO GAVE LIGHT TO THE WORLD - PART II. AB - INTRODUCTION: Nikola Tesla (1856- 1943) was a genius inventor and scientist, whose contribution to medicine is remarkable. Part I of this article reviewed special contributions of the world renowned scientist to the establishment of radiology as a new discipline in medicine. This paper deals with the use of Tesla currents in medicine. Tesla Currents in Medicine. Tesla's greatest impact on medicine is his invention of a transformer (Tesla coil) for producing high frequency and high voltage currents (Tesla currents). Tesla currents are used in diathermy, as they, while passing through the body, transform electrical energy into a therapeutic heat. In 1891, Tesla passed currents through his own body and was the first to experience their beneficial effects. He kept correspondence on electrotherapy with J. Dugan and S. H. Monell. In 1896, he used high frequency currents and designed an ozone generator for producing ozone, with powerful antiseptic and antibacterial properties. Tesla is famous for his extensive experiments with mechanical vibrations and resonance, examining their effects on the organ ism and pioneering their use for medical purposes. Tesla also designed an oscillator to relieve fatigue of the leg muscles. It is less known that Tesla's inventions (Tesla coil and wireless remote control) are widely used in modern medical equipment. Apart from this, wireless technology is nowadays widely applied in numerous diagnostic and therapeutic procedures. CONCLUSION: Nikola Tesla was the last Renais- sance figure of the modern era. Tesla bridged three centuries and two millennia by his inventions, and permanently indebted humankind by his epochal discoveries. PMID- 29693868 TI - The role of overweight and obesity in selected gynecological malignancies. AB - A review of literature data related to the effects of overweight and obesity on the development and course of selected gynecological malignancies: endometrial, breast and ovarian cancer is presented. Three hypotheses are included in an attempt to explain this rela- tionship: the adipokinine hypothesis, a hypothesis involving the effects of excessive estrogen levels, and the insulin hypothesis. PMID- 29693869 TI - A preliminary study for the treatment of cervical colposcopic lesions with the biological compound AV2. AB - OBJECTIVE: To evaluate the efficacy of Anti Viral 2 (AV2) in the regression of moderate and severe colposcopic lesions, when com- pared to placebo. MATERIALS AND METHODS: Women, aged over 18 years with a colposcopic diagnosis of moderate to severe dysplasia were randomized to receive either two applications of AV2 or placebo within four days. Both examining physician and patients were blinded to the treatment option. Follow-up colposcopy was performed on days 11, 2 1, and 60. RESULTS: A total of 50 patients were enrolled in this study. There was no statistically significant difference in screening entry criteria between the two groups. The results showed that the application of AV2 yielded a reduction of more than 50% for 21 out of 28 (75%) patients who received the active treatment versus a 0% for the comparable placebo group (p < 0.00 1). CONCLUSIONS: The authors conclude that AV2 can have a place in the treatment of colposcopically detected cervical lesions. Due to the proven broad spectrum antiviral activity of AV2, a plausible explanation is that the lesions regress due to deactivation of the virus. Further trials with larger numbers and detailed cytology and histology are needed to confirm these results. PMID- 29693870 TI - MPV, NLR, and platelet count: new hematologic markers in diagnosis of malignant ovarian tumor. AB - OBJECTIVE: Evaluation of mean platelet volume (MPV), neutrophil to lymphocyte ratio (NLR), and platelet count in the detection of malignant and benign ovarian tumors. MATERIAL AND METHODS: Sixty-six patients admitted to the present clinic over three years were in- cluded in the study. Patients diagnosed with ovarian cancer were grouped into the areas of epithelial and granulosa cell tumor diagno- sis. The values were compared to patients with benign cystic structure. Patients' preoperative hematologic parameters and their values four weeks postoperatively were analyzed. Statistical analyses were performed with SPSS software. RESULTS: MPV, NLR, and platelet count were observed at a higher rate as statistically significant in patients diagnosed with malignant ovarian cancer, compared to those with benign adnexal mass. CONCLUSION: The hemnatological parameters such as MPV, NLR, and platelet count in the detection of malignant ovarian tumors have been evaluated as useful new markers. PMID- 29693871 TI - Mucin expression profile of benign and malignant cervical tissues and correlation with clinical-pathologic parameters. AB - PURPOSE: To detect the expression of mucins in diverse benign and malignant cervical tissues of cervical disease. MATERIALS AND METHODS: 158 cases of cervical tissues were collected. Sections were stained with monoclonal antibodies against MUC1, MUC2, MIUC4, MUC5AC, and MUC20 by immunohistochemistry. RESULTS: Normal cervical epithelium showed high expr ession of MUC1I, MUC4, and MUC5AC, partial expression of MUC20, and no MUC2. With the development from chronic cervicitis, cervical intraepithelial neoplasia (CI7N) to cervical squamous cell carcinoma (SCC), the expression of MUC1, NMUC4, and MUC20 was statistically significant. The expression of MUCl was related with the depth of invasion and clinical stage of SCC. The positive rates of MUC4 and MUC20 were associated with the degree of differentiation and clinical stage of SCC. There was a correlation between the expression of MUC4, MUC 1, and MUC20 in cervical squamous lesions. CONCLUSION: Mucins may be involved in the development of cervical cancer. PMID- 29693872 TI - New biomarkers in epithelial ovarian cancer: needed or redundant? AB - OBJECTIVE: For many years, intensive research has been dedicated to the development of sensitive biomarkers to detect various malignant diseases, including for the differentiation between a benign or malignant ovarian mass. One of these biomarkers is human epididymal protein 4 (HE4), which has been shown to have a higher specificity than, and comparable sensitivity to CA 125. HE4 is included in some predictive models. These new models have not yet been widely implemented in standard clinical care. The authors investigated the perceived need for new biomarkers and prediction models among Dutch gynecologists. MATERIALS AND METHODS: A web-based survey containing 38 questions was sent to all gynecologists (in training) registered by the Dutch Society of Obstetrics and Gynecology. RESULTS: 313 respondents completed the survey (23% response rate), of which 29% were specialized in or devoted at least part of their practice to oncology. Approximately two-thirds of the respondents indicated that there is a need for a new biomarker. Respondents indicated that they would use HE4 primarily as a diagnostic tool in the case of a pelvic mass (57%), followed by screening in case of risk factors (30%), detection of recurrent disease (23%), monitoring therapy response (22%), and as a prognostic factor (10%). Only 11% would not use HE4 at all. CONCLUSION: Evaluating the need for new technologies and diagnostics, including biomarkers, is important to avoid expensive research with min- imal clinical implications. In general, there is a perceived need for a new biomarker, if it can be used to improve the accuracy of diagnosis in patients with a pelvic mass. PMID- 29693873 TI - Multiple primary cancers in BRCA 1/2 carriers - A review of literature and our observations. AB - An increasing number of patients with diagnosed synchronous or metachronous neoplasms that arc gene as well as non-gene dependent which are associated with the development of new oncological treatment, and environmental factors, prompted the authors of this study to conduct an analysis in a narrow group of patients with multiple cancers and simultaneous BRCA1I mutations (confirmed by genetic analysis). BRCA1 mutation, as well as multiple cancers were found in seven patients treated between 2007 and 2013. The patients diagnosed with a second cancer shared a uniquely common trait - a 5382insC mutation. The study describes four patients that did not carry a BRCA 1/2 mutation, yet were diagnosed with multiple cancers. A brief review of literature was performed concerning multiple cancers in women. PMID- 29693874 TI - Parameters of blood count and tumor markers: a retrospective analysis and relation to prognostic factors in ovarian cancer. AB - PURPOSE OF INVESTIGATION: The aims of study were to evaluate potential prognostic laboratory factors in ovarian cancer (blood count parameters and tumor markers) and to relate these parameters with prognostic factors. MATERIALS AND METHODS: The authors evaluated patients that underwent surgical treatment and with confirmed histopathologic diagnosis of ovarian cancer. Age, FIGO stage, type of surgery, serum levels of tumor markers, parameters of blood count, disease-free and overall survival were recorded. Mann-Whitney test was performed. The significance level was less than 0.05. RESULTS: Higher levels of CA 125, CA 15.3, and platelets were found in the group with Stage hII/I, since hemoglobin levels were higher in stage I/II (p < 0.05). CEA levels were higher in the group of non serous neoplasms (p < 0.05). Higher levels of CA125, CAIl5.3 and platelets were seen in the group histological grade 2/3 (p < 0.05). CONCLUSION: CA 125, CA 15.3, hemoglobin, and platelets can be related prognostic factors in ovarian cancer. PMID- 29693875 TI - Imiquimod cream and C02 laser vaporization in vulvar intraepithelial neoplasia (VIN) 2/3 treatment. AB - OBJECTIVES: To compare the use of topical 5% imiquimodt (IMQ) cream or CO2 laser vaponization as the treatment of vulvar inmraepithelial lesions (VIN) 2/3 and to evaluate the degrees of residual or recurrent lesions. MATERIALS AND METHODS: Twenty-nine women with VIN 2/3 were separated into two groups, according to the proposed treatments. All were submitted to collection of vulvar swabs for DNA genotyping of human papillomavirus (HPV), vulvoscopy, and biopsy of the found lesions. After treatment they were followed up in quarterly consultations to (until) possible appearance of new lesions or along one year. RESULTS: The findings were similar in effectiveness and presence of residual or recurrent lesions on the performed treatments. However, patients treated with topical 5% IMQ cream had less severe lesions in histological recurrence when compared to those submitted to the CO2 laser vaporization. CONCLUSIONS: The effectiveness of topical 5% IMQ cream was similar to that of CO2 laser vaporization. There was no difference between the treatments for the presence of residual or recurrent lesions. However, patients who received IMQ had less aggressive lesions than those submitted to the treatment with CO2 laser vaporization. PMID- 29693876 TI - The management of adnexal masses in premenopausal patients: a ten-year retrospective study at a single center. AB - PURPOSE OF INVESTIGATION: To distinguish adnexal masses as benign and malignant, and to thereby identity the suitable surgical method for these masses, in premenopausal women, by retrospectively evaluating over a ten-year period, the diagnostic parameters, such as serum CA 125 and transvaginal ultrasonography (TVS), in combination with the presence of ascites in the abdomen. MATERIALS AND METHODS: The study was conducted with 255 premenopausal patients diagnosed with adnexal masses who had been admitted to the Gaziantep University Faculty of Medicine, Clinic of Gynecology and Obstetrics, between January 2003 and January 2013. Data collected from these patients included age, menopausal state, information regarding the presence of ascites, ultrasound findings, and serum CA 125 levels. RESULTS: The mean age of the women included in the study was 32.79 +/ 8.11 (range: 18-51) years. Based on the criteria mentioned above, 152 patients were treated by laparoscopy based on a strong suspicion of benign mass, while 103 patients were treated by laparotomy, based on a strong suspicion of malignant mass. CA 125 values did not have a significant effect on malignancy risk. Based on the TVS results, three malignant masses were reported postoperatively in the patient group strongly suspected to have benign masses, while five benign masses were reported postoperatively in the patient group strongly suspected to have malignant masses.An evaluation of the present diagnostic method showed that the TVS has a positive predictive value (PPV) of 94.19% in identifying malignant masses, and a negative predictive value (NPV) of 98.22% in identifying benign masses. CONCLUSION: TVS and CA 125, along with an evaluation of menopausal status and ascites, can be an effective approach for diagnosing adnexal masses, and also for determining the proper surgical method to follow. PMID- 29693877 TI - Use of hematologic biomarkers during chemotherapy predicts survival in ovarian cancer patients. AB - OBJECTIVE: The optimal strategy for combining chemotherapy with immunotherapy in ovarian cancer patients is currently under investigation. Increasing evidence indicates that the lymphopenia induced by chemotherapy may promote homeostatic proliferation and thereby enhance antitumor immunity. Furthermore, there has been much discussion and even discord over the effects of anemia and blood transfusion in the perichemnotherapy period. The goals of this retrospective study were to determine the timing of chemotherapy induced lymphopenia and to observe perichemnotherapy hemoglobin levels, and the impact of the timing and depth of lymphopenia and anemia on clinical outcomes of ovarian cancer patients. MATERIALS AND METHODS: A chart review was performed on 115 patients identified in the electronic medical record from May 2005 until May 2011. Identified patients were only those who received at least six cycles of carboplatin and paclitaxel under the present authors' care for primary peritoneal, ovarian, or fallopian tube carcinoma. Specifically, the authors focused on lymphocyte and hemoglobin nadir and the reconstitution kinetics for this population. For each patient's lymphocyte count, nadir values were abstracted from weekly complete blood counts. They then split the population into two groups based on whether the nadir occurred at or after the nine-week mark (third cycle) for the lymphopenia data; this point was chosen because it was good for prognosis and it corresponds to patients whose trajectories bottom out. The intrachernotherapy hemoglobin levels were observed and an exploratory analysis was performed to attempt to identify a range that significantly effected patient outcomes. RESULTS: Lymiphocytes: The nadir of absolute lymphocyte concentrations is associated with platinum status and clinical response (Figure 1A). 94/115 patients had a lymphocyte count nadir after the third cycle of chemotherapy. 71/94 (75.5%) were platinum sensitive, 21/94 (22.3%) were resistant, and 2/94 (2.1%) were refractory. Of those that experienced a nadir before three cycles, ten (47.6%) were sensitive, ten (47.6%) were resistant, and one (4.7%) was refractory (p = 0.04). Considering nadir values continuously, both overall survival (OS,p = 0:0068) and progression free survival (PFS,p = 0:0321) were strongly associated with late nadir points. Twenty one of the 115 patients had a nadir value earlier than the third draw and this was associated with progressive disease, platinum resistance, poor over- all survival, and poor progression free survival. The effect sizes were great [median 0S533 vs. 66 months median PFS, 14 vs. 38 months, early vs. late nadir respectively (Figure 11B)]. Hemzoglobin: A mean Hb less than 12.5 is associated with both overall survival (OS) (HR = 2.11, 95% CI: 1.03-4.33; p= 0:042) and progression free survival (PFS) (HR = 1.91, 95% CI: l.02-3.56; p= 0:041), as were low Hb level at outset of chemotherapy and a decreasing Hb trend over the course of treatment. Furthermore, for each cycle of chemotherapy in which the hemoglobin was recorded at avalue less than 11, hazard increased, with OS (HR = 3.51, 95% CI: 1.63-7.54, p = 0:0Ol3), and PFS (HR = 2.20, 95% CI:1.12-4.33; p = 0:0223). Deeper analysis revealed that outcomes were significantly affected when a pa- tient had three or more cycles with Hb less than 11 with both 05 (HR = 2.34, 95% Cl: 1.37-4.01; Wald-Test p = 0:0020, Log Rank p = 0.00145) and PFS (HR =1.88, 95% CI: 1. 17-3.02; Wald-Test p = 0:009, Log Rank p = 0.00743). CONCLUSION: The nadir of absolute lymphocyte concentrations is an independent predictor of overall survival and progression free survival. This is an easily measurable biomarker which can be utilized for identifying patients that will be likely to respond to immunomodulation. Furthermore, this evidence showing significant improvement in OS and PFS with two or less cycles with hemoglobin < 11 sheds new light on the need for further studies on growth stimulating factors and blood transfusion during this treatment period. PMID- 29693878 TI - Clinical and ultrasound features of benign, borderline, and malignant invasive mucinous ovarian tumors. AB - OBJECTIVE: To compare clinical and sonographic features of benign, borderline, and malignant invasive mucinous ovarian tumors (MOTs). MATERIALS AND METHODS: Retrospective observational multicenter study comprising 365 women (mean age: 46.1 years) with a histologically confirmed benign, borderline or malignant invasive MOT. Clinical data (patient's age, patient's complaints), tumor markers (CA-125 and CA-1 9.9), and sonographic data (tumor size, bilaterality, morphology -unilocular, multilocular, unilocular-solid, multilocular-solid and solid-, and IOTA color score) were reviewed and compared among these three groups. Women with ultrasound evidence on intra-abdominal disease spread were excluded. RESULTS: Three hundred seventy-eight MOTs (14 women had bilateral lesions) were analyzed. Histologically, 287 tumors were benign, 51 were borderline, and 40 were malignant. No difference in patient's mean age was observed. Women with borderline or invasive tumors were less frequently asymptomatic. Tumors were larger in case of invasive lesions. Borderline and invasive tumors showed solid components and exhibited IOTA color score 3 or 4, more frequently than benign lesions (p < 0.001). However, the authors discovered that 16 out of 51 (31.4%) of borderline tumors and six out of 40 (15.0%) of invasive cancers had no solid components and a color score 1 or 2, and were considered as a benign lesion by the sonolo- gist. On the other hand, 96 out of 287 (33.4%) benign mucinous cystadenoma exhibited solid components and/or a color score of 3 or 4. CONCLUSIONS: In spite of statistical differences, the authors observed significant overlapping in ultrasound features among benign, borderline, and invasive ovarian mucinous tumors that renders a difficult accurate preoperative discrimination among these lesions. PMID- 29693879 TI - The knowledge of risk factors and prevention of breast cancer in Polish women. AB - PURPOSE: Currently, breast cancer is one of the most common malignancies among women and it constitutes a significant medical, economic, and social problem. MATERIALS AND METHODS: The study was conducted in a group of 600 healthy women (aged 18 to 88 years) between September 2011 and February 2015 living in the region of Wielkopolska (Poland) in a private gynecological practice. A survey questionnaire designed specifically for purposes of the study was a tool used to conduct the study. RESULTS: With regards to risk factors for breast cancer: 93% - familial history of breast cancer, 46% - use of hormone treatment, and 40.16% - taking contraceptive pills. CONCLUSIONS: A significant component of breast cancer prevention should be providing information regarding prevention tests and increasing accessibility to medical services. PMID- 29693880 TI - Status and awareness of cervical, breast, and colon cancer screening in a Turkish city. AB - PURPOSE OF INVESTIGATION: Mortality and morbidity rates of cervical, breast, and colorectal cancers (CRC) can be decreased via effective screening strategies. Developing countries are to be expected to establish and implement their own programs. MATERIALS AND METHODS: To evaluate regional awareness and status of cervical, breast, and CRC screening, a questionnaire-based study was conducted in 500 volunteers from a Turkish community hospital. RESULTS: Awareness rates were 57.4% for Pap smear, 61.2% for mammography, and 25.4% for CRC. Implementation rates were 19.2%, 23.9%, and 12%, respectively. Positive family history for gynecologic cancer and past cervical ablative procedure parameters were related to higher Pap smear rates. Educational level, breast self-exam, and positive Pap smear history parameters were related to higher mammography rates. Factors related to higher colorectal cancer screening rates were nulliparity and positive Pap smear history. CONCLUSION: Cancer screening rates for this Turkish city are still below the expected levels despite recently revitalized national screening program. For success, it is essential not only to educate rural populations but also to train negligent healthcare providers regularly. PMID- 29693881 TI - Analysis of symptom clusters in Chinese cervical cancer patients undergoing radiotherapy, chemoradiotherapy, or postoperative chemoradiotherapy. AB - OBJECTIVE: To assess the common symptom clusters in cervical cancer patients treated with radiotherapy alone, chemorachothierapy, or postoperative chemoradiotherapy, and evaluate differences among multi-modality treatment in these symptom clusters. MATERIALS AND METHODS: Ninety-three patients diagnosed with cervical cancer were recruited to the survey, in which destination time was the fourth friday of radiotherapy. Symptoms of patients were evaluated by the Chinese version of the 13-item M.D. Anderson Symptom Inventory (MDASI). RESULTS: Among the symptoms, lack of appetite was the most common and the most severe symptome, treatment modalities may have important effects on symptom clusters in cervical cancer patients undergoing radiotherapy. CONCLUSION: The results offer valuable information for the future development treatment-based symptom cluster intervention. PMID- 29693882 TI - Clinical outcomes and the role of adjuvant therapy sequencing in Type II uterine cancer following definitive surgical treatment. AB - PURPOSE OF INVESTIGATION: Because of rarity, consensus on adjuvant therapies for Type II endometrial cancers (BC) remains undefined. Reporting their institutional outcomes, the present authors assessed the impact of adjuvant therapies on recurrence and overall survival in women with 2009 FIGO Stage I-III Type II BC. MATERIAL AND METHODS: The authors identified 108 women, treated with definitive surgery between 2000-2013, with pathologically-confirmed Type II EC (non endometrioid [NEM, n=801 and high grade endometrioid [G3EEC, n=28]) Cox proportional hazard models were used to assess the effect of prognostic variables on disease-free (DFS) and overall survival (OS). Kaplan-Meier method was used to assess survival. RESULTS: Of the 108 women, 83 (77%) were African American (AA). Fifty-nine (55%), 12 (11%), and 37 (34%) were Stage I, II, and III, respectively. Ninety-seven patients received adjuvant therapy: 52 (radiation only), four (chemotherapy only), and 40 (combined). During follow-up (median 41 months), 44 patients (41%) recurred. Five-year DFS was 53% overall (48% [NEM], 80% [G3EEC]). Five-year OS was 75% overall (68% [NEM], 95% [G3EEC]). On multivariate analysis, lower stage and adjuvant radiation improved DFS. Higher stage, NEM, and increasing age were poor prognostic indicators of OS. CONCLUSION: Representing a large single institutional cohort for Type II BC, the present study's observed sur- vival rates are consistent with previous studies, despite the relatively high frequency of carcinosarcoma and Stage III/nodal disease. The protective effect on recurrence was not lost when radiation was delayed for chemotherapy. The present results support a multimodal adjuvant approach for treating all stages of invasive NEM EC. PMID- 29693883 TI - HPV-associated cervical cancer cells targeted by triblock copolymer gold nanoparticle curcumin combination. AB - OBJECTIVE: Curcumin (diferuloylmethane) has promising anti-cervical cancer properties but requires a stabilizing complex such as the Pluronic triblock copolymer gold nanoparticle (GNP). The objectives were to study cytotoxicity of curcumnin and to determine the effect of copolymer GNPs curcumnin complex on cancer cell necrosis. MATERIALS AND METHODS: The HeLa cells were maintained in Eagle Minimal Essential Medium, fetal bovine serum, and antibiotics, and passaged until 60% confluency was reached. The cells were exposed to either: (1) control medium, (2) 50 MUM curcumin, (3) 100 MUM curcumin, (4) 50 MUM curcumnin with copolymer GNPs complex, or (5) 100 MUM curcumnin with copolymer GNPs complex. The treated cells were incubated at 37 degrees C with 5% CO(2) in air for 24 hours, and analyzed for viability, apoptosis or necrosis using the dual stains fluorescence procedure. RESULTS: A dose-dependent increase in the HeLa necrosis was observed with increasing curcumnin concentrations. Cytotoxic effect was decreased by five- to ten-fold when the curcumin was complexed with copolymer GNPs. There were more apoptotic HeLa cells at the higher concentration of curcurnin but combination with copolymer GNPs resulted in decreased apoptosis. Cell viability was higher in curcumnin with copolymer GNPs (74.4 +/- 4.8 versus 2.3 +/- 2.2% live, mean +/- SEM, with and without copolymer GNPs, respectively). CONCLUSION: Curcumin increased HeLa cancer cell necrosis but its cytotoxicity was decreased by copolymer GNPs. The results suggested that this specific copolymer GNP did not enhance the curcumnin bioavailability in cultured cells possibly due to formation of copolymer GNP aggregates. PMID- 29693884 TI - Evaluation of the sensitivity and specificity of serum level of prostasin, CA125, LDH, AFP, and hCG+beta in epithelial ovarian cancer patients. AB - OBJECTIVES: The aim of this work was to compare and analyze the diagnostic value of serum prostasin, cancer antigen 125 (CA125), lactate dehydrogenase (LDH), alpha-fetoprotein (AFP), and human chorionic gonadotropin (hCG+beta) in epithelial ovarian cancer (EOC) and evaluate if their serum levels could be used as a potential diagnostic markers of EOC from benign tumors and healthy women. MATERIALS AND METHODS: Preoperative serum samples of 110 women (24 healthy controls, 66 ovarian benign tumors, and 20 EOC) were tested for prostasin, CA125, AFP, and hCG+beta. The level of CA125, AFP, and hCG+beta serum tumor markers were determined by electro-chemiluminescence immunoassay (ECLIA) and the serum level of prostasin was measured using enzyme-linked immunosorbent assay (ELISA) and LDH activity was measured by spectrophotometer and analyzed using SPSS version. RESULTS: The Area Under the Curve (AUC) values of prostasin, CA125, LDH, AFP, and hCG+beta for the discrimination of EOC from benign and healthy controls were, respectively, 0.89, 0.91, 0.77, 0.54, and 0.65, and significant increase in serum levels of prostasin, CA125, and LDH were observed for EOC compared with benign and control groups. CONCLUSION: The present study showed that CA 125 and LDH levels of serum increased in high stages, while prostasin level was decreased in high stages. The present results indicate that prostasin, CA125, and LDH are differentially expressed in EOC than in benign and healthy control population, that may be an indicative of a better diagnostic value, with higher sen- sitivity and specificity. Here the authors used a multimarker approach, consisting of CA125, AFP, beta hCG, prostasin, and LDH that could provide a more accurate tool for a differential diagnosis of patients with EOC. PMID- 29693885 TI - Breast cancer - Analysis of the selected risk factors. AB - : Epidemiological research for decades has focused on identifying the impact of environmental and genetic factors on the incidence of cancer. Aim of this study was to select the risk factors responsible for the increase or decrease in the odds ratio of developing breast cancer in women. MATERIALS AND METHODS: The study included healthy women with correct outcome in both subjective and objective examinations conducted by a specialist as well as women diagnosed with breast cancer on basis of histopathological examination. A total of 762 women aged 21-84 years were included into the research. RESULTS: The consumption of whole meal bread reduces the risk of breast cancer (OR = 0.30; 95% CI 0.12-0.77). The respondents consuming 100 grams of red meat such as veal, pork, and mutton a day, have the risk of developing cancer thrice as high (OR = 3.34; 95% CI 0.43-25.97). Women consuming one milk product a day in amount of 125 grams have the risk decreased (OR = 0.58; 95% CI 0.30 -1.11), compared to women not consuming dairy products at all. CONCLUSIONS: A diet rich in fruit, vegetables, and whole grains with limited consumption of red meat and the elimination of popular fast food such as fries and chips should be introduced to reduce the risk of developing breast cancer. Consumption of pasta with a low glycemic index, especially soy and whole wheat pasta in amount of 100 grams per day is advisable. PMID- 29693886 TI - Postoperative chemotherapy on placental site trophoblastic tumor in early stage: analysis of 60 cases. AB - PURPOSE OF INVESTIGATION: To review the literature of placental site trophoblastic tumor (PSTT) and explore the effect of postoperative chemotherapy in patients with Stage I. MATERIALS AND METHODS: The authors searched literature on Medline, Excerpta Medica Database (EMBASE), and other resources using the keywords "placental site trophoblastic tumor" and "PSTT" from 1981 ito 2014. RESULTS: A total number of 60 patients with Stage I disease were identified, and the presentation, treatment, tumor response, disease status, and follow-up were retrieved and reviewed. According to the authors' knowledge, 725 cases associated with PSTT have been reported in 29 nations/areas since 1981. In this series, the probability of overall survival at ten years in the group of surgery alone and postoperative chemotherapy were 96.7% and 79.1% (p = 0.199), and recurrence-free survival rates were 91.8% and 63.3%, respectively. CONCLUSION: The benefit from postoperative chemotherapy is still equivocal. There is a need for scrupulousness before adding postoperative chemotherapy. PMID- 29693887 TI - The role of sentinel node mapping with indocyanine green and endoscopic near infrared fluorescence imaging in endometrial and cervical cancer. AB - INTRODUCTION: Endometrial and cervical carcinoma are common neoplasms in gynecological oncology. The prognosis and treatment depend on the stage of the cancer according to the FIGO staging system. Stage IAl may be treated by hysterectomy or even local surgical procedures. For Stage IA2, radical hysterectomy and lymphadenectomy must be performed. Lymph node metastasis is an important prognostic factor in both cancers, however lymphadenectomy is associated with long-term complications. Thanks to the sentinel lymph node biopsy (SLNB), we can more accurately discover the staging of the primary tumor, and in case of sentinel lymph node (SLN) negative patients, can resign regional lymphadenectomy. Some researchers claim that new techniques such as indocyanine green (ICG) and endoscopic near-infrared fluorescence imaging for sentinel node mapping can be used instead of the traditional techniques. AIM: To establish the role of sentinel node mapping technique in endometrial and cervical cancer. MATERIAL AND METHODS: A retrospective study of medical records of five patients with cervical cancer (first group) Stage I and nine patients (second group) who underwent laparoscopic radical hysterectomy and SLNB or group of lymph nodes. These procedures were performed at Gynecology Department of the District Hospital in Garwolin. RESULTS: All lymph nodes were clear of metastases. All patients after histopathological diagnosis were finally referred to the Cancer Centre and Institute of Oncology due to consultation or for further treatment. CONCLUSION: Based on the present first results and literature review, intracervical ICG injection with fluorescence imaging seems to be the best SLN mapping technique, because of its simplicity, safety, and overall lower cost. More data is required to determine if the nodes identified with this technique are able to predict metastatic disease. PMID- 29693888 TI - Prognostic value of preoperative neutrophil-to-lymphocyte ratio and platelet-to lymphocyte ratio in patients with epithelial ovarian cancer. AB - PURPOSE: The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) have recently been evaluated in many cancers in prediction of survival outcomes. The purpose of this study was to investigate the impact of NLR and PLR on the prognosis of patients with epithelial ovarian cancer (EOC). MATERIALS AND METHODS: A total of 208 patients with EOC were included in the study. Hematological parameters and clinicopathological data during diagnosis were retrospectively evaluated. The cut-off values were determined by calculating receiver operating characteristic (ROC) curve analysis of the patients. RESULTS: The median over-all survival (OS) of patients with low NLR was 69 months (95% CI, 43.0-94.9) whereas high NLR was 36 months (95% CI, 29.1-42.8). The median OS with low PLR patients was 76 months (95% CI, 46.4-105.5) and high PLR was 35 months (95% CI, 28.5-41.4). In serous tumors (70.7%), the median OS with low NLR and high NLR was 54 months (95% CI, 27.9-80.0) and 34 months (95% CI, 28.2-39.7), and for the median OS with low PLR and high PLR it was 51 months (95% CI, 2 1.2-80.7) and 35 months (95% CI, 27.8-42.1), respectively. CONCLUSION: The present findings showed that the high NLR and high PLR were associated with poor prognosis and these values are significantly remarkable in EOC patients. PMID- 29693889 TI - Increased expression of LncRNA BANCR and its prognostic significance in human epithelial ovarian cancer. AB - PURPOSE: Long non-coding RNAs (lncRNAs) have been proved to play important roles in the tumorigenesis and development of human epithelial ovarian cancer (EOC). The aim of the present study was to investigate the expression and clinical value of BRAF-activated non-coding RINA (BANCR) in EOC patients. MATERIALS AND METHODS: BANCR expression was detected in 84 EOC and 36 normal ovarian epithelial tissue samples. Association between BANCR levels and clinicopathological factors and patient prognosis was also analyzed. RESULTS: BANCR expression was increased in EOC compared with normal ovarian epithelial tissues. Moreover, high expression of BANCR was closely correlated with advanced FIGO stage, higher serum, CAI125 expression level, and lymph node metastasis. Multivariate regression analysis identified BANCR overexpression as an independent unfavorable prognostic factor in EOC patients. CONCLUSIONS: These findings suggested that BANCR may act as a tumor promoter in EOC and would be a novel diagnostic and prognostic marker for this disease. PMID- 29693890 TI - Gross painless transudative ascites in a patient with ovarian cancer. AB - Transudative ascites are a rare entity in cancer which may sometimes make their diagnosis difficult. Here, the authors report an unusual case of transudative ascites in a 50-year-old woman with ovarian cancer. The patient first presented with progressive painless gross transudative ascites for the past five months with no associated nephrotic syndrome or liver cirrhosis, and chylous ascites developed on day 14 of the admission. The ascites were transudate with serum ascites albumin gradient (SAAG) above 11 g/L. Repeated screening of cancer cells from ascites revealed adenocarcinoma originated from ovary. PMID- 29693891 TI - Long-term remission of clear cell carcinoma of the cervix after chemoradiation with 109 cycles of paclitaxel: a case report and literature review. AB - BACKGROUND: Clear cell carcinoma of cervix (CCCC) is a rare cervical neoplasm that is usually associated with diethylstilbestrol (DES) exposure in utero as a primary risk factor. Advanced stage disease typically has poor outcomes and no evidence-based approach exists to guide clinicians in treating this rare disease. CASE: The authors report a case of locally advanced CCCC in a 37-year-old Caucasian female. She underwent chemoradiation therapy that included 109 courses of paclitaxel chemotherapy until no disease could be detected on imaging studies. She is now disease-free 13 years after discontinuing chemotherapy. CONCLUSION: A prolonged course of single agent paclitaxel after completing standard radiation therapy was successful in achieving remission in a patient with this rare disease. PMID- 29693892 TI - Lymphoepithelioma-like carcinoma of the uterine cervix: a case report. AB - Lymphoepithelioma-like carcinoma (LELC) is a rare variant of carcinoma of the uterine cervix, of which Epstein-Barr virus (EBV) and/or human papilloma virus (HPV) may play an important role in the pathogenesis. The authors report a case of a patient with cervical LELC who was also examined for the presence of EBV and HPV. A 31-year-old Japanese female presented with irregular genital bleeding. The biopsy showed an invasive squamous cell carcinoma. Based on the clinical data, the patient was diagnosed as having squamous cervical carcinoma, and radical hysterectomy with ovarian conservation was performed. A diagnosis of cervical LELC was then made by histological methods. An additional examination revealed that the patient was infected with HPV types 16 and 71, but not infected with EBV. PMID- 29693893 TI - Ovarian tumors: Should the cervix be examined first? AB - There is a controversy regarding ovarian metastasis in early-stage adenocareinoma of the uterine cervix. The authors present the case of a 5 1-year-old woman that at the time of diagnosis was thought to suffer from a Stage II cervical carcinoma and a synchronous ovarian carcinoma, that turned out to be an ovarian metastasis from the endocervical adenocarcinoma, as attested morphologically, histochemically, and immunohistochemically. Radical hysterectomy with oophorectomy, excision of the omentum, lymph node excision, and cytological sampling of the peritoneal cavity were carried out. It is important to always bear in mind that even low-grade adenocarcinomas of the cervix can be metastatic to the ovaries. Clinicians have to be careful when managing those cases, while further investigation is needed in order to determine the exact mechanism of those metastases and the criteria needed in order to preserve the ovaries in young patients. PMID- 29693894 TI - Benign mixed tumor of the vagina. AB - Mixed tumor of the vagina is a rare benign tumor containing both epithelial and mesenchymal components. The authors report the case of a 35-year-old woman who presented with a painless mass that had descended from the vagina in the last six months. Physical examination showed the presence of a solitary, non-tender nodule that was 3x3x2 cm in size and seemed to originate from the posterior wall of the lower vagina. The tumor was removed and pathologically examined. The findings were indicative of a mixed tumor of the vagina, and were in agreement with previous cases. No recurrence or progression occurred during the ten-month follow up. As this tumor shares common features with some other tumors, its differential diagnosis is very important. Moreover, due to the rarity of this disease, gynecologists and pathologists need to familiarize themselves with the features in order to avoid a misdiagnosis. PMID- 29693895 TI - Management of cervical dysplasia in patient with Mullerian anomaly: diagnostic and therapeutic challenges. AB - PURPOSE: The study aim was to report diagnostic and therapeutic challenges in treatment of a patient with cervical dysplasia and con- genital uterine anomaly. CASE REPORT: A 53-year-old women with Mullerian anomaly - uterus duplex (bicorporal septate uterus) and Y-shaped endocervical canal was referred due to repeated abnormal Pap smears. She underwent endocervical curettage of both canals and the endocervical septum biopsy which revealed presence of cervical intraepithelial neoplasia (CIN) III. Cervical conization was considered technically unfeasible because of abnormal cervical anatomy (lesions deep in the cervical canal on the cervical bifurcation where the cervical wall is the thickest). Classical open abdominal hysterectomy was performed. Patient had two almost equally-sized, symmetrical uterine bodies connected in the isthmico cervical region, with normal left and obstructed right hemi-vagina. Postoperative histopathological findings confirmed that dysplasia was located in the region where two endocervical canals conjoined. CONCLUSION: Diagnostic and therapeutic approach to patients with uterine anomalies has to be individualized, based on anomaly type, patient's age, reproductive history, and patient's preferences. PMID- 29693896 TI - Pericardiectomy and pericardium window creation to treat recurrent pericardial tamponade involving a borderline ovarian tumor. AB - PURPOSE OF INVESTIGATION: Pericardial effusion with cardiac tamponade is an uncommon metastatic manifestation of ovarian tumors, with only one previously reported case involving a borderline ovarian tumor (BOT). CASE: A 50-year-old woman was diagnosed and treated for a primary Stage IIc BOT. The disease recurred as an emergency pericardiocentesis eight years later, which was resected following pericardial effusion with a cardiac tamponade. This occurred two more times, and on the last occasion, drainage failed to relieve her symptoms. However, her symptoms resolved after the creation of a pericardium pleural window together with a pericardiectomy. CONCLUSION: For patients with a metastatic BOT, the creation of a pericardium pleural window and pericardiectomy is effective for recurrent pericardial tamponade, if the pericardial space is posteriorly located and/or segmented. PMID- 29693897 TI - Pelvic myeloid sarcoma: a multidisciplinary approach. AB - Myeloid sarcoma (MS) is a rare tumor mass derived from the extramedullary proliferation of blasts of one or more of myeloid lineages. It usually occurs at an anatomical site other than the bone marrow (BM). Among the anatomical site which may be involved, female genital tract is a rare localization. When MS follows a previous history of myeloid pathology it is usually associated to a poor prognosis. To date this disease was managed with exploratory laparotomy or with surgical debulking. The authors report a case of laparosc6pic diagnosis of a pelvic myeloid sarcoma in a patient previously affected by acute mycloid leukemia, evidencing the importance of minimally invasive diagnosis and subsequent multidisciplinary management. PMID- 29693898 TI - Placental site trophoblastic tumor in early stage: a case report. AB - Here, the authors present a case of a placental site trophoblastic tumor (PSTT) in a 28-year-old gravida 1 para 1 living 1 woman three months after vaginal delivery of a female infant at diagnosis in 2014. The patient was FIGO Stage I and finally underwent a total laparoscopic hysterectomy with ovarian conservation. Subsequently, the patient received two cycles of EMA/CO chemotherapy. Patient is on regular follow-up (clinical exam, beta-hCG tests, pelvic and abdominal sonography) and has shown no signs of local or systemic recurrence for 24 months. PMID- 29693899 TI - THE LABORATORY ASPECTS OF PROTEINURIA. AB - INTRODUCTION: The existence of proteinuria may be overlooked by applying the test strips. The aim of this study has been to determine the discrepancy between the findings ofproteinuria detected by test strips when compared to the results of its testing with the sulfosali- cylic acid. MATERIAL AND METHODS: The study sample consisted of 1106 subjects, who were divided into the proteinuria positive (test strips showed the presence of isolated proteinuria), and proteinuria negative group (microscopic examination revealed the presence of >=10 fresh red blood cells4sL, and/or >=1 dysmorphic erythrocyte/MUL, and/or 10>= leukocytes4uL, and or >=1 cylinder, and/or >= 1 nonsquamous epithelial cells4MUL, and/or >=100 bacteria/MUL). Both groups had the urine tested with sulfosalicylic acid. The chemical and microscopic examination of the urine was done by the analyzer LabUMat-UriSed. RESULTS: Proteinuria was confirmed with the sulfosalicylic acid test in 96.5% ofsublects from group I and in 85.3% ofsubiects from group 2. Among the patients with the negative finding of proteinuria on the test strip and with the positive sulfosalicylic acid test there was a significantly higher number of those with pathological findings of erythrocytes, leukocytes, bacteria and cylinders in the urine when compared to those of the same group with negative sulfosalicylic acid test. CONCLUSION: Sulfosalicylic acid test should be performed in cases of pathological microscopic findings in the urine in case of the presence of >=10 fresh erythrocytes4iL and/or >= 1 dysmorphic eryth- rocyte/pL and/or 10>= leukocytes/MUL and/or 1>= cylinder (except hyaline) and/or >=1 nonsquamous epithelial cells/pL and/or>= 100 bacterial pL even if the test strip examination is negative for proteinuria. PMID- 29693900 TI - IMPACT OF DENTURES ON ORAL HEALTH-RELATED QUALITY OF LIFE. AB - INTRODUCTION: Stomatoprothetic dentures are one of the factors of oral health and life quality of people of all ages. The aim of the paper is to make a connection between the oral health quality and quality of life on one side and the type of denture on the other. MATERIAL AND METHODS: This research study was conducted on the sample of 360 patients singled out in three numerically identical groups as follows: group I - patients treated with fixed dentures, group 11 - patients treated with mobile dentures, and group III -patients treated with both fixed and mobile dentures. The oral health quality was observed via five parameters: anamnestic data, symptoms of ill-functioning of basic functions instomatogenic system (chewing and speech), extra oral examination, intraoral examination, and dental abilities. For some oral health quality parameters, the index of quality was determined. RESULTS: Analyses of our three target groups of patients indicated that the patients from group I (treated with fixed dentures) suffered the least negative effects in line with the observed parameters; they are followed by patients from group III (combined dentures) and patients from group 11 (mobile dentures), respectively. CONCLUSION: Our research study showed that some oral health parameters have different impacts on health and life quality in patients treated with different stornatoprosthetic dentures. PMID- 29693901 TI - THE EFFECT OF RIGHT VENTRICULAR PACEMAKER LEAD POSITION ON FUNCTIONAL STATUS IN PATIENTS WITH PRESERVED LEFT VENTRICULAR EJECTION FRACTION. AB - INTRODUCTION: The study was aimed at assessing the difference between the right ventricle apex versus the right ventricular outflow tract lead position in functional capacity in the patients with the preserved left ventricular ejection fraction after 12 months of pacemaker stimulation. MATERIAL AND METHODS: This was a prospective, randomized, follow-up study, which lasted for 12 months. The study sample included 132 consecutive patients who were implanted with permanent anti bradicardiac pacemaker. Regarding the right ventricular lead position the patients were divided into two groups: the right ventricle apex group consisting of 61 patients with right ventricular apex lead position. The right ventricular outflow tract group included 71 patients with right ventricular outflow tract lead position. Functional capacity was assessed by Minnesota Living With Heart Failure score, New York Heart Association class and Six Minute Walk Test. Left ventricular ejection fraction was assessed by echocardiography. RESULTS: Minnesota Living With Heart Failure score and New York Heart Association class had a statistically significant improvement in both study groups. The patients from right ventricle apex group walked 20.95% (p=O.03) more in comparison to starting values. The patients from right ventricular outflow tract group walked only 13.63% (p=0.09) longer distance than the startingoneConclusion. Analysis of tests of functional status New York Heart Association class and Minnesota Living With Heart Failure questionnaire showed an even improvement in the right ventricle apex and right ventricular outflow tract groups. Analysis of 6 minute walk test showed that only the patients with the preserved left ventricular ejection fraction from the right ventricle apex group had a significant improvement after 12 months of pacemaker stimulation.. PMID- 29693902 TI - CONCOMITANT INJURIES OF ANTERIOR CRUCIATE LIGAMENT AND MENISCUS. AB - INTRODUCTION: The aim of this study was to determine the correlation between meniscal injuries with injuries of the anterior cruciate ligament, as well as risk factors for those associated injuries. MATERIAL AND METHODS: This study included 496 operated patients. Almost half of patients with meniscal injury were between the ages of 2l and 30 years. RESULTS: Meniscal injuries were diagnosed in 187 patients (38%). These patients were significantly older than the patients without meniscal injury. Meniscal injuries were significantly more frequent in patients who played sports recreationally than in professional athletes. The patients with meniscal injury underwent surgery almost four months later than the patients with preserved menisci. Meniscal injuries occurred significantly more frequently by non - contact mechanism, as a result of landing and sudden changes of direction and rhythm of running. CONCLUSION: Male patients hurt the medial meniscus more often, "bucket handle" type of lesion being much more frequent than on the lateral meniscus. The increase of body -mass index is exactly proportional to the increase in the incidence of meniscal injuries. PMID- 29693903 TI - SOCIODEMOGRAPHIC AND PSYCHIATRIC CHARACTERISTICS AMONG HOMICIDE OFFENDERS IN SERBIA - THE PROVINCE OF VOJVODINA (1996-2005). AB - INTRODUCTION: Recent studies have shown a growing correlation between violence and mental illness, but there is a higher risk of violent crimes only in certain cases of mental disorders. This study presents sociodemographic and psychiatric characteristics of homicide offenders in Serbia, in the Province of Vojvodina in a 10-year period (1996-2005). Material and Methods~ The obtained data are based on performed forensic and psychiatric expert investigatfons of 154 homicide offenders in preceding period, considering sociodemographic data, personal history and current psychiatric status. Data were analyzed using the statistical John's Macintosh programe. RESULTS: The male offenders were in the great majority (92%) as well as a low level of education (87%). A positive history of criminal acts was found in 24% of the subjects. Minority of subjects (21%) consumed alcohol on a daily basis. At the time of committing the crimes, 57% of homicide offenders were under the influence of alcohol, and just 2% of other psychoactive substances. Among the offenders who had previously received psychiatric treatment (31.2%), the most frequent diagnosis was alcohol addiction (25%) and anxiety disorders (22.9%). During the psychiatric examination 70.8% of the subjects were diagnosed with mental disorder: personality disorders (41%), alcohol addiction (84%), neurotic disorders (65%), schizophrenic psychosis (5.2%), affective disorders (3.2%), paranoid psychosis (2.6%), organic disorders (19%), psychoactive drug addiction (13%) and mental retardation (0.6%). Emotionally unstable personality disorder was dominant among personality disorders (55.6%). Diminished mental competency was established in 77.9% of subjects at the time of the homicide, being rather sever in most of them. All those diagnosed to have a psychotic disorder were mentally incompetent. CONCLUSION: Emotionally unstable disorders were the most common among the offenders who underwent forensic evaluation. A relatively low presence of psychotic disorders imposes the need for de-stigmatization particularly of the patients suffering from major mental illnesses. PMID- 29693904 TI - INFLUENCE OF BODY MASS INDEX ON IN VITRO FERTILIZATION OUTCOME IN WOMEN WITH POLYCYSTIC OVARY SYNDROME. AB - INTRODUCTION: The purpose of this study was to investigate the influence of the body mass index on the outcome of in vitro fertilization in patients with polycystic ovary syndrome. MATERIAL AND METHODS: The study sample consisted of 123 patients with polycystic ovary syndrome who completed their in vitro fertilization treatment at the Department of Gynecology and Obstetrics, Clinical Center Nis. Republic of Serbia, and they were retrospectively analyzed. The patients were divided by body mass index into two groups for the comparison of the findings. One group (normal weight) consi- sted ofwomenwithbodymass index <=25 kg/in2 (mean22.O8+/-1.90), and the other group (overweight) included women with body mass index>25 kg/in2 (mean 27.65+/-1.47). The patients underwent either the standard long gonadotrophin-releasing hormone agonist protocol or flexible multidose gonadotrophin-releasing hormone antagonist protocol. RESULTS: The normal-weight patients had a higher number of mature oncytes, significantly higher fertilization rate (p0.05). Conclusions: The findings of this study showed that the status of breast cancer screening inparticipating women was not satisfactory. Therefore, promotion of screening methods by health policy makers in Iranis necessary and given that reliance solely on education is not sufficient, it is essential to pay attention to barriers andeliminate them. PMID- 29693970 TI - Expression of CDK6 in Oral Squamous Cell Carcinomas AB - Background: CDK6 is the key factor in regulation of the cell cycle and essential for passage into the G1 phase. Italso plays an important role in the development of various tumors. In this cross-sectional study expression of the CDK6protein in oral squamous cell carcinoma (OSCC) and healthy oral mucosa of controls was assessed to determine relationswith malignant transformation and clinicopathologic factors. Method: A total of 60 samples, 45 from OSCCs and 15from healthy tissue, underwent immunohistochemistry for CDK6. Nuclear and cytoplasmic staining of keratinocyteswas considered as positive and the percentages of positive cells were calculated. Results: Expression of CDK6 wasdetected in 55.6% of OSCC samples (25 cases) and 13.3% of controls (2 cases), the difference being significant. Meanpercentage of CDK6 stained cells was 24.2+/ 29.3 in the OSCC cases and 4.33+/-2.1 in the control group, again statisticallysignificant. No relationship was detected between CDK6 expression and clinicopathologic factors. Conclusion:Overexpression of CDK6 observed in OSCC points to a role for this protein in oral carcinogenesis. PMID- 29693969 TI - Quality of Life of Nepalese Women Post Mastectomy AB - Introduction: Worldwide breast cancer is the common invasive cancer among the females. The quality of life ofwomen after treatment, which is often a mastectomy, is frequently decreased. Objective: To determine the life qualityof Nepalese women post mastectomy. Materials and Methods: One hundred seven women after a mastectomy wereselected and interviewed by using the European Organization for Research and Treatment of Cancer-Quality of LifeQuestionnaire and its Breast Specific Module to assess women's quality of life. Result: The study findings revealed agood score on global health status/quality of life. The respondents performed well on functional and symptom scales.In the Breast Specific Module, all respondents performed poor regarding sexual function and sexual enjoyment. GlobalHealth Status was found useful among the women involved in service/business/agriculture and the survivors usingbreast prosthesis. In Breast Specific Module, systemic therapy side effects showed strong statistical associations withage, marital status, occupation, education, use of breast prosthesis and co-morbidity. Body image was highly significantwith age, occupation, education, use of breast prosthesis and co-morbidity. Conclusion: Based on the study findings,counseling, and a structured educational programme is recommended to improve the QOL of women after a mastectomy. PMID- 29693971 TI - Clinical and biochemical factors for response to aspirin desensitization in aspirin-induced asthma patients - pilot study. AB - Aspirin desensitization is consideredto be an effective and well-toleratedtherapy for patients with Non-steroidalanti-inflammatory(NSAIDs)-ExacerbatedRespiratory Disease (NERD). Theaim of the present study was to investigatethe influence of aspirin desensitizationon inflammatory cell countin induced sputum and nasal lavagein fifteen NERD individuals subjectedto one-year aspirin therapy. The decreasein induced sputum count ofeosinophils and macrophages wasobserved. Clinical efficacy of aspirintherapy in improving nasal symptomsand quality of life in NERD patientswas also confirmed. PMID- 29693972 TI - [The role of the basophil activation test (BAT) in qualification for specific immunotherapy with inhalant allergens]. AB - Qualification for specific immunotherapy(SIT) according to theguidelines of the European Academyof Allergy and Clinical Immunology(EAACI) includes medical history,skin prik tests (SPT) and/or measuringthe concentration of sIgE. Itis necessary to perform additionaldiagnostic tests in case of discrepanciesbetween the history and theresults of SPT/sIgE or differencesbetween SPT and sIgE. Basophilactivation test (BAT) assesses theexpression of activation markers ofthese cells, eg. CD63 and CD203c afterstimulation. The aim of our studywas to evaluate the usefulness ofBAT in the qualification for the SIT incomparison to the SPT and sIgE andin case of discrepancies between theresults of SPT and sIgE.The study included 30 patientswith allergic rhinitis (AR) causedby allergy to house dust mite (Dermatophagoidespteronyssinus, Dp)or birch pollen qualified for SIT. Allpatients had SPT, sIgE and BAT determination.The group of patientswith allergy to birch was a controlgroup for Dp allergic and vice versa.BAT with CD63 antigen expressionwas performed using a Flow2CASTtest. Basophils were stimulated withallergen preparation (50, 500, and5000 SBU/ml concentrations). BATresults were expressed as a stimulationindex (SI). For optimal concentrationsof 50 and 500 SBU/mlparameters comparing BAT to SPTand sIgE as the gold standards wereconsecutively: sensitivity 82-100%and 93-100%, specificity 50-94% and47-89%, positive predictive value 65-94% and 61-87%, negative predictivevalue 86-100% and 93-100%. CorrelationBAT - SPT and BAT - sIgE rangedwithin 0.59 to 0.84 and 0.51 to 0.72.BAT was helpful in 2 of 30 patientswith incompatible results of SPT andsIgE.Optimal concentrations for basophilstimulation are 50 and 500 SBU/ml. BAT may be useful diagnostic tool in the qualificationfor the SIT in case of discrepancies between the resultsof SPT and sIgE. PMID- 29693973 TI - [Clinical symptoms of the allergic rhinitis and coexisting cross reactions in patients treated with the birch and/or grasses allergens against a background of the pollen exposure]. AB - During specific immunotherapy(SIT) it is recommended to monitorthe patient symptoms in relation tothe exposure of allergen which thepatient is treated. The aim of thestudy was to analyze the clinicalsymptoms of allergic rhinitis (AR)and cross reactivity in patients undergoingspecific immunotherapyusing pollen allergens (SIT) (birchand/or grasses) against the pollenexposure in 2014-2016. The studygroup, consisted of patients withpollen allergy, treated by SIT withbirch and grasses allergens, whoshowed oral allergy symptoms. Patientsof the control group were sensitiveto birch and/or grasses allergensand they were not treated withSIT. The analyses were based on theresults of questionnaires and patientsymptom diaries. Timing of thepollen seasons of birch and grasseswere similar, however the significantlyhigher concentration of birchpollen was found in 2014 and 2016,comparing to 2015. The strongestrelationship between the pollen concentrationand symptoms severitywas revealed in the study group inpatients desensitized by combinedvaccine (birch/grasses), while in thecontrol group, in patients sensitiveto both taxa. In 35.3% of patientsin the study group, a significantdecrease in symptoms after foodswas found, especially in patientsdesensitized with mixed vaccine(birch, grasses) after consumptionof vegetables and in patients desensitizedwith grasses allergens afterthe fruits and nuts. SIT has a significantimpact on the symptoms scorereduction, which could be modifiedby the changeable seasonal pollenexposure. PMID- 29693974 TI - [Acquired angioedema - clinical characteristic of the patients diagnosed in 2012 2016 with acquired C1 inhibitor deficiency]. AB - Acquired angioedema is a raredisease caused by a deficiency ofC1 esterase inhibitor with recurrentswelling symptoms. It may occur inthe course of lymphoproliferativedisorders or autoimmune diseases.Symptoms resemble hereditary angioedema,and the only differentiatingfeatures is negative family history,late onset of symptoms and accompanyinglymphoproliferative disorder.The aim of the study was to analyzethe cases of acquired angioedema.The retrospective analysis of 341patients from the registry of patientswith C1 inhibitor deficiency. Results:We identified 4 patients among 119with HAE (3.57%) diagnosed in thissame period of time 2012-2016 whofulfilled the criteria of acquired edema.In two cases the primary reasonof angioedema was lymphoproliferivedisease, in two monoclonal gammapathyof unknown reason. Weanalyzed also the results of laboratorytests C4, C1 inhibitor, C1q. In allcases the face was dominated localization.After the treatment of primarylymphoproliferive disease, in twocases, we observed total remissionof angioedema. Only one patient withgammapathy require treatment withC1 inhibitor during the attacks. Inthese case we observed both plasmaderiver, and recombinant C1 inhibitorwere effective. PMID- 29693975 TI - Assessing Breast Cancer Risk with an Artificial Neural Network AB - Objectives: Radiologists face uncertainty in making decisions based on their judgment of breast cancer risk.Artificial intelligence and machine learning techniques have been widely applied in detection/recognition of cancer.This study aimed to establish a model to aid radiologists in breast cancer risk estimation. This incorporated imagingmethods and fine needle aspiration biopsy (FNAB) for cyto-pathological diagnosis. Methods: An artificial neuralnetwork (ANN) technique was used on a retrospectively collected dataset including mammographic results, riskfactors, and clinical findings to accurately predict the probability of breast cancer in individual patients. Area underthe receiver-operating characteristic curve (AUC), accuracy, sensitivity, specificity, and positive and negative predictivevalues were used to evaluate discriminative performance. Result: The network incorporating the selected featuresperformed best (AUC = 0.955). Sensitivity and specificity of the ANN were respectively calculated as 0.82 and 0.90.In addition, negative and positive predictive values were respectively computed as 0.90 and 0.80. Conclusion: ANNhas potential applications as a decision-support tool to help underperforming practitioners to improve the positivepredictive value of biopsy recommendations. PMID- 29693976 TI - Evaluation of Osteopontin as a Biomarker in Hepatocellular Carcinomas in Egyptian Patients with Chronic HCV Cirrhosis AB - Background: Hepatocellular carcinoma (HCC) is a high incidence disease in Egypt with a poor prognosis andsurvival. Biomarkers are important for diagnosis of HCC at an early stage. Osteopontin (OPN), a glycoprotein secreted bymacrophages, osteoblasts, and T cells, is also highly expressed in a variety of tumors, such as examples in the breast, colon,and stomach. The present study aimed to correlate the serum level of OPN in HCV-positive hepatocellular carcinomapatients, with OPN expression in tumor and non-tumor liver tissues in order to identify its efficacy as a biomarkerfor diagnosis. Material and Methods: Out of total of 146 patients, 80 were selected for inclusion in the study. Bloodsamples as well as specimens of tumor and non-tumor liver tissue were collected. In addition, blood samples from 20healthy volunteers were obtained as controls. Serum OPN and alpha-fetoprotein (AFP) were evaluated by ELISA forHCC and control groups. OPN and AFP gene expression were examined by real-time PCR, after homogenization andDNA extraction from serum samples and liver tissues. Results: It was found that serum OPN levels were significantlyhigher in the HCC group compared to normal group (P=0.009), with a strong positive correlation with AFP expression.However, there was no significant difference between OPN expression in tumor and non-tumor liver tissue. Conclusion:Serum OPN is highly suggested to be a professional candidate for HCC early diagnosis, with a diagnostic ability andaccuracy equal or higher than for AFP. PMID- 29693977 TI - [Exposure to alder, hazel and birch pollen and PM10 dust concentration in Krakow in 2010-2015]. AB - PM10, one of the air pollutioncomponents has a significant effecton plant pollen by the deposition onthe surface of pollen grains, morphologicalchanges of pollen wallsand interference in the structure ofthe allergenic proteins. The aim ofthe study was to verify whether andin what weather conditions the concentrationof pollen of alder, hazeland birch coincides with the elevatedlevel of PM10 in Krakow, in 2010-2015.In the days when the alder pollen concentrationexceeded 95 PG/m3, causingsevere inhalant allergy symptomsand the concentration of hazel pollenwas >80 PG/m3 and the admissiblelevel of PM10 was exceeded, the maximumair temperature ranged from 5.1to 22.6oC, the days were dry (humidity<60%), without precipitation andmostly windless. High concentrationof birch pollen and exceeded admissiblelevel of PM10 concentration werefound in more than 60% of the days inthe city center. In 70.3% of the daysin which the birch pollen concentrationreached values that caused thesymptoms of asthma (>155 PG/m3),the dust concentration was exceeded(>50MUg/m3), and rainfall and windspeed of 1-3 m/s occurred. Symptomsin people allergic to trees pollenin Krakow can be exacerbated duringperiods when the standard limits ofPM10 are exceeded. Such situationshave occurred mostly in March (pollenof alder and hazel) and April (birchpollen), especially in the city center. PMID- 29693978 TI - Microturbine and Thermoelectric Generator Combined System: A Case Study. AB - Waste heat recovery is one of the suitable industrial applications of thermoelectrics. Thermoelectric generators (TEG) are used, commonly, only for low mid size power generation systems. The low efficiency of thermoelectric modules generally does not encourage their combination with high power and temperature sources, such as gas turbines. Nevertheless, the particular features of thermoelectric technology (no moving parts, scalability, reliability, low maintenance costs) are attractive for many applications. In this work, the feasibility of the integration of a TE generator into a cogeneration system is evaluated. The cogeneration system consists of a microturbine and heat exchangers for the production of electrical and thermal energy. The aim is to improve electric power generation by using TE modules and the "free" thermal energy supplied by the cogeneration system, through the exhaust pipe of the microturbine. Three different solutions for waste heat recovery from the exhausts gas are evaluated, from the fluid dynamics and heat transfer point of view, to find out a suitable design strategy for a combined power generation system. PMID- 29693979 TI - Diagnostic Yield of Transbronchial Biopsy in Comparison to High Resolution Computerized Tomography in Sarcoidosis Cases AB - This study aimed to evaluate the diagnostic yield of fiberoptic bronchoscopic (FOB) transbronchial biopsy andits relation with quantitative findings of high resolution computerized tomography (HRCT). A total of 83 patients,19 males and 64 females with a mean age of 45.1 years diagnosed with sarcoidosis with complete records of highresolution computerized tomography were retrospectively recruited during the time period from Feb 2005 to Jan 2015.High resolution computerized tomography scans were retrospectively assessed in random order by an experiencedobserver without knowledge of the bronchoscopic results or lung function tests. According to the radiological stagingwith HRCT, 2.4% of the patients (n=2) were stage 0, 19.3% (n=16) were stage 1, 72.3% (n=60) were stage 2 and 6.0%(n=5) were stage 3. This study showed that transbronchial lung biopsy showed positive results in 39.7% of the stage Ior II sarcoidosis patients who were diagnosed by bronchoscopy. Different high resolution computerized tomographypatterns and different scores of involvement did make a difference in the diagnostic accuracy of transbronchial biopsy(p=0.007). PMID- 29693980 TI - Association between Helicobacter pylori Infection and Cardiovascular Risk Factors among Patients in the Northern Part of Afghanistan: a Cross-Sectional Study in Andkhoy City AB - Background: The association between Helicobacter pylori infection and cardiovascular risk factors remainscontroversial. The high prevalence of H. pylori infection among Afghan patients warranted the investigation of thisassociation. The aim of the present study was to determine the association between H. pylori infection and cardiovascularrisk factors among patients visiting an outpatient clinic in Andkhoy, Afghanistan. Methods: We performed across-sectional study of 271 consecutive patients in an outpatient clinic in Andkhoy, Afghanistan from April 2017 toJune 2017. The diagnosis of H. pylori infection was achieved using an enzyme-linked immunosorbent assay test. Thepatients were divided into H. pylori positive (n=189) and H. pylori negative (n=82) groups. The association between H.pylori infection and cardiovascular risk factors was analyzed. Results: Of the total 271 study participants, 102 (37.6%)were male and 169 (62.4%) female. The mean age +/- standard deviation of the patients who were H. pylori-positiveand H. pylori-negative was 51.0 +/- 17.6 years and 51.6 +/- 17.6 years, respectively. In multivariate logistic regressionanalyses, H. pylori infection was significantly associated with diabetes mellitus (DM) (odds ratio [OR] 3.16, 95%confidence interval [CI] 1.31 7.62, P = 0.011), and body mass index (BMI) levels (OR 1.17, 95% CI 108-1.26, P <0.001). Conclusions: Our study indicated that H. pylori infection was significantly associated with DM and elevatedBMI levels in patients from an outpatient clinic in Andkhoy, Afghanistan. More aggressive measures, including DM,obesity control, and H. pylori eradication are needed. PMID- 29693981 TI - [Food hypersensitivity in patients with pollen allergy]. AB - Clinical observations indicatethe frequently reported food hypersensitivityamong patients, sensitiveto airborne allergens. Symptomsof food hypersensitivity inthis group of patients are often exacerbatedduring the pollen season.These reactions may be the resultsof cross-reactions between pollenand food allergens or food and pollenallergy coexisting. The aim ofthe study was to determine the incidenceof food hypersensitivity inpatients allergic to airborne allergens,the type of clinical manifestationsand a kind of food frequentlycausing the symptoms. Retrospectiveanalyses of case records of 55randomly selected patients with airborneallergy aged from 18 to 72 yrs(mean 55 yrs), including 28 womenranging in age from 18 years to 62yrs (mean 36 yrs) and 27 men agedfrom 18 to 72 yrs (mean 34 yrs) werecarried out. All patients underwentskin prick tests with the following allergens:grass, rye, birch, alder, hazel,mugwort, plantain, Dermatophagoidesfarinae, Dermatophagoidespteronyssinus, skin dog, cat dander,Alternaria alternata, Cladosporiumherbarum. We assessed the typeof clinical manifestations of pollenallergy and evaluated the type ofclinical manifestations of food hypersensitivityand the type of foodsthat caused it. In the examined 55patients, 15 individuals reportedfood hypersensitivity (27.2%), themost frequently after consumptionof apples, carrots, cherry, peach,hazelnut, walnut, celery and nectarines.Clinical manifestation of foodhypersensitivity was mainly oral allergysyndrome (OAS). Hypersensitivityto food above all was reportedby patients with allergic rhinitis,sensitive to grass and tree pollen.Due to the high prevalence of foodhypersensitivity in patients allergicto airborne allergens, it seems advisableto consider avoiding eatingsome foods, such as apple, carrots,cherries, peach, particularly frequentlycross-reacting with grassand trees allergens. This dietary restrictioncan prevent about 30% of patients with inhalantallergy against onset of oral allergy. PMID- 29693982 TI - [Poisonings with paracetamol, salicylates and dextromethorphan - problem evaluation based on data from Toxicological Laboratory and Poison Information Center in Krakow in 2010-2015]. AB - The aim of the paper was to studyfrequency of laboratory determinationsand toxicological informationrelated to over-the-counter drugs(OTC): paracetamol (acetaminophen),salicylates and dextromethorphan.The research was based on data fromToxicological Laboratory and PoisonInformation Center UJ CM in Krakowin years 2010-2015.Paracetamol was determined averagely102 times a year, more than50% (57 cases) were positive withconfirmation of poisoning. The leastnumber of paracetamol poisoningwas noted in 2011 (35 cases), themost were in 2015 (98 cases). In thetime span there were averagely 40salicylates check measurementsa year, less than 50% (15 cases) werepositive.Dextromethorphane was confirmedaveragely in 31 patients a year,decrease of the drug intoxicationswas noted in 2013-2015. Paracetamoland dextromethorphan were the mostoften the cause of poisoning in groupof patients 13-18 years old, salicylates- more than 30 years. In the group ofsmall children there were only a fewpoisonings with paracetamol.Toxicological information datarelated to paracetamol, salicylatesand dextromethorphan were similarto data from toxicological laboratory.Mean year numbers of drugpoisoning information were: 90 (paracetamol),14 (salicylates), 30 (dextromethorphan).The differences were in patientsage distribution. Acute poisoningswith OTC were related mainly toparacetamol, young patients (13-18 years) and young adults (19-29years). Salicylates poisoning informationwere related mainly to thegroup of adult patients (> 30 years),dextromethorphan was abused mainly by oung patients(13-18 years). There were no observed poisonings withsalicylates and dextromethorphan in children, but therewere toxicological information about paracetamol and salicylatespoisoning and overdose in group of children (1-6years). PMID- 29693983 TI - Theoretical Analysis of Two Novel Hybrid Thermoelectric-Photovoltaic Systems Based on Cu2ZnSnS4 Solar Cells. AB - The development and commercialization of Photovoltaic (PV) cells with good cost efficiency trade-off not using critical raw materials (CRMs) is one of the strategies chosen by the European Community (EC) to address the Energy Roadmap 2050. In this context Cu2ZnSnS4 (CZTS) solar cells are attracting a major interest since they have the potential to combine low price with relatively high conversion efficiencies. Although a ~9% lab scale efficiency has already been reported for CZTS this technology is still far from being competitive in terms of cost per peak-power (?/Wp) with other common materials. One possible near-future solution to increase the CZTS competiveness comes from thermoelectrics. Actually it has already been shown that Hybrid Thermoelectric-Photovoltaic Systems (HTEPVs) based on CIGS, another kesterite very similar to CZTS, can lead to a significant efficiency improvement. However it has been also clarified how the optimal hybridization strategy cannot come from the simple coupling of solar cells with commercial TEGs, but special layouts have to be implemented. Furthermore, since solar cell performances are well known to decrease with temperature, thermal decoupling strategies of the PV and TEG sections have to be taken. To address these issues, we developed a model for two different HTEPV solutions, both coupled with CZTS solar cells. In the first case we considered a Thermally-Coupled HTEPV device (TC-HTEPV) in which the TEG is placed underneath the solar cell and in thermal contact with it. The second system consists instead of an Optically-Coupled but thermally decoupled device (OC-HTEPV) in which part of the solar spectrum is focused by a non-imaging optical concentrator on the TEG hot side. For both solutions the model returns conversion efficiencies higher than that of the CZTS solar cell alone. Specifically, increases of ~30% are predicted for both kind of systems considered. PMID- 29693984 TI - Molecular methods of diagnosing allergic sensitization in patients with atopic dermatitis and infected by with Staphylococcus aureus. AB - The severity of allergic symptomsin patients with atopic dermatitis (AD)intensifies when the number of coloniespatient's of Staphylococcus aureuson patents' skin increases. Thebasic feature determining the qualityof any diagnostic test for S. aureusis its credibility. Performing a testalways carries the risk of obtainingfalse positive and/or false negativeresults. Furthermore, producing materialfor microbiological analysis ofinternal body cavities is sometimesdifficult. Therefore, in our study, wecompared the results of three tests todetermine if their results were mutuallycompatible and if they confirmedwhether S. aureus was present in patientswith AD and what was its rolein the development of the disease inthose patients.Infection with S. aureus was testedin patients with AD and healthyvolunteers using the API Staph system.The specific IgE antibodies forstaphylococcal enterotoxin A (SEA)and B (SEB) were measured usingthe UniCAP system. The secretion ofIFN-gamma, IL-2, IL-13 by peripheral bloodmononuclear cells (PBMCs) afterstimulation with SEA and SEB werestudied with Elispot assay.We found that only certain patientswith AD and S. aureus produced antibodiesagainst SEA and SEB in theacute phase of AD. The secretion ofIFN-gamma was low in patients with exacerbatedAD and S. aureus.Testing for the presence of S.aureus in the mucous membrane ofthe nasal vestibule and skin lesionsis not sufficient for complex diagnosisof the role of S. aureus in thepathomechanism of AD. Measuringthe presence of antibodies againstbacterial components in patients'serum and the reactivity of patients'immune cells against these bacterialcomponents is required in order toaccurately diagnose this role of S. aureusin a patient. PMID- 29693985 TI - Thermoelectric and Structural Characterization of Al-Doped ZnO/Y2O3 Multilayers. AB - The influence of Y2O3 nanolayers on thermoelectric performance and structure of 2% Al-doped ZnO (AZO) thin films has been studied. Multilayers based on five 50 nm thick AZO layers alternated with few nanometers thick Y2O3 layers were prepared by pulsed laser deposition on Al2O3 single crystals by alternate ablation of AZO target and Y2O3 target. The number of laser shots on Y2O3 target was maintained very low (5, 10 and 15 pulses in three separate experiments. The main phase (AZO) presents polycrystalline orientation and typical columnar growth not affected by the presence of Y2O3 nanolayers. The multilayer with 15 laser shots of Y2O3 showed best thermoelectric performance with electrical conductivity sigma 48 S/cm and Seebeck coefficient S = -82 MUV/K, which estimate power factor (S2.sigma) about 0.03 * 10-3 W m-1 K-2 at 600 K. The value of thermal conductivity (kappa) was found 10.03 W m-1 K-1 at 300 K, which is one third of typical value previously reported for bulk AZO. The figure of merit, ZT = S2.sigma.T/kappa, is calculated 9.6 * 10-4 at 600 K. These results demonstrated the feasibility of nanoengineered defects insertion for the depression of thermal conductivity. PMID- 29693986 TI - The effects of air pollution on the development of allergic diseases. AB - During the past years, air pollutioncreated by humans has becomea major problem increasing the publicawareness. The incidence of allergicdisease is high and continues to increasein populations of urban areasof Westernized countries throughoutthe world. The aim of this article is tosummarize current knowledge of theeffects of air pollution on the developmentof allergic diseases. In the paperthe effect of outdoor and indoor airpollution is described with potentialand proven mechanisms of action onthe development of allergic diseases. PMID- 29693988 TI - Fabrication Techniques for Thermoelectric Devices Based on Nanostructured Silicon. PMID- 29693987 TI - [Recent advances in the in vitro diagnosis of drug allergy]. AB - Allergic reactions to drugs area matter of great concern, both forpatients and health care professionals.The diagnosis is primarily basedon a clinical history and in vivo tests,but they have some significant limitationsin a range of clinical situations.This review presents currentlyavailable in vitro methods for theidentification of the culprit drug indrug-induced immediate reactions(specific IgE determination, basophilactivation test), T-cell-mediated drugallergy (lymphocyte transformationtest, enzyme-linked immunosorbentspot assay, cell activation markersand cytokine release) and in nonallergichypersensitivity to nonsteroidalanti-inflammatory drugs. Perspectivesfor further improvement of thein vitro diagnosis of drug allergy arealso discussed. PMID- 29693989 TI - [Skin as a place of immunomodulation]. AB - The skin is the largest organ of the human body which plays a key role not only in physiological processes such as thermoregulation and the maintenance of the correct water and electrolyte balance, but also forms an effective barrier against microorganisms, protecting the organism against harmful external factors. Moreover, the skin is an important organ involved in immune mechanisms. The skin is a place of drug application to treat various local and systemic diseases. Those drugs are proteins and peptides sensitive to digestion in gastrointestinal tract, or chemical molecules metabolized in the liver. Epicutaneous immunization (EC) is a new therapeutic method used to treat immunological disorders. The phenomenom of immunomodulation has already been exploited to treat allergic diseases and is called allergen specific immunotherapy. The authors describe the current state of knowledge of the immune regulatory mechanisms that allow to use the EC method to treat immunological diseases mediated by Th1, Tc1 or Th2 lymphocytes. The new aspect of this immunotherapy is immunopotentiation that involves components of the innate immune system, working via the TLRs. The first clinical trials give promising outcomes of the use of EC method in the treatment of multiple sclerosis and respiratory allergic diseases. PMID- 29693990 TI - Influence of Composition and Thermal Treatments on Microhardness of the Filled Skutterudite Sm(y) (Fe(x) Ni(1-x)4Sb12. AB - Samples belonging to the series Sm(y)(Fe(x)Ni(1-x)4Sb12 were heated in Ar atmosphere up to 400 degrees C and cooled down to room temperature several times, with the aim to evaluate the effect of thermal cycles on microhardness. The treatment temperature was chosen in correspondence of the maximum ZT value, in order to simulate the operating conditions of the material in a thermoelectric device. Vickers measurements allowed to detect the effect of both composition and thermal treatments on the microhardness properties of the material. A decrease in the microhardness value was observed prior to thermal treatments with increasing Fe amount, due to the substitution of Ni by the larger Fe atom. Moreover, almost all compositions show an increase in the hardness of the skutterudite phase as a consequence of thermal cycles, accounting for the Sb enrichment of skutterudite. This evidence suggests also a possible improvement of the preparation procedure in order to obtain a stoichiometric Sb amount within the skutterudite. Samples were prepared by direct reaction of pure elements at 950 degrees C followed by thermal treatment at 620 degrees C. The composition and microstructure of the obtained samples were investigated by X-ray powder diffraction, and by optical and electronic microscopy. PMID- 29693991 TI - [Honey bee venom allergy diagnostics]. AB - Honey bee venom (Apis mellifera)is a mixture of many components,both amines, peptides enzymes andtoxins. Most of the enzymes are allergenswith different allergenic potential.It may affect not only to thesymptoms, it may also contribute tothe success of immunotherapy. Insome cases the problem of a bee venomallergy diagnosis is difficult dueto the imperfection of the classicaldiagnostic methods. In the presentwork reports in the literature regardingthe bee venom allergy diagnosison the basis of identification of thevenom allergen sIgE to componentsare summarized.The use of recombinant allergenshas allowed for the study of sIgEagainst the allergenic components,and thus determination of the individualprofile of allergy. Extending thetest panel of bee venom componentsto rApi m10 and rApi m3 comparedto rApi m1 increases the diagnosticsensitivity by identifying new allergensthat are not always present inthe available preparations used in immunotherapy. PMID- 29693992 TI - [Acute renal failure associated with Stevens-Johnson syndrome - case study]. AB - Stevens-Johnson syndrome isan acute, life-threatening, necroticskin and mucosal reaction, mostoften caused by drugs. This casepresents 81-year old Patient withStevens-Johnson syndrome causedby amoxicillin, complicated by acuterenal failure. PMID- 29693993 TI - Ocular outcomes in 4-year old prematurely born children. AB - Purpose: The aim of the study wasto assess functional and structuralophthalmologic outcomes in 4-year oldvery low birth weight children (VLBW). Material and Methods: A group of 82 VLBW children including: (1)children without retinopathy of prematurity- group O (n = 30), (2) childrenwith retinopathy of prematurity with noindications for laser coagulation- group1 (n = 20 ), (3) children with retinopathyof prematurity treated with lasercoagulation - group 2 (n = 32) wereenrolled. Functional (visual acuity,visual evoked potentials, stereopsis,color vision test) and structural (anterioreye segment examination andfundoscopy) outcome, cycloplegicrefraction, intraocular pressure andangle of squint were examined in allchildren. Developmental Test of VisualPerception was also assessed. Results: Very good visual acuitywas presented in 56 (68.3%) patients,good visual acuity in 11 (13.4%) children,visual acuity between 0.4 and 0.2in 13 (15.9%) and unfavorable function(equal or less than 0.1) was observedin 2 (2.4%) children. Twenty-three patients(28.1%) were myopic, 57 patients(69.5%) were hyperopic. Astigmatism> 1D occurred in 49 (59.8%) patients.Anisometropia larger than 2 D occurredin 7 patients (8.7%). There was nostatistical difference between frequencyof mentioned above complicationsbetween the groups. Abnormal VEPresults were more common (14 children-54%) in group 2 as comparedto other groups (group 0 - 7 children-25%, group 1 - 4 children -24%; p =0.044). Moreover, the lower percentageof group 2 children presented stereopsisvision (46.9%, group 0 - 93.3%,group 1 - 90%; p<0.05). Children withretinopathy of prematurity treated withlaser coagulation had significantlylower Developmental Test of VisualPerceptions scores. In group 1, in 1child naevus pigmentosus of the eyelidwas observed, in group 2 in one childeyeball atrophy in the right eye andaphakia in the left eye were diagnosed.In 1 child in group 0 optic disc drusenwere observed, in 2 children optic discswere pale. In 2 children in group 2retinal detachment stage 5 was diagnosed. Conclusion: An important factor affecting final ophthalomolgicalassessment in prematurely born children isretinopathy of prematurity treated with laser coagulaion.Children with retinopathy of prematurity without lasercoagulation had examinations results comparable wihchildren without retinopathy of prematurity. Diode laserphotocoagulation is an effective method of treatment fotactive stages of retinopathy of prematurity. PMID- 29693994 TI - Ultrasound evaluation of inferior facial angle (IFA) in a population of normal fetuses at 11-13 weeks (+6 days) gestation. AB - : Retrognathia is a common featureof many fetal anomalies that may bediagnosed during ultrasound examination.The most common methodused for the diagnosis of this conditionis the inferior facial angle (IFA). Theexisting reference ranges for IFA havebeen established for the fetuses at 18-28 weeks gestation and may be not applicablein the first trimester. The aimof the study was to document changesof IFA from 11+0 to 13+6 weeks gestation,to verify the reproducibility of IFAcalculations obtained by the same examinerand to investigate the possibleassociation between IFA values at thefirst and second trimester scans. Material and Methods: A prospectivestudy was performed in 512 singletonpregnancies during the firsttrimester ultrasound exam. IFA wascalculated by measuring the anglemade by the cross-section of a lineorthogonal to the forehead at the levelof nasofrontal suture and the line fromthe tip of the mentum to the anteriorborder of the more protrusive lip. In100 cases, stored images were usedto calculate IFA twice by the sameexaminer. In a second trimester scan,IFA was measured again in 215 fetuses. Results: The median IFA value atthe time of the first trimester (IFA-1)was 880 (IQR: 8.0) and decreased withcrown-rump length (CRL) and biparietaldiameter (BPD). A moderate negativecorrelation was shown betweenIFA-1 and CRL (r= 0.3; p<0.001) as wellas between IFA-1 and BPD-1 (r= 0.176;p=0.010). An intraclass correlationcoefficient (ICC) of 0.87 (95% CI: 0.81- 0.91) confirmed strong intraobserveragreement between two IFA measurements.In 215 fetuses that underwenta second trimester screening, themedian IFA-2 was significantly lowercompared to IFA-1(215) (750; IQR: 10.0vs.870; IQR: 8.0; p<0.001), and therewas no correlation between IFA1215 andIFA-2 (r= -0.024; p=0.731). Conclusions: In the first trimester,IFA decreases with CRL and BPD.When performed by the same operator,measurement of IFA is reproducible. There is no correlationbetween the IFA values in the first and second trimesters. PMID- 29693996 TI - Child's dignity in suffering and death. AB - The magnitude of unfair, absurd,pointless suffering we cannot acceptor understand makes it a phenomenonwhich defies human logic - especiallywhen it concerns children. The sourceof suffering of a dying child is pain,fear, failure to satisfy the basic humanneeds and concern about the parents.It is also heightened by medical procedures,including treatments aimedat preventing the unavoidable death.Such actions, resulting from the fearof death and a lack of acceptance ofdeath as the end of life burdened withsuffering, pose a risk to the child's fundamentalrights and violate the sourceof human freedom - one's inalienabledignity.Our priority should be to unconditionallyrespect the children's rightspostulated by Korczak, to ensurethat while providing holistic care fora dying child, their dignity is alwaysconsidered the greatest good. PMID- 29693995 TI - [Analysis of histological type and staging of cervical cancer as prognostic factors among women treated in the Department of Gynecology and Oncology, Jagiellonian University in the years 2001-2014]. AB - Introduction: Cervical cancer (CC)is the fourth most common, in termsof incidence of new cases, cancer inwomen and the third leading cause ofcancer deaths in women worldwide.Survival of patients with CC dependson many factors, including the typeof cancer, grading, FIGO staging andtreatment. Material and Methods: Analysis of survival of 524 patients diagnosedwith invasive and non-invasive CC dependingon histopathologic diagnosis,clinical staging, tumor grading andcombination of therapy. Results: The 2-fold increase in therisk of death at diagnosis in order ofHSIL> ca planoepitheliale> adenocarcinoma>sarcoma was noted. Grading2 and 3 significantly reduces the averagesurvival in patients diagnosed withCC. The higher staging, the shorter theaverage survival. Each pass by oneFIGO stage was shown to increasethe risk of death by 46%. The risk ofdeath increases by 4% with every yearof woman's life. The longest averagesurvival, 72 months, characterized agroup of women undergoing curettage,followed by radical hysterectomy/trachelectomy and lymphadenectomywithout adiuvant radio-/ chemotherapy.The shortest survival, 26.9 months,was observed in the group treated withcurettage followed by chemoradiation. Conclusions: Histopathology, clinical staging, grading, age andcombination of treatment proved to besignificant factors affecting survival inwomen with CC. PMID- 29693997 TI - MUm- and nm-Sized Catalytic Structures in Heat Sources for Thermoelectric Generators. AB - Micro- and nano-structural organization and its influence on the efficiency of catalysts used in the heat sources for permeable thermoelectric generators were investigated. Two types of catalyst were studied-elemental platinum on aluminum oxide granulate Pt/Al2O3 and mixed transition-metal catalyst on fibrous silicon dioxide Co-Cr-Pd-Sr/SiO2. The distribution of active components in catalytic structures which contribute to the maximum combustion completeness of organic fuel in heat sources was investigated. Practically full conversion of hydrocarbons was achieved already with 1 mass.% of platinum in the Pt/Al2O3 catalyst with sub-MUm- and nm-sized particles placed at the input of the gas-air mixture into the channel of the permeable thermoelement. The propane-butane conversion rate of 97% for the catalyst Co-Cr-Pd/SiO2 with was further enhanced by addition of 0.5 mass.% of Sr. The catalytic centers are formed by CoCr2O4 nanocrystals (10 to 40 nm in size) with Pd promotor in form of single crystals on the fibrous SiO2 matrix. PMID- 29693998 TI - [Klotho not only antiageing protein]. AB - Klotho, the gene encoding theantiaging protein, was discovered in1997 and named after a Greek Goddeswho spun the thread of life. Numerousexperiments on mice confirmed thatdestruction of the klotho gene or lossof klotho function leads to an acceleratedaging and premature death.In addition to shortened life span,klotho deficient mice demonstratedchanges in functioning of multipleorgans, ectopic calcification, enhanceddevelopment of arteriosclerosis,osteoporosis and atrophy of skin. Incontrast, overexpression of a gene inmice inhibited aging and prolongedsurvival. The multisystemic phenotypeinduced by Klotho deficiency indicatesthat Klotho works on a variety oforgans. Klotho is highly expressedin the kidney, brain, and to a lesserextent in other organs. Protein Klothoexists in two forms: membrane andsecreted which play different functions.Membrane Klotho function asan obligate co-receptor required forsignaling for the phosphaturic factorFGF23, regulates calcium-phosphatehomeostasis through renal ion transportin addition to modulation of PTHand 1,25(OH)2D3. Soluble klotho functionsas a humoral factor and regulatesthe activity of several ion channels andtransporters. The secreted Klotho canalso inhibit oxydative stres and theinsulin and insulin like growth factor 1(IGF-1) pathways. The discovery of theprotein klotho led to the identificationof new axes connecting endocrinedisturbances in the homeostasis ofthe calcium-phosphate to the aging ofthe organism. Klotho deficiency maynot only be a trigger for acceleratedaging but also in development of age--associated diseases, including hypertension,osteoporosis, cardiovasculardisease, and CKD. Conceivably, betterunderstanding of Klotho protein mightprovide a novel treatment strategy foraging and age-associated diseases. PMID- 29693999 TI - [The most recent developments in diagnosis and treatment of multiple myeloma]. AB - Recently a great progress in thediagnosis and treatment of multiplemyeloma has been made. Substantialrevisions in diagnostic criteria were introduced.As a result a neoplasm calledvery high risk asymptomatic myelomais currently regarded a disease thatneeds to be treated. The comprehensionof progression mechanism andclonal evolution not only helped tounderstand the disease course butmight contribute to expand treatmentoptions and individualize the therapy.Modern triple therapy containing IMiDsand proteasome inhibitors resultedin the higher response rate than everbefore which led to triple therapy incorporationas a frontline treatment.U.S. Food and Drug Administration(FDA) registered for new drugs in2015 (two monoclonal antibodies andtwo oral drugs) in relapsed/refractorymyeloma. Together with currently existingdrugs it considerably expendedthe therapeutically spectrum. Evendrugs that are not effective when usedas a monotherapy like panobinostatand elotuzumab play important rolein complex therapy, particularly inrefractory patients. The most recenttrials dedicated to the role of the noveldrugs in the induction phase suggestthat high-dose therapy followed byautologous stem cell transplantationimprove progression free survivaland quality of life. Myeloma treatmentschedules incorporate more and moreinnovative immunotherapy methods:adoptive T-cell therapies, vaccinesand monoclonal antibodies. Althoughmultiple myeloma is still regardedincurable neoplasm, due to betterdisease understanding and access tonovel drugs, we are getting closer thanever before to evolve therapy that willprovide long-lasting effects or at leastconverting it into the chronic slowlydeveloping disease. PMID- 29694000 TI - [Microangiopathy CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) - a chalange for general practitioner]. AB - Small cerebral vessel disease is arelatively new group of angiopathiesdiagnosed more frequently thanks tocommon availability of neuroimaging.The most frequent and the mostknown disease which belongs to thisgroup is CADASIL (cerebral autosomaldominant arteriopathy with subcorticalinfarcts and leukoencephalopathy).Despite the name, it is a generalizedsmall vessel disease, in whichsymptoms of brain damage dominate.The disease manifests as recurrentischemic strokes, progressing dementia,migraine and mental disorders symptoms which usually appear in 4-5decade of life in patients without typicalrisk factors for vascular disease. Inneuroimaging hyperintense changesand small ischemic foci disseminatedin the cerebral white matter are seen.CADASIL is caused by mutations inthe NOTCH 3 gene, which lead to thedegeneration and loss of smooth musclecells in small arteries. The diseaseis diagnosed on the basis of the resultof the genetic test and microscopicexamination of blood vessels in thematerial derived from a skin or skinmusclebiopsy. Since more and morefrequently new techniques of neuroimagingreveal changes in the cerebralwhite matter - often asymptomatic or/and mistakenly diagnosed as demyelinatinglesions - only knowledge aboutCADASIL and other microangiopathiesallows to avoid diagnostic errors. PMID- 29694001 TI - [Hypoglycemia due to antibodies to exogenous insulin in a patient with type 2 diabetes - a case report of treatment with new generation oral hypoglycemic agents]. AB - : Hypoglycemic syndromes associatedwith immune reactions againstinsulin are rare phenomena describedpredominantly in Asians. Steroidtherapy, immunosuppression or plasmapheresisis often required. Case report: A 73-year-old Whitewoman with a 20 year history of type2 diabetes was admitted to hospitaldue to recurrent incidents of hypoglycemiathat started several monthsafter insulin initiation (lispro 75/25)and increased in severity over thenext 5 years. They were accompaniedby postprandial hyperglycemia upto 25 mmol/l. The patient's glycatedhemoglobin (HbA1c) was 70 mmol/mol (8.6%). During hypoglycemicepisodes recorded serum C peptidewas 0.57-0.73 nmol/l (1.7-2.2 ng/ml),while insulin concentration exceeded7000 pmol/l (1000 mIU/l). Surreptitiousinsulin administration was ruled out aswas, based on diagnostic imaging, thepresence of an insulin secreting tumor.Anti-insulin antibody (AIA) level measuredby 125I-insulin binding method was92.5% (normal < 8.2%). Hypoglycemicepisodes occurred for four days afterdiscontinuation of insulin therapyand then resolved completely. Goodglycemic control was maintained withmetformin, acarbose and dapagliflozin.Three months later dapagliflozin wasreplaced with vildagliptine due to poortolerance of a SGLT 2 inhibitor. Patient'sHbA1c was 54 mmol/mol (7.1%),total fasting insulin level 2577 pmol/land AIA binding 85.9%. Over the nextyear the patient has not experiencedhypoglycemia and maintained goodglycemic control, as HbA1c level was 53mmol/l (7.0%) and AIA binding 39.5%. Conclusions: In this rare case ofa patient with diabetes and hypoglycemicsyndrome related to AIA, weachieved a rapid and stable remissionof hypoglycemia without immunosuppression.Good glycemic control, despite 20-year historyof diabetes was achieved with oral hypoglycemic agents. PMID- 29694002 TI - [Giant supernumerary parathyroid adenoma as a cause of persistent primary hyperparathyroidism in a patient with a multiglandular parathyroid disease]. AB - Despite the significant progressthat has been made in recent years inparathyroid imaging, improvementsin surgical techniques and availabilityof surgical quality control based onintraoperative parathyroid hormonelevels (PTH) assay, approximately1-5% of patients undergoing surgeryhave state of persistent hyperparathyroidism.The most common causes ofpersistent hyperparathyroidism are:limited surgical experience, a failure torecognize multiglandular parathyroiddisease, ectopic parathyroid adenomalocation, insufficient range of resectionof diseased parathyroid glands,parathyroid capsule tearing leadingto parathyromathosis, as well as parathyroidcancer. In this clinical observationthe case of a 52-years old man isdescribed who underwent surgicalremoval of 2 parathyroid adenomas,and within few days he was found tohave persistent hypercalcemia. Aftercompleting the diagnostic imaging andbiochemical work-up that patient underwentbilateral neck re-explorationwith removal of ectopic giant supernumeraryparathyroid adenoma (60mm in diameter and 22.8 g in weight)which was localized in the upper partof the posterior mediastinum, resultingin stable normocalcemia afterwards. PMID- 29694003 TI - [Outline of the history of caesarean section - from ancient times to the end of 17th Century]. AB - Problems with the childbirth accompaniedthe human civilizationsince its beginning. From the ancienttimes, physicians and other peoplespecializing in healing, tried to helpwomen in this special moment of life.At the base of this exceptional meaningof childbirth for humans lies thefact, that if something is going wrongthere are two victims - mother and thechild.As a result, many times there hadbeen very dramatic attempts of helpin this the most difficult journey whichin his life every man is undergoing. Inthis paper a comprehensive review ofliterature about the history of caesareansection from ancient times to theend of 17th century was done. PMID- 29694004 TI - Nanostructured Tetrahedrite Synthesis for Thermoelectric Applications. AB - Nowadays, a big challenge in the thermoelectric field is the identification of efficient thermoelectric materials but inexpensive, easy to synthesize, and comprised of Earth-abundant elements. On this basis, tetrahedrite mineral family (Cu(12-x)Tr(x)Sb4S13 where Tr = Cu, Mn, Fe, Co, Ni, Zn) seems to be an attractive p-Type Pb-free thermoelectric material, showing a relatively high conversion efficiency. In this work, a solvothermal synthesis method was developed for undoped tetrahedrite Cu12Sb4S13 and the introduction of Zn and Ni as substituents of copper was also tested. The influence of the stoichiometry and the synthesis conditions on the tetrahedrite phase content and density of the samples were investigated by X-ray diffraction (with profile Rietveld refinements) and scanning electron microscope (equipped with energy dispersive X-ray spectroscopy). Preliminary sintering test were performed by Open Die Pressing. PMID- 29694005 TI - Patients with diabetes mellitus have better lipid profile results compared to the controls - a retrospective study on a group of patients hospitalized due to pulmonary embolism. AB - Background: Pulmonary embolismis a clinical manifestation of venousthromboembolism (VTE), alsocomprising deep vein thrombosis. Itis considered to be a consequenceof environmental and genetic factors.The number of predisposing risk factorsis high. Some authors view VTEas a part of the cardiovascular diseasecontinuum and suggest that cardiovasculardisease risk factors suchas the metabolic syndrome or diabetesmellitus may predispose to VTE. Aim: The analysis of patients hospitalizedin the department of cardiologydue to pulmonary embolismand a multifactorial comparison of 2groups of patients i.e. with and withoutdiabetes mellitus. Patients and Methods: A retrospectiveanalysis of 11435 patientmedical records from a 7-year periodwas performed. Patients with confirmedpulmonary embolism wereenrolled for further evaluation. Sixtyseven patients (36 women and 31men), aged 70.3+/-13.3 (age range: 30-93) were divided into two groups i.e.patients with and without diabetes.The statistical analysis of the obtainedresults was performed usingSPSS 21 Software. Results: Statistically significantlyhigher total, LDL, and HDL cholesterolconcentrations were observed inpatients without diagnosed diabetes.Similar significant differences werenot observed for other cardiovascularrisk factors except for hypertensionand obesity which was more frequentin diabetic patients. Conclusions: In patients with pulmonaryembolism the prevalence of diabeteswas related to lower total, LDLand HDL cholesterol concentrations.The differences between the groupsmay be explained by more intensivemedical surveillance in patients withpreviously diagnosed diabetes. PMID- 29694006 TI - Oral mucosa lesions in patients with active Crohn's disease - a prospective study. AB - Introduction: Crohn's disease (CD)is a chronic inflammatory disease,which may involve any part of the gastrointestinaltract, including the oralcavity. Mucosal lesions in the oral cavityare described in various populations,but observations in active diseasewith severe clinical symptoms arequite rare. Objectives: To evaluate the prevalenceand nature of oral mucosa lesionsin adult patients with active CDand their correlation with clinical andlaboratory indicators of disease activity. Material and Methods: Prospectivestudy was performed in 62 patients(29 women, 33 men, age 18-49 years)admitted between December 2010 andFebruary 2013 to the gastroenterologydepartment with a confirmed diagnosisof CD and exacerbations of symptoms,and 40 sex- and gender-matchedhealthy volunteers. CD activity wasclassified according to clinical andblood parameters, and the CD activityindex (CDAI). We examined: blood morphology,hemoglobin and CRP levels,BMI. Examination of the oral cavity includeda detailed interview and physicalexamination, based on the WHOrecommendations. Results: In patients with activeCD we found: increased CDAIscore (258.4+/-21.5), higher CRP levels(24.6+/-1.3 mg/l) and platelet count, anemiawith significantly reduced RBC andhemoglobin level, and reduced BMI, incomparison to controls. The specificfor CD symptoms were found in themouth: indurated tag polypoid lesionson vestibular retromolar region in12.9% of patients, cobblestoning of themucosa in 9.7%, diffuse asymptomaticbuccal swelling in 16.2%, mucogingivitisin 19.4% of patients. Oral nonspecificlesions were more frequent: angularcheilitis in 29.1%, atrophic glossitis in14.5% of patients. Oral lesions correlatedwith hemoglobin and CRP concentrations(r=-0.431 and r=0.437; respectively;p<0.001), platelet count (r=0.45;p<0.003), CDAI (r=0.421; p<0.001) andBMI (r=0.307; p<0.006). No correlationhas been found between specific ornon specific lesions and location ofinflammatory changes in the gastrointestinaltract. Conclusions: Changes in the oral mucosa in adult patientswith active CD are frequent. They should be correlatedwith other clinical symptoms of gastrointestinal tract and biochemicalparameters in patients with CD. The nature of thesechanges may have an impact on the further therapeutic approach. PMID- 29694007 TI - Minimally invasive direct coronary artery bypass (MIDCAB) - safety assessment in own material. AB - Introduction: Minimally invasivedirect coronary artery bypass (MIDCAB)allows achieving similar safetyand efficacy, with markedly reducedpost-operative length of stay whencompared to conventional surgicalrevascularization. Despite promisingresults, a small number of minimallyinvasive procedures are performed inPoland. The aim of the study is to assessshort- and long-term outcome ofMIDCAB revascularization in order toevaluate the safety of the procedure. Materials and Methods: Retrospectiveobservational study analyzing 38consecutive patients who underwentMIDCAB procedure between 2014 to2016 in the Department of CardiovascularSurgery and Transplantologyat the John Paul II Hospital, Krakow.Perioperative data was obtained frompatient medical records and the medianfollow-up period valued 17.3months. Results: No postoperative deathsand only 1 case of postoperativemyocardial infarction were observed.Throughout the follow-up period, thesurvival rate and freedom from MACCErate valued 100%, with only 1 caseof repeated revascularization. Conclusions: Minimally invasiverevascularization is a safe procedurewhich can be performed with excellentshort- and long-term outcome inlow-risk patients. PMID- 29694008 TI - [Estimation of the consumption frequency of high glucose corn syrup by patients with hypertension]. AB - : Hypertension is a major health problemin modern times, due to its highprevalence. This is an important riskfactor for cardiovascular disease, whichare the main cause of death in developedcountries.The component of prevention andnon-pharmacological treatment of hypertensionis a proper diet. More andmore often an adequate supply of sugarsin the diet is emphasized. In recentyears particular attention was paid tothe consumption of HFCS (high fructosecorn syrup), which is present inmany processed foods.The aim of this study was to estimatethe frequency of consumption ofHFCS products among patients with hypertension. Material and Methods: The studyinvolved 108 people diagnosed withhypertension, who attended to the HypertensiveClinic in Krakow. The studywas conducted in the form of FoodFrequency Questionnaire (FFQ) of 24selected beverages and solid products,which are a source of HFCS. In addition,the survey included 6 questions aboutnutrition knowledge on HFCS. The examinationtook place from October 2014.to March 2015. Results: The vast majority of patientsindicated consumption of productswith HFSC. The most popularproducts proved to be sweets (especiallychocolate bars, wafers) and fruitdrinks and nectars. Frequent consumptionof cola drinks was also observed,which were more often chosen by menthan women. Younger respondents (<55years old) more often than respondentsover 55. years old chose sweets. At thesame time our survey indicated unsatisfactorylevel of nutritional knowledge onHFCS among patients. Conclusions: The consumption ofHFCS in patients with hypertensionis common, at low knowledge of itsharmful effects on health. Thereforethere is apparent need for dietary educationof patients with hypertension inthis area. PMID- 29694009 TI - [Health awareness and cooperation with the patient in the therapeutic process in a population of patients with chronic kidney disease in the center of Gdansk]. AB - : Chronic kidney disease (CKD) isconsidered as a disease of civilizationof the XXI century. The increaseof patients with CKD is associatedwith a higher incidence of hypertension,diabetes and aging. Hypertensionoccurs in 60-90% of patientswith CKD. It is worth to underline thatthe nephroprotective therapy can delayor even stop the progression ofCKD to end-stage renal disease. Thetherapy nephroprotective should beunderstood as both pharmacologicaland nonpharmacological treatment.The aim of this study was toevaluate the health awareness ofpatients with CKD, as well as thedegree of patient compliance especiallyin terms of pharmacologicaland non-pharmacological treatment. Material and Methods: A crosssectionalsurvey was offered for1300 patients with CKD who are areunder the care of the Department ofNephrology, Transplantology and InternalMedicine, University Hospitalin Gdansk. 972 patients (M/F) (74.8%)responded positively to participate inthe study Results: It was shown that 91.2%of the patients measured blood pressureat home. 41.2% measured bloodpressure everyday and 54.2% of patientsused at least one non-pharmacologicaltreatment for hypertension.71.7% of patients declared that buyall drugs prescribed by the doctor.53.4% of patients used the possibilityof substitution drugs prescribedby a doctor for cheaper preparationsrecommended by the pharmacist.85.7% of patients taking medicinesaccording to doctor's advice (frequency,dose). Conclusions: The results of thestudy indicate that the education ofpatients, the therapeutic process andtheir health awareness are good, especiallyamong patients treated withperitoneal dialysis. It should be continuedas educational program because these activitiesmay contribute to improving the prognosis and quality oflife. A patients after kidney transplantation are particularlyvulnerable to the effects of failure to comply with recommendations. PMID- 29694010 TI - Creation and Ordering of Oxygen Vacancies at WO3-delta and Perovskite Interfaces. AB - Changes in the structure and composition resulting from oxygen deficiency can strongly impact the physical and chemical properties of transition-metal oxides, which may lead to new functionalities for novel electronic devices. Oxygen vacancies (VO) can be readily formed to accommodate the lattice mismatch during epitaxial thin film growth. In this paper, the effects of substrate strain and oxidizing power on the creation and distribution of VO in WO3-delta thin films are investigated in detail. An 18O2 isotope-labeled time-of-flight secondary-ion mass spectrometry study reveals that WO3-delta films grown on SrTiO3 substrates display a significantly larger oxygen vacancy gradient along the growth direction compared to those grown on LaAlO3 substrates. This result is corroborated by scanning transmission electron microscopy imaging, which reveals a large number of defects close to the interface to accommodate interfacial tensile strain, leading to the ordering of VO and the formation of semi-aligned Magneli phases. The strain is gradually released and a tetragonal phase with much better crystallinity is observed at the film/vacuum interface. The changes in the structure resulting from oxygen defect creation are shown to have a direct impact on the electronic and optical properties of the films. PMID- 29694011 TI - Efficient and Stable CsPb(Br/I)3@Anthracene Composites for White Light-Emitting Devices. AB - Inorganic perovskite quantum dots bear many unique properties that make them potential candidates for optoelectronic applications, including color display and lighting. However, the white emission with inorganic perovskite quantum dots has rarely been realized due to the anion-exchange reaction. Here, we proposed a one pot preparation to fabricate inorganic perovskite quantum dot-based white light emitting composites by introducing anthracene as a blue emission component. The as-prepared white light-emitting composite exhibited a photoluminescence quantum yield of 41.9%. By combining CsPb(Br/I)3@anthracene composites with UV light emitting device (LED) chips, white light-emitting devices with a color rendering index of 90 were realized with tunable color temperature from warm white to cool white. These results can promote the application of inorganic perovskite quantum dots in the field of white LEDs. PMID- 29694013 TI - Metal-Organic-Framework-Derived N-Doped Hierarchically Porous Carbon Polyhedrons Anchored on Crumpled Graphene Balls as Efficient Selenium Hosts for High Performance Lithium-Selenium Batteries. AB - Developing carbon scaffolds showing rational pore structures as cathode hosts is essential for achieving superior electrochemical performances of lithium-selenium (Li-Se) batteries. Hierarchically porous N-doped carbon polyhedrons anchored on crumpled graphene balls (NPC/CGBs) are synthesized by carbonizing a zeolitic imidazolate framework-8 (ZIF-8)/CGB composite precursor, producing an unprecedented effective host matrix for high-performance Li-Se batteries. Mesoporous CGBs obtained by one-pot spray pyrolysis are used as a highly conductive matrix for uniform polyhedral ZIF-8 growth. During carbonization, ZIF 8 polyhedrons on mesoporous CGBs are converted into N-doped carbon polyhedrons showing abundant micropores, forming a high-surface-area, high-pore-volume hierarchically porous NPC/CGB composite whose small unique pores effectively confine Se during melt diffusion, thereby providing conductive electron pathways. Thus, the integrated NPC/CGB-Se composite ensures high Se utilization originating from complete electrochemical reactions between Se and Li ions. The NPC/CGB-Se composite cathode exhibits high discharge capacities (998 and 462 mA h g-1 at the 1st and 1000th cycles, respectively, at a 0.5 C current density), good capacity retention (68%, calculated from the 3rd cycle), and excellent rate capability. A discharge capacity of 409 mA h g-1 is achieved even at an extremely high (15.0 C) current density. PMID- 29694012 TI - Defects and Chirality in the Nanoparticle-Directed Assembly of Spherocylindrical Shells of Virus Coat Proteins. AB - Virus coat proteins of small isometric plant viruses readily assemble into symmetric, icosahedral cages encapsulating noncognate cargo, provided the cargo meets a minimal set of chemical and physical requirements. While this capability has been intensely explored for certain virus-enabled nanotechnologies, additional applications require lower symmetry than that of an icosahedron. Here, we show that the coat proteins of an icosahedral virus can efficiently assemble around metal nanorods into spherocylindrical closed shells with hexagonally close packed bodies and icosahedral caps. Comparison of chiral angles and packing defects observed by in situ atomic force microscopy with those obtained from molecular dynamics models offers insight into the mechanism of growth, and the influence of stresses associated with intrinsic curvature and assembly pathways. PMID- 29694014 TI - Indigoid Photoswitches: Visible Light Responsive Molecular Tools. AB - Indigoid photoswitches comprise a class of chromophores that are derived from the parent and well-known indigo dye. Different from most photoswitches their core structures absorb in the visible region of the spectrum in both isomeric states even without substitutions, which makes them especially interesting for applications not tolerant of high-energy UV light. Also different from most current photoswitching systems, they provide highly rigid structures that undergo large yet precisely controllable geometry changes upon photoisomerization. The favorable combination of pronounced photochromism, fast and efficient photoreactions, and high thermal bistability have led to a strongly increased interest in indigoid photoswitches over the last years. As a result, intriguing applications of these chromophores as reversible triggering units in supramolecular and biological chemistry, the field of molecular machines, or smart molecules have been put forward. In this Account current developments in the synthesis, mechanistic understanding of light responsiveness, advantageous properties as phototools, and new applications of indigoid photoswitches are summarized with the focus on hemithioindigo, hemiindigo, and indigo as key examples. Many methods for the synthesis of hemithioindigos are known, but derivatives with a fourth substituent at the double bond could not easily be prepared because of the resulting increased steric hindrance in the products. Recent efforts in our laboratory have provided two different methods to prepare these highly promising photoswitches in very efficient ways. One method is especially designed for the introduction of sterically hindered ketones while the second one allows rapid structural diversification in only three high-yielding synthetic steps. Given the lesser prominence of indigoid photoswitches, mechanistic understanding of their excited state behavior and therefore rational design opportunities for photophysical properties are also much less developed compared to, for example, azobenzenes or stilbenes. By testing different substitution patterns, we were able to produce strongly beneficial property combinations in hemithioindigo, hemiindigo, or indigo photoswitches, for example, red-light responsiveness together with very high thermal bistability of the switching states. This is of particular importance for photopharmacological and biological applications of these switches to reduce the damage from high-energy light and to enable deep penetration of the light into tissues. An additional ground state twisting in hemithioindigo allowed us to control the type of light induced bond rotation simply by the polarity of the solvent. With the aid of time resolved spectroscopy and quantum yield measurements, we could show that in apolar cyclohexane exclusive double bond rotation takes place while in polar DMSO sole single bond rotation is observed. Such precise control over geometrical changes is of great interest for the construction of future sophisticated molecular machinery. In this field, we have introduced hemithioindigo photoswitches as novel core structure for molecular motors providing very fast directional motions upon irradiation with visible light. The mechanism of the directional rotation adheres to a four-step process, which could directly be observed in situ with a slower second-generation motor. Further applications of indigoid photoswitches were made in our laboratory in the realms of photocontrolled folding and host-guest chemistry as well as in molecular digital information processing showcasing the great versatility and enormous future promise of indigoid photoswitches. PMID- 29694015 TI - Ultrasonic Preparation of Porous Silica-Dye Microspheres: Sensors for Quantification of Urinary Trimethylamine N-Oxide. AB - Trimethylamine N-oxide (TMAO), the N-oxide metabolite of trimethylamine (TMA), is a key index in the determination of a wide variety of human cardiac or kidney diseases. A colorimetric sensor array comprising ultrasonically prepared silica dye microspheres was developed for rapid, portable, and sensitive detection of urinary TMAO. To prepare the sensor array, 13 different organically modified silica (ormosil)-dye composites were synthesized from the hydrolysis/pyrolysis of ultrasonically sprayed organosiloxane precursors under optimized reaction conditions; the resulting products are uniformly sized nanoporous microspheres that are effective colorimetric sensors for various volatile analytes. The effective quantification of aqueous TMAO (which is not volatile) was based on sensing the volatile TMA produced from a simple catalytic reduction of TMAO in situ. RGB color-change patterns from digital images of the sensor array permit precise discrimination among a wide range of TMAO concentrations (10-750 MUM) in simulated urine samples; both hierarchical cluster analysis and principal component analysis achieve >99% accuracy in data classification. The calculated limit of detection of urinary TMAO is ~4 MUM, which is substantially below the median level of healthy subjects (~380 MUM). The array of sensors could be simplified to only a couple of strongly responsive elements for the ease of field use, and the process could be developed as a point-of-care tool in combination with digital imaging for the early diagnosis of cardiovascular or kidney diseases from the measurement of fasting urinary level of TMAO. PMID- 29694016 TI - Ultrabright Polymer-Dot Transducer Enabled Wireless Glucose Monitoring via a Smartphone. AB - Optical methods such as absorptiometry, fluorescence, and surface plasmon resonance have long been explored for sensing glucose. However, these schemes have not had the clinical success of electrochemical methods for point-of-care testing because of the limited performance of optical sensors and the bulky instruments they require. Here, we show that an ultrasensitive optical transducer can be used for wireless glucose monitoring via a smartphone. The optical transducer combines oxygen-sensitive polymer dots (Pdots) with glucose oxidase that sensitively detect glucose when oxygen is consumed in the glucose oxidation reaction. By judicious design of the Pdots with ultralong phosphorescence lifetime, the transducer exhibited a significantly enhanced sensitivity by 1 order of magnitude as compared to the one in a previous study. As a result, the optical images of subcutaneous glucose level obtained with the smartphone camera could be utilized to clearly distinguish between euglycemia and hyperglycemia. We further developed an image processing algorithm and a software application that was installed on a smartphone. Real-time dynamic glucose monitoring in live mice was demonstrated with the smartphone and the implanted Pdot transducer. PMID- 29694017 TI - Switchable Underwater Bubble Wettability on Laser-Induced Titanium Multiscale Micro-/Nanostructures by Vertically Crossed Scanning. AB - We present here a kind of novel multiscale TiO2 square micropillar arrays on titanium sheets through vertically crossed scanning of femtosecond laser. This multiscale micro-/nanostructure is ascribed to the combination of laser ablation/shock compression/debris self-deposition, which shows superaerophobicity in water with a very small sliding angle. The laser-induced sample displays switchable bubble wettability in water via heating in a dark environment and ultraviolet (UV) irradiation in alcohol. After heating in a dark environment (0.5 h), the ablated titanium surface shows superaerophilicity in water with a bubble contact angle (BCA) of ~4 degrees , which has a great ability of capturing bubbles in water. After UV irradiation in alcohol (1 h), the sample recovered its superaerophobicity in water and the BCA turns into 156 degrees . The mechanism of reversible switching is believed as the chemical conversion between Ti-OH and Ti O. It is worth noting that our proposed switching strategy is time-saving and the switch wetting cycle costs only 1.5 h. Then we repeat five switching cycles on the reversibility and the method shows excellent reproducibility and stability. Moreover, laser-induced samples with different scanning spacing (50-120 MUm) are fabricated and all of them show switchable underwater bubble wettability via the above tunable methods. Finally, we fabricate hybrid-patterned microstructures to show different patterned bubbles in water on the heated samples. We believe the original works will provide some new insights to researchers in bubble manipulation and gas collection fields. PMID- 29694018 TI - Dual Carbon-Confined SnO2 Hollow Nanospheres Enabling High Performance for the Reversible Storage of Alkali Metal Ions. AB - To explore a universal electrode material for the high-performance electrochemical storage of Li+, Na+, and K+ ions remains a big challenge. Herein, we propose a "trinity" strategy to coat the SnO2 hollow nanospheres using the dual carbon layer from the polydopamine-derived nitrogen-doped carbon and graphene. Thereinto, hollow structures with sufficient void space could buffer the volume expansion, whereas dual carbon-confined strategy could not only elastically prevent the aggregation of nanoparticle and ensure the structural integrity but also immensely improve the conductivity and endow high rate properties. Benefiting from the effective strategy and specific structure, the dual carbon-confined SnO2 hollow nanosphere (denoted as G@C@SnO2) can serve as the universal host material for alkali metal ions and enable their rapid and reversible storage. As expected, the resulting G@C@SnO2 as a universal anode material shows reversible alkali-metal-ion storage with high performance. We believe this that strategy could pave the way for constructing other metal-oxide based dual carbon-confined high-performance materials for the future energy storage applications. PMID- 29694019 TI - Evolution of Structural and Electrical Properties of Carbon Films from Amorphous Carbon to Nanocrystalline Graphene on Quartz Glass by HFCVD. AB - Direct growth of graphene films on glass is of great importance but has so far met with limited success. The noncatalytic property of glass results in the low decomposition ability of hydrocarbon precursors, especially at reduced temperatures (<1000 degrees C), and therefore amorphous carbon (a-C) films are more likely to be obtained. Here, we report the hydrogen influence on the structural and electrical properties of carbon films deposited on quartz glass at 850 degrees C by hot-filament chemical vapor deposition (HFCVD). The results revealed that the obtained a-C films were all graphitelike carbon films. Structural transition of the deposited films from a-C to nanocrystalline graphene was achieved by raising the hydrogen dilution ratios from 10 to over 80%. On the basis of systematic structural and chemical characterizations, a schematic process with three steps including sp2 chain aggregation, aromatic ring formation, and sp3 bond etching was proposed to interpret the structural evolution. The nanocrystalline graphene films grown on glass by HFCVD exhibited good electrical performance with a carrier mobility of 36.76 cm2/(V s) and a resistivity of 5.24 * 10-3 Omega cm over an area of 1 cm2. Temperature-dependent electrical characterizations revealed that the electronic transport in carbon films was dominated by defect, localized, and extended states, respectively, when increasing the temperature from 75 to 292 K. The nanocrystalline graphene films presented higher carrier mobility and lower carrier concentration than those of a C films, which was mainly attributed to their smaller conductive activation energy. The present investigation provides an effective way for direct growth of graphene films on glass at reduced temperatures and also offers useful insights into the understanding of structural and electrical relationship between a-C and graphene. PMID- 29694020 TI - Dynamic Measurement of Low Contact Angles by Optical Microscopy. AB - Precise measurement of contact angles is an important challenge in surface science, in the design and characterization of materials and in many crystallization experiments. Here we present a novel technique for measuring the contact angles of droplets between about 2 degrees and 30 degrees , with the lowest experimental uncertainty at the lower end of this range, typically +/-0.1 degrees . The lensing effect of a droplet interface produces the appearance of bright circles in low-aperture light, whose diameter is related to the contact angle. The technique requires no specialized equipment beyond an ordinary optical microscope, and may be used to study the dynamic evolution of the contact angle in situ during an experiment. PMID- 29694021 TI - Correction to Homogeneous Coating with an Anion-Exchange Ionomer Improves the Cycling Stability of Secondary Batteries with Zinc Anodes. PMID- 29694022 TI - Correction to ADAP-GC 3.0: Improved Peak Detection and Deconvolution of Co eluting Metabolites from GC/TOF-MS Data for Metabolomics Studies. PMID- 29694023 TI - Rapid Amorphization in Metastable CoSeO3.H2O Nanosheets for Ultrafast Lithiation Kinetics. AB - The realization of high-performance anode materials with high capacity at fast lithiation kinetics and excellent cycle stability remains a significant but critical challenge for high-power applications such as electric vehicles. Two dimensional nanostructures have attracted considerable research interest in electrochemical energy storage devices owing to their intriguing surface effect and significantly decreased ion-diffusion pathway. Here we describe rationally designed metastable CoSeO3.H2O nanosheets synthesized by a facile hydrothermal method for use as a Li ion battery anode. This crystalline nanosheet can be steadily converted into amorphous phase at the beginning of the first Li+ discharge cycling, leading to ultrahigh reversible capacities of 1100 and 515 mAh g-1 after 1000 cycles at a high rate of 3 and 10 A g-1, respectively. The as obtained amorphous structure experiences an isotropic stress, which can significantly reduce the risk of fracture during electrochemical cycling. Our study offers a precious opportunity to reveal the ultrafast lithiation kinetics associated with the rapid amorphization mechanism in layered cobalt selenide nanosheets. PMID- 29694025 TI - Direct Visualization of Barrier Crossing Dynamics in a Driven Optical Matter System. AB - A major impediment to a more complete understanding of barrier crossing and other single-molecule processes is the inability to directly visualize the trajectories and dynamics of atoms and molecules in reactions. Rather, the kinetics are inferred from ensemble measurements or the position of a transducer ( e. g., an AFM cantilever) as a surrogate variable. Direct visualization is highly desirable. Here, we achieve the direct measurement of barrier crossing trajectories by using optical microscopy to observe position and orientation changes of pairs of Ag nanoparticles, i. e. passing events, in an optical ring trap. A two-step mechanism similar to a bimolecular exchange reaction or the Michaelis-Menten scheme is revealed by analysis that combines detailed knowledge of each trajectory, a statistically significant number of repetitions of the passing events, and the driving force dependence of the process. We find that while the total event rate increases with driving force, this increase is due to an increase in the rate of encounters. There is no drive force dependence on the rate of barrier crossing because the key motion for the process involves a random (thermal) radial fluctuation of one particle allowing the other to pass. This simple experiment can readily be extended to study more complex barrier crossing processes by replacing the spherical metal nanoparticles with anisotropic ones or by creating more intricate optical trapping potentials. PMID- 29694024 TI - Multidirection Piezoelectricity in Mono- and Multilayered Hexagonal alpha-In2Se3. AB - Piezoelectric materials have been widely used for sensors, actuators, electronics, and energy conversion. Two-dimensional (2D) ultrathin semiconductors, such as monolayer h-BN and MoS2 with their atom-level geometry, are currently emerging as new and attractive members of the piezoelectric family. However, their piezoelectric polarization is commonly limited to the in-plane direction of odd-number ultrathin layers, largely restricting their application in integrated nanoelectromechanical systems. Recently, theoretical calculations have predicted the existence of out-of-plane and in-plane piezoelectricity in monolayer alpha-In2Se3. Here, we experimentally report the coexistence of out-of plane and in-plane piezoelectricity in monolayer to bulk alpha-In2Se3, attributed to their noncentrosymmetry originating from the hexagonal stacking. Specifically, the corresponding d33 piezoelectric coefficient of alpha-In2Se3 increases from 0.34 pm/V (monolayer) to 5.6 pm/V (bulk) without any odd-even effect. In addition, we also demonstrate a type of alpha-In2Se3-based flexible piezoelectric nanogenerator as an energy-harvesting cell and electronic skin. The out-of-plane and in-plane piezoelectricity in alpha-In2Se3 flakes offers an opportunity to enable both directional and nondirectional piezoelectric devices to be applicable for self-powered systems and adaptive and strain-tunable electronics/optoelectronics. PMID- 29694026 TI - Directed Evolution of Heterologous tRNAs Leads to Reduced Dependence on Post transcriptional Modifications. AB - Heterologous tRNA:aminoacyl tRNA synthetase pairs are often employed for noncanonical amino acid incorporation in the quest for an expanded genetic code. In this work, we investigated one possible mechanism by which directed evolution can improve orthogonal behavior for a suite of Methanocaldococcus jannaschii ( Mj) tRNATyr-derived amber suppressor tRNAs. Northern blotting demonstrated that reduced expression of heterologous tRNA variants correlated with improved orthogonality. We suspected that reduced expression likely minimized nonorthogonal interactions with host cell machinery. Despite the known abundance of post-transcriptional modifications in tRNAs across all domains of life, few studies have investigated how host enzymes may affect behavior of heterologous tRNAs. Therefore, we measured tRNA orthogonality using a fluorescent reporter assay in several modification-deficient strains, demonstrating that heterologous tRNAs with high expression are strongly affected by some native E. coli RNA modifying enzymes, whereas low abundance evolved heterologous tRNAs are less affected by these same enzymes. We employed mass spectrometry to map ms2i6A37 and Psi39 in the anticodon arm of two high abundance tRNAs (Nap1 and tRNAOptCUA), which provides (to our knowledge) the first direct evidence that MiaA and TruA post-transcriptionally modify evolved heterologous amber suppressor tRNAs. Changes in total tRNA modification profiles were observed by mass spectrometry in cells hosting these and other evolved suppressor tRNAs, suggesting that the demonstrated interactions with host enzymes might disturb native tRNA modification networks. Together, these results suggest that heterologous tRNAs engineered for specialized amber suppression can evolve highly efficient suppression capacity within the native post-transcriptional modification landscape of host RNA processing machinery. PMID- 29694027 TI - Ion Mobility Spectrometer-Fragmenter-Ion Mobility Spectrometer Analogue of a Triple Quadrupole for High-Resolution Ion Analysis at Atmospheric Pressure. AB - Two differential mobility analyzers (DMAs) acting as narrow band mobility filters are coupled in series, with a thermal fragmentation cell placed in between, such that parent ions selected in DMA1 are fragmented in the cell at atmospheric pressure, and their product ions are analyzed on DMA2. Additional mass spectrometer analysis is performed for ion identification purposes. A key feature of the tandem DMA is the short residence time (~0.2 ms) of ions in the analyzer, compared to tens of milliseconds in drift tube ion mobility spectrometers (IMS). Ion fragmentation within the analyzer and associated mobility tails are therefore negligible for a DMA but not necessarily so in conventional IMS. This advantage of the DMA is demonstrated here by sharply defined product ion mobility peaks. Ambient pressure ion fragmentation has been previously demonstrated by both purely thermal means as well as rapidly oscillating intense electric fields. Our purely thermal fragmentation cell here achieves temperatures up to 700 degrees C measured inside the heating coil of a cylindrical ceramic heater, through whose somewhat colder axis we direct a beam of mobility-selected ions. We investigate tandem separation of chloride adducts from the explosives EGDN, nitroglycerine (NG), PETN, and RDX and from deprotonated TNT. Atmospheric pressure fragmentation of the first three ions yields one or several previously reported fragments, providing highly distinctive tandem DMA channels for explosive identification at 1 atm. RDX ions had not been previously fragmented at ambient pressure, yet [RDX + Cl]- converts up to 7% (at 300 degrees C) into a 166 m/ z product. The known high thermal resilience of TNT is confirmed here by its rather modest conversion, even when the ceramic is heated to 700 degrees C. At this temperature some previously reported fragments are found, but their mobilities are fairly close to each other and to the one of the far more abundant parent ion, making their identification by mobility alone problematic. We anticipate that moderately higher fragmenter temperatures will produce smaller fragments with mobilities readily separated from that of [TNT - H]-. PMID- 29694028 TI - Noncompetitive Homogeneous Detection of Small Molecules Using Synthetic Nanopeptamer-Based Luminescent Oxygen Channeling. AB - Our group has previously developed immunoassays for noncompetitive detection of small molecules based on the use of phage borne anti-immunocomplex peptides. Recently, we substituted the phage particles by biotinylated synthetic anti immunocomplex peptides complexed with streptavidin and named these constructs nanopeptamers. In this work, we report the results of combining AlphaLisa, a commercial luminescent oxygen channeling bead system, with nanopeptamers for the development of a noncompetitive homogeneous assay for the detection of small molecules. The signal generation of AlphaLisa assays relies on acceptor-donor bead proximity induced by the presence of the analyte (a macromolecule) simultaneously bound by antibodies immobilized on the surface of these beads. In the developed assay, termed as nanoAlphaLisa, bead proximity is sustained by the presence of a small model molecule (atrazine, MW = 215) using an antiatrazine antibody captured on the acceptor bead and an atrazine nanopeptamer on the donor bead. Atrazine is one of the most used pesticides worldwide, and its monitoring in water has relevant human health implications. NanoAlphaLisa allowed the homogeneous detection of atrazine down to 0.3 ng/mL in undiluted water samples in 1 h, which is 10-fold below the accepted limit in drinking water. NanoAlphaLisa has the intrinsic advantages for automation and high-throughput, simple, and fast homogeneous detection of target analytes that AlphaLisa assay provides. PMID- 29694029 TI - Triboluminescence from Pharmaceutical Formulations. AB - Triboluminescence (TL) is shown to enable selective detection of trace crystallinity within nominally amorphous solid dispersions (ASDs). ASDs are increasingly used for the preparation of pharmaceutical formulations, the physical stability of which can be negatively impacted by trace crystallinity introduced during manufacturing or storage. In the present study, TL measurements of a model ASD consisting of griseofulvin in polyethylene glycol produced limits of detection of 140 ppm. Separate studies of the particle size dependence of sucrose crystals and the dependence on polymorphism in clopidogrel bisulfate particles are both consistent with a mechanism for TL closely linked to the piezoelectric response of the crystalline fraction. Whereas disordered polymeric materials cannot support piezoelectric activity, molecular crystals produced from homochiral molecules adopt crystal structures that are overwhelmingly symmetry allowed for piezoelectricity. Consequently, TL may provide a broadly applicable and simple experimental route for sensitive detection of trace crystallinity within nominally amorphous materials. PMID- 29694030 TI - Polynuclear Cu4L4 Copper(II) Aminyl Radical Coordination Complexes. AB - We describe the structural features and magnetic properties of two polynuclear copper(II) complexes containing a redox-active ligand. These neutral complexes each bear the formula RL4Cu4 (R = tBu, Me) with the ligand in a dianion-aminyl radical oxidation state. X-ray data and density functional theory calculations support an aminyl-type radical character in these complexes, making these the first polynuclear metal aminyl radical complexes. PMID- 29694032 TI - Synthesis, Crystal Structure, and Photoluminescence of the Boron-Aluminum-Silicon Nitride Phosphor Sr3BAl5Si9N20:Eu. AB - Single crystals of new boron-aluminum-silicon nitrides, Sr3BAl5Si9N20 and Sr2.91Eu0.09BAl5Si9N20, were synthesized by heating binary nitride mixtures at 2030 degrees C under a N2 pressure of 0.85 MPa. The X-ray diffraction spots from single crystals of these two compounds were indexed with the trigonal cell parameters a = 22.7406(8) A, c = 5.7066(2) A and a = 22.7439(8) A, c = 5.7050(2) A, respectively, and the crystal structures were determined to have the space group P3 c1, with B atoms situated at planar 3-fold-coordinated N sites. A three dimensional framework structure is constructed for these materials based on the sharing of N atoms of Al/Si-N4 tetrahedra and B-N3 triangles. In this framework, Sr/Eu atoms are located at three sites, surrounded by 10 N atoms. Single crystals of Sr2.91Eu0.09BAl5Si9N20 emitted yellow light with a peak wavelength of 565 nm and a full width at half-maximum of 106 nm under 450 nm light irradiation. The emission intensity of these crystals at 200 degrees C was found to be 12% of the intensity at 25 degrees C. PMID- 29694031 TI - Enantioselective Total Syntheses of Methanoquinolizidine-Containing Akuammiline Alkaloids and Related Studies. AB - The akuammiline alkaloids are a structurally diverse class of bioactive natural products isolated from plants found in various parts of the world. A particularly challenging subset of akuammiline alkaloids are those that contain a methanoquinolizidine core. We describe a synthetic approach to these compounds that has enabled the first total syntheses of (+)-strictamine, (-)-2( S) cathafoline, (+)-akuammiline, and (-)-Psi-akuammigine. Our strategy relies on the development of the reductive interrupted Fischer indolization reaction to construct a common pentacyclic intermediate bearing five contiguous stereocenters, in addition to late-stage formation of the methanoquinolizidine framework using a deprotection-cyclization cascade. The total syntheses of (-) Psi-akuammigine and (+)-akuammiline mark the first preparations of akuammiline alkaloids containing both a methanoquinolizidine core and vicinal quaternary centers. Lastly, we describe the bioinspired reductive rearrangements of (+) strictamine and (+)-akuammiline to ultimately provide (-)-10-demethoxyvincorine and a new analogue thereof. PMID- 29694033 TI - Quantum Dot-PNA Conjugates for Target-Catalyzed RNA Detection. AB - Detection of pathogenic nucleic acids remains one of the most reliable approaches for the diagnosis of a broad range of diseases. Current PCR-based methods require experienced personnel and cannot be easily used for point-of-care diagnostics, making alternative strategies for the sensitive, reliable, and cost-efficient detection of pathogenic nucleic acids highly desirable. Here, we report an enzyme free method for the fluorometric detection of RNA that relies on a target-induced fluorophore transfer onto a semiconductor quantum dot (QD), uses PNA probes as selective recognition elements and can be read out with simple and inexpensive equipment. For QD-PNA conjugates with optimized PNA content, limits of detection of dengue RNA in the range of 10 pM to 100 nM can be realized within 5 h in the presence of a high excess of noncomplementary RNA. PMID- 29694034 TI - Site-Specific Antibody Functionalization Using Tetrazine-Styrene Cycloaddition. AB - Biologics, such as antibody-drug conjugates, are becoming mainstream therapeutics. Consequently, methods to functionalize biologics without disrupting their native properties are essential for identifying, characterizing, and translating candidate biologics from the bench to clinical practice. Here, we present a method for site-specific, carboxy-terminal modification of single-chain antibody fragments (scFvs). ScFvs displayed on the surface of yeast were isolated and functionalized by combining intein-mediated expressed protein ligation (EPL) with inverse electron-demand Diels-Alder (IEDDA) cycloaddition using a styrene tetrazine pair. The high thiol concentration required to trigger EPL can hinder the subsequent chemoselective ligation reactions; therefore, the EPL reaction was used to append styrene to the scFv, limiting tetrazine exposure to damaging thiols. Subsequently, the styrene-functionalized scFv was reacted with tetrazine conjugated compounds in an IEDDA cycloaddition to generate functionalized scFvs that retain their native binding activity. Rapid functionalization of yeast surface-derived scFv in a site-directed manner could find utility in many downstream laboratory and preclinical applications. PMID- 29694035 TI - Optimized Lennard-Jones Parameters for Druglike Small Molecules. AB - Meaningful efforts in computer-aided drug design (CADD) require accurate molecular mechanical force fields to quantitatively characterize protein-ligand interactions, ligand hydration free energies, and other ligand physical properties. Atomic models of new compounds are commonly generated by analogy from the predefined tabulated parameters of a given force field. Two widely used approaches following this strategy are the General Amber Force Field (GAFF) and the CHARMM General Force Field (CGenFF). An important limitation of using pretabulated parameter values is that they may be inadequate in the context of a specific molecule. To resolve this issue, we previously introduced the General Automated Atomic Model Parameterization (GAAMP) for automatically generating the parameters of atomic models of small molecules, using the results from ab initio quantum mechanical (QM) calculations as target data. The GAAMP protocol uses QM data to optimize the bond, valence angle, and dihedral angle internal parameters, and atomic partial charges. However, since the treatment of van der Waals interactions based on QM is challenging and may often be unreliable, the Lennard Jones 6-12 parameters are kept unchanged from the initial atom types assignments (GAFF or CGenFF), which limits the accuracy that can be achieved by these models. To address this issue, a new set of Lennard-Jones 6-12 parameters was systematically optimized to reproduce experimental neat liquid densities and enthalpies of vaporization for a large set of 430 compounds, covering a wide range of chemical functionalities. Calculations of the hydration free energy indicate that optimal accuracy for these models is achieved when the molecule water van der Waals dispersion is rescaled by a factor of 1.115. The final optimized model yields an average unsigned error of 0.79 kcal/mol in the hydration free energies. PMID- 29694036 TI - Radical Carbofluorination of Unactivated Alkenes with Fluoride Ions. AB - The copper-assisted radical carbofluorination of unactivated alkenes with fluoride ions is described. With [Cu(L3)F2]H2O (L3 = 4,4'-di(methoxycarbonyl) 2,2'-bipyridine) as the fluorine source and [Ag(DMPhen)(MeCN)]BF4 (DMPhen = 2,9 dimethyl-1,10-phenanthroline) as the chloride scavenger, the reaction of unactivated alkenes with CCl4 in acetonitrile provided the corresponding carbofluorination products in satisfactory yields. The protocol exhibited a wide functional group compatibility and broad substrate scope and could be extended to the use of a variety of activated alkyl chlorides other than CCl4. A copper catalyzed fluorotrifluoromethylation of unactivated alkenes was then successfully developed with CsF as the fluorine source and Umemoto's reagent as the trifluoromethylating agent. A mechanism involving the fluorine atom transfer from Cu(II)-F complexes to alkyl radicals is proposed. PMID- 29694038 TI - Rapid and Robust Yeast-Mediated Pathway Refactoring Generates Multiple New Bottromycin-Related Metabolites. AB - Heterologous expression of biosynthetic gene clusters (BGCs) represents an attractive route to the production of new natural products, but is often hampered by poor yields. It is therefore important to develop tools that enable rapid refactoring, gene insertion/deletion, and targeted mutations in BGCs. Ideally, these tools should be highly efficient, affordable, accessible, marker free, and flexible for use with a wide range of BGCs. Here, we present a one-step yeast based method that enables efficient, cheap, and flexible modifications to BGCs. Using the BGC for the antibiotic bottromycin, we showcase multiple modifications including refactoring, gene deletions and targeted mutations. This facilitated the construction of an inducible, riboswitch-controlled pathway that achieved a 120-fold increase in pathway productivity in a heterologous streptomycete host. Additionally, an unexpected biosynthetic bottleneck resulted in the production of a suite of new bottromycin-related metabolites. PMID- 29694039 TI - Structure-Guided Design, Synthesis, and Characterization of Next-Generation Meprin beta Inhibitors. AB - The metalloproteinase meprin beta emerged as a current drug target for the treatment of a number of disorders, among those fibrosis, inflammatory bowel disease and Morbus Alzheimer. A major obstacle in the development of metalloprotease inhibitors is target selectivity to avoid side effects by blocking related enzymes with physiological functions. Here, we describe the structure-guided design of a novel series of compounds, based on previously reported highly active meprin beta inhibitors. The bioisosteric replacement of the sulfonamide scaffold gave rise to a next generation of meprin inhibitors. Selected compounds based on this novel amine scaffold exhibit high activity against meprin beta and also remarkable selectivity over related metalloproteases, i.e., matrix metalloproteases and A disintegrin and metalloproteinases. PMID- 29694037 TI - CHARMM Drude Polarizable Force Field for Glycosidic Linkages Involving Pyranoses and Furanoses. AB - We present an extension of the CHARMM Drude polarizable force field to enable modeling of polysaccharides containing pyranose and furanose monosaccharides. The new force field parameters encompass 1<->2, 1->3, 1->4, and 1->6 pyranose furanose linkages, 2->1 and 2->6 furanose-furanose linkages, 2->2, 2->3, and 2->4 furanose-pyranose, and 1<->1, 1->2, 1->3, 1->4, and 1->6 pyranose-pyranose linkages. For the glycosidic linkages, both simple model compounds and the full disaccharides with methylation at the reducing end were used for parameter optimization. The model compounds were chosen to be monomers or glycosidic-linked dimers of tetrahydropyran (THP) and tetrahydrofuran (THF). Target data for optimization included one- and two-dimensional potential energy scans of omega and the Phi/Psi glycosidic dihedral angles in the model compounds and full disaccharides computed by quantum mechanical (QM) RIMP2/cc-pVQZ single point energies on MP2/6-31G(d) optimized structures. Also included in the target data are extensive sets of QM gas phase monohydrate water-saccharide interactions, dipole moments, and molecular polarizabilities for both model compounds and full disaccharides. The resulting polarizable model is shown to be in good agreement with a range of QM data, offering a significant improvement over the additive CHARMM36 carbohydrate force field, as well as experimental data including crystal structures and conformational properties of disaccharides and a trisaccharide in aqueous solution. PMID- 29694040 TI - Nuclear Ensemble Approach with Importance Sampling. AB - We show that the importance sampling technique can effectively augment the range of problems where the nuclear ensemble approach can be applied. A sampling probability distribution function initially determines the collection of initial conditions for which calculations are performed, as usual. Then, results for a distinct target distribution are computed by introducing compensating importance sampling weights for each sampled point. This mapping between the two probability distributions can be performed whenever they are both explicitly constructed. Perhaps most notably, this procedure allows for the computation of temperature dependent observables. As a test case, we investigated the UV absorption spectra of phenol, which has been shown to have a marked temperature dependence. Application of the proposed technique to a range that covers 500 K provides results that converge to those obtained with conventional sampling. We further show that an overall improved rate of convergence is obtained when sampling is performed at intermediate temperatures. The comparison between calculated and the available measured cross sections is very satisfactory, as the main features of the spectra are correctly reproduced. As a second test case, one of Tully's classical models was revisited, and we show that the computation of dynamical observables also profits from the importance sampling technique. In summary, the strategy developed here can be employed to assess the role of temperature for any property calculated within the nuclear ensemble method, with the same computational cost as doing so for a single temperature. PMID- 29694041 TI - Gold Ultrathin Nanorods with Controlled Aspect Ratios and Surface Modifications: Formation Mechanism and Localized Surface Plasmon Resonance. AB - We synthesized gold ultrathin nanorods (AuUNRs) by slow reductions of gold(I) in the presence of oleylamine (OA) as a surfactant. Transmission electron microscopy revealed that the lengths of AuUNRs were tuned in the range of 5-20 nm while keeping the diameter constant (~2 nm) by changing the relative concentration of OA and Au(I). It is proposed on the basis of time-resolved optical spectroscopy that AuUNRs are formed via the formation of small (<2 nm) Au spherical clusters followed by their one-dimensional attachment in OA micelles. The surfactant OA on AuUNRs was successfully replaced with glutathionate or dodecanethiolate by the ligand exchange approach. Optical extinction spectroscopy on a series of AuUNRs with different aspect ratios (ARs) revealed a single intense extinction band in the near-IR (NIR) region due to the longitudinal localized surface plasmon resonance (LSPR), the peak position of which is red-shifted with the AR. The NIR bands of AuUNRs with AR < 5 were blue-shifted upon the ligand exchange from OA to thiolates, in sharp contrast to the red shift observed in the conventional Au nanorods and nanospheres (diameter >10 nm). This behavior suggests that the NIR bands of thiolate-protected AuUNRs with AR < 5 are not plasmonic in nature, but are associated with a single-electron excitation between quantized states. The LSPR band was attenuated by thiolate passivation that can be explained by the direct decay of plasmons into an interfacial charge transfer state (chemical interface damping). The LSPR wavelengths of AuUNRs are remarkably longer than those of the conventional AuNRs with the same AR, demonstrating that the miniaturization of the diameter to below ~2 nm significantly affects the optical response. The red shift of the LSPR band can be ascribed to the increase in the effective mass of electrons in AuUNRs. PMID- 29694042 TI - Vibrational Sampling and Solvent Effects on the Electronic Structure of the Absorption Spectrum of 2-Nitronaphthalene. AB - The influence of vibrational motion on electronic excited state properties is investigated for the organic chromophore 2-nitronaphtalene in methanol. Specifically, the performance of two vibrational sampling techniques - Wigner sampling and sampling from an ab initio molecular dynamics trajectory- is assessed, in combination with implicit and explicit solvent models. The effects of the different sampling/solvent combinations on the energy and electronic character of the absorption bands are analyzed in terms of charge transfer and exciton size, computed from the electronic transition density. The absorption spectra obtained using sampling techniques and its underlying properties are compared to those of the electronic excited states calculated at the Franck Condon equilibrium geometry. It is found that the absorption bands of the vibrational ensembles are red-shifted compared to the Franck-Condon bright states, and this red-shift scales with the displacement from the equilibrium geometry. Such displacements are found larger and better described when using ensembles from the harmonic Wigner distribution than snapshots from the molecular dynamics trajectory. Particularly relevant is the torsional motion of the nitro group that quenches the charge transfer character of some of the absorption bands. This motion, however, is better described in the molecular dynamics trajectory. Thus, none of the vibrational sampling approaches can satisfactorily capture all important aspects of the nuclear motion. The inclusion of solvent also red-shifts the absorption bands with respect to the gas phase. This red shift scales with the charge-transfer character of the bands and is found larger for the implicit than for the explicit solvent model. The advantages and drawbacks of the different sampling and solvent models are discussed to guide future research on the calculation of UV-vis spectra of nitroaromatic compounds. PMID- 29694043 TI - Rate Coefficient Measurements and Theoretical Analysis of the OH + ( E) CF3CH?CHCF3 Reaction. AB - Rate coefficients, k, for the gas-phase reaction of the OH radical with ( E) CF3CH?CHCF3 (( E)-1,1,1,4,4,4-hexafluoro-2-butene, HFO-1336mzz(E)) were measured over a range of temperatures (211-374 K) and bath gas pressures (20-300 Torr; He, N2) using a pulsed laser photolysis-laser-induced fluorescence (PLP-LIF) technique. k1( T) was independent of pressure over this range of conditions with k1(296 K) = (1.31 +/- 0.15) * 10-13 cm3 molecule-1 s-1 and k1( T) = (6.94 +/- 0.80) * 10-13exp[-(496 +/- 10)/ T] cm3 molecule-1 s-1, where the uncertainties are 2sigma, and the pre-exponential term includes estimated systematic error. Rate coefficients for the OD reaction were also determined over a range of temperatures (262-374 K) at 100 Torr (He). The OD rate coefficients were ~15% greater than the OH values and showed similar temperature dependent behavior with k2( T) = (7.52 +/- 0.44) * 10-13exp[-(476 +/- 20)/ T] and k2(296 K) = (1.53 +/- 0.15) * 10-13 cm3 molecule-1 s-1. The rate coefficients for reaction 1 were also measured using a relative rate technique between 296 and 375 K with k1(296 K) measured to be (1.22 +/- 0.1) * 10-13 cm3 molecule-1 s-1, in agreement with the PLP-LIF results. In addition, the 296 K rate coefficient for the O3 + ( E) CF3CH?CHCF3 reaction was determined to be <5.2 * 10-22 cm3 molecule-1 s-1. A theoretical computational analysis is presented to interpret the observed positive temperature dependence for the addition reaction and the significant decrease in OH reactivity compared to the ( Z)-CF3CH?CHCF3 stereoisomer reaction. The estimated atmospheric lifetime of ( E)-CF3CH?CHCF3, due to loss by reaction with OH, is estimated to be ~90 days, while the actual lifetime will depend on the location and season of its emission. Infrared absorption spectra of ( E) CF3CH?CHCF3 were measured and used to estimate the 100 year time horizon global warming potentials (GWP) of 32 (atmospherically well-mixed) and 14 (lifetime adjusted). PMID- 29694044 TI - 15-Hydroxygermacranolides as Sources of Structural Diversity: Synthesis of Sesquiterpene Lactones by Cyclization and Rearrangement Reactions. Experimental and DFT Study. AB - A study on the electrophile-induced rearrangement of two 15 hydroxygermacranolides, salonitenolide and artemisiifolin, was carried out. These compounds underwent electrophilic intramolecular cyclizations or acid-mediated rearrangements to give sesquiterpene lactones with different skeletons such as eudesmanolides, guaianolides, amorphanolides, or other germacranolides. The cyclization that gives guaianolides can be considered a biomimetic route to this type of sesquiterpene lactones. The use of acetone as a solvent changes the reactivity of the two starting germacranolides to the acid catalysts, with a 4,15 diol acetonide being the main product obtained. The delta-amorphenolide obtained by intramolecular cyclization of this acetonide is a valuable intermediate for accessing the antimalarials artemisinin and its derivatives. Mechanistic proposals for the transformations are raised, and to provide support them, quantum chemical calculations [DFT B3LYP/6-31+G(d,p) level] were undertaken. PMID- 29694045 TI - On the Unusual Synclinal Conformations of Hexafluorobutadiene and Structurally Similar Molecules. AB - An explanation is presented for the unusual conformations of some molecules that contain the C?C-C?C core, namely, butadienes, biphenyls, and styrenes. Small substituents often induce a synclinal conformation, which brings the substituents into close proximity, and sometimes, there is no anticlinal minimum at all. This would not be predicted from steric repulsion arguments nor would it be expected that atoms that are nonbonded in a Lewis structure would approach closer than the sum of their van der Waals radii. Atomic energies calculated according to the quantum theory of atoms in molecules (QTAIM) do not show a consistent pattern for these structurally similar molecules, nor are intersubstituent bond paths consistently found, nor favorable diatomic interaction energies calculated using the interacting quantum atoms (IQA) scheme. Instead, the synclinal conformations are found to be driven by the attraction energy of the electron distribution of the carbon atoms and the nuclei of the molecule. PMID- 29694046 TI - One-Dimensional Organic-Inorganic Hybrid Perovskite Incorporating Near-Infrared Absorbing Cyanine Cations. AB - Hybrid perovskite crystals with organic and inorganic structural components are able to combine desirable properties from both classes of materials. Electronic interactions between the anionic inorganic framework and functional organic cations (such as chromophores or semiconductors) can give rise to unusual photophysical properties. Cyanine dyes are a well known class of cationic organic dyes with high extinction coefficients and tunable absorption maxima all over the visible and near-infrared spectrum. Here we present the synthesis and characterization of an original 1D hybrid perovskite composed of NIR-absorbing cyanine cations and polyanionic lead halide chains. This first demonstration of a cyanine-perovskite hybrid material is paving the way to a new class of compounds with great potential for applications in photonic devices. PMID- 29694047 TI - Evidence of Electron Capture of an Outgoing Photoelectron Wave by a Nonvalence State in (C6F6) n. AB - Frequency-resolved photoelectron spectra are presented for (C6F6) n- with n = 1-5 that show that C6F6- is solvated by neutral C6F6 molecules. Direct photodetachment channels of C6F6- are observed for all n, leaving the neutral in the S0 ground state or triplet states, T1 and T2. For n >= 2, an additional indirect electron loss channel is observed when the triplet-state channels open. This indirect emission appears to arise from the electron capture of the outgoing photoelectron s-wave by a neutral solvent molecule through an anion nonvalence state. The same process is not observed for the S0 detachment channel because the outgoing electron wave is predominantly a p-wave. Our results show that anion nonvalence states can act as electron-accepting states in cluster environments and can be viewed as precursor states for diffuse states of liquid C6F6. PMID- 29694048 TI - Topochemical Engineering of Cellulose-Based Functional Materials. AB - Topochemical engineering is a method of designing the fractionation (disassembly) and fabrication (assembly) of highly engineered functional materials using a combination of molecular and supramolecular techniques. Cellulose is one of the naturally occurring biopolymers, currently considered to be an important raw material for the design and development of sustainable products and processes. This feature article deals with new insights into how cellulose can be processed and functionalized using topochemical engineering in order to create functional fibers, enhance biopolymer dissolution in water-based solvents, and control the shaping of porous materials. Subsequently, topochemical engineering of cellulose offers a variety of morphological structures such as highly engineered fibers, functional cellulose beads, and reactive powders that find relevant applications in pulp bleaching, enzyme and antimicrobial drug carriers, ion exchange resins, photoluminescent materials, waterproof materials, fluorescent materials, flame retardants, and template materials for inorganic synthesis. The topochemical engineering of biopolymers and biohybrids is an exciting and emerging area of research that can boost the design of new bioproducts with novel functionalities and technological advancements for biobased industries. PMID- 29694049 TI - Low-Threshold Lasing from 2D Homologous Organic-Inorganic Hybrid Ruddlesden Popper Perovskite Single Crystals. AB - Organic-inorganic hybrid two-dimensional (2D) perovskites have recently attracted great attention in optical and optoelectronic applications due to their inherent natural quantum-well structure. We report the growth of high-quality millimeter sized single crystals belonging to homologous two-dimensional (2D) hybrid organic inorganic Ruddelsden-Popper perovskites (RPPs) of (BA)2(MA) n-1Pb nI3 n+1 ( n = 1, 2, and 3) by a slow evaporation at a constant-temperature (SECT) solution growth strategy. The as-grown 2D hybrid perovskite single crystals exhibit excellent crystallinity, phase purity, and spectral uniformity. Low-threshold lasing behaviors with different emission wavelengths at room temperature have been observed from the homologous 2D hybrid RPP single crystals. Our result demonstrates that solution-growth homologous organic-inorganic hybrid 2D perovskite single crystals open up a new window as a promising candidate for optical gain media. PMID- 29694050 TI - Lipid Nanoparticle Formulations for Enhanced Co-delivery of siRNA and mRNA. AB - Although mRNA and siRNA have significant therapeutic potential, their simultaneous delivery has not been previously explored. To facilitate the treatment of diseases associated with aberrant gene upregulation and downregulation, we sought to co-formulate siRNA and mRNA in a single lipidoid nanoparticle (LNP) formulation. We accommodated the distinct molecular characteristics of mRNA and siRNA in a formulation consisting of an ionizable and biodegradable amine-containing lipidoid, cholesterol, DSPC, DOPE, and PEG-lipid. Surprisingly, the co-formulation of siRNA and mRNA in the same LNP enhanced the efficacy of both drugs in vitro and in vivo. Compared to LNPs encapsulating siRNA only, co-formulated LNPs improved Factor VII gene silencing in mice from 44 to 87% at an siRNA dose of 0.03 mg/kg. Co-formulation also improved mRNA delivery, as a 0.5 mg/kg dose of mRNA co-formulated with siRNA induced three times the luciferase protein expression compared to when siRNA was not included. As not all gene therapy applications require both RNA drugs, we sought to extend the benefit of co-formulated LNPs to formulations encapsulating only a single type of RNA. We accomplished this by substituting the "helper" RNA with a negatively charged polymer, polystyrenesulfonate (PSS). LNPs containing PSS mediated the same level of protein silencing or expression as standard LNPs using 2-3-fold less RNA. For example, LNPs formulated with and without PSS induced 50% Factor VII silencing at siRNA doses of 0.01 and 0.03 mg/kg, respectively. Together, these studies demonstrate potent co-delivery of siRNA and mRNA and show that inclusion of a negatively charged "helper polymer" enhances the efficacy of LNP delivery systems. PMID- 29694051 TI - Protein Aggregation and Performance Optimization Based on Microconformational Changes of Aromatic Hydrophobic Regions. AB - Protein aggregation is a key concern in biopharmaceutical development and manufacturing. There is growing interest in understanding how the changes in protein microconformation affect the aggregation behavior. This study selected several representative proteins and first manipulated microconformational changes of the aromatic hydrophobic regions of proteins, especially tryptophan residues, by using amine or guanidine additives. The effects of the interactions between the additives and proteins on the aromatic hydrophobic regions could be grouped into three categories: exposure to solvent, burial into core, and no change. The microconformational parameters of the tryptophan residue, including fluorescence peak position (lambdam), degree of hydrolysis, solvent accessible surface area ( SAS), and packing density ( Den), were obtained by steady-state fluorescence spectroscopy, proteolysis coupled with electrophoresis, and molecular dynamics simulation. Furthermore, the aggregation degrees of globular proteins with distinct surface aromatic hydrophobilities under mechanical stress were investigated. A strong correlation was observed between protein aggregation and the microconformational changes of the aromatic hydrophobic regions incurred by amine or guanidine additives. Protein aggregation was enhanced when the aromatic hydrophobic regions were exposed to the solvent but suppressed when the additives led to burial of the aromatic hydrophobic regions with lower-polarity microenvironment. These findings shed light on the relationship between protein aggregation and molecular conformation and paved way for future preformulation studies of therapeutic proteins. PMID- 29694052 TI - Oxime Ligation via in situ Oxidation of N-Phenylglycinyl Peptides. AB - Mild conditions for oxime ligations via in situ generation of alpha-imino amide intermediates are reported. The evaluation of a variety of N-terminal N phenylglycine residues revealed that a metal-free, chemoselective oxidation was possible using oxygen as the only oxidant in buffer at pH 7.0. Moreover, selective unmasking of an inert residue by addition of potassium ferricyanide is demonstrated. These simple and mild conditions, which can be fine-tuned by the electronic properties of the N-phenylglycine residue, offer unique advantages over conventional approaches for oxime ligations. PMID- 29694053 TI - Potency of a Scalable Nanoparticulate Subunit Vaccine. AB - Nanoparticulate vaccines can potentiate immune responses by site-specific drainage to lymph nodes (LNs). This approach may benefit from a nanoparticle engineering method with fine control over size and codelivery of antigen and adjuvant. Here, we applied the flash nanocomplexation (FNC) method to prepare nanovaccines via polyelectrolyte complexation of chitosan and heparin to coencapsulate the VP1 protein antigen from enterovirus 71, which causes hand-foot mouth disease (HFMD), with tumor necrosis factor alpha (TNF) or CpG as adjuvants. FNC allows for reduction of the nanovaccine size to range from 90 to 130 nm with relatively narrower size distribution and a high payload capacity. These nanovaccines reached both proximal and distal LNs via subcutaneous injection and subsequently exhibited prolonged retention in the LNs. The codelivery induced strong immune activation toward a Th1 response in addition to a potent Th2 response, and conferred effective protection against lethal virus challenge comparable to that of an approved inactivated viral vaccine in mouse models of both passive and active immunization setting. In addition, these nanovaccines also elicited strong IgA titers, which may offer unique advantages for mucosal protection. This study addresses the issues of size control, antigen bioactivity retention, and biomanufacturing to demonstrate the translational potential of a subunit nanovaccine design. PMID- 29694054 TI - High-Throughput Monitoring of Single Vesicle Fusion Using Freestanding Membranes and Automated Analysis. AB - In vivo membrane fusion primarily occurs between highly curved vesicles and planar membranes. A better understanding of fusion entails an accurate in vitro reproduction of the process. To date, supported bilayers have been commonly used to mimic the planar membranes. Soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins that induce membrane fusion usually have limited fluidity when embedded in supported bilayers. This alters the kinetics and prevents correct reconstitution of the overall fusion process. Also, observing content release across the membrane is hindered by the lack of a second aqueous compartment. Recently, a step toward resolving these issues was achieved by using membranes spread on holey substrates. The mobility of proteins was preserved but vesicles were prone to bind to the substrate when reaching the edge of the hole, preventing the observation of many fusion events over the suspended membrane. Building on this recent advance, we designed a method for the formation of pore-spanning lipid bilayers containing t-SNARE proteins on Si/SiO2 holey chips, allowing the observation of many individual vesicle fusion events by both lipid mixing and content release. With this setup, proteins embedded in the suspended membrane bounced back when they reached the edge of the hole which ensured vesicles did not bind to the substrate. We observed SNARE-dependent membrane fusion with the freestanding bilayer of about 500 vesicles. The time between vesicle docking and fusion is ~1 s. We also present a new multimodal open source software, Fusion Analyzer Software, which is required for fast data analysis. PMID- 29694055 TI - Experimental Observation of a Generalized Thouless Pump with a Single Spin. AB - Adiabatic cyclic modulation of a one-dimensional periodic potential will result in quantized charge transport, which is termed the Thouless pump. In contrast to the original Thouless pump restricted by the topology of the energy band, here we experimentally observe a generalized Thouless pump that can be extensively and continuously controlled. The extraordinary features of the new pump originate from interband coherence in nonequilibrium initial states, and this fact indicates that a quantum superposition of different eigenstates individually undergoing quantum adiabatic following can also be an important ingredient unavailable in classical physics. The quantum simulation of this generalized Thouless pump in a two-band insulator is achieved by applying delicate control fields to a single spin in diamond. The experimental results demonstrate all principal characteristics of the generalized Thouless pump. Because the pumping in our system is most pronounced around a band-touching point, this work also suggests an alternative means to detect quantum or topological phase transitions. PMID- 29694056 TI - Spin-Orbit Coupling and Electronic Correlations in Sr_{2}RuO_{4}. AB - We investigate the interplay of spin-orbit coupling (SOC) and electronic correlations in Sr_{2}RuO_{4} using dynamical mean-field theory. We find that SOC does not affect the correlation-induced renormalizations, which validates Hund's metal picture of ruthenates even in the presence of the sizable SOC relevant to these materials. Nonetheless, SOC is found to change significantly the electronic structure at k points where a degeneracy applies in its absence. We explain why these two observations are consistent with one another and calculate the effects of SOC on the correlated electronic structure. The magnitude of these effects is found to depend on the energy of the quasiparticle state under consideration, leading us to introduce the notion of an energy-dependent quasiparticle spin orbit coupling lambda^{*}(omega). This notion is generally applicable to all materials in which both the spin-orbit coupling and electronic correlations are sizable. PMID- 29694057 TI - Decay Rate of the Nuclear Isomer ^{229}Th(3/2^{+},7.8 eV) in a Dielectric Sphere, Thin Film, and Metal Cavity. AB - The main decay channels of the anomalous low-energy 3/2^{+}(7.8+/-0.5 eV) isomeric level of the ^{229}Th nucleus, namely the gamma emission and internal conversion, inside a dielectric sphere, dielectric thin film, and conducting spherical microcavity are investigated theoretically, taking into account the effect of media interfaces. It is shown that (1) the gamma decay rate of the nuclear isomer inside a dielectric thin film and dielectric microsphere placed in a vacuum or in a metal cavity can decrease (increase) in dozen of times, (2) the gamma activity of the distributed source as a function of time can be nonexponential, and (3) the metal cavity, whose size is of the order of the radiation wavelength, does not affect the probability of the internal conversion in ^{229}Th, because the virtual photon attenuates at much shorter distances and the reflected wave is very weak. PMID- 29694058 TI - Predicting Shear Transformation Events in Metallic Glasses. AB - Shear transformation is the elementary process for plastic deformation of metallic glasses, the prediction of the occurrence of the shear transformation events is therefore of vital importance to understand the mechanical behavior of metallic glasses. In this Letter, from the view of the potential energy landscape, we find that the protocol-dependent behavior of shear transformation is governed by the stress gradient along its minimum energy path and we propose a framework as well as an atomistic approach to predict the triggering strains, locations, and structural transformations of the shear transformation events under different shear protocols in metallic glasses. Verification with a model Cu_{64}Zr_{36} metallic glass reveals that the prediction agrees well with athermal quasistatic shear simulations. The proposed framework is believed to provide an important tool for developing a quantitative understanding of the deformation processes that control mechanical behavior of metallic glasses. PMID- 29694059 TI - Single-Shot Carrier-Envelope Phase Determination of Long Superintense Laser Pulses. AB - The impact of the carrier-envelope phase (CEP) of an intense multicycle laser pulse on the radiation of an electron beam during nonlinear Compton scattering is investigated. We have identified a CEP effect specific to the ultrarelativistic regime. When the electron beam counterpropagates with the laser pulse, pronounced high-energy x-ray double peaks emerge near the backward direction relative to the initial electron motion. This is achieved in the relativistic interaction domain, where both the electron energy is required to be lower than for the electron reflection condition at the laser peak and the stochasticity effects in the photon emission need to be weak. The asymmetry parameter of the double peaks in the angular radiation distribution is shown to serve as a sensitive measure for the CEP of up to 10-cycle long laser pulses and can be applied for the characterization of extremely strong laser pulses in present and near future laser facilities. PMID- 29694060 TI - Ising-like Models with Energy-Volume Coupling. AB - We consider a regular assembly of singly occupied cells with two accessible volumes. Coupled to cell volumes are interaction energies between nearest neighbors that lead to a phase transition with a critical point. We find that these compressible cell models can serve as Ising-like prototypes of the one component liquid-liquid and isostructural solid-solid phase transitions that originate in the short-range features of the intermolecular potential. The mean field solutions provide hints concerning the analytical form of the equation of state of liquid water. PMID- 29694061 TI - Erratum: Shrinking of Rapidly Evaporating Water Microdroplets Reveals their Extreme Supercooling [Phys. Rev. Lett. 120, 015501 (2018)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.120.015501. PMID- 29694062 TI - Abnormal Strain Rate Sensitivity Driven by a Unit Dislocation-Obstacle Interaction in bcc Fe. AB - The interaction between an edge dislocation and a sessile vacancy cluster in bcc Fe is investigated over a wide range of strain rates from 10^{8} down to 10^{3} s^{-1}, which is enabled by employing an energy landscape-based atomistic modeling algorithm. It is observed that, at low strain rates regime less than 10^{5} s^{-1}, such interaction leads to a surprising negative strain rate sensitivity behavior because of the different intermediate microstructures emerged under the complex interplays between thermal activation and applied strain rate. Implications of our findings regarding the previously established global diffusion model are also discussed. PMID- 29694063 TI - Self-Induced Backaction Optical Pulling Force. AB - We achieve long-range and continuous optical pulling in a periodic photonic crystal background, which supports a unique Bloch mode with the self-collimation effect. Most interestingly, the pulling force reported here is mainly contributed by the intensity gradient force originating from the self-induced backaction of the object to the self-collimation mode. This force is sharply distinguished from the widely held conception of optical tractor beams based on the scattering force. Also, this pulling force is insensitive to the angle of incidence and can pull multiple objects simultaneously. PMID- 29694064 TI - Nonreciprocal Thermal Material by Spatiotemporal Modulation. AB - The thermal properties of a material with a spatiotemporal modulation, in the form of a traveling wave, in both the thermal conductivity and the specific heat capacity are studied. It is found that these materials behave as materials with an internal convectionlike term that provides them with nonreciprocal properties, in the sense that the heat flux has different properties when it propagates in the same direction or in the opposite one to the modulation of the parameters. An effective medium description is presented which accurately describes the modulated material, and numerical simulations support this description and verify the nonreciprocal properties of the material. It is found that these materials are promising candidates for the design of thermal diodes and other advanced devices for the control of the heat flow at all scales. PMID- 29694065 TI - Unidirectional Wave Vector Manipulation in Two-Dimensional Space with an All Passive Acoustic Parity-Time-Symmetric Metamaterials Crystal. AB - Exploring the concept of non-Hermitian Hamiltonians respecting parity-time symmetry with classical wave systems is of great interest as it enables the experimental investigation of parity-time-symmetric systems through the quantum classical analogue. Here, we demonstrate unidirectional wave vector manipulation in two-dimensional space, with an all passive acoustic parity-time-symmetric metamaterials crystal. The metamaterials crystal is constructed through interleaving groove- and holey-structured acoustic metamaterials to provide an intrinsic parity-time-symmetric potential that is two-dimensionally extended and curved, which allows the flexible manipulation of unpaired wave vectors. At the transition point from the unbroken to broken parity-time symmetry phase, the unidirectional sound focusing effect (along with reflectionless acoustic transparency in the opposite direction) is experimentally realized over the spectrum. This demonstration confirms the capability of passive acoustic systems to carry the experimental studies on general parity-time symmetry physics and further reveals the unique functionalities enabled by the judiciously tailored unidirectional wave vectors in space. PMID- 29694066 TI - Floquet Engineering in Quantum Chains. AB - We consider a one-dimensional interacting spinless fermion model, which displays the well-known Luttinger liquid (LL) to charge density wave (CDW) transition as a function of the ratio between the strength of the interaction U and the hopping J. We subject this system to a spatially uniform drive which is ramped up over a finite time interval and becomes time periodic in the long-time limit. We show that by using a density matrix renormalization group approach formulated for infinite system sizes, we can access the large-time limit even when the drive induces finite heating. When both the initial and long-time states are in the gapless (LL) phase, the final state has power-law correlations for all ramp speeds. However, when the initial and final state are gapped (CDW phase), we find a pseudothermal state with an effective temperature that depends on the ramp rate, both for the Magnus regime in which the drive frequency is very large compared to other scales in the system and in the opposite limit where the drive frequency is less than the gap. Remarkably, quantum defects (instantons) appear when the drive tunes the system through the quantum critical point, in a realization of the Kibble-Zurek mechanism. PMID- 29694067 TI - Periodically Driven Array of Single Rydberg Atoms. AB - An array of single Rydberg atoms driven by a temporally modulated atom-field detuning is studied. The periodic modulation effectively modifies the Rabi coupling, leading to unprecedented dynamics in the presence of Rydberg-Rydberg interactions, in particular, blockade enhancement, antiblockades, and state dependent population trapping. Interestingly, the Schrieffer-Wolf transformation reveals a fundamental process in Rydberg gases, correlated Rabi coupling, which stems from the extended nature of the Rydberg-Rydberg interactions. Also, the correlated coupling provides an alternative depiction for the Rydberg blockade, exhibiting a nontrivial behavior in the presence of periodic modulation. The dynamical localization of a many-body configuration in a driven Rydberg lattice is discussed. PMID- 29694068 TI - Spin-Torque Excitation of Perpendicular Standing Spin Waves in Coupled YIG/Co Heterostructures. AB - We investigate yttrium iron garnet (YIG)/cobalt (Co) heterostructures using broadband ferromagnetic resonance (FMR). We observe an efficient excitation of perpendicular standing spin waves (PSSWs) in the YIG layer when the resonance frequencies of the YIG PSSWs and the Co FMR line coincide. Avoided crossings of YIG PSSWs and the Co FMR line are found and modeled using mutual spin pumping and exchange torques. The excitation of PSSWs is suppressed by a thin aluminum oxide interlayer but persists with a copper interlayer, in agreement with the proposed model. PMID- 29694069 TI - Next-to-Next-to-Leading-Order QCD Corrections to the Transverse Momentum Distribution of Weak Gauge Bosons. AB - The transverse momentum spectra of weak gauge bosons and their ratios probe the underlying dynamics and are crucial in testing our understanding of the standard model. They are an essential ingredient in precision measurements, such as the W boson mass extraction. To fully exploit the potential of the LHC data, we compute the second-order [next-to-next-to-leading-order (NNLO)] QCD corrections to the inclusive-p_{T}^{W} spectrum as well as to the ratios of spectra for W^{-}/W^{+} and Z/W. We find that the inclusion of NNLO QCD corrections considerably improves the theoretical description of the experimental CMS data and results in a substantial reduction of the residual scale uncertainties. PMID- 29694070 TI - Odd-Time Reversal PT Symmetry Induced by an Anti-PT-Symmetric Medium. AB - We introduce an optical system (a coupler) obeying parity-time (PT) symmetry with odd-time reversal, T^{2}=-1. It is implemented with two birefringent waveguides embedded in an anti-PT-symmetric medium. The system possesses properties that are untypical for most physical systems with the conventional even-time reversal. Having a symmetry-protected degeneracy of the linear modes, the coupler allows for the realization of a coherent switch operating with a superposition of binary states that are distinguished by their polarizations. When a Kerr nonlinearity is taken into account, each linear state, being doubly degenerated, bifurcates into several distinct nonlinear modes, some of which are dynamically stable. The nonlinear modes are characterized by amplitude and by polarization and come in PT conjugate pairs. PMID- 29694071 TI - Coherent Electron Transfer at the Ag/Graphite Heterojunction Interface. AB - Charge transfer in transduction of light to electrical or chemical energy at heterojunctions of metals with semiconductors or semimetals is believed to occur by photogenerated hot electrons in metal undergoing incoherent internal photoemission through the heterojunction interface. Charge transfer, however, can also occur coherently by dipole coupling of electronic bands at the heterojunction interface. Microscopic physical insights into how transfer occurs can be elucidated by following the coherent polarization of the donor and acceptor states on the time scale of electronic dephasing. By time-resolved multiphoton photoemission spectroscopy (MPP), we investigate the coherent electron transfer from an interface state that forms upon chemisorption of Ag nanoclusters onto graphite to a sigma symmetry interlayer band of graphite. Multidimensional MPP spectroscopy reveals a resonant two-photon transition, which dephases within 10 fs completing the coherent transfer. PMID- 29694072 TI - Exceeding the Asymptotic Limit of Polymer Drag Reduction. AB - The drag of turbulent flows can be drastically decreased by adding small amounts of high molecular weight polymers. While drag reduction initially increases with polymer concentration, it eventually saturates to what is known as the maximum drag reduction (MDR) asymptote; this asymptote is generally attributed to the dynamics being reduced to a marginal yet persistent state of subdued turbulent motion. Contrary to this accepted view, we show that, for an appropriate choice of parameters, polymers can reduce the drag beyond the suggested asymptotic limit, eliminating turbulence and giving way to laminar flow. At higher polymer concentrations, however, the laminar state becomes unstable, resulting in a fluctuating flow with the characteristic drag of the MDR asymptote. Our findings indicate that the asymptotic state is hence dynamically disconnected from ordinary turbulence. PMID- 29694073 TI - Stochastic Model of Breakdown Nucleation under Intense Electric Fields. AB - A plastic response due to dislocation activity under intense electric fields is proposed as a source of breakdown. A model is formulated based on stochastic multiplication and arrest under the stress generated by the field. A critical transition in the dislocation population is suggested as the cause of protrusion formation leading to subsequent arcing. The model is studied using Monte Carlo simulations and theoretical analysis, yielding a simplified dependence of the breakdown rates on the electric field. These agree with experimental observations of field and temperature breakdown dependencies. PMID- 29694075 TI - Higher-Order Fermi-Liquid Corrections for an Anderson Impurity Away from Half Filling. AB - We study the higher-order Fermi-liquid relations of Kondo systems for arbitrary impurity-electron fillings, extending the many-body quantum theoretical approach of Yamada and Yosida. It includes, partly, a microscopic clarification of the related achievements based on Nozieres' phenomenological description: Filippone, Moca, von Delft, and Mora [Phys. Rev. B 95, 165404 (2017)PRBMDO2469 995010.1103/PhysRevB.95.165404]. In our formulation, the Fermi-liquid parameters such as the quasiparticle energy, damping, and transport coefficients are related to each other through the total vertex Gamma_{sigmasigma^{'};sigma^{'}sigma}(omega,omega^{'};omega^{'},omega), which may be regarded as a generalized Landau quasiparticle interaction. We obtain exactly this function up to linear order with respect to the frequencies omega and omega^{'} using the antisymmetry and analytic properties. The coefficients acquire additional contributions of three-body fluctuations away from half filling through the nonlinear susceptibilities. We also apply the formulation to nonequilibrium transport through a quantum dot, and clarify how the zero-bias peak evolves in a magnetic field. PMID- 29694074 TI - Metastable Prepores in Tension-Free Lipid Bilayers. AB - The formation and closure of aqueous pores in lipid bilayers is a key step in various biophysical processes. Large pores are well described by classical nucleation theory, but the free-energy landscape of small, biologically relevant pores has remained largely unexplored. The existence of small and metastable "prepores" was hypothesized decades ago from electroporation experiments, but resolving metastable prepores from theoretical models remained challenging. Using two complementary methods-atomistic simulations and self-consistent field theory of a minimal lipid model-we determine the parameters for which metastable prepores occur in lipid membranes. Both methods consistently suggest that pore metastability depends on the relative volume ratio between the lipid head group and lipid tails: lipids with a larger head-group volume fraction (or shorter saturated tails) form metastable prepores, whereas lipids with a smaller head group volume fraction (or longer unsaturated tails) form unstable prepores. PMID- 29694076 TI - Observation of Dynamical Super-Efimovian Expansion in a Unitary Fermi Gas. AB - We report an observation of a dynamical super Efimovian expansion in a strongly interacting Fermi gas by engineering time dependent external harmonic trap frequencies. When the trap frequency is tailored as [1/4t^{2}+1/t^{2}lambdalog^{2}(t/t_{*})]^{1/2}, where t_{*} and lambda are two controllable parameters, and the change is faster than a critical value, the expansion of such a quantum gas shows novel dynamics that share the same characteristics as the super Efimov effect. A clear double-log periodicity with discrete geometric scaling emerges for the cloud size in the expansion. The universality of such scaling dynamics is verified both in the noninteracting and in the unitarity limit of Fermi gas. Moreover, the measured energy scaling reveals that the potential and internal energy also show double-log periodicity with a pi/2 phase difference, but the total energy is monotonically decreased. Observing super Efimovian evolution represents a paradigm in probing universal properties and allows us in a new way to study many-body nonequilibrium dynamics with experiments. PMID- 29694077 TI - Chaos in Dirac Electron Optics: Emergence of a Relativistic Quantum Chimera. AB - We uncover a remarkable quantum scattering phenomenon in two-dimensional Dirac material systems where the manifestations of both classically integrable and chaotic dynamics emerge simultaneously and are electrically controllable. The distinct relativistic quantum fingerprints associated with different electron spin states are due to a physical mechanism analogous to a chiroptical effect in the presence of degeneracy breaking. The phenomenon mimics a chimera state in classical complex dynamical systems but here in a relativistic quantum setting henceforth the term "Dirac quantum chimera," associated with which are physical phenomena with potentially significant applications such as enhancement of spin polarization, unusual coexisting quasibound states for distinct spin configurations, and spin selective caustics. Experimental observations of these phenomena are possible through, e.g., optical realizations of ballistic Dirac fermion systems. PMID- 29694078 TI - Narrow Escape of Interacting Diffusing Particles. AB - The narrow escape problem deals with the calculation of the mean escape time (MET) of a Brownian particle from a bounded domain through a small hole on the domain's boundary. Here we develop a formalism which allows us to evaluate the nonescape probability of a gas of diffusing particles that may interact with each other. In some cases the nonescape probability allows us to evaluate the MET of the first particle. The formalism is based on the fluctuating hydrodynamics and the recently developed macroscopic fluctuation theory. We also uncover an unexpected connection between the narrow escape of interacting particles and thermal runaway in chemical reactors. PMID- 29694079 TI - Minimum Action Path Theory Reveals the Details of Stochastic Transitions Out of Oscillatory States. AB - Cell state determination is the outcome of intrinsically stochastic biochemical reactions. Transitions between such states are studied as noise-driven escape problems in the chemical species space. Escape can occur via multiple possible multidimensional paths, with probabilities depending nonlocally on the noise. Here we characterize the escape from an oscillatory biochemical state by minimizing the Freidlin-Wentzell action, deriving from it the stochastic spiral exit path from the limit cycle. We also use the minimized action to infer the escape time probability density function. PMID- 29694080 TI - Control of Nuclear Dynamics through Conical Intersections and Electronic Coherences. AB - The effect of nuclear dynamics and conical intersections on electronic coherences is investigated employing a two-state, two-mode linear vibronic coupling model. Exact quantum dynamical calculations are performed using the multiconfiguration time-dependent Hartree method. It is found that the presence of a nonadiabatic coupling close to the Franck-Condon point can preserve electronic coherence to some extent. Additionally, the possibility of steering the nuclear wave packets by imprinting a relative phase between the electronic states during the photoionization process is discussed. It is found that the steering of nuclear wave packets is possible given that a coherent electronic wave packet embodying the phase difference passes through a conical intersection. A conical intersection close to the Franck-Condon point is thus a necessary prerequisite for control, providing a clear path towards attochemistry. PMID- 29694081 TI - Momentum-Space Josephson Effects. AB - The Josephson effect is a prominent phenomenon of quantum supercurrents that has been widely studied in superconductors and superfluids. Typical Josephson junctions consist of two real-space superconductors (superfluids) coupled through a weak tunneling barrier. Here we propose a momentum-space Josephson junction in a spin-orbit coupled Bose-Einstein condensate, where states with two different momenta are coupled through Raman-assisted tunneling. We show that Josephson currents can be induced not only by applying the equivalent of "voltages," but also by tuning tunneling phases. Such tunneling-phase-driven Josephson junctions in momentum space are characterized through both full mean field analysis and a concise two-level model, demonstrating the important role of interactions between atoms. Our scheme provides a platform for experimentally realizing momentum-space Josephson junctions and exploring their applications in quantum-mechanical circuits. PMID- 29694082 TI - Identification of a Catalytically Highly Active Surface Phase for CO Oxidation over PtRh Nanoparticles under Operando Reaction Conditions. AB - Pt-Rh alloy nanoparticles on oxide supports are widely employed in heterogeneous catalysis with applications ranging from automotive exhaust control to energy conversion. To improve catalyst performance, an atomic-scale correlation of the nanoparticle surface structure with its catalytic activity under industrially relevant operando conditions is essential. Here, we present x-ray diffraction data sensitive to the nanoparticle surface structure combined with in situ mass spectrometry during near ambient pressure CO oxidation. We identify the formation of ultrathin surface oxides by detecting x-ray diffraction signals from particular nanoparticle facets and correlate their evolution with the sample's enhanced catalytic activity. Our approach opens the door for an in-depth characterization of well-defined, oxide-supported nanoparticle based catalysts under operando conditions with unprecedented atomic-scale resolution. PMID- 29694083 TI - Quantum Dynamics of H_{2} Trapped within Organic Clathrate Cages. AB - The rotational and translational dynamics of molecular hydrogen trapped within beta-hydroquinone clathrate (H_{2}@beta-HQ)-a practical example of a quantum particle trapped within an anisotropic confining potential-were investigated using inelastic neutron scattering and Raman spectroscopy. High-resolution vibrational spectra, including those collected from the VISION spectrometer at Oak Ridge National Laboratory, indicate relatively strong attractive interaction between guest and host with a strikingly large splitting of rotational energy levels compared with similar guest-host systems. Unlike related molecular systems in which confined H_{2} exhibits nearly free rotation, the behavior of H_{2}@beta HQ is explained using a two-dimensional (2D) hindered rotor model with barrier height more than 2 times the rotational constant (-16.2 meV). PMID- 29694084 TI - Enhanced Communication with the Assistance of Indefinite Causal Order. AB - In quantum Shannon theory, the way information is encoded and decoded takes advantage of the laws of quantum mechanics, while the way communication channels are interlinked is assumed to be classical. In this Letter, we relax the assumption that quantum channels are combined classically, showing that a quantum communication network where quantum channels are combined in a superposition of different orders can achieve tasks that are impossible in conventional quantum Shannon theory. In particular, we show that two identical copies of a completely depolarizing channel become able to transmit information when they are combined in a quantum superposition of two alternative orders. This finding runs counter to the intuition that if two communication channels are identical, using them in different orders should not make any difference. The failure of such intuition stems from the fact that a single noisy channel can be a random mixture of elementary, noncommuting processes, whose order (or lack thereof) can affect the ability to transmit information. PMID- 29694085 TI - Cosmological Signature of the Standard Model Higgs Vacuum Instability: Primordial Black Holes as Dark Matter. AB - For the current central values of the Higgs boson and top quark masses, the standard model Higgs potential develops an instability at a scale of the order of 10^{11} GeV. We show that a cosmological signature of such instability could be dark matter in the form of primordial black holes seeded by Higgs fluctuations during inflation. The existence of dark matter might not require physics beyond the standard model. PMID- 29694086 TI - Elliptic Double-Box Integrals: Massless Scattering Amplitudes beyond Polylogarithms. AB - We derive an analytic representation of the ten-particle, two-loop double-box integral as an elliptic integral over weight-three polylogarithms. To obtain this form, we first derive a fourfold, rational (Feynman-)parametric representation for the integral, expressed directly in terms of dual-conformally invariant cross ratios; from this, the desired form is easily obtained. The essential features of this integral are illustrated by means of a simplified toy model, and we attach the relevant expressions for both integrals in ancillary files. We propose a normalization for such integrals that renders all of their polylogarithmic degenerations pure, and we discuss the need for a new "symbology" of mixed iterated elliptic and polylogarithmic integrals in order to bring them to a more canonical form. PMID- 29694088 TI - Ion Correlation Effects in Salt-Doped Block Copolymers. AB - We apply classical density functional theory to study how salt changes the microphase morphology of diblock copolymers. Polymers are freely jointed and one monomer type favorably interacts with ions, to account for the selective solvation that arises from different dielectric constants of the microphases. By including correlations from liquid state theory of an unbound reference fluid, the theory can treat chain behavior, microphase separation, ion correlations, and preferential solvation, at the same coarse-grained level. We show good agreement with molecular dynamics simulations. PMID- 29694087 TI - Probing the Single-Particle Character of Rotational States in ^{19}F Using a Short-Lived Isomeric Beam. AB - A beam containing a substantial component of both the J^{pi}=5^{+}, T_{1/2}=162 ns isomeric state of ^{18}F and its 1^{+}, 109.77-min ground state is utilized to study members of the ground-state rotational band in ^{19}F through the neutron transfer reaction (d,p) in inverse kinematics. The resulting spectroscopic strengths confirm the single-particle nature of the 13/2^{+} band-terminating state. The agreement between shell-model calculations using an interaction constructed within the sd shell, and our experimental results reinforces the idea of a single-particle-collective duality in the descriptions of the structure of atomic nuclei. PMID- 29694089 TI - Limit on Excitation and Stabilization of Atoms in Intense Optical Laser Fields. AB - Atomic excitation in strong optical laser fields has been found to take place even at intensities exceeding saturation. The concomitant acceleration of the atom in the focused laser field has been considered a strong link to, if not proof of, the existence of the so-called Kramers-Henneberger (KH) atom, a bound atomic system in an intense laser field. Recent findings have moved the importance of the KH atom from being purely of theoretical interest toward real world applications; for instance, in the context of laser filamentation. Considering this increasing importance, we explore the limits of strong-field excitation in optical fields, which are basically imposed by ionization through the spatial field envelope and the field propagation. PMID- 29694090 TI - Thermal Transport and Phonon Hydrodynamics in Strontium Titanate. AB - We present a study of thermal conductivity, kappa, in undoped and doped strontium titanate in a wide temperature range (2-400 K) and detecting different regimes of heat flow. In undoped SrTiO_{3}, kappa evolves faster than cubic with temperature below its peak and in a narrow temperature window. Such behavior, previously observed in a handful of solids, has been attributed to a Poiseuille flow of phonons, expected to arise when momentum-conserving scattering events outweigh momentum-degrading ones. The effect disappears in the presence of dopants. In SrTi_{1-x}Nb_{x}O_{3}, a significant reduction in lattice thermal conductivity starts below the temperature at which the average inter-dopant distance and the thermal wavelength of acoustic phonons become comparable. In the high-temperature regime, thermal diffusivity becomes proportional to the inverse of temperature, with a prefactor set by sound velocity and Planckian time (tau_{p}=(h/k_{B}T)). PMID- 29694091 TI - Relaxation Dynamics of a Granular Pile on a Vertically Vibrating Plate. AB - Nonlinear relaxation dynamics of a vertically vibrated granular pile is experimentally studied. In the experiment, the flux and slope on the relaxing pile are measured by using a high-speed laser profiler. The relation of these quantities can be modeled by the nonlinear transport law assuming the uniform vibrofluidization of an entire pile. The fitting parameter in this model is only the relaxation efficiency, which characterizes the energy conversion rate from vertical vibration into horizontal transport. We demonstrate that this value is a constant independent of experimental conditions. The actual relaxation is successfully reproduced by the continuity equation with the proposed model. Finally, its specific applicability toward an astrophysical phenomenon is shown. PMID- 29694092 TI - Measurement of Transverse Wakefields Induced by a Misaligned Positron Bunch in a Hollow Channel Plasma Accelerator. AB - Hollow channel plasma wakefield acceleration is a proposed method to provide high acceleration gradients for electrons and positrons alike: a key to future lepton colliders. However, beams which are misaligned from the channel axis induce strong transverse wakefields, deflecting beams and reducing the collider luminosity. This undesirable consequence sets a tight constraint on the alignment accuracy of the beam propagating through the channel. Direct measurements of beam misalignment-induced transverse wakefields are therefore essential for designing mitigation strategies. We present the first quantitative measurements of transverse wakefields in a hollow plasma channel, induced by an off-axis 20 GeV positron bunch, and measured with another 20 GeV lower charge trailing positron probe bunch. The measurements are largely consistent with theory. PMID- 29694093 TI - Polarizability of Helium, Neon, and Argon: New Perspectives for Gas Metrology. AB - With dielectric-constant gas thermometry, the molar polarizability of helium, neon, and argon has been determined with relative standard uncertainties of about 2 parts per million. A series of isotherms measured with the three noble gases and two different experimental setups led to this unprecedented level of uncertainty. These data are crucial for scientists in the field of gas metrology, working on pressure and temperature standards. Furthermore, with the new benchmark values for neon and argon, theoretical calculations, today about 3 orders of magnitude larger in uncertainty, can be checked and improved. PMID- 29694094 TI - Coherent Structures and Spectral Energy Transfer in Turbulent Plasma: A Space Filter Approach. AB - Plasma turbulence at scales of the order of the ion inertial length is mediated by several mechanisms, including linear wave damping, magnetic reconnection, the formation and dissipation of thin current sheets, and stochastic heating. It is now understood that the presence of localized coherent structures enhances the dissipation channels and the kinetic features of the plasma. However, no formal way of quantifying the relationship between scale-to-scale energy transfer and the presence of spatial structures has been presented so far. In the Letter we quantify such a relationship analyzing the results of a two-dimensional high resolution Hall magnetohydrodynamic simulation. In particular, we employ the technique of space filtering to derive a spectral energy flux term which defines, in any point of the computational domain, the signed flux of spectral energy across a given wave number. The characterization of coherent structures is performed by means of a traditional two-dimensional wavelet transformation. By studying the correlation between the spectral energy flux and the wavelet amplitude, we demonstrate the strong relationship between scale-to-scale transfer and coherent structures. Furthermore, by conditioning one quantity with respect to the other, we are able for the first time to quantify the inhomogeneity of the turbulence cascade induced by topological structures in the magnetic field. Taking into account the low space-filling factor of coherent structures (i.e., they cover a small portion of space), it emerges that 80% of the spectral energy transfer (both in the direct and inverse cascade directions) is localized in about 50% of space, and 50% of the energy transfer is localized in only 25% of space. PMID- 29694095 TI - Deciphering mRNA Sequence Determinants of Protein Production Rate. AB - One of the greatest challenges in biophysical models of translation is to identify coding sequence features that affect the rate of translation and therefore the overall protein production in the cell. We propose an analytic method to solve a translation model based on the inhomogeneous totally asymmetric simple exclusion process, which allows us to unveil simple design principles of nucleotide sequences determining protein production rates. Our solution shows an excellent agreement when compared to numerical genome-wide simulations of S. cerevisiae transcript sequences and predicts that the first 10 codons, which is the ribosome footprint length on the mRNA, together with the value of the initiation rate, are the main determinants of protein production rate under physiological conditions. Finally, we interpret the obtained analytic results based on the evolutionary role of the codons' choice for regulating translation rates and ribosome densities. PMID- 29694096 TI - Fine Grained Chaos in AdS_{2} Gravity. AB - Quantum chaos can be characterized by an exponential growth of the thermal out-of time-order four-point function up to a scrambling time u[over ^]_{*}. We discuss generalizations of this statement for certain higher-point correlation functions. For concreteness, we study the Schwarzian theory of a one-dimensional time reparametrization mode, which describes two-dimensional anti-de Sitter space (AdS_{2}) gravity and the low-energy dynamics of the Sachdev-Ye-Kitaev model. We identify a particular set of 2k-point functions, characterized as being both "maximally braided" and "k-out of time order," which exhibit exponential growth until progressively longer time scales u[over ^]_{*}^{(k)}~(k-1)u[over ^]_{*}. We suggest an interpretation as scrambling of increasingly fine grained measures of quantum information, which correspondingly take progressively longer time to reach their thermal values. PMID- 29694097 TI - Revealing the Link between Structural Relaxation and Dynamic Heterogeneity in Glass-Forming Liquids. AB - Despite the use of glasses for thousands of years, the nature of the glass transition is still mysterious. On approaching the glass transition, the growth of dynamic heterogeneity has long been thought to play a key role in explaining the abrupt slowdown of structural relaxation. However, it still remains elusive whether there is an underlying link between structural relaxation and dynamic heterogeneity. Here, we unravel the link by introducing a characteristic time scale hiding behind an identical dynamic heterogeneity for various model glass forming liquids. We find that the time scale corresponds to the kinetic fragility of liquids. Moreover, it leads to scaling collapse of both the structural relaxation time and dynamic heterogeneity for all liquids studied, together with a characteristic temperature associated with the same dynamic heterogeneity. Our findings imply that studying the glass transition from the viewpoint of dynamic heterogeneity is more informative than expected. PMID- 29694098 TI - Strong Coupling Corrections in Quantum Thermodynamics. AB - Quantum systems strongly coupled to many-body systems equilibrate to the reduced state of a global thermal state, deviating from the local thermal state of the system as it occurs in the weak-coupling limit. Taking this insight as a starting point, we study the thermodynamics of systems strongly coupled to thermal baths. First, we provide strong-coupling corrections to the second law applicable to general systems in three of its different readings: As a statement of maximal extractable work, on heat dissipation, and bound to the Carnot efficiency. These corrections become relevant for small quantum systems and vanish in first order in the interaction strength. We then move to the question of power of heat engines, obtaining a bound on the power enhancement due to strong coupling. Our results are exemplified on the paradigmatic non-Markovian quantum Brownian motion. PMID- 29694099 TI - Properties of Nuclei up to A=16 using Local Chiral Interactions. AB - We report accurate quantum Monte Carlo calculations of nuclei up to A=16 based on local chiral two- and three-nucleon interactions up to next-to-next-to-leading order. We examine the theoretical uncertainties associated with the chiral expansion and the cutoff in the theory, as well as the associated operator choices in the three-nucleon interactions. While in light nuclei the cutoff variation and systematic uncertainties are rather small, in ^{16}O these can be significant for large coordinate-space cutoffs. Overall, we show that chiral interactions constructed to reproduce properties of very light systems and nucleon-nucleon scattering give an excellent description of binding energies, charge radii, and form factors for all these nuclei, including open-shell systems in A=6 and 12. PMID- 29694100 TI - Laser Cooled YbF Molecules for Measuring the Electron's Electric Dipole Moment. AB - We demonstrate one-dimensional sub-Doppler laser cooling of a beam of YbF molecules to 100 MUK. This is a key step towards a measurement of the electron's electric dipole moment using ultracold molecules. We compare the effectiveness of magnetically assisted and polarization-gradient sub-Doppler cooling mechanisms. We model the experiment and find good agreement with our data. PMID- 29694101 TI - Toward a Definition of Complexity for Quantum Field Theory States. AB - We investigate notions of complexity of states in continuous many-body quantum systems. We focus on Gaussian states which include ground states of free quantum field theories and their approximations encountered in the context of the continuous version of the multiscale entanglement renormalization ansatz. Our proposal for quantifying state complexity is based on the Fubini-Study metric. It leads to counting the number of applications of each gate (infinitesimal generator) in the transformation, subject to a state-dependent metric. We minimize the defined complexity with respect to momentum-preserving quadratic generators which form su(1,1) algebras. On the manifold of Gaussian states generated by these operations, the Fubini-Study metric factorizes into hyperbolic planes with minimal complexity circuits reducing to known geodesics. Despite working with quantum field theories far outside the regime where Einstein gravity duals exist, we find striking similarities between our results and those of holographic complexity proposals. PMID- 29694102 TI - Subpercent-Scale Control of 3D Low Modes of Targets Imploded in Direct-Drive Configuration on OMEGA. AB - Multiple self-emission x-ray images are used to measure tomographically target modes 1, 2, and 3 up to the end of the target acceleration in direct-drive implosions on OMEGA. Results show that the modes consist of two components: the first varies linearly with the laser beam-energy balance and the second is static and results from physical effects including beam mistiming, mispointing, and uncertainty in beam energies. This is used to reduce the target low modes of low adiabat implosions from 2.2% to 0.8% by adjusting the beam-energy balance to compensate these static modes. PMID- 29694103 TI - Pulsar TeV Halos Explain the Diffuse TeV Excess Observed by Milagro. AB - Milagro observations have found bright, diffuse TeV emission concentrated along the galactic plane of the Milky Way. The intensity and spectrum of this emission is difficult to explain with current models of hadronic gamma-ray production, and has been named the "TeV excess." We show that TeV emission from pulsars naturally explains this excess. Recent observations have detected "TeV halos" surrounding pulsars that are either nearby or particularly luminous. Extrapolating this emission to the full population of Milky Way pulsars indicates that the ensemble of "subthreshold" sources necessarily produces bright TeV emission diffusively along the Milky Way plane. Models indicate that the TeV halo gamma-ray flux exceeds that from hadronic gamma rays above an energy of ~500 GeV. Moreover, the spectrum and intensity of TeV halo emission naturally matches the TeV excess. Finally, we show that upcoming HAWC observations will resolve a significant fraction of the TeV excess into individual TeV halos, conclusively confirming, or ruling out, this model. PMID- 29694104 TI - Coupling between Inclusions and Membranes at the Nanoscale. AB - The activity of cell membrane inclusions (such as ion channels) is influenced by the host lipid membrane, to which they are elastically coupled. This coupling concerns the hydrophobic thickness of the bilayer (imposed by the length of the channel, as per the hydrophobic matching principle) but also its slope at the boundary of the inclusion. However, this parameter has never been measured so far. We combine small-angle x-ray scattering data and a complete elastic model to measure the slope for the model gramicidin channel and show that it is surprisingly steep in two membrane systems with very different elastic properties. This conclusion is confirmed and generalized by the comparison with recent results in the simulation literature and with conductivity measurements. PMID- 29694105 TI - Driven-Dissipative Supersolid in a Ring Cavity. AB - Supersolids are characterized by the counterintuitive coexistence of superfluid and crystalline order. Here we study a supersolid phase emerging in the steady state of a driven-dissipative system. We consider a transversely pumped Bose Einstein condensate trapped along the axis of a ring cavity and coherently coupled to a pair of degenerate counterpropagating cavity modes. Above a threshold pump strength the interference of photons scattered into the two cavity modes results in an emergent superradiant lattice, which spontaneously breaks the continuous translational symmetry towards a periodic atomic pattern. The crystalline steady state inherits the superfluidity of the Bose-Einstein condensate, thus exhibiting genuine properties of a supersolid. A gapless collective Goldstone mode correspondingly appears in the superradiant phase, which can be nondestructively monitored via the relative phase of the two cavity modes on the cavity output. Despite cavity-photon losses the Goldstone mode remains undamped, indicating the robustness of the supersolid phase. PMID- 29694108 TI - Terahertz Pulse Generation in Underdense Relativistic Plasmas: From Photoionization-Induced Radiation to Coherent Transition Radiation. AB - Terahertz to far-infrared emission by two-color, ultrashort optical pulses interacting with underdense helium gases at ultrahigh intensities (>10^{19} W/cm^{2}) is investigated by means of 3D particle-in-cell simulations. The terahertz field is shown to be produced by two mechanisms occurring sequentially, namely, photoionization-induced radiation (PIR) by the two-color pulse, and coherent transition radiation (CTR) by the wakefield-accelerated electrons escaping the plasma. We exhibit laser-plasma parameters for which CTR proves to be the dominant process, providing terahertz bursts with field strength as high as 100 GV/m and energy in excess of 10 mJ. Analytical models are developed for both the PIR and CTR processes, which correctly reproduce the simulation data. PMID- 29694110 TI - Nonequilibrium Thermodynamics of Hydrate Growth on a Gas-Liquid Interface. AB - We develop a continuum-scale phase-field model to study gas-liquid-hydrate systems far from thermodynamic equilibrium. We design a Gibbs free energy functional for methane-water mixtures that recovers the isobaric temperature composition phase diagram under thermodynamic equilibrium conditions. The proposed free energy is incorporated into a phase-field model to study the dynamics of hydrate formation on a gas-liquid interface. We elucidate the role of initial aqueous concentration in determining the direction of hydrate growth at the interface, in agreement with experimental observations. Our model also reveals two stages of hydrate growth at an interface-controlled by a crossover in how methane is supplied from the gas and liquid phases-which could explain the persistence of gas conduits in hydrate-bearing sediments and other nonequilibrium phenomena commonly observed in natural methane hydrate systems. PMID- 29694112 TI - Double Scaling in the Relaxation Time in the beta-Fermi-Pasta-Ulam-Tsingou Model. AB - We consider the original beta-Fermi-Pasta-Ulam-Tsingou system; numerical simulations and theoretical arguments suggest that, for a finite number of masses, a statistical equilibrium state is reached independently of the initial energy of the system. Using ensemble averages over initial conditions characterized by different Fourier random phases, we numerically estimate the time scale of equipartition and we find that for very small nonlinearity it matches the prediction based on exact wave-wave resonant interaction theory. We derive a simple formula for the nonlinear frequency broadening and show that when the phenomenon of overlap of frequencies takes place, a different scaling for the thermalization time scale is observed. Our result supports the idea that the Chirikov overlap criterion identifies a transition region between two different relaxation time scalings. PMID- 29694109 TI - Prospects for Detecting Gravitational Waves at 5 Hz with Ground-Based Detectors. AB - We propose an upgrade to Advanced LIGO (aLIGO), named LIGO-LF, that focuses on improving the sensitivity in the 5-30 Hz low-frequency band, and we explore the upgrade's astrophysical applications. We present a comprehensive study of the detector's technical noises and show that with technologies currently under development, such as interferometrically sensed seismometers and balanced homodyne readout, LIGO-LF can reach the fundamental limits set by quantum and thermal noises down to 5 Hz. These technologies are also directly applicable to the future generation of detectors. We go on to consider this upgrade's implications for the astrophysical output of an aLIGO-like detector. A single LIGO-LF can detect mergers of stellar-mass black holes (BHs) out to a redshift of z?6 and would be sensitive to intermediate-mass black holes up to 2000 M_{?}. The detection rate of merging BHs will increase by a factor of 18 compared to aLIGO. Additionally, for a given source the chirp mass and total mass can be constrained 2 times better than aLIGO and the effective spin 3-5 times better than aLIGO. Furthermore, LIGO-LF enables the localization of coalescing binary neutron stars with an uncertainty solid angle 10 times smaller than that of aLIGO at 30 Hz and 4 times smaller when the entire signal is used. LIGO-LF also significantly enhances the probability of detecting other astrophysical phenomena including the tidal excitation of neutron star r modes and the gravitational memory effects. PMID- 29694111 TI - Time Crystal Platform: From Quasicrystal Structures in Time to Systems with Exotic Interactions. AB - Time crystals are quantum many-body systems that, due to interactions between particles, are able to spontaneously self-organize their motion in a periodic way in time by analogy with the formation of crystalline structures in space in condensed matter physics. In solid state physics properties of space crystals are often investigated with the help of external potentials that are spatially periodic and reflect various crystalline structures. A similar approach can be applied for time crystals, as periodically driven systems constitute counterparts of spatially periodic systems, but in the time domain. Here we show that condensed matter problems ranging from single particles in potentials of quasicrystal structure to many-body systems with exotic long-range interactions can be realized in the time domain with an appropriate periodic driving. Moreover, it is possible to create molecules where atoms are bound together due to destructive interference if the atomic scattering length is modulated in time. PMID- 29694113 TI - Gravity and the Spin-2 Planar Schrodinger Equation. AB - A Schrodinger equation proposed for the Girvin-MacDonald-Platzman gapped spin-2 mode of fractional quantum Hall states is found from a novel nonrelativistic limit, applicable only in 2+1 dimensions, of the massive spin-2 Fierz-Pauli field equations. It is also found from a novel null reduction of the linearized Einstein field equations in 3+1 dimensions, and in this context a uniform distribution of spin-2 particles implies, via a Brinkmann-wave solution of the nonlinear Einstein equations, a confining harmonic oscillator potential for the individual particles. PMID- 29694114 TI - Positron-Induced Luminescence. AB - We report on the observation that low-energy positrons incident on a phosphor screen produce significantly more luminescence than electrons do. For two different wide-band-gap semiconductor phosphors (ZnS:Ag and ZnO:Zn), we compare the luminescent response to a positron beam with the response to an electron beam. For both phosphors, the positron response is significantly brighter than the electron response, by a factor that depends strongly on incident energy (0-5 keV). Positrons with just a few tens of electron-volts of energy (for ZnS:Ag) or less (for ZnO:Zn) produce as much luminescence as is produced by electrons with several kilo-electron-volts. We attribute this effect to valence band holes and excited electrons produced by positron annihilation and subsequent Auger processes. These results demonstrate a valuable approach for addressing long standing questions about luminescent materials. PMID- 29694115 TI - Decoherence-Free Interaction between Giant Atoms in Waveguide Quantum Electrodynamics. AB - In quantum-optics experiments with both natural and artificial atoms, the atoms are usually small enough that they can be approximated as pointlike compared to the wavelength of the electromagnetic radiation with which they interact. However, superconducting qubits coupled to a meandering transmission line, or to surface acoustic waves, can realize "giant artificial atoms" that couple to a bosonic field at several points which are wavelengths apart. Here, we study setups with multiple giant atoms coupled at multiple points to a one-dimensional (1D) waveguide. We show that the giant atoms can be protected from decohering through the waveguide, but still have exchange interactions mediated by the waveguide. Unlike in decoherence-free subspaces, here the entire multiatom Hilbert space (2^{N} states for N atoms) is protected from decoherence. This is not possible with "small" atoms. We further show how this decoherence-free interaction can be designed in setups with multiple atoms to implement, e.g., a 1D chain of atoms with nearest-neighbor couplings or a collection of atoms with all-to-all connectivity. This may have important applications in quantum simulation and quantum computing. PMID- 29694116 TI - Quantum Steering Beyond Instrumental Causal Networks. AB - We theoretically predict, and experimentally verify with entangled photons, that outcome communication is not enough for hidden-state models to reproduce quantum steering. Hidden-state models with outcome communication correspond, in turn, to the well-known instrumental processes of causal inference but in the one-sided device-independent scenario of one black-box measurement device and one well characterized quantum apparatus. We introduce one-sided device-independent instrumental inequalities to test against these models, with the appealing feature of detecting entanglement even when communication of the black box's measurement outcome is allowed. We find that, remarkably, these inequalities can also be violated solely with steering, i.e., without outcome communication. In fact, an efficiently computable formal quantifier-the robustness of noninstrumentality-naturally arises, and we prove that steering alone is enough to maximize it. Our findings imply that quantum theory admits a stronger form of steering than known until now, with fundamental as well as practical potential implications. PMID- 29694117 TI - Systematic Onset of Periodic Patterns in Random Disk Packings. AB - We report evidence of a surprising systematic onset of periodic patterns in very tall piles of disks deposited randomly between rigid walls. Independently of the pile width, periodic structures are always observed in monodisperse deposits containing up to 10^{7} disks. The probability density function of the lengths of disordered transient phases that precede the onset of periodicity displays an approximately exponential tail. These disordered transients may become very large when the channel width grows without bound. For narrow channels, the probability density of finding periodic patterns of a given period displays a series of discrete peaks, which, however, are washed out completely when the channel width grows. PMID- 29694118 TI - Kern, Kadic, and Wegener Reply. PMID- 29694119 TI - One-Dimensional Nature of Superconductivity at the LaAlO_{3}/SrTiO_{3} Interface. AB - We examine superconductivity in LaAlO_{3}/SrTiO_{3} channels with widths that transition from the 1D to the 2D regime. The superconducting critical current is independent of the channel width and increases approximately linearly with the number of parallel channels. Signatures of electron pairing outside of the superconducting regime are also found to be independent of the channel width. Collectively, these results indicate that superconductivity exists at the boundary of these channels and is absent within the interior region of the channels. The intrinsic 1D nature of superconductivity at the LaAlO_{3}/SrTiO_{3} interface imposes strong physical constraints on possible electron pairing mechanisms. PMID- 29694121 TI - Normal Stresses, Contraction, and Stiffening in Sheared Elastic Networks. AB - When elastic solids are sheared, a nonlinear effect named after Poynting gives rise to normal stresses or changes in volume. We provide a novel relation between the Poynting effect and the microscopic Gruneisen parameter, which quantifies how stretching shifts vibrational modes. By applying this relation to random spring networks, a minimal model for, e.g., biopolymer gels and solid foams, we find that networks contract or develop tension because they vibrate faster when stretched. The amplitude of the Poynting effect is sensitive to the network's linear elastic moduli, which can be tuned via its preparation protocol and connectivity. Finally, we show that the Poynting effect can be used to predict the finite strain scale where the material stiffens under shear. PMID- 29694120 TI - Observation of the Self-Modulation Instability via Time-Resolved Measurements. AB - Self-modulation of an electron beam in a plasma has been observed. The propagation of a long (several plasma wavelengths) electron bunch in an overdense plasma resulted in the production of multiple bunches via the self-modulation instability. Using a combination of a radio-frequency deflector and a dipole spectrometer, the time and energy structure of the self-modulated beam was measured. The longitudinal phase space measurement showed the modulation of a long electron bunch into three bunches with an approximately 200 keV/c amplitude momentum modulation. Demonstrating this effect is a breakthrough for proton driven plasma accelerator schemes aiming to utilize the same physical effect. PMID- 29694122 TI - Matching Matched Filtering with Deep Networks for Gravitational-Wave Astronomy. AB - We report on the construction of a deep convolutional neural network that can reproduce the sensitivity of a matched-filtering search for binary black hole gravitational-wave signals. The standard method for the detection of well-modeled transient gravitational-wave signals is matched filtering. We use only whitened time series of measured gravitational-wave strain as an input, and we train and test on simulated binary black hole signals in synthetic Gaussian noise representative of Advanced LIGO sensitivity. We show that our network can classify signal from noise with a performance that emulates that of match filtering applied to the same data sets when considering the sensitivity defined by receiver-operator characteristics. PMID- 29694123 TI - No-Go Theorem for Nonstandard Explanations of the tau->K_{S}pinu_{tau} CP Asymmetry. AB - The CP asymmetry in tau->K_{S}pinu_{tau}, as measured by the BABAR collaboration, differs from the standard model prediction by 2.8sigma. Most nonstandard interactions do not allow for the required strong phase needed to produce a nonvanishing CP asymmetry, leaving only new tensor interactions as a possible mechanism. We demonstrate that, contrary to previous assumptions in the literature, the crucial interference between vector and tensor phases is suppressed by at least 2 orders of magnitude due to Watson's final-state interaction theorem. Furthermore, we find that the strength of the relevant CP violating tensor interaction is strongly constrained by bounds from the neutron electric dipole moment and D-D[over -] mixing. These observations together imply that it is extremely difficult to explain the current tau->K_{S}pinu_{tau} measurement in terms of physics beyond the standard model originating in the ultraviolet. PMID- 29694124 TI - Scattering Amplitudes from Intersection Theory. AB - We use Picard-Lefschetz theory to prove a new formula for intersection numbers of twisted cocycles associated with a given arrangement of hyperplanes. In a special case when this arrangement produces the moduli space of punctured Riemann spheres, intersection numbers become tree-level scattering amplitudes of quantum field theories in the Cachazo-He-Yuan formulation. PMID- 29694125 TI - Crystal Graph Convolutional Neural Networks for an Accurate and Interpretable Prediction of Material Properties. AB - The use of machine learning methods for accelerating the design of crystalline materials usually requires manually constructed feature vectors or complex transformation of atom coordinates to input the crystal structure, which either constrains the model to certain crystal types or makes it difficult to provide chemical insights. Here, we develop a crystal graph convolutional neural networks framework to directly learn material properties from the connection of atoms in the crystal, providing a universal and interpretable representation of crystalline materials. Our method provides a highly accurate prediction of density functional theory calculated properties for eight different properties of crystals with various structure types and compositions after being trained with 10^{4} data points. Further, our framework is interpretable because one can extract the contributions from local chemical environments to global properties. Using an example of perovskites, we show how this information can be utilized to discover empirical rules for materials design. PMID- 29694126 TI - Nonlocality, Correlations, and Magnetotransport in a Spatially Modulated Two Dimensional Electron Gas. AB - It is shown that the classical commensurability phenomena in weakly modulated two dimensional electron systems is a manifestation of the intrinsic properties of the correlation functions describing a homogeneous electron gas in a magnetic field. The theory demonstrates the importance for consideration of nonlocal response and removes the gap between classical and quantum approaches to magnetotransport in such systems. PMID- 29694127 TI - Topological Phase Transitions in Zinc-Blende Semimetals Driven Exclusively by Electronic Temperature. AB - We show that electronic phase transitions in zinc-blende semimetals with quadratic band touching (QBT) at the center of the Brillouin zone, like GaBi, InBi, or HgTe, can occur exclusively due to a change of the electronic temperature without the need to involve structural transformations or electron phonon coupling. The commonly used Kohn-Sham density-functional methods based on local and semilocal density functionals employing the local density approximation (LDA) or generalized gradient approximations (GGAs), however, are not capable of describing such phenomena because they lack an intrinsic temperature dependence and account for temperature only via the occupation of bands, which essentially leads only to a shift of the Fermi level without changing the shape or topology of bands. Kohn-Sham methods using the exact temperature-dependent exchange potential, not to be confused with the Hartree-Fock exchange potential, on the other hand, describe such phase transitions. A simple modeling of correlation effects can be achieved by screening of the exchange. In the considered zinc blende compounds the QBT is unstable at low temperatures and a transition to electronic states without QBT takes place. In the case of HgTe and GaBi Weyl points of type I and type II, respectively, emerge during the transitions. This demonstrates that Kohn-Sham methods can describe such topological phase transitions provided they are based on functionals more accurate than those within the LDA or GGA. Moreover, the electronic temperature is identified as a handle to tune topological materials. PMID- 29694128 TI - Directly Detecting MeV-Scale Dark Matter Via Solar Reflection. AB - If dark matter (DM) particles are lighter than a few MeV/c^{2} and can scatter off electrons, their interaction within the solar interior results in a considerable hardening of the spectrum of galactic dark matter received on Earth. For a large range of the mass versus cross section parameter space, {m_{e},sigma_{e}}, the "reflected" component of the DM flux is far more energetic than the end point of the ambient galactic DM energy distribution, making it detectable with existing DM detectors sensitive to an energy deposition of 10 10^{3} eV. After numerically simulating the small reflected component of the DM flux, we calculate its subsequent signal due to scattering on detector electrons, deriving new constraints on sigma_{e} in the MeV and sub-MeV range using existing data from the XENON10/100, LUX, PandaX-II, and XENON1T experiments, as well as making projections for future low threshold direct detection experiments. PMID- 29694129 TI - Deep Potential Molecular Dynamics: A Scalable Model with the Accuracy of Quantum Mechanics. AB - We introduce a scheme for molecular simulations, the deep potential molecular dynamics (DPMD) method, based on a many-body potential and interatomic forces generated by a carefully crafted deep neural network trained with ab initio data. The neural network model preserves all the natural symmetries in the problem. It is first-principles based in the sense that there are no ad hoc components aside from the network model. We show that the proposed scheme provides an efficient and accurate protocol in a variety of systems, including bulk materials and molecules. In all these cases, DPMD gives results that are essentially indistinguishable from the original data, at a cost that scales linearly with system size. PMID- 29694130 TI - Simple Rules Govern the Patterns of Arctic Sea Ice Melt Ponds. AB - Climate change, amplified in the far north, has led to rapid sea ice decline in recent years. In the summer, melt ponds form on the surface of Arctic sea ice, significantly lowering the ice reflectivity (albedo) and thereby accelerating ice melt. Pond geometry controls the details of this crucial feedback; however, a reliable model of pond geometry does not currently exist. Here we show that a simple model of voids surrounding randomly sized and placed overlapping circles reproduces the essential features of pond patterns. The only two model parameters, characteristic circle radius and coverage fraction, are chosen by comparing, between the model and the aerial photographs of the ponds, two correlation functions which determine the typical pond size and their connectedness. Using these parameters, the void model robustly reproduces the ponds' area-perimeter and area-abundance relationships over more than 6 orders of magnitude. By analyzing the correlation functions of ponds on several dates, we also find that the pond scale and the connectedness are surprisingly constant across different years and ice types. Moreover, we find that ponds resemble percolation clusters near the percolation threshold. These results demonstrate that the geometry and abundance of Arctic melt ponds can be simply described, which can be exploited in future models of Arctic melt ponds that would improve predictions of the response of sea ice to Arctic warming. PMID- 29694131 TI - Quantum Metrology beyond the Classical Limit under the Effect of Dephasing. AB - Quantum sensors have the potential to outperform their classical counterparts. For classical sensing, the uncertainty of the estimation of the target fields scales inversely with the square root of the measurement time T. On the other hand, by using quantum resources, we can reduce this scaling of the uncertainty with time to 1/T. However, as quantum states are susceptible to dephasing, it has not been clear whether we can achieve sensitivities with a scaling of 1/T for a measurement time longer than the coherence time. Here, we propose a scheme that estimates the amplitude of globally applied fields with the uncertainty of 1/T for an arbitrary time scale under the effect of dephasing. We use one-way quantum computing-based teleportation between qubits to prevent any increase in the correlation between the quantum state and its local environment from building up and have shown that such a teleportation protocol can suppress the local dephasing while the information from the target fields keeps growing. Our method has the potential to realize a quantum sensor with a sensitivity far beyond that of any classical sensor. PMID- 29694132 TI - Magnetic Field Control of Cycloidal Domains and Electric Polarization in Multiferroic BiFeO_{3}. AB - The magnetic field induced rearrangement of the cycloidal spin structure in ferroelectric monodomain single crystals of the room-temperature multiferroic BiFeO_{3} is studied using small-angle neutron scattering. The cycloid propagation vectors are observed to rotate when magnetic fields applied perpendicular to the rhombohedral (polar) axis exceed a pinning threshold value of ~5 T. In light of these experimental results, a phenomenological model is proposed that captures the rearrangement of the cycloidal domains, and we revisit the microscopic origin of the magnetoelectric effect. A new coupling between the magnetic anisotropy and the polarization is proposed that explains the recently discovered magnetoelectric polarization perpendicular to the rhombohedral axis. PMID- 29694133 TI - Topological Band Theory for Non-Hermitian Hamiltonians. AB - We develop the topological band theory for systems described by non-Hermitian Hamiltonians, whose energy spectra are generally complex. After generalizing the notion of gapped band structures to the non-Hermitian case, we classify "gapped" bands in one and two dimensions by explicitly finding their topological invariants. We find nontrivial generalizations of the Chern number in two dimensions, and a new classification in one dimension, whose topology is determined by the energy dispersion rather than the energy eigenstates. We then study the bulk-edge correspondence and the topological phase transition in two dimensions. Different from the Hermitian case, the transition generically involves an extended intermediate phase with complex-energy band degeneracies at isolated "exceptional points" in momentum space. We also systematically classify all types of band degeneracies. PMID- 29694106 TI - Measurement of the Ratio of Branching Fractions B(B_{c}^{+} >J/psitau^{+}nu_{tau})/B(B_{c}^{+}->J/psiMU^{+}nu_{MU}). AB - A measurement is reported of the ratio of branching fractions R(J/psi)=B(B_{c}^{+}->J/psitau^{+}nu_{tau})/B(B_{c}^{+}->J/psiMU^{+}nu_{MU}), where the tau^{+} lepton is identified in the decay mode tau^{+} >MU^{+}nu_{MU}nu[over -]_{tau}. This analysis uses a sample of proton-proton collision data corresponding to 3.0 fb^{-1} of integrated luminosity recorded with the LHCb experiment at center-of-mass energies of 7 and 8 TeV. A signal is found for the decay B_{c}^{+}->J/psitau^{+}nu_{tau} at a significance of 3 standard deviations corrected for systematic uncertainty, and the ratio of the branching fractions is measured to be R(J/psi)=0.71+/-0.17(stat)+/-0.18(syst). This result lies within 2 standard deviations above the range of central values currently predicted by the standard model. PMID- 29694134 TI - Rotational Energy as Mass in H_{3}^{+} and Lower Limits on the Atomic Masses of D and ^{3}He. AB - We have made precise measurements of the cyclotron frequency ratios H_{3}^{+}/HD^{+} and H_{3}^{+}/^{3}He^{+} and observe that different H_{3}^{+} ions result in different cyclotron frequency ratios. We interpret these differences as due to the molecular rotational energy of H_{3}^{+} changing its inertial mass. We also confirm that certain high J, K rotational levels of H_{3}^{+} have mean lifetimes exceeding several weeks. From measurements with the lightest H_{3}^{+} ion we obtain lower limits on the atomic masses of deuterium and helium-3 with respect to the proton. PMID- 29694136 TI - Demonstration of a Sensitive Method to Measure Nuclear-Spin-Dependent Parity Violation. AB - Nuclear-spin-dependent parity violation (NSD-PV) effects in atoms and molecules arise from Z^{0} boson exchange between electrons and the nucleus, and from the magnetic interaction between electrons and the parity-violating nuclear anapole moment. We demonstrate measurements of NSD-PV that use an enhancement of the effect in diatomic molecules, here using the test system ^{138}Ba^{19}F. Our sensitivity surpasses that of any previous atomic parity violation measurement. We show that systematic errors can be suppressed to at least the level of the present statistical sensitivity. We measure the matrix element W of the NSD-PV interaction with total uncertainty deltaW/(2pi)<0.7 Hz, for each of two configurations where W must have different signs. This sensitivity would be sufficient to measure NSD-PV effects of the size anticipated across a wide range of nuclei including ^{137}Ba in ^{137}BaF, where |W|/(2pi)~5 Hz is expected. PMID- 29694137 TI - Computationally Efficient Nonlinear Bell Inequalities for Quantum Networks. AB - The correlations in quantum networks have attracted strong interest with new types of violations of the locality. The standard Bell inequalities cannot characterize the multipartite correlations that are generated by multiple sources. The main problem is that no computationally efficient method is available for constructing useful Bell inequalities for general quantum networks. In this work, we show a significant improvement by presenting new, explicit Bell type inequalities for general networks including cyclic networks. These nonlinear inequalities are related to the matching problem of an equivalent unweighted bipartite graph that allows constructing a polynomial-time algorithm. For the quantum resources consisting of bipartite entangled pure states and generalized Greenberger-Horne-Zeilinger (GHZ) states, we prove the generic nonmultilocality of quantum networks with multiple independent observers using new Bell inequalities. The violations are maximal with respect to the presented Tsirelson's bound for Einstein-Podolsky-Rosen states and GHZ states. Moreover, these violations hold for Werner states or some general noisy states. Our results suggest that the presented Bell inequalities can be used to characterize experimental quantum networks. PMID- 29694135 TI - Solitonic Dispersive Hydrodynamics: Theory and Observation. AB - Ubiquitous nonlinear waves in dispersive media include localized solitons and extended hydrodynamic states such as dispersive shock waves. Despite their physical prominence and the development of thorough theoretical and experimental investigations of each separately, experiments and a unified theory of solitons and dispersive hydrodynamics are lacking. Here, a general soliton-mean field theory is introduced and used to describe the propagation of solitons in macroscopic hydrodynamic flows. Two universal adiabatic invariants of motion are identified that predict trapping or transmission of solitons by hydrodynamic states. The result of solitons incident upon smooth expansion waves or compressive, rapidly oscillating dispersive shock waves is the same, an effect termed hydrodynamic reciprocity. Experiments on viscous fluid conduits quantitatively confirm the soliton-mean field theory with broader implications for nonlinear optics, superfluids, geophysical fluids, and other dispersive hydrodynamic media. PMID- 29694138 TI - Bell Test over Extremely High-Loss Channels: Towards Distributing Entangled Photon Pairs between Earth and the Moon. AB - Quantum entanglement was termed "spooky action at a distance" in the well-known paper by Einstein, Podolsky, and Rosen. Entanglement is expected to be distributed over longer and longer distances in both practical applications and fundamental research into the principles of nature. Here, we present a proposal for distributing entangled photon pairs between Earth and the Moon using a Lagrangian point at a distance of 1.28 light seconds. One of the most fascinating features in this long-distance distribution of entanglement is as follows. One can perform the Bell test with human supplying the random measurement settings and recording the results while still maintaining spacelike intervals. To realize a proof-of-principle experiment, we develop an entangled photon source with 1 GHz generation rate, about 2 orders of magnitude higher than previous results. Violation of Bell's inequality was observed under a total simulated loss of 103 dB with measurement settings chosen by two experimenters. This demonstrates the feasibility of such long-distance Bell test over extremely high-loss channels, paving the way for one of the ultimate tests of the foundations of quantum mechanics. PMID- 29694139 TI - Surface and 3D Quantum Hall Effects from Engineering of Exceptional Points in Nodal-Line Semimetals. AB - We show that, under a strong magnetic field, a 3D nodal-line semimetal is driven into a topological insulating phase in which the electronic transport takes place at the surface of the material. When the magnetic field is perpendicular to the nodal ring, the surface states of the semimetal are transmuted into Landau states which correspond to exceptional points, i.e., branch points in the spectrum of a non-Hermitian Hamiltonian which arise upon the extension to complex values of the momentum. The complex structure of the spectrum then allows us to express the number of zero-energy flat bands in terms of a new topological invariant counting the number of exceptional points. When the magnetic field is parallel to the nodal ring, we find that the bulk states are built from the pairing of surfacelike evanescent waves, giving rise to a 3D quantum Hall effect with a flat level of Landau states residing in parallel 2D slices of the 3D material. The Hall conductance is quantized in either case in units of e^{2}/h, leading in the 3D Hall effect to a number of channels growing linearly with the section of the surface and opening the possibility to observe a macroscopic chiral current at the surface of the material. PMID- 29694140 TI - Field-Driven Quantum Criticality in the Spinel Magnet ZnCr_{2}Se_{4}. AB - We report detailed dc and ac magnetic susceptibilities, specific heat, and thermal conductivity measurements on the frustrated magnet ZnCr_{2}Se_{4}. At low temperatures, with an increasing magnetic field, this spinel material goes through a series of spin state transitions from the helix spin state to the spiral spin state and then to the fully polarized state. Our results indicate a direct quantum phase transition from the spiral spin state to the fully polarized state. As the system approaches the quantum criticality, we find strong quantum fluctuations of the spins with behaviors such as an unconventional T^{2} dependent specific heat and temperature-independent mean free path for the thermal transport. We complete the full phase diagram of ZnCr_{2}Se_{4} under the external magnetic field and propose the possibility of frustrated quantum criticality with extended densities of critical modes to account for the unusual low-energy excitations in the vicinity of the criticality. Our results reveal that ZnCr_{2}Se_{4} is a rare example of a 3D magnet exhibiting a field-driven quantum criticality with unconventional properties. PMID- 29694141 TI - Noninvasive Quantum Measurement of Arbitrary Operator Order by Engineered Non Markovian Detectors. AB - The development of solid-state quantum technologies requires the understanding of quantum measurements in interacting, nonisolated quantum systems. In general, a permanent coupling of detectors to a quantum system leads to memory effects that have to be taken into account in interpreting the measurement results. We analyze a generic setup of two detectors coupled to a quantum system and derive a compact formula in the weak-measurement limit that interpolates between an instantaneous (text-book type) and almost continuous-detector dynamics-dependent-measurement. A quantum memory effect that we term "system-mediated detector-detector interaction" is crucial to observe noncommuting observables simultaneously. Finally, we propose a mesoscopic double-dot detector setup in which the memory effect is tunable and that can be used to explore the transition to non-Markovian quantum measurements experimentally. PMID- 29694142 TI - Bell Inequality, Einstein-Podolsky-Rosen Steering, and Quantum Metrology with Spinor Bose-Einstein Condensates. AB - We propose an experiment, where the Bell inequality is violated in a many-body system of massive particles. The source of correlated atoms is a spinor F=1 Bose Einstein condensate residing in an optical lattice. We characterize the complete procedure-the local operations, the measurements, and the inequality-necessary to run the Bell test. We show how the degree of violation of the Bell inequality depends on the strengths of the two-body correlations and on the number of scattered pairs. We show that the system can be used to demonstrate the Einstein Podolsky-Rosen paradox. Also, the scattered pairs are an excellent many-body resource for the quantum-enhanced metrology. Our results apply to any multimode system where the spin-changing collision drives the scattering into separate regions. The presented inquiry shows that such a system is versatile as it can be used for the tests of nonlocality, quantum metrology, and quantum information. PMID- 29694143 TI - Transition to the Ultimate Regime in Two-Dimensional Rayleigh-Benard Convection. AB - The possible transition to the so-called ultimate regime, wherein both the bulk and the boundary layers are turbulent, has been an outstanding issue in thermal convection, since the seminal work by Kraichnan [Phys. Fluids 5, 1374 (1962)PFLDAS0031-917110.1063/1.1706533]. Yet, when this transition takes place and how the local flow induces it is not fully understood. Here, by performing two-dimensional simulations of Rayleigh-Benard turbulence covering six decades in Rayleigh number Ra up to 10^{14} for Prandtl number Pr=1, for the first time in numerical simulations we find the transition to the ultimate regime, namely, at Ra^{*}=10^{13}. We reveal how the emission of thermal plumes enhances the global heat transport, leading to a steeper increase of the Nusselt number than the classical Malkus scaling Nu~Ra^{1/3} [Proc. R. Soc. A 225, 196 (1954)PRLAAZ1364 502110.1098/rspa.1954.0197]. Beyond the transition, the mean velocity profiles are logarithmic throughout, indicating turbulent boundary layers. In contrast, the temperature profiles are only locally logarithmic, namely, within the regions where plumes are emitted, and where the local Nusselt number has an effective scaling Nu~Ra^{0.38}, corresponding to the effective scaling in the ultimate regime. PMID- 29694145 TI - Prediction of Intrinsic Ferromagnetic Ferroelectricity in a Transition-Metal Halide Monolayer. AB - The realization of multiferroics in nanostructures, combined with a large electric dipole and ferromagnetic ordering, could lead to new applications, such as high-density multistate data storage. Although multiferroics have been broadly studied for decades, ferromagnetic ferroelectricity is rarely explored, especially in two-dimensional (2D) systems. Here we report the discovery of 2D ferromagnetic ferroelectricity in layered transition-metal halide systems. On the basis of first-principles calculations, we reveal that a charged CrBr_{3} monolayer exhibits in-plane multiferroicity, which is ensured by the combination of orbital and charge ordering as realized by the asymmetric Jahn-Teller distortions of octahedral Cr?Br_{6} units. As an example, we further show that (CrBr_{3})_{2}Li is a ferromagnetic ferroelectric multiferroic. The explored phenomena and mechanism of multiferroics in this 2D system not only are useful for fundamental research in multiferroics but also enable a wide range of applications in nanodevices. PMID- 29694147 TI - Extreme Field Sensitivity of Magnetic Tunneling in Fe-Doped Li_{3}N. AB - The magnetic properties of dilute Li_{2}(Li_{1-x}Fe_{x})N with x~0.001 are dominated by the spin of single, isolated Fe atoms. Below T=10 K the spin relaxation times become temperature independent indicating a crossover from thermal excitations to the quantum tunneling regime. We report on a strong increase of the spin-flip probability in transverse magnetic fields that proves the resonant character of this tunneling process. Longitudinal fields, on the other hand, lift the ground-state degeneracy and destroy the tunneling condition. An increase of the relaxation time by 4 orders of magnitude in applied fields of only a few milliTesla reveals exceptionally sharp tunneling resonances. Li_{2}(Li_{1-x}Fe_{x})N represents a comparatively simple and clean model system that opens the possibility to study quantum tunneling of the magnetization at liquid helium temperatures. PMID- 29694150 TI - Localized Magnetic Moments with Tunable Spin Exchange in a Gas of Ultracold Fermions. AB - We report on the experimental realization of a state-dependent lattice for a two orbital fermionic quantum gas with strong interorbital spin exchange. In our state-dependent lattice, the ground and metastable excited electronic states of ^{173}Yb take the roles of itinerant and localized magnetic moments, respectively. Repulsive on-site interactions in conjunction with the tunnel mobility lead to spin exchange between mobile and localized particles, modeling the coupling term in the well-known Kondo Hamiltonian. In addition, we find that this exchange process can be tuned resonantly by varying the on-site confinement. We attribute this to a resonant coupling to center-of-mass excited bound states of one interorbital scattering channel. PMID- 29694149 TI - Particle-Size-Exclusion Clogging Regimes in Porous Media. AB - From observations of the progressive deposition of noncolloidal particles by geometrical exclusion effects inside a 3D model porous medium, we get a complete dynamic view of particle deposits over a full range of regimes from transport over a long distance to clogging and caking. We show that clogging essentially occurs in the form of an accumulation of elements in pore size clusters, which ultimately constitute regions avoided by the flow. The clusters are dispersed in the medium, and their concentration (number per volume) decreases with the distance from the entrance; caking is associated with the final stage of this effect (for a critical cluster concentration at the entrance). A simple probabilistic model, taking into account the impact of clogging on particle transport, allows us to quantitatively predict all these trends up to a large cluster concentration, based on a single parameter: the clogging probability, which is a function of the confinement ratio. This opens the route towards a unification of the different fields of particle transport, clogging, caking, and filtration. PMID- 29694151 TI - Double Gamow-Teller Transitions and its Relation to Neutrinoless betabeta Decay. AB - We study the double Gamow-Teller (DGT) strength distribution of ^{48}Ca with state-of-the-art large-scale nuclear shell model calculations. Our analysis shows that the centroid energy of the DGT giant resonance depends mostly on the isovector pairing interaction, while the resonance width is more sensitive to isoscalar pairing. Pairing correlations are also key in neutrinoless betabeta (0nubetabeta) decay. We find a simple relation between the centroid energy of the ^{48}Ca DGT giant resonance and the 0nubetabeta decay nuclear matrix element. More generally, we observe a very good linear correlation between the DGT transition to the ground state of the final nucleus and the 0nubetabeta decay matrix element. The correlation, which originates on the dominant short-range character of both transitions, extends to heavier systems including several betabeta emitters and also holds in energy-density functional results. Our findings suggest that DGT experiments can be a very valuable tool to obtain information on the value of 0nubetabeta decay nuclear matrix elements. PMID- 29694146 TI - MICROSCOPE Mission: First Constraints on the Violation of the Weak Equivalence Principle by a Light Scalar Dilaton. AB - The existence of a light or massive scalar field with a coupling to matter weaker than gravitational strength is a possible source of violation of the weak equivalence principle. We use the first results on the Eotvos parameter by the MICROSCOPE experiment to set new constraints on such scalar fields. For a massive scalar field of mass smaller than 10^{-12} eV (i.e., range larger than a few 10^{5} m), we improve existing constraints by one order of magnitude to |alpha|<10^{-11} if the scalar field couples to the baryon number and to |alpha|<10^{-12} if the scalar field couples to the difference between the baryon and the lepton numbers. We also consider a model describing the coupling of a generic dilaton to the standard matter fields with five parameters, for a light field: We find that, for masses smaller than 10^{-12} eV, the constraints on the dilaton coupling parameters are improved by one order of magnitude compared to previous equivalence principle tests. PMID- 29694152 TI - Detecting Kondo Entanglement by Electron Conductance. AB - Quantum entanglement between an impurity spin and electrons nearby is a key property of the single-channel Kondo effects. We show that the entanglement can be detected by measuring electron conductance through a double quantum dot in an orbital Kondo regime. We derive a relation between the entanglement and the conductance, when the SU(2) spin symmetry of the regime is weakly broken. The relation reflects the universal form of many-body states near the Kondo fixed point. Using it, the spatial distribution of the entanglement-hence, the Kondo cloud-can be detected, with breaking of the symmetry spatially nonuniformly by electrical means. PMID- 29694148 TI - First Measurement of Monoenergetic Muon Neutrino Charged Current Interactions. AB - We report the first measurement of monoenergetic muon neutrino charged current interactions. MiniBooNE has isolated 236 MeV muon neutrino events originating from charged kaon decay at rest (K^{+}->MU^{+}nu_{MU}) at the NuMI beamline absorber. These signal nu_{MU}-carbon events are distinguished from primarily pion decay in flight nu_{MU} and nu[over -]_{MU} backgrounds produced at the target station and decay pipe using their arrival time and reconstructed muon energy. The significance of the signal observation is at the 3.9sigma level. The muon kinetic energy, neutrino-nucleus energy transfer (omega=E_{nu}-E_{MU}), and total cross section for these events are extracted. This result is the first known-energy, weak-interaction-only probe of the nucleus to yield a measurement of omega using neutrinos, a quantity thus far only accessible through electron scattering. PMID- 29694153 TI - Searching for Supersolidity in Ultracold Atomic Bose Condensates with Rashba Spin Orbit Coupling. AB - We developed a functional integral formulation for the stripe phase of spinor Bose-Einstein condensates with Rashba spin-orbit coupling. The excitation spectrum is found to exhibit double gapless band structures, identified to be two Goldstone modes resulting from spontaneously broken internal gauge symmetry and translational invariance symmetry. The sound velocities display anisotropic behavior with the lower branch vanishing in the direction perpendicular to the stripe in the x-y plane. At the transition point between the plane-wave phase and the stripe phase, physical quantities such as fluctuation correction to the ground-state energy and quantum depletion of the condensates exhibit discontinuity, characteristic of the first-order phase transition. Despite strong quantum fluctuations induced by Rashba spin-orbit coupling, we show that the supersolid phase is stable against quantum depletion. Finally, we extend our formulation to finite temperatures to account for interactions between excitations. PMID- 29694154 TI - Time-Dependent Wave Packet Dynamics Calculations of Cross Sections for Ultracold Scattering of Molecules. AB - Because the de Broglie wavelength of ultracold molecules is very large, the cross sections for collisions of molecules at ultracold temperatures are always computed by the time-independent quantum scattering approach. Here, we report the first accurate time-dependent wave packet dynamics calculation for reactive scattering of ultracold molecules. Wave packet dynamics calculations can be applied to molecular systems with more dimensions and provide real-time information on the process of bond rearrangement and/or energy exchange in molecular collisions. Our work thus makes possible the extension of rigorous quantum calculations of ultracold reaction properties to polyatomic molecules and adds a new powerful tool for the study of ultracold chemistry. PMID- 29694155 TI - Impact of Beads and Drops on a Repellent Solid Surface: A Unified Description. AB - We investigate freely expanding sheets formed by ultrasoft gel beads, and liquid and viscoelastic drops, produced by the impact of the bead or drop on a silicon wafer covered with a thin layer of liquid nitrogen that suppresses viscous dissipation thanks to an inverse Leidenfrost effect. Our experiments show a unified behavior for the impact dynamics that holds for solids, liquids, and viscoelastic fluids and that we rationalize by properly taking into account elastocapillary effects. In this framework, the classical impact dynamics of solids and liquids, as far as viscous dissipation is negligible, appears as the asymptotic limits of a universal theoretical description. A novel material dependent characteristic velocity that includes both capillary and bulk elasticity emerges from this unified description of the physics of impact. PMID- 29694156 TI - Limited Resources Induce Bistability in Microtubule Length Regulation. AB - The availability of protein is an important factor for the determination of the size of the mitotic spindle. Involved in spindle-size regulation is kinesin-8, a molecular motor and microtubule (MT) depolymerase, which is known to tightly control MT length. Here, we propose and analyze a theoretical model in which kinesin-induced MT depolymerization competes with spontaneous polymerization while supplies of both tubulin and kinesin are limited. In contrast to previous studies where resources were unconstrained, we find that, for a wide range of concentrations, MT length regulation is bistable. We test our predictions by conducting in vitro experiments and find that the bistable behavior manifests in a bimodal MT length distribution. PMID- 29694157 TI - Densification of Supercritical Carbon Dioxide Accompanied by Droplet Formation When Passing the Widom Line. AB - Thermal density fluctuations of supercritical CO_{2} were explored using small angle neutron scattering (SANS), whose amplitude (susceptibility) and correlation length show the expected maximum at the Widom line. At low pressure, the susceptibility is in excellent agreement with the evaluated values on the basis of mass density measurements. At about 20 bar beyond the Widom line, SANS shows the formation of droplets accompanied by an enhanced number density of the supercritical fluid. The corresponding borderline is interpreted as a Frenkel line separating gas- and liquidlike regimes. PMID- 29694158 TI - Comment on "Experimental Evidence for Sign Reversal of the Hall Coefficient in Three-Dimensional Metamaterials". PMID- 29694159 TI - Rules for Phase Shifts of Quantum Oscillations in Topological Nodal-Line Semimetals. AB - Nodal-line semimetals are topological semimetals in which band touchings form nodal lines or rings. Around a loop that encloses a nodal line, an electron can accumulate a nontrivial pi Berry phase, so the phase shift in the Shubnikov-de Haas (SdH) oscillation may give a transport signature for the nodal-line semimetals. However, different experiments have reported contradictory phase shifts, in particular, in the WHM nodal-line semimetals (W=Zr/Hf, H=Si/Ge, M=S/Se/Te). For a generic model of nodal-line semimetals, we present a systematic calculation for the SdH oscillation of resistivity under a magnetic field normal to the nodal-line plane. From the analytical result of the resistivity, we extract general rules to determine the phase shifts for arbitrary cases and apply them to ZrSiS and Cu_{3}PdN systems. Depending on the magnetic field directions, carrier types, and cross sections of the Fermi surface, the phase shift shows rich results, quite different from those for normal electrons and Weyl fermions. Our results may help explore transport signatures of topological nodal-line semimetals and can be generalized to other topological phases of matter. PMID- 29694160 TI - Kondo Impurities Coupled to a Helical Luttinger Liquid: RKKY-Kondo Physics Revisited. AB - We show that the paradigmatic Ruderman-Kittel-Kasuya-Yosida (RKKY) description of two local magnetic moments coupled to propagating electrons breaks down in helical Luttinger liquids when the electron interaction is stronger than some critical value. In this novel regime, the Kondo effect overwhelms the RKKY interaction over all macroscopic interimpurity distances. This phenomenon is a direct consequence of the helicity (realized, for instance, at edges of a time reversal invariant topological insulator) and does not take place in usual (nonhelical) Luttinger liquids. PMID- 29694161 TI - Coherently Enhanced Wireless Power Transfer. AB - Extraction of electromagnetic energy by an antenna from impinging external radiation is at the basis of wireless communications and wireless power transfer (WPT). The maximum of transferred energy is ensured when the antenna is conjugately matched, i.e., when it is resonant and it has an equal coupling with free space and its load. This condition, however, can be easily affected by changes in the environment, preventing optimal operation of a WPT system. Here, we introduce the concept of coherently enhanced WPT that allows us to bypass this difficulty and achieve dynamic control of power transfer. The approach relies on coherent excitation of the waveguide connected to the antenna load with a backward propagating signal of specific amplitude and phase. This signal creates a suitable interference pattern at the load resulting in a modification of the local wave impedance, which in turn enables conjugate matching and a largely increased amount of extracted energy. We develop a simple theoretical model describing this concept, demonstrate it with full-wave numerical simulations for the canonical example of a dipole antenna, and verify experimentally in both near field and far-field regimes. PMID- 29694163 TI - Nonlinear Decay and Plasma Heating by a Toroidal Alfven Eigenmode. AB - We demonstrate theoretically that a toroidal Alfven eigenmode (TAE) can parametrically decay into a geodesic acoustic mode and kinetic TAE in a toroidal plasma. The corresponding threshold condition for the TAE amplitude is estimated to be |deltaB_{?}/B_{0}|~O(10^{-4}). Here, deltaB_{?} and B_{0} are, respectively, the perturbed magnetic field of the pump TAE and the equilibrium magnetic field. This novel decay process, in addition to contributing to the nonlinear saturation of energetic-particle or alpha-particle driven TAE instability, could also contribute to the heating as well as regulating the transports of thermal plasmas. PMID- 29694162 TI - Stimulated X-Ray Emission Spectroscopy in Transition Metal Complexes. AB - We report the observation and analysis of the gain curve of amplified Kalpha x ray emission from solutions of Mn(II) and Mn(VII) complexes using an x-ray free electron laser to create the 1s core-hole population inversion. We find spectra at amplification levels extending over 4 orders of magnitude until saturation. We observe bandwidths below the Mn 1s core-hole lifetime broadening in the onset of the stimulated emission. In the exponential amplification regime the resolution corrected spectral width of ~1.7 eV FWHM is constant over 3 orders of magnitude, pointing to the buildup of transform limited pulses of ~1 fs duration. Driving the amplification into saturation leads to broadening and a shift of the line. Importantly, the chemical sensitivity of the stimulated x-ray emission to the Mn oxidation state is preserved at power densities of ~10^{20} W/cm^{2} for the incoming x-ray pulses. Differences in signal sensitivity and spectral information compared to conventional (spontaneous) x-ray emission spectroscopy are discussed. Our findings build a baseline for nonlinear x-ray spectroscopy for a wide range of transition metal complexes in inorganic chemistry, catalysis, and materials science. PMID- 29694164 TI - Quasistationary Plasma Predator-Prey System of Coupled Turbulence, Drive, and Sheared E*B Flow During High Performance DIII-D Tokamak Discharges. AB - A new, long-lived limit cycle oscillation (LCO) regime has been observed in the edge of near zero torque high performance DIII-D tokamak plasma discharges. These LCOs are localized and composed of density turbulence, gradient drives, and E*B velocity shear damping (E and B are the local radial electric and total magnetic fields). Density turbulence sequentially acts as a predator (via turbulence transport) of profile gradients and a prey (via shear suppression) to the E*B velocity shear. Reported here for the first time is a unique spatiotemporal variation of the local E*B velocity, which is found to be essential for the existence of this system. The LCO system is quasistationary, existing from 3 to 12 plasma energy confinement times (~30-900 LCO cycles) limited by hardware constraints. This plasma system appears to contribute strongly to the edge transport in these high performance and transient-free plasmas, as evident from oscillations in transport relevant edge parameters at LCO time scale. PMID- 29694165 TI - Associating Imidazoles: Elucidating the Correlation between the Static Dielectric Permittivity and Proton Conductivity. AB - Broadband dielectric spectroscopy is employed to investigate the impact of supramolecular structure on charge transport and dynamics in hydrogen-bonded 2 ethyl-4-methylimidazole and 4-methylimidazole. Detailed analyses reveal (i) an inverse relationship between the average supramolecular chain length and proton conductivity and (ii) no direct correlation between the static dielectric permittivity and proton conductivity in imidazoles. These findings raise fundamental questions regarding the widespread notion that extended supramolecular hydrogen-bonded networks facilitate proton conduction in hydrogen bonding materials. PMID- 29694166 TI - First-Principles Study of Charge Diffusion between Proximate Solid-State Qubits and Its Implications on Sensor Applications. AB - Solid-state qubits from paramagnetic point defects in solids are promising platforms to realize quantum networks and novel nanoscale sensors. Recent advances in materials engineering make it possible to create proximate qubits in solids that might interact with each other, leading to electron spin or charge fluctuation. Here we develop a method to calculate the tunneling-mediated charge diffusion between point defects from first principles and apply it to nitrogen vacancy (NV) qubits in diamond. The calculated tunneling rates are in quantitative agreement with previous experimental data. Our results suggest that proximate neutral and negatively charged NV defect pairs can form a NV-NV molecule. A tunneling-mediated model for the source of decoherence of the near surface NV qubits is developed based on our findings on the interacting qubits in diamond. PMID- 29694167 TI - Generalized Entanglement Entropies of Quantum Designs. AB - The entanglement properties of random quantum states or dynamics are important to the study of a broad spectrum of disciplines of physics, ranging from quantum information to high energy and many-body physics. This Letter investigates the interplay between the degrees of entanglement and randomness in pure states and unitary channels. We reveal strong connections between designs (distributions of states or unitaries that match certain moments of the uniform Haar measure) and generalized entropies (entropic functions that depend on certain powers of the density operator), by showing that Renyi entanglement entropies averaged over designs of the same order are almost maximal. This strengthens the celebrated Page's theorem. Moreover, we find that designs of an order that is logarithmic in the dimension maximize all Renyi entanglement entropies and so are completely random in terms of the entanglement spectrum. Our results relate the behaviors of Renyi entanglement entropies to the complexity of scrambling and quantum chaos in terms of the degree of randomness, and suggest a generalization of the fast scrambling conjecture. PMID- 29694168 TI - Multicritical Point on the de Almeida-Thouless Line in Spin Glasses in d>6 Dimensions. AB - The de Almeida-Thouless (AT) line in Ising spin glasses is the phase boundary in the temperature T and magnetic field h plane below which replica symmetry is broken. Using perturbative renormalization group (RG) methods, we show that, when the dimension d of space is just above six, there is a multicritical point (MCP) on the AT line, which separates a low-field regime, in which the critical exponents have mean-field values, from a high-field regime, where the RG flows run away to infinite coupling strength; as d approaches six from above, the MCP approaches the zero-field critical point exponentially in 1/(d-6). Thus, on the AT line, perturbation theory for the critical properties breaks down at a sufficiently large magnetic field even above 6 dimensions, as well as for all nonzero fields when d<=6, as was known previously. We calculate the exponents at the MCP to first order in epsilon=d-6>0. The fate of the MCP as d increases from just above six to infinity is not known. PMID- 29694169 TI - Noncontextual Wirings. AB - Contextuality is a fundamental feature of quantum theory necessary for certain models of quantum computation and communication. Serious steps have therefore been taken towards a formal framework for contextuality as an operational resource. However, the main ingredient of a resource theory-a concrete, explicit form of free operations of contextuality-was still missing. Here we provide such a component by introducing noncontextual wirings: a class of contextuality-free operations with a clear operational interpretation and a friendly parametrization. We characterize them completely for general black-box measurement devices with arbitrarily many inputs and outputs. As applications, we show that the relative entropy of contextuality is a contextuality monotone and that maximally contextual boxes that serve as contextuality bits exist for a broad class of scenarios. Our results complete a unified resource-theoretic framework for contextuality and Bell nonlocality. PMID- 29694171 TI - Synthetic Landau Levels and Spinor Vortex Matter on a Haldane Spherical Surface with a Magnetic Monopole. AB - We present a flexible scheme to realize exact flat Landau levels on curved spherical geometry in a system of spinful cold atoms. This is achieved by applying the Floquet engineering of a magnetic quadrupole field to create a synthetic monopole field in real space. The system can be exactly mapped to the electron-monopole system on a sphere, thus realizing Haldane's spherical geometry for fractional quantum Hall physics. This method works for either bosons or fermions. We investigate the ground-state vortex pattern for an s-wave interacting atomic condensate by mapping this system to the classical Thompson's problem. The distortion and stability of the vortex pattern are further studied in the presence of dipolar interaction. Our scheme is compatible with the current experimental setup, and may serve as a promising route of investigating quantum Hall physics and exotic spinor vortex matter on curved space. PMID- 29694172 TI - Brillouin Light Scattering by Magnetic Quasivortices in Cavity Optomagnonics. AB - A ferromagnetic sphere can support optical vortices in the form of whispering gallery modes and magnetic quasivortices in the form of magnetostatic modes with nontrivial spin textures. These vortices can be characterized by their orbital angular momenta. We experimentally investigate Brillouin scattering of photons in the whispering gallery modes by magnons in the magnetostatic modes, zeroing in on the exchange of the orbital angular momenta between the optical vortices and magnetic quasivortices. We find that the conservation of the orbital angular momentum results in different nonreciprocal behavior in the Brillouin light scattering. New avenues for chiral optics and optospintronics can be opened up by taking the orbital angular momenta as a new degree of freedom for cavity optomagnonics. PMID- 29694173 TI - Theory of a Quantum Scanning Microscope for Cold Atoms. AB - We propose and analyze a scanning microscope to monitor "live" the quantum dynamics of cold atoms in a cavity QED setup. The microscope measures the atomic density with subwavelength resolution via dispersive couplings to a cavity and homodyne detection within the framework of continuous measurement theory. We analyze two modes of operation. First, for a fixed focal point the microscope records the wave packet dynamics of atoms with time resolution set by the cavity lifetime. Second, a spatial scan of the microscope acts to map out the spatial density of stationary quantum states. Remarkably, in the latter case, for a good cavity limit, the microscope becomes an effective quantum nondemolition device, such that the spatial distribution of motional eigenstates can be measured backaction free in single scans, as an emergent quantum nondemolition measurement. PMID- 29694174 TI - Anti-Aging in Ultrastable Metallic Glasses. AB - As ultrastable metallic glasses (UMGs) are promising candidates to solve the stability issues of conventional metallic glasses, their study is of exceptional interest. By means of x-ray photon correlation spectroscopy, we have investigated the stability of UMGs at the atomic level. We find a clear signature of ultrastability at the atomic level that results in slower relaxation dynamics of UMGs with respect to conventional (rapidly quenched) metallic glasses, and in a peculiar acceleration of the dynamics by near T_{g} annealing. This surprising phenomenon, called here anti-aging, can be understood in the framework of the potential energy landscape. For all samples, the structural relaxation process can be described with a highly compressed shape of the density fluctuations, unaffected by thermal treatments and regardless of the ultrastability of the glass. PMID- 29694175 TI - Suppressing Two-Plasmon Decay with Laser Frequency Detuning. AB - Three-dimensional laser-plasma interaction simulations show that laser frequency detuning by an amount achievable with current laser technology can be used to suppress the two-plasmon decay (TPD) instability and the corresponding hot electron generation. For the plasma conditions and laser configuration in a direct-drive inertial confinement fusion implosion on the OMEGA laser, the simulations show that ~0.7% laser frequency detuning is sufficient to eliminate TPD-driven hot-electron generation in current experiments. This allows for higher ablation pressures in future implosion designs by using higher laser intensities. PMID- 29694177 TI - Near-K-Edge Double and Triple Detachment of the F^{-} Negative Ion: Observation of Direct Two-Electron Ejection by a Single Photon. AB - Double and triple detachment of the F^{-}(1s^{2}2s^{2}2p^{6}) negative ion by a single photon have been investigated in the photon energy range 660 to 1000 eV. The experimental data provide unambiguous evidence for the dominant role of direct photodouble detachment with a subsequent single-Auger process in the reaction channel leading to F^{2+} product ions. Absolute cross sections were determined for the direct removal of a (1s+2p) pair of electrons from F^{-} by the absorption of a single photon. PMID- 29694178 TI - Anomalous Rabi Oscillations in Multilevel Quantum Systems. AB - We show that the excitation probability of a state within a manifold of levels undergoes Rabi oscillations with the frequency determined by the energy difference between the states and not by the pulse area, for sufficiently strong pulses. The population and coherence remains in the two-level subsystem formed by the initial and target state even at Rabi frequencies exceeding the energy difference. The observed dynamics can be useful in nonlinear spectroscopy and quantum state preparation. PMID- 29694179 TI - Proposal for Quantum Simulation via All-Optically-Generated Tensor Network States. AB - We devise an all-optical scheme for the generation of entangled multimode photonic states encoded in temporal modes of light. The scheme employs a nonlinear down-conversion process in an optical loop to generate one- and higher dimensional tensor network states of light. We illustrate the principle with the generation of two different classes of entangled tensor network states and report on a variational algorithm to simulate the ground-state physics of many-body systems. We demonstrate that state-of-the-art optical devices are capable of determining the ground-state properties of the spin-1/2 Heisenberg model. Finally, implementations of the scheme are demonstrated to be robust against realistic losses and mode mismatch. PMID- 29694176 TI - Improved Limit on Neutrinoless Double-beta Decay of ^{76}Ge from GERDA Phase II. AB - The GERDA experiment searches for the lepton-number-violating neutrinoless double beta decay of ^{76}Ge (^{76}Ge->^{76}Se+2e^{-}) operating bare Ge diodes with an enriched ^{76}Ge fraction in liquid argon. The exposure for broad-energy germanium type (BEGe) detectors is increased threefold with respect to our previous data release. The BEGe detectors feature an excellent background suppression from the analysis of the time profile of the detector signals. In the analysis window a background level of 1.0_{-0.4}^{+0.6}*10^{-3} counts/(keV kg yr) has been achieved; if normalized to the energy resolution this is the lowest ever achieved in any 0nubetabeta experiment. No signal is observed and a new 90% C.L. lower limit for the half-life of 8.0*10^{25} yr is placed when combining with our previous data. The expected median sensitivity assuming no signal is 5.8*10^{25} yr. PMID- 29694180 TI - Ultracold Anions for High-Precision Antihydrogen Experiments. AB - Experiments with antihydrogen (H[over -]) for a study of matter-antimatter symmetry and antimatter gravity require ultracold H[over -] to reach ultimate precision. A promising path towards antiatoms much colder than a few kelvin involves the precooling of antiprotons by laser-cooled anions. Because of the weak binding of the valence electron in anions-dominated by polarization and correlation effects-only few candidate systems with suitable transitions exist. We report on a combination of experimental and theoretical studies to fully determine the relevant binding energies, transition rates, and branching ratios of the most promising candidate La^{-}. Using combined transverse and collinear laser spectroscopy, we determined the resonant frequency of the laser cooling transition to be nu=96.592 713(91) THz and its transition rate to be A=4.90(50)*10^{4} s^{-1}. Using a novel high-precision theoretical treatment of La^{-} we calculated yet unmeasured energy levels, transition rates, branching ratios, and lifetimes to complement experimental information on the laser cooling cycle of La^{-}. The new data establish the suitability of La^{-} for laser cooling and show that the cooling transition is significantly stronger than suggested by a previous theoretical study. PMID- 29694181 TI - Ionization-Induced Self-Channeling of an Ultrahigh-Power Subnanosecond Microwave Beam in a Neutral Gas. AB - Ionization-induced self-channeling of a <=500 MW, 9.6 GHz, <1 ns microwave beam injected into air at ~4.5*10^{3} Pa or He at ~10^{3} Pa is experimentally demonstrated for the first time. The plasma, generated by the impact ionization of the gas driven by the microwave beam, has a radial density distribution reducing towards the beam axis, where the microwave field is highest, because the ionization rate is a decreasing function of the microwave amplitude. This forms a plasma channel which prevents the divergence of the microwave beam. The experimental data obtained using various diagnostic methods are in good agreement with the results of analytical calculations, as well as particle in cell Monte Carlo collisional modeling. PMID- 29694182 TI - Dynamical Quantum Phase Transitions in Spin Chains with Long-Range Interactions: Merging Different Concepts of Nonequilibrium Criticality. AB - We theoretically study the dynamics of a transverse-field Ising chain with power law decaying interactions characterized by an exponent alpha, which can be experimentally realized in ion traps. We focus on two classes of emergent dynamical critical phenomena following a quantum quench from a ferromagnetic initial state: The first one manifests in the time-averaged order parameter, which vanishes at a critical transverse field. We argue that such a transition occurs only for long-range interactions alpha<=2. The second class corresponds to the emergence of time-periodic singularities in the return probability to the ground-state manifold which is obtained for all values of alpha and agrees with the order parameter transition for alpha<=2. We characterize how the two classes of nonequilibrium criticality correspond to each other and give a physical interpretation based on the symmetry of the time-evolved quantum states. PMID- 29694183 TI - Fate of Large-Scale Structure in Modified Gravity After GW170817 and GRB170817A. AB - The coincident detection of gravitational waves (GW) and a gamma-ray burst from a merger of neutron stars has placed an extremely stringent bound on the speed of GWs. We showed previously that the presence of gravitational slip (eta) in cosmology is intimately tied to modifications of GW propagation. This new constraint implies that the only remaining viable source of gravitational slip is a conformal coupling to gravity in scalar-tensor theories, while viable vector tensor theories cannot now generate gravitational slip at all. We discuss structure formation in the remaining viable models, demonstrating that (i) the dark-matter growth rate must now be at least as fast as in general relativity (GR), with the possible exception of that beyond the Horndeski model, and (ii) if there is any scale dependence at all in the slip parameter, it is such that it takes the GR value at large scales. We show a consistency relation that must be violated if gravity is modified. PMID- 29694184 TI - Optimal Classical Simulation of State-Independent Quantum Contextuality. AB - Simulating quantum contextuality with classical systems requires memory. A fundamental yet open question is what is the minimum memory needed and, therefore, the precise sense in which quantum systems outperform classical ones. Here, we make rigorous the notion of classically simulating quantum state independent contextuality (QSIC) in the case of a single quantum system submitted to an infinite sequence of measurements randomly chosen from a finite QSIC set. We obtain the minimum memory needed to simulate arbitrary QSIC sets via classical systems under the assumption that the simulation should not contain any oracular information. In particular, we show that, while classically simulating two qubits tested with the Peres-Mermin set requires log_{2}24~4.585 bits, simulating a single qutrit tested with the Yu-Oh set requires, at least, 5.740 bits. PMID- 29694185 TI - Alloy Engineering of Topological Semimetal Phase Transition in MgTa_{2 x}Nb_{x}N_{3}. AB - Dirac, triple-point, and Weyl fermions represent three topological semimetal phases, characterized with a descending degree of band degeneracy, which have been realized separately in specific crystalline materials with different lattice symmetries. Here we demonstrate an alloy engineering approach to realize all three types of fermions in one single material system of MgTa_{2-x}Nb_{x}N_{3}. Based on symmetry analysis and first-principles calculations, we map out a phase diagram of topological order in the parameter space of alloy concentration and crystalline symmetry, where the intrinsic MgTa_{2}N_{3} with the highest symmetry hosts the Dirac semimetal phase, which transforms into the triple-point and then the Weyl semimetal phases with increasing Nb concentration that lowers the crystalline symmetries. Therefore, alloy engineering affords a unique approach for the experimental investigation of topological transitions of semimetallic phases manifesting different fermionic behaviors. PMID- 29694186 TI - Self-Heating Dark Matter via Semiannihilation. AB - The freeze-out of dark matter (DM) depends on the evolution of the DM temperature. The DM temperature does not have to follow the standard model one, when the elastic scattering is not sufficient to maintain the kinetic equilibrium. We study the temperature evolution of the semiannihilating DM, where a pair of the DM particles annihilate into one DM particle and another particle coupled to the standard model sector. We find that the kinetic equilibrium is maintained solely via semiannihilation until the last stage of the freeze-out. After the freeze-out, semiannihilation converts the mass deficit to the kinetic energy of DM, which leads to nontrivial evolution of the DM temperature. We argue that the DM temperature redshifts like radiation as long as the DM self interaction is efficient. We dub this novel temperature evolution as self heating. Notably, the structure formation is suppressed at subgalactic scales like keV-scale warm DM but with GeV-scale self-heating DM if the self-heating lasts roughly until the matter-radiation equality. The long duration of the self heating requires the large self-scattering cross section, which in turn flattens the DM density profile in inner halos. Consequently, self-heating DM can be a unified solution to apparent failures of cold DM to reproduce the observed subgalactic scale structure of the Universe. PMID- 29694187 TI - Current Flow in the Bubble and Stripe Phases. AB - The spontaneous ordering of spins and charges in geometric patterns is currently under scrutiny in a number of different material systems. A topic of particular interest is the interaction of such ordered phases with itinerant electrons driven by an externally imposed current. It not only provides important information on the charge ordering itself but potentially also allows manipulating the shape and symmetry of the underlying pattern if current flow is strong enough. Unfortunately, conventional transport methods probing the macroscopic resistance suffer from the fact that the voltage drop along the sample edges provides only indirect information on the bulk properties because a complex current distribution is elicited by the inhomogeneous ground state. Here, we promote the use of surface acoustic waves to study these broken-symmetry phases and specifically address the bubble and stripe phases emerging in high quality two-dimensional electron systems in GaAs/AlGaAs heterostructures as prototypical examples. When driving a unidirectional current, we find a surprising discrepancy between the sound propagation probing the bulk of the sample and the voltage drop along the sample edges. Our results prove that the current-induced modifications observed in resistive transport measurements are in fact a local phenomenon only, leaving the majority of the sample unaltered. More generally, our findings shed new light on the extent to which these ordered electron phases are impacted by an external current and underline the intrinsic advantages of acoustic measurements for the study of such inhomogeneous phases. PMID- 29694170 TI - Precision Measurement of the e^{+}e^{-}->Lambda_{c}^{+}Lambda[over -]_{c}^{-} Cross Section Near Threshold. AB - The cross section of the e^{+}e^{-}->Lambda_{c}^{+}Lambda[over -]_{c}^{-} process is measured with unprecedented precision using data collected with the BESIII detector at sqrt[s]=4574.5, 4580.0, 4590.0 and 4599.5 MeV. The nonzero cross section near the Lambda_{c}^{+}Lambda[over -]_{c}^{-} production threshold is cleared. At center-of-mass energies sqrt[s]=4574.5 and 4599.5 MeV, the higher statistics data enable us to measure the Lambda_{c} polar angle distributions. From these, the Lambda_{c} electric over magnetic form-factor ratios (|G_{E}/G_{M}|) are measured for the first time. They are found to be 1.14+/ 0.14+/-0.07 and 1.23+/-0.05+/-0.03, respectively, where the first uncertainties are statistical and the second are systematic. PMID- 29694190 TI - Local Real-Space View of the Achiral 1T-TiSe_{2} 2*2*2 Charge Density Wave. AB - The transition metal dichalcogenide 1T-TiSe_{2}-two-dimensional layered material undergoing a commensurate 2*2*2 charge density wave (CDW) transition with a weak periodic lattice distortion (PLD) below ~200 K. Scanning tunneling microscopy (STM) combined with intentionally introduced interstitial Ti atoms allows us to go beyond the usual spatial resolution of STM and to intimately probe the three dimensional character of the PLD. Furthermore, the inversion-symmetric achiral nature of the CDW in the z direction is revealed, contradicting the claimed existence of helical CDW stacking and associated chiral order. This study paves the way to a simultaneous real-space probing of both charge and structural reconstructions in CDW compounds. PMID- 29694189 TI - First Determination of the Level Structure of an sd-Shell Hypernucleus, _{Lambda}^{19}F. AB - We report on the first observation of gamma rays emitted from an sd-shell hypernucleus, _{Lambda}^{19}F. The energy spacing between the ground state doublet, 1/2^{+} and 3/2^{+} states, of _{Lambda}^{19}F is determined to be 315.5+/-0.4(stat)_{-0.5}^{+0.6}(syst) keV by measuring the gamma-ray energy of the M1(3/2^{+}->1/2^{+}) transition. In addition, three gamma-ray peaks are observed and assigned as E2(5/2^{+}->1/2^{+}), E1(1/2^{-}->1/2^{+}), and E1(1/2^{ }->3/2^{+}) transitions. The excitation energies of the 5/2^{+} and 1/2^{-} states are determined to be 895.2+/-0.3(stat)+/-0.5(syst) and 1265.6+/ 1.2(stat)_{-0.5}^{+0.7}(syst) keV, respectively. It is found that the ground state doublet spacing is well described by theoretical models based on existing s and p-shell hypernuclear data. PMID- 29694191 TI - New Gauss-Bonnet Black Holes with Curvature-Induced Scalarization in Extended Scalar-Tensor Theories. AB - In the present Letter, we consider a class of extended scalar-tensor-Gauss-Bonnet (ESTGB) theories for which the scalar degree of freedom is excited only in the extreme curvature regime. We show that in the mentioned class of ESTGB theories there exist new black-hole solutions that are formed by spontaneous scalarization of the Schwarzschild black holes in the extreme curvature regime. In this regime, below certain mass, the Schwarzschild solution becomes unstable and a new branch of solutions with a nontrivial scalar field bifurcates from the Schwarzschild one. As a matter of fact, more than one branch with a nontrivial scalar field can bifurcate at different masses, but only the first one is supposed to be stable. This effect is quite similar to the spontaneous scalarization of neutron stars. In contrast to the standard spontaneous scalarization of neutron stars, which is induced by the presence of matter, in our case, the scalarization is induced by the curvature of the spacetime. PMID- 29694192 TI - Mechanistic Insights into Human Brain Impact Dynamics through Modal Analysis. AB - Although concussion is one of the greatest health challenges today, our physical understanding of the cause of injury is limited. In this Letter, we simulated football head impacts in a finite element model and extracted the most dominant modal behavior of the brain's deformation. We showed that the brain's deformation is most sensitive in low frequency regimes close to 30 Hz, and discovered that for most subconcussive head impacts, the dynamics of brain deformation is dominated by a single global mode. In this Letter, we show the existence of localized modes and multimodal behavior in the brain as a hyperviscoelastic medium. This dynamical phenomenon leads to strain concentration patterns, particularly in deep brain regions, which is consistent with reported concussion pathology. PMID- 29694193 TI - Charge-Spin Correlation in van der Waals Antiferromagnet NiPS_{3}. AB - Strong charge-spin coupling is found in a layered transition-metal trichalcogenide NiPS_{3}, a van der Waals antiferromagnet, from studies of the electronic structure using several experimental and theoretical tools: spectroscopic ellipsometry, x-ray absorption, photoemission spectroscopy, and density functional calculations. NiPS_{3} displays an anomalous shift in the optical spectral weight at the magnetic ordering temperature, reflecting strong coupling between the electronic and magnetic structures. X-ray absorption, photoemission, and optical spectra support a self-doped ground state in NiPS_{3}. Our work demonstrates that layered transition-metal trichalcogenide magnets are useful candidates for the study of correlated-electron physics in two-dimensional magnetic materials. PMID- 29694188 TI - Search for Neutrinoless Double-beta Decay in ^{76}Ge with the Majorana Demonstrator. AB - The Majorana Collaboration is operating an array of high purity Ge detectors to search for neutrinoless double-beta decay in ^{76}Ge. The Majorana Demonstrator comprises 44.1 kg of Ge detectors (29.7 kg enriched in ^{76}Ge) split between two modules contained in a low background shield at the Sanford Underground Research Facility in Lead, South Dakota. Here we present results from data taken during construction, commissioning, and the start of full operations. We achieve unprecedented energy resolution of 2.5 keV FWHM at Q_{betabeta} and a very low background with no observed candidate events in 9.95 kg yr of enriched Ge exposure, resulting in a lower limit on the half-life of 1.9*10^{25} yr (90% C.L.). This result constrains the effective Majorana neutrino mass to below 240 520 meV, depending on the matrix elements used. In our experimental configuration with the lowest background, the background is 4.0_{-2.5}^{+3.1} counts/(FWHM t yr). PMID- 29694194 TI - Chaotic Dynamical Ferromagnetic Phase Induced by Nonequilibrium Quantum Fluctuations. AB - We investigate the robustness of a dynamical phase transition against quantum fluctuations by studying the impact of a ferromagnetic nearest-neighbor spin interaction in one spatial dimension on the nonequilibrium dynamical phase diagram of the fully connected quantum Ising model. In particular, we focus on the transient dynamics after a quantum quench and study the prethermal state via a combination of analytic time-dependent spin wave theory and numerical methods based on matrix product states. We find that, upon increasing the strength of the quantum fluctuations, the dynamical critical point fans out into a chaotic dynamical phase within which the asymptotic ordering is characterized by strong sensitivity to the parameters and initial conditions. We argue that such a phenomenon is general, as it arises from the impact of quantum fluctuations on the mean-field out of equilibrium dynamics of any system which exhibits a broken discrete symmetry. PMID- 29694195 TI - Electrical Spin Driving by g-Matrix Modulation in Spin-Orbit Qubits. AB - In a semiconductor spin qubit with sizable spin-orbit coupling, coherent spin rotations can be driven by a resonant gate-voltage modulation. Recently, we have exploited this opportunity in the experimental demonstration of a hole spin qubit in a silicon device. Here we investigate the underlying physical mechanisms by measuring the full angular dependence of the Rabi frequency, as well as the gate voltage dependence and anisotropy of the hole g factor. We show that a g-matrix formalism can simultaneously capture and discriminate the contributions of two mechanisms so far independently discussed in the literature: one associated with the modulation of the g factor, and measurable by Zeeman energy spectroscopy, the other not. Our approach has a general validity and can be applied to the analysis of other types of spin-orbit qubits. PMID- 29694196 TI - Spectrum Control through Discrete Frequency Diffraction in the Presence of Photonic Gauge Potentials. AB - By using optical phase modulators in a fiber-optical circuit, we theoretically and experimentally demonstrate large control over the spectrum of an impinging signal, which may evolve analogously to discrete diffraction in spatial waveguide arrays. The modulation phase acts as a photonic gauge potential in the frequency dimension, realizing efficient control of the central frequency and bandwidth of frequency combs. We experimentally achieve a 50 GHz frequency shift and threefold bandwidth expansion of an impinging comb, as well as the frequency analogue of various refraction phenomena, including negative refraction and perfect focusing in the frequency domain, both for discrete and continuous incident spectra. Our study paves a promising way towards versatile frequency management for optical communications and signal processing using time modulation schemes. PMID- 29694197 TI - Testing the Role of Recollision in N_{2}^{+} Air Lasing. AB - It has been known for many years that during filamentation of femtosecond light pulses in air, gain is observed on the B to X transition in N_{2}^{+}. While the gain mechanism remains unclear, it has been proposed that recollision, a process that is fundamental to much of strong field science, is critical for establishing gain. We probe this hypothesis by directly comparing the influence of the ellipticity of the pump light on gain in air filaments. Then, we decouple filamentation from gain by measuring the gain in a thin gas jet that we also use for high harmonic generation. The latter allows us to compare the dependence of the gain on the ellipticity of the pump with the dependence of the high harmonic signal on the ellipticity of the fundamental. We find that gain and harmonic generation have very different behavior in both filaments and in the jet. In fact, in a jet we even measure gain with circular polarization. Thus, we establish that recollision does not play a significant role in creating the inversion. PMID- 29694198 TI - Edge-Induced Shear Banding in Entangled Polymeric Fluids. AB - Despite decades of research, the question of whether solutions and melts of highly entangled polymers exhibit shear banding as their steady state response to a steadily imposed shear flow remains controversial. From a theoretical viewpoint, an important unanswered question is whether the underlying constitutive curve of shear stress sigma as a function of shear rate gamma[over ] (for states of homogeneous shear) is monotonic, or has a region of negative slope, dsigma/dgamma[over ]<0, which would trigger banding. Attempts to settle the question experimentally via velocimetry of the flow field inside the fluid are often confounded by an instability of the free surface where the sample meets the outside air, known as "edge fracture." Here we show by numerical simulation that in fact even only very modest edge disturbances-which are the precursor of full edge fracture but might well, in themselves, go unnoticed experimentally-can cause strong secondary flows in the form of shear bands that invade deep into the fluid bulk. Crucially, this is true even when the underlying constitutive curve is monotonically increasing, precluding true bulk shear banding in the absence of edge effects. PMID- 29694199 TI - Dipolar Spin Ice States with a Fast Monopole Hopping Rate in CdEr_{2}X_{4} (X=Se, S). AB - Excitations in a spin ice behave as magnetic monopoles, and their population and mobility control the dynamics of a spin ice at low temperature. CdEr_{2}Se_{4} is reported to have the Pauling entropy characteristic of a spin ice, but its dynamics are three orders of magnitude faster than the canonical spin ice Dy_{2}Ti_{2}O_{7}. In this Letter we use diffuse neutron scattering to show that both CdEr_{2}Se_{4} and CdEr_{2}S_{4} support a dipolar spin ice state-the host phase for a Coulomb gas of emergent magnetic monopoles. These Coulomb gases have similar parameters to those in Dy_{2}Ti_{2}O_{7}, i.e., dilute and uncorrelated, and so cannot provide three orders faster dynamics through a larger monopole population alone. We investigate the monopole dynamics using ac susceptometry and neutron spin echo spectroscopy, and verify the crystal electric field Hamiltonian of the Er^{3+} ions using inelastic neutron scattering. A quantitative calculation of the monopole hopping rate using our Coulomb gas and crystal electric field parameters shows that the fast dynamics in CdEr_{2}X_{4} (X=Se, S) are primarily due to much faster monopole hopping. Our work suggests that CdEr_{2}X_{4} offer the possibility to study alternative spin ice ground states and dynamics, with equilibration possible at much lower temperatures than the rare earth pyrochlore examples. PMID- 29694200 TI - Experimental Observation of Classical Dynamical Monodromy. AB - A Hamiltonian system is said to have nontrivial monodromy if its fundamental action-angle loops do not return to their initial topological state at the end of a closed circuit in angular momentum-energy space. This process has been predicted to have consequences which can be seen in dynamical systems, called dynamical monodromy. Using an apparatus consisting of a spherical pendulum subject to magnetic potentials and torques, we observe nontrivial monodromy by the associated topological change in the evolution of a loop of trajectories. PMID- 29694202 TI - Defect-Induced Hedgehog Polarization States in Multiferroics. AB - Continuous developments in nanotechnology require new approaches to materials synthesis that can produce novel functional structures. Here, we show that nanoscale defects, such as nonstoichiometric nanoregions (NSNRs), can act as nano building blocks for creating complex electrical polarization structures in the prototypical multiferroic BiFeO_{3}. An array of charged NSNRs are produced in BiFeO_{3} thin films by tuning the substrate temperature during film growth. Atomic-scale scanning transmission electron microscopy imaging reveals exotic polarization rotation patterns around these NSNRs. These polarization patterns resemble hedgehog or vortex topologies and can cause local changes in lattice symmetries leading to mixed-phase structures resembling the morphotropic phase boundary with high piezoelectricity. Phase-field simulations indicate that the observed polarization configurations are mainly induced by charged states at the NSNRs. Engineering defects thus may provide a new route for developing ferroelectric- or multiferroic-based nanodevices. PMID- 29694203 TI - Topological Maxwell Metal Bands in a Superconducting Qutrit. AB - We experimentally explore the topological Maxwell metal bands by mapping the momentum space of condensed-matter models to the tunable parameter space of superconducting quantum circuits. An exotic band structure that is effectively described by the spin-1 Maxwell equations is imaged. Threefold degenerate points dubbed Maxwell points are observed in the Maxwell metal bands. Moreover, we engineer and observe the topological phase transition from the topological Maxwell metal to a trivial insulator, and report the first experiment to measure the Chern numbers that are higher than one. PMID- 29694204 TI - Direct Visualization of Valence Electron Motion Using Strong-Field Photoelectron Holography. AB - Watching the valence electron move in molecules on its intrinsic timescale has been one of the central goals of attosecond science and it requires measurements with subatomic spatial and attosecond temporal resolutions. The time-resolved photoelectron holography in strong-field tunneling ionization holds the promise to access this realm. However, it remains to be a challenging task hitherto. Here we reveal how the information of valence electron motion is encoded in the hologram of the photoelectron momentum distribution (PEMD) and develop a novel approach of retrieval. As a demonstration, applying it to the PEMDs obtained by solving the time-dependent Schrodinger equation for the prototypical molecule H_{2}^{+}, the attosecond charge migration is directly visualized with picometer spatial and attosecond temporal resolutions. Our method represents a general approach for monitoring attosecond charge migration in more complex polyatomic and biological molecules, which is one of the central tasks in the newly emerging attosecond chemistry. PMID- 29694205 TI - Solvable Model for Dynamic Mass Transport in Disordered Geophysical Media. AB - We present an analytically solvable model for transport in geophysical materials on large length and time scales. It describes the flow of gas to a complicated absorbing boundary over long periods of time. We find a solution to this model using Green's function techniques, and apply the solution to three absorbing networks of increasing complexity. PMID- 29694206 TI - In situ X-Ray Diffraction of Shock-Compressed Fused Silica. AB - Because of its widespread applications in materials science and geophysics, SiO_{2} has been extensively examined under shock compression. Both quartz and fused silica transform through a so-called "mixed-phase region" to a dense, low compressibility high-pressure phase. For decades, the nature of this phase has been a subject of debate. Proposed structures include crystalline stishovite, another high-pressure crystalline phase, or a dense amorphous phase. Here we use plate-impact experiments and pulsed synchrotron x-ray diffraction to examine the structure of fused silica shock compressed to 63 GPa. In contrast to recent laser driven compression experiments, we find that fused silica adopts a dense amorphous structure at 34 GPa and below. When compressed above 34 GPa, fused silica transforms to untextured polycrystalline stishovite. Our results can explain previously ambiguous features of the shock-compression behavior of fused silica and are consistent with recent molecular dynamics simulations. Stishovite grain sizes are estimated to be ~5-30 nm for compression over a few hundred nanosecond time scale. PMID- 29694207 TI - Atomic Dynamics in Simple Liquid: de Gennes Narrowing Revisited. AB - The de Gennes narrowing phenomenon is frequently observed by neutron or x-ray scattering measurements of the dynamics of complex systems, such as liquids, proteins, colloids, and polymers. The characteristic slowing down of dynamics in the vicinity of the maximum of the total scattering intensity is commonly attributed to enhanced cooperativity. In this Letter, we present an alternative view on its origin through the examination of the time-dependent pair correlation function, the van Hove correlation function, for a model liquid in two, three, and four dimensions. We find that the relaxation time increases monotonically with distance and the dependence on distance varies with dimension. We propose a heuristic explanation of this dependence based on a simple geometrical model. This finding sheds new light on the interpretation of the de Gennes narrowing phenomenon and the alpha-relaxation time. PMID- 29694209 TI - Interacting Multiscale Acoustic Vortices as Coherent Excitations in Dust Acoustic Wave Turbulence. AB - In this work, using three-dimensional intermittent dust acoustic wave turbulence in a dusty plasma as a platform and multidimensional empirical mode decomposition into different-scale modes in the 2+1D spatiotemporal space, we demonstrate the experimental observation of the interacting multiscale acoustic vortices, winding around wormlike amplitude hole filaments coinciding with defect filaments, as the basic coherent excitations for acoustic-type wave turbulence. For different decomposed modes, the self-similar rescaled stretched exponential lifetime histograms of amplitude hole filaments, and the self-similar power spectra of dust density fluctuations, indicate that similar dynamical rules are followed over a wide range of scales. In addition to the intermode acoustic vortex pair generation, propagation, or annihilation, the intra- and intermode interactions of acoustic vortices with the same or opposite helicity, their entanglement and synchronization, are found to be the key dynamical processes in acoustic wave turbulence, akin to the interacting multiscale vortices around wormlike cores observed in hydrodynamic turbulence. PMID- 29694210 TI - Bright Soliton to Quantum Droplet Transition in a Mixture of Bose-Einstein Condensates. AB - Attractive Bose-Einstein condensates can host two types of macroscopic self-bound states: bright solitons and quantum droplets. Here, we investigate the connection between them with a Bose-Bose mixture confined in an optical waveguide. We show theoretically that, depending on atom number and interaction strength, solitons and droplets can be smoothly connected or remain distinct states coexisting only in a bistable region. We measure their spin composition, extract their density for a broad range of parameters, and map out the boundary of the region separating solitons from droplets. PMID- 29694208 TI - Demonstration of Single-Barium-Ion Sensitivity for Neutrinoless Double-Beta Decay Using Single-Molecule Fluorescence Imaging. AB - A new method to tag the barium daughter in the double-beta decay of ^{136}Xe is reported. Using the technique of single molecule fluorescent imaging (SMFI), individual barium dication (Ba^{++}) resolution at a transparent scanning surface is demonstrated. A single-step photobleach confirms the single ion interpretation. Individual ions are localized with superresolution (~2 nm), and detected with a statistical significance of 12.9sigma over backgrounds. This lays the foundation for a new and potentially background-free neutrinoless double-beta decay technology, based on SMFI coupled to high pressure xenon gas time projection chambers. PMID- 29694201 TI - First Results from CUORE: A Search for Lepton Number Violation via 0nubetabeta Decay of ^{130}Te. AB - The CUORE experiment, a ton-scale cryogenic bolometer array, recently began operation at the Laboratori Nazionali del Gran Sasso in Italy. The array represents a significant advancement in this technology, and in this work we apply it for the first time to a high-sensitivity search for a lepton-number violating process: ^{130}Te neutrinoless double-beta decay. Examining a total TeO_{2} exposure of 86.3 kg yr, characterized by an effective energy resolution of (7.7+/-0.5) keV FWHM and a background in the region of interest of (0.014+/ 0.002) counts/(keV kg yr), we find no evidence for neutrinoless double-beta decay. Including systematic uncertainties, we place a lower limit on the decay half-life of T_{1/2}^{0nu}(^{130}Te)>1.3*10^{25} yr (90% C.L.); the median statistical sensitivity of this search is 7.0*10^{24} yr. Combining this result with those of two earlier experiments, Cuoricino and CUORE-0, we find T_{1/2}^{0nu}(^{130}Te)>1.5*10^{25} yr (90% C.L.), which is the most stringent limit to date on this decay. Interpreting this result as a limit on the effective Majorana neutrino mass, we find m_{betabeta}<(110-520) meV, where the range reflects the nuclear matrix element estimates employed. PMID- 29694211 TI - Unsupervised Calculation of Free Energy Barriers in Large Crystalline Systems. AB - The calculation of free energy differences for thermally activated mechanisms in the solid state are routinely hindered by the inability to define a set of collective variable functions that accurately describe the mechanism under study. Even when possible, the requirement of descriptors for each mechanism under study prevents implementation of free energy calculations in the growing range of automated material simulation schemes. We provide a solution, deriving a path based, exact expression for free energy differences in the solid state which does not require a converged reaction pathway, collective variable functions, Gram matrix evaluations, or probability flux-based estimators. The generality and efficiency of our method is demonstrated on a complex transformation of C15 interstitial defects in iron and double kink nucleation on a screw dislocation in tungsten, the latter system consisting of more than 120 000 atoms. Both cases exhibit significant anharmonicity under experimentally relevant temperatures. PMID- 29694212 TI - Competing Charge Density Waves Probed by Nonlinear Transport and Noise in the Second and Third Landau Levels. AB - Charge density waves (CDWs) in the second and third Landau levels (LLs) are investigated by both nonlinear electronic transport and noise. The use of a Corbino geometry ensures that only bulk properties are probed, with no contribution from edge states. Sliding transport of CDWs is revealed by narrow band noise in reentrant quantum Hall states R2a and R2c of the second LL, as well as in pinned CDWs of the third LL. Competition between various phases-stripe, pinned CDW, or fractional quantum Hall liquid-in both LLs are clearly revealed by combining noise data with maps of conductivity versus magnetic field and bias voltage. PMID- 29694214 TI - Spontaneous Scalarization of Black Holes and Compact Stars from a Gauss-Bonnet Coupling. AB - We identify a class of scalar-tensor theories with coupling between the scalar and the Gauss-Bonnet invariant that exhibit spontaneous scalarization for both black holes and compact stars. In particular, these theories formally admit all of the stationary solutions of general relativity, but these are not dynamically preferred if certain conditions are satisfied. Remarkably, black holes exhibit scalarization if their mass lies within one of many narrow bands. We find evidence that scalarization can occur in neutron stars as well. PMID- 29694213 TI - Erratum: Fully Differential Vector-Boson-Fusion Higgs Production at Next-to-Next to-Leading Order [Phys. Rev. Lett. 115, 082002 (2015)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.115.082002. PMID- 29694215 TI - Scaling Law for Three-Body Collisions of Identical Fermions with p-Wave Interactions. AB - We experimentally confirmed the threshold behavior and scattering length scaling law of the three-body loss coefficients in an ultracold spin-polarized gas of ^{6}Li atoms near a p-wave Feshbach resonance. We measured the three-body loss coefficients as functions of temperature and scattering volume, and we found that the threshold law and the scattering length scaling law hold in limited temperature and magnetic field regions. We also found that the breakdown of the scaling laws is due to the emergence of the effective-range term. This work is an important first step towards a full understanding of the loss of identical fermions with p-wave interactions. PMID- 29694216 TI - Superchiral Light Generation on Degenerate Achiral Surfaces. AB - A novel route of superchiral near-field generation is demonstrated based on geometrically achiral systems supporting degenerate and spatially superimposed plasmonic modes. Such systems generate a single-handed chiral near field with simultaneous zero far-field circular dichroism. The phenomenon is theoretically elucidated with a rotating dipole model, which predicts a uniform single-handed chiral near field that flips handedness solely by reversing the handedness of the source. This property allows detection of pure background free molecular chirality through near-field light-matter interaction, which is experimentally demonstrated in the precise identification of both handedness of a chiral molecule on a single substrate with about four orders of magnitude enhancement in detection sensitivity compared to its conventional volumetric counterpart. PMID- 29694217 TI - Optical Chirality in Nonlinear Optics: Application to High Harmonic Generation. AB - Optical chirality (OC)-one of the fundamental quantities of electromagnetic fields-corresponds to the instantaneous chirality of light. It has been utilized for exploring chiral light-matter interactions in linear optics, but has not yet been applied to nonlinear processes. Motivated to explore the role of OC in the generation of helically polarized high-order harmonics and attosecond pulses, we first separate the OC of transversal and paraxial beams to polarization and orbital terms. We find that the polarization-associated OC of attosecond pulses corresponds approximately to that of the pump in the quasimonochromatic case, but not in the multichromatic pump cases. We associate this discrepancy with the fact that the polarization OC of multichromatic pumps vary rapidly in time along the optical cycle. Thus, we propose new quantities, noninstantaneous polarization associated OC, and time-scale-weighted polarization-associated OC, and show that these quantities link the chirality of multichromatic pumps and their generated attosecond pulses. The presented extension to OC theory should be useful for exploring various nonlinear chiral light-matter interactions. For example, it stimulates us to propose a tricircular pump for generation of highly elliptical attosecond pulses with a tunable ellipticity. PMID- 29694218 TI - Hydro-osmotic Instabilities in Active Membrane Tubes. AB - We study a membrane tube with unidirectional ion pumps driving an osmotic pressure difference. A pressure-driven peristaltic instability is identified, qualitatively distinct from similar tension-driven Rayleigh-type instabilities on membrane tubes. We discuss how this instability could be related to the function and biogenesis of membrane bound organelles, in particular, the contractile vacuole complex. The unusually long natural wavelength of this instability is in agreement with that observed in cells. PMID- 29694219 TI - Highly Charged Rydberg Ions from the Coulomb Explosion of Clusters. AB - Ion emission from a nanoplasma produced in the interaction of intense optical laser pulses with argon clusters is studied resolving simultaneously charge states and recoil energies. By applying appropriate static electric fields we observe that a significant fraction of the ions Ar^{q+} (q=1-7) has electrons with binding energies lower than 150 meV; i.e., n_{Ryd}>=15 levels are populated. Charge state changes observed on a MUs time scale can be attributed to electron emission due to autoionizing Rydberg states, indicating that high-l Rydberg levels are populated as well. The experiments support theoretical predictions that a significant fraction of delocalized electrons, which are bound with hundreds of eV to the nanoplasma after the laser exposure, fill up meV bound ion states in the adiabatic expansion. We expect the process to be relevant for the long-term evolution of expanding laser-induced dense plasmas in general. PMID- 29694220 TI - Publisher's Note: 94 beta-Decay Half-Lives of Neutron-Rich _{55}Cs to _{67}Ho: Experimental Feedback and Evaluation of the r-Process Rare-Earth Peak Formation [Phys. Rev. Lett. 118, 072701 (2017)]. AB - This corrects the article DOI: 10.1103/PhysRevLett.118.072701. PMID- 29694221 TI - Distance-Dependent Sign Reversal in the Casimir-Lifshitz Torque. AB - The Casimir-Lifshitz torque between two biaxially polarizable anisotropic planar slabs is shown to exhibit a nontrivial sign reversal in its rotational sense. The critical distance a_{c} between the slabs that marks this reversal is characterized by the frequency omega_{c}~c/2a_{c} at which the in-planar polarizabilities along the two principal axes are equal. The two materials seek to align their principal axes of polarizabilities in one direction below a_{c}, while above a_{c} their axes try to align rotated perpendicular relative to their previous minimum energy orientation. The sign reversal disappears in the nonretarded limit. Our perturbative result, derived for the case when the differences in the relative polarizabilities are small, matches excellently with the exact theory for uniaxial materials. We illustrate our results for black phosphorus and phosphorene. PMID- 29694222 TI - Quantum Forces from Dark Matter and Where to Find Them. AB - We observe that sub-GeV dark matter (DM) induces Casimir-Polder forces between nucleons that can be accessed by experiments from nuclear to molecular scales. We calculate the nucleon-nucleon potentials arising in the DM effective theory and note that their main features are fixed by dimensional analysis and the optical theorem. Molecular spectroscopy and neutron scattering turn out be DM search experiments and are found to be complementary to nucleon-based DM direct detection. Existing data set limits on DM with mass up to ~3-50 MeV and with effective interaction up to the O(10-100) MeV scale, constraining a region typically difficult to reach for other experiments. PMID- 29694223 TI - Dielectric Modulation of Ion Transport near Interfaces. AB - Ion mobility and ionic conductance in nanodevices are known to deviate from bulk behavior, a phenomenon often attributed to surface effects. We demonstrate that dielectric mismatch between the electrolyte and the surface can qualitatively alter ionic transport in a counterintuitive manner. Instead of following the polarization-induced modulation of the concentration profile, mobility is enhanced or reduced by changes in the ionic atmosphere near the interface and affected by a polarization force parallel to the surface. In addition to revealing this mechanism, we explore the effect of salt concentration and electrostatic coupling. PMID- 29694224 TI - Coherent Spin Amplification Using a Beam Splitter. AB - We report spin amplification using a capacitive beam splitter in n-type GaAs where the spin polarization is monitored via a transverse electron focusing measurement. It is shown that partially spin-polarized current injected by the emitter can be precisely controlled, and the spin polarization associated with it can be amplified by the beam splitter, such that a considerably high spin polarization of around 50% can be obtained. Additionally, the spin remains coherent as shown by the observation of quantum interference. Our results illustrate that spin-polarization amplification can be achieved in materials without strong spin-orbit interaction. PMID- 29694225 TI - Derivation of the Boltzmann Equation for Financial Brownian Motion: Direct Observation of the Collective Motion of High-Frequency Traders. AB - A microscopic model is established for financial Brownian motion from the direct observation of the dynamics of high-frequency traders (HFTs) in a foreign exchange market. Furthermore, a theoretical framework parallel to molecular kinetic theory is developed for the systematic description of the financial market from microscopic dynamics of HFTs. We report first on a microscopic empirical law of traders' trend-following behavior by tracking the trajectories of all individuals, which quantifies the collective motion of HFTs but has not been captured in conventional order-book models. We next introduce the corresponding microscopic model of HFTs and present its theoretical solution paralleling molecular kinetic theory: Boltzmann-like and Langevin-like equations are derived from the microscopic dynamics via the Bogoliubov-Born-Green-Kirkwood Yvon hierarchy. Our model is the first microscopic model that has been directly validated through data analysis of the microscopic dynamics, exhibiting quantitative agreements with mesoscopic and macroscopic empirical results. PMID- 29694226 TI - Modified Kelvin Equations for Capillary Condensation in Narrow and Wide Grooves. AB - We consider the location and order of capillary condensation transitions occurring in deep grooves of width L and depth D. For walls that are completely wet by liquid (contact angle theta=0) the transition is continuous and its location is not sensitive to the depth of the groove. However, for walls that are partially wet by liquid, where the transition is first order, we show that the pressure at which it occurs is determined by a modified Kelvin equation characterized by an edge contact angle theta_{E} describing the shape of the meniscus formed at the top of the groove. The dependence of theta_{E} on the groove depth D relies, in turn, on whether corner menisci are formed at the bottom of the groove in the low density gaslike phase. While for macroscopically wide grooves these are always present when theta<45 degrees we argue that their formation is inhibited in narrow grooves. This has a number of implications including that the local pinning of the meniscus and location of the condensation transition is different depending on whether the contact angle is greater or less than a universal value theta^{*}~31 degrees . Our arguments are supported by detailed microscopic density functional theory calculations that show that the modified Kelvin equation remains highly accurate even when L and D are of the order of tens of molecular diameters. PMID- 29694227 TI - gamma-Ray Generation from Plasma Wakefield Resonant Wiggler. AB - A flexible gamma-ray radiation source based on the resonant laser-plasma wakefield wiggler is proposed. The wiggler is achieved by inducing centroid oscillations of a short laser pulse in a plasma channel. Electrons (self )injected in such a wakefield experience both oscillations due to the transverse electric fields and energy gain due to the longitudinal electric field. The oscillations are significantly enhanced when the laser pulse centroid oscillations are in resonance with the electron betatron oscillations, extending the radiation spectrum to the gamma-ray range. The polarization of the radiation can be easily controlled by adjusting the injection of the laser pulse into the plasma channel. PMID- 29694228 TI - Evasion of No-Hair Theorems and Novel Black-Hole Solutions in Gauss-Bonnet Theories. AB - We consider a general Einstein-scalar-Gauss-Bonnet theory with a coupling function f(phi). We demonstrate that black-hole solutions appear as a generic feature of this theory since a regular horizon and an asymptotically flat solution may be easily constructed under mild assumptions for f(phi). We show that the existing no-hair theorems are easily evaded, and a large number of regular black-hole solutions with scalar hair are then presented for a plethora of coupling functions f(phi). PMID- 29694229 TI - Neutron Spin Resonance in the 112-Type Iron-Based Superconductor. AB - We use inelastic neutron scattering to study the low-energy spin excitations of the 112-type iron pnictide Ca_{0.82}La_{0.18}Fe_{0.96}Ni_{0.04}As_{2} with bulk superconductivity below T_{c}=22 K. A two-dimensional spin resonance mode is found around E=11 meV, where the resonance energy is almost temperature independent and linearly scales with T_{c} along with other iron-based superconductors. Polarized neutron analysis reveals the resonance is nearly isotropic in spin space without any L modulations. Because of the unique monoclinic structure with additional zigzag arsenic chains, the As 4p orbitals contribute to a three-dimensional hole pocket around the Gamma point and an extra electron pocket at the X point. Our results suggest that the energy and momentum distribution of the spin resonance does not directly respond to the k_{z} dependence of the fermiology, and the spin resonance intrinsically is a spin-1 mode from singlet-triplet excitations of the Cooper pairs in the case of weak spin-orbital coupling. PMID- 29694230 TI - Controlled Viscosity in Dense Granular Materials. AB - We experimentally investigate the fluidization of a granular material subject to mechanical vibrations by monitoring the angular velocity of a vane suspended in the medium and driven by an external motor. On increasing the frequency, we observe a reentrant transition, as a jammed system first enters a fluidized state, where the vane rotates with high constant velocity, and then returns to a frictional state, where the vane velocity is much lower. While the fluidization frequency is material independent, the viscosity recovery frequency shows a clear dependence on the material that we rationalize by relating this frequency to the balance between dissipative and inertial forces in the system. Molecular dynamics simulations well reproduce the experimental data, confirming the suggested theoretical picture. PMID- 29694231 TI - Shedding First Light on the Alveolar Epithelial Glycocalyx. PMID- 29694107 TI - Measurement of the Splitting Function in pp and Pb-Pb Collisions at sqrt[s_{NN}]=5.02 TeV. AB - Data from heavy ion collisions suggest that the evolution of a parton shower is modified by interactions with the color charges in the dense partonic medium created in these collisions, but it is not known where in the shower evolution the modifications occur. The momentum ratio of the two leading partons, resolved as subjets, provides information about the parton shower evolution. This substructure observable, known as the splitting function, reflects the process of a parton splitting into two other partons and has been measured for jets with transverse momentum between 140 and 500 GeV, in pp and PbPb collisions at a center-of-mass energy of 5.02 TeV per nucleon pair. In central PbPb collisions, the splitting function indicates a more unbalanced momentum ratio, compared to peripheral PbPb and pp collisions.. The measurements are compared to various predictions from event generators and analytical calculations. PMID- 29694232 TI - Loss of myogenic potential and fusion capacity of muscle stem cells isolated from contractured muscle in children with cerebral palsy. AB - Cerebral palsy (CP) is the most common cause of pediatric neurodevelopmental and physical disability in the United States. It is defined as a group of motor disorders caused by a nonprogressive perinatal insult to the brain. Although the brain lesion is nonprogressive, there is a progressive, lifelong impact on skeletal muscles, which are shorter, spastic, and may develop debilitating contractures. Satellite cells are resident muscle stem cells that are indispensable for postnatal growth and regeneration of skeletal muscles. Here we measured the myogenic potential of satellite cells isolated from contractured muscles in children with CP. When compared with typically developing (TD) children, satellite cell-derived myoblasts from CP differentiated more slowly (slope: 0.013 (SD 0.013) CP vs. 0.091 (SD 0.024) TD over 24 h, P < 0.001) and fused less (fusion index: 21.3 (SD 8.6) CP vs. 81.3 (SD 7.7) TD after 48 h, P < 0.001) after exposure to low-serum conditions that stimulated myotube formation. This impairment was associated with downregulation of several markers important for myoblast fusion and myotube formation, including DNA methylation-dependent inhibition of promyogenic integrin-beta 1D (ITGB1D) protein expression levels ( 50% at 42 h), and ~25% loss of integrin-mediated focal adhesion kinase phosphorylation. The cytidine analog 5-Azacytidine (5-AZA), a demethylating agent, restored ITGB1D levels and promoted myogenesis in CP cultures. Our data demonstrate that muscle contractures in CP are associated with loss of satellite cell myogenic potential that is dependent on DNA methylation patterns affecting expression of genetic programs associated with muscle stem cell differentiation and muscle fiber formation. PMID- 29694233 TI - Functional features of the "finger" domain of the DEG/ENaC channels MEC-4 and UNC 8. AB - UNC-8 and MEC-4 are two members of the degenerin/epithelial Na+ channel (DEG/ENaC) family of voltage-independent Na+ channels that share a high degree of sequence homology and functional similarity. For example, both can be hyperactivated by genetic mutations [UNC-8(d) and MEC-4(d)] that induce neuronal death by necrosis. Both depend in vivo on chaperone protein MEC-6 for function, as demonstrated by the finding that neuronal death induced by hyperactive UNC-8 and MEC-4 channels is prevented by null mutations in mec-6. UNC-8 and MEC-4 differ functionally in three major ways: 1) MEC-4 is calcium permeable, whereas UNC-8 is not; 2) UNC-8, but not MEC-4, is blocked by extracellular calcium and magnesium in the micromolar range; and 3) MEC-6 increases the number of MEC-4 channels at the cell surface in oocytes but does not have this effect on UNC-8. We previously reported that Ca2+permeability of MEC-4 is conferred by the second transmembrane domain. We show here that the extracellular "finger" domain of UNC 8 is sufficient to mediate inhibition by divalent cations and that regulation by MEC-6 also depends on this region. Thus, our work confirms that the finger domain houses residues involved in gating of this channel class and shows for the first time that the finger domain also mediates regulation by chaperone protein MEC-6. Given that the finger domain is the most divergent region across the DEG/ENaC family, we speculate that it influences channel trafficking and function in a unique manner depending on the channel subunit. PMID- 29694234 TI - Expanding the therapeutic index of radiation therapy by normal tissue protection. AB - Normal tissue damages induced by radiation therapy remain dose-limiting factors in radiation oncology and this is still true despite recent advances in treatment planning and delivery of image-guided radiation therapy. Additionally, as the number of long-term cancer survivors increases, unacceptable complications emerge and dramatically reduce the patients' quality of life. This means that patients and clinicians expect discovery of new options for the therapeutic management of radiation-induced complications. Over the past four decades, research has enhanced our understanding of the pathophysiological, cellular and molecular processes governing normal tissue toxicity. Those processes are complex and involve the cross-talk between the various cells of a tissue, including fibroblasts, endothelial, immune and epithelial cells as well as soluble paracrine factors including growth factors and proteases. We will review the translatable pharmacological approaches that have been developed to prevent, mitigate, or reverse radiation injuries based upon the targeting of cellular and signalling pathways. We will summarize the different steps of the research strategy, from the definition of initial biological hypotheses to preclinical studies and clinical translation. We will also see how novel research and therapeutic hypotheses emerge along the way as well as briefly highlight innovative approaches based upon novel radiotherapy delivery procedures. PMID- 29694237 TI - Diagnosis and Management of Patients with Obstructive Sleep Apnea in Primary Care. Ready or Not? PMID- 29694235 TI - Observe the Latch: A Missing Link in Physician Training! PMID- 29694238 TI - How Many FOXs Are There on The Road to Pulmonary Hypertension? PMID- 29694236 TI - Outcomes of Video-Assisted Teaching for Latching in Postpartum Women: A Randomized Controlled Trial. AB - BACKGROUND: Latching is an important process of breastfeeding and should be taught and practiced by the postpartum mother. OBJECTIVE: The objective is to compare latching outcomes between video-assisted and routine teaching methods among postpartum women. MATERIALS AND METHODS: A randomized controlled trial was conducted. Postpartum women who had deliveries without complications were randomized into two groups: 14 cases in the video-assisted teaching group and 14 cases in a routine teaching group. In the first group, the mothers were taught breastfeeding benefits, latching methods, and breastfeeding positions and practiced breastfeeding in a controlled setting for a 30-minute period and watched a 6-minute video with consistent content. In the second group, the mothers were taught a normal 30-minute period and then practiced breastfeeding. In both groups, Latching on, Audible swallowing, the Type of nipples, Comfort, and Help (LATCH) scores were assessed at 24-32 and 48-56 hours after the breastfeeding teaching modals. Demographic data and LATCH scores were collected and analyzed. RESULTS: There were no statistically significant differences in the mothers' ages, occupations, marital status, religion, education, income, infants' gestational age, body mass index, nipple length, route of delivery, and time to first latching between the video-assisted and routine breastfeeding teaching groups. First and second LATCH score assessments had shown no significant differences between both breastfeeding teaching groups. CONCLUSION: The video assisted breastfeeding teaching did not improve latching outcomes when it was compared with routine teaching. PMID- 29694240 TI - Analysis of a Novel pncA Mutation for Susceptibility to Pyrazinamide Therapy. PMID- 29694239 TI - Nausea and vomiting after exposure to non-ionic contrast media: incidence and risk factors focusing on preparatory fasting. AB - OBJECTIVE: To prospectively evaluate the incidence of nausea and vomiting after exposure to non-ionic iodinated contrast media (ICM), and to identify potential risk factors, with a focus on fasting duration for solid food and fluids, separately. METHODS: From January to March 2017, 1175 patients (605 males, 570 females; median age, 60 years; range, 20-91 years) undergoing ICM-enhanced CT were included in this study. Patients received instructions for a 6 h preparatory fast from solid food. Nausea and vomiting after ICM exposure were assessed on a 3 point scale (mild, moderate, severe). Patients' characteristics and the fasting duration were evaluated to identify risk factors using logistic regression analysis. RESULTS: Of the 1175 patients, 34 [2.9%; 95% confidence interval (CI) (2.0-4.0)] experienced mild nausea. No patients experienced vomiting [95% CI (0.0000-0.0005)]. 1173 (99.8%) carried out a 6 h fast, and the median fasting durations were 14 h for solid food (interquartile range, 12.5-15.5 h) and 11 h for fluid (interquartile range, 0-13.5 h), respectively. Fasting durations for solid food and fluids were not associated with nausea on univariate regression analyses (p = 0.282-1.000 and 0.146-1.000, respectively). Multivariate regression analysis revealed that a history of drug hypersensitivity [odds ratio = 4.33; 95% CI (1.85-17.52); p = 0.039] was independent risk factors for nausea, whereas iobitridol was less nauseous [odds ratio = 0.32; 95% CI (0.11-0.90); p = 0.032]. CONCLUSION: Mild nausea occurred in 2.9% of patients and none vomited in our study population with a 6 h preparatory fast from solid food. Many patients underwent excessive fasting for fluids as well as solid food and their fasting durations were not associated with nausea. Advances in knowledge: We firstly evaluated fasting durations for solid food and fluids, and their impacts on vomiting or nausea after ICM exposure with an instruction of 6 h preparatory fast for solid food: many patients underwent excessive fasting for fluids and the fasting duration was unrelated to nausea. PMID- 29694241 TI - A 1.5-Year Follow-Up of Parent Training and Atomoxetine for Attention Deficit/Hyperactivity Disorder Symptoms and Noncompliant/Disruptive Behavior in Autism. AB - OBJECTIVE: To examine status of children with autism spectrum disorder (ASD) 10 months after a 34-week clinical trial of atomoxetine (ATX) and parent training (PT). METHODS: In a 2 * 2 design, 128 children with ASD and attention deficit/hyperactivity disorder (ADHD) were randomly assigned ATX, PT+placebo, PT+ATX, or placebo alone. PT was weekly for 10 weeks, and then monthly. ATX/placebo was titrated over 6 weeks [<=1.8 mg/kg/d], and then maintained until week 10. Responders continued to week 34 or nonresponse. Placebo nonresponders had a 10-week ATX open trial; ATX nonresponders were treated clinically. All continued to week 34. With no further treatment from the study, all were invited to follow-up (FU) at 1.5 years postbaseline; 94 (73%) participated. Changes from Week 34 to FU and from baseline to FU were tested by one-way analysis of variance or chi-squared test. PT versus no PT was tested by chi-squared test, Fisher's exact test, Welch's t-test, Student's t-test, and Mann-Whitney's U test. RESULTS: For the whole sample, the primary outcomes (parent-rated ADHD on the Swanson, Nolan, and Pelham [SNAP] scale and noncompliance on the Home Situations Questionnaire [HSQ]) deteriorated mildly from week 34 to FU, but were still substantially better than baseline (SNAP: t = 12.177, df = 93, p < 0.001; HSQ: t = 8.999, df = 93, p < 0.001). On the SNAP, 61% improved >=30% from baseline (67% did at week 34); on noncompliance, 56% improved >=30% from baseline (77% did at week 34). Outcomes with PT were not significantly better than without PT (SNAP p = 0.30; HSQ p = 0.27). Originally assigned treatment groups did not differ significantly. Only 34% still took ATX; 27% were taking stimulants; and 25% took no medication. CONCLUSIONS: The majority retained their 34-week end-of-study improvement 10 months later, even though most participants stopped ATX. For some children, ATX continuation may not be necessary for continued benefit or other drugs may be necessary. Cautious individual clinical experimentation may be justified. Twelve sessions of PT made little long-term difference. ClinicalTrials.gov Identifier: Atomoxetine, Placebo and Parent Management Training in Autism (Strattera) (NCT00844753). PMID- 29694242 TI - Endostar, a Modified Endostatin Induces Vascular Normalization to Improve Chemotherapy Efficacy Through Suppression of Src Signaling Pathway. AB - Pathological angiogenesis can be a significant barrier to effective cancer therapy. Recent evidence suggests that Endostar may induce vascular normalization, thereby improving tumor perfusion and systemic chemotherapy. However, the molecular mechanism by which Endostar makes chemotherapy more effective remains to be fully elucidated. In this study, established 4T1 breast tumor-bearing animals treated with Endostar were evaluated at serial time points for treatment-associated changes in vascular architecture. As a result, Endostar induced a morphologically and functionally normalized vascular network. Combined Endostar and doxorubicin exhibited significant antitumor (34% of control size) and antimetastatic effects (29% of control metastatic nodules) in vivo. Finally, a two-dimensional gel electrophoresis and MALDIQ-TOF MS/MS-based proteomics approach was used to identify differentially expressed proteins involved in vascular normalization during Endostar administration. SRCIN1 was detected as one of the most significantly increased proteins. SRCIN1 is a novel Src-binding protein that regulates Src activation through C-terminal Src kinase, and attenuated Src activation during Endostar treatment was further confirmed by immunoblotting. Collectively, these data provided a molecular basis for vascular normalization, which were associated with the observed synergistic effect in vivo. PMID- 29694243 TI - Budget impact analysis of long-acting injectable aripiprazole once-monthly 400 mg in bipolar I disorder in the USA. AB - AIM: To estimate the budget impact (BI) of introducing aripiprazole once-monthly 400 mg/300 mg (AOM 400) in the maintenance monotherapy treatment of bipolar I disorder versus long-acting injectables, oral antipsychotics and best supportive care. METHODS: A BI model was developed from a US-payer perspective using treatment-related, hospitalization and adverse event management cost estimates for a hypothetical 1,000,000-member health plan over a 5-year period. RESULTS: Market share of AOM 400 was predicted to increase from 0.6% in Year 1 (current scenario) to 1.3% in Year 5 (predicted scenario), with predicted increases for paliperidone palmitate, asenapine and cariprazine. Treatment-related costs explained the BI increase, while adverse event and hospitalization costs were reduced. The per member per month incremental cost ranged from US$0.06 to US$0.26 in Years 1-5. The largest increases were predicted for paliperidone palmitate. CONCLUSION: As market shares of atypical antipsychotics are predicted to increase, payers may wish to re-evaluate their use. PMID- 29694244 TI - Cost-effectiveness of long-acting injectable aripiprazole once-monthly 400 mg in bipolar I disorder in the USA. AB - AIM: To evaluate the cost-effectiveness of aripiprazole once-monthly 400/300 mg (AOM 400) in maintenance monotherapy treatment of bipolar I disorder (BP-I). METHODS: A de novo lifetime Markov model was developed for BP-I using available data for AOM 400 and relevant comparators. Base-case analysis considered costs and outcomes from the US payer perspective. RESULTS: The cost per quality adjusted life year gained with AOM 400 versus comparators ranged from US$2007 versus oral asenapine to dominance (i.e., lower cost with quality-adjusted life gain) versus long-acting injectable risperidone, paliperidone palmitate, oral cariprazine and best supportive care. Patients treated with AOM 400 were estimated to have fewer mood episodes and hospitalizations per patient (5.37) than comparators (6.33, asenapine or cariprazine; 6.54, risperidone long-acting injectable; 7.64, paliperidone palmitate; and 8.93, best supportive care). Sensitivity analyses showed results were robust to parameter uncertainty. CONCLUSION: AOM 400 may be considered cost effective in the maintenance monotherapy treatment of BP-I in adults. PMID- 29694245 TI - Computational Analysis of Cell Dynamics in Videos with Hierarchical-Pooled Deep Convolutional Features. AB - Computational analysis of cellular appearance and its dynamics is used to investigate physiological properties of cells in biomedical research. In consideration of the great success of deep learning in video analysis, we first introduce two-stream convolutional networks (ConvNets) to automatically learn the biologically meaningful dynamics from raw live-cell videos. However, the two stream ConvNets lack the ability to capture long-range video evolution. Therefore, a novel hierarchical pooling strategy is proposed to model the cell dynamics in a whole video, which is composed of trajectory pooling for short-term dynamics and rank pooling for long-range ones. Experimental results demonstrate that the proposed pipeline effectively captures the spatiotemporal dynamics from the raw live-cell videos and outperforms existing methods on our cell video database. PMID- 29694246 TI - Development and Validation of RAPID: A Patient-Specific Monte Carlo Three Dimensional Internal Dosimetry Platform. AB - This work describes the development and validation of a patient-specific Monte Carlo internal dosimetry platform called RAPID (Radiopharmaceutical Assessment Platform for Internal Dosimetry). RAPID utilizes serial PET/CT or SPECT/CT images to calculate voxelized three-dimensional (3D) internal dose distributions with the Monte Carlo code Geant4. RAPID's dosimetry calculations were benchmarked against previously published S-values and specific absorbed fractions (SAFs) calculated for monoenergetic photon and electron sources within the Zubal phantom and for S-values calculated for a variety of radionuclides within spherical tumor phantoms with sizes ranging from 1 to 1000 g. The majority of the S-values and SAFs calculated in the Zubal Phantom were within 5% of the previously published values with the exception of a few 10 keV photon SAFs that agreed within 10%, and one value within 16%. The S-values calculated in the spherical tumor phantoms agreed within 2% for 177Lu, 131I, 125I, 18F, and 64Cu, within 3.5% for 211At and 213Bi, within 6.5% for 153Sm, 111In, 89Zr, and 223Ra, and within 9% for 90Y, 68Ga, and 124I. In conclusion, RAPID is capable of calculating accurate internal dosimetry at the voxel-level for a wide variety of radionuclides and could be a useful tool for calculating patient-specific 3D dose distributions. PMID- 29694247 TI - Protein half-life determines expression of proteostatic networks in podocyte differentiation. AB - Podocytes are highly specialized, epithelial, postmitotic cells, which maintain the renal filtration barrier. When adapting to considerable metabolic and mechanical stress, podocytes need to accurately maintain their proteome. Immortalized podocyte cell lines are a widely used model for studying podocyte biology in health and disease in vitro. In this study, we performed a comprehensive proteomic analysis of the cultured human podocyte proteome in both proliferative and differentiated conditions at a depth of >7000 proteins. Similar to mouse podocytes, human podocyte differentiation involved a shift in proteostasis: undifferentiated podocytes have high expression of proteasomal proteins, whereas differentiated podocytes have high expression of lysosomal proteins. Additional analyses with pulsed stable-isotope labeling by amino acids in cell culture and protein degradation assays determined protein dynamics and half-lives. These studies unraveled a globally increased stability of proteins in differentiated podocytes. Mitochondrial, cytoskeletal, and membrane proteins were stabilized, particularly in differentiated podocytes. Importantly, protein half lives strongly contributed to protein abundance in each state. These data suggest that regulation of protein turnover of particular cellular functions determines podocyte differentiation, a paradigm involving mitophagy and, potentially, of importance in conditions of increased podocyte stress and damage.-Schroeter, C. B., Koehler, S., Kann, M., Schermer, B., Benzing, T., Brinkkoetter, P. T., Rinschen, M. M. Protein half-life determines expression of proteostatic networks in podocyte differentiation. PMID- 29694248 TI - ADAR1 attenuates allogeneic graft rejection by suppressing miR-21 biogenesis in macrophages and promoting M2 polarization. AB - ADAR1 (adenosine deaminase acting on double-stranded RNA 1) is an RNA-editing enzyme that mediates adenosine-to-inosine RNA editing events, an important post transcriptional modification mechanism that can alter the coding properties of mRNA or regulate microRNA biogenesis. ADAR1 also regulates the innate immune response. Here, we have demonstrated that ADAR1 expression increased in LPS stimulated macrophages. Silencing ADAR1 by using small interfering RNA in macrophages resulted in the pronounced polarization of macrophages to M1, whereas ADAR1 overexpression promoted M2 polarization, which indicated that ADAR1 can inhibit macrophage hyperpolarization and prevent immune hyperactivity. The RNA RNP immunoprecipitation binding assay demonstrated a direct interaction between ADAR1 and miR-21 precursor. Significant up-regulation in IL-10 and down regulation in miR-21 were observed in ADAR1-overexpressing macrophages. We evaluated miR-21 target mRNAs and macrophage polarization signaling pathways and found that forkhead box protein O1 (Foxo1) was up-regulated in cells that overexpressed ADAR1. In a mouse allogeneic skin transplantation model, grafts in the ADAR1-overexpressed group survived longer and suffered less immune cell infiltration. In ADAR1-overexpressed recipients, splenic macrophages were significantly polarized to M2, and levels of sera IL-10 were markedly higher than those in the control group. In summary, ADAR1 modulates macrophage M2 polarization via the ADAR1-miR-21-Foxo1-IL-10 axis, thereby suppressing allogeneic graft rejection.-Li, J., Xie, J., Liu, S., Li, X., Zhang, D., Wang, X., Jiang, J., Hu, W., Zhang, Y., Jin, B., Zhuang, R., Yin, W. ADAR1 attenuates allogeneic graft rejection by suppressing miR-21 biogenesis in macrophages and promoting M2 polarization. PMID- 29694249 TI - Olmesartan combined with renal denervation reduces blood pressure in association with sympatho-inhibitory and aldosterone-reducing effects in hypertensive mice with chronic kidney disease. AB - BACKGROUND: Augmented sympathetic nerve activity (SNA) and renin-angiotensin aldosterone system (RAAS) activity are involved in the pathogenesis of hypertension (HT) accompanied by chronic kidney disease (CKD). Oxidative stress in the hypothalamus increases SNA in HT. Administration of an angiotensin IotaIota receptor blocker (olmesartan; OLM) or renal denervation (RDN) exerts an antihypertensive effect in HT with CKD; however, the precise mechanisms of the combination therapy are not fully elucidated. In the present study, we examined whether combination therapy with OLM and RDN reduces both SNA by decreasing oxidative stress in the hypothalamus and RAAS activity in hypertensive mice with CKD. METHODS AND RESULTS: In 5/6-nephrectomized ICR-mice (Nx-mice) at 4-weeks after nephrectomy, systolic blood pressure (SBP) was significantly increased, accompanied by increased SNA and albuminuria compared with control-mice. Nx-mice were orally administered OLM, vehicle, or underwent RDN during OLM administration, and divided into Nx-OLM, Nx-VEH, and Nx-OLM/RDN groups, respectively. In Nx-OLM and Nx-OLM/RDN compared with Nx-VEH at 8-weeks after treatment, SBP was significantly decreased and both SNA and oxidative stress levels in the hypothalamus were significantly suppressed, without worsened creatinine clearance. In Nx-OLM and Nx-OLM/RDN compared with Nx-VEH, albuminuria was also suppressed, and the heart per body weight was decreased. In Nx-OLM/RDN, but not in Nx-OLM, the plasma aldosterone concentration was significantly decreased compared with Nx-VEH. CONCLUSION: These findings suggest that combination therapy with OLM/RDN has antihypertensive effects in association with suppressing SNA by reducing oxidative stress in the hypothalamus and the plasma aldosterone concentration in hypertensive mice with CKD. PMID- 29694250 TI - Hypertension, risk factors and coronary artery stenosis: A case-control study. AB - Although hypertension is introduced as a major risk factor for cardiovascular diseases (CVDs), our knowledge about the nature of the association is hindered. The aim of this study was to assess the concurrent associations of several factors including serologic, anthropometric and coronary artery stenosis (CAS) with blood pressure. This is a case-control study on 163 hypertensive patients (SBP > 140 mmHg or DBP > 80 mmHg) and 227 healthy participants. All participants underwent angiography due to classic symptoms of CVDs. Controlling for other study variables, significant associations between CAS (OR yes/no = 1.99, 95%CI: 1.18-3.34 P = 0.006), BMI (kg/m2) (OR = 1.08, 95%CI: 1.03-1.14, P = 0.002) and age (year) (OR = 1.03, 95%CI = 1.005-1.05, p = 0.01) with hypertension were found. However, according to the results of the stratified analysis, no such associations were found among those with significant CAS. BMI and age were the only significant predictors of hypertension among participants with no CAS. Abdominal obesity was not remained in the final model regardless of the presence or absence of stenosis. As expected, stenosis itself was significantly associated with hypertension. This study suggested that BMI and age are the most powerful predictors of hypertension among those without CAS. As the result, it can be concluded that CAS alters the association between several factors and hypertension. PMID- 29694251 TI - Cardiovascular risk after preeclampsia: The effect of communicating risk factors on intended healthy behavior. AB - OBJECTIVE: We studied the effect of communicating cardiovascular risk factors on intended healthy behavior in women with a history of preeclampsia or uncomplicated pregnancy. METHODS: Intention for healthy behavior was assessed before and after cardiovascular risk assessment. Changes were calculated for women with and without cardiovascular risk factors. RESULTS: In women with cardiovascular risk factors, the intention to quit smoking increased; whereas, intended healthy diet and sufficient exercise did not change. In participants without risk factors, none of the healthy behaviors changed. CONCLUSION: Communicating risk factors alone does not seem to be effective as an intervention to achieve lifestyle changes. PMID- 29694252 TI - The Effect of the 50 g Glucose Challenge Test on The Thiol/Disulfide Homeostasis in Pregnancy. AB - AIM: A 50 g glucose challenge test (GCT) is recommended for screening all pregnant women for gestational diabetes mellitus. In this study, the effect of GCT on the thiol/disulfide balance was investigated. METHODS: One-hundred women that underwent a 50 g GCT at 24-28 weeks of gestation (63 positive and 37 negative results) were evaluated in terms of thiol/disulfide in serum samples at test hours 0 and 1. RESULTS: Compared to the baseline values (hour 0), after the glucose load (hour 1), the thiol and native thiol/total thiol (p < 0.0001) of the GCT-positive women were reduced whereas the values of glucose, disulfide, disulfide/native thiol, disulfide/total thiol (p < 0.0001) and total thiol increased (p = 0.018). CONCLUSION: In GCT-positive pregnant individuals, the glucose load increases oxidative stress by changing the thiol/disulfide homeostasis. Such an effect is not observed in healthy pregnancies. PMID- 29694253 TI - Serum levels of proinflammatory, anti-inflammatory cytokines, and RANKL/OPG in synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome. AB - OBJECTIVE: To measure the expression of proinflammatory, anti-inflammatory cytokines, and receptor activator NK-kappaB ligand (RANKL)/osteoprotegerin (OPG) in synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome, and to assess the relationship between those factors and disease activity. METHODS: We studied 30 cases of SAPHO syndrome and 15 healthy controls. According to the Visual Analogue Scale (VAS) pain scores and Bath Ankylosing Spondylitis Activity Index (BASDAI), patients were divided into active group and stable group. The serum levels of IFN-gamma, TNF-alpha, TGF-beta1, IL-1beta, IL-4, IL-6, IL-8, IL 17A, IL-22, RANKL, and OPG were determined by ELISA. RESULTS: The active group IL 6 (2.34 +/- 1.31 pg/ml), IL-8 (36.41 +/- 12.93 pg/ml), and IL-17A (29.17 +/- 4.01 pg/ml) levels were significantly higher than those in the stable group (p < .01) and healthy controls (p < .01). RANKL in active group (73.43 +/- 57.07 pg/ml) was significantly higher than the ones in other groups (p < .0001), with increased RANKL/OPG ratio in the active group compared with other groups (p < .05). While the level of TGF-beta1 in the active group was significantly lower than that in the stable and control groups (p < .0001). There was no significant difference with clinical significance were found in IFN-gamma, TNF-alpha, IL-1beta, IL-4, IL 22, and OPG. CONCLUSION: In active SAPHO patients, there was an anomaly of proinflammatory and anti-inflammatory cytokines balance in SAPHO syndrome. PMID- 29694254 TI - Acute and Subchronic Toxicological Evaluations of Allium rotundum L.: A Dietary Plant from Iran. AB - Allium rotundum L. is a dietary plant with diverse nutritional and herbal applications. According to its widespread application in Iranians' diets, understanding the possible adverse effects and toxic activities could be of major importance. The aim of this study was to establish the acute and subchronic toxicity profile of the hydroalcoholic extract of Allium rotundum on male and female Wistar rats. The acute study indicated no adverse effect or toxic activity after administration of the extract, suggesting that the LD50 value is up to 5,000 mg/kg body weight for the extract. The subchronic study at three doses (250, 500, and 750 mg/kg body weight/day) supported the results of acute study and revealed that no abnormal change or toxicity was induced by the extract in both male and female Wistar rats. All the biochemical and hematological parameters of the treated rats were in historical range after long-term administration of the extract. The histopathological examination also revealed no lesion or alteration in the tissue of vital organs (kidney, liver, heart, lung, and spleen). The NOAEL (no observed adverse effect level) value was high enough (greater than 750 mg/kg body weight/ day) to conclude the nontoxic nature of this extract. The safety of this extract was affirmed by the acute and subchronic toxic studies and suggested that this plant could be a proper and effective dietary plant due to its high nutritive value and inherent therapeutic properties. PMID- 29694255 TI - Serum prolactin level in chronic urticaria: Is bromocriptine inducing remission in chronic urticaria? AB - BACKGROUND: Chronic urticaria (CU) is a disturbing disease with a negative impact on quality of life. Despite of several clinical studies on CU patients, its pathogenesis is poorly understood. Prolactin (PRL) is peptide hormone has immunomodulatory effects in some immune inflammatory skin diseases. AIM: To elucidate any possible relationship between the immunomodulatory effects of PRL and CU. Besides, the study aims to investigate the crucial role of antiprolactin drugs in the management of CU patients. PATIENTS AND METHODS: The serum PRL level of 40 female patients with CU was measured using the electrochemiluminescence immunoassay. The activity of CU was assessed by European Academy of Allergology and Clinical Immunology; Global Allergy and Asthma European Network; European Dermatology Forum (EAACI/GA2LEN/EDF) activity score. Patients with high PRL level had been given anti prolactin therapy to normalize their PRL levels. Then, the disease activity was reassessed in these patients. RESULTS: The serum PRL level was high in 8 of 40 (20%) patients (43.18 +/- 12.81). Half of patients with high PRL level had remission after treatment of hyperprolactinemia (p = .001). CONCLUSIONS: Serum PRL levels could not be considered as a marker of the disease activity in CU patients. PMID- 29694256 TI - Associations of circulating CXCR3-PD-1+CD4+T cells with disease activity of systemic lupus erythematosus. AB - OBJECTIVES: Which helper CD4+ T cell subset contributes to autoantibodies generation and severity of end-organ involvement in lupus patients remains to be explored. Our research aims to investigate the roles of circulating Tfh (cTfh) cell subsets and corresponding CXCR5- Th cells in lupus patients and their correlation with SLE disease activity index 2000 (SLEDAI). METHODS: Peripheral blood mononuclear cells (PBMCs) were isolated from blood of systemic lupus erythematosus (SLE) patients as well as healthy donors. The proportion of Th cell subsets classified from cell surface markers (CD45RO, CXCR5, CXCR3, CCR6, PD-1, ICOS, and CCR7) is detected by flow cytometry. RESULTS: We found no difference in the frequency of CD45RO+CXCR5+CD4+ T cells between SLE patients and health controls. As previously reported, SLE patients showed an increase in the percentage of CXCR5+PD-1+, CXCR5+ICOS+PD-1+ and CXCR5+CCR7loPD-1hi cTfh subset, however, none of these populations had correlation with SLEDAI. Therefore, we further investigated the CXCR5- subsets, and surprisingly we found that the frequency of CXCR3-PD-1+ subset was correlated with SLEDAI, ds-DNA IgG, anti nucleosome antibody, C3, and C4 independent of CXCR5. Consistently, CXCR3-PD 1+CD45RO+CD4+T cells expressed factors associated with B-cell-help for the autoantibody production. CONCLUSION: CXCR3-PD-1+CD4+T cells are a sensitive indicator to assess SLE disease activity and might contribute B cell help and the generation of autoantibodies in patients. PMID- 29694257 TI - Functional assessment of rat pulmonary flavin-containing monooxygenase activity. AB - The expression of flavin-containing monooxygenase (FMO) varies extensively between human and commonly used preclinical species such as rat and mouse. The aim of this study was to investigate the pulmonary FMO activity in rat using benzydamine. Furthermore, the contribution of rat lung to the clearance of benzydamine was investigated using an in vivo pulmonary extraction model. Benzydamine N-oxygenation was observed in lung microsomes and lung slices. Thermal inactivation of FMO and CYP inhibition suggested that rat pulmonary N oxygenation is predominantly FMO mediated while any contribution from CYPs is negligible. The predicted lung clearance (CLlung) estimated from microsomes and slices was 16 +/- 0.6 and 2.1 +/- 0.3 mL/min/kg, respectively. The results from in vivo pulmonary extraction indicated no pulmonary extraction following intravenous and intra-arterial dosing to rats. Interestingly, the predicted CLlung using rat lung microsomes corresponded to approximately 35% of rat CLliver suggesting that the lung makes a smaller contribution to the whole body clearance of benzydamine. Although benzydamine clearance in rat appears to be predominantly mediated by hepatic metabolism, the data suggest that the lung may also make a smaller contribution to its whole body clearance. PMID- 29694259 TI - Encoding of Novel Verbal Instructions for Prospective Action in the Lateral Prefrontal Cortex: Evidence from Univariate and Multivariate Functional Magnetic Resonance Imaging Analysis. AB - Verbal instructions are central to humans' capacity to learn new behaviors with minimal training, but the neurocognitive mechanisms involved in verbally instructed behaviors remain puzzling. Recent functional magnetic resonance imaging (fMRI) evidence suggests that the right middle frontal gyrus and dorsal premotor cortex (rMFG-dPMC) supports the translation of symbolic stimulus response mappings into sensorimotor representations. Here, we set out to (1) replicate this finding, (2) investigate whether this region's involvement is specific to novel (vs. trained) instructions, and (3) study whether rMFG-dPMC also shows differences in its (voxel) pattern response indicative of general cognitive processes of instruction implementation. Participants were shown instructions, which they either had to perform later or merely memorize. Orthogonal to this manipulation, the instructions were either entirely novel or had been trained before the fMRI session. Results replicate higher rMFG-dPMC activation levels during instruction implementation versus memorization and show how this difference is restricted to novel, but not trained, instruction presentations. Pattern similarity analyses at the voxel level further reveal more consistent neural pattern responses in rMFG-dPMC during the implementation of novel versus trained instructions. In fact, this more consistent neural pattern response seemed to be specific to the first instruction presentation and disappeared after the instruction had been applied once. These results further support a role of rMFG-dPMC in the implementation of novel task instructions and highlight potentially important differences in studying this region's gross activation levels versus (the consistency of) its response patterns. PMID- 29694258 TI - Graded Ultra-Translucent Zirconia (5Y-PSZ) for Strength and Functionalities. AB - Ultra-translucent zirconias are drawing immense attention due to their fascinating esthetic appearance. However, the high translucency came at the expense of diminishing strength along with the reduced ability of transformation toughening due to the increased cubic zirconia content. We aim to address these issues by infiltrating glass on the surface of an ultra-translucent zirconia (5Y PSZ). Glasses of different shades can be used and the resulting graded glass/zirconia layer is expected to improve the material's flexural strength without compromising its esthetics. We also aim to elucidate how clinically relevant surface treatments-namely, air abrasion, glazing, or polishing-affect the fracture resistance of these zirconias with a high cubic content. All surface treatments were performed on bar-shaped (2 * 3 * 25 mm3) and plate-shaped (12 * 12 * 1 mm3) specimens, which were then subjected to a 4-point bending test and translucency measurements, respectively. 5Y-PSZ proved to be significantly more translucent than 3Y-TZP but also much weaker. Our hypothesis was accepted, as the strength of the glass-infiltrated ultra-translucent 5Y-PSZ (582 +/- 20 MPa) is over 70% higher than its uninfiltrated counterpart (324 +/- 57 MPa). Its strength is also over 25% higher than the highly polished 5Y-PSZ (467 +/- 38 MPa). In addition, the translucency of 5Y-PSZ (translucency parameter [ TP] = 34, contrast ratio [ CR] = 0.31) is not affected by glass infiltration ( TP = 34, CR = 0.32) when the residual surface glass is removed by gentle polishing using 6- and then 3-um diamond grits. Finally, both air abrasion and the presence of a glaze layer on the tensile surface decreased flexural strength significantly, being 274 +/- 55 and 211 +/- 21 MPa, respectively. With a combined high strength and translucency, the newly developed glass-infiltrated 5Y-PSZ may be considered a suitable material for next-generation, damage-resistant, and esthetic dental restorations. PMID- 29694260 TI - Contralateral Delay Activity Indexes Working Memory Storage, Not the Current Focus of Spatial Attention. AB - Contralateral delay activity (CDA) has long been argued to track the number of items stored in visual working memory (WM). Recently, however, Berggren and Eimer [Berggren, N., & Eimer, M. Does contralateral delay activity reflect working memory storage or the current focus of spatial attention within visual working memory? Journal of Cognitive Neuroscience, 28, 2003-2020, 2016] proposed the alternative hypothesis that the CDA tracks the current focus of spatial attention instead of WM storage. This hypothesis was based on the finding that, when two successive arrays of memoranda were placed in opposite hemifields, CDA amplitude was primarily determined by the position and number of items in the second display, not the total memory load across both displays. Here, we considered the alternative interpretation that participants dropped the first array from WM when they encoded the second array because the format of the probe display was spatially incompatible with the initial sample display. In this case, even if the CDA indexes active storage rather than spatial attention, CDA activity would be determined by the second array. We tested this idea by directly manipulating the spatial compatibility of sample and probe displays. With spatially incompatible displays, we replicated Berggren and Eimer's findings. However, with spatially compatible displays, we found clear evidence that CDA activity tracked the full storage load across both arrays, in line with a WM storage account of CDA activity. We propose that expectations of display compatibility influenced whether participants viewed the arrays as parts of a single extended event or two independent episodes. Thus, these findings raise interesting new questions about how event boundaries may shape the interplay between passive and active representations of task-relevant information. PMID- 29694261 TI - Neuronal Encoding in Prefrontal Cortex during Hierarchical Reinforcement Learning. AB - Reinforcement learning models have proven highly effective for understanding learning in both artificial and biological systems. However, these models have difficulty in scaling up to the complexity of real-life environments. One solution is to incorporate the hierarchical structure of behavior. In hierarchical reinforcement learning, primitive actions are chunked together into more temporally abstract actions, called "options," that are reinforced by attaining a subgoal. These subgoals are capable of generating pseudoreward prediction errors, which are distinct from reward prediction errors that are associated with the final goal of the behavior. Studies in humans have shown that pseudoreward prediction errors positively correlate with activation of ACC. To determine how pseudoreward prediction errors are encoded at the single neuron level, we trained two animals to perform a primate version of the task used to generate these errors in humans. We recorded the electrical activity of neurons in ACC during performance of this task, as well as neurons in lateral prefrontal cortex and OFC. We found that the firing rate of a small population of neurons encoded pseudoreward prediction errors, and these neurons were restricted to ACC. Our results provide support for the idea that ACC may play an important role in encoding subgoals and pseudoreward prediction errors to support hierarchical reinforcement learning. One caveat is that neurons encoding pseudoreward prediction errors were relatively few in number, especially in comparison to neurons that encoded information about the main goal of the task. PMID- 29694262 TI - Personality Traits and Adaptive HIV Disease Management: Relationships with Engagement in Care and Condomless Anal Intercourse Among Highly Sexually Active Sexual Minority Men Living with HIV. AB - PURPOSE: The purpose of this study was to identify systematic relationships between personality domains and engagement in HIV care and secondary HIV prevention among sexual minority men living with HIV. METHODS: This cross sectional study examined the relationships between general personality traits of the Five-Factor Model of personality (e.g., Neuroticism and Conscientiousness) and engagement in medical care and condomless anal intercourse among a sample of highly sexually active sexual minority men living with HIV (N = 60). RESULTS: Conscientiousness (B = -0.01, P < 0.05), Openness (B = -0.03, P < 0.05), and Extraversion (B = -0.03, P < 0.001) were each associated with engaging in fewer episodes of condomless anal intercourse and Conscientiousness alone was significantly related to having fewer sexual partners (B = -0.04, P < 0.001). Conscientiousness (odds ratio [OR] = 1.07, confidence interval [CI]: 1.01-1.13) and Extraversion (OR = 1.13, CI: 1.04-1.22) were both associated significantly with prevention service use. Conscientiousness alone was related to engagement in HIV medical case management (B = -0.11, P < 0.05), whereas both Conscientiousness (B = 0.41, P < 0.0001) and Neuroticism (B = -0.64, P < 0.001) were associated with perceived health. Furthermore, compared with the normative sample for the NEO-Personality Inventory-Revised, men in our sample scored significantly higher on Neuroticism and significantly lower on Conscientiousness (Ps < 0.05). CONCLUSION: These findings suggest that enduring individual differences may account, in part, for some of the high levels of condomless anal intercourse reported by this group, as well as engagement in and use of prevention services. We suggest strategies for engaging this group in secondary HIV prevention programs and initiatives. PMID- 29694263 TI - The decrease in phase angle measured by bioelectrical impedance analysis reflects the increased locomotive syndrome risk in community-dwelling people: The Yakumo study. AB - OBJECTIVES: The locomotive syndrome (LS) risk test has recently been advocated for the evaluation of physical ability. Phase angle measurement by bioelectrical impedance analysis (BIA) is an indicator of cellular health and muscle mass. We aimed to investigate how muscle mass and phase angle are related to LS risk stage. METHODS: A prospective cohort study was conducted in 311 patients who were undergoing a health checkup. All participants performed the two-step test, stand up test, and 25-question geriatric locomotive function scale components of the LS risk test. Muscle mass and phase angle were measured using BIA. A comparison study was conducted among the three LS risk stages. RESULTS: In the trend test, phase angle decreased significantly as the LS risk stage progressed, whereas muscle mass did not show a significant difference. After adjusting for age and sex, phase angle showed a significant difference among all LS risk stages. Muscle mass did not show a significant difference between no risk and stage 1. CONCLUSION: Compared to muscle mass, phase angle more strongly reflects LS risk and becomes significantly reduced at later LS risk stages. Phase angle can be a useful screening tool for LS risk. PMID- 29694264 TI - Does Power Reduce Temporal Discounting? Commentary on Joshi and Fast (2013). PMID- 29694265 TI - Too Hot to Handle: A Case Report of Extreme Pyrexia After MDMA Ingestion. AB - Hyperpyrexia is a well-documented adverse effect of 3,4 methylenedioxymethamphetamine (MDMA) and is associated with a poor prognosis. There are currently limited published records of patients surviving a pyrexia of or greater than 43 degrees C after MDMA intake. Rapid cooling and multiorgan support in an intensive care setting may offer patients the best chance of recovery. We present the case of a 16-year-old male who was admitted to our tertiary, adult intensive care unit (ICU) for unrecordable pyrexia (>43 degrees C) after reported ecstasy intake. The patient went on to develop severe multiorgan failure and profound disseminated intravascular coagulopathy. Initial patient management focused on rapid cooling using an endovascular cooling catheter and rigorous monitoring and treatment of autonomic symptoms, followed by subsequent surgical therapy (fasciotomy) and multiorgan support. The patient eventually achieved a good clinical outcome after 4 weeks of management in the ICU, and was discharged well to his local hospital. Despite multiple end-organ dysfunctions and often severely poor prognosis, survival after severe hyperpyrexia induced by MDMA intake is possible with proper management and organ support in an appropriate intensive care environment. PMID- 29694266 TI - Comparison of Carba NP-Direct, Carbapenem Inactivation Method, and beta-CARBA Tests for Detection of Carbapenemase Production in Enterobacteriaceae. AB - Rapid and accurate detection of carbapenemase-producing isolates are extremely important for management of antimicrobial therapy and the implementation of infection control measures. We evaluated the performance of Carba NP-direct, carbapenem inactivation method (CIM), and the commercial beta-CARBA tests for detection of carbapenemase production in Enterobacteriaceae. Enterobacteriaceae isolates with previously characterized carbapenemase types (n = 110) and non carbapenemase-producing Escherichia coli (n = 15) isolates were tested. Sensitivities of Carba NP-direct, CIM, and beta-CARBA tests were 99.0%, 92.7%, and 93.6%, respectively, while specificity was 100% for all three tests. For beta CARBA test, a 60-min incubation time instead of 30 increased the sensitivity to 98.1%, and lessened false negativity, particularly with OXA-48-like producers. Our results showed that Carba NP-direct, CIM, and beta-CARBA tests are useful tools for the reliable detection of carbapenemase activity in enterobacterial isolates. Carba NP-direct is a simple, rapid, and low-cost test for routine use. PMID- 29694267 TI - Treatment and comorbidities of multiple sclerosis in an employed population in Japan: analysis of health claims data. AB - AIM: Use real-world data to investigate the treatment, comorbidities and prevalence of multiple sclerosis (MS) in an employed Japanese population. METHODS: Data from the Japanese Medical Data Center health insurance claims database were analyzed (January 2005-November 2014). Patients with claims associated with an MS diagnosis were identified (n = 494) and comorbidities and prescribed treatments were investigated. MS prevalence within the database was calculated for each calendar year (2011-2013) Results: IFN-beta and prednisolone were the most commonly prescribed treatments. Common comorbidities included astigmatism and gastric ulcer. Within the database, MS prevalence increased from 0.015 to 0.016%. CONCLUSION: MS prevalence increased from 2011 to 2013. Some comorbidities were considered unrelated to MS owing to how physicians use disease codes for reimbursement. PMID- 29694268 TI - A Rose by Any Other Name? A Subtle Linguistic Cue Impacts Anger and Corresponding Policy Support in Intractable Conflict. AB - Given the central role of anger in shaping adversarial policy preferences in the context of intergroup conflict, its reduction may promote conflict resolution. In the current work, we drew on psycholinguistic research on the role of language in generating emotions to explore a novel, extremely subtle means of intervention. Specifically, we hypothesized that phrasing conflict-relevant policies in noun form (vs. verb form) would reduce anger and impact policy support correspondingly. Results across three experimental studies in the context of the Israeli-Palestinian conflict supported these expectations for both support for concessions (Studies 1-3) and retaliatory policies (Study 3), with reduction in anger mediating the salutary impact of noun form (vs. verb form) on policy support. These results expand our understanding of the influence of language on emotions and policies in the context of conflict and have applied relevance for conflict-resolution efforts. PMID- 29694269 TI - Larva Migrans of Baylisascaris potosis In Experimental Animals. AB - Occurrence of clinical signs by infection with Baylisascaris potosis, the roundworm of kinkajous ( Potos flavus), in mice, rats, and rabbit were studied, and the migration behavior of larvae in mice were compared with that of Baylisascaris transfuga, the roundworm of bears ( Ursus spp.). Three groups of 8 mice, 3 groups of 6 rats, and 3 groups of 2 rabbits were inoculated with either 10, 100, or 1,000 B. potosis eggs. The other 8 mice were inoculated with 1,000 B. transfuga eggs. Animals were monitored for the occurrence of clinical signs until 60 days postinoculation (DPI). The carcass, viscera, brain, and eyes of each of 6 mice inoculated with 1,000 eggs of B. potosis or B. transfuga at 60 DPI were removed individually, and the number of larvae was counted. One mouse inoculated with 100 B. potosis eggs showed rolling at 27 DPI, and 1 larva was found in the medulla oblongata of this mouse. No clinical signs were observed in the other mice or in the rats and rabbits. A mean of 387.2 larvae was recovered from mice inoculated with 1,000 B. potosis eggs, and a mean of 422.0 larvae from mice inoculated with 1,000 B. transfuga eggs. The highest number of larvae was recovered from the carcasses for both B. potosis and B. transfuga. In the viscera, higher numbers of B. transfuga larvae (mean 131.8) were seen than B. potosis larvae (mean 33.1). In the brain, only 1 larva was detected in 1/6 mice inoculated with 1,000 B. potosis eggs, whereas a mean of 21 larvae was detected in mice inoculated with 1,000 B. transfuga eggs. A few larvae (range 0-1) were detected in the eyes of both mice inoculated with B. potosis or B. transfuga eggs. The result indicated that B. potosis larvae do not show a higher tendency to migrate into the brain of mice than B. transfuga larvae. However, 1 mouse inoculated with 100 eggs had 1 larva in the central nervous system and showed a serious neurological sign. This result may underline a potential risk of B. potosis to cause neural larva migrans in humans. PMID- 29694270 TI - Higher Incidence Rates of Comorbidities in Patients with Psoriatic Arthritis Compared with the General Population Using U.S. Administrative Claims Data. AB - BACKGROUND: Psoriatic arthritis (PsA) is associated with multiple comorbid conditions, including cardiovascular (CV) comorbidities that impose a considerable burden on patients. Effective management of PsA requires an understanding of comorbidity profiles. OBJECTIVE: To compare the frequency and incidence rates of comorbidities and hospitalizations among newly diagnosed PsA patients and a matched general population without PsA, using large national claims databases in the United States. METHODS: This retrospective observational study used MarketScan databases from January 1, 2008, to September 30, 2015, to identify adult patients with newly diagnosed PsA (i.e., no PsA diagnosis during the 1 year before the first observed PsA diagnosis). The earliest date of PsA diagnosis was defined as the index date. Patients with no PsA diagnosis any time during the study period (controls) were directly matched to PsA patients with demographic characteristics. All patients had >= 2 years of medical and pharmacy coverage before the index date and >= 1 year of follow-up. Incident rates per 100 person-years for comorbidities of interest were evaluated. The hazard ratios of having various comorbid conditions for PsA patients were estimated by Cox proportional hazards models. All-cause and CV-related hospitalizations during the follow-up period were evaluated. RESULTS: A total of 14,898 PsA patients and 35,037 matched controls met the study criteria. Compared with controls, PsA patients had a higher risk of CV disorders (incidence rate = 6.5 vs. 5.8; HR = 1.46; 95% CI = 1.37-1.56) and a higher risk of the majority of the specific CV disorders (hypertension, hyperlipidemia, coronary artery disease, cerebrovascular disease, peripheral vascular disease). PsA patients also had a higher risk for any autoimmune disease (incidence rate = 8.4 vs. 1.6; HR = 18.26; 95% CI = 17.18 19.40) and most autoimmune categories (psoriasis, ankylosing spondylitis, rheumatoid arthritis, multiple sclerosis, and other autoimmune disorders). Rates of other PsA-related comorbidities (diabetes, anxiety, fatigue, smoking, alcohol use, obesity or overweight, depression, osteoporosis, uveitis, eczema, and gout) were also significantly higher for PsA patients. The all-cause hospitalization rate was higher among PsA patients than controls (24.9% vs. 16.2%; P < 0.001). The CV-related hospitalization rate varied depending on whether the CV condition was the primary discharge diagnosis only or was any diagnosis on the inpatient claims. The rates of coronary artery disease hospitalizations were significantly higher in PsA patients than in controls with both methods of analysis (primary diagnosis: 0.8% vs. 0.5%; P < 0.001; nonprimary diagnosis: 3.2% vs. 2.2%; P < 0.001). CONCLUSIONS: This retrospective U.S.-based claims study found that PsA patients had a high comorbidity burden. Compared with the non-PsA population, PsA patients were associated with a higher incidence of CV comorbidities, autoimmune diseases, and other PsA-related comorbidities and a higher rate of all-cause and CV-related hospitalizations. Understanding these comorbidity profiles may provide insight on the effect of comorbid conditions on disease management and health care utilization associated with PsA. DISCLOSURES: This study was funded by Novartis. Kaine is a paid consultant for Novatis. Hur and Palmer are Novartis employees and stockowners. Song and Kim work for Truven Health Analytics, which received funding from Novartis to conduct this study. PMID- 29694271 TI - The psychosocial impact of assistive device scale: Italian validation in a cohort of nonambulant people with neuromotor disorders. AB - The importance of adaptive seating system on body structure and function is widely accepted, but its impact on psychosocial aspects needs more consideration by health professionals. This article describes the Italian validation of the Psychosocial Impact of Assistive Device Scale (IT-PIADS) for non-ambulant people with neuromotor disorders. Once agreement has been given by the original authors, the scale was translated and adapted to the Italian culture. The IT-PIADS was administered to different wheelchairs users with heterogeneous diagnosis. The internal consistency and test-retest reliability were examined. Its concurrent validity was evaluated with the Italian version of the WheelCon-M-SF. The IT PIADS was administered to 87 subjects. Cronbach's alpha was 0.92 (p < 0.05), and the test-retest reliability (ICC) for competence, adaptability and self-esteem subscales were 0.96, 0.90, 0.93, respectively. The Pearson correlation coefficient of the IT-PIADS with the WheelCon-M-I-SF scores showed significant data for competence and adaptability subscales. Psychosocial perception on assistive devices can be reliably measure. The IT-PIADS showed good psychometric properties and it is possible to confirm its validity for clinical and research purposes. Nevertheless, before using this measure with greater confidence, further psychometric properties tests of the IT-PIADS are recommended. PMID- 29694272 TI - Effect of Mouthguard Use on Metabolic and Cardiorespiratory Responses to Aerobic Exercise in Males. AB - PURPOSE: This study investigated the physiological effects of wearing a mouthguard during submaximal treadmill exercise. METHOD: Twenty-four recreationally active males (Mage = 21.3 +/- 2.4 years, Mheight = 1.78 +/- 0.06 m, Mweight = 81.9 +/- 10.6 kg, Mbody mass index = 25.8 +/- 3.4 kg.m-2) performed incremental, continuous exercise at 2, 4, 6, and 8 mph (3.2, 6.4, 9.7, 12.9 kph) for 5 min at each speed on a motor-driven treadmill on 2 separate occasions in a randomized, crossover, counterbalanced design while wearing or not wearing a self adaptable "boil and bite" mouthguard. Respiratory rate (RR), tidal volume (VT), ventilation (VE), oxygen consumption (VO2), respiratory exchange ratio (RER), and heart rate (HR) data were averaged during the last 60 s of each exercise stage; blood lactate (LA) was measured before exercise and 3 min and 10 min following exercise. RESULTS: Repeated-measures analysis of variance revealed that mouthguard use failed to alter the response of RR, VT, VE, VO2, RER, and HR to treadmill exercise (p > .05), although each variable did increase in magnitude as a result of increasing treadmill speed (p < .001). Although increasing to above resting values at both 3 min and 10 min (p < .001) after cessation of exercise, LA levels also displayed no differences with mouthguard use (p > .05). CONCLUSION: Despite predictable increases in respiratory, metabolic, and cardiovascular variables in response to incremental exercise, the presence of a mouthguard failed to affect the magnitude or nature of these physiological responses. PMID- 29694273 TI - Awareness of the Medicare Part D Low-Income Subsidy among Older non-Hispanic Blacks and Hispanics. AB - Using nationally representative data from the Health and Retirement Study, this study examined (1) whether awareness of the Medicare Part D Low-Income Subsidy (LIS) varies by race and ethnicity among beneficiaries age 65 and older (N = 1,504), and (2) the impact of factors associated with health benefits knowledge and need for assistance on LIS awareness. Logistic regression results showed that compared with older non-Hispanic Whites, older non-Hispanic Blacks (odds ratio [OR] = .61, p < .001) and Hispanics (OR = .55, p < .01) were less likely to be aware of the LIS. Ethnic differences in LIS awareness were largely explained by language or Spanish-speaking preference (OR = 1.07, p = .808). However, accounting for demographics, health and socioeconomic status, and language did not reduce racial disparities (OR = .63, p < .01). Differences in LIS awareness among racial and ethnic minority groups highlight the need for culturally and linguistically sensitive community-based education, communication, programs, and services that increase knowledge of and access to this critical support. PMID- 29694274 TI - Risk assessment of N-nitrosodiethylamine (NDEA) and N-nitrosodiethanolamine (NDELA) in cosmetics. AB - N-nitrosamines and their precursors found in cosmetics may be carcinogenic in humans. Thus the aim of this study was to carry out risk assessment for N nitrosamines (N-nitrosodiethanolamine [NDELA], N-nitrosodiethylamine [NDEA]) and amines (triethanolamine [TEA], diethanolamine [DEA]) levels in cosmetics determined using validated liquid chromatography-tandem mass spectrometry (LC MS/MS) procedures. NDELA and NDEA concentrations were present at levels of "not detected" (N.D.) to 596.5 MUg/kg and N.D. to 40.9 MUg/kg, respectively. TEA and DEA concentrations ranged from N.D. to 860 MUg/kg and N.D. to 26.22 MUg/kg, respectively. The nitrite concentration (3-2250 mg/l), number of nitrosating agents to a maximum 5, and pH (3.93-10.09) were also assessed. The impact of N nitrosamine formation on the levels of TEA, DEA, nitrite, and other nitrosating agents was also examined. N-nitrosamine concentrations correlated with the number of nitrosating agents and nitrite concentrations. Data demonstrated that higher nitrite concentrations and a greater number of nitrosating agents increased NDELA and NDEA yields. Further, the presence of TEA and DEA exerted a significant influence on N-nitrosamine formation. Risk assessments, including the margin of exposure (MOE) and lifetime cancer risk (LCR) for N-nitrosamines and margin of safety (MOS) for amines, were calculated using product type, use pattern, and concentrations. Exposure to maximum amounts of NDELA and NDEA resulted in MOE > 10,000 (based upon the benchmark dose lower confidence limit 10%) and LCR <1 * 10 5, respectively. In addition, TEA and DEA concentrations in cosmetic samples resulted in MOS values >100. Therefore, no apparent safety concerns were associated with cosmetic products containing NDELA, NDEA, TEA, and DEA in this study. However, since amines and nitrosating agents produce carcinogenic nitrosamines, their use in cosmetics needs to be minimized to levels as low as technically feasible. PMID- 29694275 TI - A regressive formula of perversity: Wertham and the women of comics. AB - This essay serves as a close reading of psychiatrist Fredric Wertham's 1950s descriptions and critiques of female comics characters. I draw on archival sources as well as relevant texts in the study of gender and sexuality. Additionally, I integrate ideas from two of his close associates, folklorist Gershon Legman and psychiatrist Hilde Mosse, whose contributions to Seduction of the Innocent are woven-often invisibly-throughout that text. The character of Wonder Woman serves as a touchstone, but other provocative female figures that Wertham found objectionable in mid-twentieth-century comics accompany her. My goal is to illuminate Wertham's understanding of what he viewed as the "regressive formula of perversity" enacted through women's representations in comics, particularly those female characters who played active roles. Although not all of these concerns are tied to lesbian identity, they do all touch on broader notions of queerness vis-a-vis deviant sexual and gender expression. PMID- 29694276 TI - "Flabulously" femme: Queer fat femme women's identities and experiences. AB - This article explores how queer fat femme women experience, negotiate, and resist heteronormativity, misogyny, and fatphobia, alongside other intersecting oppressions. By analyzing fat femmes' narratives presented in blogs and personal essays, this article examines themes including: the role of femme in fat queers (re)claiming femininities, the masculinizing and/or feminizing effects of "fatness" for queer femmes, the mutual constitution of fatphobia and femmephobia, femme fa(t)shion, fat femme (in)visibility, and the importance of intersectional conceptions of queer fat femininities. In doing so, this article argues that "queer fat femme" subjectivities offer fat and femme queers unique and significant opportunities for articulating resistant subjectivities, creating communities, and challenging oppressions. PMID- 29694277 TI - Inhibition of BDNF signaling in the paraventricular nucleus of the hypothalamus lowers acute stress-induced pressor responses. AB - Brain-derived neurotrophic factor (BDNF) expression increases in the paraventricular nucleus of the hypothalamus (PVN) during stress, and our recent studies indicate that BDNF induces sympathoexcitatory and hypertensive responses when injected acutely or overexpressed chronically in the PVN. However, it remained to be investigated whether BDNF is involved in the mediation of stress induced cardiovascular responses. Here we tested the hypothesis that inhibition of the high-affinity BDNF receptor TrkB in the PVN diminishes acute stress induced cardiovascular responses. Male Sprague-Dawley rats were equipped with radiotelemetric transmitters for blood pressure measurement. BDNF-TrkB signaling was selectively inhibited by viral vector-mediated bilateral PVN overexpression of a dominant-negative truncated TrkB receptor (TrkB.T1, n = 7), while control animals ( n = 7) received green fluorescent protein (GFP)-expressing vector injections. Rats were subjected to acute water and restraint stress 3-4 wk after vector injections. We found that body weight, food intake, baseline mean arterial pressure (MAP), and heart rate were unaffected by TrkB.T1 overexpression. However, peak MAP increases were significantly reduced in the TrkB.T1 group compared with GFP both during water stress (GFP: 39 +/- 2 mmHg, TrkB.T1: 27 +/- 4 mmHg; P < 0.05) and restraint stress (GFP: 41 +/- 3 mmHg, TrkB.T1: 34 +/- 2 mmHg; P < 0.05). Average MAP elevations during the poststress period were also significantly reduced after both water and restraint stress in the TrkB.T1 group compared with GFP. In contrast, heart rate elevations to both stressors remained unaffected by TrkB.T1 overexpression. Our results demonstrate that activation of BDNF high-affinity TrkB receptors within the PVN is a major contributor to acute stress-induced blood pressure elevations. NEW & NOTEWORTHY We have shown that inhibition of the high-affinity brain-derived neurotrophic factor receptor TrkB in the paraventricular nucleus of the hypothalamus significantly reduces blood pressure elevations to acute stress without having a significant impact on resting blood pressure, body weight, and food intake. PMID- 29694278 TI - Signals driving the adaptation of saccades that require spatial updating. AB - Saccades adapt to persistent natural or artificially imposed dysmetrias. The characteristics and circuitry of saccade adaptation have been revealed using a visually guided task (VGT) where the vectors of the target step and the intended saccade command are the same. However, in real life, another saccade occasionally intervenes before the saccade to the target occurs. This necessitates an updating of the intended saccade to account for the intervening saccadic displacement, which dissociates the visual target signal and the intended saccade command. We determined whether the adaptation process is similar for VGT and updated saccades by studying the transfer of adaptation between them. The ultimate visual target was dissociated from the intended saccade command with double-step saccade tasks (DSTs) in which two targets are flashed sequentially at different locations while the monkey maintains fixation. The resulting saccades toward the first and second targets occur in the dark. The transfer of visually guided saccade adaptation to the second saccades of a DST and vice versa depended on the eccentricity of the second visual target, and not the second saccade command. If a target with the same eccentricity as the adapted target appears briefly during the intersaccadic interval of a DST, more adaptation transfers. Because a brief appearance of the visual target either before the first saccade or during the intersaccadic interval influences how much adaptation transfer the second saccade will express, the processing of adaptation and DST updating may overlap. NEW & NOTEWORTHY Adaptation and the spatial updating of saccades are thought to be independent processes. When we dissociate the visual target and the intended saccade command, the transfer of visually guided saccade adaptation to the saccades of the double step saccade tasks (DST) and vice versa is driven by a visual not motor error. The visual target has an effect until the second saccade of a DST occurs. Therefore, the processing of adaptation and the spatial updating of saccades may overlap. PMID- 29694280 TI - Model-based deconstruction of cortical evoked potentials generated by subthalamic nucleus deep brain stimulation. AB - Parkinson's disease is associated with altered neural activity in the motor cortex. Chronic high-frequency deep brain stimulation (DBS) of the subthalamic nucleus (STN) is effective in suppressing parkinsonian motor symptoms and modulates cortical activity. However, the anatomical pathways responsible for STN DBS-mediated cortical modulation remain unclear. Cortical evoked potentials (cEP) generated by STN DBS reflect the response of cortex to subcortical stimulation, and the goal of this study was to determine the neural origin of STN DBS generated cEP using a two-step approach. First, we recorded cEP over ipsilateral primary motor cortex during different frequencies of STN DBS in awake healthy and unilateral 6-OHDA-lesioned parkinsonian rats. Second, we used a detailed, biophysically based model of the thalamocortical network to deconstruct the neural origin of the recorded cEP. The in vivo cEP included short (R1)-, intermediate (R2)-, and long-latency (R3) responses. Model-based cortical responses to simulated STN DBS matched remarkably well the in vivo responses. The short-latency response was generated by antidromic activation of layer 5 pyramidal neurons, whereas recurrent activation of layer 5 pyramidal neurons via excitatory axon collaterals reproduced the intermediate-latency response. The long-latency response was generated by polysynaptic activation of layer 2/3 pyramidal neurons via the cortico-thalamic-cortical pathway. Antidromic activation of the hyperdirect pathway and subsequent intracortical and cortico thalamo-cortical synaptic interactions were sufficient to generate cortical potential evoked by STN DBS, and orthodromic activation through basal ganglia thalamus-cortex pathways was not required. These results demonstrate the utility of cEP to determine the neural elements activated by STN DBS that might modulate cortical activity and contribute to the suppression of parkinsonian symptoms. NEW & NOTEWORTHY Subthalamic nucleus (STN) deep brain stimulation (DBS) is increasingly used to treat Parkinson's disease (PD). Cortical potentials evoked by STN DBS in patients with PD exhibit consistent short-latency (1-3 ms), intermediate-latency (5-15 ms), and long-latency (18-25 ms) responses. The short latency response occurs as a result of antidromic activation of the hyperdirect pathway comprising corticosubthalamic axons. However, the neural origins of intermediate- and long-latency responses remain elusive, and the dominant view is that these are produced through the orthodromic pathway (basal ganglia-thalamus cortex). By combining in vivo electrophysiology with computational modeling, we demonstrate that antidromic activation of the cortico-thalamic-cortical pathway is sufficient to generate the intermediate- and long-latency cortical responses to STN DBS. PMID- 29694279 TI - Stable long-term BCI-enabled communication in ALS and locked-in syndrome using LFP signals. AB - Restoring communication for people with locked-in syndrome remains a challenging clinical problem without a reliable solution. Recent studies have shown that people with paralysis can use brain-computer interfaces (BCIs) based on intracortical spiking activity to efficiently type messages. However, due to neuronal signal instability, most intracortical BCIs have required frequent calibration and continuous assistance of skilled engineers to maintain performance. Here, an individual with locked-in syndrome due to brain stem stroke and an individual with tetraplegia secondary to amyotrophic lateral sclerosis (ALS) used a simple communication BCI based on intracortical local field potentials (LFPs) for 76 and 138 days, respectively, without recalibration and without significant loss of performance. BCI spelling rates of 3.07 and 6.88 correct characters/minute allowed the participants to type messages and write emails. Our results indicate that people with locked-in syndrome could soon use a slow but reliable LFP-based BCI for everyday communication without ongoing intervention from a technician or caregiver. NEW & NOTEWORTHY This study demonstrates, for the first time, stable repeated use of an intracortical brain computer interface by people with tetraplegia over up to four and a half months. The approach uses local field potentials (LFPs), signals that may be more stable than neuronal action potentials, to decode participants' commands. Throughout the several months of evaluation, the decoder remained unchanged; thus no technical interventions were required to maintain consistent brain-computer interface operation. PMID- 29694282 TI - Invariant and heritable local cortical organization as revealed by fMRI. AB - Neural interactions in local cortical networks critically depend on the distance between interacting elements: the shorter the distance, the stronger the interactions. Here we quantified these interactions in six cortical areas of 854 individuals, including monozygotic and dizygotic twins, nontwin siblings, and nonrelated individuals. We found that the strength of zero-lag correlation between prewhitened, resting-state, blood level oxygenation-dependent functional magnetic resonance imaging time series decreased with distance as a power law. The rate of decrease, b, varied among individuals by ~1.9*, was highly correlated between hemispheres, but differed among areas (by ~1.2*) in a systematic fashion, becoming progressively less steep from frontal to occipital areas. With respect to twin status, b was significantly correlated between monozygotic twins, less so between dizygotic twins or nontwin siblings, and not at all in nonrelated individuals. These results quantify the lawful, distance-related cortical interactions and demonstrate, for the first time, the heritability of their power law. NEW & NOTEWORTHY Local cortical circuitry involves orderly neuronal interactions. A key feature of these interactions is that they are stronger the closer the interacting neurons. Here we quantified this crucial dependence of neural interactions on distance with functional magnetic resonance imaging and found that the strength of interactions decreases with distance as a power law that is very similar in all cortical lobes and heritable. These findings identify an invariant and heritable property of local cortical organization. PMID- 29694281 TI - Distinct frequency bands in the local field potential are differently tuned to stimulus drift rate. AB - Local field potential (LFP) recorded with a microelectrode reflects the activity of several neural processes, including afferent synaptic inputs, microcircuit level computations, and spiking activity. Objectively probing their contribution requires a design that allows dissociation between these potential contributors. Earlier reports have shown that the primate lateral geniculate nucleus (LGN) has a higher temporal frequency (drift rate) cutoff than the primary visual cortex (V1), such that at higher drift rates inputs into V1 from the LGN continue to persist, whereas output ceases, permitting partial dissociation. Using chronic microelectrode arrays, we recorded spikes and LFP from V1 of passively fixating macaques while presenting sinusoidal gratings drifting over a wide range. We further optimized the gratings to produce strong gamma oscillations, since recent studies in rodent V1 have reported LGN-dependent narrow-band gamma oscillations. Consistent with earlier reports, power in higher LFP frequencies (above ~140 Hz) tracked the population firing rate and were tuned to preferred drift rates similar to those for spikes. Significantly, power in the lower (up to ~40 Hz) frequencies increased transiently in the early epoch after stimulus onset, even at high drift rates, and had preferred drift rates higher than for spikes/high gamma. Narrow-band gamma (50-80 Hz) power was not strongly correlated with power in high or low frequencies and had much lower preferred temporal frequencies. Our results demonstrate that distinct frequency bands of the V1 LFP show diverse tuning profiles, which may potentially convey different attributes of the underlying neural activity. NEW & NOTEWORTHY In recent years the local field potential (LFP) has been increasingly studied, but interpreting its rich frequency content has been difficult. We use a stimulus manipulation that generates different tuning profiles for low, gamma, and high frequencies of the LFP, suggesting contributions from potentially different sources. Our results have possible implications for design of better neural prosthesis systems and brain-machine interfacing applications. PMID- 29694283 TI - Letter--Incorporating Real-World Evidence and Patient Value Criteria into Value Based Frameworks for Relapsed/Refractory Multiple Myeloma. AB - DISCLOSURES: Orlowski has received research funding from Amgen, BioTheryX, Bristol-Myers Squibb, Celgene Corporation, and Takeda Pharmaceuticals; honoraria from Amgen, Bristol-Myers Squibb, Celgene Corporation, Janssen, Millennium Pharmaceuticals, and Onyx Pharmaceuticals; and is a member of advisory boards for Amgen, Bristol-Myers Squibb, Celgene Corporation, Incyte, Kite, Legend Biotech, Sanofi-Aventis, and Takeda Pharmaceuticals. PMID- 29694284 TI - Publicly Funded Oral Chronic Hepatitis B Treatment Patterns in Ontario over 16 Years: An Ecologic Study. AB - BACKGROUND: Reimbursement for the use of hepatitis B virus (HBV) treatments has not been previously reported for public payers. OBJECTIVE: To describe the number of users and total cost of HBV treatments over the last 16 years among residents of Ontario, Canada, who were covered by the public drug program. METHODS: We conducted a repeated cross-sectional study for HBV treatments reimbursed by the public drug program in Ontario from January 1, 2000, to December 31, 2015. We projected total spending to 2020 based on current utilization trends. RESULTS: HBV drug users per year increased 30-fold, from 132 users in 2000 to 4,035 users in 2015. Total spending on HBV treatments increased 150-fold, from $136,368 annually in 2000 to $21.0 million in 2015. The spending on HBV agents is projected to increase by 65%, with an estimated drug cost of $34.6 million by 2020. CONCLUSIONS: Although not reimbursed as first-line therapy, tenofovir disoproxil fumarate has become the most commonly reimbursed HBV treatment and was associated with an increase in HBV treatment use and total spending. Results of this study found that rapid growth of HBV treatments led to a sustained increase in spending for public payers in Ontario. DISCLOSURES: This study was funded by grants from the Ontario Ministry of Health and Long-Term Care (MOHLTC) and Ontario Strategy for Patient-Orientated Research (SPOR) Support Unit, which is supported by the Canadian Institutes of Health Research and the Province of Ontario. This study was also supported by the Institute for Clinical Evaluative Sciences (ICES), a non-profit research institute sponsored by the Ontario MOHLTC. The opinions, results, and conclusions reported in this article are those of the authors and are independent from the funding sources. No endorsement by ICES or the Ontario MOHLTC is intended or should be inferred. Parts of this material are based on data and information compiled and provided by the Canadian Institute for Health Information (CIHI). However, the analyses, conclusions, opinions and statements expressed herein are those of the authors and not necessarily those of CIHI. Mamdani has received honoraria from Boehringer Ingelheim, Pfizer, Bristol Myers Squibb, and Bayer. Janssen has received research support, consulting, and/or speaking fees from Gilead, Roche, Merck, AbbVie, Bristol-Myers Squibb, Arbutus, Janssen, and MedImmune. No other authors have any conflicts of interest to declare. PMID- 29694144 TI - Suppression of Excited Upsilon States Relative to the Ground State in Pb-Pb Collisions at sqrt[s]_{NN}=5.02 TeV. AB - The relative yields of Upsilon mesons produced in pp and Pb-Pb collisions at sqrt[s_{NN}]=5.02 TeV and reconstructed via the dimuon decay channel are measured using data collected by the CMS experiment. Double ratios are formed by comparing the yields of the excited states, Upsilon(2S) and Upsilon(3S), to the ground state, Upsilon(1S), in both Pb-Pb and pp collisions at the same center-of mass energy. The double ratios, [Upsilon(nS)/Upsilon(1S)]_{Pb Pb}/[Upsilon(nS)/Upsilon(1S)]_{pp}, are measured to be 0.308+/-0.055(stat)+/ 0.019(syst) for the Upsilon(2S) and less than 0.26 at 95% confidence level for the Upsilon(3S). No significant Upsilon(3S) signal is found in the Pb-Pb data. The double ratios are studied as a function of collision centrality, as well as Upsilon transverse momentum and rapidity. No significant dependencies are observed. PMID- 29694285 TI - Real-World Health Care Costs Based on Medication Adherence and Risk of Stroke and Bleeding in Patients Treated with Novel Anticoagulant Therapy. AB - BACKGROUND: With the lack of real-world evidence, the challenge for drug reimbursement policy decision makers is to understand medication adherence behavior among users of novel oral anticoagulants (NOACs) and its effect on overall cost savings. No study has examined and quantified the burden of cost in high-risk patients taking NOAC therapy. OBJECTIVE: To examine the association of cost with adherence, comorbidity, and risk of stroke and bleeding in patients taking NOACs (rivaroxaban and dabigatran). METHODS: A retrospective cohort study used deidentified data from a commercial managed care database affiliated with Optum Clinformatics Data Mart (January 1, 2010-December 31, 2012). Patients aged 18 years and older with >= 1 diagnosis of atrial fibrillation/flutter, > 1 NOAC prescription, 6-month pre-index and 12-month post-index continuous enrollment, and CHA2DS2-VASc score >= 1 were included. Adherence was calculated using proportion of days covered (PDC >= 80%) over an assessment period of 3, 6, and 12 months and compared based on level of comorbidity, stroke, and bleeding risk. The adjusted annual health care costs per patient (drug, medical, and total) were calculated using multivariable gamma regression controlling for demographic and clinical characteristics and compared across groups based on adherence over 12 months, baseline level of comorbidity, and risk of stroke and bleeding. RESULTS: Of 25,120 NOAC patients, 2,981 patients were included in the final cohort. Based on a PDC threshold of >= 80%, the adherence rate over 3, 6, and 12 months was 72%, 65%, and 54%, respectively. For all time periods, the level of adherence significantly increased (P < 0.001), with an increase in stroke risk (based on CHA2DS2VASc scores of 1, 2-3, and 4+); comorbidity (Charlson Comorbidity Index scores of 0, 1-2, and 3+); and risk of bleeding (HAS-BLED scores of 0-1, 2, and 3+). Adjusted all-cause total cost calculated for a 12-month period was significantly lower ($29,742 vs. $33,609) among adherent versus nonadherent users. Drug cost was higher ($5,595 vs. $2,233) among adherent versus nonadherent patients but was offset by lower medical costs ($23,544 vs. $30,485) costs. The overall cost significantly increased for patients with a high risk of bleeding and a high level of comorbidity. CONCLUSIONS: Adherence to NOAC therapy led to a reduction in overall health care cost, since higher drug costs were offset by lower medical (inpatient and outpatient) costs among adherent patients. Cost information based on adherence and risk of stroke and bleeding can help formulary decision makers to assess risk-benefit and help clinicians in developing interventions to reduce patient burden. DISCLOSURES: Funding to acquire the data source was provided by the University of Rhode Island College of Pharmacy, Kingston, to support PhD dissertation work. Deshpande is currently an employee of Pharmerit International. PMID- 29694286 TI - Primary Nonadherence to Oral Anticoagulants in Patients with Atrial Fibrillation: Real-World Data from a Population-Based Cohort. AB - BACKGROUND: Primary nonadherence (not filling a first prescription) is an important yet unstudied aspect of adherence to oral anticoagulant (OAC) therapy. OBJECTIVE: To estimate the rates of primary nonadherence to OACs and determine associated factors in real-world practice. METHODS: This population-based retrospective cohort study set in the Valencia region of Spain (about 5 million inhabitants) included all patients with atrial fibrillation who were newly prescribed OACs during 2011-2014 (N = 18,715). Primary nonadherence was obtained by linking electronic prescription and dispensing data and assessed by type of OAC-vitamin K antagonists (VKAs) or non-VKA oral anticoagulants (NOACs). Covariates were obtained from diverse databases, including electronic medical records. Multivariate logistic regression models were used to assess characteristics associated with primary nonadherence, adjusting for a propensity score to minimize confounding by indication. RESULTS: Primary nonadherence to OACs was 5.62% (VKA 4.29% vs. NOAC 10.81%; P < 0.001), with varying rates among specific drugs (acenocoumarol 4.2%, warfarin 10.9%, apixaban 5.0%, dabigatran 7.9%, and rivaroxaban 15.5%). After adjusting for potential confounders, the likelihood of not filling the first prescription was higher for NOAC patients than for VKA patients (OR = 2.76, 95% CI = 2.41-3.15). High coinsurance in the older groups (OR = 2.63, 95% CI = 1.47-4.69 for patients aged 66-75 years and OR = 3.02, 95% CI = 1.58-5.76 for patients aged > 75 years); being a non-Spanish European (OR = 1.49, 95% CI = 1.12-1.99); and having dementia (OR = 1.72, 95% CI = 1.37-2.16) were positively associated with primary nonadherence. Electronic transmission of prescriptions (OR = 0.85, 95% CI = 0.74-0.96); liver disease (OR = 0.73, 95% CI = 0.54-0.99); and polypharmacy (OR = 0.59, 95% CI = 0.50-0.70) were inversely associated with primary nonadherence. CONCLUSIONS: Overall, primary nonadherence to OACs was relatively low (5%). However, important differences were found between VKAs and NOACs. After adjustment, patients prescribed NOACs nearly tripled the likelihood of nonadherence compared with patients prescribed VKAs, which could negatively affect their effectiveness in clinical practice. Identified correlates were similar to those shown in the limited evidence for other medications. DISCLOSURES: This work was partially supported by the 2013 Collaboration Agreement between the Fundacion para el Fomento de la Investigacion Sanitaria y Biomedica (FISABIO) from the Valencia Ministry of Health and Boehringer Ingelheim, a nonconditioned program to conduct independent research in chronic health care, pharmacoepidemiology, and medical practice variation. Rodriguez-Bernal was funded by the Instituto de Salud Carlos III, Spanish Ministry of Health, and cofinanced by the European Regional Development Fund (grant number RD12/0001/0005). The views presented here are those of the authors and not necessarily those of the FISABIO Foundation, the Valencia Ministry of Health, or the study sponsors. The funding sources had no access to study data and did not participate in any way in the design or conduct of the study, data analysis, decisions regarding the dissemination of findings, the development of the manuscript, or its publication. Peiro has received fees for participation in scientific meetings and courses sponsored by Novartis and Ferrer International. In 2014, Sanfelix-Gimeno participated in an advisory meeting of Boehringer Ingelheim. Garcia-Sempere is a former employee of Boehringer Ingelheim. Rodriguez-Bernal and Hurtado have no relationships relevant to the contents of this article to disclose. This work was previously submitted as an abstract (podium presentation) at the 31st International Society of Pharmacoepidemiology (ISPE) Annual Conference; August 22-26, 2015; Boston, Massachusetts. PMID- 29694287 TI - One-Year Outcomes of an Integrated Multiple Sclerosis Disease Management Program. AB - BACKGROUND: Multiple sclerosis (MS) is associated with high total health care cost, the majority of which is attributable to medications. Patients with MS are less likely to experience relapses, emergency department (ED) visits, and hospitalizations when they are adherent to disease-modifying treatments. Disease management programs are hypothesized to improve medication adherence thereby improving clinical and economic outcomes. OBJECTIVE: To evaluate the clinical and economic effects of a specialty pharmacy and chronic disease management program for patients with MS from a health plan perspective. METHODS: This study was a retrospective analysis using prescription drug claims, medical claims, and electronic medical record information (2013-2015) 1 year before and after enrollment in the disease management program for members with 24 months of continuous health plan coverage. Medication adherence was calculated using proportion of days covered (PDC). Relapse rate was defined as an MS outpatient visit associated with a corticosteroid dispense within 7 days of the visit or an MS hospitalization. Disease progression was assessed using the Modified Expanded Disability Status Scale (mEDSS). Resource use included outpatient visits, ED visits, and hospitalizations. Cost information was collected as health plan-paid amount and was reported in 2013 U.S. dollars. RESULTS: The analysis included 377 patients (mean age 55 years, 76.4% female). After enrollment in the program, 78.7% of the study group had a PDC of >= 0.80 compared with 70.0% before enrollment (P < 0.001). There was no difference in MS relapse rate (0.25 after vs. 0.45 before, P = 0.11) or mEDSS score (3.77 after vs. 3.76 before, P = 0.19). Health care resource utilization was minimal and did not change significantly throughout the study period: mean outpatient visits (13.09 after vs. 13.78 before, P = 0.69); mean ED visits (0.18 after vs. 0.16 before, P = 0.60); and mean hospitalizations (0.12 after vs. 0.12 before, P = 1.00). This nonsignificant finding remained when the analysis was limited to MS-related visits only. Average annual health plan spend per patient on MS medications significantly increased ($55,835 after vs. $40,883 before, P < 0.001). CONCLUSIONS: Specialty pharmacy and chronic disease management for patients with MS can increase the proportion of patients adherent to medication. The increase in health plan spend on MS medications is not offset by savings in health care resource utilization. DISCLOSURES: This study was funded by Kaiser Permanente Washington Health Research Institute and Kaiser Permanente Washington Pharmacy Administration. The authors have no disclosures to report. PMID- 29694291 TI - Letter--Use of Objectives in Research Articles. AB - DISCLOSURES: No funding supported this project. The authors have no conflicts of interest to declare. PMID- 29694288 TI - Predicting Adherence to Chronic Disease Medications in Patients with Long-term Initial Medication Fills Using Indicators of Clinical Events and Health Behaviors. AB - BACKGROUND: Efforts at predicting long-term adherence to medications have been focused on patients filling typical month-long supplies of medication. However, prediction remains difficult for patients filling longer initial supplies, a practice that is becoming increasingly common as a method to enhance medication adherence. OBJECTIVES: To (a) extend methods involving short-term filling behaviors and (b) develop novel variables to predict adherence in a cohort of patients receiving longer initial prescriptions. METHODS: In this retrospective cohort study, we used claims from a large national insurer to identify patients initiating a 90-day supply of oral medications for diabetes, hypertension, and hyperlipidemia (i.e., statins). Patients were included in the cohort if they had continuous database enrollment in the 180 days before and 365 days after medication initiation. Adherence was measured in the subsequent 12 months using the proportion of days covered metric. In total, 125 demographic, clinical, and medication characteristics at baseline and in the first 30-120 days after initiation were used to predict adherence using logistic regression models. We used 10-fold cross-validation to assess predictive accuracy by discrimination (c statistic) measures. RESULTS: In total, 32,249 patients met the inclusion criteria, including 14,930 patients initiating statins, 12,887 patients initiating antihypertensives, and 4,432 patients initiating oral hypoglycemics. Prediction using only baseline variables was relatively poor (cross-validated c statistic = 0.644). Including indicators of acute clinical conditions, health resource utilization, and short-term medication filling in the first 120 days greatly improved predictive ability (0.823). A model that incorporated all baseline characteristics and predictors within the first 120 days after medication initiation more accurately predicted future adherence (0.832). The best performing model that included all 125 baseline and postbaseline characteristics had strong predictive ability (0.837), suggesting the utility of measuring these novel postbaseline variables in this population. CONCLUSIONS: We demonstrate that long-term, 12-month adherence in patients filling longer supplies of medication can be strongly predicted using a combination of clinical, health resource utilization, and medication filling characteristics before and after treatment initiation. DISCLOSURES: This work was supported by an unrestricted grant from CVS Health to Brigham and Women's Hospital. Shrank and Matlin were employees and shareholders at CVS Health at the time of this study; they report no financial interests in products or services that are related to this subject. Spettell is an employee of, and shareholder in, Aetna. This research was previously presented at the 2016 Annual Conference of the International Society for Pharmacoepidemiology; August 25-28, 2016; Dublin, Ireland. PMID- 29694289 TI - Economic Burden Associated with Receiving Inhaled Corticosteroids with Leukotriene Receptor Antagonists or Long-Acting Beta Agonists as Combination Therapy in Older Adults. AB - BACKGROUND: There is a paucity of literature on the health care expenditures associated with different pharmacologic treatments in older adults with asthma that is not well controlled on inhaled corticosteroids (ICS). OBJECTIVE: To compare asthma-related and all-cause health care expenditures associated with leukotriene receptor antagonists (LTRA) versus long-acting beta agonists (LABA) when added to ICS in older adults with asthma. METHODS: A retrospective cohort was constructed using 2009-2010 Medicare fee-for-service medical and pharmacy claims from a 10% random sample of beneficiaries continuously enrolled in Parts A, B, and D in 2009. The sample comprised patients who were aged 65 years and older, diagnosed with asthma, and treated exclusively with ICS + LABA or ICS + LTRA. Outcomes assessed were asthma-related expenditures (medical, pharmacy, and total) and all-cause health care expenditures (medical, pharmacy, and total). Outcomes were measured from the date of the first prescription for the add-on treatment (LABA or LTRA in combination with ICS) after having at least a 4-month "wash-in" period in which patients were receiving no controller, ICS alone, or ICS plus the add-on treatment of the follow-up period. Patients were followed until death, switching to or adding the other add-on treatment, or the end of the study (December 31, 2010). Multivariable regression models with nonparametric bootstrapped standard errors were used to compare all-cause and asthma-related expenditures per patient per month (PPPM) between ICS + LABA and ICS + LTRA users. All models were adjusted for demographics, comorbidities, and county-level health care access variables. RESULTS: The primary analysis included 14,702 patients, of whom 12,940 were treated with ICS + LABA and 1,762 were treated with ICS + LTRA. The mean (SD) follow-up periods were 12.3 (+/- 5.7) months for the ICS + LABA group and 15.3 (+/- 5.1) months for the ICS + LTRA group. Adjusted asthma-related expenditures PPPM were $400 for the ICS + LTRA group compared with $286 for the ICS + LABA group (P < 0.001). However, adjusted total all-cause expenditure PPPM was significantly lower for patients treated with ICS + LTRA ($6,087 for ICS + LTRA compared with $6,975 for ICS + LABA, P = 0.029). CONCLUSIONS: Older adults with asthma often experience economic burden from asthma and other chronic illnesses. Compared with ICS + LTRA, ICS + LABA was associated with lower asthma-related expenditures but with higher all-cause expenditures in older adults. DISCLOSURES: Support for this study was provided by the University of Pittsburgh School of Pharmacy and the Pittsburgh Claude D. Pepper Older Americans Independence Center (NIA P30 AGAG024827). C. Thorpe reports grants from the National Institute of Aging during the conduct of this study. The other authors have nothing to disclose. PMID- 29694293 TI - Development of a Pharmacoeconomic Model to Demonstrate the Effect of Clinical Pharmacist Involvement in Diabetes Management. AB - BACKGROUND: A data collection tool was developed and nationally deployed to clinical pharmacists (CPs) working in advanced practice provider roles within the Department of Veterans Affairs to document interventions and associated clinical outcomes. Intervention and short-term clinical outcome data derived from the tool were used to populate a validated clinical outcomes modeling program to predict long-term clinical and economic effects. OBJECTIVE: To predict the long-term effect of CP-provided pharmacotherapy management on outcomes and costs for patients with type 2 diabetes. METHODS: Baseline patient demographics and biomarkers were extracted for type 2 diabetic patients having > 1 encounter with a CP using the tool between January 5, 2013, and November 20, 2014. Treatment biomarker values were extracted 12 months after the patient's initial visit with the CP. The number of visits with the CP was extracted from the electronic medical record, and duration of visit time was quantified by Current Procedural Terminology codes. Simulation modeling was performed on 3 patient cohorts-those with a baseline hemoglobin A1c of 8% to < 9%, 9% to < 10%, and >= 10%-to estimate long-term cost and clinical outcomes using modeling based on pivotal trial data (the Archimedes Model). A sensitivity analysis was conducted to assess the extent to which our results were dependent on assumptions related to program effectiveness and costs. RESULTS: A total of 7,310 patients were included in the analysis. Analysis of costs and events on 2-, 3-, 5-, and 10-year time horizons demonstrated significant reductions in major adverse cardiovascular events (MACEs), myocardial infarctions (MIs), episodes of acute heart failure, foot ulcers, and foot amputations in comparison with a control group receiving usual guideline-directed medical care. In the cohort with a baseline A1c of >= 10%, the absolute risk reduction was 1.82% for MACE, 1.73% for MI, 2.43% for acute heart failure, 5.38% for foot ulcers, and 2.03% for foot amputations. The incremental cost-effectiveness ratios for cost per quality-adjusted life-year during the 2-, 3-, 5-, and 10-year time horizons were cost-effective for the cohorts of patients with a baseline A1c of 9% to < 10% and >= 10%. CONCLUSIONS: CPs acting as advanced practice providers reduced A1c from baseline for veterans with type 2 diabetes compared with modeled usual care. Archimedes modeling of the A1c reductions projects a decreased incidence of diabetes complications and overall health care spending when compared with modeled usual care. DISCLOSURES: There was no outside funding source or sponsor for this project. None of the authors report any conflicts of interest. The views expressed in this article are those of the authors and do not necessarily reflect the views or policies of the U.S. Department of Veterans Affairs. Preliminary data from this project were previously presented in abstract form at the Academy of Managed Care Pharmacy 27th Annual Meeting and Expo; April 8-10, 2015; in San Diego, California. PMID- 29694292 TI - The Effect of Plan Type and Comprehensive Medication Reviews on High-Risk Medication Use. AB - BACKGROUND: In 2007, the Centers for Medicare & Medicaid Services (CMS) instituted a star rating system using performance outcome measures to assess Medicare Advantage Prescription Drug (MAPD) and Prescription Drug Plan (PDP) providers. OBJECTIVE: To assess the relationship between 2 performance outcome measures for Medicare insurance providers, comprehensive medication reviews (CMRs), and high-risk medication use. METHODS: This cross-sectional study included Medicare Part C and Part D performance data from the 2014 and 2015 calendar years. Performance data were downloaded per Medicare contract from the CMS. We matched Medicare insurance provider performance data with the enrollment data of each contract. Mann Whitney U and Spearman rho tests and a hierarchical linear regression model assessed the relationship between provider characteristics, high-risk medication use, and CMR completion rate outcome measures. RESULTS: In 2014, an inverse correlation between CMR completion rate and high-risk medication use was identified among MAPD plan providers. This relationship was further strengthened in 2015. No correlation was detected between the CMR completion rate and high-risk medication use among PDP plan providers in either year. A multivariate regression found an inverse association with high-risk medication use among MAPD plan providers in comparison with PDP plan providers in 2014 (beta = -0.358, P < 0.001) and 2015 (beta = -0.350, P < 0.001), the CMR completion rate in 2015 (beta = -0.221, P < 0.001), and enrollee population size in 2015 (beta = -0.203, P = 0.001). CONCLUSIONS: This study found that MAPD plan providers and higher CMR completion rates were associated with lower use of high-risk medications among beneficiaries. DISCLOSURES: No outside funding supported this study. Silva Almodovar reports a fellowship funded by SinfoniaRx, Tucson, Arizona, during the time of this study. The other authors have nothing to disclose. PMID- 29694290 TI - The Effect of Clinical Pharmacist-Led Comprehensive Medication Management on Chronic Disease State Goal Attainment in a Patient-Centered Medical Home. AB - BACKGROUND: Clinical pharmacy services were initiated at 7 of 11 clinics within a primary care network (PCN), which was designated as a patient-centered medical home and was affiliated with a large academic medical center in October 2014. The goal of the service was to target patients with uncontrolled chronic conditions, specifically diabetes. Patients met with a clinical pharmacist through individual clinic and telephonic appointments, in addition to usual appointments with physicians as needed. While managing patients with diabetes, many clinicians assess a patient's hemoglobin A1c (A1c), along with blood pressure and cholesterol, as indicators of disease state control and cardiovascular risk. These 3 parameters were combined into a bundled response score (BRS) in order to assess whether the addition of the clinical pharmacy service had a positive effect on patient therapeutic goal attainment rates for these areas. OBJECTIVES: To assess the effect of pharmacist-led comprehensive medication management (CMM) on therapeutic goal attainment rates for glycemic, blood pressure, and dyslipidemia outcomes in PCN patients, which was represented by a BRS based on how many therapeutic goals were met. METHODS: This retrospective study was conducted using patients seen in clinics within the PCN between October 1, 2014, and October 31, 2015. Patients were included in the intervention group if they were actively managed by a PCN pharmacist and had a diagnosis of diabetes. A control group included patients without access to a PCN pharmacist and was matched to the intervention group by baseline A1c results. Based on current clinical practice guidelines, therapeutic goals for the BRS were set as A1c <= 8%, blood pressure <= 140/90 mmHg, and prescription of a moderate- to high intensity statin for dyslipidemia. In addition to the primary outcome, the individual components of the BRS were assessed, as well as the average number of medications used between groups. RESULTS: There were 95 patients included in the intervention group, with 132 patients included in the usual care group. Patients in the intervention group had significantly higher rates of therapeutic goal attainment for the 3 endpoints (40% vs. 12%, P < 0.001). The intervention group had statistically significantly higher improvements in the individual areas of A1c, blood pressure, and statin goal attainment. There were no significant differences in the number of medications for diabetes or antihypertensive medications used between groups at the time of study termination. CONCLUSIONS: This study demonstrated that the addition of CMM services provided by clinical pharmacists in this PCN had a positive effect on therapeutic goal attainment rates for patients with diabetes. This finding suggests that the integration of clinical pharmacists into primary care clinics could have positive effects on the clinical outcomes of diabetic patients in glycemic control, blood pressure, and statin treatment, in accordance with current guidelines. DISCLOSURES: Support for this study was provided to Wilson by the National Center for Advancing Translational Sciences, National Institutes of Health, through grant number ULI TR001860. The content of this article is solely the responsibility of the authors and does not necessarily represent the views of the National Institutes of Health. The authors have nothing additional to disclose. PMID- 29694294 TI - Characterization of a Western Pacific Zika Virus Strain in Australian Aedes aegypti. AB - Zika virus (ZIKV) is a globally emerging arbovirus responsible for widespread epidemics in the western Pacific, the Americas, and Asia. The virus predominately circulates in urban transmission cycles between Aedes aegypti and humans. Australia is considered at risk to outbreaks of ZIKV due to the presence of A. aegypti populations in northern areas of the state of Queensland. Furthermore, close proximity to epidemic regions has led to almost 50% of imported cases reported since 2012 originating in the Pacific region. We conducted the first vector competence experiments with A. aegypti from three Australian populations for a western Pacific strain of ZIKV. When exposed to bloodmeals containing between 105 and 108 tissue culture infectious dose (TCID)50/mL of virus, infection, dissemination, and transmission, rates were <10%. In comparison to using frozen virus stock, exposing mosquitoes to freshly cultured virus also did not increase infection or transmission rates. It was only when bloodmeal titers exceeded 108 TCID50/mL that infection rates approached 50% and transmission rates increased to >20%. However, this concentration of virus is considerably higher than levels previously reported in blood samples from viremic humans. The Australian A. aegypti tested appear to express a midgut barrier to ZIKV infection, as 50% of mosquitoes that became infected developed a disseminated infection, and 50% of those mosquitoes transmitted the virus. Overall, these results suggest that while Australian A. aegypti strains are able to transmit the western Pacific ZIKV strain, they are relatively inefficient vectors of the virus. PMID- 29694296 TI - Situating Cyberzone: Black lesbian identity in comics. AB - Cyberzone is a fitting place to start any discussion around Black lesbian identity in comics, as it is the first comic book that this researcher could find which features a Black lesbian female lead superheroine. Cyberzone was self published by Jimmie Robinson in 1994 and later re-vamped into a mini-comic series called Amanda and Gunn with Image Comics. First, this article deconstructs Cyberzone through the lens of Cultural Prism Theory (CPT). Second, this article situates Cyberzone within the framework of CPT to address Cyberzone's place within the comic book ecosystem. Finally, this essay offers a close reading of Cyberzone, issues #1-#4, against the backdrop of the intersectional framework Black Queer Identity Matrix. During this process, the researcher demonstrates how Cyberzone is a powerful site of resistant cultural commentary. PMID- 29694295 TI - Psychological Functioning of Women Taking Illicit Drugs during Pregnancy and the Growth and Development of Their Offspring in Early Childhood. AB - OBJECTIVE: The aim of this research was to assess psychosocial history and psychological functioning in women who use drugs during pregnancy and determine how drug exposure affects child development. METHODS: Pregnant women using marijuana (n = 38) and cocaine (n = 35) and receiving methadone maintenance (n = 24), along with a control (n = 49) group of pregnant women, were enrolled and followed every six months through 18-24 months postnatally. RESULTS: There was a significantly higher incidence of mental illness among mothers in the drug-using groups. Prenatal stress and late-term drug severity scores were significantly higher in the mothers who used cocaine and methadone, who were also more likely to have abuse and incarceration histories. At 12 months, there were significantly higher rates of drug use in the marijuana group. Anxiety scores were highest in the methadone group. At 18 to 24 months, the methadone group reported significantly more stress, and methadone and marijuana groups had significantly higher anxiety and depression scores. At birth, neonates from the methadone and marijuana groups had significantly smaller head circumferences, with the smallest values in the methadone group. At one year, children in the cocaine group had significantly lower Bayley Scales of Infant Development-Third Edition (Bayley III) cognitive and motor scores. At 18 to 24 months, children in the methadone group had significantly smaller head circumferences and Bayley-III cognitive scores. Children in the methadone and cocaine groups had a significantly higher incidence of atypical neurological examinations at 6 to 9 and 18 to 24 months. CONCLUSIONS: Mothers in the methadone and cocaine groups presented with more severe prenatal drug use and psychosocial risk factors relative to women who used primarily marijuana. Children in the cocaine and methadone groups were neurologically atypical relative to others at study end. Mothers in the marijuana group reported chronic drug use as well as anxiety and depression at follow-up. At birth, children in the marijuana group were smaller, but this resolved with time. Similarly, children in the cocaine group had motor and cognitive delays that resolved by age two. Children in the methadone group had persistent growth and cognitive deficits. Their mothers demonstrated more anxiety, depression, and stress, the combination of which left these women and children liable to face ongoing psychosocial struggle and psychological distress. Dual interventions for mother and child should be considered in attempting to optimize outcome. PMID- 29694297 TI - Survival angst: Reading Hothead Paisan in the Trump era. AB - This essay considers Diane DiMassa's 1990s comic book series Hothead Paisan: Homicidal Lesbian Terrorist alongside the recent rise and visibility of White supremacist movements following the 2016 United States election. While Hothead's acts of queer revenge primarily target White heterosexual cismen, several issues feature Hothead taking aim at neo-Nazis and the KKK. Exploring the way in which Hothead's relationship to debility and capacity is mediated by her gender, sexuality, and race, the essay argues that a biopolitical approach, including the recent scholarly turn to the non-human, can provide a useful framework for approaching interlocking systems of violence and oppression that go beyond traditional intersectional models of resistance. PMID- 29694298 TI - Do Older Adults and Those Recovered from Low Back Injury Share Common Muscle Activation Adaptations? AB - Theoretical models suggest trunk muscle activation compensates for spinal systems impairments. The purpose of this study was to determine if two populations (older adults and those recovered from a lower back injury (rLBI)) with spinal system impairments have similar muscle activation patterns to each other, but differ from controls. Trunk electromyograms collected from 12 older adults, 16 rLBI, and 19 controls during two dynamic tasks showed that older adults and rLBI had higher activation amplitudes, sustained temporal and more synergistic activation relative to controls. However, differences found between older adults and rLBI suggest that spinal system impairments differed between groups or that recent pain (rLBI) uniquely influenced muscle activation. This sheds light on our understanding of the relationship between spinal system impairments and muscle activation. PMID- 29694299 TI - "There is no such thing as a straight woman": Queer female representations in South Asian graphic narratives. AB - This essay provides a brief overview of some recent Indian and Bangladeshi comics and graphic novels, whether print-based or online, which feature queer female characters. The essay contextualizes these texts with respect to the anti-LGBTQ+ legal climate in South Asian countries, but also places them within a larger trajectory of literary representations of queer (female) love in the Indian subcontinent. The texts under examination range from print graphic novels and indie comics anthologies in India to comic strips brought out by queer activists working for LGBTQ+education and advocacy in Bangladesh. Taken together, they offer diverse portrayals of female-centric love and desire that challenge hetero patriarchal representations of desi women. PMID- 29694300 TI - Representations of same-sex relationships between female characters in all-ages comics: Princess Princess Ever After and Lumberjanes. AB - Representations of lesbian, gay, bisexual, transgender, and queer (LGBTQ) characters in comics for an all-ages readership have emerged in the United States in the early twenty-first century. This essay examines the narrative constructions of same-sex relationships between female characters in two all-ages speculative fiction comics, Princess Princess Ever After by Katie O'Neill, and Lumberjanes, created by Shannon Watters, Grace Ellis, Noelle Stevenson, and Brooke Allen. PMID- 29694302 TI - Introduction: "Suffering Sappho!": Lesbian content and queer female characters in comics. AB - Comics have been an important locus of queer female identity, community, and politics for generations. Whether taking the form of newspaper strips, comic books, or graphic novels and memoirs, the medium has a long history of featuring female same-sex attraction, relationships, and identity. This special issue explores the past place, current presence, and possible future status of lesbianism in comics. It features essays about cartoonists such as Jennifer Camper, characters such as Wonder Woman, and titles such as Lumberjanes. This special issue also includes a roundtable that examines underrepresented identities in lesbian comics. These pieces address subjects ranging from the depiction of a Latina lesbian protagonist in AMERICA: The Life and Times of America Chavez and the debut of the first lead Black lesbian female superheroine in Cyberzone to the presentation of queer women in graphic novels from South Asia and the experience of re-reading Hothead Paisan in the age of Trump. PMID- 29694301 TI - Willingness to provide a hair sample for drug testing among electronic dance music party attendees. AB - BACKGROUND: Nondisclosure of drug use on surveys is common, and many drug users unknowingly ingest adulterant or replacement drugs, which leads to underreporting of use of these drugs. Biological testing can complement survey research, and hair testing is an appealing method, as many drugs are detectable for months post use. We examined willingness to donate a hair sample to be tested among those surveyed in a population at high risk for consuming adulterated drugs-electronic dance music (EDM) party attendees. METHODS: We surveyed 933 adults entering EDM parties in New York City in 2017. Hair donation response rates and reasons for refusal were examined from this cross-sectional study. RESULTS: A third (n = 312; 33.4%) provided a hair sample. Lack of interest (21.0%), lack of time (19.8%), not wanting a lock of hair cut (17.7%), and disinterest in having hair cut in public (13.8%) were the main reported reasons for refusal; 4.7% refused because they could not receive results. Past-year drug users were more likely to fear identification than nonusers (P < .001). Asian participants were at lower odds of providing a hair sample (adjusted odds ratio [aOR] = 0.53, 95% confidence interval [CI] = 0.32-0.87), and those reporting past-year use of LSD (aOR = 1.62, 95% CI = 1.11-2.35), opioids (nonmedical; aOR = 1.93, 95% CI = 1.25-2.99), and/or methamphetamine (aOR = 3.43, 95% CI = 1.36-8.62) were at higher odds of providing a sample than nonusers of these drugs. CONCLUSIONS: Only a third of participants provided a hair sample, and we found individual-level differences regarding willingness to provide a sample. Factors contributing to refusal should be considered to increase response rates and generalizability of results. PMID- 29694303 TI - Cannabinoid receptor 2: a potential novel therapeutic target for sepsis? AB - OBJECTIVE: Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. It is the most common cause of death among critically ill patients in non-coronary intensive care units and the incidence continues to rise. Although advanced management was applied, the prognosis of sepsis patients remains poor. As a G-protein coupled receptor, cannabinoid receptor 2 (CB2R) was implicated in a wide variety of diseases. In this study, we aimed to investigate the role of CB2R in sepsis. METHODS: Literature search was performed using "sepsis" and "Cannabinoid Receptor" as search terms in PubMed, EMbase, and the Cochrane Library. RESULTS AND DISCUSSION: Briefly, 97 records were identified by the search strategy, of which 76 were duplicate or irrelevant publications. With the anti-inflammatory and immunomodulatory effects, CB2R is a novel and promising therapeutic target in the management of sepsis. Indeed, specific CB2R agonists have been reported to attenuate leukocyte recruitment, oxidative burst, systemic inflammatory mediator release, bacteremia, and lung tissue damage, while improving survival in different sepsis models. In addition, autophagy has also been implicated in the protective role of CB2R activation in sepsis. However, almost all of the current outcomes result from animal studies or in vitro cultured cells. Due to the lack of clinical evidence and the ambiguous mechanisms underlying, the clinical application of CB2R stimulation in sepsis is limited. Further studies are needed to delineate the therapeutic effect and the related pathways of CB2R agonists in sepsis. PMID- 29694304 TI - Does the Internet provide patients or clinicians with useful information regarding faecal incontinence? An observational study. AB - BACKGROUND: The Internet has become an important platform for information communication. This study aim to investigate the utility of social media and search engines to disseminate faecal incontinence information. METHODS: We looked into Social media platforms and search engines. There was not a direct patient recruitment and any available information from patients was already on public domain at the time of search. A quantitative analysis of types and volumes of information regarding faecal incontinence was made. RESULTS: Twelve valid pages were identified on Facebook: 5 (41%) pages were advertising commercial incontinence products, 4 (33%) pages were dedicated to patients support groups and 3 (25%) pages provided healthcare information. Also we found 192 Facebook posts. On Twitter, 2890 tweets were found of which 51% tweets provided healthcare information; 675 (45%) were sent by healthcare professionals to patients, 530 tweets (35.3%) were between healthcare professionals, 201 tweets (13.4%) were from medical journals or scientific books and 103 tweets (7%) were from hospitals or clinics with information about events and meetings. The second commonest type of tweets was advertising commercial incontinence products 27%. Patients tweeted to exchange information and advice between themselves (20.5%). In contrast, search engines as Google/Yahoo/Bing had a higher proportion of healthcare information (over 70%). CONCLUSION: Internet appears to have potential to be a useful platform for patients to learn about faecal incontinence and share information; however, given one lack of focus of available data, patients may struggle to identify valid and useful information. PMID- 29694305 TI - The use of local anesthesia to perform lower limb revascularization in the fragile patient with critical limb ischemia. AB - Patients with critical limb ischemia are usually compromised, frequently making administration of general or regional anesthesia problematic. We treated 3 fragile patients presenting contraindications to undertake traditional anesthetic techniques for lower limb revascularization, in whom local anesthesia with conscious sedation was used to complete the operation. An axillo-bifemoral, a unilateral axillo-femoral and a femoro-femoral bypass were performed. Procedure was uneventful in all three cases despite the coexistence of specific surgical challenges (distal anastomosis at the profunda in two cases, redo surgery and scarred groin in the third). Surgical revascularization under local anesthesia may be considered in selected high risk patients. PMID- 29694306 TI - Totally laparoscopic resection and extraction of specimens via transanal route in synchronous colon and gastric cancer. AB - INTRODUCTION: Synchronous colon and gastric cancer is a rare clinical entity. In the present case, it is aimed to show that in a patient with synchronous colon and gastric cancer, laparoscopic resection can be safely performed and both specimens can be delivered through a natural orifice. In our knowledge, this is the first example showing the delivery of the gastric resection specimen through the anus in a human being. CASE REPORT: Sixty-six years old male patient with an upper gastrointestinal bleeding and obstruction symptoms was admitted to our department and the evaluation revealed an advanced stage gastric and a synchronous colon cancer. A laparoscopic palliative subtotal gastrectomy with a subtotal colectomy was performed. All anastomoses were performed intracorporeally and colectomy and subtotal gastrectomy specimens were successfully delivered via trans-anal route without any difficulty. Despite major abdominal organ resections, the patients required quite less analgesics in the postoperative period. DISCUSSION: Specimen extraction through the natural orifices eliminates the need and problems of performing additional abdominal incisions to the patients which also leads to reduced postoperative pain. Synchronous surgical procedures do not prevent the natural orifice surgery. PMID- 29694307 TI - Laparoscopic cholecystectomy for acute cholecystitis: are intended operative approach, timing and outcome affected by BMI? A multicenter retrospective study. AB - BACKGROUND: Laparoscopy is the gold-standard for cholecystectomy after acute cholecystitis, but the issue is controversial in obese subjects. PATIENTS AND METHODS: We reviewed 464 patients operated for acute cholecystitis (59 open and 405 laparoscopic) over the last five years at St Orsola University Hospital Bologna and Umberto I University Hospital-Rome, comparing retrospectively: 1) BMI < 30 (397 patients) and BMI =/> 30 (67 patients) and moreover 2) BMI < 25 (207 patients) and BMI =/> 25 (257 patients). RESULTS: In the first comparison, obese patients showed higher cardiovascular co-morbidity (61.1% vs 44.5%, p=0.01), worse symptoms (Murphy's sign positive in 92.5% vs 80.8%, p=0.02; fever >38.5 degrees C in 88.0% vs 76.0 %, p=0.02) and significant radiologic imaging (95.5% vs 85.1%, p=0.01) of acute cholecystitis. Laparoscopy was used in 83.6% of obese patients vs 87.9% without any difference, and operative time or conversion rate were similar. According to Tokyo Guidelines 2013, the number of patients who underwent surgery within 3 days or after 6 weeks was similar without statistical difference between the two groups. Hospital stay, morbidity and mortality were similar. Complications were seen in 25.4% of obese patients vs 15.9% (p= 0.03), mainly represented by wound infections. The second comparison did show no difference between two groups BMI =/>25 and BMI < 25. CONCLUSIONS: Our retrospective multicenter study showed no difference related to intended operative approach, timing and outcome in higher BMI versus lower BMI patients operated for acute cholecystitis. PMID- 29694308 TI - Severe neurological complication following adjustable gastric banding. AB - AIM: In the last years with the increase of bariatric surgery, first of all as a result of new indications, a rise in the incidence of nutrient-related complications has been observed. Currently little is known about the impact of post-bariatric malnutrition and neurological complications. Wernicke's encephalopathy is a severe neurological syndrome which occurs as a result of thiamine deficiency. Wernicke-Korsakoff syndrome must be considered a serious neurological complication of bariatric surgery with significant morbidity and mortality, with rapidly progressing neurological symptoms, and must be treated immediately. CASE REPORT: We report the case of a 35 years-old male patient, affected by morbid obesity, anxious-depressive syndrome and alcohol use disorder, who after adjustable gastric banding implanted in another hospital developed a severe malnutrition and neurological syndrome. The patient showed poor adherence to the follow-up and to the dietary indications and after all, we needed to place a PEG for enteral nutrition in order to resolve the malnutrition condition and the neurological syndrome. Our experience emphasizes that preoperative selection and assessment of a patient's nutritional status according to guidelines, is required to identify potential problems, and that bariatric surgeons or physicians caring for patient who have undergone bariatric surgery should be familiar with the constellation of nutritional and neurological disorder that may occur after surgery. CONCLUSION: We want to remark the importance of preoperative selection of the patients, the follow-up and the cooperation between patient and physician in order to obtain the best result and avoid severe complications. PMID- 29694309 TI - Malakoplakia of the large intestine: an incidental extremely rare finding. AB - Malakoplakia is a rare inflammatory disease, most commonly found in the urinary tract. It appears be related to a functional deficiency of macrophages, resulting in an inability to destroy digested bacteria and it is associated with various conditions that cause immunodeficiency. A rare case of malakoplakia of the colon in a healthy 68-year old male is presented. The patient underwent emergency surgery with colon resection and an end stoma with closure of the distal bowel (Hartmann's procedure), due to incarcerated ventral hernia and sigmoid-colon rupture. He underwent reversal of the Hartmann's procedure four months after the initial operation. The histological examination from the anastomotic rings revealed Michaelis-Gutmann bodies that are pathognomonic of malakoplakia. He received per os ciprofloxacin, bethanecol and ascorbic acid for 12 months. Follow up endoscopy did not exhibit any signs of the disease. A case of a healthy patient presenting with malakoplakia without any underlying disease that causes immunodeficiency is extremely rare. Treatment of malakoplakia involves the eradication of microorganisms. Cholinergic agonists, such as bethanechol and ascorbic acid, as well as antimicrobial treatment with trimpethoprim/sulphamethoxazol and rifampicin are most commonly being used. Long term antimicrobial treatment has been reported (6 months to 3 years). PMID- 29694310 TI - Superior vena cava syndrome due to central port catheter thrombosis: a real life threatening condition. AB - Superior vena cava syndrome (SVCS) represents undoubtedly a rare life-threatening condition. Herein, we present a rare case of a 69-year-old woman, with a history of hepatic flexure tumor and an indwelling central venous port, presenting with acute signs and symptoms of SVCS due to thrombosis of the catheter. The patient was treated with intravenous anticoagulation and fibrinolytic therapy and showed regression of symptoms. It is reported that central venous catheters are routinely used in clinical practice mainly in oncological cases for chemotherapy, parenteral nutrition or dialysis. However, complications related to implantation technique, care, or maintenance of these catheters may arise. High index of suspicion for SVCS should always arise when a patient presents with common symptoms and long-term central catheters, in order to avoid unfavorable outcomes. Local thrombolysis appears to be a safe and effective therapy for port catheter associated thrombosis. PMID- 29694311 TI - Primary abdominal wall endometriosis: presentation of rarely seen two cases. AB - Abdominal wall endometriosis is a pathology which usually develops after preceding surgeries on the surgical incision line and shows clinical manifestation especially during menstrual cycle. However, primary abdominal wall endometriosis is seen very rarely and it is a condition developing without a previous history of surgery. In this paper, we aimed to provide a contribution to the theories of pathogenesis of the disease by presenting two cases of primary abdominal wall endometriosis in two patients without previous history of surgery. PMID- 29694312 TI - A case of peduncolated Brunner's gland hamartoma. AB - AIM: To report a case of Brunner's gland hamartoma (BGH) in patient treated with surgical resection. CASE REPORT: A 73 years old male patient that was admitted with melena. The preoperative investigations suggested a suspected duodenal large polypoidal mass. A local resection was performed. Surgical resection is actually considered the best treatment for this lesion. DISCUSSION: Brunner's glands were first described by Brunner in 1688. Hamartoma designates an excessive focal overgrowth of mature normal cells and tissues, composed of identical cellular elements. Most patients with Brunner's gland hamartoma are asymptomatic or have nonspecific complaints. CONCLUSION: BHG is a rare tumor arising from the Brunner's gland of the duodenum, considered entirely benign, although there have been occasionally reports of malignant foci inside. PMID- 29694313 TI - Paget's disease of the male breast: case report and a point of view from actual literature. AB - INTRODUCTION: Paget disease of the nipple in man is a very rare breast cancer, and there are not standard procedures or guidelines. In any cases, a Paget's disease could hide an invasive ductal breast cancer. CASE DESCRIPTION: We report the case of a 77-years old man affected by Alzheimer's disease, who presented to our attention because of an ulcerated palpable mass in the right nipple. A biopsy of the lesion showed "intra-epidermic proliferation of epitelioid cells, associated with linfo-plasmacellular infiltration of superficial dermis, compatible with Paget's disease (pTis)". We discussed the case in the multidisciplinary meeting and decided to subject the patient to surgery, so a right mastectomy plus sentinel lymph node biopsy (SLNB) were performed. Histo pathological examination revealed "invasive ductal carcinoma of the breast, associated with a small component of in situ ductal carcinoma and Paget's disease of the nipple with superficial ulceration". Resection margins were free. Sentinel lymph node was negative. Biological features were as follows: ER 95%, PR 60%, Her 2/neu 1+, Ki-67 35%. The patient was discharged in the third post-operative day in good conditions. In the following weeks the patient's healing process was good and free of complications. CONCLUSIONS: Clinical recognition of Paget's disease is very important also in man, because it can be the alarm bell for an underlying invasive ductal breast cancer, often more aggressive than in woman. PMID- 29694314 TI - Using reversed items in Likert scales: A questionable practice. AB - BACKGROUND: The use of positively worded items and reversed forms aims to reduce response bias and is a commonly used practice nowadays. The main goal of this research is to analyze the psychometric implications of the use of positive and reversed items in measurement instruments. METHOD: A sample of 374 participants was tested aged between 18 and 73 (M=33.98; SD=14.12), 62.60% were women. A repeated measures design was used, evaluating the participants with positive, reversed, and combined forms of a self-efficacy test. RESULTS: When combinations of positive and reversed items are used in the same test the reliability of the test is flawed and the unidimensionality of the test is jeopardized by secondary sources of variance. In addition, the variance of the scores is reduced, and the means differ significantly from those in tests in which all items are either positive or reversed, but not combined. CONCLUSIONS: The results of this study present a trade-off between a potential acquiescence bias when items are positively worded and a potential different understanding when combining regular and reversed items in the same test. The specialized literature recommends combining regular and reversed items for controlling for response style bias, but these results caution researchers in using them as well after accounting for the potential effect of linguistic skills and the findings presented in this study. PMID- 29694315 TI - Is intelligence equivalent to executive functions? AB - BACKGROUND: Since the mid 19th century, cognitive and behavioral neurosciences have attempted to find the neurological bases of intellectual abilities. During the early 20th century the psychometric concept of "intelligence" was coined; and toward the end of the 20th century the neuropsychological concept of "executive functions" was introduced. Controversies, however, remain about the unity or heterogeneity of so-called executive functions. METHODS: It is proposed that two major executive functions could be separated: metacognitive -or intelectual- and emotional/motivational. A similar distinction has been suggested by several authors. Standard definitions of intelligence implicitly assume that executive functions represent the fundamental components of intelligence. RESULTS: Research has demonstrated that, if considered as a whole, executive functions only partially correspond to the psychometric concept of intelligence; whereas some specific executive functions clearly correspond to intelligence, some others do not involve intelligence. CONCLUSIONS: If using a major distinction between metacognitive -or simply "intellectual"-executive functions, and emotional/ motivational -or simply non-intellectual-executive functions, it becomes evident that general intelligence can be equated with metacognitive executive functions but not with emotional/ motivational executive functions. PMID- 29694317 TI - Psychophysiological response to social stressors: Relevance of sex and age. AB - BACKGROUND: Understanding the factors involved in the psychophysiological response of people in acute stressful situations is crucial to the prevention and treatment of stress-related health problems. We aim to integrate the results of studies investigating the role of sex and age in the inter-individual variability in several biomarkers of the stress response. METHODS: We summarize the main findings of our research group and other laboratories regarding sex and age related differences in the psychophysiological response to psychosocial stress. RESULTS: Sex-related differences in the stress response are observed in blood pressure and cortisol, but not in heart rate, heart rate variability, or salivary alpha-amylase. Additionally, age may explain differences in cortisol levels and basal sympathetic nervous system activity. CONCLUSIONS: The results highlight the importance of taking sex and age into account in order to understand the stress response and its possible negative effects on health. PMID- 29694316 TI - Mindfulness-based stress reduction in adolescents with mental disorders: A randomised clinical trial. AB - BACKGROUND: Currently, there is a strong movement to implement mindfulness interventions with young people. The objective of this randomised clinical trial was to assess the potential effects of a mindfulness-based stress reduction (MBSR) programme for adolescent outpatients in mental health facilities in Cordoba, Spain. METHOD: A total of 101 adolescents aged 13-16 years old, receiving psychological or psychiatric treatment for various disorders, were eligible for the study. The participants’ scores on mindfulness, self esteem, perceived stress, state-trait anxiety and other psychological symptoms were examined at two time-points. Eighty adolescents completed the study (MBSR+TAU group = 41; TAU group = 39). RESULTS: The MBSR+TAU group showed a statistically significant decrease in anxiety state compared to the treatment-as usual (TAU) group. No statistically significant differences were found between groups on the other scores, but the intervention was observed to have a greater impact on the MBSR+TAU group than in the TAU group, especially in reducing symptoms of depression, anxiety, paranoia and perceived stress. CONCLUSION: These results suggest that MBSR may be a useful adjunct treatment for adolescents in mental health facilities. PMID- 29694318 TI - Well-being in schizotypy: The effect of subclinical psychotic experiences. AB - BACKGROUND: Schizotypy is a multidimensional construct that includes positive, negative, and disorganized dimensions. The healthy schizotypal model suggests that positive schizotypal features could be associated with better psychological functioning. The aim of this study was to analyze whether schizotypal features are associated with subjective and psychological well-being, and consider whether psychotic-like experiences affect well-being. METHOD: These relationships were investigated in two hundred non-clinical Spanish adults (mean age = 34.80, S.D . = 14.20). RESULTS: Negative schizotypal features were associated with lower well being, whereas positive schizotypal features were related with greater well being. Individuals with subclinical psychotic experiences scored lower for psychological well-being than individuals without these experiences. CONCLUSIONS: The study suggests that some positive features may be beneficial for well-being while others are associated with lower well-being. PMID- 29694319 TI - Victimisation through bullying and cyberbullying: Emotional intelligence, severity of victimisation and technology use in different types of victims. AB - BACKGROUND: Bullying and cyberbullying are global public health problems. However, very few studies described prevalence, similarities and differences among face-to-face victims, cybervictims and students who are victimised through both bullying and cyberbullying. This study was conducted to describe these different patterns of victimisation and severity of victimisation, emotional intelligence and technology use in different types of victims. METHOD: A total number of 2,139 secondary school students from 22 schools, randomly selected from all provinces of Andalusia, Spain, participated in this study. Information about bullying, cyberbullying, social networking sites use and perceived emotional intelligence was collected. RESULTS: Face-to-face victimisation only is the most common type of victimisation followed by mixed victimisation. Cybervictimisation only is rare. Mixed victims score higher in severity of bullying and present higher emotional attention than face-to-face victims. CONCLUSIONS: Most victims of cyberbullying are also face-to-face victims. Holistic approach that focuses on different problems at the same time seems to be needed to tackle these behaviours. PMID- 29694320 TI - Agreement on reporting acts of aggression in couples in a community sample. AB - BACKGROUND: Agreement about acts of aggression in couples on the Conflict Tactics Scales (CTS-2) was evaluated. METHOD: We conducted a quota sampling method to recruit a community sample of 590 heterosexual adult couples from the Region of Madrid (Spain). RESULTS: Prevalence rates based on the maximum dyadic report identified more aggressive behaviors than did individual reports of perpetration and victimization in men and women. Partner agreement about physical and psychological aggression was significant and moderate. However, partners agreed that Negotiation of Conflicts and Positive Behaviors assessed with the Dyadic Adjustment Scale were higher than the behaviors of the Physical Assault Scale. CONCLUSIONS: Correction factors are provided to estimate the prevalence of aggressive behavior and injuries when we only had individual reports of aggression. Partner agreement reveals the existence of variables at the individual level that significantly influence the assessment of aggression in the couple. PMID- 29694321 TI - Problematic Internet use, maladaptive future time perspective and school context. AB - BACKGROUND: Spain is among the European countries with the highest prevalence of adolescents at risk of Internet addiction, a problem that could be linked to youth unemployment and leaving education early. This research evaluated the role of three variables relative to school context on Problematic Internet Use (PIU) and on the relationship between PIU and Maladaptive Future Time Perspective (MFTP, defined as an excessive focus on the present and a fatalistic attitude towards the future, a variable that had not previously been studied in terms of its relationship to adolescents' PIU). METHOD: The study was carried out with 1288 adolescents, aged 12 to 16 years old, enrolled at 31 secondary schools in Madrid, Spain. RESULTS: As expected, we found that MFTP and hostile treatment by teachers were associated with an increase in PIU, whereas school appreciation was associated with a decrease in PIU. In addition, hostile treatment by teachers had a moderate effect on the MFTP-PIU relationship. CONCLUSIONS: In order to prevent PIU it is important to foster confidence in adolescents in their own potential to build the future from the present through positive interaction with teachers, stimulating an appreciation of school within these digital natives' peer group culture. PMID- 29694322 TI - Adolescents' sensitivity to children's supernatural thinking: A preparation for parenthood? AB - BACKGROUND: Young children often use magical explanations to account for ordinary phenomena (e.g., "The sun's not out today because it is mad"). We labeled these explanations supernatural thinking. Previous research reports that supernatural thinking attributed to preschool-age children evokes both positive affect and perceptions of helplessness from both adults and older (14-17 years old) but not younger (10-13 years old) adolescents. In this study, we asked if cues of cognitive immaturity are more influential in affecting adolescents' judgments of children than physical cues (faces). METHOD: 245 adolescents aged between 10 and 17 rated pairs of children who physically and/or cognitively resembled either a 4 to 7-year-old or an 8- to 10-year-old child in three between-subject conditions (Consistent, Inconsistent, Faces-Only) for 14 traits classified into four trait dimensions (Positive Affect, Negative Affect, Intelligence, Helplessness). RESULTS: For both younger and older adolescents, cognitive cues had a greater influence on judgments than facial cues. However, only the older adolescents demonstrated a positive bias for children expressing immature supernatural thinking. CONCLUSIONS: Adopting an evolutionary developmental perspective, we interpreted this outcome in late (but not early) adolescence as preparation for potential parenthood. PMID- 29694323 TI - They do not suffer like us: The differential attribution of social pain as a dehumanization criterion in children. AB - BACKGROUND: Social pain is considered a feature of humanity. The goal of this study was to confirm whether children, like adults, dehumanise out-group members attributing them less capacity to experience social pain than to in-group members. METHODS: A total of 119 participants aged between 9 and 13 years responded to a questionnaire which collected information about situations that caused physical pain and situations that caused social pain. The task of the participants was to indicate to what extent they considered that two persons (a member of the in-group and a member of an out-group) would experience pain in each situation. RESULTS: The results indicated that there was a higher estimate of social pain suffered by in-group members. There were no significant differences in the case of situations that generated physical in the groups. CONCLUSIONS: The results were analysed from the dehumanisation perspective. PMID- 29694324 TI - Do cooperative learning and family involvement improve variables linked to academic performance? AB - BACKGROUND: One of the most serious problems in the Spanish education system is the high percentage of school failure in Compulsory Secondary Education. The aim of this study is to analyze the influence of a socio-educational program based on cooperative learning and family involvement on a series of variables related to academic performance, paying particular attention to the differences between retained and non-retained students. METHODOLOGY: A two-group quasi-experimental design incorporating pre-testing and post-testing was used. The study involved 146 students in the experimental group and 123 in the control group, 8 teachers, and 89 parents or other family members. RESULTS: The program was observed to have a positive effect on self-image, study habits, satisfaction with the subject, maternal support and control, and opinions about the school. In addition, the results for non-retained students are better. CONCLUSION: Cooperative work and family involvement in education affect the variables which research links to improving school performance. PMID- 29694325 TI - Teaching quality: High school students' autonomy and competence. AB - BACKGROUND: How teachers manage class learning and interact with students affects students’ motivation and engagement. However, it could be that the effect of students’ representation of teaching quality on the students’ motivation varies between classes. METHOD: Students from 90 classes participated in the study. We used multilevel random structural equation modeling to analyze whether the relationship of the students’ perception of teaching quality (as an indicator of the students’ mental representation) and students’ motivation varies between classes, and if this variability depends on the class assessment of teaching quality (as an indicator of teaching quality). RESULTS: The effect of teachers’ structure on the regression slope of student perception of student competence was .127. The effect of teachers’ autonomy support on the regression slope of student perception of student autonomy was .066. CONCLUSIONS: With this study we contribute a more detailed description of the relationship between teaching quality, competence and autonomy. PMID- 29694327 TI - Factorial invariance and norms of the 30-item shortened-version of the Revised Child Anxiety and Depression Scale (RCADS-30). AB - BACKGROUND: Anxiety and depressive disorders are among the most common mental disorders during childhood and adolescence. As the 30-item shortened version of the Revised Child Anxiety and Depression Scale (RCADS-30) exhibits excellent psychometric properties, it is one of the most commonly used scales for the initial detection and assessment of these symptoms in children and adolescents. This is because of the advantage of its brevity when compared to the 47-item version. The aim of this study was to analyse factorial invariance according to sex, age, and format used to administer the test, and to identify the RCADS-30 subscales. METHOD: A sample of 3,708 Spanish children and adolescents aged between 7 and 18 years old (M = 12.0 years, SD = 2.8) participated in the study. RESULTS: The factorial structure of the RCADS-30 is invariant according to sex, age, and format used to administer the scale. CONCLUSIONS: The RCADS-30 exhibited excellent factorial invariance for the variables analysed, confirming its usability for different types of sample and administration formats. PMID- 29694326 TI - Development and validation of the Relaxation-Mindfulness Scale for Adolescents (EREMIND-A). AB - BACKGROUND: The aim of this investigation was to validate the Relaxation Mindfulness Scale for Adolescents (EREMIND-A), consisting of 18 items and three factors (Attention-Concentration in the present moment; Relaxation (abilities and attitudes); and Sensory awareness/Contemplation/Interiority). METHOD: The validation was done with a sample of Secondary Education and Baccalaureate students from four different centres in Spain (n = 1.120). EFA and CFA of the EREMIND-A were performed and construct and incremental validities calculated. RESULTS: Initial results confirm the validity and reliability of the scale. CONCLUSIONS: There is a need for a broader conceptualization of mindfulness, as well as the inclusion and analysis of other related and cross-cutting concepts. The research in this sense will propitiate the adaptation of the Mindfulness Based Interventions to the reality of the adolescents in the educational centers, where relaxation and the interiority are aspects to be taken into consideration. PMID- 29694329 TI - Correlation of platelet to lymphocyte and neutrophil to lymphocyte ratio with hormonal and metabolic parameters in women with PCOS. AB - Background The purpose of our study is to evaluate the association of platelet-to lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) with hormonal and metabolic parameters in patients with polycystic ovarian syndrome (PCOS) in order to assess whether these ratios may become useful tools during the evaluation of the severity of low grade inflammation. Methods The present study is based in secondary outcomes from a prospectively collected patient database. A total of 266 women with PCOS participated in this study and blood a complete blood count examination (CBC) that was used for the calculation of PLR and NLR was available in 182 patients. Results Association statistics revealed that PLR had a significant correlation to 17-OH progesterone (r = -0.177, p = 0.024) and Matsuda index values (r = 0.234, p = 0.009), whereas NLR was correlated with follicle stimulating hormone (FSH) (r = -0.204, p = 0.007), free testosterone (r = 320, p < 0.001), Delta4-androstendione (r = 0.234, p = 0.003), sex hormone binding globulin (SHBG) (r = -0.350, p < 0.002) and high-density lipoprotein (HDL) (r = 0.171, p = 0.039). Conclusion According to the findings of our study, both PLR and NLR seem to be correlated with some hormonal and metabolic indices. This association is clearer in the case of NLR and serum androgens as it seems to be positively affected by their levels. PLR and NLR were not affected by the presence of obesity. PMID- 29694328 TI - Assessing self-determination in youth with and without disabilities: The Spanish version of the AIR self-determination scale. AB - BACKGROUND: Acting in a self-determined manner, that is, using problem-solving or decision-making strategies, strongly depends on the opportunities the person is given to do so by the context. In fact, context can either facilitate or thwart the opportunities of adolescents and young adults for self-determined action, though there is, to date, a lack of instruments within the Spanish context to assess these opportunities. METHOD: This study aims to address this need by adapting and validating the AIR self-determination scale to the Spanish context with a sample of young Spanish people with and without disabilities. RESULTS: The results showed acceptable psychometric properties of validity and reliability, and stressed differences in school and home opportunities for developing self determination depending on the presence or absence of disability. CONCLUSIONS: The Spanish version of the AIR self-determination scale stands as a psychometrically robust instrument to assess capacities and opportunities for acting in a self-determined manner in all young people. Implications based on the differences in contextual opportunities arising from the presence of disability are also further discussed. PMID- 29694330 TI - Reflections on Nursing Educational Advancement Within Diverse and Evolving National Cultural Contexts. AB - As the development of nursing education becomes increasingly internationalized, it is tempting to focus on universal aspects of the discipline rather than explicitly emphasizing the distinct national cultures and contexts within which our profession and its educational styles and approaches have evolved. Capitalizing on an opportunity for comparative critical reflection on the relevant political, economic and social histories that have underpinned the development of nursing education in China, Brazil and Canada - three countries united by shared values about equity and access to health services - we sought to deconstruct the manner in which these forces have shaped the national differences in the way we conceptualize and deliver nursing education. On this basis, we examined the implications for the advancement of nursing education within each national context, recognizing the fundamental relevance of indepth critical reflection for optimizing nursing's advocacy capacity within each of our national health care and policy systems. PMID- 29694331 TI - Synthesis and characterization of the removal of organic pollutants in effluents. AB - The use of a large number of organic pollutants results in the accumulation of effluents at the places of production and the environment. These substances are, therefore, dangerous for living organisms and can cause heavy environmental damage. Hence, to cure these problems certain methods were used for the elimination of organic effluents. Indeed, the methods of elimination through magnetic adsorption and/or separation prove to be effective in the treatment of certain wastes, but the effectiveness of each one of these methods depends on several characteristics and also present limitations according to the pollutants they adsorb. This review examines on the one hand the capacity of certain elements of these methods in the elimination of certain pollutants and on the other hand the advantages and limits of these methods. Elements like biochars, biosorbents and composite materials are used due to their very strong porosity which makes it possible for them to develop an important contact surface with the external medium, at low costs, and the possibility of producing them from renewable sources. The latter still run up however against the problems of formation of mud and regeneration. Depollution by magnetic separation is also used due to its capacity to mitigate the disadvantages of certain methods which generally lead to the formation of mud and overcoming also the difficulties like obtaining an active material and at the same time being able to fix the pollutants present in the effluents to treat and sensitize them to external magnetic fields. PMID- 29694332 TI - Synergistic effect of shape-selective silver nanostructures decorating reduced graphene oxide nanoplatelets for enhanced cytotoxicity against breast cancer. AB - Graphene-based nanomaterials contain unique physicochemical properties and have been widely investigated due to a variety of applications particularly in cancer therapy. Furthermore, Ag has been known for its extensive historical background for biomedical applications. Therefore, conjugation of shape-selective Ag nanostructures with graphene may provide new horizons for pharmaceutical applications such as cancer treatments. Here we report on the synthesis of Ag nanoparticles (NPs)/reduced graphene oxide (AgNPs/RGO) conjugate nanomaterials containing various shapes of AgNPs by a novel and simple synthesis route using the deformation of dimethylformamide (DMF) as the reducing and coupling agent. The cytotoxicity and anticancer properties of AgNPs, AgNPs/RGO conjugate nanomaterials, RGO and graphene oxide (GO) were probed against MDA-MB-231 cancer and MCF-10A normal human breast cells in vitro. The AgNPs/RGO nanocomposites exhibited a strong anticancer effect by penetration and apoptosis in cancer cells as well as the lowest influence on the viability of normal cells. It was found that cancer cell viability not only depends on the geometry of Ag nanostructures but also on the interaction between AgNPs and RGO nanoplatelets. It is suggested that AgNPs/RGO conjugate nanomaterials with various shapes of AgNPs is a promising therapeutic platform for cancer therapy. PMID- 29694333 TI - Effect of taste masking technology on fast dissolving oral film: dissolution rate and bioavailability. AB - Fast dissolving oral film is a stamp-style, drug-loaded polymer film with rapid disintegration and dissolution. This new kind of drug delivery system requires effective taste masking technology. Suspension intermediate and liposome intermediate were prepared, respectively, for the formulation of two kinds of fast dissolving oral films with the aim of studying the effect of taste masking technology on the bioavailability of oral films. Loratadine was selected as the model drug. The surface pH of the films was close to neutral, avoiding oral mucosal irritation or side effects. The thickness of a 2 cm * 2 cm suspension oral film containing 10 mg of loratadine was 100 MUm. Electron microscope analysis showed that liposomes were spherical before and after re-dissolution, and drugs with obvious bitterness could be masked by the encapsulation of liposomes. Dissolution of the two films was superior to that of the commercial tablets. Rat pharmacokinetic experiments showed that the oral bioavailability of the suspension film was significantly higher than that of the commercial tablets, and the relative bioavailability of the suspension film was 175%. Liposomal film produced a certain amount of improvement in bioavailability, but lower than that of the suspension film. PMID- 29694334 TI - Flexible transparent conducting films with embedded silver networks composed of bimodal-sized nanoparticles for heater application. AB - A facile one-pot synthetic method for preparing the Ag nanoparticle inks with a bimodal size distribution was newly devised and they were successfully employed as a conducting filler to form the metal-mesh type transparent conducting electrodes on the flexible substrate. Bimodal-sized Ag nanoparticles were synthesized through the polyol process, and their size variation was occurred via finely tuned composition ratio between Ag+ ions and polymeric capping agents. The prepared bimodal-sized Ag nanoparticles exhibited the form of well-dispersed Ag nanoparticle inks without adding any dispersants and dispersion process. By filling the patterned micro-channels engraved on the flexible polymer substrate using a bimodal-sized Ag nanoparticle ink, a metal-mesh type transparent electrode (transmittance: 90% at 550 nm, haze: 1.5, area: 8 * 8 cm2) was fabricated. By applying DC voltage to the mesh type electrode, a flexible transparent joule heater was successfully achieved with a performance of 4.5 degrees C s-1 heat-up rate at a low input power density. PMID- 29694336 TI - A role for the GDAP1 gene in the molecular pathogenesis of Charcot-Marie-Tooth disease. AB - In 2002 a series of mutations in the GDAP1 gene were reported in patients suffering from Charcot-Marie-Tooth disease manifesting as early-onset, progressive distal-muscle wasting and weakness. The molecular etiology of Charcot Marie-Tooth -GDAP1 disease has been elucidated but its pathogenesis remains unclear, especially given the seemingly contradictory function of the GDAP1 protein. Expression of GDAP1 is observed almost exclusively in neuronal cells, however, the GDAP1 protein is present in mitochondria, where it plays a role in fission, a ubiquitous process occurring in all cells. While GDAP1 contains two glutathione S-transferase (GST) domains, its GST activity is in fact very limited. Additionally, despite GDAP1 affecting mitochondrial functionality, and hence being of great importance to cellular function, the GDAP1-associated Charcot-Marie-Tooth disease is mainly characterized by axonal degeneration. Finally, mutations in the GDAP1 gene may be inherited in a recessive or dominant manner. Given the way such varied observations are hard to reconcile with one another, the investigation of GDAP1 is at one and the same time a difficult but also challenging endeavour. The purpose of this review is to summarize the current knowledge on the GDAP1 protein and its function in the cell. A further part is the characterization of GDAP1-associated Charcot-Marie-Tooth disease, its symptoms and course, as well as an outlining of the possible mechanisms underpinning the disorder. PMID- 29694335 TI - MYSM1 Is Essential for Maintaining Hematopoietic Stem Cell (HSC) Quiescence and Survival. AB - BACKGROUND Histone H2A deubiquitinase MYSM1 has recently been shown to be essential for hematopoiesis and hematopoietic stem cell (HSC) function in both mice and humans. However, conventional MYSM1 knockouts cause partial embryonic lethality and growth retardation, and it is difficult to convincingly remove the effects of environmental factors on HSC differentiation and function. MATERIAL AND METHODS MYSM1 conditional knockout (cKO) mice were efficiently induced by using the Vav1-cre transgenic system. The Vav-Cre MYSM1 cKO mice were then analyzed to verify the intrinsic role of MYSM1 in hematopoietic cells. RESULTS MYSM1 cKO mice were viable and were born at normal litter sizes. At steady state, we observed a defect in hematopoiesis, including reduced bone marrow cellularity and abnormal HSC function. MYSM1 deletion drives HSCs from quiescence into rapid cycling, and MYSM1-deficient HSCs display impaired engraftment. In particular, the immature cycling cKO HSCs have elevated reactive oxygen species (ROS) levels and are prone to apoptosis, resulting in the exhaustion of the stem cell pool during stress response to 5-FU. CONCLUSIONS Our study using MYSM1 cKO mice confirms the important role of MYSM1 in maintaining HSC quiescence and survival. PMID- 29694337 TI - Experimental cerebral hemispherectomy in rodent models. A systematic review of current literature. AB - Cerebral hemispherectomy is a neurosurgical procedure that involves surgically removing one hemisphere of the brain, used as a therapeutic option in severe cases of intractable epilepsy. Several animal models have contributed to our understanding of the underlying neuromechanisms. The review was based on a PubMed search using the terms "hemispherectomy" and "mouse" or "rat" or "rodent", with no limitation of year of study or language. We identified a series of elements that were collected and analyzed that add up to our contemporary knowledge of this procedure. Our search returned 29 articles out of which only 15 are relevant to our purposes. Most of the current literature is concerned with the different molecular and electrophysiological issues of neuroplasticity, exhibiting the neurochemical background on which brain plasticity is founded. Experimental neurosurgery is quintessential in understanding the process in which various pathologies respond to in vivo animal models and recreating conditions otherwise difficult or impossible to obtain in humans. The aim of our study was to evaluate the current literature on the modern comprehension that animal models offer for histopathological, neurochemical and microsurgical research. In addition, the review is focused on the neuroplastic/compensatory mechanisms developed after hemispherectomy. Further research is of vital importance in exploring neurotherapeutical aspects of neuroplasticity in central nervous system (CNS) diseases. PMID- 29694338 TI - Cerebral hypoperfusion in autism spectrum disorder. AB - Cerebral hypoperfusion, or insufficient blood flow in the brain, occurs in many areas of the brain in patients diagnosed with autism spectrum disorder (ASD). Hypoperfusion was demonstrated in the brains of individuals with ASD when compared to normal healthy control brains either using positron emission tomography (PET) or single-photon emission computed tomography (SPECT). The affected areas include, but are not limited to the: prefrontal, frontal, temporal, occipital, and parietal cortices; thalami; basal ganglia; cingulate cortex; caudate nucleus; the limbic system including the hippocampal area; putamen; substantia nigra; cerebellum; and associative cortices. Moreover, correlations between symptom scores and hypoperfusion in the brains of individuals diagnosed with an ASD were found indicating that the greater the autism symptom pathology, the more significant the cerebral hypoperfusion or vascular pathology in the brain. Evidence suggests that brain inflammation and vascular inflammation may explain a part of the hypoperfusion. There is also evidence of a lack of normal compensatory increase in blood flow when the subjects are challenged with a task. Some studies propose treatments that can address the hypoperfusion found among individuals diagnosed with an ASD, bringing symptom relief to some extent. This review will explore the evidence that indicates cerebral hypoperfusion in ASD, as well as the possible etiological aspects, complications, and treatments. PMID- 29694339 TI - MeCP2 in central nervous system glial cells: current updates. AB - avMethyl-CpG binding protein 2 (MeCP2) is an epigenetic regulator, which preferentially binds to methylated CpG dinucleotides in DNA. MeCP2 mutations have been linked to Rett syndrome, a neurodevelopmental disorder characterized by severe intellectual disability in females. Earlier studies indicated that loss of MeCP2 function in neuronal cells was the sole cause of Rett syndrome. Subsequent studies have linked MeCP2 expression in CNS glial cells to Rett syndrome pathogenesis. In this review, we have discussed the role of MeCP2 in glial subtypes, astrocytes, oligodendrocytes and microglia, and how loss of MeCP2 function in these cells has a profound influence on both glial and neuronal function. PMID- 29694340 TI - Possible role of hippocampal GPR55 in spatial learning and memory in rats. AB - Endocannabinoids (eCBs) are involved in the hippocampal mechanisms of spatial learning and memory in rats. Although eCBs exert many of their actions on spatial learning and memory via CB1 receptors, the putative cannabinoid receptor GPR55 (expressed in the hippocampus, cortex, forebrain, cerebellum and striatum) seems to be also involved. To investigate the potential role of GPR55 in spatial learning and memory, Wistar rats received bilateral infusions of lysophosphatidylinositol (LPI, GPR55-agonist) into the hippocampus 5-minutes before training-phase in the Barnes-maze (BM). This manipulation increased the use of serial navigation while preventing the learning of spatial navigation strategy and decreasing the use of random activity to find the escape-tunnel in the BM. In contrast, CID16020046 (GPR55-antagonist) increased the use of random activity at the expense of spatial and serial navigation strategies. Finally, CID16020046 significantly reduced the time spent in the target zone during a retention test. Our results suggest: (i) a potential role of GPR55 in developing navigation strategies; (ii) a prospective function for LPI acting in hippocampal CA1 (probably via GPR55) to perform a serial navigation strategy; and (iii) a potential role of GPR55 in the mechanisms involved in spatial memory (object placement memory). PMID- 29694341 TI - Long-term behavioral, histological, biochemical and hematological evaluations of amyloid beta-induced Alzheimer's disease in rat. AB - Alzheimer's disease (AD) is a mental impairment and neural degeneration which causes progressive loss of memory and cognitive functions. This age-dependent illness is associated with extracellular amyloid plaques accumulation and twisted neurofibrillary tangles. Amyloid plaques are experimentally generated in animal models in order to investigate the disease process. In this study, we followed a rat model of AD for over a year. Wistar rats were divided randomly into two groups as control group (surgery without injection Abeta), and experimental group (two-sided intrahippocampal amyloid-beta injection into hippocampus). From each group, three animals were investigated 42 days after injection, and the remaining four animals were studied after one year. All animals were tested for learning abilities and memory. Finally, samples from blood, brain, heart, kidney, liver, colon and spleen were examined. In the experimental group, the size of amyloid plaques were increased significantly after one year ??r??nand learning abilities and memory were concomitantly decreased. Onsets of various other conditions such as liver and kidney disorders, diabetes, and metabolic syndrome were observed, which indicates that the animals may be prone to cardiovascular disorders and ischemia. PMID- 29694342 TI - Effects of postural and cognitive difficulty levels on the standing of healthy young males on an unstable platform. AB - Standing on an unstable platform requires continuous effort of the neuro musculoskeletal system. The aim of the present study is to evaluate the ability to remain standing on an unstable platform at different levels of postural and cognitive difficulty. Healthy young males stood in the sagittal plane on an unstable platform supported by a pair of springs with modifiable stiffness. The balance test also assessed different levels of vision and cognitive function. Linear and nonlinear metrics of standing, based on motion captured kinematic data, were assessed to analyze the stability of standing. Results showed that vision plays a significant role in maintaining balance in terms of linear metrics. Elimination of visual feedback changed the direction of body sway and increased standing instability. Placement of low stiffness springs led to unstable standing. The cognitive dual task, however, had no effect on the stability metrics and merely could be revealed in the simplest test condition. Standing on an unstable platform was closely related to visual feedback and decreasing the spring stiffness significantly reduced stability. The roles of cognitive involvement were subdued by increasing the postural difficulty in standing on an unstable platform. PMID- 29694343 TI - Correction: Brain-Computer Interface-Based Communication in the Completely Locked In State. AB - [This corrects the article DOI: 10.1371/journal.pbio.1002593.]. PMID- 29694344 TI - Elective induction of labor at 39 weeks among nulliparous women: The impact on maternal and neonatal risk. AB - OBJECTIVE: Optimal management of pregnancies at 39 weeks gestational age is unknown. Therefore, we sought to perform a comparative effectiveness analysis of elective induction of labor (eIOL) at 39 weeks among nulliparous women with non anomalous singleton, vertex fetuses as compared to expectant management (EM) which included IOL for medical or obstetric indications or at 41 weeks in undelivered mothers. MATERIALS AND METHODS: A Monte Carlo micro-simulation model was constructed modeling two mutually exclusive health states: eIOL at 39 weeks, or EM with IOL for standard medical or obstetrical indications or at 41 weeks if undelivered. Health state distribution probabilities included maternal and perinatal outcomes and were informed by a review of the literature and data derived from the Consortium of Safe Labor. Analyses investigating preferences for maternal versus infant health were performed using weighted utilities. Primary outcome was determining which management strategy posed less maternal and neonatal risk. Secondary outcomes were rates of cesarean deliveries, maternal morbidity and mortality, stillbirth, neonatal morbidity and mortality, and preferences regarding the importance of maternal and perinatal health. RESULTS: A management strategy of eIOL at 39 weeks resulted in less maternal and neonatal risk as compared to EM with IOL at 41 weeks among undelivered patients. Cesarean section rates were higher in the EM arm (35.9% versus 13.9%, p<0.01). When analysis was performed only on patients with an unfavorable cervix, 39 week eIOL still resulted in fewer cesarean deliveries as compared to EM (8.0% versus 26.1%, p<0.01). There was no statistical difference in maternal mortality (eIOL 0% versus EM 0.01%, p = 0.32) but there was an increase in maternal morbidity among the EM arm (21.2% versus 16.5, p<0.01). There were more stillbirths (0.13% versus 0%, p<0.0003), neonatal deaths (0.25% versus 0.12%, p< 0.03), and neonatal morbidity (12.1% versus 9.4%, p<0.01) in the EM arm as compared to the eIOL arm. Preference modeling revealed that 39 week eIOL was favored over EM. CONCLUSIONS AND RELEVANCE: Mathematical modeling revealed that eIOL at 39 weeks resulted in lower population risks as compared to EM with induction of labor at 41 weeks. Specifically, eIOL at 39 weeks resulted in a lower cesarean section rate, lower rates of maternal morbidity, fewer stillbirths and neonatal deaths, and lower rates of neonatal morbidity. PMID- 29694345 TI - Diffusivity in the core of chronic multiple sclerosis lesions. AB - BACKGROUND: Diffusion tensor imaging (DTI) has been suggested as a potential biomarker of disease progression, neurodegeneration and de/remyelination in MS. However, the pathological substrates that underpin alterations in brain diffusivity are not yet fully delineated. We propose that in highly cohesive fiber tracts: 1) a relative increase in parallel (axial) diffusivity (AD) may serve as a measure of increased extra-cellular space (ESC) within the core of chronic MS lesions and, as a result, may provide an estimate of the degree of tissue destruction, and 2) the contribution of the increased extra-cellular water to perpendicular (radial) diffusivity (RD) can be eliminated to provide a more accurate assessment of membranal (myelin) loss. OBJECTIVE: The purpose of this study was to isolate the contribution of extra-cellular water and demyelination to observed DTI indices in the core of chronic MS lesions, using the OR as an anatomically cohesive tract. METHOD: Pre- and post-gadolinium (Gd) enhanced T1, T2 and DTI images were acquired from 75 consecutive RRMS patients. In addition, 25 age and gender matched normal controls were imaged using an identical MRI protocol (excluding Gd). The optic radiation (OR) was identified in individual patients using probabilistic tractography. The T2 lesions were segmented and intersected with the OR. Average eigenvalues were calculated within the core of OR lesions mask. The proportion of extra-cellular space (ECS) within the lesional core was calculated based on relative increase of AD, which was then used to normalise the perpendicular eigenvalues to eliminate the effect of the expanded ECS. In addition, modelling was implemented to simulate potential effect of various factors on lesional anisotropy. RESULTS: Of 75 patients, 41 (55%) demonstrated sizable T2 lesion volume within the ORs. All lesional eigenvalues were significantly higher compared to NAWM and controls. There was a strong correlation between AD and RD within the core of OR lesions, which was, however, not seen in OR NAWM of MS patients or normal controls. In addition, lesional anisotropy (FA) was predominantly driven by the perpendicular diffusivity, while in NAWM and in OR of normal controls all eigenvectors contributed to variation in FA. Estimated volume of ECS component constituted significant proportion of OR lesional volume and correlated significantly with lesional T1 hypointensity. While perpendicular diffusivity dropped significantly following normalisation, it still remained higher compared with diffusivity in OR NAWM. The "residual" perpendicular diffusivity also showed a substantial reduction of inter-subject variability. Both observed and modelled diffusion data suggested anisotropic nature of water diffusion in ESC. In addition, the simulation procedure offered a possible explanation for the discrepancy in relationship between eigenvalues and anisotropy in lesional tissue and NAWM. CONCLUSION: This paper presents a potential technique for more reliably quantifying the effects of neurodegeneration (tissue loss) versus demyelination in OR MS lesions. This may provide a simple and effective way for applying single tract diffusion analysis in MS clinical trials, with particular relevance to pro-remyelinating and neuroprotective therapeutics. PMID- 29694346 TI - Aminopeptidase secreted by Chromobacterium sp. Panama inhibits dengue virus infection by degrading the E protein. AB - Dengue virus (DENV) is the most prevalent and burdensome arbovirus transmitted by Aedes mosquitoes, against which there is only a limited licensed vaccine and no approved drug treatment. A Chromobacterium species, C. sp. Panama, isolated from the midgut of A. aegypti is able to inhibit DENV replication within the mosquito and in vitro. Here we show that C. sp. Panama mediates its anti-DENV activity through secreted factors that are proteinous in nature. The inhibitory effect occurs prior to virus attachment to cells, and is attributed to a factor that destabilizes the virion by promoting the degradation of the viral envelope protein. Bioassay-guided fractionation, coupled with mass spectrometry, allowed for the identification of a C. sp. Panama-secreted neutral protease and an aminopeptidase that are co-expressed and appear to act synergistically to degrade the viral envelope (E) protein and thus prevent viral attachment and subsequent infection of cells. This is the first study characterizing the anti-DENV activity of a common soil and mosquito-associated bacterium, thereby contributing towards understanding how such bacteria may limit disease transmission, and providing new tools for dengue prevention and therapeutics. PMID- 29694347 TI - Rational metareasoning and the plasticity of cognitive control. AB - The human brain has the impressive capacity to adapt how it processes information to high-level goals. While it is known that these cognitive control skills are malleable and can be improved through training, the underlying plasticity mechanisms are not well understood. Here, we develop and evaluate a model of how people learn when to exert cognitive control, which controlled process to use, and how much effort to exert. We derive this model from a general theory according to which the function of cognitive control is to select and configure neural pathways so as to make optimal use of finite time and limited computational resources. The central idea of our Learned Value of Control model is that people use reinforcement learning to predict the value of candidate control signals of different types and intensities based on stimulus features. This model correctly predicts the learning and transfer effects underlying the adaptive control-demanding behavior observed in an experiment on visual attention and four experiments on interference control in Stroop and Flanker paradigms. Moreover, our model explained these findings significantly better than an associative learning model and a Win-Stay Lose-Shift model. Our findings elucidate how learning and experience might shape people's ability and propensity to adaptively control their minds and behavior. We conclude by predicting under which circumstances these learning mechanisms might lead to self-control failure. PMID- 29694348 TI - Oral microbiota reveals signs of acculturation in Mexican American women. AB - The oral microbiome has been linked to a number of chronic inflammatory conditions, including obesity, diabetes, periodontitis, and cancers of the stomach and liver. These conditions disproportionately affect Mexican American women, yet few studies have examined the oral microbiota in this at-risk group. We characterized the 16S rDNA oral microbiome in 369 non-smoking women enrolled in the MD Anderson Mano a Mano Mexican American Cohort Study. Lower bacterial diversity, a potential indicator of oral health, was associated with increased age and length of US residency among recent immigrants. Grouping women by overarching bacterial community type (e.g., "Streptococcus," "Fusobacterium," and "Prevotella" clusters), we observed differences across a number of acculturation related variables, including nativity, age at immigration, time in the US, country of longest residence, and a multi-dimensional acculturation scale. Participants in the cluster typified by higher abundance of Streptococcus spp. exhibited the lowest bacterial diversity and appeared the most acculturated as compared to women in the "Prevotella" group. Computationally-predicted functional analysis suggested the Streptococcus-dominated bacterial community had greater potential for carbohydrate metabolism while biosynthesis of essential amino acids and nitrogen metabolism prevailed among the Prevotella-high group. Findings suggest immigration and adaption to life in the US, a well-established mediator of disease risk, is associated with differences in oral microbial profiles in Mexican American women. These results warrant further investigation into the joint and modifying effects of acculturation and oral bacteria on the health of Mexican American women and other immigrant populations. The oral microbiome presents an easily accessible biomarker of disease risk, spanning biological, behavioral, and environmental factors. PMID- 29694350 TI - Predicting seasonal influenza transmission using functional regression models with temporal dependence. AB - This paper proposes a novel approach that uses meteorological information to predict the incidence of influenza in Galicia (Spain). It extends the Generalized Least Squares (GLS) methods in the multivariate framework to functional regression models with dependent errors. These kinds of models are useful when the recent history of the incidence of influenza are readily unavailable (for instance, by delays on the communication with health informants) and the prediction must be constructed by correcting the temporal dependence of the residuals and using more accessible variables. A simulation study shows that the GLS estimators render better estimations of the parameters associated with the regression model than they do with the classical models. They obtain extremely good results from the predictive point of view and are competitive with the classical time series approach for the incidence of influenza. An iterative version of the GLS estimator (called iGLS) was also proposed that can help to model complicated dependence structures. For constructing the model, the distance correlation measure [Formula: see text] was employed to select relevant information to predict influenza rate mixing multivariate and functional variables. These kinds of models are extremely useful to health managers in allocating resources in advance to manage influenza epidemics. PMID- 29694351 TI - Zika virus infection and microcephaly: Evidence regarding geospatial associations. AB - BACKGROUND: Although the Zika virus (ZIKV) epidemic ceased to be a public health emergency by the end of 2016, studies to improve knowledge about this emerging disease are still needed, especially those investigating a causal relationship between ZIKV in pregnant women and microcephaly in neonates. However, there are still many challenges in describing the relationship between ZIKV and microcephaly. The few studies focusing on the epidemiological profile of ZIKV and its changes over time are largely limited to systematic reviews of case reports and dispersal mapping of ZIKV spread over time without quantitative methods to analyze patterns and their covariates. Since Brazil has been at the epicenter of the ZIKV epidemic, this study examines the geospatial association between ZIKV and microcephaly in Brazil. METHODS: Our study is categorized as a retrospective, ecological study based on secondary databases. Data were obtained from January to December 2016, from the following data sources: Brazilian System for Epidemiological Surveillance, Disease Notification System, System for Specialized Management Support, and Brazilian Institute of Geography and Statistics. Data were aggregated by municipality. Incidence rates were estimated per 100,000 inhabitants. Analyses consisted of mapping the aggregated incidence rates of ZIKV and microcephaly, followed by a Getis-Ord-Gi spatial cluster analysis and a Bivariate Local Moran's I analysis. RESULTS: The incidence of ZIKV cases is changing the virus's spatial pattern, shifting from Brazil's Northeast region to the Midwest and North regions. The number of municipalities in clusters of microcephaly incidence is also shifting from the Northeast region to the Midwest and North, after a time lag is considered. Our findings suggest an increase in microcephaly incidence in the Midwest and North regions, associated with high levels of ZIKV infection months before. CONCLUSION: The greatest burden of microcephaly shifted from the Northeast to other Brazilian regions at the beginning of 2016. Brazil's Midwest region experienced an increase in microcephaly incidence associated with ZIKV incidence. This finding highlights an association between an increase in ZIKV infection with a rise in microcephaly cases after approximately three months. PMID- 29694349 TI - Control of yeast retrotransposons mediated through nucleoporin evolution. AB - Yeasts serve as hosts to several types of genetic parasites. Few studies have addressed the evolutionary trajectory of yeast genes that control the stable co existence of these parasites with their host cell. In Saccharomyces yeasts, the retrovirus-like Ty retrotransposons must access the nucleus. We show that several genes encoding components of the yeast nuclear pore complex have experienced natural selection for substitutions that change the encoded protein sequence. By replacing these S. cerevisiae genes with orthologs from other Saccharomyces species, we discovered that natural sequence changes have affected the mobility of Ty retrotransposons. Specifically, changing the genetic sequence of NUP84 or NUP82 to match that of other Saccharomyces species alters the mobility of S. cerevisiae Ty1 and Ty3. Importantly, all tested housekeeping functions of NUP84 and NUP82 remained equivalent across species. Signatures of natural selection, resulting in altered interactions with viruses and parasitic genetic elements, are common in host defense proteins. Yet, few instances have been documented in essential housekeeping proteins. The nuclear pore complex is the gatekeeper of the nucleus. This study shows how the evolution of this large, ubiquitous eukaryotic complex can alter the replication of a molecular parasite, but concurrently maintain essential host functionalities regarding nucleocytoplasmic trafficking. PMID- 29694352 TI - Effects of loxoprofen on the apical root resorption during orthodontic tooth movement in rats. AB - Studies have revealed that severe apical root resorption during tooth movement is caused by the noninfective inflammatory reaction of apical root tissues. We hypothesized that loxoprofen can suppress apical root resorption during tooth movement. Cyclic tensile force (CTF) of 10 kPa was applied to the human pulp cells for 48 hours by the Flexcell Strain Unit. Loxoprofen (10 and 100 MUM) was added to the culture cells, and expression of cyclooxygenase (COX)-1, COX-2, interleukin (IL)-1beta, receptor activator of nuclear factor kappa-B ligand (RANKL), tumor necrosis factor (TNF)-alpha, and macrophage colony-stimulating factor (M-CSF) were examined. To determine the effects of loxoprofen sodium on apical root reabsorption during tooth movement, the upper first molars of 7-week old rats were subjected to mesial movement by 10g force for 30 days with or without the oral administration of loxoprofen. Gene expression and protein concentration of COX-1, COX-2, IL-1beta, TNF-alpha, RANKL and M-CSF were significantly higher in the CTF group than in the control group. However, these levels were decreased by loxoprofen administration. After orthodontic tooth movement, the expression of IL-1beta, TNF-alpha, RANKL and M-CSF decreased in the loxoprofen group than in the control group by immunohistochemical staining. In comparison to control group, less number of odontoclasts and a decrease in the amount of apical root resorption was observed in the loxoprofen group. Many osteoclasts became visible on the pressure side of the alveolar bone in the both groups, and the amount of tooth movement did not show a significant difference. These findings demonstrate that severe apical root resorption may be suppressed by loxoprofen administration, without a disturbance of tooth movement. PMID- 29694353 TI - The influence of abrupt increases in seawater pCO2 on plankton productivity in the subtropical North Pacific Ocean. AB - We conducted a series of experiments to examine short-term (2-5 days) effects of abrupt increases in the partial pressure of carbon dioxide (pCO2) in seawater on rates of primary and bacterial production at Station ALOHA (22 degrees 45' N, 158 degrees W) in the North Pacific Subtropical Gyre (NPSG). The majority of experiments (8 of 10 total) displayed no response in rates of primary production (measured by 14C-bicarbonate assimilation; 14C-PP) under elevated pCO2 (~1100 MUatm) compared to ambient pCO2 (~387 MUatm). In 2 of 10 experiments, rates of 14C-PP decreased significantly (~43%) under elevated pCO2 treatments relative to controls. Similarly, no significant differences between treatments were observed in 6 of 7 experiments where bacterial production was measured via incorporation of 3H-leucine (3H-Leu), while in 1 experiment, rates of 3H-Leu incorporation measured in the dark (3H-LeuDark) increased more than 2-fold under high pCO2 conditions. We also examined photoperiod-length, depth-dependent (0-125 m) responses in rates of 14C-PP and 3H-Leu incorporation to abrupt pCO2 increases (to ~750 MUatm). In the majority of these depth-resolved experiments (4 of 5 total), rates of 14C-PP demonstrated no consistent response to elevated pCO2. In 2 of 5 depth-resolved experiments, rates of 3H-LeuDark incorporation were lower (10% to 15%) under elevated pCO2 compared to controls. Our results revealed that rates of 14C-PP and bacterial production in this persistently oligotrophic habitat generally demonstrated no or weak responses to abrupt changes in pCO2. We postulate that any effects caused by changes in pCO2 may be masked or outweighed by the role that nutrient availability and temperature play in controlling metabolism in this ecosystem. PMID- 29694354 TI - Clinical significance of fragmented QRS complexes or J waves in patients with idiopathic ventricular arrhythmias. AB - BACKGROUND: Idiopathic ventricular fibrillation (IVF) can cause sudden cardiac death. Previous studies have reported that J waves and fragmented QRS complexes (f-QRS) are arrhythmogenic markers and predictors of cardiac events. We evaluated the prevalence and clinical significance of J waves and f-QRS in patients with IVF. METHODS: We studied 81 patients who received an implantable cardioverter defibrillator (ICD) due to IVF between October 1999 and June 2015. We assessed the prevalence of J waves and f-QRS using electrocardiograms (ECGs). Patients were classified into three groups: J wave group (n = 35), f-QRS group (n = 20), or normal ECG group (n = 26). The control group included 81 subjects without heart disease who were matched for age, sex, and race. We compared syncope, sudden cardiac arrest, and appropriate ICD shock between the three groups. RESULTS: The follow-up duration was 4.1 years. J waves and f-QRS were more frequent in patients with IVF than in control subjects (43.2%, 21% vs. 24.7%, 19.7%, P < 0.001). Out of the three groups, clinical cardiac events were most frequent in the f-QRS group (50% vs. 45.7% vs. 11.5%, P = 0.028). A comparison of the combined group of J wave and f-QRS versus the normal ECG group revealed that the combined group had a higher frequency of clinical cardiac events than the normal ECG group (47.3% vs. 11.5%, respectively, P = 0.009). CONCLUSIONS: Patients with IVF had higher prevalence of f-QRS or J waves. And patients with f QRS or J waves were at higher risk of recurrent ventricular fibrillation. PMID- 29694355 TI - Future climate change scenarios in Central America at high spatial resolution. AB - The objective of this work is to assess the downscaling projections of climate change over Central America at 8-km resolution using the Eta Regional Climate Model, driven by the HadGEM2-ES simulations of RCP4.5 emission scenario. The narrow characteristic of continent supports the use of numerical simulations at very high-horizontal resolution. Prior to assessing climate change, the 30-year baseline period 1961-1990 is evaluated against different sources of observations of precipitation and temperature. The mean seasonal precipitation and temperature distribution show reasonable agreement with observations. Spatial correlation of the Eta, 8-km resolution, simulations against observations show clear advantage over the driver coarse global model simulations. Seasonal cycle of precipitation confirms the added value of the Eta at 8-km over coarser resolution simulations. The Eta simulations show a systematic cold bias in the region. Climate features of the Mid-Summer Drought and the Caribbean Low-Level Jet are well simulated by the Eta model at 8-km resolution. The assessment of the future climate change is based on the 30-year period 2021-2050, under RCP4.5 scenario. Precipitation is generally reduced, in particular during the JJA and SON, the rainy season. Warming is expected over the region, but stronger in the northern portion of the continent. The Mid-Summer Drought may develop in regions that do not occur during the baseline period, and where it occurs the strength may increase in the future scenario. The Caribbean Low-Level Jet shows little change in the future. Extreme temperatures have positive trend within the period 2021-2050, whereas extreme precipitation, measured by R50mm and R90p, shows positive trend in the eastern coast, around Costa Rica, and negative trends in the northern part of the continent. Negative trend in the duration of dry spell, which is an estimate based on evapotranspiration, is projected in most part of the continent. Annual mean water excess has negative trends in most part of the continent, which suggests decreasing water availability in the future scenario. PMID- 29694357 TI - Development of a statistical model for cervical cancer cell death with irreversible electroporation in vitro. AB - PURPOSE: The aim of this study was to develop a statistical model for cell death by irreversible electroporation (IRE) and to show that the statistic model is more accurate than the electric field threshold model in the literature using cervical cancer cells in vitro. METHODS: HeLa cell line was cultured and treated with different IRE protocols in order to obtain data for modeling the statistical relationship between the cell death and pulse-setting parameters. In total, 340 in vitro experiments were performed with a commercial IRE pulse system, including a pulse generator and an electric cuvette. Trypan blue staining technique was used to evaluate cell death after 4 hours of incubation following IRE treatment. Peleg-Fermi model was used in the study to build the statistical relationship using the cell viability data obtained from the in vitro experiments. A finite element model of IRE for the electric field distribution was also built. Comparison of ablation zones between the statistical model and electric threshold model (drawn from the finite element model) was used to show the accuracy of the proposed statistical model in the description of the ablation zone and its applicability in different pulse-setting parameters. RESULTS: The statistical models describing the relationships between HeLa cell death and pulse length and the number of pulses, respectively, were built. The values of the curve fitting parameters were obtained using the Peleg-Fermi model for the treatment of cervical cancer with IRE. The difference in the ablation zone between the statistical model and the electric threshold model was also illustrated to show the accuracy of the proposed statistical model in the representation of ablation zone in IRE. CONCLUSIONS: This study concluded that: (1) the proposed statistical model accurately described the ablation zone of IRE with cervical cancer cells, and was more accurate compared with the electric field model; (2) the proposed statistical model was able to estimate the value of electric field threshold for the computer simulation of IRE in the treatment of cervical cancer; and (3) the proposed statistical model was able to express the change in ablation zone with the change in pulse-setting parameters. PMID- 29694356 TI - Impact of confinement housing on study end-points in the calf model of cryptosporidiosis. AB - BACKGROUND: Diarrhea is the second leading cause of death in children < 5 years globally and the parasite genus Cryptosporidium is a leading cause of that diarrhea. The global disease burden attributable to cryptosporidiosis is substantial and the only approved chemotherapeutic, nitazoxanide, has poor efficacy in HIV positive children. Chemotherapeutic development is dependent on the calf model of cryptosporidiosis, which is the best approximation of human disease. However, the model is not consistently applied across research studies. Data collection commonly occurs using two different methods: Complete Fecal Collection (CFC), which requires use of confinement housing, and Interval Collection (IC), which permits use of box stalls. CFC mimics human challenge model methodology but it is unknown if confinement housing impacts study end points and if data gathered via this method is suitable for generalization to human populations. METHODS: Using a modified crossover study design we compared CFC and IC and evaluated the impact of housing on study end-points. At birth, calves were randomly assigned to confinement (n = 14) or box stall housing (n = 9), or were challenged with 5 x 107 C. parvum oocysts, and followed for 10 days. Study end-points included fecal oocyst shedding, severity of diarrhea, degree of dehydration, and plasma cortisol. FINDINGS: Calves in confinement had no significant differences in mean log oocysts enumerated per gram of fecal dry matter between CFC and IC samples (P = 0.6), nor were there diurnal variations in oocyst shedding (P = 0.1). Confinement housed calves shed significantly more oocysts (P = 0.05), had higher plasma cortisol (P = 0.001), and required more supportive care (P = 0.0009) than calves in box stalls. CONCLUSION: Housing method confounds study end-points in the calf model of cryptosporidiosis. Due to increased stress data collected from calves in confinement housing may not accurately estimate the efficacy of chemotherapeutics targeting C. parvum. PMID- 29694358 TI - The goal of ape pointing. AB - Captive great apes regularly use pointing gestures in their interactions with humans. However, the precise function of this gesture is unknown. One possibility is that apes use pointing primarily to direct attention (as in "please look at that"); another is that they point mainly as an action request (such as "can you give that to me?"). We investigated these two possibilities here by examining how the looking behavior of recipients affects pointing in chimpanzees (Pan troglodytes) and bonobos (Pan paniscus). Upon pointing to food, subjects were faced with a recipient who either looked at the indicated object (successful look) or failed to look at the indicated object (failed-look). We predicted that, if apes point primarily to direct attention, subjects would spend more time pointing in the failed-look condition because the goal of their gesture had not been met. Alternatively, we expected that, if apes point primarily to request an object, subjects would not differ in their pointing behavior between the successful-look and failed-look conditions because these conditions differed only in the looking behavior of the recipient. We found that subjects did differ in their pointing behavior across the successful-look and failed-look conditions, but contrary to our prediction subjects spent more time pointing in the successful-look condition. These results suggest that apes are sensitive to the attentional states of gestural recipients, but their adjustments are aimed at multiple goals. We also found a greater number of individuals with a strong right hand than left-hand preference for pointing. PMID- 29694360 TI - A comparative analysis of terrestrial arthropod assemblages from a relict forest unveils historical extinctions and colonization differences between two oceanic islands. AB - During the last few centuries oceanic island biodiversity has been drastically modified by human-mediated activities. These changes have led to the increased homogenization of island biota and to a high number of extinctions lending support to the recognition of oceanic islands as major threatspots worldwide. Here, we investigate the impact of habitat changes on the spider and ground beetle assemblages of the native forests of Madeira (Madeira archipelago) and Terceira (Azores archipelago) and evaluate its effects on the relative contribution of rare endemics and introduced species to island biodiversity patterns. We found that the native laurel forest of Madeira supported higher species richness of spiders and ground beetles compared with Terceira, including a much larger proportion of indigenous species, particularly endemics. In Terceira, introduced species are well-represented in both terrestrial arthropod taxa and seem to thrive in native forests as shown by the analysis of species abundance distributions (SAD) and occupancy frequency distributions (OFD). Low abundance range-restricted species in Terceira are mostly introduced species dispersing from neighbouring man-made habitats while in Madeira a large number of true rare endemic species can still be found in the native laurel forest. Further, our comparative analysis shows striking differences in species richness and composition that are due to the geographical and geological particularities of the two islands, but also seem to reflect the differences in the severity of human-mediated impacts between them. The high proportion of introduced species, the virtual absence of rare native species and the finding that the SADs and OFDs of introduced species match the pattern of native species in Terceira suggest the role of man as an important driver of species diversity in oceanic islands and add evidence for an extensive and severe human-induced species loss in the native forests of Terceira. PMID- 29694359 TI - Body silhouettes as a tool to reflect obesity in the past. AB - Life course data on obesity may enrich the quality of epidemiologic studies analysing health consequences of obesity. However, achieving such data may require substantial resources. We investigated the use of body silhouettes in adults as a tool to reflect obesity in the past. We used large population-based samples to analyse to what extent self-reported body silhouettes correlated with the previously measured (9-23 years) body mass index (BMI) from both measured (European Community Respiratory Health Survey, N = 3 041) and self-reported (Respiratory Health In Northern Europe study, N = 3 410) height and weight. We calculated Spearman correlation between BMI and body silhouettes and ROC-curve analyses for identifying obesity (BMI >=30) at ages 30 and 45 years. Spearman correlations between measured BMI age 30 (+/-2y) or 45 (+/-2y) and body silhouettes in women and men were between 0.62-0.66 and correlations for self reported BMI were between 0.58-0.70. The area under the curve for identification of obesity at age 30 using body silhouettes vs previously measured BMI at age 30 (+/-2y) was 0.92 (95% CI 0.87, 0.97) and 0.85 (95% CI 0.75, 0.95) in women and men, respectively; for previously self-reported BMI, 0.92 (95% CI 0.88, 0.95) and 0.90 (95% CI 0.85, 0.96). Our study suggests that body silhouettes are a useful epidemiological tool, enabling retrospective differentiation of obesity and non obesity in adult women and men. PMID- 29694361 TI - Natural enemy defense, provisioning and oviposition site selection as maternal strategies to enhance offspring survival in a sub-social bug. AB - The influence of maternal defense against natural enemies, maternal provisioning and oviposition site selection on offspring survival before and after hatching were examined in a semelparous pentatomid bug, Ramosiana insignis. Oviposition occurs on leaves of Schoepfia schreberi, or surrounding vegetation from which nymphs migrate to feed exclusively on S. schreberi flower buds. Oviposition is asynchronous; the mother lays additional eggs immediately prior to hatching of the core brood that rapidly consume the additional eggs. In the absence of maternal defense egg masses were more heavily parasitized, suffered ant predation and an increased prevalence of sibling cannibalism. Maternal provisioning in the form of addition eggs significantly reduced the prevalence of sibling cannibalism of core brood eggs. Migration of the core brood away from the oviposition site was also significantly higher in the absence of maternal provisioning. If not consumed, additional eggs were capable of producing viable progeny of both sexes, indicating that they were in fact marginal progeny. The average clutch size on non-host vegetation was numerically greater than clutches laid on host trees (borderline significant P = 0.058). A greater number of additional eggs were deposited with clutches laid on non-host vegetation compared to those on the host plant. Egg masses on non-host vegetation were less likely to be discovered by parasitoids, compared to those on the host tree. Overall, clutches on non-host vegetation produced one third more offspring than clutches on the host tree. We conclude that R. insignis females present a remarkable combination of maternal defense, provisioning of additional eggs and oviposition site selection as strategies to enhance offspring survival in both the egg and nymph stages. PMID- 29694362 TI - Unexpected spatial impact of treatment plant discharges induced by episodic hydrodynamic events: Modelling Lagrangian transport of fine particles by Northern Current intrusions in the bays of Marseille (France). AB - Our study highlights the Lagrangian transport of solid particles discharged at the Marseille Wastewater Treatment Plant (WWTP), located at Cortiou on the southern coastline. We focused on episodic situations characterized by a coastal circulation pattern induced by intrusion events of the Northern Current (NC) on the continental shelf, associated with SE wind regimes. We computed, using MARS3D RHOMA and ICHTHYOP models, the particle trajectories from a patch of 5.104 passive and conservative fine particles released at the WWTP outlet, during 2 chosen representative periods of intrusion of the NC in June 2008 and in October 2011, associated with S-SE and E-SE winds, respectively. Unexpected results highlighted that the amount of particles reaching the vulnerable shorelines of both northern and southern bays accounted for 21.2% and 46.3% of the WWTP initial patch, in June 2008 and October 2011, respectively. Finally, a conceptual diagram is proposed to highlight the mechanisms of dispersion within the bays of Marseille of the fine particles released at the WWTP outlet that have long been underestimated. PMID- 29694363 TI - Stimulated enrichment of Clostridium difficile specific IgA in mature cow's milk. AB - Cow milk products enriched with Clostridium difficile (C. diff.) specific IgA are possible alternative therapeutics against C. diff. associated diarrhea. A persistently high level of C. diff. specific IgA in mature milk triggered by continuous immunizations of dairy cows against C. diff. was hypothesized. Nine Brown Swiss cows were repeatedly vaccinated against C. diff. and divided into low responder (LR) and high responder (HR) cows, as measured by their production of anti-C. diff. specific IgA in milk (threshold: 8.0 MUg anti-C. diff. specific IgA/mL on average). Total and C. diff. specific IgA were quantified in bovine milk and blood using a sandwich ELISA. Important milk production factors were analyzed per lactation stage. Milk yield, milk fats and proteins were significantly different (P < 0.05) in the early lactation stage when the treated with the untreated cows (n = 30) were compared. In contrast to the "before treatment control" values, the HR's milk anti-C. diff. IgA was approximately 80% higher at any lactation stage, and the HR's total milk IgA increased up to 72% in the late lactation stage. The LR's total milk IgA differed from the baseline by roughly 47% only in the late lactation stage. The total and specific IgA contents in milk were more influenced by the anti-C. diff. immunizations than in blood. The correlations between anti-C. diff. specific IgA, total IgA and the main production factors in milk were classified as weak (I r I < 0.5), except for the close relation of anti-C. diff. specific IgA and total IgA (r = 0.69). To conclude, a sustainable C. diff. specific IgA enrichment in milk can be achieved by continuous immunization of dairy cows, provided a potent and well-formulated anti-C. diff. vaccine is given to dairy cows preselected due to their proven anti C. diff. receptivity. PMID- 29694364 TI - Capturing multi-stage fuzzy uncertainties in hybrid system dynamics and agent based models for enhancing policy implementation in health systems research. AB - BACKGROUND: In practical research, it was found that most people made health related decisions not based on numerical data but on perceptions. Examples include the perceptions and their corresponding linguistic values of health risks such as, smoking, syringe sharing, eating energy-dense food, drinking sugar sweetened beverages etc. For the sake of understanding the mechanisms that affect the implementations of health-related interventions, we employ fuzzy variables to quantify linguistic variable in healthcare modeling where we employ an integrated system dynamics and agent-based model. METHODOLOGY: In a nonlinear causal-driven simulation environment driven by feedback loops, we mathematically demonstrate how interventions at an aggregate level affect the dynamics of linguistic variables that are captured by fuzzy agents and how interactions among fuzzy agents, at the same time, affect the formation of different clusters(groups) that are targeted by specific interventions. RESULTS: In this paper, we provide an innovative framework to capture multi-stage fuzzy uncertainties manifested among interacting heterogeneous agents (individuals) and intervention decisions that affect homogeneous agents (groups of individuals) in a hybrid model that combines an agent-based simulation model (ABM) and a system dynamics models (SDM). Having built the platform to incorporate high-dimension data in a hybrid ABM/SDM model, this paper demonstrates how one can obtain the state variable behaviors in the SDM and the corresponding values of linguistic variables in the ABM. CONCLUSIONS: This research provides a way to incorporate high-dimension data in a hybrid ABM/SDM model. This research not only enriches the application of fuzzy set theory by capturing the dynamics of variables associated with interacting fuzzy agents that lead to aggregate behaviors but also informs implementation research by enabling the incorporation of linguistic variables at both individual and institutional levels, which makes unstructured linguistic data meaningful and quantifiable in a simulation environment. This research can help practitioners and decision makers to gain better understanding on the dynamics and complexities of precision intervention in healthcare. It can aid the improvement of the optimal allocation of resources for targeted group (s) and the achievement of maximum utility. As this technology becomes more mature, one can design policy flight simulators by which policy/intervention designers can test a variety of assumptions when they evaluate different alternatives interventions. PMID- 29694365 TI - A preliminary investigation into the early embryo death syndrome (EEDS) at the world's largest green turtle rookery. AB - Raine Island hosts the largest nesting aggregation of green turtles in the world, but nest emergence success and hence recruitment of hatchlings off the beach appear to have significantly declined since the 1990s. Nests destroyed by subsequent nesting turtles, and nest failure due to flooding account for most of the nest failure, but many nests still have poor hatch success even when undisturbed and flood-free. In undisturbed, flood-free nests that experience high mortality, embryos typically die at a very early stage of development, a phenomenon we term early embryo death syndrome (EEDS). Previous research indicates that EEDS is correlated with the number of females nesting at Raine Island during a nesting season. Here, we monitor nest temperature and oxygen (PO2) and carbon dioxide (PCO2) partial pressures during the first week after nest construction to discover if they are associated with EEDS. Our investigation found that the proportion of early embryo death was greatest in two nests that experienced the highest nest temperature, lowest PO2 and highest PCO2 during the first week of incubation suggesting that these variables either by themselves or in combination may be the underlying cause of EEDS. These two nests were located adjacent to maturing nests, so the high temperature and more extreme PO2s and PCO2s are most likely to be caused by the combined metabolism of embryos in the mature nests. Although this conclusion is based on just two nests and needs to be substantiated in future studies, it would appear that the laying of new nests in the close location to mature nests could be a significant cause of hatch failure at high density nesting sea turtle rookeries around the world. PMID- 29694366 TI - System steganalysis with automatic fingerprint extraction. AB - This paper tries to tackle the modern challenge of practical steganalysis over large data by presenting a novel approach whose aim is to perform with perfect accuracy and in a completely automatic manner. The objective is to detect changes introduced by the steganographic process in those data objects, including signatures related to the tools being used. Our approach achieves this by first extracting reliable regularities by analyzing pairs of modified and unmodified data objects; then, combines these findings by creating general patterns present on data used for training. Finally, we construct a Naive Bayes model that is used to perform classification, and operates on attributes extracted using the aforementioned patterns. This technique has been be applied for different steganographic tools that operate in media files of several types. We are able to replicate or improve on a number or previously published results, but more importantly, we in addition present new steganalytic findings over a number of popular tools that had no previous known attacks. PMID- 29694367 TI - Non-canonical role of the SNARE protein Ykt6 in autophagosome-lysosome fusion. AB - The autophagosomal SNARE Syntaxin17 (Syx17) forms a complex with Snap29 and Vamp7/8 to promote autophagosome-lysosome fusion via multiple interactions with the tethering complex HOPS. Here we demonstrate that, unexpectedly, one more SNARE (Ykt6) is also required for autophagosome clearance in Drosophila. We find that loss of Ykt6 leads to large-scale accumulation of autophagosomes that are unable to fuse with lysosomes to form autolysosomes. Of note, loss of Syx5, the partner of Ykt6 in ER-Golgi trafficking does not prevent autolysosome formation, pointing to a more direct role of Ykt6 in fusion. Indeed, Ykt6 localizes to lysosomes and autolysosomes, and forms a SNARE complex with Syx17 and Snap29. Interestingly, Ykt6 can be outcompeted from this SNARE complex by Vamp7, and we demonstrate that overexpression of Vamp7 rescues the fusion defect of ykt6 loss of function cells. Finally, a point mutant form with an RQ amino acid change in the zero ionic layer of Ykt6 protein that is thought to be important for fusion competent SNARE complex assembly retains normal autophagic activity and restores full viability in mutant animals, unlike palmitoylation or farnesylation site mutant Ykt6 forms. As Ykt6 and Vamp7 are both required for autophagosome-lysosome fusion and are mutually exclusive subunits in a Syx17-Snap29 complex, these data suggest that Vamp7 is directly involved in membrane fusion and Ykt6 acts as a non conventional, regulatory SNARE in this process. PMID- 29694368 TI - Quantification of endogenous and exogenous protein expressions of Na,K-ATPase with super-resolution PALM/STORM imaging. AB - Transient transfection of fluorescent fusion proteins is a key enabling technology in fluorescent microscopy to spatio-temporally map cellular protein distributions. Transient transfection of proteins may however bypass normal regulation of expression, leading to overexpression artefacts like misallocations and excess amounts. In this study we investigate the use of STORM and PALM microscopy to quantitatively monitor endogenous and exogenous protein expression. Through incorporation of an N-terminal hemagglutinin epitope to a mMaple3 fused Na,K-ATPase (alpha1 isoform), we analyze the spatial and quantitative changes of plasma membrane Na,K-ATPase localization during competitive transient expression. Quantification of plasma membrane protein density revealed a time dependent increase of Na,K-ATPase, but no increase in size of protein clusters. Results show that after 41h transfection, the total plasma membrane density of Na,K ATPase increased by 63% while the endogenous contribution was reduced by 16%. PMID- 29694369 TI - Wearable sensors detect childhood internalizing disorders during mood induction task. AB - There is a significant need to develop objective measures for identifying children under the age of 8 who have anxiety and depression. If left untreated, early internalizing symptoms can lead to adolescent and adult internalizing disorders as well as comorbidity which can yield significant health problems later in life including increased risk for suicide. To this end, we propose the use of an instrumented fear induction task for identifying children with internalizing disorders, and demonstrate its efficacy in a sample of 63 children between the ages of 3 and 7. In so doing, we extract objective measures that capture the full six degree-of-freedom movement of a child using data from a belt worn inertial measurement unit (IMU) and relate them to behavioral fear codes, parent-reported child symptoms and clinician-rated child internalizing diagnoses. We find that IMU motion data, but not behavioral codes, are associated with parent-reported child symptoms and clinician-reported child internalizing diagnosis in this sample. These results demonstrate that IMU motion data are sensitive to behaviors indicative of child psychopathology. Moreover, the proposed IMU-based approach has increased feasibility of collection and processing compared to behavioral codes, and therefore should be explored further in future studies. PMID- 29694370 TI - Bayesian reanalysis of null results reported in medicine: Strong yet variable evidence for the absence of treatment effects. AB - Efficient medical progress requires that we know when a treatment effect is absent. We considered all 207 Original Articles published in the 2015 volume of the New England Journal of Medicine and found that 45 (21.7%) reported a null result for at least one of the primary outcome measures. Unfortunately, standard statistical analyses are unable to quantify the degree to which these null results actually support the null hypothesis. Such quantification is possible, however, by conducting a Bayesian hypothesis test. Here we reanalyzed a subset of 43 null results from 36 articles using a default Bayesian test for contingency tables. This Bayesian reanalysis revealed that, on average, the reported null results provided strong evidence for the absence of an effect. However, the degree of this evidence is variable and cannot be reliably predicted from the p value. For null results, sample size is a better (albeit imperfect) predictor for the strength of evidence in favor of the null hypothesis. Together, our findings suggest that (a) the reported null results generally correspond to strong evidence in favor of the null hypothesis; (b) a Bayesian hypothesis test can provide additional information to assist the interpretation of null results. PMID- 29694371 TI - Voltage-dependent inward currents in smooth muscle cells of skeletal muscle arterioles. AB - Voltage-dependent inward currents responsible for the depolarizing phase of action potentials were characterized in smooth muscle cells of 4th order arterioles in mouse skeletal muscle. Currents through L-type Ca2+ channels were expected to be dominant; however, action potentials were not eliminated in nominally Ca2+-free bathing solution or by addition of L-type Ca2+ channel blocker nifedipine (10 MUM). Instead, Na+ channel blocker tetrodotoxin (TTX, 1 MUM) reduced the maximal velocity of the upstroke at low, but not at normal (2 mM), Ca2+ in the bath. The magnitude of TTX-sensitive currents recorded with 140 mM Na+ was about 20 pA/pF. TTX-sensitive currents decreased five-fold when Ca2+ increased from 2 to 10 mM. The currents reduced three-fold in the presence of 10 mM caffeine, but remained unaltered by 1 mM of isobutylmethylxanthine (IBMX). In addition to L-type Ca2+ currents (15 pA/pF in 20 mM Ca2+), we also found Ca2+ currents that are resistant to 10 MUM nifedipine (5 pA/pF in 20 mM Ca2+). Based on their biophysical properties, these Ca2+ currents are likely to be through voltage-gated T-type Ca2+ channels. Our results suggest that Na+ and at least two types (T- and L-) of Ca2+ voltage-gated channels contribute to depolarization of smooth muscle cells in skeletal muscle arterioles. Voltage-gated Na+ channels appear to be under a tight control by Ca2+ signaling. PMID- 29694372 TI - Data quality and timeliness of outbreak reporting system among countries in Greater Mekong subregion: Challenges for international data sharing. AB - Cross-border disease transmission is a key challenge for prevention and control of outbreaks. Variation in surveillance structure and national guidelines used in different countries can affect their data quality and the timeliness of outbreak reports. This study aimed to evaluate timeliness and data quality of national outbreak reporting for four countries in the Mekong Basin Disease Surveillance network (MBDS). Data on disease outbreaks occurring from 2010 to 2015 were obtained from the national disease surveillance reports of Cambodia, Lao PDR, Myanmar, and Vietnam. Data included total cases, geographical information, and dates at different timeline milestones in the outbreak detection process. Nine diseases or syndromes with public health importance were selected for the analysis including: dengue, food poisoning & diarrhea, severe diarrhea, diphtheria, measles, H5N1 influenza, H1N1 influenza, rabies, and pertussis. Overall, 2,087 outbreaks were reported from the four countries. The number of outbreaks and number of cases per outbreak varied across countries and diseases, depending in part on the outbreak definition used in each country. Dates on index onset, report, and response were >95% complete in all countries, while laboratory confirmation dates were 10%-100% incomplete in most countries. Inconsistent and out of range date data were observed in 1%-5% of records. The overall timeliness of outbreak report, response, and public communication was within 1-15 days, depending on countries and diseases. Diarrhea and severe diarrhea outbreaks showed the most rapid time to report and response, whereas diseases such as rabies, pertussis and diphtheria required a longer time to report and respond. The hierarchical structure of the reporting system, data collection method, and country's resources could affect the data quality and timeliness of the national outbreak reporting system. Differences in data quality and timeliness of outbreak reporting system among member countries should be considered when planning data sharing strategies within a regional network. PMID- 29694373 TI - Treatment pathways of Japanese prostate cancer patients - A retrospective transition analysis with administrative data. AB - BACKGROUND: Limited availability of real-world data that describe treatment patterns of Japanese prostate cancer (PCA) patients. METHODS: A biweekly transition analysis of PCA treatment was performed for patients with PCA diagnosis and a specific treatment between 2010 and 2015. To account for different cancer stages, two patient populations were analyzed. The first group consisted of patients on medication for hormone-sensitive prostate cancer (HSPC). The second group is comprised of patients who ended up receiving specific therapy for castration-resistant prostate cancer (CRPC). For each treatment, the average of treatment duration and the portion of patients transitioning to a consecutive treatment was calculated. RESULTS: We identified 59,626 patients from the Japanese administrative database with a PCA diagnosis and specific treatment. In the first year of our observational study 786 patients commenced a HSPC treatment and 695 received a CRPC specific therapy Among the HSPC group, we found that combination hormonal therapy, comprised of a gonadotrophin releasing hormone agonist or antagonist with an antiandrogen was more common than monotherapy. The results of the CRPC group indicated that chemotherapy administration was for a shorter time period in a real-world setting as compared to published clinical studies. CONCLUSION: Utilizing a novel method to visualize real-world treatment pathways for PCA patients we found that real treatment pathways are in line with international guidelines. PMID- 29694374 TI - Answering hastily retards learning. AB - Appropriate decisions involve at least two aspects: the speed of the decision and the correctness of the decision. Although a quick and correct decision is generally believed to work favorably, these two aspects may be interdependent in terms of overall task performance. In this study, we scrutinized learning behaviors in an operant task in which rats were required to poke their noses into either of two holes by referring to a light cue. All 22 rats reached the learning criterion, an 80% correct rate, within 4 days of testing, but they were diverse in the number of sessions spent to reach the learning criterion. Individual analyses revealed that the mean latency for responding was negatively correlated with the number of sessions until learning, suggesting that the rats that responded more rapidly to the cues learned the task more slowly. For individual trials, the mean latency for responding in correct trials (LC) was significantly longer than that in incorrect trials (LI), suggesting that, on average, long deliberation times led to correct answers in the trials. The success ratio before learning was not correlated with the learning speed. Thus, deliberative decision making, rather than overall correctness, is critical for learning. PMID- 29694375 TI - Prevalence of burnout in paediatric nurses: A systematic review and meta analysis. AB - INTRODUCTION: Although burnout in paediatric nurses has been addressed in previous research, the heterogeneous nature of the results obtained and of the variables studied highlights the need for a detailed analysis of the literature. OBJECTIVE: The aim of this study was to analyse the literature on burnout characteristics, reported prevalence, severity and risk factors, to achieve a better understanding of the risk of emotional exhaustion, depersonalisation and feelings of low personal accomplishment. METHOD: For this purpose, we carried out a systematic review and meta-analysis of the literature. The databases consulted were CINAHL, LILACS, PubMed, the Proquest Platform (Proquest Health & Medical Complete), Scielo and Scopus. This study used the search equation "burnout AND "pediatric nurs*"", and was conducted in July 2017. RESULTS: The search produced 34 studies targeting burnout in paediatric nurses, with no restrictions on the date of publication. Many of these studies detected moderate-high values for the three dimensions of burnout, and highlighted sociodemographic, psychological and job-related variables associated with this syndrome. The sample population for the meta-analysis was composed of 1600 paediatric nurses. The following prevalence values were obtained: (i) emotional exhaustion, 31% (95% CI: 25-37%); (ii) depersonalisation, 21% (95% CI: 11-33%); (iii) low personal accomplishment, 39% (95% CI: 28-50%). CONCLUSIONS: A significant number of paediatric nurses were found to have moderate-high levels of emotional exhaustion and depersonalisation, and low levels of personal accomplishment. These nurses, therefore, were either experiencing burnout or at high risk of suffering it in the future. These results support the need for further study of the risk factors for burnout in paediatric nurses. They also highlight the importance of developing interventions or therapies to help prevent or attenuate the above symptoms, thus helping nurses cope with the workplace environment and with situations that may lead to burnout. PMID- 29694376 TI - Pulmonary arterial enlargement predicts long-term survival in COPD patients. AB - RATIONALE: Pulmonary artery enlargement (PAE) is associated with exacerbations in Chronic Obstructive Pulmonary Disease (COPD) and with survival in moderate to severe patients. The potential role of PAE in survival prediction has not been compared with other clinical and physiological prognostic markers. METHODS: In 188 patients with COPD, PA diameter was measured on a chest CT and the following clinical and physiological parameters registered: age, gender, smoking status, pack-years history, dyspnea, lung function, exercise capacity, Body Mass Index, BODE index and history of exacerbations in year prior to enrolment. Proportional Cox regression analysis determined the best predictor of all cause survival. RESULTS: During 83 months (+/-42), 43 patients died. Age, pack-years history, smoking status, BMI, FEV1%, six minute walking distance, Modified Medical Research Council dyspnea scale, BODE index, exacerbation rate prior to enrollment, PA diameter and PAE (diameter>=30mm) were associated with survival. In the multivariable analysis, age (HR: 1.08; 95%CI: 1.03-1.12, p<0.001) and PAE (HR: 2.78; 95%CI: 1.35-5.75, p = 0.006) were the most powerful parameters associated with all-cause mortality. CONCLUSIONS: In this prospective observational study of COPD patients with mild to moderate airflow limitation, PAE was the best predictor of long-term survival along with age. PMID- 29694377 TI - A framework for the estimation of the proportion of true discoveries in single nucleotide variant detection studies for human data. AB - Any single nucleotide variant detection study could benefit from a fast and cheap method of measuring the quality of variant call list. It is advantageous to be able to see how the call list quality is affected by different variant filtering thresholds and other adjustments to the study parameters. Here we look into a possibility of estimating the proportion of true positives in a single nucleotide variant call list for human data. Using whole-exome and whole-genome gold standard data sets for training, we focus on building a generic model that only relies on information available from any variant caller. We assess and compare the performance of different candidate models based on their practical accuracy. We find that the generic model delivers decent accuracy most of the time. Further, we conclude that its performance could be improved substantially by leveraging the variant quality metrics that are specific to each variant calling tool. PMID- 29694378 TI - Comparison of acupuncture and other drugs for chronic constipation: A network meta-analysis. AB - The objective of this study was to compare the efficacy and side effects of acupuncture, sham acupuncture and drugs in the treatment of chronic constipation. Randomized controlled trials (RCTs) assessing the effects of acupuncture and drugs for chronic constipation were comprehensively retrieved from electronic databases (such as PubMed, Cochrane Library, Embase, CNKI, Wanfang Database, VIP Database and CBM) up to December 2017. Additional references were obtained from review articles. With quality evaluations and data extraction, a network meta analysis (NMA) was performed using a random-effects model under a frequentist framework. A total of 40 studies (n = 11032) were included: 39 were high-quality studies and 1 was a low-quality study. NMA showed that (1) acupuncture improved the symptoms of chronic constipation more effectively than drugs; (2) the ranking of treatments in terms of efficacy in diarrhoea-predominant irritable bowel syndrome was acupuncture, polyethylene glycol, lactulose, linaclotide, lubiprostone, bisacodyl, prucalopride, sham acupuncture, tegaserod, and placebo; (3) the ranking of side effects were as follows: lactulose, lubiprostone, bisacodyl, polyethylene glycol, prucalopride, linaclotide, placebo and tegaserod; and (4) the most commonly used acupuncture point for chronic constipation was ST25. Acupuncture is more effective than drugs in improving chronic constipation and has the least side effects. In the future, large-scale randomized controlled trials are needed to prove this. Sham acupuncture may have curative effects that are greater than the placebo effect. In the future, it is necessary to perform high-quality studies to support this finding. Polyethylene glycol also has acceptable curative effects with fewer side effects than other drugs. PMID- 29694379 TI - Short-term microbial effects of a large-scale mine-tailing storage facility collapse on the local natural environment. AB - We investigated the impacts of the Mount Polley tailings impoundment failure on chemical, physical, and microbial properties of substrates within the affected watershed, comprised of 70 hectares of riparian wetlands and 40 km of stream and lake shore. We established a biomonitoring network in October of 2014, two months following the disturbance, and evaluated riparian and wetland substrates for microbial community composition and function via 16S and full metagenome sequencing. A total of 234 samples were collected from substrates at 3 depths and 1,650,752 sequences were recorded in a geodatabase framework. These data revealed a wealth of information regarding watershed-scale distribution of microbial community members, as well as community composition, structure, and response to disturbance. Substrates associated with the impact zone were distinct chemically as indicated by elevated pH, nitrate, and sulphate. The microbial community exhibited elevated metabolic capacity for selenate and sulfate reduction and an abundance of chemolithoautotrophs in the Thiobacillus thiophilus/T. denitrificans/T. thioparus clade that may contribute to nitrate attenuation within the affected watershed. The most impacted area (a 6 km stream connecting two lakes) exhibited 30% lower microbial diversity relative to the remaining sites. The tailings impoundment failure at Mount Polley Mine has provided a unique opportunity to evaluate functional and compositional diversity soon after a major catastrophic disturbance to assess metabolic potential for ecosystem recovery. PMID- 29694380 TI - An improved inverse-type Ca2+ indicator can detect putative neuronal inhibition in Caenorhabditis elegans by increasing signal intensity upon Ca2+ decrease. AB - Sensory processing is regulated by the coordinated excitation and inhibition of neurons in neuronal circuits. The analysis of neuronal activities has greatly benefited from the recent development of genetically encoded Ca2+ indicators (GECIs). These molecules change their fluorescence intensities or colours in response to changing levels of Ca2+ and can, therefore, be used to sensitively monitor intracellular Ca2+ concentration, which enables the detection of neuronal excitation, including action potentials. These GECIs were developed to monitor increases in Ca2+ concentration; therefore, neuronal inhibition cannot be sensitively detected by these GECIs. To overcome this difficulty, we hypothesised that an inverse-type of GECI, whose fluorescence intensity increases as Ca2+ levels decrease, could sensitively monitor reducing intracellular Ca2+ concentrations. We, therefore, developed a Ca2+ indicator named inverse-pericam 2.0 (IP2.0) whose fluorescent intensity decreases 25-fold upon Ca2+ binding in vitro. Using IP2.0, we successfully detected putative neuronal inhibition by monitoring the decrease in intracellular Ca2+ concentration in AWCON and ASEL neurons in Caenorhabditis elegans. Therefore, IP2.0 is a useful tool for studying neuronal inhibition and for the detailed analysis of neuronal activities in vivo. PMID- 29694381 TI - Modeling the temporal periodicity of growth increments based on harmonic functions. AB - Age estimation methods based on hard structures require a process of validation to confirm the periodical pattern of growth marks. Among such processes, one of the most used is the marginal increment ratio (MIR), which was stated to follow a sinusoidal cycle in a population. Despite its utility, in most cases, its implementation has lacked robust statistical analysis. Accordingly, we propose a modeling approach for the temporal periodicity of growth increments based on single and second order harmonic functions. For illustrative purposes, the MIR periodicities for two geoduck species (Panopea generosa and Panopea globosa) were modeled to identify the periodical pattern of growth increments in the shell. This model identified an annual periodicity for both species but described different temporal patterns. The proposed procedure can be broadly used to objectively define the timing of the peak, the degree of symmetry, and therefore, the synchrony of band deposition of different species on the basis of MIR data. PMID- 29694382 TI - Association of objectively measured physical activity and sedentary time with arterial stiffness in women with systemic lupus erythematosus with mild disease activity. AB - OBJECTIVES: To examine the association of objectively measured physical activity (PA) intensity levels and sedentary time with arterial stiffness in women with systemic lupus erythematosus (SLE) with mild disease activity and to analyze whether participants meeting the international PA guidelines have lower arterial stiffness than those not meeting the PA guidelines. METHODS: The study comprised 47 women with SLE (average age 41.2 [standard deviation 13.9]) years, with clinical and treatment stability during the 6 months prior to the study. PA intensity levels and sedentary time were objectively measured with triaxial accelerometry. Arterial stiffness was assessed through pulse wave velocity, evaluated by Mobil-O-Graph(r) 24h pulse wave analysis monitor. RESULTS: The average time in moderate to vigorous PA in bouts of >=10 consecutive minutes was 135.1+/-151.8 minutes per week. There was no association of PA intensity levels and sedentary time with arterial stiffness, either in crude analyses or after adjusting for potential confounders. Participants who met the international PA guidelines did not show lower pulse wave velocity than those not meeting them (b = -0.169; 95% CI: -0.480 to 0.143; P = 0.280). CONCLUSIONS: Our results suggest that PA intensity levels and sedentary time are not associated with arterial stiffness in patients with SLE. Further analyses revealed that patients with SLE meeting international PA guidelines did not present lower arterial stiffness than those not meeting the PA guidelines. Future prospective research is needed to better understand the association of PA and sedentary time with arterial stiffness in patients with SLE. PMID- 29694384 TI - Mismatch negativity reflects asymmetric pre-attentive harmonic interval discrimination. AB - OBJECTIVE: Western music is based on intervals; thus, interval discrimination is important for distinguishing the character of melodies or tracking melodies in polyphonic music. In this study the encoding of intervals in simultaneously presented sound is studied. STUDY DESIGN: In an electrophysiological experiment in 15 normal-hearing non-musicians, major thirds or fifths were presented in a controlled oddball paradigm. Harmonic intervals were created by simultaneously presented sinusoidals with randomized root frequency. Mismatch negativity (MMN) responses were measured with an EEG recording. The discrimination index was calculated in a psychoacoustic experiment. RESULTS: A clear MMN response was found for the major third but not for the fifth. The neural generators were located within the auditory cortices. Psychoacoustically, no evidence was found that the subjects were able to detect the deviants. CONCLUSIONS: We conclude that pre-attentive discrimination of harmonic interval size is, in principle, possible in listeners without musical training although simultaneous presentation makes it harder to distinguish compared to non-overlapping intervals. Furthermore we see a difference in the response to infrequent dissonant stimuli in consonant standard stimuli compared to the opposite, rare consonant stimuli in dissonant standard stimuli. PMID- 29694383 TI - BA9 lineage of respiratory syncytial virus from across the globe and its evolutionary dynamics. AB - Respiratory syncytial virus (RSV) is an important pathogen of global significance. The BA9 is one of the most predominant lineages of the BA genotype of group B RSV that has acquired a 60bp duplication in its G protein gene. We describe the local and global evolutionary dynamics of the second hyper variable region in the C- terminal of the G protein gene of the BA9 lineage. A total of 418 sequences (including 31 study and 387 GenBank strains) from 29 different countries were used for phylogenetic analysis. This analysis showed that the study strains clustered with BA (BA9 and BA8) and SAB4 genotype of group B RSV. We performed time-scaled evolutionary clock analyses using Bayesian Markov chain Monte Carlo methods. We also carried out glycosylation, selection pressure, mutational, entropy and Network analyses of the BA9 lineage. The time to the most recent common ancestor (tMRCA) of the BA genotype and BA9 lineage were estimated to be the years 1995 (95% HPD; 1987-1997) and 2000 (95% HPD; 1998-2001), respectively. The nucleotide substitution rate of the BA genotype [(4.58*10-3 (95% HPD; 3.89-5.29*10-3) substitution/site/year] was slightly faster than the BA9 lineage [4.03*10-3 (95% HPD; 4.65-5.2492*10-3)]. The BA9 lineage was categorized into 3 sub lineages (I, II and III) based on the Bayesian and Network analyses. The local transmission pattern suggested that BA9 is the predominant lineage of BA viruses that has been circulating in India since 2002 though showing fluctuations in its effective population size. The BA9 lineage established its global distribution with report from 23 different countries over the past 16 years. The present study augments our understanding of RSV infection, its epidemiological dynamics warranting steps towards its overall global surveillance. PMID- 29694385 TI - Measurement of intracellular concentration of fluorescently-labeled targets in living cells. AB - Estimations of intracellular concentrations of fluorescently-labeled molecules within living cells are very important for guidance of biological experiments and interpretation of their results. Here we propose a simple and universal approach for such estimations. The approach is based upon common knowledge that the dye fluorescence is directly proportional to its quantum yield and the number of its molecules and that a coefficient of proportionality is determined by spectral properties of the dye and optical equipment used to record fluorescent signals. If two fluorescent dyes are present in the same volume, then a ratio of their concentrations is equal to a ratio of their fluorescence multiplied by some dye- and equipment-dependent coefficient. Thus, if the coefficient and concentration of one dye is known then the concentration of another dye can be determined. Here we have demonstrated how to calculate this coefficient (called a ratio factor) and how to use it for concentration measurements of fluorescently tagged molecules. As an example of how this approach can be used, we estimated a concentration of exogenously expressed neuronal Ca2+ sensor protein, hippocalcin, tagged by a fluorescent protein in a dendritic tree of rat hippocampal neurons loaded via a patch pipette with Alexa Fluor dye of known concentration. The new approach should allow performing a fast, inexpensive and reliable quantitative analysis of fluorescently-labeled targets in different parts of living cells. PMID- 29694386 TI - Attenuation of choroidal neovascularization by dietary intake of omega-3 long chain polyunsaturated fatty acids and lutein in mice. AB - Dietary omega-3 long-chain polyunsaturated fatty acids (LCPUFAs) and lutein each protect against age-related macular degeneration (AMD). We here examined the effects of omega-3 LCPUFAs and lutein supplementation in a mouse model of AMD. Mice were assigned to four groups: (1) a control group fed an omega-3 LCPUFA-free diet, (2) a lutein group fed an omega-3 LCPUFA-free diet with oral administration of lutein, (3) an omega-3 group fed an omega-3 LCPUFA-supplemented diet, and (4) an omega-3 + lutein group fed an omega-3 LCPUFA-supplemented diet with oral administration of lutein. Mice were fed the defined diets beginning 2 weeks before, and received lutein with an oral gavage needle beginning 1 week before, induction of choroidal neovascularization (CNV) by laser photocoagulation. The area of CNV measured in choroidal flat-mount preparations was significantly reduced in mice fed omega-3 LCPUFAs or lutein compared with those in the control group, and it was reduced in an additive manner in those receiving both omega-3 LCPUFAs and lutein. The concentrations of various inflammatory mediators in the retina or choroid were reduced in mice fed omega-3 LCPUFAs or lutein, but no additive effect was apparent. The generation of reactive oxygen species (ROS) in chorioretinal lesions revealed by dihydroethidium staining as well as the expression of NADPH oxidase 4 (Nox4) in the retina revealed by immunohistofluorescence and immunoblot analyses were attenuated by omega-3 LCPUFAs and lutein in a synergistic manner. Our results thus show that dietary intake of omega-3 LCPUFAs and lutein attenuated CNV in an additive manner and in association with suppression of inflammatory mediator production, ROS generation, and Nox4 expression. Dietary supplementation with both omega-3 LCPUFAs and lutein warrants further study as a means to protect against AMD. PMID- 29694387 TI - Finding overlapping communities in multilayer networks. AB - Finding communities in multilayer networks is a vital step in understanding the structure and dynamics of these layers, where each layer represents a particular type of relationship between nodes in the natural world. However, most community discovery methods for multilayer networks may ignore the interplay between layers or the unique topological structure in a layer. Moreover, most of them can only detect non-overlapping communities. In this paper, we propose a new community discovery method for multilayer networks, which leverages the interplay between layers and the unique topology in a layer to reveal overlapping communities. Through a comprehensive analysis of edge behaviors within and across layers, we first calculate the similarities for edges from the same layer and the cross layers. Then, by leveraging these similarities, we can construct a dendrogram for the multilayer networks that takes both the unique topological structure and the important interplay into consideration. Finally, by introducing a new community density metric for multilayer networks, we can cut the dendrogram to get the overlapping communities for these layers. By applying our method on both synthetic and real-world datasets, we demonstrate that our method has an accurate performance in discovering overlapping communities in multilayer networks. PMID- 29694388 TI - Transcriptomic study to understand thermal adaptation in a high temperature tolerant strain of Pyropia haitanensis. AB - Pyropia haitanensis, a high-yield commercial seaweed in China, is currently undergoing increasing levels of high-temperature stress due to gradual global warming. The mechanisms of plant responses to high temperature stress vary with not only plant type but also the degree and duration of high temperature. To understand the mechanism underlying thermal tolerance in P. haitanensis, gene expression and regulation in response to short- and long-term temperature stresses (SHS and LHS) was investigated by performing genome-wide high-throughput transcriptomic sequencing for a high temperature tolerant strain (HTT). A total of 14,164 differential expression genes were identified to be high temperature responsive in at least one time point by high-temperature treatment, representing 41.10% of the total number of unigenes. The present data indicated a decrease in the photosynthetic and energy metabolic rates in HTT to reduce unnecessary energy consumption, which in turn facilitated in the rapid establishment of acclimatory homeostasis in its transcriptome during SHS. On the other hand, an increase in energy consumption and antioxidant substance activity was observed with LHS, which apparently facilitates in the development of resistance against severe oxidative stress. Meanwhile, ubiquitin-mediated proteolysis, brassinosteroids, and heat shock proteins also play a vital role in HTT. The effects of SHS and LHS on the mechanism of HTT to resist heat stress were relatively different. The findings may facilitate further studies on gene discovery and the molecular mechanisms underlying high-temperature tolerance in P. haitanensis, as well as allow improvement of breeding schemes for high temperature-tolerant macroalgae that can resist global warming. PMID- 29694389 TI - Site-specific glycosaminoglycan content is better maintained in the pericellular matrix than the extracellular matrix in early post-traumatic osteoarthritis. AB - INTRODUCTION: One of the characteristics of early osteoarthritis (OA) is the loss of fixed charged density (FCD) of glycosaminoglycans in the superficial zone of articular cartilage. However, possible local changes in the FCD content of the pericellular matrix (PCM) are not fully understood. Hence, our aim was to investigate the effect of unilateral anterior cruciate ligament transection (ACLT) in rabbit knees on estimated FCD in the PCM compared to that in the ECM, and relate these results with cell morphology. METHODS: Articular cartilage samples were collected from ACLT, contralateral and intact control knee joints from lateral and medial femoral condyles and tibial plateaus, and from the femoral groove and patella. Histological samples were prepared and stained with Safranin-O to estimate the FCD content around the chondrocytes in the PCM and the ECM with digital densitometry. RESULTS: As a result of ACLT, the greatest decreases in the FCD content of the PCM were observed in the superficial zone of the lateral femoral condyle (p = 0.02), medial tibial plateau (p = 0.002) and patellar (p < 0.001) cartilage. The normalized FCD content of the PCM compared to the surrounding ECM was increased most in the femoral condyles (p < 0.01) and medial tibial plateau (p = 0.02) cartilage. The high normalized FCD content of the PCM in the superficial zone of lateral femoral condyle cartilage was consistent with the round cell morphology in that location. CONCLUSIONS: In conclusion, we suggest that certain sites in the knee joint, particularly the lateral femoral condyle cartilage, experience less FCD loss in the PCM than in the ECM in early post-traumatic OA, which could lead to altered cell shape. PMID- 29694390 TI - Benthic macrofauna bioturbation and early colonization in newly flooded coastal habitats. AB - How will coastal soils in areas newly flooded with seawater function as habitat for benthic marine organisms? This research question is highly relevant as global sea level rise and coastal realignment will cause flooding of soils and form new marine habitats. In this study, we tested experimentally the capacity of common marine polychaetes, Marenzelleria viridis, Nereis (Hediste) diversicolor and Scoloplos armiger to colonize and modify the biogeochemistry of the newly established Gyldensteen Coastal Lagoon, Denmark. All tested polychaetes survived relatively well (28-89%) and stimulated carbon dioxide release (TCO2) by 97-105% when transferred to newly flooded soils, suggesting that soil characteristics are modified rapidly by colonizing fauna. A field survey showed that the pioneering benthic community inside the lagoon was structurally different from the marine area outside the lagoon, and M. viridis and S. armiger were not among the early colonizers. These were instead N. diversicolor and Polydora cornuta with an abundance of 1603 and 540 ind m-2, respectively. Considering the species-specific effects of N. diversicolor on TCO2 release and its average abundance in the lagoon, we estimate that organic carbon degradation was increased by 219% in the first year of flooding. We therefore conclude that early colonizing polychaetes modify the soils and may play an important role in the ecological and successional developments, e.g. C cycling and biodiversity, in newly flooded coastal ecosystems. Newly flooded soils have thus a strong potential to develop into well-functioning marine ecosystems. PMID- 29694391 TI - Persian leopard's (Panthera pardus saxicolor) unnatural mortality factors analysis in Iran. AB - Due to the relatively low offspring survival rate, surviving adult leopards play a critical role in the species' viability. The unnatural mortality of leopards, caused by human activities can seriously compromise the species' long-term population survival. An analysis of spatial distribution and sex ratio of unnatural mortality of 147 recorded Persian leopard (Panthera pardus saxicolor) carcasses during a fifteen-year period (from 2000-2015) in Iran indicated that road mortality is the second most frequent cause of unnatural mortality of Persian leopards' after illegal hunting (or prey poisoning, such as poisoned meat) by villagers, shepherds and military forces. The greatest percent of unnatural mortality events were recorded in the Golestan provinc in the north of Iran and eastern most parts of the Hyrcanian forests. Using distribution models of species, based on road accident locations as species data, we mapped the species' distribution and critical areas of unnatural mortality of Persian leopard that can be used in prioritizing leopard-human conflicts management. Our results showed that mortality records were significantly higher in non-protected compared to protected areas. Males constituted 65 percent of the records used in the study as males dispersed more widely compared to the females. This imbalance can have severe demographic effects. A large proportion of leopards' activity, occurrence area, and habitat lies in non-protected areas, which is mirrored by the greater number of unnatural mortality outside protected areas. Most of the incidents were due to human factors, thus management interventions such as traffic speed limitations, signs, cameras, and faunal bridges as well as increasing public participation and awareness (especially among rural communities) will positively affect the species' conservation programs. This research aimed to produce unnatural mortality of leopards' risk map throughout Iran and discuss the different aspects of this phenomenon, major human-caused threats and the efficiency of the legal protected areas in satisfying the species' ecological requirements. We propose management interventions such as traffic speed limitations, signs, cameras, and faunal bridges as well as increasing public awareness and participation, especially among rural communities, to support the species' conservation. PMID- 29694392 TI - Development and validation of a dementia screening tool for primary care in Taiwan: Brain Health Test. AB - OBJECTIVES: To develop a simple dementia screening tool to assist primary care physicians in identifying patients with cognitive impairment among subjects with memory complaints or at a high risk for dementia. DESIGN: The Brain Health Test (BHT) was developed by several experienced neurologists, psychiatrists, and clinical psychologists in the Taiwan Dementia Society. Validation of the BHT was conducted in the memory clinics of various levels of hospitals in Taiwan. PARTICIPANTS: All dementia patients at the memory clinics who met the inclusion criteria of age greater or equal to 50 years were enrolled. Besides the BHT, the Mini-Mental State Examination and Clinical Dementia Rating were used to evaluate the cognition state of the patients and the severity of dementia. RESULTS: The BHT includes two parts: a risk evaluation and a cognitive test (BHT-cog). Self or informants reports of memory decline or needing help from others to manage money or medications were significantly associated with cognitive impairment. Among the risk factors evaluated in the BHT, a total risk score greater or equal to 8 was defined as a high risk for dementia. The total score for the finalized BHT-cog was 16. When the cutoff value for the BHT-cog was set to 10 for differentiating dementia and a normal mental state, the sensitivity was 91.5%, the specificity was 87.3%, the positive predictive value was 94.8%, and the negative predictive value was 80.1% The area under the receiver operating characteristic curve between dementia and healthy subjects was 0.958 (95% CI = 0.941-0.975). CONCLUSIONS: The BHT is a simple tool that may be useful in primary care settings to identify high-risk patients to target for cognitive screening. PMID- 29694393 TI - Replacement of fish oil with palm oil: Effects on growth performance, innate immune response, antioxidant capacity and disease resistance in Nile tilapia (Oreochromis niloticus). AB - This study was conducted to investigate the effects of replacing dietary fish oil (FO) with palm oil (PO) in juvenile Nile tilapia, Oreochromis niloticus (9.34+/- 0.02g initial weight) with emphasis on growth performance, digestive enzyme activities as well as serum biochemical parameters. Also, lysozyme activity (LYZ), respiratory burst (RB), superoxide dismutase (SOD), catalase (CAT) and resistance to Streptococcus iniae were investigated. Fish were stocked in 15 rectangular fiber glass tanks (150* 60* 40 cm) at 40 fish per tank with water maintained at 210 litres. Fish were fed five isonitrogenous (33% crude protein) and isolipidic (10% lipid) diets with PO included at 0% (0% PO), 25% (25% PO), 50% (50%PO), 75% (75% PO) and 100% (100% PO) for 8 weeks. The findings demonstrated that growth, and feed utilization was not compromised when PO was used in place of FO either partially or totally. Except for protease activity which was not significantly altered, lipase and amylase activities were significantly altered when FO was replaced with PO. There were no significant differences among treatments for CAT, SOD and LYZ. Serum malondialdehyde (MDA) in fish fed 100% PO was significantly lower than all other groups whiles total antioxidant capacity (TAC) of fish fed 0% PO was significantly higher than all other groups. Fish fed 0% PO, 25% PO and 50% PO had glutathione reductase (GR) significantly higher than fish fed 75% PO and 100% PO. RB in fish fed 0% PO were significantly lower than fish fed 75% PO and 100% PO. Also, fish fed 0% PO had significantly lower total protein (TP) compared with groups fed 50% PO and 75% PO. Fish fed diets with PO had similar resistance ability to Streptococcus iniae as those fed diets with FO. However, the liver function was likely to be compromised due to the increase in aspartate amino transferase (AST) and alkaline phosphatas (ALP) along increasing PO inclusion levels. AST, total protein, triacylglycerol (TAG) and low-density lipoprotein cholesterol (LDL-C) were significantly higher (p<0.05) in groups fed higher levels of PO. This study therefore concludes that feeding tilapia fingerlings with diets containing PO affects antioxidant and innate immune parameters negatively due to the reduction in LYS, TAC, GR, MDA, CAT, SOD and GSHpx. PMID- 29694394 TI - Differential processing of nociceptive input within upper limb muscles. AB - The cutaneous silent period is an inhibitory evoked response that demonstrates a wide variety of responses in muscles of the human upper limb. Classically, the cutaneous silent period results in a characteristic muscle pattern of extensor inhibition and flexor facilitation within the upper limb, in the presence of nociceptive input. The aims of the current study were: 1) to primarily investigate the presence and characteristics of the cutaneous silent period response across multiple extensor and flexor muscles of the upper limb, and 2) to secondarily investigate the influence of stimulation site on this nociceptive reflex response. It was hypothesized that the cutaneous silent period would be present in all muscles, regardless of role (flexion/extension) or the stimulation site. Twenty-two healthy, university-age adults (14 males; 8 females; 23 +/- 5 yrs) participated in the study. Testing consisted of three different stimulation sites (Digit II, V, and II+III nociceptive stimulation) during a low intensity, sustained muscle contraction, in which, 7 upper limb muscles were monitored via surface EMG recording electrodes. Distal muscles of the upper limb presented with the earliest reflex onset times, longest reflex duration, and lowest level of EMG suppression when compared to the more proximal muscles, regardless of extensor/flexor role. Additionally, the greatest overall inhibitory influence was expressed within the distal muscles. In conclusion, the present study provides a new level of refinement within the current understanding of the spinal organization associated with nociceptive input processing and the associated motor control of the upper limb. Subsequently, these results have further implications on the impact of nociception on supraspinal processing. PMID- 29694395 TI - Transcriptome analysis of pecan seeds at different developing stages and identification of key genes involved in lipid metabolism. AB - Pecan is an economically important nut crop tree due to its unique texture and flavor properties. The pecan seed is rich of unsaturated fatty acid and protein. However, little is known about the molecular mechanisms of the biosynthesis of fatty acids in the developing seeds. In this study, transcriptome sequencing of the developing seeds was performed using Illumina sequencing technology. Pecan seed embryos at different developmental stages were collected and sequenced. The transcriptomes of pecan seeds at two key developing stages (PA, the initial stage and PS, the fast oil accumulation stage) were also compared. A total of 82,155 unigenes, with an average length of 1,198 bp from seven independent libraries were generated. After functional annotations, we detected approximately 55,854 CDS, among which, 2,807 were Transcription Factor (TF) coding unigenes. Further, there were 13,325 unigenes that showed a 2-fold or greater expression difference between the two groups of libraries (two developmental stages). After transcriptome analysis, we identified abundant unigenes that could be involved in fatty acid biosynthesis, degradation and some other aspects of seed development in pecan. This study presents a comprehensive dataset of transcriptomic changes during the seed development of pecan. It provides insights in understanding the molecular mechanisms responsible for fatty acid biosynthesis in the seed development. The identification of functional genes will also be useful for the molecular breeding work of pecan. PMID- 29694396 TI - I'll emulate you...only if you want me to: The impact of ingroup norms and status on the identification-assimilation relationship. AB - High identifiers are generally more willing to affiliate to their group and, as a result, perceive themselves and behave as prototypical members of their group. But is this always the case? The present research investigates the when and the why of the positive relationship between ingroup identification and assimilation by focusing on the role of the content of the injunctive ingroup norm (collectivistic vs. individualistic) and the ingroup status. Two experiments showed a positive identification-assimilation relationship in the low-status group when the ingroup norm was collectivistic, but not when the norm was individualistic. Moreover, the relationship was unreliable in the high-status group, regardless of the content of the norm. In a third study, these findings were extended to a more general measure of group affiliation (i.e., the need to belong). This research suggests that the greater tendency of high identifiers to assimilate to their group-and, more generally, to affiliate to groups-is accounted for by conformity motivations and strategies aimed at coping with an unfavorable social identity. PMID- 29694397 TI - Ancient DNA from latrines in Northern Europe and the Middle East (500 BC-1700 AD) reveals past parasites and diet. AB - High-resolution insight into parasitic infections and diet of past populations in Northern Europe and the Middle East (500 BC- 1700 AD) was obtained by pre concentration of parasite eggs from ancient latrines and deposits followed by shotgun sequencing of DNA. Complementary profiling of parasite, vertebrate and plant DNA proved highly informative in the study of ancient health, human-animal interactions as well as animal and plant dietary components. Most prominent were finding of soil-borne parasites transmitted directly between humans, but also meat-borne parasites that require consumption of raw or undercooked fish and pork. The detection of parasites for which sheep, horse, dog, pig, and rodents serves as definitive hosts are clear markers of domestic and synanthropic animals living in closer proximity of the respective sites. Finally, the reconstruction of full mitochondrial parasite genomes from whipworm (Ascaris lumbricoides) and roundworm species (Trichuris trichiura and Trichuris muris) and estimates of haplotype frequencies elucidates the genetic diversity and provides insights into epidemiology and parasite biology. PMID- 29694398 TI - Commensurate incidence and outcomes of liver enzyme elevation between anti-tumor necrosis factor users with or without prior hepatitis B virus infections. AB - BACKGROUND AND OBJECTIVE: Potential hepatoxicity is an important clinical concern when administering immunosuppressive therapies to patients infected by hepatitis B virus (HBV). Tumor necrosis factor inhibitors (anti-TNF) increase the likelihood of hepatitis consequent to HBV reactivation, but reported risks and outcomes vary. We determined the risks of liver enzyme elevation in anti rheumatic drug users from an HBV-endemic region with differing HBV serostatus. METHODS: We established retrospective cohorts with rheumatoid arthritis, ankylosing spondylitis, or psoriasis/psoriatic arthritis who: 1) received anti TNF agents from 1 January 2004 to 30 June 2013; 2) received care from 1 June 2011 to 30 June 2013 but only ever used conventional disease-modifying anti-rheumatic drugs (DMARDs). Serology results defined three subgroups: HBV surface antigen positive (HBsAg+), HBsAg negative/HBV core antibody positive (HBsAg-/HBcAb+), or uninfected. We compared incidences of serum alanine aminotransferase (ALT) exceeding twice the upper reference limit between HBV serostatus subgroups in each treatment cohort. RESULTS: Among 783 patients treated with anti-TNF (n = 472) or DMARDs only (n = 311), HBsAg-/HBcAb+ anti-TNF users had incidence of ALT elevation commensurate with uninfected counterparts (6.1 vs. 6.0/100 person years), compared to 19.6/100 person-years in HBsAg+ patients (standardized rate ratio 3.3, 95% CI 1.3-8.2); none effected had severe or fatal hepatitis and ALT levels in all HBsAg-/HBcAb+ patients remained stable, mostly normalizing spontaneously, or after moderating treatment. Patterns of of ALT elevation associated with differing HBV serostatus in the DMARD cohort, resembled those in anti-TNF users. CONCLUSIONS: In this large HBV-endemic cohort, the absolute incidence of ALT elevation in anti-TNF users was more than three-fold higher in HBsAg+ patients than in uninfected counterparts; however, no such association was evident in patients with HBsAg-/HBcAb+ serotype, whose risk and outcomes of liver enzyme elevation were similar to uninfected patients, suggesting that anti-TNF use by HBsAg-/HBcAb+ patients is probably safe. PMID- 29694399 TI - Fluorescent reporter lines for auxin and cytokinin signalling in barley (Hordeum vulgare). AB - The phytohormones auxin and cytokinin control development and maintenance of plant meristems and stem cell systems. Fluorescent protein reporter lines that monitor phytohormone controlled gene expression programmes have been widely used to study development and differentiation in the model species Arabidopsis, but equivalent tools are still missing for the majority of crop species. Barley (Hordeum vulgare) is the fourth most abundant cereal crop plant, but knowledge on these important phytohormones in regard to the barley root and shoot stem cell niches is still negligible. We have now analysed the role of auxin and cytokinin in barley root meristem development, and present fluorescent protein reporter lines that allow to dissect auxin and cytokinin signalling outputs in vivo. We found that application of either auxin or cytokinin to barley seedlings negatively impacts root meristem growth. We further established a barley cytokinin reporter, TCSnew, which revealed significant cytokinin signalling in the stele cells proximal to the QC, and in the differentiated root cap cells. Application of exogenous cytokinin activated signalling in the root stem cell niche. Commonly employed auxin reporters DR5 or DR5v2 failed to respond to auxin in barley. However, analysis of putative auxin signalling targets barley PLETHORA1 (HvPLT1) is expressed in a similar pattern as its orthologue AtPLT1 from Arabidopsis, i.e. in the QC and the surrounding cells. Furthermore, the PINFORMED1 (HvPIN1) auxin efflux carrier was found to be expressed in root and shoot meristems, where it polarly localized to the plasma membrane. HvPIN1 expression is negatively regulated by cytokinin and its intracellular localisation is sensitive to brefeldinA (BFA). With this study, we provide the first fluorescent reporter lines as a tool to study auxin and cytokinin signalling and response pathways in barley. PMID- 29694401 TI - The ecological services of plant communities in parks for climate control and recreation-A case study in Shanghai, China. AB - Mitigating extreme heat in urban areas is beneficial and sometimes critical to human health. Thriving plant communities in community parks play an important role in mitigating extreme heat through providing cooling effect, while inevitably affecting how people perceive the benefits of using community parks for recreation. Thus, the impacts of plant communities on the thermal environment should be quantified to determine the optimal structure of the plant community. The goal would be to harmonize the functions of improving the thermal environment with the preferences people have related to the recreational benefits of plant communities with various levels of vegetation density. In this paper, the correlations between the structural characteristics of plant communities and their function in mitigating the thermal environment were investigated on calm summer days in Xincheng Central Park, Minhang District, Shanghai, China. In addition to analyzing the plant communities present and their effects on the park microclimate, a questionnaire was employed to determine the plant community preferences of recreational park users. The results showed that plant communities could reduce the air temperature by 1.23-2.42 degrees C and increase the relative humidity by 2.4-4.2% during the daytime. The microclimate conditions in plant communities with varying vegetation densities were significantly different. The canopy density and leaf area index primarily controlled the temperature reduction, while the canopy density and total canopy cover ratio primarily controlled the increase in humidity; meanwhile, these correlations varied at different times of the day. Moreover, most of the park users preferred a moderately dense plant community which met their environmental perceptions for recreation in parks. Age or education level variables of park users would also predict preferences for different plant community densities. Ultimately, one plant community pattern with appropriate canopy density (60%), leaf area index (>=3) and canopy cover ratio (total 0.80-1.20, with 0.6-0.75 for trees and 0.20 0.45 for shrubs/woodland area) was recommended, which would harmonize the functions of the mitigation of the thermal environment with most people's perception of a desirable vegetation density. PMID- 29694400 TI - A diffusion-matched principal component analysis (DM-PCA) based two-channel denoising procedure for high-resolution diffusion-weighted MRI. AB - Over the past several years, significant efforts have been made to improve the spatial resolution of diffusion-weighted imaging (DWI), aiming at better detecting subtle lesions and more reliably resolving white-matter fiber tracts. A major concern with high-resolution DWI is the limited signal-to-noise ratio (SNR), which may significantly offset the advantages of high spatial resolution. Although the SNR of DWI data can be improved by denoising in post-processing, existing denoising procedures may potentially reduce the anatomic resolvability of high-resolution imaging data. Additionally, non-Gaussian noise induced signal bias in low-SNR DWI data may not always be corrected with existing denoising approaches. Here we report an improved denoising procedure, termed diffusion matched principal component analysis (DM-PCA), which comprises 1) identifying a group of (not necessarily neighboring) voxels that demonstrate very similar magnitude signal variation patterns along the diffusion dimension, 2) correcting low-frequency phase variations in complex-valued DWI data, 3) performing PCA along the diffusion dimension for real- and imaginary-components (in two separate channels) of phase-corrected DWI voxels with matched diffusion properties, 4) suppressing the noisy PCA components in real- and imaginary-components, separately, of phase-corrected DWI data, and 5) combining real- and imaginary components of denoised DWI data. Our data show that the new two-channel (i.e., for real- and imaginary-components) DM-PCA denoising procedure performs reliably without noticeably compromising anatomic resolvability. Non-Gaussian noise induced signal bias could also be reduced with the new denoising method. The DM PCA based denoising procedure should prove highly valuable for high-resolution DWI studies in research and clinical uses. PMID- 29694402 TI - Improvement in racial disparities in years of life lost in the USA since 1990. AB - OBJECTIVE: To examine changes in cause-specific Years of Life Lost (YLL) by age, race, and sex group in the USA from 1990 to 2014. METHODS: 60 million death reports from the National Center for Health Statistics (NCHS) were categorized by age group, sex, race, and cause of death. YLL were calculated using age-specific life expectancies. Age groups were: infants <1, children 1-19, adults 20-64, and older adults 65+. RESULTS: Blacks have historically experienced more years of life lost than whites or other racial groups in the USA. In the year 1990 the YLL per 100,000 population was 21,103 for blacks, 14,160 for whites, and 7,417 for others. Between 1990 and 2014 overall YLL in the USA improved by 10%, but with marked variations in the rate of change across age, race, and sex groups. Blacks (all ages, both sexes) showed substantial improvement with a 28% reduction in YLL, compared to whites (all ages, both sexes) who showed a 4% reduction. Among blacks, improvements were seen in all age groups: reductions of 43%, 48%, 28%, and 25% among infants, children, adults, and older adults, respectively. Among whites, reductions of 33%, 44%, and 18% were seen in infants, children, and older adults, but there was a 6% increase in YLL among white adults. YLL increased by 18% in white adult females and declined 1% in white adult males. American Indian/Alaska Native women also had worsening in YLL, with an 8% increase. Asian Pacific Islanders consistently had the lowest YLL across all ages. Whites had a higher proportion of YLL due to overdose; blacks had a higher proportion due to homicide at younger ages and to heart disease at older ages. CONCLUSIONS: Race based disparities in YLL in the USA since 1990 have narrowed considerably, largely as a result of improvements among blacks compared to whites. Adult white and American Indian / Alaskan Native females have experienced worsening YLL, while white males have experienced essentially no change. If recent trajectories continue, adult black/white disparities in YLL will continue to narrow. PMID- 29694403 TI - Bacillus megaterium strains derived from water and soil exhibit differential responses to the herbicide mesotrione. AB - The intense use of herbicides for weed control in agriculture causes selection pressure on soil microbiota and water ecosystems, possibly resulting in changes to microbial processes, such as biogeochemical cycles. These xenobiotics may increase the production of reactive oxygen species and consequently affect the survival of microorganisms, which need to develop strategies to adapt to these conditions and maintain their ecological functionality. This study analyzed the adaptive responses of bacterial isolates belonging to the same species, originating from two different environments (water and soil), and subjected to selection pressure by herbicides. The effects of herbicide Callisto and its active ingredient, mesotrione, induced different adaptation strategies on the cellular, enzymatic, and structural systems of two Bacillus megaterium isolates obtained from these environments. The lipid saturation patterns observed may have affected membrane permeability in response to this herbicide. Moreover, this may have led to different levels of responses involving superoxide dismutase and catalase activities, and enzyme polymorphisms. Due to these response systems, the strain isolated from water exhibited higher growth rates than did the soil strain, in evaluations made in oligotrophic culture media, which would be more like that found in semi-pristine aquatic environments. The influence of the intracellular oxidizing environments, which changed the mode of degradation of mesotrione in our experimental model and produced different metabolites, can also be observed in soil and water at sites related to agriculture. Since the different metabolites may present different levels of toxicity, we suggest that this fact should be considered in studies on the fate of agrochemicals in different environments. PMID- 29694404 TI - Characteristics of the gait adaptation process due to split-belt treadmill walking under a wide range of right-left speed ratios in humans. AB - The adaptability of human bipedal locomotion has been studied using split-belt treadmill walking. Most of previous studies utilized experimental protocol under remarkably different split ratios (e.g. 1:2, 1:3, or 1:4). While, there is limited research with regard to adaptive process under the small speed ratios. It is important to know the nature of adaptive process under ratio smaller than 1:2, because systematic evaluation of the gait adaptation under small to moderate split ratios would enable us to examine relative contribution of two forms of adaptation (reactive feedback and predictive feedforward control) on gait adaptation. We therefore examined a gait behavior due to on split-belt treadmill adaptation under five belt speed difference conditions (from 1:1.2 to 1:2). Gait parameters related to reactive control (stance time) showed quick adjustments immediately after imposing the split-belt walking in all five speed ratios. Meanwhile, parameters related to predictive control (step length and anterior force) showed a clear pattern of adaptation and subsequent aftereffects except for the 1:1.2 adaptation. Additionally, the 1:1.2 ratio was distinguished from other ratios by cluster analysis based on the relationship between the size of adaptation and the aftereffect. Our findings indicate that the reactive feedback control was involved in all the speed ratios tested and that the extent of reaction was proportionally dependent on the speed ratio of the split-belt. On the contrary, predictive feedforward control was necessary when the ratio of the split-belt was greater. These results enable us to consider how a given split belt training condition would affect the relative contribution of the two strategies on gait adaptation, which must be considered when developing rehabilitation interventions for stroke patients. PMID- 29694405 TI - Initial prejudices create cross-generational intergroup mistrust. AB - The present investigation modeled the emergence and persistence of intergroup bias and discrimination in artificial societies. Initial unfair prejudices held by members of a dominant group elicit confirmatory behavior (diminished cooperation) from members of a subordinate group via a self-fulfilling prophecy. Further, when individual learning is tempered by conformity to peers, inaccurate beliefs about the stigmatized subordinate group persist long-term. Even completely replacing dominant group members with enlightened individuals through generational change is inadequate to break the cycle of intergroup distrust and non-collaboration. The longer the enlightenment of a society is delayed, the more intergroup trust is irretrievably lost. PMID- 29694406 TI - Impact of point-of-care ultrasound on clinical decision-making at an urban emergency department in Tanzania. AB - BACKGROUND: Point of care ultrasound (PoCUS) is an efficient, inexpensive, safe, and portable imaging modality that can be particularly useful in resource-limited settings. However, its impact on clinical decision making in such settings has not been well studied. The objective of this study is to describe the utilization and impact of PoCUS on clinical decision making at an urban emergency department in Dar es Salaam, Tanzania. METHODS: This was a prospective descriptive cross sectional study of patients receiving PoCUS at Muhimbili National Hospital's Emergency Medical Department (MNH EMD). Data on PoCUS studies during a period of 10 months at MNH EMD was collected on consecutive patients during periods when research assistants were available. Data collected included patient age and sex, indications for ultrasound, findings, interpretations, and provider-reported diagnostic impression and disposition plan before and after PoCUS. Descriptive statistics, including medians and interquartile ranges, and counts and percentages, are reported. Pearson chi squared tests and p-values were used to evaluate categorical data for significant differences. RESULTS: PoCUS data was collected for 986 studies performed on 784 patients. Median patient age was 32 years; 56% of patients were male. Top indications for PoCUS included trauma, respiratory presentations, and abdomino-pelvic pain. The most frequent study types performed were eFAST, cardiac, and obstetric or gynaecologic studies. Overall, clinicians reported that the use of PoCUS changed either diagnostic impression or disposition plan in 29% of all cases. Rates of change in diagnostic impression or disposition plan increased to 45% in patients for whom more than one PoCUS study type was performed. CONCLUSIONS: In resource-limited emergency care settings, PoCUS can be utilized for a wide range of indications and has substantial impact on clinical decision making, especially when more than one study type is performed. PMID- 29694407 TI - Oligomeric interfaces as a tool in drug discovery: Specific interference with activity of malate dehydrogenase of Plasmodium falciparum in vitro. AB - Malaria remains a major threat to human health, as strains resistant to current therapeutics are discovered. Efforts in finding new drug targets are hampered by the lack of sufficiently specific tools to provide target validation prior to initiating expensive drug discovery projects. Thus, new approaches that can rapidly enable drug target validation are of significant interest. In this manuscript we present the crystal structure of malate dehydrogenase from Plasmodium falciparum (PfMDH) at 2.4 A resolution and structure-based mutagenic experiments interfering with the inter-oligomeric interactions of the enzyme. We report decreased thermal stability, significantly decreased specific activity and kinetic parameters of PfMDH mutants upon mutagenic disruption of either oligomeric interface. In contrast, stabilization of one of the interfaces resulted in increased thermal stability, increased substrate/cofactor affinity and hyperactivity of the enzyme towards malate production at sub-millimolar substrate concentrations. Furthermore, the presented data show that our designed PfMDH mutant could be used as specific inhibitor of the wild type PfMDH activity, as mutated PfMDH copies were shown to be able to self-incorporate into the native assembly upon introduction in vitro, yielding deactivated mutant:wild-type species. These data provide an insight into the role of oligomeric assembly in regulation of PfMDH activity and reveal that recombinant mutants could be used as probe tool for specific modification of the wild type PfMDH activity, thus offering the potential to validate its druggability in vivo without recourse to complex genetics or initial tool compounds. Such tool compounds often lack specificity between host or pathogen proteins (or are toxic in in vivo trials) and result in difficulties in assessing cause and effect-particularly in cases when the enzymes of interest possess close homologs within the human host. Furthermore, our oligomeric interference approach could be used in the future in order to assess druggability of other challenging human pathogen drug targets. PMID- 29694408 TI - Vitexin attenuates lipopolysaccharide-induced acute lung injury by controlling the Nrf2 pathway. AB - BACKGROUND: A major feature of acute lung injury (ALI) is excessive inflammation in the lung. Vitexin is an active component from medicinal plants which has antioxidant and anti-inflammatory activities. Oxidative stress and inflammation play important roles in the pathophysiological processes in ALI. In the current study, we investigate the effect and potential mechanisms of Vitexin on lipopolysaccharide (LPS)-induced ALI. METHODS: ALI was induced by LPS intratracheal instillation in C57BL/6 wild-type mice and Nrf2 gene knocked down (Nrf2-/-) mice. One hour before LPS challenge, Vitexin or vehicle intraperitoneal injection was performed. Bronchoalveolar lavage fluid and lung tissues were examined for lung inflammation and injury at 24 h after LPS challenge. RESULTS: Our animal study's results showed that LPS-induced recruitment of neutrophils and elevation of proinflammatory cytokine levels were attenuated by Vitexin treatment. Vitexin decreased lung edema and alveolar protein content. Moreover, Vitexin activated nuclear factor erythroid-2-related factor 2 (Nrf2), and increased the activity of its target gene heme oxygenase (HO)-1. The LPS-induced reactive oxygen species were inhibited by Vitexin. In addition, the activation of the nucleotide-binding domain and leucine-rich repeat PYD-containing protein 3 (NLRP3) inflammasome was suppressed by Vitexin. However, these effects of Vitexin were abolished in the Nrf2-/- mice. Our cell studies showed that Vitexin enhanced the expression of Nrf2 and HO-1 activity. Moreover, reactive oxygen species (ROS) and IL-1beta productions were reduced in Vitexin-treated cells. However, knockdown of Nrf2 by siRNA in RAW cells reversed the benefit of Vitexin. CONCLUSIONS: Vitexin suppresses LPS-induced ALI by controlling Nrf2 pathway. PMID- 29694409 TI - Punk's not dead. Fungi for tinder at the Neolithic site of La Draga (NE Iberia). AB - This paper presents the study of the fungi remains preserved in the waterlogged deposits of the Neolithic site of La Draga. These resources had the potential of being used as food and medicine, but also as tinder. Fire was without a doubt one of the most important resources for past people. It was used for lighting, heating, processing food and other materials, cooking and protection, and also possessed social and ritual significance. Hearths are one of the most common features at archaeological sites, but very often little attention is paid to the question of how these fires were lit, and they are seldom reflected in the archaeological record. In order to produce fire by percussion, an intermediate material is required between the sparks and the fuel. Fruiting bodies of fungi are a potential form of tinder, but are less inclined to be well-preserved than other materials. This paper presents the fungal fruiting bodies found at the Neolithic site of La Draga and discusses the meaning of their presence within the archaeological context of the site and European Prehistory. PMID- 29694410 TI - Winter and spring climatic conditions influence timing and synchrony of calving in reindeer. AB - In a context of climate change, a mismatch has been shown to occur between some species' reproductive phenology and their environment. So far, few studies have either documented temporal trends in calving phenology or assessed which climatic variables influence the calving phenology in ungulate species, yet the phenology of ungulates' births affects offspring survival and population's recruitment rate. Using a long-term dataset (45 years) of birth dates of a semi-domesticated reindeer population in Kaamanen, North Finland, we show that calving season has advanced by ~ 7 days between 1970 and 2016. Advanced birth dates were associated with lower precipitation and a reduced snow cover in April and warmer temperatures in April-May. Improved females' physical condition in late gestation due to warmer temperatures in April-May and reduced snow conditions in April probably accounted for such advance in calving date. On the other hand, a lengthening of the calving season was reported following a warmer temperature in January, a higher number of days when mean temperature exceeds 0 degrees C in October-November and a decreasing snow cover from October to November. By affecting the inter-individual heterogeneity in the plastic response of females' calving date to better climatic conditions in fall and winter, climatic variability contributed to weaken the calving synchrony in this herd. Whether variability in climatic conditions form environmental cues for the adaptation of calving phenology by females to climate change is however uncertain, but it is likely. As such this study enhances our understanding on how reproductive phenology of ungulate species would be affected by climate change. PMID- 29694411 TI - Unusual morphological adaptations and processes associated with viviparity in an epizoic dermapteran. AB - Matrotrophic viviparity is a reproductive pattern in which offspring develop inside a female's body which provides gas exchange and nutrients necessary for development. Besides placental mammals, structural and physiological aspects of matrotrophic viviparity are poorly characterized. In insects, the majority of species is oviparous, i.e. lay eggs, and viviparous reproduction has been reported only in 11 out of 44 orders, including earwigs (Dermaptera). Among dermapterans, matrotrophic viviparity has been reported in two epizoic subgroups: Arixeniidae and Hemimeridae. Here, we provide morphological evidence for distinct adaptations for this mode of viviparity in embryonic and maternal tissues in a representative of the latter subgroup, Hemimerus talpoides. Our study reveals a novel mechanism of maternal contribution to embryonic development which operates during oogenesis and involves characteristic modification of endoplasmic reticulum cisternae. Conspicuous and apparently inactive para-crystalline stacks of the endoplasmic reticulum are deposited in the oocyte cytoplasm and become activated during early embryonic development. Our analyses indicate additionally that in Hemimerus, transformed follicular/ovarian cells (on the mother's side) and an evagination of the dorsal vessel (on the embryo's side) converge to form a cephalic vesicle, structure analogous to a placenta. The cellular architecture of this unusual "cephalic placenta" points to its participation in an exchange of low molecular weight substances between a mother and developing embryo. PMID- 29694412 TI - The influence of alendronate and tooth extraction on the incidence of osteonecrosis of the jaw among osteoporotic subjects. AB - BACKGROUND: Although bisphosphonate-related osteonecrosis of the jaw (ONJ) develops mainly after tooth extractions (TEs), the strength of the association between them and how the existence of the disease among bisphosphonate (BP) treated osteoporotic patients exposed to TE remain uncertain. METHODS: A nationwide retrospective cohort study investigated the influence of alendronate and TE on the development of ONJ. RESULTS: Incidence of ONJ following long-term alendronate therapy was 262/100,000 person-years, while no event developed in the control group on raloxifene. Overall prevalence of ONJ in osteoporotic subjects receiving alendronate was estimated at 0.34% which rose to 2.16% after TE. Multiple logistic regression analysis, adjusted for the potential confounders, showed TE (adjusted odds ratio, 9.60 [4.33-21.29]), drug duration exceeding 3 years (3.00 [1.33-6.76]), and concomitant rheumatoid arthritis (4.94 [1.64 14.90]) were independent predictors of ONJ. CONCLUSIONS: This article strengthens the relationship between ONJ and BPs. Among osteoporotic patients exposed to alendronate, TE confers a 9.6-fold increased risk for ONJ and it should be performed with caution irrespective of drug duration. PMID- 29694413 TI - Proline oxidase controls proline, glutamate, and glutamine cellular concentrations in a U87 glioblastoma cell line. AB - L-Proline is a multifunctional amino acid that plays an essential role in primary metabolism and physiological functions. Proline is oxidized to glutamate in the mitochondria and the FAD-containing enzyme proline oxidase (PO) catalyzes the first step in L-proline degradation pathway. Alterations in proline metabolism have been described in various human diseases, such as hyperprolinemia type I, velo-cardio-facial syndrome/Di George syndrome, schizophrenia and cancer. In particular, the mutation giving rise to the substitution Leu441Pro was identified in patients suffering of schizophrenia and hyperprolinemia type I. Here, we report on the expression of wild-type and L441P variants of human PO in a U87 glioblastoma human cell line in an attempt to assess their effect on glutamate metabolism. The subcellular localization of the flavoenzyme is not altered in the L441P variant, for which specific activity is halved compared to the wild-type PO. While this decrease in activity is significantly less than that previously proposed, an effect of the substitution on the enzyme stability is also apparent in our studies. At 24 hours of growth from transient transfection, the intracellular level of proline, glutamate, and glutamine is decreased in cells expressing the PO variants as compared to control U87 cells, reaching a similar figure at 72 h. On the other hand, the extracellular levels of the three selected amino acids show a similar time course for all clones. Furthermore, PO overexpression does not modify to a significant extent the expression of GLAST and GLT-1 glutamate transporters. Altogether, these results demonstrate that the proline pathway links cellular proline levels with those of glutamate and glutamine. On this side, PO might play a regulatory role in glutamatergic neurotransmission by affecting the cellular concentration of glutamate. PMID- 29694414 TI - First detection of Wolbachia in the New Zealand biota. AB - Wolbachia is one of the most widespread intracellular bacteria on earth, estimated to infect between 40 and 66% of arthropod species in most ecosystems that have been surveyed. Their significance rests not only in their vast distribution, but also in their ability to modify the reproductive biology of their hosts, which can ultimately affect genetic diversity and speciation of infected populations. Wolbachia has yet to be formally identified in the fauna of New Zealand which has high levels of endemic biodiversity and this represents a gap in our understanding of the global biology of Wolbachia. Using High Throughput Sequencing (HTS) of host DNA in conjunction with traditional molecular techniques we identified six endemic Orthoptera species that were positive for Wolbachia infection. In addition, short-sequence amplification with Wolbachia specific primers applied to New Zealand and introduced invertebrates detected a further 153 individuals positive for Wolbachia. From these short-range DNA amplification products sequence data was obtained for the ftsZ gene region from 86 individuals representing 10 host species. Phylogenetic analysis using the sequences obtained in this study reveals that there are two distinct Wolbachia bacteria lineages in New Zealand hosts belonging to recognised Wolbachia supergroups (A and B). These represent the first described instances of Wolbachia in the New Zealand native fauna, including detection in putative parasitoids of infected Orthoptera suggesting a possible transmission path. Our detection of Wolbachia infections of New Zealand species provides the opportunity to study local transmission of Wolbachia and explore their role in the evolution of New Zealand invertebrates. PMID- 29694415 TI - Fragmentation, integration and macroprudential surveillance of the US financial industry: Insights from network science. AB - Drawing on recent contributions inferring financial interconnectedness from market data, our paper provides new insights on the evolution of the US financial industry over a long period of time by using several tools coming from network science. Relying on a Time-Varying Parameter Vector AutoRegressive (TVP-VAR) approach on stock market returns to retrieve unobserved directed links among financial institutions, we reconstruct a fully dynamic network in the sense that connections are let to evolve through time. The financial system analysed consists of a large set of 155 financial institutions that are all the banks, broker-dealers, insurance and real estate companies listed in the Standard & Poors' 500 index over the 1993-2014 period. Looking alternatively at the individual, then sector-, community- and system-wide levels, we show that network sciences' tools are able to support well-known features of the financial markets such as the dramatic fall of connectivity following Lehman Brothers' collapse. More importantly, by means of less traditional metrics, such as sectoral interface or measurements based on contagion processes, our results document the co-existence of both fragmentation and integration phases between firms independently from the sectors they belong to, and doing so, question the relevance of existing macroprudential surveillance frameworks which have been mostly developed on a sectoral basis. Overall, our results improve our understanding of the US financial landscape and may have important implications for risk monitoring as well as macroprudential policy design. PMID- 29694416 TI - The chloroplast genome sequence of bittersweet (Solanum dulcamara): Plastid genome structure evolution in Solanaceae. AB - Bittersweet (Solanum dulcamara) is a native Old World member of the nightshade family. This European diploid species can be found from marshlands to high mountainous regions and it is a common weed that serves as an alternative host and source of resistance genes against plant pathogens such as late blight (Phytophthora infestans). We sequenced the complete chloroplast genome of bittersweet, which is 155,580 bp in length and it is characterized by a typical quadripartite structure composed of a large (85,901 bp) and small (18,449 bp) single-copy region interspersed by two identical inverted repeats (25,615 bp). It consists of 112 unique genes from which 81 are protein-coding, 27 tRNA and four rRNA genes. All bittersweet plastid genes including non-functional ones and even intergenic spacer regions are transcribed in primary plastid transcripts covering 95.22% of the genome. These are later substantially edited in a post transcriptional phase to activate gene functions. By comparing the bittersweet plastid genome with all available Solanaceae sequences we found that gene content and synteny are highly conserved across the family. During genome comparison we have identified several annotation errors, which we have corrected in a manual curation process then we have identified the major plastid genome structural changes in Solanaceae. Interpreted in a phylogenetic context they seem to provide additional support for larger clades. The plastid genome sequence of bittersweet could help to benchmark Solanaceae plastid genome annotations and could be used as a reference for further studies. Such reliable annotations are important for gene diversity calculations, synteny map constructions and assigning partitions for phylogenetic analysis with de novo sequenced plastomes of Solanaceae. PMID- 29694418 TI - Correction: Sequence variation in Plasmodium falciparum merozoite surface protein 2 is associated with virulence causing severe and cerebral malaria. AB - [This corrects the article DOI: 10.1371/journal.pone.0190418.]. PMID- 29694417 TI - Executive function impairments in fibromyalgia syndrome: Relevance of clinical variables and body mass index. AB - BACKGROUND: Several investigations suggest the presence of deterioration of executive function in fibromyalgia syndrome (FMS). The study quantified executive functions in patients with FMS. A wide array of functions was assessed, including updating, shifting and inhibition, as well as decision making and mental planning. Moreover, clinical variables were investigated as possible mediators of executive dysfunction, including pain severity, psychiatric comorbidity, medication and body mass index (BMI). METHODS: Fifty-two FMS patients and 32 healthy controls completed a battery of 14 neuropsychological tests. Clinical interviews were conducted and the McGill Pain Questionnaire, Beck Depression Inventory, State-Trait Anxiety Inventory, Fatigue Severity Scale and Oviedo Quality of Sleep Questionnaire were presented. RESULTS: Patients performed poorer than controls on the Letter Number Sequencing, Arithmetic and Similarities subtests of the Wechsler Adult Intelligence Scale, the Spatial Span subtest of the Wechsler Memory Scale, an N-back task, a verbal fluency task, the Ruff Figural Fluency Test, the Inhibition score of the Stroop Test, the Inhibition and Shifting scores of the Five Digits Test, the Key Search Test and the Zoo Map Task. Moreover, patients exhibited less steep learning curves on the Iowa Gambling Task. Among clinical variables, BMI and pain severity explained the largest proportion of performance variance. CONCLUSIONS: This study demonstrated impairments in executive functions of updating, shifting inhibition, decision making and planning in FMS. While the mediating role of pain in cognitive impairments in FMS had been previously established, the influence of BMI is a novel finding. Overweight and obesity should be considered by FMS researchers, and in the treatment of the condition. PMID- 29694419 TI - T cell mediated immunity after combination therapy with intralesional PV-10 and blockade of the PD-1/PD-L1 pathway in a murine melanoma model. AB - Intralesional (IL) injection of Rose Bengal (PV-10) induces regression of injected and uninjected lesions in several murine tumor models. In this study, we investigated the anti-tumor response of combining IL PV-10 with blockade of the PD-1 / PD-L1 pathway and the role of immune cell populations in eliciting this response. To investigate the role of T cell subsets in mediating an immune response, B16 or M05 melanoma-bearing mice received combination therapy as well as CD8+, CD4+, or CD25+ depleting antibodies. Tumor growth was measured. T cells were collected from spleens or tumors, and phenotype, activation markers, and reactivity were measured. Splenocytes from mice treated with combination therapy had increased OVA antigen-specific CD8+ T cells in M05-tumor-bearing mice. Depletion of CD4+ T cells or regulatory T cells (Tregs) in combination with IL PV 10 and anti-PD-1 antibody treatment resulted in an enhanced anti-tumor effect. Treatment with CD8+ depleting antibody abrogated anti-tumor immunity. These results support a clinical study for the safety and anti-tumor immune responses with combination therapy of IL PV-10 and PD-1/PD-L1 blockade. PMID- 29694420 TI - Early post-transplant serum IgA level is associated with IgA nephropathy recurrence after kidney transplantation. AB - IgA nephropathy (IgAN), the most frequent primary glomerulonephritis, affects young patients and is associated with a high risk of progression to end-stage renal disease. Consequently, patients with IgAN constitute an important proportion of candidates for kidney transplantation. Several studies showed a significant risk of IgAN recurrence on kidney graft, but the risks factors for recurrence remain to be accurately evaluated. Indeed, early identification of at risk patients may allow the optimization of treatment and the reduction of recurrence rate on the graft. In the present work, we studied the relationship between post-transplant serum IgA (sIgA) levels and the risk of IgAN recurrence after kidney transplantation. Recipients with IgAN had higher levels of sIgA as compared to patients with other nephropathies (p<0.05). The prevalence of IgAN recurrence was 20.8% during the period of analysis (mean follow-up of 6 +/- 3.2 years). Serum IgA levels at M6, M12 and M24 post-transplant were significantly higher in patients with IgAN recurrence as compared to those without (p = 0.009, p = 0.035 and p = 0.029, respectively). Using receiver operating curve (ROC), sIgA at M6 and M12 post-transplant were significantly associated with IgAN recurrence (AUC = 0.771, p = 0.004 and AUC = 0.767, p = 0.016, respectively), while serum creatinine and proteinuria were not. Serum IgA level at month 6 was significantly associated with the occurrence of post-transplant IgA recurrence, whether it was analyzed as a continuous or a categorical variable. After successive adjustment on age, gender and proteinuria, sIgA remained a significant risk factor of post-transplant IgAN recurrence. Finally, survival free of IgAN recurrence was significantly better in patients with sIgA<222 mg/dL at month 6 as compare to IgAN patients with sIgA>=222 mg/dL (p = 0.03). Thus, the present work supports a link between post-transplant sIgA levels and IgAN recurrence and suggests that sIgA may be a valuable predictive biomarker of IgAN recurrence in kidney transplant recipients. PMID- 29694422 TI - Correction: Five-year study of the effects of simulated nitrogen deposition levels and forms on soil nitrous oxide emissions from a temperate forest in northern China. AB - [This corrects the article DOI: 10.1371/journal.pone.0189831.]. PMID- 29694421 TI - The chloroplast genome of Cerasus humilis: Genomic characterization and phylogenetic analysis. AB - Cerasus humilis is endemic to China and is a new fruit tree species with economic and environmental benefits, with potential developmental and utilization applications. We report the first complete chloroplast genome sequence of C. humilis. Its genome is 158,084 bp in size, and the overall GC content is 36.8%. An inverted repeats (IR) of 52,672 bp in size is separated by a large single-copy (LSC) region of 86,374 bp and a small single-copy (SSC) region of 19,038 bp. The chloroplast genome of C. humilis contains 131 genes including 90 protein-coding genes, 33 transfer RNA genes, and 8 ribosomal RNA genes. The genome has a total 510 simple sequence repeats (SSRs). Of these, 306, 149, and 55 were found in the LSC, IR, and SSC regions, respectively. In addition, a comparison of the boundaries of the LSC, SSC, and IR regions of ten other Prunus species exhibited an overall high degree of sequence similarity, with slight variations in the IR boundary region which included gene deletions, insertions, expansions, and contractions. C. humilis lost the ycf1 gene at the IRA/SSC border and it has the largest ycf1 gene at the IRB/SSC border among these Prunus species, whereas the rps19 gene was inserted at the IRB/LSC junction. Furthermore, phylogenetic reconstruction using 61 conserved coding-protein genes clustered C. humilis with Prunus tomentosa. Thus, the complete chloroplast genome sequence of C. humilis provides a rich source of genetic information for studies on Prunus taxonomy, phylogeny, and evolution, as well as lays the foundation for further development and utilization of C. humilis. PMID- 29694423 TI - Computer-assisted teaching of bilateral sagittal split osteotomy: Learning curve for condylar positioning. AB - Bilateral sagittal split osteotomy (BSSO) is a widely-performed procedure in orthognathic surgery for the correction of dentofacial deformity. Condylar positioning is a critical step during BSSO to maximize functional and morphological results. The unsuitable positioning of condyles represents one of the causative mechanisms that may induce temporomandibular joint noxious effects after BSSO. Repositioning devices can assist surgeons in maintaining the preoperative condylar position; however, empirical repositioning methods based on experience gained are still commonly used. Trainee learning curves are difficult to assess. The aim of this study was to evaluate the relevance of computer assisted surgery in the acquisition of condylar positioning skills. Forty-eight patients underwent BSSO performed by six maxillofacial trainees (four junior residents and two senior experienced residents). A condyle positioning system (CPS) was used by a senior surgeon to record a condylar position score during the procedure. Firstly, scores were recorded when the trainee manually positioned the condyle without access to the CPS score (phase 1) and then when the trainee positioned the condyle and performed osteosynthesis with visual access to the CPS score (phase 2). Six parameters describing condylar three-dimensional motions were assessed: translational motion from top to bottom (TB), back to front (BF), and left to right (LR), axial rotation (AR), sagittal rotation (SR), frontal rotation (FR), and a total score (TS). There were no significant differences between junior and senior residents in condyle positioning without access to the CPS. Condyles were significantly better positioned during phase 2 with access to the CPS (p<0.001). Over time, use of the CPS (phase 2) produced significantly quicker improvements in scores (p = 0.042). For those teaching surgeries to trainees, computer-assisted devices can potentially result in more rapid learning curves than traditional "observations-imitation" models. Use of a CPS by trainees facilitated condylar repositioning that resulted in an accurate occlusal result and avoidance of adverse effects on the temporomandibular joint. PMID- 29694424 TI - Weather impacts expressed sentiment. AB - We conduct the largest ever investigation into the relationship between meteorological conditions and the sentiment of human expressions. To do this, we employ over three and a half billion social media posts from tens of millions of individuals from both Facebook and Twitter between 2009 and 2016. We find that cold temperatures, hot temperatures, precipitation, narrower daily temperature ranges, humidity, and cloud cover are all associated with worsened expressions of sentiment, even when excluding weather-related posts. We compare the magnitude of our estimates with the effect sizes associated with notable historical events occurring within our data. PMID- 29694425 TI - From theory to experimental design-Quantifying a trait-based theory of predator prey dynamics. AB - Successfully applying theoretical models to natural communities and predicting ecosystem behavior under changing conditions is the backbone of predictive ecology. However, the experiments required to test these models are dictated by practical constraints, and models are often opportunistically validated against data for which they were never intended. Alternatively, we can inform and improve experimental design by an in-depth pre-experimental analysis of the model, generating experiments better targeted at testing the validity of a theory. Here, we describe this process for a specific experiment. Starting from food web ecological theory, we formulate a model and design an experiment to optimally test the validity of the theory, supplementing traditional design considerations with model analysis. The experiment itself will be run and described in a separate paper. The theory we test is that trophic population dynamics are dictated by species traits, and we study this in a community of terrestrial arthropods. We depart from the Allometric Trophic Network (ATN) model and hypothesize that including habitat use, in addition to body mass, is necessary to better model trophic interactions. We therefore formulate new terms which account for micro-habitat use as well as intra- and interspecific interference in the ATN model. We design an experiment and an effective sampling regime to test this model and the underlying assumptions about the traits dominating trophic interactions. We arrive at a detailed sampling protocol to maximize information content in the empirical data obtained from the experiment and, relying on theoretical analysis of the proposed model, explore potential shortcomings of our design. Consequently, since this is a "pre-experimental" exercise aimed at improving the links between hypothesis formulation, model construction, experimental design and data collection, we hasten to publish our findings before analyzing data from the actual experiment, thus setting the stage for strong inference. PMID- 29694427 TI - Prevalence and risk factors for pelvic organ prolapse in Kilimanjaro, Tanzania: A population based study in Tanzanian rural community. AB - INTRODUCTION: The prevalence and risk-factors of pelvic organ prolapse (POP) in Tanzania are unknown. To help elucidate the problem, we assessed POP and associated risk-factors among Tanzanian women by deploying the POP-Q classification system. METHOD: A cross sectional community based study conducted in Hai, Rombo and Same Districts, Kilimanjaro Region, Tanzania. Women aged 18-90 were recruited through multi-stage random sampling from January to May 2015. Home based questionnaire interviews were performed and the women were subsequently invited to the nearest health clinic for pelvic examination. Trained physicians used the POP-Q classification system to assess the POP stage. RESULTS: A total of 1195 women were interviewed and invited for pelvic examination; 1063(89%) women presented at the clinic of whom 1047(88%) accepted a clinical examination. Of 1047 examined women, 64.6% had an anatomical POP stage II-IV and 6.7% had a severe POP that descended 1 cm or more below the hymen. POP stage II-IV was associated with being aged 35+ years, being a farmer, doing petty trading and having delivered 3 times or more. Severe POP was associated with carrying heavy objects for >= 5 hours (OR 4.70;1.67-13.2), having delivered 5 times or more (OR 10.2;2.22-48.6) and having delivered at home (OR 2.40;1.36-4.22). CONCLUSION: POP is a common condition among rural Tanzanian women where 64.6% are having POP grade II-IV and 6.7% are having a severe POP descending 1 cm or more below the hymen. Risk-factors are increasing age, heavy lifting, high parity and home delivery. PMID- 29694426 TI - Effects of tumor necrosis factor inhibitors and tocilizumab on the glycosylated hemoglobin levels in patients with rheumatoid arthritis; an observational study. AB - Rheumatoid arthritis (RA) and diabetes mellitus (DM) are associated with inflammation. We tried to investigate the influence of tumor necrosis factor inhibitors (TNFi) and tocilizumab (TCZ) on the glucose metabolism of RA patients. RA patients in whom treatment with TNFi or TCZ was initiated from 2008 to 2015 were studied based on their medical records. We analyzed patients whose glycosylated hemoglobin (HbA1c) levels were measured both before and 3 months after the initiation of these biologic agents. The association between HbA1c reduction and the treatment was evaluated. From 971 cases treated with these biologic agents, 221 cases whose medical records of HbA1c were available, were included (TNFi, n = 154; TCZ, n = 67). Both the TNFi and TCZ groups had significantly lower HbA1c values at 1 month and 3 months after the initiation of treatment (TNFi, p<0.001; TCZ, p<0.001). Although the pretreatment HbA1c values did not differ (TNFi, 6.2%; TCZ, 6.2%; p = 0.532), the 3-month treatment HbA1c values were lower (TNFi, 6.1%; TCZ, 5.8%; p = 0.010) and the changes in HbA1c (DeltaHbA1c) were greater (TNFi, 0.1%; TCZ, 0.4%; p<0.001) in the TCZ group. The reduction of HbA1c-defined by the achievement of a DeltaHbA1c of >=0.5%-was associated with baseline diagnosis of diabetes mellitus, baseline diabetes treatment, hospitalization, medical change during the observation period, and TCZ. In the multivariate logistic regression analysis, TCZ was associated with the reduction of HbA1c in comparison to TNFi (adjusted OR = 5.59, 95% CI = 2.56 12.2; p<0.001). The HbA1c levels in RA patients were significantly lower after the initiation of TNFi or TCZ. Our study suggests that TCZ decreases the HbA1c levels in RA patients to a greater extent than TNFi. PMID- 29694428 TI - Differences in vaping topography in relation to adherence to exclusive electronic cigarette use in veterans. AB - BACKGROUND: Understanding vaping patterns of electronic cigarette (EC) use is important to understand the real-life exposure to EC vapor. Long term information on vaping topography in relation to tobacco cigarette (TC) smoking cessation success has not been explored. METHODS: Observational non-blinded study where active TC smokers were asked to replace TC with EC over 4 weeks (replacement phase, RP) followed by exclusive EC use for an additional 12 weeks (maintenance phase, MP). TC use and EC compliance was monitored weekly. Subjects were classified as success or failure whether or not they completed the protocol. Vaping information was stored and downloaded directly from the EC device and averaged per calendar day for analysis. RESULTS: From 25 subjects that followed the protocol, sixteen succeeded in completing the RP and 8 the MP (32%). No significant differences in baseline characteristics were noted between subjects in the success and failure groups including markers of nicotine addiction, plasma cotinine levels or smoking history. Success subjects showed significantly longer puff duration (seconds per vape) and total overall vapor exposure (number of vapes x average vape duration or vape-seconds) in both study phases. Furthermore, subjects in the success group continued to increase the number of vapes, device voltage and wattage significantly as they transitioned into the MP. After an initial drop, subjects in the success group were able to regain plasma cotinine levels comparable to their TC use while subjects in the failure group could not. Cotinine levels significantly correlated with the average number of daily vapes and vapes-seconds, but not with other vaping parameters. CONCLUSION: The topography of smokers who adhere to exclusive EC use reflects a progressive and dynamic device adaptation over weeks to maintain baseline cotinine levels. The higher inhaled volume over time should be considered when addressing the potential toxic effects of EC and the variable EC adherence when addressing public health policies regarding their use. PMID- 29694429 TI - An effective content-based image retrieval technique for image visuals representation based on the bag-of-visual-words model. AB - For the last three decades, content-based image retrieval (CBIR) has been an active research area, representing a viable solution for retrieving similar images from an image repository. In this article, we propose a novel CBIR technique based on the visual words fusion of speeded-up robust features (SURF) and fast retina keypoint (FREAK) feature descriptors. SURF is a sparse descriptor whereas FREAK is a dense descriptor. Moreover, SURF is a scale and rotation invariant descriptor that performs better in the case of repeatability, distinctiveness, and robustness. It is robust to noise, detection errors, geometric, and photometric deformations. It also performs better at low illumination within an image as compared to the FREAK descriptor. In contrast, FREAK is a retina-inspired speedy descriptor that performs better for classification-based problems as compared to the SURF descriptor. Experimental results show that the proposed technique based on the visual words fusion of SURF FREAK descriptors combines the features of both descriptors and resolves the aforementioned issues. The qualitative and quantitative analysis performed on three image collections, namely Corel-1000, Corel-1500, and Caltech-256, shows that proposed technique based on visual words fusion significantly improved the performance of the CBIR as compared to the feature fusion of both descriptors and state-of-the-art image retrieval techniques. PMID- 29694430 TI - Genome comparison of different Zymomonas mobilis strains provides insights on conservation of the evolution. AB - Zymomonas mobilis has the special Entner-Doudoroff (ED) pathway and it has excellent industrial characteristics, including low cell mass formation, high specific productivity,ethanol yield, notable ethanol tolerance and wide pH range, a relatively small genome size. In this study, the genome sequences of NRRL B 14023 and NRRL B-12526 were sequenced and compared with other strains to explore their evolutionary relationships and the genetic basis of Z. mobilis. The comparative genomic analyses revealed that the 8 strains share a conserved core chromosomal backbone. ZM4, NRRL B-12526, NRRL B-14023, NCIMB 11163 and NRRL B 1960 share 98% sequence identity across the whole genome sequences. Highly similar plasmids and CRISPR repeats were detected in these strains. A whole genome phylogenetic tree of the 8 strains indicated that NRRL B-12526, NRRL B 14023 and ATCC 10988 had a close evolutionary relationship with the strain ZM4. Furthermore, strains ATCC29191 and ATCC29192 had distinctive CRISPR with a far distant relationship. The size of the pan-genome was 1945 genes, including 1428 core genes and 517 accessory genes. The genomes of Z. mobilis were highly conserved; particularly strains ZM4, NRRL B-12526, NRRL B-14023, NCIMB 11163 and NRRL B-1960 had a close genomic relationship. This comparative study of Z. mobilis presents a foundation for future functional analyses and applications. PMID- 29694431 TI - The timing of growth faltering has important implications for observational analyses of the underlying determinants of nutrition outcomes. AB - BACKGROUND: Growth faltering largely occurs in the first 23 months after birth and is thought to be largely determined by various harmful or protective socioeconomic conditions. Children 23 months or younger, however, have only been partially exposed to these conditions, implying that statistical associations between these conditions and child growth may be substantially smaller in samples that include younger children. OBJECTIVES: To test the prediction that associations between child anthropometric outcomes and various socioeconomic conditions are systematically different for older and younger children. METHODS: We analyzed data for 699,421 children aged 0-59 months, drawn from 125 DHS implemented between 1992 and 2014 in 57 countries. The outcome variables were height-for-age Z scores (HAZ) and stunting (HAZ<-2), and weight-for-height z scores (WHZ) and wasting (WHZ<-2). Independent variables included household wealth, parental education, maternal height, demographic factors, and exposure to WASH and health services. We used age-disaggregated regressions to examine how the associations between dependent and independent variables vary across different child age ranges. RESULTS: Non-parametric regression results reaffirmed that most linear growth faltering and wasting takes place prior to 23 months of age. Estimates of the magnitude of association with wealth, education and improved toilet use from HAZ regressions are systematically larger in the sample of children 24-59 months than in the 0-23 month or 0-59 month samples; the reverse is true for WHZ regressions. CONCLUSIONS: Previous observational analyses appear to substantially underestimate the protective impacts of a wide range of underlying determinants on stunting. Conversely, wasting rates are typically low for children 24-59 months, implying that associations between underlying conditions and wasting may be stronger for children 0-23 months of age. Such analyses should pay closer attention to age disaggregation; researchers should be aware of the age effect reported in the current study and present analysis stratified by age. PMID- 29694432 TI - Enhanced production of polysaccharides and triterpenoids in Ganoderma lucidum fruit bodies on induction with signal transduction during the fruiting stage. AB - Ganoderma lucidum is a medicinal mushroom that has been widely used in East Asia for the treatment of various diseases. The pharmacological activity of this fungus is primarily attributable to the polysaccharides and triterpenoids. In this study, to obtain the fruit bodies with improved content of active constituents, we examined the effect of salicylic acid (SA) and calcium ion on the biosynthesis of polysaccharides and triterpenoids by spraying the chemicals during the fruiting. To explore the underlying mechanisms for the variation, the transcripts of related genes involved in the polysaccharide and triterpenoid biosynthesis were measured. Results showed that Ca2+ had no effect on production of polysaccharides and triterpenoids, whereas SA increased triterpenoid content by 23.32%, compared to the control, but it had little influence on polysaccharide production. Interestingly, the combined induction increased polysaccharide and triterpenoid content by 9.02% and 13.61%, respectively, compared to the control. Under Ca2+ induction, the transcript of ugp gene in the polysaccharide biosynthetic pathway up-regulated in all three stages (mycelium, primordium, and fruit body), while pgm and gls gave no response in the mycelium and primordium stages, and up-regulated in the fruit body stage. Differently, six key triterpenoid biosynthetic genes including hmgr, hmgs, mvd, fps, sqs, and ls did not respond to the induction. In the case of SA and combined induction, pgm and ugp were up-regulated in all three stages, while gls showed an increased expression in the primordium stage and no response in other stages. The six triterpenoid biosynthetic genes were up-regulated in all three stages. The present study provides a useful approach to producing G. lucidum fruit bodies with high polysaccharide and triterpenoid content. This is important to the G. lucidum industry. PMID- 29694433 TI - Influence of beta-blocker therapy on the risk of infections and death in patients at high risk for stroke induced immunodepression. AB - BACKGROUND: Stroke-induced immunodepression is a well characterized complication of acute ischemic stroke. In experimental studies beta-blocker therapy reversed stroke-induced immunodepression, reduced infection rates and mortality. Recent, heterogeneous studies in stroke patients could not provide evidence of a protective effect of beta-blocker therapy. Aim of this study is to investigate the potential preventive effect of beta-blockers in subgroups of patients at high risk for stroke-induced immunodepression. METHODS: Data from a prospectively derived registry of major stroke patients receiving endovascular therapy between 2011-2017 in a tertiary stroke center (University Medical Center Gottingen. Germany) was used. The effect of beta-blocker therapy on pneumonia, urinary tract infection, sepsis and mortality was assessed using multivariate logistic regression analysis. RESULTS: Three hundred six patients with a mean age of 72 +/ 13 years and a median NIHSS of 16 (IQR 10.75-20) were included. 158 patients (51.6%) had pre-stroke- and continued beta-blocker therapy. Beta-blocker therapy did not reduce the incidence of pneumonia (OR 0.78, 95% CI 0.31-1.92, p = 0.584), urinary tract infections (OR 1.51, 0.88-2.60, p = 0.135), sepsis (OR 0.57, 0.18 1.80, p = 0.334) or mortality (OR 0.59, 0.16-2.17, p = 0.429). Strokes involving the insula and anterio-medial cortex increased the risk for pneumonia (OR 4.55, 2.41-8.56, p<0.001) and sepsis (OR 4.13, 1.81-9.43, p = 0.001), while right hemispheric strokes increased the risk for pneumonia (OR 1.60, 0.92-2.77, p = 0.096). There was a non-significantly increased risk for urinary tract infections in patients with beta-blocker therapy and insula/anterio-medial cortex strokes (OR 3.12, 95% CI 0.88-11.05, p = 0.077) with no effect of beta-blocker therapy on pneumonia, sepsis or mortality in both subgroups. CONCLUSIONS: In major ischemic stroke patients, beta-blocker therapy did not lower post-stroke infection rates and was associated with urinary tract infections in a subgroup with insula/anterio-medial strokes. PMID- 29694434 TI - Haptoglobin and hemopexin inhibit vaso-occlusion and inflammation in murine sickle cell disease: Role of heme oxygenase-1 induction. AB - During hemolysis, hemoglobin and heme released from red blood cells promote oxidative stress, inflammation and thrombosis. Plasma haptoglobin and hemopexin scavenge free hemoglobin and heme, respectively, but can be depleted in hemolytic states. Haptoglobin and hemopexin supplementation protect tissues, including the vasculature, liver and kidneys. It is widely assumed that these protective effects are due primarily to hemoglobin and heme clearance from the vasculature. However, this simple assumption does not account for the consequent cytoprotective adaptation seen in cells and organs. To further address the mechanism, we used a hyperhemolytic murine model (Townes-SS) of sickle cell disease to examine cellular responses to haptoglobin and hemopexin supplementation. A single infusion of haptoglobin or hemopexin (+/- equimolar hemoglobin) in SS-mice increased heme oxygenase-1 (HO-1) in the liver, kidney and skin several fold within 1 hour and decreased nuclear NF-KB phospho-p65, and vaso occlusion for 48 hours after infusion. Plasma hemoglobin and heme levels were not significantly changed 1 hour after infusion of haptoglobin or hemopexin. Haptoglobin and hemopexin also inhibited hypoxia/reoxygenation and lipopolysaccharide-induced vaso-occlusion in SS-mice. Inhibition of HO-1 activity with tin protoporphyrin blocked the protections afforded by haptoglobin and hemopexin in SS-mice. The HO-1 reaction product carbon monoxide, fully restored the protection, in part by inhibiting Weibel-Palade body mobilization of P selectin and von Willebrand factor to endothelial cell surfaces. Thus, the mechanism by which haptoglobin and hemopexin supplementation in hyperhemolytic SS mice induces cytoprotective cellular responses is linked to increased HO-1 activity. PMID- 29694435 TI - Invasion of sorghum in the Americas by a new sugarcane aphid (Melanaphis sacchari) superclone. AB - In the United States (US), the sugarcane aphid (SCA) Melanaphis sacchari (Zehnter) (Hemiptera: Aphididae) was introduced in the 1970s, however at that time it was only considered a pest of sugarcane. In 2013, a massive outbreak of M. sacchari occured on sorghum, resulting in significant economic damage to sorghum grown in North America including the US, Mexico, and Puerto Rico. The aim of the present study was to determine if the SCA pest emergence in American sorghum resulted from the introduction of new genotypes. To this end we used microsatellite markers and COI sequencing to compare the genetic diversity of SCA populations collected in the Americas after the 2013 SCA outbreak on sorghum (during 2013-2017) to older samples collected before the pest outbreak (during 2007-2009). Our results show that the SCA outbreak in the Americas and the Caribbean observed since 2013 belong to populations exhibiting low genetic diversity and consisting of a dominant clonal lineage, MLL-F, which colonizes Sorghum spp. and sugarcane. The comparison of MLL-F specimens collected post-2013 with specimens collected in Louisiana in 2007 revealed that both populations are genetically distinct, according to COI sequencing and microsatellite data analyses. Our result suggest that MLL-F is a new invasive genotype introduced into the Americas that has spread rapidly across sorghum growing regions in the US, Mexico, Honduras and the Caribbean. The origin of this introduction is either Africa or Asia, with Asia being the most probable source. PMID- 29694436 TI - Freshwater reservoir offsets and food crusts: Isotope, AMS, and lipid analyses of experimental cooking residues. AB - Freshwater reservoir offsets (FROs) occur when AMS dates on charred, encrusted food residues on pottery predate a pot's chronological context because of the presence of ancient carbon from aquatic resources such as fish. Research over the past two decades has demonstrated that FROs vary widely within and between water bodies and between fish in those water bodies. Lipid analyses have identified aquatic biomarkers that can be extracted from cooking residues as potential evidence for FROs. However, lacking has been efforts to determine empirically how much fish with FROs needs to be cooked in a pot with other resources to result in significant FRO on encrusted cooking residue and what percentage of fish C in a residue is needed to result in the recovery of aquatic biomarkers. Here we provide preliminary assessments of both issues. Our results indicate that in historically-contingent, high alkalinity environments <20% C from fish may result in a statistically significant FRO, but that biomarkers for aquatic resources may be present in the absence of a significant FRO. PMID- 29694437 TI - A molecular dynamics study of adenylyl cyclase: The impact of ATP and G-protein binding. AB - Adenylyl cyclases (ACs) catalyze the biosynthesis of cyclic adenosine monophosphate (cAMP) from adenosine triphosphate (ATP) and play an important role in many signal transduction pathways. The enzymatic activity of ACs is carefully controlled by a variety of molecules, including G-protein subunits that can both stimulate and inhibit cAMP production. Using homology models developed from existing structural data, we have carried out all-atom, microsecond-scale molecular dynamics simulations on the AC5 isoform of adenylyl cyclase and on its complexes with ATP and with the stimulatory G-protein subunit Gsalpha. The results show that both ATP and Gsalpha binding have significant effects on the structure and flexibility of adenylyl cyclase. New data on ATP bound to AC5 in the absence of Gsalpha notably help to explain how Gsalpha binding enhances enzyme activity and could aid product release. Simulations also suggest a possible coupling between ATP binding and interactions with the inhibitory G protein subunit Galphai. PMID- 29694438 TI - "That's what you do for people you love": A qualitative study of social support and recovery from a musculoskeletal injury. AB - BACKGROUND: Social support has been identified as a significant factor in facilitating better health outcomes following injury. However, research has primarily focused on the role of social support from the perspective of the person experiencing an injury. Limited research has examined the experiences of the family members and friends of a person with injury. This study aims to explore the perceptions and experiences of social support and recovery following a transport-related musculoskeletal injury (MSI) in a population of injured persons and their family members and friends. METHODS: This study was conducted using a phenomenological qualitative research design. In-depth semi-structured interviews were conducted with ten persons with MSI, recruited via the Transport Accident Commission (TAC) in Victoria, Australia. Seven family members and friends were also interviewed. The data was analysed using constant comparative method and thematic analysis. RESULTS: Several themes were identified including: (1) key sources and types of support received, (2) relationship development and (3) challenges of providing and receiving support. Participants with MSI reported stories about how the social network provided emotional and tangible support. Family members and friends confirmed the supportive acts provided to the participants with MSI. Positive iterative changes in relationships were reported by the participants with MSI. Participants with MSI, their family members and friends described several difficulties including loss of independence, feeling like a burden, and the impact of caring on health and well-being. CONCLUSIONS: The role of social support is complex given the multitude of people involved in the recovery process. The findings of this study suggest that persons with MSI may benefit from support groups and maintenance of existing support networks. Furthermore, family members and friends engaged in the recovery process may benefit from support in this role. PMID- 29694439 TI - Decision making process and factors contributing to research participation among general practitioners: A grounded theory study. AB - INTRODUCTION: The participation of general practitioners (GPs) in primary care research is variable and often poor. We aimed to develop a substantive and empirical theoretical framework to explain GPs' decision-making process to participate in research. METHODS: We used the grounded theory approach to construct a substantive theory to explain the decision-making process of GPs to participate in research activities. Five in-depth interviews and four focus group discussions were conducted among 21 GPs. Purposeful sampling followed by theoretical sampling were used to attempt saturation of the core category. Data were collected using semi-structured open-ended questions. Interviews were recorded, transcribed verbatim and checked prior to analysis. Open line-by-line coding followed by focus coding were used to arrive at a substantive theory. Memoing was used to help bring concepts to higher abstract levels. RESULTS: The GPs' decision to participate in research was attributed to their inner drive and appreciation for primary care research and their confidence in managing their social and research environments. The drive and appreciation for research motivated the GPs to undergo research training to enhance their research knowledge, skills and confidence. However, the critical step in the GPs' decision to participate in research was their ability to align their research agenda with priorities in their social environment, which included personal life goals, clinical practice and organisational culture. Perceived support for research, such as funding and technical expertise, facilitated the GPs' participation in research. In addition, prior experiences participating in research also influenced the GPs' confidence in taking part in future research. CONCLUSIONS: The key to GPs deciding to participate in research is whether the research agenda aligns with the priorities in their social environment. Therefore, research training is important, but should be included in further measures and should comply with GPs' social environments and research support. PMID- 29694440 TI - Characterization of recent and minimally passaged Brazilian dengue viruses inducing robust infection in rhesus macaques. AB - The macaque is widely accepted as a suitable model for preclinical characterization of dengue vaccine candidates. However, the only vaccine for which both preclinical and clinical efficacy results were reported so far showed efficacy levels that were substantially different between macaques and humans. We hypothesized that this model's predictive capacity may be improved using recent and minimally passaged dengue virus isolates, and by assessing vaccine efficacy by characterizing not only the post-dengue virus challenge viremia/RNAemia but also the associated-cytokine profile. Ten recent and minimally passaged Brazilian clinical isolates from the four dengue virus serotypes were tested for their infectivity in rhesus macaques. For the strains showing robust replication capacity, the associated-changes in soluble mediator levels, and the elicited dengue virus-neutralizing antibody responses, were also characterized. Three isolates from dengue virus serotypes 1, 2 and 4 induced viremia of high magnitude and longer duration relative to previously reported viremia kinetics in this model, and robust dengue virus-neutralizing antibody responses. Consistent with observations in humans, increased MCP-1, IFN-gamma and VEGF-A levels, and transiently decreased IL-8 levels were detected after infection with the selected isolates. These results may contribute to establishing a dengue macaque model showing a higher predictability for vaccine efficacy in humans. PMID- 29694441 TI - Cellular metabolism and oxidative stress as a possible determinant for longevity in small breed and large breed dogs. AB - Among species, larger animals tend to live longer than smaller ones, however, the opposite seems to be true for dogs-smaller dogs tend to live significantly longer than larger dogs across all breeds. We were interested in the mechanism that may allow for small breeds to age more slowly compared with large breeds in the context of cellular metabolism and oxidative stress. Primary dermal fibroblasts from small and large breed dogs were grown in culture. We measured basal oxygen consumption (OCR), proton leak, and glycolysis using a Seahorse XF96 oxygen flux analyzer. Additionally, we measured rates of reactive species (RS) production, reduced glutathione (GSH) content, mitochondrial content, lipid peroxidation (LPO) damage and DNA (8-OHdg) damage. Our data suggests that as dogs of both size classes age, proton leak is significantly higher in older dogs, regardless of size class. We found that all aspects of glycolysis were significantly higher in larger breeds compared with smaller breeds. We found significant differences between age classes in GSH concentration, and a negative correlation between DNA damage in puppies and mean breed lifespan. Interestingly, RS production showed no differences across size and age class. Thus, large breed dogs may have higher glycolytic rates, and DNA damage, suggesting a potential mechanism for their decreased lifespan compared with small breed dogs. PMID- 29694443 TI - Correction: Deregulation of KSHV latency conformation by ER-stress and caspase dependent RAD21-cleavage. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006596.]. PMID- 29694442 TI - Epicardial and visceral adipose tissue in relation to subclinical atherosclerosis in a Chinese population. AB - BACKGROUND: Body fatness is associated with risk of coronary heart disease and it has been postulated that epicardial adipose tissue (EAT) may have a particularly detrimental effect because of its localized toxic effects. We therefore aimed to examine the association between EAT and coronary artery calcification and compared this with associations for visceral adipose tissue (VAT) and other regional fat depots. METHODS: We conducted a cross-sectional study of 487 Chinese participants aged 50 years old and above, living in Singapore. Participants, free from known diabetes mellitus and coronary heart diseases, completed interviews, a health screening to evaluate obesity and cardiovascular disease risk factors, and computed tomography scans of the abdomen and coronary arteries. Associations between regional fat depots and subclinical atherosclerosis defined as CAC> = 100 were determined by multiple logistic regression analysis. RESULTS: Epicardial adipose tissue (EAT) was highly correlated with visceral adipose tissue (VAT) (Pearson r = 0.72) and trunk fat mass (r = 0.66). The age and sex-adjusted odd ratio (OR) (in 1-SD increase) of subclinical atherosclerosis was 1.28 (1.01-1.61) for EAT and 1.40 (1.04-1.88) for VAT. These associations were weaker and non significant after adjusting for markers of dyslipidemia and hyperglycemia. Total body fat, subcutaneous abdominal fat, and leg, arm and trunk fat mass were not significantly associated with atherosclerosis. CONCLUSION: VAT and EAT showed similar associations with coronary artery calcification and the associations could be mediated by traditional risk factors in this ethnic Chinese population. PMID- 29694444 TI - One-carbon metabolism biomarkers and genetic variants in relation to colorectal cancer risk by KRAS and BRAF mutation status. AB - Disturbances in one-carbon metabolism, intracellular reactions involved in nucleotide synthesis and methylation, likely increase the risk of colorectal cancer (CRC). However, results have been inconsistent. To explore whether this inconsistency could be explained by intertumoral heterogeneity, we evaluated a comprehensive panel of one-carbon metabolism biomarkers and some single nucleotide polymorphisms (SNPs) in relation to the risk of molecular subtypes of CRC defined by mutations in the KRAS and BRAF oncogenes. This nested case-control study included 488 CRC cases and 947 matched controls from two population-based cohorts in the Northern Sweden Health and Disease Study. We analyzed 14 biomarkers and 17 SNPs in prediagnostic blood and determined KRAS and BRAF mutation status in tumor tissue. In a multivariate network analysis, no variable displayed a strong association with the risk of specific CRC subtypes. A non synonymous SNP in the CTH gene, rs1021737, had a stronger association compared with other variables. In subsequent univariate analyses, participants with variant rs1021737 genotype had a decreased risk of KRAS-mutated CRC (OR per allele = 0.72, 95% CI = 0.50, 1.05), and an increased risk of BRAF-mutated CRC (OR per allele = 1.56, 95% CI = 1.07, 2.30), with weak evidence for heterogeneity (Pheterogeneity = 0.01). This subtype-specific SNP association was not replicated in a case-case analysis of 533 CRC cases from The Cancer Genome Atlas (P = 0.85). In conclusion, we found no support for clear subtype-specific roles of one-carbon metabolism biomarkers and SNPs in CRC development, making differences in CRC molecular subtype distributions an unlikely explanation for the varying results on the role of one-carbon metabolism in CRC development across previous studies. Further investigation of the CTH gene in colorectal carcinogenesis with regards to KRAS and BRAF mutations or other molecular characteristics of the tumor may be warranted. PMID- 29694446 TI - Clinical, biochemical and genetic risk factors for 30-day and 5-year mortality in 518 adult patients subjected to cardiopulmonary bypass during cardiac surgery - the INFLACOR study. AB - There is increasing evidence that genetic variability influences patients' early morbidity after cardiac surgery performed using cardiopulmonary bypass (CPB). The use of mortality as an outcome measure in cardiac surgical genetic association studies is rare. We publish the 30-day and 5-year survival analyses with focus on pre-, intra-, postoperative variables, biochemical parameters, and genetic variants in the INFLACOR (INFLAmmation in Cardiac OpeRations) cohort. In a prospectively recruited cohort of 518 adult Polish Caucasians, who underwent cardiac surgery in which CPB was used, the clinical data, biochemical parameters, IL-6, soluble ICAM-1, TNFalpha, soluble E-selectin, and 10 single nucleotide polymorphisms were evaluated for their association with 30-day and 5-year mortality. The 30-day mortality was associated with: pre-operative prothrombin international normalized ratio, intra-operative blood lactate, postoperative serum creatine phosphokinase, and acute kidney injury requiring renal replacement therapy (AKI-RRT) in logistic regression. Factors that determined the 5-year survival included: pre-operative NYHA class, history of peripheral artery disease and severe chronic obstructive pulmonary disease, intra-operative blood transfusion; and postoperative peripheral hypothermia, myocardial infarction, infection, and AKI-RRT in Cox regression. Serum levels of IL-6 and ICAM-1 measured three hours after the operation were associated with 30-day and 5-year mortality, respectively. The ICAM1 rs5498 was associated with 30-day and 5-year survival with borderline significance. Different risk factors determined the early (30-day) and late (5-year) survival after adult cardiac surgery in which cardiopulmonary bypass was used. Future genetic association studies in cardiac surgical patients should account for the identified chronic and perioperative risk factors. PMID- 29694445 TI - Survival predictors in anuric patients on peritoneal dialysis: A prospective, multicenter, propensity score-matched cohort study. AB - Prevalent anuric peritoneal dialysis (PD) patients usually have higher mortality than PD patients with residual urine volume. We aimed to evaluate the predictors of survival in anuric PD patients. Anuric PD patients (n = 505, <100 mL of daily urine) enrolled in Korean nationwide prospective cohort were analyzed. Survived and non-survived anuric PD patients were compared by propensity score matching analysis with a ratio of two to one. The propensity method was used to adjust for patient age, dialysis duration, and presence of diabetes. Among the total anuric PD patients, non-survived patients showed a significantly older age, higher incidence of diabetes, coronary artery disease, and arrhythmia, and lower serum creatinine and albumin. After propensity score matching, multivariate Cox regression analysis for patient survival showed a decreasing risk as serum albumin increased (HR = 0.347, p = 0.0094). Analysis using the receiver-operating characteristic (ROC) curve showed that survival could be predicted with a sensitivity of 59.4% and a specificity of 63.2% using a cutoff value of 3.6 g/dL of serum albumin in unmatched total PD patients. The beneficial impact of high albumin level on death was significantly greater for patients with older age (>=50 years), no diabetes, low ultrafiltration (UF) volume (<1000 mL/day), and low levels of serum creatinine (<10 mg/dL), total cholesterol (<177.5 mg/dL), ferritin (<100 ng/mL), and high-sensitivity C-reactive protein (hs-CRP) (<0.1 mg/dL). Survival in anuric PD patients was associated with age, comorbidities, and nutritional factors such as creatinine and albumin. After adjustment by propensity score matching, serum albumin level was an independent predictor for survival in anuric PD patients. PMID- 29694447 TI - Pharmacological versus genetic inhibition of heme oxygenase-1 - the comparison of metalloporphyrins, shRNA and CRISPR/Cas9 system. AB - Inhibition of heme oxygenase-1 (HO-1, encoded by HMOX1), a cytoprotective, anti apoptotic and anti-inflammatory enzyme, may serve as a valuable therapy in various pathophysiological processes, including tumorigenesis. We compared the effect of chemical inhibitors - metalloporphyrins, with genetic tools - shRNA and CRISPR/Cas9 systems, to knock-down (KD)/knock-out (KO) HO-1 expression/activity. 293T cells were incubated with metalloporphyrins, tin and zinc protoporphyrins (SnPPIX and ZnPPIX, respectively) or were either transduced with lentiviral vectors encoding different shRNA sequences against HO-1 or were modified by CRISPR/Cas9 system targeting HMOX1. Metalloporphyrins decreased HO activity but concomitantly strongly induced HO-1 mRNA and protein in 293T cells. On the other hand, only slight basal HO-1 inhibition in shRNA KD 293T cell lines was confirmed on mRNA and protein level with no significant effect on enzyme activity. Nevertheless, silencing effect was much stronger when CRISPR/Cas9-mediated knock out was performed. Most of the clones harboring mutations within HMOX1 locus did not express HO-1 protein and failed to increase bilirubin concentration after hemin stimulation. Furthermore, CRISPR/Cas9-mediated HO-1 depletion decreased 293T viability, growth, clonogenic potential and increased sensitivity to H2O2 treatment. In summary, we have shown that not all technologies can be used for inhibition of HO activity in vitro with the same efficiency. In our hands, the most potent and comprehensible results can be obtained using genetic tools, especially CRISPR/Cas9 approach. PMID- 29694448 TI - Novel laccase-like multicopper oxidases from the Myrothecium roridum fungus - production enhancement, identification and application in the dye removal process. AB - The aim of this study was to overproduce, identify and apply novel laccase-like multicopper oxidases (LMCOs) from Myrothecium roridum in a dye removal process. LMCOs' production was enhanced by modifying the medium and adding copper ions. After purification, two proteins, LMCO1 and LMCO2, with molecular masses of 46.7 and 66.3 kDa were discovered. Peptide analysis by mass spectrometry revealed that they belong to the cupredoxin superfamily. Characteristic peptide sequences were obtained for MCOs and bilirubin oxidases. Crude enzymes were applied in a dye decolorization process. Supplementation with 1 mM of vanillin allowed an almost complete elimination of the Indigo carmine within 3 hours. The dye was removed from a solution containing metals, surfactants and organic solvents. The in-gel assessment of the activity and decolorization ability of MCOs, followed by protein extraction and SDS-PAGE, confirmed that only LMCO2 was responsible for the dye removal. MCOs produced by Myrothecium sp. have been poorly studied before. The obtained results broaden knowledge on this subject and may contribute to the development of an eco-friendly method of dye elimination. PMID- 29694449 TI - Appraising the Evidence Supporting Choosing Wisely(r) Recommendations. AB - Despite the growing enthusiasm surrounding the Choosing Wisely(r) campaign, little is known regarding the evidence underlying these recommendations. We extracted references for all 320 recommendations published through August, 2014, including the 10 adult and pediatric recommendations published by the Society for Hospital Medicine. We then categorized each item by evidence strength, and then assessed a sample of referenced clinical practice guidelines (CPGs) using the validated Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. Among all recommendations, 70.3% cited CPGs, whereas 22.2% cited primary research as their highest level of evidence. Moreover, 7.8% cited case series, review articles, editorials, or lower quality data as their highest level of evidence. Hospital medicine recommendations were more likely to cite CPGs (90%) as their highest level of evidence. Among the sampled CPGs, the median overall score obtained using AGREE II was 54.2% (IQR 33.3%-70.8%), whereas among hospital medicine-referenced CPGs, the median overall score was 58.3% (IQR 50.0% 83.3%). These findings suggest that Choosing Wisely(r) recommendations vary in terms of evidence strength. PMID- 29694450 TI - Focused Ethnography of Diagnosis in Academic Medical Centers. AB - BACKGROUND: Approaches of trainees to diagnosis in teaching hospitals are poorly understood. Identifying cognitive and system-based barriers and facilitators to diagnosis may improve diagnosis in these settings. METHODS: We conducted a focused ethnography of trainees at 2 academic medical centers to understand the barriers and facilitators to diagnosis. Field notes regarding the diagnostic process (eg, information gathering, integration and interpretation, working diagnosis) and the work system (eg, team members, organization, technology and tools, physical environment, tasks) were recorded. Following observations, focus groups and interviews were conducted to understand the viewpoints, problems, and solutions to improve diagnosis. RESULTS: Between January 2016 and May 2016, 4 teaching teams (4 attendings, 4 senior residents, 9 interns, and 12 medical students) were observed for 168 h. Observations of diagnosis during care led to identification of the following 4 key themes: (a) diagnosis is a social phenomenon; (b) data necessary to make diagnoses are fragmented; (c) distractions interfere with the diagnostic process; and (d) time pressures impede diagnostic decision-making. These themes suggest that specific interventions tailored to the academic setting such as team-based discussions of diagnostic workups, scheduling diagnostic time-outs during the day, and strategies to "protect" learners from interruptions might prove to be useful in improving the process of diagnosis. Future studies that implement these ideas (either alone or within a multimodal intervention) appear to be necessary. CONCLUSIONS: Diagnosis in teaching hospitals is a unique process that requires improvement. Contextual insights gained from this ethnography may be used to inform future interventions. PMID- 29694451 TI - Continuous Physiologic Monitoring: False Alarms and Overdiagnosis. PMID- 29694452 TI - Current Perspectives on Transport Medicine in Pediatric Hospital Medicine Fellowships. AB - Transport medicine (TM) is a Pediatric Hospital Medicine (PHM) Core Competency and part of the proposed PHM fellowship curricular framework. No published TM curricula are available. This cross-sectional study was designed to determine attitudes toward TM training among PHM fellowship stakeholders and conduct a TM curriculum needs assessment. Unique, web-based, anonymous surveys for PHM fellows, graduates, and program directors (PDs) were administered, with response rates of 57%, 37%, and 44%, respectively. Fellows' interest in completing a TM rotation is greater than their perceived interest by PDs (P = .06). Graduates who completed a TM rotation were more likely to recommend a TM rotation than those who did not (P = .001). Perceived barriers included lack of a formal TM curriculum and time constraints. Stabilizing patients and triage of referrals were deemed important learning objectives, and active learning strategies were prioritized. Curriculum design should focus on topics specific to the transport process and environment. PMID- 29694453 TI - Cardiac Troponins in Low-Risk Pulmonary Embolism Patients: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Patients with low-risk pulmonary embolism (PE) should be considered as per current scoring systems for ambulatory treatment. However, there is uncertainty whether patients with low scores and positive troponins should require hospitalization. METHODS: We searched MEDLINE, SCOPUS, and Cochrane Library databases from inception to December 2016 and collected longitudinal studies that evaluated the prognostic value of troponins in patients with low risk PE. The primary outcome measure was 30-day all-cause mortality. We calculated odds ratio (OR), likelihood ratios (LRs), and 95% confidence intervals (CI) by using randomeffects models. RESULTS: The literature search identified 117 candidate articles, of which 16 met the criteria for review. Based on pulmonary embolism severity index (PESI) or simplified PESI score, 1.2% was the all-cause mortality rate across 2,662 participants identified as low-risk. A positive troponin status in patients with low-risk PE was associated with an increased risk of 30-day all-cause mortality (odds ratio [OR]: 4.79; 95% confidence interval [CI]: 1.11 to 20.68). The pooled likelihood ratios (LRs) for all-cause mortality were positive LR 2.04 (95% CI, 1.53 to 2.72) and negative LR 0.072 (95% CI, 0.37 to 1.40). CONCLUSIONS: The use of positive troponin status as a predictor of increased mortality in low-risk PE patients exhibited relatively poor performance given the crossed negative LR CI (1.0) and modest positive LR. Larger prospective trials must be conducted to elucidate if patients with low risk PE and positive troponin status can avoid hospitalization. PMID- 29694454 TI - "We've Learned It's a Medical Illness, Not a Moral Choice": Qualitative Study of the Effects of a Multicomponent Addiction Intervention on Hospital Providers' Attitudes and Experiences. AB - BACKGROUND: Substance use disorders (SUD) represent a national epidemic with increasing rates of SUD-related hospitalizations. However, most hospitals lack expertise or systems to directly address SUD. Healthcare professionals feel underprepared and commonly hold negative views toward patients with SUD. Little is known about how hospital interventions may affect providers' attitudes and experiences toward patients with SUD. OBJECTIVE: To explore interprofessional hospital providers' perspectives on how integrating SUD treatment and care systems affect providers' attitudes, beliefs, and experiences. DESIGN: In-depth semi-structured interviews and focus groups. The study was part of a formative evaluation of the Improving Addiction Care Team (IMPACT), an interprofessional hospital-based addiction medicine service with rapid-access pathways to post hospital SUD treatment. SETTING: Single urban academic hospital in Portland, Oregon. PARTICIPANTS: Multidisciplinary hospital providers. MEASUREMENTS: We conducted a thematic analysis using an inductive approach at a semantic level. RESULTS: Before IMPACT, participants felt that hospitalization did not address addiction, leading to untreated withdrawal, patients leaving against medical advice, chaotic care, and staff "moral distress." Participants felt that IMPACT "completely reframes" addiction as a treatable chronic disease, improving patient engagement and communication, and humanizing care. Participants valued post hospital SUD treatment pathways and felt having systems to address SUD reduced burnout and provided relief. Providers noted that IMPACT had limited ability to address poverty or engage highly ambivalent patients. CONCLUSIONS: Providers' distress of caring for patients with SUD is not inevitable. Hospital-based SUD interventions can reframe providers' views of addiction and may have significant implications for clinical care and providers' well-being. PMID- 29694455 TI - Relative Weights for Pediatric Inpatients: Children Now Have a Scale of Their Own. PMID- 29694456 TI - A Matter of Urgency: Reducing Clinical Text Message Interruptions During Educational Sessions. AB - BACKGROUND: Text messaging is increasingly replacing paging as a tool to reach physicians on medical wards. However, this phenomenon has resulted in high volumes of nonurgent messages that can disrupt the learning climate. OBJECTIVE: Our objective was to reduce nonurgent educational interruptions to residents on general internal medicine. DESIGN, SETTING, PATIENTS: This was a quality improvement project conducted at an academic hospital network. Measurements and interventions took place on 8 general internal medicine inpatient teaching teams. INTERVENTION: Interventions included (1) refining the clinical communication process in collaboration with nursing leadership; (2) disseminating guidelines with posters at nursing stations; (3) introducing a noninterrupting option for message senders; (4) audit and feedback of messages; (5) adding an alert for message senders advising if a message would interrupt educational sessions; and (6) training and support to nurses and residents. MEASUREMENTS: Interruptions (text messages, phone calls, emails) received by institution-supplied team smartphones were tracked during educational hours using statistical process control charts. A 1-month record of text message content was analyzed for urgency at baseline and following the interventions. RESULTS: The interruption frequency decreased from a mean of 0.92 (95% CI, 0.88 to 0.97) to 0.59 (95% CI, 0.51 to0.67) messages per team per educational hour from January 2014 to December 2016. The proportion of nonurgent educational interruptions decreased from 223/273 (82%) messages over one month to 123/182 (68%; P < .01). CONCLUSIONS: Creation of communication guidelines and modification of text message interface with feedback from end-users were associated with a reduction in nonurgent educational interruptions. Continuous audit and feedback may be necessary to minimize nonurgent messages that disrupt educational sessions. PMID- 29694457 TI - Tissue Isn't the Issue. PMID- 29694459 TI - Characterizing Hospitalizations for Pediatric Concussion and Trends in Care. AB - BACKGROUND: Children hospitalized for concussion may be at a higher risk for persistent symptoms, but little is known about this subset of children. OBJECTIVE: Delineate a cohort of children admitted for concussion, describe care practices received, examine factors associated with prolonged length of stay (LOS) or emergency department (ED) readmission, and investigate changes in care over time. DESIGN, SETTING: Retrospective analysis of data submitted by 40 pediatric hospitals to the Pediatric Health Information System. PATIENTS: Children 0 to 17 years old admitted with a primary diagnosis of concussion from 2007 to 2014. MEASUREMENTS: Descriptive statistics characterized this cohort and care practices delivered, logistic regression identified factors associated with a LOS of =2 days and ED readmission, and trend analyses assessed changes in care over time. RESULTS: Of the 10,729 children admitted for concussion, 68.7% received intravenous pain or antiemetic medications. Female sex, adolescent age, and having government insurance were all associated (P = .02) with increased odds of LOS = 2 days and ED revisit. Proportions of children receiving intravenous ondansetron (slope = 1.56, P = .001) and ketorolac (slope = 0.61, P < .001) increased over time, and use of neuroimaging (slope = -1.75, P < .001) decreased. CONCLUSIONS: Although concussions are usually selflimited, hospitalized children often receive intravenous therapies despite an unclear benefit. Factors associated with prolonged LOS and ED revisit were similar to predictors of postconcussive syndrome. Since there has been an increased use of specific therapeutics, prospective evaluation of their relationship with concussion recovery could lay the groundwork for evidenced-based admission criteria and optimize recovery. PMID- 29694458 TI - Hospital Readmissions in Patients with Cirrhosis: A Systematic Review. AB - BACKGROUND: Hospital readmission is a significant problem for patients with complex chronic illnesses such as liver cirrhosis. PURPOSE: We aimed to describe the range of readmission risk in patients with cirrhosis and the impact of the model for end-stage liver disease (MELD) score. DATA SOURCES: We conducted a systematic review of studies identified in Ovid MEDLINE, PubMed, EMBASE, CINAHL, the Cochrane Library, Scopus, Google Scholar, and ClinicalTrials.gov from 2000 to May 2017. STUDY SELECTION: We examined studies that reported early readmissions (up to 90 days) in patients with cirrhosis. Studies were excluded if they did not examine the association between readmission and at least 1 variable or intervention. DATA EXTRACTION: Two reviewers independently extracted data on study design, setting, population, interventions, comparisons, and detailed information on readmissions. DATA SYNTHESIS: Of the 1363 records reviewed, 26 studies met the inclusion and exclusion criteria. Of these studies, 21 were retrospective, and there was significant variation in the inclusion and exclusion criteria. The pooled estimate of 30-day readmissions was 26%(95% confidence interval [CI], 22%-30%). Few studies examined readmission preventability or the relationship between readmissions and social determinants of health. Reasons for readmission were highly variable. An increased MELD score was associated with readmissions in most studies. Readmission was associated with increased mortality. CONCLUSIONS: Hospital readmissions frequently occur in patients with cirrhosis and are associated with liver disease severity. The impact of functional and social factors on readmissions is unclear. PMID- 29694460 TI - Development of Hospitalization Resource Intensity Scores for Kids (H-RISK) and Comparison across Pediatric Populations. AB - BACKGROUND: In the Medicare population, measures of relative severity of illness (SOI) for hospitalized patents have been used in prospective payment models. Similar measures for pediatric populations have not been fully developed. OBJECTIVE: To develop hospitalization resource intensity scores for kids (H-RISK) using pediatric relative weights (RWs) for SOI and to compare hospital types on case-mix index (CMI). DESIGN/METHODS: Using the 2012 Kids' Inpatient Database (KID), we developed RWs for each All Patient Refined Diagnosis Related Group (APR DRG) and SOI level. RW corresponded to the ratio of the adjusted mean cost for discharges in an APR-DRG SOI combination over adjusted mean cost of all discharges in the dataset. RWs were applied to every discharge from 3,117 hospitals in the database with at least 20 discharges. RWs were then averaged at the hospital level to provide each hospital's CMI. CMIs were compared by hospital type using Kruskal- Wallis tests. RESULTS: The overall adjusted mean cost of weighted discharges in Healthcare Cost and Utilization Project KID 2012 was $6,135 per discharge. Solid organ and bone marrow transplantations represented 4 of the 10 highest procedural RWs (range: 35.5 to 91.7). Neonatal APRDRG SOIs accounted for 8 of the 10 highest medical RWs (range: 19.0 to 32.5). Free standing children's hospitals yielded the highest median (interquartile range [IQR]) CMI (2.7 [2.2-3.1]), followed by urban teaching hospitals (1.8 [1.3-2.6]), urban nonteaching hospitals (1.1 [0.9-1.5]), and rural hospitals (0.8 [0.7-0.9]; P < .001). CONCLUSIONS: H-RISK for populations of pediatric admissions are sensitive to detection of substantial differences in SOI by hospital type. PMID- 29694461 TI - Value-Based Purchasing for Hospital-Acquired Venous Thromboembolism: Too Much, Too Soon. PMID- 29694462 TI - Physiologic Monitor Alarm Rates at 5 Children's Hospitals. AB - Alarm fatigue has been linked to patient morbidity and mortality in hospitals due to delayed or absent responses to monitor alarms. We sought to describe alarm rates at 5 freestanding children's hospitals during a single day and the types of alarms and proportions of patients monitored by using a point-prevalence, cross sectional study design. We collected audible alarms on all inpatient units and calculated overall alarm rates and rates by alarm type per monitored patient per day. We found a total of 147,213 alarms during the study period, with 3-fold variation in alarm rates across hospitals among similar unit types. Across hospitals, onequarter of monitored beds were responsible for 71%, 61%, and 63% of alarms in medical-surgical, neonatal intensive care, and pediatric intensive care units, respectively. Future work focused on addressing nonactionable alarms in patients with the highest alarm counts may decrease alarm rates. PMID- 29694463 TI - Predictors of Long-Term Temporomandibular Disorder Pain Intensity: An 8-Year Cohort Study. AB - AIMS: To investigate, in individuals with pain-related temporomandibular disorder (TMD), the association of long-term pain intensity with baseline health-related quality of life (HRQoL) and jaw functional limitation. METHODS: Of 513 cases with baseline pain-related TMD (masticatory muscle and/or temporomandibular joint [TMJ] pain), 273 were reevaluated after 8 years, and 258 of them had complete baseline data for Jaw Functional Limitation Scale (JFLS) scores and HRQoL measured by the Physical Component Summary (PCS) and Mental Component Summary (MCS) scores of the 12-item Short Form Health Survey and follow-up data for Characteristic Pain Intensity (CPI) from the Graded Chronic Pain Scale. Secondary analyses of existing data quantified the effects of primary (PCS, MCS) and secondary (JFLS) predictors on follow-up CPI by using multivariable linear regression. Sensitivity analyses considered differences between the included participants (n = 258) and those who were not included (n = 255) by using inverse probability weighting. Interactions of baseline predictors with age, sex, and baseline CPI were evaluated using multivariable linear regression. RESULTS: The score for baseline PCS, but not MCS or JFLS, was associated with follow-up CPI (P = .012). One standard deviation (SD = 9.0)-higher baseline PCS score predicted an overall 3.2-point-lower follow-up CPI (95% confidence interval -5.8 to -0.7) after adjusting for age, sex, MCS, JFLS, and baseline CPI scores. However, the effect of PCS score was not uniform: the association between PCS and follow-up CPI scores was statistically significant for participants with baseline CPI >= 51.3/100 and clinically significant for participants with baseline CPI >= 68.7/100. Adjustment for TMD treatments and sensitivity analyses had negligible effect. CONCLUSION: In participants with moderate to severe baseline TMD pain intensity, higher baseline physical HRQoL predicted lower TMD pain intensity at 8 years follow-up. PCS score could contribute to a multifactorial long-term TMD pain prediction model. PMID- 29694464 TI - Effects of a Physical Therapy Protocol in Patients with Chronic Migraine and Temporomandibular Disorders: A Randomized, Single-Blinded, Clinical Trial. AB - AIMS: To investigate the effects of adding orofacial treatment to cervical physical therapy in patients with chronic migraine and temporomandibular disorders (TMD). METHODS: A total of 45 participants with chronic migraine and TMD aged 18 to 65 years were randomized into two groups: a cervical group (CG) and a cervical and orofacial group (COG). Both groups continued their medication regimens for migraine treatment and received physical therapy. The CG received physical therapy only in the cervical region, and the COG received physical therapy in both the cervical and orofacial regions. Both groups received six sessions of treatment that consisted of manual therapy and therapeutic exercise in the cervical region or the cervical and orofacial regions. Scores on the Craniofacial Pain and Disability Inventory (CF-PDI) and the Headache Impact Test (HIT-6) were primary outcome variables, and the secondary outcome variables were scores on the Tampa Scale for Kinesiophobia (TSK-11), pain intensity measured on a visual analog scale (VAS), pressure pain thresholds (PPTs) in the temporal, masseter (2 points, M1 and M2) and extratrigeminal (wrist) regions, and maximal mouth opening (MMO). Data were recorded at baseline, posttreatment, and after 12 weeks of follow-up. The alpha level was set at .05 for all tests and two-way repeated-measures analysis of variance (ANOVA) for within- and between-group interactions. RESULTS: There were 22 CG participants (13.6% men and 86.4% women) and 23 COG participants (13% men and 87% women). The ANOVA analysis revealed statistically significant differences for group * time interaction in CF-PDI, HIT 6 in the last follow-up, pain intensity, PPTs in the trigeminal region, and MMO (P < .05), with a medium-large magnitude of effect. No statistically significant differences were found in the PPTs of the extratrigeminal region or in the TSK-11 (P > .05). CONCLUSION: Both groups reported a significant improvement in CF-PDI, HIT-6, and pain intensity. Cervical and orofacial treatment was more effective than cervical treatment alone for increasing PPTs in the trigeminal region and producing pain-free MMO. Physical therapy alone was not effective for increasing the PPTs in the extratrigeminal region (wrist) or decreasing the level of TSK-11. PMID- 29694465 TI - Melatonin Treatment in Patients with Burning Mouth Syndrome: A Triple-Blind, Placebo-Controlled, Crossover Randomized Clinical Trial. AB - AIMS: To evaluate the efficacy of melatonin compared to placebo in reducing pain associated with burning mouth syndrome (BMS), as well as side effects of treatment and effects on sleep quality, anxiety, and serum and salivary melatonin levels. METHODS: In this triple-blind, randomized clinical trial, 20 BMS patients (mean age +/- standard deviation: 64.4 +/- 11.5 years; range: 35 to 82 years) were enrolled to receive melatonin (12 mg/day) or placebo for 8 weeks in a crossover design. After treatment, changes in pain from baseline were ascertained by patient self-assessment with a verbal category scale and a visual analog scale. Secondary outcomes included evaluation of changes in sleep quality and anxiety. Data were subjected to analysis of variance (ANOVA), Fisher exact test, paired t test, Wilcoxon signed rank test, or chi-square test, as appropriate. RESULTS: Melatonin was not superior to placebo in reducing pain. Melatonin significantly improved anxiety scores, though without strong clinical relevance. Independent of treatment, sleep quality did not significantly change during the trial, although melatonin slightly increased the number of hours slept. After active treatment, the mean +/- standard error serum melatonin level peaked at 1,520 +/- 646 pg/mL. A generally safe pharmacologic profile of melatonin was observed, and the placebo and melatonin treatments resulted in similar adverse effects. CONCLUSION: Within the limitations of this study, melatonin did not exhibit higher efficacy than placebo in relieving pain in BMS patients. PMID- 29694466 TI - Computer-Aided Design/Computer-Assisted Manufacture-Derived Needle Guide for Injection of Botulinum Toxin into the Lateral Pterygoid Muscle in Patients with Oromandibular Dystonia. AB - AIMS: To evaluate the effectiveness and safety of botulinum toxin administration into the inferior head of the lateral pterygoid muscle of patients with jaw opening dystonia by using a computer-aided design/computer-assisted manufacture (CAD/CAM)-derived needle guide. METHODS: A total of 17 patients with jaw opening dystonia were enrolled. After the patient's computed tomography (CT) scan was imported and fused with a scan of a plaster cast model of the maxilla, the optimal needle insertion site over the lateral pterygoid muscle was determined using the NobelClinician software. A total of 13 patients were injected both with and without the guide, and 4 patients underwent guided injection alone. The therapeutic effects of botulinum toxin injection and its associated complications were statistically compared between the guided and unguided procedures using paired t test. RESULTS: Botulinum toxin therapy was performed 42 and 32 times with and without the guides, respectively. The needle was easily inserted without any complications in all procedures. There was a significant difference (P < .001) between the mean comprehensive improvements observed with (66.3%) and without (54.4%) the guides. CONCLUSION: The findings suggest that the use of needle guides during the injection of botulinum toxin into the inferior head of the lateral pterygoid muscle is very useful for aiding the accurate and safe administration of botulinum toxin therapy for jaw opening dystonia. PMID- 29694467 TI - Continuous Dentoalveolar Neuropathic Pain Response to Repeated Intravenous Ketamine Infusions: A Case Report. AB - This article describes a case of continuous dentoalveolar neuropathic pain in which relief was obtained following repeated administration of intravenous infusions of a subanesthetic dose of ketamine. A 50-year-old female presented in 2006 with a 1-year history of constant sharp pain in the gingiva surrounding the maxillary left second premolar and second molar rated as 10/10 on a pain intensity scale. After multiple systemic medications failed to adequately manage the patient's pain, partial pain reduction was obtained (4/10) with daily use of methadone 50 mg in combination with application of a topical compound including lidocaine, amitriptyline, and carbamazepine to the affected area as needed. In July 2012, for reasons unrelated to the neuropathic pain condition, the patient underwent extraction of the maxillary right second premolar under intravenous sedation. Initially, a subanesthetic dose of ketamine was added to the sedation regimen for postoperative pain management; however, due to subsequent improvement of the dentoalveolar neuropathic pain, repeated intravenous infusions were recommended for further pain management. The patient's neuropathic pain condition was successfully managed by a total of five intravenous ketamine infusions repeated over a 4-year period of time. The patient's daily use of methadone was progressively reduced and finally discontinued. This case suggests a possible role for intravenous infusions of subanesthetic doses of ketamine as an adjuvant management option in patients suffering from intractable dentoalveolar continuous neuropathic pain conditions. PMID- 29694468 TI - Exploding Head Syndrome as Aura of Migraine with Brainstem Aura: A Case Report. AB - This article reports a case of exploding head syndrome (EHS) as an aura of migraine with brainstem aura (MBA). A middle-aged man presented with intermittent episodes of a brief sensation of explosion in the head, visual flashing, vertigo, hearing loss, tinnitus, confusion, ataxia, dysarthria, and bilateral visual impairment followed by migraine headache. The condition was diagnosed as MBA. Explosive head sensation, sensory phenomena, and headaches improved over time with nortriptyline. This case shows that EHS can present as a primary aura symptom in patients with MBA. PMID- 29694469 TI - Finding a receptor design for selective recognition of perrhenate and pertechnetate: hydrogen vs. halogen bonding. AB - Receptors bearing hydrogen and halogen bond donors for recognition of perrhenate and pertechnetate were designed and studied. Acyclic hosts with N-H and C-H binding sites showed the best selectivity for TcO4- and ReO4- over spherical and more basic tetrahedral anions. PMID- 29694470 TI - Tuning chemoselectivity in O-/N-arylation of 3-aryl-1,2,4-oxadiazolones with ortho-(trimethylsilyl)phenyl triflates via aryne insertion. AB - Herein, we first describe finely tunable chemoselectivity in arylation of 3-aryl 1,2,4-oxadiazolones with ortho-(trimethylsilyl)phenyl triflates, including O arylation enabled by catalytic amount of silver nitrate and metal-free N arylation. Both the arylation reactions can tolerate a series of functional groups, and afford the corresponding products in moderate to good yields. PMID- 29694471 TI - Lead-free, air-stable hybrid organic-inorganic perovskite resistive switching memory with ultrafast switching and multilevel data storage. AB - Organolead halide perovskites exhibit excellent optoelectronic and photovoltaic properties such as a wide range of light absorption and tunable band gaps. However, the presence of toxic elements and chemical instability under an ambient atmosphere hindered lead halide perovskites from real device applications because of environmental issues and stability. Here, we demonstrate a resistive switching memory device based on a lead-free bismuth halide perovskite (CH3NH3)3Bi2I9 (MABI). The active layer of the device can be easily prepared by solvent engineering. The nonvolatile memory based on MABI layers has reliable retention properties (~104 s), endurance (300 cycles), and switching speed (100 ns), as well as environmental stability. Moreover, the control of the compliance current leads to multilevel data storage with four resistance states, which can be applied to high-density memory devices. These results suggest that MABI has potential applications in information storage. PMID- 29694472 TI - Phosphorescent inner filter effect-based sensing of xanthine oxidase and its inhibitors with Mn-doped ZnS quantum dots. AB - Overexpression and crystallization of uric acid have been recognized as the course of hyperuricemia and gout, which is produced via xanthine oxidase (XOD) catalyzed oxidation of xanthine. Therefore, the medicinal therapy of hyperuricemia and gout is majorly based on the inhibition of the XOD enzymatic pathway. The spectroscopic nature of xanthine and uric acid, namely both absorption (near the ultraviolet region) and emission (non-fluorescent) characteristics, hinders optical assay development for XOD analysis. Therefore, the state-of-the-art analysis of XOD and the screening of XOD inhibitors are majorly based on chromatography. Here, we found the near ultraviolet absorption of uric acid overlapped well with the absorption of a large bandgap semiconductor quantum dots, ZnS. On the other hand, the intrinsic weak fluorescence of ZnS QDs can be substantially improved via transition metal ion doping. Therefore, herein, we developed an inner filter effect-based assay for XOD analysis and inhibitor screening with Mn-doped ZnS QDs. The phosphorescence of Mn-doped ZnS QDs could be quenched by uric acid generated from xanthine catabolism by XOD, leading to the phosphorescence turn-off detection of XOD with a limit of detection (3sigma) of 0.02 U L-1. Furthermore, the existence of XOD inhibitors could inhibit the XOD enzymatic reaction, resulting in weakened phosphorescence quenching. Therefore, the proposed assay could also be explored for the facile screening analysis of XOD inhibitors, which is important for the potential medicinal therapy of hyperuricemia and gout. PMID- 29694473 TI - An 800 nm driven NaErF4@NaLuF4 upconversion platform for multimodality imaging and photodynamic therapy. AB - Multimodality imaging-guided therapy based on lanthanide-doped upconversion nanoparticles (UCNPs) has become a trend in cancer theranostics. However, the overheating effect of 980 nm excitation in photodynamic therapy (PDT) and the difficulties in optimizing multimodality imaging integration within a single particle are still challenges. Herein, 800 nm driven NaErF4@NaLuF4 UCNPs have been explored for optimized multimodality imaging and near-infrared (NIR) triggered PDT. Our results confirmed that the optimal ~5 nm shell thickness can well balance the enhancement of upconversion luminescence and the attenuation of energy transfer efficiency from Er3+ towards a photosensitizer, to achieve efficient production of singlet oxygen (1O2) for PDT under 800 nm excitation. Furthermore, the as-obtained NaErF4@NaLuF4 UCNPs showed effective and applicable performance for upconversion luminescence (UCL) imaging, X-ray computed tomography (CT), and high-field T2 magnetic resonance imaging (MRI). This nanomaterial can serve as an excellent theranostic agent for multimodality imaging and image-guided therapy. PMID- 29694474 TI - Highly penetrative liposome nanomedicine generated by a biomimetic strategy for enhanced cancer chemotherapy. AB - Liposome nanomedicine has been successfully applied for cancer chemotherapy in patients. However, in general, the therapeutic efficacy is confined by its limited accumulation and penetration in solid tumors. Here, we established a biomimetic strategy for the preparation of highly penetrative liposome nanomedicine for enhanced chemotherapeutic efficacy. By applying this unique type of nanomedicine, membrane proteins on the cancer cells are used as highly penetrative targeting ligands. Biomimetic liposomes are highly stable, exhibiting a superior in vitro homologous targeting ability, and a 2.25-fold deeper penetration in 3D tumor spheroids when compared to conventional liposome nanomedicine. The fluorescence/photoacoustic dual-modal imaging approach demonstrated enhanced tumor accumulation and improved tumor penetration of the biomimetic liposome in C6 glioma tumor-bearing nude mice. Following the intravenous administration of biomimetic liposome nanomedicine, the tumor inhibition rate reached up to 93.3%, which was significantly higher when compared to that of conventional liposome nanomedicine (69.3%). Moreover, histopathological analyses demonstrated that biomimetic liposome nanomedicine has limited side effects. Therefore, these results suggested that a cancer cell membrane-based biomimetic strategy may provide a breakthrough approach for enhancing drug penetration and improving treatment efficacy, holding a great promise for further clinical studies. PMID- 29694475 TI - Marrying SPR excitation and metal-support interactions: unravelling the contribution of active surface species in plasmonic catalysis. AB - Plasmonic catalysis takes advantage of the surface plasmon resonance (SPR) excitation to drive or accelerate chemical transformations. In addition to the plasmonic component, the control over metal-support interactions in these catalysts is expected to strongly influence the performances. For example, CeO2 has been widely employed towards oxidation reactions due to its oxygen mobility and storage properties, which allow for the formation of Ce3+ sites and adsorbed oxygen species from metal-support interactions. It is anticipated that these species may be activated by the SPR excitation and contribute to the catalytic activity of the material. Thus, a clear understanding of the role played by the SPR-mediated activation of surface oxide species at the metal-support interface is needed in order to take advantage of this phenomenon. Herein, we describe and quantify the contribution from active surface oxide species at the metal-support interface (relative to O2 from air) to the activities in green SPR-mediated oxidation reactions. We employed CeO2 decorated with Au NPs (Au/CeO2) as a model plasmonic catalyst and the oxidation of p-aminothiophenol (PATP) and aniline as proof-of-concept transformations. We compared the results with SiO2 decorated with Au NPs (Au/SiO2), in which the formation of surface oxide species at the metal-support interface is not expected. We found that the SPR-mediated activation of surface oxide species at the metal-support interface in Au/CeO2 played a pivotal role in the detected activities, being even higher than the contribution coming from the activation of O2 from air. PMID- 29694476 TI - The surface plasmon-induced hot carrier effect on the catalytic activity of CO oxidation on a Cu2O/hexoctahedral Au inverse catalyst. AB - The intrinsic correlation between an enhancement of catalytic activity and the flow of hot electrons generated at metal-oxide interfaces suggests an intriguing way to control catalytic reactions and is a significant subject in heterogeneous catalysis. Here, we show surface plasmon-induced catalytic enhancement by the peculiar nanocatalyst design of hexoctahedral (HOH) Au nanocrystals (NCs) with Cu2O clusters. We found that this inverse catalyst comprising a reactive oxide for the catalytic portion and a metal as the source of electrons by localized surface plasmon resonance (localized SPR) exhibits a change in catalytic activity by direct hot electron transfer or plasmon-induced resonance energy transfer (PIRET) when exposed to light. We prepared two types of inverse catalysts, Cu2O at the vertex sites of HOH Au NCs (Cu2O/Au vertex site) and a HOH Au NC-Cu2O core shell structure (HOH Au@Cu2O), to test the structural effect on surface plasmons. Under broadband light illumination, the Cu2O/Au vertex site catalyst showed 30 90% higher catalytic activity and the HOH Au@Cu2O catalyst showed 10-30% higher catalytic activity than when in the dark. Embedding thin SiO2 layers between the HOH Au NCs and the Cu2O verified that the dominant mechanism for the catalytic enhancement is direct hot electron transfer from the HOH Au to the Cu2O. Finite difference time domain calculations show that a much stronger electric field was formed on the vertex sites after growing the Cu2O on the HOH Au NCs. These results imply that the catalytic activity is enhanced when hot electrons, created from photon absorption on the HOH Au metal and amplified by the presence of surface plasmons, are transferred to the reactive Cu2O. PMID- 29694477 TI - Unraveling the solvent induced welding of silver nanowires for high performance flexible transparent electrodes. AB - A solution processed metal nanowire network is a promising flexible transparent electrode to replace brittle metal oxides for printable optoelectronics applications, but suffers from the issue of pseudo contact between nanowires. Herein, using volatile solvent mists as a powerful "zipper", we demonstrate a simple and rapid method to effectively weld silver nanowires, which dramatically improves the conductivity and robustness of the silver nanowire network based flexible transparent electrodes. We reveal that for a stacked network structure, the unique wedge-shaped nanogaps between the long nanowires and substrate provide a strong capillary force during solvent evaporation, which is much larger than that between zero-dimensional nanoparticles and gives a decisive contribution for nanowire junction welding, and this nanowire-substrate interplay force is positively related to the wettability of the substrate. At the same time, the dissolution-reprecipitation of the capping agent on the silver nanowire surface as the natural adhesive can fix the network on the substrate tightly, which enhances the robustness of the network. Our approach solves two key issues in solution-processed transparent electrodes in one simple step, and is compatible with various mild solution-processed optoelectronic devices, especially those containing heat-sensitive or chemical-sensitive materials. Moreover, a new type of invisible infrared encryption display is demonstrated based on this approach. PMID- 29694478 TI - Multi-layered tumor-targeting photothermal-doxorubicin releasing nanotubes eradicate tumors in vivo with negligible systemic toxicity. AB - Multi-layered single-walled carbon nanotubes, termed SWNT@BSA@Au-S-PEG-FA@DOX, which integrate photothermal therapy with small molecule drug delivery, were prepared using a facile layer-by-layer assembly process. Oxidized and cut single walled carbon nanotubes (SWNTs) were coated with bovine serum albumin (BSA) to provide abundant active sites for the nucleation of Au seeds, which are subsequently converted into gold nanoparticles (Au NPs) by in situ reduction. The resulting SWNT@BSA@Au material exhibits ideal photothermal properties. Further modification of the nanomaterial with folic acid terminated-polyglycol (FA-PEG SH) and subsequent loading with doxorubicin (DOX) afford the SWNT@BSA@Au-S-PEG FA@DOX. The FA terminated PEG endows the material with high water-dispersibility, biocompatibility and cancer cell selectivity. A high drug loading ratio for DOX of up to 590% was achieved, with the drug release being pH and temperature dependent, adding to the selectivity of the system. High efficacy of the SWNT@BSA@Au-S-PEG-FA@DOX material, when combined with photothermal therapy (irradiation of the tumor with an 808 nm laser, 1 W cm-2 for 5 min, 24 h after systemic injection of the nanomedicine), was demonstrated in vivo, resulting in complete tumor eradication. Remarkably, the side effects are negligible with only minor damage to normal tissues including the liver and kidneys being observed. PMID- 29694479 TI - Dimerization of boryl- and amino-substituted acetylenes by B2C2 four-membered ring formation. AB - Boryl- and amino-substituted acetylenes bearing diphenylboryl or 9 borabicyclononyl groups were synthesized. X-ray diffraction analyses revealed the dimerized structures of these acetylenes via the formation of B2C2 four-membered rings. Spectroscopic studies and DFT calculations indicated that these dimers can dissociate to afford monomeric acetylenes, and that the equilibrium constant for the dissociation depends on the structure of the boryl substituents. PMID- 29694485 TI - Grain engineering by ultrasonic substrate vibration post-treatment of wet perovskite films for annealing-free, high performance, and stable perovskite solar cells. AB - Perovskite solar cells (PSCs) have gained great interest, owing to a fast increase in their power conversion efficiency (PCE), within a few years. However, their wide application and scale-up are hampered due to multiple obstacles, such as chemical instability, which leads to a short lifetime, and their complicated reaction and crystallization, which requires thermal annealing. Here, we address these issues using the ultrasonic substrate vibration post treatment (SVPT) applied on the as-spun perovskite wet films, so as to achieve a uniform, microscale and stable mixed-halide and mixed-cation perovskite layer, (FAPbI3)0.85(MAPbBr3)0.15, without the need for a conventional thermal annealing step. This is achieved by the creation of fluid micromixing and in situ annealing within the solution, caused by the ultrasonic excitation of the wet film. The optoelectronic properties of the perovskite films subjected to the SVPT, including photoemission, carrier lifetime and band gap, are remarkably improved compared to the conventionally annealed films. When incorporated into a planar PSC, a maximum PCE of 18.55% was achieved, compared to 15.17% for the control device, with high reproducibility and no hysteresis, and the device retained 80% of its initial PCE, over a period of 20 days of storage under ambient conditions. PMID- 29694489 TI - Speech-language therapy program for mouth opening in patients with oral and oropharyngeal cancer undergoing adjuvant radiotherapy: a pilot study. AB - Purpose Assess the effectiveness of an orofacial myofunctional therapeutic program in patients with oral or oropharyngeal cancer submitted to adjuvant radiotherapy through pre- and post-program comparison of maximum mandibular opening. Methods Prospective study involving five adult patients and five elderly patients postoperatively to oral cavity/oropharynx surgery who were awaiting the beginning of radiotherapy or had undergone fewer than five treatment sessions. The study participants had their maximum jaw opening measured using a sliding caliper at the beginning and end of the program. Two mobility exercises and three mandibular traction exercises were selected and weekly monitored presentially for 10 weeks. Descriptive data and pre- and post-therapy comparative measures were statistically analyzed using the Wilcoxon test. Results Ten patients (two women and eight men) with mean age of 58.4 years, median of 57.0 years, completed the therapeutic program. They presented mean maximum mandibular opening of 31.6 +/- 11.7 and 36.4 +/- 8.0 mm pre- and post-therapy, respectively (p =0.021). Conclusion The proposed orofacial myofunctional therapeutic program increased the maximum jaw opening of patients referred to adjuvant radiotherapy for oral cavity or oropharynx cancer treatment. PMID- 29694490 TI - BUNDLE OF MEASURES TO SUPPORT INTRAHOSPITAL EXCLUSIVE BREASTFEEDING: EVIDENCE OF SYSTEMATIC REVIEWS. AB - OBJECTIVE: To identify the main recommendations found in systematic reviews regarding exclusive breastfeeding protective factors. DATA SOURCE: Integrative review based on the guiding question: What evidence is found in literature regarding the protective factors of exclusive breastfeeding during the intrahospital period? A search was conducted in the Cochrane Library, PubMed/MEDLINE and LILACS database using the keyword "Breast Feeding" and the word "Breastfeeding". Systematic reviews published from 2007 to 2016 that answered the guiding question were included in the study, whereas systematic reviews that analyzed breastfeeding of preterm infants and breastfeeding of children with orofacial malformation were excluded. The sample included eight systematic reviews. DATA SYNTHESIS: The recommendations related to the protective factors for exclusive in-hospital breastfeeding found in the systematic reviews were: early skin-to-skin contact, rooming-in care, intervention for treating painful nipples during breastfeeding, restriction of infant supplementation, baby led breastfeeding and educational interventions and support for mothers during hospital stay. The proposed measures included the six practices presented as protective factors. CONCLUSIONS: The review enabled the identification of evidence to support the recommended measures from delivery room to hospital discharge, with the aim of encouraging breastfeeding and preventing intrahospital weaning. PMID- 29694491 TI - MULTIDISCIPLINARY AND MOTIVATIONAL INTERVENTION FOR THE TREATMENT OF LOW INCOME BRAZILIAN OBESE ADOLESCENTS: PILOT STUDY. AB - OBJECTIVE: To test a multidisciplinary and motivational intervention for the treatment of Brazilian obese and low-income adolescents (Z score>2 BMI-for-age) that used nutritional counseling without dietary control. METHODS: An intervention protocol was developed including periodical nutritional education workshops, individual nutritional counseling guided by the stages of eating behavior of the Trans Theoretical Model of Behavior Change, physical exercise, psychological counseling, recreational activities, and clinical follow-up for 13 months in a sample of 21 adolescents (11-17 years old). RESULTS: The rate of treatment withdrawal (9.5%) was lower than that seen in dietary control studies (30-60%). Initially, 70% of the sample was in the pre-contemplation behavior stage and, in the end, 100% of the remaining adolescents were in the stages of action or maintenance. There was a mean reduction in BMI-for-age (p=0.038) and visceral fat (M+/-SD=3.67+/-1.19 and 2.78+/-0.78 cm, p=0.02, initial and final, respectively). The percentage of fat mass decreased and that of lean mass increased (42+/-5 and 38+/-8, p=0.04, 58+/-6 and 61+/-8%, p=0.03, respectively). CONCLUSIONS: The intervention seems to be effective in generating a lifestyle change, accompanied by anthropometric profile and body composition improvement. The intervention protocol may offer easy adaptation and low-cost methodology for health services, with high adherence and low abandonment rates. PMID- 29694492 TI - Validation of single measurement of 12-hour urine excretion for estimation of sodium and potassium intake. A longitudinal study. AB - BACKGROUND: Evaluation of sodium and potassium intake can be carried out using different methods. Biological markers are able to capture intra and inter individual variability and are used as separate measurements of consumption. The aim of this study was to test the validity of a single measurement of urinary sodium and potassium excretion as representative of habitual intake. DESIGN AND SETTING: Longitudinal study, federal university. METHODS: Food consumption data from a sample of adult university students and public servants (25 to 74 years old) were collected through 24-hour records and 12-hour urinary sodium and potassium excretion at five different times over a one-year period. The dietary data were entered into a nutritional research data software system and the sodium and potassium intakes were estimated. The variables were tested for normal distribution using the Kolmogorov-Smirnov test. One-way analysis of variance or the Kruskal-Wallis test was used to evaluate means. Correlations between measurements using Pearson or Spearman coefficients were calculated. The degree of agreement between the five measurements was given by the intraclass correlation coefficient. RESULTS: Satisfactory agreement was found between the five measurements of urinary sodium and potassium excretion over a year, with little variability in consumption. CONCLUSION: A single measurement of urinary sodium and potassium accurately estimated the usual average consumption of these electrolytes. This can be used in population-based studies. PMID- 29694493 TI - Translation and validation of the Brown attention-deficit disorder scale for use in Brazil: identifying cases of attention-deficit/hyperactivity disorder among samples of substance users and non-users. Cross-cultural validation study. AB - BACKGROUND: The Brown Attention-Deficit Disorder Scale (BADDS) was developed as a self-report assessment that was designed to screen for presence of symptoms of attention deficit hyperactivity disorder (ADHD). The objective here was to translate and validate the adult self-report BADDS for use in Brazil. DESIGN AND SETTING: Cross-cultural validation study conducted in an addiction unit at a public university hospital. METHODS: This study included a control group (n = 100) and a drug-user group (n = 100). Both groups included subjects aged 18 to 60 years old. The control group had no prior diagnosis of drug addiction and the drug-user group included participants with a diagnosis of addiction. Each participant answered Brazilian Portuguese translations of both the BADDS and the Adult Attention Deficit Hyperactivity Disorder Self-Report Scale (ASRS) questionnaires, in paper-and-pencil format. RESULTS: The drug-user group scored higher than the control group on both scales. The mean scores on ASRS were 27.26 (standard deviation, SD: 11.99) and 25.85 (SD: 8.65) respectively (P > 0.05). The mean scores on BADDS were 79.56 (SD: 29.61) and 79.31 (SD: 18.09), respectively (P > 0.05). Cronbach's alpha for BADDS was 0.95. BADDS presented fair sensitivity (72% accuracy) and fair specificity (88% accuracy). CONCLUSION: This study provides discriminative validity evidence for use of BADDS among Brazilian adults with substance-use disorders. PMID- 29694494 TI - Asilidae (Diptera) of two Atlantic Forest protected areas of Rio de Janeiro, Southeastern Brazil. AB - As few Asilidae inventories of Rio de Janeiro areas have been published, there are many data gaps. This paper aims to contribute to the knowledge of richness, abundance and distribution of this family in this State. From January 2013 to March 2014, insects were collected monthly using Malaise traps and every two months using entomological nets in the Reserva Biologica Uniao (REBIO), and Estacao Ecologica Estadual de Guaxindiba (EEEG). 682 specimens of Asilidae were collected in the present study, distributed in 31 genera and 51 species (20 identified and 31 unidentified), 527 of REBIO (in 19 genera and 38 species - 14 identified and 24 unidentified), and 155 specimens of EEEG (in 12 genera and 19 species - 6 identified and 13 unidentified). Leptogaster was the most abundant genus being L. tropica (Curran 1934) the most abundant species in the REBIO, with 268 specimens and Leptogaster sp., with 54 specimens, the most abundant in the EEEG. All records of genera and species in the present study are new in the REBIO and EEEG, wich contribute to the knowledge of the Asilidae geographic distribution and richness in the State of Rio de Janeiro. PMID- 29694495 TI - In vivo assessment of cyto/genotoxic, antigenotoxic and antifungal potential of Costus spiralis (Jacq.) Roscoe leaves and stems. AB - Costus spiralis is a Brazilian native plant used in popular medicine, but the safety of this therapeutic use needs investigation. So, the aim of this study was to evaluate the cytogenotoxic and antigenotoxic effects of C. spiralis leaves or stems aqueous extracts on Allium cepa root cells. Moreover, a phytochemical screening and an antioxidant and antifungal activities evaluation were performed. C. spiralis aqueous extracts presented cytotoxicity, but no mutagenicity was observed. When the antigenotoxicity was evaluated, C. spiralis leaves aqueous extract presented preventive and modulatory effects on A. cepa root cells, reducing the sodium azide cytogenotoxic effects. In contrast, C. spiralis stems aqueous extract enhanced the sodium azide cytogenotoxicity in some conditions. The phytochemical screening revealed the presence of phenolic compounds in C. spiralis. When total phenolic content was determined, the leaves presented 73% more phenolic content than stems. Corroborating this data, C. spiralis leaves antioxidant potential was 30% higher than C. spiralis stems. However, these extracts did not present antifungal activity against Candida spp. In conclusion, empirical utilization of C. spiralis aqueous extracts should be avoided. Moreover, the cytotoxic effect of C. spiralis leaves and stems can play an important role in anticancer therapy and must be deeply studied. PMID- 29694496 TI - Persistence of auxinic herbicides applied on pasture and toxicity for succeeding crops. AB - The aim of this work was to determine the persistence of auxinic herbicides applied on tropical pasture and toxicity for succeeding crops. The herbicides were applied in an area of dystrophic red-yellow latosol with pasture infested of weeds. At 40, 80, and 280 days after application of herbicide, the soil samples were collected at depths of 0 to 20 cm. Soil with residues of 2,4-D, 2,4-D + picloram, triclopyr, and a soil without herbicide application were analyzed with six replicates. Seven crops were cultivated in these soils: cucumber (Cucumis sativus L.), velvet bean [Mucuna pruriens (L.) DC.], pigeon pea [Cajanus cajan (L.) Millsp.], alfalfa (Medicago sativa L.), lablab bean [Lablab purpureus (L.) Sweet], corn (Zea mays L.), and sorghum [Sorghum bicolor (L.) Moench]. The plants of cucumber, pigeon pea, and alfalfa were the most susceptible to the auxinic herbicide residues. However, the lablab bean was the only one among the dicot evaluated that showed tolerance to the 2,4-D + picloram residual when cultivated in soils at 280 days after application of herbicide. Corn and sorghum showed lower chlorophyll content in soils with 2,4-D + picloram residual up to 80 days after application of herbicide. PMID- 29694497 TI - Nutritional Evaluation of Non-Conventional Vegetables in Brazil. AB - The objective of this study was to characterize the nutritional compounds of interest present in vegetables known as non-conventional, in Brazil. The following evaluations were carried out: antioxidant activity, phenolic compounds, vitamin C, calories, carbohydrates, humidity, lipids, proteins, fiber, acidity and quantification of minerals (P, K, Ca, Mg, S, Cu, Fe, Mn, Zn and B). The species studied were Amaranthus hybridus L., Amaranthus viridis L., Basella alba L., Eryngium campestre L., Hibiscus sabdariffa L., Lactuca canadensis L., Rumex acetosa L., Stachys byzantina K. Koch, Tropaeolum majus L. and Xanthosoma sagittifolium L. Representative samples of plant structures of interest were harvested from each species suitable for human consumption such as leaves, flowers and flower buds. The results were submitted to multivariate analysis - principal components analysis (PCA). All the species present nutritional compounds of interest in different levels among the evaluated structures. PMID- 29694498 TI - Production, characterization and toxicology assay of creatine pegylated nanoliposome with polysorbate 80 for brain delivery. AB - Creatine acts intracellularly as energy buffer and storage, demonstrating protective effects in animal models of neurodegenerative diseases. However, its permeability throught blood-brain barrier (BBB) is reduced. The aim of the present study was developing a carrier to facilitate the delivery of creatine to the central nervous system. Creatine nanoliposomes were produced, characterized and assayed in models of toxicity in vitro and in vivo. Particles showed negative zeta potential (-12,5 mV), polydispersity index 0.237 and medium-size of 105 nm, which was confirmed by transmission electron microscopy (TEM) images. Toxicity assay in vitro was evaluated with blank liposomes (no drug) or creatine nanoliposomes at concentrations of 0.02 and 0.2 mg/mL, that did not influence the viability of Vero cells. The result. of the comet assay that the nanoliposomes are not genotoxic, togeher with cell viability demonstrated that the nanoliposomes are not toxic. Besides, in vivo assays not demonstrate toxicity in hematological and biochemical markers of young rats. Nevertheless, increase content of creatine in the cerebral cortex tissue after subchronic treatment was observed. Altogether, results indicate increase permeability of creatine to the BBB that could be used as assay for in vivo studies to confirm improved effect than free creatine. PMID- 29694499 TI - Deformation of Mitochondrial Cristae in Human Neural Progenitor Cells Exposed to Valproic Acid. AB - Neural development represents a dynamic process where mitochondrial integrity is decisive for neuronal activity. Structural changes in these organelles may be related to neurological disorders. Valproic acid (VPA) is an anticonvulsive drug commonly used for epilepsy treatment and its use is associated to increased risk of neuropsychiatric disorders. Recently we showed changes in shape and membrane potential in mitochondria from human neural progenitor cells (NPCs) exposed to VPA (da Costa et al. 2015). Here, we applied transmission electron microscopy and electron tomography to evaluate mitochondrial damage caused by VPA in NPCs. Results showed mitochondrial cristae disorganization in a dose dependent manner. Disturbance in mitochondrial ultrastructure may influence metabolism, leading to synaptic plasticity and neurogenesis impairment. These data contribute to understanding VPA exposure potential effects on brain development. PMID- 29694500 TI - Synthesis and antimicrobial activity of new amino derivatives of pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2-d]pyrimidine. AB - Annulated thienopyrimidine derivatives attracted big interest of the scientific community due to their broad spectrum of biological activities among which are the inhibition of phosphodiesterase, antiproliferative and antimicrobial activities. As a continuation of our studies on the synthesis and biological activity of fused thieno[3,2-d]pyrimidine derivatives, the goal of this paper is the synthesis and study of the properties of compounds containing different heterocycles such as fused thieno[2,3-b]pyridine and tetrazolo[1,5-c]pyrimidine in the same molecule. Thus, starting from the ethyl 1-amino-5-isopropyl-8,8 dimethyl-8,9-dihydro-6H-pyrano[4,3-d]thieno[2,3-b]pyridine-2-carboxylate 1, efficient methods for obtaining new 8-amino-5-isopropyl-2,2-dimethyl-10 (methylthio)-1,4-dihydro-2H-pyrano[4'',3'':4',5']pyrido[3',2':4,5]thieno[3,2 d]pyrimidines 6 and thieno[2,3-e]tetrazolo[1,5-c]pyrimidine 8 are described. The spectroscopic results showed that compound 8 in the solid state is exclusively in the tetrazolo tautomeric form, while in solution an azide-tetrazole equilibrium is present 8A/T. The possible antimicrobial activity of newly synthesized compounds against some gram-positive and gram-negative bacilli strains has been evaluated. The biological tests evidenced that some of them showed promising antimicrobial activity. Two compounds showed similar activity to the one of the used reference drug. The study of structure-activity relationships revealed that the activity of a compound depends mostly on the nature of substituent R1R2. According to the predicted docking studies our compounds could be DnaG inhibitors. PMID- 29694501 TI - Productive potential of cassava plants (Manihot esculenta Crantz) propagated by leaf buds. AB - New techniques of rapid multiplication of cassava (Manihot esculenta Crantz) have been developed, requiring technical support for large-scale use. This work main to evaluate the agronomic performance of plantlets obtained by leaf buds technique against stem cuttings in the field conditions. The work was conducted using the randomized block design in a factorial scheme with 3 varieties (BRS Kiriris, 98150-06, 9624-09) * 4 origins of the plantlets (conventional - stem cuttings of 20 cm length, leaf buds of the upper, middle and inferior stem part) * 2 agrochemicals (control and treated). There was a remarkable decrease in some agronomic traits that ranged from 23% (number of branches) to 62% (shoot weight) when using leaf buds plantlets. The treatment of plantlets with agrochemicals promoted significant increases in all traits, ranging from 26% (number of roots per plant) to 46% (shoot weight). The plantlets originating from leaf buds of the upper and middle parts were able to generate stem-like plants similar to stem derived ones. Despite its lower agronomic performance under field conditions, multiplication by leaf buds may generate five times the number of propagules in comparison with the conventional multiplication, and therefore it could be a viable alternative for rapid cassava multiplication. PMID- 29694502 TI - LncRNA HULC mediates radioresistance via autophagy in prostate cancer cells. AB - Prostate cancer (PCa) is the second leading cause of cancer death in men. Irradiation is one of the available options for treatment of PCa, however, approximately 10-45% of PCa are resistant to irradiation. We aimed to explore the role of long non-coding RNA highly upregulated in liver cancer (HULC) in the sensitivity of PCa cells to irradiation. Survival rate, cell apoptosis, cycle, expressions of related proteins, and caspase-3 activity were assessed to explore the effects of HULC on sensitivity of PCa cells to irradiation. Expression of HULC in DU-145, PC3, LNCaP, and RWPE-1 cells was determined and the influence of HULC on DU-145 cells was explored. Then, PC3 cells aberrantly expressing HULC were implanted into NOD-SCID mice for tumor xenograft study. Changes of autophagy after aberrant expression of HULC in vivo and in vitro were tested. Furthermore, the interacted protein of HULC and involved signaling pathway were investigated. In PC3 and LNCaP cells under irradiation, survival rate and cell cycle were decreased and apoptosis was increased by HULC knockdown. HULC knockdown arrested PC3 cells at G0/G1 phase. DU-145 was sensitive to irradiation, and resistance to irradiation of DU-145 cells was enhanced by HULC overexpression. Moreover, HULC knockdown enhanced the sensitivity of PC3 xenografts to irradiation. HULC knockdown promoted autophagy through interaction with Beclin-1 and inhibition of mTOR, resulting in increased apoptosis. HULC knockdown improved sensitivity of PCa cells to irradiation both in vivo and in vitro. HULC suppressed Beclin-1 phosphorylation, thereby reduced autophagy, involving the mTOR pathway. PMID- 29694503 TI - Neonatal tobacco smoke reduces thermogenesis capacity in brown adipose tissue in adult rats. AB - Maternal smoking is a risk factor for progeny obesity. We have previously shown, in a rat model of neonatal tobacco smoke exposure, a mild increase in food intake and a considerable increase in visceral adiposity in the adult offspring. Males also had secondary hyperthyroidism, while females had only higher T4. Since brown adipose tissue (BAT) hypofunction is related to obesity, here we tested the hypothesis that higher levels of thyroid hormones are not functional in BAT, suggesting a lower metabolic rate. We evaluated autonomic nerve activity in BAT and its function in adult rats that were exposed to tobacco smoke during lactation. At birth, litters were adjusted to 3 male and 3 female pups/litter. From postnatal day (PND) 3 to 21, Wistar lactating rats and their pups were divided into SE group, smoke-exposed in a cigarette smoking machine (4 times/day) and C group, exposed to filtered air. Offspring were sacrificed at PND180. Adult SE rats of both genders had lower interscapular BAT autonomic nervous system activity, with higher BAT mass but no change in morphology. BAT UCP1 and CPT1a protein levels were decreased in the SE groups of both genders. Male SE rats had lower beta3-AR, TRalpha1, and TRbeta1 expression while females showed lower PGC1alpha expression. BAT Dio2 mRNA and hypothalamic POMC and MC4R levels were similar between groups. Hypothalamic pAMPK level was higher in SE males and lower in SE females. Thus, neonatal cigarette smoke exposure induces lower BAT thermogenic capacity, which can be obesogenic at adulthood. PMID- 29694504 TI - Influence of expiratory positive airway pressure on cardiac autonomic modulation at rest and in submaximal exercise in COPD patients. AB - The aim of this study was to evaluate the effect of expiratory positive airway pressure (EPAP) on heart rate variability (HRV) indices at rest and during 6-min walk test (6MWT) in chronic obstructive pulmonary disease (COPD) patients. Fifteen moderate to severe COPD patients were randomized and evaluated with and without (Non-EPAP) a 5 cmH2O EPAP device. Respiratory rate (RR) was collected at rest (5 min), during the 6MWT (5 min), and at recovery (5 min). Indices of HRV were computed in the time domain, in the frequency domain, and nonlinear analysis. For EPAP and Non-EPAP during the 6MWT, we found an increased mean heart rate (HR) (P=0.001; P=0.001) while mean RR (P=0.001; P=0.015) and RR tri index decreased (P=0.006; P=0.028). Peripheral oxygen saturation (P=0.019) increased at rest only in the EPAP group. In EPAP, correlations were found between forced expiratory volume in 1 s (FEV1) and low frequency (LF) sympathetic tonus (P=0.05; r=-0.49), FEV1 and high frequency (HF) parasympathetic tonus at rest (P=0.05; r=0.49), lactate at rest and LF during the 6MWT (P=0.02; r=-0.57), and lactate at rest and HF during 6MWT (P=0.02; r=0.56). Through a linear regression model, we found that lactate at rest explained 27% of the alterations of LF during 6MWT. The use of 5 cmH2O EPAP improved autonomic cardiac modulation and its complexity at rest in COPD patients. Although it did not influence the performance of the 6MWT, the EPAP device caused alterations in resting lactate concentration with an effect on sympatho-vagal control during the test. PMID- 29694505 TI - TNF-alpha inhibits SCF, ghrelin, and substance P expressions through the NF kappaB pathway activation in interstitial cells of Cajal. AB - Ulcerative colitis is a chronic inflammatory disease of the colon where intestinal motility is disturbed. Interstitial cells of Cajal (ICC) are required to maintain normal intestinal motility. In the present study, we assessed the effect of tumor necrosis factor-alpha (TNF-alpha) on viability and apoptosis of ICC, as well as on the expression of stem cell factor (SCF), ghrelin, and substance P. ICC were derived from the small intestines of Swiss albino mice. Cell viability and apoptosis were measured using CCK-8 assay and flow cytometry, respectively. ELISA was used to measure the concentrations of IL-1beta, IL-6, ghrelin, substance P, and endothelin-1. Quantitative RT-PCR was used to measure the expression of SCF. Western blotting was used to measure the expression of apoptosis-related proteins, interleukins, SCF, and NF-kappaB signaling pathway proteins. TNF-alpha induced inflammatory injury in ICC by decreasing cell viability and increasing apoptosis and levels of IL-1beta and IL-6. TNF-alpha decreased the levels of SCF, ghrelin, and substance P, but had no effect on endothelin-1. TNF-alpha down-regulated expressions of SCF, ghrelin, and substance P by activating the NF-kappaB pathway in ICC. In conclusion, TNF-alpha down regulated the expressions of SCF, ghrelin, and substance P via the activation of the NF-kappaB pathway in ICC. PMID- 29694506 TI - Dietary intake and eating behavior in depot medroxyprogesterone acetate users: a systematic review. AB - Because of weight gain, women often discontinue hormonal contraception, especially depot medroxyprogesterone acetate (DMPA). Our objective was to conduct a systematic review of studies describing dietary intake or eating behavior in DMPA users to understand whether the use of DMPA is associated with changes in dietary habits and behaviors leading to weight gain. We searched the PubMed, POPLINE, CENTRAL Cochrane, Web of Science, and EMBASE databases for reports published in English between 1980 and 2017 examining dietary intake or eating behavior in healthy women in reproductive age and adolescents using DMPA (150 mg/mL). Of the 749 publications screened, we excluded 742 due to duplicates (96), not addressing the key research question (638), not reporting dietary intake data (4), and not evaluating the relationship of body weight and dietary or eating behaviors (4). We identified seven relevant studies, including one randomized placebo-controlled trial, one non-randomized paired clinical trial, and five cohort studies. The randomized trial found no association and the other reports were inconsistent. Findings varied from no change in dietary intake or eating behavior with DMPA use to increased appetite in the first six months of DMPA use. Few studies report dietary intake and eating behavior in DMPA users and the available data are insufficient to conclude whether DMPA use is associated with changes in dietary habits or behavior leading to weight gain. PMID- 29694507 TI - Protective effect of yerba mate intake on the cardiovascular system: a post hoc analysis study in postmenopausal women. AB - The prevalence of cardiovascular and metabolic diseases is increased in postmenopausal women, which contributes to the burden of illnesses in this period of life. Yerba mate (Ilex paraguariensis) is a native bush from Southern South America. Its leaves are rich in phenolic components, which may have antioxidant, vasodilating, hypocholesterolemic, and hypoglycemic proprieties. This post hoc analysis of the case-control study nested in the Obesity and Bone Fracture Cohort evaluated the consumption of yerba mate and the prevalence of hypertension, dyslipidemia, and coronary diseases in postmenopausal women. Ninety-five postmenopausal women were included in this analysis. A questionnaire was applied to evaluate the risk factors and diagnosis of cardiovascular diseases and consumption of yerba mate infusion. Student's t-test and chi-square test were used to assess significant differences between groups. The group that consumed more than 1 L/day of mate infusion had significantly fewer diagnoses of coronary disease, dyslipidemia, and hypertension (P<0.049, P<0.048, and P<0.016, respectively). Furthermore, the serum levels of glucose were lower in the group with a higher consumption of yerba mate infusion (P<0.013). The serum levels of total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides were similar between the groups. This pragmatic study points out the benefits of yerba mate consumption for the cardiovascular and metabolic systems. The ingestion of more than 1 L/day of mate infusion was associated with fewer self-reported cardiovascular diseases and lower serum levels of glucose. Longitudinal studies are needed to evaluate the association between yerba mate infusion and reduction of cardiovascular diseases in postmenopausal women. PMID- 29694508 TI - Andrographolide protects mouse astrocytes against hypoxia injury by promoting autophagy and S100B expression. AB - Andrographolide (ANDRO) has been studied for its immunomodulation, anti inflammatory, and neuroprotection effects. Because brain hypoxia is the most common factor of secondary brain injury after traumatic brain injury, we studied the role and possible mechanism of ANDRO in this process using hypoxia-injured astrocytes. Mouse cortical astrocytes C8-D1A (astrocyte type I clone from C57/BL6 strains) were subjected to 3 and 21% of O2 for various times (0-12 h) to establish an astrocyte hypoxia injury model in vitro. After hypoxia and ANDRO administration, the changes in cell viability and apoptosis were assessed using CCK-8 and flow cytometry. Expression changes in apoptosis-related proteins, autophagy-related proteins, main factors of JNK pathway, ATG5, and S100B were determined by western blot. Hypoxia remarkably damaged C8-D1A cells evidenced by reduction of cell viability and induction of apoptosis. Hypoxia also induced autophagy and overproduction of S100B. ANDRO reduced cell apoptosis and promoted cell autophagy and S100B expression. After ANDRO administration, autophagy related proteins, S-100B, JNK pathway proteins, and ATG5 were all upregulated, while autophagy-related proteins and s100b were downregulated when the jnk pathway was inhibited or ATG5 was knocked down. ANDRO conferred a survival advantage to hypoxia-injured astrocytes by reducing cell apoptosis and promoting autophagy and s100b expression. Furthermore, the promotion of autophagy and s100b expression by ANDRO was via activation of jnk pathway and regulation of ATG5. PMID- 29694509 TI - Beetle (Ulomoides dermestoides) fat improves diabetes: effect on liver and pancreatic architecture and on PPARgamma expression. AB - Ulomoides dermestoides is a beetle traditionally consumed to treat diabetes. In this study, we performed a composition analysis of U. dermestoides to obtain the principal fractions, which were used to assess the effect on glycemia, liver and pancreatic architecture, and PPARgamma and GLUT4 expression. Normal mice and alloxan-induced diabetic mice were administered fractions of chitin, protein or fat, and the acute hypoglycemic effect was evaluated. A subacute study involving daily administration of these fractions to diabetic mice was also performed over 30 days, after which the liver and pancreas were processed by conventional histological techniques and stained with hematoxylin and eosin to evaluate morphological changes. The most active fraction, the fat fraction, was analyzed by gas chromatography-mass spectrometry (GC-MS), and PPARgamma and GLUT4 mRNA expressions were determined in 3T3-L1 adipocytes. The protein and fat fractions exhibited hypoglycemic effects in the acute as well as in the 30-day study. Only the fat fraction led to elevated insulin levels and reduced glycemia, as well as lower intake of water and food. In the liver, we observed recovery of close hepatic cords in the central lobule vein following treatment with the fat fraction, while in the pancreas there was an increased density and percentage of islets and number of cells per islet, suggesting cellular regeneration. The GC-MS analysis of fat revealed three fatty acids as the major components. Finally, increased expression of PPARgamma and GLUT4 was observed in 3T3-L1 adipocytes, indicating an antidiabetic effect. PMID- 29694510 TI - Exploration of gene functions for esophageal squamous cell carcinoma using network-based guilt by association principle. AB - Gene networks have been broadly used to predict gene functions based on guilt by association (GBA) principle. Thus, in order to better understand the molecular mechanisms of esophageal squamous cell carcinoma (ESCC), our study was designed to use a network-based GBA method to identify the optimal gene functions for ESCC. To identify genomic bio-signatures for ESCC, microarray data of GSE20347 were first downloaded from a public functional genomics data repository of Gene Expression Omnibus database. Then, differentially expressed genes (DEGs) between ESCC patients and controls were identified using the LIMMA method. Afterwards, construction of differential co-expression network (DCN) was performed relying on DEGs, followed by gene ontology (GO) enrichment analysis based on a known confirmed database and DEGs. Eventually, the optimal gene functions were predicted using GBA algorithm based on the area under the curve (AUC) for each GO term. Overall, 43 DEGs and 67 GO terms were gained for subsequent analysis. GBA predictions demonstrated that 13 GO functions with AUC>0.7 had a good classification ability. Significantly, 6 out of 13 GO terms yielded AUC>0.8, which were determined as the optimal gene functions. Interestingly, there were two GO categories with AUC>0.9, which included cell cycle checkpoint (AUC=0.91648), and mitotic sister chromatid segregation (AUC=0.91597). Our findings highlight the clinical implications of cell cycle checkpoint and mitotic sister chromatid segregation in ESCC progression and provide the molecular foundation for developing therapeutic targets. PMID- 29694511 TI - Long non-coding RNA-ROR aggravates myocardial ischemia/reperfusion injury. AB - Long non-coding RNAs (lncRNAs) play an important role in the pathogenesis of cardiovascular diseases, especially in myocardial infarction and ischemia/reperfusion (I/R). However, the underlying molecular mechanism remains unclear. In this study, we determined the role and the possible underlying molecular mechanism of lncRNA-ROR in myocardial I/R injury. H9c2 cells and human cardiomyocytes (HCM) were subjected to either hypoxia/reoxygenation (H/R), I/R or normal conditions (normoxia). The expression levels of lncRNA-ROR were detected in serum of myocardial I/R injury patients, H9c2 cells, and HCM by qRT-PCR. Then, levels of lactate dehydrogenase (LDH), malondialdehyde (MDA), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX) were measured by kits. Cell viability, apoptosis, apoptosis-associated factors, and p38/MAPK pathway were examined by MTT, flow cytometry, and western blot assays. Furthermore, reactive oxygen species (ROS) production was determined by H2DCF-DA and MitoSOX Red probes with flow cytometry. NADPH oxidase activity and NOX2 protein levels were measured by lucigenin chemiluminescence and western blot. Results showed that lncRNA-ROR expression was increased in I/R patients and in H/R treatment of H9c2 cells and HCM. Moreover, lncRNA-ROR significantly promoted H/R-induced myocardial injury via stimulating release of LDH, MDA, SOD, and GSH-PX. Furthermore, lncRNA-ROR decreased cell viability, increased apoptosis, and regulated expression of apoptosis-associated factors. Additionally, lncRNA-ROR increased phosphorylation of p38 and ERK1/2 expression and inhibition of p38/MAPK, and rescued lncRNA-ROR induced cell injury in H9c2 cells and HCM. ROS production, NADPH oxidase activity, and NOX2 protein levels were promoted by lncRNA-ROR. These data suggested that lncRNA-ROR acted as a therapeutic agent for the treatment of myocardial I/R injury. PMID- 29694512 TI - Quality of life on hemodialysis and inflammation: a descriptive analysis. AB - Chronic kidney disease (CKD) is highly prevalent worldwide. Patients with CKD on hemodialysis are more likely to present behavioral changes and worse quality of life as a result of their routine and complications. They also have higher levels of cytokines. The aim of this study is to assess the relationship between the inflammatory profile and quality of life measured by KDOQL-SF36 in hemodialysis outpatients. Patients older than 21 years of age and on routine hemodialysis for at least 6 months with treatment on a regular weekly basis were included and their anthropometric parameters and serum inflammatory markers were evaluated. Thirty patients consented to participate. Homocysteine (Hcy) levels were correlated with worse glomerular filtration rate (GFR; P=0.003) and creatinine (P=0.002). IL-6 was not correlated with worse nutritional status taking into account body mass index (BMI; kg/m2; P=0.83). On the other hand, TNF-alpha was positively correlated with albumin (P=0.008), nutritional status by BMI (P=0.04), and nutritional status by arm circumference area (P=0.04). IL-6 was correlated with activity limitation (P=0.02) and Hcy with work status (P=0.04). Hcy was correlated with nutritional status and inflammatory markers. In this population, the majority of the sections in KDOQL-SF36 were not correlated with cytokines levels. PMID- 29694514 TI - [Between military engineering and medical architecture: representations by Alexandre Rodrigues Ferreira about the city of Belem in the late eighteenth century]. AB - This paper discusses Alexandre Rodrigues Ferreira's conceptions about the urbanization of Belem, rooted in natural history and social medicine, as expressed in the work of Antonio Nunes Ribeiro Sanches. The influence of military engineering on its constitution in the 1600s and the spread of this fortress town are investigated, emphasizing Ferreira's criticisms of the geostrategic centrality in the development of the city. The urban reforms of the 1700s under the precepts of medical architecture are then presented, such as the building of the Royal Military Hospital and the water supply system. The concept of the civil city is presented, as expressed in the urban redevelopments, with the building of symbols of state power, areas for leisure and conviviality, and housing. PMID- 29694513 TI - miR-27a protects human mitral valve interstitial cell from TNF-alpha-induced inflammatory injury via up-regulation of NELL-1. AB - MicroRNAs (miRNAs) have been reported to be associated with heart valve disease, which can be caused by inflammation. This study aimed to investigate the functional impacts of miR-27a on TNF-alpha-induced inflammatory injury in human mitral valve interstitial cells (hMVICs). hMVICs were subjected to 40 ng/mL TNF alpha for 48 h, before which the expressions of miR-27a and NELL-1 in hMVICs were altered by stable transfection. Trypan blue staining, BrdU incorporation assay, flow cytometry detection, ELISA, and western blot assay were performed to detect cell proliferation, apoptosis, and the release of proinflammatory cytokines. We found that miR-27a was lowly expressed in response to TNF-alpha exposure in hMVICs. Overexpression of miR-27a rescued hMVICs from TNF-alpha-induced inflammatory injury, as cell viability and BrdU incorporation were increased, apoptotic cell rate was decreased, Bcl-2 was up-regulated, Bax and cleaved caspase-3/9 were down-regulated, and the release of IL-1beta, IL-6, and MMP-9 were reduced. NELL-1 was positively regulated by miR-27a, and NELL-1 up regulation exhibited protective functions during TNF-alpha-induced cell damage. Furthermore, miR-27a blocked JNK and Wnt/beta-catenin signaling pathways, and the blockage was abolished when NELL-1 was silenced. This study demonstrated that miR 27a overexpression protected hMVICs from TNF-alpha-induced cell damage, which might be via up-regulation of NELL-1 and thus modulation of JNK and Wnt/beta catenin signaling pathways. PMID- 29694516 TI - Looking ahead to 2019: 25 years of Historia, Ciencias, Saude - Manguinhos. PMID- 29694515 TI - [Eliasz Cynamon and the Rio Doce Program (SESP): contribution of sources to the history of health and sanitation actions in Brazil, 1952-1960]. AB - Research into the work of Szachna Eliasz Cynamon in the Rio Doce Valley Program (1952-1960) is presented. The key sources are from the Department of Archives and Documentation and the Department of Sanitation and Environmental Health at Fiocruz, as well as the family's own archive. At the time, the rates of malaria in the region were high. Born in Poland, Cynamon migrated to Brazil in the 1930s while still a child, where he graduated in sanitary engineering. He was hired to work in Colatina (Espirito Santo) and Governador Valadares (Minas Gerais) between 1952 and 1960, focusing on sewage and water treatment and supply, while also holding sanitation education courses for the local people as part of a Brazil-USA cooperation agreement. PMID- 29694517 TI - [Cinema and the spread of sanitation]. PMID- 29694518 TI - Unexpected healers: Chinese medicine in the age of global migration (Lima and California, 1850-1930). AB - The massive waves of Chinese migrants arriving in California and Lima in the second half of the nineteenth century played a crucial role in expanding Chinese medicine in both settings. From the late 1860s on, herbalists expanded their healing system beyond their ethnic community, transforming Chinese medicine into one of the healing practices most widely adopted by the local population. This article uses a comparative approach to examine the diverging trajectories of Chinese healers in Peru and the USA, as well as the social and political factors that determined how this foreign medical knowledge adapted to its new environments. PMID- 29694519 TI - The scientific authorship of Doctor Chernoviz, from the popularization of medicine to professional training: the Dicionario de medicina popular, 1842-1890. AB - This article reflects on the scientific authorship of Pedro Luiz Napoleao Chernoviz, based on his Dicionario de medicina popular, which was published in six editions between 1842 and 1890. The first part of the text discusses Chernoviz's position within the regimes of scientific authorship which were present in the medical community in Rio de Janeiro. Next, we analyze the author's arguments justifying a text that popularized medical science while this field strove for exclusivity in the practice of medicine. Finally, we suggest new meanings around Chernoviz's scientific authorship based on how the Dicionario was used and read by an initiated public. PMID- 29694520 TI - [The challenges of occupational health: historical and contemporary problems]. PMID- 29694521 TI - [The power of history]. PMID- 29694522 TI - [Occupational therapy: a female profession]. AB - An analysis and description is given for the possible reasons why occupational therapy is seen as a female profession. An analytical narrative-style literature review is offered in conjunction with qualitative data analysis. The entry of women to the workplace was shrouded in stereotypes associated with the female gender, determining typically female professions. The stereotypes of skill in caregiving and tasks that required fine motor skills, kindness, and patience were the qualities required for the first occupational therapists and determined the gendered nature of the profession. Changes in gender stereotypes are today taking place in a context of debates, and this discussion could help garner greater recognition and value for the profession. PMID- 29694523 TI - [Almas delirantes (1925) by Luis Cebola: the poetics of the human psyche and the physician as mediator between the universe of mental illness and society]. AB - Luis Cebola's 1925 work Almas delirantes [Delusional Souls] presented various psychopathologies through metaphorical and lyrical portraits rather than from a medical/ scientific point of view, showing that he perceived his patients as more than objects of scientific study in a process of identification, empathy, and compassion. Cebola defined psychopathological states according to contrast with normality, but stressed that these diseases could arise in any individual, and the book simultaneously acted as a warning to readers. The text also publicized the Museum of Madness [Museu da Loucura], which he created at the Casa de Saude do Telhal, and the art produced by his patients, positioning himself as a messenger between the closed universe of the psychiatric hospital and Portuguese society. PMID- 29694524 TI - Cancer in Ceara: shaping a medical and social problem, 1940-1954. AB - This article addresses the shaping of cancer as a relevant medical and social problem in the Brazilian state of Ceara from 1940 to 1954. While this disease initially garnered little importance on the local medical and health agenda, and was considered a problem for philanthropy, a group of physicians and allies brought cancer to the public health agenda and led to the Campaign Against Cancer in 1954. This group's ability to unite internal and external allies with a broader reach portrayed cancer as a relevant medical and social problem in Ceara. We demonstrate this new portrayal in medical articles, institutional documents, biographies, newspapers, and other documents produced on and by the characters involved with anticancer activities in Ceara. PMID- 29694525 TI - [The use of animal-assisted therapy: a bioethical question]. AB - This paper addresses ethical questions concerning animal-assisted therapy (zootherapy). While it has been documented for centuries in several cultures and is resistant to urban and technological developments, it combines multiple moral and vulnerable agents, constituting a dilemma whose fair and consensual solution calls for new perspectives, like environmental bioethics. Through analyses of scientific texts, the arguments and values intrinsic to decisions about how and when to use animals as medical resources are systematized. Using bioethics as a method, reflections are offered about the potential solutions dependent on the multidimensional communication between the players from the three pillars of sustainability - environment, society, and economy - involved in this global ethical question, focusing on conservation and sustainable production. PMID- 29694527 TI - Psyche meets matter: body and personhood in the medical-scientific project of Nise da Silveira. AB - In the early 1900s, Brazilian psychiatry was marked by the use of controversial treatments, like electroconvulsive therapy, psychosurgery, and insulin coma therapy. In 1946, the Brazilian physician Nise da Silveira took the front line in criticizing these treatments by setting up a creative activities studio in the National Psychiatric Center (Centro Psiquiatrico Nacional), in Rio de Janeiro. The article examines the theoretical basis for Silveira's medical-scientific project, drawing on documental sources and fieldwork with the study group at the Museum of Images from the Unconscious (Museu de Imagens do Inconsciente), maintained by her disciples. It is argued that her thinking constituted a rejection of the assumptions of physicalism and mechanism and was closer to the ontology of vitalism and romanticism. PMID- 29694528 TI - [On shipwrecks and rescues: a recent social history of science in Argentina]. PMID- 29694526 TI - [The poetry of Augusto dos Anjos and fin de siecle neuropsychiatry]. AB - Augusto dos Anjos, from Paraiba, Brazil, occupies a singular place in Brazilian literature, defying alignment with any one literary style. His poetry is marked by anguished verse, by existential dimensions and a vocabulary replete with scientific terms. His work is of great interest to neuropsychiatry, not just for the abundance of related terms, but also because it reflects conceptions from neuroscience at the turn of the twentieth century. This study focuses on his literary output from a dual perspective: by identifying how his poetry reflects the organicist tendency in psychiatry at the time, as generally personified in the figure of Emil Kraepelin, and by exploring the ideological content of the work, like the Darwinist perspective and the tension between dualism and materialistic monism. PMID- 29694529 TI - Carlos Chagas in the "war of the rivers:" the passage of the Instituto Oswaldo Cruz commission up the Yaco river (Alto Purus, federal territory of Acre, 1913). AB - The writing of the Relatorio sobre as condicoes medico-sanitarias do vale do Amazonas (Report on the medical and sanitary conditions in the Amazon Valley) is analyzed from the perspective of the macro- and micropolitical implications of the Instituto Oswaldo Cruz's expedition to the departments in the federal territory of Acre. The analysis focuses on the interactions between Carlos Chagas, Pacheco Leao, and Joao Pedroso and judges, doctors, and rubber barons from the Yaco and Caete rivers at the town of Sena Madureira, capital of Alto Purus, in January 1913. The scientific report was also influenced by the contact the commission members had with the major players in the rubber industry and their resulting immersion in local and regional political conflicts. PMID- 29694531 TI - [Psychosocial support center and territory: human space, communication, and interdisciplinarity]. AB - The psychiatric reform is addressed from a theoretical and conceptual perspective through the concept of territory, which is analyzed as human space, as communication, and as related to the way interdisciplinary knowledge is produced. These concepts (territory and interdisciplinarity) were identified in a semistructured interview with the psychiatrist and professor Pedro Gabriel Delgado, who classified them as operative. We conclude that this understanding enables theory and practice to be configured as praxis, producing meanings and transformations and enabling close ties between the functioning of community based services and the transformation of the relationship between insanity and society. PMID- 29694530 TI - [Exploring connections between the social construction of the child and health practices]. AB - This article seeks to correlate the different social meanings attributed to children with health actions directed toward this group starting in nineteenth century Brazil. The study reviews the literature based on the social concept of "being a child" and its correlation with policies and practices in public health and child care, focusing on actions undertaken within the framework of primary health care. Three different conceptions of the meaning of "child" were identified. The interrelations between transformations in the social construction of the notion of child were investigated, along with the different political and technological proposals involving children in Brazil, indicating the contemporary challenge of developing care technologies that will strengthen children with regard to rights. PMID- 29694532 TI - Reconsidering the peripheral in global health. PMID- 29694534 TI - [Between fear and audacity: paradoxes in Brazilian modernization]. PMID- 29694533 TI - [Mosquitos and the State in the report by the head of the Rural Sanitation and Prophylaxis Service of Bahia, 1922]. AB - In 1923, Doctor Sebastiao Barroso, head of the Rural Sanitation and Prophylaxis Service of Bahia, submitted a report on the previous year's activities. The document contains information on initiatives coordinated by the entity on rural epidemics and prophylaxis, accompanied by a compilation of the reports by the professionals responsible for the rural prophylaxis units and tables containing data on the different regions in the state, notifications received, and expenses. The section of this document presented here enables us to investigate the state's role in addressing public health issues in a context marked by recurring outbreaks of epidemics, especially yellow fever. PMID- 29694535 TI - Statelessness, exodus, and health: forced internal displacement and health services. PMID- 29694536 TI - Access to public spaces and physical activity for Mexican adult women. AB - The aim of this article was to explore the association between access to public spaces and physical activity for adult women, controlling and testing interactions with sociodemographic and public spaces characteristics. We combined sociodemographic data from a survey with the adult (18-65 years of age) women population of Tijuana, Mexico, conducted in 2014 (N = 2,345); with data from a 2013 study on public spaces in the same city. We evaluated access to public spaces by the presence and total area of public spaces in buffers of 400, 800, 1,000 and 1,600m around the participants' homes. We measured physical activity with the short version of the International Physical Activity Questionnaire (IPAQ short). We employed multinomial logistic models to evaluate the association between access to public spaces and physical activity, and tested for interactions between access to public spaces and public spaces quality and sociodemographic characteristics. We observed no interaction between access to public spaces and public spaces quality in their effect on physical activity. There was an association between the presence of public spaces in the 400m buffer, and higher odds of being in the low physical activity level (as opposed to being in the moderate level) (coefficient: 0.50; 95%CI: 0.13; 0.87). Participants who used public transport were less likely to be in the low physical activity level (coefficient: -0.57; 95%CI: -0.97; -0.17). We suggest that, in this population, the access to public spaces might be less relevant for physical activity than other elements of the urban environment and sociodemographic characteristics. PMID- 29694537 TI - Health services management modalities in the Brazilian Unified National Health System: a narrative review of research production in Public Health (2005-2016). AB - The current study aimed to systematically analyze trends and priorities in the theoretical and conceptual approaches and empirical studies on specific health services management modalities in the Brazilian Unified National Health System. A narrative review of the literature identified, in 33 publications, the location and nature of services, management models, methodological procedures, and study outcomes. The research deals mainly with the models' conceptual and legal characteristics and management practices, in addition to addressing contracts, procurement, human resources, financing, and control mechanisms. In conclusion, the literature is limited and concentrated in the State of Sao Paulo, showing little theoretical diversity and methodological weaknesses, while it is nonconclusive as to the superiority of one management model over another. New evaluation studies are needed that are capable of comparing different models and assessing their performance and their effects on the quality of health services' provision, the population's health, and the health system's organization. PMID- 29694538 TI - [Health of the Brazilian Unified National Health System's workers: diagnoses, resistance and alternatives]. PMID- 29694539 TI - Accuracy of partial protocol to assess prevalence and factors associated with dental caries in schoolchildren between 8-12 years of age. AB - The aim of this study was to test accuracy and reliability of a partial protocol (PP) of oral examination involving the permanent first molars. This cross sectional study was carried out in two stages. First, a cross-sectional study was performed in a representative sample of 1,211 children using DMFT-index in a full mouth protocol (FM). A PP was simulated from FM data using only data from the permanent first molars. A second part was performed with 202 children examined by a gold standard examiner (FM) and three dentists using the PP to assess its reliability. Accuracy of PP was assessed by sensitivity/specificity/predictive positive and negative values. Inter-examiner reliability in comparison with gold standard examiner was assessed using weighted kappa. The prevalence of dental caries observed using DMFT index was 32.4% and was 30.2% for PP . The PP presented high sensitivity (93.1%; 95%CI: 91.5-94.5), showing similar magnitude of association's measures for all associated factors investigated. When compared with the gold standard FM examination, all examiners obtained high parameters of sensitivity and specificity (around 90%). Predictive negative values were higher than predictive positive values for the examiners. This study showed that this partial protocol involving the permanent first molars is accurate and reliable as a screening tool to assess dental caries prevalence and associated factors in schoolchildren. PMID- 29694540 TI - Border policies and health of refugee populations. PMID- 29694541 TI - An empirical assessment of the Healthy Early Childhood Program in Rio Grande do Sul State, Brazil. AB - We investigate the effect of a family-based primary health care program (Healthly Early Childhood Program) on infant mortality in the state of Rio Grande do Sul, Brazil. We estimate infant mortality's counterfactual trajectories using the differences-in-differences approach, combined with the use of longitudinal data for all municipalities in the state of Rio Grande do Sul. Our main result is that the program reduced the number of deaths caused by external causes. The length of exposure to the program seems to potentiate the effects. For the number of deaths by general causes, there is no evidence of impact. Our findings are consistent with the nature of the program that aims to improve adults care with children. The Healthly Early Childhood Program is effective in reducing the number of avoidable deaths in infants. PMID- 29694542 TI - [A comparative study of primary care health promotion practices in Florianopolis, Santa Catarina State, Brazil, and Toronto, Ontario, Canada]. AB - The study aimed to compare the experiences with the organization of universal public healthcare systems in relation to health promotion in primary care units in Florianopolis, Santa Catarina State, Brazil, and Toronto, Ontario, Canada. This was a descriptive exploratory study with a qualitative approach in primary care units. Data were collected with semi-structured interviews containing questions on health promotion practices, with 25 health professionals in Florianopolis and 10 in Toronto. The data were discussed using thematic analysis, identifying the practices, difficulties, and facilities in health promotion. In the two cities, 60% of health professionals and health administrators had not received any specific knowledge on health promotion during their training. As for health promotion skills, health professionals in Toronto identified them with autonomy and social determinants, while in Florianopolis they were related to health education and community participation. In both cities, health promotion practices are targeted to individual and collective activities. The motivation to act comes from interdisciplinarity and the demands raised by the population. Health promotion is a relevant form of care and stimulus for individual and community autonomy, in light of social determinants. Such practices aim at comprehensive health for the community, but there are limits in the teams that still conduct disease-centered activities. Resources are limited, requiring inter sector actions to improve quality of life. Healthcare centers on the hegemonic model, and progress is needed to achieve a positive approach to health and social determinants. PMID- 29694543 TI - A framework to assess management performance in district health systems: a qualitative and quantitative case study in Iran. AB - The aim was to design a district health management performance framework for Iran's healthcare system. The mixed-method study was conducted between September 2015 and May 2016 in Tabriz, Iran. In this study, the indicators of district health management performance were obtained by analyzing the 45 semi-structured surveys of experts in the public health system. Content validity of performance indicators which were generated in qualitative part were reviewed and confirmed based on content validity index (CVI). Also content validity ratio (CVR) was calculated using data acquired from a survey of 21 experts in quantitative part. The result of this study indicated that, initially, 81 indicators were considered in framework of district health management performance and, at the end, 53 indicators were validated and confirmed. These indicators were classified in 11 categories which include: human resources and organizational creativity, management and leadership, rules and ethics, planning and evaluation, district managing, health resources management and economics, community participation, quality improvement, research in health system, health information management, epidemiology and situation analysis. The designed framework model can be used to assess the district health management and facilitates performance improvement at the district level. PMID- 29694544 TI - Occurrence of Stroke and Reduced Ejection Fraction in Patients with Chagas Disease. PMID- 29694545 TI - Association of Severity of Coronary Lesions with Bone Mineral Density in Postmenopausal Women. AB - BACKGROUND: Coronary artery disease (CAD) and osteoporosis (OP) are common diseases in postmenopausal women. In both cross-sectional and longitudinal epidemiologic studies, low bone mass has been related to increased frequency of CAD. However, available data on the relationship between bone mineral density (BMD) and severity of coronary lesions is limited. OBJECTIVE: To investigate association between the BMD and severity of coronary lesions assessed by Gensini score in postmenopausal women. METHODS: This study included 122 postmenopausal women who were diagnosed with CAD. These patients were divided into two groups according to the severity of coronary lesions assessed by the Gensini score - patients with mild coronary lesions (Gensini score < 25) and patients with severe coronary lesions (Gensini score >= 25). Femoral neck mineral density was measured with dual energy X-ray absorptiometry (DXA). RESULTS: The study included postmenopausal women aged 64.31 +/- 4.71 years, 85 of whom (69.7%) exhibited severe coronary lesions. Participants with severe coronary lesions had a significantly higher T score than did those with mild coronary lesions at the femoral neck (p < 0.05). The mean T-score was -0.84 +/- 1.01 in mild coronary lesions group, -1.42 +/- 1.39 in severe coronary lesions group (p < 0.05). Multivariable logistic regression analysis showed that osteopenia-osteoporosis at the Femoral neck (odds ratio 2.73; 95% confidence interval 1.06 to 6.13) was associated with an increased risk of developing severe coronary lesions. The multiple regression model showed that T-scores (b = -0.407, SE = 0.151, p=0.007) were the independent predictors of Gensini score. CONCLUSION: The relationship between severity of coronary lesions and BMD was significant in postmenopausal women. BMD, a low-cost technique involving minimal radiation exposure, widely used for osteoporosis screening, is a promising marker of severity of coronary lesions. PMID- 29694546 TI - Subclinical Anthracycline-Induced Cardiotoxicity in the Long - Term Follow-Up of Lymphoma Survivors: A Multi-Layer Speckle Tracking Analysis. AB - BACKGROUND: Anthracycline generates progressive left ventricular dysfunction associated with a poor prognosis. OBJECTIVES: The purpose of this study was to evaluate whether layer-specific strain analysis could assess the subclinical left ventricular dysfunction after exposure to anthracycline. METHODS: Forty-two anthracycline-treated survivors of large B-cell non-Hodgkin lymphoma, aged 55.83 +/- 17.92 years (chemotherapy group) and 27 healthy volunteers, aged 51.39 +/- 13.40 years (control group) were enrolled. The cumulative dose of epirubicin in chemotherapy group was 319.67 +/- 71.71mg/m2. The time from last dose of epirubicin to the echocardiographic examination was 52.92 +/- 22.32 months. Global longitudinal (GLS), circumferential (GCS) and radial strain (GRS), subendocardial, mid and subepicardial layer of longitudinal (LS-ENDO, LS-MID, LS EPI) and circumferential strain (CS-ENDO, CS-MID, CS-EPI) values were analyzed. Transmural strain gradient was calculated as differences in peak systolic strain between the subendocardial and subepicardial layers. A value of p < 0.05 was considered significant. RESULTS: Conventional parameters of systolic and diastolic function showed no significant difference between two groups. Compared with controls, patients had significantly lower GCS and GLS. Multi-layer speckle tracking analysis showed significant reduction of circumferential strain of subendocardial layer, transmural CS gradient and longitudinal strain of all three layers. In contrast, the two groups did not differ in transmural longitudinal strain gradient and radial strains. CONCLUSIONS: It proved the preferential impairment of subendocardial deformation in long-term survivors after exposure to anthracycline. Multi-layer speckle tracking echocardiography might facilitate the longitudinal follow-up of this at-risk patient cohort. PMID- 29694548 TI - Cardiovascular Diseases in Indigenous Populations: An Indicator Of Inequality. PMID- 29694547 TI - Echocardiographic Assessment of Ventricular Function in Young Patients with Asthma. AB - BACKGROUND: Despite significant advances in understanding the pathophysiology and management of asthma, some of systemic effects of asthma are still not well defined. OBJECTIVES: To compare heart function, baseline physical activity level, and functional exercise capacity in young patients with mild-to-moderate asthma and healthy controls. METHODS: Eighteen healthy (12.67 +/- 0.39 years) and 20 asthmatics (12.0 +/- 0.38 years) patients were enrolled in the study. Echocardiography parameters were evaluated using conventional and tissue Doppler imaging (TDI). RESULTS: Although pulmonary acceleration time (PAT) and pulmonary artery systolic pressure (PASP) were within normal limits, these parameters differed significantly between the control and asthmatic groups. PAT was lower (p < 0.0001) and PASP (p < 0.0002) was higher in the asthma group (114.3 +/- 3.70 ms and 25.40 +/- 0.54 mmHg) than the control group (135.30 +/- 2.28 ms and 22.22 +/- 0.40 mmHg). The asthmatic group had significantly lower early diastolic myocardial velocity (E', p = 0.0047) and lower E' to late (E'/A', p = 0.0017) (13.75 +/- 0.53 cm/s and 1.70 +/- 0.09, respectively) compared with control group (15.71 +/- 0.34 cm/s and 2.12 +/- 0.08, respectively) at tricuspid valve. In the lateral mitral valve tissue Doppler, the asthmatic group had lower E' compared with control group (p = 0.0466; 13.27 +/- 0.43 cm/s and 14.32 +/- 0.25 cm/s, respectively), but there was no statistic difference in the E'/A' ratio (p = 0.1161). Right isovolumetric relaxation time was higher (p = 0.0007) in asthmatic (57.15 +/- 0.97 ms) than the control group (52.28 +/- 0.87 ms), reflecting global myocardial dysfunction. The right and left myocardial performance indexes were significantly higher in the asthmatic (0.43 +/- 0.01 and 0.37 +/- 0.01, respectively) compared with control group (0.40 +/- 0.01 and 0.34 +/- 0.01, respectively) (p = 0.0383 and p = 0.0059, respectively). Physical activity level, and distance travelled on the six-minute walk test were similar in both groups. CONCLUSION: Changes in echocardiographic parameters, evaluated by conventional and TDI, were observed in mild-to-moderate asthma patients even with normal functional exercise capacity and baseline physical activity level. Our results suggest that the echocardiogram may be useful for the early detection and evoluation of asthma-induced cardiac changes. PMID- 29694549 TI - What is the Role of Two-Dimensional Speckle Tracking Echocardiography in the Diagnosis and Management of Anthracycline-Induced Cardiotoxicity? PMID- 29694550 TI - Case 2 / 2018 - Coronary-Cavitary Fistula of Right Ventricular Coronary Artery 5 Years after its Occlusion by Interventional Catheterization. PMID- 29694551 TI - The Interface between Osteoporosis and Atherosclerosis in Postmenopausal Women. PMID- 29694553 TI - Partial Prosthetic Mitral Valve Dehiscence: Transapical Percutaneous Closure. PMID- 29694552 TI - Natriuretic Peptide and Clinical Evaluation in the Diagnosis of Heart Failure Hemodynamic Profile: Comparison with Tissue Doppler Echocardiography. AB - BACKGROUND: Physical examination and B-type natriuretic peptide (BNP) have been used to estimate hemodynamics and tailor therapy of acute decompensated heart failure (ADHF) patients. However, correlation between these parameters and left ventricular filling pressures is controversial. OBJECTIVE: This study was designed to evaluate the diagnostic accuracy of physical examination, chest radiography (CR) and BNP in estimating left atrial pressure (LAP) as assessed by tissue Doppler echocardiogram. METHODS: Patients admitted with ADHF were prospectively assessed. Diagnostic characteristics of physical signs of heart failure, CR and BNP in predicting elevation (> 15 mm Hg) of LAP, alone or combined, were calculated. Spearman test was used to analyze the correlation between non-normal distribution variables. The level of significance was 5%. RESULTS: Forty-three patients were included, with mean age of 69.9 +/- 11.1years, left ventricular ejection fraction of 25 +/- 8.0%, and BNP of 1057 +/- 1024.21 pg/mL. Individually, all clinical, CR or BNP parameters had a poor performance in predicting LAP >= 15 mm Hg. A clinical score of congestion had the poorest performance [area under the receiver operating characteristic curve (AUC) 0.53], followed by clinical score + CR (AUC 0.60), clinical score + CR + BNP > 400 pg/mL (AUC 0.62), and clinical score + CR + BNP > 1000 pg/mL (AUC 0.66). CONCLUSION: Physical examination, CR and BNP had a poor performance in predicting a LAP >= 15 mm Hg. Using these parameters alone or in combination may lead to inaccurate estimation of hemodynamics. PMID- 29694554 TI - Propafenone Overdose: From Cardiogenic Shock to Brugada Pattern. PMID- 29694555 TI - Practical Implications of Myocardial Viability Studies. AB - Many non-invasive methods, such as imaging tests, have been developed aiming to add a contribution to existing studies in estimating patients' prognosis after myocardial injury. This prognosis is proportional to myocardial viability, which is evaluated in coronary artery disease and left ventricular dysfunction patients only. While myocardial viability represents the likelihood of a dysfunctional muscle (resulting from decreased oxygen supply for coronary artery obstruction), hibernation represents post-interventional functional recovery itself. This article proposes a review of pathophysiological basis of viability, diagnostic methods, prognosis and future perspectives of myocardial viability. An electronic bibliographic search for articles was performed in PubMed, Lilacs, Cochrane and Scielo databases, according to pre-established criteria. The studies showed the ability of many imaging techniques in detecting viable tissues in dysfunctional areas of left ventricle resulting from coronary artery injuries. These techniques can identify patients who may benefit from myocardial revascularization and indicate the most appropriate treatment. PMID- 29694557 TI - Yellow Fever and Cardiovascular Disease: An Intersection of Epidemics. PMID- 29694556 TI - Exercise Training Attenuates Sympathetic Activity and Improves Morphometry of Splenic Arterioles in Spontaneously Hipertensive Rats. AB - BACKGROUND: Alterations in the structure of resistance vessels contribute to elevated systemic vascular resistance in hypertension and are linked to sympathetic hyperactivity and related lesions in target organs. OBJECTIVE: To assess the effects of exercise training on hemodynamic and autonomic parameters, as well as splenic arteriolar damages in male Wistar Kyoto (WKY) and Spontaneously Hypertensive Rats (SHR). METHODS: Normotensive sedentary (WKYS) and trained (WKYT) rats, and hypertensive sedentary (SHRS) and trained (SHRT) rats were included in this study. After 9 weeks of experimental protocol (swimming training or sedentary control), arterial pressure (AP) and heart rate (HR) were recorded in freely moving rats. We assessed the autonomic control of the heart by sympathetic and vagal autonomic blockade. Morphometric analyses of arterioles were performed in spleen tissues. The statistical significance level was set at p < 0.05. RESULTS: Resting bradycardia was observed in both trained groups (WKYT: 328.0 +/- 7.3 bpm; SHRT: 337.0 +/- 5.2 bpm) compared with their respective sedentary groups (WKYS: 353.2 +/- 8.5 bpm; SHRS: 412.1 +/- 10.4 bpm; p < 0.001). Exercise training attenuated mean AP only in SHRT (125.9 +/- 6.2 mmHg) vs. SHRS (182.5 +/- 4.2 mmHg, p < 0.001). The WKYT showed a higher vagal effect (?HR: 79.0 +/- 2.3 bpm) compared with WKYS (?HR: 67.4 +/- 1.7 bpm; p < 0.05). Chronic exercise decreased sympathetic effects on SHRT (?HR: -62.8 +/- 2.8 bpm) in comparison with SHRS (?HR: -99.8 +/- 9.2 bpm; p = 0.005). The wall thickness of splenic arterioles in SHR was reduced by training (332.1 +/- 16.0 um2 in SHRT vs. 502.7 +/- 36.3 um2 in SHRS; p < 0.05). CONCLUSIONS: Exercise training attenuates sympathetic activity and AP in SHR, which may be contributing to the morphological improvement of the splenic arterioles. PMID- 29694558 TI - Traditional knowledge and uses of medicinal plants by the inhabitants of the islands of the Sao Francisco river, Brazil and preliminary analysis of Rhaphiodon echinus (Lamiaceae). AB - This study aimed to carry out an ethnobotanical survey of medicinal plants used by inhabitants of the Rodeadouro Island, Jatoba Island and Massangano Island, located in The Submedium Sao Francisco River Valley. Also phytochemicals and preliminary pharmacological tests were performed to species most cited by the community. Ethnobotanical data were collected through observation visits and semi structured interviews with 12 key informants. We calculated the relative importance (RI), the percentage of agreement related to the main uses (cAMU) and use value (UV). The aerial parts of Rhaphiodon echinus (Ness & Mart.) Schauer were used to obtain the lyophilizate (LYO-Re), crude ethanol extract (CEE-Re) and their hexanic (HEX-Re), chloroform (CLO-Re) and ethyl acetate (EA-Re) fractions. The microdilution technique was used for determining Minimum inhibitory concentration (MIC) for selected microorganisms. Already the spasmolytic effect was evaluated in isolated uterus fragments of Wistar rats, pre contracted with KCl 60 mM. We found 34 species cited, belonging to 22 families. The most plants were grown by locals. There were 51 different diseases, but the main indication was infectious and parasitic diseases. The species R. echinus was the most reported and it was indicated for urinary tract infection and dysmenorrhea. The screening revealed a higher prevalence of flavonoids, tannins, lignans and saponins in LYO-Re and AE-Re. Already terpene compounds were more present in HEX Re and CLO-Re. The RE-Re fraction stood out with strong effect against E. coli and S. aureus while CEE-Re has moderate effect against gram-negative bacteria. The evaluation of the spasmolytic activity showed that LYO-Re, CEE-Re and HEX-Re fractions have similar activity, with partial effect and concentration-dependent response. This work brought about knowledge and use of medicinal plants by the riparian of the Sao Francisco River. It also revealed the importance of other methodologies for scientific evidence for the popular use of R. echinus. PMID- 29694559 TI - Abundance and population structure of Plesionika narval (Fabricius, 1787) in the Northeastern Atlantic. AB - Analysis of abundance and population structure of Plesionika narval was performed on data concerning 5,255 specimens obtained from 62 fishing sets carried out off the Madeira archipelago (Northeastern Atlantic) between 2004 and 2008 in a depth range from 101 to 350 m. Abundance ranged from 0.01 to 19.74 specimens-per-trap and significant differences were found between seasons, probably as a result of an increment of population in the spring during the recruitment season. The analysis of size distribution revealed that the carapace length (CL) ranged from 2.45 to 28.61 mm and that mean female size consistently exceeded that of males. Differences in mean CL were statistically significant between depth strata and seasons. Of the specimens sampled, 57.00% were males, 41.88% females and 1.42% undetermined. Sex ratio also differed significantly between seasons according to depth strata, consolidating the hypothesis of the existence of seasonal migrations related with the reproductive cycle of this species. Ovigerous females showed larger sizes and occurred all year around and remain in shallow waters in winter, summer and autumn and move to deeper waters in spring. The highest frequency of ovigerous females was recorded in summer, between 151 and 200 m deep supporting the hypothesis that spawning of this species occurs in shallow waters, especially in late summer. PMID- 29694560 TI - Rearing two fruit flies pests on artificial diet with variable pH. AB - Fruit flies (Diptera: Tephritidae) are considered the main fruit pests worldwide. In Brazil, two species are predominant: the South American fruit fly, Anastrepha fraterculus and the Mediterranean fruit fly, Ceratitis capitata. In this study, we evaluated the effect of artificial diets with variable pH in their larval development and adult performance. The experiments were carried out in the laboratory at 25 +/- 2 degrees C, 70 +/- 10% RH and 12:12h (L:D) photoperiod. Semisolid diets with pH values of 6.0, 5.0, 4.0, 3.0, 2.0, 1.5, and 1.0, adjusted by adding hydrochloric acid were tested. Results indicated that the diet with pH 6.0 did not support larval development of both species of fruit fly. Diets with greater acidic pH values did not allow egg, larvae or pupae development and adult reproduction of A. fraterculus. For C. capitata , the pH of artificial diet exerts greater influence compared to A. fraterculus on the duration and viability of the larval stage, number of pupae, sex ratio and longevity of males. PMID- 29694561 TI - Weight-length relationships of six shrimp species caught off the Madeira Archipelago, Northeastern Atlantic. AB - Length and weight relationships and descriptive statistics are reported for six shrimp species caught off the Madeira archipelago between 1983 and 2014 using bottom and floating traps from depths ranging from 50 to 1,300 m. The parameter b ranged between 2.36 for Plesionika ensis and 2.97 for Plesionika williamsi. All species showed a pattern of negative allometric growth. To the authors' knowledge all weight-length relationships presented herein are recorded for the first time from the Madeira area, and in the cases of Ligur ensiferus and Plesionika ensis are the first references worldwide. PMID- 29694562 TI - Feeding preference of the shredder Phylloicus sp. for plant leaves of Chrysophyllum oliviforme or Miconia chartacea after conditioning in streams from different biomes. AB - Macroinvertebrate shredders consume preferably leaves conditioned by fungi and bacteria which offer greater palatability to them. Plant species in Cerrado present high concentration of chemical elements such as lignin and cellulose, phenols and tanins thus making them less attractive for shredders consumption and limiting the palatability. This study aimed to evaluate the feeding preference of a macroinvertebrate shredder of the genus Phylloicus for plant material from two different biomes (Cerrado and Mata Atlantica), after conditioning in a stream of Mata Atlantica and observing their physical and chemical characteristics. Senescent leaves were collected, monthly from the litterfall of riparian vegetation in a 500 m stretch of a stream in each biome from August 2014 to January 201. The most abundant species in each stream was selected for the experiment. The experimental design consisted in with two treatments. The first (T1) comprised leaf discs from Chrysophyllum oliviforme (Cerrado species) together with leaf discs of Miconia chartacea (Atlantic Forest species) which were conditioned in the Atlantic Forest stream. The second treatment (T2) involved leaf discs of Miconia chartacea conditioned in Mata Altlantica and Cerrado streams. Both tests had showed significant differences between the two treatments (T1 and T2). For T1, there was consumption of M. chartacea leaf discs by Phylloicus sp., but there was no consumption of C. oliviforme discs. For T2, there was preference for M. chartaceae leaves conditioned in a stream of Mata Atlantica than in Cerrado stream. The results showed that Phylloicus sp., had presented preference for food detritus of the Mata Antlantica biome and rejection to the one from Cerrado biome. PMID- 29694563 TI - Distribution of cysts of Strongyluris sp. (Nematoda) in the pallial system of Achatina fulica Bowdich, 1822 from Vila Dois Rios and Vila do Abraao, Ilha Grande, Angra dos Reis, Rio de Janeiro. AB - This work aimed to assessing Strongyluris sp. cysts distribution pattern in the several inner organs from pallial system of Achatina fulica Bowdich, 1822. Also we verified if there is a relationship between the mollusk size and the number of specimens from parasites collected from two touristic villages in Ilha Grande (Angra dos Reis, Rio de Janeiro state): Vila Dois Rios (VDR) and Vila do Abraao (ABR). The samples were obtained through a field work conducted bimonthly during 2007, 2008, 2010, and 2011, at both locations. Height and width were measured from shells collected, and the all specimens were classified in different classes: class 1 - <4.0 cm, class 2 - 4.1-9.0 cm and class 3 - < 9.0 cm. After the specimens were dissected in order to find and count the number cysts in the pallial system. In specimens from both locations, the pulmonary and secondary veins showed a high number of cysts. No significance difference was found both in the abundance of cysts among the specimens in ABR (p=0.138) and VDR (p=0.181). Achatina fulica showed different intensities of cyst infection based on the size classes: the class-3 specimens, at both locations, showed the greatest cyst average (ABR Anova F= 3.8; p=0.02); (VDR T of Student T= -2.04; p=0.04). The results suggested that the highest number of cysts in the vascularized area in pallial system of A. fulica was a consequence of a greater hemolymph circulation in that area, delivering more nutrients for larvae development. We think that bigger individuals host a higher number of cysts, as they usually present a larger biomass and a larger area of the pallial system, allowing an efficient parasite colonization. Other possible explanation could be the long exposure of the molluscs of class 3 to the parasites, which allowed a longer time to the larvae to allocate themselves. PMID- 29694564 TI - First record of Eremionycha bahiana (Boheman) infesting Tabebuia sp. PMID- 29694565 TI - Raillietiella mottae (Pentastomida: Raillietiellidae) infecting Ameiva ameiva (Squamata: Teiidae) in Araripe Plateau, Northeast Brazil. AB - We investigated the infection by pulmonary parasites in the lizard Ameiva ameiva (Teiidae) inhabiting the Environmental Protection Area of Araripe (APA-Araripe). A total of 45 specimens were collected in three areas between the cities of Varzea Alegre and Barbalha. A Pentastomid species (Raillietiella mottae) was parasitizing (nine specimens) a male of A. ameiva with a prevalence of 2.22% considering all lizards collected in the region and prevalence of 50% considering only rainforest environment. The Pentastomids infection rates shown in this study are similar to data found for infections of other insectivorous lizards. Raillietiella mottae is considered a generalist parasite, which uses insects as intermediate hosts. The results of this study represent the first record of a Pentastomid infecting this species of lizard in South America. PMID- 29694566 TI - Four-years of monitoring a breeding colony of black-necked stilt (Himantopus mexicanus ) on the Rio Grande do Norte State coast, Brazil. PMID- 29694567 TI - Religiosity as a possible protective factor against "binge drinking" among 12 year-old students: a population-based study. AB - Associated with positive impacts on health, religiosity has presented itself as a possible protection factor against alcohol consumption by teenagers. This study evaluated the prevalence of binge drinking and its association with religiosity among 12-year-old students, from Diamantina, State of Minas Gerais. Statistical analyses involved chi-square Pearson (p < 0,05) and Poisson regression with robust variance. The sample included a census of 588 students. Participation in religious activities was associated with no binge drinking (PR = 0,823; 95% CI: 0,717 - 0,945); and consumption of alcoholic beverages by the best friend was associated with binge drinking (PR = 1.554; 95% CI: 1,411-1,711). It was concluded that religiosity was associated with no consumption of alcoholic beverages in binge drinking sessions. PMID- 29694568 TI - [Factors associated with being underweight among elderly community-dwellers from seven Brazilian cities: the FIBRA Study]. AB - The aim of this study was to assess the prevalence of being underweight among the elderly according to demographic and socioeconomic characteristics, health related behaviors, diseases and health status. This was a cross-sectional multi center study with 3,478 community-dwelling elders (>= 65 years). The dependent variable was the prevalence of being underweight, classified by Body Mass Index < 22kg/m2. Adjusted prevalence rate ratios were estimated using multivariable Poisson regression. The mean age was 72.9 years and 12.0% of the elderly were underweight (CI95%:10.9-13.1). Aged elderly >= 80 years, former and current smokers, those who reported appetite loss and those classified as pre-frail or frail (PR=1.41; CI95%:1.09-1.82) presented a higher prevalence of being underweight. Individuals who received medical diagnosis of hypertension, diabetes and rheumatism had the lowest underweight prevalence observed. The results highlight the importance of nutritional status assessment and monitoring among the elderly, with emphasis on the most vulnerable subgroups, particularly the frail elderly, taking into account the health consequences of low weight. PMID- 29694569 TI - Overweight and associated factors in Quilombolas from the middle San Francisco, Bahia, Brazil. AB - The aim of this article was to analyze the prevalence of overweight and associated factors in adult quilombolas (inhabitants of black communities) from the Middle San Francisco, Bahia. Cross-sectional study with a sample of 112 adults. Overweight was evaluated by body mass index (BMI). Linear regression was used to test associations. The mean age of the participants was 42.1 (standard deviation 18.5) years and there was a predominance of females (55.4%). The prevalence of overweight was 27.7% (95% confidence interval: 19.3;36.1), with a mean BMI of 23.1 (+/- 3.8) kg/m2. Factors that remained associated in multiple linear regression analysis (p < 0.05) were female gender, negative self assessment of health, and increased mean arterial pressure (adjusted R2 0.326). The increase in BMI among quilombolas was associated with female gender, negative self-assessment of health and higher mean blood pressure levels. PMID- 29694570 TI - Health as science and the biological body as an artifact: the case of Brazil's national TV news program Jornal Nacional. AB - This article presents the findings of a study of the coverage of health, science and technology during 2012 by the Jornal Nacional, a national television news program in Brazil produced by the Rede Globo de Televisao. A total of 246 news stories addressing health-related topics were analyzed, half of which addressed scientific research, technological innovation and hospital care, and were shown to represent a doctor-centered discourse. The findings also show that 82% of the news stories concerning science and technology advertise products that are about to be introduced onto the market, illustrating the commercial nature of this research. The article discusses two aspects portrayed by these news stories that characterize the biological body as an artifact: the construction of a virtual and fragmented body through the diffusion of images of the inside of the body; and the importance of biotechnological issues, which leaves life processes open to molecular manipulation and alteration. The study also questions the nature culture hybridization present in biotechnological objects. PMID- 29694571 TI - The quality of life of health professionals working in the prison system. AB - This study aimed to evaluate the Quality of Work Life (QWL) of health professionals in prisons and identify QWL-associated factors. This is an exploratory, descriptive and cross-sectional survey conducted in five prisons. The study included 29 health professionals, who answered the TQWL-42 questionnaire. Results were obtained through descriptive statistics and multiple linear regressions. QWL was higher among women, younger workers, professionals with incomplete higher education or who have been working at the prison for 4 to 6 years. QWL overall assessment was 69.55 points. We observed that variables gender and education and biological/physiological and environmental/organizational spheres are associated with the overall assessment of QWL. PMID- 29694572 TI - Childhood and longevity: vulnerabilities, continuities and discontinuities. PMID- 29694573 TI - Fall-related admission and mortality in older adults in Brazil: trend analysis. AB - OBJECTIVE: To analyze the trend of fall-related morbidity and mortality in older adults in Brazil from 1996 to 2012. METHOD: This is an ecological study of fall related admission and mortality rate trends in older adults by gender, Brazilian regions, and Brazilian state capitals using data from the Hospital Information System of the Unified Healthcare System (SIH-SUS) and from the National Mortality Information System (SIM). Trend analyses were based on polynomial regression models. RESULTS: Mortality rates increased in all regions and state capitals, and admission trends varied in regions and state capitals. The admission rates in 1996 and 2012 were 2.58 and 41.37 per 10,000 older adults, respectively, and the mortality rates per 10,000 older adults increased from 1.25 in 1996 to 3.75 in 2012. Males mortality rates were higher during the entire period. CONCLUSION: Fall-related mortality and admission rates increased in Brazil but varied by gender and state of residence. The results of this study do not only monitor the problem over time but may also help plan technological and human resources to prevent and control falls. PMID- 29694574 TI - Sexual violence against children: authors, victims and consequences. AB - The scope of this study was to identify the characteristics of sexual abuse against children including the profiles of the victims and the perpetrators, and associated factors notified in a health service of reference with the database of the Brazilian Case Registry Database, in a city in the south of Brazil. Categorical variables are presented in prevalence with 95% confidence intervals. There were 489 notifications from 2008 to 2014 of confirmed or suspected child sexual abuse. The majority was related to female victims, but the repeated abuse was reported mainly with male victims. In most cases, the abuse took place at the victims' or perpetrators' homes and the main perpetrators of abuse were male and acquainted with the victims. Twelve victims have contracted sexually transmitted infections; pregnancies were six, five of them legally terminated. This study highlights that the child sexual abuse profiles were similar in almost all of Brazilian regions, showing that it is possible to have a coordinated national action to prevent this offence. PMID- 29694575 TI - Evolution of accesses to information on breast cancer and screening on the Brazilian National Cancer Institute website: an exploratory study. AB - Delays in diagnosis due to low Breast Cancer awareness are widespread in Brazil maybe owing to ineffective strategies to raise attention on early diagnosis. As a proxy of collective interest in BC screanning (BCS) we studied the monthly accesses to BC and BCS webpages in INCA's website along 48 months. A log analyzer built a time serie (2006-2009) of BC and BCS monthly means, which oscilations were studied by analysis of variance (ANOVA). We found significant increasing accesses to BC and transient "attention peaks". Enlargement in BC/BCS differences along all period were caused by increasing accesses to BC and decreasing/minor/stable oscillations to SBC pages. These results are consistent with previous reports on increasing interest to BC contrasting with indifference on BCS. In the context of an exploratory study, we discussed some aspects: weakness of a "prevention culture"; lack of confidence in health system and screening programs; "celebrity effect" in the context of media framing; collective perception of risks heightened by perception of social vulnerability. Findings suggest that culture-tailored communication strategies would be necessary to inform Brazilian people about BCS. Future research is needed to study social perceptions and constructions on BC topics. PMID- 29694576 TI - Awareness about falls and elderly people's exposure to household risk factors. AB - OBJECTIVES: to describe the awareness about falls among elderly people living in their households in communities, to measure the other risks that they are exposed to in their homes and to evaluate the influence that knowledge on falling brings in the adoption of preventative measures. METHOD: The FRAQ-Brazil questionnaire was used on 473 elderly people as well as a questionnaire on elderly people being exposed to 20 household risk factors. Associations between the variables were analyzed using the chi-squared test with a confidence interval of 95%. RESULTS: The age range was between 60 and 95 years with the average being 70.6 years. The majority of those interviewed were female (58.4%) who were earning 2 minimum wages (46.3%). The average amount of correct answers given with the use of the FRAQ-Brazil questionnaire was 19.5 out of 32 points and the elderly participants were, on average, exposed to 7.8 household risk factors. 180 of them stated that they had already received information on falls. CONCLUSION: The majority of the elderly population displayed little knowledge on falls and were exposed to a variety of daily risk factors. Individuals who were more advanced in years and who had more knowledge on falls, were exposed to less household risk factors. This may well have been due to the adoption of preventative measures through changing domestic environment. PMID- 29694577 TI - Self-reported hypertension in adults residing in Campinas, Brazil: prevalence, associated factors and control practices in a population-based study. AB - OBJECTIVES: Evaluate the prevalence of self-reported hypertension in adults aged 20 to 59 years as well as identify associated factors, the use of health services and disease control practices according to the possession or not of a private healthcare plan. METHODS: A population-based, cross-sectional study was conducted in the city of Campinas, Brazil, involving 957 adults. RESULTS: The prevalence of self-reported hypertension was 14.1%, with greater frequencies found among women, individuals aged >= 40 years, those who declared their skin color to be black, those with less schooling, those who did not practice active leisure activities, ex-smokers, overweight or obese individuals and those who rated their own health as not being excellent/very good. No inequalities were detected between individuals with hypertension covered by a private healthcare plan or the Brazilian public healthcare system with regard to access to services, the use of disease-controlling medications and having received counseling on how to manage the disease. However, differences were found regarding the practice of physical activity and diet. CONCLUSION: Despite the equity disclosed in access to health care, the present findings demonstrate that an insufficient proportion of adults adopt changes in lifestyle to control hypertension, underscoring the central role of public health administrators. PMID- 29694578 TI - [Trajectory in narratives: experiences of mental illness and the city of Belo Horizonte]. AB - The article seeks to understand the relationships established between mentally ill patients cared for in the open community service network and the city of Belo Horizonte, state capital of Minas Gerais. It is understood that the experience of mental illness is capable of generating narratives that seek to give meaning to suffering and help people to negotiate everyday decisions. The biographical method was used for the construction of narratives of life trajectories of the three participants of the study. The biographical narratives revealed diverse experiences associated with mental illness as well as different meanings attributed to this condition. However, interestingly, these stories have a common pattern, often associated with marginal convivialities with the conventions of order, family and work. There is a break with the striking invisibility in asylums, as open services provide the social movement and manipulation of social codes, creating new territorial delimitations and interpretations. However, the need for empirical studies that address themes such as family relations, housing conditions and income of this population is paramount in order to broaden the right to health discussions for the right to housing, work, the right and to a place in the city. PMID- 29694579 TI - Condom use in last sexual intercourse among undergraduate students: how many are using them and who are they? AB - A cross-sectional study was conducted to measure the prevalence of condom use in the last sexual intercourse and associated factors among university students. Undergraduate students from a public university aged 18 and over of the Rio Grande (RS) campuses were eligible. A systematic single-stage sampling was used, based on class lists and self-administered questionnaire. Descriptive, bivariate and multivariable analyses were employed, with Poisson regression for the latter two. Most of the 1,215 university students included in the analysis were aged 20 to 29 (65.6%) and 69.3% began their sexual life before the age of 18. The prevalence of condom use in the last intercourse was 41.5% (95%CI: 38.7-44.3). Male gender, lower age group, condom use at first sexual intercourse, older age of onset of sexual activity, not having a partner and casual partner in the last sexual intercourse increased the likelihood of condom use. PMID- 29694580 TI - [Profile of spending on the treatment of rheumatoid arthritis for patients of the Unified Health System in the state of Minas Gerais - 2008-2013]. AB - Rheumatoid arthritis (RA) is a chronic condition that affects about 1% of the adult population. In a historical cohort of Minas Gerais State, 11,573 RA patients registered in the Outpatient Information System (SIA) between 2008 and 2013 were identified. For this study we adopted the public funding body's perspective and the values were adjusted by the national inflation index (IPCA) of December 2015. Etanercept was the most expensive treatment. The mean cohort age was 52 years old and most of the patients were women. Multiple regression analysis indicated a negative association between higher expenditure and age, female sex, and diagnosis at entry in the cohort and positive association between high expenditure and the Human Development Index (HDI) of the municipality and use of tumor necrosis factor agents. This study identified the factors that have an impact on RA drug treatment expenditure. Also, we showed that methods that enable extracting demographic and expenditure data of administrative information systems may represent important tools in the construction of economic studies to subsidize economic health evaluations, especially from the standpoint of the managers. PMID- 29694581 TI - Concurrent and face validity of the MacArthur scale for assessing subjective social status: Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). AB - This work assessed the concurrent and face validity of the MacArthur scale, which attempts to capture subjective social status in society, neighborhood and work contexts. The study population comprised a convenience sample made up of 159 adult participants of the ELSA-Brasil cohort study conducted in Minas Gerais between 2012 and 2014. The analysis was conducted drawing on Conceptual Metaphor Theory and using corpus linguistic methods. Concurrent validity was shown to be moderate for the society ladder (Kappaw = 0.55) and good for the neighborhood (Kappaw = 0.60) and work (Kappaw = 0,67) ladders. Face validity indicated that the MacArthur scale really captures subjective social status across indicators of socioeconomic position, thus confirming that it is a valuable tool for the study of social inequalities in health Brazil. PMID- 29694582 TI - [Satisfaction with care received in pediatric emergency services: impact of family interaction and emotional disturbance]. AB - This study addresses the relationship between two key elements in satisfaction with pediatric emergency services, namely emotional disturbance and family interaction. The main goal is to determine whether family cohesion and adaptability and anger may be associated with differential levels of satisfaction among parents whose children were attended in pediatric emergency units. It is a descriptive study for which a sample of 711 parents whose children were attended in 6 pediatric emergency services was studied. The Spanish version of the State Trait Anger Expression Inventory-2 (Staxi-2), the Satisfaction with Healthcare Services Scale and the Family Adaptability and Cohesion Evaluation Scale (Faces) were used respectively. Data analysis included a Spearman bivariate correlations analysis, Kruskal Wallis, Mann-Whitney test and path-analysis using a structural equations model. The results support the hypothesis that higher levels of family cohesion and adaptability as well as lower levels of anger are associated with higher levels of satisfaction among parents. PMID- 29694583 TI - Food and nutrition insecurity indicators associated with iron deficiency anemia in Brazilian children: a systematic review. AB - This study aimed to review food and nutrition insecurity indicators associated with iron deficiency anemia in Brazilian children below 5 years. We searched in electronic databases (SciELO, Lilacs, and Medline) and selected studies by titles, abstracts and full-text reading. Of the 1,023 studies analyzed, 11 fit the inclusion criteria. The results of the studies evidenced that iron deficiency anemia in Brazilian children was associated with sociodemographic and health indicators (male, age below 24 months, children of adolescent mothers, respiratory infections, diarrhea, low maternal schooling, parents' working conditions, nursery time, lack of basic sanitation, maternal anemia, lack of ferrous sulfate use by the mother and/or child and late onset of prenatal care), nutritional indicators (low birth weight, diet characteristics, such as the habit of milk consumption close to meals, low exclusive and full breastfeeding time) and economic indicators (low per capita income). The food and nutrition insecurity analyzed in this study from the perspective of different indicators is associated with iron deficiency anemia in children under 5 years in Brazil. PMID- 29694584 TI - [Factors associated with the need for oral treatment of elderly Brazilians: a multilevel analysis]. AB - The aims of this study were to estimate the prevalence of prosthetic requirements and dental treatment needs among the elderly Brazilian population and the associations with contextual and individual determinants. Data were taken from the Brazilian Oral Health Survey (SB Brasil 2010) and a sample of 7,619 Brazilian people aged 65-74 years were investigated. Multilevel logistic regression models were used to estimate the odds ratio (OR) and 95% confidence intervals between treatment needs and contextual variables (Municipal Human Development Index, Gini coefficient and oral health coverage in the Family Health Strategy) and individual (gender, income, education and skin color). The prevalence of treatment need ranged from municipalities (p < 0.05). Of the individual variables, gender was associated with dental treatment need (OR = 1.18, 95% CI 1.05 to 1.31); lower education and non-white skin were risk factors (OR = 1.18; 95% CI 1.05 to 1.31 and OR = 1.28, 95% CI 1.15 to 1.43); the non-white skin color represented a risk factor (OR = 1.83; 95% CI 1,38- 2,42) and for the need for prosthesis income was a protection factor (OR = 0.39; 95% CI 0, 30-.51). The results showed an association between the individual factors and treatment needs. PMID- 29694585 TI - Association between sociodemographic and health factors and the practice of walking in a rural area. AB - : The regular practice of walking can contribute to a better quality of life, reducing the risk of cardiovascular disease. OBJECTIVE: To assess the association between sociodemographic and health factors related to adult practice of walking in the Brazilian rural context. METHODS: Cross-sectional study of 567 adults. The outcome variable was the regular practice of walking (>=150 minutes per week) and the explanatory variables were sociodemographic factors, anthropometric measures, laboratory tests and self-perceived health. The chi-square test and Poisson regression were used in analysis, considering p <= 0.05. RESULTS: Only 34.7% of the population practices walking regularly. Women (PR 0.84, 95% CI 0.78-0.89), age of 31-45 years (OR 1.11, 95% CI 1.02-1.22, comparing to 18-30 years), and self-perception of poor/fair health (OR 0.90, 95% CI 0.84-0.97 comparing to people with great/good health) remained independently associated with regular practice of walking. Conclusion Age between 31 and 45 years and males were positively associated with walking and the perception of poor/fair health had negative association. These findings may suggest that public policies to encourage physical activity in urban areas should also be applied to rural areas. PMID- 29694586 TI - [Guidance on breastfeeding in primary health care and the association with exclusive breastfeeding]. AB - This article aims to analyze the association between guidance on breastfeeding in primary health care and exclusive breastfeeding. It involved a cross-sectional study conducted in 2013 in the city of Rio de Janeiro, Brazil, by means of interviews with 429 mothers of infants below six months of age in primary care units. We estimated adjusted prevalence ratios by Poisson regression. In the final model, the variables associated with the outcome (p <= 0.05) were retained. The prevalence of exclusive breastfeeding was 50.1%. In multivariate analysis, guidance on exclusive breastfeeding in primary care was directly associated with the outcome (PR = 1.32). Maternal income < 1 minimum wage (PR = 0.77), previous breastfeeding experience for less than 6 months (PR = 0.73), not living with a partner (PR = 0.76), non-exclusive breastfeeding at discharge (PR = 0.78), alcohol consumption (OR = 0.57), guidance on pumping breast milk (PR = 0.53), pacifier use (PR = 0, 74) and baby's age in months (PR = 0.78) were associated inversely with the outcome. Guidance on exclusive breastfeeding favored it, while inadequate guidance and practices were associated with a lower prevalence of the outcome. PMID- 29694589 TI - Exposure to fluoride of children during the critical age for dental fluorosis, in the semiarid region of Brazil. AB - : There is a concern about the increasing prevalence of dental fluorosis, which depends on the dose of fluoride (F) to which children are subjected during tooth formation. Environmental temperature affects water intake and therefore it would be important to assess whether children living in the semiarid region are exposed to an excessive dose of F. Therefore, the objective of this study was to determine the total dose of F to which children are exposed during the critical age for dental fluorosis, with diet (water and food) and toothpaste as F sources, in the semiarid region of Brazil. METHODOLOGY: 26 children aged 25.2 +/- 9.1 months, residents in Feira de Santana, State of Bahia (with F in the public water supply) were selected. Duplicate-diet, water, products from toothbrushing and toothpaste samples were collected. F concentration was determined using an ion specific electrode, after proper sample preparation. RESULTS: the mean and standard deviation of dose (mg F/kg/day) from diet, toothpaste and total were respectively: 0.016 +/- 0.010; 0.030 +/- 0.039 and 0.047 +/- 0.043. CONCLUSIONS: the children evaluated living in the semiarid region are not exposed to a risk dose for dental fluorosis. PMID- 29694590 TI - Caries prevalence among Brazilian indigenous population of urban areas based on the 2010 National Oral Health Survey. AB - It is important to have an epidemiological understanding of oral diseases among indigenous persons, in order to contribute with the organization of health services for these populations. The SB Brasil 2010 database was used to compare the prevalence of dental caries among 308 self-identified indigenous and 37,211 non-indigenous individuals from urban areas, in the following age/age-groups: 5, 12, 15-19, 35-44, 65-74. The study also analyzed the effect of the complex sample design and the sample weight in the outcomes. Kruskal-Wallis, Wilcoxon Scores (Rank Sums), logistic and multiple linear regressions were used for statistical analysis. The mean dmft index for indigenous and non-indigenous children aged five were 4.02 +/- 4.01 and 2.41 +/- 3.35, respectively, and 46% of non-native and 30.8% of native children were caries-free. The mean DMFT for indigenous and non-indigenous were 10.90 +/- 11.69 and 10.93 +/- 11.58, respectively, for all age groups when not taking into account the sample weight effect. When considering the complex sample design and the sample weight effect, the study found a statistical significant difference. The results lend credence to suspicions that in Brazil there are disparities in the patterns of caries between self-identified indigenous and non-indigenous individuals. PMID- 29694591 TI - [Health, pain and daily activities among elderly people practicing Lian Gong and sedentary elderly people]. AB - It is a well-known fact that the practice of physical activity on a regular basis among elderly people contributes to the prevention and reduction of pain, as well as promote active ageing. Based on this premise, the scope of this study was to evaluate the presence of chronic pain among elderly people attended in a primary health care unit in a city in the interior of Sao Paulo State, Brazil, by comparing those who practice Chinese gymnastics (Lian Gong) and the sedentary. Sixty elderly people were divided between 30 sedentary and 30 who participate in a group practicing Lian Gong. The presence of pain was assessed through the Nordic Questionnaire on Musculoskeletal Symptoms, already adapted and validated for Brazilian culture. When questioned about pain in the last seven days, the Lian Gong group showed a higher presence (62,3%) of pain when compared to the sedentary group, although they had fewer difficulties in performing daily activities (55,5%). Among the active elderly the presence of lower back pain was statistically inferior (p < 0.05) when comparing the groups. The practice of Lian Gong was associated to a more positive perception of one's health, less use of medicines, as well as the adopting of self-care practices and the feeling of fewer impairments in performing daily activities. PMID- 29694592 TI - Suicide attempts: epidemiologic trends towards geoprocessing. AB - In order to study data about suicide attempts and do the mapping of occurrence areas, it was developed an ecologic and exploring study, making use of techniques of geoprocessing, based on confirmed cases of suicide attempts. Cases of self poisoning were included in the urban area of Campina Grande county, in the period of 2010-2013. A total of 446 suicide attempts were geo-referred, pointing up an incidence of 120 cases out of each 100,000 inhabitants. The sample was mostly feminine (66.4%), and 62.3% being up to 30 years old. Kernel's map remarked hot spot areas. Compared to surrounding areas the suicide risk of populations within the hot spots was increased (38%; Relative Risk = 1.38; p= 0.0029), with an average estimative of 165 suicide attempts out of 100,000 inhabitants. Through identification of hot spots and index of living conditions of the neighborhoods, it is possible to set priorities in terms of public policies for the prevention of suicide attempts and control of the marketing of substances that are potentially toxic. PMID- 29694593 TI - [Spatial and differential income pattern of households of adolescents and young adults who are victims of maxillofacial injuries resulting from firearm aggression]. AB - The study investigated the spatial pattern of cases of maxillofacial injury resulting from firearm aggression among teenagers and young adults and analyzed the comparison of income differentials in these areas based on the residence of the victims. This is a cross-sectional study with data from victims attended in three hospitals in Belo Horizonte, State of Minas Gerais, from January 2008 to December 2010. The addresses of the victims were georeferenced by geocoding. Randomness and point density trends were analyzed using Ripley's K function and Kernel maps. The spatial interaction between the homes of adolescents and young adults was verified through the K12 function. Records of 218 cases of assault with a male predominance (89.9%) and young adults (70.6%) were found. Household clusters were distributed on an aggregate basis in the urban space with a confidence level of 99% and similar spatial aggregation levels. The hotspots converged on 7 shantytowns or neighboring regions with higher income population revealing spread of events. Hotspots focused on slums with a history of crimes linked to drug trafficking. The incorporation of space in the dynamics of events showed that the economic condition in isolation did not limit victimization. PMID- 29694594 TI - Food security in indigenous and peasant populations: a systematic review. AB - Food security and the vulnerability among indigenous and peasant populations has become a topic of interest to public health all around the world, leading to the investigation about measurement, classification and factors that determine it. This systematic review aims to describe the situation of food security in indigenous and peasant communities, and the methods used for evaluation. The literature search was performed on the Pub Med (5), ScienceDirect (221) and Scopus (377) databases searching for publications between 2004 and 2015, a total of 603 items were located with the search engines. At the end of the screening process and after adding the items found in the gray literature, 25 papers were obtained to write the review. In the 11 years evaluated between 2004 and 2015, scientific activity around the theme was poor with just 4.54% of the publications on this subject, but for 2011 the percentage increased to 13 publications, 63%. Various factors that influence the development of food insecurity are climate change, the diversity of agriculture, globalization and market westernization. PMID- 29694595 TI - Predictors of suicidal ideation and depressive symptoms among adolescents in Chiapas, Mexico. AB - The aim of this study was to assess the presence of suicidal ideation and depressive symptoms among adolescents in Chiapas, Mexico based on predictor variables. A cross-sectional study adopting an ex post facto design was conducted with a non-probability sample of 4,759 students of both sexes with an average age of 18.4 years and using the following tools: the Center for Epidemiologic Studies Depression Scale, Roberts' Suicidal Ideation Scale, the Impulsiveness Scale (IS), and the Rosenberg Self-Esteem Scale. The mean score obtained by the suicidal ideation scale was 0.2, which is lower than that reported by other studies, while the mean score for depressive symptoms was similar to those in the literature. The prevalence of suicidal ideation was 7.8%, which is lower than reported in national and international studies. Multivariable logistic regression showed that impulsiveness (OR = 1.907) and depressive symptoms (OR = 9.006) lead to a twofold and ninefold increase in the likelihood of suicidal ideation, respectively. The findings also showed a strong association between suicidal ideation and depressive symptoms, showing that the latter is a predictor of suicidal ideation among adolescents. PMID- 29694596 TI - Integrality in Brazil and Venezuela: similarities and complementarities. AB - This study aims to compare Primary Health Care (PHC) in Brazil and Venezuela, considering its characteristics as to integrality. It has a qualitative approach, using documental analysis, semi-structured interviews with key informants and field diary notes. We observed the three realms of integrality inherent to the health work process: comprehensive and holistic care, the individual viewed as a complex being with multiple needs, requiring the connection of various health knowledge; continuity of care in institutional micro-policy with interprofessional articulation, in order to consider individual care; continuity of care in macro-policy, when a shift to other levels of care is needed; intersectoriality was also included, when the needs of an individual and community require a cross-sectoral coordination, with action on determinants and conditionants of the health-disease process. It is worth highlighting the natural tendency to include a comprehensive community medical training. We conclude that those countries strengthened by democracy draw their integrality practices closer, as well as the construction of social and health policies for underprivileged populations to achieve equity. PMID- 29694597 TI - [Pregnancy and abortion experience among children, adolescents and youths living on the streets]. AB - The aim of this study is to identify the prevalence of pregnancy and abortion experience, along with associated factors among street children, adolescents and youths in Porto Alegre and Rio Grande, RS, Brazil. The sampling method in this cross-sectional study was Respondent-Driven Sampling (RDS), innovative in research about hidden populations. Interviews were conducted with 307 subjects, aged 10 to 21 years. In multivariate analysis, Poisson regression with a robust error variance was used. Most of this sample were males, with no contact with school and family. Almost half of the participants had been on the street for five years or more, spending more than 15 hours per day on the streets. The prevalence of pregnancy experience was 29.3%, independently associated with being a girl, having 10 sexual partners or more in the last year, having a fixed sexual partner in the last year, and being older. The prevalence of abortion experience was 10.4%, independently associated with not living with the family, having more than two pregnancies, and being younger. The high prevalence of pregnancy and abortion experience highlights the need for the development of better sexual and reproductive health policies focused on this population. PMID- 29694598 TI - The medical archive work process: new perspectives concerning health care. AB - Generally, medical archive studies are restricted to the analysis of documents. Its activities achieve little expressiveness beyond the theories of scientific management, hampering the perception that care production may occur during these activities. This study aims to analyze hospital medical archive sector professionals' work process from the dynamics of micro-policy articulated with institutional analysis. As a descriptive qualitative research theoretically based on micro-policy of the health work process and Institutional Analysis, this study identifies with analyzers daily issues of the medical archive that can disclose strategies developed by health workers and disputes that occur on a daily basis. Therefore, it was possible to recognize in two hospitals that these workers held important knowledge about the dynamics of the health work process. As facilitators of user care process, they establish their own strategies in the dynamics of care that reflect directly on the care dimension of these hospitals. In this perspective, the introduction of new investigations about this work process allows us to diversify the debate about health care and broaden the scope of research referred to public health. PMID- 29694599 TI - [Circumstances and consequences of care: characterization of the family caregiver in palliative care]. AB - Family caregivers play an important role in advanced disease patient care. The goal of this study was to characterize the family caregiver in palliative care, evaluating the circumstances and consequences of care and preparation for the loss of the loved one. This is a quantitative, prospective and longitudinal study. The sample consisted of 60 family caregivers, mostly women, married with an average age of 44.53 years. Most caregivers cohabit with the patient, and they spend the greater part of their day caring for the patient and a significant part quit their jobs or reduce working hours to be with the patient. The highest burden caregivers also showed higher levels of anxiety, depression, somatization and less social support. The most dysfunctional family caregivers reported little social support and those caregivers who were less prepared for the death of the patient showed more symptoms of peritraumatic dissociative experience. Most caregivers were aware of the severity of the illness of their family member and the proximity of death, and considered that the patient was very well taken care of in the palliative care service. PMID- 29694600 TI - Evaluation of E. coli inhibition by plain and polymer-coated silver nanoparticles. AB - Escherichia coli causes various ailments such as septicemia, enteritis, foodborne illnesses, and urinary tract infections which are of concern in the public health field due to antibiotic resistance. Silver nanoparticles (AgNP) are known for their biocompatibility and antibacterial activity, and may prove to be an alternative method of treatment, especially as wound dressings. In this study, we compared the antibacterial efficacy of two polymer-coated silver nanoparticles either containing 10% Ag (Ag 10% + Polymer), or 99% Ag (AgPVP) in relation to plain uncoated silver nanoparticles (AgNP). Atomic force microscopy was used to characterize the nanoparticles, and their antibacterial efficacy was compared by the minimum inhibitory concentration (MIC) and bacterial growth curve assays, followed by molecular studies using scanning electron microscopy (SEM) and (qRT- PCR). AgNP inhibited the growth of E. coli only at 0.621 mg/mL, which was double the concentration required for both coated nanoparticles (0.312 mg/mL). Similarly, bacterial growth was impeded as early as 8 h at 0.156 mg/mL of both coated nanoparticles as compared to 0.312 mg/mL for plain AgNP. SEM data showed that nanoparticles damaged the cell membrane, resulting in bacterial cell lysis, expulsion of cellular contents, and complete disintegration of some cells. The expression of genes associated with the TCA cycle (aceF and frdB) and amino acid metabolism (gadB, metL, argC) were substantially downregulated in E. coli treated with nanoparticles. The reduction in the silver ion (Ag+) concentration of polymer-coated AgNP did not affect their antibacterial efficacy against E. coli. PMID- 29694601 TI - Distribution and risk factors of Ascarididae and other geohelminths in the soil of Uberlandia, Minas Gerais, Brazil. AB - Among the geohelminths, parasites from the Ascarididae family have a significant role in the human and animal health. This research aims to determine the prevalence of Ascarididae species in the soil in different areas located in a city of Minas Gerais State, Brazil (South America). The study was developed in squares, parks, sports clubs, orchards and municipal children's schools. Samples of sand/soil/grass were collected from January to August 2014. The optical microscope screening was performed through formal-ether and spontaneous sedimentation techniques. Out of the 183 collected samples, eight (4.4%) belonged to parks, 16 (8.7%) to sports clubs, 76 (41.5%) to squares, 23 (12.6%) to orchards, and 60 (32.8%) to schools. Out of the total, 28 (15.3%) contained Ascarididae eggs. Higher levels of positivity were demonstrated in the raining season (25.0%), in samples collected in the southern region of the town (25.1%), on ground soils (27.3%). Twenty-three (12.6%) were detected by the formal-ether sedimentation technique and 10 (5.5%) by spontaneous sedimentation technique. Therefore, it was concluded that the soils in the city of Uberlandia are contaminated with eggs and larvae of geohelminths, enabling dissemination of illnesses among animals and human beings. PMID- 29694602 TI - Is the telomere length associated with neurocognitive disabilities in HIV-1 infected subjects? AB - OBJECTIVE: We evaluated the association between cognitive deficits and leukocyte telomere length (LTL) in HIV-1-infected individuals. DESIGN: 73 HIV-1-infected patients undergoing neuropsychological evaluation and 91 healthy controls were included in this study. Fifteen HIV-1 positive patients did not have cognitive disorders whereas 26 had asymptomatic neurocognitive disorder (ANI), 13 presented mild to moderate neurocognitive disorder (MND), and 10 had HIV-associated dementia (HAD). METHODS: DNA from the peripheral blood of HIV-1-infected patients was used for measurement of telomere length by real-time PCR. HIV-1 viral load was determined in blood. RESULTS: LTL decreased with age in healthy controls (p=0.0001). Regardless of the HIV status, age-matched LTL from HIV patients, including those with ANI and MND, were shortened in comparison to the healthy control group (p=0.0073); however, no association was found among the HIV-1 infected individuals with cognitive deficits (p=0.01). In addition, no gender related association with LTL was observed (p=0.80), smoking, physical exercise, and plasma viral load were not correlated to telomere length (p=0.66). CONCLUSIONS: We concluded that leukocyte telomere length may not be a marker of cellular senescence in individuals with HIV infection and neurocognitive disorders. PMID- 29694603 TI - Report of East-Central South African Chikungunya virus genotype during the 2016 outbreak in the Alagoas State, Brazil. AB - Chikungunya virus (CHIKV) causes a self-limiting disease characterized by the onset of fever, skin rash and persistent arthralgia. In the last decade, it has emerged as a serious public health problem causing several outbreaks around the world. Here, we report the CHIKV genotype characterization during the 2016 CHIKV outbreak in Alagoas State, Brazil. Partial E1 sequence from CHIKV-positive samples coming from different cities of Alagoas were submitted to DNA sequencing followed by phylogenetic analysis thus characterizing the virus genotype. The circulating CHIKV virus in Alagoas during 2016 outbreak belongs to the East Central South African genotype. In this way, virus genotyping to monitoring the spread of CHIKV is needed to continued surveillance supporting the development of prevention strategies, mainly in endemic areas of mosquitoes and arboviruses co circulation. PMID- 29694604 TI - Analysis of the Role of Physicians in the Cessation of Cigarette Smoking Based on Medical Specialization. AB - OBJECTIVE: Physicians do not adequately use their unique professional privilege to prevent patients from smoking. The aim of this study was to investigate the type and extent of advice given to patients by physicians of different medical specialties regarding smoking cessation. METHODS: In total, 317 volunteer physicians were included in this study. The participants rated their attitudes toward the smoking habits of their patients by completing a questionnaire. The approaches used to address the smoking habits of patients significantly differed among physicians working at polyclinics, clinics and emergency service departments (p<0.001). Physicians working at clinics exhibited the highest frequency of inquiring about the smoking habits of their patients, while physicians working at emergency service departments exhibited the lowest frequency. RESULTS: Physicians from different medical specialties significantly differed in their responses. Physicians specializing in lung diseases, thoracic surgery, and cardiology were more committed to preventing their patients from cigarette smoking. CONCLUSIONS: The role of physicians, particularly pulmonologists and thoracic surgeons, is critical in the fight against cigarette smoking. Promoting physician awareness of this subject is highly important in all other branches of medicine. PMID- 29694605 TI - Neuroprotective effects of erythropoietin on rat retinas subjected to oligemia. AB - OBJECTIVES: Erythropoietin may have neuroprotective potential after ischemia of the central nervous system. Here, we conducted a study to characterize the protective effects of erythropoietin on retinal ganglion cells and gliotic reactions in an experimentally induced oligemia model. METHODS: Rats were subjected to global oligemia by bilateral common carotid artery occlusion and then received either vehicle or erythropoietin via intravitreal injection after 48 h; they were euthanized one week after the injection. The densities of retinal ganglion cells and contents of glial fibrillary acidic protein (astrocytes/Muller cells) and cluster of differentiation 68 clone ED1 (microglia/macrophages), assessed by fluorescence intensity, were evaluated in frozen retinal sections by immunofluorescence and epifluorescence microscopy. RESULTS: Retinal ganglion cells were nearly undetectable one week after oligemia compared with the sham controls; however, these cells were partially preserved in erythropoietin-treated retinas. The contents of glial fibrillary acidic protein and cluster of differentiation 68 clone ED1, markers for reactive gliosis, were significantly higher in retinas after bilateral common carotid artery occlusion than those in both sham and erythropoietin-treated retinas. CONCLUSIONS: The number of partially preserved retinal ganglion cells in the erythropoietin-treated group suggests that erythropoietin exerts a neuroprotective effect on oligemic/ischemic retinas. This effect could be related to the down-modulation of glial reactivity, usually observed in hypoxic conditions, clinically observed during glaucoma or retinal artery occlusion conditions. Therefore, glial reactivity may enhance neurodegeneration in hypoxic conditions, like normal-tension glaucoma and retinal ischemia, and erythropoietin is thus a candidate to be clinically applied after the detection of decreased retinal blood flow. PMID- 29694606 TI - Cardiovascular abnormalities in patients with oral cleft: a clinical electrocardiographic-echocardiographic study. AB - OBJECTIVES: The present study aims to describe the clinical, electrocardiographic, and echocardiographic cardiological findings in a group of patients with oral clefts. METHODS: This is a prospective cross-sectional study on 70 children (age range from 13 days to 19 years) with oral clefts who attended the multidisciplinary program of a university hospital from March 2013 to September 2014. The patients were evaluated by a pediatric cardiologist and underwent detailed anamnesis, physical examination, electrocardiogram, and echocardiogram. RESULTS: Sixty percent of the patients were male; 55.7% presented with cleft lip and palate, and 40.0% presented with health complaints. Comorbidities were found in 44.3%. Relevant pregnancy, neonatal, family and personal antecedents were present in 55.7%, 27.1%, 67.2%, and 24.3% of the patients, respectively. Regarding the antecedents, 15.2% of the patients presented with a cardiac murmur, 49.0% with a familial risk of developing plurimetabolic syndrome, and 6% with family antecedents of rheumatic fever. Electrocardiographic evaluation showed one case of atrioventricular block. Echocardiograms were abnormal in 35.7% of the exams, including 5 cases of mitral valve prolapse - one of which was diagnosed with rheumatic heart disease. CONCLUSION: The finding of a family risk of developing plurimetabolic syndrome and a diagnosis of rheumatic heart disease indicates that patients with oral clefts may be more prone to developing acquired heart disease. Thus, our findings highlight the importance of anamnesis and methodological triangulation (clinical electrocardiographic-echocardiographic) in the investigation of patients with oral clefts and emphasize that cardiological follow-up to evaluate acquired and/or rhythm heart diseases is necessary. This strategy permits comorbidity prevention and individualized planned treatment. PMID- 29694608 TI - Congenital occipital myelocele. PMID- 29694607 TI - Clinical and laboratory characteristics associated with referral of hospitalized elderly to palliative care. AB - Objective To investigate clinical and laboratory characteristics associated with referral of acutely ill older adults to exclusive palliative care. Methods A retrospective cohort study based on 572 admissions of acutely ill patients aged 60 years or over to a university hospital located in Sao Paulo, Brazil, from 2009 to 2013. The primary outcome was the clinical indication for exclusive palliative care. Comprehensive geriatric assessments were used to measure target predictors, such as sociodemographic, clinical, cognitive, functional and laboratory data. Stepwise logistic regression was used to identify independent predictors of palliative care. Results Exclusive palliative care was indicated in 152 (27%) cases. In the palliative care group, in-hospital mortality and 12 month cumulative mortality amounted to 50% and 66%, respectively. Major conditions prompting referral to palliative care were advanced dementia (45%), cancer (38%), congestive heart failure (25%), stage IV and V renal dysfunction (24%), chronic obstructive pulmonary disease (8%) and cirrhosis (4%). Major complications observed in the palliative care group included delirium (p<0.001), infections (p<0.001) and pressure ulcers (p<0.001). Following multivariate analysis, male sex (OR=2.12; 95%CI: 1.32-3.40), cancer (OR=7.36; 95%CI: 4.26-13.03), advanced dementia (OR=12.6; 95%CI: 7.5-21.2), and albumin levels (OR=0.25; 95%CI: 0.17 0.38) were identified as independent predictors of referral to exclusive palliative care. Conclusion Advanced dementia and cancer were the major clinical conditions associated with referral of hospitalized older adults to exclusive palliative care. High short-term mortality suggests prognosis should be better assessed and discussed with patients and families in primary care settings. PMID- 29694609 TI - European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30: factorial models to Brazilian cancer patients. AB - Objective To evaluate the psychometric properties of the seven theoretical models proposed in the literature for European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), when applied to a sample of Brazilian cancer patients. Methods Content and construct validity (factorial, convergent, discriminant) were estimated. Confirmatory factor analysis was performed. Convergent validity was analyzed using the average variance extracted. Discriminant validity was analyzed using correlational analysis. Internal consistency and composite reliability were used to assess the reliability of instrument. Results A total of 1,020 cancer patients participated. The mean age was 53.3+/-13.0 years, and 62% were female. All models showed adequate factorial validity for the study sample. Convergent and discriminant validities and the reliability were compromised in all of the models for all of the single items referring to symptoms, as well as for the "physical function" and "cognitive function" factors. Conclusion All theoretical models assessed in this study presented adequate factorial validity when applied to Brazilian cancer patients. The choice of the best model for use in research and/or clinical protocols should be centered on the purpose and underlying theory of each model. PMID- 29694610 TI - Bronchial hygiene techniques in patients on mechanical ventilation: what are used and why? AB - Objective To analyze and describe the maneuvers most commonly used in clinical practice by physical therapists and the reasons for choosing them. Methods A prospective multicenter study using a questionnaire. The sample consisted of physical therapists from five hospitals (three private hospitals, a teaching hospital and a public hospital). Results A total of 185 questionnaires were filled in. Most professionals had graduated 6 to 10 years before and over had over 10 years of intensive care unit experience. The most often used maneuvers were vibrocompression, hyperinflation, postural drainage, tracheal suction and motor mobilization. The most frequent reason for choosing these maneuvers was "I notice they are more efficient in clinical practice." Conclusion Physical therapy is mostly based on individual experience acquired in the clinical practice, and not on the scientific literature. PMID- 29694611 TI - Evaluation of survivin immunoexpression in the differentiation of high- and low grade breast ductal carcinoma in situ. AB - Objective To evaluate the expression of survivin protein in low- and high-grade ductal carcinoma in situ. Methods Breast tissue fragments obtained by incisional biopsy and surgical procedures of 37 women with ductal carcinoma in situ of the breast were subdivided into two groups: Group A, composed of women with low-grade ductal carcinoma in situ, and Group B, women with high-grade ductal carcinoma in situ. Survivin protein expression test was performed by immunohistochemistry, using a monoclonal antibody clone I2C4. The criterion to evaluate survivin immunoexpression was based on the percentage of neoplastic cells that presented brown-gold staining. This criterion was positive when the percentage of stained cells was >=10%. Results The survivin protein was expressed in 22 out of 24 cases of high-grade ductal carcinoma in situ (78%), whereas, in Group A, of low-grade ductal carcinoma in situ (n=13), it was positive in only 6 cases (21.40%; p=0.004). Conclusion The frequency of expression of survivin was significantly higher in the group of patients with high-grade ductal carcinoma in situ compared to those in the low-grade ductal carcinoma in situ group. PMID- 29694612 TI - Sociodemographic factors associated with pregnant women's level of knowledge about oral health. AB - Objective To evaluate knowledge on oral health and associated sociodemographic factors in pregnant women. Methods A cross-sectional study with a sample of 195 pregnant women seen at the Primary Care Unit Paraisopolis I, in Sao Paulo (SP), Brazil. For statistical analysis, chi2 or Fisher's exact test and multiple logistic regression were used. A significance level of 5% was used in all analyses. Results Schooling level equal to or greater than 8 years and having one or two children were associated with an adequate knowledge about oral health. Conclusion Oral health promotion strategies during prenatal care should take into account sociodemographic aspects. PMID- 29694613 TI - Is Zika virus outbreak a solved issue in Brazil? PMID- 29694614 TI - Is quality of life associated with compliance to pharmacoterapy in patients with chronic kidney disease undergoing maintenance hemodialysis? AB - Objective To analyzed the association of quality of life and compliance to drug treatment in chronic kidney disease patients. Methods The Short Form Health Survey was used to evaluate the quality of life of these patients, and the therapeutic complexity index was verified. The Morisky-Green test and the Brief Medication Questionnaire were applied to check compliance to drug therapy. Results A total of 197 patients were included. The Morisky-Green test and Brief Medication Questionnaire showed that most patients had low compliance to treatment (50.3% and 80.6%, respectively). Compliance was highly associated with gender (male) and slightly associated with complexity of therapy, mental health, and social aspects. Conclusion We observed a slight association between compliance to pharmacotherapy and quality of life and complexity of therapy, and a strong association with gender. PMID- 29694615 TI - Criminal liability of medical professionals in the Sao Paulo State Court of Appeals. AB - Objective To collect criminal justice data involving medical professionals in the Sao Paulo State Court of Appeals and to establish the number of criminal proceedings involving said professionals, the content of the accusations and the conviction rate per specialty. Methods A keyword search was carried out in the State Appellate Court case law website with the term "medical error" for decisions rendered from January 1st, 2011 to December 31st, 2016, and the subject "criminal law" was selected. Results A total of 34 cases met the inclusion criteria and were analyzed. Lower court's convictions accounted to 73.5% of the cases, with a slight tendency towards increase over the years. The number of cases per medical specialty was ten cases of clinical emergency, eight of obstetrics, seven of surgery, three of pediatrics (one case was related to pediatrics and obstetrics), two of orthopedic surgery, two of clinical director, one anesthesiologist and one nonemergency internal medicine physician. Among these cases, 6 were related to bodily injury, 26 to homicide and 2 criminal contempt. Conclusion The physicians most exposed to medical error were from surgical specialties, probably due to the higher rate of complications associated with the procedures, and emergency physicians, professionals who need greater qualification. PMID- 29694617 TI - Patient safety and the value of pharmaceutical intervention in a cancer hospital. AB - Objective To demonstrate economic impact of pharmaceutical evaluation in detection and prevention of errors in antineoplastic prescriptions. Methods This was an observational and retrospective study performed in a cancer hospital. From July to August 2016 pharmacists checked prescriptions of antineoplastic and adjuvant drugs. Drug-related problems observed were classified and analyzed concerning drug, pharmaceutical intervention, acceptability and characteristic of the error. In case of problem related to dose, we calculated a deviation percentage related with correct dose and value spent or saved. Data were analyzed using descriptive statistics with frequency and percentage. Results A total of 6,104 prescriptions and 12,128 medications were evaluated. Drug-related problems were identified in 274 (4.5%) prescriptions. Most of them was due to lack of information (n=117; 36.1%). Problems associated with dose accounted for 32.1% (n=98) of the total. In 13 cases (13.3%) ranging of prescribed dose was 50% greater than the correct dose. Intercepted drug-related problems provided savings of R$54.081,01 and expenses of R$20.863,36, therefore resulting in a positive balance of R$33.217,65. Each intervention promoted saving of R$126,78 with an acceptance rate of 98%. Main pharmaceutical interventions were information inclusion (n=117; 36.1%) and dose change (n=97; 29.9%). All errors were classified as error with no harm. Conclusion Simple actions such as prescription checking are able to identify and prevent drug-related problems, avoid financial losses and add immeasurable value to patient safety. PMID- 29694616 TI - Association between hypovitaminosis D and frequency of pulmonary exacerbations in children and adolescents with cystic fibrosis. AB - Objective We evaluated the association between vitamin D levels and nutritional status, pulmonary function and pulmonary exacerbations in children and adolescents with cystic fibrosis. Methods 25-hydroxyvitamin D (25(OH)D) levels of 37 children and adolescents were retrospectively evaluated. Pulmonary function, body mass index, height for age, and pulmonary exacerbations episodes were associated with vitamin D levels divided into two groups: sufficient (>=30ng/mL) and hypovitaminosis (<30ng/mL). Results Hypovitaminosis D (25(OH)D <30ng/mL) was observed in 54% of subjects. The mean level of 25(OH)D was 30.53+/-12.14ng/mL. Pulmonary function and nutritional status were not associated with vitamin D levels. Pulmonary exacerbations over a 2-year period (p=0.007) and the period from measurement up to the end of the follow-up period (p=0.002) were significantly associated with vitamin D levels. Conclusion Hypovitaminosis D was associated with higher rates of pulmonary exacerbations in this sample of children and adolescents with cystic fibrosis. Hypovitaminosis D should be further studied as a marker of disease severity in cystic fibrosis. Further prospective and randomized studies are necessary to investigate causality of this association. PMID- 29694618 TI - Chemotherapy protocols and incidence of oral mucositis. An integrative review. AB - This review aimed to analyze the scientific production on severity of oral mucositis as an adverse effect of chemotherapy. To this end, we performed a search at PubMed databases combining the keywords "oral mucositis" and "chemotherapy protocol". To describe the investigation, the following variables were considered: journal, year/place, study design, sample, protocol used and incidence of oral mucositis. A total of 547 articles were retrieved, of which 26 were selected. Out of these 26, only 2 reported severity of oral mucositis; the others only reported the presence of the condition. Protocols for treating different types of carcinoma were evaluated in 16 (61.53%) studies, for hematological malignancies in 6 (23.07%), and for hematopoietic stem cell transplantation in 4 (15.4%). Protocols for hematopoietic stem cell transplantation entail a high risk for oral mucositis, just as chemotherapy with cytarabine and high-dose 5-fluorouracil, alkylating agents and platinumbased compounds. To provide the best prevention and treatment for oral mucositis, it is essential to know the chemotherapy protocols used and their effects on the oral cavity. PMID- 29694619 TI - Functional magnetic resonance imaging for clinical evaluation of uterine contractility. AB - Uterine contractility out of the gestational phase, during the menstrual cycle and the habitual functional variations of the organ, this is one of the responsible mechanisms for reproduction and fertility, due to its direct action in the mechanisms conducting the spermatozoa to the ovule and in the decidual implantation. Pathologies such as uterine leiomyoma, endometriosis, adenomyosis, polycystic ovarian syndrome, as well as the use of intrauterine devices and oral contraceptives, may alter a functionality of uterine contractility. Thus, magnetic resonance imaging with ultrafast sequences provides a dynamic evaluation (cine-MRI) and thus the correlation of uterine contractility quality in patients with current infertility or pathologies. PMID- 29694620 TI - Critical review of cancer mortality using hospital records and potential years of life lost. AB - Objective To determine and discuss cancer mortality rates in southern Brazil between 1988 and 2012. Methods This was a critical review of literature based on analysis of data concerning incidence and mortality of prostate cancer, breast cancer, bronchial and lung cancer, and uterine and ovarian cancer. Data were collected from the online database of the Brazil Instituto Nacional de Cancer Jose Alencar Gomes da Silva. Results The southern Brazil is the leading region of cancer incidence and mortality. Data on the cancer profile of this population are scarce especially in the States of Santa Catarina and Parana. We observed inconsistency between data from hospital registers and death recorded. Conclusion Both cancer incidence and the mortality are high in Brazil. In addition, Brazil has great numbers of registers and deaths for cancer compared to worldwide rates. Regional risk factors might explain the high cancer rates. PMID- 29694621 TI - Correlation between physical examination and three-dimensional gait analysis in the assessment of rotational abnormalities in children with cerebral palsy. AB - Objective To evaluate the correlation between physical examination data concerning hip rotation and tibial torsion with transverse plane kinematics in children with cerebral palsy; and to determine which time points and events of the gait cycle present higher correlation with physical examination findings. Methods A total of 195 children with cerebral palsy seen at two gait laboratories from 2008 and 2016 were included in this study. Physical examination measurements included internal hip rotation, external hip rotation, mid-point hip rotation and the transmalleolar axis angle. Six kinematic parameters were selected for each segment to assess hip rotation and shank-based foot rotation. Correlations between physical examination and kinematic measures were analyzed by Spearman correlation coefficients, and a significance level of 5% was considered. Results Comparing physical examination measurements of hip rotation and hip kinematics, we found moderate to strong correlations for all variables (p<0.001). The highest coefficients were seen between the mid-point hip rotation on physical examination and hip rotation kinematics (rho range: 0.48-0.61). Moderate correlations were also found between the transmalleolar axis angle measurement on physical examination and foot rotation kinematics (rho range 0.44-0.56; p<0.001). Conclusion These findings may have clinical implications in the assessment and management of transverse plane gait deviations in children with cerebral palsy. PMID- 29694622 TI - Evaluation of radiofrequency electronic system in intraoperative monitoring of surgical textiles. AB - Objective To test performance of SurgiSafe(r), a radiofrequency electronic device to detect surgical textiles during operations as compared to manual counting. Methods Surgical sponges with radiofrequency TAGs were placed in the abdominal cavity of a pig submitted to laparotomy, in randomly distributed sites. The TAGs were counted manually and also using SurgiSafe(r). Positive and negative predictive values, sensitivity, specificity and time required for counting were analyzed for both methods. Results Through the analysis of 35 surgical cycles, SurgiSafe(r) immediately identified all sponges, with specificity, sensitivity, positive and negative predictive values of 100%. Although not statistically significant, the manual count had sensitivity of 99.72% and specificity of 99.90%. Conclusion SurgiSafe(r) proved to be an effective device to identify surgical sponges in vivo, in real time; and its use as an adjuvant to manual counting is very helpful to increase patient's safety. PMID- 29694623 TI - Comparison between subjective and objective evaluations of self-care performance in elderly inpatients. AB - Objetive To identify the functional status in self-care performance of elderly inpatients, through subjective and objective evaluations. Methods Fifty-five pairs of elderly and their respective caregivers of both sexes were submitted to subjective (self-rating and rating by caregivers) and objective assessment. The Performance Test of Activities of Daily Living and items in the Instrumental Activities of Daily Living scale were used. Functional status was rated 1 (unable to perform task), 2 (able to perform task with assistance) or 3 (able to perform task unassisted). The agreement rate among different self-rating and rating by caregivers, and objective assessment was calculated by dividing the number of identical responses by the total. Results Most elderly patients and caregivers were women (58.2% and 83.6%, respectively). The mean age was 80 years for elderly patients and 58.7 years for caregivers. Low schooling levels (1 to 4 years) prevailed among elderly patients (65.4%), while caregivers often had complete high education (32.7%). Functional status (FN=1, 2 and 3) varied between tasks, and the agreement rate between assessment methods ranged from 58 to 98.1%, particularly in comparisons involving objective assessment. Conclusion Self reported data and data contributed by caregivers must be compared with performance data collected via objective assessment for a reliable appreciation of the true functional status of older adults. PMID- 29694624 TI - Sericin and swimming on histomorphometric parameters of denervated plantar muscle in Wistar rats. AB - Objective To analyze the combined effects of the silk protein sericin and swimming exercise on histomorphometry of the plantar muscle in Wistar rats. Methods Forty adult rats were randomly allocated into 5 groups comprising 8 animals each, as follows: Control, Injury, Sericin, Swim, and Swim plus Sericin. Three days after crushing of the sciatic nerve the rats in the Swim and Swim plus Sericin Groups were submitted to swimming exercise for 21 days. Rats were then euthanized and the plantar muscle harvested and processed. Results Cross sectional area, peripheral nuclei and muscle fiber counts, nucleus/fiber ratio and smallest muscle fiber width did not differ significantly between groups. Morphological analysis revealed hypertrophic fibers in the Swim Group and evident muscle damage in the Swim plus Sericin and Injury Groups. The percentage of intramuscular collagen was apparently maintained in the Swim Group compared to remaining groups. Conclusion Combined treatment with sericin and swimming exercise did not improve muscle properties. However, physical exercise alone was effective in maintaining intramuscular connective tissue and preventing progression of deleterious effects of peripheral nerve injury. PMID- 29694625 TI - Assessment and enrolment process for liver transplantation: nursing management through quality indicators. AB - Objective To establish, measure and analyze quality indicators in the evaluation and enrolment process of patients in a liver transplant program. Methods A quantitative and non-experimental research, with data collected from the database of a liver transplant program, from September 2012 to September 2014. Descriptive statistics were used to analyze the quality indicators identified. Results We analyzed 1,311 visits in the transplant outpatient clinic, most males (66.7%), white (65.1%), mean age of 53 (+/-12.5) years, from the Southeastern Region (91.2%), and from the State of Sao Paulo (80.8%). The indicators measured were efficiency of patient admission process (54.8%), efficiency of evaluation of transplant indication (39.9%), efficacy of treatment of patients seen in the program (21.8%), and waiting time to inclusion in the waiting list, median of 84 days (36-142). Conclusion The quality indicators analyzed in this study enabled a quantitative view of the process, facilitating management of results and benchmarking with other transplant centers. Continuous monitoring can optimize resource allocation and planning of services in patient's admission process. PMID- 29694626 TI - Association of different biomarkers of renal function with D-dimer levels in patients with type 1 diabetes mellitus (renal biomarkers and D-dimer in diabetes). AB - Objective This study aimed to evaluate the association between different renal biomarkers with D-Dimer levels in diabetes mellitus (DM1) patients group classified as: low D-Dimer levels (< 318 ng/mL), which included first and second D-Dimer tertiles, and high D-Dimer levels (>= 318 ng/mL), which included third D Dimer tertile. Materials and methods D-Dimer and cystatin C were measured by ELISA. Creatinine and urea were determined by enzymatic method. Estimated glomerular filtration rate (eGFR) was calculated using CKD-EPI equation. Albuminuria was assessed by immunoturbidimetry. Presence of renal disease was evaluated using each renal biomarker: creatinine, urea, cystatin C, eGFR and albuminuria. Bivariate logistic regression analysis was performed to assess which renal biomarkers are associated with high D-Dimer levels and odds ratio was calculated. After, multivariate logistic regression analysis was performed to assess which renal biomarkers are associated with high D-Dimer levels (after adjusting for sex and age) and odds ratio was calculated. Results Cystatin C presented a better association [OR of 9.8 (3.8-25.5)] with high D-Dimer levels than albuminuria, creatinine, eGFR and urea [OR of 5.3 (2.2-12.9), 8.4 (2.5 25.4), 9.1 (2.6-31.4) and 3.5 (1.4-8.4), respectively] after adjusting for sex and age. All biomarkers showed a good association with D-Dimer levels, and consequently, with hypercoagulability status, and cystatin C showed the best association among them. Conclusion Therefore, cystatin C might be useful to detect patients with incipient diabetic kidney disease that present an increased risk of cardiovascular disease, contributing to an early adoption of reno and cardioprotective therapies. PMID- 29694627 TI - Expression of miR-155, miR-146a, and miR-326 in T1D patients from Chile: relationship with autoimmunity and inflammatory markers. AB - Objective The aim of this research was to analyze the expression profile of miR 155, miR-146a, and miR-326 in peripheral blood mononuclear cells (PBMC) of 47 patients with type 1 diabetes mellitus (T1D) and 39 control subjects, as well as the possible association with autoimmune or inflammatory markers. Subjects and methods Expression profile of miRs by means of qPCR using TaqMan probes. Autoantibodies and inflammatory markers by ELISA. Statistical analysis using bivariate correlation. Results The analysis of the results shows an increase in the expression of miR-155 in T1D patients in basal conditions compared to the controls (p < 0.001) and a decreased expression level of miR-326 (p < 0.01) and miR-146a (p < 0.05) compared T1D patients to the controls. miR-155 was the only miRs associated with autoinmmunity (ZnT8) and inflammatory status (vCAM). Conclusion Our data show a possible role of miR-155 related to autoimmunity and inflammation in Chilean patients with T1D. PMID- 29694628 TI - Papillary thyroid microcarcinoma: characteristics at presentation, and evaluation of clinical and histological features associated with a worse prognosis in a Latin American cohort. AB - Objective We aimed to describe the presentation of papillary microcarcinoma (PTMC) and identify the clinical and histological features associated with persistence/recurrence in a Latin American cohort. Subjects and methods Retrospective study of PTMC patients who underwent total thyroidectomy, with or without radioactive iodine (RAI), and who were followed for at least 2 years. Risk of recurrence was estimated with ATA 2009 and 2015 classifications, and risk of mortality with 7th and 8th AJCC/TNM systems. Clinical data obtained during follow-up were used to detect structural and biochemical persistence/recurrence. Results We included 209 patients, predominantly female (90%), 44.5 +/- 12.6 years old, 183 (88%) received RAI (90.4 +/- 44.2 mCi), followed-up for a median of 4.4 years (range 2.0-7.8). The 7th and 8th AJCC/TNM system classified 89% and 95.2% of the patients as stage I, respectively. ATA 2009 and ATA 2015 classified 70.8% and 78.5% of the patients as low risk, respectively. Fifteen (7%) patients had persistence/recurrence during follow-up. In multivariate analysis, only lymph node metastasis was associated with persistence/recurrence (coefficient beta 4.0, p = 0.016; 95% CI 1.3-12.9). There were no PTMC related deaths. Conclusions Our series found no mortality and low rate of persistence/recurrence associated with PTMC. Lymph node metastasis was the only feature associated with recurrence in multivariate analysis. The updated ATA 2015 and 8th AJCC/TNM systems classified more PTMCs than previous classifications as low risk of recurrence and mortality, respectively. PMID- 29694629 TI - Diagnosis and treatment of hypoparathyroidism: a position statement from the Brazilian Society of Endocrinology and Metabolism. AB - Objective To present an update on the diagnosis and treatment of hypoparathyroidism based on the most recent scientific evidence. Materials and methods The Department of Bone and Mineral Metabolism of the Sociedade Brasileira de Endocrinologia e Metabologia (SBEM; Brazilian Society of Endocrinology and Metabolism) was invited to prepare a document following the rules set by the Guidelines Program of the Associacao Medica Brasileira (AMB; Brazilian Medical Association). Relevant papers were retrieved from the databases MEDLINE/PubMed, LILACS, and SciELO, and the evidence derived from each article was classified into recommendation levels according to scientific strength and study type. Conclusion An update on the recent scientific literature addressing hypoparathyroidism is presented to serve as a basis for the diagnosis and treatment of this condition in Brazil. PMID- 29694630 TI - Cardiovascular risk in rural workers and its relation with body mass index. AB - Objective Evaluate the propensity of cardiovascular risk in rural workers and, through the Framingham Risk Score (FRS), relate this risk with the classification of Body Mass Index (BMI). Subjects and methods This study is characterized as descriptive and exploratory, with the participation of 138 subjects, ranging between 25-73 years old. Clinical and laboratory analysis of the risk factors contained in the FRS were performed, in addition to the determination of BMI, blood pressure, smoking and physical inactivity. Results The procedures indicated a low risk of a coronary event in 10 years with 70.3% of the population. In contrast, 88.4% of the subjects were overweight. It was evidenced a risk improvement as the BMI increased, since 96.4% of high-risk cases were overweight or obese. Conclusion Results suggest larger prevalence of intermediary or high FRS for women with higher BMI, which was not observed in men. PMID- 29694631 TI - Humoral hypercalcemia of pregnancy treated with bisphosphonates. AB - Hypercalcemia can be hazardous during pregnancy, most cases being due to primary hyperparathyroidism. We report a case of hypercalcemia with suppressed PTH levels necessitating treatment with bisphosphonates during pregnancy. A 38-year-old woman at the 26th week gestation was admitted because of symptomatic hypercalcemia. She did not take any medication that could influence her calcium levels. Physical examination was unremarkable. Laboratory tests on admission were: calcium 12.7 mg/dL (8.5-10.5 mg/dL), phosphorus 1.8 mg/dL (2.5-4.5 mg/dL) and PTH on 3 consecutive tests 1.2, 1.3 and 1.2 pg/mL (15-65 pg/mL). Her 24h urine calcium was 900 mg, 25-OH-D 40 ng/mL (30-58 ng/mL) and 1,25-OH-D 99 pg/mL (80-146 for women in the third trimester). Abdominal ultrasound revealed multiple hypervascular liver lesions consistent with hemangiomas by MRI. Breast and neck ultrasound were normal, and chest CT revealed few non-significant 0.3-0.7 cm pulmonary nodules with no change after an interval of 3 months. She was treated with isotonic saline, loop diuretics and calcitonin. Despite this treatment, calcium levels remained high (14.1 mg/dL), and pamidronate was initiated. On 35th week gestation, she underwent a cesarean section complicated by hypocalcemia of the newborn. Eight weeks after delivery, her calcium levels are 9.4 mg/dL and PTH 18 mg/dL. According to the extensive workup and the post-partum normalization of PTH and calcium levels, we conclude that excessive secretion of placental PTHrP was the cause of hypercalcemia in this patient. No significant adverse effect of bisphosphonate on the mother or baby were seen at the short term follow up. PMID- 29694632 TI - Influence of maternal weight gain on birth weight: a gestational diabetes cohort. AB - Objective Our objective was to evaluate gestational weight gain (GWG) patterns and their relation to birth weight. Subjects and methods We prospectively enrolled 474 women with gestational diabetes mellitus (GDM) at a university hospital (Porto Alegre, Brazil, November 2009-May 2015). GWG was categorized according to the 2009 Institute of Medicine guidelines; birth weight was classified as large (LGA) or small (SGA) for gestational age. Adjusted relative risks (aRRs) and 95% confidence intervals (95% CIs) were determined. Results Adequate GWG occurred in 121 women [25.5%, 95% CI: 22, 30%]; excessive, in 180 [38.0%, 95% CI: 34, 43%]; and insufficient, in 173 [36.5%, 95% CI: 32, 41%]. In women with normal body mass index (BMI), the prevalence of SGA was higher in those with insufficient compared to adequate GWG (30% vs. 0%, p < 0.001). In women with BMI >= 25 kg/m2, excessive GWG increased the prevalence of LGA [aRR 2.58, 95% CI: 1.06, 6.29] and protected from SGA [aRR 0.25, 95% CI: 0.10, 0.64]. Insufficient vs. adequate GWG did not influence the prevalence of SGA [aRR 0.61, 95% CI: 0.31, 1.22]; insufficient vs. excessive GWG protected from LGA [aRR 0.46, 95% CI: 0.23, 0.91]. Conclusions One quarter of this cohort achieved adequate GWG, indicating that specific ranges have to be tailored for GDM. To prevent inadequate birth weight, excessive GWG in women with higher BMI and less than recommended GWG in normal BMI women should be avoided; less than recommended GWG may be suitable for overweight and obese women. PMID- 29694633 TI - A possible association between the -2518 A>G MCP-1 polymorphism and insulin resistance in school children. AB - Objective Monocyte chemoattractant protein 1 (MCP-1) has been suggested to be involved in the pathophysiology of insulin resistance (IR); therefore, variants in the MCP-1 gene may contribute to the development of this disease. The aim of this study was to analyze the relationship of the -2518 A>G MCP-1 (rs1024611) gene polymorphism with insulin resistance in Mexican children. Subjects and methods A cross-sectional study was performed in 174 children, including 117 children without insulin resistance and 57 children with IR, with an age range of 6-11 years. Levels for serum insulin and high-sensitivity C-reactive protein were determined. The -2518 A>G MCP-1 polymorphism was identified by the polymerase chain reaction-restriction fragment length polymorphism method. Insulin resistance was defined as a HOMA-IR in the upper 75th percentile, which was >= 2.4 for all children. Results Genotype frequencies of the rs1024611 polymorphism for the insulin-sensitive group were 17% AA, 48% AG and 35% GG, and the frequency of G allele was 59%, whereas frequencies for the insulin-resistant group were 12% AA, 37% AG and 51% GG, and the frequency of G allele was 69%. The genotype and allele frequencies between groups did not show significant differences. However, the GG genotype was the most frequent in children with IR. The GG genotype was associated with insulin resistance (OR = 2.2, P = 0.03) in a genetic model. Conclusion The -2518 A>G MCP-1 gene polymorphism may be related to the development of insulin resistance in Mexican children. PMID- 29694634 TI - Higher fiber intake is associated with lower blood pressure levels in patients with type 1 diabetes. AB - Objective The present investigation sought to evaluate the potential association between dietary fiber intake and blood pressure (BP) in adult patients with type 1 diabetes (T1D). Subjects and methods A cross-sectional study was carried out in 111 outpatients with T1D from Porto Alegre, Brazil. Patients were predominantly male (56%) and white (88%), with a mean age of 40 +/- 10 years, diabetes duration of 18 +/- 9 years, BMI 24.8 +/- 3.85 kg/m2, and HbA1c 9.0 +/- 2.0%. After clinical and laboratory evaluation, dietary intake was evaluated by 3-day weighed diet records, whose reliability was confirmed by 24-h urinary nitrogen output. Patients were stratified into two groups according to adequacy of fiber intake in relation to American Diabetes Association (ADA) recommendations: below recommended daily intake (< 14g fiber/1000 kcal) or at/above recommended intake (>= 14g/1000 kcal). Results Patients in the higher fiber intake group exhibited significantly lower systolic (SBP) (115.9 +/- 12.2 vs 125.1 +/- 25.0 mmHg, p = 0.016) and diastolic blood pressure (DBP) (72.9 +/- 9.2 vs 78.5 +/- 9.3 mmHg, p = 0.009), higher energy intake (2164.0 +/- 626.0 vs 1632.8 +/- 502.0 kcal, p < 0.001), and lower BMI (24.4 +/- 3.5 vs 26.2 +/- 4.8, p = 0.044). Linear regression modelling, adjusted for age, energy intake, sodium intake, and BMI, indicated that higher fiber intake was associated with lower SBP and DBP levels. No significant between-group differences were observed with regard to duration of diabetes, glycemic control, insulin dosage, or presence of hypertension, nephropathy, or retinopathy. Conclusion We conclude that fiber consumption meeting or exceeding current ADA recommendations is associated with lower SBP and DBP in patients with T1D. PMID- 29694636 TI - (Epi) Genetics and the complexity of diabetes mellitus. PMID- 29694635 TI - Outcomes of patients with bone metastases from differentiated thyroid cancer. AB - Objective Bone metastases (BM) from differentiated thyroid cancer (DTC) are associated with poor survival rates. Due to the low frequency of this entity, we performed a multicentric retrospective study that aimed to evaluate the presentation, outcome and causes of death in this population. Subjects and methods We reviewed file records from 10 databases. BM were diagnosed by: i) biopsy and/or ii) radioiodine (RAI) bone uptake + elevated thyroglobulin (Tg) levels and/or c) bone uptake of 18-FDG in the PET-CT scan + elevated Tg levels. Results Fifty-two patients with DTC were included (44% male, mean age 54 years); 58% had papillary histology. BM were synchronous with DTC diagnosis in 46% of the participating cases. BM were symptomatic in 65% of the cases. Multiple BM were present in 65% of patients, while simultaneous metastatic disease in additional sites was found in 69%. Ninety-eight percent of patients received treatment for the BM, which included RAI therapy in 42 patients; 30 of them received cumulative RAI doses that were larger than 600 mCi 131I. The mean follow-up after a BM diagnosis was 34 months. The 2- and 5-year survival rates after diagnosis of the first BM were 64% and 38%, respectively. The status on the last evaluation was DTC-related death in 52% of the patients; 26% of them died from direct complications of BM or their treatments. Conclusion BM are usually radioiodine refractory and are associated with a short overall survival, although most of the patients died of causes not directly related to the BM. PMID- 29694637 TI - Increased insulin sensitivity in individuals with neurofibromatosis type 1. AB - Objects To compare insulin resistance (IR) and metabolic aspects of patients with neurofibromatosis type 1 (NF1) and individuals without the disease. Subjects and methods Forty patients with NF1 were matched by sex, age, and body mass index (BMI) to 40 controls from the community. Blood samples were collected for biochemical assessment. Homeostasis model assessment adiponectin (HOMA-AD), Homeostasis model assessment insulin resistance (HOMA-IR), and adiponectin/leptin ratio (ALR) were used to identify IR. Results The median HOMA-IR values were similar between the groups. However, the HOMA-AD value was significantly lower and the ALR significantly higher in the NF1 group. Fasting blood glucose (FBG), leptin, and visfatin levels of patients with NF1 were significantly lower, although adiponectin levels were significantly higher than those in the controls. Fasting insulin and blood glucose levels 2 hours after administration of 75 g of dextrose, glycated hemoglobin, and resistin showed no significant differences between groups. The HOMA-AD correlated with BMI, FBG, blood glucose levels 2 hours after administration of 75 g of dextrose, fasting insulin, glycated hemoglobin, adiponectin, leptin, visfatin, ALR, and HOMA-IR. The ALR correlated with BMI leptin, visfatin, and adiponectin. Conclusions Lower levels of FBG, leptin, visfatin, and HOMA-AD, and higher adiponectin levels and ALR may be related to increased insulin sensitivity and lower occurrence of type 2 diabetes mellitus in patients with NF1. PMID- 29694638 TI - A review of Cushing's disease treatment by the Department of Neuroendocrinology of the Brazilian Society of Endocrinology and Metabolism. AB - The treatment objectives for a patient with Cushing's disease (CD) are remission of hypercortisolism, adequate management of co-morbidities, restoration of the hypothalamic-pituitary-adrenal axis, preservation of fertility and pituitary function, and improvement of visual defects in cases of macroadenomas with suprasellar extension. Transsphenoidal pituitary surgery is the main treatment option for the majority of cases, even in macroadenomas with low probability of remission. In cases of surgical failure, another subsequent pituitary surgery might be indicated in cases with persistent tumor imaging at post surgical magnetic resonance imaging (MRI) and/or pathology analysis of adrenocorticotropic hormone-positive (ACTH+) positive pituitary adenoma in the first procedure. Medical treatment, radiotherapy and adrenalectomy are the other options when transsphenoidal pituitary surgery fails. There are several options of medical treatment, although cabergoline and ketoconazole are the most commonly used alone or in combination. Novel treatments are also addressed in this review. Different therapeutic approaches are frequently needed on an individual basis, both before and, particularly, after surgery, and they should be individualized. The objective of the present review is to provide the necessary information to achieve a more effective treatment for CD. It is recommended that patients with CD be followed at tertiary care centers with experience in treating this condition. PMID- 29694639 TI - Assessing endocrine and immune parameters in human immunodeficiency virus infected patients before and after the immune reconstitution inflammatory syndrome. AB - Objective The present study compares immune and endocrine parameters between HIV infected patients who underwent the Immune Reconstitution Inflammatory Syndrome (IRIS-P) during antiretroviral therapy (ART) and HIV-patients who did not undergo the syndrome (non-IRIS-P). Materials and methods Blood samples were obtained from 31 HIV-infected patients (15 IRIS-P and 16 non-IRIS-P) before ART (BT) and 48 +/- 2 weeks after treatment initiation (AT). Plasma Interleukin-6 (IL-6) and Interleukin-18 (IL-18) were determined by ELISA. Cortisol, dehydroepiandrosterone sulfate (DHEA-S) and thyroxin concentrations were measured using chemiluminescence immune methods. Results Concentrations of IL-6 (7.9 +/- 1.9 pg/mL) and IL-18 (951.5 +/- 233.0 pg/mL) were significantly higher (p < 0.05) in IRIS-P than in non-IRIS-P (3.9 +/- 1.0 pg/mL and 461.0 +/- 84.4 pg/mL, respectively) BT. Mean T4 plasma level significantly decreased in both groups of patients after treatment (p < 0.05). In both groups cortisol levels were similar before and after ART (p > 0.05). Levels of DHEA-S in IRIS-P decreased AT (1080.5 +/- 124.2 vs. 782.5 +/- 123.8 ng/mL, p < 0.05) and they were significantly lower than in non-IRIS-P (782.5 +/- 123.8 vs. 1203.7 +/- 144.0 ng/mL, p < 0.05). IRIS-P showed higher values of IL-6 and IL-18 BT and lower levels of DHEA-S AT than in non-IRIS-P. Conclusion These parameters could contribute to differentiate IRIS-P from non-IRIS-P. The significant decrease in DHEA-S levels in IRIS-P after ART might suggest a different adrenal response in these patients, which may reflect the severity of the disease. PMID- 29694641 TI - The Janus faces of thyroid carcinoma. PMID- 29694640 TI - The relationship between of ACE I/D and the MTHFR C677T polymorphisms in the pathophysiology of type 2 diabetes mellitus in a population of Brazilian obese patients. AB - Objectives This study aimed to evaluate the frequencies of the angiotensin converting enzyme (ACE) gene insertion/deletion (I/D) and methylenetetrahydrofolate reductase (MTHFR) gene C677T polymorphisms in obese patients with and without type 2 diabetes mellitus (T2DM). Subjects and methods These polymorphisms were analyzed by polymerase chain reaction in 125 patients with obesity, 47 (T2DM) and 78 (Control Group). Results No significant difference was found on comparing the T2DM and Control Groups in respect to the genotypic frequencies of the polymorphisms - (II: 13.3% vs. 12.0%; ID: 37.8% vs. 37.3; DD: 48.9% vs. 50.7%; CC: 36.2% vs. 39.0%; CT: 46.8% vs. 49.3%; TT: 17.0% vs. 11.7%), and alleles (I: 32.2% vs. 30.7%; D: 67.8% vs. 69.3%; C: 59.6% vs. 63.6%; T: 40.4% vs. 36.4%) and their synergisms in the pathophysiology of T2DM. On analyzing the T2DM Group, there were no significant differences in the presence of complications. In this population of Brazilian obese patients, no correlation was found between the ACE and MTHFR polymorphisms in the development of T2DM. Conclusion Analyzing only the group with diabetes, there was also no relationship between these polymorphisms and comorbidities. PMID- 29694643 TI - Quantitative analysis of the perimeniscal position of the inferior lateral genicular artery (ILGA): magnetic resonance imaging study. AB - PURPOSE: The inferior lateral genicular artery (ILGA) passes around the lateral knee joint, adjacent to the lateral meniscus (LM). ILGA injuries in total knee arthroplasty or arthroscopic surgery can result in recurrent hemarthrosis or painful pseudoaneurysms. Detailed information about the perimeniscal position of the ILGA relative to the LM is necessary to avoid these complications. METHODS: 3 T MR images of 100 knees (mean age 36.3 +/- 11.2 years) were retrospectively reviewed. The perimeniscal area was divided into four regions: the anterior, middle, popliteal hiatus, and posterior zones. In each zone, the ILGA diameter, superoinferior position (assessed as the height of the ILGA from the LM base), and distance between the meniscocapsular junction and the ILGA were measured. RESULTS: The distance between the ILGA and meniscocapsular junction was significantly smaller in the middle zone than in the other three zones (anterior 5.3 +/- 0.8 mm, middle 1.4 +/- 0.4 mm, popliteal hiatus 6.1 +/- 1.0 mm, and posterior 5.6 +/- 1.5 mm, p < 0.05). In the superoinferior position, the height of the ILGA was 3.4 +/- 0.9 mm in the anterior zone, 0.4 +/- 1.3 mm in the middle zone, - 1.9 +/- 1.8 mm in the popliteal hiatus zone, and - 1.3 +/- 4.3 mm in the posterior zone. When the LM bottom is the base, the ILGA was located superiorly in the anterior zone, close to the base in the middle zone, and inferiorly in the popliteal hiatus zone. CONCLUSIONS: To avoid ILGA injury, close attention is necessary during surgical procedures involving the meniscocapsular junction of the LM, especially at the meniscal base in the middle zone. PMID- 29694642 TI - Final analysis of the JALSG Ph+ALL202 study: tyrosine kinase inhibitor-combined chemotherapy for Ph+ALL. AB - The Japan Adult Leukemia Study Group (JALSG) Ph+ALL202 study reported a high complete remission (CR) rate for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) patients treated with imatinib-combined chemotherapy. However, the long-term treatment efficacy remains uncertain. Here, we report a final analysis of the JALSG Ph+ALL202 study. The outcomes were compared with those of the JALSG ALL93 and ALL97 studies, which were conducted in the pre-imatinib era. Ninety-nine newly diagnosed Ph+ALL patients were enrolled in Ph+ALL202 (median age, 45 years; median follow-up, 4.5 years). CR was achieved in 96/99 (97%) patients. Fifty-nine of these 96 patients (61%) underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT) in their first CR (CR1). The 5-year overall and disease-free survival (DFS) rates were 50 and 43%, respectively, which were significantly higher compared to those in the pre imatinib era (15 and 19%, respectively). Multivariate analysis revealed that imatinib administration, allo-HSCT in CR1, and a white blood cell count < 30 * 109/L were favorable independent prognostic factors for long-term DFS. Improved odds of receiving allo-HSCT and a lower relapse rate leaded to good long-term outcomes. The 3-year DFS tended to be higher in PCR-negative than that in PCR positive patients (29 vs. 14%) in the non-HSCT patients, and this tendency was also seen in the allo-HSCT patients (59 vs. 50%). The higher rate of CR upon imatinib use may have contributed to these improvements. PMID- 29694644 TI - Neurological disease in the aftermath of terrorism: a review. AB - The purpose of our review is to discuss current knowledge on long-term sequelae and neurological disorders in the aftermath of a terrorist attack. The specific aspects of both psychological and physical effects are mentioned in more detail in this review. Also, the outcomes such as stress-related disorders, cardiovascular disease, and neurodegenerative disease are explained. Moreover, PTSD and posttraumatic structural brain changes are a topic for further investigations of the patients suffering from these attacks. Not only the direct victims are prone to the after effects of the terroristic attacks, but the rescue workers, physicians, witnesses and worldwide citizens may also be affected by PTSD and other neurological diseases as well. The determination of a whole series of risk factors for developing neurological disorders can be a means to set up early detection, preventative measures, to refine treatment and thus to gain better outcome in the future. PMID- 29694645 TI - Effects of ultrasound-guided botulinum toxin type-A injections with a specific approach in spastic cerebral palsy. AB - The aim of this study was to detect effects of ultrasound-guided botulinum toxin type-A (US-guided BoNT-A) injections prepared according to lower extremity innervation zones on spasticity and motor function in 3-16 years children with diplegic and hemiplegic spastic cerebral palsy. This study included 25 patients between 3 and 16 years of age who admitted to our clinic in 2017, were being followed in our clinic with a diagnosis of cerebral palsy, had BoNT-A injections due to lower extremity spasticity. The US-guided BoNT-A injections were administered into the spastic muscles using a specific approach according to innervation zones of muscle. Modified Ashworth Scale (MAS) and Gross Motor Functional Classification System (GMFCS) were assessed at the baseline, and 4 and 12 weeks after the BoNT-A injections. Minimum and maximum ages of the patients were 45 and 192 months, and gender distribution was 8 females and 17 males. Significant decreases in the MAS scores of the knee and ankle tones were measured 4 and 12 weeks after the BoNT-A injection when compared to the baseline scores (p < 0.025). Hip muscle tonus only decreased 12 weeks after the injection (p < 0.025). In parallel with a reduction in spasticity GMFCS improved from 3 to 2 in the 4th and 12th weeks. US-guided BoNT-A injections with Euro-musculus approach is a practical and effective method to perform injections into proper points of proper muscles in children with spastic cerebral palsy. PMID- 29694647 TI - Atrial fibrillation and hypertension: State of the art. AB - Atrial fibrillation and hypertension are often coexistent. Their incidence increases with advancing age and they are responsible for considerable morbidity and mortality. The relation between theses 2 diseases has long been discussed and determined by clinical studies. Left ventricular hypertrophy and left atrial remodeling during hypertension favor the development of atrial fibrillation. AF during hypertension increases the risk of thromboembolic complications and heart failure. In patients with hypertension, pharmacological treatment may control the cardiac structural changes and retard or prevent the occurrence of atrial fibrillation. In case of atrial fibrillation, treatment should be focused on the control of heart rate and rhythm and the prevention of thromboembolic accidents. A strict control of blood pressure is highly required in this situation. PMID- 29694646 TI - Impairment of chondrocyte proliferation after exposure of young murine cartilage to an aged systemic environment in a heterochronic parabiosis model. AB - AIM: The aim of this study was to investigate whether an aged systemic environment could impair young cartilage tissue in mice. METHODS: Mice differing in age were randomly divided into three groups. Group 1 was the experimental group (Y/O group) consisting of the heterochronic parabiosis model (2-month old/12-month-old, young/old). Group 2 was the surgical control group (Y/Y group) with the isochronic parabiosis model (2-month-old/2-month-old, young/young). Group 3 consisted of the ageing control mice (2-month-old alone, Y group). Young knee cartilages collected from all three groups at 4 months after surgery were compared. Fluorescence molecular tomography (FMT) was used to confirm whether the two mice in parabiosis shared a common blood circulation at 2 weeks after surgery. The knee joints of young mice were examined radiologically at 4 months after surgery. Histological scoring was assigned to grade the severity of osteoarthritis (OA). Immunohistochemistry and quantitative reverse transcription polymerase chain reaction were used to evaluate OA-related protein expression and gene expression, and chondrocyte proliferation was determined with EdU staining. RESULTS: FMT imaging confirmed cross-circulation in the parabiotic pairs. The percentage of EdU-positive chondrocytes in young mice from the Y/O group was significantly lower compared with those of the Y/Y and Y groups (p <0.05 for both). There was no statistically significant difference in the mRNA expression of collagen type II (Col2), collagen type X (Col10), and matrix metalloproteinase 13 (MMP13) among the three groups (P>0.05), but expression of sex-determining region Y box 9 (Sox9) mRNA in young cartilage from the Y/O group was markedly attenuated compared to those in the Y/Y and Y groups (p <0.05 for both). In the Y/O group, mRNA expression of runt-related transcription factor 2 (Runx2) in young cartilage was significantly increased compared to the Y/Y and Y groups (p <0.05 for both). The changes in Col2, Col10, MMP13, Runx2 and Sox9 at the protein level mimicked the alterations found at the mRNA level. Loss of cartilage proteoglycan in young mice from the Y/O group was significantly greater compared to the Y/Y and Y groups (p <0.05 for both), despite the lack of significant difference among the three groups in OARIS and osteophytosis scores. CONCLUSION: Heterochronic parabiosis exerts a negative effect on chondrocyte proliferation in the knee cartilage of young mice. PMID- 29694648 TI - Prosthetic valve endocarditis: clinical, bacteriological and therapeutic aspects. AB - BACKGROUND: The prosthetic valve endocarditis(PVE) is a serious complication of valve replacement surgery. The aim of this work was to analyze the clinical and echocardiography characters of the PVE, deduce surgery indication, and determinate the prognostic factors Methods :We presented a retrospective descriptive study from 2000 to 2014 which included 30 patients hospitalized in department of cardiology in la Rabta hospital for certain PVE according to DUCKES criteria. RESULTS: Our study consisted of 18 male patients with sex ratio of 1.5 ,the mean age was 44 years; These PVE were early in 6 cases and delayed in 24 cases. Fever was present in 28 patients..splenomegaly was present in 7 patients and cutaneous signs were present in 6 patients Blood cultures were negatives in 16 patients .Staphylococcus was isolated in 7 cases (23.3%), a streptococcus in 5 cases (16.6%), a gram negative bacillus in 1 case (3, 3%) and one enterococci in 1 case (3.3%).The transesophageal and transthoracic echocardiography performed in all patients showed vegetation for 17 patients, a Dishence of prosthetic valve in 14 patients, prosthesis obstruction in two patients and annular abscess in 4 patients . 22 complications were reported in 21 patients; il was an hemodynamic complication in 13 cases , a septic complication (uncontrolled infection ) in three patients, embolic complication (ischemic transit stroke ) in 4 cases and mixed (hemodynamic and septic) in one patient. The indication for surgery was retained in 18 patients; the need for early surgery was because of congestive heart failure in 14 patients and uncontrolled infection in 4 patients ; but it was performed in 13cases with a period between 1 and 30 days the operation the global mortality was about 30%. he predictors factors of mortality released from our study are: the early character of EPV, heart failure, uncontrolled infection, staphylococcal endocarditis and dishence of prosthesis with significant regurgitation. CONCLUSION: PVE is still a serious complication leading to high mortality . Combined medical and surgical treatment is recommended. PMID- 29694649 TI - Prognostic value of Ki67: comparison of the proliferation index between meningiomas with and without infiltration of glial tissue. AB - BACKGROUND: Although generally considered benign, meningiomas can cause significant morbidity and mortality. Histologic grade is the most useful morphologic predictor of recurrence. OBJECTIVES: To compare Ki67 labeling index between meningioma grade I and meningioma grade II with brain invasion. METHODS: We analyzed 20 primary meningioma, 10 of which were grade I and 10 of which were grade II. Ki67 proliferative indices were determined in all cases. RESULTS: The patient population consisted of 9 males and 11 females with mean age of 60 years. For meningioma grade I, the Ki67 labeling index varied between 1 and 15% with an average of 3.1%. A diagnosis of gradeII meningiomas was made solely on the basis of brain invasion. The immunohistochemical study noted that the Ki67 index varied between 1 and 20% with an average of 6,8%. CONCLUSION: The Ki67 labeling index shows a significant increase from grade I to grade II. It may provide useful prognostic information. PMID- 29694650 TI - Value of euroscore II to predict operative mortality in infectious endocarditis surgery. AB - BACKGROUND: Stratification of surgical risk is an important step in cardiac surgery, often based on the estimation of operative mortality. The EuroSCORE II (ES II) incorporates several factors in the calculation of mortality, but few are specific to Infectious endocarditis (IE). AIM: Our study is aimed to evaluate the predictive power of the Es II in the surgery of IE and to test its discriminating power according to certain specific parameters of the IE. METHODS: 55 surgical procedures were carried out between January 2000 and June 2012 (37 EI on native valves and 18 on prosthesis). The mortality observed was compared with the mortality predicted by Es II. The discriminant capacity of the Es II model was tested using the receiver operating characteristic (ROC) curve model by comparing the areas under the curve (AsC). RESULTS: For our cohort The observed mortality was 30.9 % , the mortality predicted by Es II was 10.5%. in general, the EsII discriminatory capacity for mortality was satisfactory: the ROC AsC was 0,76. By analyzing the subgroups of the endocarditis, Es II lost its discriminating power: theROC AsC was: 0.64 for staphylococcal, 0.62 for the annular abscess and 0.56 for endocarditis on prosthesis. CONCLUSION: The EuroSCORE II model has a satisfactory discriminating power in the IE. However, analysis of subgroups leads to decrease in this discriminating power. Thus, some specific parameters of the IE, which do not appear in the EuroSCORE II model, should be taken into accountwhen analyzing mortality. PMID- 29694651 TI - Antiglaucomatous treatments and ocular surface. AB - BACKGROUND: the antiglaucomatous treatments interact with the ocular surface and can induce its alteration which may affect the therapeutic results Aim : to describe the interactions between the ocular surface and anti-glaucoma medications and to propose practical attitudes to prevent and manage this issue. METHODS: a retrospective study about 100 patients with a primary opened angle glaucoma treated with anti-glaucomatous drops containing preservatives. We performed an exhaustive examination of the ocular surface with fluorescein instillation to search superficial punctuate keratitis and to evaluate the break up time. All patients had a Schirmer test I. RESULTS: our patients were under monotherapy in 46% ,two medications in 36%, three medications in 11% and four medications in 7% .Beta-blockers were statistically related to the conjunctival hyperaemia (p = 0.014), BUT alteration (p = 0.001) and Schirmer test <= 5 mm (p = 0.0001). Prostaglandin analogues were statistically related to a Schirmer test <= 5 mm (p = 0.02). The use of more than two anti-glaucomatous medications was linked to the severity of the clinical signs. CONCLUSIONS: anti glaucoma drops affect the ocular surface through several mechanisms: allergic reaction, direct and indirect toxicity of the active agents as well as their preservatives. The risk is increased by the prior ocular surface abnormalities in these patients. This disease influences the quality of life and leads to poor adherence to treatment. PMID- 29694652 TI - Impact of pregnancy on sexuality : a cross-sectional study of 100 tunisian women. AB - BACKGROUND: Pregnancy is a period during which anatomical, physiological and psychological changes may affect couple sexuality. AIM: To determine the knowledge and practices in sexuality, and identify the particularities of the sexual function during pregnancy. METHODS: A cross-sectional, descriptive and analytical study of pregnant women who responded to a questionnaire sent by Internet through a social network. RESULTS: Ninety-one percent of the 100 enrolled women were aged 25 to 34 years; 97% had a university education, and 66% were in the third quarter. Ninety-four percent of women thought that sexual intercourse is possible during pregnancy. The main reason to continue having sex during pregnancy was to have pleasure for either partner (87%). The reasons not to have sex were mainly fatigue (63%) and discomfort (51%). The main sources of information were the Internet (82%) and physicians (70%). During pregnancy, 92% of women continued to have sex with, however, a reduced frequency compared to the period before pregnancy. Fifty-five percent of women had a decreased desire level, and sexual satisfaction was also decreased in 43% of women. Sexual desire and lubrication were present half the time or more in the second quarter in, respectively, 69% and 55% of pregnant women. The difference with pregnant women in the first and third quarters was statistically significant. CONCLUSION: Our study focused on women who had most often access to scientific information about pregnancy and sexuality. The pleasure was the main reason to continue having sexual activity. The second quarter was the most sexually "rich" period. PMID- 29694653 TI - Clinical factors predictive of traumatic brain injuries in case of mild traumatic brain injury in children: case-control study. AB - BACKGROUND: Mild head injury (MHI) is very common in children and the problem is a lack of consensus criteria for the indication of a brain CT. OBJECTIVE: To determine predictors of cranio-cerebral lesions (CCL) in the case of MHI in children. METHODS: Case-control study over a period of 3 years. Included children aged 1 month to 15 years, were those admitted to the department of Pediatric Emergencies for MHI and had performed a brain CT. The principal outcome was the presence of traumatic brain injury. Statistical analysis focused on univariate and multivariate tests was done using SPSS version 16.0. RESULTS: We included 418 children. The median age was 6 years with a sex ratio of 2.24. The main mechanisms of trauma were the traffic accident. Cerebral CT proved to be abnormal in 191 children (45.7%). The main lesions found were the skull fractures, brain contusion and epidural hematoma. Predictors retained after logistic regression were the presence of an initial loss of consciousness regardless of its duration (p = 0.007), hematoma of the scalp (p = < 0.0001) and at least one clinical sign for a fracture of the skull base (p = 0.016). CONCLUSION: In case of MHI in children, the initial loss of consciousness, the presence of a hematoma of the scalp and the presence of at least one sign in favor of the skull base fracture seem most predictive of cranio-cerebral lesions. PMID- 29694654 TI - Prevalence and risk factors of pressure ulcers in a Tunisian hospital. AB - BACKGROUND: the aim of thisstudywas to investigate the prevalence of pressure ulcers in hospitalized patients at the Charles Nicolle Hospital in Tunis, measure the risk of their occurrence, analyzepreventive and curative measuresundertaken and evaluatefactorspredisposing to pressure ulcers. METHODS: A one-day survey was performed in all hospitalized patients. Emergency services, neonatology and pediatrics were excluded. The Braden scale was used to measure the patient's risk for the development of pressure ulcers. Analysis of risk factors was performed using SPSS version 19 software. RESULTS: A total of 473 patients was included. The mean age was 52.26 years. Nearly 10% of patients had a moderate or a high risk of developing pressure ulcers with a Braden score less than 18. The prevalence of patients with pressure ulcers was 5.3% with a prevalence of 4.7% of nosocomial pressure ulcer. There was no significant difference in prevalence between medical and surgical services. The prevalence was relatively more important in intensive care and general surgery. The most frequent sites were sacrum and heels. Stages 3 (46.4%) and 2 (37.5%) were the mainly stages descriped. Evaluation of management of bedsores formed revealed that half was treated with modern wound dressings. Statistical analysis revealed that a Braden score <18 is correlated with pressure ulcers ( 96% of patients with bedsores. Patients transferred from other services, patients recently operated or those with probably inadequate diet seem to be more at risk of developing pressure ulcers. In contrast, age and sex were not identified as significant risk factors. CONCLUSION: pressure ulcer remains a significant problem in hospital. This problem is preventable when applying adequate prevention but its management requires a multidisciplinary approach. PMID- 29694655 TI - Pseudo papillary and solid tumor of the pancreas: a rare tumor and a difficult diagnosis. AB - The pseudopapillary and solid tumor of the pancreas is a rare disease that accounts for 2% of pancreatic tumors. It affects mainly young, female adults. The clinical features are not specific, hence the diagnostic difficulty and the importance of imaging. The diagnosis is based on pathological examination coupled with immunohistochemistry. The aim of our work was to report the difficulty of the diagnostic procedure in a patient with a pancreatic cystic tumor. PMID- 29694656 TI - T-cell/histiocyte-rich large B-cell lymphoma of stomach: a rare variant of gastric B cell lymphoma. PMID- 29694657 TI - Lumbar hernia in a newborn revealing Lumbo-costovertebral syndrome. PMID- 29694658 TI - Bilateral hypertrophy of the lacrimal gland revealing systemic sarcoidosis. PMID- 29694659 TI - Delivering growth factors through a polymeric scaffold to cell cultures containing both nucleus pulposus and annulus fibrosus. AB - AIM: The aim of this in vitro experimental study was to design a novel, polyvinyl alcohol(PVA)-basedpolymericscaffold that permits the controlled release of insulin-likegrowthfactor1(IGF-1)/bonemorphogenetic protein-2(BMP-2) following intervertebral disc administration. MATERIAL AND METHODS: The drug delivery system was composed of two different solutions that formed a scaffold within seconds after coming into contact with each other. We performed swelling,pH,temperature tests and analysis of the controlled release of growth factors from this system.The release kinetics of the growth factors was determined through enzyme linked immunosorbent assay(ELISA). Cell proliferation and viability was monitored with microscopy and analyzed using an MTT assay and acridine orange/propidium iodide(AO/PI) staining. Chondroadherin(CHAD), hypoxiainduciblefactor-1alpha(HIF-1alpha),collagentypeII(COL2A1) gene expressions were determined with quantitative real-timepolymerasechainreaction(qRT-PCR) analysis to show the effects of IGF-1/BMP-2 administration on annulus fibrosus cell(AFC)/nucleus pulposus cell(NPC) cultures. RESULTS: The scaffold allowed for the controlled release of IGF-1 and BMP-2 in different time intervals. It was observed that as the application time increased, the number of cells and the degree of extracellular matrix development increased in AFC/NPC cultures. AO/PI staining and an MTT analysis showed that cells retained their specific morphology and continued to proliferate. It was observed that HIF-1alpha and CHAD expression increased in a time-dependent manner, and there wasn't any COL2A1 expression in the AFC/NPC cultures. CONCLUSION: The designed scaffold may be used as an alternative method for intervertebral disc administration of growth factors after further in vivo studies. We believe that such prototype scaffolds may be an innovative technology in targeted drug therapies after reconstructive neurosurgeries. PMID- 29694660 TI - Effect of surgery on the long-term functional outcome of moyamoya disease: a meta analysis. AB - Background Moymoya disease was a cerebrovascular condition, complicated by the recurrent stroke after surgery treatment. The accurate rate of good outcome and prognosis remained controversial. We aimed to summary and calculate the rate under the uniform definition of good outcome, evaluating the long-term effect of surgery. Methods Through systematically searching several databases, we included eligible studies measuring outcomes with the modified Rankin Scale (mRS), Glasgow Outcome Scale (GOS) and Kim's category. Single group rates were transformed and synthesized to yielding the mean weighted probability. Sensitivity analyses were conducted to check the robustness of overall effect. Subgroup analyses were stratified by study type, population, age phase, presentation, surgical procedure and outcome measurement. Results The overall estimated rate of good outcome was 0.87 (95%CI, 0.84 0.90), with substantial heterogeneity. In the subgroup analyses, the outcome measured with GOS led to the highest rate of 91%, while Kim's category the lowest rate of 82%. The combined bypass surgery group resulted in a higher good outcome rate of 0.92 (95%CI, 0.89 0.96) than the indirect bypass group of 0.83% (95%CI, 0.78 0.88). Conclusions MMD after surgical treatment could achieve a good outcome rate of 87%. Kim's category reflected the functional outcome better, resulting in a good outcome rate of 82%. The combined bypass surgery led to better outcomes than indirect bypass. PMID- 29694661 TI - Morphological Characteristics of Posterior Cerebral Circulation: An Analysis Based on Non-Invasive Imaging. AB - AIM: Study was performed to provide measurements of the posterior cerebral circulation using non-invasive imaging modality. MATERIAL AND METHODS: 120 patients aged from 12 to 76 years were analyzed using CT angiography. Measurements of vertebral arteries (VA), basilar artery, posterior cerebral arteries (PCA) and posterior communicating arteries were obtained. Basilar artery appearance and curvature was also noted. Differences between sides, genders and age groups were evaluated. RESULTS: Mean diameter of left VA was 2.36 +/- 0.81 mm, and mean diameter of right VA was 2.14 +/- 0.79 mm. Mean length of basilar artery in man was 34.07 +/- 5.53 mm, and in woman 30,79 +/- 4.18 mm. There was significant difference in basilar artery length between genders, man had a longer basilar artery (p 0.01). There was significant difference in basilar artery diameters of patients younger and older than 60 years, older patients had statistically larger diameter, 3.17 +/- 0.76 mm, to 2.87 +/- 0.57 mm in younger (p 0.05). In 36.7% basilar artery was straight, in 47.5% it was convex to right, while in 14.2% of the patients it was convex to left. Mean diameter of left P1 was 1.80 +/- 0.58 mm, and of right 1.87 +/- 0.54 mm. There was no statistically significant difference between diameters of left and right P1 segments of PCA and also between genders (p 0.05). CONCLUSION: Modern non-invasive imaging modalities can provide precise and useful information for vessels analysis. This information may be useful for planning and performing neuro-interventional procedures as well as posterior cranial fossa surgeries. PMID- 29694662 TI - Technique of localizing the central sulcus under awaking anesthesia for treatmeat of gliomas in/or near motor areas. AB - AIM: This study aimed to study the protective effect of intraoperative awakening and central sulcus location on motor function for patients with gliomas located in motor areas. METHODS: A total of 68 patients with gliomas in motor areas were intubated with a laryngeal mask and rapidly underwent craniotomy without scalp clips and awakening, followed by localization of the central sulcus by somatosensory evoked potential. To protect brain function, we resected the greatest degree of tumor as possible and then finished the close-skull under an awakened state or general anesthesia. RESULTS: All the patients underwent operation successfully. Except for the emergence of new nervous dysfunction in six patients, most patients' neurological functions did not deteriorate or even showed improvements. In addition, there were no complications or postoperative painful memories for the patients. Resection of gliomas in motor areas with intraoperative awakening and localization of central sulcus can ensure the largest possible resection of the tumor while protecting brain function. CONCLUSION: Here, we describe a simple and effective surgical procedure for the operation of the central sulcus and awakening during operation. The technique of localizing the central sulcus under awakening anesthesia can improve the prognosis for patients with gliomas in motor areas. PMID- 29694663 TI - A Novel Candidate Molecule in the Pathological Grading of Gliomas: ELABELA. AB - AIM: To investigate the possible role of ELABELA (ELA) in the histopathological grading of gliomas. MATERIAL AND METHODS: We retrospectively assessed pathological specimens of patients who underwent surgery for intracranial space occupying lesions. Only primary glioma specimens were included in this study. We enrolled 11 patients histologically diagnosed with low-grade glioma and 22 patients with high-grade glioma. The ELA antibody was applied to 4?6-?m-thick sections obtained from paraffin blocks. Histoscores were calculated using the distribution and intensity of staining immunoreactivity. An independent sample t test was used for two-point inter-group assessments, whereas one-way analysis of variance was used for the other assessments. p < 0.05 was considered statistically significant. RESULTS: The histoscores of the control brain, low grade glioma, and high-grade glioma tissues were found to be 0.08, 0.37, and 0.92, respectively. The difference in ELA immunoreactivity between the control brain tissue and glioma tissue was statistically significant (p < 0.05). In addition, a statistically significant increase was observed in ELA immunoreactivity in high-grade glioma tissues compared with that in low-grade glioma tissues (p < 0.05). CONCLUSION: ELA has an angiogenetic role in the progression of glial tumors. ELA, which is an endogenous ligand of the apelin receptor, activates the apelinergic system and causes the progression of glial tumors. Further studies with a large number of patients are necessary to investigate the angiogenetic role of ELA in glial tumors. PMID- 29694664 TI - Systematic Evaluation of Promising Clinical Trials-Gene Silencing for the Treatment of Glioblastoma. AB - AIM: The aim of this study was to systematically investigate the role of artificial small interfering RNA (siRNA) molecules in glioblastoma treatment and to give a detailed overview of the literature concerning studies performed in this field worldwide in the last 31 years. MATERIAL AND METHODS: Articles about clinical trials conducted between December 1, 1949 and November 8, 2017, were identified from the Cochrane Collaboration, the Cochrane Library, Ovid MEDLINE, ProQuest, the National Library of Medicine, and PubMed electronic databases, using the terms "post transcriptional gene silencing," "small interfering RNA," "siRNA," and "glioblastoma," either individually or combined (?"OR?" and ?"AND"), without language and country restrictions. Articles that met the examination criteria were included in the study. After descriptive statistical evaluation, the results were reported in frequency (%). RESULTS: After scanning 2.752 articles, five articles were found that met the research criteria. CONCLUSION: Examination of full texts of the five identified articles provided no sufficient evidence for research conducted with regard to the use of gene silencing via siRNAs in glioblastoma treatment. To be able to evaluate the clinical use of siRNAs, there is an urgent need for in-vivo studies and for trials with randomized, controlled, and clinical designs that provide long-term functional outcomes. PMID- 29694665 TI - Systematic Evaluation of Desmopressin Applied to the Patients with Aneurysmal Subarachnoid Haemorrhage in the light of the Literature. AB - AIM: This study discusses the management of patients with the syndrome of inappropriate antidiuretic hormone secretion (SIADH), developed after subarachnoid hemorrhage, in a comparative manner in light of the literature. MATERIAL AND METHODS: Without country or language restrictions, articles with high evidential value found in electronic databases were compared to our patients' data. RESULTS: After the literature review, three articles were included for systematic evaluation. Desmopressin was applied to the patients for the treatment of hyponatremia, volume contraction, and negative sodium balance caused by SIADH. However, it was not used for preventing re-bleeding. CONCLUSION: To prevent the development of this complication (SIADH), the use of desmopressin, an analogue of vasopressin, is important in routine clinical practice. PMID- 29694666 TI - Comparison of Dorsal Intercostal Artery Perforator Propeller Flaps and Bilateral Rotation Flaps in Reconstruction of Myelomeningocele Defects. AB - AIM: Bilateral rotation flaps are considered the workhorse flaps in reconstruction of myelomeningocele defects. Since the introduction of perforator flaps in the field of reconstructive surgery, perforator flaps have been used increasingly in the reconstruction of various soft tissue defects all over the body because of their appreciated advantages. The aim of this study was to compare the complications and surgical outcomes between bilateral rotation flaps and dorsal intercostal artery perforator (DICAP) flaps in the soft tissue reconstruction of myelomeningocele defects. MATERIAL AND METHODS: Between January 2005-February 2017, we studied 47 patients who underwent reconstruction of myelomeningocele defects. Patient demographics, operative data, and postoperative data were reviewed retrospectively and are included in the study. RESULTS: We found no statistically significant differences in patient demographics and surgical complications between these two groups; this may be due to small sample size. With regard to complications-partial flap necrosis, cerebrospinal fluid (CSF) leakage, necessity for reoperation, and wound infection-DICAP propeller flaps were clinically superior to rotation flaps. Partial flap necrosis was associated with CSF leakage and wound infection, and CSF leakage was associated with wound dehiscence. CONCLUSION: Although surgical outcomes obtained with DICAP propeller flaps were clinically superior to those obtained with rotation flaps, there was no statistically significant difference between the two patient groups. A well-designed comparative study with adequate sample size is needed. Nonetheless, we suggest using DICAP propeller flaps for reconstruction of large myelomeningocele defects. PMID- 29694667 TI - Change of Sagittal Spinopelvic Parameters after Selective and Non-Selective Fusion in Lenke Type 1 Adolescent Idiopathic Scoliosis Patients. AB - AIM: Lenke Type 1, the main thoracic curve type, is the most common spinal curve pattern in adolescent idiopathic scoliosis (AIS). The aim of this study was to compare the postoperative changes of both sagittal spinal and spinopelvic parameters in patients with Lenke Type 1 AIS who underwent selective and non selective fusion surgery. MATERIAL AND METHODS: We conducted a retrospective study among 53 Lenke Type 1 AIS patients who underwent corrective surgery at our centre between 2006 and 2012. Patients were classified as group 1 if they underwent selective surgery and as group 2 if they underwent non-selective surgery. Surgical results of preoperative and postoperative sagittal and spinopelvic measurements, pelvic tilt (PT), pelvic incidence (PI), sacral slope (SS), lumbar lordosis (LL) and thoracic kyphosis (TK) values were analysed using the SURGIMAP Software (Nemaris Inc. USA) measurement system. RESULTS: In both groups, a comparison of pre- and postoperative sagittal spinal parameters did not show a statistically significant difference. In both groups, pre- and postoperative measurements of LL and TK did not show a statistically significant difference. CONCLUSION: After selective and non-selective surgery, sagittal spinal and spinopelvic parameters are not affected in the middle term. We think that the long-term studies to be done in this regard will increasingly require the necessity of keeping pelvis in mind while evaluating the sagittal plan in the AIS surgery. PMID- 29694669 TI - The impact of BCR-ABL1 transcript type on tyrosine kinase inhibitor responses and outcomes in patients with chronic myeloid leukemia. AB - Although the majority of patients with chronic myeloid leukemia do well with treatment with tyrosine kinase inhibitors (TKIs), some patients still have inferior outcomes. There are many factors that might play a part, including the different BCR-ABL1 transcript types at baseline. The current study was performed to determine the possible impact of different transcripts on the treatment responses and outcomes of patients with chronic myeloid leukemia who are receiving TKI therapy. The authors performed a systematic literature search by using the terms "b2a2/b3a2," "e13a2/e14a2," or "transcript type." e14a2 was the more common transcript type. The majority of the studies demonstrated no significant difference regarding age, sex, leukocyte counts, and hemoglobin levels between patients with the e13a2 and e14a2 transcripts. However, in approximately one-half of the studies, the e14a2 transcript was associated with higher platelet counts. Almost no studies demonstrated a significant association between disease risk scores and transcript types. In the majority of studies, having the e14a2 transcript was associated with earlier, deeper, and higher molecular response rates. Although better event-free survival was observed in patients with the e14a2 transcript in some of the studies, the majority demonstrated that transcript type did not have an impact on progression-free and overall survival. Treatment-free remission currently is a topic of much interest, and to the authors' knowledge there are limited data with conflicting results regarding the possible effects of transcript types on the outcomes of patients after discontinuation of TKIs. Because having the e14a2 transcript appears to be related to a favorable outcome, choosing second-generation TKIs for frontline therapy might be a convenient approach in patients with chronic myeloid leukemia with the e13a2 transcript. The authors believe this finding warrants further investigation. PMID- 29694668 TI - A Link Between Alzheimer's and Type II Diabetes Mellitus? Ca+2 -Mediated Signal Control and Protein Localization. AB - We propose protein localization dependent signal activation (PLDSA) as a model to describe pre-existing protein partitioning between the cytosol, and membrane surface, as a means to modulate signal activation, specificity, and robustness. We apply PLDSA to explain possible molecular links between type II diabetes mellitus (T2DM) and Alzheimer's disease (AD) by describing Ca+2 -mediated interactions between the Src non-receptor tyrosine kinase and p52Shc adaptor protein. We suggest that these interactions may serve as a contributing factor to disease development and progression. In particular, we propose that signaling response is regulated, in part, by Ca+2 -mediated partitioning of lipid-bound and soluble forms of Src and p52shc. Thus, protein-protein interactions that drive signaling in response to extracellular ligand binding are also mediated by partitioning of signaling proteins between membrane-bound and soluble populations. We propose that PLDSA effects may explain, in part, the evolutionary basis of promiscuous protein interaction domains and their importance in cellular function. PMID- 29694670 TI - Tiered Approach to Resilience Assessment. AB - Regulatory agencies have long adopted a three-tier framework for risk assessment. We build on this structure to propose a tiered approach for resilience assessment that can be integrated into the existing regulatory processes. Comprehensive approaches to assessing resilience at appropriate and operational scales, reconciling analytical complexity as needed with stakeholder needs and resources available, and ultimately creating actionable recommendations to enhance resilience are still lacking. Our proposed framework consists of tiers by which analysts can select resilience assessment and decision support tools to inform associated management actions relative to the scope and urgency of the risk and the capacity of resource managers to improve system resilience. The resilience management framework proposed is not intended to supplant either risk management or the many existing efforts of resilience quantification method development, but instead provide a guide to selecting tools that are appropriate for the given analytic need. The goal of this tiered approach is to intentionally parallel the tiered approach used in regulatory contexts so that resilience assessment might be more easily and quickly integrated into existing structures and with existing policies. PMID- 29694671 TI - Recommendations for the Evaluation for Autoimmune Liver Disease in Nonalcoholic Fatty Liver Disease. PMID- 29694672 TI - Characterization of Solibacillus silvestris strain AM1 that produces amyloid bioemulsifier. AB - Solibacillus silvestris AM1 was the first strain from the genus to be reported for the production of a functional amyloid and its potential use as a surface active agent, a thermostable glycoprotein amyloid bioemulsifier BE-AM1 capable of influencing environment and biofilm formation. Phylogenetic analysis based on 16S rRNA gene, molecular characterization studies on the basis of DNA-DNA hybridization and chemotaxonomic fatty acid methyl ester (FAME) analysis showed that S. silvestris AM1 as a strain matches with the type strain S. silvestris HR3 23. But strain AM1 differs from the type strain HR3-23 in carbon substrate utilization studies along with amyloid bioemulsifier production ability with potential industrial and environmental applications. S. silvestris AM1 exhibited bioemulsifier production at wide range of factors like pH and NaCl concentrations, while temperature influenced the bioemulsifier production indirectly (since it affected the growth). Bioemulsifier production was observed even at oligotrophic conditions (0.5 mg ml-1 ) seen usually in its native environment. In this study, we have characterized the amyloid producing S. silvestris AM1 taxonomically and also analyzed 16S rDNA of 103 sequences of Solibacillus sp. available, which indicated the possibility of new species in this genus and can be studied for industrially and environmentally important biomolecules. PMID- 29694673 TI - An Assessment of the Skeletal Fracture Patterns Resulting from Fatal High (?3 m) Free Falls. AB - The injury patterns resulting from fatal high (?3 m) free falls have previously been documented in clinical and medico-legal contexts; however, details relating specifically to the skeletal blunt force trauma (BFT) have been limited. This study aimed to augment what is known of the skeletal fracture patterns resulting from fatal high free falls. Skeletal trauma was analyzed from full-body postmortem computed tomography scans of 95 individuals who died following a high free fall. Fracture patterns were documented using the five general anatomical regions, axial and appendicular regions, and postcranial unilateral and bilateral regions. Patterns were analyzed in the context of the extrinsic and intrinsic variables that may influence fractures using multiple logistic regression. Fracture patterns involved all aspects of the skeleton, with 98.9% exhibiting polytrauma, and were influenced primarily by the height fallen, manner of death, and landing surface. This improved understanding of fracture patterns will augment anthropological interpretations of the mechanism of BFT in cases of suspected high falls. PMID- 29694675 TI - Recurrence quantification analysis of radiologists' scanpaths when interpreting mammograms. AB - PURPOSE: The purpose of this study was to Propose a classifier based on recurrence quantification analysis (RQA) metrics for distinguishing experts' scanpaths from those of less-experienced readers and to explore the association of spatiotemporal dynamics of the mammographic scanpaths with the characteristics of cases and radiologists using RQA metrics. MATERIALS AND METHODS: Eye movements were recorded from eight radiologists (two cohorts: four experienced and four less-experienced) while reading 120 mammograms (59 cancer, 61 normal). Ten RQA measures were extracted for each recorded scanpath. The measures described the temporal distribution of recurrent fixations as well as laminar and deterministic eye movements. Recurrent fixations are fixations that are located close to a previously fixated point in a scanpath. Deterministic eye movements represent looking back and forth between two locations, while laminar eye movements indicate detailed scanning of an area with consecutive fixations. The RQA metrics along with six conventional eye-tracking parameters were used to construct a classifier for distinguishing experts' scanpaths from those of less-experienced readers. Leave-one-out cross validation was used for evaluating the classifier. For each reader cohort, the ANOVA analysis was done to study the relationship of RQA measures with breast density, case pathology, readers' expertise, and readers' decisions on the case. The proportions of laminar and deterministic movements involved fixations in the location of lesions were also compared for two reader cohorts using two proportion z-tests. RESULTS: All RQA measures differed significantly between scanpaths of experienced readers and those of less experienced readers. The classifier achieved an area under the receiver operating characteristic curve of 0.89 (0.87-0.91) for detecting experts' scanpaths. Proportionately more refixations and laminar and deterministic sequences were in the location of the lesion for the experienced cohort compared to the less experienced cohort (all P-values < 0.001). Eight and four RQA measures differed between normal and cancer cases for the experienced and less experienced readers, respectively. None of metrics differed between fatty and dense breasts for the less experienced readers, while two measures resulted into a significant difference for the experienced readers. For experts, six measures differed significantly between true negatives and false positives and nine were significantly different between true positives and false negatives. For the less experienced cohort, the corresponding figures were seven and one measures, respectively. CONCLUSION: The RQA measures can quantify the differences among experienced and less experienced radiologists. They also capture differences among experts' scanpaths related to case pathology and radiologists' decisions on the case. PMID- 29694676 TI - Prediction of Fractures in Men Using Bone Microarchitectural Parameters Assessed by High-Resolution Peripheral Quantitative Computed Tomography-The Prospective STRAMBO Study. AB - Areal bone mineral density (aBMD) poorly identifies men at high fracture risk. Our aim was to assess prediction of fractures in men by bone microarchitectural measures. At baseline, 825 men aged 60 to 87 years had the assessment of bone microarchitecture at distal radius and distal tibia by high-resolution peripheral QCT (HR-pQCT; XtremeCT-I, Scanco Medical, Bruttisellen, Switzerland). Bone strength was estimated by micro-finite element analysis. During the prospective 8 year follow-up, 105 men sustained fractures (59 vertebral fractures in 49 men and 70 nonvertebral fractures in 68 men). After adjustment for age, body mass index (BMI), prior falls, and fractures, most HR-pQCT measures at both skeletal sites predicted fractures. After further adjustment for aBMD, low distal radius trabecular number (Tb.N) was most strongly associated with higher fracture risk (hazard ratio [HR] = 1.63 per SD, 95% confidence interval [CI] 1.31-2.03, p < 0.001). In similar models, low Tb.N was associated with higher risk of major osteoporotic fracture (HR = 1.80 per SD, p < 0.001), vertebral fracture (HR = 1.78 per SD, p < 0.01) and nonvertebral fracture (HR = 1.46 per SD, p < 0.01). In comparison with the reference model (age, BMI, falls, fractures, aBMD), the adjustment for distal radius Tb.N increased the estimated fracture probability in men who sustained fractures versus those who did not have ones (difference = 4.1%, 95% CI 1.9-6.3%, p < 0.001). However, the adjustment for distal radius Tb.N did not increase the area under the curve (AUC, p = 0.37). Similar results were found for distal radius trabecular separation (Tb.Sp) and connectivity density (Conn. D). They were predictive of all fracture types and increased the estimated fracture risk, but not AUC, in men who had incident fractures. Thus, poor distal radius trabecular microarchitecture is predictive of fracture after adjustment for age, BMI, falls, fractures, and aBMD. Although distal radius Tb.N, Conn. D, and Tb.Sp improve the discrimination between men who will or who will not have fracture, they do not provide clinically relevant improvement of fracture prediction in older men. (c) 2018 American Society for Bone and Mineral Research. PMID- 29694677 TI - Interseason variability in isokinetic strength and poor correlation with Nordic hamstring eccentric strength in football players. AB - In elite sport, the use of strength testing to establish muscle function and performance is common. Traditionally, isokinetic strength tests have been used, measuring torque during concentric and eccentric muscle action. A device that measures eccentric hamstring muscle strength while performing the Nordic hamstring exercise is now also frequently used. The study aimed to investigate the variability of isokinetic muscle strength over time, for example, between seasons, and the relationship between isokinetic testing and the new Nordic hamstring exercise device. All teams (n = 18) eligible to compete in the premier football league in Qatar underwent a comprehensive strength assessment during their periodic health evaluation at Aspetar Orthopaedic and Sports Medicine Hospital in Qatar. Isokinetic strength was investigated for measurement error, and correlated to Nordic hamstring exercise strength. Of the 529 players included, 288 players had repeated tests with 1/2 seasons between test occasions. Variability (measurement error) between test occasions was substantial, as demonstrated by the measurement error (approximately 25 Nm, 15%), whether separated by 1 or 2 seasons. Considering hamstring injuries, the same pattern was observed among injured (n = 60) and uninjured (n = 228) players. A poor correlation (r = .35) was observed between peak isokinetic hamstring eccentric torque and Nordic hamstring exercise peak force. The strength imbalance between limbs calculated for both test modes was not correlated (r = .037). There is substantial intraindividual variability in all isokinetic test measures, whether separated by 1 or 2 seasons, irrespective of injury. Also, eccentric hamstring strength and limb-to-limb imbalance were poorly correlated between the isokinetic and Nordic hamstring exercise tests. PMID- 29694678 TI - Expanding the Political Philosophy Dimension of the RISP Model: Examining the Conditional Indirect Effects of Cultural Cognition. AB - This article attempts to connect literatures from the Risk Information Seeking and Processing (RISP) model and cultural cognition theory. We do this by assessing the relationship between the two prominent cultural cognition variables (i.e., group and grid) and risk perceptions. We then examine whether these risk perceptions are associated with three outcomes important to the RISP model: information seeking, systematic processing, and heuristic processing, through a serial mediation model. We used 2015 data collected from 10 communities across the United States to test our hypotheses. Our results show that people high on group and low on grid (egalitarian communitarians) show greater risk perceptions regarding water quality issues. Moreover, these higher levels of perceived risk translate into increased information seeking, systematic processing of information, and lower heuristic processing through intervening variables from the RISP model (e.g., negative emotions and information insufficiency). These results extend the extant literature by expanding on the treatment of political ideology within the RISP model literature and taking a more nuanced approach to political beliefs in accordance with the cultural cognitions literature. Our article also expands on the RISP literature by looking at information-processing variables. PMID- 29694674 TI - Local anaesthetics and regional anaesthesia versus conventional analgesia for preventing persistent postoperative pain in adults and children. AB - BACKGROUND: Regional anaesthesia may reduce the rate of persistent postoperative pain (PPP), a frequent and debilitating condition. This review was originally published in 2012 and updated in 2017. OBJECTIVES: To compare local anaesthetics and regional anaesthesia versus conventional analgesia for the prevention of PPP beyond three months in adults and children undergoing elective surgery. SEARCH METHODS: We searched CENTRAL, MEDLINE, and Embase to December 2016 without any language restriction. We used a combination of free text search and controlled vocabulary search. We limited results to randomized controlled trials (RCTs). We updated this search in December 2017, but these results have not yet been incorporated in the review. We conducted a handsearch in reference lists of included studies, review articles and conference abstracts. We searched the PROSPERO systematic review registry for related systematic reviews. SELECTION CRITERIA: We included RCTs comparing local or regional anaesthesia versus conventional analgesia with a pain outcome beyond three months after elective, non-orthopaedic surgery. DATA COLLECTION AND ANALYSIS: At least two review authors independently assessed trial quality and extracted data and adverse events. We contacted study authors for additional information. We presented outcomes as pooled odds ratios (OR) with 95% confidence intervals (95% CI), based on random-effects models (inverse variance method). We analysed studies separately by surgical intervention, but pooled outcomes reported at different follow-up intervals. We compared our results to Bayesian and classical (frequentist) models. We investigated heterogeneity. We assessed the quality of evidence with GRADE. MAIN RESULTS: In this updated review, we identified 40 new RCTs and seven ongoing studies. In total, we included 63 RCTs in the review, but we were only able to synthesize data on regional anaesthesia for the prevention of PPP beyond three months after surgery from 41 studies, enrolling a total of 3143 participants in our inclusive analysis.Evidence synthesis of seven RCTs favoured epidural anaesthesia for thoracotomy, suggesting the odds of having PPP three to 18 months following an epidural for thoracotomy were 0.52 compared to not having an epidural (OR 0.52 (95% CI 0.32 to 0.84, 499 participants, moderate quality evidence). Simlarly, evidence synthesis of 18 RCTs favoured regional anaesthesia for the prevention of persistent pain three to 12 months after breast cancer surgery with an OR of 0.43 (95% CI 0.28 to 0.68, 1297 participants, low quality evidence). Pooling data at three to 8 months after surgery from four RCTs favoured regional anaesthesia after caesarean section with an OR of 0.46, (95% CI 0.28 to 0.78; 551 participants, moderate-quality evidence). Evidence synthesis of three RCTs investigating continuous infusion with local anaesthetic for the prevention of PPP three to 55 months after iliac crest bone graft harvesting (ICBG) was inconclusive (OR 0.20, 95% CI 0.04 to 1.09; 123 participants, low quality evidence). However, evidence synthesis of two RCTs also favoured the infusion of intravenous local anaesthetics for the prevention of PPP three to six months after breast cancer surgery with an OR of 0.24 (95% CI 0.08 to 0.69, 97 participants, moderate-quality evidence).We did not synthesize evidence for the surgical subgroups of limb amputation, hernia repair, cardiac surgery and laparotomy. We could not pool evidence for adverse effects because the included studies did not examine them systematically, and reported them sparsely. Clinical heterogeneity, attrition and sparse outcome data hampered evidence synthesis. High risk of bias from missing data and lack of blinding across a number of included studies reduced our confidence in the findings. Thus results must be interpreted with caution. AUTHORS' CONCLUSIONS: We conclude that there is moderate-quality evidence that regional anaesthesia may reduce the risk of developing PPP after three to 18 months after thoracotomy and three to 12 months after caesarean section. There is low-quality evidence that regional anaesthesia may reduce the risk of developing PPP three to 12 months after breast cancer surgery. There is moderate evidence that intravenous infusion of local anaesthetics may reduce the risk of developing PPP three to six months after breast cancer surgery.Our conclusions are considerably weakened by the small size and number of studies, by performance bias, null bias, attrition and missing data. Larger, high-quality studies, including children, are needed. We caution that except for breast surgery, our evidence synthesis is based on only a few small studies. On a cautionary note, we cannot extend our conclusions to other surgical interventions or regional anaesthesia techniques, for example we cannot conclude that paravertebral block reduces the risk of PPP after thoracotomy. There are seven ongoing studies and 12 studies awaiting classification that may change the conclusions of the current review once they are published and incorporated. PMID- 29694680 TI - Chiral Lithium Amido Zincates for Enantioselective 1,2-Additions: Auto-assembling Reagents Involving a Fully Recyclable Ligand. AB - A methodology consisting in carrying out enantioselective nucleophilic 1,2 additions (ee values up to 97 %) from cheap, easily accessible, and never described before, chiral lithium amido zincates is presented. These multicomponent reactants auto-assemble when mixing, in a 1:1 ratio, a homoleptic diorganozinc (R2 Zn) with a chiral lithium amide (CLA). The latter, obtained after a single reductive amination, plays the role of the chiral inductor and is fully recoverable thanks to a simple acid-base wash, allowing being recycled and re-use without loss of stereochemical information. PMID- 29694679 TI - Sequence-Selective Recognition of Peptides in Aqueous Solution: A Supramolecular Approach through Micellar Imprinting. AB - Sequence-selective recognition of peptides in water has been one of the most important and yet unsolved problems in bioorganic and supramolecular chemistry. The motivation comes from not only the importance of these molecules in biology but also the fundamental challenges involved in the research. Molecular imprinting in doubly cross-linked surfactant micelles offers a unique solution to this problem by creating a "supramolecular code" on the micelle surface that matches the structural features of the peptide chain. Hydrophobic "dimples" are constructed on imprinted micelles that match the hydrophobic side chains of the peptide precisely in size and shape. Polar binding functionalities are installed at correct positions to interact with specific acidic and basic groups on the peptide. Secondary hydrogen-bonding and electrostatic interactions are introduced through imprinting to enhance the binding affinity and specificity further. Binding affinities of tens of nanomolar are readily achieved in water for biological peptides with over a dozen residues. Excellent binding selectivity is observed even for subtly different peptides. The synthesis of these protein-sized nanoparticles involves a one-pot reaction complete within 2 days; purification requires nothing but precipitation and solvent washing. These features make the molecularly imprinted nanoparticles (MINPs) highly promising peptide-binding "artificial antibodies" for chemical and biological applications. PMID- 29694681 TI - Annexin A5 Involvement in Bone Overgrowth at the Enthesis. AB - Little is known about the molecular mechanisms of enthesis formation in mature animals. Here, we report that annexin A5 (Anxa5) plays a critical role in the regulation of bone ridge outgrowth at the entheses. We found that Anxa5 is highly expressed in the entheses of postnatal and adult mice. In Anxa5-deficient (Anxa5 /- ) mice, the sizes of bone ridge outgrowths at the entheses of the tibias and femur were increased after age 7 weeks. Bone overgrowth was not observed at the fibrous enthesis where the fibrocartilage layer does not exist. More ALP expressing cells were observed in the fibrocartilage layer in Anxa5-/- mice than in wild-type (WT) mice. Calcein and Alizarin Red double labeling revealed more mineralized areas in Anxa5-/- mice than WT mice. To examine the effects of mechanical forces, we performed tenotomy in which transmission of contractile forces by the tibial muscle was impaired by surgical muscle release. In tenotomized mice, bone overgrowth at the enthesis in Anxa5-/- mice was decreased to a level comparable to that in WT mice at 8 weeks after the operation. The tail suspended mice also showed a decrease in bone overgrowth to similar levels in Anxa5-/- and WT mice at 8 weeks after hindlimb unloading. These results suggest that bone overgrowth at the enthesis requires mechanical forces. We further examined effects of Anxa5 gene knockdown (KD) in primary cultures of osteoblasts, chondrocytes, and tenocytes in vitro. Anxa5 KD increased ALP expression in tenocytes and chondrocytes but not in osteoblasts, suggesting that increased ALP activity in the fibrocartilaginous tissue in Anxa5-/- mice is directly caused by Anxa5 deletion in tenocytes or fibrocartilage cells. These data indicate that Anxa5 prevents bone overgrowth at the enthesis, whose formation is mediated through mechanical forces and modulating expression of mineralization regulators. (c) 2018 American Society for Bone and Mineral Research. PMID- 29694682 TI - Human Dose-Response Data for Francisella tularensis and a Dose- and Time Dependent Mathematical Model of Early-Phase Fever Associated with Tularemia After Inhalation Exposure. AB - Military health risk assessors, medical planners, operational planners, and defense system developers require knowledge of human responses to doses of biothreat agents to support force health protection and chemical, biological, radiological, nuclear (CBRN) defense missions. This article reviews extensive data from 118 human volunteers administered aerosols of the bacterial agent Francisella tularensis, strain Schu S4, which causes tularemia. The data set includes incidence of early-phase febrile illness following administration of well-characterized inhaled doses of F. tularensis. Supplemental data on human body temperature profiles over time available from de-identified case reports is also presented. A unified, logically consistent model of early-phase febrile illness is described as a lognormal dose-response function for febrile illness linked with a stochastic time profile of fever. Three parameters are estimated from the human data to describe the time profile: incubation period or onset time for fever; rise time of fever; and near-maximum body temperature. Inhaled dose dependence and variability are characterized for each of the three parameters. These parameters enable a stochastic model for the response of an exposed population through incorporation of individual-by-individual variability by drawing random samples from the statistical distributions of these three parameters for each individual. This model provides risk assessors and medical decisionmakers reliable representations of the predicted health impacts of early phase febrile illness for as long as one week after aerosol exposures of human populations to F. tularensis. PMID- 29694683 TI - An Integrated Scenario Ensemble-Based Framework for Hurricane Evacuation Modeling: Part 2-Hazard Modeling. AB - Hurricane track and intensity can change rapidly in unexpected ways, thus making predictions of hurricanes and related hazards uncertain. This inherent uncertainty often translates into suboptimal decision-making outcomes, such as unnecessary evacuation. Representing this uncertainty is thus critical in evacuation planning and related activities. We describe a physics-based hazard modeling approach that (1) dynamically accounts for the physical interactions among hazard components and (2) captures hurricane evolution uncertainty using an ensemble method. This loosely coupled model system provides a framework for probabilistic water inundation and wind speed levels for a new, risk-based approach to evacuation modeling, described in a companion article in this issue. It combines the Weather Research and Forecasting (WRF) meteorological model, the Coupled Routing and Excess STorage (CREST) hydrologic model, and the ADvanced CIRCulation (ADCIRC) storm surge, tide, and wind-wave model to compute inundation levels and wind speeds for an ensemble of hurricane predictions. Perturbations to WRF's initial and boundary conditions and different model physics/parameterizations generate an ensemble of storm solutions, which are then used to drive the coupled hydrologic + hydrodynamic models. Hurricane Isabel (2003) is used as a case study to illustrate the ensemble-based approach. The inundation, river runoff, and wind hazard results are strongly dependent on the accuracy of the mesoscale meteorological simulations, which improves with decreasing lead time to hurricane landfall. The ensemble envelope brackets the observed behavior while providing "best-case" and "worst-case" scenarios for the subsequent risk-based evacuation model. PMID- 29694684 TI - Cyclodestructive procedures for non-refractory glaucoma. AB - BACKGROUND: Glaucoma is a leading cause of blindness worldwide. It results in a progressive loss of peripheral vision and, in late stages, loss of central vision leading to blindness. Early treatment of glaucoma aims to prevent or delay vision loss. Elevated intraocular pressure (IOP) is the main causal modifiable risk factor for glaucoma. Aqueous outflow obstruction is the main cause of IOP elevation, which can be mitigated either by increasing outflow or reducing aqueous humor production. Cyclodestructive procedures use various methods to target and destroy the ciliary body epithelium, the site of aqueous humor production, thereby lowering IOP. The most common approach is laser cyclophotocoagulation. OBJECTIVES: To assess the effectiveness and safety of cyclodestructive procedures for the management of non-refractory glaucoma (i.e. glaucoma in an eye that has not undergone incisional glaucoma surgery). We also aimed to compare the effect of different routes of administration, laser delivery instruments, and parameters of cyclophotocoagulation with respect to IOP control, visual acuity, pain control, and adverse events. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (which contains the Cochrane Eyes and Vision Trials Register) (2017, Issue 8); Ovid MEDLINE; Embase.com; LILACS; the metaRegister of Controlled Trials (mRCT) and ClinicalTrials.gov. The date of the search was 7 August 2017. We also searched the reference lists of reports from included studies. SELECTION CRITERIA: We included randomized controlled trials of participants who had undergone cyclodestruction as a primary treatment for glaucoma. We included only head-to head trials that had compared cyclophotocoagulation to other procedural interventions, or compared cyclophotocoagulation using different types of lasers, delivery methods, parameters, or a combination of these factors. DATA COLLECTION AND ANALYSIS: Two review authors independently screened search results, assessed risks of bias, extracted data, and graded the certainty of the evidence in accordance with Cochrane standards. MAIN RESULTS: We included one trial (92 eyes of 92 participants) that evaluated the efficacy of diode transscleral cyclophotocoagulation (TSCPC) as primary surgical therapy. We identified no other eligible ongoing or completed trial. The included trial compared low-energy versus high-energy TSCPC in eyes with primary open-angle glaucoma. The trial was conducted in Ghana and had a mean follow-up period of 13.2 months post-treatment. In this trial, low-energy TSCPC was defined as 45.0 J delivered, high-energy as 65.5 J delivered; it is worth noting that other trials have defined high- and low energy TSCPC differently. We assessed this trial to have had low risk of selection bias and reporting bias, unclear risk of performance bias, and high risk of detection bias and attrition bias. Trial authors excluded 13 participants with missing follow-up data; the analyses therefore included 40 (85%) of 47 participants in the low-energy group and 39 (87%) of 45 participants in the high energy group.Control of IOP, defined as a decrease in IOP by 20% from baseline value, was achieved in 47% of eyes, at similar rates in the low-energy group and the high-energy groups; the small study size creates uncertainty about the significance of the difference, if any, between energy settings (risk ratio (RR) 1.03, 95% confidence interval (CI) 0.64 to 1.65; 79 participants; low-certainty evidence). The difference in effect between energy settings based on mean decrease in IOP, if any exists, also was uncertain (mean difference (MD) -0.50 mmHg, 95% CI -5.79 to 4.79; 79 participants; low-certainty evidence).Decreased vision was defined as the proportion of participants with a decrease of 2 or more lines on the Snellen chart or one or more categories of visual acuity when unable to read the eye chart. Twenty-three percent of eyes had a decrease in vision. The size of any difference between the low-energy group and the high-energy group was uncertain (RR 1.22, 95% CI 0.54 to 2.76; 79 participants; low-certainty evidence). Data were not available for mean visual acuity and proportion of participants with vision change defined as greater than 1 line on the Snellen chart.The difference in the mean number of glaucoma medications used after cyclophotocoagulation was similar when comparing treatment groups (MD 0.10, 95% CI -0.43 to 0.63; 79 participants; moderate-certainty evidence). Twenty percent of eyes were retreated; the estimated effect of energy settings on the need for retreatment was inconclusive (RR 0.76, 95% CI 0.31 to 1.84; 79 participants; low certainty evidence). No data for visual field, cost effectiveness, or quality-of life outcomes were reported by the trial investigators.Adverse events were reported for the total study population, rather than by treatment group. The trial authors stated that most participants reported mild to moderate pain after the procedure, and many had transient conjunctival burns (percentages not reported). Severe iritis occurred in two eyes and hyphema occurred in three eyes. No instances of hypotony or phthisis bulbi were reported. The only adverse outcome that was reported by the treatment group was atonic pupil (RR 0.89 in the low-energy group, 95% CI 0.47 to 1.68; 92 participants; low-certainty evidence). AUTHORS' CONCLUSIONS: There is insufficient evidence to evaluate the relative effectiveness and safety of cyclodestructive procedures for the primary procedural management of non-refractory glaucoma. Results from the one included trial did not compare cyclophotocoagulation to other procedural interventions and yielded uncertainty about any difference in outcomes when comparing low-energy versus high-energy diode TSCPC. Overall, the effect of laser treatment on IOP control was modest and the number of eyes experiencing vision loss was limited. More research is needed specific to the management of non-refractory glaucoma. PMID- 29694685 TI - Effects of 24 Months of Treatment With Romosozumab Followed by 12 Months of Denosumab or Placebo in Postmenopausal Women With Low Bone Mineral Density: A Randomized, Double-Blind, Phase 2, Parallel Group Study. AB - Over 12 months, romosozumab increased bone formation and decreased bone resorption, resulting in increased bone mineral density (BMD) in postmenopausal women with low BMD (NCT00896532). Herein, we report the study extension evaluating 24 months of treatment with romosozumab, discontinuation of romosozumab, alendronate followed by romosozumab, and romosozumab followed by denosumab. Postmenopausal women aged 55 to 85 years with a lumbar spine (LS), total hip (TH), or femoral neck T-score <=-2.0 and >=-3.5 were enrolled and randomly assigned to placebo, one of five romosozumab regimens (70 mg, 140 mg, 210 mg monthly [QM]; 140 mg Q3M; 210 mg Q3M) for 24 months, or open-label alendronate for 12 months followed by romosozumab 140 mg QM for 12 months. Eligible participants were then rerandomized 1:1 within original treatment groups to placebo or denosumab 60 mg Q6M for an additional 12 months. Percentage change from baseline in BMD and bone turnover markers (BTMs) at months 24 and 36 and safety were evaluated. Of 364 participants initially randomized to romosozumab, placebo, or alendronate, 315 completed 24 months of treatment and 248 completed the extension. Romosozumab markedly increased LS and TH BMD through month 24, with largest gains observed with romosozumab 210 mg QM (LS = 15.1%; TH = 5.4%). Women receiving romosozumab who transitioned to denosumab continued to accrue BMD, whereas BMD returned toward pretreatment levels with placebo. With romosozumab 210 mg QM, bone formation marker P1NP initially increased after treatment initiation and gradually decreased to below baseline by month 12, remaining below baseline through month 24; bone resorption marker beta-CTX rapidly decreased after treatment, remaining below baseline through month 24. Transition to denosumab further decreased both BTMs, whereas after transition to placebo, P1NP returned to baseline and beta-CTX increased above baseline. Adverse events were balanced between treatment groups through month 36. These data suggest that treatment effects of romosozumab are reversible upon discontinuation and further augmented by denosumab. (c) 2018 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc. PMID- 29694686 TI - Assessing Transboundary Wildfire Exposure in the Southwestern United States. AB - We assessed transboundary wildfire exposure among federal, state, and private lands and 447 communities in the state of Arizona, southwestern United States. The study quantified the relative magnitude of transboundary (incoming, outgoing) versus nontransboundary (i.e., self-burning) wildfire exposure based on land tenure or community of the simulated ignition and the resulting fire perimeter. We developed and described several new metrics to quantify and map transboundary exposure. We found that incoming transboundary fire accounted for 37% of the total area burned on large parcels of federal and state lands, whereas 63% of the area burned was burned by ignitions within the parcel. However, substantial parcel to parcel variation was observed for all land tenures for all metrics. We found that incoming transboundary fire accounted for 66% of the total area burned within communities versus 34% of the area burned by self-burning ignitions. Of the total area burned within communities, private lands contributed the largest proportion (36.7%), followed by national forests (19.5%), and state lands (15.4%). On average seven land tenures contributed wildfire to individual communities. Annual wildfire exposure to structures was highest for wildfires ignited on state and national forest land, followed by tribal, private, and BLM. We mapped community firesheds, that is, the area where ignitions can spawn fires that can burn into communities, and estimated that they covered 7.7 million ha, or 26% of the state of Arizona. Our methods address gaps in existing wildfire risk assessments, and their implementation can help reduce fragmentation in governance systems and inefficiencies in risk planning. PMID- 29694687 TI - Sclerostin Neutralizing Antibody Treatment Enhances Bone Formation but Does Not Rescue Mechanically Induced Delayed Healing. AB - During bone healing, tissue formation processes are governed by mechanical strain. Sost/sclerostin, a key Wnt signaling inhibitor and mechano-sensitive pathway, is downregulated in response to mechanical loading. Sclerostin neutralizing antibody (SclAb) increases bone formation. Nevertheless, it remains unclear whether sclerostin inhibition can rescue bone healing in situations of mechanical instability, which otherwise delay healing. We investigated SclAb's influence on tissue formation in a mouse femoral osteotomy, stabilized with rigid or semirigid external fixation. The different fixations allowed different magnitudes of interfragmentary movement during weight bearing, thereby influencing healing outcome. SclAb or vehicle (veh) was administeredand bone healing was assessed at multiple time points up to day 21 postoperatively by in vivo micro-computed tomography, histomorphometry, biomechanical testing, immunohistochemistry, and gene expression. Our results show that SclAb treatment caused a greater bone volume than veh. However, SclAb could not overcome the characteristic delayed healing of semirigid fixation. Indeed, semirigid fixation resulted in delayed healing with a prolonged endochondral ossification phase characterized by increased cartilage, lower bone volume fraction, and less bony bridging across the osteotomy gap than rigid fixation. In a control setting, SclAb negatively affected later stages of healing under rigid fixation, evidenced by the high degree of endosteal bridging at 21 days in the rigid-SclAb group compared with rigid-veh, indicating delayed fracture callus remodeling and bone marrow reconstitution. Under rigid fixation, Sost and sclerostin expression at the gene and protein level, respectively, were increased in SclAb compared with veh-treated bones, suggesting a negative feedback mechanism. Our results suggest that SclAb could be used to enhance overall bone mass but should be carefully considered in bone healing. SclAb may help to increase bone formation early in the healing process but not during advanced stages of fracture callus remodeling and not to overcome delayed healing in semirigid fixation. (c) 2018 American Society for Bone and Mineral Research. PMID- 29694688 TI - Quantitative susceptibility mapping and 23 Na imaging-based in vitro characterization of blood clotting kinetics. AB - Blood clotting is a fundamental biochemical process in post-hemorrhagic hemostasis. Although the varying appearance of coagulating blood in T1 - and T2 weighted images is widely used to qualitatively determine bleeding age, the technique permits only a rough discrimination of coagulation stages, and it remains difficult to distinguish acute and chronic hemorrhagic stages because of low T1 - and T2 -weighted signal intensities in both instances. To investigate new biomedical parameters for magnetic resonance imaging-based characterization of blood clotting kinetics, sodium imaging and quantitative susceptibility mapping (QSM) were compared with conventional T1 - and T2 -weighted imaging, as well as with biochemical hemolysis parameters. For this purpose, a blood-filled spherical agar phantom was investigated daily for 14 days, as well as after 24 days at 7 T after initial preparation with fresh blood. T1 - and T2 -weighted sequences, a three-dimensional (3D) gradient echo sequence and a density-adapted 3D radial projection reconstruction pulse sequence for 23 Na imaging were applied. For hemolysis estimations, free hemoglobin and free potassium concentrations were measured photometrically and with the direct ion-selective electrode method, respectively, in separate heparinized whole-blood samples along the same timeline. Initial mean susceptibility was low (0.154 +/- 0.020 ppm) and increased steadily during the course of coagulation to reach up to 0.570 +/- 0.165 ppm. The highest total sodium (NaT) values (1.02 +/- 0.06 arbitrary units) in the clot were observed initially, dropped to 0.69 +/- 0.13 arbitrary units after one day and increased again to initial values. Compartmentalized sodium (NaS) showed a similar signal evolution, and the NaS/NaT ratio steadily increased over clot evolution. QSM depicts clot evolution in vitro as a process associated with hemoglobin accumulation and transformation, and enables the differentiation of the acute and chronic coagulation stages. Sodium imaging visualizes clotting independent of susceptibility and seems to correspond to clot integrity. A combination of QSM and sodium imaging may enhance the characterization of hemorrhage. PMID- 29694689 TI - Quantifying shorebird habitat in managed wetlands by modeling shallow water depth dynamics. AB - Over 50% of Western Hemisphere shorebird species are in decline due to ongoing habitat loss and degradation. In some regions of high wetland loss, shorebirds are heavily reliant on a core network of remaining human-managed wetlands during migration journeys in the spring and fall. While most refuges have been designed and managed to match the habitat needs of waterfowl, shorebirds typically require much shallower water (<10 cm deep). Traditional static habitat modeling approaches at relatively coarse spatial and temporal resolution are insufficient to capture dynamic changes within this narrow water depth range. Our objectives were to (1) develop a method to quantify shallow water habitat distributions in inland non-tidal wetlands, and (2) to assess how water management practices affect the amount of shorebird habitat in Sacramento National Wildlife Refuge Complex. We produced water depth distributions and modeled optimal habitat (<10 cm deep) within 23 managed wetlands using high-resolution topography and fixed point water depth records. We also demonstrated that habitat availability, specifically suitable water depth ranges, can be tracked from satellite imagery and high-resolution topography. We found that wetlands with lower topographic roughness may have a higher potential to provide shorebird habitat and that strategically reducing water levels could increase habitat extent. Over 50% of the wetlands measured provided optimal habitat across <10% of their area at the peak of migration in early April, and most provided a brief duration of shallow water habitat. Reducing water volumes could increase the proportion of optimal habitat by 1-1,678% (mean = 294%) compared to actual volumes measured at peak spring migration in 2016. For wetlands with a high habitat potential, beginning wetland drawdown earlier and extending drawdown time could dramatically improve habitat conditions at the peak of shorebird migration. Our approach can be adapted to track dynamic hydrologic changes at broader spatial scales as additional high-resolution topographic (e.g., lidar, drone imagery photogrammetry) and optical remote sensing data (e.g., planet imagery, drone photography) become available. PMID- 29694690 TI - Pd-Catalyzed Selective Remote Ring Opening of Polysubstituted Cyclopropanols. AB - The distant functionalization of omega-ene cyclopropanols is induced by a Pd catalyzed Heck reaction triggering a "metal-walk" and selective ring-opening of the three-membered ring. This approach provides a new class of acyclic aldehydes possessing concomitantly a stereodefined double bond and a quaternary carbon stereocenter alpha to the carbonyl group. PMID- 29694691 TI - The Difference Se Makes: A Bio-Inspired Dppf-Supported Nickel Selenolate Complex Boosts Dihydrogen Evolution with High Oxygen Tolerance. AB - Inspired by the metal active sites of [NiFeSe]-hydrogenases, a dppf-supported nickel(II) selenolate complex (dppf=1,1'-bis(diphenylphosphino)ferrocene) shows high catalytic activity for electrochemical proton reduction with a remarkable enzyme-like H2 evolution turnover frequency (TOF) of 7838 s-1 under an Ar atmosphere, which markedly surpasses the activity of a dppf-supported nickel(II) thiolate analogue with a low TOF of 600 s-1 . A combined study of electrochemical experiments and DFT calculations shed light on the catalytic process, suggesting that selenium atom as a bio-inspired proton relay plays a key role in proton exchange and enhancing catalytic activity of H2 production. For the first time, this type of Ni selenolate-containing electrocatalyst displays a high degree of O2 and H2 tolerance. Our results should encourage the development of the design of highly efficient oxygen-tolerant Ni selenolate molecular catalysts. PMID- 29694692 TI - Copper-Catalyzed One-Pot Borylative Aldolisation beta-Fluoride Elimination for the Formal Addition of Acrylates to Carbonyl Moieties. AB - Herein, we report the copper-catalyzed domino borylation/aldolisation of methyl 2 fluoroacrylate with carbonyl compounds followed by an elimination to give Morita Baylis-Hillman (MBH) analogues. The optimal conditions described were shown to be compatible with a wide range of aldehydes and ketones. Unprecedented MBH adducts derived from ketones were efficiently synthesized. PMID- 29694693 TI - Transvaginal repair for anterior rectocele - a video vignette. PMID- 29694694 TI - Resection with primary anastomosis vs nonrestorative resection for perforated diverticulitis with peritonitis: a systematic review and meta-analysis. AB - AIM: It is still controversial whether the optimal operation for perforated diverticulitis with peritonitis is primary anastomosis (PRA) or nonrestorative resection (NRR). The aim of this systematic review and meta-analysis was to evaluate mortality and morbidity rates following emergency resection for perforated diverticulitis with peritonitis and ostomy reversal, as well as ostomy nonreversal rates. METHOD: The Pubmed, EMBASE, Cochrane Library, MEDLINE via Ovid, CINAHL and Web of Science databases were systematically searched. Mortality was the primary end-point. A subgroup meta-analysis of randomized controlled trials was performed in addition to a meta-analysis of all eligible studies. Odds ratios (ORs) and mean difference (MD) were calculated for dichotomous and continuous outcomes, respectively. RESULTS: Seventeen studies, including three randomized controlled trials (RCTs), involving 1016 patients (392 PRA vs 624 NRR) were included. Overall, mortality was significantly lower in patients with PRA compared with patients with NRR [OR (95% CI) = 0.38 (0.24, 0.60), P < 0.0001]. Organ/space surgical site infection (SSI) [OR (95% CI) = 0.25 (0.10, 0.63), P = 0.003], reoperation [OR (95% CI) = 0.48 (0.25, 0.91), P = 0.02] and ostomy nonreversal rates [OR (95% CI) = 0.27 (0.09, 0.84), P = 0.02] were significantly decreased in PRA. In the RCTs, the mortality rate did not differ [OR (95% CI) = 0.46 (0.15, 1.38), P = 0.17]. The mean operating time for PRA was significantly longer than for NRR [MD (95% CI) = 19.96 (7.40, 32.52), P = 0.002]. Organ/space SSI [OR (95% CI) = 0.28 (0.09, 0.82), P = 0.02] was lower after PRA. Ostomy nonreversal rates were lower after PRA. The difference was not statistically significant [OR (95% CI) = 0.26 (0.06, 1.11), P = 0.07]. However, it was clinically significant [number needed to treat/harm (95% CI) = 5 (3.1, 8.9)]. CONCLUSION: This meta-analysis found that organ/space SSI rates as well as ostomy nonreversal rates were decreased in PRA at the cost of prolonging the operating time. PMID- 29694695 TI - Quorum-sensing inhibitor potential of trans-anethole aganist Pseudomonas aeruginosa. AB - AIMS: Quorum sensing (QS) is a cell-cell communication system used by a broad spectrum of pathogenic bacteria to control the expression of their virulence genes. The interruption of QS systems of pathogenic bacteria has been considered as a novel way to fight bacterial diseases. In this study, trans-anethole, the main component of anise (Pimpinella anisum) oil was examined for its QS inhibitor (QSI) potential in an attempt to identify novel QSI compound effective against opportunistic pathogen Pseudomonas aeruginosa. METHODS AND RESULTS: The preliminary screening of QSI capacity of trans-anethole was determined using a quorum-sensing inhibitor screen (QSIS) assay. The QSIS assay indicated that trans anethole has QSI properties. QSI capacity of trans-anethole was further confirmed by lasB-gfp fussion assay and virulence factor assays. A sub-MIC of trans anethole reduced the expression of lasB by 57%, elastase production by 59%, protease production by 56%, pyocyanin production by 95% and swarming motility by 68% without inhibiting growth of Pseudomonas aeruginosa PA01. Molecular docking and protein-ligand interaction studies were performed to understand the molecular mechanism underlying inhibitory activity of trans-anethole. The results of these analysis suggested that trans-anethole fits within the binding site of the LasR protein of P. aeruginosa. CONCLUSION: Trans-anethole has the potential to inhibit QS-regulated virulence factors in P. aeruginosa by binding to LasR protein, similar to its natural ligand N-(3-oxododecanoyl)-l-homoserine lactone. SIGNIFICANCE AND IMPACT OF THE STUDY: In this study, for the first time, it was demonstrated that trans-anethole has the potential to disrupt bacterial communication and can be developed as a novel QSI to combat with P. aeruginosa and other clinically significant pathogens. PMID- 29694696 TI - Transanal minimally invasive approach for the resection of retrorectal tumour - a video vignette. PMID- 29694697 TI - The functional outcome of sacral nerve stimulation for faecal incontinence can be improved by using lead model 3889 and a standardized implantation technique. AB - AIM: Sacral nerve stimulation has been recognized as an effective treatment option for faecal incontinence when conservative therapy has failed. Refinement of the procedural technique and the use of a curved stylet may improve the functional outcome. Our aim was to explore the relationship between lead model, functional outcome, stimulation amplitude and the need for extra visits during the first year of follow-up. METHOD: Patient data from May 2009 to February 2017, which were prospectively collected in a local database, were extracted and analysed for differences between lead model and improvement in incontinence scores, stimulation amplitude and the need for additional visits during the first year of follow-up. RESULTS: A foramen lead model 3093(straight stylet) was used in 134 patients and lead model 3889(curved stylet) was used in 40 patients. There were no differences in baseline characteristics or incontinence scores. Comparing results between the two lead models we found that the improvement (delta value) in the Wexner score at 6 months' follow-up (P = 0.05) and the St Mark's score at 12 months' follow-up (P = 0.02) was greater in patients implanted with lead model 3889(curved stylet) compared with patients implanted with lead model 3093(straight stylet). Patients implanted with lead model 3889 (curved stylet) were less likely to have to alter the stimulation amplitude or pole configuration during the first year of follow-up (P = 0.04). No difference was found for stimulation amplitude (P = 0.170) or the need for additional visits (P = 0.663). CONCLUSION: Lead model 3889 (curved stylet) improves functional results compared with lead model 3093 (straight stylet) during the first year of follow-up. Lead model 3889 (curved stylet) reduces the need for reprogramming but has no influence on stimulation amplitude or the number of additional visits required. PMID- 29694698 TI - Using imaging spectroscopy to detect variation in terrestrial ecosystem productivity across a water-stressed landscape. AB - A central challenge to understanding how climate anomalies, such as drought and heatwaves, impact the terrestrial carbon cycle, is quantification and scaling of spatial and temporal variation in ecosystem gross primary productivity (GPP). Existing empirical and model-based satellite broadband spectra-based products have been shown to miss critical variation in GPP. Here, we evaluate the potential of high spectral resolution (10 nm) shortwave (400-2,500 nm) imagery to better detect spatial and temporal variations in GPP across a range of ecosystems, including forests, grassland-savannas, wetlands, and shrublands in a water-stressed region. Estimates of GPP from eddy covariance observations were compared against airborne hyperspectral imagery, collected across California during the 2013-2014 HyspIRI airborne preparatory campaign. Observations from 19 flux towers across 23 flight campaigns (102 total image-flux tower pairs) showed GPP to be strongly correlated to a suite of spectral wavelengths and band ratios associated with foliar physiology and chemistry. A partial least squares regression (PLSR) modeling approach was then used to predict GPP with higher validation accuracy (adjusted R2 = 0.71) and low bias (0.04) compared to existing broadband approaches (e.g., adjusted R2 = 0.68 and bias = -5.71 with the Sims et al. model). Significant wavelengths contributing to the PLSR include those previously shown to coincide with Rubisco (wavelengths 1,680, 1,740, and 2,290 nm) and Vcmax (wavelengths 1,680, 1,722, 1,732, 1,760, and 2,300 nm). These results provide strong evidence that advances in satellite spectral resolution offer significant promise for improved satellite-based monitoring of GPP variability across a diverse range of terrestrial ecosystems. PMID- 29694699 TI - Biosynthesis and Heterologous Production of Vioprolides: Rational Biosynthetic Engineering and Unprecedented 4-Methylazetidinecarboxylic Acid Formation. AB - Vioprolides are a promising class of anticancer and antifungal lead compounds produced by the myxobacterium Cystobacter violaceus Cb vi35. Previously nothing had been reported about their biosynthesis, including the origin of the unusual 4 methylazetidinecarboxylic acid (MAZ) moiety. We describe the vioprolide biosynthetic gene cluster and solve the production obstacle by expression in three heterologous hosts. Starting from unstable production in the wild type at the single-digit mg L-1 scale, we developed a stable host that eventually allowed for yields of up to half a gram per liter in fermenters. Gene inactivations coupled with isotope feeding studies identified an S-adenosylmethionine (SAM) dependent enzyme and a methyltransferase as being responsible for the generation of the MAZ building block by a proposed mechanism unprecedented in bacteria. Furthermore, nonnatural vioprolide derivatives were generated via rational genetic engineering. PMID- 29694700 TI - Transformation of Sugars into Chiral Polyols over a Heterogeneous Catalyst. AB - Transformation of sugars, while maintaining the intrinsic stereochemical structure, is desirable. However, such a transformation requires multistep synthesis with protection and deprotection of the OH groups. Herein, a new method for selective transformation of sugar derivatives into chiral building blocks and a diol synthon, with retention of the intrinsic configuration (stereo- and regioselectively), is demonstrated. The method is based on the selective recognition of cis-vicinal OH groups in sugars and leads to the one-pot removal of the cis-vicinal OH groups, without protection of OH groups (except the OH group of the hemiacetal group), over a heterogeneous CeO2 -supported ReOx and Pd (ReOx -Pd/CeO2 ) catalyst by using H2 as a reducing agent. PMID- 29694701 TI - Normothermic Machine Perfusion of Donor Livers Without the Need for Human Blood Products. PMID- 29694702 TI - WATER II (80-150 mL) procedural outcomes. AB - OBJECTIVES: To present early safety and feasibility data from a multicentre prospective study (WATER II) of aquablation in the treatment of symptomatic men with large-volume benign prostatic hyperplasia (BPH). METHODS: Between September and December 2017, 101 men with moderate-to-severe BPH symptoms and prostate volume of 80-150 mL underwent aquablation in a prospective multicentre international clinical trial. Baseline demographics and standardized postoperative management variables were carefully recorded in a central independently monitored database. Surgeons answered analogue scale questionnaires on intra-operative technical factors and postoperative management. Adverse events up to 1 month were adjudicated by an independent clinical events committee. RESULTS: The mean (range) prostate volume was 107 (80-150) mL. The mean (range) operating time was 37 (15-97) min and aquablation resection time was 8 (3-15) min. Adequate adenoma resection was achieved with a single pass in 34 patients and with additional passes in 67 patients (mean 1.8 treatment passes), all in a single operating session. Haemostasis was achieved using either a Foley balloon catheter placed in the bladder under traction (n = 98, mean duration 18 h) or direct tamponade using a balloon inflated in the prostate fossa (n = 3, mean duration 15 h). No patient required electrocautery for haemostasis at the time of the primary procedure. The mean length of stay after the procedure was 1.6 days (range same day to 6 days). The Clavien-Dindo grade >=2 event rate observed at 1 month was 29.7%. Bleeding complications were recorded in 10 patients (9.9%) during the index procedure hospitalization prior to discharge, and included six (5.9%) peri-operative transfusions. CONCLUSIONS: Aquablation is feasible and safe in treating men with men with large prostates (80-150 mL). The 6-month efficacy data are being accrued and will be presented in future publications (ClinicalTrials.gov number, NCT03123250). PMID- 29694703 TI - Mechanisms underlying blood pressure reduction by dietary inorganic nitrate. AB - Nitric oxide (NO) importantly contributes to cardiovascular homeostasis by regulating blood flow and maintaining endothelial integrity. Conversely, reduced NO bioavailability is a central feature during natural ageing and in many cardiovascular disorders, including hypertension. The inorganic anions nitrate and nitrite are endogenously formed after oxidation of NO synthase (NOS)-derived NO and are also present in our daily diet. Knowledge accumulated over the past two decades has demonstrated that these anions can be recycled back to NO and other bioactive nitrogen oxides via serial reductions that involve oral commensal bacteria and various enzymatic systems. Intake of inorganic nitrate, which is predominantly found in green leafy vegetables and beets, has a variety of favourable cardiovascular effects. As hypertension is a major risk factor of morbidity and mortality worldwide, much attention has been paid to the blood pressure reducing effect of inorganic nitrate. Here, we describe how dietary nitrate, via stimulation of the nitrate-nitrite-NO pathway, affects various organ systems and discuss underlying mechanisms that may contribute to the observed blood pressure-lowering effect. PMID- 29694704 TI - Self-reported snoring is associated with chronic kidney disease independent of metabolic syndrome in middle-aged and elderly Chinese. AB - AIMS/INTRODUCTION: To investigate the correlation between snoring and chronic kidney disease (CKD), and explore whether metabolic syndrome (MetS) plays an important role in this relationship among middle-aged and elderly Chinese. MATERIALS AND METHODS: The participants included in the present study were categorized into three subgroups based on self-reported snoring frequency (regularly [>=3 times per week], occasionally [between 'regularly' and 'never'] or never [<1 time per month]). An estimated glomerular filtration rate <60 mL/min/1.73 m2 was considered as CKD. We diagnosed MetS based on the 2004 Chinese Diabetes Society criteria. We explored the relationship between snoring and CKD by using multiple logistic regressions. RESULTS: The frequency of MetS, MetS components and CKD was dramatically higher in regular snorers than in non-snorers and occasional snorers. The odds ratios for MetS and all the MetS elements, except for hyperglycemia, increased progressively with the snoring frequency (P < 0.001). Upon additional adjustment for other MetS components, snoring was not significantly related with hypertension; however, the associations between snoring frequency and overweight/obesity and dyslipidemia became attenuated, but still remained statistically significant (P < 0.01). Interestingly, odds ratios for CKD also increasingly augmented with snoring frequency (P < 0.001). Upon further adjustment for individual MetS components or MetS, regular snoring also resulted in a significantly increased odds ratio for CKD (odds ratio 1.72; P = 0.034) relative to non-snoring. CONCLUSIONS: Self-reported snoring is closely associated with CKD independent of MetS among middle-aged and elderly Chinese. PMID- 29694705 TI - Crystal structures of APRT from Francisella tularensis - an N-H...N hydrogen bond imparts adenine specificity in adenine phosporibosyltransferases. AB - : Francisella tularensisis, the causative agent of tularemia has been classified as a category A bioterrorism agent. Here, we present the crystal structure of apo and adenine bound form of the adenine phosphoribosyltransferase (APRT) from Francisella tularensis. APRT is an enzyme involved in the salvage of adenine (a 6 aminopurine), converting it to AMP. The purine salvage pathway relies on two essential and distinct enzymes to convert 6-aminopurine and 6-oxopurines into corresponding nucleotides. The mechanism by which these enzymes differentiate different purines is not clearly understood. Analysis of the structures of apo and adenine-bound APRT from F. tularensis, together with all other available structures of APRTs, suggests that (a) the base-binding loop is stabilized by a cluster of aromatic and conformation-restricting proline residues, and (b) an N H...N hydrogen bond between the base-binding loop and the N1 atom of adenine is the key interaction that differentiates adenine from 6-oxopurines. These observations were corroborated by bioinformatics analysis of ~ 4000 sequences of APRTs (with 80% identity cutoff), which confirmed that the residues conferring rigidity to the base-binding loop are highly conserved. Furthermore, an F23A mutation on the base-binding loop severely affects the efficiency of the enzyme. We extended our analysis to the structure and sequences of APRTs from the Trypanosomatidae family with a destabilizing insertion on the base-binding loop and propose the mechanism by which these evolutionarily divergent enzymes achieve base specificity. Our results suggest that the base-binding loop not only confers appropriate affinity but also provides defined specificity for adenine. ENZYME: EC 2.4.2.7 DATABASE: Structural data are available in Protein Data Bank (PDB) under the accession numbers 5YW2 and 5YW5. PMID- 29694706 TI - Liver transplantation for alcoholic hepatitis: Being consistent about where to set the bar. PMID- 29694707 TI - Efficacy and safety of a hexanic extract of Serenoa repens (Permixon(r) ) for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH): systematic review and meta-analysis of randomised controlled trials and observational studies. AB - OBJECTIVES: To comprehensively evaluate the efficacy and safety of the hexanic extract of Serenoa repens (HESr, Permixon(r) ; Pierre Fabre Medicament, Castres, France), at a dose of 320 mg daily, as monotherapy for the treatment of lower urinary tract symptoms associated with benign prostatic hyperplasia (LUTS/BPH). MATERIALS AND METHODS: We conducted a systematic review and meta-analysis of randomised controlled trials (RCTs) and prospective observational studies in patients with LUTS/BPH identified through searches in Medline, Web of Knowledge (Institute for Scientific Information), Scopus, the Cochrane Library, and bibliographic references up to March 2017. Articles studying S. repens extracts other than Permixon were excluded. Data were collected on International Prostate Symptom Score (IPSS), maximum urinary flow rate (Qmax ), nocturia, quality of life, prostate volume, sexual function, and adverse drug reactions (ADRs). Data obtained from RCTs and observational studies were analysed jointly and separately using a random effects model. A sub-group analysis was performed of studies that included patients on longer-term treatment (>=1 year). RESULTS: Data from 27 studies (15 RCTs and 12 observational studies) were included for meta-analysis (total N = 5 800). Compared with placebo, the HESr was associated with 0.64 (95% confidence interval [CI] -0.98 to -0.31) fewer voids/night (P < 0.001) and an additional mean increase in Qmax of 2.75 mL/s (95% CI 0.57 to 4.93; P = 0.01). When compared with alpha-blockers, the HESr showed similar improvements on IPSS (weighted mean difference [WMD] 0.57, 95% CI -0.27 to 1.42; P = 0.18) and a comparable increase in Qmax to tamsulosin (WMD -0.02, 95% CI -0.71 to 0.66; P = 0.95). Efficacy assessed using the IPSS was similar after 6 months of treatment between the HESr and 5alpha-reductase inhibitors (5ARIs). Analysis of all available published data for the HESr showed a mean improvement in IPSS from baseline of -5.73 points (95% CI -6.91 to -4.54; P < 0.001). HESr did not negatively affect sexual function and no clinically relevant effect was observed on prostate-specific antigen. Prostate volume decreased slightly. Similar efficacy results were seen in patients treated for >=1 year (n = 447). The HESr had a favourable safety profile, with gastrointestinal disorders being the most frequent ADR (mean incidence of 3.8%). CONCLUSION: The present meta-analysis, which includes all available RCTs and observational studies, shows that the HESr (Permixon) reduced nocturia and improved Qmax compared with placebo and had a similar efficacy to tamsulosin and short-term 5-ARI in relieving LUTS. HESr (Permixon) appears to be an efficacious and well-tolerated therapeutic option for the long-term medical treatment of LUTS/BPH. PMID- 29694708 TI - Aqueous biphasic systems in the separation of food colorants. AB - Aqueous biphasic systems (ABS) composed of polypropylene glycol and carbohydrates, two benign substances are proposed to separate two food colorants (E122 and E133). ABS are promising extractive platforms, particularly for biomolecules, due to their aqueous and mild nature (pH and temperature), reduced environmental impact and processing costs. Another major aspect considered, particularly useful in downstream processing, is the "tuning" ability for the extraction and purification of these systems by a proper choice of the ABS components. In this work, our intention is to show the concept of ABS as an alternative and volatile organic solvent-free tool to separate two different biomolecules in a simple way, so simple that teachers can effectively adopt it in their classes to explain the concept of bioseparation processes. Informative documents and general information about the preparation of binodal curves and their use in the partition of biomolecules is available in this work to be used by teachers in their classes. In this sense, the students use different carbohydrates to build ABS, then study the partition of two food color dyes (synthetic origin), thus evaluating their ability on the separation of both food colorants. Through these experiments, the students get acquainted with ABS, learn how to determine solubility curves and perform extraction procedures using colorant food additives, that can also be applied in the extraction of various (bio)molecules. (c) 2018 by The International Union of Biochemistry and Molecular Biology, 46:390-397, 2018. PMID- 29694709 TI - Identification of N-acyl homoserine lactone-degrading bacteria isolated from rainbow trout (Oncorhynchus mykiss). AB - AIMS: A variety of pathogens use quorum sensing (QS) to control the expression of their virulence factors. QS interference has hence been proposed as a promising antivirulence strategy. The specific aim of this study was to isolate bacteria from trout tissue able to degrade N-acyl homoserine lactones (AHL), a QS molecule family. METHODS AND RESULTS: In total 132 isolates were screened for AHL degradation using Chromobacterium violaceum CV026 as a biosensor. Twenty-four quorum-quenching (QQ) isolates were identified biochemically and characterized using 16S rDNA sequencing. They belong to Bacillus, Enterobacter, Citrobacter, Acinetobacter, Agrobacterium, Pseudomonas and Stentrophomonas genera. Four Bacillus spp. showed the highest and fastest QQ activity. AHL degradation proved to be enzymatic in most isolates (except for Stentrophomonas spp. and Pseudomonas sp.) as QQ activity could be destroyed by heat and/or proteinase K treatments. All QQ activity proved to be cell-bound except for Pseudomonas sp., where it could be detected in the supernatant. The results of aiiA gene homology analysis revealed the presence of aiiA gene encoding AHL lactonase in all examined isolates except Pseudomonas syringae and Enterobacter cloacae. The HXHXDH motif conserved in all AHL lactonases and considered to be essential for AHL degradation was detected in all AiiAs after sequence alignment. CONCLUSIONS: Some known and novel QQ bacteria were isolated from trouts and characterized in terms of enzymatic or nonenzymatic AHL degradation activity and their extracellular or intracellular location. In addition, an aiiA gene and its HXHXDH motif were detected in most isolates. SIGNIFICANCE AND IMPACT OF THE STUDY: We could isolate and identify some novel QQ bacteria including Enterobacter hormaechei, Acinetobacter radioresistens and Citrobacter gillenii. The aiiA gene was detected for the first time in these strains as well as in Stenotrophomonas maltophilia. Our QQ isolates could be used for biocontrol of bacterial infections in aquaculture. PMID- 29694710 TI - Strategies That Reduce 90-Day Readmissions and Inpatient Costs After Liver Transplantation. AB - Liver transplantation (LT) is hospital-resource intensive and associated with high rates of readmission. We have previously shown a reduction in 30-day readmission rates by implementing a specifically designed protocol to increase access to outpatient care. The aim of this work is to determine if the strategies that reduce 30-day readmission after LT were effective in also reducing 90-day readmission rates and costs. A protocol was developed to reduce inpatient readmissions after LT that expanded outpatient services and provided alternatives to readmission. The 90-day readmission rates and costs were compared before and after implementing strategies outlined in the protocol. Multivariable analysis was used to control for potential confounding factors. Over the study period, 304 adult primary LTs were performed on patients with a median biological Model for End-Stage Liver Disease of 22. There were 112 (37%) patients who were readmitted within 90 days of transplant. The readmission rates before and after implementation of the protocol were 53% and 26%, respectively (P < 0.001). The most common reason for readmission was elevated liver tests/rejection (24%). In multivariable analysis, the protocol remained associated with avoiding readmission (odds ratio, 0.33; 95% confidence interval, 0.20-0.55; P < 0.001). The median length of stay after transplant before and after protocol implementation was 8 days and 7 days, respectively. A greater proportion of patients were discharged to hospital lodging after protocol implementation (10% versus 19%; P = 0.03). The 90-day readmission costs were reduced by 55%, but the total 90-day costs were reduced by only 2.7% because of higher outpatient costs and index admission costs. In conclusion, 90-day readmission rates and readmission costs can be reduced by improving access to outpatient services and hospital-local lodging. Total 90-day costs were similar between the 2 groups because of higher outpatient costs after the protocol was introduced. PMID- 29694711 TI - The involvement of phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) and MYPT1 isoform expression in NO/cGMP mediated differential vasoregulation of cerebral arteries compared to systemic arteries. AB - AIM: Constitutive release of NO blunts intrinsic and stimulated contractile activity in cerebral arteries (CA). Here, we explored whether phosphorylation and expression levels of the PKG-sensitive, leucine zipper positive (LZ+ ) splice variants of the regulatory subunit of myosin phosphatase (MYPT1) are involved and whether its expression is associated with higher cGMP sensitivity. METHODS: Vascular contractility was investigated by wire myography. Phosphorylation of MYPT1 was determined by Western blotting. RESULTS: Constitutive phosphorylation of MYPT1-T696 and T853 was lower and that of S695 and S668 was higher in cerebral arteries from the circulus arteriosus (CA-w) than in femoral arteries (FA), while total MYPT1 expression was not different. In CA-w but not in FA, L-NAME lowered phosphorylation of S695/S668 and increased phosphorylation of T696/T853 and of MLC20 -S19, plus basal tone. The increase in basal tone was attenuated in CA-w and basilar arteries (BA) from heterozygous MYPT1-T696A/+ mice. Compared to FA, expression of the LZ+ -isoform was ~2-fold higher in CA-w coincident with a higher sensitivity to DEA-NONOate, cinaciguat and Y27632 in BA and 8-Br-cGMP (1 MUmol/L) in pre-constricted (pCa 6.1) alpha-toxin permeabilized CAs. In contrast, 6-Bnz-cAMP (10 MUmol/L) relaxed BA and FA similarly by ~80%. CONCLUSION: Our results indicate that (i) regulation of the intrinsic contractile activity in CA involves phosphorylation of MYPT1 at T696 and S695/S668, (ii) the higher NO/cGMP/PKG sensitivity of CAs can be ascribed to the higher expression level of the LZ+ -MYPT1 isoform and (iii) relaxation by cAMP/PKA pathway is less dependent on the expression level of the LZ+ splice variants of MYPT1. PMID- 29694712 TI - Reply. PMID- 29694713 TI - Older and wiser? Changes in unprofessional content on urologists' social media after transition from residency to practice. AB - OBJECTIVE: To characterize changes in the frequency and nature of unprofessional content on urologists' Facebook accounts during the transition from residency to practice. METHODS: Facebook was queried with the names of all 2015 US urology graduates 1 year after completion of residency. We identified unprofessional and potentially objectionable content on the public Facebook accounts using a rubric based on professionalism guidelines by the American Urological Association, the American Medical Association and the Accreditation Council for Graduate Medical Education. Comparisons of unprofessional content were made with data from this cohort collected at the completion of residency. To assess how professional identities were reflected on social media, we determined which urologists self identified as a urologist on Facebook and any changes in their unprofessional content. RESULTS: Of 281 urologists, 198 (70%) had publicly identifiable Facebook accounts. Of these, 85 (43%) contained any unprofessional or potentially objectionable content, including 35 (18%) with explicitly unprofessional content. Examples included images of and references to intoxication, explicit profanity, and offensive comments about patients. Of the 201 Facebook accounts that had been publicly identifiable at the completion of residency, most profiles (182, 91%) had remained public; of the 19 that were no longer public, about half had previously contained unprofessional content. Similarly, of the 80 urologists without public profiles 1 year previously, most (64, 80%) had remained unidentifiable on Facebook; of the 16 accounts that had since become publicly identifiable, half had unprofessional content. Among the urologists on Facebook overall, 11 (6%) had posted new unprofessional or potentially objectionable content since entering practice. Comparing this cohort in practice vs at the completion of residency, there were no significant differences in how many urologists had public Facebook accounts (70% vs 71%) or whose accounts had concerning content (43% vs 40%). The presence of unprofessional content at the completion of residency strongly predicted having unprofessional content later in practice. More urologists overall self-identified as being a urologist on Facebook, and a larger proportion of these profiles also displayed unprofessional content (53% vs 47% 1 year previously). CONCLUSION: Most urologists maintained public Facebook accounts after the transition to practice, and about half of these contained unprofessional or potentially objectionable content. Amidst their increasing self-identification as urologists on social media, the majority of practising urologists had posted concerning content, which could have an impact on their professional identities and public perceptions of the specialty. PMID- 29694715 TI - Evolution of pituitary surgery in a tertiary centre. PMID- 29694714 TI - Contribution and interaction of the low-density lipoprotein cholesterol to high density lipoprotein cholesterol ratio and triglyceride to diabetes in hypertensive patients: A cross-sectional study. AB - AIMS/INTRODUCTION: Hypertension is one of the most significant risk factors for diabetes. The present study aimed to investigate the associations of lipid profiles, including the ratio of low-density lipoprotein cholesterol (LDL-C)-to high-density lipoprotein cholesterol (HDL-C) and triglyceride (TG) levels, as well as their interactions, with type 2 diabetes in hypertensive patients. MATERIALS AND METHODS: Hypertensive patients without a history of diabetes and hypolipidemic agents were enrolled continuously at the Hypertension Clinic, Zhongshan Hospital, Fudan University (Shanghai, China) from 2014 to 2016. General clinical data, including body mass index, blood pressure, fasting glucose and 2-h post-load glucose levels, and lipid profiles, were collected. The LDL-C/HDL-C ratio, TG/HDL-C ratio and TC/HDL-C ratio were separately calculated. Statistical analyses were carried out by using SPSS software (version 13.0). RESULTS: In total, 935 hypertensive patients were included, of which 114 patients (12.2%) were diagnosed with diabetes. After multivariate adjustments, the LDL-C/HDL-C ratio and TG levels had the most significant and independent associations with diabetes. In the multivariate logistic regression, the LDL-C/HDL-C ratio and TG were independently associated with diabetes. After the interaction variable was included, the LDL-C/HDL-C ratio remained independently associated with diabetes, but TG was replaced by TG*LDL-C/HDL-C. CONCLUSIONS: In conclusion, elevated LDL C/HDL-C ratios and TG levels were associated with diabetes in patients with hypertension, with an interactive effect of the LDL-C/HDL-C ratio and TG on diabetes in the hypertensive population. PMID- 29694716 TI - Anal cytological lesions and HPV infection in individuals at increased risk for anal cancer. AB - BACKGROUND: Anal cytology may be useful for evaluating lesions associated with human papillomavirus (HPV) in individuals at increased risk for anal cancer. METHODS: Liquid-based cytology was used to assess anal cytological lesions among human immunodeficiency virus (HIV)-infected and HIV-uninfected men who have sex with men (MSM). The Linear Array HPV genotyping test was used for HPV detection. RESULTS: This cross-sectional study included 1021 MSM, of whom 388 were HIV infected (38.0%). Anal cytological lesions (atypical squamous cells of undetermined significance or more severe [ASCUS+]) were observed in 32.5% and 53.2% of the HIV-uninfected and HIV-infected individuals, respectively (P < .0001). The highest ASCUS + prevalence was observed among >=45-year-old HIV uninfected MSM (37.3%) and 25-to 29-year-old HIV-infected MSM (66.7%). High-grade squamous intraepithelial lesions (HSILs) peaked in >= 45-year-old HIV-uninfected subjects and 35- to 39-year-old HIV-infected subjects. Individuals with anal infections with high-risk (HR) HPV types were 3 to 4 times more likely to have an ASCUS + report. An HPV-16 and/or HPV-18 infection increased the odds of HSIL or more severe cytology (HSIL+) for HIV-infected MSM almost 4 times. MSM concurrently infected with HR and low-risk HPVs were significantly more likely to have low-grade squamous intraepithelial lesions or more severe cytology (LSIL+) than those infected with only HR types. No significant associations were found between cytological abnormalities and the HIV load and nadir and current CD4 + counts. CONCLUSIONS: The prevalence of anal cytological lesions is high in MSM, even in HIV-infected individuals treated with combined antiretroviral therapy. In these subjects, HSILs occur more frequently and at a younger age in comparison with HIV-uninfected counterparts. Specific diagnostic procedures should be implemented to manage individuals at increased risk for anal cancer with an abnormal anal Papanicolaou test. Cancer Cytopathol 2018. (c) 2018 American Cancer Society. PMID- 29694717 TI - Hydrogenation of CO2 to Formate over Ruthenium Immobilized on Solid Molecular Phosphines. AB - Formic acid is a promising hydrogen storage medium and can be produced by catalytic hydrogenation of CO2 . Molecular ruthenium complexes immobilized on phosphine polymers have been found to exhibit excellent productivity and selectivity in the catalytic hydrogenation of CO2 under mild conditions. The polymeric analog of 1,2-bis(diphenylphosphino)ethane exhibited the highest activity and turnover numbers up to 13 170 were obtained in a single run. This catalyst was already active at 40 degrees C and with a catalyst loading of only 0.0006 mol %. Recycling experiments revealed a loss of activity after the first run, followed by a gradual decrease during the subsequent runs. This is attributed to a change in the catalytically active complex during the hydrogenation reaction. High selectivity towards formate and low leaching were maintained in the absence of CO formation. Based on the catalyst characterization, a mechanism for the CO2 hydrogenation is proposed. PMID- 29694719 TI - U-Shaped Association Between Serum Uric Acid Level and Risk of Mortality: A Cohort Study. AB - OBJECTIVE: In addition to the controversy regarding the association of hyperuricemia with cardiovascular disease (CVD) mortality, few studies have examined the impact of a low uric acid level on mortality. We undertook the present study to evaluate the relationship between both low and high uric acid levels and the risk of all-cause and cause-specific mortality in a large sample of Korean adults over a full range of uric acid levels. METHODS: A cohort study was performed in 375,163 South Korean men and women who underwent health check ups from 2002 to 2012. Vital status and cause of death were ascertained from the national death records. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for mortality outcomes were estimated using Cox proportional hazards regression analysis. RESULTS: During a total of 2,060,721.9 person-years of follow-up, 2,020 participants died, with 287 CVD deaths and 963 cancer deaths. Low and high uric acid levels were associated with increased all-cause, CVD, and cancer mortality. The multivariable-adjusted HRs for all-cause mortality in the lowest uric acid categories (<3.5 mg/dl for men and <2.5 mg/dl for women) compared with the sex-specific reference category were 1.58 (95% CI 1.18-2.10) and 1.80 (95% CI 1.10-2.93), respectively. Corresponding HRs in the highest uric acid categories (>=9.5 mg/dl for men and >=8.5 mg/dl for women) were 2.39 (95% CI 1.57-3.66) and 3.77 (95% CI 1.17-12.17), respectively. CONCLUSION: In this large cohort study of men and women, both low and high uric acid levels were predictive of increased mortality, supporting a U-shaped association between serum uric acid levels and adverse health outcomes. PMID- 29694718 TI - Diversification of transcription factor-DNA interactions and the evolution of gene regulatory networks. AB - Sequence-specific transcription factors (TFs) bind short DNA sequences in the genome to regulate the expression of target genes. In the last decade, numerous technical advances have enabled the determination of the DNA-binding specificities of many of these factors. Large-scale screens of many TFs enabled the creation of databases of TF DNA-binding specificities, typically represented as position weight matrices (PWMs). Although great progress has been made in determining and predicting binding specificities systematically, there are still many surprises to be found when studying a particular TF's interactions with DNA in detail. Paralogous TFs' binding specificities can differ in subtle ways, in a manner that is not immediately apparent from looking at their PWMs. These differences affect gene regulatory outputs and enable TFs to rewire transcriptional networks over evolutionary time. This review discusses recent observations made in the study of TF-DNA interactions that highlight the importance of continued in-depth analysis of TF-DNA interactions and their inherent complexity. This article is categorized under: Biological Mechanisms > Regulatory Biology. PMID- 29694720 TI - Pharmacokinetics and drug interactions of medications used to treat hepatitis C virus infection in the setting of chronic kidney disease and kidney transplantation. AB - Hepatitis C infection in patients with chronic kidney disease or kidney transplant carries higher morbidity and mortality compared to noninfected patients. Historically, patients with advanced kidney disease and kidney transplant recipients were undertreated given the multiple adverse effects and limited efficacy of interferon-based therapies for chronic hepatitis C. The development of direct-acting antivirals in the past few years has opened an unprecedented opportunity for treating these populations. However, the impaired renal clearance of some of these medications in patients with kidney disease, and the potential interactions of antiviral therapies with immunosuppressants after kidney transplantation, present some challenges in choosing the proper regimen. This review provides an overview of the essential pharmacokinetics and drug interactions of relevant antiviral therapies in the treatment of chronic hepatitis C in patients with advanced kidney disease and after kidney transplantation. PMID- 29694721 TI - Hepatitis C virus infection in kidney transplantation-changing paradigms with novel agents. AB - Hepatitis C virus (HCV) is a common cause of increased morbidity and mortality in kidney transplant patients. It is associated with posttransplant glomerulonephritis, chronic allograft nephropathy, and New Onset Diabetes after Transplant (NODAT). In the past, HCV was difficult to treat due to the presence of interferon alpha-based therapies that were difficult to tolerate and were associated with adverse side-effects, such as the risk of rejection. With the advent of oral directly acting antiviral therapies, the landscape for HCV and transplantation has changed. These agents are highly effective and well tolerated with minimal side-effects. Sustained viral response rates in excess of 90% are achieved with most current treatment regimens active against all HCV genotypes. These new agents may show an improvement in graft and patient survival while essentially eliminating the risk of acute rejection from the use of prior interferon-based HCV therapies. These agents may also result in an improvement in organ allocation for HCV donor/HCV recipient transplantation. This review is meant to discuss the epidemiology of HCV, the new oral direct-acting antiviral agents (DAAs) and future opportunities for research in the field of HCV related transplantation. PMID- 29694722 TI - Transplantation of hepatitis C virus infected kidneys into hepatitis C virus uninfected recipients. AB - Long wait times for kidney transplant and the high risk of mortality on dialysis have prompted investigation into strategies to increase organ allocation and decrease discard rates of potentially viable kidneys. Organs from hepatitis C virus (HCV) antibody positive donors are often rejected; nearly 500 HCV-infected kidneys are discarded annually in the United States. Due the opioid epidemic, the number of HCV-infected donors has increased because of a rise in both new HCV infections and drug-related deaths. In the past 5 years, HCV has been transformed into a curable illness with direct-acting antiviral therapies (DAAs) that are effective in >95% of patients treated and are extremely well tolerated. Recent data has shown several direct-acting antiviral combinations are safe and effective after kidney transplant, and can achieve the same high cure rate seen in the general population and without increasing the rate of acute rejection. Because of this, strategies to decrease discard of HCV-infected organs have been devised. Two recent studies have transplanted HCV-uninfected dialysis patients with kidneys from donors actively infected with HCV; recipients were treated with DAA in the peri-transplant period. More research is needed to determine the safety and efficacy of this approach, but it has the potential to dramatically increase the donor pool of available kidneys, shorten waitlist times and ultimately decreases mortality in patients waiting for kidney transplant. PMID- 29694723 TI - Timing of hepatitis C virus infection treatment in kidney transplant candidates. AB - Hepatitis C virus (HCV) infection is prevalent in patients with kidney disease including transplant candidates and recipients. It is associated with increased morbidity and mortality in end-stage renal disease patients and also increases the risk of allograft rejection and decreases allograft and patient survival post transplant. Newly developed direct acting antivirals have revolutionized the way HCV is treated. Whether patients are treated before or after kidney transplantation, the cure rates with direct acting antivirals are >90%. Great debate has formed revolving the optimal timing to treat kidney transplant candidates. On the one hand, treatment before transplantation decreases early post-transplant complications related to HCV. On the other, postponing treatment until after transplantation opens the possibility of transplanting a kidney from a HCV positive donor, which is associated with shorter waiting time and improved organ utilization by expanding the organ donor pool. Most patients living in an area where waiting time is reduced by accepting an HCV positive kidney would benefit by the strategy of treatment post-transplantation, but this decision needs to be individualized in a patient-by-patient basis given that there are special circumstances (i.e., severe HCV-related extrahepatic manifestations, availability of live donors, etc.) in which treatment before transplant might be preferred. PMID- 29694724 TI - Introduction to hepatitis C virus infection: Overview and history of hepatitis C virus therapies. AB - Chronic hepatitis C virus (HCV) infection is an infection that affects over 71 million people worldwide that primarily leads to significant morbidity and mortality through its predisposition to liver fibrosis, cirrhosis, and liver cancer. In addition, extrahepatic manifestations, such as mixed cryoglobulinaemia associated vasculitis including renal disease, or type II diabetes are frequently encountered in chronically infected individuals. HCV treatment aims to permanently eradicate the virus in order to prevent both liver and extra-hepatic manifestations. Over two decades after the HCV discovery, treatments have evolved from nonspecific immune modulating therapies based on interferon to specific drug combinations, targeting viral proteins. In the present review, we give an overview of HCV infection with a special emphasis on the history of the treatment of viral hepatitis C and the substantial improvement in efficacy and tolerability profile with the recent development of new direct-acting antiviral therapies. PMID- 29694725 TI - Preface. PMID- 29694726 TI - Treatment and management options for the hepatitis C virus infected kidney transplant candidate. AB - A substantial body of literature has unequivocally established that prevalent hepatitis C virus infection in chronic kidney disease (CKD), end stage renal disease (ESRD) and kidney transplant recipients is associated with a negative impact on patient survival. As a consequence of remarkable work that explained the details of the hepatitis C virus (HCV) genome, a class of drugs referred to as the direct-acting antiviral (DAA) agents were developed that targeted specific key sites in viral replication. Large clinical trials in the HCV-infected general population followed soon after that demonstrated cure rates exceeding 95%. Treatment paradigms have been further refined and expanded to populations of patients that were initially excluded from the large pivotal trials. This includes the CKD and ESRD patients for whom there are now safe and effective DAAs available as well. In this context, the focus of decision making has shifted from initially demonstrating safety and efficacy to now identifying which patient should receive therapy and at what point in their CKD/ESRD journey. The specific issue of timing of treatment is particularly relevant to the HCV-infected ESRD patient who is being considered for kidney transplantation. The option of treating with DAAs prior to the transplant or alternatively delaying therapy and treating in the posttransplant period will be influenced by several factors, including patient preference, the extent of liver injury, the availability of a living or deceased donor, and more recently the option of transplanting a kidney from HCV-positive donor. The latter has been associated with the advantage of shortened waiting times and expansion of the organ donor pool. The optimal timing and choice of therapy will be the result of a decision that has been individualized for each patient as a consequence of a process of clear communication involving the patient, primary care physician, nephrologist, gastroenterologist (GI)/hepatologist, and local transplant center. PMID- 29694727 TI - The prevention of hepatitis C virus transmission to hemodialysis patients and staff members. AB - In this review article, we cover 4 topics very relevant to those involved in the care of hemodialysis (HD) patients and in the management of a HD unit. We start with an overview of the progress made over the last 25 years to reduce hepatitis C virus (HCV) transmission in HD. Next, we discuss the potential strategies to prevent the residual ongoing transmission of HCV to HD patients. Third, we discuss the actions to be taken if a seroconversion for HCV is nevertheless detected in a HD patient. Finally, we briefly discuss how best to protect HD staff members from occupationally acquired HCV infection. PMID- 29694728 TI - Rationale for treatment of hepatitis C virus infection in end-stage renal disease patients who are not kidney transplant candidates. AB - Hepatitis C virus (HCV) infection is a common problem in patients treated with maintenance hemodialysis (HD) and is associated with an increased morbidity and mortality and lower quality of life. The major causes of HCV-associated mortality are liver and cardiovascular-related death. HCV-infected HD patients have a higher prevalence of inflammation-related metabolic and vascular diseases, leading to high rates of cardiovascular mortality in patients with end-stage renal disease. In the current era of highly effective direct-acting antiviral regimens, HCV treatment may also confer hepatic, cardiovascular and other morbidity and mortality benefits even to dialysis-dependent patients who do not qualify for kidney transplantation. Currently, the most accepted regimens in this patient population include elbasvir/grazoprevir and glecaprevir/pibrentasvir. PMID- 29694729 TI - Treatment of hepatitis C virus infection in patients with mixed cryoglobulinemic syndrome and cryoglobulinemic glomerulonephritis. AB - Cryoglobulinemia is a common extrahepatic manifestation of infection with hepatitis C virus (HCV). When signs and symptoms of systemic vasculitis or glomerulonephritis occur in the presence of circulating cryoglobulins, this syndrome is called "mixed cryoglobulinemia syndrome" (MCS). Historically, interferon-based therapies in HCV have been associated with lower rates of viral cure in patients with MCS than in the general HCV-infected population. The advent of direct-acting antiviral therapies have revolutionized the treatment of HCV, dramatically increasing rates of cure. Early studies of first-generation protease inhibitors (telaprevir and boceprevir) in combination with interferon and ribavirin demonstrated HCV cure rates of 67% and complete clinical response rates of vasculitis symptoms in 60% of patients with MCS; however, regimens were poorly tolerated by patients, 22% discontinued treatment early. More recently, all-oral, interferon-free regimens have become available and combination therapies are now being approved for patients with and without renal impairment. Patients with HCV MCS achieved sustained virologic response in 297 out of 313 patients (95%) treated with direct-acting antiviral therapy, and 85% had a complete or partial clinical response of MCS symptoms. Current direct-acting antiviral therapies are well tolerated in patients with HCV-MCS and only 1.6% discontinued treatment early. Patients with cryoglobulinemic glomerulonephritis also had an excellent cure rate (94%). The majority improved; 17/52 (33%) experienced full remission and 15/52 (29%) experienced partial remission. There were no reports of worsening kidney function in patients treated with direct-acting antiviral therapies. Less than 5% of patients with HCV-MCS treated with IFN-free direct-acting antiviral therapy required immunosuppression. However, patients with severe vasculitis appear to still require concomitant immunosuppression. PMID- 29694731 TI - How to Obtain CME/CNE Credit for this Learning Activity: Please visit www.wileyhealthlearning.com to receive credit for this activity. PMID- 29694730 TI - Rationale for treating hepatitis C virus infection in patients with mild to moderate chronic kidney disease. AB - Hepatitis C virus infection (HCV) is highly prevalent in patients with chronic kidney disease (CKD) and kidney transplant recipients. Little information exists on treatment in patients with CKD stages 2 to 3, where CKD progression might be slowed by HCV treatment. These patients are not considered a high priority for HCV treatment in most international guidelines. Although some recently published guidelines propose universal treatment, others are still recommending it only in high priority groups. In this review, we evaluate current evidence of HCV infection impact on CKD progression, on cardiovascular and metabolic risk, and the benefits of HCV infection treatment to improve cardiovascular and metabolic outcomes. We made special focus on the benefits of HCV infection treatment in patients with stages 2 to 3 CKD to avoid CKD progression. PMID- 29694732 TI - Pharmacokinetic Interaction Between Fingolimod and Carbamazepine in Healthy Subjects. AB - This open-label, single-sequence study in healthy subjects investigated the effects of steady-state carbamazepine on the pharmacokinetic (PK) profile of a single 2-mg dose of fingolimod. In period 1, a single oral dose of fingolimod 2 mg (day 1) was followed by PK and safety assessments up to 36 days. In period 2, carbamazepine was administered in flexible, up-titrated doses (600 mg twice daily maximum) for 49 days. Fingolimod was administered on day 35, followed by a study completion evaluation (day 71). The PK analysis included 23 of 26 of the enrolled subjects (88.5%). Coadministration of fingolimod at steady-state carbamazepine concentrations resulted in increased fingolimod CL/F by 67% through the induction of CYP3A4, a cytochrome with negligible involvement in fingolimod clearance in an uninduced state. Fingolimod Cmax was reduced by 18% and AUCinf by 40%, as was T1/2 (106 vs 163 hours). A similar trend was observed for fingolimod-P. Models linking fingolimod-P blood concentrations to lymphocyte count or annual relapse rate suggest that such a decrease would have a low impact on the treatment effect. However, in the absence of efficacy data of fingolimod at doses lower than the therapeutic dose, their coadministration should be used with caution. PMID- 29694733 TI - Rational design of peptide affinity ligands for the purification of therapeutic enzymes. AB - Non-mAb biologics represent a growing class of therapeutics under clinical development. Although affinity chromatography is a potentially attractive approach for purification, the development of platform technologies, such as Protein A for mAbs, has been challenging due to the inherent chemical and structural diversity of these molecules. Here, we present our studies on the rapid development of peptide affinity ligands for the purification of biologics using a prototypical enzyme therapeutic in clinical use. Employing a suite of de novo rational and combinatorial design strategies we designed and screened a library of peptides on microarray platforms for their ability to bind to the target with high affinity and selectivity in cell culture fluid. Lead peptides were evaluated on resin in batch conditions and compared with a commercially available resin to evaluate their efficacy. Two lead candidates identified from microarray studies provided high binding capacity to the target while demonstrating high selectivity against culture contaminants and product variants compared to a commercial resin system. These findings provide a proof-of-concept for developing affinity peptide-based bioseparations processes for a target biologic. Peptide affinity ligand design and screening approaches presented in this work can also be easily translated to other biologics of interest. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:987-998, 2018. PMID- 29694734 TI - Bio-preparation of (R)-DMPM using whole cells of Pseudochrobactrum asaccharolyticum WZZ003 and its application on kilogram-scale synthesis of fungicide (R)-metalaxyl. AB - Methyl (R)-N-(2,6-dimethylphenyl)alaninate ((R)-DMPM) is a key chiral intermediate for the production of (R)-metalaxyl, which is one of the best selling fungicides. A new strain, Pseudochrobactrum asaccharolyticum WZZ003, was identified as a biocatalyst for the enantioselective hydrolysis of (R,S)-DMPM. The key parameters including pH, temperature, rotation speed and substrate concentrations were optimized in the enantioselective hydrolysis of (R,S)-DMPM. After the 48 h hydrolysis of 256 mM (R,S)-DMPM under the optimized reaction conditions, the enantiomeric excess of product (e.e.p ) was up to 99% and the conversion was nearly 50%. Subsequently, the unhydrolyzed (S)-DMPM was converted to (R,S)-DMPM through the n-butanal-catalyzed racemization. Furthermore, stereoselective hydrolysis of (R,S)-DMPM catalyzed by whole cells of P. asaccharolyticum WZZ003 was scaled up to kilogram-scale, offering (R)-MAP-acid with 98.6% e.e.p and 48.0% yield. Moreover, (R)-metalaxyl was prepared at kilogram scale after subsequent esterification and coupling reactions. Therefore, a practical production process of (R)-DMPM and (R)-metalaxyl with the prospect of industrialization was developed in this study. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:921-928, 2018. PMID- 29694735 TI - The expanded cytometry concept. PMID- 29694736 TI - A "golden age" in skull base and rhinology research. PMID- 29694737 TI - Installation address. PMID- 29694738 TI - Protect yourself from workplace violence. PMID- 29694739 TI - Be a leader in philanthropy. PMID- 29694740 TI - County soda tax a courageous decision. PMID- 29694741 TI - Dental therapy dogs. Can man's best friend help your practice? PMID- 29694742 TI - Chicago takes smokeless tobacco out of the park. PMID- 29694743 TI - Where can I turn to for career advice?. PMID- 29694744 TI - Dispelling five dento-legal myths. PMID- 29694745 TI - The kids are all right. PMID- 29694747 TI - Hanging out with Jeri Coffey. PMID- 29694746 TI - Elisa Ochoa creates a practice to address the specific needs of Pilsen. PMID- 29694748 TI - Things ain't as bad as you think. PMID- 29694749 TI - A BRIEF OVERVIEW OF THE HISTORY OF AMERICAN INDIAN NURSES. AB - This historical overview is a compilation of information from multiple archival sources; it provides a perspective of the course of events contributing to the present nursing shortage among American Indians. The review begins in the late 1800s by identifying educational assimilation efforts, the role offield nurses and field matrons in introducing Western healthcare to American Indians,followed by examples of American Indian nursing programs and early American Indian nurses and their contributions, and concludes with information about current American Indian nursing programs and recruitment efforts particularly the Recruitment and Retention of American Indians into Nursing (RAIN) program, introduced in the 1990s. PMID- 29694750 TI - A COMPARISON OF TEACHING METHODS BUILDING CULTURAL COMPETENCY INFORMED BY CONTACT THEORY. AB - This study examines students' levels of cultural competency before and after taking three different semester-long courses dealing with diversity and cultural competence with each course representing a different teaching methodology. A new 20-item survey, designed for students across disciplines, was used to measure cultural competency among 226 students from the fall of2012 to the spring of2 015. Differences were examined between scores before and after taking each class, as well as differences between classes. There were significant improvements in all three groups, and a significant difference between two of the three classes in the improvement of scores. PMID- 29694751 TI - CULTURAL NURSING ANDROGOGIES WITH FOREIGN-EDUCATED PHYSICIANS ENROLLED IN BSN TO MSN PROGRAM. AB - Many health-care organizations and associations recommend that registered nurses be culturally competent and technologically savvy to compete in today's global society. This article reports both traditional and innovative technology-based teaching strategies that increased cultural competencies in nursing students in a BSNIMSN program for foreign-educated physicians. The Inventory for Assessing the Process of/Cultural Competency among Healthcare Professionals-Revised, was used at the beginning and at the end of the program. Cultural simulation scenarios and critical-reflection essay were some of the strategies used. The program prepared culturally competent advanced practice nurses while creating a smooth transition for the students to adapt to and acculturate into the cultures of the United States and nursing. PMID- 29694752 TI - PLANNING FOR DIVERSITY: EVALUATION OF A VOLUNTEER DISASTER RESPONSE PROGRAM. AB - The United States 'population is growing and diversifying rapidly. The nation is also experiencing an increase in the frequency and magnitude of disasters. Yet, most organizations that respond to these disaster events operate with a homogenous volunteer base - largely, white, middle class, and older. To improve program reach and effectiveness, diversifying volunteer pools is increasingly important. This article presents an evaluation of one response organization attempting to diversify its volunteer base geographically, ethnically, and linguistically, to better serve disaster survivors. Drawing on interviews with program leadership, the results, highlight two needs: 1) clear communication about the definition and rationale of diversity throughout the organization and 2) implementation of volunteer recruitment methods to address these goals. PMID- 29694753 TI - PATIENT ENGAGEMENT AND MEANINGFUL USE: ASSESSING THE IMPACT OF THE EHR INCENTIVE PROGRAM ON CULTURAL COMPETENCE IN HEALTHCARE. AB - This paper examines the importance and increasing need for health care practitioners to develop cultural competence in an effort to engage patients in their care to minimize the health disparities that are found in predominately ethnic minority populations. Although Meaningful Use requires data collection related to race and ethnicity, there is no evidence to support that the data is being used to engage patients in a culturally competent way. Lessons learned from the field of education regarding strategies used to develop cultural competence in the teaching profession can be applied in the health care field. This paper argues that cultural competence and patient engagement are clearly linked. PMID- 29694754 TI - CREATING PROTOCOLS FOR TRUSTWORTHINESS IN QUALITATIVE RESEARCH. AB - be provided within the document. One option is the creation of a trustworthiness protocol with details noting the characteristic of rigor, the process used to document the rigor, and then a timeline directing the planned time for conducting trustworthiness activities. After reviewing several documents, an actual plan of conducting trustworthiness as not found. Thus, these authors set out to create a trustworthiness protocol designed not only for the dissertation, but aframework for others who must create similar trustworthiness protocols for their research. The purpose of this article is to provide a reference for the trustworthiness plan, a dissertation example and showcase a trustworthiness protocol that may be used as an example to other qualitative researchers embarking on the creation of a trustworthiness protocol that is concrete and clear. PMID- 29694755 TI - Steroid Prophylaxis: The knowledge and practices of New Zealand General Dental Practitioners. AB - OBJECTIVE: To describe the knowledge and practices of New Zealand (NZ) General Dental Practitioners (GDPs) concerning the use of steroid prophylaxis. METHODS: An online survey was conducted in 2013 involving a sample of 500 NZ GDPs who met inclusion criteria and had email addresses on the Dental Council register. RESULTS: A total of 214 dentists responded, giving a 44.5% response rate after accounting for undelivered questionnaires. Nearly two-thirds (61 .7%) did not currently recommend corticosteroid prophylaxis, although nearly three-quarters (74.8%) believed that dental treatment posed a potential risk to patients with adrenal suppression. Over half (53.4%) believed that oral corticosteroids could cause adrenocortical suppression, and a similar proportion (58.3%) believed that a specific dose of oral prednisolone of 7.5 mg per day could do so. Most practitioners (79.6%) supported the formulation of steroid prophylaxis guidelines. CONCLUSION: Despite most NZ GDPs believing the dental setting to pose a risk of adrenal crisis for patients taking corticosteroids, there is some confusion among dentists identifying at-risk patients and their ability to manage if such an event was to occur in their practices. There is further confusion over whether steroid prophylaxis is warranted for perceived at-risk patients, and which regime to follow when it is. There is an associated tendency to be over cautious when determining the need for steroid prophylaxis, and to rely on their undergraduate steroid prophylaxis guidelines when doing so. There is a need for evidence-based guidelines to be formulated by an expert panel. PMID- 29694756 TI - An Investigation of the Views of Parents in Otago on Dental Care for Primary School-Aged Children by the Community Oral Health Service Prior to the Introduction of the Hub-Based Clinic System. AB - BACKGROUND AND OBJECTIVES: Prior to the introduction of the Southern District Health Board's reconfigured Community Oral Health Service in Otago, a project was undertaken with parents to investigate their knowledge, understanding and views of the historical School Dental Service and of the Community Oral Health Service that was being introduced. METHODS: Focus groups were run during 2011 in ten selected schools (parents with children in years 1-8) across two areas in Otago to represent ur ban and rural settings and to represent parents who were already travelling to dental services. RESULTS: Parents valued the traditional School Dental Service in Otago highly, generally agreeing that the service based in schools was accessible and convenient for parents and children. Rural parents who had always taken their children to dental appointments viewed it as a normal process, accepting that there could not be a service located in every school. Parents were aware that facilities were out-of-date. They highlighted the challenges of locating therapists since they started moving from school to school in the later 1990s and felt it was difficult for children seeing different therapists at each recall. There were diverse views on the proposed new system. Some parents felt that school-aged children should go to dental clinics on their own or with peers, while other parents welcomed the opportunity to attend when their child was having health care. CONCLUSION: It appears that the Community Oral Health Services should have an ongoing process to seek the views of parents and children about the service. PMID- 29694757 TI - Final year dental students in New Zealand: Self-reported confidence levels prior to BDS graduation. AB - BACKGROUND AND OBJECTIVES: It is expected that the graduating dental student will have acquired the skills and knowledge to confidently treat most circumstances that they may encounter in private practice. The aims of this study were to evaluate final year dental students' self-reported levels of confidence in expected core skills just prior to graduation and to explore their career intentions both directly after graduating as well as in the longer term. METHODS: After ethical approval was obtained, a survey and participant information sheet was distributed to all final year undergraduate dental students in 2014. Statistical analysis was carried out using SPSS version 22.0 with the alpha value set at 0.05. RESULTS: The response rate was 69% (58/84). Most (44.8%) were going to be working in New Zealand private practices with 34.5% definitely considering specializing. The majority reported high self-confidence levels for sealant restorations (96.6%) and radiography (94.8%), while very few were confident in carrying out soft tissue biopsies (1 .8%) or restoring dental implants and treating medical emergencies (10.5%). Some gender differences were found. CONCLUSIONS: The general finding was that most NZ graduates perceived themselves to be confident in managing the most fundamental aspects of general practice. Similar to their counterparts around the world, they will benefit from further mentoring and additional exposure to the more complex clinical tasks such as the restoration of implants and soft tissue biopsies. PMID- 29694758 TI - Dental clearance unsuccesful: cleidocranial dysplasia diagnosed at a relief of pain clinic. AB - A 55-year-old woman presented to Whangarei Base Hospital Emergency Department with a mandibular swelling adjacent to her unerupted tooth 48. She had never had dental radiographs taken, having had a dental clearance 20 years earlier. She wore full dentures. A panoramic dental radiograph revealed 44 unerupted teeth. Based on the clinical, oral and radiographic examinations a diagnosis of cleidocranial dysplasia (CCD) was confirmed. The patient had not been diagnosed with CCD prior to her hospital visit. Treatment included staged extractions of superficial mandibular supernumeraries and enucleation of the mandibular cyst, attempting to avoid pathological fracture. This would be followed by a six-month review and then annually as required. The case outlines the value of dental radiography in dental practice. Little is known about the prevalence of CCD in New Zealand and this is an area where future research could be conducted. PMID- 29694759 TI - Sir John Walsh Research Institute Research Day 2014. PMID- 29694761 TI - Letter to the Editor. PMID- 29694760 TI - Sir John Walsh Research Institute Research Day 2015. PMID- 29694762 TI - [Membranous nephropathy - the most commonly diagnosed glomerulopathy in patients who underwent renal biopsy in the Department of Internal Medicine, Nephrology and Endocrinology St. Queen Jadwiga Clinical District Hospital No. 2 in Rzeszow]. AB - We retrospectively analysedthe results of 120 renal biopsy, performedin 52 women, 62 men and 6children hospitalized mainly in theDepartment of Internal Medicine,Nephrology and Endocrinology St.Queen Jadwiga Clinical District HospitalNo. 2 in Rzeszow from 2013 to2016. The average age of patients onwhom renal biopsy was performedamounts to 44 (7-78) years. The mostcommon indications for renal biopsywere nephrotic syndrome in 47 patients(37.3%), non-nephrotic proteinuriain 31 patients (24.6%), worseningrenal function in 22 patients(17.5%), coexistence proteinuria withhematuria in 16 patients (12.7%), nephriticsyndrome in 9 patients (7.1%)as well as an isolated hematuria in 1patient (0.8%). Membranous glomerulonephritiswas the most commonhistological diagnosis observed inbiopsies, and was diagnosed in 19patients (15.1%). In 14 patients wediagnosed lupus nephritis (11.1%).With the same frequency we diagnosedfocal glomerulosclerosis, andmesangioproliferative glomerulonephritis(11 patients, 8,7%). Membraneproliferativeglomerulonephritis wasdiagnosed in 10 patients (7.9%).Other nephropathy accounted forless than 8% of all diagnoses. Mostpatients with membranous nephropathy(8 patients, 61%) had antibodiesagainst phospholipase A2 receptor.All patients with a diagnosis of membranousnephropathy received the renin-angiotensin-aldosterone systemblockade, and 13 patients (68.4%) receivedimmunosuppressive therapy.Complete remission was achieved in 11 patients (64.7%)with primary membranous nephropathy. In 35 patients(27.8%) of all patients who underwent renal biopsy theyhad complications after procedure in the form of small andclinically insignificant perirenal hematomas. Hematuriawas observed in 7 cases (5.56%). In one case, due to retroperitonealbleeding, the patient required a transfusion ofblood products. PMID- 29694763 TI - Effects of Rapid Solidification on Phase Formation and Microstructure Evolution of AgSbTe2-Based Thermoelectric Compounds. AB - We report on rapid solidification of an Ag(16.7)Sb(30.0)Te(53.3) compound using planar flow casting to stabilize the delta-AgSbTe2 single phase and avoid precipitation of the interconnected Sb2Te3 phase, which leads to deterioration of thermoelectric properties. Rapidly solidified samples are in form of flakes with different thickness (60-400 MUm). Precipitation of Sb2Te3 phase is fully inhibited in thin flakes (thickness below 100 MUm), which consist of an homogeneous delta-AgSbTe2 matrix, whereas isolated Sb2Te3 precipitates, dispersed throughout the delta-AgSbTe2 matrix, were found in thick flakes (thickness above 100 MUm). The lattice parameter of the delta-AgSbTe2 phase progressively increases with the cooling rate, indicating progressive supersaturation of the matrix for high degree of supercooling. Bulk specimens were prepared by hot pressing of the rapidly solidified flakes to evaluate thermoelectric properties. After sintering of the rapidly solidified flakes, the differential scanning calorimetry (DSC) traces indicates partial decomposition of the non equilibrium delta-AgSbTe2 into the stable phases. Measurements of the thermoelectric transport properties indicate the positive effects of rapid solidification on thermal conductivity and Seebeck coefficient and its negative effect on electrical conductivity, suggesting an operative way to improve thermoelectric performance. PMID- 29694764 TI - [Metformin-new potential medicine in pain treatment?] AB - Metformin, a drug of biguanide class, is now one of the most widely used drugs in the treatment of type 2 diabetes. It activates adenosine monophosphate-activated protein kinase (AMPK) and through AMPK activation, inhibits the mammalian target of rapamycin (mTOR) pathway. Recent literature has explored metformin as an option in pain management, given its role in the AMP-activated protein kinase (AMPK) pathway and its ability to modulate pain in animal models. Based on a variety of preclinical pain models, it is now clear that mTOR signaling plays a major role in the sensitization of the nervous system in chronic pain conditions. The activation of AMPK with metformin has led to decreased pain in neuropathic and postsurgical pain models, suggesting that these drugs and this mechanism of actin might be effective in humans. Despite the strong preclinical rationale, there are only very few data considered the utility of metformin as a potential pan therapeutic in humans. Further, randomized studies were needed to identify the role of metformin in pain perception and chronic pain conditions in humans. PMID- 29694765 TI - [The gastrointestinal tract microbiom in connective tissue diseases]. AB - Factors such as genetics, the environment,infections, and the humanbody microbiota, mainly gastrointestinaltract microbiota may play a rolein the pathogenesis of autoimmunedisorders. There is an increasing evidencethat suggest an association betweengastrointestinal tract dysbiosis,and in particular gut dysbiosis, andconnective tissue diseases but it stillremains unclear whether alterationsin the microbiome are a pathogeniccause or an effect of autoimmunedisease. Given the strong variabilityand abundance of microbes living inclose relation with human host, it becomesa difficult task to define whatshould be considered the normal orthe favorable microbiome. Furtherstudies are needed to establish howthe human microbiome contributes todisease susceptibility, and to characterizethe role of microbial diversity inthe pathogenesis of connective tissuediseases and their clinical manifestations.The identification of dysbiosisspecific for certain connective tissuediseases may help in the developmentof an individualized managementfor each patient. This review aims tosummarize current data on the role ofthe gastrointestinal tract microbiomein connective tissue diseases. PMID- 29694766 TI - Long-term follow-up after Holmium:YAG laser revascularization combined with autologous bone marrow derived stem cells implantation. AB - Background: Coronary artery diseaseis a major cause of death worldwide.Despite different standard revascularizationoptions, significant numberof patients remains not suitable for anytreatment. The aim of the study was toevaluate long term outcome of patientswith diffuse coronary artery disease,treated with autologous stem cells injectionscombined with transmyocardiallaser revascularization. Material and Methods: 9 patients underwentHolmium:YAG laser revascularizationand autologous bone marrowderived stem cells implantation between2007 and 2009 in the Department of CardiovascularSurgery and Transplantology,John Paul II Hospital, Krakow andwere subsequently followed up in 2015. Results: The mean follow-up periodwas 73 months. The mean CCSclass significantly improved (1.4+/-0.5vs 3.3+/-1.0; p<0.001) and cardiac relatedhospitalizations significantly decreased(1.1+/-0.8 vs 3.1+/-2.1; p<0.001). One deathdue to heart failure was observed. Themean LVEF increased from 38% to 42%(p>0.05). Conclusions: Clinical status improvementwas observed with low mortalityrate in the long-term follow-up. Nonew regional wall motion abnormalitieswere observed, and the increase ofglobal ejection fraction was noted. PMID- 29694767 TI - [Percutaneous coronary intervention and minimally invasive aortic valve replacement for patients with aortic valve disease and coronary artery disease]. AB - Objectives: To report the resultsof hybrid approach combining percutaneouscoronary intervention (PCI)and minimally invasive aortic valvereplacement through right anteriorminithoracotomy (RT-AVR) for patientswith aortic valve disease andcoronary artery disease. Materials and Methods: Retrospectiveanalysis of 53 hybrid RT-AVR/PCI procedures where RT-AVR wasperformed first in the operating roomand followed immediately by PCI performedin the catheterization laboratory. Results: Predicted with Euro-SCORE II and observed hospital mortalitywas 8.7+/-2.9% and 1.9% respectively.Hospital and intensive careunit length of stay were 5.6+/-2.4 and1.8+/-1.4 days respectively. Biologicalaortic valve prosthesis was implantedin 40 (75.5%) patients. PCI of LAD wasperformed in 5 patients (9.4%), of Dgin 10 (18.9%) patients, of Mg or Cx in21 (39.6%) patients, of PDA or RCA in25 (47.2%) patients. Two vessels andthree vessels PCI were performed in5 (9.4%) and 3 (5.7%) patients respectively.DES were used during PCI in42 (79.2%) patients. Dual antiplatelettherapy with 75 mg of Aspirin and 75mg of Clopidogrel started after RTAVR/PCI. Complications occurredin 16 (30.2%) patients after hybridRT-AVR/PCI procedure. Prolongedabove 24 hours mechanical ventilationtime was necessary in 3 patients(5.7%). Renal insufficiency occurredin 4 (7.5%), stroke in 1 (1.9%) patient.Pacemaker was implanted in 2 (3.8%)patients after surgery. Conversion toconventional surgery through mediansternotomy was performed in 1 patient(1.9%), surgical revision due topostoperative bleeding in 2 patients(3.8%). No perioperative myocardialinfarction and no mediastinitis wasdiagnosed after RT-AVR/PCI procedure.Postoperative chest blooddrainage was 245.0+/-181.0 ml. Red blood cells transfusionwas required in 10 (18.9%) patients. Conclusions: The hybrid RT AVR/PCI procedure forthese high risk patients with aortic valve disease and coronaryartery disease presented in our series favourablemortality results compared to predicted with EuroSCOREII mortality for conventional cardiac surgery. PMID- 29694768 TI - [The influence of living conditions and lifestyle on the anxiety level in women in the postpartum period-questionnaire study]. AB - Introduction: Due to the high incidence of postpartum anxiety disorders and their serious health and social consequences, it is essential to analyze the possible risk factors to identify groups of women particularly vulnerable to cover their proper care and control. The aim of our study was to investigate the relationship between the anxiety in women in the postpartum period, and their living conditions and lifestyle. Materials and Methods: The study was conducted from April to July 2016. We included 102 women in the postpartum period, living in the city of Cracow and the Cracow district. The study was based on a survey of our own authorship, State Anxiety Inventory (STAI) and the Jurczynski's Inventory of Health Behavior (IZZ). Results: The anxiety level in women in the postpartum period depends on the conditions of life and health behaviors. The level of health behavior of women in the postpartum period is an average and independent of age, number of children, and the material situation. Residents of cities, women with higher education, who planned pregnancy, have a higher level of health behavior. Good housing conditions have a positive influence on health behavior. Low levels of health behavior significantly affect the severity of maternal anxiety. Residents of the village, women with lower education and who not planning pregnancy have higher levels of anxiety during the postpartum period. Anxiety level of women in the postpartum period is inversely proportional to their housing conditions. Women with a job have lower levels of anxiety than non working. The anxiety level in women in childbirth does not depend on age or financial situation. Conclusions: The anxiety level in women in the postpartum period, significantly depends on the living conditions and health behaviors. Verification of distinguished factors should be applied appropriately in health promotional activities and prevention programs. PMID- 29694769 TI - [Surgical treatment results of chronic pericardial tamponade]. AB - Objective: To report the efficacy ofchronic pericardial effusion treatmentwith pericardial window creation throughvideo-assisted thoracoscopic surgeryand pericardial drainage througha small subxiphoid incision. Material and Methods: Retrospectiveanalysis of 31 patients after pericardialwindow creation through video-assistedthoracoscopic surgery (PW group) and77 patients where pericardial drainagethrough small subxiphoid incision (PDgroup) was performed. Echocardiographyexaminations were performed todocument pericardial tamponade andpericardial effusion recurrence. Results: Length of surgery was20.5+/-5.4 minutes in the PD group and25.8+/-6.4 minutes in the PW group,p<0.001. Amount of fluid evacuatedfrom pericardium during surgery was483+/-191 ml and 521+/-253 ml in PD andPW groups respectively, p=0.654.Postoperative drainage was maintainedlonger (4.3+/-1.4 days vs. 3.2+/-1.0,p<0.001) and the amount of fluid drainedafter surgery was higher (497+/-351ml vs. 309+/-231 ml, p=0.031) in the PWgroup. The amount of pericardial fluidat the end of hospitalization was statisticallysignificantly higher in the PDgroup compared with the PW group(8.9+/ 4.9 mm vs. 4.9+/-3.2 mm, p<0.001).Hospital stay was 5.7+/-2.7 days in thePD group and 6.1+/-3.4 in the PW group,p=0.112. No patient died duringhospitalization period in either group.Mortality within 30 days after surgerywas 2.6% in the PD and 3.2% in the PWgroup (p=0.642). In the PW group therewere 4 conversions to right minithoracotomydue to dense pleural adhesions.Pericardial effusion recurrenceoccurred in 9 patients (12.0%) in the PDgroup and none was observed (0.0%) inthe PW group (p=0.042) within 30 daysafter surgery. Conclusion: Pericardial window creationthrough video-assisted thoracoscopicsurgery should be consideredthe preferred method over pericardialdrainage through a small subxiphoidincision for chronic pericardial effusionand pericardial tamponade treatment toreduce the frequency of pericardial effusionreoccurrence. PMID- 29694770 TI - Protein-bound uremic toxins - biological effects and impact on morbidity in patients with chronic kidney disease. AB - Cardiovascular complicationsare the main cause of increasedmortality in patients with chronic kidneydisease. Besides traditional riskfactors, accumulated uremic toxinscontribute to the accelerated atherosclerosis,which is accompanied bythe progression of chronic kidneydisease. Increased clearance of toxinswith low molecular weight doesnot significantly improve survival ofhemodialysis patients, and thereforethe role and influence of other toxins,including protein-bound solutes(PBS) is intensively investigated. Inour work, PBS is discussed on theexample of indoxyl sulphate and pcresolsulphate. These substancesare highly bound to proteins andremoved from the circulation duringdialysis to a small extent only.In our article, pathophysiological effects,the impact on the progressionof chronic kidney disease and thesurvival of patients were discussed.We also assessed available methodsof removing toxins from the system. PMID- 29694771 TI - [Thyroid and aging: the present state of art]. AB - Aging is associated with importantchanges in thyroid hormone secretion,metabolism, and action. Itremains unclear, however, whetheraltered activity of the hypothamic-pituitary-thyroid axis represents physiologicchanges in thyroid function orwhether they are secondary to thyroiddysfunction. The prevalence ofthyroid disorders increases with age,but because some thyroid associatedsymptoms are similar to symptomsof the aging process, these disordersare relatively rarely diagnosed. On theother hand, because of the possiblepresence of chronic, non-thyroidalillnesses or pharmacotherapy, diagnosisof thyroid disorders in olderpopulations is often much more challengingthan in young people. Progressmade in better understandingof thyroid disorders in older peoplehas thrown a new light on the managementof patients with these disorders,the clinical picture of which isoften atypical. Therefore, physiciansneed a high index of suspicion to detectthyroid dysfunction in an olderperson with multiple comorbiditiesand chronic polypharmacy. The purposeof this article is to review thepresent state of knowledge on theage-related changes in hypothalamicpituitary-thyroid axis activity and todiscuss the clinical course, diagnosisand treatment of thyroid disorders inthe elderly. PMID- 29694772 TI - Right-sided aortic arch with aberrant left subclavian artery and hearing loss in patient with abnormal cardiomediastinal contours in routine chest X-ray. AB - Although the development oftechnologically advanced imagingtechniques has progressively reducedthe use of chest X-ray in clinicalpractice, it is still an invaluabletool to evaluate different diseases ofthe respiratory and cardiovascularsystems. We are presenting a caseof a 55-year-old male with arterialhypertension, severe mixed hearingloss who was referred to an internalmedicine ward due to abnormal mediastinaland cardiac contours observedin a routine chest X-ray. Thefinding was linked to an anomalousaortic course what was confirmedwithin transthoracic echocardiography.The computed tomography angiographyof the whole aorta revealedthe right sided aortic arch (RSAA)with four large arteries arising fromthe aortic arch, including the aberrantleft subclavian artery compressingthe esophagus causing thoughno symptoms. Since RSAA might beassociated with other cardiovasculardiseases and genetic disorders including22q11.2 deletion syndrome,we have conducted a complex diagnosticswhich showed additionallya decreased level of lymphocytes.The patient did not consent to geneticdiagnostics and was qualifiedfor conservative treatment of his disorders.In conclusion, a plain chestradiograph with the assessmentof heart silhouette must not be neglectedin cardiologic diagnostics.The identification of even asymptomaticaortic anatomic variant shouldbe followed by the whole aorta angiographyand a detailed assessmentof the patient. RSAA bears potentialrisk of tracheostomy bleeding, unforeseenproblems in transradialcoronary procedures and potentialproblems during thyroid surgery,also because of abnormal recurrentlaryngeal nerves' course. PMID- 29694773 TI - [Merkel cell carcinoma of the facial skin. Cases presentation and general rules of treatment]. AB - Merkel cell carcinoma is an aggressive,malignant, neuroendocrinetumor of the skin. The aim of thestudy is to present the clinical pictures,methods and results of treatmentof MCC in the Clinic of MaxillofacialSurgery in Rzeszow in years2003 2010. Changes were located onthe skin of the face of four patients.All patients were treated surgically,the primary change was removed. Recurrenceafter surgical treatment wasobserved in all patients. The observationsconfirmed the data from theliterature about the incidence of MCCover 75 years of age, aggressivenessand difficulties in treatment of thisdisease. PMID- 29694774 TI - [The first three docents of urology in Poland]. PMID- 29694776 TI - Apparent Softening of Wet Graphene Membranes on a Microfluidic Platform. AB - Graphene is regarded as the toughest two-dimensional material (highest in-plane elastic properties) and, as a consequence, it has been employed/proposed as an ultrathin membrane in a myriad of microfluidic devices. Yet, an experimental investigation of eventual variations on the apparent elastic properties of a suspended graphene membrane in contact with air or water is still missing. In this work, the mechanical response of suspended monolayer graphene membranes on a microfluidic platform is investigated via scanning probe microscopy experiments. A high elastic modulus is measured for the membrane when the platform is filled with air, as expected. However, a significant apparent softening of graphene is observed when water fills the microfluidic system. Through molecular dynamics simulations and a phenomenological model, we associate such softening to a water induced uncrumpling process of the suspended graphene membrane. This result may bring substantial modifications on the design and operation of microfluidic devices which exploit pressure application on graphene membranes. PMID- 29694775 TI - Potent Macromolecule-Sized Poration of Lipid Bilayers by the Macrolittins, A Synthetically Evolved Family of Pore-Forming Peptides. AB - Pore-forming peptides with novel functions have potential utility in many biotechnological applications. However, the sequence-structure-function relationships of pore forming peptides are not understood well enough to empower rational design. Therefore, in this work, we used synthetic molecular evolution to identify a novel family of peptides that are highly potent and cause macromolecular poration in synthetic lipid vesicles at low peptide concentration and at neutral pH. These unique 26-residue peptides, which we call macrolittins, release macromolecules from lipid bilayer vesicles made from zwitterionic PC lipids at peptide to lipid ratios as low as 1:1000, a property that is almost unprecedented among known membrane permeabilizing peptides. The macrolittins exist as membrane-spanning alpha-helices. They cause dramatic bilayer thinning and form large pores in planar supported bilayers. The high potency of these peptides is likely due to their ability to stabilize bilayer edges by a process that requires specific electrostatic interactions between peptides. PMID- 29694777 TI - Plasmonic Effects of Silver Nanoparticles Embedded in the Counter Electrode on the Enhanced Performance of Dye-Sensitized Solar Cells. AB - The plasmonic effects of silver (Ag) nanoparticles (NPs) with various morphologies (sphere, rod, and prism) embedded into the platinum (Pt) counter electrodes (CEs) of dye-sensitized solar cells (DSCs) were systematically investigated. It was shown that the power conversion efficiencies (PCEs) of the incorporated devices are notably improved from 7.60%, for the reference device without Ag NPs, to 8.10, 8.68, and 8.55% with Ag nanospheres, nanorods, and nanoprism devices, respectively. Moreover, the photocurrent and fill factor enhancement is attributed to the better optical and electrical properties of the integrated devices. Among all of the NP morphologies studied, Ag nanorods offer the best improvement to the device efficiency, as they have longitudinal localized surface plasmon resonance (L-LSPR) and strong scattering effects correlate within the morphology. PMID- 29694779 TI - Interplay between Polarizability and Hydrogen Bond Network of Water: Reparametrizing the Flexible Single-Point-Charge Water Model by the Nonlinear Adaptive Force Matching Approach. AB - An adaptive force matching (AFM) scheme using the nonlinear optimization to reparametrize the three-site, flexible, and polarizable single-point-charge (SPC) water model is reported. We compare the radial distribution functions of the intermolecular oxygen-oxygen, oxygen-hydrogen, and hydrogen-hydrogen distances with the recent scattering experiments, the previous AFM-fitting water model (MP2f), and the atomic multipole expanded AMOEBA model. Our nonpolarizable SPC 3f(0) model captures the feature of the first solvation shell of bulk water. With the ad hoc inclusion of the isotropic polarizability, the polarizable SPC-3f(0.6) water model recovers the many-body effect of the second solvation shell. In the n body decomposition analysis, the SPC-3f(0) model predicts the best agreement with MP2/aug-cc-pVTZ calculations with the use of the low-dimensional (H2O)4-ring and (H2O)6-ring clusters. For the comparison using the three-dimensional (H2O)6-prism and (H2O)16-4444a clusters, SPC-3f(0.6) predicts the results consistent with those of AMOEBA and MP2 levels. For simulating a water-cluster-dominant system such as supercritical water, SPC-3f(0) well characterizes the combination mode of bending and stretching at 5300 cm-1. PMID- 29694778 TI - Repurposed HisC Aminotransferases Complete the Biosynthesis of Some Methanobactins. AB - Methanobactins (Mbns) are ribosomally produced, post-translationally modified bacterial natural products with a high affinity for copper. MbnN, a pyridoxal 5' phosphate-dependent aminotransferase, performs a transamination reaction that is the last step in the biosynthesis of Mbns produced by several Methylosinus species. Our bioinformatic analyses indicate that MbnNs likely derive from histidinol-phosphate aminotransferases (HisCs), which play a key role in histidine biosynthesis. A comparison of the HisC active site with the predicted MbnN structure suggests that MbnN's active site is altered to accommodate the larger and more hydrophobic substrates necessary for Mbn biosynthesis. Moreover, we have confirmed that MbnN is capable of catalyzing the final transamination step in Mbn biosynthesis in vitro and in vivo. We also demonstrate that without this final modification, Mbn exhibits significantly decreased stability under physiological conditions. An examination of other Mbns and Mbn operons suggests that N-terminal protection of this family of natural products is of critical importance and that several different means of N-terminal stabilization have evolved independently in Mbn subfamilies. PMID- 29694780 TI - Combination of Amorphous Silk Fiber Spinning and Postspinning Crystallization for Tough Regenerated Silk Fibers. AB - An artificial spinning system using regenerated silk fibroin solutions is adopted to produce high-performance silk fibers. In previous studies, alcohol-based agents, such as methanol or ethanol, were used to coagulate silk dope solutions, producing silk fiber with poor mechanical properties compared with those of native silk fibers. The alcohol-based coagulation agents induce rapid beta-sheet crystallization of the silk molecules, which inhibits subsequent alignment of the beta-sheet crystals. Here, we induce gradual beta-sheet formation to afford adequate beta-sheet alignment similar to that of native silk fiber. To this aim, we developed an amorphous silk fiber spinning process that prevents fast beta sheet formation in silk molecules by using tetrahydrofuran (THF) as a coagulation solvent. In addition, we apply postdrawing to the predominantly amorphous silk fibers to induce beta-sheet formation and orientation. The resultant silk fibers showed a 2.5-fold higher extensibility, resulting in 1.5-fold tougher silk fibers compared with native Bombyx mori silk fiber. The amorphous silk fiber spinning process developed here will pave the way to the production of silk fibers with desired mechanical properties. PMID- 29694781 TI - Composite Reinforcement by Magnetic Control of Fiber Density and Orientation. AB - The flexural rigidity of cylindrical specimens, composed of epoxy reinforced by short, magnetized glass fibers, was enhanced using weak magnetic fields (<100 mT). By spatially controlling the magnitude and direction of the field, and thereby the torques and forces acting locally on the fibers, the orientation and concentration of the fillers in the matrix could be tuned prior to curing. Unidirectional alignment of the fibers, achieved using an air-core solenoid, improved the contribution of the fibers to the flexure modulus by a factor of 3. When a ring-shaped permanent magnet was utilized, the glass fibers were migrated preferentially near the rod boundary, and as a result, the contribution of the fibers to the flexure modulus doubled. The fiber length, density, and orientation distributions were extracted by MUCT image analysis, allowing comparison of the experimental flexure modulus to a modified rule of mixtures prediction. The ability to magnetically control the fiber distribution in reinforced composites demonstrated in this study may be applied in the fabrication of complex micro- and macroscale structures with spatially variable anisotropy, allowing features such as crack diversion, strengthening of highly loaded regions, as well as economic management of materials and weight. PMID- 29694782 TI - Influence of Hydrostatic Pressure on the Corrosion Behavior of Superhydrophobic Surfaces on Bare and Oxidized Aluminum Substrates. AB - It is generally recognized that superhydrophobic surfaces in water may be used for corrosion resistance due to the entrapped air in the solid/liquid interface and could find potential applications in the protection of ship hull. For a superhydrophobic surface, as its immersion depth into water increases, the resultant hydrostatic pressure is also increased, and the entrapped air can be squeezed out much more easily. It is therefore predicted that high hydrostatic pressure would cause an unexpected decrease in corrosion resistance for the vessels in deep water (e.g., submarines) because of the unstable entrapped air. In this work, in order to clarify the role of hydrostatic pressure in the corrosion behavior of superhydrophobic surfaces, two typical superhydrophobic surfaces (SHSs) were prepared on bare and oxidized aluminum substrates, respectively, and then were immersed into the NaCl aqueous solutions with different depths of ~0 cm (hydrostatic pressure ~0 kPa), 10 cm (1 kPa), and 150 cm (15 kPa). It was found out for the SHSs on the oxidized Al, as the hydrostatic pressure increased, the corrosion behavior became severe. However, for the SHSs on the bare Al, their corrosion behavior was complex due to hydrostatic pressure. It was found that the corrosion resistance under 1 kPa was the highest. Further mechanism analysis revealed that this alleviated corrosion behavior under 1 kPa resulted from suppressing the oxygen diffusion through the liquid and reducing the subsequent corrosion rate as compared with 0 kPa, whereas the relatively low hydrostatic pressure (HP) could stabilize the entrapped air and hence enhance the corrosion resistance, compared with 15 kPa. The present study therefore provided a fundamental understanding for the applications of SHSs to prevent the corrosion, especially for various vessels in deep water. PMID- 29694783 TI - Microwave Spectrum and Molecular Structure of the Chiral Tagging Candidate, 3,3,3 Trifluoro-1,2-epoxypropane and Its Complex with the Argon Atom. AB - The rotational spectrum of the chiral tagging candidate molecule, 3,3,3-trifluoro 1,2-epoxypropane (TFO), and of its heterodimer with the argon atom, is obtained using Fourier transform microwave spectroscopy from 5.6 to 18.1 GHz. With a strong, simple rotational spectrum, TFO shows promise for applications in chiral analysis through the conversion of enantiomers into spectroscopically distinct diastereomeric species through noncovalent attachment. The structure of the argon complex of TFO, determined from analysis of the microwave spectrum, is extremely similar to that previously found for ethylene oxide-argon but quite different from that suggested for propylene oxide-argon. PMID- 29694784 TI - Covalent Organic Framework Functionalized with 8-Hydroxyquinoline as a Dual-Mode Fluorescent and Colorimetric pH Sensor. AB - Real-time and accurate detection of pH in aqueous solution is of great significance in chemical, environmental, and engineering-related fields. We report here the use of 8-hydroxyquinoline-functionalized covalent organic framework (COF-HQ) for dual-mode pH sensing. In the fluorescent mode, the emission intensity of COF-HQ weakened as the pH decreased, and also displayed a good linear relationship against pH in the range from 1 to 5. In addition, COF-HQ showed discernible color changes from yellow to black as the acidity increased and can be therefore used as a colorimetric pH sensor. All these changes are reversible and COF-HQ can be recycled for multiple detection runs owing to its high hydrolytical stability. It can be further assembled into a mixed matrix membrane for practical applications. PMID- 29694785 TI - Dielectric Behavior and Phase Behavior of Block Copolymer PEO13-PPO30-PEO13 Aqueous Solution. AB - Dielectric spectroscopy can be applied to study the structure and dynamics of block polymer. In this work, dielectric measurements of block copolymer Pluronic L64 solution are carried out in the frequency range between 40 Hz and 110 MHz with variable temperatures and concentrations. We analyze the phase behavior of the PEO13-PPO30-PEO13 (Pluronic L64) aqueous system according to the concentration/temperature-dependence of direct current conductivity. The result indicates the sensitivity of the phase behavior and conductivity of the Pluronic L64 solution to temperature. Besides, two relaxations were observed: relaxation 1 (0.5 MHz) is related to the gelation process, while relaxation 2 (5 MHz) is caused by the interface polarization. On the basis of relaxation 2, the volume fraction and permittivity of the particle were calculated. The formations of the block copolymer micelle and gel are monitored successfully by the temperature/concentration-dependence of the dielectric parameters and the volume fraction. PMID- 29694786 TI - Overproduction of Fatty Acid Ethyl Esters by the Oleaginous Yeast Yarrowia lipolytica through Metabolic Engineering and Process Optimization. AB - Recent advances in the production of biofuels by microbes have attracted attention due to increasingly limited fossil fuels. Biodiesels, especially fatty acid ethyl esters (FAEEs), are considered a potentially fully sustainable fuel in the near future due to similarities with petrodiesels and compatibility with existing infrastructure. However, biosynthesis of FAEEs is limited by the supply of precursor lipids and acetyl-CoA. In the present study, we explored the production potential of an engineered biosynthetic pathway coupled to the addition of ethanol in the oleaginous yeast Yarrowia lipolytica. This type of yeast is able to supply a greater amount of precursor lipids than species typically used. To construct the FAEEs synthesis pathway, WS genes that encode wax ester synthases (WSs) from different species were codon-optimized and heterologously expressed in Y. lipolytica. The most productive engineered strain was found to express a WS gene from Marinobacter hydrocarbonoclasticus strain DSM 8798. To stepwisely increase FAEEs production, we optimized the promoter of WS overexpression, eliminated beta-oxidation by deleting the PEX10 gene in our engineered strains, and redirected metabolic flux toward acetyl-CoA. The new engineered strain, coupled with an optimized ethanol concentration, led to an approximate 5.5-fold increase in extracellular FAEEs levels compared to the wild type strain and a maximum FAEEs titer of 1.18 g/L in shake flask cultures. In summary, the present study demonstrated that an engineered Y. lipolytica strain possessed a high capacity for FAEEs production and may serve as a platform for more efficient biodiesel production in the future. PMID- 29694787 TI - Hierarchical Coupling of First-Principles Molecular Dynamics with Advanced Sampling Methods. AB - We present a seamless coupling of a suite of codes designed to perform advanced sampling simulations, with a first-principles molecular dynamics (MD) engine. As an illustrative example, we discuss results for the free energy and potential surfaces of the alanine dipeptide obtained using both local and hybrid density functionals (DFT), and we compare them with those of a widely used classical force field, Amber99sb. In our calculations, the efficiency of first-principles MD using hybrid functionals is augmented by hierarchical sampling, where hybrid free energy calculations are initiated using estimates obtained with local functionals. We find that the free energy surfaces obtained from classical and first-principles calculations differ. Compared to DFT results, the classical force field overestimates the internal energy contribution of high free energy states, and it underestimates the entropic contribution along the entire free energy profile. Using the string method, we illustrate how these differences lead to different transition pathways connecting the metastable minima of the alanine dipeptide. In larger peptides, those differences would lead to qualitatively different results for the equilibrium structure and conformation of these molecules. PMID- 29694788 TI - Reduction of Thermal Conductivity in Nanowires by Combined Engineering of Crystal Phase and Isotope Disorder. AB - Nanowires are a versatile platform to investigate and harness phonon and thermal transport phenomena in nanoscale systems. With this perspective, we demonstrate herein the use of crystal phase and mass disorder as effective degrees of freedom to manipulate the behavior of phonons and control the flow of local heat in silicon nanowires. The investigated nanowires consist of isotopically pure and isotopically mixed nanowires bearing either a pure diamond cubic or a cubic rhombohedral polytypic crystal phase. The nanowires with tailor-made isotopic compositions were grown using isotopically enriched silane precursors 28SiH4, 29SiH4, and 30SiH4 with purities better than 99.9%. The analysis of polytypic nanowires revealed ordered and modulated inclusions of lamellar rhombohedral silicon phases toward the center in otherwise diamond-cubic lattice with negligible interphase biaxial strain. Raman nanothermometry was employed to investigate the rate at which the local temperature of single suspended nanowires evolves in response to locally generated heat. Our analysis shows that the lattice thermal conductivity in nanowires can be tuned over a broad range by combining the effects of isotope disorder and the nature and degree of polytypism on phonon scattering. We found that the thermal conductivity can be reduced by up to ~40% relative to that of isotopically pure nanowires, with the lowest value being recorded for the rhombohedral phase in isotopically mixed 28Si x30Si1- x nanowires with composition close to the highest mass disorder ( x ~ 0.5). These results shed new light on the fundamentals of nanoscale thermal transport and lay the groundwork to design innovative phononic devices. PMID- 29694789 TI - Long-Term Outcomes of the ADRENAL Trial. PMID- 29694790 TI - The role of mass spectrometry in the characterization of biologic protein products. AB - INTRODUCTION: Mass spectrometry (MS) is widely used in the characterization of biomolecules including peptide and protein therapeutics. These biotechnology products have seen rapid growth over the past few decades and continue to dominate the global pharmaceutical market. Advances in MS instrumentation and techniques have enhanced protein characterization capabilities and supported an increased development of biopharmaceutical products. Areas covered: This review describes recent developments in MS-based biotherapeutic analysis including sequence determination, post-translational modifications (PTMs) and higher order structure (HOS) analysis along with improvements in ionization and dissociation methods. An outlook of emerging applications of MS in the lifecycle of product development such as comparability, biosimilarity and quality control practices is also presented. Expert commentary: MS-based methods have established their utility in the analysis of new biotechnology products and their lifecycle appropriate implementation. In the future, MS will likely continue to grow as one of the leading protein identification and characterization techniques in the biopharmaceutical industry landscape. PMID- 29694791 TI - Genetic Variant Q63R of Cannabinoid Receptor 2 Causes Differential ERK Phosphorylation in Human Immune Cells. AB - BACKGROUND: The cannabinoid receptor 2 (CB2R) is primarily expressed in immune tissues and implicated in immune regulation. In models of inflammatory diseases, modulation of CB2R alters function of immune cells and affects the progression of disease. We therefore believe that CB2R modulation could be a promising therapy for inflammatory diseases. In humans, the nonsynonymous mutation Q63R, the most common variant of the CB2 receptor, has been found to be associated with multiple diseases, including idiopathic arthritis, obesity, and celiac diseases. However, it is not clear whether the Q63R variant indeed alters signaling of CB2R and whether the change in a specific signaling pathway contributes to the pathogenesis of inflammatory diseases. Better understanding of the signaling downstream of CB2R in immune cells may provide a molecular base for better usage of CB2R modulators. METHODS: We studied the signaling caused by CB2R activation in cell lines and primary immune cells possessing Q63R variant. RESULTS: We found that activation of CB2R in immune cells by either an endogenous (2-AG) or a synthetic (CP5,940) ligand causes transient phosphorylation of extracellular signal-regulated kinases (ERK). Phosphorylation of ERK in immune cells due to activation of CB2R is coupled to Gi protein. In human peripheral blood mononuclear cells, phosphorylation of ERK caused by CB2R activation is especially intense in B cells and T cells. CONCLUSIONS: Activation of both CB2R variants 63Q and 63R causes phosphorylation of ERK. However, the signal intensity caused by 63R activation is relatively weaker than that caused by 63Q activation. PMID- 29694792 TI - Response to Trametinib of a Pulmonary Langerhans Cell Histiocytosis Harboring a MAP2K1 Deletion. PMID- 29694793 TI - Death of the Endothelium in Sepsis: Understanding the Crime Scene. PMID- 29694795 TI - A Pilot Study of the Effect of Green Kiwifruit on Human Intestinal Fermentation Measured by Hydrogen and Methane Breath Testing. AB - We investigated the impact of the ingestion of two green kiwifruit (Actinidia deliciosa var. Hayward) and one Royal Gala apple on breath hydrogen and methane production in humans. Consumption of two green kiwifruit led to no evidence of carbohydrate malabsorption (0/20), whereas consumption of one apple was associated with carbohydrate malabsorption in 6/20 participants (P = .008). There were no significant differences in the area under the curve for hydrogen or methane breath concentrations after consumption of the two fruits. Rates of lactose and fructose breath tests in this cohort were within expected parameters. Green kiwifruit are not associated with clinically significant carbohydrate malabsorption compared with apples in this pilot study. PMID- 29694794 TI - Unexpected Response Profiles Seen in Hepatitis C Virus-Infected Patients Treated with Sofosbuvir Plus Ribavirin: Five Case Reports. AB - Direct-acting antivirals (DAAs) have been proved as potent agents in the new era of Hepatitis C therapeutics. DAA has evolved to prove highly efficacious treatment rates and sustained virological response in hepatitis C virus (HCV) treated patients and has shown minimal side effects, but in this study, we reported five cases that showed unusual response toward the use of DAA. The diagnosis was an unusual response of abruptly high viral titers and liver function tests (LFTs) in patients who received DAA combination therapy. The patients received sofosbuvir (400 mg) and ribavirin for 6 months. Although 6 month long recommended DAA combination therapy with ribavirin cleared HCV after 6 months, during the treatment period, five patients experienced unusually and unexpectedly high viral loads and LFTs level in the middle of therapy tenure and then sudden decline of viral titers after completion of treatment. This is the first study to describe the unusual response shown by patients treated with sofosbuvir-based combined therapy that experienced abrupt and marked rise in viral loads during the initial months of treatment followed by sudden elimination of virus during last 2 months of treatment. Although satisfactory response to DAA is well reported, clinicians and policy makers should deliberate upon the exceptions and ensure the proper implementation of International guidelines with modifications according to this population, if necessary. PMID- 29694796 TI - Chlamydia Retesting Among Safety-Net Clinic Patients: Infertility Prevention Project. AB - BACKGROUND: Due to high reinfection rates, the Centers for Disease Control and Prevention (CDC) recommend retesting everyone diagnosed with chlamydia after treatment. However, retesting rates are often low, and research on retesting is limited. METHODS: Infertility Prevention Project (IPP) was a national chlamydia screening and treatment project in the United States. We completed a retrospective longitudinal analysis using IPP testing data from 8,266 women with at least 1 positive test result from 2010 to 2013. We calculated the proportion of women retested 2-12 months after a chlamydia diagnosis and used Cox proportional hazards models to explore associated factors. RESULTS: Only 32% of women had evidence of retesting by 12 months of follow-up. Being younger (multivariate hazard ratio [mHR]: 0.96; 95% confidence interval [CI]: 0.95-0.96), black (mHR: 1.29; 95% CI: 1.12-1.50), or attending a county sexually transmitted diseases (STD; mHR: 1.91; 95% CI: 1.68-2.17), county family planning (mHR: 1.53; 95% CI: 1.39-1.69), or school-based (mHR: 2.34; 95% CI: 2.07-2.65) clinic relative to a nonprofit community health clinic were associated with increased retesting rates. CONCLUSIONS: Less than one-third of women are retested. Our results show that some clinic settings may have systematic differences which facilitate retesting, such as use of automated reminders, closed patient populations, and makeup of patient populations. Investigation of clinical environments through site visits and further data analyses may be keys to improving retesting rates. PMID- 29694797 TI - Meta-Analysis of the Relation Between IL10 Promoter Polymorphisms and Autoimmune Liver Disease Risk. AB - BACKGROUND: Single nucleotide polymorphisms of the IL10 gene have been linked to the occurrence of autoimmune liver disease. METHODS: We performed a meta-analysis to assess the association between three IL10 promoter polymorphisms (rs1800896, rs1800871, and rs1800872) and the risk of autoimmune hepatitis, primary biliary cholangitis, and primary sclerosing cholangitis. RESULTS: In total, 1420 articles were initially identified through database retrieval. After screening, seven eligible articles were ultimately included in the meta-analysis. A fixed-effect model was used for all Mantel-Haenszel statistics due to the absence of large between-study heterogeneity (all I2 < 50%, p > 0.1). No association between any of the studied polymorphisms and risk of autoimmune liver disease was detected in the allele, homozygote, heterozygote, dominant, recessive, or carrier genetic models (passociation > 0.05). Potential publication bias was excluded using Begg's and Egger's tests. Similar negative results were observed in subgroup analyses and in an analysis of the three haplotypes of rs1800896/rs1800871/rs1800872 (G/C/C, A/C/C, and A/T/A). CONCLUSION: Our meta analysis strongly suggests that the IL10 rs1800896, rs1800871, and rs1800872 polymorphisms are not associated with the risk of autoimmune liver disease. PMID- 29694798 TI - Regeneration of the Rhopalium and the Rhopalial Nervous System in the Box Jellyfish Tripedalia cystophora. AB - Cubozoans have the most intricate visual apparatus within Cnidaria. It comprises four identical sensory structures, the rhopalia, each of which holds six eyes of four morphological types. Two of these eyes are camera-type eyes that are, in many ways, similar to the vertebrate eye. The visual input is used to control complex behaviors, such as navigation and obstacle avoidance, and is processed by an elaborate rhopalial nervous system. Several studies have examined the rhopalial nervous system, which, despite a radial symmetric body plan, is bilaterally symmetrical, connecting the two sides of the rhopalium through commissures in an extensive neuropil. The four rhopalia are interconnected by a nerve ring situated in the oral margin of the bell, and together these structures constitute the cubozoan central nervous system. Cnidarians have excellent regenerative capabilities, enabling most species to regenerate large body areas or body parts, and some species can regenerate completely from just a few hundred cells. Here we test whether cubozoans are capable of regenerating the rhopalia, despite the complexity of the visual system and the rhopalial nervous system. The results show that the rhopalia are readily regrown after amputation and have developed most, if not all, neural elements within two weeks. Using electrophysiology, we investigated the functionality of the regrown rhopalia and found that they generated pacemaker signals and that the lens eyes showed a normal response to light. Our findings substantiate the amazing regenerative ability in Cnidaria by showing here the complex sensory system of Cubozoa, a model system proving to be highly applicable in studies of neurogenesis. PMID- 29694800 TI - About the Cover. PMID- 29694799 TI - Differential ROS Generation in Response to Stress in Symbiodinium spp. AB - Oxidative stress inside cells occurs when the production of reactive oxygen species (ROS) is no longer efficiently counterbalanced by the generation of antioxidants. In this study, we measured the intracellular production of ROS, including hydrogen peroxide (H2O2), superoxide (O2-), and singlet oxygen (1O2), in cultured dinoflagellates of the genus Symbiodinium under thermal and oxidative stress. ROS tagged with fluorescent probes were measured by flow cytometry. Dissimilar Symbiodinium internal transcribed spacer 2 (ITS2) clades or phylotypes (A1, B2, E, F1) produced ROS in different quantities in response to stress. For example, when comparing the control (26 degrees C) to the high-temperature treatment (35 degrees C), Symbiodinium E showed no change in the intracellular concentrations of any of the ROS; but phylotype A1 displayed a 10-fold increase in the overall ROS concentration and a 4-fold increase in O2-. Under oxidative stress, when 8 mmol l-1 H2O2 was added to the cells, these same two Symbiodinium phylotypes increased their overall concentrations of ROS, but only Symbiodinium E showed an increase in the concentrations of O2- (2*) and 1O2 (3*). Therefore, not only were the stress responses of the various Symbiodinium phylotypes different but also the responses of individual phylotypes to thermal and oxidative stress were different in terms of ROS production. Variation in the quality and quantity of ROS generation and its implications for subsequent antioxidant production suggest that different stress mechanisms are at play. While our experiments were done under laboratory conditions that did not necessarily mirror ecological ones, these results provide new insight into processes inside Symbiodinium cells during stress events and add new explanations for a phylotype's susceptibility to stress. PMID- 29694801 TI - Combining Factors That Individually Enhance Memory in Lymnaea. AB - When applied individually, thermal stress (1 hour at 30 degrees C) and ( )epicatechin (a flavonol found in green tea, e.g.) each enhance long-term memory formation following operant conditioning of Lymnaea aerial respiratory behavior. Snails demonstrate enhanced long-term memory formation when trained in epicatechin-treated pond water or when placed in 30 degrees C pond water for 1 hour, 1 hour prior to training in pond water. We ask here whether the combined application of epicatechin + thermal stress enhances long-term memory retention length beyond the maximal lengths of the individual factors alone. We report that the applied combination of epicatechin + thermal stress has a synergistic memory enhancing effect; that is, when the two are applied in combination, memory persists longer than when either is applied alone. We then ask whether quercetin, a heat shock protein blocker, will affect the memory enhancement produced by the combined treatment of thermal stress and epicatechin. We report that quercetin does not decrease the memory enhancement of epicatechin, but it does decrease the memory enhancement by thermal stress; and it also decreases the memory persistence of snails exposed to both treatments in combination. PMID- 29694802 TI - Symbiont Identity Influences Patterns of Symbiosis Establishment, Host Growth, and Asexual Reproduction in a Model Cnidarian-Dinoflagellate Symbiosis. AB - The genus Symbiodinium is physiologically diverse and so may differentially influence symbiosis establishment and function. To explore this, we inoculated aposymbiotic individuals of the sea anemone Exaiptasia pallida (commonly referred to as "Aiptasia"), a model for coral symbiosis, with one of five Symbiodinium species or types (S. microadriaticum, S. minutum, phylotype C3, S. trenchii, or S. voratum). The spatial pattern of colonization was monitored over time via confocal microscopy, and various physiological parameters were measured to assess symbiosis functionality. Anemones rapidly formed a symbiosis with the homologous symbiont, S. minutum, but struggled or failed to form a long-lasting symbiosis with Symbiodinium C3 or S. voratum, respectively. Symbiodinium microadriaticum and S. trenchii were successful but reached their peak density two weeks after S. minutum. The spatial pattern of colonization was identical for all Symbiodinium taxa that were ultimately successful, starting in the oral disk and progressing to the tentacles, before invading the column and, finally, the pedal disk. In all cases, proliferation through the anemone's tentacles was patchy, suggesting that symbionts were being expelled into the gastrovascular cavity and re-phagocytosed by the host. However, the timing of these various spatial events differed between the different Symbiodinium taxa. Furthermore, S. microadriaticum and S. trenchii were less beneficial to the host, as indicated by lower rates of photosynthesis, anemone growth, and pedal laceration. This study enhances our understanding of the link between symbiont identity and the performance of the overall symbiosis, which is important for understanding the potential establishment and persistence of novel host-symbiont pairings. Importantly, we also provide a baseline for further studies on this topic with the globally adopted "Aiptasia" model system. PMID- 29694803 TI - Stolonial Movement: A New Type of Whole-Organism Behavior in Porifera. AB - Sponges (phylum Porifera) traditionally are represented as inactive, sessile filter-feeding animals devoid of any behavior except filtering activity. However, different time-lapse techniques demonstrate that sponges are able to show a wide range of coordinated but slow whole-organism behavior. The present study concerns a peculiar type of such behavior in the psychrophilic demosponge Amphilectus lobatus: stolonial movement. During stolonial movement, sponges produce outgrowths (stolons) that crawl along a substrate with a speed of 4.4 +/- 2.2 MUm min-1 and branch, thus forming a complex net covering a considerable area of a substrate. This net is used by sponges to search for new points with appropriate environmental conditions for individual relocation. After such points are found, all cells of the parental sponge migrate through stolons, leaving a naked parental skeleton, forming one or several filial sponges in the new location. Thus, stolonial movement combines traits of crawling along the substrate and asexual reproduction. This behavior relies on massive cell dedifferentiation followed by coordinated cell migration to the point of new sponge body formation and their subsequent differentiation into specialized cell types. PMID- 29694804 TI - Shifting Balance of Protein Synthesis and Degradation Sets a Threshold for Larval Growth Under Environmental Stress. AB - Exogenous environmental factors alter growth rates, yet information remains scant on the biochemical mechanisms and energy trade-offs that underlie variability in the growth of marine invertebrates. Here we study the biochemical bases for differential growth and energy utilization (as adenosine triphosphate [ATP] equivalents) during larval growth of the bivalve Crassostrea gigas exposed to increasing levels of experimental ocean acidification (control, middle, and high pCO2, corresponding to ~400, ~800, and ~1100 uatm, respectively). Elevated pCO2 hindered larval ability to accrete both shell and whole-body protein content. This negative impact was not due to an inability to synthesize protein per se, because size-specific rates of protein synthesis were upregulated at both middle and high pCO2 treatments by as much as 45% relative to control pCO2. Rather, protein degradation rates increased with increasing pCO2. At control pCO2, 89% of cellular energy (ATP equivalents) utilization was accounted for by just 2 processes in larvae, with protein synthesis accounting for 66% and sodium potassium transport accounting for 23%. The energetic demand necessitated by elevated protein synthesis rates could be accommodated either by reallocating available energy from within the existing ATP pool or by increasing the production of total ATP. The former strategy was observed at middle pCO2, while the latter strategy was observed at high pCO2. Increased pCO2 also altered sodium potassium transport, but with minimal impact on rates of ATP utilization relative to the impact observed for protein synthesis. Quantifying the actual energy costs and trade-offs for maintaining physiological homeostasis in response to stress will help to reveal the mechanisms of resilience thresholds to environmental change. PMID- 29694805 TI - Suicide: A Silent Contributor to Opioid-Overdose Deaths. PMID- 29694806 TI - Parental Mosaicism in "De Novo" Epileptic Encephalopathies. PMID- 29694807 TI - Kidney Diseases Associated with Human Immunodeficiency Virus Infection. PMID- 29694808 TI - Case 13-2018: A 53-Year-Old Man with Cardiomyopathy and Recurrent Ventricular Tachycardia. PMID- 29694809 TI - Toxidrome Recognition in Chemical-Weapons Attacks. PMID- 29694810 TI - The Long Ride Home. PMID- 29694811 TI - Paving the Way for Improved Treatment of Acute Stroke with Tenecteplase. PMID- 29694812 TI - Magnetic Resonance Imaging and Cardiac Devices. PMID- 29694813 TI - Strategies for Reducing Opioid-Overdose Deaths - Lessons from Canada. PMID- 29694814 TI - Noninvasive Ablation of Ventricular Tachycardia. PMID- 29694817 TI - Prazosin for Post-Traumatic Stress Disorder. PMID- 29694818 TI - In Utero Protein Therapy for an Inherited Developmental Disorder. PMID- 29694816 TI - Azithromycin to Reduce Childhood Mortality in Sub-Saharan Africa. AB - BACKGROUND: We hypothesized that mass distribution of a broad-spectrum antibiotic agent to preschool children would reduce mortality in areas of sub-Saharan Africa that are currently far from meeting the Sustainable Development Goals of the United Nations. METHODS: In this cluster-randomized trial, we assigned communities in Malawi, Niger, and Tanzania to four twice-yearly mass distributions of either oral azithromycin (approximately 20 mg per kilogram of body weight) or placebo. Children 1 to 59 months of age were identified in twice yearly censuses and were offered participation in the trial. Vital status was determined at subsequent censuses. The primary outcome was aggregate all-cause mortality; country-specific rates were assessed in prespecified subgroup analyses. RESULTS: A total of 1533 communities underwent randomization, 190,238 children were identified in the census at baseline, and 323,302 person-years were monitored. The mean (+/-SD) azithromycin and placebo coverage over the four twice yearly distributions was 90.4+/-10.4%. The overall annual mortality rate was 14.6 deaths per 1000 person-years in communities that received azithromycin (9.1 in Malawi, 22.5 in Niger, and 5.4 in Tanzania) and 16.5 deaths per 1000 person-years in communities that received placebo (9.6 in Malawi, 27.5 in Niger, and 5.5 in Tanzania). Mortality was 13.5% lower overall (95% confidence interval [CI], 6.7 to 19.8) in communities that received azithromycin than in communities that received placebo (P<0.001); the rate was 5.7% lower in Malawi (95% CI, -9.7 to 18.9), 18.1% lower in Niger (95% CI, 10.0 to 25.5), and 3.4% lower in Tanzania (95% CI, -21.2 to 23.0). Children in the age group of 1 to 5 months had the greatest effect from azithromycin (24.9% lower mortality than that with placebo; 95% CI, 10.6 to 37.0). Serious adverse events occurring within a week after administration of the trial drug or placebo were uncommon, and the rate did not differ significantly between the groups. Evaluation of selection for antibiotic resistance is ongoing. CONCLUSIONS: Among postneonatal, preschool children in sub Saharan Africa, childhood mortality was lower in communities randomly assigned to mass distribution of azithromycin than in those assigned to placebo, with the largest effect seen in Niger. Any implementation of a policy of mass distribution would need to strongly consider the potential effect of such a strategy on antibiotic resistance. (Funded by the Bill and Melinda Gates Foundation; MORDOR ClinicalTrials.gov number, NCT02047981 .). PMID- 29694815 TI - Tenecteplase versus Alteplase before Thrombectomy for Ischemic Stroke. AB - BACKGROUND: Intravenous infusion of alteplase is used for thrombolysis before endovascular thrombectomy for ischemic stroke. Tenecteplase, which is more fibrin specific and has longer activity than alteplase, is given as a bolus and may increase the incidence of vascular reperfusion. METHODS: We randomly assigned patients with ischemic stroke who had occlusion of the internal carotid, basilar, or middle cerebral artery and who were eligible to undergo thrombectomy to receive tenecteplase (at a dose of 0.25 mg per kilogram of body weight; maximum dose, 25 mg) or alteplase (at a dose of 0.9 mg per kilogram; maximum dose, 90 mg) within 4.5 hours after symptom onset. The primary outcome was reperfusion of greater than 50% of the involved ischemic territory or an absence of retrievable thrombus at the time of the initial angiographic assessment. Noninferiority of tenecteplase was tested, followed by superiority. Secondary outcomes included the modified Rankin scale score (on a scale from 0 [no neurologic deficit] to 6 [death]) at 90 days. Safety outcomes were death and symptomatic intracerebral hemorrhage. RESULTS: Of 202 patients enrolled, 101 were assigned to receive tenecteplase and 101 to receive alteplase. The primary outcome occurred in 22% of the patients treated with tenecteplase versus 10% of those treated with alteplase (incidence difference, 12 percentage points; 95% confidence interval [CI], 2 to 21; incidence ratio, 2.2; 95% CI, 1.1 to 4.4; P=0.002 for noninferiority; P=0.03 for superiority). Tenecteplase resulted in a better 90-day functional outcome than alteplase (median modified Rankin scale score, 2 vs. 3; common odds ratio, 1.7; 95% CI, 1.0 to 2.8; P=0.04). Symptomatic intracerebral hemorrhage occurred in 1% of the patients in each group. CONCLUSIONS: Tenecteplase before thrombectomy was associated with a higher incidence of reperfusion and better functional outcome than alteplase among patients with ischemic stroke treated within 4.5 hours after symptom onset. (Funded by the National Health and Medical Research Council of Australia and others; EXTEND-IA TNK ClinicalTrials.gov number, NCT02388061 .). PMID- 29694819 TI - Prenatal Correction of X-Linked Hypohidrotic Ectodermal Dysplasia. AB - Genetic deficiency of ectodysplasin A (EDA) causes X-linked hypohidrotic ectodermal dysplasia (XLHED), in which the development of sweat glands is irreversibly impaired, an condition that can lead to life-threatening hyperthermia. We observed normal development of mouse fetuses with Eda mutations after they had been exposed in utero to a recombinant protein that includes the receptor-binding domain of EDA. We administered this protein intraamniotically to two affected human twins at gestational weeks 26 and 31 and to a single affected human fetus at gestational week 26; the infants, born in week 33 (twins) and week 39 (singleton), were able to sweat normally, and XLHED-related illness had not developed by 14 to 22 months of age. (Funded by Edimer Pharmaceuticals and others.). PMID- 29694820 TI - Metastatic Prostate Cancer. PMID- 29694821 TI - Colon Cutoff Sign. PMID- 29694822 TI - Prostate Cancer Metastasis - Fueled by Fat? PMID- 29694823 TI - More on Adjuvant Therapy in Resected Melanoma. PMID- 29694824 TI - PFO Closure for Cryptogenic Stroke. PMID- 29694826 TI - Orbital Apex Syndrome. PMID- 29694827 TI - Hormone-induced spawning of the critically endangered northern corroboree frog Pseudophryne pengilleyi. AB - Fundamental knowledge of the optimal hormone concentrations required to stimulate amplexus and spawning in breeding pairs of amphibians is currently lacking, hindering our understanding of the proximate mechanisms underpinning mating behaviour. The present study investigated the effects of: (1) the dose of a gonadotropin-releasing hormone analogue (GnRH-a) administered; (2) male-female hormone administration interval; and (3) topical application of GnRH-a, on spawning success in the northern corroboree frog. Administration of GnRH-a at doses of 0.5, 1.0 and 2.0MUgg-1 were highly successful, with a significantly greater proportion of hormone-treated pairs ovipositing (89-100%) compared with the 0MUgg-1 treatment (22%). Of the hormone-treated pairs, those receiving 0.5MUgg-1 GnRH-a exhibited the highest fertilisation success (61%). Administration of GnRH-a to males and females simultaneously (0h) was more effective than injecting males either 48 or 24h before the injection of females. Overall, administration of GnRH-a was highly successful at inducing spawning in northern corroboree frogs. For the first time, we also effectively induced spawning following the topical application of GnRH-a to the ventral pelvic region. Topical application of GnRH-a eliminates the need for specialised training in amphibian injection, and will allow assisted reproductive technologies to be adopted by a greater number of captive facilities globally. PMID- 29694825 TI - Birth Outcomes for Pregnant Women with HIV Using Tenofovir-Emtricitabine. AB - BACKGROUND: In a previous trial of antiretroviral therapy (ART) involving pregnant women with human immunodeficiency virus (HIV) infection, those randomly assigned to receive tenofovir, emtricitabine, and ritonavir-boosted lopinavir (TDF-FTC-LPV/r) had infants at greater risk for very premature birth and death within 14 days after delivery than those assigned to receive zidovudine, lamivudine, and ritonavir-boosted lopinavir (ZDV-3TC-LPV/r). METHODS: Using data from two U.S.-based cohort studies, we compared the risk of adverse birth outcomes among infants with in utero exposure to ZDV-3TC-LPV/r, TDF-FTC-LPV/r, or TDF-FTC with ritonavir-boosted atazanavir (ATV/r). We evaluated the risk of preterm birth (<37 completed weeks of gestation), very preterm birth (<34 completed weeks), low birth weight (<2500 g), and very low birth weight (<1500 g). Risk ratios with 95% confidence intervals were estimated with the use of modified Poisson models to adjust for confounding. RESULTS: There were 4646 birth outcomes. Few infants or fetuses were exposed to TDF-FTC-LPV/r (128 [2.8%]) as the initial ART regimen during gestation, in contrast with TDF-FTC-ATV/r (539 [11.6%]) and ZDV-3TC-LPV/r (954 [20.5%]). As compared with women receiving ZDV 3TC-LPV/r, women receiving TDF-FTC-LPV/r had a similar risk of preterm birth (risk ratio, 0.90; 95% confidence interval [CI], 0.60 to 1.33) and low birth weight (risk ratio, 1.13; 95% CI, 0.78 to 1.64). As compared to women receiving TDF-FTC-ATV/r, women receiving TDF-FTC-LPV/r had a similar or slightly higher risk of preterm birth (risk ratio, 1.14; 95% CI, 0.75 to 1.72) and low birth weight (risk ratio, 1.45; 95% CI, 0.96 to 2.17). There were no significant differences between regimens in the risk of very preterm birth or very low birth weight. CONCLUSIONS: The risk of adverse birth outcomes was not higher with TDF FTC-LPV/r than with ZDV-3TC-LPV/r or TDF-FTC-ATV/r among HIV-infected women and their infants in the United States, although power was limited for some comparisons. (Funded by the National Institutes of Health and others.). PMID- 29694828 TI - The idebenone metabolite QS10 restores electron transfer in complex I and coenzyme Q defects. AB - Idebenone is a hydrophilic short-chain coenzyme (Co) Q analogue, which has been used as a potential bypass of defective complex I in both Leber Hereditary Optic Neuropathy and OPA1-dependent Dominant Optic Atrophy. Based on its potential antioxidant effects, it has also been tested in degenerative disorders such as Friedreich's ataxia, Huntington's and Alzheimer's diseases. Idebenone is rapidly modified but the biological effects of its metabolites have been characterized only partially. Here we have studied the effects of quinones generated during in vivo metabolism of idebenone with specific emphasis on 6-(9-carboxynonyl)-2,3 dimethoxy-5-methyl-1,4-benzoquinone (QS10). QS10 partially restored respiration in cells deficient of complex I or of CoQ without inducing the mitochondrial permeability transition, a detrimental effect of idebenone that may offset its potential benefits [Giorgio et al. (2012) Biochim. Biophys. Acta 1817: 363-369]. Remarkably, respiration was largely rotenone-insensitive in complex I deficient cells and rotenone-sensitive in CoQ deficient cells. These findings indicate that, like idebenone, QS10 can provide a bypass to defective complex I; and that, unlike idebenone, QS10 can partially replace endogenous CoQ. In zebrafish (Danio rerio) treated with rotenone, QS10 was more effective than idebenone in allowing partial recovery of respiration (to 40% and 20% of the basal respiration of untreated embryos, respectively) and allowing zebrafish survival (80% surviving embryos at 60 h post-fertilization, a time point at which all rotenone-treated embryos otherwise died). We conclude that QS10 is potentially more active than idebenone in the treatment of diseases caused by complex I defects, and that it could also be used in CoQ deficiencies of genetic and acquired origin. PMID- 29694829 TI - Mitochondrial cAMP-PKA signaling: What do we really know? AB - Mitochondria are key organelles for cellular homeostasis. They generate the most part of ATP that is used by cells through oxidative phosphorylation. They also produce reactive oxygen species, neurotransmitters and other signaling molecules. They are important for calcium homeostasis and apoptosis. Considering the role of this organelle, it is not surprising that most mitochondrial dysfunctions are linked to the development of pathologies. Various mechanisms adjust mitochondrial activity according to physiological needs. The cAMP-PKA signaling emerged in recent years as a direct and powerful mean to regulate mitochondrial functions. Multiple evidence demonstrates that such pathway can be triggered from cytosol or directly within mitochondria. Notably, specific anchor proteins target PKA to mitochondria whereas enzymes necessary for generation and degradation of cAMP are found directly in these organelles. Mitochondrial PKA targets proteins localized in different compartments of mitochondria, and related to various functions. Alterations of mitochondrial cAMP-PKA signaling affect the development of several physiopathological conditions, including neurodegenerative diseases. It is however difficult to discriminate between the effects of cAMP-PKA signaling triggered from cytosol or directly in mitochondria. The specific roles of PKA localized in different mitochondrial compartments are also not completely understood. The aim of this work is to review the role of cAMP-PKA signaling in mitochondrial (patho)physiology. PMID- 29694830 TI - Celastrol attenuates symptoms of preeclampsia in rats by inhibiting matrix metalloproteinase-9. AB - Preeclampsia is reported in pregnant women around the world and often causes maternal/fetal mortality and morbidity. In the current study, we assessed the efficacy of celastrol on a rat preeclampsia model induced by Nomega-nitro-L arginine methyl ester hydrochloride (L-NAME). Pregnant rats were administered L NAME to establish preeclampsia. A total of 48 animals were randomly assigned into 4 groups (n = 12 each): control, control plus celastrol treatment (control+celastrol), preeclampsia, and preeclampsia plus celastrol. Physiological parameters including total urine protein, urine volume and blood pressure were evaluated. Urinary messenger RNA (mRNA) levels of podocin and nephrin were determined using RT-PCR. Further, levels of serum placenta growth factor (PlGF), matrix metalloproteinase (MMP)-9 and renal renal soluble fms-like tyrosine kinase 1 (sFlt-1) were also measured. In rats with preeclampsia, there were robust increases in total urine protein, urine volume and blood pressure, which were significantly attenuated in rats treated with celastrol. Urinary mRNA levels of podocin and nephrin, as well as PlGF, MMP-9 and sFlt-1, were all reversed in preeclampsia plus celastrol group compared to rats in the preeclampsia group without celastrol treatments. MMP-9 overexpression in rats completely abolished the alleviating effect of celastrol. We hereby presented the first evidence that celastrol attenuated preeclampsia symptoms in an L-NAME-induced rat model of preeclampsia through inhibition of MMP-9 expression, supporting the potential therapeutic value of celastrol in the treatment of preeclampsia. PMID- 29694831 TI - Atorvastatin in nano-particulate formulation abates muscle and liver affliction when coalesced with coenzyme Q10 and/or vitamin E in hyperlipidemic rats. AB - AIMS: Statins are the most widely used to lower elevated low-density lipoprotein levels and preventing cardiovascular diseases in humans. However, about 20% of patients treated with this medication suffer from statin-related myalgia. To this end, this study investigated the potential effect of nano-particulate formulation in alleviating the muscles and liver damage either alone or when co-administered with nano coenzyme Q10 and nano vitamin E. MATERIALS AND METHODS: Male Wistar rats were fed normal diet or high-fat diet for 12 weeks, following which rats were treated with either (i) atorvastatin (5 or 20 mg/kg/day, p.o.) or (ii) atorvastatin with CoQ10 (10 mg/kg/day, p.o.) (iii) and/or vitamin E (30 mg/kg/day, p.o.) in free particle or nanoparticle forms for another 4 weeks. In all rats, serum total cholesterol (CH), triglycerides (TGs), low (LDL) and high (HDL) density lipoproteins, alanine (ALT) and aspartate (AST) transaminases, alkaline phosphatase (ALP), creatine kinase (CK), albumin (ALB), as well as hepatic malondialdehyde (MDA) and antioxidants "reduced glutathione (GSH) and superoxide dismutase (SOD)" were measured. Additionally quadriceps muscles and liver tissues were used for histopathological examination. KEY FINDINGS: The antihyperlipidemic effect of statins was not altered when formulated as nanoparticles; albeit the former showed a prominent reduction in the liver and muscle enzymes and histopathological alterations together with a marked decline in the oxidative stress as compared to the free particulate form. These results were augmented when atorvastatin was combined with CoQ10 and/or Vit.E. SIGNIFICANCE: Nanoparticulate formulation alleviated the statins induced liver and muscle damage especially when combined with CoQ10 and/or Vit.E. PMID- 29694832 TI - Cdc14 Phosphatase Promotes TORC1-Regulated Autophagy in Yeast. AB - Cdc14 protein phosphatase is critical for late mitosis progression in budding yeast, although its orthologs in other organisms, including mammalian cells, function as stress-responsive phosphatases. We found herein unexpected roles of Cdc14 in autophagy induction after nutrient starvation and target of rapamycin complex 1 (TORC1) kinase inactivation. TORC1 kinase phosphorylates Atg13 to repress autophagy under nutrient-rich conditions, but if TORC1 becomes inactive upon nutrient starvation or rapamycin treatment, Atg13 is rapidly dephosphorylated and autophagy is induced. Cdc14 phosphatase was required for optimal Atg13 dephosphorylation, pre-autophagosomal structure formation, and autophagy induction after TORC1 inactivation. In addition, Cdc14 was required for sufficient induction of ATG8 and ATG13 expression. Moreover, Cdc14 activation provoked autophagy even under normal conditions. This study identified a novel role of Cdc14 as the stress-responsive phosphatase for autophagy induction in budding yeast. PMID- 29694833 TI - Insights into the Role of the Peroxisomal Ubiquitination Machinery in Pex13p Degradation in the Yeast Hansenula polymorpha. AB - The import of matrix proteins into peroxisomes in yeast requires the action of the ubiquitin-conjugating enzyme Pex4p and a complex consisting of the ubiquitin E3 ligases Pex2p, Pex10p and Pex12p. Together, this peroxisomal ubiquitination machinery is thought to ubiquitinate the cycling receptor protein Pex5p and members of the Pex20p family of co-receptors, a modification that is required for receptor recycling. However, recent reports have demonstrated that this machinery plays a role in additional peroxisome-associated processes. Hence, our understanding of the function of these proteins in peroxisome biology is still incomplete. Here, we identify a role for the peroxisomal ubiquitination machinery in the degradation of the peroxisomal membrane protein Pex13p. Our data demonstrate that Pex13p levels build up in cells lacking members of this machinery and also establish that Pex13p undergoes rapid degradation in wild-type cells. Furthermore, we show that Pex13p is ubiquitinated in wild-type cells and also establish that Pex13p ubiquitination is reduced in cells lacking a functional peroxisomal E3 ligase complex. Finally, deletion of PEX2 causes Pex13p to build up at the peroxisomal membrane. Taken together, our data provide further evidence that the role of the peroxisomal ubiquitination machinery in peroxisome biology goes much deeper than receptor recycling alone. PMID- 29694835 TI - Antihypertensive drug-candesartan attenuates TRAIL resistance in human lung cancer via AMPK-mediated inhibition of autophagy flux. AB - Angiotensin II type 1 receptor blockers (ARBs) are widely used as antihypertensive drugs. Candesartan is an ARB that has also been known for its anticancer effects but the exact molecular mechanism is remaining elusive. In this research, we showed for the first time that candesartan treatment significantly sensitized human lung adenocarcinoma cells to Tumor necrosis factor related apoptosis-inducing ligand (TRAIL)-mediated apoptosis by targeting TRAIL DR5. TRAIL selectively kills cancer cells by binding to death receptors on the cell membrane, beyond the levels causing minimal toxicity in normal cells. However, some non-small-cell lung carcinoma (NSCLC) patients are resistant to TRAIL treatment in clinical trials due to inactivation of the death receptors during cytoprotective autophagy. The molecular mechanisms underlying candesartan induced TRAIL-mediated apoptosis involved the downstream of AMPK phosphorylation resulting inhibition of autophagy flux, recruitment of death receptor 5 (DR5) and activation of apoptotic caspase cascade. Candesartan treatment also inhibits the expression of anti-apoptotic protein c-FLIP. Furthermore, blocking DR5 signaling using DR5 siRNA negatively regulated the apoptotic pathway and also induced autophagy flux, demonstrating the cytoprotective role of autophagy responsible for treatment resistance. This suggests that candesartan can be used to sensitize tumors to TRAIL treatment and may represent a useful strategy for human adenocarcinoma patients to overcome TRAIL resistance. Candesartan in combination with TRAIL also could be a novel therapeutic treatment for patients presenting both conditions of hypertension and lung cancer. PMID- 29694834 TI - Utilization of 13C-labeled amino acids to probe the alpha-helical local secondary structure of a membrane peptide using electron spin echo envelope modulation (ESEEM) spectroscopy. AB - Electron spin echo envelope modulation (ESEEM) spectroscopy in combination with site-directed spin labeling (SDSL) has been established as a valuable biophysical technique to provide site-specific local secondary structure of membrane proteins. This pulsed electron paramagnetic resonance (EPR) method can successfully distinguish between alpha-helices, beta-sheets, and 310-helices by strategically using 2H-labeled amino acids and SDSL. In this study, we have explored the use of 13C-labeled residues as the NMR active nuclei for this approach for the first time. 13C-labeled d5-valine (Val) or 13C-labeled d6 leucine (Leu) were substituted at a specific Val or Leu residue (i), and a nitroxide spin label was positioned 2 or 3 residues away (denoted i-2 and i-3) on the acetylcholine receptor M2delta (AChR M2delta) in a lipid bilayer. The 13C ESEEM peaks in the FT frequency domain data were observed for the i-3 samples, and no 13C peaks were observed in the i-2 samples. The resulting spectra were indicative of the alpha-helical local secondary structure of AChR M2delta in bicelles. This study provides more versatility and alternative options when using this ESEEM approach to study the more challenging recombinant membrane protein secondary structures. PMID- 29694837 TI - Planarian flatworms as a new model system for understanding the epigenetic regulation of stem cell pluripotency and differentiation. AB - Planarian flatworms possess pluripotent stem cells (neoblasts) that are able to differentiate into all cell types that constitute the adult body plan. Consequently, planarians possess remarkable regenerative capabilities. Transcriptomic studies have revealed that gene expression is coordinated to maintain neoblast pluripotency, and ensure correct lineage specification during differentiation. But as yet they have not revealed how this regulation of expression is controlled. In this review, we propose that planarians represent a unique and effective system to study the epigenetic regulation of these processes in an in vivo context. We consolidate evidence suggesting that although DNA methylation is likely present in some flatworm lineages, it does not regulate neoblast function in Schmidtea mediterranea. A number of phenotypic studies have documented the role of histone modification and chromatin remodelling complexes in regulating distinct neoblast processes, and we focus on four important examples of planarian epigenetic regulators: Nucleosome Remodeling Deacetylase (NuRD) complex, Polycomb Repressive Complex (PRC), the SET1/MLL methyltransferases, and the nuclear PIWI/piRNA complex. Given the recent advent of ChIP-seq in planarians, we propose future avenues of research that will identify the genomic targets of these complexes allowing for a clearer picture of how neoblast processes are coordinated at the epigenetic level. These insights into neoblast biology may be directly relevant to mammalian stem cells and disease. The unique biology of planarians will also allow us to investigate how extracellular signals feed into epigenetic regulatory networks to govern concerted neoblast responses during regenerative polarity, tissue patterning, and remodelling. PMID- 29694836 TI - In vitro evaluation of structural analogs of diallyl sulfide as novel CYP2E1 inhibitors for their protective effect against xenobiotic-induced toxicity and HIV replication. AB - Diallyl sulfide (DAS) has been shown to prevent xenobiotic (e.g. ethanol, acetaminophen) induced toxicity and disease (e.g. HIV-1) pathogenesis. DAS imparts its beneficial effect by inhibiting CYP2E1-mediated metabolism of xenobiotics, especially at high concentration. However, DAS also causes toxicity at relatively high dosages and with long exposure times. Therefore, the goal of the current study was to investigate the structural analogs of DAS for their improved toxicity profiles and their effectiveness in reducing xenobiotic-induced toxicity and HIV-1 replication. Previously, we identified commercially available analogs that possessed CYP2E1 inhibitory capacity greater than or equal to that of DAS. In this study, we evaluated the toxicity and efficacy of these analogs using hepatocytes, monocytes, and astrocytes where CYP2E1 plays an important role in xenobiotic-mediated toxicity. Our results showed that thiophene, allyl methyl sulfide, diallyl ether, and 2-prop-2-enoxyacetamide are significantly less cytotoxic than DAS in these cells. Moreover, these analogs reduced ethanol- and acetaminophen-induced toxicity in hepatocytes and HIV-1 replication in monocytes more effectively than DAS. Overall, our findings are significant in terms of using these DAS analogs as a tool in vitro and in vivo, especially to examine chronic xenobiotic-induced toxicity and disease pathogenesis that occurs through the CYP2E1 pathway. PMID- 29694838 TI - Human antimicrobial peptides and cancer. AB - Antimicrobial peptides (AMPs) have long been a topic of interest for entomologists, biologists, immunologists and clinicians because of these agents' intriguing origins in insects, their ubiquitous expression in many life forms, their capacity to kill a wide range of bacteria, fungi and viruses, their role in innate immunity as microbicidal and immunoregulatory agents that orchestrate cross-talk with the adaptive immune system, and, most recently, their association with cancer. We and others have theorized that surveillance through epithelial cell-derived AMPs functions to keep the natural flora of microorganisms in a steady state in different niches such as the skin, the intestines, and the mouth. More recently, findings related to specific activation pathways of some of these AMPs have led investigators to associate them with pro-tumoral activity; i.e., contributing to a tumorigenic microenvironment. This area is still in its infancy as there are intriguing yet contradictory findings demonstrating that while some AMPs have anti-tumoral activity and are under-expressed in solid tumors, others are overexpressed and pro-tumorigenic. This review will introduce a new paradigm in cancer biology as it relates to AMP activity in neoplasia to address the following questions: Is there evidence that AMPs contribute to tumor promoting microenvironments? Can an anti-AMP strategy be of use in cancer therapy? Do AMPs, expressed in and released from tumors, contribute to compositional shifting of bacteria in cancerous lesions? Can specific AMP expression characteristics be used one day as early warning signs for solid tumors? PMID- 29694839 TI - Physicochemical properties of polysaccharides from Lentinus edodes under high pressure cooking treatment and its enhanced anticancer effects. AB - This study was to investigate the physicochemical properties and anticancer effects of polysaccharides from Lentinus edodes extracted under high pressure cooking treatment (HPLPS) in vitro and in vivo. The extraction efficiency was improved. The main molecular weight of HPLPS was about 540 and about 227 kDa. And the inhibitory effects on HepG2 and HeLa cells of HPLPS were significantly increased (p < 0.05). The in vivo anticancer effect on H22 tumor bearing mice model was evaluated. The tumor growth inhibitory rate of HPLPS-H was 67.66%. The activities of ALT and AST were decreased. The activities of SOD, CAT, GSH-Px were notably increased. The expressions of IL-2 and TNF-alpha were increased while the expression of VEGF was decreased. These results suggested that high pressure assisted extracted polysaccharides from Lentinus edodes might be effectively used for the treatment of hepatocellular carcinoma through its antioxidant and immunomodulatory effects. PMID- 29694841 TI - Effects of electrical stimulation of the rat vestibular labyrinth on c-Fos expression in the hippocampus. AB - Several studies have demonstrated that electrical activation of the peripheral vestibular system can evoke field potential, multi-unit neuronal activity and acetylcholine release in the hippocampus (HPC). However, no study to date has employed the immediate early gene protein, c-Fos, to investigate the distribution of activation of cells in the HPC following electrical stimulation of the vestibular system. We found that vestibular stimulation increased the number of animals expressing c-Fos in the dorsal HPC compared to sham control rats (P <= 0.02), but not in the ventral HPC. c-Fos was also expressed in an increased number of animals in the dorsal dentate gyrus (DG) compared to sham control rats (P <= 0.0001), and to a lesser extent in the ventral DG (P <= 0.006). The results of this study show that activation of the vestibular system results in a differential increase in the expression of c-Fos across different regions of the HPC. PMID- 29694840 TI - Synthesis and characterization of cross linked enzyme aggregates of serine hydroxyl methyltransferase from Idiomerina leihiensis. AB - A thermo-stable purified serine hydroxymethyltransferase (SHMT; 418 AA) was used for the carrier free immobilization using pectin as a coach molecule and formaldehyde as a cross-linker. The purified protein was cross linked with formaldehyde in the presence of pectin to form stable and active aggregates. The cross-linked enzyme aggregates [CLEAs] of SHMT showed improved catalytic properties and reusability. The SHMT-CLEAs showed a noteworthy change in the thermo-stability and activity compared to its free counterpart. The optimum activity for free SHMT was reported at 55 degrees C and pH 7.5 which SHMT CLEAs showed maximum activity at 60 degrees C and pH 8.0. Similarly, the CLEAs were noticed to increase the thermo-stability in comparison to free enzyme. The divalent salt ion Ca2+ and Ba2+ were found to enhance the activity at 1 and 5 mM of concentrations while Ni+, Co2+ and Zn2+ strongly inhibited the activity of both free as well as CLEAs. The Vmax and km values for free SHMT were recorded to be 1.21 MUM s-1 and 272 MUM while for CLEAs Vmax 1.42 MUM s-1 and km 248.6 MUM was recorded. Thus, a 120% increase in the Vmax was recorded for SHMT-CLEAs. The CLEAs were also found to be more stable at pH 6.5 and 8.5 pHs and retained 50% of its original activity for 180 and 200 min respectively. The CLEAs also retained 72% of its activity after 12 repetitive cycles of d-phenylserine hydrolysis. Also, the synthesized CLEAs retained more than 60% of its original activity after 10 days of incubation at 25 degrees C in comparison to free enzyme which loses more than 90% of its residual activity. Thus, with improved thermostability and activity the CLEAs of SHMT can be used repetitively at industrial scale for the synthesis of commercially important amino acids. PMID- 29694842 TI - Baseline striatal and nigral interneuronal protein levels in two distinct mice strains differ in accordance with their MPTP susceptibility. AB - Epidemiological studies reveal an ethnicity-based bias in prevalence of Parkinson's disease (PD), deriving from the differences that exist between Caucasians and African or Asian populations. Experimental mice models provide a scope to analyse the cellular mechanisms of differential susceptibility to PD. C57BL/6J mice, for instance, are more susceptible to MPTP-induced Parkinsonism whereas CD-1 mice are resistant. In PD-pathogenesis, interneuronal contribution is also likely, although they comprise only 5-10% of the striatal cells. The interneurons harbour calcium binding proteins, like calretinin (Cal-R) and parvalbumin (PV), which are crucial in Ca2+ homeostasis for preventing calcium induced excitotoxicity. GAD-67-immunoreactive interneurons are the other prominent set of GABAergic interneurons. In PD, dopamine loss up-regulates GAD-67 expression in striatal projection neurons and other basal ganglia circuit. We studied the possible contribution of interneurons in determining variable susceptibility by assessing the expression of calretinin, PV and GAD-67 in both striatum and substantia nigra pars compacta (SNpc) in two distinct mice strains, i.e. C57BL/6J and CD-1 under normal conditions, using unbiased stereology for quantification of immunoreactive cells and immunoblotting. The vulnerable C57BL/6J had lesser basal parvalbumin expression in both nigra and striatum whereas the calretinin levels were low only in the striatum. GAD-67 expression showed no perceptible differences in the striatum or SNpc of either of the strains. Differential expression of calcium buffering/binding proteins under normal physiological condition proffers a role for interneurons in the differential susceptibility to PD. Thus, even the baseline susceptibility indices i.e. without using the neurotoxin; can provide vital mechanistic insights into PD pathogenesis. PMID- 29694843 TI - Structural and lipid peroxidation effects of lead on rat hippocampus and its attenuation by hydrogen rich water. AB - Despite the well-known toxicity and the efforts to control its exposure, lead still has a serious health concern, particularly in young ages. Chelation therapy cannot correct the neurocognitive effects of chronic exposure. So, there is a requirement to test different protective agents for lead intoxication. Hydrogen rich water (HRW) has gained attraction recently as an antioxidant. Four groups of rats received sodium acetate, HRW, lead acetate (LA), or LA plus HRW for 8 weeks. Oxidative stress, histological and immunohistochemistry using p53 antibody were used to investigate the toxic effect of lead and the possible HRW protective effect in rat hippocampus. Results showed that HRW corrected the elevated malondialdehyde levels (MDA) and restore the lead-induced depletion of antioxidant enzymes; glutathione reductase (GR), catalase (CAT) and superoxide dismutase (SOD). HRW does not affect the diminished nitric oxide (NO) level in the LA-treated group. Moreover, HRW reversed the LA-induced histological and immunohistochemical changes. It significantly decreased the percentage of the apoptotic index. We concluded that HRW protects the neurons against lead-induced oxidative stress and has anti-apoptotic effects without a noticeable change in NO level which already was diminished by LA. PMID- 29694845 TI - Interoceptive inference: From computational neuroscience to clinic. AB - The central and autonomic nervous systems can be defined by their anatomical, functional and neurochemical characteristics, but neither functions in isolation. For example, fundamental components of autonomically mediated homeostatic processes are afferent interoceptive signals reporting the internal state of the body and efferent signals acting on interoceptive feedback assimilated by the brain. Recent predictive coding (interoceptive inference) models formulate interoception in terms of embodied predictive processes that support emotion and selfhood. We propose interoception may serve as a way to investigate holistic nervous system function and dysfunction in disorders of brain, body and behaviour. We appeal to predictive coding and (active) interoceptive inference, to describe the homeostatic functions of the central and autonomic nervous systems. We do so by (i) reviewing the active inference formulation of interoceptive and autonomic function, (ii) survey clinical applications of this formulation and (iii) describe how it offers an integrative approach to human physiology; particularly, interactions between the central and peripheral nervous systems in health and disease. PMID- 29694846 TI - Reproductive and developmental toxicity of potassium perfluorohexanesulfonate in CD-1 mice. AB - Potassium perfluorohexanesulfonate (K+PFHxS) was evaluated for reproductive/developmental toxicity in CD-1 mice. Up to 3 mg/kg-d K+PFHxS was administered (n = 30/sex/group) before mating, for at least 42 days in F0 males, and for F0 females, through gestation and lactation. F1 pups were directly dosed with K+PFHxS for 14 days after weaning. There was an equivocal decrease in live litter size at 1 and 3 mg/kg-d, but the pup-born-to-implant ratio was unaffected. Adaptive hepatocellular hypertrophy was observed, and in 3 mg/kg-d F0 males, it was accompanied by concomitant decreased serum cholesterol and increased alkaline phosphatase. There were no other toxicologically significant findings on reproductive parameters, hematology/clinical pathology/TSH, neurobehavioral effects, or histopathology. There were no treatment-related effects on postnatal survival, development, or onset of preputial separation or vaginal opening in F1 mice. Consistent with previous studies, our data suggest that the potency of PFHxS is much lower than PFOS in rodents. PMID- 29694847 TI - Cardio-protection of ultrafine granular powder for Salvia miltiorrhiza Bunge against myocardial infarction. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Myocardial infarction (MI) is considered as the major inducer to the morbidity and mortality related to coronary occlusion. Salvia miltiorrhiza Bunge is widely applied in the clinic for the prevention and treatment of heart diseases. The preparation of traditional herb decoction (THD) is not only time consuming but also difficult to keep uniform for every time. New usage form of Salvia miltiorrhiza Bunge with characteristics of convenience, uniform and efficiency is needed. AIM OF THE STUDY: The aims of present study were to investigate the cardio-protection of ultrafine granular powder (UGP) of Salvia miltiorrhiza Bunge; and further compare the characteristics of UGP with THD. MATERIALS AND METHODS: MI was induced by ligation of the left anterior descending coronary artery near the main pulmonary artery. Cardio-protection of UGP or THD was evaluated based on two sets of experiments, one was acute myocardial infarction (AMI) through 7 days preventive administration, and the other one was chronic cardiac remodeling through 28 days therapeutic administration. Hemodynamic measurement was conducted to evaluate heart function and histopathological detection was used to evaluate heart structure. RESULTS: No significant improvement of heart structure and function was detected for preventive administration of UGP or THD on AMI rats. While, more significant improvements on left ventricular systolic and diastolic function were detected with therapeutic treatment with 0.81 g/kg UGP than same dose of THD on rats against chronic cardiac remodeling. Both UGP and THD showed the protective effects on heart structure, especially against fibrosis with long-term therapeutic treatment. CONCLUSIONS: As a new usage form of Salvia miltiorrhiza Bunge, UGP showed significant cardio-protection against myocardial remodeling with therapeutic treatment. Comparing with THD, UGP also holds the advantages of uniform, convenience and efficiency. PMID- 29694848 TI - Customizable cap implants for neurophysiological experimentation. AB - BACKGROUND: Several primate neurophysiology laboratories have adopted acrylic free, custom-fit cranial implants. These implants are often comprised of titanium or plastic polymers, such as polyether ether ketone (PEEK). Titanium is favored for its mechanical strength and osseointegrative properties whereas PEEK is notable for its lightweight, machinability, and MRI compatibility. Recent titanium/PEEK implants have proven to be effective in minimizing infection and implant failure, thereby prolonging experiments and optimizing the scientific contribution of a single primate. NEW METHOD: We created novel, customizable PEEK 'cap' implants that contour to the primate's skull. The implants were created using MRI and/or CT data, SolidWorks software and CNC-machining. RESULTS: Three rhesus macaques were implanted with a PEEK cap implant. Head fixation and chronic recordings were successfully performed. Improvements in design and surgical technique solved issues of granulation tissue formation and headpost screw breakage. COMPARISON WITH EXISTING METHODS: Primate cranial implants have traditionally been fastened to the skull using acrylic and anchor screws. This technique is prone to skin recession, infection, and implant failure. More recent methods have used imaging data to create custom-fit titanium/PEEK implants with radially extending feet or vertical columns. Compared to our design, these implants are more surgically invasive over time, have less force distribution, and/or do not optimize the utilizable surface area of the skull. CONCLUSIONS: Our PEEK cap implants served as an effective and affordable means to perform electrophysiological experimentation while reducing surgical invasiveness, providing increased strength, and optimizing useful surface area. PMID- 29694849 TI - Regulation mechanisms and implications of sperm membrane hyperpolarization. AB - Mammalian sperm are unable to fertilize the egg immediately after ejaculation. In order to gain fertilization competence, they need to undergo a series of biochemical and physiological modifications inside the female reproductive tract, known as capacitation. Capacitation correlates with two essential events for fertilization: hyperactivation, an asymmetric and vigorous flagellar motility, and the ability to undergo the acrosome reaction. At a molecular level, capacitation is associated to: phosphorylation cascades, modification of membrane lipids, alkalinization of the intracellular pH, increase in the intracellular Ca2+ concentration and hyperpolarization of the sperm plasma membrane potential. Hyperpolarization is a crucial event in capacitation since it primes the sperm to undergo the exocytosis of the acrosome content, essential to achieve fertilization of the oocyte. PMID- 29694844 TI - In vivo methods for acute modulation of gene expression in the central nervous system. AB - Accurate and timely expression of specific genes guarantees the healthy development and function of the brain. Indeed, variations in the correct amount or timing of gene expression lead to improper development and/or pathological conditions. Almost forty years after the first successful gene transfection in in vitro cell cultures, it is currently possible to regulate gene expression in an area-specific manner at any step of central nervous system development and in adulthood in experimental animals in vivo, even overcoming the very poor accessibility of the brain. Here, we will review the diverse approaches for acute gene transfer in vivo, highlighting their advantages and disadvantages with respect to the efficiency and specificity of transfection as well as to brain accessibility. In particular, we will present well-established chemical, physical and virus-based approaches suitable for different animal models, pointing out their current and future possible applications in basic and translational research as well as in gene therapy. PMID- 29694850 TI - The telopode- and filopode-projecting heterogeneous stromal cells of the human sclera niche. AB - Telocytes (TCs) are stromal cells defined by the presence of long and slender prolongations (telopodes). They are a biologically and functionally heterogeneous population that has not been previously investigated in the sclera. The purpose of this study is to investigate the presence and characteristics of scleral telocytes through a combined immunohistochemical and transmission electron microscopy (TEM) study using samples from ten adult patients. Stromal cells with a TC-like morphology expressed CD34, CD45, CD105, vimentin and occasionally CD68 but were negative for collagen III, CD31, CD133, and CD146. Conjunctival epithelial cells expressed CD45, CD105, CD146, and vimentin. These phenotypes support a scleral niche with immune TCs and haematopoietic stem cells (HSCs). In TEM, we often found spindle-shaped stromal cells projecting telopodes or filopodes, with extremely long nuclei extended even within those prolongations. We separated these cells into a light subtype, which contained a complete set of organelles, and a dark subtype, consisting of undifferentiated stem/progenitor cells. The light cells contained dense vesicles, Weibel-Palade bodies, and rounded alpha-granule-like structures. These storage areas for the von Willebrand factor (vWF) are known to express selectins that are critically involved in HSC homing and could also indicate endothelial progenitors. The dark cells were scarcely myoid, populated the episcleral perivascular niches and the scleral stroma, and were equipped with lipid storage areas such as lamellar bodies and lipid droplets (LDs). Previously, unreported intranuclear LDs were found in these cells, which is characteristic of an HSC population. It appears that the human scleral stroma is a niche harbouring TC-like cells with immune and HSC phenotypes, and the mere presence or characteristics of telopodes are not enough to differentiate them. PMID- 29694851 TI - Optimal mean arterial pressure in comatose survivors of out-of-hospital cardiac arrest: An analysis of area below blood pressure thresholds. AB - AIM OF THE STUDY: To determine the optimal mean arterial pressure (MAP) during the early-to-intermediate phase care of comatose survivors of out-of-hospital cardiac arrest (OHCA). METHODS: We identified consecutive comatose survivors of OHCA with an initial shockable rhythm. Using blood pressure-over-time plots, we calculated the area below pre-specified MAP thresholds (ABT; mmHg*hours) during the first 96 h of admission. We used incremental MAP thresholds ranging between 65 and 85 mmHg. Logistic regression analyses were used to examine the association between ABT and clinical outcomes for each MAP threshold and to adjust for age, duration of cardiac arrest, and bystander CPR. The primary outcome was severe neurological dysfunction as defined by a cerebral performance category (CPC) >=3. RESULTS: We identified 122 consecutive OHCA patients meeting inclusion criteria. The rate of the primary outcome was 33%. There was a significant association between ABT and the rate of the primary outcome when MAP thresholds of 60 (p = 0.01), 65 (p < 0.01), 70 (p < 0.01), 75 (p < 0.01), and 80 mmHg (p < 0.01) were used. This association was lost once a MAP threshold of 85 mmHg was reached (p = 0.63). In the adjusted analysis, the association between ABT and the primary outcome was no longer present when the MAP threshold reached 75 mmHg. CONCLUSIONS: In comatose survivors of OHCA with an initial shockable rhythm, higher ABT is associated with increased rates of severe neurological dysfunction when MAP thresholds <75 mmHg are used. The current findings support the hypothesis that higher MAP targets (>=75 mmHg) may be indicated in this patient population. PMID- 29694852 TI - Back to basics: A methodological perspective on marble-burying behavior as a screening test for psychiatric illness. AB - Animal models of human psychiatric illness are valuable frameworks to investigate the etiology and neurobiology underlying the human conditions. Accurate behavioral measures that can be used to characterize animal behavior, thereby contributing to a model's validity, are crucial. One such measure, i.e. the rodent marble-burying test (MBT), is often applied as a measure of anxiety- and compulsive-like behaviors. However, the test is characterized by noteworthy between-laboratory methodological differences and demonstrates positive treatment responses to an array of pharmacotherapies that are often of little translational value. Therefore, using a naturalistic animal model of obsessive-compulsive disorder, i.e. the deer mouse (Peromyscus maniculatus bairdii), the current investigation attempted to illuminate the discrepancies reported in literature by means of a methodological approach to the MBT. Five key aspects of the test that vary between laboratories, viz. observer/scoring, burying substrate, optional avoidance, the use of repeated testing, and determinations of locomotor activity, have been investigated. Following repeated MB tests in four different burying substrates and in two zone configurations, we have demonstrated that 1) observer bias may contribute to the significant differences in findings reported, 2) MB seems to be a natural exploratory response to a novel environment, rather than being triggered by aberrant cognition, 3) burying substrates with a small particle size and higher density deliver the most accurate results with respect to the burying phenotype, and 4) to exclude the influence of normal exploratory behavior on the number of marbles being covered, assessments of marble-burying should be based on pre-occupation with the objects itself. PMID- 29694853 TI - NADPH oxidase, oxidative stress and fibrosis in systemic sclerosis. AB - Systemic sclerosis (SSc) is an autoimmune disease characterized by damage of small vessels, immune abnormalities and exaggerated production of extracellular matrix. The etiology of the disease is unknown and the pathogenesis ill defined. However, there is consistent evidence that oxidative stress contributes to the establishment and progression of the disease. This review examines the most relevant research regarding the involvement of free radicals and of nicotinamide adenine dinucleotide phosphate oxidases (NADPH oxidases; NOX) in the pathogenesis of systemic sclerosis. PMID- 29694855 TI - Structure of Transmembrane Helix 8 and Possible Membrane Defects in CFTR. AB - The cystic fibrosis transmembrane conductance regulator (CFTR) is an ion channel that regulates the flow of anions across epithelia. Mutations in CFTR cause cystic fibrosis. CFTR belongs to the ATP-binding cassette transporter superfamily, and gating is controlled by phosphorylation and ATP binding and hydrolysis. Recently obtained ATP-free and ATP-bound structures of zebrafish CFTR revealed an unwound segment of transmembrane helix (TM) 8, which appears to be a unique feature of CFTR not present in other ATP-binding cassette transporter structures. Here, using MUs-long molecular dynamics simulations, we investigate the interactions formed by this TM8 segment with nearby helices in both ATP-free and ATP-bound states. We highlight ATP-dependent interactions as well as the structural role of TM8 in maintaining the functional architecture of the pore via interactions common to both the ATP-bound and ATP-free state. The results of the molecular dynamics simulations are discussed in the context of the gating mechanism of CFTR. PMID- 29694854 TI - S-nitrosoglutathione reductase (GSNOR) inhibitor as an immune modulator in experimental autoimmune encephalomyelitis. AB - We previously reported that S-nitrosoglutathione (GSNO), an endogenous nitric oxide carrier, attenuated TH17-mediated immune responses in experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Cellular GSNO homeostasis is regulated via its synthesis by reaction between nitric oxide and glutathione and its enzymatic catabolism by GSNO reductase (GSNOR). In this study, we evaluated potential of reversible inhibitor of GSNOR (N6022) in comparison with exogenous GSNO in immunopathogenesis of EAE. Daily treatment of EAE mice with N6022 or exogenous GSNO significantly attenuated the clinical disease of EAE, but N6022 treatment showed greater efficacy than GSNO. Both N6022 and exogenous GSNO treatments increased the spleen levels of GSNO, as documented by increased protein-associated S-nitrosothiols, and inhibited polarization and CNS effector function of proinflammatory TH17 cells while inducing the polarization and CNS effector function of anti-inflammatory CD4+ CD25+ FOXP3- regulatory T (Treg) cells. Moreover, N6022 further attenuated TH1 while inducing TH2 and CD4+ CD25+ FOXP3+ Treg in their polarization and CNS effector functions. Similar to GSNO, the N6022 treatment protected against the EAE disease induced demyelination. However, neither exogenous GSNO nor N6022 treatment did not cause significant systemic lymphopenic effect as compared to FTY720. Taken together, these data document that optimization of cellular GSNO homeostasis by GSNOR inhibitor (N6022) in NO metabolizing cells attenuates EAE disease via selective inhibition of pro-inflammatory subsets of CD4+ cells (TH1/TH17) while upregulating anti-inflammatory subsets of CD4+ cells (TH2/Treg) without causing lymphopenic effects and thus offers a potential treatment option for MS/EAE. PMID- 29694856 TI - T7 RNA Polymerase Discriminates Correct and Incorrect Nucleoside Triphosphates by Free Energy. AB - RNA polymerase (RNAP) is the primary machine responsible for transcription. Its ability to distinguish between correct (cognate) and incorrect (noncognate) nucleoside triphosphates (NTPs) is important for fidelity control in transcription. In this work, we investigated the substrate selection mechanism of T7 RNAP from the perspective of energetics. The dissociation free energies were determined for matched and unmatched base pairs in the preinsertion complex using the umbrella sampling method. A clear hydrogen-bond-rupture peak is observed in the potential of mean force curve for a matched base pair, whereas no such peaks are present in the position of mean force profiles for unmatched ones. The free energy barrier could prevent correct substrates from being separated from the active site. Therefore, when NTPs diffuse into the active site, correct ones will stay for chemistry once they establish effective base pairing contacts with the template nucleotide, whereas incorrect ones will be withdrawn from the active site and rejected back to solution. This result provides an important energy evidence for the substrate selection mechanism of RNAP. Then we elucidated energetics and molecular details for correct NTP binding to the active site of the insertion complex. Our observations reveal that strong interactions act on the triphosphate of NTP to constrain its movement, whereas relatively weak interactions serve to position the base in the correct conformation. Triple interactions, hydrophobic contacts from residues M635 and Y639, base stacking from the 3' RNA terminal nucleotide, and base pairing from the template nucleotide act together to position the NTP base in a catalytically competent conformation. At last, we observed that incorrect NTPs cannot be as well stabilized as the correct one in the active site when they are misincorporated in the insertion site. It is expected that our work can be helpful for comprehensively understanding details of this basic step in genetic transcription. PMID- 29694857 TI - Synergistic SHAPE/Single-Molecule Deconvolution of RNA Conformation under Physiological Conditions. AB - Structural RNA domains are widely involved in the regulation of biological functions, such as gene expression, gene modification, and gene repair. Activity of these dynamic regions depends sensitively on the global fold of the RNA, in particular, on the binding affinity of individual conformations to effector molecules in solution. Consequently, both the 1) structure and 2) conformational dynamics of noncoding RNAs prove to be essential in understanding the coupling that results in biological function. Toward this end, we recently reported observation of three conformational states in the metal-induced folding pathway of the tRNA-like structure domain of Brome Mosaic Virus, via single-molecule fluorescence resonance energy transfer studies. We report herein selective 2' hydroxyl acylation analyzed by primer extension (SHAPE)-directed structure predictions as a function of metal ion concentrations ([Mn+]) to confirm the three-state folding model, as well as test 2 degrees structure models from the literature. Specifically, SHAPE reactivity data mapped onto literature models agrees well with the secondary structures observed at 0-10 mM [Mg2+], with only minor discrepancies in the E hairpin domain at low [Mg2+]. SHAPE probing and SHAPE-directed structure predictions further confirm the stepwise unfolding pathway previously observed in our single-molecule studies. Of special relevance, this means that reduction in the metal-ion concentration unfolds the 3' pseudoknot interaction before unfolding the long-range stem interaction. This work highlights the synergistic power of combining 1) single-molecule Forster resonance energy transfer and 2) SHAPE-directed structure-probing studies for detailed analysis of multiple RNA conformational states. In particular, single molecule guided deconvolution of the SHAPE reactivities permits 2 degrees structure predictions of isolated RNA conformations, thereby substantially improving on traditional limitations associated with current structure prediction algorithms. PMID- 29694858 TI - Competitive Binding of Mg2+ and Na+ Ions to Nucleic Acids: From Helices to Tertiary Structures. AB - Nucleic acids generally reside in cellular aqueous solutions with mixed divalent/monovalent ions, and the competitive binding of divalent and monovalent ions is critical to the structures of nucleic acids because of their polyanionic nature. In this work, we first proposed a general and effective method for simulating a nucleic acid in mixed divalent/monovalent ion solutions with desired bulk ion concentrations via molecular dynamics (MD) simulations and investigated the competitive binding of Mg2+/Na+ ions to various nucleic acids by all-atom MD simulations. The extensive MD-based examinations show that single MD simulations conducted using the proposed method can yield desired bulk divalent/monovalent ion concentrations for various nucleic acids, including RNA tertiary structures. Our comprehensive analyses show that the global binding of Mg2+/Na+ to a nucleic acid is mainly dependent on its structure compactness, as well as Mg2+/Na+ concentrations, rather than the specific structure of the nucleic acid. Specifically, the relative global binding of Mg2+ over Na+ is stronger for a nucleic acid with higher effective surface charge density and higher relative Mg2+/Na+ concentrations. Furthermore, the local binding of Mg2+/Na+ to a phosphate of a nucleic acid mainly depends on the local phosphate density in addition to Mg2+/Na+ concentrations. PMID- 29694859 TI - Effect of Methylation on Local Mechanics and Hydration Structure of DNA. AB - Cytosine methylation affects mechanical properties of DNA and potentially alters the hydration fingerprint for recognition by proteins. The atomistic origin for these effects is not well understood, and we address this via all-atom molecular dynamics simulations. We find that the stiffness of the methylated dinucleotide step changes marginally, whereas the neighboring steps become stiffer. Stiffening is further enhanced for consecutively methylated steps, providing a mechanistic origin for the effect of hypermethylation. Steric interactions between the added methyl groups and the nonpolar groups of the neighboring nucleotides are responsible for the stiffening in most cases. By constructing hydration maps, we found that methylation also alters the surface hydration structure in distinct ways. Its resistance to deformation may contribute to the stiffening of DNA for deformational modes lacking steric interactions. These results highlight the sequence- and deformational-mode-dependent effects of cytosine methylation. PMID- 29694860 TI - Unusual Isothermal Hysteresis in DNA i-Motif pH Transitions: A Study of the RAD17 Promoter Sequence. AB - We have interrogated the isothermal folding behavior of the DNA i-motif of the human telomere, dC19, and a high-stability i-motif-forming sequence in the promoter of the human DNA repair gene RAD17 using human physiological solution and temperature conditions. We developed a circular-dichroism-spectroscopy-based pH titration method that is followed by analysis of titration curves in the derivative domain and found that the observed pH-dependent folding behavior can be significantly different and, in some cases, multiphasic, with a dependence on how rapidly i-motif folding is induced. Interestingly, the human telomere sequence exhibits unusual isothermal hysteresis in which the unfolding process always occurs at a higher pH than the folding process. For the RAD17 i-motif, rapid folding by injection into a low-pH solution results in triphasic unfolding behavior that is completely diminished when samples are slowly folded in a stepwise manner via pH titration. Chemical footprinting of the RAD17 sequence and pH titrations of dT-substituted mutants of the RAD17 sequence were used to develop a model of RAD17 folding and unfolding. These results may provide valuable information pertinent to i-motif use in sensors and materials, as well as insight into the potential biological activity of i-motif-forming sequences under stepwise or instantaneous changes in pH. PMID- 29694861 TI - Coarse-Grain Modeling of Shear-Induced Binding between von Willebrand Factor and Collagen. AB - Von Willebrand factor (VWF) is a large multimeric protein that aids in blood clotting. Near injury sites, hydrodynamic force from increased blood flow elongates VWF, exposing binding sites for platelets and collagen. To investigate VWF binding to collagen that is exposed on injured arterial surfaces, Brownian dynamics simulations are performed with a coarse-grain molecular model. Accounting for hydrodynamic interactions in the presence of a stationary surface, shear flow conditions are modeled. Binding between beads in coarse-grain VWF and collagen sites on the surface is described via reversible ligand-receptor-type bond formation, which is governed via Bell model kinetics. For conditions in which binding is energetically favored, the model predicts a high probability for binding at low shear conditions; this is counter to experimental observations but in agreement with what prior modeling studies have revealed. To address this discrepancy, an additional binding criterion that depends on the conformation of a submonomer feature in the model local to a given VWF binding site is implemented. The modified model predicts shear-induced binding, in very good agreement with experimental observations; this is true even for conditions in which binding is significantly favored energetically. Biological implications of the model modification are discussed in terms of mechanisms of VWF activity. PMID- 29694863 TI - Insights into the Aggregation Mechanism of PolyQ Proteins with Different Glutamine Repeat Lengths. AB - Polyglutamine (polyQ) diseases, including Huntington's disease, result from the aggregation of an abnormally expanded polyQ repeat in the affected protein. The length of the polyQ repeat is essential for the disease's onset; however, the molecular mechanism of polyQ aggregation is still poorly understood. Controlled conditions and initiation of the aggregation process are prerequisites for the detection of transient intermediate states. We present an attenuated total reflection Fourier-transform infrared spectroscopic approach combined with protein immobilization to study polyQ aggregation dependent on the polyQ length. PolyQ proteins were engineered mimicking the mammalian N-terminus fragment of the Huntingtin protein and containing a polyQ sequence with the number of glutamines below (Q11), close to (Q38), and above (Q56) the disease threshold. A monolayer of the polyQ construct was chemically immobilized on the internal reflection element of the attenuated total reflection cell, and the aggregation was initiated via enzymatic cleavage. Structural changes of the polyQ sequence were monitored by time-resolved infrared difference spectroscopy. We observed faster aggregation kinetics for the longer sequences, and furthermore, we could distinguish beta-structured intermediates for the different constructs, allowing us to propose aggregation mechanisms dependent on the repeat length. Q11 forms a beta-structured aggregate by intermolecular interaction of stretched monomers, whereas Q38 and Q56 undergo conformational changes to various beta-structured intermediates, including intramolecular beta-sheets. PMID- 29694862 TI - Multivalent Binding of a Ligand-Coated Particle: Role of Shape, Size, and Ligand Heterogeneity. AB - We utilize a multiscale modeling framework to study the effect of shape, size, and ligand composition on the efficacy of binding of a ligand-coated particle to a substrate functionalized with the target receptors. First, we show how molecular dynamics along with steered molecular dynamics calculations can be used to accurately parameterize the molecular-binding free energy and the effective spring constant for a receptor-ligand pair. We demonstrate this for two ligands that bind to the alpha5beta1-domain of integrin. Next, we show how these effective potentials can be used to build computational models at the meso- and continuum-scales. These models incorporate the molecular nature of the receptor ligand interactions and yet provide an inexpensive route to study the multivalent interaction of receptors and ligands through the construction of Bell potentials customized to the molecular identities. We quantify the binding efficacy of the ligand-coated-particle in terms of its multivalency, binding free-energy landscape, and the losses in the configurational entropies. We show that 1) the binding avidity for particle sizes less than 350 nm is set by the competition between the enthalpic and entropic contributions, whereas that for sizes above 350 nm is dominated by the enthalpy of binding; 2) anisotropic particles display higher levels of multivalent binding compared to those of spherical particles; and 3) variations in ligand composition can alter binding avidity without altering the average multivalency. The methods and results presented here have wide applications in the rational design of functionalized carriers and also in understanding cell adhesion. PMID- 29694864 TI - Molecular Dynamics of the Association of L-Selectin and FERM Regulated by PIP2. AB - Phosphatidylinositol 4,5-bisphosphate (PIP2) acts as a signaling lipid, mediating membrane trafficking and recruitment of proteins to membranes. A key example is the PIP2-dependent regulation of the adhesion of L-selectin to the cytoskeleton adaptors of the N-terminal subdomain of ezrin-radixin-moesin (FERM). The molecular details of the mediating behavior of multivalent anionic PIP2 lipids in this process, however, remain unclear. Here, we use coarse-grained molecular dynamics simulation to explore the mechanistic details of PIP2 in the transformation, translocation, and association of the FERM/L-selectin complex. We compare membranes of different compositions and find that anionic phospholipids are necessary for both FERM and the cytoplasmic domain of L-selectin to absorb on the membrane surface. The subsequent formation of the FERM/L-selectin complex is strongly favored by the presence of PIP2, which clusters around both proteins and triggers a conformational transition in the cytoplasmic domain of L-selectin. We are able to quantify the effect of PIP2 on the association free energy of the complex by means of a potential of mean force. We conclude that PIP2 behaves as an adhesive agent to enhance the stability of the FERM/L-selectin complex and identify key residues involved. The molecular information revealed in this study highlights the specific role of membrane lipids such as PIP2 in protein translocation and potential signaling. PMID- 29694865 TI - Rotation-Activated and Cooperative Zipping Characterize Class I Viral Fusion Protein Dynamics. AB - Class I viral fusion proteins are alpha-helical proteins that facilitate membrane fusion between viral and host membranes through large conformational transitions. Although prefusion and postfusion crystal structures have been solved for many of these proteins, details about how they transition between these states have remained elusive. This work presents the first, to our knowledge, computational survey of transitions between pre- and postfusion configurations for several class I viral fusion proteins using structure-based models to analyze their dynamics. As suggested by their structural similarities, all proteins share common mechanistic features during their transitions that can be characterized by a diffusive rotational search followed by cooperative N- and C-terminal zipping. Instead of predicting a stable spring-loaded intermediate, our model suggests that helical bundle formation is mediated by N- and C-terminal interactions late in the transition. Shared transition features suggest a global mechanism in which fusion is activated by slow protein-core rotation. PMID- 29694866 TI - How Robust Is the Mechanism of Folding-Upon-Binding for an Intrinsically Disordered Protein? AB - The mechanism of interaction of an intrinsically disordered protein (IDP) with its physiological partner is characterized by a disorder-to-order transition in which a recognition and a binding step take place. Even if the mechanism is quite complex, IDPs tend to bind their partner in a cooperative manner such that it is generally possible to detect experimentally only the disordered unbound state and the structured complex. The interaction between the disordered C-terminal domain of the measles virus nucleoprotein (NTAIL) and the X domain (XD) of the viral phosphoprotein allows us to detect and quantify the two distinct steps of the overall reaction. Here, we analyze the robustness of the folding of NTAIL upon binding to XD by measuring the effect on both the folding and binding steps of NTAIL when the structure of XD is modified. Because it has been shown that wild type XD is structurally heterogeneous, populating an on-pathway intermediate under native conditions, we investigated the binding to 11 different site directed variants of NTAIL of one particular variant of XD (I504A XD) that populates only the native state. Data reveal that the recognition and the folding steps are both affected by the structure of XD, indicating a highly malleable pathway. The experimental results are briefly discussed in the light of previous experiments on other IDPs. PMID- 29694867 TI - Lipid Configurations from Molecular Dynamics Simulations. AB - The extent to which current force fields faithfully reproduce conformational properties of lipids in bilayer membranes, and whether these reflect the structural principles established for phospholipids in bilayer crystals, are central to biomembrane simulations. We determine the distribution of dihedral angles in palmitoyl-oleoyl phosphatidylcholine from molecular dynamics simulations of hydrated fluid bilayer membranes. We compare results from the widely used lipid force field of Berger et al. with those from the most recent C36 release of the CHARMM force field for lipids. Only the CHARMM force field produces the chain inequivalence with sn-1 as leading chain that is characteristic of glycerolipid packing in fluid bilayers. The exposure and high partial charge of the backbone carbonyls in Berger lipids leads to artifactual binding of Na+ ions reported in the literature. Both force fields predict coupled, near-symmetrical distributions of headgroup dihedral angles, which is compatible with models of interconverting mirror-image conformations used originally to interpret NMR order parameters. The Berger force field produces rotamer populations that correspond to the headgroup conformation found in a phosphatidylcholine lipid bilayer crystal, whereas CHARMM36 rotamer populations are closer to the more relaxed crystal conformations of phosphatidylethanolamine and glycerophosphocholine. CHARMM36 alone predicts the correct relative signs of the time-average headgroup order parameters, and reasonably reproduces the full range of NMR data from the phosphate diester to the choline methyls. There is strong motivation to seek further experimental criteria for verifying predicted conformational distributions in the choline headgroup, including the 31P chemical shift anisotropy and 14N and CD3 NMR quadrupole splittings. PMID- 29694868 TI - Vesicle Adhesion and Fusion Studied by Small-Angle X-Ray Scattering. AB - We have studied the adhesion state (also denoted by docking state) of lipid vesicles as induced by the divalent ions Ca2+ or Mg2+ at well-controlled ion concentration, lipid composition, and charge density. The bilayer structure and the interbilayer distance in the docking state were analyzed by small-angle x-ray scattering. A strong adhesion state was observed for DOPC:DOPS vesicles, indicating like-charge attraction resulting from ion correlations. The observed interbilayer separations of ~1.6 nm agree quantitatively with the predictions of electrostatics in the strong coupling regime. Although this phenomenon was observed when mixing anionic and zwitterionic (or neutral) lipids, pure anionic membranes (DOPS) with highest charge density sigma resulted in a direct phase transition to a multilamellar state, which must be accompanied by rupture and fusion of vesicles. To extend the structural assay toward protein-controlled docking and fusion, we have characterized reconstituted N-ethylmaleimide sensitive factor attachment protein receptors in controlled proteoliposome suspensions by small-angle x-ray scattering. PMID- 29694869 TI - FRET Detects the Size of Nanodomains for Coexisting Liquid-Disordered and Liquid Ordered Phases. AB - Biomembranes with as few as three lipid components can form coexisting liquid disordered (Ld) and liquid-ordered (Lo) phases. In the coexistence region of Ld and Lo phases, the lipid mixtures 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC)/1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC)/chol or brain sphingomyelin (bSM)/DOPC/chol form micron-scale domains that are easily visualized with light microscopy. Although large domains are not observed in the mixtures DSPC/1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine (POPC)/chol and bSM/POPC/chol, lateral heterogeneity is nevertheless detected using techniques with nanometer-scale spatial resolution. We propose a simple and accessible method to measure domain sizes below optical resolution (~200 nm). We measured nanodomain size for the latter two mixtures by combining experimental Forster resonance energy transfer data with a Monte-Carlo-based analysis. We found a domain radius of 7.5-10 nm for DSPC/POPC/chol, similar to values obtained previously by neutron scattering, and ~5 nm for bSM/POPC/chol, slightly smaller than measurable by neutron scattering. These analyses also detect the domain-size transition that is observed by fluorescence microscopy in the four-component lipid mixture bSM/DOPC/POPC/chol. Accurate measurements of fluorescent-probe partition coefficients are especially important for the analysis; therefore, we exploit three different methods to measure the partition coefficient of fluorescent molecules between Ld and Lo phases. PMID- 29694870 TI - Protein Partitioning into Ordered Membrane Domains: Insights from Simulations. AB - Cellular membranes are laterally organized into domains of distinct structures and compositions by the differential interaction affinities between various membrane lipids and proteins. A prominent example of such structures are lipid rafts, which are ordered, tightly packed domains that have been widely implicated in cellular processes. The functionality of raft domains is driven by their selective recruitment of specific membrane proteins to regulate their interactions and functions; however, there have been few general insights into the factors that determine the partitioning of membrane proteins between coexisting liquid domains. In this work, we used extensive coarse-grained and atomistic molecular dynamics simulations, potential of mean force calculations, and conceptual models to describe the partitioning dynamics and energetics of a model transmembrane domain from the linker of activation of T cells. We find that partitioning between domains is determined by an interplay between protein-lipid interactions and differential lipid packing between raft and nonraft domains. Specifically, we show that partitioning into ordered domains is promoted by preferential interactions between peptides and ordered lipids, mediated in large part by modification of the peptides by saturated fatty acids (i.e., palmitoylation). Ordered phase affinity is also promoted by elastic effects, specifically hydrophobic matching between the membrane and the peptide. Conversely, ordered domain partitioning is disfavored by the tight molecular packing of the lipids therein. The balance of these dominant drivers determines partitioning. In the case of the wild-type linker of activation of T cells transmembrane domain, these factors combine to yield enrichment of the peptide at Lo/Ld interfaces. These results define some of the general principles governing protein partitioning between coexisting membrane domains and potentially explain previous disparities among experiments and simulations across model systems. PMID- 29694871 TI - Synergism of Antimicrobial Frog Peptides Couples to Membrane Intrinsic Curvature Strain. AB - Mixtures of the frog peptides magainin 2 and PGLa are well-known for their pronounced synergistic killing of Gram-negative bacteria. We aimed to gain insight into the underlying biophysical mechanism by interrogating the permeabilizing efficacies of the peptides as a function of stored membrane curvature strain. For Gram-negative bacterial-inner-membrane mimics, synergism was only observed when the anionic bilayers exhibited significant negative intrinsic curvatures imposed by monounsaturated phosphatidylethanolamine. In contrast, the peptides and their mixtures did not exhibit significant activities in charge-neutral mammalian mimics, including those with negative curvature, which is consistent with the requirement of charge-mediated peptide binding to the membrane. Our experimental findings are supported by computer simulations showing a significant decrease of the peptide-insertion free energy in membranes upon shifting intrinsic curvatures toward more positive values. The physiological relevance of our model studies is corroborated by a remarkable agreement with the peptide's synergistic activity in Escherichia coli. We propose that synergism is related to a lowering of a membrane-curvature-strain-mediated free-energy barrier by PGLa that assists membrane insertion of magainin 2, and not by strict pairwise interactions of the two peptides as suggested previously. PMID- 29694872 TI - Dynamics of a Protein Chain Motor Driving Helical Bacteria under Stress. AB - The wall-less, helical bacterial genus Spiroplasma has a unique propulsion system; it is not driven by propeller-like flagella but by a membrane-bound, cytoplasmic, linear motor that consists of a contractile chain of identical proteins spanning the entire cell length. By a coordinated spread of conformational changes of the proteins, kinks propagate in pairs along the cell body. However, the mechanisms for the initiation or delay of kinks and their coordinated spread remain unclear. Here, we show how we manipulate the initiation of kinks, their propagation velocities, and the time between two kinks for a single cell trapped in an optical line potential. By interferometric three dimensional shape tracking, we measured the cells' deformations in response to various external stress situations. We observed a significant dependency of force generation on the cells' local ligand concentrations (likely ATP) and ligand hydrolysis, which we altered in different ways. We developed a mechanistic, mathematical model based on Kramer's rates, describing the subsequent cooperative and conformational switching of the chain's proteins. The model reproduces our experimental observations and can explain deformation characteristics even when the motor is driven to its extreme. Nature has invented a set of minimalistic mechanical driving concepts. To understand or even rebuild them, it is essential to reveal the molecular mechanisms of such protein chain motors, which need only two components-coupled proteins and ligands-to function. PMID- 29694873 TI - Quantifying the Precision of Single-Molecule Torque and Twist Measurements Using Allan Variance. AB - Single-molecule manipulation techniques have provided unprecedented insights into the structure, function, interactions, and mechanical properties of biological macromolecules. Recently, the single-molecule toolbox has been expanded by techniques that enable measurements of rotation and torque, such as the optical torque wrench (OTW) and several different implementations of magnetic (torque) tweezers. Although systematic analyses of the position and force precision of single-molecule techniques have attracted considerable attention, their angle and torque precision have been treated in much less detail. Here, we propose Allan deviation as a tool to systematically quantitate angle and torque precision in single-molecule measurements. We apply the Allan variance method to experimental data from our implementations of (electro)magnetic torque tweezers and an OTW and find that both approaches can achieve a torque precision better than 1 pN . nm. The OTW, capable of measuring torque on (sub)millisecond timescales, provides the best torque precision for measurement times ?10 s, after which drift becomes a limiting factor. For longer measurement times, magnetic torque tweezers with their superior stability provide the best torque precision. Use of the Allan deviation enables critical assessments of the torque precision as a function of measurement time across different measurement modalities and provides a tool to optimize measurement protocols for a given instrument and application. PMID- 29694874 TI - Extended-Depth 3D Super-Resolution Imaging Using Probe-Refresh STORM. AB - Single-molecule localization microscopy methods for super-resolution fluorescence microscopy such as STORM (stochastic optical reconstruction microscopy) are generally limited to thin three-dimensional (3D) sections (<=600 nm) because of photobleaching of molecules outside the focal plane. Although multiple focal planes may be imaged before photobleaching by focusing progressively deeper within the sample, image quality is compromised in this approach because the total number of measurable localizations is divided between detection planes. Here, we solve this problem on fixed samples by developing an imaging method that we call probe-refresh STORM (prSTORM), which allows bleached fluorophores to be straightforwardly replaced with nonbleached fluorophores. We accomplish this by immunostaining the sample with DNA-conjugated antibodies and then reading out their distribution using fluorescently-labeled DNA-reporter oligonucleotides that can be fully replaced in successive rounds of imaging. We demonstrate that prSTORM can acquire 3D images over extended depths without sacrificing the density of localizations at any given plane. We also show that prSTORM can be adapted to obtain high-quality, 3D multichannel images with extended depth that would be challenging or impossible to achieve using established probe methods. PMID- 29694875 TI - Influence of Micropatterning on Human Periodontal Ligament Cells' Behavior. AB - The periodontal ligament (PDL) is highly ordered connective tissue located between the alveolar bone and cementum. An aligned and organized architecture is required for its physiological function. We applied micropatterning technology to arrange PDL cells in 10- or 20-MUm-wide extracellular protein patterns. Cell and nuclear morphology, cytoskeleton, proliferation, differentiation, and matrix metalloproteinase system expression were investigated. Micropatterning clearly elongated PDL cells with a low cell-shape index and low spreading area. The nucleus was also elongated as nuclear height increased, but the nuclear volume remained intact. The cytoskeleton was rearranged to form prominent bundles at cells' peripheral regions. Moreover, proliferation was promoted by 10- and 20-MUm micropatterning. Osteogenesis and adipogenesis were each inhibited, but micropatterning increased PDL cells' stem cell markers. beta-catenin was expelled to cytoplasm. YAP/TAZ nuclear localization and activity both decreased, which might indicate their role in micropatterning-regulated differentiation. Collagen Iota expression increased in micropatterned groups. It might be due to the decreased expression of matrix metalloproteinase-1, 2 and the tissue inhibitor of metalloproteinase-1 gene expression elevation in micropatterned groups. The findings of this study provide insight into the effects of a micropatterned surface on PDL cell behavior and may be applicable in periodontal tissue regeneration. PMID- 29694876 TI - Magnetic Field Changes Macrophage Phenotype. AB - Macrophages play a crucial role in homeostasis, regeneration, and innate and adaptive immune responses. Functionally different macrophages have different shapes and molecular phenotypes that depend on the actin cytoskeleton, which is regulated by the small GTPase RhoA. The naive M0 macrophages are slightly elongated, proinflammatory M1 are round, and M2 antiinflammatory macrophages are elongated. We have recently shown in the rodent model system that genetic or pharmacologic interference with the RhoA pathway deregulates the macrophage actin cytoskeleton, causes extreme macrophage elongation, and prevents macrophage migration. Here, we report that an exposure of macrophages to a nonuniform magnetic field causes extreme elongation of macrophages and has a profound effect on their molecular components and organelles. Using immunostaining and Western blotting, we observed that magnetic force rearranges the macrophage actin cytoskeleton, the Golgi complex, and the cation channel receptor TRPM2, and modifies the expression of macrophage molecular markers. We have found that the magnetic-field-induced alterations are very similar to changes caused by RhoA interference. We also analyzed magnetic-field-induced forces acting on macrophages and found that the location and alignment of magnetic-field-elongated macrophages correlate very well with the simulated distribution and orientation of such magnetic force lines. PMID- 29694878 TI - Calsequestrin-Mediated Mechanism for Cellular Calcium Transient Alternans. PMID- 29694877 TI - Cytoskeleton Remodeling Induces Membrane Stiffness and Stability Changes of Maturing Reticulocytes. AB - Reticulocytes, the precursors of erythrocytes, undergo drastic alterations in cell size, shape, and deformability during maturation. Experimental evidence suggests that young reticulocytes are stiffer and less stable than their mature counterparts; however, the underlying mechanism is yet to be fully understood. Here, we develop a coarse-grained molecular-dynamics reticulocyte membrane model to elucidate how the membrane structure of reticulocytes contributes to their particular biomechanical properties and pathogenesis in blood diseases. First, we show that the extended cytoskeleton in the reticulocyte membrane is responsible for its increased shear modulus. Subsequently, we quantify the effect of weakened cytoskeleton on the stiffness and stability of reticulocytes, via which we demonstrate that the extended cytoskeleton along with reduced cytoskeleton connectivity leads to the seeming paradox that reticulocytes are stiffer and less stable than the mature erythrocytes. Our simulation results also suggest that membrane budding and the consequent vesiculation of reticulocytes can occur independently of the endocytosis-exocytosis pathway, and thus, it may serve as an additional means of removing unwanted membrane proteins from reticulocytes. Finally, we find that membrane budding is exacerbated when the cohesion between the lipid bilayer and the cytoskeleton is compromised, which is in accord with the clinical observations that erythrocytes start shedding membrane surface at the reticulocyte stage in hereditary spherocytosis. Taken together, our results quantify the stiffness and stability change of reticulocytes during their maturation and provide, to our knowledge, new insights into the pathogenesis of hereditary spherocytosis and malaria. PMID- 29694879 TI - Positive Feedback Mechanisms among Local Ca Releases, NCX, and ICaL Ignite Pacemaker Action Potentials. PMID- 29694880 TI - Modeling the Dynamics of Cdc42 Oscillation in Fission Yeast. PMID- 29694883 TI - Adrenergic Modulation Regulates the Dendritic Excitability of Layer 5 Pyramidal Neurons In Vivo. AB - The excitability of the apical tuft of layer 5 pyramidal neurons is thought to play a crucial role in behavioral performance and synaptic plasticity. We show that the excitability of the apical tuft is sensitive to adrenergic neuromodulation. Using two-photon dendritic Ca2+ imaging and in vivo whole-cell and extracellular recordings in awake mice, we show that application of the alpha2A-adrenoceptor agonist guanfacine increases the probability of dendritic Ca2+ events in the tuft and lowers the threshold for dendritic Ca2+ spikes. We further show that these effects are likely to be mediated by the dendritic current Ih. Modulation of Ih in a realistic compartmental model controlled both the generation and magnitude of dendritic calcium spikes in the apical tuft. These findings suggest that adrenergic neuromodulation may affect cognitive processes such as sensory integration, attention, and working memory by regulating the sensitivity of layer 5 pyramidal neurons to top-down inputs. PMID- 29694881 TI - MIRO-1 Determines Mitochondrial Shape Transition upon GPCR Activation and Ca2+ Stress. AB - Mitochondria shape cytosolic calcium ([Ca2+]c) transients and utilize the mitochondrial Ca2+ ([Ca2+]m) in exchange for bioenergetics output. Conversely, dysregulated [Ca2+]c causes [Ca2+]m overload and induces permeability transition pore and cell death. Ablation of MCU-mediated Ca2+ uptake exhibited elevated [Ca2+]c and failed to prevent stress-induced cell death. The mechanisms for these effects remain elusive. Here, we report that mitochondria undergo a cytosolic Ca2+-induced shape change that is distinct from mitochondrial fission and swelling. [Ca2+]c elevation, but not MCU-mediated Ca2+ uptake, appears to be essential for the process we term mitochondrial shape transition (MiST). MiST is mediated by the mitochondrial protein Miro1 through its EF-hand domain 1 in multiple cell types. Moreover, Ca2+-dependent disruption of Miro1/KIF5B/tubulin complex is determined by Miro1 EF1 domain. Functionally, Miro1-dependent MiST is essential for autophagy/mitophagy that is attenuated in Miro1 EF1 mutants. Thus, Miro1 is a cytosolic Ca2+ sensor that decodes metazoan Ca2+ signals as MiST. PMID- 29694882 TI - Cardiac mTORC1 Dysregulation Impacts Stress Adaptation and Survival in Huntington's Disease. AB - Huntington's disease (HD) is a dominantly inherited neurological disorder caused by CAG-repeat expansion in exon 1 of Huntingtin (HTT). But in addition to the neurological disease, mutant HTT (mHTT), which is ubiquitously expressed, impairs other organ systems. Indeed, epidemiological and animal model studies suggest higher incidence of and mortality from heart disease in HD. Here, we show that the protein complex mTORC1 is dysregulated in two HD mouse models through a mechanism that requires intrinsic mHTT expression. Moreover, restoring cardiac mTORC1 activity with constitutively active Rheb prevents mortality and relieves the mHTT-induced block to hypertrophic adaptation to cardiac stress. Finally, we show that chronic mTORC1 dysregulation is due in part to mislocalization of endogenous Rheb. These data provide insight into the increased cardiac-related mortality of HD patients, with cardiac mHTT expression inhibiting mTORC1 activity, limiting heart growth, and decreasing the heart's ability to compensate to chronic stress. PMID- 29694884 TI - Topographic Reorganization of Cerebrovascular Mural Cells under Seizure Conditions. AB - Reorganization of the neurovascular unit has been suggested in the epileptic brain, although the dynamics and functional significance remain unclear. Here, we tracked the in vivo dynamics of perivascular mural cells as a function of electroencephalogram (EEG) activity following status epilepticus. We segmented the cortical vascular bed to provide a size- and type-specific analysis of mural cell plasticity topologically. We find that mural cells are added and removed from veins, arterioles, and capillaries after seizure induction. Loss of mural cells is proportional to seizure severity and vascular pathology (e.g., rigidity, perfusion, and permeability). Treatment with platelet-derived growth factor subunits BB (PDGF-BB) reduced mural cell loss, vascular pathology, and epileptiform EEG activity. We propose that perivascular mural cells play a pivotal role in seizures and are potential targets for reducing pathophysiology. PMID- 29694885 TI - Wnt Signaling Mediates LTP-Dependent Spine Plasticity and AMPAR Localization through Frizzled-7 Receptors. AB - The structural and functional plasticity of synapses is critical for learning and memory. Long-term potentiation (LTP) induction promotes spine growth and AMPAR accumulation at excitatory synapses, leading to increased synaptic strength. Glutamate initiates these processes, but the contribution from extracellular modulators is not fully established. Wnts are required for spine formation; however, their impact on activity-mediated spine plasticity and AMPAR localization is unknown. We found that LTP induction rapidly increased synaptic Wnt7a/b protein levels. Acute blockade of endogenous Wnts or loss of postsynaptic Frizzled-7 (Fz7) receptors impaired LTP-mediated synaptic strength, spine growth, and AMPAR localization at synapses. Live imaging of SEP-GluA1 and single-particle tracking revealed that Wnt7a rapidly promoted synaptic AMPAR recruitment and trapping. Wnt7a, through Fz7, induced CaMKII-dependent loss of SynGAP from spines and increased extrasynaptic AMPARs by PKA phosphorylation. We identify a critical role for Wnt-Fz7 signaling in LTP-mediated synaptic accumulation of AMPARs and spine plasticity. PMID- 29694887 TI - The NLRP3 Inflammasome Suppresses Protective Immunity to Gastrointestinal Helminth Infection. AB - Inflammasomes promote immunity to microbial pathogens by regulating the function of IL-1-family cytokines such as IL-18 and IL-1beta. However, the roles for inflammasomes during parasitic helminth infections remain unclear. We demonstrate that mice and humans infected with gastrointestinal nematodes display increased IL-18 secretion, which in Trichuris-infected or worm antigen-treated mice and in macrophages co-cultured with Trichuris antigens or exosome-like vesicles was dependent on the NLRP3 inflammasome. NLRP3-deficient mice displayed reduced pro inflammatory type 1 cytokine responses and augmented protective type 2 immunity, which was reversed by IL-18 administration. NLRP3-dependent suppression of immunity partially required CD4+ cells but was apparent even in Rag1-/- mice that lack adaptive immune cells, suggesting that NLRP3 influences both innate and adaptive immunity. These data highlight a role for NLRP3 in limiting protective immunity to helminths, suggesting that targeting the NLRP3 inflammasome may be an approach for limiting the disease burden associated with helminth infections. PMID- 29694888 TI - Gut Microbiota-Derived Tryptophan Metabolites Modulate Inflammatory Response in Hepatocytes and Macrophages. AB - The gut microbiota plays a significant role in the progression of fatty liver disease; however, the mediators and their mechanisms remain to be elucidated. Comparing metabolite profile differences between germ-free and conventionally raised mice against differences between mice fed a low- and high-fat diet (HFD), we identified tryptamine and indole-3-acetate (I3A) as metabolites that depend on the microbiota and are depleted under a HFD. Both metabolites reduced fatty-acid- and LPS-stimulated production of pro-inflammatory cytokines in macrophages and inhibited the migration of cells toward a chemokine, with I3A exhibiting greater potency. In hepatocytes, I3A attenuated inflammatory responses under lipid loading and reduced the expression of fatty acid synthase and sterol regulatory element-binding protein-1c. These effects were abrogated in the presence of an aryl-hydrocarbon receptor (AhR) antagonist, indicating that the effects are AhR dependent. Our results suggest that gut microbiota could influence inflammatory responses in the liver through metabolites engaging host receptors. PMID- 29694886 TI - Multiplexed Quantitation of Intraphagocyte Mycobacterium tuberculosis Secreted Protein Effectors. AB - The pathogenic potential of Mycobacterium tuberculosis largely depends on ESX secretion systems exporting members of the multigenic Esx, Esp, and PE/PPE protein families. To study the secretion and regulation patterns of these proteins while circumventing immune cross-reactions due to their extensive sequence homologies, we developed an approach that relies on the recognition of their MHC class II epitopes by highly discriminative T cell receptors (TCRs) of a panel of T cell hybridomas. The latter were engineered so that each expresses a unique fluorescent reporter linked to specific antigen recognition. The resulting polychromatic and multiplexed imaging assay enabled us to measure the secretion of mycobacterial effectors inside infected host cells. We applied this novel technology to a large panel of mutants, clinical isolates, and host-cell types to explore the host-mycobacteria interplay and its impact on the intracellular bacterial secretome, which also revealed the unexpected capacity of phagocytes from lung granuloma to present mycobacterial antigens via MHC class II. PMID- 29694889 TI - Pro-inflammation Associated with a Gain-of-Function Mutation (R284S) in the Innate Immune Sensor STING. AB - The cellular sensor stimulator of interferon genes (STING) initiates type I interferon (IFN) and cytokine production following association with cyclic dinucleotides (CDNs) generated from intracellular bacteria or via a cellular synthase, cGAS, after binding microbial or self-DNA. Although essential for protecting the host against infection, unscheduled STING signaling is now known to be responsible for a variety of autoinflammatory disorders. Here, we report a gain-of-function mutation in STING (R284S), isolated from a patient who did not require CDNs to augment activity and who manifested a constitutively active phenotype. Control of the Unc-51-like autophagy activating kinase 1 (ULK1) pathway, which has previously been shown to influence STING function, was potently able to suppress STING (R284S) activity to alleviate cytokine production. Our findings add to the growing list of inflammatory syndromes associated with spontaneous STING signaling and provide a therapeutic strategy for the treatment of STING-induced inflammatory disease. PMID- 29694890 TI - Infection Reveals a Modification of SIRT2 Critical for Chromatin Association. AB - Sirtuin 2 is a nicotinamide-adenine-dinucleotide-dependent deacetylase that regulates cell processes such as carcinogenesis, cell cycle, DNA damage, and infection. Subcellular localization of SIRT2 is crucial for its function but is poorly understood. Infection with the bacterial pathogen Listeria monocytogenes, which relocalizes SIRT2 from the cytoplasm to the chromatin, provides an ideal stimulus for the molecular study of this process. In this report, we provide a map of SIRT2 post-translational modification sites and focus on serine 25 phosphorylation. We show that infection specifically induces dephosphorylation of S25, an event essential for SIRT2 chromatin association. Furthermore, we identify a nuclear complex formed by the phosphatases PPM1A and PPM1B, with SIRT2 essential for controlling H3K18 deacetylation and SIRT2-mediated gene repression during infection and necessary for a productive Listeria infection. This study reveals a molecular mechanism regulating SIRT2 function and localization, paving the way for understanding other SIRT2-regulated cellular processes. PMID- 29694891 TI - Selective Antagonists of the Bronchiolar Epithelial NF-kappaB-Bromodomain Containing Protein 4 Pathway in Viral-Induced Airway Inflammation. AB - The mechanisms by which the mammalian airway detects invading viral pathogens to trigger protective innate neutrophilic inflammation are incompletely understood. We observe that innate activation of nuclear factor kappaB (NF-kappaB)/RelA transcription factor indirectly activates atypical BRD4 histone acetyltransferase (HAT) activity, RNA polymerase II (Pol II) phosphorylation, and secretion of neutrophilic chemokines. To study this pathway in vivo, we developed a conditional knockout of RelA in distal airway epithelial cells; these animals have reduced mucosal BRD4/Pol II activation and neutrophilic inflammation to viral patterns. To further understand the role of BRD4 in vivo, two potent, highly selective small-molecule BRD4 inhibitors were developed. These well tolerated inhibitors disrupt the BRD4 complex with Pol II and histones, completely blocking inducible epithelial chemokine production and neutrophilia. We conclude that RelA-BRD4 signaling in distal tracheobronchiolar epithelial cells mediates acute inflammation in response to luminal viral patterns. These potent BRD4 antagonists are versatile pharmacological tools for investigating BRD4 functions in vivo. PMID- 29694892 TI - Cell Autonomous and Non-cell Autonomous Regulation of SMC Progenitors in Pulmonary Hypertension. AB - Pulmonary hypertension is a devastating disease characterized by excessive vascular muscularization. We previously demonstrated primed platelet-derived growth factor receptor beta+ (PDGFR-beta+)/smooth muscle cell (SMC) marker+ progenitors at the muscular-unmuscular arteriole border in the normal lung, and in hypoxia-induced pulmonary hypertension, a single primed cell migrates distally and expands clonally, giving rise to most of the pathological smooth muscle coating of small arterioles. Little is known regarding the molecular mechanisms underlying this process. Herein, we show that primed cell expression of Kruppel like factor 4 and hypoxia-inducible factor 1-alpha (HIF1-alpha) are required, respectively, for distal migration and smooth muscle expansion in a sequential manner. In addition, the HIF1-alpha/PDGF-B axis in endothelial cells non-cell autonomously regulates primed cell induction, proliferation, and differentiation. Finally, myeloid cells transdifferentiate into or fuse with distal arteriole SMCs during hypoxia, and Pdgfb deletion in myeloid cells attenuates pathological muscularization. Thus, primed cell autonomous and non-cell autonomous pathways are attractive therapeutic targets for pulmonary hypertension. PMID- 29694894 TI - The Secretion of miR-200s by a PKCzeta/ADAR2 Signaling Axis Promotes Liver Metastasis in Colorectal Cancer. AB - Most colorectal cancer (CRC)-related deaths are due to liver metastases. PKCzeta is a tumor suppressor in CRC with reduced expression in metastasis. Given the importance of microRNAs (miRNAs) in regulating cellular plasticity, we performed an unbiased screening and identified the miR-200 family as the most relevant miRNAs downregulated by PKCzeta deficiency. The regulation of the intracellular levels of miR-200 by PKCzeta is post-transcriptional and involves their secretion in extracellular vesicles. Here, we identified ADAR2 as a direct substrate of PKCzeta in CRC cells. Phosphorylation of ADAR2 regulates its editing activity, which is required to maintain miR-200 steady-state levels, suggesting that the PKCzeta/ADAR2 axis regulates miR-200 secretion through RNA editing. Loss of this axis results in epithelial-to-mesenchymal transition (EMT) and increased liver metastases, which can be inhibited in vivo by blocking miR-200 release. Therefore, the PKCzeta/ADAR2 axis is a critical regulator of CRC metastases through modulation of miR-200 levels. PMID- 29694893 TI - SETDB2 Links E2A-PBX1 to Cell-Cycle Dysregulation in Acute Leukemia through CDKN2C Repression. AB - Acute lymphoblastic leukemia (ALL) is associated with significant morbidity and mortality, necessitating further improvements in diagnosis and therapy. Targeted therapies directed against chromatin regulators are emerging as promising approaches in preclinical studies and early clinical trials. Here, we demonstrate an oncogenic role for the protein lysine methyltransferase SETDB2 in leukemia pathogenesis. It is overexpressed in pre-BCR+ ALL and required for their maintenance in vitro and in vivo. SETDB2 expression is maintained as a direct target gene of the chimeric transcription factor E2A-PBX1 in a subset of ALL and suppresses expression of the cell-cycle inhibitor CDKN2C through histone H3K9 tri methylation, thus establishing an oncogenic pathway subordinate to E2A-PBX1 that silences a major tumor suppressor in ALL. In contrast, SETDB2 was relatively dispensable for normal hematopoietic stem and progenitor cell proliferation. SETDB2 knockdown enhances sensitivity to kinase and chromatin inhibitors, providing a mechanistic rationale for targeting SETDB2 therapeutically in ALL. PMID- 29694895 TI - Cooperative Domain Formation by Homologous Motifs in HOIL-1L and SHARPIN Plays A Crucial Role in LUBAC Stabilization. AB - The linear ubiquitin chain assembly complex (LUBAC) participates in inflammatory and oncogenic signaling by conjugating linear ubiquitin chains to target proteins. LUBAC consists of the catalytic HOIP subunit and two accessory subunits, HOIL-1L and SHARPIN. Interactions between the ubiquitin-associated (UBA) domains of HOIP and the ubiquitin-like (UBL) domains of two accessory subunits are involved in LUBAC stabilization, but the precise molecular mechanisms underlying the formation of stable trimeric LUBAC remain elusive. We solved the co-crystal structure of the binding regions of the trimeric LUBAC complex and found that LUBAC-tethering motifs (LTMs) located N terminally to the UBL domains of HOIL-1L and SHARPIN heterodimerize and fold into a single globular domain. This interaction is resistant to dissociation and plays a critical role in stabilizing trimeric LUBAC. Inhibition of LTM-mediated HOIL-1L/SHARPIN dimerization profoundly attenuated the function of LUBAC, suggesting LTM as a superior target of LUBAC destabilization for anticancer therapeutics. PMID- 29694896 TI - High-Dimensional Phenotyping Identifies Age-Emergent Cells in Human Mammary Epithelia. AB - Aging is associated with tissue-level changes in cellular composition that are correlated with increased susceptibility to disease. Aging human mammary tissue shows skewed progenitor cell potency, resulting in diminished tumor-suppressive cell types and the accumulation of defective epithelial progenitors. Quantitative characterization of these age-emergent human cell subpopulations is lacking, impeding our understanding of the relationship between age and cancer susceptibility. We conducted single-cell resolution proteomic phenotyping of healthy breast epithelia from 57 women, aged 16-91 years, using mass cytometry. Remarkable heterogeneity was quantified within the two mammary epithelial lineages. Population partitioning identified a subset of aberrant basal-like luminal cells that accumulate with age and originate from age-altered progenitors. Quantification of age-emergent phenotypes enabled robust classification of breast tissues by age in healthy women. This high-resolution mapping highlighted specific epithelial subpopulations that change with age in a manner consistent with increased susceptibility to breast cancer. PMID- 29694898 TI - Th1-like Plasmodium-Specific Memory CD4+ T Cells Support Humoral Immunity. PMID- 29694897 TI - Glioblastoma Model Using Human Cerebral Organoids. AB - We have developed a cancer model of gliomas in human cerebral organoids that allows direct observation of tumor initiation as well as continuous microscopic observations. We used CRISPR/Cas9 technology to target an HRasG12V-IRES-tdTomato construct by homologous recombination into the TP53 locus. Results show that transformed cells rapidly become invasive and destroy surrounding organoid structures, overwhelming the entire organoid. Tumor cells in the organoids can be orthotopically xenografted into immunodeficient NOD/SCID IL2RG-/- animals, exhibiting an invasive phenotype. Organoid-generated putative tumor cells show gene expression profiles consistent with mesenchymal subtype human glioblastoma. We further demonstrate that human-organoid-derived tumor cell lines or primary human-patient-derived glioblastoma cell lines can be transplanted into human cerebral organoids to establish invasive tumor-like structures. Our results show potential for the use of organoids as a platform to test human cancer phenotypes that recapitulate key aspects of malignancy. PMID- 29694899 TI - To Make a Long Spindle Short: Nuclear Envelope Breakdown during Meiosis. AB - In fission yeast, the nuclear envelope (NE) remains intact during mitosis and meiosis I but is compromised during meiosis II. In this issue of Cell Reports, Flor-Parra et al. (2018) demonstrate that this NE alteration regulates meiosis II spindle disassembly and the ploidy of meiotic products. PMID- 29694900 TI - Importin alpha and vNEBD Control Meiotic Spindle Disassembly in Fission Yeast. AB - In metazoans, the nuclear envelope (NE) breakdown (NEBD) occurs during "open" mitosis and meiosis. In the fission yeast Schizosaccharomyces pombe, the mitosis and the first meiotic division (MI) are "closed," during which the NE is maintained. Intriguingly, during the second meiotic division (MII), the NE is also maintained, but nuclear and cytoplasmic molecules are mixed similarly to open mitosis, a phenomenon of unknown biological significance called "virtual" NEBD (vNEBD). Here, we show that importin-alpha-dependent nucleocytoplasmic transport regulates spindle disassembly late in anaphase B at MI, as previously reported for mitosis. At MII, however, spindle dissolution is triggered by vNEBD early in anaphase B, a mechanism that short-circuits the nucleocytoplasmic transport system. We demonstrate that the sequential action of these two spindle disassembly systems regulates the spatiotemporal order and ploidy of the meiotic products. PMID- 29694901 TI - Single-Cell RNA-Seq Reveals Transcriptional Heterogeneity in Latent and Reactivated HIV-Infected Cells. AB - Despite effective treatment, HIV can persist in latent reservoirs, which represent a major obstacle toward HIV eradication. Targeting and reactivating latent cells is challenging due to the heterogeneous nature of HIV-infected cells. Here, we used a primary model of HIV latency and single-cell RNA sequencing to characterize transcriptional heterogeneity during HIV latency and reactivation. Our analysis identified transcriptional programs leading to successful reactivation of HIV expression. PMID- 29694902 TI - Rapid Neuromodulation of Layer 1 Interneurons in Human Neocortex. AB - Inhibitory interneurons govern virtually all computations in neocortical circuits and are in turn controlled by neuromodulation. While a detailed understanding of the distinct marker expression, physiology, and neuromodulator responses of different interneuron types exists for rodents and recent studies have highlighted the role of specific interneurons in converting rapid neuromodulatory signals into altered sensory processing during locomotion, attention, and associative learning, it remains little understood whether similar mechanisms exist in human neocortex. Here, we use whole-cell recordings combined with agonist application, transgenic mouse lines, in situ hybridization, and unbiased clustering to directly determine these features in human layer 1 interneurons (L1 INs). Our results indicate pronounced nicotinic recruitment of all L1-INs, whereas only a small subset co-expresses the ionotropic HTR3 receptor. In addition to human specializations, we observe two comparable physiologically and genetically distinct L1-IN types in both species, together indicating conserved rapid neuromodulation of human neocortical circuits through layer 1. PMID- 29694903 TI - P2Y12R-Dependent Translocation Mechanisms Gate the Changing Microglial Landscape. AB - Microglia are an exquisitely tiled and self-contained population in the CNS that do not receive contributions from circulating monocytes in the periphery. While microglia are long-lived cells, the extent to which their cell bodies are fixed and the molecular mechanisms by which the microglial landscape is regulated have not been determined. Using chronic in vivo two-photon imaging to follow the microglial population in young adult mice, we document a daily rearrangement of the microglial landscape. Furthermore, we show that the microglial landscape can be modulated by severe seizures, acute injury, and sensory deprivation. Finally, we demonstrate a critical role for microglial P2Y12Rs in regulating the microglial landscape through cellular translocation independent of proliferation. These findings suggest that microglial patrol the CNS through both process motility and soma translocation. PMID- 29694905 TI - Obesity Suppresses Cell-Competition-Mediated Apical Elimination of RasV12 Transformed Cells from Epithelial Tissues. AB - Recent studies have revealed that newly emerging transformed cells are often eliminated from epithelial tissues via cell competition with the surrounding normal epithelial cells. This cancer preventive phenomenon is termed epithelial defense against cancer (EDAC). However, it remains largely unknown whether and how EDAC is diminished during carcinogenesis. In this study, using a cell competition mouse model, we show that high-fat diet (HFD) feeding substantially attenuates the frequency of apical elimination of RasV12-transformed cells from intestinal and pancreatic epithelia. This process involves both lipid metabolism and chronic inflammation. Furthermore, aspirin treatment significantly facilitates eradication of transformed cells from the epithelial tissues in HFD fed mice. Thus, our work demonstrates that obesity can profoundly influence competitive interaction between normal and transformed cells, providing insights into cell competition and cancer preventive medicine. PMID- 29694904 TI - beta Cell GLP-1R Signaling Alters alpha Cell Proglucagon Processing after Vertical Sleeve Gastrectomy in Mice. AB - Bariatric surgery, such as vertical sleeve gastrectomy (VSG), causes high rates of type 2 diabetes remission and remarkable increases in postprandial glucagon like peptide-1 (GLP-1) secretion. GLP-1 plays a critical role in islet function by potentiating glucose-stimulated insulin secretion; however, the mechanisms remain incompletely defined. Therefore, we applied a murine VSG model to an inducible beta cell-specific GLP-1 receptor (GLP-1R) knockout mouse model to investigate the role of the beta cell GLP-1R in islet function. Our data show that loss of beta cell GLP-1R signaling decreases alpha cell GLP-1 expression after VSG. Furthermore, we find a beta cell GLP-1R-dependent increase in alpha cell expression of the prohormone convertase required for the production of GLP-1 after VSG. Together, the findings herein reveal two concepts. First, our data support a paracrine role for alpha cell-derived GLP-1 in the metabolic benefits observed after VSG. Second, we have identified a role for the beta cell GLP-1R as a regulator of alpha cell proglucagon processing. PMID- 29694906 TI - Rif1 Binding and Control of Chromosome-Internal DNA Replication Origins Is Limited by Telomere Sequestration. AB - The Saccharomyces cerevisiae telomere-binding protein Rif1 plays an evolutionarily conserved role in control of DNA replication timing by promoting PP1-dependent dephosphorylation of replication initiation factors. However, ScRif1 binding outside of telomeres has never been detected, and it has thus been unclear whether Rif1 acts directly on the replication origins that it controls. Here, we show that, in unperturbed yeast cells, Rif1 primarily regulates late replicating origins within 100 kb of a telomere. Using the chromatin endogenous cleavage ChEC-seq technique, we robustly detect Rif1 at late-replicating origins that we show are targets of its inhibitory action. Interestingly, abrogation of Rif1 telomere association by mutation of its Rap1-binding module increases Rif1 binding and origin inhibition elsewhere in the genome. Our results indicate that Rif1 inhibits replication initiation by interacting directly with origins and suggest that Rap1-dependent sequestration of Rif1 increases its effective concentration near telomeres, while limiting its action at chromosome-internal sites. PMID- 29694907 TI - Structural Basis for a Bimodal Allosteric Mechanism of General Anesthetic Modulation in Pentameric Ligand-Gated Ion Channels. AB - Ion channel modulation by general anesthetics is a vital pharmacological process with implications for receptor biophysics and drug development. Functional studies have implicated conserved sites of both potentiation and inhibition in pentameric ligand-gated ion channels, but a detailed structural mechanism for these bimodal effects is lacking. The prokaryotic model protein GLIC recapitulates anesthetic modulation of human ion channels, and it is accessible to structure determination in both apparent open and closed states. Here, we report ten X-ray structures and electrophysiological characterization of GLIC variants in the presence and absence of general anesthetics, including the surgical agent propofol. We show that general anesthetics can allosterically favor closed channels by binding in the pore or favor open channels via various subsites in the transmembrane domain. Our results support an integrated, multi site mechanism for allosteric modulation, and they provide atomic details of both potentiation and inhibition by one of the most common general anesthetics. PMID- 29694908 TI - Prediction of citrullination sites by incorporating k-spaced amino acid pairs into Chou's general pseudo amino acid composition. AB - As one of the most important and common protein post-translational modifications, citrullination plays a key role in regulating various biological processes and is associated with several human diseases. The accurate identification of citrullination sites is crucial for elucidating the underlying molecular mechanisms of citrullination and designing drugs for related human diseases. In this study, a novel bioinformatics tool named CKSAAP_CitrSite is developed for the prediction of citrullination sites. With the assistance of support vector machine algorithm, the highlight of CKSAAP_CitrSite is to adopt the composition of k-spaced amino acid pairs surrounding a query site as input. As illustrated by 10-fold cross-validation, CKSAAP_CitrSite achieves a satisfactory performance with a Sensitivity of 77.59%, a Specificity of 95.26%, an Accuracy of 89.37% and a Matthew's correlation coefficient of 0.7566, which is much better than those of the existing prediction method. Feature analysis shows that the N-terminal space containing pairs may play an important role in the prediction of citrullination sites, and the arginines close to N-terminus tend to be citrullinated. The conclusions derived from this study could offer useful information for elucidating the molecular mechanisms of citrullination and related experimental validations. A user-friendly web-server for CKSAAP_CitrSite is available at 123.206.31.171/CKSAAP_CitrSite/. PMID- 29694909 TI - Expansion, retention and loss in the Acyl-CoA synthetase "Bubblegum" (Acsbg) gene family in vertebrate history. AB - Fatty acids (FAs) constitute a considerable fraction of all lipid molecules with a fundamental role in numerous physiological processes. In animals, the majority of complex lipid molecules are derived from the transformation of FAs through several biochemical pathways. Yet, for FAs to enroll in these pathways they require an activation step. FA activation is catalyzed by the rate limiting action of Acyl-CoA synthases. Several Acyl-CoA enzyme families have been previously described and classified according to the chain length of FAs they process. Here, we address the evolutionary history of the ACSBG gene family which activates, FAs with >16 carbons. Currently, two different ACSBG gene families, ACSBG1 and ACSBG2, are recognized in vertebrates. We provide evidence that a wider and unequal ACSBG gene repertoire is present in vertebrate lineages. We identify a novel ACSBG-like gene lineage which occurs specifically in amphibians, ray finned fishes, coelacanths and cartilaginous fishes named ACSBG3. Also, we show that the ACSBG2 gene lineage duplicated in the Theria ancestor. Our findings, thus offer a far richer understanding on FA activation in vertebrates and provide key insights into the relevance of comparative and functional analysis to perceive physiological differences, namely those related with lipid metabolic pathways. PMID- 29694910 TI - Design of Arab Diabetes Gene-Centric Array (ADGCA) in population with an epidemic of Type 2 Diabetes: A population specific SNP evaluation. AB - In the case of diabetes and other complex diseases, the challenge has always been to find genetic markers that explain the excess risk associated with development of the disease. In the last 12 years, advances in genotyping technology provided substantial development in the discovery of loci contributing to Type 2 diabetes (T2D) susceptibility. Therefore, the aim of this study is to custom design, for the first time in Arab world, an "Arab Diabetes Gene Centric Array" (ADGCA) that assays 643, 745 SNP markers including 50,617 diabetes associated SNPs. The array content was designed after comprehensive literature search prioritizing Diabetes associated SNPs. PCA was performed to evaluate the relationship between world populations and the Saudi population in building the backbone for the array. A genotype data matrix for PCA analysis was produced by including the genotypes of the 270 HapMap samples including JPT, CHB, YRI and CEU to genotypes of the 1457 Saudi samples. Imputation was executed using IMPUTE2 software and the 1000GP Phase III reference panel. All markers incorporated to ADGCA were validated. Quality checks and evaluation of its capacity and performance as a platform for genetic screening for T2D was performed using the latest stastical tools available. We were successful in designing ADGCA as a custom made chip array designed with a motive to capture genetic variation in loci known or reported to be associated with the development of T2D. However, implementation of ADGCA is currently being performed by our research group using 2000 DNA samples respectively from diabetic and non diabetic individuals which could further validate the use of ADGSA in genetic screening of T2D. PMID- 29694911 TI - Dietary choline supplementation in adult rats improves performance on a test of recognition memory. AB - In two experiments adult rats (aged at least 6 months at the start of the procedure) received a diet enriched with added choline for a period of 10 weeks; control subjects were maintained on a standard diet during this time. All rats then underwent the spontaneous object recognition (SOR) procedure in which they were exposed to a pair of objects and then tested, after a retention interval, to a display with one object changed. Exploration of the changed object indicates retention and use of information acquired during the exposure phase. All subjects showed retention with a 24-h interval (Experiments 1 and 2) and when retested after a further 24 h (Experiment 1). But when tested for the first time after a 48-h interval (Experiment 2), control subjects showed no evidence of retention, exploring both objects equally, whereas those given the dietary supplement continued to show a preference for the changed object. This supports the conclusion that dietary choline supplementation can enhance performance on a task regarded as a test of declarative memory, and will do so even when the supplementations is given in adulthood. PMID- 29694912 TI - Individual differences in conditioned fear are associated with levels of adolescent/early adult alcohol consumption and instrumental extinction. AB - Previous research has shown a relationship between alcohol exposure and conditioned fear, but the nature of this relationship remains unclear. We determined whether chronic intermittent access to alcohol during adolescence and early adulthood would alter or be associated with the level of conditioned fear to an auditory cue in male Long Evans rats. Rats received 6 weeks of chronic intermittent access to 20% alcohol or water from PND 26-66 and began behavioral testing 10 days later. We found no evidence that voluntary alcohol consumption altered fear. However, we found that rats that consumed more alcohol had lower fear, as measured with conditioned suppression of lever-pressing and conditioned freezing to an auditory cue. We have previously shown that higher levels of alcohol consumption are correlated with faster instrumental extinction learning. Therefore, we determined whether instrumental extinction would be directly associated with conditioned fear in rats never given alcohol access. As predicted, we found that rats that exhibited faster instrumental extinction also exhibited lower conditioned fear, as measured with conditioned suppression of lever-pressing and conditioned freezing. Our results suggest that at least part of the relationship between alcohol consumption levels and fear learning differences may be due to pre-existing individual differences. In addition, our finding that conditioned fear and instrumental extinction abilities (both separately associated with alcohol consumption levels) are associated with each other suggests that alcohol consumption levels may be a marker that can distinguish two separate phenotypes that encompass a wide variety of learning traits. PMID- 29694913 TI - Effects of taurine on striatal dopamine transporter expression and dopamine uptake in SHR rats. AB - Dopaminergic deficits in the prefrontal cortex and striatum have been attributed to the pathogenesis of attention-deficit hyperactivity disorder (ADHD). Our recent study revealed that high-dose taurine improves hyperactive behavior and brain-functional signals in SHR rats. This study investigates the effect of taurine on the SHR striatum by detecting the spontaneous alternation, DA transporter (DAT) level, dopamine uptake and brain-derived neurotrophic factor (BDNF) expression. A significant increase in the total arm entries was detected in both WKY and SHR rats fed with low-dose taurine but not in those fed with high dose taurine. Notably, significantly increased spontaneous alternation was observed in SHR rats fed with high-dose taurine. Significantly higher striatal DAT level was detected in WKY rats fed with low-dose taurine but not in SHR rats, whereas significantly reduced striatal DAT level was detected in SHR rats fed with high-dose taurine but not in WKY rats. Significantly increased dopamine uptake was detected in the striatal synaptosomes of both WKY and SHR rats fed with low-dose taurine. Conversely, significantly reduced dopamine uptake was detected in the striatal synaptosomes of SHR rats fed with high-dose taurine. Accordingly, a negative correlation was detected between striatal dopamine uptake and spontaneous alternation in SHR rats fed with low or high-dose taurine. Significantly increased BDNF was detected in the striatum of both WKY and SHR rats fed with low or high-dose taurine. These findings indicate that different dosages of taurine have opposite effects on striatal DAT expression and dopamine uptake, suggesting high-dose taurine as a possible candidate for ADHD treatment. PMID- 29694914 TI - The origin of GSKIP, a multifaceted regulatory factor in the mammalian Wnt pathway. AB - GSK3beta interacting protein (GSKIP) is a naturally occurring negative regulator of GSK3beta and retains both the Protein Kinase A Regulatory subunit binding (PKA RII) domain and GSK3beta interacting domain. Of these two domains, we found that PKA-RII is required for forming a working complex comprising PKA/GSKIP/GSK3beta/Drp1 to influence phosphorylation of Drp1 Ser637. In this study, bioinformatics and experimental explorations re-analyzing GSKIP's biofunctions suggest that the evolutionarily conserved Domain of Unknown Function (DUF727) is an ancestral prototype of GSKIP in prokaryotes, and acquired the C terminal GSK3beta binding site (tail) in invertebrates except for Saccharomyces spp., after which the N-terminal PKA-RII binding region (head) evolved in vertebrates. These two regions mutually influence each other and modulate GSKIP binding to GSK3beta in yeast two-hybrid assays and co-immunoprecipitation. Molecular modeling showed that mammalian GSKIP could form a dimer through the L130 residue (GSK3beta binding site) rather than V41/L45 residues. In contrast, V41/L45P mutant facilitated a gain-of-function effect on GSKIP dimerization, further influencing binding behavior to GSK3beta compared to GSKIP wild-type (wt). The V41/L45 residues are not only responsible for PKA RII binding that controls GSK3beta activity, but also affect dimerization of GSKIP monomer, with net results of gain-of-function in GSKIP-GSK3beta interaction. In addition to its reported role in modulating Drp1, Ser637 phosphorylation caused mitochondrial elongation; we postulated that GSKIP might be involved in the Wnt signaling pathway as a scavenger to recruit GSK3beta away from the beta-catenin destruction complex and as a competitor to compete for GSK3beta binding, resulting in accumulation of S675 phosphorylated beta-catenin. PMID- 29694915 TI - Bcl-xL deamidation is regulated by multiple ion transporters and is intramolecularly catalyzed. AB - In susceptible tumor cells, DNA-damaging antineoplastic agents induce an increase in intracellular pH during the premitochondrial stage of apoptosis. The rate of nonenzymatic deamidation of two asparagines in the anti-apoptotic protein Bcl-xL is accelerated by this increase in pH. Deamidation of these asparagines is a signal for the degradation of Bcl-xL, which is a component of the apoptotic response to DNA damage. It has previously been shown that the increase in pH is mediated by the ion transporter Na+/H+ exchanger 1 in some cells. Here we demonstrate that one or more additional ion transporters also have a role in the regulation of Bcl-xL deamidation in at least some tumor cell lines and fibroblasts. As a second, independent finding, we report that there are histidines in close proximity to the Bcl-xL deamidation sites that are highly conserved in land-dwelling species and we present evidence that deamidation of human Bcl-xL is intramolecularly catalyzed in a manner that is dependent upon these histidines. Further, we present evidence that these histidines act as a pH sensitive switch that enhances the effect of the increase in pH on the rate of Bcl-xL deamidation. The conservation of such histidines implies that human Bcl-xL is in essence "designed" to be deamidated, which provides further evidence that deamidation serves as a bona fide regulatory post-translational modification of Bcl-xL. PMID- 29694916 TI - Perception as a Route for Motor Skill Learning: Perspectives from Neuroscience. AB - Learning a motor skill requires physical practice that engages neural networks involved in movement. These networks have also been found to be engaged during perception of sensory signals associated with actions. Nonetheless, despite extensive evidence for the existence of such sensory-evoked neural activity in motor pathways, much less is known about their contribution to learning and actual changes in behavior. Primate studies usually involve an overlearned task while studies in humans have largely focused on characterizing activity of the action observation network (AON) in the context of action understanding, theory of mind, and social interactions. Relatively few studies examined neural plasticity induced by perception and its role in transfer of motor knowledge. Here, we review this body of literature and point to future directions for the development of alternative, physiologically grounded ways in which sensory signals could be harnessed to improve motor skills. PMID- 29694917 TI - Longitudinal Structural and Functional Brain Network Alterations in a Mouse Model of Neuropathic Pain. AB - Neuropathic pain affects multiple brain functions, including motivational processing. However, little is known about the structural and functional brain changes involved in the transition from an acute to a chronic pain state. Here we combined behavioral phenotyping of pain thresholds with multimodal neuroimaging to longitudinally monitor changes in brain metabolism, structure and connectivity using the spared nerve injury (SNI) mouse model of chronic neuropathic pain. We investigated stimulus-evoked pain responses prior to SNI surgery, and one and twelve weeks following surgery. A progressive development and potentiation of stimulus-evoked pain responses (cold and mechanical allodynia) were detected during the course of pain chronification. Voxel-based morphometry demonstrated striking decreases in volume following pain induction in all brain sites assessed - an effect that reversed over time. Similarly, all global and local network changes that occurred following pain induction disappeared over time, with two notable exceptions: the nucleus accumbens, which played a more dominant role in the global network in a chronic pain state and the prefrontal cortex and hippocampus, which showed lower connectivity. These changes in connectivity were accompanied by enhanced glutamate levels in the hippocampus, but not in the prefrontal cortex. We suggest that hippocampal hyperexcitability may contribute to alterations in synaptic plasticity within the nucleus accumbens, and to pain chronification. PMID- 29694919 TI - New potential biomarkers of oxidative stress in Mytilus galloprovincialis: Analytical validation and overlap performance. AB - The aim of the present report was to develop and validate new automated spectrophotometric assays for measurement of total antioxidant capacity (TAC), thiols, and advanced oxidation protein products (AOPP) in mussel gills, digestive gland and hemolymph samples, and to evaluate their possible utility in biomonitoring programs. Total antioxidant capacity (TAC) was measured by different methods: trolox equivalent antioxidant capacity (TEAC1 and TEAC2), cupric reducing antioxidant capacity (CUPRAC), and ferric reducing ability of plasma (FRAP). The assays were precise, accurate and provided low limits of detection. When oxidative stress was promoted by inducing hypoxia and the behaviour of these biomarkers between hypoxic and controls mussels were compared, statistically significant differences were observed in all biomarkers and tissues evaluated. The results of the present study demonstrated that these biomarkers, not previously studied in mussels, show a potential use as biomarkers of oxidative stress in this species since they were validated and showed changes under a state of oxidative stress. PMID- 29694918 TI - Psychosocial Stress Delays Recovery of Postoperative Pain Following Incisional Surgery in the Rat. AB - Psychosocial factors such as anxiety, depression and catastrophizing, commonly associated with established chronic pain, also may be associated with an increased risk of chronic postsurgical pain (CPSP) when present preoperatively. We used a repeat social defeat (RSD) paradigm to induce psychosocial stress in rodents prior to incisional surgery of the paw. Mixed effects growth curve models were utilized to examine resolution of mechanical hypersensitivity in rats for four weeks following surgery. Eight days following surgery, immunohistochemistry was conducted to examine glial activation as well as evoked neuronal activation in the spinal cord. Here we document that RSD resulted in reduced weight gain and increased depressive symptoms prior to surgery. Rats exposed to RSD displayed delayed resolution of mechanical hypersensitivity in the ipsilateral paw following surgery compared to non-defeated rats. Prior exposure to RSD significantly increased microglial activation and neuronal sensitization (pERK IR) within the ipsilateral spinal cord. In conclusion, we found that chronic social stress alters the neurobiological response to surgical injury, resulting in slowed recovery. This model maybe useful for future interventional studies examining the mechanistic interactions between depression and risk of CPSP. PMID- 29694920 TI - A polypeptide based podophyllotoxin conjugate for the treatment of multi drug resistant breast cancer with enhanced efficiency and minimal toxicity. AB - : Podophyllotoxin (PPT) is a chemotherapeutic agent which has shown significant activity against P-glycoprotein (P-gp) mediated multi drug resistant cancer cells. However, because of the poor aqueous solubility and high toxicity, PPT cannot be used in clinical cancer therapy. In order to enhance the efficiency and reduce side effect of PPT, a polypeptide based PPT conjugate PLG-g-mPEG-PPT was developed and used for the treatment of multi drug resistant breast cancer. The PLG-g-mPEG-PPT was prepared by conjugating PPT to poly(l-glutamic acid)-g-methoxy poly(ethylene glycol) (PLG-g-mPEG) via ester bonds. The PPT conjugates self assembled into nanoparticles with average sizes about 100 nm in aqueous solution. Western blotting assay showed that the PLG-g-mPEG-PPT could effectively inhibit the expression of P-gp in the multiple drug resistant MCF-7/ADR cells. In vitro cytotoxicity assay indicated that the resistance index (RI) values of PLG-g-mPEG PPT on different drug-resistant cancer cell lines exhibited 57-270 folds reduction than of traditional microtubule inhibitor chemotherapeutic drug PTX or DTX. Hemolysis assay demonstrated that the conjugation greatly decreased the hemolytic activity of free PPT. Maximum tolerated dose (MTD) of PLG-g-mPEG-PPT increased greatly (13.3 folds) as compared to that of free PPT. In vivo study showed that the PLG-g-mPEG-PPT conjugate remarkably enhanced the antitumor efficacy against MCF-7/ADR xenograft tumors with a tumor suppression rate (TSR) of 82.5%, displayed significantly improved anticancer efficacy as compared to free PPT (TSR = 37.1%) with minimal toxicity when both of the two formulations were used in MTD. STATEMENT OF SIGNIFICANCE: The development of multiple drug resistance (MDR) of cancer cells is the main cause of chemotherapy failure. The over-expression of P-glycoprotein (P-gp) has been recognized to be the most important cause of MDR in cancer. Podophyllotoxin (PPT) is a chemotherapeutic agent which has shown strong activity against P-gp mediated multidrug resistant cancer cells by simultaneously inhibiting the over-expression of P-gp and the growth of cancer cells. However, PPT can not be used in clinical cancer treatment due to its poor aqueous solubility and high toxicity. Herein, we developed a polypeptide based PPT conjugate PLG-g-mPEG-PPT by conjugating PPT to poly(l glutamic acid)-g-methoxy poly(ethylene glycol). The PLG-g-mPEG-PPT shows significantly decreased hemolytic activity, greatly improved maximum tolerated dose and remarkably enhanced antitumor efficacy against MCF-7/ADR xenograft tumors as compared to free PPT. PMID- 29694921 TI - Socio-sexual processing in cortical circuits. AB - How does social and sexual information processing map onto cortical circuits? Addressing this question has been difficult, because of a lack of circuit oriented social neuroscience and an absence of measurements from interacting brains. Recent work showed social information is already differentially processed in the primary sensory cortices. Converging evidence suggests that prefrontal areas contribute to social interaction processing and determining social hierarchies. In social interactions, we identify gender in split seconds, but after centuries of anatomy we are still unable to distinguish male and female cortices. Novel data reinforce the idea of a bisexual layout of cortical anatomy. Physiological analysis, however, provided evidence for sex differences in cortical processing. Unlike other cortical circuits, sexual processing circuits undergo major rewiring and expansion during puberty and show lasting damage from childhood abuse. PMID- 29694922 TI - Vestibular signals in primate cortex for self-motion perception. AB - The vestibular peripheral organs in our inner ears detect transient motion of the head in everyday life. This information is sent to the central nervous system for automatic processes such as vestibulo-ocular reflexes, balance and postural control, and higher cognitive functions including perception of self-motion and spatial orientation. Recent neurophysiological studies have discovered a prominent vestibular network in the primate cerebral cortex. Many of the areas involved are multisensory: their neurons are modulated by both vestibular signals and visual optic flow, potentially facilitating more robust heading estimation through cue integration. Combining psychophysics, computation, physiological recording and causal manipulation techniques, recent work has addressed both the encoding and decoding of vestibular signals for self-motion perception. PMID- 29694923 TI - Behavioral readout of spatio-temporal codes in olfaction. AB - Neural recordings performed at an increasing scale and resolution have revealed complex, spatio-temporally precise patterns of activity in the olfactory system. Multiple models may explain the functional consequences of the spatio-temporal olfactory code, but the link to behavior remains unclear. Recent evidence in the field suggests a behavioral sensitivity to both fine spatial and temporal features in the code. How these features and combinations of features give rise to olfactory behavior is the subject of active research in the field. Modern genetic and optogenetic methods show great promise in testing the link between olfactory codes and behavior. PMID- 29694925 TI - Strain-specific effects of crowding on long-term memory formation in Lymnaea. AB - Crowding of snails is a stress that obstructs long-term memory (LTM) formation following operant conditioning of aerial respiratory behaviour in Lymnaea stagnalis. In previous experiments, snails of the same strain/population were used for both the crowding and the operant conditioning training. However, there are different strains/populations of Lymnaea stagnalis exhibiting different cognitive abilities. We asked whether Lymnaea of one strain/population are able to determine that they are of a different strain/population. We did this by asking if LTM formation would continue to be obstructed if we crowded snails with a different species of pond snail (Helisoma = Planorbella) or with different strains/populations of Lymnaea stagnalis. Using an inbred strain, the W-strain, we crowded the W-strain with seven other Lymnaea strains/populations as well as with Helisoma. The results of a 2-Way ANOVA followed by a Tukey's Post-hoc analysis showed that W-strain snails when crowded with another strain/population of Lymnaea or with Helisoma formed LTM formation. That is, the memory test session statistically met the criteria for LTM formation. Thus, one strain/population of snails determines that another strain/population is different from it. The differentness means that crowding now does not obstruct LTM formation. PMID- 29694924 TI - Loss of tafazzin results in decreased myoblast differentiation in C2C12 cells: A myoblast model of Barth syndrome and cardiolipin deficiency. AB - Barth syndrome (BTHS) is an X-linked genetic disorder resulting from mutations in the tafazzin gene (TAZ), which encodes the transacylase that remodels the mitochondrial phospholipid cardiolipin (CL). While most BTHS patients exhibit pronounced skeletal myopathy, the mechanisms linking defective CL remodeling and skeletal myopathy have not been determined. In this study, we constructed a CRISPR-generated stable tafazzin knockout (TAZ-KO) C2C12 myoblast cell line. TAZ KO cells exhibit mitochondrial deficits consistent with other models of BTHS, including accumulation of monolyso-CL (MLCL), decreased mitochondrial respiration, and increased mitochondrial ROS production. Additionally, tafazzin deficiency was associated with impairment of myocyte differentiation. Future studies should determine whether alterations in myogenic determination contribute to the skeletal myopathy observed in BTHS patients. The BTHS myoblast model will enable studies to elucidate mechanisms by which defective CL remodeling interferes with normal myocyte differentiation and skeletal muscle ontogenesis. PMID- 29694926 TI - GH prevents adipogenic differentiation of mesenchymal stromal stem cells derived from human trabecular bone via canonical Wnt signaling. AB - The imbalance between osteogenesis and adipogenesis, which naturally accompanies bone marrow senescence, may contribute to the development of bone-associated diseases, like osteoporosis. In the present study, using primary human mesenchymal stromal cells (hMSCs) isolated from trabecular bone, we assessed the possible effect of GH on hMSC differentiation potential into adipocytes. GH (5 ng/ml) significantly inhibited the lipid accumulation in hMSCs cultured for 14 days in lipogenic medium. GH decreased the expression of the adipogenic genes, CCAAT/enhancer-binding protein alpha (C/EBPalpha) and adiponectin (ADN) as well as the expression of two lipogenesis-related enzymes, lipoprotein lipase (LPL) and acethylCoA carboxylase (ACACA). In parallel, GH induced an increase in the gene expression and protein levels of osterix (OSX) and osteoprotegerin (OPG). These effects were ascribed to enhanced Wnt signaling as GH significantly reduced Wnt inhibitors, Dickkopf 1 (DKK1) and the secreted frizzled protein 2 (SFRP2), and increased the expression of an activator of Wnt, Wnt3. Accordingly, the expression of beta-catenin and its nuclear levels were raised. Wnt involvement in GH anti-adipogenic effect was further confirmed by the silencing of beta-catenin. In silenced hMSC, both the inhibitory effect of GH on the expression of the adipogenic genes, ADN and C/EBPalpha and the lipogenesis enzymes LPL and ACACA, were prevented together with the stimulatory effect of GH on the osteogenic genes OSX and OPG. The present study supports the hypothesis that when GH secretion declines as in aging, the fat in the bone-marrow cavities increases and the osteogenic capacity of the MSC pool is reduced due to a decrease in Wnt signaling. PMID- 29694927 TI - Transcription factor mechanisms guiding motor neuron differentiation and diversification. AB - The embryonic generation of motor neurons is a complex process involving progenitor patterning, fate specification, differentiation, and maturation. Throughout this progression, the differential expression of transcription factors has served as our road map for the eventual cell fate of nascent motor neurons. Recent findings from in vivo and in vitro models of motor neuron development have expanded our understanding of how transcription factors govern motor neuron identity and their individual regulatory mechanisms. With the advent of next generation sequencing approaches, researchers now have unprecedented access to the gene regulatory dynamics involved in motor neuron development and are uncovering new connections linking neurodevelopment and neurodegenerative disease. PMID- 29694928 TI - Elucidation of active site dynamics of papain and the effect of encapsulation within cationic and anionic reverse micelles. AB - In this study, steady state, solvation dynamics and rotational dynamics experiments have been carried out on a system of DACIA-tagged papain in bulk water and inside the water pool of cationic (cetyltrimethylammonium bromide, CTAB) and anionic (sodium bis(2-ethylhexyl)sulfosuccinate, AOT) reverse micelles with varying water contents (W0 = 20 to 50). While the absorption and emission maxima and the excited state lifetime did not show any noticeable change with the variation of the size of the reverse micelle, the change in solvation time, Stokes shift, rotational correlation time and residual anisotropy with the change in reverse micellar size were quite revealing. The average solvation time and Stokes shift of papain in bulk water are 0.22 ns and 125 cm-1 respectively, which increase to 0.96 ns and 718 cm-1 while inside CTAB reverse micelle of W0 = 20. The solvation time and Stokes shift values decrease with the increase in the size of reverse micelle, approaching the corresponding values in bulk water when W0 = 50. The solvation time and Stokes shift of the DACIA-tagged papain was found to be high while inside AOT reverse micelle also (0.47 ns and 438 cm-1 respectively when W0 = 20), but there was no monotonous variation with the change in size of micellar size as in the case with CTAB reverse micelle. From the anisotropy studies, it was seen that inside CTAB and AOT reverse micelles, there is a significant amount of residual anisotropy, which is absent in the case of DACIA tagged papain in bulk water. The rotational correlation times were also found to be higher inside the reverse micelles than those in bulk water. Both residual anisotropy and rotational correlation time were found to be more in the case with AOT reverse micelle than with CTAB reverse micelle. These behaviours could be explained based on the electrostatic forces acting between the papain having a positive surface charge and the reverse micelles of cationic CTAB and anionic AOT. PMID- 29694929 TI - 3-Acetyl-8-methoxy-2[H]-chromen-2-one derived Schiff bases as potent antiproliferative agents: Insight into the influence of 4(N)-substituents on the in vitro biological activity. AB - A series of 3-acetyl-8-methoxycoumarin appended thiosemicarbazones (1-4) was prepared from the reaction of 3-acetyl-8-methoxycoumarin with 4(N)-substituted thiosemicarbazides in a view of ascertaining their biological properties with the change of N-terminal substitution in the thiosemicarbazide moiety. Comprehensive characterization was brought about by various spectral and analytical methods. The molecular structures of all the compounds were determined by single crystal X ray diffraction analysis. Binding studies with Calf thymus DNA (CT-DNA) and proteins such as Bovine Serum Albumin (BSA) and Human Serum Albumin (HSA) indicated an intercalative mode of binding with DNA and static quenching mechanism with proteins. The compounds cleaved plasmid DNA (pBR322) and acted well as free radical scavengers. A good spectrum of antimicrobial activity was observed against four bacterial and five fungal pathogens. The compounds exhibited profound antiproliferative activity on MCF-7 (human breast cancer) and A549 (human lung carcinoma) cell lines. Assay on human normal keratinocyte cell line HaCaT showed that the compounds were non-toxic to normal cells. PMID- 29694930 TI - Comparative study of binding interactions between porphyrin systems and aromatic compounds of biological importance by multiple spectroscopic techniques: A review. AB - The specific spectroscopic and redox properties of porphyrins predestine them to fulfill the role of sensors during interacting with different biologically active substances. Monitoring of binding interactions in the systems porphyrin biologically active compound is a key question not only in the field of physiological functions of living organisms, but also in environmental protection, notably in the light of the rapidly growing drug consumption and concurrently the production of drug effluents. Not always beneficial action of drugs on natural porphyrin systems induces to further studies, with commercially available porphyrins as the model systems. Therefore the binding process between several water-soluble porphyrins and a series of biologically active compounds (e.g. caffeine, guanine, theophylline, theobromine, xanthine, uric acid) has been studied in different aqueous solutions analyzing their absorption and steady state fluorescence spectra, the porphyrin fluorescence lifetimes and their quantum yields. The magnitude of the binding and fluorescence quenching constants values for particular quenchers decreases in a series: uric acid > guanine > caffeine > theophylline > theobromine > xanthine. In all the systems studied there are characters of static quenching, as a consequence of the pi-pi-stacked non-covalent and non-fluorescent complexes formation between porphyrins and interacting compounds, accompanied simultaneously by the additional specific binding interactions. The porphyrin fluorescence quenching can be explain by the photoinduced intermolecular electron transfer from aromatic compound to the center of the porphyrin molecule, playing the role of the binding site. Presented results can be valuable for designing of new fluorescent porphyrin chemosensors or monitoring of drug traces in aqueous solutions. The obtained outcomes have also the toxicological and medical importance, providing insight into the interactions of the water-soluble porphyrins with biologically active substances. PMID- 29694931 TI - Urinary potassium excretion and its association with acute kidney injury in the intensive care unit. AB - PURPOSE: Using urinary indices as a quick bedside test to assist management of oliguria and acute kidney injury (AKI) has long been sought. This study assessed whether urinary potassium excretion is related to simultaneously calculated creatinine clearance (CrCl) and can predict AKI in the critically ill. MATERIALS AND METHODS: In this prospective cohort study, the correlation between 2-h urinary potassium excretion and simultaneously calculated CrCl of 61 critically ill patients was assessed by Pearson's correlation coefficient, and their ability to predict AKI (>=stage 1 KDIGO) in the subsequent 7 days was assessed by area under the receiver-operating-characteristic (AUROC) curve. RESULTS: Urinary potassium excretion (median 6.2 mmol, range 0.8-24.3) correlated linearly with CrCl (correlation coefficient: 0.58, 95% confidence interval [CI] 0.38-0.72; p = 0.001), and had a moderate ability to predict subsequent AKI (n = 19 [31%]; AUROC 0.747, 95%CI 0.620-0.850; p = 0.001), especially in patients without prior exposure to furosemide within 24-h (correlation coefficient 0.61, 95%CI 0.41 0.76; AUROC 0.789, 95%CI 0.654-0.890; p = 0.001, respectively). CONCLUSIONS: Urinary potassium excretion correlates with CrCl and predicts AKI in the critically ill without recent furosemide exposure. Given 2-h urinary potassium excretion can be measured easily, its potential as a marker of renal function deserves further study. PMID- 29694932 TI - Six-month longitudinal associations between cognitive functioning and distress among the community-based elderly in Hong Kong: A cross-lagged panel analysis. AB - Although previous studies have extensively documented the cross-sectional relationship between cognitive impairment and psychological distress, findings relating to their longitudinal associations remains mixed. The present study examines the longitudinal associations and mutual influence between cognitive functioning and psychological distress across six months among community-dwelling elderly in Hong Kong. A total of 162 older adults (40 males; Mage = 69.8 years, SD = 6.4) were administered objective and subjective measures of cognitive functioning, as well as self-reported ratings of distress, at two time points six months apart. Using structural equation modeling, we tested the cross-lagged relationships between cognitive functioning and distress. Our cross-lagged model indicated that cognitive functioning at baseline significantly predicted subsequent psychological distress. However, distress was not significantly associated with subsequent cognitive functioning. Additionally, the objective and subjective measures of cognitive functioning were not significantly correlated. These findings suggested that distress may occur as a consequence of poorer cognitive functioning in elderly, but not vice versa. The lack of correlation between objective and subjective cognitive measures suggested that the participants may not have adequate insight into their cognitive abilities. The implications of these findings are discussed. PMID- 29694933 TI - The unique and interactive effects of anxiety sensitivity and emotion dysregulation in relation to posttraumatic stress, depressive, and anxiety symptoms among trauma-exposed firefighters. AB - BACKGROUND: Firefighters are chronically exposed to traumatic events. Relatedly, past work has documented high rates of psychiatric problems, such as posttraumatic stress symptoms and depression, among firefighters. Less is known regarding anxiety symptoms among firefighters. Moreover, little work has examined risk/maintenance factors related to these symptoms among firefighters. Doing so may be important to developing interventions tailored to trauma-exposed firefighters. The current study examined symptoms of posttraumatic stress, depression, panic disorder, and social anxiety among trauma-exposed firefighters. PROCEDURE: Using structural equation modeling, the main and interactive effects of anxiety sensitivity and emotion dysregulation were examined in relation to these symptom outcomes. Participants included 787 male urban firefighters reporting at least one past traumatic event. RESULTS: There was a statistically significant main effect of anxiety sensitivity on each outcome. Emotion dysregulation exerted a statistically significant main effect on posttraumatic stress, depression, and social anxiety symptoms. Interactive effects of anxiety sensitivity and emotion dysregulation did not reach statistical significance but examination of effect sizes suggests that interactive effects may be present for posttraumatic stress symptoms (R2 = 0.011), depression (R2 = 0.008), and panic (R2 = 0.016) such that emotion dysregulation is more strongly related to outcomes when anxiety sensitivity levels are relatively lower. All effects were evident after controlling for trauma severity and history of armed forces service. CONCLUSION: Overall, results suggest that anxiety sensitivity and emotion dysregulation represent unique risk/maintenance factors related to a broad range of emotional symptoms among trauma-exposed firefighters. These findings replicate patterns found among the general population and extend the findings to potentially vulnerable firefighters. PMID- 29694934 TI - Comparison of the long-term treatment outcomes of women and men diagnosed with schizophrenia over a period of 20 years. A prospective study. PMID- 29694935 TI - Does dissociation mediate the relationship between childhood trauma and hallucinations, delusions in first episode psychosis? AB - BACKGROUND: Childhood trauma has been linked to the presence of delusions and hallucinations in psychosis, although the mechanisms underlying this relationship require elucidation. Dissociation, characterized by disruptions to the integrative functioning of several core mental domains, has emerged as a potential mechanism. There is a paucity of research using a clinician-rated measure of dissociation to test the indirect effect of dissociation on the relationship between childhood trauma and psychotic symptoms. This study aimed to investigate whether dissociation mediated both the relationships between childhood trauma and hallucinations, and childhood trauma and delusions utilizing a clinician-administered measure of dissociation, namely the Structured Clinical Interview for DSM-IV Dissociative Disorders - Revised (SCID-D-R). METHOD: Sixty six first-episode psychosis (FEP) participants completed a research interview and questionnaires. Information about experiences of childhood trauma, psychosis, dissociation, general psychopathology and demographics were collected. RESULTS: When using the SCID-D-R, childhood trauma positively correlated with dissociation. Further, dissociation mediated the relationship between childhood trauma and delusions. Contrary to previous findings, we found no relationship between dissociation and hallucinations and no mediating effect of dissociation on the association between childhood trauma and hallucinations. The results of the SCID-D-R differed significantly from those of the Dissociative Experiences Scale-II (DES-II) which were consistent with previous research. CONCLUSIONS: Our findings are the first to use a clinician-rated measure to test the mediating effect of dissociation on the relationship between childhood trauma and positive symptoms (i.e., hallucinations and delusions). Given the discrepancies in results between the SCID-D-R and DES-II, how dissociation is measured in future research is an important consideration. The results add to a body of work that increasingly recognizes the importance of dissociative symptoms on the relationship between childhood trauma and psychosis. The results suggest that dissociative symptoms should be part of routine assessment in those with a history of trauma and present to FEP services. PMID- 29694936 TI - Linking genome signatures of selection and adaptation in non-model plants: exploring potential and limitations in the angiosperm Amborella. AB - Selective sweeps may be caused by environmental conditions that select for a gene function or trait at one locus, causing reduced variation at neighboring sites due to linkage, with specific non-selected variants being swept along with the selected variant. For many species, genomic and environmental data are available to test hypotheses that environmental conditions are correlated with selected regions. Most genomic studies relating selection to environment use model organisms or crop species; typically, these studies have genomic data from large numbers of individuals and extensive environmental data. Here, we review studies associating selective sweeps with environment and consider the impediments to successful application of these methods to non-model species. We present an initial investigation into linking genomic regions of selection to environmental conditions in the narrowly distributed, non-model plant Amborella trichopoda (Amborellaceae), the sister species to all other living flowering plants and one of over 2500 plant species endemic to New Caledonia. PMID- 29694937 TI - Migration of plasticizers from poly(vinyl chloride) and multilayer infusion bags using selective extraction and GC-MS. AB - Flexible poly(vinyl chloride) (PVC) is widely used in the pharmaceutical industry for the manufacture of medical devices (tubes, probes, bags, primary packaging, etc.). The objective of the present study was to develop a procedure to evaluate the migration potential of nine plastic additives in aqueous infusion bags (NaCl 0.9% and glucose 5%): five phthalates, one adipate, two alkylphenols, and benzophenone. Two types of materials were analyzed: (i) new and outdated plasticized PVC (containing 40% of diethylhexyl phthalate DEHP); and (ii) tri laminate polyethylene-polyamide-polypropylene, a multilayer material presumably exempt from DEHP. In addition, we evaluated the migration of plasticizers from PVC raw materials (film and grain) under controlled conditions to compare the migration levels according to Regulation 2011/10. Solid phase extraction and liquid-liquid extraction with gas-chromatography coupled to mass spectrometry were used in all tests. The migration of DEHP in PVC grain exceeded the maximum regulated level of 5000 MUg/kg, whereas the levels were much lower in films. In new PVC bags, DEHP was the only compound detected at 4.31 +/- 0.5 MUg/L in NaCl 0.9% and 4.29 +/- 0.25 MUg/L in glucose 5% serums, whereas the levels increased 10 times in three-year shelf-life bags. In multilayer bags, DEHP was not found but instead, two plasticizers were detected namely dibuthylphthalate (DBP) and diethylphthalate (DEP) at 0.7 +/- 0.1 MUg/L and 4.14 +/- 0.6 MUg/L, respectively. These plasticizers are not mentioned as additives allowed in materials intended for parenteral use (European Pharmacopoeia 8.0, 3.1.5. and 3.1.6.). Caprolactam was tentatively identified and could have stemmed from the polyamide of the multilayer composite. The levels of phthalates remained low but not negligible and might constitute a risk to public health in the case of reiterative infusions. PMID- 29694938 TI - Short-chain fatty acids administration is protective in colitis-associated colorectal cancer development. AB - Reduced short-chain fatty acids (SCFAs) have been reported in patients with ulcerative colitis, and increased intake of dietary fiber has shown to be clinically beneficial for colitis. Whether SCFAs suppress tumorigenesis in colitis-associated colorectal cancer remains unknown. The chemopreventive effect of SCFAs in colitis-associated colorectal cancer was evaluated in this study. Model of colitis-associated colorectal cancer in male BALB/c mice was induced by azoxymethane (AOM) and dextran sodium sulfate (DSS). SCFAs mix (67.5 mM acetate, 40 mM butyrate, 25.9 mM propionate) was administered in drink water during the study period. Macroscopic and histological studies were performed to examine the colorectal inflammation and tumorigenesis in AOM/DSS-induced mice treated with or without SCFA mix. The effects of SCFAs mix on colonic epithelial cellular proliferation were also assessed using Ki67 immunohistochemistry and TUNEL staining. The administration of SCFAs mix significantly reduced the tumor incidence and size in mice with AOM/DSS-induced colitis associated colorectal cancer. SCFAs mix protected from AOM/DSS-induced colorectal cancer by improving colon inflammation and disease activity index score as well as suppressing the expression of proinflammatory cytokines including IL-6, TNF-alpha and IL-17. A decrease in cell proliferation markers and an increase in TUNEL-positive tumor epithelial cells were also demonstrated in AOM/DSS mice treated with SCFAs mix. SCFAs mix administration prevented development of tumor and attenuated the colonic inflammation in a mouse model of colitis-associated colorectal cancer. SCFAs mix may be a potential agent in the prevention and treatment of colitis associated colorectal cancer. PMID- 29694939 TI - Peracetylated hydroxytyrosol, a new hydroxytyrosol derivate, attenuates LPS induced inflammatory response in murine peritoneal macrophages via regulation of non-canonical inflammasome, Nrf2/HO1 and JAK/STAT signaling pathways. AB - The present study was designed to investigate the anti-inflammatory effects of a new derivative of hydroxytyrosol (HTy), peracetylated hydroxytyrosol (Per-HTy), compared with its parent, HTy, on lipopolysaccharide (LPS)-stimulated murine macrophages as well as potential signaling pathways involved. In particular, we attempted to characterize the role of the inflammasome underlying Per-HTy possible anti-inflammatory effects. Isolated murine peritoneal macrophages were treated with HTy or its derivative in the presence or absence of LPS (5 MUg/ml) for 18 h. Cell viability was determined using sulforhodamine B (SRB) assay. Nitric oxide (NO) production was analyzed by Griess method. Production of pro inflammatory cytokines was evaluated by enzyme-linked immunosorbent assay (ELISA) and inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2, janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway (STAT3), haem oxigenase 1 (HO1), nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression and mitogen-activated protein kinases (MAPKs) activation was determined by Western blot. Per-HTy significantly reduced the levels of NO and pro-inflammatory cytokines as well as both COX-2 and iNOS expressions. Furthermore, Per-HTy treatment inhibited STAT3 and increased Nrf2 and HO1 protein levels in murine macrophages exposed to LPS. In addition, Per-HTy anti inflammatory activity was related with an inhibition of non-canonical nucleotide binding domain (NOD)-like receptor (NLRP3) inflammasome pathways by decreasing pro-inflammatory interleukin (IL)-1beta and IL-18 cytokine levels as consequence of regulation of cleaved caspase-11 enzyme. These results support that this new HTy derivative may offer a new promising nutraceutical therapeutic strategy in the management of inflammatory-related pathologies. PMID- 29694940 TI - Gene-gene interaction for nonsyndromic cleft lip with or without cleft palate in Chilean case-parent trios. AB - OBJECTIVE: Nonsyndromic cleft lip with or without cleft palate (NSCL/P) is a birth defect for which several genes susceptibility genes been proposed. Consequently, it has been suggested that many of these genes belong to common inter-related pathways during craniofacial development gene-gene interaction. We evaluated the presence of gene-gene interaction for single nucleotide polymorphisms within interferon regulatory factor 6 (IRF6), muscle segment homeobox 1 (MSX1), bone morphogenetic protein 4 (BMP4) and transforming growth factor 3 (TGFB3) genes in NSCL/P risk in Chilean case-parent trios. DESIGN: From previous studies, we retrieved genotypes for 13 polymorphic variants within these four genes in 152 case-parent trios. Using the trio package (R) we evaluate the gene-gen interaction in genetic markers pairs applying a 1 degrees -of-freedom test (1df) and a confirmatory 4 degrees -of-freedom (4df) test for epistasis followed by both a permutation test and a Benjamini-Hochberg test for multiple comparisons adjustment. RESULTS: We found evidence of gene-gene interaction for rs6446693 (MSX1) and rs2268625 (TGFB3) (4df p = 0.024; permutation p = 0.015, Benjamini-Hochberg p = 0.001). CONCLUSIONS: A significant gene-gene interaction was detected for rs6446693 (MSX1) and rs2268625 (TGFB3). This finding is concordant with research in animal models showing that MSX1 and TGFB3 are expressed in common molecular pathways acting in an epistatic manner during maxillofacial development. PMID- 29694941 TI - Knowledge, attitudes, and practices towards epilepsy among general practitioners in rural Bolivia: Results before and after a training program on epilepsy. AB - INTRODUCTION: Epilepsy represents a major health problem in low- and middle income countries where treatment gap (TG) levels are high. The reduction of epilepsy TG in the rural area of the Chaco region, Plurinational State of Bolivia, has been the aim of many projects based on the reinforcement of the primary care setting. To plan educational campaigns directed to the healthcare professionals, it is necessary to establish their baseline knowledge level. The objective of our study was to assess the baseline level of knowledge, attitudes, and practices (KAP) towards epilepsy among general practitioners (GPs) of the rural communities of the Chaco region. METHODS: The study was conducted in three departments of Bolivia. All the GPs living in these areas were invited to participate in the study consisting of two training modules six months apart from each other, each with two-day duration. They answered a validated questionnaire to evaluate the KAP towards epilepsy before and after the courses. RESULTS: Fifty GPs [30 men (60%); mean age: 32.1+/-5.8years] participated in the first training course. After six months, 31 GPs (62%) [19 men (61.3%); mean age: 33+/-5.0years] participated in the second module. Before the training, the majority of GPs declared a low level of satisfaction about their epilepsy knowledge, which improved after the courses. A change in practices was recorded after the training, with an increased confidence to manage antiepileptic treatment. CONCLUSION: Our study showed the significant impact of specific training programs on epilepsy among GPs. PMID- 29694942 TI - Growth and current production of mixed culture anodic biofilms remain unaffected by sub-microscale surface roughness. AB - Bioelectrochemical systems couple electricity demand/supply to the metabolic redox reactions of microorganisms. Generally, electrodes act not only as electron acceptors/donors, but also as physical support for an electroactive biofilm. The microorganism-electrode interface can be modified by changing the chemical and/or topographical features of the electrode surface. Thus far, studies have reported conflicting results on the impact of the electrode surface roughness on the growth and current production of biofilms. Here, the surface roughness of the glassy carbon electrodes was successfully modified at the sub-microscale using micro electrodischarge machining, while preserving the surface chemistry of the parent glassy carbon. All microbial electrodes showed similar startup time, maximum current density, charge transport ability across the biofilm and biomass production. Interestingly, an increase in the average surface cavity depth was observed for the biofilm top layer as a function of the electrode surface roughness (from 7 MUm to 16 MUm for a surface roughness of 5 nm to 682 nm, respectively). These results indicated that the surface roughness at a sub microscale does not significantly impact the attachment or current production of mixed culture anodic biofilms on glassy carbon. Likely earlier observations were associated with changes in surface chemistry, rather than surface topography. PMID- 29694943 TI - Geochemical signature of NORM waste in Brazilian oil and gas industry. AB - The Brazilian Nuclear Energy Agency (CNEN) is responsible for any radioactive waste storage and disposal in the country. The storage of radioactive waste is carried out in the facilities under CNEN regulation and its disposal is operated, managed and controlled by the CNEN. Oil NORM (Naturally Occurring Radioactive Materials) in this article refers to waste coming from oil exploitation. Oil NORM has called much attention during the last decades, mostly because it is not possible to determine its primary source due to the actual absence of a regulatory control mechanism. There is no efficient regulatory tool which allows determining the origin of such NORM wastes even among those facilities under regulatory control. This fact may encourage non-authorized radioactive material transportation, smuggling and terrorism. The aim of this project is to provide a geochemical signature for oil NORM waste using its naturally occurring isotopic composition to identify its origin. The here proposed method is the modeling of radioisotopes normally present in oil pipe contamination such as 228Ac, 214Bi and 214Pb analyzed by gamma spectrometry. The specific activities of elements from different decay series are plotted in a scatter diagram. This method was successfully tested with gamma spectrometry analyses of oil sludge NORM samples from four different sources obtained from Petrobras reports for the Campos Basin/Brazil. PMID- 29694944 TI - Looking for bipolarity in antidepressant discontinuation manic states: Update and diagnostic considerations of the phenomenon. AB - BACKGROUND: Antidepressant withdrawal manic states are intriguing and under recognized phenomena. The associated patho-physiological pathways are ill defined and the inclusion of the phenomena in the bipolar spectrum disorders is questionable. This study aims to update a review on antidepressant discontinuation manic states published in 2008 and to look for hints alluding to bipolar disorder in the affected published cases and in the literature. It also reviews the different hypotheses proposed to explain discontinuation mania. METHODS: We searched Pubmed using the key words: 'antidepressant withdrawal' or 'antidepressant discontinuation' plus 'mania' or 'hypomania' from January 2008 until January 2018. RESULTS: Five new eligible reports were identified since the last review in 2008, involving the antidepressants Amitriptyline, Fluoxetine, Escitalopram and Mirtazapine. Hypotheses involve the implication of Catecholamines, Acetylcholine and Serotonin in the pathophysiology of this paradoxical phenomenon. Careful analysis of the total 29 cases revealed psychiatric histories in favor of a bipolar spectrum disorder in 12 individuals while five were already known to have bipolar disorder. LIMITATIONS: This review is based on case reports with associated recall bias, and lack of in-depth description at times. CONCLUSIONS: Antidepressant discontinuation manic or hypomanic states do not occur randomly. An individual susceptibility to bipolar disorder must be considered. PMID- 29694945 TI - Serum Obestatin: A Biomarker of Cardiovascular and All-Cause Mortality in Hemodialysis Patients. AB - BACKGROUND: Recent experimental studies have suggested that obestatin, a proposed anorexigenic gut hormone and a physiological opponent of acyl-ghrelin, has protective cardiovascular effects. We tested the hypothesis that obestatin is independent of inflammatory mediators and/or acyl-ghrelin in predicting outcomes of the maintenance hemodialysis (MHD) population. METHODS: It was a 6-year cohort study on 261 MHD patients. Obestatin, acyl-ghrelin, adipokines (leptin and adiponectin), markers of inflammation and nutrition, prospective all-cause and cardiovascular mortality were studied. RESULTS: During the follow-up, 160 patients died in total, with 74 deaths due to cardiovascular causes. For each ng/mL increase in baseline obestatin level in fully adjusted models (including malnutrition-inflammation score, Interleukin-6 [IL-6], adipokines and acyl ghrelin), the hazard for death from all causes was 0.90 (95% CI 0.81-0.99) and for cardiovascular death 0.85 (95% CI 0.73-0.99). However, these associations were more robust in the subgroup of patients aged above 71 years: 0.85 (95% CI 0.73-0.98) for all-cause death and 0.66 (95% CI 0.52-0.85) for cardiovascular death. An interaction between high IL-6 (above median) and low obestatin (below median) levels for increased risk of all-cause mortality (synergy index [SI] 5.14, p = 0.001) and cardiovascular mortality (SI 4.81, p = 0.02) emerged in the development of multivariable adjusted models. Interactions were also observed between obestatin, Tumor necrosis factor-alpha, adipokines and acyl-ghrelin, which were associated with mortality risk. CONCLUSION: Serum obestatin behaves as a biomarker for cardiovascular and all-cause mortality in MHD patients. The prognostic ability of obestatin in this regard is independent of inflammation, nutritional status, acyl-ghrelin's and adipokines' activity and is modified by age being very prominent in patients older than 71 years. PMID- 29694946 TI - Is Human Papilloma Virus Associated with Breast Cancer? A Review of the Molecular Evidence. AB - BACKGROUND: Although the association of human papillomavirus (HPV) with many cancers is well established, the involvement of HPV in breast cancer remains controversial. The purpose of this study is to perform a comprehensive review of the results and methods used to demonstrate that HPV markers are present in human breast cancer, and how well these studies fulfil the criteria for proving the viral etiology of a cancer. STUDY DESIGN: We conducted a search for molecular studies published until November 2016 that relate human breast cancer to HPV. RESULTS: Forty-three original molecular studies were found, some of which compared cases to nonneoplastic controls. Some investigations did not identify HPV in mammary tissue, but others identified it with different frequencies of positivity, varying between 1.2 and 86%. In most case-control studies (21/24 studies), positivity in cases was found to be higher than in controls, but odds ratios and confidence intervals were not reported. CONCLUSION: The results are controversial. However, they arouse a great interest in the potential participation of HPV in breast carcinogenesis, but rather as an essential cause effect participant, at least as a co-participant in some cases. The circumstance of HPV positivity in breast cancer can be criticized, but the elements that clearly demonstrate it in a number of cases are also relevant. PMID- 29694947 TI - Amyloidoma of Stomach: A Case Report. AB - OBJECTIVE: Amyloidomas are tumor-like deposits of amyloid. Amyloidoma of the gastrointestinal tract is rare. To the best of our knowledge, this is the first instance of diagnosis of an amyloidoma in the gastrointestinal tract by fine needle aspiration (FNA). STUDY DESIGN: We report a case of a 64-year-old male with a history of ulcerative colitis and primary sclerosing cholangitis who was incidentally found to have a mass in the stomach wall. RESULTS: Initially thought to be gastrointestinal stromal tumor, FNA demonstrated the lesion to be amyloidoma with a prominent giant cell reaction. This was further confirmed by mass spectrometry. This is the only case report of diagnosis of a gastric amyloidoma by FNA. CONCLUSION: The presence of a florid giant cell reaction in the absence of ulceration or an inflammatory or neoplastic lesion should alert the pathologist to the possibility of an amyloidoma. This is the only case report of diagnosis of a gastric amyloidoma by FNA. PMID- 29694948 TI - Baseline High-Sensitivity C-Reactive Protein Predicts Macrovascular and Microvascular Complications of Type 2 Diabetes: A Population-Based Study. AB - BACKGROUND/AIMS: This prospective study is aimed at examining the predictive value of high-sensitivity C-reactive protein (hs-CRP) for coronary heart disease (CHD) events and microvascular complications of type 2 diabetes mellitus (T2DM). METHODS: A population-based study (NCT02958579) was conducted on 1,301 participants with T2DM (mean follow-up of 7.5 years). Risk assessment for vascular events was done at baseline, and serum hs-CRP was measured. End points of this study include CHD events, diabetic retinopathy, neuropathy, and diabetic kidney disease. Individuals with unavailable data or hs-CRP >20 mg/L were excluded. The discrimination and reclassification improvement of study end points were tested after addition of hs-CRP to traditional risk factors. RESULTS: Median serum hs-CRP was 2.00 ranging from 0.1 to 17 mg/L. Hazards ratio of each SD increment in baseline hs-CRP was 1.028 (1.024-1.032) for CHD, 1.025 (1.021-1.029) for diabetic neuropathy, 1.037 (1.030-1.043) for diabetic retinopathy, and 1.035 (1.027-1.043) for diabetic kidney disease. The addition of hs-CRP to traditional risk factors of vascular complications of T2DM improved discrimination of all end points (p < 0.001). Net reclassification improvement ranged from 8% for diabetic neuropathy to 31% for diabetic kidney disease (p < 0.05). CONCLUSION: Baseline hs CRP predicts both of CHD events and microvascular complications of patients with T2D. PMID- 29694949 TI - Overexpression of Annexin A2 Receptor Inhibits Neovascularization via the Promotion of Kruppel-Like Transcription Factor 2. AB - BACKGROUND/AIMS: Annexin A2 receptor (AX2R) can mediate annexin A2 signalling and induce apoptosis in a variety of cells, but its role in neovascularization (NV) remains unclear. Kruppel-like transcription factor 2 (KLF2) is known to be expressed in a range of cell types and to participate in a number of processes during development and disease, such as endothelial homeostasis, vasoregulation and vascular growth/remodelling. The aim of our study was to investigate the role of AX2R in NV and the plausible molecular mechanism. METHODS: We constructed a eukaryotic overexpression plasmid for AX2R (Lenti-AX2R) by using polymerase chain reaction (PCR). The full-length human AX2R gene was transfected into human retinal endothelial cells (HRECs) and human umbilical vein endothelial cells (HUVECs) using lentivirus vectors to overexpress AX2R. All experiments were divided into three groups: control, negative control (Lenti-EGFP), and Lenti AX2R.Cell proliferation, cell migration, tube formation, mouse aortic ring assays and mouse matrigel plug assay were applied to analyse the effect of AX2R in NV. Furthermore, we conducted flow cytometry to evaluate whether AX2R could influence the cell cycle. A series of cell cycle-related proteins including cyclin A1, cyclin B1, cyclin D1, cyclin E1, CDK1, and p-CDC2 were detected by WB. The mRNA and protein levels of KLF2, vascular endothelial growth factor (VEGF) and vascular endothelial growth factor receptor 2 (VEGFR2) were further quantified by RT-PCR and WB to reveal the possible mechanism. RESULTS: Overexpression of AX2R significantly inhibited cell proliferation, migration and tube formation in both types of endothelial cells (ECs), HRECs and HUVECs. It also suppressed vessel sprouting in the mouse aortic ring assay and NV in mouse matrigel plug assay. Furthermore, infection with Lenti-AX2R lentivirus arrested the cell cycle in S/G2 and influenced the expression of a series of cell cycle-related proteins. We also found that the overexpression of AX2R increased the expression of KLF2, mediating VEGF and VEGFR2. CONCLUSIONS: Overexpression of AX2R contributes to the inhibition of NV via suppressing KLF2 ubiquitin-dependent protein degradation, which might therefore be a therapeutic option for NV. It could be considered more broadly as an anti-angiogenic agent in the treatment of neovascular-related diseases in the future. PMID- 29694950 TI - Is Sclerostin Level Associated with Cardiovascular Diseases in Hemodialysis Patients? AB - BACKGROUND/AIMS: The objective of this study is to evaluate the relation between sclerostin, arterial stiffness, and cardiovascular events (CVE) in hemodialysis patients (HD). METHODS: Sclerostin level and carotid-femoral pulse wave velocity (PWV) in 97 HD patients and sclerostin level in 40 controls were measured. RESULTS: Sclerostin level was significantly higher in patients than in controls. Sclerostin associated positively with age, male gender, cardiovascular disease, statin use, BMI, and PWV while negatively with alkaline phosphatase, parathormone (PTH), Kt/V, cinacalcet and vitamin D use in univariable correlation analyses. Sclerostin associated positively with male gender and statin use but negatively with PTH in multivariate regression analyses. During observation, 30 fatal or nonfatal CVEs were observed. While univariate correlation analysis showed a positive association between PWV and sclerostin, there was no relation between the two in multivariate regression analysis. CONCLUSION: Further studies are needed to understand the role of sclerostin in predicting PWV changes in HD patients. PMID- 29694951 TI - Vanishing 17-Hydroxyprogesterone Concentrations in 21-Hydroxylase Deficiency. AB - We present a boy with a genetically proven congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. While massively elevated 17-hydroxyprogesterone (17-OHP) concentrations after birth led to the diagnosis, 17-OHP concentrations became immeasurable starting with the second year of life even though the dose of hydrocortisone was continuously decreased to ~7 mg/m2/day. Furthermore, 17-OHP levels were immeasurable during the ACTH test and after withdrawing hydrocortisone medication. In contrast, ACTH levels increased after cessation of hydrocortisone treatment suggesting complete primary adrenal cortex failure. We discuss this case based on the differential diagnosis of complete adrenal cortex failure including other genetic causes in addition to CAH, prednisolone treatment, autoimmune adrenalitis, adrenoleukodystrophy, CMV infection, and adrenal hemorrhage infarction. The most likely disease in our boy is autoimmune adrenalitis, which is difficult to prove years after the onset of the disease. Treatment of CAH had masked the classical symptoms of complete adrenal cortex insufficiency leading to delayed diagnosis in this case. PMID- 29694952 TI - Dysbiosis in Functional Bowel Disorders. AB - Functional bowel disorders (FBD) resemble a group of diseases of the gastrointestinal (GI) tract that are without a clear pathogenesis; the best known is probably the "irritable bowel syndrome" (IBS). Only recently we have been able to explore the role of the gut microbiota in FBD due to progress in microbiological analytic techniques. There are different ways to explore the role of the gut microbiota and its dysbiosis in FBD. Comparison of the microbial composition in a group of patients with FBD, for example, with IBS to a group of healthy volunteers is one way. Studies have shown that the microbiota in FBD is different from that of healthy controls, but the recorded differences are not necessarily specific for FBD, they may also occur in other diseases. Another approach to explore the role of the gut microbiota in FBD is to challenge the existing "flora" with novel bacteria (probiotics) or with nutritional substrates that stimulate bacterial growth (prebiotics). More than 60 such trials including several thousand patients have been performed in IBS. These studies have produced mixed outcome: some probiotics appear to be better than others, and some appear to work only for a part of the IBS symptoms and not for all. An extreme form of this approach is the transfer of an entire microbiota from 1 healthy person to another, called fecal microbiota transplantation. This has rarely been tested in FBD but is not without risk in benign disorders. PMID- 29694953 TI - Obestatin, a Ghrelin-Cognate Protein, and Clinical Outcomes in Hemodialysis Patients. PMID- 29694954 TI - Remote Monitoring of Automated Peritoneal Dialysis Improves Personalization of Dialytic Prescription and Patient's Independence. AB - BACKGROUND: Remote monitoring (RM) supports a healthcare model that enhances patients' self-management. We evaluated the utility of RM in patients undergoing automated peritoneal dialysis (APD). METHODS: We observed 37 -RM-APD patients, 16 incidents, and 21 prevalents switched from traditional APD (T-APD). We observed the number of changes for APD prescription, the frequency of visits, and PD adequacy parameters during 1 year of RM utilization in APD. RESULTS: The APD prescriptions were modified more frequently in RM-APD vs. T-APD in incident (p = 0.002) and prevalent patients (p = 0.045). Visits were significant less in -RM APD than in T-APD for incident patient (p = 0.008). No significant difference was found between prevalent populations. PD adequacy was similar in both groups. CONCLUSIONS: Our results demonstrate that RM allows an efficient use of healthcare resources, helping to improve personalization of APD prescription and to intervene early with "trouble shooting", thereby reducing the frequency of in person visits for emergency problems. PMID- 29694955 TI - Interim Results of a Phase II Study of Hypofractionated Radiotherapy with Concurrent Temozolomide Followed by Adjuvant Temozolomide in Patients over 70 Years Old with Newly Diagnosed Glioblastoma. AB - OBJECTIVE: In this phase II study, we investigate clinical outcomes and tolerability of hypofractionated radiotherapy (HRT) combined with temozolomide (TMZ) to treat elderly patients with glioblastoma (GBM). METHODS: Patients 70 years of age or older with newly diagnosed GBM received HRT to a dose of 34 Gy given in ten fractions over 2 weeks, delivered with concurrent and adjuvant TMZ. RESULTS: In this interim analysis, ten patients were enrolled on trial from 12/1/2015 to 4/5/2017. With a median follow-up of 9 months (range 3-12 months), median progression-free survival (PFS) was 6 months. The median overall survival (OS) has not been reached. Estimated 1-year OS and PFS rates were 53.3 and 44.4%, respectively. All patients completed the full course of RT, with no patients developing grade 3 or higher adverse events from treatment. CONCLUSIONS: The preliminary results of our phase II trial suggest HRT delivered over 2 weeks with concurrent and adjuvant TMZ is well tolerated in elderly patients with GBM without compromising clinical outcomes. PMID- 29694956 TI - Multiples of Median-Transformed, Normalized Reference Ranges of Steroid Profiling Data Independent of Age, Sex, and Units. AB - BACKGROUND/AIMS: The high complexity of pediatric reference ranges across age, sex, and units impairs clinical application and comparability of steroid hormone data, e.g., in congenital adrenal hyperplasia (CAH). We developed a multiples-of median (MoM) normalization tool to overcome this major drawback in pediatric endocrinology. METHODS: Liquid chromatography tandem mass spectrometry data comprising 10 steroid hormones representing 905 controls (555 males, 350 females, 0 to > 16 years) from 2 previous datasets were MoM transformed across age and sex. Twenty-three genetically proven CAH patients were included (21-hydroxylase deficiency [21OHD], n = 19; 11beta-hydroxylase deficiency [11OHD], n = 4). MoM cutoffs for single steroids predicting 21OHD and 11OHD were computed and validated through new, independent patients (21OHD, n = 8; adrenal cortical carcinoma, n = 6; obesity, n = 40). RESULTS: 21OHD and 11OHD patients showed disease-typical, easily recognizable MoM patterns independent of age, sex, and concentration units. Two single-steroid cutoffs indicated 21OHD: 3.87 MoM for 17 hydroxyprogesterone (100% sensitivity and 98.83% specificity) and 12.28 MoM for 21-deoxycortisol (94.74% sensitivity and 100% specificity). A cutoff of 13.18 MoM for 11-deoxycortisol indicated 11OHD (100% sensitivity and 100% specificity). CONCLUSIONS: Age- and sex-independent MoMs are straightforward for a clinically relevant display of multi-steroid patterns. In addition, defined single-steroid MoMs can serve alone as predictors of 21OHD and 11OHD. Finally, MoM transformation offers substantial enhancement of routine and scientific steroid hormone data exchange due to improved comparability. PMID- 29694957 TI - Reliability of Vessel Density Measurements in the Peripapillary Retina and Correlation with Retinal Nerve Fiber Layer Thickness in Healthy Subjects Using Optical Coherence Tomography Angiography. AB - PURPOSE: To evaluate the reliability of vessel density measurements in the peripapillary retina using optical coherence tomography angiography (OCT-A) and to analyze the correlation with retinal nerve fiber layer (RNFL) thickness in healthy subjects. METHOD: Thirty-five healthy volunteers were recruited in the study. The optic disc region was scanned three times with spectral-domain OCT (SD OCT) and split-spectrum amplitude decorrelation angiography by two skilled examiners. Vessel density of the peripapillary retina was automatically calculated by the software RTVue-XR (version 2015.1.1.98). The RNFL thickness on the optic nerve head was measured by SD-OCT. The coefficient of variation (CV), coefficient of repeatability, and intraclass correlation coefficients (ICC) were calculated for intraobserver repeatability. The Bland-Altman analysis was used to determine interobserver reproducibility. Correlations between peripapillary retinal vessel density and RNFL thickness were analyzed using a multivariable linear regression. RESULTS: The mean age of the volunteers was 47.0 +/- 29.7 years. The intraobserver repeatability in different sectors of the peripapillary retina was good with a high coefficient of repeatability, low CV (< 0.2%), and high ICC (0.847-0.952). The interobserver reproducibility was also good in different sectors, but should be interpreted with caution due to the difference bias caused by different observers in some quadrants. There was a significant positive correlation between vessel density and RNFL thickness; optic disc rim area and disc area were negatively related to vessel density (p = 0.008 and p = 0.001, respectively). CONCLUSION: Vessel density measurements showed good repeatability and reproducibility by OCT-A in the peripapillary retina, the vessel density was positively related to RNFL thickness and negatively related to optic disc area and rim area. PMID- 29694958 TI - Current Mechanistic Concepts in Ischemia and Reperfusion Injury. AB - Ischemia-reperfusion injury is associated with serious clinical manifestations, including myocardial hibernation, acute heart failure, cerebral dysfunction, gastrointestinal dysfunction, systemic inflammatory response syndrome, and multiple organ dysfunction syndrome. Ischemia-reperfusion injury is a critical medical condition that poses an important therapeutic challenge for physicians. In this review article, we present recent advances focusing on the basic pathophysiology of ischemia-reperfusion injury, especially the involvement of reactive oxygen species and cell death pathways. The involvement of the NADPH oxidase system, nitric oxide synthase system, and xanthine oxidase system are also described. When the blood supply is re-established after prolonged ischemia, local inflammation and ROS production increase, leading to secondary injury. Cell damage induced by prolonged ischemia-reperfusion injury may lead to apoptosis, autophagy, necrosis, and necroptosis. We highlight the latest mechanistic insights into reperfusion-injury-induced cell death via these different processes. The interlinked signaling pathways of cell death could offer new targets for therapeutic approaches. Treatment approaches for ischemia-reperfusion injury are also reviewed. We believe that understanding the pathophysiology ischemia-reperfusion injury will enable the development of novel treatment interventions. PMID- 29694959 TI - Prognostic Impact of DNA Repair Protein Expression in Non-Small Cell Lung Cancers Treated with Platinum-Based Chemotherapy and Subsequent Curative Lung Resection. AB - OBJECTIVE: Multimodal treatments that include preoperative platinum-based chemotherapy are fundamental to the treatment of advanced non-small cell lung cancer (NSCLC). This study aimed to investigate the predictive value of DNA repair protein expression in surgically resected NSCLCs in terms of prognosis and responses to platinum-containing chemotherapy. METHODS: This retrospective study included 136 patients with NSCLC who were treated with preoperative platinum based chemotherapy, followed by curative lung resection. ATM, RAD51, LKB1, H2AX, and SIRT1 expression levels were analyzed in resected tumor specimens via immunostaining and were used to classify patients and compare survival and responses to chemotherapy. RESULTS: SIRT1 expression correlated significantly with improved responses to platinum-based chemotherapy (odds ratio, 2.28; p = 0.024), progression-free survival (hazard ratio [HR], 0.74; p = 0.036), overall survival (HR, 0.63; p = 0.006), and tumor-bearing survival (HR, 0.62; p = 0.014). After adjusting for clinical variables, the HR of SIRT1 expression remained significant for overall survival (HR, 0.59; p = 0.039) but not for progression free survival (HR, 0.74; p = 0.183). No prognostic stratification was observed for the other 4 markers. CONCLUSION: Patients with SIRT1-expressing NSCLC had superior responses to chemotherapy and longer survival durations than those with SIRT1-negative cancer. PMID- 29694961 TI - Autophagy: A Role in the Apoptosis, Survival, Inflammation, and Development of the Retina. AB - Autophagy is a lysosomal degradation process that maintains cellular homeostasis by removing dysfunctional organelles and unfolded proteins. Increasing evidence has shown that autophagy proteins are involved in retinal physiology and pathology and that defective autophagy contributes to retinal degeneration. In retinal diseases, autophagy plays a dual role: promoting retinal cell survival and death. Autophagy at a normal level helps retinal cells defend themselves against harmful stress; however, excessive autophagy results in retinal deterioration. Both synergistic and antagonistic roles of autophagy and apoptosis in the retina have been reported in the literature. In this review, we summarize the roles of autophagy in the development of the retina and retinal diseases. This review highlights the importance of autophagy in retinal diseases, and targeting autophagy may provide a new therapeutic approach for retinal diseases. PMID- 29694960 TI - Kynurenine Pathway in Autism Spectrum Disorders in Children. AB - BACKGROUND: There is increasing evidence that altered immune responses play a role in the pathogenesis of autism spectrum disorders (ASD), together with dysfunction of the serotonergic and glutamatergic systems. Since the kynurenine (KYN) pathway that degrades tryptophan (TRP) is activated in various neuroinflammatory states, we aimed to determine whether this pathway is activated in ASD. METHODS: Sixty-five pediatric ASD patients (including 52 boys) were enrolled from an epidemiological survey covering 2 counties in Norway; 30 (46.5%) of these patients were diagnosed with childhood autism, 16 (24.6%) with Asperger syndrome, 12 (18.5%) with atypical autism, 1 (1.5%) with Rett syndrome, and 6 (9.2%) with other ASD. The serum levels of the following markers were measured in the children with ASD and compared to those in 30 healthy children: TRP, KYN, kynurenic acid (KA), 3-hydroxykynurenine, and quinolinic acid. RESULTS: The mean serum level of KA was significantly lower in the ASD group than in the healthy controls (28.97 vs. 34.44 nM, p = 0.040), while the KYN/KA ratio was significantly higher in the ASD group (61.12 vs. 50.39, p = 0.006). The same relative values were found when comparing the childhood autism subgroup with the controls. Also, the mean serum level of TRP was significantly lower in children with a subdiagnosis of childhood autism than in those with Asperger syndrome (67.26 vs. 77.79 MUM, p = 0.020). CONCLUSION: Our study indicates that there is an increased neurotoxic potential and also a possible lower KYN aminotransferase activity in ASD. PMID- 29694962 TI - Premature Mortality Due to Malignancies of the Central Nervous System in Canada, 1980-2010. AB - BACKGROUND: In this study, we investigated whether there has been an improvement in premature mortality due to central nervous system (CNS) cancers among the Canadian population from 1980 through 2010. METHODS: Mortality data for CNS cancers were obtained from World Health Organization mortality database. Years of life lost (YLL) was estimated using Canadian life tables. Average lifespan shortened (ALSS) was calculated and defined as the ratio of YLL relative to the expected lifespan. RESULTS: Over this study period, we observed decreases in age standardized rates to the World Standard Population for mortality due to CNS cancers from 5.3 to 4.1 per 100,000 men, and from 3.6 to 2.9 per 100,000 women. Average YLL decreased from 23.6 to 21.5 years of life among men, and from 27.0 to 23.1 years among women in 1980 and 2010, respectively. The ALSS showed that men with CNS cancers lost 30.1% of their life span and women lost 32.5% in 1980, whereas they lost 25.8 and 26.6% in 2010, respectively. CONCLUSION: Our study shows that -Canadian people with CNS cancers have had their lives prolonged at the end of the study period. PMID- 29694963 TI - Treatment of Macular Degeneration with Sildenafil: Results of a Two-Year Trial. AB - OBJECTIVE: To evaluate PDE5/6 inhibition with sildenafil to reduce choroidal ischemia and treat age-related macular degeneration. METHODS: Sildenafil was prescribed to treat participants with macular degenerations or macular dystrophies measured by spectral-domain optical coherence tomography, color fundus photography, enhanced depth imaging, and best-corrected visual acuity. RESULTS: No change in calcified drusen was noted. Vitelliform-type soft drusen were not substantially changed. A participant with Best vitelliform macular dystrophy had a significant improvement in vision as well as in photoreceptor and ellipsoid layers. CONCLUSIONS: Our research supports sildenafil as a safe treatment for age-related and vitelliform macular degenerations. Thickened Bruch's membrane reduces the beneficial effect of perfusion increase, but all eyes appear to benefit from PDE6. Notably, maintenance or improvement in the photoreceptor layer may be the most significant result of sildenafil and is consistent with PDE6 inhibition. Thus, sil-denafil treatment of macular degeneration offers significant potential for vision retention and recovery. PMID- 29694965 TI - Low Expression of LncRNA Cancer Susceptibility Candidate 2 and its Clinical Significance in Cancer Tissues. AB - BACKGROUND/AIMS: Long noncoding RNA (lncRNA) cancer susceptibility candidate 2 (CASC2) is downregulated in various cancers and involved in both tumorigenesis and progression. The aim of this study was to assess the prognostic value of lncRNA CASC2 in cancer patients. METHODS: We searched the Web of Science, PubMed, EMBASE, China National Knowledge Infrastructure (CNKI), and the Wanfang database to identify studies evaluating the prognostic value of lncRNA CASC2 in cancer patients. Pooled hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals (CIs) were calculated using fixed-effects/random-effects models. RESULTS: A total of eight studies were included. The combined results showed that lncRNA CASC2 was significantly associated with decreased overall survival (OS) (HR = 0.37, 95% CI, 0.27-0.46, P < 0.001). Subgroup analyses further indicated that low expression of lncRNA CASC2 predicted decreased OS in cancer patients. Additionally, low CASC2 expression levels in cancer tissues appeared to be correlated with advanced clinical staging (OR = 3.32, 95% CI, 2.29-4.80, P < 0.001). CONCLUSIONS: Low CASC2 expression appears to be predictive of poor OS and advanced tumor stage in multiple cancers. CASC2 expression may serve as unfavorable prognostic factor for clinical outcomes in cancer patients. PMID- 29694964 TI - Associations of Pulse and Blood Pressure with Hippocampal Volume by APOE and Cognitive Phenotype: The Alzheimer's Disease Neuroimaging Initiative (ADNI). AB - BACKGROUND: It is increasingly evident that high blood pressure can promote reduction in global and regional brain volumes. While these effects may preferentially affect the hippocampus, reports are inconsistent. METHODS: Using data from the Alzheimer's Disease Neuroimaging Initiative (ADNI), we examined the relationships of hippocampal volume to pulse pressure (PPR) and systolic (SBP) and diastolic (DBP) blood pressure according to apolipoprotein (APOE) E4 positivity and cognitive status. The ADNI data included 1,308 participants: Alzheimer disease (AD = 237), late mild cognitive impairment (LMCI = 454), early mild cognitive impairment (EMCI = 254), and cognitively normal (CN = 365), with up to 24 months of follow-up. RESULTS: Higher quartiles of PPR were significantly associated with lower hippocampal volumes (Q1 vs. Q4, p = 0.034) in the CN and AD groups, but with increasing hippocampal volume (Q1, p = 0.008; Q2, p = 0.020; Q3, p = 0.017; Q4 = reference) in the MCI groups. In adjusted stratified analyses among non-APOE E4 carriers, the effects in the CN (Q1 vs. Q4, p = 0.006) and EMCI groups (Q1, p = 0.002; Q2, p = 0.013; Q3, p = 0.002; Q4 = reference) remained statistically significant. Also, higher DBP was significantly associated with higher hippocampal volume (p = 0.002) while higher SBP was significantly associated with decreasing hippocampal volume in the EMCI group (p = 0.015). CONCLUSION: Changes in PPR, SBP, and DBP differentially influenced hippocampal volumes depending on the cognitive and APOE genotypic categories. PMID- 29694966 TI - Gastric Adenocarcinomas in Central Tunisia: Evolution Specificities through Two Decades and Relation with Helicobacter pylori. AB - INTRODUCTION: In developed countries, authors have reported variations over time in the seat and histological type of gastric adenocarcinomas, which were explained by Helicobacter pylori infection (HPI) incidence changes. In North African countries and the Arabic world, epidemiological changes in gastric adenocarcinomas are still unknown. Our study aims to explore and to describe those changes in central Tunisia. MATERIALS AND METHODS: This is a retrospective observational and descriptive study including 876 cases based on the National Central Tunisian Register of Cancers over a period of 21 years. Two groups were formed and compared (group A: 337 patients from 1995 to 2005; group B: 539 patients from 2006 to 2015). RESULTS: HPI decreased from 32.6% in group A to 11.2% in group B (p < 0.05). Signet ring cell carcinomas increased in 2 decades from 14% in group A to 36% in group B (p < 0.05). Proximal cancers were 16.61% in group A and increased to 19.66% in group B (p = 0.3). Total gastrectomy rate was 10.4% in group A versus 23.2% in group B (p < 0.05). CONCLUSION: This study has shown a significant increase of signet ring cell carcinomas with a simultaneous decrease in HPI in the last decade in central Tunisia. PMID- 29694967 TI - Underlying Signaling Pathways and Therapeutic Applications of Pulsed Electromagnetic Fields in Bone Repair. AB - Pulsed electromagnetic field (PEMF) stimulation, as a prospective, noninvasive, and safe physical therapy strategy to accelerate bone repair has received tremendous attention in recent decades. Physical PEMF stimulation initiates the signaling cascades, which effectively promote osteogenesis and angiogenesis in an orchestrated spatiotemporal manner and ultimately enhance the self-repair capability of bone tissues. Considerable research progresses have been made in exploring the underlying cellular and subcellular mechanisms of PEMF promotion effect in bone repair. Moreover, the promotion effect has shown strikingly positive benefits in the treatment of various skeletal diseases. However, many preclinical and clinical efficacy evaluation studies are still needed to make PEMFs more effective and extensive in clinical application. In this review, we briefly introduce the basic knowledge of PEMFs on bone repair, systematically elaborate several key signaling pathways involved in PEMFs-induced bone repair, and then discuss the therapeutic applications of PEMFs alone or in combination with other available therapies in bone repair, and evaluate the treatment effect by analyzing and summarizing recent literature. PMID- 29694968 TI - A Rare Cause of Juvenile Stroke: Extracranial Carotid Artery Aneurysm with Venous Complete Reconstruction of the Carotid Bifurcation. AB - Extracranial carotid artery aneurysms (ECAA) are a rare cause of embolic stroke. The underlying etiology is variable, with atherosclerosis being the most common entity in older subjects. Several treatments have been developed over the last 20 years, but the preferred method remains unknown. Notwithstanding the widespread use of endovascular techniques, surgical reconstruction by means of a bifurcated venous bypass graft should be applied in younger patients. In this way, it is possible to avoid major concerns about the development of long-term intrastent restenosis, and also to spare the external carotid artery which represents the main branch for the ipsilateral cerebral and facial perfusion. We propose ECAA resection and interposition of the inverted great saphenous vein to both the internal and external carotid artery by means the use of a tributary, i.e., the Giacomini vein. PMID- 29694969 TI - Clinical Features of Hereditary Angioedema in Korean Patients: A Nationwide Multicenter Study. AB - BACKGROUND: Hereditary angioedema (HAE) is a genetically heterogeneous autosomal dominant disorder characterized by recurrent episodes of nonpruritic, nonpitting edema increasing after puberty. It can be fatal due to laryngeal or gastrointestinal (GI) involvement with varied and changing frequency of mortality according to studies published from the Western countries. Epidemiological and clinical data of HAE in Asian countries are sparse. We sought to examine the clinical characteristics of HAE patients in Korea. METHODS: Patients diagnosed with HAE at 15 tertiary hospitals across the country until 2016 were retrospectively reviewed. RESULTS: A total of 65 patients diagnosed with HAE by 2016 were identified. The prevalence of HAE was estimated at 1.3/1,000,000 in Korea. Of the 65 patients, 21 (32.3%) were males. A total of 90.8% patients had type I HAE, while the remaining 9.2% patients had type II HAE. The first symptom developed after 20 years in 73.8% of patients, with a mean age 28.4 +/- 14.1 years. The age at diagnosis was 36.5 +/- 15.8 years, with a mean time delay of 7.8 +/- 10.5 years. While the face (82.3%) and extremities (upper 71.0%, lower 62.9%) were the most frequently involved, the GI tract was affected in 40.5% of Korean HAE patients. Prophylaxis was maintained in 62.5% of patients. There was no reported case of death from HAE so far. CONCLUSIONS: The clinical manifestation and severity of HAE may vary according to ethnicity. HAE is more infrequent and GI involvement is less likely in Korea compared with Western countries. PMID- 29694970 TI - Repetitive Negative Thinking and Its Role in Perinatal Mental Health. AB - BACKGROUND: There is evidence that anxiety is common, perhaps even more prevalent than depression, in the post-partum period. In this review we propose adopting a transdiagnostic approach to perinatal mental health: to delineate psychopathology and identify potential underlying cognitive mechanisms such as repetitive negative thinking (RNT). SAMPLING AND METHODS: We provide an overview of key studies of RNT in perinatal mental health and suggest directions for future work. We propose the value of examining post-partum depression and anxiety, and their co-occurrence, and of testing whether the psychological mechanisms that predict and maintain depression and anxiety also play a role in these conditions in the post-partum period. Further, given that psychological distress often first emerges in the antenatal phase, we make a case for investigating RNT across the perinatal period - i.e., in antenatal and postnatal women. RESULTS AND CONCLUSIONS: RNT may be a modifiable risk factor which can be targeted in pregnancy to prevent depression and anxiety in new mothers. PMID- 29694971 TI - Scores Obtained from a Simple Cognitive Test of Visuospatial Episodic Memory Performed Decades before Death Are Associated with the Ultimate Presence of Alzheimer Disease Pathology. AB - BACKGROUND: Community- or population-based longitudinal studies of cognitive ability with a brain donation end point offer an opportunity to examine relationships between pathology and cognitive state prior to death. Discriminating the earliest signs of dementing disorders, such as Alzheimer disease (AD), is necessary to undertake early interventions and treatments. METHODS: The neuropathological profile of brains donated from The University of Manchester Longitudinal Study of Cognition in Normal Healthy Old Age, including CERAD (Consortium to Establish a Registry for Alzheimer's Disease) and Braak stage, was assessed by immunohistochemistry. Cognitive test scores collected 20 years prior to death were correlated with the extent of AD pathology present at death. RESULTS: Baseline scores from the Memory Circle test had the ability to distinguish between individuals who developed substantial AD pathology and those with no, or low, AD pathology. Predicted test scores at the age of 65 years also discriminated between these pathology groups. The addition of APOE genotype further improved the discriminatory ability of the model. CONCLUSIONS: The results raise the possibility of identifying individuals at future risk of the neuropathological changes associated with AD over 20 years before death using a simple cognitive test. This work may facilitate early interventions, therapeutics and treatments for AD by identifying at-risk and minimally affected (in pathological terms) individuals. PMID- 29694973 TI - Sustained Erythroid Response in a Patient with Myelofibrosis Receiving Concomitant Treatment with Ruxolitinib and Deferasirox. AB - Iron overload (IOL) due to transfusion-dependent anemia is a serious adverse effect in patients with myelofibrosis (MF). Recent studies have shown that the oral iron chelator deferasirox may prevent multiple organ damage due to IOL in MF. However, it is not clear whether deferasirox may contribute to revert transfusion-dependent anemia. Here, we present a patient with transfusion dependent intermediate-2 MF according to the International Prognostic Scoring System treated with ruxolitinib in combination with deferasirox. In addition to a reduced serum ferritin level, the patient required less blood transfusions, ultimately resulting in long-lasting transfusion-free survival. PMID- 29694972 TI - Quality of Life in People with Young-Onset Alzheimer's Dementia and Frontotemporal Dementia. AB - AIMS: The aims of this study were to compare quality of life (QOL) in people with young-onset Alzheimer's (AD) and frontotemporal (FTD) dementia, explore variables associated with QOL, and compare QOL in young-onset dementia (YOD) and late-onset dementia (LOD). METHODS: Cross-sectional data from a Nordic multicenter study of 50 community-dwelling participants with AD and 38 with FTD were included. A comparison group consisted of 100 people with LOD. QOL was measured using self reported Euro-QOL 5-Dimension and the proxy version of Quality of Life in Alzheimer's Disease (QOL-AD) questionnaire. Neuropsychiatric symptoms and needs were assessed using the Cornell Scale for Depression in Dementia (CSDD), Neuropsychiatric Inventory (NPI), and Camberwell Assessment of Needs in the Elderly. Multiple linear regression and multilevel modeling was used to determine variables associated with QOL. RESULTS: We found no differences between the two YOD groups in QOL. The variables associated with QOL were scores on the CSDD, NPI, and unmet needs. The proxy QOL-AD score in YOD was significantly higher compared to LOD (median 36.0 [IQR 10.0] vs. 33.0 [IQR 9.0]). CONCLUSION: The QOL in Nordic people with YOD was better compared to people with LOD. Our results show depressive symptoms to be associated with QOL irrespective of age and diagnosis. PMID- 29694974 TI - IL-33 and Its Receptor ST2 after Inhaled Allergen Challenge in Allergic Asthmatics. AB - BACKGROUND: Previous murine models have demonstrated interleukin (IL)-33 to be an important mediator of type-2 inflammation and to promote airway hyperresponsiveness in allergic asthma. A number of inflammatory cells produce IL 33 and eosinophils express ST2 mRNA. The relationship between IL-33 and eosinophils in allergic asthma, however, remains unclear. OBJECTIVE: The aim of this work was to evaluate in vitro the effect of allergen inhalation on IL-33 levels and expression of its receptor (ST2L) on eosinophils in allergic asthmatics, and the effect of IL-33 stimulation on eosinophil activity. METHODS: Plasma and sputum IL-33, soluble ST2 (sST2) levels, and ST2L expression on eosinophils were measured in 10 healthy controls and 10 allergic asthmatics. Asthmatics underwent allergen and diluent inhalation challenges. Blood and sputum samples were collected to measure IL-33, sST2, and ST2L eosinophil expression before and 24 h after allergen inhalation. Purified blood eosinophils from allergic asthmatics were incubated overnight with IL-33 to assess ST2 and intracellular IL-5 expression. RESULTS: Baseline levels of IL-33 in sputum and sST2 in plasma and sputum were similar in allergic asthmatics compared to healthy controls. In addition, there was no difference in blood or sputum eosinophil ST2L expression in healthy controls versus allergic asthmatics. Eosinophil ST2L expression was significantly increased 24 h postallergen inhalation in allergic asthmatics. In vitro stimulation of human eosinophils with IL-33 and LPS significantly increased eosinophil ST2L expression and IL-33 stimulation increased intracellular IL-5 expression, which was attenuated by treatment with sST2 and ST2 blockade. CONCLUSION AND CLINICAL RELEVANCE: In mild asthmatics, there was a significant upregulation of ST2 surface expression on eosinophils from blood and sputum following allergen inhalation challenge. In vitro, IL-33 stimulation of eosinophils increases both ST2 membrane expression and IL-5 production. These results support a role for IL-33 in causing allergen-induced eosinophilia. Blockade of IL-33 and ST2 signaling may present a novel therapeutic avenue for asthma treatment. PMID- 29694975 TI - Draft Genome Sequence of Bacillus cereus CITVM-11.1, a Strain Exhibiting Interesting Antifungal Activities. AB - Bacillus cereus is a gram-positive, spore-forming bacterium possessing an important and historical record as a human-pathogenic bacterium. However, several strains of this species exhibit interesting potential to be used as plant growth promoting rhizobacteria. Here, we report the draft genome sequence of B. cereus strain CITVM-11.1, which consists of 37 contig sequences, accounting for 5,746,486 bp (with a GC content of 34.8%) and 5,752 predicted protein-coding sequences. Several of them could potentially be involved in plant-bacterium interactions and may contribute to the strong antagonistic activity shown by this strain against the charcoal root rot fungus, Macrophomina phaseolina. This genomic sequence also showed a number of genes that may confer this strain resistance against several polluting heavy metals and for the bioconversion of mycotoxins. PMID- 29694976 TI - Studying Effects and Process in Psychotherapy for Personality Disorders. AB - This presentation gives an overview of the methods used for research on the process and outcome of psychotherapy. Possibilities as well as difficulties will be discussed, such as the conflict between internal and external validity and standardized versus individualized procedures as some of the issues deserving particular attention for research on psychotherapy for personality disorder patients. It is argued that good psychotherapy research is also good psychotherapy research for personality disorders, with heterogeneity, ego syntony, and ambivalent motivation needing special attention. Adaptations of and alternatives for randomized clinical trials will be discussed. PMID- 29694977 TI - Mitochondrial Perturbation Contributing to Cognitive Decline in Streptozotocin Induced Type 1 Diabetic Rats. AB - BACKGROUND/AIMS: Mitochondrial perturbation is a well-established cause of cognitive decline, but as yet it is unclear how mitochondria-associated neuronal abnormalities in type 1 diabetic (T1DM) brain contribute to cognitive decline. METHODS: The streptozotocin (STZ)-induced mouse model of T1DM was used. The Morris water maze test was applied to assess the effect of T1DM on learning and memory. We detected changes in mitochondrial morphology, function and dynamics. Furthermore, we employed metabolomic analysis to reveal the underlying mechanisms of mitochondrial perturbation which contribute to cognitive decline. RESULTS: Our results show that T1DM impairs mitochondrial dynamics, morphology and function in neurons, associated with a decline in cognitive ability. Metabolomic analyses revealed that T1DM mainly affects metabolic pathways involved in mitochondrial energy failure and impairs the antioxidative system. CONCLUSION: These results lay the basis for understanding the underlying mitochondria-associated causes of T1DM-associated cognitive decline and may provide a potential treatment strategy for this condition in future. PMID- 29694978 TI - Caries and Periodontitis: Contesting the Conventional Wisdom on Their Aetiology. AB - We review the literature on the oral microbiome and the role of the microbiota in the development of dental caries and periodontitis. While most research has been focused on identifying one or more specific determinants of these diseases, the results have provided limited predictive value and have not been able to explain the variation in the distribution of these diseases observed in epidemiological or clinical studies. Drawing on existing knowledge about the nature of the oral microbiota, we suggest that a stochastic model based on the Weiner process provides simple and parsimonious explanations for the pathogenesis of both caries and periodontitis, making few assumptions, and providing explanations for phenomena that have hitherto proved difficult, or have required complex arguments, to explain. These diseases occur as the result of the dental hard tissues and periodontal tissues integrating the random "noise" caused by normal metabolic activities of commensal microorganisms in the dental biofilm. The processes that result in the progression and regression of caries and periodontitis may be considered as "natural," rather than pathological, even if, when left unchecked over long periods of time, they can result in the development of pathologies. The likelihood of progression or regression can be influenced by other determinants, but these processes will nevertheless occur in the absence of such influences. The distributional characteristics of the model approximate the findings of epidemiological studies indicating that, for both caries and periodontitis, there will be few sites affected in the early period after the eruption of the permanent dentition, but in those older there is an almost linear relationship with increasing age; furthermore, the longer a site survives without being affected, the less likely that it will be affected. We discuss the clinical and public health importance of these findings. PMID- 29694979 TI - Promotion of Tumor Growth by ADAMTS4 in Colorectal Cancer: Focused on Macrophages. AB - BACKGROUND/AIMS: ADAMTSs (A disintegrin and metalloprotease domains with thrombospondins motifs) are a family of extracellular proteases that have been related to both oncogenic and tumor-suppressive functions. The aim of the present study was to investigate: 1) the mutation, copy-number alterations, and expression profile of ADAMTSs in colorectal cancer and 2) whether ADAMTSs participate in colorectal cancer (CRC) progression and invasion. METHODS: The mutation, copy-number alterations, and expression profile of ADAMTSs in CRC were analyzed in the TCGA cohort using cBioportal. ADAMTS4 expression in tumor tissues and cell lines were determined by immunostaining and real-time quantitative PCR. The role of ADAMTS-4 in CRC progression and the underlying mechanisms were studied by using short hairpin RNA-mediated knockdown of ADAMTS4. The effects of ADAMTS4 in cell proliferation and invasion were determined by clone formation assay and transwell migration assay, respectively. Macrophages were depleted by liposomal clodronate in immune-competent BALB/c mice and tumor growth was analyzed. RESULTS: ADAMTS4 was differentially expressed in CRC and predicted a poor prognosis. Elevated ADAMTS4 expression was closely associated with larger tumor size, enhanced TNM stage, and a poor clinical outcome in patients with CRC. ADAMTS4 knockdown had no inhibitory implications on cell proliferation and invasion in vitro, but significantly attenuated tumor growth in vivo. Mechanistically, we revealed that ADAMTS4 was associated macrophages infiltration and polarization in the tumor microenvironment of CRC. Macrophage depletion largely abolished the promotive effect of ADAMTS4 on tumor growth in the immune competent BALB/c mice. CONCLUSION: ADAMTS4 seemed to be a promising prognostic indicator in CRC. The novel link between ADAMTS4 and macrophages mirrors the potential regulatory roles of ADAMTSs in the inflammatory microenvironment of cancers. PMID- 29694981 TI - CircRNA-Cdr1as Exerts Anti-Oncogenic Functions in Bladder Cancer by Sponging MicroRNA-135a. AB - BACKGROUND/AIMS: CircRNAs regulate gene expression in different malignancies. However, the role of Cdr1as in the tumourigenesis of bladder cancer and its potential mechanisms remain unknown. METHODS: qRT-PCR was used to detect Cdr1as and target miRNA expression in bladder cancer tissues and cell lines. Biological functional experiments were performed to detect the effects of Cdr1as on the biological behaviour of bladder cancer cells in vivo and in vitro. Bioinformatic analysis was utilised to predict potential miRNA target sites on Cdr1as. Ago2 RNA binding protein immunoprecipitation assay, RNA antisense purification assay, biotin pull down assay and RNA FISH were performed to detect the interaction between Cdr1as and target miRNAs. Western blot was used to determine the expression level of p21 in bladder cancer cells. RESULTS: Cdr1as was significantly down-regulated in bladder cancer tissues compared with adjacent normal tissues. Overexpression of Cdr1as inhibited the proliferation, invasion and migration of bladder cancer cells in vitro and slowed down tumour growth in vivo. Cdr1as sponged multiple miRNAs in bladder cancer. Moreover, Cdr1as directly bound to miR-135a and inhibited its activity in bladder cancer. CONCLUSION: Cdr1as is down-regulated and sponges multiple miRNAs in bladder cancer. It exerts anti-oncogenic functions by sponging microRNA-135a. PMID- 29694980 TI - A Twelve-Week Moderate Exercise Programme Improved Symptoms of Depression, Insomnia, and Verbal Learning in Post-Aneurysmal Subarachnoid Haemorrhage Patients: A Comparison with Meningioma Patients and Healthy Controls. AB - OBJECTIVES: Deficits in psychological functioning, cognitive functioning, and sleep are frequently experienced by individuals who have survived aneurysmal subarachnoid haemorrhage (aSAH). Exercise has been shown to improve these domains; to date, it has never been explored in patients following aSAH. The aim of this exploratory study is to compare the effects of an exercise programme in this population with another patient group, and a group of healthy controls. METHODS: The present study explored the effects of 12 weeks of moderate aerobic exercise training on 15 aSAH patients, 16 meningioma patients, and 17 healthy controls. Data on symptoms of depression, hypochondria, perceived stress, satisfaction with life, verbal learning and memory, and subjective and objective sleep, were gathered at baseline, following intervention, and at 6-month follow up. RESULTS: aSAH patients and meningioma patients had decreased symptoms of depression and insomnia at follow-up. While perceived stress decreased in the meningioma group, in aSAH patients it increased. Total learning performance increased in all three groups. CONCLUSIONS: An exercise programme had a positive effect on symptoms of depression, insomnia, and verbal learning in patients following aSAH. No positive changes in other domains were observed. This may be due to the cautious approach taken with regard to exercise intensity. PMID- 29694982 TI - UCP3 Ablation Exacerbates High-Salt Induced Cardiac Hypertrophy and Cardiac Dysfunction. AB - BACKGROUND/AIMS: Excessive salt intake and left ventricular hypertrophy (LVH) are both critical for the development of hypertension and heart failure. The uncoupling protein 3 (UCP3) plays a cardio-protective role in early heart failure development. However, the potential role for UCP3 in salt intake and LVH is unclear. METHODS: UCP3-/- and C57BL/6 mice were placed on either a normal-salt (NS, 0.5%) or a high-salt (HS, 8%) diet for 24 weeks. The cardiac function, endurance capacity, energy expenditure, and mitochondrial functional capacity were measured in each group. RESULTS: Elevated blood pressure was only observed in HS-fed UCP3-/- mice. High salt induced cardiac hypertrophy and dysfunction were observed in both C57BL/6 and UCP3-/- mice. However, the cardiac lesions were more profound in HS-fed UCP3-/- mice. Furthermore, HS-fed UCP3-/-mice experienced more severe mitochondrial respiratory dysfunction compared with HS-fed C57BL/6 mice, represented by the decreased volume of oxygen consumption and heat production at the whole-body level. CONCLUSION: UCP3 protein was involved in the incidence of high-salt induced hypertension and the progression of cardiac dysfunction in the early stages of heart failure. UCP3 ablation exacerbated high salt-induced cardiac hypertrophy and cardiac dysfunction. PMID- 29694983 TI - Nintedanib in Severe Idiopathic Pulmonary Fibrosis: Effectiveness through Compassion. PMID- 29694984 TI - Camel Milk Ameliorates 5-Fluorouracil-Induced Renal Injury in Rats: Targeting MAPKs, NF-kappaB and PI3K/Akt/eNOS Pathways. AB - BACKGROUND/AIMS: The clinical utility of 5-fluorouracil (5-FU) is limited by its nephrotoxicity. Camel milk (CM) has previously displayed beneficial effects in toxicant-induced nephropathies. The current study aimed to investigate the potential of CM to attenuate 5-FU-induced nephrotoxicity in rats. METHODS: Renal tissues were studied in terms of oxidative stress, inflammation and apoptosis. The levels of renal injury markers, inflammatory cytokines along with NOX-1, Nrf 2 and HO-1 were assessed by ELISA. The expression of MMP-2, MMP-9, NF-kappaBp65, p53, Bax and PCNA were detected by Immunohistochemistry. To gain an insight into the molecular signaling mechanisms, we determined the effect of CM on MAPKs, NF kappaB and PI3K/Akt/eNOS pathways by Western blotting. RESULTS: CM lowered 5-FU triggered increase of creatinine, BUN, Kim-1 and NGAL renal injury biomarkers and attenuated the histopathological aberrations. It suppressed oxidative stress and augmented renal antioxidant armory (GSH, SOD, GPx, TAC) with restoration of NOX 1, Nrf-2 and HO-1 levels. CM also suppressed renal inflammation as indicated by inhibition of MPO, TNF-alpha, IL-1beta, IL-18 and MCP-1 proinflammatory mediators and downregulation of MMP-2 and MMP-9 expression with boosting of IL-10. Regarding MAPKs signaling, CM suppressed the phosphorylation of p38 MAPK, JNK1/2 and ERK1/2 and inhibited NF-kappaB activation. For apoptosis, CM downregulated p53, Bax, CytC and caspase-3 proapoptotic signals with enhancement of Bcl-2 and PCNA. It also enhanced PI3K p110alpha, phospho-Akt and phospho-eNOS levels with augmentation of renal NO, favoring cell survival. Equally important, CM preconditioning enhanced 5-FU cytotoxicity in MCF-7, HepG-2, HCT-116 and PC-3 cells, thus, justifying their concomitant use. CONCLUSION: The current findings pinpoint, for the first time, the marked renoprotective effects of CM that were mediated via ROS scavenging, suppression of MAPKs and NF-kappaB along with activation of PI3K/Akt/eNOS pathway. PMID- 29694985 TI - The Neutrophil to Lymphocyte Ratio May Predict Benefit from Chemotherapy in Lung Cancer. AB - BACKGROUND/AIMS: The objectives of this study were to evaluate the impact of the neutrophil to lymphocyte ratio (NLR) and platelet to lymphocyte ratio (PLR) on overall survival (OS) and to explore the value of changes in the NLR and PLR with treatment as a response indicator. METHODS: A total of 934 patients were eligible for retrospective analysis between 2008 and 2014. The pretreatment and post treatment PLR and NLR in all patients were calculated based on complete blood counts. Univariate and multivariate Cox regression analyses were performed to determine the associations of the PLR and NLR with OS. RESULTS: The pretreatment NLR and PLR were correlated with different disease status and response to chemotherapy. Patients with lower NLR and PLR had a significantly better complete response (CR) rate to chemotherapy versus those with a higher NLR and PLR (p< 0.001). The NLR and PLR were sustained in patients who obtained a CR compared with moderate or poor response patients. The lower NLR of pretreatment was independently associated with a favourable prognosis in whole patients with lung cancer (HR: 0.69, 95% CI, 0.55-0.85, p< 0.001). In the patients under control after chemotherapy, the NLR of post-chemotherapy had a greater impact on survival, and the low NLR level maintained during chemotherapy was identified a predictor for favourable survival. PLR was not an independent prognostic indicator in the whole cohort or any subgroups. CONCLUSION: Our results suggested that NLR was well-connected with outcomes and response to chemotherapy in patients with lung cancer. As a response indicator, NLR may predict benefit from chemotherapy and improve patient selection. PMID- 29694986 TI - "Kissing Nodules" in Saber-Sheath Trachea. PMID- 29694987 TI - [Improved diagnostics and therapeutic decision making in traumatic peripheral nerve lesions using MR-neurography]. AB - INTRODUCTION: The correct diagnosis of peripheral nerve injuries is essential for choosing the correct treatment in nerve surgery. Especially, nerve defects require early diagnosis to provide quick surgical reconstruction and prevent long term disabilities. Recent developments in MR-neurography provide surgeons with a diagnostic tool delivering precise information on the structure and possibly function of nerves. Here we describe a series of cases, that benefited from preoperative MR-neurography to identify the correct type of injury. MATERIAL AND METHODS: We demonstrate five traumatic nerve injuries which were evaluated using high-resolution MR-neurography imaging for therapeutic planning, combined with standard clinical, electrophysiological and sonography diagnostics. We show the clinical feasibility, benefit of this new technique for nerve surgery and the correlation of preoperative MR-neurography images to the intraoperative situation (in surgically managed cases). RESULTS: Two cases were successfully treated without surgery based on the intact nerve-integrity found in the MR-neurography, despite pathological electrophysiology and inconclusive sonography. In three cases, the MR-Neurography enabled a precise diagnosis and localization of the nerve lesion. Thereby, a precise surgical reconstruction of the nerve lesion was achieved, confirming the matching of MR-neurography findings and intraoperative situs. DISCUSSION: Although, systematic clinical analyses are not available yet, our data suggest that MR-neurography can help surgeons to correctly define the type of nerve injury and thus identify the appropriate treatment preoperatively. In the presented cases, MR-neurography correctly diagnosed the type of injury and therefore allowed adequate planning and decision making between non-surgical treatment, neurolysis or nerve reconstruction. We believe that MR-neurography is an emerging tool for nerve surgeons to improve the treatment of nerve injuries. CONCLUSION: MR-neurography delivers decisive information on the nerve lesion and helps to identify the necessity to operate and the correct surgical treatment. PMID- 29694988 TI - The Role of Lung Ultrasound in Viral Lower Respiratory Tract Infections. AB - Despite being a bedside technique under rapid development and diffusion, lung ultrasound has not been often used in the management of viral low respiratory tract infections, although these infections represent a significant burden of care in neonatology and pediatrics. The aim of this article is to review the lung ultrasound findings and the evidence-based data available on this topic. Guidance on bedside imaging interpretation and future research direction are also discussed in this article. PMID- 29694989 TI - Is Less Invasive Surfactant Administration Necessary or "Only" Helpful or Just a Fashion? AB - In the 1990s, the most relevant pillars in the treatment of neonatal respiratory distress syndrome (RDS) have been improvements in ventilation strategies, the introduction of exogenous surfactant replacement therapy, and the use of antenatal steroids. Lately, in addition to the standard INSURE (INtubation SURfactant administration-Extubation) method to administer surfactant, a new technique has been gaining increasing popularity. It is the so-called less invasive surfactant administration (LISA) method, which has shown promising results in preventing bronchopulmonary dysplasia development and in reducing mortality in preterm neonates. The rationale behind this technique is to avoid positive pressure ventilation and the endotracheal tube, being surfactant delivered through a thin catheter while the neonate is maintained on continuous positive airway pressure. Given the paucity of large-scale randomized trials on LISA method to prove its effects on short- and long-term outcomes, some questions still remain unanswered. Then, uncertainty regarding the feasibility of this maneuver needs to be better clarified before gaining wide acceptance in routine clinical practice. In our report, we aim at hypothesizing the main mechanisms behind the efficacy of LISA, considering it as a single maneuver in a comprehensive approach for RDS management in the delivery room. PMID- 29694990 TI - Respiratory Instability and Hypoxemia Episodes in Preterm Infants. AB - Oxygenation instability is a very common problem in the premature infant that manifests as intermittent hypoxemia episodes (HEs). These are particularly frequent in premature infants who are on mechanical ventilation beyond the first weeks after birth. However, they can also occur in spontaneously breathing infants. Some of these episodes are due to central apnea, but in ventilated infants, they are frequently due to contractions of the abdominal musculature that can splint the respiratory pump, resulting in periods of decreased lung volume and hypoventilation. HEs are often followed by periods of hyperoxemia that results from excessive oxygen supplementation given to correct the hypoxemia. These episodes increase in frequency with postnatal age and are more common in infants with chronic lung disease. Although the evidence is not conclusive, their detrimental effects on the infant's neurologic, ocular, and respiratory system may be significant. There is no specific treatment for HEs, but several interventions are available to ameliorate the severity and duration of the episodes. Further research is needed to define the impact of HEs on the preterm infant's developing central nervous system and other organ systems and to develop effective strategies to prevent these episodes. PMID- 29694991 TI - Bronchopulmonary Dysplasia: Can We Agree on a Definition? AB - The advances in obstetric and neonatal care over the last half century have resulted in changes in pathophysiology and clinical presentation of bronchopulmonary dysplasia (BPD). In contrast to the original description of BPD by Northway et al as a severe lung injury in relatively mature preterm infants, the most common form of BPD currently is characterized by chronic respiratory insufficiency in extremely preterm infants. This evolution in the presentation of BPD, along with changes in respiratory support strategies such as increased use of nasal cannula oxygen, has presented a unique challenge to find a definition that describes the severity of lung damage and predict the long-term respiratory outcomes with some accuracy.The limitations of current definitions of BPD include inconsistent correlation with long-term respiratory outcomes, inability to classify infants dying from severe respiratory failure prior to 36 weeks' postmenstrual age, and potential inappropriate categorization of infants on nasal cannula oxygen or with extrapulmonary causes of respiratory failure. In the long term, the aim for a new definition of BPD is to develop a classification based on the pathophysiology and objective lung function evaluation providing a more accurate assessment for individual patients. Until then, a consensus definition that encompasses current clinical practices, provides reasonable prediction of later respiratory outcomes, and is relatively simple to use should be achieved. PMID- 29694992 TI - Respiratory Syncytial Virus in Otherwise Healthy Prematurely Born Infants: A Forgotten Majority. AB - Healthy, premature infants <=35 weeks' gestational age (wGA) are universally recognized to be at an increased risk of perinatal morbidity and mortality. Serious respiratory syncytial virus (RSV) lower respiratory tract infection imposes an additional burden of illness on these infants following hospitalization. Incurred morbidities relative to term infants include longer lengths of hospital stay, admission to intensive care, and need for oxygen and mechanical ventilation, all of which are associated with increased hospital costs. The highest morbidities are experienced by premature infants who are youngest (<3 months' chronological age) and are of lower gestational age. Short- and long-term follow-up indicates that healthy preterm infants both of lower gestational age and who are late preterm have obstructive lung function at baseline, which is further compromised by RSV-related infection during infancy. There is increasing evidence that childhood exposure to an episode of RSV infection may set the stage for an abnormal respiratory function trajectory, which, in adulthood, leads to chronic obstructive pulmonary disease. Healthy premature infants <32 wGA merit RSV prophylaxis based on existing data, whereas moderate- and high-risk preterm infants 32 to 35 wGA should be selectively and cost-effectively targeted for prophylaxis using validated risk scoring tools and country-specific thresholds for funding. PMID- 29694994 TI - Predicting the Future: Delivery Room Planning of Congenital Heart Disease Diagnosed by Fetal Echocardiography. AB - Advances in prenatal imaging have improved the examination of the fetal cardiovascular system. Fetal echocardiography facilitates the prenatal diagnosis of congenital heart disease (CHD) and through sequential examination, allows assessment of fetal cardiac hemodynamics, predicting the evolution of anatomical and functional cardiovascular abnormalities in utero and during the transition to a postnatal circulation at delivery. This approach allows detailed diagnosis with prenatal counseling and enables planning to define perinatal management, selecting the fetuses at a risk of postnatal hemodynamic instability who are likely to require a specialized delivery plan. The prenatal diagnosis and management of critical neonatal CHD has been shown to play an important role in improving the outcome of newborns with these conditions, allowing timely stabilization of the circulation prior to cardiac intervention or surgery, thus reducing the risk of perioperative morbidity and mortality. Diagnostic protocols aimed at risk-stratifying severity and potential postnatal compromise in fetuses with CHD have been developed to identify those who may require special intervention at birth or within the first days of life. In addition, new methodologies are being studied to improve the accuracy of prediction of disease severity. Perinatal management of neonates with a prenatal diagnosis of CHD requires a close collaboration between obstetric, neonatal, and cardiology services. In this article, the management of fetuses with CHD will be discussed, along with summarizing the in utero and fetal echocardiographic findings used for risk stratification of newborns with CHD and reviewing the basic principles used for planning for neonatal resuscitation and initial transitional care of these complex newborns. PMID- 29694993 TI - New Ventilator Strategies: High-Frequency Oscillatory Ventilation Combined with Volume Guarantee. AB - High-frequency oscillatory ventilation (HFOV) has been proposed as an alternative method of invasive ventilation in immature infants to prevent ventilator lung injury. To better control the size of the high-frequency tidal volume and to prevent large tidal volumes, a new strategy of controlling the tidal volume during HFOV (VThf) has been developed, HFOV-volume guarantee (VG). Data from preclinical, neonatal animal studies in normal and surfactant-depleted lungs have demonstrated the feasibility of this technique to directly control the VThf in the normal compliance and low compliance situations. Different I:E ratios also can modify the effect of CO2 washout during HFOV combined with VG in a different way as without the VG modality. Finally, clinical use of this technique in newborn infants has demonstrated the possibility of using very high frequency combined with constant very low VThf to decrease the risk of lung trauma related to the ventilator. PMID- 29694995 TI - Respiratory Support in Bronchiolitis: Trial Evidence. AB - Acute viral lower respiratory tract infection is frequently associated with hypoxemia and respiratory distress, sometimes progressing to hypercarbia and respiratory failure. In recent years, trials have assessed the effects of oxygen supplementation and respiratory support with high-flow oxygen therapy. An oxygen saturation target of 90% is as safe and clinically effective as 94% in infants with bronchiolitis. Trials of high-flow humidified oxygen have demonstrated safety, but as yet poorly demarcated an appropriate place for use within the clinical course of the disease. Effective trials of continuous positive airway pressure are lacking and urgently required. The trials reported to date have highlighted the need for common outcomes in relation to treatment failure. PMID- 29694996 TI - Surgery for Congenital Heart Disease: Improvements in Outcomes. AB - Cardiac surgery for congenital heart disease has changed dramatically since the first surgery in 1938. During the early era, children underwent surgery at older ages often with palliative procedures before their corrective operation. Not surprisingly, in the early era, there was considerably higher early and late mortality, including the additive risks of having more than one procedure and a long period of living with an unphysiological palliated circulation. Over time with advances in noninvasive diagnosis, surgical approach, cardiopulmonary bypass techniques, and team-based care, outcomes have improved. Children now undergo corrective surgery at a younger age and have fewer palliative procedures. Short term outcome as measured by the commonly used metric "procedural early mortality" (i.e., death before hospital discharge or less than 30 days following a surgical procedure) is now as low as 1 or 2% for many low-to-moderate complexity procedures. Late outcomes have also improved with long-term survival of hospital survivors for simple lesions being close to population controls. Late outcomes for more complex defects still show diminishing survival relative to a control population. Examination of the causes of death provides insights into areas in which clinical improvements may further improve the outlook for children with complex congenital heart disease. PMID- 29694997 TI - Role of Lactoferrin in Neonates and Infants: An Update. AB - Lactoferrin is one of the most represented and important bioactive proteins in human and mammal milk. In humans, lactoferrin is responsible for several actions targeting anti-infective, immunological, and gastrointestinal domains in neonates, infants, and young children. Evidence-based data vouch for the ability of supplemented lactoferrin to prevent sepsis and necrotizing enterocolitis in preterm infants and to reduce the burden of morbidity related to gastrointestinal and respiratory pathogens in young children. However, several issues remain pending regarding answers and clarification related to quality control, correct intakes, optimal schedules and schemes of supplementations, interactions with probiotics, and different types of milk and formulas. This review summarizes the current evidence regarding lactoferrin and discusses the areas in need of further guidance prior to the adoption of strategies that include a routine use of lactoferrin in neonates and young children. PMID- 29694998 TI - Mesenchymal Stromal Cell Therapy for Respiratory Complications of Extreme Prematurity. AB - Bronchopulmonary dysplasia remains the main complication of extreme preterm birth. Research over the past 10 years suggests the potential for stem cell-based therapies to prevent and/or restore organ damage in extreme preterm infants. Mesenchymal stromal cells, in particular, have advanced as the forerunner among various cell therapies based on very promising preclinical studies in animal models of neonatal lung injury. Early phase clinical trials are now underway to determine the safety and feasibility of this cell therapy in preterm infants at risk of developing bronchopulmonary dysplasia. This review will summarize the current rationale for testing mesenchymal stromal cells in this patient population and highlight the gaps in our knowledge to safely harness the full repair potential of cell-based therapies. PMID- 29694999 TI - Novel Approaches to the Study of Neonatal Infections. AB - The pathogenesis of neonatal infection is incompletely understood. Neonatal immune immaturity and the microbial factors of virulence only partially explain the interindividual differences in the protective responses to the most common neonatal pathogens. Stratification of infants into high- and low-risk groups through epidemiological studies has been invaluable in designing preventive strategies and reducing the burden of neonatal infection. The discovery of the role of maternal antibodies (Abs) as, for instance, anti-capsular polysaccharide group B streptococcal (GBS) Abs, in protecting newborn infants against neonatal GBS sepsis, has been a milestone in the unraveling of the molecular underpinnings of susceptibility to infection in the neonatal age. Future work should aim at defining the cellular and molecular differences in the neonatal immune responses that account for individual susceptibility and resistance to common neonatal pathogens. The interplay between the genetic and immune backgrounds of the infant, changes in the infant's microbiome, maternal factors, and the pathogen's characteristics needs to be accurately described through human studies. Precise phenotyping and dissection of the clinical heterogeneity of neonatal infection should identify cohorts that can be studied through different study methodologies. Term and preterm infants should be investigated according to the most likely underlying mechanism, single-gene disorders and multifactorial predisposition, respectively. Novel technologies, including genotyping studies, exome and genome sequencing, analysis of the microbiome, and the study of the metabolome, are nowadays established and available and can be integrated to gain a better insight into the unexplained bases of individual susceptibility to neonatal infections. PMID- 29695000 TI - New Diagnostic Possibilities for Neonatal Sepsis. AB - Progress in neonatal care has decrease morbidity and mortality due to neonatal sepsis (NS). Although diagnosis of sepsis continues to rely on blood culture, this method is too slow and limited by false-negative results. There are numerous sepsis biomarkers that have been evaluated for the early diagnosis of NS, but, to date, there is no single ideal biomarker, though novel biomarkers are becoming more sophisticated and specific in their clinical applications. This review provides an overview of the current diagnostic approaches available or under development for diagnosing NS. PMID- 29695002 TI - Changes in the Messenger RNA Expression of Toll-Like Receptors 2 and 4 in Healthy Infants According to Age. AB - BACKGROUND: Toll-like receptors (TLRs) are potentially useful indicators of several pediatric disease states. Here, we explore the mechanisms by which inflammation is regulated by interactions between microbiota and the host. Little data are available regarding the expression of TLRs in postnatal healthy infants. TLR 2 and TLR4 are extracellular TLRs that act as innate immune receptors by recognizing a wide range of endogenous ligands and microorganisms. METHODS: The aim of this study was to use real-time polymerase chain reaction to investigate the expression of the messenger RNAs (mRNAs) of TLR2 and TLR4 in blood samples obtained from healthy full-term infants and toddlers. RESULTS: We analyzed the mRNA expression levels of TLRs in 88 healthy term children separated according to age. The median expression level of TLR2 was 1.49 +/- 1.10 arbitrary units (AU) (n = 25) in infants younger than 3 months, 0.67 +/- 0.72 AU (n = 25) in infants aged between 3 and 12 months, and 0.03 +/- 0.02 AU (n= 38) in infants older than 12 months. The median expression level of TLR4 was 1.25 +/- 0.79 AU (n = 25) in infants younger than 3 months, 0.75 +/- 0.54 AU (n = 25) in infants aged 3 to 12 months, and 0.44 +/- 0.28 AU (n = 38) in infants older than 12 months. There was difference in the mRNA expression level of TLR2 and TLR4 between infants aged 0 to 3 and 3 to 12 months and those aged more than 1 year (p < 0.0001 and p < 0.0001, respectively) CONCLUSION: We found that the expression levels of TLR2 and TLR4 were associated with age. In particular, we observed that their expression increased during the suckling period and then clearly decreased once the infants reached 1 year of age (p < 0.001). These findings could be related to microbial colonization and the immune system. PMID- 29695001 TI - The Mother-Child Relationship during the First Months of Life: Preliminary Considerations in Preterm as Compared with Term Mother-Infant Dyads. AB - INTRODUCTION: From the prognostic perspective, the quality of the mother-child relationship during the first months of life has been variously associated with different factors such as the child's psychomotor/cognitive development and emotional-behavioral disorders. METHODS: The main aim of this study was to describe, at term age and 3 months of corrected age, the features and the prevalent patterns of the mother-child relationship in a group of 20 mother preterm infant dyads and to compare them with those of a group of 20 mother-term infant dyads. RESULTS: A relatively high rate of inadequate dyadic synchrony was found in our sample of preterms at 40 weeks of gestational age (half of the sample analyzed). The quality of the dyadic relationship and the prevalent patterns of the mother-child relationship were found to differ between the two groups we studied; moreover, the subjects at risk of relational problems remained substantially the same during the first 3 months of life. DISCUSSION: These data underline that in preterm children, the first weeks of life, coinciding with their hospitalization, represent a crucial time for establishing a valid dyadic relationship and for considering and planning any preventive interventions; after all, the earlier the risk of relational problems becomes a real possibility, the more likely it is to negatively impact on a child's overall development. PMID- 29695003 TI - Capacities and Competences for Drug Evaluation in European Neonatal Intensive Care Units: A Survey and Key Issues for Improvement. AB - BACKGROUND: Multicenter neonatal clinical trials aim to provide evidence-based drug evaluation, but recruiting neonates requires collaboration, standard procedures, and trained neonatologists. METHODS: A questionnaire based on a previous Delphi study was sent to European neonatal intensive care units (NICUs) to collect their research experience and identify areas for improvement. RESULTS: Of 247 NICUs,79 (32%) responded: 69 were level III units and 10 were level II units. In level III centers, 62% had medical staff dedicated to research and 65% conducted regular in-house audits. Similarities were observed in the median number of trials per year (level II: 2; level III: 5), Good Clinical Practice training (level II: 78%; level III: 66%), and standard operating procedures (level II: 63%; level III: 71%). Most NICUs had access to scientific advice for trial design, conduct, data management, and regulatory aspects. Involvement of patient advocacy groups was more common in level II units (level II: 75%; level III: 59%). A "quality" score of 34 "quality" research items was calculated for all centers (mean: 23.2 +/- 6.2; range: 6-34). CONCLUSION: Research experience and processes vary across Europe. Harmonizing research practices and setting standards will allow building a European neonatal network for effective, safe, and quality neonatal drug development. PMID- 29695004 TI - Video Comment on Payal Saxena et al. PMID- 29695005 TI - Video Comment on Kenta Hamada et al. PMID- 29695006 TI - Video Comment on Torsten Beyna et al. PMID- 29695007 TI - Endoscopic ultrasound-guided fine-needle aspiration of solid pancreatic lesions: striving for perfection. PMID- 29695008 TI - Spiraling your insertion: a glimpse into the future of colonoscopy. PMID- 29695009 TI - [French comment on article Learning curve and competence for volumetric laser endomicroscopy in Barrett's esophagus using cumulative sum analysis]. PMID- 29695010 TI - [French comment on article Lymph node metastasis in early gastric adenocarcinoma in the United States of America]. PMID- 29695012 TI - Video Comment on Tomoaki Tashima et al. PMID- 29695011 TI - [French comment on article Stylet slow-pull versus standard suction for endoscopic ultrasound-guided fine-needle aspiration of solid pancreatic lesions: a multicenter randomized trial]. PMID- 29695013 TI - Determining Inappropriate Medication Alerts from "Inaccurate Warning" Overrides in the Intensive Care Unit. AB - OBJECTIVE: This article aims to understand provider behavior around the use of the override reason "Inaccurate warning," specifically whether it is an effective way of identifying unhelpful medication alerts. MATERIALS AND METHODS: We analyzed alert overrides that occurred in the intensive care units (ICUs) of a major academic medical center between June and November 2016, focused on the following high-significance alert types: dose, drug-allergy alerts, and drug-drug interactions (DDI). Override appropriateness was analyzed by two independent reviewers using predetermined criteria. RESULTS: A total of 268 of 26,501 ICU overrides (1.0%) used the reason "Inaccurate warning," with 93 of these overrides associated with our included alert types. Sixty-one of these overrides (66%) were identified to be appropriate. Twenty-one of 30 (70%) dose alert overrides were appropriate. Forty of 48 drug-allergy alert overrides (83%) were appropriate, for reasons ranging from prior tolerance (n = 30) to inaccurate ingredient matches (n = 5). None of the 15 DDI overrides were appropriate. CONCLUSION: The "Inaccurate warning" reason was selectively used by a small proportion of providers and overrides using this reason identified important opportunities to reduce excess alerts. Potential opportunities include improved evaluation of dosing mechanisms based on patient characteristics, inclusion of institutional dosing protocols to alert logic, and evaluation of a patient's prior tolerance to a medication that they have a documented allergy for. This resource is not yet routinely used for alert tailoring at our institution but may prove to be a valuable resource to evaluate available alerts. PMID- 29695014 TI - Chronic Nerve Compression Accelerates the Progression of Diabetic Peripheral Neuropathy in a Rat Model: A Study of Gene Expression Profiling. AB - OBJECTIVE: This article investigates the role of chronic nerve compression in the progression of diabetic peripheral neuropathy (DPN) by gene expression profiling. METHODS: Chronic nerve compression was created in streptozotocin (STZ)-induced diabetic rats by wrapping a silicone tube around the sciatic nerve (SCN). Neurological deficits were evaluated using pain threshold test, motor nerve conduction velocity (MNCV), and histopathologic examination. Differentially expressed genes (DGEs) and metabolic processes associated with chronic nerve compression were analyzed. RESULTS: Significant changes in withdrawal threshold and MNCV were observed in diabetic rats 6 weeks after diabetes induction, and in DPN rats 4 weeks after diabetes induction. Histopathologic examination of the SCN in DPN rats presented typical changes of myelin degeneration in DPN. Function analyses of DEGs demonstrated that biological processes related to inflammatory response, extracellular matrix component, and synaptic transmission were upregulated after diabetes induction, and chronic nerve compression further enhanced those changes. While processes related to lipid and glucose metabolism, response to insulin, and apoptosis regulation were inhibited after diabetes induction, chronic nerve compression further enhanced these inhibitions. CONCLUSION: Our study suggests that additional silicone tube wrapping on the SCN of rat with diabetes closely mimics the course and pathologic findings of human DPN. Further studies are needed to verify the effectiveness of this rat model of DPN and elucidate the roles of the individual genes in the progression of DPN. PMID- 29695016 TI - ? PMID- 29695015 TI - [Renal affection in malignant lymphoma: imaging patterns in magnet resonance imaging]. PMID- 29695017 TI - ? PMID- 29695018 TI - Compliance on Mandatory Data Reporting in Registered Obstetrics Trials. AB - BACKGROUND: The Food and Drug Administration's (FDA's) Amendments Act established a legal mandate requiring registration of certain drug, device, and biologics trials in ClinicalTrials.gov prior to patient enrollment. One provision of the act requires investigators to report trial results in ClinicalTrials.gov within 1 year of completion. Preliminary evidence suggests that overall compliance rates are inadequate, and rates specific to obstetrics have not been investigated. OBJECTIVE: The purpose of this study was to examine the rate of compliance for mandatory reporting of results from obstetrics trials to ClinicalTrials.gov and to determine whether compliance rates were associated with funding type. STUDY DESIGN: We performed a registry-based study of clinical trials pertaining to obstetrics. ClinicalTrials.gov was cross-referenced with Drugs@FDA to determine which trials required mandatory reporting. We used obstetrics trials registered on ClinicalTrials.gov with at least 1 US site. Phase 0, Phase 1, and trials not reporting a phase were excluded. Furthermore, only trials of interventions approved by the FDA were retained. RESULTS: Our search returned 973 trials, of which 325 (33.4%) were screened for eligibility. Of the 325 completed trials, 74 (22.8% or 7.6% of the total) met all inclusion criteria and were evaluated for compliance. Thirty-seven of these trials (50%) did not list results, whereas the remaining 37 trials (50%) contained results on ClinicalTrials.gov. Trials funded by the National Institutes of Health (87.5%; 7/8) and industry (80%; 12/15) had higher rates of compliance than trials funded by other (43.9%; 18/41) or unspecified (0%; 0/10) sources. CONCLUSION: Half of all applicable obstetrics trials did not report results. Furthermore, rates of compliance appeared to vary by funding source, with trials funded by the National Institutes of Health or industry appearing to have a higher rate of compliance to mandatory data reporting. Greater awareness of federal regulations is needed, and changes should be implemented to increase reporting. PMID- 29695019 TI - Duration of Spontaneous Active Labor and Perinatal Outcomes Using Contemporary Labor Curves. AB - OBJECTIVE: Evaluate the association between spontaneous active labor duration utilizing contemporary labor curves and risk of adverse outcomes. MATERIALS AND METHODS: This is a retrospective cohort study from January 2012 to January 2015. Subjects were nulliparous, 18 to 44 years, with a cephalic, singleton >=37 weeks in spontaneous labor. Subjects were placed into three subgroups, defined by active labor duration from 6 to 10 cm as less than the median, the median-95th, and >95th percentile based on contemporary labor curves published by Zhang et al. We evaluated the association between subgroups and cesarean delivery, chorioamnionitis, estimated blood loss, Apgar score < 7 at 5 minutes, and neonatal intensive care unit admission using logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI). RESULTS: Six-hundred forty two women met the inclusion criteria. Compared with women whose active labor was less than the median, the risk of cesarean was higher in the median-95th percentile ([adjusted OR, aOR] 3.1, 95% CI 1.8-5.5) and the >95th percentile ([aOR] 6.8, 95% CI 3.9-11.7) subgroups. There was an increased odds of chorioamnionitis in the median-95th percentile subgroup ([aOR] 2.5, 95% CI 1.1-5.9). CONCLUSION: Chorioamnionitis and cesarean delivery increased significantly as labor duration exceeded the median. This study provides a better understanding regarding the potential risk of cesarean and chorioamnionitis using contemporary labor curves. PMID- 29695021 TI - Pre-Clinical Model to Study Recurrent Venous Thrombosis in the Inferior Vena Cava. AB - BACKGROUND: Patients undergoing deep vein thrombosis (VT) have over 30% recurrence, directly increasing their risk of post-thrombotic syndrome. Current murine models of inferior vena cava (IVC) VT model host one thrombosis event. OBJECTIVE: We aimed to develop a murine model to study IVC recurrent VT in mice. MATERIALS AND METHODS: An initial VT was induced using the electrolytic IVC model (EIM) with constant blood flow. This approach takes advantage of the restored vein lumen 21 days after a single VT event in the EIM demonstrated by ultrasound. We then induced a second VT 21 days later, using either EIM or an IVC ligation model for comparison. The control groups were a sham surgery and, 21 days later, either EIM or IVC ligation. IVC wall and thrombus were harvested 2 days after the second insult and analysed for IVC and thrombus size, gene expression of fibrotic markers, histology for collagen and Western blot for citrullinated histone 3 (Cit-H3) and fibrin. RESULTS: Ultrasound confirmed the first VT and its progressive resolution with an anatomical channel allowing room for the second thrombus by day 21. As compared with a primary VT, recurrent VT has heavier walls with significant up-regulation of transforming growth factor beta (TGF-beta), elastin, interleukin (IL)-6, matrix metallopeptidase 9 (MMP9), MMP2 and a thrombus with high citrullinated histone-3 and fibrin content. CONCLUSION: Experimental recurrent thrombi are structurally and compositionally different from the primary VT, with a greater pro-fibrotic remodelling vein wall profile. This work provides a VT recurrence IVC model that will help to improve the current understanding of the biological mechanisms and directed treatment of recurrent VT. PMID- 29695020 TI - Significant Hypo-Responsiveness to GPVI and CLEC-2 Agonists in Pre-Term and Full Term Neonatal Platelets and following Immune Thrombocytopenia. AB - Neonatal platelets are hypo-reactive to the tyrosine kinase-linked receptor agonist collagen. Here, we have investigated whether the hypo-responsiveness is related to altered levels of glycoprotein VI (GPVI) and integrin alpha2beta1, or to defects in downstream signalling events by comparison to platelet activation by C-type lectin-like receptor 2 (CLEC-2). GPVI and CLEC-2 activate a Src- and Syk-dependent signalling pathway upstream of phospholipase C (PLC) gamma2. Phosphorylation of a conserved YxxL sequence known as a (hemi) immunotyrosine based-activation-motif (ITAM) in both receptors is critical for Syk activation. Platelets from human pre-term and full-term neonates display mildly reduced expression of GPVI and CLEC-2, as well as integrin alphaIIbbeta3, accounted for at the transcriptional level. They are also hypo-responsive to the two ITAM receptors, as shown by measurement of integrin alphaIIbbeta3 activation, P selectin expression and Syk and PLCgamma2 phosphorylation. Mouse platelets are also hypo-responsive to GPVI and CLEC-2 from late gestation to 2 weeks of age, as determined by measurement of integrin alphaIIbbeta3 activation. In contrast, the response to G protein-coupled receptor agonists was only mildly reduced and in some cases not altered in neonatal platelets of both species. A reduction in response to GPVI and CLEC-2, but not protease-activated receptor 4 (PAR-4) peptide, was also observed in adult mouse platelets following immune thrombocytopenia, whereas receptor expression was not impaired. Our results demonstrate developmental differences in platelet responsiveness to GPVI and CLEC 2, and also following immune platelet depletion leading to reduced Syk activation. The rapid generation of platelets during development or following platelet depletion is achieved at the expense of signalling by ITAM-coupled receptors. PMID- 29695022 TI - Catheter-Related Arterial Thrombosis in Neonates and Children: A Systematic Review. AB - Catheter-related arterial thrombosis (CAT) is increasingly recognized in children. Available data are scarce and based on expert opinions. This systematic review aimed to identify knowledge on paediatric CAT. Among 3,484 publications, 22 met inclusion criteria. Fourteen reported on CAT due to umbilical arterial catheter (UAC), two to extremity indwelling catheter (EIC), one to both and five to cardiac catheter (CC). The overall cumulative incidence of CAT was 21% (95% confidence interval [CI], 13-31) with a relative incidence of 20% (95% CI, 10-33) for UAC and 11% (95% CI, 3-21) for CC-related CAT. The incidence of EIC-related CAT ranged from 3.4 to 63%. Clinical presentation of CAT included symptoms of acute limb ischaemia (79%, 95% CI, 54-97), arterial hypertension (55%, 95% CI, 23 86) and congestive heart failure (28%, 95% CI, 7-53). Underlying conditions of UAC-related CAT included prematurity (70%, 95% CI, 31-98), respiratory distress syndrome (56%, 95% CI, 46-65), asphyxia (41%, 95% CI, 15-69), infection (32%, 95% CI, 13-55), persistent ductus arteriosus (28%, 95% CI, 13-45), meconium aspiration (16%, 95% CI, 8-25) and congenital heart disease (9%, 95% CI, 2-19). Congenital heart disease was the likely condition in EIC- and CC-related CAT. Antithrombotic treatment included thrombolysis (71%, 95% CI, 47-91), heparin (70%, 95% CI, 41-94) and thrombectomy (46%, 95% CI, 10-95) alone or in combination. Complete resolution rate of CAT was 82% (95% CI, 65-96). Long-term complications included arterial hypertension (26%, 95% CI, 0-66) and limb amputation (12%, 95% CI, 1-31). The overall all-cause mortality rate was 7% (95% CI, 2-14). In conclusion, CAT occurs at an increased incidence in neonates and children and is potentially associated with poor outcome. However, limited data are available on paediatric CAT. This systematic review identifies the rationale for further studies on CAT in paediatric patients. PMID- 29695023 TI - The Performance of CT versus MRI in the Differential Diagnosis of Cerebral Venous Thrombosis. AB - BACKGROUND: Cerebral venous thrombosis (CVT) is a rare disease, and with poor prognosis. Computed tomography (CT) and magnetic resonance imaging (MRI) are the most commonly used image modalities for patients with non-specific neurologic symptoms. We present here a meta-analysis to assess the accuracy of CT and MRI in the differential diagnosis of CVT and cerebral venous sinus thrombosis (CVST). MATERIALS AND METHODS: A comprehensive search of the PubMed, EMBASE, Web of Science, Cochrane Database and Chinese Biomedical (CBM) databases was conducted prior to March 20, 2017. In this report, we assess the methodological quality of each article individually and perform a meta-analysis to obtain the summary of the diagnostic accuracy of CT and MRI in correctly identifying CVT and CVST. RESULTS: Twenty-four eligible articles comprising 48 studies (4,595 cases) were included. The pooled sensitivity for CT-CVT/CT-CVST groups is 0.79 (95% confidence interval [CI]: 0.76, 0.82)/0.81(95% CI: 0.78, 0.84), and pooled specificity is 0.90 (95% CI: 0.89, 0.91)/0.89 (0.88, 0.91), with an area under the curve (AUC) for the summary receiver operating characteristic (SROC) of 0.9314/0.9161, respectively. No significant heterogeneity and publication bias was observed across each study. For MRI-CVT/MRI-CVST, the pooled sensitivity is 0.82 (95% CI: 0.78, 0.85)/0.80 (95% CI: 0.76, 0.83), and pooled specificity is 0.92 (95% CI: 0.91, 0.94)/0.91(0.89, 0.92), with an AUC for the SROC of 0.9221/0.9273, respectively. CONCLUSION: This meta-analysis indicates that both CT and MRI have a high level of diagnostic accuracy in the differential diagnosis of CVT and CVST, independent of stage, target for analysis or analysis methods. They could be chosen as alternative sub-optimal gold standards for diagnosing CVT and CVST, especially in emergency. PMID- 29695024 TI - Importance of timing in staging head and neck cancer: cervical adenopathy post tonsillectomy mimicking malignancy. PMID- 29695025 TI - Prospective associations of age at complementary feeding and exclusive breastfeeding duration with body mass index at 5-6 years within different risk groups. AB - BACKGROUND: Children with overweight or obesity are at risk for developing obesity in adulthood. Certain maternal characteristics, such as ethnicity, education, body mass index (BMI) or neighbourhood, are determinants for childhood overweight risk. There are large variations in how mothers differing in these characteristics feed their infants. Therefore, associations of age at complementary feeding, exclusive breast feeding duration with childhood overweight may differ in these groups. Understanding these associations would be essential to develop overweight prevention strategies. OBJECTIVES: The objective of this study is to study the associations of age at complementary feeding, exclusive breastfeeding duration with BMI-standard deviation score (SDS) at 5-6 years within risk groups. METHODS: Using data from the Amsterdam Born Children and their Development study, a population-based birth cohort (n = 4495), we formed groups of children at varying risk of overweight according to maternal characteristics of ethnicity, education, pre-pregnancy BMI and neighbourhood. Linear and logistic regression analyses were conducted. RESULTS: Complementary feeding after 5 months of age was associated with lower BMI-SDS in children of mothers of Dutch ethnicity (B: -0.12; 95% CI: -0.21, -0.04), medium-level education (-0.19; -0.30, -0.08), normal BMI (-0.08; -0.16, -0.01) and high-risk neighbourhood (-0.16; -0.29, -0.02). Compared with exclusive breastfeeding for <3 months, exclusive breastfeeding for >=6 months was associated with lower BMI-SDS in groups of medium-level education (-0.28; 0.44, -0.11), normal BMI (-0.18; 0.29, -0.08) and medium-risk (-0.18; -0.33, -0.04) and high-risk (-0.22; -0.42, 0.02) neighbourhoods. CONCLUSIONS: Associations between infant feeding practices and childhood BMI may differ between risk groups, implying that overweight prevention strategies should be group-specific. PMID- 29695026 TI - Diverticulum formation from interposed colonic graft following oesophageal reconstruction. PMID- 29695027 TI - Colo-ureteric fistula: a rare complication in colorectal surgery. PMID- 29695028 TI - Giant Brunner's gland adenoma of the duodenum manifested by melena. PMID- 29695029 TI - Paediatric acute care: Highlights from the Paediatric Acute Care-Advanced Paediatric Life Support Conference, Gold Coast, 2017. AB - The Paediatric Acute Care Conference is an annual conference organised by APLS Australia to advance paediatric acute care topics for clinicians in pre-hospital medicine, EDs, acute paediatrics, intensive care and anaesthesia. The Conference 2017 was held at Surfers Paradise, Queensland. We provide a summary of some of the presentations. PMID- 29695030 TI - Gangrenous giant Meckel's diverticulitis masquerading acute appendicitis: a surgical conundrum. PMID- 29695031 TI - The grabbing of the baton. PMID- 29695032 TI - Editorial Tribute: Mark A. Sperling, MD, Editor-in-Chief, Pediatric Diabetes 2000 2017. PMID- 29695033 TI - Action of the Metalloproteinases in Gonadal Remodeling during Sex Reversal in the Sequential Hermaphroditism of the Teleostei Fish Synbranchus marmoratus (Synbranchiformes: Synbranchidae). AB - Teleostei present great plasticity regarding sex change. During sex reversal, the whole gonad including the germinal epithelium undergoes significant changes, remodeling, and neoformation. However, there is no information on the changes that occur within the interstitial compartment. Considering the lack of information, especially on the role played by metalloproteinases (MMPs) in fish gonadal remodeling, the aim of this study was to evaluate the action of MMPs on gonads of sex reversed females of Synbranchus marmoratus, a fresh water protogynic diandric fish. Gonads were processed for light microscopy and blood samples were used for the determination of plasma sex steroid levels. During sex reversal, degeneration of the ovaries occurred and were gradually replaced by the germinal tissue of the male. The action of the MMPs induces significant changes in the interstitial compartment, allowing the reorganization of germinal epithelium. Leydig cells also showed an important role in female to male reversion. The gonadal transition coincides with changes in circulating sex steroid levels throughout sex reversion. The action of the MMPs, in the gonadal remodeling, especially on the basement membrane, is essential for the establishment of a new functional germinal epithelium. PMID- 29695034 TI - Multi-Detector Computed Tomography Imaging Techniques in Arterial Injuries. AB - Cross-sectional imaging has become a critical aspect in the evaluation of arterial injuries. In particular, angiography using computed tomography (CT) is the imaging of choice. A variety of techniques and options are available when evaluating for arterial injuries. Techniques involve contrast bolus, various phases of contrast enhancement, multiplanar reconstruction, volume rendering, and maximum intensity projection. After the images are rendered, a variety of features may be seen that diagnose the injury. This article provides a general overview of the techniques, important findings, and pitfalls in cross sectional imaging of arterial imaging, particularly in relation to computed tomography. In addition, the future directions of computed tomography, including a few techniques in the process of development, is also discussed. PMID- 29695035 TI - Variation in the Microbiome, Trichothecenes, and Aflatoxins in Stored Wheat Grains in Wuhan, China. AB - Contamination by fungal and bacterial species and their metabolites can affect grain quality and health of wheat consumers. In this study, sequence analyses of conserved DNA regions of fungi and bacteria combined with determination of trichothecenes and aflatoxins revealed the microbiome and mycotoxins of wheat from different silo positions (top, middle, and bottom) and storage times (3, 6, 9, and 12 months). The fungal community in wheat on the first day of storage (T0) included 105 classified species (81 genera) and 41 unclassified species. Four species had over 10% of the relative abundance: Alternaria alternata (12%), Filobasidium floriforme (27%), Fusarium graminearum (12%), and Wallemia sebi (12%). Fungal diversity and relative abundance of Fusarium in wheat from top silo positions were significantly lower than at other silo positions during storage. Nivalenol and deoxynivalenol in wheat were 13-34% higher in all positions at 3 months compared to T0, and mycotoxins in wheat from middle and bottom positions at 6 to 12 months were 24-57% higher than at T0. The relative abundance of toxigenic Aspergillus and aflatoxins were low at T0 and during storage. This study provides information on implementation and design of fungus and mycotoxin management strategies as well as prediction models. PMID- 29695036 TI - Development of PZT Actuated Valveless Micropump. AB - A piezoelectrically actuated valveless micropump has been designed and developed. The principle components of this system are piezoelectrically actuated (PZT) metal diaphragms and a complete fluid flow system. The design of this pump mainly focuses on a cross junction, which is generated by a nozzle jet attached to a pump chamber and the intersection of two inlet channels and an outlet channel respectively. During each PZT diaphragm vibration cycle, the junction connecting the inlet and outlet channels with the nozzle jet permits consistencies in fluidic momentum and resistances in order to facilitate complete fluidic path throughout the system, in the absence of any physical valves. The entire micropump structure is fabricated as a plate-by-plate element of polymethyl methacrylate (PMMA) sheets and sandwiched to get required fluidic network as well as the overall device. In order to identify the flow characteristics, and to validate the test results with numerical simulation data, FEM analysis using ANSYS was carried out and an eigenfrequency analysis was performed to the PZT diaphragm using COMSOL Multiphysics. In addition, the control system of the pump was designed and developed to change the applied frequency to the piezoelectric diaphragms. The experimental data revealed that the maximum flow rate is 31.15 mL/min at a frequency of 100 Hz. Our proposed design is not only for a specific application but also useful in a wide range of biomedical applications. PMID- 29695037 TI - Antioxidative, Antiproliferative and Antimicrobial Activities of Phenolic Compounds from Three Myrcia Species. AB - Myrcia bella Cambess., Myrcia fallax (Rich.) DC. and Myrcia guianensis (Aubl.) DC. (Myrtaceae) are trees found in Brazilian Cerrado. They have been widely used in folk medicine for the treatment of gastrointestinal disorders, hemorrhagic and infectious diseases. Few reports have been found in the literature connecting their phenolic composition and biological activities. In this regard, we have profiled the main phenolic constituents of Myrcia spp. leaves extracts by ESI(−)Q-TOF-MS. The main constituents found were ellagic acid (M. bella), galloyl glucose isomers (M. guianensis) and hexahydroxydiphenic (HHDP) acid derivatives (M. fallax). In addition, quercetin and myricetin derivatives were also found in all Myrcia spp. extracts. The most promising antioxidant activity, measured by 2,2-diphenyl-1-picrylhydrazyl (DPPH) scavenging activity, was found for M. fallax extracts (EC50 8.61 ± 0.22 µg·mL−1), being slightly less active than quercetin and gallic acid (EC50 2.96 ± 0.17 and 2.03 ± 0.02 µg·mL−1, respectively). For in vitro antiproliferative activity, M. guianensis showed good activity against leukemia (K562 TGI = 7.45 µg·mL−1). The best antimicrobial activity was observed for M. bella and M. fallax to Escherichia coli (300 and 250 µg·mL−1, respectively). In conclusion, the activities found are closely related to the phenolic composition of these plants. PMID- 29695038 TI - Evaluating the Implementation of a Twitter-Based Foodborne Illness Reporting Tool in the City of St. Louis Department of Health. AB - Foodborne illness is a serious and preventable public health problem affecting 1 in 6 Americans with cost estimates over $50 billion annually. Local health departments license and inspect restaurants to ensure food safety and respond to reports of suspected foodborne illness. The City of St. Louis Department of Health adopted the HealthMap Foodborne Dashboard (Dashboard), a tool that monitors Twitter for tweets about food poisoning in a geographic area and allows the health department to respond. We evaluated the implementation by interviewing employees of the City of St. Louis Department of Health involved in food safety. We interviewed epidemiologists, environmental health specialists, health services specialists, food inspectors, and public information officers. Participants viewed engaging innovation participants and executing the innovation as challenges while they felt the Dashboard had relative advantage over existing reporting methods and was not complex once in place. This study is the first to examine practitioner perceptions of the implementation of a new technology in a local health department. Similar implementation projects should focus more on process by developing clear and comprehensive plans to educate and involve stakeholders prior to implementation. PMID- 29695039 TI - Efficient Protein Expression and Virus-Induced Gene Silencing in Plants Using a Crinivirus-Derived Vector. AB - Plant virus-based vectors are valuable tools for recombinant gene expression and functional genomics for both basic and applied research. In this study, Lettuce infectious yellows virus (LIYV) of the genus Crinivirus was engineered into a virus vector that is applicable for efficient protein expression and virus induced gene silencing (VIGS) in plants. We examined gene replacement and “add a gene” strategies to develop LIYV-derived vectors for transient expression of the green fluorescent protein (GFP) reporter in Nicotiana benthamiana plants. The latter yielded higher GFP expression and was further examined by testing the effects of heterologous controller elements (CEs). A series of five vector constructs with progressively extended LIYV CP sgRNA CEs were tested, the longest CE gave the highest GFP expression but lower virus accumulation. The whitefly transmissibility of the optimized vector construct to other host plants, and the capability to accommodate and express a larger gene, a 1.8 kb β-glucuronidase (GUS) gene, were confirmed. Furthermore, the LIYV vector was also validated VIGS by silencing the endogenous gene, phytoene desaturase (PDS) in N. benthamiana plants, and the transgene GFP in N. benthamiana line 16c plants. Therefore, LIYV-derived vectors could provide a technical reference for developing vectors of other economically important criniviruses. PMID- 29695041 TI - An Improved Fast Self-Calibration Method for Hybrid Inertial Navigation System under Stationary Condition. AB - The navigation accuracy of the inertial navigation system (INS) can be greatly improved when the inertial measurement unit (IMU) is effectively calibrated and compensated, such as gyro drifts and accelerometer biases. To reduce the requirement for turntable precision in the classical calibration method, a continuous dynamic self-calibration method based on a three-axis rotating frame for the hybrid inertial navigation system is presented. First, by selecting a suitable IMU frame, the error models of accelerometers and gyros are established. Then, by taking the navigation errors during rolling as the observations, the overall twenty-one error parameters of hybrid inertial navigation system (HINS) are identified based on the calculation of the intermediate parameter. The actual experiment verifies that the method can identify all error parameters of HINS and this method has equivalent accuracy to the classical calibration on a high precision turntable. In addition, this method is rapid, simple and feasible. PMID- 29695040 TI - Gastroprotective and Antioxidant Activity of Kalanchoe brasiliensis and Kalanchoe pinnata Leaf Juices against Indomethacin and Ethanol-Induced Gastric Lesions in Rats. AB - Kalanchoe brasiliensis and Kalanchoe pinnata are used interchangeably in traditional medicine for treating peptic ulcers and inflammatory problems. In this context, this study aims to characterize the chemical constituents and evaluate the gastroprotective activity of the leaf juices of the two species in acute gastric lesions models. Thin Layer Chromatography (TLC) and Ultra High Performance Liquid Chromatography coupled to Mass Spectrometer (UHPLC-MS) were performed for chemical characterization. Wistar rats were pre-treated orally with leaf juices (125, 250 and 500 mg/kg) or ranitidine (50 mg/kg). The peaks observed in the chromatogram of K. brasiliensis showed similar mass spectra to flavonoid glycosides derived from patuletin and eupafolin, while K. pinnata showed mass spectra similar to compounds derived from quercetin, patuletin, eupafolin and kaempferol. K. brasiliensis at all doses and K. pinnata at doses of 250 mg/kg and 500 mg/kg significantly reduced the lesions in the ethanol induction model. In the indomethacin induction model, both species showed significant results at doses of 250 and 500 mg/kg. Also, the pre-treatment with leaf juices increased the antioxidant defense system, glutathione (GSH), whereas malondialdehyde (MDA), myeloperoxidase (MPO), interleukin-1β (IL-1β) and tumor necrosis factor α (TNF-α) levels were significantly decreased. Treatment with leaf juices led to the upregulation of zone occludes-1 (ZO-1) and the downregulation of inducible nitric oxide synthase (iNOS) and factor nuclear-κβ transcription (NF-κB-p65), while also showing a cytoprotective effect and maintaining mucus production. These findings show that the leaf juices of the two species showed gastroprotective effects on ethanol and gastric indomethacin injury which were a consequence of gastric inflammation suppression, antioxidant activity and the maintenance of cytoprotective defenses and mucosal structure architecture. PMID- 29695042 TI - A Microdialysis in Adjuvant Arthritic Rats for Pharmacokinetics-Pharmacodynamics Modeling Study of Geniposide with Determination of Drug Concentration and Efficacy Levels in Dialysate. AB - Microdialysis, a sampling method for pharmacokinetics-pharmacodynamics (PK-PD) modeling in preclinical and clinical studies, is a convenient in vivo sampling technique. Geniposide (GE), an iridoid glycoside compound, is the major active ingredient of Gardenia jasminoides Ellis fruit which has an anti-inflammatory effect. In this study, an articular cavity microdialysis sampling system for adjuvant arthritic (AA) rats was established to study the effect of GE on the release of prostaglandin E2 (PGE2) in AA rats induced by Freund's complete adjuvant (FCA). An UHPLC-MS/MS method was developed to determine the concentrations of GE and PGE2 in the dialysate. Through the determination of drug concentrations and PGE2 efficacy levels in the dialysate, the developed methods were successfully applied to set up concentration-time and effect-time profiles followed by PK-PD modeling of GE's effect on decreasing PGE2 release after oral administration of GE. The effect was well described by the developed PK-PD modeling, indicating that GE may play an anti-inflammatory role via decreasing AA induced elevated PGE2 levels. In the selection of suitable endogenous small molecules as effect markers, the establishment of AA rat joint-cavity microdialysis is an attractive technique for rational PK-PD studies. PMID- 29695044 TI - A Feasible One-Step Synthesis of Hierarchical Zeolite Beta with Uniform Nanocrystals via CTAB. AB - A hierarchical zeolite Beta has been prepared by a feasible one-pot and one-step method, which is suitable for application in industrial production. The synthesis is a simple hydrothermal process with low-cost raw materials, without adding alcohol or adding seeds, and without aging, recrystallization, and other complex steps. The hierarchical zeolite Beta is a uniform nanocrystal (20-50 nm) aggregation with high external surface area (300 m2/g) and mesoporous volume (0.50 cm3/g), with the mesoporous structure composed of intercrystal and intracrystal pores. As an acid catalyst in benzylation of naphthalene with benzyl chloride, the hierarchical zeolite Beta has shown high activity in the bulky molecule reaction due to its introduction of mesostructure. PMID- 29695043 TI - Different Dose-Dependent Modes of Action of C-Type Natriuretic Peptide on Pseudomonas aeruginosa Biofilm Formation. AB - We have previously shown that the C-type Natriuretic Peptide (CNP), a peptide produced by lungs, is able to impact Pseudomonasaeruginosa physiology. In the present work, the effect of CNP at different concentrations on P. aeruginosa biofilm formation was studied and the mechanisms of action of this human hormone on P. aeruginosa were deciphered. CNP was shown to inhibit dynamic biofilm formation in a dose-dependent manner without affecting the bacterial growth at any tested concentrations. The most effective concentrations were 1 and 0.1 µM. At 0.1 µM, the biofilm formation inhibition was fully dependent on the CNP sensor protein AmiC, whereas it was only partially AmiC-dependent at 1 µM, revealing the existence of a second AmiC-independent mode of action of CNP on P. aeruginosa. At 1 µM, CNP reduced both P. aeruginosa adhesion on glass and di-rhamnolipid production and also increased the bacterial membrane fluidity. The various effects of CNP at 1 µM and 0.1 µM on P. aeruginosa shown here should have major consequences to design drugs for biofilm treatment or prevention. PMID- 29695045 TI - Molecular Analysis of Sensory Axon Branching Unraveled a cGMP-Dependent Signaling Cascade. AB - Axonal branching is a key process in the establishment of circuit connectivity within the nervous system. Molecular-genetic studies have shown that a specific form of axonal branching—the bifurcation of sensory neurons at the transition zone between the peripheral and the central nervous system—is regulated by a cyclic guanosine monophosphate (cGMP)-dependent signaling cascade which is composed of C-type natriuretic peptide (CNP), the receptor guanylyl cyclase Npr2, and cGMP-dependent protein kinase Iα (cGKIα). In the absence of any one of these components, neurons in dorsal root ganglia (DRG) and cranial sensory ganglia no longer bifurcate, and instead turn in either an ascending or a descending direction. In contrast, collateral axonal branch formation which represents a second type of axonal branch formation is not affected by inactivation of CNP, Npr2, or cGKI. Whereas axon bifurcation was lost in mouse mutants deficient for components of CNP-induced cGMP formation; the absence of the cGMP-degrading enzyme phosphodiesterase 2A had no effect on axon bifurcation. Adult mice that lack sensory axon bifurcation due to the conditional inactivation of Npr2-mediated cGMP signaling in DRG neurons demonstrated an altered shape of sensory axon terminal fields in the spinal cord, indicating that elaborate compensatory mechanisms reorganize neuronal circuits in the absence of bifurcation. On a functional level, these mice showed impaired heat sensation and nociception induced by chemical irritants, whereas responses to cold sensation, mechanical stimulation, and motor coordination are normal. These data point to a critical role of axon bifurcation for the processing of acute pain perception. PMID- 29695046 TI - Laser Scribed Graphene Biosensor for Detection of Biogenic Amines in Food Samples Using Locally Sourced Materials. AB - In foods, high levels of biogenic amines (BA) are the result of microbial metabolism that could be affected by temperatures and storage conditions. Thus, the level of BA is commonly used as an indicator of food safety and quality. This manuscript outlines the development of laser scribed graphene electrodes, with locally sourced materials, for reagent-free food safety biosensing. To fabricate the biosensors, the graphene surface was functionalized with copper microparticles and diamine oxidase, purchased from a local supermarket; and then compared to biosensors fabricated with analytical grade materials. The amperometric biosensor exhibits good electrochemical performance, with an average histamine sensitivity of 23.3 µA/mM, a lower detection limit of 11.6 µM, and a response time of 7.3 s, showing similar performance to biosensors constructed from analytical grade materials. We demonstrated the application of the biosensor by testing total BA concentration in fish paste samples subjected to fermentation with lactic acid bacteria. Biogenic amines concentrations prior to lactic acid fermentation were below the detection limit of the biosensor, while concentration after fermentation was 19.24 ± 8.21 mg histamine/kg, confirming that the sensor was selective in a complex food matrix. The low-cost, rapid, and accurate device is a promising tool for biogenic amine estimation in food samples, particularly in situations where standard laboratory techniques are unavailable, or are cost prohibitive. This biosensor can be used for screening food samples, potentially limiting food waste, while reducing chances of foodborne outbreaks. PMID- 29695047 TI - A Combined NMR-Computational Study of the Interaction between Influenza Virus Hemagglutinin and Sialic Derivatives from Human and Avian Receptors on the Surface of Transfected Cells. AB - The development of small-molecule inhibitors of influenza virus Hemagglutinin could be relevant to the opposition of the diffusion of new pandemic viruses. In this work, we made use of Nuclear Magnetic Resonance (NMR) spectroscopy to study the interaction between two derivatives of sialic acid, Neu5Ac-α-(2,6)-Gal β-(1-4)-GlcNAc and Neu5Ac-α-(2,3)-Gal-β-(1-4)-GlcNAc, and hemagglutinin directly expressed on the surface of recombinant human cells. We analyzed the interaction of these trisaccharides with 293T cells transfected with the H5 and H1 variants of hemagglutinin, which thus retain their native trimeric conformation in such a realistic environment. By exploiting the magnetization transfer between the protein and the ligand, we obtained evidence of the binding event, and identified the epitope. We analyzed the conformational features of the glycans with an approach combining NMR spectroscopy and data-driven molecular dynamics simulations, thus obtaining useful information for an efficient drug design. PMID- 29695049 TI - Properties of Basil and Lavender Essential Oils Adsorbed on the Surface of Hydroxyapatite. AB - The research conducted in this study presented for the first time results of physico-chemical properties and in vitro antimicrobial activity of hydroxyapatite plant essential oil against Gram-positive bacteria (methicillin-resistant Staphylococcus aureus (MRSA) and S. aureus 0364) and Gram-negative bacteria (Escherichia coli ATCC 25922). The samples were studied by scanning electron microscopy (SEM) and Fourier transform infrared (FTIR) spectroscopy to determine the morphology and structure of the nanocomposites of hydroxyapatite coated with basil (HAp-B) and lavender (HAp-L) essential oils (EOs). The values of the BET specific surface area (SBET), total pore volume (VP) and pore size (DP) were determined. The results for the physico-chemical properties of HAp-L and HAp-B revealed that lavender EOs were well adsorbed on the surface of hydroxyapatite, whereas basil EOs showed a poor adsorption on the surface of hydroxyapatite. We found that the lavender EOs hydroxyapatite (HAp-L) exhibited a very good inhibitory growth activity. The value of the minimum inhibitory concentration (MIC) related to growth bacteria was 0.039 mg/mL for MRSA, 0.02 mg/mL for S. aureus and 0.039 mg/mL E. coli ATCC 25922. The basil EO hydroxyapatite (HAp-B) showed poor inhibition of bacterial cell growth. The MIC value was 0.625 mg/mL for the HAp-B sample in the presence of the MRSA bacteria, 0.313 mg/mL in the presence of S. aureus and 0.078 mg/mL for E. coli ATCC 25922. PMID- 29695050 TI - Adherence to National Dietary Guidelines in Association with Oral Health Impact on Quality of Life. AB - We aimed to assess the association between oral health, in terms of its impact on quality of life, and diet quality expressed as adherence to dietary guidelines. We analyzed cross-sectional data from the French NutriNet-Santé general population-based e-cohort (N = 18,263 adults; mean age = 56.5 ± 13.8 years). The main independent variable, oral health-related quality of life, was assessed in 2016 with the GOHAI instrument (maximum score = 60). The main dependent variable, diet’s nutritional quality, was assessed with the mPNNS GS score (maximum score = 13.5) measuring adherence to French dietary guidelines and computed on the basis of repeated 24-h dietary records. Multivariable linear regression models were fit. Mean GOHAI score was 54.5 ± 4.3 and mean mPNNS GS score was 7.7 ± 1.6. Among participants aged 18-64 years, those scoring ≤50 on GOHAI (poor oral health with a detrimental impact on quality of life) were less likely to adhere to dietary guidelines than participants scoring 57-60 points (good oral health) (beta = −0.18, 95% CI: −0.26, −0.09; p < 0.0001). Among participants aged 65+ years, those scoring 51-56 points on GOHAI (average oral health with some negative impact on quality of life) were less likely to adhere to dietary guidelines than were participants scoring in the range 57-60 (beta = −0.23, 95% CI: −0.33, −0.13; p < 0.0001). The findings suggested modest age-dependent associations between oral health related quality of life and diet quality. Confirmation is needed longitudinally with representative samples and accounting for diet quality evolution. PMID- 29695051 TI - Catalytic Oxidation of Soot on a Novel Active Ca-Co Dually-Doped Lanthanum Tin Pyrochlore Oxide. AB - A novel active Ca-Co dually-doping pyrochlore oxide La2−xCaxSn2−yCoyO7 catalyst was synthesized by the sol-gel method for catalytic oxidation of soot particulates. The microstructure, atomic valence, reduction, and adsorption performance were investigated by X-ray powder diffraction (XRD), scanning electron microscope (SEM), Fourier-transform infrared spectroscopy (FT-IR), X-ray photoelectron spectroscopy (XPS), H2-TPR (temperature programmed reduction), and in situ diffuse reflection infrared Fourier transformed (DRIFTS) techniques. Temperature programmed oxidation (TPO) tests were performed with the mixture of soot-catalyst under tight contact conditions to evaluate the catalytic activity for soot combustion. Synergetic effect between Ca and Co improved the structure and redox properties of the solids, increased the surface oxygen vacancies, and provided a suitable electropositivity for oxide, directly resulting in the decreased ignition temperature for catalyzed soot oxidation as low as 317 °C. The presence of NO in O2 further promoted soot oxidation over the catalysts with the ignition temperature decreased to about 300 °C. The DRIFTS results reveal that decomposition of less stable surface nitrites may account for NO2 formation in the ignition period of soot combustion, which thus participate in the auxiliary combustion process. PMID- 29695048 TI - Mecasermin in Insulin Receptor-Related Severe Insulin Resistance Syndromes: Case Report and Review of the Literature. AB - Mutations in the insulin receptor (INSR) gene underlie rare severe INSR-related insulin resistance syndromes (SIR), including insulin resistance type A, Rabson Mendenhall syndrome and Donohue syndrome (DS), with DS representing the most severe form of insulin resistance. Treatment of these cases is challenging, with the majority of DS patients dying within the first two years of life. rhIGF-I (mecasermin) has been reported to improve metabolic control and increase lifespan in DS patients. A case report and literature review were completed. We present a case involving a male patient with DS, harbouring a homozygous mutation in the INSR gene (c.591delC). Initial rhIGF-I application via BID (twice daily) injection was unsatisfactory, but continuous subcutaneous rhIGF-I infusion via an insulin pump improved weight development and diabetes control (HbA1c decreased from 10 to 7.6%). However, our patient died at 22 months of age during the course of a respiratory infection in in Libya. Currently available data in the literature comprising more than 30 treated patients worldwide seem to support a trial of rhIGF-I in SIR. rhIGF-I represents a treatment option for challenging SIR cases, but careful consideration of the therapeutic benefits and the burden of the disease is warranted. Continuous application via pump might be advantageous compared to single injections. PMID- 29695052 TI - Sulforaphane Modulates Joint Inflammation in a Murine Model of Complete Freund's Adjuvant-Induced Mono-Arthritis. AB - Rheumatoid arthritis (RA) is characterized by inflammation of one or more joints, and affects ~1% of the adult population worldwide. Sulforaphane (SFN) is a natural compound that has been suggested as an antioxidant. Here, SFN’s effects were evaluated in a murine mono-arthritis model. Mono-arthritis was induced in mice by a single intra-articular injection of Complete Freund’s Adjuvant (CFA-10 µg/joint, in 10 µL) into the ipsilateral joint. The contralateral joint received an equal volume of PBS. On the 4th day post-joint inflammation induction, animals received either SFN (10 mg/kg) or vehicle (3% DMSO in saline), intraperitoneally (i.p.), twice a day for 3 days. Joint swelling and secondary mechanical allodynia and hyperalgesia were evaluated over 7 days post-CFA. After this period, animals were culled and their blood and synovial fluid samples were collected for analysis of cell populations, cytokine release and thioredoxin reductase (TrxR) activity. Knee joint samples were also collected for histology. SFN reduced joint swelling and damage whilst increasing the recruitment of Ly6C+ and Ly6G+ cells to CFA-injected joints. SFN-treated animals presented down-regulation of CD11b and CD62L on synovial fluid Ly6G+ cells. Synovial fluid samples obtained from CFA-injected joints and plasma samples of SFN-treated mice presented higher levels of IL-6 and increased activity of TrxR, in comparison with controls. These results indicate that SFN reduces knee joint damage by modulating cell activation/migration to the joints, cytokine production and increasing the activity of TrxR, and therefore, may represent an alternative treatment to joint inflammation. PMID- 29695054 TI - Effects of Environmental Air Pollution on Pulmonary Function Level of Residents in Korean Industrial Complexes. AB - This study aims to identify environmental air pollution adversely affecting pulmonary function among a community-based general population living in Korean industrial complexes. A total of 1963 residents participated in a pulmonary function test (PFT). The sample population consisted of an exposed group (n = 1487) living within a radius of 5 km of industrial complexes and a control group (n = 476) living over a radius of 10 km from the industrial complexes in Gwangyang and Yeosu cities. PFT results were calculated for each resident of the study population. On-site questionnaire surveys with face-to-face interviews were also conducted to collect more detailed information on personal lifestyles, medical history, exposure to air pollution, and respiratory disease and related symptoms. A total of 486 measured samples were collected by eight automated air monitoring stations installed in four counties of Gwangyang and four counties of Yeosu in South Korea from January 2006 to February 2007. Mean levels of SO2 (0.012 ppm), CO (0.648 ppm), NO2 (0.02 ppm), O3 (0.034 ppm), and PM10 (43.07 μg/m3), collected within a radius of 5 km, were significantly higher than those collected over a radius of 10 km from Gwangyang and Yeosu industrial complexes. Prevalence odds ratio (OR) of abnormal pulmonary function in the exposed group of residents (<5 km) was elevated at 1.24 (95% CI 0.71-1.96), but not statistically significant (p > 0.05). In multiple linear regression analysis, forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) levels significantly declined as SO2, CO, and O3 levels increased when adjusting for age, sex, body mass index (BMI), alcohol, smoking, secondhand smoke, and respiratory disease and related symptoms (n = 1963) (p < 0.05). These results suggest that exposure to air pollution affects pulmonary function levels of residents living in Korean industrial complexes. PMID- 29695053 TI - VEGF (Vascular Endothelial Growth Factor) and Fibrotic Lung Disease. AB - Interstitial lung disease (ILD) encompasses a group of heterogeneous diseases characterised by varying degrees of aberrant inflammation and fibrosis of the lung parenchyma. This may occur in isolation, such as in idiopathic pulmonary fibrosis (IPF) or as part of a wider disease process affecting multiple organs, such as in systemic sclerosis. Anti-Vascular Endothelial Growth Factor (anti VEGF) therapy is one component of an existing broad-spectrum therapeutic option in IPF (nintedanib) and may become part of the emerging therapeutic strategy for other ILDs in the future. This article describes our current understanding of VEGF biology in normal lung homeostasis and how changes in its bioavailability may contribute the pathogenesis of ILD. The complexity of VEGF biology is particularly highlighted with an emphasis on the potential non-vascular, non angiogenic roles for VEGF in the lung, in both health and disease. PMID- 29695055 TI - Efficacy of a Moderately Low Carbohydrate Diet in a 36-Month Observational Study of Japanese Patients with Type 2 Diabetes. AB - We previously showed that a non-calorie-restricted, moderately low-carbohydrate diet (mLCD) is more effective than caloric restriction for glycemic and lipid profile control in patients with type 2 diabetes. To determine whether mLCD intervention is sustainable, effective, and safe over a long period, we performed a 36-month observational study. We sequentially enrolled 200 patients with type 2 diabetes and taught them how to follow the mLCD. We compared the following parameters pre- and post-dietary intervention in an outpatient setting: glycated hemoglobin (HbA1c), body weight, lipid profile (total cholesterol, low and high density lipoprotein cholesterol, triglycerides), systolic and diastolic blood pressure, liver enzymes (aspartate aminotransferase, alanine aminotransferase), and renal function (urea nitrogen, creatinine, estimated glomerular filtration rate). Data from 157 participants were analyzed (43 were lost to follow-up). The following parameters decreased over the period of study: HbA1c (from 8.0 +/- 1.5% to 7.5 +/- 1.3%, p < 0.0001) and alanine aminotransferase (from 29.9 +/- 23.6 to 26.2 +/- 18.4 IL/L, p = 0.009). Parameters that increased were high-density lipoprotein cholesterol (from 58.9 +/- 15.9 to 61.2 +/- 17.4 mg/dL, p = 0.001) and urea nitrogen (from 15.9 +/- 5.2 to 17.0 +/- 5.4 mg/dL, p = 0.003). Over 36 months, the mLCD intervention showed sustained effectiveness (without safety concerns) in improving HbA1c, lipid profile, and liver enzymes in Japanese patients with type 2 diabetes. PMID- 29695056 TI - Burden of Serious Fungal Infections in Argentina. AB - The number of fungal infections at any given time in Argentina is not known. Here we estimate the burden of serious fungal infections in Argentina for the first time. Specific population statistics were searched from multiple sources, local literature was identified, and estimates made. Some additional data were sourced from the Ministry of Health, the Global Initiative for Asthma (GINA) program, and national haematology and transplant societies. Argentina has a population of 43.8 million, with 25% of this total being children under 15 years. The predicted candidemia annual incidence is 2193 cases, with 50% occurring in the ICU. At a 6% prevalence rate, an estimated 593,695 women suffer from recurrent vulvovaginal candidiasis. Invasive aspergillosis is relatively common because of high smoking and chronic obstructive pulmonary disease (COPD) rates, with 268 cases in immunocompromised patients and another 1938 in the 168,000 COPD patients admitted to hospital. Asthma is also common, affecting 14% of adults, and so allergic bronchopulmonary aspergillosis (ABPA) and severe asthma with fungal sensitization (SAFS) are major problems. An estimated 432 cases of cryptococcal meningitis (CM) 90% of them in AIDS patients-and 1177 cases of Pneumocystis pneumonia (PCP) occur each year. The estimated annual case number of disseminated histoplasmosis is 404 in AIDS patients, almost as frequent as CM. Paracoccidioidomycosis annual incidence is estimated at 219, and coccidioidomycosis at 16 cases. At least 881,023 people (>2.01%) in Argentina are affected by a serious fungal disease annually, with considerable morbidity and mortality. PMID- 29695057 TI - Effects of UV-B Radiation on the Content of Bioactive Components and the Antioxidant Activity of Prunella vulgaris L. Spica during Development. AB - The effects of UV-B radiation on the content of bioactive components and the antioxidant activity of Prunella vulgaris L. spica during development were studied. The experimental design involved two levels of UV-B radiation intensity (0 and 120 MUW cm-2 nm-1). The results showed that the contents of total flavonoids, rosmarinic acid, caffeic acid and hyperoside, as well as the antioxidant capacities (DPPH? and ABTS*+ scavenging activities), in the spicas significantly decreased during spica development. The content of salviaflaside in the spicas significantly increased during development. The highest contents of total flavonoids, rosmarinic acid, and caffeic acid and the highest antioxidant activities were found in spicas in the full-flowering stage, while the highest content of hyperoside was found in spicas in the bud stage. In addition, the highest content of salviaflaside was found in spicas in the mature-fruiting stage. UV-B radiation significantly promoted the synthesis of secondary metabolites, increased the contents of the main bioactive components in the three developmental stages of isolated dried spicas, and significantly increased the DPPH? and ABTS*+ scavenging activities of P. vulgaris spicas in the mature fruiting stage. Moreover, the total flavonoids content was positively correlated with the DPPH? and ABTS*+ scavenging activities, and the correlation with the DPPH? scavenging activity was very strong. This result shows that the highest contents of the main bioactive components in the spicas were not all found in the same developmental stages of P. vulgaris. Our research revealed that the best stage for harvesting P. vulgaris spica was between the bud stage and the full flowering stage since harvesting at this point provides a higher content of bioactive components and a higher antioxidant capacity, which is relevant for medicinal applications. PMID- 29695058 TI - HPLC-ED Analysis of Phenolic Compounds in Three Bosnian Crataegus Species. AB - The aim of this work was the qualitative and quantitative determination of selected phenolic compounds in three Crataegus species grown in Bosnia. Crataegus plants are consumed for medicinal purposes and as foodstuff in the form of canned fruit, jam, jelly, tea, and wine. Two samples of plant material, dry leaves with flowers, and berries of three Crataegus species—Crataegus rhipidophylla Gand., Crataegus x subsphaericea Gand., and Crataegus x macrocarpa Hegetschw.—were analyzed. Twelve ethanolic extracts were isolated from the selected plant material using Soxhlet and ultrasound extraction, respectively. Soxhlet extraction proved to be more effective than ultrasound extraction. A simple and sensitive method, high-performance liquid chromatography with electrochemical detection, HPLC-ED, was used for the simultaneous determination of phenolic acids and flavonoids in Crataegus species. The content of gallic acid in the extracts ranged from 0.001 to 0.082 mg/g dry weight (DW), chlorogenic acid from 0.19 to 8.70 mg/g DW, and rutin from 0.03 to 13.49 mg/g DW. Two flavonoids, vitexin and hyperoside, commonly found in chemotaxonomic investigations of Crataegus species, were not detected in the examined extracts. In general, leaves with flowers samples are richer in gallic acid and rutin, whereas the berries samples are richer in chlorogenic acid. Distinct similarities were found in the relative distribution of gallic acid among the three species. Extracts of C. x macrocarpa had the highest content of all detected compounds, while significant differences were found in rutin content, depending on the plant organ. To the best of our knowledge, this is the first study reporting content of phenolic compounds in Crataegus rhipidophylla Gand., Crataegus x subsphaericea, and Crataegusxmacrocarpa from Bosnia. PMID- 29695060 TI - The Course of Parturition Affects Piglet Condition at Birth and Survival and Growth through the Nursery Phase. AB - The aim of this study was to relate the course of parturition to the condition of piglets at birth, based on umbilical cord blood acid-base values, and relate the condition at birth to neonatal survival and performance up to 10 weeks of life. Data were collected from 37 spontaneous unassisted parturitions, and neonatal performance was based on observations of 516 piglets. Stillbirth rate increased from 2% in the first piglets, to 17% in piglets born 13th in the litter or later. This was aggravated in sows with longer than average stage II of parturition. Umbilical cord blood values also reflected the effect of birth order, with pH decreasing and lactate increasing in the course of parturition. Interestingly, sows that had a long expulsion stage of parturition also took longer to give birth to the first four piglets (r = 0.74), suggesting that sows with complicated parturition were already experiencing problems at the start of expulsion of piglets. Piglets with signs of asphyxia, based on umbilical blood lactate higher than 4.46 mmol/L, were slower to start suckling, had a higher risk of neonatal mortality, and had a slower growth rate over the first 10 weeks of life. PMID- 29695059 TI - Synthesis and Guest Recognition of Switchable Pt-Salphen Based Molecular Tweezers. AB - Molecular tweezers are artificial receptors that have an open cavity generated by two recognition units pre-organized by a spacer. Switchable molecular tweezers, using a stimuli-responsive spacer, are particularly appealing as prototypes of the molecular machines that combine mechanical motion and allosteric recognition properties. In this present study, the synthesis of switchable molecular tweezers composed of a central terpyridine unit substituted in 4,4″ positions by two Pt(II)-salphen complexes is reported. The terpyridine ligand can be reversibly converted upon Zn(II) coordination from a free ‘U’-shaped closed form to a coordinated ‘W’ open form. This new substitution pattern enables a reverse control of the mechanical motion compared to the previously reported 6,6″ substituted terpyridine-based tweezers. Guest binding studies with aromatic guests showed an intercalation of coronene in the cavity created by the Pt-salphen moieties in the closed conformation. The formation of 1:1 host-guest complex was investigated by a combination of NMR studies and DFT calculations. PMID- 29695061 TI - Use of Leukocyte Platelet (L-PRF) Rich Fibrin in Diabetic Foot Ulcer with Osteomyelitis (Three Clinical Cases Report). AB - In this study, the use of fibrin rich in leukocytes and platelets (L-PRF) was explored to heal osteomyelitis ulcers in a diabetic foot. The goal was to standardize the utilization of L-PRF in patients with osteomyelitis to direct it for healing. L-PRF was obtained autologously from the peripheral blood of the diabetic patients (n = 3) having osteomyelitis and skin lesions for at least six months. The L-PRF and supernatant serum were inserted into the skin lesion to the bone after a surgical debridement. The evolution of lesions over time was analyzed. All three patients showed positivity to the Probe-to-Bone test and Nuclear Magnetic Resonance detected cortico-periosteal thickening and/or outbreaks of spongy cortical osteolysis in adjacency of the ulcer. The infections were caused by Cocci Gram-positive bacteria, such as S. Aureus, S. β hemolytic, S. Viridans and Bacilli; and Gram-negative such as Pseudomonas, Proteus, Enterobacter; and yeast, Candida. The blood count did not show any significant alterations. To date, all three patients have healed skin lesions (in a patient for about two years) with no evidence of infection. These preliminary results showed that L-PRF membranes could be a new method of therapy in such problematic diseases. Overall, the L-PRF treatment in osteomyelitis of a diabetic foot seems to be easy and cost-effective by regenerative therapy of chronic skin lesions. In addition, it will improve our understanding of wound healing. PMID- 29695063 TI - Displacement and Strain Measurement up to 1000 degrees C Using a Hollow Coaxial Cable Fabry-Perot Resonator. AB - We present a hollow coaxial cable Fabry-Perot resonator for displacement and strain measurement up to 1000 °C. By employing a novel homemade hollow coaxial cable made of stainless steel as a sensing platform, the high-temperature tolerance of the sensor is dramatically improved. A Fabry-Perot resonator is implemented on this hollow coaxial cable by introducing two highly-reflective reflectors along the cable. Based on a nested structure design, the external displacement and strain can be directly correlated to the cavity length of the resonator. By tracking the shift of the amplitude reflection spectrum of the microwave resonator, the applied displacement and strain can be determined. The displacement measurement experiment showed that the sensor could function properly up to 1000 °C. The sensor was also employed to measure the thermal strain of a steel plate during the heating process. The stability of the novel sensor was also investigated. The developed sensing platform and sensing configurations are robust, cost-effective, easy to manufacture, and can be flexibly designed for many other measurement applications in harsh high temperature environments. PMID- 29695062 TI - Perceived Discrimination and Binge Eating Disorder; Gender Difference in African Americans. AB - Environmental stressors, such as perceived discrimination (PD), are linked to Binge Eating Disorder (BED). The current study investigated the association between PD and BED among African Americans, and the variation in such an association based on gender. Data of the National Survey of American Life (NSAL), 2001-2003, with a nationally-representative sample of African American adults, were used (n = 3516). The independent variable in the study was PD. The dependent variable was BED, measured using the Composite International Diagnostic Interview (CIDI). Socio-demographics (age, education, employment, and marital status) were covariates, and gender was the moderator variable. Survey logistic regressions with and without gender × PD interaction terms were used for data analysis. In the pooled sample, PD was associated with higher odds of BED, net of socio demographic factors. Models also showed a significant gender × PD interaction term suggesting a stronger association between PD and BED for women, compared to men. Gender specific models showed an association between PD and BED among female, but not male, African Americans. Although a link may exist between PD and BED among African Americans, the magnitude of this association depends on gender, with a stronger association among females than males. This finding is in line with the literature that has shown gender-specific consequences of environmental stress for African Americans. PMID- 29695064 TI - Spoofing Detection Using GNSS/INS/Odometer Coupling for Vehicular Navigation. AB - Location information is one of the most vital information required to achieve intelligent and context-aware capability for various applications such as driverless cars. However, related security and privacy threats are a major holdback. With increasing focus on using Global Navigation Satellite Systems (GNSS) for autonomous navigation and related applications, it is important to provide robust navigation solutions, yet signal spoofing for illegal or covert transportation and misleading receiver timing is increasing and now frequent. Hence, detection and mitigation of spoofing attacks has become an important topic. Several contributions on spoofing detection have been made, focusing on different layers of a GNSS receiver. This paper focuses on spoofing detection utilizing self-contained sensors, namely inertial measurement units (IMUs) and vehicle odometer outputs. A spoofing detection approach based on a consistency check between GNSS and IMU/odometer mechanization is proposed. To detect a spoofing attack, the method analyses GNSS and IMU/odometer measurements independently during a pre-selected observation window and cross checks the solutions provided by GNSS and inertial navigation solution (INS)/odometer mechanization. The performance of the proposed method is verified in real vehicular environments. Mean spoofing detection time and detection performance in terms of receiver operation characteristics (ROC) in sub-urban and dense urban environments are evaluated. PMID- 29695065 TI - Isolation of High Purity Anthocyanin Monomers from Red Cabbage with Recycling Preparative Liquid Chromatography and Their Photostability. AB - Anthocyanins from red cabbage are of great importance for their applications in the food industry as natural colorants and their beneficial effects on human wellness as natural antioxidants. This study aimed to develop an effective method for the isolation of anthocyanins with the help of a combination of alternate recycling and direct recycling preparative liquid chromatography. Ten major components of anthocyanins from red cabbage were isolated and their structures were identified by HPLC-MS/MS. Meanwhile, the stability of the isolated anthocyanins under various light conditions was also investigated so as to provide data for their storage. In sum, the results showed that twin column recycling preparative chromatography is an effective method for the isolation of anthocyanin monomers with similar structures. Besides, the stability of various anthocyanins from red cabbage was related to the number of acylated groups and mainly affected by illumination. PMID- 29695066 TI - Learning Perfectly Secure Cryptography to Protect Communications with Adversarial Neural Cryptography. AB - Researches in Artificial Intelligence (AI) have achieved many important breakthroughs, especially in recent years. In some cases, AI learns alone from scratch and performs human tasks faster and better than humans. With the recent advances in AI, it is natural to wonder whether Artificial Neural Networks will be used to successfully create or break cryptographic algorithms. Bibliographic review shows the main approach to this problem have been addressed throughout complex Neural Networks, but without understanding or proving the security of the generated model. This paper presents an analysis of the security of cryptographic algorithms generated by a new technique called Adversarial Neural Cryptography (ANC). Using the proposed network, we show limitations and directions to improve the current approach of ANC. Training the proposed Artificial Neural Network with the improved model of ANC, we show that artificially intelligent agents can learn the unbreakable One-Time Pad (OTP) algorithm, without human knowledge, to communicate securely through an insecure communication channel. This paper shows in which conditions an AI agent can learn a secure encryption scheme. However, it also shows that, without a stronger adversary, it is more likely to obtain an insecure one. PMID- 29695067 TI - A Review of the Piezoelectric Electromechanical Impedance Based Structural Health Monitoring Technique for Engineering Structures. AB - The birth of smart materials such as piezoelectric (PZT) transducers has aided in revolutionizing the field of structural health monitoring (SHM) based on non destructive testing (NDT) methods. While a relatively new NDT method known as the electromechanical (EMI) technique has been investigated for more than two decades, there are still various problems that must be solved before it is applied to real structures. The technique, which has a significant potential to contribute to the creation of one of the most effective SHM systems, involves the use of a single PZT for exciting and sensing of the host structure. In this paper, studies applied for the past decade related to the EMI technique have been reviewed to understand its trend. In addition, new concepts and ideas proposed by various authors are also surveyed, and the paper concludes with a discussion of the potential directions for future works. PMID- 29695068 TI - Cationic Liposomes Carrying siRNA: Impact of Lipid Composition on Physicochemical Properties, Cytotoxicity and Endosomal Escape. AB - In recent year, cationic liposomes have gained a lot of attention for siRNA delivery. Despite this, intracellular barriers as endosomal escape and cytosolic delivery of siRNA still represent a challeng, as well as the cytotoxicity due to cationic lipids. To address these issues, we developed four liposomal formulations, composed of two different cationic lipids (DOTAP and DC Cholesterol) and different ratio of co-lipids (cholesterol and DOPE). The objective is to dissect these impacts on siRNA efficacy and cytotoxicity. Liposomes were complexed to siRNA at six different N/P molar ratios, physico chemical properties were characterized, and consequently, N/P 2.5, 5 and 10 were selected for in vitro experiments. We have shown that cytotoxicity is influenced by the N/P ratio, the concentration of cationic lipid, as well as the nature of the cationic lipid. For instance, cell viability decreased by 70% with liposomes composed of DOTAP/Cholesterol/DOPE 1/0.75/0.5 at a N/P ratio 10, whereas the same formulation at a N/P ratio of 2.5 was safe. Interestingly, we have observed differences in terms of mRNA knock-down efficiency, whereas the transfection rate was quite similar for each formulation. Liposomes containing 50% of DOPE induced a mRNA silencing of around 80%. This study allowed us to highlight crucial parameters in order to develop lipoplexes which are safe, and which induce an efficient intracytoplasmic release of siRNA. PMID- 29695069 TI - Mobile Exergaming in Adolescents' Everyday Life-Contextual Design of Where, When, with Whom, and How: The SmartLife Case. AB - Exergames, more specifically console-based exergames, are generally enjoyed by adolescents and known to increase physical activity. Nevertheless, they have a reduced usage over time and demonstrate little effectiveness over the long term. In order to increase playing time, mobile exergames may increase potential playing time, but need to be engaging and integrated in everyday life. The goal of the present study was to examine the context of gameplay for mobile exergaming in adolescents’ everyday life to inform game design and the integration of gameplay into everyday life. Eight focus groups were conducted with 49 Flemish adolescents (11 to 17 years of age). The focus groups were audiotaped, transcribed, and analyzed by means of thematic analysis via Nvivo 11 software (QSR International Pty Ltd., Victoria, Australia). The adolescents indicated leisure time and travel time to and from school as suitable timeframes for playing a mobile exergame. Outdoor gameplay should be restricted to the personal living environment of adolescents. Besides outdoor locations, the game should also be adaptable to at-home activities. Activities could vary from running outside to fitness exercises inside. Furthermore, the social context of the game was important, e.g., playing in teams or meeting at (virtual) meeting points. Physical activity tracking via smart clothing was identified as a motivator for gameplay. By means of this study, game developers may be better equipped to develop mobile exergames that embed gameplay in adolescents’ everyday life. PMID- 29695071 TI - Evaluation of Oral Mucositis Occurrence in Oncologic Patients under Antineoplastic Therapy Submitted to the Low-Level Laser Coadjuvant Therapy. AB - Low-level laser therapy has been widely used in treating many conditions, including oral mucositis. The purpose of this study was to evaluate the occurrence of oral mucositis in patients undergoing antineoplastic therapy submitted to preventive and therapeutic treatment with low-level laser therapy. This cross-sectional study was carried out with 51 children and adolescents of both sexes with malignant neoplasias who developed oral mucositis and underwent low-level laser therapy. Data were collected on sex, age, type and degree of neoplasia, region affected, and remission time. 64.7% of the patients were male and were between 3 and 6 years of age (39.2%). Acute lymphoid leukemia was the most frequent neoplasm (37.3%). Regarding the maximum oral mucositis, grade 2 (41.2%) was predominant, with jugal mucosa (29.9%) and tongue (17.7%) being the most affected regions. The majority of cases presented lesion remission time between 4 and 7 days (44.0%). Most patients were young, male, and diagnosed with acute lymphoid leukemia. Predominance of grade 2 oral mucositis was observed, with jugal mucosa and tongue being the most affected regions, with the majority of cases presenting lesion remission time between 4 and 7 days. Low-level laser therapy has been shown to be an essential therapy in the prevention and treatment of these lesions, since it is a non-invasive and low-cost method. PMID- 29695072 TI - Evaluation of Two Compressed Air Foam Systems for Culling Caged Layer Hens. AB - Outbreaks of avian influenza (AI) and other highly contagious poultry diseases continue to be a concern for those involved in the poultry industry. In the situation of an outbreak, emergency depopulation of the birds involved is necessary. In this project, two compressed air foam systems (CAFS) were evaluated for mass emergency depopulation of layer hens in a manure belt equipped cage system. In both experiments, a randomized block design was used with multiple commercial layer hens treated with one of three randomly selected depopulation methods: CAFS, CAFS with CO2 gas, and CO2 gas. In Experiment 1, a Rowe manufactured CAFS was used, a selection of birds were instrumented, and the time to unconsciousness, brain death, altered terminal cardiac activity and motion cessation were recorded. CAFS with and without CO2 was faster to unconsciousness, however, the other parameters were not statistically significant. In Experiment 2, a custom Hale based CAFS was used to evaluate the impact of bird age, a selection of birds were instrumented, and the time to motion cessation was recorded. The difference in time to cessation of movement between pullets and spent hens using CAFS was not statistically significant. Both CAFS depopulate caged layers, however, there was no benefit to including CO2. PMID- 29695073 TI - Design, Synthesis, and Docking Studies of New Torin2 Analogs as Potential ATR/mTOR Kinase Inhibitors. AB - Targeting DNA damage and response (DDR) pathway has become an attractive approach in cancer therapy. The key mediators involved in this pathway are ataxia telangiectasia-mutated kinase (ATM) and ataxia telangiectasia-mutated, Rad3 related kinase (ATR). These kinases induce cell cycle arrest in response to chemo and radio-therapy and facilitate DNA repair via their major downstream targets. Targeting ATP-binding site of these kinases is currently under study. Torin2 is a second generation ATP competitive mTOR kinase inhibitor (EC50 = 250 pmol/L) with better pharmacokinetic profile. Torin2 also exhibits potent biochemical and cellular activity against ATM (EC50 = 28 nmol/L) and ATR (EC50 = 35 nmol/L) kinases. In this study, eight new Torin2 analogs were designed and synthesized through multistep synthesis. All the synthesized compounds were characterized by NMR and mass analysis. The newly synthesized analogs were evaluated for their anti-cancer activity via CellTiter-Glo(r) assay. Additionally, compounds 13 and 14 also showed significant inhibition for ATR and mTOR substrates, i.e., p-Chk1 Ser 317 and p70 S6K Thr 389, respectively. Compounds 13 and 14 displayed promising anti-cancer activity with HCT-116 cell lines in the preliminary study. Further, a comparative model of ATR kinase was generated using the SWISS-MODEL server and validated using PROCHECK, ProSA analysis. Synthesized compounds were docked into the ATP-binding site to understand the binding modes and for the rational design of new inhibitors. PMID- 29695070 TI - The Novel Roles of Connexin Channels and Tunneling Nanotubes in Cancer Pathogenesis. AB - Neoplastic growth and cellular differentiation are critical hallmarks of tumor development. It is well established that cell-to-cell communication between tumor cells and "normal" surrounding cells regulates tumor differentiation and proliferation, aggressiveness, and resistance to treatment. Nevertheless, the mechanisms that result in tumor growth and spread as well as the adaptation of healthy surrounding cells to the tumor environment are poorly understood. A major component of these communication systems is composed of connexin (Cx)-containing channels including gap junctions (GJs), tunneling nanotubes (TNTs), and hemichannels (HCs). There are hundreds of reports about the role of Cx-containing channels in the pathogenesis of cancer, and most of them demonstrate a downregulation of these proteins. Nonetheless, new data demonstrate that a localized communication via Cx-containing GJs, HCs, and TNTs plays a key role in tumor growth, differentiation, and resistance to therapies. Moreover, the type and downstream effects of signals communicated between the different populations of tumor cells are still unknown. However, new approaches such as artificial intelligence (AI) and machine learning (ML) could provide new insights into these signals communicated between connected cells. We propose that the identification and characterization of these new communication systems and their associated signaling could provide new targets to prevent or reduce the devastating consequences of cancer. PMID- 29695074 TI - Socioeconomic Status and Self-Rated Oral Health; Diminished Return among Hispanic Whites. AB - Background. An extensive body of knowledge has documented weaker health effects of socio-economic status (SES) for Blacks compared to Whites, a phenomenon also known as Blacks’ diminished return. It is, however, unknown whether the same diminished return also holds for other ethnic minorities such as Hispanics or not. Aim. Using a nationally representative sample, the current study aimed to compare Non-Hispanic and Hispanic Whites for the effects of SES on self-rated oral health. Methods. For the current cross-sectional study, we used data from the Collaborative Psychiatric Epidemiology Surveys (CPES), 2001-2003. With a nationally representative sampling, CPES included 11,207 adults who were either non-Hispanic Whites (n = 7587) or Hispanic Whites (n = 3620. The dependent variable was self-rated oral health, treated as dichotomous measure. Independent variables were education, income, employment, and marital status. Ethnicity was the focal moderator. Age and gender were covariates. Logistic regressions were used for data analysis. Results. Education, income, employment, and marital status were associated with oral health in the pooled sample. Although education, income, employment, and marital status were associated with oral health in non Hispanic Whites, none of these associations were found for Hispanic Whites. Conclusion. In a similar pattern to Blacks’ diminished return, differential gain of SES indicators exists between Hispanic and non-Hispanic Whites, with a disadvantage for Hispanic Whites. Diminished return of SES should be regarded as a systemically neglected contributing mechanism behind ethnic oral health disparities in the United States. Replication of Blacks’ diminished return for Hispanics suggests that these processes are not specific to ethnic minority groups, and non-White groups gain less because they are not enjoying the privilege and advantage of Whites. PMID- 29695075 TI - Update on Multiple Ovulations in Dairy Cattle. AB - This review updates the causal mechanisms and risk factors for multiple ovulations (MOV) in cattle. Clearly, MOV can lead to twin pregnancies, which negatively affects the health, production, and reproduction of cows. Therefore, a better understanding of the factors causing MOV may help to reduce twinning. Multiple ovulations occur after two or more follicles deviate and achieve codominance. The MOV rate is influenced by a complex network of hormones. For example, MOV is more common during periods of low progesterone (P4), that is, in anovulatory cattle or when luteolysis coincides with the selection of the future ovulatory follicle. There is also strong evidence for the luteinizing hormone (LH) being the primary factor leading to codominance, as high P4 concentrations suppress the transient LH surges and can reduce the ovulation rate in cattle or even inhibit deviation. Rates of MOV are increased in older and higher-producing dairy cows. Increased milk production and dry matter intake (DMI) increases hormone clearance, including P4; however, the association between milk yield and MOV has not been consistent. Additional risk factors for MOV include ovarian cysts, diet, season, and genetics. PMID- 29695076 TI - Smart Crack Control in Concrete through Use of Phase Change Materials (PCMs): A Review. AB - Cracks in concrete structures present a threat to their durability. Therefore, numerous research studies have been devoted to reducing concrete cracking. In recent years, a new approach has been proposed for controlling temperature related cracking—utilization of phase change materials (PCMs) in concrete. Through their ability to capture heat, PCMs can offset temperature changes and reduce gradients in concrete structures. Nevertheless, they can also influence concrete properties. This paper presents a comprehensive overview of the literature devoted to using PCMs to control temperature related cracking in concrete. First, types of PCMs and ways of incorporation in concrete are discussed. Then, possible uses of PCMs in concrete technology are discussed. Further, the influences of PCMs on concrete properties (fresh, hardened, durability) are discussed in detail. This is followed by a discussion of modelling techniques for PCM-concrete composites and their performance. Finally, a summary and the possible research directions for future work are given. This overview aims to assure the researchers and asset owners of the potential of this maturing technology and bring it one step closer to practical application. PMID- 29695077 TI - Role of Bioreactor Technology in Tissue Engineering for Clinical Use and Therapeutic Target Design. AB - Micro and small bioreactors are well described for use in bioprocess development in pre-production manufacture, using ultra-scale down and microfluidic methodology. However, the use of bioreactors to understand normal and pathophysiology by definition must be very different, and the constraints of the physiological environment influence such bioreactor design. This review considers the key elements necessary to enable bioreactors to address three main areas associated with biological systems. All entail recreation of the in vivo cell niche as faithfully as possible, so that they may be used to study molecular and cellular changes in normal physiology, with a view to creating tissue-engineered grafts for clinical use; understanding the pathophysiology of disease at the molecular level; defining possible therapeutic targets; and enabling appropriate pharmaceutical testing on a truly representative organoid, thus enabling better drug design, and simultaneously creating the potential to reduce the numbers of animals in research. The premise explored is that not only cellular signalling cues, but also mechano-transduction from mechanical cues, play an important role. PMID- 29695078 TI - The Relationship between Urbanization, the Built Environment, and Physical Activity among Older Adults in Taiwan. AB - Urbanization and ageing are global phenomena and offer unique challenges in different countries. A supportive environment plays a critical role in addressing the issue of behavioral change and health promotion among older adults. Many studies in the U.S., EU, and Australia have considered promoting physical activity in the community based on ecological models, whereas very few Asian studies have examined the relationships among urbanization, the built environment and physical activity in elderly at the ecological level, especially from a multi level perspective. Due to the prevalence of post-war baby boomers and a very low birth-rate, the older population (aged 65 years old and older) in Taiwan has increased rapidly since 2011 and has exceeded the younger generation (0-14 years old) in 2017. Hence, the purpose of this study was first to examine the degree of urbanization in townships and the status of related built environments in Taiwan and then to investigate whether the built environment is associated with recommended amounts of physical activity among older adults. Three national datasets and a multi-level design were used in this research. Data at the individual level was obtained from the 2009 National Health Interview Survey (NHIS) which was taken from June 2009 to February 2010. Ecological data was obtained from the 2006 National Land Use Investigation of the National Geographic Information System and the 2010 Population and Housing Census. The analyses included a descriptive analysis, a bivariate analysis, a multiple logistic regression, and a multi-level analysis, utilizing a mostly hierarchical linear model (HLM). The results showed a significant relationship between factors at the environmental levels and physical activity in older adults. Urbanization, the built environment, and the median income of townships were positively correlated to the physical activity of the older adults. After controlling for individual level factors, urbanization still exhibited this correlation. Parks and green spaces were associated with achieving the recommended amount of physical activity. However, there was no relationship after controlling for factors at the individual level. Detailed discussions were provided. PMID- 29695079 TI - The Role of Adipokines in Intervertebral Disc Degeneration. AB - Intervertebral disc degeneration (IDD) is an important cause of low back pain. Recent evidence suggests that in addition to abnormal and excessive mechanical loading, inflammation may be a key driver for both IDD and low back pain. Obesity, a known mechanical risk factor of IDD, is now increasingly being recognized as a systemic inflammatory state with adipokines being postulated as likely inflammatory mediators. The aim of this review was to summarize the current literature regarding the inflammatory role of adipokines in the pathophysiology of IDD. A systematic literature search was performed using the OVID Medline, EMBASE and PubMed databases to identify all studies assessing IDD and adipokines. Fifteen studies were included in the present review. Leptin was the most commonly assessed adipokine. Ten of 15 studies were conducted in humans; three in rats and two in both humans and rats. Studies focused on a variety of topics ranging from receptor identification, pathway analysis, genetic associations, and proteonomics. Currently, data from both human and animal experiments demonstrate significant effects of leptin and adiponectin on the internal milieu of intervertebral discs. However, future studies are needed to determine the molecular pathway relationships between adipokines in the pathophysiology of IDD as avenues for future therapeutic targets. PMID- 29695080 TI - Fabrication and Adsorption Behavior of Magnesium Silicate Hydrate Nanoparticles towards Methylene Blue. AB - Magnesium silicate as a high-performance adsorption material has attracted increasing attention for the removal of organic dye pollution. Here, we prepared a series of magnesium silicate hydrates (MSH) in a hydrothermal route, and carefully investigated the corresponding adsorption behavior towards methylene blue (MB) as well as the effect of surface charge on adsorption capacity. The results show that surface charge plays a key role in the adsorption performance of MSH for MB, a negative surface charge density follows the increase of Si/Mg feeding ratio from 1.00 to 1.75, and furthermore the higher negative charge favors the improvement of the adsorption capacity. Among four investigated samples (MSH = 1.00, 1.25, 1.50, and 1.75), MSH-1.75 has the highest negative surface charge and shows the largest adsorption capacity for MB. For example, the equilibrium adsorption quantity is 307 mg·g−1 for MSH-1.75, which is 35% higher than that of 227 mg·g−1 for MSH-1.00. Besides, for MSH 1.75, the as-prepared sample with negative charge exhibits ca. 36% higher adsorption quantity compared to the sample at the zero point of charge (pHZPC). Furthermore, magnesium silicate hydrate material with Si/Mg feeding ratio = 1.75 demonstrates the promising removal efficiency of beyond 98% for methylene blue in 10 min, and the maximum adsorption capacity of 374 mg·g−1 calculated from the Langmuir isotherm model. PMID- 29695081 TI - Assessing the Effects of Alloxydim Phototransformation Products by QSAR Models and a Phytotoxicity Study. AB - Once applied, an herbicide first makes contact with leaves and soil. It is known that photolysis can be one of the most important processes of dissipation of herbicides in the field. However, degradation does not guarantee detoxification and can give rise to byproducts that could be more toxic and/or persistent than the active substance. In this work, the photodegradation of alloxydim herbicide in soil and leaf cuticle surrogates was studied and a detailed study on the phytotoxicity of the main byproduct on sugar beet, tomato, and rotational crops was performed. Quantitative structure-activity relationship (QSAR) models were used to obtain a first approximation of the possible ecotoxicological and environmental implications of the alloxydim and its degradation product. The results show that alloxydim is rapidly degraded on carnauba and sandy loam soil surfaces, two difficult matrices to analyze and not previously studied with alloxydim. Two transformation products that formed in both matrices were identified: alloxydim Z-isomer and imine derivative (mixture of two tautomers). The phytotoxicity of alloxydim and the major byproduct shows that tomato possesses high sensitivity to the imine byproduct, while wheat crops are inhibited by the parent compound. This paper demonstrates the need to further investigate the behavior of herbicide degradation products on target and nontarget species to determine the adequate use of herbicidal products to maximize productivity in the context of sustainable agriculture. PMID- 29695082 TI - Marine Omega-3 Fatty Acids, Complications of Pregnancy and Maternal Risk Factors for Offspring Cardio-Metabolic Disease. AB - Marine omega-3 polyunsaturated fatty acids (n-3 PUFA) are important nutrients during periods of rapid growth and development in utero and infancy. Maternal health and risk factors play a crucial role in birth outcomes and subsequently offspring cardio-metabolic health. Evidence from observational studies and randomized trials have suggested a potential association of maternal intake of marine n-3 PUFAs during pregnancy with pregnancy and birth outcomes. However, there is inconsistency in the literature on whether marine n-3 PUFA supplementation during pregnancy can prevent maternal complications of pregnancy. This narrative literature review summarizes recent evidence on observational and clinical trials of marine n-3 PUFA intake on maternal risk factors and effects on offspring cardio-metabolic health. The current evidence generally does not support a role of maternal n-3 PUFA supplementation in altering the incidence of gestational diabetes, pregnancy-induced hypertension, or pre-eclampsia. It may be that benefits from marine n-3 PUFA supplementation are more pronounced in high risk populations, such as women with a history of complications of pregnancy, or women with low marine n-3 PUFA intake. Discrepancies between studies may be related to differences in study design, dosage, fatty acid interplay, and length of treatment. Further prospective double-blind studies are needed to clarify the impact of long-chain marine n-3 PUFAs on risk factors for cardio-metabolic disease in the offspring. PMID- 29695084 TI - Residual Error Based Anomaly Detection Using Auto-Encoder in SMD Machine Sound. AB - Detecting an anomaly or an abnormal situation from given noise is highly useful in an environment where constantly verifying and monitoring a machine is required. As deep learning algorithms are further developed, current studies have focused on this problem. However, there are too many variables to define anomalies, and the human annotation for a large collection of abnormal data labeled at the class-level is very labor-intensive. In this paper, we propose to detect abnormal operation sounds or outliers in a very complex machine along with reducing the data-driven annotation cost. The architecture of the proposed model is based on an auto-encoder, and it uses the residual error, which stands for its reconstruction quality, to identify the anomaly. We assess our model using Surface-Mounted Device (SMD) machine sound, which is very complex, as experimental data, and state-of-the-art performance is successfully achieved for anomaly detection. PMID- 29695083 TI - The Commonly Used Bactericide Bismerthiazol Promotes Rice Defenses against Herbivores. AB - Chemical elicitors that enhance plant resistance to pathogens have been extensively studied, however, chemical elicitors that induce plant defenses against insect pests have received little attention. Here, we found that the exogenous application of a commonly used bactericide, bismerthiazol, on rice induced the biosynthesis of constitutive and/or elicited jasmonic acid (JA), jasmonoyl-isoleucine conjugate (JA-Ile), ethylene and H2O2 but not salicylic acid. These activated signaling pathways altered the volatile profile of rice plants. White-backed planthopper (WBPH, Sogatella furcifera) nymphs and gravid females showed a preference for feeding and/or oviposition on control plants: survival rates were better and more eggs were laid than on bismerthiazol-treated plants. Moreover, bismerthiazol treatment also increased both the parasitism rate of WBPH eggs laid on plants in the field by Anagrus nilaparvatae, and also the resistance of rice to the brown planthopper (BPH) Nilaparvata lugens and the striped stem borer (SSB) Chilo suppressalis. These findings suggest that the bactericide bismerthiazol can induce the direct and/or indirect resistance of rice to multiple insect pests, and so can be used as a broad-spectrum chemical elicitor. PMID- 29695085 TI - The Sequence of Two Bacteriophages with Hypermodified Bases Reveals Novel Phage Host Interactions. AB - Bacteriophages SP-15 and ΦW-14 are members of the Myoviridae infecting Bacillus subtilis and Delftia (formerly Pseudomonas) acidovorans, respectively. What links them is that in both cases, approximately 50% of the thymine residues are replaced by hypermodified bases. The consequence of this is that the physico chemical properties of the DNA are radically altered (melting temperature (Tm), buoyant density and susceptibility to restriction endonucleases). Using 454 pyrosequencing technology, we sequenced the genomes of both viruses. Phage ΦW 14 possesses a 157-kb genome (56.3% GC) specifying 236 proteins, while SP-15 is larger at 222 kb (38.6 mol % G + C) and encodes 318 proteins. In both cases, the phages can be considered genomic singletons since they do not possess BLASTn homologs. While no obvious genes were identified as being responsible for the modified base in ΦW-14, SP-15 contains a cluster of genes obviously involved in carbohydrate metabolism. PMID- 29695086 TI - To Decipher the Mycoplasma hominis Proteins Targeting into the Endoplasmic Reticulum and Their Implications in Prostate Cancer Etiology Using Next Generation Sequencing Data. AB - Cancer was initially considered a genetic disease. However, recent studies have revealed the connection between bacterial infections and growth of different types of cancer. The enteroinvasive strain of Mycoplasma hominis alters the normal behavior of host cells that may result in the growth of prostate cancer. The role of M. hominis in the growth and development of prostate cancer still remains unclear. The infection may regulate several factors that influence prostate cancer growth in susceptible individuals. The aim of this study was to predict M. hominis proteins targeted into the endoplasmic reticulum (ER) of the host cell, and their potential role in the induction of prostate cancer. From the whole proteome of M. hominis, 19 proteins were predicted to be targeted into the ER of host cells. The results of our study predict that several proteins of M. hominis may be targeted to the host cell ER, and possibly alter the normal pattern of protein folding. These predicted proteins can modify the normal function of the host cell. Thus, the intercellular infection of M. hominis in host cells may serve as a potential factor in prostate cancer etiology. PMID- 29695087 TI - Contribution of Tumor Endothelial Cells in Cancer Progression. AB - Tumor progression depends on the process of angiogenesis, which is the formation of new blood vessels. These newly formed blood vessels supply oxygen and nutrients to the tumor, supporting its progression and providing a gateway for tumor metastasis. Tumor angiogenesis is regulated by the balance between angiogenic activators and inhibitors within the tumor microenvironment. Because the newly formed tumor blood vessels originate from preexisting normal vessels, tumor blood vessels, and tumor endothelial cells (TECs) have historically been considered to be the same as normal blood vessels and endothelial cells; however, evidence of TECs’ distinctive abnormal phenotypes has increased. In addition, it has been revealed that TECs constitute a heterogeneous population. Thus, TECs that line tumor blood vessels are important targets in cancer therapy. We have previously reported that TECs induce cancer metastasis. In this review, we describe recent studies on TEC abnormalities related to cancer progression to provide insight into new anticancer therapies. PMID- 29695088 TI - Synthesis and Acaricidal Activities of Scopoletin Phenolic Ether Derivatives: QSAR, Molecular Docking Study and in Silico ADME Predictions. AB - Thirty phenolic ether derivatives of scopoletin modified at the 7-hydroxy position were synthesized, and their structures were confirmed by IR, 1H-NMR, 13C NMR, MS and elemental analysis. Preliminary acaricidal activities of these compounds against female adults of Tetranychus cinnabarinus (Boisduval) were evaluated using the slide-dip method. The results indicated that some of these compounds exhibit more pronounced acaricidal activity than scopoletin, especially compounds 32, 20, 28, 27 and 8 which exhibited about 8.41-, 7.32-, 7.23-, 6.76-, and 6.65-fold higher acaricidal potency. Compound 32 possessed the the most promising acaricidal activity and exhibited about 1.45-fold higher acaricidal potency against T. cinnabarinus than propargite. Statistically significant 2D QSAR model supports the observed acaricidal activities and reveals that polarizability (HATS5p) was the most important parameter controlling bioactivity. 3D-QSAR (CoMFA: q2 = 0.802, r2 = 0.993; CoMSIA: q2 = 0.735, r2 = 0.965) results show that bulky substituents at R4, R1, R2 and R5 (C6, C3, C4, and C7) positions, electron positive groups at R5 (C7) position, hydrophobic groups at R1 (C3) and R2 (C4), H-bond donors groups at R1 (C3) and R4 (C6) will increase their acaricidal activity, which provide a good insight into the molecular features relevant to the acaricidal activity for further designing novel acaricidal agents. Molecular docking demonstrates that these selected derivatives display different bide modes with TcPMCA1 from lead compound and they interact with more key amino acid residues than scopoletin. In silico ADME properties of scopoletin and its phenolic ether derivatives were also analyzed and showed potential to develop as good acaricidal candidates. PMID- 29695089 TI - Social Network Analysis Applied to a Historical Ethnographic Study Surrounding Home Birth. AB - Safety during birth has improved since hospital delivery became standard practice, but the process has also become increasingly medicalised. Hence, recent years have witnessed a growing interest in home births due to the advantages it offers to mothers and their newborn infants. The aims of the present study were to confirm the transition from a home birth model of care to a scenario in which deliveries began to occur almost exclusively in a hospital setting; to define the social networks surrounding home births; and to determine whether geography exerted any influence on the social networks surrounding home births. Adopting a qualitative approach, we recruited 19 women who had given birth at home in the mid 20th century in a rural area in Spain. We employed a social network analysis method. Our results revealed three essential aspects that remain relevant today: the importance of health professionals in home delivery care, the importance of the mother’s primary network, and the influence of the geographical location of the actors involved in childbirth. All of these factors must be taken into consideration when developing strategies for maternal health. PMID- 29695091 TI - Theoretical Investigations of the Hexagonal Germanium Carbonitride. AB - The structural, mechanical, elastic anisotropic, and electronic properties of hexagonal germanium carbonitride (h-GeCN) are systematically investigated using the first-principle calculations method with the ultrasoft pseudopotential scheme in the frame of generalized gradient approximation in the present work. The h GeCN are mechanically and dynamically stable, as proved by the elastic constants and phonon spectra, respectively. The h-GeCN is brittle because the ratio B/G and Poisson’s ratio v of the h-GeCN are less than 1.75 and 0.26, respectively. For h-GeCN, from brittleness to ductility, the transformation pressures are 5.56 GPa and 5.63 GPa for B/G and Poisson’s ratio v, respectively. The h-GeCN exhibits the greater elastic anisotropy in Young’s modulus and the sound velocities. In addition, the calculated band structure of h-GeCN reveals that there is no band gap for h-GeCN with the HSE06 hybrid functional, so the h-GeCN is metallic. PMID- 29695090 TI - Scale-Up Synthesis and Identification of GLYX-13, a NMDAR Glycine-Site Partial Agonist for the Treatment of Major Depressive Disorder. AB - GLYX-13, a NMDAR glycine-site partial agonist, was discovered as a promising antidepressant with rapidly acting effects but no ketamine-like side effects. However, the reported synthetic process route had deficiencies of low yield and the use of unfriendly reagents. Here, we report a scaled-up synthesis of GLYX-13 with an overall yield of 30% on the hectogram scale with a column chromatography free strategy, where the coupling and deprotection reaction conditions were systematically optimized. Meanwhile, the absolute configuration of precursor compound of GLYX-13 was identified by X-ray single crystal diffraction. Finally, the activity of GLYX-13 was verified in the cortical neurons of mice through whole-cell voltage-clamp technique. PMID- 29695092 TI - Towards an Electrochemical Immunosensor System with Temperature Control for Cytokine Detection. AB - The cytokine interleukin-13 (IL-13) plays a major role in airway inflammation and is a target of new anti-asthmatic drugs. Hence, IL-13 determination could be interesting in assessing therapy success. Thus, in this work an electrochemical immunosensor for IL-13 was developed and integrated into a fluidic system with temperature control for read-out. Therefore, two sets of results are presented. First, the sensor was set up in sandwich format on single-walled carbon nanotube electrodes and was read out by applying the hydrogen peroxide-hydroquinone horseradish peroxidase (HRP) system. Second, a fluidic system was built up with an integrated heating function realized by Peltier elements that allowed a temperature-controlled read-out of the immunosensor in order to study the influence of temperature on the amperometric read-out. The sensor was characterized at the temperature optimum of HRP at 30 degrees C and at 12 degrees C as a reference for lower performance. These results were compared to a measurement without temperature control. At the optimum operation temperature of 30 degrees C, the highest sensitivity (slope) was obtained compared to lower temperatures and a limit of detection of 5.4 ng/mL of IL-13 was calculated. Taken together, this approach is a first step towards an automated electrochemical immunosensor platform and shows the potential of a temperature-controlled read out. PMID- 29695094 TI - Stand-Off Detection of Alcohol Vapors Exhaled by Humans. AB - Early detection of humans under the influence of alcohol in public places (workplace, public gathering) is particularly important for safety reasons. In this article, the theoretical analysis of stand-off detection of alcohol in the air exhaled by humans as well as experimental results of the developed experimental setup is presented. The concept of differential absorption of two laser beams at different wavelengths was used. The idea of using standard deviation of the relative difference of the amplitudes of two signals to detect the alcohol was applied for the first time. The idea was verified by the experiments and it was shown that a reliable device can be developed that can efficiently detect alcohol concentration in the exhaled air at the level of 0.3 mg/L (0.63‰). Moreover, the concept of such device examining humans entering a specific area was proposed. The results of this article may be useful to scientists or engineers working on alcohol detection in human blood. PMID- 29695093 TI - Furthering the Evidence of the Effectiveness of Employment Strategies for People with Mental Disorders in Europe: A Systematic Review. AB - (1) Purpose: This systematic review aims to assess the effectiveness of strategies used in the professional (re)integration of persons with mental disorders (MD) in European countries; (2) Methods: We conducted a search for scientific publications available in relevant electronic databases (Medline, PsycINFO, CDR-HTA, CDR-DARE, and Cochrane Library). The present study collected evidence on the effectiveness, from 2011 to 2016, of employment strategies for persons with MDs; (3) Results: A total of 18 studies were included, representing 5216 participants (aged 18-65, mean age of 38.5 years old) from 7 countries. Job access programs demonstrated effectiveness in four out of six studies. Return to work (RTW) interventions showed significant positive results in two studies, while four studies did not refer to effectiveness. There were inconsistent results in another four studies; (4) Conclusions: Our findings highlight the complexities of the implementation of employment strategies (job access and return to work). Job access strategies seem to improve employment outcomes. The effectiveness of return to work strategies remains unclear. The involvement and commitment of physicians, employment specialists, and employers, and employees capacity for self-care seem decisive for employment re-integration success. Further analyses are needed to assess the cost-effectiveness of these interventions and corroborate our results, with longer follow-ups. PMID- 29695095 TI - Effect of Drought on Agronomic Traits of Rice and Wheat: A Meta-Analysis. AB - Drought has been one of the most important limiting factors for crop production, which deleteriously affects food security worldwide. The main objective of the present study was to quantitatively assess the effect of drought on the agronomic traits (e.g., plant height, biomass, yield, and yield components) of rice and wheat in combination with several moderators (e.g., drought stress intensity, rooting environment, and growth stage) using a meta-analysis study. The database was created from 55 published studies on rice and 60 published studies on wheat. The results demonstrated that drought decreased the agronomic traits differently between rice and wheat among varying growth stages. Wheat and rice yields decreased by 27.5% and 25.4%, respectively. Wheat grown in pots showed greater decreases in agronomic traits than those grown in the field. Rice showed opposite growing patterns when compared to wheat in rooting environments. The effect of drought on rice increased with plant growth and drought had larger detrimental influences during the reproductive phase (e.g., blooming stage, filling stage, and maturity). However, an exception was found in wheat, which had similar decreased performance during the complete growth cycle. Based on these results, future droughts could produce lower yields of rice and wheat when compared to the current drought. PMID- 29695096 TI - Protection of Spleen Tissue of gamma-ray Irradiated Mice against Immunosuppressive and Oxidative Effects of Radiation by Adenosine 5' Monophosphate. AB - The immune system is very sensitive to radiation. This study revealed that adenosine 5′-monophosphate (5′-AMP) increased the DNA contents of the spleen and the spleen index of irradiated mice. Moreover, the exogenous 5′ AMP could significantly repair the ultra-structure of the damaged spleen through transmission electron microscopy. When indicators of the mouse immune system were assessed, the flow cytometry and enzyme-linked immunosorbent assay (ELISA) revealed that the administration of exogenous 5′-AMP could reduce the apoptosis in the splenic cells. It could also regulate the transition of cells towards S phase, increase the proportion of CD4+ and CD8+ cellular subsets, and enhance the secretion of interleukin-2 (IL-2), IL-4, IL-10, and interferon γ (IFN-γ). These effects were associated with a decrease in oxidative stress, as evidenced by changes in superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), catalase (CAT), reduced glutathione (GSH), and malondialdehyde (MDA) levels of spleen tissues. These results suggested that exogenous 5′-AMP could repair the damaged spleen, increase the spleen index, and regulate the cell cycles and apoptosis. There was an increase in the production of various cytokines and play a protective role on the immune system of irradiated mice by dynamically adjusting the REDOX balance. PMID- 29695097 TI - Maternal DHA Status during Pregnancy Has a Positive Impact on Infant Problem Solving: A Norwegian Prospective Observation Study. AB - Docosahexaenoic acid (DHA, 22:6, n-3) is a long-chain polyunsaturated fatty acid necessary for normal brain growth and cognitive development. Seafood and dietary supplements are the primary dietary sources of DHA. This study addresses the associations between DHA status in pregnant women and healthy, term-born infant problem-solving skills assessed using the Ages and Stages Questionnaire. The fatty acid status of maternal red blood cells (RBCs) was assessed in the 28th week of gestation and at three months postpartum. The infants’ fatty acid status (RBC) was assessed at three, six, and twelve months, and problem-solving skills were assessed at six and twelve months. Maternal DHA status in pregnancy was found to be positively associated with infants’ problem-solving skills at 12 months. This association remained significant even after controlling for the level of maternal education, a surrogate for socio-economic status. The infants’ DHA status at three months was associated with the infants’ problem solving at 12 months. The results accentuate the importance for pregnant and lactating women to have a satisfactory DHA status from dietary intake of seafood or other sources rich in DHA. PMID- 29695098 TI - Body Weight Estimation for Dose-Finding and Health Monitoring of Lying, Standing and Walking Patients Based on RGB-D Data. AB - This paper describes the estimation of the body weight of a person in front of an RGB-D camera. A survey of different methods for body weight estimation based on depth sensors is given. First, an estimation of people standing in front of a camera is presented. Second, an approach based on a stream of depth images is used to obtain the body weight of a person walking towards a sensor. The algorithm first extracts features from a point cloud and forwards them to an artificial neural network (ANN) to obtain an estimation of body weight. Besides the algorithm for the estimation, this paper further presents an open-access dataset based on measurements from a trauma room in a hospital as well as data from visitors of a public event. In total, the dataset contains 439 measurements. The article illustrates the efficiency of the approach with experiments with persons lying down in a hospital, standing persons, and walking persons. Applicable scenarios for the presented algorithm are body weight-related dosing of emergency patients. PMID- 29695099 TI - Infrastructure for Integration of Legacy Electrical Equipment into a Smart-Grid Using Wireless Sensor Networks. AB - At present, the standardisation of electrical equipment communications is on the rise. In particular, manufacturers are releasing equipment for the smart grid endowed with communication protocols such as DNP3, IEC 61850, and MODBUS. However, there are legacy equipment operating in the electricity distribution network that cannot communicate using any of these protocols. Thus, we propose an infrastructure to allow the integration of legacy electrical equipment to smart grids by using wireless sensor networks (WSNs). In this infrastructure, each legacy electrical device is connected to a sensor node, and the sink node runs a middleware that enables the integration of this device into a smart grid based on suitable communication protocols. This middleware performs tasks such as the translation of messages between the power substation control centre (PSCC) and electrical equipment in the smart grid. Moreover, the infrastructure satisfies certain requirements for communication between the electrical equipment and the PSCC, such as enhanced security, short response time, and automatic configuration. The paper’s contributions include a solution that enables electrical companies to integrate their legacy equipment into smart-grid networks relying on any of the above mentioned communication protocols. This integration will reduce the costs related to the modernisation of power substations. PMID- 29695100 TI - Design and Performance of a 1 ms High-Speed Vision Chip with 3D-Stacked 140 GOPS Column-Parallel PEs ?. AB - We have developed a high-speed vision chip using 3D stacking technology to address the increasing demand for high-speed vision chips in diverse applications. The chip comprises a 1/3.2-inch, 1.27 Mpixel, 500 fps (0.31 Mpixel, 1000 fps, 2 × 2 binning) vision chip with 3D-stacked column-parallel Analog to-Digital Converters (ADCs) and 140 Giga Operation per Second (GOPS) programmable Single Instruction Multiple Data (SIMD) column-parallel PEs for new sensing applications. The 3D-stacked structure and column parallel processing architecture achieve high sensitivity, high resolution, and high-accuracy object positioning. PMID- 29695101 TI - Triphlorethol A, a Dietary Polyphenol from Seaweed, Decreases Sleep Latency and Increases Non-Rapid Eye Movement Sleep in Mice. AB - In our previous studies, we have demonstrated that marine polyphenol phlorotannins promote sleep through the benzodiazepine site of the gamma aminobutyric acid type A (GABAA) receptors. In this follow-up study, the sleep promoting effects of triphlorethol A, one of the major phlorotannin constituents, were investigated. The effect of triphlorethol A on sleep-wake architecture and profiles was evaluated based on electroencephalogram and electromyogram data from C57BL/6N mice and compared with the well-known hypnotic drug zolpidem. Oral administration of triphlorethol A (5, 10, 25, and 50 mg/kg) dose-dependently decreased sleep latency and increased sleep duration during pentobarbital-induced sleep in imprinting control region mice. Triphlorethol A (50 mg/kg) significantly decreased sleep latency and increased the amount of non-rapid eye movement sleep (NREMS) in C57BL/6N mice, without affecting rapid eye movement sleep (REMS). There was no significant difference between the effects of triphlorethol A at 50 mg/kg and zolpidem at 10 mg/kg. Triphlorethol A had no effect on delta activity (0.5-4 Hz) of NREMS, whereas zolpidem significantly decreased it. These results not only support the sleep-promoting effects of marine polyphenol phlorotannins, but also suggest that the marine polyphenol compound triphlorethol A is a promising structure for developing novel sedative hypnotics. PMID- 29695102 TI - Dendrimeric Antigens for Drug Allergy Diagnosis: A New Approach for Basophil Activation Tests. AB - Dendrimeric Antigens (DeAns) consist of dendrimers decorated with multiple units of drug antigenic determinants. These conjugates have been shown to be a powerful tool for diagnosing penicillin allergy using in vitro immunoassays, in which they are recognized by specific IgE from allergic patients. Here we propose a new diagnostic approach using DeAns in cellular tests, in which recognition occurs through IgE bound to the basophil surface. Both IgE molecular recognition and subsequent cell activation may be influenced by the tridimensional architecture and size of the immunogens. Structural features of benzylpenicilloyl-DeAn and amoxicilloyl-DeAn (G2 and G4 PAMAM) were studied by diffusion Nuclear Magnetic Resonance (NMR) experiments and are discussed in relation to molecular dynamics simulation (MDS) observations. IgE recognition was clinically evaluated using the basophil activation test (BAT) for allergic patients and tolerant subjects. Diffusion NMR experiments, MDS and cellular studies provide evidence that the size of the DeAn, its antigen composition and tridimensional distribution play key roles in IgE-antigen recognition at the effector cell surface. These results indicate that the fourth generation DeAns induce a higher level of basophil activation in allergic patients. This approach can be considered as a potential complementary diagnostic method for evaluating penicillin allergy. PMID- 29695103 TI - High-Throughput GLP-Capable Target Cell Visualization Assay for Measuring Cell Mediated Cytotoxicity. AB - One of the primary effector functions of immune cells is the killing of virus infected or malignant cells in the body. Natural killer (NK) and CD8 effector T cells are specialized for this function. The gold standard for measuring such cell-mediated cytolysis has been the chromium release assay, in which the leakage of the radioactive isotope from damaged target cells is being detected. Flow cytometry-based single cell analysis of target cells has recently been established as a non-radioactive alternative. Here we introduce a target cell visualization assay (TVA) that applies similar target cell staining approaches as used in flow cytometry but based on single cell computer image analysis. Two versions of TVA are described here. In one, the decrease in numbers of calcein stained, i.e., viable, target cells is assessed. In the other, the CFSE/PI TVA, the increase in numbers of dead target cells is established in addition. TVA assays are shown to operate with the same sensitivity as standard chromium release assays, and, leaving data audit trails in form of scanned (raw), analyzed, and quality-controlled images, thus meeting requirements for measuring cell-mediated cytolysis in a regulated environment. PMID- 29695104 TI - The Tryptophan Decarboxylase in Solanum lycopersicum. AB - Melatonin plays an important role in plant growth, development, and environmental stress. In this study, a systematic analysis of tomato tryptophan decarboxylase (SlTrpDC), which is the first enzyme of melatonin biosynthesis, was conducted by integrating structural features, phylogenetic relationships, an exon/intron feature, and a divergent expression profile. The results determined that the tomato genome encoded five members (SlTrpDC1-SlTrpDC5). The phylogenetic relationships indicated that gene expansion was proposed as the major mode of evolution of the TrpDC genes from the different plant algae species to the higher plants species. The analyses of the exon/intron configurations revealed that the intron loss events occurred during the structural evolution of the TrpDCs in plants. Additionally, the RNA-seq and qRT-PCR analysis revealed that the expression of the SlTrpDC3 was high in all of the tested tissues, while the SlTrpDC4 and SlTrpDC5 were not expressed. The expression patterns of the remaining two (SlTrpDC1 and SlTrpDC2) were tissue-specific, which indicated that these genes may play important roles within the different tissues. No expression difference was observed in the tomato plants in response to the biotic stresses. This study will expand the current knowledge of the roles of the TrpDC genes in tomato growth and development. PMID- 29695105 TI - Efficient Computational Design of a Scaffold for Cartilage Cell Regeneration. AB - Due to the sensitivity of mammalian cell cultures, understanding the influence of operating conditions during a tissue generation procedure is crucial. In this regard, a detailed study of scaffold based cell culture under a perfusion flow is presented with the aid of mathematical modelling and computational fluid dynamics (CFD). With respect to the complexity of the case study, this work focuses solely on the effect of nutrient and metabolite concentrations, and the possible influence of fluid-induced shear stress on a targeted cell (cartilage) culture. The simulation set up gives the possibility of predicting the cell culture behavior under various operating conditions and scaffold designs. Thereby, the exploitation of the predictive simulation into a newly developed stochastic routine provides the opportunity of exploring improved scaffold geometry designs. This approach was applied on a common type of fibrous structure in order to increase the process efficiencies compared with the regular used formats. The suggested topology supplies a larger effective surface for cell attachment compared to the reference design while the level of shear stress is kept at the positive range of effect. Moreover, significant improvement of mass transfer is predicted for the suggested topology. PMID- 29695106 TI - BSG and MCT1 Genetic Variants Influence Survival in Multiple Myeloma Patients. AB - Multiple myeloma (MM) is a haematologic malignancy characterized by the presence of atypical plasma cells. Basigin (BSG, CD147) controls lactate export through the monocarboxylic acid transporter 1 (MCT1, SLC16A1) and supports MM survival and proliferation. Additionally, BSG is implicated in response to treatment with immunomodulatory drugs (thalidomide and its derivatives). We investigated the role of single nucleotide polymorphisms (SNPs) in the gene coding for BSG and SLC16A1 in MM. Following an in silico analysis, eight SNPs (four in BSG and four in SLC16A1) predicted to have a functional effect were selected and analyzed in 135 MM patients and 135 healthy individuals. Alleles rs4919859 C, rs8637 G, and haplotype CG were associated with worse progression-free survival (p = 0.006, p = 0.017, p = 0.002, respectively), while rs7556664 A, rs7169 T and rs1049434 A (all in linkage disequilibrium (LD), r2 > 0.98) were associated with better overall survival (p = 0.021). Similar relationships were observed in thalidomide-treated patients. Moreover, rs4919859 C, rs8637 G, rs8259 A and the CG haplotype were more common in patients in stages II-III of the International Staging System (p < 0.05), while rs8259 A correlated with higher levels of β-2-microglobulin and creatinine (p < 0.05). Taken together, our results show that BSG and SLC16A1 variants affect survival, and may play an important role in MM. PMID- 29695107 TI - Microstructure and Deformation Response of TRIP-Steel Syntactic Foams to Quasi Static and Dynamic Compressive Loads. AB - The implementation of hollow S60HS glass microspheres and Fillite 106 cenospheres in a martensitically transformable AISI 304L stainless steel matrix was realized by means of metal injection molding of feedstock with varying fractions of the filler material. The so-called TRIP-steel syntactic foams were studied with respect to their behavior under quasi-static compression and dynamic impact loading. The interplay between matrix material behavior and foam structure was discussed in relation to the findings of micro-structural investigations, electron back scatter diffraction EBSD phase analyses and magnetic measurements. During processing, the cenospheres remained relatively stable retaining their shape while the glass microspheres underwent disintegration associated with the formation of pre-cracked irregular inclusions. Consequently, the AISI 304L/Fillite 106 syntactic foams exhibited a higher compression stress level and energy absorption capability as compared to the S60HS-containing variants. The α ′ -martensite kinetic of the steel matrix was significantly influenced by material composition, strain rate and arising deformation temperature. The highest ferromagnetic α ′ -martensite phase fraction was detected for the AISI 304L/S60HS batches and the lowest for the TRIP-steel bulk material. Quasi-adiabatic sample heating, a gradual decrease in strain rate and an enhanced degree of damage controlled the mechanical deformation response of the studied syntactic foams under dynamic impact loading. PMID- 29695108 TI - Kinetic Modeling of Corn Fermentation with S. cerevisiae Using a Variable Temperature Strategy. AB - While fermentation is usually done at a fixed temperature, in this study, the effect of having a controlled variable temperature was analyzed. A nonlinear system was used to model batch ethanol fermentation, using corn as substrate and the yeast Saccharomyces cerevisiae, at five different fixed and controlled variable temperatures. The lower temperatures presented higher ethanol yields but took a longer time to reach equilibrium. Higher temperatures had higher initial growth rates, but the decay of yeast cells was faster compared to the lower temperatures. However, in a controlled variable temperature model, the temperature decreased with time with the initial value of 40 ? C. When analyzing a time window of 60 h, the ethanol production increased 20% compared to the batch with the highest temperature; however, the yield was still 12% lower compared to the 20 ? C batch. When the 24 h’ simulation was analyzed, the controlled model had a higher ethanol concentration compared to both fixed temperature batches. PMID- 29695109 TI - EPDM Rubber Modified by Nitrogen Plasma Immersion Ion Implantation. AB - Ethylene-propylene diene monomer rubber (EPDM) was treated by plasma immersion ion implantation (PIII) with nitrogen ions of 20 keV energy and fluence from 1013 to 1016 ions/cm2. The Fourier-transform infrared attenuated total reflection spectra, atomic force microscopy and optical microscopy showed significant structure changes of the surface. The analysis of an interface of PIII treated EPDM rubber with polyurethane binder showed a cohesive character of the adhesion joint fracture at the presence of solvent and interpreted as covalent bond network formation between the PIII treated rubber and the adhesive. PMID- 29695110 TI - In Vitro Activity of 30 Essential Oils against Bovine Clinical Isolates of Prototheca zopfii and Prototheca blaschkeae. AB - Protothecal mastitis poses an emergent animal health problem in dairy herds, with a high impact on dairy industries, causing heavy economic losses. Current methods of treating protothecal infections are ineffective, and no drug is licensed for use in cattle. The aim of the present study was to check the antialgal activity of 30 chemically defined essential oils (EOs) against Prototheca zopfii and Prototheca blaschkeae isolated from the milk of dairy cows with mastitis. A microdilution test was carried out to estimate the antialgal effectiveness of the selected chemically defined EOs. The microdilution test showed different degrees of inhibition among the examined Prototheca species. The activity of some of the examined EOs seem interesting. In particular, Citrus paradisi yielded the lowest minimal inhibitory concentration values (0.75%) for both algal species. P. zopfii appeared to be more sensitive to EOs in comparison to P. blaschkeae. The present study investigated the in vitro susceptibility of P. zopfii and P. blaschkeae to a wide range of EOs, obtained from different botanical families. Further investigations are necessary to evaluate the efficacy of EO-based formulations intended for the disinfection of both udder and milking products. PMID- 29695111 TI - Effect of Laminating Pressure on Polymeric Multilayer Nanofibrous Membranes for Liquid Filtration. AB - In the new century, electrospun nanofibrous webs are widely employed in various applications due to their specific surface area and porous structure with narrow pore size. The mechanical properties have a major influence on the applications of nanofiber webs. Lamination technology is an important method for improving the mechanical strength of nanofiber webs. In this study, the influence of laminating pressure on the properties of polyacrylonitrile (PAN) and polyvinylidene fluoride (PVDF) nanofibers/laminate was investigated. Heat-press lamination was carried out at three different pressures, and the surface morphologies of the multilayer nanofibrous membranes were observed under an optical microscope. In addition, air permeability, water filtration, and contact angle experiments were performed to examine the effect of laminating pressure on the breathability, water permeability and surface wettability of multilayer nanofibrous membranes. A bursting strength test was developed and applied to measure the maximum bursting pressure of the nanofibers from the laminated surface. A water filtration test was performed using a cross-flow unit. Based on the results of the tests, the optimum laminating pressure was determined for both PAN and PVDF multilayer nanofibrous membranes to prepare suitable microfilters for liquid filtration. PMID- 29695112 TI - High Sensitive pH Sensor Based on AlInN/GaN Heterostructure Transistor. AB - The AlInN/GaN high-electron-mobility-transistor (HEMT) indicates better performances compared with the traditional AlGaN/GaN HEMTs. The present work investigated the pH sensor functionality of an analogous HEMT AlInN/GaN device with an open gate. It was shown that the Al0.83In0.17N/GaN device demonstrates excellent pH sense functionality in aqueous solutions, exhibiting higher sensitivity (−30.83 μA/pH for AlInN/GaN and −4.6 μA/pH for AlGaN/GaN) and a faster response time, lower degradation and good stability with respect to the AlGaN/GaN device, which is attributed to higher two-dimensional electron gas (2DEG) density and a thinner barrier layer in Al0.83In0.17N/GaN owning to lattice matching. On the other hand, the open gate geometry was found to affect the pH sensitivity obviously. Properly increasing the width and shortening the length of the open gate area could enhance the sensitivity. However, when the open gate width is too larger or too small, the pH sensitivity would be suppressed conversely. Designing an optimal ratio of the width to the length is important for achieving high sensitivity. This work suggests that the AlInN/GaN-based 2DEG carrier modulated devices would be good candidates for high performance pH sensors and other related applications. PMID- 29695113 TI - Presentation Attack Detection for Iris Recognition System Using NIR Camera Sensor. AB - Among biometric recognition systems such as fingerprint, finger-vein, or face, the iris recognition system has proven to be effective for achieving a high recognition accuracy and security level. However, several recent studies have indicated that an iris recognition system can be fooled by using presentation attack images that are recaptured using high-quality printed images or by contact lenses with printed iris patterns. As a result, this potential threat can reduce the security level of an iris recognition system. In this study, we propose a new presentation attack detection (PAD) method for an iris recognition system (iPAD) using a near infrared light (NIR) camera image. To detect presentation attack images, we first localized the iris region of the input iris image using circular edge detection (CED). Based on the result of iris localization, we extracted the image features using deep learning-based and handcrafted-based methods. The input iris images were then classified into real and presentation attack categories using support vector machines (SVM). Through extensive experiments with two public datasets, we show that our proposed method effectively solves the iris recognition presentation attack detection problem and produces detection accuracy superior to previous studies. PMID- 29695114 TI - Do Low Income Youth of Color See "The Bigger Picture" When Discussing Type 2 Diabetes: A Qualitative Evaluation of a Public Health Literacy Campaign. AB - : As Type 2 diabetes spikes among minority and low-income youth, there is an urgent need to tackle the drivers of this preventable disease. The Bigger Picture (TBP) is a counter-marketing campaign using youth-created, spoken-word public service announcements (PSAs) to reframe the epidemic as a socio-environmental phenomenon requiring communal action, civic engagement and norm change. METHODS: We examined whether and how TBP PSAs advance health literacy among low-income, minority youth. We showed nine PSAs, asking individuals open-ended questions via questionnaire, then facilitating a focus group to reflect upon the PSAs. RESULTS: Questionnaire responses revealed a balance between individual vs. public health literacy. Some focused on individual responsibility and behaviors, while others described socio-environmental forces underlying risk. The focus group generated a preponderance of public health literacy responses, emphasizing future action. Striking sociopolitical themes emerged, reflecting tensions minority and low income youth experience, such as entrapment vs. liberation. CONCLUSION: Our findings speak to the structural barriers and complexities underlying diabetes risk, and the ability of spoken word medium to make these challenges visible and motivate action. PRACTICE IMPLICATIONS: Delivering TBP content to promote interactive reflection has potential to change behavioral norms and build capacity to confront the social, economic and structural factors that influence behaviors. PMID- 29695115 TI - Application of Recycled Ceramic Aggregates for the Production of Mineral-Asphalt Mixtures. AB - This paper describes a method of designing and producing innovative mineral asphalt mixtures, which utilize waste aggregate from the recycling of sanitary ceramics. The work presents the basic properties of the ceramic material, the investigation concerning the microstructure of the aggregate obtained from the grinding of waste, and a comparison with the images obtained for the aggregates usually employed in mineral-asphalt mixtures. The mixtures were designed for the application in the wearing course. Four series of mixtures were prepared. In the first and second, the ceramic aggregate constituted a partial substitute for dolomite, whereas in the third, we substituted granodiorite, and the fourth series contained only dolomite. The mixtures were examined for the content of soluble binder, the bulk density of samples, the presence of voids, the space filled with binder, and the susceptibility to water and frost corrosion. The obtained results were compared with the standard requirements. The microstructure as well as the contact zone in the considered mineral-asphalt mixtures are presented based on research conducted by means of a scanning electron microscope (SEM). PMID- 29695116 TI - Phenolic Profiling and Antioxidant Capacity of Eugenia uniflora L. (Pitanga) Samples Collected in Different Uruguayan Locations. AB - The use of nutrient-rich foods to enhance the wellness, health and lifestyle habits of consumers is globally encouraged. Native fruits are of great interest as they are grown and consumed locally and take part of the ethnobotanic knowledge of the population. Pitanga is an example of a native fruit from Uruguay, consumed as a jelly or an alcoholic beverage. Pitanga has a red-violet pigmentation, which is a common trait for foods that are a good source of antioxidants. Hence, fruits from different Uruguayan regions were analyzed via miniaturized sample preparation method, HPLC-DAD-ESI/MSn and RP-HPLC-DAD techniques to identify and quantify phenolic compounds, respectively. The antioxidant capacity was evaluated via DPPH and ORAC (Oxygen Radical Absorbance Capacity) assays. A multivariate linear regression was applied to correlate the observed antioxidant capacity with the phenolic content. Furthermore, Principal Components Analysis was performed to highlight characteristics between the various samples studied. The main results indicated differences between northern and southern Uruguayan samples. Delphinidin-3-hexoside was present in southern samples (mean of 293.16 µmol/100 g dry weight (DW)) and absent in the sample collected in the north (sample 3). All the samples contain high levels of cyanidin-3-hexoside, but a noticeable difference was found between the northern sample (150.45 µmol/100 g DW) and the southern sample (1121.98 µmol/100 g DW). The antioxidant capacity (mean ORAC of 56370 µmol Trolox®/100 g DW) were high in all the samples compared to the Food and Drug Administration (FDA) database of similar berry-fruits. The results of this study highlight the nutraceutical value of a native fruit that has not been exploited until now. PMID- 29695117 TI - Seasonal Influenza Vaccination in Health Care Workers. A Pre-Post Intervention Study in an Italian Paediatric Hospital. AB - Despite relevant recommendations and evidences on the efficacy of influenza vaccination in health care workers (HCWs), vaccination coverage rates in Europe and Italy currently do not exceed 25%. Aim of the study is to measure the variations in vaccination coverage rates in an Italian pediatric hospital after a promotion campaign performed in the period October-December 2017. The design is a pre-post intervention study. The intervention is based on a wide communication campaign and an expanded offer of easy vaccination on site. The study was carried out at Bambino Gesù Children’s hospital in Rome, Italy, on the whole population of HCWs. Univariate and multivariate statistical analyses were performed. Vaccination coverage rate increased in 2017/18 campaign compared with the 2016/17 one (+95 HCWs vaccinated; +4.4%). The highest increases were detected in males (+45.7%), youngest employees (+142.9%), mean age of employment (+175%), other HCWs (+209.1%), Emergency Area (+151.6%) and Imaging Diagnostic Department (+200.0%). At multivariate logistic regression, working in some departments and being nurses represents a higher risk of being unvaccinated. Although the vaccination coverage rate remained low, a continuous increase of the coverage rate and development of a different consciousness in HCWs was highlighted. The study significantly identified the target for future campaigns. PMID- 29695119 TI - Deep Kalman Filter: Simultaneous Multi-Sensor Integration and Modelling; A GNSS/IMU Case Study. AB - Bayes filters, such as the Kalman and particle filters, have been used in sensor fusion to integrate two sources of information and obtain the best estimate of unknowns. The efficient integration of multiple sensors requires deep knowledge of their error sources. Some sensors, such as Inertial Measurement Unit (IMU), have complicated error sources. Therefore, IMU error modelling and the efficient integration of IMU and Global Navigation Satellite System (GNSS) observations has remained a challenge. In this paper, we developed deep Kalman filter to model and remove IMU errors and, consequently, improve the accuracy of IMU positioning. To achieve this, we added a modelling step to the prediction and update steps of the Kalman filter, so that the IMU error model is learned during integration. The results showed our deep Kalman filter outperformed the conventional Kalman filter and reached a higher level of accuracy. PMID- 29695118 TI - Effect of Amelogenin Coating of a Nano-Modified Titanium Surface on Bioactivity. AB - The interactions between implants and host tissues depend on several factors. In particular, a growing body of evidence has demonstrated that the surface texture of an implant influences the response of the surrounding cells. The purpose of this study is to develop new implant materials aiming at the regeneration of periodontal tissues as well as hard tissues by coating nano-modified titanium with amelogenin, which is one of the main proteins contained in Emdogain®. We confirmed by quartz crystal microbalance evaluation that amelogenin is easy to adsorb onto the nano-modified titanium surface as a coating. Scanning electron microscopy, scanning probe microscopy, X-ray photoelectron spectroscopy, and Fourier-transform infrared spectroscopy analyses confirmed that amelogenin coated the nano-modified titanium surface following alkali-treatment. In vitro evaluation using rat bone marrow and periodontal ligament cells revealed that the initial adhesion of both cell types and the induction of hard tissue differentiation such as cementum were improved by amelogenin coating. Additionally, the formation of new bone in implanted surrounding tissues was observed in in vivo evaluation using rat femurs. Together, these results suggest that this material may serve as a new implant material with the potential to play a major role in the advancement of clinical dentistry. PMID- 29695120 TI - The Status of Musculoskeletal Disorders and Its Influence on the Working Ability of Oil Workers in Xinjiang, China. AB - The purpose of this study was to investigate the status of musculoskeletal disorders (MSDs) and its influence on the working ability of oil workers, and to provide a theoretical basis for helping lessen the burden of MSDs and improve the man-machine environment of oil workers. The cluster sampling method was used to study 2000 workers who had been employed for more than 1 year in this field. We investigated the prevalence rate and the work ability index (WAI). A total of 1935 valid questionnaires were collected, a response rate of 96.75%. There were 1639 people who had suffered from MSDs in the past year, a prevalence rate of 84.7%. The damage detection rate in female oil workers was higher than in males, and the damage detection rate in workers aged 30 to 45 years was higher than that in the other two age groups. The detection rate in less highly-educated oil workers was higher than that in more highly-educated workers. The detection rate in divorced workers was higher than that in other groups. The detection rate in workers between the number of working years of 18 to 25 years was higher than in the other two groups. The detection rate in workers with a high professional title was significantly higher than that in lower-titled workers (p < 0.05). The results showed that the WAI scores of the subjects with MSDs were significantly lower than for subjects without MSDs (p < 0.05). In a logistic regression analysis, sex, number of working years and WAI index all had an impact on MSDs. We concluded that due to the demands of their role, the oil workers had serious MSDs that influenced their working ability. PMID- 29695121 TI - Antibacterial Effects of Magnetically-Controlled Ag/Fe3O4 Nanoparticles. AB - This paper presents the use of a magnetic manipulation device to remotely control the movement of Ag/Fe3O4 nanoparticles (NPs) for enhancing the antibacterial effect of Ag particles in aqueous suspensions containing Escherichia coli (E.coli). The Ag/Fe3O4 magnetic NPs were prepared by co-precipitation method where the Ag particles are simultaneously synthesized with the Fe3O4 particles to form Ag and Fe3O4 nanocomposite materials. The manipulation system utilized a homogeneous rotating magnetic field to carry out magnetic stirring of NPs in the petri dishes containing bacterial suspensions. The optimum magnetron parameters and best antibacterial effects were implemented with six different concentrations from 0.6 wt % to 6.6 wt % of the NPs at driving frequencies from 50 rpm to 200 rpm for 3 min. The highest antibacterial effect of 99.4% was achieved at 5.4 wt % of NPs and the driving frequency of 100 rpm. A time-dependent antibacterial effect in 0.1 wt % of Ag/Fe3O4 was also observed. The results indicate that the use of specific rotating magnetic fields to manipulate Ag/Fe3O4 magnetic NPs can significantly improve the antibacterial efficacy. Due to the good biocompatibility of the Ag NPs, the presented technique can be applied to clean water resources in the future. PMID- 29695122 TI - Dietary Polyphenol Intake and Depression: Results from the Mediterranean Healthy Eating, Lifestyle and Aging (MEAL) Study. AB - Background: The epidemiological evidence for a relation between dietary polyphenol intake and depression is limited. Therefore, the aim of this study was to assess the association between habitual dietary intake of total polyphenols, their classes, subclasses and individual compounds and depressive symptoms among the participants of the Mediterranean healthy Eating, Lifestyle and Aging (MEAL) study. Methods: Demographic and dietary characteristics of 1572 adults living in southern Italy were analyzed. Food frequency questionnaires and Phenol-Explorer were used to calculate habitual dietary intakes of polyphenols. The Center for Epidemiologic Studies Depression Scale (CES-D-10) was used as screening tool for depressive symptoms. Multivariate logistic regression analyses were used to test associations and were expressed as odds ratio (OR) and 95% confidence intervals (CI). Results: A total of 509 individuals reported having depressive symptoms. Based on multivariate logistic regression analyses, total polyphenol intake was not associated with depressive symptoms. After adjustment for potential confounding factors, dietary intake of phenolic acid (OR = 0.64, 95% CI: 0.44, 0.93), flavanones (OR = 0.54, 95% CI: 0.32, 0.91), and anthocyanins (OR = 0.61, 95% CI: 0.42, 0.89) showed significant inverse association with depressive symptoms, when comparing the highest with the lowest quartile. Moreover, flavanones and anthocyanins, were associated with depressive symptoms in a dose response manner. Among individual compounds, inverse association was observed for quercetin (OR = 0.53, 95% CI: 0.32, 0.86) and naringenin (OR = 0.51, 95% CI: 0.30, 0.85), for the highest versus lowest quartile of intake. When taking into consideration the major sources of the polyphenols, only citrus fruits and wine consumption was inversely associated with depressive symptoms (Q4 vs. Q1: OR= 0.51, 95% CI: 0.35, 0.75; Q4 vs. Q1: OR = 0.53, 95% CI: 0.38, 0.74, respectively). Conclusions: Higher dietary intake of flavonoid may be inversely associated with depressive symptoms. Further studies are needed to definitively confirm these observed associations. PMID- 29695123 TI - Different Hemodynamic Responses of the Primary Motor Cortex Accompanying Eccentric and Concentric Movements: A Functional NIRS Study. AB - The literature contains limited evidence on how our brains control eccentric movement. A higher activation is expected in the contralateral motor cortex (M1) but consensus has not yet been reached. Therefore, the present study aimed to compare patterns of M1 activation between eccentric and concentric movements. Nine healthy participants performed in a randomized order three sets of five repetitions of eccentric or concentric movement with the dominant elbow flexors over a range of motion of 60° at two velocities (30°/s and 60°/s). The tests were carried out using a Biodex isokinetic dynamometer with the forearm supported in the horizontal plane. The peak torque values were not significantly different between concentric and eccentric movements (p = 0.42). Hemodynamic responses of the contralateral and ipsilateral M1 were measured with a near infrared spectroscopy system (Oxymon MkIII, Artinis). A higher contralateral M1 activity was found during eccentric movements (p = 0.04, η² = 0.47) and at the velocity of 30°/s (p = 0.039, η² = 0.48). These preliminary findings indicate a specific control mechanism in the contralateral M1 to produce eccentric muscle actions at the angular velocities investigated, although the role of other brain areas in the motor control network cannot be excluded. PMID- 29695124 TI - Genome-Wide Comparison Reveals a Probiotic Strain Lactococcus Lactis WFLU12 Isolated from the Gastrointestinal Tract of Olive Flounder (Paralichthys Olivaceus) Harboring Genes Supporting Probiotic Action. AB - Our previous study has shown that dietary supplementation with Lactococcus lactis WFLU12 can enhance the growth of olive flounder and its resistance against streptococcal infection. The objective of the present study was to use comparative genomics tools to investigate genomic characteristics of strain WFLU12 and the presence of genes supporting its probiotic action using sequenced genomes of L. lactis strains. Dispensable and singleton genes of strain WFLU12 were found to be more enriched in genes associated with metabolism (e.g., energy production and conversion, and carbohydrate transport and metabolism) than pooled dispensable and singleton genes in other L. lactis strains, reflecting WFLU12 strain-specific ecosystem origin and its ability to metabolize different energy sources. Strain WFLU12 produced antimicrobial compounds that could inhibit several bacterial fish pathogens. It possessed the nisin gene cluster (nisZBTCIPRKFEG) and genes encoding lysozyme and colicin V. However, only three other strains (CV56, IO-1, and SO) harbor a complete nisin gene cluster. We also found that L. lactis WFLU12 possessed many other important functional genes involved in stress responses to the gastrointestinal tract environment, dietary energy extraction, and metabolism to support the probiotic action of this strain found in our previous study. This strongly indicates that not all L. lactis strains can be used as probiotics. This study highlights comparative genomics approaches as very useful and powerful tools to select probiotic candidates and predict their probiotic effects. PMID- 29695125 TI - Nanoscale Topographical Characterization of Orbital Implant Materials. AB - The search for an ideal orbital implant is still ongoing in the field of ocular biomaterials. Major limitations of currently-available porous implants include the high cost along with a non-negligible risk of exposure and postoperative infection due to conjunctival abrasion. In the effort to develop better alternatives to the existing devices, two types of new glass-ceramic porous implants were fabricated by sponge replication, which is a relatively inexpensive method. Then, they were characterized by direct three-dimensional (3D) contact probe mapping in real space by means of atomic force microscopy in order to assess their surface micro- and nano-features, which were quantitatively compared to those of the most commonly-used orbital implants. These silicate glass-ceramic materials exhibit a surface roughness in the range of a few hundred nanometers (Sq within 500-700 nm) and topographical features comparable to those of clinically-used “gold-standard” alumina and polyethylene porous orbital implants. However, it was noted that both experimental and commercial non porous implants were significantly smoother than all the porous ones. The results achieved in this work reveal that these porous glass-ceramic materials show promise for the intended application and encourage further investigation of their clinical suitability. PMID- 29695126 TI - Flow Injection Analysis with Direct UV Detection Following Electric Field Driven Membrane Extraction. AB - A method for on-line matrix elimination to enable selective quantification of ultraviolet absorbing analytes by a flow-injection analysis procedure is described. Selectivity is achieved by electric field driven extraction across a polymer inclusion membrane. The method was demonstrated on the example of the determination of naproxen from spiked human urine. Membranes of 10 MUm thickness were employed which consisted of 7.5 mg cellulose triacetate as base polymer, 5 mg of o-nitrophenyl octyl ether as plasticizer and 7.5 mg of Aliquat 336 as cationic carrier. Ten MUL of sample was introduced into a continuous stream of background solution consisting of 100 uM aqueous NaClO4 with a flow rate of 2 MUL/min while applying a voltage of 150 V to the extraction cell. The target ion was electrokinetically transported across the membrane and enriched in 1.5 MUL of a stagnant acceptor solution. This was subsequently pumped past a flow-through UV detector for quantification. The method showed a linear range from 5 to 200 uM with a correlation coefficient of 0.9978 and a reproducibility of typically 7% (n = 8). The detection limit of the method for naproxen was 2 uM. PMID- 29695127 TI - Multi-Layer Artificial Neural Networks Based MPPT-Pitch Angle Control of a Tidal Stream Generator. AB - Artificial intelligence technologies are widely investigated as a promising technique for tackling complex and ill-defined problems. In this context, artificial neural networks methodology has been considered as an effective tool to handle renewable energy systems. Thereby, the use of Tidal Stream Generator (TSG) systems aim to provide clean and reliable electrical power. However, the power captured from tidal currents is highly disturbed due to the swell effect and the periodicity of the tidal current phenomenon. In order to improve the quality of the generated power, this paper focuses on the power smoothing control. For this purpose, a novel Artificial Neural Network (ANN) is investigated and implemented to provide the proper rotational speed reference and the blade pitch angle. The ANN supervisor adequately switches the system in variable speed and power limitation modes. In order to recover the maximum power from the tides, a rotational speed control is applied to the rotor side converter following the Maximum Power Point Tracking (MPPT) generated from the ANN block. In case of strong tidal currents, a pitch angle control is set based on the ANN approach to keep the system operating within safe limits. Two study cases were performed to test the performance of the output power. Simulation results demonstrate that the implemented control strategies achieve a smoothed generated power in the case of swell disturbances. PMID- 29695128 TI - Rapid Determination of the Geographical Origin of Chinese Red Peppers (Zanthoxylum Bungeanum Maxim.) Based on Sensory Characteristics and Chemometric Techniques. AB - In this paper, principal component analysis (PCA), linear discriminant analysis (LDAp, artificial neural networks (ANN), and support vector machine (SVM) were applied to discriminate the geographical origin of Chinese red peppers (Zanthoxylum bungeanum Maxim.). The models based on color, smell and taste may discriminate quickly and effectively the geographical origin of Chinese red peppers from different regions, but the successful identification rates may vary with different kinds of parameters and chemometric methods. Among them, all models based on taste indexes showed an excellent ability to discriminate the geographical origin of Chinese red peppers with correct classifications of 100% for the training set and the 100% for test set. The present study provided a simple, efficient, inexpensive, practical and fast method to discriminate the geographical origin of Chinese red peppers from different regions, which was of great importance for both consumers and producers. PMID- 29695129 TI - Depth Reconstruction from Single Images Using a Convolutional Neural Network and a Condition Random Field Model. AB - This paper presents an effective approach for depth reconstruction from a single image through the incorporation of semantic information and local details from the image. A unified framework for depth acquisition is constructed by joining a deep Convolutional Neural Network (CNN) and a continuous pairwise Conditional Random Field (CRF) model. Semantic information and relative depth trends of local regions inside the image are integrated into the framework. A deep CNN network is firstly used to automatically learn a hierarchical feature representation of the image. To get more local details in the image, the relative depth trends of local regions are incorporated into the network. Combined with semantic information of the image, a continuous pairwise CRF is then established and is used as the loss function of the unified model. Experiments on real scenes demonstrate that the proposed approach is effective and that the approach obtains satisfactory results. PMID- 29695130 TI - HtrA1 Is Specifically Up-Regulated in Active Keloid Lesions and Stimulates Keloid Development. AB - Keloids occur after failure of the wound healing process; inflammation persists, and various treatments are ineffective. Keloid pathogenesis is still unclear. We have previously analysed the gene expression profiles in keloid tissue and found that HtrA1 was markedly up-regulated in the keloid lesions. HtrA1 is a serine protease suggested to play a role in the pathogenesis of various diseases, including age-related macular degeneration and osteoarthritis, by modulating extracellular matrix or cell surface proteins. We analysed HtrA1 localization and its role in keloid pathogenesis. Thirty keloid patients and twelve unrelated patients were enrolled for in situ hybridization, immunohistochemical, western blot, and cell proliferation analyses. Fibroblast-like cells expressed more HtrA1 in active keloid lesions than in surrounding lesions. The proportion of HtrA1 positive cells in keloids was significantly higher than that in normal skin, and HtrA1 protein was up-regulated relative to normal skin. Silencing HtrA1 gene expression significantly suppressed cell proliferation. HtrA1 was highly expressed in keloid tissues, and the suppression of the HtrA1 gene inhibited the proliferation of keloid-derived fibroblasts. HtrA1 may promote keloid development by accelerating cell proliferation and remodelling keloid-specific extracellular matrix or cell surface molecules. HtrA1 is suggested to have an important role in keloid pathogenesis. PMID- 29695131 TI - Cucurbit[n]uril (n = 6, 7) Based Carbon-Gold Hybrids with Peroxidase-Like Activity. AB - Despite the combination of molecular recognition and local electric field enhancement endowing cucurbit[n]uril-capped metallic nanoparticles, indicating great potential in a variety of areas, prior work has paid little attention to carbonizing cucurbit[n]uril on the surface of gold nanoparticles, which may propose new carbon-gold hybrid materials with interesting applications. In this work, we developed a simple and cost-effective method to prepare carbon-gold hybrids by carbonizing cucurbit[n]uril modified gold nanoparticles. The as prepared cucurbit[n]uril based carbon and carbon-gold hybrid materials have shown to possess peroxidase-like activity. All cucurbit[n]uril based nanomaterials exhibited high catalytic activity over a pH range 2-6 and more tolerant to high temperature (up to 60 degrees C) when compared to natural horseradish peroxidase. PMID- 29695132 TI - Estimation of the Toxicity of Different Substituted Aromatic Compounds to the Aquatic Ciliate Tetrahymena pyriformis by QSAR Approach. AB - Nowadays, quantitative structure-activity relationship (QSAR) methods have been widely performed to predict the toxicity of compounds to organisms due to their simplicity, ease of implementation, and low hazards. In this study, to estimate the toxicities of substituted aromatic compounds to Tetrahymena pyriformis, the QSAR models were established by the multiple linear regression (MLR) and radial basis function neural network (RBFNN). Unlike other QSAR studies, according to the difference of functional groups (−NO2, −X), the whole dataset was divided into three groups and further modeled separately. The statistical characteristics for the models are obtained as the following: MLR: n = 36, R2 = 0.829, RMS (root mean square) = 0.192, RBFNN: n = 36, R2 = 0.843, RMS = 0.167 for Group 1; MLR: n = 60, R2 = 0.803, RMS = 0.222, RBFNN: n = 60, R2 = 0.821, RMS = 0.193 for Group 2; MLR: n = 31 R2 = 0.852, RMS = 0.192; RBFNN: n = 31, R2 = 0.885, RMS = 0.163 for Group 3, respectively. The results were within the acceptable range, and the models were found to be statistically robust with high external predictivity. Moreover, the models also gave some insight on those characteristics of the structures that most affect the toxicity. PMID- 29695133 TI - Direct Electron Transfer of Dehydrogenases for Development of 3rd Generation Biosensors and Enzymatic Fuel Cells. AB - Dehydrogenase based bioelectrocatalysis has been increasingly exploited in recent years in order to develop new bioelectrochemical devices, such as biosensors and biofuel cells, with improved performances. In some cases, dehydrogeases are able to directly exchange electrons with an appropriately designed electrode surface, without the need for an added redox mediator, allowing bioelectrocatalysis based on a direct electron transfer process. In this review we briefly describe the electron transfer mechanism of dehydrogenase enzymes and some of the characteristics required for bioelectrocatalysis reactions via a direct electron transfer mechanism. Special attention is given to cellobiose dehydrogenase and fructose dehydrogenase, which showed efficient direct electron transfer reactions. An overview of the most recent biosensors and biofuel cells based on the two dehydrogenases will be presented. The various strategies to prepare modified electrodes in order to improve the electron transfer properties of the device will be carefully investigated and all analytical parameters will be presented, discussed and compared. PMID- 29695134 TI - Label-Free Impedance Sensing of Aflatoxin B1 with Polyaniline Nanofibers/Au Nanoparticle Electrode Array. AB - Aflatoxin B1 (AFB1) is produced by the Aspergillus flavus and Aspergillus parasiticus group of fungi which is most hepatotoxic and hepatocarcinogenic and occurs as a contaminant in a variety of foods. AFB1 is mutagenic, teratogenic, and causes immunosuppression in animals and is mostly found in peanuts, corn, and food grains. Therefore, novel methodologies of sensitive and expedient strategy are often required to detect mycotoxins at the lowest level. Herein, we report an electrochemical impedance sensor that selectively detects AFB1 at the lowest level by utilizing polyaniline nanofibers (PANI) coated with gold (Au) nanoparticles composite based indium tin oxide (ITO) disk electrodes. The Au-PANI nanocomposites were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD) spectroscopy, and electrochemical impedance spectroscopy (EIS). The composite electrode exhibited a 14-fold decrement in |Z|1Hz in comparison with the bare electrode. The Au-PANI acted as an effective sensing platform having high surface area, electrochemical conductivity, and biocompatibility which enabled greater loading deposits of capture antibodies. As a result, the presence of AFB1 was screened with high sensitivity and stability by monitoring the changes in impedance magnitude (|Z|) in the presence of a standard iron probe which was target specific and proportional to logarithmic AFB1 concentrations (CAFB1). The sensor exhibits a linear range 0.1 to 100 ng/mL with a detection limit (3) of 0.05 ng/mL and possesses good reproducibility and high selectivity against another fungal mycotoxin, Ochratoxin A (OTA). With regard to the practicability, the proposed sensor was successfully applied to spiked corn samples and proved excellent potential for AFB1 detection and development of point-of-care (POC) disease sensing applications. PMID- 29695135 TI - General Practitioners' Perceptions of Heat Health Impacts on the Elderly in the Face of Climate Change-A Qualitative Study in Baden-Wurttemberg, Germany. AB - Heat health impacts (HHI) on the elderly are a growing concern in the face of climate change and aging populations. General practitioners (GPs) have an important role in health care for the elderly. To inform the development of effective prevention measures, it is important to investigate GPs’ perceptions of HHI. Twenty four qualitative expert interviews were conducted with GPs and analyzed using the framework approach. GPs were generally aware of heat health impacts, focusing on cardiovascular morbidity and volume imbalances. Perceptions of mortality and for instance impacts on respiratory diseases or potentially risky drugs in heat waves partly diverged from findings in literature. GPs judged the current relevance of HHI differently depending on their attitudes towards: (i) sensitivity of the elderly, (ii) status of nursing care and (iii) heat exposure in Baden-Württemberg. Future relevance of HHI was perceived to be increasing by most GPs. The main cause identified for this was population aging, while impacts of climate change were judged as uncertain by many. GPs’ perceptions, partly diverging from literature, show that GPs’ knowledge and awareness on HHI and climate change needs to be strengthened. However, they also emphasize the need for more research on HHI in the ambulant health care setting. Furthermore, GPs perceptions suggest that strong nursing care and social networks for elderly are major elements of a climate resilient health system. PMID- 29695136 TI - Polymer-Surfactant System Based Amorphous Solid Dispersion: Precipitation Inhibition and Bioavailability Enhancement of Itraconazole. AB - The rapid release of poorly water-soluble drugs from amorphous solid dispersion (ASD) is often associated with the generation of supersaturated solution, which provides a strong driving force for precipitation and results in reduced absorption. Precipitation inhibitors, such as polymers and surfactants, are usually used to stabilize the supersaturated solution by blocking the way of kinetic or thermodynamic crystal growth. To evaluate the combined effect of polymers and surfactants on maintaining the supersaturated state of itraconazole (ITZ), various surfactants were integrated with enteric polymer hydroxypropyl methylcellulose acetate succinate (HPMC AS) to develop polymer-surfactant based solid dispersion. The supersaturation stability was investigated by in vitro supersaturation dissolution test and nucleation induction time measurement. Compared to the ASD prepared with HPMC AS alone, the addition of d-alpha tocopheryl polyethylene glycol 1000 succinate (TPGS) exhibited a synergistic effect on precipitation inhibition. The results indicated that the TPGS not only significantly reduced the degree of supersaturation which is the driving force for precipitation, but also provided steric hindrance to delay crystal growth by absorbing onto the surface of small particles. Subsequently, the formulations were evaluated in vivo in beagle dogs. Compared with commercial product Sporanox®, the formulation prepared with HPMC AS/TPGS exhibited a 1.8-fold increase in the AUC (0-24 h) of ITZ and a 1.43-fold increase of hydroxyitraconazole (OH-ITZ) in the plasma. Similarly, the extent of absorption was increased by more than 40% when compared to the formulation prepared with HPMC AS alone. The results of this study demonstrated that the ASD based on polymer-surfactant system could obviously inhibit drug precipitation in vitro and in vivo, which provides a new access for the development of ASD for poorly water soluble drug. PMID- 29695138 TI - Organ-Specific MicroRNAs (MIR122, 137, and 206) Contribute to Tissue Characteristics and Carcinogenesis by Regulating Pyruvate Kinase M1/2 (PKM) Expression. AB - Pyruvate kinase is known as the glycolytic enzyme catalyzing the final step in glycolysis. In mammals, two different forms of it exist, i.e., pyruvate kinase M1/2 (PKM) and pyruvate kinase L/R (PKLR). Also, PKM has two isoforms, i.e., PKM1 and PKM2. These genes have tissue-specific distribution. Namely, PKM1 is distributed in high-energy-demanding organs, such as brain and muscle. Also, PKM2 is distributed in various other organs, such as the colon. On the other hand, PKLR is distributed in liver and red blood cells (RBCs). Interestingly, PKM2 has been recognized as one of the essential genes for the cancer-specific energy metabolism termed the “Warburg effect”. However, the mechanism(s) underlying this fact have remained largely unclear. Recently, we found that some organ-specific microRNAs (miRNAs, MIR) regulate PKM isoform expression through direct targeting of polypyrimidine tract binding protein 1 (PTBP1), which is the splicer responsible for PKM2-dominant expression. In this study, we examined whether this machinery was conserved in the case of other PTBP1- and PKM targeting miRNAs. We focused on the MIRs 122, 137, and 206, and investigated the expression profiles of each of these miRNAs in tissues from mouse and human organs. Also, we examined the regulatory mechanisms of PKM isoform expression by testing each of these miRNAs in human cancer cell lines. Presently, we found that brain-specific MIR137 and muscle-specific MIR206 predominantly induced PKM1 expression through direct targeting of PTBP1. Also, liver-specific MIR122 suppressed the expression of both PKM1 and PKM2, which action occurred through direct targeting of PKM to enable the expression of PKLR. Moreover, the expression levels of these miRNAs were downregulated in cancer cells that had originated from these tissues, resulting in PKM2 dominance. Our results suggest that the organ-specific distribution of miRNAs is one of the principal means by which miRNA establishes characteristics of a tissue and that dysregulation of these miRNAs results in cancer development through a change in the ratio of PKM isoform expression. Also, our results contribute to cancer diagnosis and will be useful for cancer-specific therapy for the Warburg effect in the near future. PMID- 29695139 TI - Comparative Analysis of Repetitive DNA between the Main Vectors of Chagas Disease: Triatoma infestans and Rhodnius prolixus. AB - Chagas disease or American trypanosomiasis affects six to seven million people worldwide, mostly in Latin America. This disease is transmitted by hematophagous insects known as "kissing bugs" (Hemiptera, Triatominae), with Triatoma infestans and Rhodnius prolixus being the two most important vector species. Despite the fact that both species present the same diploid chromosome number (2n = 22), they have remarkable differences in their total DNA content, chromosome structure and genome organization. Variations in the DNA genome size are expected to be due to differences in the amount of repetitive DNA sequences. The T. infestans genome wide analysis revealed the existence of 42 satellite DNA families. BLAST searches of these sequences against the R. prolixus genome assembly revealed that only four of these satellite DNA families are shared between both species, suggesting a great differentiation between the Triatoma and Rhodnius genomes. Fluorescence in situ hybridization (FISH) location of these repetitive DNAs in both species showed that they are dispersed on the euchromatic regions of all autosomes and the X chromosome. Regarding the Y chromosome, these common satellite DNAs are absent in T. infestans but they are present in the R. prolixus Y chromosome. These results support a different origin and/or evolution in the Y chromosome of both species. PMID- 29695140 TI - Low-Cycle Fatigue Behavior of 10CrNi3MoV High Strength Steel and Its Undermatched Welds. AB - The use of high strength steel allows the design of lighter, more slender and simpler structures due to high strength and favorable ductility. Nevertheless, the increase of yield strength does not guarantee the corresponding improvement of fatigue resistance, which becomes a major concern for engineering structure design, especially for the welded joints. The paper presents a comparison of the low cycle fatigue behaviors between 10CrNi3MoV high strength steel and its undermatched weldments. Uniaxial tension tests, Push-pull, strain-controlled fatigue tests were conducted on base metal and weldments in the strain range of 0.2-1.2%. The monotonic and cyclic stress-strain curves, stress-life, strain-life and energy-life in terms of these materials were analyzed for fatigue assessment of materials discrepancy. The stress-life results of base metal and undermatched weld metal exhibit cyclic softening behaviors. Furthermore, the shapes of 10CrNi3MoV steel hysteresis loops show a satisfactory Masing-type behavior, while the weld metal shows a non-Masing type behavior. Strain, plastic and total strain energy density amplitudes against the number of reversals to failure results demonstrate that the undermatched weld metal presents a higher resistance to fatigue crack initiation than 10CrNi3MoV high strength steel. Finally, fatigue fracture surfaces of specimens were compared by scanning electron microscopy to identify the differences of crack initiation and the propagation between them. PMID- 29695137 TI - Targeting GLI Transcription Factors in Cancer. AB - Aberrant activation of hedgehog (Hh) signaling has been observed in a wide variety of tumors and accounts for more than 25% of human cancer deaths. Inhibitors targeting the Hh signal transducer Smoothened (SMO) are widely used and display a good initial efficacy in patients suffering from basal cell carcinoma (BCC); however, a large number of patients relapse. Though SMO mutations may explain acquired therapy resistance, a growing body of evidence suggests that the non-canonical, SMO-independent activation of the Hh pathway in BCC patients can also account for this adverse effect. In this review, we highlight the importance of glioma-associated oncogene (GLI) transcription factors (the main downstream effectors of the canonical and the non-canonical Hh cascade) and their putative role in the regulation of multiple oncogenic signaling pathways. Moreover, we discuss the contribution of the Hh signaling to malignant transformation and propose GLIs as central hubs in tumor signaling networks and thus attractive molecular targets in anti-cancer therapies. PMID- 29695142 TI - Influence of Annealing on Microstructure and Mechanical Properties of a Nanocrystalline CrCoNi Medium-Entropy Alloy. AB - An equiatomic CrCoNi medium-entropy alloy was subjected to high-pressure torsion. This process led to a refinement of the microstructure to a grain size of about 50 nm, combined with a strong increase in the materials hardness. Subsequently, the thermodynamic stability of the medium entropy alloy was evaluated by isothermal and isochronal heat treatments. Annealed samples were investigated by scanning and transmission electron microscopy as well as X-ray diffraction, and were subjected to tensile tests to establish microstructure-property relationships. Furthermore, a comparison of mechanical properties with a grade 316L stainless steel was performed in order to evaluate if the CrCoNi alloy is competitive with commercially available structural materials in the nanocrystalline state. A minority phase embedded in the face-centered cubic matrix of the CrCoNi alloy could be observed in multiple annealed states, as well as the as-received and high-pressure torsion processed material. For 200 h of annealing at 500 °C, it was determined that the minority phase has a hexagonal-closed-packed crystal structure. A possible explanation for the formation of the phase is a preferential segregation of Co to stacking faults. PMID- 29695141 TI - Insights into the Structure, Function, and Ligand Discovery of the Large Neutral Amino Acid Transporter 1, LAT1. AB - The large neutral amino acid transporter 1 (LAT1, or SLC7A5) is a sodium- and pH independent transporter, which supplies essential amino acids (e.g., leucine, phenylalanine) to cells. It plays an important role at the Blood-Brain Barrier (BBB) where it facilitates the transport of thyroid hormones, pharmaceuticals (e.g., l-DOPA, gabapentin), and metabolites into the brain. Moreover, its expression is highly upregulated in various types of human cancer that are characterized by an intense demand for amino acids for growth and proliferation. Therefore, LAT1 is believed to be an important drug target for cancer treatment. With the crystallization of the arginine/agmatine antiporter (AdiC) from Escherichia Coli, numerous homology models of LAT1 have been built to elucidate the substrate binding site, ligand-transporter interaction, and structure function relationship. The use of these models in combination with molecular docking and experimental testing has identified novel chemotypes of ligands of LAT1. Here, we highlight the structure, function, transport mechanism, and homology modeling of LAT1. Additionally, results from structure-function studies performed on LAT1 are addressed, which have enhanced our knowledge of the mechanism of substrate binding and translocation. This is followed by a discussion on ligand- and structure-based approaches, with an emphasis on elucidating the molecular basis of LAT1 inhibition. Finally, we provide an exhaustive summary of different LAT1 inhibitors that have been identified so far, including the recently discovered irreversible covalent inhibitors. PMID- 29695143 TI - Transient forebrain ischemia induces impairment in cognitive performance prior to extensive neuronal cell death in Mongolian gerbil (Meriones unguiculatus). AB - In Mongolian gerbils, bilateral common carotid artery occlusion (BCCAO) for several minutes induces ischemia, due to an incomplete circle of Willis, resulting in delayed neuronal cell death in the Cornet d'Ammon 1 (CA1) region of the hippocampus. Neuronal cell death in the hippocampus and changes in behavior were examined after BCCAO was performed for 5 min in the gerbils. One day after BCCAO, the pyramidal neurons of the CA1 region of the hippocampus showed degenerative changes (clumped chromatin in nuclei). At 5 and 10 days after BCCAO, extensive neuronal cell death was observed in the hippocampal CA1 region. Cognitive performance was evaluated by using the radial maze and passive avoidance tests. In the radial maze test, which examines win-stay performance, the number of errors was significantly higher in ischemic gerbils than in sham operated gerbils on days 1 and 2 post-operation. In the passive avoidance test, the latency and freezing times were significantly shorter in ischemic gerbils than in sham-operated gerbils on the days 1, 2, and 4-6 post-operation. These results indicate that transient forebrain ischemia impairs cognitive performance, even immediately after the ischemic insult when there are only subtle signs of neuronal cell death. PMID- 29695144 TI - Speckle-tracking analysis of myocardial deformation in correlation to age in healthy horses. AB - An effect of aging on cardiac morphology and function has been shown in humans. In horses, cardiac wall motion analysis using two-dimensional speckle tracking (2D-ST) has not yet been reported. Our study included 57 horses of different warmblood breeds between 3 and 30 years old. Age had a significant influence on left ventricular free wall (LVFW) systolic strain rate (p <= 0.05) and early diastolic relaxation (p <= 0.01). In the interventricular septum (IVS), systolic (p <= 0.01) and late diastolic (p <= 0.05) contraction velocities also increased with age. In our study, 2D-ST revealed important information on myocardial function, which was most evident in the LVFW, where measurements were highly reproducible. Aging seems to be associated with structural changes within the myocardium and with decreasing contraction capacity in old animals. These physiological, age-related processes should be considered when performing cardiac wall motion analysis of the 2D-ST results for the LVFW and IVS in horses. PMID- 29695145 TI - Sciatic nerve leachate of cattle causes neuronal differentiation of PC12 cells via ERK1/2 signaling pathway. AB - Previous studies have shown that the sciatic nerve has neurotrophic activity, and nerve regeneration, differentiation, and axon outgrowth can be modulated by different sciatic nerve preparations. However, numerous animals may have to be sacrificed to obtain enough sciatic nerves to make a sciatic nerve preparation. Some studies have demonstrated that the role of sciatic nerve preparations in neural differentiation depends on the neurotrophins that Schwann cells secrete, and these factors are highly conserved among different species. To reduce the use of experimental animals, in this study, we made a leachate by using the sciatic nerve of cattle and explored its effect on neuronal differentiation of rat PC12 cells (a useful model for studying neuronal differentiation). Results showed the neurite outgrowth of PC12 cells treated with the cattle sciatic nerve leachate for 3, 6, and 9 days was significantly improved, and the expressions of beta3 tubulin and microtubule-associated protein 2 (two neuron-specific proteins) were increased. Moreover, the ERK1/2 signaling pathway was activated after PC12 cells were incubated with cattle sciatic nerve leachate for 9 days. Thus, a sciatic nerve leachate obtained from cattle can effectively induce neuronal differentiation of rat PC12 cells via ERK1/2 signaling pathway. PMID- 29695146 TI - Isolation and characterization of Korean porcine deltacoronavirus strain KNU16 07. AB - Porcine deltacoronavirus (PDCoV) has emerged in several pig-raising countries and has been a causative pathogen associated with diarrheal diseases in South Korea since 2014. In the present study, we were able to isolate and cultivate a Korean PDCoV strain (KNU16-07) in cell culture and investigate its pathogenicity. PDCoV inoculated piglets showed watery diarrhea accompanied by acute enteritis in the natural host. Sequencing analysis demonstrated the genetic stability of KNU16-07 for at least thirty serial passages. PMID- 29695147 TI - Epidemiologic features of inflammatory bowel disease in Western Blacksea region of Turkey for the last 10 years: retrospective cohort study. AB - Background/Aims: There are only a few epidemiological study about inflammatory bowel disease in the last 10 years in Turkey, especially in Western Blacksea region. In our study, we aimed to identify the changes in the incidence and the prevalence of inflammatory bowel disease in Western Blacksea region at the last 10 years. Methods: Totally 223 patients with inf lammatory bowel disease (160 ulcerative colitis, 63 Crohn's disease) were enrolled in the study followed up between 2004 to 2013 years. The epidemiological characteristics of patients were recorded. Results: The prevalences were 12.53/105 and 31.83/105 for Crohn's disease and ulcerative colitis respectively. Mean annual incidences increased from 0.99/105 and 0.45/105 for ulcerative colitis and Crohn's disease (2004 to 2005 years) to 4.87/105 and 2.09/105 for ulcerative colitis and Crohn's disease respectively (2011 to 2013 years). While the prevalence was higher in urban areas in Crohn's disease (12.60/105 ), it was higher in rural areas in ulcerative colitis (36.17/105 ). In ulcerative colitis, mean annual incidences were 2.91/105 and 2.86/105 for urban and rural areas respectively. In Crohn's disease, they were 1.37/105 and 1.08/105 for urban and rural areas respectively. Conclusions: The incidence of inflammatory bowel disease seems to increase in Western Blacksea region at the last 10 years. This increment is more prevalent in rural areas. PMID- 29695148 TI - Accuracy of Endoscopic Diagnosis for Mild Atrophic Gastritis Infected with Helicobacter pylori. AB - BACKGROUND/AIMS: This study examined the accuracy of endoscopic evaluation for determining the Helicobacter pylori infection status in patients with mild atrophy who might not exhibit characteristic endoscopic findings. METHODS: Forty endoscopists determined the H. pylori infection status of 50 randomly presented H. pylori-positive and H. pylorinegative cases on the basis of a list of established findings. RESULTS: The median clinical endoscopy experience was 7 years (range, 1-35 years), including 22 board-certified endoscopists (55%) of the Japan Gastroenterological Endoscopy Society. The mean accuracy rate of endoscopic diagnosis was 67% and was unrelated to experience status (experienced vs. trainee: 69% vs. 65%, p=0.089) and total years of experience (R2 =0.022). The most frequently selected endoscopic findings were regular arrangement of collecting venules (59%), atrophy (45%), and red streak (22%), which had fair accuracy rates of 67%, 65%, and 73%, respectively. By contrast, the accuracy rates of nodularity (89%) and mucosal swelling (77%) were highest. The 20 endoscopists who more frequently identified these findings diagnosed H. pylori infection significantly more accurately than did the other endoscopists (71% vs. 64%, p=0.008). CONCLUSIONS: Careful attention to nodularity and mucosal swelling in patients with mild atrophy may enhance diagnosis, enable prompt treatment, and avoid possible long-term carcinogenesis. PMID- 29695149 TI - Changes in the Hippocampal Volume and Shape in Early-Onset Mild Cognitive Impairment. AB - OBJECTIVE: The aim of this study was to examine the change in the hippocampal volume and shape in early-onset mild cognitive impairment (EO-MCI) associated with the APOE epsilon4 carrier state. METHODS: This study had 50 subjects aged 55 63 years, all of whom were diagnosed with MCI at baseline via the Korean version of the Consortium to Establish a Registry for Alzheimer's Disease Assessment Packet. The EO-MCI patients were divided into the MCI continued (MCIcont) and Alzheimer's disease (AD) converted (ADconv) groups 2 years later. The hippocampal volume and shape were measured for all the subjects. The local shape analysis (LSA) was used to conduct based on the 2-year-interval magnetic resonance imaging scans. RESULTS: There was a significant correlation between APOE epsilon4 allele and hippocampal volume atrophy. Over two years, the volume reduction in the left hippocampus was found to be faster than that in the right hippocampus, especially in the APOE epsilon4 carriers. LSA showed that the 2 subfields were significantly affected in the left hippocampus. CONCLUSION: These results suggest that the possession of APOE epsilon4 allele may lead to greater predilection for left hippocampal atrophy in EO-MCI, and some specific subfields of the hippocampus may be more prominently involved. PMID- 29695150 TI - Modulation of Electrophysiology by Transcranial Direct Current Stimulation in Psychiatric Disorders: A Systematic Review. AB - OBJECTIVE: Transcranial direct current stimulation (tDCS) is a non-invasive neuromodulation technique increasingly used to relieve symptoms of psychiatric disorders. Electrophysiologic markers, such as electroencephalography (EEG) and event-related potentials (ERP), have high temporal resolution sensitive to detect plastic changes of the brain associated with symptomatic improvement following tDCS application. METHODS: We performed systematic review to identify electrophysiological markers that reflect tDCS effects on plastic brain changes in psychiatric disorders. A total of 638 studies were identified by searching PubMed, Embase, psychINFPO. Of these, 21 full-text articles were assessed eligible and included in the review. RESULTS: Although the reviewed studies were heterogeneous in their choices of tDCS protocols, targeted electrophysiological markers, and disease entities, their results strongly support EEG/ERPs to sensitively reflect plastic brain changes and the associated symptomatic improvement following tDCS. CONCLUSION: EEG/ERPs may serve a potent tool in revealing the mechanisms underlying psychiatric symptoms, as well as in localizing the brain area targeted for stimulation. Future studies in each disease entities employing consistent tDCS protocols and electrophysiological markers would be necessary in order to substantiate and further elaborate the findings of studies included in the present systematic review. PMID- 29695151 TI - Cognitive Behavioral Therapy for Insomnia Reduces Hypnotic Prescriptions. AB - OBJECTIVE: This study determined whether cognitive behavioral therapy for insomnia (CBT-i) decreased the need for sleep medications and produced better treatment outcomes than pharmacotherapy alone. METHODS: We reviewed data from patients with insomnia in the outpatient clinic of a general hospital between 2009 and 2015. We compared 41 patients who received five sessions of CBT-i with 100 age- and sex-matched patients who received pharmacotherapy only. We evaluated the change in prescription for sleep (i.e., antidepressants, hypnotics, and others) between the first and last visits using repeated measures analysis of variance (ANOVA). Clinical global impressions and completion status at the last visit were assessed using the chisquare test. RESULTS: We found a significant decrease in the prescription rate and the dosage of hypnotics among patients who received CBT-i when compared with control patients. There was no significant change in the dosage of antidepressants between the two groups. Achievement of case closure was better in the CBT-i group at the trend level. Clinical global impression at the last visit was not significantly different. CONCLUSION: These results show that CBT-i reduces the need for hypnotics among insomnia patients. Our results indicate that CBT-i offers additional benefits beyond improving sleep characteristics and thus provides another reason for recommending CBT-i as a first-line treatment for insomnia. PMID- 29695153 TI - Classics in Chemical Neuroscience: Risperidone. AB - After the identification of the influence of serotonergic receptors in ameliorating the negative symptoms associated with schizophrenia, atypical antipsychotics were developed by incorporating dopamine and serotonin antagonism. Risperidone, sold under the trade name Risperdal, was the second atypical antipsychotic developed following clozapine but quickly became a first-line treatment for acute and chronic schizophrenia because of its preferential side effect profile. Despite initial Food and Drug Administration approval 25 years ago, risperidone continues to be a fundamental treatment for schizophrenia, bipolar I disorder, and autism-related irritability. It is on the World Health Organization's List of Essential Medicines for its balance of efficacy, safety, tolerability, and cost-effectiveness. In this review, we highlight the history and importance of risperidone as an atypical antipsychotic, in addition to its chemical synthesis, manufacturing, drug metabolism and pharmacokinetics, pharmacology, structure-activity relationship, indications, and adverse effects. PMID- 29695152 TI - The Benefits of Indirect Exposure to Trauma: The Relationships among Vicarious Posttraumatic Growth, Social Support, and Resilience in Ambulance Personnel in China. AB - OBJECTIVE: Ambulance personnel who witness trauma experienced by patients have been reported to experience positive changes, known as vicarious posttraumatic growth (VPTG). We examined VPTG and its relationship with social support and resilience among ambulance personnel. METHODS: The sample (n=227) was recruited from six emergency centers in China. The measures included the Posttraumatic Growth Inventory (PTGI), the Social Support Rating Scale (SSRS), and the 10-item Connor-Davidson Resilience Scale (CD-RISC-10). Structure Equation Modeling (SEM) and the bootstrapping procedure were used to examine indirect effects. RESULTS: The participants' mean score for VPTG was 68.96 (SD=15.51). Social support had significant direct effects on resilience (beta=0.51, p<0.001) and VPTG (beta=0.25, p=0.001), and resilience (beta=0.58, p<0.001) had a significant direct effect on VPTG. Furthermore, social support had a significant indirect effect (0.51*0.58=0.30, p<0.001) on VPTG through resilience. CONCLUSION: Although the nature of the work of ambulance personnel is not expected to change, the negative effects of the trauma they encounter can be reduced by providing them with more support resources and interventions to foster their resilience, which in turn, promote VPTG. PMID- 29695154 TI - Effects of Astaxanthin and Docosahexaenoic-Acid-Acylated Astaxanthin on Alzheimer's Disease in APP/PS1 Double-Transgenic Mice. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder with the characteristics of senile plaques, neuroinflammation, neurofibrillary tangles, and destruction of synapse structure stability. Previous studies have verified the protective effects of astaxanthin (AST). However, whether synthesized docosahexaenoic-acid-acylated AST diesters (AST-DHA) could delay AD pathogenesis remains unclear. In the present study, APP/PSEN1 (APP/PS1) double-transgenic mice were administrated with AST and AST-DHA for 2 months. The results of radial 8-arm maze and Morris water maze tests showed that AST-DHA exerted more significant effects than AST in enhancing learning and memory levels of APP/PS1 mice. Further mechanical studies suggested that AST-DHA was superior to AST in regulating the parameters of oxidative stress, reducing tau hyperphosphorylation, suppressing neuroinflammation, and regulating inflammasome expression and activation in APP/PS1 mice. The findings suggested that AST-DHA attenuated cognitive disorders by reducing pathological features in APP/PS1 mice, suggesting that AST-DHA might be a potential therapeutic agent for AD. PMID- 29695156 TI - Innovative Strategy Based on a Novel Carbon-Black-beta-Cyclodextrin Nanocomposite for the Simultaneous Determination of the Anticancer Drug Flutamide and the Environmental Pollutant 4-Nitrophenol. AB - In the present work, a noncovalent and eco-friendly approach was proposed to prepare a carbon-black/beta-cyclodextrin (CB/beta-CD) nanocomposite. CB/beta-CD nanocomposite-modified screen-printed carbon electrodes were applied for the simultaneous determination of the anticancer drug flutamide (Flut) and the environmental pollutant 4-nitrophenol (4-NP). The electrochemical performance of the proposed sensor relied on the conductivity of CB, the different binding strengths of the guests (Flut and 4-NP) to the host (beta-CD), and the different reduction potentials of the nitroaromatic compounds. Fascinatingly, the proposed sensor exhibited an excellent electrochemical performance with high sensitivity, selectivity, and reproducibility. The obtained wide linear ranges were 0.05-158.3 and 0.125-225.8 MUM for Flut and 4-NP. The low detection limits of 0.016 and 0.040 MUM with the higher sensitivities of 5.476 and 9.168 MUA MUM-1 cm-2 were achieved for the determination of Flut and 4-NP, respectively. The practical feasibility of the proposed sensor was studied in tap-water and human-serum samples. PMID- 29695155 TI - Influence of Substrate Bonding and Surface Morphology on Dynamic Organic Layer Growth: Perylenetetracarboxylic Dianhydride on Au(111). AB - We investigated the dynamics of the initial growth of the first epitaxial layers of perylenetetracarboxylic dianhydride (PTCDA) on the Au(111) surface with high lateral resolution using the aberration-corrected spectro-microscope SMART. With this instrument, we could simultaneously study the different adsorption behaviors and layer growth on various surface areas consisting of either a distribution of flat (111) terraces, separated by single atomic steps ("ideal surface"), or on areas with a high density of step bunches and defects ("realistic surface"). The combined use of photoemission electron microscopy, low-energy electron microscopy, and MU-spot X-ray absorption provided a wealth of new information, showing that the growth of the archetype molecule PTCDA not only has similarities but also has significant differences when comparing Au(111) and Ag(111) substrate surfaces. For instance, under otherwise identical preparation conditions, we observed different growth mechanisms on different surface regions, depending on the density of step bunches. In addition, we studied the spatially resolved desorption behavior which also depends on the substrate morphology. PMID- 29695157 TI - Structural Basis of the Molecular Switch between Phosphatase and Mutase Functions of Human Phosphomannomutase 1 under Ischemic Conditions. AB - The human phosphomannomutases PMM1 and PMM2 catalyze the interconversion of hexose 6-phosphates and hexose 1-phosphates. The two isoforms share 66% sequence identity and have kinetic properties similar to those of mutases in vitro but differ in their functional roles in vivo. Though the physiological role of PMM2 is catalysis of the mutase reaction that provides the mannose 1-phosphate (Man-1 P) essential for protein glycosylation, PMM1 is thought to provide a phosphohydrolase activity in the presence of inosine monophosphate (IMP), converting glucose 1,6-bisphosphate (Glu-1,6-P2) to glucose 6-phosphate (Glu-6 P), rescuing glycolysis during brain ischemia. To uncover the structural basis of how IMP binding converts PMM1 from a mutase to a phosphatase, the 1.93 A resolution structure of PMM1 complexed with IMP was determined. The structure reveals IMP bound at the substrate recruitment site, thus inhibiting the mutase activity while simultaneously activating a phosphatase activity (IMP Kact = 1.5 MUM) resulting from the hydrolysis of the phospho-enzyme. The bound structure and site-directed mutagenesis confirm that the long-range electrostatic interactions provided by Arg180 and Arg183 conserved in PMM1 are the major contributors to IMP binding, and their oblation removes phosphatase but not mutase activity. These residues are not present in the PMM2 isoform, which consequently lacks significant phosphatase activity in the presence of IMP. T2 relaxation nuclear magnetic resonance and small angle X-ray scattering together support the hypothesis that binding of IMP to PMM1 favors an enzyme conformation that is catalytically competent for water attack at the phosphoaspartyl intermediate. Such a mechanism may be generalizable to other enzymes that act through covalent intermediates. PMID- 29695158 TI - Accurate Methyl Group Dynamics in Protein Simulations with AMBER Force Fields. AB - An approach is presented to directly simulate the dynamics of methyl groups in protein side-chains, as accessible via NMR spin relaxation measurements, by all atom MD simulations. The method, which does not rely on NMR information or any system-specific adjustable parameters, is based on calculating the time correlation functions (TCFs) of the C-H bonds in methyl groups and explicitly takes the truncation of the TCFs due to overall tumbling of the molecule into account. Using ubiquitin as a model protein, we show (i) that an accurate description of the methyl dynamics requires reparametrization of the potential energy barriers of methyl group rotation in the AMBER ff99SB*-ILDN force field (and related parameter sets), which was done with CCSD(T) coupled cluster calculations of isolated dipeptides as reference, and (ii) that the TIP4P/2005 solvation model yields overall tumbling correlation times that are in close agreement with experimental data. The methyl axis squared order parameters Saxis2 and associated correlation times tauf, obtained within the Lipari-Szabo formalism, are in good agreement with the values derived from NMR deuterium relaxation experiments. Importantly, the relaxation rates and spectral densities derived from MD and NMR agree as well, enabling a direct comparison without assumptions inherent to simplified motional models. PMID- 29695159 TI - Polymeric Sorbent with Controlled Surface Polarity: An Alternate for Solid-Phase Extraction of Nerve Agents and Their Markers from Organic Matrix. AB - Extraction and identification of lethal nerve agents and their markers in complex organic background have a prime importance from the forensic and verification viewpoint of the Chemical Weapons Convention (CWC). Liquid-liquid extraction with acetonitrile and commercially available solid phase silica cartridges are extensively used for this purpose. Silica cartridges exhibit limited applicability for relatively polar analytes, and acetonitrile extraction shows limited efficacy toward relatively nonpolar analytes. The present study describes the synthesis of polymeric sorbents with tunable surface polarity, their application as a solid-phase extraction (SPE) material against nerve agents and their polar as well as nonpolar markers from nonpolar organic matrices. In comparison with the acetonitrile extraction and commercial silica cartridges, the new sorbent showed better extraction efficiency toward analytes of varying polarity. The extraction parameters were optimized for the proposed method, which included ethyl acetate as an extraction solvent and n-hexane as a washing solvent. Under optimized conditions, method linearity ranged from 0.10 to 10 MUg mL-1 ( r2 = 0.9327-0.9988) for organophosphorus esters and 0.05-20 MUg mL-1 ( r2 = 0.9976-0.9991) for nerve agents. Limits of detection (S:N = 3:1) in the SIM mode were found in the range of 0.03-0.075 MUg mL-1 for organophosphorus esters and 0.015-0.025 MUg mL-1 for nerve agents. Limits of quantification (S:N = 10:1) were found in the range of 0.100-0.25 MUg mL-1 for organophosphorus esters and 0.05-0.100 MUg mL-1 for nerve agents in the SIM mode. The recoveries of the nerve agents and their markers ranged from 90.0 to 98.0% and 75.0 to 95.0% respectively. The repeatability and reproducibility (with relative standard deviations (RSDs) %) for organophosphorus esters were found in the range of 1.35 8.61% and 2.30-9.25% respectively. For nerve agents, the repeatability range from 1.00 to 7.75% and reproducibility were found in the range of 2.17-6.90%. PMID- 29695160 TI - An Adaptive Pipeline To Maximize Isobaric Tagging Data in Large-Scale MS-Based Proteomics. AB - Isobaric tagging is the method of choice in mass-spectrometry-based proteomics for comparing several conditions at a time. Despite its multiplexing capabilities, some drawbacks appear when multiple experiments are merged for comparison in large sample-size studies due to the presence of missing values, which result from the stochastic nature of the data-dependent acquisition mode. Another indirect cause of data incompleteness might derive from the proteomic typical data-processing workflow that first identifies proteins in individual experiments and then only quantifies those identified proteins, leaving a large number of unmatched spectra with quantitative information unexploited. Inspired by untargeted metabolomic and label-free proteomic workflows, we developed a quantification-driven bioinformatic pipeline (Quantify then Identify (QtI)) that optimizes the processing of isobaric tandem mass tag (TMT) data from large-scale studies. This pipeline includes innovative features, such as peak filtering with a self-adaptive preprocessing pipeline optimization method, Peptide Match Rescue, and Optimized Post-Translational Modification. QtI outperforms a classical benchmark workflow in terms of quantification and identification rates, significantly reducing missing data while preserving unmatched features for quantitative comparison. The number of unexploited tandem mass spectra was reduced by 77 and 62% for two human cerebrospinal fluid and plasma data sets, respectively. PMID- 29695161 TI - Target-Induced Horseradish Peroxidase Deactivation for Multicolor Colorimetric Assay of Hydrogen Sulfide in Rat Brain Microdialysis. AB - Hydrogen sulfide (H2S) is important for normal neural functions, which involves protecting neurons from oxidative stress and neuronal transmission modulation in brain. The detection of H2S is significant for revealing its role in the diagnosis of various disease. In this study, a novel multicolor colorimetric assay based on the etching of gold nanorods (Au NRs) is proposed to evaluate H2S level with the naked eye. This measurement relies on the catalytic oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) via horseradish peroxidase (HRP) to produce TMB2+, which could etch the Au NRs quickly and accompany with a distinct color change. The vivid colors can be easily distinguished with the naked eye without any sophisticated instruments. The presence of H2S can cause the deactivation of HRP, which affects the amount of TMB2+ produced and consequently affects the color changing of the system. Based on this mechanism, a simple but sensitive multicolor colorimetric assay is developed for H2S detection with a linear range of 0.05-50 MUM. The proposed method is demonstrated for monitoring extracellular H2S in rat brain coupled with microdialysate. PMID- 29695162 TI - Synthesis and Transistor Application of Bis[1]benzothieno[6,7- d:6',7'- d']benzo[1,2- b:4,5- b']dithiophenes. AB - Four bis[1]benzothieno[6,7- d:6',7'- d']benzo[1,2- b:4,5- b']dithiophene (BBTBDT) derivatives bearing substituents on the molecular long axis were synthesized, and their transistor performance was evaluated. Among the obtained compounds, OFET devices based on the 2,9-diphenyl-substituted derivative (1d) on a beta-PTS modified Si/SiO2 substrate yielded the best morphological and crystalline structures, resulting in the highest hole mobility, as high as 0.16 cm2 V-1 s-1, and a low threshold voltage of -8 V. In the solid state, 1d formed a highly ordered and crystalline edge-on structure, which facilitated effective carrier transport. The detailed structure-property relationships were also disclosed by GIWAXS analysis, atomic force microscopy measurements, and theoretical calculations. PMID- 29695163 TI - Virtual Issue on New Physical Insights. PMID- 29695164 TI - Virtual Issue on New Physical Insights. PMID- 29695165 TI - Pharmacokinetics/Pharmacodynamics of Dabigatran 75 mg Twice Daily in Patients With Nonvalvular Atrial Fibrillation and Severely Impaired Renal Function. AB - INTRODUCTION: Dabigatran etexilate is an oral direct thrombin inhibitor. Dabigatran excretion is 80% renal, so exposure increases with severity of renal failure. The US Food and Drug Administration-approved dabigatran etexilate 75 mg twice daily (BID) for patients with nonvalvular atrial fibrillation (NVAF) having severely impaired renal function (creatinine clearance: 15-30 mL/min), based on post hoc pharmacokinetic modeling. We assessed dabigatran exposure at trough and peak levels in patients with NVAF and severely impaired renal function and compared with model predictions. METHODS: Patients received dabigatran etexilate (75 mg BID) for >=7 days before blood sampling; Cpre,ss (steady-state predose concentration; trough) was taken 10 to 16 hours postdose (prior to next dose), and C2,ss (steady-state concentration; peak) was taken 2 hours (+/- 30 minutes) postdose. Pharmacodynamic parameters at baseline (Ebase), trough concentrations (Epre,ss), and peak concentrations (E2,ss) were assessed by established coagulation assays. RESULTS: Of the 150 patients screened, 60 were treated, of which 40% were male and 78.3% were white; median age was 84 years. Cpre,ss values (n = 51) were close to pharmacokinetic modeling predictions with a geometric mean (gMean) of 155 ng/mL, geometric coefficient of variation (gCV) of 76.9%, and range of 15.6 to 498 ng/mL. The C2,ss values (n = 59) had a gMean of 202 ng/mL, gCV of 70.6%, and range of 42.0 to 680 ng/mL. Pharmacodynamic effects on coagulation paralleled dabigatran concentrations. Eleven (18.3%) patients had >=1 adverse event (AE); pharmacokinetic results for these patients versus those without AEs (n = 49) were Cpre, ss: gMean = 206 versus 145 ng/mL, gCV = 64.0% versus 78.3%; C2,ss: gMean = 243 versus 193 ng/mL, gCV = 68.9% versus 70.8%. All bleeding events (8 events in 5 patients) were considered minor by the investigators. CONCLUSION: Dabigatran exposure levels largely confirmed earlier pharmacokinetic predictions, supporting the use of dabigatran etexilate 75 mg BID in patients with NVAF and severely impaired renal function. Pharmacodynamic results were also in agreement with earlier studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT01896297. PMID- 29695167 TI - The Most Important Financial Year of Your Life: Recommendations for the Transition From Resident to Practicing Pediatrician. PMID- 29695166 TI - Reducing Waste and Increasing the Usability of Psychiatry Research: The Family of EQUATOR Reporting Guidelines and One of Its Newest Members: The PRISMA-DTA Statement. PMID- 29695168 TI - Cortical spreading depression as a site of origin for migraine: Role of CGRP. AB - Premise Migraine is a complex neurologic disorder that leads to significant disability, yet remains poorly understood. Problem One potential triggering mechanism in migraine with aura is cortical spreading depression, which can activate the trigeminal nociceptive system both peripherally and centrally in animal models. A primary neuropeptide of the trigeminal system is calcitonin gene related peptide, which is a potent vasodilatory peptide and is currently a major therapeutic target for migraine treatment. Despite the importance of both cortical spreading depression and calcitonin gene-related peptide in migraine, the relationship between these two players has been relatively unexplored. However, recent data suggest several potential vascular and neural connections between calcitonin gene-related peptide and cortical spreading depression. Conclusion This review will outline calcitonin gene-related peptide-cortical spreading depression connections and propose a model in which cortical spreading depression and calcitonin gene-related peptide act at the intersection of the vasculature and cortical neurons, and thus contribute to migraine pathophysiology. PMID- 29695169 TI - Association of Prediabetes With Higher Coronary Atherosclerotic Burden Among Patients With First Diagnosed Acute Coronary Syndrome. AB - Diabetes mellitus (DM) is associated with more extensive coronary atherosclerosis and more vulnerable plaque phenotypes. However, DM should not be considered a homogeneous and purely binary entity in terms of risk assessment. We evaluated the impact of prediabetic status on coronary atherosclerosis burden in patients with first-time acute coronary syndrome (ACS) who underwent urgent coronary angiography. The patients were divided into DM, prediabetes, and control groups. The 3-vessel disease (TVD) rates and SYNTAX and Gensini scoring systems for defining atherosclerotic burden were compared. The study was conducted in 469 consecutive patients admitted with a diagnosis of ACS. Of these, 250 patients were admitted at the first occurrence of ACS undergoing diagnostic coronary angiography. SYNTAX and Gensini scores and TVD rates were higher in prediabetic patients than in nondiabetic patients ( P = .004, P = .008, and P = .014, respectively), but similar in prediabetic and diabetic patients ( P = .912, P = .773, and P = 1.000, respectively). Coronary atherosclerosis burden is more advanced in prediabetic patients than in nondiabetic patients and is comparable between prediabetic and diabetic patients at first presentation of ACS. Cardiologists should not miss the opportunity to diagnose prediabetes and DM when patients present with an ACS. PMID- 29695170 TI - A Survey of Rabbit Handling Methods Within the United Kingdom and the Republic of Ireland. AB - Rabbits are commonly kept in a variety of settings, including homes, laboratories, and veterinary clinics. Despite the popularity of keeping this prey species, little research has investigated current methods of handling. The aim of this study was to examine the experience of caregivers (owners and keepers) in using five handling methods commonly referred to in books written for companion animal (pet) owners and veterinary and/or laboratory personnel. An online survey was completed by 2644 respondents, representing all three of these groups, and breeders. Data were acquired to determine sources that participants used to gain knowledge of different handling methods, the methods they used and for what purposes they used them, and their perceptions of any associated difficulties or welfare concerns. Results indicated that participants most frequently used the method of supporting a rabbit's body against a person's chest, which was considered the easiest and most welfare-friendly method of the handling methods explored. "Scruffing with rear support" was the least used method and was considered to be distressing and painful for the rabbit. As rabbits are a terrestrial prey species, being picked up is likely an innately stressful experience. Additional research is encouraged to explore the experience of rabbits during handling to identify methods that can be easily used with the fewest welfare compromises. PMID- 29695171 TI - Retroperitoneal Robotic Partial Nephrectomy: Systematic Review and Cumulative Analysis of Comparative Outcomes. AB - OBJECTIVES: To compare the outcomes of retroperitoneal vs transperitoneal approach for robot-assisted partial nephrectomy (RAPN). MATERIALS AND METHODS: A systematic review of the literature was performed through January 2018 using PubMed, Scopus, and Ovid databases. Article selection proceeded according to the search strategy based on PRISMA criteria. Only studies comparing retroperitoneal to transperitoneal approach for RAPN were deemed eligible for inclusion. RESULTS: Seven retrospective case-control studies were identified and included in the analysis, with a total number of 1379 patients (866 for transperitoneal group; 513 for retroperitoneal group). In the retroperitoneal group, tumors were slightly larger [weighted mean difference (WMD): 0.29 cm; 95% confidence interval (CI): 0.04-0.54; p = 0.02], and more frequently located posterior/lateral (odds ratio: 0.61; 95% CI: 0.41-0.90; p = 0.01). In two of the studies only posterior tumors had been included. Both operating time (WMD 20.17 min; 95% CI 6.46-33.88; p = 0.004) and estimated blood loss (WMD 54.57 mL; 95% CI 6.73-102.4; p = 0.03) were significantly lower in the retroperitoneal group. In addition, length of stay was significantly shorter in the retroperitoneal group (WMD 0.46 days; CI 95% 0.15-0.76; p = 0.003). No differences were found regarding overall (p = 0.67) and major (p = 0.82) postoperative complications, warm ischemia time (p = 0.96), and positive surgical margins (p = 0.95). CONCLUSIONS: Retroperitoneal RAPN can offer in select patients similar outcomes to those of the most common transperitoneal RAPN. Furthermore, it may be particularly advantageous for posterior upper pole and perihilar tumors and associated with reduction in operative time and hospital stay. Robotic surgeons should be ideally familiar with both approaches to adapt their surgical strategy to confront renal neoplasms from a position of technical advantage and ultimately optimize outcomes. PMID- 29695172 TI - Relationship Between Metabolic Syndrome Severity and Kidney Function as Related to Gender: A Population-Based Longitudinal Study. AB - The purpose of this study was to explore the relationship between the metabolic syndrome severity Z-score and kidney function by gender. We also examined the estimated glomerular filtration rate in relation to other known risk factors. The study used was a population-based prospective longitudinal research design. A total of 4,838 participants (2,683 females and 2,155 males) included individuals aged >30 years who were undergoing a health examination from 2006 to 2014 in Pingzhen City, Taiwan. In the initial generalized estimated equation model analysis, which included the covariates of age of first visit, period between the first and current visit, and metabolic syndrome severity Z-score, the results indicated that the interaction between age and metabolic syndrome severity Z score is significantly related to the estimated glomerular filtration rate for males ( p = .040). For females, the interaction between age and metabolic syndrome severity Z-score was not significant, but a higher metabolic syndrome severity Z-score was significantly associated with lower estimated glomerular filtration rate ( p = .001). After controlling for the confounders, unhealthy behaviors, and comorbidities, the metabolic syndrome severity Z-score was still a negative predictor of estimated glomerular filtration rate in both the male ( p = .005) and female ( p = .023) models. PMID- 29695173 TI - Conditioned media from human osteoarthritic synovium induces inflammation in a synoviocyte cell line. AB - AIM: Osteoarthritis (OA) is a whole joint pathology involving cartilage, synovial membrane, meniscus, subchondral bone, and infrapatellar fat pad (IFP). Synovitis has been widely documented in OA suggesting its important role in pathogenesis. The aim of this study was to investigate the role of different joint tissues in promoting synovitis. MATERIALS AND METHODS: Conditioned media (CM) from cartilage, synovial membrane, meniscus, and IFP were generated from tissues of five patients undergoing total knee replacement and used to stimulate a human fibroblast-like synoviocytes cell line (K4IM). Cytokines, chemokines, and metalloproteases release was analyzed in all CM by Bio-Plex Assay and sulfated glycosaminoglycan (GAG) content by dimethylmethylene blue assay. Gene expression of several markers was evaluated by real-time PCR in K4IM cells stimulated with the CM obtained from joint tissues. RESULTS: CM from all tissues produced high levels of IL-6, IL-8, and CCL2. CCL21, MMP-3, and -13 levels were detected in all CM except IFP. MMP-10 was present only in CM of cartilage and synovial tissues. IL-1beta, IL-15, TNF-alpha, CCL5, and CCL19 were undetectable. However, only K4IM cells stimulated by the CM from OA synovium showed an increase of IL-6, CXCL-8, CCL21, MMP10, and IL-1beta expression. CONCLUSION: Our study showed that K4IM might be a suitable in vitro model for evaluating different cellular pathways in OA studies. Importantly, we demonstrated that in OA, all joint tissues might be involved in the progression of synovitis with a predominant role of synovial membrane itself compared to the other joint tissues. PMID- 29695175 TI - Effects of mindfulness-based stress reduction on prenatal stress, anxiety and depression. AB - Low well-being is common among Chinese pregnant women but few effective interventions currently exist to improve prenatal stress and negative emotions. Mindfulness-based stress reduction (MBSR) has been proved to be effective in reducing stress and rarely studies were focused on Chinese pregnant women. The aim of the current paper is to investigate the effects of 8-week MBSR on prenatal stress, anxiety and depression among Chinese pregnant women. A sample of 66 pregnant women randomly allocated into either the MBSR group (n=34) or the control group (n=32). Participants in the MBSR group received a group 8-week, 90 min each time intervention. The results found a significant interaction between time and condition for prenatal stress (F=45.51, p<0.001, eta 2=0.427), anxiety (F=19.30, p<0.001, eta 2=0.240), while depression showed no time-by-group interaction (F=0.29, p=0.589, eta 2=0.005). As for the sub-scale of state anxiety, while there was only no time effect (F=3.68, p=0.060, eta 2=0.057). The findings of this study preliminary indicated effects of the MBSR intervention on self-reported prenatal stress and anxiety in comparison to a treatment-as-usual control. Effect on depression was not observed may due to the low level of depression of participants. This study provides preliminary evidence that MBSR is suitable for Chinese pregnant women and be effective in decreasing prenatal stress, anxiety. PMID- 29695174 TI - Preparation of psoralen polymer-lipid hybrid nanoparticles and their reversal of multidrug resistance in MCF-7/ADR cells. AB - Multidrug resistance (MDR) is the leading cause of failure for breast cancer in the clinic. Thus far, polymer-lipid hybrid nanoparticles (PLN) loaded chemotherapeutic agents has been used to overcome MDR in breast cancer. In this study, we prepared psoralen polymer-lipid hybrid nanoparticles (PSO-PLN) to reverse drug resistant MCF-7/ADR cells in vitro and in vivo. PSO-PLN was prepared by the emulsification evaporation-low temperature solidification method. The formulation, water solubility and bioavailability, particle size, zeta potential and entrapment efficiency, and in vitro release experiments were optimized in order to improve the activity of PSO to reverse MDR. Optimal formulation: soybean phospholipids 50 mg, poly(lactic-co-glycolic) acid (PLGA) 15 mg, PSO 3 mg, and Tween-80 1%. The PSO-PLN possessed a round appearance, uniform size, exhibited no adhesion. The average particle size was 93.59 +/- 2.87 nm, the dispersion co efficient was 0.249 +/- 0.06, the zeta potential was 25.47 +/- 2.84 mV. In vitro analyses revealed that PSO resistance index was 3.2, and PSO-PLN resistance index was 5.6, indicating that PSO-PLN versus MCF-7/ADR reversal effect was significant. Moreover, PSO-PLN is somewhat targeted to the liver, and has an antitumor effect in the xenograft model of drug-resistant MCF-7/ADR cells. In conclusion, PSO-PLN not only reverses MDR but also improves therapeutic efficiency by enhancing sustained release of PSO. PMID- 29695176 TI - Markers of Thrombin Generation Are Associated With Long-Term Clinical Outcome in Patients With ST-Segment Elevation Myocardial Infarction. AB - Hypercoagulability in ST-segment elevation myocardial infarction (STEMI) as related to long-term clinical outcome is not clarified. We aimed to investigate whether prothrombin fragment 1+2 (F1+2), d-dimer, and endogenous thrombin potential (ETP) measured in the acute phase of STEMI were associated with outcome. Blood samples were drawn median 24 hours after symptom onset in 987 patients with STEMI. Median follow-up time was 4.6 years. Primary outcome was a composite of all-cause mortality, reinfarction, stroke, unscheduled revascularization, or rehospitalization for heart failure; secondary outcome was total mortality. The number of combined end points/total mortality was 195/79. Higher levels of d-dimer and F1+2 were observed with both end points (all P < .005), whereas ETP was significantly lower ( P < .01). Dichotomized at medians, increased risk was observed for levels above median for F1+2 and d-dimer (combined end point P = .020 and P = .010 and total mortality P < .001, both), while an inverse pattern was observed for ETP ( P < .02, both). Adjusting for covariates, d-dimer was still associated with reduced risk of total mortality ( P = .034) and receiver operating characteristic curve analyses showed area under the curve of 0.700 (95% confidence interval, 0.640-0.758). The hypercoagulable state in acute STEMI seems to be of importance for clinical outcome. PMID- 29695177 TI - Clinical Manifestation of Patients With Atypical Hemolytic Uremic Syndrome With the C3 p.I1157T Variation in the Kinki Region of Japan. AB - The gain-of-function variation p.I1157T in C3 was previously identified in 8 patients with atypical hemolytic uremic syndrome (aHUS) at Mie University Hospital. In the present study, we identified another 11 patients with aHUS with this variation, including 10 pediatric patients (onset age: 1-16 years). The variation seems to be geographically concentrated around Mie Prefecture in Japan. Fifteen of the 19 patients with aHUS experienced infection as probable triggering events. All 19 patients had renal dysfunction. Seven patients, including 2 from the previous study and 5 from the present study, were treated with eculizumab, with all showing a good response with hematological normalization. Among the 5 eculizumab-treated patients in the present study, 3 had an ambiguous diagnosis of aHUS due to low-grade hemolysis even with elevated levels of lactate dehydrogenase and bilirubin. In those cases, in-house targeted DNA sequencing identified the C3 p.I1157T variation carriers, which enabled the early initiation of treatment with eculizumab. The present study supports the early introduction of eculizumab in patients with aHUS, especially pediatric patients. PMID- 29695178 TI - Sepsis-Induced Coagulopathy and Japanese Association for Acute Medicine DIC in Coagulopathic Patients with Decreased Antithrombin and Treated by Antithrombin. AB - Disseminated intravascular coagulation (DIC) in patients with sepsis represents a critical condition. Thus, a simple and rapid diagnosis is required. The purpose of this study was to compare the performances of a recently developed Sepsis Induced Coagulopathy (SIC) with the Japanese Association for Acute Medicine (JAAM) DIC. Four hundred nine patients with sepsis having coagulopathy and antithrombin activity of less than 70% and treated with antithrombin were retrospectively analyzed, and the SIC and JAAM-DIC criteria on days 1 (before treatment), 2, 4, and 7 were compared. The prevalence of JAAM-DIC on day 1 was significantly higher than that of SIC (91.4% vs 81.8%, P = .003), but there were no differences on days 2, 4, and 7. The mortality rates in the SIC and JAAM-DIC groups were both 23.3%. The specificity to 28-day mortality on day 1 was higher in the SIC group (15.8% vs 9.2%, P = .013). There were no differences in sensitivity on days 1, 2, 4, and 7. Mortality was significantly different between SIC-positive and SIC-negative groups on days 2, 4, and 7 ( P < .01, respectively), while significant differences were seen between JAAM-DIC-positive and JAAM-DIC-negative groups only on days 4 and 7 ( P < .05, .01, respectively). In summary, the SIC characteristics were similar to the JAAM-DIC group, and the classifications were comparable in terms of mortality prediction. The SIC scoring system is simple, easy to use, and adaptable to the new sepsis definitions and offers an important approach to evaluating patients in emergency and critical care settings. PMID- 29695179 TI - Extraction of the same novel homoglycan mixture from two different strains of Bifidobacterium animalis and three strains of Bifidobacterium breve. AB - Three strains of Bifidobacterium breve (JCM 7017, JCM 7019 and JCM 2258) and two strains of Bifidobacterium animalis subsp. lactis (AD011 and A1dOxR) were grown in broth cultures or on plates, and a standard exopolysaccharide extraction method was used in an attempt to recover exocellular polysaccharides. When the extracted materials were analysed by NMR it was clear that mixtures of polysaccharides were being isolated including exopolysaccharides (EPS) cell wall polysaccharides and intracellular polysaccharides. Treatment of the cell biomass from the B. breve strains, or the B. animalis subsp. lactis AD011 strain, with aqueous sodium hydroxide provided a very similar mixture of polysaccharides but without the EPS. The different polysaccharides were partially fractionated by selective precipitation from an aqueous solution upon the addition of increasing percentages of ethanol. The polysaccharides extracted from B. breve JCM 7017 grown in HBM media supplemented with glucose (or isotopically labelled D-glucose 1-13C) were characterised using 1D and 2D-NMR spectroscopy. Addition of one volume of ethanol generated a medium molecular weight glycogen (Mw=1*105 Da, yield 200 mg/l). The addition of two volumes of ethanol precipitated an intimate mixture of a low molecular weight beta-(1->6)-glucan and a low molecular weight beta-(1->6)-galactofuranan which could not be separated (combined yield 46 mg/l). When labelled D-glucose-1-13C was used as a carbon supplement, the label was incorporated into >95% of the anomeric carbons of each polysaccharide confirming they were being synthesised in situ. Similar 1H NMR profiles were obtained for polysaccharides recovered from the cells of B. animalis subsp. lactis AD011and A1dOxR (in combination with an EPS), B. breve JCM 7017, B. breve JCM 7019, B. breve JCM 2258 and from an EPS (-ve) mutant of B. breve 7017 (a non-EPS producer). PMID- 29695180 TI - Are probiotic treatments useful on fibromyalgia syndrome or chronic fatigue syndrome patients? A systematic review. AB - Evidence suggests that the gut microbiota might play an important role in fibromyalgia syndrome (FMS) and chronic fatigue syndrome (CFS). Our goal is to systematically review the reported effect of probiotic treatments in patients diagnosed with FMS or CFS. A systematic review was carried out using 14 databases (PubMed, Cochrane Library, Scopus, PsycINFO, and others) in February 2016 to search for randomised controlled trials (RCTs) and pilot studies of CFS or FMS patient, published in the last ten years (from 2006 to 2016). The Jadad scale was used to asseverate the quality of the clinical trials considered. Two studies (n=83) met the inclusion criteria, which were performed in CFS patients and both studies were considered as a 'High range of quality score'. The administration of Lactobacillus casei strain Shirota in CFS patients, over the course of 8 weeks, reduced anxiety scores. Likewise, this probiotic changed the faecal composition following 8 weeks of treatment. Additionally, the treatment with Bifidobacterium infantis 35624 in CFS patients, during the same period, reduced inflammatory biomarkers. The evidence about the usefulness of probiotics in CFS and FMS patients remains limited. The studied strains of probiotics have demonstrated a significant effect on modulating the anxiety and inflammatory processes in CFS patients. However, more experimental research, focusing mainly on the symptoms of the pathologies studied, is needed. PMID- 29695181 TI - Anti-obesity properties of the strain Bifidobacterium animalis subsp. lactis CECT 8145 in Zucker fatty rats. AB - We evaluated the effect of oral administration of Bifidobacterium animalis subsp. lactis CECT 8145 strain in Zucker fatty rats. The Zucker fatty rats were randomly divided into two groups (n=10 each) and administered either B. animalis subsp. lactis CECT 8145 (1010 cfu/day) suspended in skim milk, or skim milk alone (control group). Each treatment was administered in drinking bottles from week 5 until week 17 of age. A lean Zucker rat group (standard group) was included to provide normal values for the Zucker strain. This group was administered skim milk in the drinking bottle for the same experimental period as Zucker fatty rats. Body weight gain was greater in the fatty control group than in the fatty rats treated daily with B. animalis subsp. lactis CECT 8145. Furthermore, dry and liquid food intake significantly decreased in the treated Zucker fatty group and these rats also showed decreased plasma ghrelin levels as compared with the Zucker fatty control group. B. animalis subsp. lactis CECT 8145 intake also decreased plasma tumour necrosis factor-alpha (a proinflammatory cytokine) and plasma malondialdehyde (a biomarker of oxidative stress). Moreover, the ratio plasma total cholesterol/plasma cholesterol transported by high-density lipoproteins, considered as an index for cardiovascular disease, also significantly decreased in the Zucker fatty rats treated with B. animalis subsp. lactis CECT 8145. By contrast, this bacterial strain significantly increased plasma adiponectin (an insulin-sensitising adipokine), but did not produce significant effects on triglyceride levels or glucose metabolism biomarkers. Although further research is required to confirm B. animalis subsp. lactis CECT 8145 is an efficient anti-obesity treatment in humans, the results obtained in this study are promising and point to the health and anti-obesity properties of this bacterial strain. PMID- 29695182 TI - The application of in vitro human intestinal models on the screening and development of pre- and probiotics. AB - The importance of the gut microbiota community on host's health and disease has long been recognised and is well documented. The development of pro- and prebiotic interventions offers an opportunity for the modulation of the gut microbiota towards long lasting health. In vitro fermentation models were developed as a powerful tool to study the impact of pro- and prebiotics on the gut microbiota under tightly controlled conditions, which allow dynamic sampling over time in reactors mimicking different colon regions. These models have been further evolved to suit specific experimental purposes, e.g. including immobilised faecal microbiota, peristaltic movement, mucin microcosm and the ability to perform treatments in parallel. In this review we discuss the advantages, disadvantages and technical considerations of the most frequently used models. We further focus on recent advances in the application of these models in prebiotics and probiotics research and outline their predictability for clinical research. PMID- 29695183 TI - Efficacy of Bacillus coagulans Unique IS2 in treatment of irritable bowel syndrome in children: a double blind, randomised placebo controlled study. AB - The efficacy of the probiotic strain, Bacillus coagulans Unique IS2 in the treatment of Irritable Bowel Syndrome (IBS) was evaluated in children. A total of 141 children of either sex in the age group 4-12 years, diagnosed with IBS according to the Rome III criteria, participated in the double-blind randomised controlled trial. Children received either B. coagulans Unique IS2 chewable tablets or placebo once daily for eight weeks followed by a two week follow-up period. Reduction in pain intensity as well as other symptoms associated with Irritable Bowel Syndrome like abdominal discomfort, bloating, distension, sense of incomplete evacuation, straining at stool, urgency of bowel movement, passage of gas and mucus, and bowel habit satisfaction were assessed. B. coagulans Unique IS2 treated group showed a greater reduction in pain scores as evaluated by a weekly pain intensity scale. There was a significant reduction (P<0.0001) in pain intensity in the probiotic treated group (7.6+/-0.98) as compared to the placebo group (4.2+/-1.41) by the end of the treatment period (8 weeks). There was also a significant improvement in stool consistency as well as reduction in abdominal discomfort, bloating, staining, urgency, incomplete evacuation and passage of gas. Bowel habit satisfaction and global assessment of relief was also observed in the B. coagulans Unique IS2 treated group as compared to the placebo group. This study demonstrates the efficacy of B. coagulans Unique IS2 in reducing the symptoms of Irritable Bowel Syndrome in children in the age group of 4-12 years. PMID- 29695184 TI - Risk and protective factors of posttraumatic stress disorder among African American women living with HIV. AB - We sought to examine risk and protective factors for Posttraumatic Stress Disorder (PTSD) among African American women living with HIV. This is a cross sectional analysis of baseline data from a randomized trial of an HIV stigma reduction intervention. We examined data from two-hundred and thirty-nine African American women living with HIV. We examined whether age, marital status, level of education, internalized HIV-related stigma, and social support as potential protective and risk factors for PTSD symptoms using logistic regression. We analyzed bi-variate associations between each variable and PTSD symptoms, and constructed a multivariate logistic regression model adjusting for all variables. We found 67% reported clinically significant PTSD symptoms at baseline. Our results suggest that age, education, and internalized stigma were found to be associated with PTSD symptoms (p < 0.001), with older age and more education as protective factors and stigma as a risk factor for PTSD. Therefore, understanding this relationship may help improve assessment and treatment through evidence- based and trauma-informed strategies. PMID- 29695185 TI - Externalized Ureteral Catheter Versus Double-J Stent in Tubeless Percutaneous Nephrolithotomy for Upper Urinary Stones: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: The objective of this meta-analysis was to compare the efficacy and safety of externalized ureteral catheter (EUC) and Double-J stent (DJS) in tubeless percutaneous nephrolithotomy (PCNL) for patients with upper urinary stones based on published literature. MATERIALS AND METHODS: A comprehensive literature search using Pubmed, Embase, and Cochrane Library was performed to find studies comparing outcomes of EUC and DJS for treating patients with upper urinary stones up to December 2017. Seven studies, which included 863 patients from 5 randomized controlled trials (RCTs) and 2 non-RCTs published between 2009 and 2017, met our inclusion criteria and were included in this systematic review and meta-analysis. Between-studies heterogeneity was assessed and sensitivity analysis was conducted based on RCTs. RESULTS: The stent-related symptoms were higher for DJS compared with EUC (odds ratio [OR]: 0.09; confidence interval [95% CI]: 0.01-0.61; p = 0.01). No significant differences were found in minor (Clavien I-II) complications (OR: 1.37; 95% CI: 0.93-2.01; p = 0.11), major (Clavien III-V) complications (OR: 1.38; 95% CI: 0.73-2.60; p = 0.32), hemoglobin drop (weighted mean difference [WMD]: -1.43 g/L; 95% CI: -3.65 to 0.78; p = 0.2), pain score (VAS) (WMD: 0.01; 95% CI: -0.28 to 0.29; p = 0.95), analgesic required (OR: 1.02; 95% CI: 0.77-1.34; p = 0.91), stone-free rate (risk ratio: 0.98; 95% CI: 0.9-1.07; p = 0.67), duration of hospitalization (WMD: -0.21 days; 95% CI: 0.86 to 0.44; p = 0.53), and operative times (WMD: -7.59 minutes; 95% CI: -18.81 to 3.64; p = 0.19). CONCLUSION: We concluded that compared with DJS, EUC is also an effective alternative for patients with upper urinary stones in tubeless PCNL and could help patients by reducing stent-related discomfort and avoiding cystoscopy for DJS removal. However, the inherent limitations of the included studies should be considered, and well-designed RCTs with further large sample size should be performed to validate our findings. PMID- 29695186 TI - Corrigendum. AB - Westerlund, M. U. (2018). The usage of digital resources by Swedish suicide bereaved in their grief work: A survey study. OMEGA. doi: 10.1177/0030222818765807 In this article, Figure 2 was not correct. The correct figure is given here. [Figure: see text] Also, the first paragraph on page 10 should read as follows: Figure 2 shows the rate at which the respondents visit online support groups and memorial websites, respectively. In the total sample, 260 respondents (80%) reported that they were members of an online support group, but 3 (1%) reported that they never visited it. Thus, there were 257 (79%) active support group users in the sample ( Figure 2 , left side). Further, 126 (39%) respondents reported that they had utilized memorial websites, but 20 (6%) reported that they never visited it. Thus, there were 106 (32%) active memorial website users in the sample ( Figure 2 , right side). Taken together, there were 271 (83%) respondents who used either support groups or memorial websites (digital resources) to some degree and 56 (73%) respondents who never used such resources or did not use them actively. The first line of the third paragraph on page 18 should read as follows: The present study shows that a majority of the respondents use digital resources (i.e., online support groups and/or memorial websites) in their grief work ( Figure 2 ) and that reading posts is the most common activity (Table 1). PMID- 29695187 TI - Restoring NAD(+) Levels with NAD(+) Intermediates, the Second Law of Thermodynamics, and Aging Delay. AB - The hypothesis regarding the role of increased nicotinamide adenine dinucleotide (NAD+) levels with reference to the fundamental concepts of aging and entropy is presented. Considering the second law of thermodynamics, NAD+ seems the appropriate candidate for reversing many aging-associated pathologies. NAD+ is presented as an essential compound that enables organisms to stay highly organized and well maintained, with a lower entropy state. PMID- 29695188 TI - The power of popular opinion in everyday primary care provision in urban India. AB - Studies of power in health care settings in low- and middle-income countries largely describe providers' exercise of discretionary power in frontline roles, leaving under-specified the macro-institutions and mechanisms of power that drive health care outcomes. In this study I conceptualise providers' actions not in terms of discretionary power but as obligatory responses to 'authority' over them. Authority denotes an actor's rightfully held social power over others, who accept to follow that actor's directives. Explaining authority's workings entails studying how it operates from its subjects' perspectives. I analyse in particular the authority of popular opinion-which derives from citizens' claims to state services-over primary care doctors in municipal health facilities in Pune, India. Through year-long ethnographic fieldwork, I examine doctors' experience of popular opinion, social relations between doctors and communities, and the institutional history of state-provided urban primary care. Findings show that doctors routinely confront popular disregard for their services. But under conditions of long-standing neglect of municipal services, tenuous state-society relations, and an avid, widely preferred private sector, doctors appear unable and wary to deliver more than minimum clinical care. Their circumscribed response reflects mechanisms by which the power of popular opinion, under policy neglect, impels them to maintain a deficient status quo. PMID- 29695189 TI - A multidimensional approach to talent identification and selection in high-level youth Australian Football players. AB - There is limited research in talent identification in youth Australian Football (AF), especially the factors that underpin selection into higher-level development programs. Therefore, this study explored age-related differences in high-level youth AF players and investigated characteristics influencing selection into a high-level development program. Anthropometry (stature, sitting height, body mass), maturity (estimated age at peak height velocity), motor competence (Korperkoordinationstest fur Kinder), fitness (change of direction speed, lower body power and upper body muscular endurance) and coach skill ratings (kicking, marking and handballing) of 277 state academy players (U13-U15) were assessed. MANOVAs identified significant age-related differences for anthropometry, fitness, and coach skill ratings. Furthermore, 90.9 and 90.0% of U15 selected and deselected players were classified correctly. Selected players were more mature, taller, heavier, more explosive, faster at changing directions, and had superior kick technique and marking results. These results demonstrate considerable age-group performance outcome differences, highlighting that high level academies should aim to select or deselect after 15 years of age. Additionally, it appears earlier maturing players are favoured for selection into a high-level academy. While practitioners must consider the confounding effect of maturation, early maturing players may be favoured for their ability to withstand increasing demands in higher-level youth AF. PMID- 29695190 TI - Attachment hierarchies for Spanish adolescents: family, peers and romantic partner figures. AB - BACKGROUND: Attachment Theory has become one of the leading theories in human development. Nonetheless, empirical studies focusing on how attachment unfolds during adolescence are still scarce particularly in Spain, due to the lack of adequate measures. OBJECTIVE: This study aims to validate the Important People Interview (IPI) in a shorter questionnaire version (Important People- Questionnaire; IP-Q); to analyse the changes in different affiliative bonds to multiple figures -family, peers, romantic partners - over the course of adolescence; and to identify boys' and girls' hierarchical ordering of their specific attachment bonds. METHOD: 1025 Spanish adolescents, aged 12-17 years old completed the IP-Q. RESULTS: The results showed that the IP-Q has convergent and divergent validity. Moreover, this measure indicated that peers overtake some family members in proximity-seeking and support-seeking, but not in the overall hierarchical ordering of the attachment bond during adolescence. CONCLUSIONS: The bond with the romantic partner increases in terms of scoring on the affiliative subscales as adolescence progresses. There are significant gender differences among the hierarchy patterns of attachment for boys and girls. Developmental changes in adolescent attachment are discussed. PMID- 29695191 TI - High Glucose Inhibits Neural Stem Cell Differentiation Through Oxidative Stress and Endoplasmic Reticulum Stress. AB - Maternal diabetes induces neural tube defects by suppressing neurogenesis in the developing neuroepithelium. Our recent study further revealed that high glucose inhibited embryonic stem cell differentiation into neural lineage cells. However, the mechanism whereby high glucose suppresses neural differentiation is unclear. To investigate whether high glucose-induced oxidative stress and endoplasmic reticulum (ER) stress lead to the inhibition of neural differentiation, the effect of high glucose on neural stem cell (the C17.2 cell line) differentiation was examined. Neural stem cells were cultured in normal glucose (5 mM) or high glucose (25 mM) differentiation medium for 3, 5, and 7 days. High glucose suppressed neural stem cell differentiation by significantly decreasing the expression of the neuron marker Tuj1 and the glial cell marker GFAP and the numbers of Tuj1+ and GFAP+ cells. The antioxidant enzyme superoxide dismutase mimetic Tempol reversed high glucose-decreased Tuj1 and GFAP expression and restored the numbers of neurons and glial cells differentiated from neural stem cells. Hydrogen peroxide treatment imitated the inhibitory effect of high glucose on neural stem cell differentiation. Both high glucose and hydrogen peroxide triggered ER stress, whereas Tempol blocked high glucose-induced ER stress. The ER stress inhibitor, 4-phenylbutyrate, abolished the inhibition of high glucose or hydrogen peroxide on neural stem cell differentiation. Thus, oxidative stress and its resultant ER stress mediate the inhibitory effect of high glucose on neural stem cell differentiation. PMID- 29695192 TI - Dynamic structure based pharmacophore modeling of the Acetylcholinesterase reveals several potential inhibitors. AB - Acetylcholinesterase is a critical enzyme that regulates neurotransmission by catalyzing the breakdown of neurotransmitter acetylcholine in synapses of the nervous system. It is an important target for therapeutic drugs that treat Alzheimer's disease. Since, the degree of flexibility of the side chains of the residues in the active-site gorge of Acetylcholinesterase is diverse it results in different bound ligand conformations. The side-chain conformations of Ser293, Tyr341, Leu76, and Val73 are flexible, while the side-chain conformations of Tyr72, Tyr 124, Ser125, Phe295, and Arg296 appear to be fixed. In this study, multi-conformation dynamic pharmacophore models from the donepezyl-binding pocket based on highly populated structures chosen from molecular dynamics simulations were used for screening compounds that can properly bind acetylcholinesterase. Based on these structures, three pharmacophore models were generated. Consequently, 14 hits were retrieved as final candidates by utilizing virtual screening of ZINC database and molecular docking. PMID- 29695193 TI - Efficacy and Safety of Atypical Antipsychotics for Behavioral and Psychological Symptoms of Dementia Among Community Dwelling Adults. AB - INTRODUCTION: Options for the treatment of the behavioral and psychological symptoms of dementia (BPSD) are limited. Atypical antipsychotics are often used but have questionable efficacy and are generally considered high risk. Therefore, the objective of this study is to evaluate the efficacy and safety of using any atypical antipsychotic for the treatment of BPSD among outpatients. METHODS: Retrospective observational study of an academic outpatient memory disorders clinic. Participants included any community-dwelling patient with a diagnosis of dementia, not trauma induced, with documented BPSD treated with an atypical antipsychotic for at least 2 weeks. Medical records were reviewed from January 1, 1990 to March 23, 2010. Safety outcomes were documented from the time of antipsychotic initiation, and behavioral/psychological efficacy outcomes were documented beginning 2 weeks after antipsychotic therapy was initiated, until the last documentation available. RESULTS: A total of 87 distinct antipsychotic treatment periods for 81 unique patients were included. Antipsychotic treatment was continued for more than a year in 33% of patients and only 17% of patients discontinued antipsychotic treatment over the entire period. The behavioral/psychological outcomes improved for 24 (28%) treatments, remained stable for 17 (20%) treatments, and worsened for 46 (53%) treatments. Adverse events were reported by 53% of patients, with the most common adverse events being metabolic, fall related, type, and vascular. Few adverse events were severe. The odds ratio of adverse events per every 90-day increase in duration of treatment was 1.20 ( P = 0.02). CONCLUSION: Antipsychotic treatment improved behavioral/psychological symptoms for less than one-third of patients and increased the potential risk of adverse events for more than half of patients. PMID- 29695194 TI - Diffusional interaction behavior of NSAIDs in lipid bilayer membrane using molecular dynamics (MD) simulation: Aspirin and Ibuprofen. AB - In this research, for the first time, molecular dynamics (MD) method was used to simulate aspirin and ibuprofen at various concentrations and in neutral and charged states. Effects of the concentration (dosage), charge state, and existence of an integral protein in the membrane on the diffusion rate of drug molecules into lipid bilayer membrane were investigated on 11 systems, for which the parameters indicating diffusion rate and those affecting the rate were evaluated. Considering the diffusion rate, a suitable score was assigned to each system, based on which, analysis of variance (ANOVA) was performed. By calculating the effect size of the indicative parameters and total scores, an optimum system with the highest diffusion rate was determined. Consequently, diffusion rate controlling parameters were obtained: the drug-water hydrogen bond in protein-free systems and protein-drug hydrogen bond in the systems containing protein. PMID- 29695195 TI - Serum levels of carotenoids in patients with osteonecrosis of the femoral head are lower than in healthy, community-living people. AB - PURPOSE: Oxidative stress is closely associated with the pathogenesis of nontraumatic osteonecrosis of the femoral head (ONFH). This study aimed to determine whether the serum levels of antioxidant nutrients were decreased in patients with ONFH. METHODS: We analyzed the serum levels of antioxidant nutrients in 39 patients with ONFH (ONFH group) and 78 age- and gender-matched healthy people (control group) who voluntarily participated in the Yakumo study, which is a comprehensive health examination program. We measured and compared the serum levels of alpha-tocopherol (vitamin E) and total carotenoids, including zeaxanthin/lutein, beta-cryptoxanthin, lycopene, alpha-carotene, and beta carotene, in the ONFH and control groups using high-performance liquid chromatography. RESULTS: The mean serum levels of total carotenoids were significantly lower in the ONFH group than in the control group (2.36 +/- 1.26 and 3.79 +/- 2.36 umol/l, respectively, p < 0.001). However, no significant difference was found in alpha-tocopherol between the two groups (26.37 +/- 6.90 umol/l in the ONFH group and 26.24 +/- 6.28 umol/l in the control group, p = 0.920). Among each carotenoid, the serum levels of zeaxanthin/lutein, lycopene, and beta-carotene were significantly lower in the ONFH group than in the control group ( p < 0.001). CONCLUSIONS: The serum levels of carotenoids were lower in patients with ONFH than in healthy, community-living people. This result suggests that carotenoids may be related to the pathogenesis of ONFH. PMID- 29695196 TI - Performance of cooling materials and their composites in maintaining freezing temperature during irradiation and transportation of bone allografts. AB - PURPOSE: Bone allografts supplied by University Malaya Medical Centre Bone Bank are sterilized by gamma radiation at 25 kGy in dry ice (DI) to minimize radiation effects. Use of cheaper and easily available cooling materials, gel ice (GI) and ice pack (IP), was explored. Composites of DI and GI were also studied for the use in routine transportations and radiation process. METHODS: (a) Five dummy bones were packed with DI, GI, or IP in a polystyrene box. The bone temperatures were monitored while the boxes were placed at room temperature over 96 h. Durations for each cooling material maintaining freezing temperatures below -40 degrees C, -20 degrees C, and 0 degrees C were obtained from the bone temperature over time profiles. (b) Composites of DI (20, 15, 10, 5, and 0 kg) and GI were used to pack five dummy bones in a polystyrene box. The durations maintaining varying levels of freezing temperature were compared. RESULTS: DI (20 kg) maintained temperature below -40 degrees C for 76.4 h as compared to 6.3 h in GI (20 bags) and 4.0 h in IP (15 packs). Composites of 15DI (15 kg DI and 9 GI bags) and 10DI (10 kg DI and 17 GI bags) maintained the temperature below -40 degrees C for 61 and 35.5 h, respectively. CONCLUSION: Composites of DI and GI can be used to maintain bones in deep frozen state during irradiation, thus avoiding radiation effects on biomechanical properties. Sterile frozen bone allograft with preserved functional properties is required in clinical applications. PMID- 29695197 TI - The paradoxical body: A glimpse of a deeper truth through relatives' stories. AB - BACKGROUND: People with progressive cancer experience that their bodies change due to disease and/or treatment. The body is integral to the unity of the human being, a unity that must be perceived as whole if dignity shall be experienced. Relatives are in touch with the suffering bodies of their dear ones, physically, socially, mentally, and existentially, and thus the relatives' experiences of the bodies of their dear ones might yield insight into the concept of dignity. AIM: The aim of this study is to explore relatives' experiences of the patients' bodily changes from a perspective of dignity. RESEARCH DESIGN AND METHOD: A total of 12 relatives from a hospice in Norway were interviewed. Gadamer's ontological hermeneutics inspired the interpretation. Ethical considerations: The principles of voluntariness, confidentiality, withdrawal, and anonymity were respected during the whole research process. The Norwegian Social Science Data Services approved the study. RESULTS AND CONCLUSION: The conversations about the body were conversations about ambivalent or paradoxical matters that shed light on the concept of dignity. The results show that the relatives got in touch with elements that otherwise would have remained tacit and unspoken, and which gave glimpses of a deeper truth, which might reveal the core of dignity. Furthermore, the relatives' confirmation of the ambivalence might be understood as a strong ethical obligation to treat the other with dignity. The confirmation may also reveal the relatives' unselfish love of the other, which can be understood as the core of ethics and ethos. Finally, the results reveal the relatives' limited insight into their dear ones' bodily changes, and we discuss the challenges of truly seeing the other. Body knowledge and the relationship between body and dignity as phenomena cannot be ignored and needs more attention and articulation in clinical nursing practice and in nursing research. PMID- 29695198 TI - Effect of moral empowerment program on moral distress in intensive care unit nurses. AB - BACKGROUND: Moral distress has been experienced by about 67% of critical care nurses which causes many complications such as job dissatisfaction, loss of capacity for caring, and turnover for nurses and poor quality of care for patients as well as health system. OBJECTIVE: The purpose of this research was to provide a moral empowerment program to nursing directors, school of nursing, and the heads of hospitals to reduce moral distress in nurses and improve the quality of care. METHODS: This research was a randomized clinical trial conducted in two groups and three stages before, after 2 weeks, and 1 month after the intervention in order to evaluate the changes in moral distress of 60 nurses working in adults' intensive care unit wards of Al-Zahra teaching hospital of Isfahan University of Medical Sciences. Data were collected using the standard Hamric's Moral Distress Scale (2012) and analyzed using SPSS software version 22. Ethical considerations: This study was approved by the Ethics Committee of Isfahan University of Medical Sciences, Isfahan, Iran. RESULTS: Results showed that in the three stages, there was no significant difference between the mean score of moral distress before (4.12 +/- 2.70), 2 weeks after (4.23 +/- 2.70), and 1 month after the intervention (4.04 +/- 2.54) in the control group (p > 0.05), while in the experimental group, there was a significant difference between the three stages (p < 0.05). The mean score of moral distress in the experimental group before intervention (4.05 +/- 2.26) and 2 weeks after the intervention (3.38 +/- 2.11) was not significant (p > 0.05). However, this score significantly decreased 1 month after the intervention (2.64 +/- 2.23; p < 0.05). CONCLUSION: In this research, it was observed that moral empowerment program has been effective in reducing the mean score of moral distress. Therefore, it is recommended that nursing managers and hospital directors implement empowerment program, in order to reduce the moral distress of nurses and improve the quality of care. PMID- 29695199 TI - Increased miR-21-3p in injured brain microvascular endothelial cells following traumatic brain injury aggravates blood-brain barrier damage by promoting cellular apoptosis and inflammation through targeting MAT2B. AB - Our recent papers have reported that increased miR-21-5p in brain following traumatic brain injury (TBI) could improve the neurological outcome through alleviating blood-brain barrier (BBB) damage. miR-21-3p is another mature miRNA derived from pre-miR-21 after Dicer Procession other than miR-21-5p. Its roles in various diseases, such as tumors and myocardial disease aroused great interest for research in recent years. To further explore the function and underlying mechanism of miR-21, especially miR-21-3p in regulating the pathological development of BBB damage after TBI, we designed this research and focused on studying the impact of miR-21-3p on apoptosis and inflammation in brain microvascular endothelial cells (BMVECs), the major cellular component of BBB. We performed controlled cortical impact on mouse brain, and employed the oxygen glucose deprivation/reoxygenation (OGD)-treated bEnd.3 cells injury model. We found that miR-21-3p level in BMVECs from injured cerebral cortex of controlled cortical impact (CCI) mice, and bEnd.3 cells with OGD treatment were both increased after injury. For in-vitro experiments, downregulation on miR-21-3p level by transfecting miR-21-3p antagomir in cultured cells alleviated OGD induced BBB damage, characterized by decreased BBB leakage and increased expression of tight junction proteins. Besides, miR-21-3p antagomir could suppress cell death by anti-apoptosis, and control inflammatory response by inhibiting the activity of NF-kappaB signaling. Using luciferase reporter assay and a MAT2B-silenced shRNA vector, we further proved that miR-21-3p exerted above functions through targeting MAT2B. In addition, in-vivo experiments also confirmed that intracerebroventricular infusion of miR-21-3p antagomir could alleviate BBB leakage after TBI. It reduced Evans Blue extravasation and promoted the expression of tight junction proteins, thus contributed to improve the neurological outcome of CCI mice. Taken together, increased miR-21-3p in BMVECs after TBI was bad for restoration of injured BBB. Downregulation on miR-21-3p level in injured brain could be a promising therapeutic strategy for BBB damage after TBI. PMID- 29695201 TI - Systematic review of barriers and facilitators to voluntary medical male circumcision in priority countries and programmatic implications for service uptake. AB - Voluntary medical male circumcision (VMMC) is an effective biomedical HIV prevention strategy. There is a need to identify key barriers and facilitators to VMMC uptake in priority countries to improve uptake. In this paper, we report findings from a systematic review of the barriers and facilitators of VMMC uptake, comparing them across countries in order to provide programmers critical information to design effective VMMC uptake interventions. Our review followed PRISMA protocol. Twenty three articles from 10 of the 14 priority countries were included. The top three barriers cited were: MC negatively perceived as being practiced by other or foreign cultures and religions, fear of pain caused by the procedure, and perceptions of VMMC as not helpful/needed. The top four facilitators cited in most countries were: Belief that VMMC reduces health risks and improves hygiene, family and peer support of MC, and enhanced sexual performance and satisfaction. The barriers and facilitators highlighted in this paper can help inform programmatic strategies in these countries. More research is needed to ensure that all sub-populations are being adequately reached. By applying this information to new research and programming, these countries can achieve greater VMMC uptake - and thus reductions in HIV transmission and prevalence. PMID- 29695202 TI - Can Short-term Economic Policies Hurt the Health of the Poor? Demonetization in India. AB - In November 2016, the Government of India (GOI) demonetized the commonly used Rs500 and Rs1,000 denominations. This was a short-term economic policy, known as notebandi, implemented as a means to address black money, counterfeit currencies, and terrorist activities. Notebandi was unrolled in a chaotic, confusing, and complex manner, leaving many people with limited access to cash in their daily activities. And the poor, who tend to earn their livelihoods from cash, were faced with economic exclusion and even destitution. In this paper, we argue that demonetization had disproportionately negative consequences on the poor and trace the main pathways between demonetization and the health of the poor. We conclude by calling on public health researchers to monitor and evaluate the health consequences of India's latest demonetization and to rapidly assess future policy initiatives in order to help advise governments in devising and implementing economic policies that does not harm the health of people, especially the poor. PMID- 29695200 TI - Nucleotide variants in prion-related protein (testis-specific) gene (PRNT) and effects on Chinese and Mongolian sheep phenotypes. AB - Studies of the ovine prion-related protein (testis-specific) gene (PRNT), including studies of genetic diversity, have highlighted its potential relationship to scrapie infection and economically important ovine traits. PRNT was previously reported to be highly polymorphic in Portuguese sheep. To characterize genetic polymorphisms in this gene in Asian sheep, a direct sequencing method was used to detect polymorphic loci in PRNT in 285 individual sheep from four Chinese and one Mongolian breeds. Seven SNP variants in PRNT were identified, including three novel variants (g.93G>A, g.162G>T, and g.190A>G) and four previously reported variants (g.17 C>T, g.112G>C, g.129C>T, and g.144A>G). In the five breeds that we analyzed, the mutation frequencies of g.190A>G in Lanzhou Fat-tail sheep (LFTS) and g.129C>T in the other four varieties were high (F>0.5). Moreover, thirteen different haplotypes that had a comparable distribution in the tested breeds were also identified; 'C-G-G-C-A-G-A' occurred at the highest frequency in the five sheep breeds. Additionally, we previously explored the significance of relationships between polymorphisms in PRNP or PRND and ovine growth performance. Here, we also performed correlation analysis in all tested loci. These loci polymorphisms were significantly associated with ten different growth traits (P<0.05), except for g.93G>A. Meanwhile, in contrast to a previous study, there was no significant association between the seven SNP loci analyzed and our previously reported sheep PRND or PRNP insertion/deletion mutations. Our findings may provide new insights into polymorphic variation in ovine PRNT, which may contribute to genetic improvements in economic traits that are important for sheep breeding. PMID- 29695203 TI - Carbon monoxide ameliorates murine T-cell-dependent colitis through the inhibition of Th17 differentiation. AB - Recent studies have identified carbon monoxide (CO) as a potential therapeutic molecule for the treatment of inflammatory diseases including intestinal inflammation. In the present study, we explored the efficacy and the mechanisms of action of CO-releasing molecule (CORM)-A1 in T-cell transfer induced colitis model in mice. In addition, the impact of CORM-A1 on the T helper (Th) cell differentiation was evaluated using naive CD4+ T cells isolated from the spleens in Balb/c mice. The results showed that CORM-A1 conferred protection against the development of intestinal inflammation and attenuated Th17 cell differentiation. Hence, the observed immunomodulatory effects of CORM-A1 could be useful for developing novel therapeutic approaches for managing intestinal inflammation through the regulation of Th17 differentiation. PMID- 29695205 TI - Perispinal etanercept advances as a neurotherapeutic. PMID- 29695204 TI - Outreach Strategies to Recruit Low-Income African American Men to Participate in Health Promotion Programs and Research: Lessons From the Men of Color Health Awareness (MOCHA) Project. AB - African American men continue to bear a disproportionate share of the burden of disease. Engaging these men in health research and health promotion programs especially lower-income, African American men who are vulnerable to chronic disease conditions such as obesity and heart disease-has historically proven quite difficult for researchers and public health practitioners. The few effective outreach strategies identified in the literature to date are largely limited to recruiting through hospital clinics, churches, and barbershops. The Men of Color Health Awareness (MOCHA) project is a grassroots, community-driven initiative that has developed a number of innovative outreach strategies. After describing these strategies, we present data on the demographic and health characteristics of the population reached using these methods, which indicate that MOCHA has been highly effective in reaching this population of men. PMID- 29695206 TI - Efficacy and safety of oral paracetamol versus oral ibuprofen for closure of patent ductus arteriosus in preterm infants: a randomized controlled trial. AB - OBJECTIVE: The objective of this study is to evaluate the efficacy and safety of oral paracetamol versus oral ibuprofen in the treatment of hemodynamically significant patent ductus arteriosus (hsPDA) in preterm infants. STUDY DESIGN: An interventional randomized case-control study, registered in ClinicalTrials.gov (NCT03265782), was conducted on 60 preterm infants with gestational age <=34 weeks, postnatal age of 2-7 d and color Doppler echocardiographic evidence of hsPDA. Neonates were randomly assigned to two groups: 30 received oral ibuprofen and 30 received oral paracetamol. With failure of ductal closure, a second course of ibuprofen or paracetamol was given. The included newborns were subjected to detailed history, clinical examination, laboratory investigations that included complete blood count, renal, and liver function tests and echocardiographic evaluation. RESULTS: Oral paracetamol was as effective as ibuprofen for the closure of patent ductus arteriosus (PDA) with one course of treatment (p > .05). Moreover, oral paracetamol was superior to ibuprofen among neonates who needed second course of treatment with significant decrease in end diastolic flow velocity in the left pulmonary artery (0.35 +/- 0.09 versus 0.19 +/- 0.06, p = .014), right ventricular systolic pressure (40.50 +/- 12.91 versus 20.50 +/- 0.58, p = .016) and left atrium to aortic root ratio (1.23 +/- 0.14 versus 1.07 +/- 0.04, p = .046) when compared to ibuprofen group. Furthermore, the mean difference between pre- and post-treatment PDA size was significantly higher in the paracetamol group compared with ibuprofen group after the second course of treatment (1.07 +/- 0.32 versus 0.73 +/- 0.38, p = .024). Oral paracetamol was comparable with ibuprofen in terms of the rate of non-surgical ductal closure [28 (93.3%) versus 24 (80%), p = .591]. In addition, oral paracetamol was as safe as oral ibuprofen in terms of gastrointestinal perforation or bleeding, necrotizing enterocolitis, bronchopulmonary dysplasia, intraventricular hemorrhage, thrombocytopenia, hepatic or renal dysfunction. CONCLUSIONS: Oral paracetamol is an effective and well-tolerated first-line drug treatment for PDA in premature infants. PMID- 29695207 TI - Polysomnography for the management of oxygen supplementation therapy in infants with chronic lung disease of prematurity. AB - AIM: Some infants with bronchopulmonary dysplasia (BPD) may require oxygen supplementation at home but a role for overnight polysomnography (PSG) in the management of home oxygen therapy has been rarely described. METHODS: Forty-one infants with BPD born at less than 30 weeks gestational age were discharged with continuous home oxygen supplementation therapy between 2010 and 2013. PSG data were recorded on oxygen supplementation versus room air at median corrected age of 2 months (range 1-5 months) (first PSG after discharge to home). Those infants who continued oxygen supplementation therapy at home had at least one more PSG before oxygen therapy was discontinued (last PSG). We also collected PSG data in 10 healthy term infants (median age 3.5 months; range 2-4 months). RESULTS: In infants with BPD in room air, increased numbers of central apneas, hypopneas, and SaO2 desaturations were the predominant PSG features with a median apnea-hypopnea index (AHI) of 16.8 events per hour (range 0-155). On oxygen supplementation therapy, median AHI dramatically improved (2.2, range 0-22; p < .001) and was not different from control infants (2.0, range 0-3.9; p = .31). AHI on room air at the last PSG when home oxygen was ceased was 4.1 per hour (range 0-13.8) slightly higher than in healthy infants. CONCLUSION: Central sleep disordered breathing in infants with BPD dramatically normalizes with low flow nasal cannula home oxygen therapy and improves with age. Mild central sleep disordered breathing remains detectable, although much improved, when compared with healthy infants at the time when the decision to cease home oxygen therapy was made by the physician. PMID- 29695208 TI - Comparison of modified agonist, mild-stimulation and antagonist protocols for in vitro fertilization in patients with diminished ovarian reserve. AB - Objective To compare the efficacy of three protocols for ovarian stimulation in patients with diminished ovarian reserve during in vitro fertilization (IVF) treatment. Methods This prospective randomized study enrolled patients with diminished ovarian reserve who underwent cycles of IVF or intracytoplasmic sperm injection. The patients were randomly divided into three groups: a modified gonadotrophin releasing hormone (GnRH) agonist protocol (group A); (ii) a mild stimulation protocol (group B); or (iii) an antagonist protocol (group C). Demographic characteristics, clinical variables and pregnancy outcomes were compared between the groups. Results A total of 116 patients were enrolled in the study: 54 in group A, 52 in group B and 60 in group C. Group B (32.69%) had a significantly higher cycle cancellation rate compared with groups A (11.11%) and C (16.67%). The early abortion rate of group C (44.44%) was significantly higher than group A (12.50%), but not significantly different from group B (16.67%). There were no significant differences in the clinical pregnancy rates and live birth rates among the three groups. Conclusion A modified GnRH agonist protocol achieved a comparable pregnancy rate to those of the mild stimulation protocol and antagonist protocol, whilst having lower cycle cancellation and early abortion rates. PMID- 29695209 TI - Prognostic scores for colorectal cancer with peritoneal metastases treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. AB - BACKGROUND: Selecting colorectal patients for HIPEC-surgery needs improvement. The study aim was to improve the colorectal peritoneal score (COREP) and to compare it with three other scores: peritoneal-surface disease-severity score (PSDS), colorectal-peritoneal metastases prognostic-surgical-score (COMPASS), and the CEA/PCI ratio. METHOD: Twelve preoperative factors were chosen to evaluate for COREP score modification. Criteria from logistical analyses were set to qualify for the modified COREP score (mCOREP). Odds ratios were used to assign score points for the eligible factors with open/close laparotomy prediction as endpoint. mCOREP was applied internally and compared with the original COREP, PSDS, COMPASS, and CEA/PCI ratio. Odds ratios, hazard ratios, and Kaplan-Meier curves were used for comparison. RESULTS: Seven factors qualified for mCOREP: CEA, CA 19-9, CA-125, C-reactive protein, albumin, platelet count and signet-cell histology. mCOREP was superior to the original COREP. mCOREP and COMPASS scores were the only scores with independent prognostic value. The mCOREP had the best discriminatory ability between its prognostic groupings. mCOREP 11 + had 9 months survival with half of patients being open/close surgery. CONCLUSION: The mCOREP has successfully been simplified while still improving its prognostic ability. The mCOREP and COMPASS scores have independent prognostic value. Patients with mCOREP 11 + may not benefit from treatment. PMID- 29695211 TI - Continuation of oral nutritional supplementation supports continued growth in nutritionally at-risk children with picky eating behaviour: A post-intervention, observational follow-up study. AB - Objectives To evaluate the 120-day post-intervention growth trajectory of picky eating children aged 2 to 6 years who previously completed a 90-day, randomized, controlled trial of oral nutritional supplementation (ONS) plus dietary counselling (DC) (SDC, n = 98) compared with DC alone (n = 105). Methods A total of 203 children were included. Children were free to consume ONS during follow up. Information on ONS consumption was collected. Weight-for-age percentile (WAP) and height-for-age percentile (HAP) were measured at Day 90 (beginning) and Day 210 (end point). Results Despite continued weight gain, there was a significant decline in WAP in both groups during the post-intervention period. However, children who took ONS voluntarily had a smaller loss in WAP compared with those who did not. Children in the SDC group showed no difference in a decline in HAP between those who took ONS during follow-up and those who did not. However, children in the DC group showed a marginally larger decline in HAP in those who did not take ONS during the follow-up compared with those who did. Conclusions Continued parental self-administration of ONS to their children slows down the loss of growth percentiles, supporting continued weight gain in picky-eating children at nutritional risk. PMID- 29695212 TI - Random placenta margin incision in cesarean section for placenta previa: some clarifications. PMID- 29695213 TI - The economic burden of occupational non-melanoma skin cancer due to solar radiation. AB - Solar ultraviolet (UV) radiation is the second most prevalent carcinogenic exposure in Canada and is similarly important in other countries with large Caucasian populations. The objective of this article was to estimate the economic burden associated with newly diagnosed non-melanoma skin cancers (NMSCs) attributable to occupational solar radiation exposure. Key cost categories considered were direct costs (healthcare costs, out-of-pocket costs (OOPCs), and informal caregiver costs); indirect costs (productivity/output costs and home production costs); and intangible costs (monetary value of the loss of health related quality of life (HRQoL)). To generate the burden estimates, we used secondary data from multiple sources applied to computational methods developed from an extensive review of the literature. An estimated 2,846 (5.3%) of the 53,696 newly diagnosed cases of basal cell carcinoma (BCC) and 1,710 (9.2%) of the 18,549 newly diagnosed cases of squamous cell carcinoma (SCC) in 2011 in Canada were attributable to occupational solar radiation exposure. The combined total for direct and indirect costs of occupational NMSC cases is $28.9 million ($15.9 million for BCC and $13.0 million for SCC), and for intangible costs is $5.7 million ($0.6 million for BCC and $5.1 million for SCC). On a per-case basis, the total costs are $5,670 for BCC and $10,555 for SCC. The higher per case cost for SCC is largely a result of a lower survival rate, and hence higher indirect and intangible costs. Our estimates can be used to raise awareness of occupational solar UV exposure as an important causal factor in NMSCs and can highlight the importance of occupational BCC and SCC among other occupational cancers. PMID- 29695210 TI - Recent advances in automated protein design and its future challenges. AB - INTRODUCTION: Protein function is determined by protein structure which is in turn determined by the corresponding protein sequence. If the rules that cause a protein to adopt a particular structure are understood, it should be possible to refine or even redefine the function of a protein by working backwards from the desired structure to the sequence. Automated protein design attempts to calculate the effects of mutations computationally with the goal of more radical or complex transformations than are accessible by experimental techniques. Areas covered: The authors give a brief overview of the recent methodological advances in computer-aided protein design, showing how methodological choices affect final design and how automated protein design can be used to address problems considered beyond traditional protein engineering, including the creation of novel protein scaffolds for drug development. Also, the authors address specifically the future challenges in the development of automated protein design. Expert opinion: Automated protein design holds potential as a protein engineering technique, particularly in cases where screening by combinatorial mutagenesis is problematic. Considering solubility and immunogenicity issues, automated protein design is initially more likely to make an impact as a research tool for exploring basic biology in drug discovery than in the design of protein biologics. PMID- 29695214 TI - Intraluminal Brachytherapy Using a Self-Expandable Stent Loaded With Linear Iodine-125 Seeds in a Patient With Reiterative Recurrence of Cancer-Associated Vein Obstruction: A Case Report With 3 Months of Follow-Up. AB - Cancer-associated vein obstruction (CAVO) is a common complication in oncological patients, but the effective therapeutic options are scant. We report a patient with reiterative recurrent CAVO who was successfully treated with intraluminal brachytherapy using a self-expandable stent loaded with linear radioactive iodine 125 seeds (RIS) strand. During follow-up, her clinical symptoms were well improved. Three-month imaging follow-up revealed satisfactory patency of the iliofemoral vein, and the stents combined with RIS strands performed well. No serious complications associated with the implantation of stent and RIS strands were documented in any of the sessions. Intraluminal brachytherapy using a self expandable stent loaded with linear RIS may be a safe and effective option for CAVO as long as it includes not only blood flow restoration but also brachytherapy administration for cancer. PMID- 29695215 TI - High Background Incidence of Spontaneous Subcapsular Adrenal Gland Hyperplasia of Tg.rasH2 Mice Used in 26-week Carcinogenicity Studies. AB - The Tg.rasH2 model was accepted by regulatory agencies worldwide for 26-week carcinogenicity assays as an alternative to the standard 2-year assays in conventional mice in 2003. Several references documenting spontaneous nonneoplastic findings and incidences of spontaneous tumors in the Tg.rasH2 mice have been published. The purpose of this publication is to add adrenal gland subcapsular hyperplasia to the database pertaining to spontaneous lesions noted in Tg.rasH2 mice, review physiology related to this finding, and discuss its significance. The incidence of spontaneous subcapsular adrenal gland hyperplasia was determined in control Tg.rasH2 mice from nine 26-week carcinogenicity studies carried out within the last 5 years at two contract research organizations. Incidence of this finding ranged from 56% to 79% in males and 88% to 100% in females, with an incidence average of 62% in males and 93% in females. Adrenal gland subcapsular hyperplasia is a common finding in male and female Tg.rasH2 mice that did not progress to neoplasia in Tg.rasH2 mice. In general, it tends to be more frequent and severe in females in comparison to males. PMID- 29695216 TI - Family-Only Perpetrators of Intimate Partner Violence: A Systematic Review. AB - This article presents the first systematic review of family-only intimate partner violence (IPV) perpetrators (as originally proposed by Holtzworth-Munroe & Stuart). The aims of the present review were to summarize and describe the prevalence of the family-only perpetrator subtype, as well as to investigate what characteristics were associated with perpetrators within this subtype. Electronic literature searches in several databases (e.g., PsychINFO, Web of Science, and PubMed) were carried out. Of the 3,434 studies identified, 30 studies met the inclusion criteria as well as the methodological quality criteria. Thematic analyses were conducted, where several themes and subthemes were identified. The proportion of family-only perpetrators, averaged across sample types, was 47.5%. Drawing on the thematic analyses of the reviewed studies, family-only perpetrators presented as a less violent subtype, displaying several pro-social personality traits, as well as a lower degree of psychopathology. The findings were in line with Holtzworth-Munroe and Stuart's predictions. The findings also demonstrated the utility of a 2-fold typology, consisting of a family-only and a generally violent (GV) subtype, as well as the need to reconsider the one-size fits-all approach to IPV treatment. We also included a discussion of the terminology of the subtypes and propose an adoption of the terms "partner only violent" and "generally violent" subtypes. PMID- 29695217 TI - Regular QRS complex tachycardia: think outside the box. PMID- 29695218 TI - Female Participation in Household Decision Making and the Justification of Wife Beating in Bangladesh. AB - We examined female participation in household decision making and its association with the justification of wife beating in Bangladesh. We used nationally representative data from the 2014 Bangladesh Demographic and Health Survey. Our sample consisted of currently married women of age 15 to 49 years ( n = 16,463). Chi-square tests and multilevel logistic regression models were performed. Approximately 84% of women in the survey were participants in at least one household decision, and 72% reported that wife beating is not justified in any circumstance. Women who reported their participation in at least one type of household decision less frequently reported that wife beating could be justified than those who did not participate in any household decisions (adjusted odds ratio = 1.49; 95% confidence interval = [1.25, 1.78]). In addition to participation in household decision making, other factors including age at first marriage, females' and their husbands' education, religion, parity, contraceptive use, and socioeconomic status were associated with the justification of wife beating. The results indicate that female participation in household decision making is significantly associated with the justification of wife beating in Bangladesh. Further study is needed, but the results suggest that policy makers should consider interventions proven to empower women and lead to increased participation in decision making as methods that may reduce domestic violence against women. PMID- 29695219 TI - Analysis of the Explanatory Variables of the Differences in Perceptions of Cyberbullying: A Role-Based-Model Approach. AB - The controversies that exist regarding the delimitation of the cyberbullying construct demonstrate the need for further research focused on determining the criteria that shape the structure of the perceptions that adolescents have of this phenomenon and on seeking explanations of this behavior. The objectives of this study were to (a) construct possible explanatory models of the perception of cyberbullying from identifying and relating the criteria that form this construct and (b) analyze the influence of previous cyber victimization and cyber aggression experiences in the construction of explanatory models of the perception of cyberbullying. The sample consisted of 2,148 adolescents (49.1% girls; SD = 0.5) aged from 12 to 16 years ( M = 13.9 years; SD = 1.2). The results have shown that previous cyber victimization and cyber aggression experiences lead to major differences in the explanatory models to interpret cyber-abusive behavior as cyberbullying episodes, or as social relationship mechanisms, or as a revenge reaction. We note that the aggressors' explanatory model is based primarily on a strong reciprocal relationship between the imbalance of power and intentionality, that it functions as a link promoting indirect causal relationships of the anonymity and repetition factors with the cyberbullying construct. The victims' perceptual structure is based on three criteria-imbalance of power, intentionality, and publicity-where the key factor in this structure is the intention to harm. These results allow to design more effective measures of prevention and intervention closely tailored to addressing directly the factors that are considered to be predictors of risk. PMID- 29695220 TI - Trauma History and Social Support Among American Indian/Alaska Native and Non Native Survivors of Intimate Partner Violence. AB - Social support (SS) is one of the most important protective factors against the deleterious effects of trauma exposure on mental health, but only a few studies have looked at predictors of SS among trauma-exposed populations. This study examines what predicts SS from friends, family, and other significant individuals in an ethnically diverse group of 61 women residing in Alaskan shelters for women who have experienced Intimate Partner Violence (IPV). Results from bivariate tests indicated that survivors who identified as American Indian or Alaska Native (AIAN) reported significantly higher SS from family ( M = 5.04, SD = 1.74) in comparison with those who do not identify as AIAN ( M = 3.80, SD = 2.31), t(56) = 2.24, p < .05. Income was positively correlated with higher SS from friends, r(59) = .33, p < .05. Lifetime history of interpersonal trauma was significantly and negatively related to variation in SS across multiple domains. When sociodemographic variables, trauma history, and violent relationship history were entered into a multiple regression, this model predicted 34% ( p < .001) of the variance in Overall SS and 22% ( p < .01), 32% ( p < .001), and 17% ( p < .05) of SS from family, friends, and other significant individuals, respectively. Taken together, these preliminary results suggest that income, race, lifetime interpersonal trauma history, and number of violent partners are important predictors of SS among women IPV survivors residing in shelters. PMID- 29695221 TI - Parts Unknown: Risk Factors of Intimate Partner Violence in Azerbaijan, Kyrgyzstan, Tajikistan, and Moldova. AB - Extant research has argued that there are variations in predictors of intimate partner violence (IPV) across nations and it is necessary to examine country specific correlates of IPV. Much remains unknown about factors that affect risk of IPV in transitional countries. Specifically, we explore risk factors for IPV among four former nations of the Soviet Union-Azerbaijan, Kyrgyzstan, Tajikistan, and Moldova-with data from the nationally representative Demographic and Health Surveys. Rates of physical abuse were similar within Tajikistan (18.96%) and Moldova (18.38%), while Kyrgyzstan (20.62%) had the highest prevalence and Azerbaijan (9.29%) had the lowest prevalence. In contrast, the prevalence of sexual abuse was very similar across the four countries and was much lower (between 1.00% and 3.50%) than cross-national estimates of physical abuse. Findings suggest that many of the same risk factors of IPV in developing and developed nations influence risk of IPV in transitional nations. Across the four former Soviet nations included in analyses, the experience of controlling behaviors, husband's alcohol use, and witnessing IPV or experiencing abuse during childhood were all significantly associated with risk of physical and sexual abuse later in life. Indeed, the intergenerational transmission of violence may be a cross-national phenomenon. In addition, equality in decision making did not have an effect on risk of physical and sexual violence, except for risk of physical abuse in Moldova. This may be due to the historical context of these nations. Taken together, findings suggest that country context may influence individual risk factors of IPV. PMID- 29695222 TI - A Thematic Analysis of the Impact of MY MASCULINITY HELPS as a Tool for Sexual Violence Prevention. AB - The purpose of this study is to explore the impact of an educational documentary, MY MASCULINITY HELPS ( MMH), as a sexual violence prevention tool. MMH is a short (i.e., 31 min) educational documentary that explores the role of African American men and boys in the prevention of sexual violence. Participants ( N = 88) completed an electronic, qualitative questionnaire after viewing the documentary and data collected were analyzed and interpreted using thematic analysis. Findings from the study highlighted the power of documentary film to impact knowledge, beliefs, social norms related to masculinity and the role of African American men as allies, empowerment, and commitment to action. Implications of MMH as a prosocial bystander behavior intervention and educational tool are discussed. PMID- 29695223 TI - What Clinicians Say About the Experience of Working With Individuals on Community Treatment Orders. AB - OBJECTIVE: Community treatment orders (CTOs) refer to a variety of legal schemes that require a person with a serious mental illness to follow a plan of treatment and supervision while living in the community. Use of CTOs has been controversial, and they have been the subject of a considerable amount of quantitative and qualitative research. This article reports the results of a systematic review of qualitative studies focused on understanding the views and experiences of clinicians who work with individuals on CTOs. METHODS: Relevant databases and gray literature were searched for articles that used a qualitative methodology for data collection and analysis to examine clinicians' perspectives. CTOs were defined as various legal schemes, including court-ordered outpatient commitment and renewable conditional-leave provisions initiated while a person is an inpatient in a psychiatric unit. Mandatory treatment and supervision required after a person has been charged with or convicted of committing a criminal offense was not considered. RESULTS: Fourteen articles met inclusion criteria. They represented the views of more than 700 clinicians from six international jurisdictions. Three themes were identified: endorsement of the benefits of CTOs despite tensions both within and between clinicians concerning several aspects of CTOs; belief that medication compliance is a central aspect of CTOs; and acknowledgment that there is room for improvement in CTO implementation, monitoring, and administration. Strategies for reducing tensions and improving administration of CTOs are discussed. CONCLUSIONS: Clinicians view CTOs as providing benefits to their clients but struggle with the coercive nature of these tools. PMID- 29695224 TI - Availability of Outpatient Addiction Treatment and Use of Emergency Department Services Among Medicaid Enrollees. AB - OBJECTIVE: The study examined whether the number of outpatient addiction programs accepting Medicaid in South Carolina counties is linked to repeat use of the emergency department for addiction-related conditions. METHODS: The study included the population all adult Medicaid enrollees (N=2,401) in South Carolina with at least one addiction-related emergency service visit in 2012 or 2013. A random-effects logistic regression model was used to examine the association between outpatient addiction treatment availability and repeat use by Medicaid enrollees of emergency services for addiction-related conditions. RESULTS: Enrollees in counties with two or more programs that accept Medicaid were less likely to have a repeat addiction-related emergency service visit than enrollees in counties with only one program that accepts Medicaid. CONCLUSIONS: Availability of outpatient addiction treatment may reduce the need for addiction related emergency services. Research is needed to explore potential causal mechanisms underlying this observed relationship. PMID- 29695225 TI - Inpatient Volume and Quality of Mental Health Care Among Patients With Unipolar Depression. AB - OBJECTIVE: The relationship between inpatient volume and the quality of mental health care remains unclear. This study examined the association between inpatient volume in psychiatric hospital wards and quality of mental health care among patients with depression admitted to wards in Denmark. METHODS: In a nationwide, population-based cohort study, 17,971 patients (N=21,120 admissions) admitted to psychiatric hospital wards between 2011 and 2016 were identified from the Danish Depression Database. Inpatient volume was categorized into quartiles according to the individual ward's average caseload volume per year during the study period: low volume (quartile 1, <102 inpatients per year), medium volume (quartile 2, 102-172 inpatients per year), high volume (quartile 3, 173-227 inpatients per year) and very high volume (quartile 4, >227 inpatients per year). Quality of mental health care was assessed by receipt of process performance measures reflecting national clinical guidelines for care of depression. RESULTS: Compared with patients admitted to low-volume psychiatric hospital wards, patients admitted to very-high-volume wards were more likely to receive a high overall quality of mental health care (>=80% of the recommended process performance measures) (adjusted relative risk [ARR]=1.78, 95% confidence interval [CI]=1.02-3.09) as well as individual processes of care, including a somatic examination (ARR=1.35, CI=1.03-1.78). CONCLUSIONS: Admission to very-high-volume psychiatric hospital wards was associated with a greater chance of receiving guideline-recommended process performance measures for care of depression. PMID- 29695226 TI - Impact of Agency Receipt of Incentives and Reminders on Engagement and Continuity of Care for Clients With Co-Occurring Disorders. AB - OBJECTIVE: This study examined whether having co-occurring substance use and mental disorders influenced treatment engagement or continuity of care and whether offering financial incentives, client-specific electronic reminders, or a combination to treatment agencies improved treatment engagement and continuity of care among clients with co-occurring disorders. METHODS: The study used a randomized cluster design to assign agencies (N=196) providing publicly funded substance use disorder treatment in Washington State to a research arm: incentives only, reminders only, incentives and reminders, and a control condition. Data were analyzed for 76,044 outpatient, 32,797 residential, and 39,006 detoxification admissions from Washington's treatment data system. Multilevel logistic regressions were conducted, with clients nested within agencies, to examine the effect of the interventions on treatment engagement and continuity of care. RESULTS: Compared with clients with a substance use disorder only, clients with co-occurring disorders were less likely to engage in outpatient treatment or have continuity of care after discharge from residential treatment, but they were more likely to have continuity of care after discharge from detoxification. The interventions did not influence treatment engagement or continuity of care, except the reminders had a positive impact on continuity of care after residential treatment among clients with co-occurring disorders. CONCLUSIONS: In general, the interventions did not result in improved treatment engagement or continuity of care. The limited number of significant results supporting the influence of incentives and alerts on treatment engagement and continuity of care add to the mixed findings reported by previous research. Multiple interventions may be needed for performance improvement. PMID- 29695227 TI - SSR marker development and intraspecific genetic divergence exploration of Chrysanthemum indicum based on transcriptome analysis. AB - BACKGROUND: Chrysanthemum indicum L., an important ancestral species of the flowering plant chrysanthemum, can be used as medicine and for functional food development. Due to the lack of hereditary information for this species and the difficulty of germplasm identification, we herein provide new genetic insight from the perspective of intraspecific transcriptome comparison and present single sequence repeat (SSR) molecular marker recognition technology. RESULTS: Through the study of a diploid germplasm (DIWNT) and a tetraploid germplasm (DIWT), the following outcome were obtained. (1) A significant difference in Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) annotations for specific homologous genes was observed using the OrthoMCL method for the identification of homologous gene families between the two cytotypes. Ka/Ks analysis of common, single-copy homologous family members also revealed a greater difference among genes that experienced positive selection than among those experiencing positive selection. (2) Of more practical value, 2575 SSR markers were predicted and partly verified. We used TaxonGap as a visual tool to inspect genotype uniqueness and screen for high-performance molecular loci; we recommend four primers of 65 randomly selected primers with a combined identification success rate of 88.6% as priorities for further development of DNA fingerprinting of C. indicum germplasm. CONCLUSIONS: The SSR technology based on next-generation sequencing was proved to be successful in the identification of C. indicum germplasms. And the information on the intraspecfic genetic divergence generated by transcriptome comparison deepened the understanding of this complex species' nature. PMID- 29695228 TI - Impact of clinical trial participation on survival in patients with castration resistant prostate cancer: a multi-center analysis. AB - BACKGROUND: Clinical trial (CT) participation may confer access to new, potentially active agents before their general availability. This study aimed to investigate the potential survival benefit of participation in investigational CTs of novel hormonal, chemotherapeutic, and radiopharmaceutical agents in patients with castration-resistant prostate cancer (CRPC). METHODS: This multi center, retrospective analysis included 299 consecutive patients with newly diagnosed, non-metastatic or metastatic CRPC between September 2009 and March 2017. Of these, 65 (21.7%) patients participated in CTs pertaining to systemic treatment targeting CRPC and 234 (78.3%) patients received pre-established, standard systemic treatment outside of a CT setting. The survival advantage of CT participation regarding cancer-specific survival (CSS) was investigated. RESULTS: An Eastern Cooperative Oncology Group performance status (ECOG PS) >=2 at CRPC diagnosis was found in a lower proportion CT participants than in non participants (4.6% vs. 14.9%; p = 0.033). During the median follow-up period of 16.0 months, CT participants exhibited significantly higher 2-year CSS survival rates (61.3% vs. 42.4%; p = 0.003) than did non-participants. Multivariate analysis identified prostate-specific antigen and alkaline phosphatase levels at CRPC onset, Gleason score >= 8, ECOG PS >=2, less number of docetaxel cycles administered, and non-participation in CTs as independent predictors for a lower risk of CSS. CONCLUSIONS: Patients diagnosed with CRPC who participated in CTs exhibited longer CSS durations than non-participants who received pre established, standard systemic therapy outside of a CT setting. Our findings imply that CT participation is associated with CSS, and that CT participation should be offered to patients with CRPC whenever indicated. PMID- 29695229 TI - Rituximab for auto-immune alveolar proteinosis, a real life cohort study. AB - BACKGROUND: Whole lung lavage is the current standard therapy for pulmonary alveolar proteinosis (PAP) that is characterized by the alveolar accumulation of surfactant. Rituximab showed promising results in auto-immune PAP (aPAP) related to anti-GM-CSF antibody. METHODS: We aimed to assess efficacy of rituximab in aPAP in real life and all patients with aPAP in France that received rituximab were retrospectively analyzed. RESULTS: Thirteen patients were included. No patients showed improvement 6 months after treatment, but, 4 patients (30%) presented a significant decrease of alveolar-arterial difference in oxygen after 1 year. One patient received lung transplantation and one patient was lost of follow-up within one year. Although a spontaneous improvement cannot be excluded in these 4 patients, improvement was more frequent in patients naive to prior specific therapy and with higher level of anti-GM-CSF antibodies evaluated by ELISA. No serious adverse event was evidenced. CONCLUSIONS: These data do not support rituximab as a second line therapy for patients with refractory aPAP. PMID- 29695231 TI - Malaria-related ideational factors and other correlates associated with intermittent preventive treatment among pregnant women in Madagascar. AB - BACKGROUND: The Malagasy Ministry of Health aimed to achieve 80% coverage of intermittent preventive treatment of malaria among pregnant women (IPTp) in targeted districts by 2015. However, IPTp coverage rates of have remained fairly static over the past few years. METHODS: During a cross-sectional household survey, mothers of children under the age of 2 years were asked about their most recent pregnancy. The primary outcome of interest was a mother receiving two or more doses of sulfadoxine-pyrimethamine (SP) (IPTp2) during their last pregnancy, at least one of which was obtained from a health provider. Multilevel analysis was used to account for community-level factors. Correlates included exposure to communication messages, the number of antenatal care (ANC) visits made by the woman, her household wealth, and other sociodemographic characteristics. RESULTS: Over one-tenth (11.7%) of women received two or more doses of SP, at least one of which was obtained during an ANC visit. Two-thirds (68.3%) of women who consulted a health provider but did not take IPTp attributed this to not being offered the medication by their health provider. The odds of a woman receiving IPTp2 varied with her knowledge, attitudes, and perceived social norms related to IPTp and ANC and exposure to malaria messages. General malaria ideation, specifically the perceived severity of and perceived susceptibility to malaria, however, was not associated with increased odds of receiving IPTp2. A large variation in the odds of receiving IPTp2 was due to community-level factors that the study did not examine. CONCLUSIONS: Health communication programmes should aim to improve IPTp/ANC-specific ideation, particularly the norms of seeking regular care during pregnancy and taking any prescribed medication. While ANC attendance is necessary, it was not sufficient to meet IPTp2 coverage. Women surveyed in Madagascar rely on health providers to prescribe SP according to national policy. At the same time, stock-outs prevent health providers from prescribing SP. The large observed community-level variation in IPTp2 coverage is likely due to supply-side factors, such as SP availability and health-provider ideation and practices. PMID- 29695230 TI - Incisional hernia and its impact on health-related quality of life after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy: a national prospective cohort study. AB - BACKGROUND: To evaluate the incidence of incisional hernia (IH) after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS + HIPEC) and its impact on health-related quality of life (HRQoL). METHOD: From June 2006 until June 2016, 152 patients were followed after CRS + HIPEC at Aarhus University Hospital, a single national center. Patients were seen postoperatively in an outpatient clinic at 3, 6, 12, 18, 24, 36 48, and 60 months. Clinical examinations at these follow-up visits were used to evaluate IH events prospectively. The incidence of IH was estimated using competing risk analysis and is presented as the cumulative incidence proportion (CIP). We expected the incidence to be 15% at 12 months. HRQoL was assessed at 12 months by the Short Form (SF-36) questionnaire, which we used to compare patients with an IH to patients without an IH. RESULTS: The median follow-up time was 16.6 months [range 0.9-62.0]. During this period, 14/152 (9.2%) patients developed an IH. The 1-year CIP was 5.9% [95% CI 2.9; 10.4] (n = 8), and the 2-year CIP was 9.2% [95% CI 5.3; 14.5] (n = 14). Patients with an IH were significantly older (67 years [range 48 72]) compared to patients without IH (60 years [range 24-75], p <= 0.01). The rate of postoperative complications between patients with and without IH was comparable, except that a greater proportion of patients with IH had a fascial dehiscence (21.4%) compared to patients without an IH (3.6%). Reponses to the SF 36 show that patients with an IH report lower HRQoL with regard to Role-physical (mean difference - 32.9 [95% CI - 60.6; - 5.3]) and Role-emotional (mean difference - 20.2 [95% CI - 43.4; 3.1]), meaning a reduction in work and daily activities due to their physical and psychological health. We found no general decrease in HRQoL. CONCLUSION: CRS + HIPEC do not increase the risk of IH as measured within 12 months postoperatively, contrary to expectations. However, patients with an IH report a limitation in daily activities, which can best be explained by changes in physical and psychological health. A larger cohort from multiple centres is necessary to verify our findings. PMID- 29695232 TI - Biocompatibility assessment of single-walled carbon nanotubes using Saccharomyces cerevisiae as a model organism. AB - BACKGROUND: Single-walled carbon nanotubes (SWCNTs) have many potential applications in various fields. Especially, the unique physicochemical properties make them as the prime candidates for applications in biomedical fields. However, biocompatibility of SWCNTs has been a major concern for their applications. In the study, biocompatibility of oxidized SWCNTs (O-SWCNTs) was assessed using Saccharomyces cerevisiae (S. cerevisiae) as a model organism. RESULTS: Cell proliferation and viability were significantly changed after exposure to O-SWCNTs (188.2 and 376.4 mg/L) for 24 h. O-SWCNTs were internalized in cells and distributed in cytoplasm, vesicles, lysosomes and cell nucleus. The average O SWCNTs contents in S. cerevisiae were ranged from 0.18 to 4.82 mg/g during the exposure from 0 to 24 h, and the maximum content was reached at 18 h after exposure. Both penetration and endocytosis were involved in the internalization of O-SWCNTs in S. cerevisiae, and endocytosis was the main pathway. Cellular structures and morphology were changed after exposure to O-SWCNTs, such as undulating appearance at the membrane, shrinking of the cytosol, increased numbers of lipid droplets and disruption of vacuoles. ROS and antioxidant enzymes activities were observably changed following exposure. For the treatment at 376.4 mg/L, 20.8% of the total cells was undergone apoptosis. Decrease of mitochondrial transmembrane potential and leakage of cytochrome c from mitochondria were observed after exposure. Moreover, expression levels of apoptosis-related genes were significantly increased. CONCLUSIONS: O-SWCNTs can internalize in S. cerevisiae cells via direct penetration and endocytosis, and distribute in cytoplasm, vesicles, lysosomes and cell nucleus. Besides, O-SWCNTs (188.2 and 376.4 mg/L) can induce apoptosis in S. cerevisiae cells, and oxidative stress is involved in activation of the mitochondria-dependent apoptotic pathway. PMID- 29695233 TI - Apigetrin inhibits adipogenesis in 3T3-L1 cells by downregulating PPARgamma and CEBP-alpha. AB - BACKGROUND: Apigetrin, a flavonoid found in many plant leaves and seeds, has been known to possess antimutagenic, anti-cancer, antioxidant and anti-inflammatory properties. Here, we are investigating the effect of the apigetrin on adipocytes differentiation in 3T3-L1 adipocytes, and elucidating the mechanism of its action. METHODS: Lipids accumulation was measured by Oil Red O staining and cell cycle was analyzed by flow cytometry. The antioxidant effect of apigetrin was evaluated against hydrogen peroxide. The expression of various genes, involved in adipogenesis and inflammation, was studied by real-time PCR. RESULTS: Our results showed that apigterin treatment inhibited significantly lipid accumulation without effect on cell viability at 100 MUM, and it exerted the anti-adipogenic effect during the early stages of differentiation. Flow cytometry analysis showed that apigenin-7-O-glucoside (Ap7G) inhibited cell proliferation during mitotic clonal expansion and caused cell cycle delay. Quantitative PCR analysis revealed that the mRNA levels of C/EBP-alpha, PPAR-gamma, SREBP-1c and FAS were suppressed after apigetrin treatment at 100 MUM. Moreover, the mRNA level of pro inflammatory genes (TNF-alpha and IL-6) were suppressed after apigterin treatment, at high concentration preadipocyte cells. CONCLUSION: Taken together, these results indicated that apigenin-7-O-glucoside inhibits adipogenesis of 3T3 L1 preadipocytes at early stage of adipogenesis. PMID- 29695234 TI - Cost-effectiveness and budget impact analyses of a colorectal cancer screening programme in a high adenoma prevalence scenario using MISCAN-Colon microsimulation model. AB - BACKGROUND: The Basque Colorectal Cancer Screening Programme began in 2009 and the implementation has been complete since 2013. Faecal immunological testing was used for screening in individuals between 50 and 69 years old. Colorectal Cancer in Basque country is characterized by unusual epidemiological features given that Colorectal Cancer incidence is similar to other European countries while adenoma prevalence is higher. The object of our study was to economically evaluate the programme via cost-effectiveness and budget impact analyses with microsimulation models. METHODS: We applied the Microsimulation Screening Analysis (MISCAN)-Colon model to predict trends in Colorectal Cancer incidence and mortality and to quantify the short- and long-term effects and costs of the Basque Colorectal Cancer Screening Programme. The model was calibrated to the Basque demographics in 2008 and age-specific Colorectal Cancer incidence data in the Basque Cancer Registry from 2005 to 2008 before the screening begun. The model was also calibrated to the high adenoma prevalence observed for the Basque population in a previously published study. The multi-cohort approach used in the model included all the cohorts in the programme during 30 years of implementation, with lifetime follow-up. Unit costs were obtained from the Basque Health Service and both cost effectiveness analysis and budget impact analysis were carried out. RESULTS: The goodness-of-fit of the model adaptation to observed programme data was evidence of validation. In the cost-effectiveness analysis, the savings from treatment were larger than the added costs due to screening. Thus, the Basque programme was dominant compared to no screening, as life expectancy increased by 29.3 days per person. The savings in the budget analysis appeared 10 years after the complete implementation of the programme. The average annual budget was ?73.4 million from year 2023 onwards. CONCLUSIONS: This economic evaluation showed a screening intervention with a major health gain that also produced net savings when a long follow-up was used to capture the late economic benefit. The number of colonoscopies required was high but remain within the capacity of the Basque Health Service. So far in Europe, no other population Colorectal Cancer screening programme has been evaluated by budget impact analysis. PMID- 29695235 TI - Echocardiographic characteristics of primary malignant pericardial mesothelioma and outcomes analysis: a retrospective study. AB - BACKGROUND: Little is known about the echocardiographic characteristics of primary malignant pericardial mesothelioma (PPM) due to its rarity. The aim of this study was to explore the sex-specific echocardiographic patterns of PPM and risk factors for in-hospital mortality. METHODS: A retrospective information retrieval was conducted for cases of PPM reported from China during 1981 and 2015. The diagnosis was made by histopathological examinations and only cases with echocardiographic descriptions were included. Data on the clinical and echocardiographic findings were collected. Difference in clinical, sex-specific echocardiographic characteristics and findings across different time periods were assessed. Logistic regression analysis was performed to explore echocardiographic risk factors for in-hospital mortality. RESULTS: A total of 64 patients with PPM were included, with a mean age of 39.2 +/- 15.6 years and minor male dominance (40, 62.5%). The most common echocardiographic presentations were pericardial effusion (55, 85.9%), pericardial masses (36.4%) and thickening (17.3%), respectively. The positive rate of pericardiocentesis was only 20.9%. Six patients (15.4%) died among 39 cases reporting in-hospital outcome. Logistics analysis identified no clinical or echocardiographic parameters associated with in-hospital mortality (all P > 0.05). CONCLUSIONS: The echocardiographic signs of PPM are basically nonspecific with massive pericardial effusion as the most common sign, although no echocardiographic gender differences or association with in-hospital mortality could be identified. PMID- 29695236 TI - Associations between comorbidities, their treatment and survival in patients with interstitial lung diseases - a claims data analysis. AB - BACKGROUND: Interstitial lung diseases (ILDs) are associated with a high burden of disease. However, data on the prognostic impact of comorbidities and comorbidity-related pharmaceutical treatments in patients with various ILDs remain sparse. METHODS: Using longitudinal claims data from a German Statutory Health Insurance Fund, we assessed comorbidity in ILD subtypes and associated drug treatments. Baseline comorbidity was assessed via the Elixhauser Comorbidity Index that was amended by ILD-relevant conditions. Drug treatment was assessed on the substance level using the ATC-codes of drugs prescribed at the time of ILD diagnosis. Subsequently, the comorbid conditions (main analysis) and pharmaceutical substances (secondary analysis) with a meaningful association to survival were identified for the complete ILD cohort and within the subtype strata. For this, we applied multivariate Cox models using a LASSO selection process and visualized the findings within comorbidomes. RESULTS: In the 36,821 patients with ILDs, chronic obstructive pulmonary disease (COPD), arterial hypertension, and ischaemic heart disease (IHD) were the most prevalent comorbidities. The majority of patients with cardiovascular diseases received pharmaceutical treatment, while, in other relevant comorbidities, treatment quotas were low (COPD 46%, gastro-oesophageal reflux disease 65%). Comorbidities had a clinically meaningful detrimental effect on survival that tended to be more pronounced in the case of untreated conditions (e.g. hazard ratios for treated IHD 0.97 vs. 1.33 for untreated IHD). Moreover, comorbidity impact varied substantially between distinct subtypes. CONCLUSIONS: Our analyses suggest that comorbid conditions and their treatment profile significantly affect mortality in various ILDs. Therefore, comprehensive comorbidity assessment and management remains important in any ILD. PMID- 29695237 TI - Amphotericin B suppresses M2 phenotypes and B7-H1 expression in macrophages to prevent Raji cell proliferation. AB - BACKGROUND: Macrophages in the tumor microenvironment play a critical role in tumorigenesis and anti-cancer drug resistance. Burkitt's lymphoma (BL) is a B cell non-Hodgkin's lymphoma with dense macrophage infiltration. However, the role for macrophages in BL remains largely unknown. METHODS: B7-H1, a transmembrane glycoprotein in the B7 family, suppresses T cell activation and proliferation and induces the apoptosis of activated T cells. The expression of B7-H1 in BL clinical tissues was determined by streptavidin-peroxidase immunohistochemistry. The mutual regulation between macrophages and BL Raji cells was investigated in a co-culture system. The cell proliferation and cell cycle distribution of Raji cells were determined using BrdU staining coupled with flow cytometry. CD163, CD204 and B7-H1 expression was assessed by flow cytometry and Western blot. Cell invasion was analyzed by Transwell assay. The expression of cytokines was detected by quantitative RT-PCR. Immunofluorescence and allogeneic T-cell proliferation assays were used to compare the expression of B7-H1, p-STAT6, or p STAT3 and CD3+ T cell proliferation treated with or without amphotericin B. RESULTS: B7-H1 was highly expressed in tumor infiltration macrophages in most clinical BL tissues. In vitro, Raji cells synthesized IL-4, IL-6, IL-10 and IL-13 to induce CD163, CD204 and B7-H1 expression in co-cultured macrophages, which in turn promoted Raji cell proliferation and invasion. Interestingly, antifungal agent amphotericin B not only inhibited STAT6 phosphorylation to suppress the M2 polarization of macrophages, but also promoted CD3+ T cell proliferation by regulating B7-H1 protein expression in macrophages. CONCLUSION: Amphotericin B might represent a novel immunotherapeutic approach to treat patients with BL. PMID- 29695238 TI - Mass media and risk factors for cancer: the under-representation of age. AB - BACKGROUND: Increasing age is a risk factor for developing cancer. Yet, older people commonly underestimate this risk, are less likely to be aware of the early symptoms, and are more likely to be diagnosed with advanced stage cancer. Mass media are a key influence on the public's understanding health issues, including cancer risk. This study investigates how news media have represented age and other risk factors in the most common cancers over time. METHODS: Eight hundred articles about the four most common cancers (breast, prostate, lung and colorectal) published within eight UK national newspapers in 2003, 2004, 2013 and 2014 were identified using the Nexis database. Relevant manifest content of articles was coded quantitatively and subjected to descriptive statistical analysis in SPSS to identify patterns across the data. RESULTS: Risk was presented in half of the articles but this was rarely discussed in any depth and around a quarter of all articles introduced more than one risk factor, irrespective of cancer site. Age was mentioned as a risk factor in approximately 12% of all articles and this varied by cancer site. Age was most frequently reported in relation to prostate cancer and least often in articles about lung cancer. Articles featuring personal narratives more frequently focused on younger people and this was more pronounced in non-celebrity stories; only 15% of non celebrity narratives were about people over 60. Other common risks discussed were family history and genetics, smoking, diet, alcohol, and environmental factors. Family history and genetics together featured as the most common risk factors. Risk factor reporting varied by site and family history was most commonly associated with breast cancer, diet with bowel cancer and smoking with lung cancer. CONCLUSION: Age and older adults were largely obscured in media representation of cancer and cancer experience. Indeed common risk factors in general were rarely discussed in any depth. Our findings will usefully inform the development of future cancer awareness campaigns and media guidelines. It is important that older adults appreciate their heightened risk, particularly in the context of help-seeking decisions. PMID- 29695239 TI - Bortezomib prevents cytarabine resistance in MCL, which is characterized by down regulation of dCK and up-regulation of SPIB resulting in high NF-kappaB activity. AB - BACKGROUND: The addition of high-dose cytarabine to the treatment of mantle cell lymphoma (MCL) has significantly prolonged survival of patients, but relapses are common and are normally associated with increased resistance. To elucidate the mechanisms responsible for cytarabine resistance, and to create a tool for drug discovery investigations, we established a unique and molecularly reproducible cytarabine resistant model from the Z138 MCL cell line. METHODS: Effects of different substances on cytarabine-sensitive and resistant cells were evaluated by assessment of cell proliferation using [methyl-14C]-thymidine incorporation and molecular changes were investigated by protein and gene expression analyses. RESULTS: Gene expression profiling revealed that major transcriptional changes occur during the initial phase of adaptation to cellular growth in cytarabine containing media, and only few key genes, including SPIB, are deregulated upon the later development of resistance. Resistance was shown to be mediated by down regulation of the deoxycytidine kinase (dCK) protein, responsible for activation of nucleoside analogue prodrugs. This key event, emphasized by cross-resistance to other nucleoside analogues, did not only effect resistance but also levels of SPIB and NF-kappaB, as assessed through forced overexpression in resistant cells. Thus, for the first time we show that regulation of drug resistance through prevention of conversion of pro-drug into active drug are closely linked to increased proliferation and resistance to apoptosis in MCL. Using drug libraries, we identify several substances with growth reducing effect on cytarabine resistant cells. We further hypothesized that co-treatment with bortezomib could prevent resistance development. This was confirmed and show that the dCK levels are retained upon co-treatment, indicating a clinical use for bortezomib treatment in combination with cytarabine to avoid development of resistance. The possibility to predict cytarabine resistance in diagnostic samples was assessed, but analysis show that a majority of patients have moderate to high expression of dCK at diagnosis, corresponding well to the initial clinical response to cytarabine treatment. CONCLUSION: We show that cytarabine resistance potentially can be avoided or at least delayed through co-treatment with bortezomib, and that down-regulation of dCK and up-regulation of SPIB and NF-kappaB are the main molecular events driving cytarabine resistance development. PMID- 29695240 TI - Convalescent Plasmodium falciparum-specific seroreactivity does not correlate with paediatric malaria severity or Plasmodium antigen exposure. AB - BACKGROUND: Antibody immunity is thought to be essential to prevent severe Plasmodium falciparum infection, but the exact correlates of protection are unknown. Over time, children in endemic areas acquire non-sterile immunity to malaria that correlates with development of antibodies to merozoite invasion proteins and parasite proteins expressed on the surface of infected erythrocytes. RESULTS: A 1000 feature P. falciparum 3D7 protein microarray was used to compare P. falciparum-specific seroreactivity during acute infection and 30 days after infection in 23 children with uncomplicated malaria (UM) and 25 children with retinopathy-positive cerebral malaria (CM). All children had broad P. falciparum antibody reactivity during acute disease. IgM reactivity decreased and IgG reactivity increased in convalescence. Antibody reactivity to CIDR domains of "virulent" PfEMP1 proteins was low with robust reactivity to the highly conserved, intracellular ATS domain of PfEMP1 in both groups. Although children with UM and CM differed markedly in parasite burden and PfEMP1 exposure during acute disease, neither acute nor convalescent PfEMP1 seroreactivity differed between groups. Greater seroprevalence to a conserved Group A-associated ICAM binding extracellular domain was observed relative to linked extracellular CIDRalpha1 domains in both case groups. Pooled immune IgG from Malawian adults revealed greater reactivity to PfEMP1 than observed in children. CONCLUSIONS: Children with uncomplicated and cerebral malaria have similar breadth and magnitude of P. falciparum antibody reactivity. The utility of protein microarrays to measure serological recognition of polymorphic PfEMP1 antigens needs to be studied further, but the study findings support the hypothesis that conserved domains of PfEMP1 are more prominent targets of cross reactive antibodies than variable domains in children with symptomatic malaria. Protein microarrays represent an additional tool to identify cross-reactive Plasmodium antigens including PfEMP1 domains that can be investigated as strain-transcendent vaccine candidates. PMID- 29695241 TI - Novel risk genes identified in a genome-wide association study for coronary artery disease in patients with type 1 diabetes. AB - BACKGROUND: Patients with type 1 diabetes are more at risk of coronary artery disease than the general population. Although evidence points to a genetic risk there have been no study investigating genetic risk factors of coronary artery disease specific to individuals with type 1 diabetes. To identify low frequency and common genetic variations associated with coronary artery disease in populations of individuals with type 1 diabetes. METHODS: A two-stage genome wide association study was conducted. The discovery phase involved the meta-analysis of three genome-wide association cohorts totaling 434 patients with type 1 diabetes and coronary artery disease (cases) and 3123 T1D individuals with no evidence of coronary artery disease (controls). Replication of the top association signals (p < 10-5) was performed in five additional independent cohorts totaling 585 cases and 2612 controls. RESULTS: One locus (rs115829748, located upstream of the MAP1B gene) reached the statistical threshold of 5 * 10-8 for genome-wide significance but did not replicate. Nevertheless, three single nucleotide polymorphisms provided suggestive evidence for association with coronary artery disease in the combined studies: CDK18 rs138760780 (OR = 2.60 95% confidence interval [1.75-3.85], p = 2.02 * 10-6), FAM189A2 rs12344245 (OR = 1.85 [1.41-2.43], p = 8.52 * 10-6) and PKD1 rs116092985 (OR = 1.53 [1.27-1.85], p = 1.01 * 10-5). In addition, our analyses suggested that genetic variations at the ANKS1A, COL4A2 and APOE loci previously found associated with coronary artery disease in the general population could have stronger effects in patients with type 1 diabetes. CONCLUSIONS: This study suggests three novel candidate genes for coronary artery disease in the subgroup of patients affected with type 1 diabetes. The detected associations deserve to be definitively validated in additional epidemiological studies. PMID- 29695242 TI - Elucidation of the anti-hyperammonemic mechanism of Lactobacillus amylovorus JBD401 by comparative genomic analysis. AB - BACKGROUND: Recent experimental evidence showed that lactobacilli could be used as potential therapeutic agents for hyperammonemia. However, lack of understanding on how lactobacilli reduce blood ammonia levels limits application of lactobacilli to treat hyperammonemia. RESULTS: We report the finished and annotated genome sequence of L. amylovorus JBD401 (GenBank accession no. CP012389). L. amylovorus JBD401 reducing blood ammonia levels dramatically was identified by high-throughput screening of several thousand probiotic strains both within and across Lactobacillus species in vitro. Administration of L. amylovorus JBD401 to hyperammonemia-induced mice reduced the blood ammonia levels of the mice to the normal range. Genome sequencing showed that L. amylovorus JBD401 had a circular chromosome of 1,946,267 bp with an average GC content of 38.13%. Comparative analysis of the L. amylovorus JBD401 genome with L. acidophilus and L. amylovorus strains showed that L. amylovorus JBD401 possessed genes for ammonia assimilation into various amino acids and polyamines Interestingly, the genome of L. amylovorus JBD401 contained unusually large number of various pseudogenes suggesting an active stage of evolution. CONCLUSIONS: L. amylovorus JBD401 has genes for assimilation of free ammonia into various amino acids and polyamines which results in removal of free ammonia in intestinal lumen to reduce the blood ammonia levels in the host. This work explains the mechanism of how probiotics reduce blood ammonia levels. PMID- 29695244 TI - Impact of differences in adenoma and proximal serrated polyp detection rate on the long-term effectiveness of FIT-based colorectal cancer screening. AB - BACKGROUND: Both the adenoma detection rate (ADR) and proximal serrated polyp detection rate (PSPDR) vary among endoscopists. It is unclear how these variations influence colorectal cancer (CRC) screening effectiveness. We evaluated the effect of variation in these detection rates on the long-term impact of fecal immunochemical test (FIT) based screening. METHODS: The Adenoma and Serrated pathway to Colorectal CAncer (ASCCA) model was set up to simulate the Dutch national biennial FIT-based CRC screening program between 2014 and 2044. Adherence to FIT and colonoscopy was 73 and 92%. Besides a 'no screening scenario', several screening scenarios varying in ADR and PSPDR were evaluated. Using the available literature on colonoscopy miss rates led to a base-case ADR of 59% and PSPDR of 11%, which were varied with intervals of 3 and 2%. RESULTS: Compared to no screening, FIT-screening in the base-case scenario reduced long term mortality with 51.8%. At a fixed PSPDR of 11%, an increase in ADR from 44 to 62% would result in a 10.7% difference in mortality reduction. Using a fixed ADR of 59%, changing the PSPDR from 3 to 15% did not substantially influence long term mortality (51.0 to 52.3%). CONCLUSIONS: An increase in ADR gradually reduces CRC burden in a FIT-based screening program, whereas an increase in PSPDR only minimally influences long-term outcomes at a population-level. The limited effect of the PSPDR can be explained by the limited sensitivity of FIT for serrated polyps (SPs). Other triage modalities aiming to detect relevant SPs should be explored. PMID- 29695243 TI - Complex evolution of the GSTM gene family involves sharing of GSTM1 deletion polymorphism in humans and chimpanzees. AB - BACKGROUND: The common deletion of the glutathione S-transferase Mu 1 (GSTM1) gene in humans has been shown to be involved in xenobiotic metabolism and associated with bladder cancer. However, the evolution of this deletion has not been investigated. RESULTS: In this study, we conducted comparative analyses of primate genomes. We demonstrated that the GSTM gene family has evolved through multiple structural variations, involving gene duplications, losses, large inversions and gene conversions. We further showed experimentally that the GSTM1 was polymorphically deleted in both humans and also in chimpanzees, through independent deletion events. To generalize our results, we searched for genic deletions that are polymorphic in both humans and chimpanzees. Consequently, we found only two such deletions among the thousands that we have searched, one of them being the GSTM1 deletion and the other surprisingly being another metabolizing gene, the UGT2B17. CONCLUSIONS: Overall, our results support the emerging notion that metabolizing gene families, such as the GSTM, NAT, UGT and CYP, have been evolving rapidly through gene duplication and deletion events in primates, leading to complex structural variation within and among species with unknown evolutionary consequences. PMID- 29695245 TI - Identification of genomic regions and candidate genes for chicken meat ultimate pH by combined detection of selection signatures and QTL. AB - BACKGROUND: The understanding of the biological determinism of meat ultimate pH, which is strongly related to muscle glycogen content, is a key point for the control of muscle integrity and meat quality in poultry. In the present study, we took advantage of a unique model of two broiler lines divergently selected for the ultimate pH of the pectoralis major muscle (PM-pHu) in order to decipher the genetic control of this trait. Two complementary approaches were used: detection of selection signatures generated during the first five generations and genome wide association study for PM-pHu and Sartorius muscle pHu (SART-pHu) at the sixth generation of selection. RESULTS: Sixty-three genomic regions showed significant signatures of positive selection. Out of the 10 most significant regions (detected by HapFLK or FLK method with a p-value below 1e-6), 4 were detected as soon as the first generation (G1) and were recovered at each of the four following ones (G2-G5). Another four corresponded to a later onset of selection as they were detected only at G5. In total, 33 SNPs, located in 24 QTL regions, were significantly associated with PM-pHu. For SART-pHu, we detected 18 SNPs located in 10 different regions. These results confirmed a polygenic determinism for these traits and highlighted two major QTL: one for PM-pHu on GGA1 (with a Bayes Factor (BF) of 300) and one for SART-pHu on GGA4 (with a BF of 257). Although selection signatures were enriched in QTL for PM-pHu, several QTL with strong effect haven't yet responded to selection, suggesting that the divergence between lines might be further increased. CONCLUSIONS: A few regions of major interest with significant selection signatures and/or strong association with PM-pHu or SART-pHu were evidenced for the first time in chicken. Their gene content suggests several candidates associated with diseases of glycogen storage in humans. The impact of these candidate genes on meat quality and muscle integrity should be further investigated in chicken. PMID- 29695246 TI - Transcriptomic analysis between self- and cross-pollinated pistils of tea plants (Camellia sinensis). AB - BACKGROUND: Self-incompatibility (SI) is a major barrier that obstructs the breeding process in most horticultural plants including tea plants (Camellia sinensis). The aim of this study was to elucidate the molecular mechanism of SI in tea plants through a high throughput transcriptome analysis. RESULTS: In this study, the transcriptomes of self- and cross-pollinated pistils of two tea cultivars 'Fudingdabai' and 'Yulv' were compared to elucidate the SI mechanism of tea plants. In addition, the ion components and pollen tube growth in self- and cross-pollinated pistils were investigated. Our results revealed that both cultivars had similar pollen activities and cross-pollination could promote the pollen tube growth. In tea pistils, the highest ion content was potassium (K+), followed by calcium (Ca2+), magnesium (Mg2+) and phosphorus (P5+). Ca2+ content increased after self-pollination but decreased after cross-pollination, while K+ showed reverse trend with Ca2+. A total of 990 and 3 common differentially expressed genes (DEGs) were identified in un-pollinated vs. pollinated pistils and self- vs. cross-pollinated groups after 48 h, respectively. Function annotation indicated that three genes encoding UDP-glycosyltransferase 74B1 (UGT74B1), Mitochondrial calcium uniporter protein 2 (MCU2) and G-type lectin S receptor-like serine/threonine-protein kinase (G-type RLK) might play important roles during SI process in tea plants. CONCLUSION: Ca2+ and K+ are important signal for SI in tea plants, and three genes including UGT74B1, MCU2 and G-type RLK play essential roles during SI signal transduction. PMID- 29695248 TI - Use of the self-organising map network (SOMNet) as a decision support system for regional mental health planning. AB - BACKGROUND: Decision-making in mental health systems should be supported by the evidence-informed knowledge transfer of data. Since mental health systems are inherently complex, involving interactions between its structures, processes and outcomes, decision support systems (DSS) need to be developed using advanced computational methods and visual tools to allow full system analysis, whilst incorporating domain experts in the analysis process. In this study, we use a DSS model developed for interactive data mining and domain expert collaboration in the analysis of complex mental health systems to improve system knowledge and evidence-informed policy planning. METHODS: We combine an interactive visual data mining approach, the self-organising map network (SOMNet), with an operational expert knowledge approach, expert-based collaborative analysis (EbCA), to develop a DSS model. The SOMNet was applied to the analysis of healthcare patterns and indicators of three different regional mental health systems in Spain, comprising 106 small catchment areas and providing healthcare for over 9 million inhabitants. Based on the EbCA, the domain experts in the development team guided and evaluated the analytical processes and results. Another group of 13 domain experts in mental health systems planning and research evaluated the model based on the analytical information of the SOMNet approach for processing information and discovering knowledge in a real-world context. Through the evaluation, the domain experts assessed the feasibility and technology readiness level (TRL) of the DSS model. RESULTS: The SOMNet, combined with the EbCA, effectively processed evidence-based information when analysing system outliers, explaining global and local patterns, and refining key performance indicators with their analytical interpretations. The evaluation results showed that the DSS model was feasible by the domain experts and reached level 7 of the TRL (system prototype demonstration in operational environment). CONCLUSIONS: This study supports the benefits of combining health systems engineering (SOMNet) and expert knowledge (EbCA) to analyse the complexity of health systems research. The use of the SOMNet approach contributes to the demonstration of DSS for mental health planning in practice. PMID- 29695247 TI - Impact on birth weight of maternal smoking throughout pregnancy mediated by DNA methylation. AB - BACKGROUND: Cigarette smoking has severe adverse health consequences in adults and in the offspring of mothers who smoke during pregnancy. One of the most widely reported effects of smoking during pregnancy is reduced birth weight which is in turn associated with chronic disease in adulthood. Epigenome-wide association studies have revealed that smokers show a characteristic "smoking methylation pattern", and recent authors have proposed that DNA methylation mediates the impact of maternal smoking on birth weight. The aims of the present study were to replicate previous reports that methylation mediates the effect of maternal smoking on birth weight, and for the first time to investigate whether the observed mediation effects are sex-specific in order to account for known sex specific differences in methylation levels. METHODS: Methylation levels in the cord blood of 313 newborns were determined using the Illumina HumanMethylation450K Beadchip. A total of 5,527 CpG sites selected on the basis of evidence from the literature were tested. To determine whether the observed association between maternal smoking and birth weight was attributable to methylation, mediation analyses were performed for significant CpG sites. Separate analyses were then performed in males and females. RESULTS: Following quality control, 282 newborns eventually remained in the analysis. A total of 25 mothers had smoked consistently throughout the pregnancy. The birthweigt of newborns whose mothers had smoked throughout pregnancy was reduced by >200g. After correction for multiple testing, 30 CpGs showed differential methylation in the maternal smoking subgroup including top "smoking methylation pattern" genes AHRR, MYO1G, GFI1, CYP1A1, and CNTNAP2. The effect of maternal smoking on birth weight was partly mediated by the methylation of cg25325512 (PIM1); cg25949550 (CNTNAP2); and cg08699196 (ITGB7). Sex-specific analyses revealed a mediating effect for cg25949550 (CNTNAP2) in male newborns. CONCLUSION: The present data replicate previous findings that methylation can mediate the effect of maternal smoking on birth weight. The analysis of sex-dependent mediation effects suggests that the sex of the newborn may have an influence. Larger studies are warranted to investigate the role of both the identified differentially methylated loci and the sex of the newborn in mediating the association between maternal smoking during pregnancy and birth weight. PMID- 29695249 TI - Aortic flow patterns and wall shear stress maps by 4D-flow cardiovascular magnetic resonance in the assessment of aortic dilatation in bicuspid aortic valve disease. AB - BACKGROUND: In patients with bicuspid valve (BAV), ascending aorta (AAo) dilatation may be caused by altered flow patterns and wall shear stress (WSS). These differences may explain different aortic dilatation morphotypes. Using 4D flow cardiovascular magnetic resonance (CMR), we aimed to analyze differences in flow patterns and regional axial and circumferential WSS maps between BAV phenotypes and their correlation with ascending aorta dilatation morphotype. METHODS: One hundred and one BAV patients (aortic diameter <= 45 mm, no severe valvular disease) and 20 healthy subjects were studied by 4D-flow CMR. Peak velocity, flow jet angle, flow displacement, in-plane rotational flow (IRF) and systolic flow reversal ratio (SFRR) were assessed at different levels of the AAo. Peak-systolic axial and circumferential regional WSS maps were also estimated. Unadjusted and multivariable adjusted linear regression analyses were used to identify independent correlates of aortic root or ascending dilatation. Age, sex, valve morphotype, body surface area, flow derived variables and WSS components were included in the multivariable models. RESULTS: The AAo was non-dilated in 24 BAV patients and dilated in 77 (root morphotype in 11 and ascending in 66). BAV phenotype was right-left (RL-) in 78 patients and right-non-coronary (RN-) in 23. Both BAV phenotypes presented different outflow jet direction and velocity profiles that matched the location of maximum systolic axial WSS. RL-BAV velocity profiles and maximum axial WSS were homogeneously distributed right-anteriorly, however, RN-BAV showed higher variable profiles with a main proximal-posterior distribution shifting anteriorly at mid-distal AAo. Compared to controls, BAV patients presented similar WSS magnitude at proximal, mid and distal AAo (p = 0.764, 0.516 and 0.053, respectively) but lower axial and higher circumferential WSS components (p < 0.001 for both, at all aortic levels). Among BAV patients, RN BAV presented higher IRF at all levels (p = 0.024 proximal, 0.046 mid and 0.002 distal AAo) and higher circumferential WSS at mid and distal AAo (p = 0.038 and 0.046, respectively) than RL-BAV. However, axial WSS was higher in RL-BAV compared to RN-BAV at proximal and mid AAo (p = 0.046, 0.019, respectively). Displacement and axial WSS were independently associated with the root morphotype, and circumferential WSS and SFRR with the ascending-morphotype. CONCLUSIONS: Different BAV-phenotypes present different flow patterns with an anterior distribution in RL-BAV, whereas, RN-BAV patients present a predominant posterior outflow jet at the sinotubular junction that shifts to anterior or right anterior in mid and distal AAo. Thus, RL-BAV patients present a higher axial WSS at the aortic root while RN-BAV present a higher circumferential WSS in mid and distal AAo. These results may explain different AAo dilatation morphotypes in the BAV population. PMID- 29695250 TI - Effectiveness of the 'Girls Active' school-based physical activity programme: A cluster randomised controlled trial. AB - BACKGROUND: Globally, adolescent girls' physical activity (PA) levels are low. The 'Girls Active' secondary school-based programme, developed by the Youth Sport Trust, aims to increase PA in adolescent girls. This paper explores the effectiveness of the 'Girls Active' school-based PA programme. METHODS: A random sample of girls aged 11-14 from 20 secondary schools (Midlands, UK) participated in a two-arm cluster randomised controlled trial. Ten schools received Girls Active and 10 continued with usual practice. Measurements were taken at baseline, seven- and 14-month follow-up. PRIMARY OUTCOME: wrist-worn accelerometer measured moderate- to vigorous-intensity PA (MVPA). SECONDARY OUTCOMES: overall PA, light PA, sedentary time, body composition, and psychosocial outcomes. Generalised estimating equations, adjusted for school cluster and potential confounders, were used and A priori subgroup analysis was undertaken. Micro-costing and cost consequence analyses were conducted using bespoke collection methods on programme delivery information. Outcomes for the cost-consequence analysis were health related quality of life measured by the Child Health Utility-9D and service use. RESULTS: Overall, 1752 pupils participated, 1211 (69.1%) provided valid 14-month accelerometer data. No difference in MVPA (mins/day; 95% confidence intervals) was found at 14 months (1.7; -0.8 to 4.3), there was at seven months (2.4; 0.1 to 4.7). Subgroup analyses showed significant intervention effects on 14-month in larger schools (3.9; 1.39 to 6.09) and in White Europeans (3.1; 0.60 to 6.02) and in early maturers (5.1; 1.69 to 8.48) at seven months. The control group did better in smaller schools at 14-months (-4.38; -7.34 to -1.41). Significant group differences were found in 14-month identified motivation (-0.09; -0.18 to -0.01) and at seven months in: overall PA (1.39 mg/day; 0.1 to 2.2), after-school sedentary time (-4.7; -8.9 to -0.6), whole day (5.7; 1.0 to 10.5) and school day (4.5; 0.25 to 8.75) light PA, self-esteem. Small, statistically significant, differences in some psychosocial variables favoured control schools. Micro costing demonstrated that delivering the programme resulted in a range of time and financial costs at each school. Cost-consequence analysis demonstrated no effect of the programme for health related quality of life or service use. CONCLUSIONS: Compared with usual practice, 'Girls Active' did not affect 14-month MVPA. TRIAL REGISTRATION: ISRCTN10688342. PMID- 29695251 TI - Efficacy and mechanism of steep pulse irreversible electroporation technology on xenograft model of nude mice: a preclinical study. AB - BACKGROUND: Steep pulse therapy can irreversible electrically brackdown of tumor membrance and cause cell death. In previous studies, we investigated the effect of steep pulsed electroporation on the killing of large cell lung cancer cell line L981- in vitro, and determined the best parameters for killing lung cancer cells by steep pulse technology. But the optimal parameters and the mechanisms of steep pulse irreversible electroporation technology on nude mouse tumor model are unclear. METHODS: Three settings of steep pulse therapy parameters were applied to the nude mouse model. An in vivo imaging system was employed to observe the effect of different parameters on the mouse model. The pathological changes of the tumor tissue and immunofluorescence data on Caspase-3 protein expression were recorded. RESULTS: Under the in vivo imaging system, the steep pulse had an obvious inhibitory effect on the transplanted tumor in the nude mouse model. Pathological tests showed that occurrence of necrosis and apoptosis and expression of Caspase-3 protein in the tumor tissue were increased compared to those in the normal tissue. CONCLUSIONS: Steep pulse irreversible electroporation technology showed a promising antitumor effect in the nude mouse tumor model. With splint-type electrode, the best treatment parameters determined for the nude mouse tumor model were voltage amplitude 2000 V/cm, pulse width 100 MUs, pulse frequency 1 Hz, pulse number 60, and repeat time 3. Moreover, steep pulse induced coagulative necrosis of tumor tissue by cell apoptosis. PMID- 29695252 TI - YAP/TAZ regulates TGF-beta/Smad3 signaling by induction of Smad7 via AP-1 in human skin dermal fibroblasts. AB - BACKGROUND: Transcription factors YAP and TAZ function as the primary mediators of the Hippo pathway. Yet, crosstalk of YAP and TAZ with other signaling pathways remains relatively unexplored. We have explored the impact of YAP and TAZ levels on the TGF-beta/Smad signaling pathway in human skin dermal fibroblasts. METHODS: YAP and TAZ levels in dermal fibroblasts were reduced in dermal fibroblasts by siRNA-mediated knockdown. The effects of YAP and TAZ reduction on TGF-beta/Smad signaling were examined by quantitative real-time PCR, Western analysis, and immunostaining. Luciferase reporter assays and electrophoretic mobility shift assays were conducted to investigate the transcription factor DNA-binding and transcriptional activities. RESULTS: Knockdown of both YAP and TAZ (YAP/TAZ), but not either separately, impaired TGF-beta1-induced Smad3 phosphorylation and Smad3 transcriptional activity, thereby inhibiting the expression of TGF-beta target genes. This reduction by reduced levels of YAP/TAZ results from induction of inhibitory Smad7, which inhibits Smad3 phosphorylation and activity by TGF-beta1. Conversely, prevention of Smad7 induction restores Smad3 phosphorylation and Smad3 transcriptional activity in fibroblasts that have reduced YAP/TAZ. In agreement with these findings, inhibition of YAP/TAZ transcriptional activity, similar to the reduction of YAP/TAZ levels, also significantly induced Smad7 and impaired TGF-beta/Smad signaling. Further investigations revealed that reduced levels of YAP/TAZ led to induction of activator protein-1 (AP-1) activity, Activated AP-1 bound to DNA sequences in the Smad7 gene promoter, and deletion of these AP-1 binding sequences substantially reduced Smad7 promoter reporter activity. CONCLUSION: YAP/TAZ functions in concert with transcription factor AP-1 and Smad7 to regulate TGF-beta signaling, in human dermal fibroblasts. Reduction of YAP/TAZ levels leads to activation of AP-1 activity, which induces Smad7. Smad7 suppresses the TGF-beta pathway. PMID- 29695253 TI - MicroRNA expression profiling for the prediction of resistance to neoadjuvant radiochemotherapy in squamous cell carcinoma of the esophagus. AB - BACKGROUND: MicroRNAs (miRNAs) play an important role in cancer biology. Neoadjuvant radiochemotherapy followed by surgery is a standard treatment for locally advanced esophageal squamous cell carcinoma (ESCC). However, a subset of patients do not respond. We evaluated whether miRNA profiles can predict resistance to radiochemotherapy. METHODS: Formalin-fixed, paraffin-embedded pretherapeutic biopsies of patients treated by radiochemotherapy followed by esophagectomy were analyzed. The response was determined by histopathological tumor regression grading. miRNA profiling was performed by microarray analysis (Agilent platform) in 16 non-responders and 15 responders. Differentially expressed miRNAs were confirmed by real-time quantitative PCR (qRT-PCR) in an expanded cohort of 53 cases. RESULTS: The miRNA profiles within and between non responders and responders were highly similar (r = 0.96, 0.94 and 0.95). However, 12 miRNAs were differentially expressed (> twofold; p <= 0.025): non-responders showed upregulation of hsa-miR-1323, hsa-miR-3678-3p, hsv2-miR-H7-3p, hsa-miR 194*, hsa-miR-3152, kshv-miR-K12-4-3p, hsa-miR-665 and hsa-miR-3659 and downregulation of hsa-miR-126*, hsa-miR-484, hsa-miR-330-3p and hsa-miR-3653. qRT PCR analysis confirmed the microarray findings for hsa-miR-194* and hsa-miR-665 (p < 0.001 each) with AUC values of 0.811 (95% CI 0.694-0.927) and 0.817 (95% CI 0.704-0.930), respectively, in ROC analysis. CONCLUSIONS: Our results indicate that miRNAs are involved in the therapeutic response in ESCC and suggest that miRNA profiles could facilitate pretherapeutic patient selection. PMID- 29695254 TI - Atherosclerosis T1-weighted characterization (CATCH): evaluation of the accuracy for identifying intraplaque hemorrhage with histological validation in carotid and coronary artery specimens. AB - BACKGROUND: Coronary high intensity plaques (CHIPs) detected using cardiovascular magnetic resonance (CMR) coronary atherosclerosis T1-weighted characterization with integrated anatomical reference (CATCH) have been shown to be positively associated with high-risk morphology observed on intracoronary optical coherence tomography (OCT). This study sought to validate whether CHIPs detected on CATCH indicate the presence of intraplaque hemorrhage (IPH) through ex vivo imaging of carotid and coronary plaque specimens, with histopathology as the standard reference. METHODS: Ten patients scheduled to undergo carotid endarterectomy underwent CMR with the conventional T1-weighted (T1w) sequence. Eleven carotid atherosclerotic plaques removed at carotid endarterectomy and six coronary artery endarterectomy specimens removed from patients undergoing coronary artery bypass grafting (CABG) were scanned ex vivo using both the conventional T1w sequence and CATCH. Both in vivo and ex vivo images were examined for the presence of IPH. The sensitivity, specificity, and Cohen Kappa (k) value of each scan were calculated using matched histological sections as the reference. k value between each scan in the discrimination of IPH was also computed. RESULTS: A total of 236 in vivo locations, 328 ex vivo and matching histology locations were included for the analysis. Sensitivity, specificity, and k value were 76.7%, 95.3%, and 0.75 for in vivo T1w imaging, 77.2%, 97.4%, and 0.78 for ex vivo T1w imaging, and 95.0%, 92.1%, and 0.84 for ex vivo CATCH, respectively. Moderate agreement was reached between in vivo T1w imaging, ex vivo T1w imaging, and ex vivo CATCH for the detection of IPH: between in vivo T1w imaging and ex vivo CATCH (k = 0.68), between ex vivo T1w imaging and ex vivo CATCH (k = 0.74), between in vivo T1w imaging and ex vivo T1w imaging (k = 0.83). None of the coronary artery plaque locations showed IPH. CONCLUSION: This study demonstrated that carotid CHIPs detected by CATCH can be used to assess for IPH, a high-risk plaque feature. PMID- 29695256 TI - Metabolic distress in lipid & one carbon metabolic pathway through low vitamin B 12: a population based study from North India. AB - BACKGROUND: Dyslipidemia and hyper-homocysteinemia are the major independent risk factors of cardio vascular disease. Deficiency of folate and vitamin B-12 are associated with both hyper-homocysteinemia and dyslipidemia. The aim of the study is to evaluate the relationship of homocysteine and its associated dietary determinant levels (Folate and Vitamin B-12) with lipids and obesity parameters (WC, BMI, WHR) in North Indian population. METHODS: The participants were recruited under a major government funded project through household survey covering 15 villages of Haryana, India. Participants were both males and females, between age group 30-65 years, from a north Indian community. Initially 1634 individuals were recruited, of which 1374 were considered for analysis as they were not found to be on any kind of medication for high blood pressure, CAD, diabetes or any other disorder, and had no missing data. 5 mL of intravenous blood sample was collected after obtaining written informed consent from the participants. Homocysteine, folate and vitamin B12 levels were estimated through Immulite 1000 by chemi-luminescence technique. Triglyceride, total cholesterol and HDL-C were estimated by spectrophotometry technique using commercial kits. The values for LDL and VLDL were calculated using Friedwald's equation. Height, weight, waist circumference (WC), hip circumference (HC) was measured over light clothing. Statistical analysis for data was performed using SPSS 16.0 version. RESULTS: All the lipid indices, except HDL, showed a trend of negative correlation with homocysteine after controlling for confounders, though not significant. No association was found between obesity (WC, BMI, WHR) and homocysteine in the present study. Vitamin B-12 deficiency was significantly associated with both hyper-homocysteinemia and low HDL. Folate was found to have significantly reduced risk for high TC & LDL. CONCLUSIONS: The "hcy-lipid" hypothesis does not seem to be complementing in the present studied population. The population is vulnerable to severe under-nutrition due to the association of vitamin B-12 with HDL, leading to metabolic disturbance in both the pathways; lipid and one carbon metabolic pathway. Co-factors such as ethnicity, cultural practices, and lifestyle & dietary habits must be considered while making public health policies to control diseases. PMID- 29695255 TI - Temporomandibular joint arthritis in juvenile idiopathic arthritis, now what? AB - BACKGROUND: Arthritis involving the temporomandibular joint (TMJ) complicates 40 96% of cases of juvenile idiopathic arthritis (JIA), potentially leading to devastating changes to form and function. Optimal evaluation and management of this joint remains a matter of ongoing discussion. METHODS: We performed a PubMed search for all articles with keywords "temporomandibular" and "arthritis", covering the dates 2002 through February 28, 2018. A separate PubMed search was performed for all articles with keywords "temporomandibular joint", "arthritis", and "treatment" covering the same dates. FINDINGS: The TMJ is a particularly challenging joint to assess, both clinically and with imaging studies. Clinical assessment of the TMJ is hampered by the low sensitivity of joint pain as well as the absence of physical exam findings early in the disease process. As with all joints, plain radiography and computed tomography only detect arthritic sequelae. Additionally, there is mixed data on the sensitivity of ultrasound, leaving magnetic resonance imaging (MRI) as the optimal diagnostic modality. However, several recent studies have shown that non-arthritic children can have subtle findings on MRI consistent with TMJ arthritis, such as joint effusion and contrast enhancement. Consequently, there has been an intense effort to identify features that can be used to differentiate mild TMJ arthritis from normal TMJs, such as the ratio of the enhancement within the TMJ itself compared to the enhancement in surrounding musculature. With respect to treatment of TMJ arthritis, there is minimal prospective data on medical therapy of this complicated joint. Retrospective studies have suggested that the response to medical therapy of the TMJ may lag behind that of other joints, prompting use of intraarticular (IA) therapy. Although most studies have shown short-term effectiveness of corticosteroids, the long-term safety of this therapy on local growth as well as on the development of IA heterotopic bone have prompted recommendations to limit use of IA corticosteroids. Severe TMJ disease from JIA can also be managed non-operatively with splints in a growing child, as well as with surgery. CONCLUSION: In this review, we summarize literature on the diagnosis and management of TMJ arthritis in JIA and suggest a diagnostic and therapeutic algorithm for children with refractory TMJ arthritis. PMID- 29695257 TI - Comparative omics and feeding manipulations in chicken indicate a shift of the endocrine role of visceral fat towards reproduction. AB - BACKGROUND: The mammalian adipose tissue plays a central role in energy-balance control, whereas the avian visceral fat hardly expresses leptin, the key adipokine in mammals. Therefore, to assess the endocrine role of adipose tissue in birds, we compared the transcriptome and proteome between two metabolically different types of chickens, broilers and layers, bred towards efficient meat and egg production, respectively. RESULTS: Broilers and layer hens, grown up to sexual maturation under free-feeding conditions, differed 4.0-fold in weight and 1.6-fold in ovarian-follicle counts, yet the relative accumulation of visceral fat was comparable. RNA-seq and mass-spectrometry (MS) analyses of visceral fat revealed differentially expressed genes between broilers and layers, 1106 at the mRNA level (FDR <= 0.05), and 203 at the protein level (P <= 0.05). In broilers, Ingenuity Pathway Analysis revealed activation of the PTEN-pathway, and in layers increased response to external signals. The expression pattern of genes encoding fat-secreted proteins in broilers and layers was characterized in the RNA-seq and MS data, as well as by qPCR on visceral fat under free feeding and 24 h-feed deprivation. This characterization was expanded using available RNA-seq data of tissues from red junglefowl, and of visceral fat from broilers of different types. These comparisons revealed expression of new adipokines and secreted proteins (LCAT, LECT2, SERPINE2, SFTP1, ZP1, ZP3, APOV1, VTG1 and VTG2) at the mRNA and/or protein levels, with dynamic gene expression patterns in the selected chicken lines (except for ZP1; FDR/P <= 0.05) and feed deprivation (NAMPT, SFTPA1 and ZP3) (P <= 0.05). In contrast, some of the most prominent adipokines in mammals, leptin, TNF, IFNG, and IL6 were expressed at a low level (FPKM/RPKM< 1) and did not show differential mRNA expression neither between broiler and layer lines nor between fed vs. feed-deprived chickens. CONCLUSIONS: Our study revealed that RNA and protein expression in visceral fat changes with selective breeding, suggesting endocrine roles of visceral fat in the selected phenotypes. In comparison to gene expression in visceral fat of mammals, our findings points to a more direct cross talk of the chicken visceral fat with the reproductive system and lower involvement in the regulation of appetite, inflammation and insulin resistance. PMID- 29695258 TI - Cells responsible for liver mass regeneration in rats with 2 acetylaminofluorene/partial hepatectomy injury. AB - BACKGROUND: Whether hepatic progenitor cells (HPCs)/oval cells regenerate liver mass upon chronic liver injury is controversial in mice and has not been conclusively proven in humans and rats. In this study, we examined which cell type-hepatocytes or oval cells-mediates liver regeneration in the classic rat 2 acetylaminofluorene (AAF)/partial hepatectomy (PH) injury where AAF reversibly blocks hepatocyte proliferation, thereby inducing oval cell expansion after the regenerative stimulus of PH. METHODS: We employed lineage tracing of dipeptidyl peptidase IV (DPPIV, a hepatocyte canalicular enzyme)-positive hepatocytes by subjecting rats with DPPIV-chimeric livers to AAF/PH, AAF/PH/AAF (continuous AAF after AAF/PH to nonselectively inhibit regenerating hepatocytes), or AAF/PH/retrorsine injury (2-dose retrorsine after AAF/PH to specifically and irreversibly block existing hepatocytes); through these methods, we determined hepatocyte contribution to liver regeneration. To determine the oval cell contribution to hepatocyte regeneration, we performed DPPIV(+) oval cell transplantation combined with AAF/PH injury or AAF/PH/retrorsine injury in DPPIV deficient rats to track the fate of DPPIV(+) oval cells. RESULTS: DPPIV-chimeric livers demonstrated typical oval cell activation upon AAF/PH injury. After cessation of AAF, DPPIV(+) hepatocytes underwent extensive proliferation to regenerate the liver mass, whereas oval cells underwent hepatocyte differentiation. Upon AAF/PH/AAF injury where hepatocyte proliferation was inhibited by continuous AAF treatment following AAF/PH, oval cells extensively expanded in an undifferentiated state but did not produce hepatocytes. By substituting retrorsine for AAF administration following AAF/PH (AAF/PH/retrorsine), oval cells regenerated large-scale hepatocytes. CONCLUSIONS: Hepatocyte self-replication provides the majority of hepatocyte regeneration, with supplementary contribution from oval cells in rats under AAF/PH injury. Oval cells expand and maintain in an undifferentiated state upon continuously nonselective liver injury, whereas they can significantly regenerate hepatocytes in a noncompetitive environment. PMID- 29695259 TI - Porcine pulmonary valve decellularization with NaOH-based vs detergent process: preliminary in vitro and in vivo assessments. AB - BACKGROUND: Glutaraldehyde fixed xenogeneic heart valve prosthesis are hindered by calcification and lack of growth potential. The aim of tissue decellularization is to remove tissue antigenicity, avoiding the use of glutaraldehyde and improve valve integration with low inflammation and host cell recolonization. In this preliminary study, we investigated the efficacy of a NaOH based process for decellularization and biocompatibility improvement of porcine pulmonary heart valves in comparison to a detergent-based process (SDS-SDC0, 5%). METHODS: Native cryopreserved porcine pulmonary heart valves were treated with detergent and NaOH-based processes. Decellularization was assessed by Hematoxylin and eosin/DAPI/alpha-gal/SLA-I staining and DNA quantification of native and processed leaflets, walls and muscles. Elongation stress test investigated mechanical integrity of leaflets and walls (n = 3 tests/valve component) of valves in the native and treated groups (n = 4/group). Biochemical integrity (collagen/elastin/glycosaminoglycans content) of leaflet-wall and muscle of the valves (n = 4/group) was assessed and compared between groups with trichrome staining (Sirius Red/Miller/Alcian blue). Secondly, a preliminary in vivo study assessed biocompatibility (CD3 and CD68 immunostaining) and remodeling (Hematoxylin and eosin/CD31 and ASMA immunofluorescent staining) of NaOH processed valves implanted in orthotopic position in young Landrace pigs, at 1 (n = 1) and 3 months (n = 2). RESULTS: Decellularization was better achieved with the NaOH-based process (92% vs 69% DNA reduction in the wall). Both treatments did not significantly alter mechanical properties. The detergent-based process induced a significant loss of glycosaminoglycans (p < 0,05). In vivo, explanted valves exhibited normal morphology without any sign of graft dilatation, degeneration or rejection. Low inflammation was noticed at one and three months follow-up (1,8 +/- 3,03 and 0,9836 +/- 1,3605 CD3 cells/0,12 mm2 in the leaflets). In one animal, at three months we documented minimal calcification in the area of sinus leaflet and in one, microthrombi formation on the leaflet surface at 1 month. The endoluminal side of the valves showed partial reendothelialization. CONCLUSIONS: NaOH-based process offers better porcine pulmonary valve decellularization than the detergent process. In vivo, the NaOH processed valves showed low inflammatory response at 3 months and partial recellularization. Regarding additional property of securing, this treatment should be considered for the new generation of heart valves prosthesis. Graphical abstract of the study. PMID- 29695260 TI - A single-arm pilot study of guided self-help treatment based cognitive behavioral therapy for bulimia nervosa in Japanese clinical settings. AB - OBJECTIVE: Guided self-help treatments based on cognitive behavioral therapy (CBT GSH) are regarded as a first-line effective treatment for bulimia nervosa (BN). With limited application for CBT-GSH in Japanese clinical settings, we conducted a single arm pilot study in order to confirm the acceptability and availability of CBT-GSH in Japan. RESULTS: 25 women with BN received 16-20 sessions of face-to face CBT-GSH. Primary outcomes were the completion rate of intervention and abstinence rates from objective bingeing and purging as assessed by the Eating Disorder Examination. Secondary outcomes were other self-report measurements of the frequency of bingeing and purging, and characteristic psychopathologies of eating disorders. Assessments were conducted before CBT as baseline as well as after CBT. 92% (23/25) of the participants completed the CBT sessions. After CBT GSH, 40% (10/25) of the participants (intention-to-treat) achieved symptom abstinence. The mean binge and purge episodes during the previous 28 days improved from 21.88 to 10.96 (50% reduction) and from 22.44 to 10.88 (52% reduction), each (before CBT-GSH to after CBT-GSH), and the within-group effect sizes were medium (Cohen's d = 0.67, 0.65, each). Our study provided a preliminary evidence about the feasibility of CBT-GSH in Japanese clinical settings for the future. Trial registration This study was registered retrospectively in the national UMIN Clinical Trials Registry on July 10, 2013 (registration ID: UMIN000011120). PMID- 29695261 TI - Sticky small target: an effective sampling tool for tsetse fly Glossina fuscipes fuscipes Newstead, 1910. AB - BACKGROUND: Small targets comprising panels of blue and insecticide-treated black netting material each 0.25 * 0.25 m have been shown to attract and kill Glossina fuscipes fuscipes Newstead, 1910 (Diptera: Glossinidae) thereby reducing its population density by over 90% in field trials. However, their attractive ability has not been fully exploited for sampling purposes. Therefore, in this study we assessed the effectiveness of using sticky small targets as sampling tools for G. f. fuscipes in western Kenya. We also determined the influence of colour on the landing response of female and male flies on sticky small targets. METHODS: Using a series of randomised block experiments, the numbers of tsetse flies caught with sticky small targets were compared with those caught with biconical traps. A negative binomial regression was used to model fly catches. Odds ratios as measures of association between the landing response on the blue or black panel of the sticky small target and the sex of flies were obtained from a multiple logistic regression. RESULTS: The results showed that sticky small targets caught 13.5 and 3.6 times more female and male tsetse flies than biconical traps (Z = 9.551, P < 0.0001 and Z = 5.978, P < 0.0001, respectively). Females had a 1.7 times likelihood of landing on the black panel than males (Z = 2.25, P = 0.025). CONCLUSION: This study suggests that sticky small targets are an effective sampling tool for G. f. fuscipes. Therefore, we recommend the use of sticky small targets as an alternative to biconical traps for observational and experimental investigations of G. f. fuscipes. PMID- 29695262 TI - Hypericum perforatum to improve post-operative Pain Outcome after monosegmental Spinal microdiscectomy (HYPOS): a study protocol for a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Spinal disc herniation is a frequently occurring degenerative disease of the spine. Many patients undergoing surgery suffer from radicular pain, known as memory pain, beginning from the third post-operative day. This results in the prescription of high-dose opioid medications. In homeopathy, Hypericum perforatum is known as a remedy for unbearable, shooting or jabbing pain especially when neural damage is involved. Reduction of pain after application of H. perforatum has been observed in previous studies. This study is aimed to investigate whether homeopathic H. perforatum in a potentisation of C200 leads to the reduction of post-operative pain and a decrease of pain medication compared to placebo. METHODS/DESIGN: This is a monocentric, double-blind, randomised placebo controlled trial conducted at the Department of Neurosurgery at the Community Hospital Herdecke, Germany. One hundred study participants are being recruited from inpatients undergoing elective, monosegmental, lumbar microdiscectomy surgery. Patients are randomly allocated to receive homeopathic treatment or placebo in addition to usual pain management after surgery. The primary clinical outcome is pain reduction after 3 days of inpatient care as measured by pain reduction of subjective pain on a 100-mm Visual Analogue Scale (VAS) at the third post-operative day. Statistical analysis will be carried out by means of a covariance model with adjustment for baseline values and patient expectation for all randomised patients. DISCUSSION: This study is the first trial of classical homeopathy that will evaluate the efficacy of homeopathic H. perforatum after monosegmental spinal microdiscectomy. We intend to clarify the potential of homoeopathic H. perforatum to reduce surgery-associated pain. TRIAL REGISTRATION: German Clinical Trials Register, ID: DRKS00007913 . Registered on 17 October 2014. EudraCT - Nr: 2013-001383-31. Data sets from the German Clinical Trials Register (DRKS, Deutsches Register Klinischer Studien) are updated every 4 weeks automatically to the International Clinical Trials Registry Platform of World Health Organisation: http://apps.who.int/trialsearch/ . Responsibilities Sponsor: Witten/Herdecke University Alfred-Herrhausen-Strabetae 50 58,448 Witten Deputy of the sponsor: Dr. Wolfgang Eglmeier (Head of Centre for Clinical Trials Witten/Herdecke) Alfred-Herrhausen-Strabetae 50 58,448 Witten E-mail: wolfgang.eglmeier@uni-wh.de Principal investigator: Prof. Dr. med. Wolfram Scharbrodt Community Hospital Herdecke Department for Neurosurgery Gerhard-Kienle Weg 4 58,313 Herdecke w.scharbrodt@gemeinschaftskrankenhaus.de Project coordination: Christa Raak Faculty for Health (Department for Integrative and Anthroposophic Medicine) University Witten/Herdecke gGmbh Gerhard-Kienle-Weg 4 58,313 Herdecke christa.raak@uni-wh.de Project manager/data analysis/biometry: Prof. Dr. Thomas Ostermann Faculty for Health (Department for Psychology and Psychotherapy) University Witten/Herdecke gGmbh Alfred-Herrhausen-Strabetae 50 58,448 Witten thomas.ostermann@uni-wh.de. PMID- 29695263 TI - DNA barcoding of morphologically characterized mosquitoes belonging to the subfamily Culicinae from Sri Lanka. AB - BACKGROUND: Vectors of mosquito-borne diseases in Sri Lanka, except for malaria, belong to the subfamily Culicinae, which includes nearly 84% of the mosquito fauna of the country. Hence, accurate and precise species identification of culicine mosquitoes is a crucial factor in implementing effective vector control strategies. During the present study, a combined effort using morphology and DNA barcoding was made to characterize mosquitoes of the subfamily Culicinae for the first time from nine districts of Sri Lanka. Cytochrome c oxidase subunit 1 (cox1) gene from the mitochondrial genome and the internal transcribed spacer 2 (ITS2) region from the nuclear ribosomal DNA were used for molecular characterization. RESULTS: According to morphological identification, the field collected adult mosquitoes belonged to 5 genera and 14 species, i.e. Aedes aegypti, Ae. albopictus, Ae. pallidostriatus, Aedes sp. 1, Armigeres sp. 1, Culex bitaeniorhynchus, Cx. fuscocephala, Cx. gelidus, Cx. pseudovishnui, Cx. quinquefasciatus, Cx. tritaeniorhynchus, Cx. whitmorei, Mansonia uniformis and Mimomyia chamberlaini. Molecular analyses of 62 cox1 and 36 ITS2 sequences were exclusively comparable with the morphological identifications of all the species except for Ae. pallidostriatus and Aedes sp. 1. Although the species identification of Armigeres sp. 1 specimens using morphological features was not possible during this study, DNA barcodes of the specimens matched 100% with the publicly available Ar. subalbatus sequences, giving their species status. Analysis of all the cox1 sequences (14 clades supported by strong bootstrap value in the Neighbor-Joining tree and interspecific distances of > 3%) showed the presence of 14 different species. This is the first available DNA sequence in the GenBank records for morphologically identified Ae. pallidostriatus. Aedes sp. 1 could not be identified morphologically or by publicly available sequences. Aedes aegypti, Ae. albopictus and all Culex species reported during the current study are vectors of human diseases. All these vector species showed comparatively high diversity. CONCLUSIONS: The current study reflects the significance of integrated systematic approach and use of cox1 and ITS genetic markers in mosquito taxonomy. Results of DNA barcoding were comparable with morphological identifications and, more importantly, DNA barcoding could accurately identify the species in the instances where the traditional morphological identification failed due to indistinguishable characters of damaged specimens and the presence of subspecies. PMID- 29695264 TI - Improved dietary diversity of school adolescent girls in the context of urban Northwest Ethiopia: 2017. AB - BACKGROUND: Undiversified diet increases the vulnerability of adolescents for different nutritional problems. Therefore, this study assessed dietary and associated factors among school adolescent girls in Gondar city, northwest Ethiopia. METHODS: A cross-sectional study was conducted from March to April 2017. Simple random sampling technique was used to select 778 adolescent school girls. A structured questionnaire was used to collect data. Multivariable logistic regression analysis was fitted to identify significant factors of dietary diversity. Adjusted Odds Ratio (AOR) with 95% confidence interval was used to show the strength of association, while a P-value< 0.05 of was used to declare the significance of association. RESULTS: This finding indicated that adolescent girls who met minimum dietary diversity with were 75.4% (95%CI (72.3, 78.6). School type (AOR = 3.17, 95%CI: 1.90, 5.28) and residence (AOR = 2.0, 95%CI: 0.84, 3.01) were significantly associated with adequate dietary diversity. CONCLUSIONS: Dietary practice of adolescent girls is good in Gondar City Administration. School type and residence of adolescents were significantly associated with minimum dietary diversity. Thus, Special attention needs to be paid on government school and rural adolescents to improve the intake of variety diet. PMID- 29695265 TI - Antimicrobial resistance among clinically relevant bacterial isolates in Accra: a retrospective study. AB - OBJECTIVE: The aim of this study was to determine the antimicrobial resistance pattern of bacterial isolates from different specimens at various hospitals and private diagnostic service laboratories in Ghana. RESULTS: A retrospective data of culture and sensitivity test results from 2016 were extracted from the microbiology record book of six laboratories in Accra, Ghana. The data included type of clinical specimen, sex of patient, name of bacterial isolate and antibiotic resistance profile. A total of 16.6% (n = 10,237) resistant isolates were obtained, however, the proportions of resistant isolates varied significantly between laboratories. High resistance towards tetracycline, ampicillin, cotrimoxazole and cephalosporins, but low towards amoxiclav and aminoglycosides, was observed. This study identified E. coli and Staphylococcus species as the major resistant bacteria from clinical specimen in Accra and the highest prevalence of the isolates was found in urine specimens in all six laboratories (69.1%, n = 204; 52.6%, n = 36; 52.3%, n = 350; 37.9%, n = 298; 53%, n = 219; 62.1%, n = 594) and in female patients (81.4, 50 and 69.5%). Regular surveillance and local susceptibility pattern analysis is extremely important in selecting the most appropriate and effective antibiotic for the treatment of bacterial infections. PMID- 29695266 TI - Three-dimensional reconstruction of root shape in the moth orchid Phalaenopsis sp.: a biomimicry methodology for robotic applications. AB - OBJECTIVE: Within the field of biorobotics, an emerging branch is plant-inspired robotics. Some effort exists in particular towards the production of digging robots that mimic roots; for these, a deeper comprehension of the role of root tip geometry in excavation would be highly desirable. Here we demonstrate a photogrammetry-based pipeline for the production of computer and manufactured replicas of moth orchid root apexes. RESULTS: Our methods yields faithful root reproductions. This can be used either for quantitative studies aimed at comparing different root morphologies, or directly to implement a particular root shape in a biorobot. PMID- 29695267 TI - Evaluation of the "Foundations in Knowledge Translation" training initiative: preparing end users to practice KT. AB - BACKGROUND: Current knowledge translation (KT) training initiatives are primarily focused on preparing researchers to conduct KT research rather than on teaching KT practice to end users. Furthermore, training initiatives that focus on KT practice have not been rigorously evaluated and have focused on assessing short term outcomes and participant satisfaction only. Thus, there is a need for longitudinal training evaluations that assess the sustainability of training outcomes and contextual factors that may influence outcomes. METHODS: We evaluated the KT training initiative "Foundations in KT" using a mixed-methods longitudinal design. "Foundations in KT" provided training in KT practice and included three tailored in-person workshops, coaching, and an online platform for training materials and knowledge exchange. Two cohorts were included in the study (62 participants, including 46 "Foundations in KT" participants from 16 project teams and 16 decision-maker partners). Participants completed self-report questionnaires, focus groups, and interviews at baseline and at 6, 12, 18, and 24 months after the first workshop. RESULTS: Participant-level outcomes include survey results which indicated that participants' self-efficacy in evidence-based practice (F(1,8.9) = 23.7, p = 0.001, n = 45), KT activities (F(1,23.9) = 43.2, p < 0.001, n = 45), and using evidence to inform practice increased over time (F(1,11.0) = 6.0, p = 0.03, n = 45). Interviews and focus groups illustrated that participants' understanding of and confidence in using KT increased from baseline to 24 months after the workshop. Interviews and focus groups suggested that the training initiative helped participants achieve their KT project objectives, plan their projects, and solve problems over time. Contextual factors include teams with high self-reported organizational capacity and commitment to implement at the start of their project had buy-in from upper management that resulted in secured funding and resources for their project. Training initiative outcomes include participants who applied the KT knowledge and skills they learned to other projects by sharing their knowledge informally with coworkers. Sustained spread of KT practice was observed with five teams at 24 months. CONCLUSIONS: We completed a longitudinal evaluation of a KT training initiative. Positive participant outcomes were sustained until 24 months after the initial workshop. Given the emphasis on implementing evidence and the need to train implementers, these findings are promising for future KT training. PMID- 29695268 TI - Scaling up ART adherence clubs in the public sector health system in the Western Cape, South Africa: a study of the institutionalisation of a pilot innovation. AB - BACKGROUND: In 2011, a decision was made to scale up a pilot innovation involving 'adherence clubs' as a form of differentiated care for HIV positive people in the public sector antiretroviral therapy programme in the Western Cape Province of South Africa. In 2016 we were involved in the qualitative aspect of an evaluation of the adherence club model, the overall objective of which was to assess the health outcomes for patients accessing clubs through epidemiological analysis, and to conduct a health systems analysis to evaluate how the model of care performed at scale. In this paper we adopt a complex adaptive systems lens to analyse planned organisational change through intervention in a state health system. We explore the challenges associated with taking to scale a pilot that began as a relatively simple innovation by a non-governmental organisation. RESULTS: Our analysis reveals how a programme initially representing a simple, unitary system in terms of management and clinical governance had evolved into a complex, differentiated care system. An innovation that was assessed as an excellent idea and received political backing, worked well whilst supported on a small scale. However, as scaling up progressed, challenges have emerged at the same time as support has waned. We identified a 'tipping point' at which the system was more likely to fail, as vulnerabilities magnified and the capacity for adaptation was exceeded. Yet the study also revealed the impressive capacity that a health system can have for catalysing novel approaches. CONCLUSIONS: We argue that innovation in largescale, complex programmes in health systems is a continuous process that requires ongoing support and attention to new innovation as challenges emerge. Rapid scaling up is also likely to require recourse to further resources, and a culture of iterative learning to address emerging challenges and mitigate complex system errors. These are necessary steps to the future success of adherence clubs as a cornerstone of differentiated care. Further research is needed to assess the equity and quality outcomes of a differentiated care model and to ensure the inclusive distribution of the benefits to all categories of people living with HIV. PMID- 29695269 TI - Effect of a single intra-articular injection of bupivacaine on synovial fluid prostaglandin E2 concentrations in normal canine stifles. AB - OBJECTIVE: To identify if synovial fluid prostaglandin E2 increases in response to a single intra-articular dose of bupivacaine in the normal canine stifle. RESULTS: There were no significant differences in synovial fluid prostaglandin E2 (PGE2) concentrations between treatment groups or over time within bupivacaine or saline groups. Samples requiring >= 3 arthrocentesis attempts had significantly higher PGE2 concentrations compared to samples requiring 1 or 2 attempts. Following correction for number of arthrocentesis attempts, PGE2 concentrations were significantly higher than baseline at 24 and 48 h in the bupivacaine group; however there were no significant differences between the bupivacaine and saline groups. In normal dogs, a single bupivacaine injection did not cause significant synovial inflammation, as measured by PGE2 concentrations, compared to saline controls. Future research should minimize aspiration attempts and include evaluation of the synovial response to bupivacaine in clinical cases with joint disease. PMID- 29695270 TI - Distinct T-helper cell responses to Staphylococcus aureus bacteremia reflect immunologic comorbidities and correlate with mortality. AB - BACKGROUND: The dysregulated host immune response that defines sepsis varies as a function of both the immune status of the host and the distinct nature of the pathogen. The degree to which immunocompromising comorbidities or immunosuppressive medications affect the immune response to infection is poorly understood because these patients are often excluded from studies about septic immunity. The objectives of this study were to determine the immune response to a single pathogen (Staphylococcus aureus) among a diverse case mix of patients and to determine whether comorbidities affect immune and clinical outcomes. METHODS: Blood samples were drawn from 95 adult inpatients at multiple time points after the first positive S. aureus blood culture. Cox proportional hazards modeling was used to determine the associations between admission neutrophil counts, admission lymphocyte counts, cytokine levels, and 90-day mortality. A nested case-control flow cytometric analysis was conducted to determine T-helper type 1 (Th1), Th2, Th17, and regulatory T-cell (Treg) subsets among a subgroup of 28 patients. In a secondary analysis, we categorized patients as either having immunocompromising disorders (human immunodeficiency virus and hematologic malignancies), receiving immunosuppressive medications, or being not immunocompromised. RESULTS: Higher neutrophil-to-lymphocyte count ratios and higher Th17 cytokine responses relative to Th1 cytokine responses early after infection were independently associated with mortality and did not depend on the immune state of the patient (HR 1.93, 95% CI 1.17-3.17, p = 0.01; and HR 1.13, 95% CI 1.01-1.27, p = 0.03, respectively). On the basis of flow cytometric analysis of CD4 T-helper subsets, an increasing Th17/Treg response over the course of the infection was most strongly associated with increased mortality (HR 4.41, 95% CI 1.69-11.5, p < 0.01). This type of immune response was most common among patients who were not immunocompromised. In contrast, among immunocompromised patients who died, a decreasing Th1/Treg response was most common. CONCLUSIONS: The association of both increased Th17 responses and increased neutrophil counts relative to lymphocyte counts with mortality suggests that an overwhelming inflammatory response is detrimental. However, the differential responses of patients according to immune state suggest that immune status is an important clinical indicator that should be accounted for in the management of septic patients, as well as in the development of novel immunomodulatory therapies. PMID- 29695271 TI - Essential oils of Citrus aurantifolia, Anthemis nobile and Lavandula officinalis: in vitro anthelmintic activities against Haemonchus contortus. AB - BACKGROUND: Infections of sheep with gastrointestinal parasites, especially Haemonchus contortus, have caused serious losses in livestock production, particularly after the emergence of resistance to conventional anthelmintics. The search for new anthelmintic agents, especially those of botanical origin, has grown substantially due to the perspective of less contamination of meat and milk, as well as other advantages related to their cost and accessibility in less developed countries. The aim of this study was to evaluate the in vitro anthelmintic activity of essential oils of the plant species Citrus aurantifolia, Anthemis nobile and Lavandula officinalis against the main developmental stages of the parasite H. contortus. RESULTS: Plant species were selected based on substantial ethnopharmacological information. Analysis of the composition of each oil by gas chromatography coupled to mass spectrometry (GC-MS) demonstrated the presence of limonene (56.37%), isobutyl angelate (29.26%) and linalool acetate (35.97%) as the major constituents in C. aurantifolia, A. nobile and L. officinalis, respectively. Different concentrations of each oil were tested in vitro for their capacity to inhibit egg hatching (EHT), larval development (LDT) and adult worm motility (AWMT) using a multidrug-resistant strain of H. contortus (Embrapa 2010). The IC50 values obtained for the oils of C. aurantifolia, A. nobile and L. officinalis were 0.694, 0.842 and 0.316 mg/ml in the EHT and 0.044, 0.117 and 0.280 mg/ml in the LDT, respectively. The three oils were able to inhibit adult worm motility completely within the first 8-12 h of observation in the AWMT. CONCLUSIONS: The present results demonstrate significant anthelmintic activity of the three oils against the different developmental stages of H. contortus. Furthermore, this study is of ethnopharmacological importance by validating the anthelmintic activity of the oils studied. Although new experiments are necessary, these data contribute to the development of pharmaceutical-veterinary products for sheep farming by opening up new therapeutic possibilities against gastrointestinal infections caused by H. contortus. PMID- 29695272 TI - The influence of the number of screws and additional surgical procedures on outcome in hallux valgus treatment. AB - BACKGROUND: Surgical treatment of hallux valgus (HV) is one of the major flagships of orthopedic surgeons. Due to relatively unsatisfactory radiological and clinical outcomes, the search for the best surgical technique and causes for unsatisfactory outcomes continues. The objective was to investigate associations of the number of screws and additional surgical techniques for HV with radiological and clinical outcome after reversed L-shaped osteotomy (ReveL). METHODS: A retrospective cohort study of adults from a single University Hospital between 2004 and 2013 was performed. The primary exposure was the number of screws (one vs two) used for osseous fixation after ReveL. The secondary exposure was an additional surgical technique for HV (e.g., Akin osteotomy). The primary outcome was a radiological recurrence of HV (HV angle (HVA) > 15 degrees ) at last follow-up. The secondary outcomes were limited patient satisfaction, complication, revision surgery, and elective hardware removal. Odds ratio (OR) and 95% confidence interval (CI) were estimated by logistic regression adjusting for confounders. RESULTS: The recurrence was 45% less likely with the use of one screw, independent of age, sex, additional technique, and preoperative HVA (odds ratio (ORadjusted) = 0.55 [95% CI 0.30-0.98], p = 0.043). The recurrence was 162% more likely with an additional surgical technique for HV (ORadjusted = 2.62 [1.24 5.52], p = 0.011). CONCLUSION: In ReveL for HV, a single screw (instead of two screws) may be sufficient enough for a similar or even better outcome, which may also reduce costs. Additional surgical procedures for HV may be refrained from if possible. Due to limitations of a retrospective study, results may need validation with clinical trials. PMID- 29695273 TI - Stereotactic body radiotherapy for central lung tumors, yes we can! AB - BACKGROUND: SBRT is standard therapy for early stage lung cancer. Toxicity in central tumors has been a concern. RTOG 0813 showed that central SBRT is safe and effective. We report our experience with central SBRT. METHODS: We reviewed the records of patients treated with SBRT for central lung tumors (< 2 cm of the carina). Patients included primary lung cancer and recurrence following surgery and? or conventional radiotherapy. All patients underwent 4DCT simulation and treatment planning was done with IMRT or VMAT techniques. Dose to the PTV was prescribed to the 95% isodose line. RESULTS: Seventy patients, between 5/09 and 4/13, were treated. Patients had early non-small cell lung cancer (n = 13) or locally recurrent lung cancer (n = 29) and pulmonary oligometastases (n = 28). Fifty-seven percent of the patients received BED of 132 with a schedule of 60Gy in 12 Gy fractions. Median follow up time was 18.3 months, 4/70 patients experienced local failure (6%). Median OS for the whole cohort was 4.6 years (CI 3-7 years). Ten patients had grade 1-2 radiation pneumonitis. One patient developed fatal bronchial bleeding. CONCLUSIONS: SBRT for central tumors is safe and effective in patients with central disease, reiradiation, recurrence following surgery and in oligometastes. PMID- 29695274 TI - A new scale for the evaluation of clinical practice guidelines applicability: development and appraisal. AB - BACKGROUND: This study aimed to develop the clinical practice guidelines applicability evaluation (CPGAE-V1.0) scale and to evaluate its validity and reliability. METHODS: One hundred fifty assessors were invited to rate two rounds of importance scoring of the applicability indicators by using the 5-point Likert scale. Approved indicators formed the CPGAE-V1.0 scale, consisting of 19 items, arranged into 4 domains. We enrolled eligible clinicians from 8 institutions to evaluate 9 clinical practice guidelines using the CPGAE-V1.0 scale. Content validity, construct validity, internal reliability, intra-rater reliability, and responsiveness were analyzed. RESULTS: A total of 220 clinicians participated, and the response rate was 98.6% (217/220). The CPGAE-V1.0 scale had favorable content validity. The four-factor model produced acceptable fit indices. The scale had an excellent internal consistency and item discrimination. It could identify the degree of applicability of the different dimensions between different guidelines. In all domains, 77.8% (7/9) of CPGs in the minimum-scoring domain were concentrated in the "coordination of support" domain. CONCLUSIONS: The CPGAE-V1.0 scale is a valid and reliable instrument for measuring the applicability of CPG. PMID- 29695275 TI - Ectopic thymoma in the paratracheal region of the middle mediastinum: a rare case report and literature review. AB - BACKGROUND: Thymomas generally arise from the thymus in the anterior mediastinum. Ectopic thymomas arising in the middle mediastinum are rare. We present a case of a thymoma arising from the ectopic thymic tissue in the right paratracheal region. CASE PRESENTATION: The patient was a 67-year-old male who underwent an enhanced-computed tomography examination as preoperative staging for colon cancer. A 20-mm nodule in the right paratracheal region was found incidentally. Fluorodeoxyglucose (FDG) accumulation was detected in this solitary nodule by FDG positron emission tomography, mimicking an enlarged, possibly malignant lymph node. The tumor was removed by thoracoscopic surgery, and a postoperative pathological diagnosis of type AB thymoma was made. Foci of ectopic thymic tissues were found adjacent to the thymoma. The patient was disease-free and without recurrence 2 years postoperatively. CONCLUSIONS: Including the present case, 13 cases of ectopic paratracheal thymoma have been reported in the English literature, all of which were found on the right side of the paratracheal region. Although ectopic thymomas in the paratracheal region are rare, thymomas may be considered as a differential diagnosis for a paratracheal nodule. PMID- 29695276 TI - India's NCD strategy in the SDG era: are there early signs of a paradigm shift? AB - BACKGROUND: The Sustainable Development Goals (SDGs) are seen in most corners as the embodiment of a more inclusive and holistic development approach, key to addressing the numerous and urgent challenges the world faces. In the health realm, a true SDG approach will require a five-fold paradigm shift according to Buse and Hawkes. This article explores whether early traces of this paradigm shift can already be witnessed in the Indian context, focusing on Non Communicable Diseases (NCDs) more in particular. DISCUSSION: By now, NCDs make up a large health burden in India, both individually and on the health system. Inspired by an SDG vision, tackling NCDs will require a comprehensive approach rooted in preventive, curative and rehabilitative services. In India, some early momentum in this respect can already be witnessed, certainly in addressing the first two challenges identified by Buse and Hawkes, leadership and intersectoral coherence, and a shift from treatment to prevention. A central plan addressing health through an inter-sectoral approach has shaped the trajectory so far, moving away from silos to engagement with sectors beyond health. New guidelines addressing comprehensive primary healthcare propose a community outreach and preventive approach for NCDs. At a broader level, NCD prevention is also closely linked to tackling the so called "commercial determinants of health" and will require among others strong (central and state level) regulation, teaming up with global advocacy networks and capitalizing on global frameworks, where they exist. Strong political leadership will be indispensable for this, and is according to Buse and Hawkes closely linked to seeing health as a right and the government as accountable when it comes to providing for the right to health through its policies and actions. CONCLUSION: National stewardship will thus be key, via a more adaptive network governance structure with the central level coordinating with the state level to ensure implementation, while also engaging with other stakeholders, sectors, the private sector and civil society. As one can expect, networked governance, necessary for the battle against NCDs, is a work in progress in India. In sum, some of the early (paradigm shift) signs are encouraging, but by and large it is still too early to assess whether a real paradigm shift has taken place. PMID- 29695277 TI - Challenges in the management of cardiovascular emergencies in Sub-Saharan Africa: a case report of acute heart failure complicating infective endocarditis in a semi-urban setting in Cameroon. AB - BACKGROUND: Infective endocarditis is a deadly disease if not promptly treated with antibiotics either in association with cardiac surgery or not. Cardiac complications are the most common complications seen in infective endocarditis. Heart failure remains the most common cause of mortality and the most common indication for cardiac surgery in patients with infective endocarditis which is increasingly available in resource limited settings. CASE PRESENTATION: We report a case of native valve infective endocarditis of the aortic valve in a 27-year old female in a semi-urban setting in Cameroon complicated by severe aortic valve regurgitation and heart failure. She presented with a 2 month history of fever and a 2 weeks history of rapidly worsening shortness of breath. Emergency cardiac surgery was indicated which unfortunately could not be performed leading to the death of the patient. CONCLUSIONS: In spite of improvement in availability of diagnostic and therapeutic modalities for cardiovascular emergencies, affordability is still a challenge. Universal health coverage is advocated else the ravages of premature mortality from cardiovascular diseases may continue to remain unchecked in Sub-Saharan Africa. PMID- 29695278 TI - Global landscape assessment of screening technologies for medicine quality assurance: stakeholder perceptions and practices from ten countries. AB - BACKGROUND: The spread of substandard and falsified (SF) medical products constitutes a growing global public health concern. Some countries use portable, handheld screening technologies (STs) in the field to accelerate detection of SF medicines and reduce the number of medicine samples that undergo costly and time consuming confirmatory analysis. METHODS: A multi-country, multi-stakeholder landscape assessment utilizing qualitative methodology was used to examine practices and perceptions related to the use of STs. Qualitative interview guides were designed using the results of a literature review and comprised of open ended questions with the study participants, who were from national medicine regulatory authorities, pharmaceutical manufacturers, pharmacies, and distributors. Ten geographically and economically diverse countries were selected: Argentina, China, Egypt, India, Jordan, Mexico, Nigeria, Philippines, the United States, and Zimbabwe. Of the completed 53 interviews, 32 were in person, 16 were phone interviews, and 5 were via written questionnaires. RESULTS: Data analysis shows a wide variation in understanding and usage of STs in different sectors. Virtually all of the study participants indicated a lack of objective, accessible information on STs to advise them on what technologies would be beneficial for their needs. Study participants also described their ideal capabilities of the next generation of STs, including shareable spectral libraries, lower acquisition costs, lesser training requirements, and in-country maintenance and technical support. CONCLUSION: The results and recommendations presented in this article can be used to help regulators communicate and justify their needs to acquire and invest in new STs. There is a need for additional standardized, trustworthy and scientifically sound evaluations of STs, and to support regulators to effectively deploy the most promising technologies. ST manufacturers can take into account some of the limitations of the technologies the interviewees identified in this article, such as a dearth of technologies, which provide quantitative information about the active ingredient, and take steps to address them to better serve their customers. These results and recommendations, can catalyze research and actionable interventions into the development, review, application, and use of STs. PMID- 29695279 TI - MutationalPatterns: comprehensive genome-wide analysis of mutational processes. AB - BACKGROUND: Base substitution catalogues represent historical records of mutational processes that have been active in a cell. Such processes can be distinguished by various characteristics, like mutation type, sequence context, transcriptional and replicative strand bias, genomic distribution and association with (epi)-genomic features. RESULTS: We have created MutationalPatterns, an R/Bioconductor package that allows researchers to characterize a broad range of patterns in base substitution catalogues to dissect the underlying molecular mechanisms. Furthermore, it offers an efficient method to quantify the contribution of known mutational signatures within single samples. This analysis can be used to determine whether certain DNA repair mechanisms are perturbed and to further characterize the processes underlying known mutational signatures. CONCLUSIONS: MutationalPatterns allows for easy characterization and visualization of mutational patterns. These analyses willsupport fundamental research into mutational mechanisms and may ultimately improve cancer diagnosis and treatment strategies. MutationalPatterns is freely available at http://bioconductor.org/packages/MutationalPatterns . PMID- 29695280 TI - Shaping neuroplasticity by using powered exoskeletons in patients with stroke: a randomized clinical trial. AB - BACKGROUND: The use of neurorobotic devices may improve gait recovery by entraining specific brain plasticity mechanisms, which may be a key issue for successful rehabilitation using such approach. We assessed whether the wearable exoskeleton, EksoTM, could get higher gait performance than conventional overground gait training (OGT) in patients with hemiparesis due to stroke in a chronic phase, and foster the recovery of specific brain plasticity mechanisms. METHODS: We enrolled forty patients in a prospective, pre-post, randomized clinical study. Twenty patients underwent EksoTM gait training (EGT) (45 min/session, five times/week), in addition to overground gait therapy, whilst 20 patients practiced an OGT of the same duration. All individuals were evaluated about gait performance (10 m walking test), gait cycle, muscle activation pattern (by recording surface electromyography from lower limb muscles), frontoparietal effective connectivity (FPEC) by using EEG, cortico-spinal excitability (CSE), and sensory-motor integration (SMI) from both primary motor areas by using Transcranial Magnetic Stimulation paradigm before and after the gait training. RESULTS: A significant effect size was found in the EGT-induced improvement in the 10 m walking test (d = 0.9, p < 0.001), CSE in the affected side (d = 0.7, p = 0.001), SMI in the affected side (d = 0.5, p = 0.03), overall gait quality (d = 0.8, p = 0.001), hip and knee muscle activation (d = 0.8, p = 0.001), and FPEC (d = 0.8, p = 0.001). The strengthening of FPEC (r = 0.601, p < 0.001), the increase of SMI in the affected side (r = 0.554, p < 0.001), and the decrease of SMI in the unaffected side (r = - 0.540, p < 0.001) were the most important factors correlated with the clinical improvement. CONCLUSIONS: EksoTM gait training seems promising in gait rehabilitation for post-stroke patients, besides OGT. Our study proposes a putative neurophysiological basis supporting EksoTM after-effects. This knowledge may be useful to plan highly patient-tailored gait rehabilitation protocols. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03162263 . PMID- 29695281 TI - Quantitative study of medicinal plants used by the communities residing in Koh-e Safaid Range, northern Pakistani-Afghan borders. AB - BACKGROUND: The residents of remote areas mostly depend on folk knowledge of medicinal plants to cure different ailments. The present study was carried out to document and analyze traditional use regarding the medicinal plants among communities residing in Koh-e-Safaid Range northern Pakistani-Afghan border. METHODS: A purposive sampling method was used for the selection of informants, and information regarding the ethnomedicinal use of plants was collected through semi-structured interviews. The collected data was analyzed through quantitative indices viz. relative frequency citation, use value, and family use value. The conservation status of medicinal plants was enumerated with the help of International Union for Conservation of Nature Red List Categories and Criteria (2001). Plant samples were deposited at the Herbarium of Botany Department, University of Peshawar for future reference. RESULTS: One hundred eight informants including 72 male and 36 female were interviewed. The informants provided information about 92 plants species used in the treatment of 53 ailments. The informant reported maximum number of species used for the treatment of diabetes (16 species), followed by carminatives (12 species), laxatives (11 species), antiseptics (11 species), for cough (10 species), to treat hepatitis (9 species), for curing diarrhea (7 species), and to cure ulcers (7 species), etc. Decoction (37 species, i.e., 40%) was the common method of recipe preparation. Most familiar medicinal plants were Withania coagulans, Caralluma tuberculata, and Artemisia absinthium with relative frequency (0.96), (0.90), and (0.86), respectively. The relative importance of Withania coagulans was highest (1.63) followed by Artemisia absinthium (1.34), Caralluma tuberculata (1.20), Cassia fistula (1.10), Thymus linearis (1.06), etc. This study allows identification of novel uses of plants. Abies pindrow, Artemisia scoparia, Nannorrhops ritchiana, Salvia reflexa, and Vincetoxicum cardiostephanum have not been reported previously for their medicinal importance. The study also highlights many medicinal plants used to treat chronic metabolic conditions in patients with diabetes. CONCLUSIONS: The folk knowledge of medicinal plants species of Koh-e Safaid Range was unexplored. We, for the first time, conducted this quantitative study in the area to document medicinal plants uses, to preserve traditional knowledge, and also to motivate the local residents against the vanishing wealth of traditional knowledge of medicinal flora. The vast use of medicinal plants reported shows the significance of traditional herbal preparations among tribal people of the area for their health care. Knowledge about the medicinal use of plants is rapidly disappearing in the area as a new generation is unwilling to take interest in medicinal plant use, and the knowledgeable persons keep their knowledge a secret. Thus, the indigenous use of plants needs conservational strategies and further investigation for better utilization of natural resources. PMID- 29695283 TI - Survey of farmers' knowledge of cassava mosaic disease and their preferences for cassava cultivars in three agro-ecological zones in Benin. AB - BACKGROUND: Cassava is an important crop in Africa that is widely cultivated for its starchy tuberous root, which constitutes a major source of dietary carbohydrates. Cassava mosaic disease (CMD) is the most devastating disease affecting cassava in Africa and causes enormous losses in yield. In Benin, specifically, cultivars resistant to CMD are not commonly planted, and even when CMD is observed in fields, farmers do not implement control measures, presumably because they lack proper knowledge and training. Our study aimed to evaluate farmers' knowledge of CMD to determine whether there is consistency between farmers' criteria for selecting cassava cultivars and the currently CMD recommended cassava varieties. METHODS: We conducted structured interviews with 369 farmers in 20% of townships in each of three agro-ecological zones in Benin between November 2015 and February 2016. Farmers were selected randomly in each household, and their fields were assessed for CMD incidence and severity. RESULTS: All farmers surveyed, representing a broad demographic pool with regard to education level, age group, and years of experience in cassava production, successfully recognized CMD symptoms in photos, but most (98.60%) said they did not know the causes and vectors of the disease. Most farmers (93.51%) reported that they obtain planting material from neighboring fields or their own fields. In total, 52 unique cultivars were identified, of which 3 (5.76%) were preferred based on their yield and precocity and 3 (5.76%) were preferred based on taste or ability for transformation. The assessment of disease incidence and severity showed that the areas most affected by CMD were Come Township (37.77% of fields affected) and agro-ecological zone VIII (26.33%). CONCLUSION: Farmers already know how to recognize the symptoms of CMD and could implement control measures against it if they are trained by researchers. Across all surveyed areas, we identified six preferred cultivars based on the four most commonly stated preference criteria (precocity, yield, gari, and taste. Our results suggest that farmers will be more likely to use CMD-resistant cultivars and clean plant material if the plants meet their existing preference criteria. We suggest that CMD-resistant cultivars will be embraced only if the recommended cultivars are strategically aligned with the characteristics desirable to the cassava farmers in each region. PMID- 29695282 TI - Effects of desiccation stress on adult female longevity in Aedes aegypti and Ae. albopictus (Diptera: Culicidae): results of a systematic review and pooled survival analysis. AB - BACKGROUND: Transmission dynamics of mosquito-borne viruses such as dengue, Zika and chikungunya are affected by the longevity of the adult female mosquito. Environmental conditions influence the survival of adult female Aedes mosquitoes, the primary vectors of these viruses. While the association of temperature with Aedes mortality has been relatively well-explored, the role of humidity is less established. The current study's goals were to compile knowledge of the influence of humidity on adult survival in the important vector species Aedes aegypti and Ae. albopictus, and to quantify this relationship while accounting for the modifying effect of temperature. METHODS: We performed a systematic literature review to identify studies reporting experimental results informing the relationships among temperature, humidity and adult survival in Ae. aegypti and Ae. albopictus. Using a novel simulation approach to harmonize disparate survival data, we conducted pooled survival analyses via stratified and mixed effects Cox regression to estimate temperature-dependent associations between humidity and mortality risk for these species across a broad range of temperatures and vapor pressure deficits. RESULTS: After screening 1517 articles, 17 studies (one in semi-field and 16 in laboratory settings) met inclusion criteria and collectively reported results for 192 survival experiments. We review and synthesize relevant findings from these studies. Our stratified model estimated a strong temperature dependent association of humidity with mortality in both species, though associations were not significant for Ae. albopictus in the mixed effects model. Lowest mortality risks were estimated around 27.5 degrees C and 21.5 degrees C for Ae. aegypti and Ae. albopictus, respectively, and mortality increased non linearly with decreasing humidity. Aedes aegypti had a survival advantage relative to Ae. albopictus in the stratified model under most conditions, but species differences were not significant in the mixed effects model. CONCLUSIONS: Humidity is associated with mortality risk in adult female Ae. aegypti in controlled settings. Data are limited at low humidities, temperature extremes, and for Ae. albopictus, and further studies should be conducted to reduce model uncertainty in these contexts. Desiccation is likely an important factor in Aedes population dynamics and viral transmission in arid regions. Models of Aedes-borne virus transmission may be improved by more comprehensively representing humidity effects. PMID- 29695284 TI - Dosimetric feasibility of 4DCT-ventilation imaging guided proton therapy for locally advanced non-small-cell lung cancer. AB - BACKGROUND: The principle aim of this study is to incorporate 4DCT ventilation imaging into functional treatment planning that preserves high-functioning lung with both double scattering and scanning beam techniques in proton therapy. METHODS: Eight patients with locally advanced non-small-cell lung cancer were included in this study. Deformable image registration was performed for each patient on their planning 4DCTs and the resultant displacement vector field with Jacobian analysis was used to identify the high-, medium- and low-functional lung regions. Five plans were designed for each patient: a regular photon IMRT vs. anatomic proton plans without consideration of functional ventilation information using double scattering proton therapy (DSPT) and intensity modulated proton therapy (IMPT) vs. functional proton plans with avoidance of high-functional lung using both DSPT and IMPT. Dosimetric parameters were compared in terms of tumor coverage, plan heterogeneity, and avoidance of normal tissues. RESULTS: Our results showed that both DSPT and IMPT plans gave superior dose advantage to photon IMRTs in sparing low dose regions of the total lung in terms of V5 (volume receiving 5Gy). The functional DSPT only showed marginal benefit in sparing high functioning lung in terms of V5 or V20 (volume receiving 20Gy) compared to anatomical plans. Yet, the functional planning in IMPT delivery, can further reduce the low dose in high-functioning lung without degrading the PTV dosimetric coverages, compared to anatomical proton planning. Although the doses to some critical organs might increase during functional planning, the necessary constraints were all met. CONCLUSIONS: Incorporating 4DCT ventilation imaging into functional proton therapy is feasible. The functional proton plans, in intensity modulated proton delivery, are effective to further preserve high functioning lung regions without degrading the PTV coverage. PMID- 29695285 TI - The polymorphisms of LCR, E6, and E7 of HPV-58 isolates in Yunnan, Southwest China. AB - BACKGROUD: Variations in HPV LCR/E6/E7 have been shown to be associated with the viral persistence and cervical cancer development. So far, there are few reports about the polymorphisms of the HPV-58 LCR/E6/E7 sequences in Southwest China. This study aims to characterize the gene polymorphisms of the HPV-58 LCR/E6/E7 sequences in women of Southwest China, and assess the effects of variations on the immune recognition of viral E6 and E7 antigens. METHODS: Twelve LCR/E6/E7 of the HPV-58 isolates were amplified and sequenced. A neighbor-joining phylogenetic tree was constructed by MEGA 7.0, followed by the secondary structure prediction of the related proteins using PSIPRED v3.3. The selection pressure acting on the HPV-58 E6 and E7 coding regions was estimated by Bayes empirical Bayes analysis of PAML 4.8. Meanwhile, the MHC class-I and II binding peptides were predicted by the ProPred-I server and ProPred server. The transcription factor binding sites in the HPV-58 LCR were analyzed using the JASPAR database. RESULTS: Twenty nine SNPs (20 in the LCR, 3 in the E6, 6 in the E7) were identified at 27 nucleotide sites across the HPV-58 LCR/E6/E7. From the most variable to the least variable, the nucleotide variations were LCR > E7 > E6. The combinations of all the SNPs resulted in 11 unique sequences, which were clustered into the A lineage (7 belong to A1, 2 belong to A2, and 2 belong to A3). An insertion (TGTCAGTTTCCT) was found between the nucleotide sites 7280 and 7281 in 2 variants, and a deletion (TTTAT) was found between 7429 and 7433 in 1 variant. The most common non-synonymous substitution V77A in the E7 was observed in the sequences encoding the alpha-helix. 63G in the E7 was determined to be the only one positively selected site in the HPV-58 E6/E7 sequences. Six non-synonymous amino acid substitutions (including S71F and K93 N in the E6, and T20I, G41R, G63S/D, and V77A in the E7) were affecting multiple putative epitopes for both CD4+ and CD8+ T-cells. In the LCR, C7265G and C7266T were the most variable sites and were the potential binding sites for the transcription factor SOX10. CONCLUSION: These results provide an insight into the intrinsic geographical relatedness and biological differences of the HPV-58 variants, and contribute to further research on the HPV-58 epidemiology, carcinogenesis, and therapeutic vaccine development. PMID- 29695286 TI - A microorganisms' journey between plant generations. AB - BACKGROUND: Plants are colonized by a great diversity of microorganisms which form a microbiota and perform additional functions for their host. This microbiota can thus be considered a toolbox enabling plants to buffer local environmental changes, with a positive influence on plant fitness. In this context, the transmission of the microbiota to the progeny represent a way to ensure the presence of beneficial symbionts within the habitat. Examples of such transmission have been mainly described for seed transmission and concern a few pathogenic microorganisms. We investigated the transmission of symbiotic partners to plant progeny within clonal plant network. METHODS: We used the clonal plant Glechoma hederacea as plant model and forced newly emitted clonal progeny to root in separated pots while controlling the presence of microorganisms. We used an amplicon sequencing approach of 16S and 18S rRNA targeting bacteria/archaea and fungi respectively to describe the root microbiota of mother and clonal-plant offspring. RESULTS: We demonstrated the vertical transmission of a significant proportion of the mother plants' symbiotic bacteria and fungi to the daughters. Interestingly, archaea were not transmitted to the daughter plants. Transmitted communities had lower richness, suggesting a filtration during transmission. We found that the transmitted pool of microorganisms was similar among daughters, constituting the heritability of a specific cohort of microorganisms, opening a new understanding of the plant holobiont. We also found significant effects of distance to the mother plant and of growth time on the richness of the microbiota transmitted. CONCLUSIONS: In this clonal plant, microorganisms are transmitted between individuals through connections, thereby ensuring the availability of microbe partners for the newborn plants as well as the dispersion between hosts for the microorganisms. This previously undescribed ecological process allows the dispersal of microorganisms in space and across plant generations. As the vast majority of plants are clonal, this process might be therefore a strong driver of ecosystem functioning and assembly of plant and microorganism communities in a wide range of ecosystems. PMID- 29695287 TI - The importance of endoscopic ultrasound fine-needle aspiration in the diagnosis of solid pseudopapillary tumor of the pancreas: two case reports. AB - BACKGROUND: Solid pseudopapillary tumor of the pancreas, otherwise known as solid and cystic tumor or Frantz tumor, is an unusual form of pancreatic carcinoma, with unknown etiopathogenesis, that accounts for 0.2 to 2.7% of all pancreatic tumors. It is defined as an exocrine pancreatic neoplasia that mainly affects women between the second and third decade of life, and its management is not well defined. Endoscopic ultrasound offers a key anatomical advantage in accessing the pancreas and endoscopic ultrasound fine-needle aspiration has become the gold standard method for the diagnosis of pancreatic lesions. CASE PRESENTATION: Case 1: A 31-year-old white Hispanic woman presented with epigastric pain for 5 months. An abdominal ultrasound revealed a single 2 cm nodule in the uncinate process of her pancreas. Endoscopic ultrasound showed a regular, well-defined solid lesion with alternating cystic areas at the uncinate process of her pancreas, measuring 1.7 * 1.4 cm; endoscopic ultrasound fine-needle aspiration was then performed with cytopathological analysis compatible with solid pseudopapillary tumor. Body computed tomography confirmed the absence of metastases and she underwent conventional duodenopancreatectomy. However, she died 4 days after surgery due to postoperative surgical complications. Case 2: A 35-year-old Hispanic woman presented with left upper quadrant abdominal pain for 3 months, associated with a palpable mass at this region. A computed tomography scan showed a solitary nodule in the pancreatic body. Endoscopic ultrasound showed a regular, well-defined, homogeneous lesion with small anechoic (cystic) areas, measuring 2 * 2 cm, in between the pancreatic body and neck. Endoscopic ultrasound fine-needle aspiration was performed and cytopathological analysis was suggestive of a pseudopapillary solid tumor. She underwent a body-tail laparoscopic pancreatectomy with splenectomy. Nine months after the diagnosis, she remains asymptomatic, continuing regular follow-up in the oncology out patient clinic. CONCLUSIONS: Solid pseudopapillary tumor is a rare pancreatic malignancy. Endoscopic ultrasound fine-needle aspiration is the gold standard method to characterize and diagnose this type of pancreatic lesion, making this an invaluable tool to help guide clinical management and improve the preoperative diagnostic yield. PMID- 29695288 TI - Evaluation of a bone morphogenetic protein 6 variant as a cause of iron loading. AB - BACKGROUND: Atypical iron overload without variation in the five clinically associated hereditary hemochromatosis genes is now recognized; however, their etiology remains unknown. Since the identification of iron overload in the bone morphogenetic protein 6 (Bmp6) knockout mouse, the search has been on for clinically pathogenic variants in the BMP6 gene. A recent report proposes that variants in the pro-peptide region of BMP6 are the underlying cause of several cases of iron overload. We performed targeted next-generation sequencing on three cases of atypical iron overload with Asian ethnicity and identified a p.Q118dup (aka p.E112indelEQ, p.Q115dup, p.Q118_L119insQ) variant in BMP6. The purpose of this study was to characterize the molecular function of the identified BMP6 variant. Molecular characterization by immunofluorescence microscopy and Western blotting of transfected cells, bioinformatics, and population analyses was performed. RESULTS: In contrast to reports for other BMP6 pro-peptide variants in this region, our data indicates that this variant does not affect the function of the mature BMP6 protein. CONCLUSIONS: Our data suggest that assignment of disease causation in clinical cases of iron overload to pro-peptide variants in BMP6 should thus be treated with caution and requires biological characterization. PMID- 29695289 TI - Mortality risk after clinical management of recurrent and metastatic adenoid cystic carcinoma. AB - BACKGROUND: Management of locoregional recurrence (LRR) and distant metastasis (DM) in adenoid cystic carcinoma (ACC) is guided by limited data. We investigated mortality risks in patients diagnosed and treated for recurrent ACC. METHODS: A retrospective review of ACC patients treated from 1989 to 2016 identified 36 patients with LRR or DM. High-risk disease was defined as skull base involvement (for LRR) or International Registry of Lung Metastases Group III/IV or extrapulmonary site of metastasis (for DM). Kaplan-Meier method, log-rank tests, and Cox proportional hazards were used for time-to-event analysis. RESULTS: Among 20 LRR and 16 DM patients, the median times to recurrence were 51 and 50 months, respectively. The median follow-up post-recurrence was 37.5 months (interquartile range (IQR)16.5-56.5). Post-recurrence 3-year overall survival (OS) was 78.5%, 73.3% for LRR and 85.1% for DM (p = 0.62). High-risk recurrences were associated with worse 3-year OS (68.8% for high-risk and 92.3% for low-risk, chi2 = 10.4, p = 0.001). Among LRR patients, 90% had surgery as part of their treatment. Multimodality therapy, age, and histopathologic features (size, margins, solid histology, lymphovascular or perineural invasion) were not associated with PFS or OS. High-risk LRR was the only variable associated with OS (chi2 = 5.9, p = 0.01). Among DM patients, six were initially managed with observation and ten received surgery, RT, or systemic therapy. Upfront therapy was not associated with improved PFS or OS. High-risk DM was the only variable associated with OS (chi2 = 4.7, p = 0.03). CONCLUSIONS: High-risk LRR and DM were associated with decreased 3-year OS. More effective therapies are needed for high-risk ACC recurrences. PMID- 29695290 TI - An international survey on hybrid imaging: do technology advances preempt our training and education efforts? AB - BACKGROUND: Hybrid PET/CT and PET/MRI are increasingly important technologies in the evaluation of malignancy and require cooperation between radiologists and specialists in molecular imaging. The aim of our study was to probe the mindsets of radiological and nuclear medicine professionals in regard to current hybrid imaging practice and to assess relevant training aspirations and perceived shortfalls, particularly amongst young professionals. In this context, we initiated an international survey on "Hybrid Imaging Training". METHODS: An online survey was prepared on-line and launched on October-2, 2016. It was composed of 17 multiple-choice and open questions regarding the professional background, a perspective on hybrid imaging training efforts and lessons to be learned from disparate craft groups. The survey ran for 2 weeks. We report total responses per category and individual free-text responses. RESULTS: In total, 248 responses were collected with a mean age of all responders of (41 +/- 11) y. Overall, 36% were within the target age range of (20-35) y. Across all responders, the majority (72%) commented on there being too few hybrid imaging experts in their country, whereas only 1% said that there were too many. Three quarters of the responders were in favour of a curriculum allowing sub specialisation in hybrid imaging. With respect to reporting of hybrid imaging, confidence increased with age. The average rating across all responders on the level of cooperation among the two specialties suggested a low overall level of satisfaction. However, the survey feedback indicated the local (on-site) cooperation being somewhat better than the perceived cooperation between the relevant associations on a European level. CONCLUSION: We consider these results to represent an appropriate cross-section of professional opinions of imaging experts across different demographic and hierarchical levels. Collectively they provide evidence supporting a need to address current shortfalls in developing hybrid imaging expertise through national educational plans, and, thus, contribute to helping improve patient care. PMID- 29695291 TI - DNA topoisomerase IIbeta stimulates neurite outgrowth in neural differentiated human mesenchymal stem cells through regulation of Rho-GTPases (RhoA/Rock2 pathway) and Nurr1 expression. AB - BACKGROUND: DNA topoisomerase IIbeta (topo IIbeta) is known to regulate neural differentiation by inducing the neuronal genes responsible for critical neural differentiation events such as neurite outgrowth and axon guidance. However, the pathways of axon growth controlled by topo IIbeta have not been clarified yet. Microarray results of our previous study have shown that topo IIbeta silencing in neural differentiated primary human mesenchymal stem cells (hMSCs) significantly alters the expression pattern of genes involved in neural polarity, axonal growth, and guidance, including Rho-GTPases. This study aims to further analyze the regulatory role of topo IIbeta on the process of axon growth via regulation of Rho-GTPases. METHODS AND RESULTS: For this purpose, topo IIbeta was silenced in neurally differentiated hMSCs. Cells lost their morphology because of topo IIbeta deficiency, becoming enlarged and flattened. Additionally, a reduction in both neural differentiation efficiency and neurite length, upregulation in RhoA and Rock2, downregulation in Cdc42 gene expression were detected. On the other hand, cells were transfected with topo IIbeta gene to elucidate the possible neuroprotective effect of topo IIbeta overexpression on neural-induced hMSCs. Topo IIbeta overexpression prompted all the cells to exhibit neural cell morphology as characterized by longer neurites. RhoA and Rock2 expressions were downregulated, whereas Cdc42 expression was upregulated. Nurr1 expression level correlated with topo IIbeta in both topo IIbeta-overexpressed and -silenced cells. Furthermore, differential translocation of Rho-GTPases was detected by immunostaining in response to topo IIbeta. CONCLUSION: Our results suggest that topo IIbeta deficiency could give rise to neurodegeneration through dysregulation of Rho-GTPases. However, further in-vivo research is needed to demonstrate if re regulation of Rho GTPases by topo IIbeta overexpression could be a neuroprotective treatment in the case of neurodegenerative diseases. PMID- 29695292 TI - A biomarker study in long-lasting amnestic mild cognitive impairment. AB - BACKGROUND: Mild cognitive impairment (MCI) is a heterogeneous syndrome resulting from Alzheimer's disease (AD) as well as to non-AD and non-neurodegenerative conditions. A subset of patients with amnestic MCI (aMCI) present with an unusually long-lasting course, a slow rate of clinical neuropsychological progression, and evidence of focal involvement of medial temporal lobe structures. In the present study, we explored positron emission tomography (PET) and cerebrospinal fluid (CSF) biomarkers in a sample of subjects with aMCI with such clinical features in order to provide in vivo evidence to improve disease characterisation in this subgroup. METHODS: Thirty consecutive subjects with aMCI who had long-lasting memory impairment (more than 4 years from symptom onset) and a very slow rate of cognitive progression were included. All subjects underwent fluorodeoxyglucose-positron emission tomography (FDG-PET) metabolic imaging. A measure of cerebral amyloid load, by PET and/or CSF, was obtained in 26 of 30 subjects. The mean clinical follow-up was 58.3 +/- 10.1 months. RESULTS: No patient progressed to dementia during the follow-up. The typical AD FDG-PET pattern of temporoparietal hypometabolism was not present in any of the subjects. In contrast, a selective medial temporal lobe hypometabolism was present in all subjects, with an extension to frontolimbic regions in some subjects. PET imaging showed absent or low amyloid load in the majority of samples. The values were well below those reported in prodromal AD, and they were slightly elevated in only two subjects, consistent with the CSF beta-amyloid (1-42) protein values. Notably, no amyloid load was present in the hippocampal structures. CONCLUSIONS: FDG-PET and amyloid-PET together with CSF findings questioned AD pathology as a unique neuropathological substrate in this aMCI subgroup with long-lasting disease course. The possibility of alternative pathological conditions, such as argyrophilic grain disease, primary age-related tauopathy or age-related TDP-43 proteinopathy, known to spread throughout the medial temporal lobe and limbic system structures should be considered in these patients with MCI. PMID- 29695293 TI - Comment on "A new method for treating fecal incontinence by implanting stem cells derived from human adipose tissue: preliminary findings of a randomized double blind clinical trial". AB - In the study by Sarveazad et al. adipose tissue-derived stem cells were injected to reinforce anal sphincter repair. The authors came to the conclusion that injection of stem cells during repair surgery for fecal incontinence may cause replacement of fibrous tissue, which may be a key point in treatment of fecal incontinence. The authors emphasized in their "Discussion" section that the ability of stem cells to differentiate into muscle fibers, replacing the fibrous tissue at the site of repair, is their main action, which may not be accurate. We think that healing of repaired anal sphincter begins with granulation tissue formation, which then matures into fibrous tissue that becomes infiltrated by muscle fibers from the approximated cut ends of the sphincter, resulting in regain of sphincter muscle continuity. This is supported by many experimental studies that have evaluated local injection of stem cells during sphincteroplasty in rats and shown that the injected stem cells do not differentiate into muscle fibers but may induce healing by a strong fibrous tissue. Further studies are needed to determine the main mechanism of action of mesenchymal stems cells in augmenting anal sphincter repair. PMID- 29695295 TI - An updated protocol for a systematic review of implementation-related measures. AB - BACKGROUND: Implementation science is the study of strategies used to integrate evidence-based practices into real-world settings (Eccles and Mittman, Implement Sci. 1(1):1, 2006). Central to the identification of replicable, feasible, and effective implementation strategies is the ability to assess the impact of contextual constructs and intervention characteristics that may influence implementation, but several measurement issues make this work quite difficult. For instance, it is unclear which constructs have no measures and which measures have any evidence of psychometric properties like reliability and validity. As part of a larger set of studies to advance implementation science measurement (Lewis et al., Implement Sci. 10:102, 2015), we will complete systematic reviews of measures that map onto the Consolidated Framework for Implementation Research (Damschroder et al., Implement Sci. 4:50, 2009) and the Implementation Outcomes Framework (Proctor et al., Adm Policy Ment Health. 38(2):65-76, 2011), the protocol for which is described in this manuscript. METHODS: Our primary databases will be PubMed and Embase. Our search strings will be comprised of five levels: (1) the outcome or construct term; (2) terms for measure; (3) terms for evidence-based practice; (4) terms for implementation; and (5) terms for mental health. Two trained research specialists will independently review all titles and abstracts followed by full-text review for inclusion. The research specialists will then conduct measure-forward searches using the "cited by" function to identify all published empirical studies using each measure. The measure and associated publications will be compiled in a packet for data extraction. Data relevant to our Psychometric and Pragmatic Evidence Rating Scale (PAPERS) will be independently extracted and then rated using a worst score counts methodology reflecting "poor" to "excellent" evidence. DISCUSSION: We will build a centralized, accessible, searchable repository through which researchers, practitioners, and other stakeholders can identify psychometrically and pragmatically strong measures of implementation contexts, processes, and outcomes. By facilitating the employment of psychometrically and pragmatically strong measures identified through this systematic review, the repository would enhance the cumulativeness, reproducibility, and applicability of research findings in the rapidly growing field of implementation science. PMID- 29695296 TI - Automated screening of research studies for systematic reviews using study characteristics. AB - BACKGROUND: Screening candidate studies for inclusion in a systematic review is time-consuming when conducted manually. Automation tools could reduce the human effort devoted to screening. Existing methods use supervised machine learning which train classifiers to identify relevant words in the abstracts of candidate articles that have previously been labelled by a human reviewer for inclusion or exclusion. Such classifiers typically reduce the number of abstracts requiring manual screening by about 50%. METHODS: We extracted four key characteristics of observational studies (population, exposure, confounders and outcomes) from the text of titles and abstracts for all articles retrieved using search strategies from systematic reviews. Our screening method excluded studies if they did not meet a predefined set of characteristics. The method was evaluated using three systematic reviews. Screening results were compared to the actual inclusion list of the reviews. RESULTS: The best screening threshold rule identified studies that mentioned both exposure (E) and outcome (O) in the study abstract. This screening rule excluded 93.7% of retrieved studies with a recall of 98%. CONCLUSIONS: Filtering studies for inclusion in a systematic review based on the detection of key study characteristics in abstracts significantly outperformed standard approaches to automated screening and appears worthy of further development and evaluation. PMID- 29695294 TI - The hologenome concept of evolution after 10 years. AB - The holobiont (host with its endocellular and extracellular microbiome) can function as a distinct biological entity, an additional organismal level to the ones previously considered, on which natural selection operates. The holobiont can function as a whole: anatomically, metabolically, immunologically, developmentally, and during evolution. Consideration of the holobiont with its hologenome as an independent level of selection in evolution has led to a better understanding of underappreciated modes of genetic variation and evolution. The hologenome is comprised of two complimentary parts: host and microbiome genomes. Changes in either genome can result in variations that can be selected for or against. The host genome is highly conserved, and genetic changes within it occur slowly, whereas the microbiome genome is dynamic and can change rapidly in response to the environment by increasing or reducing particular microbes, by acquisition of novel microbes, by horizontal gene transfer, and by mutation. Recent experiments showing that microbiota can play an initial role in speciation have been suggested as an additional mode of enhancing evolution. Some of the genetic variations can be transferred to offspring by a variety of mechanisms. Strain-specific DNA analysis has shown that at least some of the microbiota can be maintained across hundreds of thousands of host generations, implying the existence of a microbial core. We argue that rapid changes in the microbiome genome could allow holobionts to adapt and survive under changing environmental conditions thus providing the time necessary for the host genome to adapt and evolve. As Darwin wrote, "It is not the strongest of the species that survives but the most adaptable". PMID- 29695297 TI - Better governance, better access: practising responsible data sharing in the METADAC governance infrastructure. AB - BACKGROUND: Genomic and biosocial research data about individuals is rapidly proliferating, bringing the potential for novel opportunities for data integration and use. The scale, pace and novelty of these applications raise a number of urgent sociotechnical, ethical and legal questions, including optimal methods of data storage, management and access. Although the open science movement advocates unfettered access to research data, many of the UK's longitudinal cohort studies operate systems of managed data access, in which access is governed by legal and ethical agreements between stewards of research datasets and researchers wishing to make use of them. Amongst other things, these agreements aim to respect the reasonable expectations of the research participants who provided data and samples, as expressed in the consent process. Arguably, responsible data management and governance of data and sample use are foundational to the consent process in longitudinal studies and are an important source of trustworthiness in the eyes of those who contribute data to genomic and biosocial research. METHODS: This paper presents an ethnographic case study exploring the foundational principles of a governance infrastructure for Managing Ethico-social, Technical and Administrative issues in Data ACcess (METADAC), which are operationalised through a committee known as the METADAC Access Committee. METADAC governs access to phenotype, genotype and 'omic' data and samples from five UK longitudinal studies. FINDINGS: Using the example of METADAC, we argue that three key structural features are foundational for practising responsible data sharing: independence and transparency; interdisciplinarity; and participant-centric decision-making. We observe that the international research community is proactively working towards optimising the use of research data, integrating/linking these data with routine data generated by health and social care services and other administrative data services to improve the analysis, interpretation and utility of these data. The governance of these new complex data assemblages will require a range of expertise from across a number of domains and disciplines, including that of study participants. Human mediated decision-making bodies will be central to ensuring achievable, reasoned and responsible decisions about the use of these data; the METADAC model described in this paper provides an example of how this could be realised. PMID- 29695298 TI - Pyruvate is a prospective alkalizer to correct hypoxic lactic acidosis. AB - Type A lactic acidosis resulted from hypoxic mitochondrial dysfunction is an independent predictor of mortality for critically ill patients. However, current therapeutic agents are still in shortage and can even be harmful. This paper reviewed data regarding lactic acidosis treatment and recommended that pyruvate might be a potential alkalizer to correct type A lactic acidosis in future clinical practice. Pyruvate is a key energy metabolic substrate and a pyruvate dehydrogenase (PDH) activator with several unique beneficial biological properties, including anti-oxidant and anti-inflammatory effects and the ability to activate the hypoxia-inducible factor-1 (HIF-1alpha) - erythropoietin (EPO) signal pathway. Pyruvate preserves glucose metabolism and cellular energetics better than bicarbonate, lactate, acetate and malate in the efficient correction of hypoxic lactic acidosis and shows few side effects. Therefore, application of pyruvate may be promising and safe as a novel therapeutic strategy in hypoxic lactic acidosis correction accompanied with multi-organ protection in critical care patients. PMID- 29695299 TI - Emergency transportation interventions for reducing adverse pregnancy outcomes in low- and middle-income countries: a systematic review protocol. AB - BACKGROUND: Transportation interventions seek to decrease delay in reaching a health facility for emergency obstetric care and are, thus, believed to contribute to reductions in such adverse pregnancy and childbirth outcomes as maternal deaths, stillbirths, and neonatal mortality in low- and middle-income countries (LMICs). However, there is limited empirical evidence to support this hypothesis. The objective of the proposed review is to summarize and critically appraise evidence regarding the effect of emergency transportation interventions on outcomes of labor and delivery in LMICs. METHODS: The following databases will be searched from inception to March 31, 2018: MEDLINE/PubMed, EMBASE, Web of Science, EBSCO (PsycINFO and CINAHL), the Cochrane Pregnancy and Child Birth Group's Specialized Register, and the Cochrane Central Register of Controlled Trials. We will search for studies in the grey literature through Google and Google Scholar. We will solicit unpublished reports from such relevant agencies as United Nations Fund for Population Activities (UNFPA), the World Health Organization (WHO), the United Nations Children's Fund (UNICEF), the United States Agency for International Development (USAID), and the United Kingdom Department for International Development (DfID) among others. Data generated from the search will be managed using Endnote Version 7. We will perform quantitative data synthesis if studies are homogenous in characteristics and provide adequate outcome data for meta-analysis. Otherwise, data will be synthesized, using the narrative synthesis approach. DISCUSSION: Among the many barriers that women in LMICs face in accessing life-saving interventions during labor and delivery, lack of access to emergency transportation is particularly important. This review will provide a critical summary of evidence regarding the impact of transportation interventions on outcomes of pregnancy and childbirth in LMICs. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017080092. PMID- 29695300 TI - A language-based sum score for the course and therapeutic intervention in primary progressive aphasia. AB - BACKGROUND: With upcoming therapeutic interventions for patients with primary progressive aphasia (PPA), instruments for the follow-up of patients are needed to describe disease progression and to evaluate potential therapeutic effects. So far, volumetric brain changes have been proposed as clinical endpoints in the literature, but cognitive scores are still lacking. This study followed disease progression predominantly in language-based performance within 1 year and defined a PPA sum score which can be used in therapeutic interventions. METHODS: We assessed 28 patients with nonfluent variant PPA, 17 with semantic variant PPA, 13 with logopenic variant PPA, and 28 healthy controls in detail for 1 year. The most informative neuropsychological assessments were combined to a sum score, and associations between brain atrophy were investigated followed by a sample size calculation for clinical trials. RESULTS: Significant absolute changes up to 20% in cognitive tests were found after 1 year. Semantic and phonemic word fluency, Boston Naming Test, Digit Span, Token Test, AAT Written language, and Cookie Test were identified as the best markers for disease progression. These tasks provide the basis of a new PPA sum score. Assuming a therapeutic effect of 50% reduction in cognitive decline for sample size calculations, a number of 56 cases is needed to find a significant treatment effect. Correlations between cognitive decline and atrophy showed a correlation up to r = 0.7 between the sum score and frontal structures, namely the superior and inferior frontal gyrus, as well as with left sided subcortical structures. CONCLUSION: Our findings support the high performance of the proposed sum score in the follow-up of PPA and recommend it as an outcome measure in intervention studies. PMID- 29695301 TI - Health in Yemen: losing ground in war time. AB - BACKGROUND: The effect of the ongoing war in Yemen on maternal and child health (MCH) has not been comprehensively assessed. Providing a situational analysis at the governorate level is critical to assist in planning a response and allocating resources. METHODS: We used multiple national- and governorate-level data sources to provide estimates of 12 relevant MCH indicators in 2016 around child vaccination, and child and maternal nutritional status, and the change in these estimates for the period 2013-2016 based on shock variables including change in gross domestic product, burden of airstrikes per 1000 population, change in access to untreated water sources and unimproved toilets, and change in wheat flour prices. We also used findings from the Global Burden of Disease 2016 study. RESULTS: Vaccine coverage decreased for all antigens between 2013 and 2016 among children 12-23 months. The largest decrease, 36.4% for first-dose measles vaccine, was in Aden. Among children under the age of five, incidence of diarrhea was at 7.0 (5.5-8.9) episodes per person-year. The prevalence of moderate and severe child anemia ranged from 50.9% (24.9-73.1) in Sana'a City to 97.8% (94.1 99.2) in Shabwah in 2016. Prevalence of underweight among women of reproductive age ranged from 15.3% (8.1-24.6) in Sana'a city to 32.1% (24.1-39.7) in Hajjah, with a national average of 24.6% (18.7-31.5). CONCLUSIONS: The war and siege on Yemen has had a devastating impact on the health of women and children. Urgent efforts to secure food, essential medicines, antibiotics, deworming medicine, and hygiene kits, and cold chains for immunization are needed. Yemen is in dire need of clean water and proper sanitation to reduce the spread of disease, especially diarrhea. PMID- 29695302 TI - Associations among unit leadership and unit climates for implementation in acute care: a cross-sectional study. AB - BACKGROUND: Nurse managers have a pivotal role in fostering unit climates supportive of implementing evidence-based practices (EBPs) in care delivery. EBP leadership behaviors and competencies of nurse managers and their impact on practice climates are widely overlooked in implementation science. The purpose of this study was to examine the contributions of nurse manager EBP leadership behaviors and nurse manager EBP competencies in explaining unit climates for EBP implementation in adult medical-surgical units. METHODS: A multi-site, multi-unit cross-sectional research design was used to recruit the sample of 24 nurse managers and 553 randomly selected staff nurses from 24 adult medical-surgical units from 7 acute care hospitals in the Northeast and Midwestern USA. Staff nurse perceptions of nurse manager EBP leadership behaviors and unit climates for EBP implementation were measured using the Implementation Leadership Scale and Implementation Climate Scale, respectively. EBP competencies of nurse managers were measured using the Nurse Manager EBP Competency Scale. Participants were emailed a link to an electronic questionnaire and asked to respond within 1 month. The contributions of nurse manager EBP leadership behaviors and competencies in explaining unit climates for EBP implementation were estimated using mixed-effects models controlling for nurse education and years of experience on current unit and accounting for the variability across hospitals and units. Significance level was set at alpha < .05. RESULTS: Two hundred sixty four staff nurses and 22 nurse managers were included in the final sample, representing 22 units in 7 hospitals. Nurse manager EBP leadership behaviors (p < .001) and EBP competency (p = .008) explained 52.4% of marginal variance in unit climate for EBP implementation. Leadership behaviors uniquely explained 45.2% variance. The variance accounted for by the random intercepts for hospitals and units (p < .001) and years of nursing experience in current unit (p < .05) were significant but level of nursing education was not. CONCLUSION: Nurse managers are significantly related to unit climates for EBP implementation primarily through their leadership behaviors. Future implementation studies should consider the leadership of nurse managers in creating climates supportive of EBP implementation. PMID- 29695303 TI - Histone H4 acetylation regulates behavioral inter-individual variability in zebrafish. AB - BACKGROUND: Animals can show very different behaviors even in isogenic populations, but the underlying mechanisms to generate this variability remain elusive. We use the zebrafish (Danio rerio) as a model to test the influence of histone modifications on behavior. RESULTS: We find that laboratory and isogenic zebrafish larvae show consistent individual behaviors when swimming freely in identical wells or in reaction to stimuli. This behavioral inter-individual variability is reduced when we impair the histone deacetylation pathway. Individuals with high levels of histone H4 acetylation, and specifically H4K12, behave similarly to the average of the population, but those with low levels deviate from it. More precisely, we find a set of genomic regions whose histone H4 acetylation is reduced with the distance between the individual and the average population behavior. We find evidence that this modulation depends on a complex of Yin-yang 1 (YY1) and histone deacetylase 1 (HDAC1) that binds to and deacetylates these regions. These changes are not only maintained at the transcriptional level but also amplified, as most target regions are located near genes encoding transcription factors. CONCLUSIONS: We suggest that stochasticity in the histone deacetylation pathway participates in the generation of genetic independent behavioral inter-individual variability. PMID- 29695304 TI - The impact of social organizations on HIV/AIDS prevention knowledge among migrants in Hefei, China. AB - BACKGROUND: There is a growing recognition of the need to provide HIV/AIDS prevention and care to migrant workers. Social involvement, a type of social capital, is considered a 'critical enabler' of effective HIV/AIDS prevention. Designated participation in formal community groups by the government (e.g., political parties) and informal, voluntary local networks by NGOs (e.g., alumni association, cultural & sports club) play different roles in HIV prevention. The objective of this study is to assess the impact of different types of social organizations on HIV/AIDS prevention knowledge among migrant workers. METHODS: A cross-sectional study of 758 migrants was conducted in Hefei, Anhui Province, China. Data were collected through a self-reported questionnaire. Logistic regression was used to assess associations between different social organizations and HIV/AIDS prevention. RESULTS: Migrants who participated in social organizations had a higher awareness of HIV/AIDS knowledge than migrants who do not participate in social organizations. Higher levels of HIV/AIDS knowledge is associated with positive HIV/AIDS behaviors for people who attended political parties (odds ratio [OR] = 3.49, 95% CI: 1.22-9.99). This effect is not significant for alumni association. For both political parties and alumni association members (OR = 0.19, 95% CI: 0.06-0.66, OR = 0.20, 95% CI: 0.08-0.61, respectively), people who exhibited higher levels of HIV/AIDS knowledge had more negative attitudes than those with less knowledge. CONCLUSION: Social organizations play an important role in improving HIV/AIDS knowledge and behavior in migrants, providing a great opportunity for HIV/AIDS prevention. PMID- 29695306 TI - Severe caries are a clue for child neglect: a case report. AB - BACKGROUND: Child abuse and neglect have strong negative effects on the well being of children, not only during childhood but also later in life. Therefore, early recognition is important. CASE PRESENTATION: We describe a 4-year-old Caucasian boy who had severe dental caries. This was a result of insufficient dental care: he refused to brush his teeth and drank sweetened drinks. We considered this dental neglect to be a manifestation of child neglect and social services were consequently called in to help the family. CONCLUSIONS: There is a strong association between child abuse and neglect and dental caries. Abused children often have severe dental caries and in children who had dental caries, child abuse and neglect is often established. An important factor is insufficient parenting; therefore, we believe that severe dental caries is an important indicator for child abuse and neglect. PMID- 29695307 TI - Use of dietary indices to control for diet in human gut microbiota studies. AB - BACKGROUND: Environmental factors have a large influence on the composition of the human gut microbiota. One of the most influential and well-studied is host diet. To assess and interpret the impact of non-dietary factors on the gut microbiota, we endeavoured to determine the most appropriate method to summarise community variation attributable to dietary effects. Dietary habits are multidimensional with internal correlations. This complexity can be simplified by using dietary indices that quantify dietary variance in a single measure and offer a means of controlling for diet in microbiota studies. However, to date, the applicability of different dietary indices to gut microbiota studies has not been assessed. Here, we use food frequency questionnaire (FFQ) data from members of the TwinsUK cohort to create three different dietary measures applicable in western-diet populations: The Healthy Eating Index (HEI), the Mediterranean Diet Score (MDS) and the Healthy Food Diversity index (HFD-Index). We validate and compare these three indices to determine which best summarises dietary influences on gut microbiota composition. RESULTS: All three indices were independently validated using established measures of health, and all were significantly associated with microbiota measures; the HEI had the highest t values in models of alpha diversity measures, and had the highest number of associations with microbial taxa. Beta diversity analyses showed the HEI explained the greatest variance of microbiota composition. In paired tests between twins discordant for dietary index score, the HEI was associated with the greatest variation of taxa and twin dissimilarity. CONCLUSIONS: We find that the HEI explains the most variance in, and has the strongest association with, gut microbiota composition in a western (UK) population, suggesting that it may be the best summary measure to capture gut microbiota variance attributable to habitual diet in comparable populations. PMID- 29695309 TI - Evaluation of reference lactation length in Chios dairy sheep. AB - Definition and establishment of a fixed reference lactation length could provide useful tools for on-farm comparison of ewes and flock management as well as genetic evaluations for the breeding programme. The objectives of this study were to (i) evaluate different reference lactation lengths for the Chios dairy sheep and (ii) define the most suitable reference length for the breed. A total of 260 042 test-day milk records from 24 474 ewes in 130 flocks collected between 2003 and 2014 were used; 15 different lactation lengths were evaluated ranging from 120 to 260 days, defined at 10-day intervals as reference for the Chios sheep. The evaluation criteria included: (a) heritability and repeatability of milk yield in each reference lactation, (b) genetic correlation of reference lactation milk yield with actual lactation milk yield and yield at first test-day record and (c) correlated response in reference lactation milk yield from selection based on first test-day milk yield. The latter emulates genetic gains achieved for milk yield based on early lactation selection. Heritability and repeatability estimates of reference lactation milk yield and genetic correlation with actual lactation yield favoured long reference lactations (180 to 230 days). On the contrary, correlation with first test-day record milk yield was higher for short lactations (120 to 170 days). Moreover, selection on first test-day record milk yield would lead to a correlated response in reference yield in 220 days equal to 85% of the highest estimate achieved in the maximum reference length of 260 days (190 days when only considering first lactation milk yield). Based on the results of the present study, an overall reference lactation length for the Chios breed of 220 days post-lambing and a first lactation reference length of 190 days post lambing are recommended. PMID- 29695305 TI - Cross-sectional associations of plasma vitamin D with cerebral beta-amyloid in older adults at risk of dementia. AB - BACKGROUND: Vitamin D deficiency is associated with an increased risk of Alzheimer's disease and increased beta-amyloid (Abeta) in animals. Hence we sought to investigate the relationship between plasma 25-hydroxyvitamin D (25(OH)D) and cerebral Abeta in older adults with subjective memory complaints. METHODS: This is a secondary analysis of the Multidomain Alzheimer Preventive Trial. Participants were 178 dementia-free individuals aged 70 years or older with data on plasma 25(OH)D and cerebral Abeta load assessed by [18F]-florbetapir positron emission tomography. Plasma 25(OH)D was measured at study baseline using a commercially available electro-chemiluminescence competitive binding assay. Standard uptake value ratios (SUVRs) were generated using the cerebellum as a reference. Brain regions assessed included the cortex, anterior cingulate, anterior putamen, caudate, hippocampus, medial orbitofrontal cortex, occipital cortex, parietal cortex, pons, posterior cingulate, posterior putamen, precuneus, semioval centre and temporal cortex. Associations were explored using fully adjusted multiple linear regression models. RESULTS: Participants had a mean (SD) age of 76.2 years (4.4) and 59.6% were female. The mean (SD) plasma 25(OH)D level was 22.4 ng/ml (10.8) and the mean (SD) cortical SUVR was 1.2 (0.2). We did not find any cross-sectional associations (p > 0.05) between baseline 25(OH)D levels and Abeta in any of the brain regions studied. CONCLUSIONS: These preliminary results suggest that circulating 25(OH)D is not associated with cerebral Abeta in older adults. Further longitudinal studies with the measurement of mid-life vitamin D status are required to explore the relationship between vitamin D and Abeta accrual over time, thereby circumventing the shortfalls of a cross sectional study. PMID- 29695310 TI - Effectiveness of Probiotic for Primary Prevention of Clostridium difficile Infection: A Single-Center Before-and-After Quality Improvement Intervention at a Tertiary-Care Medical Center. AB - OBJECTIVETo evaluate probiotics for the primary prevention of Clostridium difficile infection (CDI) among hospital inpatients.DESIGNA before-and-after quality improvement intervention comparing 12-month baseline and intervention periods.SETTINGA 694-bed teaching hospital.INTERVENTIONWe administered a multispecies probiotic comprising L. acidophilus (CL1285), L. casei (LBC80R), and L. rhamnosus (CLR2) to eligible antibiotic recipients within 12 hours of initial antibiotic receipt through 5 days after final dose. We excluded (1) all patients on neonatal, pediatric and oncology wards; (2) all individuals receiving perioperative prophylactic antibiotic recipients; (3) all those restricted from oral intake; and (4) those with pancreatitis, leukopenia, or posttransplant. We defined CDI by symptoms plus C. difficile toxin detection by polymerase chain reaction. Our primary outcome was hospital-onset CDI incidence on eligible hospital units, analyzed using segmented regression.RESULTSThe study included 251 CDI episodes among 360,016 patient days during the baseline and intervention periods, and the incidence rate was 7.0 per 10,000 patient days. The incidence rate was similar during baseline and intervention periods (6.9 vs 7.0 per 10,000 patient days; P=.95). However, compared to the first 6 months of the intervention, we detected a significant decrease in CDI during the final 6 months (incidence rate ratio, 0.6; 95% confidence interval, 0.4-0.9; P=.009). Testing intensity remained stable between the baseline and intervention periods: 19% versus 20% of stools tested were C. difficile positive by PCR, respectively. From medical record reviews, only 26% of eligible patients received a probiotic per the protocol.CONCLUSIONSDespite poor adherence to the protocol, there was a reduction in the incidence of CDI during the intervention, which was delayed ~6 months after introducing probiotic for primary prevention.Infect Control Hosp Epidemiol 2018;765-770. PMID- 29695308 TI - The presence of human mesenchymal stem cells of renal origin in amniotic fluid increases with gestational time. AB - BACKGROUND: Established therapies for managing kidney dysfunction such as kidney dialysis and transplantation are limited due to the shortage of compatible donated organs and high costs. Stem cell-based therapies are currently under investigation as an alternative treatment option. As amniotic fluid is composed of fetal urine harboring mesenchymal stem cells (AF-MSCs), we hypothesized that third-trimester amniotic fluid could be a novel source of renal progenitor and differentiated cells. METHODS: Human third-trimester amniotic fluid cells (AFCs) were isolated and cultured in distinct media. These cells were characterized as renal progenitor cells with respect to cell morphology, cell surface marker expression, transcriptome and differentiation into chondrocytes, osteoblasts and adipocytes. To test for renal function, a comparative albumin endocytosis assay was performed using AF-MSCs and commercially available renal cells derived from kidney biopsies. Comparative transcriptome analyses of first, second and third trimester-derived AF-MSCs were conducted to monitor expression of renal-related genes. RESULTS: Regardless of the media used, AFCs showed expression of pluripotency-associated markers such as SSEA4, TRA-1-60, TRA-1-81 and C-Kit. They also express the mesenchymal marker Vimentin. Immunophenotyping confirmed that third-trimester AFCs are bona fide MSCs. AF-MSCs expressed the master renal progenitor markers SIX2 and CITED1, in addition to typical renal proteins such as PODXL, LHX1, BRN1 and PAX8. Albumin endocytosis assays demonstrated the functionality of AF-MSCs as renal cells. Additionally, upregulated expression of BMP7 and downregulation of WT1, CD133, SIX2 and C-Kit were observed upon activation of WNT signaling by treatment with the GSK-3 inhibitor CHIR99201. Transcriptome analysis and semiquantitative PCR revealed increasing expression levels of renal-specific genes (e.g., SALL1, HNF4B, SIX2) with gestational time. Moreover, AF-MSCs shared more genes with human kidney cells than with native MSCs and gene ontology terms revealed involvement of biological processes associated with kidney morphogenesis. CONCLUSIONS: Third-trimester amniotic fluid contains AF-MSCs of renal origin and this novel source of kidney progenitors may have enormous future potentials for disease modeling, renal repair and drug screening. PMID- 29695311 TI - Incidence of pneumonia in nursing home residents in Germany: results of a claims data analysis. AB - Pneumonia is one of the most common infectious diseases with a high mortality, especially in the elderly population. To date, there have been only a few population-based studies dealing with the incidence of pneumonia in nursing homes (NHs). We conducted a cohort study using data from a large German statutory health insurance fund. Between 2010 and 2014, 127 227 NH residents 65 years and older were analysed. For the calculation of incidences per 100 person-years (PY) and 95% confidence intervals (CIs), we assessed the first diagnosis of pneumonia during the time in NH. We compared the rates between sexes, age groups, care levels, and comorbidities and we performed a multivariate Cox regression analysis. The mean age in the cohort was 84.0 years (74.6% female). A total of 19 183 incident cases led to an overall 5-year-incidence of 11.8 per 100 PY (95% CI 11.7-12.0). The incidence in men was substantially higher than in women. Rates were highest in the first month after NH placement. Our study revealed that the incidence of pneumonia is high in German NH residents and especially in males. Due to demographic changes, pneumonia will likely be increasingly relevant in the health care of the elderly and institutionalised population. PMID- 29695313 TI - Effects of Ketamine Compared with Urethane Anesthesia on Vestibular Sensory Evoked Potentials and Systemic Physiology in Mice. AB - The injectable anesthetic mixture ketamine-xylazine is commonly used for electrophysiologic experiments in laboratory animals, especially rodents. General anesthesia can induce significant changes in systemic physiology, including those that compromise neural function, thus introducing research confounds. The extent of such concerns varies by agent. Here in mice, we compared the effects of ketamine-xylazine and urethane-xylazine anesthesia on systemic physiologic parameters and the vestibular sensory evoked potential (VsEP), a tool used commonly to assess peripheral vestibular function. Urethane-xylazine anesthesia provided longer anesthesia, prolonged survival times, and less compromised respiratory and cardiovascular function, compared with ketamine-xylazine. In the absence of countermeasures, mice anesthetized with either ketamine-xylazine or urethane-xylazine showed evidence of hypoxemia and fluctuations in brain temperature, heart rate, respiration rate, and VsEP response latency. The levels of hypoxemia had no effect on VsEP response parameters over the period of study (2 to 5 h). Hypoxemia was effectively countered with O2 supplementation, which stabilized respiratory rates and improved mean survival times by 160% in mice anesthetized with ketamine-xylazine. Monitoring and controlling brain temperature reduced variation in VsEP latency. VsEP thresholds, latencies, and amplitudes did not differ between mice under ketamine-xylazine compared with urethane-xylazine when the brain temperature was held at the same set point. These findings demonstrate that urethane-xylazine provides improved systemic physiologic conditions during anesthesia in mice and may be substituted for ketamine-xylazine in studies using the VsEP to evaluate peripheral vestibular function. Such advantages may prove useful to research in other neuroscience areas and might reduce the number of animals used to achieve adequate sample sizes. PMID- 29695312 TI - Microbial Preparations (Probiotics) for the Prevention of Clostridium difficile Infection in Adults and Children: An Individual Patient Data Meta-analysis of 6,851 Participants. AB - OBJECTIVETo determine whether probiotic prophylaxes reduce the odds of Clostridium difficile infection (CDI) in adults and children.DESIGNIndividual participant data (IPD) meta-analysis of randomized controlled trials (RCTs), adjusting for risk factors.METHODSWe searched 6 databases and 11 grey literature sources from inception to April 2016. We identified 32 RCTs (n=8,713); among them, 18 RCTs provided IPD (n=6,851 participants) comparing probiotic prophylaxis to placebo or no treatment (standard care). One reviewer prepared the IPD, and 2 reviewers extracted data, rated study quality, and graded evidence quality.RESULTSProbiotics reduced CDI odds in the unadjusted model (n=6,645; odds ratio [OR] 0.37; 95% confidence interval [CI], 0.25-0.55) and the adjusted model (n=5,074; OR, 0.35; 95% CI, 0.23-0.55). Using 2 or more antibiotics increased the odds of CDI (OR, 2.20; 95% CI, 1.11-4.37), whereas age, sex, hospitalization status, and high-risk antibiotic exposure did not. Adjusted subgroup analyses suggested that, compared to no probiotics, multispecies probiotics were more beneficial than single-species probiotics, as was using probiotics in clinical settings where the CDI risk is >=5%. Of 18 studies, 14 reported adverse events. In 11 of these 14 studies, the adverse events were retained in the adjusted model. Odds for serious adverse events were similar for both groups in the unadjusted analyses (n=4,990; OR, 1.06; 95% CI, 0.89-1.26) and adjusted analyses (n=4,718; OR, 1.06; 95% CI, 0.89-1.28). Missing outcome data for CDI ranged from 0% to 25.8%. Our analyses were robust to a sensitivity analysis for missingness.CONCLUSIONSModerate quality (ie, certainty) evidence suggests that probiotic prophylaxis may be a useful and safe CDI prevention strategy, particularly among participants taking 2 or more antibiotics and in hospital settings where the risk of CDI is >=5%.TRIAL REGISTRATIONPROSPERO 2015 identifier: CRD42015015701Infect Control Hosp Epidemiol 2018;771-781. PMID- 29695314 TI - Disclosure of adverse events: a data linkage study reporting patient experiences among Australian adults aged >= 45 years. AB - Objective Since Australia initiated national open disclosure standards in 2002, open disclosure policies have been adopted in all Australian states and territories. Yet, research evidence regarding their adoption is limited. The aim of the present study was to determine the frequency with which patients who report an adverse event had information disclosed to them about the incident, including whether they participated in a formal open disclosure process, their experiences of the process and the extent to which these align with the current New South Wales (NSW) policy.Methods A cross-sectional survey about patient experiences of disclosure associated with an adverse event was administered to a random sample of 20000 participants in the 45 and Up Study who were hospitalised in NSW, Australia, between January and June 2014.Results Of the 18993 eligible potential participants, completed surveys were obtained from 7661 (40% response rate), with 474 (7%) patients reporting an adverse event. Of those who reported an adverse event, a significant majority reported an informal or bedside disclosure (91%; 430/474). Only 79 patients (17%) participated in a formal open disclosure meeting. Most informal disclosures were provided by nurses, with only 25% provided by medical practitioners.Conclusions Experiences of open disclosure may be enhanced by informing patients of their right to full disclosure in advance of or upon admission to hospital, and recognition of and support for informal or bedside disclosure for appropriate types of incidents. A review of the open disclosure guidelines in relation to the types of adverse events that require formal open disclosure and those more suitable to informal bedside disclosure is indicated. Guidelines for bedside disclosure should be drafted to assist medical practitioners and other health professionals facilitate and improve their communications about adverse events. Alignment of formal disclosure with policy requirements may also be enhanced by training multidisciplinary teams in the process.What is known about the topic? While open disclosure is required in all cases of serious adverse events, patients' experiences are variable, and lack of, or poor quality disclosures are all too common.What does this paper add? This paper presents experiences reported by patients across New South Wales in a large cross-sectional survey. Unlike previous studies of open disclosure, recently hospitalised patients were identified and invited using data linkage with medical records. Findings suggest that most patients receive informal disclosures rather than a process that aligns with the current policy guidance.What are the implications for practitioners? Experiences of open disclosure may be enhanced by informing patients of their right to full disclosure in advance of or upon admission to hospital, and recognition of and support for informal or bedside disclosure for appropriate types of incidents. PMID- 29695315 TI - Annoyance to different noise sources is associated with atrial fibrillation in the Gutenberg Health Study. AB - BACKGROUND: Annoyance is a common reaction in populations exposed to environmental noise and is associated with cardiovascular diseases. We investigated for the first time the existence of an association between noise annoyance and atrial fibrillation (AF). METHODS AND RESULTS: Cross-sectional data from 14,639 participants of the Gutenberg Health Study were collected between 2007 and 2012. Annoyance from road traffic, aircraft, railways, industrial/construction and neighbourhood noise during daytime and sleep were collected from all participants through questionnaires using a 5-point scale. AF was assessed via self-reported medical history and/or documentation of AF on the study electrocardiogram. 80% of the study participants were annoyed by noise to a certain degree. The major sources of annoyance during daytime and sleep were aircraft, road traffic and neighbourhood noise. We found significant associations between annoyance (per point increase) and AF for aircraft noise annoyance during daytime (odds ratio (OR) 1.04; 95% confidence interval (CI) 1.00-1.08) and during sleep (OR 1.09; 95% CI 1.05-1.13), road traffic noise annoyance during sleep (OR 1.15; 95% CI 1.08-1.22), neighbourhood noise annoyance during daytime (OR 1.14; 95% CI 1.09-1.20) and during sleep (OR 1.14; 95% CI 1.07-1.21), industrial noise annoyance during daytime (OR 1.11; 95% CI 1.04-1.18) and railway noise annoyance during sleep (OR 1.13; 95% CI 1.04-1.22). Different degrees of annoyance were not associated with changes in cardiovascular risk factors. DISCUSSION: The results suggest for the first time that noise annoyance is associated with AF. Further studies are warranted to gain insight in the mechanisms underlying the noise annoyance-disease relationship. PMID- 29695316 TI - Pain catastrophizing behaviors and their relation to poor patient-reported outcomes after scapular muscle reattachment. AB - HYPOTHESIS: We hypothesized that the patient-reported status following treatment of traumatic scapular muscle detachment would improve from the preoperative status and that higher pain catastrophizing scores would be more common in patients with poor postsurgical outcomes. METHODS: We studied 50 patients who met the diagnostic criteria for scapular muscle detachment and in whom rehabilitation failed. American Shoulder and Elbow Surgeons (ASES) scores were collected preoperatively and postoperatively. Patients completed a 7-point global rating of change scale, the Pain Catastrophizing Scale (PCS), and a 10-point satisfaction scale (0-3, not satisfied [NS]; 4-6, moderately satisfied [MS]; or 7-10, highly satisfied [HS]) focused on current shoulder use. Statistical analyses compared preoperative and postoperative ASES scores, compared the 3 levels of satisfaction and ASES scores, and compared ASES scores in patients with low PCS scores (LPCS) (<20) versus high PCS scores (HPCS) (>=20). Significance was set at P < .05. RESULTS: ASES scores significantly improved following surgery (42 +/- 20 preoperatively and 73 +/- 21 postoperatively) (P < .001), and the global rating of change score was 2 +/- 2. There were 39 LPCS patients (mean PCS, 7 +/- 6) and 11 HPCS patients (mean PCS, 34 +/- 8). HPCS patients had significantly lower postoperative ASES scores (53 +/- 18) than LPCS patients (79 +/- 18) (P < .001). The MS patients (n = 11) had significantly higher ASES scores than the NS patients (n = 10) (P = .003), while the HS patients (n = 29) had significantly greater ASES scores than the other groups (P <= .001). Of the HPCS patients, 90% were in the NS and MS groups compared with 10% in the HS group. CONCLUSIONS: Surgical restoration for scapular muscle detachment can result in meaningful improvement in outcomes. Pain catastrophizing negatively affected the self reported outcome scores. PMID- 29695317 TI - Influence of joint kinematics on polyethylene wear in anatomic shoulder joint arthroplasty. AB - BACKGROUND: Despite the positive results in total shoulder arthroplasties (TSAs), a higher revision rate is documented compared with total hip and knee replacements. Wear is the possible main cause of TSA failure in the long-term. This study investigated the effect of joint kinematics and the influence of the rotator cuff on the polyethylene wear performance in an anatomic TSA. METHODS: Lifting a load of 2 kg with an abduction/adduction of 0 degrees to 90 degrees was simulated for 2 * 106 cycles as a primary motion using a fully kinematic joint simulator. A combined rotation in anteversion-retroversion of +/-5 degrees and +/-10 degrees was also simulated. The force in the superior-inferior direction and the axial joint compression were applied under force control based on in vivo data of the shoulder. A soft tissue restraint model was used to simulate an intact and an insufficient rotator cuff. RESULTS: The highest wear rate in the intact rotator cuff group was 58.90 +/- 1.20 mg/106 cycles with a combined rotation of +/-10 degrees . When an insufficient rotator cuff was simulated, the highest polyethylene wear rate determined was 79.67 +/- 4.18 mg/106 cycles. CONCLUSIONS: This study confirms a high dependency of the polyethylene wear behavior and dimension on the joint kinematics in total shoulder replacement. This can be explained by an increasing cross-shear stress on the polyethylene component. The results obtained indicate that additional combined kinematics are an indispensable part of wear tests on anatomic shoulder replacements. PMID- 29695318 TI - Impact of fliD and virulence plasmid pSEV on response of chicken embryo fibroblasts to Salmonella Enteritidis. AB - Salmonella Enteritidis is the main serovar of poultry origin in humans, but its complex interaction with certain avian cells is still not fully understood. Previously we identified several genes significantly induced in chicken embryo fibroblasts (CEFs) by the wild-type strain S. Enteritidis 11 (SE 11). In the present study, we raised the question whether virulence-attenuated mutants of this strain would induce altered expression of the newly identified fibroblast genes associated with immune and non-immune functions of CEFs. Gene expression was evaluated by real-time PCR following challenge by the parental strain SE 11 and its virulence attenuated mutants lacking flagellin gene fliD only or fliD and the serovar-specific virulence plasmid pSEV. As a result, deletion mutants induced a lower expression of all immune genes, but an increased expression of the non-immune genes G0S2 and ENO2 relative to the parental strain. Our data indicate the importance of flagella and pSEV in modulation of virulence and host response in this model. We demonstrated, for the first time ever, an increased induction of survival genes G0S2 and ENO2 by virulence-attenuated mutants of S. Enteritidis. PMID- 29695319 TI - Reduction of mycoplasmal lesions and clinical signs by vaccination against Mycoplasma hyorhinis. AB - Porcine mycoplasmal pneumonia is a significant disease problem in the swine industry. The causative agents include Mycoplasma hyopneumoniae and Mycoplasma hyorhinis. M. hyopneumoniae is the major pathogen contributing to the porcine respiratory disease complex, but is difficult to isolate from the respiratory tract and tonsils, whereas M. hyorhinis is not. Although M. hyorhinis is commonly detected in the lungs, the role of M. hyorhinis as a cause of pneumonia remains unclear. Current vaccines for porcine mycoplasmal pneumonia only include M. hyopneumoniae, not M. hyorhinis. M. hyopneumoniae vaccines are widely used, but disease still occurs because of poor vaccine efficacy and possibly the presence of M. hyorhinis. In this study, an inactivated vaccine containing a mixture of M. hyorhinis and M. hyopneumoniae was generated and evaluated for safety, immunogenicity, and protective efficacy against challenge with M. hyorhinis in pigs. The inactivated vaccine induced an antibody response and reduced pneumonic lesions in the lungs and tracheas compared with the non-vaccinated group. PMID- 29695320 TI - Interactive effects of dexamethasone and opsonized Mycoplasma bovis on bovine neutrophil function in vitro. AB - Previously we had reported that exposure to high levels of glucocorticoids, and to unopsonized Mycoplasma bovis, has a negative interactive effect on bovine neutrophil function in vitro, and this interactive effect was a function of M. bovis strain differences. Here we hypothesized that in vitro treatment of bovine neutrophils by glucocorticoid would impair phagocytosis of opsonized M. bovis compared to non-treated neutrophils and such impairment would be a function of M. bovis strain differences. Neutrophils isolated from 20 mid-lactation cows were treated with immunosuppressive dose of 5 * 10-4 M dexamethasone or placebo and incubated with one of four opsonized M. bovis strains that had been isolated from bovine origin. After incubation neutrophil function measured included: percentage reduction in log10 of M. bovis CFU/ml, percentage of phagocytizing neutrophils, phagocytized M. bovis per neutrophil, and killed M. bovis per neutrophil. Least square means of all neutrophil groups were contrasted using linear mixed-effects models. Effects due to strain, treatment, and their interaction on neutrophil function measured by the number of phagocytized M. bovis per neutrophil and number of killed M. bovis per neutrophil were different (P < 0.05). However, no significant strain by treatment interaction effect on percentage reduction in log10 of M. bovis CFU/ml was found. Neither a strain nor a strain by treatment interaction was found to affect the percentage phagocytizing neutrophils. These findings might explain in part the association of stressful events with subsequent outbreaks of Mycoplasma bovis associated bovine diseases. PMID- 29695321 TI - Increased number of tissue factor protein expressing thrombocytes in canine idiopathic immune mediated hemolytic anemia. AB - Dogs suffering from canine idiopathic immune mediated hemolytic anemia (cIIMHA) are at great risk of dying particularly in the first two weeks after the diagnosis is made. This high mortality risk may be associated with the development of thromboembolism (TE) and/or disseminated intravascular coagulation (DIC) resulting in organ failure. The exact mechanism of the development of TE and/or DIC in cIIMHA is still undetermined. Therefore, this study investigates the presence of tissue factor (TF) in thrombocytes of dogs suffering from cIIMHA, using OptiPrepTM for the isolation of blood cells and immunocytochemistry (ICC) to visualize TF on thrombocytes. The normalised TF quantity, acquired with 'colour deconvolution' (ImageJ plug in), revealed that in cIIMHA dogs the fraction TF positive thrombocytes was statistically significant higher (P < 0.001; mean 0.79; n = 7) compared to the fraction TF positive thrombocytes of the healthy dogs (mean 0.43; n = 9). We further have indications that the fraction of TF positive thrombocytes decreases with time and therapy, but that the progression rate differs individually. Since cIIMHA dogs have more thrombocytes that are TF-positive compared to healthy dogs, this may explain the increased risk to develop TE and DIC. Furthermore, it seems that the number of TF-positive thrombocytes in cIIMHA dogs remains high during the first two weeks of the disease, the time when the animals are at greatest health risk. PMID- 29695322 TI - Transcriptome analysis of bovine lymphocytes stimulated by Atractylodis macrocephalae Koidz. polysaccharides in vitro. AB - Our previous studies demonstrated that total polysaccharides isolated from Atractylodis macrocephalae Koidz. (RAMPtp) had a therapeutic effect on bovine subclinical mastitis and an immunomodulatory effect on the lymphocytes from the supramammary lymph node (SMLN) in cows. To investigate the potential molecules involved in the immunomodulation, the present study identified 243 differentially expressed genes (DEGs) in RAMPtp-stimulated SMLN lymphocytes by RNA-seq. GO/KEGG enrichment analyses identified 47 significantly enriched gene ontology (GO) terms and 9 canonical pathways. These findings indicated that RAMPtp might stimulate lymphocytes to modulate productions of cytokines and chemokines through multiple compounds, targets and pathways. In particular, the Jak-STAT signaling pathway might be primarily involved in the immunomodulation. The therapeutic effect of RAMPtp on bovine subclinical mastitis may be attributed to activation of SMLN lymphocytes by injection of the polysaccharides in the area of SMLN in cows. PMID- 29695323 TI - Evaluation of mycobacteria-specific gamma interferon and antibody responses before and after a single intradermal skin test in cattle naturally exposed to M. avium subsp. paratuberculosis and experimentally infected with M. bovis. AB - This study reports on the diagnostic potential of IFN-gamma release assays and serology for Mycobacterium bovis in six naturally M. avium subsp. paratuberculosis (Map) exposed bulls of which four were intratracheally infected with a Belgian field strain of M. bovis. Heparinized blood, serum and fecal samples were collected at regular time intervals for mycobacteria-specific IFN gamma release assays, antibody analysis and for Map culture respectively. Single intradermal skin test (SIT) with bovine tuberculin (PPD-B) was performed on day 115 and animals were sacrificed on day 133 after M. bovis infection. Organs were collected and stored for histopathological examination, modified Ziehl-Neelsen staining and bacteriological analysis of M. bovis and Map by culture and RT-PCR. Prior to infection five animals showed positive IFN-gamma responses to avian PPD (PPD-A) and four were positive in Map PCR (IS900) on faeces. Three M. bovis infected animals reacted as early as day 14 with sustained higher PPD-B than PPD A specific IFN-gamma responses, whereas the fourth animal (with the strongest PPD A response prior to infection) showed sustained higher PPD-B specific IFN-gamma levels only a day 56 after infection. Two of the infected animals had a sustained positive IFN-gamma response to the ESAT-6/CFP-10/TB7.7 (QuantiFERON(r)-TB Gold) peptide cocktail as early as day 14, among which the animal with the initial high PPD-A response. Later during infection, positive responses were found to ESAT-6 peptides in three infected bulls and to CFP-10 peptides in all four infected bulls. One of the control animals reacted intermittently to the ESAT 6/CFP10/TB7.7 cocktail. Prior to SIT, weak but positive MPB83/MBP70 specific antibody responses were detected in two of the infected bulls. All four M. bovis infected bulls reacted with a positive skin test and showed, as reported by others, increased mycobacteria specific IFN-gamma production and increased positive responses in MPB83/MBP70 specific serology after SIT. At autopsy, M. bovis lesions were detected in all four experimentally infected bulls. Our results indicate that in Map exposed cattle, M. bovis diagnosis using IFN-gamma assays needs a combination of PPD-B/A and ESAT-6/CFP10 for early and optimal sensitivity and that sensitivity of MPB83/MBP70 serodiagnosis is dramatically increased by prior skin testing. Map exposure did not interfere with the development of SIT in M. bovis infected animals, but resulted in a false positive M. bovis specific IFN-gamma and antibody response after SIT in one of the two control animals (which remained negative in skin-test). PMID- 29695324 TI - Detection of Mycobacterium bovis infection in African buffaloes (Syncerus caffer) using QuantiFERON(r)-TB Gold (QFT) tubes and the Qiagen cattletype(r) IFN-gamma ELISA. AB - African buffaloes (Syncerus caffer) are wildlife maintenance hosts of Mycobacterium bovis, the cause of bovine tuberculosis. Consequently, M. bovis infected buffaloes pose a transmission risk for cattle and other wildlife species. Previously, a modification to the Qiagen QuantiFERON(r)-TB Gold (QFT) system, using QFT tubes and an in-house bovine interferon-gamma (IFN-gamma) ELISA, was evaluated for the detection of M. bovis infection in buffaloes. Subsequently, Qiagen has developed a commercially available cattletype(r) IFN gamma ELISA for the detection of antigen-specific IFN-gamma release in ruminants. The aim of this study was to investigate the use of QFT tubes and the cattletype(r) IFN-gamma ELISA, in a cattletype IFN-gamma release assay (IGRA), to detect M. bovis infection in African buffaloes. The test agreements between the cattletype IGRA, single comparative intradermal skin test (SCITT) and Bovigam(r) 1G IGRA in two M. bovis-exposed buffalo populations (n = 134 and n = 92) were calculated and kappa coefficients ranged from 0.65 (95% CI 0.48-0.82) to 0.86 (95% CI 0.72-0.99). Increasing the QFT incubation time in one M. bovis-exposed buffalo cohort (n = 92), from 20 to 40 h, had no effect on the cattletype IGRA test results. Inter-assay and intra-assay reproducibility determination for the cattletype IGRA produced coefficient of variations (CV) <9.1% and <1.7%, respectively. A total of 21/21 known M. bovis-unexposed buffaloes tested negative in the cattletype IGRA. Moreover, the cattletype IGRA test result values were significantly greater for 13 M. bovis culture-positive buffaloes compared with 14 M. bovis-exposed culture-negative (P < .01) and 21 M. bovis-unexposed (P < .001) buffaloes, respectively. These findings suggest that the combination of QFT tubes and the cattletype(r) IFN-gamma ELISA is a promising new diagnostic assay for the detection of M. bovis infection in African buffaloes. However, further research is needed to evaluate the sensitivity and specificity of the assay in larger African buffalo populations. PMID- 29695325 TI - Cruciate ligament degeneration and stifle joint synovitis in 56 dogs with intact cranial cruciate ligaments: Correlation of histological findings and numbers and phenotypes of inflammatory cells with age, body weight and breed. AB - The majority of dogs with ruptured cranial cruciate ligaments (crCLs) have inflammatory changes of the stifle joint suggesting that synovitis is an important factor which is involved in the development of degenerative ligament changes. Detailed information is not available concerning the possible occurrence of inflammatory changes in the stifle joint synovium of dogs with macroscopically intact crCLs and its correlation with presence and severity of degenerative changes of the crCLs. Therefore, the purpose of this study was to examine post mortem tissue samples of 56 dogs with non-ruptured crCLs histologically for the presence of inflammatory and degenerative changes of the stifle joint synovium and cruciate ligaments, respectively. In 25/56 (44.6%) dogs, histology showed that both lymphoplasmacytic synovitis and degenerative alterations of the crCLs were present. In these dogs, there was a significant positive statistical correlation between the severity of synovitis and degenerative crCL lesions. The results suggest that synovitis in the stifle joints of dogs with non-ruptured crCLs is a frequent event and probably is involved in the development of degenerative lesions occurring in canine crCLs. Also, the severity of crCL degeneration in these 25 dogs was significantly correlated with their age and body weight. In 2/56 (3.6%) cases, only lymphoplasmacytic synovitis was found in the absence of degenerative crCL lesions. In 15/56 (26.8%) dogs, only degenerative lesions of the crCLs without synovitis were present. Statistically, a significant correlation was found between the severity of degenerative alterations and age and body weight of these dogs. Phenotyping of inflammatory cells by immunohistochemistry showed that the synovium of dogs which histologically had lymphoplasmacytic synovitis was infiltrated with CD3+ T lymphocytes, CD79+ B lymphocytes, major histocompatibility class II antigen (MHC class II)+ cells and macrophages expressing CD163 or S100/A8/S100A9 (calprotectin), while tartrate-resistant acid phosphatase (TRAP)+ cells were absent. Quantification and statistical evaluation of inflammatory cell types in the inflamed synovium revealed that the numbers of lymphocytic cells and macrophages were significantly correlated with the severity of synovitis. These findings indicate that, besides T and B lymphocytes, both pro- and anti inflammatory macrophages play a role in the development of degenerative crCL alterations. PMID- 29695326 TI - R-Phycoerythrin-labeled Mannheimia haemolytica for the simultaneous measurement of phagocytosis and intracellular reactive oxygen species production in bovine blood and bronchoalveolar lavage cells. AB - The present study aimed to validate the use of R-phycoerythrin (R-PE)-labeled Mannheimia haemolytica to simultaneously stimulate phagocytosis and intracellular production of reactive oxygen species (ROS) by blood phagocytes in bronchoalveolar lavage (BAL) fluid. Initially, R-PE-labeled M. haemolytica was inactivated using a water bath at 60 degrees C for 60 min. Afterwards, R-PE labelling of bacteria was confirmed by flow cytometry. The geometric mean fluorescence intensity of R-PE-labeled bacteria (FL2 detector, 585 +/- 42 nm) was analyzed by flow cytometry and was 41.5-fold higher than the respective unlabeled controls, confirming the success of bacterial conjugation to R-PE. Phagocytosis and intracellular production of ROS by blood neutrophils and monocytes, and by BAL CD14+ macrophages, in 12 healthy 6-month-old male calves were then performed using R-PE-labeled bacteria and 2',7'-dichlorofluorescein diacetate (DCFH-DA) as probes. Confocal microscopy was used to confirm phagocytosis of R-PE-labeled M. haemolytica by phagocytes and to exclude erroneous measurements of bacteria adhering to the leukocyte membrane. The present study showed that there is no difference in the ROS production without stimulus and in the presence of M. haemolytica by peripheral blood neutrophils and monocytes, in contrast to the increased ROS production by local alveolar macrophages upon stimulation by M. haemolytica. This emphasizes the importance of alveolar macrophages in the maintenance of homeostasis and health of the respiratory system, which can be supported during the inflammatory process by the rapid recruitment of neutrophils with high microbicidal and phagocytic capacity. The method described here provides an easy and feasible tool to measure phagocytosis and intracellular ROS production by phagocytes, especially when commonly used probes for intracellular ROS production were used, such as DCFH-DA and dihydrorhodamine 123. PMID- 29695327 TI - High sensitivity troponin: The Sisyphean pursuit of zero percent miss rate for acute coronary syndrome in the ED. AB - BACKGROUND: The United States Food and Drug Administration recently approved a high sensitivity troponin (hsTn) assay for use. Recent literature has investigated the diagnostic accuracy of hsTn for acute coronary syndrome (ACS) in the emergency department (ED) and its use in accelerated diagnostic protocols. OBJECTIVE: This article evaluates the existing literature and discusses incorporation of hsTn testing into ED clinical practice based on best available evidence. DISCUSSION: Interpretation of this literature for clinical application is challenging due to heterogeneity across studies with regards to the hsTn assays examined, time intervals for delta troponin tests, and study populations. The high sensitivity of these assays is predicated upon the ability of the physician to clinically determine a patient to have a low pre-test probability of disease. Physicians may further ensure maximal sensitivity by defining the cut off for a positive value as the limit of detection and utilizing delta troponin testing. These assays do not obviate the need to consider follow-up for risk stratification for discharged patients. Higher sensitivity compared to standard troponin tests comes at the expense of lower specificity. Indiscriminate testing may translate to greater numbers of abnormal troponin results in patients with non-ACS syndromes, potentially leading to increased healthcare costs, hospital admissions, increased ED lengths of stay, and unnecessary interventions. CONCLUSION: As hsTn becomes more widespread, it is imperative emergency physicians understand its potential and limitations. Knowledge of test characteristics is vital to ensure appropriate use. Further study of hsTn is required to optimize use. PMID- 29695328 TI - The ravages of COPD. PMID- 29695329 TI - Orban not delivering health for Hungary. PMID- 29695330 TI - UK COPD treatment: failing to progress. PMID- 29695331 TI - Sexual harassment and abuse-the sinister underbelly. PMID- 29695332 TI - Social lobbying: a call to arms for public health. PMID- 29695333 TI - Offline: The legacy and lessons of May '68. PMID- 29695334 TI - Claims of sexual harassment and assault threaten UN agency. PMID- 29695335 TI - Winnie Mpanju-Shumbusho: leader in the fight against malaria. PMID- 29695336 TI - Stories of shame. PMID- 29695337 TI - Healthier lives for all Africans. PMID- 29695338 TI - Surgical surveillance in resource-poor settings. PMID- 29695339 TI - The hepatitis B epidemic in China should receive more attention. PMID- 29695340 TI - Prophylactic repair to prevent midline incisional hernia. PMID- 29695341 TI - Mesh augmentation for midline abdominal closure. PMID- 29695342 TI - Prophylactic mesh augmentation in midline laparotomy. PMID- 29695343 TI - Prevention of dementia by targeting risk factors. PMID- 29695344 TI - Prevention of dementia by targeting risk factors. PMID- 29695346 TI - Department of Error. PMID- 29695345 TI - Prevention of dementia by targeting risk factors - Authors' reply. PMID- 29695347 TI - Department of Error. PMID- 29695349 TI - Quality of life after multicatheter breast brachytherapy. PMID- 29695350 TI - Plotting a route to a universal influenza vaccine. PMID- 29695348 TI - Quality-of-life results for accelerated partial breast irradiation with interstitial brachytherapy versus whole-breast irradiation in early breast cancer after breast-conserving surgery (GEC-ESTRO): 5-year results of a randomised, phase 3 trial. AB - BACKGROUND: Previous results from the GEC-ESTRO trial showed that accelerated partial breast irradiation (APBI) using multicatheter brachytherapy in the treatment of early breast cancer after breast-conserving surgery was non-inferior to whole-breast irradiation in terms of local control and overall survival. Here, we present 5-year results of patient-reported quality of life. METHODS: We did this randomised controlled phase 3 trial at 16 hospitals and medical centres in seven European countries. Patients aged 40 years or older with 0-IIA breast cancer were randomly assigned (1:1) after breast-conserving surgery (resection margins >=2 mm) to receive either whole-breast irradiation of 50 Gy with a boost of 10 Gy or APBI using multicatheter brachytherapy. Randomisation was stratified by study centre, tumour type, and menopausal status, with a block size of ten and an automated dynamic algorithm. There was no masking of patients or investigators. The primary endpoint of the trial was ipsilateral local recurrence. Here, we present 5-year results of quality of life (a prespecified secondary endpoint). Quality-of-life questionnaires (European Organisation for Research and Treatment of Cancer QLQ-C30, breast cancer module QLQ-BR23) were completed before radiotherapy (baseline 1), immediately after radiotherapy (baseline 2), and during follow-up. We analysed the data according to treatment received (as-treated population). Recruitment was completed in 2009, and long term follow-up is continuing. The trial is registered at ClinicalTrials.gov, number NCT00402519. FINDINGS: Between April 20, 2004, and July 30, 2009, 633 patients had accelerated partial breast irradiation and 551 patients had whole breast irradiation. Quality-of-life questionnaires at baseline 1 were available for 334 (53%) of 663 patients in the APBI group and 314 (57%) of 551 patients in the whole-breast irradiation group; the response rate was similar during follow up. Global health status (range 0-100) was stable in both groups: at baseline 1, APBI group mean score 65.5 (SD 20.6) versus whole-breast irradiation group 64.6 (19.6), p=0.37; at 5 years, APBI group 66.2 (22.2) versus whole-breast irradiation group 66.0 (21.8), p=0.94. The only moderate, significant difference (difference of 10-20 points) between the groups was found in the breast symptoms scale. Breast symptom scores were significantly higher (ie, worse) after whole breast irradiation than after APBI at baseline 2 (difference of means 13.6, 95% CI 9.7-17.5; p<0.0001) and at 3-month follow-up (difference of means 12.7, 95% CI 9.8-15.6; p<0.0001). INTERPRETATION: APBI with multicatheter brachytherapy was not associated with worse quality of life compared with whole-breast irradiation. This finding supports APBI as an alternative treatment option after breast conserving surgery for patients with early breast cancer. FUNDING: German Cancer Aid. PMID- 29695351 TI - Global spread of antibiotic-resistant bacteria and mass-gathering religious events. PMID- 29695353 TI - Corrections. PMID- 29695352 TI - 2018 WHO hand hygiene campaign: preventing sepsis in health care and the path to universal health coverage. PMID- 29695354 TI - It's too soon to pull the plug on antibiotic cycling. PMID- 29695355 TI - It's too soon to pull the plug on antibiotic cycling - Authors' reply. PMID- 29695356 TI - Colistin versus colistin plus meropenem for severe infections. PMID- 29695357 TI - Colistin versus colistin plus meropenem for severe infections. PMID- 29695358 TI - Colistin versus colistin plus meropenem for severe infections Authors' reply. PMID- 29695359 TI - Low procalcitonin, community acquired pneumonia, and antibiotic therapy. PMID- 29695360 TI - Low procalcitonin, community acquired pneumonia, and antibiotic therapy - Authors' reply. PMID- 29695361 TI - Influenza: the role of the Middle East and north Africa? PMID- 29695362 TI - Constantly high incidence of scarlet fever in Germany. PMID- 29695363 TI - Adverse pregnancy outcomes due to Chlamydia trachomatis. PMID- 29695364 TI - North Korea and the Global Fund. PMID- 29695365 TI - Neglected tropical diseases: securing sustainability. PMID- 29695368 TI - Hookworm in the eye. PMID- 29695369 TI - Psychosocial Factors of Health Professionals' Intention to Use a Decision Aid for Down Syndrome Screening: Cross-Sectional Quantitative Study. AB - BACKGROUND: Decisions about prenatal screening for Down syndrome are difficult for women, as they entail risk, potential loss, and regret. Shared decision making increases women's knowledge of their choices and better aligns decisions with their values. Patient decision aids foster shared decision making but are rarely used in this context. OBJECTIVE: One of the most promising strategies for implementing shared decision making is distribution of decision aids by health professionals. We aimed to identify factors influencing their intention to use a DA during prenatal visit for decisions about Down syndrome screening. METHODS: We conducted a cross-sectional quantitative study. Using a Web panel, we conducted a theory-based survey of health professionals in Quebec province (Canada). Eligibility criteria were as follows: (1) family physicians, midwives, obstetrician-gynecologists, or trainees in these professions; (2) involved in prenatal care; and (3) working in Quebec province. Participants watched a video depicting a health professional using a decision aid during a prenatal consultation with a woman and her partner, and then answered a questionnaire based on an extended version of the theory of planned behavior, including some of the constructs of the theoretical domains framework. The questionnaire assessed 8 psychosocial constructs (attitude, anticipated regret, subjective norm, self identity, moral norm, descriptive norm, self-efficacy, and perceived control), 7 related sets of behavioral beliefs (advantages, disadvantages, emotions, sources of encouragement or discouragement, incentives, facilitators, and barriers), and sociodemographic data. We performed descriptive, bivariate, and multiple linear regression analyses to identify factors influencing health professionals' intention to use a decision aid. RESULTS: Among 330 health professionals who completed the survey, 310 met the inclusion criteria: family physicians, 55.2% (171/310); obstetrician-gynecologists, 33.8% (105/310); and midwives, 11.0% (34/310). Of these, 80.9% were female (251/310). Mean age was 39.6 (SD 11.5) years. Less than half were aware of any decision aids at all. In decreasing order of importance, factors influencing their intention to use a decision aid for Down syndrome prenatal screening were as follows: self-identity (beta=.325, P<.001), attitude (beta=.297, P<.001), moral norm (beta=.288, P<.001), descriptive norm (beta=.166, P<.001), and anticipated regret (beta=.099, P=.003). Underlying behavioral beliefs significantly related to intention were that the use of a decision aid would promote decision making (beta=.117, 95% CI 0.043-0.190), would reassure health professionals (beta=.100, 95% CI 0.024-0.175), and might require more time than planned for the consultation (beta=-.077, 95% CI -0.124 to 0.031). CONCLUSIONS: We identified psychosocial factors that could influence health professionals' intention to use a decision aid about Down syndrome screening. Strategies should remind them of the following: (1) using a decision aid for this purpose should be a common practice, (2) it would be expected of someone in their societal role, (3) the experience of using it will be satisfying and reassuring, and (4) it is likely to be compatible with their moral values. PMID- 29695370 TI - Effects of a 12-Week Digital Care Program for Chronic Knee Pain on Pain, Mobility, and Surgery Risk: Randomized Controlled Trial. AB - BACKGROUND: Chronic knee pain, most commonly caused by knee osteoarthritis, is a prevalent condition which in most cases can be effectively treated through conservative, non-surgical care involving exercise therapy, education, psychosocial support, and weight loss. However, most people living with chronic knee pain do not receive adequate care, leading to unnecessary use of opiates and surgical procedures. OBJECTIVE: Assess the efficacy of a remotely delivered digital care program for chronic knee pain. METHODS: We enrolled 162 participants into a randomized controlled trial between January and March 2017. Participants were recruited from participating employers using questionnaires for self assessment of their knee pain, and randomized into treatment (n=101) and control (n=61) groups. Participants in the treatment group were enrolled in the Hinge Health digital care program for chronic knee pain. This is a remotely delivered, home-based 12-week intervention that includes sensor-guided exercise therapy, education, cognitive behavioral therapy, weight loss, and psychosocial support through a personal coach and team-based interactions. The control group received three education pieces regarding self-care for chronic knee pain. Both groups had access to treatment-as-usual. The primary outcome was the Knee Injury and Osteoarthritis Outcome Score (KOOS) Pain subscale and KOOS Physical Function Shortform (KOOS-PS). Secondary outcomes were visual analog scales (VAS) for pain and stiffness respectively, surgery intent, and self-reported understanding of the condition and treatment options. Outcome measures were analyzed by intention to treat (excluding 7 control participants who received the digital care program due to administrative error) and per protocol. RESULTS: In an intent-to-treat analysis the digital care program group had a significantly greater reduction in KOOS Pain compared to the control group at the end of the program (greater reduction of 7.7, 95% CI 3.0 to 12.3, P=.002), as well as a significantly greater improvement in physical function (7.2, 95% CI 3.0 to 11.5, P=.001). This was also reflected in the secondary outcomes VAS pain (12.3, 95% CI 5.4 to 19.1, P<.001) and VAS stiffness (13.4, 95% CI 5.6 to 21.1, P=.001). Participants' self-reported likelihood (from 0% to 100%) of having surgery also reduced more strongly in the digital care program group compared to the control group over the next 1 year ( 9.4 percentage points, pp, 95% CI -16.6 to -2.2, P=.01), 2 years (-11.3 pp, 95% CI -20.1 to -2.5, P=.01), and 5 years (-14.6 pp, 95% CI -23.6 to -5.5, P=.002). Interest in surgery (from 0 to 10) also reduced more so in the digital care program compared to control group (-1.0, 95% CI -1.7 to -0.2, P=.01). Participants' understanding of the condition and treatment options (on a scale from 0 to 4) increased more substantially for participants in the digital care program than those in the control group (0.9, 95% CI 0.6 to 1.3, P<.001). In an analysis on participants that completed the intervention (per protocol analysis) all primary and secondary outcomes remained significant at greater effect magnitudes compared to intention to treat, with those completing the program showing a 61% (95% CI 48 to 74) reduction in VAS pain compared to 21% (95% CI 5 to 38) in the control group (P<.001). Accounting for the cost of administering the program, we estimate net cost savings on surgery alone of US $4340 over 1 year and $7900 over 5 years for those participants completing the digital care program compared to those in the control group receiving treatment-as-usual. In an exploratory subgroup analysis including only participants exhibiting clinical symptoms of osteoarthritis the program proved equally effective. CONCLUSIONS: This trial provides strong evidence that a comprehensive 12-week digital care program for chronic knee pain, including osteoarthritis, yields significantly improved outcomes for pain, physical function, stiffness, surgery risk, and understanding of the condition, compared to a control group. TRIAL REGISTRATION: International Standard Randomized Controlled Trial Number (ISRCTN) 13307390; http://www.isrctn.com/ISRCTN13307390 (Archived by WebCite at http://www.webcitation.org/6ycwjGL73). PMID- 29695371 TI - Worker Preferences for a Mental Health App Within Male-Dominated Industries: Participatory Study. AB - BACKGROUND: Men are less likely to seek help for mental health problems, possibly because of stigma imposed by cultural masculine norms. These tendencies may be amplified within male-dominated workplaces such as the emergency services or transport industries. Mobile apps present a promising way to provide access to mental health support. However, little is known about the kinds of mental health technologies men would be willing to engage with, and no app can be effective if the intended users do not engage with it. OBJECTIVE: The goal of this participatory user research study was to explore the perceptions, preferences, and ideas of workers in male-dominated workplaces to define requirements for a mental health app that would be engaging and effective at improving psychological well-being. METHODS: Workers from male-dominated workplaces in rural, suburban, and urban locations took part in an exploratory qualitative study involving participatory workshops designed to elicit their perspectives and preferences for mental health support and the design of an app for mental health. Participants generated a number of artifacts (including draft screen designs and promotional material) designed to reify their perceptions, tacit knowledge, and ideas. RESULTS: A total of 60 workers aged between 26 and 65 years, 92% (55/60) male, from male-dominated workplaces in rural (16/60, 27%), suburban (14/60, 23%), and urban (30/60, 50%) locations participated in one of the 6 workshops, resulting in 49 unique feature ideas and 81 participant-generated artifacts. Thematic analysis resulted in a set of feature, language, and style preferences, as well as characteristics considered important by participants for a mental health app. The term "mental health" was highly stigmatized and disliked by participants. Tools including a mood tracker, self-assessment, and mood-fix tool were highly valued, and app characteristics such as brevity of interactions, minimal on-screen text, and a solutions-oriented approach were considered essential by participants. Some implementation strategies based on these findings are included in the discussion. CONCLUSIONS: Future mental health mobile phone apps targeting workers in male dominated workplaces need to consider language use and preferred features, as well as balance the preferences of users with the demands of evidence-based intervention. In addition to informing the development of mental health apps for workers in male-dominated industries, these findings may also provide insights for mental health technologies, for men in general, and for others in high-stigma environments. PMID- 29695372 TI - ComprehENotes, an Instrument to Assess Patient Reading Comprehension of Electronic Health Record Notes: Development and Validation. AB - BACKGROUND: Patient portals are widely adopted in the United States and allow millions of patients access to their electronic health records (EHRs), including their EHR clinical notes. A patient's ability to understand the information in the EHR is dependent on their overall health literacy. Although many tests of health literacy exist, none specifically focuses on EHR note comprehension. OBJECTIVE: The aim of this paper was to develop an instrument to assess patients' EHR note comprehension. METHODS: We identified 6 common diseases or conditions (heart failure, diabetes, cancer, hypertension, chronic obstructive pulmonary disease, and liver failure) and selected 5 representative EHR notes for each disease or condition. One note that did not contain natural language text was removed. Questions were generated from these notes using Sentence Verification Technique and were analyzed using item response theory (IRT) to identify a set of questions that represent a good test of ability for EHR note comprehension. RESULTS: Using Sentence Verification Technique, 154 questions were generated from the 29 EHR notes initially obtained. Of these, 83 were manually selected for inclusion in the Amazon Mechanical Turk crowdsourcing tasks and 55 were ultimately retained following IRT analysis. A follow-up validation with a second Amazon Mechanical Turk task and IRT analysis confirmed that the 55 questions test a latent ability dimension for EHR note comprehension. A short test of 14 items was created along with the 55-item test. CONCLUSIONS: We developed ComprehENotes, an instrument for assessing EHR note comprehension from existing EHR notes, gathered responses using crowdsourcing, and used IRT to analyze those responses, thus resulting in a set of questions to measure EHR note comprehension. Crowdsourced responses from Amazon Mechanical Turk can be used to estimate item parameters and select a subset of items for inclusion in the test set using IRT. The final set of questions is the first test of EHR note comprehension. PMID- 29695374 TI - Relevance of Trust Marks and CE Labels in German-Language Store Descriptions of Health Apps: Analysis. AB - BACKGROUND: In addition to mandatory CE marking ("CE" representing Conformite Europeenne, with the CE marking being a symbol of free marketability in the European Economic Area) for medical devices, there are various seals, initiatives, action groups, etc, in the health app context. However, whether manufacturers use them to distinguish their apps and attach relevance to them is unclear. OBJECTIVE: The objective was to take a snapshot of quality seals, regulatory marks, and other orientation aids available on the German app market and to determine whether manufacturers deem such labels relevant enough to apply them to their apps, namely as reflected by mentions in app description texts in a typical app store (ie, Apple's App Store). METHODS: A full survey of the metadata of 103,046 apps from Apple's German App Store in the Medicine and Health & Fitness categories was carried out. For apps with German-language store descriptions (N=8767), these were automatically searched for the occurrence of relevant keywords and validated manually (N=41). In addition, the websites of various app seal providers were checked for assigned seals. RESULTS: Few manufacturers referenced seals in the descriptions (5/41), although this would have been expected more often based on the seals we were able to identify from the seal providers' Web pages, and there were 34 of 41 that mentioned CE status in the descriptions. Two apps referenced an app directory curated by experts; however, this is not an alternative to CE marks and seals of approval. CONCLUSIONS: Currently, quality seals seem to be irrelevant for manufacturers. In line with regulatory requirements, mentions of medical device status are more frequent; however, neither characteristic is effective for identifying high quality apps. To improve this situation, a possibly legally obligatory, standardized reporting system should be implemented. PMID- 29695373 TI - Impact of the Growing Healthy mHealth Program on Maternal Feeding Practices, Infant Food Preferences, and Satiety Responsiveness: Quasi-Experimental Study. AB - BACKGROUND: Infancy is an important life stage for obesity prevention efforts. Parents' infant feeding practices influence the development of infants' food preferences and eating behaviors and subsequently diet and weight. Mobile health (mHealth) may provide a feasible medium through which to deliver programs to promote healthy infant feeding as it allows low cost and easy access to tailored content. OBJECTIVE: The objective of this study was to describe the effects of an mHealth intervention on parental feeding practices, infant food preferences, and infant satiety responsiveness. METHODS: A quasi-experimental study was conducted with an mHealth intervention group (Growing Healthy) and a nonrandomized comparison group ("Baby's First Food"). The intervention group received access to a free app with age-appropriate push notifications, a website, and an online forum that provided them with evidence-based advice on infant feeding for healthy growth from birth until 9 months of age. Behavior change techniques were selected using the Behaviour Change Wheel framework. Participants in both groups completed three Web-based surveys, first when their infants were less than 3 months old (baseline, T1), then at 6 months (time 2, T2), and 9 months of age (time 3, T3). Surveys included questions on infant feeding practices and beliefs (Infant Feeding Questionnaire, IFQ), satiety responsiveness (Baby Eating Behaviour Questionnaire), and infant's food exposure and liking. Multivariate linear regression models, estimated using maximum likelihood with bootstrapped standard errors, were fitted to compare continuous outcomes between the intervention groups, with adjustment for relevant covariates. Multivariate logistic regression adjusting for the same covariates was performed for categorical outcomes. RESULTS: A total of 645 parents (Growing Healthy: n=301, Baby's First Food: n=344) met the eligibility criteria and were included in the study, reducing to a sample size of 546 (Growing Healthy: n=234, Baby's First Food: n=312) at T2 and a sample size of 518 (Growing Healthy: n=225, Baby's First Food: n=293) at T3. There were approximately equal numbers of boy and girl infants, and infants were aged less than 3 months at baseline (Growing Healthy: mean 7.0, SD 3.7 weeks; Baby's First Food: mean 7.9, SD 3.8 weeks), with Growing Healthy infants being slightly younger than Baby's First Food infants (P=.001). All but one (IFQ subscale "concerns about infant overeating or becoming overweight" at T2) of the measured outcomes did not differ between Growing Healthy and Baby's First Food. CONCLUSIONS: Although mHealth can be effective in promoting some health behaviors and offers many advantages in health promotion, the results of this study suggest that design and delivery characteristics needed to maximize the impact of mHealth interventions on infant feeding are uncertain. The sensitivity of available measurement tools and differences in baseline characteristics of participants may have also affected the results. PMID- 29695375 TI - A Comparison and Calibration of a Wrist-Worn Blood Pressure Monitor for Patient Management: Assessing the Reliability of Innovative Blood Pressure Devices. AB - BACKGROUND: Clinical guidelines recommend monitoring of blood pressure at home using an automatic blood pressure device for the management of hypertension. Devices are not often calibrated against direct blood pressure measures, leaving health care providers and patients with less reliable information than is possible with current technology. Rigorous assessments of medical devices are necessary for establishing clinical utility. OBJECTIVE: The purpose of our study was 2-fold: (1) to assess the validity and perform iterative calibration of indirect blood pressure measurements by a noninvasive wrist cuff blood pressure device in direct comparison with simultaneously recorded peripheral and central intra-arterial blood pressure measurements and (2) to assess the validity of the measurements thereafter of the noninvasive wrist cuff blood pressure device in comparison with measurements by a noninvasive upper arm blood pressure device to the Canadian hypertension guidelines. METHODS: The cloud-based blood pressure algorithms for an oscillometric wrist cuff device were iteratively calibrated to direct pressure measures in 20 consented patient participants. We then assessed measurement validity of the device, using Bland-Altman analysis during routine cardiovascular catheterization. RESULTS: The precalibrated absolute mean difference between direct intra-arterial to wrist cuff pressure measurements were 10.8 (SD 9.7) for systolic and 16.1 (SD 6.3) for diastolic. The postcalibrated absolute mean difference was 7.2 (SD 5.1) for systolic and 4.3 (SD 3.3) for diastolic pressures. This is an improvement in accuracy of 33% systolic and 73% diastolic with a 48% reduction in the variability for both measures. Furthermore, the wrist cuff device demonstrated similar sensitivity in measuring high blood pressure compared with the direct intra-arterial method. The device, when calibrated to direct aortic pressures, demonstrated the potential to reduce a treatment gap in high blood pressure measurements. CONCLUSIONS: The systolic pressure measurements of the wrist cuff have been iteratively calibrated using gold standard central (ascending aortic) pressure. This improves the accuracy of the indirect measures and potentially reduces the treatment gap. Devices that undergo auscultatory (indirect) calibration for licensing can be greatly improved by additional iterative calibration via intra-arterial (direct) measures of blood pressure. Further clinical trials with repeated use of the device over time are needed to assess the reliability of the device in accordance with current and evolving guidelines for informed decision making in the management of hypertension. TRIAL REGISTRATION: ClinicalTrials.gov NCT03015363; https://clinicaltrials.gov/ct2/show/NCT03015363 (Archived by WebCite at http://www.webcitation.org/6xPZgseYS). PMID- 29695376 TI - Clinical Relation Extraction Toward Drug Safety Surveillance Using Electronic Health Record Narratives: Classical Learning Versus Deep Learning. AB - BACKGROUND: Medication and adverse drug event (ADE) information extracted from electronic health record (EHR) notes can be a rich resource for drug safety surveillance. Existing observational studies have mainly relied on structured EHR data to obtain ADE information; however, ADEs are often buried in the EHR narratives and not recorded in structured data. OBJECTIVE: To unlock ADE-related information from EHR narratives, there is a need to extract relevant entities and identify relations among them. In this study, we focus on relation identification. This study aimed to evaluate natural language processing and machine learning approaches using the expert-annotated medical entities and relations in the context of drug safety surveillance, and investigate how different learning approaches perform under different configurations. METHODS: We have manually annotated 791 EHR notes with 9 named entities (eg, medication, indication, severity, and ADEs) and 7 different types of relations (eg, medication-dosage, medication-ADE, and severity-ADE). Then, we explored 3 supervised machine learning systems for relation identification: (1) a support vector machines (SVM) system, (2) an end-to-end deep neural network system, and (3) a supervised descriptive rule induction baseline system. For the neural network system, we exploited the state-of-the-art recurrent neural network (RNN) and attention models. We report the performance by macro-averaged precision, recall, and F1-score across the relation types. RESULTS: Our results show that the SVM model achieved the best average F1-score of 89.1% on test data, outperforming the long short-term memory (LSTM) model with attention (F1-score of 65.72%) as well as the rule induction baseline system (F1-score of 7.47%) by a large margin. The bidirectional LSTM model with attention achieved the best performance among different RNN models. With the inclusion of additional features in the LSTM model, its performance can be boosted to an average F1-score of 77.35%. CONCLUSIONS: It shows that classical learning models (SVM) remains advantageous over deep learning models (RNN variants) for clinical relation identification, especially for long-distance intersentential relations. However, RNNs demonstrate a great potential of significant improvement if more training data become available. Our work is an important step toward mining EHRs to improve the efficacy of drug safety surveillance. Most importantly, the annotated data used in this study will be made publicly available, which will further promote drug safety research in the community. PMID- 29695377 TI - A Kinematic Sensor and Algorithm to Detect Motor Fluctuations in Parkinson Disease: Validation Study Under Real Conditions of Use. AB - BACKGROUND: A new algorithm has been developed, which combines information on gait bradykinesia and dyskinesia provided by a single kinematic sensor located on the waist of Parkinson disease (PD) patients to detect motor fluctuations (On- and Off-periods). OBJECTIVE: The goal of this study was to analyze the accuracy of this algorithm under real conditions of use. METHODS: This validation study of a motor-fluctuation detection algorithm was conducted on a sample of 23 patients with advanced PD. Patients were asked to wear the kinematic sensor for 1 to 3 days at home, while simultaneously keeping a diary of their On- and Off-periods. During this testing, researchers were not present, and patients continued to carry on their usual daily activities in their natural environment. The algorithm's outputs were compared with the patients' records, which were used as the gold standard. RESULTS: The algorithm produced 37% more results than the patients' records (671 vs 489). The positive predictive value of the algorithm to detect Off-periods, as compared with the patients' records, was 92% (95% CI 87.33%-97.3%) and the negative predictive value was 94% (95% CI 90.71%-97.1%); the overall classification accuracy was 92.20%. CONCLUSIONS: The kinematic sensor and the algorithm for detection of motor-fluctuations validated in this study are an accurate and useful tool for monitoring PD patients with difficult-to-control motor fluctuations in the outpatient setting. PMID- 29695379 TI - Common Mitochondrial Haplogroups and Cutaneous Squamous Cell Carcinoma Risk. AB - Background: Cutaneous squamous cell carcinoma (cSCC) is the second most common cancer in United States, and its incidence is substantially higher in men than women, but the reasons for the difference are unknown. We explored whether common mitochondrial DNA (mtDNA) haplogroups, which have been associated with cancer risk, and in particular squamous cell carcinoma risk arising in other organs, could explain this biological sex difference in cSCC susceptibility.Methods: We performed a retrospective cohort study using data from the Genetic Epidemiology Research in Adult Health and Aging cohort composed of 67,868 non-Hispanic white subjects (7,701 cSCC cases and 60,167 controls). Genotype information on >665,000 SNPs was generated using Affymetrix Axiom arrays designed to maximize genome-wide coverage, and 102 high-quality mtDNA SNPs were used to determine mtDNA haplogroups. Associations between each mtDNA haplogroup and cSCC risk were evaluated by logistic regression analysis adjusting for age, sex, and population stratification using ancestry principal components.Results: cSCC was more common in men (15.4% vs. 8.4% for women). Nine common mtDNA haplogroups (frequency >=1%) were identified in addition to the most common haplogroup, H, used as the reference group. No association with cSCC risk was detected for any of the mtDNA haplogroups or overall or sex-stratified analyses.Conclusions: Common mitochondrial variation is not associated with cSCC risk.Impact: This well powered study refutes the hypothesis that common mitochondrial haplogroups play a role in the differential sex predilection of cSCCs. Cancer Epidemiol Biomarkers Prev; 27(7); 838-41. (c)2018 AACR. PMID- 29695378 TI - Comparing the Effects of Combined Oral Contraceptives Containing Progestins With Low Androgenic and Antiandrogenic Activities on the Hypothalamic-Pituitary Gonadal Axis in Patients With Polycystic Ovary Syndrome: Systematic Review and Meta-Analysis. AB - BACKGROUND: Different products of combined oral contraceptives (COCs) can improve clinical and biochemical findings in patients with polycystic ovary syndrome (PCOS) through suppression of the hypothalamic-pituitary-gonadal (HPG) axis. OBJECTIVE: This systematic review and meta-analysis aimed to compare the effects of COCs containing progestins with low androgenic and antiandrogenic activities on the HPG axis in patients with PCOS. METHODS: We searched PubMed, Scopus, Google Scholar, ScienceDirect, and Web of Science databases (1980-2017) to identify randomized controlled trials or nonrandomized studies investigating the effect of COCs containing progestins with low androgenic and antiandrogenic activities, including the products containing desogestrel, cyproterone acetate, and drospirenone, on the HPG axis in patients with PCOS. In this meta-analysis, fixed and random effect models were used. Outcomes of interest were weighted mean differences (WMD) of hormonal parameters, including the follicle-stimulating hormone (FSH), luteinizing hormone (LH), LH-to-FSH ratio, estradiol, total testosterone, and sex hormone-binding globulin. Potential sources of heterogeneity were investigated using meta-regression and subgroup analyses. Subgroup analyses were performed based on the used progestin compound and treatment duration. We assessed quality of included studies and their risk of bias using Cochrane guidelines. Publication bias was assessed using Egger test and funnel plot. RESULTS: COC use was significantly associated with a decrease in gonadotropin levels, including FSH and LH. Use of products containing cyproterone acetate was associated with a decrease in FSH levels after 3 months (WMD=-0.48; 95% CI -0.81 to -0.15), 6 months (WMD=-2.33; 95% CI -3.48 to -1.18), and 12 months (WMD=-4.70; 95% CI -4.98 to -4.42) and a decrease in LH levels after 3 months (WMD=-3.57; 95% CI -5.14 to -1.99), 6 months (WMD=-5.68; 95% CI -9.57 to 1.80), and 12 months (WMD=-11.60; 95% CI -17.60 to -5.60). Use of COCs containing drospirenone for 6 months decreased FSH (WMD=-0.93; 95% CI -1.79 to -0.08) and LH (WMD=-4.59; 95% CI -7.53 to -1.66) levels. Data for products containing desogestrel were few, but this compound generally had no statistically significant influence on gonadotropin levels similar to that observed with COCs containing cyproterone acetate and drospirenone. Use of COCs was not associated with any significant change in LH-to-FSH ratio. COCs containing cyproterone acetate showed maximum effect on gonadotropin suppression. COCs containing cyproterone acetate significantly decreased estradiol concentrations, whereas those containing drospirenone exhibited no such effect. All COCs demonstrated improvement in androgenic profile and had the same effects on total testosterone and sex hormone-binding globulin concentrations. Progestin compound and treatment duration had no statistically significant effects on changing total testosterone and sex hormone-binding globulin levels. CONCLUSIONS: COCs containing cyproterone acetate can effectively suppress gonadotropins, leading to a decrease in androgenic parameters. Although different products of COCs could significantly suppress the androgenic profile, it seems that products containing cyproterone acetate are more effective in suppressing gonadotropin and estradiol levels in patients with PCOS. PMID- 29695380 TI - Association between Nonsteroidal Anti-Inflammatory Drugs and Colorectal Cancer: A Population-Based Case-Control Study. AB - Background: COX-2 overexpression may contribute to colorectal cancer occurrence. Aspirin and nonsteroidal anti-inflammatory drugs (NSAIDs) can reduce colorectal cancer recurrence, but the efficacy of primary prevention in Asian populations is still elusive. Thus, we examined the primary preventive efficacy of aspirin and NSAIDs on colorectal cancer incidence in Taiwan.Methods: A nested case-control study was conducted using the National Health Insurance Research Database (NHIRD) in Taiwan. We identified patients with diagnosis of colorectal cancer from 2005 to 2013 in the Registry of Catastrophic Illness Patient Database. We selected patients without colorectal cancer from the Longitudinal Health Insurance Database as the controls and matched them with cases. NSAID exposure was defined as at least two prescriptions 13 to 48 months prior to the index date. Conditional logistic regression models were performed to evaluate the association between NSAID use and colorectal cancer.Results: A total of 65,208 colorectal cancer cases and 65,208 matched controls were identified. Patients with aspirin use had a lower risk of colorectal cancer compared with nonusers [adjusted OR (AOR) = 0.94, 95% confidence interval (CI) = 0.90-0.99]. NSAID use was associated with lower incidence of colorectal cancer (AOR = 0.96; 95% CI = 0.92-1.00). When examining colon or rectal cancer, similar decreased risks were observed. Patients taking more cumulative days of NSAIDs use tended to experience a more protective effect on colorectal cancer, but no dose-response effects were noted.Conclusions: Aspirin and NSAIDs were associated with a reduced risk of colorectal cancer development among a study cohort in an Asian population.Impact: This study provided a possible chemoprevention for colorectal cancer in an Asian population. Cancer Epidemiol Biomarkers Prev; 27(7); 737-45. (c)2018 AACR. PMID- 29695382 TI - Internal Versus External Compression of a Left Ventricular Assist Device Outflow Graft: Diagnosis With Intravascular Ultrasound and Treatment With Stenting. PMID- 29695381 TI - Pulmonary Capillary Wedge Pressure Patterns During Exercise Predict Exercise Capacity and Incident Heart Failure. AB - BACKGROUND: Single measurements of left ventricular filling pressure at rest lack sensitivity for identifying heart failure with preserved ejection fraction (HFpEF) in patients with dyspnea on exertion. We hypothesized that exercise hemodynamic measurements (ie, changes in pulmonary capillary wedge pressure [PCWP] indexed to cardiac output [CO]) may more sensitively differentiate HFpEF and non-HFpEF disease states, reflect aerobic capacity, and forecast heart failure outcomes in individuals with normal PCWP at rest. METHODS AND RESULTS: We studied 175 patients referred for cardiopulmonary exercise testing with hemodynamic monitoring: controls (n=33), HFpEF with resting PCWP>=15 mm Hg (n=32), and patients with dyspnea on exertion with normal resting PCWP and left ventricular ejection fraction (DOE-nlrW; n=110). Across 1835 paired PCWP-CO measurements throughout exercise, we used regression techniques to define normative bounds of "PCWP/CO slope" in controls and tested the association of PCWP/CO slope with exercise capacity and composite cardiac outcomes (defined as cardiac death, incident resting PCWP elevation, or heart failure hospitalization) in the DOE-nlrW group. Relative to controls (PCWP/CO slope, 1.2+/-0.4 mm Hg/L/min), patients with HFpEF had a PCWP/CO slope of 3.4+/-1.9 mm Hg/L/min. We used a threshold (2 SD above the mean in controls) of 2 mm Hg/L/min to define abnormal. PCWP/CO slope >2 in DOE-nlrW patients was common (n=45/110) and was associated with reduced peak Vo2 (P<0.001) and adverse cardiac outcomes after adjustment for age, sex, and body mass index (hazard ratio, 3.47; P=0.03) at a median 5.3-year follow-up. CONCLUSIONS: Elevated PCWP/CO slope during exercise (>2 mm Hg/L/min) is common in DOE-nlrW and predicts exercise capacity and heart failure outcomes. These findings suggest that current definitions of HFpEF based on single measures during rest are insufficient and that assessment of exercise PCWP/CO slope may refine early HFpEF diagnosis. PMID- 29695383 TI - Allelic Polymorphisms of KIRs and HLAs Predict Favorable Responses to Tyrosine Kinase Inhibitors in CML. AB - Response to tyrosine kinase inhibitors (TKIs) is variable in chronic myeloid leukemia (CML), and elevated natural killer (NK) cells during TKI therapy are positively correlated with superior outcomes. NK cell function involves interactions of their killer immunoglobulin-like receptors (KIRs) and human leukocyte antigen (HLA) class I on target cells, and the avidity of KIR-HLA interactions depends on the combination of KIR and HLA alleles. We hypothesized that KIR and HLA polymorphisms may influence response to TKIs. KIR and HLA allele genotyping was performed by next-generation sequencing for 76 CML cases, and association with clinical outcome was analyzed. Second-generation TKIs as first line therapy and patients' sex (female) were strongly associated with achievement of complete molecular response (CMR: MR4.0) after 2 years (P < 0.001 and P = 0.002, respectively). After adjustment for these two characteristics, several KIR alleles remained associated with achievement of MR4.0: KIR2DL4*005/011 or *008 (HR = 1.797, P = 0.032); KIR2DS4*003 or *007/010 (HR = 3.348, P < 0.001); KIR3DL1*005 (HR = 2.746, P = 0.003); and KIR3DL2*009 or *010 [HR = 1.980 (1.109 3.524), P = 0.021]. Strong linkage among these alleles exists, implying that they comprise favorable KIR allele haplotypes. Allelic polymorphisms of KIR3DL1 and HLA-B determine their differential avidity into strong/weak or no interaction. Patients carrying noninteracting KIR3DL1 and HLA-B allele pairs achieved better outcomes than those with strongly interacting pairs, and KIR3DL1*005 associated with a positive outcome among patients with weak-interacting pairs. Thus, KIR3DL1*005 and its associated haplotypes associated with superior TKI therapeutic effects. The combinations of these KIR and HLA alleles may correlate with potent NK cell immunity against CML. Cancer Immunol Res; 6(6); 745-54. (c)2018 AACR. PMID- 29695385 TI - Hospitals do not recognise dementia in a third of patients admitted with other conditions. PMID- 29695384 TI - Endovascular Therapy in Ischemic Stroke With Acute Large-Vessel Occlusion: Recovery by Endovascular Salvage for Cerebral Ultra-Acute Embolism Japan Registry 2. AB - BACKGROUND: Endovascular therapy has been shown to be effective in patients with acute cerebral large-vessel occlusion, but real-world efficacies are unknown. METHODS AND RESULTS: We conducted a prospective registry at 46 centers between October 2014 and January 2017. Eligible patients were those who were aged 20 years or older, with acute cerebral large-vessel occlusion, and who were hospitalized within 24 hours of the onset. We enrolled both consecutive patients who were treated with or without endovascular therapy. Endovascular therapy included thrombectomy, balloon angioplasty, stenting, local fibrinolysis, and piercing. The primary outcome was a favorable outcome as defined by a modified Rankin Scale of 0 to 2 at 90 days after onset. Secondary outcomes were modified Rankin Scale of 0 to 1 and mortality. Safety outcomes were intracerebral hemorrhage or a recurrence of ischemic stroke. We constructed the 2242 (1121 each) propensity score-matched patients cohort based on a propensity score for endovascular therapy and estimated the adjusted odds ratio, followed by sensitivity analyses on original 2399 (1278 in endovascular therapy versus 1121 in no endovascular therapy) patients. In the propensity score-matched cohort, favorable outcomes were observed in 35.3% and 30.7% of patients in the endovascular therapy and no endovascular therapy groups, respectively (P=0.02). The adjusted odds ratio for the favorable outcome was 1.44 (95% confidence interval, 1.10-1.86, P=0.007). The efficacy of endovascular therapy in achieving favorable outcomes did not differ between our subgroups and in the sensitivity analyses. CONCLUSIONS: Endovascular therapy decreased disabilities at 90 days in real-world patients with acute cerebral large-vessel occlusion. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02419794. PMID- 29695386 TI - The relationship between intimate partner violence reported at the first antenatal booking visit and obstetric and perinatal outcomes in an ethnically diverse group of Australian pregnant women: a population-based study over 10 years. AB - OBJECTIVES: Intimate partner violence (IPV) is a global health issue affecting mainly women and is known to escalate during pregnancy and impact negatively on obstetric and perinatal outcomes. The aim of this study is to determine the incidence of IPV in a pregnant multicultural population and to determine the relationship between IPV reported at booking interview and maternal and perinatal outcomes. DESIGN: This is a retrospective population-based data study. We analysed routinely collected data (2006-2016) from the ObstetriX system on a cohort of pregnant women. SETTING AND PARTICIPANTS: 33 542 women giving birth in a major health facility in Western Sydney. PRIMARY OUTCOMES: Incidence of IPV, association with IPV and other psychosocial variables and maternal and perinatal outcomes. RESULT: 4.3% of pregnant women reported a history of IPV when asked during the routine psychosocial assessment. Fifty-four per cent were not born in Australia, and this had increased significantly over the decade. Women born in New Zealand (7.2%) and Sudan (9.1%) were most likely to report IPV at the antenatal booking visit, with women from China and India least likely to report IPV. Women who reported IPV were more likely to report additional psychosocial concerns including Edinburgh Postnatal Depression Scale scores > 13 (7.6%), thoughts of self-harm (2.4%), childhood abuse (23.6%), and a history of anxiety and depression (34.2%). Women who reported IPV were more likely to be Australian born, smoke and be multiparous and to have been admitted for threatened preterm labour (Adjusted Odds Ratio (AOR) 1.8, 95% CI 1.28 to 2.39). CONCLUSIONS: A report of IPV at the first antenatal booking visit is associated with a higher level of reporting on all psychosocial risks, higher antenatal admissions, especially for threatened preterm labour. More research is needed regarding the effectiveness of current IPV screening for women from other countries. PMID- 29695387 TI - Controlled cohort evaluation of the LiveLighter mass media campaign's impact on adults' reported consumption of sugar-sweetened beverages. AB - OBJECTIVE: To evaluate the LiveLighter 'Sugary Drinks' campaign impact on awareness, knowledge and sugar-sweetened beverage (SSB) consumption. DESIGN: Cohort study with population surveys undertaken in intervention and comparison states at baseline (n=900 each), with 78% retention at follow-up (intervention: n=673; comparison: n=730). Analyses tested interactions by state (intervention, comparison) and time (baseline, follow-up). SETTING AND PARTICIPANTS: Adults aged 25-49 years residing in the Australian states of Victoria and South Australia. INTERVENTION: The 6-week mass media campaign ran in Victoria in October/November 2015. It focused on the contribution of SSBs to the development of visceral 'toxic fat', graphically depicted around vital organs, and ultimately serious disease. Paid television advertising was complemented by radio, cinema, online and social media advertising, and stakeholder and community engagement. PRIMARY OUTCOME MEASURE: Self-reported consumption of SSBs, artificially sweetened drinks and water. SECONDARY OUTCOME MEASURES: Campaign recall and recognition; knowledge of the health effects of overweight and SSB consumption; perceived impact of SSB consumption on body weight and of reduced consumption on health. RESULTS: A significant reduction in frequent SSB consumption was observed in the intervention state (intervention: 31% compared with 22%, comparison: 30% compared with 29%; interaction p<0.01). This was accompanied by evidence of increased water consumption (intervention: 66% compared with 73%; comparison: 68% compared with 67%; interaction p=0.09) among overweight/obese SSB consumers. This group also showed increased knowledge of the health effects of SSB consumption (intervention: 60% compared with 71%, comparison: 63% compared with 59%; interaction p<0.05) and some evidence of increased prevalence of self-referent thoughts about SSB's relationship to weight gain (intervention: 39% compared with 45%, comparison: 43% compared with 38%; interaction p=0.06). CONCLUSIONS: The findings provide evidence of reduced SSB consumption among adults in the target age range following the LiveLighter campaign. This is notable in a context where public health campaigns occur against a backdrop of heavy commercial product advertising promoting increased SSB consumption. PMID- 29695388 TI - Hypomorphic citrullinaemia due to mutated ASS1 with episodic ataxia. AB - Children with citrullinaemia commonly present in the neonatal period with life threatening hyperammonaemia and progressive encephalopathy. Less often, 'hypomorphic' or mild late-onset childhood or adult-onset forms may be seen with intermittent neurological symptoms or acute crisis in pregnancy. We describe an 11-year-old boy with late-onset citrullinaemia manifesting as brief episodes of ataxia triggered by minor febrile illnesses, significant citrullinaemia, mild hyperammonaemia, normal neurological examination and mild cerebellar atrophy. Targeted gene sequencing showed a homozygous, missense mutation c.815G>A (p.R272H) in exon 12 of ASS1 gene resulting in the amino acid substitution of histidine for arginine at codon 272. Our case highlights the importance of recognising urea cycle defects as a cause of intermittent neurological symptoms such as ataxia. Type-1 citrullinaemia may remain hypomorphic and needs a high index of suspicion. PMID- 29695389 TI - Previously misdiagnosed linear IgA dermatosis resolved with dapsone. AB - This is the case of a 25-year-old African American woman with a 3-week history of itching with burning, blistering lesions on her torso and extremities. Medical history was unremarkable. Medical treatments included three visits to urgent care, where she was treated with antivirals, oral and topical steroids, antibiotics and antifungals unsuccessfully. We performed a skin biopsy, and immunoflorescent studies revealed a linear deposition of IgA antigen at the basement membrane. The clinical diagnosis of linear IgA dermatosis (LAD) was established, with no eliciting cause, other than potential occupational exposure to Chlamydophila psittaci via her employment in a pet store. This is the first case to our knowledge to report such an association. However, confirmation of the exposure would only establish correlation, not causality. Resolution of symptoms and blisters was achieved with dapsone treatment. Accordingly, we highlight the crucial importance of reviewing exposures, along with the potential aetiology of LAD. PMID- 29695390 TI - Epilepsy under my skin? AB - A 44-year-old male patient was admitted to the hospital for observation after an unwitnessed syncope. Physical examination revealed skin purpura and bilateral tongue haematoma. Laboratory studies were unremarkable. Radiological imaging showed no abnormalities of the vasculature, signs of thrombosis or brain anomalies. Biopsy of a purpuric lesion revealed extravasation of erythrocytes. After excluding several causes of both syncope and purpura, the typical location of these thoracocervicofacial purpura, the tongue haematoma and an elevated prolactin level (which came back later) led to the diagnosis of an epileptic seizure. The patient was referred to the neurology department for follow-up. Within 3 weeks, the purpura were completely resolved, and the patient remained free of seizures during follow-up. In case of an unwitnessed syncope, an epileptic seizure should be carefully considered and thoracocervicofacial purpura can be the pivotal manifestation leading to this diagnosis. PMID- 29695391 TI - Recurrence of a totally occluded aneurysm after treatment with a pipeline embolization device. AB - Treatment with a pipeline embolization device (PED) is widely accepted as an excellent option for patients harboring giant, wide neck, saccular intracranial aneurysms. It has been shown to be safe and very effective. We describe a previously unreported case of a large middle cerebral artery aneurysm, related to the carotid tip, that was treated with a PED and coils. The 6 month follow-up angiogram demonstrated complete occlusion of the aneurysm. However, the 9 month angiogram revealed recurrent filling of the aneurysm sac. To our knowledge, this is the first report to describe recanalization of an aneurysm totally occluded on the control angiography after treatment with a PED. Unanswered questions include the mechanism of recanalization and the need for additional control angiograms and MRI following a previous examination revealing total aneurysm occlusion. PMID- 29695392 TI - Unusual case of simple urinary bladder melanosis with complete resolution. AB - A 66-year-old man presented with a long history of recurrent attacks of urinary retention and lower urinary tract symptoms. Flexible cystoscopy showed a urethral stricture. Follow-up cystoscopy 7 years later for recurrent symptoms demonstrated unusual extensive mucosal brown to black pigmentation, which proved histopathologically to be a simple bladder melanosis. Follow-up demonstrated complete resolution over a period of 1 year with no specific treatment. In this report, we highlighted a rare bladder abnormality with uncertain natural history. PMID- 29695393 TI - Not quite Pott's puffy tumour. AB - Pott's puffy tumour (PPT) is characterised by a subperiosteal abscess associated with osteomyelitis of the frontal bone-a rare complication of frontal sinusitis, more common in the paediatric population. We describe a case mimicking PPT, where abscess extension was facilitated by previous surgery. Usually patients with PPT would be systemically unwell, but our patient, a 63-year-old Caucasian man, was systemically well with a large swelling of his forehead. A CT was performed to evaluate possible intracranial and intracerebral complications such as epidural, subdural and brain abscesses. Emergent surgical drainage was performed with prolonged administration of antibiotic therapy. 12 weeks later, he had recollection in the frontal sinus requiring incision and drainage. 6 weeks afterwards, he underwent planned Lothrop procedure and endoscopic sinus surgery. Although clinically the patient presented with overwhelming features of PPT, we emphasise that PPT involves osteomyelitis of frontal bone, which is absent in our case. PMID- 29695394 TI - Unique case of non-neutropaenic typhlitis in an immunosuppressed liver transplant patient. PMID- 29695395 TI - Aspiration of a small bowel video capsule: a rare complication. PMID- 29695397 TI - Management of complete tracheal rings in a neonate with tetralogy of Fallot. PMID- 29695396 TI - Burkholderia cepacia: a rare cause of bacterial keratitis. AB - We describe the first clinical case of Burkholderia cepacia keratitis registered in Southeast Asia. A man in his mid-70s with underlying poorly controlled diabetes mellitus came with complaints of painful red left eye for 4 days. This was accompanied with photophobia and blurring of vision after being injured by a wooden particle while cutting grass. Slit-lamp examination showed a paracentral anterior corneal stromal infiltrates with overlying epithelial defect. Culture of the corneal smear isolated B. cepacia that was sensitive to ceftazidime, meropenem and bactrim (trimethorprim and sulfomethoxazole). Topical ceftazidime was given intensively to the patient and the infection resolved after 6 weeks of treatment. PMID- 29695398 TI - Chromatin Immunoprecipitation and DNA Sequencing Identified a LIMS1/ILK Pathway Regulated by LMO1 in Neuroblastoma. AB - BACKGROUND/AIM: Overall survival for the high-risk group of neuroblastoma (NB) remains at 40-50%. An integrative genomics study revealed that LIM domain only 1 (LMO1) encoding a transcriptional regulator to be an NB-susceptibility gene with a tumor-promoting activity, that needs to be revealed. MATERIALS AND METHODS: We conducted chromatin immunoprecipitation and DNA sequencing analyses and cell proliferation assays on two NB cell lines. RESULTS: We identified three genes regulated by LMO1 in the cells, LIM and senescent cell antigen-like domains 1 (LIMS1), Ras suppressor protein 1 (RSU1) and relaxin 2 (RLN2). LIMS1 and RSU1 encode proteins functioning with integrin-linked kinase (ILK), and inhibition of LIMS1, ILK or RLN2 by shRNA reduced cell proliferation of the NB cells, which was also suppressed with an ILK inhibiting compound Cpd 22. CONCLUSION: The downstream of LMO1-regulatory cascade includes a tumor-promoting LIMS1/ILK pathway, which has a potential to be a novel therapeutic target. PMID- 29695399 TI - HIF-1alpha and mTOR - Possible Novel Strategies of Targeted Therapies in p16 positive and -negative HNSCC. AB - BACKGROUND/AIM: Targeted therapy in head and neck squamous cell carcinoma (HNSCC) is limited. HIF-1alpha and mTOR are involved in the formation of local tumor progression and distant metastasis. The present study analyzed the influence of well-established tyrosine kinase inhibitors nilotinib, dasatinib, erlotinib and gefitinib on the expression of HIF-1alpha and mTOR in p16-positive and -negative squamous cancer cells (SCC) in vitro in order to develop novel strategies in the treatment of HNSCC. MATERIALS AND METHODS: Expression of HIF-1alpha and mTOR was analyzed by using Sandwich-ELISA in p16-negative and p16-positive SCC after treatment with nilotinib, dasatinib, erlotinib and gefitinib (20 MUmol/l, 24-96 h of incubation). RESULTS: All substances significantly reduced mTOR expression in both, p16-negative and p16-positive SCC (p<0.05). HIF-1alpha expression was significantly reduced by all tested substances in p16-negative SCC. However, a statistically significant increase of HIF-1alpha was observed in p16-positive SCC. CONCLUSION: This is the first study to investigate the alteration of expression levels of HIF-1alpha and mTOR under selective tyrosine kinase inhibition in both p16-positive and -negative SCC. Our findings provide novel insights for a better understanding of HIF-1alpha and mTOR in the tumor biology of HNSCC and their interaction with selective small-molecule inhibitors. PMID- 29695400 TI - Admixture Mapping Links RACGAP1 Regulation to Prostate Cancer in African Americans. AB - BACKGROUND/AIM: Prostate cancer is the most common malignancy in US males. African American men have higher incidence and mortality rates than European Americans. Five single nucleotide polymorphisms are associated with PCa. We hypothesized haplotypes inferred from these SNPs are also associated with PCa. PATIENTS AND METHODS: We genotyped SNPs in a case-control admixture mapping study. SNP haplotypes inferred for 157 PCa cases and 150 controls were used in the regression analysis. RESULTS: We found an association between "GTCCC", "ATTCT", and "ACCCC" haplotypes and PCa after ancestry adjustment (OR=3.62, 95%CI=1.42-9.21, p=0.0070; OR=7.89, 95%CI=2.36-26.31, p=0.0008; OR=4.34, 95%CI=1.75-10.78, p=0.0016). The rs615382 variant disrupts the recombination signal binding protein with immunoglobulin kappa J binding site in Rac GTPase activating protein 1 (RACGAP1). CONCLUSION: Disruption of notch 1 mediated repression of RACGAP1 may contribute to PCa in African Americans. PMID- 29695401 TI - Cytogenetics of Spindle Cell/Pleomorphic Lipomas: Karyotyping and FISH Analysis of 31 Tumors. AB - BACKGROUND: Spindle cell/pleomorphic lipomas are benign tumors. Here, we present our cytogenetic data on 31 such tumors. MATERIALS AND METHODS: G-banding chromosome analysis and (in selected cases) fluorescence in situ hybridization (FISH) using probes for FOXO1, RB1, and HMGA2 were performed. RESULTS: Rearrangements of chromosome 13 were found in 58% of tumors. Chromosomes 6, 1, 12, and 11 were also involved in 42%, 26%, 26%, and 23% of tumors, respectively. FISH analysis showed heterozygous deletion of RB1 in seven samples with chromosome 13 aberrations. In four of them, FOXO1 was also deleted. In two tumors with 12q15 rearrangements, FISH confirmed that HMGA2 was targeted. CONCLUSION: Structural rearrangements of 13q or losses of an entire chromosome 13 are the most common cytogenetic aberrations in spindle cell/pleomorphic lipomas. However, cytogenetic variation exists similarly to what is found in other lipomas, suggesting that various pathways may be responsible for tumorigenesis. PMID- 29695402 TI - EGFR L861Q Mutation in a Metastatic Solid-pseudopapillary Neoplasm of the Pancreas. AB - Solid-pseudopapillary neoplasm of the pancreas (SPN) is a rare neoplasm that is typically indolent in nature. Surgical resection is the preferred method of treatment and often associated with a good prognosis. Local invasion and metastasis have been reported in a small subset of patients. Currently, there are limited data on the molecular mutation profile of invasive and metastatic SPN. In this report, we present the case of a 38-year-old female with a locally-invasive and unresectable SPN that, despite exhaustive chemoradiotherapy, progressed to liver metastasis. Pyrosequencing of the primary pancreatic tumor antecedent to metastasis showed an uncommon EGFR mutation at L861Q in the kinase domain of exon 21. This finding, if confirmed in additional cases of metastatic SPN, would support preoperative testing for EGFR mutation analysis to detect aggressive SPNs. PMID- 29695403 TI - The Contribution of MMP-7 Genotypes to Colorectal Cancer Susceptibility in Taiwan. AB - BACKGROUND/AIM: Matrix metalloproteinases (MMPs) play important roles in inflammation and carcinogenesis, but the genotypic role of MMP-7 has never been investigated in colorectal cancer (CRC) among the Taiwanese. Therefore, in this study we aimed to evaluate the contribution of MMP-7 genotypes to the risk of CRC in Taiwan. MATERIALS AND METHODS: In this case-control study, MMP-7 A-181G and C 153T promoter genotypes were determined and their association with CRC risk were investigated among 362 CRC patients and 362 age- and gender-matched healthy controls. In addition, the interaction of MMP-7 genotypes and personal behaviors were also examined. RESULTS: The percentages of variant AG and GG for MMP-7 A 181G genotypes were 10.5% and 1.7% in the CRC group and 11.9% and 2.2% in the control group, respectively (p for trend=0.7145). The allelic frequency distribution analysis showed that the variant G allele of MMP-7 A-181G conferred a slight but non-significant decreased CRC susceptibility to the wild-type C allele (odds ratio (OR)=0.86, 95% confidence interval (CI)=0.64-1.31, p=0.37). Taiwanese all harbour the CC genotype at MMP-7 C-153T. As for the gene-lifestyle interaction, there were no obvious joint effects of MMP-7 A-181G genotype on the risk of CRC among ever smoker, alcohol drinker, non-smoker or non-drinker subgroups. No statistically significant correlation was observed between MMP-7 A 181G genotypic distributions and age, gender, tumor size, location or metastasis status. CONCLUSION: The genotypes of MMP-7 A-181G may play an indirect role in determining personal susceptibility to CRC and prognosis. The further genotyping work on MMP-7 and other genes (such as other MMPs, oncogenes and tumor suppression genes) on CRC susceptibility and prognosis, should be taken into consideration spontaneously in the precision medicine era. PMID- 29695405 TI - Should we recommend e-cigarettes to help smokers quit? PMID- 29695404 TI - Establishment and Characteristics of a Novel Mantle Cell Lymphoma-derived Cell Line and a Bendamustine-resistant Subline. AB - BACKGROUND/AIM: Bendamustine hydrochloride (BH) is a key therapeutic agent for mantle cell lymphoma (MCL), while the mechanism underlying BH-resistance has not been verified. MATERIALS AND METHODS: We compared molecular/biological characteristics of a newly-generated MCL-derived cell line KPUM-YY1 and its BH resistant subline KPUM-YY1R. RESULTS: The growth-inhibitory IC50 for BH was 20 MUM in KPUM-YY1 cells, while cell proliferation was not inhibited by up to 60 MUM BH in KPUM-YY1R cells. Compared to KPUM-YY1 cells, gene expression profiling in KPUM-YY1R cells revealed up-regulation of 312 genes, including ABCB1 encoding P glycoprotein (P-gp), and microsomal glutathione S-transferase 1 (MGST1). Addition of either a P-gp inhibitor or a GST inhibitor, at least partly, restored sensitivity to BH in KPUM-YY1R cells. In addition, KPUM-YY1R cells showed cross resistance against various anti-MCL chemotherapeutics. CONCLUSION: BH resistance is mediated by overlapping mechanisms with overexpression of ABCB1 and MGST1, and is potentially accompanied by multidrug resistance in MCL. PMID- 29695406 TI - A novel association of campomelic dysplasia and hydrocephalus with an unbalanced chromosomal translocation upstream of SOX9. AB - Campomelic dysplasia is a rare skeletal dysplasia characterized by Pierre Robin sequence, craniofacial dysmorphism, shortening and angulation of long bones, tracheobronchomalacia, and occasionally sex reversal. The disease is due to mutations in SOX9 or chromosomal rearrangements involving the long arm of Chromosome 17 harboring the SOX9 locus. SOX9, a transcription factor, is indispensible in establishing and maintaining neural stem cells in the central nervous system. We present a patient with angulation of long bones and external female genitalia on prenatal ultrasound who was subsequently found to harbor the chromosomal abnormality 46, XY, t(6;17) (p21.1;q24.3) on prenatal genetic testing. Comparative genomic hybridization revealed deletions at 6p21.1 and 17q24.3, the latter being 2.3 Mb upstream of SOX9 Whole-exome sequencing did not identify pathogenic variants in SOX9, suggesting that the 17q24.3 deletion represents a translocation breakpoint farther upstream of SOX9 than previously identified. At 2 mo of age the patient developed progressive communicating ventriculomegaly and thinning of the cortical mantle without clinical signs of increased intracranial pressure. This case suggests ventriculomegaly in some cases represents not a primary impairment of cerebrospinal fluid dynamics, but an epiphenomenon driven by a genetic dysregulation of neural progenitor cell fate. PMID- 29695407 TI - Healthcare professionals' understanding of the legislation governing research involving adults lacking mental capacity in England and Wales: a national survey. AB - OBJECTIVE: To examine health and social care professionals' understanding of the legislation governing research involving adults lacking mental capacity in England and Wales. METHODS: A cross-sectional online survey was conducted using a series of vignettes. Participants were asked to select the legally authorised decision-maker in each scenario and provide supporting reasons. Responses were compared with existing legal frameworks and analysed according to their level of concordance. RESULTS: One hundred and twenty-seven professionals participated. Levels of discordance between responses and the legal frameworks were high across all five scenarios (76%-82%). Nearly half of the participants (46%) provided responses that were discordant in all scenarios. Only two participants (2%) provided concordant responses across all five scenarios. DISCUSSION: Participants demonstrated a lack of knowledge about the legal frameworks, the locus of authority and the legal basis for decision-making. The findings raise concern about the accessibility of research for those who lack capacity, the ability to conduct research involving such groups and the impact on the evidence base for their care. CONCLUSION: This is the first study to examine health and social care professionals' knowledge and understanding of the dual legal frameworks in the UK. Health and social care professionals' understanding and attitudes towards research involving adults with incapacity may warrant further in-depth exploration. The findings from this survey suggest that greater training and education is required. PMID- 29695408 TI - Ethics of routine: a critical analysis of the concept of 'routinisation' in prenatal screening. AB - In the debate surrounding the introduction of non-invasive prenatal testing (NIPT) in prenatal screening programmes, the concept of routinisation is often used to refer to concerns and potential negative consequences of the test. A literature analysis shows that routinisation has many different meanings, which can be distinguished in three major versions of the concept. Each of these versions comprises several inter-related fears and concerns regarding prenatal screening and particularly regarding NIPT in three areas: (1) informed choice, (2) freedom to choose and (3) consequences for people with a disability. Three of the strongest arguments raised under the flag of routinisation are assessed for their validity: the threat that NIPT poses to informed choice, the potential increase in uptake of first-trimester prenatal screening and its consequences for social pressure to participate in screening or terminate affected pregnancies, and the negative consequences for disabled people. These routinisation arguments lack empirical or normative ground. However, the results of this analysis do not imply that no attention should be paid to possible problems surrounding the introduction of NIPT. At least two problems remain and should be addressed: there should be an ongoing debate about the requirements of informed choice, particularly related to an expanded scope of prenatal screening. Also, reproductive autonomy can only be achieved when expecting parents' options are variegated, real and valuable, so that they can continue to choose whether or not to screen or to terminate a pregnancy. PMID- 29695409 TI - Soy Phosphatidylglycerol Reduces Inflammation in a Contact Irritant Ear Edema Mouse Model In Vivo. AB - We have previously shown that phosphatidylglycerol (PG) regulates the function of keratinocytes, the predominant cells that compose the epidermis, inhibiting the proliferation of rapidly dividing keratinocytes. In particular, soy PG, a PG mixture with a high proportion of polyunsaturated fatty acids, is efficacious at inhibiting these proliferating keratinocytes. Psoriasis is a skin disorder characterized by hyperproliferation of keratinocytes and inflammation. Data in the lung suggest that PG in pulmonary surfactant inhibits inflammation. To investigate the possibility of using PG containing polyunsaturated fatty acids for the treatment of psoriasis, we examined the effect of soy PG on inflammation induced by the application of 12-O-tetradecanoylphorbol 13-acetate (TPA), a contact irritant, to mouse ears in vivo. We monitored ear thickness and weight as a measure of ear edema, as well as CD45-positive immune cell infiltration. Our results indicate that soy PG when applied together with 1,25-dihydroxyvitamin D3 (vitamin D), an agent known to acutely disrupt the skin barrier, suppressed ear edema and inhibited the infiltration of CD45-positive immune cells. On the other hand, neither PG nor vitamin D alone was effective. The combination also decreased tumor necrosis factor-alpha (TNFalpha) levels. This result suggested the possibility that PG was not permeating the skin barrier efficiently. Therefore, in a further study we applied PG in a penetration-enhancing vehicle and found that it inhibited inflammation induced by the phorbol ester and decreased CD45-positive immune cell infiltration. Our results suggest the possibility of using soy PG as a topical treatment option for psoriasis. PMID- 29695411 TI - Influences: Childhood, boyhood, and youth. PMID- 29695410 TI - Cerivastatin Nanoliposome as a Potential Disease Modifying Approach for the Treatment of Pulmonary Arterial Hypertension. AB - In this study we investigated nanoliposome as an approach to tailoring the pharmacology of cerivastatin as a disease-modifying drug for pulmonary arterial hypertension (PAH). Cerivastatin encapsulated liposomes with an average diameter of 98 +/- 27 nm were generated by a thin film and freeze-thaw process. The nanoliposomes demonstrated sustained drug-release kinetics in vitro and inhibited proliferation of pulmonary artery (PA) smooth muscle cells with significantly less cellular cytotoxicity as compared with free cerivastatin. When delivered by inhalation to a rat model of monocrotaline-induced PAH, cerivastatin significantly reduced PA pressure from 55.13 +/- 9.82 to 35.56 +/- 6.59 mm Hg (P < 0.001) and diminished PA wall thickening. Echocardiography showed that cerivastatin significantly reduced right ventricle thickening (monocrotaline: 0.34 +/- 0.02 cm vs. cerivastatin: 0.26 +/- 0.02 cm; P < 0.001) and increased PA acceleration time (monocrotaline: 13.98 +/- 1.14 milliseconds vs. cerivastatin: 21.07 +/- 2.80 milliseconds; P < 0.001). Nanoliposomal cerivastatin was equally effective or slightly better than cerivastatin in reducing PA pressure (monocrotaline: 67.06 +/- 13.64 mm Hg; cerivastatin: 46.31 +/- 7.64 mm Hg vs. liposomal cerivastatin: 37.32 +/- 9.50 mm Hg) and improving parameters of right ventricular function as measured by increasing PA acceleration time (monocrotaline: 24.68 +/- 3.92 milliseconds; cerivastatin: 32.59 +/- 6.10 milliseconds vs. liposomal cerivastatin: 34.96 +/- 7.51 milliseconds). More importantly, the rate and magnitude of toxic cerivastatin metabolite lactone generation from the intratracheally administered nanoliposomes was significantly lower as compared with intravenously administered free cerivastatin. These studies show that nanoliposome encapsulation improved in vitro and in vivo pharmacologic and safety profile of cerivastatin and may represent a safer approach as a disease-modifying therapy for PAH. PMID- 29695412 TI - Dimerization of the voltage-sensing phosphatase controls its voltage-sensing and catalytic activity. AB - Multimerization is a key characteristic of most voltage-sensing proteins. The main exception was thought to be the Ciona intestinalis voltage-sensing phosphatase (Ci-VSP). In this study, we show that multimerization is also critical for Ci-VSP function. Using coimmunoprecipitation and single-molecule pull-down, we find that Ci-VSP stoichiometry is flexible. It exists as both monomers and dimers, with dimers favored at higher concentrations. We show strong dimerization via the voltage-sensing domain (VSD) and weak dimerization via the phosphatase domain. Using voltage-clamp fluorometry, we also find that VSDs cooperate to lower the voltage dependence of activation, thus favoring the activation of Ci-VSP. Finally, using activity assays, we find that dimerization alters Ci-VSP substrate specificity such that only dimeric Ci-VSP is able to dephosphorylate the 3-phosphate from PI(3,4,5)P3 or PI(3,4)P2 Our results indicate that dimerization plays a significant role in Ci-VSP function. PMID- 29695413 TI - Altered Excitability and Local Connectivity of mPFC-PAG Neurons in a Mouse Model of Neuropathic Pain. AB - The medial prefrontal cortex (mPFC) plays a major role in both sensory and affective aspects of pain. There is extensive evidence that chronic pain produces functional changes within the mPFC. However, our understanding of local circuit changes to defined subpopulations of mPFC neurons in chronic pain models remains unclear. A major subpopulation of mPFC neurons project to the periaqueductal gray (PAG), which is a key midbrain structure involved in endogenous pain suppression and facilitation. Here, we used laser scanning photostimulation of caged glutamate to map cortical circuits of retrogradely labeled cortico-PAG (CP) neurons in layer 5 (L5) of mPFC in brain slices prepared from male mice having undergone chronic constriction injury (CCI) of the sciatic nerve. Whole-cell recordings revealed a significant reduction in excitability for L5 CP neurons contralateral to CCI in the prelimbic (PL), but not infralimbic (IL), region of mPFC. Circuit mapping showed that excitatory inputs to L5 CP neurons in both PL and IL arose primarily from layer 2/3 (L2/3) and were significantly reduced in CCI mice. Glutamate stimulation of L2/3 and L5 elicited inhibitory inputs to CP neurons in both PL and IL, but only L2/3 input was significantly reduced in CP neurons of CCI mice. We also observed significant reduction in excitability and L2/3 inhibitory input to CP neurons ipsilateral to CCI. These results demonstrating region and laminar specific changes to mPFC-PAG neurons suggest that a unilateral CCI bilaterally alters cortical circuits upstream of the endogenous analgesic network, which may contribute to persistence of chronic pain.SIGNIFICANCE STATEMENT Chronic pain is a significant unresolved medical problem that is refractory to traditional analgesics and can negatively affect emotional health. The role of central circuits in mediating the persistent nature of chronic pain remains unclear. Local circuits within the medial prefrontal cortex (mPFC) process ascending pain inputs and can modulate endogenous analgesia via direct projections to the periaqueductal gray (PAG). However, the mechanisms by which chronic pain alters intracortical circuitry of mPFC-PAG neurons are unknown. Here, we report specific changes to local circuits of mPFC-PAG neurons in mice displaying chronic pain behavior after nerve injury. These findings provide evidence for a neural mechanism by which chronic pain disrupts the descending analgesic system via functional changes to cortical circuits. PMID- 29695415 TI - Canonical TGF-beta Signaling Negatively Regulates Neuronal Morphogenesis through TGIF/Smad Complex-Mediated CRMP2 Suppression. AB - Functional neuronal connectivity requires proper neuronal morphogenesis and its dysregulation causes neurodevelopmental diseases. Transforming growth factor-beta (TGF-beta) family cytokines play pivotal roles in development, but little is known about their contribution to morphological development of neurons. Here we show that the Smad-dependent canonical signaling of TGF-beta family cytokines negatively regulates neuronal morphogenesis during brain development. Mechanistically, activated Smads form a complex with transcriptional repressor TG interacting factor (TGIF), and downregulate the expression of a neuronal polarity regulator, collapsin response mediator protein 2. We also demonstrate that TGF beta family signaling inhibits neurite elongation of human induced pluripotent stem cell-derived neurons. Furthermore, the expression of TGF-beta receptor 1, Smad4, or TGIF, which have mutations found in patients with neurodevelopmental disorders, disrupted neuronal morphogenesis in both mouse (male and female) and human (female) neurons. Together, these findings suggest that the regulation of neuronal morphogenesis by an evolutionarily conserved function of TGF-beta signaling is involved in the pathogenesis of neurodevelopmental diseases.SIGNIFICANCE STATEMENT Canonical transforming growth factor-beta (TGF beta) signaling plays a crucial role in multiple organ development, including brain, and mutations in components of the signaling pathway associated with several human developmental disorders. In this study, we found that Smads/TG interacting factor-dependent canonical TGF-beta signaling regulates neuronal morphogenesis through the suppression of collapsin response mediator protein-2 (CRMP2) expression during brain development, and that function of this signaling is evolutionarily conserved in the mammalian brain. Mutations in canonical TGF beta signaling factors identified in patients with neurodevelopmental disorders disrupt the morphological development of neurons. Thus, our results suggest that proper control of TGF-beta/Smads/CRMP2 signaling pathways is critical for the precise execution of neuronal morphogenesis, whose impairment eventually results in neurodevelopmental disorders. PMID- 29695414 TI - mTORC1 Is Transiently Reactivated in Injured Nerves to Promote c-Jun Elevation and Schwann Cell Dedifferentiation. AB - Schwann cells (SCs) are endowed with a remarkable plasticity. When peripheral nerves are injured, SCs dedifferentiate and acquire new functions to coordinate nerve repair as so-called repair SCs. Subsequently, SCs redifferentiate to remyelinate regenerated axons. Given the similarities between SC dedifferentiation/redifferentiation in injured nerves and in demyelinating neuropathies, elucidating the signals involved in SC plasticity after nerve injury has potentially wider implications. c-Jun has emerged as a key transcription factor regulating SC dedifferentiation and the acquisition of repair SC features. However, the upstream pathways that control c-Jun activity after nerve injury are largely unknown. We report that the mTORC1 pathway is transiently but robustly reactivated in dedifferentiating SCs. By inducible genetic deletion of the functionally crucial mTORC1-subunit Raptor in mouse SCs (including male and female animals), we found that mTORC1 reactivation is necessary for proper myelin clearance, SC dedifferentiation, and consequently remyelination, without major alterations in the inflammatory response. In the absence of mTORC1 signaling, c-Jun failed to be upregulated correctly. Accordingly, a c-Jun binding motif was found to be enriched in promoters of genes with reduced expression in injured mutants. Furthermore, using cultured SCs, we found that mTORC1 is involved in c-Jun regulation by promoting its translation, possibly via the eIF4F-subunit eIF4A. These results provide evidence that proper c-Jun elevation after nerve injury involves also mTORC1-dependent post transcriptional regulation to ensure timely dedifferentiation of SCs.SIGNIFICANCE STATEMENT A crucial evolutionary acquisition of vertebrates is the envelopment of axons in myelin sheaths produced by oligodendrocytes in the CNS and Schwann cells (SCs) in the PNS. When myelin is damaged, conduction of action potentials along axons slows down or is blocked, leading to debilitating diseases. Unlike oligodendrocytes, SCs have a high regenerative potential, granted by their remarkable plasticity. Thus, understanding the mechanisms underlying SC plasticity may uncover new therapeutic targets in nerve regeneration and demyelinating diseases. Our work reveals that reactivation of the mTORC1 pathway in SCs is essential for efficient SC dedifferentiation after nerve injury. Accordingly, modulating this signaling pathway might be of therapeutic relevance in peripheral nerve injury and other diseases. PMID- 29695416 TI - Deletion of Inflammasome Components Is Not Sufficient To Prevent Fatal Inflammation in Models of Familial Hemophagocytic Lymphohistiocytosis. AB - Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory condition that occurs in patients with genetic defects of cytotoxicity (familial HLH [FHL]) or secondary to other immunological disorders such as juvenile idiopathic arthritis. HLH is characterized by elevated levels of serum IL-18 and other cytokines. Moreover, a novel clinical entity has been recently identified in which constitutive NLRC4 inflammasome activation leads to severe HLH. Altogether, these clinical observations suggest that inflammasome activation is a central event in the development of all HLH forms and that inflammasome blockade could alleviate inflammation in FHL patients. To formally address this question, we invalidated genes encoding for Caspase-1 or the inflammasome adapter ASC in perforin deficient mice that were subsequently infected with lymphocytic or mouse choriomeningitis virus as models of FHL. These deletions nearly abrogated IL-18 production occurring during HLH in all models. However, they did not reduce serum IFN-gamma levels at the peak of the inflammatory reaction nor did they modulate inflammatory parameters at mid and late stages or fatal outcome. These data show that inflammasome blockade is not sufficient to prevent cytokine storm and lethality in mouse models of FHL and suggest that different pathophysiological mechanisms underlie HLH in genetic defects of cytotoxicity and genetic forms of inflammasome activation. PMID- 29695417 TI - Platelet-Activating Factor-Induced Reduction in Contact Hypersensitivity Responses Is Mediated by Mast Cells via Cyclooxygenase-2-Dependent Mechanisms. AB - Platelet-activating factor (PAF) stimulates numerous cell types via activation of the G protein-coupled PAF receptor (PAFR). PAFR activation not only induces acute proinflammatory responses, but it also induces delayed systemic immunosuppressive effects by modulating host immunity. Although enzymatic synthesis and degradation of PAF are tightly regulated, oxidative stressors, such as UVB, chemotherapy, and cigarette smoke, can generate PAF and PAF-like molecules in an unregulated fashion via the oxidation of membrane phospholipids. Recent studies have demonstrated the relevance of the mast cell (MC) PAFR in PAFR-induced systemic immunosuppression. The current study was designed to determine the exact mechanisms and mediators involved in MC PAFR-mediated systemic immunosuppression. By using a contact hypersensitivity model, the MC PAFR was not only found to be necessary, but also sufficient to mediate the immunosuppressive effects of systemic PAF. Furthermore, activation of the MC PAFR induces MC-derived histamine and PGE2 release. Importantly, PAFR-mediated systemic immunosuppression was defective in mice that lacked MCs, or in MC-deficient mice transplanted with histidine decarboxylase- or cyclooxygenase-2-deficient MCs. Lastly, it was found that PGs could modulate MC migration to draining lymph nodes. These results support the hypothesis that MC PAFR activation promotes the immunosuppressive effects of PAF in part through histamine- and PGE2-dependent mechanisms. PMID- 29695418 TI - Role of Complement in a Rat Model of Paclitaxel-Induced Peripheral Neuropathy. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is a painful and debilitating side effect of cancer chemotherapy with an unclear pathogenesis. Consequently, the available therapies for this neuropathic pain syndrome are inadequate, leading to a significantly reduced quality of life in many patients. Complement, a key component of the innate immune system, has been associated with neuroinflammation, a potentially important trigger of some types of neuropathic pain. However, the role of complement in CIPN remains unclear. To address this issue, we developed a C3 knockout (KO) rat model and induced CIPN in these KO rats and wild-type littermates via the i.p. administration of paclitaxel, a chemotherapeutic agent associated with CIPN. We then compared the severity of mechanical allodynia, complement activation, and intradermal nerve fiber loss between the groups. We found that 1) i.p. paclitaxel administration activated complement in wild-type rats, 2) paclitaxel-induced mechanical allodynia was significantly reduced in C3 KO rats, and 3) the paclitaxel-induced loss of intradermal nerve fibers was markedly attenuated in C3 KO rats. In in vitro studies, we found that paclitaxel-treated rat neuronal cells activated complement, leading to cellular injury. Our findings demonstrate a previously unknown but pivotal role of complement in CIPN and suggest that complement may be a new target for the development of novel therapeutics to manage this painful disease. PMID- 29695419 TI - Hepatitis C Virus NS5A Protein Promotes the Lysosomal Degradation of Hepatocyte Nuclear Factor 1alpha via Chaperone-Mediated Autophagy. AB - Hepatitis C virus (HCV) infection is closely associated with type 2 diabetes. We reported that HCV infection induces the lysosomal degradation of hepatocyte nuclear factor 1 alpha (HNF-1alpha) via interaction with HCV nonstructural protein 5A (NS5A) protein, thereby suppressing GLUT2 gene expression. The molecular mechanisms of selective degradation of HNF-1alpha caused by NS5A are largely unknown. Chaperone-mediated autophagy (CMA) is a selective lysosomal degradation pathway. Here, we investigated whether CMA is involved in the selective degradation of HNF-1alpha in HCV-infected cells and observed that the pentapeptide spanning from amino acid (aa) 130 to aa 134 of HNF-1alpha matches the rule for the CMA-targeting motif, also known as KFERQ motif. A cytosolic chaperone protein, heat shock cognate protein of 70 kDa (HSC70), and a lysosomal membrane protein, lysosome-associated membrane protein type 2A (LAMP-2A), are key components of CMA. Immunoprecipitation analysis revealed that HNF-1alpha was coimmunoprecipitated with HSC70, whereas the Q130A mutation (mutation of Q to A at position 130) of HNF-1alpha disrupted the interaction with HSC70, indicating that the CMA-targeting motif of HNF-1alpha is important for the association with HSC70. Immunoprecipitation analysis revealed that increasing amounts of NS5A enhanced the association of HNF-1alpha with HSC70. To determine whether LAMP-2A plays a role in the degradation of HNF-1alpha protein, we knocked down LAMP-2A mRNA by RNA interference; this knockdown by small interfering RNA (siRNA) recovered the level of HNF-1alpha protein in HCV J6/JFH1-infected cells. This result suggests that LAMP-2A is required for the degradation of HNF-1alpha. Immunofluorescence study revealed colocalization of NS5A and HNF-1alpha in the lysosome. Based on our findings, we propose that HCV NS5A interacts with HSC70 and recruits HSC70 to HNF-1alpha, thereby promoting the lysosomal degradation of HNF-1alpha via CMA.IMPORTANCE Many viruses use a protein degradation system, such as the ubiquitin-proteasome pathway or the autophagy pathway, for facilitating viral propagation and viral pathogenesis. We investigated the mechanistic details of the selective lysosomal degradation of hepatocyte nuclear factor 1 alpha (HNF 1alpha) induced by hepatitis C virus (HCV) NS5A protein. Using site-directed mutagenesis, we demonstrated that HNF-1alpha contains a pentapeptide chaperone mediated autophagy (CMA)-targeting motif within the POU-specific domain of HNF 1alpha. The CMA-targeting motif is important for the association with HSC70. LAMP 2A is required for degradation of HNF-1alpha caused by NS5A. We propose that HCV NS5A interacts with HSC70, a key component of the CMA machinery, and recruits HSC70 to HNF-1alpha to target HNF-1alpha for CMA-mediated lysosomal degradation, thereby facilitating HCV pathogenesis. We discovered a role of HCV NS5A in CMA dependent degradation of HNF-1alpha. Our results may lead to a better understanding of the role of CMA in the pathogenesis of HCV. PMID- 29695420 TI - Human Cytomegalovirus Protein pUL38 Prevents Premature Cell Death by Binding to Ubiquitin-Specific Protease 24 and Regulating Iron Metabolism. AB - Human cytomegalovirus (HCMV) protein pUL38 has been shown to prevent premature cell death by antagonizing cellular stress responses; however, the underlying mechanism remains unknown. In this study, we identified the host protein ubiquitin-specific protease 24 (USP24) as an interaction partner of pUL38. Mutagenesis analysis of pUL38 revealed that amino acids TFV at positions 227 to 230 were critical for its interaction with USP24. Mutant pUL38 TFV/AAA protein did not bind to USP24 and failed to prevent cell death induced by pUL38-deficient HCMV infection. Knockdown of USP24 suppressed the cell death during pUL38 deficient HCMV infection, suggesting that pUL38 achieved its function by antagonizing the function of USP24. We investigated the cellular pathways regulated by USP24 that might be involved in the cell death phenotype by testing several small-molecule compounds known to have a protective effect during stress induced cell death. The iron chelators ciclopirox olamine and Tiron specifically protected cells from pUL38-deficient HCMV infection-induced cell death, thus identifying deregulated iron homeostasis as a potential mechanism. Protein levels of nuclear receptor coactivator 4 (NCOA4) and lysosomal ferritin degradation, a process called ferritinophagy, were also regulated by pUL38 and USP24 during HCMV infection. Knockdown of USP24 decreased NCOA4 protein stability and ferritin heavy chain degradation in lysosomes. Blockage of ferritinophagy by genetic inhibition of NCOA4 or Atg5/Atg7 prevented pUL38-deficient HCMV infection-induced cell death. Overall, these results support the hypothesis that pUL38 binds to USP24 to reduce ferritinophagy, which may then protect cells from lysosome dysfunction-induced cell death.IMPORTANCE Premature cell death is considered a first line of defense against various pathogens. Human cytomegalovirus (HCMV) is a slow-replicating virus that encodes several cell death inhibitors, such as pUL36 and pUL37x1, which allow it to overcome both extrinsic and intrinsic mitochondrion-mediated apoptosis. We previously identified HCMV protein pUL38 as another virus-encoded cell death inhibitor. In this study, we demonstrated that pUL38 achieved its activity by interacting with and antagonizing the function of the host protein ubiquitin-specific protease 24 (USP24). pUL38 blocked USP24 mediated ferritin degradation in lysosomes, which could otherwise be detrimental to the lysosome and initiate cell death. These novel findings suggest that iron metabolism is finely tuned during HCMV infection to avoid cellular toxicity. The results also provide a solid basis for further investigations of the role of USP24 in regulating iron metabolism during infection and other diseases. PMID- 29695421 TI - A novel marsupial hepatitis A virus corroborates complex evolutionary patterns shaping the genus Hepatovirus. AB - The discovery of nonprimate hepatoviruses illuminated the evolutionary origins of hepatitis A virus (HAV) in small mammals. Marsupials are ancient mammals that diverged during the Jurassic from other Eutheria. Viruses from marsupials may thus provide important insight into virus evolution. To investigate Hepatovirus macroevolutionary patterns, we sampled 112 opossums in northeastern Brazil. A novel marsupial HAV (MHAV) was detected in a Brazilian Common Opossum (Didelphis aurita) by nested RT-PCR. MHAV concentration in liver was high at 2.5x109 RNA copies/gram and about 1000-fold higher than in other solid organs, suggesting hepatotropism. Hepatovirus seroprevalence in D. aurita was 26.6% using an ELISA. End-point titers in confirmatory immunofluorescence assays were high and marsupial antibodies co-localized with anti-HAV control sera, suggesting specificity of serological detection. MHAV showed all genomic hallmarks defining hepatoviruses, including late domain motifs likely involved in quasi-envelope acquisition, a predicted C-terminal pX extension of VP1, strong avoidance of CpG dinucleotides and a type 3 internal ribosomal entry site. Translated polyprotein gene sequence distances of at least 23.7% to other hepatoviruses suggested MHAV represents a novel Hepatovirus species. Conserved predicted cleavage sites suggested similarities in polyprotein processing between HAV and MHAV. MHAV was nested within rodent hepatoviruses in phylogenetic reconstructions, suggesting an ancestral hepatovirus host switch from rodents into marsupials. Co-phylogenetic reconciliations of host and hepatovirus phylogenies confirmed that host independent macroevolutionary patterns shaped the phylogenetic relationships of extant hepatoviruses. Although Marsupials are synanthropic and consumed as wild game in Brazil, HAV community protective immunity may limit the zoonotic potential of MHAV.IMPORTANCE The hepatitis A virus (HAV) is an ubiquitous cause of acute hepatitis in humans. Recent findings revealed the evolutionary origins of HAV and the genus Hepatovirus defined by HAV in small mammals. The factors shaping the genealogy of extant hepatoviruses are unclear. We sampled marsupials, one of the most ancient mammalian lineages and identified a novel marsupial HAV (MHAV). The novel MHAV shared specific features with HAV, including hepatotropism, genome structure and a common ancestor in phylogenetic reconstructions. Co-evolutionary analyses revealed that host-independent evolutionary patterns contributed most to the current phylogeny of hepatoviruses and that MHAV was the most drastic example of a cross-order host switch of any hepatovirus observed so far. The divergence of marsupials from other mammals offers unique opportunities to investigate HAV species barriers and whether mechanisms of HAV immune control are evolutionarily conserved. PMID- 29695422 TI - Interferon-Stimulated Gene (ISG)-Expression Screening Reveals the Specific Antibunyaviral Activity of ISG20. AB - Bunyaviruses pose a significant threat to human health, prosperity, and food security. In response to viral infections, interferons (IFNs) upregulate the expression of hundreds of interferon-stimulated genes (ISGs), whose cumulative action can potently inhibit the replication of bunyaviruses. We used a flow cytometry-based method to screen the ability of ~500 unique ISGs from humans and rhesus macaques to inhibit the replication of Bunyamwera orthobunyavirus (BUNV), the prototype of both the Peribunyaviridae family and the Bunyavirales order. Candidates possessing antibunyaviral activity were further examined using a panel of divergent bunyaviruses. Interestingly, one candidate, ISG20, exhibited potent antibunyaviral activity against most viruses examined from the Peribunyaviridae, Hantaviridae, and Nairoviridae families, whereas phleboviruses (Phenuiviridae) largely escaped inhibition. Similar to the case against other viruses known to be targeted by ISG20, the antibunyaviral activity of ISG20 is dependent upon its functional RNase activity. Through use of an infectious virus-like particle (VLP) assay (based on the BUNV minigenome system), we confirmed that gene expression from all 3 viral segments is strongly inhibited by ISG20. Using in vitro evolution, we generated a substantially ISG20-resistant BUNV and mapped the determinants of ISG20 sensitivity/resistance. Taking all the data together, we report that ISG20 is a broad and potent antibunyaviral factor but that some bunyaviruses are remarkably ISG20 resistant. Thus, ISG20 sensitivity/resistance may influence the pathogenesis of bunyaviruses, many of which are emerging viruses of clinical or veterinary significance.IMPORTANCE There are hundreds of bunyaviruses, many of which cause life-threatening acute diseases in humans and livestock. The interferon (IFN) system is a key component of innate immunity, and type I IFNs limit bunyaviral propagation both in vitro and in vivo Type I IFN signaling results in the upregulation of hundreds of IFN-stimulated genes (ISGs), whose concerted action generates an "antiviral state." Although IFNs are critical in limiting bunyaviral replication and pathogenesis, much is still unknown about which ISGs inhibit bunyaviruses. Using ISG-expression screening, we examined the ability of ~500 unique ISGs to inhibit Bunyamwera orthobunyavirus (BUNV), the prototypical bunyavirus. Using this approach, we identified ISG20, an interferon stimulated exonuclease, as a potent inhibitor of BUNV. Interestingly, ISG20 possesses highly selective antibunyaviral activity, with multiple bunyaviruses being potently inhibited while some largely escape inhibition. We speculate that the ability of some bunyaviruses to escape ISG20 may influence their pathogenesis. PMID- 29695424 TI - Morphologic and Genomic Analyses of New Isolates Reveal a Second Lineage of Cedratviruses. AB - Giant viruses have been isolated and characterized in different environments, expanding our knowledge about the biology of these unique microorganisms. In the last 2 years, a new group was discovered, the cedratviruses, currently composed of only two isolates and members of a putative new family, "Pithoviridae," along with previously known pithoviruses. Here we report the isolation and biological and genomic characterization of two novel cedratviruses isolated from samples collected in France and Brazil. Both viruses were isolated using Acanthamoeba castellanii as a host cell and exhibit ovoid particles with corks at either extremity of the particle. Curiously, the Brazilian cedratvirus is ~20% smaller and presents a shorter genome of 460,038 bp, coding for fewer proteins than other cedratviruses. In addition, it has a completely asyntenic genome and presents a lower amino acid identity of orthologous genes (~73%). Pangenome analysis comprising the four cedratviruses revealed an increase in the pangenome concomitant with a decrease in the core genome with the addition of the two novel viruses. Finally, phylogenetic analyses clustered the Brazilian virus in a separate branch within the group of cedratviruses, while the French isolate is closer to the previously reported Cedratvirus lausannensis Taking all together, we propose the existence of a second lineage of this emerging viral genus and provide new insights into the biodiversity and ubiquity of these giant viruses.IMPORTANCE Various giant viruses have been described in recent years, revealing a unique part of the virosphere. A new group among the giant viruses has recently been described, the cedratviruses, which is currently composed of only two isolates. In this paper, we describe two novel cedratviruses isolated from French and Brazilian samples. Biological and genomic analyses showed viruses with different particle sizes, genome lengths, and architecture, revealing the existence of a second lineage of this new group of giant viruses. Our results provide new insights into the biodiversity of cedratviruses and highlight the importance of ongoing efforts to prospect for and characterize new giant viruses. PMID- 29695423 TI - E1B-55K-Mediated Regulation of RNF4 SUMO-Targeted Ubiquitin Ligase Promotes Human Adenovirus Gene Expression. AB - Human adenovirus (HAdV) E1B-55K is a multifunctional regulator of productive viral replication and oncogenic transformation in nonpermissive mammalian cells. These functions depend on E1B-55K's posttranslational modification with the SUMO protein and its binding to HAdV E4orf6. Both early viral proteins recruit specific host factors to form an E3 ubiquitin ligase complex that targets antiviral host substrates for proteasomal degradation. Recently, we reported that the PML-NB-associated factor Daxx represses efficient HAdV productive infection and is proteasomally degraded via a SUMO-E1B-55K-dependent, E4orf6-independent pathway, the details of which remained to be established. RNF4, a cellular SUMO targeted ubiquitin ligase (STUbL), induces ubiquitinylation of specific SUMOylated proteins and plays an essential role during DNA repair. Here, we show that E1B-55K recruits RNF4 to the insoluble nuclear matrix fraction of the infected cell to support RNF4/Daxx association, promoting Daxx PTM and thus inhibiting this antiviral factor. Removing RNF4 from infected cells using RNA interference resulted in blocking the proper establishment of viral replication centers and significantly diminished viral gene expression. These results provide a model for how HAdV antagonize the antiviral host responses by exploiting the functional capacity of cellular STUbLs. Thus, RNF4 and its STUbL function represent a positive factor during lytic infection and a novel candidate for future therapeutic antiviral intervention strategies.IMPORTANCE Daxx is a PML-NB associated transcription factor that was recently shown to repress efficient HAdV productive infection. To counteract this antiviral measurement during infection, Daxx is degraded via a novel pathway including viral E1B-55K and host proteasomes. This virus-mediated degradation is independent of the classical HAdV E3 ubiquitin ligase complex, which is essential during viral infection to target other host antiviral substrates. To maintain a productive viral life cycle, HAdV E1B-55K early viral protein inhibits the chromatin-remodeling factor Daxx in a SUMO-dependent manner. In addition, viral E1B-55K protein recruits the STUbL RNF4 and sequesters it into the insoluble fraction of the infected cell. E1B-55K promotes complex formation between RNF4- and E1B-55K-targeted Daxx protein, supporting Daxx posttranslational modification prior to functional inhibition. Hence, RNF4 represents a novel host factor that is beneficial for HAdV gene expression by supporting Daxx counteraction. In this regard, RNF4 and other STUbL proteins might represent novel targets for therapeutic intervention. PMID- 29695425 TI - Mapping and Engineering Functional Domains of the Assembly-Activating Protein of Adeno-associated Viruses. AB - Adeno-associated viruses (AAVs) encode a unique assembly-activating protein (AAP) within their genomes that is essential for capsid assembly. Studies to date have focused on establishing the role of AAP as a chaperone that mediates the stability, nucleolar transport, and assembly of AAV capsid proteins. Here, we map structure-function correlates of AAP using secondary structure analysis, followed by deletion and substitutional mutagenesis of specific domains, namely, the N terminal hydrophobic region (HR), conserved core (CC), proline-rich region (PRR), threonine/serine-rich region (T/S), and basic region (BR). First, we establish that the centrally located PRR and T/S are flexible linker domains that can either be deleted completely or replaced by heterologous functional domains that enable ancillary functions such as fluorescent imaging or increased AAP stability. We also demonstrate that the C-terminal BR domains can be substituted with heterologous nuclear or nucleolar localization sequences that display various abilities to support AAV capsid assembly. Further, by replacing the BR domain with immunoglobulin (IgG) Fc domains, we assessed AAP complexation with AAV capsid subunits and demonstrate that the hydrophobic region (HR) and the conserved core (CC) in the AAP N terminus are the sole determinants for viral protein (VP) recognition. However, VP recognition alone is not sufficient for capsid assembly. Our study sheds light on the modular structure-function correlates of AAP and provides multiple approaches to engineer AAP that might prove useful toward understanding and controlling AAV capsid assembly.IMPORTANCE Adeno-associated viruses (AAVs) encode a unique assembly-activating protein (AAP) within their genomes that is essential for capsid assembly. Understanding how AAP acts as a chaperone for viral assembly could help improve efficiency and potentially control this process. Our studies reveal that AAP has a modular architecture, with each module playing a distinct role and can be engineered for carrying out new functions. PMID- 29695426 TI - Structural and Functional Features of the Reovirus sigma1 Tail. AB - Mammalian orthoreovirus attachment to target cells is mediated by the outer capsid protein sigma1, which projects from the virion surface. The sigma1 protein is a homotrimer consisting of a filamentous tail, which is partly inserted into the virion; a body domain constructed from beta-spiral repeats; and a globular head with receptor-binding properties. The sigma1 tail is predicted to form an alpha-helical coiled coil. Although sigma1 undergoes a conformational change during cell entry, the nature of this change and its contributions to viral replication are unknown. Electron micrographs of sigma1 molecules released from virions identified three regions of flexibility, including one at the midpoint of the molecule, that may be involved in its structural rearrangement. To enable a detailed understanding of essential sigma1 tail organization and properties, we determined high-resolution structures of the reovirus type 1 Lang (T1L) and type 3 Dearing (T3D) sigma1 tail domains. Both molecules feature extended alpha helical coiled coils, with T1L sigma1 harboring central chloride ions. Each molecule displays a discontinuity (stutter) within the coiled coil and an unexpectedly seamless transition to the body domain. The transition region features conserved interdomain interactions and appears rigid rather than highly flexible. Functional analyses of reoviruses containing engineered sigma1 mutations suggest that conserved residues predicted to stabilize the coiled-coil to-body junction are essential for sigma1 folding and encapsidation, whereas central chloride ion coordination and the stutter are dispensable for efficient replication. Together, these findings enable modeling of full-length reovirus sigma1 and provide insight into the stabilization of a multidomain virus attachment protein.IMPORTANCE While it is established that different conformational states of attachment proteins of enveloped viruses mediate receptor binding and membrane fusion, less is understood about how such proteins mediate attachment and entry of nonenveloped viruses. The filamentous reovirus attachment protein sigma1 binds cellular receptors; contains regions of predicted flexibility, including one at the fiber midpoint; and undergoes a conformational change during cell entry. Neither the nature of the structural change nor its contribution to viral infection is understood. We determined crystal structures of large sigma1 fragments for two different reovirus serotypes. We observed an unexpectedly tight transition between two domains spanning the fiber midpoint, which allows for little flexibility. Studies of reoviruses with engineered changes near the sigma1 midpoint suggest that the stabilization of this region is critical for function. Together with a previously determined structure, we now have a complete model of the full-length, elongated reovirus sigma1 attachment protein. PMID- 29695427 TI - Complex and dynamic interactions between parvovirus capsids, transferrin receptors and antibodies control cell infection and host range. AB - Antibody and receptor binding are key virus/host interactions that control host range and determine the success of infection. Canine and feline parvovirus capsids bind the transferrin receptor type-1 (TfR) to enter host cells, and specific structural interactions appear necessary to prepare the stable capsids for infection. Here we define the details of binding, competition, and occupancy of wild-type and mutant parvovirus capsids with purified receptors and antibodies. TfR/capsid binding interactions depended on the TfR species and varied widely, with no direct relationship between binding affinity and infection. Capsids bound feline, raccoon, and black-backed jackal TfRs at high affinity, but barely bound canine TfRs, which mediated infection efficiently. TfRs from different species also occupied capsids to different levels, with an estimated 1-2 feline TfRs but 12 black-backed jackal TfRs binding each capsid. Multiple alanine substitutions within loop 1 on the capsid surface reduced TfR binding, but substitutions within loop 3 did not, suggesting that loop 1 directly engaged the TfR and loop 3 sterically affected that interaction. Binding and competition between different TfRs and/or antibodies showed complex relationships. Both antibodies 14 and E competed capsids off TfRs, but antibody E could also compete capsids off itself and antibody 14, likely by inducing capsid structural changes. In some cases, the initial TfR or antibody binding event affected subsequent TfR binding, suggesting that capsid structure changes occur after TfR or antibody binding and may impact infection. This shows that precise, host-specific TfR/capsid interactions, beyond simple attachment, are important for successful infection.IMPORTANCE Host receptor binding is a key step during viral infection, and may control both infection and host range. In addition to binding, some viruses require specific interactions with host receptors in order to infect, and anti-capsid antibodies can potentially disrupt these interactions, leading to neutralization. Here, we examine the interactions between parvovirus capsids, the receptors from different hosts, and anti-capsid antibodies. We show that interactions between parvovirus capsids and host-specific TfRs vary in both affinity and in the numbers of receptors bound, with complex effects on infection. In addition, antibodies binding to two sites on the capsids had different effects on TfR/capsid binding. These experiments confirm that receptor and antibody binding to parvovirus capsids are complex processes and the infection outcome is not determined simply by the affinity of attachment. PMID- 29695428 TI - Electrostatic Interactions between Hendra Virus Matrix Proteins Are Required for Efficient Virus-Like-Particle Assembly. AB - Hendra virus (HeV) is a zoonotic paramyxovirus belonging to the genus Henipavirus HeV is highly pathogenic, and it can cause severe neurological and respiratory illnesses in both humans and animals, with an extremely high mortality rate of up to 70%. Among the genes that HeV encodes, the matrix (M) protein forms an integral part of the virion structure and plays critical roles in coordinating viral assembly and budding. Nevertheless, the molecular mechanism of this process is not fully elucidated. Here, we determined the crystal structure of HeV M to 2.5-A resolution. The dimeric structural configuration of HeV M is similar to that of Newcastle disease virus (NDV) M and is fundamental to protein stability and effective virus-like-particle (VLP) formation. Analysis of the crystal packing revealed a notable interface between the alpha1 and alpha2 helices of neighboring HeV M dimers, with key residues sharing degrees of sequence conservation among henipavirus M proteins. Structurally, a network of electrostatic interactions dominates the alpha1-alpha2 interactions, involving residues Arg57 from the alpha1 helix and Asp105 and Glu108 from the alpha2 helix. The disruption of the alpha1-alpha2 interactions using engineered charge reversal substitutions (R57E, R57D, and E108R) resulted in significant reduction or abrogation of VLP production. This phenotype was reversible with an R57E E108R mutant that was designed to partly restore salt bridge contacts. Collectively, our results define and validate previously underappreciated regions of henipavirus M proteins that are crucial for productive VLP assembly.IMPORTANCE Hendra virus is a henipavirus associated with lethal infections in humans. It is classified as a biosafety level 4 (BSL4) agent, and there are currently no preventive or therapeutic treatments available against HeV. Vital to henipavirus pathogenesis, the structural protein M has been implicated in viral assembly and budding, as well as host-virus interactions. However, there is no structural information available for henipavirus M, and the basis of M-driven viral assembly is not fully elucidated. We demonstrate the first three-dimensional structure of a henipavirus M protein. We show the dimeric organization of HeV M as a basic unit for higher-order oligomerization. Additionally, we define key regions/residues of HeV M that are required for productive virus-like-particle formation. These findings provide the first insight into the mechanism of M driven assembly in henipavirus. PMID- 29695429 TI - Lack of Transmission of Chronic Wasting Disease to Cynomolgus Macaques. AB - Chronic wasting disease (CWD) is a fatal prion disease that can infect deer, elk and moose. CWD was first recognized in captive deer kept in wildlife facilities in Colorado from 1967-1979. CWD has now been detected in 25 states of the USA, 2 Canadian provinces, South Korea, Norway and Finland. It is currently unknown if humans are susceptible to CWD infection. Understanding the health risk from consuming meat and/or products from CWD-infected cervids is a critical human health concern. Prior research using transgenic mouse models and in vitro conversion assays suggest that a significant species barrier exists between CWD and humans. To date, published epidemiologic studies of humans consuming cervids in CWD endemic areas have found no evidence to confirm CWD transmission to humans. Previously, we reported data from ongoing cross-species CWD transmission studies using two species of non-human primates as models. Squirrel monkeys (SM) and Cynomolgus macaques (CM) were inoculated by either intracerebral or oral routes with brain homogenates from CWD-infected deer and elk containing high levels of infectivity. SM were highly susceptible to CWD infection while CM were not. In the current study, we present new data for seven CWD-inoculated CM euthanized from 11-13 years post CWD-inoculation and eight additional uninoculated control CM. New and archival CM tissues were screened for prion infection using the ultrasensitive RT-QuIC assay, immunohistochemistry and immunoblot. In this study, there was no clinical, pathological or biochemical evidence suggesting that CWD was transmitted from cervids to CM.IMPORTANCE Chronic wasting disease (CWD) is a fatal prion disease found in deer, elk and moose. Since first discovered in the late 1960's, CWD has now spread to at least 25 states of the USA, 2 Canadian provinces, South Korea, Norway and Finland. Eradication of CWD from endemic areas is very unlikely and additional spread will occur. As the range and prevalence of CWD increases, so will the potential for human exposure to CWD prions. It is currently unknown if CWD poses a risk to human health. However, determining this risk is critical to prevent a similar scenario as what occurred when mad cow disease was found to be transmissible to humans. In the current study, we used cynomolgus macaque monkeys as a surrogate model for CWD transmission to humans. After 13 years, no evidence for CWD transmission to macaques was detected clinically or using highly sensitive prion disease screening assays. PMID- 29695430 TI - The S Gene Is Necessary but Not Sufficient for the Virulence of Porcine Epidemic Diarrhea Virus Novel Variant Strain BJ2011C. AB - The recently emerged highly virulent variants of porcine epidemic diarrhea virus (PEDV) have caused colossal economic losses to the worldwide swine industry. In this study, we investigated the viral virulence determinants by constructing a series of chimeric mutants between the highly virulent strain BJ2011C and the avirulent strain CHM2013. When tested in the 2-day-old piglet model, wild-type (WT) BJ2011C caused severe diarrhea and death of the piglets within 72 h. In contrast, its chimeric derivative carrying the S gene from CHM2013 (BJ2011C-SCHM) was avirulent to the piglets. Moreover, reciprocal substitution of the BJ2011C S gene (CHM2013-SBJ) did not enable CHM2013 to gain any virulence. However, when the whole structural protein-coding region of BJ2011C (CHM2013-SPBJ) was swapped, CHM2013 started to gain the ability to efficiently colonize the intestinal tract and caused diarrhea in piglets. A further gain of virulence required additional acquisition of the 3' untranslated region (UTR) of BJ2011C, and the resultant virus (CHM2013-SP + 3UTRBJ) caused more severe diarrhea and death of piglets. Together, our findings suggest that the virulence of PEDV epidemic strains is a multigenic event and that the S gene is only one of the necessary determinants.IMPORTANCE The recently emerged highly virulent PEDV variants are the major cause of the global porcine epidemic diarrhea (PED) pandemic. The S gene of the variants undergoes remarkable variations and has been thought to be the virulence determinant for the enhanced pathogenesis. Our studies here showed that the S gene is only part of the story and that full virulence requires cooperation from other genes. Our findings provide insight into the pathogenic mechanism of the highly virulent PEDV variants and have implications for future vaccine development. PMID- 29695431 TI - Timeliness of Proteolytic Events Is Prerequisite for Efficient Functioning of the Alphaviral Replicase. AB - Polyprotein processing has an important regulatory role in the life cycle of positive-strand RNA viruses. In the case of alphaviruses, sequential cleavage of the nonstructural polyprotein (ns-polyprotein) at three sites eventually yields four mature nonstructural proteins (nsPs) that continue working in complex to replicate viral genomic RNA and transcribe subgenomic RNA. Recognition of cleavage sites by viral nsP2 protease is guided by short sequences upstream of the scissile bond and, more importantly, by the spatial organization of the replication complex. In this study, we analyzed the consequences of the artificially accelerated processing of the Semliki Forest virus ns-polyprotein. It was found that in mammalian cells, not only the order but also the correct timing of the cleavage events is essential for the success of viral replication. Analysis of the effects of compensatory mutations in rescued viruses as well as in vitro translation and trans-replicase assays corroborated our findings and revealed the importance of the V515 residue in nsP2 for recognizing the P4 position in the nsP1/nsP2 cleavage site. We also extended our conclusions to Sindbis virus by analyzing the properties of the hyperprocessive variant carrying the N614D mutation in nsP2. We conclude that the sequence of the nsP1/nsP2 site in alphaviruses is under selective pressure to avoid the presence of sequences that are recognized too efficiently and would otherwise lead to premature cleavage at this site before completion of essential tasks of RNA synthesis or virus-induced replication complex formation. Even subtle changes in the ns polyprotein processing pattern appear to lead to virus attenuation.IMPORTANCE The polyprotein expression strategy is a cornerstone of alphavirus replication. Three sites within the ns-polyprotein are recognized by the viral nsP2 protease and cleaved in a defined order. Specific substrate targeting is achieved by the recognition of the short sequence upstream of the scissile bond and a correct macromolecular assembly of ns-polyprotein. Here, we highlighted the importance of the timeliness of proteolytic events, as an additional layer of regulation of efficient virus replication. We conclude that, somewhat counterintuitively, the cleavage site sequences at the nsP1/nsP2 and nsP2/nsP3 junctions are evolutionarily selected to be recognized by protease inefficiently, to avoid premature cleavages that would be detrimental for the assembly and functionality of the replication complex. Understanding the causes and consequences of viral polyprotein processing events is important for predicting the properties of mutant viruses and should be helpful for the development of better vaccine candidates and understanding potential mechanisms of resistance to protease inhibitors. PMID- 29695432 TI - A Chikungunya Virus trans-Replicase System Reveals the Importance of Delayed Nonstructural Polyprotein Processing for Efficient Replication Complex Formation in Mosquito Cells. AB - Chikungunya virus (CHIKV) is a medically important alphavirus that is transmitted by Aedes aegypti and Aedes albopictus mosquitoes. The viral replicase complex consists of four nonstructural proteins (nsPs) expressed as a polyprotein precursor and encompasses all enzymatic activities required for viral RNA replication. nsPs interact with host components of which most are still poorly understood, especially in mosquitos. A CHIKV trans-replicase system that allows the uncoupling of RNA replication and nsP expression was adapted to mosquito cells and subsequently used for analysis of universal and host-specific effects of 17 different nonstructural polyprotein (ns-polyprotein) mutations. It was found that mutations blocking nsP enzymatic activities as well as insertions of enhanced green fluorescent protein (EGFP) into different nsPs had similar effects on trans-replicase activity regardless of the host (i.e., mammalian or mosquito). Mutations that slow down or accelerate ns-polyprotein processing generally had no effect or reduced trans-replicase activity in mammalian cells, while in mosquito cells most of them increased trans-replicase activity prominently. Increased RNA replication in mosquito cells was counteracted by an antiviral RNA interference (RNAi) response. Substitution of the W258 residue in the membrane binding peptide of nsP1 resulted in a temperature-sensitive defect, in the context of both the trans-replicase and infectious CHIKV. The defect was compensated for by secondary mutations selected during passaging of mutant CHIKV. These findings demonstrate the value of alphavirus trans-replicase systems for studies of viral RNA replication and virus-host interactions.IMPORTANCE Chikungunya virus is an important mosquito-transmitted human pathogen. This virus actively replicates in mosquitoes, but the underlying molecular mechanisms and interactions of viral and host components are poorly understood. This is partly due to the lack of reliable systems for functional analysis of viral nonstructural polyproteins (ns polyproteins) and nonstructural proteins (nsPs) in mosquito cells. Adaption of a CHIKV trans-replicase system allowed study of the effects of mutations in the ns polyprotein on RNA replication in cells derived from mammalian and mosquito hosts. We found that a slowdown of ns-polyprotein processing facilitates replication complex formation and/or functioning in mosquito cells and that this process is antagonized by the natural RNAi defense system present in mosquito cells. The mosquito-adapted CHIKV trans-replicase system represents a valuable tool to study alphavirus-mosquito interactions at the molecular level and to develop advanced antiviral strategies. PMID- 29695434 TI - Regulation of Apolipoprotein E Trafficking by Hepatitis C Virus-induced Autophagy. AB - Apolipoprotein E (ApoE) plays an important role in the maturation and infectivity of hepatitis C virus (HCV). By analyzing the subcellular localization of ApoE in Huh7 hepatoma cells that harbored an HCV subgenomic RNA replicon, we found that ApoE colocalized with autophagosomes. This colocalization was marginally detected in HCV-infected cells apparently due to the depletion of ApoE by HCV, as the treatment with bafilomycin A1 (BafA1), a vacuolar ATPase inhibitor that inhibits autophagic protein degradation, partially restored the ApoE level and enhanced its colocalization with autophagosomes in HCV-infected cells. The role of HCV induced autophagy in the degradation of ApoE was further supported by the observations that nutrient starvation, which induces autophagic protein degradation, led to the loss of ApoE in HCV subgenomic RNA replicon cells, and the knockdown of ATG7, a protein essential for the formation of autophagic vacuoles, increased the ApoE level in cells with productive HCV replication. Interesting, the inhibition of autophagy by ATG7 knockdown reduced the colocalization of ApoE with the HCV E2 envelope protein and the HCV titers released from cells. In contrast, the treatment of cells with BafA1 enhanced the colocalization of ApoE and HCV E2 and increased both intracellular and extracellular HCV titers. These results indicated that autophagy played an important role in the trafficking of ApoE in HCV-infected cells. While it led to autophagic degradation of ApoE, it also promoted the interaction between ApoE and HCV E2 to enhance the production of infectious progeny viral particles.ImportanceHepatitis C virus (HCV) is one of the most important human pathogens. Its virion is associated with apolipoprotein E (ApoE), which enhances its infectivity. HCV induces autophagy to enhance its replication. In this report, we demonstrate that autophagy plays an important role in the trafficking of ApoE in HCV-infected cells. This leads to the degradation of ApoE by autophagy. However, if the autophagic protein degradation is inhibited, ApoE is stabilized and colocalized with autophagosomes. This leads to its enhanced colocalization with the HCV E2 envelope protein and increased production of infectious progeny viral particles. If autophagy is inhibited by suppressing the expression of ATG7, a gene essential for the formation of autophagosomes, the colocalization of ApoE with E2 is reduced, resulting in the reduction of progeny viral titers. These results indicate an important role of autophagy in the transport of ApoE to promote the production of infectious HCV particles. PMID- 29695433 TI - KRAB-ZFP Repressors Enforce Quiescence of Oncogenic Human Herpesviruses. AB - Cancer-causing herpesviruses infect nearly every human and persist indefinitely in B lymphocytes in a quiescent state known as latency. A hallmark of this quiescence or latency is the presence of extrachromosomal viral genomes with highly restricted expression of viral genes. Silencing of viral genes ensures both immune evasion by the virus and limited pathology to the host, yet how multiple genes on multiple copies of viral genomes are simultaneously silenced is a mystery. In a unifying theme, we report that both cancer-causing human herpesviruses, despite having evolved independently, are silenced through the activities of two members of the Kruppel-associated box (KRAB) domain-zinc finger protein (ZFP) (KRAB-ZFP) epigenetic silencing family, revealing a novel STAT3 KRAB-ZFP axis of virus latency. This dual-edged antiviral strategy restricts the destructive ability of the lytic phase while promoting the cancer-causing latent phase. These findings also unveil roles for KRAB-ZFPs in silencing of multicopy foreign genomes with the promise of evicting herpesviruses to kill viral cancers bearing clonal viral episomes.IMPORTANCE Despite robust immune responses, cancer causing viruses Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV) persist for life. This persistence is accomplished partly through a stealth mechanism that keeps extrachromosomal viral genomes quiescent. Quiescence, or latency, ensures that not every cell harboring viral genomes is killed directly through lytic activation or indirectly via the immune response, thereby evicting virus from host. For the host, quiescence limits pathology. Thus, both virus and host benefit from quiescence, yet how quiescence is maintained through silencing of a large set of viral genes on multiple viral genomes is not well understood. Our studies reveal that members of a gene silencing family, the KRAB-ZFPs, promote quiescence of both cancer-causing human viruses through simultaneous silencing of multiple genes on multicopy extrachromosomal viral genomes. PMID- 29695437 TI - The Authors Reply. PMID- 29695435 TI - Critical Role of the Human T-Cell Leukemia Virus Type 1 Capsid N-Terminal Domain for Gag-Gag Interactions and Virus Particle Assembly. AB - The retroviral Gag protein is the main structural protein responsible for virus particle assembly and release. Like human immunodeficiency virus type 1 (HIV-1) Gag, human T-cell leukemia virus type 1 (HTLV-1) has a structurally conserved capsid (CA) domain, including a beta-hairpin turn and a centralized coiled-coil like structure of six alpha helices in the CA amino-terminal domain (NTD), as well as four alpha-helices in the CA carboxy-terminal domain (CTD). CA drives Gag oligomerization, which is critical for both immature Gag lattice formation and particle production. The HIV-1 CA CTD has previously been shown to be a primary determinant for CA-CA interactions, and while both the HTLV-1 CA NTD and CTD have been implicated in Gag-Gag interactions, our recent observations have implicated the HTLV-1 CA NTD as encoding key determinants that dictate particle morphology. Here, we have conducted alanine-scanning mutagenesis in the HTLV-1 CA NTD nucleotide-encoding sequences spanning the loop regions and amino acids at the beginning and ends of alpha-helices due to their structural dissimilarity from the HIV-1 CA NTD structure. We analyzed both Gag subcellular distribution and efficiency of particle production for these mutants. We discovered several important residues (i.e., M17, Q47/F48, and Y61). Modeling implicated that these residues reside at the dimer interface (i.e., M17 and Y61) or at the trimer interface (i.e., Q47/F48). Taken together, these observations highlight the critical role of the HTLV-1 CA NTD in Gag-Gag interactions and particle assembly, which is, to the best of our knowledge, in contrast to HIV-1 and other retroviruses.IMPORTANCE Retrovirus particle assembly and release from infected cells is driven by the Gag structural protein. Gag-Gag interactions, which form an oligomeric lattice structure at a particle budding site, are essential to the biogenesis of an infectious virus particle. The CA domain of Gag is generally thought to possess the key determinants for Gag-Gag interactions, and the present study has discovered several critical amino acid residues in the CA domain of HTLV-1 Gag, an important cancer-causing human retrovirus, which are distinct from that of HIV-1 as well as other retroviruses studied to date. Altogether, our results provide important new insights into a poorly understood aspect of HTLV-1 replication that significantly enhances our understanding of the molecular nature of Gag-Gag interaction determinants crucial for virus particle assembly. PMID- 29695438 TI - Nanoparticle Tracking Analysis of Urine to Detect Exosomes Can Be Confounded by Albuminuria. PMID- 29695436 TI - The Association of Mediterranean and DASH Diets with Mortality in Adults on Hemodialysis: The DIET-HD Multinational Cohort Study. AB - Background Mediterranean and Dietary Approaches to Stop Hypertension (DASH) diets associate with lower cardiovascular and all-cause mortality in the general population, but the benefits for patients on hemodialysis are uncertain.Methods Mediterranean and DASH diet scores were derived from the GA2LEN Food Frequency Questionnaire within the DIET-HD Study, a multinational cohort study of 9757 adults on hemodialysis. We conducted adjusted Cox regression analyses clustered by country to evaluate the association between diet score tertiles and all-cause and cardiovascular mortality (the lowest tertile was the reference category).Results During the median 2.7-year follow-up, 2087 deaths (829 cardiovascular deaths) occurred. The adjusted hazard ratios (95% confidence intervals) for the middle and highest Mediterranean diet score tertiles were 1.20 (1.01 to 1.41) and 1.14 (0.90 to 1.43), respectively, for cardiovascular mortality and 1.10 (0.99 to 1.22) and 1.01 (0.88 to 1.17), respectively, for all cause mortality. Corresponding estimates for the same DASH diet score tertiles were 1.01 (0.85 to 1.21) and 1.19 (0.99 to 1.43), respectively, for cardiovascular mortality and 1.03 (0.92 to 1.15) and 1.00 (0.89 to 1.12), respectively, for all-cause mortality. The association between DASH diet score and all-cause death was modified by age (P=0.03); adjusted hazard ratios for the middle and highest DASH diet score tertiles were 1.02 (0.81 to 1.29) and 0.70 (0.53 to 0.94), respectively, for younger patients (<=60 years old) and 1.05 (0.93 to 1.19) and 1.08 (0.95 to 1.23), respectively, for older patients.Conclusions Mediterranean and DASH diets did not associate with cardiovascular or total mortality in hemodialysis. PMID- 29695439 TI - Elucidating the Role of the Ventrolateral Prefrontal Cortex in Economic Decision Making. PMID- 29695440 TI - Is There a Role for Pattern Separation during Sleep? PMID- 29695442 TI - Sterols and stanols as novel tracers of waterbird population dynamics in freshwater ponds. AB - With the expansion of urban centres in the mid-twentieth century and the post 1970 decrease in pesticides, populations of double-crested cormorants (Phalacrocorax auritus) and ring-billed gulls (Larus delawarensis) around Lake Ontario (Canada and USA) have rapidly rebounded, possibly to unprecedented numbers. Along with the use of traditional palaeolimnological methods (e.g. stable isotopes, biological proxies), we now have the capacity to develop specific markers for directly tracking the presence of waterbirds on nesting islands. Here, we apply the use of lipophilic sterols and stanols from both plant and animal-faecal origins as a reliable technique, independent of traditional isotopic methods, for pinpointing waterbird arrival and population growth over decadal timescales. Sterol and stanol concentrations measured in the guano samples of waterbird species were highly variable within a species and between the three species of waterbirds examined. However, cholesterol was the dominant sterol in guano, and phytosterols were also high in ring-billed gull guano. This variability highlights a specialist piscivorous diet for cormorants compared to a generalist, omnivorous diet for gulls, which may now often include grain and invertebrates from agricultural fields. A ratio that includes cholesterol and sitosterol plus their aerobically reduced products (cholestanol, stigmastanol) best explained the present range of bird abundance across the islands and was significantly correlated to sedimentary delta15N. Overall, we demonstrate the use of sterols and stanols as a direct means for tracking the spatial and temporal presence of waterbirds on islands across Lake Ontario, and probably elsewhere. PMID- 29695441 TI - Pulmonary ventilation-perfusion mismatch: a novel hypothesis for how diving vertebrates may avoid the bends. AB - Hydrostatic lung compression in diving marine mammals, with collapsing alveoli blocking gas exchange at depth, has been the main theoretical basis for limiting N2 uptake and avoiding gas emboli (GE) as they ascend. However, studies of beached and bycaught cetaceans and sea turtles imply that air-breathing marine vertebrates may, under unusual circumstances, develop GE that result in decompression sickness (DCS) symptoms. Theoretical modelling of tissue and blood gas dynamics of breath-hold divers suggests that changes in perfusion and blood flow distribution may also play a significant role. The results from the modelling work suggest that our current understanding of diving physiology in many species is poor, as the models predict blood and tissue N2 levels that would result in severe DCS symptoms (chokes, paralysis and death) in a large fraction of natural dive profiles. In this review, we combine published results from marine mammals and turtles to propose alternative mechanisms for how marine vertebrates control gas exchange in the lung, through management of the pulmonary distribution of alveolar ventilation ([Formula: see text]) and cardiac output/lung perfusion ([Formula: see text]), varying the level of [Formula: see text] in different regions of the lung. Man-made disturbances, causing stress, could alter the [Formula: see text] mismatch level in the lung, resulting in an abnormally elevated uptake of N2, increasing the risk for GE. Our hypothesis provides avenues for new areas of research, offers an explanation for how sonar exposure may alter physiology causing GE and provides a new mechanism for how air breathing marine vertebrates usually avoid the diving-related problems observed in human divers. PMID- 29695443 TI - Movement patterns and athletic performance of leopards in the Okavango Delta. AB - Although leopards are the most widespread of all the big cats and are known for their adaptability, they are elusive and little is known in detail about their movement and hunting energetics. We used high-resolution GPS/IMU (inertial measurement unit) collars to record position, activity and the first high-speed movement data on four male leopards in the Okavango Delta, an area with high habitat diversity and habitat fragmentation. Leopards in this study were generally active and conducted more runs during the night, with peaks in activity and number of runs in the morning and evening twilight. Runs were generally short (less than 100 m) and relatively slow (maximum speed 5.3 m s-1, mean of individual medians) compared to other large predators. Average daily travel distance was 11 km and maximum daily travel distance was 29 km. No direct correlation was found between average daily temperature and travel distance or between season and travel distance. Total daily energy requirements based on locomotor cost and basal metabolic rate varied little between individuals and over time. This study provides novel insights into movement patterns and athletic performance of leopards through quantitative high-resolution measurement of the locomotor, energetic, spatial and temporal movement characteristics. The results are unbiased by methodological and observational limitations characteristic of previous studies and demonstrate the utility of applying new technologies to field studies of elusive nocturnal species. PMID- 29695444 TI - Systematic conservation planning for intraspecific genetic diversity. AB - Intraspecific diversity informs the demographic and evolutionary histories of populations, and should be a main conservation target. Although approaches exist for identifying relevant biological conservation units, attempts to identify priority conservation areas for intraspecific diversity are scarce, especially within a multi-specific framework. We used neutral molecular data on six European freshwater fish species (Squalius cephalus, Phoxinus phoxinus, Barbatula barbatula, Gobio occitaniae, Leuciscus burdigalensis and Parachondrostoma toxostoma) sampled at the riverscape scale (i.e. the Garonne-Dordogne river basin, France) to determine hot- and coldspots of genetic diversity, and to identify priority conservation areas using a systematic conservation planning approach. We demonstrate that systematic conservation planning is efficient for identifying priority areas representing a predefined part of the total genetic diversity of a whole landscape. With the exception of private allelic richness (PA), classical genetic diversity indices (allelic richness, genetic uniqueness) were poor predictors for identifying priority areas. Moreover, we identified weak surrogacies among conservation solutions found for each species, implying that conservation solutions are highly species-specific. Nonetheless, we showed that priority areas identified using intraspecific genetic data from multiple species provide more effective conservation solutions than areas identified for single species or on the basis of traditional taxonomic criteria. PMID- 29695445 TI - Adiposity signals predict vocal effort in Alston's singing mice. AB - Advertisement displays often seem extravagant and expensive, and are thought to depend on the body condition of a signaller. Nevertheless, we know little about how signallers adjust effort based on condition, and few studies find a strong relationship between natural variation in condition and display. To examine the relationship between body condition and signal elaboration more fully, we characterized physiological condition and acoustic displays in a wild rodent with elaborate vocalizations, Alston's singing mouse, Scotinomys teguina We found two major axes of variation in condition-one defined by short-term fluctuations in caloric nutrients, and a second by longer-term variation in adiposity. Among acoustic parameters, song effort was characterized by high rates of display and longer songs. Song effort was highly correlated with measures of adiposity. We found that leptin was a particularly strong predictor of display effort. Leptin is known to influence investment in other costly traits, such as immune function and reproduction. Plasma hormone levels convey somatic state to a variety of tissues, and may govern trait investment across vertebrates. Such measures offer new insights into how animals translate body condition into behavioural and life history decisions. PMID- 29695447 TI - Social conformity and propagation of information in collective U-turns of fish schools. AB - Moving animal groups such as schools of fishes or flocks of birds often undergo sudden collective changes of their travelling direction as a consequence of stochastic fluctuations in heading of the individuals. However, the mechanisms by which these behavioural fluctuations arise at the individual level and propagate within a group are still unclear. In this study, we combine an experimental and theoretical approach to investigate spontaneous collective U-turns in groups of rummy-nose tetra (Hemigrammus rhodostomus) swimming in a ring-shaped tank. U turns imply that fish switch their heading between the clockwise and anticlockwise direction. We reconstruct trajectories of individuals moving alone and in groups of different sizes. We show that the group decreases its swimming speed before a collective U-turn. This is in agreement with previous theoretical predictions showing that speed decrease facilitates an amplification of fluctuations in heading in the group, which can trigger U-turns. These collective U-turns are mostly initiated by individuals at the front of the group. Once an individual has initiated a U-turn, the new direction propagates through the group from front to back without amplification or dampening, resembling the dynamics of falling dominoes. The mean time between collective U-turns sharply increases as the size of the group increases. We develop an Ising spin model integrating anisotropic and asymmetrical interactions between fish and their tendency to follow the majority of their neighbours nonlinearly (social conformity). The model quantitatively reproduces key features of the dynamics and the frequency of collective U-turns observed in experiments. PMID- 29695446 TI - Functional MRI in the Nile crocodile: a new avenue for evolutionary neurobiology. AB - Crocodilians are important for understanding the evolutionary history of amniote neural systems as they are the nearest extant relatives of modern birds and share a stem amniote ancestor with mammals. Although the crocodilian brain has been investigated anatomically, functional studies are rare. Here, we employed functional magnetic resonance imaging (fMRI), never tested in poikilotherms, to investigate crocodilian telencephalic sensory processing. Juvenile Crocodylus niloticus were placed in a 7 T MRI scanner to record blood oxygenation level dependent (BOLD) signal changes during the presentation of visual and auditory stimuli. Visual stimulation increased BOLD signals in rostral to mid-caudal portions of the dorso-lateral anterior dorsal ventricular ridge (ADVR). Simple auditory stimuli led to signal increase in the rostromedial and caudocentral ADVR. These activation patterns are in line with previously described projection fields of diencephalic sensory fibres. Furthermore, complex auditory stimuli activated additional regions of the caudomedial ADVR. The recruitment of these additional, presumably higher-order, sensory areas reflects observations made in birds and mammals. Our results indicate that structural and functional aspects of sensory processing have been likely conserved during the evolution of sauropsids. In addition, our study shows that fMRI can be used to investigate neural processing in poikilotherms, providing a new avenue for neurobiological research in these critical species. PMID- 29695448 TI - Stick insect in Burmese amber reveals an early evolution of lateral lamellae in the Mesozoic. AB - Extant stick and leaf insects commonly imitate twigs or leaves, with lateral lamellae used to enhance crypsis or achieve mimicry for protection. However, the origin and early evolution of such lateral expansions among Phasmatodea are unknown, because all known Mesozoic phasmatodeans hitherto lack preserved evidence of such structures. We report here the first Mesozoic stick insect, Elasmophasma stictum gen. et sp. nov., with well-preserved, thin, lateral lamellae on the thoracic pleura, the terga of abdominal segments I-X and the ventrolateral margins of all femora. This new species, from the mid-Cretaceous amber of northern Myanmar, has a clear, stick-like body and is assigned to Euphasmatodea. The abdominal structures of E. stictum exhibit traces of multiple expansions of the terga, suggesting that such structure might have been an early development of body expansions used to improve crypsis for stick or leaf insects when they sprawled on twigs or leaves. PMID- 29695449 TI - Towards European harmonisation of contagious equine metritis diagnosis through interlaboratory trials. AB - The performance of culture and PCR methods routinely used to diagnose contagious equine metritis (CEM) was evaluated and compared by two interlaboratory trials involving a total of 24 European laboratories, including 22 National Reference Laboratories for CEM. Samples were swab specimens artificially contaminated with bacteria present in the genital tract of Equidae, some with and some without Taylorella equigenitalis, the causative agent of CEM, and T asinigenitalis, responsible for possible misidentification as T equigenitalis Throughout both interlaboratory trials, PCR performed better in terms of specificity and sensitivity than the culture method, supporting the assertion that PCR should be accepted for CEM diagnosis. However, the culture performance during the second interlaboratory trial was better than during the first one, suggesting that the expertise of participants improved. This reveals the advantage of regular interlaboratory trials to constantly improve the expertise of laboratories. It also shows the need to develop new culture media that are more selective and/or better geared to the metabolism of T equigenitalis in order to improve the bacteriological diagnosis of CEM. PMID- 29695450 TI - Case series: periocular habronemiasis in five horses in the Netherlands. AB - In tropical and subtropical climates, infection of periocular tissue by Habronema larvae is a recognised cause of conjunctivitis or blepharitis. To the authors' knowledge, only a few cases of habronemiasis have been described in Western Europe, and it has not been documented previously in the Netherlands. The objective of this report is to describe the occurrence of five cases of (peri)ocular habronemiasis in the Netherlands, of which four date from the past few years. The diagnosis was based on the history, clinical signs and histopathologic examination of biopsy specimens. A granulomatous conjunctivitis/dermatitis and sulphur-like granules were present in all cases. Histopathology showed an eosinophilic granulomatous inflammation, and three out of five (60 per cent) samples revealed one or more nematodes on section. Treatment combinations with surgical excision, local corticosteroid and/or anthelmintic drugs were used. Furthermore, all horses received ivermectin or moxidectin. Treatment resulted in healing of the lesions in four horses. One case, which was refractory to treatment, resolved spontaneously after the onset of colder weather. This case series suggests an increased prevalence of (peri)ocular habronemiasis in the Netherlands. This diagnosis should therefore be considered when being presented with a horse with granulomatous conjunctivitis/dermatitis in Western Europe, especially during the summer months. PMID- 29695451 TI - Genomic investigation of porcine periweaning failure to thrive syndrome (PFTS). AB - Porcine periweaning failure to thrive syndrome (PFTS) can be defined by anorexia, lethargy, progressive debilitation and compulsive behaviours that occur in seemingly healthy pigs within two to threeweeks of weaning in the absence of any known infectious, nutritional, management or environmental factors. A genetic component has been hypothesised for this syndrome. In the present study, 119 commercial pigs (80 cases and 39 controls) were genotyped with the porcine 80K single nucleotide polymorphism-chip and were analysed with logistic regression and two Fixation Index-based approaches. The analyses revealed several regions on chromosomes 1, 3, 6 and 11 with moderate divergence between cases and controls, particularly three haplotypes on SSC3 and 11. The gene-based analyses of the candidate regions revealed the presence of genes that have been reported to be associated with phenotypes like PFST including depression (PDE10A) and intestinal villous atrophy (CUL4A). It is important to increase the effort of collecting more samples to improve the power of these analyses. PMID- 29695452 TI - PPARgamma agonist pioglitazone reverses pulmonary hypertension and prevents right heart failure via fatty acid oxidation. AB - Right ventricular (RV) heart failure is the leading cause of death in pulmonary arterial hypertension (PAH). Peroxisome proliferator-activated receptor gamma (PPARgamma) acts as a vasoprotective metabolic regulator in smooth muscle and endothelial cells; however, its role in the heart is unclear. We report that deletion of PPARgamma in cardiomyocytes leads to biventricular systolic dysfunction and intramyocellular lipid accumulation in mice. In the SU5416/hypoxia (SuHx) rat model, oral treatment with the PPARgamma agonist pioglitazone completely reverses severe PAH and vascular remodeling and prevents RV failure. Failing RV cardiomyocytes exhibited mitochondrial disarray and increased intramyocellular lipids (lipotoxicity) in the SuHx heart, which was prevented by pioglitazone. Unbiased ventricular microRNA (miRNA) arrays, mRNA sequencing, and lipid metabolism studies revealed dysregulation of cardiac hypertrophy, fibrosis, myocardial contractility, fatty acid transport/oxidation (FAO), and transforming growth factor-beta signaling in the failing RV. These epigenetic, transcriptional, and metabolic alterations were modulated by pioglitazone through miRNA/mRNA networks previously not associated with PAH/RV dysfunction. Consistently, pre-miR-197 and pre-miR-146b repressed genes that drive FAO (Cpt1b and Fabp4) in primary cardiomyocytes. We recapitulated our major pathogenic findings in human end-stage PAH: (i) in the pressure-overloaded failing RV (miR-197 and miR-146b up-regulated), (ii) in peripheral pulmonary arteries (miR-146b up-regulated, miR-133b down-regulated), and (iii) in plexiform vasculopathy (miR-133b up-regulated, miR-146b down-regulated). Together, PPARgamma activation can normalize epigenetic and transcriptional regulation primarily related to disturbed lipid metabolism and mitochondrial morphology/function in the failing RV and the hypertensive pulmonary vasculature, representing a therapeutic approach for PAH and other cardiovascular/pulmonary diseases. PMID- 29695453 TI - Fundamental science behind today's important medicines. AB - Today's most transformative medicines exist because of fundamental discoveries that were made without regard to practical outcome and with their relevance to therapeutics only appearing decades later. PMID- 29695454 TI - Targeting protein biotinylation enhances tuberculosis chemotherapy. AB - Successful drug treatment for tuberculosis (TB) depends on the unique contributions of its component drugs. Drug resistance poses a threat to the efficacy of individual drugs and the regimens to which they contribute. Biologically and chemically validated targets capable of replacing individual components of current TB chemotherapy are a major unmet need in TB drug development. We demonstrate that chemical inhibition of the bacterial biotin protein ligase (BPL) with the inhibitor Bio-AMS (5'-[N-(d biotinoyl)sulfamoyl]amino-5'-deoxyadenosine) killed Mycobacterium tuberculosis (Mtb), the bacterial pathogen causing TB. We also show that genetic silencing of BPL eliminated the pathogen efficiently from mice during acute and chronic infection with Mtb Partial chemical inactivation of BPL increased the potency of two first-line drugs, rifampicin and ethambutol, and genetic interference with protein biotinylation accelerated clearance of Mtb from mouse lungs and spleens by rifampicin. These studies validate BPL as a potential drug target that could serve as an alternate frontline target in the development of new drugs against Mtb. PMID- 29695455 TI - Alloreactive fetal T cells promote uterine contractility in preterm labor via IFN gamma and TNF-alpha. AB - Healthy pregnancy is the most successful form of graft tolerance, whereas preterm labor (PTL) may represent a breakdown in maternal-fetal tolerance. Although maternal immune responses have been implicated in pregnancy complications, fetal immune responses against maternal antigens are often not considered. To examine the fetal immune system in the relevant clinical setting, we analyzed maternal and cord blood in patients with PTL and healthy term controls. We report here that the cord blood of preterm infants has higher amounts of inflammatory cytokines and a greater activation of dendritic cells. Moreover, preterm cord blood is characterized by the presence of a population of central memory cells with a type 1 T helper phenotype, which is absent in term infants, and an increase in maternal microchimerism. T cells from preterm infants mount a robust proliferative, proinflammatory response to maternal antigens compared to term infants yet fail to respond to third-party antigens. Furthermore, we show that T cells from preterm infants stimulate uterine myometrial contractility through interferon-gamma and tumor necrosis factor-alpha. In parallel, we found that adoptive transfer of activated T cells directly into mouse fetuses resulted in pregnancy loss. Our findings indicate that fetal inflammation and rejection of maternal antigens can contribute to the signaling cascade that promotes uterine contractility and that aberrant fetal immune responses should be considered in the pathogenesis of PTL. PMID- 29695456 TI - Human fetal immune cells fight back. AB - Immune dysregulation begins in utero, influenced by inflammation, maternal microchimerism, and the activation of fetal immune responses (Frascoli et al, this issue). PMID- 29695457 TI - A digital microfluidic system for serological immunoassays in remote settings. AB - Serosurveys are useful for assessing population susceptibility to vaccine preventable disease outbreaks. Although at-risk populations in remote areas could benefit from this type of information, they face several logistical barriers to implementation, such as lack of access to centralized laboratories, cold storage, and transport of samples. We describe a potential solution: a compact and portable, field-deployable, point-of-care system relying on digital microfluidics that can rapidly test a small volume of capillary blood for disease-specific antibodies. This system uses inexpensive, inkjet-printed digital microfluidic cartridges together with an integrated instrument to perform enzyme-linked immunosorbent assays (ELISAs). We performed a field validation of the system's analytical performance at Kakuma refugee camp, a remote setting in northwestern Kenya, where we tested children aged 9 to 59 months and caregivers for measles and rubella immunoglobulin G (IgG). The IgG assays were determined to have sensitivities of 86% [95% confidence interval (CI), 79 to 91% (measles)] and 81% [95% CI, 73 to 88% (rubella)] and specificities of 80% [95% CI, 49 to 94% (measles)] and 91% [95% CI, 76 to 97% (rubella)] (measles, n = 140; rubella, n = 135) compared with reference tests (measles IgG and rubella IgG ELISAs from Siemens Enzygnost) conducted in a centralized laboratory. These results demonstrate a potential role for this point-of-care system in global serological surveillance, particularly in remote areas with limited access to centralized laboratories. PMID- 29695458 TI - Transitions in electronic cigarette use among adults in the Population Assessment of Tobacco and Health (PATH) Study, Waves 1 and 2 (2013-2015). AB - INTRODUCTION: This study assessed patterns of e-cigarette and cigarette use from Wave 1 to Wave 2 among adult e-cigarette users at Wave 1 of the Population Assessment of Tobacco and Health (PATH) Study. METHODS: We examined changes in e cigarette use frequency at Wave 2 among adult e-cigarette users at Wave 1 (unweighted n=2835). Adjusted prevalence ratios (aPR) were calculated using a predicted marginal probability approach to assess correlates of e-cigarette discontinuance and smoking abstinence at Wave 2. RESULTS: Half (48.8%) of adult e cigarette users at Wave 1 discontinued their use of e-cigarettes at Wave 2. Among dual users of e-cigarettes and cigarettes at Wave 1, 44.3% maintained dual use, 43.5% discontinued e-cigarette use and maintained cigarette smoking and 12.1% discontinued cigarette use at Wave 2, either by abstaining from cigarette smoking only (5.1%) or discontinuing both products (7.0%). Among dual users at Wave 1, daily e-cigarette users were more likely than non-daily users to report smoking abstinence at Wave 2 (aPR=1.40, 95% CI 1.02 to 1.91). Using a customisable device (rather than a non-customisable one) was not significantly related to smoking abstinence at Wave 2 (aPR=1.14, 95% CI 0.81 to 1.60). CONCLUSIONS: This study suggests that e-cigarette use patterns are highly variable over a 1-year period. This analysis provides the first nationally representative estimates of transitions among US adult e-cigarette users. Future research, including additional waves of the PATH Study, can provide further insight into long-term patterns of e-cigarette use critical to understanding the net population health impact of e-cigarettes in USA. PMID- 29695459 TI - The Impact of Income and Taxation in a Price-Tiered Cigarette Market - findings from the ITC Bangladesh Surveys. AB - BACKGROUND: Taxing tobacco is among the most effective measures of tobacco control. However, in a tiered market structure where multiple tiers of taxes coexist, the anticipated impact of tobacco taxes on consumption is complex. This paper investigates changing smoking behaviour in lieu of changing prices and changing income. The objective of the paper is to evaluate the effectiveness of change in prices (through taxes) and change in income in a price-tiered cigarette market. METHOD: A panel dataset from the International Tobacco Control Bangladesh surveys is used for analysis. For preliminary analysis transition matrices are developed. Next, probit and multinomial logit regression models are used to identify the effects of changes in prices and changes in income along with other control variables. FINDINGS: Transition matrices show significant movement of smokers across price tiers from one wave to another. Regression results show that higher income raises the probability to up-trade and decreases the probability to down-trade. Results also show that higher prices raises the probability to up trade and reduces the probability to down-trade. Although not significant, there exists a negative relationship between the probability to down-trade and the probability to intend to quit. CONCLUSION: It is evident from the results that a price-tiered market provides smokers more opportunities to accommodate their smoking behaviour when faced with price and income change. Therefore, tiered structure of the tax system should be replaced with uniform taxes. Moreover, overall cigarette taxes need to be raised to an extent so that it off-sets any positive effects of income growth. PMID- 29695460 TI - Vatican beats Italy 1-0 in the tobacco endgame. AB - 'The Holy See cannot be cooperating with a practice that is clearly harming the health of people'. This is the reason behind Pope Francis banning the sale of tobacco products inside the Vatican in January 2018. Just outside the Holy See, in Italy, cigarette sales produce around ?13 billion of fiscal revenues every year. In Italy, proposals to increase tobacco taxation are systematically rejected and new tobacco company plants have been officially inaugurated in recent years by representatives of State. The national branch of the Red Cross also shows ambivalent attitudes towards the tobacco industry, from which it has accepted significant funding in disregard of the recommendations of the International Federation of Red Cross. Against this backdrop, it is wishful thinking to imagine that tobacco sales and consumption in Italy will be substantially reduced in the near future. To counteract this situation, more than 30 Italian scientific associations/organisations launched a Manifesto, so far ignored by public authorities, indicating a set of measures whose gradual implementation at country level may lead to a tobacco endgame within the next few decades. Authors of this article would like to express their support for Pope Francis' enlightened decision and plead with politicians worldwide to follow his example, thus acting more decisively against tobacco. PMID- 29695461 TI - Response by Lee et al to Letter Regarding Article, "Predictive Value of Pulse Pressure in Acute Ischemic Stroke for Future Major Vascular Events". PMID- 29695462 TI - Brain Ischemia Induces Diversified Neuroantigen-Specific T-Cell Responses That Exacerbate Brain Injury. AB - BACKGROUND AND PURPOSE: Autoimmune responses can occur when antigens from the central nervous system are presented to lymphocytes in the periphery or central nervous system in several neurological diseases. However, whether autoimmune responses emerge after brain ischemia and their impact on clinical outcomes remains controversial. We hypothesized that brain ischemia facilitates the genesis of autoimmunity and aggravates ischemic brain injury. METHODS: Using a mouse strain that harbors a transgenic T-cell receptor to a central nervous system antigen, MOG35-55 (myelin oligodendrocyte glycoprotein) epitope (2D2), we determined the anatomic location and involvement of antigen-presenting cells in the development of T-cell reactivity after brain ischemia and how T-cell reactivity impacts stroke outcome. Transient middle cerebral artery occlusion and photothrombotic stroke models were used in this study. We also quantified the presence and status of T cells from brain slices of ischemic patients. RESULTS: By coupling transfer of labeled MOG35-55-specific (2D2) T cells with tetramer tracking, we show an expansion in reactivity of 2D2 T cells to MOG91-108 and MOG103-125 in transient middle cerebral artery occlusion and photothrombotic stroke models. This reactivity and T-cell activation first occur locally in the brain after ischemia. Also, microglia act as antigen-presenting cells that effectively present MOG antigens, and depletion of microglia ablates expansion of 2D2 reactive T cells. Notably, the adoptive transfer of neuroantigen-experienced 2D2 T cells exacerbates Th1/Th17 responses and brain injury. Finally, T-cell activation and MOG-specific T cells are present in the brain of patients with ischemic stroke. CONCLUSIONS: Our findings suggest that brain ischemia activates and diversifies T-cell responses locally, which exacerbates ischemic brain injury. PMID- 29695463 TI - Population-Based Assessment of the Long-Term Risk of Seizures in Survivors of Stroke. AB - BACKGROUND AND PURPOSE: We sought to determine the long-term risk of seizures after stroke according to age, sex, race, and stroke subtype. METHODS: We performed a retrospective cohort study using administrative claims from 2 complementary patient data sets. First, we analyzed data from all emergency department visits and hospitalizations in California, Florida, and New York from 2005 to 2013. Second, we evaluated inpatient and outpatient claims from a nationally representative 5% random sample of Medicare beneficiaries. Our cohort consisted of all adults at the time of acute stroke hospitalization without a prior history of seizures. Our outcome was seizure occurring after hospital discharge for stroke. Poisson regression and demographic data were used to calculate age-, sex-, and race-standardized incidence rate ratios (IRR). RESULTS: Among 777 276 patients in the multistate cohort, the annual incidence of seizures was 1.68% (95% confidence interval [CI], 1.67%-1.70%) after stroke versus 0.15% (95% CI, 0.15%-0.15%) among the general population (IRR, 7.3; 95% CI, 7.3-7.4). By 8 years, the cumulative rate of any emergency department visit or hospitalization for seizure was 9.27% (95% CI, 9.16%-9.38%) after stroke versus 1.21% (95% CI, 1.21%-1.22%) in the general population. Stroke was more strongly associated with a subsequent seizure among patients <65 years of age (IRR, 12.0; 95% CI, 11.9-12.2) than in patients >=65 years of age (IRR, 5.5; 95% CI, 5.4-5.5) and in the multistate analysis, the association between stroke and seizure was stronger among nonwhite patients (IRR, 11.0; 95% CI, 10.8-11.2) than among white patients (IRR, 7.3; 95% CI, 7.2-7.4). Risks were especially elevated after intracerebral hemorrhage (IRR, 13.3; 95% CI, 13.0-13.6) and subarachnoid hemorrhage (IRR, 13.2; 95% CI, 12.8-13.7). Our study of Medicare beneficiaries confirmed these findings. CONCLUSIONS: Almost 10% of patients with stroke will develop seizures within a decade. Hemorrhagic stroke, nonwhite race, and younger age seem to confer the greatest risk of developing seizures. PMID- 29695464 TI - Distribution of Lacunar Infarcts in Asians With Intracerebral Hemorrhage: A Magnetic Resonance Imaging and Amyloid Positron Emission Tomography Study. AB - BACKGROUND AND PURPOSE: We evaluated whether lacunes in centrum semiovale (lobar lacunes) were associated with cerebral amyloid angiopathy (CAA) markers in an Asian intracerebral hemorrhage (ICH) population. METHODS: One hundred ten patients with primary ICH were classified as CAA-ICH (n=24; mean age, 70.9+/ 13.9) or hypertensive ICH (n=86; mean age, 59.3+/-13.0) according to the presence of strictly lobar (per modified Boston criteria) or strictly deep bleeds (both ICH and cerebral microbleeds), respectively. Lacunes were evaluated in the supratentorial area and classified as lobar or classical deep based on the location. A subgroup of 36 patients also underwent Pittsburgh Compound B positron emission tomography to measure cerebral amyloid deposition and global standardized uptake value ratio were calculated. RESULTS: Lobar lacunes were more frequent in CAA-ICH than hypertensive ICH (29.2 versus 11.6%; P=0.036). In multivariable models, lobar lacunes were associated with lobar cerebral microbleed (odds ratio, 6.8; 95% confidence interval, 1.6-29.9; P=0.011) after adjustment for age, sex, hypertension, and white matter hyperintensity. In 15 CAA ICH and 21 hypertensive ICH patients with Pittsburgh Compound B positron emission tomography, correlation analyses between lobar lacune counts and global standardized uptake value ratio showed positive association (rho=0.40; P=0.02) and remained significant after adjustment for age (r=0.34; P=0.04). CONCLUSIONS: Our findings expand on recent work showing that lobar lacunes are more frequent in CAA-ICH than hypertensive ICH. Their independent association with lobar cerebral microbleeds and brain amyloid deposition suggests a relationship with CAA even in an Asian cohort with overall higher hypertensive load. PMID- 29695465 TI - Perimesencephalic Hemorrhage: A Review of Epidemiology, Risk Factors, Presumed Cause, Clinical Course, and Outcome. AB - BACKGROUND AND PURPOSE: We systematically reviewed the literature on epidemiology, risk factors, presumed cause, clinical course, and outcome of perimesencephalic hemorrhage. METHODS: PubMed, Embase, and the Cochrane Library were searched until March 2016. Quality assessment was done by 2 authors independently. Pooled prevalence ratios and pooled odds ratios with 95% confidence intervals were calculated for data extracted from case-control studies. RESULTS: We included 208 papers. The incidence of perimesencephalic hemorrhage is ~0.5 per 100.000 person-years, men are more often affected, and no risk factors were confirmed. Two decision analyses both found that a single, high quality computed tomography angiography is the preferred diagnostic approach. Short-term complications, such as hydrocephalus or cranial nerve palsies, are rare, and usually transient, with the exception of acute symptomatic hydrocephalus necessitating treatment in 3% of patients. Lacunar infarcts in the brain stem were convincingly described in 4 patients only. Fatal rebleeding after installment of anticoagulation in the initial days after the hemorrhage was described in 1 patient. At long-term follow-up, death related to the hemorrhage has not been reported, disability is found in 0% to 6%, and neuropsychological sequelae are suggested. CONCLUSIONS: A single, high-quality computed tomography angiography is the preferred diagnostic strategy. Short-term complications are rare and often transient. Long-term outcome is excellent with respect to disability and death, but high-quality studies focused at neuropsychological sequelae are needed. PMID- 29695467 TI - Letter by Bhargava Regarding Article, "Predictive Value of Pulse Pressure in Acute Ischemic Stroke for Future Major Vascular Events". PMID- 29695466 TI - Innovative Magnetic Resonance Imaging Markers of Hereditary Cerebral Amyloid Angiopathy at 7 Tesla. AB - BACKGROUND AND PURPOSE: The aim of the present study is to explore whether using 7 Tesla magnetic resonance imaging, additional brain changes can be observed in hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) patients as compared with the established magnetic resonance imaging features of sporadic cerebral amyloid angiopathy. METHODS: The local institutional review board approved this prospective cohort study. In all cases, informed consent was obtained. This prospective parallel cohort study was conducted between 2012 and 2014. We performed T2*-weighted magnetic resonance imaging performed at 7 Tesla in presymptomatic mutation carriers (n=11, mean age 35+/-12 years), symptomatic HCHWA-D patients (n=15, mean age 45+/-14 years), and in control subjects (n=29, mean age 45+/-14 years). Images were analyzed for the presence of changes that have not been reported before in sporadic cerebral amyloid angiopathy and HCHWA D. Innovative observations comprised intragyral hemorrhaging and cortical changes. The presence of these changes was systematically assessed in all participants of the study. RESULTS: Symptomatic HCHWA-D-patients had a higher incidence of intragyral hemorrhage (47% [7/15], controls 0% [0/29], P<0.001), and a higher incidence of specific cortical changes (40% [6/15] versus 0% [0/29], P<0.005). In presymptomatic HCHWA-D-mutation carriers, the prevalence of none of these markers was increased compared with control subjects. CONCLUSIONS: The presence of cortical changes and intragyral hemorrhage are imaging features of HCHWA-D that may help recognizing sporadic cerebral amyloid angiopathy in living patients. PMID- 29695468 TI - Misdiagnosis of Cerebral Vein Thrombosis in the Emergency Department. AB - BACKGROUND AND PURPOSE: Rates of cerebral venous thrombosis (CVT) misdiagnosis in the emergency department and outcomes associated with misdiagnosis have been underexplored. METHODS: Using administrative data, we identified adults with CVT at New York, California, and Florida hospitals from 2005 to 2013. Our primary outcome was probable misdiagnosis of CVT, defined as a treat-and-release emergency department visit for headache or seizure within 14 days before CVT. In addition, logistic regression was used to compare rates of clinical outcomes in patients with and without probable CVT misdiagnosis. We performed a confirmatory study at 2 tertiary care centers. RESULTS: We identified 5966 patients with CVT in whom 216 (3.6%; 95% confidence interval [CI], 1.1%-4.1%) had a probable misdiagnosis of CVT. After adjusting for demographics, risk factors for CVT, and the Elixhauser comorbidity index, probable CVT misdiagnosis was not associated with in-hospital mortality (odds ratio, 0.14; 95% CI, 0.02-1.05), intracerebral hemorrhage (odds ratio, 0.97; 95% CI, 0.57-1.65), or unfavorable discharge disposition (odds ratio, 0.90; 95% CI, 0.61-1.32); a longer length of hospital stay was seen among misdiagnosed patients with CVT (odds ratio, 1.62; 95% CI, 1.04-2.50). In our confirmatory cohort, probable CVT misdiagnosis occurred in 8 of 134 patients with CVT (6.0%; 95% CI, 2.6%-11.4%). CONCLUSIONS: In a large, heterogeneous multistate cohort, probable misdiagnosis of CVT occurred in 1 of 30 patients but was not associated with the adverse clinical outcomes included in our study. PMID- 29695470 TI - Illicit drug use should not be a crime, says Royal College of Physicians. PMID- 29695469 TI - More Than Meets the Eye: Cerebrovascular Disease in Sickle Cell Disease Is About More Than Sickling. PMID- 29695471 TI - Anticholinergic drugs and dementia in older adults. PMID- 29695472 TI - NHS accountable care organisations would be unlawful, campaigners tell High Court. PMID- 29695475 TI - Arm and leg reflexes in degenerative cervical myelopathy. PMID- 29695474 TI - Mobile phone sign of degenerative cervical myelopathy. PMID- 29695476 TI - Depression and anxiety in patients with cancer. PMID- 29695473 TI - Age and sex of surgeons and mortality of older surgical patients: observational study. AB - OBJECTIVE: To investigate whether patients' mortality differs according to the age and sex of surgeons. DESIGN: Observational study. SETTING: US acute care hospitals. PARTICIPANTS: 100% of Medicare fee-for-service beneficiaries aged 65 99 years who underwent one of 20 major non-elective surgeries between 2011 and 2014. MAIN OUTCOME MEASURE: Operative mortality rate of patients, defined as death during hospital admission or within 30 days of the operative procedure, after adjustment for patients' and surgeons' characteristics and indicator variables for hospitals. RESULTS: 892 187 patients who were treated by 45 826 surgeons were included. Patients' mortality was lower for older surgeons than for younger surgeons: the adjusted operative mortality rates were 6.6% (95% confidence interval 6.5% to 6.7%), 6.5% (6.4% to 6.6%), 6.4% (6.3% to 6.5%), and 6.3% (6.2% to 6.5%) for surgeons aged under 40 years, 40-49 years, 50-59 years, and 60 years or over, respectively (P for trend=0.001). There was no evidence that adjusted operative mortality differed between patients treated by female versus male surgeons (adjusted mortality 6.3% for female surgeons versus 6.5% for male surgeons; adjusted odds ratio 0.97, 95% confidence interval 0.93 to 1.01). After stratification by sex of surgeon, patients' mortality declined with age of surgeon for both male and female surgeons (except for female surgeons aged 60 or older); female surgeons in their 50s had the lowest operative mortality. CONCLUSION: Using national data on Medicare beneficiaries in the US, this study found that patients treated by older surgeons had lower mortality than patients treated by younger surgeons. There was no evidence that operative mortality differed between male and female surgeons. PMID- 29695478 TI - Troubled rebuild of Stockholm's landmark hospital has cost twice as much as planned. PMID- 29695477 TI - Links between age and sex of surgeons and patients' outcomes. PMID- 29695479 TI - MHRA bans valproate prescribing for women not in pregnancy prevention programme. PMID- 29695480 TI - Collaborative procurement: five minutes with . . . Des Breen. PMID- 29695482 TI - Exploring low mood in a person with cancer. PMID- 29695483 TI - Anger as Alfie's Army protests outside Alder Hey. PMID- 29695484 TI - Illinois hospitals cope with outbreak of bleeding linked to tainted cannabinoids. PMID- 29695481 TI - Anticholinergic drugs and risk of dementia: case-control study. AB - OBJECTIVES: To estimate the association between the duration and level of exposure to different classes of anticholinergic drugs and subsequent incident dementia. DESIGN: Case-control study. SETTING: General practices in the UK contributing to the Clinical Practice Research Datalink. PARTICIPANTS: 40 770 patients aged 65-99 with a diagnosis of dementia between April 2006 and July 2015, and 283 933 controls without dementia. INTERVENTIONS: Daily defined doses of anticholinergic drugs coded using the Anticholinergic Cognitive Burden (ACB) scale, in total and grouped by subclass, prescribed 4-20 years before a diagnosis of dementia. MAIN OUTCOME MEASURES: Odds ratios for incident dementia, adjusted for a range of demographic and health related covariates. RESULTS: 14 453 (35%) cases and 86 403 (30%) controls were prescribed at least one anticholinergic drug with an ACB score of 3 (definite anticholinergic activity) during the exposure period. The adjusted odds ratio for any anticholinergic drug with an ACB score of 3 was 1.11 (95% confidence interval 1.08 to 1.14). Dementia was associated with an increasing average ACB score. When considered by drug class, gastrointestinal drugs with an ACB score of 3 were not distinctively linked to dementia. The risk of dementia increased with greater exposure for antidepressant, urological, and antiparkinson drugs with an ACB score of 3. This result was also observed for exposure 15-20 years before a diagnosis. CONCLUSIONS: A robust association between some classes of anticholinergic drugs and future dementia incidence was observed. This could be caused by a class specific effect, or by drugs being used for very early symptoms of dementia. Future research should examine anticholinergic drug classes as opposed to anticholinergic effects intrinsically or summing scales for anticholinergic exposure. TRIAL REGISTRATION: Registered to the European Union electronic Register of Post-Authorisation Studies EUPAS8705. PMID- 29695486 TI - KRAS fluorescence in situ hybridisation testing for the detection and diagnosis of pancreatic adenocarcinoma. AB - AIMS: The aim of our study was to analyse correlations between KRAS mutation status, chromosomal changes that affect KRAS status in cells from pancreatic tumours. METHODS: We collected 69 cases of surgically resected pancreatic ductal adenocarcinoma (PDA) and seven cases of chronic pancreatitis (CP). Chromosomal abnormalities of KRAS and CEP12 were detected using fluorescence in situ hybridisation (FISH). RESULTS: The number of CEP12 signals per cell ranged from 1.78 to 2.04 and 1.46 to 4.88 in CP and PDA samples, respectively, while the number of KRAS signals per cell ranged from 1.94 to 2.06 and 1.88 to 8.18 in CP and PDA samples, respectively. The 'chromosomal instability index', which was defined as the percentage of cells with any chromosomal abnormality, was over 5.7 times greater in PDA than in CP. We performed KRAS mutation analysis by direct sequencing and found that tumours with KRAS mutations have a significantly higher mean KRAS signal per cell from PDA samples compared with tumours with wild-type KRAS. KRAS amplification was noted in 10% of cases. Although we found that lymph node metastasis and distal metastasis of PDA were more frequent in cases with KRAS amplification, this was not correlated with overall survival. Using a threshold of 40%, we found that the chromosomal instability index robustly discriminated PDA cells from CP cells. CONCLUSIONS: Based on these findings, we concluded that FISH testing of KRAS using cytology samples may represent an accurate approach for the diagnosis of PDA. PMID- 29695487 TI - Johan Auwerx: Sowing the seeds of translational research. AB - Auwerx studies the signaling networks that underlie mitochondrial function and metabolism. PMID- 29695488 TI - Characterization of LAMP1-labeled nondegradative lysosomal and endocytic compartments in neurons. AB - Despite widespread distribution of LAMP1 and the heterogeneous nature of LAMP1 labeled compartments, LAMP1 is routinely used as a lysosomal marker, and LAMP1 positive organelles are often referred to as lysosomes. In this study, we use immunoelectron microscopy and confocal imaging to provide quantitative analysis of LAMP1 distribution in various autophagic and endolysosomal organelles in neurons. Our study demonstrates that a significant portion of LAMP1-labeled organelles do not contain detectable lysosomal hydrolases including cathepsins D and B and glucocerebrosidase. A bovine serum albumin-gold pulse-chase assay followed by ultrastructural analysis suggests a heterogeneity of degradative capacity in LAMP1-labeled endolysosomal organelles. Gradient fractionation displays differential distribution patterns of LAMP1/2 and cathepsins D/B in neurons. We further reveal that LAMP1 intensity in familial amyotrophic lateral sclerosis-linked motor neurons does not necessarily reflect lysosomal deficits in vivo. Our study suggests that labeling a set of lysosomal hydrolases combined with various endolysosomal markers would be more accurate than simply relying on LAMP1/2 staining to assess neuronal lysosome distribution, trafficking, and functionality under physiological and pathological conditions. PMID- 29695489 TI - Dynamics of sister chromatid resolution during cell cycle progression. AB - Faithful genome transmission in dividing cells requires that the two copies of each chromosome's DNA package into separate but physically linked sister chromatids. The linkage between sister chromatids is mediated by cohesin, yet where sister chromatids are linked and how they resolve during cell cycle progression has remained unclear. In this study, we investigated sister chromatid organization in live human cells using dCas9-mEGFP labeling of endogenous genomic loci. We detected substantial sister locus separation during G2 phase irrespective of the proximity to cohesin enrichment sites. Almost all sister loci separated within a few hours after their respective replication and then rapidly equilibrated their average distances within dynamic chromatin polymers. Our findings explain why the topology of sister chromatid resolution in G2 largely reflects the DNA replication program. Furthermore, these data suggest that cohesin enrichment sites are not persistent cohesive sites in human cells. Rather, cohesion might occur at variable genomic positions within the cell population. PMID- 29695491 TI - Nest box exploration may stimulate breeding physiology and alter mRNA expression in the medial preoptic area of female European starlings. AB - Environmental resources are proposed to fine-tune the timing of breeding, yet how they may do so remains unclear. In female European starlings (Sturnus vulgaris), nest cavities are limited resources that are necessary for breeding. Females that explore nest cavities, compared with those that do not, readily perform sexually motivated behaviors. We assigned female starlings to aviaries with: (1) no nest boxes, (2) nest boxes, or (3) nest boxes, plants, flowing water, insects and berries to test the hypothesis that environmental resources alter neural systems to stimulate mating behavior. Compared with other females, females that were housed with and explored nest boxes had higher estradiol, higher preproenkephalin (PENK) mRNA and lower levels of D1 and D2 dopamine receptor mRNA in the medial preoptic area (mPOA); a region in which opioids and dopamine modify female sexual behaviors and sexual motivation. Additionally, in the mPOA, PENK and tyrosine hydroxylase mRNA positively predicted, whereas estrogen receptor beta mRNA negatively predicted, nest box exploration. In the ventromedial hypothalamus (a region in which estradiol acts to stimulate sexual behavior), estrogen receptor alpha mRNA was highest in females that had access to but did not explore nest cavities. It is likely that seasonal increases in estradiol modify mRNA in the mPOA to facilitate nest cavity exploration. It is also possible that nest cavity exploration further alters gene expression in the mPOA, functioning to coordinate mating with resource availability. Thus, nest cavity exploration may be a form of self-stimulation that alters neural systems to fine-tune sexual behavior. PMID- 29695492 TI - VDR signaling inhibits cancer-associated-fibroblasts' release of exosomal miR-10a 5p and limits their supportive effects on pancreatic cancer cells. PMID- 29695490 TI - Acetylation-Dependent Recruitment of the FACT Complex and Its Role in Regulating Pol II Occupancy Genome-Wide in Saccharomyces cerevisiae. AB - Histone chaperones, chromatin remodelers, and histone modifying complexes play a critical role in alleviating the nucleosomal barrier for DNA-dependent processes. Here, we have examined the role of two highly conserved yeast (Saccharomyces cerevisiae) histone chaperones, facilitates chromatin transcription (FACT) and Spt6, in regulating transcription. We show that the H3 tail contributes to the recruitment of FACT to coding sequences in a manner dependent on acetylation. We found that deleting a H3 histone acetyltransferase Gcn5 or mutating lysines on the H3 tail impairs FACT recruitment at ADH1 and ARG1 genes. However, deleting the H4 tail or mutating the H4 lysines failed to dampen FACT occupancy in coding regions. Additionally, we show that FACT depletion reduces RNA polymerase II (Pol II) occupancy genome-wide. Spt6 depletion leads to a reduction in Pol II occupancy toward the 3'-end, in a manner dependent on the gene length. Severe transcription and histone-eviction defects were also observed in a strain that was impaired for Spt6 recruitment (spt6Delta202) and depleted of FACT. Importantly, the severity of the defect strongly correlated with wild-type Pol II occupancies at these genes, indicating critical roles for Spt6 and Spt16 in promoting high-level transcription. Collectively, our results show that both FACT and Spt6 are important for transcription globally and may participate during different stages of transcription. PMID- 29695493 TI - Toll and Toll-like receptor signalling in development. AB - The membrane receptor Toll and the related Toll-like receptors (TLRs) are best known for their universal function in innate immunity. However, Toll/TLRs were initially discovered in a developmental context, and recent studies have revealed that Toll/TLRs carry out previously unanticipated functions in development, regulating cell fate, cell number, neural circuit connectivity and synaptogenesis. Furthermore, knowledge of their molecular mechanisms of action is expanding and has highlighted that Toll/TLRs function beyond the canonical NF kappaB pathway to regulate cell-to-cell communication and signalling at the synapse. Here, we provide an overview of Toll/TLR signalling and discuss how this signalling pathway regulates various aspects of development across species. PMID- 29695494 TI - Human rights-based approach to unintentional injury prevention. AB - Unintentional injury remains an important global public health issue, and efforts to address it are often hampered by a lack of visibility, leadership, funding, infrastructure, capacity and evidence of effective solutions. The growing support for a socioecological model and a systems approach to prevention-along with the acknowledgement that injury prevention can be a byproduct of salutogenic design and activities-has increased opportunities to integrate unintentional injury prevention into other health promotion and disease prevention agendas. It has also helped to integrate it into the broader human development agenda through the Sustainable Development Goals. This growing support provides new opportunities to use a human rights-based approach to address the issue. The human rights-based approach is based on the idea that all members of society have social, economic and cultural rights and that governments are responsible and accountable for upholding those rights. It incorporates a systems approach, addresses inequity and places an emphasis on the most vulnerable corners of humanity. It also leverages legal statutes and provides organisations with the opportunity to build existing international goals and benchmarks into their monitoring efforts. This paper describes the approach and highlights how it can leverage attention and investment to address current challenges for unintentional injury. PMID- 29695495 TI - Multiple Arginine Residues Are Methylated in Drosophila Mre11 and Required for Survival Following Ionizing Radiation. AB - Mre11 is a key player for DNA double strand break repair. Previous studies have shown that mammalian Mre11 is methylated at multiple arginines in its C-terminal Glycine-Arginine-Rich motif (GAR) by protein arginine methyltransferase PRMT1. Here, we found that the Drosophila Mre11 is methylated at arginines 559, 563, 565, and 569 in the GAR motif by DART1, the Drosophila homolog of PRMT1. Mre11 interacts with DART1 in S2 cells, and this interaction does not require the GAR motif. Arginines methylated Mre11 localizes exclusively in the nucleus as soluble nuclear protein or chromatin-binding protein. To study the in vivo functions of methylation, we generated the single Arg-Ala and all Arginines mutated flies. We found these mutants were sensitive to ionizing radiation. Furthermore, Arg-Ala mutated flies had no irradiation induced G2/M checkpoint defect in wing disc and eye disc. Thus, we provided evidence that arginines in Drosophila Mre11 are methylated by DART1 methytransferase and flies loss of arginine methylation are sensitive to irradiation. PMID- 29695496 TI - oxLDL-mediated cellular senescence is associated with increased NADPH oxidase p47phox recruitment to caveolae. AB - Atherosclerosis develops as a consequence of inflammation and cell senescence. In critical factors involved in the atherosclerotic changes, reactive oxygen species (ROS) generation is considered a leading cause. While NADPH oxidases, particularly NOX2, are the main sources of ROS, how they are regulated in the disease is incompletely understood. In addition, how caveolae, the membrane structure implicated in oxLDL deposition under vascular endothelia, is involved in the oxLDL-mediated ROS production remains mostly elusive. We report here that macrophages exposed to oxLDL up-regulate its caveolin-1 expression, and the latter in turn up-regulates NOX2 p47phox level. This combination effect results in increased cellular senescence. Interestingly, oxLDL treatment causes the p47phox residing in the cytosol to translocate to the caveolae. Immunoprecipitation assays confirms that cavelin-1 is in high degree association with p47phox. These results suggest caveolin-1 may serve as the membrane target for p47phox and as a switch for ROS production following oxLDL exposure. Our results reveal a previously unknown molecular event in oxLDL-mediated cellular ageing, and may provide a target for clinical intervention for atherosclerosis. PMID- 29695499 TI - Pitfalls of antinuclear antibody detection in systemic lupus erythematosus: the positive experience of a national multicentre study. PMID- 29695498 TI - Validation of the ANCA-associated vasculitis patient-reported outcomes (AAV-PRO) questionnaire. AB - OBJECTIVES: To finalise and validate a disease-specific patient-reported outcome (PRO) measure: the ANCA-associated vasculitis patient-reported outcome (AAV-PRO) questionnaire. Using a 35-item candidate questionnaire developed following 50 qualitative interviews in the UK, USA and Canada, a longitudinal survey was conducted to determine the final scale structure and validate the AAV-PRO. METHODS: Participants were recruited via Vasculitis UK and the Vasculitis Patient Powered Research Network. The 35-item candidate questionnaire was completed at baseline and 3 months; UK participants completed the EuroQol-5D-5L (EQ-5D-5L), while US participants completed a test-retest exercise, 3-5 days after baseline. Scale structure was defined using exploratory factor analysis (EFA) and Rasch analysis. Convergent and known groups validity, test-retest reliability and longitudinal construct validity were assessed. RESULTS: There were 626 participants with AAV; >25% reporting 'active disease'. EFA and Rasch analysis supported a 29-item profile measure comprising six domains: 'organ-specific symptoms', 'systemic symptoms', 'treatment side effects', 'social and emotional impact', 'concerns about the future' and 'physical function'. Mean domain scores were higher for participants with 'active disease' versus 'remission' (p<0.001). Construct validity was demonstrated by correlations between domain scores and the EQ-5D-5L (range r=-0.55 to 0.78), all p<0.0001. In participants reporting 'no change' (n=97) during the test-retest, intraclass correlation coefficient values were high (range 0.89-0.96) for each domain. CONCLUSIONS: The AAV-PRO, a new disease-specific PRO measure for AAV, has good face and construct validity, is reliable, feasible and discriminates among disease states. PMID- 29695500 TI - Comparison of individually tailored versus fixed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: results of a multicentre, randomised controlled, phase III trial (MAINRITSAN2). AB - OBJECTIVE: To compare individually tailored, based on trimestrial biological parameter monitoring, to fixed-schedule rituximab reinfusion for remission maintenance of antineutrophil cytoplasm antibody (ANCA)-associated vasculitides (AAVs). METHODS: Patients with newly diagnosed or relapsing granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) in complete remission after induction therapy were included in an open-label, multicentre, randomised controlled trial. All tailored-arm patients received a 500 mg rituximab infusion at randomisation, with rituximab reinfusion only when CD19+B lymphocytes or ANCA had reappeared or ANCA titre rose markedly based on trimestrial testing until month 18. Controls received a fixed 500 mg rituximab infusion on days 0 and 14 postrandomisation, then 6, 12 and 18 months after the first infusion. The primary endpoint was the number of relapses (new or reappearing symptom(s) or worsening disease with Birmingham Vasculitis Activity Score (BVAS)>0) at month 28 evaluated by an independent Adjudication Committee blinded to treatment group. RESULTS: Among the 162 patients (mean age: 60 years; 42% women) included, 117 (72.2%) had GPA and 45 (27.8%) had MPA. Preinclusion induction therapy included cyclophosphamide for 100 (61.7%), rituximab for 61 (37.6%) and methotrexate for 1 (0.6%). At month 28, 21 patients had suffered 22 relapses: 14/81 (17.3%) in 13 tailored-infusion recipients and 8/81 (9.9%) in 8 fixed-schedule patients (p=0.22). The tailored-infusion versus fixed-schedule group, respectively, received 248 vs 381 infusions, with medians (IQR) of 3 (2-4) vs 5 (5-5) administrations. CONCLUSION: AAV relapse rates did not differ significantly between individually tailored and fixed-schedule rituximab regimens. Individually tailored-arm patients received fewer rituximab infusions. TRIAL REGISTRATION NUMBER: NCT01731561; Results. PMID- 29695501 TI - Design of a heme-binding peptide motif adopting a beta-hairpin conformation. AB - Heme-binding proteins constitute a large family of catalytic and transport proteins. Their widespread presence as globins and as essential oxygen and electron transporters, along with their diverse enzymatic functions, have made them targets for protein design. Most previously reported designs involved the use of alpha-helical scaffolds, and natural peptides also exhibit a strong preference for these scaffolds. However, the reason for this preference is not well-understood, in part because alternative protein designs, such as those with beta-sheets or hairpins, are challenging to perform. Here, we report the computational design and experimental validation of a water-soluble heme-binding peptide, Pincer-1, composed of predominantly beta-scaffold secondary structures. Such heme-binding proteins are rarely observed in nature, and by designing such a scaffold, we simultaneously increase the known fold space of heme-binding proteins and expand the limits of computational design methods. For a beta scaffold, two tryptophan zipper beta-hairpins sandwiching a heme molecule were linked through an N-terminal cysteine disulfide bond. beta-Hairpin orientations and residue selection were performed computationally. Heme binding was confirmed through absorbance experiments and surface plasmon resonance experiments (KD = 730 +/- 160 nm). CD and NMR experiments validated the beta-hairpin topology of the designed peptide. Our results indicate that a helical scaffold is not essential for heme binding and reveal the first designed water-soluble, heme binding beta-hairpin peptide. This peptide could help expand the search for and design space to cytoplasmic heme-binding proteins. PMID- 29695497 TI - Transcriptomic Studies of Malaria: a Paradigm for Investigation of Systemic Host Pathogen Interactions. AB - Transcriptomics, the analysis of genome-wide RNA expression, is a common approach to investigate host and pathogen processes in infectious diseases. Technical and bioinformatic advances have permitted increasingly thorough analyses of the association of RNA expression with fundamental biology, immunity, pathogenesis, diagnosis, and prognosis. Transcriptomic approaches can now be used to realize a previously unattainable goal, the simultaneous study of RNA expression in host and pathogen, in order to better understand their interactions. This exciting prospect is not without challenges, especially as focus moves from interactions in vitro under tightly controlled conditions to tissue- and systems-level interactions in animal models and natural and experimental infections in humans. Here we review the contribution of transcriptomic studies to the understanding of malaria, a parasitic disease which has exerted a major influence on human evolution and continues to cause a huge global burden of disease. We consider malaria a paradigm for the transcriptomic assessment of systemic host-pathogen interactions in humans, because much of the direct host-pathogen interaction occurs within the blood, a readily sampled compartment of the body. We illustrate lessons learned from transcriptomic studies of malaria and how these lessons may guide studies of host-pathogen interactions in other infectious diseases. We propose that the potential of transcriptomic studies to improve the understanding of malaria as a disease remains partly untapped because of limitations in study design rather than as a consequence of technological constraints. Further advances will require the integration of transcriptomic data with analytical approaches from other scientific disciplines, including epidemiology and mathematical modeling. PMID- 29695502 TI - Insights into the binding behavior of native and non-native cytochromes to photosystem I from Thermosynechococcus elongatus. AB - The binding of photosystem I (PS I) from Thermosynechococcus elongatus to the native cytochrome (cyt) c6 and cyt c from horse heart (cyt cHH) was analyzed by oxygen consumption measurements, isothermal titration calorimetry (ITC), and rigid body docking combined with electrostatic computations of binding energies. Although PS I has a higher affinity for cyt cHH than for cyt c6, the influence of ionic strength and pH on binding is different in the two cases. ITC and theoretical computations revealed the existence of unspecific binding sites for cyt cHH besides one specific binding site close to P700 Binding to PS I was found to be the same for reduced and oxidized cyt cHH Based on this information, suitable conditions for cocrystallization of cyt cHH with PS I were found, resulting in crystals with a PS I:cyt cHH ratio of 1:1. A crystal structure at 3.4-A resolution was obtained, but cyt cHH cannot be identified in the electron density map because of unspecific binding sites and/or high flexibility at the specific binding site. Modeling the binding of cyt c6 to PS I revealed a specific binding site where the distance and orientation of cyt c6 relative to P700 are comparable with cyt c2 from purple bacteria relative to P870 This work provides new insights into the binding modes of different cytochromes to PS I, thus facilitating steps toward solving the PS I-cyt c costructure and a more detailed understanding of natural electron transport processes. PMID- 29695503 TI - Structure-guided design and functional characterization of an artificial red light-regulated guanylate/adenylate cyclase for optogenetic applications. AB - Genetically targeting biological systems to control cellular processes with light is the concept of optogenetics. Despite impressive developments in this field, underlying molecular mechanisms of signal transduction of the employed photoreceptor modules are frequently not sufficiently understood to rationally design new optogenetic tools. Here, we investigate the requirements for functional coupling of red light-sensing phytochromes with non-natural enzymatic effectors by creating a series of constructs featuring the Deinococcus radiodurans bacteriophytochrome linked to a Synechocystis guanylate/adenylate cyclase. Incorporating characteristic structural elements important for cyclase regulation in our designs, we identified several red light-regulated fusions with promising properties. We provide details of one light-activated construct with low dark-state activity and high dynamic range that outperforms previous optogenetic tools in vitro and expands our in vivo toolkit, as demonstrated by manipulation of Caenorhabditis elegans locomotor activity. The full-length crystal structure of this phytochrome-linked cyclase revealed molecular details of photoreceptor-effector coupling, highlighting the importance of the regulatory cyclase element. Analysis of conformational dynamics by hydrogen-deuterium exchange in different functional states enriched our understanding of phytochrome signaling and signal integration by effectors. We found that light-induced conformational changes in the phytochrome destabilize the coiled-coil sensor effector linker, which releases the cyclase regulatory element from an inhibited conformation, increasing cyclase activity of this artificial system. Future designs of optogenetic functionalities may benefit from our work, indicating that rational considerations for the effector improve the rate of success of initial designs to obtain optogenetic tools with superior properties. PMID- 29695504 TI - AMP-activated protein kinase selectively inhibited by the type II inhibitor SBI 0206965. AB - Inhibition of the metabolic regulator AMP-activated protein kinase (AMPK) is increasingly being investigated for its therapeutic potential in diseases where AMPK hyperactivity results in poor prognoses, as in established cancers and neurodegeneration. However, AMPK-inhibitory tool compounds are largely limited to compound C, which has a poor selectivity profile. Here we identify the pyrimidine derivative SBI-0206965 as a direct AMPK inhibitor. SBI-0206965 inhibits AMPK with 40-fold greater potency and markedly lower kinase promiscuity than compound C and inhibits cellular AMPK signaling. Biochemical characterization reveals that SBI 0206965 is a mixed-type inhibitor. A co-crystal structure of the AMPK kinase domain/SBI-0206965 complex shows that the drug occupies a pocket that partially overlaps the ATP active site in a type IIb inhibitor manner. SBI-0206965 has utility as a tool compound for investigating physiological roles for AMPK and provides fresh impetus to small-molecule AMPK inhibitor therapeutic development. PMID- 29695505 TI - Dimerization site 2 of the bacterial DNA-binding protein H-NS is required for gene silencing and stiffened nucleoprotein filament formation. AB - The bacterial nucleoid-associated protein H-NS is a DNA-binding protein, playing a major role in gene regulation. To regulate transcription, H-NS silences genes, including horizontally acquired foreign genes. Escherichia coli H-NS is 137 residues long and consists of two discrete and independent structural domains: an N-terminal oligomerization domain and a C-terminal DNA-binding domain, joined by a flexible linker. The N-terminal oligomerization domain is composed of two dimerization sites, dimerization sites 1 and 2, which are both required for H-NS oligomerization, but the exact role of dimerization site 2 in gene silencing is unclear. To this end, we constructed a whole set of single amino acid substitution variants spanning residues 2 to 137. Using a well-characterized H-NS target, the slp promoter of the glutamic acid-dependent acid resistance (GAD) cluster promoters, we screened for any variants defective in gene silencing. Focusing on the function of dimerization site 2, we analyzed four variants, I70C/I70A and L75C/L75A, which all could actively bind DNA but are defective in gene silencing. Atomic force microscopy analysis of DNA-H-NS complexes revealed that all of these four variants formed condensed complexes on DNA, whereas WT H NS formed rigid and extended nucleoprotein filaments, a conformation required for gene silencing. Single-molecule stretching experiments confirmed that the four variants had lost the ability to form stiffened filaments. We conclude that dimerization site 2 of H-NS plays a key role in the formation of rigid H-NS nucleoprotein filament structures required for gene silencing. PMID- 29695506 TI - A structural study of the complex between neuroepithelial cell transforming gene 1 (Net1) and RhoA reveals a potential anticancer drug hot spot. AB - The GTPase RhoA is a major player in many different regulatory pathways. RhoA catalyzes GTP hydrolysis, and its catalysis is accelerated when RhoA forms heterodimers with proteins of the guanine nucleotide exchange factor (GEF) family. Neuroepithelial cell transforming gene 1 (Net1) is a RhoA-interacting GEF implicated in cancer, but the structural features supporting the RhoA/Net1 interaction are unknown. Taking advantage of a simple production and purification process, here we solved the structure of a RhoA/Net1 heterodimer with X-ray crystallography at 2-A resolution. Using a panel of several techniques, including molecular dynamics simulations, we characterized the RhoA/Net1 interface. Moreover, deploying an extremely simple peptide-based scanning approach, we found that short peptides (penta- to nonapeptides) derived from the protein/protein interaction region of RhoA could disrupt the RhoA/Net1 interaction and thereby diminish the rate of nucleotide exchange. The most inhibitory peptide, EVKHF, spanning residues 102-106 in the RhoA sequence, displayed an IC50 of ~100 MUm without further modifications. The peptides identified here could be useful in further investigations of the RhoA/Net1 interaction region. We propose that our structural and functional insights might inform chemical approaches for transforming the pentapeptide into an optimized pseudopeptide that antagonizes Net1-mediated RhoA activation with therapeutic anticancer potential. PMID- 29695507 TI - A low-complexity region in the YTH domain protein Mmi1 enhances RNA binding. AB - Mmi1 is an essential RNA-binding protein in the fission yeast Schizosaccharomyces pombe that eliminates meiotic transcripts during normal vegetative growth. Mmi1 contains a YTH domain that binds specific RNA sequences, targeting mRNAs for degradation. The YTH domain of Mmi1 uses a noncanonical RNA-binding surface that includes contacts outside the conserved fold. Here, we report that an N-terminal extension that is proximal to the YTH domain enhances RNA binding. Using X-ray crystallography, NMR, and biophysical methods, we show that this low-complexity region becomes more ordered upon RNA binding. This enhances the affinity of the interaction of the Mmi1 YTH domain with specific RNAs by reducing the dissociation rate of the Mmi1-RNA complex. We propose that the low-complexity region influences RNA binding indirectly by reducing dynamic motions of the RNA binding groove and stabilizing a conformation of the YTH domain that binds to RNA with high affinity. Taken together, our work reveals how a low-complexity region proximal to a conserved folded domain can adopt an ordered structure to aid nucleic acid binding. PMID- 29695508 TI - Ankyrin repeat and single KH domain 1 (ANKHD1) drives renal cancer cell proliferation via binding to and altering a subset of miRNAs. AB - Clear cell renal cell carcinoma (ccRCC) represents the most common kidney cancer worldwide. Increased cell proliferation associated with abnormal microRNA (miRNA) regulation are hallmarks of carcinogenesis. Ankyrin repeat and single KH domain 1 (ANKHD1) is a highly conserved protein found to interact with core cancer pathways in Drosophila; however, its involvement in RCC is completely unexplored. Quantitative PCR studies coupled with large-scale genomics data sets demonstrated that ANKHD1 is significantly up-regulated in kidneys of RCC patients when compared with healthy controls. Cell cycle analysis revealed that ANKHD1 is an essential factor for RCC cell division. To understand the molecular mechanism(s) utilized by ANKHD1 to drive proliferation, we performed bioinformatics analyses that revealed that ANKHD1 contains a putative miRNA-binding motif. We screened 48 miRNAs with tumor-enhancing or -suppressing activities and found that ANKHD1 binds to and regulates three tumor-suppressing miRNAs (i.e. miR-29a, miR-205, and miR-196a). RNA-immunoprecipitation assays demonstrated that ANKHD1 physically interacts with its target miRNAs via a single K-homology domain, located in the C terminus of the protein. Functionally, we discovered that ANKHD1 positively drives ccRCC cell mitosis via binding to and suppressing mainly miR-29a and to a lesser degree via miR-196a/205, leading to up-regulation in proliferative genes such as CCDN1. Collectively, these data identify ANKHD1 as a new regulator of ccRCC proliferation via specific miRNA interactions. PMID- 29695509 TI - Myc phosphorylation in its basic helix-loop-helix region destabilizes transient alpha-helical structures, disrupting Max and DNA binding. AB - Myelocytomatosis proto-oncogene transcription factor (Myc) is an intrinsically disordered protein with critical roles in cellular homeostasis and neoplastic transformation. It is tightly regulated in the cell, with Myc phosphorylation playing a major role. In addition to the well-described tandem phosphorylation of Thr-52 and Ser-62 in the Myc transactivation domain linked to its degradation, P21 (RAC1)-activated kinase 2 (PAK2)-mediated phosphorylation of serine and threonine residues in the C-terminal basic helix-loop-helix leucine zipper (bHLH LZ) region regulates Myc transcriptional activity. Here we report that PAK2 preferentially phosphorylates Myc twice, at Thr-358 and Ser-373, with only a minor fraction being modified at the previously identified Thr-400 site. For transcriptional activity, Myc binds E-box DNA elements, requiring its heterodimerization with Myc-associated factor X (Max) via the bHLH-LZ regions. Using isothermal calorimetry (ITC), we found that Myc phosphorylation destabilizes this ternary protein-DNA complex by decreasing Myc's affinity for Max by 2 orders of magnitude, suggesting a major effect of phosphorylation on this complex. Phosphomimetic substitutions revealed that Ser-373 dominates the effect on Myc-Max heterodimerization. Moreover, a T400D substitution disrupted Myc's affinity for Max. ITC, NMR, and CD analyses of several Myc variants suggested that the effect of phosphorylation on the Myc-Max interaction is caused by secondary structure disruption during heterodimerization rather than by a change in the structurally disordered state of Myc or by phosphorylation-induced electrostatic repulsion in the heterodimer. Our findings provide critical insights into the effects of PAK2-catalyzed phosphorylation of Myc on its interactions with Max and DNA. PMID- 29695510 TI - Development of scientific exercise guidelines for adults with spinal cord injury. PMID- 29695511 TI - How does light-intensity physical activity associate with adult cardiometabolic health and mortality? Systematic review with meta-analysis of experimental and observational studies. AB - AIM: To assess the relationship between time spent in light physical activity and cardiometabolic health and mortality in adults. DESIGN: Systematic review and meta-analysis. DATA SOURCES: Searches in Medline, Embase, PsycInfo, CINAHL and three rounds of hand searches. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Experimental (including acute mechanistic studies and physical activity intervention programme) and observational studies (excluding case and case control studies) conducted in adults (aged >=18 years) published in English before February 2018 and reporting on the relationship between light physical activity (<3 metabolic equivalents) and cardiometabolic health outcomes or all cause mortality. STUDY APPRAISAL AND SYNTHESIS: Study quality appraisal with QUALSYST tool and random effects inverse variance meta-analysis. RESULTS: Seventy two studies were eligible including 27 experimental studies (and 45 observational studies). Mechanistic experimental studies showed that short but frequent bouts of light-intensity activity throughout the day reduced postprandial glucose ( 17.5%; 95% CI -26.2 to -8.7) and insulin (-25.1%; 95% CI -31.8 to -18.3) levels compared with continuous sitting, but there was very limited evidence for it affecting other cardiometabolic markers. Three light physical activity programme intervention studies (n ranging from 12 to 58) reduced adiposity, improved blood pressure and lipidaemia; the programmes consisted of activity of >150 min/week for at least 12 weeks. Six out of eight prospective observational studies that were entered in the meta-analysis reported that more time spent in daily light activity reduced risk of all-cause mortality (pooled HR 0.71; 95% CI 0.62 to 0.83). CONCLUSIONS: Light-intensity physical activity could play a role in improving adult cardiometabolic health and reducing mortality risk. Frequent short bouts of light activity improve glycaemic control. Nevertheless, the modest volume of the prospective epidemiological evidence base and the moderate consistency between observational and laboratory evidence inhibits definitive conclusions. PMID- 29695512 TI - Individual participant data analysis of two trials on aldosterone blockade in myocardial infarction. AB - BACKGROUND: Two recent randomised trials studied the benefit of mineralocorticoid receptor antagonists (MRAs) in ST-segment elevation myocardial infarction (STEMI) irrespective or in absence of heart failure. The studies were both undersized to assess hard clinical endpoints. A pooled analysis was preplanned by the steering committees. METHODS: We conducted a prespecified meta-analysis of patient-level data of patients with STEMI recruited in two multicentre superiority trials, randomised within 72 hours after symptom onset. Patients were allocated (1:1) to two MRA regimens: (1) an intravenous bolus of potassium canrenoate (200 mg) followed by oral spironolactone (25 mg once daily) versus standard therapy or (2) oral eplerenone (25-50 mg) versus placebo. The primary and key secondary outcomes, all-cause death and the composite of all-cause death or resuscitated sudden death, respectively, were assessed in the intention-to-treat population using a Cox model stratified on the study identifier. RESULTS: Patients were randomly assigned to receive (n=1118) or not the MRA regimen (n=1123). After a median follow-up time of 188 days, the primary and secondary outcomes occurred in 5 (0.4%) and 17 (1.5%) patients (adjusted HR (adjHR) 0.31, 95% CI 0.11 to 0.86, p=0.03) and 6 (0.5%) and 22 (2%) patients (adjHR 0.26, 95% CI 0.10 to 0.65, p=0.004) in the MRA and control groups, respectively. There were also trends towards lower rates of cardiovascular death (p=0.06) and ventricular fibrillation (p=0.08) in the MRA group. CONCLUSION: Our analysis suggests that compared with standard therapy, MRA regimens are associated with a reduction of death and death or resuscitated sudden death in STEMI. PMID- 29695513 TI - Interventional management of paravalvular leak. PMID- 29695514 TI - Triple antithrombotic therapy after ACS and PCI in patients on chronic oral anticoagulation: update. PMID- 29695515 TI - Novel role of prostate apoptosis response-4 tumor suppressor in B-cell chronic lymphocytic leukemia. AB - Prostate apoptosis response-4 (Par-4), a proapoptotic tumor suppressor protein, is downregulated in many cancers including renal cell carcinoma, glioblastoma, endometrial, and breast cancer. Par-4 induces apoptosis selectively in various types of cancer cells but not normal cells. We found that chronic lymphocytic leukemia (CLL) cells from human patients and from Eu-Tcl1 mice constitutively express Par-4 in greater amounts than normal B-1 or B-2 cells. Interestingly, knockdown of Par-4 in human CLL-derived Mec-1 cells results in a robust increase in p21/WAF1 expression and decreased growth due to delayed G1-to-S cell-cycle transition. Lack of Par-4 also increased the expression of p21 and delayed CLL growth in EMU-Tcl1 mice. Par-4 expression in CLL cells required constitutively active B-cell receptor (BCR) signaling, as inhibition of BCR signaling with US Food and Drug Administration (FDA)-approved drugs caused a decrease in Par-4 messenger RNA and protein, and an increase in apoptosis. In particular, activities of Lyn, a Src family kinase, spleen tyrosine kinase, and Bruton tyrosine kinase are required for Par-4 expression in CLL cells, suggesting a novel regulation of Par-4 through BCR signaling. Together, these results suggest that Par-4 may play a novel progrowth rather than proapoptotic role in CLL and could be targeted to enhance the therapeutic effects of BCR-signaling inhibitors. PMID- 29695516 TI - Phase 1 study of the PI3Kdelta inhibitor INCB040093 +/- JAK1 inhibitor itacitinib in relapsed/refractory B-cell lymphoma. AB - Because both phosphatidylinositol 3-kinase delta (PI3Kdelta) and Janus kinase (JAK)-signal transducer and activator of transcription pathways contribute to tumor cell proliferation and survival in B-cell malignancies, their simultaneous inhibition may provide synergistic treatment efficacy. This phase 1 dose escalation/expansion study assessed the safety, efficacy, pharmacokinetics, and pharmacodynamics of INCB040093, a selective PI3Kdelta inhibitor, as monotherapy or combined with itacitinib (formerly INCB039110), a selective JAK1 inhibitor, in adult patients with relapsed or refractory (R/R) B-cell lymphomas. Final results are reported. Overall, 114 patients were treated (monotherapy, n = 49; combination therapy, n = 72 [7 patients crossed over from monotherapy to combination]). INCB040093 100 mg twice daily (monotherapy) and INCB040093 100 mg twice daily + itacitinib 300 mg once daily (combination) were the recommended phase 2 doses. One dose-limiting toxicity (gastrointestinal bleed secondary to gastric diffuse large B-cell lymphoma [DLBCL] regression) occurred with monotherapy. The most common serious adverse events with monotherapy were pneumonia (n = 5) and pyrexia (n = 4), and with combination Pneumocystis jiroveci pneumonia (n = 5), pneumonia (unrelated to P jiroveci; n = 5), and pyrexia (n = 4). Grade 3 or higher transaminase elevations were less common with combination. INCB040093 was active across the B-cell lymphomas; 63% of patients (5/8) with follicular lymphoma responded to monotherapy. Adding itacitinib provided promising activity in select subtypes, with responses of 67% (14/21) in classic Hodgkin lymphoma (vs 29% [5/17] with monotherapy) and 31% (4/13) in nongerminal center B-cell-like DLBCL. INCB040093 with/without itacitinib was tolerated and active in this study, and is a promising treatment strategy for patients with select R/R B-cell lymphomas. This trial was registered at www.clinicaltrials.gov as #NCT01905813. PMID- 29695517 TI - Associations between cohabitation status, treatment, and outcome in AML patients: a national population-based study. PMID- 29695518 TI - Ixazomib, an oral proteasome inhibitor, induces rapid mobilization of hematopoietic progenitor cells in mice. PMID- 29695519 TI - Detection of Influenza A and B Viruses and Respiratory Syncytial Virus by Use of Clinical Laboratory Improvement Amendments of 1988 (CLIA)-Waived Point-of-Care Assays: a Paradigm Shift to Molecular Tests. AB - An accurate laboratory diagnosis of influenza, respiratory syncytial virus (RSV), and other respiratory viruses can help to guide patient management, antiviral therapy, infection prevention strategies, and epidemiologic monitoring. Influenza has been the primary driver of rapid laboratory testing due to its morbidity and mortality across all ages, the availability of antiviral therapy, which must be given early to have an effect, and the constant threat of new pandemic strains. Over the past 30 years, there has been an evolution in viral diagnostic testing, from viral culture to rapid antigen detection, and more recently, to highly sensitive nucleic acid amplification tests (NAAT), as well as a trend to testing at the point of care (POC). Simple rapid antigen immunoassays have long been the mainstay for POC testing for influenza A and B viruses and respiratory syncytial virus (RSV) but have been faulted for low sensitivity. In 2015, the first POC NAAT for the detection of influenza was approved by the Food and Drug Administration (FDA), ushering in a new era. In 2017, the FDA reclassified rapid influenza diagnostic tests (RIDTs) from class I to class II devices with new minimum performance standards and a requirement for annual reactivity testing. Consequently, many previously available RIDTs can no longer be purchased in the United States. In this review, recent developments in Clinical Laboratory Improvement Amendments of 1988 (CLIA)-waived testing for respiratory virus infections will be presented, with the focus on currently available FDA-cleared rapid antigen and molecular tests primarily for influenza A and B viruses and RSV. PMID- 29695520 TI - A Bead-Based Flow Cytometric Assay for Monitoring Yersinia pestis Exposure in Wildlife. AB - Yersinia pestis is the causative agent of plague and is considered a category A priority pathogen due to its potential for high transmissibility and the significant morbidity and mortality it causes in humans. Y. pestis is endemic to the western United States and much of the world, necessitating programs to monitor for this pathogen on the landscape. Elevated human risk of plague infection has been spatially correlated with spikes in seropositive wildlife numbers, particularly rodent-eating carnivores, which are frequently in contact with the enzootic hosts and the associated arthropod vectors of Y. pestis In this study, we describe a semiautomated bead-based flow cytometric assay developed for plague monitoring in wildlife called the F1 Luminex plague assay (F1-LPA). Based upon Luminex/Bio-Plex technology, the F1-LPA targets serological responses to the F1 capsular antigen of Y. pestis and was optimized to analyze antibodies eluted from wildlife blood samples preserved on Nobuto filter paper strips. In comparative evaluations with passive hemagglutination, the gold standard tool for wildlife plague serodiagnosis, the F1-LPA demonstrated as much as 64* improvement in analytical sensitivity for F1-specific IgG detection and allowed for unambiguous classification of IgG status. The functionality of the F1-LPA was demonstrated for coyotes and other canids, which are the primary sentinels in wildlife plague monitoring, as well as felids and raccoons. Additionally, assay formats that do not require species-specific immunological reagents, which are not routinely available for several wildlife species used in plague monitoring, were determined to be functional in the F1-LPA. PMID- 29695521 TI - Emerging Multidrug-Resistant Candida duobushaemulonii Infections in Panama Hospitals: Importance of Laboratory Surveillance and Accurate Identification. AB - Candida duobushaemulonii, a yeast closely related to Candida auris, is thought to cause infections in rare cases and is often misidentified. In October 2016, the Panamanian Ministry of Health implemented laboratory surveillance for C. auris Suspected C. auris isolates were forwarded to the national reference laboratory for identification by matrix-assisted laser desorption ionization-time of flight mass spectrometry and antifungal susceptibility testing. Between November 2016 and May 2017, 17 of 36 (47%) isolates suspected to be C. auris were identified as C. duobushaemulonii. These 17 isolates were obtained from 14 patients at six hospitals. Ten patients, including three children, had bloodstream infections, and MICs for fluconazole, voriconazole, and amphotericin B were elevated. No resistance to echinocandins was observed. C. duobushaemulonii causes more invasive infections than previously appreciated and poses a substantial problem, given its resistance to multiple antifungals. Expanded laboratory surveillance is an important step in the detection and control of such emerging pathogens. PMID- 29695522 TI - Whole-Genome Sequencing of Aggregatibacter Species Isolated from Human Clinical Specimens and Description of Aggregatibacter kilianii sp. nov. AB - Aggregatibacter species are commensal bacteria of human mucosal surfaces that are sometimes involved in serious invasive infections. During the investigation of strains cultured from various clinical specimens, we encountered a coherent group of 10 isolates that could not be allocated to any validly named species by phenotype, mass spectrometry, or partial 16S rRNA gene sequencing. Whole-genome sequencing revealed a phylogenetic cluster related to but separate from Aggregatibacter aphrophilus The mean in silico DNA hybridization value for strains of the new cluster versus A. aphrophilus was 56% (range, 53.7 to 58.0%), whereas the average nucleotide identity was 94.4% (range, 93.9 to 94.8%). The new cluster exhibited aggregative properties typical of the genus Aggregatibacter Key phenotypic tests for discrimination of the new cluster from validly named Aggregatibacter species are alanine-phenylalanine-proline arylamidase, N acetylglucosamine, and beta-galactosidase. The name Aggregatibacter kilianii is proposed, with PN_528 (CCUG 70536T or DSM 105094T) as the type strain. PMID- 29695523 TI - ThermoMixer-Aided Endpoint Quaking-Induced Conversion (EP-QuIC) Permits Faster Sporadic Creutzfeldt-Jakob Disease (sCJD) Identification than Real-Time Quaking Induced Conversion (RT-QuIC). PMID- 29695524 TI - Evaluation of Targeted Next-Generation Sequencing for Detection of Bovine Pathogens in Clinical Samples. AB - The laboratory diagnosis of infectious diseases, especially those caused by mixed infections, is challenging. Routinely, it requires submission of multiple samples to separate laboratories. Advances in next-generation sequencing (NGS) have provided the opportunity for development of a comprehensive method to identify infectious agents. This study describes the use of target-specific primers for PCR-mediated amplification with the NGS technology in which pathogen genomic regions of interest are enriched and selectively sequenced from clinical samples. In the study, 198 primers were designed to target 43 common bovine and small ruminant bacterial, fungal, viral, and parasitic pathogens, and a bioinformatics tool was specifically constructed for the detection of targeted pathogens. The primers were confirmed to detect the intended pathogens by testing reference strains and isolates. The method was then validated using 60 clinical samples (including tissues, feces, and milk) that were also tested with other routine diagnostic techniques. The detection limits of the targeted NGS method were evaluated using 10 representative pathogens that were also tested by quantitative PCR (qPCR), and the NGS method was able to detect the organisms from samples with qPCR threshold cycle (CT ) values in the 30s. The method was successful for the detection of multiple pathogens in the clinical samples, including some additional pathogens missed by the routine techniques because the specific tests needed for the particular organisms were not performed. The results demonstrate the feasibility of the approach and indicate that it is possible to incorporate NGS as a diagnostic tool in a cost-effective manner into a veterinary diagnostic laboratory. PMID- 29695525 TI - Ultra-High-Resolution Mass Spectrometry for Identification of Closely Related Dermatophytes with Different Clinical Predilections. AB - In the present study, an innovative top-down liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the identification of clinically relevant fungi is tested using a model set of dermatophyte strains. The methodology characterizes intact proteins derived from Trichophyton species, which are used as parameters of differentiation. To test its resolving power compared to that of traditional Sanger sequencing and matrix-assisted laser desorption ionization time of flight mass spectrometry (MALDI-TOF), 24 strains of closely related dermatophytes, Trichophyton rubrum, T. violaceum, T. tonsurans, T. equinum, and T. interdigitale, were subjected to this new approach. Using MS/MS and different deconvolution algorithms, we identified hundreds of individual proteins, with a subpopulation of these used as strain- or species-specific markers. Three species, i.e., T. rubrum, T. violaceum, and T. interdigitale, were identified correctly down to the species level. Moreover, all isolates associated with these three species were identified correctly down to the strain level. In the T. tonsurans-equinum complex, eight out of 12 strains showed nearly identical proteomes, indicating an unresolved taxonomic conflict already apparent from previous phylogenetic data. In this case, it was determined with high probability that only a single species can be present. Our study successfully demonstrates applicability of the mass spectrometric approach to identify clinically relevant filamentous fungi. Here, we present the first proof-of-principle study employing the mentioned technology to differentiate microbial pathogens. The ability to differentiate fungi at the strain level sets the stage to improve patient outcomes, such as early detection of strains that carry resistance to antifungals. PMID- 29695526 TI - Approach to Diagnosis of Cardiovascular Implantable-Electronic-Device Infection. AB - Device infection remains a significant challenge as clinical indications for cardiovascular implantable electronic device (CIED) therapy continue to expand beyond the prevention and treatment of cardiac arrhythmias. Patients receiving CIED therapy are now older and have significant comorbidities, placing them at higher risk of complications, including infection. CIED infection warrants complete device removal, as retention is associated with an unacceptably high risk of relapse and increased mortality. However, accurate diagnosis of CIED infections remains a significant challenge that is based on a combination of findings on physical examination, microbiological and laboratory testing, and advanced imaging, such as transesophageal echocardiography or positron emission tomography. Isolating a causative pathogen and performing susceptibility testing are crucial for appropriate choice, route, and duration of antimicrobial therapy. In this review, we present an evidence-based approach to diagnosis of CIED infection. PMID- 29695527 TI - Development and Evaluation of a Novel Loop-Mediated Isothermal Amplification Assay for Diagnosis of Cutaneous and Visceral Leishmaniasis. AB - A novel pan-Leishmania loop-mediated isothermal amplification (LAMP) assay for the diagnosis of cutaneous and visceral leishmaniasis (CL and VL) that can be used in near-patient settings was developed. Primers were designed based on the 18S ribosomal DNA (rDNA) and the conserved region of minicircle kinetoplast DNA (kDNA), selected on the basis of high copy number. LAMP assays were evaluated for CL diagnosis in a prospective cohort trial of 105 patients in southwest Colombia. Lesion swab samples from CL suspects were collected and were tested using the LAMP assay, and the results were compared to those of a composite reference of microscopy and/or culture in order to calculate diagnostic accuracy. LAMP assays were tested on samples (including whole blood, peripheral blood mononuclear cells, and buffy coat) from 50 suspected VL patients from Ethiopia. Diagnostic accuracy was calculated against a reference standard of microscopy of splenic or bone marrow aspirates. To calculate analytical specificity, 100 clinical samples and isolates from fever-causing pathogens, including malaria parasites, arboviruses, and bacteria, were tested. We found that the LAMP assay had a sensitivity of 95% (95% confidence interval [CI], 87.2% to 98.5%) and a specificity of 86% (95% CI, 67.3% to 95.9%) for the diagnosis of CL. With VL suspects, the sensitivity of the LAMP assay was 92% (95% CI, 74.9% to 99.1%) and its specificity was 100% (95% CI, 85.8% to 100%) in whole blood. For CL, the LAMP assay is a sensitive tool for diagnosis and requires less equipment, time, and expertise than alternative CL diagnostics. For VL, the LAMP assay using a minimally invasive sample is more sensitive than the gold standard. Analytical specificity was 100%. PMID- 29695528 TI - Setup, Validation, and Quality Control of a Centralized Whole-Genome-Sequencing Laboratory: Lessons Learned. AB - Routine use of whole-genome analysis for infectious diseases can be used to enlighten various scenarios pertaining to public health, including identification of microbial pathogens, relating individual cases to an outbreak of infectious disease, establishing an association between an outbreak of food poisoning and a specific food vehicle, inferring drug susceptibility, source tracing of contaminants, and study of variations in the genome that affect pathogenicity/virulence. We describe the setup, validation, and ongoing verification of a centralized whole-genome-sequencing (WGS) laboratory to carry out sequencing for these public health functions for the National Infection Services, Public Health England, in the United Kingdom. The performance characteristics and quality control metrics measured during validation and verification of the entire end-to-end process (accuracy, precision, reproducibility, and repeatability) are described and include information regarding the automated pass and release of data to service users without intervention. PMID- 29695529 TI - Do Selective Serotonin Reuptake Inhibitor Antidepressant Drugs Promote Atherosclerosis? PMID- 29695530 TI - Modeling Venous Thrombosis In Vitro: More Than Just (Valve) Pocket Change. PMID- 29695531 TI - TIMPing the Aorta: Smooth Muscle Cell-Specific Deletion of BMAL1 Limits Murine Abdominal Aortic Aneurysm Development. PMID- 29695532 TI - PTEN (Phosphatase and Tensin Homolog) Connection in Hereditary Hemorrhagic Telangiectasia 2. PMID- 29695533 TI - Recent Advances in the Development of Cardiovascular Biomarkers. PMID- 29695534 TI - Letter by Hartwig et al Regarding Article, "Evaluation of the Pleiotropic Effects of Statins: A Reanalysis of the Randomized Trial Evidence Using Egger Regression". PMID- 29695535 TI - Response by Labos et al to Letter Regarding Article, "Evaluation of the Pleiotropic Effects of Statins: A Reanalysis of the Randomized Trial Evidence Using Egger Regression". PMID- 29695536 TI - Correction to: Macrophage-Associated Lipin-1 Enzymatic Activity Contributes to Modified Low-Density Lipoprotein-Induced Proinflammatory Signaling and Atherosclerosis. PMID- 29695537 TI - Aquatic-terrestrial transitions of feeding systems in vertebrates: a mechanical perspective. AB - Transitions to terrestrial environments confront ancestrally aquatic animals with several mechanical and physiological problems owing to the different physical properties of water and air. As aquatic feeders generally make use of flows of water relative to the head to capture, transport and swallow food, it follows that morphological and behavioral changes were inevitably needed for the aquatic animals to successfully perform these functions on land. Here, we summarize the mechanical requirements of successful aquatic-to-terrestrial transitions in food capture, transport and swallowing by vertebrates and review how different taxa managed to fulfill these requirements. Amphibious ray-finned fishes show a variety of strategies to stably lift the anterior trunk, as well as to grab ground-based food with their jaws. However, they still need to return to the water for the intra-oral transport and swallowing process. Using the same mechanical perspective, the potential capabilities of some of the earliest tetrapods to perform terrestrial feeding are evaluated. Within tetrapods, the appearance of a mobile neck and a muscular and movable tongue can safely be regarded as key factors in the colonization of land away from amphibious habitats. Comparative studies on taxa including salamanders, which change from aquatic feeders as larvae to terrestrial feeders as adults, illustrate remodeling patterns in the hyobranchial system that can be linked to its drastic change in function during feeding. Yet, the precise evolutionary history in form and function of the hyolingual system leading to the origin(s) of a muscular and adhesive tongue remains unknown. PMID- 29695538 TI - Does medical students' gender affect their clinical learning of gynaecological examination? A retrospective cohort study. AB - INTRODUCTION: Medical graduates should be competent in gynaecological examination as well as associated skills including speculum use and swabbing. Male and female medical students may have different opportunities to practise these skills in clinical environments, potentially impacting on confidence and competence. This study explores this further via reviewing students' learning experience in genitourinary medicine (GUM) and obstetrics and gynaecology (O&G) clinics. METHODS: Cross-sectional study of 759 year 4 and year 5 University of Birmingham medical students via an online questionnaire. This explored degree of participation, impact of gender and self-reported confidence. RESULTS: Overall response rate was 31% (233/759). Students of either gender who observed an examination being performed by a clinician were more likely to perform the same examination. Female students reported more opportunities to practise gynaecological examination and associated skills. Female students were more likely to be granted consent to perform speculum examinations, vaginal swabbing and vaginal bimanual examinations. Sixty-five per cent of male students felt that their gender affected their learning experience with female patients. Despite this, there was no significant difference in self-reported confidence level in performing gynaecological examinations between genders at the end of placement. CONCLUSION: The majority of male students perceived that their gender impacted their clinical experience in O&G and GUM. Self-reported confidence levels were unaffected, which could reflect varying approaches to competence between genders. The link between observing examinations and subsequent opportunities to practise is key. This could demonstrate students developing rapport and trust with patients, and clinicians' roles as gatekeepers. PMID- 29695539 TI - Reply to Drancourt, "Culturing Stools To Detect Mycobacterium tuberculosis". PMID- 29695540 TI - Photo Quiz: Hematuria in a 26-Year-Old Male with AIDS. PMID- 29695541 TI - Answer to May 2018 Photo Quiz. PMID- 29695543 TI - Closing The Brief Case: A "Fresh" Pair of Contact Lenses. PMID- 29695542 TI - The Brief Case: A "Fresh" Pair of Contact Lenses. PMID- 29695544 TI - Culturing Stools To Detect Mycobacterium tuberculosis. PMID- 29695545 TI - A New Polysaccharide with a Long Evolutionary History. PMID- 29695547 TI - An Improved In Vivo Methodology to Visualise Tumour Induced Changes in Vasculature Using the Chick Chorionic Allantoic Membrane Assay. AB - BACKGROUND/AIM: Decreasing the vascularity of a tumour has proven to be an effective strategy to suppress tumour growth and metastasis. Anti-angiogenic therapies have revolutionized the treatment of advanced-stage cancers, however there is still demand for further improvement. This necessitates new experimental models that will allow researchers to reliably study aspects of angiogenesis. The aim of this study was to demonstrate an in vivo technique in which the highly vascular and accessible chorioallantoic membrane (CAM) of the chick embryo is used to study tumour-induced changes in the macro and microvessels. MATERIALS AND METHODS: Two cancer cell lines (human melanoma (C8161) and human prostate cancer (PC3)) were selected as model cells. Human dermal fibroblasts were used as a control. One million cells were labelled with green fluorescent protein and implanted on the CAM of the chick embryo at embryonic development day (EDD) 7 and angiogenesis was evaluated at EDDs 10, 12 and 14. A fluorescently-tagged lectin (lens culinaris agglutinin (LCA)) was injected intravenously into the chick embryo to label endothelial cells. The LCA is known to label the luminal surface of endothelial cells, or dextrans, in the CAM vasculature. Macrovessels were imaged by a hand-held digital microscope and images were processed for quantification. Microvessels were evaluated by confocal microscopy. Tumour invasion was assessed by histological and optical sectioning. RESULTS: Tumour cells (C8161 and PC3) produced quantifiable increases in the total area covered by blood vessels, compared to fibroblasts when assessed by digital microscopy. Tumour invasion could be demonstrated by both histological and optical sectioning. The most significant changes in tumour vasculature observed were in the microvascular structures adjacent to the tumour cells, which showed an increase in the endothelial cell coverage. Additionally, tumour intravasation and tumour thrombus formation could be detected in the areas adjacent to tumour cells. The fragility of tumour blood vessels could be demonstrated when tumour cells seeded on a synthetic scaffold were grown on CAM. CONCLUSION: We report on a modification to a well-studied CAM in vivo assay, which can be effectively used to study tumour induced changes in macro and microvasculature. PMID- 29695546 TI - Considerations Regarding Embryo Culture Conditions: From Media to Epigenetics. AB - There are numerous reports on embryo culture media and conditions in the laboratory, as the subject is multifaceted and complex, reflecting the variation in practice. In this scoping review, we attempt to approach the topic of culture media and conditions from the practitioners' perspective aiming to highlight, in a comprehensive fashion, important aspects regarding the options available, introduce points of debate and controversy, while maintaining the viewpoint of the practicing embryologist's concerns. PMID- 29695548 TI - Zanamivir Diminishes Lung Damage in Influenza A Virus-infected Mice by Inhibiting Nitric Oxide Production. AB - BACKGROUND/AIM: Severe pulmonary influenza A virus (IAV) infection causes lung inflammation and expression of inducible nitric oxide synthase (iNOS), leading to overproduction of nitric oxide (NO). We studied whether zanamivir reduces pulmonary inflammation through inhibition of NO production in mice. MATERIALS AND METHODS: We treated IAV-infected mice daily with intranasal zanamivir. Controls were infected and either placebo-treated or untreated, or not infected and placebo-treated. Mice were weighed daily. After euthanasia on day 3, lungs were excised and bronchoalveolar lavage was performed and fluid nitrite concentration was determined. Lungs were analyzed microscopically. iNOS and IAV RNA levels in lungs were assessed using quantitative reverse transcription-polymerase chain reaction (RT-qPCR). RESULTS: Mice undergoing zanamivir treatment had less weight loss, viral replication, and lung damage, as well as significant reductions of local NO and iNOS mRNA synthesis (p<0.05). CONCLUSION: Zanamivir is associated with an anti-inflammatory effect mediated through inhibition of NO production in IAV-infected mice. PMID- 29695549 TI - In Vitro Anti-tumor Activity of Azulene Amide Derivatives. AB - BACKGROUND/AIM: There exist few research articles regarding the anticancer activity of azulene-related compounds. We investigated here the relative cytotoxicity of 10 azulene amide derivatives against cancer and normal cells. MATERIALS AND METHODS: Cytotoxicity against four human oral squamous cell carcinoma (OSCC) cell lines and three human oral normal cells (gingival fibroblasts, periodontal ligament fibroblasts and pulp cells) was determined by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetra-zolium bromide method. Antitumor activity was evaluated by tumor-specificity (TS) (ratio of mean 50% cytotoxic concentration (CC50) against normal cells to that against OSCC cell lines) and potency-selectivity expression (PSE) (ratio of TS to CC50 against tumor cells). Apoptosis-inducing activity was evaluated by cleavage of poly ADP ribose polymerase and caspase-3 with western blot analysis. RESULTS: N Propylguaiazulenecarboxamide [1] showed the highest TS and PSE values, compared to that of doxorubicin, and induced apoptosis in two OSCC cell lines. QSAR analysis demonstrated that their tumor-specificity of azulene amide derivatives was correlated with hydrophobicity and molecular shape. CONCLUSION: Compound [1] can be considered as a lead compound for manufacturing new anticancer drug candidates. PMID- 29695551 TI - Invasion-inhibiting Effects of Gaseous Components in Cigarette Smoke on Mouse Rectal Carcinoma Colon-26 Cells. AB - We investigated the anti-metastatic action of nicotine- and tar-removed cigarette smoke extract (CSE) on highly metastatic mouse Colon-26 cells using syngeneic BALB/c mice. Colon-26 cells were injected into the spleen of mice, cells were grown in the spleen as the primary lesion, and some metastasized from the spleen to liver and established a metastatic lesion. CSE (10, 30, and 100%) was intraperitoneally administered daily to the mice for 14 days after tumor inoculation. As a result, the relative spleen weights of CSE-administered mice did not differ significantly from those of the control mice. However, the relative liver weights of CSE 30%-administered mice significantly decreased compared to control mice. In order to identify the active component in CSE, we examined the action of methyl vinyl ketone (MVK) on the invasiveness of Colon-26 cells. MVK significantly reduced the invasiveness of cells. MVK may be a candidate active component of CSE. PMID- 29695550 TI - The Association of Matrix Metalloproteinase-1 Promoter Polymorphisms with Breast Cancer. AB - BACKGROUND/AIM: The family of matrix metalloproteinases (MMPs) are responsible for the homeostasis of extracellular matrix components and their genetic polymorphisms may be associated with cancer susceptibility. The serum levels of MMP-1 have been reported to be lower in breast cancer patients than healthy subjects. In the current study, we aimed at investigating the contribution of a polymorphism in the promoter region of MMP-1 to breast cancer in Taiwan. MATERIALS AND METHODS: The MMP-1 rs1799705 polymorphic genotypes were genotyped among 1,232 breast cancer patients and 1,232 healthy controls by the typical polymerase chain reaction-restriction fragment length polymorphism methodology. RESULTS: The percentages of 2G/2G, 1G/2G, and 1G/1G for MMP1 -1607 genotypes were 35.4, 40.6 and 24.0% in the breast cancer group and 34.1, 43.6, and 22.3% in the healthy control group (p trend=0.3025), respectively. The odds ratios (ORs) after adjusting for age, smoking and alcohol drinking status for those carrying 1G/2G and 1G/1G genotypes at MMP1 -1607 were 0.93 (95%CI=0.76-1.11, p=0.2390) and 1.01 (95%CI=0.77-1.23, p=0.7377), respectively, compared to those carrying the wild type 2G/2G genotype. Supporting this finding, the adjusted OR for those carrying the 1G allele at MMP-1 -1607 was 1.03 (95%CI=0.91-1.18, p=0.8860), compared to those carrying the wild-type 2G allele. Our findings suggest that the polymorphic genotypes at MMP1 promoter -1607 investigated in the current study, may not play a major role in determining cancer susceptibility to breast cancer in Taiwan. Other early diagnostic and predictive markers are urgently needed for personalized and precise breast cancer detection and therapy. PMID- 29695552 TI - Activated Ductal Proliferation Induced by N-Nitrosobis (2-oxopropyl)amine in Fat infiltrated Pancreas of KK-Ay Mice. AB - BACKGROUND/AIM: Our aim was to investigate whether tissue with fatty infiltration within the lobes of the pancreas (scattered FI) is sensitive to carcinogen induced pancreatic ductal proliferation. MATERIALS AND METHODS: Seven-week-old female C57BL/6J, C57BL/6J-Ay, KK-Ay, and ICR mice were subcutaneously treated with N-nitrosobis(2-oxopropyl) amine at a dose of 80 mg/kg body weight, and the differences in damage-induced cell proliferation and their biochemical data were compared 2 days after. RESULTS: Scattered FI in the pancreas was obvious only in KK-Ay mice, which have high serum lipid, leptin and insulin levels, and cell proliferation both in pancreatic and common bile ducts was enhanced only in KK-Ay mice by the carcinogen treatment. CONCLUSION: Scattered FI in the pancreas per se can be an important factor for carcinogenesis. The genetic background causing scattered FI of the pancreas should be further investigated. PMID- 29695553 TI - Elevated EGF Levels in the Blood Serum of Dogs with Periodontal Diseases and Oral Tumours. AB - BACKGROUND/AIM: Paradontopathy and neoplasms of the oral cavity represent one of the greatest challenges in human and animal dentistry. EGF plays a key role in maintaining the integrity and proper rate of cell proliferation in normal oral epithelium. The aim of the present study was to study serum levels of EGF in dogs diagnosed with periodontal diseases and oral cavity tumours. MATERIALS AND METHODS: The samples comprised of cancerous tissue sections and serum obtained from dogs of various breeds, aged between 5-13 years. Serum EGF concentrations were measured by an immunoenzymatic method. RESULTS: The median for EGF concentration in serum of dogs suffered from severe periodontal diseases was greater when compared to the control group. EGF concentration in dogs with malignant tumours was significantly higher than in those with non-malignant growths. A positive correlation between EGF concentration and tumour size was also observed. EGF level in dogs diagnosed with benign tumours was comparable to the control group. CONCLUSION: The blood serum level of EGF increases significantly in patients with malignant oral tumours and advanced periodontal disease. In malignant tumours, the high level of EGF correlates with the size and invasiveness of the neoplasm. PMID- 29695554 TI - Total Skin Electron Beam Therapy with Rotary Dual Technique as Palliative Treatment for Mycosis Fungoides. AB - BACKGROUND/AIM: The aim of the study was to retrospectively assess the efficacy and toxicity of total skin electron beam therapy (TSEBT) in patients with primary cutaneous T-cell lymphoma (MF, mycosis fungoides) at various stages of development. PATIENTS AND METHODS: Treatment results of 40 patients with MF stage IB-III, treated between 2001 and 2015, were reviewed. Median total dose was 32 Gy, delivered to the entire skin surface. Median follow-up was 60 months. RESULTS: Clinical complete response was documented in 29 and partial response in 11 patients. The clinical response significantly influenced overall survival (OS) (p=0.002) and progression-free survival (PFS) (p<0.001). Mean OS was 76 months. Mean PFS was 48.9 months and current one- and two-year PFS were 67.5% and 55%, respectively. A statistically significant correlation was found between partial and total remission time and stages of the lymphoma (p=0.015). CONCLUSION: TSEBT is an efficient and well-tolerated palliative treatment for symptomatic primary cutaneous T-cell lymphoma. PMID- 29695555 TI - Laminarin Promotes Immune Responses and Reduces Lactate Dehydrogenase But Increases Glutamic Pyruvic Transaminase in Normal Mice In Vivo. AB - BACKGROUND/AIM: Laminarin, a typical component of fungal cell walls, has been shown to induce immune responses in both adult and larval locusts. We investigated the effects of laminarin on immune response and glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT) and lactate dehydrogenase (LDH) levels in normal mice. MATERIALS AND METHODS: Thirty-six normal BALB/c mice were randomly divided into four groups and treatments were provided by gavage. Group I mice acted as normal control; mice of groups II-IV received laminarin at different doses (100 MUl at 1, 2.5 and 5.0 mg/mouse in double-distilled water, respectively). All animals were treated for 14 days and were weighed, blood was collected for determination of cell markers, liver and spleen samples were weighed. Spleens were used for phagocytosis and determination of natural killer (NK) cell activity and cell proliferation by flow cytometric assay. RESULTS: Laminarin reduced the body weights and weights of liver and spleen. Laminarin increased CD3, CD19 and Mac-3 cell populations at 2.5 and 5 mg/mouse, however, these did not affect CD11b marker levels. Laminarin (1 and 5 mg/mouse) reduced macrophage phagocytosis from peripheral blood mononuclear cells, but did not affect phagocytosis by macrophages from the peritoneal cavity. At an effector:target ratio of 50:1, laminarin reduced NK cell cytotoxic activity at all levels, but at a ratio of 25:1, only at 1 mg treatment. Laminarin did not affect T-cell and B-cell proliferation. Laminarin increased the level of GPT and reduced that of LDH at all doses, indicating laminarin can protect against liver injury. Laminarin is worthy of investigation in future experiments on improving immune responses. PMID- 29695556 TI - Reduction of Potential Risk for Skin Toxicity in Megavoltage Radiotherapy Using a Novel Rigid Couch. AB - AIM: In this study, we clarified changes of the surface dose to a low-density material on a carbon couch and verified whether a novel rigid couch (HM couch) could reduce the surface dose. MATERIALS AND METHODS: We measured the surface dose using only a carbon couch (iBeam Couchtop STANDARD; BrainLab), a low-density material (Styrofoam board) on the carbon couch, and an HM couch for 6 and 10 MV photon beams. RESULTS: A 5-cm styrofoam board placed on the carbon couch reduced the surface dose by approximately 7-9%, while it had no impact on the depth dose profile; however, in use, such a thickness may cause collision of the patient with the gantry head. The HM couch reduced the surface dose by approximately 7-9% and shifted the depth dose profile by approximately 0.4 cm in the depth direction compared to the carbon couch. CONCLUSION: The HM couch has the potential to reduce skin toxicity and is expected to be useful in clinical practice instead of carbon couches. PMID- 29695557 TI - Effects of Medium Molecular Weight Heparinyl Arginine on Scorpion Venom-induced Pulmonary Edema in Rats. AB - BACKGROUND/AIM: The aim of this study was to examine the inhibitory action of medium molecular weight heparinyl amino acid derivatives (MHADs) on scorpion venom (SV)-induced acute pulmonary edema. MATERIALS AND METHODS: SV was injected into the tail vein of rats after MHAD pre-treatment. An hour later, lungs were removed from each experimental animal, followed by measurement of the lung/body index (LBI) and Na+/K+ ratio of the pulmonary tissue as indices for acute pulmonary edema. RESULTS: Medium molecular weight heparinyl arginine (MHR) administered rats exhibited significantly lower LBI and Na+/K+ ratios compared to control rats. Although the mechanism of inhibitory action of MHR on pulmonary edema is unclear, MHR inhibited the vascular permeability increase by SV because both LBI and Na+/K+ ratio of the pulmonary tissue remained at almost normal values. CONCLUSION: MHR may prevent scorpion venom-induced acute pulmonary edema and thus makes a good candidate for clinical use. PMID- 29695558 TI - In Vitro Antitumor Activity of Alkylaminoguaiazulenes. AB - BACKGROUND/AIM: Guaiazulene (1,4-dimethyl-7-isopropylazulene) is present in several essential oils of medicinal and aromatic plants. There exist few studies that investigated the anticancer activity of guaiazulenes. We investigated the relative cytotoxicity of 10 alkylaminoguaiazulene derivatives towards both cancer and normal cells. MATERIALS AND METHODS: Cytotoxicity towards four human oral squamous cell carcinoma (OSCC) cell lines and five types of human normal oral cells (gingival fibroblasts, periodontal ligament fibroblasts, pulp cells and keratinocytes, gingival epithelial progenitors) was determined by the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) method. Tumor specificity (TS) was evaluated as the ratio of the mean 50% cytotoxic concentration against normal oral cells to that against OSCC cell lines. Apoptosis-inducing activity was evaluated by cleavage of poly ADP-ribose polymerase and caspsase-3 with western blot analysis. RESULTS: Validity of the present TS measurement method was confirmed using methotrexate. With increasing length of the alkyl group of alkylaminoguaiazulene derivatives, cytotoxicity increased. Introduction of oxygen, nitrogen or sulfur atom into the alkyl group slightly reduced cytotoxicity. Most compounds had very low TS, no synergistic action with methotrexate and doxorubicin, nor did they induce apoptosis of OSCC cells. On the other hand, compound [10], containing a morpholino group, induced apoptosis of OSCC cells. CONCLUSION: The cytotoxicity of alkylaminoguaiazulenes is not always coupled with TS and apoptosis-inducing activity. PMID- 29695559 TI - Amentoflavone Inhibits ERK-modulated Tumor Progression in Hepatocellular Carcinoma In Vitro. AB - BACKGROUND/AIM: A previous study indicated that amentoflavone inhibits tumor growth of breast cancer. However, the anti-cancer effects and mechanism of amentoflavone in hepatocellular carcinoma (HCC) have not been elucidated. The aim of the present study was to verify the effect of amentoflavone on tumor progression in HCC. MATERIALS AND METHODS: HCC SK-Hep1 cells were treated with different concentrations of amentoflavone or 10 MUM PD98059 (extracellular signal regulated kinases (ERK) inhibitor) for 48 h, respectively, and then cell viability, NF-kappaB activation, levels of tumor progression-associated proteins, and cell invasion were evaluated with 3-(4,5-Dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT), NF-kappaB reporter gene assay, western blotting, and cell invasion assay. RESULTS: The results demonstrated that both amentoflavone and PD98059 not only significantly reduced cell viability, NF kappaB activation, and cell invasion, but also inhibited the expression of tumor progression-associated proteins. In addition, we found that amentoflavone suppresses ERK phosphorylation. CONCLUSION: The results of the present study suggest that amentoflavone down-regulates ERK-modulated tumor progression in HCC. PMID- 29695560 TI - Association of Pro-apoptotic Bad Gene Expression Changes with Benign Thyroid Nodules. AB - BACKGROUND/AIM: This study aimed to investigate the role of the mitochondrial apoptotic pathway in benign thyroid nodules. MATERIALS AND METHODS: Paired samples of nodular and normal tissues were collected from 26 patients with nodular goiters undergoing thyroidectomy. Variable expression of Bcl-2, Bax and Bad genes were evaluated by quantitative PCR. RESULTS: Expression level of Bad gene in nodules was found to be significantly decreased compared to normal tissues (p=0.049). A positive correlation was observed between nodule size and Bad expression levels (correlation coefficient=0.563, p=0.004); and this correlation was stronger in hot nodules (n=18, correlation coefficient=0.689, p=0.003). No significant difference was observed between nodular and normal tissue expressions of Bax and Bcl-2. CONCLUSION: These results suggest that Bad expression correlates with the size of benign thyroid nodules and also its relatively lower expression in nodules, warrant further investigation. PMID- 29695561 TI - Circulating microRNAs as Novel Biomarkers for Atherosclerosis. AB - BACKGROUND/AIM: In this study, we determined the expression of selected circulating microRNAs (miRNA) and their potential roles as biomarkers in patients with atherosclerosis and a control group. MATERIALS AND METHODS: In order to obtain insight into miRNA expression levels in atherosclerosis, we analyzed miRNA expression levels by real-time polymerase chain reaction (RT-PCR) in case (n=89) and healthy control (n=93) groups. Receiver operating characteristic curve analysis was performed to assess the diagnostic capability of miRNAs. RESULTS: miRNA221 and miRNA221 expression levels were significantly lower in patients than controls (p=0.011 and p=0.004, respectively). Receiver operator curve analysis demonstrated that expression levels of miRNA221 [area under curve (AUC)=0.623, p=0.0086) and miRNA222 (AUC=0.654, p=0.0006) were significantly different between groups. There were positive correlations between miRNA122a and triglyceride (p=0.046) and very-low-density lipoprotein (p=0.029) levels. CONCLUSION: miRNA221 and miRNA222 could be convenient biomarkers for diagnosis of atherosclerosis. PMID- 29695562 TI - Biodistribution, Pharmacokinetics and Efficacy of 188Re(I)-Tricarbonyl-Labeled Human Serum Albumin Microspheres in an Orthotopic Hepatoma Rat Model. AB - BACKGROUND/AIM: The biodistribution, pharmacokinetics and therapeutic evaluation of 188Re-human serum albumin microspheres (188Re-HSAM) by labeling with 188Re(I) tricarbonyl ion (188Re(OH2)3(CO)3)+) were investigated in a GP7TB orthotopic hepatoma rat model. MATERIALS AND METHODS: Male F344 rats received intrahepatic inoculations with GP7TB 1 mm3 cubes. The efficacy of 188Re-HSAM was examined following a single-dose treatment via the intraarterial route. Rats were monitored for survival until death. RESULTS: The labeling efficiency of the 188Re HSAM was about 80%. After intraarterial administration of 188Re-HSAM, radioactivity in tumors accumulated from 18.41+/-3.48 %ID/g at 1 h to 12.43+/ 4.70 %ID/g at 24 h. The tumor/liver ratios ranged from 3.03 at 1 h to 1.89 at 72 h. The major uptake organs of 188Re-HSAM were liver (73.35%ID to 48.92%ID), tumor (10.54%ID to 3.51%ID) and kidney (7.48 %ID to 0.14%ID). The T1/2lambdaz of 188Re HSAM was 259.34 h after intraarterial injection. The AUC(0->96 h) of 188Re-HSAM was 0.69 h*% ID/g. In the efficacy study, the median survival time for the rat (n=6), that received normal saline was 80 d. The median survival times for the mice treated with 10 mCi (n=4), 5.2 mCi (n=6) and 2.9 mCi (n=3) of 188Re-HSAM were 130 d (p=0.003), 106 d (p=0.002) and 83.5 d (p=0.617), respectively. The increase in life span of 10 mCi, 5.2 mCi and 2.9 mCi of 188Re-HSAM were 62.5%, 32.5% and 4.4%, respectively. CONCLUSION: Administration of 188Re-HSAM demonstrated better survival time and therapeutic efficacy at the higher dose in the GP7TB hepatoma model. These results suggested that intraarterial administration of 188Re-HSAM could provide a benefit and promising strategy for delivery of radiotherapeutics in oncology applications. PMID- 29695563 TI - Clinical Application of Bone Morphogenetic Protein-2 Microcarriers Fabricated by the Cryopolymerization of Gelatin Methacrylate for the Treatment of Radial Fracture in Two Dogs. AB - Bone morphogenetic protein-2 (BMP-2) effectively induces bone healing. However, the efficacy of BMP-2 relies heavily on its delivery vehicle because of its short half-life. We utilized a microcarrier fabricated by the cryopolymerization of gelatin methacrylate (cryoGelMA) infused with bone morphogenetic protein-2 (cryoGelMA-BMP-2) for the sustained and localized release of growth factors. Two dogs with radius and ulnar fractures were treated with implanted cryoGelMA-BMP-2 to accelerate bone healing. The cases were followed up for 6 months and 2 months after surgery, respectively. Distinctive healing processes were observed. The operated limb regained its premorbid function, the fracture line disappeared, and the gait was functionally stable. Implantation of cryoGelMA-BMP-2 resulted in the successful healing of bone fractures. PMID- 29695565 TI - Patient Height, Weight, BMI and Age as Predictors of Gracilis Muscle Free-Flap Mass in Lower Extremity Reconstruction. AB - BACKGROUND: Gracilis muscle flap is commonly used for the reconstruction of defects of the lower extremities. Preoperative evaluation of gracilis muscle dimension is a key aspect in surgical planning. This study aimed to determine whether patient height, weight, body mass index (BMI) and age are reliable proxy measurements of the mass of gracilis muscle flap. PATIENTS AND METHODS: Twenty two patients treated for lower extremity reconstruction with free gracilis flap between December 2010 and December 2014 were considered. The relationships between the mass of gracilis muscle and patient height, weight, BMI and age were assessed with Pearson's product moment correlation coefficient. Defect size, mass of gracilis muscle resected and surgical outcomes were also evaluated. RESULTS: There was a moderate correlation between the mass of the gracilis muscle and patient height (r=0.4), weight (r=0.4), and BMI (r=0.3), and moderate inverse correlation with age (r=-0.04). Lower extremities defects ranged in size from 3*4 cm (12 cm2) to 26*11 cm (286 cm2) with a mean of 81.6 cm2 All defects were reconstructed with the gracilis muscle, which required a resection ranging between 3 g and 105 g (mean=37.4 g) to adapt the flap to the recipient site. Complete flap loss was observed in one case. CONCLUSION: In our series, the mass of the gracilis muscle flap was predictable in relation to height, weight, BMI, and age, which can be considered reliable proxy measurements. This will contribute to adequate flap selection for microsurgical reconstruction of lower extremity defects. PMID- 29695564 TI - Diurnal Variation of Melatonin Concentration in the Cerebrospinal Fluid of Unanesthetized Microminipig. AB - BACKGROUND/AIM: The aim of this study was to develop a method for sequentially collecting cerebrospinal fluid (CSF) from an unanesthetized microminipig, which shares many physiological and anatomical similarities with humans, such as diurnality, and investigate the diurnal variation of melatonin concentration in the CSF. MATERIALS AND METHODS: A catheter was placed percutaneously into the subarachnoid space of an anesthetized animal, and the tip of the catheter was placed into the cisterna magna under X-ray. We then sequentially collected CSF at light-on and -off times from the unanesthetized animal for several weeks. After catheter placement, a period of one week or more was necessary to relieve the contamination of RBCs in the CSF. RESULTS: A higher melatonin level in the CSF was noted during lights-off time, and the level was higher than that in the serum. CONCLUSION: This model of sequential collection of CSF will contribute to research in brain functions. PMID- 29695566 TI - A Pathological Study Using 2014 WHO Criteria Reveals Poor Prognosis of Grade 3 Ovarian Endometrioid Carcinomas. AB - BACKGROUND/AIM: The purpose of this study was to compare the clinical behavior of several grades of endometrioid carcinoma (EC) compared to high-grade serous carcinoma (HGSC), based on World Health Organization 2014 criteria. MATERIALS AND METHODS: Clinicopathological features were compared between all grades of EC and HGSC, and between HGSC and either grade 1/2 or grade 3 EC. RESULTS: Sixty-five patients with EC and 214 with HGSC were identified. Among patients with EC, 56 displayed 1/2 EC and nine had grade 3 EC. The progression-free (PFS) and overall (OS) survival of patients with grade 1/2 EC were better than of those of patients with HGSC; however, PFS and OS did not statistically differ between patients with grade 3 EC and those with HGSC. Grade 1/2 EC, but not grade 3, was a better prognostic factor compared with HGSC. CONCLUSION: A grading system for EC would be beneficial for the accurate prognosis of ovarian cancer. PMID- 29695567 TI - Impact of Sarcopenia in Patients with Unresectable Locally Advanced Esophageal Cancer Receiving Chemoradiotherapy. AB - BACKGROUND: Esophageal cancer often involves direct invasion of adjacent organs and patient survival rates are low. Sarcopenia has been reported to be associated with a poor prognosis in several types of malignancies. However, the impact of sarcopenia on the long-term survival of patients with unresectable locally advanced esophageal cancer remains unclear. PATIENTS AND METHODS: A total of 48 patients undergoing definitive chemoradiotherapy at our Institution from October 2012 to December 2015 were enrolled; their data were compared according to patient skeletal muscle index (SMI): low SMI (sarcopenia group), n=34; normal SMI (non-sarcopenia group), n=14. RESULTS: There were no significant differences in the incidence of severe adverse events and dose reduction rate between the two groups. The incidence of nutritional support was significantly higher in the groups with sarcopenia than in the non-sarcopenia group (44.1% vs. 7.1%, p=0.077). Response rates were significantly lower in the sarcopenia group than in the non-sarcopenia group (43.8% vs. 78.6%, p=0.025). The overall survival rate in the group with sarcopenia was significantly lower than that in the non-sarcopenia group (3-year: 36.95% vs. 63.9%, p=0.018). CONCLUSION: Sarcopenia prior to treatment may worsen the long-term survival of patients with unresectable locally advanced esophageal cancer. Further well-designed prospective trials are needed to estimate whether adequate nutritional support has a favorable impact on therapeutic outcomes in this population. PMID- 29695568 TI - Meta-analysis of Robot-assisted Versus Laparoscopic Surgery for Rectal Cancer. AB - BACKGROUND/AIM: A meta-analysis was conducted to evaluate and compare the short- and long-term outcomes of robot-assisted (RAS) and conventional laparoscopic surgery (LAS) for rectal cancer. MATERIALS AND METHODS: We searched MEDLINE for relevant papers published between 2010 and December 2017 by using specific search terms. We analyzed outcomes over short- and long-term periods. RESULTS: We identified 23 papers reporting results that compared RAS for rectal cancer with LAS. Our meta-analysis included 4,348 patients with rectal cancer; 2,068 had undergone RAS, and 2,280 had undergone LAS. In the short- and long-term period, 27 and 7 outcome variables were examined, respectively. RAS for rectal cancer was significantly associated with a greater operative time and a lower conversion rate to open surgery in the short-term, and results in almost similar outcomes in the long-term, compared to LAS. CONCLUSION: RAS may be an acceptable surgical treatment option compared to LAS for rectal cancer. PMID- 29695569 TI - The Use of TissuGlu(r) Surgical Adhesive for Mastectomy With or Without Lymphonodectomy. AB - BACKGROUND/AIM: Using drains after breast surgery is a preventive, but invasive measure to reduce seroma formation. A polyurethane-based tissue adhesive (TissuGlu(r)) might facilitate drainage-free wound healing after mastectomy in a non-invasive manner. PATIENTS AND METHODS: Retrospectively, data from 84 patients (42 receiving TissuGlu(r), 42 receiving a drainage) who underwent mastectomy, were collected (90 days postoperative follow-up). Study endpoints were defined as the number of fluid-related postoperative clinical interventions, cumulative volume of postoperative wound fluid, duration of hospitalization and postoperative complications. RESULTS: In the entirety of postoperative interventions, no significant difference could be demonstrated (p=0.298). The drainage arm showed significantly less seroma aspirations (p=0.024) and complications (p=0.012). A significantly reduced length of hospitalization (p<0.001) and less cumulative wound secretion volume (p<0.001) appeared in the TissuGlu(r) group. CONCLUSION: The polyurethane-based tissue adhesive is a less invasive alternative to drain use in mastectomy. PMID- 29695570 TI - Predicting Survival After Whole-brain Irradiation for Cerebral Metastases in Patients with Cancer of the Bladder. AB - BACKGROUND/AIM: This study aimed to create a predictive tool for estimating the remaining lifespan of patients after whole-brain irradiation (WBI) for cerebral metastases from bladder cancer. PATIENTS AND METHODS: In 34 of these patients clinical parameters were analyzed for survival including age at start of WBI, gender, Karnofsky score, number of cerebral metastases and involvement of extra cranial sites of metastasis. RESULTS: Involvement of extra-cranial sites (14%) and Karnofsky score (9%) showed the greatest difference regarding 6-month survival and were considered for the tool. Points were assigned based on the following: no involvement of extra-cranial sites=1 point, involvement of extra cranial sites=0 points, Karnofsky score >=70=1 point, Karnofsky score <=60=0 points. Patients' scores were 0, 1 or 2 points with 6-month survival rates of 13%, 27% and 50%, respectively. CONCLUSION: Based on two clinical parameters, a tool was developed that may help estimate the lifespan of patients irradiated for cerebral metastases from bladder cancer. PMID- 29695571 TI - Heat Shock Protein 27 Expression in EUS-FNA Samples Can Predict Gemcitabine Sensitivity in Pancreatic Cancer. AB - BACKGROUND/AIM: Gemcitabine (GEM) sensitivity can help select the appropriate treatment for pancreatic cancer. We examined the association between HSP27 expression and GEM sensitivity. MATERIALS AND METHODS: A total of 19 patients with unresectable pancreatic cancer who underwent endoscopic ultrasonography guided fine needle aspiration (EUS-FNA) were enrolled and treated with GEM alone. We measured the expression of heat shock protein 27 (HSP27) and phosphorylated HSP27(p-HSP27) in EUS-FNA samples and evaluated the effects of GEM treatment. RESULTS: The rate of GEM resistance was significantly higher in patients who showed overexpression of p-HSP27 (p<0.05). When we set the cut-off p-HSP27 (Ser82) detection rate at 51.6%, the group with a detection rate of >51.6% showed a significantly lower survival rate, and GEM was administered for a shorter period of time (p<0.05). CONCLUSION: It was suggested that the HSP27 expression in EUS-FNA samples was useful for predicting GEM sensitivity. PMID- 29695572 TI - The Feasibility and Efficacy of Laparoscopic Extended Total Mesorectal Excision for Locally Advanced Lower Rectal Cancer. AB - BACKGROUND/AIM: Extended total mesorectal excision (ETME) is defined as en bloc resection of the adjacent organs outside the mesorectal fascia, that is indicated in cases with locally advanced lower rectal cancer (T4 tumor). The aim of this study was to evaluate the clinical and oncological outcomes of laparoscopic ETME (L-ETME) for locally advanced lower rectal cancer. PATIENTS AND METHODS: The present study analyzed clinical outcomes and oncological outcomes of 11 consecutive patients who underwent L-ETME for cT4 lower rectal cancer in Nagasaki Medical Center between 2012 and 2015. RESULTS: Of the 11 patients, 7 underwent neoadjuvant therapy, and 7 underwent pelvic node dissection. One case (7.1%) underwent resection of anterior organs (prostate), 6 cases (54.5%) had resection of the lateral organs (neurovascular bundle, hypogastric nerve, pelvic plexus, ovary, and internal iliac blood vessels) and 4 cases (36.4%) had resection of both anterior and lateral organs. In all cases enrolled in this study, R0 resection was achieved. The median operation time and intraoperative blood loss were 416 min and 350 ml, respectively. The postoperative complication rate was 18.2% (2/11). The 3-year overall survival rate was 79.5%, and the 3-year local recurrence-free survival rate was 87.5%. There was no mortality and no re operation in this series. CONCLUSION: The results of the present study suggest that L-ETME is feasible and has efficacy for locally advanced lower rectal cancer. PMID- 29695573 TI - Fat-forming Solitary Fibrous Tumor of the Kidney - A Case Report and Literature Review. AB - Fat-forming solitary fibrous tumors arising from the kidney are extremely rare, with only few cases reported so far. We report the case of a 49-year-old patient investigated for lumbar pain and diagnosed preoperatively with a large retroperitoneal tumor destroying the right kidney. The patient was submitted to surgery, the tumor being resected en bloc with right nephrectomy. The histopathological studies demonstrated the presence of a hemangiopericytoma-like tumor with adipocytary component; the immunohistochemical studies demonstrated the presence of cluster of differentiation 34 (CD34), while human melanoma black (HMB45) staining was negative. Therefore, the diagnostic of fat-forming solitary fibrous tumor of the kidney was established. The postoperative outcome was uneventful, the patient being discharged on the sixth postoperative day. In conclusion, although fat-forming solitary fibrous tumor of the kidney is a very rare entity, this diagnosis should be taken into consideration whenever a large retroperitoneal mass with high adipose content and renal invasion is described at the preoperative studies. PMID- 29695574 TI - Biweekly Gemcitabine/Nab-Paclitaxel as First-line Treatment for Advanced Pancreatic Cancer. AB - BACKGROUND/AIM: During recent years, a survival advantage was reported for first line treatment of advanced pancreatic cancer with two new regimens, FOLFIRINOX and gemcitabine/nab-paclitaxel, over gemcitabine monotherapy. Gemcitabine/nab paclitaxel administration on days 1, 8 and 15 of a 4-week cycle is associated with some practical disadvantages. We adopted a biweekly regimen with the same dose density. PATIENTS AND METHODS: Patients with Eastern Cooperative Oncology Group performance status 0-2 diagnosed with advanced histologically or cytologically confirmed pancreatic cancer and no prior treatment were included in the study. Study combination included 1.5 g/m2 gemcitabine and 175 mg/m2 nab paclitaxel given every 2 weeks. Survival analysis was performed using the Kaplan Meier method. RESULTS: Forty-six patients were treated with this regimen. Adverse events were similar to those of the original regimen. Median progression-free and overall survival were 5 and 10 months, respectively. CONCLUSION: Biweekly gemcitabine/nab-paclitaxel seems to have a similar safety and efficacy profile as the original regimen. PMID- 29695575 TI - Laparoscopic Left Hepatectomy for Ruptured Hepatocellular Carcinoma Controlled After Transcatheter Arterial Embolization: Case Report and Review of the Literature. AB - BACKGROUND: Although spontaneous tumour rupture is a life-threatening complication of hepatocellular carcinoma (HCC), staged hepatectomy for HCC controlled after transcatheter arterial embolization (TAE) could provide a better prognosis. Laparoscopic liver resection (LLR) has been accepted worldwide and has been expanded from minor resection to anatomical major resection. We herein report the first case of pure laparoscopic left hepatectomy for ruptured HCC controlled after TAE. CASE REPORT: A 66-year-old man was transferred to our Institute because of abdominal pain and decreased consciousness. Ruptured HCC in segment IV and massive intra-abdominal haemorrhage were diagnosed. Emergency TAE was performed, achieving haemostasis. Reduction of intra-abdominal haemorrhage was confirmed at the 3-month follow-up, and no intrahepatic metastasis or peritoneal dissemination was present. Therefore, we performed elective laparoscopic left hepatectomy for the remaining HCC 110 days after TAE. Although dense adhesion was found in the upper right peritoneal cavity and greater omentum enveloping the remaining haemorrhage on the underside of the liver, there was no disseminated involvement in the peritoneal cavity. The operative time was 194 minutes, and intraoperative blood loss was 100 g. The postoperative course was uneventful, and the patient was discharged on postoperative day 6. CONCLUSION: Major LLR may be an option for staged hepatectomy in patients with ruptured HCC controlled after TAE. PMID- 29695576 TI - Systemic Immune-inflammation Index Predicts Survival of Patients After Curative Resection for Non-small Cell Lung Cancer. AB - BACKGROUND: The systemic immune-inflammation index (SII) is reported to be associated with clinical outcomes and has been proven to be a promising prognostic indicator in several solid tumor types. To the best of our knowledge, however, no studies regarding SII in patients with resectable non-small cell lung cancer (NSCLC) are available. MATERIALS AND METHODS: Three hundred forty-one patients with NSCLC who underwent surgery at our Institution between 2008 and 2012 were included. The SII was calculated using the formula: platelet count * neutrophil/lymphocyte count. The optimal cut-off value was calculated using the Cutoff Finder (http://molpath.charite.de/cutoff). Univariate and multivariate analyses were calculated by the Cox proportional hazards regression model. RESULTS: The optimal cut-off value was 471.2*109/l for SII. A low SII was associated with female gender, never smoking status, adenocarcinoma histology, higher pathological TNM stage and low level of serum C-reactive protein, but not age, serum carcinoembryonic antigen or cytokeratin 19 fragment level. Patients of the low SII group had a significantly better 5-year overall survival than those with high SII (83.61% vs. 60.39%, p<0.001). Multivariate analysis revealed that the SII was a significant independent predictive indicator for cancer-specific survival (p=0.007). CONCLUSION: This is the first study to demonstrate that the SII could represent an independent prognostic factor for patients with resectable NSCLC. PMID- 29695577 TI - Clinical Significance of the Neutrophil-to-Lymphocyte Ratio in Endocrine Therapy for Stage IV Breast Cancer. AB - BACKGROUND: Studies have found that patients with cancer exhibit abnormal leukocyte fractions, such as elevated neutrophil count and diminished lymphocyte count, and that the neutrophil-to-lymphocyte ratio (NLR) provides a surrogate marker for prognosis and response to treatment of patients after radical surgery for several different types of cancer. However, few reports have addressed the association between the NLR and response to endocrine therapy. In this study, we carried out a clinical investigation to confirm whether or not the NLR predicted the response to endocrine therapy of stage IV breast cancer. PATIENTS AND METHODS: The study subjects were 34 patients who underwent endocrine therapy as initial drug therapy for stage IV breast cancer. The correlation between NLR and prognosis, including the efficacy of endocrine therapy, was evaluated retrospectively. RESULTS: Among the 34 patients, the NLR was high in 10 (29.4%) and low in 24 (70.6%). In analysis of outcomes, the group with low NLR had a significant prolongation of progression-free survival (p=0.003), time to treatment failure (p=0.031), and overall survival (p=0.013) compared to the group with high NLR. Univariate analysis of progression-free survival found that responding to treatment [hazard ratio (HR)=4.310, p=0.004] and low NLR (HR=3.940, p=0.016) were factors associated with a favorable prognosis. Multivariate analysis also showed that responding to treatment (HR=4.329, p=0.006) and low NLR (HR=3.930, p=0.008) were independent factors associated with a favorable prognosis. CONCLUSION: Our results suggested that the NLR may represent a predictive marker for response to endocrine therapy in stage IV breast cancer. PMID- 29695578 TI - cDNA Microarray Analysis and Influx Transporter OATP1B1 in Liver Cells After Exposure to Gadoxetate Disodium, a Gadolinium-based Contrast Agent in MRI Liver Imaging. AB - BACKGROUND/AIM: Gadoxetate disodium (Primovist or Eovist) is extensively used as a hepatospecific contrast agent during magnetic resonance imaging (MRI) examinations. However, there is no information determining whether gadoxetate disodium has a cytotoxic impact and/or affects relative gene expression on liver cells. In the current study, we investigated the effects of gadoxetate disodium on cytotoxicity and the levels of gene expression in human normal Chang Liver cells. MATERIALS AND METHODS: The cytotoxic effect was detected via methyl thiazolyl tetrazolium (MTT) assay and 4',6-diamidino-2-phenylindole (DAPI) staining. mRNA expression was monitored by cDNA microarray and quantitative PCR (qPCR) analysis. The protein levels were determined by western blotting. RESULTS: Gadoxetate disodium at 5 and 10 mM failed to induce any cell cytotoxicity and morphological changes in Chang Liver cells. Our data demonstrated that gadoxetate disodium significantly enhanced the expression of 29 genes and suppressed that of 27. The SLCO1C1 (solute carrier organic anion transporter family member 1C1) mRNA expression was also increased by 2.62-fold (p-value=0.0006) in gadoxetate disodium-treated cells. Furthermore, we also checked and found that gadoxetate disodium up-regulated organic anion transporter polypeptide 1B1 (OATP1B1) protein level and increased OATP uptake transporter gene SLCO1C1 mRNA expression. CONCLUSION: Our results provide evidence regarding that gadoxetate disodium might be no cytotoxic effects on liver cells. PMID- 29695580 TI - Clinical Implications of Transbronchial Biopsy for Surgically-resected Non-small Cell Lung Cancer. AB - BACKGROUND/AIM: Lung biopsies might cause metastasis and/or dissemination. The aim of this study was to review our institutional experience and analyze the outcomes of resection for non-small cell lung cancer (NSCLC), in patients who had received preoperative transbronchial biopsy using fiberoptic bronchoscopy with fluoroscopic imaging (BFS). PATIENTS AND METHODS: The medical records of consecutive patients between 2010 and 2015 were retrospectively reviewed. Patients were divided into two groups (BFS and Non-BFS). Overall survival (OS) curves and recurrence-free survival (RFS) curves were plotted using the Kaplan Meier method. Cox regression analyses were used to evaluate the hazard ratio (HR) with the endpoint OS or RFS. RESULTS: We studied the medical records of 531 patients. The 5-year OS rate was 91.8% and 79.8%, in the BFS group and in the Non BFS group, respectively (p<0.001). BFS was an independent factor associated with RFS HR=2.164 (95%CI=1.399-2.346). CONCLUSION: Preoperative BFS is a prognostic factor in patients receiving surgery for NSCLC. PMID- 29695579 TI - Superficial Spreading-type Gastric Cancer with Situs Inversus Totalis. AB - Situs inversus totalis (SIT) is a congenital anomaly characterized by a complete mirror-image transposition of the thoracic and abdominal viscera. We report on a rare case of superficial spreading gastric cancer associated with SIT in a 66 year-old woman referred to our hospital for examination of gastric cancer initially diagnosed by medical check-up. Esophagogastroduodenoscopy showed a slightly depressed lesion in the lesser curvature side of the stomach. Abdominal contrast-enhanced computed tomography showed complete transposition of the abdominal viscera, confirming SIT. The patient underwent total gastrectomy with regional lymph node dissection and Roux-en-Y reconstruction. Gross examination of the surgically resected specimen showed a slightly depressed lesion measuring 12*8 cm in diameter, and histopathology confirmed the diagnosis of signet-ring cell carcinoma, confined to the gastric mucosal layer without lymph node metastasis. The postoperative course was favorable, and the patient has been well without evidence of recurrence for 11 years following the operation. To the best of our knowledge, this is only the second case of a superficial spreading-type gastric cancer in a patient with SIT reported in the English literature. PMID- 29695581 TI - Celiac Trunk Stenosis Treated by Resection and Splenic Patch Reconstruction - A Case Report and Literature Review. AB - Celiac trunk stenosis is a relatively common finding; the most common causes of this obstruction are median arcuate ligament syndrome, pancreatitis, local invasion of various malignancies originating from the pancreatic body, atherosclerosis or it can be idiopathic. However, most such cases remain asymptomatic for a long period of time, especially due to the presence of a patent collateral circulation originating from the superior mesenteric artery. In certain cases, the patient might become symptomatic, diffuse post-prandial pain being reported. We present the case of a 51-year-old patient diagnosed with celiac axis stenosis who was initially submitted to surgery with the preoperative suspicion of median arcuate ligament syndrome; however, the patient reported the persistence of the abdominal symptoms, leading to suspicion of idiopathic celiac axis stenosis. The patient underwent reoperation, the celiac trunk stenosis being resected, and the continuity of the vascular axis being established using a splenic artery patch. The postoperative course was uneventful, the patient presenting an adequate hepatic blood flow in the first day postoperatively. PMID- 29695582 TI - Surgical Management of a Giant Pheochromocytoma. AB - Pheochromocytomas are rare tumors arising from chromaffin cells of the adrenal medulla and extramedullary sympathetic ganglia. The incidence of asymptomatic disease is rising due to increased detection rates from widespread use of computed tomography. We describe a case of one of the largest documented pheochromocytomas resected in the United States, an 18-cm tumor in a patient who presented with exertional dyspnea, abdominal pain, constipation, weight loss, and intermittent hypertension. After biochemical and appropriate imaging workup, the patient underwent an open resection of the mass. PMID- 29695584 TI - Copper Deficiency Anemia and Neutropenia Due to Ketogenic Diet. AB - Copper deficiency is an uncommon cause of hematologic abnormalities in children that is often overlooked or misdiagnosed. Although cases have been reported because of malabsorption syndromes or after gastrointestinal surgeries, we report a case of copper deficiency-associated anemia and neutropenia in a child because of dietary restrictions, specifically, transitioning from a formula-based ketogenic diet to a pureed food-based ketogenic diet. On copper supplementation, the patient's anemia and neutropenia resolved. To our knowledge, this report is the first revealing copper deficiency anemia and neutropenia developing because of a ketogenic diet. PMID- 29695583 TI - Relevance of Abusive Head Trauma to Intracranial Hemorrhages and Bleeding Disorders. AB - BACKGROUND: Bleeding disorders and abusive head trauma (AHT) are associated with intracranial hemorrhage (ICH), including subdural hemorrhage (SDH). Because both conditions often present in young children, the need to screen for bleeding disorders would be better informed by data that include trauma history and are specific to young children. The Universal Data Collection database contains information on ICH in subjects with bleeding disorders, including age and trauma history. Study objectives were to (1) characterize the prevalence and calculate the probabilities of any ICH, traumatic ICH, and nontraumatic ICH in children with congenital bleeding disorders; (2) characterize the prevalence of spontaneous SDH on the basis of bleeding disorder; and (3) identify cases of von Willebrand disease (vWD) that mimic AHT. METHODS: We reviewed subjects <4 years of age in the Universal Data Collection database. ICH was categorized on the basis of association with trauma. Prevalence and probability of types of ICH were calculated for each bleeding disorder. RESULTS: Of 3717 subjects, 255 (6.9%) had any ICH and 206 (5.5%) had nontraumatic ICH. The highest prevalence of ICH was in severe hemophilia A (9.1%) and B (10.7%). Of the 1233 subjects <2 years of age in which the specific location of any ICH was known, 13 (1.1%) had spontaneous SDH (12 with severe hemophilia; 1 with type 1 vWD). The findings in the subject with vWD were not congruent with AHT. CONCLUSIONS: In congenital bleeding disorders, nontraumatic ICH occurs most commonly in severe hemophilia. In this study, vWD is not supported as a "mimic" of AHT. PMID- 29695585 TI - Mortality After Pediatric Arterial Ischemic Stroke. AB - OBJECTIVES: Cerebrovascular disease is among the top 10 causes of death in US children, but risk factors for mortality are poorly understood. Within an international registry, we identify predictors of in-hospital mortality after pediatric arterial ischemic stroke (AIS). METHODS: Neonates (0-28 days) and children (29 days-<19 years) with AIS were enrolled from January 2003 to July 2014 in a multinational stroke registry. Death during hospitalization and cause of death were ascertained from medical records. Logistic regression was used to analyze associations between risk factors and in-hospital mortality. RESULTS: Fourteen of 915 neonates (1.5%) and 70 of 2273 children (3.1%) died during hospitalization. Of 48 cases with reported causes of death, 31 (64.6%) were stroke-related, with remaining deaths attributed to medical disease. In multivariable analysis, congenital heart disease (odds ratio [OR]: 3.88; 95% confidence interval [CI]: 1.23-12.29; P = .021), posterior plus anterior circulation stroke (OR: 5.36; 95% CI: 1.70-16.85; P = .004), and stroke presentation without seizures (OR: 3.95; 95% CI: 1.26-12.37; P = .019) were associated with in-hospital mortality for neonates. Hispanic ethnicity (OR: 3.12; 95% CI: 1.56-6.24; P = .001), congenital heart disease (OR: 3.14; 95% CI: 1.75 5.61; P < .001), and posterior plus anterior circulation stroke (OR: 2.71; 95% CI: 1.40-5.25; P = .003) were associated with in-hospital mortality for children. CONCLUSIONS: In-hospital mortality occurred in 2.6% of pediatric AIS cases. Most deaths were attributable to stroke. Risk factors for in-hospital mortality included congenital heart disease and posterior plus anterior circulation stroke. Presentation without seizures and Hispanic ethnicity were also associated with mortality for neonates and children, respectively. Awareness and study of risk factors for mortality represent opportunities to increase survival. PMID- 29695586 TI - GREB1 isoforms regulate proliferation independent of ERalpha co-regulator activities in breast cancer. AB - Activation of the transcription factor estrogen receptor alpha (ERalpha) and the subsequent regulation of estrogen-responsive genes play a crucial role in the development and progression of the majority of breast cancers. One gene target of ERalpha, growth regulation by estrogen in breast cancer 1 (GREB1), is associated with proliferation and regulation of ERalpha activity in estrogen-responsive breast cancer cells. The GREB1 gene encodes three distinct isoforms: GREB1a, GREB1b and GREB1c, whose molecular functions are largely unknown. Here, we investigate the role of these isoforms in regulation of ERalpha activity and proliferation. Interaction between GREB1 and ERalpha was mapped to the amino terminus shared by all GREB1 variants. Analysis of isoform-specific regulation of ERalpha activity suggests none of the GREB1 isoforms possess potent co-regulator activity. Exogenous expression of GREB1a resulted in elevated expression of some ER-target genes, independent of ERalpha activity. Despite this slight specificity of GREB1a for gene regulation, exogenous expression of either GREB1a or GREB1b resulted in decreased proliferation in both ER-positive and ER-negative breast carcinoma cell lines, demonstrating an ER-independent function of GREB1. Interestingly, we show an increase in the expression of GREB1b and GREB1c mRNA in malignant breast tissue compared to normal patient samples, suggesting a selective preference for these isoforms during malignant transformation. Together, these data suggest GREB1a has an isoform-specific function as a transcriptional regulator while all isoforms share an ER-independent activity that regulates proliferation. PMID- 29695587 TI - Reproducibility crisis in science or unrealistic expectations? PMID- 29695588 TI - Mindin deficiency in macrophages protects against foam cell formation and atherosclerosis by targeting LXR-beta. AB - Mindin, which is a highly conserved extracellular matrix protein, has been documented to play pivotal roles in regulating angiogenesis, inflammatory processes, and immune responses. The aim of the present study was to assess whether mindin contributes to the development of atherosclerosis. A significant up-regulation of Mindin expression was observed in the serum, arteries and atheromatous plaques of ApoE-/- mice after high-fat diet treatment. Mindin-/-ApoE /- mice and macrophage-specific mindin overexpression in ApoE-/- mice (Lyz2 mindin-TG) were generated to evaluate the effect of mindin on the development of atherosclerosis. The Mindin-/-ApoE-/- mice exhibited significantly ameliorated atherosclerotic burdens in the entire aorta and aortic root and increased atherosclerotic plaque stability. Moreover, bone marrow transplantation further demonstrated that mindin deficiency in macrophages was largely responsible for the alleviated atherogenesis. The Lyz2-mindin-TG mice exhibited the opposite phenotype. Mindin deficiency enhanced foam cell formation by increasing the expression of cholesterol effectors, including ABCA1 and ABCG1. The mechanistic study indicated that mindin ablation promoted LXR-beta expression via a direct interaction. Importantly, LXR-beta inhibition largely reversed the ameliorating effect of mindin deficiency on foam cell formation and ABCA1 and ABCG1 expression. The present study demonstrated that mindin deficiency serves as a novel mediator that protects against foam cell formation and atherosclerosis by directly interacting with LXR-beta. PMID- 29695589 TI - ABBY: A phase 2 randomized trial of crenezumab in mild to moderate Alzheimer disease. AB - OBJECTIVE: To evaluate the safety and efficacy of crenezumab in patients with mild to moderate Alzheimer disease (AD). METHODS: In this phase 2 trial, 431 patients with mild to moderate AD 50 to 80 years of age were randomized 2:1 (crenezumab:placebo). Patients received low-dose subcutaneous crenezumab 300 mg or placebo every 2 weeks (n = 184) or high-dose intravenous crenezumab 15 mg/kg or placebo every 4 weeks (n = 247) for 68 weeks. Primary outcome measures were change in Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog12) and Clinical Dementia Rating-Sum of Boxes scores from baseline to week 73. RESULTS: The primary and secondary endpoints were not met. In an exploratory post hoc analysis, a reduction in decline on the ADAS-Cog12 was observed in the high dose group. Separation from the placebo group on the ADAS-Cog12 was greatest in the milder subsets of AD patients and reached statistical significance in the group with Mini-Mental State Examination scores of 22 to 26. In both groups, there was a significant increase in CSF beta-amyloid1-42 levels that correlated with crenezumab CSF levels. The overall rate of adverse events was balanced between groups. One case of amyloid-related imaging abnormalities indicative of vasogenic edema or effusions was reported. CONCLUSIONS: Although prespecified criteria for testing treatment effects were not met, these data suggest a potential treatment effect in patients with mild AD treated with high-dose crenezumab. Together with the safety profile for crenezumab, these data support the exploration of crenezumab treatment at even higher doses in patients with early AD. CLINICALTRIALSGOV IDENTIFIER: NCT 01343966. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, for people with AD, crenezumab does not significantly improve cognition or function at 18 months. The study is rated Class II because <80% of enrolled patients completed the study. PMID- 29695590 TI - Effectiveness of opicapone and switching from entacapone in fluctuating Parkinson disease. AB - OBJECTIVE: To evaluate the effectiveness of opicapone as add-on to levodopa and the effects of switching from entacapone over 1 year of treatment in patients with fluctuating Parkinson disease. METHODS: After completion of a placebo- and entacapone-controlled double-blind study of opicapone (5, 25, or 50 mg), 495 patients continued to a 1-year extension phase in which patients were treated with opicapone. Patients began with once-daily opicapone 25 mg for 1 week, followed by individually tailored levodopa and/or opicapone dose adjustments. The primary efficacy variable was the change from baseline in absolute "off" time based on patient diaries. Other outcomes included proportion of responders, scale based assessments, and standard safety assessments. RESULTS: One year of treatment with opicapone reduced "off" time by a half-hour (33.8 minutes) vs the open-label baseline and >2 hours (126.9 minutes) vs the double-blind baseline. Whereas patients who were originally treated with opicapone 50 mg in the double blind phase maintained their efficacy, switching treatments led to further decreases in "off" time (-64.9, -39.3, -27.5, and -23.0 minutes for switching from placebo, entacapone, and opicapone 5 and 25 mg, respectively). Dyskinesia was the most frequently reported adverse event (14.5%) and was managed by adjustment of dopaminergic therapy. No new safety concerns were observed with long-term opicapone administration. CONCLUSION: Long-term use of opicapone provided sustained efficacy over 1 year. Switching from entacapone to opicapone led to enhanced efficacy under the conditions of the study. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with Parkinson disease and end-of-dose motor fluctuations, long-term use (52 weeks) of opicapone is well tolerated and reduces "off" time. PMID- 29695591 TI - Anatomo-functional basis of restless legs syndrome. PMID- 29695593 TI - Longitudinal decline in structural networks predicts dementia in cerebral small vessel disease. AB - OBJECTIVE: To determine whether longitudinal change in white matter structural network integrity predicts dementia and future cognitive decline in cerebral small vessel disease (SVD). To investigate whether network disruption has a causal role in cognitive decline and mediates the association between conventional MRI markers of SVD with both cognitive decline and dementia. METHODS: In the prospective longitudinal SCANS (St George's Cognition and Neuroimaging in Stroke) Study, 97 dementia-free individuals with symptomatic lacunar stroke were followed with annual MRI for 3 years and annual cognitive assessment for 5 years. Conversion to dementia was recorded. Structural networks were constructed from diffusion tractography using a longitudinal registration pipeline, and network global efficiency was calculated. Linear mixed-effects regression was used to assess change over time. RESULTS: Seventeen individuals (17.5%) converted to dementia, and significant decline in global cognition occurred (p = 0.0016). Structural network measures declined over the 3-year MRI follow-up, but the degree of change varied markedly between individuals. The degree of reductions in network global efficiency was associated with conversion to dementia (B = -2.35, odds ratio = 0.095, p = 0.00056). Change in network global efficiency mediated much of the association of conventional MRI markers of SVD with cognitive decline and progression to dementia. CONCLUSIONS: Network disruption has a central role in the pathogenesis of cognitive decline and dementia in SVD. It may be a useful disease marker to identify that subgroup of patients with SVD who progress to dementia. PMID- 29695594 TI - Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: The MIRROR study. AB - OBJECTIVE: To assess dose-response effects of the anti-CD20 monoclonal antibody ofatumumab on efficacy and safety outcomes in a phase 2b double-blind study of relapsing forms of multiple sclerosis (RMS). METHODS: Patients (n = 232) were randomized to ofatumumab 3, 30, or 60 mg every 12 weeks, ofatumumab 60 mg every 4 weeks, or placebo for a 24-week treatment period, with a primary endpoint of cumulative number of new gadolinium-enhancing lesions (per brain MRI) at week 12. Relapses and safety/tolerability were assessed, and CD19+ peripheral blood B lymphocyte counts measured. Safety monitoring continued weeks 24 to 48 with subsequent individualized follow-up evaluating B-cell repletion. RESULTS: The cumulative number of new lesions was reduced by 65% for all ofatumumab dose groups vs placebo (p < 0.001). Post hoc analysis (excluding weeks 1-4) estimated a >=90% lesion reduction vs placebo (week 12) for all cumulative ofatumumab doses >=30 mg/12 wk. Dose-dependent CD19 B-cell depletion was observed. Notably, complete depletion was not necessary for a robust treatment effect. The most common adverse event was injection-related reactions (52% ofatumumab, 15% placebo), mild to moderate severity in 97%, most commonly associated with the first dose and diminishing on subsequent dosing. CONCLUSION: Imaging showed that all subcutaneous ofatumumab doses demonstrated efficacy (most robust: cumulative doses >=30 mg/12 wk), with a safety profile consistent with existing ofatumumab data. This treatment effect also occurred with dosage regimens that only partially depleted circulating B cells. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for patients with RMS, ofatumumab decreases the number of new MRI gadolinium-enhancing lesions 12 weeks after treatment initiation. PMID- 29695595 TI - Transient swelling in the globus pallidus and substantia nigra in childhood suggests SENDA/BPAN. PMID- 29695592 TI - Clinical spectrum and prognostic value of CNS MOG autoimmunity in adults: The MOGADOR study. AB - OBJECTIVE: To describe clinical and radiologic features associated with myelin oligodendrocyte glycoprotein antibodies (MOG-Ab) in a large French nationwide adult cohort, to assess baseline prognostic features of MOG-Ab-associated diseases after a first acute demyelinating syndrome, and to evaluate the clinical value of MOG-Ab longitudinal analysis. METHODS: Clinical data were obtained from 197 MOG-Ab-positive patients >=18 years of age. Complete imaging data were available in 108, and 54 serum samples were eligible for longitudinal evaluation. For survival analysis comparison, 169 aquaporin-4 antibody (AQP4-Ab)-positive patients from the NOMADMUS database were included. RESULTS: Median age at onset was 36.46 (range 18.0-76.8) years, and patients were predominantly white (92.9%) with male:female ratio, 1.1. Clinical phenotype at onset included optic neuritis or myelitis in 90.86%, isolated brainstem or encephalopathy syndromes in 6.6%, and a combination of syndromes in 2.5%. Distinctive brain MRI findings in MOG-Ab positive patients were thalamic and pontine lesions. Cortical and leptomeningeal lesions were found in 16.3% and 6.1%, respectively. The probability of reaching a first relapse after 2 and 5 years was 44.8% and 61.8%, respectively. MOG-Ab positive patients were at lower risk at presentation of further clinical relapse (hazard ratio [HR] 0.45, 95% confidence interval [CI] 0.26-0.79) compared to AQP4 Ab-positive individuals. MOG-Ab-positive individuals had a lower risk of reaching Disability Status Scale score of 3.0 (HR 0.46, 95% CI 0.22-0.94) and visual acuity of 20/100 (HR 0.23, 95% CI 0.07-0.72). Finally, MOG-Ab titers were higher at relapse than in remission (p = 0.009). CONCLUSION: In adults, MOG-Ab associated disease extends beyond clinical and radiologic abnormalities in the optic nerve and spinal cord. Despite the relapsing course, the overall visual and motor outcome is better compared with AQP4-Ab-positive patients. PMID- 29695597 TI - Involvement of the central somatosensory system in restless legs syndrome: A neuroimaging study. AB - OBJECTIVE: To investigate morphologic changes in the somatosensory cortex and the thickness of the corpus callosum subdivisions that provide interhemispheric connections between the 2 somatosensory cortical areas. METHODS: Twenty-eight patients with severe restless legs syndrome (RLS) symptoms and 51 age-matched healthy controls were examined with high-resolution MRI at 3.0 tesla. The vertex wise analysis in conjunction with a novel cortical surface classification method was performed to assess the cortical thickness across the whole-brain structures. In addition, the thickness of the midbody of the corpus callosum that links postcentral gyri in the 2 hemispheres was measured. RESULTS: We demonstrated that a morphologic change occurred in the brain somatosensory system in patients with RLS compared to controls. Patients with RLS exhibited a 7.5% decrease in average cortical thickness in the bilateral postcentral gyrus (p < 0.0001). Accordingly, there was a substantial decrease in the corpus callosum posterior midbody (p < 0.008) wherein the callosal fibers are connected to the postcentral gyrus, suggesting altered white matter properties in the somatosensory pathway. CONCLUSION: Our results provide in vivo evidence of morphologic changes in the primary somatosensory system, which could be responsible for the sensory functional symptoms of RLS. These results provide a better understanding of the pathophysiology underlying the RLS sensory symptoms and could lead to a potential imaging marker for RLS. PMID- 29695596 TI - Amyloid deposition and brain structure as long-term predictors of MCI, dementia, and mortality. AB - OBJECTIVES: To test the hypothesis that brain structural integrity (i.e., hippocampal [HIP] volume), white matter lesions (WMLs), and beta-amyloid deposition are associated with long-term increased risk of incident dementia and mortality in 183 cognitively normal individuals and patients with mild cognitive impairment (MCI) aged 80 years and older. METHODS: All participants had a brain structural MRI scan and PET scan with 11C-labeled Pittsburgh compound B in 2009 and were reexamined yearly through 2015 (mean follow-up time 5.2 +/- 1.3 years). RESULTS: In the last evaluation through 2010-2015, 56 (31%) participants were cognitively normal, 67 (37%) had MCI, and 60 (33%) had dementia. Fifty-seven (31%) died during follow-up, and 20 (35%) developed dementia before their death. All 3 biomarkers were independent predictors of incident dementia in all participants. After adjusting for the risk of dying, amyloid deposition and WMLs remained strong predictors. Of the 60 participants with incident dementia, 54 (90%) had at least one imaging abnormality. Participants with no biomarker positivity had a very low risk of dementia (16%), while 75% of the participants with the 3 biomarkers progressed to dementia. HIP volume and beta-amyloid deposition were associated with death only in participants with MCI. CONCLUSIONS: This study showed the presence of more than one biomarker was a stronger long term predictor of incident dementia than any biomarker alone. After adjusting for the risk of dying, amyloid deposition and WMLs were stronger predictors of dementia than HIP volume. The risk of dying during follow-up was associated with both neurodegeneration and amyloid deposition, especially in individuals with MCI. PMID- 29695598 TI - Preapproval and postapproval evidence on drugs for multiple sclerosis. AB - OBJECTIVE: To review the evidence supporting the European Union marketing authorization of drugs for multiple sclerosis (MS) and assess how far postmarketing research addresses information gaps at the time of approval. METHODS: Through its database, we identified drugs approved by the European Medicines Agency and gathered data on pivotal trials from the European Public Assessment Reports and corresponding publications. We searched Medline, Embase, Cochrane Library, and trial registries for postmarketing randomized controlled trials testing the drugs identified in any form of the disease. RESULTS: Since approval of interferon and glatiramer up to 2017, the Agency has examined 10 drugs for the treatment of MS, and 8 were included in this study: alemtuzumab, daclizumab, dimethyl fumarate, fampridine, fingolimod, peginterferon-beta-1a, natalizumab, and teriflunomide. We analyzed 16 pivotal trials enrolling almost 16,000 participants. Eleven compared new drugs to placebo, 5 to interferon-beta 1a. Annualized relapse rate was the primary outcome in two-thirds and coprimary with disability progression in the 2 studies of alemtuzumab. Of the 52 postmarketing trials, 24 reported final results and 28 were ongoing, terminated, or completed but no results were available. None directly compared the approved drugs, thus leaving their respective therapeutic values unknown. Data on the prevention of disease progression were scarce: none of the disease-modifying drugs showed any effect on disability progression. CONCLUSION: The lack of comparative evidence and data on clinical effectiveness hamper the assessment of therapeutic value and place in therapy of drugs approved for MS. PMID- 29695599 TI - Time to separate MOG-Ab-associated disease from AQP4-Ab-positive neuromyelitis optica spectrum disorder. PMID- 29695600 TI - Brain pathology is related to total daily physical activity in older adults. AB - OBJECTIVE: To test the hypothesis that brain pathology is associated with total daily physical activity proximate to death in older adults. METHODS: We studied brain autopsies from 428 decedents of the Rush Memory and Aging Project. The quantity of all physical activity was measured continuously for up to 10 days with actigraphy (Actical; Philips Healthcare, Bend, OR). Multiple regression analyses controlling for age and sex were used to examine the relation of brain indexes to total daily physical activity and other clinical covariates proximate to death. RESULTS: Average total daily activity was 1.53 * 105 counts/d (SD 1.14 * 105 counts/d), and mean age at death was 90.6 (SD 6.12) years. Nigral neuronal loss (estimate -0.232, standard error [SE] = 0.070, p = 0.001) and macroinfarcts (estimate -0.266, SE 0.112, p = 0.017) were independently associated with total daily physical activity proximate to death, accounting for an additional 2.4% of the variance of total daily activity. Other postmortem indexes (Alzheimer disease, Lewy bodies, TAR DNA-binding protein 43, hippocampal sclerosis, microinfarcts, atherosclerosis, arteriolosclerosis, and cerebral amyloid angiopathy) were not associated with total daily activity. In 295 cases (70%), we derived a measure of white matter tissue integrity from postmortem brain MRI. This metric accounted for an additional 5.8% of the variance of total daily physical activity when controlling for age, sex, nigral neuronal loss, and macroinfarcts. CONCLUSION: Macroinfarcts, nigral neuronal loss, and white matter pathologies are related to total daily physical activity in older adults, but further studies are needed to explain its pathologic basis more fully. PMID- 29695601 TI - Veterinary neurology. PMID- 29695602 TI - Quantifying the mechanical and histological properties of thrombus analog made from human blood for the creation of synthetic thrombus for thrombectomy device testing. AB - BACKGROUND: Untreated ischemic stroke can lead to severe morbidity and death, and as such, there are numerous endovascular blood-clot removal (thrombectomy) devices approved for human use. Human thrombi types are highly variable and are typically classified in qualitative terms - 'soft/red,' 'hard/white,' or 'aged/calcified.' Quantifying human thrombus properties can accelerate the development of thrombus analogs for the study of thrombectomy outcomes, which are often inconsistent among treated patients. METHODS: 'Soft'human thrombi were created from blood samples ex vivo (ie, human blood clotted in sample vials) and tested for mechanical properties using a hybrid rheometer material testing system. Synthetic thrombus materials were also mechanically tested and compared with the 'soft' human blood clots. RESULTS: Mechanical testing quantified the shear modulus and dynamic (elastic) modulus of volunteer human thrombus samples. This data was used to formulate a synthetic blood clot made from a composite polymer hydrogel of polyacrylamide and alginate (PAAM-Alg). The PAAM-Alg interpenetrating network of covalently and ionically cross-linked polymers had tunable elastic and shear moduli properties and shape memory characteristics. CONCLUSIONS: Due to its adjustable properties, PAAM-Alg can be modified to mimic various thrombi classifications. Future studies will include obtaining and quantitatively classifying patient thrombectomy samples and altering the PAAM-Alg to mimic the results for use with in vitro thrombectomy studies. PMID- 29695603 TI - Intermediate catheter placement distal to the cerebral aneurysm during flow diversion embolization with the Surpass device. AB - PURPOSE: We present the preliminary angiographic and clinical results of the combined utilization of an AXS Catalyst 5 (Cat5) distal access catheter and a Surpass flow diverter (SFD) for the endovascular treatment of intracranial aneurysms. MATERIALS AND METHODS: Interventional neuroradiology case records were evaluated retrospectively to identify patients treated with an SFD in combination with Cat5. Demographic data, technical success, location of the catheter tip, aneurysm occlusion rate, and procedure-related morbidity and mortality were noted. RESULTS: The analysis yielded 24 patients with 25 aneurysms with a mean age of 52.3+/-19.7 years. The mean aneurysm diameter was 15.7+/-8.8 mm. Twenty one were anterior circulation (seven supraclinoid, one middle cerebral, one anterior choroidal and 12 petrocavernous) and four were posterior circulation (three basilar tip, one posterior inferior cerebellar) aneurysms. Only two of these aneurysms were re-treatments for recurrences. For SFD deployment, the distal tip of Cat5 was placed intradurally and at, or distal to, M1 segment in 88% and 48% of patients, respectively. Aneurysms were bypassed with Cat5 in 80% of the procedures. In one patient, flow diversion was abandoned totally due to arterial tortuosity. With the exclusion of this patient, the technical success rate was 91.7%. There was no permanent procedure-related morbidity or mortality. Of the 22 aneurysms treated successfully with the Surpass device, 20 had imaging follow-up at 6.3+/-3.8 months and 95% were totally occluded. CONCLUSION: The Cat5 catheter, which was manufactured for the navigation of large-bore stent-like devices, is a useful adjunct to the Surpass device and allowed us to deploy the device safely. PMID- 29695604 TI - Electrostatic self-cleaning gecko-like adhesives. AB - This paper describes the use of the electrostatic element of an electrostatic/gecko-like adhesive to repel dust particles, which have been shown to significantly affect adhesion and reliability. The result is a non destructive, non-contact cleaning method that can be used in conjunction with other cleaning techniques, many of which rely on physical contact between the fibrillar adhesive and substrate. The paper focuses on experimental evaluation of the repulsion of 100 MUm glass beads as a function of wave shape, frequency, phase number and electrode direction in relation to the gecko-like features. Results show that a two-phase square wave with the lowest practically feasible frequency can remove 100 MUm glass beads from a directional gecko-like adhesive with up to 70% efficiency. Finally, using the optimized electrostatic cleaning properties, results show an approximately 25% recovery in shear stress on a rough glass for three contaminated directional gecko-like adhesives after contact with a dusty table. PMID- 29695605 TI - Alginate foam-based three-dimensional culture to investigate drug sensitivity in primary leukaemia cells. AB - The development of assays for evaluating the sensitivity of leukaemia cells to anti-cancer agents is becoming an important aspect of personalized medicine. Conventional cell cultures lack the three-dimensional (3D) structure of the bone marrow (BM), the extracellular matrix and stromal components which are crucial for the growth and survival of leukaemia stem cells. To accurately predict the sensitivity of the leukaemia cells in an in vitro assay a culturing system containing the essential components of BM is required. In this study, we developed a porous calcium alginate foam-based scaffold to be used for 3D culture. The new 3D culture was shown to be cell compatible as it supported the proliferation of both normal haematopoietic and leukaemia cells. Our cell differential assay for myeloid markers showed that the porous foam-based 3D culture enhanced myeloid differentiation in both leukaemia and normal haematopoietic cells compared to two-dimensional culture. The foam-based scaffold reduced the sensitivity of the leukaemia cells to the tested antileukaemia agents in K562 and HL60 leukaemia cell line model and also primary myeloid leukaemia cells. This observation supports the application of calcium alginate foams as scaffold components of the 3D cultures for investigation of sensitivity to antileukaemia agents in primary myeloid cells. PMID- 29695608 TI - Managing the threat to reflective writing. PMID- 29695607 TI - Timing of gene expression in a cell-fate decision system. AB - During development, morphogens provide extracellular cues allowing cells to select a specific fate by inducing complex transcriptional programs. The mating pathway in budding yeast offers simplified settings to understand this process. Pheromone secreted by the mating partner triggers the activity of a MAPK pathway, which results in the expression of hundreds of genes. Using a dynamic expression reporter, we quantified the kinetics of gene expression in single cells upon exogenous pheromone stimulation and in the physiological context of mating. In both conditions, we observed striking differences in the timing of induction of mating-responsive promoters. Biochemical analyses and generation of synthetic promoter variants demonstrated how the interplay between transcription factor binding and nucleosomes contributes to determine the kinetics of transcription in a simplified cell-fate decision system. PMID- 29695609 TI - Bitopic Binding Mode of an M1 Muscarinic Acetylcholine Receptor Agonist Associated with Adverse Clinical Trial Outcomes. AB - The realization of the therapeutic potential of targeting the M1 muscarinic acetylcholine receptor (mAChR) for the treatment of cognitive decline in Alzheimer's disease has prompted the discovery of M1 mAChR ligands showing efficacy in alleviating cognitive dysfunction in both rodents and humans. Among these is GSK1034702 (7-fluoro-5-methyl-3-[1-(oxan-4-yl)piperidin-4-yl]-1H benzimidazol-2-one), described previously as a potent M1 receptor allosteric agonist, which showed procognitive effects in rodents and improved immediate memory in a clinical nicotine withdrawal test but induced significant side effects. Here we provide evidence using ligand binding, chemical biology and functional assays to establish that rather than the allosteric mechanism claimed, GSK1034702 interacts in a bitopic manner at the M1 mAChR such that it can concomitantly span both the orthosteric and an allosteric binding site. The bitopic nature of GSK1034702, together with the intrinsic agonist activity and a lack of muscarinic receptor subtype selectivity reported here, all likely contribute to the adverse effects of this molecule in clinical trials. Although they impart beneficial effects on learning and memory, we conclude that these properties are undesirable in a clinical candidate due to the likelihood of adverse side effects. Rather, our data support the notion that "pure" positive allosteric modulators showing selectivity for the M1 mAChR with low levels of intrinsic activity would be preferable to provide clinical efficacy with low adverse responses. PMID- 29695606 TI - Augmenting endogenous repair of soft tissues with nanofibre scaffolds. AB - As our ability to engineer nanoscale materials has developed we can now influence endogenous cellular processes with increasing precision. Consequently, the use of biomaterials to induce and guide the repair and regeneration of tissues is a rapidly developing area. This review focuses on soft tissue engineering, it will discuss the types of biomaterial scaffolds available before exploring physical, chemical and biological modifications to synthetic scaffolds. We will consider how these properties, in combination, can provide a precise design process, with the potential to meet the requirements of the injured and diseased soft tissue niche. Finally, we frame our discussions within clinical trial design and the regulatory framework, the consideration of which is fundamental to the successful translation of new biomaterials. PMID- 29695610 TI - Epidermal expression of a sterol biosynthesis gene regulates root growth by a non cell-autonomous mechanism in Arabidopsis. AB - The epidermis is hypothesized to play a signalling role during plant development. One class of mutants showing defects in signal transduction and radial patterning are those in sterol biosynthesis. The expectation is that living cells require sterols, but it is not clear that all cell types express sterol biosynthesis genes. The HYDRA1 (HYD1) gene of Arabidopsis encodes sterol Delta8-Delta7 isomerase, and although hyd1 seedlings are defective in radial patterning across several tissues, we show that the HYD1 gene is expressed most strongly in the root epidermis. Transgenic activation of HYD1 transcription in the epidermis of hyd1 null mutants reveals a major role in root patterning and growth. HYD1 expression in the vascular tissues and root meristem, though not endodermis or pericycle, also leads to some phenotypic rescue. Phenotypic rescue is associated with rescued patterning of the PIN1 and PIN2 auxin efflux carriers. The importance of the epidermis in controlling root growth and development is proposed to be, in part, due to its role as a site for sterol biosynthesis, and auxin is a candidate for the non-cell-autonomous signal. PMID- 29695611 TI - GSK-3 promotes S-phase entry and progression in C. elegans germline stem cells to maintain tissue output. AB - Adult C. elegans germline stem cells (GSCs) and mouse embryonic stem cells (mESCs) exhibit a non-canonical cell cycle structure with an abbreviated G1 phase and phase-independent expression of Cdk2 and cyclin E. Mechanisms that promote the abbreviated cell cycle remain unknown, as do the consequences of not maintaining an abbreviated cell cycle in these tissues. In GSCs, we discovered that loss of gsk-3 results in reduced GSC proliferation without changes in differentiation or responsiveness to GLP-1/Notch signaling. We find that DPL-1 transcriptional activity inhibits CDK-2 mRNA accumulation in GSCs, which leads to slower S-phase entry and progression. Inhibition of dpl-1 or transgenic expression of CDK-2 via a heterologous germline promoter rescues the S-phase entry and progression defects of the gsk-3 mutants, demonstrating that transcriptional regulation rather than post-translational control of CDK-2 establishes the abbreviated cell cycle structure in GSCs. This highlights an inhibitory cascade wherein GSK-3 inhibits DPL-1 and DPL-1 inhibits cdk-2 transcription. Constitutive GSK-3 activity through this cascade maintains an abbreviated cell cycle structure to permit the efficient proliferation of GSCs necessary for continuous tissue output. PMID- 29695613 TI - Cytochrome P450 2J2: Potential Role in Drug Metabolism and Cardiotoxicity. AB - Drug-induced cardiotoxicity may be modulated by endogenous arachidonic acid (AA) derived metabolites known as epoxyeicosatrienoic acids (EETs) synthesized by cytochrome P450 2J2 (CYP2J2). The biologic effects of EETs, including their protective effects on inflammation and vasodilation, are diverse because, in part, of their ability to act on a variety of cell types. In addition, CYP2J2 metabolizes both exogenous and endogenous substrates and is involved in phase 1 metabolism of a variety of structurally diverse compounds, including some antihistamines, anticancer agents, and immunosuppressants. This review addresses current understanding of the role of CYP2J2 in the metabolism of xenobiotics and endogenous AA, focusing on the effects on the cardiovascular system. In particular, we have promoted here the hypothesis that CYP2J2 influences drug induced cardiotoxicity through potentially conflicting effects on the production of protective EETs and the metabolism of drugs. PMID- 29695612 TI - Neural stem cell quiescence and stemness are molecularly distinct outputs of the Notch3 signalling cascade in the vertebrate adult brain. AB - Neural stem cells (NSCs) in the adult vertebrate brain are found in a quiescent state and can preserve long-lasting progenitor potential (stemness). Whether and how these two properties are linked, and to what extent they can be independently controlled by NSC maintenance pathways, is unresolved. We have previously identified Notch3 signalling as a major quiescence-promoting pathway in adult NSCs of the zebrafish pallium. We now show that Notch3 also controls NSC stemness. Using parallel transcriptomic characterizations of notch3 mutant NSCs and adult NSC physiological states, we demonstrate that a set of potentially direct Notch3 target genes distinguishes quiescence and stemness control. As a proof of principle, we focus on one 'stemness' target, encoding the bHLH transcription factor Hey1, that has not yet been analysed in adult NSCs. We show that abrogation of Hey1 function in adult pallial NSCs in vivo, including quiescent NSCs, leads to their differentiation without affecting their proliferation state. These results demonstrate that quiescence and stemness are molecularly distinct outputs of Notch3 signalling, and identify Hey1 as a major Notch3 effector controlling NSC stemness in the vertebrate adult brain. PMID- 29695614 TI - The Drug-Drug Interaction Potential of Antiviral Agents for the Treatment of Chronic Hepatitis C Infection. AB - Several safe and highly effective direct-acting antiviral (DAA) drugs for chronic hepatitis C virus (HCV) have been developed and greatly increase the number of therapeutic options available to successfully treat HCV infection. However, because treatment regimens contain at least two drugs (e.g., elbasvir and grazoprevir, glecaprevir and pibrentasvir, or sofosbuvir with daclatasvir, simeprevir, ledipasvir, or velpatasvir) and up to five drugs (ombitasvir/paritaprevir/ritonavir plus dasabuvir with or without ribavirin), the potential for drug-drug interactions (DDIs) becomes an important consideration for HCV-infected individuals with comorbidities that require concomitant medications, such as human immunodeficiency virus/HCV coinfection or immunosuppression after liver transplantation. This review details the pharmacokinetics and DDI potential of approved DAAs for the treatment of HCV infection. PMID- 29695615 TI - Metabolism of a 5HT6 Antagonist, 2-Methyl-1-(Phenylsulfonyl)-4-(Piperazin-1-yl) 1H-Benzo[d]imidazole (SAM-760): Impact of Sulfonamide Metabolism on Diminution of a Ketoconazole-Mediated Clinical Drug-Drug Interaction. AB - SAM-760 [(2-methyl-1-(phenylsulfonyl)-4-(piperazin-1-yl)-1H-benzo[d]imidazole)], a 5HT6 antagonist, was investigated in humans for the treatment of Alzheimer's disease. In liver microsomes and recombinant cytochrome P450 (P450) isozymes, SAM 760 was predominantly metabolized by CYP3A (~85%). Based on these observations and an expectation of a 5-fold magnitude of interaction with moderate to strong CYP3A inhibitors, a clinical DDI study was performed. In the presence of ketoconazole, the mean Cmax and area under the plasma concentration-time curve from time zero extrapolated to infinite time values of SAM-760 showed only a modest increase by 30% and 38%, respectively. In vitro investigation of this unexpectedly low interaction was undertaken using [14C]SAM-760. Radiometric profiling in human hepatocytes confirmed all oxidative metabolites previously observed with unlabeled SAM-760; however, the predominant radiometric peak was an unexpected polar metabolite that was insensitive to the pan-P450 inhibitor 1 aminobenzotriazole. In human hepatocytes, radiometric integration attributed 43% of the total metabolism of SAM-760 to this non-P450 pathway. Using an authentic standard, this predominant metabolite was confirmed as benzenesulfinic acid. Additional investigation revealed that the benzenesulfinic acid metabolite may be a novel, nonenzymatic, thiol-mediated reductive cleavage of an aryl sulfonamide group of SAM-760. We also determined the relative contribution of P450 to the metabolism of SAM-760 in human hepatocytes by following the rate of formation of oxidative metabolites in the presence and absence of P450 isoform-specific inhibitors. The P450-mediated oxidative metabolism of SAM-760 was still primarily attributed to CYP3A (33%), with minor contributions from P450 isoforms CYP2C19 and CYP2D6. Thus, the disposition of [14C]SAM-760 in human hepatocytes via novel sulfonamide metabolism and CYP3A verified the lower than expected clinical DDI when SAM-760 was coadministered with ketoconazole. PMID- 29695616 TI - Abundance of Phase 1 and 2 Drug-Metabolizing Enzymes in Alcoholic and Hepatitis C Cirrhotic Livers: A Quantitative Targeted Proteomics Study. AB - To predict the impact of liver cirrhosis on hepatic drug clearance using physiologically based pharmacokinetic (PBPK) modeling, we compared the protein abundance of various phase 1 and phase 2 drug-metabolizing enzymes (DMEs) in S9 fractions of alcoholic (n = 27) or hepatitis C (HCV, n = 30) cirrhotic versus noncirrhotic (control) livers (n = 25). The S9 total protein content was significantly lower in alcoholic or HCV cirrhotic versus control livers (i.e., 38.3 +/- 8.3, 32.3 +/- 12.8, vs. 51.1 +/- 20.7 mg/g liver, respectively). In general, alcoholic cirrhosis was associated with a larger decrease in the DME abundance than HCV cirrhosis; however, only the abundance of UGT1A4, alcohol dehydrogenase (ADH)1A, and ADH1B was significantly lower in alcoholic versus HCV cirrhotic livers. When normalized to per gram of tissue, the abundance of nine DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, CYP1A2, ADH1A, ADH1B, aldehyde oxidase (AOX)1, and carboxylesterase (CES)1) in alcoholic cirrhosis and five DMEs (UGT1A6, UGT1A4, CYP3A4, UGT2B7, and CYP1A2) in HCV cirrhosis was <25% of that in control livers. The abundance of most DMEs in cirrhotic livers was 25% to 50% of control livers. CES2 abundance was not affected by cirrhosis. Integration of UGT2B7 abundance in cirrhotic livers into the liver cirrhosis (Child Pugh C) model of Simcyp improved the prediction of zidovudine and morphine PK in subjects with Child Pugh C liver cirrhosis. These data demonstrate that protein abundance data, combined with PBPK modeling and simulation, can be a powerful tool to predict drug disposition in special populations. PMID- 29695617 TI - Pathways for maintenance of telomeres and common fragile sites during DNA replication stress. AB - Oncogene activation during tumour development leads to changes in the DNA replication programme that enhance DNA replication stress. Certain regions of the human genome, such as common fragile sites and telomeres, are particularly sensitive to DNA replication stress due to their inherently 'difficult-to replicate' nature. Indeed, it appears that these regions sometimes fail to complete DNA replication within the period of interphase when cells are exposed to DNA replication stress. Under these conditions, cells use a salvage pathway, termed 'mitotic DNA repair synthesis (MiDAS)', to complete DNA synthesis in the early stages of mitosis. If MiDAS fails, the ensuing mitotic errors threaten genome integrity and cell viability. Recent studies have provided an insight into how MiDAS helps cells to counteract DNA replication stress. However, our understanding of the molecular mechanisms and regulation of MiDAS remain poorly defined. Here, we provide an overview of how DNA replication stress triggers MiDAS, with an emphasis on how common fragile sites and telomeres are maintained. Furthermore, we discuss how a better understanding of MiDAS might reveal novel strategies to target cancer cells that maintain viability in the face of chronic oncogene-induced DNA replication stress. PMID- 29695618 TI - Bacterial transmembrane signalling systems and their engineering for biosensing. AB - Every living cell possesses numerous transmembrane signalling systems that receive chemical and physical stimuli from the environment and transduce this information into an intracellular signal that triggers some form of cellular response. As unicellular organisms, bacteria require these systems for survival in rapidly changing environments. The receptors themselves act as 'sensory organs', while subsequent signalling circuits can be regarded as forming a 'neural network' that is involved in decision making, adaptation and ultimately in ensuring survival. Bacteria serve as useful biosensors in industry and clinical diagnostics, in addition to producing drugs for therapeutic purposes. Therefore, there is a great demand for engineered bacterial strains that contain transmembrane signalling systems with high molecular specificity, sensitivity and dose dependency. In this review, we address the complexity of transmembrane signalling systems and discuss principles to rewire receptors and their signalling outputs. PMID- 29695620 TI - Interlaboratory Comparison of the Pneumococcal Multiplex Opsonophagocytic Assays and Their Level of Agreement for Determination of Antibody Function in Pediatric Sera. AB - Opsonophagocytic assays are used to measure functional antibodies important in protection against pneumococcal capsular antigens. There have been efforts to standardize these methods, as the assays are commonly used to measure vaccine immunogenicity. We report here the results from three international laboratories using their own methods, based on the recommended WHO standard method. We tested 30 pediatric sera, before and after administration of a 13-valent conjugate pneumococcal vaccine, against all 13 serotypes. The three laboratories demonstrated good agreement using their own standardized multiplex opsonophagocytosis assay protocols, particularly postimmunization for those serotypes in the vaccine. While serotype-specific IgG methods have already been internationally standardized and are currently used as a measure of vaccine immunogenicity, this report demonstrates that despite minor differences in methods and a minor variation in response to nonvaccine serotypes, the results from opsonophagocytic assays across the three laboratories may be compared with confidence.IMPORTANCE When measuring a functional antibody response to pneumococcal immunization, it is imperative that a specific, reproducible, accurate, and standardized assay with acceptable inter- and intra-assay variation be advocated internationally to allow for meaningful comparison of results between laboratories. We report here the results of a collaboration between 3 international laboratories testing 30 pediatric samples against the 13 serotypes in Prevenar13. PMID- 29695619 TI - Critical review: involvement of endoplasmic reticulum stress in the aetiology of Alzheimer's disease. AB - The endoplasmic reticulum (ER) stress response is regarded as an important process in the aetiology of Alzheimer's disease (AD). The accumulation of pathogenic misfolded proteins and the disruption of intracellular calcium (Ca2+) signalling are considered to be fundamental mechanisms that underlie the induction of ER stress, leading to neuronal cell death. Indeed, a number of studies have proposed molecular mechanisms linking ER stress to AD pathogenesis based on results from in vitro systems and AD mouse models. However, stress responsivity was largely different between each mouse model, even though all of these models display AD-related pathologies. While several reports have shown elevated ER stress responses in amyloid precursor protein (APP) and presenilin 1 (PS1) double-transgenic (Tg) AD mouse models, we and other groups, in contrast, observed no such ER stress response in APP-single-Tg or App-knockin mice. Therefore, it is debatable whether the ER stress observed in APP and PS1 double Tg mice is due to AD pathology. From these findings, the roles of ER stress in AD pathogenesis needs to be carefully addressed in future studies. In this review, we summarize research detailing the relationship between ER stress and AD, and analyse the results in detail. PMID- 29695621 TI - Beaver Fever: Whole-Genome Characterization of Waterborne Outbreak and Sporadic Isolates To Study the Zoonotic Transmission of Giardiasis. AB - Giardia causes the diarrheal disease known as giardiasis; transmission through contaminated surface water is common. The protozoan parasite's genetic diversity has major implications for human health and epidemiology. To determine the extent of transmission from wildlife through surface water, we performed whole-genome sequencing (WGS) to characterize 89 Giardia duodenalis isolates from both outbreak and sporadic infections: 29 isolates from raw surface water, 38 from humans, and 22 from veterinary sources. Using single nucleotide variants (SNVs), combined with epidemiological data, relationships contributing to zoonotic transmission were described. Two assemblages, A and B, were identified in surface water, human, and veterinary isolates. Mixes of zoonotic assemblages A and B were seen in all the community waterborne outbreaks in British Columbia (BC), Canada, studied. Assemblage A was further subdivided into assemblages A1 and A2 based on the genetic variation observed. The A1 assemblage was highly clonal; isolates of surface water, human, and veterinary origins from Canada, United States, and New Zealand clustered together with minor variation, consistent with this being a panglobal zoonotic lineage. In contrast, assemblage B isolates were variable and consisted of several clonal lineages relating to waterborne outbreaks and geographic locations. Most human infection isolates in waterborne outbreaks clustered with isolates from surface water and beavers implicated to be outbreak sources by public health. In-depth outbreak analysis demonstrated that beavers can act as amplification hosts for human infections and can act as sources of surface water contamination. It is also known that other wild and domesticated animals, as well as humans, can be sources of waterborne giardiasis. This study demonstrates the utility of WGS in furthering our understanding of Giardia transmission dynamics at the water-human-animal interface.IMPORTANCEGiardia duodenalis causes large numbers of gastrointestinal illness in humans. Its transmission through the contaminated surface water/wildlife intersect is significant, and the water-dwelling rodents beavers have been implicated as one important reservoir. To trace human infections to their source, we used genome techniques to characterize genetic relationships among 89 Giardia isolates from surface water, humans, and animals. Our study showed the presence of two previously described genetic assemblages, A and B, with mixed infections detected from isolates collected during outbreaks. Study findings also showed that while assemblage A could be divided into A1 and A2, A1 showed little genetic variation among animal and human hosts in isolates collected from across the globe. Assemblage B, the most common type found in the study surface water samples, was shown to be highly variable. Our study demonstrates that the beaver is a possible source of human infections from contaminated surface water, while acknowledging that theirs is only one role in the complex cycle of zoonotic spread. Mixes of parasite groups have been detected in waterborne outbreaks. More information on Giardia diversity and its evolution using genomics will further the understanding of the epidemiology of spread of this disease-causing protozoan. PMID- 29695622 TI - BGLF2 Increases Infectivity of Epstein-Barr Virus by Activating AP-1 upon De Novo Infection. AB - Epstein-Barr virus (EBV) is a human gammaherpesvirus that causes infectious mononucleosis and several malignancies, such as endemic Burkitt lymphoma and nasopharyngeal carcinoma. Herpesviruses carry genes that can modify cell functions, including transcription and ubiquitination, thereby facilitating viral growth and survival in infected cells. Using a reporter screening system, we revealed the involvement of several EBV gene products in such processes. Of these, BGLF2 activated the AP-1 signaling pathway through phosphorylation of p38 and c-Jun N-terminal kinase (JNK). Knockout of the BGLF2 gene did not affect viral gene expression and viral genome DNA replication, but resulted in marked reduction of progeny titer. We also found that the BGLF2 disruption resulted in significant loss of infectivity upon de novo infection. Interestingly, expression of a binding partner, BKRF4, repressed the activation of AP-1 by BGLF2. These results shed light on the physiological role of the tegument protein BGLF2.IMPORTANCE Epstein-Barr virus (EBV), an oncogenic gammaherpesvirus, carries ~80 genes. While several genes have been investigated extensively, most lytic genes remain largely unexplored. Therefore, we cloned 71 EBV lytic genes into an expression vector and used reporter assays to screen for factors that activate signal transduction pathways, viral and cellular promoters. BGLF2 activated the AP-1 signaling pathway, likely by interacting with p38 and c-Jun N-terminal kinase (JNK), and increased infectivity of the virus. We also revealed that BKRF4 can negatively regulate AP-1 activity. Therefore, it is suggested that EBV exploits and modifies the AP-1 signaling pathway for its replication and survival. PMID- 29695623 TI - Tracking Polymicrobial Metabolism in Cystic Fibrosis Airways: Pseudomonas aeruginosa Metabolism and Physiology Are Influenced by Rothia mucilaginosa Derived Metabolites. AB - Due to a lack of effective immune clearance, the airways of cystic fibrosis patients are colonized by polymicrobial communities. One of the most widespread and destructive opportunistic pathogens is Pseudomonas aeruginosa; however, P. aeruginosa does not colonize the airways alone. Microbes that are common in the oral cavity, such as Rothia mucilaginosa, are also present in cystic fibrosis patient sputum and have metabolic capacities different from those of P. aeruginosa Here we examine the metabolic interactions of P. aeruginosa and R. mucilaginosa using stable-isotope-assisted metabolomics. Glucose-derived 13C was incorporated into glycolysis metabolites, namely, lactate and acetate, and some amino acids in R. mucilaginosa grown aerobically and anaerobically. The amino acid glutamate was unlabeled in the R. mucilaginosa supernatant but incorporated the 13C label after P. aeruginosa was cross-fed the R. mucilaginosa supernatant in minimal medium and artificial-sputum medium. We provide evidence that P. aeruginosa utilizes R. mucilaginosa-produced metabolites as precursors for generation of primary metabolites, including glutamate.IMPORTANCEPseudomonas aeruginosa is a dominant and persistent cystic fibrosis pathogen. Although P. aeruginosa is accompanied by other microbes in the airways of cystic fibrosis patients, few cystic fibrosis studies show how P. aeruginosa is affected by the metabolism of other bacteria. Here, we demonstrate that P. aeruginosa generates primary metabolites using substrates produced by another microbe that is prevalent in the airways of cystic fibrosis patients, Rothia mucilaginosa These results indicate that P. aeruginosa may get a metabolic boost from its microbial neighbor, which might contribute to its pathogenesis in the airways of cystic fibrosis patients. PMID- 29695624 TI - New CRISPR Mutagenesis Strategies Reveal Variation in Repair Mechanisms among Fungi. AB - We have created new vectors for clustered regularly interspaced short palindromic repeat (CRISPR) mutagenesis in Candida albicans, Saccharomyces cerevisiae, Candida glabrata, and Naumovozyma castellii These new vectors permit a comparison of the requirements for CRISPR mutagenesis in each of these species and reveal different dependencies for repair of the Cas9 double-stranded break. Both C. albicans and S. cerevisiae rely heavily on homology-directed repair, whereas C. glabrata and N. castellii use both homology-directed and nonhomologous end joining pathways. The high efficiency of these vectors permits the creation of unmarked deletions in each of these species and the recycling of the dominant selection marker for serial mutagenesis in prototrophs. A further refinement, represented by the "Unified" Solo vectors, incorporates Cas9, guide RNA, and repair template into a single vector, thus enabling the creation of vector libraries for pooled screens. To facilitate the design of such libraries, we have identified guide sequences for each of these species with updated guide selection algorithms.IMPORTANCE CRISPR-mediated genome engineering technologies have revolutionized genetic studies in a wide range of organisms. Here we describe new vectors and guide sequences for CRISPR mutagenesis in the important human fungal pathogens C. albicans and C. glabrata, as well as in the related yeasts S. cerevisiae and N. castellii The design of these vectors enables efficient serial mutagenesis in each of these species by leaving few, if any, exogenous sequences in the genome. In addition, we describe strategies for the creation of unmarked deletions in each of these species and vector designs that permit the creation of vector libraries for pooled screens. These tools and strategies promise to advance genetic engineering of these medically and industrially important species. PMID- 29695625 TI - Ectopic Expression of the ydaS and ydaT Genes of the Cryptic Prophage Rac of Escherichia coli K-12 May Be Toxic but Do They Really Encode Toxins?: a Case for Using Genetic Context To Understand Function. PMID- 29695626 TI - Rapid Gene Concatenation for Genetic Rescue of Multigene Mutants in Candida albicans. AB - The biological function of a gene is often probed through its interactions with other genes. This general approach has been especially useful to build knowledge about poorly understood genes upon the bedrock of well-characterized genes. Genetic interaction analysis requires the construction of strains with mutations in two or more genes. Single-gene mutants of microbial pathogens are generally validated through introduction of a wild-type copy of the affected gene to create a complemented or reconstituted strain, followed by testing for restoration of a wild-type phenotype. This practice, formalized as one of Falkow's "molecular Koch's postulates" ensures that the phenotype of the mutant depends upon the known mutation. However, multigene mutants are seldom validated because of the labor required to assemble multiple genomic segments into a vector that can be introduced into the mutant strain. We present here an approach, concatemer assembly for rescue of mutant abilities (CARMA), that circumvents this impediment through an in vivo recombinational assembly strategy that does not require cloning at all. Our results show that CARMA allows genetic rescue of two double gene mutant strains of the fungal pathogen Candida albicansIMPORTANCE Our understanding of new genes is often built upon the knowledge of well characterized genes. One avenue toward revealing such connections involves creation of strains with mutations in two or more defined genes to permit genetic interaction analysis. Strain manipulations can yield unexpected mutations at loci outside the defined targeted genes. In this report, we describe a method for rapid validation of multigene mutants, thus allowing an appraisal of the contribution of the defined targeted genes to the strain's phenotype. PMID- 29695627 TI - Reply to Jobling, "Ectopic Expression of the ydaS and ydaT Genes of the Cryptic Prophage Rac of Escherichia coli K-12 May Be Toxic but Do They Really Encode Toxins?: a Case for Using Genetic Context To Understand Function". PMID- 29695629 TI - Jack Halpern (1925-2018): Pioneer of homogeneous catalysis. PMID- 29695628 TI - An atypical N-ethylmaleimide sensitive factor enables the viability of nematode resistant Rhg1 soybeans. AB - N-ethylmaleimide sensitive factor (NSF) and alpha-soluble NSF attachment protein (alpha-SNAP) are essential eukaryotic housekeeping proteins that cooperatively function to sustain vesicular trafficking. The "resistance to Heterodera glycines 1" (Rhg1) locus of soybean (Glycine max) confers resistance to soybean cyst nematode, a highly damaging soybean pest. Rhg1 loci encode repeat copies of atypical alpha-SNAP proteins that are defective in promoting NSF function and are cytotoxic in certain contexts. Here, we discovered an unusual NSF allele (Rhg1 associated NSF on chromosome 07; NSFRAN07 ) in Rhg1+ germplasm. NSFRAN07 protein modeling to mammalian NSF/alpha-SNAP complex structures indicated that at least three of the five NSFRAN07 polymorphisms reside adjacent to the alpha-SNAP binding interface. NSFRAN07 exhibited stronger in vitro binding with Rhg1 resistance-type alpha-SNAPs. NSFRAN07 coexpression in planta was more protective against Rhg1 alpha-SNAP cytotoxicity, relative to WT NSFCh07 Investigation of a previously reported segregation distortion between chromosome 18 Rhg1 and a chromosome 07 interval now known to contain the Glyma.07G195900 NSF gene revealed 100% coinheritance of the NSFRAN07 allele with disease resistance Rhg1 alleles, across 855 soybean accessions and in all examined Rhg1+ progeny from biparental crosses. Additionally, we show that some Rhg1-mediated resistance is associated with depletion of WT alpha-SNAP abundance via selective loss of WT alpha-SNAP loci. Hence atypical coevolution of the soybean SNARE-recycling machinery has balanced the acquisition of an otherwise disruptive housekeeping protein, enabling a valuable disease resistance trait. Our findings further indicate that successful engineering of Rhg1-related resistance in plants will require a compatible NSF partner for the resistance-conferring alpha-SNAP. PMID- 29695630 TI - CRISPR/Cas9-mediated genome editing in a reef-building coral. AB - Reef-building corals are critically important species that are threatened by anthropogenic stresses including climate change. In attempts to understand corals' responses to stress and other aspects of their biology, numerous genomic and transcriptomic studies have been performed, generating a variety of hypotheses about the roles of particular genes and molecular pathways. However, it has not generally been possible to test these hypotheses rigorously because of the lack of genetic tools for corals. Here, we demonstrate efficient genome editing using the CRISPR/Cas9 system in the coral Acropora millepora We targeted the genes encoding fibroblast growth factor 1a (FGF1a), green fluorescent protein (GFP), and red fluorescent protein (RFP). After microinjecting CRISPR/Cas9 ribonucleoprotein complexes into fertilized eggs, we detected induced mutations in the targeted genes using changes in restriction-fragment length, Sanger sequencing, and high-throughput Illumina sequencing. We observed mutations in ~50% of individuals screened, and the proportions of wild-type and various mutant gene copies in these individuals indicated that mutation induction continued for at least several cell cycles after injection. Although multiple paralogous genes encoding green fluorescent proteins are present in A. millepora, appropriate design of the guide RNA allowed us to induce mutations simultaneously in more than one paralog. Because A. millepora larvae can be induced to settle and begin colony formation in the laboratory, CRISPR/Cas9-based gene editing should allow rigorous tests of gene function in both larval and adult corals. PMID- 29695632 TI - Selective Targeting and Eradication of LGR5+ Cancer Stem Cells Using RSPO Conjugated Doxorubicin Liposomes. AB - Cancer stem cells (CSC) that may account for only a small fraction of tumor mass were found to play crucial roles during tumor initiating, progression, and metastasis. However, they are usually difficult to be treated and notoriously resilient to drug eradication. In this study, we aimed at the Wnt signaling characteristic of CSCs and designed a liposomal drug delivery system to target CSCs. Liposomes decorated with RSPO1 on the surface were constructed for specific interactions with the Wnt pathway coreceptor LGR5. Doxorubicin carried by the RSPO1-liposomes was more effective at lower concentrations than the same drug loaded in PEG-liposomes. More importantly, we showed using a patient-derived xenograft tumor model where LGR5+ CSCs coexisted with LGR5- cells, the RSPO1 liposomes were able to access more CSC cells and deliver the drug specifically and efficiently. Such a focused effect in eradicating LGR5+ cells led to massive tumor tissue necrosis and growth inhibition even when only a fraction of the conventional drug dose was used. These data clearly demonstrated the advantages of CSC-targeted drug delivery and would support the development of such approaches as a new cancer treatment strategy. Mol Cancer Ther; 17(7); 1475-85. (c)2018 AACR. PMID- 29695631 TI - Improving the In Vivo Efficacy of an Anti-Tac (CD25) Immunotoxin by Pseudomonas Exotoxin A Domain II Engineering. AB - Tac (CD25) is expressed on multiple hematologic malignancies and is a target for cancer therapies. LMB-2 is an extremely active anti-Tac recombinant immunotoxin composed of an Fv that binds to Tac and a 38-kDa fragment of Pseudomonas exotoxin A (PE38). Although LMB-2 has shown high cytotoxicity toward Tac-expressing cancer cells in clinical trials, its efficacy was hampered by the formation of anti-drug antibodies against the immunogenic bacterial toxin and by dose-limiting off target toxicity. To reduce toxin immunogenicity and nonspecific toxicity, we introduced six point mutations into domain III that were previously shown to reduce T-cell immunogenicity and deleted domain II from the toxin, leaving only the 11aa furin cleavage site, which is required for cytotoxic activity. Although this strategy has been successfully implemented for mesothelin and CD22-targeting immunotoxins, we found that removal of domain II significantly lowered the cytotoxic activity of anti-Tac immunotoxins. To restore cytotoxic activity in the absence of PE domain II, we implemented a combined rational design and screening approach to isolate highly active domain II-deleted toxin variants. The domain II deleted variant with the highest activity contained an engineered disulfide bridged furin cleavage site designed to mimic its native conformation within domain II. We found that this approach restored 5-fold of the cytotoxic activity and dramatically improved the MTD. Both of these improvements led to significantly increased antitumor efficacy in vivo We conclude that the next generation anti-Tac immunotoxin is an improved candidate for targeting Tac expressing malignancies. Mol Cancer Ther; 17(7); 1486-93. (c)2018 AACR. PMID- 29695633 TI - ASTX660, a Novel Non-peptidomimetic Antagonist of cIAP1/2 and XIAP, Potently Induces TNFalpha-Dependent Apoptosis in Cancer Cell Lines and Inhibits Tumor Growth. AB - Because of their roles in the evasion of apoptosis, inhibitor of apoptosis proteins (IAP) are considered attractive targets for anticancer therapy. Antagonists of these proteins have the potential to switch prosurvival signaling pathways in cancer cells toward cell death. Various SMAC-peptidomimetics with inherent cIAP selectivity have been tested clinically and demonstrated minimal single-agent efficacy. ASTX660 is a potent, non-peptidomimetic antagonist of cIAP1/2 and XIAP, discovered using fragment-based drug design. The antagonism of XIAP and cIAP1 by ASTX660 was demonstrated on purified proteins, cells, and in vivo in xenograft models. The compound binds to the isolated BIR3 domains of both XIAP and cIAP1 with nanomolar potencies. In cells and xenograft tissue, direct antagonism of XIAP was demonstrated by measuring its displacement from caspase-9 or SMAC. Compound-induced proteasomal degradation of cIAP1 and 2, resulting in downstream effects of NIK stabilization and activation of noncanonical NF-kappaB signaling, demonstrated cIAP1/2 antagonism. Treatment with ASTX660 led to TNFalpha-dependent induction of apoptosis in various cancer cell lines in vitro, whereas dosing in mice bearing breast and melanoma tumor xenografts inhibited tumor growth. ASTX660 is currently being tested in a phase I-II clinical trial (NCT02503423), and we propose that its antagonism of cIAP1/2 and XIAP may offer improved efficacy over first-generation antagonists that are more cIAP1/2 selective. Mol Cancer Ther; 17(7); 1381-91. (c)2018 AACR. PMID- 29695635 TI - Mechanisms of Acquired Resistance to Trastuzumab Emtansine in Breast Cancer Cells. AB - The receptor tyrosine kinase HER2 is overexpressed in approximately 20% of breast cancer, and its amplification is associated with reduced survival. Trastuzumab emtansine (Kadcyla, T-DM1), an antibody-drug conjugate that is comprised of trastuzumab covalently linked to the antimitotic agent DM1 through a stable linker, was designed to selectively deliver DM1 to HER2-overexpressing tumor cells. T-DM1 is approved for the treatment of patients with HER2-positive metastatic breast cancer following progression on trastuzumab and a taxane. Despite the improvement in clinical outcome, many patients who initially respond to T-DM1 treatment eventually develop progressive disease. The mechanisms that contribute to T-DM1 resistance are not fully understood. To this end, we developed T-DM1-resistant in vitro models to examine the mechanisms of acquired T DM1 resistance. We demonstrate that decreased HER2 and upregulation of MDR1 contribute to T-DM1 resistance in KPL-4 T-DM1-resistant cells. In contrast, both loss of SLC46A3 and PTEN deficiency play a role in conferring resistance in BT 474M1 T-DM1-resistant cells. Our data suggest that these two cell lines acquire resistance through distinct mechanisms. Furthermore, we show that the KPL-4 T-DM1 resistance can be overcome by treatment with an inhibitor of MDR1, whereas a PI3K inhibitor can rescue PTEN loss-induced resistance in T-DM1-resistant BT-474M1 cells. Our results provide a rationale for developing therapeutic strategies to enhance T-DM1 clinical efficacy by combining T-DM1 and other inhibitors that target signaling transduction or resistance pathways. Mol Cancer Ther; 17(7); 1441-53. (c)2018 AACR. PMID- 29695634 TI - Tumor-Independent Host Secretomes Induced By Angiogenesis and Immune-Checkpoint Inhibitors. AB - The levels of various circulating blood proteins can change in response to cancer therapy. Monitoring therapy-induced secretomes (TIS) may have use as biomarkers for establishing optimal biological effect (such as dosing) or identifying sources of toxicity and drug resistance. Although TIS can derive from tumor cells directly, nontumor "host" treatment responses can also impact systemic secretory programs. For targeted inhibitors of the tumor microenvironment, including antiangiogenic and immune-checkpoint therapies, host TIS could explain unexpected collateral "side effects" of treatment. Here, we describe a comparative transcriptomic and proteomic analysis of host TIS in tissues and plasma from cancer-free mice treated with antibody and receptor tyrosine kinase inhibitors (RTKI) of the VEGF, cMet/ALK, and PD-1 pathways. We found that all cancer therapies elicit TIS independent of tumor growth, with systemic secretory gene change intensity higher in RTKIs compared with antibodies. Our results show that host TIS signatures differ between drug target, drug class, and dose. Notably, protein and gene host TIS signatures were not always predictive for each other, suggesting limitations to transcriptomic-only approaches to clinical biomarker development for circulating proteins. Together, these are the first studies to assess and compare "off-target" host secretory effects of VEGF and PD-1 pathway inhibition that occur independent of tumor stage or tumor response to therapy. Testing treatment impact on normal tissues to establish host-mediated TIS signatures (or "therasomes") may be important for identifying disease agnostic biomarkers to predict benefits (or limitations) of drug combinatory approaches. Mol Cancer Ther; 17(7); 1602-12. (c)2018 AACR. PMID- 29695636 TI - Targeting AKT with Oridonin Inhibits Growth of Esophageal Squamous Cell Carcinoma In Vitro and Patient-Derived Xenografts In Vivo. AB - Overexpression or activation of AKT is very well known to control cell growth, survival, and gene expression in solid tumors. Oridonin, an inflammatory medical and diterpenoid compound isolated from Rabdosia rubescens, has exhibited various pharmacologic and physiologic properties, including antitumor, antibacterial, and anti-inflammatory effects. In this study, we demonstrated that oridonin is an inhibitor of AKT and suppresses proliferation of esophageal squamous cell carcinoma (ESCC) in vitro and in vivo The role of AKT in ESCC was studied using immuno-histochemical analysis of a tumor microarray, the effect of AKT knockdown on cell growth, and treatment of cells with MK-2206, an AKT inhibitor. Oridonin blocked AKT kinase activity and interacted with the ATP-binding pocket of AKT. It inhibited growth of KYSE70, KYSE410, and KYSE450 esophageal cancer cells in a time- and concentration-dependent manner. Oridonin induced arrest of cells in the G2-M cell-cycle phase, stimulated apoptosis, and increased expression of apoptotic biomarkers, including cleaved PARP, caspase-3, caspase-7, and Bims in ESCC cell lines. Mechanistically, we found that oridonin diminished the phosphorylation and activation of AKT signaling. Furthermore, a combination of oridonin and 5-fluorouracil or cisplatin (clinical chemotherapeutic agents) enhanced the inhibition of ESCC cell growth. The effects of oridonin were verified in patient-derived xenograft tumors expressing high levels of AKT. In summary, our results indicate that oridonin acts as an AKT inhibitor to suppress the growth of ESCC by attenuating AKT signaling. Mol Cancer Ther; 17(7); 1540-53. (c)2018 AACR. PMID- 29695637 TI - A High-Content Screening of Anticancer Compounds Suggests the Multiple Tyrosine Kinase Inhibitor Ponatinib for Repurposing in Neuroblastoma Therapy. AB - Novel druggable targets have been discovered in neuroblastoma (NB), paving the way for more effective treatments. However, children with high-risk NB still show high mortality rates prompting for a search of novel therapeutic options. Here, we aimed at repurposing FDA-approved drugs for NB treatment by performing a high content screening of a 349 anticancer compounds library. In the primary screening, we employed three NB cell lines, grown as three-dimensional (3D) multicellular spheroids, which were treated with 10 MUmol/L of the library compounds for 72 hours. The viability of 3D spheroids was evaluated using a high content imaging approach, resulting in a primary hit list of 193 compounds. We selected 60 FDA-approved molecules and prioritized drugs with multi-target activity, discarding those already in use for NB treatment or enrolled in NB clinical trials. Hence, 20 drugs were further tested for their efficacy in inhibiting NB cell viability, both in two-dimensional and 3D models. Dose response curves were then supplemented with the data on side effects, therapeutic index, and molecular targets, suggesting two multiple tyrosine kinase inhibitors, ponatinib and axitinib, as promising candidates for repositioning in NB. Indeed, both drugs showed induction of cell-cycle block and apoptosis, as well as inhibition of colony formation. However, only ponatinib consistently affected migration and inhibited invasion of NB cells. Finally, ponatinib also proved effective inhibition of tumor growth in orthotopic NB mice, providing the rationale for its repurposing in NB therapy. Mol Cancer Ther; 17(7); 1405-15. (c)2018 AACR. PMID- 29695638 TI - Molecular Profile of Advanced Thyroid Carcinomas by Next-Generation Sequencing: Characterizing Tumors Beyond Diagnosis for Targeted Therapy. AB - Next-generation sequencing (NGS) for molecular diagnostics allows simultaneous testing of activating oncogenes and tumor suppressor mutations in multiple signal pathways. Extended mutational profiling of advanced thyroid cancers may enhance considerations for targeted therapies. We analyzed clinically derived molecular profiling of 216 patients with advanced thyroid carcinoma using NGS (Ion Torrent Personal Genome Machine) from April 2012 to February 2014. We examined substitutions and small indels in 46 or 50 cancer-related genes using Ampliseq Cancer Hotspot panel in respect to tumor diagnosis and clinical correlations.Mutations were common in advanced thyroid carcinomas 154 (71%) predominately in targetable MAPK pathway (146/216, 68%), and several PI3K/AKT pathway (8, 4%; six as comutations). BRAF V600E mutation associated with papillary (94/139, 68%), poorly differentiated (4/39, 10%), and anaplastic (3/12, 25%) carcinomas. NRAS mutations occurred in follicular (5/12, 42%) and poorly differentiated thyroid carcinoma (12/39, 31%). Tumor suppressor mutations (16, 7%) occurred predominantly in TP53 in Hurthle cell (2/5, 40%, the only mutation), in anaplastic (3/12, 25%) and poorly differentiated thyroid carcinoma (4/39, 10%) some as comutations and in papillary thyroid carcinoma (5/139, 4%) always a comutation. Kaplan-Meier analysis of patients with poorly differentiated thyroid carcinoma containing activating mutations who received targeted therapeutics showed improved survival compared to similarly treated patients without mutations in targetable pathways (P = 0.02). In conclusion, MAPK pathway is the predominant target for therapy in advance thyroid carcinomas; adding NGS enables the identification of comutations associated with resistance (PI3K/AKT). Within poorly differentiated thyroid carcinoma, the molecular profile may hold prognostic value in the era of targeted therapy. Mol Cancer Ther; 17(7); 1575-84. (c)2018 AACR. PMID- 29695639 TI - Chronotherapy with defective circadian clock? PMID- 29695640 TI - Association of VAMP5 and MCC genetic polymorphisms with increased risk of Hirschsprung disease susceptibility in Southern Chinese children. AB - Hirschsprung disease (HSCR) is a genetic disorder characterized by the absence of neural crest cells in parts of the intestine. This study aims to investigate the association of vesicle-associated membrane protein 5 (VAMP5) and mutated in colorectal cancer (MCC) genetic polymorphisms and their correlated risks with HSCR. We examined the association in four polymorphisms (rs10206961, rs1254900 and rs14242 in VAMP5, rs11241200 in MCC) and HSCR susceptibility in a Southern Chinese population composed of 1473 cases and 1469 controls. Two variants in VAMP5 were replicated as associated with HSCR. Interestingly, we clarified SNPs rs10206961 and rs1254900 in VAMP5 are more essential for patients with long segment aganglionosis (LHSCR). Relatively high expression correlation was observed between VAMP5 and MCC using data from public database showing there may exist potential genetic interactions. SNP interaction was cross-examined by logistic regression and multifactor dimensionality reduction analysis revealing that VAMP5 rs1254900 and MCC rs11241200 were interacting significantly, thereby contributing to the risk of HSCR. The results suggest that significant associations of the rs10206961 and rs14242 in VAMP5 with an increased risk of HSCR in Southern Chinese, especially in LHSCR patients. This study provided new evidence of epistatic association of VAMP5 and MCC with increased risk of HSCR. PMID- 29695641 TI - Oxidative stress-mediated senescence in mesenchymal progenitor cells causes the loss of their fibro/adipogenic potential and abrogates myoblast fusion. AB - Sarcopenia is the age-related loss of skeletal muscle mass and function. Skeletal muscle comprises diverse progenitor cells, including mesenchymal progenitor cells (MPCs), which normally support myogenic cell function but cause a decline in skeletal muscle function after differentiating into fibrous/adipose tissue. Cellular senescence is a form of persistent cell cycle arrest caused by cellular stress, including oxidative stress, and is accompanied by the acquisition of senescence-associated secretory phenotype (SASP). Here, we found gammaH2AX+ senescent cells appeared in the interstitium in skeletal muscle, corresponding in position to that of MPCs. H2O2 mediated oxidative stress in 2G11 cells, a rat MPC clone previously established in our laboratory, successfully induced senescence, as shown by the upregulation of p21 and SASP factors, including IL-6. The senescent 2G11 cells lost their fibro/adipogenic potential, but, intriguingly, coculture of myoblasts with senescent 2G11 cells abrogated the myotube formation, which coincided with the downregulation of myomaker, a muscle-specific protein involved in myogenic cell fusion; however, forced expression of myomaker could not rescue this abrogation. These results suggest that senescent MPCs in aged rat skeletal muscle lose their fibro/adipogenic potential, but differ completely from undifferentiated progenitor cells in that senescent MPCs suppress myoblast fusion and thereby potentially accelerate sarcopenia. PMID- 29695642 TI - Novel role of autophagy-associated Pik3c3 gene in gonadal white adipose tissue browning in aged C57/Bl6 male mice. AB - Adipose tissue dysfunction is associated with inflammation, metabolic syndrome and other diseases in aging. Recent work has demonstrated that compromised autophagy activity in aging adipose tissue promotes ER stress responses, contributing to adipose tissue and systemic inflammation in aging. Phosphatidylinositol 3-kinase catalytic subunit type 3 (Pik3c3) is an 887 amino acid lipid kinase that regulates intracellular membrane trafficking and autophagy activity. To address the mechanistic link between autophagy and ER stress response in aging adipose tissue, we generated a line of adipose tissue-specific Pik3c3 knock out (~mutant mice) with the Fabp4 (Fatty acid binding protein 4) promoter driven Cre recombinase system. We found elevated ER stress response signaling with reduced autophagy activity without any significant change on adiposity or glucose tolerance in early life of Pik3c3 mutant mice. Interestingly, middle- and old-aged mutant mice exhibited improved glucose tolerance (GTT) and reduced adiposity compared to age and sex-matched littermates. In addition, adipose tissue-specific Pik3c3 mutants display reduced expression of adiposity-associated genes with the signature of adipose tissue browning phenotypes in old age. Overall, the results suggest that altered adipose tissue characteristics due to autophagy inhibition early in life has beneficial effects that promote adipose tissue browning and improves glucose tolerance in late-life. PMID- 29695644 TI - Comment on Environmental monitoring through the use of silica-based TLD 2017 J. Radiol. Prot. 37 761-779. PMID- 29695643 TI - Swiprosin-1/EFhd2 - another piece in the puzzle of tauopathy? PMID- 29695645 TI - Non-invasive measurement of cardiac output in children with repaired coarctation of the aorta using electrical cardiometry compared to transthoracic Doppler echocardiography. AB - OBJECTIVE: To evaluate the equivalence of the ICON(r) electrical cardiometry (EC) haemodynamic monitor to measure cardiac output (CO) relative to transthoracic Doppler echocardiography (TTE) in paediatric patients with repaired coarctation of the aorta (CoA). APPROACH: A group of n = 28 CoA patients and n = 27 matched controls were enrolled. EC and TTE were performed synchronously on each participant and CO measurements compared using linear regression and Bland-Altman analysis. The CoA group was further subdivided into two groups, with n = 10 and without n = 18 increased left ventricular outflow tract velocity (iLVOTv) for comparison. MAIN RESULTS: CO measurements from EC and TTE in controls showed a strong correlation (R = 0.80, p < 0.001) and an acceptable percentage error (PE) of 28.1%. However, combining CoA and control groups revealed a moderate correlation (R = 0.57, p < 0.001) and a poor PE (44.2%). We suspected that the CO in a subset of CoA participants with iLVOTv was overestimated by TTE. Excluding the iLVOTv CoA participants improved the correlation (R = 0.77, p < 0.001) and resulted in an acceptable PE of 31.2%. SIGNIFICANCE: CO measurements in paediatric CoA patients in the absence of iLVOTv are clinically equivalent between EC and TTE. The presence of iLVOTv may impact the accuracy of CO measurement by TTE, but not EC. PMID- 29695646 TI - Three-dimensional nitrogen and sulfur co-doped holey-reduced graphene oxide frameworks anchored with MoO2 nanodots for advanced rechargeable lithium-ion batteries. AB - In this manuscript, we synthesize a porous three-dimensional anode material consisting of molybdenum dioxide nanodots anchored on nitrogen (N)/sulfur (S) co doped reduced graphene oxide (GO) (3D MoO2/NP-NSG) through hydrothermal, lyophilization and thermal treatment. First, the NP-NSG is formed via hydrothermal treatment using graphene oxide, hydrogen peroxide (H2O2), and thiourea as the co-dopant for N and S, followed by calcination of the N/S co doped GO in the presence of ammonium molybdate tetrahydrate to obtain the 3D MoO2/NP-NSG product. This novel material exhibits a series of out-bound electrochemical performances, such as superior conductivity, high specific capacity, and excellent stability. As an anode for lithium-ion batteries (LIBs), the MoO2/NP-NSG electrode has a high initial specific capacity (1376 mAh g-1), good cycling performance (1250 mAh g-1 after 100 cycles at a current density of 0.2 A g-1), and outstanding Coulombic efficiency (99% after 450 cycles at a current density of 1 A g-1). Remarkably, the MoO2/NP-NSG battery exhibits exceedingly good rate capacities of 1021, 965, 891, 760, 649, 500 and 425 mAh g-1 at different current densities of 200, 500, 1000, 2000, 3000, 4000 and 5000 mA g 1, respectively. The superb electrochemical performance is owed to the high porosity of the 3D architecture, the synergistic effect contribution from N and S co-doped in the reduced graphene oxide (rGO), and the uniform distribution of MoO2 nanodots on the rGO surface. PMID- 29695647 TI - A case of TSH-secreting pituitary adenoma with cyclic fluctuations in serum TSH levels. AB - A 29-year-old man was referred to our department due to adrenal insufficiency with the inappropriate secretion of TSH (SITSH). Magnetic resonance imaging revealed a pituitary tumor. A weak TSH response in the TRH test, elevated sex hormone binding globulin (SHBG) levels, and the absence of a family medical history of SITSH or TRbeta gene mutations supported the diagnosis of TSH secreting pituitary adenoma (TSHoma). However, complete TSH suppression and a blunted cholesterol response in the T3 suppression test as well as normal glycoprotein alpha-subunit (alpha-GSU) levels were not compatible with TSHoma. Since TSH, FT3, and FT4 spontaneously returned to normal ranges after admission, he was discharged. One month after his discharge, thyrotoxicosis with elevated serum TSH levels relapsed. After admission, his serum TSH levels returned to within the normal range. After his discharge from the second admission, his serum TSH levels fluctuated in accordance with serum FT3 and FT4 levels and symptoms, such as palpitations. Ten months after his discharge, he was admitted to our department again due to adrenal insufficiency and thyrotoxicosis with elevated serum TSH levels, suggesting cyclic SITSH. Although resistance to thyroid hormone (RTH) was not completely excluded, the pituitary tumor was removed by transsphenoidal surgery (TSS). A pathological diagnosis confirmed TSHoma. We herein report a case of TSHoma in which serum TSH, FT3, and FT4 levels fluctuated periodically. To the best of our knowledge, this is the first case report of "cyclic TSHoma", which needs to be considered when making a differential diagnosis of SITSH. PMID- 29695648 TI - Allometric Relationships for Cardiac Size and Longitudinal Function in Healthy Chinese Adults - Normal Ranges and Clinical Correlates. AB - BACKGROUND: Cardiac size measurements require indexing to body size. Allometric indexing has been investigated in Caucasian populations but a range of different values for the so-called allometric power exponent (b) have been proposed, with uncertainty as to whether allometry offers clinical utility above body surface area (BSA)-based indexing. We derived optimal values for b in normal echocardiograms and validated them externally in cardiac patients. METHODS AND RESULTS: Values for b were derived in healthy adult Chinese males (n=1,541), with optimal b for left ventricular mass (LVM) of 1.66 (95% confidence interval 1.41 1.92). LV hypertrophy (LVH) defined as indexed LVM >75 g/m1.66 was associated with adverse outcomes in an external validation cohort (n=738) of patients with acute coronary syndrome (odds ratio for reinfarction: 2.4 (1.1-5.4)). In contrast, LVH defined by BSA-based indexing or allometry using exponent 2.7 exhibited no significant association with outcomes (P=NS for both). Cardiac longitudinal function also varied with body size: septal and RV free wall s', TAPSE and lateral e' all scaled allometrically (b=0.3-0.9). CONCLUSIONS: An optimal b of 1.66 for LVM in healthy Chinese was found to validate well, with superior clinical utility both to that of BSA-based indexing and to b=2.7. The effect of allometric indexing of cardiac function requires further study. PMID- 29695649 TI - STF-083010, an inhibitor of XBP1 splicing, attenuates acute renal failure in rats by suppressing endoplasmic reticulum stress-induced apoptosis and inflammation. AB - Endoplasmic reticulum (ER) stress is one of the driving forces of ischemia/reperfusion (IR)-induced acute renal failure (ARF). STF-083010, an inhibitor of the endonuclease activity of inositol-requiring enzyme-1 (IRE1), has the potential to block the initiation of a prolonged unfolded protein response (UPR) that is stimulated by ER stress and alleviates the impairments due to ER stress. In the current study, it was hypothesized that STF-083010 was capable of ameliorating ER stress-related damages in IR-induced ARF. Rats were administrated with STF-083010 and were subjected to induction of ARF using a ligation method. Then the effect of STF-083010 administration on the renal structure and function, oxidative stress, and inflammation in model rats was assessed. Furthermore, the levels of expression of UPR members and downstream effectors regulating apoptosis were detected as well. The results showed that establishment of the ARF model induced ER stress and impaired the renal structure and function. Administration of STF-083010 ameliorated impairments in the structure and function of the kidneys and the effect was associated with the suppressed oxidative stress and inflammation. At the molecular level, STF-083010 inhibited the prolonged UPR by downregulating the expressions of GRP78, p-IRE1, XBP1s, CHOP, and caspase 3, partially explaining the decreased apoptotic rate. The current study evaluated the potential of STF-083010 in treating ER stress-induced symptoms in ARF for the first time, and the findings demonstrated that STF-083010 resulted in effective treatment outcomes of ARF. PMID- 29695650 TI - Suberoylanilide hydroxamic acid during in vitro culture improves development of dog-pig interspecies cloned embryos but not dog cloned embryos. AB - This study was conducted to investigate whether the treatment of dog to pig interspecies somatic cell nuclear transfer (iSCNT) embryos with a histone deacetylase inhibitor, to improve nuclear reprogramming, can be applied to dog SCNT embryos. The dog to pig iSCNT embryos were cultured in fresh porcine zygote medium-5 (PZM-5) with 0, 1, or 10 uM suberoylanilide hydroxamic acid (SAHA) for 6 h, then transferred to PZM-5 without SAHA. Although there were no significant differences in cleavage rates, the rates of 5-8-cell stage embryo development were significantly higher in the 10 uM group (19.5 +/- 0.8%) compared to the 0 uM groups (13.4 +/- 0.8%). Acetylation of H3K9 was also significantly higher in embryos beyond the 4-cell stage in the 10 uM group compared to the 0 or 1 uM groups. Treatment with 10 uM SAHA for 6 h was chosen for application to dog SCNT. Dog cloned embryos with 0 or 10 uM SAHA were transferred to recipients. However, there were no significant differences in pregnancy and delivery rates between the two groups. Therefore, it can be concluded that although porcine oocytes support nuclear reprogramming of dog fibroblasts, treatment with a histone deacetylase inhibitor that supports nuclear reprogramming in dog to pig iSCNT embryos was not sufficient for reprogramming in dog SCNT embryos. PMID- 29695652 TI - Total Aortic Arch Replacement after Thoracic Endovascular Aortic Repair Using Left Subclavian Arterial Perfusion. AB - We present the case of an 86-year-old male with an aortic arch saccular aneurysm who underwent zone 1 thoracic endovascular aortic repair (TEVAR) with debranching from the right subclavian artery to the left carotid and left subclavian arteries. The patient developed a type Ia endoleak 1 month later. Postoperative contrast computed tomography (CT) showed a hematoma around the aneurysm, concerning for impending rupture. He thus underwent emergency endograft removal and replacement with a one-branched graft using selective cerebral perfusion via the left subclavian artery perfusion. The left subclavian artery was used for systemic and cerebral perfusion without need for cannulation of the cervical arteries. The patient was successfully discharged 6 months after surgery. PMID- 29695651 TI - Degradation of maternal factors during preimplantation embryonic development. AB - During oogenesis, oocytes accumulate a large set of proteins derived from the maternal genome. These proteins, known as maternal proteins, are not only required for oocyte maturation and fertilization, but also implicated in subsequent embryonic development. However, most maternal proteins are degraded and their amino acid components are utilized for newly synthesized proteins from the embryonic genome. This process is known as the oocyte-to-embryo transition; because it occurs over a short period, mechanisms involving massive degradation of maternal proteins have been proposed. Intracellular protein degradation mechanisms can be broadly classified into two types. The first is the ubiquitin proteasome system, a highly selective pathway in which ubiquitylated proteins are degraded by proteasomes. The second mechanism is autophagy, which involves lysosome-mediated degradation of cytoplasmic components. In this review, we describe recent advances in the understanding of autophagy, focusing on its role in early embryonic development. PMID- 29695653 TI - Pulmonary Resection for Lung Cancer Following Transcatheter Aortic Valve Implantation for Severe Aortic Valve Stenosis: A Case Report. AB - An 82-year-old woman was referred to our hospital because of dyspnea on effort. Echocardiography revealed severe aortic valve stenosis (AS). Simultaneously, chest computed tomography (CT) revealed a 19-mm nodule in the lower lobe of the right lung, and bronchoscopic biopsy revealed adenocarcinoma. She underwent transcatheter aortic valve implantation (TAVI) for severe AS. Three weeks later, she underwent lower lobectomy of the right lung and mediastinal dissection for the lung cancer. Her postoperative course was good, and she was discharged 8 days postoperatively. In conclusion, we encountered a patient who successfully underwent pulmonary resection for lung cancer following TAVI for severe AS. We suggest that pulmonary resection following TAVI is an acceptable choice for lung cancer in patients with severe AS because of the lack of a need for cardiopulmonary bypass, the high safety and efficacy of two-stage therapy, and the short period between the two therapies. PMID- 29695654 TI - Associations of Common Genetic Variants on IL-17 Genes and Carotid Intima-Media Thickness. AB - AIM: Atherosclerosis is a chronic inflammatory process of the arterial wall and carotid intima-media thickness (cIMT) is regarded as its early marker. Several members of the IL-17 family are involved in pro-inflammatory functions. The specific aim of the study was to explore the relationships of common genetic variants on IL-17 genes with cIMT thickening. METHODS: In the discovery stage, 146 SNPs on 11 IL-17 genes were screened for their relationships with cIMT by a case-control study that enrolled 284 and 464 subjects who had thicker and normal cIMT, respectively. Findings were replicated by an independent case-control study that enrolled 282 subjects who had thicker cIMT and 282 age-sex-matched subjects who had normal cIMT. RESULTS: Among 134 eligible SNPs in the discovery study, only IL-17RC rs279545 was significantly correlated with cIMT (p=6.9*10-5). The rs279545 and 2 nearby linked SNPs rs55847610 and rs3846167 were included in the validation study. We found that the rs279545*G, rs55847610*G, and rs3846167*C were correlated with significantly higher likelihoods of having thicker cIMT. The corresponding multivariate-adjusted ORs were 1.462 (95% CI: 1.055-2.027), 1.481 (95% CI:1.090-2.013), and 1.589 (95% CI: 1.147-2.200), respectively. Analyses of rs279545-rs55847610 haplotypes showed that the multivariate-adjusted OR for A-A haplotype was significantly decreased (OR=0.665, 95% CI: 0.487-0.908) and for G-G haplotype was significantly increased (OR=1.539, 95% CI: 1.097-2.161). CONCLUSIONS: We first correlated cIMT, a preclinical clinical cardiovascular marker, with IL-17RC, the key molecule in the IL-17 signaling pathway. Our results indicated that IL-17RC may play critical role in the development of atherosclerotic diseases. PMID- 29695655 TI - Drug-Coated Balloon vs. Conventional Balloon Angioplasty in Dialysis Patients With Symptomatic Femoropopliteal Disease - A Matched Comparison. AB - BACKGROUND: Recent randomized trials have shown the treatment benefits of use of a drug-coated balloon (DCB) over conventional percutaneous transluminal angioplasty (PTA) in patients with femoropopliteal disease. However, the effectiveness and safety of DCB for dialysis patients remain unclear.Methods and Results:Consecutive dialysis patients, who underwent PTA or DCB for femoropopliteal disease, were assessed retrospectively via 2:1 propensity score matching. Effectiveness and safety endpoints, including binary restenosis, clinically driven target lesion revascularization (CD-TLR), amputations, major adverse cardiac events (MACE), and deaths, were compared between groups. A total of 278 dialysis patients with 339 limbs were eligible for matching: 84 limbs from 77 patients treated with PTA and 46 limbs from 37 patients treated with DCB were compared after matching. Baseline patient and lesion characteristics were not different between groups. Patients treated with DCB had significantly higher rates of freedom from binary restenosis (52.4% vs. 18.6%, P<0.001) and CD-TLR (56.4% vs. 25.9%, P=0.001) at 2 years compared with patients treated with PTA. Both groups had similar outcomes for amputation, MACE, and death. Cox proportional analysis showed that treatment with DCB was independently associated with a reduction of binary restenosis (hazard ratio [HR] 0.368, P=0.001) and CD TLR (HR 0.390, P=0.004). CONCLUSIONS: This study suggested superior 2-year outcomes using DCB compared with PTA and similar safety profiles in dialysis patients with femoropopliteal disease. PMID- 29695656 TI - In-Hospital Bleeding and Utility of a Maintenance Dose of Prasugrel 2.5 mg in High Bleeding Risk Patients With Acute Coronary Syndrome. AB - BACKGROUND: Data on bleeding events in Japanese patients with acute coronary syndrome (ACS) are insufficient. In addition, the efficacy and safety of a maintenance dose of prasugrel 2.5 mg/day in high bleeding risk patients are unknown.Methods and Results:We prospectively enrolled 1,167 consecutive patients with suspected ACS and undergoing percutaneous coronary intervention. The maintenance dose of prasugrel 2.5 mg/day was prescribed for patients with a low body weight (<=50 kg), elderly (>=75 years), or renal insufficiency (eGFR <=30 mL/min/1.73 m2). In-hospital events were assessed in 992 ACS patients treated with drug-eluting stents. Excluding 29 in-hospital deaths, out-of-hospital events were assessed in 963 ACS patients. The primary safety outcome measure was major bleeding (Bleeding Academic Research Consortium types 3 and 5). The incidence of in-hospital major bleeding was 3.4%. Multivariate analysis showed that being elderly, low body weight, renal insufficiency, stroke history, femoral approach, and mechanical support usage were independent predictors of in-hospital major bleeding. The cumulative 1-year incidence of out-of-hospital major bleeding was not significantly different between the prasugrel 2.5 mg/day (n=284) and 3.75 mg/day (n=487) groups (1.6% vs. 0.7%, log-rank P=0.24). That of out-of-hospital definite or probable stent thrombosis was 0% in both groups. CONCLUSIONS: The maintenance dose of adjusted prasugrel 2.5 mg/day seems to be one option in ACS patients at high bleeding risk. PMID- 29695657 TI - Coexistence of IL-6 -572C/G and ICAM-1 K469E Polymorphisms among Patients with Sudden Sensorineural Hearing Loss. AB - Sudden sensorineural hearing loss (SSNHL) is a multifactorial disease, and its etiology remains elusive. SSNHL is possibly caused by both the environmental factors and genetic alterations. Recently, several studies suggested that inflammation may be involved in the pathogenesis of SSNHL, and certain gene polymorphisms may have correlations with SSNHL. Interleukin 6 (IL-6) functions both as a pro-inflammatory cytokine and an anti-inflammatory factor. Intercellular adhesion molecule-1 (ICAM-1) is a member of the immunoglobulin family that is also involved in inflammation response. Importantly, the IL-6 gene promoter contains a single nucleotide polymorphism (SNP), -572C/G, and ICAM-1 gene contains a SNP (A/G) in the protein-coding region, Lys (AAG)/Glu (GAG) at codon 469, known as K469E polymorphism. However, there is no study about the ICAM 1 gene polymorphism among SSNHL patients. In this study, we explored the relationship between SSNHL with IL-6 -572C/G and ICAM-1 K469E polymorphisms. We conducted a case-control study including 75 SSNHL patients and 165 healthy controls and analyzed the distribution and odds ratios of IL-6 and ICAM-1 genotypes. The frequency of the G allele at IL-6 -572C/G polymorphism was significantly higher among SSNHL patients than that among healthy individuals. In multivariate analysis, the coexistence of IL-6 -572G allele (GG/CG) and E allele (EE/KE) of ICAM-1 K469E polymorphism was significantly associated with an increased SSNHL risk (P < 0.001). In conclusion, we propose that the combination of IL-6 -572C/G and ICAM-1 K469E polymorphisms have a synergistic effect on the onset of SSNHL. PMID- 29695658 TI - Structure-Activity Relationships and Docking Studies of Hydroxychavicol and Its Analogs as Xanthine Oxidase Inhibitors. AB - Hydroxychavicol (HC), which is obtained from the leaves of Piper betle LINN. (Piperaceae), inhibits xanthine oxidase (XO) with an IC50 value of 16.7 uM, making it more potent than the clinically used allopurinol (IC50=30.7 uM). Herein, a structure-activity relationship analysis of the polar part analogs of HC was conducted and an inhibitor was discovered with a potency 13 times that of HC. Kinetic studies have revealed that HC and its active analog inhibit XO in an uncompetitive manner. The binding structure prediction of these inhibitor molecules to the XO complex with xanthine suggested that both compounds (HC and its analog) could simultaneously form hydrogen bonds with xanthine and XO. PMID- 29695659 TI - Effects and Safety of Sodium Glucose Cotransporter 2 Inhibitors in Diabetes Patients With Drug-Refractory Advanced Heart Failure. AB - BACKGROUND: This study aimed to investigate the effect and safety of sodium glucose cotransporter 2 inhibitors (SGLT2-Is) in patients with drug-refractory heart failure (HF).Methods and Results:In 12 diabetic patients with advanced HF, SGLT2-Is were added to the treatment regimen. At 6 months after administration, improvements in New York Heart Association class and reduction in B-type natriuretic peptide levels were observed, in particular in patients with high right atrial pressure. During follow-up, they had neither cardiac events nor adverse side effects. CONCLUSIONS: SGLT2-Is may be useful and safe in diabetic patients with drug-refractory HF, in particular accompanied by right-sided HF. PMID- 29695660 TI - Gut Microbial Dysbiosis in Heart Failure - Is It a Future Therapeutic Target or Not? PMID- 29695661 TI - Enhanced delignification of lignocellulosic substrates by Pichia GS115 expressed recombinant laccase. AB - Utilization of energy-rich crop residues by ruminants is restricted by the presence of lignin, which is recalcitrant to digestion. Application of lignin degrading enzymes on the lignocellulosic biomass exposes the cellulose for easy digestion by ruminants. Laccases have been found to be considerably effective in improving the digestibility by way of delignification. However, laccase yields from natural hosts are not sufficient for industrial scale applications, which restricts their use. A viable option would be to express the laccase gene in compatible hosts to achieve higher production yields. A codon-optimized synthetic variant of Schizophyllum commune laccase gene was cloned into a pPIC9K vector and expressed in P. pastoris GS115 (his4) under the control of an alcohol oxidase promoter. Colonies were screened for G418 resistance and the methanol utilization phenotype was established. The transformant yielded a laccase activity of 344 U.mL-1 after 5 days of growth at 30 degrees C (0.019 g.mL-1 wet cell weight). The laccase protein produced by the recombinant Pichia clone was detected as two bands with apparent molecular weights of 55 kDa and 70 kDa on SDS-PAGE. Activity staining on native PAGE confirmed the presence of bioactive laccase. Treatment of five common crop residues with recombinant laccase recorded a lignin loss ranging between 1.64% in sorghum stover, to 4.83% in finger millet, with an enhancement in digestibility ranging between 8.71% in maize straw to 24.61% in finger millet straw. Treatment with recombinant laccase was effective in enhancing the digestibility of lignocellulosic biomass for ruminant feeding through delignification. To date, a number of hosts have been adventured to produce laccase in large quantities, but, to our knowledge, there are no reports of the expression of laccase protein from Schizophyllum commune in Pichia pastoris, and also on the treatment of crop residues using recombinant laccase for ruminant feeding. PMID- 29695662 TI - A high-throughput method for screening of L-tyrosine high-yield strains by Saccharomyces cerevisiae. AB - A biosensor screening assay based on the synthesis of betaxanthin was applied to relatively high throughput screening of the L-tyrosine mutant library. In the assays, fluorescence output showed a linear relationship between extracellular L tyrosine content and yellow pigment formation. In addition, the yellow pigment accumulation of the L-tyrosine high-yield strain can be easily distinguished with the naked eye compared with the wild-type strain. As a result, numerous mutants that exhibited significantly increased coloration, were screened out after random mutagenesis, and p-coumaric acid production in mutants NK-A3 and NK-B4, were remarkably improved by 4-fold more than that of the wild-type strain. In general, this study provides a novel strategy for screening mutant libraries in the search for highly L-tyrosine-producing strains. PMID- 29695670 TI - Peripheral clear cell variant of calcifying epithelial odontogenic tumor devoid of calcification. AB - A clear cell variant of calcifying epithelial odontogenic tumor (CCEOT) affecting an extraosseous site is described. A 60-year-old male patient presented with gingival swelling on the lingual side of the anterior mandible. The results of biopsy suggested clear cell odontogenic carcinoma, and marginal resection of the mandible was performed. The resected specimen was composed of eosinophilic and clear cells with deposits of amyloid-like material. The clear cells exhibited granules that were positive for PAS. There was no calcification in the resected lesion. Based on these features, the conclusive diagnosis was peripheral CCEOT without calcification. No signs of recurrence were evident after 3 years of follow-up. PMID- 29695671 TI - Marginal sealing of relocated cervical margins of mesio-occluso-distal overlays. AB - We investigated the effect of cervical marginal relocation (CMR) on marginal sealing with two different viscosity resin composites, before adhesive cementation of composite computer-aided design/computer-assisted manufacture mesio-occluso-distal (MOD) overlays. Standardized MOD cavities prepared in 39 human molars were randomly assigned to three groups. The proximal margins on the mesial side were located 1 mm below the cementoenamel junction. On the distal side of the tooth, the margins were located 1 mm above the cementoenamel junction. In Groups 1 and 2, mesial proximal boxes were elevated with a hybrid composite (GC Essentia MD) and a flowable composite (GC G-aenial Universal Flo), respectively. CMR was not performed in Group 3. The overlays were adhesively cemented, and interfacial leakage was quantified by scoring the depth of silver nitrate penetration along the adhesive interfaces. Leakage score at the dentin CMR composite interface did not significantly differ between the two tested composites but was significantly lower for Group 3. In all groups, scores were significantly higher at the dentin interface than at the enamel interface. These results indicate that the performance of flowable and microhybrid resin composites, as indicated by marginal sealing ability, is comparable for CMR. PMID- 29695672 TI - Comparison of post-operative analgesic efficacy of tolfenamic acid and robenacoxib in ovariohysterectomized cats. AB - The objective of this study was to evaluate the efficacy of a non-selective COX inhibitor (tolfenamic acid) and a selective COX-2 inhibitor (robenacoxib) for post-operative pain control in cats. Thirty cats undergoing ovariohysterectomy were randomly divided into three groups: the control (placebo) group, the tolfenamic acid (4 mg/kg/day) group, and the robenacoxib (1 mg/kg/day) group. Non steroidal anti-inflammatory drugs (NSAIDs) were administered orally 2 hr before anesthesia induction and 24 and 48 hr post-operation. Buccal mucosal bleeding times (BMBTs) were assessed prior to anesthesia induction. Colorado pain scores and composite pain scores were evaluated in a blinded fashion before induction and 2, 8, 24, 30 and 48 hr post-operation. The Colorado pain scores of cats receiving robenacoxib were significantly lower than those of cats in the control group at 30 (P=0.0126) and 48 (P=0.0439) hr post-operation. The composite pain scores of cats from the robenacoxib group were lower than those of cats in the control group at 30 (P=0.0299) and 48 (P=0.0103) hr post-operation. The Colorado pain scores of cats receiving tolfenamic acid were significantly lower than those of cats in the control group at 30 hr (P=0.0186) post-operation. The composite pain scores in cats in the tolfenamic acid group were lower than the scores of cats in the control group at 24 (P=0.0403) and 48 (P=0.0413) hr post-operation. BMBTs remained within normal limits in all groups. Both tolfenamic acid and robenacoxib are useful for post-operative pain control in cats. PMID- 29695673 TI - Molecular surveillance of canine distemper virus in diarrhoetic puppies in northeast China from May 2014 to April 2015. AB - To trace the prevalence of canine distemper virus (CDV) in diarrhoetic dogs, a total of 201 stool samples were collected in the Heilongjiang province of northeastern China from May 2014 to April 2015. The 201 fecal samples were subjected to the detection of CDV by using RT-PCR targeting the partial N gene, phylogenetic analysis based on the complete H gene, and co-infection analysis. Results indicated that 24.88% (50/201) of the samples were positive for CDV. The fifty CDV samples exhibited an overall co-infection rate of 94% (47/50) with four enteric viruses (82%, 41/50) and five bacteria (72%, 36/50). The positivity rate of CDV exhibited differences among regions, seasons, ages and immunization status. Phylogenetic analysis of the complete H genes (n=6) revealed that the CDV strains identified in our study belonged to the Asia-1 group, and showed genetic diversities. These data provide evidence that there are a number of genetically diverse CDV Asia-1 strains circulating in diarrhoetic dogs in northeastern China; the CDV-affected animals exhibit the high co-infection with other enteric viruses and bacteria. PMID- 29695675 TI - [Analysis of Acidic Tar Dyes in High-Protein Foods: Achievement of Improved Recoveries and Shortened Operation Time by Loading Sample Extract onto Polyamide Columns at pH 8.5]. AB - The recoveries of xanthene dyes in the analysis of acidic tar-dyes in high protein foods were improved by loading them onto polyamide columns at pH 8.5, instead of using the conventional pH 3-4 solution. The experimental scale was reduced to approximately half that of the conventional method. Furthermore, instead of eliminating the organic solvent in the extract by evaporation, the extract was diluted with water prior to PA column cleanup in order to reduce the ratio of organic solvent so that acidic tar-dyes would be better retained on the column. The above two procedures shortened the operation time and allowed for a simpler protocol. With this method, the recoveries of erythrosine, phloxine, and rose bengal from salted cod roe were 82, 88, and 74%, respectively. The recovery percentages were greatly improved compared to those achieved by conventional column loading at pH 3.5 (26, 44, and 18%, respectively). The recoveries of azo dyes (Amaranth, New Coccine, Allura Red AC, Tartrazine, Sunset Yellow FCF) were also improved from 41-66 to 79-99%. PMID- 29695674 TI - Induction of myosin light chain kinase and CPI-17 by TGF-beta accelerates contractile activity in intestinal epithelial cells. AB - Epithelial-mesenchymal transition (EMT) is an orchestral and functional change in epithelial cells. Many signaling pathways are involved in EMT, and transforming growth factor-beta (TGF-beta) is considered to be one of the most important factors in induction of EMT. In this study, we treated the rat intestinal epithelial cell line (IEC-6) with TGF-beta1 as a signaling stimulant. Gross analysis of IEC-6 cells showed typical characteristics of epithelial cells such as cuboidal morphology and cell-cell contact, whereas treatment with TGF-beta1 (10 ng/ml-1) for 7 days produced robust, spindle-shaped morphology. Immunocytochemistry analysis showed distinct E-cadherin staining in IEC-6 cells, but weak and faint in EMT cells. EMT cells showed positive expression of alpha SMA and tenascin-C but IEC-6 cells did not. Quantitative real-time PCR analysis showed that myosin light chain kinase and C-kinase potentiated protein phosphatase-1 inhibitor (CPI-17) mRNAs were significantly upregulated in EMT cells. Immunocytochemistry analysis also showed that EMT cells strongly expressed CPI-17 but IEC-6 cells did not. A collagen gel contraction assay revealed that EMT cells had greatly increased contraction compared with control cells. These results suggest that the increased contractile activity induced by TGF-beta in EMT cells may be attributable to the upregulation of molecules responsible for myosin phosphorylation/de-phosphorylation. PMID- 29695676 TI - [Notable Adverse Events Associated with Concomitant Use of Health Foods and Drugs Derived from the Analysis of HFNet Data on the Safety and Effectiveness of Health Foods]. AB - Health foods are commonly consumed at their own discretion by patients with various diseases who are also being treated with conventional drugs. Both health foods and drugs are diverse, and enormous numbers of possible combinations exist, so that it is very difficult to identify adverse events that may occur due to their interactions. Here, we analyzed the characteristics of adverse events related to the concomitant use of health foods and drugs using data from the "Information system on safety and effectiveness for health foods (HFNet)" website (https://hfnet.nibiohn.go.jp/) compiled by the Food Function and Labeling Department of the National Institute of Health and Nutrition of Japan. We identified 64 reports and 71 patients, and characterized them according to symptom severity and drug classification. The analysis revealed that symptoms of liver dysfunction were mainly reported in patients receiving high-risk drugs, such as antiepileptic, antineoplastic, antiarrhythmic, and antithrombotic drugs, concomitantly with health foods or drugs. However, journal articles describing health food and drug interactions generally did not provide sufficient information about the ingredients of the health foods. PMID- 29695677 TI - [Inactivating Effect of Heat-Denatured Lysozyme on Murine Norovirus in Bread Fillings]. AB - In this study, we investigated the viability of murine norovirus strain 1 (MNV 1), a surrogate for human norovirus, in bread fillings used for making stuffed buns and pastries. The inactivating effect of heat-denatured lysozyme, which was recently reported to have an antiviral effect, on MNV-1 contaminating the bread fillings was also examined. MNV-1 was inoculated into two types of fillings (chocolate cream, marmalade jam) at 4.5 log PFU/g, and the bread fillings were stored at 4C for 5 days. MNV-1 remained viable in the bread fillings during storage. However, addition of 1% heat-denatured lysozyme to the fillings resulted in a decrease of MNV-1 infectivity immediately after inoculation, in both fillings. On the fifth day of storage, MNV-1 infectivity was decreased by 1.2 log PFU/g in chocolate cream and by 0.9 log PFU/g in marmalade jam. Although the mechanism underlying the anti-norovirus effect of heat-denatured lysozyme has not been clarified, our results suggest that heat-denatured lysozyme can be used as an inactivating agent against norovirus in bread fillings. PMID- 29695678 TI - [Analysis of Safety Alerts Associated with Dietary Supplements from Japan and Overseas]. AB - The prevalence of dietary supplement use has increased in Japan, and consumers can purchase supplements from foreign countries through the internet. Therefore, it is important to consider both domestic and overseas safety alerts to prevent adverse events associated with dietary supplement use. We have been collecting global safety alerts associated with dietary supplements and providing this information to the public via the "Information system on safety and effectiveness for health foods (HFNet)" website. In this study, we analyzed the characteristics of safety alerts from 2010 to 2016 in HFNet (total: 2,124 alerts). The most common reason for alerts was illegal adulteration with pharmaceutical substances (85%), and sexual enhancement or weight loss products accounted for 68% of all alerts. Most alerts were based on market surveillance reports or recall information. However, 181 adverse event reports were identified, and most of them were related to weight loss or disease treatment in patients. In Japan, a majority of the adverse events was caused by products intended for weight loss or purchased online, and young female users were commonly involved. These findings should be helpful for prevention of adverse events associated with dietary supplement use. PMID- 29695679 TI - First report of the occurrence and whole-genome characterization of Edwardsiella tarda in the false killer whale (Pseudorca crassidens). AB - Although several Edwardsiella tarda infections have been reported, its pathogenic role in marine mammals has not been investigated at the genome level. We investigated the genome of E. tarda strain KC-Pc-HB1, isolated from the false killer whale (Pseudorca crassidens) found bycaught in South Korea. The obtained genome was similar to that of human pathogenic E. tarda strains, but distinct from other Edwardsiella species. Although type III and VI secretion systems, which are essential for the virulence of other Edwardsiella species, were absent, several virulence-related genes involved in the pathogenesis of E. tarda were found in the genome. These results provide important insights into the E. tarda infecting marine mammals and give valuable information on potential virulence factors in this pathogen. PMID- 29695680 TI - Proliferative changes in the adrenal medulla of aged Chinese native pigs. AB - Four aged retired Chinese native pigs, three females and one male, estimated as over 10-year-old, were subjected to autopsy because of infertility due to aging. Grossly, nodular lesions were found bilaterally in the adrenal medulla of all four pigs. Based on the gross and the histopathological findings, they were diagnosed as either medullary nodular hyperplasia or pheochromocytoma. Immunohistochemically, proliferating cells of all these lesions were immuno positive for chromogranin-A, indicating adrenal medulla-derived. Ultrastructurally, cytoplasmic neurosecretory granules suggestive of secretion were observed in these proliferating cells. There have been only limited numbers of reports on adrenal medullar proliferative changes including pheochromocytoma in pigs. The present cases will provide a valuable information for the characterization of similar changes in animals and human. PMID- 29695681 TI - Investigation of genetic diversity and epidemiological characteristics of Pasteurella multocida isolates from poultry in southwest China by population structure, multi-locus sequence typing and virulence-associated gene profile analysis. AB - Fowl cholera caused by Pasteurella multocida has always been a disease of global importance for poultry production. The aim of this study was to obtain more information about the epidemiology of avian P. multocida infection in southwest China and the genetic characteristics of clinical isolates. P. multocida isolates were characterized by biochemical and molecular-biological methods. The distributions of the capsular serogroups, the phenotypic antimicrobial resistance profiles, lipopolysaccharide (LPS) genotyping and the presence of 19 virulence genes were investigated in 45 isolates of P. multocida that were associated with clinical disease in poultry. The genetic diversity of P. multocida strains was performed by 16S rRNA and rpoB gene sequence analysis as well as multilocus sequence typing (MLST). The results showed that most (80.0%) of the P. multocida isolates in this study represented special P. multocida subspecies, and 71.1% of the isolates showed multiple-drug resistance. 45 isolates belonged to capsular types: A (100%) and two LPS genotypes: L1 (95.6%) and L3 (4.4%). MLST revealed two new alleles (pmi77 and gdh57) and one new sequence type (ST342). ST129 types dominated in 45 P. multocida isolates. Isolates belonging to ST129 were with the genes ompH+plpB+ptfA+tonB, whereas ST342 included isolates with fur+hgbA+tonB genes. Population genetic analysis and the MLST results revealed that at least one new ST genotype was present in the avian P. multocida in China. These findings provide novel insights into the epidemiological characteristics of avian P. multocida isolates in southwest China. PMID- 29695683 TI - Taxonomic revision of the genus Mesechinus (Mammalia: Erinaceidae) with description of a new species. AB - Hedgehogs in the genus Mesechinus (Family Erinaceidae), which include two currently recognized species (M. dauuricus and M. hughi), are distributed from northeast Mongolia to the upper Amur Basin in Russia and adjacent areas in northeast and northern China. In recent years, a population of Mesechinus hedgehogs was discovered from Mt. Gaoligong, southwestern Yunnan, China, far from the known distribution range of the genus. Furthermore, these hedgehogs are the only known population to be distributed at elevations higher than 2 100 m and in sympatry with gymnures. To evaluate the taxonomic status of these hedgehogs, we examined specimens representing Mesechinus taxa in China and further conducted morphometric and karyotypic analyses. Our results supported the existence of four species in China. Specifically, we identified the hedgehogs from Mt. Gaoligong as a new species, Mesechinus wangi sp. nov., and recognized M. miodon, previously considered as a synonym of either M. dauuricus or M. hughi, as a distinct species. Interestingly, we observed a supernumerary M4 on all specimens of Mesechinus wangi sp. nov., which is an extremely rare event in the evolution of mammalian dentition. PMID- 29695682 TI - A Systematic Review of the Natural Virome of Anopheles Mosquitoes. AB - Anopheles mosquitoes are vectors of human malaria, but they also harbor viruses, collectively termed the virome. The Anopheles virome is relatively poorly studied, and the number and function of viruses are unknown. Only the o'nyong nyong arbovirus (ONNV) is known to be consistently transmitted to vertebrates by Anopheles mosquitoes. A systematic literature review searched four databases: PubMed, Web of Science, Scopus, and Lissa. In addition, online and print resources were searched manually. The searches yielded 259 records. After screening for eligibility criteria, we found at least 51 viruses reported in Anopheles, including viruses with potential to cause febrile disease if transmitted to humans or other vertebrates. Studies to date have not provided evidence that Anopheles consistently transmit and maintain arboviruses other than ONNV. However, anthropophilic Anopheles vectors of malaria are constantly exposed to arboviruses in human bloodmeals. It is possible that in malaria-endemic zones, febrile symptoms may be commonly misdiagnosed. It is also possible that anophelines may be inherently less competent arbovirus vectors than culicines, but if true, the biological basis would warrant further study. This systematic review contributes a context to characterize the biology, knowledge gaps, and potential public health risk of Anopheles viruses. PMID- 29695684 TI - Effects of Recombinant Circularly Permuted Tumor Necrosis Factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) (Recombinant Mutant Human TRAIL) in Combination with 5-Fluorouracil in Human Colorectal Cancer Cell Lines HCT116 and SW480. AB - BACKGROUND Circularly permuted tumor necrosis factor-related apoptosis-inducing ligand, a mutant form of tumor necrosis factor-related apoptosis-inducing ligand, is an effective antitumor cytokine. However, its antitumor effect in colorectal cancer is unclear. This study assessed the antitumor effect of circularly permuted tumor necrosis factor-related apoptosis-inducing ligand alone or with 5 fluorouracil in colorectal cancer cells in vitro and explored the underlying mechanisms. MATERIAL AND METHODS We used the (3-(4,5-dimethylthiazol-2-yl)-5-(3 carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) (MTS) assay to analyze cell proliferation inhibition. The apoptotic effects of circularly permuted tumor necrosis factor-related apoptosis-inducing ligand, 5-fluorouracil, or both in human colorectal cancer cells were evaluated using flow cytometry. Furthermore, the levels of apoptosis-related proteins were examined by Western blotting. RESULTS Compared to either agent alone, cotreatment with 5-fluorouracil and circularly permuted tumor necrosis factor-related apoptosis-inducing ligand showed obvious antitumor effects and induced significant apoptosis of colorectal cancer cells. 5-Fluorouracil enhanced circularly permuted tumor necrosis factor related apoptosis-inducing ligand-induced apoptosis by increasing death receptor 4 and 5 levels in HCT116 cells, but only of death receptor 4 in SW480 cells. Moreover, 5-fluorouracil plus circularly permuted tumor necrosis factor-related apoptosis-inducing ligand increased apoptosis-related protein levels such as cleaved caspase-3, caspase-8, and poly-ADP-ribose polymerase and downregulated that of the survival protein B-cell lymphoma-extra-large. Pretreatment with the pan-caspase inhibitor, z-VAD-FMK, attenuated the caspase-dependent apoptosis induced by circularly permuted tumor necrosis factor-related apoptosis-inducing ligand alone or combined with 5-fluorouracil. CONCLUSIONS Cotreatment with 5 fluorouracil and circularly permuted tumor necrosis factor-related apoptosis inducing ligand showed enhanced antitumor effects on colorectal cancer cells. PMID- 29695685 TI - Malposition of Peripherally Inserted Central Catheter Into the Right Inferior Thyroid Vein: A Case Report. AB - BACKGROUND A peripherally inserted central catheter (PICC) causes few serious complications but can be malpositioned. To avoid malpositioning, ultrasound guidance is widely used. Here, we report the case of a patient who received a PICC that was inserted under ultrasound guidance, but the catheter tip accidentally entered the right inferior thyroid vein. CASE REPORT A 58-year-old woman was scheduled for reconstructive mammoplasty. After general anesthesia, a PICC was inserted via the right basilic vein. The PICC was inserted under guidance using a portable ultrasound machine with a high-frequency linear transducer. The tip of the guide wire and catheter were confirmed by ultrasound to be in the right subclavian vein, not in the right internal jugular vein, during insertion. However, the chest X-ray performed after the PICC insertion showed that the catheter had moved into the right inferior thyroid vein. CONCLUSIONS Malpositioning of a PICC can occur into any small vein. Ultrasound should be used not only to avoid malpositioning into the IJV, but also to confirm the proper position of the catheter tip during PICC insertion. PMID- 29695687 TI - [Epigenetic Mechanisms of Blood-Pressure Regulation]. AB - The role of epigenetic mechanisms involved in blood-pressure regulation has been reviewed. It is known that some periods in early pre- and postnatal ontogenesis are very sensitive to some environmental and endogenous influences. These periods are characterized as highly vulnerable to the formation of a complex of epigenetic changes that may determine the trajectory of the further formation of physiological systems involved in the blood-pressure regulation. Early life influences on these systems may predispose an individual to the development of hypertensive disease in further life. In some cases, the transmission of epigenetic changes to the next generations may resolve the contradiction between the high heritability of arterial hypertensive disease and the low total contribution of polymorphic DNA variants in the population variability of blood pressure values. PMID- 29695688 TI - [Human Genetic Predisposition to Diseases Caused by Viruses from Flaviviridae Family]. AB - The identification of human predisposition genes to severe forms of infectious diseases is important for understanding the mechanisms of pathogenesis, as well as for the detection of the risk groups. This will allow one to carry out targeted vaccination and preventive therapy. The most common approaches to the genetic risk estimation include conducting association studies, in which the groups of patients and control individuals are compared using both preliminarily selected candidate genes and using genome-wide analysis. To search for genetic variants predisposed to severe forms of infectious diseases, it is expedient to form a control that consists of patients with clinically proven infections with asymptomatic or mild forms of the disease. The examples of the use of these approaches to identify genetic factors that predispose one to severe forms of infections caused by viruses from the Flaviviridae family are considered in the review. At present, a number of genetic markers associated with predisposition to tick-borne encephalitis, West Nile fever, and Dengue fever have already been detected. These associations must be confirmed in independent samples. Genetic variants, for which the association with spontaneous recovery during infection with hepatitis C virus, patient's reaction on antiviral drugs, and the development of liver fibrosis was established, were also detected. The gene variants with more pronounced phenotypic effects will probably be found during further studies; they can be used in clinical practice as prognostic markers of the course and outcomes of infection with the Flaviviridae, as well as of the response to treatment. PMID- 29695686 TI - [Functional Characterization of Septin Complexes]. AB - Septins belong to a family of conserved GTP-binding proteins found in majority of eukaryotic species except for higher plants. Septins form nonpolar complexes that further polymerize into filaments and associate with cell membranes, thus comprising newly acknowledged cytoskeletal system. Septins participate in a variety of cell processes and contribute to various pathophysiological states, including tumorigenesis and neurodegeneration. Here, we review the structural and functional properties of septins and the regulation of their dynamics with special emphasis on the role of septin filaments as a cytoskeletal system and its interaction with actin and microtubule cytoskeletons. We also discuss how septins compartmentalize the cell by forming local protein-anchoring scaffolds and by providing barriers for the lateral diffusion of the membrane proteins. PMID- 29695689 TI - [Role of the Nucleolus in Rearrangements of the IGH Locus]. AB - The review summarizes the results from a series of studies focusing on the role that the nucleolus plays in maturation of the IGH locus and the choice of its partner genes in leukemia-associated translocations. The role of nuclear compartmentalization and nuclear localization of translocated oncogenes in ectopic activation of their transcription is discussed. PMID- 29695690 TI - [Overexpression of microRNAs miR-9, -98, and -199 Correlates with the Downregulation of HK2 Expression in Colorectal Cancer]. AB - Glycolysis activation is one of the main features of energy metabolism in cancer cells that is associated with the increase in glycolytic enzyme synthesis, primarily, hexokinases (HKs), in many types of tumors. Conversely, in colorectal cancer (CRC) the decrease in the expression of HK2 gene, which encodes one of the key rate-limiting enzyme of glycolysis, was revealed, thus, the study of the mechanisms of its inhibition in CRC is of particular interest. To search for potential microRNAs, inhibiting the expression of HK2 in CRC, we have performed the analysis of data from "The Cancer Genome Atlas" (TCGA) and five microRNA-mRNA target interaction databases (TargetScan, DIANA microT, mirSVR (miRanda), PicTar, and miRTarBase) using original CrossHub software. Seven microRNAs containing binding site on mRNA HK2, which expression is negatively correlated with HK2 expression, were selected for further analysis. The expression levels of these microRNAs and mRNA HK2 were estimated by quantitative PCR on a set of CRC samples. It has been shown, that the expression of three microRNAs (miR-9-5p, -98 5p, and -199-5p) was increased and correlated negatively with mRNA level of HK2 gene. Thus, downregulation of HK2 gene may be caused by its negative regulation through microRNAs miR-9-5p, -98-5p, and -199-5p. PMID- 29695691 TI - [Identification of Fusion Transcripts in Leukemic Cells by Whole-Transcriptome Sequencing]. AB - Genetic aberrations in leukemia often lead to the formation of expressed chimeric genes, which should be assessed for proper diagnosis and therapy. Modern methods of molecular diagnostic mainly allow to identify already known fusion genes. RNAseq is an efficient tool for identification of rare and novel chimeric transcripts. Here we present the results of the whole transcriptome analysis of bone marrow samples from five patients with acute myeloblastic leukemia and one, with myelodysplastic syndrome. The whole-transcriptome analysis was performed using Illumina/Solexa approach. We found rare or unknown chimeric transcripts including ETV6-MDS1, MN1-ETV6, OAZ1-PTMA, and MLLT10-GRIA4. Each of these transcripts was confirmed by RT-PCR and Sanger sequencing. PMID- 29695692 TI - [Multiplex Genotyping of Allelic Variants of Genes Involved in Metabolizing Antileukemic Drugs]. AB - A biochip, primer set, and genotyping protocol were developed to simultaneously address 16 single nucleotide polymorphisms in antileukemic drug metabolism genes, including TPMT, ITPA, MTHFR, SLCO1B1, SLC19A1, NR3C1, GRIA1, ASNS, MTRR, and ABCB1. The genotyping procedure included a one-round multiplex polymerase chain reaction (PCR) with simultaneous incorporation of a fluorescent label into the PCR product and subsequent hybridization on a biochip with immobilized probes. The method was used to test 65 DNA samples of leukemia patients. Fluorescence signal intensity ratios in pairs of wild-type and respective mutant sequence probes were analyzed for all polymorphic markers and demonstrated high accuracy of genotyping. The reliability of genotype determination using the biochip was confirmed by direct Sanger sequencing. PMID- 29695693 TI - [Functional Responses to the Chronic Activation of 5-HT1A Receptors in Mice with Genetic Predisposition to Catalepsy]. AB - The effects of chronic 5-HT1A receptor activation on the behavior, functional activity of 5-HT1A receptors, and expression of key genes of the brain 5-HT system were studied in mice of the catalepsy-prone CBA strain and the catalepsy resistant C57BL/6 strain. Chronic treatment with 8-Hydroxy-2-(di-n-propyl amino)tetralin (8-OH-DPAT) (1.0 mg/kg i.p., 14 days) led to a significant decrease in the hypothermic response to acute administration of 8-OH-DPAT in CBA and C57BL/6 mice, which indicates the desensiti-zation of 5-HT1A receptors in both strains. Pretreatment with the 5-HT7 receptor agonist SB 269970 did not affect the hypothermic response to the acute administration of 8-OH-DPAT, which suggests an independent functional response of 5-HT1A receptors. The treatment did not induce any changes in the behavior in the open field paradigm in CBA mice, but significantly increased the total path, the time spent in the center, and the number of rearings in C57BL/6 mice, which indicates the enhancement of locomotor and exploratory activity in C57BL/6 mice. The chronic activation of 5 HT1A receptor downregulated 5-HT1A gene expression, as well as the expression of the gene that encodes tryptophan hydroxylase 2, a key enzyme of 5-HT biosynthesis, in the midbrain and the expression of the gene that encodes the 5 HT2A receptor in the frontal cortex of CBA, but not C57BL/6 mice. The obtained data provide a new evidence on the receptor-gene cross talk in the brain 5-HT system that may underlie the loss of pharmacological efficacy of 5-HT1A receptor agonists. In turn, the loss of the behavioral response and compensatory alterations in key genes of the brain 5-HT system in CBA mice suggests that catalepsy-prone and -resistant genotypes demonstrate different sensibility to the effects of drugs. PMID- 29695694 TI - [Maturation and Antigen Loading Protocols Influence Activity of Anticancer Dendritic Cells]. AB - The practical use of dendritic cell-based vaccines in anticancer therapy is limited by a lack of standards for dendritic cell (DC) generation, as well as standard procedures for controlling their activation and the technique of DC loading with nucleic acids encoding tumor antigens. Analyzing the currently available data, the most promising cocktails for DC maturation were selected and a comparative study of the cocktails and time of maturation on the capacity of DC to activate T-cell immune response has been performed. A study of the expression of surface markers and the production of IL-12, IL-6, and IL-10 cytokines, as well as the efficacy of T-cell activation showed that the use of the standard 7 day maturation protocol is preferable to the 4-day maturation protocol. Cocktails composed of TNF-alpha, IL-lbeta, IFN-alpha, IFN-gamma, and poly(I:C), as well as TNF-alpha, IL-lbeta, IFN-gamma, R848, and PGE2 were shown to be the most efficient activators of DCs. A comparison of the efficacy of different methods of DNA transfection into DCs and RNA delivery using alphavirus vectors demonstrated the superiority of magnet-assisted transfection (MATra) to other protocols. PMID- 29695695 TI - [Increase in Bacterial Resistance to Antibiotics after Cancer Therapy with Platinum-Based Drugs]. AB - The use of platinum-based anticancer drugs is limited by both their side effects and their effect on normal microflora's metagenome. Drugs that possess mutagenic and genotoxic properties may cause mutations in microbial genomes that contribute to the emergence of resistance to antimicrobial preparations and the development of complications after chemotherapy. The effects of cisplatin and oxaliplatin on microorganisms were studied using bacterial biosensors - E. coli strains MG1655 pKatG-lux, which reacts to the generation of hydrogen peroxide; MG1655 pSoxS-lux, which reacts to the superoxide anion radical; and the MG1655 pColD-lux strain, which detects DNA damage. The biosensor tests demonstrated high levels of genotoxicity for both drugs and some differences in the spectrum of reactive oxygen species generated. Ascor-bate reduced genotoxicity of cisplatin by 41%. Nonlethal doses of cisplatin induced a three- to sevenfold increase in the frequency of the mutations that confer the resistance of E. coli to rifampicin and ciprof loxacin. Ascorbate also reduced frequency of the mutations by 65%. Thus, the effect of these drugs was probably associated with the generation of reactive oxygen species and induction of SOS response. The risk of secondary antibiotic-resistant infections may be decreased by applying antioxidants and antimutagens. At the same time, these increases may also decrease the anti tumoral action of these compounds. PMID- 29695696 TI - [DNA Bearing Bulky Fluorescent and Photoreactive Damage in Both Strands as Substrates of the Nucleotide Excision Repair System]. AB - Model DNA molecules that contain bulky lesions in both strands have been created, and their properties as substrates of the nucleotide excision repair (NER) system have been analyzed. The modified nucleoside, 5-[3-(4-azido-2,3,5,6 tetrafluorobenzamido)-1-propoxypropyl]-2'-deoxycytidine (dC^(FAB)), or the nonnucleoside fragment, N-[6-(9-anthracenylcarbamoyl)hexanoyl]-3-amino-1,2 propanediol (nAnt), have been inserted as damage in certain positions of the first DNA strand ("0"). The position of N-[6-5(6) fluoresceinylcarbamoyl]hexanoyl] -3-amino-1,2-propanediol (nFlu) has been varied within the second DNA strand. This residue has been located opposite the removable damaging fragment of the first strand at positions -20, -10, -4, 0, +3, and +8 relative to the first lesion. It has been demonstrated that the presence of nFlu at the -4, 0, or +3 position of the second strand significantly reduces the thermostability of DNA duplexes, especially in the case of nAnt-DNA and completely excludes the possibility of NER-catalyzed excision from dC^(FAB)- and nAnt-containing 137-meric DNA with the second lesion at these positions. The introduction of nFlu at positions -20, -10, or +8 differently affects the excision efficiency of dC^(FAB)- and nAnt-containing fragments from the first strand. The excision efficiency of dC^(FAB)-containing fragments from extended double-damaged DNA is as high as from DNA that contains a single dC^(FAB) damage, while the excision of nAnt-containing fragments occurs with 80-90% lower efficiency from double-damaged DNA occurs from DNA that contains the single nAnt insert. The nFlu insert differently affects the interaction of the sensory XPC HR23B dimer with dC^(FAB)- and nAnt-containing DNAs, although in all cases, this interaction occurs with increased efficiency compared to that with single-damaged DNAs. No direct correlation between the thermostability of the DNA duplex and XPC DNA affinity on the one hand, and the excision efficiency of lesions on the other hand has been shown. The absence of the correlation may be caused by both functional features of variable multiprotein complexes involved in the recognition and verification of damage during NER and the sensitivity of the complexes to the structure of the damage and damage-surrounding DNA. The results are important for understanding the NER mechanism of elimination of bulky damage located in both DNA strands. PMID- 29695698 TI - [Protection of Lymphocytes Against HIV using Lentivirus Vector Carrying a Combination of TRIM5alpha-HRH Genes and microRNA Against CCR5]. AB - Gene therapy is considered a promising approach to treating infections caused by human immunodeficiency virus (HIV). One strategy is to introduce antiviral genes into cells in order to impart resistance to HIV. In this work, the antiviral activity of new anti-HIV lentiviral vector pT has been studied. The vector carries a combination that consists of two identical artificial miRNA mic13lg and the TRIM5alpha-HRH gene. Two mic13lg microRNAs suppress the expression of the CCR5 gene, which encodes the HIV coreceptor and, thus, prevents the penetration of R5-tropic HIV strains into the cell. It has been shown that pT effectively inhibits the expression of CCR5 in both the HT1080 CCR5-EGFP model cell line and in human primary lymphocytes. The second line of protection against R5- and X4 tropic HIV is provided by the TRIM5alpha-HRH protein, which binds virus capsids after the virus enters the cell. Indeed, when infecting cells of the SupT1 line, which contains four copies of the vector per cell, with the X-4 tropic HIV, more than 1000-fold suppression of viral replication has been observed. The process of generation of the pT vector and conditions of transduction of CD4^(+) lymphocytes were optimized for testing the antiviral activity of the vector on primary human lymphocytes. As a result, the transduction efficiency for the pT vector was 28%. After infection with the R5-tropic strain of the virus, the survival of cells in the culture of lymphocytes with the vector was significantly higher than in the control. However, the complete suppression of HIV replication was not achieved, presumably due to the inadequate fraction of cells that carry the vector in culture. In the future, it is planned to find the best way to enrich the lymphocyte culture with modified cells to increase resistance to HIV. PMID- 29695697 TI - [Enhancement of Na,K-ATPase Activity as a Result of Removal of Redox Modifications from Cysteine Residues of the al Subunit: the Effect of Reducing Agents]. AB - Na,K-ATPase is a transmembrane enzyme that creates a gradient of sodium and potassium, which is necessary for the viability of animal cells. The activity of Na,K-ATPase depends on the redox status of the cell, decreasing with oxidative stress and hypoxia. Previously, we have shown that the key role in the redox sensitivity of Na,K-ATPase is played by the regulatory glutathionylation of cysteine residues of the catalytic alpha subunit, which leads to the inhibition of the enzyme. In this study, the effect of reducing agents (DTT, ME, TCEP) on the level of glutathionylation of the alpha subunit of Na,K-ATPase from rabbit kidneys and the enzyme activity has been evaluated. We have found that the reducing agents partially deglutathionylate the protein, which leads to its activation. It was impossible to completely remove glutathionylation from the native rabbit kidney protein. The treatment of a partially denatured protein on the PVDF membrane with reducing agents (TCEP, NaBH4) also does not lead to the complete deglutathionylation of the protein. The obtained data indicate that Na,K ATPase isolated from rabbit kidneys has both regulatory and basal glutathionylation, which appears to play an important role in the redox regulation of the function of Na, K-ATPase in mammalian tissues. PMID- 29695699 TI - [Novel Glycyrrhetinic Acid Derivative Soloxolone Methyl Inhibits the Inflammatory Response and Tumor Growth in vivo]. AB - Due to wide spreading of inflammatory disease and imperfection of available anti inflammatory drugs, mainly associated with their serious side effects, searching for new anti-inflammatory agents is a pressing problem. Natural triterpenoids and their synthetic analogs are a promising source of new drugs. In this study, we have investigated the anti-inflammatory and antitumor effects in vivo of the glycyrrhetinic acid derivative soloxolone methyl (SM), or methyl 2-cyano-3,12 dioxo-18betaH-olean-9(ll),l(2)-dien-30-oate. SM was shown to efficiently suppress the development of edema in a mouse model of carrageenan- or histamine-induced acute inflammation. SM also inhibited the tumor growth and reduced the tumor cell count in the ascitic fluid in mice bearing Krebs-2 carcinoma, the development of which is accompanied by an inflammatory process in the surrounding tissues. PMID- 29695700 TI - [Rabies Virus Glycoprotein with a Consensus Amino Acid Sequence and a Lysosome Targeting Signal Causes Effective Production of Antibodies in DNA-Immunized Mice]. AB - Safe and effective anti-rabies vaccines are intensely sought worldwide. DNA vaccines have already shown their efficacy and safety and have occupied a special place in the field. Two prototype anti-rabies DNA vaccines were compared for the potential to induce virus-specific antibody production. One vector contained a codon-optimized gene with a territory-adapted consensus sequence of the rabies virus glycoprotein. The other one expressed the same glycoprotein in fusion with a c-CD63 lysosome targeting motif at the C terminus. ELISA of serum samples from immunized mice showed that the c-CD63 variant induced more efficient antibody production and shifted the IgG2a/IgG1 ratio towards the Th2-type immune response. The results gave grounds to believe that the approach successfully applied to the rabies glycoprotein may help to develop new-generation anti-rabies vaccines. PMID- 29695701 TI - [Detection of DNA Methylation by Dnmt3a Methyltransferase using Methyl-Dependent Restriction Endonucleases]. AB - DNA methylation at cytosine residues in CpG sites by DNA methyltransferases (MTases) is associated with various cell processes. Eukaryotic MTase Dnmt3a is the key enzyme that establishes the de novo methylation pattern. A new in vitro assay for DNA methylation by murine MTase Dnmt3a was developed using methyl dependent restriction endonucleases (MD-REs), which specifically cleave methylated DNA. The Dnmt3a catalytic domain (Dnmt3a-CD) was used together with KroI and PcsI MD-REs. The assay consists in consecutive methylation and cleavage of fluorescently labeled DNA substrates, then the reaction products are visualized in polyacrylamide gel to determine the DNA methylation efficiency. Each MD-RE was tested with various substrates, including partly methylated ones. PcsI was identified as an optimal MD-RE. PcsI recognizes two methylated CpG sites located 7 bp apart, the distance roughly corresponding to the distance between the active centers of the Dnmt3a-CD tetramer. An optimal substrate was designed to contain two methylated cytosine residues and two target cytosines in the orientation suitable for methylation by Dnmt3a-CD. The assay is reliable, simple, and inexpensive and, unlike conventional methods, does not require radioactive compounds. The assay may be used to assess the effectiveness of Dnmt3a inhibitors as potential therapeutic agents and to investigate the features of the Dnmt3a-CD function. PMID- 29695702 TI - [Prediction of Bacterial and Archaeal Allergenicity with AllPred Program]. AB - Nowadays, allergic disorders have become one of the most important social problems in the world. This can be related to the advent of new allergenic agents in the environment, as well as an increasing density of human contact with known allergens, including various proteins. Thus, the development of computer programs designed for the prediction of allergenic properties of proteins becomes one of the urgent tasks of mo dern bioinformatics. Previously we developed a web accessible Allpred Program (http://www-bionet.sscc.ru/ psd/cgi bin/programs/Allpred/allpred.cgi) that allows users to assess the allergenicity of proteins by taking into account the characteristics of their spatial structure. In this paper, using AllPred, we predicted the allergenicity of proteins from 462 archaea and bacteria species for which a complete genome was available. The segregation of considered proteins on archaea and bacteria has shown that allergens are predicted more often among archaea than among bacteria. The division of these proteins into groups according to their intracellular localization has revealed that the majority of allergenic proteins were among the secreted proteins. The application of methods for predicting the level of gene expression of microorganisms based on DNA sequence analysis showed a statistically significant relationship between the expression level of the proteins and their allergenicity. This analysis has revealed that potentially allergenic proteins were more common among highly expressed proteins. Sorting microorganisms into the pathogenic and nonpathogenic groups has shown that pathogens can potentially be more allergenic because of a statistically significant greater number of allergens predicted among their proteins. PMID- 29695703 TI - [BCIgEPRED-a Dual-Layer Approach for Predicting Linear IgE Epitopes]. AB - Allergy is a common health problem worldwide, especially food allergy. Since B cell epitopes that are recognized by the IgE antibodies act as antigenic determinants for allergy, they play a vital role in diagnostics. Hence, knowledge of an IgE binding epitope in a protein is of particular interest for identifying aller-genic proteins. Though IgE epitopes maybe conformational or linear, identification of the later is useful especially in food allergens that undergo processing or digestion. Very few computational tools are available for the prediction of linear IgE epitopes. Here we report a prediction system that predicts the exact linear IgE epitope. Since our earlier study on linear B cell epitope prediction demonstrated the effectiveness of using an exact epitope dataset (in contrast to epitope containing region datasets), the dataset in this study uses only experimentally verified exact IgE, IgG, IgM and IgA epitopes. Models for Support Vector Machine (SVM) and Random Forest (RF) were constructed adopting Dipeptide Deviation from the Expected mean (DDE) feature vector. Extensive validation procedures including five-fold cross validation and two different independent dataset tests have been performed to validate the proposed method, which achieved a balanced accuracy ranging from 74 to 78% with area under receiver operator curve greater than 0.8. Performance of the proposed method was observed to be better (accuracy difference of 16-28%) in comparison to the existing available method. The proposed method is developed as a standalone tool that could be used for predicting IgE epitopes as well as to be incorporated into any allergen prediction toolhttps://github.com/brsaran/BCIgePred. PMID- 29695704 TI - Human adipose tissue protein analyses using capillary western blot technology. AB - A capillary western blot (Wes(r)) technology has recently been validated for analyses of cell culture lysate proteins, but whether it is reliable for human tissue proteins is unknown. We compared traditional western blotting to the Wes(r) capillary western method to quantitate the relative amount of human adipose tissue CD36, the ratio of phosphorylated Erk1/2 (pErk1/2) to total Erk1/2 during insulin clamp or after niacin treatment and the fold increase in pAktS473 (Akt phosphorylation on Ser473) in response to feeding. The results from these two methods were highly correlated (r = 0.932 for CD36, r = 0.905 for pErk1/2:Erk1/2, r = 0.923 for the change in pAkt/Akt, P < 0.001). On Wes(r) we observed the distinct peaks around the expected molecular weights for these proteins with decreasing peak areas with serial dilutions of loading protein amount. Wes(r) and traditional western blot both had linear dynamic ranges for CD36, Erk1/2 and Akt. Due to differences in signal responsiveness for pAkt/Akt, we employed a calibrator sample and log transformation of data to allow proper comparisons. The Wes(r) approach required less sample than the traditional western blot and less technician/assay time, while achieving high sensitivity and good reproducibility. Capillary western technology (Wes(r)) provides a satisfactory alternative for analyses of human adipose tissue proteins. PMID- 29695705 TI - Dietary patterns and type 2 diabetes among Ghanaian migrants in Europe and their compatriots in Ghana: the RODAM study. AB - BACKGROUND/OBJECTIVES: We aimed to study the associations of dietary patterns (DPs) with type 2 diabetes (T2D) among Ghanaian adults. SUBJECTS/METHODS: In the multi-centre, cross-sectional RODAM (Research on Obesity and Diabetes among African Migrants) study (n = 4543), three overall DPs ("mixed", "rice, pasta, meat and fish," and "roots, tubers and plantain") and two site-specific DPs per study site (rural Ghana, urban Ghana and Europe) were identified by principal component analysis. The DPs-T2D associations were calculated by logistic regression models. RESULTS: Higher adherence to the "rice, pasta, meat and fish" DP (characterized by legumes, rice/pasta, meat, fish, cakes/sweets, condiments) was associated with decreased odds of T2D, adjusted for socio-demographic factors, total energy intake and adiposity measures (odds ratio (OR)per 1 SD = 0.80; 95% confidence interval (CI) = 0.70-0.92). Similar DPs and T2D associations were discernible in urban Ghana and Europe. In the total study population, neither the "mixed" DP (whole grain cereals, sweet spreads, dairy products, potatoes, vegetables, poultry, coffee/tea, sodas/juices, olive oil) nor the "roots, tubers and plantain" DP (refined cereals, fruits, nuts/seeds, roots/tubers/plantain, fermented maize products, legumes, palm oil, condiments) was associated with T2D. Yet, after the exclusion of individuals with self reported T2D, the "roots, tubers and plantain" DP was inversely associated with T2D (ORper 1 SD = 0.88; 95% CI = 0.69-1.12). CONCLUSION: In this Ghanaian population, DPs characterized by the intake of legumes, fish, meat and confectionery were inversely associated with T2D. The effect of a traditional oriented diet (typical staples, vegetables and legumes) remains unclear. PMID- 29695706 TI - Evaluation of a 12-week lifestyle education intervention with or without partial meal replacement in Thai adults with obesity and metabolic syndrome: a randomised trial. AB - BACKGROUND/OBJECTIVES: There have been no studies examining the efficacy of meal replacement (MR) on weight loss and metabolic syndrome (MS) improvement in Southeast Asians. Thus, we undertook a 12-week randomised trial to evaluate the effect of a lifestyle education intervention alone (LEI) or with partial MR (LEI + MR) in obese Thai adults with MS. SUBJECTS/METHODS: A total of 110 patients were randomised to receive either LEI or LEI + MR. Both groups received LEI to achieve weight loss. LEI + MR group additionally received two MR daily to replace either breakfast, lunch or dinner. Mean +/- SE body mass index of all participants was 34.6 +/- 0.6 kg/m2, mean +/- SE age was 42.5 +/- 1.1 years and 83% of patients were female. Both groups were compared for anthropometric and cardiometabolic indices at 12-week. Body weight was also compared at weeks 38 and 64. RESULTS: At 12 weeks, both groups exhibited statistically significant percentage weight loss (%WL) compared to initial weight but greater %WL was observed in LEI + MR compared to LEI, 2.9% vs. 1.5%, respectively (p < 0.05). MS criteria such as waist circumference and blood pressure improved significantly in both groups compared to baseline. However, improvement in fasting plasma glucose (FPG) was only significant in LEI + MR, and more participants with impaired FPG at baseline in LEI + MR (42.9%) than LEI (19%) returned to normal FPG at 12 weeks (p < 0.05). HbA1c, fasting insulin and HOMA-IR in LEI + MR were significantly lower than with LEI. At the end of the 12-week intervention period, 16% of participants no longer fulfilled MS criteria. A statistically significant weight loss from baseline persisted until 38 weeks but no longer reached statistically significant difference between groups CONCLUSIONS: LEI and LEI + MR were acceptable and led to improvement in weight and MS. LEI + MR group exhibited additional weight reduction and glycemic benefits at 12 weeks. PMID- 29695707 TI - High orange juice consumption with or in-between three meals a day differently affects energy balance in healthy subjects. AB - Sugar-containing beverages like orange juice can be a risk factor for obesity and type 2 diabetes although the underlying mechanisms are less clear. We aimed to investigate if intake of orange juice with or in-between meals differently affects energy balance or metabolic risk. Twenty-six healthy adults (24.7 +/- 3.2 y; BMI 23.2 +/- 3.2 kg/m2) participated in a 4-week cross-over intervention and consumed orange juice (20% of energy requirement) either together with 3 meals/d (WM) or in-between 3 meals/d (BM) at ad libitum energy intake. Basal and postprandial insulin sensitivity (primary outcome), daylong glycaemia, glucose variability and insulin secretion were assessed. Body fat mass was measured by air-displacement plethysmography. After BM-intervention, fat mass increased (+1.0 +/- 1.8 kg; p < 0.05) and postprandial insulin sensitivity tended to decrease (DeltaMatsudaISI: -0.89 +/- 2.3; p = 0.06). By contrast, after WM-intervention fat mass and gamma-glutamyl transferase (GGT) decreased (-0.30 +/- 0.65 kg; -2.50 +/- 3.94; both p < 0.05), whereas glucose variability was higher (DeltaMAGE: +0.45 +/- 0.59, p < 0.05). Daylong glycaemia, insulin secretion, changes in basal insulin sensitivity, and triglycerides did not differ between WM- and BM interventions (all p > 0.05). In young healthy adults, a conventional 3-meal structure with orange juice consumed together with meals had a favorable impact on energy balance, whereas juice consumption in-between meals may contribute to a gain in body fat and adverse metabolic effects. PMID- 29695708 TI - Angiopoietin-like protein 3 and 4 in obesity, type 2 diabetes mellitus, and malnutrition: the effect of weight reduction and realimentation. AB - BACKGROUND: Angiopoietin-like proteins (ANGPTLs) 3 and 4 are circulating factors that participate in the regulation of lipid and glucose metabolism. SUBJECTS AND METHODS: We measured serum ANGPTL3 and 4 levels in 23 patients with obesity, 40 patients with obesity and type 2 diabetes mellitus (T2DM), 22 patients with anorexia nervosa (AN), 15 subjects undergoing 72-h fasting, and 12 patients with short bowel syndrome (SBS), and their changes after very-low-calorie diet (VLCD), bariatric surgery, partial realimentation, acute fasting, and parenteral nutrition in order to assess their possible role in metabolic regulations. RESULTS: Serum ANGPTL4 levels were higher in obese subjects without/with T2DM (94.50 +/- 9.51 and 134.19 +/- 7.69 vs. 50.34 +/- 4.22 ng/ml, p < 0.001) and lower in subjects with AN relative to healthy control subjects (38.22 +/- 4.48 vs. 65.80 +/- 7.98 ng/ml, p = 0.002), while serum ANGPTL3 levels demonstrated inverse tendency. Nutritional status had no effect on ANGPTL3 and 4 mRNA expression in adipose tissue. Fasting decreased ANGPTL3 and increased ANGPTL4 levels, while VLCD reduced only ANGPTL3. Bariatric surgery and realimentation of AN or SBS patients had no effect on either ANGPTL. Multiple regression analysis identified BMI as an independent predictor of ANGPTL3; and BMI and HbA1c as independent predictors of ANGPTL4, respectively. CONCLUSIONS: Taken together, our data suggest that serum ANGPTL3 and 4 levels are influenced by nutritional status and fasting and could be involved in the metabolic disturbances present in obesity and AN. PMID- 29695709 TI - Longitudinal association between egg consumption and the risk of cardiovascular disease: interaction with type 2 diabetes mellitus. AB - BACKGROUND/OBJECTIVES: It remains unclear if high egg consumption has beneficial or adverse effects on cardiometabolic health. The present study prospectively evaluated the longitudinal association between egg-consumption levels and incident cardiovascular disease (CVD) among Korean adults. SUBJECTS/METHODS: We conducted a prospective cohort study of 9248 Korean adults aged 40-69 years without CVD or cancer at the baseline from the Korean Genome and Epidemiology Study, Ansung-Ansan cohort, South Korea. The egg intake of the participants was estimated using a validated semiquantitative food frequency questionnaire at the baseline and the second follow-up examination and categorized into quartiles. CVD cases were identified using biennial questionnaires and confirmed through repeated in-depth personal interviews. Hazard ratios (HR) and 95% confidence interval (CI) were analyzed using Cox proportional hazard regression. RESULTS: During the average follow-up of 7.3 years, 570 cases of CVD were newly diagnosed. After adjusting for multiple confounding variables, egg-intake levels were not associated with CVD incidence (HR: 1.14, 95% CI: 0.87-1.49, P for trend: 0.7). However, the association was modified by type 2 diabetes mellitus (T2DM) status. Egg consumption was significantly associated with an increased risk for incident CVD among participants with T2DM; individuals with the highest egg intake (4.2 +/ 0.04 eggs/week) had a 2.8 times higher incidence of CVD (HR: 2.81, 95% CI: 1.25 6.30, P for trend: 0.02) than those with the lowest egg intake (0.1 +/- 0.02 eggs/week). However, no association was observed among individuals without T2DM (HR: 1.03, 95% CI: 0.77-1.38, P for trend: 0.8). CONCLUSIONS: Higher egg consumption may increase the risk for CVD in Korean patients with T2DM. Our findings provide a basis for the development of an optimal dietary cholesterol intake guideline for the Korean population. PMID- 29695711 TI - Aqueous rechargeable zinc/sodium vanadate batteries with enhanced performance from simultaneous insertion of dual carriers. AB - Rechargeable aqueous zinc-ion batteries are promising energy storage devices due to their high safety and low cost. However, they remain in their infancy because of the limited choice of positive electrodes with high capacity and satisfactory cycling performance. Furthermore, their energy storage mechanisms are not well established yet. Here we report a highly reversible zinc/sodium vanadate system, where sodium vanadate hydrate nanobelts serve as positive electrode and zinc sulfate aqueous solution with sodium sulfate additive is used as electrolyte. Different from conventional energy release/storage in zinc-ion batteries with only zinc-ion insertion/extraction, zinc/sodium vanadate hydrate batteries possess a simultaneous proton, and zinc-ion insertion/extraction process that is mainly responsible for their excellent performance, such as a high reversible capacity of 380 mAh g-1 and capacity retention of 82% over 1000 cycles. Moreover, the quasi-solid-state zinc/sodium vanadate hydrate battery is also a good candidate for flexible energy storage device. PMID- 29695710 TI - Maternal obesity during lactation may protect offspring from high fat diet induced metabolic dysfunction. AB - BACKGROUND/OBJECTIVES: The current obesity epidemic has spurred exploration of the developmental origin of adult heath and disease. A mother's dietary choices and health can affect both the early wellbeing and lifelong disease-risk of the offspring. SUBJECTS/METHODS: To determine if changes in the mother's diet and adiposity have long-term effects on the baby's metabolism, independently from a prenatal insult, we utilized a mouse model of diet-induced-obesity and cross fostering. All pups were born to lean dams fed a low fat diet but were fostered onto lean or obese dams fed a high fat diet. This study design allowed us to discern the effects of a poor diet from those of mother's adiposity and metabolism. The weaned offspring were placed on a high fat diet to test their metabolic function. RESULTS: In this feeding challenge, all male (but not female) offspring developed metabolic dysfunction. We saw increased weight gain in the pups nursed on an obesity-resistant dam fed a high fat diet, and increased pathogenesis including liver steatosis and adipose tissue inflammation, when compared to pups nursed on either obesity-prone dams on a high fat diet or lean dams on a low fat diet. CONCLUSION: Exposure to maternal over-nutrition, through the milk, is sufficient to shape offspring health outcomes in a sex- and organ specific manner, and milk from a mother who is obesity-prone may partially protect the offspring from the insult of a poor diet. PMID- 29695712 TI - Adherence to a Mediterranean diet and long-term changes in weight and waist circumference in the EPIC-Italy cohort. AB - Excessive calorie intake and physical inactivity are considered key determinants of the rapid worldwide increase in obesity prevalence, however the relationship between diet and weight gain is complex. We investigated associations between adherence to a Mediterranean diet and long-term changes in weight and waist circumference in volunteers recruited to the Italian section of the prospective European Prospective Investigation into Cancer and Nutrition (EPIC). We investigated 32,119 cohort members who provided anthropometric measures at recruitment and updated information on recall a mean of 12 years later. Adherence to a Mediterranean diet was assessed using the Italian Mediterranean Index (score range 0-11). Associations between index score and weight and waist changes were assessed by multivariate linear regression models. Risks of developing overweight/obesity and abdominal obesity were investigated by multivariate logistic models. Increasing Italian Mediterranean Index score (indicating better adherence) was associated with lower 5-year weight change in volunteers of normal weight at baseline (beta -0.12, 95% CI -0.16 to -0.08 for 1 tertile increase in score), but not in those overweight/obese at baseline (P interaction between Index score and BMI 0.0001). High adherence was also associated with reduced risk of becoming overweight/obese (OR 0.91, 95% CI 0.84-0.99 third vs. first tertile); smaller 5-year change in waist circumference (beta -0.09, 95% CI -0.14 to -0.03 for 1 tertile increase in score); and lower risk of abdominal obesity (OR 0.91, 95% CI 0.84-0.99 third vs. first tertile). Adherence to a traditional Italian Mediterranean diet may help prevent weight gain and abdominal obesity. PMID- 29695713 TI - Autonomic reinnervation and functional regeneration in autologous transplanted submandibular glands in patients with severe keratoconjunctivitis sicca. AB - Autologous submandibular gland (SMG) transplantation has been proved to ameliorate the discomforts in patients with severe keratoconjunctivitis sicca. The transplanted glands underwent a hypofunctional period and then restored secretion spontaneously. This study aims to investigate whether autonomic nerves reinnervate the grafts and contribute to the functional recovery, and further determine the origin of these nerves. Parts of the transplanted SMGs were collected from the epiphora patients, and a rabbit SMG transplantation model was established to fulfill the serial observation on the transplanted glands with time. The results showed that autonomic nerves distributed in the transplanted SMGs and parasympathetic ganglionic cells were observed in the stroma of the glands. Low-dense and unevenly distributed cholinergic axons, severe acinar atrophy and fibrosis were visible in the patients' glands 4-6 months post transplantation, whereas the cholinergic axon density and acinar area were increased with time. The acinar area or the secretory flow rate of the transplanted glands was statistically correlated with the cholinergic axon density in the rabbit model, respectively. Meanwhile, large cholinergic nerve trunks were found to locate in the temporal fascia lower to the gland, and sympathetic plexus concomitant with the arteries was observed both in the adjacent fascia and in the stroma of the glands. In summary, the transplanted SMGs are reinnervated by autonomic nerves and the cholinergic nerves play a role in the morphological and functional restoration of the glands. Moreover, these autonomic nerves might originate from the auriculotemporal nerve and the sympathetic plexus around the supplying arteries. PMID- 29695714 TI - Strain-engineered inverse charge-funnelling in layered semiconductors. AB - The control of charges in a circuit due to an external electric field is ubiquitous to the exchange, storage and manipulation of information in a wide range of applications. Conversely, the ability to grow clean interfaces between materials has been a stepping stone for engineering built-in electric fields largely exploited in modern photovoltaics and opto-electronics. The emergence of atomically thin semiconductors is now enabling new ways to attain electric fields and unveil novel charge transport mechanisms. Here, we report the first direct electrical observation of the inverse charge-funnel effect enabled by deterministic and spatially resolved strain-induced electric fields in a thin sheet of HfS2. We demonstrate that charges driven by these spatially varying electric fields in the channel of a phototransistor lead to a 350% enhancement in the responsivity. These findings could enable the informed design of highly efficient photovoltaic cells. PMID- 29695715 TI - Real-life achievement of lipid-lowering treatment targets in the DIAbetes and LifEstyle Cohort Twente: systemic assessment of pharmacological and nutritional factors. AB - BACKGROUND/OBJECTIVES: Lowering low-density lipoprotein cholesterol (LDLc) in type 2 diabetes mellitus is of paramount importance in preventing cardiovascular disease. However, treatment targets for LDLc are often not reached. We studied the prevalence of LDLc target achievement in a real-life population of type 2 diabetes mellitus patients in secondary care, and investigated whether in those not on target, there is room for intensifying pharmacological and lifestyle management according to current treatment guidelines. SUBJECTS/METHODS: We performed a cross-sectional analysis in the DIAbetes and LifEstyle Cohort Twente 1 (DIALECT-1; n = 450, age 63 +/- 9 years, 58% men, diabetes duration 11 (7-18) years). At baseline, we determined plasma LDLc concentration, pharmacological treatment (i.e., statin use), and lifestyle (physical activity and dietary intake). Patients were divided according to LDLc < 1.8, LDLc 1.8-2.5, and LDLc > 2.5 mmol/l. Dietary intake was collected from a validated Food Frequency Questionnaire (177 items) and we determined guideline adherence for different food groups. Physical activity was assessed with the Short Questionnaire to ASsess Health enhancing behavior. RESULTS: LDLc data were available in 428 type 2 diabetes mellitus patients. LDLc <= 2.5 mmol/l was achieved in 317 patients (76%). In total, 76% of patients used statins, in those with LDLc > 2.5 mmol/l, this was 44%. Adherence to lifestyle guidelines was not different between the LDLc groups and was as follows: body mass index 6%, physical activity 59%, vegetables 7%, fruit 28%, legumes 59%, nuts 14%, dairy 19%, fish 36%, tea 8%, fats 66%, red meat 12%, processed meat 2%, alcohol 71%, sweetened beverages 34%, and sodium 12%. CONCLUSIONS: In type 2 diabetes mellitus patients in secondary health care, the target LDLc is achieved by three quarters of patients. Increasing statin treatment could be a first step to improve LDLc. In addition, there are ample opportunities for lifestyle management through increasing adherence to lifestyle guidelines. PMID- 29695716 TI - Regulation of Yki/Yap subcellular localization and Hpo signaling by a nuclear kinase PRP4K. AB - Hippo (Hpo) signaling pathway controls tissue growth by regulating the subcellular localization of Yorkie (Yki)/Yap via a cytoplasmic kinase cassette containing an upstream kinase Hpo/MST1/2 and a downstream kinase Warts (Wts)/Lats1/2. Here we show that PRP4K, a kinase involved in mRNA splicing, phosphorylates Yki/Yap in the nucleus to prevent its nuclear accumulation and restrict Hpo pathway target gene expression. PRP4K inactivation accelerates whereas excessive PRP4K inhibits Yki-driven tissue overgrowth. PRP4K phosphorylates a subset of Wts/Lats1/2 sites on Yki/Yap to inhibit the binding of Yki/Yap to the Scalloped (Sd)/TEAD transcription factor and exclude Yki/Yap nuclear localization depending on nuclear export. Furthermore, PRP4K inhibits proliferation and invasiveness of cultured breast cancer cells and its high expression correlates with good prognosis in breast cancer patients. Our study unravels an unanticipated layer of Hpo pathway regulation and suggests that PRP4K mediated Yki/Yap phosphorylation in the nucleus provides a fail-safe mechanism to restrict aberrant pathway activation. PMID- 29695717 TI - Magnetically tunable bidirectional locomotion of a self-assembled nanorod-sphere propeller. AB - Field-driven direct assembly of nanoscale matter has impact in disparate fields of science. In microscale systems, such concept has been recently exploited to optimize propulsion in viscous fluids. Despite the great potential offered by miniaturization, using self-assembly to achieve transport at the nanoscale remains an elusive task. Here we show that a hybrid propeller, composed by a ferromagnetic nanorod and a paramagnetic microsphere, can be steered in a fluid in a variety of modes, from pusher to puller, when the pair is dynamically actuated by a simple oscillating magnetic field. We exploit this unique design to build more complex structures capable of carrying several colloidal cargos as microscopic trains that quickly disassemble at will under magnetic command. In addition, our prototype can be extended to smaller nanorods below the diffraction limit, but still dynamically reconfigurable by the applied magnetic field. PMID- 29695718 TI - Exercise induces new cardiomyocyte generation in the adult mammalian heart. AB - Loss of cardiomyocytes is a major cause of heart failure, and while the adult heart has a limited capacity for cardiomyogenesis, little is known about what regulates this ability or whether it can be effectively harnessed. Here we show that 8 weeks of running exercise increase birth of new cardiomyocytes in adult mice (~4.6-fold). New cardiomyocytes are identified based on incorporation of 15N thymidine by multi-isotope imaging mass spectrometry (MIMS) and on being mononucleate/diploid. Furthermore, we demonstrate that exercise after myocardial infarction induces a robust cardiomyogenic response in an extended border zone of the infarcted area. Inhibition of miR-222, a microRNA increased by exercise in both animal models and humans, completely blocks the cardiomyogenic exercise response. These findings demonstrate that cardiomyogenesis can be activated by exercise in the normal and injured adult mouse heart and suggest that stimulation of endogenous cardiomyocyte generation could contribute to the benefits of exercise. PMID- 29695720 TI - Blackbody radiation shift assessment for a lutetium ion clock. AB - The accuracy of state-of-the-art atomic clocks is derived from the insensitivity of narrow optical atomic resonances to environmental perturbations. Two such resonances in singly ionized lutetium have been identified with potentially lower sensitivities compared to other clock candidates. Here we report measurement of the most significant unknown atomic property of both transitions, the static differential scalar polarizability. From this, the fractional blackbody radiation shift for one of the transitions is found to be -1.36(9) * 10-18 at 300 K, the lowest of any established optical atomic clock. In consideration of leading systematic effects common to all ion clocks, both transitions compare favorably to the most accurate ion-based clocks reported to date. This work firmly establishes Lu+ as a promising candidate for a future generation of more accurate optical atomic clocks. PMID- 29695719 TI - The multiple myeloma risk allele at 5q15 lowers ELL2 expression and increases ribosomal gene expression. AB - Recently, we identified ELL2 as a susceptibility gene for multiple myeloma (MM). To understand its mechanism of action, we performed expression quantitative trait locus analysis in CD138+ plasma cells from 1630 MM patients from four populations. We show that the MM risk allele lowers ELL2 expression in these cells (Pcombined = 2.5 * 10-27; betacombined = -0.24 SD), but not in peripheral blood or other tissues. Consistent with this, several variants representing the MM risk allele map to regulatory genomic regions, and three yield reduced transcriptional activity in plasmocytoma cell lines. One of these (rs3777189-C) co-locates with the best-supported lead variants for ELL2 expression and MM risk, and reduces binding of MAFF/G/K family transcription factors. Moreover, further analysis reveals that the MM risk allele associates with upregulation of gene sets related to ribosome biogenesis, and knockout/knockdown and rescue experiments in plasmocytoma cell lines support a cause-effect relationship. Our results provide mechanistic insight into MM predisposition. PMID- 29695721 TI - Conformational dynamics in crystals reveal the molecular bases for D76N beta-2 microglobulin aggregation propensity. AB - Spontaneous aggregation of folded and soluble native proteins in vivo is still a poorly understood process. A prototypic example is the D76N mutant of beta-2 microglobulin (beta2m) that displays an aggressive aggregation propensity. Here we investigate the dynamics of beta2m by X-ray crystallography, solid-state NMR, and molecular dynamics simulations to unveil the effects of the D76N mutation. Taken together, our data highlight the presence of minor disordered substates in crystalline beta2m. The destabilization of the outer strands of D76N beta2m accounts for the increased aggregation propensity. Furthermore, the computational modeling reveals a network of interactions with residue D76 as a keystone: this model allows predicting the stability of several point mutants. Overall, our study shows how the study of intrinsic dynamics in crystallo can provide crucial answers on protein stability and aggregation propensity. The comprehensive approach here presented may well be suited for the study of other folded amyloidogenic proteins. PMID- 29695722 TI - Global profiling of protein-DNA and protein-nucleosome binding affinities using quantitative mass spectrometry. AB - Interaction proteomics studies have provided fundamental insights into multimeric biomolecular assemblies and cell-scale molecular networks. Significant recent developments in mass spectrometry-based interaction proteomics have been fueled by rapid advances in label-free, isotopic, and isobaric quantitation workflows. Here, we report a quantitative protein-DNA and protein-nucleosome binding assay that uses affinity purifications from nuclear extracts coupled with isobaric chemical labeling and mass spectrometry to quantify apparent binding affinities proteome-wide. We use this assay with a variety of DNA and nucleosome baits to quantify apparent binding affinities of monomeric and multimeric transcription factors and chromatin remodeling complexes. PMID- 29695723 TI - Long-term viability and function of transplanted islets macroencapsulated at high density are achieved by enhanced oxygen supply. AB - Transplantation of encapsulated islets can cure diabetes without immunosuppression, but oxygen supply limitations can cause failure. We investigated a retrievable macroencapsulation device wherein islets are encapsulated in a planar alginate slab and supplied with exogenous oxygen from a replenishable gas chamber. Translation to clinically-useful devices entails reduction of device size by increasing islet surface density, which requires increased gas chamber pO2. Here we show that islet surface density can be substantially increased safely by increasing gas chamber pO2 to a supraphysiological level that maintains all islets viable and functional. These levels were determined from measurements of pO2 profiles in islet-alginate slabs. Encapsulated islets implanted with surface density as high as 4,800 islet equivalents/cm3 in diabetic rats maintained normoglycemia for more than 7 months and provided near-normal intravenous glucose tolerance tests. Nearly 90% of the original viable tissue was recovered after device explantation. Damaged islets failed after progressively shorter times. The required values of gas chamber pO2 were predictable from a mathematical model of oxygen consumption and diffusion in the device. These results demonstrate feasibility of developing retrievable macroencapsulated devices small enough for clinical use and provide a firm basis for design of devices for testing in large animals and humans. PMID- 29695724 TI - Simultaneous lancet-free monitoring of alcohol and glucose from low-volumes of perspired human sweat. AB - A lancet-free, label-free biosensor for simultaneous detection of sweat glucose and alcohol was demonstrated using zinc oxide thin films integrated into a nanoporous flexible electrode system. Sensing was achieved from perspired human sweat at low volumes (1-3 MUL), comparable to ambient conditions without external stimulation. Zinc oxide thin film electrodes were surface functionalized with alcohol oxidase enzyme and with glucose oxidase enzyme towards developing an affinity biosensor specific to the physiological relevant range of alcohol comprising of 0-2 drinks (0-50 mg/dl) and physiologically relevant range of glucose ranging from hypo- to hyper-glycaemia (50-130 mg/dl) in perspired human sweat. Sensing was achieved by measuring impedance changes associated with alcohol and glucose binding onto the sensor interface using electrochemical impedance spectroscopy with a dynamic range from 0.01-200 mg/dl and a limit of detection of 0.01 mg/dl for alcohol in human sweat. Sensor calibration in synthetic sweat containing interferents (25-200 mg/dl) and comparison using regression and Bland-Altman analysis of sweat sensor performance was done with BACtrack(r). Combinatorial detection of glucose and ethanol in perspired human sweat and comparison of sweat sensor performance with Accu-Chek(r) blood glucose monitoring system that we expect would be relevant for pre-diabetics and diabetics for monitoring their glucose levels and alcohol consumption. PMID- 29695725 TI - miR-9 upregulation leads to inhibition of erythropoiesis by repressing FoxO3. AB - MicroRNAs (miRNAs) are emerging as critical regulators of normal and malignant hematopoiesis. In previous studies of acute myeloid leukemia miR-9 overexpression was commonly observed. Here, we show that ectopic expression of miR-9 in vitro and in vivo significantly blocks differentiation of erythroid progenitor cells with an increase in reactive oxygen species (ROS) production. Consistent with this observation, ROS scavenging enzymes, including superoxide dismutase (Sod2), Catalase (Cat), and glutathine peroxidase (Gpx1), are down-regulated by miR-9. In addition, miR-9 suppresses expression of the erythroid transcriptional regulator FoxO3, and its down-stream targets Btg1 and Cited 2 in erythroid progenitor cells, while expression of a constitutively active form of FoxO3 (FoxO3-3A) reverses miR-9-induced suppression of erythroid differentiation, and inhibits miR 9-induced ROS production. Thus, our findings indicate that aberrant expression of miR-9 blocks erythropoiesis by deregulating FoxO3-mediated pathways, which may contribute to the ineffective erythropoiesis observed in patients with hematological malignancies. PMID- 29695726 TI - Label-free non-invasive quantitative measurement of lipid contents in individual microalgal cells using refractive index tomography. AB - Microalgae are promising candidates for biofuel production due to their high lipid content. To facilitate utilization of the microalgae for biofuel, rapid quantification of the lipid contents in microalgae is necessary. However, conventional methods based on the chemical extraction of lipids require a time consuming destructive extraction process. Here, we demonstrate label-free, non invasive, rapid quantification of the lipid contents in individual micro-algal cells measuring the three-dimensional refractive index tomograms. We measure three-dimensional refractive index distributions within Nannochloropsis oculata cells and find that lipid droplets are identifiable in tomograms by their high refractive index. In addition, we alter N. oculata under nitrogen deficiency by measuring the volume, lipid weight, and dry cell weight of individual cells. Characterization of individual cells allows correlative analysis between the lipid content and size of individual cells. PMID- 29695727 TI - Functional and Morphological Changes in the Deep Lumbar Multifidus Using Electromyography and Ultrasound. AB - Surface electromyography (sEMG) studies have indicated that chronic low back pain (cLBP) involves altered electromyographic activity and morphological structure of the lumbar multifidus (LM) beyond pain perception; however, most studies have evaluated the superficial lumbar multifidus. It is difficult to record electromyography (EMG) signals from the deep multifidus (DM) to determine the neuromuscular activation patterns, making it difficult to determine the relationship between functional and structural changes in cLBP. We developed a novel method to record intramuscular EMG signals in the DM based on the sEMG system and fine-wire electrodes. We measured EMG signals of the DM in 24 cLBP patients and 26 pain-free healthy controls to identify changes in neuromuscular activation. We also used ultrasound to measure DM muscle thickness, cross sectional area, and contraction activity to identify potential relationships between EMG activity and structural damage. cLBP patients had decreased average EMG and root mean square, but increased median frequency and mean power frequency. Average EMG was positively correlated with contractile activity, but not statistically correlated with noncontractile anatomical abnormalities. Our results suggest that cLBP alters the neuromuscular activation patterns and morphological structure of the contractile activity of the DM, providing insights into the mechanisms underlying pain perception. PMID- 29695728 TI - Analysis of Optimal Sequential State Discrimination for Linearly Independent Pure Quantum States. AB - Recently, J. A. Bergou et al. proposed sequential state discrimination as a new quantum state discrimination scheme. In the scheme, by the successful sequential discrimination of a qubit state, receivers Bob and Charlie can share the information of the qubit prepared by a sender Alice. A merit of the scheme is that a quantum channel is established between Bob and Charlie, but a classical communication is not allowed. In this report, we present a method for extending the original sequential state discrimination of two qubit states to a scheme of N linearly independent pure quantum states. Specifically, we obtain the conditions for the sequential state discrimination of N = 3 pure quantum states. We can analytically provide conditions when there is a special symmetry among N = 3 linearly independent pure quantum states. Additionally, we show that the scenario proposed in this study can be applied to quantum key distribution. Furthermore, we show that the sequential state discrimination of three qutrit states performs better than the strategy of probabilistic quantum cloning. PMID- 29695729 TI - Cerebral oxygen saturation and peripheral perfusion in the extremely premature infant with intraventricular and/or pulmonary haemorrhage early in life. AB - Extremely preterm infants are at higher risk of pulmonary (PH) and intraventricular (IVH) haemorrhage during the transitioning physiology due to immature cardiovascular system. Monitoring of haemodynamics can detect early abnormal circulation that may lead to these complications. We described time frequency relationships between near infrared spectroscopy (NIRS) cerebral regional haemoglobin oxygen saturation (CrSO2) and preductal peripheral perfusion index (PI), capillary oxygen saturation (SpO2) and heart rate (HR) in extremely preterm infants in the first 72 h of life. Patients were sub-grouped in infants with PH and/or IVH (N H = 8) and healthy controls (N C = 11). Data were decomposed in wavelets allowing the analysis of localized variations of power. This approach allowed to quantify the percentage of time of significant cross correlation, semblance, gain (transfer function) and coherence between signals. Ultra-low frequencies (<0.28 mHz) were analyzed as slow and prolonged periods of impaired circulation are considered more detrimental than transient fluctuations. Cross-correlation between CrSO2 and oximetry (PI, SpO2 and HR) as well as in phase semblance and gain between CrSO2 and HR were significantly lower while anti phase semblance between CrSO2 and HR was significantly higher in PH-IVH infants compared to controls. These differences may reflect haemodynamic instability associated with cerebrovascular autoregulation and hemorrhagic complications observed during the transitioning physiology. PMID- 29695731 TI - A Novel Method for Investigating the Role of Reflux Pattern in Color Doppler Ultrasound for Grading of Varicocele. AB - Varicocele is the most common correctable cause of infertility. Color Doppler Ultrasound (CDUS) has a sensitivity of 97% and specificity of 94% for diagnosing this condition. This study aimed to propose a new pattern of scrotal Doppler for predicting the severity of varicocele. An observational study was conducted from January 2016 to January 2017 on 120 testes units in 60 patients. Scrotal CDUS and semen analysis were done in all participants. Patients were evaluated for reflux pattern, pampiniform venous plexus diameter, and venous reflux time. The ultrasonography parameters and semen analysis data were compared to assess the correlations between the results. The reflux pattern and vein diameters had a significant correlation. Also, a significant correlation was detected between the reflux pattern and reflux time. There was a significant correlation between the reflux pattern and two parameters of semen analysis namely sperm count and its motility. In conclusion, the reflux pattern classification suggested in this study can be used as a useful predictor of varicocele severity and sperm parameters in patients with varicocele. PMID- 29695732 TI - Direct evidence for alpha ether linkage between lignin and carbohydrates in wood cell walls. AB - Cross-linking between lignin and polysaccharide in plant cell-wall determines physical, chemical, and biological features of lignocellulosic biomass. Since Erdmann's first report in 1866, numerous studies have suggested the presence of a bond between hemicelluloses and lignin; however, no clear evidence for this interaction has been reported. We describe the first direct proof of covalent bonding between plant cell-wall polysaccharides and lignin. Nuclear magnetic resonance spectroscopy was used to observe the long-range correlations through an alpha-ether bond between lignin and the primary hydroxyl group of a mannose residue in glucomannan. Complete signal assignment of the cognate structural units was also achieved. Thus, we identified lignin-carbohydrate bonds by complete connectivity analysis from the phenylpropane unit to the carbohydrate moiety. PMID- 29695733 TI - Extreme air pollution events in Hokkaido, Japan, traced back to early snowmelt and large-scale wildfires over East Eurasia: Case studies. AB - To identify the unusual climate conditions and their connections to air pollutions in a remote area due to wildfires, we examine three anomalous large scale wildfires in May 2003, April 2008, and July 2014 over East Eurasia, as well as how products of those wildfires reached an urban city, Sapporo, in the northern part of Japan (Hokkaido), significantly affecting the air quality. NASA's MERRA-2 (the Modern-Era Retrospective analysis for Research and Applications, Version 2) aerosol re-analysis data closely reproduced the PM2.5 variations in Sapporo for the case of smoke arrival in July 2014. Results show that all three cases featured unusually early snowmelt in East Eurasia, accompanied by warmer and drier surface conditions in the months leading to the fires, inducing long-lasting soil dryness and producing climate and environmental conditions conducive to active wildfires. Due to prevailing anomalous synoptic scale atmospheric motions, smoke from those fires eventually reached a remote area, Hokkaido, and worsened the air quality in Sapporo. In future studies, continuous monitoring of the timing of Eurasian snowmelt and the air quality from the source regions to remote regions, coupled with the analysis of atmospheric and surface conditions, may be essential in more accurately predicting the effects of wildfires on air quality. PMID- 29695730 TI - Significant loss of mitochondrial diversity within the last century due to extinction of peripheral populations in eastern gorillas. AB - Species and populations are disappearing at an alarming rate as a direct result of human activities. Loss of genetic diversity associated with population decline directly impacts species' long-term survival. Therefore, preserving genetic diversity is of considerable conservation importance. However, to assist in conservation efforts, it is important to understand how genetic diversity is spatially distributed and how it changes due to anthropogenic pressures. In this study, we use historical museum and modern faecal samples of two critically endangered eastern gorilla taxa, Grauer's (Gorilla beringei graueri) and mountain gorillas (Gorilla beringei beringei), to directly infer temporal changes in genetic diversity within the last century. Using over 100 complete mitochondrial genomes, we observe a significant decline in haplotype and nucleotide diversity in Grauer's gorillas. By including historical samples from now extinct populations we show that this decline can be attributed to the loss of peripheral populations rather than a decrease in genetic diversity within the core range of the species. By directly quantifying genetic changes in the recent past, our study shows that human activities have severely impacted eastern gorilla genetic diversity within only four to five generations. This rapid loss calls for dedicated conservation actions, which should include preservation of the remaining peripheral populations. PMID- 29695734 TI - East Asian Winter Monsoon Impacts the ENSO-related Teleconnections and North American Seasonal Air Temperature Prediction. AB - El Nino-Southern Oscillation (ENSO) is a key feature for seasonal weather and climate prediction in the extra-tropics since related sea surface temperature anomalies induce precipitation anomalies that generate poleward propagating Rossby waves and teleconnections. The East Asian winter monsoon (EAWM) is driven by processes originating over the Asian continent and, to a lesser degree, by ENSO-related tropical convection. EAWM also strongly affects convection and precipitation patterns over the western tropical Pacific by cold air outbreaks reaching equatorial latitudes. Hence, one can expect a modulating effect of EAWM on the generation of Rossby wave trains related to ENSO. By increasing the convective heating over the western Pacific, strong EAWM strengthens the Pacific Walker circulation, and weakens (strengthens) the El Nino (La Nina) related effects on the extra-tropics via a modulation of the Pacific North America teleconnection pattern. Our results indicate that, for seasonal prediction over North America, along with ENSO the variability of EAWM should also be taken into account. The climate anomalies over the North America for the same phase of ENSO are significantly different for strong and weak EAWM. PMID- 29695735 TI - Integrative annotation and knowledge discovery of kinase post-translational modifications and cancer-associated mutations through federated protein ontologies and resources. AB - Many bioinformatics resources with unique perspectives on the protein landscape are currently available. However, generating new knowledge from these resources requires interoperable workflows that support cross-resource queries. In this study, we employ federated queries linking information from the Protein Kinase Ontology, iPTMnet, Protein Ontology, neXtProt, and the Mouse Genome Informatics to identify key knowledge gaps in the functional coverage of the human kinome and prioritize understudied kinases, cancer variants and post-translational modifications (PTMs) for functional studies. We identify 32 functional domains enriched in cancer variants and PTMs and generate mechanistic hypotheses on overlapping variant and PTM sites by aggregating information at the residue, protein, pathway and species level from these resources. We experimentally test the hypothesis that S768 phosphorylation in the C-helix of EGFR is inhibitory by showing that oncogenic variants altering S768 phosphorylation increase basal EGFR activity. In contrast, oncogenic variants altering conserved phosphorylation sites in the 'hydrophobic motif' of PKCbetaII (S660F and S660C) are loss-of function in that they reduce kinase activity and enhance membrane translocation. Our studies provide a framework for integrative, consistent, and reproducible annotation of the cancer kinomes. PMID- 29695736 TI - Overactive autophagy is a pathological mechanism underlying premature suture ossification in nonsyndromic craniosynostosis. AB - Nonsyndromic craniosynostosis (NSC) is the most common craniosynostosis with the primary defect being one or more fused sutures. In contrast to syndromic craniosynostosis, the etiopathogenesis of NSC is largely unknown. Here we show that autophagy, a major catabolic process required for the maintenance of bone homeostasis and bone growth, is a pathological change associated with NSC. Using calvarial suture mesenchymal cells (SMCs) isolated from the fused and unfused sutures of NSC patients, we demonstrate that during SMC differentiation, the level of the autophagosomal marker LC3-II increases as osteogenic differentiation progresses, particularly at differentiation day 7, a stage concurrent with mineralization. In fused SMCs, autophagic induction was more robust than that in unfused SMCs, which consequently led to enhanced mineralized nodule formation. Perturbation of autophagy with rapamycin or wortmannin promoted or inhibited the ossification of SMCs, respectively. Our findings suggest that autophagy is essential for the osteogenic differentiation of SMCs and that overactive autophagy is a molecular abnormality underlying premature calvarial ossification in NSC. PMID- 29695737 TI - Multi-lectin Affinity Chromatography and Quantitative Proteomic Analysis Reveal Differential Glycoform Levels between Prostate Cancer and Benign Prostatic Hyperplasia Sera. AB - Currently prostate-specific antigen is used for prostate cancer (PCa) screening, however it lacks the necessary specificity for differentiating PCa from other diseases of the prostate such as benign prostatic hyperplasia (BPH), presenting a clinical need to distinguish these cases at the molecular level. Protein glycosylation plays an important role in a number of cellular processes involved in neoplastic progression and is aberrant in PCa. In this study, we systematically interrogate the alterations in the circulating levels of hundreds of serum proteins and their glycoforms in PCa and BPH samples using multi-lectin affinity chromatography and quantitative mass spectrometry-based proteomics. Specific lectins (AAL, PHA-L and PHA-E) were used to target and chromatographically separate core-fucosylated and highly-branched protein glycoforms for analysis, as differential expression of these glycan types have been previously associated with PCa. Global levels of CD5L, CFP, C8A, BST1, and C7 were significantly increased in the PCa samples. Notable glycoform-specific alterations between BPH and PCa were identified among proteins CD163, C4A, and ATRN in the PHA-L/E fraction and among C4BPB and AZGP1 glycoforms in the AAL fraction. Despite these modest differences, substantial similarities in glycoproteomic profiles were observed between PCa and BPH sera. PMID- 29695738 TI - MALAT1: An Epigenetic Regulator of Inflammation in Diabetic Retinopathy. AB - Despite possessing limited protein-coding potential, long non-coding RNAs (lncRNAs) have been implicated in a myriad of pathologic conditions. Most well documented in cancer, one prominent intergenic lncRNA known as MALAT1 is notorious for its role in impacting epigenetic mechanisms. In this study, we established a novel epigenetic paradigm for MALAT in diabetic retinopathy (DR) by employing siRNA-mediated MALAT1 knockdown in human retinal endothelial cells (HRECs), a Malat1 knockout animal model, vitreous humor from diabetic patients, pharmacological inhibitors for histone and DNA methylation, RNA immunoprecipitation, western blotting, and a unique DNA methylation array to determine glucose-related alterations in MALAT1. Our findings indicated that MALAT1 is capable of impacting the expressions of inflammatory transcripts through its association with components of the PRC2 complex in diabetes. Furthermore, the vitreous humors from diabetic patients revealed increased expressions of MALAT1, TNF-alpha, and IL-6. Intriguingly, our DNA methylation array demonstrated that transient high glucose exposure in HRECs does not contribute to significant methylation alterations at CpG sites across the MALAT1 gene. However, global inhibition of DNA methyltransferases induced significant increases in MALAT1 and associated inflammatory transcripts in HRECs. Our findings collectively demonstrate the importance of MALAT1 in inflammation and epigenetic regulation in DR. PMID- 29695740 TI - Magnetic carboxyl functional nanoporous polymer: synthesis, characterization and its application for methylene blue adsorption. AB - Magnetic carboxyl functional nanoporous polymer (MCFNP) was chemically fabricated by incorporation of magnetic Fe3O4 precursor into the carboxyl functional nanoporous polymer (CFNP). The as-synthesized MCFNP was characterized and used as an adsorbent for rapid adsorption removal of methylene blue (MB) from wastewater. Several experimental parameters affecting the adsorption efficiency were investigated including initial pH, adsorbent dosage, initial MB concentration, contact time and temperature. The adsorption behavior of MCFNP displayed that adsorption kinetics and isotherms could be well fitted to the pseudo-second-order and Langmuir models, respectively. The experimental results showed that MCFNP was an effective adsorbent with a maximum adsorption capacity of 57.74 mg g-1 for MB at 298 K. The negative free energy (DeltaG) and positive enthalpy change (DeltaH) confirmed that the adsorption reaction was a spontaneous and endothermic process. In addition, ethanol was used as an effective extractant for the regeneration of MCFNP, and the adsorption efficiency could remain 80% after the ninth regeneration cycle. PMID- 29695739 TI - The Phytophthora cactorum genome provides insights into the adaptation to host defense compounds and fungicides. AB - Phytophthora cactorum is a homothallic oomycete pathogen, which has a wide host range and high capability to adapt to host defense compounds and fungicides. Here we report the 121.5 Mb genome assembly of the P. cactorum using the third generation single-molecule real-time (SMRT) sequencing technology. It is the second largest genome sequenced so far in the Phytophthora genera, which contains 27,981 protein-coding genes. Comparison with other Phytophthora genomes showed that P. cactorum had a closer relationship with P. parasitica, P. infestans and P. capsici. P. cactorum has similar gene families in the secondary metabolism and pathogenicity-related effector proteins compared with other oomycete species, but specific gene families associated with detoxification enzymes and carbohydrate active enzymes (CAZymes) underwent expansion in P. cactorum. P. cactorum had a higher utilization and detoxification ability against ginsenosides-a group of defense compounds from Panax notoginseng-compared with the narrow host pathogen P. sojae. The elevated expression levels of detoxification enzymes and hydrolase activity-associated genes after exposure to ginsenosides further supported that the high detoxification and utilization ability of P. cactorum play a crucial role in the rapid adaptability of the pathogen to host plant defense compounds and fungicides. PMID- 29695742 TI - No association between heart failure and cancer. PMID- 29695741 TI - Comparing SVM and ANN based Machine Learning Methods for Species Identification of Food Contaminating Beetles. AB - Insect pests, such as pantry beetles, are often associated with food contaminations and public health risks. Machine learning has the potential to provide a more accurate and efficient solution in detecting their presence in food products, which is currently done manually. In our previous research, we demonstrated such feasibility where Artificial Neural Network (ANN) based pattern recognition techniques could be implemented for species identification in the context of food safety. In this study, we present a Support Vector Machine (SVM) model which improved the average accuracy up to 85%. Contrary to this, the ANN method yielded ~80% accuracy after extensive parameter optimization. Both methods showed excellent genus level identification, but SVM showed slightly better accuracy for most species. Highly accurate species level identification remains a challenge, especially in distinguishing between species from the same genus which may require improvements in both imaging and machine learning techniques. In summary, our work does illustrate a new SVM based technique and provides a good comparison with the ANN model in our context. We believe such insights will pave better way forward for the application of machine learning towards species identification and food safety. PMID- 29695743 TI - Baby's heart defects can signal mother's CVD risk. PMID- 29695744 TI - Novel genetic variant linked with high LDL-C levels. PMID- 29695745 TI - Publisher Correction: Pathways of cellular internalisation of liposomes delivered siRNA and effects on siRNA engagement with target mRNA and silencing in cancer cells. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29695747 TI - Publisher Correction: Spatial Organization of the Gastrointestinal Microbiota in Urban Canada Geese. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29695746 TI - Gold nanoparticle-mediated laser stimulation induces a complex stress response in neuronal cells. AB - Stimulation of neuronal cells generally resorts to electric signals. Recent advances in laser-based stimulation methods could present an alternative with superior spatiotemporal resolution. The avoidance of electronic crosstalk makes these methods attractive for in vivo therapeutic application. In particular, nano mediators, such as gold nanoparticles, can be used to transfer the energy from a laser pulse to the cell membrane and subsequently activate excitable cells. Although the underlying mechanisms of neuronal activation have been widely unraveled, the overall effect on the targeted cell is not understood. Little is known about the physiological and pathophysiological impact of a laser pulse targeted onto nanoabsorbers on the cell membrane. Here, we analyzed the reaction of the neuronal murine cell line Neuro-2A and murine primary cortical neurons to gold nanoparticle mediated laser stimulation. Our study reveals a severe, complex and cell-type independent stress response after laser irradiation, emphasizing the need for a thorough assessment of this approach's efficacy and safety. PMID- 29695748 TI - Ridge-furrow with plastic film and straw mulch increases water availability and wheat production on the Loess Plateau. AB - Mulching is critical for increasing water availability and hence winter wheat production in dryland farming systems. A two-year study was conducted to assess the effects of mulches on soil water storage (SWS), temperature, water use efficiency (WUE) and yields of winter wheat on the Loess Plateau. Four treatments were examined: conventional flat planting (CK), straw mulch (FPS), transparent plastic film mulch (FPP) and ridge-furrow with plastic film-mulched ridge and straw-mulched furrow (RFPS). Compared with CK, RFPS greatly increased SWS from 0 60 cm, FPP increased SWS from 0-40 cm, and FPS slightly increased SWS from 0-60 cm; however, FPP significantly (P < 0.05) decreased SWS from 61-100 cm. RFPS and FPP increased soil temperatures in cold seasons relative to CK, especially in RFPS (2.0-2.3 degrees C). Meanwhile, the rate of soil temperature increase was greater in RFPS and FPP than in CK but was lower in FPS. Mean yields were significantly increased in RFPS (56.78%), FPP (44.72%) and FPS (9.57%), and WUE was significantly increased in RFPS (44.04%) and in FPP (37.50%) compared with CK (P < 0.05). We conclude that ridge-furrow planting with plastic film-mulched ridge and straw-mulched furrow has a good potential for raising winter wheat production on the Loess Plateau. PMID- 29695749 TI - Oncolytic viruses as engineering platforms for combination immunotherapy. AB - To effectively build on the recent successes of immune checkpoint blockade, adoptive T cell therapy and cancer vaccines, it is critical to rationally design combination strategies that will increase and extend efficacy to a larger proportion of patients. For example, the combination of anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA4) and anti-programmed cell death protein 1 (PD1) immune checkpoint inhibitors essentially doubles the response rate in certain patients with metastatic melanoma. However, given the heterogeneity of cancer, it seems likely that even more complex combinations of immunomodulatory agents may be required to obtain consistent, durable therapeutic responses against a broad spectrum of cancers. This carries serious implications in terms of toxicities for patients, feasibility for care providers and costs for health care systems. A compelling solution is offered by oncolytic viruses (OVs), which can be engineered to selectively replicate within and destroy tumour tissue while simultaneously augmenting antitumour immunity. In this Opinion article, we argue that the future of immunotherapy will include OVs that function as multiplexed immune-modulating platforms expressing factors such as immune checkpoint inhibitors, tumour antigens, cytokines and T cell engagers. We illustrate this concept by following the trials and tribulations of tumour-reactive T cells from their initial priming through to the execution of cytotoxic effector function in the tumour bed. We highlight the myriad opportunities for OVs to help overcome critical barriers in the T cell journey, leading to new synergistic mechanisms in the battle against cancer. PMID- 29695750 TI - Anti-VEGF therapy - a role in obesity-related breast cancer. PMID- 29695751 TI - A wheat caffeic acid 3-O-methyltransferase TaCOMT-3D positively contributes to both resistance to sharp eyespot disease and stem mechanical strength. AB - Plant caffeic acid 3-O-methyltransferase (COMT) has been implicated in the lignin biosynthetic pathway through catalyzing the multi-step methylation reactions of hydroxylated monomeric lignin precursors. However, genetic evidence for its function in plant disease resistance is poor. Sharp eyespot, caused primarily by the necrotrophic fungus Rhizoctonia cerealis, is a destructive disease in hexaploid wheat (Triticum aestivum L.). In this study, a wheat COMT gene TaCOMT 3D, is identified to be in response to R. cerealis infection through microarray based comparative transcriptomics. The TaCOMT-3D gene is localized in the long arm of the chromosome 3D. The transcriptional level of TaCOMT-3D is higher in sharp eyespot-resistant wheat lines than in susceptible wheat lines, and is significantly elevated after R. cerealis inoculation. After R. cerealis inoculation and disease scoring, TaCOMT-3D-silenced wheat plants exhibit greater susceptibility to sharp eyespot compared to unsilenced wheat plants, whereas overexpression of TaCOMT-3D enhances resistance of the transgenic wheat lines to sharp eyespot. Moreover, overexpression of TaCOMT-3D enhances the stem mechanical strength, and lignin (particular syringyl monolignol) accumulation in the transgenic wheat lines. These results suggest that TaCOMT-3D positively contributes to both wheat resistance against sharp eyespot and stem mechanical strength possibly through promoting lignin (especially syringyl monolignol) accumulation. PMID- 29695753 TI - Whole-kidney single-cell transcriptomics identifies new cell types. PMID- 29695752 TI - GATM mutations cause mitochondrial abnormalities and kidney failure. PMID- 29695754 TI - Crystalline polymer nanofibers with ultra-high strength and thermal conductivity. AB - Polymers are widely used in daily life, but exhibit low strength and low thermal conductivity as compared to most structural materials. In this work, we develop crystalline polymer nanofibers that exhibit a superb combination of ultra-high strength (11 GPa) and thermal conductivity, exceeding any existing soft materials. Specifically, we demonstrate unique low-dimensionality phonon physics for thermal transport in the nanofibers by measuring their thermal conductivity in a broad temperature range from 20 to 320 K, where the thermal conductivity increases with increasing temperature following an unusual ~T1 trend below 100 K and eventually peaks around 130-150 K reaching a metal-like value of 90 W m-1 K 1, and then decays as 1/T. The polymer nanofibers are purely electrically insulating and bio-compatible. Combined with their remarkable lightweight-thermal mechanical concurrent functionality, unique applications in electronics and biology emerge. PMID- 29695755 TI - Clinical Utility Gene Card for: autosomal dominant myotonia congenita (Thomsen Disease). PMID- 29695757 TI - A breath-holding adaptation. PMID- 29695756 TI - Disease-causing variants in TCF4 are a frequent cause of intellectual disability: lessons from large-scale sequencing approaches in diagnosis. AB - High-throughput sequencing (HTS) of human genome coding regions allows the simultaneous screen of a large number of genes, significantly improving the diagnosis of non-syndromic intellectual disabilities (ID). HTS studies permit the redefinition of the phenotypical spectrum of known disease-causing genes, escaping the clinical inclusion bias of gene-by-gene Sanger sequencing. We studied a cohort of 903 patients with ID not reminiscent of a well-known syndrome, using an ID-targeted HTS of several hundred genes and found de novo heterozygous variants in TCF4 (transcription factor 4) in eight novel patients. Piecing together the patients from this study and those from previous large-scale unbiased HTS studies, we estimated the rate of individuals with ID carrying a disease-causing TCF4 mutation to 0.7%. So far, TCF4 molecular abnormalities were known to cause a syndromic form of ID, Pitt-Hopkins syndrome (PTHS), which combines severe ID, developmental delay, absence of speech, behavioral and ventilation disorders, and a distinctive facial gestalt. Therefore, we reevaluated ten patients carrying a pathogenic or likely pathogenic variant in TCF4 (eight patients included in this study and two from our previous ID-HTS study) for PTHS criteria defined by Whalen and Marangi. A posteriori, five patients had a score highly evocative of PTHS, three were possibly consistent with this diagnosis, and two had a score below the defined PTHS threshold. In conclusion, these results highlight TCF4 as a frequent cause of moderate to profound ID and broaden the clinical spectrum associated to TCF4 mutations to nonspecific ID. PMID- 29695758 TI - Identification of a novel MIP frameshift mutation associated with congenital cataract in a Chinese family by whole-exome sequencing and functional analysis. AB - PURPOSE: To detect the underlying pathogenesis of congenital cataract in a four generation Chinese family. METHODS: Whole-exome sequencing (WES) of family members (III:4, IV:4, and IV:6) was performed. Sanger sequencing and bioinformatics analysis were subsequently conducted. Full-length WT-MIP or K228fs MIP fused to HA markers at the N-terminal was transfected into HeLa cells. Next, quantitative real-time PCR, western blotting and immunofluorescence confocal laser scanning were performed. RESULTS: The age of onset for nonsyndromic cataracts in male patients was by 1-year old, earlier than for female patients, who exhibited onset at adulthood. A novel c.682_683delAA (p.K228fs230X) mutation in main intrinsic protein (MIP) cosegregated with the cataract phenotype. The instability index and unfolded states for truncated MIP were predicted to increase by bioinformatics analysis. The mRNA transcription level of K228fs-MIP was reduced compared with that of WT-MIP, and K228fs-MIP protein expression was also lower than that of WT-MIP. Immunofluorescence images showed that WT-MIP principally localized to the plasma membrane, whereas the mutant protein was trapped in the cytoplasm. CONCLUSIONS: Our study generated genetic and primary functional evidence for a novel c.682_683delAA mutation in MIP that expands the variant spectrum of MIP and help us better understand the molecular basis of cataract. PMID- 29695759 TI - A novel wet-lab teaching model for trabeculectomy surgery. PMID- 29695760 TI - Association between obstructive sleep apnea and optic neuropathy: a Taiwanese population-based cohort study. AB - PURPOSE: Obstructive sleep apnea (OSA) is associated with many systemic diseases including diabetes, hypertension, stroke, and cardiovascular disease. The aim of our study was to investigate the association between OSA and optic neuropathy (ON), and to evaluate the efficacy of treatment for OSA on the risk of ON. METHODS: We used the data from the Longitudinal Health Insurance Database, which involved one million insurants from Taiwan National Health Insurance program (Taiwan NHI). RESULTS: OSA patients had a 1.95-fold higher risk of ON compared with non-OSA patients in all age group. The risk was significantly higher (adjusted hazard ratio: 4.21) in the group aged <45 years and male individuals (adjusted hazard ratio: 1.93). Meanwhile, sleep apnea was associated with ON regardless of the existence of comorbidity or not. OSA patients treated with continuous positive airway pressure (CPAP) had an adjusted 2.31-fold higher hazard of developing ON compared to controls, and those without any treatment had an adjusted 1.82-fold higher hazard of developing ON compared to controls. Moreover, ON patients had a 1.45-fold higher risk of OSA, and those aged between 45 and 64 years (hazard ratio: 1.76) and male individuals (hazard ratio: 1.55) had highest risk. CONCLUSIONS: Our study showed that OSA increased the risk of developing ON after controlling the comorbidities; however, treatment with CPAP did not reduce the risk of ON. Further large population study accessing to medical records about the severity of OSA and treatment for OSA is needed to clarify the efficacy of treatment for OSA in reducing the risk of ON. PMID- 29695761 TI - Epigenetic variability in conversion to psychosis: novel findings from an innovative longitudinal methylomic analysis. AB - Conversion to psychosis is a longitudinal process during which several epigenetic changes have been described. We tested the hypothesis that epigenetic variability in the methylomes of ultra-high risk (UHR) individuals may contribute to the risk of conversion. We studied a longitudinal cohort of UHR individuals (n = 39) and compared two groups (converters, n = 14 vs. non-converters, n = 25). A longitudinal methylomic study was conducted using Infinium HumanMethylation450 BeadChip covering half a million cytosine-phosphate-guanine (CpG) sites across the human genome from whole-blood samples. We used two statistical methods to investigate the variability of methylation probes. (i) The search for longitudinal variable methylation probes (VMPs) based on median comparisons identified two VMPs in converters only. The first CpG was located in the MACROD2 gene and the second CpG was in an intergenic region at 8q24.21. (ii) The detection of outliers using variance analysis related to private epimutations identified a dozen CpGs in converters only and highlighted two genes (RAC1 and SPHK1) from the sphingolipid signaling pathway. Our study is the first to support increased methylome variability during conversion to psychosis. We speculate that stochastic factors could increase DNA methylation variability and have a role in the complex pathophysiology of conversion to psychosis as well as in other psychiatric diseases. PMID- 29695762 TI - Prevalence of under and over weight in children with neurodisability, using body composition measures. AB - We aimed to compare rates of under and overweight in children with different neurodevelopmental disorders (NDD) by measuring weight, height/length, arm-to-leg bioelectrical impedance (BIA) and subscapular and triceps skinfolds in 146 children aged 4-16 years attending special schools. Z scores were calculated and skinfolds and lean mass Z scores were further adjusted for height. Underweight was found in 9% (14) children (body mass index (BMI) < 2nd) but only 3% (4) had skinfolds <5th centile. Overweight was much commoner, with 41% (58) children having BMI > 95th and 20% (14) had skinfolds >95th centile. Children with cerebral palsy were very short with low BMI and lean mass, but only 8% (3) had skinfolds <5th centile. The children with Down syndrome were also very short and once adjusted for height, half had skinfolds >95th centile. We conclude that overweight and raised body fat is now common in children with NDD, even when the BMI is low. PMID- 29695763 TI - Phase angle and mortality: a systematic review. AB - BACKGROUND/OBJECTIVES: The phase angle, expressed through bioelectrical impedance, has been studied as a prognostic marker in several health conditions. As this issue is still conflicting, the question whether this parameter correlates with mortality in the most diverse clinical situations remains. Therefore, this study aimed to evaluate the relationship between phase angle and mortality through a systematic review of the literature. SUBJECTS/METHODS: This research was conducted in electronic databases (Pubmed, Embase, Cochrane, Lilacs, Scielo, e Scopus), and included studies that had phase angle as a variable of interest and mortality/survival as an outcome. Data were extracted independently by two reviewers and disagreements were assessed by a third reviewer. RESULTS: Forty-eight of 455 papers were assessed and an amount of 42 showed a correlation between phase angle and mortality. CONCLUSIONS: Phase angle seems to be a good indicator for mortality in many clinical situations and can be used in screening individuals prone to this outcome. PMID- 29695764 TI - Integrative network analyses of wilt transcriptome in chickpea reveal genotype dependent regulatory hubs in immunity and susceptibility. AB - Host specific resistance and non-host resistance are two plant immune responses to counter pathogen invasion. Gene network organizing principles leading to quantitative differences in resistant and susceptible host during host specific resistance are poorly understood. Vascular wilt caused by root pathogen Fusarium species is complex and governed by host specific resistance in crop plants, including chickpea. Here, we temporally profiled two contrasting chickpea genotypes in disease and immune state to better understand gene expression switches in host specific resistance. Integrative gene-regulatory network elucidated tangible insight into interaction coordinators leading to pathway determination governing distinct (disease or immune) phenotypes. Global network analysis identified five major hubs with 389 co-regulated genes. Functional enrichment revealed immunome containing three subnetworks involving CTI, PTI and ETI and wilt diseasome encompassing four subnetworks highlighting pathogen perception, penetration, colonization and disease establishment. These subnetworks likely represent key components that coordinate various biological processes favouring defence or disease. Furthermore, we identified core 76 disease/immunity related genes through subcellular analysis. Our regularized network with robust statistical assessment captured known and unexpected gene interaction, candidate novel regulators as future biomarkers and first time showed system-wide quantitative architecture corresponding to genotypic characteristics in wilt landscape. PMID- 29695765 TI - Phase I study of nab-paclitaxel, gemcitabine, and bevacizumab in patients with advanced cancers. AB - BACKGROUND: We performed a phase I modified 3 + 3 dose escalation study to evaluate the safety and activity of bevacizumab plus gemcitabine and nab paclitaxel in patients with advanced solid tumours. METHODS: Patients were given fixed dose gemcitabine plus increasing doses of nab-paclitaxel and bevacizumab. Toxicity, response, and association with VEGF polymorphism was analysed. RESULTS: The study enrolled 110 patients who had undergone a median of 3 prior lines of therapy. The median age was 60 years (range, 17-85 years), and 55 patients (50%) had gemcitabine-refractory disease. We observed 3 dose-limiting toxicities during dose escalation and 3 DLTs in expansion cohorts. Dose escalation to 150 mg/m2 nab paclitaxel and 15 mg/kg bevacizumab with 1000 mg/m2 of gemcitabine was well tolerated with no MTD. One patient with gemcitabine-refractory peritoneal papillary carcinoma had a complete response, 13 patients (13%) had partial responses, and 54 patients (52%) had stable disease >=12 weeks. Exploratory VEGF single nucleotide polymorphism (SNP) analysis was performed on 13 patients. CONCLUSIONS: The combination of gemcitabine, nab-paclitaxel, and bevacizumab is safe, well-tolerated, and has activity in advanced malignancies, including gemcitabine-refractory tumours. Based on this study, the recommended phase 2 dose is gemcitabine 1000 mg/m2, nab-paclitaxel 125 mg/m2, and bevacizumab 15 mg/kg. VEGF polymorphism data should be evaluated in future bevacizumab-based trials. PMID- 29695766 TI - Vinorelbine, cyclophosphamide and 5-FU effects on the circulating and intratumoural landscape of immune cells improve anti-PD-L1 efficacy in preclinical models of breast cancer and lymphoma. AB - BACKGROUND: Anti-PD-1 and anti-PD-L1 checkpoint inhibitors (CIs) are clinically active in many types of cancer. However, only a minority of patients achieve a complete and/or long-lasting clinical response. We studied the effects of different doses of three widely used, orally active chemotherapeutics (vinorelbine, cyclophosphamide and 5-FU) over local and metastatic tumour growth, and the landscape of circulating and tumour-infiltrating immune cells involved in CI activity. METHODS: Immunocompetent Balb/c mice were used to generate models of breast cancer (BC) and B-cell lymphoma. Vinorelbine, cyclophosphamide and 5-FU (alone or in combination with CIs), were given at low-dose metronomic, medium, or maximum tolerable dosages. RESULTS: Cyclophosphamide increased circulating myeloid derived suppressor cells (MDSC). Vinorelbine, cyclophosphamide and 5-FU reduced circulating APCs. Vinorelbine and cyclophosphamide (at medium/high doses) reduced circulating Tregs. Cyclophosphamide (at low doses) and 5-FU (at medium doses) slightly increased circulating Tregs. Cyclophosphamide was the most potent drug in reducing circulating CD3+CD8+ and CD3+CD4+ T cells. Vinorelbine, cyclophosphamide and 5-FU reduced the number of circulating B cells, with cyclophosphamide showing the most potent effect. Vinorelbine reduced circulating NKs, whereas cyclophosphamide and 5-FU, at low doses, increased circulating NKs. In spite of reduced circulating T, B and NK effector cells, preclinical synergy was observed between chemotherapeutics and anti-PD-L1. Most-effective combinatorial regimens where associated with neoplastic lesions enriched in B cells, and, in BC-bearing mice (but not in mice with lymphoma) also in NK cells. CONCLUSIONS: Vinorelbine, cyclophosphamide and 5-FU have significant preclinical effects on circulating and tumour-infiltrating immune cells and can be used to obtain synergy with anti-PD-L1. PMID- 29695768 TI - Association between single-nucleotide polymorphisms and adverse events in nivolumab-treated non-small cell lung cancer patients. AB - BACKGROUND: Treatment with PD-1 inhibitors can be hampered by severe auto-immune related toxicities. Our objective was to identify single-nucleotide polymorphisms (SNPs) in genes previously associated with auto-immunity, which are associated with toxicities in nivolumab-treated NSCLC patients. This was in order to identify patients prone to develop severe toxicities and to gain more insight into the underlying pathobiology. METHODS: We analysed 322 nivolumab-treated patients and assessed the association with toxicities for seven SNPs in four genes, which are considered contributors to PD-1-directed T-cell responses, i.e., PDCD1, PTPN11, ZAP70 and IFNG. Every SNP was tested for its association with toxicity endpoints. Significant associations were tested in a validation cohort. RESULTS: A multivariable analysis in the exploration cohort showed that homozygous variant patients for PDCD1 804C>T (rs2227981) had decreased odds for any grade treatment-related toxicities (n = 96; OR 0.4; 95% CI 0.2-1.0; p = 0.039). However, this result could not be validated (n = 85; OR 0.9; 95% CI 0.4 1.9; p = NS). CONCLUSIONS: Our results show that it is unlikely that the investigated SNPs have a clinical implication in predicting toxicity. A finding, even though negative, that is considered timely and instructive towards further research in biomarker development for checkpoint inhibitor treatments. PMID- 29695767 TI - Cutaneous neurofibromas in the genomics era: current understanding and open questions. AB - Cutaneous neurofibromas (cNF) are a nearly ubiquitous symptom of neurofibromatosis type 1 (NF1), a disorder with a broad phenotypic spectrum caused by germline mutation of the neurofibromatosis type 1 tumour suppressor gene (NF1). Symptoms of NF1 can include learning disabilities, bone abnormalities and predisposition to tumours such as cNFs, plexiform neurofibromas, malignant peripheral nerve sheath tumours and optic nerve tumours. There are no therapies currently approved for cNFs aside from elective surgery, and the molecular aetiology of cNF remains relatively uncharacterised. Furthermore, whereas the biallelic inactivation of NF1 in neoplastic Schwann cells is critical for cNF formation, it is still unclear which additional genetic, transcriptional, epigenetic, microenvironmental or endocrine changes are important. Significant inroads have been made into cNF understanding, including NF1 genotype-phenotype correlations in NF1 microdeletion patients, the identification of recurring somatic mutations, studies of cNF-invading mast cells and macrophages, and clinical trials of putative therapeutic targets such as mTOR, MEK and c-KIT. Despite these advances, several gaps remain in our knowledge of the associated pathogenesis, which is further hampered by a lack of translationally relevant animal models. Some of these questions may be addressed in part by the adoption of genomic analysis techniques. Understanding the aetiology of cNF at the genomic level may assist in the development of new therapies for cNF, and may also contribute to a greater understanding of NF1/RAS signalling in cancers beyond those associated with NF1. Here, we summarise the present understanding of cNF biology, including the pathogenesis, mutational landscape, contribution of the tumour microenvironment and endocrine signalling, and the historical and current state of clinical trials for cNF. We also highlight open access data resources and potential avenues for future research that leverage recently developed genomics-based methods in cancer research. PMID- 29695769 TI - Suppression of TGFbeta-mediated conversion of endothelial cells and fibroblasts into cancer associated (myo)fibroblasts via HDAC inhibition. AB - BACKGROUND: Cancer-associated fibroblasts (CAFs) support tumour progression and invasion, and they secrete abundant extracellular matrix (ECM) that may shield tumour cells from immune checkpoint or kinase inhibitors. Targeting CAFs using drugs that revert their differentiation, or inhibit their tumour-supportive functions, has been considered as an anti-cancer strategy. METHODS: We have used human and murine cell culture models, atomic force microscopy (AFM), microarray analyses, CAF/tumour cell spheroid co-cultures and transgenic fibroblast reporter mice to study how targeting HDACs using small molecule inhibitors or siRNAs re directs CAF differentiation and function in vitro and in vivo. RESULTS: From a small molecule screen, we identified Scriptaid, a selective inhibitor of HDACs 1/3/8, as a repressor of TGFbeta-mediated CAF differentiation. Scriptaid inhibits ECM secretion, reduces cellular contraction and stiffness, and impairs collective cell invasion in CAF/tumour cell spheroid co-cultures. Scriptaid also reduces CAF abundance and delays tumour growth in vivo. CONCLUSIONS: Scriptaid is a well tolerated and effective HDACi that reverses many of the functional and phenotypic properties of CAFs. Impeding or reversing CAF activation/function by altering the cellular epigenetic regulatory machinery could control tumour growth and invasion, and be beneficial in combination with additional therapies that target cancer cells or immune cells directly. PMID- 29695771 TI - Differential expression of IL-6/IL-6R and MAO-A regulates invasion/angiogenesis in breast cancer. AB - BACKGROUND: Monoamine oxidases (MAO) are mitochondrial enzymes functioning in oxidative metabolism of monoamines. The action of MAO-A has been typically described in neuro-pharmacological domains. Here, we have established a co relation between IL-6/IL-6R and MAO-A and their regulation in hypoxia induced invasion/angiogenesis. METHODS: We employed various in-vitro and in-vivo techniques and clinical samples. RESULTS: We studied a co-relation among MAO-A and IL-6/IL-6R and tumour angiogenesis/invasion in hypoxic environment in breast cancer model. Activation of IL-6/IL-6R and its downstream was found in hypoxic cancer cells. This elevation of IL-6/IL-6R caused sustained inhibition of MAO-A in hypoxic environment. Inhibition of IL-6R signalling or IL-6R siRNA increased MAO-A activity and inhibited tumour angiogenesis and invasion significantly in different models. Further, elevation of MAO-A with 5-azacytidine (5-Aza) modulated IL-6 mediated angiogenesis and invasive signatures including VEGF, MMPs and EMT in hypoxic breast cancer. High grade invasive ductal carcinoma (IDC) clinical specimen displayed elevated level of IL-6R and depleted MAO-A expression. Expression of VEGF and HIF-1alpha was unregulated and loss of E Cadherin was observed in high grade IDC tissue specimen. CONCLUSIONS: Suppression of MAO-A by IL-6/IL-6R activation promotes tumour angiogenesis and invasion in hypoxic breast cancer environment. PMID- 29695770 TI - Systemic immune response induced by oxaliplatin-based neoadjuvant therapy favours survival without metastatic progression in high-risk rectal cancer. AB - BACKGROUND: Systemic failure remains a challenge in rectal cancer. We investigated the possible systemic anti-tumour immune activity invoked within oxaliplatin-based neoadjuvant therapy. METHODS: In two high-risk patient cohorts, we assessed the circulating levels of the fms-like tyrosine kinase 3 ligand (Flt3L), a factor reflecting both therapy-induced myelosuppression and activation of tumour antigen-presenting dendritic cells, at baseline and following induction chemotherapy and sequential chemoradiotherapy, both modalities containing oxaliplatin. The primary end point was progression-free survival (PFS). RESULTS: In both cohorts, the median Flt3L level was significantly higher at completion of each sequential modality than at baseline. The 5-year PFS (most events being metastatic progression) was 68% and 71% in the two cohorts consisting of 33% and 52% T4 cases. In the principal cohort, a high Flt3L level following the induction chemotherapy was associated with low risk for a PFS event (HR: 0.15; P < 0.01). These patients also had available dose scheduling and toxicity data, revealing that oxaliplatin dose reduction during chemoradiotherapy, undertaken to maintain compliance to the radiotherapy protocol, was associated with advantageous PFS (HR: 0.47; P = 0.046). CONCLUSION: In high-risk rectal cancer, oxaliplatin containing neoadjuvant therapy may promote an immune response that favours survival without metastatic progression. PMID- 29695772 TI - Effects of self-monitoring of daily salt intake estimated by a simple electrical device for salt reduction: a cluster randomized trial. AB - Recently, a simple device for self-monitoring of daily salt intake was developed, and it is recommended by The Japanese Society of Hypertension. This study aimed to investigate the effects of this device on salt reduction and on lowering blood pressure. In this single blinded, cluster randomized controlled trial, families were randomly assigned to either an intervention or a control group. Participants in both groups attended lectures about salt reduction, but only the intervention group used the self-monitoring device to estimate their daily salt intake. The main outcome measure was the difference in the estimated daily salt intake by spot urine between the two groups after 4 weeks. The secondary outcome was the difference in blood pressure. A total of 105 families (158 participants) were randomized. The mean daily salt intake was 9.04 (SD 1.77) g/day in the control group and 9.37 (SD 2.13) g/day in the intervention group at baseline. After 4 weeks, the mean daily salt intake was 8.97 (SD 1.97) g/day in the control group and 8.60 (SD 2.25) g/day in the intervention group; the mean difference between the two groups was -0.50 g/day (95% confidence interval (CI) -0.95, -0.05; P = 0.030). The mean difference in systolic blood pressure was -4.4 mm Hg (95% CI 8.7, -0.1; P = 0.044). This is the first randomized controlled trial to demonstrate the effectiveness of a device for self-monitoring of salt intake with a significant reduction in daily salt intake and systolic blood pressure. PMID- 29695773 TI - Stromal interaction molecule 1 modulates blood pressure via NO production in vascular endothelial cells. AB - In vascular endothelial cells, store-operated calcium entry (SOCE) activates endothelial NO synthase (eNOS) and regulates nitric oxide (NO) production as well as flow-dependent mechanical stimuli. Stromal interaction molecule 1, or STIM1, was recently identified to be essential for SOCE, acting as a calcium sensor for intracellular calcium stores. However, how STIM1 affects endothelial function and blood pressure (BP) remains unclear. We generated STIM1 fl/fl mice and vascular endothelial cell-specific STIM1 knockout mice using the Cre-loxP system, and conducted experiments using these mice to clarify the physiological role of STIM1 in vascular endothelial function and BP as follows: (1) SOCE was analyzed in isolated aortic endothelial cells by calcium add-back with fluorescent Ca2+ indicators. Phosphorylation of eNOS and NO production were evaluated by immunoblotting and the NO indicator, respectively. (2) Tension of aortic rings was measured in 10-week-old mice in response to acetylcholine. (3) BP was measured in 10-week-old mice by the telemetry system. The results were: (1) SOCE, eNOS activation, and NO production were suppressed by ~50-60% in endothelial cells from STIM1 knockout. (2) Endothelium-dependent vasodilation was decreased in aortic rings from STIM1 knockout mice, whereas endothelium-independent relaxation was not altered. (3) STIM1 knockout mice exhibited significant BP elevation, especially in nighttime. (124.3 +/- 2.5/99.2 +/- 3.9 vs. 114.1 +/- 3.2/83.6 +/- 1.7 (nighttime, mmHg), 109.7 +/- 1.7/83.0 +/- 3.0 vs. 104.8 +/- 3.3/73.7 +/- 1.6 (daytime, mmHg), knockout vs. control, respectively). In conclusion, STIM1 in vascular endothelial cell modulates vascular function through NO production and has a major role in regulating BP, especially in the active time. PMID- 29695774 TI - Characterization of the enhancer and promoter landscape of inflammatory bowel disease from human colon biopsies. AB - Inflammatory bowel disease (IBD) is a chronic intestinal disorder, with two main types: Crohn's disease (CD) and ulcerative colitis (UC), whose molecular pathology is not well understood. The majority of IBD-associated SNPs are located in non-coding regions and are hard to characterize since regulatory regions in IBD are not known. Here we profile transcription start sites (TSSs) and enhancers in the descending colon of 94 IBD patients and controls. IBD-upregulated promoters and enhancers are highly enriched for IBD-associated SNPs and are bound by the same transcription factors. IBD-specific TSSs are associated to genes with roles in both inflammatory cascades and gut epithelia while TSSs distinguishing UC and CD are associated to gut epithelia functions. We find that as few as 35 TSSs can distinguish active CD, UC, and controls with 85% accuracy in an independent cohort. Our data constitute a foundation for understanding the molecular pathology, gene regulation, and genetics of IBD. PMID- 29695775 TI - The plant hormone abscisic acid regulates the growth and metabolism of endophytic fungus Aspergillus nidulans. AB - Plant hormones are well known chemical signals that regulate plant growth, development, and adaptation. However, after comparative transcriptome and metabolite analysis, we found that the plant hormone abscisic acid (ABA) also affect the growth and metabolism of endophytic fungus Aspergillus nidulans. There were 3148 up-regulated and 3160 down-regulated genes identified during 100 nM ABA induction. These differentially expressed genes (DEGs) were mainly involved in: RNA polymerase and basal transcription factors; ribosome biogenesis, protein processing, proteasome, and ubiquitin mediated proteolysis; nucleotide metabolism and tri-carboxylic acid (TCA) cycle; cell cycle and biosynthesis of secondary metabolites. Production of mycotoxins, which have insect-resistance or anti pathogen activity, was also changed with ABA induction. This study provides the first global view of ABA induced transcription and metabolite changes in endophytic fungus, which might suggest a potential fungus-plant cross-talk via ABA. PMID- 29695776 TI - Correlation of the Dzyaloshinskii-Moriya interaction with Heisenberg exchange and orbital asphericity. AB - Chiral spin textures of a ferromagnetic layer in contact to a heavy non-magnetic metal, such as Neel-type domain walls and skyrmions, have been studied intensively because of their potential for future nanomagnetic devices. The Dyzaloshinskii-Moriya interaction (DMI) is an essential phenomenon for the formation of such chiral spin textures. In spite of recent theoretical progress aiming at understanding the microscopic origin of the DMI, an experimental investigation unravelling the physics at stake is still required. Here we experimentally demonstrate the close correlation of the DMI with the anisotropy of the orbital magnetic moment and with the magnetic dipole moment of the ferromagnetic metal in addition to Heisenberg exchange. The density functional theory and the tight-binding model calculations reveal that inversion symmetry breaking with spin-orbit coupling gives rise to the orbital-related correlation. Our study provides the experimental connection between the orbital physics and the spin-orbit-related phenomena, such as DMI. PMID- 29695777 TI - A SUMO-dependent feedback loop senses and controls the biogenesis of nuclear pore subunits. AB - While the activity of multiprotein complexes is crucial for cellular metabolism, little is known about the mechanisms that collectively control the expression of their components. Here, we investigate the regulations targeting the biogenesis of the nuclear pore complex (NPC), the macromolecular assembly mediating nucleocytoplasmic exchanges. Systematic analysis of RNA-binding proteins interactomes, together with in vivo and in vitro assays, reveal that a subset of NPC mRNAs are specifically bound by Hek2, a yeast hnRNP K-like protein. Hek2 dependent translational repression and protein turnover are further shown to finely tune the levels of NPC subunits. Strikingly, mutations or physiological perturbations altering pore integrity decrease the levels of the NPC-associated SUMO protease Ulp1, and trigger the accumulation of sumoylated versions of Hek2 unable to bind NPC mRNAs. Our results support the existence of a quality control mechanism involving Ulp1 as a sensor of NPC integrity and Hek2 as a repressor of NPC biogenesis. PMID- 29695778 TI - Magnetic Field Enhanced Superconductivity in Epitaxial Thin Film WTe2. AB - In conventional superconductors an external magnetic field generally suppresses superconductivity. This results from a simple thermodynamic competition of the superconducting and magnetic free energies. In this study, we report the unconventional features in the superconducting epitaxial thin film tungsten telluride (WTe2). Measuring the electrical transport properties of Molecular Beam Epitaxy (MBE) grown WTe2 thin films with a high precision rotation stage, we map the upper critical field Hc2 at different temperatures T. We observe the superconducting transition temperature T c is enhanced by in-plane magnetic fields. The upper critical field Hc2 is observed to establish an unconventional non-monotonic dependence on temperature. We suggest that this unconventional feature is due to the lifting of inversion symmetry, which leads to the enhancement of Hc2 in Ising superconductors. PMID- 29695779 TI - A dual role for glucocorticoid-induced leucine zipper in glucocorticoid function: tumor growth promotion or suppression? AB - Glucocorticoids (GCs), important therapeutic tools to treat inflammatory and immunosuppressive diseases, can also be used as part of cancer therapy. In oncology, GCs are used as anticancer drugs for lymphohematopoietic malignancies, while in solid neoplasms primarily to control the side effects of chemo/radiotherapy treatments. The molecular mechanisms underlying the effects of GCs are numerous and often overlapping, but not all have been elucidated. In normal, cancerous, and inflammatory tissues, the response to GCs differs based on the tissue type. The effects of GCs are dependent on several factors: the tumor type, the GC therapy being used, the expression level of the glucocorticoid receptor (GR), and the presence of any other stimuli such as signals from immune cells and the tumor microenvironment. Therefore, GCs may either promote or suppress tumor growth via different molecular mechanisms. Stress exposure results in dysregulation of the hypothalamic-pituitary-adrenal axis with increased levels of endogenous GCs that promote tumorigenesis, confirming the importance of GCs in tumor growth. Most of the effects of GCs are genomic and mediated by the modulation of GR gene transcription. Moreover, among the GR-induced genes, glucocorticoid-induced leucine zipper (GILZ), which was cloned and characterized primarily in our laboratory, mediates many GC anti-inflammatory effects. In this review, we analyzed the possible role for GILZ in the effects GCs have on tumors cells. We also suggest that GILZ, by affecting the immune system, tumor microenvironment, and directly cancer cell biology, has a tumor-promoting function. However, it may also induce apoptosis or decrease the proliferation of cancer cells, thus inhibiting tumor growth. The potential therapeutic implications of GILZ activity on tumor cells are discussed here. PMID- 29695781 TI - The Bexsero Neisseria meningitidis serogroup B vaccine antigen NHBA is a high affinity chondroitin sulfate binding protein. AB - Neisseria meningitidis is a Gram-negative bacterial pathogen that causes life threatening meningitis and septicemia. Neisseria Heparin Binding Antigen (NHBA) is an outer membrane protein that binds heparin and heparan sulfate and DNA. This protein is one of the four antigens in the meningococcal serogroup B vaccine Bexsero. In the current study, we sought to define the full glycan-binding repertoire of NHBA to better understand its role in meningococcal pathogenesis and vaccine efficacy. Glycan array analysis revealed binding to 28 structures by recombinant NHBA. Surface plasmon resonance was used to confirm the binding phenotype and to determine the affinity of the interactions. These studies revealed that the highest affinity binding of NHBA was with chondroitin sulfate (KD = 5.2 nM). This affinity is 10-fold higher than observed for heparin. Analysis of binding with well-defined disaccharides of the different chondroitin sulfate types demonstrated that the most preferred ligand has a sulfate at the 2 position of the GlcA/IdoA and 6 position of the GalNAc, which is an equivalent structure to chondroitin sulfate D. Chondroitin sulfate is widely expressed in human tissues, while chondroitin sulfate D is predominantly expressed in the brain and may constitute a new receptor structure for meningococci. PMID- 29695780 TI - Structural basis for GPR40 allosteric agonism and incretin stimulation. AB - Activation of free fatty acid receptor 1 (GPR40) by synthetic partial and full agonists occur via distinct allosteric sites. A crystal structure of GPR40-TAK 875 complex revealed the allosteric site for the partial agonist. Here we report the 2.76-A crystal structure of human GPR40 in complex with a synthetic full agonist, compound 1, bound to the second allosteric site. Unlike TAK-875, which acts as a Galphaq-coupled partial agonist, compound 1 is a dual Galphaq and Galphas-coupled full agonist. compound 1 binds in the lipid-rich region of the receptor near intracellular loop 2 (ICL2), in which the stabilization of ICL2 by the ligand is likely the primary mechanism for the enhanced G protein activities. The endogenous free fatty acid (FFA), gamma-linolenic acid, can be computationally modeled in this site. Both gamma-linolenic acid and compound 1 exhibit positive cooperativity with TAK-875, suggesting that this site could also serve as a FFA binding site. PMID- 29695782 TI - Can anti-obesity drugs be repurposed to treat cocaine addiction? PMID- 29695783 TI - alpha7 Nicotinic receptor-modulating agents reverse the hyperdopaminergic tone in the MAM model of schizophrenia. AB - Recent evidence has emerged supporting a role for the cholinergic system in schizophrenia, including the potential of alpha7 modulators as a treatment strategy. However, preclinical studies to date have relied on studies in normal systems rather than on a validated developmental model of schizophrenia. Furthermore, there have been only few studies on whether orthosteric and allosteric modulators have differential impacts in such models. Thus, we investigated the effects of alpha7 agonists and positive allosteric modulators (PAMs) on dopamine (DA) neuron activity in the ventral tegmental area (VTA) in the methylazoxymethanol acetate (MAM) developmental disruption model of schizophrenia. Four different drugs were evaluated: PNU282987 (full agonist), SSR180711 (partial agonist) NS1738 (PAM type I) and PNU120596 (PAM type II). PNU120596 increased the number of spontaneously active VTA DA neurons in normal rats. In contrast, PNU282987 and SSR180711 reduced the hyperdopaminergic tone in MAM rats. This appeared to be due to effects on DA afferent regulation, in that PNU282987 or SSR180711 infusion into the ventral hippocampus of MAM rats replicated the decrease in the number of spontaneously active VTA DA neurons. In contrast, infusion of the same drugs into the basolateral amygdala increased the number of spontaneously active VTA DA neurons in normal rats without impacting MAM rats. These data suggest that alpha7 receptors may represent a promising target in the development of new pharmacological therapies for schizophrenia. PMID- 29695784 TI - Gold-catalyzed stereoselective cycloisomerization of allenoic acids for two types of common natural gamma-butyrolactones. AB - gamma-(E)-Vinylic and gamma-alkylic gamma-butyrolactones are two different types of lactones existing extensively in animals and plants and many of them show interesting biological activities. Nature makes alkylic gamma-butyrolactones by many different enzymatic lactonization processes. Scientists have been mimicking the natural strategy by developing new catalysts. However, direct and efficient access to gamma-(E)-vinylic gamma-butyrolactones is still extremely limited. Here, we wish to present our modular allene approach, which provides an efficient asymmetric approach to (E)-vinylic gamma-butyrolactones from allenoic acids by identifying a new gold complex as the catalyst. Based on this cycloisomerization strategy, the first syntheses of racemic xestospongiene and xestospongienes E, F, G, and H have been realized and the absolute configurations of the chiral centers in xestospongienes E and F have been revised. In addition, by applying a C-O bond cleavage-free hydrogenation, the syntheses of naturally occurring gamma-alkylic gamma-lactones, (R)-4-tetradecalactone, (S)-4-tetradecalactone, (R)-gamma palmitolactone, and (R)-4-decalactone, have also been achieved. PMID- 29695785 TI - Methodical about Methods. PMID- 29695786 TI - Dnmt2 mediates intergenerational transmission of paternally acquired metabolic disorders through sperm small non-coding RNAs. AB - The discovery of RNAs (for example, messenger RNAs, non-coding RNAs) in sperm has opened the possibility that sperm may function by delivering additional paternal information aside from solely providing the DNA 1 . Increasing evidence now suggests that sperm small non-coding RNAs (sncRNAs) can mediate intergenerational transmission of paternally acquired phenotypes, including mental stress2,3 and metabolic disorders4-6. How sperm sncRNAs encode paternal information remains unclear, but the mechanism may involve RNA modifications. Here we show that deletion of a mouse tRNA methyltransferase, DNMT2, abolished sperm sncRNA mediated transmission of high-fat-diet-induced metabolic disorders to offspring. Dnmt2 deletion prevented the elevation of RNA modifications (m5C, m2G) in sperm 30-40 nt RNA fractions that are induced by a high-fat diet. Also, Dnmt2 deletion altered the sperm small RNA expression profile, including levels of tRNA-derived small RNAs and rRNA-derived small RNAs, which might be essential in composing a sperm RNA 'coding signature' that is needed for paternal epigenetic memory. Finally, we show that Dnmt2-mediated m5C contributes to the secondary structure and biological properties of sncRNAs, implicating sperm RNA modifications as an additional layer of paternal hereditary information. PMID- 29695787 TI - Loss of KLHL6 promotes diffuse large B-cell lymphoma growth and survival by stabilizing the mRNA decay factor roquin2. AB - Kelch-like protein 6 (KLHL6) is an uncharacterized gene mutated in diffuse large B-cell lymphoma (DLBCL). Here we report that KLHL6 assembles with cullin3 to form a functional cullin-RING ubiquitin ligase. Mutations in KLHL6 inhibit its ligase activity by disrupting the interaction with cullin3. Loss of KLHL6 favours DLBCL growth and survival both in vitro and in xenograft models. We further established that the mRNA decay factor roquin2 is a substrate of KLHL6. Degradation of roquin2 is dependent on B-cell receptor activation, and requires the integrity of the Tyr691 residue in roquin2 that is essential for its interaction with KLHL6. A non-degradable roquin2(Y691F) mutant requires its RNA-binding ability to phenocopy the effect of KLHL6 loss. Stabilization of roquin2 promotes mRNA decay of the tumour suppressor and NF-kappaB pathway inhibitor, tumour necrosis factor alpha-inducible gene 3. Collectively, our findings uncover the tumour suppressing mechanism of KLHL6. PMID- 29695789 TI - Dissecting the roles of miR-140 and its host gene. PMID- 29695790 TI - XMAP215 joins microtubule nucleation team. PMID- 29695788 TI - TFAP2C regulates transcription in human naive pluripotency by opening enhancers. AB - Naive and primed pluripotent human embryonic stem cells bear transcriptional similarity to pre- and post-implantation epiblast and thus constitute a developmental model for understanding the pluripotent stages in human embryo development. To identify new transcription factors that differentially regulate the unique pluripotent stages, we mapped open chromatin using ATAC-seq and found enrichment of the activator protein-2 (AP2) transcription factor binding motif at naive-specific open chromatin. We determined that the AP2 family member TFAP2C is upregulated during primed to naive reversion and becomes widespread at naive specific enhancers. TFAP2C functions to maintain pluripotency and repress neuroectodermal differentiation during the transition from primed to naive by facilitating the opening of enhancers proximal to pluripotency factors. Additionally, we identify a previously undiscovered naive-specific POU5F1 (OCT4) enhancer enriched for TFAP2C binding. Taken together, TFAP2C establishes and maintains naive human pluripotency and regulates OCT4 expression by mechanisms that are distinct from mouse. PMID- 29695791 TI - Reply to 'Dissecting the role of miR-140 and its host gene'. PMID- 29695792 TI - XMAP215 is a microtubule nucleation factor that functions synergistically with the gamma-tubulin ring complex. AB - How microtubules (MTs) are generated in the cell is a major question in understanding how the cytoskeleton is assembled. For several decades, gamma tubulin has been accepted as the universal MT nucleator of the cell. Although there is evidence that gamma-tubulin complexes are not the sole MT nucleators, identification of other nucleation factors has proven difficult. Here, we report that the well-characterized MT polymerase XMAP215 (chTOG/Msps/Stu2p/Alp14/Dis1 homologue) is essential for MT nucleation in Xenopus egg extracts. The concentration of XMAP215 determines the extent of MT nucleation. Even though XMAP215 and the gamma-tubulin ring complex (gamma-TuRC) possess minimal nucleation activity individually, together, these factors synergistically stimulate MT nucleation in vitro. The amino-terminal TOG domains 1-5 of XMAP215 bind to alphabeta-tubulin and promote MT polymerization, whereas the conserved carboxy terminus is required for efficient MT nucleation and directly binds to gamma-tubulin. In summary, XMAP215 and gamma-TuRC together function as the principal nucleation module that generates MTs in cells. PMID- 29695793 TI - CsrA and its regulators control the time-point of ColicinE2 release in Escherichia coli. AB - The bacterial SOS response is a cellular reaction to DNA damage, that, among other actions, triggers the expression of colicin - toxic bacteriocins in Escherichia coli that are released to kill close relatives competing for resources. However, it is largely unknown, how the complex network regulating toxin expression controls the time-point of toxin release to prevent premature release of inefficient protein concentrations. Here, we study how different regulatory mechanisms affect production and release of the bacteriocin ColicinE2 in Escherichia coli. Combining experimental and theoretical approaches, we demonstrate that the global carbon storage regulator CsrA controls the duration of the delay between toxin production and release and emphasize the importance of CsrA sequestering elements for the timing of ColicinE2 release. In particular, we show that ssDNA originating from rolling-circle replication of the toxin producing plasmid represents a yet unknown additional CsrA sequestering element, which is essential in the ColicinE2-producing strain to enable toxin release by reducing the amount of free CsrA molecules in the bacterial cell. Taken together, our findings show that CsrA times ColicinE2 release and reveal a dual function for CsrA as an ssDNA and mRNA-binding protein, introducing ssDNA as an important post-transcriptional gene regulatory element. PMID- 29695794 TI - A phase transformable ultrastable titanium-carboxylate framework for photoconduction. AB - Porous titanium oxide materials are attractive for energy-related applications. However, many suffer from poor stability and crystallinity. Here we present a robust nanoporous metal-organic framework (MOF), comprising a Ti12O15 oxocluster and a tetracarboxylate ligand, achieved through a scalable synthesis. This material undergoes an unusual irreversible thermally induced phase transformation that generates a highly crystalline porous product with an infinite inorganic moiety of a very high condensation degree. Preliminary photophysical experiments indicate that the product after phase transformation exhibits photoconductive behavior, highlighting the impact of inorganic unit dimensionality on the alteration of physical properties. Introduction of a conductive polymer into its pores leads to a significant increase of the charge separation lifetime under irradiation. Additionally, the inorganic unit of this Ti-MOF can be easily modified via doping with other metal elements. The combined advantages of this compound make it a promising functional scaffold for practical applications. PMID- 29695795 TI - Cryo-EM reveals the structural basis of microtubule depolymerization by kinesin 13s. AB - Kinesin-13s constitute a distinct group within the kinesin superfamily of motor proteins that promote microtubule depolymerization and lack motile activity. The molecular mechanism by which kinesin-13s depolymerize microtubules and are adapted to perform a seemingly very different activity from other kinesins is still unclear. To address this issue, here we report the near atomic resolution cryo-electron microscopy (cryo-EM) structures of Drosophila melanogaster kinesin 13 KLP10A protein constructs bound to curved or straight tubulin in different nucleotide states. These structures show how nucleotide induced conformational changes near the catalytic site are coupled with movement of the kinesin-13 specific loop-2 to induce tubulin curvature leading to microtubule depolymerization. The data highlight a modular structure that allows similar kinesin core motor-domains to be used for different functions, such as motility or microtubule depolymerization. PMID- 29695796 TI - Mitochondrial NADP+-dependent isocitrate dehydrogenase deficiency increases cisplatin-induced oxidative damage in the kidney tubule cells. AB - Mitochondrial NADP+-dependent isocitrate dehydrogenase (IDH2) plays an important role in the formation of NADPH, which is critical for the maintenance of mitochondrial redox balance. Cis-diamminedichloroplatinum II (cisplatin), an effective anticancer drug, induces oxidative stress-related nephrotoxicity, limiting its use. Therefore, we investigated whether IDH2, which is a critical enzyme in the NADPH-associated mitochondrial antioxidant system, is involved in cisplatin nephrotoxicity. Idh2 gene-deleted (Idh2-/-) mice and wild-type (Idh2 +/+ ) littermates were treated with cisplatin, with or without 2-(2,2,6,6 tetramethylpiperidin-1-oxyl-4-ylamino)-2-oxoethyl) triphenylphosphonium chloride (Mito-T), a mitochondria-specific antioxidant. Cisplatin-induced renal functional and morphological impairments were greater in Idh2-/- mice than in Idh2 +/+ mice. Mito-T mitigated those impairments in both Idh2-/- and Idh2 +/+ mice and this mitigation was greater in Idh2-/- than in Idh2 +/+ mice. Cisplatin impaired IDH2 function in the mitochondria, decreasing mitochondrial NADPH and GSH levels and increasing H2O2 generation; protein, lipid, and DNA oxidation; mitochondrial damage; and apoptosis. These cisplatin-induced changes were much more severe in Idh2-/- mice than in Idh2 +/+ mice. Mito-T treatment attenuated cisplatin-induced alterations in both Idh2-/- and Idh2 +/+ mice and this mitigation was greater in Idh2-/- than in Idh2 +/+ mice. Altogether, these data demonstrate that cisplatin induces the impairment of the mitochondrial IDH2-NADPH-GSH antioxidant system and IDH2 deficiency aggravates cisplatin-induced mitochondrial oxidative damage, inducing more severe nephrotoxicity. This suggests that the mitochondrial IDH2 NADPH-GSH antioxidant system is a target for the prevention of cisplatin-induced kidney cell death. PMID- 29695798 TI - Dual Doppler Effect in Wedge-Type Photonic Crystals. AB - The dual Doppler effect, in the simultaneous occurrence of both normal and inverse Doppler effect in one moving two-dimensional wedge-type photonic crystal, is proposed. An improved finite-different time-domain algorithm is used to verify this phenomenon. The spatial Fourier Transformation has been applied to complex electrical field data to reveal the mechanism. The harmonics with negative spatial frequencies show a lagging phase evolution, while those with positive spatial frequencies show a front phase evolution. Different wedge-type photonic crystals are designed to filter out the required harmonics based on the systematic study of spatial Fourier Transformation and wave vector diagram. Our work paves a new way for Doppler cooling of atomic gases, radar deception, invisibility cloaks, microstructure dual frequency interferometer and so on. PMID- 29695797 TI - A biallelic 36-bp insertion in PIBF1 is associated with Joubert syndrome. AB - Biallelic pathogenic variants in PIBF1 have been identified as one of the genetic etiologies of Joubert syndrome. We report a two-year-old girl with global developmental delay, facial dysmorphism, hypotonia, enlarged cystic kidneys, molar tooth sign, and thinning of corpus callosum. A novel homozygous 36-bp insertion in PIBF1 (c.1181_1182ins36) was identified by exome sequencing as the likely cause of her condition. This is the second publication demonstrating the cause and effect relationship between PIBF1 and Joubert syndrome. PMID- 29695800 TI - CRISPR expands insight into the mechanisms of ALS and FTD. PMID- 29695799 TI - Novel Type III Polyketide Synthases Biosynthesize Methylated Polyketides in Mycobacterium marinum. AB - Mycobacterial pathogenesis is hallmarked by lipidic polyketides that decorate the cell envelope and mediate infection. However, factors mediating persistence remain largely unknown. Dynamic cell wall remodeling could facilitate the different pathogenic phases. Recent studies have implicated type III polyketide synthases (PKSs) in cell wall alterations in several bacteria. Comparative genome analysis revealed several type III pks gene clusters in mycobacteria. In this study, we report the functional characterization of two novel type III PKSs, MMAR_2470 and MMAR_2474, in Mycobacterium marinum. These type III pkss belong to a unique pks genomic cluster conserved exclusively in pathogenic mycobacteria. Cell-free reconstitution assays and high-resolution mass spectrometric analyses revealed methylated polyketide products in independent reactions of both proteins. MMAR_2474 protein exceptionally biosynthesized methylated alkyl resorcinol and methylated acyl-phloroglucinol products from the same catalytic core. Structure-based homology modeling, product docking, and mutational studies identified residues that could facilitate the distinctive catalysis of these proteins. Functional investigations in heterologous mycobacterial strain implicated MMAR_2474 protein to be vital for mycobacterial survival in stationary biofilms. Our investigations provide new insights into type III PKSs conserved in pathogenic mycobacterial species. PMID- 29695801 TI - Dirac cone intensity asymmetry and surface magnetic field in V-doped and pristine topological insulators generated by synchrotron and laser radiation. AB - Effect of magnetization generated by synchrotron or laser radiation in magnetically-doped and pristine topological insulators (TIs) is presented and analyzed using angle-resolved photoemission spectroscopy. It was found that non equal photoexcitation of the Dirac cone (DC) states with opposite momenta and spin orientation indicated by the asymmetry in photoemission intensity of the DC states is accompanied by the k||-shift of the DC states relative to the non-spin polarized conduction band states located at k|| = 0. We relate the observed k|| shift to the induced surface in-plane magnetic field and corresponding magnetization due to the spin accumulation. The direction of the DC k||-shift and its value are changed with photon energy in correlation with variation of the sign and magnitude of the DC states intensity asymmetry. The theoretical estimations describe well the effect and predict the DC k||-shift values which corroborate the experimental observations. This finding opens new perspectives for effective local magnetization manipulation. PMID- 29695802 TI - Obesity exacerbates colitis-associated cancer via IL-6-regulated macrophage polarisation and CCL-20/CCR-6-mediated lymphocyte recruitment. AB - Colorectal cancer (CRC) is one of the most lethal cancers worldwide in which the vast majority of cases exhibit little genetic risk but are associated with a sedentary lifestyle and obesity. Although the mechanisms underlying CRC and colitis-associated colorectal cancer (CAC) remain unclear, we hypothesised that obesity-induced inflammation predisposes to CAC development. Here, we show that diet-induced obesity accelerates chemically-induced CAC in mice via increased inflammation and immune cell recruitment. Obesity-induced interleukin-6 (IL-6) shifts macrophage polarisation towards tumour-promoting macrophages that produce the chemokine CC-chemokine-ligand-20 (CCL-20) in the CAC microenvironment. CCL-20 promotes CAC progression by recruiting CC-chemokine-receptor-6 (CCR-6)-expressing B cells and gammadelta T cells via chemotaxis. Compromised cell recruitment as well as inhibition of B and gammadelta T cells protects against CAC progression. Collectively, our data reveal a function for IL-6 in the CAC microenvironment via lymphocyte recruitment through the CCL-20/CCR-6 axis, thereby implicating a potential therapeutic intervention for human patients. PMID- 29695803 TI - Demographic causes of adult sex ratio variation and their consequences for parental cooperation. AB - The adult sex ratio (ASR) is a fundamental concept in population biology, sexual selection, and social evolution. However, it remains unclear which demographic processes generate ASR variation and how biases in ASR in turn affect social behaviour. Here, we evaluate the demographic mechanisms shaping ASR and their potential consequences for parental cooperation using detailed survival, fecundity, and behavioural data on 6119 individuals from six wild shorebird populations exhibiting flexible parental strategies. We show that these closely related populations express strikingly different ASRs, despite having similar ecologies and life histories, and that ASR variation is largely driven by sex differences in the apparent survival of juveniles. Furthermore, families in populations with biased ASRs were predominantly tended by a single parent, suggesting that parental cooperation breaks down with unbalanced sex ratios. Taken together, our results indicate that sex biases emerging during early life have profound consequences for social behaviour. PMID- 29695804 TI - Targeted mutagenesis in wheat microspores using CRISPR/Cas9. AB - CRISPR/Cas9 genome editing is a transformative technology that will facilitate the development of crops to meet future demands. However, application of gene editing is hindered by the long life cycle of many crop species and because desired genotypes generally require multiple generations to achieve. Single celled microspores are haploid cells that can develop into double haploid plants and have been widely used as a breeding tool to generate homozygous plants within a generation. In this study, we combined the CRISPR/Cas9 system with microspore technology and developed an optimized haploid mutagenesis system to induce genetic modifications in the wheat genome. We investigated a number of factors that may affect the delivery of CRISPR/Cas9 reagents into microspores and found that electroporation of a minimum of 75,000 cells using 10-20 ug DNA and a pulsing voltage of 500 V is optimal for microspore transfection using the Neon transfection system. Using multiple Cas9 and sgRNA constructs, we present evidence for the seamless introduction of targeted modifications in an exogenous DsRed gene and two endogenous wheat genes, including TaLox2 and TaUbiL1. This study demonstrates the value and feasibility of combining microspore technology and CRISPR/Cas9-based gene editing for trait discovery and improvement in plants. PMID- 29695805 TI - Chemical diversity in a metal-organic framework revealed by fluorescence lifetime imaging. AB - The presence and variation of chemical functionality and defects in crystalline materials, such as metal-organic frameworks (MOFs), have tremendous impact on their properties. Finding a means of identifying and characterizing this chemical diversity is an important ongoing challenge. This task is complicated by the characteristic problem of bulk measurements only giving a statistical average over an entire sample, leaving uncharacterized any diversity that might exist between crystallites or even within individual crystals. Here, we show that by using fluorescence imaging and lifetime analysis, both the spatial arrangement of functionalities and the level of defects within a multivariable MOF crystal can be determined for the bulk as well as for the individual constituent crystals. We apply these methods to UiO-67 to study the incorporation of functional groups and their consequences on the structural features. We believe that the potential of the techniques presented here in uncovering chemical diversity in what is generally assumed to be homogeneous systems can provide a new level of understanding of materials properties. PMID- 29695806 TI - Rigid and concave, 2,4-cis-substituted azetidine derivatives: A platform for asymmetric catalysis. AB - A series of single enantiomer, 2,4-cis-disubstituted amino azetidines were synthesised and used as ligands for copper-catalysed Henry reactions of aldehydes with nitromethane. Optimisation of ligand substituents and the reaction conditions was conducted. The enantiomeric excess of the formed products was highest when alkyl aldehydes were employed in the reaction (>99% e.e.). The absolute stereochemistry of one representative azetidine derivative salt was determined by analysis of the Flack parameter of an XRD single crystal structure. The origin of selectivity in catalysis was investigated computationally, revealing the importance of the amino-substituent in determining the stereochemical outcome. A racemic platinum complex of a cis-disubstituted azetidine is examined by XRD single crystal structure analysis with reference to its steric parameters, and analogies to the computationally determined copper complex catalyst are drawn. A preliminary example of the use of a cis disubstituted azetidine scaffold in thiourea H-bonding catalyst is noted in the supporting information. PMID- 29695807 TI - Radiating pattern of surge-current-induced THz light in near-field and far-field zone. AB - We generate the THz wave on the surface of an unbiased GaAs crystal by illuminating femtosecond laser pulses with a 45 degrees incidence angle, and investigate its propagation properties comprehensively both in a near-field and in a far-field zone by performing a knife-edge scan measurement. In the near field zone, i.e. 540 MUm away from the generation point, we found that the beam simply takes a Gaussian shape of which width follows well a behavior predicted by a paraxial wave equation. In the far-field zone, on the other hand, it takes a highly anisotropic shape; whereas the beam profile maintains a Gaussian shape along the normal to the plane of incidence, it takes satellite peak structures along the direction in parallel to the plane of incidence. From the comparison with simulation results obtained by using a dipole radiation model, we demonstrated that this irregular beam pattern is attributed to the combined effect of the position-dependent phase retardation of the THz waves and the diffraction-limited size of the initial beam which lead to the interference of the waves in the far-field zone. Also, we found that this consideration accounting for a crossover of THz beam profile to the anisotropic non-Gaussian beam in the far-field zone can be applied for a comprehensive understanding of several other THz beam profiles obtained previously in different configurations. PMID- 29695809 TI - Author Correction: Establishment of the most comprehensive ITS2 barcode database to date of the traditional medicinal plant Rhodiola (Crassulaceae). AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29695808 TI - Uncovering inherent cellular plasticity of multiciliated ependyma leading to ventricular wall transformation and hydrocephalus. AB - Specialized, differentiated cells often perform unique tasks that require them to maintain a stable phenotype. Multiciliated ependymal cells (ECs) are unique glial cells lining the brain ventricles, important for cerebral spinal fluid circulation. While functional ECs are needed to prevent hydrocephalus, they have also been reported to generate new neurons: whether ECs represent a stable cellular population remains unclear. Via a chemical screen we found that mature ECs are inherently plastic, with their multiciliated state needing constant maintenance by the Foxj1 transcription factor, which paradoxically is rapidly turned over by the ubiquitin-proteasome system leading to cellular de differentiation. Mechanistic analyses revealed a novel NF-kappaB-independent IKK2 activity stabilizing Foxj1 in mature ECs, and we found that known IKK2 inhibitors including viruses and growth factors robustly induced Foxj1 degradation, EC de differentiation, and hydrocephalus. Although mature ECs upon de-differentiation can divide and regenerate multiciliated ECs, we did not detect evidence supporting EC's neurogenic potential. PMID- 29695810 TI - Dynamic Metasurface Aperture as Smart Around-the-Corner Motion Detector. AB - Detecting and analysing motion is a key feature of Smart Homes and the connected sensor vision they embrace. At present, most motion sensors operate in line-of sight Doppler shift schemes. Here, we propose an alternative approach suitable for indoor environments, which effectively constitute disordered cavities for radio frequency (RF) waves; we exploit the fundamental sensitivity of modes of such cavities to perturbations, caused here by moving objects. We establish experimentally three key features of our proposed system: (i) ability to capture the temporal variations of motion and discern information such as periodicity ("smart"), (ii) non line-of-sight motion detection, and (iii) single-frequency operation. Moreover, we explain theoretically and demonstrate experimentally that the use of dynamic metasurface apertures can substantially enhance the performance of RF motion detection. Potential applications include accurately detecting human presence and monitoring inhabitants' vital signs. PMID- 29695811 TI - Associations of obstructive sleep apnea with truncal skeletal muscle mass and density. AB - Sarcopenia has been associated with several conditions relevant to obstructive sleep apnea (OSA), such as aging and obesity, but a direct relationship between OSA and skeletal muscle alterations has not been identified. This study investigated associations between computed tomography (CT)-measured skeletal muscle indices and OSA severity. Analyzed were 334 patients who underwent polysomnography to diagnose OSA. Lumbar skeletal muscles were assessed with CT for the skeletal muscle mass index (SMI, cross-sectional area, normalized for height squared) and skeletal muscle density (SMD, fat infiltration). The apnea hypopnea index (AHI) correlated positively with the SMI and negatively with SMD in both men and women. The AHI was weakly associated with SMI only in men (beta = 0.11, P = 0.017) after adjustment for the body mass index (BMI) (BMI: beta = 0.61, P < 0.001 in men, beta = 0.65, P < 0.001 in women). The association of AHI and SMD was not significant after adjustment for BMI (BMI: beta = -0.42, P < 0.001 in men, beta = -0.64, P < 0.001 in women). Severity of OSA correlated with increases in skeletal muscle mass rather than muscle depletion and skeletal muscle adiposity. These associations were limited compared with the stronger associations between obesity and skeletal muscles. PMID- 29695812 TI - Skeletal muscle phosphatidylcholine and phosphatidylethanolamine respond to exercise and influence insulin sensitivity in men. AB - Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) composition in skeletal muscle have been linked to insulin sensitivity. We evaluated the relationships between skeletal muscle PC:PE, physical exercise and insulin sensitivity. We performed lipidomics and measured PC and PE in m. vastus lateralis biopsies obtained from 13 normoglycemic normal weight men and 13 dysglycemic overweight men at rest, immediately after 45 min of cycling at 70% maximum oxygen uptake, and 2 h post-exercise, before as well as after 12 weeks of combined endurance- and strength-exercise intervention. Insulin sensitivity was monitored by euglycemic-hyperinsulinemic clamp. RNA-sequencing was performed on biopsies, and mitochondria and lipid droplets were quantified on electron microscopic images. Exercise intervention for 12 w enhanced insulin sensitivity by 33%, skeletal muscle levels of PC by 21%, PE by 42%, and reduced PC:PE by 16%. One bicycle session reduced PC:PE by 5%. PC:PE correlated negatively with insulin sensitivity (beta = -1.6, P < 0.001), percent area of mitochondria (rho = -0.52, P = 0.035), and lipid droplet area (rho = 0.55, P = 0.017) on EM pictures, and negatively with oxidative phosphorylation and mTOR based on RNA-sequencing. In conclusion, PC and PE contents of skeletal muscle respond to exercise, and PC:PE is inversely related to insulin sensitivity. PMID- 29695814 TI - Predictability of Arctic sea ice on weather time scales. AB - The field of Arctic sea ice prediction on "weather time scales" is still in its infancy with little existing understanding of the limits of predictability. This is especially true for sea ice deformation along so-called Linear Kinematic Features (LKFs) including leads that are relevant for marine operations. Here the potential predictability of the sea ice pack in the wintertime Arctic up to ten days ahead is determined, exploiting the fact that sea ice-ocean models start to show skill at representing sea ice deformation at high spatial resolutions. Results are based on ensemble simulations with a high-resolution sea ice-ocean model driven by atmospheric ensemble forecasts. The predictability of LKFs as measured by different metrics drops quickly, with predictability being almost completely lost after 4-8 days. In contrast, quantities such as sea ice concentration or the location of the ice edge retain high levels of predictability throughout the full 10-day forecast period. It is argued that the rapid error growth for LKFs is mainly due to the chaotic behaviour of the atmosphere associated with the low predictability of near surface wind divergence and vorticity; initial condition uncertainty for ice thickness is found to be of minor importance as long as LKFs are initialized at the right locations. PMID- 29695813 TI - Molecular design of radiocopper-labelled Affibody molecules. AB - The use of long-lived positron emitters 64Cu or 61Cu for labelling of Affibody molecules may improve breast cancer patients' stratification for HER-targeted therapy. Previous animal studies have shown that the use of triaza chelators for 64Cu labelling of synthetic Affibody molecules is suboptimal. In this study, we tested a hypothesis that the use of cross-bridged chelator, CB-TE2A, in combination with Gly-Glu-Glu-Glu spacer for labelling of Affibody molecules with radiocopper would improve imaging contrast. CB-TE2A was coupled to the N-terminus of synthetic Affibody molecules extended either with a glycine (designation CB TE2A-G-ZHER2:342) or Gly-Glu-Glu-Glu spacer (CB-TE2A-GEEE-ZHER2:342). Biodistribution and targeting properties of 64Cu-CB-TE2A-G-ZHER2:342 and 64Cu-CB TE2A-GEEE-ZHER2:342 were compared in tumor-bearing mice with the properties of 64Cu-NODAGA-ZHER2:S1, which had the best targeting properties in the previous study. 64Cu-CB-TE2A-GEEE-ZHER2:342 provided appreciably lower uptake in normal tissues and higher tumor-to-organ ratios than 64Cu-CB-TE2A-G-ZHER2:342 and 64Cu NODAGA-ZHER2:S1. The most pronounced was a several-fold difference in the hepatic uptake. At the optimal time point, 6 h after injection, the tumor uptake of 64Cu CB-TE2A-GEEE-ZHER2:342 was 16 +/- 6%ID/g and tumor-to-blood ratio was 181 +/- 52. In conclusion, a combination of the cross-bridged CB-TE2A chelator and Gly-Glu Glu-Glu spacer is preferable for radiocopper labelling of Affibody molecules and, possibly, other scaffold proteins having high renal re-absorption. PMID- 29695815 TI - Yucca fern shaped CuO nanowires on Cu foam for remitting capacity fading of Li ion battery anodes. AB - To remit capacity fading of lithium ion battery (LIB) anodes, freestanding yucca fern shaped CuO nanowires (NWs) on Cu foams are fabricated as anodes by combining facile and scalable anodization of copper foams followed by calcination. The porous and radial configuration of the hierarchical CuO NWs on the Cu foam substrate guarantees the remarkably improved electrochemical performance with durable cycle stability and excellent rate capability compared with CuO NWs on Cu foils. The reversible capacity remains 461.5 mAh/g after 100 repeated cycles at a current density of 100 mA/g, and a capacity of 150.6 mAh/g even at a high rate of 1000 mA/g. By examining the surface morphology of the cycled samples, possible performance fading route is proposed. The 3D CuO NWs network with a porous architecture simutaneously reduces the ion diffusion distances, promotes the electrolyte permeation and electronic conductivity. This novel strategy might open a new window to develop durable CuO based composite anodes for LIBs. PMID- 29695816 TI - Comparative study on differentiation of cervical-loop cells and Hertwig's epithelial root sheath cells under the induction of dental follicle cells in rat. AB - Cervical loop cells (CLC) and Hertwig's epithelial root sheath (HERS) cells are believed to play critical roles in distinct developmental patterns between rodent incisors and molars, respectively. However, the differences in differentiation between CLC and HERS cells, and their response to inductions from dental follicle cells, remain largely unknown. In present study, CLC and HERS cells, as well as incisor dental follicle (IF) cells and molar dental follicle (MF) cells were isolated from post-natal 7-day rats. IF and MF cell derived conditioned medium (CM) was obtained for induction of CLC and HERS cells. In vitro experiments, we found that, under the induction of dental follicle cell derived CM, CLC cells maintained the epithelial polygonal-shapes and formed massive minerals, while part of HERS cells underwent shape transformation and generated granular minerals. CLC cells expressed higher enamel-forming and mineralization related genes, while HERS cells showed opposite expression patterns of BMP2, BMP4, AMBN and AMGN. In vivo, CLC cells generated enamel-like tissues while HERS cells formed cementum-periodontal ligament-like structures. Taken together, CLC and HERS cells present distinct differentiation patterns under the inductions from dental follicle cells. PMID- 29695818 TI - Author Correction: Direct reprogramming of fibroblasts into skeletal muscle progenitor cells by transcription factors enriched in undifferentiated subpopulation of satellite cells. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has been fixed in the paper. PMID- 29695819 TI - Postpartum psychiatric disorders. PMID- 29695817 TI - Therapeutic endocannabinoid augmentation for mood and anxiety disorders: comparative profiling of FAAH, MAGL and dual inhibitors. AB - Recent studies have demonstrated anxiolytic potential of pharmacological endocannabinoid (eCB) augmentation approaches in a variety of preclinical models. Pharmacological inhibition of endocannabinoid-degrading enzymes, such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), elicit promising anxiolytic effects in rodent models with limited adverse behavioral effects, however, the efficacy of dual FAAH/MAGL inhibition has not been investigated. In the present study, we compared the effects of FAAH (PF-3845), MAGL (JZL184) and dual FAAH/MAGL (JZL195) inhibitors on (1) anxiety-like behaviors under non stressed and stressed conditions, (2) locomotor activity and body temperature, (3) lipid levels in the brain and (4) cognitive functions. Behavioral analysis showed that PF-3845 or JZL184, but not JZL195, was able to prevent restraint stress-induced anxiety in the light-dark box assay when administered before stress exposure. Moreover, JZL195 treatment was not able to reverse foot shock induced anxiety-like behavior in the elevated zero maze or light-dark box. JZL195, but not PF-3845 or JZL184, decreased body temperature and increased anxiety-like behavior in the open-field test. Overall, JZL195 did not show anxiolytic efficacy and the effects of JZL184 were more robust than that of PF 3845 in the models examined. These results showed that increasing either endogenous AEA or 2-AG separately produces anti-anxiety effects under stressful conditions but the same effects are not obtained from simultaneously increasing both AEA and 2-AG. PMID- 29695820 TI - Characterization of germ cell differentiation in the male mouse through single cell RNA sequencing. AB - Spermatogenesis in the mouse has been extensively studied for decades. Previous methods, such as histological staining or bulk transcriptome analysis, either lacked resolution at the single-cell level or were focused on a very narrowly defined set of factors. Here, we present the first comprehensive, unbiased single cell transcriptomic view of mouse spermatogenesis. Our single-cell RNA-seq (scRNA seq) data on over 2,500 cells from the mouse testis improves upon stage marker detection and validation, capturing the continuity of differentiation rather than artificially chosen stages. scRNA-seq also enables the analysis of rare cell populations masked in bulk sequencing data and reveals new insights into the regulation of sex chromosomes during spermatogenesis. Our data provide the basis for further studies in the field, for the first time providing a high-resolution reference of transcriptional processes during mouse spermatogenesis. PMID- 29695821 TI - Author Correction: Correlative Evaluation of Mental and Physical Workload of Laparoscopic Surgeons Based on Surface Electromyography and Eye-tracking Signals. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29695823 TI - Author Correction: The hippocampus as a predictive map. AB - In the version of this article initially published, equation (7) read. PMID- 29695822 TI - Dacarbazine depletes the ovarian reserve in mice and depletion is enhanced with age. AB - Dacarbazine is commonly administered for the treatment of cancers prevalent in reproductive age females. However, investigations of off-target effects of dacarbazine on the ovary are limited. We assessed the impact of dacarbazine on the ovarian reserve of primordial follicles, essential for fertility. Eight week and 6 month old C57BL/6 J mice were administered with dacarbazine or saline on day (d)0 and d7, then sacrificed after 12 hours (h), or 14d (n = 4-5/group). Follicle numbers, follicle density, serum AMH and corpora lutea were quantified and estrous cyclicity monitored. In reproductively young mice, dacarbazine did not affect primordial follicle numbers at 12 h, but resulted in a 36% reduction at 14d (p < 0.05). Dacarbazine-mediated primordial follicle depletion was accelerated with age, with a 24% (p < 0.05) and 36% (p < 0.01) reduction at 12 h and 14d. Follicle density remained unchanged between treatment groups at either age. Dacarbazine depleted antral follicles at 14d (p < 0.05), at both ages. Despite partial reduction of antral follicles, serum AMH, estrous cyclicity and corpora lutea (indicative of ovulation) remained unchanged between treatment groups, at both ages. Importantly, diminished ovarian reserve can result in premature ovarian insufficiency and infertility, thus, fertility preservation options should be considered for young female patients prior to dacarbazine treatment. PMID- 29695824 TI - Postpartum psychiatric disorders. AB - Pregnancy is a complex and vulnerable period that presents a number of challenges to women, including the development of postpartum psychiatric disorders (PPDs). These disorders can include postpartum depression and anxiety, which are relatively common, and the rare but more severe postpartum psychosis. In addition, other PPDs can include obsessive-compulsive disorder, post-traumatic stress disorder and eating disorders. The aetiology of PPDs is a complex interaction of psychological, social and biological factors, in addition to genetic and environmental factors. The goals of treating postpartum mental illness are reducing maternal symptoms and supporting maternal-child and family functioning. Women and their families should receive psychoeducation about the illness, including evidence-based discussions about the risks and benefits of each treatment option. Developing effective strategies in global settings that allow the delivery of targeted therapies to women with different clinical phenotypes and severities of PPDs is essential. PMID- 29695825 TI - Publisher Correction: Inhibitory modulation of cytochrome c oxidase activity with specific near-infrared light wavelengths attenuates brain ischemia/reperfusion injury. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29695826 TI - EUS-guided methylene blue injection to facilitate endoscopic cannulation of an obscured pancreatic duct orifice after ampullectomy. PMID- 29695827 TI - The curious case of Rapunzel syndrome: a rare non-Trichobezoar. PMID- 29695828 TI - Elbasvir/grazoprevir in black adults with hepatitis C virus infection: a pooled analysis of phase 2/3 clinical trials. AB - OBJECTIVES: Although direct-acting antiviral regimens have dramatically improved the treatment of hepatitis C virus (HCV) infection, there is some evidence that black race may be an independent predictor of treatment failure. We report a retrospective analysis of black participants receiving elbasvir/grazoprevir (EBR/GZR) in nine phase 2/3 clinical trials. METHODS: Black participants with chronic HCV genotype 1 or 4 (GT1 or GT4) infection who received EBR 50 mg/GZR 100 mg once daily for 12 weeks, or in combination with ribavirin for 16 weeks, were included. The primary end point was sustained virologic response 12 weeks after completion of therapy (SVR12, HCV RNA < 15 IU/mL). RESULTS: Compared with nonblack participants (n = 1310), black participants (n = 332) were more likely to have chronic kidney disease stage 4/5 (9.2% vs. 31.0%, respectively), while other comorbidities were similar between the groups. In black and nonblack participants receiving EBR/GZR for 12 weeks, SVR12 rates were 93.7% (282/301) and 94.2% (1072/1138) in those with GT1 infection, and 93.8% (15/16) and 94.6% (88/93) in those with GT4 infection. SVR12 was 100.0% (15/15) in black participants and 97.5% (77/79) in nonblack participants with GT1 infection receiving EBR/GZR plus ribavirin for 16 weeks. Rates of drug-related adverse events (AEs) were 30% vs. 36.6%, and serious AEs were 7.6% vs. 3.4% in black and nonblack participants, respectively. CONCLUSION: EBR/GZR showed high efficacy in black participants with HCV GT1 or GT4 infection and was generally well tolerated, with a safety profile similar to that reported overall in phase 2/3 clinical trials. PMID- 29695829 TI - A new model to predict the influence of surface temperature on contact angle. AB - The measurement of the equilibrium contact angle (ECA) of a weakly evaporating sessile drop becomes very challenging when the temperatures are higher than ambient temperature. Since the ECA is a critical input parameter for numerical simulations of diabatic processes, it is relevant to know the variation of the ECA with the fluid and wall temperatures. Several research groups have studied the effect of temperature on ECA either experimentally, with direct measures, or numerically, using molecular dynamic simulations. However, there is some disagreement between the authors. In this paper two possible theoretical models are presented, describing how the ECA varies with the surface temperature. These two models (called Decreasing Trend Model and Unsymmetrical Trend Model, respectively) are compared with experimental measurements. Within the experimental errors, the equilibrium contact angle shows a decrease with increasing surface temperatures on the hydrophilic surface. Conversely the ECA appears approximately constant on hydrophobic surfaces for increasing wall temperatures. The two conclusions for practical applications for weakly evaporating conditions are that (i) the higher the ECA, the smaller is the effect of the surface temperature, (ii) a good evaluation of the decrease of the ECA with the surface temperature can be obtained by the proposed DTM approach. PMID- 29695830 TI - Development of a 3D seed morphological tool for grapevine variety identification, and its comparison with SSR analysis. AB - Grapevine (Vitis vinifera L.) is one of the classical fruits of the Old World. Among the thousands of domesticated grapevine varieties and variable wild sylvestris populations, the range of variation in pip morphology is very wide. In this study we scanned representative samples of grape pip populations, in an attempt to probe the possibility of using the 3D tool for grape variety identification. The scanning was followed by mathematical and statistical analysis using innovative algorithms from the field of computer sciences. Using selected Fourier coefficients, a very clear separation was obtained between most of the varieties, with only very few overlaps. These results show that this method enables the separation between different Vitis vinifera varieties. Interestingly, when using the 3D approach to analyze couples of varieties, considered synonyms by the standard 22 SSR analysis approach, we found that the varieties in two of the considered synonym couples were clearly separated by the morphological analysis. This work, therefore, suggests a new systematic tool for high resolution variety discrimination. PMID- 29695831 TI - Deletion at the 5'-end of Estonian ASFV strains associated with an attenuated phenotype. AB - African swine fever (ASF) was introduced into the Eastern European Union in 2014 and led to considerable mortality among wild boar. In contrast, unexpected high antibody prevalence was reported in hunted wild boar in north-eastern Estonia. One of the causative virus strains was recently characterized. While it still showed rather high virulence in the majority of experimentally infected animals, one animal survived and recovered completely. Here, we report on the follow-up characterization of the isolate obtained from the survivor in the acute phase of infection. As a first step, three in vivo experiments were performed with different types of pigs: twelve minipigs (trial A), five domestic pigs (trial B), and five wild boar (trial C) were inoculated. 75% of the minipigs and all domestic pigs recovered after an acute course of disease. However, all wild boar succumbed to infection within 17 days. Representative samples were sequenced using NGS-technologies, and whole-genomes were compared to ASFV "Georgia 2007/1". The alignments indicated a deletion of 14560 base pairs at the 5' end, and genome reorganization by duplication. The characteristic deletion was confirmed in all trial samples and local field samples. In conclusion, an ASFV variant was found in Estonia that showed reduced virulence. PMID- 29695832 TI - APOBEC3B and APOBEC mutational signature as potential predictive markers for immunotherapy response in non-small cell lung cancer. AB - Non-small cell lung cancer (NSCLC) is known to carry heavy mutation load. Besides smoking, cytidine deaminase APOBEC3B plays a key role in the mutation process of NSCLC. APOBEC3B is also reported to be upregulated and predicts bad prognosis in NSCLC. However, targeting APOBEC3B high NSCLC is still a big challenge. Here we show that APOBEC3B upregulation is significantly associated with immune gene expression, and APOBEC3B expression positively correlates with known immunotherapy response biomarkers, including: PD-L1 expression and T-cell infiltration in NSCLC. Importantly, APOBEC mutational signature is specifically enriched in NSCLC patients with durable clinical benefit after immunotherapy and APOBEC mutation count can be better than total mutation in predicting immunotherapy response. In together, this work provides evidence that APOBEC3B upregulation and APOBEC mutation count can be used as novel predictive markers in guiding NSCLC checkpoint blockade immunotherapy. PMID- 29695833 TI - Chronic expression of wild-type Ret receptor in the mammary gland induces luminal tumors that are sensitive to Ret inhibition. AB - The receptor tyrosine kinase Ret, a key gain-of-function mutated oncoprotein in thyroid carcinomas, has recently been implicated in other cancer types. While Ret copy number gains and mutations have been reported at low frequencies in breast tumors, we and others have reported that Ret is overexpressed in about 40% of human tumors and this correlates with poor patient prognosis. Ret activation regulates numerous intracellular pathways related to proliferation and inflammation, but it is not known whether abnormal Ret expression is sufficient to induce mammary carcinomas. Using a novel doxycycline-inducible transgenic mouse model with the MMTV promoter controlling Ret expression, we show that overexpression of wild-type Ret in the mammary epithelium produces mammary tumors, displaying a morphology that recapitulates characteristics of human luminal breast tumors. Ret-evoked tumors are estrogen receptor positive and negative for progesterone receptor. Moreover, tumors rapidly regress after doxycycline withdrawal, indicating that Ret is the driving oncoprotein. Using next-generation sequencing, we examined the levels of transcripts in these tumors, confirming a luminal signature. Ret-evoked tumors have been passaged in mice and used to test novel therapeutic approaches. Importantly, we have determined that tumors are resistant to endocrine therapy, but respond successfully to treatment with a Ret kinase inhibitor. Our data provide the first compelling evidence for an oncogenic role of non-mutated Ret in the mammary gland and are an incentive for clinical development of Ret as a cancer biomarker and therapeutic target. PMID- 29695834 TI - Contribution of three-dimensional architecture and tumor-associated fibroblasts to hepcidin regulation in breast cancer. AB - Hepcidin is a peptide hormone that negatively regulates iron efflux and plays an important role in controlling the growth of breast tumors. In patients with breast cancer, the combined expression of hepcidin and its membrane target, ferroportin, predict disease outcome. However, mechanisms that control hepcidin expression in breast cancer cells remain largely unknown. Here, we use three dimensional breast cancer spheroids derived from cell lines and breast cancer patients to probe mechanisms of hepcidin regulation in breast cancer. We observe that the extent of hepcidin induction and pathways of its regulation are markedly changed in breast cancer cells grown in three dimensions. In monolayer culture, BMPs, particularly BMP6, regulate hepcidin transcription. When breast cancer cells are grown as spheroids, there is a >10-fold induction in hepcidin transcripts. Microarray analysis combined with knockdown experiments reveal that GDF-15 is the primary mediator of this change. The increase in hepcidin as breast cells develop a three-dimensional architecture increases intracellular iron, as indicated by an increase in the iron storage protein ferritin. Immunohistochemical staining of human breast tumors confirms that both GDF-15 and hepcidin are expressed in breast cancer specimens. Further, levels of GDF-15 are significantly correlated with levels of hepcidin at both the mRNA and protein level in patient samples, consistent with a role for GDF-15 in control of hepcidin in human breast tumors. Inclusion of tumor-associated fibroblasts in breast cancer spheroids further induces hepcidin. This induction is mediated by fibroblast-dependent secretion of IL-6. Breast cancer cells grown as spheroids are uniquely receptive to IL-6-dependent induction of hepcidin by tumor associated fibroblasts, since IL-6 does not induce hepcidin in cells grown as monolayers. Collectively, our results suggest a new paradigm for tumor-mediated control of iron through the control of hepcidin by tumor architecture and the breast tumor microenvironment. PMID- 29695835 TI - Exploiting TERT dependency as a therapeutic strategy for NRAS-mutant melanoma. AB - Targeting RAS is one of the greatest challenges in cancer therapy. Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis. Thus far, there are no clinical agents available to effectively target NRAS or any other RAS oncogene. An alternative approach is to identify and target critical tumor vulnerabilities or non-oncogene addictions that are essential for tumor survival. We investigated the consequences of NRAS blockade in NRAS-mutant melanoma and show that decreased expression of the telomerase catalytic subunit, TERT, is a major consequence. TERT silencing or treatment of NRAS-mutant melanoma with the telomerase-dependent telomere uncapping agent, 6-thio-2'-deoxyguanosine (6-thio-dG), led to rapid cell death, along with evidence of both telomeric and non-telomeric DNA damage, increased ROS levels, and upregulation of a mitochondrial antioxidant adaptive response. Combining 6-thio-dG with the mitochondrial inhibitor Gamitrinib attenuated this adaptive response and more effectively suppressed NRAS-mutant melanoma. Our study uncovers a robust dependency of NRAS-mutant melanoma on TERT, and provides proof-of-principle for a new combination strategy to combat this class of tumors, which could be expanded to other tumor types. PMID- 29695836 TI - Striatopallidal neurons control avoidance behavior in exploratory tasks. AB - The dorsal striatum has been linked to decision-making under conflict, but the mechanism by which striatal neurons contribute to approach-avoidance conflicts remains unclear. We hypothesized that striatopallidal dopamine D2 receptor (D2R) expressing neurons promote avoidance, and tested this hypothesis in two exploratory approach-avoidance conflict paradigms in mice: the elevated zero maze and open field. Genetic elimination of D2Rs on striatopallidal neurons (iMSNs), but not other neural populations, increased avoidance of the open areas in both tasks, in a manner that was dissociable from global changes in movement. Population calcium activity of dorsomedial iMSNs was disrupted in mice lacking D2Rs on iMSNs, suggesting that disrupted output of iMSNs contributes to heightened avoidance behavior. Consistently, artificial disruption of iMSN output with optogenetic stimulation heightened avoidance of open areas of these tasks, while inhibition of iMSN output reduced avoidance. We conclude that dorsomedial striatal iMSNs control approach-avoidance conflicts in exploratory tasks, and highlight this neural population as a potential target for reducing avoidance in anxiety disorders. PMID- 29695837 TI - In vitro synthesis of gene-length single-stranded DNA. AB - Single-stranded DNA (ssDNA) increases the likelihood of homology directed repair with reduced cellular toxicity. However, ssDNA synthesis strategies are limited by the maximum length attainable, ranging from a few hundred nucleotides for chemical synthesis to a few thousand nucleotides for enzymatic synthesis, as well as limited control over nucleotide composition. Here, we apply purely enzymatic synthesis to generate ssDNA greater than 15 kilobases (kb) using asymmetric PCR, and illustrate the incorporation of diverse modified nucleotides for therapeutic and theranostic applications. PMID- 29695838 TI - Leukocyte telomere length and diet in the apparently healthy, middle-aged Asklepios population. AB - Telomere length is a prognostic biomarker for aging diseases. As it is unknown whether diet plays a role in these associations, we aimed to assess the impact of diet on telomere length. Moreover, given that telomere length is modulated by oxidative stress and inflammation, an additional goal was to evaluate whether the latter may mediate possible telomere - diet associations. Southern blot measured leukocyte telomere length and food frequency questionnaire data were compared for 2509 apparently healthy men and women (~35 to 55 years) from the Asklepios population. No significant associations were found between telomere length and overall dietary characteristics, such as dietary diversity, quality, equilibrium, and the dietary inflammatory index. Exploratory analysis of individual dietary variables revealed that a higher daily intake of deep fried potato products was associated with shorter telomeres (P = 0.002, 151 bp per 100 g/day), also in both sexes separately. Deep fried potato product consumption was also significantly associated with C-reactive protein (P = 0.032) and uric acid (P = 0.042), but not other inflammation and oxidative stress markers. These results suggest an at most limited association between overall dietary patterns and telomere length in the general population. Nevertheless, the association between telomere length and deep fried potato product intake warrants additional research. PMID- 29695841 TI - Pulmonary Regnase-1 orchestrates the interplay of epithelium and adaptive immune systems to protect against pneumonia. AB - Inhaled pathogens including Pseudomonas aeruginosa initially encounter airway epithelial cells (AECs), which are poised to evoke cell-intrinsic innate defense, affecting second tier of hematopoietic cell-mediated immune reaction. However, it is largely unknown how pulmonary immune responses mediated by a variety of immune cells are coordinated. Here we show that Regnase-1, an endoribonuclease expressed in AECs and immune cells, plays an essential role in coordinating innate responses and adaptive immunity against P. aeruginosa infection. Intratracheal treatment of mice with heat-killed P. aeruginosa resulted in prolonged disappearance of Regnase-1 consistent with sustained expression of Regnase-1 target inflammatory genes, whereas the transcription factor NF-kappaB was only transiently activated. AEC-specific deletion of Regnase-1 not only augmented innate defenses against P. aeruginosa but also enhanced secretion of Pseudomonas specific IgA and Th17 accumulation in the lung, culminating in conferring significant resistance against P. aeruginosa re-infection in vivo. Although Regnase-1 directly controls distinct sets of genes in each of AECs and T cells, degradation of Regnase-1 in both cell types is beneficial for maximizing acquired immune responses. Collectively, these results demonstrate that Regnase-1 orchestrates AEC-mediated and immune cell-mediated host defense against pulmonary bacterial infection. PMID- 29695840 TI - A screen of Crohn's disease-associated microbial metabolites identifies ascorbate as a novel metabolic inhibitor of activated human T cells. AB - Microbial metabolites are an emerging class of mediators influencing CD4+ T-cell function. To advance the understanding of direct causal microbial factors contributing to Crohn's disease, we screened 139 predicted Crohn's disease associated microbial metabolites for their bioactivity on human CD4+ T-cell functions induced by disease-associated T helper 17 (Th17) polarizing conditions. We observed 15 metabolites with CD4+ T-cell bioactivity, 3 previously reported, and 12 unprecedented. A deeper investigation of the microbe-derived metabolite, ascorbate, revealed its selective inhibition on activated human CD4+ effector T cells, including IL-17A-, IL-4-, and IFNgamma-producing cells. Mechanistic assessment suggested the apoptosis of activated human CD4+ T cells associated with selective inhibition of energy metabolism. These findings suggest a substantial rate of relevant T-cell bioactivity among Crohn's disease-associated microbial metabolites, and evidence for novel modes of bioactivity, including targeting of T-cell energy metabolism. PMID- 29695839 TI - Repression of let-7a cluster prevents adhesion of colorectal cancer cells by enforcing a mesenchymal phenotype in presence of liver inflammation. AB - The liver is the most common site of metastasis in patients with colorectal cancer, and colorectal cancer liver metastasis (CRLM) is associated with poor rates of survival. However, CRLM occurs infrequently in livers exhibiting signs of hepatitis or cirrhosis, suggesting a role for inflammation in attenuating CRLM. The molecular mechanisms driving this phenomenon remain unclear. The aim of this study was to confirm the mechanism by which liver inflammation inhibits CRLM. We used BALB/c animal models of inflammatory liver diseases to confirm that liver inflammation inhibits CRLM, and then elucidated the molecular mechanisms governing that process. Out data showed that liver inflammation induces IFN-gamma expression, which then downregulates expression of the let-7a cluster through IRF 1 in colorectal cancer cells. Finally, we showed that modulation of let-7a expression regulated the epithelial-mesenchymal transition in colorectal cancer cell lines, and inhibited their capacity to metastasize in vivo. Cumulatively, we clarified the critical role played by the IFN-gamma/IRF-1/let-7a cluster/EMT pathway in regulating the spread of circulating colorectal cancer cells to the liver, and highlighted the critical role that the hepatitis microenvironment plays in modulating that process. PMID- 29695842 TI - A new role for Zinc limitation in bacterial pathogenicity: modulation of alpha hemolysin from uropathogenic Escherichia coli. AB - Metal limitation is a common situation during infection and can have profound effects on the pathogen's success. In this report, we examine the role of zinc limitation in the expression of a virulence factor in uropathogenic Escherichia coli. The pyelonephritis isolate J96 carries two hlyCABD operons that encode the RTX toxin alpha-hemolysin. While the coding regions of both operons are largely conserved, the upstream sequences, including the promoters, are unrelated. We show here that the two hlyCABD operons are differently regulated. The hly II operon is efficiently silenced in the presence of zinc and highly expressed when zinc is limited. In contrast, the hly I operon does not respond to zinc limitation. Genetic studies reveal that zinc-responsive regulation of the hly II operon is controlled by the Zur metalloregulatory protein. A Zur binding site was identified in the promoter sequence of the hly II operon, and we observe direct binding of Zur to this promoter region. Moreover, we find that Zur regulation of the hly II operon modulates the ability of E. coli J96 to induce a cytotoxic response in host cell lines in culture. Our report constitutes the first description of the involvement of the zinc-sensing protein Zur in directly modulating the expression of a virulence factor in bacteria. PMID- 29695843 TI - Identification of QTN and candidate genes for Salinity Tolerance at the Germination and Seedling Stages in Rice by Genome-Wide Association Analyses. AB - To facilitate developing rice varieties tolerant to salt stress, a panel of 208 rice mini-core accessions collected from 25 countries were evaluated for 13 traits associated with salt tolerance (ST) at the germination and seedling stages. The rice panel showed tremendous variation for all measured ST traits and eight accessions showing high levels of ST at either and/or both the germination and seedling stages. Using 395,553 SNP markers covering ~372 Mb of the rice genome and multi-locus mixed linear models, 20 QTN associated with 11 ST traits were identified by GWAS, including 6 QTN affecting ST at the germination stage and 14 QTN for ST at the seedling stage. The integration of bioinformatic with haplotype analyses for the ST QTN lets us identify 22 candidate genes for nine important ST QTN (qGR3, qSNK1, qSNK12, qSNC1, qSNC6, qRNK2, qSDW9a, qSST5 and qSST9). These candidate genes included three known ST genes (SKC1, OsTZF1 and OsEATB) for QTN qSNK1 qSST5 and qSST9. Candidate genes showed significant phenotypic differences in ST traits were detected between or among 2-4 major haplotypes. Thus, our results provided useful materials and genetic information for improving rice ST in future breeding and for molecular dissection of ST in rice. PMID- 29695844 TI - Remote quantum entanglement between two micromechanical oscillators. AB - Entanglement, an essential feature of quantum theory that allows for inseparable quantum correlations to be shared between distant parties, is a crucial resource for quantum networks 1 . Of particular importance is the ability to distribute entanglement between remote objects that can also serve as quantum memories. This has been previously realized using systems such as warm2,3 and cold atomic vapours4,5, individual atoms 6 and ions7,8, and defects in solid-state systems9 11. Practical communication applications require a combination of several advantageous features, such as a particular operating wavelength, high bandwidth and long memory lifetimes. Here we introduce a purely micromachined solid-state platform in the form of chip-based optomechanical resonators made of nanostructured silicon beams. We create and demonstrate entanglement between two micromechanical oscillators across two chips that are separated by 20 centimetres . The entangled quantum state is distributed by an optical field at a designed wavelength near 1,550 nanometres. Therefore, our system can be directly incorporated in a realistic fibre-optic quantum network operating in the conventional optical telecommunication band. Our results are an important step towards the development of large-area quantum networks based on silicon photonics. PMID- 29695845 TI - Low-loss plasmon-assisted electro-optic modulator. AB - For nearly two decades, researchers in the field of plasmonics 1 -which studies the coupling of electromagnetic waves to the motion of free electrons near the surface of a metal 2 -have sought to realize subwavelength optical devices for information technology3-6, sensing7,8, nonlinear optics9,10, optical nanotweezers 11 and biomedical applications 12 . However, the electron motion generates heat through ohmic losses. Although this heat is desirable for some applications such as photo-thermal therapy, it is a disadvantage in plasmonic devices for sensing and information technology 13 and has led to a widespread view that plasmonics is too lossy to be practical. Here we demonstrate that the ohmic losses can be bypassed by using 'resonant switching'. In the proposed approach, light is coupled to the lossy surface plasmon polaritons only in the device's off state (in resonance) in which attenuation is desired, to ensure large extinction ratios between the on and off states and allow subpicosecond switching. In the on state (out of resonance), destructive interference prevents the light from coupling to the lossy plasmonic section of a device. To validate the approach, we fabricated a plasmonic electro-optic ring modulator. The experiments confirm that low on chip optical losses, operation at over 100 gigahertz, good energy efficiency, low thermal drift and a compact footprint can be combined in a single device. Our result illustrates that plasmonics has the potential to enable fast, compact on chip sensing and communications technologies. PMID- 29695846 TI - Earthquake-induced transformation of the lower crust. AB - The structural and metamorphic evolution of the lower crust has direct effects on the lithospheric response to plate tectonic processes involved in orogeny, including subsidence of sedimentary basins, stability of deep mountain roots and extension of high-topography regions. Recent research shows that before orogeny most of the lower crust is dry, impermeable and mechanically strong 1 . During an orogenic event, the evolution of the lower crust is controlled by infiltration of fluids along localized shear or fracture zones. In the Bergen Arcs of Western Norway, shear zones initiate as faults generated by lower-crustal earthquakes. Seismic slip in the dry lower crust requires stresses at a level that can only be sustained over short timescales or local weakening mechanisms. However, normal earthquake activity in the seismogenic zone produces stress pulses that drive aftershocks in the lower crust 2 . Here we show that the volume of lower crust affected by such aftershocks is substantial and that fluid-driven associated metamorphic and structural transformations of the lower crust follow these earthquakes. This provides a 'top-down' effect on crustal geodynamics and connects processes operating at very different timescales. PMID- 29695847 TI - Stabilized entanglement of massive mechanical oscillators. AB - Quantum entanglement is a phenomenon whereby systems cannot be described independently of each other, even though they may be separated by an arbitrarily large distance 1 . Entanglement has a solid theoretical and experimental foundation and is the key resource behind many emerging quantum technologies, including quantum computation, cryptography and metrology. Entanglement has been demonstrated for microscopic-scale systems, such as those involving photons2-5, ions 6 and electron spins 7 , and more recently in microwave and electromechanical devices8-10. For macroscopic-scale objects8-14, however, it is very vulnerable to environmental disturbances, and the creation and verification of entanglement of the centre-of-mass motion of macroscopic-scale objects remains an outstanding goal. Here we report such an experimental demonstration, with the moving bodies being two massive micromechanical oscillators, each composed of about 10 12 atoms, coupled to a microwave-frequency electromagnetic cavity that is used to create and stabilize the entanglement of their centre-of-mass motion15 17. We infer the existence of entanglement in the steady state by combining measurements of correlated mechanical fluctuations with an analysis of the microwaves emitted from the cavity. Our work qualitatively extends the range of entangled physical systems and has implications for quantum information processing, precision measurements and tests of the limits of quantum mechanics. PMID- 29695848 TI - Quaternary stereocentres via an enantioconvergent catalytic SN1 reaction. AB - The unimolecular nucleophilic substitution (SN1) mechanism features prominently in every introductory organic chemistry course. In principle, stepwise displacement of a leaving group by a nucleophile via a carbocationic intermediate enables the construction of highly congested carbon centres. However, the intrinsic instability and high reactivity of the carbocationic intermediates make it very difficult to control product distributions and stereoselectivity in reactions that proceed via SN1 pathways. Here we report asymmetric catalysis of an SN1-type reaction mechanism that results in the enantioselective construction of quaternary stereocentres from racemic precursors. The transformation relies on the synergistic action of a chiral hydrogen-bond-donor catalyst with a strong Lewis-acid promoter to mediate the formation of tertiary carbocationic intermediates at low temperature and to achieve high levels of control over reaction enantioselectivity and product distribution. This work provides a foundation for the enantioconvergent synthesis of other fully substituted carbon stereocentres. PMID- 29695850 TI - Make codes for research integrity practical. PMID- 29695849 TI - A massive core for a cluster of galaxies at a redshift of 4.3. AB - Massive galaxy clusters have been found that date to times as early as three billion years after the Big Bang, containing stars that formed at even earlier epochs1-3. The high-redshift progenitors of these galaxy clusters-termed 'protoclusters'-can be identified in cosmological simulations that have the highest overdensities (greater-than-average densities) of dark matter4-6. Protoclusters are expected to contain extremely massive galaxies that can be observed as luminous starbursts 7 . However, recent detections of possible protoclusters hosting such starbursts8-11 do not support the kind of rapid cluster-core formation expected from simulations 12 : the structures observed contain only a handful of starbursting galaxies spread throughout a broad region, with poor evidence for eventual collapse into a protocluster. Here we report observations of carbon monoxide and ionized carbon emission from the source SPT2349-56. We find that this source consists of at least 14 gas-rich galaxies, all lying at redshifts of 4.31. We demonstrate that each of these galaxies is forming stars between 50 and 1,000 times more quickly than our own Milky Way, and that all are located within a projected region that is only around 130 kiloparsecs in diameter. This galaxy surface density is more than ten times the average blank-field value (integrated over all redshifts), and more than 1,000 times the average field volume density. The velocity dispersion (approximately 410 kilometres per second) of these galaxies and the enormous gas and star formation densities suggest that this system represents the core of a cluster of galaxies that was already at an advanced stage of formation when the Universe was only 1.4 billion years old. A comparison with other known protoclusters at high redshifts shows that SPT2349-56 could be building one of the most massive structures in the Universe today. PMID- 29695851 TI - Cap drug prices with policy - here's how. PMID- 29695852 TI - Order must spring from chaos in Italian research. PMID- 29695853 TI - Geoengineering might speed glacier melt. PMID- 29695855 TI - Planet-hunter launch, epilepsy drug and NASA's next chief. PMID- 29695854 TI - Challenge anti-Semitism. PMID- 29695856 TI - A photo celebration of scientists at work. PMID- 29695857 TI - Can the world kick its fossil-fuel addiction fast enough? PMID- 29695858 TI - Climate talks are not enough. PMID- 29695859 TI - The science photos worth seeing. PMID- 29695860 TI - Nutrient limitation suppresses the temperature dependence of phytoplankton metabolic rates. AB - Climate warming has the potential to alter ecosystem function through temperature dependent changes in individual metabolic rates. The temperature sensitivity of phytoplankton metabolism is especially relevant, since these microorganisms sustain marine food webs and are major drivers of biogeochemical cycling. Phytoplankton metabolic rates increase with temperature when nutrients are abundant, but it is unknown if the same pattern applies under nutrient-limited growth conditions, which prevail over most of the ocean. Here we use continuous cultures of three cosmopolitan and biogeochemically relevant species (Synechococcus sp., Skeletonema costatum and Emiliania huxleyi) to determine the temperature dependence (activation energy, Ea) of metabolism under different degrees of nitrogen (N) limitation. We show that both CO2 fixation and respiration rates increase with N supply but are largely insensitive to temperature. Ea of photosynthesis (0.11 +/- 0.06 eV, mean +/- SE) and respiration (0.04 +/- 0.17 eV) under N-limited growth is significantly smaller than Ea of growth rate under nutrient-replete conditions (0.77 +/- 0.06 eV). The reduced temperature dependence of metabolic rates under nutrient limitation can be explained in terms of enzyme kinetics, because both maximum reaction rates and half-saturation constants increase with temperature. Our results suggest that the direct, stimulating effect of rising temperatures upon phytoplankton metabolic rates will be circumscribed to ecosystems with high-nutrient availability. PMID- 29695861 TI - Cascading effects on bacterial communities: cattle grazing causes a shift in the microbiome of a herbivorous caterpillar. AB - Large mammalian herbivores greatly influence the functioning of grassland ecosystems. Through plant consumption, excreta, and trampling, they modify biodiversity, nutrient cycling, and soil properties. Grazing mammals can also alter soil and rhizosphere bacterial communities, but their effect on the microbiome of other animals in the habitat (i.e., insects) is unknown. Using an experimental field approach and Illumina MiSeq 16S rRNA gene sequencing, we analyzed the influence of cattle grazing on the microbial community of spring webworm caterpillars, Ocnogyna loewii. Our experimental setup included replicated grazed and non-grazed paddocks from which caterpillars were collected twice (first-second and fourth-fifth instar). The caterpillars' microbiome is composed mostly of Proteobacteria and Firmicutes, and contains a potential symbiont from the genus Carnobacterium (55% of reads). We found that grazing significantly altered the microbiome composition of late instar caterpillars, probably through changes in diet (plant) composition and availability. Furthermore, the microbiome composition of early instar caterpillars significantly differed from late instar caterpillars in 221 OTUs (58 genera). Pseudomonas and Acinetobacter were dominant in early instars, while Carnobacterium and Acinetobacter were dominant in late instars. This study provides new ecological perspectives on the cascading effects mammalian herbivores may have on the microbiome of other animals in their shared habitat. PMID- 29695862 TI - Critical roles of TRPV2 channels, histamine H1 and adenosine A1 receptors in the initiation of acupoint signals for acupuncture analgesia. AB - Acupuncture is one of the most promising modalities in complimentary medicine. However, the underlying mechanisms are not well understood yet. We found that in TRPV2 knockout male mice, acupuncture-induced analgesia was suppressed with a decreased activation of mast cells in the acupoints stimulated. The mast cell stabilizer sodium cromolyn could suppress the release of adenosine in the acupoints on male rats. A direct injection of adenosine A1 receptor agonist or histamine H1 receptor agonist increased beta-endorphin in the cerebral-spinal fluid in the acute adjuvant arthritis male rats and thus replicated the analgesic effect of acupuncture. These observations suggest that the mast cell is the central structure of acupoints and is activated by acupuncture through TRPV2 channels. The mast cell transduces the mechanical stimuli to acupuncture signal by activating either H1 or A1 receptors, therefore triggering the acupuncture effect in the subject. These findings might open new frontiers for acupuncture research. PMID- 29695863 TI - LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis. AB - The linear ubiquitin chain assembly complex (LUBAC) is required for optimal gene activation and prevention of cell death upon activation of immune receptors, including TNFR1 1 . Deficiency in the LUBAC components SHARPIN or HOIP in mice results in severe inflammation in adulthood or embryonic lethality, respectively, owing to deregulation of TNFR1-mediated cell death2-8. In humans, deficiency in the third LUBAC component HOIL-1 causes autoimmunity and inflammatory disease, similar to HOIP deficiency, whereas HOIL-1 deficiency in mice was reported to cause no overt phenotype9-11. Here we show, by creating HOIL-1-deficient mice, that HOIL-1 is as essential for LUBAC function as HOIP, albeit for different reasons: whereas HOIP is the catalytically active component of LUBAC, HOIL-1 is required for LUBAC assembly, stability and optimal retention in the TNFR1 signalling complex, thereby preventing aberrant cell death. Both HOIL-1 and HOIP prevent embryonic lethality at mid-gestation by interfering with aberrant TNFR1 mediated endothelial cell death, which only partially depends on RIPK1 kinase activity. Co-deletion of caspase-8 with RIPK3 or MLKL prevents cell death in Hoil 1-/- (also known as Rbck1-/-) embryos, yet only the combined loss of caspase-8 with MLKL results in viable HOIL-1-deficient mice. Notably, triple-knockout Ripk3 /-Casp8-/-Hoil-1-/- embryos die at late gestation owing to haematopoietic defects that are rescued by co-deletion of RIPK1 but not MLKL. Collectively, these results demonstrate that both HOIP and HOIL-1 are essential LUBAC components and are required for embryogenesis by preventing aberrant cell death. Furthermore, they reveal that when LUBAC and caspase-8 are absent, RIPK3 prevents RIPK1 from inducing embryonic lethality by causing defects in fetal haematopoiesis. PMID- 29695864 TI - Cryo-EM structure of the gasdermin A3 membrane pore. AB - Gasdermins mediate inflammatory cell death after cleavage by caspases or other, unknown enzymes. The cleaved N-terminal fragments bind to acidic membrane lipids to form pores, but the mechanism of pore formation remains unresolved. Here we present the cryo-electron microscopy structures of the 27-fold and 28-fold single ring pores formed by the N-terminal fragment of mouse GSDMA3 (GSDMA3-NT) at 3.8 and 4.2 A resolutions, and of a double-ring pore at 4.6 A resolution. In the 27 fold pore, a 108-stranded anti-parallel beta-barrel is formed by two beta hairpins from each subunit capped by a globular domain. We identify a positively charged helix that interacts with the acidic lipid cardiolipin. GSDMA3-NT undergoes radical conformational changes upon membrane insertion to form long, membrane-spanning beta-strands. We also observe an unexpected additional symmetric ring of GSDMA3-NT subunits that does not insert into the membrane in the double-ring pore, which may represent a pre-pore state of GSDMA3-NT. These structures provide a basis that explains the activities of several mutant gasdermins, including defective mutants that are associated with cancer. PMID- 29695865 TI - Deep mitochondrial origin outside the sampled alphaproteobacteria. AB - Mitochondria are ATP-generating organelles, the endosymbiotic origin of which was a key event in the evolution of eukaryotic cells 1 . Despite strong phylogenetic evidence that mitochondria had an alphaproteobacterial ancestry 2 , efforts to pinpoint their closest relatives among sampled alphaproteobacteria have generated conflicting results, complicating detailed inferences about the identity and nature of the mitochondrial ancestor. While most studies support the idea that mitochondria evolved from an ancestor related to Rickettsiales3-9, an order that includes several host-associated pathogenic and endosymbiotic lineages10,11, others have suggested that mitochondria evolved from a free-living group12-14. Here we re-evaluate the phylogenetic placement of mitochondria. We used genome resolved binning of oceanic metagenome datasets and increased the genomic sampling of Alphaproteobacteria with twelve divergent clades, and one clade representing a sister group to all Alphaproteobacteria. Subsequent phylogenomic analyses that specifically address long branch attraction and compositional bias artefacts suggest that mitochondria did not evolve from Rickettsiales or any other currently recognized alphaproteobacterial lineage. Rather, our analyses indicate that mitochondria evolved from a proteobacterial lineage that branched off before the divergence of all sampled alphaproteobacteria. In light of this new result, previous hypotheses on the nature of the mitochondrial ancestor6,15,16 should be re-evaluated. PMID- 29695866 TI - Genomic variation in 3,010 diverse accessions of Asian cultivated rice. AB - Here we analyse genetic variation, population structure and diversity among 3,010 diverse Asian cultivated rice (Oryza sativa L.) genomes from the 3,000 Rice Genomes Project. Our results are consistent with the five major groups previously recognized, but also suggest several unreported subpopulations that correlate with geographic location. We identified 29 million single nucleotide polymorphisms, 2.4 million small indels and over 90,000 structural variations that contribute to within- and between-population variation. Using pan-genome analyses, we identified more than 10,000 novel full-length protein-coding genes and a high number of presence-absence variations. The complex patterns of introgression observed in domestication genes are consistent with multiple independent rice domestication events. The public availability of data from the 3,000 Rice Genomes Project provides a resource for rice genomics research and breeding. PMID- 29695867 TI - Architecture of an HIV-1 reverse transcriptase initiation complex. AB - Reverse transcription of the HIV-1 RNA genome into double-stranded DNA is a central step in viral infection 1 and a common target of antiretroviral drugs 2 . The reaction is catalysed by viral reverse transcriptase (RT)3,4 that is packaged in an infectious virion with two copies of viral genomic RNA 5 each bound to host lysine 3 transfer RNA (tRNALys3), which acts as a primer for initiation of reverse transcription6,7. Upon viral entry into cells, initiation is slow and non processive compared to elongation8,9. Despite extensive efforts, the structural basis of RT function during initiation has remained a mystery. Here we use cryo electron microscopy to determine a three-dimensional structure of an HIV-1 RT initiation complex. In our structure, RT is in an inactive polymerase conformation with open fingers and thumb and with the nucleic acid primer template complex shifted away from the active site. The primer binding site (PBS) helix formed between tRNALys3 and HIV-1 RNA lies in the cleft of RT and is extended by additional pairing interactions. The 5' end of the tRNA refolds and stacks on the PBS to create a long helical structure, while the remaining viral RNA forms two helical stems positioned above the RT active site, with a linker that connects these helices to the RNase H region of the PBS. Our results illustrate how RNA structure in the initiation complex alters RT conformation to decrease activity, highlighting a potential target for drug action. PMID- 29695868 TI - Structure of the alternative complex III in a supercomplex with cytochrome oxidase. AB - Alternative complex III (ACIII) is a key component of the respiratory and/or photosynthetic electron transport chains of many bacteria1-3. Like complex III (also known as the bc1 complex), ACIII catalyses the oxidation of membrane-bound quinol and the reduction of cytochrome c or an equivalent electron carrier. However, the two complexes have no structural similarity4-7. Although ACIII has eluded structural characterization, several of its subunits are known to be homologous to members of the complex iron-sulfur molybdoenzyme (CISM) superfamily 8 , including the proton pump polysulfide reductase9,10. We isolated the ACIII from Flavobacterium johnsoniae with native lipids using styrene maleic acid copolymer11-14, both as an independent enzyme and as a functional 1:1 supercomplex with an aa3-type cytochrome c oxidase (cyt aa3). We determined the structure of ACIII to 3.4 A resolution by cryo-electron microscopy and constructed an atomic model for its six subunits. The structure, which contains a [3Fe-4S] cluster, a [4Fe-4S] cluster and six haem c units, shows that ACIII uses known elements from other electron transport complexes arranged in a previously unknown manner. Modelling of the cyt aa3 component of the supercomplex revealed that it is structurally modified to facilitate association with ACIII, illustrating the importance of the supercomplex in this electron transport chain. The structure also resolves two of the subunits of ACIII that are anchored to the lipid bilayer with N-terminal triacylated cysteine residues, an important post translational modification found in numerous prokaryotic membrane proteins that has not previously been observed structurally in a lipid bilayer. PMID- 29695870 TI - An optical-frequency synthesizer using integrated photonics. AB - Optical-frequency synthesizers, which generate frequency-stable light from a single microwave-frequency reference, are revolutionizing ultrafast science and metrology, but their size, power requirement and cost need to be reduced if they are to be more widely used. Integrated-photonics microchips can be used in high coherence applications, such as data transmission 1 , highly optimized physical sensors 2 and harnessing quantum states 3 , to lower cost and increase efficiency and portability. Here we describe a method for synthesizing the absolute frequency of a lightwave signal, using integrated photonics to create a phase coherent microwave-to-optical link. We use a heterogeneously integrated III V/silicon tunable laser, which is guided by nonlinear frequency combs fabricated on separate silicon chips and pumped by off-chip lasers. The laser frequency output of our optical-frequency synthesizer can be programmed by a microwave clock across 4 terahertz near 1,550 nanometres (the telecommunications C-band) with 1 hertz resolution. Our measurements verify that the output of the synthesizer is exceptionally stable across this region (synthesis error of 7.7 * 10-15 or below). Any application of an optical-frequency source could benefit from the high-precision optical synthesis presented here. Leveraging high-volume semiconductor processing built around advanced materials could allow such low cost, low-power and compact integrated-photonics devices to be widely used. PMID- 29695872 TI - Celebrating 20 years of Nature Neuroscience. PMID- 29695869 TI - Cryo-EM structure of substrate-bound human telomerase holoenzyme. AB - The enzyme telomerase adds telomeric repeats to chromosome ends to balance the loss of telomeres during genome replication. Telomerase regulation has been implicated in cancer, other human diseases, and ageing, but progress towards clinical manipulation of telomerase has been hampered by the lack of structural data. Here we present the cryo-electron microscopy structure of the substrate bound human telomerase holoenzyme at subnanometre resolution, showing two flexibly RNA-tethered lobes: the catalytic core with telomerase reverse transcriptase (TERT) and conserved motifs of telomerase RNA (hTR), and an H/ACA ribonucleoprotein (RNP). In the catalytic core, RNA encircles TERT, adopting a well-ordered tertiary structure with surprisingly limited protein-RNA interactions. The H/ACA RNP lobe comprises two sets of heterotetrameric H/ACA proteins and one Cajal body protein, TCAB1, representing a pioneering structure of a large eukaryotic family of ribosome and spliceosome biogenesis factors. Our findings provide a structural framework for understanding human telomerase disease mutations and represent an important step towards telomerase-related clinical therapeutics. PMID- 29695873 TI - Does the handicap principle explain the evolution of dimorphic ornaments? AB - *We reinvestigate a new model based on the handicap hypothesis.*We show the handicap hypothesis does not explain male dimorphisms.*The results are due to the 'playing-the-field' assumption of the model.*The generality of the 'playing-the field' assumption is suspect.*The evolutionary stability of the proposed new equilibrium is questionable. PMID- 29695871 TI - Low field magneto-tunable photocurrent in CoFe2O4 nanostructure films for enhanced photoelectrochemical properties. AB - Efficient solar to hydrogen conversion using photoelectrochemical (PEC) process requires semiconducting photoelectrodes with advanced functionalities, while exhibiting high optical absorption and charge transport properties. Herein, we demonstrate magneto-tunable photocurrent in CoFe2O4 nanostructure film under low applied magnetic fields for efficient PEC properties. Photocurrent is enhanced from ~1.55 mA/cm2 to ~3.47 mA/cm2 upon the application of external magnetic field of 600 Oe leading to ~123% enhancement. This enhancement in the photocurrent is attributed to the reduction of optical bandgap and increase in the depletion width at CoFe2O4/electrolyte interface resulting in an enhanced generation and separation of the photoexcited charge carriers. The reduction of optical bandgap in the presence of magnetic field is correlated to the shifting of Co2+ ions from octahedral to tetrahedral sites which is supported by the Raman spectroscopy results. Electrochemical impedance spectroscopy results confirm a decrease in the charge transfer resistance at the CoFe2O4/electrolyte interface in the presence of magnetic field. This work evidences a coupling of photoexcitation properties with magnetic properties of a ferromagnetic-semiconductor and the effect can be termed as magnetophototronic effect. PMID- 29695874 TI - Diffusion of a new intermediate product in a simple 'classical-Schumpeterian' model. AB - This paper deals with the problem of new intermediate products within a simple model, where production is circular and goods enter into the production of other goods. It studies the process by which the new good is absorbed into the economy and the structural transformation that goes with it. By means of a long-period method the forces of structural transformation are examined, in particular the shift of existing means of production towards the innovation and the mechanism of differential growth in terms of alternative techniques and their associated systems of production. We treat two important Schumpeterian topics: the question of technological unemployment and the problem of 'forced saving' and the related problem of an involuntary reduction of real consumption per capita. It is shown that both phenomena are potential by-products of the transformation process. PMID- 29695876 TI - How can we accelerate progress on civil registration and vital statistics? PMID- 29695877 TI - Public health round-up. PMID- 29695878 TI - Taking up Africa's cancer challenge. AB - Botswana, Kenya and Rwanda have started to provide cancer care in their national efforts to achieve universal coverage of health services. Tatum Anderson reports. PMID- 29695879 TI - Randall Packard: learning to learn from global health history. AB - The World Health Organization marks its 70 years this month on 7 April. Randall Packard tells Fiona Fleck why today's global health leaders can learn from the past. PMID- 29695880 TI - Multicontaminant air pollution in Chinese cities. AB - Objective: To investigate multicontaminant air pollution in Chinese cities, to quantify the urban population affected and to explore the relationship between air pollution and urban population size. Methods: We obtained data for 155 cities with 276 million inhabitants for 2014 from China's air quality monitoring network on concentrations of fine particulate matter measuring under 2.5 MUm (PM2.5), coarse particulate matter measuring 2.5 to 10 MUm (PM10), nitrogen dioxide (NO2), sulfur dioxide (SO2) and ozone (O3). Concentrations were considered as high, if they exceeded World Health Organization (WHO) guideline limits. Findings: Overall, 51% (142 million) of the study population was exposed to mean annual multicontaminant concentrations above WHO limits - east China and the megacities were worst affected. High daily levels of four-contaminant mixtures of PM2.5, PM10, SO2 and O3 and PM2.5, PM10, SO2 and NO2 occurred on up to 110 days in 2014 in many cities, mainly in Shandong and Hebei Provinces. High daily levels of PM2.5, PM10 and SO2 occurred on over 146 days in 110 cities, mainly in east and central China. High daily levels of mixtures of PM2.5 and PM10, PM2.5 and SO2, and PM10 and SO2 occurred on over 146 days in 145 cities, mainly in east China. Surprisingly, multicontaminant air pollution was less frequent in cities with populations over 10 million than in smaller cities. Conclusion: Multicontaminant air pollution was common in Chinese cities. A shift from single-contaminant to multicontaminant evaluations of the health effects of air pollution is needed. China should implement protective measures during future urbanization. PMID- 29695881 TI - Untreated depression and tuberculosis treatment outcomes, quality of life and disability, Ethiopia. AB - Objective: To investigate the association between comorbid depression and tuberculosis treatment outcomes, quality of life and disability in Ethiopia. Methods: The study involved 648 consecutive adults treated for tuberculosis at 14 primary health-care facilities. All were assessed at treatment initiation (i.e. baseline) and after 2 and 6 months. We defined probable depression as a score of 10 or above on the nine-item Patient Health Questionnaire. Data on treatment default, failure and success and on death were obtained from tuberculosis registers. Quality of life was assessed using a visual analogue scale and we calculated disability scores using the World Health Organization's Disability Assessment Scale. Using multivariate Poisson regression analysis, we estimated the association between probable depression at baseline and treatment outcomes and death. Results: Untreated depression at baseline was independently associated with tuberculosis treatment default (adjusted risk ratio, aRR: 9.09; 95% confidence interval, CI: 6.72 to 12.30), death (aRR: 2.99; 95% CI: 1.54 to 5.78), greater disability (beta: 0.83; 95% CI: 0.67 to 0.99) and poorer quality of life (beta: -0.07; 95% CI: -0.07 to -0.06) at 6 months. Participants with probable depression had a lower mean quality-of-life score than those without (5.0 versus 6.0, respectively; P < 0.001) and a higher median disability score (22.0 versus 14.0, respectively; P < 0.001) at 6 months. Conclusion: Untreated depression in people with tuberculosis was associated with worse treatment outcomes, poorer quality of life and greater disability. Health workers should be given the support needed to provide depression care for people with tuberculosis. PMID- 29695882 TI - Prevention of mother-to-child transmission of HIV: a cross-sectional study in Malawi. AB - Objective: To estimate the use and outcomes of the Malawian programme for the prevention of mother-to-child transmission (MTCT) of human immunodeficiency virus (HIV). Methods: In a cross-sectional analysis of 33 744 mother-infant pairs, we estimated the weighted proportions of mothers who had received antenatal HIV testing and/or maternal antiretroviral therapy and infants who had received nevirapine prophylaxis and/or HIV testing. We calculated the ratios of MTCT at 4 26 weeks postpartum for subgroups that had missed none or at least one of these four steps. Findings: The estimated uptake of antenatal testing was 97.8%; while maternal antiretroviral therapy was 96.3%; infant prophylaxis was 92.3%; and infant HIV testing was 53.2%. Estimated ratios of MTCT were 4.7% overall and 7.7% for the pairs that had missed maternal antiretroviral therapy, 10.7% for missing both maternal antiretroviral therapy and infant prophylaxis and 11.4% for missing maternal antiretroviral therapy, infant prophylaxis and infant testing. Women younger than 19 years were more likely to have missed HIV testing (adjusted odds ratio, aOR: 4.9; 95% confidence interval, CI: 2.3-10.6) and infant prophylaxis (aOR: 6.9; 95% CI: 1.2-38.9) than older women. Women who had never started maternal antiretroviral therapy were more likely to have missed infant prophylaxis (aOR: 15.4; 95% CI: 7.2-32.9) and infant testing (aOR: 13.7; 95% CI: 4.2-83.3) than women who had. Conclusion: Most women used the Malawian programme for the prevention of MTCT. The risk of MTCT increased if any of the main steps in the programme were missed. PMID- 29695883 TI - Antibiotic stewardship interventions in hospitals in low-and middle-income countries: a systematic review. AB - Objective: To review the effectiveness of antibiotic stewardship interventions in hospitals in low- and middle-income countries. Methods: We searched MEDLINE(r), Embase(r), Cochrane Central Register of Controlled Trials and regional indexes for studies of interventions to improve appropriate prescribing and use of antibiotics for hospitalized patients in low- and middle-income countries. We included controlled trials, controlled before-and-after studies and interrupted time-series studies published up to December 2017. We report prescribing, clinical and microbiological outcomes using a narrative approach. Findings: We screened 7342 original titles and abstracts, assessed 241 full-text articles and included 27 studies from 2 low-income and 11 middle-income countries. We found a medium (11 studies) or high risk (13 studies) of bias. Generally, all types of interventions (structural, persuasive and enabling) and intervention bundles were reported to improve prescribing and clinical outcomes. However, the studied interventions and reported outcomes varied widely. The most frequent intervention was procalcitonin-guided antibiotic treatment (8 of 27 studies, all randomized controlled trials). The intervention was associated with a relative risk for patients receiving antibiotics ranging between 0.40 and 0.87. Conclusion: The majority of studies reported a positive effect of hospital antibiotic stewardship interventions. However, we cannot draw general conclusions about the effectiveness of such interventions in low- and middle-income countries because of low study quality, heterogeneity of interventions and outcomes, and under representation of certain settings. To strengthen the evidence base, action needs to be taken to address these shortcomings. PMID- 29695884 TI - Regulatory evaluation of biosimilars throughout their product life-cycle. AB - The World Health Assembly in 2014 adopted a resolution that recognized the importance of increasing access to biotherapeutic products, of improving their affordability and of ensuring their quality, safety and efficacy. Biosimilars are biotherapeutic products similar to already licensed reference products and are usually developed after patents on the original products have expired. Their introduction into the market is likely to reduce the costs of medicines substantially, thereby improving the availability of treatment for patients. However, there are barriers to market access for biosimilars. This article discusses the factors that give rise to these barriers and explains the importance of regulatory oversight throughout the product life-cycle of biosimilars. The paper also describes the role regulators can play in increasing confidence in biosimilars use by: (i) establishing regulatory oversight of biosimilars throughout their life-cycle, from development to post-licensing oversight, and ensuring that only high-quality, safe and efficacious biosimilars are available on the market; (ii) ensuring regulatory authorities have adequate capacity to assess and monitor the quality, safety and efficacy of biosimilars throughout their life-cycle; and (iii) monitoring the use of biosimilars in public health systems in collaboration with other stakeholders. PMID- 29695885 TI - Post-earthquake health-service support, Nepal. AB - Problem: Seven months after the April 2015 Nepal earthquake, and as relief efforts were scaling down, health authorities faced ongoing challenges in health service provision and disease surveillance reporting. Approach: In January 2016, the World Health Organization recruited and trained 12 Nepalese medical doctors to provide technical assistance to the health authorities in the most affected districts by the earthquake. These emergency support officers monitored the recovery of health services and reconstruction of health facilities, monitored stocks of essential medicines, facilitated disease surveillance reporting to the health ministry and assisted in outbreak investigations. Local setting: In December 2015 the people most affected by the earthquake were still living in temporary shelters, provision of health services was limited and only five out of 14 earthquake-affected districts were reporting surveillance data to the health ministry. Relevant changes: From mid-2016, health facilities were gradually able to provide the same level of services as in unaffected areas, including paediatric and adolescent services, follow-up of tuberculosis patients, management of respiratory infections and first aid. The number of districts reporting surveillance data to the health ministry increased to 13 out of 14. The proportion of health facilities reporting medicine stock-outs decreased over 2016. Verifying rumours of disease outbreaks with field-level evidence, and early detection and containment of outbreaks, allowed district health authorities to focus on recovery and reconstruction. Lessons learnt: Local medical doctors with suitable experience and training can augment the disaster recovery efforts of health authorities and alleviate their burden of work in managing public health challenges during the recovery phase. PMID- 29695886 TI - Building a global atlas of zoonotic viruses. PMID- 29695887 TI - A global campaign to combat ageism. PMID- 29695888 TI - Corrigendum. AB - [This corrects the article on p. 127 in vol. 83, PMID: 15744405.]. PMID- 29695889 TI - Connecting the dots: Illusory pattern perception predicts belief in conspiracies and the supernatural. AB - A common assumption is that belief in conspiracy theories and supernatural phenomena are grounded in illusory pattern perception. In the present research we systematically tested this assumption. Study 1 revealed that such irrational beliefs are related to perceiving patterns in randomly generated coin toss outcomes. In Study 2, pattern search instructions exerted an indirect effect on irrational beliefs through pattern perception. Study 3 revealed that perceiving patterns in chaotic but not in structured paintings predicted irrational beliefs. In Study 4, we found that agreement with texts supporting paranormal phenomena or conspiracy theories predicted pattern perception. In Study 5, we manipulated belief in a specific conspiracy theory. This manipulation influenced the extent to which people perceive patterns in world events, which in turn predicted unrelated irrational beliefs. We conclude that illusory pattern perception is a central cognitive mechanism accounting for conspiracy theories and supernatural beliefs. PMID- 29695890 TI - The Flexibility of Fertility Preferences in a Context of Uncertainty. PMID- 29695891 TI - Veto player theory and reform making in Western Europe. AB - Veto player theory generates predictions about governments' capacity for policy change. Due to the difficulty of identifying significant laws needed to change the policy status quo, evidence about governments' ability to change policy has been mostly provided for a limited number of reforms and single-country studies. To evaluate the predictive power of veto player theory for policy making across time, policy areas and countries, a dataset was gathered that incorporates about 5,600 important government reform measures in the areas of social, labour, economic and taxation policy undertaken in 13 Western European countries from the mid-1980s until the mid-2000s. Veto player theory is applied in a combined model with other central theoretical expectations on policy change derived from political economy (crisis-driven policy change) and partisan theory (ideology driven policy change). Robust support is found that governments introduce more reform measures when economic conditions are poor and when the government is positioned further away from the policy status quo. No empirical support is found for predictions of veto player theory in its pure form, where no differentiation between government types is made. However, the findings provide support for the veto player theory in the special case of minimal winning cabinets, where the support of all government parties is sufficient (in contrast to minority cabinets) and necessary (in contrast to oversized cabinets) for policy change. In particular, it is found that in minimal winning cabinets the ideological distance between the extreme government parties significantly decreases the government's ability to introduce reforms. These findings improve our understanding of reform making in parliamentary democracies and highlight important issues and open questions for future applications and tests of the veto player theory. PMID- 29695892 TI - Intra-Campaign Changes in Voting Preferences: The Impact of Media and Party Communication. AB - An increasing number of citizens change and adapt their party preferences during the electoral campaign. We analyze which short-term factors explain intra campaign changes in voting preferences, focusing on the visibility and tone of news media reporting and party canvassing. Our analyses rely on an integrative data approach, linking data from media content analysis to public opinion data. This enables us to investigate the relative impact of news media reporting as well as party communication. Inherently, we overcome previously identified methodological problems in the study of communication effects on voting behavior. Our findings reveal that campaigns matter: Especially interpersonal party canvassing increases voters' likelihood to change their voting preferences in favor of the respective party, whereas media effects are limited to quality news outlets and depend on individual voters' party ambivalence. PMID- 29695893 TI - Association of increased levels of plasma tumor necrosis factor alpha with primary open-angle glaucoma. AB - Purpose: Retinal ganglion cell (RGC) death is a key feature of glaucoma. Elevated levels of tumor necrosis factor alpha (TNF-alpha), a pro-inflammatory cytokine, can induce RGC apoptosis and play a critical role in glaucomatous neurodegeneration. Based on the possible role of inflammation and oxidative stress in the pathogenesis of primary open-angle glaucoma (POAG), we investigated the association between plasma levels of TNF-alpha and POAG or its clinical indices in comparison to non-glaucomatous controls. Patients and methods: In a case-control retrospective cohort of 51 POAG cases and 88 controls, plasma TNF alpha levels were measured using an enzyme-linked immunosorbent assay (ELISA). The assay was performed in duplicates on an automated ELISA analyzer. Results: Mean TNF-alpha level was significantly elevated in POAG cases (1.88 +/- 2.17 pg/mL) than the controls (0.93 +/- 1.49 pg/mL; p = 0.003). The overall dose response trend was significant (chi2 = 6.12, df = 2; p = 0.047). No statistical difference was seen in age, gender and systemic disease distribution. A modest negative and significant correlation was seen between TNF-alpha level and number of antiglaucoma medications, an important clinical index of POAG severity. Moreover, logistic regression analysis showed that the risk of POAG was most significantly affected by TNF-alpha level and not by age and sex. Conclusion: High systemic level of an inflammatory cytokine, TNF-alpha, is associated with POAG; however, its possible use as a biomarker for early glaucoma diagnosis and/or disease severity needs further investigation. PMID- 29695894 TI - Paeoniflorin improves cardiac function and decreases adverse postinfarction left ventricular remodeling in a rat model of acute myocardial infarction. AB - Background: Paeoniflorin (PF) is the active component of Paeonia lactiflora Pall. or Paeonia veitchii Lynch. This study was, therefore, aimed to evaluate the improvement and mechanism of the PF on ventricular remodeling in rats with acute myocardial infarction (AMI). Materials and methods: In this study, AMI model was established by ligating the anterior descending coronary artery in Wistar rats. After 4 weeks gavage of PF, the apparent signs and the left ventricle weight index of Wistar rats were observed. The left ventricular ejection fraction (LVEF) was evaluated by Doppler ultrasonography. Changes in cardiac morphology were observed by pathologic examination, and apoptosis was observed by the terminal deoxynucleotidyl transferase dUTP nick end labeling assay. In addition, enzyme linked immunosorbent assay was used to detect the expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6) interleukin-10 (IL-10) and brain natriuretic peptide (BNP). Immunohistochemistry and Western blot method were applied to detect Caspase-3 and Caspase-9. Results: Compared with the model control, the survival conditions of rats in all treatment groups were generally improved after PF treatment. LVEF was significantly increased, and both left ventricular end-diastolic inner diameter and left ventricular end-systolic inner diameter were significantly reduced. Moreover, pathologic examination showed that the myocardium degeneration of the rats treated with PF was decreased, including neater arrangement, more complete myofilament, more uniform gap and less interstitial collagen fibers. Furthermore, the mitochondrial structure of cardiomyocytes was significantly improved. The ultrastructure was clear, and the arrangement of myofilament was more regular. Also, the expression of Caspase-3 and Caspase-9 was inhibited, and apoptosis was obviously reduced in the PF treatment groups. BNP, TNF-alpha and IL-6 were also decreased and IL-10 was increased in the treated rats. Conclusion: PF could significantly improve the LVEF of rats. It decreased adverse left ventricular remodeling after myocardial infarction in rat models. The potential mechanism could be that PF decreased and inhibited BNP, TNF-alpha and IL-6, increased IL-10 and further inhibited the expression of Caspase-3 and Caspase-9, thus promoting ventricular remodeling. PMID- 29695896 TI - Complex interrelations between self-reported oral health attitudes and behaviors, the oral health status, and oral health-related quality of life. AB - Purpose: The purpose of this study was to develop and test a moderated mediation model that was able to describe the relationships between oral health-related attitudes and behaviors, oral health status (OHS), and oral health-related quality of life. The hypothesized relations corresponded to research questions such as "is a person's oral health predicted by the actions that person takes in order to prevent oral health conditions?" and "do individuals with better oral health also have higher levels of oral health-related quality of life?". Materials and methods: A cross-sectional correlational study with selected predictor variables was conducted in Cluj-Napoca, Romania, among 191 participants, enrolled in the fourth and sixth years of study at the Dentistry School of the Medicine and Pharmacology, University of Cluj-Napoca. Participants completed the Hiroshima University Dental Behavior Inventory (HUDBI) questionnaire targeting specific behavior and attitude with respect to their dental self-care, Oral Health Impact Profile (OHIP) short questionnaire for measuring oral health-related quality of life, and the current OHS was assessed objectively using Decayed, Missing, Filled Teeth/Surfaces (DMFT) index. Statistical analyses were done using structural equation modeling software. Results: Our research showed relevant associations between HUDBI, DMFT, and OHIP. The relationship between HUDBI and OHIP was mediated by DMFT. Furthermore, HUDBI worked as a moderator between DMFT and OHIP. Thus, our study revealed a case for moderated mediation, which is usually ignored in similar research. Conclusion: The "straightforward" causality between oral health-related behavior and the actual OHS must be considered with caution, as well as their impact on the oral health-related quality of life. Further research is needed to investigate the interaction between variables, the strength of the interrelations and the magnitude of their interactions, and the confidence that can be placed in these measurements, with respect to the general population and/or those lacking domain specific education. PMID- 29695895 TI - Randomized trial of betahistine mesilate tablets as augmentation for oxcarbazepine and carbamazepine in treating vestibular paroxysmia. AB - Background: Vestibular paroxysmia (VP) is a rare episodic peripheral vestibular disorder. This study was conducted to compare the efficacy and acceptability of carbamazepine (CBZ) plus betahistine mesilate tablets (BMT) (CBZ+BMT) and oxcarbazepine (OXC) plus BMT (OXC+BMT) in treating VP, and investigated whether the synergistic effect could be increased along with the increased dose of BMT. Methods: VP patients were recruited and randomly assigned to receive CBZ+BMT or OXC+BMT. The doses of CBZ and OXC were set to 200 and 300 mg/time, twice daily, respectively. The doses of BMT were set to 12 and 18 mg/time, twice daily. Half of the patients in each group received BMT 12 mg/time and the other half received BMT 18 mg/time. The treatment was continued for 12 weeks. The vertigo frequency, vertigo score, vertigo duration, response rate, and drug-related side effects were analyzed. Results: In total, 92 patients in the CBZ+BMT group and 93 patients in the OXC+BMT group completed this trial. After 12 weeks of treatment, the two groups had similar average vertigo frequency, average vertigo score, average vertigo duration, and response rate. But the incidence of side effects was significantly higher in the CBZ+BMT group than in the OXC+BMT group (p=0.04). Subgroup analysis found that patients receiving BMT (18 mg) had greater reductions in average vertigo frequency, average vertigo duration, and average vertigo score, and higher response rates than patients receiving BMT (12 mg). Conclusion: These results demonstrated that OXC+BMT may be suitable as an alternative method in VP patients with CBZ hypersensitivity, and the synergistic effect could be increased along with the increased dose of BMT. PMID- 29695897 TI - Patients' perception and adherence to vaginal dilator therapy: a systematic review and synthesis employing symbolic interactionism. AB - Background: Vaginal dilator (VD) therapy is often recommended for women receiving pelvic radiation therapy or experiencing pain and discomfort during intercourse, as well as for women with a congenital malformation of the vagina. VD use has both physical and psychological benefits; however, it often causes pain, discomfort, and adverse emotions, including embarrassment and loss of modesty, which often result in low adherence to therapy. Objectives: The aims of this study were to explore the use and adherence of VD therapy in women, identify barriers and facilitators of therapy adherence, and suggest improvement strategies from the theoretical perspective of symbolic interactionism. Methods: A systematic review of the literature was conducted using PubMed, CINAHL, and Scopus databases, with no year restrictions. Articles addressing the experience of women using VD therapy, as well as barriers and facilitators of therapy adherence were selected and analyzed. Then, the theoretical perspective of symbolic interactionism was introduced and applied to synthesize the results. Results: A total of 21 articles were selected for the review. Most of the reviewed studies explored VD therapy in women who had undergone pelvic radiation therapy for gynecological cancer. Women's adherence to the therapy ranged between 25% and 89.2%, with great variance in definitions and methods for assessing therapy adherence. Among the five categories of identified barriers to therapy adherence, "unhelpful circumstances" and "negative perceptions toward the VD" were the two most frequently mentioned. The two most frequently reported facilitators of adherence among the six identified categories were "supportive interactions with health care providers" and "risk perception and positive outcome expectancies". On the basis of the perspective of symbolic interactionism, strategies for strengthening interactions with others (eg, health care providers, significant others, and support groups) are discussed in detail. Conclusion: Strategic intervention regarding the decisive factors identified in the review can benefit women by enhancing their experience and adherence to VD therapy. PMID- 29695898 TI - Critical regulation of inflammation via class A scavenger receptor. AB - Background: Inflammation is an important cause of COPD. Alveolar macrophages are the major innate immune cells that have an important role in COPD pathology. Class A scavenger receptor (SR-A) is a pattern recognition receptor expressed on macrophages. This study investigates the role of SR-A in COPD progression via regulation of inflammation. Patients and methods: SR-A expression in COPD patients and control subjects (smokers and nonsmokers without COPD) was measured by immunohistochemistry, immunofluorescence, and real-time PCR. The cytokine levels in BAL were measured by enzyme-linked immunosorbent assay. To further prove our hypothesis, we treated RAW264.7 cells that overexpress SR-A with lipopolysaccharides, poly(I:C), cigarette smoke extract, and H1N1 influenza separated from patients for 24 h and examined the levels of inflammatory cytokines. Results: In both groups, COPD and smokers without COPD, SR-A expression level was upregulated in alveolar macrophages. SR-A mRNA level was positively correlated with inflammatory cytokines and negatively correlated with FEV1% predicted in COPD patients. In RAW-SR-A cells, level of inflammatory cytokines was significantly higher when compared with control ones. Conclusion: SR-A could increase inflammation stimulated by cigarette smoke extracts, bacteria, and virus, leading to long-term inflammation in COPD, and thus might be used as a new therapeutic target for COPD treatment. PMID- 29695899 TI - Chest pain in patients with COPD: the fascia's subtle silence. AB - COPD is a progressive condition that leads to a pathological degeneration of the respiratory system. It represents one of the most important causes of mortality and morbidity in the world, and it is characterized by the presence of many associated comorbidities. Recent studies emphasize the thoracic area as one of the areas of the body concerned by the presence of pain with percentages between 22% and 54% in patients with COPD. This article analyzes the possible causes of mediastinal pain, including those less frequently taken into consideration, which concern the role of the fascial system of the mediastinum. The latter can be a source of pain especially when a chronic pathology is altering the structure of the connective tissue. We conclude that to consider the fascia in daily clinical activity may improve the therapeutic approach toward the patient. PMID- 29695900 TI - The link between chronic obstructive pulmonary disease phenotypes and histological subtypes of lung cancer: a case-control study. AB - Background: COPD is considered an independent risk factor for lung cancer. COPD and lung cancer are both very heterogeneous diseases, and the study herein investigates the link between COPD phenotypes and specific histological subtypes of lung cancer. Methods: This case-control study comprised 2,283 patients with newly diagnosed pathological lung cancer and 2,323 non-lung cancer controls. All participants underwent pulmonary function tests. The diagnosis of COPD was based on Global Initiative for Chronic Obstructive Lung Disease criteria. Subtypes of the two diseases were categorized according to 2015 World Health Organization classification of lung cancer and computer quantification of airway collapse on maximum expiratory flow volume. ORs were estimated using logistic regression analysis. Results: The prevalence of COPD was higher (32.8%) in lung cancer patients compared to controls (16.0%). After adjustment for age, sex, body-mass index, and smoking status, the presence of COPD significantly increased the risk of lung cancer (OR 2.88, 95% CI 2.48-3.34) and all common histological subtypes (ORs 2.04-5.26). Both emphysema-predominant and non-emphysema-predominant phenotypes of COPD significantly increased the risk of lung cancer (OR 4.43, 95% CI 2.85-6.88; OR 2.82, 95% CI 2.40-3.31). Higher risk of squamous-cell carcinoma and small-cell lung cancer was observed in patients with the emphysema predominant than the non-emphysema-predominant phenotype (OR 1.73, 95% CI 1.03 2.89; OR 3.74, 95% CI 1.64-8.53). Conclusion: COPD was an independent risk factor for lung cancer and all common histological subtypes. Both emphysema-predominant and non-emphysema-predominant phenotypes of COPD significantly increased the risk of lung cancer. Relative to non-emphysema-predominant phenotype of COPD, emphysema-predominant phenotype had a higher risk of squamous-cell carcinoma and small-cell lung cancer. PMID- 29695901 TI - The association of neuron-derived orphan receptor 1 with pulmonary vascular remodeling in COPD patients. AB - Introduction: Chronic hypoxia-induced pulmonary vascular remodeling is a feature of chronic obstructive pulmonary disease (COPD). Our previous reports indicate that neuron-derived orphan receptor 1 (NOR1) promoted pulmonary smooth muscle cell proliferation in vitro. But it remains unclear whether NOR1 participated into hypoxia-induced pulmonary vascular remodeling in COPD patients. Patients and methods: For this study, we collected peripheral lung tissues of 26 male COPD patients with or without hypoxemia. We detected the pulmonary vascular remodeling in all the peripheral lung tissues. Primary human pulmonary arterial smooth muscle cells were also cultured in vitro and stimulated with hypoxia or normoxia. Cell proliferation and protein levels were detected. Results: COPD patients with hypoxemia showed significantly enlarged pulmonary vessels wall thickness and increased protein levels of HIF-1alpha, smooth muscle actin, cyclin D1, and NOR1 when compared with those in normoxic patients. Moreover, hypoxia induced human pulmonary arterial smooth muscle cell proliferation and NOR1 overexpression in vitro. The plasmid-based NOR1 gene overexpression markedly promoted DNA synthesis and proliferation in hypoxia or normoxic cells. Human NOR1 gene-specific siRNA intensively suppressed DNA synthesis and proliferation. Transfection of NOR1 overexpression plasmid raised cyclin D1 protein levels, which could be significant inhibited by NOR1-specific siRNA or a CDK4/6 inhibitor PD0332991. Conclusion: We concluded that NOR1 upregulation is associated with hypoxia induced pulmonary vascular remodeling in COPD via promoting human pulmonary arterial smooth muscle cell proliferation. PMID- 29695902 TI - Randomized, double-blind, placebo-controlled trial to assess the efficacy and safety of three doses of co-suspension delivery technology glycopyrronium MDI in Japanese patients with moderate-to-severe COPD. AB - Purpose: Due to the burden of COPD in Japan, new pharmacologic treatments are needed to meet patient requirements. This study assessed the efficacy and safety of glycopyrronium (GP) delivered via metered dose inhaler (MDI) in Japanese patients with moderate-to-severe COPD. Methods: This Phase IIb, multicenter, randomized, double-blind, 7-day, crossover study compared GP MDI 28.8, 14.4, and 7.2 MUg with placebo MDI (all administered as two inhalations, twice daily). The primary endpoint was change from baseline in morning pre-dose trough forced expiratory volume in 1 second (FEV1) on Day 8. Secondary endpoints included FEV1 area under the curve from 0 to 2 hours (AUC0-2) and peak change from baseline in FEV1 on Days 1 and 8 and forced vital capacity AUC0-2 on Day 8. Safety was also assessed. ClinicalTrials.gov Identifier: NCT03256552; http://www.ClinicalTrials.gov. Results: Sixty-six patients were randomized and 62 were included in the modified intent-to-treat population (mean age 67.5 years). All three GP MDI doses significantly improved change from baseline in morning pre dose trough FEV1 on Day 8 compared with placebo MDI (least squares mean differences 108-131 mL; all p<0.0001). Significant improvements in secondary efficacy endpoints were also observed for all three GP MDI doses compared with placebo MDI (all p<0.0001). Dose-response plateaued at GP MDI 14.4 MUg. No significant safety findings were observed with any GP MDI dose or placebo MDI. Conclusions: The results of this study suggest that GP MDI 14.4 MUg (7.2 MUg per inhalation) is the most appropriate dose for use in Phase III studies in Japanese patients with moderate-to-severe COPD. PMID- 29695903 TI - Dual-responsive dithio-polydopamine coated porous CeO2 nanorods for targeted and synergistic drug delivery. AB - Objective: The aim was to produce the first report of assembling degradable stimuli-responsive dithio-polydopamine coating with a cancer target unit for synergistic and targeted drug delivery. Methods: A multifunctional drug delivery system was constructed by coating a dual-responsive dithio-polydopamine (PDS) on porous CeO2 nanorods and subsequent conjugation of lactose derivative, where the PDS was formed by self-polymerization of dithio-dopamine (DOPASS). Results: The multifunctional drug delivery system displayed excellent cancer targeted ability resulting from the conjugation of lactose derivative, which could specifically recognize the overexpressed asialoglycoprotein receptors on the surface of HepG2 cells. It also showed a dual-responsive property of glutathione and pH, achieving controllable drug release from the cleavage of disulfide bond and subsequent degradation of PDS in cancer cells. Moreover, the degradation of PDS led to the exposure of CeO2 nanorods, which has a synergistic anticancer effect due to its cytotoxicity to cancer cells. Conclusion: This work presents a good example of a rational design towards synergistic and targeted DDS for cancer chemotherapies. PMID- 29695905 TI - Tanshinol borneol ester on nanostructured lipid carriers has longer brain and systemic effector retention and better antioxidant activity in vivo. AB - Background: Tanshinol borneol ester (DBZ) is a hybrid of danshensu (DSS) and borneol and has anti-ischemic activity in animals. However, its low water solubility and short half-life limit its clinical application. Methods: We prepared polyethylene glycol (PEG)-modified and DBZ-loaded nanostructured lipid carriers (DBZ-PEG-NLC) and DBZ-NLC, and examined their physical characteristics, such as particle size, zeta potential, entrapment efficiency and drug loading. The in vitro stability and pharmacokinetics in rats as well as antioxidant activity of DBZ-PEG-NLC and DBZ-NLC in a C57BL/6 mouse model of ischemia/reperfusion-related brain injury were investigated. The levels of DBZ and its hydrolyzed DSS in rat plasma and brain microdialysates were determined by liquid chromatography-mass spectroscopy/mass spectroscopy analysis. Results: We found that the mean particle size and entrapment efficacy of DBZ-PEG-NLC were similar to that of DBZ-NLC. The DBZ-PEG-NLC, like DBZ-NLC, released DBZ in a biphasic manner with initially burst release and then prolonged slow release in vitro. Intravenous injection of DBZ-PEG-NLC resulted in significantly higher levels and longer retention periods of DBZ and DSS in plasma and the brains than DBZ-NLC and DBZ in rats. Finally, treatment with DBZ-PEG-NLC achieved a better antioxidant activity than DBZ or DBZ-NLC in mouse model of ischemia/reperfusion by reducing the levels of brain malondialdehyde, but increasing the levels of brain superoxide dismutase and glutathione. Conclusion: DBZ-PEG-NLC is a preferable option to deliver DBZ for sustainable release of DSS and borneol in vivo, and may serve as a promising drug for effective therapy of ischemic cardiovascular and cerebrovascular diseases. PMID- 29695906 TI - Silica nanoparticle-induced oxidative stress and mitochondrial damage is followed by activation of intrinsic apoptosis pathway in glioblastoma cells. AB - Introduction: Recently, the focus of oncological research has been on the optimization of therapeutic strategies targeted at malignant diseases. Nanomedicine utilizing silicon dioxide nanoparticles (SiNPs) is one such strategy and is rapidly developing as a promising tool for cancer diagnosis, imaging, and treatment. Nevertheless, little is known about the mechanisms of action of SiNPs in brain tumors. Materials and methods: Here, we explored the effects of 5-15 nm SiNPs in the human glioblastoma cell line LN229. In this respect, MTT assays, microscopic observations, flow cytometry analyses, and luminescent assays were performed. Moreover, RT-qPCR and Western blot analyses were done to determine gene and protein expressions. Results: We demonstrated that SiNPs triggered evident cytotoxicity, with microscopic observations of the nuclei, annexin V fluorescein isothiocyanate/propidium iodide staining, and elevated caspase 3/7 activity, suggesting that SiNPs predominantly induced apoptotic death in LN229 cells. We further showed the occurrence of oxidative stress induced by enhanced reactive oxygen-species generation. This effect was followed by deregulated expression of genes encoding the antioxidant enzymes SOD1, SOD2, and CAT, and impaired mitochondria function. SiNP- induced mitochondrial dysfunction was characterized by membrane-potential collapse, ATP depletion, elevated expression of BAX, PUMA, and NOXA with simultaneous downregulation of BCL2/BCL2L1, and activation of caspase 9. Moreover, RT-qPCR and Western blot analyses demonstrated increased levels of the endoplasmic reticulum stress markers GRP78, GRP94, and DDIT3, as well as strongly increased expressions of the IL1B and COX2 genes, suggesting activation of endoplasmic reticulum stress and a proinflammatory response. Conclusions: Altogether, our data indicate that in LN229 cells, SiNPs evoke cell death via activation of the intrinsic apoptosis pathway and suggest that other aspects of cellular function may also be affected. As such, SiNPs represent a potentially promising agent for facilitating further progress in brain cancer therapy. However, further exploration of SiNP long-term toxicity and molecular effects is necessary prior to their widespread application. PMID- 29695904 TI - Antimicrobial hydrogels: promising materials for medical application. AB - The rapid emergence of antibiotic resistance in pathogenic microbes is becoming an imminent global public health problem. Local application of antibiotics might be a solution. In local application, materials need to act as the drug delivery system. The drug delivery system should be biodegradable and prolonged antibacterial effect should be provided to satisfy clinical demand. Hydrogel is a promising material for local antibacterial application. Hydrogel refers to a kind of biomaterial synthesized by a water-soluble natural polymer or a synthesized polymer, which turns into gel according to the change in different signals such as temperature, ionic strength, pH, ultraviolet exposure etc. Because of its high hydrophilicity, unique three-dimensional network, fine biocompatibility and cell adhesion, hydrogel is one of the suitable biomaterials for drug delivery in antimicrobial areas. In this review, studies from the past 5 years were reviewed, and several types of antimicrobial hydrogels according to different ingredients, different preparations, different antimicrobial mechanisms, different antimicrobial agents they contained and different applications, were summarized. The hydrogels loaded with metal nanoparticles as a potential method to solve antibiotic resistance were highlighted. Finally, future prospects of development and application of antimicrobial hydrogels are suggested. PMID- 29695907 TI - Insomnia in hospitalized psychiatric patients: prevalence and associated factors. AB - Objectives: To quantify and describe the prevalence of insomnia in hospitalized psychiatric patients and to investigate the associations between insomnia and demographic and clinical factors in hospitalized psychiatric patients. Methods: The participants included 203 individuals hospitalized for psychiatric treatment at an academic medical center. Demographic information, psychiatric diagnoses, current psychotropic medication use, and history of substance use were collected. Insomnia screening was performed using the Insomnia Severity Index. Depressive and anxiety symptoms were also evaluated using the Generalized Anxiety Disorder questionnaire and the Patient Health Questionnaire. Restless legs syndrome (RLS) symptoms were evaluated using the Restless Legs Syndrome Rating Scale (RLSRS). Statistical analysis was conducted to detect the prevalence of insomnia among the participants and to examine possible associations among psychiatric disorders, psychotropic medications, and RLS. Results: Out of the 203 participants that completed the survey, 67.4% were found to have insomnia and 14.3% were found to have RLS. The severity of insomnia was found to be associated with the presence of RLS, depressive and anxious symptomatology, suicidal ideation, use of selective serotonin reuptake inhibitors, and use of benzodiazepines. PMID- 29695908 TI - The functional and structural characteristics of the emotion network in alexithymia. AB - Background: Alexithymia is a multifaceted personality trait characterized by emotional dysfunction. Methods: In this study, the functional and structural features of the emotion network in alexithymia were investigated using resting state functional MRI (rsfMRI), voxel-based morphometry (VBM), functional connectivity (FC) analysis, and diffusion tensor imaging (DTI). Alexithymic and non-alexithymic students were recruited from the local university. The intrinsic neural activity and gray matter density of the brain regions in the emotion network were measured using rsfMRI and VBM; the FC and structural connectivity of the brain regions in the emotion network were measured using FC analysis and DTI. Results: The altered intrinsic neural activity in V1, rostral dorsal anterior cingulate cortex, and left amygdala, and the weak FC between V1 and left superior temporal gyrus and V1 and left paracentral lobule in alexithymia subjects were identified. However, no alteration of the structure and structural connectivity of the emotion network was identified. Conclusion: The results indicated that the development of alexithymia might have been caused only by slight alteration of the neural activity. Furthermore, the results suggest that noninvasive treatment technologies for improving the brain activity are suitable for alexithymic individuals. PMID- 29695909 TI - Increase in spleen volume as a predictor of oxaliplatin toxicity. AB - Background: Oxaliplatin is a nonconventional third-generation platinum compound. It is an important chemotherapeutic agent in regimens used in gastrointestinal carcinomas as well as other malignancies. Oxaliplatin toxicity profile includes neurotoxicity, hepatotoxicity, and splenomegaly. The primary aim of this study was to measure the spleen volume of patients on oxaliplatin therapy before and during chemotherapy to detect any increase in splenic size as a biomarker for early oxaliplatin toxicity. Methods: This was a prospective pilot study conducted at the American University of Beirut-Medical Center. Fifty patients newly started on oxaliplatin were included. The spleen volume was measured from the patients' baseline CT scan using the IntelliSpace Portal upgraded system (using Response Evaluation Criteria In Solid Tumors [RECIST]), for each follow-up CT scan. Side effects were evaluated at each patient visit and graded according to the severity. Results: Thirty-seven (74%) patients developed an increase in spleen size. Thirty-three (66%) sampled patients developed peripheral neuropathy (all grades) at 3 months, whereas only two (4%) patients developed grade 3 neuropathy. Only one (3%) patient who developed an increase in spleen size also developed grade 3 peripheral neuropathy - a result that is significantly different (p<0.001) when comparing patients with an increase in spleen size who also developed peripheral neuropathy of other grades. Conclusion: An increase in spleen volume possibly precedes a significant peripheral neuropathy which could be a potential marker for oxaliplatin-induced toxicity. PMID- 29695910 TI - Total hip arthroplasty following arthrodesis: a single-center experience of 17 patients. AB - Purpose: We aimed to present our experience with total hip arthroplasty in patients with previous hip arthrodesis. Patients and methods: This was a retrospective study, in which clinical and radiological outcomes of total hip arthroplasty performed in 17 patients (mean age 54.2+/-8.5 years; age range 33-68 years; female to male ratio 10/7) with previous arthrodesis in our clinic between 2001 and 2014 were reviewed. Patients were followed up for 6.7+/-2.8 years (range 3-12 years) after the operation and evaluated for ipsilateral knee pain, range of motion, walking capacity, and leg-length discrepancy. The clinical outcome was assessed by the Harris Hip Score. Results: The outcome of arthroplasty was good or excellent in 14 of 17 patients (82.3%), fair in two patients (11.8%), and failure in one patient (5.9%). The Harris Hip Score increased to 79.8+/-9.8 postoperatively from a preoperative score of 40.9+/-10.1 (p<0.01). Pain-free hip was obtained in 15 patients (88.2%), and range of motion was 88 degrees . Fourteen patients (82.4%) reported a significant decrease in back pain, and 11 patients (64.7%) in ipsilateral knee pain. Ten patients (58.8%) were able to walk normally, five patients (29.4%) walked with slight Trendelenburg gait without support, and two patients (11.8%) with severe Trendelenburg gait using arm rests. The mean leg-length discrepancy was 1.1 cm (range 0-3 cm). The complications were peroneal nerve palsy (n=3), superficial wound infection (n=3), hip dislocation (n=2), and heterotopic ossification (n=3). Conclusion: If it is well planned, conversion of hip arthrodesis to total hip arthroplasty is a successful and safe procedure, which increases patients' functionality. PMID- 29695911 TI - Amantadine extended-release capsules for levodopa-induced dyskinesia in patients with Parkinson's disease. AB - Levodopa-induced dyskinesia (LID) is a common motor complication in patients with Parkinson's disease on chronic levodopa therapy. The management of LID is important as dyskinesia can be disabling and impair quality of life. Currently, there are limited treatment options for the medical management of LID. Amantadine extended-release capsules (GocovriTM) is the first medication that received US Food and Drug Administration approval for the treatment of LID. The following is a review of the pharmacodynamics, efficacy and safety profile, and current state of treatment of amantadine for LID. PMID- 29695912 TI - Tranexamic acid reduces intraoperative occult blood loss and tourniquet time in obese knee osteoarthritis patients undergoing total knee arthroplasty: a prospective cohort study. AB - Purpose: Obesity can result in increased blood loss, which is correlated with poor prognosis in total knee arthroplasty (TKA). Clinical application of tranexamic acid is effective in reducing blood loss in TKA. However, most previous studies focused on the effect of tranexamic acid in the whole population, neglecting patients with specific health conditions, such as obesity. We hypothesized that tranexamic acid would reduce blood loss to a greater extent in obese patients than in those of normal weight. Patients and methods: A total of 304 patients with knee osteoarthritis treated with TKA from October 2013 to March 2015 were separated into tranexamic, non-tranexamic, obese, and non-obese groups. The demographic characteristics, surgical indices, and hematological indices were all recorded. We first investigated the ability of intravenous tranexamic acid to reduce intraoperative blood loss in knee osteoarthritis patients undergoing unilateral TKA. Second, we performed subgroup analysis to compare the effects of tranexamic acid between obese and non-obese patients separately. Results: Of the 304 patients, 146 (52.0%) received tranexamic acid and 130 (42.8%) were obese. In the analysis of the whole group, both the actual and occult blood loss volume were lower in the tranexamic acid group (both P < 0.05). Tourniquet time was shorter in the tranexamic acid group (P < 0.05). In subgroup analysis, tranexamic acid was shown to reduce theoretical and actual blood loss in both the obese and non-obese groups (P < 0.05). Tranexamic acid reduced occult blood loss and tourniquet time in the obese group (P < 0.05), while no such effects were observed in the non-obese group (P > 0.05). Conclusion: Tranexamic acid can reduce occult blood loss and tourniquet time in obese patients to a greater extent than in patients of normal weight. Therefore, obese knee osteoarthritis patients undergoing TKA can benefit more from tranexamic acid. PMID- 29695913 TI - Combination of SIRT1 and Src overexpression suggests poor prognosis in luminal breast cancer. AB - Objectives: 1) Analyze the correlation of SIRT1 and Src with human breast cancer (BC) prognosis; 2) explore the roles of SIRT1 and Src in BC cell proliferation, tumor invasion, and metastasis; and 3) analyze the correlation and interaction between SIRT1 and Src. Materials and methods: 1) Tissue microarray was used to analyze the expression of SIRT1 and Src in human BC tissues and the correlation between protein expression and cancer prognosis; 2) CCK8 assay was used to determine the influence of SIRT1 and Src inhibitors on BC cell proliferation; 3) Transwell migration assay and wound healing assay were used to determine the effect of SIRT1 and Src inhibitors on BC cell migration and invasion; and 4) Western blotting was used to analyze the correlation and interaction between SIRT1 and Src. Results: 1) Combination of SIRT1 and/or Src positivity is a prognosis factor in BC, especially in luminal type; 2) MCF-7 cell proliferation is suppressed by SIRT1 inhibitor Ex527, and cell migration and invasion were inhibited by Src inhibitor bosutinib; 3) combined with Ex527, bosutinib has a significantly increased effect on MCF-7 cell migration suppression; and 4) there is a positive association between SIRT1 and Src both in BC tissues and in MCF-7 cells. Conclusion: 1) SIRT1 and Src overexpression are both correlated with poor prognosis in human BC; 2) SIRT1 + Src (SIRT1 and/or Src positivity) is a fine prognosis model for luminal-type BC; 3) SIRT1 is a copromotor of Src in BC migration and invasion, but not in cell proliferation; and 4) our results suggest a potential interaction or a common regulation pathway between SIRT1 and Src expression and activity. PMID- 29695915 TI - Expression of pyruvate kinase M2 in human bladder cancer and its correlation with clinical parameters and prognosis. AB - Background: Pyruvate kinase M2 (PKM2) is a key regulator of the Warburg effect and has critical functions in glycolysis, contributing to the Warburg effect, tumor growth, angiogenesis, cell division, metastasis, and apoptosis. The high expression of PKM2 in various solid tumors renders it a potential biomarker of tumorigenesis and tumor invasion, but the expression and role of PKM2 in bladder cancer have not been studied extensively. Patients and methods: Western blot and immunohistochemistry (IHC) were used to measure the expression of PKM2, and quantitative real-time polymerase chain reaction (PCR) was performed to determine PKM2 mRNA levels. The relationships between PKM2 expression and clinicopathological parameters and prognosis were analyzed using the Kaplan-Meier plots and a Cox proportional hazards regression model. Results: Compared with paired adjacent normal bladder tissues, PKM2 mRNA and protein levels were found to be higher in urothelial carcinoma of the bladder (UCB) samples by real-time PCR and Western blot. By IHC, high expression of PKM2 was seen in 117 of 215 UCBs (54.4%) and in eight of 90 adjacent normal bladder tissues (8.9%). The expression of PKM2 was significantly associated with grade, stage, and lymph node status (P<0.001). In the univariate survival analysis, a significant association between PKM2 expression and shorter patient survival was observed (P<0.001). In different subsets of UCB patients, we found that PKM2 expression was a prognostic factor in patients with G2 (P=0.009), G3 (P<0.001), pTa/pTis (P=0.006), pT1, pT2-4, and pN- disease (P<0.001). Importantly, PKM2 expression (P=0.003), with tumor histological grade (P<0.001), pT (P<0.001), and pN status (P=0.005), was a significant independent prognostic parameter in the multivariate analysis. Conclusion: PKM2 protein and mRNA are upregulated in UCBs and may serve as molecular markers for a poor prognosis in patients with UCB. PMID- 29695917 TI - Four cycles of adriamycin and cyclophosphamide followed by four cycles of docetaxel (NSABP-B27) with concomitant trastuzumab as neoadjuvant therapy for high-risk, early-stage, HER2-positive breast cancer patients. AB - Background: The majority of breast cancer patients in Jordan are diagnosed at a young age and present with metastatic or locally advanced disease. The National Surgical Adjuvant Breast and Bowel Project Protocol B27 (NSABP-B27) (four cycles of adriamycin and cyclophosphamide [AC] followed by four cycles of docetaxel) is a standard neoadjuvant regimen in our institution. In this study, we report the efficacy of adding trastuzumab to docetaxel in this regimen for high-risk human epidermal growth factor receptor 2 (HER2)-positive early-stage disease. Patients and methods: Consecutive HER2-positive breast cancer patients treated with this regimen were included. Treatment was given at standard doses and schedules as reported in NSABP-B27. Trastuzumab was given with docetaxel and then continued for 1 year. Results: A total of 121 patients (mean age 45.4 years) were included. The majority had high-risk features including large tumor size, positive axillary lymph nodes, and grade III disease. Three patients did not complete the planned cycles of AC due to a lack of response. Eight (6.6%) patients missed at least one cycle of docetaxel. Following neoadjuvant therapy, 119 patients underwent surgery, of whom 59 (49.6%) patients achieved pathological complete response. The response was higher in node-negative patients (64.0 vs 45.7%; P=0.03) and in hormone receptor-negative disease patients (69.7 vs 41.9%; P=0.018). Breast conserving surgery was performed in 21.5% of the patients. The median disease free survival (DFS) for the whole group was not reached while the 3- and 5-year DFS rates were 84.2 and 74.1%, respectively. Conclusion: Trastuzumab added to the NSABP-B27 regimen is a unique combination. When used in high-risk patients, as in our study, outcomes similar to reported data were achieved without unexpected toxicities. PMID- 29695914 TI - Role of the NFkappaB-signaling pathway in cancer. AB - Cancer is a group of cells that malignantly grow and proliferate uncontrollably. At present, treatment modes for cancer mainly comprise surgery, chemotherapy, radiotherapy, molecularly targeted therapy, gene therapy, and immunotherapy. However, the curative effects of these treatments have been limited thus far by specific characteristics of tumors. Abnormal activation of signaling pathways is involved in tumor pathogenesis and plays critical roles in growth, progression, and relapse of cancers. Targeted therapies against effectors in oncogenic signaling have improved the outcomes of cancer patients. NFkappaB is an important signaling pathway involved in pathogenesis and treatment of cancers. Excessive activation of the NFkappaB-signaling pathway has been documented in various tumor tissues, and studies on this signaling pathway for targeted cancer therapy have become a hot topic. In this review, we update current understanding of the NFkappaB-signaling pathway in cancer. PMID- 29695916 TI - Investigation of LEP and LEPR polymorphisms with the risk of hepatocellular carcinoma: a case-control study in Eastern Chinese Han population. AB - Background: Leptin (LEP) and LEP receptor (LEPR) polymorphisms may be associated with the development of cancer. Methods: In this study, we selected five functional LEP and LEPR single-nucleotide polymorphisms (SNPs) and conducted a case-control study to determine the relationship of LEP and LEPR polymorphisms with hepatocellular carcinoma (HCC) risk in Eastern Chinese Han population. There were 584 HCC cases and 923 cancer-free controls included in our study. HCC patients and controls were fully matched by age and sex. SNPscanTM genotyping method was used to analyze the genotyping of LEP rs2167270 G>A, rs7799039 A>G, LEPR rs6588147 G>A, rs1137100 G>A, and rs1137101 G>A SNPs. Results: We found that LEP rs7799039 A>G and rs2167270 G>A polymorphisms were associated with the susceptibility of HCC in this population (LEP rs7799039 A>G: GG vs AA: adjusted odds ratio [OR]=2.03, 95% CI, 1.22-3.38, P=0.006 and GG vs AA/AG: adjusted OR=1.97, 95% CI, 1.20-3.22, P=0.007; rs2167270 G>A: AA vs GG: adjusted OR=2.03, 95% CI, 1.10-3.75, P=0.024 and AA vs GG/GA: adjusted OR=2.01, 95% CI, 1.10-3.68, P=0.023). However, LEPR rs6588147 G>A polymorphism decreased the risk of HCC (GA vs GG: adjusted OR=0.62, 95% CI, 0.45-0.86, P=0.005 and AA/GA vs GG: adjusted OR=0.64, 95% CI, 0.47-0.88, P=0.007). Conclusion: This case-control study highlights that LEP rs7799039 A>G and rs2167270 G>A polymorphisms increase the susceptibility to HCC; however, LEPR rs6588147 G>A polymorphism may be a protective factor for HCC in Eastern Chinese Han population. PMID- 29695918 TI - Overexpression of high mobility group box 1 contributes to progressive clinicopathological features and poor prognosis of human bladder urothelial carcinoma. AB - Background: High mobility group box 1 (HMGB1), a versatile protein with intranuclear and extracellular functions, plays an important role in a variety of human cancers. However, the clinical/prognostic significance of HMGB1 expression in human bladder urothelial carcinoma (BUC) remains unclear. The aim of this study was to investigate the HMGB1 expression in human BUC with regard to its clinical and prognostic significance. Patients and methods: HMGB1 mRNA and protein expressions in tumor and paired normal bladder tissues were detected in 20 BUC cases by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. HMGB1 protein expression in 165 primary BUC tissues was evaluated by immunohistochemistry (IHC), and its correlations with clinicopathological characteristics and prognosis were also analyzed. Student's t-test, chi2 test, Kaplan-Meier plots, and Cox proportional hazard regression model were performed to analyze the data. Results: By using qRT-PCR and Western blot, the upregulated expression of HMGB1 mRNA and protein was detected in BUC, compared with paired normal tissue (P<0.05). By using IHC, high HMGB1 expression was examined in 84 of 165 (51.0%) BUC cases. High HMGB1 expression was significantly correlated with poorer differentiation and higher T and N classification (all P<0.05). Univariate analysis showed that high HMGB1 expression was significantly associated with a shortened patients' overall survival (OS) and disease-free survival (DFS; both P<0.001). In different subgroups of BUC patients, HMGB1 expression was a prognostic factor in patients with different histological grades or T classification (all P<0.05), pN- (both P<0.001) for OS and DFS, and pT1/pN- (P<0.05) for OS. HMGB1 expression, as well as pT and pN status, was an independent prognostic factor for both OS (P=0.001, hazard ratio [HR] =2.973, 95% confidence interval [CI] =1.550-5.704) and DFS (P<0.001, HR =3.019, 95% CI =1.902 4.792) in multivariate analysis. Conclusion: Overexpression of HMGB1 may be a new independent molecular marker for the poor prognosis of patients with BUC. PMID- 29695919 TI - Efficacy of pemetrexed-based regimens in advanced non-small cell lung cancer patients with activating epidermal growth factor receptor mutations after tyrosine kinase inhibitor failure: a systematic review. AB - Pemetrexed-based chemotherapy regimens (pem regimens) are the standard first-line treatment option in patients with non-squamous non-small cell lung cancer (NSCLC). The objective of this systematic review was to assess the efficacy of pemetrexed in the context of epidermal growth factor receptor (EGFR) mutation positive NSCLC following the failure of EGFR-tyrosine kinase inhibitor (TKI) treatment. We searched biomedical literature databases (PubMed, EMBASE, and the Cochrane library) and conference proceedings for studies evaluating the efficacy of pemetrexed monotherapy or pemetrexed combined with platinum or any other chemotherapeutic agent in EGFR-mutation-positive NSCLC after EGFR-TKI failure. We extracted data of primary outcomes of interest (progression-free survival [PFS], overall survival [OS], and overall response rate [ORR]). The weighted median PFS, OS, and ORR were then calculated. Of 83 potentially relevant studies, eight (three randomized studies and five retrospective studies) were identified (involving 1,193 patients) and included in this systematic review, with 640 patients receiving pem regimens. The weighted median PFS, median OS, and ORR for patients treated with pem regimens were 5.09 months, 15.91 months, and 30.19%, respectively. Our systematic review results showed a favorable efficacy profile of pem regimens in NSCLC patients with EGFR mutation after EGFR-TKI failure. PMID- 29695920 TI - Profile of apalutamide in the treatment of metastatic castration-resistant prostate cancer: evidence to date. AB - Advances in therapies have led to the approval of six therapeutic agents since 2004, each demonstrating overall survival benefit in randomized studies, and these have significantly improved the outlook for men facing metastatic castration-resistant prostate cancer (CRPC). More recently, efforts have been directed at trying to effect change at earlier phases of the disease. Apalutamide (ARN-509), a second-generation androgen receptor antagonist, recently received approval in the nonmetastatic (M0) CRPC space. Similar to enzalutamide, apalutamide inhibits the binding of androgen to androgen receptor (AR), nuclear translocation of the androgen-AR complex, and binding of AR transcription complex to DNA-binding sites and transcription elements. Phase I and II trial experience demonstrates the safety and tolerability of apalutamide, as well as its efficacy in effecting prostate-specific antigen response and radiographic-free survival in CRPC. US Food and Drug Administration approval in M0 CRPC was granted following positive results from the phase III SPARTAN study, where apalutamide demonstrated significant improvements in metastasis-free survival and time to symptomatic progression as compared to placebo. PMID- 29695922 TI - Characterization of enterotoxin A-producing Staphylococcus aureus. AB - Purpose: This study aims to characterize the wild-type staphylococcal enterotoxin A (SEA)-producing Staphylococcus aureus. Materials and methods: We identified 29 wild-type sea-positive S. aureus isolates from dairy and meat samples, as well as from patients, measured the amount of SEA produced under favorable cultivation conditions using enzyme-linked immunosorbent assay and sea mRNA transcriptional level and investigated the phage type as well as genetic diversity by means of pulsed-field gel electrophoresis and multilocus sequence typing. Results: Among 29 sea-positive isolates, 22 were from food sources (including one outbreak case) and seven from clinical patients. Five enterotoxin gene profiles, namely, sea (14 isolates), sea+sec (9 isolates), sea+seb (4 isolates), sea+seb+sec (1 isolate) and sea+seb+sed (1 isolate), were identified. Multilocus sequence typing generated sequence type (ST)1 (13 isolates), ST6 (5 isolates), ST59 (3 isolates), ST239 (3 isolates), ST5 (2 isolates), ST188 (2 isolate) and ST15 (1 isolate). The amount of SEA per 108 colony-forming unit (CFU) after 24 h of incubation was 1.1 33.5 (mean, 8.74; SD, 7.7) ng/108 CFU. The amount of SEA per hour incubation in the log growth phase was 0.1-12.0 (mean, 2.37; SD, 3.06) ng/108 CFU. Overall, 54.2% of SEA was produced in the log growth phase. Both the transcriptional level of sea mRNA and the amount of SEA in the log growth phase correlated well with the amount of SEA after 24 h of cultivation. Four isolates, namely, SA-212, SA 217, SA-340 and SA-341, were categorized to be of high SEA production (877-1,109 ng/mL, 24 h). The total amount of SEA was mainly based on the amount of SEA in 108 CFU, not the relatively fixed bacterial cell counts (21.1-43*108 CFU/mL). Seven isolates from patients all carried the FMu3A phage, whereas 21 of the 22 isolates from the environmental sources all carried the FSa3ms phage. Conclusion: The present study exhibits varied SEA production capacity of the wild sea positive S. aureus strains. An apparent boundary in phage types between strains from the clinical samples and strains from the environment was also identified. PMID- 29695921 TI - Understanding antibiotic resistance via outer membrane permeability. AB - Collective antibiotic drug resistance is a global threat, especially with respect to Gram-negative bacteria. The low permeability of the bacterial outer cell wall has been identified as a challenging barrier that prevents a sufficient antibiotic effect to be attained at low doses of the antibiotic. The Gram negative bacterial cell envelope comprises an outer membrane that delimits the periplasm from the exterior milieu. The crucial mechanisms of antibiotic entry via outer membrane includes general diffusion porins (Omps) responsible for hydrophilic antibiotics and lipid-mediated pathway for hydrophobic antibiotics. The protein and lipid arrangements of the outer membrane have had a strong impact on the understanding of bacteria and their resistance to many types of antibiotics. Thus, one of the current challenges is effective interpretation at the molecular basis of the outer membrane permeability. This review attempts to develop a state of knowledge pertinent to Omps and their effective role in solute influx. Moreover, it aims toward further understanding and exploration of prospects to improve our knowledge of physicochemical limitations that direct the translocation of antibiotics via bacterial outer membrane. PMID- 29695923 TI - Antibiotic sensitivities of coagulase-negative staphylococci and Staphylococcus aureus in hip and knee periprosthetic joint infections: does this differ if patients meet the International Consensus Meeting Criteria? AB - Introduction: Coagulase-negative staphylococci (CoNS) are the main pathogens responsible for prosthetic joint infections (PJIs). As normal inhabitants of human skin, it is often difficult to define if they are contaminants, or if they have an active role in initiating infection. This study aims to evaluate differences in CoNS organisms (Staphylococcus hominis, Staphylococcus capitis, Staphylococcus haemolyticus, Staphylococcus warneri) and Staphylococcus aureus in terms of isolation rate and antimicrobial susceptibility from patients who met the International Consensus Meeting (ICM) criteria for PJIs and those who did not. Methods: Staphylococci isolates from January 2014 to December 2015 retrieved from patients undergoing revision joint arthroplasty were classified in accordance with criteria established by the ICM of Philadelphia. Results: As per the consensus classification, 50 CoNS and 39 S. aureus infections were recognized as pathogens, while 16 CoNS and four S. aureus were considered as contaminants. Frequency of isolation of S. aureus was significantly higher in infected patients than in those without infection, while no significant differences were observed among CoNS. Resistance to levofloxacin, erythromycin, gentamicin trimethoprim/sulfamethoxazole, and rifampicin was significantly more frequent in S. haemolyticus than in the other species, as well as resistance to erythromycin and gentamicin in S. hominis. In comparison to S. aureus, CoNS were significantly more resistant to daptomycin and gentamicin and more susceptible to rifampicin. Conclusion: CoNS, other than Staphylococcus epidermidis, are frequently isolated from PJIs, and their infective role and antimicrobial susceptibility need to be assessed on an individual patient basis. S. haemolyticus seems to emerge as responsible for PJI in a large volume of patients, and its role needs to be further investigated, also considering its pattern of resistance. PMID- 29695924 TI - Cardiovascular effects of sodium glucose cotransporter 2 inhibitors. AB - As the first cardiovascular (CV) outcome trial of a glucose-lowering agent to demonstrate a reduction in the risk of CV events in patients with type 2 diabetes mellitus (T2DM), the EMPAgliflozin Removal of Excess Glucose: Cardiovascular OUTCOME Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME(r)) trial, which investigated the sodium glucose cotransporter 2 (SGLT2) inhibitor empagliflozin, has generated great interest among health care professionals. CV outcomes data for another SGLT2 inhibitor, canagliflozin, have been published recently in the CANagliflozin CardioVascular Assessment Study (CANVAS) Program, as have CV data from the retrospective real-world study Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors (CVD-REAL), which compared SGLT2 inhibitors with other classes of glucose-lowering drugs. This review discusses the results of these three studies and, with a focus on EMPA-REG OUTCOME, examines the possible mechanisms by which SGLT2 inhibitors may reduce CV risk in patients with T2DM. PMID- 29695925 TI - Primary IgA nephropathy: current challenges and future prospects. AB - IgA nephropathy (IgAN) is the most common form of primary glomerulonephritis worldwide, exhibiting a variable clinical and pathological course and significantly contributing to the global burden of chronic kidney disease and end stage renal disease. Current standards of care focus on optimization of antihypertensive and antiproteinuric therapies (typically renin- angiotensin system blockade) to reduce disease progression. Much recent attention has focused on whether additional immunosuppression confers better outcomes than supportive management alone, and indeed, several trials have demonstrated renoprotective effects following the use of oral corticosteroids. However, results have been inconsistent, and perceived benefits must be balanced against risks and adverse effects associated with generalized immunosuppression, as highlighted by the high profile STOP-IgAN and TESTING clinical trials. Recent translational research in vitro and animal models of IgAN have generated greater insight into potential therapeutic targets for this complex autoimmune disease. Deeper understanding of the roles of the mucosal immune barrier, complement activation and deposition, T cell dependent and independent mechanisms of B cell activation, and of the deposition and downstream inflammatory signaling pathways of nephritogenic polymeric IgA1 complexes (e.g., signaling of immune receptors via spleen tyrosine kinase) has formed the rationale for the development of novel agents and clinical trials of more targeted therapies. However, translating findings into clinical practice is challenging, with many immunopathological features of IgAN specific to humans. Recent comprehensive reviews outline current understanding of mechanisms of IgAN as well as ongoing and future clinical trials; it is not our aim to replicate this here. Instead, we take a mechanistic approach to current treatment strategies, outlining advantages and limitations of each before exploring ongoing research with potential translation into future targeted therapies for this complex disease. PMID- 29695926 TI - Pre-emptive multimodal analgesia with tramadol and ketamine-lidocaine infusion for suppression of central sensitization in a dog model of ovariohysterectomy. AB - Objectives: The effects of pre-emptive infusion of ketamine-lidocaine with tramadol on the suppression of central sensitization were investigated in a dog ovariohysterectomy model. Patients and methods: Twelve dogs were randomly assigned to two groups: ketamine-lidocaine-tramadol (KLT) and tramadol (T) groups. Both groups received intravenous tramadol 4 mg/kg body weight as premedication. Immediately after induction, the KLT group received ketamine and lidocaine at 0.5 and 2 mg/kg loading dose, followed by continuous rate infusion of 50 and 100 ug/kg/min, respectively, for 2 hours. Dogs in T group received saline bolus and continuous rate infusion at equi-volume. Intraoperatively, hemodynamic responses to surgical stimulation were recorded, whereas postoperative pain was evaluated using an algometer and short form of the Glasgow composite measure pain scale. Results: Intraoperatively, hemodynamic responses to surgical stimulation were obtunded to a greater degree in KLT compared to T group. Postoperatively, the pain scores increased only for the first hour in KLT group, compared to 12 hours in T group. Mechanical thresholds at the abdomen decreased postoperatively between 12 and 60 hours in KLT group versus the entire 72 hours in T group. Thresholds at tibia and radius in both groups increased in the immediate 1 hour postoperatively, but decreased thereafter. Significant decrement of thresholds from baseline were detected in the tibia at 24, 42, and 60 hours in KLT group compared to 24-72 hours in T group, and in the radius between 36 and 48 hours in T group, but none in KLT group. Conclusion: Addition of pre-emptive ketamine-lidocaine infusion to single intravenous dose of tramadol enhanced attenuation of central sensitization and improved intra- and postoperative analgesia. PMID- 29695927 TI - Non-Hispanic Black-White disparities in pain and pain management among newly admitted nursing home residents with cancer. AB - Background: Racial disparities in pain management persist across health care settings and likely extend into nursing homes. No recent studies have evaluated racial disparities in pain management among residents with cancer in nursing homes at time of admission. Methods: Using a cross-sectional study design, we compared reported pain and pain management between non-Hispanic White and non Hispanic Black newly admitted nursing home residents with cancer (n=342,920) using the de-identified Minimum Data Set version 3.0. Pain management strategies included the use of scheduled analgesics, pro re nata analgesics, and non pharmacological methods. Presence of pain was based on self-report when residents were able, and staff report when unable. Robust Poisson models provided estimates of adjusted prevalence ratios (aPR) and 95% CIs for reported pain and pain management strategies. Results: Among nursing home residents with cancer, ~60% reported pain with non-Hispanic Blacks less likely to have both self-reported pain (aPR [Black versus White]: 0.98, 95% CI: 0.97-0.99) and staff-reported pain (aPR: 0.89, 95% CI: 0.86-0.93) documentation compared with Non-Hispanic Whites. While most residents received some pharmacologic pain management, Blacks were less likely to receive any compared with Whites (Blacks: 66.6%, Whites: 71.1%; aPR: 0.98, 95% CI: 0.97-0.99), consistent with differences in receipt of non pharmacologic treatments (Blacks: 25.8%, Whites: 34.0%; aPR: 0.98, 95 CI%: 0.96 0.99). Conclusion: Less pain was reported for Black compared with White nursing home residents and White residents subsequently received more frequent pain management at admission. The extent to which unequal reporting and management of pain persists in nursing homes should be further explored. PMID- 29695928 TI - Association of expression of DRD2 rs1800497 polymorphism with migraine risk in Han Chinese individuals. AB - Background: Previous studies suggested that single-nucleotide polymorphisms in dopamine receptor D2 (DRD2) are the susceptibility loci for migraine. This study was aimed at evaluating the contribution of DRD2 rs1800497 and its expression to migraine risk in Han Chinese subjects. Methods: In total, 250 patients with migraine and 250 age- and sex-matched control subjects were included in this study. TaqMan allelic discrimination assay was used for DRD2 rs1800497 genotyping. Plasma DRD2 concentration was determined using enzyme-linked immunosorbent assay. Results: Significant associations were observed for the rs1800497 genotype (c2=6.37, p=0.041) and allele (c2=4.69, p=0.03; odds ratio [OR]=1.33, 95% CI=1.03-1.72, power=58%) frequencies between the migraine and control groups. Sex analysis indicated a positive association for rs1800497 between female patients with migraine and control individuals (genotype: c2=7.84, p=0.019; allele: c2=6.60, p=0.010; OR=1.61, 95% CI=1.12-2.30, power=73.4%). Furthermore, a significant association was observed only in female patients with migraine without aura (MO) (genotype: c2=6.88, p=0.032; allele: c2=5.65, p=0.017; OR=1.59, 95% CI=1.08-2.36, power=65.1%). The mean plasma DRD2 levels in the control group (mean+/-SD: 24.20+/-2.78) were significantly lower than those in the migraine with aura (MA) (30.86+/-3.69, p<0.0001) and MO groups (31.88+/-4.99, p<0.0001). Additionally, there was a sex-based difference in DRD2 expression in the MA (male vs female: 29.46+/-3.59 vs 32.27+/-3.27, p<0.01) and MO groups (male vs female: 29.18+/-3.50 vs 34.58+/-4.84, p<0.0001). Moreover, plasma DRD2 levels in patients were significantly different among the three genotypes (CC vs CT vs TT: 24.76+/-3.76 vs 30.93+/-3.85 vs 37.06+/-3.95, p<0.0001). Similar results were observed both in the MA (CC vs CT vs TT: 25.09+/-3.84 vs 28.57+/-2.84 vs 33.37+/ 1.58, p<0.0001) and MO groups (CC vs CT vs TT: 24.65+/-3.79 vs 31.65+/-3.86 vs 38.29+/-3.74, p<0.0001). Conclusion: Our case-control study suggested that the DRD2 polymorphism rs1800497 was significantly associated with the risk of migraine in Han Chinese females. Additionally, the plasma DRD2 level was high in patients with migraine. Females with migraine had considerably higher DRD2 levels than males with migraine. DRD2 expression may be regulated by DRD2 rs1800497 genotype in patients with migraine. PMID- 29695929 TI - Migraine attacks among medical students in Soochow University, Southeast China: a cross-sectional study. AB - Purpose: Migraine is one of the most common primary headache disorders and is burdensome to both the individual and society, influencing the academic performance and quality of daily lives of medical students worldwide. This study aimed to investigate the migraine prevalence in a sample of university medical students in China and to examine the features and typical trigger factors of migraine among these students. Patients and methods: From May 2016 to August 2016, a total of 1,060 medical students who were enrolled in Soochow University in Jiangsu Province in China were chosen through stratified random sampling. A self-administered questionnaire that included the ID MigraineTM for screening of migraine cases was used to collect data. The frequency, severity, duration of migraine attacks, and relevant trigger factors were measured for migraine cases. In total, 986 students completed the questionnaire. Results: The overall migraine prevalence among students was 7.91%, with 4.64% in male and 9.84% in female students. Junior-grade students had a higher migraine prevalence than senior students (prevalence of migraine of year 1 to year 5 undergraduates: 10.83%, 8.9% vs. 6.25%, 4.42%, 5.33%, P<0.05; prevalence of migraine of year 1 to year 3 graduates: 9.68%, 9.71% vs. 6.38%, P<0.05). Students with a positive family history were more likely to suffer migraine than those without (OR=8.48, 95% CI: 4.33-16.59). Stress (n=73, 93.59%), lack of sleep (n=72, 92.31%), and change of sleeping time (n=68, 87.18%) were the top three trigger factors among the students. Conclusion: Migraine was common among medical students from a university in China, and especially higher in female and junior-grade students, and those with a family history of migraine. Reducing stress and improving sleep quality might be effective to reduce migraine attacks in this population. PMID- 29695930 TI - Management of hemorrhage in gastrointestinal stromal tumors: a review. AB - Gastrointestinal stromal tumors (GISTs) are relatively common mesenchymal tumors. They originate from the wall of hollow viscera and may be found in any part of the digestive tract. The prognosis of patients with stromal tumors depends on various risk factors, including size, location, presence of mitotic figures, and tumor rupture. Emergency surgery is often required for stromal tumors with hemorrhage. The current literature suggests that stromal tumor hemorrhage indicates poor prognosis. Although the optimal treatment options for hemorrhagic GISTs are based on surgical experience, there remains controversy with regard to optimum postoperative management as well as the classification of malignant potential. This article reviews the biological characteristics, diagnostic features, prognostic factors, treatment, and postoperative management of GISTs with hemorrhage. PMID- 29695931 TI - The role of the pathology department in the preanalytical phase of molecular analyses. AB - After introducing the new molecules for the treatment of patients with tumoral pathology, the therapeutical decision will be taken depending on the molecular profile performed upon the harvested tissues. This major modification makes the molecular and morphological analysis an essential part in the clinical management of patients and the pathologist plays an important role in this process. The quality and reproducibility of the results are imperative today and they depend on both the reliability of the molecular techniques and the quality of the tissue we use in the process. Also, the genomics and proteomics techniques, used increasingly often, require high-quality tissues, and pathology laboratories play a very significant role in the management of all phases of this process. In this paper the parameters which must be followed in order to obtain optimal results within the techniques which analyze nucleic acids and proteins were reviewed. PMID- 29695932 TI - Quantitative assessment of the clinical susceptibility of calcium-sensing receptor polymorphisms in cancer patients. AB - Background: Accumulating evidence has suggested a relationship between calcium sensing receptor (CASR) polymorphisms and cancer risk in different types of cancer; however, the findings from epidemiologic studies have been conflicting. The purpose of this meta-analysis was to assess the clinical susceptibility of CASR polymorphisms in cancer patients. Materials and methods: This study systematically searched MEDLINE and EMBASE databases for eligible articles through March 2017. The strength of association was expressed as odds ratio and 95% CI. Publication bias, heterogeneity, sensitivity analysis, and subgroup analyses were also examined. Results: Fourteen related case-control studies were finally identified to be included in the present analysis. The pooled result showed that no significant associations were found among CASR rs1801725, rs1042636, rs12485716, rs4678174, rs1801726, rs17251221, rs10934578, and rs2270916 polymorphisms and cancer risk under all genetic models (P>0.05). The relationship between CASR rs1801725 polymorphism and risk of cancer was consistent in the subgroup analyses, and robust in sensitivity analysis. No publication bias was presented in our pooled-analysis. Conclusion: The current evidence for our pooled analysis suggests that the CASR polymorphisms are not associated with an increased risk of cancer. Further larger studies are still necessary to warrant and validate the findings in the current meta-analysis. PMID- 29695933 TI - Genetic variants in the nucleotide excision repair pathway genes and gastric cancer susceptibility in a southern Chinese population. AB - Background: Potentially functional polymorphisms can modulate protein activities and host's DNA repair capacity, thereby influencing cancer susceptibility. The association of the polymorphisms in the nucleotide excision repair core pathway genes and gastric cancer susceptibility remains largely unknown. Methods: Here, we systematically analyzed the associations between nine polymorphisms in four key genes (XPA, ERCC1, ERCC2, and ERCC4) in the nucleotide excision repair pathway and gastric cancer risk in a Chinese population including 1142 patients and 1173 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to estimate the risk associations. Results: We observed that ERCC1 rs2298881 CA variant genotype was associated with an increased gastric cancer risk (CA vs. CC: adjusted OR [AOR]=1.33, 95% CI=1.09-1.62; dominant model: AOR=1.32, 95% CI=1.10 1.60). However, ERCC1 rs3212986 AA variant genotype was identified as a protective factor for gastric cancer (AA vs. CC: AOR=0.73, 95% CI=0.54-0.98; recessive model: AOR=0.72, 95% CI=0.54-0.96). Genotype-based mRNA expression analysis further indicated that the rs2298881 A allele was associated with decreased ERCC1 mRNA expression. Conclusion: In all, these results indicated that the ERCC1 polymorphisms may affect the risk of gastric cancer in the Chinese Han population. PMID- 29695935 TI - The 2015 and 2016 terrorist attacks in France: was there a short-term impact on hospitalizations for cardiovascular disease? AB - Background: The terrorist attacks in Paris and Nice in 2015 and 2016 generated widespread emotional stress in France. Given that acute emotional stress is a well-known trigger for cardiovascular disease, we investigated whether these attacks had any short-term impact on hospitalizations for acute cardiovascular disease in France. Methods: Annual hospital discharge data from 2009 to 2016 were extracted from the French Hospital Discharge Database. All hospitalizations with a primary diagnosis of acute coronary syndrome, heart failure, or stroke were selected. Generalized additive Poisson models were used to differentiate "unusual" variations in daily hospitalization numbers in the 15 days following the attacks from the expected background hospitalization rate. Results: The average daily number of hospitalizations was 396.4 for acute coronary syndrome, 598.6 for heart failure, and 334.6 for stroke. The daily mean number of hospitalizations for heart failure and stroke was higher in the 15 days following each attack compared with the reference periods. However, multivariate analysis showed no significant variation in the risk of hospitalization in the days following the attacks. Interpretation: Watching events unfold on television, no matter how dramatic, was not a sufficiently potent trigger for cardiovascular disease, although it may have led to an increase in hospitalizations for stress or anxiety. The 2015 and 2016 terrorist attacks do not seem to have had any measurable short-term impact on hospitalizations for cardiovascular disease either in the Paris and Nice regions or in the rest of France. PMID- 29695934 TI - MicroRNA-142-3p is involved in regulation of MGMT expression in glioblastoma cells. AB - Background: Glioblastoma multiforme (GBM) is the most malignant brain tumor, and there is no effective treatment strategy. Patients with GBM have a median overall survival of only 14.6 months. Current treatment consists of safe and maximal surgical excision, followed by concurrent chemoradiotherapy and maintenance chemotherapy. There are several obstacles that hinder the effectiveness of this aggressive treatment. Temozolomide (TMZ) is an oral alkylating drug that acts through alkylating the O6 position of guanine in DNA that leads to cell death. However, the expression and enzymatic activity of the DNA repair protein MGMT limits the therapeutic benefit from treatment with TMZ. MGMT reduces the efficacy of alkylating drugs by removing the methyl or alkyl group from damaged O6 methylguanine. Expression levels of MGMT play an important role in the outcome of GBM patients. miRNAs are a group of small regulatory RNAs that control target gene expression by binding to mRNAs. miR-142-3p has been found to be an important factor in the development and maintenance of the oncogenic state. Results: In this study, we sought to investigate whether miR-142-3p can regulate MGMT gene expression in GBM cells. Here, we show that miR-142-3p downregulates MGMT expression through binding to the 3'-UTR of MGMT mRNA, thus affecting protein translation. Responsiveness to TMZ was significantly enhanced after transfection with miR-142-3p. Overexpression of miR-142-3p also sensitized GBM cells to alkylating drugs. Conclusion: Above all, our findings demonstrate that miR-142-3p plays a critical role in regulating MGMT expression, has great potential for future clinical applications, and acts as a new diagnostic marker for this intractable disease. PMID- 29695936 TI - Invasive meningococcal disease without meningitis: a forgotten diagnosis. AB - Neisseria meningitidis, a Gram-negative diplococcus, is an uncommon cause of pneumonia. There have been only about 344 cases reported worldwide from 1906 to 2015. To our knowledge, there have been only 3 cases reported in the USA in the past 2 decades. We present a case of a 72-year-old male with a past medical history of severe COPD, obstructive sleep apnea, and stage I lung cancer status post-stereotactic body radiation therapy 1 year ago, who was admitted with a 6 day history of productive cough with yellowish sputum, shortness of breath, extreme myalgias, and fatigue. Chest X-ray revealed an infiltrative process in the left lower lung field and left-sided pleural effusion. Blood cultures grew beta-lactamase-negative N. meningitidis after 24 hours. Our patient was initially treated with broad-spectrum antibiotics, which were later switched to amoxicillin to complete a total of 14 days of antibiotics. Diagnosing meningococcal pneumonia requires a high level of suspicion, as sputum cultures may be falsely positive due to asymptomatic carriage of the organism in the upper respiratory tract in up to 10% of outpatient population. We highlight this case as early recognition and treatment is critical. The case fatality rate for N. meningitidis pneumonia has been reported to be higher compared with meningococcal meningitis. PMID- 29695937 TI - Effect of mindfulness and yoga on quality of life for elementary school students and teachers: results of a randomized controlled school-based study. AB - Objective: To assess the impact of a yoga curriculum in an elementary school on student quality of life, and to assess teacher and staff perception of potential barriers to, and benefits of, introducing yoga and mindfulness into the classroom. Methods: A randomized controlled trial was utilized to assess the impact of a brief intervention on third-grade students who screened positive for symptoms of anxiety. Students were randomized to an intervention group of 20 students receiving small-group yoga/mindfulness activities for 8 weeks between October 2016 and February 2017, and a control group of 32 students receiving care as usual. The Brief Multidimensional Students' Life Satisfaction Scale-Peabody Treatment Progress Battery and the Pediatric Quality of Life Inventory (PedsQL) served as outcomes. Teachers were invited to participate in two professional development sessions about introducing yoga and mindfulness into the classroom, and completed a survey following each of the sessions. Results: In generalized estimating equation models adjusted for time, the yoga-based intervention was associated with a 14.17 unit increase in student emotional PedsQL (p-value 0.001) and a 7.43 unit increase in psychosocial PedsQL (p-value 0.01). Results were not attenuated by adjustment. Teachers and staff reported using yoga more frequently in the classroom following the second of two professional development sessions (p value <0.05). Perceived barriers to introducing yoga to the classroom were similar at two data collection time points, while perceived benefits remained high. Conclusion: The intervention was associated with a significant improvement in emotional and psychosocial quality of life in the intervention group when compared to the control group, suggesting that yoga/mindfulness interventions may improve symptoms of anxiety among students. Yoga/mindfulness activities may facilitate stress management among elementary school students and may be added as a complement to social and emotional learning activities. PMID- 29695938 TI - Association between a parent's brand passion and a child's brand passion: a moderated moderated-mediation model. AB - Purpose: Both marketing scholars and brand managers have noted the importance of brand passion. They have increasingly emphasized how brand passion influences consumers' psychological states and behaviors. In contrast, an almost negligible effort has been made to study whether the individual's brand passion can be transferred to others. Methods: Using consumer socialization theory and emotional contagion theory as a lens, this study explores whether airline brand passion can be transferred from a parent to a child. To this end, a convenience sample of (N = 202) parent-child dyads was utilized to test the moderated moderated-mediation hypotheses. Results: The results provide evidence that parents' airline passion can be translated into the child's airline passion via emotional contagion for daughters who live with their parents but not those who live independently of their parents. Similarly, parents' airline passion can be transferred to sons regardless of their geographical distance. The implications, limitations, and agendas for future research are discussed in depth. PMID- 29695939 TI - Effectiveness of school- and family-based interventions to prevent gaming addiction among grades 4-5 students in Bangkok, Thailand. AB - Purpose: This study aimed to assess the effectiveness of Participatory Learning School and Family Based Intervention Program for Preventing Game Addiction by Developing Self-Regulation of gaming addiction among students of grades 4 and 5 in Bangkok. Methods: A quasi-experimental study was implemented among students of grades 4 and 5 at primary schools in Bangkok selected through multistage random sampling. Two comparable schools were randomly assigned to either the intervention or control group. Then, 310 students in the randomly selected classrooms were allocated to each group. The intervention group received the self regulation program with school and family involvement to prevent gaming addiction. Master teachers attended in-house training on prevention of gaming addiction in children. Parents of these children received a gaming addiction prevention manual and guidelines. The program lasted 8 weeks. The control group received no intervention. Knowledge and Attitude About Gaming Questionnaire, Game Addiction Screening Test (GAST), and Game Addiction Protection Scale were utilized to assess subjects at baseline, immediately after, and 3 months post intervention. Descriptive statistics, chi-square, and independent t-test were used to describe characteristics of the participants, and repeated measures ANOVA was analyzed to test the effectiveness of the intervention. Results: The findings revealed that there were significant differences in knowledge, attitude, self regulation, and gaming addiction behaviors (p < 0.05) immediately and 3 months post-intervention. Positive effects of the intervention included increase in knowledge, attitude, and self-regulation, whereas the GAST score was significantly decreased (p < 0.05) immediately and 3 months after the program. Conclusion: The program based on self-regulation and school and family participation is effective for preventing gaming addiction in students of grades 4 and 5 in Bangkok, Thailand. PMID- 29695940 TI - Camus's L'etranger and the first description of a man with Asperger's syndrome. AB - The continued discussion about the meaning of Camus's famous novel, L'etranger, provoked a re-reading, and this, in turn, led to its clinical analysis and further investigation. The book rests entirely on the thoughts, words and actions of its central character, Meursault, and these were found to show impairment of social relationships, communication and interaction, with other traits diagnostic of the Asperger's subgroup of the autism spectrum disorder. It was then found that Camus had based Meursault on his close friend Galindo, and a search was therefore made for evidence of Galindo's character; this revealed him to be an intelligent but odd person, who exhibited the characteristic impairment of social and personal behavior of Asperger's syndrome. Thus, Camus had recognized and understood his friend's strange behavior before Asperger's syndrome had been defined; his use of it for the creation of Meursault is therefore the first published account of a man with this disorder. Many of the interpretations and ideas developed from Meursault's words, thoughts and actions must now be reconsidered, as they are a misreading of the words and behavior of a man with Asperger's syndrome. The outcome of this clinical examination of L'etranger is unique; it shows that a precise account of a person with a neurobehavioral disorder was made by a novelist before the disorder had been clinically defined. PMID- 29695941 TI - A naturalistic study on the relationship among resilient factors, psychiatric symptoms, and psychosocial functioning in a sample of residential patients with psychosis. AB - Objective: Resilience is a multidimensional process of adaptation aimed to overcome stressful or traumatic life experiences; only in the last few years it has been considered as a personal resource in psychosis and schizophrenia. This study aimed to assess the relationship between intrapersonal and interpersonal resilience factors and schizophrenia, particularly whether and how resilience can improve the course of psychotic illness. Patients and methods: In this observational study, all patients recruited had to fulfill the following inclusion criteria: diagnosis of schizophrenia spectrum disorder (Diagnostic and Statistical Manual of Mental Disorders-5); aged between 18 and 65 years; provided written informed consent; to be clinically stable (Clinical Global Impression Scale <3); history of illness >=5 years; to be compliant with antipsychotic therapy over the last year; and regular submission to periodic monthly psychiatric visits. Patients were evaluated through the following scales: Resilience Scale for Adults (RSA) for resilience; Brief Psychiatric Rating Scale Anchored version (BPRS-A), Scale for the Assessment of Negative Symptoms (SANS), and Scale for the Assessment of Positive Symptoms (SAPS) for psychotic symptomatology; and Life Skills Profile (LSP) for psychosocial functioning. Statistical analysis was performed by SPSS. Partial correlations were evaluated to assess the relationship between RSA total scores and subscores and BPRS-A, SANS, SAPS, and LSP total scores, removing the common variance among variables. Then, a series of hierarchical multiple linear regression models were used to examine the association between resilience, psychopathology, and psychosocial functioning. Results: A statistically significant negative correlation among intrapersonal resilience factors and BPRS-A total score emerged, predicting psychiatric symptoms severity and explaining approximately 31% of the BPRS-A variance; otherwise, only the interpersonal resilience factors associated with social support were statistically and positively correlated with LSP total score, predicting psychosocial functioning and explaining the 11% of LSP variance. Conclusion: The specific contribution that resilience factors may have in predicting the severity of symptoms and the extent of psychosocial functioning emphasizes the importance of personalizing treatment for patients affected by schizophrenia, promoting personal resources, and translating them into better outcomes. PMID- 29695942 TI - Genotype-phenotype correlation among beta-thalassemia and beta-thalassemia/HbE disease in Thai children: predictable clinical spectrum using genotypic analysis. AB - Introduction: Beta-thalassemia is a group of inherited hemolytic anemias and one of the most common genetic disorders in Thailand. The clinical spectrum of beta thalassemia disease ranges from mild to severe clinical symptoms including mild beta-thalassemia intermedia (TI) and severe beta-thalassemia major (TM). Objective: This study aimed to determine the correlation between beta-globin gene (HBB) mutations and their phenotypic manifestations by evaluating patients' clinical characteristics, transfusion requirements, growth and hematologic parameters, and hemoglobin typing among pediatric patients treated at Phramongkutklao Hospital. Materials and methods: Seventy beta-thalassemia patients, including 63 with beta-thalassemia/hemoglobin E (HbE) and 7 with either homozygous or compound heterozygous beta-thalassemia, were enrolled in this study. Their clinical presentation, growth parameters and laboratory findings were reviewed and analyzed. The mean follow-up time was 10.52+/-5.62 years. Mutation analysis in each individual was performed using multiplex amplification refractory mutation system (M-ARMS), direct DNA sequencing of beta-globin gene and gap PCR for 3.4 kb deletion detection. Results: All 7 homozygous and compound heterozygous beta-thalassemia patients were classified in TM. Among 63 patients with beta-thalassemia/HbE, 58 were classified in TM and 4 were classified in TI. Mean age at diagnosis was 0.8+/-0.49 years for homozygous or compound heterozygous beta-thalassemia and 3.43+/-3.5 years for beta-thalassemia/HbE. The most common HBB mutation was HBB:c.126_129delCTTT [codon 41/42 (-TCTT)] found in 34 alleles (48.6%). The height for age was also lower in homozygous beta thalassemia patients (<3rd percentile) compared to compound heterozygous beta thalassemia patients (25-50th percentile). Conclusion: This study revealed a genotype-phenotype correlation of the most prevalent beta-thalassemia in Thai children using diagnostic capacity in genotypic analysis of HBB mutation. Our findings can provide a better prediction of clinical manifestation and severity by early identification of the type of the HBB mutations. PMID- 29695943 TI - Bosutinib in chronic myeloid leukemia: patient selection and perspectives. AB - During recent years, the therapeutic landscape in chronic myeloid leukemia (CML) has changed significantly. Since the clinical introduction of tyrosine kinase inhibitors (TKIs) approximately 15 years ago, patients' concerns have shifted from reduced life expectancy toward long-term toxicities of TKI, depth of remission, and the probability of successful treatment discontinuation. Patients with newly diagnosed CML in chronic phase (at least with a Sokal score not exceeding intermediate) may now expect an almost normal life expectancy. However, even if almost 30% of all newly diagnosed chronic-phase patients might eventually be facing the prospect of a life without CML-specific treatment, based on current knowledge, most, if not all, patients would have to undergo an expected minimum of 5-8 years of TKI treatment and the majority would face a life-long exposure to the side-effects of TKIs. At present, 5 different TKIs are licensed for the treatment of CML, that is, imatinib, which is a first-generation TKI (including its generic derivatives); nilotinib, dasatinib, and bosutinib, which are second generation TKIs; as well as ponatinib, which is a so-called third-generation TKI and is supposed to be used for patients harboring the T315I-mutation. One of the important, yet unanswered questions is the choice of the best possible TKI upfront for each individual patient. Bosutinib is currently licensed for patients with CML after failure or intolerance of at least 2 other TKIs. It can also be prescribed according to label if after failure of the first TKI therapy, another option does not seem feasible. This review focuses on the existing data on clinical efficacy, tolerability, and side effects of bosutinib treatment in CML patients with the aim to identify patient characteristics and treatment scenarios most suitable for treatment with bosutinib. PMID- 29695944 TI - Multiple mini-interview as a predictor of performance in the objective structured clinical examination among Physician Associates in the United Kingdom: a cohort study. AB - Introduction: Patient satisfaction and health care outcomes are directly linked to useful communication skills. Therefore, excellent interpersonal skills are imperative for health care professionals. Multiple mini-interview (MMI) is designed as a selection tool to assess the communication skills of applicants in medical schools during the admission process. However, objective structured clinical examination (OSCE) assesses students' communication and clinical skills at the end of their academic terms. Recently, Anglia Ruskin University, Chelmsford, UK, adopted MMI in the selection process for the first cohort of MSc Physician Associate trainees for the academic year 2015-2016. This study aimed to determine the likelihood of MMI as a predictor of future performance of communication skills in the OSCE. Materials and methods: The anonymous data of the average scores of communication skills attained in MMI and OSCE at the end of year 1 were collected for 30 students from the Physician Associate program team. Subsequently, Pearson's correlation was computed to determine the relationship between the average scores of communication skills attained in MMI, and OSCE during trimester 2 and trimester 3 by the Physician Associate trainees. Results: The study showed positive correlation between the scores of communication skills attained in MMI and OSCE during trimester 2 (r=0.956, n=30, p<0.001) and trimester 3 (r=0.966, n=30, p<0.001). Conclusion: The study provides empirical evidence for the validity of MMI as a predictor of future performance of Physician Associate trainees' communication skills during subsequent OSCEs. PMID- 29695945 TI - Thinking About Denial. AB - This essay considers the frequent and varied uses of 'denial' in modern political discourse, suggests the specific psychoanalytic meanings the term has acquired and asks how useful this Freudian concept may be for historians. It notes the debates among historians over the uses of psychoanalysis, but argues that concepts such as 'denial', 'disavowal', 'splitting' and 'negation' can help us to understand both individual and group behaviour. The authors dwell, especially, on 'disavowal' and argue it can provide a particularly useful basis for exploring how and why states of knowing and not knowing co-exist. Historical examples are utilized to explore these states of mind: most briefly, a fragment from a report about the war criminals, produced by an American psychiatrist at the Nuremberg Trial; at greater length, the political arguments and historical writings of an eighteenth-century slave-owner; and finally, a case in a borough of London in the late-twentieth-century, where the neglect, abuse and murder of a child was shockingly 'missed' by a succession of social agencies and individuals, who had evidence of the violence available to them. PMID- 29695946 TI - The Romani Minority, Coercive Sterilization, and Languages of Denial in the Czech Lands. AB - Sterilizations of Romani women in socialist Czechoslovakia, either carried out without proper consent, or coerced through substantial financial incentive, were first reported in 1978. Yet these practices did not end with the fall of communism, and it took until 2005 for this to be officially acknowledged by the Czech government. This article draws on published and unpublished documents, as well as oral history interviews, to trace the history of efforts to expose such practices, 'come to terms' with their existence, and change social attitudes in relation to the Romani minority in the Czech lands. These exposures have uncovered instances of denial, and have also offered up a variety of ways of understanding the mental and social mechanisms that might have enabled silences, refusals or disavowals with regard to human rights abuses. Under Communism, dissidents associated with Charter 77 elaborated these through the philosophical concepts of phenomenology; after the transition to democracy, a more psychological and therapeutic language came to the fore. I argue that the Czech case suggests that the historiography of denial and disavowal could be enriched by looking beyond the framework of psychoanalysis: by taking into account how historical actors, sometimes with opposing worldviews, have comprehended these processes within the languages of their own culture and period. PMID- 29695947 TI - New Probabilistic Multi-Graph Decomposition Model to Identify Consistent Human Brain Network Modules. AB - Many recent scientific efforts have been devoted to constructing the human connectome using Diffusion Tensor Imaging (DTI) data for understanding large scale brain networks that underlie higher-level cognition in human. However, suitable network analysis computational tools are still lacking in human brain connectivity research. To address this problem, we propose a novel probabilistic multi-graph decomposition model to identify consistent network modules from the brain connectivity networks of the studied subjects. At first, we propose a new probabilistic graph decomposition model to address the high computational complexity issue in existing stochastic block models. After that, we further extend our new probabilistic graph decomposition model for multiple networks/graphs to identify the shared modules cross multiple brain networks by simultaneously incorporating multiple networks and predicting the hidden block state variables. We also derive an efficient optimization algorithm to solve the proposed objective and estimate the model parameters. We validate our method by analyzing both the weighted fiber connectivity networks constructed from DTI images and the standard human face image clustering benchmark data sets. The promising empirical results demonstrate the superior performance of our proposed method. PMID- 29695948 TI - Event-Based Color Segmentation With a High Dynamic Range Sensor. AB - This paper introduces a color asynchronous neuromorphic event-based camera and a methodology to process color output from the device to perform color segmentation and tracking at the native temporal resolution of the sensor (down to one microsecond). Our color vision sensor prototype is a combination of three Asynchronous Time-based Image Sensors, sensitive to absolute color information. We devise a color processing algorithm leveraging this information. It is designed to be computationally cheap, thus showing how low level processing benefits from asynchronous acquisition and high temporal resolution data. The resulting color segmentation and tracking performance is assessed both with an indoor controlled scene and two outdoor uncontrolled scenes. The tracking's mean error to the ground truth for the objects of the outdoor scenes ranges from two to twenty pixels. PMID- 29695949 TI - Quantifying Motor Impairment in Movement Disorders. AB - Until recently the assessment of many movement disorders has relied on clinical rating scales that despite careful design are inherently subjective and non linear. This makes accurate and truly observer-independent quantification difficult and limits the use of sensitive parametric statistical methods. At last, devices capable of measuring neurological problems quantitatively are becoming readily available. Examples include the use of oculometers to measure eye movements and accelerometers to measure tremor. Many applications are being developed for use on smartphones. The benefits include not just more accurate disease quantification, but also consistency of data for longitudinal studies, accurate stratification of patients for entry into trials, and the possibility of automated data capture for remote follow-up. In this mini review, we will look at movement disorders with a particular focus on Parkinson's disease, describe some of the limitations of existing clinical evaluation tools, and illustrate the ways in which objective metrics have already been successful. PMID- 29695950 TI - Both Hypo-Connectivity and Hyper-Connectivity of the Insular Subregions Associated With Severity in Children With Autism Spectrum Disorders. AB - Some studies identified hypo-connectivity, while others showed hyper-connectivity of the insula in the autism spectrum disorders (ASD). These contradictory findings leave open the question of whether and to what extent functional connectivity of the insula is altered and how functional connectivity of the insula is associated with the severity of ASD. A newly emerging insular atlas that comprises multiple functionally differentiated subregions provides a new framework to interpret the functional significance of insular findings and uncover the mechanisms underlying the severity of ASD. Using the new insular atlas, the present study aimed to investigate the distinct functional connectivity of the insular subregions and their associations with ASD severity in a cohort of 49 children with ASD and 33 typically developing (TD) subjects. We found that compared with TD group, the ASD group showed different connectivity patterns in the left ventral agranular insula, right ventral dysgranular and granular insula, and dorsal dysgranular insula, characterized by significant hyper-connectivity and/or hypo-connectivity with special brain regions. Furthermore, both the hypo-connectivity and hyper-connectivity patterns of the insular subregions were significantly associated with the severity of ASD symptoms. Our research demonstrated distinct functional connectivity patterns of the insular subregions and emphasized the importance of the subdivisions within the insula to the potential impact of functional difference in children with ASD. Moreover, these results might help us to better understand the mechanisms underlying the symptoms in children with ASD and might elucidate potential biomarkers for clinical applications. PMID- 29695951 TI - Dynamic Neural State Identification in Deep Brain Local Field Potentials of Neuropathic Pain. AB - In neuropathic pain, the neurophysiological and neuropathological function of the ventro-posterolateral nucleus of the thalamus (VPL) and the periventricular gray/periaqueductal gray area (PVAG) involves multiple frequency oscillations. Moreover, oscillations related to pain perception and modulation change dynamically over time. Fluctuations in these neural oscillations reflect the dynamic neural states of the nucleus. In this study, an approach to classifying the synchronization level was developed to dynamically identify the neural states. An oscillation extraction model based on windowed wavelet packet transform was designed to characterize the activity level of oscillations. The wavelet packet coefficients sparsely represented the activity level of theta and alpha oscillations in local field potentials (LFPs). Then, a state discrimination model was designed to calculate an adaptive threshold to determine the activity level of oscillations. Finally, the neural state was represented by the activity levels of both theta and alpha oscillations. The relationship between neural states and pain relief was further evaluated. The performance of the state identification approach achieved sensitivity and specificity beyond 80% in simulation signals. Neural states of the PVAG and VPL were dynamically identified from LFPs of neuropathic pain patients. The occurrence of neural states based on theta and alpha oscillations were correlated to the degree of pain relief by deep brain stimulation. In the PVAG LFPs, the occurrence of the state with high activity levels of theta oscillations independent of alpha and the state with low level alpha and high-level theta oscillations were significantly correlated with pain relief by deep brain stimulation. This study provides a reliable approach to identifying the dynamic neural states in LFPs with a low signal-to-noise ratio by using sparse representation based on wavelet packet transform. Furthermore, it may advance closed-loop deep brain stimulation based on neural states integrating multiple neural oscillations. PMID- 29695952 TI - Physiological Processes Underlying Short Interval Intracortical Facilitation in the Human Motor Cortex. AB - Short interval intracortical facilitation (SICF) may be elicited by a paired pulse transcranial magnetic stimulation (TMS) paradigm, whereby a suprathreshold first stimulus (S1) precedes a perithreshold second stimulus (S2). Other facilitatory circuits can be probed by TMS such as intracranial facilitation, however the cortical contributions to these circuits may lie partially outside of M1. SICF as such represents a unique analog to M1 inhibitory circuits such as short interveal intracortical circuits. The aim of the present study was to provide insight into the physiological processes underlying the development of SICF using the threshold tracking TMS technique which was recently demonstrated to have significant reliability. TMS studies were undertaken on 35 healthy controls, using either a 90 mm circular and 70 mm figure of eight coil, and one of two targets (0.2 and 1.0 mV) tracked. The motor evoked potential (MEP) responses were recorded from the abductor pollicis brevis. SICF was consistently evident between interstimulus intervals (ISI) of 1-5 ms (P < 0.001), with two peaks occurring ISIs 1.5 and 3 ms when using the circular coil. A significant SICF reduction (F = 5.631, P < 0.05) was evident with the higher tracking target, while SICF increased when stimulating with the figure of eight coil. While there was a correlation between SICF and CSP duration, there was no relationship between SICF and SICI or ICF. Age appeared to have no influence on SICF, SICI, or ICF. Findings from the present work suggest that SICF appears to be mediated by I wave facilitation. PMID- 29695953 TI - Autoimmune Neurological Conditions Associated With Zika Virus Infection. AB - Zika virus (ZIKV) is an emerging flavivirus rapidly spreading throughout the tropical Americas. Aedes mosquitoes is the principal way of transmission of the virus to humans. ZIKV can be spread by transplacental, perinatal, and body fluids. ZIKV infection is often asymptomatic and those with symptoms present minor illness after 3 to 12 days of incubation, characterized by a mild and self limiting disease with low-grade fever, conjunctivitis, widespread pruritic maculopapular rash, arthralgia and myalgia. ZIKV has been linked to a number of central and peripheral nervous system injuries such as Guillain-Barre syndrome (GBS), transverse myelitis (TM), meningoencephalitis, ophthalmological manifestations, and other neurological complications. Nevertheless, mechanisms of host-pathogen neuro-immune interactions remain incompletely elucidated. This review provides a critical discussion about the possible mechanisms underlying the development of autoimmune neurological conditions associated with Zika virus infection. PMID- 29695954 TI - Connexin-Mediated Functional and Metabolic Coupling Between Astrocytes and Neurons. AB - The central nervous system (CNS) requires sophisticated regulation of neuronal activity. This modulation is partly accomplished by non-neuronal cells, characterized by the presence of transmembrane gap junctions (GJs) and hemichannels (HCs). This allows small molecule diffusion to guarantee neuronal synaptic activity and plasticity. Astrocytes are metabolically and functionally coupled to neurons by the uptake, binding and recycling of neurotransmitters. In addition, astrocytes release metabolites, such as glutamate, glutamine, D-serine, adenosine triphosphate (ATP) and lactate, regulating synaptic activity and plasticity by pre- and postsynaptic mechanisms. Uncoupling neuroglial communication leads to alterations in synaptic transmission that can be detrimental to neuronal circuit function and behavior. Therefore, understanding the pathways and mechanisms involved in this intercellular communication is fundamental for the search of new targets that can be used for several neurological disease treatments. This review will focus on molecular mechanisms mediating physiological and pathological coupling between astrocytes and neurons through GJs and HCs. PMID- 29695955 TI - GLYX-13 Ameliorates Schizophrenia-Like Phenotype Induced by MK-801 in Mice: Role of Hippocampal NR2B and DISC1. AB - Background: Evidence supports that the hypofunction of N-methyl-D-aspartate receptor (NMDAR) and downregulation of disrupted-in-schizophrenia 1 (DISC1) contribute to the pathophysiology of schizophrenia. N-Methyl D-aspartate receptor subtype 2B (NR2B)-containing NMDAR are associated with cognitive dysfunction in schizophrenia. GLYX-13 is an NMDAR glycine-site functional partial agonist and cognitive enhancer that does not induce psychotomimetic side effects. However, it remains unclear whether NR2B plays a critical role in the GLYX-13-induced alleviation of schizophrenia-like behaviors in mice. Methods: The effect of GLYX 13 was tested by observing changes in locomotor activity, novel object recognition ability, and prepulse inhibition (PPI) induced by dizocilpine (known as MK-801) in mice. Lentivirus-mediated NR2B knockdown in the hippocampus was assessed to confirm the role of NR2B in GLYX-13 pathophysiology, using Western blots and immunohistochemistry. Results: The systemic administration of GLYX-13 (0.5 and 1 mg/kg, i.p.) ameliorates MK-801 (0.5 mg/kg, i.p.)-induced hyperlocomotion, deficits in memory, and PPI in mice. Additionally, GLYX-13 normalized the MK-801-induced alterations in signaling molecules, including NR2B and DISC1 in the hippocampus. Furthermore, we found that NR2B knockdown produced memory and PPI deficits without any changes in locomotor activity. Notably, DISC1 levels significantly decreased by NR2B knockdown. However, the effective dose of GLYX-13 did not alleviate the memory and PPI dysfunctions or downregulation of DISC1 induced by NR2B knockdown. Conclusion: Our results suggest GLYX-13 as a candidate for schizophrenia treatment, and NR2B and DISC1 in the hippocampus may account for the molecular mechanisms of GLYX-13. PMID- 29695957 TI - Can Embodied Contemplative Practices Accelerate Resilience Training and Trauma Recovery? PMID- 29695958 TI - Action Choice and Outcome Congruency Independently Affect Intentional Binding and Feeling of Control Judgments. AB - Sense of agency (SoA) refers to the subjective experience that one is in control of their actions and the consequences of these actions. The SoA is a complex phenomenon, influenced by a weighted combination of various prospective (pre movement) and retrospective (post-movement) processes and factors related to action choice, action selection fluency, action-outcome associations and higher level inferences. In the current study, we examined the effect of the congruency between actions and outcomes in a context where the choice-level of actions was varied from 1 to 4. The actions consisted of right, left, up and down key presses while the outcomes were visual representations of the actions (i.e., right, left, up and down-pointing arrowheads). Participants performed either an instructed action or freely selected an action among two, three, or four alternatives. Each action randomly produced either a congruent or an incongruent outcome, depending on the matching between the direction of the key press and the direction of the outcome arrowhead. Participants estimated the delay between their actions and the observed outcomes and reported their feeling of control (FoC) over the outcomes. Interval estimations were used as an indirect measure of the SoA to quantify the intentional binding effect, which refers to the perceived temporal attraction between voluntary actions and their outcomes. The results showed that both intentional binding and FoC were enhanced as the choice-level was increased from 1 to 4. Additionally, intentional binding and FoC over the outcomes were stronger when actions produced congruent compared to incongruent outcomes. These results provide additional evidence that both intentional binding and FoC are sensitive to the number of action alternatives and the congruency between actions and their outcomes. Importantly, the current study suggests that these prospective and retrospective cues might independently influence intentional binding and FoC judgments. PMID- 29695956 TI - Interfacing Graphene-Based Materials With Neural Cells. AB - The scientific community has witnessed an exponential increase in the applications of graphene and graphene-based materials in a wide range of fields, from engineering to electronics to biotechnologies and biomedical applications. For what concerns neuroscience, the interest raised by these materials is two fold. On one side, nanosheets made of graphene or graphene derivatives (graphene oxide, or its reduced form) can be used as carriers for drug delivery. Here, an important aspect is to evaluate their toxicity, which strongly depends on flake composition, chemical functionalization and dimensions. On the other side, graphene can be exploited as a substrate for tissue engineering. In this case, conductivity is probably the most relevant amongst the various properties of the different graphene materials, as it may allow to instruct and interrogate neural networks, as well as to drive neural growth and differentiation, which holds a great potential in regenerative medicine. In this review, we try to give a comprehensive view of the accomplishments and new challenges of the field, as well as which in our view are the most exciting directions to take in the immediate future. These include the need to engineer multifunctional nanoparticles (NPs) able to cross the blood-brain-barrier to reach neural cells, and to achieve on-demand delivery of specific drugs. We describe the state-of-the art in the use of graphene materials to engineer three-dimensional scaffolds to drive neuronal growth and regeneration in vivo, and the possibility of using graphene as a component of hybrid composites/multi-layer organic electronics devices. Last but not least, we address the need of an accurate theoretical modeling of the interface between graphene and biological material, by modeling the interaction of graphene with proteins and cell membranes at the nanoscale, and describing the physical mechanism(s) of charge transfer by which the various graphene materials can influence the excitability and physiology of neural cells. PMID- 29695959 TI - PyMUS: Python-Based Simulation Software for Virtual Experiments on Motor Unit System. AB - We constructed a physiologically plausible computationally efficient model of a motor unit and developed simulation software that allows for integrative investigations of the input-output processing in the motor unit system. The model motor unit was first built by coupling the motoneuron model and muscle unit model to a simplified axon model. To build the motoneuron model, we used a recently reported two-compartment modeling approach that accurately captures the key cell type-related electrical properties under both passive conditions (somatic input resistance, membrane time constant, and signal attenuation properties between the soma and the dendrites) and active conditions (rheobase current and afterhyperpolarization duration at the soma and plateau behavior at the dendrites). To construct the muscle unit, we used a recently developed muscle modeling approach that reflects the experimentally identified dependencies of muscle activation dynamics on isometric, isokinetic and dynamic variation in muscle length over a full range of stimulation frequencies. Then, we designed the simulation software based on the object-oriented programing paradigm and developed the software using open-source Python language to be fully operational using graphical user interfaces. Using the developed software, separate simulations could be performed for a single motoneuron, muscle unit and motor unit under a wide range of experimental input protocols, and a hierarchical analysis could be performed from a single channel to the entire system behavior. Our model motor unit and simulation software may represent efficient tools not only for researchers studying the neural control of force production from a cellular perspective but also for instructors and students in motor physiology classroom settings. PMID- 29695960 TI - Memory Synapses Are Defined by Distinct Molecular Complexes: A Proposal. AB - Synapses are diverse in form and function. While there are strong evidential and theoretical reasons for believing that memories are stored at synapses, the concept of a specialized "memory synapse" is rarely discussed. Here, we review the evidence that memories are stored at the synapse and consider the opposing possibilities. We argue that if memories are stored in an active fashion at synapses, then these memory synapses must have distinct molecular complexes that distinguish them from other synapses. In particular, examples from Aplysia sensory-motor neuron synapses and synapses on defined engram neurons in rodent models are discussed. Specific hypotheses for molecular complexes that define memory synapses are presented, including persistently active kinases, transmitter receptor complexes and trans-synaptic adhesion proteins. PMID- 29695961 TI - Altered Functional Connectivity of Insular Subregions in Alzheimer's Disease. AB - Recent researches have demonstrated that the insula is the crucial hub of the human brain networks and most vulnerable region of Alzheimer's disease (AD). However, little is known about the changes of functional connectivity of insular subregions in the AD patients. In this study, we collected resting-state functional magnetic resonance imaging (fMRI) data including 32 AD patients and 38 healthy controls (HCs). By defining three subregions of insula, we mapped whole brain resting-state functional connectivity (RSFC) and identified several distinct RSFC patterns of the insular subregions: For positive connectivity, three cognitive-related RSFC patterns were identified within insula that suggest anterior-to-posterior functional subdivisions: (1) an dorsal anterior zone of the insula that exhibits RSFC with executive control network (ECN); (2) a ventral anterior zone of insula, exhibits functional connectivity with the salience network (SN); (3) a posterior zone along the insula exhibits functional connectivity with the sensorimotor network (SMN). In addition, we found significant negative connectivities between the each insular subregion and several special default mode network (DMN) regions. Compared with controls, the AD patients demonstrated distinct disruption of positive RSFCs in the different network (ECN and SMN), suggesting the impairment of the functional integrity. There were no differences of the positive RSFCs in the SN between the two groups. On the other hand, several DMN regions showed increased negative RSFCs to the sub region of insula in the AD patients, indicating compensatory plasticity. Furthermore, these abnormal insular subregions RSFCs are closely correlated with cognitive performances in the AD patients. Our findings suggested that different insular subregions presented distinct RSFC patterns with various functional networks, which are differently affected in the AD patients. PMID- 29695962 TI - Inhibition of NMDA Receptors Prevents the Loss of BDNF Function Induced by Amyloid beta. AB - Brain-derived neurotrophic factor (BDNF) plays important functions in cell survival and differentiation, neuronal outgrowth and plasticity. In Alzheimer's disease (AD), BDNF signaling is known to be impaired, partially because amyloid beta (Abeta) induces truncation of BDNF main receptor, TrkB-full length (TrkB FL). We have previously shown that such truncation is mediated by calpains, results in the formation of an intracellular domain (ICD) fragment and causes BDNF loss of function. Since calpains are Ca2+-dependent proteases, we hypothesized that excessive intracellular Ca2+ build-up could be due to dysfunctional N-methyl-d-aspartate receptors (NMDARs) activation. To experimentally address this hypothesis, we investigated whether TrkB-FL truncation by calpains and consequent BDNF loss of function could be prevented by NMDAR blockade. We herein demonstrate that a NMDAR antagonist, memantine, prevented excessive calpain activation and TrkB-FL truncation induced by Abeta25 35. When calpains were inhibited by calpastatin, BDNF was able to increase the dendritic spine density of neurons exposed to Abeta25135. Moreover, NMDAR inhibition by memantine also prevented Abeta-driven deleterious impact of BDNF loss of function on structural (spine density) and functional outcomes (synaptic potentiation). Collectively, these findings support NMDAR/Ca2+/calpains mechanistic involvement in Abeta-triggered BDNF signaling disruption. PMID- 29695963 TI - The Effects of PPAR Stimulation on Cardiac Metabolic Pathways in Barth Syndrome Mice. AB - Aim: Tafazzin knockdown (TazKD) in mice is widely used to create an experimental model of Barth syndrome (BTHS) that exhibits dilated cardiomyopathy and impaired exercise capacity. Peroxisome proliferator-activated receptors (PPARs) are a group of nuclear receptor proteins that play essential roles as transcription factors in the regulation of carbohydrate, lipid, and protein metabolism. We hypothesized that the activation of PPAR signaling with PPAR agonist bezafibrate (BF) may ameliorate impaired cardiac and skeletal muscle function in TazKD mice. This study examined the effects of BF on cardiac function, exercise capacity, and metabolic status in the heart of TazKD mice. Additionally, we elucidated the impact of PPAR activation on molecular pathways in TazKD hearts. Methods: BF (0.05% w/w) was given to TazKD mice with rodent chow. Cardiac function in wild type-, TazKD-, and BF-treated TazKD mice was evaluated by echocardiography. Exercise capacity was evaluated by exercising mice on the treadmill until exhaustion. The impact of BF on metabolic pathways was evaluated by analyzing the total transcriptome of the heart by RNA sequencing. Results: The uptake of BF during a 4-month period at a clinically relevant dose effectively protected the cardiac left ventricular systolic function in TazKD mice. BF alone did not improve the exercise capacity however, in combination with everyday voluntary running on the running wheel BF significantly ameliorated the impaired exercise capacity in TazKD mice. Analysis of cardiac transcriptome revealed that BF upregulated PPAR downstream target genes involved in a wide spectrum of metabolic (energy and protein) pathways as well as chromatin modification and RNA processing. In addition, the Ostn gene, which encodes the metabolic hormone musclin, is highly induced in TazKD myocardium and human failing hearts, likely as a compensatory response to diminished bioenergetic homeostasis in cardiomyocytes. Conclusion: The PPAR agonist BF at a clinically relevant dose has the therapeutic potential to attenuate cardiac dysfunction, and possibly exercise intolerance in BTHS. The role of musclin in the failing heart should be further investigated. PMID- 29695964 TI - Root Extract of Polygonum cuspidatum Siebold & Zucc. Ameliorates DSS-Induced Ulcerative Colitis by Affecting NF-kappaB Signaling Pathway in a Mouse Model via Synergistic Effects of Polydatin, Resveratrol, and Emodin. AB - Background:Polygonum cuspidatum Siebold & Zucc. (PCS) has antibacterial properties and may prevent Ulcerative colitis (UC) but related molecular mechanism remains unknown. NF-kappaB signaling pathway is associated with inflammatory responses and its inactivation may be critical for effective therapy of UC. Methods: UC mouse (C57BL/6J) model was established by using dextran sulfate sodium (DSS). The extract of PCS (PCSE) was prepared by using ethanol and its main ingredients were measured by HPLC. Thirty-two UC mice were evenly assigned into DG (received vehicle control), LG (0.1 g/kg PCSE daily), MG (0.2 g/kg PCSE daily) and HG (0.4 g/kg PCSE daily) groups. Meanwhile, 8 healthy mice were assigned as a control group (CG). Serum pharmacokinetics of PCS was measured by using HPLC. After 8-day treatment, weight, colon length and disease activity index (DAI) were measured. Inflammatory cytokines and oxidant biomarkers were measured by ELISA kits. The levels of cytokines, and key molecules in NF-kappaB pathway, were measured by using Western Blot. The effects of main ingredients of PCSE on cytokines and NF-kappaB signaling pathway were explored by using intestinal cells of a mouse UC model. The normality criterion was evaluated using the Saphiro-Wilk test. The quantitative variables were compared using the paired Student's-t test. Results: The main ingredients of PCSE were polydatin, resveratrol and emodin. Polydatin may be transformed into resveratrol in the intestine of the mice. PCSE prevented DSS-caused weight loss and colon length reduction, and improved histopathology of UC mice (P < 0.05). PCSE treatment increased the serum levels of IL-10 and reduced the levels of IL-1 beta, IL-6 and TNF-alpha (P < 0.05). PCSE increased the activities of SOD, CAT, GPX and reduced the level of MDA, BCL-2, beta-arrestin, NF-kappaB p65 and the activity of MPO (P < 0.05). The combination of polydatin, resveratrol or emodin, and or PCSE exhibited higher inhibitory activities for cytokines and NF-kappaB signaling related molecules than any one of the three ingredients with same concentration treatment. Conclusion: Oral administration of PCSE suppressed NF-kappaB signaling pathway and exerts its anti-colitis effects via synergistic effects of polydatin, resveratrol or emodin. PMID- 29695965 TI - Effects of Phytochemically Characterized Extracts From Syringa vulgaris and Isolated Secoiridoids on Mediators of Inflammation in a Human Neutrophil Model. AB - Aim of the study: The aim of the present study was to investigate the effects of phytochemically characterized extracts connected with the traditional use (infusions and ethanolic extracts) of different parts of Syringa vulgaris (common lilac) on the pro-inflammatory functions of neutrophils. Active compounds were isolated from the most promising extract(s) using bioassay-guided fractionation, and their activity and molecular mechanisms of action were determined. Methods: The extracts were characterized using a HPLC-DAD- MSn method. The effects on ROS, MMP-9, TNF-alpha, IL-8, and MCP-1 production by neutrophils were measured using luminol-dependent chemiluminescence and enzyme-linked immunosorbent assay (ELISA) methods. The effects on p38MAPK, ERK1/2, JNK phosphorylation, and NF-kB p65 translocation were determined using western blots. Results: The major compounds detected in the extracts and infusions belong to structural groups, including caffeic acid derivatives, flavonoids, and iridoids. All extracts and infusions were able to significantly reduce ROS and IL-8 production. Bioassay-guided fractionation led to the isolation of the following secoiridoids: 2" epiframeroside, oleonuezhenide, oleuropein, ligstroside, neooleuropein, hydroxyframoside, and framoside. Neooleuropein appeared to be the most active compound in the inhibition of cytokine production by attenuating the MAP kinase pathways. Conclusion: The present study demonstrated that common lilac, which is a traditionally used medicinal plant in Europe, is a valuable source of active compounds, especially neooleuropein. PMID- 29695966 TI - Adverse Drug Reactions in Hospitalized Patients: Results of the FORWARD (Facilitation of Reporting in Hospital Ward) Study. AB - Background: Adverse drug reactions (ADRs) are an important public health problem, representing a major cause of morbidity and mortality. However, several countries have no recent studies available. Since 2014, a prospective active pharmacovigilance project, aimed to improve ADRs monitoring in hospital wards (FORWARD) was performed in Sicily. This study, as part of FORWARD project, was aimed to describe ADRs occurred during the hospital stay in Internal Medicine wards. ADRs related to hospital admission, characteristics and preventability of ADRs were also evaluated. Methods: Demographic, clinical, and pharmacological data on patients admitted to six wards of Internal Medicine, from 2014 to 2015, were collected by trained, qualified monitors, who screened all medical records. The rate of ADRs occurred during hospital stay and those leading to hospitalization were analyzed. A descriptive analysis of the reactions, suspected drugs, and associated factors was performed according to the setting analyzed. Results: During the study period, 4,802 admissions were recorded; in 3.2% of them ADRs occurred during hospital stay while in 6.2%, admission was due to ADRs. The duration of hospital stay was longer in patients who experienced ADRs during hospitalization, compared to patients without ADRs [median days 12 (Q1-Q3: 8-17) vs. 9 (6-13)]; p < 0.001). Females [OR1.39 (95% CI 1.03-1.93)] and patients taking >= 4 drugs [OR1.46 (95% CI 1.06-2.03)] were more likely to experience ADRs during hospital stay, as well as to be admitted because of ADRs [female: OR1.75 (95% CI 1.37-2.24); >= 4 drugs: OR2.14 (95% CI 1.67-2.74)]. The most frequent ADRs occurred during hospital stay were cutaneous (26.8%), general (13.4%), vascular (13.4%), and cardiac (11.5%) disorders and the drug classes mainly involved were anti-bacterials (38.2%) and antithrombotic agents (21.7%). ADRs were serious in 44.6% and probably preventable in 69.4%. Gastrointestinal (27.7%), hematological (26.5%), metabolic (18.1%), and nervous (16.1%) disorders were the main ADRs cause of hospitalization, primarily due to antithrombotic agents (39.0%) RAS-inhibitors (13.9%), NSAIDs (11.9%), and diuretics (9.0%). Only 12.9% of them was not preventable. Conclusion: Adverse drug reactions occurred during hospitalization or contributing to admission to Internal Medicine wards were considerable and most of them were preventable. Females and patients taking many medications were more likely to present ADRs both during hospital stay or as cause of admission. PMID- 29695967 TI - Influence of APOA5 Locus on the Treatment Efficacy of Three Statins: Evidence From a Randomized Pilot Study in Chinese Subjects. AB - Pharmacogenetics or pharmacogenomics approaches are important for addressing the individual variabilities of drug efficacy especially in the era of precision medicine. One particular interesting gene to investigate is APOA5, which has been repeatedly linked with the inter-individual variations of serum triglycerides. Here, we explored APOA5-statin interactions in 195 Chinese subjects randomized to rosuvastatin (5-10 mg/day), atorvastatin (10-20 mg/day), or simvastatin (40 mg/day) for 12 weeks by performing a targeted genotyping analysis of the APOA5 promoter SNP rs662799 (-1131T > C). There were no significant differences between the treatment arms for any of the statin-induced changes in clinical biomarkers. Reductions in LDL cholesterol were influenced by the APOA5 genotype in all three treatment groups. By contrast, changes in HDL cholesterol, and triglycerides were only affected by the APOA5 genotype in the atorvastatin and simvastatin groups and not in the rosuvastatin group. Our results suggest that future studies may need to consider stratifying subjects not only by genetic background but also by prescribed statin type. PMID- 29695968 TI - Neurosteroid Transport in the Brain: Role of ABC and SLC Transporters. AB - Neurosteroids, comprising pregnane, androstane, and sulfated steroids can alter neuronal excitability through interaction with ligand-gated ion channels and other receptors and have therefore a therapeutic potential in several brain disorders. They can be formed in brain cells or are synthesized by an endocrine gland and reach the brain by penetrating the blood-brain barrier (BBB). Especially sulfated steroids such as pregnenolone sulfate (PregS) and dehydroepiandrosterone sulfate (DHEAS) depend on transporter proteins to cross membranes. In this review, we discuss the involvement of ATP-binding cassette (ABC)- and solute carrier (SLC)-type membrane proteins in the transport of these compounds at the BBB and in the choroid plexus (CP), but also in the secretion from neurons and glial cells. Among the ABC transporters, especially BCRP (ABCG2) and several MRP/ABCC subfamily members (MRP1, MRP4, MRP8) are expressed in the brain and known to efflux conjugated steroids. Furthermore, several SLC transporters have been shown to mediate cellular uptake of steroid sulfates. These include members of the OATP/SLCO subfamily, namely OATP1A2 and OATP2B1, as well as OAT3 (SLC22A3), which have been reported to be expressed at the BBB, in the CP and in part in neurons. Furthermore, a role of the organic solute transporter OSTalpha-OSTbeta (SLC51A/B) in brain DHEAS/PregS homeostasis has been proposed. This transporter was reported to be localized especially in steroidogenic cells of the cerebellum and hippocampus. To date, the impact of transporters on neurosteroid homeostasis is still poorly understood. Further insights are desirable also with regard to the therapeutic potential of these compounds. PMID- 29695969 TI - Genetic Association of Drug Response to Erlotinib in Chinese Advanced Non-small Cell Lung Cancer Patients. AB - The efficacy of erlotinib treatment for advanced non-small cell lung cancer (NSCLC) is due to its action as an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Patients treated with erlotinib experience different drug responses. The effect of germline mutations on therapeutic responses and adverse drug responses (ADRs) to erlotinib in Chinese patients requires elucidation. Sixty Han Chinese advanced non-small cell lung cancer patients received erlotinib monotherapy and, for each participant, 76 candidate genes (related to EGFR signaling, drug metabolism and drug transport pathways) were sequenced and analyzed. The single-nucleotide polymorphisms (SNPs) rs1042640 in UGT1A10, rs1060463, and rs1064796 in CYP4F11, and rs2074900 in CYP4F2 were significantly associated with therapeutic responses to erlotinib. Rs1064796 in CYP4F11 and rs10045685 in UGT3A1 were significantly associated with adverse drug reaction. Moreover, analysis of a validation cohort confirmed the significant association between rs10045685 in UGT3A1 and erlotinib adverse drug response(unadjusted p = 0.015). This study provides comprehensive, systematic analyses of genetic variants associated with responses to erlotinib in Chinese advanced non-small cell lung cancer patients. Newly-identified SNPs may serve as promising markers to predict responses and safety in erlotinib-treated advanced non-small cell lung cancer patients after chemotherapy doublet. PMID- 29695971 TI - Ammonia Excretion in an Osmoregulatory Syncytium Is Facilitated by AeAmt2, a Novel Ammonia Transporter in Aedes aegypti Larvae. AB - The larvae of the mosquito Aedes aegypti inhabit ammonia rich septic tanks in tropical regions of the world that make extensive use of these systems, explaining the prevalence of disease during dry seasons. Since ammonia (NH3/[Formula: see text]) is toxic to animals, an understanding of the physiological mechanisms of ammonia excretion permitting the survival of A. aegypti larvae in high ammonia environments is important. We have characterized a novel ammonia transporter, AeAmt2, belonging to the Amt/MEP/Rh family of ammonia transporters. Based on the amino acid sequence, the predicted topology of AeAmt2 consists of 11 transmembrane helices with an extracellular N-terminus and a cytoplasmic C-terminus region. Alignment of the predicted AeAmt2 amino acid sequence with other Amt/MEP proteins from plants, bacteria, and yeast highlights the presence of conserved residues characteristic of ammonia conducting channels in this protein. AeAmt2 is expressed in the ionoregulatory anal papillae of A. aegypti larvae where it is localized to the apical membrane of the epithelium. dsRNA-mediated knockdown of AeAmt2 results in a significant decrease in [Formula: see text] efflux from the anal papillae, suggesting a key role in facilitating ammonia excretion. The effect of high environmental ammonia (HEA) on expression of AeAmt2, along with previously characterized AeAmt1, AeRh50-1, and AeRh50-2 in the anal papillae was investigated. We show that changes in expression of ammonia transporters occur in response to acute and chronic exposure to HEA, which reflects the importance of these transporters in the physiology of life in high ammonia habitats. PMID- 29695970 TI - Sport-Specific Assessment of the Effectiveness of Neuromuscular Training in Young Athletes. AB - Neuromuscular training in young athletes improves performance and decreases the risk of injuries during sports activities. These effects are primarily ascribed to the enhancement of muscle strength and power but also balance, speed and agility. However, most studies have failed to demonstrate significant improvement in these abilities. This is probably due to the fact that traditional tests do not reflect training methods (e.g., plyometric training vs. isometric or isokinetic strength testing, dynamic balance training vs. static balance testing). The protocols utilized in laboratories only partially fulfill the current needs for testing under sport-specific conditions. Moreover, laboratory testing usually requires skilled staff and a well equipped and costly infrastructure. Nevertheless, experience demonstrates that high-technology and expensive testing is not the only way to proceed. A number of physical fitness field tests are available today. However, the low reliability and limited number of parameters retrieved from simple equipment used also limit their application in competitive sports. Thus, there is a need to develop and validate a functional assessment platform based on portable computerized systems. Variables obtained should be directly linked to specific features of particular sports and capture their complexity. This is essential for revealing weak and strong components of athlete performance and design of individually-tailored exercise programs. Therefore, identifying the drawbacks associated with the assessment of athlete performance under sport-specific conditions would provide a basis for the formation of an innovative approach to their long-term systematic testing. This study aims (i) to review the testing methods used for the evaluation of the effect of neuromuscular training on sport-specific performance in young athletes, (ii) to introduce stages within the Sport Longlife Diagnostic Model, and (iii) to propose future research in this topic. Analysis of the literature identified gaps in the current standard testing methods in terms of their low sensitivity in discriminating between athletes of varied ages and performance levels, insufficent tailoring to athlete performance level and individual needs, a lack of specificity to the requirements of particular sports and also in revealing the effect of training. In order to partly fill in these gaps, the Sport Longlife Diagnostic Model was proposed. PMID- 29695972 TI - Exercise Protects Against Defective Insulin Signaling and Insulin Resistance of Glucose Transport in Skeletal Muscle of Angiotensin II-Infused Rat. AB - Objectives: The present study investigated the impact of voluntary exercise on insulin-stimulated glucose transport and the protein expression and phosphorylation status of the signaling molecules known to be involved in the glucose transport process in the soleus muscle as well as other cardiometabolic risks in a rat model with insulin resistance syndrome induced by chronic angiotensin II (ANGII) infusion. Materials and Methods: Male Sprague-Dawley rats were assigned to sedentary or voluntary wheel running (VWR) groups. Following a 6 week period, rats in each group were subdivided and subcutaneously administered either normal saline or ANGII at 100 ng/kg/min for 14 days. Blood pressure, glucose tolerance, insulin-stimulated glucose transport and signaling proteins, including insulin receptor (IR), insulin receptor substrate 1 (IRS-1), Akt, Akt substrate of 160 kDa (AS160), AMPKalpha, c-Jun NH2-terminal kinase (JNK), p38 MAPK, angiotensin converting enzyme (ACE), ANGII type 1 receptor (AT1R), ACE2, Mas receptor (MasR) and oxidative stress marker in the soleus muscle, were evaluated. Results: Exercise protected against the insulin resistance of glucose transport and defective insulin signaling molecules in the soleus muscle; this effect was associated with a significant increase in AMPK Thr172 (43%) and decreases in oxidative stress marker (31%) and insulin-induced p38 MAPK Thr180/Tyr182 (45%) and SAPK/JNK Thr183/Tyr185 (25%), without significant changes in expression of AT1R, AT2R, ACE, ACE2, and MasR when compared to the sedentary rats given ANGII infusion. At the systemic level, VWR significantly decreased body weight, fat weight, and systolic blood pressure as well as improved serum lipid profiles. Conclusion: Voluntary exercise can alleviate insulin resistance of glucose transport and impaired insulin signaling molecules in the soleus muscle and improve whole-body insulin sensitivity in rats chronically administered with ANGII. PMID- 29695973 TI - Different Levels of Expression of the Clock Protein PER and the Glial Marker REPO in Ensheathing and Astrocyte-Like Glia of the Distal Medulla of Drosophila Optic Lobe. AB - Circadian plasticity of the visual system of Drosophila melanogaster depends on functioning of both the neuronal and glial oscillators. The clock function of the former is already quite well-recognized. The latter, however, is much less known and documented. In this study we focus on the glial oscillators that reside in the distal part of the second visual neuropil, medulla (dMnGl), in vicinity of the PIGMENT-DISPERSING FACTOR (PDF) releasing terminals of the circadian clock ventral Lateral Neurons (LNvs). We reveal the heterogeneity of the dMnGl, which express the clock protein PERIOD (PER) and the pan-glial marker REVERSED POLARITY (REPO) at higher (P1) or lower (P2) levels. We show that the cells with stronger expression of PER display also stronger expression of REPO, and that the number of REPO-P1 cells is bigger during the day than during the night. Using a combination of genetic markers and immunofluorescent labeling with anti PER and REPO Abs, we have established that the P1 and P2 cells can be associated with two different types of the dMnGl, the ensheathing (EnGl), and the astrocyte-like glia (ALGl). Surprisingly, the EnGl belong to the P1 cells, whereas the ALGl, previously reported to play the main role in the circadian rhythms, display the characteristics of the P2 cells (express very low level of PER and low level of REPO). Next to the EnGl and ALGl we have also observed another type of cells in the distal medulla that express PER and REPO, although at very low levels. Based on their morphology we have identified them as the T1 interneurons. Our study reveals the complexity of the distal medulla circadian network, which appears to consist of different types of glial and neuronal peripheral clocks, displaying molecular oscillations of higher (EnGl) and lower (ALGl and T1) amplitudes. PMID- 29695974 TI - Plant Secondary Metabolites Modulate Insect Behavior-Steps Toward Addiction? AB - Plants produce a diversity of secondary metabolites (PSMs) that serve as defense compounds against herbivores and microorganisms. In addition, some PSMs attract animals for pollination and seed dispersal. In case of pollinating insects, PSMs with colors or terpenoids with fragrant odors attract pollinators in the first place, but when they arrive at a flower, they are rewarded with nectar, so that the pollinators do not feed on flowers. In order to be effective as defense chemicals, PSMs evolved as bioactive substances, that can interfere with a large number of molecular targets in cells, tissues and organs of animals or of microbes. The known functions of PSMs are summarized in this review. A number of PSMs evolved as agonists or antagonists of neuronal signal transduction. Many of these PSMs are alkaloids. Several of them share structural similarities to neurotransmitters. Evidence for neuroactive and psychoactive PSMs in animals will be reviewed. Some of the neuroactive PSMs can cause addiction in humans and other vertrebrates. Why should a defense compound be addictive and thus attract more herbivores? Some insects are food specialists that can feed on plants that are normally toxic to other herbivores. These specialists can tolerate the toxins and many are stored in the insect body as acquired defense chemicals against predators. A special case are pyrrolizidine alkaloids (PAs) that are neurotoxic and mutagenic in vertebrates. PAs are actively sequestered by moths of the family Arctiidae and a few other groups of arthropods. In arctiids, PAs are not only used for defense, but also serve as morphogens for the induction of male coremata and as precursors for male pheromones. Caterpillars even feed on filter paper impregnated with pure PAs (that modulate serotonin receptors in vertebrates and maybe even in insects) and thus show of behavior with has similarities to addiction in vertebrates. Not only PA specialists, but also many monophagous herbivores select their host plants according to chemical cues i.e., PSMs) and crave for plants with a particular PSMs, again a similarity to addiction in vertebrates. PMID- 29695975 TI - Characterizing the Key Metabolic Pathways of the Neonatal Mouse Heart Using a Quantitative Combinatorial Omics Approach. AB - The heart of a newborn mouse has an exceptional capacity to regenerate from myocardial injury that is lost within the first week of its life. In order to elucidate the molecular mechanisms taking place in the mouse heart during this critical period we applied an untargeted combinatory multiomics approach using large-scale mass spectrometry-based quantitative proteomics, metabolomics and mRNA sequencing on hearts from 1-day-old and 7-day-old mice. As a result, we quantified 1.937 proteins (366 differentially expressed), 612 metabolites (263 differentially regulated) and revealed 2.586 differentially expressed gene loci (2.175 annotated genes). The analyses pinpointed the fructose-induced glycolysis pathway to be markedly active in 1-day-old neonatal mice. Integrated analysis of the data convincingly demonstrated cardiac metabolic reprogramming from glycolysis to oxidative phosphorylation in 7-days old mice, with increases of key enzymes and metabolites in fatty acid transport (acylcarnitines) and beta oxidation. An upsurge in the formation of reactive oxygen species and an increase in oxidative stress markers, e.g., lipid peroxidation, altered sphingolipid and plasmalogen metabolism were also evident in 7-days mice. In vitro maintenance of physiological fetal hypoxic conditions retained the proliferative capacity of cardiomyocytes isolated from newborn mice hearts. In summary, we provide here a holistic, multiomics view toward early postnatal changes associated with loss of a tissue regenerative capacity in the neonatal mouse heart. These results may provide insight into mechanisms of human cardiac diseases associated with tissue regenerative incapacity at the molecular level, and offer a prospect to discovery of novel therapeutic targets. PMID- 29695976 TI - Evaluation of Reference Genes for Real-Time Quantitative PCR Analysis in Larvae of Spodoptera litura Exposed to Azadirachtin Stress Conditions. AB - Azadirachtin is an efficient and broad-spectrum botanical insecticide against more than 150 kinds of agricultural pests with the effects of mortality, antifeedant and growth regulation. Real-time quantitative polymerase chain reaction (RT-qPCR) could be one of the powerful tools to analyze the gene expression level and investigate the mechanism of azadirachtin at transcriptional level, however, the ideal reference genes are needed to normalize the expression profiling of target genes. In this present study, the fragments of eight candidate reference genes were cloned and identified from the pest Spodoptera litura. In addition, the expression stability of these genes in different samples from larvae of control and azadirachtin treatments were evaluated by the computational methods of NormFinder, BestKeeper, Delta CT, geNorm, and RefFinder. According to our results, two of the reference genes should be the optimal number for RT-qPCR analysis. Furthermore, the best reference genes for different samples were showed as followed: EF-1alpha and EF2 for cuticle, beta-Tubulin and RPL7A for fat body, EF2 and Actin for midgut, EF2 and RPL13A for larva and RPL13A and RPL7A for all the samples. Our results established a reliable normalization for RT-qPCR experiments in S. litura and ensure the data more accurate for the mechanism analysis of azadirachtin. PMID- 29695977 TI - Effect of Resistance Training on Extracellular Matrix Adaptations in Skeletal Muscle of Older Rats. AB - Accumulation of connective tissue, particularly extracellular matrix (ECM) proteins, has been observed in skeletal muscles with advancing age. Resistance training (RT) has been widely recommended to attenuate age-induced sarcopenia, even though its effects on the components that control ECM turnover in skeletal muscles remain to be elucidated. Thus, the aim of this study was to determine the effects of RT on connective tissue content and gene expression of key components of ECM in the skeletal muscles of aged rats. Young (3 mo.) and older (21 mo.) adult male Wistar rats were submitted to a RT protocol (ladder climbing with 65, 85, 95, and 100% load), 3 times a week for 12 weeks. Forty-eight hours post training, the soleus (SOL) and gastrocnemius (GAS) muscles were dissected for histological and mRNA analysis. RT mitigated the age-associated increase of connective tissue content in both muscles, even though mRNA levels of COL-1 and-3 were elevated in older trained rats. Overall, RT significantly elevated the gene expression of key components of connective tissue deposition (TGFbeta and CTGF; MMP-2 and-9; TIMP-1 and-2) in the GAS and SOL muscles of older rats. In conclusion, RT blunted the age-induced accumulation of connective tissue concomitant to the upregulation of genes related to synthesis and degradation of the ECM network in the SOL and GAS muscles of older rats. Although our findings indicate that RT plays a crucial role reducing connective tissue accumulation in aged hindlimb muscles, key components of ECM turnover were paradoxically elevated. The phenotypic responses induced by RT were not accompanied by the gene expression of those components related to ECM turnover. PMID- 29695978 TI - The Effects of Altitude Training on Erythropoietic Response and Hematological Variables in Adult Athletes: A Narrative Review. AB - Background: One of the goals of altitude training is to increase blood oxygen carrying capacity in order to improve sea-level endurance performance in athletes. The elevated erythropoietin (EPO) production in hypoxia is a key factor in the achievement of enhanced hematological variables. The level of the EPO increase and acceleration of erythropoiesis depend on the duration of exposure and degree of hypoxia. Furthermore, many other factors may affect the hematological response to altitude training. Aim: The purpose of this narrative review was to: (1) analyze the kinetics of EPO and hematological variables during and after altitude training; (2) summarize the current state of knowledge about the possible causes of individual or cohort differences in EPO and hematological response to altitude training; (3) formulate practical guidelines for athletes to improve the efficiency of altitude training. Methods: A narrative review was performed following an electronic search of the databases PubMed/MEDLINE and SPORTDiscus via EBSCO for all English-language articles published between 1997 and 2017. Results: Complete unification of results from studies on EPO kinetics was difficult due to different time and frequency of blood sampling by different researchers during and after altitude training, but the data presented in the reviewed literature allowed us to detect certain trends. The results of the reviewed studies were divergent and indicated either increase or no change of hematological variables following altitude training. Factors that may affect the hematological response to altitude training include hypoxic dose, training content, training background of athletes, and/or individual variability of EPO production. Conclusions: Despite the potential benefits arising from altitude training, its effectiveness in improving hematological variables is still debatable. Further research and better understanding of factors influencing the response to altitude, as well as factors affecting the suitable measurement and interpretation of study results, are needed. PMID- 29695979 TI - Association Between TERT rs2736098 Polymorphisms and Cancer Risk-A Meta-Analysis. AB - Background: Cancer remains a leading cause of death and constitutes an enormous burden on society worldwide. The association between the human telomerase reverse transcriptase (TERT) gene variant rs2736098 polymorphisms and cancer predisposition remain inconclusive. Objective and methods: Databases including Pubmed and Embase were systematically searched from inception to September 15, 2017 to retrieve studies investigating the association between the TERT variant rs2736098 polymorphisms and cancer risk in accordance with previously determined exclusion and inclusion criteria. The pooled odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were evaluated using random or fixed effects models. Results: Thirty-one case-control studies from 29 articles with 15,837 cases and 19,263 controls were screened out after a systematic search. Pooled analysis demonstrated that the TERT variant rs2736098 G > A polymorphism was significantly correlated with cancer risk in all populations (A vs. G: OR = 1.134, 95% CI = 1.051-1.224, P = 0.001; AA vs. GG: OR = 1.280, 95% CI = 1.087 1.508, P = 0.003; GA vs. GG: OR = 1.125, 95% CI = 1.020-1.240, P = 0.018; GA/AA vs. GG: OR = 1.159, 95% CI = 1.047-1.283, P = 0.004). In the subgroup analysis based on cancer type, the TERT rs2736098 with the A allele was 1.299 times more frequent than that with the G allele (OR = 1.299, 95% CI = 1.216-1.386) under the allelic genetic model in lung cancer, and 1.152 times (OR = 1.152, 95% CI = 1.032 1.286) that in bladder cancer. Conclusions: This meta-analysis demonstrated significant correlations between the TERT variant rs2736098 polymorphisms and cancer susceptibility. The A allele in the rs2736098 G > A polymorphism contributes to susceptibility in many types of cancer, especially lung cancer and bladder cancer. PMID- 29695982 TI - Evaluating the Specificity of Cognitive Control Deficits in Schizophrenia Using Antisaccades, Functional Magnetic Resonance Imaging, and Healthy Individuals With Poor Cognitive Control. AB - Cognitive control impairments in schizophrenia (SZ) can be evaluated using antisaccade tasks and functional magnetic resonance imaging (fMRI). Studies, however, often compare people with SZ to high performing healthy people, making it unclear if antisaccade-related disruptions are specific to the disease or due to generalized deficits in cognitive control. We included two healthy comparison groups in addition to people with SZ: healthy people with high cognitive control (HCC), who represent a more typical comparison group, and healthy people with low cognitive control (LCC), who perform similarly on antisaccade measures as people with SZ. Using two healthy comparison groups may help determine which antisaccade related deficits are specific to SZ (distinguish SZ from LCC and HCC groups) and which are due to poor cognitive control (distinguish the LCC and SZ groups from the HCC group). People with SZ and healthy people with HCC or LCC performed an antisaccade task during fMRI acquisition. LCC and SZ groups showed under activation of saccade circuitry. SZ-specific disruptions were observed in the left superior temporal gyrus and insula during error trials (suppression of activation in the SZ group compared to the LCC and HCC group). Differences related to antisaccade errors may distinguish people with SZ from healthy people with LCC. PMID- 29695980 TI - Cardiac Remodeling: Endothelial Cells Have More to Say Than Just NO. AB - The heart is a highly structured organ consisting of different cell types, including myocytes, endothelial cells, fibroblasts, stem cells, and inflammatory cells. This pluricellularity provides the opportunity of intercellular communication within the organ, with subsequent optimization of its function. Intercellular cross-talk is indispensable during cardiac development, but also plays a substantial modulatory role in the normal and failing heart of adults. More specifically, factors secreted by cardiac microvascular endothelial cells modulate cardiac performance and either positively or negatively affect cardiac remodeling. The role of endothelium-derived small molecules and peptides-for instance NO or endothelin-1-has been extensively studied and is relatively well defined. However, endothelial cells also secrete numerous larger proteins. Information on the role of these proteins in the heart is scattered throughout the literature. In this review, we will link specific proteins that modulate cardiac contractility or cardiac remodeling to their expression by cardiac microvascular endothelial cells. The following proteins will be discussed: IL-6, periostin, tenascin-C, thrombospondin, follistatin-like 1, frizzled-related protein 3, IGF-1, CTGF, dickkopf-3, BMP-2 and-4, apelin, IL-1beta, placental growth factor, LIF, WISP-1, midkine, and adrenomedullin. In the future, it is likely that some of these proteins can serve as markers of cardiac remodeling and that the concept of endothelial function and dysfunction might have to be redefined as we learn more about other factors secreted by ECs besides NO. PMID- 29695983 TI - Sexual Quality of Life, Sexual Knowledge, and Attitudes of Older Adults on the Example of Inhabitants Over 60s of Bialystok, Poland. AB - Introduction: Aging has a strong influence on the quality of relationships and sexual functioning, but in itself does not cause a lack of sexual desire. Objectives: The aim of this study was to assess the quality of sexual life and define sexual knowledge and attitudes of older people on the example of residents of Bialystok, Poland at the age of 60 and over. Methods: The study included 170 people, inhabitants of Bialystok, Poland aged over 60: 85 students of the University of Healthy Senior and the University of Psychogeriatric Prophylaxis and 85 students of the University of the Third Age. The study used three standardized psychometric scales: Sexual Quality of Life Questionnaire-Male (SQoL M), Sexual Quality of Life Questionnaire-Female (SQoL-F), and Aging Sexual Knowledge and Attitudes Scale (ASKAS). Results: The overall mean score for the ASKAS scale for knowledge was 65.21 +/- 12.32 and for attitudes -124.65 +/- 22.00. The overall mean SQOL score was 62.92 +/- 18.18. Taking into account the gender of the respondents, the knowledge of men on sexuality of seniors was at the level of 63.48 +/- 12.63, while in the female group -65.74 +/- 12.23. The attitudes of men on sexuality of seniors was at the level of 128.80 +/- 21.56, while in the female group -123.38 +/- 22.05. Satisfaction with sex life among men (72.36 +/- 27.49) was significantly higher than among women (60.02 +/- 12.88). Discussion: The seniors were characterized by moderate knowledge and attitudes to sexuality of older people and the average level of sexual satisfaction. There was no significant relationship between knowledge on sexuality and sexual satisfaction in the study groups, and there was a positive correlation between attitudes toward sexuality and the satisfaction of sex life outside the group of men. In addition, a significant positive relationship was found between attitudes toward sexuality and sexual satisfaction. In order to improve the knowledge of senior citizens about sexuality of old age and to overcome the taboos that are prevalent in this topic, a structured training should be provided in this field. Such training should be carried out by specialists in the field of sexology. It is desirable to conduct in-depth studies in the assessment of knowledge, attitudes, and quality of sexual life in a larger research group, in order to get results for the population of the whole country. PMID- 29695981 TI - Cardiac Restoration Stemming From the Placenta Tree: Insights From Fetal and Perinatal Cell Biology. AB - Efficient cardiac repair and ultimate regeneration still represents one of the main challenges of modern medicine. Indeed, cardiovascular disease can derive from independent conditions upsetting heart structure and performance: myocardial ischemia and infarction (MI), pharmacological cardiotoxicity, and congenital heart defects, just to name a few. All these disorders have profound consequences on cardiac tissue, inducing the onset of heart failure over time. Since the cure is currently represented by heart transplantation, which is extremely difficult due to the shortage of donors, much effort is being dedicated to developing innovative therapeutic strategies based on stem cell exploitation. Among the broad scenario of stem/progenitor cell subpopulations, fetal and perinatal sources, namely amniotic fluid and term placenta, have gained interest due to their peculiar regenerative capacity, high self-renewal capability, and ease of collection from clinical waste material. In this review, we will provide the state-of-the-art on fetal perinatal stem cells for cardiac repair and regeneration. We will discuss different pathological conditions and the main therapeutic strategies proposed, including cell transplantation, putative paracrine therapy, reprogramming, and tissue engineering approaches. PMID- 29695984 TI - Wellbeing in Urban Greenery: The Role of Naturalness and Place Identity. AB - The aim was to investigate effects of urban greenery (high vs. low naturalness) on place identity and wellbeing, and the links between place identity and wellbeing. It was shown that participants (Gothenburg, Sweden, N = 1347) estimated a stronger attachment/closeness/belonging (emotional component of place identity), and more remembrance and thinking about and mental travel (cognitive component of place-identity) in relation to high vs. low perceived naturalness. High naturalness was also reported to generate higher wellbeing in participants than low naturalness. Furthermore, place identity was shown to predict participants' wellbeing in urban greenery, accounting for 35% of variance explained by the regression. However, there was a stronger relationship between the emotional vs. the cognitive component of place identity and wellbeing. Finally, a significant role of place identity in mediating the naturalness wellbeing relationship was shown, indicating that the naturalness-wellbeing connection can be partly accounted for by the psychological mechanisms of people place bonding. PMID- 29695985 TI - Augmented Go/No-Go Task: Mouse Cursor Motion Measures Improve ADHD Symptom Assessment in Healthy College Students. AB - Attention deficit/hyperactivity disorder (ADHD) is frequently characterized as a disorder of executive function (EF). However, behavioral tests of EF, such as go/No-go tasks, often fail to grasp the deficiency in EF revealed by questionnaire-based measures. This inability is usually attributed to questionnaires and behavioral tasks assessing different constructs of EFs. We propose an additional explanation for this discrepancy. We hypothesize that this problem stems from the lack of dynamic assessment of decision-making (e.g., continuous monitoring of motor behavior such as velocity and acceleration in choice reaching) in classical versions of behavioral tasks. We test this hypothesis by introducing dynamic assessment in the form of mouse motion in a go/No-go task. Our results indicate that, among healthy college students, self report measures of ADHD symptoms become strongly associated with performance in behavioral tasks when continuous assessment (e.g., acceleration in the mouse cursor motion) is introduced. PMID- 29695986 TI - Different Institutions and Different Values: Exploring First-Generation Student Fit at 2-Year Colleges. AB - First-generation (FG) college students (students for whom neither parent has a 4 year degree) face a number of challenges as they attempt to obtain a post secondary degree. They are more likely to come from working-class backgrounds or poverty (Reardon, 2011) and attend lower quality high schools (Warburton et al., 2001) while not benefiting from the guidance of a parent who successfully navigated the path to higher education. FG college students also contend with belonging or "fitting in" concerns due a perceived mismatch between their own values and the values implicit in institutions of higher education (Stephens et al., 2012a). Specifically, prior research has demonstrated that FG college students face an unseen disadvantage that can be attributed to the fact that middle-class norms of independence reflected in American institutions of higher education can be experienced as threatening by many FG students who have been socialized with more interdependent values commonly espoused in working-class populations. The present research examines this theory (cultural mismatch theory) in the understudied context of 2-year colleges and tests if a values-affirmation intervention (i.e., an intervention that has shown promise in addressing identity threats and belonging concerns) can be effective for FG college students at these 2-year campuses. By considering the tenets of cultural mismatch theory in the creation of the values-affirmation interventions we were able to vary different aspects of the intervention in order to examine how its effectiveness may depend on the nature and magnitude of a perceived cultural mismatch. Results from surveying faculty and students at 2-year colleges indicated that compared to traditional 4-year institutions, the norms of 2-year colleges and the motivations of FG students may be different. That is, FG student motives may be more consistent (and thus less mismatched) with the cultural context of 2-year colleges which could result in fewer belonging concerns when compared to FG students at 4-year institutions. This may carry implications for the efficacy of values-affirmation interventions and could help explicate why FG students in the current sample perceived a greater match with their college when they reflected on their interdependent values. PMID- 29695987 TI - Physiological Measures of Dopaminergic and Noradrenergic Activity During Attentional Set Shifting and Reversal. AB - Dopamine (DA) and noradrenaline (NA) are important neurotransmitters, which are suggested to play a vital role in modulating the neural circuitry involved in the executive control of cognition. One way to investigate the functions of these neurotransmitter systems is to assess physiological indices of DA and NA transmission. Here we examined how variations of spontaneous eye-blink rate and pupil size, as indirect measures of DA and NA activity, respectively, are related to performance in a hallmark aspect of executive control: attentional set shifting. We used the Intra/Extradimensional Set Shifting Task, where participants have to choose between different compound stimuli while the stimulus reward contingencies change periodically. During such rule shifts, participants have to refresh their attentional set while they reassess which stimulus-features are relevant. We found that both eye-blink rate (EBR) and pupil size increased after rule shifts, when explorative processes are required to establish stimulus reward contingencies. Furthermore, baseline pupil size was related to performance during the most difficult, extradimensional set shifting stage, whereas baseline EBR was associated with task performance prior to this stage. Our results support a range of neurobiological models suggesting that the activity of DA and NA neurotransmitter systems determines individual differences in executive functions (EF), possibly by regulating neurotransmission in prefrontal circuits. We also suggest that assessing specific, easily accessible indirect physiological markers, such as pupil size and blink rate, contributes to the comprehension of the relationship between neurotransmitter systems and EF. PMID- 29695988 TI - Acute Anxiety Predicts Components of the Cold Shock Response on Cold Water Immersion: Toward an Integrated Psychophysiological Model of Acute Cold Water Survival. AB - Introduction: Drowning is a leading cause of accidental death. In cold-water, sudden skin cooling triggers the life-threatening cold shock response (CSR). The CSR comprises tachycardia, peripheral vasoconstriction, hypertension, inspiratory gasp, and hyperventilation with the hyperventilatory component inducing hypocapnia and increasing risk of aspirating water to the lungs. Some CSR components can be reduced by habituation (i.e., reduced response to stimulus of same magnitude) induced by 3-5 short cold-water immersions (CWI). However, high levels of acute anxiety, a plausible emotion on CWI: magnifies the CSR in unhabituated participants, reverses habituated components of the CSR and prevents/delays habituation when high levels of anxiety are experienced concurrent to immersions suggesting anxiety is integral to the CSR. Purpose: To examine the predictive relationship that prior ratings of acute anxiety have with the CSR. Secondly, to examine whether anxiety ratings correlated with components of the CSR during immersion before and after induction of habituation. Methods: Forty-eight unhabituated participants completed one (CON1) 7-min immersion in to cold water (15 degrees C). Of that cohort, twenty-five completed four further CWIs that would ordinarily induce CSR habituation. They then completed two counter-balanced immersions where anxiety levels were increased (CWI-ANX) or were not manipulated (CON2). Acute anxiety and the cardiorespiratory responses (cardiac frequency [fc], respiratory frequency [fR], tidal volume [VT ], minute ventilation [ E]) were measured. Multiple regression was used to identify components of the CSR from the most life-threatening period of immersion (1st minute) predicted by the anxiety rating prior to immersion. Relationships between anxiety rating and CSR components during immersion were assessed by correlation. Results: Anxiety rating predicted the fc component of the CSR in unhabituated participants (CON1; p < 0.05, r = 0.536, r2= 0.190). After habituation immersions (i.e., cohort 2), anxiety rating predicted the fR component of the CSR when anxiety levels were lowered (CON2; p < 0.05, r = 0.566, r2= 0.320) but predicted the fc component of the CSR (p < 0.05, r = 0.518, r2= 0.197) when anxiety was increased suggesting different drivers of the CSR when anxiety levels were manipulated; correlation data supported these relationships. Discussion: Acute anxiety is integral to the CSR before and after habituation. We offer a new integrated model including neuroanatomical, perceptual and attentional components of the CSR to explain these data. PMID- 29695989 TI - Future Time Perspective Impacts Gain-Related but Not Loss-Related Intertemporal Choice. AB - Future time perspective (FTP) modulates individuals' temporal orientation in selecting their motivations and goals, which widely influences their cognitions and behaviors. However, it remains unclear how FTP exactly affects intertemporal choice. To clarify the effect of FTP on intertemporal choice, 90 college students (Mage = 21.70, SD = 1.23) were randomly assigned to the limited FTP condition (16 males, 29 females) and the open-ended FTP condition (17 males, 28 females). In the limited FTP condition, participants were instructed to imagine their states of being 70 years old, whereas in the open-ended FTP condition, they were instructed to describe their current states. All participants then completed a series of intertemporal choice tasks, in which they chose from gain- and loss related choices occurring at various time points. Results showed that the participants who received the future-imagining manipulation had more limited FTP compared with those who did not receive the manipulation, which confirmed the validity of the FTP manipulation. A 2 (FTP: limited vs. open-ended) * 2 (type of choice: gain vs. loss) repeated measures ANOVA on discount rate revealed a significant interaction between these two factors. The participants in the limited FTP condition had higher discount rates on gain-related choices but showed no difference on loss-related choices compared with the participants under the open-ended FTP condition. The results suggest that limited FTP could lower individuals' future orientation (i.e., willingness to delay an outcome) on gain related, but not on loss-related, intertemporal decision-making. PMID- 29695990 TI - Hostile Attribution Bias Mediates the Relationship Between Structural Variations in the Left Middle Frontal Gyrus and Trait Angry Rumination. AB - Angry rumination is a common mental phenomenon which may lead to negative social behaviors such as aggression. Although numerous neuroimaging studies have focused on brain area activation during angry rumination, to our knowledge no study has examined the neuroanatomical and cognitive mechanisms of this process. In this study, we conducted a voxel-based morphometry analysis, using a region of interest analysis to identify the structural and cognitive mechanisms underlying individual differences in trait angry rumination (as measured by the Angry Rumination Scale) in a sample of 82 undergraduate students. We found that angry rumination was positively correlated with gray matter density in the left middle frontal gyrus (left-MFG), which is implicated in inhibition control, working memory, and emotional regulation. The mediation analysis further revealed that hostile attribution bias (as measured by the Social Information Processing Attribution Bias Questionnaire) acted as a cognitive mechanism underlying the positive association between the left-MFG gray matter density and trait angry rumination. These findings suggest that hostile attribution bias may contribute to trait angry rumination, while the left-MFG may play an important role in the development of hostile attribution bias and trait angry rumination. The study reveals the brain mechanisms of trait angry rumination and plays a role in revealing the cognitive mechanisms of the development of trait angry rumination. PMID- 29695992 TI - Empathy, Challenge, and Psychophysiological Activation in Therapist-Client Interaction. AB - Two central dimensions in psychotherapeutic work are a therapist's empathy with clients and challenging their judgments. We investigated how they influence psychophysiological responses in the participants. Data were from psychodynamic therapy sessions, 24 sessions from 5 dyads, from which 694 therapist's interventions were coded. Heart rate and electrodermal activity (EDA) of the participants were used to index emotional arousal. Facial muscle activity (electromyography) was used to index positive and negative emotional facial expressions. Electrophysiological data were analyzed in two time frames: (a) during the therapists' interventions and (b) across the whole psychotherapy session. Both empathy and challenge had an effect on psychophysiological responses in the participants. Therapists' empathy decreased clients' and increased their own EDA across the session. Therapists' challenge increased their own EDA in response to the interventions, but not across the sessions. Clients, on the other hand, did not respond to challenges during interventions, but challenges tended to increase EDA across a session. Furthermore, there was an interaction effect between empathy and challenge. Heart rate decreased and positive facial expressions increased in sessions where empathy and challenge were coupled, i.e., the amount of both empathy and challenge was either high or low. This suggests that these two variables work together. The results highlight the therapeutic functions and interrelation of empathy and challenge, and in line with the dyadic system theory by Beebe and Lachmann (2002), the systemic linkage between interactional expression and individual regulation of emotion. PMID- 29695991 TI - Sex Hormones and Processing of Facial Expressions of Emotion: A Systematic Literature Review. AB - Background: We systematically reviewed the literature to determine the influence of sex hormones on facial emotion processing (FEP) in healthy women at different phases of life. Methods: Searches were performed in PubMed, Web of Science, PsycINFO, LILACS, and SciELO. Twenty-seven articles were included in the review and allocated into five different categories according to their objectives and sample characteristics (menstrual cycle, oral contraceptives, pregnancy/postpartum, testosterone, and progesterone). Results: Despite the limited number of studies in some categories and the existence of inconsistencies in the results of interest, the findings of the review suggest that FEP may be enhanced during the follicular phase. Studies with women taking oral contraceptives showed reduced recognition accuracy and decreased responsiveness of different brain structures during FEP tasks. Studies with pregnant women and women in the postpartum showed that hormonal changes are associated with alterations in FEP and in brain functioning that could indicate the existence of a hypervigilant state in new and future mothers. Exogenous administration of testosterone enhanced the recognition of threatening facial expressions and the activation of brain structures involved in the processing of emotional stimuli. Conclusions: We conclude that sex hormones affect FEP in women, which may have an impact in adaptive processes of the species and in the onset of mood symptoms associated with the premenstrual syndrome. PMID- 29695993 TI - The Efficacy of Eye Movement Desensitization and Reprocessing in Children and Adults Who Have Experienced Complex Childhood Trauma: A Systematic Review of Randomized Controlled Trials. AB - Background: Survivors of complex childhood trauma (CT) such as sexual abuse show poorer outcomes compared to single event trauma survivors. A growing number of studies investigate Eye Movement Desensitization and Reprocessing (EMDR) treatment for posttraumatic stress disorder (PTSD), but no systematic reviews have focused on EMDR treatment for CT as an intervention for both adults and children. This study therefore systematically reviewed all randomized controlled trials (RCTs) evaluating the effect of EMDR on PTSD symptoms in adults and children exposed to CT. Methods: Databases including PubMed, Web of Science, and PsycINFO were searched in October 2017. Randomized controlled trials which recruited adult and children with experience of CT, which compared EMDR to alternative treatments or control conditions, and which measured PTSD symptoms were included. Study methodology quality was evaluated with Platinum Standard scale. Results: Six eligible RCTs of 251 participants were included in this systematic review. The results indicated that EMDR was associated with reductions in PTSD symptoms, depression and/or anxiety both post-treatment and at follow-up compared with all other alternative therapies (cognitive behavior therapy, individual/group therapy and fluoxetine) and control treatment (pill placebo, active listening, EMDR delayed treatment, and treatment as usual). However, studies suffered from significant heterogeneity in study populations, length of EMDR treatment, length of follow-up, comparison groups, and outcome measures. One study had a high risk of bias. Discussion: This systematic review suggests that there is growing evidence to support the clinical efficacy of EMDR in treating CT in both children and adults. However, conclusions are limited by the small number of heterogenous trials. Further RCTs with standardized methodologies, as well as studies addressing real world challenges in treating CT are required. PMID- 29695994 TI - Dynamic Influence of Emotional States on Novel Word Learning. AB - Many researchers realize that it's unrealistic to isolate language learning and processing from emotions. However, few studies on language learning have taken emotions into consideration so far, so that the probable influences of emotions on language learning are unclear. The current study thereby aimed to examine the effects of emotional states on novel word learning and their dynamic changes with learning continuing and task varying. Positive, negative or neutral pictures were employed to induce a given emotional state, and then participants learned the novel words through association with line-drawing pictures in four successive learning phases. At the end of each learning phase, participants were instructed to fulfill a semantic category judgment task (in Experiment 1) or a word-picture semantic consistency judgment task (in Experiment 2) to explore the effects of emotional states on different depths of word learning. Converging results demonstrated that negative emotional state led to worse performance compared with neutral condition; however, how positive emotional state affected learning varied with learning task. Specifically, a facilitative role of positive emotional state in semantic category learning was observed but disappeared in word specific meaning learning. Moreover, the emotional modulation on novel word learning was quite dynamic and changeable with learning continuing, and the final attainment of the learned words tended to be similar under different emotional states. The findings suggest that the impact of emotion can be offset when novel words became more and more familiar and a part of existent lexicon. PMID- 29695995 TI - Cranioplasty After Severe Traumatic Brain Injury: Effects of Trauma and Patient Recovery on Cranioplasty Outcome. AB - Background: In patients with severe traumatic brain injury (sTBI) treated with decompressive craniectomy (DC), factors affecting the success of later cranioplasty are poorly known. Objective: We sought to investigate if injury- and treatment-related factors, and state of recovery could predict the risk of major complications in cranioplasty requiring implant removal, and how these complications affect the outcome. Methods: A retrospective cohort of 40 patients with DC following sTBI and subsequent cranioplasty was studied. Non-injury related factors were compared with a reference population of 115 patients with DC due to other conditions. Results: Outcome assessed 1 day before cranioplasty did not predict major complications leading to implant removal. Successful cranioplasty was associated with better outcome, whereas a major complication attenuates patient recovery: in patients with favorable outcome assessed 1 year after cranioplasty, major complication rate was 7%, while in patients with unfavorable outcome the rate was 42% (p = 0.003). Of patients with traumatic subarachnoid hemorrhage (tSAH) on admission imaging 30% developed a major complication, while none of patients without tSAH had a major complication (p = 0.014). Other imaging findings, age, admission Glasgow Coma Scale, extracranial injuries, length of stay at intensive care unit, cranioplasty materials, and timing of cranioplasty were not associated with major complications. Conclusion: A successful cranioplasty after sTBI and DC predicts favorable outcome 1 year after cranioplasty, while stage of recovery before cranioplasty does not predict cranioplasty success or failure. tSAH on admission imaging is a major risk factor for a major complication leading to implant removal. PMID- 29695996 TI - Outcomes of Interventional-MRI Versus Microelectrode Recording-Guided Subthalamic Deep Brain Stimulation. AB - In deep brain stimulation (DBS) of the subthalamic nucleus (STN) for Parkinson's disease (PD), there is debate concerning the use of neuroimaging alone to confirm correct anatomic placement of the DBS lead into the STN, versus the use of microelectrode recording (MER) to confirm functional placement. We performed a retrospective study of a contemporaneous cohort of 45 consecutive patients who underwent either interventional-MRI (iMRI) or MER-guided DBS lead implantation. We compared radial lead error, motor and sensory side effect, and clinical benefit programming thresholds, and pre- and post-operative unified PD rating scale scores, and levodopa equivalent dosages. MER-guided surgery was associated with greater radial error compared to the intended target. In general, side effect thresholds during initial programming were slightly lower in the MER group, but clinical benefit thresholds were similar. No significant difference in the reduction of clinical symptoms or medication dosage was observed. In summary, iMRI lead implantation occurred with greater anatomic accuracy, in locations demonstrated to be the appropriate functional region of the STN, based on the observation of similar programming side effect and benefit thresholds obtained with MER. The production of equivalent clinical outcomes suggests that surgeon and patient preference can be used to guide the decision of whether to recommend iMRI or MER-guided DBS lead implantation to appropriate patients with PD. PMID- 29695997 TI - The Anatomo-Electrical Network Underlying Hypermotor Seizures. AB - Purpose: Hypermotor seizures (HMS) can be triggered by different epileptogenic foci and thus common symptomatic networks generating HMS may exist among these patients. The goal of the present study was to investigate the specialized networks underlying HMS by analyzing interictal 18FDG-PET imaging and ictal stereo-electroencephalography (SEEG) recordings. Methods: Fourteen patients with HMS were retrospectively analyzed. HMS were classified into HMS1 and HMS2 according to the speed and intensity of the motor seizure behavior. Then, the interictal PET data of patients was compared with those of 18 healthy controls using statistical parametric mapping to identify regions with significant hypometabolism. Ictal SEEG recordings were reviewed to identify the spreading areas at the beginning of HMS occurrence. Results: Compared to controls, patients with HMS presented significant hypometabolism in the bilateral anterosuperior insular lobes, mesial premotor cortex (MPMC), middle cingulate cortex (MCC), as well as in the bilateral caudate nuclei. When comparing patients in the two HMS subgroups with controls, more extensive hypometabolic areas were seen in HMS1 patients than in HMS2 patients, including the orbitofrontal cortex (OFC), the temporal pole, and the anterior cingulate cortex (ACC). OFC and ventromedial prefrontal cortex was also found significantly hypometabolic in patients with HMS1 when compared with HMS2 directly. SEEG recordings further suggested that insula, MCC, and MPMC were commonly recruited at the beginning of HMS. Conclusion: We have identified a specialized interictal hypometabolic pattern in patients with HMS. A network involving the anterosuperior insula, mesiofrontal cortex (MCC-MPMC), and caudate nucleus may contribute to the generation of HMS. ACC, OFC, and temporal pole are possibly associated with the affective components of HMS. Our findings provide further insight into understanding the network basis of HMS semiology. PMID- 29695998 TI - The p53 Tumor Suppressor in the Control of Metabolism and Ferroptosis. AB - The p53 tumor suppressor continues to be distinguished as the most frequently mutated gene in human cancer. It is widely believed that the ability of p53 to induce senescence and programmed cell death underlies the tumor suppressor functions of p53. However, p53 has a number of other functions that recent data strongly implicate in tumor suppression, particularly with regard to the control of metabolism and ferroptosis (iron- and lipid-peroxide-mediated cell death) by p53. As reviewed here, the roles of p53 in the control of metabolism and ferroptosis are complex. Wild-type (WT) p53 negatively regulates lipid synthesis and glycolysis in normal and tumor cells, and positively regulates oxidative phosphorylation and lipid catabolism. Mutant p53 in tumor cells does the converse, positively regulating lipid synthesis and glycolysis. The role of p53 in ferroptosis is even more complex: in normal tissues, WT p53 appears to positively regulate ferroptosis, and this pathway appears to play a role in the ability of basal, unstressed p53 to suppress tumor initiation and development. In tumors, other regulators of ferroptosis supersede p53's role, and WT p53 appears to play a limited role; instead, mutant p53 sensitizes tumor cells to ferroptosis. By clearly elucidating the roles of WT and mutant p53 in metabolism and ferroptosis, and establishing these roles in tumor suppression, emerging research promises to yield new therapeutic avenues for cancer and metabolic diseases. PMID- 29696000 TI - Corrigendum: The Gambian Bone and Muscle Ageing Study: Baseline Data From a Prospective Observational African Sub-Saharan Study. AB - [This corrects the article on p. 219 in vol. 8, PMID: 28912754.]. PMID- 29695999 TI - A Review of the Literature Regarding Sleep and Cardiometabolic Disease in African Descent Populations. AB - : In the twenty-first century, African descent populations on both the continent of Africa and throughout the world are experiencing a high rate of both sleep disturbances and cardiometabolic diseases. The most common sleep disturbances are reduced sleep duration, insomnia, disordered circadian rhythm, and obstructive sleep apnea. Cardiometabolic diseases include hypertension, coronary artery disease, diabetes, hyperlipidemia, and the metabolic syndrome. This review seeks to call attention to new insights regarding the impact of sleep disturbance on cardiometabolic risk factors and outcomes and then apply these concepts to African descent populations, a relatively understudied population. Initial data suggest disparities in sleep quality may have an important role in current and emerging patterns of cardiometabolic disease for African descent populations both in the United States and abroad. ClinicalTrialsgov Identifier: Not applicable. PMID- 29696002 TI - Aromatic Amino Acid-Derived Compounds Induce Morphological Changes and Modulate the Cell Growth of Wine Yeast Species. AB - Yeasts secrete a large diversity of compounds during alcoholic fermentation, which affect growth rates and developmental processes, like filamentous growth. Several compounds are produced during aromatic amino acid metabolism, including aromatic alcohols, serotonin, melatonin, and tryptamine. We evaluated the effects of these compounds on growth parameters in 16 different wine yeasts, including non-Saccharomyces wine strains, for which the effects of these compounds have not been well-defined. Serotonin, tryptamine, and tryptophol negatively influenced yeast growth, whereas phenylethanol and tyrosol specifically affected non Saccharomyces strains. The effects of the aromatic alcohols were observed at concentrations commonly found in wines, suggesting a possible role in microbial interaction during wine fermentation. Additionally, we demonstrated that aromatic alcohols and ethanol are able to affect invasive and pseudohyphal growth in a manner dependent on nutrient availability. Some of these compounds showed strain specific effects. These findings add to the understanding of the fermentation process and illustrate the diversity of metabolic communication that may occur among related species during metabolic processes. PMID- 29696003 TI - Multilocus Sequence Typing Reveals a New Cluster of Closely Related Candida tropicalis Genotypes in Italian Patients With Neurological Disorders. AB - Candida tropicalis is a pathogenic yeast that has emerged as an important cause of candidemia especially in elderly patients with hematological malignancies. Infections caused by this species are mainly reported from Latin America and Asian-Pacific countries although recent epidemiological data revealed that C. tropicalis accounts for 6-16.4% of the Candida bloodstream infections (BSIs) in Italy by representing a relevant issue especially for patients receiving long term hospital care. The aim of this study was to describe the genetic diversity of C. tropicalis isolates contaminating the hands of healthcare workers (HCWs) and hospital environments and/or associated with BSIs occurring in patients with different neurological disorders and without hematological disease. A total of 28 C. tropicalis isolates were genotyped using multilocus sequence typing analysis of six housekeeping (ICL1, MDR1, SAPT2, SAPT4, XYR1, and ZWF1) genes and data revealed the presence of only eight diploid sequence types (DSTs) of which 6 (75%) were completely new. Four eBURST clonal complexes (CC2, CC10, CC11, and CC33) contained all DSTs found in this study and the CC33 resulted in an exclusive, well-defined, clonal cluster from Italy. In conclusion, C. tropicalis could represent an important cause of BSIs in long-term hospitalized patients with no underlying hematological disease. The findings of this study also suggest a potential horizontal transmission of a specific C. tropicalis clone through hands of HCWs and expand our understanding of the molecular epidemiology of this pathogen whose population structure is still far from being fully elucidated as its complexity increases as different categories of patients and geographic areas are examined. PMID- 29696001 TI - The Pivotal Role of DNA Repair in Infection Mediated-Inflammation and Cancer. AB - Pathogenic and commensal microbes induce various levels of inflammation and metabolic disease in the host. Inflammation caused by infection leads to increased production of reactive oxygen species (ROS) and subsequent oxidative DNA damage. These in turn cause further inflammation and exacerbation of DNA damage, and pose a risk for cancer development. Helicobacter pylori-mediated inflammation has been implicated in gastric cancer in many previously established studies, and Fusobacterium nucleatum presence has been observed with greater intensity in colorectal cancer patients. Despite ambiguity in the exact mechanism, infection-mediated inflammation may have a link to cancer development through an accumulation of potentially mutagenic DNA damage in surrounding cells. The multiple DNA repair pathways such as base excision, nucleotide excision, and mismatch repair that are employed by cells are vital in the abatement of accumulated mutations that can lead to carcinogenesis. For this reason, understanding the role of DNA repair as an important cellular mechanism in combatting the development of cancer will be essential to characterizing the effect of infection on DNA repair proteins and to identifying early cancer biomarkers that may be targeted for cancer therapies and treatments. PMID- 29696004 TI - Metaproteogenomic Profiling of Microbial Communities Colonizing Actively Venting Hydrothermal Chimneys. AB - At hydrothermal vent sites, chimneys consisting of sulfides, sulfates, and oxides are formed upon contact of reduced hydrothermal fluids with oxygenated seawater. The walls and surfaces of these chimneys are an important habitat for vent associated microorganisms. We used community proteogenomics to investigate and compare the composition, metabolic potential and relative in situ protein abundance of microbial communities colonizing two actively venting hydrothermal chimneys from the Manus Basin back-arc spreading center (Papua New Guinea). We identified overlaps in the in situ functional profiles of both chimneys, despite differences in microbial community composition and venting regime. Carbon fixation on both chimneys seems to have been primarily mediated through the reverse tricarboxylic acid cycle and fueled by sulfur-oxidation, while the abundant metabolic potential for hydrogen oxidation and carbon fixation via the Calvin-Benson-Bassham cycle was hardly utilized. Notably, the highly diverse microbial community colonizing the analyzed black smoker chimney had a highly redundant metabolic potential. In contrast, the considerably less diverse community colonizing the diffusely venting chimney displayed a higher metabolic versatility. An increased diversity on the phylogenetic level is thus not directly linked to an increased metabolic diversity in microbial communities that colonize hydrothermal chimneys. PMID- 29696006 TI - Corrigendum: Ebola VP40 in Exosomes Can Cause Immune Cell Dysfunction. AB - [This corrects the article on p. 1765 in vol. 7, PMID: 27872619.]. PMID- 29696005 TI - Rapid Formation of Microbe-Oil Aggregates and Changes in Community Composition in Coastal Surface Water Following Exposure to Oil and the Dispersant Corexit. AB - During the Deepwater Horizon (DWH) oil spill, massive quantities of oil were deposited on the seafloor via a large-scale marine oil-snow sedimentation and flocculent accumulation (MOSSFA) event. The role of chemical dispersants (e.g., Corexit) applied during the DWH oil spill clean-up in helping or hindering the formation of this MOSSFA event are not well-understood. Here, we present the first experiment related to the DWH oil spill to specifically investigate the relationship between microbial community structure, oil and Corexit(r), and marine oil-snow in coastal surface waters. We observed the formation of micron scale aggregates of microbial cells around droplets of oil and dispersant and found that their rate of formation was directly related to the concentration of oil within the water column. These micro-aggregates are potentially important precursors to the formation of larger marine oil-snow particles. Therefore, our observation that Corexit(r) significantly enhanced their formation suggests dispersant application may play a role in the development of MOSSFA events. We also observed that microbial communities in marine surface waters respond to oil and oil plus Corexit(r) differently and much more rapidly than previously measured, with major shifts in community composition occurring within only a few hours of experiment initiation. In the oil-amended treatments without Corexit(r), this manifested as an increase in community diversity due to the outgrowth of several putative aliphatic- and aromatic-hydrocarbon degrading genera, including phytoplankton-associated taxa. In contrast, microbial community diversity was reduced in mesocosms containing chemically dispersed oil. Importantly, different consortia of hydrocarbon degrading bacteria responded to oil and chemically dispersed oil, indicating that functional redundancy in the pre-spill community likely results in hydrocarbon consumption in both undispersed and dispersed oils, but by different bacterial taxa. Taken together, these data improve our understanding of how dispersants influence the degradation and transport of oil in marine surface waters following an oil spill and provide valuable insight into the early response of complex microbial communities to oil exposure. PMID- 29696007 TI - Bats, Coronaviruses, and Deforestation: Toward the Emergence of Novel Infectious Diseases? PMID- 29696008 TI - Absolute Enumeration of Probiotic Strains Lactobacillus acidophilus NCFM(r) and Bifidobacterium animalis subsp. lactis Bl-04 (r) via Chip-Based Digital PCR. AB - The current standard for enumeration of probiotics to obtain colony forming units by plate counts has several drawbacks: long time to results, high variability and the inability to discern between bacterial strains. Accurate probiotic cell counts are important to confirm the delivery of a clinically documented dose for its associated health benefits. A method is described using chip-based digital PCR (cdPCR) to enumerate Bifidobacterium animalis subsp. lactis Bl-04 and Lactobacillus acidophilus NCFM both as single strains and in combination. Primers and probes were designed to differentiate the target strains against other strains of the same species using known single copy, genetic differences. The assay was optimized to include propidium monoazide pre-treatment to prevent amplification of DNA associated with dead probiotic cells as well as liberation of DNA from cells with intact membranes using bead beating. The resulting assay was able to successfully enumerate each strain whether alone or in multiplex. The cdPCR method had a 4 and 5% relative standard deviation (RSD) for Bl-04 and NCFM, respectively, making it more precise than plate counts with an industry accepted RSD of 15%. cdPCR has the potential to replace traditional plate counts because of its precision, strain specificity and the ability to obtain results in a matter of hours. PMID- 29696009 TI - Diversity of Bacillus thuringiensis Strains From Qatar as Shown by Crystal Morphology, delta-Endotoxins and Cry Gene Content. AB - Bacillus thuringiensis (Bt) based insecticidal formulations have been recognized as one of the most successful, environmentally safe and sustainable method of controlling insect pests. Research teams worldwide are in search of Bt diversity giving more choices of bio-insecticides and alternatives to address insect resistance. In fact, there are many unexplored ecologies that could harbor novel Bt strains. This study is the first initiative to explore Bt strain diversity in Qatar. A collection of 700 Bt isolates was constructed. Scanning electron microscopy of Bt crystals showed different crystal forms, with a high abundance of spherical crystals compared to the bipyramidal ones. Among the spherical crystals, four different morphologies were observed. The delta-endotoxin content of parasporal crystals from each Bt isolate revealed that there are 16 different protein profiles among the isolates of the collection. On the other hand, plasmid pattern analysis showed seven different plasmid profiles. Their insecticidal activity was predicted by exploring the delta-endotoxin coding genes and conducting qualitative insecticidal bioassays. 19 smooth spherical crystal producing isolates have been identified that could be possible candidates for endotoxin production targeting Dipteran insects. Another group of 259 isolates producing bipyramidal and cuboidal crystals could target Lepidopteran and Coleopteran insects. The remaining 422 isolates have novel profiles. In conclusion, Qatari soil ecology provides a good collection and diversity of Bt isolates. In addition to strains harboring genes encoding common endotoxins, the majority are different and very promising for the search of novel insecticidal endotoxins. PMID- 29696010 TI - Characterization of a Merkel Cell Polyomavirus-Positive Merkel Cell Carcinoma Cell Line CVG-1. AB - Merkel cell polyomavirus (MCV) plays a causal role in ~80% of Merkel cell carcinomas (MCC). MCV is clonally integrated into the MCC tumor genome, which results in persistent expression of large T (LT) and small T (sT) antigen oncoproteins encoded by the early locus. In MCV-positive MCC tumors, LT is truncated by premature stop codons or deletions that lead to loss of the C terminal origin binding (OBD) and helicase domains important for replication. The N-terminal Rb binding domain remains intact. MCV-positive cell lines derived from MCC explants have been valuable tools to study the molecular mechanism of MCV induced Merkel cell carcinogenesis. Although all cell lines have integrated MCV and express truncated LT antigens, the molecular sizes of the LT proteins differ between cell lines. The copy number of integrated viral genome also varies across cell lines, leading to significantly different levels of viral protein expression. Nevertheless, these cell lines share phenotypic similarities in cell morphology, growth characteristics, and neuroendocrine marker expression. Several low-passage MCV-positive MCC cell lines have been established since the identification of MCV. We describe a new MCV-positive MCV cell line, CVG-1, with features distinct from previously reported cell lines. CVG-1 tumor cells grow in more discohesive clusters in loose round cell suspension, and individual cells show dramatic size heterogeneity. It is the first cell line to encode an MCV sT polymorphism resulting in a unique leucine (L) to proline (P) substitution mutation at amino acid 144. CVG-1 possesses a LT truncation pattern near identical to that of MKL-1 cells differing by the last two C-terminal amino acids and also shows an LT protein expression level similar to MKL-1. Viral T antigen knockdown reveals that, like other MCV-positive MCC cell lines, CVG-1 requires T antigen expression for cell proliferation. PMID- 29696011 TI - Topical Colloidal Silver for the Treatment of Recalcitrant Chronic Rhinosinusitis. AB - Background: The management of recalcitrant chronic rhinosinusitis (CRS) is challenged by difficult-to-treat polymicrobial biofilms and multidrug resistant bacteria. This has led to the search for broad-spectrum non-antibiotic antimicrobial therapies. Colloidal silver (CS) has significant antibiofilm activity in vitro and in vivo against S. aureus, MRSA, and P. aeruginosa. However, due to the lack of scientific efficacy, it is only currently used as an alternative medicine. This is the first study looking at the safety and efficacy of CS in recalcitrant CRS. Methods: Patients were included when they had previously undergone endoscopic sinus surgery and presented with signs and symptoms of sinus infection with positive bacterial cultures. Twenty-two patients completed the study. Patients were allocated to 10-14 days of culture directed oral antibiotics with twice daily saline rinses (n = 11) or 10 days of twice daily 0.015 mg/mL CS rinses (n = 11). Safety observations included pre- and post treatment serum silver levels, University of Pennsylvania Smell Identification Test (UPSIT) and adverse event (AE) reporting. Efficacy was assessed comparing microbiology results, Lund Kennedy Scores (LKS) and symptom scores using Visual Analog Scale (VAS) and Sino-Nasal Outcome Test (SNOT-22). Results: CS demonstrated good safety profile with no major adverse events, no changes in UPSIT and transient serum silver level changes in 4 patients. CS patients had 1/11 (9.09%) negative cultures, compared to 2/11 (18.18%) in the control group upon completion of the study. Whilst not statistically significant, both groups showed similar improvement in symptoms and endoscopic scores. Conclusion: This study concludes that twice daily CS (0.015 mg/mL) sinonasal rinses for 10 days is safe but not superior to culture-directed oral antibiotics. Further studies including more patients and looking at longer treatment or improving the tonicity of the solution for better tolerability should be explored. PMID- 29696012 TI - Energy Gradients Structure Microbial Communities Across Sediment Horizons in Deep Marine Sediments of the South China Sea. AB - The deep marine subsurface is a heterogeneous environment in which the assembly of microbial communities is thought to be controlled by a combination of organic matter deposition, electron acceptor availability, and sedimentology. However, the relative importance of these factors in structuring microbial communities in marine sediments remains unclear. The South China Sea (SCS) experiences significant variability in sedimentation across the basin and features discrete changes in sedimentology as a result of episodic deposition of turbidites and volcanic ashes within lithogenic clays and siliceous or calcareous ooze deposits throughout the basin's history. Deep subsurface microbial communities were recently sampled by the International Ocean Discovery Program (IODP) at three locations in the SCS with sedimentation rates of 5, 12, and 20 cm per thousand years. Here, we used Illumina sequencing of the 16S ribosomal RNA gene to characterize deep subsurface microbial communities from distinct sediment types at these sites. Communities across all sites were dominated by several poorly characterized taxa implicated in organic matter degradation, including Atribacteria, Dehalococcoidia, and Aerophobetes. Sulfate-reducing bacteria comprised only 4% of the community across sulfate-bearing sediments from multiple cores and did not change in abundance in sediments from the methanogenic zone at the site with the lowest sedimentation rate. Microbial communities were significantly structured by sediment age and the availability of sulfate as an electron acceptor in pore waters. However, microbial communities demonstrated no partitioning based on the sediment type they inhabited. These results indicate that microbial communities in the SCS are structured by the availability of electron donors and acceptors rather than sedimentological characteristics. PMID- 29696013 TI - Functional Resistance to Recurrent Spatially Heterogeneous Disturbances Is Facilitated by Increased Activity of Surviving Bacteria in a Virtual Ecosystem. AB - Bacterial degradation of organic compounds is an important ecosystem function with relevance to, e.g., the cycling of elements or the degradation of organic contaminants. It remains an open question, however, to which extent ecosystems are able to maintain such biodegradation function under recurrent disturbances (functional resistance) and how this is related to the bacterial biomass abundance. In this paper, we use a numerical simulation approach to systematically analyze the dynamic response of a microbial population to recurrent disturbances of different spatial distribution. The spatially explicit model considers microbial degradation, growth, dispersal, and spatial networks that facilitate bacterial dispersal mimicking effects of mycelial networks in nature. We find: (i) There is a certain capacity for high resistance of biodegradation performance to recurrent disturbances. (ii) If this resistance capacity is exceeded, spatial zones of different biodegradation performance develop, ranging from no or reduced to even increased performance. (iii) Bacterial biomass and biodegradation dynamics respond inversely to the spatial fragmentation of disturbances: overall biodegradation performance improves with increasing fragmentation, but bacterial biomass declines. (iv) Bacterial dispersal networks can enhance functional resistance against recurrent disturbances, mainly by reactivating zones in the core of disturbed areas, even though this leads to an overall reduction of bacterial biomass. PMID- 29696014 TI - Genetic Polymorphism at CCL5 Is Associated With Protection in Chagas' Heart Disease: Antagonistic Participation of CCR1+ and CCR5+ Cells in Chronic Chagasic Cardiomyopathy. AB - Chronic cardiomyopathy is the main clinical manifestation of Chagas disease (CD), a disease caused by Trypanosoma cruzi infection. A hallmark of chronic chagasic cardiomyopathy (CCC) is a fibrogenic inflammation mainly composed of CD8+ and CD4+ T cells and macrophages. CC-chemokine ligands and receptors have been proposed to drive cell migration toward the heart tissue of CD patients. Single nucleotide polymorphisms (SNPs) in CC-chemokine ligand and receptor genes may determine protein expression. Herein, we evaluated the association of SNPs in the CC-chemokines CCL2 (rs1024611) and CCL5 (rs2107538, rs2280788) and the CCL5/RANTES receptors CCR1 (rs3181077, rs1491961, rs3136672) and CCR5 (rs1799987) with risk and progression toward CCC. We performed a cross-sectional association study of 406 seropositive patients from endemic areas for CD in the State of Pernambuco, Northeast Brazil. The patients were classified as non-cardiopathic (A, n = 110) or cardiopathic (mild, B1, n = 163; severe, C, n = 133). Serum levels of CCL5 and CCL2/MCP-1 were elevated in CD patients but were neither associated with risk/severity of CCC nor with SNP genotypes. After logistic regression analysis with adjustment for the covariates gender and ethnicity, CCL5 -403 (rs2107538) CT heterozygotes (OR = 0.5, P-value = 0.04) and T carriers (OR = 0.5, P-value = 0.01) were associated with protection against CCC. To gain insight into the participation of the CCL5-CCR5/CCR1 axis in CCC, mice were infected with the Colombian T. cruzi strain. Increased CCL5 concentrations were detected in cardiac tissue. In spleen, frequencies of CCR1+ CD8+ T cells and CD14+ macrophages were decreased, while frequencies of CCR5+ cells were increased. Importantly, CCR1+CD14+ macrophages were mainly IL-10+, while CCR5+ cells were mostly TNF+. CCR5-deficient infected mice presented reduced TNF concentrations and injury in heart tissue. Selective blockade of CCR1 (Met-RANTES therapy) in infected Ccr5-/- mice supported a protective role for CCR1 in CCC. Furthermore, parasite antigen stimulation of CD patient blood cells increased the frequency of CCR1+CD8+ T cells and CCL5 production. Collectively, our data support that a genetic variant of CCL5 and CCR1+ cells confer protection against Chagas heart disease, identifying the CCL5-CCR1 axis as a target for immunostimulation. PMID- 29696015 TI - In Silico and Structural Analyses Demonstrate That Intrinsic Protein Motions Guide T Cell Receptor Complementarity Determining Region Loop Flexibility. AB - T-cell immunity is controlled by T cell receptor (TCR) binding to peptide major histocompatibility complexes (pMHCs). The nature of the interaction between these two proteins has been the subject of many investigations because of its central role in immunity against pathogens, cancer, in autoimmunity, and during organ transplant rejection. Crystal structures comparing unbound and pMHC-bound TCRs have revealed flexibility at the interaction interface, particularly from the perspective of the TCR. However, crystal structures represent only a snapshot of protein conformation that could be influenced through biologically irrelevant crystal lattice contacts and other factors. Here, we solved the structures of three unbound TCRs from multiple crystals. Superposition of identical TCR structures from different crystals revealed some conformation differences of up to 5 A in individual complementarity determining region (CDR) loops that are similar to those that have previously been attributed to antigen engagement. We then used a combination of rigidity analysis and simulations of protein motion to reveal the theoretical potential of TCR CDR loop flexibility in unbound state. These simulations of protein motion support the notion that crystal structures may only offer an artifactual indication of TCR flexibility, influenced by crystallization conditions and crystal packing that is inconsistent with the theoretical potential of intrinsic TCR motions. PMID- 29696016 TI - Galphai Signaling Promotes Marginal Zone B Cell Development by Enabling Transitional B Cell ADAM10 Expression. AB - The follicular (FO) versus marginal zone (MZ) B cell fate decision in the spleen depends upon BCR, BAFF, and Notch2 signaling. Whether or how Gi signaling affects this fate decision is unknown. Here, we show that direct contact with Notch ligand expressing stromal cells (OP9-Delta-like 1) cannot promote normal MZ B cell development when progenitor B cells lack Galphai proteins, or if Gi signaling is disabled. Consistent with faulty ADAM10-dependent Notch2 processing, Galphai-deficient transitional B cells had low ADAM10 membrane expression levels and reduced Notch2 target gene expression. Immunoblotting Galphai-deficient B cell lysates revealed a reduction in mature, processed ADAM10. Suggesting that Galphai signaling promotes ADAM10 membrane expression, stimulating normal transitional B cells with CXCL12 raised it, while inhibiting Galphai nucleotide exchange blocked its upregulation. Surprisingly, inhibiting Galphai nucleotide exchange in transitional B cells also impaired the upregulation of ADAM10 that occurs following antigen receptor crosslinking. These results indicate that Galphai signaling supports ADAM10 maturation and activity in transitional B cells, and ultimately Notch2 signaling to promote MZ B cell development. PMID- 29696017 TI - A Future for Autologous Hematopoietic Stem Cell Transplantation in Type 1 Diabetes. PMID- 29696018 TI - Overinterpretation and Overtreatment of Low-Titer Antibodies Against Contactin Associated Protein-2. AB - Antibodies (abs) against neural or glial antigens have become important diagnostic markers of autoimmune encephalitides. A key requirement for interpretation of any test in clinical medicine is specificity. In this work, a 35-year-old female patient with low-titer contactin-associated protein-2 abs not satisfying clinical criteria of autoimmune encephalitis is reported. The patient had a recurrent depressive disorder and, at the time of the ab study, a moderate depressive episode. Overinterpretation and misinterpretation of patient's complaints and paraclinical study results fueled the idea of an autoimmune encephalitis. It is suggested to check patients with supposedly positive ab test results critically for clinical criteria, titer cutoffs, and ab-typical epidemiological features like age and sex. PMID- 29696019 TI - High-Mobility Group Box 1-Induced Complement Activation Causes Sterile Inflammation. AB - High-mobility group box 1 (HMGB1), a well-known danger-associated molecular pattern molecule, acts as a pro-inflammatory molecule when secreted by activated immune cells or released after necrotic cell damage. HMGB1 binds to immunogenic bacterial components and augments septic inflammation. In this study, we show how HMGB1 mediates complement activation, promoting sterile inflammation. We show that HMGB1 activates the classical pathway of complement system in an antibody independent manner after binding to C1q. The C3a complement activation product in human plasma and C5b-9 membrane attack complexes on cell membrane surface are detected after the addition of HMGB1. In an acetaminophen (APAP)-induced hepatotoxicity model, APAP injection reduced HMGB1 levels and elevated C3 levels in C1q-deficient mouse serum samples, compared to that in wild-type (WT) mice. APAP-induced C3 consumption was inhibited by sRAGE treatment in WT mice. Moreover, in a mouse model of brain ischemia-reperfusion injury based on middle cerebral arterial occlusion, C5b-9 complexes were deposited on vessels where HMGB1 was accumulated, an effect that was suppressed upon HMGB1 neutralization. We propose that the HMGB1 released after cell necrosis and in ischemic condition can trigger the classical pathway of complement activation to exacerbate sterile inflammation. PMID- 29696021 TI - Soluble N-Ethylmaleimide-Sensitive Factor Attachment Protein Receptor-Derived Peptides for Regulation of Mast Cell Degranulation. AB - Vesicle-associated V-soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins and target membrane-associated T-SNAREs (syntaxin 4 and SNAP-23) assemble into a core trans-SNARE complex that mediates membrane fusion during mast cell degranulation. This complex plays pivotal roles at various stages of exocytosis from the initial priming step to fusion pore opening and expansion, finally resulting in the release of the vesicle contents. In this study, peptides with the sequences of various SNARE motifs were investigated for their potential inhibitory effects against SNARE complex formation and mast cell degranulation. The peptides with the sequences of the N-terminal regions of vesicle-associated membrane protein 2 (VAMP2) and VAMP8 were found to reduce mast cell degranulation by inhibiting SNARE complex formation. The fusion of protein transduction domains to the N-terminal of each peptide enabled the internalization of the fusion peptides into the cells equally as efficiently as cell permeabilization by streptolysin-O without any loss of their inhibitory activities. Distinct subsets of mast cell granules could be selectively regulated by the N-terminal-mimicking peptides derived from VAMP2 and VAMP8, and they effectively decreased the symptoms of atopic dermatitis in mouse models. These results suggest that the cell membrane fusion machinery may represent a therapeutic target for atopic dermatitis. PMID- 29696020 TI - Extracellular Vesicles: Packages Sent With Complement. AB - Cells communicate with other cells in their microenvironment by transferring lipids, peptides, RNA, and sugars in extracellular vesicles (EVs), thereby also influencing recipient cell functions. Several studies indicate that these vesicles are involved in a variety of critical cellular processes including immune, metabolic, and coagulatory responses and are thereby associated with several inflammatory diseases. Furthermore, EVs also possess anti-inflammatory properties and contribute to immune regulation, thus encouraging an emerging interest in investigating and clarifying mechanistic links between EVs and innate immunity. Current studies indicate complex interactions of the complement system with EVs, with a dramatic influence on local and systemic inflammation. During inflammatory conditions with highly activated complement, including after severe tissue trauma and during sepsis, elevated numbers of EVs were found in the circulation of patients. There is increasing evidence that these shed vesicles contain key complement factors as well as complement regulators on their surface, affecting inflammation and the course of disease. Taken together, interaction of EVs regulates complement activity and contributes to the pro- and anti inflammatory immune balance. However, the molecular mechanisms behind this interaction remain elusive and require further investigation. The aim of this review is to summarize the limited current knowledge on the crosstalk between complement and EVs. A further aspect is the clinical relevance of EVs with an emphasis on their capacity as potential therapeutic vehicles in the field of translational medicine. PMID- 29696024 TI - Cutaneous Vasculitis and Recurrent Infection Caused by Deficiency in Complement Factor I. AB - Cutaneous leukocytoclastic vasculitis arises from immune complex deposition and dysregulated complement activation in small blood vessels. There are many causes, including dysregulated host response to infection, drug reactions, and various autoimmune conditions. It is increasingly recognised that some monogenic autoinflammatory diseases cause vasculitis, although genetic causes of vasculitis are extremely rare. We describe a child of consanguineous parents who presented with chronic cutaneous leukocytoclastic vasculitis, recurrent upper respiratory tract infection, and hypocomplementaemia. A homozygous p.His380Arg mutation in the complement factor I (CFI) gene CFI was identified as the cause, resulting in complete absence of alternative complement pathway activity, decreased classical complement activity, and low levels of serum factor I, C3, and factor H. C4 and C2 levels were normal. The same homozygous mutation and immunological defects were also identified in an asymptomatic sibling. CFI deficiency is thus now added to the growing list of monogenic causes of vasculitis and should always be considered in vasculitis patients found to have persistently low levels of C3 with normal C4. PMID- 29696022 TI - Exosomes and Immune Response in Cancer: Friends or Foes? AB - Exosomes are a type of extracellular vesicle whose study has grown exponentially in recent years. This led to the understanding that these structures, far from being inert waste by-products of cellular functioning, are active players in intercellular communication mechanisms, including in the interactions between cancer cells and the immune system. The deep comprehension of the crosstalk between tumors and the immune systems of their hosts has gained more and more importance, as immunotherapeutic techniques have emerged as viable options for several types of cancer. In this review, we present a comprehensive, updated, and elucidative review of the current knowledge on the functions played by the exosomes in this crosstalk. The roles of these vesicles in tumor antigen presentation, immune activation, and immunosuppression are approached as the relevant interactions between exosomes and the complement system. The last section of this review is reserved for the exploration of the results from the first phase I to II clinical trials of exosomes-based cell-free cancer vaccines. PMID- 29696025 TI - Adrenergic Signaling at the Interface of Allergic Asthma and Viral Infections. AB - Upper respiratory viral infections are a major etiologic instigator of allergic asthma, and they drive severe exacerbations of allergic inflammation in the lower airways of asthma sufferers. Rhinovirus (RV), in particular, is the main viral instigator of these pathologies. Asthma exacerbations due to RV infections are the most frequent reasons for hospitalization and account for the majority of morbidity and mortality in asthma patients. In both critical care and disease control, long- and short-acting beta2-agonists are the first line of therapeutic intervention, which are used to restore airway function by promoting smooth muscle cell relaxation in bronchioles. While prophylactic use of beta2-agonists reduces the frequency and pathology of exacerbations, their role in modulating the inflammatory response is only now being appreciated. Adrenergic signaling is a component of the sympathetic nervous system, and the natural ligands, epinephrine and norepinephrine (NE), regulate a multitude of autonomic functions including regulation of both the innate and adaptive immune response. NE is the primary neurotransmitter released by post-ganglionic sympathetic neurons that innervate most all peripheral tissues including lung and secondary lymphoid organs. Thus, the adrenergic signaling pathways are in direct contact with both the central and peripheral immune compartments. We present a perspective on how the adrenergic signaling pathway controls immune function and how beta2-agonists may influence inflammation in the context of virus-induced asthma exacerbations. PMID- 29696023 TI - C-Type Lectin Receptors in Asthma. AB - Asthma is a heterogeneous disease that affects approximately 300 million people worldwide, largely in developed countries. The etiology of the disease is poorly understood, but is likely to involve specific innate and adaptive responses to inhaled microbial components that are found in allergens. Fungal-derived allergens represent a major contributing factor in the initiation, persistence, exacerbation, and severity of allergic asthma. C-type lectin like receptors, such as dectin-1, dectin-2, DC-specific intercellular adhesion molecule 3-grabbing nonintegrin, and mannose receptor, recognize many fungal-derived allergens and other structurally similar allergens derived from house dust mites (HDM). In some cases, the fungal derived allergens have been structurally and functionally identified alongside their respective receptors in both humans and mice. In this review, we discuss recent understanding on how selected fungal and HDM derived allergens as well as their known or unknown receptors shape allergic airway diseases. PMID- 29696026 TI - Allergic TH2 Response Governed by B-Cell Lymphoma 6 Function in Naturally Occurring Memory Phenotype CD4+ T Cells. AB - Transcriptional repressor B-cell lymphoma 6 (Bcl6) appears to regulate TH2 immune responses in allergies, but its precise role is unclear. We previously reported that Bcl6 suppressed IL-4 production in naive CD4+ T cell-derived memory TH2 cells. To investigate Bcl6 function in allergic responses in naturally occurring memory phenotype CD4+ T (MPT) cells and their derived TH2 (MPTH2) cells, Bcl6 manipulated mice, highly conserved intron enhancer (hcIE)-deficient mice, and reporter mice for conserved noncoding sequence 2 (CNS2) 3' distal enhancer region were used to elucidate Bcl6 function in MPT cells. The molecular mechanisms of Bcl6-mediated TH2 cytokine gene regulation were elucidated using cellular and molecular approaches. Bcl6 function in MPT cells was determined using adoptive transfer to naive mice, which were assessed for allergic airway inflammation. Bcl6 suppressed IL-4 production in MPT and MPTH2 cells by suppressing CNS2 enhancer activity. Bcl6 downregulated Il4 expression in MPTH2 cells, but not MPT cells, by suppressing hcIE activity. The inhibitory functions of Bcl6 in MPT and MPTH2 cells attenuated allergic responses. Bcl6 is a critical regulator of IL-4 production by MPT and MPTH2 cells in TH2 immune responses related to the pathogenesis of allergies. PMID- 29696027 TI - Genomics-Enabled Next-Generation Breeding Approaches for Developing System Specific Drought Tolerant Hybrids in Maize. AB - Breeding science has immensely contributed to the global food security. Several varieties and hybrids in different food crops including maize have been released through conventional breeding. The ever growing population, decreasing agricultural land, lowering water table, changing climate, and other variables pose tremendous challenge to the researchers to improve the production and productivity of food crops. Drought is one of the major problems to sustain and improve the productivity of food crops including maize in tropical and subtropical production systems. With advent of novel genomics and breeding tools, the way of doing breeding has been tremendously changed in the last two decades. Drought tolerance is a combination of several component traits with a quantitative mode of inheritance. Rapid DNA and RNA sequencing tools and high throughput SNP genotyping techniques, trait mapping, functional characterization, genomic selection, rapid generation advancement, and other tools are now available to understand the genetics of drought tolerance and to accelerate the breeding cycle. Informatics play complementary role by managing the big-data generated from the large-scale genomics and breeding experiments. Genome editing is the latest technique to alter specific genes to improve the trait expression. Integration of novel genomics, next-generation breeding, and informatics tools will accelerate the stress breeding process and increase the genetic gain under different production systems. PMID- 29696028 TI - Engineering the Chloroplast Genome of Oleaginous Marine Microalga Nannochloropsis oceanica. AB - Plastid engineering offers an important tool to fill the gap between the technical and the enormous potential of microalgal photosynthetic cell factory. However, to date, few reports on plastid engineering in industrial microalgae have been documented. This is largely due to the small cell sizes and complex cell-wall structures which make these species intractable to current plastid transformation methods (i.e., biolistic transformation and polyethylene glycol mediated transformation). Here, employing the industrial oleaginous microalga Nannochloropsis oceanica as a model, an electroporation-mediated chloroplast transformation approach was established. Fluorescent microscopy and laser confocal scanning microscopy confirmed the expression of the green fluorescence protein, driven by the endogenous plastid promoter and terminator. Zeocin resistance selection led to an acquisition of homoplasmic strains of which a stable and site-specific recombination within the chloroplast genome was revealed by sequencing and DNA gel blotting. This demonstration of electroporation mediated chloroplast transformation opens many doors for plastid genome editing in industrial microalgae, particularly species of which the chloroplasts are recalcitrant to chemical and microparticle bombardment transformation. PMID- 29696030 TI - Genetics and Physiology of the Nuclearly Inherited Yellow Foliar Mutants in Soybean. AB - Plant photosynthetic pigments are important in harvesting the light energy and transfer of energy during photosynthesis. There are several yellow foliar mutants discovered in soybean and chromosomal locations for about half of them have been deduced. Viable-yellow mutants are capable of surviving with decreased photosynthesis, while lethal-yellow mutants die shortly after germination. In addition to the decreased chlorophyll content, other features associated with yellow mutants include altered Chl a and Chl b ratio, reduction in chloroplast size and number, lower levels of other photosynthetic pigments, inability of thylakoids to stack into granum, lack of lamellae to interconnect granum and reduced size of the light harvesting complex. For some yellow mutants, temperature and/or light play a critical role in the manifestation of phenotype. Although yellow foliar mutants are viewed as undesirable for crop production, there is the possibility of these mutants to create a positive impact by reducing the total amount of chlorophyll and diverting resources toward increased biochemical photosynthetic capacity leading to increased yield. Recent advances in model plants led to the isolation and characterization of various genes associated with yellow foliar phenotype. Knowledge gained from the model plants can be applied using homology based cloning approach to isolate genes in soybean and understanding the modes of actions of the involved proteins. Identifying and characterizing yellow foliar mutants will not only aid in understanding the biosynthetic pathways involved in the photosynthetic machinery, but may also provide ways to increase soybean productivity. PMID- 29696031 TI - Putative Connections Between Nitrate Reductase S-Nitrosylation and NO Synthesis Under Pathogen Attacks and Abiotic Stresses. AB - Nitrate reductase (NR) is the key enzyme for nitrogen assimilation in plant cells and also works as an important enzymatic source of nitric oxide (NO), which then regulates plant growth and resistance to biotic and abiotic stresses. However, how NR activities are finely tuned to modulate these biological processes remain largely unknown. Here we present a SWISSPROT 3D analysis of different NR from plant sources indicating the possible sites of S-nitrosylation, and show some evidence of immunoblottings to S-nitrosated (SNO-) proteins. We also found that S nitrosylation status of NR is negatively correlated with the enzyme activity. The production of NO via NR in vitro represents only 1% of its nitrate reduction activity, possibly due to NO generated through NR reaction may deactivate the enzyme by this S-nitrosylation-mediated negative-feedback regulation. NR-mediated NO generation also plays a key role in protecting plants from abiotic stresses through activating antioxidant enzymes and increasing antioxidants. Putative connections between NR S-nitrosylation and NO biosynthesis under pathogen attacks and abiotic stresses are discussed in this Perspective. PMID- 29696029 TI - Nuclear Signaling of Plant MAPKs. AB - Mitogen-activated protein kinases (MAPKs) are conserved protein kinases in eukaryotes that establish signaling modules where MAPK kinase kinases (MAPKKKs) activate MAPK kinases (MAPKKs) which in turn activate MAPKs. In plants, they are involved in the signaling of multiple environmental stresses and developmental programs. MAPKs phosphorylate their substrates and this post-translational modification (PTM) contributes to the regulation of proteins. PTMs may indeed modify the activity, subcellular localization, stability or trans-interactions of modified proteins. Plant MAPKs usually localize to the cytosol and/or nucleus, and in some instances they may also translocate from the cytosol to the nucleus. Upon the detection of environmental changes at the cell surface, MAPKs participate in the signal transduction to the nucleus, allowing an adequate transcriptional reprogramming. The identification of plant MAPK substrates largely contributed to a better understanding of the underlying signaling mechanisms. In this review, we highlight the nuclear signaling of plant MAPKs. We discuss the activation, regulation and activity of plant MAPKs, as well as their nuclear re-localization. We also describe and discuss known nuclear substrates of plant MAPKs in the context of biotic stress, abiotic stress and development and consider future research directions in the field of plant MAPKs. PMID- 29696032 TI - A Node-Expressed Transporter OsCCX2 Is Involved in Grain Cadmium Accumulation of Rice. AB - Excessive cadmium (Cd) accumulation in grains of rice (Oryza sativa L.) is a risk to food security. The transporters in the nodes of rice are involved in the distribution of mineral elements including toxic elements to different tissues such as grains. However, the mechanism of Cd accumulation in grains is largely unknown. Here, we report a node-expressed transporter gene, OsCCX2, a putative cation/calcium (Ca) exchanger, mediating Cd accumulation in the grains of rice. Knockout of OsCCX2 caused a remarkable reduction of Cd content in the grains. Further study showed that disruption of this gene led to a reduced root-to-shoot translocation ratio of Cd. Moreover, Cd distribution was also disturbed in different levels of internode and leaf. OsCCX2 is localized to plasma membrane, and OsCCX2 is mainly expressed in xylem region of vascular tissues at the nodes. OsCCX2 might function as an efflux transporter, responsible for Cd loading into xylem vessels. Therefore, our finding revealed a novel Cd transporter involved in grain Cd accumulation, possibly via a Ca transport pathway in the nodes of rice. PMID- 29696033 TI - REDIdb 3.0: A Comprehensive Collection of RNA Editing Events in Plant Organellar Genomes. AB - RNA editing is an important epigenetic mechanism by which genome-encoded transcripts are modified by substitutions, insertions and/or deletions. It was first discovered in kinetoplastid protozoa followed by its reporting in a wide range of organisms. In plants, RNA editing occurs mostly by cytidine (C) to uridine (U) conversion in translated regions of organelle mRNAs and tends to modify affected codons restoring evolutionary conserved aminoacid residues. RNA editing has also been described in non-protein coding regions such as group II introns and structural RNAs. Despite its impact on organellar transcriptome and proteome complexity, current primary databases still do not provide a specific field for RNA editing events. To overcome these limitations, we developed REDIdb a specialized database for RNA editing modifications in plant organelles. Hereafter we describe its third release containing more than 26,000 events in a completely novel web interface to accommodate RNA editing in its genomics, biological and evolutionary context through whole genome maps and multiple sequence alignments. REDIdb is freely available at http://srv00.recas.ba.infn.it/redidb/index.html. PMID- 29696034 TI - Review of Iodine Nutrition in Iranian Population in the Past Quarter of Century. AB - Context: Iodine deficiency is one of the most important health problems worldwide. The overall aim of this study was a narrative review of the past and present status of iodine nutrition in the Iranian population to gather and provide valuable background data in this field for future studies. Evidence Acquisition: For this narrative literature review study, published internal (SID, Iran doc, Iran medex) and international (Web of knowledge, Pubmed, SCOPUS) source studies were searched using the following medical subject heading terms: Iodine, IDD (iodine deficiency disorders), UIC (urinary iodine concentration), Goiter, IQ (intelligence quotient), thyroid hormone, Iodine and pregnancy, Iodine and breast feeding, as well as Iodized salt, reporting the prevalence of iodine deficiency and iodine nutrition status of different target populations in Iran over 25 years, between 1988 - 2014, were assessed. We found 185 abstracts by literature search, of which, 161 papers that were as case reports, animal study, with lack of regional or national data were excluded after full text evaluation. Finally 24 full papers covering regional or national data on iodine nutrition of the study population were eligible for our review. Results: Iodine deficiency, as a nutritional problem, had been identified in Iran since 1968. In the years 1987 - 1989, a few studies were done to define the prevalence of iodine deficiency in the country. The first nation-wide survey was performed in 14 provinces. Based on this survey all provinces were suffering of endemic goiter. In 1989, iodine deficiency was recognized as a major problem for community health. In 1990, salt factories began to produce iodized salt and in 1996, the second national survey was performed in 26 provinces. This survey indicated that 40% of boys and 50% of girls have goiter, with a median urinary iodine excretion of 205 ug/L. The 3rd national survey in 2001 showed that the total goiter rate is 9.8% and median UIC of 165 MUg/L. In 2007, the 3th national survey was conducted 17 years after iodized salt consumption by Iranian households. In this study the total goiter rate and median urinary iodine was 5.7% and 145 MUg/L, respectively. The 5th national survey conducted in 2013, showed household consumption of iodized salt for all provinces was 98% and the median urinary iodine of school children was 161 MUg/L. Following the 5th national survey, the 1st national survey of the iodine status and thyroid function of pregnant women, conducted in 10 provinces in the different region of the country, documented a median UIC for pregnant women of 87.3 ug/L, results of this national survey clarified that despite iodine sufficiency of school children in Iran, pregnant women have moderate iodine deficiency and need iodine supplementation. Conclusions: The success of iodine deficiency control program depends on well designed programmatic steps and mandatory iodized salt consumption in certain situations. The iodine intake of school children is sufficient, however, Iranian pregnant women are suffering from moderate iodine deficiency and need iodine supplementation. PMID- 29696035 TI - Comparison of Two Calorie-Reduced Diets of Different Carbohydrate and Fiber Contents and a Simple Dietary Advice Aimed to Modify Carbohydrate Intake on Glycemic Control and Inflammatory Markers in Type 2 Diabetes: A Randomized Trial. AB - Objectives: The aim of this study was to compare the effect of a simple dietary advice with two energy-restricted diets with different carbohydrate and fiber contents on anthropometric, biochemical, and inflammatory markers over an 8-wk intervention period in individuals with diabetes. Methods: Forty-seven patients with type 2 diabetes (31 women and 16 men; age: 52.9 +/- 8.0 years, body mass index: 29.5 +/- 4.9 kg.m-2) completed an 8-wk randomized intervention trial that compared a simple dietary advice aimed to modulate carbohydrate intake (n = 13) with the two calorie-restricted (CR) diets (25% caloric restriction from total energy requirements) differing with regard to carbohydrate and fiber content, one with higher fiber (CRHF) containing 55% energy from carbohydrate plus a tablespoon of psyllium powder (n = 18) and the other with lower carbohydrate (CRLC) containing 40% energy from carbohydrate plus placebo powder (n = 16). Weight, plasma concentrations of glucose, insulin, lipids, interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) were determined at baseline and after 8 weeks. Results: The mean change of body weight and plasma lipids were not different between the groups. Fasting plasma insulin and the homeostasis model assessment of insulin resistance (HOMA-IR) were significantly lower in the CRHF group (changes from baseline values in simple advice, CRHF, and CRLC were 1.3 +/- 1.9, -1.0 +/- 1.2, and 0.3 +/- 3.1 uIL/mL for insulin and 0.5 +/- 0.7, -0.3 +/- 0.6, and 0.2 +/- 0.9 for HOMA-IR, respectively). The levels of IL-6 significantly decreased in the CRHF and CRLC groups (changes from baseline values in simple advice, CRHF, and CRLC were 7.5 +/- 6.8, -1.2 +/- 4.7, and -4.2 +/- 5.6 pg/mL, respectively). TNF-alpha levels were significantly lower only in the CRHF compared to the advice group (P < 0.05). Conclusions: Our results suggest that in comparison with simple advice to modify carbohydrate intake, a calorie restricted, moderate carbohydrate diet supplemented with psyllium has better effects on plasma insulin and pro-inflammatory cytokines in patients with type 2 diabetes. PMID- 29696036 TI - Malignancy Rates in Thyroid Nodules Classified as Bethesda Categories III and IV: Retrospective Data from a Tertiary Center. AB - Background: Thyroid fine needle aspiration (FNA) has a well-established role in the diagnosis of thyroid nodules, and the "Bethesda system for reporting thyroid cytopathology" is used to interpret FNA results. Bethesda categories III and IV encompass varying risks of malignancy. In addition, there is some debate in the literature about how to select among many acceptable treatment approaches. Objectives: To establish an association between these 2 cytological categories and malignancy rates in patients treated in a referral tertiary cancer center, where surgical treatment is recommended for all these patients. Methods: A total of 615 thyroid nodules (582 patients) were included in this retrospective study. There were 478 nodules that were classified as Bethesda category III and 137 nodules as Bethesda category IV. Electronic records were reviewed to establish a correlation between the FNA cytological results and the final histopathological analyses. Incidentally detected carcinomas were considered separately. Results: Among the bethesda category III group, 75 malignant nodules (15.7%) were coincident with the target nodule (74 patients, 16.2%). Incidental carcinomas were found in 13.8% of these patients. The remaining 403 (84.3%) target nodules were benign. Among the bethesda category IV nodules, 23 malignant nodules (16.8%) were coincident with the target nodule. Incidental carcinomas were found in 25 patients (19.7%). The other 114 target nodules were benign. A total of 46 patients (52.3%) had carcinomas in the thyroid lobe contralateral to the one containing the target nodule, and 40 patients (45.5%) had carcinomas exclusively in the contralateral lobe. Conclusions: We observed a 16% rate of malignancy in nodules classified as bethesda category III and 17% among bethesda category IV. When incidental carcinomas were included, the rates of malignancy doubled. PMID- 29696037 TI - Pharmacological Treatment in Diabetes Mellitus Type 1 - Insulin and What Else? AB - The basis of treatment in autoimmune diabetes is insulin therapy; however, many clinical cases have proven that this method does not solve all problems. Trials of causal treatment including blocking the autoimmune processes and insulin producing cells transplants were carried out. Those methods require more research to be concerned as efficient and safe ways of treatment in type 1 diabetes. The use of non-insulin adjunct treatment is a new trend. It has been successfully used in laboratories as well as clinical trials. Metformin is the most widely used drug, together with sodium-glucose co-transporters 2 (SGLT2) inhibitors, amylin analogues, glucagon-like peptide 1 (GLP-1) receptor agonists, and dipeptidyl peptidase-4 (DPP-4) inhibitors. The results of administration of these medicaments give good outcomes in patients with diabetes mellitus type 1. Most likely, in the near future, they will progressively be used in both adult and adolescent patients with type 1 diabetes. Further multicenter, randomized studies are required to evaluate the efficacy of treatment and long term safety of these drugs. PMID- 29696038 TI - Insulin Resistance Associated With Differentiated Thyroid Carcinoma: Penalized Conditional Logistic Regression Analysis of a Matched Case-Control Study Data. AB - Background: In the recent years, thyroid cancer incidence has increased worldwide. It has been questioned whether factors, such as insulin resistance, are involved in this rise. The main aim of this study was to examine the association between insulin resistance and differentiated thyroid cancer. Methods: This case-control study was performed on 30 newly diagnosed patients with differentiated thyroid cancer and 30 healthy controls. Thirty euthyroid patients recently diagnosed with differentiated thyroid cancer, based on the fine needle aspiration cytology, were examined for insulin resistance before thyroidectomy in the euthyroid state. For each patient in the case group, one healthy euthyroid individual without thyroid nodule from general population was matched based on gender, age (+/- 1 year), and body mass index (BMI) (+/- 1). Thyroid function test, thyroid antibodies, serum glucose, serum insulin, and thyroid ultrasonography was performed for all participants. Insulin resistance was defined based on homeostasis model assessment of insulin resistance (HOMA-IR) to be more than 2.5. Results: In the patient group, 24 (80%) cases were female and 6 (20%) were male. Insulin resistance was more prevalent in the case group than the control group (43.3% versus 13.3%). Insulin sensitivity index was lower in the case group than in the control group (50 and 81, respectively). There was a significant positive association between serum HOMA-IR levels and differentiated thyroid cancer (OR: 2.43 for 1 unit increase in HOMA-IR, 95% CI: 1.35 - 5.51; P = 0.001). Insulin resistance was significantly associated with differentiated thyroid cancer (OR: 4, 95 % CI: 1.27 - 17.6; P = 0.016). Conclusions: There was a significant association between insulin resistance and differentiated thyroid carcinoma. More research with a larger sample size and prospective design are needed to determine the role of this factor in the development of differentiated thyroid cancers. PMID- 29696039 TI - Thrombosis in Thyroid Cancer. AB - Background: The number of studies on venous thromboembolism (VTE) and thyroid cancer is very scarce and existing data are contradictory. This paper reviews VTE in thyroid cancer. Methods: The following words were used for a comprehensive literature review using MEDLINE database: Blood coagulation factors; thyroid hormones; blood coagulation tests; venous thromboembolism; receptors thyroid hormone; hemostasis; fibrinolysis; bleeding; blood coagulation disorders; thyroid neoplasms; Thyroid cancer, papillary; Thyroid cancer, follicular; Thyroid carcinoma, anaplastic; Thyroid cancer, Hurthle cell; Familial medullary thyroid carcinoma; venous thrombosis; Pulmonary embolism; Blood coagulation factors. The studies, which include any changes in hemostasis and thyroid cancer were included and reviewed. Results: Although few studies have shown a possible increase in VTE occurrence in thyroid cancer in patients >= 60 years old and in proximity to cancer diagnosis, other studies could not find any difference compared to general population. New thyroid cancer classification excluding common subtype(s) with benign nature, may affect the results of the future studies on association of VTE and thyroid cancer. Conclusions: Prospective studies on the occurrence of VTE in various types and severities of thyroid cancer and in different age groups are warranted, as the results would affect clinical practice on the necessity of usage of anticoagulants in some thyroid cancer groups. PMID- 29696040 TI - Adrenal Ganglioneuroblastoma in an Adult: A Rare Case Report. AB - Ganglioneuroblastoma is a primary malignant tumor of the sympathetic nervous system. It usually occurs in children and is extremely rare in adults. Here, we report a case of an adrenal ganglioneuroblastoma in a 38-year-old man. The adrenal incidentaloma was surgically removed and pathologically diagnosed as a ganglioneuroblastoma. The characteristics were described, because it is an unusual tumor based on the published reports in adults. To the best of our knowledge, fewer than 50 cases of ganglioneuroblastoma and 19 cases of adrenal ganglioneuroblastoma, including this case, are reported in the literature. PMID- 29696041 TI - Acute Transverse Myelitis in Children, Literature Review. AB - Objective: Acute transverse myelitis (ATM) is a rare inflammatory demyelinating disorder characterized by relatively acute onset of motor, sensory, and autonomic dysfunction. Children comprise 20% of total cases of ATM. In this review, we described the current literature on childhood ATM, focusing on the epidemiology, pathogenesis, clinical presentation, approach to diagnosis, differential diagnosis, treatment and outcome in the pediatric population. Materials &Methods: We searched the related articles in electronic databases such as Scopus, EMBASE, Google Scholar, and PubMed. All study designs were included and the essential key words for searching were myelitis, acute transverse myelitis, childhood transverse myelitis, and acquired demyelinating syndromes. Results: The related data focusing on the epidemiology, pathogenesis, clinical presentation, diagnostic approach and differential diagnosis, treatment and outcome of pediatric ATM were gathered and described. Conclusion: ATM is a heterogeneous disorder in children with a broad spectrum of clinical presentation, etiology, and outcome. It may be the first presentation of relapsing acquired demyelinating syndromes and also must be distinguished from compressive and noninflamatory myelopathies. Correct diagnosis is crucial for treatment and prognosis. PMID- 29696042 TI - Bone Metabolism Disorder in Epileptic Children. AB - Objective: There are frequent anti-epileptic drugs used in management of epilepsy. Anti-epileptic drugs may have some complications on bone and vitamin D metabolism. This study aimed to comparison the bone metabolism disorder in epileptic children with healthy child in Zahedan, eastern Iran from Jul 2014 to Jun 2015. Materials & Methods: This case-control study was performed on bone metabolism disorder in epileptic children between 2014-2015. Forty epileptic children were enrolled based on accessibility scheme and 40 participants randomly selected for control group from those referred to the pediatric ward and clinic of Ali Ebn Abi Talib Hospital and Ali Asghar Clinic in Zahedan City, Sistan & Baluchestan Province, eastern Iran. Blood samples were collected from all participants to assess serum calcium, phosphorus, parathyroid hormone, magnesium, vitamin D, serum albumin, creatinine random urine. Results: Of 40 epileptic children, 23 (57.5%) and 17 (42.5%) were male and female respectively, The prevalence of lower mean vitamin D levels was 37.5% for patients compared to 12.5% for controls (chi-square=6.667 and P=0.010). Of 80 participants, 15 individuals had abnormal PTH levels detected of 2 and 13 for patients and control groups, respectively (chi-square =9.928 and P=0.002). Serum calcium and magnesium levels were comparable in both groups. The status of the parameters in the classification of normal and abnormal assessed based on number of medications intake resulted that number of medications intake had no effect on the status of the parameter. Conclusion: The frequency of hyperparathyroidism and vitamin D deficiency is increased in epileptic children. PMID- 29696043 TI - Prevalence of Vitamin D Deficiency and Associated Risk Factors in Cerebral Palsy A study in North-West of Iran. AB - Objective: This study aimed to compare the prevalence of 25-hydroxyvitamin D deficiency in cerebral palsied (CP) with healthy control children and evaluate possible correlations between 25-hydroxyvitamin D and severity of CP and motor function. Materials & Methods: In this case-control study, serum levels of 25 hydroxyvitamin D were evaluated in 65 children with CP and compared with 65 healthy children referred to Tabriz Pediatric Hospital, Tabriz, northwestern Iran in 2015. Blood samples were taken to measure levels of 25-hydroxyvitamin D, calcium, phosphorus and alkaline phosphatase. Regarding 25-hydroxyvitamin D levels, patients were classified as sufficient (>=30 ng/ml), insufficient (20-30 ng/ml) and deficient (<20 ng/ml). Results: Mean 25-hydroxyvitamin D levels were 28.03+/-24.2 ng/ml in patients and 30+/-1.94 ng/ml in control group. 25 hydroxyvitamin D deficiency was seen in 44.6% of CP and 18.5% of healthy children. There was no significant difference in 25-hydroxyvitamin D levels between boys and girls, CP types and use of antiepileptics in case group. There was significant negative correlation between age and 25-hydroxyvitamin D levels (P=0.007). The correlation between 25-hydroxyvitamin D and Gross Motor Function Classification System was not significant. Conclusion: 25-hydroxyvitamin D deficiency is common in children with CP in comparison with healthy children. There was significant negative correlation between age and 25-hydroxyvitamin D levels. Routine measurement of 25-hydroxyvitamin D levels and its proper treatment is recommended to prevent its deficiency and subsequent consequences. PMID- 29696044 TI - Association between Newborns' Breastfeeding Behaviors in the First Two Hours After Birth and Drugs Used For Their Mothers in Labor. AB - Objective: Use of narcotics to relieve pain in labor affects neurobehavioral and nutritional conditions of newborns after birth. However, there are inadequate data on the effects of drugs currently used in labor. This study was performed to examine the association between newborns' breastfeeding behaviors in the first two hours after birth and drugs used for their mothers in labor in Isfahan, central Iran, from 2014 to 2016. Materials & Methods: In this descriptive analytical study, 300 women were selected who had vaginal delivery in the Labor and Gynecology Wards of Al-Zahra and Shahid Beheshti hospitals, Isfahan, Iran from 2014 to 2016. Data were collected by a demographic questionnaire and the Newborn Breastfeeding Behaviors Tool completed by the researcher as she observed the newborns during breastfeeding after birth. The data were analyzed by one-way ANOVA, chi-square test and Kruskal-Wallis test in SPSS 20. Results: There was no significant difference between demographic characteristics of the studied groups (P>0.05). In addition, there was significant difference in breastfeeding behaviors between groups. More clearly, breastfeeding ability was higher in the infants of the women administered with no drug than those of the women in the group (P=0.000). Conclusion: Physicians, nurses, and midwives can be informed about the side effects of the drugs used in labor on the newborns' breastfeeding, and improve their breastfeeding outcomes by decreasing the dose of used drug and the duration of the women's treatment with these drugs. PMID- 29696045 TI - Perception of Musical Emotion in the Students with Cognitive and Acquired Hearing Loss. AB - Objective: Hearing loss can affect the perception of emotional reaction to the music. The present study investigated whether the students with congenital hearing loss exposed to the deaf culture, percept the same emotion from the music as students with acquired hearing loss. Materials & Methods: Participants were divided into two groups; 30 students with bilaterally congenital moderate to severe hearing loss that were selected from deaf schools located in Tehran, Iran and 30 students with an acquired hearing loss with the same degree of hearing loss selected from Amiralam Hospital, Tehran, Iran and compared with the group of 30 age and gender-matched normal hearing subjects served our control in 2012. The musical stimuli consisted of three different sequences of music, (sadness, happiness, and fear) each with the duration of 60 sec. The students were asked to point to the lists of words that best matched with their emotions. Results: Emotional perception of sadness, happiness, and fear in congenital hearing loss children was significantly poorly than acquired hearing loss and normal hearing group (P<0.001). There was no significant difference in the emotional perception of sadness, happiness, and fear among the group of acquired hearing loss and normal hearing group (P=0.75), (P=1) and (P=0.16) respectively. Conclusion: Neural plasticity induced by hearing assistant devises may be affected by the time when a hearing aid was first fitted and how the auditory system responds to the reintroduction of certain sounds via amplification. Therefore, children who experienced auditory input of different sound patterns in their early childhood will show more perceptual flexibility in different situations than the children with congenital hearing loss and Deaf culture. PMID- 29696046 TI - Clinical Features and Outcome of Guillain-Barre Syndrome in Children. AB - Objective: There are no reports about the clinical presentations and outcome of Guillain-Barre syndrome (GBS) in our region, therefore, we aimed to report some mentioned findings in children diagnosed with GBS in Isfahan, central Iran. Materials & Methods: In this retrospective study, pediatric diagnosed with GBS referred to Imam Hossein Hospital, the Pediatric Referral Center of Isfahan Province, central Iran were enrolled from 2011-2014. The following data were extracted from the medical files of patients; age, gender, early signs and symptoms of GBS, neurological features, sensory and motor and autonomic involvements, sphincter dysfunction, bulbar muscle involvement, respiratory failure, cranial nerve paralysis, delay time from onset to definite diagnosis and management of GBS and the outcome. Results: Overall, 57 children with GBS aged 1 13 yr were evaluated. Frequency of GBS was significantly higher in boys than in girls (38.6% vs. 61.4%, P=0.01, OR=0.39). The most common clinical presentations were distal lower limb weakness (92.11%), reduced deep tendon reflex (DTR) (82.46%) and neuropathic pain (75.44%). 92.9% of patients had complete recovery. Conclusion: Distal lower limb weakness, reduced deep tendon reflex, and neuropathic pain are the main clinical presentation in children with GBS but in some patients, DTR may be normal or even exaggerated in early stage of disease. Revising the diagnostic criteria for GBS may be necessary. Most of our patients had complete recovery. The only death was due to autonomic involvement. Autonomic dysfunction could be associated with catastrophic outcome and patients with these clinical presentations need critical care. PMID- 29696048 TI - A Comparison of Emotional-Behavioral Problems of Siblings at the Age Range of 3-9 Year Old Children with Autism and Down Syndrome. AB - Objective: Children's emotional-behavioral problems will have a huge impact on their future. Such problems are more seen in the siblings of children with special needs. The present study aimed to compare emotional-behavioral problems in the healthy siblings of autistic children with the healthy siblings of children with Down syndrome in order to identify such children in Iran. Materials & Methods: This descriptive study was carried out in Tehran, Iran in 2016 on 174 healthy children aged between 3 and 9 yr old among whom 58 cases had autistic siblings, 58 cases had siblings with Down syndrome, and 58 cases had typically development siblings. The participants were selected using convenience sampling technique. All volunteer parents filled in SDQ Questionnaire. The study results were calculated using independent sample t-test, two-way ANOVA, and Tukey post hoc test by SPSS. Results: The mean overall score of Strengths and Difficulties Questionnaire was reported as 17.98+/-6.19 in the autism group, 11.01+/-6.56 in the Down syndrome group and 4.43+/-4.34 in the healthy group. There was a significant difference among autism, Down syndrome, and healthy groups. In the group of siblings with Down syndrome, the problems were significantly more in the age range of 3 to 7 yr old (P<0.05). However, no significant difference was observed in the scores of males and females (P>0.05). Conclusion: Siblings with autism or Down syndrome can have especial psychological effects on healthy children in families in the way that such effect will be more with autistic children. Therefore, formulating beneficial strategies for their parents is used to prevent emotional behavioral problems. PMID- 29696047 TI - Comparison of Cochlear Microphonics Magnitude with Broad and Narrow Band Stimuli in Healthy Adult Wistar Rats. AB - Objective: Cochlear microphonic (CM) is a cochlear AC electric field, recorded within, around, and remote from its sources. Nowadays it can contribute to the differential diagnosis of different auditory pathologies such as auditory neuropathy spectrum disorder (ANSD). This study compared CM waveforms (CMWs) and amplitudes with broad and narrow band stimuli in 25 healthy male young adults Wistar rats. Materials & Methods: This experimental study was accomplished in the School of Rehabilitation Sciences of Iran University of Medical Sciences, Tehran, Iran (April, 2016). Using an extratympanic technique in ECochG (Electrocochleography) recording, CMWs in response to click and tonal stimuli with different octave frequencies were recorded at a high intensity level in subjects. The CMW amplitudes were calculated by a graphical user interface (GUI) designed in MATLAB. Results: The CMW magnitude increased upon an increase in bandwidth stimulation. CM amplitude with click stimulation was larger than tonal stimuli. Across tonal stimuli, the CMW amplitudes at lower frequency tones were larger than those at higher frequency tones. Those findings were statistically significant (P<0.001). Conclusion: CMW amplitude with click as broadband stimulus was larger than those with tone bursts as narrowband stimulation. Click stimulation due to the width of spectral involves greater regions of cochlear partition. Therefore, CMW most likely is a reflection of spatial summation of voltage drops generated by hair cell groups in response to acoustic stimulation. In order to production nature of CM potentials as well as their very small magnitudes especially with tonal stimuli, thus, we recommend using click stimulation for CM potential recording. PMID- 29696049 TI - Peripheral Neuropathy in Children and Adolescents with Insulin-dependent Diabetes Mellitus. AB - Objective: Type 1 diabetes mellitus (T1DM) is a chronic immune-mediated disease. Diabetic peripheral neuropathy (DPN) is an important microvascular complication of T1DM. One of the most important risk factors for the development of DPN is poor glycemic control. We evaluated the prevalence of DPN among T1DM patients and determined the association between DPN and glycated hemoglobin (HbA1c) level. Materials & Methods: The subjects were recruited prospectively upon initial evaluation at Imam Reza Hospital, Mashhad, Iran from Jan 2013 to Jan 2015. Patients with T1DM were selected based on the inclusion criteria (i.e., age of 6<=yr and absence of other co-morbidities). DPN was assessed through electrodiagnostic studies and neurological examinations, while diabetes control was evaluated by measuring the HbA1c level. Results: Fifty patients with T1DM were enrolled in this study. The mean diabetes duration of patients was 8.38+/ 3.79 yr (mean age16.68+/-6.68 yr). The mean HbA1c level was 8.6+/-2.1% in patients without DPN and 10.5+/-3 in those with DPN (P=0.016). Overall, 24% of the subjects were presented with DPN according to nerve conduction velocity study (NCV) findings. A positive correlation was found between NCV and clinical symptoms with signs (P<0.001, r=0.45 and P<0.001, r=0.644, respectively). Sensitivity and specificity of neurological examination for DPN diagnosis were 91.7% and 63.2%, respectively. Poor diabetes control is associated with DPN. Moreover, HbA1c level was used as an index for glycemic control over the past 3 months. Conclusion: Rigid blood glucose control and periodic neurological examinations were the best strategies to prevent DPN. PMID- 29696050 TI - Are the Norms of Bayley Screening Test Appropriate for Persian Language Children? AB - Objective: We aimed to assess the distribution of the Bayley screening test by age, and compare developmental risk category distributions between Persian language children and reference norms. Materials & Methods: A representative sample of 417 children, 1 to 42-months-old, by consecutive sampling from health care centers were enrolled, during 2014 to 2015 in Tehran, Iran. The cognitive, language and motor development of children were evaluated using Bayley screening test. For determining cut-off point for the subtest scores, two cut-offs were determined for each age group, that classified children to the at risk, emerging, and competent categories. We estimated the agreement of the risk categories between the two samples using weighted kappa statistics. Results: About 70%-80% of all tests operated to the participating children were classified as normal by both norms. Weighted kappa coefficients for the five subtests ranged from 0.56 to 0.89 suggesting moderate agreement between two classification norms. Expressive and receptive communication had the lowest kappa scores (0.56 and 0.59, respectively), and classification of gross motor revealed the highest level of agreement (0.89). Conclusion: Developmental disabilities are common disorders that impose important functional limitations on the affected children. Identifying infants at risk for developmental disorders by screening is a main step to minimize complications. Dependence on reference-based norms for the Bayley screening test in Persian language children results in misclassification of risk category. PMID- 29696051 TI - Are There Neurological Symptoms in Type 1 of Gaucher Disease? AB - Objective: Gaucher disease (GD) is a rare inborn error of metabolism, classified as a lipid storage disorders. This disease is caused by a deficiency in glucocerebrosidase enzyme. It has been classified according to the presence or absence of neurological symptoms into the following types: type 1 non neuropathic, type 2 acute infantile neuropathic and type 3 or chronic neuropathic. We evaluated neurological symptoms in patients with GD1 and GD3 and compared both of these groups. Materials & Methods: Eleven patients were identified according to their clinical presentation and the presence of disease confirmed by genetic testing, from 2006-2016, at the Mofid Children Hospital Clinic, Tehran, Iran. We included eight patients with GD 1 and three patients with GD3. Careful neurological examination was performed on these patients during treatment by pediatric neurologist. Results: Patients with GD1 had some neurological symptoms including cognitive impairment, developmental disability, behavioral disorder, microcephaly and increased deep tendon reflexes (DTR). Of course, neurological signs in patients with type 3 of GD were different and were included seizures, supranuclear gaze palsy, cerebellar signs, and ataxia. Conclusion: The current nomenclature for 3 types of Gaucher disease does not meet all clinical symptoms. Patients with GD1 display many neurological deficits in young ages not reported adequately earlier. PMID- 29696052 TI - Novel Imaging Finding and Novel Mutation in an Infant with Molybdenum Cofactor Deficiency, a Mimicker of Hypoxic-Ischaemic Encephalopathy. AB - Molybdenum cofactor deficiency is a rare metabolic disorder manifesting with early onset seizures, developmental delay, microcephaly, and spasticity. In this report, we describe a three-month-old infant with neonatal onset, poorly controlled seizures, developmental delay, microcephaly, spastic quadriparesis and visual insufficiency. Magnetic resonance imaging of brain had shown cystic encephalomalacia involving bilateral parieto-occipital lobe and elevated lactate in magnetic resonance spectroscopy. Restricted diffusion noted along the corticospinal tract in our case is a novel imaging finding in patients with molybdenum cofactor deficiency. Low serum uric acid and elevated urine sulfite excretion were observed. A novel homozygous mutation was detected in exon 4 of molybdenum cofactor synthesis 2 (MOCS2) gene. Early infantile or neonatal onset seizures, developmental delay, microcephaly and cystic encephalomalacia in neuroimaging mimicking hypoxic-ischaemic encephalopathy should raise the suspect for molybdenum cofactor deficiency. Screening of all neonates for urinary sulfite metabolites would help in early diagnosis and management. Early diagnosis and treatment with cyclic pyranopterin monophosphate could arrest the progression of molybdenum cofactor deficiency type A. More research is needed to explore further treatment options in this otherwise lethal disorder. PMID- 29696053 TI - Psychological Signs as the Only Presentation of Wilson's Disease in an 11-Year Old Boy. AB - Wilson's disease (WD) is a rare autosomal recessive disease due to copper metabolism disturbance. The clinical presentation spectrum of Wilson's disease is wide and initial findings of the disease depend on the organ involved. Neurologic disorders can develop insidiously or precipitously with intention tremor, dysarthria, rigid dystonia, Parkinsonism, deterioration in school performance or behavioral changes. This article is presenting an 11-yr old boy with chief complaint of falling and upper limb spasm. He referred to the Neurology Department, Ghaem Hospital, Mashhad, northeastern Iran in 2016. His symptoms began from 6 months earlier as mood instability (prolonged spontaneous crying). He was also suffering from occasionally tremor and micrographia. Initial investigations were normal and with diagnosis of depression and psychiatric problems, he had undergone treatment with fluoxetine and risperidone. Wilson's disease should be considered in the diagnosis of all children with psychiatric and musculoskeletal symptoms. PMID- 29696054 TI - Diskitis as Manifestation of Gait Disturbance. AB - Gait disturbance is a common presentation of neurologic disease in children. Limping is a kind of gait dysfunction that occurs due to neurologic & skeletal diseases. Diskitis is an inflammatory process noted as one of the significant causes of limping especially in children aged less than 3 yr. Here we report case of diskitis and limping as the significant manifestation of Gait disturbance in A 22 months old boy from 17 Shahrivar Hospital in 2016, Rasht, northern Iran. Regarding normal neurologic exam, nervous system involvement was less possible. About 60% of gait cycle related to stance phase. PMID- 29696055 TI - The Effect of Kinesio Taping on Handgrip and Active Range of Motion of Hand in Children with Cerebral Palsy. PMID- 29696057 TI - Respect and admiration. PMID- 29696056 TI - From the black Atlantic to the bleak Pacific: Re-reading "Benito Cereno". AB - Herman Melville's novella "Benito Cereno" (1855/56) is one of the best-studied texts both within Melville's oeuvre and nineteenth-century American literature in general. In recent decades, its puzzling structure and fragmented narrative perspective as well as its symbolism and themes have been subject to critical scrutiny mostly in the context of inquiries into the text's racial politics regarding the institution of slavery. More specifically, the canonical tale about a slave uprising on the ship San Dominick, its detection by a Massachusetts-born captain and its consequences, has been discussed in the context of Paul Gilroy's black Atlantic paradigm. Few readings of the tale consider the significance of the Pacific setting of a story grounded in the transatlantic slave trade but happening far away from the center of American slavery. Taking a fresh look at Melville's tale, this essay focuses on its translation of (black) Atlantic subject matters and epistemologies onto the Pacific. Not only do I read the tale as both an Atlantic and a Pacific text, demonstrating that the institution of slavery and its specters know no geographical borders in Melville's imagination; I also argue that piracy is an important trope in this context. Anticipating the shift of piracy cases and slavery to the Pacific towards the end of the nineteenth century, it both recalls a black Atlantic and predicts a bleak Pacific of violent imperial scenarios that would come to characterize US-Pacific relations. PMID- 29696059 TI - Health marketing and behavioral change: a review of the literature. AB - Health marketing as a part of social marketing, must influence individuals, voluntarily, through various social programmes, in order to accept, reject, modify or abandon a behavior in favour of a healthier lifestyle. Acting on individual behavior change, social marketing can influence the behaviour of those who decide public policies, with positive effects in social change. In time, in order to understand and predict a behavior, a number of theories, models and tactics were developed with the aim to identify factors and mechanisms with the greatest impact in the changing process. Cognitive- social theories proved to be more effective, because they offer guidelines for conducting research in behavioral change. PMID- 29696058 TI - Our 20-year experience with experimental colonic anastomotic healing. AB - Aim: To present our experience with experimental colonic anastomoses and compare it with the results of other experienced researchers. Materials and Method: The published experimental studies of our research group up to 1996, as well as results of other researchers in this field, are demonstrated and discussed. Different actions of administered substances on the anastomotic healing were compared and represented. Various chemotherapeutic agents were evaluated in experimental models without colorectal cancer as independent risk factors for the anastomotic healing. Moreover, numerous pharmaceutical agents such as steroids, immunomodulators, vasodilators and the use of fibrin glue are also assessed in detail. Results: Cytostatics, as well as steroids, impair the colonic anastomotic healing, but the combined administration of other agents can reverse this negative effect. Fibrin glue seems to protect the colonic anastomosis, while iloprost could be a potential candidate for further exploration in patient trials. Tacrolimus, despite its immunosuppressive action, seems to promote the anastomotic healing. This observation could be useful for patients with inflammatory bowel disease under tacrolimus therapy, who undergo a non-elective colectomy. Obstructive conditions predispose to anastomotic insufficiency, and therefore, substances to avoid this threatening complication are also assessed. Tacrolimus and iloprost showed a remarkable action against anastomotic leakage under artificially obstructive conditions. Conclusion: Further studies, especially in forms of clinical protocols, are necessary in order for these results to find their place in safe daily practice. PMID- 29696060 TI - Nonalcoholic fatty liver disease: epidemiology, pathogenesis and therapeutic implications. AB - The increase of the prevalence of nonalcoholic fatty liver disease in the context of the explosive epidemy of obesity worldwide over the last decades and the emergence of new effective therapies for viral hepatitis has brought this entity to the forefront of hepatologist concerns. Today is a certainty that fatty liver can complicate with cirrhosis and hepatocellular carcinoma; moreover, nonalcoholic fatty liver disease is the main cause of cryptogenic cirrhosis and the second cause of liver transplantation. This review revises the epidemiology of the disease, brings forward some progress in pathogenesis and outlines the directions to be followed in nonalcoholic fatty liver disease prevention and therapy. Today, nonalcoholic fatty liver disease is considered to be the liver manifestation of metabolic syndome, with its same prevalence (20-30%). If the patients do not die through cardiovascular disease, it can lead to serious liver complications. PMID- 29696061 TI - Effect of fennel vaginal cream on sexual function in postmenopausal women: A double blind randomized controlled trial. AB - Objective: The aim of this study was to assess the effect of fennel on sexual function in postmenopausal women. It was a randomized controlled trial in 60 postmenopausal women with sexual dysfunction who were randomly assigned to two groups receiving either fennel vaginal cream (n=30) or placebo (n=30). Vaginal atrophy in the women was assessed using symptoms such as pallor, dryness, dyspareunia, itching and burning. The pH of the vagina and cytology of the vaginal mucosa were also measured at baseline and 8 weeks after the intervention. All participants were requested to fill out the Female Sexual Function Index (FSFI) at baseline and after 8 weeks. The intervention group was requested to use fennel vaginal cream (5 grams) every night, while the control group used placebo each night for 8 weeks. The data were analyzed using the independent t-test and Chi-square, Mann-Whitney and Wilcoxon tests. All areas of sexual function including arousal, lubrication, orgasm, sexual satisfaction and pain improved in both fennel and placebo groups after 8 weeks; however, the differences in the fennel group were more evident (p<0.05). The total FSFI score was significantly higher in the fennel group compared to the control group (8.2 +/-9.4 and 8.03+/ 10.36 before the intervention and changing to 33.79+/-0.7 and 18.99+/-1.09 after the intervention in the fennel and placebo groups, respectively; p<0.001). Discussion: According to our results, fennel vaginal cream is an effective means of improving sexual activity in postmenopausal women. The use of this product in women who have sexual dysfunction and contraindications for hormone therapy is recommended. PMID- 29696062 TI - Iron deficiency in a tertiary gastroenterology center in Romania: prevalence and significancy. AB - Introduction:Iron deficiency has been known to cause significant functional impairment, lower quality of life and higher morbidity and mortality. The aim of this study was to estimate the prevalence and significance of iron deficiency in our patients and medical staff. Material and methods:We performed a prospective cross-sectional study: In July 2016, 383 persons were screened for the presence of iron deficiency (ID): 325 patients and 58 people from the medical staff. Transferrin saturation (TSAT), serum ferritin (SF) and complete blood count were performed. Absolute ID was diagnosed if SF <100 ng/ml and TSAT <20%. Relative ID was defined by SF >100 ng/ml and TSAT <20%. Results:The group of medical staff was younger and had a greater proportion of women. The prevalence of absolute ID was 22.5% in patients and 43.1% in medical staff; relative ID was present in 15% of patients and 1.7% of medical staff. Among patients, the absolute ID was significantly correlated with the female sex (p=0.002) and pre-menopausal status (p=0.01) but did not correlate with diagnosis, age, BMI, nonsteroidal anti inflammatory drug (NSAID), aspirin or acenocoumarol consumption. The relative ID is associated with advanced age (p=0.03) and diagnosis of cancer and liver cirrhosis (p=0.01). Conclusions:Absolute ID had a high prevalence among patients (22.5%), but there was even a bigger issue among the medical staff (43.1%). Absolute ID was correlated with female sex and pre-menopausal status. Relative ID was related to advanced age, cancer and liver cirrhosis. Abbreviations: serum ferritine- SF, transferrin saturation coefficient- TSAT, iron deficiency- ID, inflammatory bowel diseases- IBD, quality of life- QoL, GI- gastrointestinal. PMID- 29696063 TI - The response of intercellular adhesion molecule-1 to exhaustive submaximal exercise and its correlation with physiological and anthropometric measures. AB - Introduction:Intercellular adhesion molecule-1 (ICAM-1) acts as the main factor in the occurrence of atherosclerosis and inflammatory diseases. This study aimed to investigate the response of ICAM-1to exhaustive submaximal exercise and its correlation with maximal oxygen consumption (VO2max), body mass index (BMI), waist-hip ratio (WHR), body fat percentage (BF %) and calories burned during exercise (CB) in healthy men. Materials and methods:Thirteen healthy men (mean +/ standard deviation: age 23 +/- 3 years, weight 78 +/- 4 kg, height 180 +/- 4 cm) cooperated in this quasi-experimental study and performed a single bout of exhaustive submaximal exercise on a cycle ergometer. Blood samples were collected from the antecubital vein before and immediately after exercise. Data were analyzed using the paired sample t-test and Pearson's correlation coefficient (alpha=0.05). Results:Exhaustive submaximal exercisehad no significant effect on serum sICAM-1. Also, there were no significant correlations between ICAM-1 induced by the exhaustive submaximal exercise and VO2max, BMI, WHR, BF % and CB. Conclusions:According to our findings, it cannot be ruled out that exhaustive submaximal exercise results in pathological and inflammatory conditions in healthy men. In Also, anthropometric and physiological parameters do not affect the response of ICAM-1 to exercise in healthy men. PMID- 29696064 TI - Long-term survival following neoadjuvant chemotherapy and concomitant radiochemotherapy in locally advanced cervical cancer: results of the Oncology Institute "Prof. Dr. Ion Chiricuta" experience. AB - Objective:to analyze the efficiency of (NACT) followed by concurrent radiochemotherapy (RCT) in patients with locally advanced cervical cancer, 5-year overall, specific and disease-free survival and the prognostic factors correlated with the response and survival. Materials and methods:207 patients with cervical carcinoma stages IIB-IIIB, who received 2-4 cycles of neoadjuvant chemotherapy followed by concurrent chemoradiation were retrospectively analyzed for an objective response (OR), overall survival (OS), and disease-specific survival (DSS) rate. All patients received platinum-based NACT followed by concurrent RCT to a total dose (TD) of 46 Gy/pelvis when patients were evaluated for surgery. Patients with favorable parametrial response optionally underwent surgery. The rest of the patients continued radiochemotherapy exclusively. Results:The baseline characteristics were: median age at diagnosis - 52 years; 82% squamous and 12% adenocarcinoma histologies; 67 patients (32.4%) with FIGO stage IIB, 87 (42%) with stage IIIA and 53 (25.6%) with stage IIIB. The OR rate was 56.5% post NACT and the complete response (CR) after exclusive RCT was 19.7% while pathological complete response (pCR) in patients that underwent surgery was 61.2%. The median follow-up was 58.3 months. Overall and disease-specific survivals at 5 years were 78% and 84%, respectively. The OS for stages IIB and IIIA was 84%, and 61% for stage IIIB while the DSS rates were 90% for stage IIB, 86% for stage IIIA and 72% for stage IIIB. The disease-free intervals (DFS) rates were 88%, 76% and 69% for stages IIB, IIIA and IIIB, respectively. Conclusions:Neoadjuvant chemotherapy followed by concurrent chemoradiation produces higher response rates and improvements in disease-specific survival and disease-free survival rates compared to RCT. PMID- 29696065 TI - Physiochemical Properties of Experimental Nano-hybrid MTA. AB - Introduction:The development of new pulp capping agents has paved the way towards the preservation of pulp vitality, which is an important goal in restorative dentistry. This study sought to assess the calcium ion release, pH and setting of mineral trioxide aggregate (MTA) Angelus, an experimental formulation of nano hybrid MTA containing nano-SiO2, nano-Al2O3 and nano-TiO2 and MTA Angelus plus nano-oxides. Methods:In this experimental study, five specimens from each material were placed in polypropylene tubes and immersed in a flask containing deionized distilled water. The amount of calcium ions released into the solution from each material was measured at 15 minutes, one hour and 24 hours using atomic absorption spectroscopy. The pH of the solutions was measured using a pH meter at the respective time points. Setting time was also assessed using a Gilmore needle. Data were analyzed using the repeated measures ANOVA. Results:The amount of released calcium ions was not significantly different among the groups (P=0.060). All materials were alkaline and the pH at 24 hours was significantly higher than the other two time points in all groups (P<0.001). The experimental group had the shortest and MTA Angelus had the longest setting time. All materials were alkaline and capable of releasing calcium. Addition of nanoparticles to MTA Angelus significantly decreased the setting time but had no effect on the release of calcium ions or pH. Abbreviations: mineral trioxide aggregate (MTA), vital pulp therapy (VPT). PMID- 29696066 TI - Metastatic neuroendocrine pancreatic tumor - Case report. AB - Rationale.Pancreatic neuroendocrine tumors (NETs) are rare neoplasms that develop from the endocrine tissues of the pancreas. They have a better overall prognosis than pancreatic adenocarcinoma. However, all commonly used classification systems reflect a separation between more indolent, well-differentiated tumors and far more aggressive poorly differentiated types that behave clinically more like small-cell carcinoma of the lung. Objective.To present the case of a 62-year-old man with an aggressive pancreatic NET, with liver, splenic and bone metastases who underwent multidisciplinary treatment including several lines of chemotherapy, somatostatin analogs and radiotherapy. Methods and Results.The patient is a smoker and an occasional drinker, known with type two diabetes mellitus (DM), receiving insulin therapy. He was diagnosed by contrast-enhanced computed tomography (CT) in January 2015 with a locally invasive pancreatic body mass, intraabdominal adenopathies and liver nodules, suggestive of metastases. Histopathological diagnosis was obtained through liver biopsy: neuroendocrine tumor with a 10-15% Ki67 proliferation index. Palliative chemotherapy with oxaliplatin and capecitabine was started in March 2015. In June 2015, Sandostatin LAR was added. In March 2016, he had progressive disease. Subsequently, in September 2016, bone metastasis was found within the T10 vertebra. He underwent radiotherapy for multiple bone metastases in February 2017. Progressive disease was again found during a CT examination in May 2017. His performance status has gradually worsened since then and he died in July 2017. Discussion.As a group, well-differentiated gastroenteropancreatic NETs are generally indolent malignancies with prolonged natural history. Intermediate-grade NETs have a slightly worse prognosis than low-grade tumors. Abbreviations: NETs - neuroendocrine tumors, NEC - neuroendocrine carcinoma, CT - computed tomography, MRI - magnetic resonance imaging, DM - diabetes mellitus, WHO - World Health Organisation, HCV - hepatitis C virus, CEA - carcinoembryonic antigen, AFP - alpha-fetoprotein, 5-HIAA - 5-Hydroxyindoleacetic acid, IHC - immunohistochemistry, EUS - endoscopic ultrasonography, EUS FNA - endoscopic ultrasonography with fine needle aspiration, CgA - chromogranin A, PRRT - peptide receptor radioligand therapy. PMID- 29696067 TI - Challenges faced by health volunteers in comprehensive health centers in the southwest of Iran: A qualitative content analysis. AB - Introduction:Health volunteers are employed to execute governmental health promotion programs in most countries around the world. The present study aimed to assess the challenges of health volunteers program to provide a better understanding of the present situation. Methods:This study was conducted using a qualitative approach. 14 participants were selected purposively selected from two comprehensive health care centers in the southwest of Iran. The data were collected through 14 semi-structured interviews, 2 observations, and 3 diaries and analyzed using content analysis. Results:Data analysis resulted in emergence four themes, namely role confusion, the inefficiency of volunteers training, the inefficiency of attraction and maintenance of volunteers, and being unknown to people. Unfertilized capacity is the main theme extracted from all themes. Conclusion:Health volunteers' perfect accomplishment of roles will have a positive impact on the provision of primary healthcare services and health objectives. Hence, comprehensive planning based on the needs of health volunteers will change them into a strong arm in the health system. Thus, managerial support and precise planning seem to be necessary for facing these challenges. PMID- 29696069 TI - Could Homeopathy Become An Alternative Therapy In Dengue Fever? An example Of 10 Case Studies. AB - Background:Dengue fever is one of the most rampant epidemics in India of late and any therapy that may help limit the sickness and hospital admissions is worth considering. In India complementary and alternative medicine physicians are medically trained and hence have a role to play in delivery of public health. Case Series:We present a retrospective case series of 10 Indian patients who were diagnosed with dengue fever and treated exclusively with homeopathic remedies at Bangalore, India. This case series demonstrates with evidence of laboratory reports that even when the platelets dropped considerably there was good result without resorting to any other means. Conclusions:A need for further, larger studies is indicated by this evidence, to precisely define the role of homeopathy in treating dengue fever. This study also emphasises the importance of individualised treatment during an epidemic for favourable results with homeopathy. Abbreviations:DF: dengue fever, NS1: non-structural protein 1 antigen, IgG: immunoglobulin G, IgM: immunoglobulin M, +ve: positive, -ve: negative, WBC: white blood cells, RBC: red blood cells, ESR: erythrocyte sedimentation rate. PMID- 29696068 TI - Gene polymorphisms of TNF-238G/A, TNF-308G/A, IL10-1082G/A, TNFAIP3, and MC4R and comorbidity occurrence in a Romanian population with psoriasis. AB - Rationale.Psoriasis is a prevalent chronic inflammatory disease with worldwide distribution affecting approximately 2% of the Caucasian population. There have been many population- and family-based studies that agree on the strong genetic component of this disease. Several studies have investigated the relationship between cytokine gene polymorphisms, psoriasis, and the occurrence of comorbidities but their data are conflicting. Objective.This study examines cytokine gene single-nucleotide polymorphisms (SNPs) in the context of psoriasis and metabolic syndrome, with a focus on the occurrence of comorbidities in psoriasis patients. The working hypothesis is that particular SNPs may predispose to an accelerated disease course and more comorbidities in psoriasis patients. Methods:This cross-sectional study was carried out in 2016 in the Dermatology Department of "Elias" University Emergency Hospital, Bucharest and included 82 psoriasis patients. Several clinical and laboratory parameters were recorded, and the presence of metabolic syndrome (MetS) was noted. Using real-time PCR, we tested for the following SNPs: rs361525, rs1800629, rs1800896, rs610604, rs17782313. Results:Disease severity was not significantly influenced by any of the five studied SNPs. Gene polymorphism of rs17782313 was found to influence the occurrence of psoriatic arthritis. In these patients, rs610604 and rs17782313 polymorphisms were associated with the presence of diabetes mellitus. Furthermore, rs17782313 influenced the presence of obesity, heterozygotes being more at risk. Our data suggested that MetS occurred independently of the five studied SNPs. Discussion.The influence of certain cytokine gene polymorphisms on multiple organ systems is justification enough for further analysis of the genetic and molecular mechanisms of metabolic syndrome development in psoriasis patients. Abbreviations:single-nucleotide polymorphisms - SNPs, metabolic syndrome - MetS. PMID- 29696070 TI - Spatial ecological networks: planning for sustainability in the long-term. AB - Humans are producing complex and often undesirable social and ecological outcomes in many landscapes around the world. To sustain biodiversity and ecosystem services in fragmented landscapes conservation planning has turned to the identification and protection of large-scale spatial ecological networks (SEN). Now widely adopted, this approach typically focuses on static connectivity, and ignores the feedbacks between changes to the network's topology and the eco evolutionary dynamics on the network. We review theory showing that diversity, stability, ecosystem functioning and evolutionary adaptation all vary nonlinearly with connectivity. Measuring and modelling an SEN's long-term dynamics is immensely challenging but necessary if our goal is sustainability. We show an example where the robustness of an SEN's ecological properties to node and link loss depends on the centrality of the nodes targeted. The design and protection of sustainable SENs requires scenarios of how landscape change affects network structure and the feedback this will have on dynamics. Once established, SEN must be monitored if their design is to be adapted to keep their dynamics within a safe and socially just operating space. When SEN are co-designed with a broad array of stakeholders and actors they can be a powerful means of creating a more positive relationship between people and nature. PMID- 29696071 TI - Building a scalable diabetic limb preservation program: four steps to success. AB - Over the past generation, limb preservation programs and diabetic foot services have begun to proliferate within academic health science centers as well as within health-care systems in general. We describe four key components for a successful program that, developed sequentially with temporal overlap, can allow the program to scale. The first component includes establishment of a 'hot foot line' for urgent emergency department/inpatient referral. The second includes development of a wound-healing clinic to address outpatient care through to remission. The third component focuses on the diabetic foot in remission to maximize ulcer-free days following healing. The fourth and final component focuses on implementation of local and widespread screening clinics to identify and triage patients into appropriate therapeutic and surveillance programs for healing, remission, and primary prevention. Along with developing each of these components, we describe discrete methods to quantify success. PMID- 29696072 TI - The relationship between social support and posttraumatic stress symptoms among youth exposed to a natural disaster. AB - Background: Children are a vulnerable population following a natural disaster, due to their age and dependence on adults. The primary presenting problem children report after disasters is posttraumatic stress symptoms (PTSS). Prior research suggests that PTSS is inversely related to social support, which is often disrupted after a disaster. Objective: This study examined the relationship between social support (from parents, teachers, and peers) and PTSS in children affected by Hurricane Katrina. The research contributes to the literature by examining the mechanisms that drive this relationship over time. Methods: In this study, 426 children were followed over four timepoints, beginning 3-7 months after Hurricane Katrina and concluding 25-27 months post-hurricane. Three path models analysed the relationship between social support (from parents, teachers, and peers, measured by the Social Support Scale for Children) and PTSS (measured by the UCLA PTSD Reaction Index). Covariates included child age, minority status, gender, perceived life threat, and actual life threat. Nonsignificant paths were trimmed from the final models. Global fit indices were examined to determine model fit. Results: In the parent and peer social support models, PTSS exhibited statistically significant effects on social support from one wave to the next. In the teacher model, this was only true between Waves 2 and 3. Social support showed a statistically significant effect on PTSS between Wave 2 and Wave 3 in the peer model (standardized estimate = -0.26, p < .0001). No paths from social support to PTSS were significant in the parent and teacher models. Conclusion: Findings support a social selection model in which PTSS undermine social support, particularly in the first two years post-disaster. If these findings are replicated, this suggests that, in cases of limited funding, PTSS should be prioritized, given their cascading effects on social support. PMID- 29696073 TI - A cross-sectional study of small mammals for tick-borne pathogen infection in northern Mongolia. AB - Background: Tick-borne pathogens (TBPs) are frequently studied in developed nations but are often neglected in emerging countries. In Mongolia, TBP research is especially sparse, with few research reports focusing upon human and domestic animal disease and tick ecology. However, little information exists on TBPs in small mammals. Methods: In this 2016 cross-sectional pilot study, we sought to uniquely study wildlife for TBPs. We live-trapped small mammals, and tested their whole blood, serum and ear biopsy samples for molecular or serological evidence of Borrelia spp., Rickettsia spp., and Anaplasma spp./Ehrlichia spp. Results: Of 64 small mammals collected, 56.0%, 39.0% and 0.0% of animals were positive by molecular assays for Borrelia spp., Rickettsia spp., and Anaplasma spp./Erhlicia spp., respectively. 41.9% were seropositive for A. phagocytophilum and 24.2% of animals were seropositive for Rickettsia rickettsii. Conclusion: This pilot data demonstrates evidence of a number of TBPs among small mammal populations in northern Mongolia and suggests the need to further investigate what role these mammals play in human and domestic animal disease. PMID- 29696075 TI - Circulating extracellular vesicles as potential biomarkers in chronic fatigue syndrome/myalgic encephalomyelitis: an exploratory pilot study. AB - Chronic Fatigue Syndrome (CFS), also known as Myalgic Encephalomyelitis (ME) is an acquired, complex and multisystem condition of unknown etiology, no established diagnostic lab tests and no universally FDA-approved drugs for treatment. CFS/ME is characterised by unexplicable disabling fatigue and is often also associated with numerous core symptoms. A growing body of evidence suggests that extracellular vesicles (EVs) play a role in cell-to-cell communication, and are involved in both physiological and pathological processes. To date, no data on EV biology in CFS/ME are as yet available. The aim of this study was to isolate and characterise blood-derived EVs in CFS/ME. Blood samples were collected from 10 Spanish CFS/ME patients and 5 matched healthy controls (HCs), and EVs were isolated from the serum using a polymer-based method. Their protein cargo, size distribution and concentration were measured by Western blot and nanoparticle tracking analysis. Furthermore, EVs were detected using a lateral flow immunoassay based on biomarkers CD9 and CD63. We found that the amount of EV enriched fraction was significantly higher in CFS/ME subjects than in HCs (p = 0.007) and that EVs were significantly smaller in CFS/ME patients (p = 0.014). Circulating EVs could be an emerging tool for biomedical research in CFS/ME. These findings provide preliminary evidence that blood-derived EVs may distinguish CFS/ME patients from HCs. This will allow offer new opportunities and also may open a new door to identifying novel potential biomarkers and therapeutic approaches for the condition. PMID- 29696076 TI - Improved resolution in extracellular vesicle populations using 405 instead of 488 nm side scatter. AB - Improvements in identification and assessment of extracellular vesicles (EVs) have fuelled a recent surge in EV publications investigating their roles as biomarkers and mediators of disease. Meaningful scientific comparisons are, however, hampered by difficulties in accurate, reproducible enumeration and characterization of EVs in biological fluids. High-sensitivity flow cytometry (FCM) is presently the most commonly applied strategy to assess EVs, yet its utility is limited by variant ability to resolve smaller EVs. Here, we propose the use of 405 nm (violet) wavelength lasers in place of 488 nm (blue) for side scatter (SSC) detection to obtain greater resolution of EVs using high sensitivity FCM. To test this hypothesis, we modelled EV resolution by violet versus blue SSC in silico and compared resolution of reference beads and biological EVs from plasma and bronchoalveolar lavage (BAL) fluid using either violet or blue wavelength SSC EV detection. Mie scatter modelling predicted that violet as compared to blue SSC increases resolution of small (100-500 nm) spherical particles with refractive indices (1.34-1.46) similar to EVs by approximately twofold in terms of light intensity and by nearly 20% in SSC signal quantum efficiency. Resolution of reference beads was improved by violet instead of blue SSC with two- and fivefold decreases in coefficients of variation for particles of 300-500 nm and 180-240 nm size, respectively. Resolution was similarly improved for detection of EVs from plasma or BAL fluid. Violet SSC detection for high-sensitivity FCM allows for significantly greater resolution of EVs in plasma and BAL compared to conventional blue SSC and particularly improves resolution of smaller EVs. Notably, the proposed strategy is readily implementable and inexpensive for machines already equipped with 405 nm SSC or the ability to accommodate 405/10 nm bandpass filters in their violet detector arrays. PMID- 29696074 TI - Glycosylated extracellular vesicles released by glioblastoma cells are decorated by CCL18 allowing for cellular uptake via chemokine receptor CCR8. AB - Cancer cells release extracellular vesicles (EVs) that contain functional biomolecules such as RNA and proteins. EVs are transferred to recipient cancer cells and can promote tumour progression and therapy resistance. Through RNAi screening, we identified a novel EV uptake mechanism involving a triple interaction between the chemokine receptor CCR8 on the cells, glycans exposed on EVs and the soluble ligand CCL18. This ligand acts as bridging molecule, connecting EVs to cancer cells. We show that glioblastoma EVs promote cell proliferation and resistance to the alkylating agent temozolomide (TMZ). Using in vitro and in vivo stem-like glioblastoma models, we demonstrate that EV-induced phenotypes are neutralised by a small molecule CCR8 inhibitor, R243. Interference with chemokine receptors may offer therapeutic opportunities against EV-mediated cross-talk in glioblastoma. PMID- 29696077 TI - Investigation of procoagulant activity in extracellular vesicles isolated by differential ultracentrifugation. AB - Tissue factor (TF) is the main initiator of coagulation and procoagulant phospholipids (PPL) are key components in promoting coagulation activity in blood. Both TF and PPL may be presented on the surface of extracellular vesicles (EVs), thus contributing to their procoagulant activity. These EVs may constitute a substantial part of pathological hypercoagulability that is responsible for triggering a higher risk of thrombosis in certain patients. The aim of this study was to describe a model system for the isolation of EVs required for investigating their effect on coagulation. Differential ultracentrifugation (DUC) with and without a single washing step was used to isolate and evaluate the procoagulant capacity of EVs from healthy volunteers through analysis of thrombin generation and PPL activity. Ultracentrifugation at 20,000 * g and 100,000 * g resulted in pellets containing larger vesicles and smaller vesicles, respectively. Isolation yield of particle concentration was assessed by nanoparticle tracking analysis. Immunoelectron microscopy and western blotting revealed vesicles positive for the commonly used EV-marker CD9. Plasma proteins and lipoproteins were co-isolated with the EVs; however, application of a washing step clearly diminished the amount of contaminants. The isolated EVs were capable of enhancing thrombin generation, mainly due to PPL predominantly present in pellets from 20,000 * g centrifugation, and correlated with the activity measured by a PPL activity assay. Thus, DUC was proficient for the isolation of EVs with minimal contamination from plasma proteins and lipoproteins, and the setup can be used to study EV-associated procoagulant activity. This may be useful in determining the procoagulant activity of EVs in patients at potentially increased risk of developing thrombosis, e.g. cancer patients. Abbreviations: TF: Tissue factor; PL: Phospholipids; EVs: Extracellular vesicles; FXa: Activated coagulation factor X; TGA: Thrombin generation assay; PPL: Procoagulant phospholipids; DUC: Differential ultracentrifugation; NTA: Nanoparticle tracking analysis; TEM: Transmission electron microscopy; SPP: Standard pool plasma; CTI: Corn trypsin inhibitor; 20K: 20,000 * g; 100K: 100,000 * g; FVIII: Coagulation factor VIII. PMID- 29696078 TI - Newt cells secrete extracellular vesicles with therapeutic bioactivity in mammalian cardiomyocytes. AB - Newts can regenerate amputated limbs and cardiac tissue, unlike mammals which lack broad regenerative capacity. Several signaling pathways involved in cell proliferation, differentiation and survival during newt tissue regeneration have been elucidated, however the factors that coordinate signaling between cells, as well as the conservation of these factors in other animals, are not well defined. Here we report that media conditioned by newt limb explant cells (A1 cells) protect mammalian cardiomyocytes from oxidative stress-induced apoptosis. The cytoprotective effect of A1-conditioned media was negated by exposing A1 cells to GW4869, which suppresses the generation of extracellular vesicles (EVs). A1-EVs are similar in diameter (~100-150 nm), structure, and share several membrane surface and cargo proteins with mammalian exosomes. However, isolated A1-EVs contain significantly higher levels of both RNA and protein per particle than mammalian EVs. Additionally, numerous cargo RNAs and proteins are unique to A1 EVs. Of particular note, A1-EVs contain numerous mRNAs encoding nuclear receptors, membrane ligands, as well as transcription factors. Mammalian cardiomyocytes treated with A1-EVs showed increased expression of genes in the PI3K/AKT pathway, a pivotal player in survival signaling. We conclude that newt cells secrete EVs with diverse, distinctive RNA and protein contents. Despite ~300 million years of evolutionary divergence between newts and mammals, newt EVs confer cytoprotective effects on mammalian cardiomyocytes. PMID- 29696079 TI - Profiling plasma extracellular vesicle by pluronic block-copolymer based enrichment method unveils features associated with breast cancer aggression, metastasis and invasion. AB - Extracellular vesicle (EV)-based liquid biopsies have been proposed to be a readily obtainable biological substrate recently for both profiling and diagnostics purposes. Development of a fast and reliable preparation protocol to enrich such small particles could accelerate the discovery of informative, disease-related biomarkers. Though multiple EV enrichment protocols are available, in terms of efficiency, reproducibility and simplicity, precipitation based methods are most amenable to studies with large numbers of subjects. However, the selectivity of the precipitation becomes critical. Here, we present a simple plasma EV enrichment protocol based on pluronic block copolymer. The enriched plasma EV was able to be verified by multiple platforms. Our results showed that the particles enriched from plasma by the copolymer were EV size vesicles with membrane structure; proteomic profiling showed that EV-related proteins were significantly enriched, while high-abundant plasma proteins were significantly reduced in comparison to other precipitation-based enrichment methods. Next-generation sequencing confirmed the existence of various RNA species that have been observed in EVs from previous studies. Small RNA sequencing showed enriched species compared to the corresponding plasma. Moreover, plasma EVs enriched from 20 advanced breast cancer patients and 20 age matched non-cancer controls were profiled by semi-quantitative mass spectrometry. Protein features were further screened by EV proteomic profiles generated from four breast cancer cell lines, and then selected in cross-validation models. A total of 60 protein features that highly contributed in model prediction were identified. Interestingly, a large portion of these features were associated with breast cancer aggression, metastasis as well as invasion, consistent with the advanced clinical stage of the patients. In summary, we have developed a plasma EV enrichment method with improved precipitation selectivity and it might be suitable for larger-scale discovery studies. PMID- 29696080 TI - Therapeutic effects of serum extracellular vesicles in liver fibrosis. AB - The lack of approved therapies for hepatic fibrosis seriously limits medical management of patients with chronic liver disease. Since extracellular vesicles (EVs) function as conduits for intercellular molecular transfer, we investigated if EVs from healthy individuals have anti-fibrotic properties. Hepatic fibrogenesis or fibrosis in carbon tetrachloride (CCl4)- or thioacetic acid induced liver injury models in male or female mice were suppressed by serum EVs from normal mice (EVN) but not from fibrotic mice (EVF). CCl4-treated mice undergoing EVN therapy also exhibited reduced levels of hepatocyte death, inflammatory infiltration, circulating AST/ALT levels and hepatic or circulating pro-inflammatory cytokines. Hepatic histology, liver function tests or circulating proinflammatory cytokine levels were unaltered in control mice receiving EVN. As determined using PKH26-labelled EVN, principal target cells included hepatic stellate cells (HSC; a normally quiescent fibroblastic cell that undergoes injury-induced activation and produces fibrosis during chronic injury) or hepatocytes which showed increased EVN binding after, respectively, activation or exposure to CCl4. In vitro, EVN decreased proliferation and fibrosis associated molecule expression in activated HSC, while reversing the inhibitory effects of CCl4 or ethanol on hepatocyte proliferation. In mice, microRNA-34c, 151-3p, -483-5p, -532-5p and -687 were more highly expressed in EVN than EVF and mimics of these microRNAs (miRs) individually suppressed fibrogenic gene expression in activated HSC. A role for these miRs in contributing to EVN actions was shown by the ability of their corresponding antagomirs to individually and/or collectively block the therapeutic effects of EVN on activated HSC or injured hepatocytes. Similarly, the activated phenotype of human LX-2 HSC was attenuated by serum EVs from healthy human subjects and contained higher miR-34c, -151-3p, 483-5p or -532-5p than EVs from hepatic fibrosis patients. In conclusion, serum EVs from normal healthy individuals are inherently anti-fibrogenic and anti fibrotic, and contain microRNAs that have therapeutic actions in activated HSC or injured hepatocytes. Abbreviations: ALT: alanine aminotransferase; AST: aspartate aminotransferase; CCl4: carbon tetrachloride; CCN2: connective tissue growth factor; E: eosin; EGFP: enhanced green fluorescent protein; EVs: extracellular vesicles; EVF: serum EVs from mice with experimental hepatic fibrosis; EVN: serum EVs from normal mice; H: hematoxylin; HSC: hepatic stellate cell; IHC: immunohistochemistry; IL: interleukin; MCP-1: monocyte chemotactic protein-1; miR: microRNA; mRNA: messenger RNA; NTA: nanoparticle tracking analysis; PCNA: proliferating cell nuclear antigen; qRT-PCR: quantitative real-time polymerase chain reaction; SDS-PAGE: sodium dodecyl sulphate - polyacrylamide gel electrophoresis; alphaSMA: alpha smooth muscle actin; TAA: thioacetic acid; TG: transgenic; TGF-beta: transforming growth factor beta; TEM: transmission electron microscopy; TNFalpha: tumour necrosis factor alpha. PMID- 29696081 TI - Proteomic analysis reveals different composition of extracellular vesicles released by two Trypanosoma cruzi strains associated with their distinct interaction with host cells. AB - Trypanosoma cruzi, the aetiologic agent of Chagas disease, releases vesicles containing a wide range of surface molecules known to affect the host immunological responses and the cellular infectivity. Here, we compared the secretome of two distinct strains (Y and YuYu) of T. cruzi, which were previously shown to differentially modulate host innate and acquired immune responses. Tissue culture-derived trypomastigotes of both strains secreted extracellular vesicles (EVs), as demonstrated by electron scanning microscopy. EVs were purified by exclusion chromatography or ultracentrifugation and quantitated using nanoparticle tracking analysis. Trypomastigotes from YuYu strain released higher number of EVs than those from Y strain, enriched with virulence factors trans sialidase (TS) and cruzipain. Proteomic analysis confirmed the increased abundance of proteins coded by the TS gene family, mucin-like glycoproteins, and some typical exosomal proteins in the YuYu strain, which also showed considerable differences between purified EVs and vesicle-free fraction as compared to the Y strain. To evaluate whether such differences were related to parasite infectivity, J774 macrophages and LLC-MK2 kidney cells were preincubated with purified EVs from both strains and then infected with Y strain trypomastigotes. EVs released by YuYu strain caused a lower infection but higher intracellular proliferation in J774 macrophages than EVs from Y strain. In contrast, YuYu strain-derived EVs caused higher infection of LLC-MK2 cells than Y strain-derived EVs. In conclusion, quantitative and qualitative differences in EVs and secreted proteins from different T. cruzi strains may correlate with infectivity/virulence during the host-parasite interaction. PMID- 29696082 TI - Oxidant status, iron homeostasis, and carotenoid levels of COPD patients with advanced disease and LTOT. AB - Background: The pathogenesis of chronic obstructive pulmonary disease (COPD) is associated with oxidative stress. Both iron (Fe) and oxygen are involved in the chemical reactions that lead to increased formation of reactive oxygen species. Oxidative reactions are prevented by antioxidants such as carotenoids. Objective: To study the differences in Fe status, carotenoid levels, healthy eating habits, and markers of inflammation and oxidative damage on proteins in subjects with severe COPD +/- long-term oxygen therapy (LTOT) and lung-healthy control subjects. Methods: Sixty-six Caucasians with advanced COPD (28 with LTOT) and 47 control subjects were included. Questionnaires about general health, lifestyle, and dietary habits were answered. Lung function tests and blood sampling were performed. Results: COPD subjects (+/-LTOT) did not demonstrate increased oxidative damage, assessed by protein carbonylation (PC), while levels of soluble transferrin receptors (sTfRs) were slightly elevated. Soluble TfRs, which is inversely related to Fe status, was negatively associated with PC. Levels of carotenoids, total and beta-cryptoxanthin, alpha- and beta-carotenes, were significantly lower in COPD subjects, and their diet contained significantly less fruits and vegetables. Lutein correlated inversely with IL-6, lycopene correlated inversely with SAT, while beta-carotene was positively associated with a Mediterranean-like diet. Conclusions: Fe could favor oxidative stress in COPD patients, suggesting a cautious use of Fe prescription to these patients. COPD subjects ate a less healthy diet than control subjects did and would, therefore, benefit by dietary counseling. COPD patients with hypoxemia are probably in particular need of a lycopene-enriched diet. PMID- 29696083 TI - Health care resource utilization and characteristics of patients with eosinophilic asthma in secondary health care in Finland. AB - Background: Eosinophilic airway inflammation is common in asthma patients and appears to be associated with severe exacerbations and loss of asthma control. Objective: To describe the resource utilization and clinical characteristics of patients with eosinophilic asthma. Design: Asthma patients >=18 years with >=1 blood eosinophil count in secondary care (South West Finland) during 2003-2013 were included. Clinical characteristics (age, lung function, body mass index, and comorbidities) and asthma-related resource utilization (hospital admissions, outpatient visits, and emergency room [ER] visits) were retrieved. Resource utilization rates were compared for patients with blood eosinophil <= or >300 cells/MUL, using adjusted negative binomial regression models. Results: Overall, 4,357 eligible patients were identified (mean age 60 years, females 68%), of which 1,927 (44%) had >300 eosinophil cells/MUL blood. Patients with <=300 and >300 eosinophil counts, exhibited similar clinical characteristics, including advanced age, poor lung function, and overweight. Comorbidities such as pneumonia, sinusitis, and nasal polyps, were more frequent among those with >300 eosinophil cells/MUL blood compared with patients with lower counts. Eosinophil counts >300 cells/MUL were associated with greater hospital admissions (rate ratio [RR] [95% confidence interval CI]: 1.13 [1.02;1.24]) and outpatient visits (RR [95% CI]: 1.11 [1.03;1.20]) compared with patients with lower eosinophil counts. Rates of ER visits were similar between the patient groups (RR [95% CI]: 0.99 [0.87;1.12]). Conclusions: Hospital admissions and outpatient visits occurred more often for patients with eosinophil counts >300 cells/uL, than for patients with lower eosinophil counts. Routine blood eosinophil screening might be useful to identify patients with an eosinophilic phenotype eligible for more targeted treatments. PMID- 29696084 TI - Graphene-based biosensors. AB - Reliable data obtained from analysis of DNA, proteins, bacteria and other disease related molecules or organisms in biological samples have become a fundamental and crucial part of human health diagnostics and therapy. The development of non invasive tests that are rapid, sensitive, specific and simple would allow patient discomfort to be prevented, delays in diagnosis to be avoided and the status of a disease to be followed up. Bioanalysis is thus a progressive discipline for which the future holds many exciting opportunities. The use of biosensors for the early diagnosis of diseases has become widely accepted as a point-of-care diagnosis with appropriate specificity in a short time. To allow a reliable diagnosis of a disease at an early stage, highly sensitive biosensors are required as the corresponding biomarkers are generally expressed at very low concentrations. In the past 50 years, various biosensors have been researched and developed encompassing a wide range of applications. This contrasts the limited number of commercially available biosensors. When it comes to sensing of biomarkers with the required picomolar (pM) sensitivity for real-time sensing of biological samples, only a handful of sensing systems have been proposed, and these are often rather complex and costly. Lately, graphene-based materials have been considered as superior over other nanomaterials for the development of sensitive biosensors. The advantages of graphene-based sensor interfaces are numerous, including enhanced surface loading of the desired ligand due to the high surface to-volume ratio, excellent conductivity and a small band gap that is beneficial for sensitive electrical and electrochemical read-outs, as well as tunable optical properties for optical read-outs such as fluorescence and plasmonics. In this paper, we review the advances made in recent years on graphene-based biosensors in the field of medical diagnosis. PMID- 29696085 TI - Hybrid graphene-ceramic nanofibre network for spontaneous neural differentiation of stem cells. AB - A challenge in regenerative medicine is governed by the need to have control over the fate of stem cells that is regulated by the physical and chemical microenvironment in vitro and in vivo. The differentiation of the stem cells into specific lineages is commonly guided by use of specific culture media. For the first time, we demonstrate that human mesenchymal stem cells are capable of turning spontaneously towards neurogenic lineage when seeded on graphene augmented, highly anisotropic ceramic nanofibres without special differentiation media, contrary to commonly thought requirement of 'soft' substrates for the same purpose. Furthermore, pro-inflammatory gene expression is simultaneously suppressed, and expression of factors promoting focal adhesion and monocytes taxis is upregulated. This opens new possibilities of using local topo-mechanical cues of the 'graphenized' scaffold surfaces to guide stem cell proliferation and differentiation, which can be used in studies of neurological diseases and cell therapy. PMID- 29696086 TI - Investigating the bioavailability of graphene quantum dots in lung tissues via Fourier transform infrared spectroscopy. AB - Biomolecular fractions affect the fate and behaviour of quantum dots (QDs) in living systems but how the interactions between biomolecules and QDs affect the bioavailability of QDs is a major knowledge gap in risk assessment analysis. The transport of QDs after release into a living organism is a complex process. The majority accumulate in the lungs where they can directly affect the inhalation process and lung architecture. Here, we investigate the bioavailability of graphene quantum dots (GQDs) to the lungs of rats by measuring the alterations in macromolecular fractions via Fourier transform infrared spectroscopy (FTIR). GQDs were intravenously injected into the rats in a dose-dependent manner (low (5 mg kg-1) and high (15 mg kg-1) doses of GQDs per body weight of rat) for 7 days. The lung tissues were isolated, processed and haematoxylin-eosin stained for histological analysis to identify cell death. Key biochemical differences were identified by spectral signatures: pronounced changes in cholesterol were found in two cases of low and high doses; a change in phosphorylation profile of substrate proteins in the tissues was observed in low dose at 24 h. This is the first time biomolecules have been measured in biological tissue using FTIR to investigate the biocompatibility of foreign material. We found that highly accurate toxicological changes can be investigated with FTIR measurements of tissue sections. As a result, FTIR could form the basis of a non-invasive pre diagnostic tool for predicting the toxicity of GQDs. PMID- 29696087 TI - Multifunctional chitosan-magnetic graphene quantum dot nanocomposites for the release of therapeutics from detachable and non-detachable biodegradable microneedle arrays. AB - Biodegradable chitosan-magnetic graphene quantum dot (MGQD) nanocomposites were prepared and investigated for the release of small and large molecular weight (MWt) therapeutics from detachable and non-detachable biodegradable microneedle arrays. The presence of MGQDs in chitosan increased the electrical conductivity and biodegradation rate of chitosan while maintaining its mechanical properties. The detachable microneedle arrays were created by including a water-soluble ring of poly(ethylene glycol) (PEG) at the base of the microneedle, which enabled the rapid detachment of the microneedle shaft from the base. The PEG ring did not impede the microneedle array performance, with mechanical properties and a drug release profile of low MWt lidocaine hydrochloride similar to microneedle arrays without the ring. Without the PEG ring, the chitosan-MGQD microneedles were electrically conductive and allowed for electrically stimulated release of large MWt therapeutics which was challenging without the stimulation. These results demonstrate that chitosan nanocomposites containing MGQDs with intrinsic photoluminescent and supermagnetic properties are promising materials for developing multifunctional microneedles for targeted and tracked transdermal drug delivery. PMID- 29696088 TI - Graphene and its derivatives as biomedical materials: future prospects and challenges. AB - Graphene and its derivatives possess some intriguing properties, which generates tremendous interests in various fields, including biomedicine. The biomedical applications of graphene-based nanomaterials have attracted great interests over the last decade, and several groups have started working on this field around the globe. Because of the excellent biocompatibility, solubility and selectivity, graphene and its derivatives have shown great potential as biosensing and bio imaging materials. Also, due to some unique physico-chemical properties of graphene and its derivatives, such as large surface area, high purity, good bio functionalizability, easy solubility, high drug loading capacity, capability of easy cell membrane penetration, etc., graphene-based nanomaterials become promising candidates for bio-delivery carriers. Besides, graphene and its derivatives have also shown interesting applications in the fields of cell culture, cell-growth and tissue engineering. In this article, a comprehensive review on the applications of graphene and its derivatives as biomedical materials has been presented. The unique properties of graphene and its derivatives (such as graphene oxide, reduced graphene oxide, graphane, graphone, graphyne, graphdiyne, fluorographene and their doped versions) have been discussed, followed by discussions on the recent efforts on the applications of graphene and its derivatives in biosensing, bio-imaging, drug delivery and therapy, cell culture, tissue engineering and cell growth. Also, the challenges involved in the use of graphene and its derivatives as biomedical materials are discussed briefly, followed by the future perspectives of the use of graphene based nanomaterials in bio-applications. The review will provide an outlook to the applications of graphene and its derivatives, and may open up new horizons to inspire broader interests across various disciplines. PMID- 29696089 TI - New routes to the functionalization patterning and manufacture of graphene-based materials for biomedical applications. AB - Graphene-based materials are being widely explored for a range of biomedical applications, from targeted drug delivery to biosensing, bioimaging and use for antibacterial treatments, to name but a few. In many such applications, it is not graphene itself that is used as the active agent, but one of its chemically functionalized forms. The type of chemical species used for functionalization will play a key role in determining the utility of any graphene-based device in any particular biomedical application, because this determines to a large part its physical, chemical, electrical and optical interactions. However, other factors will also be important in determining the eventual uptake of graphene based biomedical technologies, in particular the ease and cost of manufacture of proposed device and system designs. In this work, we describe three novel routes for the chemical functionalization of graphene using oxygen, iron chloride and fluorine. We also introduce novel in situ methods for controlling and patterning such functionalization on the micro- and nanoscales. Our approaches are readily transferable to large-scale manufacturing, potentially paving the way for the eventual cost-effective production of functionalized graphene-based materials, devices and systems for a range of important biomedical applications. PMID- 29696090 TI - The effect of graphene-poly(methyl methacrylate) fibres on microbial growth. AB - A novel class of ultra-thin fibres, which affect microbial growth, were explored. The microbial properties of poly(methyl methacrylate) fibres containing 2, 4 and 8 wt% of graphene nanoplatelets (GNPs) were studied. GNPs were dispersed in a polymeric solution and processed using pressurized gyration. Electron microscopy was used to characterize GNP and fibre morphology. Scanning electron microscopy revealed the formation of beaded porous fibres. GNP concentration was found to dictate fibre morphology. As the GNP concentration increased, the average fibre diameter increased from 0.75 to 2.71 um, while fibre porosity decreased. Gram negative bacteria Escherichia coli and Pseudomonas aeruginosa were used to investigate the properties of 2, 4 and 8 wt% GNP-loaded fibres. GNP-loaded fibres (0 wt%) were used as the negative control. The fibres were incubated for 24 h with the bacteria; bacterial colony-forming units were enumerated by adopting the colony-counting method. The presence of 2 and 4 wt% GNP-loaded fibres promoted microbial growth, while 8 wt% GNP-loaded fibres showed antimicrobial activity. These results indicate that the minimum inhibitory concentration of GNPs required within a fibre is 8 wt%. PMID- 29696091 TI - Curcumin-loaded graphene oxide flakes as an effective antibacterial system against methicillin-resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is responsible for serious hospital infections worldwide and represents a global public health problem. Curcumin, the major constituent of turmeric, is effective against MRSA but only at cytotoxic concentrations or in combination with antibiotics. The major issue in curcumin-based therapies is the poor solubility of this hydrophobic compound and the cytotoxicity at high doses. In this paper, we describe the efficacy of a composite nanoparticle made of curcumin (CU) and graphene oxide (GO), hereafter GOCU, in MRSA infection treatment. GO is a nanomaterial with a large surface area and high drug-loading capacity. GO has also antibacterial properties due mainly to a mechanical cutting of the bacterial membranes. For this physical mechanism of action, microorganisms are unlikely to develop resistance against this nanomaterial. In this work, we report the capacity of GO to support and stabilize curcumin molecules in a water environment and we demonstrate the efficacy of GOCU against MRSA at a concentration below 2 ug ml-1. Further, GOCU displays low toxicity on fibroblasts cells and avoids haemolysis of red blood cells. Our results indicate that GOCU is a promising nanomaterial against antibiotic resistant MRSA. PMID- 29696092 TI - Mechano-bactericidal mechanism of graphene nanomaterials. AB - Growing interest in the bactericidal effect of graphene and graphene-derived nanomaterials has led to the investigation and effective publication of the bactericidal effects of the substratum, many of which present highly conflicting material. The nature of bacterial cell death on graphene bio-interfaces, therefore, remains poorly understood. Here, we review recent findings on the bactericidal effect of graphene and graphene-derived nanomaterials, and proposed mechanisms of cell inactivation, due to mechanical contact with graphene materials, including lipid extraction, physical damage to membranes and pore formation. PMID- 29696093 TI - Ultrananocrystalline diamond-coated nanoporous membranes support SK-N-SH neuroblastoma endothelial cell attachment. AB - Ultrananocrystalline diamond (UNCD) has been demonstrated to have attractive features for biomedical applications and can be combined with nanoporous membranes for applications in drug delivery systems, biosensing, immunoisolation and single molecule analysis. In this study, free-standing nanoporous UNCD membranes with pore sizes of 100 or 400 nm were fabricated by directly depositing ultrathin UNCD films on nanoporous silicon nitride membranes and then etching away silicon nitride using reactive ion etching. Successful deposition of UNCD on the substrate with a novel process was confirmed with Raman spectroscopy, X-ray photoelectron spectroscopy, cross-section scanning electron microscopy (SEM) and transmission electron microscopy. Both sample types exhibited uniform geometry and maintained a clear hexagonal pore arrangement. Cellular attachment of SK-N-SH neuroblastoma endothelial cells was examined using confocal microscopy and SEM. Attachment of SK-N-SH cells onto UNCD membranes on both porous regions and solid surfaces was shown, indicating the potential use of UNCD membranes in biomedical applications such as biosensors and tissue engineering scaffolds. PMID- 29696094 TI - Aquaporin-graphene interface: relevance to point-of-care device for renal cell carcinoma and desalination. AB - The aquaporin superfamily of hydrophobic integral membrane proteins constitutes water channels essential to the movement of water across the cell membrane, maintaining homeostatic equilibrium. During the passage of water between the extracellular and intracellular sides of the cell, aquaporins act as ultra sensitive filters. Owing to their hydrophobic nature, aquaporins self-assemble in phospholipids. If a proper choice of lipids is made then the aquaporin biomimetic membrane can be used in the design of an artificial kidney. In combination with graphene, the aquaporin biomimetic membrane finds practical application in desalination and water recycling using mostly Escherichia coli AqpZ. Recently, human aquaporin 1 has emerged as an important biomarker in renal cell carcinoma. At present, the ultra-sensitive sensing of renal cell carcinoma is cumbersome. Hence, we discuss the use of epitopes from monoclonal antibodies as a probe for a point-of-care device for sensing renal cell carcinoma. This device works by immobilizing the antibody on the surface of a single-layer graphene, that is, as a microfluidic device for sensing renal cell carcinoma. PMID- 28928963 TI - Recent advances in understanding the roles of whole genome duplications in evolution. AB - Ancient whole-genome duplications (WGDs)- paleopolyploidy events-are key to solving Darwin's 'abominable mystery' of how flowering plants evolved and radiated into a rich variety of species. The vertebrates also emerged from their invertebrate ancestors via two WGDs, and genomes of diverse gymnosperm trees, unicellular eukaryotes, invertebrates, fishes, amphibians and even a rodent carry evidence of lineage-specific WGDs. Modern polyploidy is common in eukaryotes, and it can be induced, enabling mechanisms and short-term cost-benefit assessments of polyploidy to be studied experimentally. However, the ancient WGDs can be reconstructed only by comparative genomics: these studies are difficult because the DNA duplicates have been through tens or hundreds of millions of years of gene losses, mutations, and chromosomal rearrangements that culminate in resolution of the polyploid genomes back into diploid ones (rediploidisation). Intriguing asymmetries in patterns of post-WGD gene loss and retention between duplicated sets of chromosomes have been discovered recently, and elaborations of signal transduction systems are lasting legacies from several WGDs. The data imply that simpler signalling pathways in the pre-WGD ancestors were converted via WGDs into multi-stranded parallelised networks. Genetic and biochemical studies in plants, yeasts and vertebrates suggest a paradigm in which different combinations of sister paralogues in the post-WGD regulatory networks are co regulated under different conditions. In principle, such networks can respond to a wide array of environmental, sensory and hormonal stimuli and integrate them to generate phenotypic variety in cell types and behaviours. Patterns are also being discerned in how the post-WGD signalling networks are reconfigured in human cancers and neurological conditions. It is fascinating to unpick how ancient genomic events impact on complexity, variety and disease in modern life. PMID- 29696095 TI - Improving the glial differentiation of human Schwann-like adipose-derived stem cells with graphene oxide substrates. AB - There is urgent need to improve the clinical outcome of peripheral nerve injury. Many efforts are directed towards the fabrication of bioengineered conduits, which could deliver stem cells to the site of injury to promote and guide peripheral nerve regeneration. The aim of this study is to assess whether graphene and related nanomaterials can be useful in the fabrication of such conduits. A comparison is made between graphene oxide (GO) and reduced GO substrates. Our results show that the graphene substrates are highly biocompatible, and the reduced GO substrates are more effective in increasing the gene expression of the biomolecules involved in the regeneration process compared to the other substrates studied. PMID- 29696097 TI - Mechanical Validation of an MRI Compatible Stereotactic Neurosurgery Robot in Preparation for Pre-Clinical Trials. AB - The use of magnetic resonance imaging (MRI) for guiding robotic surgical devices has shown great potential for performing precisely targeted and controlled interventions. To fully realize these benefits, devices must work safely within the tight confines of the MRI bore without negatively impacting image quality. Here we expand on previous work exploring MRI guided robots for neural interventions by presenting the mechanical design and assessment of a device for positioning, orienting, and inserting an interstitial ultrasound-based ablation probe. From our previous work we have added a 2 degree of freedom (DOF) needle driver for use with the aforementioned probe, revised the mechanical design to improve strength and function, and performed an evaluation of the mechanism's accuracy and effect on MR image quality. The result of this work is a 7-DOF MRI robot capable of positioning a needle tip and orienting it's axis with accuracy of 1.37 +/- 0.06mm and 0.79 degrees +/- 0.41 degrees , inserting it along it's axis with an accuracy of 0.06 +/- 0.07mm, and rotating it about it's axis to an accuracy of 0.77 degrees +/- 1.31 degrees . This was accomplished with no significant reduction in SNR caused by the robot's presence in the MRI bore, <= 10.3% reduction in SNR from running the robot's motors during a scan, and no visible paramagnetic artifacts. PMID- 29696099 TI - Individual Test Point Fluctuations of Macular Sensitivity in Healthy Eyes and Eyes With Age-Related Macular Degeneration Measured With Microperimetry. AB - Purpose: To establish fluctuation limits, it was considered that not only overall macular sensitivity but also fluctuations of individual test points in the macula might have clinical value. Methods: Three repeated measurements of microperimetry were performed using the Standard Expert test of Macular Integrity Assessment (MAIA) in healthy subjects (N = 12, age = 23.8 +/- 1.5 years old) and in patients with age-related macular degeneration (AMD) (N = 11, age = 68.5 +/- 7.4 years old). A total of 37 macular points arranged in four concentric rings and in four quadrants were analyzed individually and in groups. Results: The data show low fluctuation of macular sensitivity of individual test points in healthy subjects (average = 1.38 +/- 0.28 dB) and AMD patients (average = 2.12 +/- 0.60 dB). Lower sensitivity points are more related to higher fluctuation than to the distance from the central point. Fixation stability showed no effect on the sensitivity fluctuation. The 95th percentile of the standard deviations of healthy subjects was, on average, 2.7 dB, ranging from 1.2 to 4 dB, depending on the point tested. Conclusion: Point analysis and regional analysis might be considered prior to evaluating macular sensitivity fluctuation in order to distinguish between normal variation and a clinical change. Translational Relevance: Statistical methods were used to compare repeated microperimetry measurements and to establish fluctuation limits of the macular sensitivity. This analysis could add information regarding the integrity of different macular areas and provide new insights into fixation points prior to the biofeedback fixation training. PMID- 29696100 TI - A Rare Case of Michelin Tire Baby Syndrome in a Newborn. AB - Kunze-Riehm syndrome also known as Michelin tire baby syndrome (MTBS) is a rare genetic condition with a characteristic generalized folding of excess skin. The diagnosis is usually made based on clinical symptoms. There are approximately only 30 cases reported in the literature and some cases were associated with non cutaneous anomalies as well. Herein, we report a case of MTBS in a five-day-old male of Iraqi origin. PMID- 29696098 TI - Collagen Fibers in the Healing Process of Rat Achilles Tendon Rupture Using Different Times of Ultrasound Therapy. AB - Objective: The aim of this study was to evaluate the organization of collagen fibers in the healing process of rat Achilles tendon rupture using different times of ultrasound therapy (TUS). Approach: Forty Wistar rats were selected. Among these, 32 were submitted to total tenotomy of the calcaneous tendon and divided into 5 groups: control group (CG, n = 8), without tenotomy or any treatment; tenotomy group (n = 8), with tenotomy and without treatment; TUS groups-TUS3 (n = 8), TUS4 (n = 8), and TUS5 (n = 8)-submitted to tenotomy and treated with TUS for 3, 4, and 5 min per effective radiating area (ERA), respectively. The animals were sacrificed on the 12th postoperative day. The tendons were surgically removed for analysis of the collagen fiber organization using the birefringence technique (OR, optical retardation). Results: The collagen fibers exhibited better aggregation and organization in the UST3, TUS4, and TUS5 groups compared with CG (p < 0.05). The TUS5 group had better response rates in intergroup comparison. Innovation: The dose response of therapeutic TUS is influenced by many variables. The scientific evidence to support the dosimetry is insufficient. The application time is an important variable to be considered in TUS. In this study, the longer the application time, the better for organization and aggregation of collagen fibers in the rat tendon. Conclusion: TUS applied for 5 min per ERA presented higher dose response to the organization of collagen fibers in the healing process of rat Achilles tendon rupture. PMID- 29696101 TI - Curriculum Design and Implementation of the Emergency Medicine Chief Resident Incubator. AB - Background Chief residents receive minimal formal training in preparation for their administrative responsibilities. There is a lack of professional development programs specifically designed for chief residents. Objective In 2015, Academic Life in Emergency Medicine designed and implemented an annual, year-long, training program and virtual community of practice for chief residents in emergency medicine (EM). This study describes the curriculum design process and reports measures of learner engagement during the first two cycles of the curriculum. Methods Kern's Six-Step Approach for curriculum development informed key decisions in the design and implementation of the Chief Resident Incubator. The resultant curriculum was created using constructivist social learning theory, with specific objectives that emphasized the needs for a virtual community of practice, longitudinal content delivery, mentorship for participants, and the facilitation of multicenter digital scholarship. The 12-month curriculum included 11 key administrative or professional development domains, delivered using a combination of digital communications platforms. Primary outcomes measures included markers of learner engagement with the online curriculum, recognized as modified Kirkpatrick Level One outcomes for digital learning. Results An average of 206 chief residents annually enrolled in the first two years of the curriculum, with an overall participation by 33% (75/227) of the allopathic EM residency programs in the United States (U.S.). There was a high level of learner engagement, with an average 13,414 messages posted per year. There were also 42 small group teaching sessions held online, which included 39 faculty and 149 chief residents. The monthly e-newsletter had a 50.7% open rate. Digital scholarship totaled 23 online publications in two years, with 67 chief resident co-authors and 21 faculty co-authors. Conclusions The Chief Resident Incubator is a virtual community of practice that provides longitudinal training and mentorship for EM chief residents. This incubator conceptual framework may be used to design similar professional development curricula across various health professions using an online digital platform. PMID- 29696102 TI - Diverticular Disease-associated Colitis: What Do We Know? A Review of Literature. AB - Diverticular disease (DD) is a leading cause of hospitalizations in developed countries affecting 30-50% of individuals older than 60 years. Identified as a distinct entity since 1980, diverticular disease-associated colitis (DAC) describes the occurrence of mucosal inflammation in a colon segment affected with DD with relative sparing of the rectum and proximal colon. Its prevalence is suggested around 1.3-3.8%. Pathogenesis is multifactorial with multiple reports noting clinicopathological overlap between DAC and inflammatory bowel disease (IBD) especially in patients with granulomatous colitis. In this setting, caution should be exercised to avoid an inappropriate diagnosis of IBD. Recurrence rates and long-term outcomes of DAC are not well defined and could range from a benign course to an overt IBD. More studies are needed in order to further characterize this entity. PMID- 29696103 TI - Conserved Histidine Adjacent to the Proximal Cluster Tunes the Anaerobic Reductive Activation of Escherichia coli Membrane-Bound [NiFe] Hydrogenase-1. AB - [NiFe] hydrogenases are electrocatalysts that oxidize H2 at a rapid rate without the need for precious metals. All membrane-bound [NiFe] hydrogenases (MBH) possess a histidine residue that points to the electron-transfer iron sulfur cluster closest ("proximal") to the [NiFe] H2-binding active site. Replacement of this amino acid with alanine induces O2 sensitivity, and this has been attributed to the role of the histidine in enabling the reversible O2-induced over-oxidation of the [Fe4S3Cys2] proximal cluster possessed by all O2-tolerant MBH. We have created an Escherichia coli Hyd-1 His-to-Ala variant and report O2-free electrochemical measurements at high potential that indicate the histidine mediated [Fe4S3Cys2] cluster-opening/closing mechanism also underpins anaerobic reactivation. We validate these experiments by comparing them to the impact of an analogous His-to-Ala replacement in Escherichia coli Hyd-2, a [NiFe]-MBH that contains a [Fe4S4] center. PMID- 29696104 TI - Anastomotic techniques for rat lung transplantation. AB - The first lung transplantation in the rat was achieved by Asimacopoulos et al using sutured anastomoses in 1971. Subsequent development of a cuffed technique to construct the anastomoses by Mizuta and colleagues in 1989 represented a breakthrough that resulted in simplification of the procedure and shorter warm ischemic times. Since then, a number of further variations on the technique of rat lung transplantation have been described. In spite of this, the procedure remains technically demanding and involves a long learning curve. This minireview describes the following new technical safeguards to further evolve the technique for cuffed anastomoses in rat lung transplantation: the use of anatomical landmarks to avoid twisting of the everted donor pulmonary vein and bronchus in the cuff, the use of the cuff tie as a landmark to avoid twisting of the anastomotic cuffs relative to the recipient vessels, distal ties on the recipient vessels to achieve a bloodless field and triangulation of the venotomy to avoid pulmonary vein tearing. PMID- 29696105 TI - Cumulative positive fluid balance is a risk factor for acute kidney injury and requirement for renal replacement therapy after liver transplantation. AB - AIM: To analyze whether fluid overload is an independent risk factor of adverse outcomes after liver transplantation (LT). METHODS: One hundred and twenty-one patients submitted to LT were retrospectively evaluated. Data regarding perioperative and postoperative variables previously associated with adverse outcomes after LT were reviewed. Cumulative fluid balance (FB) in the first 12 h and 4 d after surgery were compared with major adverse outcomes after LT. RESULTS: Most of the patients were submitted to a liberal approach of fluid administration with a mean cumulative FB over 5 L and 10 L, respectively, in the first 12 h and 4 d after LT. Cumulative FB in 4 d was independently associated with occurrence of both AKI and requirement for renal replacement therapy (RRT) (OR = 2.3; 95%CI: 1.37-3.86, P = 0.02 and OR = 2.89; 95%CI: 1.52-5.49, P = 0.001 respectively). Other variables on multivariate analysis associated with AKI and RRT were, respectively, male sex and Acute Physiology and Chronic Health Disease Classification System (APACHE II) levels and sepsis or septic shock. Mortality was shown to be independently related to AST and APACHE II levels (OR = 2.35; 95%CI: 1.1-5.05, P = 0.02 and 2.63; 95%CI: 1.0-6.87, P = 0.04 respectively), probably reflecting the degree of graft dysfunction and severity of early postoperative course of LT. No effect of FB on mortality after LT was disclosed. CONCLUSION: Cumulative positive FB over 4 d after LT is independently associated with the development of AKI and the requirement of RRT. Survival was not independently related to FB, but to surrogate markers of graft dysfunction and severity of postoperative course of LT. PMID- 29696106 TI - Evaluation of the Effect of Aminophylline in Reducing the Incidence of Acute Kidney Injury After Cardiac Surgery. AB - Objectives: Acute renal failure is a common complication of major cardiovascular surgeries (One-third of patients). Adenosine release as a vascular vasodilator increases after cardiac surgery, which reduces renal and glomerular blood flow and subsequently causes kidney ischemic damage. The present study aimed at evaluating the impact of aminophylline as an adenosine receptor antagonist on renal function after cardiac surgery hoping to find an appropriate method to reduce acute kidney injury. Methods: The patients in the intervention group received 5 mg/kg aminophylline bolus after induction of anesthesia; then, 0.25 mg/kg/hr of the drug was administered intraoperatively and up to 48 hours after surgery in the ICU cardiac surgery. Similar volume of normal saline was injected to the patients of the second group. Serum BUN, Cr, and GFR were measured pre- and postoperatively and 3 days postsurgery. Patients' 24- hour urine output and RIFLE were also calculated. Results: Those patients who received medication were extubated earlier (P = 0.018) and received lower amount of inotropic drugs (P < 0001). According to the RIFLE criteria, most of the patients experienced no change or even improved GFR and Cr amounts compared to the control group (p < 0.05). GFR and Cr value of all the patients with Cleveland score, less and more than 6, showed a significant difference between the 2 groups (P = 0.001 and P = 0.01, respectively). According to the RIFLE criteria, most of the patients experienced no change or even improved GFR. Conclusions: Aminophylline in cardiac surgery can reduce the frequency of acute kidney injury according to RIFLE criteria and could be used in the prevention of AKI as a safe and efficient modality in high-risk patients. Also, the use of this drug may reduce the need for inotropic medication at the time of surgery, intensive care unit stay length, and extubation time. PMID- 29696107 TI - Comparing the Effect of Adding Fentanyl, Sufentanil, and Placebo with Intrathecal Bupivacaine on Duration of Analgesia and Complications of Spinal Anesthesia in Patients Undergoing Cesarean Section. AB - Background: Spinal anesthesia is the method of choice for most elective and emergency Cesarean sections. To increase the duration of anesthesia and improve the quality of analgesia during and after surgery, intrathecal opioids, as adjuvant drugs, are used in combination with local anesthetics. Methods: This was a double-blind clinical trial performed on 99 patients. Women were divided into 3 groups of fentanyl, sufentanil, and placebo. For fentanyl group, 12.5 mg of bupivacaine and 25 micrograms of fentanyl; for sufentanil group, 12.5 mg of bupivacaine and 2.5 micrograms of sufentanil; and for placebo group, 12.5 mg of bupivacaine and a half mL of normal saline were injected in subarachnoid space. The sensory and motor block, hemodynamic status (mean blood pressure and heart rate), and probable complications were assessed. Results: There was no significant difference between the groups in demographic characteristics. Durations of analgesia were, respectively, 314 +/- 42.95, 312.5 +/- 34.44, and 116.1 +/- 42.24 minutes in the fentanyl, sufentanil, and placebo groups (P = 0.0001). Duration of sensory and motor block was higher in fentanyl and sufentanil groups compared with the placebo group. The highest duration of sensory and motor block was noted in sufentanil group (P = 0.0001). No significant difference was found between the groups in the hemodynamic parameters (P > 0.05). The frequency of itching in the fentanyl group was higher than sufentanil and placebo groups (P = 0.003). Also, shivering was higher in the placebo group compared with other groups (P = 0.036). Conclusions: According to the results, adding 25 microgram fentanyl or 2.5 microgram sufentanil to intrathecal bupivacaine increased the duration of analgesia and provided hemodynamic stability with no major complication. As administering intrathecal fentanyl had a similar duration of analgesia like sufentanil with faster return of motor block and ambulation, it seems that it is a preferred additive for Cesarean section surgery. PMID- 29696108 TI - Comparing the Effectiveness of Patient Control Analgesia Pump and Bolus Morphine in Controlling Pain After Cardiopulmonary Bypass Graft Surgery. AB - Background: Postoperative pain is a complex process commonly caused by surgical trauma. It is one of the major concerns of patients undergoing heart surgery. Despite new techniques and modern analgesic treatments, postoperative pain is still one of the most important controversial issues. Methods: 68 patients scheduled for elective CABG with CPB were included in a prospective, double-blind clinical trial. They were randomly divided into two groups. One group received PCA pump including morphine (group P) with underlying infusion of 0.02 mg/kg/Qh, bolus dose of 1 mg, lockout time of 15 minutes, and a maximum of 4 bolus of 0.02 mg/kg for one hour and the other group received morphine bolus (group B). Three patients were excluded from the study, and 33 and 32 patients participated in the groups P and B, respectively. Variables including age, gender, pump time, aortic clamp time, duration of surgery, complications (nausea and vomiting, GI Bleeding, and hypoxia), level of pain based on VAS, opioid consumption, hemodynamic, and sedation status were measured in both groups. Results: There was no significant difference between the groups regarding age, gender, pump time, clamp time, duration of surgery, complication, sedation score, and hemodynamic status in most of the assessment periods. By assessing the pain severity in the groups at different periods, results showed a significant difference between the groups except at enrollment, and a lower severity of pain was noted in the group P compared to the group B. The consumed opioid was significantly higher in the group P than in the group B. However, higher doses of diclofenac and paracetamol were administered in the group B compared to the group P. Conclusions: Results showed that higher morphine would be used in patients with PCA pump after extubation following heart surgery, and this increased dose of opioid was associated with better pain control and lack of complication. Therefore, PCA pump with underlying infusion could be effectively used in patients undergoing CABG that are directly assessed in intensive care unite. PMID- 29696109 TI - Comparison Between Effects of Acupuncture and Metoclopramide on Postoperative Nausea and Vomiting after Gynaecological Laparoscopy: A Randomized Controlled Trial. AB - Background: Gynaecological laparoscopy one ofthe most common operations thatis accompanied by postoperative nausea and vomiting (PONV). A non-pharmacological method of preventing PONV is acupuncture therapy. Objectives: This study is conducted to compare the effects of acupuncture and metoclopramide on post operative nausea and vomiting (PONV) after gynaecological laparoscopy. Methods: In this double-blind, randomized, clinical trial study,122female, ASA I, aged 19 46, who had been referred to the Imam Khomini Hospital (Ahvaz, Iran) and were candidates for gynaecological laparoscopy were enrolled. Eligible patients were randomly allocated into three groups group I (acupuncture; n = 40), group II (metoclopramide 0.2 mg/kg IV; n = 41), and group III (control; n = 41). In group I, acupuncture was done by inserting a special needle at point P6 in front of the elbow immediately after induction of anaesthesia and removing it before extubation and transfer of the patient to the recovery room. The occurrences of nausea and vomiting during the period of stay in the recovery room (one and two hours after surgery) were recorded through questions or clinical observation. Statistical analysis was conducted using SPSS V. 19, descriptive statistics, and the Chi-square test. Results: The acupuncture group (11.1%) showed a significant decrease in the incidence of nausea one hour after surgery compared to the metoclopramide group (33.3%) (P = 0.02), but there was no significant difference between the acupuncture and metoclopramide groups in terms of postoperative vomiting (POV) incidence one and two hours after surgery. Incidence of PONV in the acupuncture group (2.7%) was statistically significantly lower than that in the control group (28.5%), two hours after surgery (P < 0.01). Conclusions: Acupuncture is better for controlling nausea after laparoscopic surgery, compared to metoclopramide. Acupuncture is an effective method for reduction of PONV in gynaecological laparoscopy. PMID- 29696111 TI - Comparing Labetalol and Nitroglycerine on Inducing Controlled Hypotension and Intraoperative Blood Loss in Rhinoplasty: A Single-Blinded Clinical Trial. AB - Background: Uncontrolled bleeding during surgery is one of the main predisposing factors for failure of the surgeon and complications following rhinoplasty. The current study aimed at comparing the effects of nitroglycerine and labetalol on the induction of controlled hypotension and bleeding volume during septorhinoplasty. Methods: The current randomized, controlled, clinical trial enrolled 60 patients candidate for septorhinoplasty at Firoozgar hospital in Tehran, Iran, in 2 equal groups receiving either 0.1 to 1 mcg/kg/minute nitroglycerine or 2 to 4 mg/minute labetalol to achieve a mean arterial blood pressure of about 60 to 65 mmHg. In case the targeted blood pressure was not achieved, isoflurane was added. Degree of bleeding was evaluated by the volume of suctioned blood and the blood remaining in surgical gauzes. Additionally, the surgeon's satisfaction with the surgical field was evaluated by a scoring system. The collected data were, then, compared between the study groups by the statistical methods. Results: Based on the current study findings, systolic (P < 0.001), diastolic (P = 0.002), and the mean arterial blood pressures (P < 0.001) were significantly lower in the nitroglycerine group. Ninety percent of the patients in the labetalol group received isoflurane to achieve the targeted blood pressure defined as controlled hypotension. There was no significant difference between the groups regarding the volume of bleeding (P = 0.75); however, the surgeons were more satisfied with nitroglycerine than labetalol (P < 0.001). Conclusions: It was concluded that nitroglycerine had a better effect, in comparison to labetalol, on inducing the controlled hypotension in septorhinoplasty. PMID- 29696110 TI - Subcostal Transverse Abdominis Plane Block for Acute Pain Management: A Review. AB - The subcostal transverse abdominis plane (SCTAP) block is the deposition of local anesthetic in the transverse abdominis plane inferior and parallel to the costal margin. There is a growing consensus that the SCTAP block provides better analgesia for upper abdominal incisions than the traditional transverse abdominis plane block. In addition, when used as part of a four-quadrant transverse abdominis plane block, the SCTAP block may provide adequate analgesia for major abdominal surgery. The purpose of this review is to discuss the SCTAP block, including its indications, technique, local anesthetic solutions, and outcomes. PMID- 29696112 TI - Epidural Anesthesia Combined with Light General Anesthesia for a Juvenile with Charcot-Marie-Tooth Disease Undergoing Corrective Spine Surgery: A Case Report. AB - General anesthesia (GA) is associated with serious concerns in advanced cases of Charcot-Marie-Tooth (CMT). Despite several benefits of applying regional anesthesia (RA), recommendation for RA is controversial in CMT due to insufficient supporting documents and trials. We report combined epidural/general anesthesia for a 12-year-old boy with CMT disease undergoing major spine corrective surgery. This manuscript is presented not only to evaluate the costs and benefits of RA, but also to highlight the safety of neuraxial anesthesia and emphasis on the broad potential role of RA to reduce risks of GA in CMT patients. PMID- 29696113 TI - Prolotherapy and Low Level Laser Therapy: A Synergistic Approach to Pain Management in Chronic Osteoarthritis. AB - Regenerative injection therapy and low level laser therapy are alternative remedies known for their success in the treatment and symptomatic management of chronic musculoskeletal conditions. In response to the growing demand for alternative therapies in the face of the opioid epidemic, the authors conduct a literature review to investigate the potential for prolotherapy and LLLT to be used adjunctively to manage chronic osteoarthritis (OA). OA is a degenerative chronic musculoskeletal condition on the rise in North America, and is frequently treated with opioid medications. The regenerative action of prolotherapy and pain modulating effects of LLLT may make these two therapies well-suited to synergistically provide improved outcomes for osteoarthritis patients without the side effects associated with opioid use. A narrative descriptive review through multiple medical databases (Google Scholar, PubMed, and MedLine) is conducted, restricted by the use of medical subject headings. 71 articles were selected for reading in full, and 40 articles were selected for use in the study after reading in full. A review of the literature revealed good clinical results in the use of prolotherapy and LLLT separately to manage chronic musculoskeletal pain due to osteoarthritis and other chronic conditions. It is also recognized in the literature that prolotherapy works most effectively when used adjunctively with other treatments. Downsides to the use of prolotherapy include mild side effects of pain, stiffness and bruising and potential adverse events as a result of injection. This study is limited by the lack of clinical trials available involving both LLLT and prolotherapy injections used adjunctively, and by the low number of high impact literature concerning the treatment of (specifically) osteoarthritis by alternative methods. The authors suggest that practicing health care providers consider utilizing LLLT and prolotherapy together as a supplementary method in the management of chronic pain due to osteoarthritis, to minimize the long-term prescription of opioids and emphasize a less invasive treatment for this debilitating condition. PMID- 29696114 TI - The Effect of Scaphoid and Hamate Mobilization on Treatment of Patients with Carpal Tunnel Syndrome. AB - Background: This study was to evaluate the effect of hamate and scaphoid bone mobilization alongside splinting in women with carpal tunnel syndrome. Methods: In this randomized clinical trial, 40 participants were randomly assigned into 2 groups. The intervention group received splinting with scaphoid and hamate mobilization, while the control group received splinting only. Outcome variables were pain (based on visual analogue scale), symptom severity and functional status (based on Boston questionnaire), and nerve conduction study measured before and 10 weeks after the treatments. Results: At the end of study, both groups showed an improvement in pain and symptom severity, functional status as well as median nerve conduction study. Although there was no statistically significant difference between groups regarding changes in median nerve sensory and motor distal latencies; the improvement was significantly higher in pain and symptom severity as well as functional status in mobilization group (P-Value < 0.05). Conclusions: Hamate and scaphoid mobilization can be used as an effective option in women with mild to moderate carpal tunnel syndrome. Further investigation is required for determining long-term effects and cost effectiveness of mobilization in carpal tunnel syndrome. PMID- 29696115 TI - The Effect of Ketamine and Dexamethasone in Combination with Lidocaine on the Onset and Duration of Axillary Block in Hand and Forearm Soft Tissue Surgery. AB - Background: Using peripheral nerve block compared to general anesthesia has gained more popularity due to reduced postoperative pain, less need for post surgery analgesic drugs, reduced incidence of nausea, shortness of PACU time, and increased patient satisfaction. Objectives: The aim of this study was to compare the effect of ketamine and dexamethasone as additives to lidocaine on duration and onset of axillary block action. Methods: In this clinical trial, all patients who referred to Hazrat-e-Fatemeh hospital for forearm and hand soft tissue surgery with informed consent were randomly divided into three groups in order to examine the onset and duration of axillary block: lidocaine + ketamine, lidocaine + dexamethasone in axillary block, and lidocaine alone (control). Then, the onset and duration of sensory and motor blocks were measured and recorded every three minutes and after the surgery. Quantitative and qualitative variables were analyzed using ANOVA or Kruskal-Wallis test and Chi-square or Fisher exact test in SPSS v.22. Results: Duration of sensory and motor block axillary was significantly higher in lidocaine + dexamethasone group than in lidocaine + ketamine group (P < 0.05); it was also significantly higher in lidocaine + ketamine group compared to lidocaine group (P < 0.05). However, there was no significant difference in the onset of sensory and motor block axillary between the three groups (P > 0.05). Conclusions: According to the results of our study, we can conclude that adding dexamethasone or ketamine to lidocaine could improve duration of sensory and motor axillary block in patients undergoing forearm and hand soft tissue surgery. However, dexamethasone had the highest effect on duration of block axillary. We proved that dexamethasone or ketamine added to lidocaine had no effect on the onset of block axillary. PMID- 29696116 TI - Comparison of Glasgow Coma Scale, Full Outline of Unresponsiveness and Acute Physiology and Chronic Health Evaluation in Prediction of Mortality Rate Among Patients With Traumatic Brain Injury Admitted to Intensive Care Unit. AB - Background: Traumatic brain injury (TBI) is a common cause of mortality and disability worldwide. Choosing an appropriate diagnostic tool is critical in early stage for appropriate decision about primary diagnosis, medical care and prognosis. Objectives: This study aimed to compare the Glasgow coma scale (GCS), full outline of unresponsiveness (FOUR) and acute physiology and chronic health evaluation (APACHE II) with respect to prediction of the mortality rate of patients with TBI admitted to intensive care unit. Patients and Methods: This diagnostic study was conducted on 80 patients with TBI in educational hospitals. The scores of APACHE II, GCS and FOUR were recorded during the first 24 hours of admission of patients. In this study, early mortality means the patient death before 14 days and delayed mortality means the patient death 15 days after admitting to hospital. The collected data were analyzed using descriptive and inductive statistics. Results: The results showed that the mean age of the patients was 33.80 +/- 12.60. From a total of 80 patients with TBI, 16 (20%) were females and 64 (80%) males. The mortality rate was 15 (18.7%). The results showed no significant difference among three tools. In prediction of early mortality, the areas under the curve (AUCs) were 0.92 (CI = 0.95. 0.81 - 0.97), 0.90 (CI = 0.95. 0.74 - 0.94), and 0.96 (CI = 0.95. 0.87 - 0.9) for FOUR, APACHE II and GCS, respectively. In delayed mortality, the AUCs were 0.89 (CI = 0.95. 0.81-0.94), 0.94 (CI = 0.95. 0.74 - 0.97) and 0.90 (CI = 0.95. 0.87 - 0.95) for FOUR, APACHE II and GCS, respectively. Conclusions: Considering that GCS is easy to use and the FOUR can diagnose a locking syndrome along same values of subscales. These two subscales are superior to APACHI II in prediction of early mortality. Conversation APACHE II is more punctual in the prediction of delayed mortality. PMID- 29696117 TI - Comparing Three Different Modified Sitting Positions for Ease of Spinal Needle Insertion in Patients Undergoing Spinal Anesthesia. AB - Background: The most important point for performing a neuroaxial block in a sitting position is reducing lumbar lordosis, resulting in easier access to interspinous space and dura mater. There are a few studies comparing 2 different sitting positions including a traditional sitting position (TSP) versus forward bending or hamstring stretch position (HSP) as well as TSP versus squatting position (SP) for reversing the lumbar lordosis and improving access to intervertebral space for neuroaxial block. Objectives: We compared 3 different sitting positions including traditional sitting position vs. hamstring stretch position vs. squatting position and hypothesized that squatting position reverses the lumbar lordosis and reduces the number of spinal needle bone contacts more than TSP and HSP. Methods: A total of Thirty hundred and sixty ASA class I or II patients aged 18 to 60 years were scheduled for elective surgeries under spinal anesthesia were randomized into 3 groups. Our primary endpoint was the number of spinal needle-bone contacts and our secondary endpoint was ease of needle insertion or space identification. Results: Demographic data were statistically different between the study groups. There was no statistical difference between the study groups regarding the number of needle bone contacts and the ease of finding intervertebral space (P = 0.63, P = 0.56, respectively). Conclusions: There was no statistical difference between the TSP, HSP, and SP regarding the number of needle bone contacts and the ease of finding of intervertebral space. In this regard, each of these 3 positions can be used as an alternative sitting position for administration of spinal anesthesia. PMID- 29696118 TI - Anesthetic Considerations for Angelman Syndrome: Case Series and Review of the Literature. AB - Background: Angelman syndrome is a rare neurodevelopmental disorder characterized by intellectual disability, severe speech impairment, ataxia, seizures, happy demeanor, distinctive craniofacial features, high vagal tone, and gamma-amino butyric acid receptor abnormalities. The aim of this report is to review our experience of patients with Angelman syndrome undergoing anesthetic management. Methods: We retrospectively reviewed perioperative course of patients with Angelman syndrome who underwent procedures under anesthesia from 2000 to 2016. Results: Six patients with Angelman syndrome underwent 18 procedures; 14 performed under general anesthesia, and 4 with monitored anesthetic care, many for minor procedures (e.g., dental and diagnostic). Five patients had profound developmental delay and were nonverbal and 4 of them had epilepsy. The perioperative courses were uncomplicated except a 2 year-old girl having an intraoperative bronchospasm, a 16 year-old girl requiring flumazenil administration, and 28 year-old man who was electively intubated with a videolaryngoscope because of airway management concerns. No patients were documented as having postoperative pain. Conclusions: Angelman syndrome patients often require anesthesia for relatively innocuous procedures, and their speech impairment and happy demeanor can confound postoperative pain assessment. Patients can have atypical responses to benzodiazepines. Craniofacial abnormalities can complicate airway management. Although not encountered in this series, anesthesiologists need to be aware that Angelman syndrome patients have developed malignant bradydysrhythmias while anesthetized. PMID- 29696119 TI - The Results of Treating Failed Back Surgery Syndrome by Adhesiolysis: Comparing the One- and Three-Day Protocols. AB - Background: The optimal treatment of failed back surgery syndrome (FBSS) is controversial. Limited studies have demonstrated the satisfactory outcomes of percutaneous adhesiolysis in FBSS, which can be performed as a 1 day or 3 days procedure. In the current randomized clinical trial, we compared the clinical and functional outcomes of these 2 techniques. Methods: In this study, 60 patients with FBSS were randomly assigned into 2 equal groups: 1 day group and 3 days group. Before and at 4 and 12 weeks after the procedure, pain intensity was measured using visual analogue scale (VAS). The Oswestry disability index (ODI) was also completed. Pain reduction of 50% or more was defined as treatment success. Results: Significant pain relief and ODI improvement were obtained in the 2 groups with adhesiolysis (P < 0.001). However, pain intensity remained the same before and at 4 and 12 weeks after adhesiolysis. ODI score was significantly lower in 1 day group in the 1 month visit (P < 0.001). Treatment was successful in 76.7% and 83.3% of the patients in 1 day and 3 days groups, respectively (P = 0.519). Conclusions: Adhesiolysis is an effective treatment for pain relief and functional improvement in FBSS. The results of 1 day and 3 days procedures are comparable. Based on these findings, the authors recommend using 1 day technique, which can potentially decrease the patients' discomfort, hospital stay, and cost of treatment. PMID- 29696120 TI - Acute Cervical and Thoracic Ventral Side Spontaneous Spinal Epidural Hematoma Causing High Paraplegia: A Case Report. AB - Introduction: Spontaneous spinal epidural hematoma (SSEH) is a rare condition that can potentially cause paraplegia. SSEH has an increasing incidence rate and its cause remains unclear. Magnetic resonance imaging (MRI) results shows that SSEH presents a spinal epidural space-occupying lesion; therefore, emergency surgical treatment is required in some cases. MRI results of most SSEH cases showed that hematoma occurs in the dorsal or lateral side. By contrast, hematoma in the ventral side is very rarely shown. Case Presentation: A 42-year-old healthy woman developed a sudden onset of severe neck pain with mild limb weakness, gradual breathing difficulty, and high paraplegia. MRI results revealed that an SSEH was compressing her spinal cord in the ventral epidural space from C2 to T3. Upon admission, she received emergency decompressive laminectomy in a posterior approach from C3 to T1, and the epidural hematoma was evacuated through full incision of the dorsal side dural, release of cerebrospinal fluid, and intermittent incision of the ventral side dural. The symptoms of limb paralysis and breathing distress gradually improved after recover rehabilitation, and the patient was discharged with life self-care after 2 months. Conclusions: Performing early decompressive laminectomy and evacuation of hematoma on severe SSEH patients improves neurological outcomes. For patients with ventral side SSEH, the cerebrospinal fluid should be released after the incision on the dorsal side dural, and the ventral side dural should be gradually as well as intermittently clipped to evacuate the hematoma. The patient would also receive a good prognosis after the total release of the spinal cord compression. PMID- 29696121 TI - The Effect of Different Doses of Intrathecal Hyperbaric Bupivacaine Plus Sufentanil in Spinal Anesthesia for Cesarean Sections. AB - Background: Decreasing side effects and improving the quality of block in caesarean sections by appropriate dosage of local anesthetics and adjuvants could play an important role in the safe management of cesarean section. The present study aimed at comparing the effects of 3 different doses of intrathecal hyperbaric bupivacaine injected with a fixed dose of sufentanil in cesarean sections. Methods: In a double- blind randomized clinical trial, 105 candidates of elective cesarean section were randomly assigned into 3 groups of 8, 9, and 10 mg of intrathecal bupivacaine plus sufentanil 2.5 ug. The maximum level of sensory block, the intensity of motor block, and vital signs were measured at regular intervals. The incidence of hypotension and bradycardia were also recorded. Results: No significant difference was found between the maximum level of sensory block and the intensity of motor block in 3 groups. The incidences of hypotension and bradycardia as well as administration of atropine and ephedrine were comparable among the 3 groups (P > 0.05). Conclusions: According to similar effects of different doses of bupivacaine, administration of lower doses of bupivacaine (8mg) is more reasonable for spinal anesthesia for cesarean section. PMID- 29696122 TI - Comparison of Magnesium Sulfate and Tramadol as an Adjuvant to Intravenous Regional Anesthesia for Upper Extremity Surgeries. AB - Background: Intravenous Regional Anesthesia (IVRA) is a simple efficient method for providing regional anesthesia of the limbs. However, it has some limitations such as lack of postoperative analgesia. Objectives: This study aimed to compare the analgesic effects of magnesium sulfate and tramadol when added to lidocaine used for IVRA in upper limb surgery. Methods: In this double - blind randomized clinical trial, 69 patients who underwent elective upper limb surgery with IVRA were randomly allocated into 3 groups. Patients in group A, received IVRA with 0.5% lidocaine and tramadol 100 mg, in group B received IVRA with 0.5% lidocaine and magnesium sulfate 1.5 g, while in group C patients received IVRA with 0.5% lidocaine and normal saline. The onset of sensory block and the duration of postoperative analgesia pain intensity were noted in each patient. Furthermore, the incidence of postoperative nausea and vomiting, respiratory depression, and skin rash were recorded. Results: Duration of postoperative analgesia was more prolong in the tramadol group than other groups (P = 0.01). Also, the total amount of morphine consumption in the group A, group B, and C was 8.91 +/- 5.81, 11.95 +/- 4.81, 16.72 +/- 4.07 mg, respectively, which was significantly lower in the tramadol group in comparison to the other groups (P = 0.01). Conclusions: It seems that adding tramadol as an adjuvant to lidocaine during IVRA in comparison to magnesium sulfate increases duration of postoperative analgesia and decreases analgesic consumption without increasing opioid-related side effects. PMID- 29696123 TI - Comparative Analysis of the Usefulness of the GlideScope(r), Macintosh, and McCoy Laryngoscopes for Endotracheal Intubation in Patients with Obesity: A Randomized, Clinical Trial. AB - Background: Difficult intubation is dangerous and sometimes fatal, especially in patients with obesity. In difficult intubation cases the best device should be applied to decrease the risk of complications. The current study aimed at comparing laryngoscopes, Macintosh, McCoy, GlideScope(r) and devices for intubation purposes. Methods: A total of 102 patients with obesity and ASA (American society of anesthesiologists) class I or II, and body mass index (BMI) of > 30 kg/m2 were selected. After obtaining the informed consent, the patients were divided into 3 groups based on the 3 laryngoscope types. Preoperative airway assessment including the Mallampati score, thyromental distance (TMD), and neck circumference was performed and all the patients were anesthetized based on the same protocol. Subsequently, all of the patients were intubated using a Macintosh, McCoy, or GlideScope(r) laryngoscope. Laryngoscopy time, Cormack Lehane score (1 - 4), and the percentage of glottic opening (POGO; 1 - 100) were evaluated. Data were analyzed using SPSS version 16, and results were considered statistically significant at P <= 0.05. Results: There was no significant difference between demographic characteristics and preoperative airway evaluations. The shortest and longest laryngoscopy time were obtained in the GlideScope(r) and McCoy laryngoscope groups, respectively (P = 0.001). The highest Cormack-Lehane score was obtained using the GlideScope(r) method (P = 0.04). The POGO was higher and, therefore, more appropriate in the McCoy laryngoscope group (P = 0.009). A direct relationship was observed between neck circumference (P = 0.008), BMI (P = 0.023), Mallampati score (P = 0.000), and laryngoscopy. Conclusions: In the current study, the shortest and longest intubation time in patients with obesity was observed in the GlideScope(r) and the McCoy laryngoscope groups, respectively. Moreover, the direct relationships of BMI and neck circumference with laryngoscopy time were observed in all 3 groups. These results suggested using GlideScope(r) in patients with high BMI to reduce laryngoscopy time. PMID- 29696124 TI - Diagnostic Value of Sonography for Confirmation of Endotracheal Intubation in the Emergency Department. AB - Background: Intubation and maintaining airway are crucial in the management of critically ill patients in the emergency department. Correct tracheal intubation should be confirmed by the physician, otherwise oesophageal intubation could lead to hypoxia with detrimental consequences and even death. Sonography can be used to determine proper placement of the tracheal tube. Methods: In this study, 75 patients, with an indication of intubation and age older than 18 years entered the study. An emergency medicine performed real-time sonography of the trachea to evaluate the correct placement of endotracheal tube. Tube passage (snowstorm) and vocal cord angel widening (bullet sign) were evaluated, and then both lungs sliding and diaphragm movement were evaluated to confirm correct tube placement and ventilation. Results: In this study, 75 patients entered the study. The mean age of the patients was 61.12; 47 patients (62.7%) were male and 28 (37.3%) were female. The reason of intubation was the decreased level of consciousness in 22 cases (29.3%), cardiopulmonary arrest in 22 patients (29.3%), respiratory distress in 9 patients (12%), shock in 10 patients (13.3%), and seizure in 1 case. Snowstorm sign was seen in 72 patients (96%). Bullet sign was objected in 24 cases (32%). Lung sliding was seen bilaterally in 63 patients (84%) and unilaterally in 7 patients (9.3 %), but it was not noticed in 6.7% of the patients (5 patients). Conclusions: Transverse tracheal and lung sonography in the emergency department can be a fast measure to confirm correct endotracheal intubation. PMID- 29696125 TI - Comparison of Arterial Oxygenation Following Head-Down and Head-Up Laparoscopic Surgery. AB - Background: Regarding the role of gas entry in abdomen and cardiorespiratory effects, the ability of anesthesiologists would be challenged in laparoscopic surgeries. Considering few studies in this area and the relevance of the subject, this study was performed to compare the arterial oxygen alterations before operation in comparison with after surgery between laparoscopic cholecystectomy and ovarian cystectomy. Methods: In this prospective cohort, 70 consecutive women aged from 20 to 60 years who were candidate for laparoscopic cholecystectomy (n = 35) and ovarian cystectomy (n = 35) with reverse (20 degrees) and direct (30 degrees) Trendelenburg positions, respectively, with ASA class I or II were enrolled. After intubation and before operation, for the first time, the arterial blood gas from radial artery in supine position was obtained for laboratory assessment. Then, the second blood sample was collected from radial artery in supine position and sent to the lab to be assessed with the same device after 30 minutes from surgery termination. The measured variables from arterial blood gas were arterial partial pressure of oxygen (PaO2) and Oxygen saturation (SpO2) alterations. Results: Total PaO2 was higher in the first measurement. The higher values of PaO2 in cholecystectomy (upward) than in ovarian cystectomy (downward) were not significant in univariate (P = 0.060) and multivariate analysis (P = 0.654). Furthermore, higher values of SpO2 in cholecystectomy (upward) than in ovarian cystectomy (downward) were not significant in univariate (P = 0.412) and multivariate analysis (P = 0.984). Conclusions: In general, based on the results of this study, the values of PaO2 in cholecystectomy (upward) were not significantly higher than the values in cystectomy (downward) in laparoscopic surgeries when measured 30 minutes after surgery. PMID- 29696126 TI - Acute Pain Management in Emergency Department, Low Dose Ketamine Versus Morphine, A Randomized Clinical Trial. AB - Background: Ketamine, as an opium alternative, has been proposed for pain relief in the emergency department (ED). Objectives: This study was carried out to compare low dose ketamine (LDK) with morphine for pain relief in trauma patients. Methods: In this randomized double-blinded clinical trial, 300 trauma patients from the ED of 2 teaching hospitals in Tehran, Iran were enrolled and randomly divided into 2 equal groups. The 1st group received 0.2 mg/kg of ketamine while the 2nd group received 0.1 mg/kg of intravenous morphine. The pain intensity and complications were measured and compared every 15 minutes to 1 hour. Results: Fifteen minutes after drug injection in both groups, a significant reduction was found in average pain intensity compared to the initial pain (P = 0.01). At 15 minutes, no significant difference was found in both groups in regards to average pain intensity (P = 0.23). The average pain intensity at 30, 45, and 60 minutes in the group receiving morphine was lower than the ketamine group (P = 0.01, P < 0.001, P < 0.001 respectively). Two complications (drop in O2 saturation below 90% and flushing) were significantly greater in the morphine group. Conclusions: The results of this study suggest that LDK, at a dose of 0.2 mg/kg, in the earlier minutes leads to significant reduction of pain when compared to that of intravenous morphine. It also created fewer complications than morphine. PMID- 29696127 TI - Effect of Oral Clonidine on Shoulder Tip Pain and Hemodynamic Response After Laparoscopic Cholecystectomy: A Randomized Double Blind Study. AB - Background: Shoulder tip pain is a common problem after laparoscopic cholecystectomy. There are a few clinical trial studies on the effect of clonidine on post laparoscopic shoulder pain (PLSP). This study aimed at evaluating the effect of oral clonidine on PLSP in semi-sitting position and post operative hemodynamic response of patients undergoing LC surgery. Methods: This randomized controlled clinical trial was conducted on 60 patients, who were candidates for elective laparoscopic cholecystectomy surgery under general anesthesia, and were randomly allocated to clonidine and placebo groups. Patients in the clonidine group received 0.2 mg oral, 90 minutes prior to induction. Patients in the placebo group received vitamin C tablets during the same time. Postoperative pain intensity was assessed, using a visual analog scale at the emergence from anesthesia, 4 and 8 hours after the operation by an anesthetist, who was blinded to the patient group. Mean arterial blood pressure and heart rate were recorded before clonidine administration and in post-operative period. Results: The mean age was 36.85 +/- 10.93 years and the mean Body Mass was 26.34 +/- 3.46 kg/m2. Two groups were not comparable with respect to occurrence of PLSP (P = 0.739). There was a significant difference in intensity of PLSP between the 2 groups at emergence from anesthesia (P = 0.012), 4 and 8 hours after the operation (P = 0.001) between 2 groups. The clonidine group showed a larger reduction of pain intensity at these phases. The result of independent t test indicated significant differences in the MABP value between the 2 groups at the time of emergence from anesthesia (P = 0.031). The clonidine group demonstrated a lower MABP level at this time. Conclusions: Oral clonidine is not effective in preventing the PLSP. However, it alleviates PLSP intensity in the patient under LC procedure on the first post-operative hours. PMID- 29696128 TI - Electromyographic Findings After Epidural Steroid Injections in Patients with Radicular Low Back Pain: A Prospective Open-Label Study. AB - Epidural steroid injections (ESIs) are commonly used in the management of chronic lower back and leg pain. The aim of this study was to investigate the short- and long-term electromyographic and clinical outcome of patients with chronic radicular pain after ESIs. This prospective, open-label study, included patients with chronic radicular pain due to disc herniation or spinal stenosis, who underwent interlaminar, fluoroscopy-guided ESIs. Patients were assessed before ESIs, as well as after 6 and 12 months, clinically (VAS 0-10, BPI, DN4, Rolland Morris, DASS, STAI) and electromyographically for the improvement of spontaneous activity (SA) and of motor unit recruitment/interference pattern (IP/MUR). A total of 39 patients were studied, 20 (51.3%) who had a significant improvement in VAS, RM, DN4 and BPI were revealed, mainly during the first 6 months (P < 0.05). Statistically significant improvement was revealed in MUR/SA for almost all nerve roots studied. Patients with disc herniation showed a greater improvement in mean difference of MUR/SA (P < 0.05) (with a prognostic value of radicular LBP versus spinal stenosis in short- [VAS P = 0.042] and long-term improvement of pain [VAS P = 0.009]. The independent variables "MUR" and "SA" had a significant prognostic value for improvement of pain (VAS: R2 = 0.287, P = 0.032 and VAS: R2 = 0.277, P = 0.036 respectively). Electromyographic and clinical findings indicated a benefit from epidural steroid injections. Patients with disc herniation exhibited a better outcome, especially during the first 6 months post-treatment. PMID- 29696130 TI - Intraperitoneally Located Tip of Femoral Vein Catheter; Clinical Suspicion for Avoidance of Unnecessary Laparotomy. AB - Central venous catheterization is a common procedure in critical care and trauma patients. Complications are not rare and in some studies more than 15% incidence has been reported (1). Femoral vein is one of the commonest site for this purpose yet it carries complications, such as infection and misplacement. The current study reports an unexpected secondary malposition of right femoral CVC in the peritoneal cavity. It was concluded that in any case of acute abdominal issues, following insertion of femoral venous catheter, evaluation of catheter misplacement by the means of contrast injection through it can be helpful for better diagnosis, and may help avoid unnecessary surgical interventions. PMID- 29696129 TI - Controlled Hypotension During Rhinoplasty: A Comparison of Dexmedetomidine with Magnesium Sulfate. AB - Objective: The current study aimed at comparing the efficacy of dexmedetomidine and magnesium sulfate to control blood pressure (BP) during rhinoplasty and the resultant effects on the quality of surgical field in terms of bleeding and visibility. Methods: The current randomized, prospective, double-blind study was conducted on 60 patients aged 18 to 50 years classified as ASA (American Society of Anesthesiologists) physical status I who were candidates for rhinoplasty. Patients were randomly divided into 2 groups: (1) group Dex, received 1 ug/kg dexmedetomidine in 10 minutes before induction of anesthesia, followed by 0.4 - 0.6 ug/kg/hour during the maintenance of anesthesia, and (2) group Mg, received 40 mg/kg in 10 minutes before anesthesia induction followed by 10 - 15 mg/kg/hour during anesthesia maintenance. In both groups, the goal was to achieve a mean arterial pressure (MAP) of 60 - 70 mmHg. Hemodynamic variables, anesthetic, opioid, muscle relaxant requirements, and surgical field condition were recorded. Sedation score, time to reach modified Aldrete score >= 9, and adverse effects including nausea and vomiting (N&V) and shivering were recorded. Results: Controlled hypotension was achieved in both groups. There was no significant difference in MAP between the groups, but heart rate (HR) was significantly lower in the Dex group (P < 0.001), compared with that of the Mg group. Bleeding score was lower (P < 0.001) and surgeon's satisfaction score was higher (P < 0.001) in the Dex group. More patients required fentanyl (P < 0.001) or nitroglycerin (P < 0.001) and the mean fentanyl (P = 0.005) or nitroglycerin (P < 0.001) required doses were higher in the Mg group. Patients in the Dex group required more frequent administration of cisatracurium (P = 0.004). Five patients in the Dex group versus no patients in the Mg group received atropine (P = 0.023). Ramsay sedation score and time to reach modified Aldrete score >= 9 were significantly higher in the Dex group (P < 0.001 and P < 0.001, respectively). The incidence rate of N&V and shivering were similar in both groups. Conclusion: Dexmedetomidine was more effective than magnesium to achieve controlled hypotension, and provide a favorable surgical field condition. However, dexmedetomidine also heightened the risk of induced bradycardia and prolonged sedation. These are 2 important points to consider when applying this drug as a hypotensive agent during operation. PMID- 29696131 TI - Letter to: "The Effect of Different Doses of Intrathecal Hyperbaric Bupivacaine Plus Sufentanil in Spinal Anesthesia for Cesarean Sections". PMID- 29696133 TI - Classical NF-kappaB Metabolically Reprograms Sarcoma Cells Through Regulation of Hexokinase 2. AB - Background: Metabolic reprogramming has emerged as a cancer hallmark, and one of the well-known cancer-associated metabolic alterations is the increase in the rate of glycolysis. Recent reports have shown that both the classical and alternative signaling pathways of nuclear factor kappaB (NF-kappaB) play important roles in controlling the metabolic profiles of normal cells and cancer cells. However, how these signaling pathways affect the metabolism of sarcomas, specifically rhabdomyosarcoma (RMS) and osteosarcoma (OS), has not been characterized. Methods: Classical NF-kappaB activity was inhibited through overexpression of the IkappaBalpha super repressor of NF-kappaB in RMS and OS cells. Global gene expression analysis was performed using Affymetrix GeneChip Human Transcriptome Array 2.0, and data were interpreted using gene set enrichment analysis. Seahorse Bioscience XFe24 was used to analyze oxygen consumption rate as a measure of aerobic respiration. Results: Inhibition of classical NF-kappaB activity in sarcoma cell lines restored alternative signaling as well as an increased oxidative respiratory metabolic phenotype in vitro. In addition, microarray analysis indicated that inhibition of NF-kappaB in sarcoma cells reduced glycolysis. We showed that a glycolytic gene, hexokinase (HK) 2, is a direct NF-kappaB transcriptional target. Knockdown of HK2 shifted the metabolic profile in sarcoma cells away from aerobic glycolysis, and re-expression of HK2 rescued the metabolic shift induced by inhibition of NF-kappaB activity in OS cells. Conclusion: These findings suggest that classical signaling of NF-kappaB plays a crucial role in the metabolic profile of pediatric sarcomas potentially through the regulation of HK2. PMID- 29696134 TI - Lethal Zika Virus Disease Models in Young and Older Interferon alpha/beta Receptor Knock Out Mice. AB - The common small animal disease models for Zika virus (ZIKV) are mice lacking the interferon responses, but infection of interferon receptor alpha/beta knock out (IFNAR-/-) mice is not uniformly lethal particularly in older animals. Here we sought to advance this model in regard to lethality for future countermeasure efficacy testing against more recent ZIKV strains from the Asian lineage, preferably the American sublineage. We first infected IFNAR-/- mice subcutaneously with the contemporary ZIKV-Paraiba strain resulting in predominantly neurological disease with ~50% lethality. Infection with ZIKV Paraiba by different routes established a uniformly lethal model only in young mice (4-week old) upon intraperitoneal infection. However, intraperitoneal inoculation of ZIKV-French Polynesia resulted in uniform lethality in older IFNAR /- mice (10-12-weeks old). In conclusion, we have established uniformly lethal mouse disease models for efficacy testing of antivirals and vaccines against recent ZIKV strains representing the Asian lineage. PMID- 29696132 TI - Brain Metastases in Oncogene-Addicted Non-Small Cell Lung Cancer Patients: Incidence and Treatment. AB - Brain metastases (BM) are common in non-small cell lung cancer patients including in molecularly selected populations, such as EGFR-mutant and ALK-rearranged tumors. They are associated with a reduced quality of life, and are commonly the first site of progression for patients receiving tyrosine kinase inhibitors (TKIs). In this review, we summarize incidence of BM and intracranial efficacy with TKI agents according to oncogene driver mutations, focusing on important clinical issues, notably optimal first-line treatment in oncogene-addicted lung tumors with upfront BM (local therapies followed by TKI vs. TKI monotherapy). We also discuss the potential role of newly emerging late-generation TKIs as new standard treatment in oncogene-addicted lung cancer tumors compared with sequential strategies. PMID- 29696135 TI - Successful Deployment of High Flow Nasal Cannula in a Peruvian Pediatric Intensive Care Unit Using Implementation Science-Lessons Learned. AB - Acute lower respiratory infections are the leading cause of death outside the neonatal period for children less than 5 years of age. Widespread availability of invasive and non-invasive mechanical ventilation in resource-rich settings has reduced mortality rates; however, these technologies are not always available in many low- and middle-income countries due to the high cost and trained personnel required to implement and sustain their use. High flow nasal cannula (HFNC) is a form of non-invasive respiratory support with growing evidence for use in pediatric respiratory failure. Its simple interface makes utilization in resource limited settings appealing, although widespread implementation in these settings lags behind resource-rich settings. Implementation science is an emerging field dedicated to closing the know-do gap by incorporating evidence-based interventions into routine care, and its principles have guided the scaling up of many global health interventions. In 2016, we introduced HFNC use for respiratory failure in a pediatric intensive care unit in Lima, Peru using implementation science methodology. Here, we review our experience in the context of the principles of implementation science to serve as a guide for others considering HFNC implementation in resource-limited settings. PMID- 29696136 TI - Typical Kawasaki Disease Presenting With Pancreatitis and Bilateral Parotid Gland Involvement: A Case Report and Literature Review. AB - We describe the case of a 3-year child in which pancreatic and parotid gland involvement preceded the development of the classical clinical phenotype of a typical Kawasaki disease (KD). The child was referred to the Emergency Department with a story of 3 days of continuous fever associated with abdominal pain and bilaterally swelling in the parotid regions; laboratory evaluation identified markedly increased levels of total amylase, pancreatic amylase, lipase, and transaminase, and diagnosis of pancreatitis was posed. After 9 days of fever and persistence of the clinical features, the classical signs of KD appeared, and the child was treated with intravenous immunoglobulins (IVIG), showing a dramatic response with complete resolution of the clinical picture. In this work, we reviewed the literature about gastrointestinal (GI) symptoms in KD, focusing on pancreatic and hepatic involvement. This analysis highlighted that, in case of fever associated with pancreatic inflammation, KD must be considered in the spectrum of differential diagnosis, and that GI involvement in KD is frequently associated with an incomplete response to IVIG treatment. PMID- 29696137 TI - BitterSweetForest: A Random Forest Based Binary Classifier to Predict Bitterness and Sweetness of Chemical Compounds. AB - Taste of a chemical compound present in food stimulates us to take in nutrients and avoid poisons. However, the perception of taste greatly depends on the genetic as well as evolutionary perspectives. The aim of this work was the development and validation of a machine learning model based on molecular fingerprints to discriminate between sweet and bitter taste of molecules. BitterSweetForest is the first open access model based on KNIME workflow that provides platform for prediction of bitter and sweet taste of chemical compounds using molecular fingerprints and Random Forest based classifier. The constructed model yielded an accuracy of 95% and an AUC of 0.98 in cross-validation. In independent test set, BitterSweetForest achieved an accuracy of 96% and an AUC of 0.98 for bitter and sweet taste prediction. The constructed model was further applied to predict the bitter and sweet taste of natural compounds, approved drugs as well as on an acute toxicity compound data set. BitterSweetForest suggests 70% of the natural product space, as bitter and 10% of the natural product space as sweet with confidence score of 0.60 and above. 77% of the approved drug set was predicted as bitter and 2% as sweet with a confidence score of 0.75 and above. Similarly, 75% of the total compounds from acute oral toxicity class were predicted only as bitter with a minimum confidence score of 0.75, revealing toxic compounds are mostly bitter. Furthermore, we applied a Bayesian based feature analysis method to discriminate the most occurring chemical features between sweet and bitter compounds using the feature space of a circular fingerprint. PMID- 29696138 TI - Enhanced Defluoridation Capacity From Aqueous Media via Hydroxyapatite Decorated With Carbon Nanotube. AB - In this work, the potential of a novel hydroxyapatite decorated with carbon nanotube composite (CNT-HAP) for fluoride removal was investigated. The synthesized CNT-HAP composite was systematically characterized by X-ray diffraction(XRD), Fourier Transform infrared spectroscopy(FTIR), scanning electron microscope (SEM) and Brunauer-Emmett-Teller(BET). Batch adsorption experiments were conducted to investigate the defluorination capacity of CNT-HAP. The CNT-HAP composite has a maximum adsorption capacity of 11.05 mg.g-1 for fluoride, and the isothermal adsorption data were fitted by the Freundlich model to calculate the thermodynamic parameters. Thermodynamic analysis implies that the adsorption of fluoride on CNT-HAP is a spontaneous process. Furthermore, the adsorption of fluoride follows pseudo-second-order model. The effects of solution pH, co-existing anions and reaction temperature on defluorination efficiency were examined to optimize the operation conditions for fluoride adsorption. It is found that the optimized pH-value for fluoride removal by CNT-HAP composite is 6. In addition, among five common anions studied in this work, the presence of [Formula: see text] and [Formula: see text] could considerably affect the fluoride removal by CNT-HPA in aqueous media. Finally, the underlying mechanism for the fluoride removal by CNT-HAP is analyzed, and an anion exchange process is proposed. PMID- 29696139 TI - A Machine Learning Application Based in Random Forest for Integrating Mass Spectrometry-Based Metabolomic Data: A Simple Screening Method for Patients With Zika Virus. AB - Recent Zika outbreaks in South America, accompanied by unexpectedly severe clinical complications have brought much interest in fast and reliable screening methods for ZIKV (Zika virus) identification. Reverse-transcriptase polymerase chain reaction (RT-PCR) is currently the method of choice to detect ZIKV in biological samples. This approach, nonetheless, demands a considerable amount of time and resources such as kits and reagents that, in endemic areas, may result in a substantial financial burden over affected individuals and health services veering away from RT-PCR analysis. This study presents a powerful combination of high-resolution mass spectrometry and a machine-learning prediction model for data analysis to assess the existence of ZIKV infection across a series of patients that bear similar symptomatic conditions, but not necessarily are infected with the disease. By using mass spectrometric data that are inputted with the developed decision-making algorithm, we were able to provide a set of features that work as a "fingerprint" for this specific pathophysiological condition, even after the acute phase of infection. Since both mass spectrometry and machine learning approaches are well-established and have largely utilized tools within their respective fields, this combination of methods emerges as a distinct alternative for clinical applications, providing a diagnostic screening faster and more accurate-with improved cost-effectiveness when compared to existing technologies. PMID- 29696140 TI - Harnessing Nanotopography to Enhance Osseointegration of Clinical Orthopedic Titanium Implants-An in Vitro and in Vivo Analysis. AB - Despite technological advancements, further innovations in the field of orthopedics and bone regeneration are essential to meet the rising demands of an increasing aging population and associated issues of disease, injury and trauma. Nanotopography provides new opportunities for novel implant surface modifications and promises to deliver further improvements in implant performance. However, the technical complexities of nanotopography fabrication and surface analysis have precluded identification of the optimal surface features to trigger osteogenesis. We herein detail the osteoinductive potential of discrete nanodot and nanowire nanotopographies. We have examined the ability of modified titanium and titanium alloy (Ti64) surfaces to induce bone-specific gene activation and extracellular matrix protein expression in human skeletal stem cells (SSCs) in vitro, and de novo osteogenic response within a murine calvarial model in vivo. This study provides evidence of enhanced osteogenic response to nanowires 300 surface modifications, with important implications for clinical orthopedic application. PMID- 29696142 TI - Isolation and Characterization of Neural Crest-Derived Stem Cells From Adult Ovine Palatal Tissue. AB - Adult mammalian craniofacial tissues contain limited numbers of post-migratory neural crest-derived stem cells. Similar to their embryonic counterparts, these adult multipotent stem cells can undergo multi-lineage differentiation and are capable of contributing to regeneration of mesodermal and ectodermal cells and tissues in vivo. In the present study, we describe for the first time the presence of Nestin-positive neural crest-derived stem cells (NCSCs) within the ovine hard palate. We show that these cells can be isolated from the palatal tissue and are able to form neurospheres. Ovine NCSCs express the typical neural crest markers Slug and Twist, exhibit high proliferative and migratory activity and are able to differentiate into alpha smooth muscle cells and beta-III-tubulin expressing ectodermal cells. Finally, we demonstrate that oNCSCs are capable of differentiating into osteogenic, adipogenic and chondrogenic cells. Taken together, our results suggest that oNCSCs could be used as model cells to assess the efficacy and safety of autologous NCSC transplantation in a large animal model. PMID- 29696141 TI - Enhancing Understanding of the Visual Cycle by Applying CRISPR/Cas9 Gene Editing in Zebrafish. AB - During the vertebrate visual cycle, all-trans-retinal is exported from photoreceptors to the adjacent RPE or Muller glia wherein 11-cis-retinal is regenerated. The 11-cis chromophore is returned to photoreceptors, forming light sensitive visual pigments with opsin GPCRs. Dysfunction of this process perturbs phototransduction because functional visual pigment cannot be generated. Mutations in visual cycle genes can result in monogenic inherited forms of blindness. Though key enzymatic processes are well characterized, questions remain as to the physiological role of visual cycle proteins in different retinal cell types, functional domains of these proteins in retinoid biochemistry and in vivo pathogenesis of disease mutations. Significant progress is needed to develop effective and accessible treatments for inherited blindness arising from mutations in visual cycle genes. Here, we review opportunities to apply gene editing technology to two crucial visual cycle components, RPE65 and CRALBP. Expressed exclusively in the human RPE, RPE65 enzymatically converts retinyl esters into 11-cis retinal. CRALBP is an 11-cis-retinal binding protein expressed in human RPE and Muller glia. Loss-of-function mutations in either protein results in autosomal recessive forms of blindness. Modeling these human conditions using RPE65 or CRALBP murine knockout models have enhanced our understanding of their biochemical function, associated disease pathogenesis and development of therapeutics. However, rod-dominated murine retinae provide a challenge to assess cone function. The cone-rich zebrafish model is amenable to cost-effective maintenance of a variety of strains. Interestingly, gene duplication in zebrafish resulted in three Rpe65 and two Cralbp isoforms with differential temporal and spatial expression patterns. Functional investigations of zebrafish Rpe65 and Cralbp were restricted to gene knockdown with morpholino oligonucleotides. However, transient silencing, off-target effects and discrepancies between knockdown and knockout models, highlight a need for more comprehensive alternatives for functional genomics. CRISPR/Cas9 in zebrafish has emerged as a formidable technology enabling targeted gene knockout, knock-in, activation, or silencing to single base-pair resolution. Effective, targeted gene editing by CRISPR/Cas9 in zebrafish enables unprecedented opportunities to create genetic research models. This review will discuss existing knowledge gaps regarding RPE65 and CRALBP. We explore the benefits of CRISPR/Cas9 to establish innovative zebrafish models to enhance knowledge of the visual cycle. PMID- 29696143 TI - Single-Cell in Situ RNA Analysis With Switchable Fluorescent Oligonucleotides. AB - Comprehensive RNA analyses in individual cells in their native spatial contexts promise to transform our understanding of normal physiology and disease pathogenesis. Here we report a single-cell in situ RNA analysis approach using switchable fluorescent oligonucleotides (SFO). In this method, transcripts are first hybridized by pre-decoding oligonucleotides. These oligonucleotides subsequently recruit SFO to stain their corresponding RNA targets. After fluorescence imaging, all the SFO in the whole specimen are simultaneously removed by DNA strand displacement reactions. Through continuous cycles of target staining, fluorescence imaging, and SFO removal, a large number of different transcripts can be identified by unique fluorophore sequences and visualized at the optical resolution. To demonstrate the feasibility of this approach, we show that the hybridized SFO can be efficiently stripped by strand displacement reactions within 30 min. We also demonstrate that this SFO removal process maintains the integrity of the RNA targets and the pre-decoding oligonucleotides, and keeps them hybridized. Applying this approach, we show that transcripts can be restained in at least eight hybridization cycles with high analysis accuracy, which theoretically would enable the whole transcriptome to be quantified at the single molecule sensitivity in individual cells. This in situ RNA analysis technology will have wide applications in systems biology, molecular diagnosis, and targeted therapies. PMID- 29696144 TI - A Systematic Review of Clinical Functional Outcomes After Medial Stabilized Versus Non-Medial Stabilized Total Knee Joint Replacement. AB - Background: Medial stabilized total knee joint replacement (TKJR) construct is designed to closely replicate the kinematics of the knee. Little is known regarding comparison of clinical functional outcomes of patients utilising validated patient reported outcome measures (PROM) after medial stabilized TKJR and other construct designs. Purpose: To perform a systematic review of the available literature related to the assessment of clinical functional outcomes following a TKJR employing a medial stabilized construct design. Methods: The review was performed with a Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) algorithm. The literature search was performed using variouscombinations of keywords. The statistical analysis was completed using Review Manager (RevMan), Version 5.3. Results: In the nineteen unique studies identified, there were 2,448 medial stabilized TKJRs implanted in 2,195 participants, there were 1,777 TKJRs with non-medial stabilized design constructs implanted in 1,734 subjects. The final mean Knee Society Score (KSS) value in the medial stabilized group was 89.92 compared to 90.76 in the non-medial stabilized group, with the final KSS mean value difference between the two groups was statistically significant and favored the non-medial stabilized group (SMD 0.21; 95% CI: 0.01 to 0.41; p = 004). The mean difference in the final WOMAC values between the two groups was also statistically significant and favored the medial stabilized group (SMD: -0.27; 95% CI: -0.47 to -0.07; p = 0.009). Moderate to high values (I2 ) of heterogeneity were observed during the statistical comparison of these functional outcomes. Conclusion: Based on the small number of studies with appropriate statistical analysis, we are unable to reach a clear conclusion in the clinical performance of medial stabilized knee replacement construct. Level of Evidence: Level II. PMID- 29696145 TI - A Glimpse Into the Structure and Function of Atypical Type I Chaperonins. AB - Chaperonins are a subclass of molecular chaperones that assist cellular proteins to fold and assemble into their native shape. Much work has been done on Type I chaperonins, which has elucidated their elegant mechanism. Some debate remains about the details in these mechanisms, but nonetheless the roles of these in helping protein folding have been understood in great depth. In this review we discuss the known functions of atypical Type I chaperonins, highlighting evolutionary aspects that might lead chaperonins to perform alternate functions. PMID- 29696146 TI - The Use of NMR to Study Transient Carbohydrate-Protein Interactions. AB - Carbohydrates are biologically ubiquitous and are essential to the existence of all known living organisms. Although they are better known for their role as energy sources (glucose/glycogen or starch) or structural elements (chitin or cellulose), carbohydrates also participate in the recognition events of molecular recognition processes. Such interactions with other biomolecules (nucleic acids, proteins, and lipids) are fundamental to life and disease. This review focuses on the application of NMR methods to understand at the atomic level the mechanisms by which sugar molecules can be recognized by proteins to form complexes, creating new entities with different properties to those of the individual component molecules. These processes have recently gained attention as new techniques have been developed, while at the same time old techniques have been reinvented and adapted to address newer emerging problems. PMID- 29696147 TI - Drug Interactions With the Ca2+-ATPase From Sarco(Endo)Plasmic Reticulum (SERCA). AB - The sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) is an intracellular membrane transporter that utilizes the free energy provided by ATP hydrolysis for active transport of Ca2+ ions from the cytoplasm to the lumen of sarco(endo)plasmic reticulum. SERCA plays a fundamental role for cell calcium homeostasis and signaling in muscle cells and also in cells of other tissues. Because of its prominent role in many physiological processes, SERCA dysfunction is associated to diseases displaying various degrees of severity. SERCA transport activity can be inhibited by a variety of compounds with different chemical structures. Specific SERCA inhibitors were identified which have been instrumental in studies of the SERCA catalytic and transport mechanism. It has been proposed that SERCA inhibition may represent a novel therapeutic strategy to cure certain diseases by targeting SERCA activity in pathogens, parasites and cancer cells. Recently, novel small molecules have been developed that are able to stimulate SERCA activity. Such SERCA activators may also offer an innovative and promising therapeutic approach to treat diseases, such as heart failure, diabetes and metabolic disorders. In the present review the effects of pharmacologically relevant compounds on SERCA transport activity are presented. In particular, we will discuss the interaction of SERCA with specific inhibitors and activators that are potential therapeutic agents for different diseases. PMID- 29696148 TI - Using Acellular Bioactive Extracellular Matrix Scaffolds to Enhance Endogenous Cardiac Repair. AB - An inability to recover lost cardiac muscle following acute ischemic injury remains the biggest shortcoming of current therapies to prevent heart failure. As compared to standard medical and surgical treatments, tissue engineering strategies offer the promise of improved heart function by inducing regeneration of functional heart muscle. Tissue engineering approaches that use stem cells and genetic manipulation have shown promise in preclinical studies but have also been challenged by numerous critical barriers preventing effective clinical translational. We believe that surgical intervention using acellular bioactive ECM scaffolds may yield similar therapeutic benefits with minimal translational hurdles. In this review, we outline the limitations of cellular-based tissue engineering strategies and the advantages of using acellular biomaterials with bioinductive properties. We highlight key anatomic targets enriched with cellular niches that can be uniquely activated using bioactive scaffold therapy. Finally, we review the evolving cardiovascular tissue engineering landscape and provide critical insights into the potential therapeutic benefits of acellular scaffold therapy. PMID- 29696149 TI - Anti-Inflammatory Benefits of Antibiotics: Tylvalosin Induces Apoptosis of Porcine Neutrophils and Macrophages, Promotes Efferocytosis, and Inhibits Pro Inflammatory CXCL-8, IL1alpha, and LTB4 Production, While Inducing the Release of Pro-Resolving Lipoxin A4 and Resolvin D1. AB - Excessive accumulation of neutrophils and their uncontrolled death by necrosis at the site of inflammation exacerbates inflammatory responses and leads to self amplifying tissue injury and loss of organ function, as exemplified in a variety of respiratory diseases. In homeostasis, neutrophils are inactivated by apoptosis, and non phlogistically removed by neighboring macrophages in a process known as efferocytosis, which promotes the resolution of inflammation. The present study assessed the potential anti-inflammatory and pro-resolution benefits of tylvalosin, a recently developed broad-spectrum veterinary macrolide derived from tylosin. Recent findings indicate that tylvalosin may modulate inflammation by suppressing NF-kappaB activation. Neutrophils and monocyte derived macrophages were isolated from fresh blood samples obtained from 12- to 22-week-old pigs. Leukocytes exposed to vehicle or to tylvalosin (0.1, 1.0, or 10 ug/mL; 0.096-9.6 uM) were assessed at various time points for apoptosis, necrosis, efferocytosis, and changes in the production of cytokines and lipid mediators. The findings indicate that tylvalosin increases porcine neutrophil and macrophage apoptosis in a concentration- and time-dependent manner, without altering levels of necrosis or reactive oxygen species production. Importantly, tylvalosin increased the release of pro-resolving Lipoxin A4 (LXA4) and Resolvin D1 (RvD 1 ) while inhibiting the production of pro-inflammatory Leukotriene B4 (LTB4) in Ca2+ ionophore-stimulated porcine neutrophils. Tylvalosin increased neutrophil phospholipase C activity, an enzyme involved in releasing arachidonic acid from membrane stores. Tylvalosin also inhibited pro-inflammatory chemokine (C-X-C motif) ligand 8 (CXCL-8, also known as Interleukin-8) and interleukin-1 alpha (IL-1alpha) protein secretion in bacterial lipopolysaccharide-stimulated macrophages. Together, these data illustrate that tylvalosin has potent immunomodulatory effects in porcine leukocytes in addition to its antimicrobial properties. PMID- 29696150 TI - A Dynamic Connectome Supports the Emergence of Stable Computational Function of Neural Circuits through Reward-Based Learning. AB - Synaptic connections between neurons in the brain are dynamic because of continuously ongoing spine dynamics, axonal sprouting, and other processes. In fact, it was recently shown that the spontaneous synapse-autonomous component of spine dynamics is at least as large as the component that depends on the history of pre- and postsynaptic neural activity. These data are inconsistent with common models for network plasticity and raise the following questions: how can neural circuits maintain a stable computational function in spite of these continuously ongoing processes, and what could be functional uses of these ongoing processes? Here, we present a rigorous theoretical framework for these seemingly stochastic spine dynamics and rewiring processes in the context of reward-based learning tasks. We show that spontaneous synapse-autonomous processes, in combination with reward signals such as dopamine, can explain the capability of networks of neurons in the brain to configure themselves for specific computational tasks, and to compensate automatically for later changes in the network or task. Furthermore, we show theoretically and through computer simulations that stable computational performance is compatible with continuously ongoing synapse autonomous changes. After reaching good computational performance it causes primarily a slow drift of network architecture and dynamics in task-irrelevant dimensions, as observed for neural activity in motor cortex and other areas. On the more abstract level of reinforcement learning the resulting model gives rise to an understanding of reward-driven network plasticity as continuous sampling of network configurations. PMID- 29696151 TI - Effectiveness of Treatment with Endostatin in Combination with Emcitabine, Carboplatin, and Gemcitabine in Patients with Advanced Non-small Cell Lung Cancer: A Retrospective Study. AB - This study investigated the clinical efficacy, safety and tolerance of endostatin combined with gemcitabine and carboplatin for patients with advanced nonsmall cell lung cancer (NSCLC). From January 2010 to January 2014, 49 patients with advanced NSCLC were retrospectively evaluated; we defined 2 subgroups: a combination group (chemotherapy + anti-angiogenic therapy) and a chemotherapy group (chemotherapy only). The cases in the chemotherapy group received treatment with gemcitabine and carboplatin only, whereas the cases in the combination group received endostatin in combination with gemcitabine and carboplatin. The patients received 2 cycles of treatment (21 days/cycle). The clinical efficacy and adverse events were observed and compared. The disease control rate in the combination group was significantly higher compared with the chemotherapy group (P < 0.05). When comparing the cases of squamous carcinoma, the disease control rate in the combination group was significantly higher than the chemotherapy group (P < 0.05). Moreover, the progression free survival in the combination group was higher than that for the chemotherapy group, with a statistically significant difference (P < 0.05). The combination of endostatin with chemotherapeutic agents is improve to the survival of patients with advanced NSCLC favorably; the adverse events of this regimen are well tolerated. PMID- 29696153 TI - Intervention Mapping to develop a Social Cognitive Theory-based intervention for chronic pain tailored to individuals with HIV. AB - Chronic pain is an important comorbidity among individuals with HIV. Behavioral interventions are widely regarded as evidence-based, efficacious non pharmacologic interventions for chronic pain in the general population. An accepted principle in behavioral science is that theory-based, systematically developed behavioral interventions tailored to the unique needs of a target population are most likely to be efficacious. Our aim was to use Intervention Mapping to systematically develop a Social Cognitive Theory (SCT)-based intervention for chronic pain tailored to individuals with HIV that will improve pain intensity and pain-related functional impairment. Our Intervention Mapping process was informed by qualitative inquiry of 24 patients and seven providers in an HIV primary care clinic. The resulting intervention includes group and one-on one sessions and peer and staff interventionists. We also developed a conceptual framework that integrates our qualitative findings with SCT-based theoretical constructs. Using this conceptual framework as a guide, our future work will investigate the intervention's impact on chronic pain outcomes, as well as our hypothesized proximal mediators of the intervention's effect. PMID- 29696154 TI - Investigating the impact of design characteristics on statistical efficiency within discrete choice experiments: A systematic survey. AB - Objectives: This study reviews simulation studies of discrete choice experiments to determine (i) how survey design features affect statistical efficiency, (ii) and to appraise their reporting quality. Outcomes: Statistical efficiency was measured using relative design (D-) efficiency, D-optimality, or D-error. Methods: For this systematic survey, we searched Journal Storage (JSTOR), Since Direct, PubMed, and OVID which included a search within EMBASE. Searches were conducted up to year 2016 for simulation studies investigating the impact of DCE design features on statistical efficiency. Studies were screened and data were extracted independently and in duplicate. Results for each included study were summarized by design characteristic. Previously developed criteria for reporting quality of simulation studies were also adapted and applied to each included study. Results: Of 371 potentially relevant studies, 9 were found to be eligible, with several varying in study objectives. Statistical efficiency improved when increasing the number of choice tasks or alternatives; decreasing the number of attributes, attribute levels; using an unrestricted continuous "manipulator" attribute; using model-based approaches with covariates incorporating response behaviour; using sampling approaches that incorporate previous knowledge of response behaviour; incorporating heterogeneity in a model-based design; correctly specifying Bayesian priors; minimizing parameter prior variances; and using an appropriate method to create the DCE design for the research question. The simulation studies performed well in terms of reporting quality. Improvement is needed in regards to clearly specifying study objectives, number of failures, random number generators, starting seeds, and the software used. Conclusion: These results identify the best approaches to structure a DCE. An investigator can manipulate design characteristics to help reduce response burden and increase statistical efficiency. Since studies varied in their objectives, conclusions were made on several design characteristics, however, the validity of each conclusion was limited. Further research should be conducted to explore all conclusions in various design settings and scenarios. Additional reviews to explore other statistical efficiency outcomes and databases can also be performed to enhance the conclusions identified from this review. PMID- 29696152 TI - Toward Generalization of Iterative Small Molecule Synthesis. AB - Small molecules have extensive untapped potential to benefit society, but access to this potential is too often restricted by limitations inherent to the customized approach currently used to synthesize this class of chemical matter. In contrast, the "building block approach", i.e., generalized iterative assembly of interchangeable parts, has now proven to be a highly efficient and flexible way to construct things ranging all the way from skyscrapers to macromolecules to artificial intelligence algorithms. The structural redundancy found in many small molecules suggests that they possess a similar capacity for generalized building block-based construction. It is also encouraging that many customized iterative synthesis methods have been developed that improve access to specific classes of small molecules. There has also been substantial recent progress toward the iterative assembly of many different types of small molecules, including complex natural products, pharmaceuticals, biological probes, and materials, using common building blocks and coupling chemistry. Collectively, these advances suggest that a generalized building block approach for small molecule synthesis may be within reach. PMID- 29696155 TI - Conducting a randomized trial in rural and urban safety-net health centers: Added value of community-based participatory research. AB - Background: Colorectal cancer (CRC) is the second most common cancer in the US. Despite evidence that screening reduces CRC incidence and mortality, screening rates are sub-optimal with disparities by race/ethnicity, income, and geography. Rural-urban differences in CRC screening are understudied even though approximately one-fifth of the US population lives in rural areas. This focus on urban populations limits the generalizability and dissemination potential of screening interventions. Methods: Using community-based participatory research (CBPR) principles, we designed a cluster-randomized trial, adaptable to a range of settings, including rural and urban health centers. We enrolled 483 participants across 11 health centers representing 2 separate networks. Both networks serve medically-underserved communities; however one is primarily rural and one primarily urban. Results: Our goal in this analysis is to describe baseline characteristics of participants and examine setting-level differences. CBPR was a critical for recruiting networks to the trial. Patient respondents were predominately female (61.3%), African-American (66.5%), and earned <$1200 per month (87.1%). The rural network sample was older; more likely to be female, white, disabled or retired, and have a higher income, but fewer years of education. Conclusions: Variation in the samples partly reflects the CBPR process and partly reflects inherent differences in the communities. This confirmed the importance of using CBPR when planning for eventual dissemination, as it enhanced our ability to work within diverse settings. These baseline findings indicate that using a uniform approach to implementing a trial or intervention across diverse settings might not be effective or efficient. PMID- 29696156 TI - Methodology of a multispecialty outpatient Obesity Treatment Research Program. AB - Despite the large number of U.S. adults who overweight or obese, few providers have ready access to comprehensive lifestyle interventions, the cornerstone of medical obesity management. Our goal was to establish a research infrastructure embedded in a comprehensive lifestyle intervention treatment for obesity. The Obesity Treatment Research Program (OTRP) is a multi-specialty project at Mayo Clinic in Rochester, Minnesota designed to provide a high intensity, year-long, comprehensive lifestyle obesity treatment. The program includes a nutritional intervention designed to reduce energy intake, a physical activity program and a cognitive behavioral approach to increase the likelihood of long-term adherence. The behavioral intervention template incorporated the Diabetes Prevention Program and the Look AHEAD trial materials. The OTRP is consistent with national recommendations for the management of overweight and obesity in adults, but with embedded features designed to identify patient characteristics that might help predict outcomes, assure long-term follow up and support various research initiatives. Our goal was to develop approaches to understand whether there are patient characteristics that predict treatment outcomes. PMID- 29696158 TI - A novel approach for analyzing data on recurrent events with duration to estimate the combined cumulative rate of both variables over time. AB - Recurrent adverse events, once occur often continue for some duration of time in clinical trials; and the number of events along with their durations is clinically considered as a measure of severity of a disease under study. While there are methods available for analyzing recurrent events or durations or for analyzing both side by side, no effort has been made so far to combine them and present as a single measure. However, this single-valued combined measure may help clinicians assess the wholesome effect of recurrence of incident comprising events and durations. Non-parametric approach is adapted here to develop an estimator for estimating the combined rate of both, the recurrence of events as well as the event-continuation, that is the duration per event. The proposed estimator produces a single numerical value, the interpretation and meaningfulness of which are discussed through the analysis of a real-life clinical dataset. The algebraic expression of variance is derived, asymptotic normality of the estimator is noted, and demonstration is provided on how the estimator can be used in the setup of testing of statistical hypothesis. Further possible development of the estimator is also noted, to adjust for the dependence of event occurrences on the history of the process generating recurrent events through covariates and for the case of dependent censoring. PMID- 29696157 TI - Design and outcomes of the Patient Centered Outcomes Research Institute coronary heart disease cohort study. AB - Background: The Patient Centered Outcomes Research Institute (PCORI) established Clinical Data Research Networks (CDRNs) to support pragmatic research. The objective was to electronically identify, recruit, and survey coronary heart disease (CHD) patients and describe their characteristics, health status, and willingness to participate in future research. Methods: We developed a computable phenotype and assembled CHD patients 30 years or older and had visits or hospitalizations between 2009 and 2015. A sample of patients was surveyed between August 2014 and September 2015. Survey administration included the following methods: face-to-face, telephone, paper or web portal. Survey items covered broad domains including: health literacy and numeracy, and socio-demographics, physical and mental health, health behaviors, access to medical care, and willingness to participate in future research. Results: Of 5517 approached patients, 2605 completed the survey. Participants were mostly white (~88%), male (68%) and had a median age of 69 years (interquartile range [IQR] 61-76 years). Most respondents' health literacy and numeracy were adequate (83.2% and 84.3%, respectively). Only 4% of respondents reported that their overall health or physical health was excellent. The majority (~58%) reported that their health was good or very good, while 40% reported that their general and physical health were fair or poor. The majority reported that their quality of life was good to excellent (81%). Limitations in physical health and function were common, including often/always having fatigue (25%), pain (38.7%), or sleep difficulty (19.7%). A patient sample (n = 1936) was provided with a trial summary which would randomize their aspirin dose; and 63% reported that they would consider participating. Conclusion: Many patients with CHD had limitations in physical health. However, the majority reported a good or excellent quality of life. PMID- 29696159 TI - Interventionist training and intervention fidelity monitoring and maintenance for CONNECT, a nurse-led primary palliative care in oncology trial. AB - Context: Intervention fidelity is a critical component of behavioral research that has received inadequate attention in palliative care studies. With increasing focus on the need for palliative care models that can be widely disseminated and delivered by non-specialists, rigorous yet pragmatic strategies for training interventionists and maintaining intervention fidelity are needed. Objectives: (1) Describe components of a plan for interventionist training and monitoring and maintaining intervention fidelity as part of a primary palliative care trial (CONNECT) and (2) present data about perceived training effectiveness and delivery of key intervention content. Methods: Post-training evaluations, visit checklists, and visit audio-recordings. Results: Data were collected from June, 2016 through April, 2017. We include procedures for (1) identification, training and certification of oncology nurses as CONNECT interventionists; (2) monitoring intervention delivery; and (3) maintaining intervention quality. All nurses (N = 14) felt prepared to deliver key competencies after a 3-day in-person training. As assessed via visit checklists, interventionists delivered an average of 94% (SD 13%) of key content for first intervention visits and 85% (SD 14%) for subsequent visits. As assessed via audio-recordings, interventionists delivered an average of 85% (SD 8%) of key content for initial visits and 85% (SD 12%) for subsequent visits. Conclusion: We present a 3-part strategy for training interventionists and monitoring and maintaining intervention delivery in a primary palliative care trial. Training was effective in having nurses feel prepared to deliver primary palliative care skills. As assessed via nursing checklists and visit audio-recordings, intervention fidelity was high. PMID- 29696160 TI - Extensions of the mTPI and TEQR designs to include non-monotone efficacy in addition to toxicity for optimal dose determination for early phase immunotherapy oncology trials. AB - With the emergence of immunotherapy and other novel therapies, the traditional assumption that the efficacy of the study drug increases monotonically with dose levels is not always true. Therefore, dose-finding methods evaluating only toxicity data may not be adequate. In this paper, we have first compared the Modified Toxicity Probability Interval (mTPI) and Toxicity Equivalence Range (TEQR) dose-finding oncology designs for safety with identical stopping rules; we have then extended both designs to include efficacy in addition to safety - we determine the optimal dose for safety and efficacy using these designs by applying isotonic regression to the observed toxicity and efficacy rates, once the early phase trial is completed. We consider multiple types of underlying dose response curves, i.e., monotonically increasing, plateau, or umbrella-shaped. We conduct simulation studies to investigate the operating characteristics of the two proposed designs and compare them to existing designs. We found that the extended mTPI design selects the optimal dose for safety and efficacy more accurately than the other designs for most of the scenarios considered. PMID- 29696161 TI - Defining information fractions in group sequential clinical trials with multiple endpoints. AB - The group sequential design has been well understood and widely applied in designs of late phase clinical trial to enable potentially early stopping for efficacy or futility. The information fraction (IF) is one of the key elements to determine the decision boundary at the interim analyses. The family-wise error rate (FWER) control is highly critical for clinical trials with multiple endpoints to be tested. In this article, we illustrate the importance of properly defining the information fraction for each individual endpoint regarding the FWER control through the numerical evaluation and a case study. PMID- 29696162 TI - Different ways to estimate treatment effects in randomised controlled trials. AB - Background: Regarding the analysis of RCT data there is a debate going on whether an adjustment for the baseline value of the outcome variable should be made. When an adjustment is made, there is a lot of misunderstanding regarding the way this should be done. Therefore, the aims of this educational paper are: 1) to explain different methods used to estimate treatment effects in RCTs, 2) to illustrate the different methods with a real life example and 3) to give an advise on how to analyse RCT data. Methods: Longitudinal analysis of covariance, repeated measures analysis in which also the baseline value is used as outcome and the analysis of changes were theoretically explained and applied to an example dataset investigating a systolic blood pressure lowering treatment. Results: It was shown that differences at baseline should be taken into account and that regular repeated measures analysis and regular analysis of changes did not adjust for the baseline differences between the groups and therefore lead to biased estimates of the treatment effect. In the real life example, due to the differences at baseline between the treatment and control group, the different methods lead to different estimates of the treatment effect. Conclusion: Regarding the analysis of RCT data, it is advised to use longitudinal analysis of covariance or a repeated measures analysis without the treatment variable, but with the interaction between treatment and time in the model. PMID- 29696163 TI - Comparison of home fortification with two iron formulations among Kenyan children: Rationale and design of a placebo-controlled non-inferiority trial. AB - Introduction: Home fortification powders containing iron and other micronutrients have been recommended by World Health Organisation to prevent iron deficiency anaemia in areas of high prevalence. There is evidence, however, that home fortification at this iron dose may cause gastrointestinal adverse events including diarrhoea. Providing a low dose of highly absorbable iron (3 mg iron as NaFeEDTA) may be safer because the decreased amount of iron in the gut lumen can possibly reduce the burden of these adverse effects whilst resulting in similar or higher amounts of absorbed iron. Objective: To show non-inferiority of home fortification with 3 mg iron as NaFeEDTA compared with 12.5 mg iron as encapsulated ferrous fumarate, with haemoglobin response as the primary outcome. Design: 338 Kenyan children aged 12-36 months will be randomly allocated to daily home fortification with either: a) 3 mg iron as NaFeEDTA (experimental treatment), b) 12.5 mg iron as encapsulated ferrous fumarate (reference), or c) placebo. At baseline, after 30 days of intervention and within 100 days post intervention, blood samples will be assessed for primary outcome (haemoglobin concentration), iron status markers, Plasmodium parasitaemia and inflammation markers. Urine and stool samples will be assessed for hepcidin concentrations and inflammation, respectively. Adherence will be assessed by self-reporting, sachet counts and by an electronic monitoring device. Conclusion: If daily home fortification with a low dose of iron (3 mg NaFeEDTA) has similar or superior efficacy to a high dose (12.5 mg ferrous fumarate) then it would be the preferred choice for treatment of iron deficiency anaemia in children. PMID- 29696164 TI - The design and rationale of the Beijing Vascular Disease Patients Evaluation Study (BEST study). AB - Aims: Arteriosclerosis and arterial stiffness increasing are the basic pathophysiological changes of vascular-related diseases, and also the predictor factors of future cardiovascular events. Plasma biomarkers such as glucose, lipids, Homocysteine (Hcy), N-terminal pro-brain natriuretic peptide (NT-proBNP) have been shown to be involved the development of arteriosclerosis. The present study is a prospective observational and follow-up study of the characteristics of subclinical vascular disease detected by non-invasive methods that can predict progression of clinical overt vascular events in a Chinese population. Methods: The study including both genders with age of 45 years to 75 years was designed as observational research by questionnaires and 3-year follow-up with vascular functional and structural parameters evaluation without any interventions. Questionnaire was designed to survey the lifestyle, personal history, family history of the study population. Arterial function indexes such as pulse wave velocity, cardio-ankle vascular index, flow mediated vascular dilation, ankle brachial index, carotid intima-media thickness, and plasma biomarkers such as glucose, lipids, Hcy, NT-pro BNP, Glycosylated hemoglobin, insulin resistance index, uric acid are collected. The outcome is the composite of acute myocardial infarction or coronary reperfusion therapy or stroke or peripheral vascular diseases. Conclusions: 2858 subjects were enrolled into our present study at baseline, and this present study will provide important information on the metabolic related traditional and new risk factors, establish a new vascular disease early detection system and scoring systems based on comprehensive vascular disease risk factors and vascular function and structure evaluation indexes. PMID- 29696165 TI - Functional resistance activities to impact frailty: A protocol for a randomized controlled trial involving home care aide and frail older adult dyads. AB - Background: A growing number of older adults use in-home Medicaid Waiver Home and Community Based services (HCBS) to facilitate aging-in-place. A primary service of this program is Home Care Aide assistance with activities of daily living and homemaker needs. Despite the known benefits of exercise, exercise programs are currently not offered to clients in the Medicaid Waiver system. Thus, the purpose of this paper is to describe a six-month Home Care Aide-led resistance exercise intervention protocol for frail older adults receiving Medicaid waiver services. Methods/design: A randomized controlled trial will be used. We will enroll 126 Home Care Aide-client dyads for a 6-month exercise intervention. The intervention will consist of training phases to promote muscle strength, power, and endurance. We will use an intention to treat principle using mixed effects models for the quantitative outcomes. To analyze qualitative outcomes, we will use conventional content analysis to examine themes from participant program evaluations. Discussion: As greater numbers of adults age in place with frailty and employ Home Care Aides to help manage functional limitations, interventions embedded within usual care services play a critical role in bringing exercise into the home setting. The research described in this protocol will provide important knowledge about the impact of a Home Care Aide-led exercise intervention in reducing frailty in older adults. Clinical Trials Registration: ClinicalTrials.gov Identifier: NCT02942992. PMID- 29696167 TI - Reasons for participating in a randomised clinical trial: The volunteers' voices in the COSTOP trial in Uganda. AB - Introduction: The reasons why research participants join clinical trials remains an area of inquiry especially in low and middle income countries. Methods: We conducted exit interviews with participants who took part in a trial which aimed to evaluate whether long term prophylaxis with cotrimoxazole can be safely discontinued among adults who have been stabilised on antiretroviral therapy (ART). Participants were all reported to be stable on ART and had been participating in the trial for between 12 and 36 months; at the end of the trial participants were interviewed using a semi-structured questionnaire. One of the objectives of the exit interview was to find out what motivated the participants to join the research. Results: Participants gave personal reasons for joining the trial, frequently linked to their health and well-being as well as reduction of pill burden. Conclusion: We conclude that underlying reasons for joining clinical trials may extend beyond or can be different from the rationale given to the participants before enrolment by the research team. The reasons that motivate enrolment to clinical trials and research in general require further investigation in different settings. Trial registration number: ISRCTN44723643. PMID- 29696166 TI - Design, rationale and feasibility of a multidimensional experimental protocol to study early life stress. AB - There is a rapidly accumulating body of evidence regarding the influential role of early life stress (ELS) upon medical and psychiatric conditions. While self report instruments, with their intrinsic limitations of recall, remain the primary means of detecting ELS in humans, biological measures are generally limited to a single biological system. This paper describes the design, rationale and feasibility of a study to simultaneously measure neuroendocrine, immune and autonomic nervous system (ANS) responses to psychological and physiological stressors in relation to ELS. Five healthy university students were recruited by advertisement. Exclusion criteria included chronic medical conditions, psychotic disorders, needle phobia, inability to tolerate pain, and those using anti inflammatory medications. They were clinically interviewed and physiological recordings made over a two-hour period pre, during and post two acute stressors: the cold pressor test and recalling a distressing memory. The Childhood Trauma Questionnaire and the Parental Bonding Index were utilised to measure ELS. Other psychological measures of mood and personality were also administered. Measurements of heart rate, blood pressure, respiratory rate, skin conductance, skin blood flow and temporal plasma samples were successfully obtained before, during and after acute stress. Participants reported the extensive psychological and multisystem physiological data collection and stress provocations were tolerable. Most (4/5) participants indicated a willingness to return to repeat the protocol, indicating acceptability. Our protocol is viable and safe in young physically healthy adults and allows us to assess simultaneously neuroendocrine, immune and autonomic nervous system responses to stressors in persons assessed for ELS. PMID- 29696168 TI - Recruitment and retention of homeless individuals with mental illness in a housing first intervention study. AB - Background: Homeless individuals with mental illness are challenging to recruit and retain in longitudinal research studies. The present study uses information from the Vancouver site of a Canadian multi-city longitudinal randomized controlled trial on housing first interventions for homeless individuals. We were able to recruit 500 participants and retain large number of homeless individuals with mental illness; 92% of the participants completed the 6-month follow up interview, 84% the 24-month follow up, while 80% completed all follow-up visits of the study. Purpose: In this article, we describe the strategies and practices that we considered as critical for successful recruitment and retention or participants in the study. Methods: We discuss issues pertaining to research staff hiring and training, involvement of peers, relationship building with research participants, and the use of technology and social media, and managing challenging situations in the context of recruitment and retention of marginalized individuals. Conclusions: Recruitment and retention of homeless participant with mental illness in longitudinal studies is feasible. It requires flexible, unconventional and culturally competent strategies. Longitudinal research projects with vulnerable and hidden populations may benefit from extensive outreach work and collaborative approaches that are based on attitudes of mutual respect, contextual knowledge and trust. PMID- 29696169 TI - Quality of abstracts of randomized control trials in five top pain journals: A systematic survey. AB - Background: The reporting quality of abstracts of randomized control trials (RCTs) is inadequate despite the publication of consolidated standards of reporting trials extension for abstracts (CONSORT-A). We compared the reporting quality of abstracts in pain journals before and after the publication of CONSORT A. Methods: We searched MEDLINE in April-2016 for RCTs published in five pain journals: Pain, Pain Physician, European Journal of Pain, Clinical Journal of Pain and Pain Practice for pre- and post-CONSORT-A period (2005-2007 and 2013 2015). Data were extracted in duplicate from 250 abstracts for compliance with CONSORT-A, and for items known to affect reporting quality: journal endorsement of CONSORT, number of trial centers, sample-size, type of intervention, industry sponsorship and significance of results. The primary outcome was mean number of items reported and the secondary outcome was the reporting of each item. We used logistic regression and Poisson regression for analyses. Results: Most trials were single centric (76%), had sample size <100 (63%), involved pharmacological intervention (59%) and were non-industry funded (70%). The mean number of items reported was better for 2013-2015 (mean difference 0.94; 95% confidence-interval [CI]: 0.50-1.38, p < 0.001). Post-CONSORT-A, trials were more likely to report as randomized in the title (odds ratio (OR) 2.69; 95% CI 1.61-4.49), describe eligibility criteria and settings (OR 2.47; 95% CI 1.35-4.54), provide effect size and precision for primary outcome (OR 2.47; 95% CI 1.19-5.16), inform harms (OR 1.80; 95% CI 1.05-3.07) and report trial registration (OR 5.13; 95% CI 1.44 18.32). Post-CONSORT-A period (incident rate ratio (IRR) 1.15; 95% CI 1.07-1.24), endorsement of CONSORT statement by the journal (IRR 1.08; 95% CI 1.02-1.14), multi-centric studies (IRR 1.14; 95% CI 1.08-1.20), and studies with pharmacological interventions (IRR 1.07; 95% CI 1.02-1.13) were significantly associated with reporting of more items. Conclusions: Abstract reporting for trials in pain literature was better in the post-CONSORT-A period, but there is room for improvement. PMID- 29696170 TI - IntErnationaL eLeCTRicAl storm registry (ELECTRA): Background, rationale, study design, and expected results. AB - Electrical storm (ES) is defined as three or more episodes of ventricular fibrillation (VF) or ventricular tachycardia (VT) within 24 h and is associated with an increased cardiac and all-cause mortality. ES is a full arrhythmic emergency, its prevalence steadily increasing along with the number of implantable cardioverter-defibrillator implanted every year in developed countries. Nowadays, little evidence exists regarding clinical predictors of ES and their potential association on mortality and heart failure (HF), nor optimal pharmacological and non-pharmacological treatment has ever been codified. The intErnationaL eLeCTRicAl storm registry (ELECTRA) is a multicentre, observational, prospective clinical study with two major aims. First, to create an international database on ES encompassing clinical features, pharmacological management, and interventional treatment strategies. Second, to describe mortality and rehospitalization rates in patients with ES over a long follow-up. The primary endpoint is all-cause mortality 3 years after the ES index event. The main secondary endpoint is hospitalization for all causes 3 years after the ES index event. Other secondary endpoints includes ES recurrences, unclustered VTs/VFs recurrences, and hospitalizations for HF worsening. A minimum of 500 patients will be included in the registry, and all patients will be followed-up for a minimum of three years. The present paper describes the background and current rationale of the ELECTRA study and details the study design, from enrolment strategy to data collection methods to planned data analysis. A brief overview of the expected results and their potential clinical and research implications will also be presented (NCT02882139). PMID- 29696171 TI - Analyses of drug combinations using missing data shortens trial periods in phase I/II oncology trials. AB - In previous phase I/II oncology trials for drug combinations, a number of methods have been studied to determine the dose combination for the next cohort. However, there is a risk that trial durations will be unfeasibly long if methods for evaluating safety and efficacy are based on the best overall response and toxicity during trial design. In this study, we propose an approach to shorten the duration of drug trials in oncology. In this method, the dose combination to be allocated to the next cohort is decided before all data for patients in the current cohort is known and best overall response is determined. The efficacy of drug combinations in patients for whom the best overall response has not been determined is treated as missing data. The missing data mechanism is modeled by nonparametric prior processes. The probabilities of efficacy and toxicity are estimated after applying data augmentation to missing data, and the dose combination to be allocated to the next cohort is decided using these probabilities. Simulation studies from the present study show that this proposed approach would shorten trial durations without the low-performing of the trial design in comparison to existing approaches. Shortening trial durations would enable patients with the targeted disease to receive effective therapy at an earlier stage. This also enables clinical trial sponsors to use fewer patients in drug trials, which would lead to a reduction in the costs associated with clinical development. PMID- 29696172 TI - Sharing some interim data in trial monitoring can mislead or unmask trial investigators: A scenario-based survey of trial experts. AB - Background: Sharing masked interim results by the Data Safety Monitoring Board (DSMB) with non-DSMB members is an important issue that can affect trial integrity. Our survey's objective is to collect evidence to understand how seemingly masked interim results or result extrapolations are interpreted and discuss whether these results should be shared at interim. Methods: Conducted a 6 scenario-question survey asking trial experts how they interpreted three kinds of seemingly masked interim results or result extrapolation measures (interim combined event rate, adaptive conditional power and "unconditional" conditional power). Results: Thirty-one current Consolidated Standards of Reporting Trials group affiliates were invited for survey participation (February 2015). Response rate: 71.0% (22/31). About half, 52.6% (95% CI: 28.9%-74.0%), (10/19), correctly indicated that the interim combined event rate can be interpreted in three ways (drug X doing better than placebo, worse than placebo or the same) if shared at interim. The majority, 72.2% (95% CI: 46.5%-89.7%), (13/18), correctly indicated that the adaptive conditional power suggests relative treatment group effects. The majority, 53.3% (95% CI: 26.6%-77.0%), (8/15), incorrectly indicated that the "unconditional" conditional power suggests relative treatment group effects. Discussion/Conclusion: Knowledge of these three results or result extrapolation measures should not be shared outside of the DSMB at interim as they may mislead or unmask interim results, potentially introducing trial bias. For example, the interim combined event rate can be interpreted in one of three ways potentially leading to mistaken guesswork about interim results. Knowledge of the adaptive conditional power by non-DSMB members is telling of relative treatment effects thus unmasking of interim results. PMID- 29696173 TI - Safety and efficacy of endovascular therapy and gamma knife surgery for brain arteriovenous malformations in China: Study protocol for an observational clinical trial. AB - Introduction: Brain arteriovenous malformations (BAVMs) are associated with high morbidity and mortality. The treatment of BAVM remains controversial. Microinvasive treatment, including endovascular therapy and gamma knife surgery, has been the first choice in many conditions. However, the overall clinical outcome of microinvasive treatment remains unknown and a prospective trial is needed. Methods: This is a prospective, non-randomized, and multicenter observational registry clinical trial to evaluate the safety and efficacy of microinvasive treatment for BAVMs. The study will require up to 400 patients in approximately 12 or more centers in China, followed for 2 years. Main subjects of this study are BAVM patients underwent endovascular therapy and/or gamma knife surgery. The trial will not affect the choice of treatment modality. The primary outcomes are perioperative complications (safety), and postoperative hemorrhage incidence rate and complete occlusion rate (efficacy). Secondary outcomes are elimination of hemorrhage risk factors (coexisting aneurysms and arteriovenous fistula), volume reduction and remission of symptoms. Safety and efficacy of endovascular therapy, gamma knife surgery, and various combination modes of the two modalities will be compared. Operative complications and outcomes at pretreatment, post-treatment, at discharge and at 3 months, 6 months and 2 years follow-up intervals will be analyzed using the modified Rankin Scale (mRS). Discussion: The most confusion on BAVM treatment is whether to choose interventional therapy or medical therapy, and the choice of interventional therapy modes. This study will provide evidence for evaluating the safety and efficacy of microinvasive treatment in China, to characterize the microinvasive treatment strategy for BAVMs. PMID- 29696175 TI - Global perspective on colonoscopy use for colorectal cancer screening: A multi country survey of practicing colonoscopists. AB - Objectives: To examine colorectal cancer screening practices among colonoscopy specialists from 5 countries and inform public health needs in improvement of the ongoing global crisis in colorectal cancer. Methods: An online survey among colonoscopy specialists was conducted in France, Germany, the United Kingdom, Japan, and the United States. The survey covered topics on colonoscopy practices in the screening as well as in the treatment setting, as well as expected trends. Results: Participating colonoscopy specialists included 114 physicians from the United States, 81 from France, 80 from Germany, 80 from the United Kingdom, and 156 from Japan. Survey results revealed that 59%-73% of colonoscopies were performed in patients aged 50-75 years old, with 15%-23% performed in patients <50 years old. The proportion of patients with age-based versus symptom-based first colorectal cancer screening varied by country and age. Sedation protocols varied by country; however, rate of incomplete colonoscopy was low in all countries. The proportion of negative first colonoscopies decreased with age in all countries. Conclusions: This multi-country survey of real-world clinical practices suggests a need for improved participation in population age-based colorectal cancer screening and possibly younger age of screening initiation than currently recommended by guidelines. The variation among countries in the proportion of patients who received their first colonoscopy due to age-based colorectal cancer screening versus symptom-based initial colonoscopy indicates that population-based screening initiatives and improved health outcomes will benefit from public health awareness programs. PMID- 29696174 TI - Parenting program versus telephone support for Mexican parents of children with acquired brain injury: A blind randomized controlled trial. AB - Introduction: Acquired brain injury (ABI) during childhood typically causes behavior problems in the child and high levels of stress in the family. The aims of this study are: (1) to investigate the effectiveness and feasibility of a parenting intervention in improving behavior and self-regulation in Mexican children with ABI compared to telephone support; (2) to investigate the effectiveness and feasibility of a parenting intervention in improving parenting skills, parent self-efficacy and decreasing parental stress in parents of children with ABI compared to telephone support. Our secondary aims are (1) to explore the impact that parent characteristics have on the intervention outcomes; (2) to investigate if changes are maintained 3 months after the intervention. Methods: The research design is a blind randomized controlled trial (RCT). Eligible participants include children with a diagnosis of ABI, between 6 and 12 years of age, and their parents. Sixty-six children and their parents will be randomly allocated to either a parenting program group or telephone support group. The parenting program involves six face-to-face weekly group sessions of 2.5 h each. Participants in the control group receive an information sheet with behavioral strategies, and six weekly phone calls, in which strategies to improve academic skills are provided. Children and their parents are evaluated by blind assessors before the intervention, immediately after the intervention and 3 months post-intervention. Discussion: This study will be the first to evaluate the efficacy and feasibility of a parenting program for Mexican parents of children with ABI. Trial identifier: ACTRN12617000360314. PMID- 29696176 TI - Factors associated with willingness to participate in a vaccine clinical trial among elderly Hispanic patients. AB - A population specific understanding of barriers and facilitators to participation in clinical trials could improve recruitment of elderly and minority populations. We investigated how prior exposure to clinical trials and incentives were associated with likelihood of participation in a vaccine clinical trial through a questionnaire administered to 200 elderly patients in an academic general internal medicine clinic. Wilcoxon signed rank sum test compared likelihood of participation with and without monetary incentives. Logistic regression evaluated characteristics associated with intent to participate in an influenza vaccine trial, adjusted for age, gender, language, and education history. When asked about likelihood of participation if there was monetary compensation, there was a 12.2% absolute increase in those reporting that they would not participate, with a significant difference in the distribution of likelihood before and after mentioning a monetary incentive (Wilcoxon signed rank test, p = 0.001). Those with previous knowledge of clinical trials (54.4%) were more likely to report they would participate vs. those without prior knowledge (OR 2.5, 95% CI [1.2, 5.2]). The study highlights the importance of pre-testing recruitment materials and incentives in key group populations prior to implementing clinical trials. PMID- 29696177 TI - Magnitude and characteristics of clinical trials in the Kingdom of Saudi Arabia: A cross-sectional analysis. AB - The clinical trial is an important type of research design in the spectrum of translational research. The extent to which clinical trials are conducted is a reflection of the level of advancement that exists within a healthcare system. This study aims at describing the clinical trial activity within the Kingdom of Saudi Arabia since 2000 through reviewing those trials that have been registered with clinicaltrials.gov in that time period. Since February 2000, 405 trials have been registered. These trials fall into one of 22 different ICD-10 codes, and with the top four being neoplasms (92), diseases of the circulatory system (57), endocrine, nutritional and metabolic diseases (46), and diseases of the respiratory system (25). About half (200) were classified as trials with both safety and efficacy endpoints. 52% were phase IV and 28% were phase III. About 64% were randomized, and with about equal numbers of those coming from industry (86) and university sponsors (85), and smaller numbers coming from hospitals (51) and other sponsors. A total of 24 phase III university- or hospital-sponsored trials have been registered during the 15-year time period. With a population approaching 30 million and very large annual healthcare expenses, it would appear that the level of clinical trial activity within the Kingdom during the past 15 years has been rather paltry. The emphasis has been on post-marketing phase IV trials. The academic setting (i.e. universities and hospitals) has seen a new trial registered every 11 months on average. PMID- 29696178 TI - Comparison of methods for the analysis of relatively simple mediation models. AB - Background/aims: Statistical mediation analysis is an often used method in trials, to unravel the pathways underlying the effect of an intervention on a particular outcome variable. Throughout the years, several methods have been proposed, such as ordinary least square (OLS) regression, structural equation modeling (SEM), and the potential outcomes framework. Most applied researchers do not know that these methods are mathematically equivalent when applied to mediation models with a continuous mediator and outcome variable. Therefore, the aim of this paper was to demonstrate the similarities between OLS regression, SEM, and the potential outcomes framework in three mediation models: 1) a crude model, 2) a confounder-adjusted model, and 3) a model with an interaction term for exposure-mediator interaction. Methods: Secondary data analysis of a randomized controlled trial that included 546 schoolchildren. In our data example, the mediator and outcome variable were both continuous. We compared the estimates of the total, direct and indirect effects, proportion mediated, and 95% confidence intervals (CIs) for the indirect effect across OLS regression, SEM, and the potential outcomes framework. Results: OLS regression, SEM, and the potential outcomes framework yielded the same effect estimates in the crude mediation model, the confounder-adjusted mediation model, and the mediation model with an interaction term for exposure-mediator interaction. Conclusions: Since OLS regression, SEM, and the potential outcomes framework yield the same results in three mediation models with a continuous mediator and outcome variable, researchers can continue using the method that is most convenient to them. PMID- 29696180 TI - Study within a trial (SWAT) protocol. Participants' perspectives and preferences on clinical trial result dissemination: The TRUST Thyroid Trial experience. AB - Introduction: Dissemination of results of randomised controlled trials is traditionally limited to academic and professional groups rather than clinical trial participants. While there is increasing consensus that results should be communicated to trial participants, there is a lack of evidence on the most appropriate methods of dissemination. This study within a trial (SWAT) aims to address this gap by using a public and patient involvement (PPI) approach to identify, develop and evaluate a patient-preferred method of receiving trial results of the Thyroid Hormone Replacement for Subclinical Hypothyroidism Trial (TRUST). Methods: An experimental (intervention) study will be conducted using mixed methods to inform the development of and evaluation of a patient-preferred method of communication of trial results. The study will involve three consecutive phases. In the first phase, focus groups of trial participants will be conducted to identify a patient-preferred method of receiving trial results. The method will be developed and then assessed and refined by a patient and public expert group. In the second phase participants will be randomly assigned to the intervention (patient-preferred method) and comparison groups (standard dissemination method as developed by the lead study site in Glasgow, Scotland). In the third phase, a quantitative questionnaire will be used to measure and compare patient understanding of trial results between the two groups. Discussion: This protocol provides a template for other trialists who wish to enhance patient and public involvement and additionally, will provide empirical evidence on how trialists should best disseminate study results to their participants. PMID- 29696179 TI - Reducing social inequalities in access to overweight and obesity care management for adolescents: The PRALIMAP-INES trial protocol and inclusion data analysis. AB - Background: Despite social inequalities in overweight/obesity prevalence, evidence-based public health interventions to reduce them are scarce. The PRALIMAP-INES trial aimed to investigate whether a strengthened-care management for adolescents with low socioeconomic status has an equivalent effect in preventing and reducing overweight as a standard-care management for high socioeconomic status adolescents. Methods: PRALIMAP-INES was a mixed, prospective and multicenter trial including 35 state-run schools. It admitted overweight or obese adolescents, age 13-18 years old, for 3 consecutive academic years. One year interventions were implemented. Data were collected before (T0), after (T1) and post (T2) intervention. Among 2113 eligible adolescents who completed questionnaires, 1639 were proposed for inclusion and 1419 were included (220 parental refusals). Two groups were constituted according to the Family Affluence Scale (FAS) score: the less advantaged (FAS<=5) were randomly assigned to 2 groups in a 2/1 ratio. The 3 intervention groups were: advantaged with standard care management (A.S, n = 808), less advantaged with standard-care management (LA.S, n = 196), and less advantaged with standard and strengthened-care management (LA.S.S, n = 415). The standard-care management was based on the patient education principle and consisted of 5 collective sessions. The strengthened-care management was based on the proportionate universalism principle and consisted of activities adapted to needs. Inclusion results: The written parental refusal was less frequent among less advantaged and more overweight adolescents. A dramatic linear social gradient in overweight was evidenced. Discussion: The PRALIMAP-INES outcomes should inform how effectively a socially adapted public health program can avoid worsening social inequalities in overweight adolescents attending school. Trial registration: ClinicalTrials.gov (NCT01688453). PMID- 29696181 TI - Assessing the feasibility, acceptability, and potential effectiveness of a behavioral-automaticity focused lifestyle intervention for African Americans with metabolic syndrome: The Pick two to Stick to protocol. AB - Background: Metabolic syndrome (MetS) significantly increases the risk of developing diabetes and cardiovascular disease. Being physically active and eating a healthy diet can reduce MetS risk factors. Too frequently, however, studies report that the effects of interventions targeting those factors are not maintained once interventions are withdrawn. A potential solution to the problem is targeting behavioral automaticity (habit-development) to aid in initiation and maintenance of health-behavior changes. The Pick two to Stick To (P2S2), is an 8 week, theory-based hybrid (face-to-face/telecoaching) habit focused lifestyle intervention designed to increase healthful physical activity and dietary behavioral automaticity. The purpose of this article is to describe the rationale and protocol for evaluating the P2S2 program's feasibility, acceptability and potential effectiveness. Methods: Using a prospective, non-comparative design, the P2S2 program will be implemented by trained occupational therapy 'coaches' to 40 African Americans aged 40 and above with MetS recruited from the emergency department. Semi-structured interviews with participants, bi-weekly research meetings with study staff, and observations of intervention delivery will provide data for a process evaluation. Estimates of effectiveness include weight, blood pressure, waist circumference, BMI, and behavioral automaticity measures that will be collected at baseline and week 20. Conclusion: The P2S2 program could facilitate the development of healthful dietary and physical activity habits in an underserved population. Whether interventions aimed at changing habits can feasibly influence this automaticity, particularly for high-risk, low resource communities where other barriers exist, is not known. This pilot study, therefore, will fill an important gap, providing insight to inform subsequent trials. PMID- 29696182 TI - Imagine your mood: Study design and protocol of a randomized controlled micro trial using app-based experience sampling methodology to explore processes of change during relapse prevention interventions for recurrent depression. AB - Background: Relapse prevention strategies include continuation of antidepressant medication and preventive psychological interventions. This study aims to gain understanding that may inform tailoring of relapse prevention to individual differences, to improve their effects. Such treatment personalization may be based on repeated assessments within one individual, using experience sampling methodology. As a first step towards informing decisions based on this methodology, insight is needed in individual differences in risk of relapse and response to treatment, and how relapse prevention strategies may differentially target vulnerability for relapse. Methods: The smartphone application 'Imagine your mood' has been developed specifically for this study to assess emotions, imagery, cognitions, and behaviors in daily life. Parallel to the randomized controlled trial 'Disrupting the rhythm of depression', 45 remitted recurrently depressed individuals taking continuation antidepressant medication will be randomly assigned to either continuing antidepressant medication (n = 15), continuing antidepressant medication combined with an eight-session preventive cognitive therapy (n = 15), or tapering of antidepressant medication in combination with preventive cognitive therapy (n = 15). Relapse and return of depressive symptomatology over a 24-month follow-up will be assessed. Additionally, matched never depressed individuals (n = 15) will be recruited as controls. Discussion: This innovative study combines the strengths of a randomized controlled trial and experience sampling methodology in a micro-trial to explore individual differences in risk of relapse and what works for whom to prevent relapse. Results may ultimately pave the way for therapists to tailor relapse prevention strategies to individual (affective) vulnerability. Trial registration: ISRCTN15472145, retrospectively registered. PMID- 29696184 TI - Innovative design for a phase 1 trial with intra-patient dose escalation: The Crotoxin study. AB - Introduction: Crotoxin has a broad antitumor activity but has shown frequent neurotoxic toxicity. To induce tolerance and limit this toxicity, we propose a new design with intra-patient dose escalation. Methods: A new Dose Limiting Toxicity definition was used. The concept of Target Ceiling Dose was introduced. Results: Dose Limiting Toxicity was the inability to dose escalate twice. Target Ceiling Dose was the highest planned dose to be administered to a patient and could change for patients along time. Recommended Dose was defined similarly as in a (3 + 3) conventional design. Conclusion: This innovant design was used and the clinical trial is now closed for inclusions. Results will be presented later. PMID- 29696183 TI - AExaCTT - Aerobic Exercise and Consecutive Task-specific Training for the upper limb after stroke: Protocol for a randomised controlled pilot study. AB - Motor function may be enhanced if aerobic exercise is paired with motor training. One potential mechanism is that aerobic exercise increases levels of brain derived neurotrophic factor (BDNF), which is important in neuroplasticity and involved in motor learning and motor memory consolidation. This study will examine the feasibility of a parallel-group assessor-blinded randomised controlled trial investigating whether task-specific training preceded by aerobic exercise improves upper limb function more than task-specific training alone, and determine the effect size of changes in primary outcome measures. People with upper limb motor dysfunction after stroke will be allocated to either task specific training or aerobic exercise and consecutive task-specific training. Both groups will perform 60 hours of task-specific training over 10 weeks, comprised of 3 * 1 hour sessions per week with a therapist and 3 * 1 hours of home-based self-practice per week. The combined intervention group will also perform 30 minutes of aerobic exercise (70-85%HRmax) immediately prior to the 1 hour of task-specific training with the therapist. Recruitment, adherence, retention, participant acceptability, and adverse events will be recorded. Clinical outcome measures will be performed pre-randomisation at baseline, at completion of the training program, and at 1 and 6 months follow-up. Primary clinical outcome measures will be the Action Research Arm Test (ARAT) and the Wolf Motor Function Test (WMFT). If aerobic exercise prior to task-specific training is acceptable, and a future phase 3 randomised controlled trial seems feasible, it should be pursued to determine the efficacy of this combined intervention for people after stroke. PMID- 29696185 TI - Intention-to-prevent analyses for estimating human papillomavirus vaccine efficacy in clinical studies. AB - HPV vaccine efficacy trials have been conducted in populations exposed to HPV infection (i.e., sexually active individuals); participants were not excluded from participating in the trials based on their HPV status at baseline. Thus, some participants could have been infected at baseline with 1 or more vaccine HPV types. Because HPV vaccines are prophylactic and do not affect existing HPV infections, prophylactic efficacy was assessed in a per-protocol population (those not infected at enrollment to the HPV type being analyzed who also completed the 3-dose regimen of vaccine and had no protocol violations). Supportive intention-to-treat (ITT) and modified ITT, were also conducted to include those with prevalent HPV infection. ITT analyses included those who received >=1 dose of vaccine and had efficacy follow-up regardless of whether or not they were infected with HPV prior to vaccination. Efficacy in the ITT population simply reflects the amount of prevalent infection in a particular population of study subjects. Intention-to-prevent (ITP) analyses included those who received one dose of vaccine, had efficacy follow-up, and were not infected at enrollment to the HPV type being analyzed. While all of these analyses have been presented, there has been little discussion regarding their respective significance. In this methodological review, we show that an ITT analysis does not preserve an unbiased comparison of treatment groups in relation to estimating prophylactic HPV vaccine efficacy. Furthermore, ITP is more suitable at preserving an unbiased comparison of treatment groups in relation to estimating prophylactic HPV vaccine efficacy. PMID- 29696186 TI - The over-representation of significant p values in abstracts compared to corresponding full texts: A systematic review of surgical randomized trials. AB - Background: Abstracts are often the only read summaries of research findings, and it is essential that they accurately represent of the contents of the full text of the randomised control trial (RCT). We investigated whether outcomes in surgical trials were selectively reported in abstracts based on their statistical significance. Objective: To compare the proportion of significant p-values reported in abstracts to their corresponding full texts in surgical RCTs. Method: A Meta-analysis of 350 full text RCTs conducted on humans that compared a surgical intervention to any other intervention. An electronic search of MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) was conducted. All outcomes were extracted from the abstract and the full text. Frequency histograms were used to plot the distribution of numerically reported p values across the statistical significance spectrum. For each RCT, a 2 * 2 table was populated with that trial's outcomes and whether the outcome was statistically significant (p < 0.05). From each 2 * 2 table, an odds ratio (OR) was calculated describing the association between statistical significance, and reporting in the abstract. ORs were pooled in random effects meta-analysis for an overall estimate of the association. Results: A total of 8258 reported outcomes were included. Outcomes reported in a surgical RCT abstract had three times the odds of being significant when compared to the corresponding full text (OR = 3.0, 95% confidence interval 2.5-3.6, p < 0.001). This finding was consistent and not subject to heterogeneity (I2 = 0%). Both histograms demonstrated a large drop in the frequency of reported p values between 0.04 and 0.05, and after the 0.06 thresholds. Conclusions: Data presented in abstracts is biased to statistically significant outcomes. Clinicians and policy makers should do not rely solely on information presented in abstracts for their decision-making. PMID- 29696187 TI - Feasibility study design and methods for a home-based, square-stepping exercise program among older adults with multiple sclerosis: The SSE-MS project. AB - We propose a randomized controlled trial (RCT) examining the feasibility of square-stepping exercise (SSE) delivered as a home-based program for older adults with multiple sclerosis (MS). We will assess feasibility in the four domains of process, resources, management and scientific outcomes. The trial will recruit older adults (aged 60 years and older) with mild-to-moderate MS-related disability who will be randomized into intervention or attention control conditions. Participants will complete assessments before and after completion of the conditions delivered over a 12-week period. Participants in the intervention group will have biweekly meetings with an exercise trainer in the Exercise Neuroscience Research Laboratory and receive verbal and visual instruction on step patterns for the SSE program. Participants will receive a mat for home-based practice of the step patterns, an instruction manual, and a logbook and pedometer for monitoring compliance. Compliance will be further monitored through weekly scheduled Skype calls. This feasibility study will inform future phase II and III RCTs that determine the actual efficacy and effectiveness of a home-based exercise program for older adults with MS. PMID- 29696188 TI - Predicting enrollment performance of investigational centers in phase III multi center clinical trials. AB - Failure to meet subject recruitment targets in clinical trials continues to be a widespread problem with potentially serious scientific, logistical, financial and ethical consequences. On the operational level, enrollment-related issues may be mitigated by careful site selection and by allocating monitoring or training resources proportionally to the anticipated risk of poor enrollment. Such procedures require estimates of the expected recruitment performance that are sufficiently reliable to allow centers to be sensibly categorized. In this study, we investigate whether information obtained from feasibility questionnaires can potentially be used to predict which centers will and which centers will not meet their enrollment targets by means of multivariable logistic regression analysis. From a large set of 59 candidate predictors, we determined the subset that is optimal for predictive purposes using Least Absolute Shrinkage and Selection Operator (LASSO) regularization. Although the extent to which the results are generalizable remains to be determined, they indicate that the prediction accuracy of the optimal model is only a marginal improvement over the intercept only model, illustrating the difficulty of prediction in this setting. PMID- 29696190 TI - Decision on performing interim analysis for comparative clinical trials. AB - In randomized-controlled trials, interim analyses are often planned for possible early trial termination to claim superiority or futility of a new therapy. While unblinding is necessary to conduct the formal interim analysis in blinded studies, blinded data also have information about the potential treatment difference between the groups. We developed a blinded data monitoring tool that enables investigators to predict whether they observe such an unblinded interim analysis results that supports early termination of the trial. Investigators may skip some of the planned interim analyses if an early termination is unlikely. We specifically focused on blinded, randomized-controlled studies to compare binary endpoints of a new treatment with a control. Assuming one interim analysis is planned for early termination for superiority or futility, we conducted extensive simulation studies to assess the impact of the implementation of our tool on the size, power, expected number of interim analyses, and bias in the treatment effect. The numerical study showed the proposed monitoring tool does not affect size or power, but dramatically reduces the expected number of interim analyses when the effect of the treatment difference is small. The tool serves as a useful reference when interpreting the summary of the blinded data throughout the course of the trial, without losing integrity of the study. This tool could potentially save the study resources and budget by avoiding unnecessary interim analyses. PMID- 29696189 TI - Factors predisposing nursing home resident to inappropriate transfer to emergency department. The FINE study protocol. AB - Background: Each year, around one out of two nursing home (NH) residents are hospitalized in France, and about half to the emergency department (ED). These transfers are frequently inappropriate. This paper describes the protocol of the FINE study. The first aim of this study is to identify the factors associated with inappropriate transfers to ED. Methods/design: FINE is a case-control observational study. Sixteen hospitals participate. Inclusion period lasts 7 days per season in each center for a total period of inclusion of one year. All the NH residents admitted in ED during these periods are included. Data are collected in 4 times: before transfer in the NH, at the ED, in hospital wards in case of patient's hospitalization and at the patient's return to NH. The appropriateness of ED transfers (i.e. case versus control NH residents) is determined by a multidisciplinary team of experts. Results: Our primary objective is to determine the factors predisposing NH residents to inappropriate transfer to ED. Our secondary objectives are to assess the cost of the transfers to ED; study the evolution of NH residents' functional status and the psychotropic and inappropriate drugs prescription between before and after the transfer; calculate the prevalence of potentially avoidable transfers to ED; and identify the factors predisposing NH residents to potentially avoidable transfer to ED. Discussion: A better understanding of the determinant factors of inappropriate transfers to ED of NH residents may lead to proposals of recommendations of better practice in NH and would allow implementing quality improvement programs in the health organization. PMID- 29696191 TI - The reporting quality of abstracts of stepped wedge randomized trials is suboptimal: A systematic survey of the literature. AB - Background: The stepped wedge trial (SWT) design is a type of the randomized clinical trial (RCT) design in which clusters or individuals are randomly and sequentially crossed over from control to intervention over a number of time periods. Trials using SWT design have become increasingly popular in medical, behavioral and social sciences research. Therefore, complete and transparent reporting of these studies is crucial. In particular, the quality of the abstracts of their reports is important because these may be the only accessible sources for their results. Objective: The aims of this survey were to evaluate the reporting quality of SWT abstracts and to identify factors contributing to better reporting quality. Methods: We performed literature searches to identify relevant articles in English published from November 1987 to October 2016 in the following electronic databases: Medline, Embase, Web of Science, CINAHL, and PsycINFO. At least two reviewers examined the quality of abstract reporting using the 17-item CONSORT (CONsolidated Standards Of Reporting Trials) Extension for Abstracts tool. Poisson regression models for incidence rate ratio (IRR) were used to identify factors associated with reporting quality (e.g., CONSORT endorsement, the number of authors, abstract format). Results: A total of 92 eligible articles were identified. Only 6 from the 17 items were reported in more than 80% of the articles (e.g., the statement of conclusions, contact details for the corresponding author). In the multivariable analysis, the year of publication since 2008 (IRR: 1.16; 95% confidence interval (CI): 1.02, 1.33), journal endorsement of the CONSORT Statement (IRR: 1.15; 95% CI: 1.01, 1.31), and multiple authorship (IRR 1.13, 95% CI: 1.01, 1.27) were significantly associated with better reporting quality. Conclusion: The quality of reporting of SWT abstracts was suboptimal, although there have been some significant improvements since 2008. Endorsement of the CONSORT Statement by journals is an essential element of improvement strategies. Also, multiple authorship is significantly associated with better quality of abstract reporting. PMID- 29696192 TI - The dual trigger study: Rationale and study design of a prospective double-blind randomized clinical trial comparing pregnancy rates after co-administration of low dose hCG at the time of GnRH agonist trigger or 35 h later for the prevention of OHSS. AB - Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of controlled ovarian stimulation. The use of gonadotropin releasing hormone (GnRH) agonist for the trigger of oocyte maturation is effective in the prevention of OHSS although it may result in a lower pregnancy rate. The use of adjuvant low dose human chorionic gonadotropin (hCG) at the time of trigger or at the time of oocyte retrieval may improve pregnancy rates. The goal of this dual trigger study is to evaluate the safety and efficacy of the use of low dose hCG administered at the time of GnRH agonist trigger or 35 h later as well as the potential impact on pregnancy rates. The population will consist of 82 women undergoing IVF treatment who are at risk of developing OHSS. This study will be a single center prospective randomized double-blind placebo controlled trial. The randomization schedule will be administered by the Investigational Drug Services of the University. After controlled ovarian stimulation, induction of oocyte maturation will be achieved using a GnRH agonist and patients will be randomized to receive either low dose hCG 1000 IU at the time of trigger and placebo at oocyte retrieval (Study group) or placebo at the time of trigger and hCG 1500 IU at the time of oocyte retrieval (Control group). The main outcomes will be live birth rates and incidence of OHSS. Two ancillary studies will include a quality of life survey and serum assessment of independent corpus luteum function. PMID- 29696193 TI - A prospective development study of software-guided radio-frequency ablation of primary and secondary liver tumors: Clinical intervention modelling, planning and proof for ablation cancer treatment (ClinicIMPPACT). AB - Introduction: Radio-frequency ablation (RFA) is a promising minimal-invasive treatment option for early liver cancer, however monitoring or predicting the size of the resulting tissue necrosis during the RFA-procedure is a challenging task, potentially resulting in a significant rate of under- or over treatments. Currently there is no reliable lesion size prediction method commercially available. Objectives: ClinicIMPPACT is designed as multicenter-, prospective-, non-randomized clinical trial to evaluate the accuracy and efficiency of innovative planning and simulation software. 60 patients with early liver cancer will be included at four European clinical institutions and treated with the same RFA system. The preinterventional imaging datasets will be used for computational planning of the RFA treatment. All ablations will be simulated simultaneously to the actual RFA procedure, using the software environment developed in this project. The primary outcome measure is the comparison of the simulated ablation zones with the true lesions shown in follow-up imaging after one month, to assess accuracy of the lesion prediction. Discussion: This unique multicenter clinical trial aims at the clinical integration of a dedicated software solution to accurately predict lesion size and shape after radiofrequency ablation of liver tumors. Accelerated and optimized workflow integration, and real-time intraoperative image processing, as well as inclusion of patient specific information, e.g. organ perfusion and registration of the real RFA needle position might make the introduced software a powerful tool for interventional radiologists to optimize patient outcomes. PMID- 29696194 TI - Rationale and design of DUAL study: Doxycycline to Upgrade response in light chain (AL) amyloidosis (DUAL): A phase 2 pilot study of a two-pronged approach of prolonged doxycycline with plasma cell-directed therapy in the treatment of AL amyloidosis. AB - Light chain (AL) amyloidosis is a plasma cell neoplasm associated with insoluble fibril deposition from clonal immunoglobulin chains systemically. The disease is associated with high early mortality and morbidity owing to advanced organ deposition as well as lack of proven de-fibrillogenic therapies. Pre-clinical and retrospective clinical data suggests that doxycycline has benefit in AL amyloidosis. The ongoing DUAL study is a single center, open label, phase 2 study in which patients with AL amyloidosis who are undergoing clone-directed therapy for the underlying neoplasm with oral doxycycline given for 1 year to test the hypothesis that prolonged doxycycline use will be safe, feasible, and lead to reduced early mortality in systemic AL amyloidosis and hasten organ amyloid response. Clinical follow up visits will occur at monthly intervals for systemic AL patients and at 3 monthly intervals for localized AL patients. Blood tests will be collected during these time points for hematologic response assessment. Organ testing will be conducted at 3 monthly intervals and radiologic testing will be conducted at 6 monthly intervals. Research blood samples will be collected at baseline, 6 and 12 months. Other correlative studies include matrix metalloproteinases (MMP), tissue inhibitor of metalloproteinases (TIMP) testing and patient-reported outcomes. PMID- 29696195 TI - Sensitivity of adaptive enrichment trial designs to accrual rates, time to outcome measurement, and prognostic variables. AB - Adaptive enrichment designs involve rules for restricting enrollment to a subset of the population during the course of an ongoing trial. This can be used to target those who benefit from the experimental treatment. Trial characteristics such as the accrual rate and the prognostic value of baseline variables are typically unknown when a trial is being planned; these values are typically assumed based on information available before the trial starts. Because of the added complexity in adaptive enrichment designs compared to standard designs, it may be of special concern how sensitive the trial performance is to deviations from assumptions. Through simulation studies, we evaluate the sensitivity of Type I error, power, expected sample size, and trial duration to different design characteristics. Our simulation distributions mimic features of data from the Alzheimer's Disease Neuroimaging Initiative cohort study, and involve two subpopulations based on a genetic marker. We investigate the impact of the following design characteristics: the accrual rate, the time from enrollment to measurement of a short-term outcome and the primary outcome, and the prognostic value of baseline variables and short-term outcomes. To leverage prognostic information in baseline variables and short-term outcomes, we use a semiparametric, locally efficient estimator, and investigate its strengths and limitations compared to standard estimators. We apply information-based monitoring, and evaluate how accurately information can be estimated in an ongoing trial. PMID- 29696196 TI - Remission induction by Raising the dose of Remicade in RA (RRRR) study: Rationale and study protocol for a randomized controlled trial comparing for sustained clinical remission after discontinuation of infliximab in patients with rheumatoid arthritis. AB - Infliximab, an inhibitor of TNF-alpha, is one of the most widely used biological disease-modifying antirheumatic drugs. Recent studies indicated that baseline serum TNF-alpha could be considered as a key indicator for optimal dosing of infliximab for RA treatment to achieve the clinical response and its sustained remission. The Remission induction by Raising the dose of Remicade in RA (RRRR) study is an open-label, parallel group, multicenter randomized controlled trial to compare the proportions of clinical remission based on the simplified disease activity index (SDAI) after 1 year of treatment and its sustained remission rate after another 1 year between the investigational treatment strategy (for which the dose of infliximab was chosen based on the baseline serum TNF) and the standard strategy of 3 mg/kg per 8 weeks of infliximab administration in infliximab-naive patients with RA showing an inadequate response to MTX. The primary endpoint is the proportion of patients who kept discontinuation of infliximab 1 year after discontinued infliximab at the time of 54 weeks after the first administration of infliximab. The secondary endpoints are the proportion of clinical remission based on SDAI and changes in SDAI from baseline at each time point, other clinical parameters, quality of life measures and adverse events. Target sample size of randomized patients is 400 patients in total. The main results of the RRRR study are expected to be published at the end of 2017. PMID- 29696197 TI - Comparison of efficacy and tolerance between combination therapy and monotherapy as first-line chemotherapy in elderly patients with advanced gastric cancer: Study protocol for a randomized controlled trial. AB - Introduction: The combination of a fluoropyrimidine [5-fluorouracil (5-FU), capecitabine, or S-1] with a platinum analog (cisplatin or oxaliplatin) is the most widely accepted first-line chemotherapy regimen for metastatic or recurrent advanced gastric cancer (AGC), based on the results of clinical trials. However, there is little evidence to guide chemotherapy for elderly patients with AGC because of under-representation of this age group in clinical trials. Thus, the aim of this study is to determine the optimal chemotherapy regimen for elderly patients with AGC by comparing the efficacies and safeties of combination therapy versus monotherapy as first-line chemotherapy. Methods: This study is a randomized, controlled, multicenter, phase III trial. A total of 246 elderly patients (>=70 years old) with metastatic or recurrent AGC who have not received previous palliative chemotherapy will be randomly allocated to a combination therapy group or a monotherapy group. Patients randomized to the combination therapy group will receive fluoropyrimidine plus platinum combination chemotherapy (capecitabine/cisplatin, S-1/cisplatin, capecitabine/oxaliplatin, or 5-FU/oxaliplatin), and those randomized to the monotherapy group will receive fluoropyrimidine monotherapy (capecitabine, S-1, or 5-FU). The primary outcome is the overall survival of patients in each treatment group. The secondary outcomes include progression-free survival, response rate, quality of life, and safety. Discussion: We are conducting this pragmatic trial to determine whether elderly patients with AGC will obtain the same benefit from chemotherapy as younger patients. We expect that this study will help guide decision-making for the optimal treatment of elderly patients with AGC. PMID- 29696198 TI - Effectiveness of a universal classroom-based preventive intervention (PAX GBG): A research protocol for a matched-pair cluster-randomized controlled trial. AB - Introduction: The PAX Good Behavior Game (PAX GBG) is a universal classroom-based program that promotes children's mental health. In Estonia, the intervention is delivered to first grade students (aged seven to eight) within the regular school curriculum. The current work describes a protocol for a cluster-randomized controlled trial (RCT) of the PAX GBG conducted in Estonia. Design and methods: This is an ongoing, pragmatic, two-year, matched-pair, cluster-RCT conducted in Estonian elementary schools. Schools were matched to pairs based on their geographical location and number of students per classroom. One school in each pair was randomly selected to receive the intervention and the other placed on a wait-list as a control. 42 schools provided baseline data during the autumn of 2016. Data is collected at two more points in time - seven months and 19 months post-baseline. Outcomes of children's mental health and behavior are measured by the teacher- and parent-rated Strengths and Difficulties Questionnaire, parent rated Swanson, Nolan, and Pelham - IV Questionnaire and the Go/No-Go task completed by children. Teachers also rate their self-efficacy and overall classroom behavior. Discussion: This study aims to test the effectiveness of the intervention in Estonian classrooms with a newer version of the rigorously tested GBG program. To our knowledge, this study is the first to measure the effects of the intervention on children's inhibitory control, which has been associated with externalizing problems in the literature. The results from this trial will provide further understanding into how the program influences children's well being and self-control. Trial registration: ClinicalTrials.gov registry (NCT02865603). PMID- 29696199 TI - Microbiological and clinical effects of an oral hygiene regimen. AB - Objective: This study compared the additional effect of rinsing with a fluoride free and alcohol-free 0.075% cetylpyridinium chloride (CPC) mouthwash to brushing alone on dental plaque, gingival inflammation, and supragingival plaque bacteria. Methods: Adult subjects [n = 68] completed a washout period prior to baseline evaluations that evaluated gingival inflammation, gingival bleeding, dental plaque, and pocket probing depths along with microbiological analysis of supragingival plaque for bacteria. Subjects were randomized to two treatment groups: brush with fluoride toothpaste and rinse with the CPC mouthwash (test) or brush with fluoride toothpaste only (control), twice daily for the next four weeks. Subjects abstained from oral hygiene for twelve-hours prior to two-week and four-week post-treatment microbiological analysis of supragingival plaque for bacteria. Clinical assessments for gingival inflammation, gingival bleeding, dental plaque, and pocket probing depths were conducted at the four-week post treatment visit. Results: Compared to baseline, bacteria of dental plaque in the test group were reduced by 61.1% and 83.0% at the two-week and four-week evaluations, respectively (p < 0.05). Compared to baseline, bacteria of supragingival plaque in the control group were reduced by 2.3% at either post treatment evaluations (p < 0.05). Additionally, dental plaque bacteria in the test was 69.8% and 86.8% lower than the control at the two-week and four-week evaluations (p < 0.05), respectively. After four-weeks, the test group showed 14.3% less gingivitis, 11.2% less dental plaque, 7.5% less gingival bleeding compared to the control group (p < 0.05). Conclusions: Oral hygiene comprising toothbrushing and rinsing with a mouthwash containing 0.075% cetylpyridinium chloride demonstrated greater reductions of dental plaque bacteria, improving gingival health, and eliminating supragingival plaque than toothbrushing alone. PMID- 29696200 TI - A randomized control trial of an asthma self-management program for adolescents in Taiwan: A study protocol. AB - Uncontrolled asthma in adolescents can be explained by developmental changes and lack of priority for self-care activities. Limited reports on asthma self management programs for adolescents to enhance prevention behaviors in Taiwan were found. The protocol paper presents a two-armed, randomized controlled trial aiming to test the effectiveness of a newly developed self-management program for 112 adolescents with asthma in Taiwan. The primary outcome is asthma self efficacy. Data will be collected at baseline and the week 4. The findings of this study will determine the extent to which a self-management program for adolescents with asthma in Taiwan enhances asthma management self-efficacy, self management activities in asthma prevention and management, and achievement of well-controlled asthma. Trial Registration No: ACTRN12613001294741. PMID- 29696201 TI - A two-stage design for phase II trials with time-to-event endpoint using restricted follow-up. AB - In phase II oncology trials, the use of new cytostatic drugs raises some questions regarding the endpoint. Time-to-event endpoints such as Progression Free Survival have been recommended and led to new designs. In 2003, Case and Morgan proposed a design based on the comparison of the cumulative hazards at a clinically relevant timepoint. In 2013, Kwak proposed a design based on the one sample log-rank test. If all the patients are followed from their entry time to the analysis date, the Kwak and Jung's design leads to a smaller sample size as compared to the Case-Morgan's design. However, the Case and Morgan's design requires less information since it only needs to follow every patient during a fixed interval of time. We propose a trade-off between these two approaches that corresponds to an adaptation of Kwak and Jung's design when the follow-up is expected to be restricted. Our proposal is based on the one-sample log-rank test as the Kwak and Jung's design but it uses the same follow-up information as the Case-Morgan's design. Simulation study shows that our proposal allows reducing the sample size as compared to the Case-Morgan's design (median difference of 23% [15%-33%]). Type I and type II error rates are close to their nominal rates planned in the protocol. A real phase II clinical trial in cervical cancer illustrated the interest of this new design. Thus, our proposal can be recommended as an alternative to the Kwak's design when patients' follow-up is restricted. PMID- 29696202 TI - Efficacy of antiviral drug AV2 in the treatment of human papillomavirus associated precancerous lesions of the uterine cervix: A randomized placebo controlled clinical trial in Kinshasa, DR Congo. (KINVAV study). AB - Background: Cervical Cancer (CC) is a major public health problem in DR Congo; the high incidence of CC is due to the inexistence of effective screening programs based on cytology and/or HPV detection followed by appropriate treatments. This situation highlights the need to implement efficacious and inexpensive treatment methods. This study aims at evaluating the efficacy of a topical antiviral drug named AV2(r) as a treatment for HPV-associated lesions of the cervix. Methods: Women will undergo cytology sampling, HPV testing and Visual inspection of the cervix after application of 5% acetic acid (VIA). VIA-positive women will be randomized to one of two groups to receive treatment by either AV2(r)or placebo. They will undergo control examinations after two months and after six months. In case of persistent lesions on VIA, treatment by cryotherapy will be done. The primary outcomes will be the change of lesions, the clearance of HPV DNA, and the correlation of the two 2 months after treatment with AV2(r). Conclusion: This study is the first large-scale study in Africa to evaluate systematically the efficacy and safety of a topical antiviral drug for the treatment of HPV- associated lesions of the cervix. Its findings will direct the planning of suitable algorithms for CC screening and treatment. Clinical trial registration: ClinicalTrials.gov - Unique identifier: NCT02346227, registered on November 8, 2014. PMID- 29696204 TI - Estimation of treatment effects in weighted log-rank tests. AB - Non-proportional hazards have been observed in clinical trials. The log-rank test loses power and the standard Cox model generally produces biased estimates under such conditions. Weighted log-rank tests have been utilized to increase the test power; however, it is not intuitive how to interpret the test result in terms of the clinical effect. We propose a Cox-model based time-varying treatment effect estimate to complement the weighted log-rank test. The score test from the proposed model is equivalent to the weighted log-rank test, and a time-profile of the treatment effect can be obtained by fitting a time-varying covariate Cox model. Simulation results show that the proposed model preserves type-I error and achieve higher power than log-rank tests under non-proportional hazards scenarios. Whereas the standard Cox model produces biased effect estimates, the proposed model produces unbiased estimates if the weight function is correctly specified. It also achieves a better model fit and an enhanced flexibility to accommodate non-proportional hazards compared to the standard Cox model. The proposed approach makes the assumptions of the weighted log-rank test explicit and the validity of assumptions can be assessed based on prior knowledge or model goodness-of-fit. It also helps to translate the weighted log-rank test results into quantitative estimates of the treatment effect with intuitive interpretation. The proposed method can be routinely conducted to complement weighted log-rank tests, especially in the setting where non-proportional hazards are expected. PMID- 29696203 TI - CREATE Wellness: A multi-component behavioral intervention for patients not responding to traditional Cardiovascular disease management. AB - Background/Aims: Cardiovascular disease (CVD) is the leading cause of death in the US. Many patients do not benefit from traditional disease management approaches to CVD risk reduction. Here we describe the rationale, development, and implementation of a multi-component behavioral intervention targeting patients who have persistently not met goals of CVD risk factor control. Methods: Informed by published evidence, relevant theoretical frameworks, stakeholder advice, and patient input, we developed a group-based intervention (Changing Results: Engage and Activate to Enhance Wellness; "CREATE Wellness") to address the complex needs of patients with elevated or unmeasured CVD-related risk factors. We are testing this intervention in a randomized trial among patients with persistent (i.e > 2 years) sub-optimal risk factor control despite being enrolled in an advanced and highly successful CVD disease management program. Results: The CREATE Wellness intervention is designed as a 3 session, group-based intervention combining proven elements of patient activation, health system engagement skills training, shared decision making, care planning, and identification of lifestyle change barriers. Our key learnings in designing the intervention included the value of multi-level stakeholder input and the importance of pragmatic skills training to address barriers to care. Conclusions: The CREATE Wellness intervention represents an evidence-based, patient-centered approach for patients not responding to traditional disease management. The trial is currently underway at three medical facilities within Kaiser Permanente Northern California and next steps include an evaluation of efficacy, adaptation for non-English speaking patient populations, and modification of the curriculum for web- or phone-based versions. ClinicalTrialsgov Identifier: NCT02302612. PMID- 29696205 TI - Qualitative analysis of clinical research coordinators' role in phase I cancer clinical trials. AB - Background: Clinical research coordinators play a pivotal role in phase I cancer clinical trials. Purpose: We clarified the care coordination and practice for patients provided by clinical research coordinators in phase I cancer clinical trials in Japan and elucidated clinical research coordinators' perspective on patients' expectations and understanding of these trials. Method: Fifteen clinical research coordinators participated in semi-structured interviews regarding clinical practices; perceptions of patients' expectations; and the challenges that occur before, during, and after phase I cancer clinical trials. Discussion: Qualitative content analysis showed that most clinical research coordinators observed that patients have high expectations from the trials. Most listened to patients to confirm patients' understanding and reflected on responses to maintain hope, but to avoid excessive expectations; clinical research coordinators considered avoiding unplanned endings; and they aimed to establish good relationships between patients, medical staff, and among the professional team. Conclusions: Clinical research coordinators were insightful about the needs of patients and took a meticulous approach to the phase I cancer clinical trial process, allowing time to connect with patients and to coordinate the inter-professional research team. Additionally, education in advanced oncology care was valuable for comforting participants in cancer clinical trials. PMID- 29696206 TI - Searching for new biomarkers in ovarian cancer patients: Rationale and design of a retrospective study under the Mermaid III project. AB - Ovarian cancer is a silent killer and, due to late diagnosis, the primary cause of death amongst gynecological cancers, killing approximately 376 women annually in Denmark. The discovery of a specific and sensitive biomarker for ovarian cancer could improve early diagnosis, but also treatment, by predicting which patients will benefit from specific treatment strategies. The Mermaid III project is consisting of 3 parts including "Early detection, screening and long-term survival," "Biomarkers and/or prognostic markers" and "The infection theory." The present paper gives an overview of the part regarding biomarkers and/or prognostic markers, with a focus on rationale and design. The study described has 3 major branches: microRNAs, epigenetics and Next Generation Sequencing. Tissue and blood from ovarian cancer patients, already enrolled in the prospective ongoing pelvic mass cohort, will be examined. Relevant microRNAs and DNA methylation patterns will be investigated using array technology. Patient exomes will be fully sequenced, and identified genetic variations will be validated with Next Generation Sequencing. In all cases, data will be correlated with clinical information on the patient, in order to identify possible biomarkers. A thorough investigation of biomarkers in ovarian cancer, including large numbers of different markers, has never been done before. Besides from improving diagnosis and treatment, other outcomes could be markers for screening, knowledge of the molecular aspects of cancer and the discovery of new drugs. Moreover, biomarkers are a prerequisite for the development of precision medicine. This study will attack the ovarian cancer problem from several angles, thereby increasing the chance of successfully contributing to saving lives. PMID- 29696207 TI - Comparative assessment of methylcobalamin and ascorbic acid on cognitive function in post-menopausal women - A randomized, double-blind trial. AB - Introduction: A decline in cognitive function occurs as women progress through the menopausal transition. Objective: The present study was designed to compare the effect of Methylcobalamin and Ascorbic Acid on Cognitive Function in post menopausal women. Methods: A randomized, double-blind trial was conducted in postmenopausal women with mild to moderate cognitive dysfunction. Eligible 56 subjects were randomized, the effect of ascorbic acid (500 mg OD) and methylcobalamin (50 mcg OD) was compared after 12 weeks of treatment. MMSE Questionnaire was used to assess the cognitive function, and beta-amyloid42 was estimated in serum by enzyme-linked immunosorbent assay (ELISA). Results: In MMSE score, delayed verbal recall (P = 0.027), naming (P = 0.042) and repetition (P = 0.031) scores were significantly improved in ascorbic acid group when compared to baseline. The beta-amyloid42 level was decreased significantly in subjects receiving ascorbic acid (P = 0.04) when compared to Methylcobalamin group (P = 0.31). The inverse relationship between beta-amyloid42 levels and the MMSE score was found in ascorbic acid treatment (r = 0.6324, P = 0.0004). Conclusion: Based on MMSE and beta-amyloid42 results, ascorbic acid showed improvement in cognitive function among post-menopausal women when compared to methylcobalamin supplement. PMID- 29696209 TI - Supervised pelvic floor muscle training versus attention-control massage treatment in patients with faecal incontinence: Statistical analysis plan for a randomised controlled trial. AB - Introduction: Faecal incontinence affects approximately 8-9% of the adult population. The condition is surrounded by taboo; it can have a devastating impact on quality of life and lead to major limitations in daily life. Pelvic floor muscle training in combination with information and fibre supplements is recommended as first-line treatment for faecal incontinence. Despite this, the effect of pelvic floor muscle training for faecal incontinence is unclear. No previous trials have investigated the efficacy of supervised pelvic floor muscle training in combination with conservative treatment and compared this to an attention-control massage treatment including conservative treatment. The aim of this trial is to investigate if 16 weeks of supervised pelvic floor muscle training in combination with conservative treatment is superior to attention control massage treatment and conservative treatment in patients with faecal incontinence. Design: Randomised, controlled, superiority trial with two parallel arms. Methods: 100 participants with faecal incontinence will be randomised to either (1) individually supervised pelvic floor muscle training and conservative treatment or (2) attention-control massage treatment and conservative treatment. The primary outcome is participants' rating of symptom changes after 16 weeks of treatment using the Patient Global Impression of Improvement Scale. Secondary outcomes are the Vaizey Incontinence Score, the Fecal Incontinence Severity Index, the Fecal Incontinence Quality of Life Scale, a 14-day bowel diary, anorectal manometry and rectal capacity measurements. Follow-up assessment at 36 months will be conducted. Discussion: This paper describes and discusses the rationale, the methods and in particular the statistical analysis plan of this trial. PMID- 29696208 TI - Study protocol for the FITR Heart Study: Feasibility, safety, adherence, and efficacy of high intensity interval training in a hospital-initiated rehabilitation program for coronary heart disease. AB - Background: For decades, moderate intensity continuous training (MICT) has been the cornerstone of exercise prescription for cardiac rehabilitation (CR). High intensity interval training (HIIT) is now recognized in CR exercise guidelines as an appropriate and efficient modality for improving cardiorespiratory fitness, a strong predictor of mortality. However, the clinical application of HIIT in a real world CR setting, in terms of feasibility, safety, and long-term adherence, needs further investigation to address ongoing reservations. Furthermore, studies using objective measures of exercise intensity (such as heart rate; HR) have produced variable outcomes. Therefore we propose investigating the use of subjective measures (such as rating of perceived exertion (RPE)) for prescribing exercise intensity. Methods: One hundred adults with coronary artery disease (CAD) attending a hospital-initiated CR program will be randomized to 1) HIIT: 4 * 4 min high intensity intervals at 15-18 RPE interspersed with 3-min active recovery periods or 2) MICT: usual care exercise including 40 min continuous exercise at a moderate intensity corresponding to 11-13 RPE. Primary outcome is change in exercise capacity (peak VO2) following 4 weeks of exercise training. Secondary outcome measures are: feasibility, safety, exercise adherence, body composition, vascular function, inflammatory markers, intrahepatic lipid, energy intake, and dietary behavior over 12-months; and visceral adipose tissue (VAT) following 12 weeks of exercise training. Conclusions: This study aims to address the ongoing concerns regarding the practicality and safety of HIIT in CR programs. We anticipate study findings will lead to the development of a standardized protocol to facilitate CR programs to incorporate HIIT as a standard exercise option for appropriate patients. PMID- 29696210 TI - Factors influencing the enrollment in randomized controlled trials in orthopedics. AB - Background: Low enrollment rates are a threat to the external validity of clinical trials. The purpose of this study was to identify factors associated with lower enrollment rates in randomized controlled trials (RCTs) involving orthopedic procedures. Methods: We performed a search in PubMed/MEDLINE for RCTs that involved any orthopedic surgical procedure, compared different intraoperative interventions, were published in English in a peer-reviewed journal between 2003 and 2014, and reported the numbers of both enrolled and eligible subjects. The primary outcome was the enrollment rate, defined as the number of enrolled subjects divided by the number of eligible subjects. We used a meta-regression to identify factors associated with lower enrollment rates. Results: The combined estimate of enrollment rate across all 393 studies meeting inclusion criteria was 90% (95% CI: 89-92%). Trials in North America had significantly lower enrollment rates compared to trials in the rest of the world (80% vs. 92%, p < 0.0001). Trials comparing operative and non-operative treatments had significantly lower enrollment rates than trials comparing two different operative interventions (80% vs. 91%, p < 0.0001). Among trials comparing operative and non-operative interventions, there was a marked difference in enrollment rate by region: 49% in North America and 86% elsewhere (p < 0.0001). Conclusions: RCTs investigating orthopedic procedures have variable enrollment rates depending on their location and the difference between the interventions being studied. North American trials that compare operative and non operative interventions have the lowest enrollment rates. Investigators planning RCTs would be well advised to consider these data in planning recruitment efforts. PMID- 29696211 TI - Characteristics of cancer patients participating in presurgical lifestyle intervention trials exploring effects on tumor biology. AB - Background: Poor diet and insufficient physical activity are strongly associated with an increased risk of several cancers. Preclinical studies suggest that lifestyle modifications may exert favorable effects on tumor biology. Randomized controlled trials in the presurgical setting serve as an ideal means to translate this research to humans; however, little is known about the characteristics of patients who enroll in these presurgical trials versus those who do not. Methods: Screening databases from three presurgical lifestyle intervention trials for breast and prostate cancer patients conducted at Duke University Medical Center (NCT00049309) and the University of Alabama at Birmingham (NCT02224807 and NCT01886677) were combined for analysis. Demographic and anthropometric differences between enrolled vs. non-enrolled individuals were assessed using Chi square for categorical variables and t-tests for continuous variables. Results: There was no difference in participation rate when comparing minority status or overweight and obese patients. However, obese females were slightly more likely to enroll than women who were overweight (p = 0.110), a trend not seen in men. Women were also less likely than men to participate if their study site was >25 miles from their home (p = 0.034). Patients who had completed a college degree were somewhat less likely to enroll than those with less educational attainment (p = 0.072). Of those who did not enroll, 80% cited a lack of time. Conclusion: Similar to other clinical trials, lack of time is a leading barrier to enrollment, and travel/distance appears to be a greater barrier for women in presurgical studies. Larger presurgical lifestyle intervention trials will require tailored strategies to enhance recruitment. PMID- 29696212 TI - Feasibility of high-intensity interval training with hyperoxia vs. intermittent hyperoxia and hypoxia in cancer patients undergoing chemotherapy - Study protocol of a randomized controlled trial. AB - Exercise has been well demonstrated to potentially reduce chemotherapy-induced side effects and possibly aid slowing down tumor growth in cancer patients but exercise training adherence is typically low. Thus, training regimens which are perceived less strenuous but do not compromise the training-induced beneficial adaptations will help to increase adherence to exercise and reduce attrition. This 4-armed study aims to investigate the effects of high intensity interval training (HIIT) in hyperoxia versus intermittent hyperoxia and hypoxia in cancer patients undergoing chemotherapy. Forty-eight cancer patients will be randomized into either of three intervention groups or a no-training control group. Patients in the intervention groups will perform twice weekly HIIT on a cycle ergometer in hyperoxia, intermittent hyperoxia and hypoxia or normoxia. Study outcomes will be assessed before and after 4 weeks of training, while selected measures will also be performed pre- and post the first and last training session. The primary aim of this study is to investigate the feasibility, compliance, tolerance and safety of the training. Secondary endpoints will include measures of quality of life, aerobic capacity, transcutaneous oxygen saturation, red blood cell deformability, as well as the assessment of anabolic and catabolic hormone concentrations, reactive oxygen species, cytokine profiles and NK-cell cytotoxicity. To the best of our knowledge, this is the first study investigating the combined effects of exercise with modified fraction of inspired O2 in cancer patients. As such, we provide a novel approach for exercise as an adjuvant therapy in cancer patients undergoing chemotherapy. PMID- 29696213 TI - Bayesian adaptive clinical trials of combination treatments. AB - Randomized clinical trials (RCT) increasingly investigate combination therapies. Strong biological rationale or early clinical evidence commonly suggest that the effect of the combination treatment is importantly greater than the maximum effect of any of the individual treatments. While these relationships are commonly well-accepted, RCTs do not incorporate them into the design or analysis plans. We therefore propose a simple Bayesian framework for incorporating the known relationships that the effectiveness of a combination treatment exceeds that of any individual treatment, but does not necessarily exceed the sum of individual effects. We term the collation of these two relationships 'fractional additivity'. We performed a binary outcome simulation study of a response adaptive randomized three-arm clinical trial with treatment arms A, B, and A&B that allowed for dropping an inferior treatment arm and terminating the trial early for superiority during any of 4 interim analyses. We compared the Bayesian fractional additivity model to a conventional analysis by measuring the expected proportion of failures, sample size at trial termination, time to termination, and root mean squared error of final estimates. We also compared the fractional additivity model to a 'full additivity' model where the effect of A&B was assumed to be the sum of the effect of A and B. In simulation scenarios where important fractional additivity or full additivity existed, the Bayesian fractional additivity model yielded a 3-4% relative reduction in expected number of failures, and a 30%-50% relative reduction in sample size at trial termination compared to a conventional analysis. These results held true even when the Bayesian fractional additivity model employed a biased prior. The full additivity model had slightly higher gains, but too frequently terminated the trial at the first interim look. In scenarios where no or weak fractional additivity exists, the expected sample size and time to termination were similar for the Bayesian fractional additivity model with a moderately optimistic bias about fractional additivity and the conventional model. Lastly, the fractional additivity model generally yielded similar or lower root mean squared error compared to the other models. In conclusion, our proposed Bayesian fractional additivity model provides an efficient approach for estimating effects of combination treatments in clinical trials. The approach is not only highly applicable in adaptive clinical trials, but also provides added power in a conventional RCT. PMID- 29696214 TI - Matao Controlling Hypertension (MatCH) project: Rationale and design. AB - Background: Hypertension is the main risk factor for most cardiovascular diseases. A coordinated and organized system from the Brazilian Ministry of Healthy involving Family Health Strategy (FHS), a program for the prevention of chronic disease, and the Popular Pharmacy Program (PPP), which subsidizes medications for the population, could allow an earlier identification and better blood pressure (BP) control. Matao Controlling Hypertension (MatCH) is a community-based population project that aims to apply an organized, integrated and coordinated program in the city of Matao, Brazil, involving FHS and PPP in order to actively search, treat and follow-up hypertensive subjects. Method: This is a population community-based, interventional, follow-up study where all subjects aged >= 40 years assisted by the FHS program in Matao will have BP assessed monthly by trained Community Health Agents (CHA) during a domiciliary visit. Identified hypertensive subjects will be referred to FHS physicians for nonpharmacological and pharmacological treatment. Most of the hypertensive drugs used will be available through the PPP. Prevalence of hypertension, awareness, demographics and risk factors will be correlated with BP control. The population study is expected to involve approximately 18.600 subjects. The study period will be four years. Discussion: Considering that hypertension is asymptomatic in most cases, to reduce the population burden of BP-related deaths and diseases it is essential to detect and treat early all hypertensive patients. If we achieve our large-scale BP control, this program can be applied to other populations from developing countries. PMID- 29696215 TI - Perceptions and attitudes to clinical research participation in Qatar. AB - Recruitment into clinical research studies is a major challenge. This study was carried out to explore the perceptions and attitudes towards clinical research participation among the general public in Qatar. A population based questionnaire study was carried out at public events held in Qatar. Residents of Qatar, 18 years or above in age were surveyed, anonymously, following verbal consent. Descriptive and multivariate analyses were conducted. We administered 2517 questionnaires to examine clinical research participation, of which 2379 complete forms were analyzed. Those who had previously been approached to participate in research completed a more detailed assessment. Data showed that only 5.7% participants (n = 134) had previously been approached to participate in a clinical research study. Of these 63.4% (n = 85) had agreed to participate while 36.6% (n = 49) had declined. The main reasons for declining participation included: time constraint (47.8%, n = 11), 'fear' (13.0%, n = 3), lack of awareness about clinical research (8.7%, n = 2) and lack of interest (8.7%, n = 2). 'To help others' (31.8%, n = 27) and 'thought it might improve my access to health care' (24.7%, n = 21) were the prime motivators for participation. There was a general agreement among participants that their previous research experience was associated with positive outcomes for self and others, that the research conduct was ethical, and that opportunities for participation will be welcomed in future. More than ten years of stay within Qatar was a statistically significant determinant of willingness to participate, adjusted odds ratio 5.82 (95% CI 1.93-17.55), p = 0.002. Clinical research participation in Qatar needs improvement. Time constraints, lack of trust in and poor awareness about clinical research are main barriers to participation. Altruism, and improved health access are reported as prime motivators. Deeper insight in to the factors affecting clinical research participation is needed to devise evidence based policies for improvement in recruitment strategies. PMID- 29696216 TI - Effectiveness of intensive smoking reduction counselling plus combination nicotine replacement therapy in promoting long-term abstinence in patients with chronic obstructive pulmonary disease not ready to quit smoking: Protocol of the REDUQ trial. AB - Introduction: Limited tobacco dependence treatment resources exist for smoking COPD patients not ready to quit. Smoking reduction may be a viable treatment approach if it prompts quit attempts and subsequent abstinence. This article describes the protocol of the REDUQ (REDUce and Quit) study, which examines whether smoking reduction counselling plus combination nicotine replacement therapy (NRT) is (cost-)effective in achieving long-term abstinence in smoking COPD patients not ready to quit. Methods/Design: We conducted a two-centre, parallel-group, randomised controlled trial with 18 months follow-up in smoking outpatients with COPD. Patients not ready to quit within the next month but willing to reduce their smoking, were randomised to receive either intensive smoking reduction counselling plus combination NRT or a single information meeting plus self-help manual. Outcomes were assessed at baseline, 6, 12 and 18 months. The primary outcome is >= 1-year prolonged abstinence. Secondary outcomes are point prevalence abstinence, successful (i.e. >= 50%) smoking reduction, and incidence of quit attempts reported at follow-up assessments. Smoking status is biochemically verified by salivary cotinine and expired CO. Other variables include smoking-related cognitions, intention and motivation to reduce and quit smoking, withdrawal symptoms, health-related quality of life, symptoms of anxiety and depression, state of mindfulness, lung function, use of health care resources, and costs. Discussion: The outcomes of the REDUQ trial will advance knowledge on treatment of smoking COPD patients not ready to quit. If (cost )effective, the smoking reduction intervention can be offered to this difficult to-treat target group as a valuable adjunct to smoking cessation treatment. PMID- 29696217 TI - Quality of abstracts of pilot trials in heart failure: A protocol for a systematic survey. AB - Introduction: Pilot trials are initial small-scale studies done to inform the design of larger trials. Their findings like other studies are usually disseminated as peer-reviewed journal articles. Abstracts are used to introduce the contents to readers, and give a general idea about the full reports and sometimes are the only source of information available to readers. Despite their importance, the contents of abstracts of trial reports are usually not informative enough and lack the essential details. Methods and analysis: This is a protocol for a planned systematic survey with a primary aim of analyzing the reporting quality measured as the completeness of the reporting of pilot trial abstracts in heart failure. The secondary aim will be to explore factors associated with better reporting quality.Abstracts of heart failure pilot trials in humans (journal and conference abstracts) published in the English language from 1 January 1990 to 30 November 2016 will be assessed to determine the reporting quality, based on the CONSORT 2010 statement extension to randomized pilot and feasibility trials. All non-pilot/feasibility trials and non-human pilot trials will be excluded. We will search Medline (PUBMED), Cochrane controlled trials register, Scopus and African wide information databases for pilot trials in heart failure. Title and abstracts of identified studies will be screened for inclusion and data extracted independently by two reviewers in duplicate without using the full text. Reported and unreported items on the abstracts will be presented as frequencies and percentages, a descriptive analysis will be used to interpret the reporting quality and regression analysis used for characteristics associated with greater statistical reporting at 95% confidence interval. Review registration number: PROSPERO CRD42016049911. PMID- 29696218 TI - Memory-focused cognitive therapy for cocaine use disorder: Rationale, design and protocol for an external pilot randomised controlled trial. AB - Introduction: Cocaine use disorder (CUD) is a debilitating condition characterised by maladaptive cocaine-related memories and impaired cognitive and behavioural control. There are no evidence-supported pharmacotherapies and only weakly effective psychological interventions specific for CUD. Our novel Memory focused Cognitive Therapy (MFCT) aims to modify cocaine-related memories to reduce craving and drug use. Methods: This is a single-centre (outpatient), 15 week, two-arm, pilot randomised controlled trial (RCT) to address feasibility, safety, quality and preliminary efficacy. Thirty participants (adults >=18 years; current CUD) will receive ongoing standard care (treatment-as-usual [TAU]) during the study and will be randomised (1:1) to a control or intervention group. The control group will receive 3 * 90min CUD cognitive case conceptualisation assessments and 2 * 30min cocaine-related cue-induction procedures (in vivo presentation of images and objects). Experimental group participants will receive 3 * 90min CUD cognitive case conceptualisation assessments; 2 * 30min cue induction procedures; and individual MFCT (5 * 120min; daily for 1 week; with 3 relapse prevention follow-ups over 3-months). All study participants will complete research follow-ups at 1-week, 1-month and 3-months. The experimental and control groups will be compared on the mean score on the frequency version of the Craving Experience Questionnaire at 1-month (primary outcome measure). Secondary outcomes include: percentage of days abstinent and longest period of continuous abstinence from cocaine (past 28-days at 1-month follow-up); urine drug screen and CUD diagnosis (DSM-5). Conclusions: We will conduct a full external pilot RCT of a novel, MFCT for CUD. The findings will inform the case, and necessary modifications, for a substantive study. PMID- 29696219 TI - Perceived barriers to pediatrician and family practitioner participation in pediatric clinical trials: Findings from the Clinical Trials Transformation Initiative. AB - Despite legislation to stimulate pediatric drug development through clinical trials, enrolling children in trials continues to be challenging. Non investigator (those who have never served as a clinical trial investigator) providers are essential to recruitment of pediatric patients, but little is known regarding the specific barriers that limit pediatric providers from participating in and referring their patients to clinical trials. We conducted an online survey of pediatric providers from a wide variety of practice types across the United States to evaluate their attitudes and awareness of pediatric clinical trials. Using a 4-point Likert scale, providers described their perception of potential barriers to their practice serving as a site for pediatric clinical trials. Of the 136 providers surveyed, 52/136 (38%) had previously referred a pediatric patient to a trial, and only 17/136 (12%) had ever been an investigator for a pediatric trial. Lack of awareness of existing pediatric trials was a major barrier to patient referral by providers, in addition to consideration of trial risks, distance to the site, and time needed to discuss trial participation with parents. Overall, providers perceived greater challenges related to parental concerns and parent or child logistical barriers than study implementation and ethics or regulatory barriers as barriers to their practice serving as a trial site. Providers who had previously been an investigator for a pediatric trial were less likely to be concerned with potential barriers than non-investigators. Understanding the barriers that limit pediatric providers from collaboration or inhibit their participation is key to designing effective interventions to optimize pediatric trial participation. PMID- 29696220 TI - Evaluating the efficacy of an integrated motivational interviewing and multi modal exercise intervention for youth with major depression: Healthy Body, Healthy Mind randomised controlled trial protocol. AB - Background: Recent meta-analytic reviews suggest exercise can reduce depression severity among adults with major depressive disorder (MDD); however, efficacy studies with depressed youth are limited. Few studies have investigated the efficacy of multi-modal exercise interventions in this population, addressed treatment engagement, or explored the differential effects of exercise on depressive symptom profiles. Objectives: This paper describes the study protocol and recruitment pattern for an assessor blinded, two-arm randomised controlled trial investigating the efficacy of an integrated motivational interviewing (MI) and multi-modal exercise intervention in youth diagnosed with MDD. Associations between depressive symptom profiles (cognitive, somatic and affective) and psychological, physiological (fitness), and biological (blood biomarker) outcomes will also be examined. Methods: Participants aged 15-25 years with current MDD were recruited. Eligible participants were randomised and stratified according to gender and depression severity to either an immediate or delayed (control) group. The immediate group received a brief MI intervention followed by a 12-week small group exercise intervention (3 times per week for 1 h), all delivered by personal trainers. The delayed control group received the same intervention 12-weeks later. Both groups were reassessed at mid-treatment or mid-control, post treatment or post-control, and follow-up (12 weeks post-treatment). Results: 68 participants were recruited and randomly allocated to an intervention group. Conclusion: This trial will increase our understanding of the efficacy of multi modal exercise interventions for depression and the specific effects of exercise on depressive symptom profiles. It also offers a novel contribution by addressing treatment engagement in exercise efficacy trials in youth with MDD. PMID- 29696221 TI - The administration of patient-reported outcome questionnaires in cancer trials: Interviews with trial coordinators regarding their roles, experiences, challenges and training. AB - Aims: To explore cancer trial coordinators' roles and challenges in administering patient-reported outcome (PRO) questionnaires, and establish what PRO-specific training and guidance they received and needed. Methods: Eligible cancer trial coordinators experienced with PRO assessment from approved Australian sites participated in an audio-recorded, semi-structured interview (transcribed verbatim). Recruitment continued until data saturation. Transcripts underwent content analysis. Results: Twenty coordinators participated (professional training: nursing (n = 12), science/research (n = 4), both (n = 4)). PRO administration formed a minor component of most (85%) coordinators' roles. PRO administration challenges included managing 'English second language' participants, participants' companions who attempted to complete questionnaires, burdensome questionnaires, and balancing their duty of care against trial requirements. Coordinators reported inconsistencies in PRO administration, which appeared to arise as a result of confusion and inconsistent or contradictory PRO training. Inconsistencies concerned whether/when they explained the purpose of PRO assessment, which participants they approached to complete PROs, and whether they used PRO trial data to inform care.Coordinators received PRO training from various sources; most commonly study-specific start-up meetings (45%) or from colleagues (30%). Two received no PRO-specific training. Despite the challenges reported, many (55%) felt they did not need further PRO training. Conclusion: Trial coordinators receive inconsistent PRO-specific training and are often unclear how to prioritise different aspects of data quality when faced with everyday challenges, leading to inconsistent methods, missing data, poor quality data, and even bias. Agreement on how coordinators should prioritise the requirements of PRO studies is a necessary pre-requisite for the development of much-needed, consensus-based PRO administration guidelines. PMID- 29696222 TI - Parents' perceived obstacles to pediatric clinical trial participation: Findings from the clinical trials transformation initiative. AB - Enrollment of children into pediatric clinical trials remains challenging. More effective strategies to improve recruitment of children into trials are needed. This study used in-depth qualitative interviews with parents who were approached to enroll their children in a clinical trial in order to gain an understanding of the barriers to pediatric clinical trial participation. Twenty-four parents whose children had been offered the opportunity to participate in a clinical trial were interviewed: 19 whose children had participated in at least 1 clinical trial and 5 who had declined participation in any trial. Each study aspect, from the initial explanation of the study to the end of the study, can affect the willingness of parents to consent to the proposed study and future studies. Establishing trust, appropriate timing, a transparent discussion of risks and benefits oriented to the layperson, and providing motivation for children to participate were key factors that impacted parents' decisions. In order for clinical trial accrual to be successful, parents' priorities and considerations must be a central focus, beginning with initial trial design. The recommendations from the parents who participated in this study can be used to support budget allocations that ensure adequate training of study staff and improved staffing on nights and weekends. Studies of parent responses in outpatient settings and additional inpatient settings will provide valuable information on the consent process from the child's and parent's perspectives. Further studies are needed to explore whether implementation of such strategies will result in improved recruitment for pediatric clinical trials. PMID- 29696223 TI - The effect of negative randomized trials and surgeon volume on the rates of arthroscopy for patients with knee OA. AB - Publication of 2 (negative) randomized clinical trials (RCTs) in 2002 and 2008 demonstrating inefficacy of arthroscopic debridement of the knee (ADK) for osteoarthritis, and a 2004 national non-coverage Medicare determination, have decreased overall ADK utilization. However, because of potentially favorable outcomes associated with high volume, surgeons performing high arthroscopy volume may be slower to abandon performing ADK than would low volume surgeons. We examined the trends in ADKs performed by high and low volume surgeons before and after these 2 trials and the Medicare determination. New York state residents 40 years and older undergoing outpatient ADK from 1997 to 2010 were identified from a statewide database, and monthly population-based age and sex-adjusted ADK rates were calculated. We estimated the change in utilization trends over time, stratified by surgeon annual arthroscopy volume, for Medicare and non-Medicare patients. 1386 surgeons performed 29,658 ADKs during the study period, with the proportion performed by high volume surgeons increasing from 22% in 1997 to 66% in 2010. Overall monthly ADK rates declined from 2.4 to 1.3 per 100,000 population (45%) over the study period. Rates of ADK performed by high volume surgeons increased after the first RCT in the non-Medicare population and after the CMS decision in the Medicare population, and decreased after the second RCT. With more definitive evidence from the second negative trial, high volume surgeons performed less ADKs, suggesting that multiple RCTs with consistently negative results are needed to change practice of high volume surgeons. PMID- 29696224 TI - Barriers to non-small cell lung cancer trial eligibility. AB - Introduction: Cancer clinical trial (CCT) enrollment is low potentially threatening the generalizability of trial results and expedited regulatory approvals. We assessed whether type of initial patient appointment for non-small cell lung cancer (NSCLC) is associated with CCT eligibility. Methods: Using a patient-to-accrual framework, we conducted a quasi-retrospective cohort pilot study at Sidney Kimmel Comprehensive Cancer Center (SKCCC), Baltimore, Maryland. 153 NSCLC patients new to SKCCC were categorized based on type of initial appointment: patients diagnosed or treated and patients seen for a consultation. CCT eligibility was determined by comparing eligibility criteria for each open trial to the electronic medical record (EMR) of each patient at every office visit occurring within 6-months of initial visit. Results: We found no association between type of initial appointment and CCT eligibility (OR, 1.15; 95% CI, 0.49-2.73). Analyses did suggest current smokers were less likely to be eligible for trials compared to never smokers (OR, 0.15; 95% CI, 0.03-0.64), and stage 4 patients with second line therapy or greater were more likely to be eligible than stage 1 or 2 patients (OR, 5.18; 95% CI, 1.08-24.75). Additional analyses suggested most current smokers and stage 1 or 2 patients had trials available but were still ineligible. Conclusions: SKCCC has a diverse portfolio of trials available for NSCLC patients and should consider research strategies to re-examine eligibility criteria for future trials to ensure increased enrollment of current smokers and stage 1 or 2 patients. We could not confirm whether type of initial visit was related to eligibility. PMID- 29696225 TI - LOGIS (LOcalization of Ground-glass-opacity and pulmonary lesions for mInimal Surgery) registry: Design and Rationale. AB - Background and purpose: An optimal pulmonary localization technique for video assisted thoracic surgery (VATS) of small lung nodules has not yet been established. The LOcalization of Ground-glass-opacity and pulmonary lesions for mInimal Surgery (LOGIS) registry aims to establish a multicenter database and investigate the usefulness and safety of localization techniques for small pulmonary lesions in individuals undergoing VATS. Methods/Design: The LOGIS registry is a large-scale, multicenter cohort study, aiming to enroll 825 patients at 10 institutions. Based on the inclusion and exclusion criteria, all study participants with pulmonary lesions indicated for VATS will be screened and enrolled at each site. All study participants will undergo preoperative lesion localization by the hook-wire or lipiodol localization methods according to site specific methods. Within a few hours of marking, thoracoscopic surgery will be done under general anesthesia by experienced thoracoscopic surgeons. The primary endpoints are the success and complication rates of the two localization techniques. Secondary endpoints include procedure duration, recurrence rate, and all-cause mortality. Study participant enrollment will be completed within 2 years. Procedure success rates and incidence of complications will be analyzed based on computed tomography findings. Procedure duration, recurrence rate, and all-cause mortality will be compared between the two techniques. The study will require 5 years for completion, including 6 months of preparation, 3.5 years for recruitment, and 1 year of follow-up endpoint assessment. Discussion: The LOGIS registry, once complete, will provide objective comparative results regarding the usefulness and safety of the lipiodol and hook-wire localization techniques. PMID- 29696226 TI - Where are they now? Retention strategies over 25 years in the Coronary Artery Risk Development in Young Adults (CARDIA) Study. AB - Purpose: In 1991, we described the recruitment and goals for a cohort of young adults. At the time, little was known about long-term retention of young, healthy and mobile adults or minorities. We present retention strategies and rates over 25 years, and predictors of participation at the year 25 follow-up examination of the Coronary Artery Risk Development in Young Adults (CARDIA) Study, a longitudinal investigation of coronary artery disease risk factors in a biracial population initially ages 18-30 years recruited from four U.S. centers in 1985. Methods: CARDIA has employed a range of strategies to enhance retention, including two contacts per year, multiple tracking methods to locate participants lost-to-follow-up, use of birthday and holiday cards, participant newsletters, examination scheduling accommodations and monetary reimbursements, and a standing committee whose primary purpose has been to continually review retention rates and strategies and identify problems and successes. Results: For 25 years, CARDIA has maintained >90% contact with participants between examinations, over 80% at any 2-year interval, and a 72% 25-year examination attendance rate. Baseline predictors of year 25 examination attendance include white race, female sex, older age, higher education, nonsmoking and moderate alcohol consumption. Conclusion: Consistent use of multiple retention strategies, including attention to contact rates and sharing of best strategies across study centers, has resulted in high retention of a diverse, initially young, biracial cohort. PMID- 29696227 TI - Long title: Protocol for evaluating a Consultation for Suffering at work in French-speaking Switzerland. AB - Introduction: Psychosocial suffering entails human, social and economic costs. In Switzerland, 34.4% of workers report chronic work-related stress. Our medical Consultation for Suffering at Work aims to preserve-or restore-the patient's capacity to act and make decisions after a diagnosis of work-related psychological suffering; it also aims to help employees get back to or remain at work. Our hypothesis is that the dynamic of the consultation itself and adherence to its medical advice are active factors of these results. Objectives: Understand changes in patients' work and health status 12 months after a Consultation for Suffering at Work. Determine the effects of the consultation on health and working status via identified active factors: the consultation dynamic and the ability to adhere to the consultation's advice. Evaluate the consultation's effects qualitatively. Materials and Methods: This longitudinal, monocentric study with a quasi-experimental design will include patients consulting between 1 January and 31 December 2018. Changes in patients' work and health status will be analysed using data collected via questionnaires at 0, 3 and 12 months. Qualitative data will be collected via a semi-structured telephone interview 3 months after the consultation. The quantitative part will include 150-170 patients; the qualitative part will include 30. Conclusion: This exploratory research project will provide a better understanding of issues of work-related psychological suffering and effective strategies to support patients. The absence of a control group and the impossibility of applying a randomised controlled design are constraints on this study. PMID- 29696228 TI - Serious adverse events of older adults in nursing home and community intervention trials. AB - Background/Aims: Clinical trials of older adults are increasingly common, but risks of serious adverse events (SAE) may vary. We describe the incidence of SAE in two randomized trials, one community-based and one nursing home-based. Methods: We performed a secondary data analysis from two randomized clinical trials at one academic health center and 21 nursing homes involving 200 sedentary community dwellers aged 70-89 years and 185 female nursing home residents aged 65 years or older. Interventions included structured physical activity to reduce mobility disability in the Lifestyle Interventions and Independence for Elders (LIFE) study and oral cranberry capsules to reduce bacteriuria plus pyuria in nursing home residents (CRANNY) trial. We measured SAE incidence per 100 person years and incidence of protocol-related unanticipated SAE per 100 person-years in LIFE and CRANNY trials. Results: Mean age and proportion of patients with dementia in LIFE and CRANNY trials were 79.3 years and 86.4 years and 0% and 78%, respectively. There were 179 total SAE in LIFE including 8 (4%) deaths, and 116 total SAE in CRANNY including 33 (28%) deaths. SAE incidence was 33.7 (95% CI 27.2, 41.8) events per 100 person-years in LIFE and 69.4 (95% CI 49.1, 98.1) events per 100 person-years in CRANNY. No protocol-related unanticipated SAE occurred in either trial. Conclusions: The frequency and severity of SAE vary in older adults. While SAE are common in nursing home residents, protocol-related, unanticipated SAE are rare in nursing home residents and community dwellers. This finding can inform trial monitoring protocols. Trial registration: ClinicalTrials.gov identifiers: NCT01072500 and NCT01691430. PMID- 29696229 TI - Total integrated performance excellence system (TIPES): A true north direction for a clinical trial support center. AB - This paper presents the quality journey taken by a Federal organization over more than 20 years. These efforts have resulted in the implementation of a Total Integrated Performance Excellence System (TIPES) that combines key principles and practices of established quality systems. The Center has progressively integrated quality system frameworks including the Malcom Baldrige National Quality Award (MBNQA) Framework and Criteria for Performance Excellence, ISO 9001, and the Organizational Project Management Maturity Model (OPM3), as well as supplemental quality systems of ISO 15378 (packaging for medicinal products) and ISO 21500 (guide to project management) to systematically improve all areas of operations. These frameworks were selected for applicability to Center processes and systems, consistency and reinforcement of complimentary approaches, and international acceptance. External validations include the MBNQA, the highest quality award in the US, continued registration and conformance to ISO standards and guidelines, and multiple VA and state awards. With a focus on a holistic approach to quality involving processes, systems and personnel, this paper presents activities and lessons that were critical to building TIPES and establishing the quality environment for conducting clinical research in support of Veterans and national health care. PMID- 29696230 TI - Willingness of older adults to participate in a randomized trial of conservative therapies for knee pain: A prospective preference assessment. AB - Background: In preparation for a trial of physical therapy (PT) for patients with degenerative meniscal tear and knee osteoarthritis, we conducted a prospective preference assessment -- a methodology for estimating the proportion of eligible subjects who would participate in a hypothetical randomized trial. Methods: We identified patients seeking care from the practices of five orthopedic surgeons. Patients completed a survey asking about their willingness to participate in a hypothetical trial, their treatment preferences, their knee pain, and demographic variables. Results: We approached 201 eligible patients, of whom 67% (95% confidence interval [CI] 60%, 73%) completed questionnaires. Of these, 24% (95% CI 17%, 31%) were definitely and 39% (95% CI 31%, 47%) were probably willing to participate in the trial. Thirty-three percent (95% CI 23%, 43%) of subjects with no treatment preference were definitely willing to participate as compared to 9% (95% CI 1%, 17%) with treatment preference (p = .001). Patients with higher educational attainment also stated a greater willingness to participate than those with less education (p = .06). In multivariable logistic regression analysis, those with no treatment preferences had greater adjusted odds of stating they would definitely participate than those with a defined treatment preference (OR 5.2, 95% CI 1.7, 16.2), while subjects with an associate's degree or greater were more likely to state they would definitely participate than those with less education (OR 3.9, 95% CI 1.1, 14.1). Conclusion: In this prospective preference assessment, 63% (95% CI 55%, 71%) of subjects with degenerative meniscal tear expressed willingness to participate in a trial of PT modalities. Individuals with no treatment preferences were more likely to state they would participate than were those with higher education. This methodology can help investigators estimate recruitment rates, anticipate generalizability of the trial sample and create strategies to facilitate enrollment. PMID- 29696232 TI - Quantifying and visualizing site performance in clinical trials. AB - Background: One of the keys to running a successful clinical trial is the selection of high quality clinical sites, i.e., sites that are able to enroll patients quickly, engage them on an ongoing basis to prevent drop-out, and execute the trial in strict accordance to the clinical protocol. Intuitively, the historical track record of a site is one of the strongest predictors of its future performance; however, issues such as data availability and wide differences in protocol complexity can complicate interpretation. Here, we demonstrate how operational data derived from central laboratory services can provide key insights into the performance of clinical sites and help guide operational planning and site selection for new clinical trials. Methods: Our methodology uses the metadata associated with laboratory kit shipments to clinical sites (such as trial and anonymized patient identifiers, investigator names and addresses, sample collection and shipment dates, etc.) to reconstruct the complete schedule of patient visits and derive insights about the operational performance of those sites, including screening, enrollment, and drop-out rates and other quality indicators. This information can be displayed in its raw form or normalized to enable direct comparison of site performance across studies of varied design and complexity. Results: Leveraging Covance's market leadership in central laboratory services, we have assembled a database of operational metrics that spans more than 14,000 protocols, 1400 indications, 230,000 unique investigators, and 23 million patient visits and represents a significant fraction of all clinical trials run globally in the last few years. By analyzing this historical data, we are able to assess and compare the performance of clinical investigators across a wide range of therapeutic areas and study designs. This information can be aggregated across trials and geographies to gain further insights into country and regional trends, sometimes with surprising results. Conclusions: The use of operational data from Covance Central Laboratories provides a unique perspective into the performance of clinical sites with respect to many important metrics such as patient enrollment and retention. These metrics can, in turn, be used to guide operational planning and site selection for new clinical trials, thereby accelerating recruitment, improving quality, and reducing cost. PMID- 29696231 TI - Interval estimation of the overall treatment effect in a meta-analysis of a few small studies with zero events. AB - When a meta-analysis consists of a few small trials that report zero events, accounting for heterogeneity in the (interval) estimation of the overall effect is challenging. Typically, we predefine meta-analytical methods to be employed. In practice, data poses restrictions that lead to deviations from the pre-planned analysis, such as the presence of zero events in at least one study arm. We aim to explore heterogeneity estimators behaviour in estimating the overall effect across different levels of sparsity of events. We performed a simulation study that consists of two evaluations. We considered an overall comparison of estimators unconditional on the number of observed zero cells and an additional one by conditioning on the number of observed zero cells. Estimators that performed modestly robust when (interval) estimating the overall treatment effect across a range of heterogeneity assumptions were the Sidik-Jonkman, Hartung Makambi and improved Paul-Mandel. The relative performance of estimators did not materially differ between making a predefined or data-driven choice. Our investigations confirmed that heterogeneity in such settings cannot be estimated reliably. Estimators whose performance depends strongly on the presence of heterogeneity should be avoided. The choice of estimator does not need to depend on whether or not zero cells are observed. PMID- 29696233 TI - Facilitators and barriers to the successful implementation of pediatric antibacterial drug trials: Findings from CTTI's survey of investigators. AB - An urgent need exists to develop new antibacterial drugs for children. We conducted research with investigators of pediatric antibacterial drug trials to identify facilitators and barriers in the conduct of these trials. Seventy-three investigators completed an online survey assessing the importance of 15 facilitators (grouped in 5 topical categories) and the severity of 36 barriers (grouped in 6 topical categories) to implementing pediatric antibacterial drug trials. Analysis focused on the identification of key factors that facilitate the successful implementation of pediatric antibacterial drug trials and the key barriers to implementation. Almost all investigators identified two factors as very important facilitators: having site personnel for enrollment and having adequate funding. Other top factors were related to staffing. Among the barriers, factors related to parent concerns and consent were prominent, particularly obtaining parental consent when there was disagreement between parents, concerns about the number of blood draws, and concerns about the number of invasive procedures. Having overly narrow eligibility criteria was also identified as a major barrier. The survey findings suggest three areas in which to focus efforts to help facilitate ongoing drug development: (1) improving engagement with parents of children who may be eligible to enroll in a pediatric antibacterial drug trial, (2) broadening inclusion criteria to allow more participants to enroll, and (3) ensuring adequate staffing and establishing sustainable financial strategies, such as funding pediatric trial networks. The pediatric antibacterial drug trials enterprise is likely to benefit from focused efforts by all stakeholders to remove barriers and enhance facilitation. PMID- 29696234 TI - Reduce bladder cancer recurrence in patients treated for upper urinary tract urothelial carcinoma: The REBACARE-trial. AB - Background: Following radical nephro-ureterectomy for urothelial carcinoma of the upper urinary tract (UUT), the reported bladder recurrence rate of urothelial carcinoma is 22-47%. A single intravesical instillation of chemotherapy within 10 days following nephro-ureterectomy has the potential to decrease the risk of a bladder recurrence significantly. Despite recommendation by the European Association of Urology guideline to administer a single instillation postoperatively, the compliance rate is low because the risk of extravasation of chemotherapy. Aim: To reduce the risk of bladder cancer recurrence by a single intravesical instillation of Mitomycin immediately (within 3 h) before radical nephro-ureterectomy or partial ureterectomy. Methods: Adult patients (age >= 18 years) with a (suspicion of a) urothelial carcinoma of the UUT undergoing radical nephro-ureterectomy or partial ureterectomy will be eligible and will receive a single intravesical instillation of Mitomycin within 3 h before surgery. In total, 170 patients will be included in this prospective, observational study. Follow-up will be according to current guidelines. Results: The primary endpoint is the bladder cancer recurrence rate up to two years after surgery. Secondary endpoints are: a) the compliance rate; b) oncological outcome; c) possible side effects; d) the quality of life; e) the calculation of costs of a single neoadjuvant instillation with Mitomycin and f) molecular characterization of UUT tumors and intravesical recurrences. Conclusions: A single intravesical instillation of Mitomycin before radical nephro-ureterectomy or partial ureterectomy may reduce the risk of a bladder recurrence in patients treated for UUT urothelial carcinoma and will circumvent the disadvantages of current therapy. PMID- 29696235 TI - Exclusion criteria and generalizability in bipolar disorder treatment trials. AB - Objective: The current paper reviews the English-language research on exclusion criteria in bipolar disorder treatment trials and discusses how study samples compare to the general bipolar patient population. Methods: & Results: Across 8 identified studies of exclusion criteria and their impact, between 55% and 96% of people with bipolar disorder would be excluded from treatment research. The number of exclusion criteria varies across bipolar disorder treatment research, with one study estimate of a median of 7 criteria used across studies. The criteria that excluded the greatest number of potential participants were comorbid substance use disorder, suicidal risk, and comorbid medical conditions. Both studies that compared treatment responses among participants who met and did not meet exclusion criteria found no statistically significant differences. Conclusions: Most potential participants are excluded from outcome research, which creates challenges for recruitment and limits generalizability of study findings. Common exclusionary practices lead to unrepresentative samples that limit generalizability and reduce the confidence of clinicians that findings can be translated to front-line practice with bipolar disorder patients. PMID- 29696236 TI - Temporal trends and characteristics of clinical trials for which only one racial or ethnic group is eligible. AB - Background: Increasing diversity in clinical trials may be worthwhile. We examined clinical trials that restricted eligibility to a single race or ethnicity. Methods: We reviewed 19,246 trials registered on ClinicalTrials.gov through January 2013. We mapped trial ZIP-codes to U.S. Census and American Community Survey data. The outcome was whether trials required participants to be from a single racial or ethnic group. Results: In adjusted analyses, the odds of trials restricting eligibility to a single race/ethnicity increased by 4% per year (95% CI 1.01-1.08, p = .024). Behavioral (5.79% with single race/ethnicity requirements), skin-related (4.49%), and Vitamin D (6.14%) studies had higher rates of single race/ethnicity requirements. Many other trial-specific characteristics, such as funding agency and region of the U.S. in which the trial opened, were associated with eligibility restrictions. In terms of neighborhood characteristics, studies with single race eligibility requirements were more likely to be located in ZIP-codes with greater percentages of those self reporting the characteristic. For example, 35.2% (SD = 24.9%) of the population self-reported themselves as Black or African American in ZIP-codes with trials requiring participants to be Black/African American, but only 5.9% (SD = 6.9%) self-reported themselves as Black/African American in ZIP-codes with trials that required Asian ethnicity. In ZIP-codes with trials requiring Asian ethnicity, 24.6% (SD = 16.2%) self-reported as Asian. In ZIP-codes with trials requiring Hispanic/Latino ethnicity, 33.3% (SD = 28.5%) self-reported as Hispanic/Latino. Neighborhood level poverty rates and reduced English language ability were also associated with more single race eligibility requirements. Conclusions: In selected fields, there has been a modest temporal increase in single race/ethnicity inclusion requirements. Some studies may not fall under regulatory purview and hence may be less likely to include diverse samples. Conversely, some eligibility requirements may be related to health disparities research. Future work should examine whether targeted enrollment criteria facilitates development of personalized medicine or reduces trial access. PMID- 29696237 TI - The "Interval Walking in Colorectal Cancer" (I-WALK-CRC) study: Design, methods and recruitment results of a randomized controlled feasibility trial. AB - Background: Low physical activity level is associated with poor prognosis in patients with colorectal cancer (CRC). To increase physical activity, technology based platforms are emerging and provide intriguing opportunities to prescribe and monitor active lifestyle interventions. The "Interval Walking in Colorectal Cancer"(I-WALK-CRC) study explores the feasibility and efficacy a home-based interval-walking intervention delivered by a smart-phone application in order to improve cardio-metabolic health profile among CRC survivors. The aim of the present report is to describe the design, methods and recruitment results of the I-WALK-CRC study.Methods/Results: The I-WALK-CRC study is a randomized controlled trial designed to evaluate the feasibility and efficacy of a home-based interval walking intervention compared to a waiting-list control group for physiological and patient-reported outcomes. Patients who had completed surgery for local stage disease and patients who had completed surgery and any adjuvant chemotherapy for locally advanced stage disease were eligible for inclusion. Between October 1st, 2015, and February 1st, 2017, 136 inquiries were recorded; 83 patients were eligible for enrollment, and 42 patients accepted participation. Age and employment status were associated with participation, as participants were significantly younger (60.5 vs 70.8 years, P < 0.001) and more likely to be working (OR 5.04; 95%CI 1.96-12.98, P < 0.001) than non-participants. Conclusion: In the present study, recruitment of CRC survivors was feasible but we aim to better the recruitment rate in future studies. Further, the study clearly favored younger participants. The I-WALK-CRC study will provide important information regarding feasibility and efficacy of a home-based walking exercise program in CRC survivors. PMID- 29696238 TI - A gender- and culturally-sensitive weight loss intervention for Hispanic males: The ANIMO randomized controlled trial pilot study protocol and recruitment methods. AB - : Hispanic men have the highest rates of overweight and obesity when compared to men of other racial/ethnic groups, placing them at increased risk for obesity related disease. Yet, Hispanic men are grossly underrepresented in weight loss research. Tailored intervention strategies to improve obesity treatment programs for this vulnerable racial/ethnic subgroup are needed. This manuscript describes recruitment strategies, methodology, and participant characteristics of the ANIMO study, a 24-week randomized controlled pilot trial testing the effects of a gender- and culturally-sensitive weight loss intervention (GCSWLI) on body weight in Hispanic men compared to a wait-list control condition. The ANIMO study included two phases. The first phase was a 12-week GCSWLI. Participants attended weekly in-person individual sessions guided by a trained bilingual Hispanic male lifestyle coach, were prescribed a daily reduced calorie goal, and 225 min of moderate-intensity physical activity per week. In the second phase, GCSWLI participants received bi-weekly phone calls across a 12-week follow-up. Wait-list control (WLC) participants from phase 1 received the GCSWLI plus mobile health technology support. Recruitment strategies included face-to-face efforts at a swap meet (outdoor marketplace), family/friend referrals, printed advertisements and social media. Recruitment, screening, and participant enrollment occurred over three months. Overall, 143 men expressed interest in participation. Of these, 115 were screened and 78% (n = 90) were eligible to participate; 45% of enrolled participants (n = 52) completed baseline assessments and 43% (n = 50) were randomized (mean age of 43.3 +/- 11.4 years; BMI: 34.1 +/- 5.3 kg/m2; 58% Spanish monolingual). Parameter estimates from ANIMO will support future adequately powered trials for this health disparate population. Trial registration: ClinicalTrials.gov: NCT02783521. PMID- 29696239 TI - Effects and mechanism of the HECT study (hybrid exercise-cognitive trainings) in mild ischemic stroke with cognitive decline: fMRI for brain plasticity, biomarker and behavioral analysis. AB - Purpose: Cognitive decline after stroke is highly associated with functional disability. Empirical evidence shows that exercise combined cognitive training may induce neuroplastic changes that modulate cognitive function. However, it is unclear whether hybridized exercise-cognitive training can facilitate cortical activity and physiological outcome measures and further influence on the cognitive function after stroke. This study will investigate the effects of two hybridized exercise-cognitive trainings on brain plasticity, physiological biomarkers and behavioral outcomes in stroke survivors with cognitive decline. Methods and significance: This study is a single-blind randomized controlled trial. A target sample size of 75 participants is needed to obtain a statistical power of 95% with a significance level of 5%. Stroke survivors with mild cognitive decline will be stratified by Mini-Mental State Examination scores and then randomized 1:1:1 to sequential exercise-cognitive training, dual-task exercise-cognitive training or control groups. All groups will undergo training 60 min/day, 3 days/week, for a total of 12 weeks. The primary outcome is the resting-state functional connectivity and neural activation in the frontal, parietal and occipital lobes in functional magnetic resonance imaging. Secondary outcomes include physiological biomarkers, cognitive functions, physical function, daily functions and quality of life. This study may differentiate the effects of two hybridized trainings on cognitive function and health-related conditions and detect appropriate neurological and physiological indices to predict training effects. This study capitalizes on the groundwork for a non pharmacological intervention of cognitive decline after stroke. PMID- 29696240 TI - Research site mentoring: A novel approach to improving study recruitment. AB - Background/Aims: The VA Cooperative Studies Program's (CSP) Network of Dedicated Enrollment Sites (NODES) is a consortium of nine VA medical centers (VAMCs) with teams (nodes) dedicated to enhance performance, compliance, and management of CSP multi-site clinical trials. The West Haven CSP Coordinating Center (WH-CSPCC), study coordinating center for CSP #577, Colonoscopy Versus Fecal Immunochemical Test (FIT) in Reducing Mortality from Colorectal Cancer (CONFIRM) trial, and NODES piloted a "site mentoring" (hub-and-spoke) model. In this model, a node site would work one-on-one with a low enrolling CONFIRM site to identify and overcome barriers to recruitment. The aim was to determine the impact of a research site mentoring model on study recruitment and examine site-level characteristics that facilitate or impede it. Results: Sites in the mentorship pilot had an average improvement of 5 +/- 4 participants randomized per month (min -2.6; max 11.6; SD 4.3). Four of ten sites (40%) demonstrated continuous improvement in the average number of randomized participants per month after the pilot intervention and at three-month follow-up (post-intervention), as compared to the five-month period preceding the intervention. An additional two sites (20%) demonstrated improvement in the average number of randomized participants per month after the pilot intervention, and sustained that level of improvement at three-month follow-up (post-intervention). Additionally, six of ten sites (60%) demonstrated an increased number of participants screened for eligibility immediately following the intervention and at three-month follow-up (post intervention). Only one site showed a decreased monthly average of randomized participants shortly after the intervention and through the three-month follow-up period. Conclusions: The site mentoring model was successful in improving recruitment at low enrolling CONFIRM sites. An additional feasibility assessment is needed to determine if this mentoring model will be effective with other CSP trials. PMID- 29696242 TI - Fibroblast Growth Factor 23-Induced Hypophosphatemia in Acute Leukemia. AB - Fibroblast growth factor 23 (FGF23)-induced hypophosphatemia is a rare paraneoplastic syndrome of phosphate wasting that, if unrecognized, may cause tumor-induced osteomalacia. It is classically associated with benign mesenchymal tumors but occasionally has been found in patients with other malignancies. Hypophosphatemia has been associated with acute leukemia but has not previously been reported to be due to inappropriate FGF23 secretion. Here, we describe FGF23 induced severe hypophosphatemia and renal phosphate wasting associated with a mixed-phenotype Philadelphia chromosome-like acute leukemia in a previously healthy 22-year-old man. He was found to have low serum 1,25-dihydroxyvitamin D and extremely high FGF23 levels, as well as inappropriate urinary phosphorus excretion. The hypophosphatemia improved with calcitriol and oral phosphate treatment but normalized only during chemotherapy-induced ablation of the blasts. FGF23 levels declined with a reduction in peripheral blast counts. Using real time reverse transcription polymerase chain reaction, we found that the leukemia cells were the source of FGF23. To our knowledge, this is the first description of FGF23-induced hypophosphatemia associated with acute leukemia. We recommend that the FGF23 paraneoplastic syndrome be considered as a possible etiology of hypophosphatemia in patients with acute leukemia. PMID- 29696241 TI - Blood Pressure and Metabolic Effects of Acetyl-l-Carnitine in Type 2 Diabetes: DIABASI Randomized Controlled Trial. AB - Context: Acetyl-l-carnitine (ALC), a mitochondrial carrier involved in lipid oxidation and glucose metabolism, decreased systolic blood pressure (SBP), and ameliorated insulin sensitivity in hypertensive nondiabetic subjects at high cardiovascular risk. Objective: To assess the effects of ALC on SBP and glycemic and lipid control in patients with hypertension, type 2 diabetes mellitus (T2D), and dyslipidemia on background statin therapy. Design: After 4-week run-in period and stratification according to previous statin therapy, patients were randomized to 6-month, double-blind treatment with ALC or placebo added-on simvastatin. Setting: Five diabetology units and one clinical research center in Italy. Patients: Two hundred twenty-nine patients with hypertension and dyslipidemic T2D >40 years with stable background antihypertensive, hypoglycemic, and statin therapy and serum creatinine <1.5 mg/dL. Interventions: Oral ALC 1000 mg or placebo twice daily on top of stable simvastatin therapy. Outcome and Measures: Primary outcome was SBP. Secondary outcomes included lipid and glycemic profiles. Total-body glucose disposal rate and glomerular filtration rate were measured in subgroups by hyperinsulinemic-euglycemic clamp and iohexol plasma clearance, respectively. Results: SBP did not significantly change after 6-month treatment with ALC compared with placebo (-2.09 mm Hg vs -3.57 mm Hg, P = 0.9539). Serum cholesterol, triglycerides, and lipoprotein(a), as well as blood glucose, glycated hemoglobin, fasting insulin levels, homeostatic model assessment of insulin resistance index, glucose disposal rate, and glomerular filtration rate did not significantly differ between treatments. Adverse events were comparable between groups. Conclusions: Six-month oral ALC supplementation did not affect blood pressure, lipid and glycemic control, insulin sensitivity and kidney function in hypertensive normoalbuminuric and microalbuminuric T2D patients on background statin therapy. PMID- 29696243 TI - Racial/Ethnic Disparities in Cervical Cancer Screening Services Among Contractors of the Connecticut Breast and Cervical Cancer Early Detection Program. AB - Purpose: Racial/ethnic minority women are at increased risk for cervical cancer. The objective of this study is to use performance management data from the Connecticut Breast and Cervical Cancer Early Detection Program (CBCCEDP) to determine whether race/ethnicity disparities exist in human papillomavirus (HPV) co-testing uptake across CBCCEDP contractors. Methods: Secondary analysis of Connecticut's Minimum Data Elements data for 2013-2015 among 10 contractors participating in the CBCCEDP. Participants included women aged 30-64 years and eligible to receive routine cervical cancer screening services through the CBCCEDP (n=5,262). HPV co-testing uptake was compared across contractors and race/ethnicity groups within each contractor using chi-square and Fisher's exact tests as appropriate. Results: Overall, 62.9% of women received HPV co-testing services. Significant differences in co-testing rates were detected between racial/ethnic groups when data were examined across all contractors (p<0.001). Black women were least likely to receive co-testing (49.1%), while Hispanic women were most likely to receive co-testing (68.2%). When data were examined at the individual contractor level, significant differences between racial/ethnic groups were observed in 50% of the contractors. Conclusions: This study identified racial/ethnic disparities in uptake of HPV co-testing both overall and within individual contractors involved in the CBCCEDP. These findings will be used to guide program improvement with the goal of increasing quality and consistency of care for all women seeking screening services. PMID- 29696244 TI - A discontinuous Poisson-Boltzmann equation with interfacial jump: homogenisation and residual error estimate. AB - A nonlinear Poisson-Boltzmann equation with inhomogeneous Robin type boundary conditions at the interface between two materials is investigated. The model describes the electrostatic potential generated by a vector of ion concentrations in a periodic multiphase medium with dilute solid particles. The key issue stems from interfacial jumps, which necessitate discontinuous solutions to the problem. Based on variational techniques, we derive the homogenisation of the discontinuous problem and establish a rigorous residual error estimate up to the first-order correction. PMID- 29696245 TI - Longitudinal Genotype-Phenotype Association Study via Temporal Structure Auto Learning Predictive Model. AB - With rapid progress in high-throughput genotyping and neuroimaging, imaging genetics has gained significant attention in the research of complex brain disorders, such as Alzheimer's Disease (AD). The genotype-phenotype association study using imaging genetic data has the potential to reveal genetic basis and biological mechanism of brain structure and function. AD is a progressive neurodegenerative disease, thus, it is crucial to look into the relations between SNPs and longitudinal variations of neuroimaging phenotypes. Although some machine learning models were newly presented to capture the longitudinal patterns in genotype-phenotype association study, most of them required fixed longitudinal structures of prediction tasks and could not automatically learn the interrelations among longitudinal prediction tasks. To address this challenge, we proposed a novel temporal structure auto-learning model to automatically uncover longitudinal genotype-phenotype interrelations and utilized such interrelated structures to enhance phenotype prediction in the meantime. We conducted longitudinal phenotype prediction experiments on the ADNI cohort including 3,123 SNPs and 2 types of biomarkers, VBM and FreeSurfer. Empirical results demonstrated advantages of our proposed model over the counterparts. Moreover, available literature was identified for our top selected SNPs, which demonstrated the rationality of our prediction results. An executable program is available online at https://github.com/littleq1991/sparse_lowRank_regression. PMID- 29696246 TI - Chemoselective deoxygenation of ether-substituted alcohols and carbonyl compounds by B(C6F5)3-catalyzed reduction with (HMe2SiCH2)2. AB - B(C6F5)3-catalyzed deoxygenation of ether-substituted alcohols and carbonyl compounds has been developed using (HMe2SiCH2)2 as the reductant. This unique reagent shows distinct superiority over traditional one silicon-centered hydrosilanes, giving the corresponding alkanes in high yields with good tolerance of ethers, aryl halides and alkenes. The control experiments suggest that (HMe2SiCH2)2 might facilitate the approach in an intramolecular Si/O activation manner. PMID- 29696247 TI - Controlled aggregation of DNA functionalized poly(phenylene-vinylene). AB - The morphology of conjugated polymers strongly influences their optical and electronic properties and affects their performance in polymer devices. Using optical spectroscopy and atomic force microscopy, we investigate the fluorescence properties and the aggregation state of DNA-functionalized poly(phenylene vinylene). We show that polymer aggregation can be controlled in solution through ion and DNA interactions; aggregation is induced in the presence of divalent cations and can be reversed by adding sequence specific DNA. These interactions provide ways to tune polymer aggregation on the timescale of minutes and allows tuning of the polymer's optical properties. PMID- 29696248 TI - Broadband graphene-based photoacoustic microscopy with high sensitivity. AB - Photoacoustic microscopy (PAM) enables the measurement of properties associated with optical absorption within tissues and complements sophisticated technologies employing optical microscopy. An inadequate frequency response as determined by a piezoelectric ultrasonic transducer results, however, in poor depth resolution and inaccurate measurements of the coefficients of optical absorption. We developed a PAM system configured as an attenuated total reflectance sensor with a ten-layer graphene film sandwiched between a prism and water (the coupling medium) for photoacoustic (PA) wave detection. Transients of the PA pressure cause perturbations in the refractive index of the water thereby changing the polarization-dependent absorption of the graphene film. The signal in PA detection involves recording the difference in the temporal-varying reflectance intensity between the two orthogonally polarized probe beams. The graphene-based sensor has an estimated noise-equivalent-pressure sensitivity of ~550 Pa over an approximately linear pressure response from 11.0 kPa to 55.0 kPa. Moreover, it enables a much broader PA bandwidth detection of up to ~150 MHz, primarily dominated by a highly localized evanescent field. From the strong optical absorption of inherent hemoglobin, in vivo label-free PAM imaging provided a three-dimensional viewing of the microvasculature of a mouse ear. These results suggest great potential for graphene-based PAM in biomedical investigations, such as microcirculation studies. PMID- 29696249 TI - Is a cross-beta-sheet structure of low molecular weight peptides necessary for the formation of fibrils and peptide hydrogels? AB - Short peptides have emerged as versatile building blocks for supramolecular structures and hydrogels. In particular, the presence of aromatic amino acid residues and/or aromatic end groups is generally considered to be a prerequisite for initiating aggregation of short peptides into nanotubes or cross beta-sheet type fibrils. However, the cationic GAG tripeptide surprisingly violates these rules. Specifically, in water/ethanol mixtures, GAG peptides aggregate into very long crystalline fibrils at temperatures below 35 degrees C where they eventually form a spanning network structure and, thus, a hydrogel. Two gel phases are formed in this network, and they differ substantially in chirality and thickness of the underlying fibrils, their rheological parameters, and the kinetics of oligomerization, fibrilization, and gel formation. The spectroscopic data strongly suggests that the observed fibrils do not exhibit canonical cross beta-sheet structures and are indicative of a yet unknown secondary conformation. To complement our unusual experimental observations in this perspective article, we performed large-scale DFT calculations to probe the geometry and spectroscopic properties of these GAG oligomers. Most importantly, our experimental and computational results yield rather unconventional structures that are not reminiscent of classical cross-beta-sheet structures, and we give two extremely likely candidates for oligomer structures that are consistent with experimental amide I' profiles in IR and vibrational circular dichroism (VCD) spectra of the two gel phases. PMID- 29696252 TI - Stereochemistry-dependent structure of hydrogen-bonded protonated dimers: the case of 1-amino-2-indanol. AB - To understand the role of chirality in shaping biological supramolecular systems it is instructive to visualize the subtle effects of stereochemistry on the structure of model aggregates at the molecular level. Here, we apply conformer specific IR-UV double-resonance laser spectroscopy in a cold ion trap to derive a detailed description of the protonated homodimers of (1R,2S)-cis- and (1R,2R) trans-1-amino-2-indanol (c-AI2H+, t-AI2H+). Although the protonated monomers (c AIH+, t-AIH+) only differ by the chirality of one carbon atom, their conformations are clearly distinct. c-AIH+ has an intramolecular NH+O hydrogen bond (H-bond), while t-AIH+ lacks such an interaction. This has crucial consequences on the geometry and stability of the corresponding c-AI2H+ and t AI2H+ dimers. While there is a competition between intra- and intermolecular H bonds in c-AI2H+, the formation of t-AI2H+ does not require deformation of the monomers. This difference results in higher binding energies of t-AI2H+ compared to c-AI2H+. To optimize the H-bond network, the two dimers do not necessarily involve the corresponding most stable monomers. c-AI2H+ and t-AI2H+ differ in their UV photodissociation mass spectra and in their electronic spectra, which suggests different geometries also in the excited state. PMID- 29696253 TI - The surface rheological signature of the geometric isomers of an azobenzene surfactant. AB - The equilibrium and dynamic surface properties of a photosensitive azobenzene surfactant subject to illumination with UV and Vis-light leading to the respective geometric cis- and trans-isomers were studied. The adsorption layers formed by the soluble surfactant were characterized by pendant drop tensiometry and surface rheology using the oscillating bubble technique. Aqueous solutions corresponding to the geometric isomers could clearly be distinguished in terms of both their equilibrium and dynamic surface properties. The frequency dependence of the surface dilatational modulus could be described by the extended Lucassen van den Tempel (LvdT)-model. These findings can be interpreted in terms of the changes of the dipole moment. Furthermore, they shed some light on the relation between the molecular structure and macroscopic properties of the adsorption layer. PMID- 29696254 TI - Photodissociation of CF2ICF2I in solid para-hydrogen: infrared spectra of anti- and gauche-C2F4I radicals. AB - The photolysis of 1,2-diiodotetrafluoroethane (CF2ICF2I) has served as a prototypical system in ultrafast reaction dynamics. Even though the intermediates, anti- and gauche-iodotetrafluoroethyl (C2F4I) radicals, have been characterized with electron diffraction and X-ray diffraction, their infrared spectra are unreported. We report the formation and infrared identification of these radical intermediates upon ultraviolet photodissociation of CF2ICF2I in solid para-hydrogen (p-H2) at 3.3 K. Lines at 1364.9/1358.5, 1283.2, 1177.1, 1162.2, 1126.8, 837.3, 658.0, 574.2, and 555.2 cm-1 are assigned to anti-C2F4I, and lines at 1325.9, 1259.7, 1143.4, 1063.4, 921.0, and 765.3 cm-1 to gauche C2F4I. A secondary photodissociation leading to C2F4 was also observed. The assignments were derived according to behavior on secondary photolysis, comparison of the vibrational wavenumbers and the IR intensities of the observed lines with values predicted with the B3PW91/aug-cc-pVTZ-pp method. This spectral identification provides valuable information for future direct spectral probes of these important intermediates. PMID- 29696257 TI - CB3E2q (q = +/-1): a family of "hyparene" analogues with a planar pentacoordinate carbon. AB - A CB3 moiety extracted from the building units of milestone "hyparenes" (families of species with a planar pentacoordinate carbon (ppC)) was found to be a more basic building block, which can be employed to design a family of "hyparene" analogues CB3E2q (q = +/-1) also with a ppC. The majority of main group elements can feasibly serve as the E atom. Despite the number of valence electrons, the ppC atoms in the CB3E2q (q = +/-1) species were involved in three delocalized sigma orbitals and a delocalized pi orbital, so the carbon atom obeys the octet rule. The NICS studies indicated that these ppC structures are sigma and pi double aromatic. Given that most of them are less favourable in energy than their boron-centered isomers, it is remarkable that the global minimum of CB3Mg2- adopts the ppC arrangement. Such a ppC structure is also kinetically stable. Compared to previously reported anionic ppC global minima, CB3Mg2- does not contain hyper toxic beryllium and thus is much more attractive to our experimental colleagues for realizing the ppC species using negative ion photoelectron detachment spectroscopy. PMID- 29696258 TI - A label-free and blocker-free photoelectrochemical strategy for highly sensitive caspase-3 assay. AB - Herein, a new label-free and blocker-free photoelectrochemical (PEC) sensor based on bifunctional CC-DEVD-peptide modified nitrogen-doped porous carbon-ZnO nanopolyhedra/CdS hybrids is developed for highly sensitive caspase-3 assay. The developed PEC sensor shows a low detection limit of about 0.14 ng mL-1 and has promising applications in the apoptosis-associated study. PMID- 29696259 TI - Assessing the scalability of low conductivity substrates for photo-electrodes via modelling of resistive losses. AB - When scaling up photo-electrochemical processes to larger areas than conventionally studied in the laboratory, substrate performance must be taken into consideration and in this work, a methodology to assess this via an uncomplicated 2 dimensional model is outlined. It highlights that for F-doped SnO2 (FTO), which is ubiquitously used for metal oxide photoanodes, substrate performance becomes significant for moderately sized electrodes (5 cm) under no solar concentration for state of the art Fe2O3 thin films. It is demonstrated that when the process is intensified via solar concentration, current losses become quickly limiting. Methodologies to reduce the impact of substrate ohmic losses are discussed and a new strategy is proposed. Due to the nature of the photo-electrode current-potential relationship, operation at a higher potential where the photo-current saturates (before the dark current is observed) will lead to a minimum in current loss due to substrate performance. Crucially, this work outlines an additional challenge in scaling up photo-electrodes based on low conductivity substrates, and establishes that such challenges are not insurmountable. PMID- 29696266 TI - Plasmon-induced nonlinear response of silver atomic chains. AB - Nonlinear response of a linear silver atomic chain upon ultrafast laser excitation has been studied in real time using the time-dependent density functional theory. We observe the presence of nonlinear responses up to the fifth order in tunneling current, which is ascribed to the excitation of high-energy electrons generated by Landau damping of plasmons. The nonlinear effect is enhanced after adsorption of polar molecules such as water due to the enhanced damping rates during plasmon decay. Increasing the length of atomic chains also increases the nonlinear response, favoring higher-order plasmon excitation. These findings offer new insights towards a complete understanding and ultimate control of plasmon-induced nonlinear phenomena to atomic precision. PMID- 29696267 TI - Rhodium-catalyzed asymmetric hydroboration of gamma,delta-unsaturated amide derivatives: delta-borylated amides. AB - gamma,delta-Unsaturated amides in which the alkene moiety bears an aryl or heteroaryl substituent undergo regioselective rhodium-catalyzed delta-borylation by pinacolborane to afford chiral secondary benzylic boronic esters. The results contrast the gamma-borylation of gamma,delta-unsaturated amides in which the disubstituted alkene moiety bears only alkyl substituents; the reversal in regiochemistry is coupled with a reversal in the sense of pi-facial selectivity. PMID- 29696268 TI - Ligand removal and photo-activation of CsPbBr3 quantum dots for enhanced optoelectronic devices. AB - Perovskite quantum dots have recently emerged as a promising light source for optoelectronic applications. However, integrating them into devices while preserving their outstanding optical properties remains challenging. Due to their ionic nature, perovskite quantum dots are extremely sensitive and degrade on applying the simplest processes. To maintain their colloidal stability, they are surrounded by organic ligands; these prevent efficient charge carrier injection in devices and have to be removed. Here we report on a simple method, where a moderate thermal process followed by exposure to UV in air can efficiently remove ligands and increase the photo-luminescence of the room temperature synthesized perovskite quantum dot thin films. Annealing is accompanied by a red shift of the emission wavelength, usually attributed to the coalescence and irreversible degradation of the quantum dots. We show that it is actually related to the relaxation of the quantum dots upon the ligand removal, without the creation of non-radiative recombining defects. The quantum dot surface, as devoid of ligands, is subsequently photo-oxidized and smoothened upon exposure to UV in air, which drastically enhances their photo-luminescence. This adequate combination of treatments improves by more than an order of magnitude the performances of perovskite quantum dot light emitting diodes. PMID- 29696269 TI - Synthesis of CF3-containing spiro-epoxyoxindoles via the Corey-Chaykovsky reaction of N-alkyl isatins with Ph2S+CH2CF3OTf. AB - CF3-containing spiro-epoxyoxindoles were successfully prepared via the Corey Chaykovsky reaction of N-alkyl isatins with the ylide generated from Ph2S+CH2CF3OTf- with almost exclusive diastereoselectivity. Further derivatizations of these spiro-epoxyoxindoles were explored via a photochemical reaction or Lewis acid-promoted allylation. PMID- 29696270 TI - ATR-IR coupled to partial least squares regression (PLSR) for monitoring an encapsulated active molecule in complex semi-solid formulations. AB - Attenuated Total Reflectance-Infrared (ATR-IR) spectroscopy holds great promise for industrial applications as a quality control tool for complex galenic formulations. Although the technique is often promoted for the molecular information it delivers in a label free and cost effective fashion, other advantages can emerge compared to the gold standard analytical tools such as liquid chromatography coupled to mass spectrometry. The present study demonstrates how ATR-IR measurements enable accurate quantitative analysis of an active cosmetic ingredient such as Omegalight(r) encapsulated in a complex alginate based nano-capsule. The study demonstrates how precise concentrations can be obtained without the requirement for fastidious extraction and separation protocols prior to ATR-IR analysis. However, data mining remains a crucial aspect with particular emphasis on the preprocessing of the data that will be subjected to Partial Least Squares Regression (PLSR) analysis. Therefore, different pre processing methods have been evaluated to investigate the relationship between corrections applied and PLSR outcomes (i.e. precision, ratio of performance to deviation (RPD) and accuracy of the analysis). Ultimately, it has been found that, against all expectations, some of the preprocessing methods do not necessarily lead to improvements in the end result, while Extended Multiplicative Scattering Correction (EMSC) is the only one which delivers satisfying results, as defined by a Root Mean Square Error (RMSEV) of 0.07% (w/w) and a RPD greater than 30 when performing analysis over the range 0.4-8.2% (w/w). Despite the presence of large amounts of additives such as glycerol and preservatives in the formulation, implementing Leave One Out Cross Validation (LOOCV) further validates the method with a RPD of 18 and relative errors for the predicted concentrations below the 5% (w/w) threshold, hence demonstrating that ATR-IR has analytical capabilities for applications in the cosmetic industry. PMID- 29696271 TI - Intracellular endogenous glutathione detection and imaging by a simple and sensitive spectroscopic off-on probe. AB - Glutathione (GSH) exhibits many cellular functions in human pathologies. A sensitive and simple method capable of assaying GSH would be useful to understand the mechanism of GSH-related diseases. In this study, a new colorimetric and fluorescent off-on probe, 3-oxo-3H-phenoxazin-7-ylthiophene-2-carboxylate, is constructed, synthesized and applied to determine fluctuations in intracellular GSH levels selectively and sensitively. The latent fluorescent probe is designed by reacting resorufin with thiophenecarboxylate and shows high sensitivity (LOD 8.9 * 10-7 M) and off-on fluorescent response to GSH over other different physiological species in pH 7.4 buffer solutions. A new reaction mechanism based on the cut-through of thiophenecarboxylate in the probe by GSH is confirmed via the HPLC (high performance liquid chromatography) and MS (mass spectrometry) analytical methods. Moreover, the probe is successfully applied to image GSH in A549 cells and indicates fluctuations in GSH levels under the stimulation of chemicals and drugs, which is verified by the investigation of the cell lysate with a commonly used commercial assay kit. As a result, it is feasible to monitor the levels of GSH in biosamples. PMID- 29696272 TI - Bio-inspired graphene-derived membranes with strain-controlled interlayer spacing. AB - The precisely controlled size of nanoscale fluidic channels plays a critical role in resolving the permeation-selectivity trade-off in separation and filtration applications, where highly efficient gas separation and water desalination are targeted. Inspired by natural nacre where the spacing between mineral platelets changes upon applying tension as fractured mineral bridges climb over each other, bio-inspired graphene-derived membranes with sheets cross-linked by aligned covalent bonds are proposed in design, to ensure a controlled interlayer spacing ranging from 4 A to 14 A while preserving structural and mechanical stabilities by prohibiting swelling. The underlying mechanism is that the tension applied to the membrane is transferred between finite-sized graphene sheets through interlayer shear of the cross-links, which expands the interlayer gallery. First principles calculations and continuum mechanics based model analysis are combined to explore the feasibility of this protocol, by considering the microstructures of graphene-derived membranes that have recently been demonstrated to offer exceptional performance in selective mass transport. The results show that the critical size range in molecular sieving is covered by this synergetic interface- and strain-engineering approach. PMID- 29696276 TI - Efficient rare-earth free red-emitting Ca2YSbO6:Mn4+,M(M = Li+, Na+, K+, Mg2+) phosphors for white light-emitting diodes. AB - Owing to its low-cost and satisfactory luminescent-emission performance in warm white light-emitting diodes (w-LEDs), the non-rare-earth Mn4+-activated red phosphor has become a promising competitor of commercial rare-earth doped phosphor. In this study, a series of novel red-light emitting phosphors based on Ca2YSbO6:Mn4+ have been developed successfully by a conventional solid-state reaction. The structural and luminescent properties of these phosphors are systematically investigated. The as-prepared Ca2YSbO6:Mn4+ product exhibits a broad excitation band ranging from 250 to 600 nm and an abnormal intense deep-red emission centered at 680 nm with a full width at half maximum (FWHM) of ~46 nm. The optimal Mn4+ doping concentration is about 0.3 mol%, and the concentration quenching mechanism is determined to be a dipole-dipole interaction. Impressively, the Ca2YSbO6:0.003Mn4+ phosphor shows an outstanding quantum efficiency of 62.6% and an excellent thermal stability. In addition, the effect of Li+, Mg2+, Na+ and K+ dopants on the luminescent properties of Mn4+-doped Ca2YSbO6 phosphors is elucidated. Furthermore, by employing the as-prepared Ca2YSbO6:Mn4+ as a red component, a warm w-LED with high color rendering index (Ra = 87.5) and low correlated color temperature (CCT = 3255 K) can be acquired. It is believed that the present phosphor has a potential application as a supplement of the red component for warm w-LEDs. PMID- 29696278 TI - Colorimetric sensor for cimetidine detection in human urine based on d-xylose protected gold nanoparticles. AB - Herein, a simple, novel, and rapid colorimetric sensor for cimetidine (Cim) detection based on d-xylose protected gold nanoparticles (d-x@AuNPs) has been developed for the first time. The d-x@AuNPs were characterized by UV-vis, TEM and FT-IR techniques. Cimetidine causes the aggregation of d-x@AuNPs due to the formation of a strong covalent Au-N bond and electrostatic binding. As the cimetidine concentration increased, the color of the solutions gradually changed from wine-red to blue, and the large absorption band shifted from 533 to 680 nm upon d-x@AuNP aggregation. The effects of different experimental parameters were investigated. A comparative study on the detection of Cim using citrated capped AuNPs and d-x@AuNPs was presented. Under optimum conditions, the UV-vis spectra showed that the absorption ratio (A680/A533) increased linearly with the concentration of cimetidine in the range of 7 * 10-8 to 3 * 10-6 M with a correlation coefficient of 0.9956 and a limit of detection of 1 * 10-8 M without needing any complicated instruments. The selectivity of the d-x@AuNP detection system for cimetidine was excellent when compared with other ions and analytes. Due to their rapid and visible color changes, and their remarkable selectivity, the d-x@AuNPs synthesized in this study were suitable and could be applied to the detection of cimetidine in human urine. PMID- 29696277 TI - Protein environment affects the water-tryptophan binding mode. MD, QM/MM, and NMR studies of engrailed homeodomain mutants. AB - Water molecules can interact with aromatic moieties using either their O-H bonds or their lone-pairs of electrons. In proteins, water-pi interactions have been reported to occur with tryptophan and histidine residues, and dynamic exchange between O-Hpi hydrogen bonding and lone-pairpi interactions was suggested to take place, based on ab initio calculations. Here we used classical and QM/MM molecular dynamics simulations, complemented with an NMR study, to examine a specific water-indole interaction observed in the engrailed homeodomain and in its mutants. Our simulations indicate that the binding mode between water and indole can adapt to the potential created by the surrounding amino acids (and by the residues at the DNA surface in protein-DNA complexes), and support the model of dynamic switching between the O-Hpi hydrogen bonding and lone-pairpi binding modes. PMID- 29696279 TI - Ordered nanopore arrays with large interpore distances via one-step anodization. AB - Preparation of pre-patterned alumina substrates using bottom-up techniques compatible with nanotechnology applications is still a challenge. We present a novel methodology to achieve superior order in 'anodic' alumina with large interpore distances by a convenient one-step anodization process. The use of transparent insulators renders such anodic layers applicable as templates for nanostructured photovoltaic or photoelectrochemical devices. PMID- 29696280 TI - Spin transport in graphene/transition metal dichalcogenide heterostructures. AB - Since its discovery, graphene has been a promising material for spintronics: its low spin-orbit coupling, negligible hyperfine interaction, and high electron mobility are obvious advantages for transporting spin information over long distances. However, such outstanding transport properties also limit the capability to engineer active spintronics, where strong spin-orbit coupling is crucial for creating and manipulating spin currents. To this end, transition metal dichalcogenides, which have larger spin-orbit coupling and good interface matching, appear to be highly complementary materials for enhancing the spin dependent features of graphene while maintaining its superior charge transport properties. In this review, we present the theoretical framework and the experiments performed to detect and characterize the spin-orbit coupling and spin currents in graphene/transition metal dichalcogenide heterostructures. Specifically, we will concentrate on recent measurements of Hanle precession, weak antilocalization and the spin Hall effect, and provide a comprehensive theoretical description of the interconnection between these phenomena. PMID- 29696284 TI - Expanding the limit of Pd-catalyzed decarboxylative benzylations. AB - The Pd-catalyzed decarboxylative cross-coupling of electron-deficient aryl acetates with aryl bromides is reported. The method widens the scope of benzylic partners that can undergo efficient reactivity from highly activated nitrophenylacetates established previously, to a diverse series of substrates bearing modestly stabilizing groups, allowing direct access to functionalized diarylmethanes. Mechanistic studies support the role of dienolates as key intermediates in the coupling process. PMID- 29696285 TI - The role of Sox9 in collagen hydrogel-mediated chondrogenic differentiation of adult mesenchymal stem cells (MSCs). AB - Sox9 is a transcription factor that regulates chondrogenesis, but its role in the chondrogenic differentiation of mesenchymal stem cells (MSCs) triggered by materials is poorly understood. In this study, we investigated the effect of Sox9 interference on collagen-induced chondrogenesis and further collagen-based therapies for cartilage defects. In this paper, MSCs were infected with a vector carrying the Sox9 promoter and related markers were detected. A lentivirus mediated vector targeting the silencing of the Sox9 gene was used in bone marrow derived MSCs prior to being encapsulated in a collagen hydrogel. The collagen hydrogel as a sole inducer was also compared with transforming growth factor beta1 (TGF-beta1). Before being implanted into the articular cartilage defect in rats, the cell-hydrogel pellets were cultured in vitro for 14 days. The effect of Sox9 transfection on cell proliferation was evaluated by measuring the total DNA content. Safranin-O staining and a biochemistry assay were performed to assess the synthesis and secretion of glycosaminoglycan (GAG) of MSCs. The real-time fluorescent quantitative polymerase chain reaction (RT-PCR) was performed to detect the gene expression levels of Col1a1, Col2a1, Acan and Sox9. The protein expression of collagen type II and collagen type I was analyzed by immunohistochemical analysis. Collagen alone significantly increased the luciferase activity of the Sox9 promoter, which was in parallel with the upregulation of cartilage specific markers. In vitro, the chondrogenic differentiation ability of MSCs was greatly inhibited after Sox9 interference, both in the collagen and TGF-beta1-induced groups. In vivo, a further study showed that cartilage regeneration was arrested by using transfected MSCs with an injectable collagen gel or induced by TGF-beta1. The results indicated that collagen may mediate Sox9 expression by providing a biomimetic microenvironment favoring cell condensation prior to chondrogenesis. The role of Sox9 regulation by materials is similar to that by growth factors, suggesting that well-designed scaffolds may replace growth factors in chondrogenesis. Thus, interventions targeting Sox9 may help improve articular cartilage repair. PMID- 29696286 TI - From fundamental supramolecular chemistry to self-assembled nanomaterials and medicines and back again - how Sam inspired SAMul. AB - This feature article provides a personal insight into the research from my group over the past 10 years. In particular, the article explains how, inspired in 2005 by meeting my now-husband, Sam, who had cystic fibrosis, and who in 2011 went on to have a double lung transplant, I took an active decision to follow a more applied approach to some of our research, attempting to use fundamental supramolecular chemistry to address problems of medical interest. In particular, our strategy uses self-assembly to fabricate biologically-active nanosystems from simple low-molecular-weight building blocks. These systems can bind biological polyanions in highly competitive conditions, allowing us to approach applications in gene delivery and coagulation control. In the process, however, we have also developed new fundamental principles such as self-assembled multivalency (SAMul), temporary 'on-off' multivalency, and adaptive/shape-persistent multivalent binding. By targeting materials with applications in drug formulation and tissue engineering, we have discovered novel self-assembling low-molecular-weight hydrogelators based on the industrially-relevant dibenzylidenesorbitol framework and developed innovative approaches to spatially-resolved gels and functional multicomponent hybrid hydrogels. In this way, taking an application-led approach to research has also delivered significant academic value and conceptual advances. Furthermore, beginning to translate fundamental supramolecular chemistry into real-world applications, starts to demonstrate the power of this approach, and its potential to transform the world around us for the better. PMID- 29696287 TI - Tuning the structure and catalytic activity of Ru nanoparticle catalysts by single 3d transition-metal atoms in Ru12-metalloporphyrin precursors. AB - Ru nanoparticle catalysts were prepared from Ru12-metalloporphyrin complex precursors containing 3d transition-metal atoms attached to SiO2 surfaces. The single 3d metal atoms at the central position of the Ru12-metalloporphyrin complex precursors exerted a significant influence on the structures and hydrogenation performance of the Ru nanoparticles on the SiO2 surfaces. The Ru12 Cu-porphyrin complex afforded positively charged Ru nanoparticles, which would provide high activity toward aromatic hydrogenation. PMID- 29696288 TI - Stable lead(ii) boroxides. AB - The first examples of lead(ii) boroxides, [Pb(OB{CH(SiMe3)2}2)2] (1) and [{N^C}PbOB{CH(SiMe3)2}2] (5; N^C = 2-Me2NCH2C6H4), were prepared via simple protocols. These structurally characterised compounds are stable and, unlike lead(ii) alkoxides and siloxides, do not trigger uncontrolled formation of lead(ii) oxoclusters. PMID- 29696289 TI - Low-temperature plasma-enhanced atomic layer deposition of 2-D MoS2: large area, thickness control and tuneable morphology. AB - Low-temperature controllable synthesis of monolayer-to-multilayer thick MoS2 with tuneable morphology is demonstrated by using plasma enhanced atomic layer deposition (PEALD). The characteristic self-limiting ALD growth with a growth-per cycle of 0.1 nm per cycle and digital thickness control down to a monolayer are observed with excellent wafer scale uniformity. The as-deposited films are found to be polycrystalline in nature showing the signature Raman and photoluminescence signals for the mono-to-few layered regime. Furthermore, a transformation in film morphology from in-plane to out-of-plane orientation of the 2-dimensional layers as a function of growth temperature is observed. An extensive study based on high resolution transmission electron microscopy is presented to unravel the nucleation mechanism of MoS2 on SiO2/Si substrates at 450 degrees C. In addition, a model elucidating the film morphology transformation (at 450 degrees C) is hypothesized. Finally, the out-of-plane oriented films are demonstrated to outperform the in-plane oriented films in the hydrogen evolution reaction for water splitting applications. PMID- 29696290 TI - PVBA-UiO-66 using a flexible PVBA with multi-coordination groups as mixed ligands and their super adsorption towards methylene blue. AB - A series of poly-vinyl benzoic acid (PVBA) and UiO-66 materials (PVBA-UiO-66) were prepared by a mixed-linker approach. Using a flexible PVBA with multi coordination groups as mixed ligands, mesopores and uncoordinated benzoic groups were introduced into the UiO-66 crystal structures, thus leading to a special structure and functionality. The structure of the PVBA-UiO-66 was characterized by powder X-ray diffraction (PXRD), scanning electron microscopy (SEM) and nitrogen gas adsorption measurements. The adsorption property toward methylene blue (MB) of PVBA-UiO-66 was studied. The adsorption of MB by UiO-66 and PVBA (43%)-UiO-66 fit the Langmuir model and Freundlich model well. The result showed that PVBA (43%)-UiO-66 has super adsorption capacity as high as 909 mg g-1 for MB owing to the mesopores and the uncomplexed carboxyl groups which were caused by the long PVBA involved in coordination. The adsorption kinetics of MB onto PVBA (43%)-UiO-66 can be well fitted to the pseudo-second-order model. The process of adsorption MB onto PVBA-UiO-66 is spontaneous and thermodynamically favorable at 303, 313 and 323 K. PMID- 29696291 TI - Ab initio study of the CO-N2 complex: a new highly accurate intermolecular potential energy surface and rovibrational spectrum. AB - A new, highly accurate ab initio ground-state intermolecular potential-energy surface (IPES) for the CO-N2 complex is presented. Thousands of interaction energies calculated with the CCSD(T) method and Dunning's aug-cc-pVQZ basis set extended with midbond functions were fitted to an analytical function. The global minimum of the potential is characterized by an almost T-shaped structure and has an energy of -118.2 cm-1. The symmetry-adapted Lanczos algorithm was used to compute rovibrational energies (up to J = 20) on the new IPES. The RMSE with respect to experiment was found to be on the order of 0.038 cm-1 which confirms the very high accuracy of the potential. This level of agreement is among the best reported in the literature for weakly bound systems and considerably improves on those of previously published potentials. PMID- 29696292 TI - Ozone storage capacity in clathrate hydrates formed by O3 + O2 + N2 + CO2 gas mixtures. AB - Ozone storage capacity in clathrate hydrates formed from gas mixtures of O3 + O2 + N2 + CO2 was studied. It was found that in such system the amount of ozone included in the hydrate phase can be at least several times higher than for the experimentally described O3 + O2 + CO2 gas hydrates. The most promising thermobaric conditions and gas phase compositions for the formation of ozone containing hydrates from gas mixtures which include nitrogen are suggested on the basis of the obtained results. PMID- 29696293 TI - The ten things you need to know about long-term outcomes following paediatric cardiac surgery. PMID- 29696294 TI - Ten things ICU specialists need to know about direct oral anticoagulants (DOACs). PMID- 29696295 TI - Expert statement for the management of hypovolemia in sepsis. AB - Hypovolemia is frequent in patients with sepsis and may contribute to worse outcome. The management of these patients is impeded by the low quality of the evidence for many of the specific components of the care. In this paper, we discuss recent advances and controversies in this field and give expert statements for the management of hypovolemia in patients with sepsis including triggers and targets for fluid therapy and volumes and types of fluid to be given. Finally, we point to unanswered questions and suggest a roadmap for future research. PMID- 29696297 TI - Mapping and characterization of the new adult plant leaf rust resistance gene Lr77 derived from Santa Fe winter wheat. AB - KEY MESSAGE: A new gene for adult plant leaf rust resistance in wheat was mapped to chromosome 3BL. This gene was designated as Lr77. 'Santa Fe' is a hard red winter cultivar that has had long-lasting resistance to the leaf rust fungus, Puccinia triticina. The objective of this study was to determine the chromosome location of the adult plant leaf rust resistance in Santa Fe wheat. A partial backcross line of 'Thatcher' (Tc) wheat with adult plant leaf rust resistance derived from Santa Fe was crossed with Thatcher to develop a Thatcher//Tc*2/Santa Fe F6 recombinant inbred line (RIL) population. The RIL population and parental lines were evaluated for segregation of leaf rust resistance in three field plot tests and in an adult plant greenhouse test. A genetic map of the RIL population was constructed using 90,000 single-nucleotide polymorphism (SNP) markers with the Illumina Infinium iSelect 90K wheat bead array. A significant quantitative trait locus for reduction of leaf rust severity in all four tests was found on chromosome 3BL that segregated as a single adult plant resistance gene. The RILs with the allele from the resistant parent for SNP marker IWB10344 had lower leaf rust severity and a moderately resistant to moderately susceptible response compared to the susceptible RILs and Thatcher. The gene derived from Santa Fe on chromosome 3BL was designated as Lr77. Kompetitive allele-specific polymerase chain reaction assay markers linked to Lr77 on 3BL should be useful for selection of wheat germplasm with this gene. PMID- 29696296 TI - A heterogeneous response of liver and skeletal muscle fat to the combination of a Paleolithic diet and exercise in obese individuals with type 2 diabetes: a randomised controlled trial. AB - AIMS/HYPOTHESIS: The aim of the study was to investigate ectopic fat deposition and insulin sensitivity, in a parallel single-blinded randomised controlled trial, comparing Paleolithic diet alone with the combination of Paleolithic diet and exercise in individuals with type 2 diabetes. METHODS: Thirty-two individuals with type 2 diabetes with BMI 25-40 kg/m2 and 30-70 years of age followed a Paleolithic diet ad libitum for 12 weeks. In addition, study participants were randomised by computer program to either supervised combined exercise training (PD-EX group) or standard care exercise recommendations (PD group). Staff performing examinations and assessing outcomes were blinded to group assignment. Thirteen participants were analysed in each group: hepatic and peripheral insulin sensitivity were measured using the hyperinsulinaemic-euglycaemic clamp technique combined with [6,6-2H2]glucose infusion, and liver fat was assessed by proton magnetic resonance spectroscopy; both analyses were secondary endpoints. Intramyocellular lipid (IMCL) content was measured by magnetic resonance spectroscopy as a secondary analysis. All examinations were performed at Umea University Hospital, Umea, Sweden. RESULTS: Both study groups showed a median body weight loss of 7 kg. Fat mass decreased by 5.7 kg in the PD group and by 6.5 kg in the PD-EX group. Maximum oxygen uptake increased in the PD-EX group only. Liver fat showed a consistent reduction (74% decrease) in the PD group, while the response in the PD-EX group was heterogeneous (p < 0.05 for the difference between groups). IMCL content of the soleus muscle decreased by 40% in the PD group and by 22% in the PD-EX group (p < 0.05 for the difference between groups). Both groups improved their peripheral and adipose tissue insulin sensitivity, but not their hepatic insulin sensitivity. Plasma fetuin-A decreased by 11% in the PD group (p < 0.05) and remained unchanged in the PD-EX group. Liver fat changes during the intervention were correlated with changes in fetuin-A (rS = 0.63, p < 0.01). Participants did not report any important adverse events caused by the intervention. CONCLUSIONS/INTERPRETATION: A Paleolithic diet reduced liver fat and IMCL content, while there was a tissue-specific heterogeneous response to added exercise training. TRIAL REGISTRATION: ClinicalTrials.gov NCT01513798 FUNDING: Swedish Diabetes Research Foundation, County Council of Vasterbotten, Swedish Heart and Lung Foundation, King Gustav V and Queen Victoria's Foundation. PMID- 29696298 TI - Mechanisms, origin and heredity of Glu-1Ay silencing in wheat evolution and domestication. AB - KEY MESSAGE: Allotetraploidization drives Glu-1Ay silencing in polyploid wheat. The high-molecular-weight glutenin subunit gene, Glu-1Ay, is always silenced in common wheat via elusive mechanisms. To investigate its silencing and heredity during wheat polyploidization and domestication, the Glu-1Ay gene was characterized in 1246 accessions containing diploid and polyploid wheat worldwide. Eight expressed Glu-1Ay alleles (in 71.81% accessions) and five silenced alleles with a premature termination codon (PTC) were identified in Triticum urartu; 4 expressed alleles (in 41.21% accessions), 13 alleles with PTCs and 1 allele with a WIS 2-1A retrotransposon were present in wild tetraploid wheat; and only silenced alleles with PTC or WIS 2-1A were in cultivated tetra- and hexaploid wheat. Both the PTC number and position in T. urartu Glu-1Ay alleles (one in the N-terminal region) differed from its progeny wild tetraploid wheat (1-5 PTCs mainly in the repetitive domain). The WIS 2-1A insertion occurred ~ 0.13 million years ago in wild tetraploid wheat, much later than the allotetraploidization event. The Glu-1Ay alleles with PTCs or WIS 2-1A that arose in wild tetraploid wheat were fully succeeded to cultivated tetraploid and hexaploid wheat. In addition, the Glu-1Ay gene in wild einkorn inherited to cultivated einkorn. Our data demonstrated that the silencing of Glu-1Ay in tetraploid and hexaploid wheat was attributed to the new PTCs and WIS 2-1A insertion in wild tetraploid wheat, and most silenced alleles were delivered to the cultivated tetraploid and hexaploid wheat, providing a clear evolutionary history of the Glu-1Ay gene in the wheat polyploidization and domestication processes. PMID- 29696300 TI - Journey of a cystinuric patient with a long-term follow-up from a medical stone clinic: necessity to be SaFER (stone and fragments entirely removed). AB - There is a lack of studies looking at the longitudinal follow-up of patients with cystine stones. We wanted to assess the journey of cystinuric patients through our specialist metabolic stone clinic to improve the understanding of episodes, interventions and current outcomes in this patient cohort. After ethical approval, all patients who attended our metabolic stone clinic from 1994 to 2014 with at least one cystine stone episode were included in our study. Data were retrospectively analysed for patient demographics, stone episodes or intervention, clinical parameters and patient compliance. Over a period of 21 years, 16 patients with a median age of 15.5 years underwent a mean follow-up of 8.6 years (1-21 years). The mean number of surgical interventions was 3.1 (1 8/patient), but patients who were stone free after their first treatment had lower recurrences (p = 0.91) and lower number of interventions during their follow-up (2.7/patient, compared to those who were not stone free at 4/patient). During their follow-up period, patients with < 3 interventions had a significantly better renal function than those with >= 3 surgical interventions (p = 0.04). Additionally, linear regression analysis showed that eGFR was demonstrated to decline with increasing numbers of stone episodes (r2 = 0.169). It was also noted that patients who began early medical management remained stone free during follow-up compared to those who had medical management after >= 2 stone episodes, of whom all had a recurrent episode. Our long-term longitudinal study of cystine stone formers highlights that patients who are stone free and receive early metabolic stone screening and medical management after their initial presentation have the lowest recurrence rates and tend to preserve their renal function. Hence, prompt referral for metabolic assessment, and the stone and fragments entirely removed (SaFER) principles are key to preventing stone episodes and improving long-term function. PMID- 29696299 TI - Development of mRNA-based body fluid identification using reverse transcription loop-mediated isothermal amplification. AB - Identifying body fluids from forensic samples can provide valuable evidence for criminal investigations. Messenger RNA (mRNA)-based body fluid identification was recently developed, and highly sensitive parallel identification using reverse transcription polymerase chain reaction (RT-PCR) has been described. In this study, we developed reverse transcription loop-mediated isothermal amplification (RT-LAMP) as a simple, rapid assay for identifying three common forensic body fluids, namely blood, semen, and saliva, and evaluated its specificity and sensitivity. Hemoglobin beta (HBB), transglutaminase 4 (TGM4), and statherin (STATH) were selected as marker genes for blood, semen, and saliva, respectively. RT-LAMP could be performed in a single step including both reverse transcription and DNA amplification under an isothermal condition within 60 min, and detection could be conveniently performed via visual fluorescence. Marker-specific amplification was performed in each assay, and no cross-reaction was observed among five representative forensically relevant body fluids. The detection limits of the assays were 0.3 nL, 30 nL, and 0.3 MUL for blood, semen, and saliva, respectively, and their sensitivities were comparable with those of RT-PCR. Furthermore, RT-LAMP assays were applicable to forensic casework samples. It is considered that RT-LAMP is useful for body fluid identification. PMID- 29696301 TI - [Radical cystectomy and urinary diversion-what is important ?] AB - BACKGROUND: In Germany, radical cystectomy with urinary diversion is the primary therapeutic option for localized muscle invasive urothelial bladder cancer. Modifications in the pre-, peri-, and postoperative phase have significantly improved outcomes. OBJECTIVES: Different factors and parameters are directly associated with patients' outcome. An overview on how to best approach this procedure is provided in this article. MATERIALS AND METHODS: The data regarding preparation and the procedure for the radical cystectomy followed by urinary diversion are separately analyzed. RESULTS: During the preoperative phase, Fast Track and ERAS (Enhanced Recovery after Surgery) concepts should be an integral part of therapeutic management. Different aspects of such models are presented and discussed. Comorbidities such as diabetes mellitus, hypertension, malnutrition or anemia should also be treated early. In the perioperative phase, optimized fluid management and close interaction with the anesthesiologist are needed. Use of vasopressors during surgery and controlled hypotension (about 80 mm Hg) help reduce perioperative blood loss. Blood product use should be minimized. The use of epidural anesthesia to improve the stress reaction of the body improves pain management and functional recovery. Radical cystectomy is associated with the best oncological outcome, preserving functional structures to maintain a good quality of life. Nerve-sparing procedures in men and women should be used where appropriate. The use of robotic assisted radical cystectomy (RARC) is also discussed. CONCLUSION: The ileum conduit is still the most common urinary diversion worldwide. However, numerous other urinary diversions to provide patients with the highest quality of life are available. Centers with a high case load seem to be associated with an improved outcome. PMID- 29696302 TI - [Long-term follow-up of monoclonal gammopathies of undetermined significance (MGUS)]. PMID- 29696303 TI - [Chronic hepatitis C : Standard treatment and remaining challenges]. AB - BACKGROUND: Among patients with chronic hepatitis C, 20-30% develop cirrhosis and its complications within 30 years. The antiviral treatment of hepatitis C has become interferon-free, with resulting improvements in sustained virological response rates, safety and tolerability and a shorter duration of treatment. OBJECTIVE: The mechanism of action of available drugs and current treatment recommendations. MATERIAL AND METHODS: This review is based on relevant publications retrieved by a selective literature search and particularly on studies and reviews concerning the course and treatment of hepatitis C. RESULTS: The available drugs for interferon-free antiviral treatment of hepatitis C include inhibitors of the RNA-dependent RNA polymerase, NS3/4A protease, and NS5A protein of the hepatitis C virus (HCV), and ribavirin. Typically, two specific inhibitors are given in combination and the usual duration of treatment is 8-12 weeks. The antiviral drugs differ in their genotypic effectiveness and resistance barriers. The appropriate drug(s) should be chosen in consideration of the patient's hepatic and renal function and potential drug-drug interactions. All approved anti-HCV drugs are safe and well-tolerated and result in sustained virological response rates above 95%. CONCLUSION: All patients with hepatitis C, whatever their disease stage, can achieve a sustained eradication of HCV using a combination of drugs with direct antiviral activity. Viral eradication is associated with a better quality of life and with lower morbidity and mortality. PMID- 29696305 TI - Correction to: Prospective associations between recalled parental bonding and perinatal depression: a cohort study in urban and rural Turkey. AB - The article 'Prospective associations between recalled parental bonding and perinatal depression: a cohort study in urban and rural Turkey, written by Berker Duman, Vesile Senturk Cankorur, Clare Taylor and Robert Stewart was originally published electronically on the publisher's internet portal (currently SpringerLink) on January 10, 2018 without open access. PMID- 29696304 TI - The perceived effectiveness of traditional and faith healing in the treatment of mental illness: a systematic review of qualitative studies. AB - PURPOSE: This work complements a quantitative review by Nortje et al. (Lancet Psychiatry 3(2):154-170, 2016) by exploring the qualitative literature in regard to the perceived effectiveness of traditional and faith healing of mental disorders. METHOD: Qualitative studies focusing specifically on traditional and/or faith healing practices for mental illness were retrieved from eight databases. Data were extracted into basic coding sheets to facilitate the assessment of the quality of eligible papers using the COREQ. RESULTS: Sixteen articles met the inclusion criteria. Despite methodological limitations, there was evidence from the papers that stakeholders perceived traditional and/or faith healing to be effective in treating mental illness, especially when used in combination with biomedical treatment. CONCLUSION: Patients will continue to seek treatment from traditional and/or faith healers for mental illness if they perceive it to be effective regardless of alternative biomedical evidence. This provides opportunities for collaboration to address resource scarcity in low to middle income countries. PMID- 29696306 TI - Freiburg Neuropathology Case Conference : A Painless Mass Lesion of the Parietal and Occipital Bones. PMID- 29696307 TI - Stem cell therapy in bilateral osteonecrosis: computer-assisted surgery versus conventional fluoroscopic technique on the contralateral side. AB - PURPOSE: Surgical management of osteonecrosis with core decompression with stem cell therapy is a new procedure. The technique is performed with fluoroscopic guidance. This study attempts to determine if computer-navigated technique can improve the procedure. METHODS: Thirty consecutive patients with bilateral symptomatic osteonecrosis without collapse were included in this study during the year 2011. A prospective, randomized, and controlled study was conducted on 60 hips (bilateral osteonecrosis) using conventional fluoroscopy technique on one side and computer-based navigation on the contralateral side. Bone marrow aspirated from the two iliac crests was mixed before concentration. Each side received the same volume of concentrated bone marrow and the same number of cells 110,000 +/- 27,000 cells (counted as CFU-F). RESULTS: Computer navigation achieved better parallelism to the ideal position of the trocar, with better trocar placement as regards to tip-to-subchondral distance and ideal centre position within the osteonecrosis for injection of stem cells. Using computer navigation took fewer attempts to position the trocar, used less fluoroscopy time, and decreased the radiation exposure as compared with surgery performed with conventional fluoroscopy. At the most recent follow-up (6 years), increasing the precision with computer navigation resulted in less collapse (7 versus 1) and better volume of repair (13.4 versus 8.2 cm3) for hips treated with the computer assisted technique. CONCLUSIONS: The findings of this study suggest that computer navigation may be safely used in a basic procedure for injection of stem cells. PMID- 29696308 TI - Role of MDA5 and interferon-I in dendritic cells for T cell expansion by anti tumor peptide vaccines in mice. AB - Cytotoxic T lymphocytes (CTLs) are effective components of the immune system capable of destroying tumor cells. Generation of CTLs using peptide vaccines is a practical approach to treat cancer. We have previously described a peptide vaccination strategy that generates vast numbers of endogenous tumor-reactive CTLs after two sequential immunizations (prime-boost) using poly-ICLC adjuvant, which stimulates endosomal toll-like receptor 3 (TLR3) and cytoplasmic melanoma differentiation antigen 5 (MDA5). Dendritic cells (DCs) play an important role not only in antigen presentation but are critical in generating costimulatory cytokines that promote CTL expansion. Poly-ICLC was shown to be more effective than poly-IC in generating type-I interferon (IFN-I) in various DC subsets, through its enhanced ability to escape the endosomal compartment and stimulate MDA5. In our system, IFN-I did not directly function as a T cell costimulatory cytokine, but enhanced CTL expansion through the induction of IL15. With palmitoylated peptide vaccines, CD8alpha+ DCs were essential for peptide crosspresentation. For vaccine boosts, non-professional antigen-presenting cells were able to present minimal epitope peptides, but DCs were still required for CTL expansions through the production of IFN-I mediated by poly-ICLC. Overall, these results clarify the roles of DCs, TLR3, MDA5, IFN-I and IL15 in the generation of vast and effective antitumor CTL responses using peptide and poly IC vaccines. PMID- 29696310 TI - Attentional capture by alcohol-related stimuli may be activated involuntarily by top-down search goals. AB - Previous research has found that the attention of social drinkers is preferentially oriented towards alcohol-related stimuli (attentional capture). This is argued to play a role in escalating craving for alcohol that can result in hazardous drinking. According to incentive theories of drug addiction, the stimuli associated with the drug reward acquire learned incentive salience and grab attention. However, it is not clear whether the mechanism by which this bias is created is a voluntary or an automatic one, although some evidence suggests a stimulus-driven mechanism. Here, we test for the first time whether this attentional capture could reflect an involuntary consequence of a goal-driven mechanism. Across three experiments, participants were given search goals to detect either an alcoholic or a non-alcoholic object (target) in a stream of briefly presented objects unrelated to the target. Prior to the target, a task irrelevant parafoveal distractor appeared. This could either be congruent or incongruent with the current search goal. Applying a meta-analysis, we combined the results across the three experiments and found consistent evidence of goal driven attentional capture, whereby alcohol distractors impeded target detection when the search goal was for alcohol. By contrast, alcohol distractors did not interfere with target detection, whilst participants were searching for a non alcoholic category. A separate experiment revealed that the goal-driven capture effect was not found when participants held alcohol features active in memory but did not intentionally search for them. These findings suggest a strong goal driven account of attentional capture by alcohol cues in social drinkers. PMID- 29696309 TI - Persistent escalation of alcohol consumption by mice exposed to brief episodes of social defeat stress: suppression by CRF-R1 antagonism. AB - RATIONALE: Episodic bouts of social stress can precede the initiation, escalation, or relapse to disordered alcohol intake. Social stress may engender neuroadaptations in the hypothalamic-pituitary-adrenal (HPA) axis and in extrahypothalamic stress circuitry to promote the escalation of alcohol intake. OBJECTIVES: We aimed to (1) confirm a pattern of escalated drinking in socially defeated mice and to (2) test drugs that target distinct aspects of the HPA axis and extrahypothalamic neural substrates for their effectiveness in reducing murine, stress-escalated drinking. METHODS: Male C57BL/6J (B6) mice were socially defeated by resident Swiss-derived males for ten consecutive days receiving 30 bites/day. Ten days after the final defeat, cohorts of B6 mice received continuous or intermittent access to 20% EtOH (w/v) and water. After 4 weeks of drinking, mice were injected with weekly, systemic doses of the CRF-R1 antagonist, CP376395; the glucocorticoid receptor antagonist, mifepristone; the 11-beta-hydroxylase inhibitor, metyrapone; or the 5-alpha-reductase inhibitor, finasteride. RESULTS: Prior to drug treatments, defeated mice reliably consumed more EtOH than non-defeated controls, and mice given alcohol intermittently consumed more EtOH than those with continuous access. CP376395 (17-30 mg/kg) reduced continuous, but not intermittent EtOH intake (g/kg) in socially defeated mice. Mifepristone (100 mg/kg), however, increased drinking by defeated mice with intermittent access to alcohol while reducing drinking during continuous access. When administered finasteride (100 mg/kg) or metyrapone (50 mg/kg), all mice reduced their EtOH intake while increasing their water consumption. CONCLUSIONS: Mice with a history of episodic social defeat stress were selectively sensitive to the effects of CRF-R1 antagonism, suggesting that CRF-R1 may be a potential target for treating alcohol use disorders in individuals who escalate their drinking after exposure to repeated bouts of psychosocial stress. Future studies will clarify how social defeat stress may alter the expression of extrahypothalamic CRF-R1 and glucocorticoid receptors. PMID- 29696311 TI - Can we increase smokers' adherence to nicotine replacement therapy and does this help them quit? AB - OBJECTIVE: To examine the effects of five intervention components on smokers' adherence to combined nicotine patch and nicotine gum during a quit attempt and assess whether adherence is related to cessation. METHOD: Smokers interested in quitting (N = 513; 59% female; 87% White) received nicotine patch plus nicotine gum and participated in a 2x2x2x2x2 randomized factorial experiment (i.e., 32 treatment conditions) evaluating five intervention components: (1) medication adherence counseling versus none; (2) automated medication adherence calls versus none; (3) electronic medication monitoring with feedback and counseling versus e monitoring alone; (4) 26 versus 8 weeks of nicotine patch plus nicotine gum; and (5) maintenance counseling versus none. Adherence was assessed over the first 6 weeks post-target quit day via timeline follow-back (nicotine patch) and electronic medication dispenser (gum). RESULTS: In the first 6 weeks post-quit day, 12% of participants used no patches or gum, and 40% used the patch every day. Only 1.4% used both patch and gum adherently every day in the 6 weeks post target quit day. E-monitoring counseling increased gum use (from 1.9 to 2.6 pieces/day; p < .001) but did not increase abstinence. More adherent patch and gum use in the first 6 weeks were each associated with higher point-prevalence abstinence rates through 1 year. CONCLUSIONS: This large experiment with electronic monitoring of nicotine gum adherence showed that e-monitoring counseling increased gum use but not abstinence. Adherence to nicotine patch and to gum were each strongly related to abstinence, but it is unclear whether adherence increases abstinence, or relapse causes medication discontinuation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01120704. PMID- 29696312 TI - Neural bases of sensorimotor adaptation in the vocal motor system. AB - The present study used event-related potential (ERP) recordings to investigate the neural mechanisms of sensorimotor adaptation in response to altered auditory feedback (AAF) during vocal production. 12 healthy speakers were tested under a vocal motor adaptation paradigm in which the fundamental frequency (F0) of their voice auditory feedback was pitch-shifted downward by one semi-tone (- 100 cents) during vowel vocalizations. Behavioral results revealed that subjects adapted to AAF by producing opposing (upward) responses to pitch-shift stimuli, and this adaptive behavior persisted after feedback alteration was removed (washout). We found that adaptation to AAF was accompanied by a significant increase in the amplitude of a parietal ERP activity elicited after the onset of vocalization. However, no such effect was observed for pre-motor ERPs elicited before vocalization onset. Moreover, we found that adaptive vocal responses were negatively correlated with ERPs over the parietal and positively correlated with those over the fronto-central areas after vocalization onset. These findings suggest that vocal motor adaptation is mediated by sensorimotor reprogramming of feedforward motor commands through incorporating auditory feedback, which is indexed by modulation of behavioral and ERP responses to AAF. We suggest that modulation of neural activities in the parietal cortex highlights its significance as a neural interface for sensorimotor integration and indicates its critical role in vocal motor adaptation. Our findings support the notion that the parietal mechanisms are involved in driving adaptive motor behavior to cope with unexpected changes in the sensory environment to accomplish communication goals during vocal production and motor control. PMID- 29696313 TI - Using proprioception to control ongoing actions: dominance of vision or altered proprioceptive weighing? AB - Visual feedback is crucial for movement accuracy (e.g., Keele and Posner, J Exp Psychol 77:155-158, 1968). As well, proprioception has been argued to be important for the control of voluntary movements (e.g., Bagesteiro et al., Exp Brain Res 171:358-370, 2006; Rossetti et al., J Neurophysiol 74:457-463, 1995). While tendon vibration (TVib) has been used to perturb proprioceptive information during limb matching tasks (Goodwin et al., Science 175:1382-1384, 1972), the current study employed between-trial dual-muscle TVib, coupled with vision occlusion, to assess the use of vision and proprioception for the online control of voluntary movements. Participants (n = 17) performed an upper-limb reaching task (30 cm). TVib influenced both accuracy and precision of movement endpoint. Critically, variability analyses showed that participant's performance was most affected by TVib at 75% of the movement duration, even in the presence of vision. These findings demonstrate that between-trial dual-muscle tendon vibration can perturb proprioceptive feedback, and further, suggest that proprioception can be important for the online control of reaches, even when vision is available. PMID- 29696314 TI - Recalibration of vocal affect by a dynamic face. AB - Perception of vocal affect is influenced by the concurrent sight of an emotional face. We demonstrate that the sight of an emotional face also can induce recalibration of vocal affect. Participants were exposed to videos of a 'happy' or 'fearful' face in combination with a slightly incongruous sentence with ambiguous prosody. After this exposure, ambiguous test sentences were rated as more 'happy' when the exposure phase contained 'happy' instead of 'fearful' faces. This auditory shift likely reflects recalibration that is induced by error minimization of the inter-sensory discrepancy. In line with this view, when the prosody of the exposure sentence was non-ambiguous and congruent with the face (without audiovisual discrepancy), aftereffects went in the opposite direction, likely reflecting adaptation. Our results demonstrate, for the first time, that perception of vocal affect is flexible and can be recalibrated by slightly discrepant visual information. PMID- 29696315 TI - The effects of audiovisual distraction on the muscle sympathetic responses to experimental muscle pain. AB - Pain elicited by intramuscular infusion of hypertonic saline solution causes muscle sympathetic nerve activity (MSNA) to increase in some subjects, yet decrease in others. Although the direction of the response is not predictable based on baseline physiological and psychological parameters, we know that it results from sustained functional changes in specific brain regions that are responsible for the behavioral and cardiovascular responses to psychological stressors, as well as those involved in attention. The aim of this study was to investigate whether MSNA responses to experimental muscle pain in humans could be altered with an audiovisual stimulus that served to distract them from the pain. MSNA was recorded from the left common peroneal nerve of 20 young healthy individuals during a 45-min intramuscular infusion of hypertonic saline solution into the ipsilateral tibialis anterior muscle. The distracting stimulus commenced 15 min after the start of the infusion and lasted for 15 min. Fifteen subjects showed an increase in mean burst amplitude of MSNA (to 176.4 +/- 7.9% of baseline), while five showed a decrease (to 73.1 +/- 5.2% of baseline); distraction had no effect on these profiles. These results indicate that even though the subjects were attending to the audiovisual stimulus, and were presumably distracted from the pain, it failed to alter the MSNA responses to muscle pain. PMID- 29696317 TI - Cost-effectiveness analysis of surgical versus non-surgical management of acute Achilles tendon ruptures. AB - PURPOSE: An Achilles tendon rupture is a common injury that typically affects people in the middle of their working lives. The injury has a negative impact in terms of both morbidity for the individual and the risk of substantial sick leave. The aim of this study was to investigate the cost-effectiveness of surgical compared with non-surgical management in patients with an acute Achilles tendon rupture. METHODS: One hundred patients (86 men, 14 women; mean age, 40 years) with an acute Achilles tendon rupture were randomised (1:1) to either surgical treatment or non-surgical treatment, both with an accelerated rehabilitation protocol (surgical n = 49, non-surgical n = 51). One of the surgical patients was excluded due to a partial re-rupture and five surgical patients were lost to the 1-year economic follow-up. One patient was excluded due to incorrect inclusion and one was lost to the 1-year follow-up in the non surgical group. The cost was divided into direct and indirect costs. The direct cost is the actual cost of health care, whereas the indirect cost is the production loss related to the impact of the patient's injury in terms of lost ability to work. The health benefits were assessed using quality-adjusted life years (QALYs). Sampling uncertainty was assessed by means of non-parametric boot strapping. RESULTS: Pre-injury, the groups were comparable in terms of demographic data and health-related quality of life (HRQoL). The mean cost of surgical management was ?7332 compared with ?6008 for non-surgical management (p = 0.024). The mean number of QALYs during the 1-year time period was 0.89 and 0.86 in the surgical and non-surgical groups respectively. The (incremental) cost effectiveness ratio was ?45,855. Based on bootstrapping, the cost-effectiveness acceptability curve shows that the surgical treatment is 57% likely to be cost effective at a threshold value of ?50,000 per QALY. CONCLUSIONS: Surgical treatment was more expensive compared with non-surgical management. The cost effectiveness results give a weak support (57% likelihood) for the surgical treatment to be cost-effective at a willingness to pay per QALY threshold of ?50,000. This is support for surgical treatment; however, additionally cost effectiveness studies alongside RCTs are important to clarify which treatment option is preferred from a cost-effectiveness perspective. LEVEL OF EVIDENCE: I. PMID- 29696316 TI - Attention demands of postural control in non-specific chronic low back pain subjects with low and high pain-related anxiety. AB - Impaired postural control in chronic low back pain (CLBP) has been attributed to deficits in sensory and motor functions. However, it is not known if pain-related anxiety affects motor and cognitive function of postural control. The aim of this study was to compare the interactive effects of postural and cognitive function in CLBP patients with high and low pain-related anxiety and healthy subjects. Thirty-eight patients with nonspecific CLBP (19 with low and 19 with high pain related anxiety levels) and 20 asymptomatic subjects participated. Postural control was assessed by center of pressure (COP) parameters including mean total sway velocity, area, anterior-posterior (A-P), and medial-lateral (Med-Lat) range. Postural task was assessed during four conditions (eyes open with and without ankle vibration-eyes closed with and without ankle vibrations). Participants performed the postural task with or without auditory Stroop task. Average reaction time and error ratio of auditory Stroop test were calculated as measures of the cognitive task performance. Significantly reduced sway area was observed in CLBP patients with high pain-related anxiety and control subjects during the dual-task condition as compared with the single task. In addition, A-P range was significantly reduced in CLBP patients with high pain-related anxiety during dual tasking when eyes were closed with ankle vibration. In addition, only the CLBP subjects with high pain-related anxiety showed significantly longer reaction times by increasing the difficulty of standing postural task. Pain related anxiety may influence the postural cognitive interactions in CLBP patients. Furthermore, it may be considered as a contributing factor for postural strategies adopted by CLBP patients. PMID- 29696318 TI - Microfracture provides better clinical results than debridement in the treatment of acute talar osteochondral lesions using arthroscopic assisted fixation of acute ankle fractures. AB - PURPOSE: Ankle arthroscopy is a useful tool for detection and treatment of accompanying intraarticular pathologies in acute ankle fractures. The purpose of this study was to compare the treatment results of talus osteochondral lesions (OLT) with debridement and microfracture in arthroscopy assisted surgery of acute ankle fractures. METHODS: Eleven consecutive patients who were treated with arthroscopic acute debridement and 14 consecutive patients who were treated with arthroscopic acute microfracture in the treatment of ankle fracture were included in the study. All patients were controlled clinically and radiologically in the postoperative period. Ankle pain was evaluated with the visual analog score (VAS), ankle functions were assessed with American Orthopaedic Foot and Ankle Society Ankle-Hindfoot Scale (AOFAS), and osteoarthritic changes were analyzed with Van Dijk score. RESULTS: There was no significant difference between the groups in terms of age, gender, injury side and trauma mechanism (n.s). Mean time to surgery, fracture healing duration, first weight-bearing and full weight bearing, follow-up period and Van Dijk score were all similar in both groups (n.s). The AOFAS score and VAS activity score were statistically significantly better in the microfracture group (p = 0.044 and p = 0.001). CONCLUSIONS: The clinical relevance of the present study is to define the acute treatment of the first osteochondral damage that occurred simultaneously with ankle fracture, to improve postoperative functional outcomes and to prevent post-traumatic osteoarthritis. Both debridement and microfracture yield good functional outcomes in the second year of the treatment. Microfracture ensures significantly more successful clinical results than debridement. LEVEL OF EVIDENCE: Level III. PMID- 29696320 TI - Liver vascular anatomy: a refresher. AB - To prevent and decrease procedural complications, it is important to identify variants of hepatic vascular anatomy before interventional radiologic procedures, surgery, and liver transplantation. Knowledge of the vascular variants helps in selecting patients and in exploring alternative management options. Non-invasive detailed demonstration of the hepatic vascular anatomy is possible with advanced multi-detector computed tomography (CT) and magnetic resonance (MR) imaging. The objective of this review is to provide a brief overview of clinically relevant hepatic vascular anatomy and important variants. PMID- 29696319 TI - Danish Hip Arthroscopy Registry: predictors of outcome in patients with femoroacetabular impingement (FAI). AB - PURPOSE: Predictors of outcome after femoroacetabular impingement (FAI) surgery are not well-documented. This study presents data from the Danish Hip Arthroscopy Registry (DHAR) for such analyses. The purpose of this study was to identify predictors of poor outcome after FAI surgery in a Danish FAI population. The primary hypothesis was that older patients, patients with severe cartilage damage and female patients might have inferior outcome results compared with younger patients, patients with minor cartilage damage and male patients. METHODS: Radiological and surgical data as well as patient-reported outcome measures (PROM) from FAI patients in DHAR between January 2012 and May 2015 were collected. PROMs consisting of Copenhagen Hip and Groin Outcome Score (HAGOS), quality of life (EQ-5D), Hip Sports Activity Scale (HSAS) and Numeric Rating Scale (NRS) pain scores were assessed. The patients were divided into three age groups (< 25, 25-39 and >= 40 years). Cartilage injuries were classified according to International Cartilage Repair Society (ICRS) (femoral side) and modified Becks (acetabular side) classifications. A non-parametric statistic method was used to analyze the differences between the preoperative and postoperative PROM values. RESULTS: Data from 2054 FAI procedures in DHAR was collected. 53% of the procedures were done in female patients. All HAGOS sub scales, EQ-5D, HSAS and NRS pain (rest and walk) demonstrated significant improvements in all age groups at follow-up. Comparison between age groups demonstrated poorer outcomes in both older age groups when compared with the < 25 years age group at 1- and 2-year follow-ups. Higher degrees of femoral and acetabular cartilage injury did have a negative influence on outcome at follow up. Comparison between genders demonstrated lower preoperative outcomes in females and lower outcome score (HSAS) 1 and 2 years after FAI surgery. CONCLUSIONS: Age above 25 and major cartilage injury might negatively affect the outcome of surgery, however, gender could not be identified as a negative predictor of clinical outcome after FAI surgery, but might negatively affect sports participation in females. LEVEL OF EVIDENCE: III, prospective cohort study. PMID- 29696322 TI - [Minimally invasive cheilectomy]. AB - OBJECTIVES: Treatment of hallux rigidus by minimally invasive resection of the dorsal osteophytes, synovectomy and resection of the dorsal part of the metatarsal head. INDICATIONS: Hallux rigidus grades II and III CONTRAINDICATIONS: End-stage osteoarthritis of the first metatarsophalangeal joint with beginning ankylosis. SURGICAL TECHNIQUE: Osteophytes around the metatarsophalangeal joint are removed using a 1 cm incision dorsomedial, approximately 3 cm proximal of the joint space. The dorsal third of the metatarsal head is resected with a burr to improve dorsiflexion. The extent of bone resection is checked with an image intensifier. Loose bone fragments removed with a rangeur. An arthroscopy can be performed to check the completeness of bone resection, the irrigation of the joint and, if needed, to extend the synovectomy. POSTOPERATIVE MANAGEMENT: Removal of the sutures after 2 weeks. Depending on pain, the patient can change from the postoperative shoe to a normal soft, comfortable and wide shoe after 1-2 weeks. Nonsteroidal drugs can be prescribed as needed. Active and passive mobilization of the metatarsophalangeal joint is also recommended. RESULTS: The technique allows a soft-tissue-preserving resection of the osteophytes and a partial resection of the metatarsal head. The main advantages are limited soft tissue trauma and rapid rehabilitation. In all, 21 women and 17 men with hallux rigidus stages II and III (Vanore) underwent surgery. Minimum follow-up was 12 months. In 1 patient, injury of the extensor hallucis longus tendon was observed. Two patients underwent revision surgery. One patient was converted to a metatarsophalangeal fusion, while another patient received a resection arthroplasty. At the latest follow-up, the AOFAS (American Orthopaedic Foot & Ankle Society) score averaged 88.7 points. PMID- 29696321 TI - Linac-based stereotactic body radiation therapy for unresectable locally advanced pancreatic cancer: risk-adapted dose prescription and image-guided delivery. AB - BACKGROUND: Stereotactic body radiation therapy (SBRT) represents a new treatment option for locally advanced pancreatic cancer (LAPC). An accurate treatment planning with risk-adapted dose prescription with adherence to specific dose constraints for organs at risk (OARs) and the use of daily cone beam CT (CBCT) for image guidance could allow an effective and safe treatment delivery. Here, feasibility and efficacy of SBRT in LAPC treated in our cancer care center are reported. PATIENTS AND METHODS: 33 unresectable LAPC patients underwent SBRT. In order to respect OAR dose constraints, a risk-adapted dose prescription strategy was adopted, choosing between the following schedules: 42 Gy or 45 Gy in 6 daily fractions with a biologically effective dose (BED) > 70 Gy10 or 36 Gy/6 fractions (estimating a BED 57.6 Gy10). SBRT was delivered with volumetric modulated arc technique (VMAT) and flattening filter-free (FFF) mode. Image guidance was performed by means of CBCT before every treatment session. The patients were evaluated at the end of treatment for acute toxicity and at 3, 6, and 12 months for late toxicity and treatment response. RESULTS: At the time of analysis, the median follow-up was 18 months (range 5-34 months). Prior to SBRT, 24 out of 33 patients received induction chemotherapy. Although all patients were previously judged as unresectable, 6 out of 33 (18%) underwent surgery after SBRT; all of them received a BED > 70 Gy10. One-year LC and OS were 81% and 75%, respectively. A total of 12 patients (37%) had an extra-pancreatic progression. No cases of >=G3 acute or late toxicity were reported. CONCLUSION: In our experience, risk adapted dose prescription and image-guided SBRT represents an effective treatment option for LAPC patients. PMID- 29696323 TI - Routine Pathology and Postoperative Follow-Up are Not Cost-Effective in Cholecystectomy for Benign Gallbladder Disease. AB - INTRODUCTION: The incidence of gallstone disease is increasing and represents a strain on healthcare systems worldwide. Following cholecystectomy, gallbladder specimens are generally submitted for histopathologic examination and the diagnostic yield of this strategy remains questionable. This study aimed to evaluate the usefulness of routine pathologic examination of the gallbladder specimens and investigate the results of routine postoperative follow-up visits. METHODS: All cholecystectomies performed between January 2011 and July 2017 at a single center were evaluated. All gallbladder specimens were routinely pathologically examined. The outcome parameters were the macro- and microscopic gallbladder anomalies at pathology and the reported symptoms during routine follow-up visits 2-6 weeks after surgery. RESULTS: In the study period a total of 2763 patients underwent cholecystectomy, of which 2615 had a postoperative visit in the outpatient clinic. Seventy-three patients (3%) complained of persistent abdominal pain, and 29 of these patients were referred for further treatment, resulting in a resolution of symptoms in 97%. Of all gallbladder specimens, 199 (7%) displayed macroscopic anomalies and in four (2%) of these, gallbladder carcinoma was diagnosed. DISCUSSION: Selective pathologic examination of gallbladder specimens in case of macroscopic anomalies appears justified. Also routine follow-up after cholecystectomy appears not useful since 97% of patients do not report any symptoms at follow-up. A selective pathology and follow-up strategy could save significant healthcare costs. PMID- 29696324 TI - Cribriform-Morular Variant of Papillary Thyroid Carcinoma: Clinical and Pathological Features of 30 Cases. AB - BACKGROUND: Cribriform-morular variant of papillary thyroid carcinoma (CMV-PTC) is rare; it may occur in cases of familial adenomatous polyposis (FAP) or be sporadic. To clarify the clinicopathological features of CMV-PTC, the medical records of these patients were investigated retrospectively. MATERIALS AND METHODS: Between 1979 and 2016, a total of 17,062 cases with PTC underwent initial surgery at Ito Hospital. Of these, 30 (0.2%) cases histologically diagnosed with CMV-PTC were reviewed. RESULT: The patients were all women, with a mean age at the time of surgery of 24 years. Seven (23%) cases were thought to have FAP because they had colonic polyposis or a family history of FAP or APC gene mutation. The remaining 23 (77%) were thought to be sporadic. Multiple tumors were detected in 6 cases, with a solitary tumor in 24. One patient had lung metastasis at diagnosis. Eleven patients underwent total thyroidectomy or subtotal thyroidectomy, and 19 underwent lobectomy. Twenty-six (87%) patients underwent neck lymph node dissection. Three patients had tumor metastasis in central lymph nodes, but these were incidentally detected metastatic classical PTC (cPTC) based on histological examination. In this series, there were no cases of LN metastases of CMV-PTC. During a mean follow-up of 15 years, one patient had new cPTC in the remnant thyroid after initial surgery, and the other patients showed no signs of recurrence. CONCLUSION: CMV-PTC occurred in young women, their long-term prognosis was excellent. Total thyroidectomy is recommended for FAP associated CMV-PTC, but modified neck lymph node dissection is not necessary. PMID- 29696325 TI - Colonization with Multidrug-Resistant Enterobacteriaceae is Associated with Increased Mortality Following Burn Injury in Sub-Saharan Africa. AB - BACKGROUND: Multidrug-resistant (MDR) bacteria are an emerging international concern in low- and middle-income countries that threaten recent public health gains. These challenges are exacerbated in immunocompromised hosts, such as those with burn injury. This study sought to describe the epidemiology and associated clinical outcomes of burn wound colonization in a Malawian tertiary burn center. METHODS: This is a prospective analysis of burn patients presenting to Kamuzu Central Hospital in Lilongwe, Malawi, within 72 h of burn injury. A swab of each patient's primary wound was collected at admission and each subsequent week. The primary exposure was burn wound colonization with MDR bacteria, particularly Enterobacteriaceae. The primary outcome was in-hospital mortality. A log binomial model estimated the association between the exposure and outcome, adjusted for confounders. RESULTS: Ninety-nine patients were enrolled with a median age of 4 years (IQR 2-12) and a male preponderance (54%). Median total body surface area burn (TBSA) was 14% (IQR 9-25), and crude in-hospital mortality was 19%. Enterobacteriaceae were the most common MDR bacteria with 36% of patients becoming colonized. Wound colonization with MDR Enterobacteriaceae was associated with increased in-hospital mortality with a risk ratio of 1.86 (95% CI 1.38, 2.50, p < 0.001) adjusted for TBSA, burn type (scald vs. flame), sex, age, length of stay, and methicillin-resistant Staphylococcus aureus colonization. CONCLUSION: MDR bacteria, especially Enterobacteriaceae, are common and are associated with worse burn injury outcomes. In resource-poor environments, a greater emphasis on prevention of MDR bacterial colonization, improved isolation precautions, affordable diagnostics, and antibiotic stewardship are imperative. PMID- 29696327 TI - Letter to the Editor: Are American Surgical Residents Prepared for Humanitarian Deployment? A Comparative Analysis of Resident and Humanitarian Case Logs. PMID- 29696326 TI - Access to Orthopaedic Surgical Care in Northern Tanzania: A Modelling Study. AB - BACKGROUND: The global burden of musculoskeletal disease and resulting disability is enormous and is expected to increase over the next few decades. In the world's poorest regions, the paucity of information defining and quantifying the current state of access to orthopaedic surgical care is a major problem in developing effective solutions. This study estimates the number of individuals in Northern Tanzania without adequate access to orthopaedic surgical services. METHODS: A chance tree was created to model the probability of access to orthopaedic surgical services in the Northern Tanzanian regions of Arusha, Kilimanjaro, Tanga, Singida, and Manyara, with respect to four dimensions: timeliness, surgical capacity, safety, and affordability. Timeliness was estimated by the proportion of people living within a 4-h driving distance from a hospital with an orthopaedic surgeon, capacity by comparing number of surgeries performed to the number of surgeries indicated, safety by applying WHO Emergency and Essential Surgical Care infrastructure and equipment checklists, and affordability by approximating the proportion of the population protected from catastrophic out-of pocket healthcare expenditure. We accounted for uncertainty in our model with one way and probabilistic sensitivity analyses. Data sources included the Tanzanian National Bureau of Statistics and Ministry of Finance, World Bank, World Health Organization, New Zealand Ministry of Health, Google Corporation, NASA population estimator, and 2015 hospital records from Kilimanjaro Christian Medical Center, Machame Hospital, Nkoroanga Hospital, Mt. Meru Hospital, and Arusha Lutheran Medical Center. RESULTS: Under the most conservative assumptions, more than 90% of the Northern Tanzanian population does not have access to orthopaedic surgical services. CONCLUSION: There is a near absence of access to orthopaedic surgical care in Northern Tanzania. These findings utilize more precise country and region specific data and are consistent with prior published global trends regarding surgical access in Sub-Saharan Africa. As the global health community must develop innovative solutions to address the rising burden of musculoskeletal disease and support the advancement of universal health coverage, increasing access to orthopaedic surgical services will play a central role in improving health care in the world's developing regions. PMID- 29696328 TI - Does Intermittent Pringle Maneuver Increase Postoperative Complications After Hepatectomy for Hepatocellular Carcinoma? A Randomized Controlled Trial. AB - BACKGROUND: In a previous study, we have shown that intermittent Pringle maneuver (IPM) might increase postoperative complications after hepatectomy for various indications. Complications which thought to be related to IPM were ascites, pleural effusion, wound infection and intra-abdominal collection. The aim of this study was to test the hypothesis that applying IPM during hepatectomy for hepatocellular carcinoma (HCC) could increase postoperative complications. METHODS: Between January 2013 and October 2016, eligible patients who received elective open hepatectomy for HCC were randomized to have IPM or no Pringle maneuver (NPM). Occurrence of various types of postoperative complications was specifically looked for. A routine postoperative day 5 abdominal ultrasound examination and chest X-ray were done to detect and grade any radiological ascites, pleural effusion and intra-abdominal collection. RESULTS: Fifty IPM and 50 NPM patients with histological proven HCC were recruited for final analysis. Demographics and operative parameters were comparable between the two groups. The postoperative complication rates were similar (IPM 36.0 vs. NPM 28.0%, P = 0.391). However, in the IPM group, more patients developed radiological posthepatectomy ascites (42.0 vs. 22.0%, P = 0.032) and pleural effusion (66.0 vs. 38.0%, P = 0.005). In patients with histologically proven cirrhosis, there were 28 IPM and 25 NPM patients. Again, there was no difference in postoperative complication rate but more radiological posthepatectomy ascites and pleural effusion in the IPM group. CONCLUSION: This trial was not able to detect a difference in postoperative complications whether IPM was applied or not, but use of IPM was associated with more subclinical ascites and pleural effusion. (ClinicalTrials.gov NCT01759901). TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01759901. PMID- 29696329 TI - First Rib Resection for Thoracic Outlet Syndrome: The Robotic Approach. AB - OBJECTIVE: First rib resection is a well-recognized treatment option for thoracic outlet syndrome (TOS). In case of a vascular insufficiency that can be provoked and/or progressive neurologic symptoms without response to conservative treatment, surgical decompression of the space between the clavicle and the first rib is indicated. The aim of this paper is to present our experience with a new minimally invasive robotic approach using the da Vinci Surgical System(r). METHODS: Between January 2015 and October 2017, eight consecutive first rib resections in seven patients were performed at our institution. Four patients presented with neurologic (one bilateral), and three patients with vascular (venous) impairment. In all cases, a transthoracic robotic-assisted approach was used. The first rib was removed using a 3-port robotic approach with an additional 2-cm axillary incision in the first six patients. The latest resection was performed through only three thoracic ports. RESULTS: Median operative time was 108 min, and the median hospital stay was 2 days. Postoperative courses were uneventful in all patients. Clinical follow-up examinations showed relief of symptoms in all nonspecific TOS patients, and duplex ultrasonography confirmed complete vein patency in the remaining patients 3 months after surgery. CONCLUSIONS: While there are limitations in conventional transaxillary, subclavicular and supraclavicular approaches in the first rib resection, the robotic method is not only less invasive but also allows better exposure and visualization of the first rib. Furthermore, the technique takes advantage of the benefits of the da Vinci Surgical System(r) in terms of 3D visualization and improved instrument maneuverability. Our early experience clearly demonstrates these advantages, which are also supported by the very good outcomes. PMID- 29696330 TI - Patient Frailty Should Be Used to Individualize Treatment Decisions in Primary Hyperparathyroidism. AB - BACKGROUND: Primary hyperparathyroidism (PHPT) is a common endocrine disorder that predominantly affects patients >60 and is increasing in prevalence. Identifying risk factors for poor outcomes after parathyroidectomy in older adults will help tailor operative decision making. The impact of frailty on surgical outcomes in parathyroidectomy has not been established. METHODS: We performed a retrospective review of patients >=40 years who underwent parathyroidectomy in the 2005-2010 ACS NSQIP. Frailty was assessed using the modified frailty index (mFI). Multivariable regression was used to determine the association of frailty with 30-day complications, length of stay (LOS), and reoperation. RESULTS: We identified 13,123 patients >=40 who underwent parathyroidectomy for PHPT. The majority of patients were not frail, with 80% with a low NSQIP mFI score (0-1 frailty traits), 19% with an intermediate mFI score (2-3), and 0.9% with a high mFI score (>=4). Overall 30-day complications were rare, occurring in 141 (1.1%) patients. Increasing frailty was associated with an increased risk of complications with adjusted odds ratios (ORs) of 1.76 (95% CI 1.20-2.59; p = 0.004) for intermediate and 8.43 (95% CI 4.33-16.41; p < 0.001) for high mFI score. Patient age was independently associated with an increased risk of complications only when >=75, as was African-American race. Anesthesia with local, monitored anesthesia care, or regional block was the only factor associated with decreased odds of complications. A high NSQIP mFI was also associated with a significant 4.77-day adjusted increase in LOS (95% CI 4.28 5.25; p < 0.001) and increased odds of reoperation (OR 4.20, 95% CI 1.64-10.74; p = 0.003). CONCLUSION: Patient frailty is associated with increased complications, reoperation and prolonged LOS in patients undergoing parathyroidectomy for PHPT. The risks of surgical management should be weighed against potential benefits in frail patients with PHPT to individualize treatment decisions in this vulnerable population. PMID- 29696331 TI - Seeking key microorganisms for enhancing methane production in anaerobic digestion of waste sewage sludge. AB - Efficient approaches for the utilization of waste sewage sludge have been widely studied. One of them is to use it for the bioenergy production, specifically methane gas which is well-known to be driven by complex bacterial interactions during the anaerobic digestion process. Therefore, it is important to understand not only microorganisms for producing methane but also those for controlling or regulating the process. In this study, azithromycin analogs belonging to macrolide, ketolide, and lincosamide groups were applied to investigate the mechanisms and dynamics of bacterial community in waste sewage sludge for methane production. The stages of anaerobic digestion process were evaluated by measuring the production of intermediate substrates, such as protease activity, organic acids, the quantification of bacteria and archaea, and its community dynamics. All azithromycin analogs used in this study achieved a high methane production compared to the control sample without any antibiotic due to the efficient hydrolysis process and the presence of important fermentative bacteria and archaea responsible in the methanogenesis stage. The key microorganisms contributing to the methane production may be Clostridia, Cladilinea, Planctomycetes, and Alphaproteobacteria as an accelerator whereas Nitrosomonadaceae and Nitrospiraceae may be suppressors for methane production. In conclusion, the utilization of antibiotic analogs of macrolide, ketolide, and lincosamide groups has a promising ability in finding the essential microorganisms and improving the methane production using waste sewage sludge. PMID- 29696332 TI - Bacterial population dynamics in recycled mushroom compost leachate. AB - Mushrooms are an important food crop throughout the world. The most important edible mushroom is the button mushroom (Agaricus bisporus), which comprises about 30% of the global mushroom market. This species is cultivated commercially on a selective compost that is produced predominantly from wheat straw/stable bedding and chicken manure, at a moisture content of around 70% (w/w) and temperatures of up to 80 degrees C. Large volumes of water are required to achieve this moisture content, and many producers therefore collect leachate from the composting windrows and bunkers (known in the industry as "goody water") and reuse it to wet the raw ingredients. This has the benefit of recycling and saving water and has the potential to enrich beneficial microorganisms that stimulate composting, but also the risk of enhancing pathogen populations that could reduce productivity. Here, we show by 16S rRNA gene sequencing that mushroom compost leachate contains a high diversity of unknown microbes, with most of the species found affiliated with the phyla Firmicutes and Proteobacteria. However, by far the most abundant species was the thermophile Thermus thermophilus, which made up approximately 50% of the bacterial population present. Although the leachate was routinely collected and stored in an aerated central storage tank, many of the bacterial species found in leachate were facultative anaerobes. However, there was no evidence for sulfide production, and no sulfate-reducing bacterial species were detected. Because T. thermophilus is important in the high temperature phase of composting, the use of recycled leachate as an inoculum for the raw materials is likely to be beneficial for the composting process. PMID- 29696333 TI - A novel gene, encoding 3-aminobenzoate 6-monooxygenase, involved in 3 aminobenzoate degradation in Comamonas sp. strain QT12. AB - The biodegradation pathway of 3-aminobenzoate has been documented, but little is known about the sequence and biochemical properties of the proteins involved. In the present study, a 10,083-bp DNA fragment involved in 3-aminobenzoate degradation was identified in 3-aminobenzoate-degrading Comamonas sp. strain QT12. The mabA gene, whose encoded protein shares 39% amino acid sequence identity with 3-hydroxybenzoate 6-hydroxylase of Polaromonas naphthalenivorans CJ2, was identified on this DNA fragment, and the mabA-disrupted mutant was unable to grow on and convert 3-aminobenzoate. MabA was heterologously expressed in Escherichia coli and purified to homogeneity as an approximately ~ 48-kDa His tagged protein. It was characterized as 3-aminobenzoate 6-hydroxylase capable of catalyzing the conversion of 3-aminobenzoate to 5-aminosalicylate, incorporating one oxygen atom from dioxygen into the product. It contains a non-covalent but tightly bound FAD as the prosthetic group and NADH as an external electron donor. 5-Aminosalicylate was produced with equimolar consumption of NADH. The apparent Km and kcat values of the purified enzyme for 3-aminobenzoate were 158.51 +/- 4.74 MUM and 6.49 +/- 0.17 s-1, respectively, and those for NADH were 189.85 +/- 55.70 MUM and 7.41 +/- 1.39 s-1, respectively. The results suggest that mabA is essential for 3-aminobenzoate degradation in strain QT12, and that 3 aminobenzoate is the primary and physiological substrate of MabA. PMID- 29696334 TI - Evaluation of MALDI-TOF mass spectrometry for the competitiveness analysis of selected indigenous cowpea (Vigna unguiculata L. Walp.) Bradyrhizobium strains from Kenya. AB - Cowpea N2 fixation and yield can be enhanced by selecting competitive and efficient indigenous rhizobia. Strains from contrasting agro-ecologies of Kilifi and Mbeere (Kenya) were screened. Two pot experiments were established consisting of 13 Bradyrhizobium strains; experiment 1 (11 Mbeere + CBA + BK1 from Burkina Faso), experiment 2 (12 Kilifi + CBA). Symbiotic effectiveness was assessed (shoot biomass, SPAD index and N uptake). Nodule occupancy of 13 simultaneously co-inoculated strains in each experiment was analyzed by matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectrometry (MS) to assess competitiveness. Strains varied in effectiveness and competitiveness. The four most efficient strains were further evaluated in a field trial in Mbeere during the 2014 short rains. Strains from bacteroids of cowpea nodules from pot and field experiments were accurately identified as Bradyrhizobium by MALDI-TOF based on the SARAMISTM database. In the field, abundant indigenous populations 7.10 * 103 rhizobia g-1 soil, outcompeted introduced strains. As revealed by MALDI-TOF, indigenous strains clustered into six distinct groups (I, II, III, IV, V and VI), group III were most abundant occupying 80% of nodules analyzed. MALDI-TOF was rapid, affordable and reliable to identify Bradyrhizobium strains directly from nodule suspensions in competition pot assays and in the field with abundant indigenous strains thus, its suitability for future competition assays. Evaluating strain competitiveness and then symbiotic efficacy is proposed in bioprospecting for potential cowpea inoculant strains. PMID- 29696335 TI - An effective established biosensor of bifunctional probes-labeled AuNPs combined with LAMP for detection of fish pathogen Streptococcus iniae. AB - In purpose of valid Streptococcus iniae detection, we established a colorimetric biosensor using gold nanoparticles (AuNPs) labeled with dual functional probes and along with loop-mediated isothermal amplification (LAMP) assay (LAMP-AuNPs). Based on the characteristics of self-aggregation and bio-conjugation with ligands, AuNPs were chosen for observable color change in tandem with LAMP amplification method to reach high sensitivity and easy operation. Meanwhile, the improvement of dual probes that could fully utilize the LAMP product gave the biosensor a stable result exhibition. LAMP-AuNPs targeting gene ftsB, one of the ATP transporter-related genes, turned out favorable specificity in cross reaction among other fish pathogens. The detect limit of 102 CFU revealed a better sensitivity compared with polymerase chain reaction (PCR) method and AuNPs lateral flow test strip (LFTS). It was also proved to be effective by zebrafish infection model trials with less than 2-h time consumption and nearly no devices which make it a convenient biosensor for point-to-care S. iniae detection. PMID- 29696336 TI - The attachment potential and N-acyl-homoserine lactone-based quorum sensing in aerobic granular sludge and algal-bacterial granular sludge. AB - Bacteria and algae often coexist in the aerobic granular sludge (AGS) system in a photo-bioreactor, forming algal-bacterial granular sludge. In this study, the physicochemical characteristics and microbial attachment potential of the AGS and algal-bacterial granular sludge were comparatively analyzed. Results clearly showed that the larger and denser algal-bacterial granular sludge had stronger attachment potential compared to the AGS (as the control). A bioassay with Agrobacterium tumefaciens KYC55 indicated that N-acyl-homoserine lactones (AHLs) existed in both sludge types, but further investigations revealed that the relative AHL content of the algal-bacterial granular sludge obviously increased and slightly decreased during phases II and III, respectively, but was consistently higher than the AGS. Based on the EPS measurements and 3D-excitation emission matrix (3D-EEM) fluorescence spectra analysis, the enhancement of AHL based QS favored the hydrophobic protein production of algal-bacterial granular sludge, contributing to a good development of the granular sludge. In addition, it was also found that inhibition of AHLs resulted in the reduction of the protein content and attachment potential in algal-bacterial granular sludge, which was unfavorable to the structural stability of the granules. High throughput sequencing analysis showed that the microbial community of AGS was different from the algal-bacterial granular sludge; specifically, algal-bacterial granulation facilitated the abundance of AHLs and EPS producers, such as the genera Acinetobacter, Chryseobacterium, and Flavobacterium. PMID- 29696337 TI - Impact of temperature on fatty acid composition and nutritional value in eight species of microalgae. AB - Microalgae are considered a sustainable source of high-value products with health benefits. Marine algae-derived omega-3 long-chain polyunsaturated fatty acids (LC PUFA), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are considered dietary elements with effects on mental health, cognition enhancement, and cardiovascular protection. This study investigated the temperature effect on omega-3 LC-PUFA production in eight species of microalgae from various taxonomic groups, with a focus on achieving an optimal balance between omega-3 accumulation and efficient growth performance. Samples were batch-cultivated at four different temperatures, with constant light, and fatty acid methyl esters (FAME) were analyzed by gas chromatography. Several nutritional indices were calculated to assess the potential value of biomass produced for human consumption. Two promising candidates were identified suitable for batch cultivation and large scale production: Nannochloropsis oculata for EPA and Isochrysis galbana for DHA production, with optimum productivities obtained between 14 and 20 degrees C, and nutritional indices falling within the range required for nutritional benefit. PMID- 29696338 TI - Aspergillus flavus GPI-anchored protein-encoding ecm33 has a role in growth, development, aflatoxin biosynthesis, and maize infection. AB - Many glycosylphosphatidylinositol-anchored proteins (GPI-APs) of fungi are membrane enzymes, organization components, and extracellular matrix adhesins. We analyzed eight Aspergillus flavus transcriptome sets for the GPI-AP gene family and identified AFLA_040110, AFLA_063860, and AFLA_113120 to be among the top 5 highly expressed genes of the 36 family genes analyzed. Disruption of the former two genes did not drastically affect A. flavus growth and development. In contrast, disruption of AFLA_113120, an orthologue of Saccharomyces cerevisiae ECM33, caused a significant decrease in vegetative growth and conidiation, promoted sclerotial production, and altered conidial pigmentation. The A. flavus ecm33 null mutant, compared with the wild type and the complemented strain, produced predominantly aflatoxin B2 but accumulated comparable amounts of cyclopiazonic acid. It showed decreased sensitivity to Congo red at low concentrations (25-50 MUg/mL) but had increased sensitivity to calcofluor white at high concentrations (250-500 MUg/mL). Analyses of cell wall carbohydrates indicated that the alpha-glucan content was decreased significantly (p < 0.05), but the contents of chitin and beta-glucan were increased in the mutant strain. In a maize colonization study, the mutant was shown to be impaired in its infectivity and produced 3- to 4-fold lower amounts of conidia than the wild type and the complemented strain. A. flavus Ecm33 is required for proper cell wall composition and plays an important role in normal fungal growth and development, aflatoxin biosynthesis, and seed colonization. PMID- 29696339 TI - Yarrowia lipolytica morphological mutant enables lasting in situ immobilization in bioreactor. AB - In the present study, we have isolated and characterized a Yarrowia lipolytica morphological mutant growing exclusively in the pseudohyphal morphology. The gene responsible for this phenotype, YALI0E06519g, was identified as homologous to the mitosis regulation gene HSL1 from Saccharomyces cerevisiae. Taking advantage of its morphology, we achieved the immobilization of the Deltahsl1 mutant on the metallic structured packing of immobilized-cell bioreactors. We obtained significant cell retention and growth on the support during shake flask and bioreactor experiments without an attachment step prior to the culture. The system of medium aspersion on the packing ensured oxygen availability in the absence of agitation and minimized the potential release of cells in the culture medium. Additionally, the metallic packing proved its facility of cleaning and sterilization after fermentation. This combined use of morphological mutation and bioreactor design is a promising strategy to develop continuous processes for the production of recombinant protein and metabolites using Y. lipolytica. Graphical Abstract. PMID- 29696340 TI - Cardoon-based rennets for cheese production. AB - The use of crude aqueous extracts of Cynara cardunculus flowers as coagulants in the production of high-quality sheep and goat cheeses-as are the cases of several Portuguese and Spanish cheese varieties with Protected Designation of Origin status-has been maintained since ancient times. The unique rheological attributes and sensory properties characteristic of these cheeses have always suggested that this plant coagulant (and, therefore, its isolated milk-clotting proteases) could be used as alternative rennet in the dairy industry, particularly suited for the production of sheep and goat cheeses. However, the lack of standardization of C. cardunculus crude flower extracts, whose quality and performance depends on numerous factors, has always hampered the application of this plant rennet in industrial production scales. To overcome these limitations, and to aim at developing more effective solutions with potential for scalability of production and commercial application, several strategies have been undertaken in more recent years to establish new cardoon-based rennets. This review provides an overview on these developments and on the currently available solutions, which range from producing standardized formulations of native cardoon enzymes, to the optimization of the heterologous production of cardosins and cyprosins to generate synthetic versions of these milk-clotting enzymes. Challenges and emerging opportunities are also discussed. PMID- 29696341 TI - Risk stratification in hypertrophic cardiomyopathy. AB - Sudden cardiac death (SCD) is the most devastating complication of hypertrophic cardiomyopathy (HCM). The greatest challenge in the management of HCM is identifying those at increased risk, since an implantable cardioverter defibrillator (ICD) is a potentially life-saving therapy. We sought to summarize the available data on SCD in HCM and provide a clinical perspective on the current differing and somewhat conflicting data on risk stratification, with balanced guidance regarding rational clinical decision-making. Additionally, we sought to determine the status of the current implementation of guidelines compiled by HCM experts worldwide. The HCM Risk-SCD model helps improve the risk stratification of HCM patients for primary prevention of SCD by calculating an individual risk estimate that contributes to the clinical decision-making process. Improved risk stratification is important for decision-making before ICD implantation for the primary prevention of SCD. PMID- 29696342 TI - An Assessment of Institutional Capacity for Integrated Landscape Management in Eastern Cameroon. AB - Landscape approaches have become prominent in efforts to address issues of conservation and development through bringing together different actors and sectors, to reconcile diverse land uses, and promote synergies. Some have suggested that integrated landscape management approaches are consistent with the goals of REDD+ and offer a strategy to address multiple goals of climate change mitigation, biodiversity conservation, maintenance of ecosystem services, and socio-economic development. Institutional or governance arrangements have been shown to be a critical component in influencing outcomes in landscapes. Using diverse methodologies, this study investigated the capacity of institutions to support the planning, implementation, and resource mobilization needed to integrate climate change mitigation, conservation, and livelihood goals in a forest mosaic landscape in East Cameroon. Results showed that diverse institutions are present in the landscape, including institutions of relevant government agencies, local government, local non-government, the private sector, and hybrid institutions of conservation, development and research institutions. However, the overall institutional capacity for integrated landscape planning and management in the study area is limited, although some institutions exhibit increased capacity in some areas over others. Multiple strategies can be employed to build the necessary human, financial, and leadership capacity, and facilitate the institutional planning and coordination that is foundational to multi stakeholder landscape governance. Given the complexity of integrating climate change mitigation, conservation and livelihood goals in a landscape, building such institutional capacity is a long term endeavour that requires sustained effort and ongoing financial, technical and human resource support. PMID- 29696343 TI - The Significance of Land Cover Delineation on Soil Erosion Assessment. AB - The study aims to evaluate the significance of land cover delineation on soil erosion assessment. To that end, RUSLE (Revised Universal Soil Loss Equation) was implemented at the Upper Acheloos River catchment, Western Central Greece, annually and multi-annually for the period 1965-92. The model estimates soil erosion as the linear product of six factors (R, K, LS, C, and P) considering the catchment's climatic, pedological, topographic, land cover, and anthropogenic characteristics, respectively. The C factor was estimated using six alternative land use delineations of different resolution, namely the CORINE Land Cover (CLC) project (2000, 2012 versions) (1:100,000), a land use map conducted by the Greek National Agricultural Research Foundation (NAGREF) (1:20,000), a land use map conducted by the Greek Payment and Control Agency for Guidance and Guarantee Community Aid (PCAGGCA) (1:5,000), and the Landsat 8 16-day Normalized Difference Vegetation Index (NDVI) dataset (30 m/pixel) (two approximations) based on remote sensing data (satellite image acquired on 07/09/2016) (1:40,000). Since all other factors remain unchanged per each RUSLE application, the differences among the yielded results are attributed to the C factor (thus the land cover pattern) variations. Validation was made considering the convergence between simulated (modeled) and observed sediment yield. The latter was estimated based on field measurements conducted by the Greek PPC (Public Power Corporation). The model performed best at both time scales using the Landsat 8 (Eq. 13) dataset, characterized by a detailed resolution and a satisfactory categorization, allowing the identification of the most susceptible to erosion areas. PMID- 29696345 TI - Tilt table testing for syncope and collapse. AB - Head-up tilt (HUT) has long been used to examine heart rate and blood pressure adaptation to changes in position. During such studies, incidental observations noted that some test subjects experienced total or near-total transient loss of consciousness and that, in some cases, hypotension was associated with unexpected marked bradycardia compatible with a vasovagal syncope (VVS) reaction. The first report of HUT as a clinical tool to confirm a diagnosis of suspected VVS was published in 1966, and led to the concept of using HUT as a diagnostic tool for VVS. Subsequently, HUT testing, either drug-free or, if necessary, with pharmacological provocation (usually nitroglycerin) has proven to be a useful and safe modality for identifying susceptibility to VVS. In this regard, it is recognized that VVS is best diagnosed by careful history taking. Unfortunately, the history may be non-diagnostic; HUT may be helpful in such cases. However, the interpretation of HUT requires care and experience; in particular, the outcome must be consistent with the patient's clinical presentation. The reproduction of patient symptoms may not only provide a diagnosis, but also offer some comfort to the patient and family in that the medical team has documented the basis of symptoms and are thereby positioned to address therapy. PMID- 29696346 TI - Orthostatic intolerance and postural tachycardia syndrome: new insights into pathophysiology and treatment. AB - Orthostatic intolerance is characterized by symptoms of light-headedness or syncope that is provoked upon standing or in an upright posture. It is most commonly caused by postural orthostatic tachycardia syndrome (POTS) or orthostatic hypotension (OH). Its pathophysiology is complex and commonly involves abnormal autonomic nervous system regulation, autoimmunity, a hyperadrenergic state, and hypovolemia. This article reviews the pathophysiology underlying orthostatic intolerance, as well as the current treatment available. PMID- 29696347 TI - Syncope and bundle branch block : Diagnostic approach. AB - Syncope and bundle branch block are reviewed, addressing their specific clinical characteristics, natural history, initial diagnostic approach and the role and limitations of different diagnostic tests with a special focus on electrophysiological studies and implantable loop recorders. A critical review of the different published strategies to be followed in these patients is made and finally an algorithm of how to manage these patients is proposed. PMID- 29696348 TI - Perioperative radiotherapy is an independent risk factor for major LARS: a cross sectional observational study. AB - PURPOSE: Sphincter-preserving surgery for rectal cancer is often associated with low anterior resection syndrome (LARS). The aim of our study was to determine the prevalence of LARS in our institution and identify possible risk factors for LARS. Furthermore, we evaluated which of the LARS symptoms was considered most disabling by patients and whether or not there is an adaptation of the LARS score over time. METHODS: This study includes a prospective database of 100 patients who underwent total or partial mesorectal excision between January 2009 and September 2014. Patients were contacted after a median postoperative time of 38 (5-45) months to determine the LARS score and to identify LARS symptoms that were considered most disabling. Uni- and multivariate regression analysis was performed to identify risk factors for LARS and major LARS. Finally, the LARS score was evaluated over time after restoration of bowel continuity. RESULTS: Out of the 100 patients, 16 had minor LARS (score 21-29) and 51 patients had major LARS (score 30-42). Radiotherapy was an independent risk factor for major LARS (p = 0.04). For the majority of patients with major LARS (22%), fragmentation was considered the most disabling complaint. There was no correlation between interval after restoration of bowel continuity and the severity of the LARS score. CONCLUSIONS: Perioperative radiotherapy is an independent risk factor for major LARS. Fragmentation is considered the most disabling complaint in the majority of patients with major LARS. There is no significant adaptation of the LARS score over time. PMID- 29696349 TI - Mucinous components assessed by magnetic resonance imaging in primary rectal cancer tissue before and after chemoradiotherapy and tumor response. AB - BACKGROUND: Mucinous rectal carcinoma has been reported to have a lower survival rate and a poorer histologic response to chemoradiotherapy(CRT). Magnetic resonance imaging (MRI) can accurately evaluate the amount of mucin pools (MP) in primary cancer tissue. We compared the degree of MP on MRI before and after CRT with the histologic findings of resected specimens to investigate the predictors of response to CRT. METHODS: The study group comprised 205 patients with rectal adenocarcinoma who received preoperative CRT. MPs were measured on MRI before and after CRT and in resected specimens. The degree of MP was classified into five classes according to the MP area ratio: 0%, class I; 1 to 19%, class II; 20 to 49%, class III; and 50% or higher, class IV. RESULTS: The degree of MP on MRI was largely unchanged after CRT; however, the MP on MRI after CRT was underestimated in 26.3% of patients as compared with that in resected specimens. A pathological complete response was obtained in patients who initially had no MP or had an MP ratio of less than 20%. The tumor volume was significantly greater, and the rates of tumor shrinkage and T downstaging were significantly lower in patients who had an MP area ratio of 20% or higher before CRT than in those who had an MP area ratio of less than 20%. CONCLUSIONS: The MP area ratio measured on MRI before treatment was closely associated with the response to CRT and is a potentially useful predictor of treatment response. PMID- 29696350 TI - Exenatide preserves trabecular bone microarchitecture in experimental ovariectomized rat model. AB - PURPOSE: The aim of this study is to investigate effects of exenatide (Glucagon Like Peptide Agonist) replacement on bone mineral density (BMD) and microarchitecture in a surgical menopause-induced osteoporosis model in rats. METHODS: In this study, 24 female Sprague-Dawley albino mature rats were used. Rats were assigned either to the group ovariectomized administered exenatide or to the control group. Bone Mineral Density (BMD), plasma cytokine levels and histomorphometric analysis were measured. RESULTS: Ovariectomized rats showed significant decrease BMD values, trabecular counts, trabecular thickness and trabecular area. Also, significant increase trabecular separation and plasma TNF alpha (Tumor Necrosis Factor) and IL-6 (Interleukin) levels. Exenatide treatment reversed these changes and it showed a considerable protective effect on trabecular bone microarchitecture. CONCLUSIONS: Exenatide may be a candidate for use in the treatment of postmenopausal osteoporosis and anti-inflammatory properties can be attributed this effects. PMID- 29696344 TI - PAR3-PAR6-atypical PKC polarity complex proteins in neuronal polarization. AB - Polarity is a fundamental feature of cells. Protein complexes, including the PAR3 PAR6-aPKC complex, have conserved roles in establishing polarity across a number of eukaryotic cell types. In neurons, polarity is evident as distinct axonal versus dendritic domains. The PAR3, PAR6, and aPKC proteins also play important roles in neuronal polarization. During this process, either aPKC kinase activity, the assembly of the PAR3-PAR6-aPKC complex or the localization of these proteins is regulated downstream of a number of signaling pathways. In turn, the PAR3, PAR6, and aPKC proteins control various effector molecules to establish neuronal polarity. Herein, we discuss the many signaling mechanisms and effector functions that have been linked to PAR3, PAR6, and aPKC during the establishment of neuronal polarity. PMID- 29696351 TI - The effects of superovulation with gonadotropins on autoantibody levels in patients undergoing assisted reproductive cycles. AB - PURPOSE: To evaluate the effect of controlled ovarian stimulation (COH) with gonadotropins on the serum levels of autoantibodies in the women who underwent in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) cycles and to compare basal levels of these autoantibodies between groups according to history of COH. METHODS: This prospective cohort study was performed from October 2014 to March 2016 in the Royan Institute. The volunteered infertile women with regard to the inclusion criteria, who underwent IVF/ICSI cycles, were recruited. The COH was performed according to standard long GnRH agonist protocol. The mean levels of the autoantibodies including anti-nuclear, anti-smooth muscle, anti-ovarian, anti-mitochondrial, anti beta2-glycoprotein I, anti-parietal cell and anti follicle-stimulating hormone antibodies were measured at three time points: on the 3-5 days of the menstrual cycle, 1 week after starting of COH and the ovum pick-up (OPU) day. RESULTS: Of all participants (n = 189), 73 women had history of COH (group B) and 116 women did not have such history (group A). The analysis indicated that the autoantibodies changes during COH were similar in both groups. COH has no significant impact on the level of autoantibodies during the stimulation cycle. Multiple logistic regression analysis showed that the serum levels of anti-smooth muscle antibody on OPU day was the positive predictive factors for live birth following ART cycles in the studied population. CONCLUSION: No significant effect of COH on the studied autoantibodies by the time of OPU was found but further studies are required to interpret these results. PMID- 29696352 TI - [Allergic emergencies]. AB - Both anaphylactic reactions and angioedema in the head and neck area can be life threatening and require emergency treatment. Therapy needed is primarily directed by the patient's symptoms. The first measures taken should consist of immediate disruption of the allergen contact, adequate positioning of the patient, the insertion of an intravenous catheter and an emergency call. In case of cardiovascular or respiratory involvement, intramuscular +/- inhalative adrenalin is the treatment of choice. In case of cardiovascular involvement, volume substitution by intravenous catheter and oxygen administration are crucial and in lower airway obstruction, additionally short-acting beta mimetics should be inhaled. Intravenous H1-antihistamines and glucocorticoids are added. Allergic reaction confined to the skin and mucosal surfaces without respiratory involvement or to the gastrointestinal tract should also be treated with intravenous H1-antihistamines and glucocorticoids. Angioedema in the head and neck area can, however, also be associated with a life-threatening upper airway obstruction. Histamine-induced angioedema should be treated as anaphylaxis involving the upper respiratory tract. In hereditary angioedema, or in unclassified angioedema unresponsive to therapy, early airway maintenance and subcutaneous injection of bradykinin-receptor antagonist icatibant, intravenous injection of C1-inhibitor concentrate or fresh frozen plasma is recommended. The same approach should be taken for severe angiotensin converting enzyme inhibitor induced angioedema with dyspnea. Intubation by skilled personal is indicated in inspiratory stridor and dyspnea at rest. In all cases of anaphylaxis or angioemdema, patients should be surveyed until a safe remission is achieved. PMID- 29696353 TI - [Early detection of occupational skin diseases in sewer workers]. AB - BACKGROUND: Skin diseases affect 30-70% of the world population, and globally, skin cancer rates are continuously increasing. In this respect, prevention programs and early detection of skin diseases are of particular importance. OBJECTIVES: To screen sewer workers for skin diseases with regard to their work related risk. METHODS: Employees of the municipal utilities in Munich (Munchner Stadtentwasserung) underwent a whole-body examination of the skin, conducted by two dermatologists. In addition, all employees completed a paper-based questionnaire on risk behavior and preventive measures. RESULTS: We examined 81 employees (79 men, 2 women, mean age 45.7 +/- 9.5 years). Skin lesions in need of treatment were found in 30.9% (n = 25): the most frequent diagnosis was mycosis pedis (16.1%). In addition, one employee was diagnosed with basal cell carcinoma and two with actinic keratoses. According to the questionnaire, 43.5% of the employees had undergone a physician-led skin cancer screening in the past, whereas sun-protection practices were rarely applied. CONCLUSION: According to our findings, employee skin cancer screening seems to be beneficial for the detection of work-related skin diseases and is associated with a high participation rate. Furthermore, the study suggests that sewer workers have a high rate of mycosis pedis, possibly a work-related effect. PMID- 29696354 TI - [Compression bandages with and without padding : Observational controlled survey of pressure and comfort]. AB - BACKGROUND: In the context of compression therapy, padded bandages are designed to prevent skin damage, increase adherence and support the success of therapy. Routine use is discussed, because comparative studies are lacking. OBJECTIVES: This study examines effectiveness, comfort, and impact of short-stretch bandages without padding compared to underpadded bandages. PARTICIPANTS AND METHODS: In all, 61 healthy participants wore padded bandages foam or synthetic cotton wool on one leg and nonpadded bandages on the other. On both sides, a resting pressure of 50 mm Hg was generated. After 60 min resting pressure, skin condition, comfort, pain, and fitting of the bandages were assessed. RESULTS: All bandages showed pressure losses after 1 h; 82.0% of nonpadded bandages had a pressure drop of 9 mm Hg or more. The following were observed in unpadded bandages: constrictions (100.0%), severe redness (77.0%) and bruises (42.6%). Comfort was rated as pleasant by 3.3% without padding, by 83.9% with foam padding, and by 73.3% with synthetic cotton wool padding. Nonpadded compression bandages caused in 62.3% pain from 1-3 (numerical rating scale 0-10). CONCLUSIONS: Padded compression bandages maintain the therapy-relevant pressure better, provide more comfort, and cause less pain and skin problems than nonpadded compression bandages. These aspects are crucial for adherence, and therapeutic success. After 1 h of use on the healthy leg, there were obvious differences. Significantly more side effects may appear after several hours of use on previously damaged skin. Therefore, compression bandages should always be padded. PMID- 29696355 TI - Risk of mild head injury in preschool children: relationship to attention deficit hyperactivity disorder symptoms. AB - AIM: To investigate whether there is an association between mild head injury (MHI) and attention deficit hyperactivity disorder (ADHD) symptoms in preschool children. METHODS: The study included a patient group of 30 children aged 3-6 years with mild head trauma and a control group of 30 healthy and age- and sex matched children. The symptoms of ADHD were evaluated using the Conners' Parent Rating Scale-Revised Long (CPRS-RL) form. RESULTS: The mean age was 4.73 +/- 1.13 years in the patient group and 4.65 +/- 0.99 years in the control group. No significant differences were determined between the groups in terms of age, gender, parents' age and education (p > 0.05). The total subscale points as reported by the parents of the children with MHI were significantly higher than those for the control group in terms of the following subscales: oppositional, cognitive problems/inattention, hyperactivity, social problems, ADHD index, Conners' Global Index (CGI)-Irritability-Impulsiveness, CGI-Emotional Lability, CGI-Total and DSM-IV ADHD symptoms (p < 0.05). A history of previous trauma treated in emergency services was determined in eight of the 30 patients (26.7%). CONCLUSIONS: The findings of this study suggest that preschool children with MHI have more pre-injury ADHD symptoms and oppositional and emotional-behavioural symptoms than healthy children without trauma. Clinicians should screen children with MHI for ADHD symptoms and refer them for treatment when necessary. Evaluation of children presenting with MHI by a child psychiatrist may prevent repetition of injuries. PMID- 29696356 TI - Successful endoscopic third ventriculostomy in children depends on age and etiology of hydrocephalus: outcome analysis in 51 pediatric patients. AB - PURPOSE: Endoscopic third ventriculostomy (ETV) has become the method of choice in the treatment of hydrocephalus. Age and etiology could determine success rates (SR) of ETV. The purpose of this study is to assess these factors in pediatric population. METHODS: Retrospective study on 51 children with obstructive hydrocephalus that underwent ETV was performed. The patients were divided into three groups per their age at the time of the treatment: < 6, 6-24, and > 24 months of age. All ETV procedures were performed by the same neurosurgeon. RESULTS: Overall SR of ETV was 80% (40/51) for all etiologies and ages. In patients < 6 months of age SR was 56.2% (9/16), while 6-24 months of age was 88.9% (16/18) and > 24 months was 94.1% (16/17) (p = 0.012). The highest SR was obtained on aqueductal stenosis. SR of posthemorrhagic, postinfectious, and spina bifida related hydrocephalus was 60% (3/5), 50% (1/2), and 14.3% (1/7), respectively. While SR rate at the first ETV attempt was 85.3%, it was 76.9% in patients with V-P shunt performed previously (p = 0.000). CONCLUSIONS: Factors indicating a potential failure of ETV were young age and etiology such as spina bifida, other than isolated aqueductal stenosis. ETV is the method of choice even in patients with former shunting. Fast healing, distensible skulls, and lower pressure gradient in younger children, all can play a role in ETV failure. Based on our experience, ETV could be the first method of choice for hydrocephalus even in children younger than 6 months of age. PMID- 29696357 TI - Stigma experiences and perceived stigma in patients with first-episode schizophrenia in the course of 1 year after their first in-patient treatment. AB - Patients with schizophrenia suffer from stigma and discrimination due to their illness. Yet it is not well examined how experiences of stigma and discrimination express at the early illness stage and how they develop subsequently. Therefore, clinical and psycho-social correlates of stigma experiences and perceived stigma are analyzed in patients with first-episode schizophrenia over the course of 1 year after their first in-patient treatment. Questionnaire data assessed within the multi-centre-RCT "First-Episode Study" of the German Research Network on Schizophrenia were analyzed. Patients with first-episode schizophrenia were assessed 8 weeks after their first in-patient treatment (post-acute assessment) and 1 year later. N = 48 (post-acute) and N = 24 (1-year follow-up) patients provided questionnaire data appropriate for analyses, with N = 12 dyads. These data included burden due to stigma experiences (B-STE), perceived stigma (PDDQ), clinical (PANSS, CDSS, CGI, GAF, SAS) and psycho-social factors (LQLP, FSNK-self esteem, KK-Scale). Cross-lag-correlation models showed a causal relation between stigma experiences (post-acute) and reduced self-esteem after 1 year. Multiple regression models revealed different models for experienced and perceived stigma. Factors associated with higher stigma experiences were older age, worse clinical global impression, better social adjustment, lower self-esteem, and the belief that illness is not driven by chance or fate. The different associations between psycho-social factors and stigma experiences and perceived stigma demonstrate the complexity of this inter-relationship. The results have practical implications for psycho-educational and other therapeutic interventions addressing stigma coping. Since the sample was small and selective, replication studies are needed. PMID- 29696358 TI - Impact of the triglyceride level on coronary plaque components in female patients with coronary artery disease treated with statins. AB - Several studies have reported that elevated triglyceride (TG) levels may be more strongly associated with an increased risk of coronary artery disease (CAD) in females than in males. We examined gender differences in the relationship between TG levels and coronary atherosclerosis using integrated backscatter intravascular ultrasound (IB IVUS) in CAD patients treated with statins. Three hundred seventy eight CAD patients (105 females and 273 males) who underwent percutaneous coronary intervention using IB IVUS, and who were already receiving statin treatment, were included. Gray-scale and IB IVUS examinations were performed for the non-culprit segment of a coronary artery and fasting serum TG concentrations were measured. We found that TG levels were significantly correlated with increased lipid (r = 0.40, p < 0.001) and decreased fibrous (r = - 0.37, p < 0.001) plaque components in females, but not in males. Low-density lipoprotein cholesterol and high-density lipoprotein cholesterol levels were not related to either the gray-scale or IB IVUS parameters in both genders. After adjustment for conventional coronary risk factors by a multivariate stepwise regression analysis, higher TG levels in females were independently associated with increased lipid (beta = 0.31, p< 0.001) contents in coronary plaques. In conclusion, among CAD patients treated with statins, TG levels were associated with lipid-rich coronary plaques in females, but not in males. TG levels may be more important indicators of residual risk after statin treatment in females than in males. PMID- 29696359 TI - Predictors of in-hospital cardiac complications in patients with Takotsubo syndrome. AB - Takotsubo syndrome (TTS) has been recognized as a benign condition mainly due to its reversibility. However, recent researches have demonstrated that serious cardiac complications could occur during hospitalization. Thus, the aim of this study is to detect factors associated with in-hospital cardiac complications in patients with TTS. A total of 154 consecutive patients with TTS were enrolled retrospectively. In-hospital cardiac complications were observed in 61 patients (40%), including 44 patients with pulmonary edema (29%) and 25 patients with cardiogenic shock (16%). Multivariate logistic regression analysis identified lower systolic blood pressure on admission (OR 0.97, 95% CI 0.96-0.99, p = 0.001), history of diabetes mellitus (OR 2.92, 95% CI 1.01-8.41, p = 0.04), and beta-blocker use before admission (OR 16.9, 95% CI 1.57-181.7, p = 0.006) as independent predictors of in-hospital cardiac complications, while chest pain at onset was identified as a negative predictor of cardiac complications during hospitalization (OR 0.20, 95% CI 0.07-0.55, p = 0.001). Patients with cardiac complications more often needed hemodynamic support and longer hospital stay than those without (21.2 +/- 19.4 vs. 11.8 +/- 16.8 days, p = 0.002). TTS should be no longer recognized as a benign disease, but requiring careful management. We should obtain vital signs and patient's medical history carefully as soon as possible after admission to predict in-hospital cardiac complications. PMID- 29696361 TI - Comment on: Yohshino et al.: combination chemotherapy with irinotecan and gemcitabine for taxane/platinum-resistant/refractory ovarian and primary peritoneal cancer: a multicenter phase I/II trial (GOGO-Ov 6). Cancer Chemother Pharmacol (2017) 80:1239-1247. PMID- 29696360 TI - Randomized phase 2 study of gemcitabine and cisplatin with or without vitamin supplementation in patients with advanced esophagogastric cancer. AB - PURPOSE: Preclinical research and prior clinical observations demonstrated reduced toxicity and suggested enhanced efficacy of cisplatin due to folic acid and vitamin B12 suppletion. In this randomized phase 2 trial, we evaluated the addition of folic acid and vitamin B12 to first-line palliative cisplatin and gemcitabine in patients with advanced esophagogastric cancer (AEGC). METHODS: Patients with AEGC were randomized to gemcitabine 1250 mg/m2 (i.v. days 1, 8) and cisplatin 80 mg/m2 (i.v. day 1) q 3 weeks with or without folic acid (450 ug/day p.o.) and vitamin B12 (1000 ug i.m. q 9 weeks). The primary endpoint was response rate (RR). Secondary endpoints included overall survival (OS), time to progression (TTP), toxicity, and exploratory biomarker analyses. Cisplatin sensitivity and intracellular platinum levels were determined in adenocarcinoma cell lines cultured under high and low folate conditions in vitro. RESULTS: Adenocarcinoma cells cultured in medium with high folate levels were more sensitive to cisplatin and this was associated with increased intracellular platinum levels. In the randomized phase 2 clinical trial, which ran from October 2004 to September 2013, treatment was initiated in 78 of 82 randomized pts, 39 in each study arm. The RR was similar; 42.1% for supplemented patients vs. 32.4% for unsupplemented patients; p = 0.4. Median OS and TTP were 10.0 and 5.9 months for supplemented vs. 7.7 and 5.4 months for unsupplemented patients (OS, p = 0.9; TTP, p = 0.9). Plasma homocysteine was lower in the supplemented group [n = 20, 6.9 +/- 1.6 (mean +/- standard error of mean, SEM) uM; vs. 12.5 +/- 4.0 uM; p < 0.001]. There was no significant difference in the Cmax of gemcitabine and cisplatin in the two treatment groups. CONCLUSION: Folic acid and vitamin B12 supplementation do not improve the RR, PFS, or OS of cisplatin and gemcitabine in patients with AEGC. PMID- 29696362 TI - Fixation of medial malleolar fractures with magnesium bioabsorbable headless compression screws: short-term clinical and radiological outcomes in eleven patients. AB - OBJECTIVE: The purpose of this retrospective study was to evaluate the outcome of medial malleolar fractures treated with magnesium (MgYREZr) bioabsorbable compression screw fixation. MATERIALS AND METHODS: Eleven patients with a medial malleolar fracture (either isolated or accompanied by bimalleolar or trimalleolar ankle fractures) who were treated with magnesium bioabsorbable compression screws between 2015 and 2016 in our hospital were retrospectively evaluated. Patients were monitored with a mean follow-up of 17.3 +/- 4.1 months (range 12-24 months). The mechanism of injury was ground level falls in all patients. All fractures were classified as closed fractures. American Orthopedic Foot and Ankle Society's (AOFAS) scale and the visual analog scale (VAS) were used to evaluate the clinical results during the final follow-up. Bone union and a possible loss of reduction were assessed with serial radiographs. Potential complications including revision surgery and infection were recorded and reported. RESULTS: There were 11 patients (4 female, 7 male) with a mean age of 41 +/- 21.9 years (range 20-78 years). Six patients had Herscovici type C and five patients had type B fractures. At the final follow-up the mean AOFAS score was 94.9 +/- 5.7 points (range 85-100 points) and the mean VAS score was 0.4 +/- 1.2 points (range 0-4 points). Radiographic solid union was achieved in all cases. No complications were seen during the follow-up. No patients required implant removal or revision surgery. CONCLUSIONS: This is the first study that investigates the use of bioabsorbable magnesium compression screws in medial malleolar fractures. The results of this study revealed that fixation of medial malleolar fractures with bioabsorbable magnesium compression screws provides adequate fixation with good functional results. LEVEL OF EVIDENCE: Level IV, therapeutic, retrospective case series. PMID- 29696363 TI - Comparison of volarly and dorsally displaced distal radius fracture treated by volar locking plate fixation. AB - INTRODUCTION: In case of distal radius fractures (DRF) the distal fragment generally displaces either dorsally or volarly. Scientific literature however, seldom differentiates between volarly and dorsally displaced DRFs when reporting results. It is no clear, if the direction of displacement has an influence on the clinical and radiological outcome. This study was intended to evaluate the influence of displacement direction in adult patients with surgically treated Colles or Smith type fractures. PATIENTS AND METHODS: After a mean follow up (FU) time of above 5 years, 50 patients who underwent open reduction and internal fixation for DRFs (25 Smith type fractures, 25 Colles type fractures) were included. Upon FU, standard X-rays and a clinical evaluation as well as evaluation scores were raised and analysed. RESULTS: Clinical evaluation showed no difference between the Colles and the Smith group. Radiologic and clinical results for the Colles group showed diminished flexion compared to the healthy wrist, decreased radial inclination and dorsal tilt during FU and progression of osteoarthritis. For the Smith group decreased grip strength compared to the healthy wrist and osteoarthritis-progression was found. For both groups there was no correlation between radiologic values, grip strength, arthrosis grading, disability of arm, shoulder and hand score and patient rated wrist evaluation score. DISCUSSION: Decreased flexion in combination with a decreased dorsopalmar tilt might hint towards a mechanical inhibition in the Colles group. Altogether, the study showed good clinical outcome with satisfactory radiological result. As all patients showed arthrosis progression, the fracture per se is to be seen as a prearthrotic factor. It still remains unclear which measures could be taken to prevent this. PMID- 29696364 TI - Differential somatostatin, CXCR4 chemokine and endothelin A receptor expression in WHO grade I-IV astrocytic brain tumors. AB - PURPOSE: Glioblastomas represent the most common primary malignant tumor of the nervous system and the most frequent type of astrocytic tumors. Despite improved therapeutic options, prognosis has remained exceptionally poor over the last two decades. Therefore, new treatment approaches are urgently needed. An overexpression of somatostatin (SST) as well as chemokine CXCR4 and endothelin A (ETA) receptors has been shown for many types of cancer. Respective expression data for astrocytic brain tumors, however, are scarce and contradictory. METHODS: SST subtype, CXCR4 and ETA expression was comparatively evaluated in a total of 57 grade I-IV astrocytic tumor samples by immunohistochemistry using well characterized monoclonal antibodies. RESULTS: Overall, receptor expression on the tumor cells was only very low. SST5 was the most prominently expressed receptor, followed by SST3, ETA, SST2 and CXCR4. In contrast, tumor capillaries displayed strong SST2, SST3, SST5, CXCR4 and ETA expression. Presence of SST5, CXCR4 and ETA on tumor cells and of SST3, CXCR4 and ETA on microvessels gradually increased from grade II to grade IV tumors. Ki-67 values correlated significantly with CXCR4 expression on tumor cells and with vascular SST3, CXCR4 or ETA positivity. SST5 or CXCR4 positivity of tumor cells and vascular SST3 or CXCR4 expression negatively correlated with patient outcome. CONCLUSIONS: Though having some prognostic value, SST, CXCR4 or ETA expression on astrocytic tumor cells is clearly of no therapeutic relevance. Indirect targeting of these highly vascularized tumors via SST3, SST5, CXCR4 or ETA on the microvessels, in contrast, may represent a promising additional therapeutic strategy. PMID- 29696365 TI - Evidence for altered dendritic spine compartmentalization in Alzheimer's disease and functional effects in a mouse model. AB - Alzheimer's disease (AD) is associated with a progressive loss of synapses and neurons. Studies in animal models indicate that morphological alterations of dendritic spines precede synapse loss, increasing the proportion of large and short ("stubby") spines. Whether similar alterations occur in human patients, and what their functional consequences could be, is not known. We analyzed biopsies from AD patients and APP x presenilin 1 knock-in mice that were previously shown to present a loss of pyramidal neurons in the CA1 area of the hippocampus. We observed that the proportion of stubby spines and the width of spine necks are inversely correlated with synapse density in frontal cortical biopsies from non AD and AD patients. In mice, the reduction in the density of synapses in the stratum radiatum was preceded by an alteration of spine morphology, with a reduction of their length and an enlargement of their neck. Serial sectioning examined with electron microscopy allowed us to precisely measure spine parameters. Mathematical modeling indicated that the shortening and widening of the necks should alter the electrical compartmentalization of the spines, leading to reduced postsynaptic potentials in spine heads, but not in soma. Accordingly, there was no alteration in basal synaptic transmission, but long-term potentiation and spatial memory were impaired. These results indicate that an alteration of spine morphology could be involved in the early cognitive deficits associated with AD. PMID- 29696366 TI - Genetic interaction between two insulin-dependent diabetes susceptibility loci, Idd2 and Idd13, in determining immunoregulatory DN T cell proportion. AB - Several immune regulatory cell types participate in the protection against autoimmune diseases such as autoimmune diabetes. Of these immunoregulatory cells, we and others have shown that peripheral CD4-CD8- double negative (DN) T cells can induce antigen-specific immune tolerance. Particularly, we have described that diabetes-prone mice exhibit a lower number of peripheral DN T cells compared to diabetes-resistant mice. Identifying the molecular pathways that influence the size of the DN T cell pool in peripheral lymphoid organs may thus be of interest for maintaining antigen-specific immune tolerance. Hence, through immunogenetic approaches, we found that two genetic loci linked to autoimmune diabetes susceptibility, namely Idd2 and Idd13, independently contribute to the partial restoration of DN T cell proportion in secondary lymphoid organs. We now extend these findings to show an interaction between the Idd2 and Idd13 loci in determining the number of DN T cells in secondary lymphoid organs. Using bioinformatics tools, we link potential biological pathways arising from interactions of genes encoded within the two loci. By focusing on cell cycle, we validate that both the Idd2 and Idd13 loci influence RAD51 expression as well as DN T cell progression through the cell cycle. Altogether, we find that genetic interactions between Idd2 and Idd13 loci modulate cell cycle progression, which contributes, at least in part, to defining the proportion of DN T cells in secondary lymphoid organs. PMID- 29696367 TI - The distribution of HLA haplotypes in the ethnic groups that make up the Brazilian Bone Marrow Volunteer Donor Registry (REDOME). AB - The Registries of Bone Marrow Donors around the world include more than 30 million volunteer donors from 57 different countries, and were responsible for over 17,000 hematopoietic stem cell transplants in 2016. The Brazilian Bone Marrow Volunteer Donor Registry (REDOME) was established in 1993 and is the third largest registry in the world with more than 4.3 million donors. We characterized HLA allele and haplotypes frequencies from REDOME comparing them with the donor self-reported race group classification. Five-locus haplotype frequencies (A~C~B~DRB1~DQB1) were estimated for each of the six race groups, resolving phase and allelic ambiguity using the expectation-maximization (EM) algorithm. The top 100 haplotypes in the race groups were separated into eight clusters of haplotypes, based on haplotype similarity, using CLUTO. We present HLA allele and haplotype frequency data from six race groups from 2,938,259 individuals from REDOME. The most frequent haplotype was the same for all groups: A*01:01g~C*07:01g~B*08:01g~DRB1*03:01g~DQB1*02:01g. Some frequent haplotypes such as A*02:01g~C*16:01g~B*44:03~DRB1*07:01g~DQB1*02:01g was not found in people with Preta (Sub-Saharan African descent). A cluster including Branca (European) and Parda or non-informed (admixed) could be distinguished from both Preta (SubSaharan) and Indigena (Amerindian) groups, and from the Amarela (Asian) ones, which clustered with their original population. These results have implications on cross-population matching and can help in donor searches and population-based recruitment strategies. PMID- 29696368 TI - The predictive value of polysomnography combined with quality of life for treatment decision of children with habitual snoring related to adenotonsillar hypertrophy. AB - PURPOSE: Both surgical treatment and non-surgical treatment are suggested by clinicians for children with habitual snoring related to adenotonsillar hypertrophy; However, how should the decision be made remains unclear. The objective of this study was to investigate potential predictors for the treatment decision, i.e., surgical treatment vs wait and see in children with habitual snoring related to adenoidal and/or tonsillar hypertrophy. METHODS: Children with complaints of snoring and/or apnea associated with adenotonsillar hypertrophy who received polysomnography (PSG) monitoring at our Hospital were recruited. After at least 6 months, the subjects were followed up and grouped according to whether or not they had received adenoidectomy and/or tonsillectomy (AT) execution. The heights, weights, as well as the quality of life (assessed using the obstructive sleep apnea-18 (OSA-18) quality of life questionnaire) and baseline PSG of the subjects were recorded and compared. Two logistic regressions were performed to reveal the factors influencing decision-making on conducting AT. RESULTS: A total of 509 children were finally included (345 males and 164 females). Among these children, 287 eventually received AT. Significant differences in age, scores for item 1 and 5 of the OSA-18, apnea-hypopnea index, obstructive apnea index, obstructive apnea-hypopnea index (OAHI), and Lowest arterial oxygen saturation (P < 0.05) were observed between groups. By multivariate logistic regression, the factors that influenced the surgical decision were identified as follows: age < 7 years (P = 0.008: odds ratio [OR] = 1.667, 95% confidence interval [CI] 1.140 2.438), score for item 5 of OSA-18 > 4 points (P = 0.042: OR = 1.489, 95% CI 1.014-2.212) and OAHI > 1/h (P = 0.044: OR = 1.579, 95% CI 1.013-2.463). CONCLUSION: School-age children aged < 7 years, with OAHI > 1/h and mouth breathing scored > 4 points were more likely to receive AT during the disease process and thus require increased attention. PMID- 29696371 TI - Fighting the Gender Gap in Interventional Radiology: Facts and Fiction Relating to Radiation. PMID- 29696370 TI - Mesoflavibacter profundi sp. nov. Isolated from a Deep-Sea Seamount. AB - The Gram-stain-negative, rod-shaped, aerobic strain, designated YC1039T, was isolated from a seamount northern Mariana Trench in the tropical western Pacific. Phylogenetic analysis based on 16S rRNA gene sequence showed that strain YC1039T was related to the genus Mesoflavibacter and had highest 16S rRNA gene sequence similarities to Mesoflavibacter sabulilitoris GJMS-9T (98.3%) and Mesoflavibacter zeaxanthinifaciens TD-ZX30T (98.2%). The predominant cellular fatty acids were iso-C15:1 G and iso-C15:0. The polar lipid profile contained phosphatidylethanolamine, two unidentified phospholipids, and 13 unidentified lipids. The respiratory quinone was MK-6. The genomic DNA G+C content of strain YC1039T was 29.8 mol%. On the basis of the evidence presented in this study, strain YC1039T represents a novel species of the genus Mesoflavibacter, for which we propose the name Mesoflavibacter profundi sp. nov. (type strain YC1039T = KACC 19026T = CGMCC 1.16329T). PMID- 29696372 TI - Roles of autophagy in controlling stem cell identity: a perspective of self renewal and differentiation. AB - Autophagy is crucial for the removal of dysfunctional organelles and protein aggregates and for maintaining stem cell homeostasis, which includes self renewal, cell differentiation and somatic reprogramming. Loss of self-renewal capacity and pluripotency is a major obstacle to stem cell-based therapies. It has been reported that autophagy regulates stem cells under biological stimuli, starvation, hypoxia, generation of reactive oxygen species (ROS) and cellular senescence. On the one hand, autophagy is shown to play roles in self-renewal by co-function with the ubiquitin-proteasome system (UPS) to promote pluripotency associated proteins (NANOG, OCT4 and SOX2) in human embryonic stem cells (hESCs). On the other hand, autophagy activity acts as cell reprogramming processes that play an important role for clearance fate determination and upregulates neural and cardiac differentiation. Deregulation of autophagy triggers protein disorders such as neurodegenerative cardiac/muscle diseases and cancer. Therefore, understanding of the roles of the autophagy in stem cell renewal and differentiation may benefit therapeutic development for a range of human diseases. PMID- 29696373 TI - Risk factors for early viral infections after liver transplantation. AB - PURPOSE: Viral infections represent a serious threat for patients after liver transplantation (LT). The identification of risk factors during the early post transplant period might help to improve prevention of viral infections after LT. METHODS: Between 2004 and 2010, 530 adult patients underwent LT at a large university hospital serving a metropolitan region in Europe. This retrospective single-centre study analysed putative risk factors for early viral infections with herpes simplex virus-1 (HSV-1), varicella-zoster virus (VZV), Epstein-Barr virus (EBV), hepatitis A/B/C (HAV/HBV/HCV) and cytomegalovirus (CMV) in the first 3 months after LT. RESULTS: The final analysis included 501 patients of whom 126 (25.1%) had documented viral infections after LT. No significant differences could be detected between patients with or without viral infections concerning 30 and 90-day mortality. Risk factors in the early post-transplant period identified by multivariate analysis included female gender (CMV, HSV-1), the post operative need for continuous veno-venous hemofiltration (CMV), septic shock (CMV), detection of fungi (CMV) and the intraoperative amount of transfused blood (EBV). CONCLUSIONS: Enhanced vigilance regarding opportunistic infections is crucial in the management of this high-risk population of immunocompromised patients. In particular, attention should be paid to avoidable conditions that increase the risk of renal replacement therapies in the post-LT setting, especially among women. TRIAL REGISTRATION: DRKS00010672 on German Clinical Trial Register. PMID- 29696374 TI - BAALC and ERG expression levels at diagnosis have no prognosis impact on acute myeloid leukemia patients undergoing allogeneic hematopoietic stem cell transplantation. AB - Brain and acute leukemia, cytoplasmic (BAALC) and ETS-related gene (ERG) expression levels are independent prognostic factors for acute myeloid leukemia (AML); however, their prognostic impacts on AML patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) require further investigation. We studied 71 de novo AML patients treated with allo-HSCT and defined low and high expressers according to the median expression levels of BAALC and ERG at diagnosis respectively. High BAALC expression was associated with wild-type NPM1 (P = 0.000) and RUNX1 mutations (P = 0.027). High ERG expression was associated with FLT3-ITD absence (P = 0.003) and wild-type NPM1 (P = 0.001). BAALC and ERG expression levels were significantly correlated with each other (P = 0.001). Survival analyses including Kaplan-Meier curves and univariate and multivariate analysis consistently reported that there were no significant differences for both event-free survival (EFS) and overall survival (OS) (all P > 0.1), between high versus low BAALC and ERG expressers. Our study suggested that despite of their well-known adverse role in prognosis of AML, neither BAALC nor ERG expression levels at diagnosis had effect on survival of AML patients who underwent allo-HSCT. PMID- 29696376 TI - [Addendum to: Chronic heart failure in older patients : Updated national healthcare guidelines on chronic heart failure from a geriatric perspective]. PMID- 29696375 TI - Genomic characterization of Nitrospirillum amazonense strain CBAmC, a nitrogen fixing bacterium isolated from surface-sterilized sugarcane stems. AB - Nitrospirillum amazonense is a nitrogen-fixing bacterium that shows potential to promote plant growth when inoculated into sugarcane and rice plants. This microorganism has been the subject of biochemical and genetic characterization to elucidate important functions related to host plant interaction and growth promotion, including the determination of draft genome sequences of two strains, Y2 and CBAmC, the second of which is the aim of the present study. CBAmC has been isolated from sugarcane (Saccharum spp.), and is currently used in a sugarcane consortium inoculant with four other nitrogen-fixing bacterial strains. The present paper describes a significant improvement in the genome sequence and assembly for the N. amazonense strain CBAmC, and determination for the first time of a complete genome sequence for this bacterial species, using PacBio technology. The analysis of the genomic data obtained allowed the discovery of genes coding for metabolic pathways and cellular structures that may be determinant for the success of the bacterial establishment and colonization into the host sugarcane plant, besides conferring important characteristics to the inoculant. These include genes for the use of sucrose and N-glycans, biosynthesis of autoinducer molecules, siderophore production and acquisition, auxin and polyamine biosynthesis, flagellum, sigma-fimbriae, a variety of secretion systems, and a complete denitrification system. Concerning genes for nitrogenase and auxiliary proteins, it was possible to corroborate literature data that in N. amazonense these probably had originated from horizontal gene transfer, from bacteria of the Rhizobiales order. The complete genomic sequence of the CBAmC strain of N. amazonense revealed that the bacterium harbors four replicons, including three chromosomes and one chromid, a profile that coincides with that of other two strains, according to literature data, suggesting that as a replicon pattern for the species. Finally, results of phylogenomic analyses in this work support the recent reclassification of the species, separating it from the Azospirillum genus. More importantly, results of the present work shall guide subsequent studies on strain CBAmC as well as the development of a sugarcane inoculant. PMID- 29696377 TI - The effect of sexual transmission on Zika virus dynamics. AB - Zika virus is a human disease that may lead to neurological disorders in affected individuals, and may be transmitted vectorially (by mosquitoes) or sexually. A mathematical model of Zika virus transmission is formulated, taking into account mosquitoes, sexually active males and females, inactive individuals, and considering both vector transmission and sexual transmission from infectious males to susceptible females. Basic reproduction numbers are computed, and disease control strategies are evaluated. The effect of the incidence function used to model sexual transmission from infectious males to susceptible females is investigated. It is proved that for such functions that are sublinear, if the basic reproduction [Formula: see text], then the disease dies out and [Formula: see text] is a sharp threshold. Moreover, under certain conditions on model parameters and assuming mass action incidence for sexual transmission, it is proved that if [Formula: see text], there exists a unique endemic equilibrium that is globally asymptotically stable. However, under nonlinear incidence, it is shown that for certain functions backward bifurcation and Hopf bifurcation may occur, giving rise to subthreshold equilibria and periodic solutions, respectively. Numerical simulations for various parameter values are displayed to illustrate these behaviours. PMID- 29696378 TI - An aptamer-based colorimetric Pt(II) assay based on the use of gold nanoparticles and a cationic polymer. AB - A colorimetric method is described for the determination of Pt(II). It is based on the use of gold nanoparticles (AuNPs) which are known to aggregate in the presence of a cationic polymer such as poly(diallyldimethylammonium chloride) (PDDA). If, however, a mismatched aptamer (AA) electrostatically binds to PDDA, aggregation is prevented. Upon the addition of Pt(II), it will bind to the aptamer and induce the formation of a hairpin structure. Hence, interaction between aptamer and PDDA is suppressed and PDDA will induce the aggregation of the AuNPs. This is accompanied by a color change from red to blue. The effect can be observed with bare eyes and quantified by colorimetry via measurement of the ratio of absorbances at 610 nm and 520 nm. Response is linear in the 0.24-2 MUM Pt(II) concentration range, and the detection limit is 58 nM. The assay is completed within 15 min and selective for Pt(II) even in the presence of other metal ions. It was successfully applied to the rapid determination of Pt(II) in spiked soil samples. Graphical abstract Schematic representation of the method for detection of Pt(II) based on the use of a cationic polymer and gold nanoparticles. In the presence of Pt(II), aptamer interacts with the Pt(II) and prevents the interaction between aptamer and cationic polymer. Hence, cationic polymer induce the aggregation of the AuNPs and lead to the color change from red to blue. PMID- 29696379 TI - Self-assembly of single-wall carbon nanotubes during the cooling process of hot carbon gas. AB - In this work, self-assembly mechanism of single-wall carbon nanotube (SWCNT) during the annealing process of hot gaseous carbon is presented using reactive force field (ReaxFF)-based reactive molecular simulations. A series of simulations were performed on the evolution of reactive carbon gas. The simulation results show that the reactive carbon gas can be assembled into regular SWCNT without a catalyst. Five distinct stages of SWCNT self-assembly are proposed. For some initial configurations, the CNT was found to spin at an ultra high rate after the nucleation. Graphical abstract Self-assembly process of single-wall carbon nanotube from the annealing of hot gaseous carbon. PMID- 29696380 TI - Geophysical and hydrological data assimilation to monitor water content dynamics in the rocky unsaturated zone. AB - In recent years, geophysics is increasingly used to study the flow and transport processes in the vadose zone. Particularly, when the vadose zone is made up of rocks, it is difficult to install sensors in the subsurface to measure hydrological state variables directly. In these cases, the electrical resistivity tomography (ERT) represents a useful tool to monitor the hydrodynamics of the infiltration and to estimate hydraulic parameters and state variables, such as hydraulic conductivity and water content. We propose an integrated approach aimed at predicting water content dynamics in calcarenite, a sedimentary carbonatic porous rock. The uncoupled hydrogeophysical approach proposed consists in 4D ERT monitoring conducted during an infiltrometer test under falling head conditions. Capacitance probes were installed to measure water content at different depths to validate the estimations derived from ERT. A numerical procedure, based on a data assimilation technique, was accomplished by combining the model (i.e., Richards' equation) with the observations in order to provide reliable water content estimations. We have used a new data assimilation method that is easy to implement, based on the ensemble Kalman filter coupled with Brownian bridges. This approach is particularly suitable for strongly non-linear models, such as Richards' equation, in order to take into account both the model uncertainty and the observation errors. The proposed data assimilation approach was tested for the first time on field data. A reasonable agreement was found between observations and predictions confirming the ability of the integrated approach to predict water content dynamics in the rocky subsoil. PMID- 29696381 TI - Histological and cytological studies of plant infection by Erysiphe euonymi japonici. AB - Powdery mildew caused by Erysiphe euonymi-japonici (Eej) is an increasingly serious fungal disease on Euonymus japonicus that is an important ornamental plant. However, little is currently known about infection and pathogenesis of Eej on E. japonicus. Here, we report plant infection by Eej at the histological and cytological levels. Eej caused severe disease symptoms with white and snow-like colonies on leaf surfaces of E. japonicus. Microscopic observations were conducted continuously to define infection process of Eej on E. japonicus. Eej conidia germinated to produce appressorial germ tubes on leaf surfaces and formed irregular haustoria in plant epidermal cells at 6 h post-inoculation (hpi) and 12 hpi, respectively. After uptaking nutrients from host cells by haustoria, Eej formed numerous hyphae and extensive colonization on leaf surfaces at 96 hpi and finally produced abundant conidiophores and new conidia on leaf surfaces at 168 hpi. In addition, there was consistently a single nucleus in different Eej infection structures and haustorial development could be divided into three major stages, including formation of penetration peg, formation of haustorial neck and initial haustorium, and maturation of haustorium. These results provide useful information for further determination of Eej pathogenesis and finally controlling the disease. PMID- 29696382 TI - Pecs II block for intractable postherpetic neuralgia. PMID- 29696383 TI - 3D-printed, TiO2 NP-incorporated minicolumn coupled with ICP-MS for speciation of inorganic arsenic and selenium in high-salt-content samples. AB - To extend the applicability of solid phase extraction devices manufactured using 3D printing technologies, a stereolithographic 3D printer and resins incorporating titanium dioxide nanoparticles (TiO2 NPs) were employed to fabricate a demountable minicolumn with TiO2 NP-incorporated packing as a sample pretreatment device for the selective extraction of inorganic As and Se species from high-salt-content samples, and to facilitate their analyses when coupled to an inductively coupled plasma mass spectrometer. After optimization, the automatic system enabled highly sensitive determinations of As and Se species with detection limits as low as 0.004-0.033 MUg L-1 for As and 0.061-0.128 MUg L 1 for Se. Reliability was confirmed through analyses of the reference materials 1643f, SLEW-3, CASS-4, and 2670a, as well as spike analyses of samples of water and human urine. These 3D-printed minicolumns appear to be very useful for multi elemental speciation of these elements from high-salt-content samples. Thus, the incorporation of active nanomaterials into raw printing resins can enable 3D printing technologies-not only to fabricate functionalized devices for diverse sample pretreatment applications but also to encourage the future development of multifunctional devices for analytical science. Graphical abstract Schematic presentation of a demountable minicolumn fabricated using a stereolithographic 3D printer and the resins incorporating with TiO2 NPs. They were used to selectively extract As and Se species through controlling the sample acidities. PMID- 29696384 TI - Ab initio calculations of ionic hydrocarbon compounds with heptacoordinate carbon. AB - Ionic hydrocarbon compounds that contain hypercarbon atoms, which bond to five or more atoms, are important intermediates in chemical synthesis and may also find applications in hydrogen storage. Extensive investigations have identified hydrocarbon compounds that contain a five- or six-coordinated hypercarbon atom, such as the pentagonal-pyramidal hexamethylbenzene, C6(CH3)62+, in which a hexacoordinate carbon atom is involved. It remains challenging to search for further higher-coordinated carbon in ionic hydrocarbon compounds, such as seven- and eight-coordinated carbon. Here, we report ab initio density functional calculations that show a stable 3D hexagonal-pyramidal configuration of tropylium trication, (C7H7)3+, in which a heptacoordinate carbon atom is involved. We show that this tropylium trication is stable against deprotonation, dissociation, and structural deformation. In contrast, the pyramidal configurations of ionic C8H8 compounds, which would contain an octacoordinate carbon atom, are unstable. These results provide insights for developing new molecular structures containing hypercarbon atoms, which may have potential applications in chemical synthesis and in hydrogen storage. Graphical abstract Possible structural transformations of stable configurations of (C7H7)3+, which may result in the formation of the pyramidal structure that involves a heptacoordinate hypercarbon atom. PMID- 29696385 TI - Effects of Different Weight Loss Approaches on CVD Risk. AB - PURPOSE OF REVIEW: In this review, we aimed to answer the question as to whether deliberate weight loss can reduce cardiovascular events or improve cardiovascular risk factors and whether different methods of weight loss can have a differential effect on risk factor improvement. RECENT FINDINGS: It would appear that deliberate weight loss reduces total mortality by 16% in obese people with risk factors including type 2 diabetes. People with type 2 diabetes who lose at least 10% of their initial body weight reduce CVD end points by 21% with dietary weight loss while the effect is greater with the greater weight loss induced by bariatric surgery with a 32% reduction in events. Mortality reduction may vary from 29 to up to 79%. Replacing some carbohydrate with protein appears to enhance weight maintenance over 12 months and in addition lowers serum triglyceride and blood pressure. A very-low-carbohydrate diet elevates LDL cholesterol when a high saturated fat "Atkins" style approach is used, but a high unsaturated fat version is safe and effective over a 12-month period and reduces medication requirements in people with type 2 diabetes. A very-low-calorie liquid diet produces excellent weight loss in the short-term, but long-term weight loss is no different to less restrictive dieting. Weight loss lowers CVD events and total mortality and a higher protein (18-25% of energy), lower carbohydrate (< 45% of energy) diet may be superior for weight maintenance and risk factor improvement, but there are no data on event reduction. PMID- 29696388 TI - Assessment of heavy metal pollution of seston from freshwater resources poured into the Northeast Mediterranean region. AB - This study was carried out to determine the accumulation levels of heavy metals (Zn, Cd, Pb, Cu, Fe, Cr) in seston to three different freshwater resources poured into the Iskenderun Bay. Seasonal averages of physico-chemical parameters measured at stations, Arsuz Stream, Payas Stream, and Ceyhan River, are classified as Class III-contaminated water according to the temperature parameter in the summer. Payas Stream has been determined to be Class III-polluted water according to pH parameters during the summer season. Ceyhan River was found to be Class III-contaminated water according to the dissolved oxygen parameter in the autumn season. Heavy metal accumulation levels in the seston were determined Fe > Cr > Zn > Cu > Pb > Cd in Arsuz Stream, Fe > Zn > Pb > Cr > Cu > Cd in Payas Stream, and Fe > Zn > Cr > Cu > Pb > Cd in Ceyhan River. The results in this study showed that high accumulation levels in seston were determined for Fe while low accumulation levels for Cd. PMID- 29696387 TI - Electron microscopic features of the lacrimal sac mucopeptide concretions. AB - PURPOSE: The aim of this study was to examine the ultrastructural features of the mucopeptide concretions obtained from the lacrimal sac. METHODS: Mucopeptide concretions obtained from the lacrimal sacs of 10 patients during a dacryocystorhinostomy were immediately fixed for electron microscopic analysis. The surfaces were studied separately and longitudinal and transverse ultra-thin sections were obtained at different levels and all were studied using the standard protocols of scanning electron microscopy (SEM) and transmission electron microscopy (TEM). RESULTS: Mucopeptide concretions based on their extent take the shape of the lacrimal sac and nasolacrimal duct. The external surfaces and cut sections show mostly areas of homogenous deposits with occasional intervening heterogenic areas. Two distinct types of craters were noted, mostly in the heterogeneous areas. The core of the concretions was made up of extensive networks of fibril like tangles filled predominantly with granular material and red blood cells with occasional presence of granulocytes and epithelial cells. Numerous vacuoles and fissures appear to be more of artifacts than any metabolic process. No organic fibers of fungal filaments were noted within the concretions. There was no evidence of any bacterial biofilms other than few focal areas of scattered bacteria. Possible events in the development of mucopeptide concretions have been hypothesized based on the ultrastructural findings. CONCLUSION: Ultrastructural features of mucopeptide concretions from the lacrimal sac help in better understanding of their etiopathogenesis and tissue interactions. Further exploration of different stages of a concretion is needed to understand the potential factors that trigger its genesis and evolution. PMID- 29696386 TI - Tear film proteome in age-related macular degeneration. AB - PURPOSE: Age-related macular degeneration (AMD) is the main reason for blindness in elderly people in the developed countries. Current screening protocols have limitations in detecting the early signs of retinal degeneration. Therefore, it would be desirable to find novel biomarkers for early detection of AMD. Development of novel biomarkers would help in the prevention, diagnostics, and treatment of AMD. Proteomic analysis of tear film has shown promise in this research area. If an optimal set of biomarkers could be obtained from accessible body fluids, it would represent a reliable way to monitor disease progression and response to novel therapies. METHODS: Tear films were collected on Schirmer strips from a total of 22 patients (8 with wet AMD, 6 with dry AMD, and 8 control individuals). 2D electrophoresis was used to separate tear film proteins prior to their identification with matrix-assisted laser desorption/ionization time of flight spectrometer (MALDI-TOF/TOF) and matching with functional databases. RESULTS: A total of 342 proteins were identified. Most of them were previously described in various proteomic studies concerning AMD. Shootin-1, histatin-3, fidgetin-like protein 1, SRC kinase signaling inhibitor, Graves disease carrier protein, actin cytoplasmic 1, prolactin-inducible protein 1, and protein S100-A7A were upregulated in the tear film samples isolated from AMD patients and were not previously linked with this disease in any proteomic analysis. CONCLUSION: The upregulated proteins supplement our current knowledge of AMD pathogenesis, providing evidence that certain specific proteins are expressed into the tear film in AMD. As far we are aware, this is the first study to have undertaken a comprehensive in-depth analysis of the human tear film proteome in AMD patients. PMID- 29696389 TI - Heterospecific plant-soil feedback and its relationship to plant traits, species relatedness, and co-occurrence in natural communities. AB - Plant-soil feedback is one of the mechanisms affecting co-existence of species, ecological succession, and species invasiveness. However, in contrast to conspecific plant-soil feedback, general patterns in heterospecific feedback are mostly unknown. We used a meta-analysis to search for correlations between heterospecific feedback and species relatedness, functional traits, and field co occurrence patterns. We searched published literature and compiled a data set of 618 PSF interactions. We gathered data on species traits reflecting plant size and growth rate (height, specific leaf area, and life span), co-occurrence in habitats and phylogenetic distance between species pairs. We found that species grew better in soil conditioned by (i) close relatives than in conspecific soil, whereas there was no relationship with phylogeny for distantly related species, (ii) species of greater plant height (but there was no relationship with species SLA or life span), and (iii) species more frequently co-occurring in the field. The results show that heterospecific plant-soil feedback can be explained by plant traits (height) and is reflected in co-occurrence patterns. Phylogeny was a significant predictor of feedbacks over short phylogenetic distance, suggesting fast evolution of traits related to feedback. The low variability explained by the models, however, indicates that other factors such as environmental conditions possibly alter plant-soil feedback responses. PMID- 29696390 TI - Treatment costs and cost drivers among osteoporotic fracture patients in Japan: a retrospective database analysis. AB - : This study estimated the direct medical costs of osteoporotic fractures from a large claim database in Japan. We further identified several comorbidities which drove the treatment costs. The results would contribute to health economic analysis as well as understanding of individual financial burden in Japan. INTRODUCTION: The purposes of this study were to estimate treatment costs of osteoporotic fractures and to investigate the cost drivers. METHODS: Male and female patients aged 50 years and older with a hip, vertebral, or non-hip/non vert (NHNV) fracture between April 2008 and December 2016 were analyzed from claim database. Two types of costs were estimated. The incremental yearly costs of fractures and comorbidity treatments (total medical costs) were calculated by subtracting pre-fracture costs from post-fracture costs. The costs exclusive for fracture treatments (fracture treatment costs) were estimated by summing up the costs of fracture treatments within 1 year after fracture. The associations between comorbidities and costs were examined with a generalized linear model. RESULTS: Total 12,898 patients were identified (83% was female). The total medical costs of fractures were $14,592 for male-hip, $15,691 for female-hip, $4268 for male-vertebral, $3819 for female-vertebral, $3790 for male-NHNV, and $4259 for female-NHNV. The fracture treatment costs were $4506 for male-hip, $5427 for female-hip, $1022 for male-vertebral, $1044 for female-vertebral, $1035 for male-NHNV, and $1408 for female NHNV. Three comorbidities were associated with increasing fracture treatment costs whereas four comorbidities were associated with decreasing fracture treatment costs. Five comorbidities were associated with increasing total medical costs whereas one comorbidity was associated with decreasing total medical costs. CONCLUSIONS: Yearly treatment costs were increased considerably after fracture. Several comorbidities were considered to be cost drivers for osteoporotic fracture treatment. The cost estimates with different patient profile would support conducting health economic analysis in the future. PMID- 29696391 TI - The use of vacuum-assisted closure in spinal wound infections with or without exposed dura. AB - INTRODUCTION: The treatment of postoperative deep spinal wound infection involves debridement and intravenous antibiotics. Authors have previously reported success in a small series of patients treated with vacuum-assisted closure (VAC) therapy, but its use over exposed dura is controversial and the outcome has not been reported in large series. PURPOSE: To review the outcomes following the treatment of postoperative spinal infections with VAC therapy, particularly those with exposed dura. METHODS: This is a review of prospectively collected data in 42 patients, all of whom had deep postoperative spinal infections. 30 of these patients had exposed dura. All patients had an initial debridement followed by application of VAC Whitefoam (with exposed dura) or grey Granufoam (where no dura was exposed). Pressure was set at 50 mmHg with exposed dura or 125 mmHg where no dura was exposed. All patients underwent a minimum 6 week course of antibiotics. We report on the number of visits to theatre required for dressing changes and debridement and the eventual outcomes. RESULTS: Five patients required a flap reconstruction. Two patients died before definitive final closure due to other complications (pneumonia and stroke). In all the other patients, their wounds healed fully. A mean of 2.3 infection surgeries were required to eradicate infection and achieve wound closure. CONCLUSIONS: This is one of the largest studies which confirms the safety and efficacy of VAC dressings in patients with spinal wound infections, even when the dura is exposed. These slides can be retrieved under Electronic Supplementary Material. PMID- 29696392 TI - Prior infections or defence priming: what determines the risk of trematode infections in amphipod hosts? AB - Inducible defences against parasites that are only activated when needed can mitigate the cost of immune or behavioural evasion of parasites. Priming of the immune system and activation of behavioural defences can follow exposure to cues associated with imminent infection risk. In contrast, prior infection can cause immune depression or leave the host with less energy to defend itself against further infections. We investigate the priming of anti-parasite defences and the effect of prior infections in the amphipod Paracalliope fluviatilis, the second intermediate host of the trematode Coitocaecum parvum. During experimental infections, amphipods that had been primed by exposure to chemical cues (from first intermediate snail hosts infected by C. parvum) of infection risk were not better at avoiding further infection than control amphipods. All amphipods showed the same swimming behaviour, whether or not they had been primed by chemical cues from infected snails, or whether or not they were in the presence of live infective stages. In contrast, regardless of whether or not they had been exposed to control water or chemical cues from infected snails, amphipods harbouring prior infections acquired in nature were significantly more likely to acquire new parasites under controlled conditions. These results suggest that the induction of defences via external cues associated with the threat of infection do not play a role in the amphipod's anti-parasite strategy. However, prior infections may pre-dispose a host to acquire further parasites, with consequences for the distribution of parasites among host individuals and the regulation of the host population. PMID- 29696393 TI - Gastrointestinal helminths of gray wolves (Canis lupus lupus) from Sweden. AB - As the Scandinavian wolf population is limited in size, it is only rarely subject to systematic studies on its disease biology, especially gastrointestinal parasites. Therefore, this study aims to describe the prevalence of gastrointestinal helminths of gray wolves hunted on a limited license as a part of a wildlife management program. Helminths of 20 wolves were examined post mortem by macroscopy and coprology. Intestinal worms of five species were recovered from 18 wolves (90%): Uncinaria stenocephala (90%), Taenia spp. (45%), Alaria alata (25%), and Mesocestoides spp. (5%). Of the taeniid specimens typed by multiplex PCR and sequencing of the cox1 gene, 25% belonged to Taenia hydatigena and 25% to Taenia krabbei. The overall species diversity was low compared to findings from wolves of the northern hemisphere. Fecal eggs of Eucoleus boehmi were detected in 12 wolves (60%). Fecal metastrongylid larvae were found in seven individuals (39%), but PCR analyses specific for Angiostrongylus vasorum were negative. The wolves were in good body condition suggesting that the parasite infestation had no negative impact on the general health of the examined wolves. Although some of the recovered parasite species have zoonotic or veterinary impact, it is not likely that the spare wolf population pose substantial threat to human or veterinary health. PMID- 29696394 TI - Morphological, histological, and molecular description of Myxobolus ompok n. sp. (Myxosporea: Myxobolidae), a kidney myxozoan from Pabdah catfish Ompok pabda (Hamilton, 1822) (Siluriformes: Siluridae) in India. AB - In a parasitological survey of freshwater fishes near Meerut, Uttar Pradesh, India, myxozoan infections in Pabdah catfish Ompok pabda Ham. (Siluriformes: Siluridae) were found. Round plasmodia and scattered spores of Myxobolus ompok n. sp. were found in the kidney of the host. Plasmodia measuring 150-200 MUm were located in the renal interstitium. Spores of Myxobolus ompok n. sp. were elongated pyriform, 13.6-14.4 (14.8 +/- 0.42) MUm long, 5.6-6.4 (6.5 +/- 0.33) MUm wide, and 5.2-6.4 (5.9 +/- 0.43) MUm thick with two equal polar capsules measuring 8.0-8.5 (8.2 +/- 0.2) MUm in length and 1.5-2.4 (1.8 +/- 0.33) in width having six filamental turns. Both the morphology and DNA analysis of the 18S rRNA gene revealed that Myxobolus ompok n. sp. is distinct from previously described species of Myxobolus and shares no significant similarity with any other Myxobolus deposited in the GenBank database. Phylogenetic analysis inferred that this species showed the closest similarity to Myxobolus miyarii (KT001495). This is the first record of any Myxobolus sp. from O. pabda in India. PMID- 29696395 TI - Associations of intestinal helminth infections with health parameters of spring migrating female lesser scaup (Aythya affinis) in the upper Midwest, USA. AB - Thousands of lesser scaup (Aythya affinis) die during spring and fall migrations through the upper Midwest, USA, from infections with Cyathocotyle bushiensis and Sphaeridiotrema spp. (Class: Trematoda) after ingesting infected intermediate hosts, such as non-native faucet snails (Bithynia tentaculata). The lesser scaup is a species of conservation concern and is highly susceptible to these infections. We collected female lesser scaup from spring migratory stopover locations throughout Illinois and Wisconsin and assessed biochemical and morphological indicators of health in relation to intestinal helminth loads. Helminth species diversity, total trematode abundance, and the infection intensities of the trematodes C. bushiensis and Sphaeridiotrema spp. were associated with percent body fat, blood metabolites, hematological measures, and an index of foraging habitat quality. Helminth diversity was negatively associated with percent body fat, albumin concentrations, and monocytes, whereas glucose concentrations displayed a slight, positive association. Total trematode abundance was negatively associated with blood concentrations of non-esterified fatty acids and albumin. Infections of C. bushiensis were positively related to basophil levels, whereas Sphaeridiotrema spp. infection intensity was negatively associated with packed cell volume and foraging habitat quality. Thus, commonly measured health metrics may indicate intestinal parasite infections and help waterfowl managers understand overall habitat quality. Intestinal parasitic loads offer another plausible mechanism underlying the spring condition hypothesis. PMID- 29696396 TI - Amphiorchis stacyi n. sp. (Digenea: Spirorchiidae) in the heart of a green turtle from Florida, USA and the literature review of Amphiorchis (Price, 1934). AB - The present paper reports the occurrence of the seventh species in the genus Amphiorchis (Digenea: Spirorchiidae) collected from the heart of a green turtle found in Florida, USA. A taxonomic key to the species of Amphiorchis and a literature review for the genus are presented. PMID- 29696397 TI - Analysis of Bi Distribution in Epitaxial GaAsBi by Aberration-Corrected HAADF STEM. AB - The Bi content in GaAs/GaAs1 - xBi x /GaAs heterostructures grown by molecular beam epitaxy at a substrate temperature close to 340 degrees C is investigated by aberration-corrected high-angle annular dark-field techniques. The analysis at low magnification of high-angle annular dark-field scanning transmission electron microscopy images, corroborated by EDX analysis, revealed planar defect-free layers and a non-homogeneous Bi distribution at the interfaces and within the GaAsBi layer. At high magnification, the qHAADF analysis confirmed the inhomogeneous distribution and Bi segregation at the GaAsBi/GaAs interface at low Bi flux and distorted dumbbell shape in areas with higher Bi content. At higher Bi flux, the size of the Bi gathering increases leading to roughly equiaxial Bi rich particles faceted along zinc blende {111} and uniformly dispersed around the matrix and interfaces. FFT analysis checks the coexistence of two phases in some clusters: a rhombohedral pure Bi (rh-Bi) one surrounded by a zinc blende GaAs1 - xBi x matrix. Clusters may be affecting to the local lattice relaxation and leading to a partially relaxed GaAsBi/GaAs system, in good agreement with XRD analysis. PMID- 29696398 TI - Neurobehcet, multiple sclerosis or overlap syndrome? A case report. PMID- 29696399 TI - Levetiracetam-induced rhabdomyolysis: the first Italian case. PMID- 29696401 TI - Multiple approaches to associations of physical activity and adherence to the Mediterranean diet with all-cause mortality in older adults: the PREvencion con DIeta MEDiterranea study. AB - PURPOSE: Although evidence indicates that both physical activity and adherence to the Mediterranean diet (MedDiet) reduce the risk of all-cause mortality, a little is known about optimal intensities of physical activity and their combined effect with MedDiet in older adults. We assessed the separate and combined associations of leisure-time physical activity (LTPA) and MedDiet adherence with all-cause mortality. METHODS: We prospectively studied 7356 older adults (67 +/- 6.2 years) at high vascular risk from the PREvencion con DIeta MEDiterranea study. At baseline and yearly thereafter, adherence to the MedDiet and LTPA were measured using validated questionnaires. RESULTS: After 6.8 years of follow-up, we documented 498 deaths. Adherence to the MedDiet and total, light, and moderate-to vigorous LTPA were inversely associated with all-cause mortality (p < 0.01 for all) in multiple adjusted Cox regression models. The adjusted hazard of all-cause mortality was 73% lower (hazard ratio 0.27, 95% confidence interval 0.19-0.38, p < 0.001) for the combined category of highest adherence to the MedDiet (3rd tertile) and highest total LTPA (3rd tertile) compared to lowest adherence to the MedDiet (1st tertile) and lowest total LTPA (1st tertile). Reductions in mortality risk did not meaningfully differ between total, light intensity, and moderate-to-vigorous LTPA. CONCLUSIONS: We found that higher levels of LTPA, regardless of intensity (total, light and moderate-to-vigorous), and greater adherence to the MedDiet were associated separately and jointly with lower all cause mortality. The finding that light LTPA was inversely associated with mortality is relevant because this level of intensity is a feasible option for older adults. PMID- 29696402 TI - Development of Fast-Dissolving Amorphous Solid Dispersion of Itraconazole by Melt Extrusion of its Mixture with Weak Organic Carboxylic Acid and Polymer. AB - PURPOSE: The purpose of this study was to explore the feasibility of developing amorphous solid dispersion (ASD) by inducing acid-base interaction at an elevated temperature using hot melt extrusion. METHODS: Itraconazole and glutaric acid, which do not form salt with each other, were selected as, respectively, model basic drug and weak organic acid. A 1:4:1w/w mixture of itraconazole, glutaric acid and a polymer, Kollidon(r)VA64, was melt extruded at 95 degrees C. The ground extrudate was characterized by DSC and PXRD and then tested for dissolution at pH 1.2, followed by a change in pH to 5.5. RESULTS: Despite the high melting point of 168 degrees C, itraconazole dissolved in glutaric acid at around the melting temperature of acid (~98 degrees C), and physically stable ASD was produced when the formulation was extruded at 95 degrees C. Capsules containing 100-mg equivalent of itraconazole dissolved rapidly at pH 1.2 producing highly supersaturated solution. When the pH was changed from 1.2 to 5.5, very fine suspensions, facilitated by the presence of Kollidon(r)VA64, was formed. CONCLUSIONS: Physically stable ASD of itraconazole with high drug load was prepared by interaction with glutaric acid in a hot melt extruder. This may be used as a platform technology for the development ASD of most poorly water soluble basic drugs. PMID- 29696403 TI - The Effect of a Text Messaging Based HIV Prevention Program on Sexual Minority Male Youths: A National Evaluation of Information, Motivation and Behavioral Skills in a Randomized Controlled Trial of Guy2Guy. AB - : There is a paucity of literature documenting how the constructs of the Information-Motivation-Behavioral Skills (IMB) model are affected by exposure to technology-based HIV prevention programs. Guy2Guy, based on the IMB model, is the first comprehensive HIV prevention program delivered via text messaging and tested nationally among sexual minority adolescent males. Between June and November 2014, 302 14-18 year old gay, bisexual, and/or queer cisgender males were recruited across the US on Facebook and enrolled in a randomized controlled trial testing Guy2Guy versus an attention-matched control program. Among sexually inexperienced youth, those in the intervention were more than three times as likely to be in the "High motivation" group at follow-up as control youth (aOR = 3.13; P value = 0.04). The intervention effect was not significant when examined separately for those who were sexually active. HIV information did not significantly vary by experimental arm at 3 months post-intervention end, nor did behavioral skills for condom use or abstinence vary. The increase in motivation to engage in HIV preventive behavior for adolescent males with no prior sexual experience is promising, highlighting the need to tailor HIV prevention according to past sexual experience. The behavioral skills that were measured may not have reflected those most emphasized in the content (e.g., how to use lubrication to reduce risk and increase pleasure), which may explain the lack of detected intervention impact. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov ID# NCT02113956. PMID- 29696400 TI - Put "gender glasses" on the effects of phenolic compounds on cardiovascular function and diseases. AB - INTRODUCTION: The influence of sex and gender is particularly relevant in cardiovascular diseases (CVD) as well as in several aspects of drug pharmacodynamics and pharmacokinetics. Anatomical and physiological differences between the sexes may influence the activity of many drugs, including the possibility of their interaction with other drugs, bioactive compounds, foods and beverages. Phenolic compounds could interact with our organism at organ, cellular, and molecular levels triggering a preventive action against chronic diseases, including CVD. RESULTS: This article will review the role of sex on the activity of these bioactive molecules, considering the existence of sex differences in oxidative stress. It describes the pharmacokinetics of phenolic compounds, their effects on vessels, on cardiovascular system, and during development, including the role of nuclear receptors and microbiota. CONCLUSIONS: Although there is a large gap between the knowledge of the sex differences in the phenolic compounds' activity and safety, and the urgent need for more research, available data underlie the possibility that plant-derived phenolic compounds could differently influence the health of male and female subjects. PMID- 29696404 TI - Mother-to-Child Transmission of HIV and HIV-Free Survival in Swaziland: A Community-Based Household Survey. AB - In Swaziland, no data are available on the rates of HIV infection and HIV-free survival among children at the end of the breastfeeding period. We performed a national crosssectional community survey of children born 18-24 months prior to the study, in randomly selected constituencies in all 4 administrative regions of Swaziland, from April to June 2015. Mother-to-child transmission (MTCT) of HIV and HIV-free survival rates were calculated for all HIV-exposed children. The overall HIV-free survival rate at 18-24 months was 95.9% (95% CI 94.1-97.2). The estimated proportion of HIV infected children among known HIV-exposed children was 3.6% (95% CI 2.4-5.2). Older maternal age, delivering at a health facility, and receiving antenatal antiretroviral drugs were independently associated with reduced risk for child infection or death. The Swaziland program for prevention of MTCT achieved high HIV-free survival (95.9%) and low MTCT (3.6%) rates at 18 24 months of age when Option A (infant prophylaxis) of the WHO 2010 guidelines was implemented. PMID- 29696405 TI - Gastric washing by distilled water can reduce free gastric cancer cells exfoliated into the stomach lumen. AB - PURPOSE: Intragastric free cancer cells in patients with gastric cancer have rarely been studied. The purpose of this study was to investigate the detection rate of intragastric free cancer cells in gastric washes using two types of solutions during endoscopic examination. We further clarified risk factors affecting the presence of exfoliated free cancer cells. METHODS: A total of 175 patients with gastric cancer were enrolled. Lactated Ringer's solution (N = 89) or distilled water (DW; N = 86) via endoscopic working channel was sprayed onto the tumor surface, and the resultant fluid was collected for cytological examination. We compared the cancer-cell positivity rate between the two (Ringer and DW) groups. We also tested the correlation between cancer-cell positivity and clinicopathological factors in the Ringer group to identify risk factors for the presence of exfoliated cancer cells. RESULTS: The cancer-cell positivity rate was significantly higher in the Ringer group than that in the DW group (58 vs 6%). Cytomorphology in the Ringer group was well maintained, but not in the DW group. The larger tumor size (>= 20 mm) and positive lymphatic involvement were significant risk factors of exfoliated free cancer cells. CONCLUSIONS: Cancer cells can be highly exfoliated from the tumor surface into the gastric lumen by endoscopic irrigation in large gastric cancer with lymphatic involvement. Gastric washing by DW can lead to cytoclasis of free cancer cells; therefore, it may minimize the possibility of cancer-cell seeding in procedures carrying potential risks of tumor-cell seeding upon transluminal communication, such as endoscopic full-thickness resection and laparoscopy-endoscopy cooperative surgery. PMID- 29696406 TI - Cancer-adipose tissue interaction and fluid flow synergistically modulate cell kinetics, HER2 expression, and trastuzumab efficacy in gastric cancer. AB - BACKGROUND: Early local tumor invasion in gastric cancer results in likely encounters between cancer cells and submucosal and subserosal adipose tissue, but these interactions remain to be clarified. Microenvironmental mechanical forces, such as fluid flow, are known to modulate normal cell kinetics, but the effects of fluid flow on gastric cancer cells are poorly understood. We analyzed the cell kinetics and chemosensitivity in gastric cancer using a simple in vitro model that simultaneously replicated the cancer-adipocyte interaction and physical microenvironment. METHODS: Gastric cancer cells (MKN7 and MKN74) were seeded on rat adipose tissue fragment-embedded discs or collagen discs alone. To generate fluid flow, samples were placed on a rotatory shaker in a CO2 incubator. Proliferation, apoptosis, invasion, and motility-related molecules were analyzed by morphometry and immunostaining. Proteins were evaluated by western blot analysis. Chemosensitivity was investigated by trastuzumab treatment. RESULTS: Adipose tissue and fluid flow had a positive synergistic effect on the proliferative potential and invasive capacity of gastric cancer cells, and adipose tissue inhibited apoptosis in these cells. Adipose tissue upregulated ERK1/2 signaling in gastric cancer cells, but downregulated p38 signaling. Notably, adipose tissue and fluid flow promoted membranous and cytoplasmic HER2 expression and modulated chemosensitivity to trastuzumab in gastric cancer cells. CONCLUSION: We have demonstrated that cancer-adipocyte interaction and physical microenvironment mutually modulate gastric cancer cell kinetics. Further elucidation of the microenvironmental regulation in gastric cancer will be very important for the development of strategies involving molecular targeted therapy. PMID- 29696407 TI - A novel endornavirus isolated from cluster bean (Cyamopsis tetragonoloba). AB - Cluster bean (Cyamopsis tetragonoloba), also called guar, is a drought-tolerant annual legume. We conducted investigations to characterize a large dsRNA (~13-14 kbp) detected in a symptomless cluster bean genotype. The dsRNA was gel-purified and used for Illumina MiSeq sequencing. Reads were assembled, and BLASTx search results showed sequence similarity with viruses classified within the family Endornaviridae. The complete sequence of the putative endornavirus consisted of 12,895 nt and contained an open reading frame which coded for a polyprotein of 4,207 aa with conserved domains for methyltransferase, helicase, and RNA dependent RNA polymerase. The virus was named cluster bean endornavirus 1 (CBEV 1). A BLASTx search using the polyprotein sequence showed that the closest endornavirus to CBEV-1 was Hordeum vulgare endornavirus. PMID- 29696408 TI - Increasing predominance of G8P[8] species A rotaviruses in children admitted to hospital with acute gastroenteritis in Thailand, 2010-2013. AB - Rotavirus A is a well-known etiological cause of acute gastroenteritis in infants and young children worldwide. In this study, we investigated the prevalence and distribution of RVA genotypes circulating in children with acute gastroenteritis in Thailand from 2010 to 2013. A total of 1,032 fecal specimens were collected from children with an age range from neonatal to 15 years of age and tested for RVA by RT-PCR. Of these, 184 (17.8%) were positive for RVA. The highest detection rate of RVA was found in children aged between 12 and 24 months. The G1P[8] genotype was identified as the most dominant genotype (57.6%), followed by G2P[4] (12.5%), G8P[8] (10.4%), G9P[8] (7.1%), G3P[8] (4.9%), G1P[4] (2.2%), G2P[8] (1.7%), and mixed-infections of G1 and G3 in combination with P[8] (0.5%). In addition, the uncommon human rotavirus strains G4P[6] (1.1%), G9P[19] (0.5%), G12P[4] (0.5%), and G12P[6] (0.5%) were also detected in this study. Interestingly, the unusual G8P[8] strains were detected at a relatively high frequency, and phylogenetic analysis revealed that these G8 strains were genetically closely related to bovine and bovine-like human G8 rotavirus strains reported previously from Thailand, Japan, Vietnam, India and Taiwan. These G8P[8] strains displayed the DS-1-like genotype constellation of G8-P[8]-I2-R2-C2-M2-A2 N2-T2-E2-H2 (in the order VP7-VP4-VP6-VP1-VP2-VP3-NSP1-NSP2-NSP3-NSP4-NSP5/6, respectively). Overall, the data indicated a high degree of diversity of RVA genotypes, with the emergence of several uncommon RVA strains in children with acute gastroenteritis in Thailand. PMID- 29696411 TI - Lymphatic Spread of Ovarian Cancer: Can the Anatomical and Pathological Knowledge Help a Personalized Treatment? PMID- 29696409 TI - Valvular Heart Disease and Pregnancy. AB - With improving reproductive assistive technologies, advancing maternal age, and improved survival of patients with congenital heart disease, valvular heart disease has become an important cause of morbidity and mortality in pregnant women. In general, stenotic lesions, even those in the moderate range, are poorly tolerated in the face of hemodynamic changes of pregnancy. Regurgitant lesions, however, fare better due to the physiologic afterload reduction that occurs. Intervention on regurgitant valve preconception follows the same principles as a non-pregnant population. Prosthetic valves in pregnancy are increasingly commonplace, presenting new management challenges including valve deterioration and valve thrombosis. In particular, anticoagulation during pregnancy is challenging. Pregnancy is a hypercoagulable state and the risks of maternal bleeding and fetal anticoagulant risks need to be balanced. Maternal mortality and complications are lowest with warfarin use throughout pregnancy; however, fetal outcomes are best with low molecular weight heparin use. ACC/AHA guidelines recommend warfarin use, even in the first trimester, if doses are less than 5 mg/day; however, adverse fetal events are not zero at this dose. In addition, it is unclear if better monitoring of low molecular weight heparin with peak and trough anti-Xa levels would lower maternal risks as this has been inconsistently monitored in reported studies. Fortunately, with the emergence of newer data, our understanding of anticoagulant strategies in pregnancy is improving over time which should translate to better pregnancy outcomes in this higher risk population. PMID- 29696410 TI - Utility of immediate postoperative hip MRI in developmental hip dysplasia: closed vs. open reduction. AB - BACKGROUND: Magnetic resonance imaging (MRI) of the hips is being increasingly used to confirm hip reduction after surgery and spica cast placement for developmental dysplasia of the hip (DDH). OBJECTIVE: To review a single institutional experience with post-spica MRI in children undergoing closed or open hip reduction and describe the utility of MRI in directing the need for re intervention. MATERIALS AND METHODS: Seventy-four patients (52 female, 22 male) who underwent post-spica hip MRI over a 6-year period were retrospectively reviewed. One hundred and seven hips were included. Data reviewed included age at intervention, gender, type of intervention performed, MRI findings, the need for re-intervention and the interval between interventions. Gender was compared between the closed and open reduction groups via the Fisher exact test. Age at the first procedure was compared via the Wilcoxon rank test. Rates of re intervention after closed and open reduction were calculated and the reasons for re-intervention were reviewed. RESULTS: The mean age at the time of the first intervention was 16.4 months (range: 4 to 63 months). Mean age for the closed reduction group was 10.5 months (range: 4-24 months) and for the open reduction group was 23.7 months (range: 5-63 months), which was significant (P-value <0.0001). Of the 52 hips that underwent closed reduction, 16 (31%) needed re intervention. Of the 55 hips that underwent open reduction, MRI was useful in deciding re-intervention in only 1 (2%). This patient had prior multiple failed closed and open reductions at an outside institute. CONCLUSION: Post intervention hip spica MRI is useful in determining the need for re-intervention after closed hip reduction, but its role after open reduction is questionable. PMID- 29696412 TI - Characterization of the perinatal mandible growth pattern: preliminary results. AB - PURPOSE: The fetal development of the mandible is nowadays quite understood, and it is already known that craniofacial growth reaches its highest rate during the first 5 years of postnatal life. However, there are very few data focusing on the perinatal period. Thus, the present article is addressing this concern by studying the mandible morphology and its evolution around the birth with a morphometric method. METHODS: Thirty-one mandibles modelled in three dimensions from post-mortem CT-scans were analyzed. This sample was divided into two subgroups composed of, respectively, 15 fetuses (aged from 36 gestational weeks), and 16 infants (aged to 12 postnatal weeks). 17 distances, 3 angles, and 8 thicknesses were measured via the prior set of 14 landmarks, illustrating the whole mandible morphology. RESULTS: Although this methodology may depend on the image reconstruction quality, its reliability was demonstrated with low variability in the results. It highlighted two distinct growth patterns around birth: fetuses mandibles do not significantly evolve during the perinatal period, whereas, from the second postnatal weeks, most of the measurements increased in a homogeneous tendency and in correlation with age. CONCLUSIONS: The protocol developed in this study highlighted the morphologic evolution of the mandible around birth, identifying a different growth pattern from 2 postnatal weeks, probably because of the progressive activation of masticatory muscles and tongue. However, considering the small sample size, these results should be thorough, so identification and management of anatomic abnormalities could eventually be achieved. PMID- 29696413 TI - A simple, precocious, and reliable way to assess future clinical outcome in children with Perthes disease and mild femoral head involvement: correlation between MRI with diffusion-weighted and dynamic gadolinium-enhanced subtraction and Catterall and Herring classifications. AB - BACKGROUND: In children older than 5 years with a mild form of Legg-Calve-Perthes disease, the outcome is difficult to predict. In this study, we retrospectively correlated gadolinium-enhanced subtracted (DGS) and diffusion (DWI) MRI findings to the radiographic assessment according to the Catterall and Herring et al. classifications and to the final score according to Stulberg et al.: the aim was to identify a precocious, simple, and objective criterion to differentiate between forms evolving favourably and forms requiring an early surgical treatment in order to avoid femoral head deformity and subsequent osteoarthritis. METHODS: Twelve boys with unilateral mild femoral head involvement (Catterall grade 2 or grade 3) underwent DSG and DWI MR during the early phase of the disease. The absence of enhancement of the external pillar on DSG MRI and the presence of metaphyseal hyperintensity on DWI were considered to be the signs of poor outcome. These findings were correlated with the Catterall and Herring et al. classifications at the initial sclerotic stage and early fragmentation phase and with the Stulberg et al. classifications at least 5 years after the onset of the disease. RESULTS: DSG MRI findings correctly discriminated three out of four patients with a good outcome but underestimated two out of eight patients with a poor outcome. DWI findings correlated with the Catterall and Herring et al. classifications in 12 out of 12 cases. In only one case, DWI findings did not correlate with the Stulberg et al. classification. CONCLUSION: DWI MR provides an objective and accurate prognostic criterion that is relatively easy to recognise. DGS MR findings are less accurate, thus underestimating the gravity of the disease in one-fourth of the patients with a poor outcome. PMID- 29696414 TI - Management of symptomatic knee osteoarthritis in obesity: a survey of general practitioners' opinions and practice. AB - INTRODUCTION: The aim of this survey was to explore general practitioners' opinions and practices regarding the management of symptomatic knee osteoarthritis in obesity. METHODS: Questionnaires were sent electronically to members of the Royal College of General Practitioners specialty interest groups: GPs with an Interest in Nutrition Group and the Physical Activity and Life Style group. RESULTS: The response rate was 75% (142/190). The majority stated weight loss should be the first-line treatment. Half stated that community interventions were effective, and three quarters stated that bariatric surgery should be available to these patients. Two-thirds reported that their knowledge and training around obesity management was insufficient. CONCLUSION: Our survey has shown a variation in the opinions and practices amongst respondents on the management of symptomatic knee osteoarthritis in obesity. Given the projected obesity epidemic, greater training and resources are required in the community setting to enable effective management. There is support for the creation of combined ortho-bariatric services. PMID- 29696416 TI - Message from the Editor-in-Chief. PMID- 29696415 TI - Medium-term outcomes of the S-ROM modular femoral stem in revision hip replacement. AB - INTRODUCTION: The objective of this study was to analyse results achieved with the S-ROM modular stem in revision surgery. MATERIALS AND METHODS: A retrospective observational study was conducted from 2007 to 2015 including 51 patients who had a follow-up of >= 2 years and complete medical history. The mean age was 66.5 years old (34-87). The main reason for revision was aseptic loosening (38 cases, 74.5%), followed by infection (10, 19.6%), instability (2, 3.9%) and an adverse reaction associated with a metal-on-metal hip implant (1, 2%). Using the Paprosky classification, there were 22 cases of type I (43.1%), 27 of type II (52.9%) and 2 of type IIIA (4%). At the end of the follow-up, radiological parameters were assessed using Engh's criteria. Pre- and postoperative clinical status was assessed using the Harris Hip Score, a visual analogue scale and the Merle D'Aubigne score. RESULTS: The mean follow-up period was 5.7 years (2-10). The mean Harris Hip Score improved from 45.5 points (22-65) to 85.8 (55-100) (p < 0.001), and the final mean Merle D'Aubigne scores were 5.2, 4.6 and 5.6 for pain, ability to walk and mobility, respectively. Osseointegration was confirmed in all except one patient with fibrous non-union. No aseptic loosening has been recorded. Postoperative complications were deep infection in four cases (7.8%) and dislocation in three (5.9%). CONCLUSION: This study indicates good medium-term outcomes using a modular hip replacement system with porous-coated proximal sleeves in revision surgery in patients with Paprosky type I and II defects. PMID- 29696417 TI - Sinus and Upper Airway Surgery in Children. AB - PURPOSE OF REVIEW: Chronic sinus and upper airway disease in children is a common health problem encountered every day. Its pathophysiology is complicated which leads to different treatment options and approaches. We seek to review the current literature and evidence to surgical treatments. RECENT FINDINGS: Medical treatment with antibiotics and topical nasal sprays continues to be the first line treatment. Surgical interventions include adenoidectomy, balloon catheter sinuplasty (BCS), and endoscopic sinus surgery (ESS). Each modality has proven to be safe; however, its effectiveness is widely variable. More research with higher level of evidence is needed to help in choosing the right surgical treatment with optimal benefit. PMID- 29696419 TI - Bleeding related to dental treatment in patients taking novel oral anticoagulants (NOACs): a retrospective study. AB - OBJECTIVE: Several novel oral anticoagulants (NOACs) are currently prescribed for patients suffering from atrial fibrillation, pulmonary thromboembolism, and venous thrombosis. However, there is no clinical guideline for dental treatment in patients taking NOACs. This study investigated bleeding events related to various dental treatments. MATERIALS AND METHODS: This retrospective study included 120 patients (153 cases) who were prescribed NOACs and received dental procedures in the Department of Advanced General Dentistry at Yonsei University Dental Hospital from January 2014 to June 2017. The indication for NOACs, initiation of NOACs, duration of discontinuance, creatinine clearance, and type of dental treatment were investigated. Bleeding events were assessed at a follow up visit to the clinic. RESULTS: Postoperative bleeding occurred in only 9 of the 153 included cases; they comprised 2 cases of scaling, 3 cases of simple extraction, 3 cases of the first stage of implant surgery, and 1 case of resin filling. The creatinine clearance (P = .111) and duration of discontinuance (P = .222) did not differ significantly between the groups with and without bleeding events. CONCLUSIONS: Our data indicate that most dental treatments may be performed in patients taking NOACs without an increased likelihood of bleeding events regardless of the discontinuance duration. Moreover, any postoperative bleeding can be stopped by applying compressive pressure or local hemostatic agents. CLINICAL RELEVANCE: Our study suggests that patients taking NOACs who need dental treatments may have a bleeding tendency based on our retrospective data. Preoperative history taking and treatment modification should therefore be considered before performing dental surgery. PMID- 29696418 TI - Causes of Emotional Eating and Matched Treatment of Obesity. AB - PURPOSE OF THE REVIEW: Eating in response to negative emotions (EE) may be an explanatory factor of the weight regain of many dieters. This narrative review presents evidence on possible causes of EE and the association of EE with depression and obesity and discusses implications of these findings for the treatment of obesity. RECENT FINDINGS: Possible causes of EE are high dietary restraint, poor interoceptive awareness, alexithymia, emotion dysregulation and a reversed hypothalamic pituitary adrenal (HPA) stress axis. EE may be the outcome of inadequate parenting or depressive feelings in interaction with genetic susceptibility. There is also robust evidence that EE is a mediator between depression and obesity. The association of EE with depression and poor emotion regulation skills suggests that the treatment of obese people with high EE should not focus on calorie-restricted diets but on emotion regulation skills. The DEBQ (Dutch Eating Behavior Questionnaire) enables such a matched treatment of obesity. PMID- 29696420 TI - Pre-operative use of dexamethasone does not reduce incidence or intensity of bleaching-induced tooth sensitivity. A triple-blind, parallel-design, randomized clinical trial. AB - OBJECTIVES: This study evaluated the effect of the administration of pre operative dexamethasone on tooth sensitivity stemming from in-office bleaching. MATERIALS AND METHODS: A triple-blind, parallel-design, randomized clinical trial was conducted on 70 volunteers who received dexamethasone or placebo capsules. The drugs were administered in a protocol of three daily 8-mg doses of the drug, starting 48 h before the in-office bleaching treatment. Two bleaching sessions with 37.5% hydrogen peroxide gel were performed with a 1-week interval. Tooth sensitivity (TS) was recorded on visual analog scales (VAS) and numeric rating scales (NRS) in different periods up to 48 h after bleaching. The color evaluations were also performed. The absolute risk of TS and its intensity were evaluated by using Fisher's exact test. Comparisons of the TS intensity (NRS and VAS data) were performed by using the Mann-Whitney U test and a two-way repeated measures ANOVA and Tukey's test, respectively. RESULTS: In both groups, a high risk of TS (Dexa 80% x Placebo 94%) was detected. No significant difference was observed in terms of TS intensity. A whitening of approximately 3 shade guide units of the VITA Classical was detected in both groups, which were statistically similar. CONCLUSIONS: It was concluded that the administration pre-operatively of dexamethasone, in the proposed protocol, does not reduce the incidence or intensity of bleaching-induced tooth sensitivity. CLINICAL RELEVANCE: The use of dexamethasone drug before in-office bleaching treatment does not reduce incidence or intensity of tooth sensitivity. CLINICAL TRIAL REGISTRATION NUMBER: NCT02956070. PMID- 29696422 TI - Mouth-opening device as a treatment modality in trismus patients with head and neck cancer and oral submucous fibrosis: a prospective study. AB - OBJECTIVES: This study investigated the clinical effectiveness of intervention with an open-mouth exercise device designed to facilitate maximal interincisal opening (MIO) and improve quality of life in patients with head and neck (H&N) cancer and oral submucous fibrosis (OSF). MATERIALS AND METHODS: Sixty patients with H&N cancer, OSF, and trismus (MIO < 35 mm) participated in the functional rehabilitation program. An open-mouth exercise device intervention group and conventional group, each consisting of 20 patients, underwent a 12-week training and exercising program and follow-up. For the control group, an additional 20 patients were randomly selected to match the demographic characteristics of the aforementioned two groups. RESULTS: The patients' MIO improvements in the aforementioned three groups were 14.0, 10.5, and 1.3 mm, respectively. CONCLUSION: Results of this study confirm the significant improvement in average mouth-opening range. In addition, according to patient feedback, significant improvements in health-related quality of life and reductions in trismus symptoms occurred in the open-mouth exercise device group. CLINICAL RELEVANCE: This newly designed open-mouth exercise device can facilitate trismus patients with H&N cancer and OSF and improve mouth-opening range and quality of life. PMID- 29696421 TI - Treatment modalities for burning mouth syndrome: a systematic review. AB - OBJECTIVES: In the burning mouth syndrome (BMS), patients experience a burning sensation in the oral cavity with no associated injury or clinical manifestation. The etiology of this condition is still poorly understood, and therefore, treatment is challenging. The aim of this study is to perform a systematic review of treatment possibilities described in the literature for BMS. MATERIALS AND METHODS: PubMed, Embase, and SciELO databases were searched for randomized clinical trials published between 1996 and 2016. RESULTS: Following application of inclusion and exclusion criteria, 29 papers were analyzed and divided into five subcategories according to the type of treatment described: antidepressants, alpha-lipoic acid, phytotherapeutic agents, analgesic and anti-inflammatory agents, and non-pharmacological therapies. In each category, the results found were compared with regard to the methodology employed, sample size, assessment method, presence or absence of adverse effects, and treatment outcomes. CONCLUSIONS: The analysis revealed that the use of antidepressants and alpha lipoic acid has been showing promising results; however, more studies are necessary before we can have a first-line treatment strategy for patients with BMS. CLINICAL RELEVANCE: To review systematically the literature about Burning Mouth Syndrome treatment may aid the clinicians to choose the treatment modality to improve patients symptoms based on the best evidence. PMID- 29696423 TI - Patterns of interactions among patients with advanced pancreatic cancer, their caregivers, and healthcare providers during symptom discussions. AB - PURPOSE: Effective symptom discussion is an essential step to enhance symptom management in patients with advanced pancreatic cancer (APC). However, little is known about how these patients communicate their symptoms during health encounters. The purpose of this study was to develop a typology to describe patterns of interactions between patients with APC, their caregivers, and healthcare providers as regards to symptoms and symptom management. METHODS: Thematic analysis was used to analyze 37 transcripts of audio-recorded, naturally occurring encounters among APC patients, caregivers, and healthcare providers. Transcripts were drawn from the Values and Options in Cancer Care study, a larger randomized controlled communication and decision-making intervention trial, which recruited advanced cancer patients and caregivers across the USA. All transcripts from APC patients that were pre-intervention were analyzed. RESULTS: Eight unique types of interaction patterns among patients, caregivers, and healthcare providers were identified as follows: collaborative interactions, explanatory interactions, agentic interactions, checklist interactions, cross-purpose interactions, empathic interactions, admonishing interactions, and diverging interactions. CONCLUSIONS: Our findings provide a systematic description of a variety of types of interaction patterns regarding symptom discussion among APC patients, caregivers, and healthcare providers. These typologies can be used to facilitate effective communication and symptom management. PMID- 29696424 TI - Survivorship care models for breast cancer, colorectal cancer, and adolescent and young adult (AYA) cancer survivors: a systematic review. AB - BACKGROUND: Well-elucidated survivorship care models are pertinent in the long term management of cancer survivors. This review aims to update existing literature and evaluate the key components of such models with a focus on breast, colorectal, and adolescent and young adult (AYA) cancer survivors. METHODS: The PubMed electronic database were searched comprehensively for relevant publications in English through February 2017. Additional manual searches were conducted for reference lists and official guidelines published by oncology societies. Included studies addressed the correct cancer type, elaborated on each model's structure and provided patient-related outcome data to support its model's effectiveness if applicable. RESULTS: Among the 25 included studies, six articles described survivorship models applicable to all cancer types, and the remaining focused on breast cancer (n = 10), colorectal cancer (n = 3), and AYA cancer survivors (n = 6). Shared-care model was largely described for all cancer types whereas multidisciplinary model predominated for AYA cancer survivors. Upon evaluation, these models described the essential components of survivorship care fairly well except for the care coordination component. Also, the definition of time points of care was vague and noncomprehensive. CONCLUSION: The reviewed survivorship model studies were comprehensive but were limited by a lack of existing rigorous evaluation efforts to assess their effectiveness. This review further provided valuable recommendations for future methodological evaluation of such models. This review has highlighted care coordination as an area for improvement and emphasized the importance of obtaining data on the effectiveness of these survivorship models to ensure satisfactory quality of life and health outcomes. PMID- 29696425 TI - Cancer care in regional Australia from the health professional's perspective. AB - PURPOSE: This study aimed to identify the factors which health professionals believe influence clinical care and outcomes for people with cancer in regional areas of Australia. METHODS: Twelve semi-structured interviews were conducted with a variety of health professionals. Interview questions explored health professional's perspectives on barriers to cancer care for patients, factors which influence clinical care, and access to support in regional areas. Data were interpreted using an inductive thematic analysis approach. RESULTS: Two global themes were identified: rural culture and the health system. Within these global themes, health professionals discussed barriers to cancer care in regional areas, predominantly associated with travel, limited workforce, and poor communication within the health system. Participants also noted many positive aspects of cancer care in regional areas, including more personalised care for the patients and faster career progression for professionals. CONCLUSIONS: Despite several strategies to improve rural cancer care in recent times, including innovative models of care and increased infrastructure, health professionals still perceive many barriers to cancer care in regional Australia. These are predominantly associated with patient demographics, travel difficulties, and inadequate governance. However, there are also many notable benefits to receiving care in regional areas which have been absent from previous literature. These positive factors should be incorporated in efforts to enhance regional cancer care through the recruitment of health professionals to regional areas and development of regional community support networks. PMID- 29696426 TI - Cancer cost communication: experiences and preferences of patients, caregivers, and oncologists-a nationwide triad study. AB - PURPOSE: We assessed cost communication between cancer patients, caregivers, and oncologists and identified factors associated with communication concordance. METHODS: A national, multicenter, cross-sectional survey of patient-caregiver oncologist triads was performed, and 725 patient-caregiver pairs, recruited by 134 oncologists in 13 cancer centers, were studied. Discordance in preferences and experiences regarding cost communication between patients, caregivers, and oncologists were assessed. Hierarchical generalized linear models were used to identify predictors of concordance and to identity the possible association of concordance with patient satisfaction and degree of trust in the physician. RESULTS: Although the oncologists thought that patients would be affected by the cost of care, only half of them were aware of the subjective burden experienced by their patients, and the degree of concordance for this parameter was very low (weighted kappa coefficient = 0.06). Caregivers consistently showed similar preferences to those of the patients. After controlling for covariates, the education level of patients [adjusted odds ratio (aOR) for > 12 vs. < 9 years, 2.92; 95% confidence interval (CI), 1.87-4.56], actual out-of-pocket costs [aOR for >= 8 million vs. < 2 million Korean Won, 0.56; 95% CI, 0.34-0.89], and physician age (aOR for >= 55 vs. < 45 years, 1.83; 95% CI, 1.04-3.21) were significant. CONCLUSIONS: The results show underestimation by oncologists regarding the subjective financial burden on a patient, and poor patient physician concordance in cost communication. Oncologists should be more cognizant of patient OOP costs that are not indexed by objective criteria, but instead involve individual patient perceptions. PMID- 29696427 TI - Partial splenic embolization in the treatment of prolonged thrombocytopenia due to hypersplenism in metastatic cancer patients. AB - BACKGROUND: Hypersplenism-related thrombocytopenia (HST) may delay or preclude chemotherapy. Partial splenic embolization (PSE) has been used at our center to overcome prolonged HST. PATIENTS AND METHODS: Between November 2012 and April 2015, 11 PSE procedures were performed in 10 patients; 9 had metastatic colorectal cancer and 1 had widespread pancreatic cancer. PSE was performed by selective catheterization of the splenic artery followed by injection of embolic particles, ranging from 300-700 um, until a 50% reduction in the splenic parenchyma blush was achieved. RESULTS: Splenomegaly was evaluated by splenic index, mean value 970 cm3 (range, 358-2277 cm3), normal mean 120-480 cm3. Mean platelet count immediately prior to PSE was 64.5 K/UL (range, 17-104 K/UL); within 10-14 days following the procedure, it increased to 224 K/UL (range, 83 669 K/UL). Only one patient's count remained less than 100 K/UL 2 weeks after embolization. After the procedure, all patients complained of mild abdominal pain that lasted for a few days; one patient developed post-embolization syndrome. No other significant complications were observed. Mean hospital stay was 2.5 days (range, 2-5 days). Chemotherapy was resumed 7-53 days (mean, 18 days) after the procedure in nine patients. One patient did not receive chemotherapy; he underwent local treatment of liver metastasis. Prolonged thrombocytopenia recurred in four patients, one of whom was successfully retreated by PSE. CONCLUSIONS: PSE can be considered as a treatment option for HST. PMID- 29696428 TI - Heart Rate Variability and Cardiopulmonary Dysfunction in Patients with Duchenne Muscular Dystrophy: A Systematic Review. AB - Duchenne muscular dystrophy (DMD) is a genetic recessive disorder with progressive muscle weakness. Despite the general muscle wasting, degeneration and necrosis of cardiomyocytes have been the main causes of morbidity and death in individuals with DMD. Cardiac failure is generally preceded by disturbances in heart rate variability (HRV), and non-invasive measurement of the autonomic nervous system has been an important tool to predict adverse cardiovascular events. Hence, the application of HRV to study autonomic modulation in DMD individuals, and the establishment of correlations between HRV and heart/lung diseases, age, and mortality will have the potential to improve quality of life and life expectancy of individuals with DMD. In order to evaluate the state of the art in this field, we conducted a systematic search in Medline/PubMed and BVS (virtual library in health) databases. We selected 8 studies using pre-defined criteria and meta-analysis revealed decreased parasympathetic activity and increased sympathetic predominance in individuals with DMD as major observations. Moreover, there is a strong association between diminished HRV and myocardial fibrosis with DMD. These patterns are evident in patients at early-stage DMD and become more prominent as disease severity and age increase. Thus, data minning clearly indicates that HRV assessment can be used as a predictor for sudden death in individuals with DMD. The use of the HRV, which is inexpensive, ubiquitously available in clinics and hospitals, and a non-invasive analysis tool, can save lives and decrease the morbity in DMD by alerting care givers to consider autonomic nervous system intervention. PMID- 29696429 TI - The Pulmonary Artery in Pediatric Patients with Marfan Syndrome: An Underestimated Aspect of the Disease. AB - Aortic root dilatation and its complications are known to be the most important and life limiting features in patients with Marfan syndrome (MFS). Since monitoring of patients, preventive medical and surgical treatments are available nowadays, other MFS pathologies are becoming more relevant for the outcome of the disease. Main pulmonary artery (MPA) dilatation is a cardiac finding, which has not been fully investigated in children. Due to the similarities in tissue composition of the aortic and pulmonary root, MPA dilatation may cause complications and require treatment. In addition, it may be a predictor for severe connective tissue involvement. We retrospectively examined 135 pediatric patients with MFS. 8.1% showed MPA dilatation. MPA dilatation was associated with earlier occurrence of aortic dilatation, mitral valve prolapse, and systemic manifestations of MFS compared with patients without MPA dilatation (p < 0.05). The presence of MPA dilatation was also associated with a higher incidence of ectopia lentis (p < 0.05). Medical treatment was started earlier in MPA dilatation patients than in those without (p < 0.05). We conclude that MPA dilatation is a sign of more severe vascular and connective tissue involvement. Regular examination of the pulmonary artery is essential in MFS to avoid complications. As medical treatment of life threatening MFS events has improved, other features of MFS need to be investigated to improve quality of life. PMID- 29696430 TI - Subtraction CT angiography improves evaluation of significant coronary artery disease in patients with severe calcifications or stents-the C-Sub 320 multicenter trial. AB - OBJECTIVES: Diagnostic accuracy of conventional coronary CT angiography (CCTAconv) may be compromised by blooming artifacts from calcifications or stents. Blooming artifacts may be reduced by subtraction coronary CT angiography (CCTAsub) in which non-contrast and contrast CT data sets are subtracted digitally. We tested whether CCTAsub in patients with severe coronary calcification or stents reduces the number of false-positive stenosis evaluations compared with CCTAconv. METHODS: In this study, 180 symptomatic patients scheduled for invasive coronary angiography (ICA) were prospectively enrolled and CT scanned (2013-2016) at three international centers. CCTAconv, and CCTAsub data sets were reconstructed. Target segments were defined as motion-free coronary segments with a suspected stenosis (> 50% of lumen) potentially due to blooming of either calcium or stents. Target segments were evaluated with respect to misregistration artifacts from the CCTAsub reconstruction process, in which case evaluation was omitted. CCTAsub and CCTAconv were compared with ICA. Primary outcome measure was the frequency of false positives by CCTAconv versus CCTAsub to identify > 50% coronary stenosis by ICA on a per-segment level. RESULTS: After exclusion of 76 patients, 104 (14% females) with mean age 67 years and median Agatston score 852 were included. There were 136 target segments with misregistration and 121 target segments without. Accuracy calculations in target segments without misregistration showed a reduction of the false positives from 72% [95% confidence interval (CI): 63-80%] in CCTAconv to 33% (CI:25-42%) in CCTAsub, at the expense of 7% (CI:3-14%) false negatives in CCTAsub. CONCLUSIONS: In severely calcified coronary arteries or stents, CCTAsub reduces the false positive rate in well-aligned, calcified or stent segments suspected of significant stenosis on CCTAconv. Nevertheless, misregistration artifacts are frequent in CCTAsub. KEY POINTS: * A high calcium-score reduces the diagnostic accuracy in patients scanned with cardiac CT. * These patients would normally need an invasive angiogram for diagnosis. * In this prospective, multicenter study, subtraction CT, when evaluable, reduces false-positive stenosis evaluations. * Subtraction coronary CT angiography may, when evaluable, reduce excessive downstream testing. PMID- 29696431 TI - Magnetic resonance guided focused high frequency ultrasound ablation for focal therapy in prostate cancer - phase 1 trial. AB - OBJECTIVES: To evaluate the feasibility and safety of focal therapy for low intermediate risk prostate cancer (PCa) with magnetic resonance-guided high frequency focused ultrasound (MRgFUS) METHODS: This IRB-approved phase 1 prospective study enrolled eight patients with prostate specific antigen (PSA) <= 10 ng/ml, <= cT2a and Gleason score <= 7 (4 + 3) disease following informed consent. Under MRI guidance, focused high frequency ultrasound energy was delivered to ablate the target tissue. Treatment-related adverse events were recorded. Oncologic outcomes were evaluated with multiparametric MRI, PSA and TRUS biopsy at 6 months following treatment. RESULTS: Ten target lesions [six Gleason 6 lesions, two Gleason 7 (3 + 4) and two Gleason 7 (4 + 3)] were treated in eight men (prostate volume range, 25-50 cc; mean MRI time, 248 min per patient; mean sonication duration, 65 min). Mean target volume was 2.7 cc and mean post-treatment non-perfused volume was 4.3 cc. Quality of life parameters were similar between baseline and 6 months in 6/8 patients. All treated regions were negative on MRI; 4/8 patients and 6/10 target lesions (60%) were clear of disease on biopsy. One patient with 2-mm Gleason 8 disease in one of five cores from treatment site (4 + 3 disease at baseline) subsequently underwent prostatectomy with negative surgical margins. Three patients with low volume (5 15%) Gleason 6 residual disease were offered active surveillance. Mean PSA decreased from 5.06 at baseline to 3.4 ng/ml at 6 months. CONCLUSION: MRgFUS is a feasible and safe method of noninvasively ablating low-intermediate risk PCa with acceptable short-term oncologic outcomes. KEY POINTS: * Focal therapy selectively ablates locally confined, clinically significant index lesion with a margin while sparing rest of gland and adjacent vital structures. * Magnetic resonance-guided focused high frequency ultrasound surgery (MRgFUS) combines MRI with HIFU. * MRgFUS provides ability to monitor treatments in real time and allows a targeted approach for focal ablation. * MRgFUS is a feasible, safe method of noninvasively ablating low-intermediate risk PCa. * MRgFUS provides acceptable oncologic outcomes at 6 months. PMID- 29696432 TI - Mesenteric lymph nodes in MR enterography: are they reliable followers of bowel in active Crohn's disease? AB - OBJECTIVES: To demonstrate magnetic resonance enterography (MRE) features of mesenteric lymph nodes (LN) in patients with Crohn's disease (CD) and investigate whether they follow enhancement or apparent diffusion coefficient (ADC) parameters of bowel. METHODS: This study was approved by the institutional review board. A total of 788 MREs from patients with CD were retrospectively reviewed. Eighty-eight patients, aged 16-66 years, including 59 active cases, were enrolled based on inclusion criteria. In each MRE, two segments (normal and abnormal) and two LNs (regional and non-regional) were independently suggested, consensually chosen, and analyzed by two radiologists. Signal-to-noise (SNR) and contrast-to noise (CNR) ratios were calculated to assess signal intensities (SI) at 30, 60 and 180 s after contrast administration, as well as slope of enhancement (SOE). Enhancement parameters and ADC values were compared. RESULTS: Regional LNs showed significantly higher SI30, SI60 and SI180 (CNR&SNR) and lower ADC values in active vs. inactive groups (all p<0.05) without significant difference in number or size. Strong correlations were demonstrated between abnormal segments and regional LNs in active group in terms of SI30, SI60, SI180, SOE0-30 and ADC values (r = 0.679 to 0.774, all p<0.001). SI180, SOE60-180 and ADC values were moderately correlated between abnormal segments and regional LNs in inactive group (r = 0.448 to 0.595, all p<0.05). In logistic regression analyses, SOE0-30 and ADC value of regional LNs independently predicted active CD. CONCLUSION: Mesenteric LNs follow quantitative enhancement and diffusion parameters of bowel in active CD. SOE0-30 and ADC value of LN could predict disease activity. KEY POINTS: * Mesenteric LNs may strongly follow enhancement pattern of bowel in active CD. * DWI parameters of LNs and bowel were strongly correlated in active CD. * SI180 was moderately correlated between bowel and LNs in inactive CD. * DWI parameters were moderately correlated between LNs and bowel in inactive CD. * SOE0-30 and ADC value of mesenteric LN could predict disease activity. PMID- 29696434 TI - Observed Free-Play Patterns of Children with ADHD and Their Real-Life Friends. AB - Previous observational studies conducted in highly structured, analog situations indicate that children with Attention-Deficit/Hyperactivity Disorder (ADHD) mismanage their relationships with same-age peers and friends. Such structured situations may not, however, fully represent the true nature of children's play, which is typically characterized by free choice, intrinsic motivation, and spontaneity. The unique objective of the current observational study was to describe how 87 children with ADHD and 46 comparison (76% boys) aged 7-13 years behave when interacting with their real-life dyadic friends during an unstructured, free-play situation. Results indicate that dyads comprising one referred child with ADHD and an invited friend ("ADHD dyads") engaged in less cooperative play, displayed less companionship, and showed less sensitivity to friends than comparison dyads. ADHD dyads also engaged in more conflict and exhibited significantly more negative affect than comparison dyads. These findings complement and extend, possibly with somewhat enhanced ecological validity, results obtained in previous studies on the friendships of children with ADHD featuring closed-field observations and questionnaire methodology. PMID- 29696433 TI - 2D shear wave elastography combined with MELD improved prognostic accuracy in patients with acute-on-chronic hepatitis B liver failure. AB - OBJECTIVES: To evaluate accuracy of two-dimensional shear wave elastography (2D SWE) and develop and validate a new prognostic score in predicting prognosis of acute-on-chronic liver failure (ACLF) patients. METHODS: From 1 October 2013 to 30 September 2015, we consecutively enrolled 290 patients, sequentially collected data (including 2D SWE, ultrasound parameters, laboratory data and prognostic scores) and recorded patients' outcome (recovering/steady or worsening) during a 90-day follow-up period. We evaluated ability of 2D SWE to predict outcomes of acute-on-chronic hepatitis B liver failure (ACLF-HBV) patients. We developed a new score (MELD-SWE, combining MELD and SWE values) for predicting mortality risk of ACLF-HBV in 179 patients in a derivation group, and validated in 111 patients. RESULTS: 2D SWE values were higher in worsening patients than recovering/steady ones (p < 0.001). Accuracy of 2D SWE in predicting outcomes of ACLF-HBV was comparable to that of the MELD score (p = 0.441). MELD-SWE showed a significantly higher prognostic value than MELD in both derivation (AUROC, 0.80 vs. 0.76, p = 0.040) and validation (AUROC, 0.87 vs. 0.82, p = 0.018) group. CONCLUSIONS: The MELD-SWE score, combining MELD and SWE values, was superior to MELD alone for outcoming prediction in patients with ACLF-HBV. KEY POINTS: * 2D SWE is a simple prognostic evaluation tool in patients with ACLF-HBV. * MELD-SWE was created in this study: 1.3*MELD + 0.3*2D SWE (kPa). * MELD-SWE score was superior to MELD alone for outcoming prediction in ACLF-HBV. * In this study, 46.8 was the optimal cut-off value of MELD-SWE score. PMID- 29696435 TI - Parenting Interacts with Oxytocin Polymorphisms to Predict Adolescent Social Anxiety Symptom Development: A Novel Polygenic Approach. AB - Guided by a developmental psychopathology framework, research has increasingly focused on the interplay of genetics and environment as a predictor of different forms of psychopathology, including social anxiety. In these efforts, the polygenic nature of complex phenotypes such as social anxiety is increasingly recognized, but studies applying polygenic approaches are still scarce. In this study, we applied Principal Covariates Regression as a novel approach to creating polygenic components for the oxytocin system, which has recently been put forward as particularly relevant to social anxiety. Participants were 978 adolescents (49.4% girls; Mage T1 = 13.8 years). Across 3 years, questionnaires were used to assess adolescent social anxiety symptoms and multi-informant reports of parental psychological control and autonomy support. All adolescents were genotyped for 223 oxytocin single nucleotide polymorphisms (SNPs) in 14 genes. Using Principal Covariates Regression, these SNPs could be reduced to five polygenic components. Four components reflected the underlying linkage disequilibrium and ancestry structure, whereas the fifth component, which consisted of small contributions of many SNPs across multiple genes, was strongly positively associated with adolescent social anxiety symptoms, pointing to an index of genetic risk. Moreover, significant interactions were found with this polygenic component and the environmental variables of interest. Specifically, adolescents who scored high on this polygenic component and experienced less adequate parenting (i.e., high psychological control or low autonomy support) showed the highest levels of social anxiety. Implications of these findings are discussed in the context of individual-by-environment models. PMID- 29696436 TI - Prevalence of cardiovascular disease and major risk factors in patients with rheumatoid arthritis: a multinational cross-sectional study. AB - To compare the prevalence of cardiovascular disease (CVD) and major CVD risk factors among rheumatoid arthritis (RA) patients enrolled in a large US and multinational registry. We compared CVD and CVD risk factor prevalence from 11 countries enrolled in the CORRONA US and CORRONA International registries; patients from the 10 ex-US participating countries were grouped by region (Eastern Europe, Latin America, and India). Unadjusted summary data were presented for demographics and disease characteristics; comparisons for prevalence of CVD risk factors and CVD were age/gender standardized to the age/gender distribution of the US enrolled patients. Overall, 25,987 patients were included in this analysis. Compared to patients from the ex-US regions, US participants had longer disease duration and lower disease activity, yet were more likely to receive a biologic agent. Additionally, CORRONA US participants had the highest body mass index (BMI). Enrolled patients in India had the lowest BMI, were more rarely smokers, and had a low prevalence of hyperlipidemia, hypertension, and prior CVD compared to the US and other ex-US regions. Participants from Eastern Europe had a higher prevalence of hypertension and hyperlipidemia and highest prevalence of all manifestations of CVD. Differences in the prevalence of both CVD and major CVD risk factors were observed across the four regions investigated. Observed differences may be influenced by variations in both non-modifiable/modifiable characteristics of patient populations, and may contribute to heterogeneity on the observed safety of investigational and approved therapies in studies involving RA patients from different origins. PMID- 29696437 TI - Sharp decline in hydroxychloroquine dosing-analysis of 17,797 initiators from 2007 to 2016. AB - We aimed to assess the impact of ophthalmology weight-based hydroxychloroquine (HCQ) dosing guidelines on prescribing patterns. We examined initial HCQ prescription dosing between 2007 and 2016 and determined independent predictors for HCQ dosing above the previous (2011) recommended <= 6.5 mg/kg of ideal body weight (IBW)/day and the latest (2016) recommended <= 5.0 mg/kg of actual body weight (ABW)/day using logistic regression. Among 17,797 patients (82% female), the proportion of 400 mg prescribed daily dosing declined sharply from 80% in 2007-2011 to nearly 40% in 2014, whereas the proportions of 200- and 300-mg daily doses showed the opposite trends during the same periods. Accordingly, the risk of HCQ dosing above the guideline recommendations declined by more than 60%. While 36% of normal body mass index (BMI) individuals were classified as dosing above the IBW-based guideline, 66% would have received dosing above the latest ABW-based guideline. The risk of excess dosing was associated with female patients and dermatology prescribers (adjusted odds ratios >= 2 according to IBW- or ABW-based guidelines). There has been a sharp decline in HCQ dosing following ophthalmology weight-based guidelines in recent years. While this trend is likely helpful in reducing the risk of retinopathy, its potential impact on HCQ efficacy remains to be clarified. PMID- 29696438 TI - Association between smoking and gout: a meta-analysis. AB - Previous studies showed that smoking is linked with the decreased risk of gout, but the results remain controversial. The aim of this meta-analysis was to determine the associations between smoking and the risk of gout. A systematic literature search of PubMed and EMBASE was conducted. Data were extracted by two independent reviewers. The pooled odds ratio (OR) with 95% confidence interval (CI) was used to assess the strength of associations, using random effects and fixed effects models. Five studies with a total of 17,915,507 participants with 16,880 gouts were enrolled. Heterogeneity among the effect sizes of five studies was reported as I2 = 87.9%. Our meta-analysis indicated that smoking (ever- vs non-, OR = 0.87, 95% CI = 0.67-1.12) was not associated with the risk of gout in random effects model, whereas there was an association between smoking (ever- vs non-, OR = 0.70, 95% CI = 0.65-0.74) and gout risk in fixed effects model. Our finding indicates that smoking may not be involved in the risk of gout. However, further studies are still needed to confirm our results. PMID- 29696440 TI - Leptospiral Genomics and Pathogenesis. AB - Until about 15 years ago, the molecular and cellular basis for pathogenesis in leptospirosis was virtually unknown. The determination of the first full genome sequence in 2003 was followed rapidly by other whole genome sequences, whose availability facilitated the development of transposon mutagenesis and then directed mutagenesis of pathogenic Leptospira spp. The combination of genomics, transcriptomics and mutant construction and characterisation has resulted in major progress in our understanding of the taxonomy and biology of Leptospira. The most recent advances are analysed and discussed in this chapter. PMID- 29696439 TI - Acidithiobacillus ferrooxidans and its potential application. AB - The widely distributed Acidithiobacillus ferrooxidans (A. ferrooxidans) lives in extremely acidic conditions by fixing CO2 and nitrogen, and by obtaining energy from Fe2+ oxidation with either downhill or uphill electron transfer pathway and from reduced sulfur oxidation. A. ferrooxidans exists as different genomovars and its genome size is 2.89-4.18 Mb. The chemotactic movement of A. ferrooxidans is regulated by quorum sensing. A. ferrooxidans shows weak magnetotaxis due to formation of 15-70 nm magnetite magnetosomes with surface functional groups. The room- and low-temperature magnetic features of A. ferrooxidans are different from other magnetotactic bacteria. A. ferrooxidans has potential for removing sulfur from solids and gases, metals recycling from metal-bearing ores, electric wastes and sludge, biochemical production synthesizing, and metal workpiece machining. PMID- 29696441 TI - Alphatherapy, the new impetus to targeted radionuclide therapy? PMID- 29696442 TI - The best of both worlds: a hybrid approach for optimal pre- and intraoperative identification of sentinel lymph nodes. AB - PURPOSE: Hybrid image-guided surgery technologies such as combined radio- and fluorescence-guidance are increasingly gaining interest, but their added value still needs to be proven. In order to evaluate if and how fluorescence-guidance can help realize improvements beyond the current state-of-the-art in sentinel node (SN) biopsy procedures, use of the hybrid tracer indocyanine green (ICG) 99mTc-nancolloid was evaluated in a large cohort of patients. PATIENTS AND METHODS: A prospective trial was conducted (n = 501 procedures) in a heterogeneous cohort of 495 patients with different malignancies (skin malignancies, oral cavity cancer, penile cancer, prostate cancer and vulva cancer). After injection of ICG-99mTc-nanocolloid, SNs were preoperatively identified based on lymphoscintigraphy and SPECT/CT. Intraoperatively, SNs were pursued via gamma tracing, visual identification (blue dye) and/or near-infrared fluorescence imaging during either open surgical procedures (head and neck, penile, vulvar cancer and melanoma) or robot assisted laparoscopic surgery (prostate cancer). As the patients acted as their own control, use of hybrid guidance could be compared to conventional radioguidance and the use of blue dye (n = 300). This was based on reported surgical complications, overall survival, LN recurrence free survival, and false negative rates (FNR). RESULTS: A total of 1,327 SN-related hotspots were identified on 501 preoperative SPECT/CT scans. Intraoperatively, a total number of 1,643 SNs were identified based on the combination of gamma-tracing (>98%) and fluorescence-guidance (>95%). In patients wherein blue dye was used (n = 300) fluorescence-based SN detection was superior over visual blue dye-based detection (22-78%). No adverse effects related to the use of the hybrid tracer or the fluorescence-guidance procedure were found and outcome values were not negatively influenced. CONCLUSION: With ICG-99mTc nanocolloid, the SN biopsy procedure has become more accurate and independent of the use of blue dye. With that, the procedure has evolved to be universal for different malignancies and anatomical locations. PMID- 29696443 TI - Relationship between functional imaging and immunohistochemical markers and prediction of breast cancer subtype: a PET/MRI study. AB - PURPOSE: The aim of this study was to determine if functional parameters extracted from the hybrid positron emission tomography/magnetic resonance imaging (PET/MRI) correlate with the immunohistochemical markers of breast cancer (BC) lesions, to assess their ability to predict BC subtype. METHODS: This prospective study was approved by the institution's Ethics Committee, and all patients provided written informed consent. A total of 50 BC patients at diagnosis underwent PET/MRI before pharmacological and surgical treatment. For each primary lesion, the following data were extracted: morphological data including tumour node-metastasis stage and lesion size; apparent diffusion coefficient (ADC); perfusion data including forward volume transfer constant (Ktrans), reverse efflux volume transfer constant (Kep) and extravascular extracellular space volume (Ve); and metabolic data including standardized uptake value (SUV), lean body mass (SUL), metabolic tumour volume and total lesion glycolysis. Immunohistochemical reports were used to determine receptor status (oestrogen, progesterone, and human epidermal growth factor receptor 2), cellular differentiation status (grade), and proliferation index (Ki67) of the tumour lesions. Correlation studies (Mann-Whitney U test and Spearman's test), receiver operating characteristic (ROC) curve analysis, and multivariate analysis were performed. RESULTS: Association studies were performed to assess the correlations between imaging and histological prognostic markers of BC. Imaging biomarkers, which significantly correlated with biological markers, were selected to perform ROC curve analysis to determine their ability to discriminate among BC subtypes. SUVmax, SUVmean and SUL were able to discriminate between luminal A and luminal B subtypes (AUCSUVmean = 0.799; AUCSUVmax = 0.833; AUCSUL = 0.813) and between luminal A and nonluminal subtypes (AUCSUVmean = 0.926; AUCSUVmax = 0.917; AUCSUL = 0.945), and the lowest SUV and SUL values were associated with the luminal A subtype. Kepmax was able to discriminate between luminal A and luminal B subtypes (AUC = 0.779), and its highest values were associated with the luminal B subtype. Ktransmax (AUC = 0.881) was able to discriminate between luminal A and nonluminal subtypes, and the highest perfusion values were associated with the nonluminal subtype. In addition, ADC (AUC = 0.877) was able to discriminate between luminal B and nonluminal subtypes, and the lowest ADCmean values were associated with the luminal B subtype. Multivariate analysis was performed to develop a prognostic model, and the best predictive model included Ktransmax and SUVmax parameters. CONCLUSION: Using multivariate analysis of both PET and MRI parameters, a prognostic model including Ktransmax and SUVmax was able to predict the tumour subtype in 38 of 49 patients (77.6%, p < 0.001), with higher accuracy for the luminal B subtype (86.2%). PMID- 29696444 TI - Fractional CO2 laser contributes to the treatment of non-segmental vitiligo as an adjunct therapy: a systemic review and meta-analysis. AB - The treatment of stable non-segmental vitiligo is often challenging, which new therapies are being searched. Multiple clinical trials have proposed the benefits and safety of using fractional carbon dioxide (CO2) laser as an adjunct therapy to conventional treatments. This study aimed to evaluate the safety and efficacy of fractional carbon dioxide laser as a combination therapy to conventional treatments in patients with stable non-segmental vitiligo. A literature search using PubMed, EMBASE, and the Cochrane Library was performed for comparative studies among vitiligo patients treated with additional fractional CO2 laser. Clinical outcomes in the selected studies were compared, and a meta-analysis was performed via Review Manager version 5.3, according to the PRISMA guidelines. Six studies with a total of 184 patches/patients were included in the present meta analysis. The combination therapy group had significantly superior results than that of the control group (>= 75% re-pigmentation, risk ratio [RR] 2.80, 95% confidence interval [CI] 1.29-6.07; >= 50% re-pigmentation, RR 2.26, 95% CI 1.23 5.9; < 25% re-pigmentation, RR 0.57, 95% CI 0.43-0.75). Limitations of the study included the small number of studies and sample size, inadequate blinding of participants, and variation between therapy protocols. Meta-analysis revealed that using fractional CO2 laser in combination with conventional treatments is efficient and safe, and may be considered as an adjunct therapeutic option for patients with refractive non-segmental vitiligo. PMID- 29696445 TI - Resistance to vertical root fracture of apicoected teeth using different devices during two root canal irrigation procedures. AB - The aim of the present work was to measure the fracture resistance of endodontically treated teeth that were apicoected with different procedures. Seventy-two extracted human maxillary anterior teeth were included in this study. The specimens were randomly assigned to three main groups according to the apical surgery procedures and then two subgroups according to the irrigation protocols during root canal treatment and total of six groups were obtained (n = 12). Group 1: served as a control and apical surgery process was not performed in this group. Group 2: apical surgery process was performed with tungsten carbide fissure bur Group 3: apical surgery process was performed with Er:YAG laser. Subgroup a: In this group, the specimens were irrigated with %5 NaOCl. Subgroup b: 15% EDTA solution was filled into the root canal and then agitated using a 1.5 W/100 Hz diode laser. The specimens were filled and mounted in acrylic resin blocks and compression strength test was performed. Statistical analysis was performed using two-way ANOVA. The statistical analysis revealed that there were no statistical significant differences between apical surgery procedures (groups 1, 2, and 3) (p < 0.05). Apical resection procedures did not affect the fracture resistance Significant differences were determined between the subgroups (p < 0.05). Agitation of the EDTA with the diode laser reduced the fracture resistance of the specimens. The different canal irrigation techniques altered resistance to fracture; however, apical surgery procedures did not altered the resistance to fracture when compared with the control group. PMID- 29696447 TI - Preserving Cardiovascular Health in Young Children: Beginning Healthier by Starting Earlier. AB - PURPOSE OF REVIEW: The goals of this paper are to review current literature regarding maternal-fetal-pediatric diet and nutritional factors related to preserving cardiovascular health in the very young child and the emerging data implicating nutritional influences on neurodevelopmental factors. Questions related to maternal diet and influences of human milk on child's growth, neurodevelopment, and risk of developing obesity were addressed. RECENT FINDINGS: The majority of US women in their reproductive years have overweight or obese status thereby increasing the risk of developing obesity in their children. Efforts to restrict gestational weight gain, perpetuate breast-feeding, and introduce heart-healthy complementary feeding after 6 months of age are now more commonly recommended and offer practical translational approaches to prevent pediatric obesity and encourage neurodevelopment intended to support cognitive and executive function. There is growing literature on the role of maternal-fetal pediatric nutrition on cardiometabolic and neurodevelopmental health in children. Potential influences of maternal diet quality and obesity on not only birth outcomes but subsequent risk factor development in the child are increasingly apparent. Further investigation of these factors has become a major research focus in developing future diet recommendations to better inform underlying potential mechanisms and identify opportunities for primary prevention starting in utero. PMID- 29696446 TI - Photobiomodulation effects on mRNA levels from genomic and chromosome stabilization genes in injured muscle. AB - Muscle injuries are the most prevalent type of injury in sports. A great number of athletes have relapsed in muscle injuries not being treated properly. Photobiomodulation therapy is an inexpensive and safe technique with many benefits in muscle injury treatment. However, little has been explored about the infrared laser effects on DNA and telomeres in muscle injuries. Thus, the aim of this study was to evaluate photobiomodulation effects on mRNA relative levels from genes related to telomere and genomic stabilization in injured muscle. Wistar male rats were randomly divided into six groups: control, laser 25 mW, laser 75 mW, injury, injury laser 25 mW, and injury laser 75 mW. Photobiomodulation was performed with 904 nm, 3 J/cm2 at 25 or 75 mW. Cryoinjury was induced by two applications of a metal probe cooled in liquid nitrogen directly on the tibialis anterior muscle. After euthanasia, skeletal muscle samples were withdrawn and total RNA extracted for evaluation of mRNA levels from genomic (ATM and p53) and chromosome stabilization (TRF1 and TRF2) genes by real time quantitative polymerization chain reaction. Data show that photobiomodulation reduces the mRNA levels from ATM and p53, as well reduces mRNA levels from TRF1 and TRF2 at 25 and 75 mW in injured skeletal muscle. In conclusion, photobiomodulation alters mRNA relative levels from genes related to genomic and telomere stabilization in injured skeletal muscle. PMID- 29696448 TI - Temporal Modulation Detection Depends on Sharpness of Spatial Tuning. AB - Prior research has shown that in electrical hearing, cochlear implant (CI) users' speech recognition performance is related in part to their ability to detect temporal modulation (i.e., modulation sensitivity). Previous studies have also shown better speech recognition when selectively stimulating sites with good modulation sensitivity rather than all stimulation sites. Site selection based on channel interaction measures, such as those using imaging or psychophysical estimates of spread of neural excitation, has also been shown to improve speech recognition. This led to the question of whether temporal modulation sensitivity and spatial selectivity of neural excitation are two related variables. In the present study, CI users' modulation sensitivity was compared for sites with relatively broad or narrow neural excitation patterns. This was achieved by measuring temporal modulation detection thresholds (MDTs) at stimulation sites that were significantly different in their sharpness of the psychophysical spatial tuning curves (PTCs) and measuring MDTs at the same sites in monopolar (MP) and bipolar (BP) stimulation modes. Nine postlingually deafened subjects implanted with Cochlear Nucleus(r) device took part in the study. Results showed a significant correlation between the sharpness of PTCs and MDTs, indicating that modulation detection benefits from a more spatially restricted neural activation pattern. There was a significant interaction between stimulation site and mode. That is, using BP stimulation only improved MDTs at stimulation sites with broad PTCs but had no effect or sometimes a detrimental effect on MDTs at stimulation sites with sharp PTCs. This interaction could suggest that a criterion number of nerve fibers is needed to achieve optimal temporal resolution, and, to achieve optimized speech recognition outcomes, individualized selection of site-specific current focusing strategies may be necessary. These results also suggest that the removal of stimulation sites measured with poor MDTs might improve both temporal and spectral resolution. PMID- 29696449 TI - 1,4-Dioxane degradation characteristics of Rhodococcus aetherivorans JCM 14343. AB - Rhodococcus aetherivorans JCM 14343 can degrade 1,4-dioxane as a sole carbon and energy source. This study aimed to characterize this 1,4-dioxane degradation ability further, and assess the potential use of the strain for 1,4-dioxane removal in industrial wastewater. Strain JCM 14343 was able to degrade 1,4 dioxane inducibly, and its 1,4-dioxane degradation was also induced by tetrahydrofuran and 1,4-butanediol. The demonstration that 1,4-butanediol not only induced but also enhanced 1,4-dioxane degradation was a novel finding of this study. Although strain JCM 14343 appeared not to be an effective 1,4-dioxane degrader considering the maximum specific 1,4-dioxane degradation rate (0.0073 mg dioxane/mg-protein/h), half saturation concentration (59.2 mg/L), and cell yield (0.031 mg-protein/mg-1,4-dioxane), the strain could degrade over 1100 mg/L of 1,4 dioxane and maintain its degradation activity at a wide range of temperature (5 40 degrees C) and pH (4-9) conditions. This suggests the usefulness of strain JCM 14343 in 1,4-dioxane treatment under acidic and cold conditions. In addition, 1,4-dioxane degradation experiments in the presence of ethylene glycol (EG) or other cyclic ethers revealed that 1,4-dioxane degradation by strain JCM 14343 was inhibited in the presence of other cyclic ethers, but not by EG, suggesting certain applicability of strain JCM 14343 for industrial wastewater treatment. PMID- 29696450 TI - Ultraviolet Pulsed Laser-Induced Fluorescence Nonlinearity in Optically Thick Organic Samples. AB - A simple two-component model is worked out to investigate pulsed laser-induced fluorescence in complex organic samples, like biological tissues, optically thick at the excitation wavelength. Expression for emitted fluorescence signal is obtained. Saturation process is shown to be determined not only by fluorophores excited by the laser, but non-fluorescent chromophores with overlapping absorption band as well. For homogeneous samples the forms of saturation curves are determined by fluorophore's features. Experimental saturation curves of bulk paper and mice tissues ultraviolet pulsed laser-induced fluorescence are discussed considering this model. For the ns and shorter laser pulse durations with wavelength in 200-300 nm region, pulse energy density should be less than 200 MUJ/cm2 for correct quantitative comparison of fluorescence spectra of biological tissues with primarily tryptophan fluorescence. PMID- 29696451 TI - Development of a Xanthene-Based Red-Emissive Fluorescent Probe for Visualizing H2O2 in Living Cells, Tissues and Animals. AB - Hydrogen peroxide (H2O2) plays important roles in the regulation of many biological processes, and the abnormal level of H2O2 has close relation with the initiation and progression of many diseases. Herein, we describe a novel red emissive fluorescence probe (RhoB) for the visualization of H2O2 in living cells, tissues and animals. RhoB was constructed on the basis of a xanthene-based red emissive dye, and displayed nearly no fluorescence. After the treatment with H2O2, RhoB can exhibit red fluorescence with the emission wavelength at 638 nm. RhoB exhibited highly sensitive and selective response to H2O2. Density functional theory (DFT) calculations were conducted to shed light on the optical properties of RhoB, and natural bond orbital (NBO) calculations demonstrate that the boron atom shows the highest positive electricity and further support the response mechanism. RhoB was successfully applied for imaging of exogenous and endogenous H2O2 in living cells, and also can be utilized for visualizing H2O2 in living tissues and animals. PMID- 29696452 TI - Computer-aided analysis of 64- and 320-slice coronary computed tomography angiography: a comparison with expert human interpretation. AB - Routine use of CCTA to triage Emergency Department (ED) chest pain can reduce ED length of stay while providing accurate diagnoses. We evaluated the effectiveness of using Computer Aided Diagnosis in the triage of low to intermediate risk emergency chest pain patients with Coronary Computed Tomographic Angiography (CCTA). Using 64 and 320 slice CT scanners, we compared the diagnostic capability of computer aided diagnosis to human readers in 923 ED patients with chest pain. We calculated sensitivity, specificity, Positive Predictive Value and Negative Predictive Value for cases performed on each scanner. We calculated the area under the Receiver Operator Curve (ROC) comparing results for the two scanners to Computer Aided Diagnosis performance as compared to the human reader. We examined index and 30 Day outcomes by diagnosis for each scanner and the human reader. 60% of cases could be triaged by the computer. Sensitivity was approximately 85% for both scanners, with specificity at 50.6% for the 64 slice and at 56.5% for the 320 slice scanner (per person measures). The NPV was 97.8 and 97.1 for the 64 and 320 slice scanners, respectively. Results for the four major vessels were similar with negative predictive values ranging from 97 to 100%. The ROC for Computer Aided Diagnosis for the 64 and 320 Slice Scanners, using the human reader as the gold standard was 0.6794 and 0.7097 respectively. The index and 30 day outcomes were consistent for the human reader and Computer Aided Diagnosis interpretation. Although Computer Aided Diagnosis with CCTA cannot serve completely as a substitute for human reading, it offers excellent potential as a triage tool in busy EDs. PMID- 29696453 TI - Paclitaxel-coated balloon treatment for functionally nonsignificant residual coronary lesions after balloon angioplasty. AB - There is limited data on the efficacy of paclitaxel-coated balloon (PCB) compared to stents for de novo coronary lesions. The purpose of this study was to compare the efficacy of PCB treatment with stent implantation for de novo coronary lesions after successful plain old balloon angioplasty (POBA) guided by fractional flow reserve (FFR). In 200 patients scheduled for elective percutaneous coronary intervention (PCI) for de novo lesions, FFR was measured after POBA (POBA-FFR). If POBA-FFR was >= 0.75, patients were treated with PCB (PCB group, n = 78) or stent (Stent group, n = 73). If POBA-FFR was < 0.75, stent was implanted as planned (Reference group, n = 42). The primary endpoint was late lumen loss at 9 months and the secondary endpoint was adverse cardiac events (cardiac death, myocardial infarction, target lesion thrombosis, or repeat revascularization) at 12 months follow-up. There was no between-group differences in the POBA-FFR (0.87 +/- 0.05 in PCB, 0.89 +/- 0.06 in stent, p = 0.101). At 9 months, late lumen loss was significantly lower in the PCB group compared to the Stent group (0.05 +/- 0.33 vs. 0.59 +/- 0.76 mm, p < 0.001). Adverse cardiac events were not different between the PCB, Stent and Reference groups (2.6, 5.5, and 9.5% respectively; p = 0.430 for PCB vs. Stent group; p = 0.229 for the reference vs. both other groups). PCB treatment guided by POBA-FFR showed excellent 9 months angiographic and functional results, as well as comparable 12 months clinical outcomes, compared with stent implantation for de novo coronary lesions. PMID- 29696454 TI - Optimization of GaAs Nanowire Pin Junction Array Solar Cells by Using AlGaAs/GaAs Heterojunctions. AB - We optimized the performance of GaAs nanowire pin junction array solar cells by introducing AlGaAs/GaAs heterejunctions. AlGaAs is used for the p type top segment for axial junctions and the p type outer shell for radial junctions. The AlGaAs not only serves as passivation layers for GaAs nanowires but also confines the optical generation in the active regions, reducing the recombination loss in heavily doped regions and the minority carrier recombination at the top contact. The results show that the conversion efficiency of GaAs nanowires can be greatly enhanced by using AlGaAs for the p segment instead of GaAs. A maximum efficiency enhancement of 8.42% has been achieved in this study. And for axial nanowire, by using AlGaAs for the top p segment, a relatively long top segment can be employed without degenerating device performance, which could facilitate the fabrication and contacting of nanowire array solar cells. While for radial nanowires, AlGaAs/GaAs nanowires show better tolerance to p-shell thickness and surface condition. PMID- 29696455 TI - Introduction to papers from the third meeting on the Planctomycetes Verrucomicrobia-Chlamydiae bacteria: new model organisms in the omics era. PMID- 29696456 TI - Efficacy of a type 2 PRRSV modified live vaccine (PrimePacTM PRRS) against a Thai HP-PRRSV challenge. AB - The Chinese highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) has caused a severe threat to the pig population in Southeast Asian countries. The purpose of this study was to investigate the efficacy of a type 2 PRRSV modified live vaccine (PrimePacTM PRRS, lineage 7) against a Thai HP-PRRSV (10PL01, lineage 8). Three-week-old PRRSV-free pigs were randomly assigned into three groups. Vaccinated challenged group (group 1, n = 16) was immunized with PrimePacTM PRRS vaccine at 3 weeks old. The unvaccinated challenged group (group 2, n = 16) was injected with PBS at 3 weeks old, and unvaccinated unchallenged group (group 3, n = 10) was served as a negative control. At 9 weeks old, all groups, except the negative control group, were challenged with the Thai HP PRRSV. All pigs were monitored daily during 10 days post-infection (dpi) and were necropsied at 10 and 17 dpi. The results revealed that vaccinated challenged pigs showed significantly lower (p < 0.05) mean rectal temperatures, clinical respiratory scores, lung lesion scores, and levels of virus load in serum and lung tissue compared with the unvaccinated challenged pigs. Moreover, vaccinated challenged pigs exhibited PRRSV-specific serum neutralizing antibodies at the end of the experiment. Our findings indicated that the studied type 2 PRRSV vaccine provided partial protection against the Thai HP-PRRSV infection based on the body temperature, levels of viremia, and the severity of lung lesions. These results demonstrated that partial protection of PrimePacTM PRRS vaccine might be useful for controlling HP-PRRSV infection in the endemic area. PMID- 29696457 TI - Urine Flow Cytometry in the Diagnosis of Urinary Tract Infection. AB - OBJECTIVES: To determine the cut-off value of bacteria with urine flow cytometer in diagnosing urinary tract infection. METHODS: From a total of 546 patients admitted to the hospital with urinary tract infection (UTI), two urine samples were obtained for each patient. Urine samples in sterile containers were divided into two; first for urine culture and second for simultaneous measurement with UF 1000i flow cytometry device. The presence of a single type of bacteria over 103 CFU/mL in urine culture was accepted as UTI. RESULTS: Of 546 patients, 210 (38.5%) were boys and 336 (61.5%) were girls. There was no growth in 489 (89.5%) of the urine specimens and 57 (10.4%) samples showed growth (>103 CFU/ml). A threshold of 10 bacteria/MUL in flow cytometry (sensitivity = 100%) showed the best compatibility with culture. Diagnostic values in terms of sensitivity (100%), specificity (43.5%), negative predictive value (100%) and positive predictive value (17.7%) were satisfactory. CONCLUSIONS: The UF-1000i flow cytometer can give results quickly and exclude UTI using the determined number of cut-off bacteria at low cost. Thus, if Sysmex UF-1000i is used, quick and accurate results can be obtained and unnecessary laboratory tests can be prevented. Also, patient convenience can be increased. PMID- 29696458 TI - Methodological problems in the method used by IQWiG within early benefit assessment of new pharmaceuticals in Germany. AB - BACKGROUND: The decision matrix applied by the Institute for Quality and Efficiency in Health Care (IQWiG) for the quantification of added benefit within the early benefit assessment of new pharmaceuticals in Germany with its nine fields is quite complex and could be simplified. Furthermore, the method used by IQWiG is subject to manifold criticism: (1) it is implicitly weighting endpoints differently in its assessments favoring overall survival and, thereby, drug interventions in fatal diseases, (2) it is assuming that two pivotal trials are available when assessing the dossiers submitted by the pharmaceutical manufacturers, leading to far-reaching implications with respect to the quantification of added benefit, and, (3) it is basing the evaluation primarily on dichotomous endpoints and consequently leading to an information loss of usable evidence. OBJECTIVE: To investigate if criticism is justified and to propose methodological adaptations. METHODS: Analysis of the available dossiers up to the end of 2016 using statistical tests and multinomial logistic regression and simulations. RESULTS: It was shown that due to power losses, the method does not ensure that results are statistically valid and outcomes of the early benefit assessment may be compromised, though evidence on favoring overall survival remains unclear. Modifications, however, of the IQWiG method are possible to address the identified problems. CONCLUSION: By converging with the approach of approval authorities for confirmatory endpoints, the decision matrix could be simplified and the analysis method could be improved, to put the results on a more valid statistical basis. PMID- 29696459 TI - Economic evaluation of Zepatier for the management of HCV in the Italian scenario. AB - BACKGROUND: Hepatitis C virus (HCV) is a major health issue worldwide. New generation of direct-active antiviral medications is an epoch-making turning point in the management of HCV infections. OBJECTIVE: Conducing a cost effectiveness analysis comparing the combination of elbasvir/grazoprevir and sofosbuvir + pegylated interferon/ribavirin for the management of all HCV patients (even those in the initial stages of fibrosis). METHODS: A Markov model was built on the natural history of the disease to assess the efficacy of the alternatives. The outcomes are expressed in terms of quality adjusted life-years (QALYs) and result in terms of incremental cost-effectiveness ratio). RESULTS: Elbasvir/grazoprevir implies an expenditure of ?21,104,253.74 with a gain of 19,287.90 QALYs and sofosbuvir + pegylated interferon/ribavirin implies an expenditure of ?31,904,410.11 with a gain of 18,855.96 QALYs. Elbasvir/grazoprevir is thus a dominant strategy. CONCLUSION: Consideration should be given to the opportunity cost of not treating patients with a lower degree of fibrosis (F0-F2). PMID- 29696460 TI - Tackling the chronic disease burden: are there co-benefits from climate policy measures? AB - Each year, non-communicable diseases (NCDs) kill 40 million people worldwide and impose an estimated economic burden of $600 billion. Without effective policymaking, NCDs will continue to undermine health and economic systems globally. We propose that climate policy measures-such as carbon pricing-can yield significant health-related co-benefits aside from their intended greenhouse gas emission reduction. We simulate three carbon tax scenarios in the energy and food sector in Belgium and assess the resulting health-related co-benefits. These benefits originate from decreased exposure to two leading NCD risk factors: fine particulate matter and dietary regimes excessive in animal products. The carbon tax could prevent 42,300-78,800 Disability-Adjusted Life Years in Belgium, or save 0.6-1.1% of total health care expenditure and an additional 0.06-0.12% of Belgian GDP. We conclude that these health-related co-benefits should be included in the cost-benefit analysis of carbon pricing. PMID- 29696461 TI - Reduced intensity conditioning increases risk of severe cGVHD: identification of risk factors for cGVHD in a multicenter setting. AB - Chronic graft-versus-host disease (cGVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT). Aim is to identify risk factors for the development of cGVHD in a multicenter setting. Patients transplanted between 2000 and 2006 were analyzed (n = 820). Donors were HLA-identical siblings (57%), matched unrelated donors (30%), and HLA-A, B or DR antigen mismatched (13%). Reduced intensity conditioning (RIC) was given to 65% of patients. Overall incidence of cGVHD was 46% for patients surviving more than 100 days after HSCT (n = 747). Older patient age [HR 1.15, p < 0.001], prior acute GVHD [1.30, p = 0.024], and RIC [1.36, p = 0.028] increased overall cGVHD. In addition, RIC [4.85, p < 0.001], prior aGVHD [2.14, p = 0.001] and female donor to male recipient [1.80, p = 0.008] increased the risk of severe cGVHD. ATG had a protective effect for both overall [0.41, p < 0.001] and severe cGVHD [0.20, p < 0.001]. Relapse-free survival (RFS) was impaired in patients with severe cGVHD. RIC, prior aGVHD, and female-to-male donation increase the risk of severe cGVHD. ATG reduces the risk of all grades of cGVHD without hampering RFS. GVHD prophylaxis may be tailored according to the risk profile of patients. PMID- 29696462 TI - Longitudinal monitoring of liver fibrosis status by transient elastography in chronic hepatitis B patients during long-term entecavir treatment. AB - The correlation between improvement in longitudinal liver stiffness and fibrosis regression has not been properly evaluated during long-term antiviral therapy in chronic hepatitis B (CHB) patients. In this study, liver stiffness was serially performed by FibroScan(r) every 26 weeks in a prospective cohort of CHB patients receiving entecavir. Results were compared with liver biopsies at baseline and week 78. A total of 120 treatment-naive CHB patients were analyzed, in which 54 (45%) patients had fibrosis regression at 78 weeks of antiviral therapy. Liver stiffness measurement presented as a rapid-to-slow decline pattern and decreased more significantly in patients with fibrosis regression than those without improvement in fibrosis at week 78 (- 46.4 vs. - 28.6%, P < 0.001). Multivariate analysis revealed that percentage decline of 52-week and 78-week liver stiffness from baseline was independent predictive factors for fibrosis regression (OR = 46.6, P < 0.001; OR = 17.8, P = 0.002, respectively). Moreover, percentage decline of 78-week liver stiffness was moderately predictive of fibrosis regression (AUROC = 0.694, P < 0.001), while the optimal cutoff values were different between non-cirrhosis and cirrhosis patients (38 vs. 45%). Fibrosis regression could be predicted with a high positive predictive value (96%) in non cirrhosis patients and could be excluded with a high negative predictive value (94%) in cirrhosis patients. In conclusion, serial liver stiffness measurement could be applied for longitudinal monitoring of fibrosis status in CHB patients. Continuous decline of liver stiffness after effective antiviral treatment could partially reflect fibrosis regression at an optimal cutoff value. PMID- 29696463 TI - Salinity effect on the metabolic pathway and microbial function in phenanthrene degradation by a halophilic consortium. AB - With the close relationship between saline environments and industry, polycyclic aromatic hydrocarbons (PAHs) accumulate in saline/hypersaline environments. Therefore, PAHs degradation by halotolerant/halophilic bacteria has received increasing attention. In this study, the metabolic pathway of phenanthrene degradation by halophilic consortium CY-1 was first studied which showed a single upstream pathway initiated by dioxygenation at the C1 and C2 positions, and at several downstream pathways, including the catechol pathway, gentisic acid pathway and protocatechuic acid pathway. The effects of salinity on the community structure and expression of catabolic genes were further studied by a combination of high-throughput sequencing, catabolic gene clone library and real-time PCR. Pure cultures were also isolated from consortium CY-1 to investigate the contribution made by different microbes in the PAH-degrading process. Marinobacter is the dominant genus that contributed to the upstream degradation of phenanthrene especially in high salt content. Genus Halomonas made a great contribution in transforming intermediates in the subsequent degradation of catechol by using catechol 1,2-dioxygenase (C12O). Other microbes were predicted to be mediating bacteria that were able to utilize intermediates via different downstream pathways. Salinity was investigated to have negative effects on both microbial diversity and activity of consortium CY-1 and consortium CY-1 was found with a high degree of functional redundancy in saline environments. PMID- 29696464 TI - Comparison of changes of macular ganglion cell-inner plexiform layer defect between stable group and progression group in primary open-angle glaucoma. AB - PURPOSE: To compare the changes in macular ganglion cell-inner plexiform layer (GCIPL) defect between stable and progression primary open-angle glaucoma (POAG) groups. STUDY DESIGN: Retrospective observational study. METHODS: A total of 100 POAG eyes with localized retinal nerve fiber layer (RNFL) defect and corresponding macular GCIPL defect were selected for this study. Glaucoma progression was defined by either structural or functional deterioration. The number of abnormal superpixels on macular GCIPL deviation maps was calculated using a customized MATLAB program. GCIPL defect change was evaluated in two aspects: increased angular width and increased area. The defect patterns were categorized and compared between the stable and progression groups. RESULTS: The increase rate of angular width of GCIPL defect was higher in the progression group than in the stable group (P = 0.029). In respect to the area of GCIPL defect, there was no statistically significant differences between the groups (P = 0.227). Twenty-seven (27) of 100 (27.0%) eyes showed increased angular width of GCIPL defect. It was more frequent in the progression group than in the stable group (P = 0.043). Seventeen (17) of 27 (63.0%) eyes showed the away from the horizontal temporal raphe type progression and it was the most common change pattern of angular width of GCIPL defect. CONCLUSIONS: Increased angular width of GCIPL defect was the more prominent feature of change, and was more frequent in the progression group than in the stable group. Among the types of GCIPL defect classified, the away from the horizontal temporal raphe type was the most common. PMID- 29696465 TI - The use of gelatine in wound ballistics research. AB - Blocks of gelatine are used in both lethality and survivability studies for broadly the same reason, i.e. comparison of ammunition effects using a material that it is assumed represents (some part of) the human body. The gelatine is used to visualise the temporary and permanent wound profiles; elements of which are recognised as providing a reasonable approximation to wounding in humans. One set of researchers aim to improve the lethality of the projectile, and the other to understand the effects of the projectile on the body to improve survivability. Research areas that use gelatine blocks are diverse and include ammunition designers, the medical and forensics communities and designers of ballistic protective equipment (including body armour). This paper aims to provide an overarching review of the use of gelatine for wound ballistics studies; it is not intended to provide an extensive review of wound ballistics as that already exists, e.g. Legal Med 23:21-29, 2016. Key messages are that test variables, projectile type (bullet, fragmentation), impact site on the body and intermediate layers (e.g. clothing, personal protective equipment (PPE)) can affect the resulting wound profiles. PMID- 29696466 TI - Initial trabeculectomy with 5-fluorouracil with or without subconjunctival bevacizumab in the management of pseudoexfoliation glaucoma. AB - PURPOSE: To investigate the outcomes of trabeculectomy with 5-fluorouracil (5-FU) with or without subconjunctival bevacizumab in the surgical management of pseudoexfoliation glaucoma (PXG). METHODS: This retrospective study consisted of 49 cases with PXG who underwent initial trabeculectomy with 5-FU. The cases were divided into two age- and sex-matched groups. In 23 cases, subconjunctival bevacizumab was injected (1.25 mg/0.05 mL) at the end of the surgery and in 26 of them the surgery was performed without bevacizumab. The groups were evaluated for the postoperative differences of the intraocular pressure (IOP) and the number of the anti-glaucomatous medications. Independent t, Kolmogorov-Smirnov and Chi square tests were used for statistical analysis. RESULTS: The mean preoperative IOP was 30.91 +/- 4.50 mmHg under the mean number of 2.4 +/- 0.7 drops in bevacizumab group. The IOP decreased to 10.22 +/- 2.63 mmHg (first week), 10.91 +/- 1.88 mmHg (first month), 12.35 +/- 2.5 mmHg (3rd month), 12.65 +/- 2.35 mmHg (sixth month) and 12.7 +/- 1.9 mmHg at the final visit. The mean preoperative IOP was 31.27 +/- 5.60 mmHg under the mean number of 2.3 +/- 0.7 drops in without bevacizumab group. The IOP decreased to 10.08 +/- 2.59 mmHg (first week), 11.00 +/- 1.87 mmHg (first month), 12.81 +/- 2.04 (3rd month), 13.62 +/- 2.21 mmHg (sixth month) and 12.9 +/- 2.4 mmHg at the final visit. In both groups, IOP reduced significantly postoperatively. There were no significant differences between the preoperative and the postoperative IOP values. CONCLUSION: The additional benefit of single dose of intraoperative bevacizumab was not observed in trabeculectomy with 5-FU in PXG. PMID- 29696467 TI - Ocular sebaceous gland carcinoma: an update of the literature. AB - PURPOSE: To review and summarize the newest update on ocular sebaceous gland carcinoma (SGC) focusing on diagnosis and treatment. METHODS: A PubMed search was carried out using the terms "Sebaceous Carcinoma", "Meibomian Gland Carcinoma", "Sebaceous Cell Carcinoma", and "Sebaceous Gland Carcinoma". All studies published in English up to October 2017 were included in this review. RESULTS: Globally, the overall incidence of SGC is increasing making it the third most common eyelid malignancy after basal cell carcinoma (BCC) and squamous cell carcinoma. The mainstay of treatment of ocular SGC is wide surgical resection under frozen section or Moh's micrographic surgery control followed by eyelid reconstruction. Based on histopathological features, SGC can be classified according to growth pattern, cell type, and cytoarchitecture. Based on the growth pattern, they can be classified as trabecular, lobular, papillary, and BCC-like. The cell type can be classified as basaloid, basosquamous, and epidermoid. The SGC cytoarchitecture presents either as a nodular or as an infiltrative lesion. Based on immunohistochemistry, the overexpression of ZEB2, BAG3, androgen receptor, and C-erbB-2 oncoprotein is associated with poor prognosis. The tumor is associated with systemic metastasis in 8-14% and death in 10-30%. CONCLUSION: Ocular SGC is an aggressive tumor associated with poor prognosis. Early identification and appropriate treatment may help improve the prognosis. New insight into its pathogenesis and the immunohistochemical profile may lead to the development of new effective treatment strategies, along with traditional therapies. PMID- 29696468 TI - microRNA-21 Confers Neuroprotection Against Cerebral Ischemia-Reperfusion Injury and Alleviates Blood-Brain Barrier Disruption in Rats via the MAPK Signaling Pathway. AB - The mechanism contributing to blood-brain barrier (BBB) disruption, involved in poststroke edema and hemorrhagic transformation, is important but elusive. We investigated microRNA-21 (miR-21)-mediated mechanism in the disruption of BBB following cerebral ischemia-reperfusion (I/R) injury. Rats with cerebral I/R injury were prepared after middle cerebral artery occlusion and subsequent reperfusion. The underlying regulatory mechanisms of miR-382 were investigated with treatment of miR-382 mimics, miR-382 inhibitors, or SB203580 (an inhibitor of the MAPK signaling pathway) prior to I/R modeling. Compared with sham-operated rats, rats following I/R showed increased Longa's scores, ischemic hemisphere volume, cerebral infarct volume, EB content in brain tissues, enhanced levels of p38, iNOS, and MMP-9. The ectopic expression of miR-21 by mimics and MAPK signaling inhibition by SB203580 reduced Longa's scores, ischemic hemisphere volume, cerebral infarct volume, EB content in brain tissues, decreased levels of p38, MAP2K3, iNOS, and MMP-9. The luciferase activity determination showed miR-21 bound to MAP2K3 in its 3'UTR. miR-21 downregulation mediated by inhibitors appeared to yield an opposed trend. We also found that MAPK signaling inhibition by SB203580 could rescue rats with treatment of miR-382 inhibitors. The study highlights the neuroprotective role of MiR-21 during cerebral I/R injury and its preventive effect against BBB disruption by blocking the MAPK signaling pathway via targeted inhibition of MAP2K3, potentially opening a novel therapeutic avenue for the treatment of cerebral ischemia. PMID- 29696469 TI - Electromagnetic Field Redistribution in Metal Nanoparticle on Graphene. AB - Benefiting from the induced image charge on metal film, the light energy is confined on a film surface under metal nanoparticle dimer, which is called electromagnetic field redistribution. In this work, electromagnetic field distribution of metal nanoparticle monomer or dimer on graphene is investigated through finite-difference time-domain method. The results point out that the electromagnetic field (EM) redistribution occurs in this nanoparticle/graphene hybrid system at infrared region where light energy could also be confined on a monolayer graphene surface. Surface charge distribution was analyzed using finite element analysis, and surface-enhanced Raman spectrum (SERS) was utilized to verify this phenomenon. Furthermore, the data about dielectric nanoparticle on monolayer graphene demonstrate this EM redistribution is attributed to strong coupling between light-excited surface charge on monolayer graphene and graphene plasmon-induced image charge on dielectric nanoparticle surface. Our work extends the knowledge of monolayer graphene plasmon, which has a wide range of applications in monolayer graphene-related film. PMID- 29696470 TI - In vitro surface characteristics and impurity analysis of five different commercially available dental zirconia implants. AB - BACKGROUND: The aim of this study was to assess surface characteristics, element composition, and surface roughness of five different commercially available dental zirconia implants. Five zirconia implants (Bredent whiteSKYTM (I1), Straumann(r) PURE Ceramic (I2), ceramic.implant vitaclinical (I3), Zeramex(r) (I4), Ceralog Monobloc M10 (I5)) were evaluated. METHODS: The evaluation was performed by means of scanning electron microscopy (SEM), energy-dispersive X-ray spectroscopy (EDX), and confocal laser scanning microscopy (CLSM). RESULTS: The semi-quantitative element composition showed no significant impurity of any implant tested. Both the machined and the rough areas of the investigated implants were predominated by zirconium, oxygen, and carbon. Roughness values (Sa) showed highest values for I2 and I5. CONCLUSIONS: The investigated zirconia implants showed surface characteristics and roughness values close to those of conventionally produced titanium implants, making them a promising alternative. However, zirconia implants have yet to prove themselves in clinical practice and clinical controlled trials. PMID- 29696472 TI - Axillary Lymph Node Evaluation Utilizing Convolutional Neural Networks Using MRI Dataset. AB - The aim of this study is to evaluate the role of convolutional neural network (CNN) in predicting axillary lymph node metastasis, using a breast MRI dataset. An institutional review board (IRB)-approved retrospective review of our database from 1/2013 to 6/2016 identified 275 axillary lymph nodes for this study. Biopsy proven 133 metastatic axillary lymph nodes and 142 negative control lymph nodes were identified based on benign biopsies (100) and from healthy MRI screening patients (42) with at least 3 years of negative follow-up. For each breast MRI, axillary lymph node was identified on first T1 post contrast dynamic images and underwent 3D segmentation using an open source software platform 3D Slicer. A 32 * 32 patch was then extracted from the center slice of the segmented tumor data. A CNN was designed for lymph node prediction based on each of these cropped images. The CNN consisted of seven convolutional layers and max-pooling layers with 50% dropout applied in the linear layer. In addition, data augmentation and L2 regularization were performed to limit overfitting. Training was implemented using the Adam optimizer, an algorithm for first-order gradient-based optimization of stochastic objective functions, based on adaptive estimates of lower-order moments. Code for this study was written in Python using the TensorFlow module (1.0.0). Experiments and CNN training were done on a Linux workstation with NVIDIA GTX 1070 Pascal GPU. Two class axillary lymph node metastasis prediction models were evaluated. For each lymph node, a final softmax score threshold of 0.5 was used for classification. Based on this, CNN achieved a mean five-fold cross-validation accuracy of 84.3%. It is feasible for current deep CNN architectures to be trained to predict likelihood of axillary lymph node metastasis. Larger dataset will likely improve our prediction model and can potentially be a non-invasive alternative to core needle biopsy and even sentinel lymph node evaluation. PMID- 29696473 TI - Impact of PACS-EMR Integration on Radiologist Usage of the EMR. AB - The purpose of this study was to objectively quantify the impact of implementing picture archiving and communication system-electronic medical record (PACS-EMR) integration on the time required to access data in the EMR and the frequency with which data are accessed by radiologists. Time to access a clinic note in the EMR was measured before and after integration with a stopwatch and compared by t test. An IRB-approved, HIPAA-compliant retrospective review of EMR access data from security audit logs was conducted for a 14-month period spanning the integration. Correlation of these data with report signatures identified the studies in which the radiologist accessed the EMR to obtain additional clinical data. Proportions of studies with EMR access were plotted and compared before and after integration using a chi-square test. Time to access the EMR decreased from 52 to 6 s (p < 0.001). Proportion of studies with EMR access increased from 36.7% (10,175/27,773) to 44.9% (10,843/24,153) after integration (p < 0.001). Integrating PACS and the EMR substantially decreases the time to access the EMR and is associated with a significant increase in the proportion of studies for which radiologists obtain additional clinical data. PMID- 29696471 TI - Comprehensive meta-analysis reveals association between multiple imprinting disorders and conception by assisted reproductive technology. AB - PURPOSE: To determine whether a history of conception by assisted reproductive technology (ART) is associated with occurrence of one or more imprinting disorders of either maternal or paternal origin. METHODS: We implemented a systematic review of scholarly literature followed by comprehensive meta-analysis to quantitatively synthesize data from reports relating to use of ART to occurrence of any imprinting disorder of humans, including Beckwith-Wiedemann (BWS), Angelman (AS), Prader-Willi (PWS), and Silver-Russell (SRS) syndromes, as well as transient neonatal diabetes mellitus (TNDB) and sporadic retinoblasoma (RB). RESULTS: The systematic review identified 13 reports presenting unique data from 23 studies that related conception following ART to occurrence of imprinting disorders. Multiple studies of four disorder were identified, for which meta analysis yielded the following summary estimates of associations with a history of ART: AS, summary odds ratio (sOR) = 4.7 (95% confidence interval (CI) 2.6-8.5, 4 studies); BWS, sOR = 5.8 (95% CI 3.1-11.1, 8 studies); PWS, sOR = 2.2 (95% CI 1.6-3.0, 6 studies); SRS, sOR = 11.3 (95% CI 4.5-28.5, 3 studies). Only one study reported on each of TNDB and RB. CONCLUSION: Published data reveal positive associations between history of ART conception and each of four imprinting disorders. Reasons for these associations warrant further investigation. PMID- 29696474 TI - Basic training requirements for health care professionals who care for children. AB - : The European Academy of Paediatrics (EAP) is the paediatric section of the European Union of Medical Specialists (UEMS). The UEMS is responsible for the supervision and approval of training programmes in paediatrics and in its subspecialties. This implies also that EAP has the responsibility to address the training of all professionals working with children, to ensure that their paediatric competences and skills are adequate when dealing with children. The EAP has developed syllabi for paediatricians that provide standards of practice, and criteria for the assessment of competencies in trainees and training centres across Europe. The EAP recommends that all health care professionals working with children should have an officially approved training in child health in addition to formal qualifications in their own field. Moreover, the existing paediatric workforce must maintain their knowledge and skills with relevant continuous professional development and medical education in child health. CONCLUSION: There is a need to reassess the training of all health care professionals caring for children, ensuring that it supports new models of integrated and multidisciplinary care and focuses on the needs of the child and the family. A standardised, competency-based minimum paediatric training programme/curriculum should be part in the specialty curriculums. PMID- 29696475 TI - Leukemoid reaction in the pediatric population: etiologies, outcome, and implications. AB - : Leukemoid reaction (WBC > 30,000/MUL) may indicate significant medical conditions, mostly infectious. Prompted by the lack of population-based data on the presentation, characteristics, and necessary workup in children with leukemoid reaction, we searched the database of a tertiary pediatric medical center for all children presented with at least one WBC count of >= 30,000/MUL in 2009-2014. Demographic, clinical, and laboratory parameters were recorded. Children admitted with WBC < 30,000/MUL served as controls. Pneumonia was the most common diagnosis in the leukemoid reaction group, with a 5.5-fold higher prevalence of pleuropneumonia than in the control group. The leukemoid group had a longer average hospital stay (7.5 vs. 5.5 days). Patients with WBC >= 50,000/MUL had a sixfold higher rate of leukemia than patients with a lower count. There was a significant association of leukemia with low platelet count, low levels of C-reactive protein, and high levels of uric acid and lactate dehydrogenase. CONCLUSION: Children presented with a leukemoid reaction are at high risk of pneumonia, especially pleuropneumonia, and a long hospital stay. Those with WBC >= 50,000/MUL have a sixfold higher risk of leukemia. For prompt diagnosis, clinicians should be aware of the variables associated with leukemia. What is Known: * Leukemoid reaction has been associated with infectious diseases. * Leukemoid reaction at presentation in adults is correlated with high morbidity and mortality. What is New: * Children with leukemoid reaction are at high risk of pleuropneumonia. * We did not observe increased mortality in children with a leukemoid reaction. PMID- 29696476 TI - Supporting the Transition into Employment: A Study of Canadian Young Adults Living with Disabilities. AB - Objective To examine the job accommodation and benefit needs of young adults with disabilities as they transition into employment, and their perceived barriers to meeting support needs. Methods An online survey was conducted of 155 Canadian young adults with disabilities (mean age = 25.8 years). Respondents were either employed or seeking employment, and were asked about their need for health benefits, and soft (e.g., flexible scheduling) and hard accommodations (e.g., ergonomic interventions), and perceived accommodation barriers. Disability characteristics (e.g., disability type), demographic details and work context information were collected. Multivariable logistic analyses were conducted to examine the factors associated with a greater need for health benefits and hard and soft accommodations. Result Participants reported having a physical (79%), psychological (79%) or cognitive/learning disability (77%); 68% had > 1 disability. Over half (55%) were employed. Health benefits and soft accommodations were most needed by participants. Also, an average of six perceived accommodation barriers were indicated; difficulty with disability disclosure was most frequently reported. More perceived accommodation barriers were associated with a greater need for health benefits (OR 1.17, 95% CI 1.04 1.31) and soft accommodations (OR 1.13, 95% CI 1.01-1.27). A psychological disability was a associated with a greater need for health benefits (OR 2.91, 95% CI 1.09-7.43) and soft accommodations (OR 3.83, 95% CI 1.41-10.42). Discussion Employers can support the employment of young adults with disabilities through provision of extended health benefits and soft accommodations. Addressing accommodation barriers could minimize unmet workplace need, and improve employment outcomes for young adults with disabilities as they begin their career and across the life course. PMID- 29696477 TI - Imaging features of benign mass lesions in the nasal cavity and paranasal sinuses according to the 2017 WHO classification. AB - The World Health Organization (WHO) 2017 classification of head and neck tumors has been just published and has reorganized tumors of the nasal cavity and paranasal sinuses. In this classification, three new entities (seromucinous hamartoma, NUT carcinoma, and biphenotypic sinonasal sarcoma) were included, while the total number of tumors has been reduced by excluding tumors if they did not occur exclusively or predominantly in this region. Among these entities, benign tumors were classified as sinonasal papillomas, respiratory epithelial lesions, salivary gland tumors, benign soft tissue tumors, or other tumors. In contrast, inflammatory diseases often show tumor-like appearances. The imaging features of these benign tumors and tumor-like inflammatory diseases often resemble malignant tumors, and some benign lesions should be given attention in the follow-up period and before surgery to avoid recurrence, malignant transformation, or massive bleeding. Understanding the CT and MR imaging features of various benign mass lesions is clinically important for appropriate therapy. The purpose of this article is to describe the clinical characteristics and imaging features of each of clinically important nasal and paranasal benign mass lesions, as classified according to the WHO 2017 classification of head and neck tumors, along with some inflammatory diseases. PMID- 29696478 TI - Concurrent chemoradiation for locally advanced stage III non-small cell lung cancer with cisplatin, vinorelbine, and thoracic radiotherapy: a phase II study from the Galician Lung Cancer Group. AB - PURPOSE: The aim of this phase II study was to evaluate the activity and safety of the combination of cisplatin and vinorelbine with thoracic radiotherapy in unresectable locally advanced stage III non-small cell lung cancer (NSCLC). The primary endpoint was the objective response rate (ORR). Secondary objectives included toxicity profile, progression-free survival (PFS), and overall survival (OS). MATERIALS AND METHODS: A total of 48 NSCLC patients were enrolled (median age 60 years, 52% stage IIIA and 48% stage IIIB, 52% adenocarcinoma). Patients received three cycles of chemotherapy every 21 days [intravenous cisplatin 80 mg/m2 and intravenous vinorelbine 25 mg/m2 on day 1 and oral vinorelbine on day 8 (60 mg/m2)] concurrent with radiotherapy (66 Gy, administered at 1.8 Gy per day, five consecutive days per week). RESULTS: ORR was 79.2% (72.9% showing partial response and 6.3% showing complete response). With a median follow-up of 20.7 months, median PFS was 12 months and median OS was 36 months. Grade 3/4 toxicities were: neutropenia (14.5%), anaemia (6.2%), vomiting (2%), and oesophagitis (4.2%). No toxic deaths were reported. CONCLUSION: This combined regimen shows efficacy and a manageable safety profile. PFS and OS outcomes are encouraging and warrant further research. PMID- 29696480 TI - Perianal Extramammary Paget's Disease: More Than Meets the Eye. PMID- 29696479 TI - Natural Language Processing Accurately Calculates Adenoma and Sessile Serrated Polyp Detection Rates. AB - BACKGROUND: ADR is a widely used colonoscopy quality indicator. Calculation of ADR is labor-intensive and cumbersome using current electronic medical databases. Natural language processing (NLP) is a method used to extract meaning from unstructured or free text data. AIMS: (1) To develop and validate an accurate automated process for calculation of adenoma detection rate (ADR) and serrated polyp detection rate (SDR) on data stored in widely used electronic health record systems, specifically Epic electronic health record system, Provation(r) endoscopy reporting system, and Sunquest PowerPath pathology reporting system. METHODS: Screening colonoscopies performed between June 2010 and August 2015 were identified using the Provation(r) reporting tool. An NLP pipeline was developed to identify adenomas and sessile serrated polyps (SSPs) on pathology reports corresponding to these colonoscopy reports. The pipeline was validated using a manual search. Precision, recall, and effectiveness of the natural language processing pipeline were calculated. ADR and SDR were then calculated. RESULTS: We identified 8032 screening colonoscopies that were linked to 3821 pathology reports (47.6%). The NLP pipeline had an accuracy of 100% for adenomas and 100% for SSPs. Mean total ADR was 29.3% (range 14.7-53.3%); mean male ADR was 35.7% (range 19.7-62.9%); and mean female ADR was 24.9% (range 9.1-51.0%). Mean total SDR was 4.0% (0-9.6%). CONCLUSIONS: We developed and validated an NLP pipeline that accurately and automatically calculates ADRs and SDRs using data stored in Epic, Provation(r) and Sunquest PowerPath. This NLP pipeline can be used to evaluate colonoscopy quality parameters at both individual and practice levels. PMID- 29696481 TI - The Distribution of Enteric Infections Utilizing Stool Microbial Polymerase Chain Reaction Testing in Clinical Practice. AB - BACKGROUND: Gastrointestinal infection is a major cause of morbidity. We sought to characterize the pathogenic etiologies of gastrointestinal infection to identify seasonal patterns and predictors of specific infections utilizing a multiplex PCR assay in clinical practice. METHODS: We performed a cross-sectional study of 9403 patients who underwent 13,231 stool tests with a FilmArray gastrointestinal pathogen PCR panel during an episode of diarrhea from March 2015 to May 2017. Our primary outcome was the presence of a positive panel. Logistic regression was used to test for associations between season and infections. RESULTS: A positive result was found in 3426 tests (25.9%) in 2988 patients (31.8%), yielding 4667 pathogens consisting of 1469 viruses (31.5%), 2925 bacteria (62.7%), and 273 parasites (5.8%). Age less than 50 years was associated with a higher prevalence of pathogens compared to age >= 50 (p < 0.0001). The overall prevalence of a positive result for bacteria peaked in the summer (635, 29.2%), and the prevalence of viruses peaked in the winter (446, 31.8%). Compared to the winter, testing in the summer yielded a higher prevalence of bacteria (OR 1.52, 95% CI 1.33, 1.73, p < 0.0001) and lower odds of viruses (OR 0.69, 95% CI 0.58, 0.81, p < 0.0001), primarily driven by E. coli species and norovirus. CONCLUSIONS: Season was a major determinant in detecting specific pathogens. Our substantially lower positivity rate than previous reports in the literature on multiplex PCR assays may more accurately reflect true clinical practice. Recognizing the temporal distribution of enteric pathogens may help facilitate empiric treatment decisions in certain clinical situations. PMID- 29696482 TI - In vitro safety assessment of the strawberry tree (Arbutus unedo L.) water leaf extract and arbutin in human peripheral blood lymphocytes. AB - Strawberry tree (Arbutus unedo L.) leaves have long been used in the traditional medicine of the Mediterranean region. One of their most bioactive constituents is the glycoside arbutin, whose presence makes A. unedo suitable as a potential substitute for bearberry [Arctostaphylos uva ursi (L.) Spreng] leaves, an herbal preparation widely used for treating urinary tract infections. The safety and biocompatibility of strawberry tree water leaf extract have not yet been documented well. This study estimated arbutin content in strawberry tree water leaf extract (STE) using high performance liquid chromatography. Furthermore, we performed an in vitro safety assessment of the 24 h exposure to three presumably non-toxic concentrations of standardized STE and arbutin in human peripheral blood lymphocytes using the apoptosis/necrosis assay, the alkaline comet assay, and the cytokinesis-block micronucleus cytome assay. The STE was also tested for total antioxidant capacity and lipid peroxidation. At a concentration corresponding to the maximum allowable daily intake of arbutin, the tested extract was not cytotoxic, had a negligible potential for causing primary DNA damage and even hindered micronuclei formation in lymphocytes. It also showed a valuable antioxidant capacity, and did not exert marked lipid peroxidation. These promising results represent a solid frame for further development of STE-based herbal preparations. Although arbutin generally had a low DNA damaging potential, the slowing down of lymphocyte proliferation observed after 24 h of exposure points to a cytostatic effect, which merits further research. PMID- 29696483 TI - Quantification of amino acids and peptides in an ionic liquid based aqueous two phase system by LC-MS analysis. AB - Aqueous two-phase systems (ATPS) occur by the mixture of two polymers or a polymer and an inorganic salt in water. It was shown that not only polymers but also ionic liquids in combination with inorganic cosmotrophic salts are able to build ATPS. Suitable for the formation of ionic liquid-based ATPS systems are hydrophilic water miscible ionic liquids. To understand the driving force for amino acid and peptide distribution in IL-ATPS at different pH values, the ionic liquid Ammoeng 110TM and K2HPO4 have been chosen as a test system. To quantify the concentration of amino acids and peptides in the different phases, liquid chromatography and mass spectrometry (LC-MS) technologies were used. Therefore the peptides and amino acids have been processed with EZ:faastTM-Kit from Phenomenex for an easy and reliable quantification method even in complex sample matrices. Partitioning is a surface-dependent phenomenon, investigations were focused on surface-related amino acid respectively peptide properties such as charge and hydrophobicity. Only a very low dependence between the amino acids or peptides hydrophobicity and the partition coefficient was found. Nevertheless, the presented results show that electrostatic respectively ionic interactions between the ionic liquid and the amino acids or peptides have a strong impact on their partitioning behavior. PMID- 29696484 TI - Determining post-test risk in a national sample of stress nuclear myocardial perfusion imaging reports: Implications for natural language processing tools. AB - BACKGROUND: Reporting standards promote clarity and consistency of stress myocardial perfusion imaging (MPI) reports, but do not require an assessment of post-test risk. Natural Language Processing (NLP) tools could potentially help estimate this risk, yet it is unknown whether reports contain adequate descriptive data to use NLP. METHODS: Among VA patients who underwent stress MPI and coronary angiography between January 1, 2009 and December 31, 2011, 99 stress test reports were randomly selected for analysis. Two reviewers independently categorized each report for the presence of critical data elements essential to describing post-test ischemic risk. RESULTS: Few stress MPI reports provided a formal assessment of post-test risk within the impression section (3%) or the entire document (4%). In most cases, risk was determinable by combining critical data elements (74% impression, 98% whole). If ischemic risk was not determinable (25% impression, 2% whole), inadequate description of systolic function (9% impression, 1% whole) and inadequate description of ischemia (5% impression, 1% whole) were most commonly implicated. CONCLUSIONS: Post-test ischemic risk was determinable but rarely reported in this sample of stress MPI reports. This supports the potential use of NLP to help clarify risk. Further study of NLP in this context is needed. PMID- 29696485 TI - Relationship between microvascular changes, autonomic denervation, and myocardial fibrosis in Chagas cardiomyopathy: Evaluation by MRI and SPECT imaging. AB - BACKGROUND: The relationship between microvasculopathy, autonomic denervation, and myocardial fibrosis, in Chagas cardiomyopathy is incompletely understood. The aim of this study was to explore the relative extent and anatomic distribution of myocardial hypoperfusion, autonomic denervation, and myocardial scarring using Single-Photon Emission Computerized Tomography (SPECT) imaging and Magnetic Resonance Imaging (MRI). METHODS: Thirteen patients with Chagas disease all had Iodine-123-metaiodobenzylguanidine (MIBG) SPECT, 99mTc-Sestamibi (MIBI) rest stress SPECT, and gadolinium late enhancement MRI imaging within a 2-month interval. The anatomic location and extent of denervation, of stress-induced hypoperfusion and fibrosis, were assessed through image co-registration and quantification of abnormal tissue areas as a percent of total myocardium. RESULTS: The results showed a strong general anatomic concordance between areas of hypoperfusion, denervation, and fibrosis, suggesting that the three abnormal features may be correlated. Myocardial denervation was anatomically and quantitatively closely associated areas of stress hypoperfusion. CONCLUSION: Combined myocardial analysis of the extent and location of autonomic denervation, hypoperfusion, and scarring may allow for better understanding of the pathophysiology of Chagas cardiomyopathy. Autonomic myocardial denervation may be a more sensitive marker of cardiac involvement in Chagas Disease than finding by other imaging modalities. PMID- 29696486 TI - Iodine-123-metaiodobenzylguanidine cardiac SPECT imaging in the qualification of heart failure patients for ICD implantation. PMID- 29696487 TI - Religion, Nonreligion, and Deviance: Comparing Faith's and Family's Relative Strength in Promoting Social Conformity. AB - The view that religion, as a source of moral guidance and social support, can function to prevent or protect individuals, especially children and adolescents, from a range of deviant and delinquent behaviors is largely (but not completely) born out in the literature. In nations with strong religious identities such as the USA, there is a normative expectation that adolescents who identify with religion are less likely to engage in deviant behavior than those who claim no religion. The present study explores this issue using data from over 10,000 American middle school and high school youth to examine the relationship between religion, nonreligion, and various forms of deviance. Results indicate that youth who identify with a religious (rather than nonreligious) label are not less likely to be involved in deviant acts after controlling for protective factors. The effects from some of these protective factors are significant and stronger than the effects from religion. PMID- 29696488 TI - The Influence of Religion and Spirituality on HIV Prevention Among Black and Latino Men Who Have Sex with Men, New York City. AB - The influence of religion and spirituality (R/S) on HIV prevention has been understudied, especially for Black and/or Latino men who have sex with men (BLMSM), who bear a disproportionate burden of HIV, and who are part of racial/ethnic communities with high engagement in R/S. The specific aim of this study was to explore perspectives about R/S among BLMSM to inform HIV prevention strategies and reduce HIV-related health disparities. Data from 105 qualitative interviews with BLMSM were analyzed; 58 (55%) stated that R/S had no personal influence on HIV prevention. For those reporting any R/S influence, main themes were: (1) R/S positively influenced decision-making and self-respect, (2) perceived judgment and stigma by religious communities, (3) belief in a higher power, and (4) altruism. These findings can inform faith-based HIV prevention interventions for BLMSM. PMID- 29696489 TI - Tissue banking in Asia Pacific region: past, present and future. AB - Tissue banking in the Asia Pacific regions is driven by two main forces-firstly the International Atomic Energy Agency (IAEA) via Regional Co-operative Agreement projects and secondly by the Asia Pacific Association of Surgical Tissue Banking (APASTB). This overview is written in three sections: (1) History of tissue banking in individual country in the region. (2) History of APASTB. (3) History of IAEA programme in Asia Pacific region. The current status and future of the tissue banking programme in the region will be discussed. PMID- 29696490 TI - Interaction of preservation methods and radiation sterilization in human skin processing, with particular insight on the impact of the final water content and collagen disruption. Part I: process validation, water activity and collagen changes in tissues cryopreserved or processed using 50, 85 or 98% glycerol solutions. AB - Current regulatory requirements demand an in-depth understanding and validation of protocols used in tissue banking. The aim of this work was to characterize the quality of split thickness skin allografts cryopreserved or manufactured using highly concentrated solutions of glycerol (50, 85 or 98%), where tissue water activity (aw), histology and birefringence changes were chosen as parameters. Consistent aw outcomes validated the proposed processing protocols. While no significant changes in tissue quality were observed under bright-field microscopy or in collagen birefringence, in-process findings can be harnessed to fine-tune and optimize manufacturing outcomes in particular when further radiation sterilization is considered. Furthermore, exposing the tissues to 85% glycerol seems to derive the most efficient outcomes as far as aw and control of microbiological growth. PMID- 29696491 TI - Dusukasi-The Heart That Cries: An Idiom of Mental Distress Among Perinatal Women in Rural Mali. AB - Perinatal mental health problems such as depression and anxiety are prevalent in low and middle-income countries. In Mali, the lack of mental health care is compounded by few studies on mental health needs, including in the perinatal period. This paper examines the ways in which perinatal women experience and express mental distress in rural Mali. We describe a process, relying on several different qualitative research methods, to identify understandings of mental distress specific to the Malian context. Participants included perinatal women, maternal health providers, and community health workers in rural southwest Mali. Participants articulated several idioms of distress, including geleya (difficulties), tooro (pain, suffering), hamin (worries, concerns), and dusukasi (crying heart), that occur within a context of poverty, interpersonal conflict, and gender inequality. These idioms of distress were described as sharing many key features and operating on a continuum of severity that could progress over time, both within and across idioms. Our findings highlight the context dependent nature of experiences and expressions of distress among perinatal women in Mali. PMID- 29696494 TI - Heavy metal exposure has adverse effects on the growth and development of preschool children. AB - The purpose of this study was to investigate the associations between levels of lead (Pb), cadmium (Cd), chromium (Cr), and manganese (Mn) in the PM2.5 and blood and physical growth, and development parameters including birth length and weight, height, weight, body mass index (BMI), head circumference, and chest circumference in preschool children from Guiyu (e-waste exposure area) and Haojiang (the reference area). A total of 470 preschool children from Guiyu and Haojiang located in southeast coast of China were recruited and required to undergo physical examination and blood tests during the study period. Birth length and weight were obtained by birth records and questionnaire. Pb and Cd in both PM2.5 and blood were significantly higher in Guiyu than Haojiang. Remarkably, the children of Guiyu had significantly lower birth weight and length, BMI, and chest circumference when compare to their peers from the reference area (all p value < 0.05). Spearman correlation analyses showed that blood Pb was negatively correlated with height (r = -0.130, p < 0.001), weight (r = -0.169, p < 0.001), BMI (r = -0.100, p < 0.05), head circumference (r = -0.095, p < 0.05), and chest circumference (r = -0.112, p < 0.05). After adjustment for the potential confounders in further linear regression analyses, blood Pb was negatively associated with height (beta = -0.066, p < 0.05), weight (beta = 0.119, p < 0.001), head circumference (beta = -0.123, p < 0.01), and chest circumference (beta = -0.104, p < 0.05), respectively. No significant association between blood Cd, Cr, or Mn was found with any of our developmental outcomes. Taken together, lead exposure limits or delays the growth and development of preschool children. PMID- 29696495 TI - Improving arsenopyrite oxidation rate laws: implications for arsenic mobilization during aquifer storage and recovery (ASR). AB - Aquifer storage and recovery (ASR) and aquifer recharge (AR) provide technical solutions to address water supply deficits and growing future water demands. Unfortunately, the mobilization of naturally present arsenic due to ASR/AR operations has undermined its application on a larger scale. Predicting arsenic mobility in the subsurface during ASR/AR is further complicated by site-specific factors, including the arsenic mobilization mechanisms, groundwater flow conditions, and multi-phase geochemical interactions. In order to ensure safe and sustainable ASR/AR operation, a better understanding of these factors is needed. The current study thus aims to better characterize and model arsenic remobilization at ASR/AR sites by compiling and analyzing available kinetic data on arsenic mobilization from arsenopyrite under different aqueous conditions. More robust and widely applicable rate laws are developed for geochemical conditions relevant to ASR/AR. Sensitivity analysis of these new rate laws gives further insight into the controlling geochemical factors for arsenic mobilization. When improved rate laws are incorporated as the inputs for reactive transport modeling, arsenic mobilization in ASR/AR operations can be predicted with an improved accuracy. The outcomes will be used to guide groundwater monitoring and specify ASR/AR operational parameters, including water pretreatment requirements prior to injection. PMID- 29696496 TI - Transient endolymphatic hydrops after an attack of vestibular migraine: a longitudinal single case study. PMID- 29696497 TI - Cerebellar ataxia, neuropathy, vestibular areflexia syndrome (CANVAS) with chronic cough and preserved muscle stretch reflexes: evidence for selective sparing of afferent Ia fibres. AB - The aim of this study was to describe five patients with cerebellar ataxia, neuropathy and vestibular areflexia syndrome (CANVAS) with chronic cough and preserved limb muscle stretch reflexes. All five patients were in the seventh decade of age, their gait imbalance having been initiated in the fifth decade. In four patients cough antedated gait imbalance between 15 and 29 years; cough was spasmodic and triggered by variable factors. Established clinical picture included severe hypopallesthesia predominating in the lower limbs with postural imbalance, and variable degree of cerebellar axial and appendicular ataxia, dysarthria and horizontal gaze-evoked nystagmus. Upper- and lower-limb tendon jerks were preserved, whereas jaw jerk was absent. Vestibular function testing showed bilateral impairment of the vestibulo-ocular reflex. Nerve conduction studies demonstrated normal motor conduction parameters and absence or severe attenuation of sensory nerve action potentials. Somatosensory evoked potentials were absent or severely attenuated. Biceps and femoral T-reflex recordings were normal, while masseter reflex was absent or attenuated. Sympathetic skin responses were normal. Cranial MRI showed vermian and hemispheric cerebellar atrophy predominating in lobules VI, VII and VIIa. We conclude that spasmodic cough may be an integral part of the clinical picture in CANVAS, antedating the appearance of imbalance in several decades and that sparing of muscle spindle afferents (Ia fibres) is probably the pathophysiological basis of normoreflexia. PMID- 29696498 TI - Alemtuzumab as rescue therapy in a cohort of 50 relapsing-remitting MS patients with breakthrough disease on fingolimod: a multi-center observational study. AB - BACKGROUND: Relapsing-remitting multiple sclerosis (RRMS) requires efficient immunomodulatory treatment to reach "no evidence of disease activity" status at best. Alemtuzumab and fingolimod have proved to be efficient options in RRMS with active disease course. Yet, side effects and break-through disease may limit long time treatment and necessitate switch of medication. Data on efficacy and safety of alemtuzumab following fingolimod treatment are limited, but useful for clinical practice. METHODS: Clinical and MRI data of 50 RRMS patients with a history of therapy switch from fingolimod to alemtuzumab were retrospectively analyzed. Data were acquired from nine large German MS Centers from 2013 to 2016 and analyzed using descriptive statistics. RESULTS: On average, patients with disease duration of 12.9 years and median EDSS of 3.0 at baseline switched to alemtuzumab after 68 weeks of fingolimod treatment. Thereafter, patients on alemtuzumab were followed for a mean of 64 weeks. The annualized relapse rate decreased from 2.2 in the year prior to 0.34 in the following year after switching to alemtuzumab and EDSS stabilized. In a subgroup of patients (n = 23), MRI data point to a reduction in enhancing (4.47 vs. 0.26) and new/enlarging T2 lesions (5.8 vs. 0.27) after treatment adjustment. Side effects were generally as expected from published data for alemtuzumab (autoimmunity 2/50, severe infections 1/50). One patient suffered combined lethal necrotizing leukoencephalopathy and hemolytic anemia. DISCUSSION: Therapy switch was highly effective in reducing clinical and MRI surrogates of disease activity and was mainly well tolerated within one year of follow-up. Hence, alemtuzumab constitutes a promising therapy in RRMS with refractory disease activity despite fingolimod treatment. Further studies are warranted to confirm these beneficial findings and to reveal safety concerns in the longer-term follow-up. PMID- 29696499 TI - Longitudinal diffusion tensor imaging changes in early Parkinson's disease: ICICLE-PD study. AB - OBJECTIVE: To investigate whether white matter microstructural changes can be used as a predictor of worsening of motor features or cognitive decline in patients with Parkinson's disease and verify whether white matter microstructural longitudinal changes differ between patients with Parkinson's disease with normal cognition and those with mild cognitive impairment. METHODS: We enrolled 120 newly diagnosed patients with early stage Parkinson's disease (27 with mild cognitive impairment and 93 with normal cognition) along with 48 controls. Participants were part of the incidence of cognitive impairment in cohorts with longitudinal evaluation in Parkinson's disease study and were assessed at baseline and 18 months later with cognitive, motor tests and diffusion tensor imaging. The relationships between fractional anisotropy and mean diffusivity with disease status, cognitive and motor function were investigated. RESULTS: At baseline, patients with early stage Parkinson's disease had significantly higher widespread mean diffusivity relative to controls, regardless of cognitive status. In patients with Parkinson's disease/mild cognitive impairment, higher mean diffusivity was significantly correlated with lower attention and executive function scores. At follow-up frontal mean diffusivity increased significantly when comparing patients with Parkinson's disease/mild cognitive impairment with those with normal cognition. Baseline mean diffusivity was a significant predictor of worsening of motor features in Parkinson's disease. CONCLUSIONS: Mean diffusivity represents an important correlate of cognitive function and predictor of motor impairment in Parkinson's disease: DTI is potentially a useful tool in stratification of patients into clinical trials and to monitor the impact of treatment on motor function. PMID- 29696500 TI - Spatial correlation and segregation of multimodal MRI abnormalities in multiple system atrophy. AB - OBJECTIVE: The variability of the severity and regional distribution of pathological process in basal ganglia (BG) and brainstem-cerebellar systems results in clinical heterogeneity and represents the motor subtype of multiple system atrophy (MSA). This study aimed to quantify spatial patterns of multimodal MRI abnormalities in BG and stem-CB regions and define structural MRI findings that correlate with clinical characteristics. METHODS: We simultaneously measured R2*, mean diffusivity (MD), and volume in the subcortical structures (BG, thalamus, brainstem-cerebellar regions) of 39 probable MSA and 22 control subjects. Principal component analysis (PCA) and structural equation modeling (SEM) were performed to show a model consisting of multiple inter-dependencies. RESULTS: Structural MRI alterations were found to be significantly interrelated within BG as well as brainstem-cerebellar regions in MSA patients. PCA extracted four factors: three factors reflected alterations in R2*, MD and volume of the BG region including the caudate nucleus, putamen, and pallidum, and the remaining one factor represented degenerative changes in MD and volume of stem-CB region. In SEM, a latent variable reflecting brainstem-cerebellar degeneration did not show a significant correlation with the other latent variables associated with BG degeneration. Putaminal MD values and a PCA-driven factor reflecting MD values in the BG showed a significant correlation with UPDRS and UMSARS scores. CONCLUSION: Multimodal structural MRI abnormalities in MSA appear to be segregated into BG and stem-CB-related factors that can be associated with the clinical phenotype and motor severity. PMID- 29696502 TI - Tumor-treating fields as a fourth treating modality for glioblastoma: a meta analysis. AB - BACKGROUND: We aim to review the available literature on patients suffering from glioblastoma treated with tumor-treating fields (TTFields) plus radio chemotherapy or conventional radio chemotherapy alone, to compare the efficacy and safety of the two methods. METHODS: A systematic literature search was performed in PubMed, Cochrane library, and Scopus databases, in accordance with the PRISMA guidelines. Six studies met the inclusion criteria incorporating 1806 patients for the qualitative analysis and 1769 for the quantitative analysis. RESULTS: This study reveals increased median overall survival (weighted mean difference (WMD) 3.29 [95% confidence interval (CI) 2.37, 4.21]; p < 0.00001), survival at 1 year (odds ratio (OR) 1.81 [95% CI 1.41, 2.32]; p < 0.00001) and 2 years (OR 2.33 [95% CI 1.73, 3.14]; p < 0.00001), and median progression-free survival (WMD 2.35 [95% CI 1.76, 2.93]; p < 0.00001) along with progression-free survival at 6 months (WMD 6.86 [95% CI 5.91, 7.81]; p < 0.00001) for the patients treated with TTFields. Survival at 3 years was comparable between the two groups. TTFields were associated with fewer adverse events compared to chemotherapy along with similar incidence of skin irritation. CONCLUSIONS: TTFields are a safe and efficient novel treatment modality. More randomized controlled studies, with longer follow-up, are necessary to further assess the clinical outcomes of TTFields. PMID- 29696501 TI - Dynamics of land change: insights from a three-level intensity analysis of the Legedadie-Dire catchments, Ethiopia. AB - Earlier studies on land change (LC) have focused on size and magnitude, gains and losses, or land transfers between categories. Therefore, these studies have failed to simultaneously show the complete LC processes. This paper examines LCs in the Legedadie-Dire catchments in Oromia State, Ethiopia, using land-category maps with intensity analysis (IA) at three points in time. We comprehensively analyze LC to jointly encompass the rate, intensity, transition, and process. Thirty-meter US Geological Survey (USGS) Landsat imagery from 1986, 2000, and 2015 (< 10% cloud) is processed using TerrSet-LCM and ArcGIS. Six categories are identified using a maximum likelihood classification technique: settlement, cultivation, forest, water, grassland, and bare land. Then, classified maps are superimposed on the images to statistically examine changes with an IA. Considerable changes are observed among categories, except for water, between 1986-2000 and 2000-2015. Overall land change occurred quickly at first and then slowly in the second time interval. The total land area that exhibited change (1st ~ 54% and 2nd ~ 51%) exceeded the total area of persistence (1st ~ 46% and 2nd ~ 49%) across the landscape. Cultivation and human settlements were the most intensively increased categories, at the expense of grassland and bare ground. Hence, when grassland was lost, it tended to be displaced by cultivation more than other categories, which was also true with bare land. Annual intensity gains were active for forest but minimal for cultivation, implying that the gains of forest were associated with in situ reforestation practices and that the gains in cultivation were caused by its relatively large initial area under a uniform intensity concept. This study demonstrates that IA is valuable for investigating LC across time intervals and can help distinguish dormant vs. active and targeted vs. avoided land categories. PMID- 29696503 TI - Hyperbaric oxygen therapy of air embolus in the cerebral venous sinuses after intracranial surgery: a case report. AB - A case with cerebral venous air embolism (CVAE) after neurosurgery and treated with hyperbaric oxygen therapy (HBOT) is presented. This is a rare and potentially fatal complication that neurosurgeons should be aware of. A 52-year old male was diagnosed with an intracerebral hematoma. An emergency evacuation of the hematoma was performed with a craniotomy and the postoperative CT scan showed a complete evacuation of the hematoma, but it also revealed a CVAE. The patient was immediately referred to HBOT and received three sessions within 48 h. The CT scan after the first HBOT showed no CVAE, venous thrombosis, or new hematoma. PMID- 29696504 TI - Percutaneous dorsal root ganglion block for treating lumbar compression fracture related pain. AB - BACKGROUND: The pain of acute compression fracture in the lumbar spine may be refractory to conservative treatment, and surgery is not an optimal choice for the elderly or infirm individuals. Moreover, even vertebroplasty can cause many side effects such as chemical leak, adjacent segment instability, and residual pain. Percutaneous dorsal root ganglion block (PDRGB) possibly is an alternative therapeutic option. In this study, we evaluated the efficacy of pain relief and the rate of adjacent level compression fracture in patients with acute compression fracture of the lumbar spine. METHODS: We retrospectively reviewed 40 patients with lumbar compression fracture from 2013 to 2015. The patients were treated with navigation-assisted CT-guided PDRGB with steroid at the pathological level and at the adjacent level above and below. Therapeutic response was evaluated using the Numerical Rating Scale (NRS); and an optimal, acceptable, and unfavorable outcome were analyzed. RESULTS: Among the 40 patients treated, initial pain relief on the first day was dramatic, and the average NRS did not change significantly up to the first-year follow-up. The highest percentage of a good outcome, at 90% (37.5% with an optimal outcome, 52.5% with an acceptable outcome), was reported at 1 week postoperatively. The percentage of optimal outcomes increased even at the 1-year follow-up. No adjacent compression fracture was found in the group treated with PDRGB alone at the 1-year follow-up. CONCLUSIONS: PDRGB is a simple, safe, and minimally invasive procedure that showed immediate and prolonged improvement of pain in lumbar osteoporotic compression fracture patients who failed conservative treatment or had residual pain after vertebroplasty. However, continuous medication for osteoporosis was still required. PMID- 29696505 TI - Intracranial pressure monitoring in diffuse brain injury-why the developing world needs it more? AB - BACKGROUND: Use of ICP monitoring is considered to be part of "standard of care" in management of severe traumatic brain injury, but it is rarely used in developing countries. The authors present a study which evaluates the efficacy and outcomes of ICP monitoring at a high-volume trauma center in India. METHODS: Data on management and outcomes for 126 patients who were admitted with diffuse traumatic brain injury (GCS 3-8) were studied prospectively over an 18-month period. These patients were treated by one of the two specific protocols: ICP monitoring-based or non-ICP monitoring-based. The primary outcome was measured based on 2 weeks mortality and GOS-E at 1, 3, and 6 months. Secondary outcome was measured based on need for brain-specific treatment, length of ICU stay, and radiation exposure. RESULTS: Mortality in a subset of patients who underwent surgical intervention later due to increased ICP values, drop in GCS, or radiological deterioration was noted to be significantly lower in the ICP monitoring group (p = 0.03), in spite of statistically insignificant difference in overall mortality rates between groups. GOS-E scores at 1 month were significantly better (p = 0.033) in ICP monitoring group, even though they equalized at 3 and 6 months. The need for brain-specific treatment (p < 0.001), radiation exposure (p < 0.001), and length of ICU stay (p = 0.013) was significantly lower in the ICP monitoring group. CONCLUSIONS: ICP monitoring based treatment protocol helps in achieving faster recovery; lowers mortality rates in operated patients; and reduces ICU stay, radiation exposure, and the need for brain-specific treatment. PMID- 29696506 TI - Point-of-care hemoglobin A1c testing in postmortem examination. AB - Glycated hemoglobin (HbA1c) is a good marker for monitoring glycemic control, and an elevated postmortem blood HbA1c level might indicate poor glycemic control during the antemortem period. The HbA1c level can be measured as a point-of-care (POC) test. In forensic medicine, POC testing is useful for performing autopsies and postmortem inspections since POC testing is both rapid and efficient. This study evaluated HbA1c levels in the capillary and cardiac venous blood of postmortem specimens as well as the usefulness of evaluating HbA1c levels as POC testing in postmortem examinations. For HbA1c testing performed on 103 autopsy cases, a portable SD A1cCare (test) was used for the POC testing, along with a Cobas Integra 800 (comparative). There was a strong correlation between HbA1c levels from postmortem capillary and cardiac venous blood (regression equation, 0.000 + 1.000*), and between HbA1c levels of cardiac venous blood measured using the portable SD A1cCare as a POC test and the Cobas Integra 800 (regression equation, -0.532 + 1.080*). HbA1c levels measured up to 4 weeks following the autopsy with the SD A1cCare had a tendency to decline. The author concluded that HbA1c POC testing can be used during postmortem inspection and during autopsy to accurately identify patients who had uncontrolled diabetes mellitus. PMID- 29696508 TI - Has inpatient hospital treatment before and after age 65 changed as the difference between private and Medicare payment rates has widened? AB - The past decade witnessed a dramatic increase in inpatient hospital payment rates for patients with private insurance relative to payment rates for those covered by Medicare. A natural question is whether the widening private-Medicare payment rate difference had implications for the hospital care received by patients just before and after turning 65-the age at which there is a substantial shift from private to Medicare coverage. Using a large discharge dataset covering the period 2001-2011, we tracked changes at age 65 in the following dimensions of hospital care: overall hospitalization rates, case mix, referral-sensitive surgeries, length of stay, full established charges, number of procedures, mortality, and composite measures of inpatient quality and patient safety. In all cases we found either no change or a change that was small and inconsistent with payment rate changes during the study period. PMID- 29696507 TI - Safety Experience During Real-World Use of Injectable Artesunate in Public Health Facilities in Ghana and Uganda: Outcomes of a Modified Cohort Event Monitoring Study (CEMISA). AB - INTRODUCTION: Injectable artesunate (Inj AS) is the World Health Organization (WHO)-recommended product for treating severe malaria. However, despite widespread usage, there are few published safety studies involving large populations in real-world settings. In this study, we sought to assess the incidence of common adverse events (AEs) following the intake of Inj AS in real life settings. METHODS: This is a modified cohort event monitoring study involving patients who were administered with Inj AS at eight sites (four each in Ghana and Uganda) between May and December 2016. Patients were eligible for inclusion if they had severe/complicated malaria and were able and willing to participate in the study. Eligible patients were followed up by telephone or hospital or home visit on Days 7, 14, 21 and 28 after drug administration to document AEs and serious AEs (SAEs). Patients were also encouraged to report all AEs at any time during the study period. The Kaplan-Meier method was used to estimate the proportion of patients with any AEs by end of Day 28. Causality assessment was made on all AEs/SAEs using the WHO/UMC (Uppsala Monitoring Centre) causality method. RESULTS: A total of 1103 eligible patients were administered Inj AS, of which 360 patients were in Ghana and 743 in Uganda. The incidence of any AE by the end of follow-up among patients treated with AS was estimated to be 17.9% (197/1103) (95% confidence interval [CI] 15.8-20.3). The median time-to onset of any AEs was 9 days (interquartile range (IQR) = 4, 14). The top five AEs recorded among patients treated with AS were pyrexia (3.5%), abdominal pain (2.5%), diarrhoea (1.7%), cough (1.5%) and asthenia (1.5%). Most of these top five AEs occurred in the first 14 days following treatment. Regarding the relatedness of these AEs to Inj AS, 78.9% of pyrexia (30/38), 63.0% of pain (17/27), 68.4% of diarrhoea (13/19), 85.5% of cough (14/16) and 75.0% of asthenia (12/16) were assessed as 'possibly' related. There were 17 SAEs including 13 deaths. Two of the deaths are 'possibly' related to Inj AS, as were three non fatal SAEs: severe abdominal pain, failure of therapy and severe anaemia. CONCLUSION: The incidence of common AEs among patients treated with Inj AS in real-world settings was found to be relatively low. Future studies should consider larger cohorts to document rare AEs as well. CLINICALTRIALS. GOV IDENTIFIER: NCT02817919. PMID- 29696509 TI - Inhibiting IL-2 signaling and the regulatory T-cell pathway using computationally designed peptides. AB - Background Increased serum levels of soluble interleukin-2 (IL-2) receptor alpha (sIL-2Ralpha) are an indicator of poor prognosis in patients with B-cell non Hodgkin lymphoma (NHL). By binding to IL-2, sIL-2Ralpha upregulates Foxp3 expression and induces the development of regulatory T (Treg) cells. Methods To inhibit the binding of IL-2 to sIL-2Ralpha with the goal of suppressing the induction of Foxp3 and decreasing Treg cell numbers, we developed peptides by structure-based computational design to disrupt the interaction between IL-2 and sIL-2Ralpha. Each peptide was screened using an enzyme-linked immunosorbent assay (ELISA), and 10 of 22 peptides showed variable capacity to inhibit IL-2/sIL 2Ralpha binding. Results We identified a lead candidate peptide, CMD178, which consistently reduced the expression of Foxp3 and STAT5 induced by IL-2/sIL 2Ralpha signaling. Furthermore, production of cytokines (IL-2/interferon gamma [IFN-gamma]) and granules (perforin/granzyme B) was preserved in CD8+ T cells co cultured with IL-2-stimulated CD4+ T cells that had been pretreated with CMD178 compared to CD8+ cells co-cultured with untreated IL-2-stimulated CD4+ T cells where it was inhibited. Conclusions We conclude that structure-based peptide design can be used to identify novel peptide inhibitors that block IL-2/sIL 2Ralpha signaling and inhibit Treg cell development. We anticipate that these peptides will have therapeutic potential in B-cell NHL and other malignancies. PMID- 29696510 TI - Ambient PM2.5 air pollution exposure and hepatocellular carcinoma incidence in the United States. AB - PURPOSE: To conduct the first epidemiologic study prospectively examining the association between particulate matter air pollution < 2.5 um in diameter (PM2.5) exposure and hepatocellular carcinoma (HCC) risk in the U.S. METHODS: Surveillance, Epidemiology, and End Results (SEER) provided information on HCC cases diagnosed between 2000 and 2014 from 16 population-based cancer registries across the U.S. Ambient PM2.5 exposure was estimated by linking the SEER county with a spatial PM2.5 model using a geographic information system. Poisson regression with robust variance estimation was used to calculate incidence rate ratios and 95% confidence intervals (CIs) for the association between ambient PM2.5 exposure per 10 ug/m3 increase and HCC risk adjusting for individual-level age at diagnosis, sex, race, year of diagnosis, SEER registry, and county-level information on health conditions, lifestyle, demographic, socioeconomic, and environmental factors. RESULTS: Higher levels of ambient PM2.5 exposure were associated with a statistically significant increased risk for HCC (n = 56,245 cases; adjusted IRR per 10 ug/m3 increase = 1.26, 95% CI 1.08, 1.47; p < 0.01). CONCLUSIONS: If confirmed in studies with individual-level PM2.5 exposure and risk factor information, these results suggest that ambient PM2.5 exposure may be a risk factor for HCC in the U.S. PMID- 29696511 TI - TNFalpha in the Trigeminal Nociceptive System Is Critical for Temporomandibular Joint Pain. AB - Previous studies have shown that tumor necrosis factor alpha (TNFalpha) is significantly increased in complete Freund's adjuvant (CFA)-treated temporomandibular joint (TMJ) tissues. However, it is unclear whether TNFalpha in the trigeminal nociceptive system contributes to the development of TMJ pain. In the present study, we investigated the role of TNFalpha in trigeminal ganglia (TG) and spinal trigeminal nucleus caudalis (Sp5C) in CFA-induced inflammatory TMJ pain. Intra-TMJ injection of CFA (10 MUl, 5 mg/ml) induced inflammatory pain in the trigeminal nerve V2- and V3-innervated skin areas of WT mice, which was present on day 1 after CFA and persisted for at least 10 days. TNFalpha in both TG and Sp5C of WT mice was upregulated after CFA injection. The CFA-induced TMJ pain was significantly inhibited in TNFalpha KO mice. The immunofluorescence staining showed that intra-TMJ CFA injection not only enhanced co-localization of TNFalpha with Iba1 (a marker for microglia) in both TG and Sp5C but also markedly increased the expression of TNFalpha in the Sp5C neurons. By the methylated DNA immunoprecipitation assay, we also found that DNA methylation at the TNF gene promoter region in the TG was dramatically diminished after CFA injection, indicating that epigenetic regulation may be involved in the CFA-enhanced TNFalpha expression in our model. Our results suggest that TNFalpha in the trigeminal nociceptive system plays a critical role in CFA-induced inflammatory TMJ pain. PMID- 29696513 TI - Association between alcohol consumption and bone mineral density in elderly Korean men and women. AB - : In this cross-sectional study based on Korean elderly men and women, heavy alcohol intake for men was related to low whole-body BMD and light alcohol intake for women was associated with high whole-body, lumbar, and total femur BMD. PURPOSE: Alcohol is a risk factor of osteoporosis but previous studies on its effect on bone health has been controversial. The aim of this study was to evaluate the association between alcohol intake and bone mineral density in Korean elderly men and women. METHODS: Based on the Fourth and Fifth Korean National Health and Nutrition Examination Surveys (KNHANES), 2657 men and 2080 women 50 to 79 years of age were included. Bone mineral density (BMD) was measured using dual energy X-ray absorptiometry (DXA). Alcohol consumption was determined by self-administered questionnaires and classified into four groups according to sex: non-drinkers (0 g/day), light drinking (1-19 g/day men, 1-9 g/day women), moderate drinking (20-39 g/day men, 10-29 g/day women), and heavy drinking (>= 40 g/day men, >= 20 g/day women). The adjusted mean values calculated by linear regression analysis for BMD were determined according to the amount of alcohol consumed. RESULTS: Light drinkers had the highest whole-body BMD for both men (mean 1.164, SD 0.047-1.281) and women (mean 1.046, SD 0.912 1.180). Among men, mean whole-body BMD for heavy drinkers was significantly lower than that among light drinkers (P = 0.031). Among women, BMD for light drinkers was significantly higher in the whole body, lumbar, and total femur than that for non-drinkers (P < 0.001, P = 0.026, P = 0.040, respectively). CONCLUSIONS: Heavy alcohol intake may be associated with lower BMD in men while light alcohol intake may associate with higher BMD among women. Future longitudinal studies investigating the effect of alcohol consumption on bone mineral density are needed to validate the findings of this study. PMID- 29696515 TI - Use of BioglueTM to seal a difficult to treat air leak in a complicated empyema patient. AB - Surgical sealants have been used in thoracic surgery in an effort to reduce air leak duration, intercostal drain duration, length of stay and complications. They are instilled over a defect usually treated with other means. We herein present the technique of controlling a difficult to treat defect by directly instilling BioglueTM alone into a crater, caused during empyema Video-assisted thoracic surgery in a 50-year-old patient with a trapped lung. This deep crater had caused a significant air leak rendering intraoperative ventilation challenging. After instillation, the dependent lung was kept blocked. With this technique, the BioglueTM polymerized and the air leak was dramatically decreased making ventilation and eventually extubation of the patient feasible. Instillation of BioglueTM directly into a large lung defect could be a choice of action to decrease complicated air leaks, otherwise impossible to treat with other means, in patients with trapped lung. PMID- 29696512 TI - Protective Effects of Notoginsenoside R1 via Regulation of the PI3K-Akt-mTOR/JNK Pathway in Neonatal Cerebral Hypoxic-Ischemic Brain Injury. AB - Notoginsenoside R1 (NGR1) is a predominant phytoestrogen extracted from Panax notoginseng that has recently been reported to play important roles in the treatment of cardiac dysfunction, diabetic kidney disease, and acute liver failure. Studies have suggested that NGR1 may be a viable treatment of hypoxic ischemic brain damage (HIBD) in neonates by reducing endoplasmic reticulum stress via estrogen receptors (ERs). However, whether NGR1 has other neuroprotective mechanisms or long-term neuroprotective effects is unclear. In this study, oxygen glucose deprivation/reoxygenation (OGD/R) in primary cortical neurons and unilateral ligation of the common carotid artery (CCL) in 7-day-old postnatal Sprague Dawley (SD) rats followed by exposure to a hypoxic environment were used to mimic an HIBD episode. We assessed the efficacy of NGR1 by measuring neuronal damage with MTT assay and assessed brain injury by TTC staining and brain water content detection 24-48 h after OGD/HIE. Simultaneously, we measured the long term neurophysiological effects using the beam walking test (5 weeks after HI) and Morris water maze test 5-6 weeks after HI. Expression of PI3K-Akt-mTOR/JNK (24 h after HI or OGD/R) proteins was detected by Western blotting after stimulation with HI, NGR1, LY294002 (PI3K inhibitor), 740Y-P (PI3K agonist), or ICI 182780(estrogen receptors inhibitor). The results indicated that NGR1 exerted neuroprotective effects by inhibiting neuronal apoptosis and promoting cell survival via the PI3K-Akt-mTOR/JNK signaling pathways by targeting ER in neonatal hypoxic-ischemic injury. PMID- 29696516 TI - Isolation of Yeasts from Guajillo Pepper (Capsicum annuum L.) Fermentation and Study of Some Probiotic Characteristics. AB - Three yeast strains were isolated from the spontaneous fermentation of guajillo pepper: Hanseniaspora opuntiae, Pichia kudriavzevii, and Wickerhamomyces anomalus, which were identified by amplification of the ITS/5.8S ribosomal DNA. Some probiotic characteristics of these strains were evaluated and compared with one commercial probiotic yeast (Saccharomyces boulardii). The survival percentage of all the yeasts was similar to that of the commercial product. They showed different hydrophobicity characteristics with hydrocarbons, autoaggregation > 90%, and characteristics of co-aggregation with pathogenic microorganisms. The adhesion capacity to mucin of the three yeast samples was similar to the reference yeast. The antioxidant activity of the yeasts varied between 155 and 178 MUM Trolox equivalents. All exhibited cholesterol reduction capacity, and W. anomalus was able to decrease up to 83% of cholesterol after 48 h of incubation. The 7.5-fold concentrated H. opuntiae supernatant had antimicrobial activity against Salmonella enterica ser. Typhimurium ATCC 14028 and Candida albicans ENCBDM2; tests suggest this activity against S. Typhimurium is due to a proteinaceous metabolite with a weight between 10 and 30 kDa. Among the yeasts, P. kudriavzevii exhibited the highest protective effect on the viability of Lactobacillus casei Shirota in gastric and intestinal conditions. These results suggest that yeasts isolated from guajillo pepper may have a probiotic potential. PMID- 29696514 TI - Characterizing functional differences in sea anemone Hsp70 isoforms using budding yeast. AB - Marine organisms experience abiotic stressors such as fluctuations in temperature, UV radiation, salinity, and oxygen concentration. Heat shock proteins (HSPs) assist in the response of cells to these stressors by refolding and maintaining the activity of damaged proteins. The well-conserved Hsp70 chaperone family is essential for cell viability as well as the response to stress. Organisms possess a variety of Hsp70 isoforms that differ slightly in amino acid sequence, yet very little is known about their functional relevance. In this study, we undertook analysis of three principal Hsp70 isoforms NvHsp70A, B, and D from the starlet sea anemone Nematostella vectensis. The functionality of Hsp70 isoforms in the starlet sea anemone was assessed through transcriptional analysis and by heterologous expression in budding yeast Saccharomyces cerevisiae. Interestingly, these isoforms were found to not only differ in expression under stress but also appear to have functional differences in their ability to mediate the cellular stress program. These results contribute to an understanding of Hsp70 isoform specificity, their shared and unique roles in response to acute and chronic environmental stress, and the potential basis of local adaptation in populations of N. vectensis. PMID- 29696517 TI - We Didn't See It Coming, and You Should Have Thought Twice: Sexual Advances from Our Former Teachers. PMID- 29696518 TI - Pyocholethorax secondary to biliopleural fistula: a rare complication of percutaneous transhepatic biliary drainage. PMID- 29696519 TI - Esophago-pericardial fistula with development of hydro-pneumo-pericardium resulting in hemodynamic instability: an unusual complication of esophageal cancer. PMID- 29696520 TI - ESC position paper on cardiovascular toxicity of cancer treatments: challenges and expectations-authors' reply. PMID- 29696521 TI - Herbal Medicine in Ischemic Stroke: Challenges and Prospective. AB - Herbal medicines, mainly of plant source, are invaluable source for the discovery of new therapeutic agents for all sorts of human ailments. The complex pathogenesis of stroke and multifactorial effect of herbal medicine and their active constituents may suggest the promising future of natural medicine for stroke treatment. Anti-oxidant, anti-inflammatory, anti-apoptotic, neuroprotective and vascular protective effect of herbal medicines are believed to be efficacious in stroke treatment. Herbs typically have fewer reported side effects than allopathic medicine, and may be safer to use over longer period of time. Herbal medicines are believed to be more effective for the longstanding health complaints, such as stroke. Several medicinal plants and their active constituents show the promising results in laboratory research. However failure in transformation of laboratory animal research to the clinical trials has created huge challenge for the use of herbal medicine in stroke. Until and unless scientifically comprehensive evidence of the efficacy and safety of herbal medicine in ischemic stroke patients is available, efforts should be made to continue implementing treatment strategies of proven effectiveness. More consideration should be paid to natural compounds that can have extensive therapeutic time windows, perfect pharmacological targets with few side effects. Herbal medicine has excellent prospective for the treatment of ischemic stroke, but a lot of effort should be invested to transform the success of animal research to human use. PMID- 29696522 TI - Defining Acupuncture-Moxibustion: A Delphi Study Protocol. AB - BACKGROUND: With the worldwide use and modern development of acupuncture moxibustion, there is disagreement on its basic definition. There has been an obstacle for clinical practice, research, and legislation. Considering this challenge, the World Federation of Acupuncture-Moxibustion Societies proposes to develop the definition and basic scope of acupuncture-moxibustion with a Delphi study. METHODS: A reactive Delphi method will be used to ask a group of experts to rate the relevance and clarity of a predesigned initial item list. This list was generated by the steering committee through a literature review and group discussion. Forty experts will be selected from many disciplines and continents to ensure appropriate representation. Predefined rules will be applied to modify the items until a consensus is achieved. After achieving the consensus on all items through the survey round, the steering committee will form the definition and basic scope of acupuncture-moxibustion by organizing a literal statement with a detailed explanation. PMID- 29696523 TI - Occurrence of ochratoxin A in Astragalus propinquus root and its transfer to decoction. AB - The aim of this study was to conduct a survey assessing (a) the ochratoxin A (OTA) content in different samples of Astragalus propinquus root (AR), one of the fundamental herbs in traditional Chinese medicine, and (b) the rate of OTA transfer to AR decoctions that are traditionally used to reduce general weakness and increase overall vitality. A validated method of high-performance liquid chromatography with fluorescence detection (HPLC-FLD) was used to determine OTA concentrations in AR samples and AR decoctions. The limit of quantification was 0.35 ng/g; the recovery of the HPLC method for AR samples was 82%; and the relative standard deviation (SD) of repeatability was 2.6%. All 40 tested AR samples were positive, with a mean value of 451.0 ng/g (range, 28.8-1700.0 ng/g). The transfer rate of OTA to decoctions, from a naturally contaminated and homogenized AR sample (internal reference material) with a concentration of OTA of 288.9 ng/g +/- 12.3 (SD), was 83.4% +/- 8.5 (SD). We believe it is necessary to continue OTA monitoring in AR and other herbal products, estimate the actual human usual intake, and perform health risk assessment. PMID- 29696524 TI - Differences Between the Childhood Autism Rating Scale and the Social Responsiveness Scale in Assessing Symptoms of Children with Autistic Spectrum Disorder. AB - This study aimed to compare symptoms of autism spectrum disorder using the Childhood Autism Rating Scale (CARS) and the Social Responsiveness Scale (SRSTM 2) and to investigate their influencing factors. The diagnostic agreement was 92.7%, but with a fair Kappa value (0.247). Children's verbal comprehension was related to the CARS scores, and no variables were related to the SRSTM-2 scores. Generally, significant small correlations were found between the two measures in children with normal or borderline to below average verbal comprehension (rs = 0.32 ~ 0.49, p < .005), but not in those with impaired verbal comprehension. The CARS and the SRSTM-2 may contain different explicit behaviors and collect different perspectives (i.e., those of caregivers and professionals). Therefore, they appear to complement each other. PMID- 29696525 TI - Brief Report: Attentional Cueing to Images of Social Interactions is Automatic for Neurotypical Individuals But Not Those with ASC. AB - Human actions induce attentional orienting toward the target of the action. We examined the influence of action cueing in social (man throwing toward a human) and non-social (man throwing toward a tree) contexts in observers with and without autism spectrum condition (ASC). Results suggested that a social interaction enhanced the cueing effect for neurotypical participants. Participants with ASC did not benefit from non-predictive cues and were slower in social contexts, although they benefitted from reliably predictive cues. Social orienting appears to be automatic in the context of an implied social interaction for neurotypical observers, but not those with ASC. Neurotypical participants' behavior may be driven by automatic processing, while participants with ASC use an alternative, effortful strategy. PMID- 29696526 TI - Parent-Teacher Agreement on Social Skills and Behavior Problems Among Ethnically Diverse Preschoolers with Autism Spectrum Disorder. AB - Parents and teachers provide complimentary information in the assessment of preschoolers so it is important to understand parent-teacher agreement, especially for children with autism. Parents and teachers rated an ethnically diverse sample of preschoolers with autism (N = 257; 67% Latino) on the Devereux Early Childhood Assessment (LeBuffe and Naglieri in Devereux Early Childhood Assessment: User's guide, Kaplan Press, Lewisville, 1999). Correlations between parent and teacher ratings were moderate and significant for social skills (r = 0.20-0.37) but near zero for behavioral concerns. Parents rated children as having stronger social skills and fewer behavioral concerns than teachers, unlike prior research with typically developing preschoolers. Both informants rated White/other children more positively than minority children on several subscales, although agreement was similar across groups. Implications for practice are discussed. PMID- 29696527 TI - Prevalence and Characteristics of Autism Spectrum Disorder Among Spanish School Age Children. AB - The present study aims to assess the prevalence of autism spectrum disorder (ASD) in preschool and school-age children following a two-phase procedure. The screening phase was performed on a sample of 5555 children taking into account parent and teacher information. The individual assessment included the ADI-R, ADOS-2 and Wechsler scales. The estimated prevalence was 1.55% in preschoolers and 1.00% in school-age children. Between 1.84 and 2.59% of the children exhibited subclinical diagnosis. The male-to-female ratio was around 4:1. Most of the children exhibited mild and moderate nuclear symptoms, and the girls showed less severe communication problems. Previous diagnosis was found in 62-71% of the children. Prevalence estimates are close to the 1% international ratings and much higher than previous national reports suggested. PMID- 29696528 TI - Case Report: Successful Use of the Combination of Electroconvulsive Therapy and Clozapine in Treating Treatment-Resistant Schizophrenia and Catatonia in an Adult with Intellectual Disability. AB - There is paucity of empirical data regarding the use of either clozapine or electroconvulsive therapy (ECT) in the acute phase and maintenance treatment of schizophrenia in adults with intellectual disability. Herein we report the successful acute and long-term remission of psychotic symptoms and catatonia with the combination of clozapine and ECT in a 26-year-old female with moderate ID and treatment-resistant schizophrenia. To our knowledge, this is the first case example of the successful use of the combination of bilateral, standard-pulse ECT and clozapine in both acute and long-term treatment of treatment-resistant schizophrenia and catatonia in an adult with ID. Our report adds further support to the emerging evidence regarding the efficacy and safety of this combination in treatment-resistant schizophrenia. PMID- 29696529 TI - Utility of the variable flip angle 3D fast-spin echo (isoFSE) sequence on 3T MR for diagnosing vertebrobasilar artery dissection. AB - We aimed to investigate the utility of the isoFSE sequence, one of the variable flip angle 3D fast-spin echo sequences, on 3T-MR for displaying vessel walls and diagnosing vertebrobasilar artery dissection (VAD). We retrospectively evaluated 12 initial and 28 follow-up images from 12 patients diagnosed with either intracranial VAD or carotid artery dissection. The image quality for displaying the vessel wall was scored using a five-point scale (1 poor, 5 excellent) on initial T1-weighted isoFSE images for each region of the arteries. The intracranial artery dissection findings assessed at time points after onset were evaluated on initial and follow-up T1/T2-weighted isoFSE images. For small arteries, including the anterior/posterior inferior cerebellar artery, similar high scores were obtained on both unenhanced and contrast-enhanced T1-weighted isoFSE images (average: 4.7-5.0, p > 0.2). On unenhanced images, dissected vertebral arteries showed significantly lower scores than non-dissected vertebral arteries for both readers (p = 0.017 and 0.015, respectively), but the scores were high (3.9 and 4.0, respectively). Definitive findings of VAD were observed on the initial images except in one case. For all cases, definitive findings were seen on at least one of the initial or follow-up images. Temporal changes in the findings could be observed for all cases. In conclusion, we showed favorable wall visualization on T1-weighted isoFSE images and the utility of follow-up imaging using unenhanced-T1/T2-weighted and contrast-enhanced T1-weighted isoFSE sequences with acceptable scan times, which could promote the regular use of 3D black-blood vessel wall imaging. PMID- 29696530 TI - Prognostic value of the Glasgow Prognostic Score for glioblastoma multiforme patients treated with radiotherapy and temozolomide. AB - INTRODUCTION: To evaluate the prognostic value of the Glasgow Prognostic Score (GPS), the combination of C-reactive protein (CRP) and albumin, in glioblastoma multiforme (GBM) patients treated with radiotherapy (RT) and concurrent plus adjuvant temozolomide (GPS). METHODS: Data of newly diagnosed GBM patients treated with partial brain RT and concurrent and adjuvant TMZ were retrospectively analyzed. The patients were grouped into three according to the GPS criteria: GPS-0: CRP < 10 mg/L and albumin > 35 g/L; GPS-1: CRP < 10 mg/L and albumin < 35 g/L or CRP > 10 mg/L and albumin > 35 g/L; and GPS-2: CRP > 10 mg/L and albumin < 35 g/L. Primary end-point was the association between the GPS groups and the overall survival (OS) outcomes. RESULTS: A total of 142 patients were analyzed (median age: 58 years, 66.2% male). There were 64 (45.1%), 40 (28.2%), and 38 (26.7%) patients in GPS-0, GPS-1, and GPS-2 groups, respectively. At median 15.7 months follow-up, the respective median and 5-year OS rates for the whole cohort were 16.2 months (95% CI 12.7-19.7) and 9.5%. In multivariate analyses GPS grouping emerged independently associated with the median OS (P < 0.001) in addition to the extent of surgery (P = 0.032), Karnofsky performance status (P = 0.009), and the Radiation Therapy Oncology Group recursive partitioning analysis (RTOG RPA) classification (P < 0.001). The GPS grouping and the RTOG RPA classification were found to be strongly correlated in prognostic stratification of GBM patients (correlation coefficient: 0.42; P < 0.001). CONCLUSIONS: The GPS appeared to be useful in prognostic stratification of GBM patients into three groups with significantly different survival durations resembling the RTOG RPA classification. PMID- 29696531 TI - Stereotactic radiosurgery and ipilimumab for patients with melanoma brain metastases: clinical outcomes and toxicity. AB - INTRODUCTION: There is evidence that the combination of ipilimumab and stereotactic radiosurgery (SRS) for brain metastases improves outcomes. We investigated clinical outcomes, radiation toxicity, and impact of ipilimumab timing in patients treated with SRS for melanoma brain metastases. METHODS: We retrospectively identified 91 patients treated with SRS at our institution for melanoma brain metastases from 2006 to 2015. Concurrent ipilimumab administration was defined as within +/- 4 weeks of SRS procedure. Acute and late toxicities were graded with CTCAE v4.03. Overall survival (OS), local failure, distant brain failure, and failure-free survival were analyzed with the Kaplan-Meier method. OS was analyzed with Cox regression. RESULTS: Twenty-three patients received ipilimumab concurrent with SRS, 28 patients non-concurrently, and 40 patients did not receive ipilimumab. The median age was 62 years and 91% had KPS >= 80. The median follow-up time was 7.4 months. Patients who received ipilimumab had a median OS of 15.1 months compared to 7.8 months in patients who did not (p = 0.02). In multivariate analysis, ipilimumab (p = 0.02) and diagnosis-specific graded prognostic assessment (p = 0.02) were associated with OS. There were no differences in intracranial control by ipilimumab administration or timing. The incidence of radiation necrosis was 5%, with most events occurring in patients who received ipilimumab. CONCLUSIONS: Patients who received ipilimumab had improved OS even after adjusting for prognostic factors. Ipilimumab did not appear to increase risk for acute toxicity. The majority of radiation necrosis events, however, occurred in patients who received ipilimumab. Our results support the continued use of SRS and ipilimumab as clinically appropriate. PMID- 29696532 TI - Quantitative dynamic susceptibility contrast perfusion-weighted imaging-guided customized gamma knife re-irradiation of recurrent high-grade gliomas. AB - INTRODUCTION: Treatment of recurrent high-grade gliomas (rHGG) has always been challenging. This study aimed to explore the treatment effect of quantitative dynamic susceptibility contrast perfusion-weighted imaging (DSC-PWI)-guided gamma knife radiosurgery (GKRS) on rHGG. METHODS: Between April 2014 and July 2016, 26 consecutive patients were treated by quantitative DSC-PWI-guided GKRS as salvage treatment for rHGG. The gross tumor volume (GTV) was defined as the high perfusion area on absolute cerebral blood volume maps, with a cutoff value of 22 ml/100 g. The clinical target volume (CTV) encompassed the GTV by 3 mm. Overall survival (OS) and progression-free survival (PFS) were calculated by the Kaplan Meier method. Prognostic factors were tested by the log-rank (Mantel-Cox) test. RESULTS: With a median follow-up of 32 months, the median PFS after GKRS was 8 months (95% CI [6, 12]); the 1- and 2-year survival rates were 30.8 and 11.5%, respectively. The median OS was 25.5 months (95% CI [18, 40]); the 1- and 2-year survival rates were 96.2 and 57.7%, respectively. Pathology grade and CTV were identified as prognostic factors for PFS. However, none of the parameters tested were independent prognostic factors for OS among these selected patients. No severe radiotoxicity was observed among all patients. CONCLUSIONS: Quantitative DSC-PWI-guided GKRS is feasible for the treatment of rHGG and that these outcomes remain to be validated. Despite this, we think that carefully selected patients can benefit from this treatment method. PMID- 29696533 TI - Tirofiban Positively Regulates beta1 Integrin and Favours Endothelial Cell Growth on Polylactic Acid Biopolymer Vascular Scaffold (BVS). AB - An unexpectedly high incidence of thrombosis in patients that received the polylactic acid bioresorbable vascular scaffold (BVS) suggests a delayed/incomplete endothelial repair with this stent. The anti-platelet agent tirofiban stimulates endothelial cell migration and proliferation, mediated by VEGF production. We investigated the tirofiban effect on the migration and adhesion of endothelial cells to BVS, in vitro. We performed human umbilical endothelial cell (HUVEC) cultures in the presence of BVS. Tirofiban, similarly to VEGF, increased the ability of HUVEC to grow on the vascular scaffold, compared to unstimulated or abciximab-treated cells. Tirofiban increased HUVEC expression of beta1 and beta3 integrins along with collagen and fibronectin. A role for beta1 integrin in the "pro-adhesive and -migratory" signals elicited by tirofiban was suggested by use of an anti-beta1-blocking antibody that prevented poly-levo lactic acid vascular scaffold colonization. Our study suggests that tirofiban may improve the outcomes of patients receiving BVS by accelerating stent endothelization. PMID- 29696534 TI - Ascorbic Acid Attenuates Lead-Induced Alterations in the Synapses in the Developing Rat Cerebellum. AB - We evaluated the effect of lead (Pb) and ascorbic acid treatment of pregnant female rats on cerebellar development in pups. Pb was administered in drinking water (0.2% Pb acetate), and ascorbic acid (100 mg/kg) was administered through oral intubation. Fifteen female rats were randomly classified into control, Pb, and Pb plus ascorbic acid (PA) groups. The treatment of Pb and ascorbic acid treatments were terminated after birth to evaluate the effects on the gestational development of the cerebellum. At postnatal day 21 (PND21), pups were sacrificed, and blood Pb level was analyzed. Blood Pb levels of pups and dams were highest in the Pb group and reduced in the PA group. Immunohistochemistry and immunoblot assays were conducted to study the cerebellar expression levels of synaptic proteins. Along with a significant reduction in Purkinje cells, the reduction in presynaptic (synaptophysin) and postsynaptic (postsynaptic density protein 95, N methyl-D-aspartate receptor subtype 1) marker proteins was observed in Pb-exposed pups. Ascorbic acid treatment significantly prevented Pb-induced impairment in the cerebellar synaptic proteins. Hypothesizing that brain-derived neurotrophic factor (BDNF) might be affected by Pb exposure given its importance in the regulation of synaptogenesis, we observed a Pb-induced decrease and ascorbic acid mediated increase of BDNF in the cerebellum. Luxol fast blue staining and myelin basic protein analysis suggest that ascorbic acid treatment ameliorated the Pb exposure-induced reduction in the axonal fibers in the developing cerebellum. Overall, we conclude that ascorbic acid treatment during pregnancy can prevent Pb induced impairments in the cerebellar development in rats. PMID- 29696535 TI - Defluoridation using novel chemically treated carbonized bone meal: batch and dynamic performance with scale-up studies. AB - Novel defluoridating adsorbent was synthesized by chemical treatment of carbonized bone meal using aluminum sulfate and calcium oxide. Precursor for chemical treatment was prepared by partial carbonization of raw bone meal at 550 degrees C for 4 h. Maximum fluoride removal capacity was 150 mg/g when carbonized bone meal (100 g/L) was treated with aluminum sulfate (500 g/L) and calcium oxide (15 g/L). Morphological analysis revealed formation of a coating layer consisting of aluminum compounds on the precursor surface. This was verified by stretching frequency of aluminum hydroxide (602 cm-1) in the infrared spectra. Presence of hydroxylapatite (2theta = 30 degrees and 2theta = 24 degrees ) and aluminum mineral phases (2theta = 44 degrees ) in the adsorbent were identified from the X ray diffractograms. Adsorption capacity decreased from 150 mg/g (30 degrees C) to 120 mg/g (50 degrees C) indicating exothermic adsorption. Adsorption experiments under batch kinetic mode were simulated using shrinking core model. Effective fluoride diffusivity in the adsorbent and the mass transfer coefficient were estimated as 5.8 * 10-12 m2/s and 9 * 10-4 m/s, respectively. Desorption was maximum at basic pH and desorption efficiency was decreased by 31% after third cycle. Dynamic filtration with artificially fluoride-spiked solution showed that the empty bed contact time for a packed column with equal weight of carbonized and chemically treated adsorbent was 4.7 min and number of bed volumes treated (till WHO limit of 1.5 mg/L) was 340 for a column of 3-cm diameter and 18-cm length. The system was successfully tested using contaminated groundwater from an affected area. Fixed-bed column experiments were simulated from the first principles using convective pore diffusion-adsorption model for both synthetic solution and contaminated groundwater. Axial dispersion coefficient was found to be one order of magnitude less than the pore diffusivity indicating dominance of fluoride diffusion within porous network of adsorbent. The developed adsorbent exhibited antibacterial property as well. PMID- 29696536 TI - Transgenic up-regulation of Claudin-6 decreases fine diesel particulate matter (DPM)-induced pulmonary inflammation. AB - Claudin-6 (Cldn6) is a tetraspanin transmembrane protein that contributes to tight junctional complexes and has been implicated in the maintenance of lung epithelial barriers. In the present study, we tested the hypothesis that genetic up-regulation of Cldn-6 influences inflammation in mice exposed to short-term environmental diesel particulate matter (DPM). Mice were subjected to ten exposures of nebulized DPM (PM2.5) over a period of 20 days via a nose-only inhalation system (Scireq, Montreal, Canada). Using real-time RT-PCR, we discovered that the Cldn6 gene was up-regulated in control mice exposed to DPM and in lung-specific transgenic mice that up-regulate Cldn-6 (Cldn-6 TG). Interestingly, DPM did not further enhance Cldn-6 expression in Cldn-6 TG mice. DPM caused increased cell diapedesis into bronchoalveolar lavage fluid (BALF) from control mice; however, Cldn-6 TG mice had less total cells and PMNs in BALF following DPM exposure. Because Cldn-6 TG mice had diminished cell diapedesis, other inflammatory intermediates were screened to characterize the impact of increased Cldn-6 on inflammatory signaling. Cytokines that mediate inflammatory responses including TNF-alpha and IL-1beta were differentially regulated in Cldn6 TG mice and controls following DPM exposure. These results demonstrate that epithelial barriers organized by Cldn-6 mediate, at least in part, diesel-induced inflammation. Further work may show that Cldn-6 is a key target in understanding pulmonary epithelial gateways exacerbated by environmental pollution. PMID- 29696537 TI - Traits and causes of environmental loss-related chemical accidents in China based on co-word analysis. AB - Chemical accidents are major causes of environmental losses and have been debated due to the potential threat to human beings and environment. Compared with the single statistical analysis, co-word analysis of chemical accidents illustrates significant traits at various levels and presents data into a visual network. This study utilizes a co-word analysis of the keywords extracted from the Web crawling texts of environmental loss-related chemical accidents and uses the Pearson's correlation coefficient to examine the internal attributes. To visualize the keywords of the accidents, this study carries out a multidimensional scaling analysis applying PROXSCAL and centrality identification. The research results show that an enormous environmental cost is exacted, especially given the expected environmental loss-related chemical accidents with geographical features. Meanwhile, each event often brings more than one environmental impact. Large number of chemical substances are released in the form of solid, liquid, and gas, leading to serious results. Eight clusters that represent the traits of these accidents are formed, including "leakage," "poisoning," "explosion," "pipeline crack," "river pollution," "dust pollution," "emission," and "industrial effluent." "Explosion" and "gas" possess a strong correlation with "poisoning," located at the center of visualization map. PMID- 29696538 TI - Variations in individuals' exposure to black carbon particles during their daily activities: a screening study in Brazil. AB - Black carbon (BC) is a fraction of airborne PM2.5 emitted by combustion, causing deleterious effects on human health. Due to its abundance in cities, assessing personal exposure to BC is of utmost importance. Personal exposure and dose of six couples with different working routines were determined for 48 h based on 1 min mobile BC measurements and on ambient concentrations monitored simultaneously at home (outdoor) and at a suburban site. Although couples spent on average ~ 10 h together at home, the routine of each individual in other microenvironments led to 3-55% discrepancies in exposure between partners. The location of the residences and background concentrations accounted for the differences in inter couple exposure. The overall average exposure and dose by gender were not statistically different. The personal exposure and dose calculated with datasets from fixed sites were lower than the calculations using data from mobile measurements, with the largest divergences (between four and nine times) in the transport category. Even though the individuals spent only 7% of the time commuting, this activity contributed to between 17 and 20% of the integrated exposure and inhaled dose, respectively. On average, exposure was highest on bus trips, while pedestrians and bus passengers had lower doses. Open windows elevated the in-car exposure and dose four times compared to settings with closed windows. PMID- 29696539 TI - Insight into the effects of biochar as adsorbent and microwave receptor from one step microwave pyrolysis of sewage sludge. AB - The effect of biochar, derived from one-step microwave pyrolysis of sewage sludge (OMPSS), on the removal of industrial wastewater (eosin and safranine T) was investigated in this study. Meanwhile, the multiple-reuse potential of biochar as microwave receptor to raise the pyrolysis temperature was also tested during the pyrolysis process. The results showed that OMPSS prepared adsorbents had excellent adsorption performance, achieving the highest removal efficiencies of 97.3 and 95.9% for eosin and safranine T, respectively. Further analysis indicated that this was due to its appropriate porous structure and surface chemistry characteristics, where the SBET and pore volume of adsorbent AC-1 reached 459 m2/g and 0.23 cm3/g, respectively. The multiple reuses of biochar adsorbents after five times as microwave receptor was feasible, where the pyrolysis temperature could increase sharply from room temperature to 800 degrees C within 5 min. The mechanism analysis revealed that the limiting stage of adsorption was chemical sorption. This research provided an alternative way for the preparation of functional adsorbent and microwave receptor. Graphical abstract ?. PMID- 29696540 TI - Research on the effect of wall corrosion and rim seal on the withdrawal loss for a floating roof tank. AB - Storage tanks are important parts of volatile organic compound (VOC) fugitive emission sources of the petrochemical industry; the floating roof tank is the main oil storage facility at present. Based on the mechanism of withdrawal loss and the type of rim seal, octane and gasoline were taken as the research objects. A model instrument for simulating the oil loading process by the 316 stainless steel and A3 carbon steel as the test piece was designed, and the film thickness was measured by wet film thickness gauge to investigate the influence of the corrosion of the tank wall and rim seal on the withdrawal loss for floating roof tanks. It was found that withdrawal loss was directly proportional to the shell factor, and the oil thickness of the octane and gasoline increased with the strength of the wall corrosion with the same wall material and rim seal. Compared with the untreated test piece, the oil film thickness of the octane/gasoline was increased by 7.04~8.57 MUm/13.14~21.93 MUm and 5.59~11.49 MUm/11.61~25.48 MUm under the corrosion of hydrochloric acid for 32 and 75 h, respectively. The oil film thickness of octane and gasoline decreased with the increasing of the rim seal, and the oil film thickness of the octane decreased by 11.97~28.90% and 37.32~73.83% under the resilient-filled seal and the double seal, respectively. The gasoline dropped by 11.97~31.18% and 45.98~75.34% under the resilient-filled seal and the double seal, respectively. In addition, the tank surface roughness reduced the compression of the rim seal on the tank wall, and the effect of scraping decreased. The API withdrawal loss formula for a floating roof tank was recommended to take into account the effect of the rim seal to improve the accuracy of the loss evaluation. Finally, some measures of reducing the withdrawal loss were proposed. PMID- 29696541 TI - Effects and mechanisms of anionic and nonionic surfactants on biochar removal of chromium. AB - This work found that the removal of chromium by a straw-derived biochar was significantly promoted or inhibited by various surfactants. For example, the anionic surfactant sodium dodecyl benzene sulfonate (SDBS) inhibited the removal of Cr(VI) by the biochar but significantly promoted the removal of Cr(III) by the biochar. The nonionic surfactant Triton X-100 (TX-100) promoted the removal of Cr(VI) at low concentrations (< 100 mg L-1) but inhibited the removal at high concentrations. Different mechanisms were found for the two surfactants. As an anionic surfactant, surface-sorbed SDBS changed the surface functional groups of the biochar, making the biochar negative charged and changing the sorption ability of the biochar. For the nonionic TX-100, monomers and micelles in the aqueous phase had a major influence on the sorption of chromium due to the impact on the interfacial tension between the biochar and the solution phase as well as the solution pH. The results suggest that when biochar is used to treat heavy metal wastewater containing coexisting surfactants, the type and concentration of surfactants must be considered as important factors. Under certain surfactant conditions, biochar will enable the simultaneous and efficient removal of heavy metals and surfactants. PMID- 29696542 TI - Comparative analysis of cadmium-induced stress responses by the aromatic and non aromatic rice genotypes of West Bengal. AB - Constant exposure of the living ecosystems to heavy metals, like cadmium (Cd), induces a detectable change at the biochemical and genetic level. Repeated application of phosphate fertilizers in paddy fields, leads to increase in Cd content of soil. Cd being highly mobile is transported to shoot and grain, thereby entering into the food chain of animal system. In the present study, treatment of 7-day old rice seedlings with 10 MUM cadmium chloride resulted in Cd toxicity across the seven non-aromatic and six aromatic rice cultivars and landraces used for the study. Free proline and malondialdehyde content of treated samples were higher in comparison to the untreated samples, which indicated Cd induced tissue damage in plants. Photosynthetic pigment content of treated samples was also found to be much lower in comparison to the untreated samples, which is probably due to peroxidation of membrane, leading to compromised and lower photosynthetic efficiency of treated plants. At the genetic level, Randomly Amplified Polymorphic DNA assay was found to efficiently detect the genetic polymorphisms (caused by alterations in DNA bases) induced by Cd. Production of unique polymorphic bands in Cd-treated plants helps in assessment of the degree of damage Cd imparts on the plant system. Cluster analysis was performed and the rice genotypes were grouped into five distinct clusters, with IR64 and Tulsibhog in two distinct groups. Based on the variability in responses, the 13 rice genotypes were grouped into sensitive and tolerant ones. PMID- 29696543 TI - Deciphering adverse effects of heavy metals on diverse wheat germplasm on irrigation with urban wastewater of mixed municipal-industrial origin. AB - The current study provides one of the first attempts to identify tolerant, moderately sensitive, and highly sensitive wheat genotypes on the basis of heavy metal accumulation, biochemical attributes, and human health risk assessments on urban wastewater (UW) irrigation. Mean heavy metals (Fe, Co, Ni, Cu, Zn, Pb, Cd, Cr, Mn) and macro-nutrients (Na, K, Ca, Mg) levels increased in the roots, stem, and grains of studied genotypes. Except K (stem > root > grain), all metals were accumulated in highest concentrations in roots followed by stem and grains. Principal component analyses (PCA) identified three groups of UW-irrigated genotypes which were confirmed by hierarchical agglomerative cluster analyses (HACA). Wheat genotypes with the lowest metal accumulation were regarded as tolerant, whereas those with maximum accumulation were considered highly sensitive. Tolerant genotypes showed the lowest hazard quotient for heavy metals, i.e., Co, Mn, Cd, Cu, Fe, Pb, and Cr, and hazard index (HI) values (adults, 2.04; children, 2.27) than moderately and highly sensitive genotypes. Higher health risks (HI) associated with moderate (adults 2.26; children 2.53) and highly sensitive (adults 2.52; children 2.82) genotypes revealed maximum uptake of heavy metals. The heatmap showed higher mean biochemical levels of chlorophyll, carotenoids, membrane stability index (MSI%), sugars, proteins, proline, superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT) in tolerant genotypes than remaining genotypes. With the lowest metal accumulation and advanced biochemical mechanisms to cope with the adverse effects of heavy metals in their plant bodies, tolerant genotypes present a better option for cultivation in areas receiving UW or similar type of wastewater. PMID- 29696544 TI - A facile method to prepare translucent anatase thin films in monolithic structures for gas stream purification. AB - In the present work, a facile method to prepare translucent anatase thin films on cellulose acetate monolithic (CAM) structures was developed. A simple sol-gel method was applied to synthesize photoactive TiO2 anatase nanoparticles using tetra-n-butyl titanium as precursor. The immobilization of the photocatalyst on CAM structures was performed by a simple dip-coating method. The translucent anatase thin films allow the UV light penetration through the CAM internal walls. The photocatalytic activity was tested on the degradation of n-decane (model volatile organic compound-VOC) in gas phase, using a tubular lab-scale (irradiated by simulated solar light) and pilot-scale (irradiated by natural solar light or UVA light) reactors packed with TiO2-CAM structures, both equipped with compound parabolic collectors (CPCs). The efficiency of the photocatalytic oxidation (PCO) process in the degradation of n-decane molecules was studied at different operating conditions at lab-scale, such as catalytic bed size (40-160 cm), TiO2 film thickness (0.435-0.869 MUm), feed flow rate (75-300 cm3 min-1), n decane feed concentration (44-194 ppm), humidity (3 and 40%), oxygen concentration (0 and 21%), and incident UV irradiance (18.9, 29.1, and 38.4 WUV m 2). The decontamination of a bioaerosol stream was also evaluated by the PCO process, using Pseudomonas aeruginosa (Gram-negative) and Staphylococcus aureus (Gram-positive) as model bacteria. A pilot-scale unit was operated day and night, using natural sunlight and artificial UV light, to show its performance in the mineralization of n-decane air streams under real outdoor conditions. Graphical abstract Normally graphics abstract are not presented with captions/legend. The diagram is a collection of images that resume the work. PMID- 29696545 TI - Assessment of pectin-coated magnetite nanoparticles in low-energy water desalination applications. AB - Novel magnetite nanoparticles (NPs) modified with pectin coating were fabricated, characterized, and evaluated as potential draw solute in a forward osmosis (FO) process for water desalination applications. The prepared NPs had a spherical shape with an average diameter of 200 nm and saturation magnetization of 23.13 emu/g. Thermogravimetric analysis (TGA) and FTIR spectra elucidated the successful pectin coating on magnetite surface. The potential use of the fabricated NPs in water desalination was conducted via a newly developed lab scale FO system. Deionized water, saline water (0.2, 0.5, and 1 g% NaCl solution), and real well water (TDS = 0.9 g%) were used as feed solutions. In all experiments, the water flux gradually decreased along with the extension of experimental time and NaCl rejection rate by the FO membrane was measured to be higher than 95%. Moreover, it was found that the pectin-coated magnetite NPs demonstrated to be able to draw clean water across the FO membrane from well water with a remarkable salt rejection of 97%. Thus, it is believed that the proposed FO system using pectin-coated magnetite NPs as draw solute can be a promising technique for desalination of well waters in an environmental-friendly and energy-saving manner. PMID- 29696546 TI - Hydrogel chitosan sorbent application for nutrient removal from soilless plant cultivation wastewater. AB - In this study, we determined the effectiveness of removal of nutrients (nitrates and orthophosphates) from greenhouse wastewaters (GW) using non-cross-linked chitosan (CHs) and chitosan cross-linked with epichlorohydrin (CHs-ECH) in the form of hydrogel beads. GW used in the study had the following parameters: N-NO3 621.1 mg/L, P-PO4 60.8 mg/L, SO42- 605.0 mg/L, Cl- 0.9 mg/L, Ca2+ 545.0 mg/L, Mg2+ 178.0 mg/L, K+ 482.0 mg/L, hardness 113 degrees dH, and pH 6.2. The scope of the study included determination of the effect of pH on wastewater composition and effectiveness of nutrient sorption, analyses of nutrient sorption kinetics, and analyses of the effect of sorbent dose on percentage removal of nutrients from GW. CHs-ECH was able to sorb 79.4% of P-PO4 and 76.7% of N-NO3 from GW, whereas CHs to remove 92.8% of P-PO4 and 53.2% of N-NO3. PMID- 29696547 TI - Traffic-emitted metal status and uptake by Carex meyeriana Kunth and Thelypteris palustris var. pubescens Fernald growing in roadside turfy swamp in the Changbai Mountain area, China. AB - Six traffic-emitted metals (Cr, Zn, Cu, Cd, Pb, and Ni) were determined in soil and plants for below- and aboveground parts along different distances from highway to evaluate their behavior and uptake by Carex meyeriana Kunth and Thelypteris palustris var. pubescens Fernald growing in turfy swamps. The results indicated that the different plant tissues showed significantly different levels of metal content. Nonlinear regression analysis indicated that metal contents leveled off at constant values before they decreased as the distance from the roadside increased. The high R2 values of the regression model indicated good fit of the exponential function applied to depict the distribution pattern of the metal elements. It was deduced that Cr, Cu, and Cd in Thelypteris palustris var. pubescens Fernald were mainly derived from the soil; Carex meyeriana Kunth and Thelypteris palustris var. pubescens Fernald absorbed Pb mainly through the stomata from atmospheric depositions; Cr, Cu, and Cd in Carex meyeriana Kunth and Zn in Thelypteris palustris var. pubescens Fernald were mainly affected by soil and atmospheric depositions. After excluding the effects of traffic, only the bioaccumulation factor of Cd (1.34) in Carex meyeriana Kunth and the translocation factor of Zn (1.13) in Thelypteris palustris var. pubescens Fernald were greater than 1, suggesting that Carex meyeriana Kunth could be a good candidate for assimilating Cd from soils and Thelypteris palustris var. pubescens Fernald could be suitable for the phytoextraction of Zn. PMID- 29696548 TI - Semantic-Enhanced Query Expansion System for Retrieving Medical Image Notes. AB - Most current image retrieval methods require constructing semantic metadata for representing image content. To manually create semantic metadata for medical images is time-consuming, yet it is a crucial component for query expansion. We proposed a new method for searching medical image notes that uses semantic metadata to improve query expansion and leverages a knowledge model developed specifically for the medical image domain to create relevant metadata. We used a syntactic parser and the Unified Medical Language System to analyze the corpus and store text information as semantic metadata in a knowledge model. Our new method has an interactive interface that allows users to provide relevance feedback and construct new queries more efficiently. Sixteen medical professionals evaluated the query expansion module, and each evaluator had prior experience searching for medical images. When using the initial query as the baseline standard, expanded queries achieved a performance boost of 22.6% in terms of the relevance score on first ten results (P-value<0.05). When using Google as another baseline, our system performed 24.6% better in terms of relevance score on the first ten results (P-value<0.05). Overall, 75% of the evaluators said the semantic-enhanced query expansion workflow is logical, easy to follow, and comfortable to use. In addition, 62% of the evaluators preferred using our system instead of Google. Evaluators who were positive about our system found the knowledge map-based visualization of candidate medical search terms helpful in refining cases from the initial search results. PMID- 29696550 TI - Sex Ratio in Children and Adolescents Referred to the Gender Identity Development Service in the UK (2009-2016). PMID- 29696549 TI - Discolored Red Seaweed Pyropia yezoensis with Low Commercial Value Is a Novel Resource for Production of Agar Polysaccharides. AB - The red seaweed Pyropia yezoensis has been demonstrated to be a novel resource for the production of high-quality agar. P. yezoensis is grown for the food industry in large-scale Japanese mariculture operations. However, discolored P. yezoensis is mostly discarded as an industrial waste, although it has some kind of utility values. Here, we evaluated the utility of discolored P. yezoensis as a resource for agar production. The quality of agar from the discolored seaweed was comparable to that from normal seaweed. In addition, as a distinguishing characteristic, agar yield was higher from discolored seaweeds than from normal types. Moreover, we successfully used agar from discolored P. yezoensis for bacterial plate media and DNA electrophoresis gels without agarose purification. Thus, our results demonstrate that discolored P. yezoensis is suitable for agar production and use in life science research. Diverting discolored P. yezoensis from disposal to agar production provides a solution to the current industrial waste problem in mariculture, as well as a secure source of agar for research purposes. PMID- 29696551 TI - ERPs Reveal Disengagement Processes Related to Condom Use Embarrassment in Intention-Behavior Inconsistent Young Adults. AB - The use of barrier protections such as condoms has consistently been reported to reduce the acquisition of sexually transmitted infections. However, it has also been reported that the association between condom use intentions and behavior is, at best, often weak. Furthermore, embarrassment associated with purchasing condoms and negotiating their use has been shown to negatively impact the frequency of condom use. Using electroencephalography to analyze P300 event related potential components known to measure early attention allocation, we examined electrophysiological evidence of early attention disengagement for embarrassing health information. Forty young adults-34 females and six males participated in an adapted version of Posner's visual cueing paradigm. All were high in intention to use condoms, but half were intention-behavior consistent and half were intention-behavior inconsistent. Compared to intention-behavior consistent participants, those with intention-behavior inconsistency showed a reduced P300 component when attending to a visual target opposite to the field in which embarrassing self-relevant health information was presented, indicating more efficient early attention disengagement from such embarrassing health information. In conclusion, our electrophysiological data suggest that high intention alone may be not sufficient to predict adolescents' condom use behavior. PMID- 29696552 TI - Open Relationships, Nonconsensual Nonmonogamy, and Monogamy Among U.S. Adults: Findings from the 2012 National Survey of Sexual Health and Behavior. AB - People in open and other consensually nonmonogamous partnerships have been historically underserved by researchers and providers. Many studies group such partnerships together with nonconsensual nonmonogamy (NCNM) under the banner of "concurrent sexual partnerships." Discrimination from service providers poses a substantial barrier to care. Responding to such concerns, this investigation explored sociodemographic correlates with open relationships and associations between relationship structure and sexual risk, HIV/STI testing, and relationship satisfaction in a nationally representative probability sample. Data were drawn from the 2012 National Survey of Sexual Health and Behavior (n = 2270). We used multinomial logistic regression to identify correlates with relationship structure, and linear and logistic regression to investigate associations between relationship structure and testing, condom use, and relationship satisfaction. Eighty-nine percent of participants reported monogamy, 4% reported open relationships, and 8% reported NCNM. Males, gay/lesbian individuals, bisexual individuals, and those who identified as "Other, Non-Hispanic" were more likely to report open relationships. Bisexual individuals and Black, Non-Hispanic participants were more likely to report NCNM; older participants were less likely to do so. Participants in open relationships reported more frequent condom use for anal intercourse and lower relationship satisfaction than monogamous participants. NCNM participants reported more HIV testing and lower satisfaction. Identities, experiences, and behaviors within open and other consensually nonmonogamous populations should be regarded as unique and diverse, rather than conflated with those common to other relationship structures. There is a need for greater awareness of diverse relationship structures among researchers and providers, and incorporation of related content into educational programming. PMID- 29696554 TI - Domain-Specific Relationships in Sexual Measures of Impulsive Behavior. AB - Impulsivity is an important construct for understanding sexual behaviors, but behavioral and self-report measures of impulsivity often are not correlated. One possible explanation for this is that there is little shared variance in the measures because behavioral measures index impulsivity by asking questions about monetary preferences, while self-report measures index impulsivity by asking about a broad range of real-world outcomes (including those of a sexual nature) largely unrelated to money-related preferences. Undergraduate students (total N = 105; female n = 77, male n = 28) completed laboratory measures-delay discounting (DD) and probability discounting (PD)-for two different outcomes-money and sexual activity. Participants also completed the Delaying Gratification Inventory (DGI), which measures difficulty with delaying gratification (i.e., impulsivity) across different domains, including money and physical pleasures. Findings indicated that DD and PD for money were not related to any of the DGI subscales. However, DD for sexual activity was significantly related to the DGI Physical Pleasures subscale, but not other subscales. These findings suggest that the relationship between behavioral and self-report measures of impulsive choice may be stronger when both are measuring domain-specific rather than domain-general behavioral patterns, but further research is warranted. PMID- 29696553 TI - Associations Between Neighborhood Characteristics, Social Cohesion, and Perceived Sex Partner Risk and Non-Monogamy Among HIV-Seropositive and HIV-Seronegative Women in the Southern U.S. AB - Neighborhood social and physical factors shape sexual network characteristics in HIV-seronegative adults in the U.S. This multilevel analysis evaluated whether these relationships also exist in a predominantly HIV-seropositive cohort of women. This cross-sectional multilevel analysis included data from 734 women enrolled in the Women's Interagency HIV Study's sites in the U.S. South. Census tract-level contextual data captured socioeconomic disadvantage (e.g., tract poverty), number of alcohol outlets, and number of non-profits in the census tracts where women lived; participant-level data, including perceived neighborhood cohesion, were gathered via survey. We used hierarchical generalized linear models to evaluate relationships between tract characteristics and two outcomes: perceived main sex partner risk level (e.g., partner substance use) and perceived main sex partner non-monogamy. We tested whether these relationships varied by women's HIV status. Greater tract-level socioeconomic disadvantage was associated with greater sex partner risk (OR 1.29, 95% CI 1.06-1.58) among HIV seropositive women and less partner non-monogamy among HIV-seronegative women (OR 0.69, 95% CI 0.51-0.92). Perceived neighborhood trust and cohesion was associated with lower partner risk (OR 0.83, 95% CI 0.69-1.00) for HIV-seropositive and HIV seronegative women. The tract-level number of alcohol outlets and non-profits were not associated with partner risk characteristics. Neighborhood characteristics are associated with perceived sex partner risk and non-monogamy among women in the South; these relationships vary by HIV status. Future studies should examine causal relationships and explore the pathways through which neighborhoods influence partner selection and risk characteristics. PMID- 29696555 TI - Desmopressin-Induced Severe Hyponatremia with Central Pontine Myelinolysis: A Case Report. AB - Desmopressin, a synthetic vasopressin analog, is used to treat central diabetes insipidus, hemostatic disorders such as von Willebrand's disease, and nocturnal enuresis. We present the case of a 69-year-old man who developed severe hyponatremia during treatment with intranasal desmopressin at 10 ug twice daily for chronic polyuria and nocturia thought to be due to central diabetes insipidus. After 5 months of therapy, the patient noticed progressive fatigue, anorexia, dizziness, weakness, light-headedness, decreased concentration, and new onset falls. At 6 months of therapy, the patient was brought to the emergency department for altered mental status and was found to be severely hyponatremic with a serum sodium level of 96 mmol/L, down from a value of 134 mmol/L at the initiation of therapy. The intranasal desmopressin was discontinued and the patient was admitted to the intensive care unit where the hyponatremia was slowly corrected over the next week to 132 mmol/L, never increasing by more than 8 mmol/L a day, with careful fluid management. This included infusion of over 11 L of 5% dextrose to account for a high urine output, which peaked at 7.4 L in 1 day. However, while the recommended rate for sodium correction was followed, the patient's magnetic resonance imaging of the brain obtained after discharge displayed evidence of central pontine myelinolysis. Despite this finding, the patient eventually returned to his baseline mental status with no permanent neurologic deficits. PMID- 29696557 TI - In recognition of Ireland's doctor scientists: Richard Costello, Christopher Thompson, Fidelma Dunne and Douglas Veale. PMID- 29696556 TI - Long-term effect of testosterone replacement therapy on bone in hypogonadal men with Klinefelter Syndrome. AB - PURPOSE: To assess different aspects of bone damage in untreated adult patients with Klinefelter Syndrome (KS) before and during testosterone replacement therapy (TRT). METHODS: Fifteen untreated hypogonadal men with KS and 26 control subjects (C) matched for age and BMI were recruited. Sex hormone levels were measured in all subjects. Lumbar spine (LS) and femoral (neck: FN and total hip: TH) bone mineral density (BMD), trabecular bone score (TBS), hip structure analysis (HSA) and fat measures (percentage of fat mass, android/gynoid ratio and visceral adipose tissue) were evaluated by DEXA. In KS patients, blood analysis and DEXA measurements were assessed at baseline and repeated yearly for three years during TRT. RESULTS: Fat measures were significantly higher in KS than C (p < 0.01). In contrast, mean LS, FN and TH BMD were significantly reduced in KS compared to C (p < 0.01), while there was no difference in TBS. HSA revealed a significantly lower cortical thickness and significantly higher buckling ratio in KS compared to C at all femoral sites (p < 0.01). In KS patients, TRT significantly increased BMD at LS only, but did not improve TBS and HSA parameters. Fat measures were inversely associated with TBS values, and TRT did not influence this relationship. CONCLUSIONS: In untreated hypogonadal men with KS, lumbar and femoral BMD was reduced, and femoral bone quality was impaired. Adiposity seemed to have a detrimental effect on lumbar bone microarchitecture, as indirectly evaluated by TBS. However, TRT failed to remedy these negative effects on bone. PMID- 29696558 TI - Festschrift for Professor Ronan O'Connell. PMID- 29696559 TI - To tube or not to tube? Utilising a tubeless antegrade ureteric stenting system in a tertiary referral hospital. AB - INTRODUCTION: To assess the benefits and complications of developing a practice of single-stage primary ureteral stenting in a university hospital. METHODS: A practice change developed from the traditional practice of multi-stage stenting to single-episode stent placement. To evaluate this change of practice, we retrospectively analysed data of 70 patients who underwent primary tubeless antegrade ureteric stenting and compared this group to the previous 54 patients who had a covering nephrostomy. RESULTS: There was an overall success rate of 91.3% (85/93 stents having had tubeless antegrade stenting). There were no major and 33 minor complications. The comparative group of 54 patients whose stents had a covering nephrostomy had a median length of stay of 13.2 days compared to 7.4 days for the tubeless group. CONCLUSION: Single-stage primary ureteric stenting is a safe practice to employ and has universal benefits for both the patient and the health service. PMID- 29696560 TI - Prevention of Excessive Gestational Weight Gain and Postpartum Weight Retention. AB - PURPOSE OF REVIEW: The purpose of this review is to summarize the current evidence on the prevention of excessive gestational weight gain (GWG) and reduction of postpartum weight retention (PPWR) by lifestyle intervention and pharmacotherapy. RECENT FINDINGS: Recent findings demonstrate that tailored nutrition counseling and adapting certain eating patterns, supervised exercise programs aiming at achieving at least moderate level of physical activity, and interactive and monitored behavior change interventions are effective in reducing excessive GWG and PPWR. Among the pharmacologic agents, Metformin has been shown to reduce GWG. Excessive GWG and PPWR are associated with adverse maternal and neonatal outcomes. Recent evidence shows that weight during gestation and the postpartum period can be significantly reduced by more frequent nutrition counseling sessions on balanced diet focusing on healthier food choices and eating patterns, supervised moderate-intensity exercise for at least 30 min three times a week, and interactive behavior change interventions with regular feedback and follow-up. The benefits on weight are seen when these interventions are utilized together in a multimodality approach. Metformin is effective in preventing excessive GWG but has no impact on neonatal outcomes. PMID- 29696561 TI - Comparing Quality of Care in Veterans Affairs and Non-Veterans Affairs Settings. AB - BACKGROUND: Congress, veterans' groups, and the press have expressed concerns that access to care and quality of care in Department of Veterans Affairs (VA) settings are inferior to access and quality in non-VA settings. OBJECTIVE: To assess quality of outpatient and inpatient care in VA at the national level and facility level and to compare performance between VA and non-VA settings using recent performance measure data. MAIN MEASURES: We assessed Patient Safety Indicators (PSIs), 30-day risk-standardized mortality and readmission measures, and ORYX measures for inpatient safety and effectiveness; Healthcare Effectiveness Data and Information Set (HEDIS(r)) measures for outpatient effectiveness; and Consumer Assessment of Healthcare Providers and Systems Hospital Survey (HCAHPS) and Survey of Healthcare Experiences of Patients (SHEP) survey measures for inpatient patient-centeredness. For inpatient care, we used propensity score matching to identify a subset of non-VA hospitals that were comparable to VA hospitals. KEY RESULTS: VA hospitals performed on average the same as or significantly better than non-VA hospitals on all six measures of inpatient safety, all three inpatient mortality measures, and 12 inpatient effectiveness measures, but significantly worse than non-VA hospitals on three readmission measures and two effectiveness measures. The performance of VA facilities was significantly better than commercial HMOs and Medicaid HMOs for all 16 outpatient effectiveness measures and for Medicare HMOs, it was significantly better for 14 measures and did not differ for two measures. High variation across VA facilities in the performance of some quality measures was observed, although variation was even greater among non-VA facilities. CONCLUSIONS: The VA system performed similarly or better than the non-VA system on most of the nationally recognized measures of inpatient and outpatient care quality, but high variation across VA facilities indicates a need for targeted quality improvement. PMID- 29696562 TI - Pseudocirrhosis after chemotherapy in breast cancer, case reports. AB - Pseudocirrhosis is a rare hepatic complication of chemotherapy, which is morphological changes in hepatic contour that closely mimic cirrhosis. Like in classic cirrhosis, portal hypertension is common in patients with this condition. The mechanism of pseudocirrhosis is unknown to date. We report three cases of pseudocirrhosis arising in the setting of regression of breast cancer liver metastases. All the cases underwent systemic chemotherapy, and all had remarkable responses. Their hormone receptor statuses were all positive and Her2/neu statuses were all negative. They were all treated with cytotoxic chemotherapeutic agent and also hormone therapy. This report suggests clinicians should have pseudocirrhosis in mind when hormone therapy and cytotoxic chemotherapy are jointly administered. PMID- 29696563 TI - A mathematical prediction model incorporating molecular subtype for risk of non sentinel lymph node metastasis in sentinel lymph node-positive breast cancer patients: a retrospective analysis and nomogram development. AB - BACKGROUND: Molecular subtype of breast cancer is associated with sentinel lymph node status. We sought to establish a mathematical prediction model that included breast cancer molecular subtype for risk of positive non-sentinel lymph nodes in breast cancer patients with sentinel lymph node metastasis and further validate the model in a separate validation cohort. METHODS: We reviewed the clinicopathologic data of breast cancer patients with sentinel lymph node metastasis who underwent axillary lymph node dissection between June 16, 2014 and November 16, 2017 at our hospital. Sentinel lymph node biopsy was performed and patients with pathologically proven sentinel lymph node metastasis underwent axillary lymph node dissection. Independent risks for non-sentinel lymph node metastasis were assessed in a training cohort by multivariate analysis and incorporated into a mathematical prediction model. The model was further validated in a separate validation cohort, and a nomogram was developed and evaluated for diagnostic performance in predicting the risk of non-sentinel lymph node metastasis. Moreover, we assessed the performance of five different models in predicting non-sentinel lymph node metastasis in training cohort. RESULTS: Totally, 495 cases were eligible for the study, including 291 patients in the training cohort and 204 in the validation cohort. Non-sentinel lymph node metastasis was observed in 33.3% (97/291) patients in the training cohort. The AUC of MSKCC, Tenon, MDA, Ljubljana, and Louisville models in training cohort were 0.7613, 0.7142, 0.7076, 0.7483, and 0.671, respectively. Multivariate regression analysis indicated that tumor size (OR = 1.439; 95% CI 1.025-2.021; P = 0.036), sentinel lymph node macro-metastasis versus micro-metastasis (OR = 5.063; 95% CI 1.111-23.074; P = 0.036), the number of positive sentinel lymph nodes (OR = 2.583, 95% CI 1.714-3.892; P < 0.001), and the number of negative sentinel lymph nodes (OR = 0.686, 95% CI 0.575-0.817; P < 0.001) were independent statistically significant predictors of non-sentinel lymph node metastasis. Furthermore, luminal B (OR = 3.311, 95% CI 1.593-6.884; P = 0.001) and HER2 overexpression (OR = 4.308, 95% CI 1.097-16.912; P = 0.036) were independent and statistically significant predictor of non-sentinel lymph node metastasis versus luminal A. A regression model based on the results of multivariate analysis was established to predict the risk of non-sentinel lymph node metastasis, which had an AUC of 0.8188. The model was validated in the validation cohort and showed excellent diagnostic performance. CONCLUSIONS: The mathematical prediction model that incorporates five variables including breast cancer molecular subtype demonstrates excellent diagnostic performance in assessing the risk of non sentinel lymph node metastasis in sentinel lymph node-positive patients. The prediction model could be of help surgeons in evaluating the risk of non-sentinel lymph node involvement for breast cancer patients; however, the model requires further validation in prospective studies. PMID- 29696564 TI - A phase I/II randomized, controlled, clinical trial for assessment of the efficacy and safety of beta-D-mannuronic acid in rheumatoid arthritis patients. AB - BACKGROUND: Following the potent efficacy of beta-D-mannuronic acid (M2000) in phase I/II trial in ankylosing spondylitis patients, the present clinical trial was conducted to evaluate the efficacy, safety, and tolerability of this novel drug in rheumatoid arthritis (RA) patients who had inadequate response to conventional therapy. METHOD: The study was a 12-week randomized, controlled, phase I/II clinical trial with two treatment arms: M2000 and conventional treatment. Patients who had RA according to the modified American College of Rheumatology (ACR) criteria, with active disease at baseline also inadequate response to conventional therapy, were enrolled in this study. M2000 was administrated at a dose of two capsules (500 mg) per day orally during a period of 12 weeks. The primary endpoint was the proportion of patients fulfilling the ACR 20% improvement criteria after 12 weeks of M2000 therapy. Moreover, the patients were also followed up for safety. RESULTS: There were no statistically significant differences between treatment and conventional groups at baseline characteristics. The ACR20 response rate was significantly higher among M2000 treated patients than conventional-treated control, so that 74% of patients in treatment group showed an ACR20 response after 12 weeks of M2000 therapy (74 versus 16%; P = 0.011). 10% of M2000-treated patients and 57.1% of conventional treated patient's adverse events occurred during this study. CONCLUSION: Treatment with M2000 in combination with conventional therapy showed a significantly superior efficacy along with a high safety profile compared to conventional-treated patients. Thereby, M2000 might be suggested as a suitable option in the treatment of RA. PMID- 29696565 TI - Emerging role of semaphorin-3A in autoimmune diseases. AB - Autoimmune diseases (ADs) are featured by the body's immune responses being directed against its own tissues, resulting in prolonged inflammation and subsequent tissue damage. Currently, the exact pathogenesis of ADs remains not fully elucidated. Semaphorin-3A (Sema3A), a secreted member of semaphorin family, is a potent immunoregulator during all immune response stages. Sema3A has wide expression, such as in bone, connective tissue, kidney, neurons, and cartilage. Sema3A can downregulate ADs by suppressing the over-activity of both T-cell and B cell autoimmunity. Moreover, Sema3A shows the ability to enhance T-cell and B cell regulatory properties that control ADs, including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, and systemic sclerosis. However, it can also induce ADs when overexpressed. Together, these data strongly suggest that Sema3A plays a pivotal role in ADs, and it may be a promising treatment target for these diseases. In the present review, we focus on the immunological functions of Sema3A and summarize recent studies on the involvement of Sema3A in the pathogenesis of ADs; the discoveries obtained from recent findings may translate into novel therapeutic agent for ADs. PMID- 29696567 TI - Factors Influencing the Prescribing Preferences of Physicians for Drug-Naive Patients with Type 2 Diabetes Mellitus in the Real-World Setting in Japan: Insight from a Web Survey. AB - INTRODUCTION: The Japanese guidelines for type 2 diabetes mellitus (T2DM) emphasize individualization of treatment based on patient need and encourage physicians to select an appropriate oral antidiabetes drug (OAD). However, limited evidence is available on the factors influencing the selection by physicians (diabetes specialists and nonspecialists) of the first-line OAD to treat drug-naive patients with T2DM. A survey was designed to explore the treatment factors and patient characteristics that influence physicians when they choose an initial OAD to prescribe to a drug-naive patient with T2DM in a real world setting in Japan. METHODS: The 25-min web-based online survey consisted of simple and focused multiple-choice questions, and was circulated to physicians across eight selected regions in Japan. The primary endpoints were the proportions of physicians who considered particular treatment factors and patient characteristics when selecting the appropriate treatment for drug-naive T2DM patients. RESULTS: A total of 491 physicians participated in the survey. Dipeptidyl peptidase-4 inhibitors (DPP-4is) were the most-preferred first-line OADs, followed by metformin, of both specialists (69% vs. 60%) and nonspecialists (73% vs. 47%). The most influential factors when a DPP-4i was selected were found to be glycated hemoglobin (HbA1c), postprandial glucose (PPG)-lowering effect, and a low risk of hypoglycemia, which were considered by > 80% of physicians, whereas the key factors when metformin was selected were improvement in insulin resistance, low cost, low risk of hypoglycemia, and PPG- and HbA1c-lowering effects, which were considered by > 85% of physicians. Regression analysis revealed that the dominant reason for choosing DPP-4is over metformin was their ease of use in patients with renal impairment, whereas the dominant reasons for choosing metformin over DPP-4is were improvement in insulin resistance and low cost. The key patient characteristics driving the choice of DPP-4is or metformin as the first-line OAD by physicians were similar to those that influenced the treatment intensification decision (DPP-4is: PPG and renal function; metformin: age, BMI, insulin resistance, and renal function). CONCLUSION: In Japan, DPP-4is are the preferred first-line OADs, followed by metformin. The key treatment factors and patient characteristics considered when selecting DPP-4is or metformin are similar for both specialists and nonspecialists. These results may prompt further discussion of the differences in T2DM treatment between Japan and other counties. FUNDING: Novartis. PMID- 29696566 TI - Outcomes of ultrasound guided renal mass biopsies. AB - PURPOSE: The purpose of this study was to evaluate the rate of nondiagnostic ultrasound-guided renal mass biopsies (RMBs) at our institution and to determine what patient, procedural, and focal renal mass (FRM) factors were associated with nondiagnostic ultrasound-guided RMBs. METHODS: Eighty-two ultrasound-guided renal mass biopsies performed between January 2014 and October 2016 were included in our study. Biopsy outcomes (diagnostic vs. nondiagnostic) and patient, procedural, and FRM characteristics were retrospectively reviewed and recorded. Univariate statistical analyses were performed to identify biopsy characteristics that were indicative of nondiagnostic biopsy. RESULTS: Ultrasound-guided RMBs were diagnostic in 70 out of 82 cases (85%) and non-diagnostic in 12 cases (15%). Among the diagnostic biopsies, 54 (77%) were malignant cases, 94% of which were renal cell carcinoma (RCC). Of the 12 nondiagnostic cases, the final diagnosis was RCC in 4 cases and angiomyolipoma in one case; seven of the nondiagnostic cases were lost to follow-up. A weak association (p = 0.04) was found between the number of needle passes and the biopsy outcome. None of the remaining collected RMB characteristics showed a significant correlation with a diagnostic or nondiagnostic RMB. Six patients (7%) experienced complications. CONCLUSION: Ultrasound-guided renal mass biopsy is a safe and effective method for the diagnosis of renal masses with a low rate of nondiagnostic outcomes. A nondiagnostic biopsy should not be treated as a surrogate for a diagnosis since a significant number of patients with nondiagnostic biopsies have subsequently been shown to have renal malignancies. Repeat biopsy should be considered in such cases. PMID- 29696568 TI - The relationship between adiposopathy and glucose-insulin homeostasis is not affected by moderate-intensity aerobic training in healthy women with obesity. AB - The contribution of adiposopathy to glucose-insulin homeostasis remains unclear. This longitudinal study examined the potential relationship between the adiponectin/leptin ratio (A/L, a marker of adiposopathy) and insulin resistance (IR: homeostasis model assessment (HOMA)), insulin sensitivity (IS: Matsuda), and insulin response to an oral glucose tolerance test before and after a 16-week walking program, in 29 physically inactive pre- and postmenopausal women with obesity (BMI, 29-35 kg/m2; age, 47-54 years). Anthropometry, body composition, VO2max, and fasting lipid-lipoprotein and inflammatory profiles were assessed. A/L was unchanged after training (p = 0.15), despite decreased leptin levels (p < 0.05). While the Matsuda index tended to increase (p = 0.07), HOMA decreased (p < 0.05) and fasting insulin was reduced (p < 0.01) but insulin area under the curve (AUC) remained unchanged (p = 0.18) after training. Body fatness and VO2max were improved (p < 0.05) while triacylglycerols increased and HDL-CHOL levels decreased after training (p < 0.05). At baseline, A/L was positively associated with VO2max, HDL-CHOL levels, and Matsuda (0.37 < rho < 0.56; p < 0.05) but negatively with body fatness, HOMA, insulin AUC, IL-6, and hs-CRP levels (- 0.41 < rho < - 0.66; p < 0.05). After training, associations with fitness, HOMA, and inflammation were lost. Multiple regression analysis revealed A/L as an independent predictor of IR and IS, before training (partial R2 = 0.10 and 0.22), although A/L did not predict the insulin AUC pre- or post-intervention. A significant correlation was found between training-induced changes to A/L and IS (r = 0.38; p < 0.05) but not with IR or insulin AUC. Although changes in the A/L ratio could not explain improvements to glucose-insulin homeostasis indices following training, a relationship with insulin sensitivity was revealed in healthy women with obesity. PMID- 29696569 TI - Facile ring opening reaction of oxazolone enables efficient amidation for aminoisobutyric acid. AB - 4,4-Dimethyloxazolones derived from N-protected aminoisobutyric acid (AIB) are particularly known as poor electrophiles due to the steric hindrance around the carbonyl and not employed as useful intermediates for amidation whereas numerous examples have been reported to support the utility of other oxazolones in amidation. AIB is an important and strategical synthon in medicinal chemistry but the peptide bond formation of the N-protected urethane derivatives of AIB is known to be often unproductive due to the rapid formation of the stable 4,4 dimethyloxazolone via an intramolecular cyclization. We discovered that the 4,4 dimethyloxazolone of an AIB urethane is in fact an excellent electrophile that enables efficient amidation even with weakly reactive nucleophiles. The 4,4 dimethyloxazolone can be stored in a pure form and used as a reagent offering an efficient and convenient synthetic tool for generating AIB-peptide analogs. PMID- 29696570 TI - Cueing listeners to attend to a target talker progressively improves word report as the duration of the cue-target interval lengthens to 2,000 ms. AB - Endogenous attention is typically studied by presenting instructive cues in advance of a target stimulus array. For endogenous visual attention, task performance improves as the duration of the cue-target interval increases up to 800 ms. Less is known about how endogenous auditory attention unfolds over time or the mechanisms by which an instructive cue presented in advance of an auditory array improves performance. The current experiment used five cue-target intervals (0, 250, 500, 1,000, and 2,000 ms) to compare four hypotheses for how preparatory attention develops over time in a multi-talker listening task. Young adults were cued to attend to a target talker who spoke in a mixture of three talkers. Visual cues indicated the target talker's spatial location or their gender. Participants directed attention to location and gender simultaneously ("objects") at all cue target intervals. Participants were consistently faster and more accurate at reporting words spoken by the target talker when the cue-target interval was 2,000 ms than 0 ms. In addition, the latency of correct responses progressively shortened as the duration of the cue-target interval increased from 0 to 2,000 ms. These findings suggest that the mechanisms involved in preparatory auditory attention develop gradually over time, taking at least 2,000 ms to reach optimal configuration, yet providing cumulative improvements in speech intelligibility as the duration of the cue-target interval increases from 0 to 2,000 ms. These results demonstrate an improvement in performance for cue-target intervals longer than those that have been reported previously in the visual or auditory modalities. PMID- 29696571 TI - Suppression and dissolution of amyloid aggregates using ionic liquids. AB - Amyloid aggregates are composed of protein fibrils with a dominant beta-sheet structure, are water-insoluble, and are involved in the pathogenesis of many neurodegenerative diseases. Development of pharmaceuticals to treat these diseases and the design of recovery agents for amyloid-type inclusion bodies require the successful suppression and dissolution of such aggregates. Since ionic liquids (ILs) are composed of both a cation and anion and are known to suppress protein aggregation and to dissolve water-insoluble compounds such as cellulose; they may also have potential use as suppression/dissolution agents for amyloid aggregates. In the following review, we present the suppression and dissolution effects of ILs on amyloid aggregates so far reported. The protein-IL affinity (the ability of ILs to interact with amyloid proteins) was found to be the biochemical basis for ILs' suppression of amyloid formation, and the hydrogen bonding basicity of ILs might be the basis for their ability to dissolve amyloid aggregates. These findings present the potential of ILs to serve as novel pharmaceuticals to treat neurodegenerative diseases and as recovery agents for various amyloid aggregates. PMID- 29696572 TI - Comparison of Early Morbidity and Mortality Between Sleeve Gastrectomy and Gastric Bypass in High-Risk Patients for Liver Disease: Analysis of American College of Surgeons National Surgical Quality Improvement Program. AB - INTRODUCTION: Chronic liver disease is prevalent in obese patients presenting for bariatric surgery and is associated with increased postoperative morbidity and mortality (M&M). There are no comparative studies on the safety of different types of bariatric operations in this subset of patients. OBJECTIVE: The aim of this study is to compare the 30-day postoperative M&M between laparoscopic sleeve gastrectomy (LSG) and laparoscopic Roux-Y-gastric bypass (LRYGB) in the subset of patients with a model of end-stage liver disease (MELD) score >= 8. METHODS: Data for LSG and LRYGB were extracted from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database from years 2012 and 2013. MELD score was calculated using serum creatinine, bilirubin, INR, and sodium. Postoperative M&M were assessed in patients with a score >= 8 and compared for the type of operation. This was followed by analysis for MELD subcategories. Multiple logistic regression was performed to adjust for confounders. RESULTS: Out of 34,169, 9.8% of cases had MELD >= 8 and were included. Primary endpoint, 30-day M&M, was significantly lower post-LSG (9.5%) compared to LRYGB (14.7%); [AOR = 0.66(0.53, 0.83)]. Superficial wound infection, prolonged hospital stay, and unplanned readmission were more common in LRYGB. M&M post-LRYGB (30.6%) was significantly higher than LSG (15.7%) among MELD15-19 subgroup analysis. CONCLUSION: LRYGB is associated with a higher postoperative risk than LSG in patients with MELD >= 8. The difference in postoperative complications between procedures was magnified with higher MELD. This suggests that LSG might be a safer option in morbidly obese patients with higher MELD scores, especially above 15. PMID- 29696573 TI - ReShape Intragastric Balloon Complicated by Gastric Perforation and Peritonitis. AB - BACKGROUND: Obesity is a growing global epidemic with tremendous financial burden and health care costs worldwide. Restrictive surgery has emerged as the definitive treatment option to combat morbid obesity and its associated comorbidities. The advent of endoscopy has new grounds in obesity with the introduction of inflatable balloon placed in the stomach that decreases satiety by volume restriction. MATERIALS AND METHODS: We report a first case of gastric perforation with peritonitis after ReShape intragastric balloon placement that needed emergent surgical intervention. Decision was made to proceed with exploratory laparotomy, device deflation, and removal with subsequent gastric defect repair. RESULTS: Postoperative period was uneventful, drain was removed on postoperative day 2, and patient tolerated diet and was discharged home subsequently. Biopsy of the perforation site demonstrated mild non-specific chronic gastritis. CONCLUSION: In the modern era of minimal invasiveness, any new approach would roar popularity among patients and hence is of utmost importance for clinicians to be constantly educated on scientific research and innovations in their field. PMID- 29696574 TI - Optimising the Bariatric Patients' Outcome through Cardiac Rehabilitation Approach. AB - Bariatric surgery offers a therapeutic alternative with favourable weight management, cardiovascular, metabolic and functional outcomes. Bariatric individuals often have functional impairments pre-operatively that can be addressed to improve post-operative results and eventual functional independence. Multidisciplinary team offers the best approach to address peri-operative needs and sustainable weight loss thereafter. We exemplified the application of cardiac rehabilitation therapeutic model in managing two bariatric clients with specific bariatric-related challenges. Our approach focuses on adaptive physical activity, sustainable lifestyle changes to promote post-operative weight loss through education and problem solving as well as secondary prevention of cardiovascular disease. Putting emphasis on addressing physical and psychosocial barriers towards physical activity alongside nutritional aspects potentially confers sustained if not better outcomes on weight reduction and functional improvement. PMID- 29696575 TI - Prototype screwdriver stopper to avoid intracranial penetration injury. AB - Screwdriver slipping from the tapping screw head (screwdriver slip) represents a very dangerous situation that leads to the risk of entry into the intracranial operation field. We have developed a screwdriver stopper device to attach to the top of the screwdriver in order to prevent intracranial penetration injuries. We performed 48 craniotomies in our institute. The instrument is made from clear acrylic with a central hole (diameter, 3 mm). We checked the number of screwdriver slip events, as a precursor to intracranial penetration injury, in screwdrivers from five different companies, and compared the results. We used 496 tapping screws in 512 tightening procedures. Although screwdriver slip occurred at an overall rate of 17/512(3.3%), we completely avoided serious intracranial penetration injuries. No significant differences in rates of screwdriver slip were seen between the five companies (chi2 test, p = 0.997). Screwdriver slip is a precursor to intracranial penetration injury, but cannot be avoided with cross type screwdrivers. Many neurosurgeons may be operating without knowledge of the potential risk of intracranial penetration injury. The screwdriver stopper described herein may prove extremely useful for preventing intracranial penetration injuries during neurological surgery. PMID- 29696576 TI - Measuring Variation Across Dimensions of Integrated Care: The Maryland Medicaid Health Home Model. AB - Despite the proliferation of initiatives to integrate services for people with serious mental illness (SMI), measures of distinct dimensions of integration, such as spatial arrangement and care team expertise, are lacking. Such measures are needed to support organizations' assessment of progress toward integrated service delivery. We developed measures characterizing integration of behavioral, somatic, and social services to operationalize the integrated care dimensions conceived by the Agency for Healthcare Research and Quality. In a survey fielded to 46 Maryland Medicaid health homes (response rate: 96%) serving adults with SMI during 2015-2016, we found that these measures provided a useful description of variation across dimensions of integration. PMID- 29696577 TI - Expression of the serotonin receptor 2B in uveal melanoma and effects of an antagonist on cell lines. AB - Uveal melanoma (UM) is the most common primary tumor in the adult, and disseminates to the liver in half of patients. A 15-gene expression profile prognostic assay allows to determine the likelihood of metastasis in patients using their ocular tumor DNA, but a cure still remains to be discovered. The serotonin receptor 2B represents the discriminant gene of this molecular signature with the greatest impact on the prognosis of UM. However, its contribution to the metastatic potential of UM remains unexplored. The purpose of this study was to investigate the effects of a selective serotonin receptor 2B antagonist on cellular and molecular behaviours of UM cells. UM cell lines expressing high level of serotonin receptor 2B proteins were selected by Western blotting. The selective serotonin receptor 2B antagonist PRX-08066 was evaluated for its impact on UM cells using viability assays, phosphorylated histone H3 immunostainings, clonogenic assays, migration assays, invasion assays and membrane-based protein kinase phosphorylation antibody arrays. The pharmacological inhibition of the serotonin receptor 2B reduced the viability of UM cells and the population in mitosis, and impaired their clonogenicity and potential of migration. It also decreased the phosphorylation of kinases from signaling pathways classically activated by the serotonin receptor 2B, as well as kinases beta-catenin, Proline-rich tyrosine kinase 2, and Signal transducer and activator of transcription 5. Our findings support a role for the serotonin receptor 2B in the proliferation and migration of UM cells, through activation of many signaling pathways such as WNT, Focal adhesion kinase and Janus kinase/STAT. PMID- 29696578 TI - Motor function declines over time in human immunodeficiency virus and is associated with cerebrovascular disease, while HIV-associated neurocognitive disorder remains stable. AB - HIV-associated neurocognitive disorders (HAND) remain prevalent in the combined antiretroviral therapy (CART) era, especially the milder forms. Despite these milder phenotypes, we have shown that motor abnormalities persist and have quantified them with the HIV Dementia Motor Scale (HDMS). Our objectives were to replicate, in an independent sample, our prior findings that the HDMS is associated with cognitive impairment in HIV, while adding consideration of age associated comorbidities such as cerebrovascular disease, and to examine the longitudinal trajectories of cognitive and motor dysfunction. We included all participants enrolled in the Manhattan HIV Brain Bank (MHBB) from January 2007 to May 2017 who had complete baseline data (N = 164). MHBB participants undergo standardized longitudinal assessments including documentation of comorbidities and medications, blood work, the HDMS, and neurocognitive testing. We found that motor dysfunction, cognitive impairment, and cerebrovascular disease were significantly associated with each other at baseline. Cerebrovascular disease independently predicted cognitive impairment in a multivariable model. Longitudinal analysis in a subset of 78 participants with >= 4 years of follow-up showed a stable cognition but declining motor function. We conclude that the HDMS is a valid measurement of motor dysfunction in HIV-infected patients and is associated with cognitive impairment and the presence of cerebrovascular disease. Cognitive impairment is mild and stable in CART-treated HIV; however, motor function declines over time, which may be related to the accrual of comorbidities such as cerebrovascular disease. Further research should examine the mechanisms underlying motor dysfunction in HIV and its clinical impact. PMID- 29696579 TI - Does intra-individual neurocognitive variability relate to neuroinvasive disease and quality of life in West Nile Virus? AB - West Nile Virus (WNV) can be a neuroinvasive pathogen that may produce persistent mild-to-moderate neurocognitive impairments in some infected persons. Intra individual variability (IIV) is an index of a person's performance across a neuropsychological test or battery, which is an indicator of neurocognitive control and integrity of prefrontal systems. The present study examined possible associations of IIV to neurological health and well-being in WNV infection. Participants included 84 adults with a range of clinical WNV disease (31 West Nile Encephalitis, 16 West Nile Meningitis, 37 West Nile Fever) who completed the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). IIV was operationalized as covariance of variation (CoV), or the intra-individual standard deviation across 5 age-adjusted RBANS standard scores divided by the mean of standard scores. Participants were assessed for health-related quality of life (QoL) using the RAND 36-item short form health survey (SF-36). Analyses revealed that the West Nile Encephalitis group had higher neurocognitive CoV compared to the West Nile Fever group, and this difference was associated with a medium effect size (Cohen's d = .52). Mixed linear models controlling for estimated IQ, activities of daily living, depression, neuroinvasive disease groups, and fatigue showed that higher RBANS CoV was associated with lower physical, but not mental health QoL. In persons with WNV infection, there is a modest association between elevations in IIV and encephalitis, and even subtle disruptions in neuropsychological functioning show relationships with important self-reported functioning as measured by physical health quality of life. Future studies should examine whether IIV predicts long-term health outcomes (e.g., mortality) in individuals infected with WNV. PMID- 29696580 TI - Hypermnesia and the Role of Delay between Study and Test. AB - Hypermnesia is increased recall across repeated tests in the absence of any further study opportunities. Although over the years many factors have been identified that influence hypermnesia, to date not much is known about the role of delay between study and test for the effect. This study addressed the issue in four experiments. Employing both words and pictures as study material, we compared hypermnesia after shorter delay (3 min or 11.5 min) and longer delay (24 h or 1 week) between study and test. Recall occurred over three successive tests, using both free recall (Experiments 1, 2, and 4) and forced recall testing (Experiment 3). In forced recall tests, subjects are instructed to recall as many items as possible, but if unable to remember all studied items, to fill in the remaining spaces with their best guesses. With free recall testing, hypermnesia increased with delay and the effect was driven mainly by reduced item losses between tests. These results suggest a link between hypermnesia and the testing effect, which shows that demanding retrieval practice, as it happens after longer delay, can improve recall by reducing the forgetting of the practiced items. In contrast, with forced recall testing, hypermnesia decreased with delay and was even absent after longer delay. The findings indicate that recall format can influence hypermnesia and different mechanisms may mediate the effects of repeated testing in the two recall conditions. PMID- 29696581 TI - Potential biomarkers of tissue hypoxia during acute hemodilutional anemia in cardiac surgery: A prospective study to assess tissue hypoxia as a mechanism of organ injury. AB - PURPOSE: Hemodilutional anemia is associated with acute kidney injury (AKI) and mortality in patients undergoing cardiac surgery by mechanisms that may include tissue hypoxia. Our hypothesis was to assess if changes in the potential hypoxic biomarkers, including methemoglobin and erythropoietin, correlated with a decrease in hemoglobin (Hb) concentration following hemodilution on cardiopulmonary bypass (CPB). METHODS: Arterial blood samples were taken from patients (n = 64) undergoing heart surgery and CPB at baseline, during CPB, following CPB, and in the intensive care unit (ICU). Potential hypoxic biomarkers were measured, including methemoglobin, plasma Hb, and erythropoietin. Data were analyzed by repeated measures one-way analysis of variance on ranks and linear regression. RESULTS: Hemoglobin levels decreased following CPB and methemoglobin increased in the ICU (P < 0.001 for both). No correlation was observed between the change in Hb and methemoglobin (P = 0.23). By contrast, reduced Hb on CPB correlated with increased lactate, reduced pH, and increased erythropoietin levels following CPB (P <= 0.004 for all). Increased plasma Hb (P < 0.001) also correlated with plasma erythropoietin levels (P < 0.001). CONCLUSION: These data support the hypothesis that erythropoietin rather than methemoglobin is a potential biomarker of anemia-induced tissue hypoxia. The observed relationships between decreased Hb during CPB and the increase in lactate, reduced pH, and increase in erythropoietin levels suggest that early changes in plasma erythropoietin may be a pragmatic early biomarker of anemia-induced renal hypoxia. Further study is required to determine if anemia-induced increases in erythropoietin may predict AKI in patients undergoing cardiac surgery. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01883713). Registered 21 June 2013. PMID- 29696582 TI - A case of colonic varices complicated by alcoholic cirrhosis treated using balloon-occluded retrograde transvenous obliteration. AB - A 44-year-old man with cirrhosis arising from alcohol abuse manifested melena caused by the rupture of esophageal varices. He received endoscopic variceal ligation for the initial hemostasis, followed by endoscopic injection sclerotherapy as an additional consolidation therapy. A CT examination performed at the time of admission revealed collateral veins developing around the ascending colon, in which the feeding and draining vessels were identified as the superior mesenteric vein and the right testicular vein, respectively. Moreover, large nodular varices were observed in the ascending colon during a colonoscopy. To prevent the rupture of the colonic varices, balloon-occluded retrograde transvenous obliteration (B-RTO) was performed through the right testicular vein using a microballoon catheter. A CT examination performed 4 days after the B-RTO procedure revealed the disappearance of blood flow with thrombosis formation in both the colonic varices and the feeding vein. The varices in the ascending colon had completely disappeared when examined during a colonoscopy performed 4 months after the B-RTO procedure. B-RTO is a useful and minimally invasive procedure for the treatment of colonic varices to prevent bleeding. PMID- 29696583 TI - Fit-for-Purpose Immunohistochemical Biomarkers. AB - There are two aspects of immunohistochemistry (IHC) that are relevant to practicing pathologist: (1) understanding of IHC biomarker panels that are suitable for diagnostic, prognostic and predictive testing, and (2) understanding of IHC quality assurance (QA), which makes sure that the tests in these panels work as they should. The two aspects are closely linked together and call for collaborative approach between pathologists and IHC laboratory technologists as both need to be involved in developing and maintaining IHC biomarkers that are "fit-for-purpose". This article reviews the most current IHC QA concepts that are imminently material to practicing pathologists with emphasis on challenges that are specific to endocrine pathology. PMID- 29696584 TI - How to Spot Congenital Myasthenic Syndromes Resembling the Lambert-Eaton Myasthenic Syndrome? A Brief Review of Clinical, Electrophysiological, and Genetics Features. AB - Congenital myasthenic syndromes (CMS) are heterogeneous genetic diseases in which neuromuscular transmission is compromised. CMS resembling the Lambert-Eaton myasthenic syndrome (CMS-LEMS) are emerging as a rare group of distinct presynaptic CMS that share the same electrophysiological features. They have low compound muscular action potential amplitude that increment after brief exercise (facilitation) or high-frequency repetitive nerve stimulation. Although clinical signs similar to LEMS can be present, the main hallmark is the electrophysiological findings, which are identical to autoimmune LEMS. CMS-LEMS occurs due to deficits in acetylcholine vesicle release caused by dysfunction of different components in its pathway. To date, the genes that have been associated with CMS-LEMS are AGRN, SYT2, MUNC13-1, VAMP1, and LAMA5. Clinicians should keep in mind these newest subtypes of CMS-LEMS to achieve the correct diagnosis and therapy. We believe that CMS-LEMS must be included as an important diagnostic clue to genetic investigation in the diagnostic algorithms to CMS. We briefly review the main features of CMS-LEMS. PMID- 29696585 TI - Improved Bioavailability of Levodopa Using Floatable Spray-Coated Microcapsules for the Management of Parkinson's Disease. AB - Oral administration of levodopa (LD) is the gold standard in managing Parkinson's disease (PD). Although LD is the most effective drug in treating PD, chronic administration of LD induces levodopa-induced dyskinesia. A continuous and sustained provision of LD to the brain could, therefore, reduce peak-dose dyskinesia. In commercial oral formulations, LD is co-administrated with an AADC inhibitor (carbidopa) and a COMT inhibitor (entacapone) to enhance its bioavailability. Nevertheless, patients are known to take up to five tablets a day because of poor sustained-releasing capabilities that lead to fluctuations in plasma concentrations. To achieve a prolonged release of LD with the aim of improving its bioavailability, floatable spray-coated microcapsules containing all three PD drugs were developed. This gastro-retentive delivery system showed sustained release of all PD drugs, at similar release kinetics. Pharmacokinetics study was conducted and this newly developed formulation showed a more plateaued delivery of LD that is void of the plasma concentration fluctuations observed for the control (commercial formulation). At the same time, measurements of LD and dopamine of mice administered with this formulation showed enhanced bioavailability of LD. This study highlights a floatable, sustained-releasing delivery system in achieving improved pharmacokinetics data compared to a commercial formulation. PMID- 29696586 TI - Echo and the Failure of Knowing in Judith Fox's Photographic Project I Still Do: Loving and Living with Alzheimer's. AB - In relationships 'I' and 'you' become 'we'; despite individual differences, couples obtain an interdependent identity due to their shared interactions. During a serious illness, biological and biographical disruptions can put any reciprocal relationship under strain. Through intermedial analysis of Judith Fox's photographic project, I Still Do: Loving and Living with Alzheimer's (2009), I will explore ways the couple make sense of illness, how illness is communicated through text and image and also to identify the limits of representation. Here the photographs, I argue, solidify their relationship and echo the stuck-in-the-present state of mind brought on by Alzheimer's. PMID- 29696587 TI - Chia-Chen Tan and genetics in modern China. PMID- 29696588 TI - Simultaneous and systematic analysis of cellular and viral gene expression during Enterovirus 71-induced host shutoff. PMID- 29696589 TI - Single-cell metagenomics: challenges and applications. AB - With the development of high throughput sequencing and single-cell genomics technologies, many uncultured bacterial communities have been dissected by combining these two techniques. Especially, by simultaneously leveraging of single-cell genomics and metagenomics, researchers can greatly improve the efficiency and accuracy of obtaining whole genome information from complex microbial communities, which not only allow us to identify microbes but also link function to species, identify subspecies variations, study host-virus interactions and etc. Here, we review recent developments and the challenges need to be addressed in single-cell metagenomics, including potential contamination, uneven sequence coverage, sequence chimera, genome assembly and annotation. With the development of sequencing and computational methods, single-cell metagenomics will undoubtedly broaden its application in various microbiome studies. PMID- 29696590 TI - Direct nanodrug delivery for tumor targeting subject to shear-augmented diffusion in blood flow. AB - The advent of multifunctional nanoparticle has enabled numerous innovative strategies in diagnostics, imaging, and cancer therapy. Despite the intense research efforts in developing new nanoparticles and surface bonding ligands, one major obstacle in achieving highly effective treatment, including minimizing detrimental side effects, is the inability to deliver drug-carrying nanoparticles from the injection point directly to the tumor site. The present study seeks to employ a direct nanodrug delivery methodology to feed multifunctional nanoparticles directly to tumor vasculatures, sparing healthy tissue. An important aspect to examine is how the interactions between such nanoparticles and relatively large red blood cells would affect the transport and delivery efficiency of nanodrugs. So, a novel computer simulation model has been developed to study nanoparticle transport in a representative human hepatic artery system, subject to shear-induced diffusion of nanoparticles due to hydrodynamic interactions with red blood cells. The particle-size effect was also evaluated by comparing the dynamics of nanoparticles with microspheres. Results from computer simulations under physiologically realistic conditions indicate that shear induced diffusion has a significant effect on nanoparticle transport, even in large arteries. Nevertheless, as documented, direct nanodrug delivery to tumor feeding hepatic artery branches is feasible. Graphical abstract Direct nanodrug delivery from injection point to tumor-feeding artery branch. PMID- 29696591 TI - Laparoscopic versus robotic adrenalectomy: a review of the national inpatient sample. AB - BACKGROUND: Laparoscopic adrenalectomy (LA) has become the standard treatment of adrenal lesions. Recently, robotic-assisted adrenalectomy (RA) has become an option, however, short-term outcomes for RA have not been well studied and benefits over LA are debatable. The aim of this study was to explore differences in short-term outcomes between LA and RA using the national inpatient sample (NIS) database. METHODS: Patient data were collected from the NIS. All patients undergoing LA or RA from January 2009 to December 2012 were included. Univariate analysis and propensity matching were performed to look for differences between the groups. RESULTS: A total of 1006 patients (66.4% in LA group and 33.6% in RA group) were identified. Patient age group, gender, race, risk of mortality, severity of illness or indication for adrenalectomy did not differ significantly between the LA or RA cohorts. Insurance type predicted procedure type (45% of medicare patients underwent RA versus 29% of patients with private insurance, p < 0.0001). Patients living in the highest income areas were more likely to receive the laparoscopic approach (31.7 versus 17.4%, p < 0.0001). Hospital volume, bed size and teaching status of the hospital were not significant factors in the decision of RA versus LA. There was no difference in complication and conversion rates between RA versus LA. The mean length of stay was shorter in the RA group (2.2 versus 1.9 days, p = 0.03). Total charges were higher in the RA group ($42,659 versus $33,748, p < 0.0001). There was a significant trend towards more adrenalectomies being performed robotic assisted by year. Only 22% of adrenalectomies were performed robotic-assisted in 2009 compared with 48% in 2012. CONCLUSIONS: The overall benefit for RA remains small and higher total charges for RA may currently outweigh the benefits. These findings may change as more cases are performed robotically assisted and robotic technology improves. PMID- 29696592 TI - Erratum to: Imaging of Microglial Activation in Alzheimer's Disease by [11C]PBR28 PET. PMID- 29696593 TI - Reading sentences of uniform word length - II: Very rapid adaptation of the preferred saccade length. AB - In the current study we investigated whether readers adjust their preferred saccade length (PSL) during reading on a trial-by-trial basis. The PSL refers to the distance between a saccade launch site and saccade target (i.e., the word center during reading) when participants neither undershoot nor overshoot this target (McConkie, Kerr, Reddix, & Zola in Vision Research, 28, 1107-1118, 1988). The tendency for saccades longer or shorter than the PSL to under or overshoot their target is referred to as the range error. Recent research by Cutter, Drieghe, and Liversedge (Journal of Experimental Psychology: Human Perception and Performance, 2017) has shown that the PSL changes to be shorter when readers are presented with 30 consecutive sentences exclusively made of three-letter words, and longer when presented with 30 consecutive sentences exclusively made of five letter words. We replicated and extended this work by this time presenting participants with these uniform sentences in an unblocked design. We found that adaptation still occurred across different sentence types despite participants only having one trial to adapt. Our analyses suggested that this effect was driven by the length of the words readers were making saccades away from, rather than the length of the words in the rest of the sentence. We propose an account of the range error in which readers use parafoveal word length information to estimate the length of a saccade between the center of two parafoveal words (termed the Centre-Based Saccade Length) prior to landing on the first of these words. PMID- 29696594 TI - Using eye movements to understand the leakage of information during Chinese reading. AB - How is attention allocated during reading? The present eye-movement experiment used a paradigm developed by Liu and Reichle (Psychological Science, 29, 278-287, 2018) to examine object-based attention during reading: Participants were instructed to read one of two spatially overlapping sentences containing colocated target/distractor words of varying frequency. Although target-word frequency modulated fixation-duration measures on the target word, the distractor word frequency also had a smaller, independent effect. Survival analyses indicate that the distractor-word effect occurred later than the target-word effect, suggesting that subtle orthographic cues were noticed either later or occasionally, thereby modulating decisions about when to move the eyes. The theoretical ramifications of this "leakage" of information are discussed with respect to the general question of attention allocation during reading and possible differences between the reading of Chinese versus English. PMID- 29696596 TI - American Sign Language Interpreters Perceptions of Barriers to Healthcare Communication in Deaf and Hard of Hearing Patients. AB - Communication barriers between healthcare providers and patients contribute to health disparities and the effectiveness of health promotion messages. This is especially true regarding communication between providers and deaf and hard of hearing (HOH) patients due to lack of understanding of cultural and linguistic differences, ineffectiveness of various means of communication and level of health literacy within that population. This research aimed to identify American Sign Language (ASL) interpreters' perceptions of barriers to effective communication between deaf and HOH patients and healthcare providers. We conducted a survey of ASL interpreters attending the 2015 National Symposium on Healthcare Interpreting with an overall response rate of 25%. Results indicated a significant difference (p < 0.05) in all areas of preferred communication between providers and deaf/HOH patients as perceived by interpreters. ASL interpreters observed that patients did not understand provider instructions in nearly half of appointments. Eighty-one percent of interpreters said that providers "hardly ever" use "teach-back" methods with patients to ensure understanding. A focus on improving health care and health promotion efforts in the deaf/HOH community depends on improving communication, health literacy, and patient empowerment and involves holding health care organizations accountable for assuring adequate staffing of ASL interpreters and communication resources in order to reduce health disparities in this population. PMID- 29696595 TI - Delay discounting mediates the association between posterior insular cortex volume and social media addiction symptoms. AB - Addiction-like symptoms in relation to excessive and compulsive social media use are common in the general population. Because they can lead to various adverse effects, there is a growing need to understand the brain systems and processes that are involved in potential social media addiction. We focus on the morphology of the posterior subdivision of the insular cortex (i.e., the insula), because it has been shown to be instrumental to supporting the maintenance of substance addictions and problematic behaviors. Assuming that social media addiction shares neural similarities with more established ones and consistent with evidence from the neuroeconomics domain, we further examine one possible reason for this association-namely that insular morphology influences one's delay discounting and that this delay discounting contributes to exaggerated preference for immediate social media rewards and consequent addiction-like symptoms. Based on voxel-based morphometry techniques applied to MRI scans of 32 social media users, we show that the gray matter volumes of the bilateral posterior insula are negatively associated with social media addiction symptoms. We further show that this association is mediated by delay discounting. This provides initial evidence that insular morphology can be associated with potential social media addiction, in part, through its contribution to poor foresight and impulsivity as captured by delay discounting. PMID- 29696597 TI - Hookah Use Among College Students: Recent Use, Knowledge of Health Risks, Attitude and Reasons for Use. AB - Notwithstanding the efforts of health educators and other health professionals regarding tobacco and smoking cessation, research indicates that hookah smoking among college students remains a health concern. Research shows an upward trend in college students' hookah use. The purpose of this study was to identify and describe potential patterns/differences in college students' hookah use, and the relations among attitudes toward and knowledge about hookah use and use of this drug. A four-page, 20-item survey was used to collect data from participants (N = 403) and to measure participants 'recent use, knowledge of health risks, attitudes and reasons for hookah use among college students. Results indicated increased prevalence rates (53.8%) among participants of this study. Participants' recent hookah use was consistent with that of current research. Study findings supports current research, which found that college students have low negative perceptions of the health risks (addictive and detrimental properties) of hookah use. Analyses also determined that college students' attitudes toward hookah was associated with use of this drug. Regarding reasons why students may use hookah, data analysis indicated statistical significance in lifetime hookah use based on reasons for use. Study provide information for health educators creating hookah risk awareness educational programs aimed at reducing rates of hookah smoking among college students. PMID- 29696598 TI - The Personal Social Networks of Resettled Bhutanese Refugees During Pregnancy in the United States: A Social Network Analysis. AB - Women comprise 50% of the refugee population, 25% of whom are of reproductive age. Female refugees are at risk for experiencing significant hardships associated with the refugee experience, including after resettlement. For refugee women, the strength of their personal social networks can play an important role in mitigating the stress of resettlement and can be an influential source of support during specific health events, such as pregnancy. A personal social network analysis was conducted among 45 resettled Bhutanese refugee women who had given birth within the past 2 years in the Akron Metropolitan Area of Northeast Ohio. Data were collected using in-depth interviews conducted in Nepali over a 6 month period in 2016. Size, demographic characteristics of ties, frequency of communication, length of relationship, and strength of connection were the social network measures used to describe the personal networks of participants. A qualitative analysis was also conducted to assess what matters were commonly discussed within networks and how supportive participants perceived their networks to be. Overall, participants reported an average of 3 close personal connections during their pregnancy. The networks were comprised primarily of female family members whom the participant knew prior to resettlement in the U.S. Participants reported their networks as "very close" and perceived their connections to be supportive of them during their pregnancies. These results may be used to guide future research, as well as public health programming, that seeks to improve the pregnancy experiences of resettled refugee women. PMID- 29696599 TI - Multi-stage Vector-Borne Zoonoses Models: A Global Analysis. AB - A class of models that describes the interactions between multiple host species and an arthropod vector is formulated and its dynamics investigated. A host vector disease model where the host's infection is structured into n stages is formulated and a complete global dynamics analysis is provided. The basic reproduction number acts as a sharp threshold, that is, the disease-free equilibrium is globally asymptotically stable (GAS) whenever [Formula: see text] and that a unique interior endemic equilibrium exists and is GAS if [Formula: see text]. We proceed to extend this model with m host species, capturing a class of zoonoses where the cross-species bridge is an arthropod vector. The basic reproduction number of the multi-host-vector, [Formula: see text], is derived and shown to be the sum of basic reproduction numbers of the model when each host is isolated with an arthropod vector. It is shown that the disease will persist in all hosts as long as it persists in one host. Moreover, the overall basic reproduction number increases with respect to the host and that bringing the basic reproduction number of each isolated host below unity in each host is not sufficient to eradicate the disease in all hosts. This is a type of "amplification effect," that is, for the considered vector-borne zoonoses, the increase in host diversity increases the basic reproduction number and therefore the disease burden. PMID- 29696600 TI - High Cooperativity in Negative Feedback can Amplify Noisy Gene Expression. AB - Burst-like synthesis of protein is a significant source of cell-to-cell variability in protein levels. Negative feedback is a common example of a regulatory mechanism by which such stochasticity can be controlled. Here we consider a specific kind of negative feedback, which makes bursts smaller in the excess of protein. Increasing the strength of the feedback may lead to dramatically different outcomes depending on a key parameter, the noise load, which is defined as the squared coefficient of variation the protein exhibits in the absence of feedback. Combining stochastic simulation with asymptotic analysis, we identify a critical value of noise load: for noise loads smaller than critical, the coefficient of variation remains bounded with increasing feedback strength; contrastingly, if the noise load is larger than critical, the coefficient of variation diverges to infinity in the limit of ever greater feedback strengths. Interestingly, feedbacks with lower cooperativities have higher critical noise loads, suggesting that they can be preferable for controlling noisy proteins. PMID- 29696601 TI - A Simple Mathematical Model Inspired by the Purkinje Cells: From Delayed Travelling Waves to Fractional Diffusion. AB - Recently, several experiments have demonstrated the existence of fractional diffusion in the neuronal transmission occurring in the Purkinje cells, whose malfunctioning is known to be related to the lack of voluntary coordination and the appearance of tremors. Also, a classical mathematical feature is that (fractional) parabolic equations possess smoothing effects, in contrast with the case of hyperbolic equations, which typically exhibit shocks and discontinuities. In this paper, we show how a simple toy-model of a highly ramified structure, somehow inspired by that of the Purkinje cells, may produce a fractional diffusion via the superposition of travelling waves that solve a hyperbolic equation. This could suggest that the high ramification of the Purkinje cells might have provided an evolutionary advantage of "smoothing" the transmission of signals and avoiding shock propagations (at the price of slowing a bit such transmission). Although an experimental confirmation of the possibility of such evolutionary advantage goes well beyond the goals of this paper, we think that it is intriguing, as a mathematical counterpart, to consider the time fractional diffusion as arising from the superposition of delayed travelling waves in highly ramified transmission media. The case of a travelling concave parabola with sufficiently small curvature is explicitly computed. The new link that we propose between time fractional diffusion and hyperbolic equation also provides a novelty with respect to the usual paradigm relating time fractional diffusion with parabolic equations in the limit. This paper is written in such a way as to be of interest to both biologists and mathematician alike. In order to accomplish this aim, both complete explanations of the objects considered and detailed lists of references are provided. PMID- 29696602 TI - Translational Shifts in Preclinical Models of Depression: Implications for Biomarkers for Improved Treatments. AB - Understanding the neurobiology of major depressive disorder (MDD) remains one of the major challenges in neuroscience. The disease is heterogeneous in nature, and patients present with a varied symptom profile. Studies seeking to identify biomarkers for MDD diagnosis and treatment have not yet found any one candidate which achieves sufficient sensitivity and specificity. In this article, we consider whether neuropsychological impairments, specifically affective biases, could provide a behavioural biomarker. Affective biases are observed when emotional states influence cognitive function. These biases have been shown to influence a number of different cognitive domains with some specific deficits observed in MDD. It has also been possible to use these neuropsychological tests to inform the development of translational tasks for non-human species. The results from studies in rodents suggest that quantification of affective biases is feasible and may provide a reliable method to predict antidepressant efficacy as well as pro-depressant risk. Animal studies suggest that affective state induced biases in learning and memory operate over a different time course to biases influencing decision-making. The implications for these differences in terms of task validity and future ideas relating to affective biases and MDD are discussed. We also describe our most recent studies which have shown that depression-like phenotypes share a common deficit in reward-related learning and memory which we refer to as a reward-induced positive bias. This deficit is dissociable from more typical measures of hedonic behaviour and motivation for reward and may represent an important and distinct form of reward deficit linked to MDD. PMID- 29696603 TI - Reappraising Preclinical Models of Separation Anxiety Disorder, Panic Disorder, and CO2 Sensitivity: Implications for Methodology and Translation into New Treatments. AB - Separation anxiety applies to multiple forms of distress responses seen in mammals during postnatal development, including separation from a caregiver. Childhood separation anxiety disorder is an important risk factor for developing panic disorder in early adulthood, and both conditions display an increased sensitivity to elevated CO2 concentrations inhaled from the air. By interfacing epidemiological, genetic, and physiological knowledge with preclinical animal research models, it is possible to decipher the mechanisms that are central to separation anxiety and panic disorders while also suggesting possible therapies. Preclinical research models allow for environmentally controlled studies of early interferences with parental care. These models have shown that different forms of early maternal separation in mice and rats induce elevated CO2 respiratory sensitivity, an important biomarker of separation anxiety and panic disorders. In mice, this is likely due to gene-environment interactions that affect multiple behavioural and physical phenotypes after exposure to this early adversity. Although several questions regarding the causal mechanism of separation anxiety and panic disorder remain unanswered, the identification and improved understanding of biomarkers that link these mental health conditions under the guise of preclinical research models in conjunction with human longitudinal cohort studies can help resolve these issues. PMID- 29696604 TI - Genomic and Imaging Biomarkers in Schizophrenia. AB - Recent large-scale genomic studies have confirmed that schizophrenia is a polygenic syndrome and have implicated a number of biological pathways in its aetiology. Both common variants individually of small effect and rarer but more penetrant genetic variants have been shown to play a role in the pathogenesis of the disorder. No simple Mendelian forms of the condition have been identified, but progress has been made in stratifying risk on the basis of the polygenic burden of common variants individually of small effect, and the contribution of rarer variants of larger effect such as Copy Number Variants (CNVs). Pathway analysis of risk-associated variants has begun to identify specific biological processes implicated in risk for the disorder, including elements of the glutamatergic NMDA receptor complex and post synaptic density, voltage-gated calcium channels, targets of the Fragile X Mental Retardation Protein (FMRP targets) and immune pathways. Genetic studies have also been used to drive genomic imaging approaches to the investigation of brain markers associated with risk for the disorder. Genomic imaging approaches have been applied both to investigate the effect of polygenic risk and to study the impact of individual higher-penetrance variants such as CNVs. Both genomic and genomic imaging approaches offer potential for the stratification of patients and at-risk groups and the development of better biomarkers of risk and treatment response; however, further research is needed to integrate this work and realise the full potential of these approaches. PMID- 29696605 TI - Assessment of the Virological Quality of Marine and Running Surface Waters in NW Greece: A Case Study. AB - The virological quality of surface marine and running water samples collected from Igoumenitsa gulf and Kalamas river (NW Greece) was assessed from October 2012 to September 2013. Sampling sites were exposed to different land and/or anthropogenic effects. Seawater samples were collected monthly from five sampling stations (new harbor, old harbor, wastewater treatment plant outlet, protected Natura area, Drepano beach). Viral targets included human adenoviruses (hAdVs), as index human viruses, while noroviruses (NoVs) and hepatitis A virus (HAV) were also studied. Kalamas river samples were collected seasonally, from three sampling stations (Soulopoulo, Dam, Sagiada-estuaries), while viral targets included also porcine adenoviruses (pAdVs) and bovine polyoma viruses (bPyVs), as additional index viruses. All water samples were analyzed for standard bacterial indicators, as well. Physicochemical and meteorological data were also collected. Based on the standard bacterial indices, both sea and river water samples did not exceed the limits set according to Directive 2006/7/EU. However, positive samples for hAdVs were found occasionally in all sampling sites in Igoumenitsa gulf (23.3%, 14/60) showing fecal contamination of human origin. Moreover, HAV was detected once, in the sampling site of the old port (at 510 GC/L). Most of the Kalamas water samples were found positive for hAdVs (58.3%, 7/12), while human noroviruses GI (NoVGI) (8.3%, 1/12) and GII (NoVGII) (16.7%, 2/12) were also detected. HAV, pAdVs, and bovine polyomaviruses (bPyVs) were not detected in any of the analyzed samples. No statistically significant correlations were found between classic bacterial indicators and viral targets, nor between viruses and meteorological data. Overall, the present study contributed to the collection of useful data for the biomonitoring of the region, and the assessment of the overall impact of anthropogenic activities. It provided also valuable information for the evaluation of the risk of waterborne viral infections and the protection of public health. It was the first virological study in the area and one of the few in Greece. PMID- 29696606 TI - Femoral Derotational Osteotomies. AB - PURPOSE OF REVIEW: Femoral derotational osteotomies are performed to correct residual symptomatic increased femoral torsion in adolescents and adults. Typical indications are anterior knee pain caused by patellar maltracking and patellofemoral instability. There is still no consensus as to what the correct indication is and which surgical techniques lead to the best outcomes in performing a femoral derotational osteotomy. RECENT FINDINGS: Good early clinical outcomes have been reported. However, long-term studies and data on return to play are lacking. Surgery often is performed according to the surgeon's experience. There is no evidence to support decisions regarding surgical technique or level of osteotomy. Femoral derotational osteotomy is the treatment of choice in patients with symptomatic excessive anteversion and torsional malalignment of the femur. Multiple techniques have shown good clinical results with high patient satisfaction. Future studies however must focus on radiographic and clinical assessment to understand different subtypes of torsional deformity and its implication on operative therapy. PMID- 29696607 TI - Abdominal manifestations of IgG4-related disease: a pictorial review. AB - : In the last decade, autoimmune pancreatitis has become recognised as part of a wider spectrum of IgG4-related disease, typically associated with elevated serum IgG4 levels and demonstrating a response to corticosteroid therapy. Radiologically, there is imaging overlap with other benign and neoplastic conditions. This pictorial review discusses the intra-abdominal manifestations of this disease on cross-sectional imaging before and after steroid treatment and the main radiological features which help to distinguish it from other key differentials. TEACHING POINTS: * Autoimmune pancreatitis is part of a spectrum of IgG4-related disease. * Diagnosis is based on raised serum IgG4, clinical, radiological and histopathological findings. * Cross-sectional imaging can demonstrate the typical findings of abdominal IgG4-related disease. * Cross sectional imaging can be used to monitor response to corticosteroid treatment. PMID- 29696608 TI - Regulation of aging and oxidative stress pathways in aged pancreatic islets using alpha-lipoic acid. AB - Oxidative stress has been involved in the aging process and the pathogenesis of type-2 diabetes, which is a serious health problem worldwide. This study investigates the anti-aging, anti-apoptotic, and antioxidant properties of alpha lipoic acid (ALA), aiming to improve aged rat pancreatic cells. In this regard, half maximal effective concentration (EC50) of ALA based on the survival of aged pancreatic islet cells was determined as 100 uM. Following this, p38 and p53 genes expression as key factors in aging, oxidative stress biomarkers, insulin secretion, and Pdx1 protein expression were evaluated using real-time PCR, ELISA reader, and fluorescence microscope. It was revealed that ALA reduces and controls the effects of aging on beta cells mainly by suppressing p38 and p53 at the gene level (P < 0.001 and P < 0.01), respectively, reducing reactive oxygen species (P < 0.001) and enhancing levels of thiols (P < 0.05) compared with the aged islets. Furthermore, both qualitative and quantitative investigations of insulin secretion have shown that ALA can improve aged cells' function and increase insulin secretion specially in the stimulating concentration of glucose. Also, the expression of Pdx1 was considerably increased by ALA in comparison to the aged pancreatic islets (P < 0.001). As far as the authors of the present study are concerned, this is the first study, which evaluated aging associated with p38 and p53 pathways, oxidative stress parameters, and the expression of insulin in beta cells of an aged rat and reaffirmed the fact that ALA has a significant antioxidant role in reducing the aging process. PMID- 29696610 TI - Is there a Space for Post-Colonial Theory in the Socio-Psychological Research on Consequences of Colonial Past? AB - The focus of my commentary is two-fold. First, I discuss what appeared to me as the central theoretical focus of the article; the possibility to create a space, if at all, for integrating post-colonial theory into the broader research field of social and psychological studies of the consequences of colonial past. Second, I intend to show why, in my opinion, the methodological choices of the authors and the criteria adopted for corpus construction allowed for data that, although too thin to establishing the state of knowledge in the field of study on consequences of colonial past, is nevertheless very informative and thoughts provoking. My conclusions suggest that this study is an innovative attempt at describing and grasping the results of a search guided by two among the more consolidated electronic datasets currently available for English-speaking scholars. However, this study may not easily understand which can be the space to integrate post-colonial theory in the field of research on consequences of colonial past. To better reach this aim, it is perhaps necessary to build another kind of corpus, open to other languages (starting from French) and focused also on other scientific products, as books or proceedings of congress. In addition, disciplinary boundaries have to be even more explored, starting from interdisciplinary studies on education and historical culture. In spite of these limitations, I am convinced that this innovative study by Tomicic and Berardi tackles issues of relevance to any serious effort towards reflecting on long-term consequences of colonial violence and opens up to valuable new research questions and methods, to be taken into serious account and further explored in future works. PMID- 29696609 TI - Apocynin protects endothelial cells from endoplasmic reticulum stress-induced apoptosis via IRE1alpha engagement. AB - Endoplasmic reticulum (ER) stress-induced endothelial cell (EC) apoptosis has been implicated in a variety of human diseases. In addition to being regarded as an NADPH oxidase (NOX) inhibitor, apocynin (APO) exhibits an anti-apoptotic effect in various cells. The present study aimed to identify the protective role of apocynin in ER stress-mediated EC apoptosis and the underlying mechanisms. We found that ER stress resulted in a significant increase in c-Jun N-terminal kinase phosphorylation, and elicited caspase 3 cleavage and apoptosis. However, apocynin obviously attenuated EC apoptosis and this effect was partly dependent on ER stress sensor inositol-requiring enzyme 1alpha (IRE1alpha). Importantly, apocynin upregulated IRE1alpha expression in both protein and mRNA levels and promoted the pro-survival XBP1 splicing. Our results suggest that apocynin protects ECs against ER stress-induced apoptosis via IRE1alpha involvement. These findings may provide a novel mechanistic explanation for the anti-apoptotic effect of apocynin in ER stress. PMID- 29696611 TI - Dynamic right ventricular outflow tract obstruction from a pedunculated cardiac metastasis. PMID- 29696612 TI - Adipokine levels in overweight women with early-onset gestational diabetes mellitus. AB - PURPOSE: The study of adipokines in overweight women with early-onset (diagnosed before 20 weeks) gestational diabetes mellitus (GDM) could help to understand the ethiopathological mechanisms of this disorder. Our aim was to assess adipokine levels in overweight pregnant women with early-onset GDM compared to patients with standard-onset (diagnosed at 24-28 weeks) GDM and to glucose-tolerant women at the same gestational ages. METHODS: This nested case-control study included 133 overweight pregnant women: 33 with early-onset (diagnosed < 20 weeks) GDM; 40 with standard-onset (diagnosed >= 24 weeks) GDM and 60 glucose-tolerant (normal oral glucose tolerance tests < 20 and >= 24 weeks). Adiponectin, leptin, resistin, visfatin and ghrelin serum levels were measured by ELISA. RESULTS: Adiponectin serum levels were significantly lower in early-onset GDM women than in standard-onset GDM patients or controls matched for gestational age. Leptin serum levels were significantly higher in women with early-onset GDM than in controls. Women with early-onset GDM had lower adiponectin/leptin ratio than those with standard-onset GDM. There were no significant differences in resistin, ghrelin and visfatin serum levels among the participants. CONCLUSIONS: Our results suggest that, compared to overweight glucose-tolerant women and patients with standard-onset GDM, overweight women with early-onset GDM have unbalanced adipokine levels, suggesting that they have a more inflammatory profile. PMID- 29696613 TI - Thermosensitive Poloxamer 407/Poly(Acrylic Acid) Hydrogels with Potential Application as Injectable Drug Delivery System. AB - Thermosensitive hydrogels are of great interest for in situ gelling drug delivery. The thermosensitive vehicle with a gelation temperature in a range of 30-36 degrees C would be convenient to be injected as liquid and transform into gel after injection. To prepare novel hydrogels gelling near body temperature, the gelation temperature of poloxamer 407 (PX) were tailored by mixing PX with poly(acrylic acid) (PAA). The gelation behaviors of PX/PAA systems as well as the interaction mechanism were investigated by tube inversion, viscoelastic, shear viscosity, DSC, SEM, and FTIR studies. The gelation temperature of the plain PX solutions at high concentration of 18, 20, and 22% (w/w) gelled at temperature below 28 degrees C, which is out of the suitable temperature range. Mixing PX with PAA to obtain 18 and 20% (w/w) PX with 1% (w/w) PAA increased the gelation temperature to the desired temperature range of 30-36 degrees C. The intermolecular entanglements and hydrogen bonds between PX and PAA may be responsible for the modulation of the gelation features of PX. The mixtures behaved low viscosity liquid at room temperature with shear thinning behavior enabling their injectability and rapidly gelled at body temperature. The gel strength increased, while the pore size decreased with increasing PX concentration. Metronidazole, an antibiotic used for periodontitis, was incorporated into the matrices, and the drug did not hinder their gelling ability. The gels showed the sustained drug release characteristic. The thermosensitive PX/PAA hydrogel could be a promising injectable in situ gelling system for periodontal drug delivery. PMID- 29696614 TI - Multi-Layer Self-Nanoemulsifying Pellets: an Innovative Drug Delivery System for the Poorly Water-Soluble Drug Cinnarizine. AB - Beside their solubility limitations, some poorly water-soluble drugs undergo extensive degradation in aqueous and/or lipid-based formulations. Multi-layer self-nanoemulsifying pellets (ML-SNEP) introduce an innovative delivery system based on isolating the drug from the self-nanoemulsifying layer to enhance drug aqueous solubility and minimize degradation. In the current study, various batches of cinnarizine (CN) ML-SNEP were prepared using fluid bed coating and involved a drug-free self-nanoemulsifying layer, protective layer, drug layer, moisture-sealing layer, and/or an anti-adherent layer. Each layer was optimized based on coating outcomes such as coating recovery and mono-pellets%. The optimized ML-SNEP were characterized using scanning electron microscopy (SEM), differential scanning calorimetry (DSC), X-ray diffraction (XRD), in vitro dissolution, and stability studies. The optimized ML-SNEP were free-flowing, well separated with high coating recovery. SEM showed multiple well-defined coating layers. The acidic polyvinylpyrrolidone:CN (4:1) solution presented excellent drug-layering outcomes. DSC and XRD confirmed CN transformation into amorphous state within the drug layer. The isolation between CN and self-nanoemulsifying layer did not adversely affect drug dissolution. CN was able to spontaneously migrate into the micelles arising from the drug-free self-nanoemulsifying layer. ML-SNEP showed superior dissolution compared to Stugeron(r) tablets at pH 1.2 and 6.8. Particularly, on shifting to pH 6.8, ML-SNEP maintained > 84% CN in solution while Stugeron(r) tablets showed significant CN precipitation leaving only 7% CN in solution. Furthermore, ML-SNEP (comprising Kollicoat(r) Smartseal 30D) showed robust stability and maintained > 97% intact CN within the accelerated storage conditions. Accordingly, ML-SNEP offer a novel delivery system that combines both enhanced solubilization and stabilization of unstable poorly soluble drugs. PMID- 29696615 TI - Influence of cognitive impairment on the freezing of gait in non demented people with Parkinson's disease. AB - INTRODUCTION: Freezing of gait (FOG) is a motor disturbance usually appearing in advanced Parkinson's disease (PD). Cognitive and executive function seems to play an important role in this phenomenon. AIM: To investigate if cognitive and kinematic parameters correlate with FOG in PD patients without dementia. PATIENTS AND METHODS: We conducted an observational cross-sectional study. Participants were classified in two groups: freezers and non-freezers. Clinical information was obtained by Hoehn and Yahr scale, Unified Parkinson's Disease Rating Scale and balance test of Short Physical Performance Battery. Cognitive function was evaluated using Minimental Examination and the Fuld Object Memory Evaluation; executive function was assessed with the Frontal Assessment Battery test. Battery kinematic parameters were assessed by means of gait speed, cadence, stride length and stride time. RESULTS: Twenty-five participants with PD without dementia completed the evaluation. Statistical significant differences between freezers and non-freezers were found in global cognition (p = 0,02), memory (p = 0,04), executive function (p = 0,04), cadence (p = 0,02), stride length (p = 0,04) and stride time (p = 0,01). CONCLUSION: Cognitive parameters may have an important contribution to the manifestation of freezing of gait in PD. These results may have important clinical implications for developing future non-pharmacological and cognitive interventions strategies targeted to PD patients with FOG. PMID- 29696616 TI - [Analysis of the quantitative differences in the thickness of the retinal nerve fibre layer between time-domain and spectral-domain optical coherence tomography in patients with relapsing-remitting multiple sclerosis]. AB - INTRODUCTION: Optical coherence tomography (OCT) is a tool that is increasingly more commonly used in the study of neuro-degenerative diseases. AIMS: To analyse and correlate the thickness of the retinal nerve fibre layer (RNFL) by means of time-domain and spectral-domain OCT in patients with relapsing-remitting multiple sclerosis (MS), with and without a history of optic neuritis (ON). SUBJECTS AND METHODS: We conducted a cross-sectional study of the thickness (mean and by quadrants) of the RNFL of 15 disease-free subjects, 28 with MS with no prior history of ON and 18 with a history of ON. The full ophthalmologic examination included measurement of the RNFL by means of time-domain and spectral-domain tomography. RESULTS: Statistically significant differences are found between the two tomography scans on comparing the mean thickness of the RNFL of the control group (p = 0.000), the group with a history of ON (p = 0.000) and the group without ON (p = 0.000). We obtained a strong, statistically significant and directly proportional correlation between the mean thickness of the RNFL measured with the two types of tomography in the control group (rho = 0.842; p = 0.000), and the groups of eyes without ON (rho = 0.91; p = 0.000) and with ON (rho = 0.902; p = 0.000). CONCLUSIONS: There is a strong correlation between the two tomography scans in the measurement of the thickness of the RNFL in patients with MS, with and without a history of ON. Time-domain OCT quantifies greater thicknesses, and therefore both types of tomography have proven to be effective in the study of MS, although the results cannot be interchanged or extrapolated. PMID- 29696617 TI - [Clinical and neuropsychological characteristics in congenital central hypoventilation syndrome]. AB - INTRODUCTION: Congenital central hypoventilation syndrome (CCHS) syndrome is a rare disease caused by mutations in the PHOX2B gene. Patients show a reduced response to hypercapnia and hypoxia accompanied by diffuse disturbances of the autonomic nervous system and occasionaly also disturbances in neuroimaging. A specific neuropsychological profile has not been described in children and adolescents with CCHS. CASE REPORTS: We describe three cases (aged between 4 and 19 years) with different profiles of affectation in cognitive and functionality. These profiles are compared with the features described in the literature about neuropsychology in CCHS. CONCLUSIONS: The profile of functional impairment in the CCHS is variable: in case 1, a severe global developmental delay with autistic features and marked functional involvement is described. In case 2, bilateral atrophy of the hippocampus is associated with involvement in social cognition and in executive functions with moderate functional repercussion. Case 3 shows difficulties in some cognitive executive functions (planning and non-verbal fluency), but without functional repercussion. Neuropsychological assessment can help in the clinical management of these patients by determining and guiding the need for rehabilitation treatments. PMID- 29696618 TI - [Epilepsy, Mozart and his sonata K.448: is the "Mozart effect" therapeutic?] AB - AIMS: To present a review of the so-called "Mozart effect", to explain why Mozart and his sonata K.448 were chosen, and to review the available literature on the treatment of epilepsy with that sonata. DEVELOPMENT: Profuse literature exists on the cerebral mechanisms that allow us to perceive, process and respond to the musical stimulus. Cerebral plasticity, especially in people with musical training, has also been demonstrated. The "Mozart effect" arose from the finding that hearing the sonata K.448 improved cognitive abilities, but the fact that these results may be due not to the music itself but to the listener increasing arousal or enjoyment generated controversy. In this context of debate, a large number of papers about the "Mozart effect" in the field of epilepsy were published, and are reviewed in this work. CONCLUSIONS: The "Mozart effect" has a scientific basis but its nature limits the methodological quality of the research. The music of Mozart, chosen for its exquisite structure, has been able to increase even more the controversy because also it is of the taste of a great majority. It is still far from being consolidated as a non-pharmacological antiepileptic treatment, but it could increase the scientific evidence with studies whose design minimizes the cited confounding factors. PMID- 29696619 TI - [Intraoperative neurophysiological monitoring in Spain: its beginnings, current situation and future prospects]. AB - Intraoperative neurophysiological monitoring (IONM) is nowadays another tool within the operating room that seeks to avoid neurological sequels derived from the surgical act. The Spanish Neurophysiological Intra-Surgical Monitoring Association (AMINE) in collaboration with the Spanish Society of Clinical Neurophysiology (SENFC), and the IONM Working Group of the SENFC has been collecting data in order to know the current situation of the IONM in Spain by hospitals, autonomous communities including the autonomous cities of Ceuta and Melilla, the opinions of the specialists in clinical neurophysiology involved in this topic and further forecasts regarding IONM. The data was gathered from November 2015 to May 2016 through telephone contact and/or email with specialists in clinical neurophysiology of the public National Health System, and through a computerized survey that also includes private healthcare centers. With the data obtained, from the perspective of AMINE and the SENFC we consider that nowadays the field of medicine covered by IONM is considerably large and it is foreseen that it will continue to grow. Therefore, a greater number of specialists in Clinical Neurophysiology will be required, as well as the need for specific training within the specialty that involves increasing the training period of MIRs based on competencies due to the increase in techniques/procedures, as well as its complexity. PMID- 29696620 TI - [GNAO1: a new gene to consider on early-onset childhood dystonia]. PMID- 29696621 TI - [Reversible cerebral vasoconstriction syndrome following smoking cessation and treatment with bupropion]. PMID- 29696622 TI - [Infantile epileptic encephalopathy: a good genetic study should be a priority]. PMID- 29696624 TI - Therapeutic Targeting of Tumor-Associated Macrophages in Pancreatic Neuroendocrine Tumors. AB - Pancreatic neuroendocrine tumors (PNETs) represent a heterogeneous group of neuroendocrine neoplasms with varying biological behaviour and response to treatment. Although targeted therapies have been shown to improve the survival for patients at advanced stage, resistance to current therapies frequently occurs during the course of therapy. Previous reports indicate that the infiltration of tumor-associated macrophages (TAMs) in PNETs might correlate with tumor progression and metastasis formation. We aimed to evaluate the prognostic and functional impact of TAMs in human PNETs in vitro and in vivo and to investigate the effect of therapeutic targeting TAMs in a genetic PNET mouse model. TAM expression pattern was assessed immunohistochemically in human PNET tissue sections and a tissue-micro-array of PNET tumors with different functionality, stage and grading. The effect of liposomal clodronate on TAM cell viability was analysed in myeloid cell lines and isolated murine bone macrophages (mBMM). In vivo, RIP1Tag2 mice developing insulinomas were treated with liposomal clodronate or PBS-Liposomes. Tumor progression, angiogenesis and immune cell infiltration were assessed by immunohistochemistry. In human insulinomas TAM density was correlated with invasiveness and malignant behaviour. Moreover, TAM infiltration in liver metastases was significantly increased compared to primary tumors. In vitro, liposomal clodronate selectively inhibited the viability of myeloid cells and murine bone macrophages, leaving PNET tumor cell lines largely unaffected. In vivo, repeated application of liposomal clodronate to RIP1Tag2 mice significantly diminished the malignant transformation of insulinomas, which was accompanied by a reduced infiltration of F4/80 positive TAM cells and simultaneously by a decreased microvessel density, suggesting a pronounced effect of clodronate induced myeloid depletion on tumor angiogenesis. Concomitant treatment with the antiangiogenic TKI sunitinib, however, did not show any synergistic effects with liposomal clodronate. TAMs are crucial for malignant transformation in human PNET in particular in insulinomas and correlate with metastatic behaviour. Pharmacological targeting of TAMs via liposomal clodronate disrupts tumor progression in the RIP1Tag2 neuroendocrine tumor model and was associated with reduced tumor angiogenesis Based on these results, using liposomal clodronate to target proangiogenic myeloid cells could be employed as novel therapeutic avenue in highly angiogenic tumors such as PNET. This article is protected by copyright. All rights reserved. PMID- 29696625 TI - Harnessing the Potential of Emerging Digital Health and Biological Sampling Technologies for Clinical Drug Development: Promise to Reality. AB - Advances in emerging innovative technologies have led to optimistic outlooks on their transformative potential for healthcare and clinical trials.1 Given the increased attention, this white paper by the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ) presents perspectives on pharmaceutical and biotechnology industry trends for innovative digital health, adherence, and outpatient sampling technologies. As stimulus for cross company scientific dialog points to consider for adoption, implementation, and recommendations to broaden uptake are proposed. PMID- 29696626 TI - Prostatitis, other genitourinary infections and prostate cancer risk: Influence of non-steroidal anti-inflammatory drugs? Results from the EPICAP study. AB - Epidemiological studies have suggested that prostatitis may increase the risk of prostate cancer due to chronic inflammation. We studied the association between several genitourinary infections and the risk of prostate cancer based on data from the EPICAP study. EPICAP is a population-based case-control study conducted in the departement of Herault, France, between 2012 and 2014. A total of 819 incident cases and 879 controls have been face to face interviewed using a standardized questionnaire gathering information on known or suspected risk factors of prostate cancer, and personal history of genitourinary infections: prostatitis, urethritis, orchi-epididymitis, and acute pyelonephritis. Odds Ratios (OR) and their 95% confidence interval were estimated using multivariate unconditional logistic regression. Overall, 139 (18%) cases and 98 (12%) controls reported having at least one personal history of genitourinary infections (OR = 1.64 [1.23-2.20]). The risk increased with the number of infections (p-trend < 0.05). The association was specifically observed with personal history of chronic prostatitis and acute pyelonephritis (OR = 2.95 [1.26-6.92] and OR = 2.66 [1.29 5.51], respectively) and in men who did not use any non-steroidal anti inflammatory drugs (OR = 2.00 [1.37-2.91]). Our results reinforce the hypothesis that chronic inflammation, generated by a personal history of genitourinary infections, may play a role in prostate carcinogenesis. PMID- 29696627 TI - Subjective and psychological well-being in Parkinson's Disease: A systematic review. AB - OBJECTIVES: The aim of this review is to summarize studies investigating subjective and psychological well-being in patients with Parkinson's disease (PD). MATERIALS AND METHODS: A systematic and integrative review according to PRISMA criteria was performed with a literature search from inception up to September 2017 in multidisciplinary databases (PubMED, Scopus, Web of Knowledge) by combining together key words related to PD and well-being. Studies were included if: their full-text was available; they involved PD patients; focused on the selected positive dimensions; written in English. Case studies, conference proceedings, abstract, dissertations, book chapters, validation studies and reviews were excluded. Data extracted from the studies included sample characteristics, the positive dimension investigated, type of measure, study aims, design and results. One reviewer extracted details and commented results with other reviewers. The studies' quality was assessed following Kmet, Lee, and Cook. RESULTS: Out of 1425 studies extracted, 12 studies (9 quantitative, 2 qualitative, 1 mixed methods) involving 2204 patients with PD were included. Most of the studies had a cross-sectional design and/or evaluated the effect of physical rehabilitation on well-being. Articles documented that the illness could impair well-being for its progressive impact on patients' motor autonomy. Preserving motor and musculoskeletal functioning facilitate patients' experience of well-being, social contribution and the maintenance of their job. CONCLUSIONS: Research on positive resources in PD is still scarce compared to other chronic illnesses. The few available investigations suggest the need of preserving motor abilities by proper rehabilitation programs for maintaining and/or promoting patients' well-being and life engagement. PMID- 29696628 TI - A time for YAP1: Tumorigenesis, immunosuppression and targeted therapy. AB - YAP1 is one of the most important effectors of the Hippo pathway and has crosstalk with other cancer promoting pathways. YAP1 contributes to cancer development in various ways that include promoting malignant phenotypes, expansion of cancer stem cells and drug resistance of cancer cells. Because pharmacologic or genetic inhibition of YAP1 suppresses tumor progression and increases the drug sensitivity, targeting YAP1 may open a fertile avenue for a novel therapeutic approach in relevant cancers. Recent enormous studies have established the efficacy of immunotherapy, and several immune checkpoint blockades are in clinical use or in the phase of development to treat various cancer types. Immunosuppression in the tumor microenvironment (TME) induced by cancer cells, immune cells and associated stromal cells promotes tumor progression and causes drug resistance. Accumulated evidences of scientific efforts from the last few years suggest that YAP1 influences macrophages, myeloid derived suppressor cells and regulatory T-cells to facilitate immunosuppressive TME. Although the underlying mechanisms is not clearly discerned, it is evident that YAP1 activating pathways in different cellular components induce immunosuppressive TME. In this review, we summarize the evidences involved in the dual roles of YAP1 in cancer development and immunosuppression in the TME. We also discuss the possibility of YAP1 as a novel therapeutic target. PMID- 29696629 TI - Current use of monoclonal antibodies in the treatment of multiple myeloma. AB - Multiple myeloma (MM) is the second most common haematological malignancy after non-Hodgkin lymphoma. Despite the improvement in outcomes over the last decade with the introduction of novel therapies, such as immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs), MM remains an incurable disease. Patients who are both refractory to IMiDs and PIs carry a particularly dismal prognosis. The development of targeted therapy in the form of monoclonal antibodies has shifted the treatment paradigm of this disease, resulting in unprecedented response rates, even among the highest-risk patients. In this review, we will summarize the mechanism of action and provide an overview of the clinical trials that have led to the US Food and Drug Administration approval of Daratumumab and Elotuzumab, and their current use in the treatment of MM. PMID- 29696630 TI - Quantitative association between body mass index and the risk of cancer: A global Meta-analysis of prospective cohort studies. AB - Numerous studies have suggested that excess body weight is associated with increased cancer risk. To examine this putative association, we performed a systematic review and quantitative meta-analysis of cohort studies reporting body mass index (BMI) and the risk of 23 cancer types. PubMed, Embase, and Web of Science were searched for cohort studies, yielding 325 articles with 1,525,052 cases. Strong positive associations were observed between BMI and endometrial cancer (RR: 1.48), esophageal adenocarcinoma (RR: 1.45), and kidney cancer (RR: 1.20); weaker associations (RR < 1.20) were also found for several other cancer types. Interestingly, we found significant inverse associations between BMI and oral cavity (RR: 0.93), lung (RR: 0.91), premenopausal breast (RR: 0.95), and localized prostate (RR: 0.97) cancers. A male-specific association was found for colorectal cancer (p = 0.023), and a female-specific association was found for cancer in brain (p = 0.025) or kidney (p = 0.035). With respect to geography, the strongest positive association was found for total cancer in North America (p = 0.038). This comprehensive meta-analysis provides epidemiological evidence supporting the association between BMI and cancer risk. These findings can be used to drive public policies and to help guide personalized medicine in order to better manage body weight, thereby reducing the risk of developing obesity related cancer. PMID- 29696632 TI - Parabacteroides distasonis attenuates toll-like receptor 4 signaling and Akt activation and blocks colon tumor formation in high-fat diet-fed azoxymethane treated mice. AB - Gut dysbiosis may play an etiological role in colorectal tumorigenesis. We previously observed that the abundance of Parabacteroides distasonis (Pd) in stool was inversely associated with intestinal tumor burden and IL-1beta concentrations in mice. Here, we assessed the anti-inflammatory capacity of Pd membrane fraction (PdMb) in colon cancer cell lines. In addition, we tested whether Pd could suppress colon tumorigenesis in mice. Six-week old male A/J mice were fed a low-fat diet (LF), high-fat diet (HF), or HF+ whole freeze-dried Pd (HF+Pd, 0.04% w/w) for 24 weeks. After 1 week on diet, mice received 4 weekly injections of azoxymethane (AOM). PdMb robustly suppressed the production of pro inflammatory cytokines and lowered the abundance of MyD88 and pAkt (ser473) induced by E. coli lipopolysaccharide in colon cancer cell lines. Moreover, PdMb induced apoptosis in colon cancer cell lines and blocked TLR4 activation in a reporter line. Colon tumors were observed in 0% of LF (0 of 19), 25% of HF (5 of 20) and 0% of HF+Pd mice (0 of 20) (P = 0.005). The latter group also displayed a lower abundance of MyD88 and pAkt (ser473) in colonic mucosa than HF mice. Taken together, these data suggest that Pd has anti-inflammatory and anti-cancer properties that are likely mediated by the suppression of TLR4 and Akt signaling, as well as promotion of apoptosis. Further work is needed to confirm these findings in additional models and fully elaborate the mechanism of action. This article is protected by copyright. All rights reserved. PMID- 29696631 TI - Proinflammatory diet is associated with increased risk of squamous cell head and neck cancer. AB - Diets high in fruits and vegetables and low in red meat intake have been associated with decreased risk of head and neck cancer. Additionally, chronic inflammation pathways and their association with cancer have been widely described. We hypothesized a proinflammatory diet, as measured by the dietary inflammatory index (DII(r) ), is associated with increased risk of head and neck cancer. We used the Carolina Head and Neck Cancer (CHANCE) study, a population based case-control study of head and neck squamous cell carcinoma. Cases were recruited from a 46-county region in central North Carolina. Controls, frequency matched on age, race, and sex were identified through the North Carolina Department of Motor Vehicle records. The DII score, adjusted for energy using the density approach (E-DII), was calculated from a food frequency questionnaire and split into four quartiles based on the distribution among controls. Adjusted odds ratios (ORs) were estimated with unconditional logistic regression. Cases had higher E-DII scores (i.e., a more proinflammatory diet) compared with controls (mean: -0.14 vs. -1.50; p value < 0.001). When compared with the lowest quartile, the OR for the highest quartile was 2.91 (95% confidence interval (CI): 2.16 3.95), followed by 1.93 (95% CI: 1.43-2.62) for the third quartile, and 1.37 (95% CI: 1.00-1.89) for the second quartile. Both alcohol and smoking had a significant additive interaction with E-DII (smoking relative excess risk due to interaction (RERI): 2.83; 95% CI: 1.36-4.30 and alcohol RERI: 1.75; 95% CI: 0.77 2.75). These results provide additional evidence for the association between proinflammatory diet and head and neck cancer. PMID- 29696633 TI - Generation of reporter hESCs by targeting EGFP at the CD144 locus to facilitate the endothelial differentiation. AB - Reporter embryonic stem cell (ESC) lines with tissue-specific reporter genes may contribute to optimizing the differentiation conditions in vitro as well as trafficking transplanted cells in vivo. To optimize and monitor endothelial cell (EC) differentiation specifically, here we targeted the enhanced green fluorescent protein (EGFP) reporter gene at the junction of 5'UTR and exon2 of the endothelial specific marker gene CD144 using TALENs in human ESCs (H9) to generate a EGFP-CD144-reporter ESC line. The reporter cells expressed EGFP and CD144 increasingly and specifically without unexpected effects during the EC differentiation. The EC differentiation protocol was optimized and applied to EC differentiation from hiPSCs, resulting in an efficient and simplified endothelial differentiation approach. Here we created our own optimized and robust protocol for EC differentiation of hESCs and hiPSCs by generating the lineage-specific site-specific integration reporter cell lines, showing great potential to be applied in the fields such as trafficking gene and cell fate in vivo in preclinical animal models. PMID- 29696634 TI - Age matters in ALL. PMID- 29696635 TI - Effectiveness of an anger control program among veterans with PTSD and other mental health issues: A comparative study. AB - OBJECTIVE: This study examines the effectiveness of an anger management program among veterans with posttraumatic stress disorder (PTSD) and other mental health issues. METHOD: Veterans with (n = 76) and without (n = 58) PTSD completed anger management groups at the Crescenz Veterans Affairs Medical Center. Self-rated checklists of anger and PTSD symptoms (for those with PTSD) were completed before and after the group. RESULTS: Significant improvement in anger was observed in the overall sample (p < .001) but did not differ based on PTSD diagnosis. No significant PTSD symptom changes were observed. CONCLUSIONS: Veterans with broad mental health concerns benefited significantly from this anger management program, consistent with prior research. Implications for program improvement and future research are discussed. PMID- 29696636 TI - Oncolytic activity of the rhabdovirus VSV-GP against prostate cancer. AB - Oncolytic viruses, including the oncolytic rhabdovirus VSV-GP tested here, selectively infect and kill cancer cells and are a promising new therapeutic modality. Our aim was to study the efficacy of VSV-GP, a vesicular stomatitis virus carrying the glycoprotein of lymphocytic choriomeningitis virus, against prostate cancer, for which current treatment options still fail to cure metastatic disease. VSV-GP was found to infect 6 of 7 prostate cancer cell lines with great efficacy. However, susceptibility was reduced in one cell line with low virus receptor expression and in 3 cell lines after interferon alpha treatment. Four cell lines had developed resistance to interferon type I at different levels of the interferon signaling pathway, resulting in a deficient antiviral response. In prostate cancer mouse models, long-term remission was achieved upon intratumoral and, remarkably, also upon intravenous treatment of subcutaneous tumors and bone metastases. These promising efficacy data demonstrate that treatment of prostate cancer with VSV-GP is feasible and safe in preclinical models and encourage further preclinical and clinical development of VSV-GP for systemic treatment of metastatic prostate cancer. PMID- 29696637 TI - Long-term longitudinal changes in baseline PSA distribution and estimated prevalence of prostate cancer in male Japanese participants of population-based PSA screening. AB - Japan has experienced a drastic increase in the incidence of prostate cancer (PC). To assess changes in the risk for PC, we investigated baseline prostate specific antigen (PSA) levels in first-time screened men, across a 25-year period. In total, 72,654 men, aged 50-79, underwent first-time PSA screening in Gunma prefecture between 1992 and 2016. Changes in the distribution of PSA levels were investigated, including the percentage of men with a PSA above cut-off values and linear regression analyses comparing log10 PSA with age. The 'ultimate incidence' of PC and clinically significant PC (CSPC) were estimated using the PC risk calculator. Changes in the age-standardized incidence rate (AIR) during this period were analyzed. The calculated coefficients of linear regression for age versus log10 PSA fluctuated during the 25-year period, but no trend was observed. In addition, the percentage of men with a PSA above cut-off values varied in each 5-year period, with no specific trend. The 'risk calculator (RC)-based AIR' of PC and CSPC were stable between 1992 and 2016. Therefore, the baseline risk for developing PC has remained unchanged in the past 25 years, in Japan. The drastic increase in the incidence of PC, beginning around 2000, may be primarily due to increased PSA screening in the country. PMID- 29696638 TI - A simple self-report health assessment questionnaire to identify oral diseases. AB - BACKGROUND: One approach to addressing oral health disparities for at-risk populations has been to increase discussion of oral health by non-dental healthcare providers. This study examined the accuracy of a simple instrument to detect individuals with a history of dental disease, which would then allow referral for an oral health evaluation. MATERIALS AND METHODS: A two-question instrument was evaluated for the relationship to oral diseases, periodontal disease, and decayed, missing and filled teeth in 391 individuals seen in a dental school clinic for non-emergent dental care over a 3-month period. Clinical dental findings were used as outcome variables. The oral health parameters were dichotomised, using different levels of disease severity. The criteria were increased and decreased in an effort to test the robustness of our method. RESULTS: While the sensitivity outcomes with one question alone showed significant ability to predict oral disease (59-71%), the addition of a second self-assessment question increased the sensitivity (76-91%) for all oral health parameters studied. As the criteria for oral disease increased so did the sensitivity of this instrument. CONCLUSION: The results presented here offer evidence that a simple two-item questionnaire is an efficient and effective method of detecting populations at-risk for oral diseases. PMID- 29696639 TI - Virtually the ultimate research lab. AB - Virtual reality (VR) can serve as a viable platform for psychological research. The real world with many uncontrolled variables can be masked to immerse participants in complex interactive environments that are under full experimental control. However, as any other laboratory setting, these simulations are not perceived equally to reality and they also afford different behaviour. We need a better understanding of these differences, which are often related to parameters of the technical setup, to support valid interpretations of experimental results. PMID- 29696640 TI - Parental psychological control, adolescent self-criticism, and adolescent depressive symptoms: A latent change modeling approach in Belgian adolescents. AB - OBJECTIVE: At the level of both between-person differences and within-person changes across time, parental achievement-oriented psychological control may influence the development of adolescent self-criticism, which in turn may increase vulnerability for adolescent depression. METHOD: In a two-wave prospective study of 368 adolescents (age 13-17 years), Latent Change Modeling was used with Belgian adolescents' self-report measures. RESULTS: For mothers and fathers separately, adolescent self-criticism intervened in associations between achievement-oriented psychological control and adolescent depressive symptoms, at the level of both between-person differences and within-person changes. When investigating parents simultaneously, only maternal parenting was related directly and indirectly to adolescent depressive symptoms. CONCLUSIONS: Our results underscore the importance of personality-related vulnerability in associations between the parenting environment and symptoms of psychopathology during adolescent development. PMID- 29696641 TI - The pathfinder study among schoolchildren in the Republic of Moldova: dental caries experience. AB - OBJECTIVES: The aim of the present research was to evaluate the current caries experience of schoolchildren in the Republic of Moldova. METHODS: A pathfinder study was planned and executed according to the World Health Organization (WHO) recommendations. Caries experience was recorded in three large cities (the capital city and two other large cities) and four villages throughout the country. Within each site and age group, school clusters were randomly chosen. Three different age groups (6, 12 and 15 years) of schoolchildren were assessed. RESULTS: Overall, 1,100 children were examined: 724 from cities and 376 from the villages. Among the study population, 408 (37.1%) were female and 692 (62.9%) were male, 380 were 6 years of age, 365 were 12 years and 355 were 15 years. The prevalence of caries experience [decayed, missing and filled scores of > 1 for primary (dmft) and secondary (DMFT) teeth] was 87.4% (dmft score = 3.9 +/- 3.0) for 6-year-old participants, 77.53% (DMFT score = 2.7 +/- 2.3) for 12-year-old participants and 86.2% (DMFT score = 3.7 +/- 2.9) for 15-year-old participants. For the 12-year group, a higher proportion of caries-free children were detected in urban areas than in rural areas (25.5% vs. 15.5%, P = 0.003). We found more caries-free participants among 12-year-olds than among 15-year-olds (22.5% vs. 13.8%, P = 0.004). CONCLUSIONS: These WHO key index age groups may be inserted into the global oral health databank and provide a 'pathfinder' baseline for formulating and conducting future public oral health programmes in the Republic of Moldova, with an emphasis on children in rural locations. PMID- 29696643 TI - Clopidogrel Increases Dasabuvir Exposure With or Without Ritonavir, and Ritonavir Inhibits the Bioactivation of Clopidogrel. AB - Dasabuvir is mainly metabolized by cytochrome P450 (CYP) 2C8 and is predominantly used in a regimen containing ritonavir. Ritonavir and clopidogrel are inhibitors of CYP3A4 and CYP2C8, respectively. In a randomized, crossover study in 12 healthy subjects, we examined the impact of clinical doses of ritonavir (for 5 days), clopidogrel (for 3 days), and their combination on dasabuvir pharmacokinetics, and the effect of ritonavir on clopidogrel. Clopidogrel, but not ritonavir, increased the geometric mean AUC0-infinity of dasabuvir 4.7-fold; range 2.0-10.1-fold (P = 8.10-7 ), compared with placebo. Clopidogrel and ritonavir combination increased dasabuvir AUC0-infinity 3.9-fold; range 2.1-7.9 fold (P = 2.10-6 ), compared with ritonavir alone. Ritonavir decreased the AUC0 4h of clopidogrel active metabolite by 51% (P = 0.0001), and average platelet inhibition from 51% without ritonavir to 31% with ritonavir (P = 0.0007). In conclusion, clopidogrel markedly elevates dasabuvir concentrations, and patients receiving ritonavir are at risk for diminished clopidogrel response. PMID- 29696644 TI - Validating an abbreviated version of the Obsessive Beliefs Questionnaire. AB - OBJECTIVES: A shorter version of the Obsessive Beliefs Questionnaire (OBQ-44) is needed to promote the use of this measure in research and increase our understanding of cognitive phenomena maintaining obsessive-compulsive disorder (OCD). Additionally, an abbreviated version of the OBQ-44 would encourage frequent monitoring of dysfunctional beliefs in intensive care settings. This study aimed to validate a nine-item version of the questionnaire (OBQ-9). METHOD: Participants seeking intensive/residential treatment for OCD (N = 311) completed relevant measures on a weekly basis and at admission and discharge. RESULTS: A confirmatory factor analysis revealed that the OBQ-9's factor structure replicated the three-factor solution of the OBQ-44. The OBQ-9 demonstrated good psychometric properties and convergent validity and was sensitive to treatment effects. Finally, the OBQ-9 subscales predicted specific OCD dimensions over and above depressive symptoms. CONCLUSION: The OBQ-9 appears to be a psychometrically sound tool for routine outcome monitoring of dysfunctional beliefs in hospital based settings. PMID- 29696642 TI - Air pollution and incidence of cancers of the stomach and the upper aerodigestive tract in the European Study of Cohorts for Air Pollution Effects (ESCAPE). AB - Air pollution has been classified as carcinogenic to humans. However, to date little is known about the relevance for cancers of the stomach and upper aerodigestive tract (UADT). We investigated the association of long-term exposure to ambient air pollution with incidence of gastric and UADT cancer in 11 European cohorts. Air pollution exposure was assigned by land-use regression models for particulate matter (PM) below 10 um (PM10 ), below 2.5 um (PM2.5 ), between 2.5 and 10 um (PMcoarse ), PM2.5 absorbance and nitrogen oxides (NO2 and NOX ) as well as approximated by traffic indicators. Cox regression models with adjustment for potential confounders were used for cohort-specific analyses. Combined estimates were determined with random effects meta-analyses. During average follow-up of 14.1 years of 305,551 individuals, 744 incident cases of gastric cancer and 933 of UADT cancer occurred. The hazard ratio for an increase of 5 ug/m3 of PM2.5 was 1.38 (95% CI 0.99; 1.92) for gastric and 1.05 (95% CI 0.62; 1.77) for UADT cancers. No associations were found for any of the other exposures considered. Adjustment for additional confounders and restriction to study participants with stable addresses did not influence markedly the effect estimate for PM2.5 and gastric cancer. Higher estimated risks of gastric cancer associated with PM2.5 was found in men (HR 1.98 [1.30; 3.01]) as compared to women (HR 0.85 [0.5; 1.45]). This large multicentre cohort study shows an association between long-term exposure to PM2.5 and gastric cancer, but not UADT cancers, suggesting that air pollution may contribute to gastric cancer risk. PMID- 29696645 TI - The relationship between personal growth and psychological functioning in individuals treated in a partial hospital setting. AB - OBJECTIVES: We examined whether current level of personal growth and changes in personal growth predicted treatment response among participants in a partial hospital setting. METHOD: Patients (N = 269; aged 18-70 years, M = 33.6; 52.4% female) completed measures of personal growth initiative (PGI), valuing personal growth (VPG), and psychological functioning measures at treatment admission and discharge from a partial hospital. RESULTS: PGI and VPG were negatively associated with depression and positively associated with psychological well being. Baseline PGI and VPG did not predict changes in psychological functioning at discharge. PGI and VPG significantly increased following treatment, and increases were associated with decreases in depression and increases in well being over and above previously established predictors. CONCLUSIONS: Valuing personal growth for intrinsic reasons and active engagement in the personal growth process may be important characteristics to cultivate in psychotherapy as they are malleable and negatively related to depression. PMID- 29696646 TI - Gene expression differences among different MSI statuses in colorectal cancer. AB - Colorectal cancer is the third most common cancer in males and second in females. This disease can be caused by genetic and acquired/environmental factors. Microsatellite instability (MSI) is one of the major mechanisms in colorectal cancer. This mechanism is a specific condition of genetic hyper mutability that results from incompetent DNA mismatch repair. MSI has been applied to classify different colorectal cancer subtypes. However, the effects of MSI status on gene expression are largely unknown. In our study, we integrated the gene expression profile and MSI status of all CRC samples from the TCGA database, and then categorized the CRC samples into three subgroups, namely, MSI-stable, MSI-low, and MSI-high, according to the MSI status. We applied a novel computational method based on machine learning and screened the genes specifically expressed for the different colorectal cancer subtypes. The results showed the distinct mechanisms of the different colorectal cancer subtypes with MSI status and provided the genes that may be the optimal standards to further classify the various molecular subtypes of colorectal cancer with distinct MSI status. PMID- 29696647 TI - Child social and emotion functioning as predictors of therapeutic alliance in cognitive-behavioral therapy for anxiety. AB - OBJECTIVE: This study examined baseline child social and emotional functioning as predictors of therapeutic alliance during a cognitive-behavioral therapy (CBT) program for children with anxiety disorders. It was hypothesized that better social and emotional functioning at baseline would be related to stronger alliance initially and over the course of treatment. METHOD: Ninety-two anxious youth, ages 7-11 years (M age = 8.93 years, SD = 1.64; 42% female) participated. Children, caregivers, and teachers completed measures of child social and emotional functioning. Therapeutic alliance was measured using therapist-rated and observer-coded reports. RESULTS: Receiving prosocial support from peers and emotion regulation (ER) were both related to initial rating and slope of alliance. CONCLUSIONS: Child social and emotional functioning enhances our understanding of how the alliance is formed and in identifying children who might be at risk for difficulties in developing a strong therapeutic relationship. PMID- 29696649 TI - The efficacy of laser therapy: Commentary on the American Academy of Periodontology best evidence consensus meeting. PMID- 29696648 TI - A prospective evaluation of plasma polyphenol levels and colon cancer risk. AB - Polyphenols have been shown to exert biological activity in experimental models of colon cancer; however, human data linking specific polyphenols to colon cancer is limited. We assessed the relationship between pre-diagnostic plasma polyphenols and colon cancer risk in a case-control study nested within the European Prospective Investigation into Cancer and Nutrition study. Using high pressure liquid chromatography coupled to tandem mass spectrometry, we measured concentrations of 35 polyphenols in plasma from 809 incident colon cancer cases and 809 matched controls. We used multivariable adjusted conditional logistic regression models that included established colon cancer risk factors. The false discovery rate (qvalues ) was computed to control for multiple comparisons. All statistical tests were two-sided. After false discovery rate correction and in continuous log2 -transformed multivariable models, equol (odds ratio [OR] per log2 -value, 0.86, 95% confidence interval [95% CI] = 0.79-0.93; qvalue = 0.01) and homovanillic acid (OR per log2 -value, 1.46, 95% CI = 1.16-1.84; qvalue = 0.02) were associated with colon cancer risk. Comparing extreme fifths, equol concentrations were inversely associated with colon cancer risk (OR = 0.61, 95% CI = 0.41-0.91, ptrend = 0.003), while homovanillic acid concentrations were positively associated with colon cancer development (OR = 1.72, 95% CI = 1.17 2.53, ptrend < 0.0001). No heterogeneity for these associations was observed by sex and across other colon cancer risk factors. The remaining polyphenols were not associated with colon cancer risk. Higher equol concentrations were associated with lower risk, and higher homovanillic acid concentrations were associated with greater risk of colon cancer. These findings support a potential role for specific polyphenols in colon tumorigenesis. PMID- 29696650 TI - Patterns of Symbiodinium (Dinophyceae) diversity and assemblages among diverse hosts and the coral reef environment of Lizard Island, Australia. AB - Large-scale environmental disturbances may impact both partners in coral host Symbiodinium systems. Elucidation of the assembly patterns in such complex and interdependent communities may enable better prediction of environmental impacts across coral reef ecosystems. In this study, we investigated how the community composition and diversity of dinoflagellate symbionts in the genus Symbiodinium were distributed among 12 host species from six taxonomic orders (Actinaria, Alcyonacea, Miliolida, Porifera, Rhizostoma, Scleractinia) and in the reef water and sediments at Lizard Island, Great Barrier Reef before the 3rd Global Coral Bleaching Event. 454 pyrosequencing of the ITS2 region of Symbiodinium yielded 83 operational taxonomic units (OTUs) at a 97% similarity cut-off. Approximately half of the Symbiodinium OTUs from reef water or sediments were also present in symbio. OTUs belonged to six clades (A-D, F-G), but community structure was uneven. The two most abundant OTUs (100% matches to types C1 and A3) comprised 91% of reads and OTU C1 was shared by all species. However, sequence-based analysis of these dominant OTUs revealed host species specificity, suggesting that genetic similarity cut-offs of Symbiodinium ITS2 data sets need careful evaluation. Of the less abundant OTUs, roughly half occurred at only one site or in one species and the background Symbiodinium communities were distinct between individual samples. We conclude that sampling multiple host taxa with differing life history traits will be critical to fully understand the symbiont diversity of a given system and to predict coral ecosystem responses to environmental change and disturbance considering the differential stress response of the taxa within. PMID- 29696651 TI - "When illness dictates who I am": A hermeneutic approach to older adults with heart disease. AB - BACKGROUND AND PURPOSE: Heart failure (HF) is increasing in prevalence and will continue to do so with an aging population. Few studies describe, from a lifeworld perspective, the experiences of elderly people who are very ill and living with advanced HF, and how meaning about personal dignity in daily life is created. METHODS: Data were collected by in-depth interviews with 12 Portuguese older people with advanced HF. The transcribed texts from the interviews were analyzed using the phenomenological hermeneutical method. FINDINGS: The results demonstrate two main themes: the perspective of oneself as vulnerable and as a significant person. CONCLUSION: Findings demonstrate the need for health care professionals to find an approach that ensures both quality medical care and, at the same time, acknowledges the uniqueness of each subject. From the elderly people's stories, it is clear that in order to retain a sense of dignity people need to be seen and respected for who they are. The information about life stories is often used to make possible biographical oriented care. PMID- 29696652 TI - Zinc isotope fractionation during grain filling of wheat and a comparison of zinc and cadmium isotope ratios in identical soil-plant systems. AB - Remobilization of zinc (Zn) from shoot to grain contributes significantly to Zn grain concentrations and thereby to food quality. On the other hand, strong accumulation of cadmium (Cd) in grain is detrimental for food quality. Zinc concentrations and isotope ratios were measured in wheat shoots (Triticum aestivum) at different growth stages to elucidate Zn pathways and processes in the shoot during grain filling. Zinc mass significantly decreased while heavy Zn isotopes accumulated in straw during grain filling (Delta66 Znfull maturity flowering = 0.21-0.310/00). Three quarters of the Zn mass in the shoot moved to the grains, which were enriched in light Zn isotopes relative to the straw (Delta66 Zngrain-straw -0.21 to -0.310/00). Light Zn isotopes accumulated in phloem sinks while heavy isotopes were retained in phloem sources likely because of apoplastic retention and compartmentalization. Unlike for Zn, an accumulation of heavy Cd isotopes in grains has previously been shown. The opposing isotope fractionation of Zn and Cd might be caused by distinct affinities of Zn and Cd to oxygen, nitrogen, and sulfur ligands. Thus, combined Zn and Cd isotope analysis provides a novel tool to study biochemical processes that separate these elements in plants. PMID- 29696653 TI - River flow, zooplankton and dominant zooplanktivorous fish dynamics in a warm temperate South African estuary. AB - The possible links between river flow, zooplankton abundance and the responses of zooplanktivorous fishes to physico-chemical and food resource changes are assessed. To this end, the seasonal abundance, distribution and diet of the estuarine round-herring Gilchristella aestuaria and Cape silverside Atherina breviceps were studied in the Kariega Estuary. Spatio-temporal differences were determined for selected physico-chemical variables, zooplankton abundance and zooplanktivorous fish abundance and distribution. Results indicated that, following a river flood event in winter (>30 m3 s-1 ), altered physico-chemical conditions occurred throughout the estuary and depressed zooplankton stocks. Abundance of G. aestuaria was highest in spring, with this species dominant in the upper and middle zones of the estuary, while A. breviceps was dominant in summer and preferred the middle and lower zones. The catch per unit of effort of both zooplanktivores also declined significantly following the flooding, thus suggesting that these fishes are reliant on zooplankton as a primary food source for healthy populations. Copepods dominated the stomach contents of both fish species, indicating a potential for strong interspecific competition for food, particularly in the middle reaches. Temporal differences were evident in dietary overlap between the two zooplanktivorous fish species and were correlated with river flow, zooplankton availability and fish distribution. The findings of this study emphasize the close trophic linkages between zooplankton and zooplanktivorous fishes under changing estuarine environmental conditions, particularly river flow and provide important baseline information for similar studies elsewhere in South Africa and the rest of the world. PMID- 29696654 TI - The effect of casein, hydrolyzed casein, and whey proteins on urinary and postprandial plasma metabolites in overweight and moderately obese human subjects. AB - BACKGROUND: Casein and whey proteins differ in amino acid composition and absorption rate; however, the absorption rate of casein can be increased to mimic that of whey proteins by exogenous hydrolysis. In view of these compositional differences, we studied the metabolic responses to intake of casein, hydrolyzed casein, and whey proteins in overweight and moderately obese men and women by investigating select urinary and blood plasma metabolites. RESULTS: A total of 21 urinary and 23 plasma metabolites were identified by nuclear magnetic resonance spectroscopy. The postprandial plasma metabolites revealed a significant diet time interaction for isoleucine (P = 0.001) and tyrosine (P = 0.001). The level of isoleucine and tyrosine peaked 90 min postprandially with a 1.4-fold difference following intake of whey proteins compared with either casein or hydrolyzed casein. A 1.2-fold higher urinary level of lactate was observed after intake of whey proteins compared with intake of intact casein (P < 0.01). CONCLUSION: The plasma metabolites revealed different amino acid profiles reflecting the amino acid composition of casein and whey proteins. Furthermore, the results support that casein hydrolysates neither affect the postprandial amino acid absorption rate nor the amino acid level compared with that of intact casein. The urinary lactate increases following whey protein intake might indicate a higher metabolism of glucogenic amino acids. (c) 2018 Society of Chemical Industry. PMID- 29696655 TI - Determination of honey adulteration with beet sugar and corn syrup using infrared spectroscopy and genetic-algorithm-based multivariate calibration. AB - BACKGROUND: Fourier transform infrared spectroscopy (FTIR) equipped with attenuated total reflectance accessory was used to determine honey adulteration. Adulterated honey samples were prepared by adding corn syrup, beet sugar and water as adulterants to the pure honey samples in various amounts. The spectra of adulterated and pure honey samples (n = 209) were recorded between 4000 and 600 cm-1 wavenumber range. RESULTS: Genetic-algorithm-based inverse least squares (GILS) and partial least squares (PLS) methods were used to determine honey content and amount of adulterants. Results indicated that the multivariate calibration generated with GILS could produce successful models with standard error of cross-validation in the range 0.97-2.52%, and standard error of prediction between 0.90 and 2.19% (% w/w) for all the components contained in the adulterated samples. Similar results were obtained with PLS, generating slightly larger standard error of cross-validation and standard error of prediction values. CONCLUSION: The fact that the models were generated with several honey samples coming from various different botanical and geographical origins, quite successful results were obtained for the detection of adulterated honey samples with a simple Fourier transform infrared spectroscopy technique. Having a genetic algorithm for variable selection helped to build somewhat better models with GILS compared with PLS. (c) 2018 Society of Chemical Industry. PMID- 29696656 TI - Winter Meeting. Abstracts of the 209th Meeting of the Pathological Society of Great Britain & Ireland, 25-26 January 2018, London. PMID- 29696657 TI - Surgical simulation and applicant perception in otolaryngology residency interviews. AB - OBJECTIVE: The traditional resident applicant interview involves multiple oral interviews. The implementation of surgical simulations adds an additional dimension of assessment but can be perceived in a stressful way by applicants. The purpose of this project is to describe low-fidelity simulations that were implemented for the 2016 to 2017 residency interviews and obtain applicant perception of these simulations. METHODS: Six simulation modules were created, which reflected tasks used in six subspecialties within otolaryngology (pediatrics, otology, laryngology, facial plastics, rhinology, and head/neck). Applicants were guided in the procedures by both an attending and resident. Afterward, applicants were anonymously surveyed on their perception of the tasks using a 5-point Likert scale (1 = Strongly Disagree, 2 = Somewhat Disagree, 3 = Neutral, 4 = Somewhat Agree, 5 = Strongly Agree). RESULTS: A total of 41 applicants were interviewed. The following were measured: enjoyable (98.5% strongly agree, 2.5% somewhat agree; mean: 4.97; 95% confidence interval [CI], 4.92, 5.02), educational (88% strongly agree, 12% somewhat agree; mean: 4.88; 95% CI, 4.78, 4.98), recommended for future use (92.7% strongly agree, 7.3% somewhat agree; mean: 4.93; 95% CI, 4.85, 5.01), and stressful (63.5% strongly disagree, 19.5% somewhat disagree, 17% neutral; mean: 1.54; 95% CI, 1.30, 1.78). CONCLUSION: Implementation of a low-fidelity multi-station surgical simulation experience is feasible in an interview day. Majority of applicants viewed the simulations in a positive manner. Surgical simulations may provide a useful holistic evaluation of an applicant in future interviews, especially if done in a setting that minimizes stress and maximizes the educational experience. LEVEL OF EVIDENCE: 2b. Laryngoscope, 2503-2507, 2018. PMID- 29696658 TI - Effect of a grapevine-shoot waste extract on red wine aromatic properties. AB - BACKGROUND: The use of a grapevine-shoot extract (VIN) is being studied as an alternative to sulfur dioxide (SO2 ). VIN stabilizes anthocyanins and preserves polyphenolic compounds, and thus improves chromatic wine properties. In this study, selected aroma compounds (esters, C13 -norisoprenoids, oxidation and vine shoot-related compounds), sensory analysis and the olfactometric profile were determined in the wines treated with VIN at two concentrations. RESULTS: Treatment with VIN hardly modified the content of esters and oxidation-related compounds in the wines. However, the high beta-damascenone and isoeugenol contents and the increase in astringency at tasting in VIN wines were noteworthy, as were some odorant zones. All these were established as VIN markers after the chemometric data analysis. CONCLUSION: These data revealed that only the lowest dose tested may be recommended as a suitable alternative to SO2 . Although some aromatic properties of these wines may change, these changes are not considered to affect the quality of the wines negatively. These results are useful for wineries, which face having to discover the aroma-related processes in the challenge of producing SO2 -free wines without detriment to their sensory properties. (c) 2018 Society of Chemical Industry. PMID- 29696659 TI - Soil environment is a key driver of adaptation in Medicago truncatula: new insights from landscape genomics. AB - Spatial differences in environmental selective pressures interact with the genomes of organisms, ultimately leading to local adaptation. Landscape genomics is an emergent research area that uncovers genome-environment associations, thus allowing researchers to identify candidate loci for adaptation to specific environmental variables. In the present study, we used latent factor mixed models (LFMMs) and Moran spectral outlier detection/randomization (MSOD-MSR) to identify candidate loci for adaptation to 10 environmental variables (climatic, soil and atmospheric) among 43 515 single nucleotide polymorphisms (SNPs) from 202 accessions of the model legume Medicago truncatula. Soil variables were associated with a large number of candidate loci identified through both LFMMs and MSOD-MSR. Genes tagged by candidate loci associated with drought and salinity are involved in the response to biotic and abiotic stresses, while those tagged by candidates associated with soil nitrogen and atmospheric nitrogen, participate in the legume-rhizobia symbiosis. Candidate SNPs identified through both LFMMs and MSOD-MSR explained up to 56% of variance in flowering traits. Our findings highlight the importance of soil in driving adaptation in the system and elucidate the basis of evolutionary potential of M. truncatula to respond to global climate change and anthropogenic disruption of the nitrogen cycle. PMID- 29696660 TI - Mentoring Program Enhancements Supporting Effective Mentoring of Children of Incarcerated Parents. AB - Children of incarcerated parents (COIP) are at risk for a range of negative outcomes; however, participating in a mentoring relationship can be a promising intervention for these youth. This study examined the impact of mentoring and mentoring program enhancements on COIP. Secondary data analyses were conducted on an archival database consisting of 70,729 matches from 216 Big Brothers Big Sisters (BBBS) local agencies to establish the differential effects of mentoring on COIP. A subset of 45 BBBS agencies, representing 25,252 matches, participated in a telephone interview about program enhancements for better serving COIP. Results revealed that enhanced program practices, including having specific program goals, providing specialized mentor training, and receiving additional funding resulted in better outcomes for COIP matches. Specifically, specialized mentor training and receiving additional funding for serving matches containing COIP were associated with longer and stronger matches. Having specific goals for serving COIP was associated with higher educational expectations in COIP. Results are discussed in terms of benefits of a relationship-based intervention for addressing the needs of COIP and suggestions for program improvements when mentoring programs are serving this unique population of youth. PMID- 29696661 TI - Integration of pharmacokinetic-pharmacodynamic for dose optimization of doxycycline against Haemophilus parasuis in pigs. AB - The aims of this study were to establish optimal doses of doxycycline (dox) against Haemophilus parasuis on the basis of pharmacokinetic-pharmacodynamic (PK PD) integration modeling. The infected model was established by intranasal inoculation of organism in pigs and confirmed by clinical signs, blood biochemistry, and microscopic examinations. The recommended dose (20 mg/kg b.w.) was administered in pigs through intramuscular routes for PK studies. The area under the concentration 0- to 24-hr curve (AUC0-24 ), elimination half-life (T1/2ke ), and mean residence time (MRT) of dox in healthy and H. parasuis infected pigs were 55.51 +/- 5.72 versus 57.10 +/- 4.89 MUg.hr/ml, 8.28 +/- 0.91 versus 9.80 +/- 2.38 hr, and 8.43 +/- 0.27 versus 8.79 +/- 0.18 hr, respectively. The minimal inhibitory concentration (MIC) of dox against 40 H. parasuis isolates was conducted through broth microdilution method, the corresponding MIC50 and MIC90 were 0.25 and 1 MUg/ml, respectively. The Ex vivo growth inhibition data suggested that dox exhibited a concentration-dependent killing mechanism. Based on the observed AUC24 hr /MIC values by modeling PK-PD data in H. parasuis infected pigs, the doses predicted to obtain bacteriostatic, bactericidal, and elimination effects for H. parasuis over 24 hr were 5.25, 8.55, and 10.37 mg/kg for the 50% target attainment rate (TAR), and 7.26, 13.82, and 18.17 mg/kg for 90% TAR, respectively. This study provided a more optimized alternative for clinical use and demonstrated that the dosage 20 mg/kg of dox by intramuscular administration could have an effective bactericidal activity against H. parasuis. PMID- 29696662 TI - Unity in diversity: structural and functional insights into the ancient partnerships between plants and fungi. AB - Contents Summary 996 I. Introduction 996 II. An ancient, and diverse, symbiosis 998 III. Structural diversity in ancient plant-fungal partnerships 1000 IV. Mycorrhizal unity in host plant nutrition 1002 V. Plant-to-fungus carbon transfer 1003 VI. From individuals to networks 1003 VII. Diverse responses of mycorrhizal functioning to dynamic environments 1006 VIII. Summary of future research direction 1007 Acknowledgements 1006 References 1006 SUMMARY: Mycorrhizal symbiosis is an ancient and widespread mutualism between plants and fungi that facilitated plant terrestrialisation > 500 million years ago, with key roles in ecosystem functioning at multiple scales. Central to the symbiosis is the bidirectional exchange of plant-fixed carbon for fungal-acquired nutrients. Within this unifying role of mycorrhizas, considerable diversity in structure and function reflects the diversity of the partners involved. Early diverging plants form mutualisms not only with arbuscular mycorrhizal Glomeromycotina fungi, but also with poorly characterised Mucoromycotina, which may also colonise the roots of 'higher' plants as fine root endophytes. Functional diversity in these symbioses depends on both fungal and plant life histories and is influenced by the environment. Recent studies have highlighted the roles of lipids/fatty acids in plant-to-fungus carbon transport and potential contributions of Glomeromycotina fungi to plant nitrogen nutrition. Together with emerging appreciation of mycorrhizal networks as multi-species resource-sharing systems, these insights are broadening our views on mycorrhizas and their roles in nutrient cycling. It is crucial that the diverse array of biotic and abiotic factors that together shape the dynamics of carbon-for-nutrient exchange between plants and fungi are integrated, in addition to embracing the unfolding and potentially key role of Mucoromycotina fungi in these processes. PMID- 29696663 TI - Dark chocolate with a high oleic peanut oil microcapsule content. AB - BACKGROUND: In accordance with the market demand for healthier indulgent food products, the present study aimed to determine the viability of the industrial production of dark chocolate with microcapsules of high oleic peanut oil content. Microcapsules of high oleic peanut oil were added to a control formulation using variations of mixing time. RESULTS: The chocolates presented a rheology characterized by a pseudoplastic behavior adjusted to the Casson model (r > 0.98) and calorimetric behavior indicating melting onset (21 degrees C), peak melting (32 degrees C) and melting end (41 degrees C); caramelization peak (183 degrees C); and carbonization peak (237 degrees C), being considered thermal stable. The mixing time and the amount of microcapsules added to the control chocolate did not significantly influence the flow limit (11.09 +/- 1.73 Pa) or the physical characteristics of the chocolate: pH (6.74 +/- 0.14), maximum particle size (0.019 +/- 0.001 mm), water activity (0.358 +/- 0.023) and brittleness (18.61 +/- 3.74 N). However, the addition of microcapsules with a high oleic peanut oil content significantly increased the chocolate whiteness index, thixotropy and Casson's plastic viscosity, although it did not have a significant influence on the mixing time. CONCLUSION: The products obtained have a desirable quality and physical properties, being suitable for industrial production. (c) 2018 Society of Chemical Industry. PMID- 29696665 TI - Using the chronic kidney disease guidelines to evaluate the renal safety of tenofovir disoproxil fumarate in hepatitis B patients. AB - BACKGROUND: Renal dysfunction remains an issue in tenofovir disoproxil fumarate (TDF) for chronic hepatitis B (CHB) patients. AIM: To evaluate renal safety of TDF according to the Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. METHODS: We retrospectively recruited CHB patients who received either TDF or entecavir (ETV) monotherapy from January 2008 to August 2015. After excluding confounding conditions, 253 patients who received TDF were randomly matched 1:2 with 506 patients who received ETV through the propensity scores, which consisted of age, gender, cirrhosis, chronic kidney disease (CKD) and estimated glomerular filtration rate (eGFR). Renal function deterioration was defined as a drop in GFR category accompanied with a >=25% eGFR decline. Cumulative incidences of and hazard ratios (HRs) for renal dysfunction were analysed. RESULTS: The mean eGFR decline was significantly greater in the TDF group over 48 months (TDF vs ETV: 15.73 mL/min/1.73 m2 , 95% confidence interval [CI]: 13.76-17.70 vs 5.96 mL/min/1.73 m2 , 95% CI: 4.72-7.19; P < 0.001). The cumulative incidence of renal function deterioration was significantly higher in the TDF group (TDF vs ETV: 11.1%, 95% CI: 7.4-14.8 vs 1.7%, 95% CI: 1.0-2.4; P < 0.001). After adjusting for age, pre-existing CKD and diabetes, TDF was independently associated with an increased risk of renal function deterioration (HR 5.36, 95% CI: 2.16-13.35; P < 0.001). Pre-existing CKD (HR 6.71, 95% CI: 2.25 17.65), proteinuria (HR 3.39, 95% CI: 1.23-9.39), and haematuria (HR 4.25, 95% CI: 1.32-13.68) were also independent factors of renal dysfunction. CONCLUSION: By following the KDIGO guidelines, we confirmed that TDF was associated with a higher risk of renal dysfunction as compared to ETV. PMID- 29696664 TI - Atrial fibrillation patient preferences for oral anticoagulation and stroke knowledge: Results of a conjoint analysis. AB - BACKGROUND: Guidelines recommend that patients with atrial fibrillation (AF) are involved in oral anticoagulant (OAC) treatment decisions. Understanding which OAC attributes AF patients value most could help optimize treatment. OBJECTIVE: To assess the relationship between patient's stroke knowledge and their preferences for specific OAC attributes. METHODS: A cross-sectional online survey was conducted in patients with nonvalvular AF taking an OAC for stroke prevention in the United States, Canada, Germany, France, and Japan. Patients were asked about their stroke knowledge, perception of the seriousness of AF and concern about stroke, and to rank 7 OAC attributes in order of importance. A conjoint analysis was performed to determine the inherent value of 4 attributes. RESULTS: In total, 937 patients (mean age [standard deviation] 54.3 [16.6] years; 37.1% female) participated. Of these, 19.5%, 27.9%, and 29.8% had good, moderate, and low stroke knowledge, respectively; 22.8% had no stroke knowledge. Overall, 39.4% of patients (47.5% with good stroke knowledge) perceived AF as very/extremely serious. The OAC attribute ranked as most important was stroke prevention followed by major bleeding risk, other side effects, dosing frequency, antidote availability, dietary restrictions, and use with/without food. In the conjoint analysis, stroke risk reduction was the most valued property, followed by reduction in major bleeding risk, less frequent administration, and administration with/without food. Preferences did not differ with level of stroke knowledge, perception of seriousness of AF, concern of stroke, or medication burden. CONCLUSIONS: Most AF patients consider efficacy and safety to be the most important OAC attributes, whereas dosing frequency was deemed as less important. PMID- 29696666 TI - Randomised clinical trial: a leucine-metformin-sildenafil combination (NS-0200) vs placebo in patients with non-alcoholic fatty liver disease. AB - BACKGROUND: Sirtuin 1 (Sirt1) is suppressed in non-alcoholic fatty liver disease (NAFLD), while its' stimulation or overexpression results in reduced disease severity in pre-clinical NAFLD models. Leucine allosterically activates Sirt1 and synergise with other Sirt/AMPK/NO pathway activators. We developed a triple combination of leucine, metformin and sildenafil (NS-0200), which was effective in a mouse model of non-alcoholic steatohepatitis (NASH). AIM: To report the results from a Phase 2, randomised clinical trial of of NS-0200 in 91 subjects with NAFLD (liver fat >=15% by magnetic resonance imaging-proton-density fat fraction (MRI-PDFF)). METHODS: Subjects were randomised to placebo, low-dose (1.1 g leucine/0.5 g metformin/0.5 mg sildenafil) or high-dose NS-0200 (1.1 g leucine/0.5 g metformin/1.0 mg sildenafil) b.d. for 16 weeks; change in hepatic fat was assessed via MRI-PDFF, and lipid metabolism was assessed via changes in the lipidomic signature. Seventy subjects completed the trial and met a priori compliance criteria. Analyses were conducted on the full cohort and on those with alanine aminotransferase (ALT) values above median (50 U/L; n = 35). RESULTS: In the full cohort, active treatments did not separate from placebo. High dose NS 0200 reduced hepatic fat by 15.7% (relative change from baseline) in the high ALT group (P < 0.005) while low dose NS-0200 and placebo did not significantly change hepatic fat. Lipidomic analysis showed dose-responsive treatment effects in both overall and high ALT cohorts, with significant decreases in metabolically active lipids and up-regulation of fatty acid oxidation. CONCLUSION: These data support further evaluation of high-dose NS-0200 for treating NASH, especially in those with elevated ALT (NCT 02546609). PMID- 29696668 TI - Comparative symbiotic plasmid analysis indicates that symbiosis gene ancestor type affects plasmid genetic evolution. AB - : Rhizobial symbiotic plasmids play vital roles in mutualistic symbiosis with legume plants by executing the functions of nodulation and nitrogen fixation. To explore the gene composition and genetic constitution of rhizobial symbiotic plasmids, comparison analyses of 24 rhizobial symbiotic plasmids derived from four rhizobial genera was carried out. Results illustrated that rhizobial symbiotic plasmids had higher proportion of functional genes participating in amino acid transport and metabolism, replication; recombination and repair; carbohydrate transport and metabolism; energy production and conversion and transcription. Mesorhizobium amorphae CCNWGS0123 symbiotic plasmid - pM0123d had similar gene composition with pR899b and pSNGR234a. All symbiotic plasmids shared 13 orthologous genes, including five nod and eight nif/fix genes which participate in the rhizobia-legume symbiosis process. These plasmids contained nod genes from four ancestors and fix genes from six ancestors. The ancestral type of pM0123d nod genes was similar with that of Rhizobium etli plasmids, while the ancestral type of pM0123d fix genes was same as that of pM7653Rb. The phylogenetic trees constructed based on nodCIJ and fixABC displayed different topological structures mainly due to nodCIJ and fixABC ancestral type discordance. The study presents valuable insights into mosaic structures and the evolution of rhizobial symbiotic plasmids. SIGNIFICANCE AND IMPACT OF THE STUDY: This study compared 24 rhizobial symbiotic plasmids that included four genera and 11 species, illuminating the functional gene composition and symbiosis gene ancestor types of symbiotic plasmids from higher taxonomy. It provides valuable insights into mosaic structures and the evolution of symbiotic plasmids. PMID- 29696669 TI - Cost-effectiveness of multidisciplinary collaborative care versus usual care in the management of high-risk patients with diabetes in Singapore: Short-term results from a randomized controlled trial. AB - WHAT IS KNOWN AND OBJECTIVE: Economic evidence of multidisciplinary collaborative care on glycaemic improvement in uncontrolled diabetic patients is limited. Therefore, the primary objective of this study was to assess the cost effectiveness of multidisciplinary collaborative care versus usual care and the secondary objective was to assess the cost-effectiveness of these two care approaches in relation to varying glycaemic control of patients. METHODS: An economic evaluation based on a six-month randomized controlled trial involving high-risk uncontrolled diabetic Asian patients with polypharmacy and multiple comorbidities was conducted from a healthcare institution perspective. The control arm received usual care, while the intervention arm received multidisciplinary care with regular clinical pharmacist follow-up in addition to usual care. The study outcomes included glycated haemoglobin (HbA1c) change and total direct outpatient medical costs for diabetes-related care. The cost effectiveness analyses were conducted for both arms and those stratified according to baseline HbA1c (Group 1:HbA1c 7.1%-7.9%, Group 2:HbA1c >=8.0%). The incremental cost per glycaemic improvement (HbA1c improvement of 0.1% and above) per patient was examined followed by uncertainty evaluation via probabilistic sensitivity analyses. A range of willingness-to-pay (WTP) thresholds (US$165.21 to US$5000.00 per glycaemic improvement) was used in analysis. RESULTS AND DISCUSSION: Overall, the intervention arm had greater improvement in HbA1c (I: mean -0.4% [95% CI -0.6 to -0.2] vs C: mean -0.1% [95% CI -0.2 to 0.1]; P = .014) and lower mean total direct outpatient medical costs per patient in comparison with the control arm (I: US$516.77 +/- 222.10 vs C: US$607.78 +/- 268.39; P < .001). The intervention arm was the dominant strategy across varying baseline HbA1c with higher probability of Group 2 being cost-effective at higher WTP threshold. WHAT IS NEW AND CONCLUSIONS: The multidisciplinary collaborative care arm was cost-effective in managing Asian patients with varying baseline HbA1c control. The multidisciplinary collaborative care also showed greater probability of being cost-effective among Asian patients with poorly uncontrolled glycaemia. PMID- 29696670 TI - Systematic review with meta-analysis: endoscopic and histologic placebo rates in induction and maintenance trials of ulcerative colitis. AB - BACKGROUND: Regulatory requirements for claims of mucosal healing in ulcerative colitis (UC) will require demonstration of both endoscopic and histologic healing. Quantifying these rates is essential for future drug development. AIMS: To meta-analyse endoscopic and histologic placebo response and remission rates in UC randomised controlled trials (RCTs) and identify factors influencing these rates. METHODS: MEDLINE, EMBASE and the Cochrane Library were searched from inception to March 2017 for placebo-controlled trials of pharmacological interventions for UC. Endoscopic and histologic placebo rates were pooled by random effects. Mixed effects univariable and multivariable meta-regression was used to evaluate the influence of patient, intervention and trial-related study level covariates on these rates. RESULTS: Fifty-six induction (placebo n = 4171) and 8 maintenance trials (placebo n = 1011) were included. Pooled placebo endoscopic remission and response rates for induction trials were 23% [95 confidence interval (CI) 19-28%] and 35% [95% CI 27-42%] respectively, and 20% [95% CI 16-24%] for maintenance of remission. The pooled histologic placebo remission rate was 14% [95% CI 8-22%] for induction trials. High heterogeneity was observed for all outcomes (I2 56.2%-88.3%). On multivariable meta-regression, central endoscopy reading was associated with significantly lower endoscopic placebo remission rates (16% vs 25%; OR = 0.52, [95% CI 0.29-0.92], P = 0.03). On univariable meta-regression, higher histologic placebo remission was associated with concomitant corticosteroids (OR = 1.17 [95% CI 1.08-1.26], P < 0.0001, per 10% increase in corticosteroid use). CONCLUSIONS: Placebo endoscopic and histologic rates range from 14% to 35% in UC RCTs but are highly heterogeneous. Outcome standardisation may reduce heterogeneity and is needed in this field. PMID- 29696671 TI - Safety and efficacy of pasireotide in dumping syndrome-results from a phase 2, multicentre study. AB - BACKGROUND: Dumping syndrome is a prevalent complication of oesophageal and gastric surgery characterised by early (postprandial tachycardia) and late (hypoglycaemia) postprandial symptoms. AIM: To evaluate efficacy and safety of the somatostatin analogue, pasireotide in patients with dumping syndrome after bariatric or upper gastrointestinal cancer surgery. METHODS: A single-arm, open label, multicentre, intrapatient dose-escalation, phase 2 study with 4 phases: screening, 3-month SC (subcutaneous), 3-month IM (intramuscular) and 6-month optional extension IM phase. Primary endpoint was the proportion of patients without hypoglycaemia (plasma glucose <3.3 mmol/L [60 mg/dL] during an oral glucose tolerance test, OGTT) at the end of 3-month SC phase. A >=50% response rate was considered clinically relevant. RESULTS: Forty-three patients with late dumping were enrolled; 33 completed the 3-month SC phase and 23 completed the 12 month study. The proportion of patients without hypoglycaemia at month 3 (primary endpoint) was 60.5% (26 of 43; 95% confidence interval, 44.4%-75.0%). Improvement in quality of life was observed during SC phase, which was maintained in the IM phase. The proportion of patients with a rise in pulse rate of >=10 beats/min during OGTT reduced from baseline (60.5%) to month 3 (18.6%) and month 12 (27.3%). Overall (month 0-12), the most frequent (>20% of patients) adverse events were headache (34.9%); diarrhoea, hypoglycaemia (27.9% each); fatigue, nausea (23.3% each); and abdominal pain (20.9%). CONCLUSION: These results suggest that pasireotide is a promising option in patients with dumping syndrome after bariatric or upper gastrointestinal cancer surgery. PMID- 29696672 TI - Brain-heart pathway to injury in takotsubo syndrome. PMID- 29696673 TI - A Potential New Mechanism Linking Type II Diabetes Mellitus and Alzheimer's Disease. PMID- 29696674 TI - A pilot single arm observational study of sofosbuvir/ledipasvir (200 + 45 mg) in 6- to 12- year old children. AB - BACKGROUND: No available data on the use of sofosbuvir/ledipasvir combination in treatment of hepatitis C virus (HCV) infection in children 6- to 12- year old. AIM: To assess the safety and efficacy of sofosbuvir plus ledipasvir in children 6- to 12- year old with chronic HCV genotype 4 infection. METHODS: This is a pilot prospective single arm observational open-label multicentre study. A total of 20 consecutive eligible chronic HCV infected children, aged from 6- to 12- years were included in this study and treated with a fixed sofosbuvir/ledipasvir combination in half the adult dose (200/45 mg) once daily for 12 weeks. Laboratory tests including virological markers were measured at baseline, 2, 4, 8 and 12 weeks (end of treatment [EOT]), and 12 weeks after end of treatment for sustained virological response 12 (SVR12). RESULTS: The intention-to-treat (ITT) SVR12 rate was 19/20 (95%; 95% CI: 76.4%-99.1%). SVR12 was not assessed in one patient who was lost to follow-up after showing viral negativity at the EOT12. All the remaining 19 patients (100%, 95% CI: 83.18%-100%) who completed the full protocol and follow-up visits achieved SVR12 with normal liver, haematological, and renal function tests and no side effects or fatalities. CONCLUSIONS: This pilot study demonstrated that the fixed dose sofosbuvir/ledipasvir combination could be safe and effective treatment in children 6- to 12- years with chronic hepatitis C genotype 4 infection. Our pilot results might encourage larger and multicentre studies in this age group. PMID- 29696675 TI - Anodal and cathodal transcranial direct current stimulation can decrease force output of knee extensors during an intermittent MVC fatiguing task in young healthy male participants. AB - Transcranial direct current stimulation (tDCS) has the capacity to enhance force output during a short-lasting maximal voluntary contraction (MVC) as well as during a long-lasting submaximal voluntary contraction until task failure. However, its effect on an intermittent maximal effort is not known. We hypothesized that anodal tDCS applied during or before a maximal fatigue task increases the amplitude of maximal voluntary contraction (aMVC) and voluntary activation (VA) in young healthy male participants. We measured VA, potentiated twitch at rest (Ptw), root mean square electromyogram (EMG), and aMVC during a fatiguing task that consisted of 35 * 5 s MVC of knee extensors and was performed during tDCS or 10 min after the end of tDCS (sham, anodal, or cathodal treatments). No effect of tDCS was detected on the first MVC but, when compared to sham tDCS, both anodal tDCS and cathodal tDCS reduced aMVC when tDCS was applied during the task (p < .001) and only anodal tDCS reduced aMVC when applied 10 min before the task (p = .03). The reductions in aMVC were accompanied by reductions in EMG of M. vastus lateralis for both tDCS treatments as well as in Ptw only during anodal tDCS and in VA only during cathodal tDCS. Both cathodal tDCS and anodal tDCS impaired force production during an intermittent fatiguing MVC task. The detrimental effects were stronger when tDCS was applied during the task. Here, cathodal and anodal tDCS specifically affected Ptw and VA indicating different underlying mechanisms. PMID- 29696676 TI - Percutaneous axillary access for large-bore arteriotomy: A step-by-step guide. AB - The last decade has witnessed a tremendous growth in the type and complexity of transcatheter cardiovascular interventions that require large-bore access. While the common femoral artery has become the main route for these interventions, sizable cohorts of patients are unsuitable for transfemoral access due to vascular disease or small vessel caliber. Percutaneous axillary access has emerged as a feasible alternative in these patients. We provide a step-by-step guide for transaxillary large-bore access and closure for patients requiring transcatheter interventions. PMID- 29696677 TI - Introduction to this Special Issue: The characteristics of insanity and the insanity evaluation process. PMID- 29696679 TI - Canadian Conference on Medical Education, 28 April-1 May 2018, Halifax, Nova Scotia, Canada. PMID- 29696680 TI - Introduction. PMID- 29696678 TI - Barriers to foot care in patients with diabetes as identified by healthcare professionals. AB - AIMS: To seek the views of healthcare professionals as to the barriers to foot care that they perceive as having an impact on clinical outcomes and contributing to the number of amputations. METHODS: The study involved healthcare professionals from the UK attending our 2015 and 2016 Masterclass diabetic foot conferences. Admission to these conferences was open to all members of the multidisciplinary spectrum who provide care of people with diabetes and foot problems. Attendees were asked to write down concerns that they considered to constitute barriers to foot care for people with diabetes. RESULTS: A total of 425 responses were received (90.8% of the total attendance at the 2015/2016 conferences). Analysis of the responses produced eight key subject areas in which barriers to care were identified: patient referrals, communication between disciplines, access to specialist services, patient care, funding, organization of care, education and infection. Within these key areas, respondents reported poor recognition and diagnosis of foot problems, lack of awareness of the need for referral both by the person with diabetes and healthcare professionals, difficulties in the referral pathway, lack of access to multidisciplinary care, shortage of resources and lack of education of both people with diabetes and healthcare professionals. The respondents identified these barriers as contributing to delay in people with diabetes receiving specialist help. Such a delay can lead to amputation. CONCLUSIONS: The crucial barrier to diabetic foot care is delay in accessing specialist care. Until this is addressed, care will be less than optimum and amputations will continue. PMID- 29696681 TI - Sweet's syndrome with laryngoparalysis due to laryngitis. PMID- 29696682 TI - Interleukin-33 is expressed in the lesional epidermis in herpes virus infection but not in verruca vulgaris. AB - Interleukin (IL)-33 is released on cell injury and activates the immune reaction. IL-33 is involved in antiviral reaction in herpes virus infection, but the source that secretes IL-33 has not been identified. We speculate that keratinocytes injured in herpes virus infection secrete IL-33. In order to detect IL-33 in the lesional epidermis of patients with herpes virus infection, we immunostained several cutaneous herpes virus infection samples with an anti-IL-33 antibody, and compared them with cutaneous human papilloma virus (HPV) infection samples. We observed strong nuclear and mild cytoplasmic staining in epidermal keratinocytes of the lesional skin samples with herpes simplex virus and varicella zoster virus infections. However, staining was not observed in the epidermis of verruca vulgaris (VV) samples. We assumed that the strong immune reaction to herpes virus infection may depend on strong IL-33 expression in the epidermis, while very weak immune reaction in samples from patients with VV may be due to low or no expression of IL-33 in the lesional epidermis. PMID- 29696683 TI - New trends and applications in cyanation isotope chemistry. AB - In this review, newly developed cyanation methods are evaluated in regards to their usefulness in synthetic isotope chemistry. In combination with already established protocols in 13/14 C- or 11 C-isotope chemistry, this manuscript should help isotope scientists to choose the best possible method for their scientific cyanation problem, but with the main focus on 14 C-applications. Perhaps, most promising of the described novel cyanation reaction is the decarboxylation-cyanation-hydrolysis approach which makes a 1-step late-stage functionalization procedure possible. PMID- 29696685 TI - Novel compound heterozygous variants in the XPC gene identified in a Chinese xeroderma pigmentosum group C patient with ovarian teratoma. PMID- 29696686 TI - Confidence in Measurement. PMID- 29696684 TI - Fostamatinib for the treatment of adult persistent and chronic immune thrombocytopenia: Results of two phase 3, randomized, placebo-controlled trials. AB - Spleen tyrosine kinase (Syk) signaling is central to phagocytosis-based, antibody mediated platelet destruction in adults with immune thrombocytopenia (ITP). Fostamatinib, an oral Syk inhibitor, produced sustained on-treatment responses in a phase 2 ITP study. In two parallel, phase 3, multicenter, randomized, double blind, placebo-controlled trials (FIT1 and FIT2), patients with persistent/chronic ITP were randomized 2:1 to fostamatinib (n = 101) or placebo (n = 49) at 100 mg BID for 24 weeks with a dose increase in nonresponders to 150 mg BID after 4 weeks. The primary endpoint was stable response (platelets >=50 000/MUL at >=4 of 6 biweekly visits, weeks 14-24, without rescue therapy). Baseline median platelet count was 16 000/MUL; median duration of ITP was 8.5 years. Stable responses occurred in 18% of patients on fostamatinib vs. 2% on placebo (P = .0003). Overall responses (defined retrospectively as >=1 platelet count >=50 000/MUL within the first 12 weeks on treatment) occurred in 43% of patients on fostamatinib vs. 14% on placebo (P = .0006). Median time to response was 15 days (on 100 mg bid), and 83% responded within 8 weeks. The most common adverse events were diarrhea (31% on fostamatinib vs. 15% on placebo), hypertension (28% vs. 13%), nausea (19% vs. 8%), dizziness (11% vs. 8%), and ALT increase (11% vs. 0%). Most events were mild or moderate and resolved spontaneously or with medical management (antihypertensive, anti-motility agents). Fostamatinib produced clinically-meaningful responses in ITP patients including those who failed splenectomy, thrombopoietic agents, and/or rituximab. Fostamatinib is a novel ITP treatment option that targets an important mechanism of ITP pathogenesis. PMID- 29696687 TI - Cardiovascular risk factors in immune thrombocytopenia adults: Results from the CARMEN registry. PMID- 29696688 TI - Rhabdomyolysis due to bacteremia from Enterobacter cowanii caused by a rose thorn prick. PMID- 29696689 TI - Mild dystrophic epidermolysis bullosa associated with homozygous gene mutation c.6216+5G>T in type VII collagen ultrastructurally suggestive of the decreased number of anchoring fibrils. PMID- 29696690 TI - Mesencephalic dopamine neurons interfacing the shell of nucleus accumbens and the dorsolateral striatum in the rat. AB - Parallel corticostriatonigral circuits have been proposed that separately process motor, cognitive, and emotional-motivational information. Functional integration requires that interactions exist between neurons participating in these circuits. This makes it imperative to study the complex anatomical substrate underlying corticostriatonigral circuits. It has previously been proposed that dopaminergic neurons in the ventral mesencephalon may play a role in this circuit interaction. Therefore, we studied in rats convergence of basal ganglia circuits by depositing an anterograde neuroanatomical tracer into the ventral striatum together with a retrograde fluorescent tracer ipsilaterally in the dorsolateral striatum. In the mesencephalon, using confocal microscopy, we looked for possible appositions of anterogradely labeled fibers and retrogradely labeled neurons, "enhancing" the latter via intracellular injection of Lucifer Yellow. Tyrosine hydroxylase (TH) immunofluorescence served to identify dopaminergic neurons. In neurophysiological experiments, we combined orthodromic stimulation in the medial ventral striatum with recording from ventral mesencephalic neurons characterized by antidromic stimulation from the dorsal striatum. We observed terminal fields of anterogradely labeled fibers that overlap populations of retrogradely labeled nigrostriatal cell bodies in the substantia nigra pars compacta and lateral ventral tegmental area (VTA), with numerous close appositions between boutons of anterogradely labeled fibers and nigrostriatal, TH-immunopositive neurons. Neurophysiological stimulation in the medial ventral striatum caused inhibition of dopaminergic nigrostriatal neurons projecting to the ventrolateral striatal territory. Responding nigrostriatal neurons were located in the medial substantia nigra and adjacent VTA. Our results strongly suggest a functional link between ventromedial, emotional-motivational striatum, and the sensorimotor dorsal striatum via dopaminergic nigrostriatal neurons. PMID- 29696691 TI - Improved score statistics for meta-analysis in single-variant and gene-level association studies. AB - Meta-analysis is now an essential tool for genetic association studies, allowing them to combine large studies and greatly accelerating the pace of genetic discovery. Although the standard meta-analysis methods perform equivalently as the more cumbersome joint analysis under ideal settings, they result in substantial power loss under unbalanced settings with various case-control ratios. Here, we investigate the power loss problem by the standard meta-analysis methods for unbalanced studies, and further propose novel meta-analysis methods performing equivalently to the joint analysis under both balanced and unbalanced settings. We derive improved meta-score-statistics that can accurately approximate the joint-score-statistics with combined individual-level data, for both linear and logistic regression models, with and without covariates. In addition, we propose a novel approach to adjust for population stratification by correcting for known population structures through minor allele frequencies. In the simulated gene-level association studies under unbalanced settings, our method recovered up to 85% power loss caused by the standard methods. We further showed the power gain of our methods in gene-level tests with 26 unbalanced studies of age-related macular degeneration . In addition, we took the meta analysis of three unbalanced studies of type 2 diabetes as an example to discuss the challenges of meta-analyzing multi-ethnic samples. In summary, our improved meta-score-statistics with corrections for population stratification can be used to construct both single-variant and gene-level association studies, providing a useful framework for ensuring well-powered, convenient, cross-study analyses. PMID- 29696692 TI - The impact of erythropoietin and iron status on brain myelination in the newborn rat. AB - Erythropoietin (Epo) drives iron (Fe) utilization for erythropoiesis, but the potentially resultant tissue iron deficiency (ID) can also impede brain development. Conversely, Epo binds to Epo receptors (EpoR) on immature brain oligodendrocytes and neurons, promoting growth and differentiation. The objective of the study was to examine the interaction between Epo and Fe on myelination in brain development during daily Epo treatment. Male and female Sprague-Dawley rats from postnatal day (P) P4-P12 modeled premature newborns. Dam-fed Fe-sufficient (IS) or postnatal ID groups were given daily subcutaneous sham or erythropoietic Epo injections (425 U. kg-1. d-1 ), +/- oral Fe (6 mg. kg-1. d-1 ). Tissues and blood were collected and studied at P12. Epo in the ID groups, in the absence of oral Fe, stimulated microcytic ID anemia along with raising inflammatory markers. Both the microcytic anemia and inflammation improved in the ID + Epo + Fe group. Fe treatment positively impacted erythropoiesis and body Fe (ug/g) in all groups. Relative brain Fe (ug/g rat) was improved in the IS + Epo + Fe group. Brain Fe was not worsened in +Epo groups. Brain weight and brain Fe were related to plasma Epo levels. Amount of myelination was impacted by feeding type, but was not inhibited by Epo. Expression of a protein in myelin, mylein basic protein, was greater in all +Fe groups than -Fe groups. With therapeutic Epo, available body Fe was prioritized for erythropoiesis instead of brain, but Epo did not worsen brain Fe and potentially Epo improved myelination and maturation in the brain. PMID- 29696693 TI - Cardiovascular magnetic resonance assessment of 1st generation CoreValve and 2nd generation Lotus valves. AB - OBJECTIVES: We sought to compare using serial CMR, the quantity of AR and associated valve hemodynamics, following the first-generation CoreValve (Medtronic, Minneapolis, MN) and the second-generation Lotus valve (Boston Scientific, Natick, MA). BACKGROUND: Aortic regurgitation (AR) following Transcatheter Aortic Valve Replacement (TAVR) confers a worse prognosis and can be accurately quantified using cardiovascular magnetic resonance (CMR). Second generation valves have been specifically designed to reduce paravalvular AR and improve clinical outcomes. METHODS: Fifty-one patients (79.0 +/- 7.7 years, 57% male) were recruited and imaged at three time points: immediately pre- and post TAVR, and at 6 months. RESULTS: CMR-derived AR fraction immediately post-TAVR was greater in the CoreValve compared to Lotus group (11.7 +/- 8.4 vs. 4.3 +/- 3.4%, P = 0.001), as was the frequency of >=moderate AR (9/24 (37.5%) versus 0/27, P < 0.001). However, at 6 months AR fraction had improved significantly in the CoreValve group such that the two valve designs were comparable (6.4 +/- 5.0 vs 5.6 +/- 5.3%, P = 0.623), with no patient in either group having >=moderate AR. The residual peak pressure gradient immediately following TAVR was significantly lower with CoreValve compared to Lotus (14.1 +/- 5.6 vs 25.4 +/- 11.6 mmHg, P = 0.001), but again by 6 months the two valve designs were comparable (16.5 +/- 9.4 vs 19.7 +/- 10.5 mmHg, P = 0.332). There was no difference in the degree of LV reverse remodeling between the two valves at 6 months. CONCLUSION: Immediately post-TAVR, there was significantly less AR but a higher residual peak pressure gradient with the Lotus valve compared to CoreValve. However, at 6 months both devices had comparable valve hemodynamics and LV reverse remodeling. PMID- 29696694 TI - Laboratory testing in BCR-ABL1-like (Philadelphia-like) B-lymphoblastic leukemia/lymphoma. AB - BCR-ABL1-like B-lymphoblastic leukemia/lymphoma (BCR-ABL1-like B-ALL), also known as Philadelphia-like (Ph-like) ALL, is a neoplasm of B-lineage lymphoblasts characterized by a pattern of gene expression similar to that of B-ALL with the BCR-ABL1 translocation but lacking the BCR-ABL1 fusion protein. The diagnosis of BCR-ABL1-like B-ALL is associated with a high rate of relapse and poor clinical outcomes. In recognition of the difficulty in screening these leukemias for diagnostic workup, the 2016 update/revision to the World Health Organization (WHO) 2008 edition included BCR-ABL1-like B-ALL as a provisional entity. This review addresses the various clinical considerations and methodologies currently used in the pathologic diagnosis, subclassification, and molecular characterization of cases of BCR-ABL1-like B-ALL, with particular attention paid to emerging methods useful in identification of molecular lesions potentially amenable to targeted therapy. PMID- 29696695 TI - Mimicking a p53-MDM2 interaction based on a stable immunoglobulin-like domain scaffold. AB - Antibodies recognize protein targets with great affinity and specificity. However, posttranslational modifications and the presence of intrinsic disulfide bonds pose difficulties for their industrial use. The immunoglobulin fold is one of the most ubiquitous folds in nature and it is found in many proteins besides antibodies. An example of a protein family with an immunoglobulin-like fold is the Cysteine Protease Inhibitors (ICP) family I42 of the MEROPs database for protease and protease inhibitors. Members of this protein family are thermostable and do not present internal disulfide bonds. Crystal structures of several ICPs indicate that they resemble the Ig-like domain of the human T cell co-receptor CD8alpha As ICPs present 2 flexible recognition loops that vary accordingly to their targeted protease, we hypothesize that members of this protein family would be ideal to design peptide aptamers that mimic protein-protein interactions. Herein, we use an ICP variant from Entamoeba histolytica (EhICP1) to mimic the interaction between p53 and MDM2. We found that a 13 amino-acid peptide derived from p53 can be introduced in 2 variable loops (DE, FG) but not the third (BC). Chimeric EhICP1-p53 form a stable complex with MDM2 at a micromolar range. Crystal structure of the EhICP1-p53(FG)-loop variant in complex with MDM2 reveals a swapping subdomain between 2 chimeric molecules, however, the p53 peptide interacts with MDM2 as in previous crystal structures. The structural details of the EhICP1-p53(FG) interaction with MDM2 resemble the interaction between an antibody and MDM2. PMID- 29696696 TI - Engaging Stakeholders in the Development of an eHealth Intervention for Cancer Symptom Management for Rural Residents. AB - BACKGROUND: Late-stage cancer diagnoses disproportionately occur in rural residents, frequently resulting in increased need for symptom management support with minimal access to these services. Oncology Associated Symptoms and Individualized Strategies (OASIS) is an eHealth symptom self-management intervention that was developed to provide cancer symptom self-management support and address this disparity. PURPOSE: To engage stakeholders about the symptom management needs and concerns of patients with advanced cancer living in rural areas. METHODS: A 3-phased, mixed-methods design was used to (1) assess stakeholder needs and opinions; (2) develop a symptom self-management website; and (3) obtain usability feedback from potential users. Interviews with stakeholders (patients and clinic staff) from rural areas using a descriptive qualitative approach were analyzed; cross-cutting themes were identified; a symptom management web application was developed; and stakeholders completed a 12 item usability survey about the web application. RESULTS: Patients (n = 16) and clinical staff (n = 10) participated in phase 1. Three major themes were identified: "symptom experience," "symptom management," and "technology." Through an iterative process using these results and evidence from the literature, the OASIS web application was developed. Usability testing with N = 126 stakeholders demonstrated that the web application is easy to use, contains relevant content, and has pleasing graphics. No differences were found among patients, family/friends, and staff. Both frequent and infrequent internet users positively evaluated the web application. CONCLUSIONS: Rural stakeholders report significant symptom management needs, are interested in eHealth technologies, and perceived OASIS positively. Future research is needed to evaluate the feasibility, acceptability, and efficacy of OASIS. PMID- 29696697 TI - A novel double snare technique to retrieve embolized septal and left atrial appendage occluders. AB - BACKGROUND: Device embolization is the most frequent procedural complication during transcatheter closure of congenital cardiac defects. Retrieval of an embolized device may often be complicated by failure to introduce the right atrial (RA) disk hub into the sheath or difficulty in securely grasping the hub pin of RA disk. We aimed to evaluate the efficiency and success rate of device retrieval using a novel double snare technique. METHODS: We reviewed retrieval procedures of embolized atrial septal defect (ASD) or left atrial appendage (LAA) occluder using double snare technique reported from five tertiary referral centers in Korea, Japan, and Uzbekistan. A total of 16 retrieval procedures in 15 patients were reported, including 14 patients who were planned for ASD device closure while 1 patient was planned for LA appendage occlusion. RESULTS: Retrieved devices included 15 ASD occluders from six different manufacturers and one Amplantzer cardiac plug. Success rate of retrieval procedure was 100% using the double snare technique. There were no complications related to device retrieval. Most (15/16, 93.8%) of these devices could be retrieved through their original delivery sheaths. In six patients for whom retrieval was unsuccessful with conventional single snare technique and switched to double snare technique, the retrieval time was shortened significantly (P = 0.004*) by using the double snare technique. CONCLUSIONS: The double snare technique enables effective retrieval of various embolized devices. It abolishes the need of changing the sheath to a larger one in most patients. PMID- 29696698 TI - Recording routine forensic mental health evaluations should be a standard of practice in the 21st century. AB - The standard of practice for forensic interviews in criminal and delinquency cases, other than those conducted as part of brief preliminary screening evaluations or in emergency situations, should include a digital recording requirement. This standard should be adopted because of the greater availability of, and familiarity with, recording technology on the part of mental health professionals, the greater use and proven effectiveness of recording in other contexts of the criminal justice system, and the improvement in court presentation and accuracy of judicial determinations involving forensic assessments that recording will provide. The experience of practitioners with recording since professional associations last studied the issue should be taken into account, as informal data suggest it has been positive. Unfortunately, the legal system is unlikely to prompt this advance without its reconsideration by the forensic mental health professions, because current constitutional jurisprudence does not require recording and effectively makes it contingent upon request by examiners. Forensic evaluators thus have a valuable opportunity to educate the legal system on the utility and importance of this key reform, and so should adopt it as a best practice. PMID- 29696699 TI - Polymorphism of GDF9 and BMPR1B genes and their association with litter size in Markhoz goats. AB - The main objective of this study was to investigate the polymorphism of GDF9 and BMPR1B genes and their relationship with litter size in Markhoz goats. The polymorphism of GDF9 and BMPR1B genes as well-documented genes regarding fecundity in sheep and goat was investigated using RFLP-PCR and a tetra-primer amplification refractory mutation system-PCR (T-ARMS-PCR) in Markhoz goats. The 164 blood samples were collected from the raised goats in Sanandaj Markhoz goat Performance Testing Station. The DNA extraction was carried out by salting-out procedure, and then, PCR was performed using four and two pairs of primers to detect polymorphism in GDF9 and BMPR1B genes, respectively. To disclose GDF9 loci polymorphism, PCR products were digested with SspI (G3288A), PvuII (G423A), MvaI (A959C) and MspI (G1189A) restriction enzymes. The results showed that these mutations are available in tested animals. Parity had no significant effect on litter size. Also, the effects of different genotypes of GDF9 and BMPR1B had no significant effect on litter size. Further studies with a high number of animals with minimum relatedness for testing the association of these SNPs and others in the fecundity genes with reproductive traits may be worthwhile. PMID- 29696700 TI - Self-injurious behaviours in children and adults with autism spectrum disorder (ASD). AB - BACKGROUND: Self-injurious behaviours (SIB) are concerning, maladaptive behaviours that commonly occur in people with neurodevelopmental conditions and delays but seem to be particularly prevalent in children and adults with autism spectrum disorder (ASD). There has been increasing research examining the risk markers associated with the presence of SIB in people with ASD. Some of the factors associated with SIB have included cognitive abilities, adaptive functioning deficits and behaviour regulation impairments (e.g. impulsivity and repetitive behaviours). However, many of the findings in the literature are mixed and only explain a small proportion of the variance contributing to SIB. Limitations in the previous literature have centred on lack of availability of large and diverse samples, restricted age ranges and constraints of measurement. METHOD: This study characterises a clinic-referred sample of children and adults currently presenting with and without SIB using a range of standardised and parent-report measures. The sample includes 144 individuals with ASD between the ages of 2.5 and 60.1 years. RESULTS: After adjusting for multiple tests, none of the variables maintained statistical significance between the group of individuals with and without SIB, but medium to large effect sizes were noted. These variables include parent-reported early motor and toileting delays and perinatal risk, and current cognitive and social impairment. The remaining variables, including current autism severity levels, early ASD symptomatology, impulsivity, executive functioning impairments, adaptive functioning, mood and anxiety, did not differ between those with and without current engagement in SIB. CONCLUSIONS: Utilising a diverse clinic-referred sample and standardised diagnostic tools, this study explored retrospective and current correlate risk markers of SIB in individuals with ASD. In addition to impairments in current functioning, specific early developmental delays and perinatal risk factors were preliminarily associated with the presence of SIB in individuals with ASD. Together these findings suggest that a set of specific characteristics may be related to both early risk and concurrent manifestation of SIB. Identifying this set of characteristics in early development may lead to faster identification and better intervention services, but future work utilising longitudinal design and multivariate analysis is warranted. PMID- 29696701 TI - Multimarker and rare variants genomewide association studies for bone weight in Simmental cattle. AB - Bone weight, defined as the total weight of the bones in all the forequarter and hindquarter joints, can reflect somebody conformation traits and skeletal diseases. To gain a better understanding of the genetic determinants of bone weight, we used a composite strategy including multimarker and rare-marker association to perform genomewide association studies (GWAS) for that character in Simmental cattle. Our strategy consisted of three models: (i) A traditional linear mixed model (LMM) was applied (Q+K-LMM); (ii) single nucleotide polymorphisms (SNPs) with p-values less than .05 from the LMM were selected to undergo the least absolute shrinkage and selector operator (Lasso) in the second stage (LMM-Lasso); (iii) genes containing two or more rare SNPs were examined by performing the sequence kernel association test (gene-based SKAT). A total of 1,225 cattle were genotyped with an Illumina BovineHD BeadChip containing 770,000 SNPs. After the quality-control procedures, 1,217 individuals with 608,696 common SNPs and 105,787 rare SNPs (with 0.001 < minor allele frequency [MAF] <0.05) remained in the sample for analysis. A traditional LMM successfully mapped three genes associated with bone weight, while LMM-Lasso identified nine genes, which included all genes found by traditional LMM. Only a single gene, EPHB3, surpassed the significance threshold after Bonferroni correction in gene-based SKAT. In conclusion, based on functional annotation and results from previous endeavours, we believe that LCORL, RIMS2, LAP3, PRKAR2B, CHSY1, MAP2K6 and EPHB3 are candidate genes for bone weight. In general, such a comprehensive strategy for GWAS may be useful for researchers seeking to probe the full genetic architecture underlying economic traits in livestock. PMID- 29696702 TI - Mechanical properties of BiP protein determined by nano-rheology. AB - Immunoglobulin Binding Protein (BiP) is a chaperone and molecular motor belonging to the Hsp70 family, involved in the regulation of important biological processes such as synthesis, folding and translocation of proteins in the Endoplasmic Reticulum. BiP has two highly conserved domains: the N-terminal Nucleotide Binding Domain (NBD), and the C-terminal Substrate-Binding Domain (SBD), connected by a hydrophobic linker. ATP binds and it is hydrolyzed to ADP in the NBD, and BiP's extended polypeptide substrates bind in the SBD. Like many molecular motors, BiP function depends on both structural and catalytic properties that may contribute to its performance. One novel approach to study the mechanical properties of BiP considers exploring the changes in the viscoelastic behavior upon ligand binding, using a technique called nano rheology. This technique is essentially a traditional rheology experiment, in which an oscillatory force is directly applied to the protein under study, and the resulting average deformation is measured. Our results show that the folded state of the protein behaves like a viscoelastic material, getting softer when it binds nucleotides- ATP, ADP, and AMP-PNP-, but stiffer when binding HTFPAVL peptide substrate. Also, we observed that peptide binding dramatically increases the affinity for ADP, decreasing it dissociation constant (KD ) around 1000 times, demonstrating allosteric coupling between SBD and NBD domains. PMID- 29696703 TI - MCL1 gene co-expression module stratifies multiple myeloma and predicts response to proteasome inhibitor-based therapy. AB - Multiple myeloma (MM) is the second most common hematologic cancer, characterized by abnormal accumulation of plasma cells in the bone marrow. The extensive biological and clinical heterogeneity of MM hinders effective treatment and etiology research. Several molecular classification systems of prognostic impact have been proposed, but they do not predict the response to treatment nor do they correlate to plasma cell development pathways. Here we describe the classification of MM into two distinct subtypes based on the expression levels of a gene module coexpressed with MCL1 (MCL1-M), a regulator of plasma cell survival. The classification system enabled prediction of the prognosis and the response to bortezomib-based therapy. Moreover, the two MM subtypes were associated with two different plasma cell differentiation pathways (enrichment of a preplasmablast signature versus aberrant expression of B cell genes). 1q gain, harboring 63 of the 87 MCL1-M members including MCL1, was found in about 80% of the MM with upregulated MCL1-M expression. Clonal analysis showed that 1q gain tended to occur as an early clonal event. Members of MCL1-M captured both MM cell intrinsically acting signals and the signals regulating the interaction between MM cells with bone marrow microenvironment. MCL1-M members were co-expressed in mouse germinal center B cells. Together, these findings indicate that MCL1-M may play previously inadequately recognized, initiating role in the pathogenesis of MM. Our findings suggest that MCL1-M signature-based molecular clustering of MM constitutes a solid framework toward understanding the etiology of this disease and establishing personalized care. Article Summary: A pathogenic mechanism guided molecular classification would facilitate treatment decision and etiology research of multiple myeloma. On the basis of the expression levels of a gene module coexpressed with MCL1, we have established a classification scheme assigning multiple myeloma into two subtypes with distinct prognosis, treatment responses and pathogenic backgrounds. PMID- 29696704 TI - Fetal Medicine Foundation fetal and neonatal population weight charts. AB - OBJECTIVE: To develop fetal and neonatal population weight charts. The rationale was that, while reference ranges of estimated fetal weight (EFW) are representative of the whole population, the traditional approach of deriving birth-weight (BW) charts is misleading, because a large proportion of babies born preterm arise from pathological pregnancy. We propose that the reference population for BW charts, as in the case of EFW charts, should comprise all babies at a given gestational age, including those still in utero. METHODS: Two sources of data were used for this study. For both, the inclusion criteria were singleton pregnancy, dating by fetal crown-rump length at 11 + 0 to 13 + 6 weeks' gestation, availability of ultrasonographic measurements of fetal head circumference (HC), abdominal circumference (AC) and femur length (FL) and live birth of phenotypically normal neonate. Dataset 1 comprised a sample of 5163 paired measurements of EFW and BW; ultrasound examinations were carried out at 22 43 weeks' gestation and birth occurred within 2 days of the ultrasound examination. EFW was derived from the HC, AC and FL measurements using the formula reported by Hadlock et al. in 1985. Dataset 2 comprised a sample of 95 579 pregnancies with EFW obtained by routine ultrasonographic fetal biometry at 20 + 0 to 23 + 6 weeks' gestation (n = 45 034), 31 + 0 to 33 + 6 weeks (n = 19 224) or 35 + 0 to 36 + 6 weeks (n = 31 321); for the purpose of this study we included data for only one of the three visits per pregnancy. In the development of reference ranges of EFW and BW according to gestational age, the following assumptions were made: first, that EFW and BW have a common median, dependent on gestational age; and second, that deviations from the median occur in both EFW and BW and these deviations are correlated with different levels of spread for EFW and BW, dependent on gestational age. We adopted a Bayesian approach to inference, combining information from the two datasets using Markov Chain Monte Carlo sampling. The fitted model assumed that the mean log transformed measurements of EFW and BW are related to gestational age according to a cubic equation and that deviations about the mean follow a bivariate Gaussian distribution. RESULTS: In the case of EFW in Dataset 2, there was a good distribution of values < 3rd , < 5th , < 10th , > 90th , > 95th and > 97th percentiles of the reference range of EFW according to gestational age throughout the gestational age range of 20 + 0 to 36 + 6 weeks. In the case of BW, there was a good distribution of values only for the cases delivered > 39 weeks' gestation. For preterm births, particularly at 27-36 weeks, BW was below the 3rd , 5th and 10th percentiles in a very high proportion of cases, particularly in cases of iatrogenic birth. The incidence of small-for-gestational-age fetuses and neonates in the respective EFW and BW charts was higher in women of black than those of white racial origin. CONCLUSION: We established a BW chart for all babies at a given gestational age, including those still in utero, thereby overcoming the problem of underestimation of growth restriction in preterm birth. BW and EFW charts have a common median but differ in the levels of spread from the median. Copyright (c) 2018 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29696705 TI - Aligning Solution-Derived Carbon Nanotube Film with Full Surface Coverage for High-Performance Electronics Applications. AB - The main challenge for application of solution-derived carbon nanotubes (CNTs) in high performance field-effect transistor (FET) is how to align CNTs into an array with high density and full surface coverage. A directional shrinking transfer method is developed to realize high density aligned array based on randomly orientated CNT network film. Through transferring a solution-derived CNT network film onto a stretched retractable film followed by a shrinking process, alignment degree and density of CNT film increase with the shrinking multiple. The quadruply shrunk CNT films present well alignment, which is identified by the polarized Raman spectroscopy and electrical transport measurements. Based on the high quality and high density aligned CNT array, the fabricated FETs with channel length of 300 nm present ultrahigh performance including on-state current Ion of 290 uA um-1 (Vds = -1.5 V and Vgs = -2 V) and peak transconductance gm of 150 uS um-1 , which are, respectively, among the highest corresponding values in the reported CNT array FETs. High quality and high semiconducting purity CNT arrays with high density and full coverage obtained through this method promote the development of high performance CNT-based electronics. PMID- 29696706 TI - Impact of sleep on executive functioning in school-age children with Down syndrome. AB - BACKGROUND: Sleep problems have an impact on executive functioning in the general population. While children with Down syndrome (DS) are at high risk for sleep problems, the impact of these sleep problems on executive functioning in school age children with DS is less well documented. Our study examined the relationship between parent-reported and actigraphy-measured sleep duration and sleep quality with parent and teacher reports and neuropsychology assessments of executive functioning among school-age children with DS. METHOD: Thirty school-age children with DS wore an actigraph watch for a week at home at night. Their parent completed ratings of the child's sleep during that same week. Children completed a neuropsychology assessment of their inhibitory control, ability to shift and working memory. Their parents and teachers completed rating scales to assess these same constructs of executive functioning. RESULTS: Parent reports of restless sleep behaviours on the Children's Sleep Habits Questionnaire (CSHQ), but not actigraph-measured sleep period or efficiency, were predictive of parent reports of concerns with inhibitory control, shifting and working memory, and of teacher reports of inhibitory control. No measure of sleep was predictive of executive functioning as measured by the neuropsychology assessment. CONCLUSION: The study findings corroborate the preliminary literature that parent-reported sleep problems are related to executive functioning in school-age children with DS, particularly in the area of inhibitory control across home and school. These findings have implications for understanding contributing factors to academic performance and school behaviour in school-age children with DS. PMID- 29696708 TI - Erythema induratum of Bazin: Epidemiological, clinical and laboratorial profile of 54 patients. PMID- 29696707 TI - Daily adjunctive therapy with vitamin D3 and phenylbutyrate supports clinical recovery from pulmonary tuberculosis: a randomized controlled trial in Ethiopia. AB - OBJECTIVE: Immunotherapy using vitamin D (vitD3 ) and phenylbutyrate (PBA) may support standard drug regimens used to treat infectious diseases. We investigated if vitD3 + PBA enhanced clinical recovery from pulmonary tuberculosis (TB). METHODS: A randomized controlled trial was conducted in Addis Ababa, Ethiopia. Patients with smear-positive or smear-negative TB received daily oral supplementation with 5000 IU vitD3 and 2 * 500 mg PBA or placebo for 16 weeks, together with 6-month chemotherapy. Primary end-point: reduction of a clinical composite TB score at week 8 compared with baseline using modified intention-to treat (mITT, n = 348) and per-protocol (n = 296) analyses. Secondary end-points: primary and modified TB scores (week 0, 4, 8, 16, 24), sputum conversion, radiological findings and plasma 25(OH)D3 concentrations. RESULTS: Most subjects had low baseline plasma 25(OH)D3 levels that increased gradually in the vitD3 + PBA group compared with placebo (P < 0.0001) from week 0 to 16 (mean 34.7 vs. 127.4 nmol L-1 ). In the adjusted mITT analysis, the primary TB score was significantly reduced in the intervention group at week 8 (-0.52, 95% CI -0.93, 0.10; P = 0.015) while the modified TB score was reduced at week 8 (-0.58, 95% CI -1.02, -0.14; P = 0.01) and 16 (-0.34, 95% CI -0.64, -0.03; P = 0.03). VitD3 + PBA had no effect on longitudinal sputum-smear conversion (P = 0.98). Clinical adverse events were more common in the placebo group (24.3%) compared with the vitD3 + PBA group (12.6%). CONCLUSION: Daily supplementation with vitD3 + PBA may ameliorate clinical TB symptoms and disease-specific complications, while the intervention had no effect on bacterial clearance in sputum. PMID- 29696709 TI - Simple method for estimating cutaneous neurofibromas in patients with neurofibromatosis 1. PMID- 29696710 TI - Metal-Halide Perovskites for Gate Dielectrics in Field-Effect Transistors and Photodetectors Enabled by PMMA Lift-Off Process. AB - Metal-halide perovskites have emerged as promising materials for optoelectronics applications, such as photovoltaics, light-emitting diodes, and photodetectors due to their excellent photoconversion efficiencies. However, their instability in aqueous solutions and most organic solvents has complicated their micropatterning procedures, which are needed for dense device integration, for example, in displays or cameras. In this work, a lift-off process based on poly(methyl methacrylate) and deep ultraviolet lithography on flexible plastic foils is presented. This technique comprises simultaneous patterning of the metal halide perovskite with a top electrode, which results in microscale vertical device architectures with high spatial resolution and alignment properties. Hence, thin-film transistors (TFTs) with methyl-ammonium lead iodide (MAPbI3 ) gate dielectrics are demonstrated for the first time. The giant dielectric constant of MAPbI3 (>1000) leads to excellent low-voltage TFT switching capabilities with subthreshold swings ~80 mV decade-1 over ~5 orders of drain current magnitude. Furthermore, vertically stacked low-power Au-MAPbI3 -Au photodetectors with close-to-ideal linear response (R2 = 0.9997) are created. The mechanical stability down to a tensile radius of 6 mm is demonstrated for the TFTs and photodetectors, simultaneously realized on the same flexible plastic substrate. These results open the way for flexible low-power integrated (opto )electronic systems based on metal-halide perovskites. PMID- 29696711 TI - Oxygen concentration drives local adaptation in the greenlip abalone (Haliotis laevigata). AB - Understanding adaptation has become one of the major biological questions especially in the light of rapid environmental changes induced by climate change. Ocean temperatures are rising which triggers massive changes in water chemistry and thereby alters the living environment of all marine organisms. Studying adaptation, however, can be tricky because spatial genetic patterns might also occur due to random effects, for example, genetic drift. Genetic drift is reduced in very large and well-connected populations, such as in broadcast marine spawning organisms. Here, spatial genetic divergence is likely to be produced by selection. In this issue of Molecular Ecology, Sandoval-Castillo et al. (2018) investigated patterns of spatial genetic divergence and their association with environmental factors in the greenlip abalone (Haliotis laevigata). This commercially important species of mollusc is a broadcast spawner with large population sizes, rendering genetic drift an unlikely factor in the genetic divergence of wild populations. Sandoval-Castillo et al. (2018) used a ddRAD genomic approach to test for genetic divergence between sampled populations while also measuring different environmental factors, for example, water temperature and oxygen content. The majority of identified SNPs was putatively neutral and showed only low levels of genetic divergence between field sites. However, 323 candidate adaptive markers were identified that clearly separated the individuals into five different clusters. These genetic clusters correlated with environmental clusters mainly determined by water temperature and (correlated) oxygen concentration. Gene annotation of the candidate SNPs revealed a large proportion of loci being involved in biological processes influenced by oxygen availability. The study by Sandoval-Castillo et al. (2018) in this issue of Molecular Ecology exemplifies the benefits of combining genomic studies with ecological data. It is a great starting point for more detailed (gene function, physiology) as well as broader (biodiversity) investigations that might help us to better understand adaptation and predict ecosystems' resilience and resistance to environmental disturbances. In addition, this information can be applied to implement optimal conservation regime policies and sustainable harvesting strategies, hopefully protecting biodiversity as well as commercial interests in marine life. PMID- 29696712 TI - Adaptive management of animal populations with significant unknowns and uncertainties: a case study. AB - Conservation and management decision making in natural resources is challenging due to numerous uncertainties and unknowns, especially relating to understanding system dynamics. Adaptive resource management (ARM) is a formal process to making logical and transparent recurrent decisions when there are uncertainties about system dynamics. Despite wide recognition and calls for implementing adaptive natural resource management, applications remain limited. More common is a reactive approach to decision making, which ignores future system dynamics. This contrasts with ARM, which anticipates future dynamics of ecological process and management actions using a model-based framework. Practitioners may be reluctant to adopt ARM because of the dearth of comparative evaluations between ARM and more common approaches to making decisions. We compared the probability of meeting management objectives when managing a population under both types of decision frameworks, specifically in relation to typical uncertainties and unknowns. We use a population of Sandhill Cranes as our case study. We evaluate each decision process under varying levels of monitoring and ecological uncertainty, where the true underlying population dynamics followed a stochastic age-structured population model with environmentally driven vital rate density dependence. We found that the ARM framework outperformed the currently employed reactive decision framework to manage Sandhill Cranes in meeting the population objective across an array of scenarios. This was even the case when the candidate set of population models contained only naive representations of the true population process. Under the reactive decision framework, we found little improvement in meeting the population objective even if monitoring uncertainty was eliminated. In contrast, if the population was monitored without error within the ARM framework, the population objective was always maintained, regardless of the population models considered. Contrary to expectation, we found that age specific optimal harvest decisions are not always necessary to meet a population objective when population dynamics are age structured. Population managers can decrease risks and gain transparency and flexibility in management by adopting an ARM framework. If population monitoring data has high sampling variation and/or limited empirical knowledge is available for constructing mechanistic population models, ARM model sets should consider a range of mechanistic, descriptive, and predictive model types. PMID- 29696713 TI - National Cancer Societies and their public statements on alcohol consumption and cancer risk. AB - BACKGROUND AND AIMS: Studies have shown that alcohol consumption is a risk factor for oral, pharyngeal, laryngeal, esophageal, liver, colon, rectal and breast cancer. It would therefore be expected that cancer prevention organizations would incorporate these facts into their public stance on the consumption of alcohol. The aims of this study were to: (1) assess how national cancer societies in developed English-speaking countries [i.e. English-speaking countries belonging to the Organization for Economic Co-operation and Development (OECD)] communicate alcohol-related cancer risk to the public and (2) compare whether these organization's advocacy of increased alcohol taxes is in line with their advocacy of tobacco tax increases to reduce cancer risk. METHODS: We searched the websites of the following national cancer organizations for all statements related to the relationship between alcohol consumption and cancer risk: Cancer Council Australia, Canadian Cancer Society, Irish Cancer Society, Cancer Society New Zealand, Cancer Research UK and the American Cancer Society. A categorical system was developed to code the qualitative data for health statements, alcohol consumption recommendations, and tax policy recommendations. Websites were analyzed in March of 2017. RESULTS: All organizations, with the exception of the American Cancer Society and Canadian Cancer Society, state that alcohol is a group 1 carcinogen and that even low-level alcohol consumption increases risk for some cancers. Additionally, while the American Cancer Society supports increasing tobacco taxes through its cancer action network, it has not advocated for increased alcohol taxes in relation to support for tobacco tax increases. CONCLUSION: Analysis in 2017 of the websites for national cancer societies in Australia, Canada, Ireland, New Zealand, the United Kingdom and the United States including Cancer Council Australia, the Canadian Cancer Society, the Irish Cancer Society, Cancer Society New Zealand, Cancer Research UK and the American Cancer Society-shows that only the American Cancer Society and Canadian Cancer Society websites fail to state that alcohol is a group 1 carcinogen and can cause cancer at low doses, and that there is no safe threshold for cancer risk. PMID- 29696714 TI - Demand of long-term care and benefit eligibility across European countries. AB - In this paper, we study how elderly individuals adjust their informal long-term care utilization to changes in the provision of formal care. Despite this is crucial to design effective policies of formal elderly care, empirical evidence is scant due to the lack of credible identification strategies to account for the endogeneity of formal care. We propose a novel instrument, an index that captures individuals' eligibility status for the long-term care programs implemented in the region of residence. Our estimates, which are robust to a number of different specifications, suggest that higher formal care provision would lead to an increase in informal care utilization as well. In the context of current theoretical economic model of care use, this result points to the existence of a substantial unmet demand of care among older people in Europe. PMID- 29696715 TI - The association among HER2, MET and FOXP3 expression and tumor regression grading in gastric adenocarcinoma. AB - Although the introduction of the perioperative chemotherapy on the management of gastric cancer has improved patients survival, heterogeneity of clinical outcomes has been evidenced in parallel to different histopathological regression pattern of gastric cancer cells. Thus, this study evaluated the tumor regression grading (TRG) in a series of post-treatment gastric tumors and its associations with HER2, MET, and FOXP3 expression. Material of 54 gastric cancer samples was available for TRG evaluation and immunohistochemistry. We found that total and subtotal pathologic response were significantly associated to the intestinal subtype (p = 0.04) and that well-differentiated tumors were significantly correlated with total or partial response (p = 0.019). Although not associated with the TRG, FOXP3 expression in gastric tumors was associated to poorly differentiated tumors (p = 0.03), to the diffuse and mixed subtypes together (p = 0.04) and to the presence of vascular infiltration (p = 0.04), while HER2 overexpression was associated to better differentiated cases (p = 0.04) and to the absence of vascular infiltration (p = 0.02). MET expression, however, showed no association with the analyzed clinicopathological factors. This study highlights the role of tissue differentiation on pathological response to neoadjuvant chemotherapy in gastric cancer and shows no impact between FOXP3, HER2 and MET expression in terms of TRG. PMID- 29696716 TI - B7-H3 expression and its correlation with clinicopathologic features, angiogenesis, and prognosis in intrahepatic cholangiocarcinoma. AB - This study was designed to explore the expression of B7-H3 in human intrahepatic cholangiocarcinoma (ICC) and its association with the clinicopathologic factors. In the current study, the expression of B7-H3 in 45 patients with intrahepatic cholangiocarcinoma and 8 patients with hepatolithiasis was analyzed by immunohistochemistry, which revealed that B7-H3 was not expressed in hepatolithiatic tissues, but positively expressed in 57.8% (26/45) of the ICC cases. The expression of B7-H3 was significantly associated with lymph node metastases and venous invasion. A positive correlation was also observed between the expression of B7-H3 and MVD, an index for tumor angiogenesis. Further survival analysis indicated that patients with B7-H3 negative expression had higher overall survival (OS) and cancer-specific survival (CSS) rates than those with B7-H3 positive expression. Multivariate analysis revealed that B7-H3 expression was an independent prognostic indicator for poor OS and CSS of ICC patients. Our results suggest that B7-H3 may be a valuable biomarker in determining tumor progression and prognosis of intrahepatic cholangiocarcinoma. It is also a potential target for antivascular therapy of ICC. PMID- 29696717 TI - Triple negative breast cancer: new therapeutic approaches and BRCA status. AB - Treatment of triple negative breast cancer (TNBC) is a clinically challenging problem due to intriguing clinical and pathologic features of TNBC and natural or induced resistance to existing therapies. However, a great understanding of features of TNBC particularly associated with BRCA mutations has led to the development of different therapeutic approaches. Besides, identification of TNBC subtypes contribute to investigation of the underlying molecular differences and development of new strategies for the treatment of TNBC patients. In this review, we discussed the definition and characteristic properties of TNBC. We summarized an up-to-date description of the reported clinical trials of novel targeted strategies especially PARP inhibitors (PARPi) due to novel and highly potent for the treatment of TNBC. Additionally, we reviewed published studies which investigated the prevalence and types of BRCA1/2 mutation in breast cancer patients to assess and draw attention of association of BRCA status with TNBC. Consequently, the definition subtype of TNBC has important predictive value for the development of new therapeutic agents in the treatment of TNBC. Additionally, the incidence and types of mutations in BRCA-related pathways may be affected by ethnic origin and contribute to the risk of developing TNBC. PMID- 29696718 TI - Exocellular extract of Fusarium oxysporum, fungus free, is able to permeate and act selectively in skin. AB - The skin is an important gateway for Fusarium infection in humans. Our hypothesis is that metabolites produced by Fusarium oxysporum should change the barrier structure to permeate the skin. Male Wistar rats received a topical application of a solution (0.05 mg/mL) of Fusarium metabolites. The animals were euthanized 3, 6, 12, 24 h after and the skin was processed for immunostaining by laminin and E-cadherin to investigate whether the Fusarium metabolites can break the barrier of healthy skin. Other techniques were employed: H&E to study the morphology; metalloproteinase-9 (MMP-9), TUNEL, and PCNA immunostaining to evaluate the inflammation, cell death, and proliferation, respectively. There was an inflammatory response mainly centered in the dermis. Qualitatively, the skin of the experimental group showed reduced E-cadherin and laminin immunostaining at 3, 12, and 24 h. Higher intensity staining by TUNEL at 3 h, and PCNA at 6, 12, and 24 h. There was intense MMP-9 activity at 6, 12, and 24 h. None of analyses revealed any changes in the epidermis. It was concluded that the fraction was able to permeate the skin and act selectively in dermis, inducing inflammatory response, increasing MMP-9 immunostaining, inducing apoptosis, and reducing E cadherin and laminin immunostaining. PMID- 29696719 TI - Capnocytophaga canimorsus: a rare case of conservatively treated prosthetic valve endocarditis. AB - We describe a rare case of prosthetic valve endocarditis caused by the canine bacterium Capnocytophaga canimorsus in a male aged 73 years. The diagnosis of infective endocarditis was unequivocal, as it blood cultures were positive for C. canimorsus and vegetations were detected on transesophageal echocardiography; the modified Duke criteria were fulfilled. PET-CT showed intense 18 F-FDG uptake of the prosthetic valve area. The patient was treated with antibiotics alone (no surgery), and is now on life-long suppressive antibiotic therapy. To our knowledge, this is the third reported case of prosthetic valve endocarditis caused by C. canimorsus and the first one to have been treated conservatively. PMID- 29696720 TI - Bacterial biofilms: a possible mechanism for chronic infection in patients with lumbar disc herniation - a prospective proof-of-concept study using fluorescence in situ hybridization. AB - A relationship has been suggested between lumbar disc herniation (LDH) and chronic bacterial infection frequently involving Propionibacterium acnes, which is known to cause chronic infection through the formation of biofilm aggregates. The objective of the study was to assess whether a disc infection involving biofilm formation is present in patients with LDH. A total of 51 LDH patients and 14 controls were included. Bacterial DNA was detected by real-time polymerase chain reaction (PCR) in 16/51 samples in the LDH group and 7/14 controls (p = 0.215). Sequencing identified bacteria in 9/16 and 6/7 PCR positive samples in the LDH and control groups, respectively. All samples were stained using fluorescence in situ hybridization (FISH) and examined by confocal laser scanning microscopy. Microscopy demonstrated tissue-embedded bacterial aggregates with host inflammatory cells in 7/51 LDH patients and no controls. The presence of both bacterial aggregates and inflammatory cells suggests a chronic infection in a subset of LDH patients. The finding of bacterial 16S rDNA in both LDH and control disc tissue highlights the importance of microscopic observation to discriminate infection vs contamination. Our findings may have therapeutic implications, as the treatment of biofilm infections is different and more challenging than traditional infections. PMID- 29696721 TI - IL-10 polymorphisms and T-cell subsets could affect the clinical presentation and outcome of childhood immune thrombocytopenia in Egyptian population. AB - The aim is to study IL-10 polymorphisms and IL-10 level and assess their relation to T-cell subsets in childhood immune thrombocytopenia (ITP). In all, 40 (25 acute, 15 chronic) ITP child patients were investigated at time of presentation, compared to 15 healthy, age- and gender-matched controls and followed up for 1 year to determine chronic cases. Studying the effect of IL-10 promoter polymorphism was done by PCR-RFLP, IL-10 level was determined by ELISA, natural killer cells and T-cell subsets were evaluated by flow cytometry. Subjects with IL-10 promoter (1082 AA and 592 AA) genotypes had lower IL-10 levels and had lower CD4%, higher CD8%, lower CD4/CD8 ratio and lower T-reg%. IL-10 polymorphisms had no effect on NK%. IL-10 serum levels and IL-10 promoter polymorphic genotype frequencies are not different between ITP cases and controls; however, in ITP patients, IL-10 promoter (1082 AA and 592 AA) genotypes and associated lower CD4, higher CD8, lower CD4/CD8 ratio is associated with more severe thrombocytopenia at presentation and had a poorer response to first-line treatment. Patients with lower T-reg cells had a higher tendency to develop chronic ITP. IL-10 level and polymorphisms as well as disturbed T-cell subsets percentages are demonstrable effectors of immune dysfunction in ITP and can affect the presentation and outcome of childhood ITP. PMID- 29696722 TI - The first human report of mobile colistin resistance gene, mcr-1, in Finland. AB - Colistin resistance mediated by mobile mcr-1 gene has raised concern during the last years. After steep increase in mcr-1 reports, other mcr-gene variants (mcr-2 to mcr-5) have been revealed as well. In 2016, a clinical study was conducted on asymptomatic stool carriage of extended spectrum beta-lactamase (ESBL) producing Escherichia coli and Klebsiella pneumoniae among Finnish adults. All suspected ESBL producing bacterial isolates were first tested by phenotypic ESBL confirmation methods, and then further analyzed with whole genome sequencing to identify the resistance genes. We found one study subject carrying a colistin resistant E. coli with a transferrable mcr-1 gene. This multi-drug resistant isolate, although initially suspected to be an ESBL producer, did not carry any ESBL genes, but was proven to carry several other resistance genes by using whole genome sequencing. Sequence type was ST93. The mcr-1 gene was connected to IncX4 plasmid which suggests that the colistin resistance gene locates in the respective plasmid. Here, we report the finding of a mcr-1 harboring human E. coli isolate from Finland. Clinical antimicrobial resistance (AMR) rates are low in Finland, and mobile colistin resistance has not been reported previously. This highlights the importance of AMR surveillance also in populations with low levels of resistance. PMID- 29696723 TI - Design and construction of a new recombinant fusion protein (2b2t+EPC1) and its assessment for serodiagnosis of cystic echinococcosis. AB - The immunodiagnostic tests for cystic echinococcosis (CE) are mostly serological tests based on ELISA that use hydatid cyst antigens for primary screening because of its simple preparation and availability. The challenge to develop new serological methods (as compared to those based on the hydatid cyst fluid antigens) to meet the gold standard remains. Appropriate sources of antigenic material are necessary for application to improve the efficacy of immunodiagnostic tests at a population level. In the current study, a fusion protein containing the coding sequence of antigen B2t and two sequences of EPC1 antigen with some modifications was reconstructed. Using bioinformatics tools, these sequences were joined together by applying the sequence of a rigid alpha helix-forming linker to obtain an appropriate structure of a fusion protein. Synthetic recombinant fusion protein was expressed using pET28a as a vector and evaluated by indirect ELISA test for sera from patients with hepatic CE and other parasitic infections. The sensitivity of the fusion protein was lower (88.46%) than the available ELISA kit (96.15%). However, the differences in sensitivity were not statistically significant as compared to the recombinant fusion peptide with the commercial kit (p = 0.269). The specificity of the recombinant fusion protein (95.45%) was not significantly lower than the commercial kit (96.59%; p = 1.000). Moreover, surprisingly there was no difference in the cross-reactivity values of performance between the recombinant-ELISA and commercial kit. The positive and negative predictive values of the recombinant antigen were achieved as 92% and 93.33%, respectively, while for the commercial kit, they were obtained as 94.33% and 97.70%, respectively. In conclusion, as an early evaluation of these antigens the performance of our recombinant fusion protein in ELISA is relatively promising. Although, it seemed that this peptide with specific antigenic epitopes might be more appropriate for the serological evaluation of CE by use of bioinformatics tools, our findings showed that cross-reactions and a negative reaction could occur in clinical performance. This fusion protein may have utility for diagnosis in humans, but further evaluation is needed using the WHO ultrasound classification for CE. PMID- 29696724 TI - How to improve sharing and application of knowledge in care and support for people with intellectual disabilities? A systematic review. AB - BACKGROUND: To optimise care and support for people with intellectual disabilities (ID), sharing and application of knowledge is a precondition. In healthcare in general, there is a body of knowledge on bridging the 'know-do gap'. However, it is not known to what extent the identified barriers and facilitators to knowledge sharing and application also hold for the care and support of people with ID, due to its specific characteristics including long term care. Therefore, we conducted a systematic review to identify which organisational factors are enabling and/or disabling in stimulating the sharing and application of knowledge in the care and support of people with ID. METHOD: A systematic review was conducted using five electronic databases of relevant articles published in English between January 2000 and December 2015. During each phase of selection and analysis a minimum of two independent reviewers assessed all articles according to PRISMA guidelines. RESULTS: In total 2,256 articles were retrieved, of which 19 articles met our inclusion criteria. All organisational factors retrieved from these articles were categorised into three main clusters: (1) characteristics of the intervention (factors related to the tools and processes by which the method was implemented); (2) factors related to people (both at an individual and group level); and, (3) factors related to the organisational context (both material factors (office arrangements and ICT system, resources, time and organisation) and immaterial factors (training, staff, size of team)). CONCLUSION: Overall analyses of the retrieved factors suggest that they are related to each other through the preconditional role of management (i.e., practice leadership) and the key role of professionals (i.e. (in)ability to fulfill new roles). PMID- 29696726 TI - Evidence-based pathways to intervention for children with language disorders. AB - BACKGROUND: Paediatric speech and language therapist (SLT) roles often involve planning individualized intervention for specific children, working collaboratively with families and education staff, providing advice, training and coaching and raising awareness. A tiered approach to service delivery is currently recommended whereby services become increasingly specialized and individualized for children with greater needs. AIMS: To stimulate discussion regarding delivery of SLT services by examining evidence regarding the effectiveness of (1) intervention for children with language disorders at different tiers and (2) SLT roles within these tiers; and to propose an evidence based model of SLT service delivery and a flowchart to aid clinical decision making. METHODS & PROCEDURES: Meta-analyses and systematic reviews, together with controlled, peer-reviewed group studies where recent systematic reviews were not available, of interventions for children with language disorders are discussed, alongside the differing roles SLTs play in these interventions. Gaps in the evidence base are highlighted. MAIN CONTRIBUTION: The service-delivery model presented resembles the tiered model commonly used in education services, but divides individualized (Tier 3) services into Tier 3A: indirect intervention delivered by non-SLTs, and Tier 3B: direct intervention by an SLT. We report evidence for intervention effectiveness, which children might best be served by each tier, the role SLTs could take within each tier and the effectiveness of these roles. Regarding universal interventions provided to all children (Tier 1) and those targeted at children with language weaknesses or vulnerabilities (Tier 2), there is growing evidence that approaches led by education services can be effective when staff are highly trained and well supported. There is currently limited evidence regarding additional benefit of SLT-specific roles at Tiers 1 and 2. With regard to individualized intervention (Tier 3), children with complex or pervasive language disorders can progress following direct individualized intervention (Tier 3B), whereas children with milder or less pervasive difficulties can make progress when intervention is managed by an SLT, but delivered indirectly by others (Tier 3A), provided they are well trained and supported, and closely monitored. CONCLUSIONS & IMPLICATIONS: SLTs have a contribution to make at all tiers, but where prioritization for clinical services is a necessity, we need to establish the relative benefits and cost-effectiveness at each tier. Good evidence exists for SLTs delivering direct individualized intervention and we should ensure that this is available to children with pervasive and/or complex language disorders. In cases where service models are being provided which lack evidence, we strongly recommend that SLTs investigate the effectiveness of their approaches. PMID- 29696725 TI - The anticipation and outcome phases of reward and loss processing: A neuroimaging meta-analysis of the monetary incentive delay task. AB - The processing of rewards and losses are crucial to everyday functioning. Considerable interest has been attached to investigating the anticipation and outcome phases of reward and loss processing, but results to date have been inconsistent. It is unclear if anticipation and outcome of a reward or loss recruit similar or distinct brain regions. In particular, while the striatum has widely been found to be active when anticipating a reward, whether it activates in response to the anticipation of losses as well remains ambiguous. Furthermore, concerning the orbitofrontal/ventromedial prefrontal regions, activation is often observed during reward receipt. However, it is unclear if this area is active during reward anticipation as well. We ran an Activation Likelihood Estimation meta-analysis of 50 fMRI studies, which used the Monetary Incentive Delay Task (MIDT), to identify which brain regions are implicated in the anticipation of rewards, anticipation of losses, and the receipt of reward. Anticipating rewards and losses recruits overlapping areas including the striatum, insula, amygdala and thalamus, suggesting that a generalised neural system initiates motivational processes independent of valence. The orbitofrontal/ventromedial prefrontal regions were recruited only during the reward outcome, likely representing the value of the reward received. Our findings help to clarify the neural substrates of the different phases of reward and loss processing, and advance neurobiological models of these processes. PMID- 29696727 TI - Reduced embryonic blood flow impacts extracellular matrix deposition in the maturing aorta. AB - BACKGROUND: Perturbations to embryonic hemodynamics are known to adversely affect cardiovascular development. Vitelline vein ligation (VVL) is a model of reduced placental blood flow used to induce cardiac defects in early chick embryo development. The effect of these hemodynamic interventions on maturing elastic arteries is largely unknown. We hypothesize that hemodynamic changes impact maturation of the dorsal aorta (DA). RESULTS: We examined the effects of VVL on hemodynamic properties well into the maturation process and the corresponding changes in aortic dimensions, wall composition, and gene expression. In chick embryos, we found that DA blood velocity was reduced immediately postsurgery at Hamburger-Hamilton (HH) stage 18 and later at HH36, but not in the interim. Throughout this period, DA diameter adapted to maintain a constant shear stress. At HH36, we found that VVL DAs showed a substantial decrease in elastin and a modest increase in collagen protein content. In VVL DAs, up-regulation of elastic fiber-related genes followed the down-regulation of flow-dependent genes. Together, these suggest the existence of a compensatory mechanism in response to shear-induced delays in maturation. CONCLUSIONS: The DA's response to hemodynamic perturbations invokes coupled mechanisms for shear regulation and matrix maturation, potentially impacting the course of vascular development. Developmental Dynamics 247:914-923, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29696728 TI - Predictive value of eosinophils and neutrophils on clinical effects of ICS in COPD. AB - BACKGROUND AND OBJECTIVE: Inflammation is present to a variable degree and composition in patients with COPD. This study investigates associations between both eosinophils and neutrophils in blood, sputum, airway wall biopsies and bronchoalveolar lavage (BAL) and their potential use as biomarkers for clinical response to inhaled corticosteroids (ICS). METHODS: In total, 114 steroid-naive COPD patients of the Groningen Leiden Universities Corticosteroids in Obstructive Lung Disease (GLUCOLD) study using ICS or placebo during 30-month follow-up were included. Cell counts in blood, sputum, biopsies and BAL were evaluated at baseline. In addition, at baseline, 6 and 30 months, forced expiratory flow in 1 s (FEV1 ), residual volume/total lung capacity (hyperinflation) and Clinical COPD Questionnaire were evaluated. RESULTS: Cross-sectional analyses at baseline showed that higher blood eosinophils were significantly associated with higher eosinophil counts in sputum, biopsies and BAL. However, blood neutrophils did not significantly correlate with neutrophil counts in the other compartments. Baseline eosinophils and neutrophils, in whichever compartment measured, did not predict longitudinal FEV1 changes. Higher baseline biopsy eosinophils were associated with an increase in symptoms during 6- and 30-month ICS treatment. In addition, higher biopsy neutrophils were associated with a more marked reduction in hyperinflation during 6-month ICS treatment compared with placebo. CONCLUSION: Our findings indicate that blood eosinophils reflect eosinophils in other compartments, in contrast to neutrophils, in ICS-naive COPD patients. Both baseline eosinophils and neutrophils do not predict ICS-induced lung function changes over a period of 6-30 months. The associations of biopsy eosinophils with worsening respiratory symptoms and biopsy neutrophils with improvement in hyperinflation during ICS treatment deserve further investigation. PMID- 29696730 TI - Molecular interactions between vinculin and phospholipids. AB - The focal adhesion protein vinculin has been implicated in associating with soluble and membranous phospholipids. Detailed investigations over the past ten years describe the intermolecular interactions of the vinculin tail domain with soluble and membrane phospholipids. Previous studies have implied that the tail's unstructured C-terminal region affects the mechanical behavior of cells and that the same region, at the molecular level, has bi-stable behavior sensitive to different protonation states. The aim of this short communication is to discuss whether the C-terminal vinculin tail (Vt) domain interacts favorably with membrane-embedded phospholipids such as PIP2 and that the region is also an anchor for lipid membranes. PMID- 29696729 TI - Acid-regulated gene expression of Helicobacter pylori: Insight into acid protection and gastric colonization. AB - BACKGROUND: The pathogen Helicobacter pylori encounters many stressors as it transits to and infects the gastric epithelium. Gastric acidity is the predominate stressor encountered by the bacterium during initial infection and establishment of persistent infection. H. pylori initiates a rapid response to acid to maintain intracellular pH and proton motive force appropriate for a neutralophile. However, acid sensing by H. pylori may also serve as a transcriptional trigger to increase the levels of other pathogenic factors needed to subvert host defenses such as acid acclimation, antioxidants, flagellar synthesis and assembly, and CagA secretion. MATERIALS AND METHODS: Helicobacter pylori were acid challenged at pH 3.0, 4.5, 6.0 vs nonacidic pH for 4 hours in the presence of urea, followed by RNA-seq analysis and qPCR. Cytoplasmic pH was monitored under the same conditions. RESULTS: About 250 genes were induced, and an equal number were repressed at acidic pHs. Genes encoding for antioxidant proteins, flagellar structural proteins, particularly class 2 genes, T4SS/Cag PAI, Fo F1 -ATPase, and proteins involved in acid acclimation were highly expressed at acidic pH. Cytoplasmic pH decreased from 7.8 at pHout of 8.0 to 6.0 at pHout of 3.0. CONCLUSIONS: These results suggest that increasing extracellular or intracellular acidity or both are detected by the bacterium and serve as a signal to initiate increased production of protective and pathogenic factors needed to counter host defenses for persistent infection. These changes are dependent on degree of acidity and time of acid exposure, triggering a coordinated response to the environment required for colonization. PMID- 29696731 TI - Perceived stress and well-being in UK and Australian dental hygiene and dental therapy students. AB - INTRODUCTION: This study aimed to explore United Kingdom (UK) and Australian (Aus) dental hygiene and dental therapy students' (DHDTS) perception of stress and well-being during their undergraduate education. Upon qualification, DHDTS in the UK register as dental therapists (DT), and in Australia, they register as Oral Health Therapists (OHT). MATERIALS AND METHODS: A questionnaire was distributed to years 1, 2 and 3 DHDTS at the University of Portsmouth Dental Academy (UPDA) in the UK and La Trobe Rural Health School in Australia. The questionnaire consisted of 5 well-used measurement instruments which included the following: Dental Environment Stress questionnaire (DES); Depression Anxiety Stress Scales (DASS-21); Scales of Psychological Well-Being (SPWB); Valuing Questionnaire (VQ); and the Adult Hope Scale (AHS) to collect data on students' perception of levels of stress and well-being. RESULTS: A response rate of 58% (UK) and 55% (Australia) was achieved. Clinical factors and academic work were perceived as stressful for DHDTS in both the UK and Australia. The Australian DHDTS-perceived stress in the educational environment was significantly higher (P < .002) than the UK DHDTS. The majority of respondents reported levels of depression, anxiety and stress to be within the normal-to-moderate range. All students reported high levels of positive well-being, with no significant differences between the 2 groups. CONCLUSIONS: DHDTS in the UK and Australia identified sources of stress within their undergraduate education, but also perceived themselves as positively functioning individuals. PMID- 29696732 TI - Seshat: A Web service for accurate annotation, validation, and analysis of TP53 variants generated by conventional and next-generation sequencing. AB - Accurate annotation of genomic variants in human diseases is essential to allow personalized medicine. Assessment of somatic and germline TP53 alterations has now reached the clinic and is required in several circumstances such as the identification of the most effective cancer therapy for patients with chronic lymphocytic leukemia (CLL). Here, we present Seshat, a Web service for annotating TP53 information derived from sequencing data. A flexible framework allows the use of standard file formats such as Mutation Annotation Format (MAF) or Variant Call Format (VCF), as well as common TXT files. Seshat performs accurate variant annotations using the Human Genome Variation Society (HGVS) nomenclature and the stable TP53 genomic reference provided by the Locus Reference Genomic (LRG). In addition, using the 2017 release of the UMD_TP53 database, Seshat provides multiple statistical information for each TP53 variant including database frequency, functional activity, or pathogenicity. The information is delivered in standardized output tables that minimize errors and facilitate comparison of mutational data across studies. Seshat is a beneficial tool to interpret the ever growing TP53 sequencing data generated by multiple sequencing platforms and it is freely available via the TP53 Website, http://p53.fr or directly at http://vps338341.ovh.net/. PMID- 29696733 TI - Quantification of DNA methylation and hydroxymethylation in Alzheimer's disease mouse model using LC-MS/MS. AB - Ambiguous alteration patterns of 5-methylcytosine (5mC) and 5 hydroxymethylcytosine (5hmC) involved in Alzheimer's disease (AD) obstructed the mechanism investigation of this neurological disorder from epigenetic view. Here, we applied a fully quantitative and validated LC-MS/MS method to determine genomic 5mC and 5hmC in the brain cortex of 3 month-aged (12, 15, and 18 month) AD model mouse and found significant increases of 5mC and 5hmC levels in different months of AD mouse when compared with age-matched wild-type control and exhibited rising trend from 12-month to 18-month AD mouse, thereby supporting genomic DNA methylation and hydroxymethylation were positively correlated with developing AD. PMID- 29696734 TI - Pediatric Helicobacter pylori gastropathy demonstrates a unique pattern of gastric foveolar hyperplasia. AB - OBJECTIVES: Helicobacter pylori (Hp) are the most common agents causing gastric mucosal injury worldwide. Foveolar hyperplasia is a key component of the stomach's reaction to injury. This study examines histopathologic characteristics associated with Helicobacter pylori and with non- Helicobacter pylori-associated gastropathy in children and adolescents, and compares the prevalence of foveolar hyperplasia among these disease subgroups and normal control subjects. METHODS: Eighty-one gastric antral and corpus biopsies from subjects 2-19 years of age were studied. Twenty-two subjects with Helicobacter pylori gastritis were compared to 23 with non-Helicobacter pylori gastropathy and to 36 controls (normal biopsies). Foveolar length, full mucosal thickness, and the foveolar length: full mucosal thickness ratio were derived by a morphometric technique previously developed to analyze adult gastric tissue. RESULTS: Compared to controls, Helicobacter pylori gastritis demonstrated significant increases in antral foveolar length (P < .0001), full mucosal thickness (P < .0001), as well as corpus foveolar length (P < .05) and corpus full mucosal thickness (P < .05). Non-Helicobacter pylori-associated gastropathy also was characterized by increased antral foveolar length (P < .0001) and full mucosal thickness (P < .001) but corresponding corpus measurements did not differ from controls. Antral foveolar length in non-Helicobacter pylori gastropathy was increased, when compared to Helicobacter pylori gastritis (P < .05), while corpus values were not. The non-Helicobacter pylori gastropathy group demonstrated increased antral foveolar length: full mucosal thickness ratios, compared with Helicobacter pylori gastritis (P < .001) and with normal controls (P < .0001). DISCUSSION: An objective, quantitative approach to measuring foveolar hyperplasia in adults was successfully applied to pediatric biopsies and yielded a richer characterization of gastric pathology in children. Foveolar hyperplasia appears to be a generalized phenomenon in the presence of pediatric Helicobacter pylori gastritis but is limited to the antrum in non-Helicobacter pylori gastropathy. PMID- 29696735 TI - Effects of COL8A1 on the proliferation of muscle-derived satellite cells. AB - Collagen type VIII alpha 1 chain (COL8A1) is a component of the extracellular matrix. Our previous studies suggested that COL8A1 is associated with the proliferation of muscle-derived satellite cells (MDSCs). Additionally, it has been demonstrated that COL8A1 promotes the proliferation of smooth muscle cells and liver cancer cells. Therefore, we predicted that COL8A1 is associated with the proliferation of bovine MDSCs, which have potential applications in research. In this study, we constructed vectors to activate and repress COL8A1 in bovine MDSCs using the CRISPR/Cas9 technique and determined the effects of COL8A1 modulation by EdU labeling, Western blotting, and dual-luciferase reporter assays. The results showed that activation of COL8A1 increased the number of EdU positive cells and expression of the proliferation markers cyclin B1 (CCNB1) and P-AKT. The expression of P-Akt was unchanged after addition of LY294002 (a protein kinase inhibitor capable of blocking the signal transduction pathway of the phosphoinositide 3-kinase). In contrast, repression of COL8A1 reduced the number of EdU-positive cells and expression of CCNB1 and P-AKT. We also observed upregulation and downregulation of COL8A1 following the overexpression and repression of EGR1, respectively. The dual-luciferase reporter assay revealed that EGR1 regulates the promoter activity of COL8A1. To our knowledge, this is the first study demonstrating that EGR1 positively regulates the expression of COL8A1, which in turn promotes the proliferation of bovine MDSCs via the PI3 K/AKT signaling pathway. PMID- 29696736 TI - Bismuth improves efficacy of proton-pump inhibitor clarithromycin, metronidazole triple Helicobacter pylori therapy despite a high prevalence of antimicrobial resistance. AB - BACKGROUND: Helicobacter pylori (H. pylori) eradication has become increasingly difficult especially for penicillin allergy patients. AIMS: To evaluate the efficacy of adding bismuth or high-dose metronidazole to an H. pylori eradication regimen containing a proton-pump inhibitor, clarithromycin, and metronidazole in patients allergic to penicillin. METHODS: Pilot study in which penicillin allergic, treatment-naive subjects were randomized (1:1) to 14-day esomeprazole (20 mg q12h), clarithromycin (500 mg q12h), and high dose of metronidazole (400 mg q6h) with (BECM group) or without (ECM group) bismuth (600 mg q12h). Eradication was confirmed by 13 C-urea breath test 6 weeks after therapy. Antimicrobial susceptibility was assessed by the agar dilution method. Adverse events were recorded. RESULTS: Sixty-six subjects were randomized, four were lost to follow-up and eight violated the protocol. The eradication rates were 63.6% (95% CI: 47.2%-80.0%) for ECM vs 84.8% (95% CI 72.6%-97.1%) (p = .049) for BECM by intention-to-treat, 67.7% (95% CI 51.3%-84.2%) vs 90.3% (95% CI 79.9%-100%) (p = .029) by modified ITT, and 70% (95% CI 53.6%-86.4%) vs 96% (95% CI 88.3%-100%) (P = .033) by per-protocol. Metronidazole, clarithromycin, and dual-resistant rates were 74.2%, 24.2%, and 18.2%, respectively. The cure rates were significantly improved by the addition of bismuth for both clarithromycin resistant isolates (100% vs 25%, P = .024) and metronidazole-resistant isolates (94.7% vs 63.6%, P = .043). Adverse events were reported by 45.5% of subjects in ECM group and 48.5% in the BECM group (P = .805). CONCLUSIONS: This prospective trial demonstrated that while high-dose metronidazole could not completely overcome metronidazole resistance, bismuth was additive and improved the overall cure rates by 21%-26%. PMID- 29696737 TI - Estimation of concentration of radionuclides in skeletal muscle from blood, based on the data from abandoned animals in Fukushima. AB - The damage caused by the earthquake on 11 March, 2011 resulted in a serious nuclear accident in Japan. Due to the damage to the Fukushima Daiichi Nuclear Power Plant (FNPP), large amounts of radioactive substances were released into the environment. In particular, one of the largest safety concerns is radioactive cesium (134 Cs and 137 Cs). Due to the FNPP nuclear accident, a 20 km area was restricted from human activity, and various types of domestic animals were left in the zone. We collected the organs and tissues from sacrificed animals to obtain scientific data to evaluate the internal deposition of radioactive compounds. At first, we found there is a strong correlation between blood 137 Cs and organ 137 Cs with data from 44 cattle, indicating that skeletal muscle is the target organ of deposition of radioactive cesium. Second, we analyzed the relationship between blood 137 Cs and muscle 137 Cs within relatively lower radioactive concentration, suggesting that estimation of concentration of 137 Cs is possible from blood concentration of 137 Cs. Finally, we developed computer software to estimate the muscle 137 Cs concentration from blood samples. Our study contributes to the food safety of livestock products. PMID- 29696738 TI - DL-3-n-butylphthalide promotes dendrite development in cortical neurons subjected to oxygen-glucose deprivation/reperfusion. AB - The limited degree of functional recovery is closely associated with the condition of the periinfarct cortex after ischemic stroke. The model of oxygen glucose deprivation in cultured neurons could partly simulate this condition. Proper dendritic morphology is crucial for the correct wiring of neuronal function. Hence, the question of how to facilitate the plasticity of neural dendrites is of great significance. DL-3-n-butylphthalide is an efficient medication for ischemic stroke. In this study, in addition to having neuroprotective effects, DL-3-n-butylphthalide could increase the number of primary and secondary dendrites and of dendritic tips as confirmed by Sholl analysis. This study further demonstrated that DL-NBP inactivates PI3K/AKT signaling to positively regulate dendritic branching. PMID- 29696740 TI - Using the Public Involvement Impact Assessment Framework to assess the impact of public involvement in a mental health research context: A reflective case study. AB - BACKGROUND: We assess the utility of the Public Involvement Impact Assessment Framework (PiiAF) as a resource to support research teams in assessing the impact of Public Involvement across diverse research and public involvement (PI) contexts. PiiAF was developed in response to a well-documented growth in Public Involvement in health research in the United Kingdom that demands a more sophisticated evidence base to demonstrate its impact. DESIGN: We used a reflective case study approach drawing on contemporaneous meeting notes, PiiAF website resources and retrospective reflections to describe how PiiAF helped us to develop an impact assessment plan of the PI in a university-based mental health research centre. DISCUSSION: We consider key aspects of our experiences of using PiiAF as a tool to help us design an impact assessment of PI, interpret these experiences with reference to relevant theory and research and share insights that may be useful to other teams considering using PiiAF. CONCLUSION: These insights include understanding the commitment of time and effort required to develop effective PI impact assessment plans; the flexibility of PiiAF and its ability to be used in a range of research and PI contexts; and the advantages of involving all stakeholders (including the public) in the development of an PI assessment plan. PMID- 29696739 TI - Gaussia princeps luciferase: a bioluminescent substrate for oxidative protein folding. AB - Gaussia princeps luciferase (GLuc) generates an intense burst of blue light when exposed to coelenterazine in the absence of ATP. Here we show that this 5 disulfide containing enzyme can be used as a facile and convenient substrate for studies of oxidative protein folding. Reduced GLuc (rGLuc), with 10 free cysteine residues, is completely inactive as a luciferase but >60% bioluminescence activity, compared to controls, can be recovered using a range of oxidizing regimens in the absence of the exogenous shuffling activity of protein disulfide isomerase (PDI). The sulfhydryl oxidase QSOX1 can be assayed using rGLuc in a simple bioluminescence plate reader format. Similarly, low concentrations of rGLuc can be oxidized by millimolar levels of dehydroascorbate, hydrogen peroxide or much lower concentrations of sodium tetrathionate. The oxidative refolding of rGLuc in the presence of a range of glutathione redox buffers is only marginally accelerated by micromolar levels of PDI. This modest rate enhancement probably results from a relatively simple disulfide connectivity in native GLuc; reflecting two homologous domains each carrying two disulfide bonds with a single interdomain disulfide. When GLuc is reoxidized under denaturing conditions the resulting scrambled protein (sGLuc) can be used in a sensitive bioluminescence assay for reduced PDI in the absence of added exogenous thiols. Finally, the general facility by which rGLuc can recover bioluminescent activity in vitro provides a sensitive method for the assessment of inhibitors of oxidative protein folding. PMID- 29696741 TI - Outcomes of single kidney transplantation from pediatric donors: A single-center experience. AB - Kidneys from pDDs are increasingly used to narrow the huge gap between incremental demand and static supply. However, there is still controversy on the clinical outcome of SKT from pDDs. We conducted a retrospective cohort study of 452 adult recipients in our center between March 2012 and February 2017. Outcomes of 3 groups, transplants with organs from pDDs (n=50), aDDs (n=207), and LDs (n=195), were compared. The mean age and weight of pDDs were 8.98 years (range 8 months-17 years) and 30.05 kg (range 8.2-55 kg), respectively. There was no difference in 1-year (96.0%, 98.1%, and 99.0%, respectively, P=.277) and 3-year patient survival (96.0%, 98.1%, and 99.0%, respectively, P=.277) or in 1-year (96.0%, 96.6%, and 98.5%, P=.307) and 3-year (96.0%, 96.6% and 97.9%, P=.437) graft survival. SCr, eGFR, and allograft size were similar among the 3 groups at 6th month post-transplant and thereafter. Incidence of DGF was higher in patients of the aDD group than those in the pDD group (22.7% vs 10.0%, P<.001), but there was no difference in AR and infection. SKT from pDDs to adult recipients is effective and safe with acceptable outcomes, and it will be a promising expansion to the donor pool. PMID- 29696742 TI - Comparative effectiveness of hand scaling by undergraduate dental students following a two-week pre-clinical training course. AB - BACKGROUND: The Bologna reform resulted in a drastic restructuring of pre clinical training courses at the University of Zurich. The aim of this study was to assess student pre-clinical scaling/root planning skills after just 8.5 hours of manual training. MATERIAL AND METHODS: Three consecutive classes of dental students (n = 41; n = 34; n = 48) were tasked with removing lacquer concrement from the maxillary left canine on a typodont using Gracey and universal (Deppeler M23A) curettes. At baseline (prior to instruction), a timed 5-minute session of scaling/root planning was undertaken. The second scaling/root planning session was held immediately following training. Eight experienced dental hygienists and eight lay people served as positive and negative controls, using the same instruments and time limit, respectively. Instrumented teeth were collected, scanned and planimetrically analysed for the percentage of tooth surface cleaned. Statistical analyses were performed to assess the dental students' improvement after the training (Wilcoxon signed-rank test) and to compare it to that of laypeople and dental hygienists (Kruskal-Wallis rank sum test followed by Conover's post hoc test). RESULTS: At baseline, the dental students' mean scaling scores of the cleaned surfaces were not significantly different than those of laypeople (29.8%, 31.0%, 42% vs 27.9%). However, after 8.5 hours of manual training, the students' ability to clean the maxillary tooth improved significantly and they achieved mean removal values of 61.7%, 79.5% and 76% compared to the 67.4% (P < .001) of the experienced dental hygienists (Tables and ). There were no statistically significant differences between the scores achieved by students after training and those achieved by experienced dental hygienists. CONCLUSION: A shortened pre-clinical training time was sufficient for students to acquire the basic scaling/root planning skills needed in preparation for clinical training. Further research is needed to identify ways to help students consistently reach highest skill levels. PMID- 29696743 TI - Coexistence of glandular papilloma and sclerosing pneumocytoma in the bronchiole. AB - Both glandular papilloma (GP) and sclerosing pneumocytoma (SP) are rare tumors in the lung. We herein report an extremely rare case of coexistence of these two uncommon tumors. The patient was a 40-year-old Japanese woman with no chief complaint. A solitary nodule of the lung was detected using chest computed tomography. The transbronchial biopsy revealed that the tumor histologically corresponded to GP. The patient subsequently underwent partial resection of the right upper lobe. Histological examination of the resected specimens further revealed that the mass contained two different and independent elements and displayed typically histological features of GP and SP. Molecular analysis further revealed the presence of BRAF V600E and AKT1 E17K mutations in GP, whereas only AKT1 mutation was detected in SP. To our knowledge, this is the first case of coexistence of GP and SP in the bronchiole harboring common AKT1 mutation and different BRAF V600E mutational status. PMID- 29696744 TI - NGS testing for cardiomyopathy: Utility of adding RASopathy-associated genes. AB - RASopathies include a group of syndromes caused by pathogenic germline variants in RAS-MAPK pathway genes and typically present with facial dysmorphology, cardiovascular disease, and musculoskeletal anomalies. Recently, variants in RASopathy-associated genes have been reported in individuals with apparently nonsyndromic cardiomyopathy, suggesting that subtle features may be overlooked. To determine the utility and burden of adding RASopathy-associated genes to cardiomyopathy panels, we tested 11 RASopathy-associated genes by next-generation sequencing (NGS), including NGS-based copy number variant assessment, in 1,111 individuals referred for genetic testing for hypertrophic cardiomyopathy (HCM) or dilated cardiomyopathy (DCM). Disease-causing variants were identified in 0.6% (four of 692) of individuals with HCM, including three missense variants in the PTPN11, SOS1, and BRAF genes. Overall, 36 variants of uncertain significance (VUSs) were identified, averaging ~3VUSs/100 cases. This study demonstrates that adding a subset of the RASopathy-associated genes to cardiomyopathy panels will increase clinical diagnoses without significantly increasing the number of VUSs/case. PMID- 29696745 TI - A case of acrodermatitis continua of Hallopeau (ACH) successfully treated with sulfasalazine. PMID- 29696746 TI - New lactic acid bacteria for skin health via oral intake of heat-killed or live cells. AB - Lactic acid bacteria play an essential role in the food industry in the manufacture of many fermented products (cheese, yogurt, fermented vegetables, etc.). Application of these organisms is now being extended to the area of health improvement, as their probiotic activities become known. Probiotics are defined as viable microorganisms that exert a beneficial effect on the health of the host when they are ingested in sufficient quantity. Lactic acid bacteria and bifidobacteria isolated from the human intestine are the most common probiotics used for human consumption. The development of new probiotics with new beneficial effects is eagerly awaited in the food industry. This review introduces Lactococcus, which are one of the genera of lactic acid bacteria and are mainly isolated from dairy products and fermented vegetables, as new probiotics, focusing especially on Lactococcus lactis H61, which improves skin status in Japanese women with oral intake of heat-killed or live cells. The deduced mechanisms associated with the beneficial effects of strain H61 are also discussed. PMID- 29696748 TI - In Situ Generation of Silylzinc by Si-B Bond Activation Enabling Silylzincation and Silaboration of Terminal Alkynes. AB - A new protocol has been designed for the in situ generation of unstable Si-Zn species through the reaction of dialkylzinc, phosphine, and silylborane (Si-B). Successive reactions with various terminal alkynes using this protocol enabled highly controllable regio-/stereo-/chemoselective silylzincation and silaboration on demand without the need for a transition-metal catalyst. PMID- 29696747 TI - Marker chromosome genomic structure and temporal origin implicate a chromoanasynthesis event in a family with pleiotropic psychiatric phenotypes. AB - Small supernumerary marker chromosomes (sSMC) are chromosomal fragments difficult to characterize genomically. Here, we detail a proband with schizoaffective disorder and a mother with bipolar disorder with psychotic features who present with a marker chromosome that segregates with disease. We explored the architecture of this marker and investigated its temporal origin. Array comparative genomic hybridization (aCGH) analysis revealed three duplications and three triplications that spanned the short arm of chromosome 9, suggestive of a chromoanasynthesis-like event. Segregation of marker genotypes, phased using sSMC mosaicism in the mother, provided evidence that it was generated during a germline-level event in the proband's maternal grandmother. Whole-genome sequencing (WGS) was performed to resolve the structure and junctions of the chromosomal fragments, revealing further complexities. While structural variations have been previously associated with neuropsychiatric disorders and marker chromosomes, here we detail the precise architecture, human life-cycle genesis, and propose a DNA replicative/repair mechanism underlying formation. PMID- 29696749 TI - Intra-operative portal hemodynamics in pediatric LDLT: Doppler ultrasound surveillance. AB - Doppler ultrasonography is useful in monitoring intra-operative PV flow in LDLT. A retrospective cohort study included 550 pediatric recipients (<18 years) who underwent LDLT from October 2006 to August 2016 in our hospital. A total of 33 recipients (incidence 6%) were found to have insufficient intra-operative PV flow after PV reperfusion. The treatments included intra-operative stent placement (n=25), anticoagulation (n=3), thrombectomy and re-anastomosis (n=2), graft repositioning (n=1), collateral ligation (n=1), and replaced PV (n=1). The peak PV velocity, HAPSV, HARI, and HV velocity before and after the interventions were significantly improved 0(0,5.5) cm/s vs. 37.36+/-15.30 cm/s, 38.68+/-8.92 cm/s vs. 62.30+/-16.97 cm/s, 0.55+/-0.08 vs. 0.76+/-0.10, and 32.37+/-10.33 cm/s vs. 40.94+/-15.01 cm/s, respectively (P<.01). Insufficient PV flow and decreased HARI are two significant criteria indicating need for intra-operative PV management. Dramatic changes in the hepatic hemodynamics were detected after proper treatment. Immediate resolution of PV flow is feasible in pediatric LDLT. PMID- 29696750 TI - Angelman syndrome in adolescence and adulthood: A retrospective chart review of 53 cases. AB - Angelman syndrome is a neurogenetic disorder with varying clinical presentations and symptoms as the individual ages. The goal of this study was to characterize changes over time in the natural history of this syndrome in a large population. We reviewed the medical records of the 53 patients who were born prior to 2000 and seen at the Angelman Syndrome Clinic at Massachusetts General Hospital to assess neurological, sleep, behavioral, gastrointestinal, orthopedic, and ophthalmologic functioning. The average age of this cohort was 24 years. Active seizures were present in 35%, nonepileptic myoclonus in 42%, and clinically significant tremors in 55%. Anxiety was present in 57%, increasing to 71% in those ages 26-43 years. In terms of sleep, 56% reported 8 hr of sleep or more, although 43% reported frequent nocturnal awakenings. Gastrointestinal issues remain problematic with 81% having constipation and 53% gastroesophageal reflux. The majority lived in a parent's home and remained independently mobile, though scoliosis was reportedly present in 30%, and 20% had reported low bone density/osteoporosis. The results of this study suggest that the prevalence of active seizures may decrease in adulthood but that the prevalence of movement disorders such as tremor and nonepileptic myoclonus may increase. Anxiety increases significantly as individuals age while defiant behaviors appear to decrease. Sleep dysfunction typically improves as compared to childhood but remains a significant issue for many adults. Other areas that require monitoring into adulthood include gastrointestinal dysfunction, and orthopedic/mobility issues, such as reported scoliosis and bone density, and ophthalmologic disorders. PMID- 29696751 TI - Spatial organization of protein export in malaria parasite blood stages. AB - Plasmodium falciparum, which causes malaria, extensively remodels its human host cells, particularly erythrocytes. Remodelling is essential for parasite survival by helping to avoid host immunity and assisting in the uptake of plasma nutrients to fuel rapid growth. Host cell renovation is carried out by hundreds of parasite effector proteins that are exported into the erythrocyte across an enveloping parasitophorous vacuole membrane (PVM). The Plasmodium translocon for exported (PTEX) proteins is thought to span the PVM and provide a channel that unfolds and extrudes proteins across the PVM into the erythrocyte. We show that exported reporter proteins containing mouse dihydrofolate reductase domains that inducibly resist unfolding become trapped at the parasite surface partly colocalizing with PTEX. When cargo is trapped, loop-like extensions appear at the PVM containing both trapped cargo and PTEX protein EXP2, but not additional components HSP101 and PTEX150. Following removal of the block-inducing compound, export of reporter proteins only partly recovers possibly because much of the trapped cargo is spatially segregated in the loop regions away from PTEX. This suggests that parasites have the means to isolate unfoldable cargo proteins from PTEX containing export zones to avert disruption of protein export that would reduce parasite growth. PMID- 29696752 TI - Clinical implementation of AXB from AAA for breast: Plan quality and subvolume analysis. AB - PURPOSE: Two dose calculation algorithms are available in Varian Eclipse software: Anisotropic Analytical Algorithm (AAA) and Acuros External Beam (AXB). Many Varian Eclipse-based centers have access to AXB; however, a thorough understanding of how it will affect plan characteristics and, subsequently, clinical practice is necessary prior to implementation. We characterized the difference in breast plan quality between AXB and AAA for dissemination to clinicians during implementation. METHODS: Locoregional irradiation plans were created with AAA for 30 breast cancer patients with a prescription dose of 50 Gy to the breast and 45 Gy to the regional node, in 25 fractions. The internal mammary chain (IMCCTV ) nodes were covered by 80% of the breast dose. AXB, both dose-to-water and dose-to-medium reporting, was used to recalculate plans while maintaining constant monitor units. Target coverage and organ-at-risk doses were compared between the two algorithms using dose-volume parameters. An analysis to assess location-specific changes was performed by dividing the breast into nine subvolumes in the superior-inferior and left-right directions. RESULTS: There were minimal differences found between the AXB and AAA calculated plans. The median difference between AXB and AAA for breastCTV V95% , was <2.5%. For IMCCTV , the median differences V95% , and V80% were <5% and 0%, respectively; indicating IMCCTV coverage only decreased when marginally covered. Mean superficial dose increased by a median of 3.2 Gy. In the subvolume analysis, the medial subvolumes were "hotter" when recalculated with AXB and the lateral subvolumes "cooler" with AXB; however, all differences were within 2 Gy. CONCLUSION: We observed minimal difference in magnitude and spatial distribution of dose when comparing the two algorithms. The largest observable differences occurred in superficial dose regions. Therefore, clinical implementation of AXB from AAA for breast radiotherapy is not expected to result in changes in clinical practice for prescribing or planning breast radiotherapy. PMID- 29696753 TI - Biosynthetic and Functional Color-Scent Associations in Flowers of Papaver nudicaule and Their Impact on Pollinators. AB - Despite increasing evidence for biosynthetic connections between flower pigments and volatile compounds, examples of such relationships in polymorphic plant species remains limited. Herein, color-scent associations in flowers from Papaver nudicaule (Papaveraceae) have been investigated. The spectral reflectance and scent composition of flowers of four color cultivars was determined. We found that pigments and volatiles occur in specific combinations in flowers of P. nudicaule. The presence of indole in the bouquets is strongly associated with the occurrence of yellow pigments called nudicaulins, for which indole is one of the final biosynthetic precursors. Whereas yellow flowers emit an excess of indole, orange flowers consume it during nudicaulin production and lack the substance in their bouquet. By using the honeybee, Apis mellifera, evaluations were made on how color and scent affect the discrimination of these flowers by pollinators. Honeybees were able to discriminate artificial odor mixtures resembling those of the natural flower odors. Bees trained with stimuli combining colors and odors showed an improved discrimination performance. The results indicate that the indole moiety of nudicaulins and emitted indole might be products of the same biochemical pathway. We propose that conserved pathways account for the evolution of color-scent associations in P. nudicaule and that these associations positively affect flower constancy of pollinators. PMID- 29696754 TI - An Ultra-Robust and Crystalline Redeemable Hydrogen-Bonded Organic Framework for Synergistic Chemo-Photodynamic Therapy. AB - The low structural stability of hydrogen-bonded organic frameworks (HOFs) is a thorny issue retarding the development of HOFs. A rational design approach is now proposed for construction of a stable HOF. The resultant HOF (PFC-1) exhibits high surface area of 2122 m2 g-1 and excellent chemical stability (intact in concentrated HCl for at least 117 days). A new method of acid-assisted crystalline redemption is used to readily cure the thermal damage to PFC-1. With periodic integration of photoactive pyrene in the robust framework, PFC-1 can efficiently encapsulate Doxorubicin (Doxo) for synergistic chemo-photodynamic therapy, showing comparable therapeutic efficacy with the commercial Doxo yet considerably lower cytotoxicity. This work demonstrates the notorious stability issue of HOFs can be properly addressed through rational design, paving a way to develop robust HOFs and offering promising application perspectives. PMID- 29696755 TI - A Self-Reporting Photocatalyst for Online Fluorescence Monitoring of High Throughput RAFT Polymerization. AB - Translating controlled/living radical polymerization (CLRP) from batch to the high throughput production of polymer libraries presents several challenges in terms of both polymer synthesis and characterization. Although recently there have been significant advances in the field of low volume, high throughput CLRP, techniques able to simultaneously monitor multiple polymerizations in an "online" manner have not yet been developed. Here, we report our discovery that 5,10,15,20 tetraphenyl-21H,23H-porphine zinc (ZnTPP) is a self-reporting photocatalyst that can mediate PET-RAFT polymerization as well as report on monomer conversion via changes in its fluorescence properties. This enables the use of a microplate reader to conduct high throughput "online" monitoring of PET-RAFT polymerizations performed directly in 384-well, low volume microtiter plates. PMID- 29696756 TI - Female reproductive history and risk of type 2 diabetes: A prospective analysis of 126 721 women. AB - AIM: To examine the prospective associations between aspects of a woman's reproductive history and incident diabetes. METHODS: We pooled individual data from 126 721 middle-aged women from eight cohort studies contributing to the International Collaboration for a Life Course Approach to Reproductive Health and Chronic Disease Events (InterLACE). Associations between age at menarche, age at first birth, parity and menopausal status with incident diabetes were examined using generalized linear mixed models, with binomial distribution and robust variance. We stratified by body mass index (BMI) when there was evidence of a statistical interaction with BMI. RESULTS: Over a median follow-up of 9 years, 4073 cases of diabetes were reported. Non-linear associations with diabetes were observed for age at menarche, parity and age at first birth. Compared with menarche at age 13 years, menarche at <=10 years was associated with an 18% increased risk of diabetes (relative risk [RR] 1.18, 95% confidence interval [CI] 1.02-1.37) after adjusting for BMI. After stratifying by BMI, the increased risk was only observed in women with a BMI >=25 kg/m2 . A U-shaped relationship was observed between parity and risk of diabetes. Compared with pre-/peri-menopausal women, women with a hysterectomy/oophorectomy had an increased risk of diabetes (RR 1.17, 95% CI 1.07-1.29). CONCLUSIONS: Several markers of a woman's reproductive history appear to be modestly associated with future risk of diabetes. Maintaining a normal weight in adult life may ameliorate any increase in risk conferred by early onset of menarche. PMID- 29696757 TI - Intermolecular Arrangement of Fullerene Acceptors Proximal to Semiconducting Polymers in Mixed Bulk Heterojunctions. AB - Precise control of the molecular arrangements at the interface between the electron donor and acceptor in mixed bulk heterojunctions (BHJs) remains challenging, despite the correlation between structural characteristics and efficiency in organic photovoltaics (OPVs). This study reveals that the substitution patterns of linear and branched alkyl side chains on electron donating/-accepting alternating copolymers can control the positions of an acceptor molecule (C60 ) around the pi-conjugated main chains in mixed BHJs. Two dimensional solid-state NMR demonstrates a marked difference in the location of C60 in the blend films. A copolymer with an electron-accepting unit positioned in close proximity to C60 demonstrated higher OPV performance in combination with various fullerene derivatives. This molecular design offers precise control over the interfacial molecular structure, thereby paving the way for overcoming the current limitations of OPVs comprising mixed BHJs. PMID- 29696759 TI - Arno G. Motulsky, 1923-2018, Luck and Service. PMID- 29696760 TI - Oxygen isotope analysis of bacterial and fungal manganese oxidation. AB - The ability of micro-organisms to oxidize manganese (Mn) from Mn(II) to Mn(III/IV) oxides transcends boundaries of biological clade or domain. Many bacteria and fungi oxidize Mn(II) to Mn(III/IV) oxides directly through enzymatic activity or indirectly through the production of reactive oxygen species. Here, we determine the oxygen isotope fractionation factors associated with Mn(II) oxidation via various biotic (bacteria and fungi) and abiotic Mn(II) reaction pathways. As oxygen in Mn(III/IV) oxides may be derived from precursor water and molecular oxygen, we use a twofold approach to determine the isotope fractionation with respect to each oxygen source. Using both 18 O-labeled water and closed-system Rayleigh distillation approaches, we constrain the kinetic isotope fractionation factors associated with O atom incorporation during Mn(II) oxidation to -17.30/00 to -25.90/00 for O2 and -1.90/00 to +1.80/00 for water. Results demonstrate that stable oxygen isotopes of Mn(III/IV) oxides have potential to distinguish between two main classes of biotic Mn(II) oxidation: direct enzymatic oxidation in which O2 is the oxidant and indirect enzymatic oxidation in which superoxide is the oxidant. The fraction of Mn(III/IV) oxide associated oxygen derived from water varies significantly (38%-62%) among these bio-oxides with only weak relationship to Mn oxidation state, suggesting Mn(III) disproportionation may account for differences in the fraction of mineral-bound oxygen from water and O2 . Additionally, direct incorporation of molecular O2 suggests that Mn(III/IV) oxides contain a yet untapped proxy of delta18OO2 of environmental O2 , a parameter reflecting the integrated influence of global respiration, photorespiration, and several other biogeochemical reactions of global significance. PMID- 29696758 TI - MicroRNAs in hereditary and sporadic premature aging syndromes and other laminopathies. AB - Hereditary and sporadic laminopathies are caused by mutations in genes encoding lamins, their partners, or the metalloprotease ZMPSTE24/FACE1. Depending on the clinical phenotype, they are classified as tissue-specific or systemic diseases. The latter mostly manifest with several accelerated aging features, as in Hutchinson-Gilford progeria syndrome (HGPS) and other progeroid syndromes. MicroRNAs are small noncoding RNAs described as powerful regulators of gene expression, mainly by degrading target mRNAs or by inhibiting their translation. In recent years, the role of these small RNAs has become an object of study in laminopathies using in vitro or in vivo murine models as well as cells/tissues of patients. To date, few miRNAs have been reported to exert protective effects in laminopathies, including miR-9, which prevents progerin accumulation in HGPS neurons. The recent literature has described the potential implication of several other miRNAs in the pathophysiology of laminopathies, mostly by exerting deleterious effects. This review provides an overview of the current knowledge of the functional relevance and molecular insights of miRNAs in laminopathies. Furthermore, we discuss how these discoveries could help to better understand these diseases at the molecular level and could pave the way toward identifying new potential therapeutic targets and strategies based on miRNA modulation. PMID- 29696761 TI - Photochemistry of Artists' Dyes and Pigments: Towards Better Understanding and Prevention of Colour Change in Works of Art. AB - The absorption of light gives a pigment its colour and its reason for being, but it also creates excited states, that is, new molecules with an energy excess that can be dissipated through degradation pathways. Photodegradation processes provoke long-term, cumulative and irreversible colour changes (fading, darkening, blanching) of which the prediction and prevention are challenging tasks. Of all the environmental risks that affect heritage materials, light exposure is the only one that cannot be controlled without any impact on the optimal display of the exhibit. Light-induced alterations are not only associated with the pigment itself but also with its interactions with support/binder and, in turn, are further complicated by the nature of the environmental conditions. In this Minireview we investigate how chemistry, encompassing multi-scale analytical investigations of works of art, computational modelling and physical and chemical studies contributes to improve our prediction of artwork appearance before degradation and to establish effective preventive conservation strategies. PMID- 29696762 TI - Occupational Legionella pneumophila Exposure in a Street Sweeper with a Renal Transplant. PMID- 29696763 TI - Can nutcracker phenomenon cause glomerular hematuria? PMID- 29696764 TI - Using 'temporal parameters' to define the timing of renal replacement therapy in acute kidney injury? There are other better choices. PMID- 29696765 TI - Fanconi syndrome associated with SGLT2 inhibitor, canagliflozin. PMID- 29696766 TI - Anodic Hydrazine Oxidation Assists Energy-Efficient Hydrogen Evolution over a Bifunctional Cobalt Perselenide Nanosheet Electrode. AB - Water electrolysis is a promising source of hydrogen; however, technological challenges remain. Intensive efforts have focused on developing highly efficient and earth-abundant electrocatalysts for water splitting. An effective strategy is proposed, using a bifunctional tubular cobalt perselenide nanosheet electrode, in which the sluggish oxygen evolution reaction is substituted with anodic hydrazine oxidation so as to assist energy-efficient hydrogen production. Specifically, this electrode produces a current density of 10 mA cm-2 at -84 mV for hydrogen evolution and -17 mV for hydrazine oxidation in 1.0 m KOH and 0.5 m hydrazine electrolyte. An ultralow cell voltage of only 164 mV is required to generate a current density of 10 mA cm-2 for 14 hours of stable water electrolysis. PMID- 29696767 TI - Experimental Identification of the Active Site in the Heteronuclear Redox Couples [AlVOx ]+. /CO/N2 O (x=3, 4) by Gas-Phase IR Spectroscopy. AB - Cryogenic ion vibrational spectroscopy was used in combination with electronic structure calculations to identify the active site in the oxygen atom transfer reaction [AlVO4 ]+. +CO->[AlVO3 ]+. +CO2 . Infrared photodissociation spectra of messenger-tagged heteronuclear clusters demonstrate that in contrast to [AlVO4 ]+. , [AlVO3 ]+. is devoid of a terminal Al-Ot unit while the terminal V=Ot group remains intact. Thus it is the Al-Ot moiety that forms the active site in the [AlVOx ]+. /CO/N2 O (x=3, 4) redox couples, which is in line with theoretical predictions. PMID- 29696768 TI - The Discovery of a Palladium(II)-Initiated Borono-Catellani Reaction. AB - Reported is a novel palladium(II)-initiated Catellani-type reaction that utilizes widely accessible aryl boronic acids as the substrates instead of aryl halides, thereby greatly expanding the existing scope of this powerful transformation. This borono-Catellani reaction was promoted by cooperative catalysis between Pd(OAc)2 and the inexpensive 5-norbornene-2-carbonitrile. Practicality is the striking feature of the reaction: it is run open to air at ambient temperature and no phosphine ligand is needed. This mild, chemoselective, and scalable protocol is compatible with a large range of readily available functionalized aryl boronic acids and bromides, as well as terminating olefins (50 examples, 39 97 % yields). Moreover, the orthogonal reactivity between the borono-Catellani and classical Catellani reaction was demonstrated. This work is expected to open new avenues for developing novel Catellani-type reactions. PMID- 29696769 TI - CAMPEP graduate program standards should require a dedicated course in Magnetic Resonance Imaging physics. PMID- 29696770 TI - Likelihood Ratios for the Emergency Physician. AB - The concept of likelihood ratios was introduced more than 40 years ago, yet this powerful metric has still not seen wider application or discussion in the medical decision-making process. There is concern that clinicians-in-training are still being taught an oversimplified approach to diagnostic test performance and have limited exposure to likelihood ratios. Even for those familiar with likelihood ratios, they might perceive them as mathematically cumbersome in application, if not difficult to determine for a particular disease process. This article takes a conceptual approach to likelihood ratios and applies them to two clinical settings: 1) severe intracranial injury after minor head trauma and 2) suspected pulmonary embolism with shortness of breath. Likelihood ratios are the most appropriate metric for efficient rational clinical examination and can prevent unnecessary and wasteful treatments and procedures. PMID- 29696771 TI - Risk factors for the development of paclitaxel-induced neuropathy in breast cancer patients. AB - Peripheral neuropathy is a common side effect of many chemotherapeutic agents including paclitaxel. We prospectively evaluated demographic and laboratory data in a cohort of 61 woman with breast cancer prior to paclitaxel exposure to explore factors that predispose to neuropathy development. Neuropathy was graded based on the total neuropathy score reduced version (rTNS) at baseline and at 4 months after initiation of chemotherapy. A multivariate analysis identified predictors with the strongest association with a change in rTNS. Serum albumin (P = .002), paclitaxel dose (P = .001), and body surface area (P = .006) were statistically significantly associated with a positive rTNS change (worsening neuropathy). These results suggest that poor nutritional status and obesity increase the risk of paclitaxel induced neuropathy, and that screening for these factors prior to chemotherapy exposure may improve early neuropathy detection or decrease risk with dietary modifications. PMID- 29696772 TI - Water-Binding-Mediated Gelation/Crystallization and Thermosensitive Superchirality. AB - Determination of molecular structural parameters of hydrophobic cholesterol naphthalimide conjugates for water binding capabilities as well as their moisture sensitive supramolecular self-assembly were revealed. Water binding was a key factor in leading trace water-induced crystallization against gelation in apolar solvent. Ordered water molecules entrapped in self-assembly arrays revealed by crystal structures behave as hydrogen-bonding linkers to facilitate three dimensional growth into crystals rather than one-dimensional gel nanofibers. Water binding was also reflected on the supramolecular chirality inversion of vesicle self-assembly in aqueous media via heating-induced dehydration. Structural parameters that favor water binding were evaluated in detail, which could help rationally design organic building units for advancing soft materials, crystal engineering, and chiral recognition. PMID- 29696773 TI - Complex phenotype of dyskeratosis congenita and mood dysregulation with novel homozygous RTEL1 and TPH1 variants. AB - Dyskeratosis congenita (DC) is an inherited bone marrow failure syndrome caused by germline mutations in telomere biology genes. Patients have extremely short telomeres for their age and a complex phenotype including oral leukoplakia, abnormal skin pigmentation, and dysplastic nails in addition to bone marrow failure, pulmonary fibrosis, stenosis of the esophagus, lacrimal ducts and urethra, developmental anomalies, and high risk of cancer. We evaluated a patient with features of DC, mood dysregulation, diabetes, and lack of pubertal development. Family history was not available but genome-wide genotyping was consistent with consanguinity. Whole exome sequencing identified 82 variants of interest in 80 genes based on the following criteria: homozygous, <0.1% minor allele frequency in public and in-house databases, nonsynonymous, and predicted deleterious by multiple in silico prediction programs. Six genes were identified likely contributory to the clinical presentation. The cause of DC is likely due to homozygous splice site variants in regulator of telomere elongation helicase 1, a known DC and telomere biology gene. A homozygous, missense variant in tryptophan hydroxylase 1 may be clinically important as this gene encodes the rate limiting step in serotonin biosynthesis, a biologic pathway connected with mood disorders. Four additional genes (SCN4A, LRP4, GDAP1L1, and SPTBN5) had rare, missense homozygous variants that we speculate may contribute to portions of the clinical phenotype. This case illustrates the value of conducting detailed clinical and genomic evaluations on rare patients in order to identify new areas of research into the functional consequences of rare variants and their contribution to human disease. PMID- 29696774 TI - Functional independence of Taiwanese children with Prader-Willi syndrome. AB - Prader-Willi syndrome (PWS) is a genetic disorder with obesity, developmental delay, short stature, and behavioral abnormalities. The study aimed to assess the functional independence in children with PWS. The Functional Independence Measure for Children (WeeFIM) was used to evaluate 81 children with PWS (44 boys and 37 girls) with a median age of 11 years 1 month (range 2 years 8 months to 20 years 2 months) were recruited between January 2013 and December 2016. The mean total WeeFIM score was 103.8 (maximum 126). Sixty-five patients (80%) had deletion type PWS, 16 (20.0%) had nondeletion type. The scores were 103.6 +/- 18.5 for deletion and 104.8 +/- 18.3 for nondeletion type (p = .405), 104.8 +/- 19.3 in boys and 102.6 +/- 17.3 in girls (p = .293). The mean self-care, mobility, and cognition scores were 47 (maximum 56), 33 (maximum 35), and 24 (maximum 35), respectively. All total scores and 18 subscores in the three functional domains were positively correlated with age (p < .05). Most children required assistance in problem solving, comprehension, and expression. The WeeFIM identified the strengths and limitations of children with PWS and confirmed that support and supervision were needed in cognitive and self-care tasks. PMID- 29696775 TI - 38th Annual David W. Smith Workshop on Malformations and Morphogenesis: Abstracts of the 2017 Annual Meeting. AB - The 38th Annual David W. Smith Workshop on Malformations and Morphogenesis occurred on August 26th - 29th, 2017 at the Stoweflake Resort and Conference Center in Stowe, VT. The Workshop, which honors the legacy of David W Smith, brought together clinicians and researchers interested in congenital malformations and their underlying mechanisms of morphogenesis. The Workshop highlighted four themes besides mechanisms of morphogenesis and new syndromes: Disorders of Transcriptional Regulation, Dysmorphology (Syndromes and Malformations) in Minority and Unique Populations, Syndromes and Isolated Birth Defects Involving Malformations of the Developing Foregut, and the Natural History of Syndromes. This Conference Report includes the abstracts presented at the 2017 Workshop. PMID- 29696776 TI - The phenotypic spectrum of Xia-Gibbs syndrome. AB - Xia-Gibbs syndrome (XGS: OMIM # 615829) results from de novo truncating mutations within the AT-Hook DNA Binding Motif Containing 1 gene (AHDC1). To further define the phenotypic and molecular spectrum of this disorder, we established an XGS Registry and recruited patients from a worldwide pool of approximately 60 probands. Additional de novo truncating mutations were observed among 25 individuals, extending both the known number of mutation sites and the range of positions within the coding region that were sensitive to alteration. Detailed phenotypic examination of 20 of these patients via clinical records review and data collection from additional surveys showed a wider age range than previously described. Data from developmental milestones showed evidence for delayed speech and that males were more severely affected. Neuroimaging from six available patients showed an associated thinning of the corpus callosum and posterior fossa cysts. An increased risk of both scoliosis and seizures relative to the population burden was also observed. Data from a modified autism screening tool revealed that XGS shares significant overlap with autism spectrum disorders. These details of the phenotypic heterogeneity of XGS implicate specific genotype/phenotype correlations and suggest potential clinical management guidelines. PMID- 29696777 TI - A quality control method for intensity-modulated radiation therapy planning based on generalized equivalent uniform dose. AB - To ensure good quality intensity-modulated radiation therapy (IMRT) planning, we proposed the use of a quality control method based on generalized equivalent uniform dose (gEUD) that predicts absorbed radiation doses in organs at risk (OAR). We conducted a retrospective analysis of patients who underwent IMRT for the treatment of cervical carcinoma, nasopharyngeal carcinoma (NPC), or non-small cell lung cancer (NSCLC). IMRT plans were randomly divided into data acquisition and data verification groups. OAR in the data acquisition group for cervical carcinoma and NPC were further classified as sub-organs at risk (sOAR). The normalized volume of sOAR and normalized gEUD (a = 1) were analyzed using multiple linear regression to establish a fitting formula. For NSCLC, the normalized intersection volume of the planning target volume (PTV) and lung, the maximum diameter of the PTV (left-right, anterior-posterior, and superior inferior), and the normalized gEUD (a = 1) were analyzed using multiple linear regression to establish a fitting formula for the lung gEUD (a = 1). The r squared and P values indicated that the fitting formula was a good fit. In the data verification group, IMRT plans verified the accuracy of the fitting formula, and compared the gEUD (a = 1) for each OAR between the subjective method and the gEUD-based method. In conclusion, the gEUD-based method can be used effectively for quality control and can reduce the influence of subjective factors on IMRT planning optimization. PMID- 29696778 TI - Evolution of renal function and urinary biomarker indicators of inflammation on serial kidney biopsies in pediatric kidney transplant recipients with and without rejection. AB - Urinary CXCL10 and metabolites are biomarkers independently associated with TCMR. We sought to test whether these biomarkers fluctuate in association with histological severity of TCMR over short time frames. Forty-nine pairs of renal biopsies obtained 1-3 months apart from 40 pediatric renal transplant recipients were each scored for TCMR acuity score (i + t; Banff criteria). Urinary CXCL10:Cr and TCMR MDS were obtained at each biopsy and were tested for association with changes between biopsies in acuity, estimated GFR (DeltaeGFR), and 12-month DeltaeGFR. Sequential biopsies were obtained 1.8 +/- 0.8 months apart. Biopsy 1 was usually obtained under protocol (75%), and 62% percent had evidence of TCMR. Using each biopsy pair for comparison, DeltaeGFR did not predict change in acuity. By contrast, change in acuity was significantly correlated with change in urinary CXCL10:Cr (rho 0.45, P = .003) and MDS (rho 0.29, P = .04) between biopsies. The 12-month DeltaeGFR was not predicted by TCMR acuity or CXCL10:Cr at Biopsy 2; however, an inverse correlation was seen with urinary MDS (rho -0.35; P = .02). Changes in eGFR correlate poorly with evolving TCMR acuity on histology. Urinary biomarkers may be superior for non-invasive monitoring of rejection, including histological response to therapy, and may be prognostic for medium-term function. PMID- 29696779 TI - Necroptosis increases with age and is reduced by dietary restriction. AB - Necroptosis is a newly identified programmed cell death pathway that is highly proinflammatory due to the release of cellular components that promote inflammation. To determine whether necroptosis might play a role in inflammaging, we studied the effect of age and dietary restriction (DR) on necroptosis in the epididymal white adipose tissue (eWAT), a major source of proinflammatory cytokines. Phosphorylated MLKL and RIPK3, markers of necroptosis, were increased 2.7- and 1.9-fold, respectively, in eWAT of old mice compared to adult mice, and DR reduced P-MLKL and P-RIPK3 to levels similar to adult mice. An increase in the expression of RIPK1 (1.6-fold) and MLKL (2.7-fold), not RIPK3, was also observed in eWAT of old mice, which was reduced by DR in old mice. The increase in necroptosis was paralleled by an increase in 14 inflammatory cytokines, including the pro-inflammatory cytokines IL-6 (3.9-fold), TNF-alpha (4.7-fold), and IL 1beta (5.1-fold)], and 11 chemokines in old mice. DR attenuated the expression of IL-6, TNF-alpha, and IL-1beta as well as 85% of the other cytokines/chemokines induced with age. In contrast, inguinal WAT (iWAT), which is less inflammatory, did not show any significant increase with age in the levels of P-MLKL and MLKL or inflammatory cytokines/chemokines. Because the changes in biomarkers of necroptosis in eWAT with age and DR paralleled the changes in the expression of pro-inflammatory cytokines, our data support the possibility that necroptosis might play a role in increased chronic inflammation observed with age. PMID- 29696780 TI - Neurodevelopmental outcome in 22q11.2 deletion syndrome and management. AB - The 22q11.2 deletion syndrome (22q11.2 DS) places affected individuals at an increased risk for neurodevelopmental/cognitive, behavioral and social-emotional difficulties. Poor cognitive functioning and intellectual disabilities, attention and executive functioning deficits, learning disorders, emotional dysregulation and impairments in social processing are common among individuals with 22q11.2 DS. Identifying risk and protective/resilience factors that can be detected in early life and can predict neurodevelopmental outcomes for people with 22q11.2 DS is of significant clinical relevance and might allow for early detection and intervention. Given the focus of this review, we will discuss the possible contributing factors that influence the neurodevelopmental outcome in 22q1.2 DS, the cognitive phenotype in 22q11.2 DS, the different developmental trajectories across life span, and the implications for clinical practice and management. PMID- 29696781 TI - Duration of untreated psychosis and clinical outcomes of first episode psychosis: An observational and an instrumental variables analysis. AB - AIM: Duration of untreated psychosis (DUP) is considered as a key prognostic variable in psychosis. Yet, it is unclear whether a longer DUP causes worse outcomes or whether reported associations have alternative explanations. METHODS: Data from 2 cohorts of patients with first episode psychosis were used (n = 2134). Measures of DUP were assessed at baseline and outcomes at 12 months. Regression models were used to investigate the associations between DUP and outcomes. We also investigated whether any associations were replicated using instrumental variables (IV) analysis to reduce the effect of residual confounding and measurement bias. RESULTS: There were associations between DUP per 1-year increase and positive psychotic symptoms (7.0% in symptom score increase 95% confidence interval (CI) 4.0%, 10.0%, P < .001), worse recovery (risk difference [RD] 0.78, 95%, CI 0.68, 0.83, P < .001) and worse global functioning (0.62 decrease in functioning score 95% CI -1.19, -0.04, P = .035). There was no evidence of an association with negative psychotic symptoms (1.0%, 95%, CI -2.0%, 5.0%, P = .455). The IV analysis showed weaker evidence of associations in the same direction between DUP per 1-year increase and positive psychotic symptoms, recovery and global functioning. However, there was evidence of an inverse association with negative psychotic symptoms (decrease of 15.0% in symptom score 95% CI -26.0%, -3.0%, P = .016). CONCLUSIONS: We have confirmed previous findings of a positive association between positive psychotic symptoms, global functioning and recovery and DUP using regression analysis. IV analysis shows some support for these findings. Future investigation using IV analysis should be repeated in large data sets. PMID- 29696782 TI - Mutations in SZT2 result in early-onset epileptic encephalopathy and leukoencephalopathy. AB - Early-onset epileptic encephalopathies (EOEEs) are a genetically heterogeneous collection of severe epilepsies often associated with psychomotor regression. Mutations in SZT2, a known seizure threshold regulator gene, are a newly identified cause of EOEE. We present an individual with EOEE, macrocephaly, and developmental regression with compound heterozygous mutations in SZT2 as identified by whole exome sequencing. Serial imaging characterized the novel finding of progressive loss of central myelination. This case expands our clinical understanding of the SZT2-phenotype and emphasizes the role of this gene in the diagnostic investigation for EOEE and leukoencephalopathies. PMID- 29696783 TI - Pancreatic Burkitt's lymphoma presenting as an unusual cause of obstructive jaundice. PMID- 29696784 TI - Unveiling Human Cardiac Fibroblast Membrane Proteome. AB - Cardiac fibroblasts (CFs) are one of the main cell populations in the heart and play important roles in tissue homeostasis and myocardial fibrosis. The study of these cells has been hampered by the lack of reliable membrane markers: none of the antigens currently used for characterization and isolation of CFs is unique for this cell type. This issue has also raised doubts regarding a distinct identity of cardiac fibroblasts when compared to other myocardium cell populations with similar morphologies. In this work, we report a comprehensive description and functional analysis of human CFs (hCFs) membraneenriched fraction proteome by advanced mass spectrometry-based proteomic tools. A total number of 1478 proteins were identified, including 774 membrane proteins (52%). We also report the identification of a subset of 30 membrane proteins that in this workflow were only identified in hCFs by comparison with the membrane-enriched proteome lists of human cardiac stem cells, human mesenchymal stem cells, and human dermal fibroblasts. The data reported in this work are a valuable source of information for further studies aiming at defining a membrane molecular signature of human cardiac fibroblasts (hCFs), and a step forward in research regarding membrane proteins with key roles in hCF function in homeostasis and disease. PMID- 29696785 TI - Bromelain-based enzymatic debridement of chronic wounds: A preliminary report. AB - Sharp debridement is currently considered most effective for debridement of chronic wounds; however, some patients do not have access to or cannot be treated by surgical methods. This study was designed to provide a first impression of the safety and efficacy of bromelain-based enzymatic debridement of chronic wounds. Two consecutive single-arm studies assessing the enzymatic debridement efficacy of a concentrate of proteolytic enzymes enriched in bromelain in chronic wounds was conducted in 2 medical centres. Patients were treated with up to 11 consecutive 4-hour enzymatic debridement sessions and then treated until wound closure. Twenty-four patients with chronic wounds of different aetiologies were enrolled. All wounds achieved an average of 68% +/- 30% debridement in an average of 3.5 +/- 2.8 enzymatic debridement 4-hour sessions. Seventeen responding wounds (venous, diabetic, pressure, and post-traumatic aetiologies) achieved an average 85% +/- 12% debridement in 3.2 +/- 2.5 applications. Seven non-responding wounds (arterial and post-surgical aetiologies) achieved an average 26% +/- 13% debridement in 4.3 +/- 3.5 applications. No treatment-related serious adverse events were observed, and the only adverse event attributed to the enzymatic debridement was pain. These preliminary results indicate the potential safety and efficacy of bromelain-based enzymatic debridement in chronic wounds. Larger controlled studies are needed to further investigate this indication. PMID- 29696786 TI - An assessment of health, social, communication, and daily living skills of adults with Down syndrome. AB - Adults with Down syndrome (DS) are surviving longer, yet data delineating life skills are lacking. As providers are encouraged to provide a "balanced" description of DS to family members/caregivers, more quantitative data are required to accurately describe the abilities and potential of adults with DS. This study assessed health, social, communication, and daily living skills of adults with DS to describe the range of abilities and to show how increasing age contributes to functional abilities. Caregivers of an adult with DS 20 years of age or older participated in an online questionnaire. Descriptive statistics and scores from scales assessed relationships between the number of health issues reported and functional abilities, and how the abilities changed as age increased. Of 188 participants, 157 completed the survey with partial results included. Communication, independence, and social activity scores were compared to the number of congenital and non-congenital health issues reported. Linear regression results showed those with more health issues were significantly less likely to be independent and social. However, only current health issues affected communication skills. No significant correlation occurred between the number of congenital abnormalities and scores for independence/life skills as an adult. T test by age group found decreasing abilities after 40 years of age. In conclusion, quantitative data and information from this study is beneficial for providers in order to describe the potential for an individual with DS and to assist caregivers to plan accordingly for the future of their adult with DS. PMID- 29696787 TI - The ontogeny of Robin sequence. AB - The triad of micrognathia, glossoptosis, and concomitant airway obstruction defined as "Robin sequence" (RS) is caused by oropharyngeal developmental events constrained by a reduced stomadeal space. This sequence of abnormal embryonic development also results in an anatomical configuration that might predispose the fetus to a cleft palate. RS is heterogeneous and many different etiologies have been described including syndromic, RS-plus, and isolated forms. For an optimal diagnosis, subsequent treatment and prognosis, a thorough understanding of the embryology and pathogenesis is necessary. This manuscript provides an update about our current understanding of the development of the mandible, tongue, and palate and possible mechanisms involved in the development of RS. Additionally, we provide the reader with an up-to-date summary of the different etiologies of this phenotype and link this to the embryologic, developmental, and genetic mechanisms. PMID- 29696788 TI - Delayed peak response of cortisol to insulin tolerance test in patients with Prader-Willi syndrome. AB - Deaths among children with Prader-Willi syndrome (PWS) are often related to only mild or moderate upper respiratory tract infections, and many causes of death remain unexplained. Several reports have hypothesized that patients with PWS may experience latent central adrenal insufficiency. However, whether PWS subjects suffer from alteration of the hypothalamus-pituitary-adrenal (HPA) axis remains unclear. This study aimed to explore the HPA axis on PWS. We evaluated the HPA axis in 36 PWS patients (24 males, 12 females; age range, 7 months to 12 years; median age 2.0 years; interquartile range [IQR], 1.5-3.4 years) using an insulin tolerance test (ITT) in the morning between 08:00 and 11:00. For comparison, ITT results in 37 age-matched healthy children evaluated for short stature were used as controls. In PWS patients, basal levels of adrenocorticotropic hormone (ACTH) were 13.5 pg/ml (IQR, 8.3-27.5 pg/ml) and basal levels of cortisol were 18.0 MUg/dl (IQR, 14.2-23.7 MUg/dl). For all patients, cortisol levels at 60 min after stimulation were within the reference range (>18.1 MUg/dl), with a median peak of 41.5 MUg/dl (IQR, 32.3-48.6 MUg/dl). Among control children, basal level of ACTH and basal and peak levels of cortisol were 10.9 (IQR, 8.5-22.0 pg/ml), 15.6 (IQR, 11.9-21.6 MUg/dl), and 27.8 MUg/dl (IQR, 23.7-30.5 MUg/dl), respectively. Basal and peak levels of cortisol were all within normal ranges, but peak response of cortisol to ITT was delayed in the majority of PWS patients (64%). Although the mechanism remains unclear, this delay may signify the existence of central obstacle in adjustment of the HPA axis. PMID- 29696789 TI - Blended learning to teach gender in medical school. AB - BACKGROUND: Teaching gender and sexuality in medical school is critical to prepare students for future clinical practice. Yet curriculum gaps exist in teaching these topics in medical schools. To address this, medical schools are integrating gendered perspectives into their curricula. CONTEXT: Acknowledging the need to teach gender and sexuality, Western Sydney University School of Medicine introduced a lecture on 'Gendered Perspectives on Health' in 2015. However, the delivery of the content took more time than anticipated, as some students lacked a basic understanding of gender and sexuality. Engagement with the didactic teaching method was low. INNOVATION: Using blended learning techniques, a flipped classroom workshop on gender and sexuality was developed in 2016. The workshop had online components that gave basic information on gender and sexuality, which students viewed prior to the face-to-face session. Students then discussed specific gender-related topics with expert facilitators using a timed multi-station approach during the face-to-face session. A plenary session provided students with the opportunity to address any remaining questions. Evaluation suggests that the workshop increased the students' self-reported knowledge on gender and sexual health topics and services. Students also found the workshop useful and engaging. Teaching gender and sexuality in medical school is critical to prepare students for future clinical practice IMPLICATIONS: The workshop provided an engaging and informative way for students to discuss gender and sexuality. The workshop also created a safe learning environment for students to clarify their perceptions of gender and sexuality. Increasing students' knowledge and understanding of gender and sexuality promoted a gender-sensitive approach to patient care, which can help students to avoid stereotyping and to provide comprehensive care to gender-diverse groups. PMID- 29696790 TI - Efficacy of single-incision laparoscopic totally extraperitoneal repair for irreducible or incarcerated inguinal hernia. AB - INTRODUCTION: The aim of this study was to evaluate the efficacy of single incision laparoscopic surgery for totally extraperitoneal repair (SILS-TEP) of irreducible inguinal hernias and incarcerated inguinal hernias. METHODS: We performed a retrospective analysis of 194 patients, including 16 with irreducible or incarcerated hernia, who had undergone SILS-TEP from May 2016 to December 2017 at Kinki Central Hospital. The outcomes of patients with irreducible or incarcerated hernia and those with reducible hernia were compared. For irreducible or incarcerated hernia, laparoscopic exploration with hernia reduction through an intraumbilical incision was performed. If no bowel resection was needed, one-stage SILS-TEP was performed. If bowel resection was required, two-stage SILS-TEP was performed 2-3 months after the bowel resection. RESULTS: Of the 16 patients, 8 had an irreducible hernia, and 8 had an incarcerated hernia. The eight patients with an incarcerated hernia underwent emergency surgery, and among these patients, two needed single-incision laparoscopic partial resection of the ileum followed by two-stage SILS-TEP. Fourteen patients, excluding the two patients who required single-incision laparoscopic partial resection of the ileum, underwent laparoscopic exploration with hernia reduction followed by one-stage SILS-TEP. Among these 14 patients, one with an irreducible hernia required conversion to Kugel patch repair. The operative outcomes were generally comparable between the two groups. However, the operative time was longer for unilateral hernia, and more seromas were seen in the irreducible or incarcerated group. No other major complications or cases of hernia recurrence were noted in this study. CONCLUSIONS: SILS-TEP, which offers good cosmetic results, can be safely performed for irreducible or incarcerated inguinal hernia. PMID- 29696792 TI - Agkihpin, a Distinct SVTLE from the Venom of Gloydius halys Pallas: Purification, Characterization and Structure-Activity Determination. AB - Blood clots produced by snake-venom thrombin-like enzymes (SVTLEs) are cleared rapidly, which makes SVTLEs attractive as potential candidates for antithrombotic therapy. We isolated a SVTLE, agkihpin, from the venom of Gloydius halys Pallas. Agkihpin was confirmed to a single-chain TLE with molecular mass of 25.5 kD, pI of 7.43, optimal pH of 8.0 (hydrolyzing TAME), linked carbohydrate absent, and weak fibrinogen clotting activity. It was also found that (i) G. halys might be the latest species in SVTLEs phylogenetic tree; (ii) different level of conservation was shown among the SVTLEs from the Viperidae snakes. Some of those site may account for different activities exhibited by those SVTLEs, especially position 181, at which a fibrinogenolytic activity increase was found when a basic and larger amino acid substituted by a neutral and smaller one; (iii) an extra alpha-helix constructed with a 'Pro + acidic amino acid + aromatic amino acid' pattern was found in the SVTLEs from Gloydius and Agkistrodon snakes, although it does not necessarily imply an effect on the fibrinogenolytic activity of the SVTLEs. This study provided some new insight into the activity of SVTLE. PMID- 29696791 TI - Lifelong reduction in complex IV induces tissue-specific metabolic effects but does not reduce lifespan or healthspan in mice. AB - Loss of SURF1, a Complex IV assembly protein, was reported to increase lifespan in mice despite dramatically lower cytochrome oxidase (COX) activity. Consistent with this, our previous studies found advantageous changes in metabolism (reduced adiposity, increased insulin sensitivity, and mitochondrial biogenesis) in Surf1 /- mice. The lack of deleterious phenotypes in Surf1-/- mice is contrary to the hypothesis that mitochondrial dysfunction contributes to aging. We found only a modest (nonsignificant) extension of lifespan (7% median, 16% maximum) and no change in healthspan indices in Surf1-/- vs. Surf1+/+ mice despite substantial decreases in COX activity (22%-87% across tissues). Dietary restriction (DR) increased median lifespan in both Surf1+/+ and Surf1-/- mice (36% and 19%, respectively). We measured gene expression, metabolites, and targeted expression of key metabolic proteins in adipose tissue, liver, and brain in Surf1+/+ and Surf1-/- mice. Gene expression was differentially regulated in a tissue-specific manner. Many proteins and metabolites are downregulated in Surf1-/- adipose tissue and reversed by DR, while in brain, most metabolites that changed were elevated in Surf1-/- mice. Finally, mitochondrial unfolded protein response (UPRmt )-associated proteins were not uniformly altered by age or genotype, suggesting the UPRmt is not a key player in aging or in response to reduced COX activity. While the changes in gene expression and metabolism may represent compensatory responses to mitochondrial stress, the important outcome of this study is that lifespan and healthspan are not compromised in Surf1-/- mice, suggesting that not all mitochondrial deficiencies are a critical determinant of lifespan. PMID- 29696793 TI - KBG syndrome patient due to 16q24.3 microdeletion presenting with a paratesticular rhabdoid tumor: Coincidence or cancer predisposition? AB - KBG syndrome is a rare autosomal dominant disorder caused by constitutive haploinsufficiency of the ankyrin repeat domain-containing protein 11 (ANKRD11) being the result of either loss-of-function gene variants or 16q24.3 microdeletions. The syndrome is characterized by a variable clinical phenotype comprising a distinct facial gestalt and variable neurological involvement. ANKRD11 is frequently affected by loss of heterozygosity in cancer. It influences the ligand-dependent transcriptional activation of nuclear receptors and tumor suppressive function of tumor protein TP53. ANKRD11 thus serves as a candidate tumor suppressor gene and it has been speculated that its haploinsufficiency may lead to an increased cancer risk in KBG syndrome patients. While no systematic data are available, we report here on the second KBG syndrome patient who developed a malignancy. At 17 years of age, the patient was diagnosed with a left sided paratesticular extrarenal malignant rhabdoid tumor. Genetic investigations identified a somatic truncating gene variant in SMARCB1, which was not present in the germline, and a constitutional de novo 16q24.3 microdeletion leading to a loss of the entire ANKRD11 locus. Thus, KBG syndrome was diagnosed, which was in line with the clinical phenotype of the patient. At present, no specific measures for cancer surveillance can be recommended for KBG syndrome patients. However, a systematic follow-up and inclusion of KBG syndrome patients in registries (e.g., those currently established for cancer prone syndromes) will provide empiric data to support or deny an increased cancer risk in KBG syndrome in the future. PMID- 29696794 TI - Impact of non-ideal analyte behavior on the separation of protein aggregates by asymmetric flow field-flow fractionation. AB - Asymmetric flow field-flow fractionation is a valuable tool for the characterization of protein aggregates in biotechnology owing to its broad size range and unique separation principle. However, in practice asymmetric flow field flow fractionation is non-trivial to use due to the major deviations from theory and the influence on separation by various factors that are not fully understood. Here, we report methods to assess the non-ideal effects that influence asymmetric flow field-flow fractionation separation and for the first time identify experimentally the main factors that impact it. Furthermore, we propose new approaches to minimize such non-ideal behavior, showing that by adjusting the mobile phase composition (pH and ionic strength) the resolution of asymmetric flow field-flow fractionation separation can be drastically improved. Additionally, we propose a best practice method for new proteins. PMID- 29696795 TI - The approved Italian version of the comprehensive assessment of at-risk mental states (CAARMS-ITA): Field test and psychometric features. AB - AIM: The Comprehensive Assessment of At-Risk Mental States (CAARMS) was specifically developed to assess and detect young people at ultra-high risk (UHR) of developing psychosis. The current study was undertaken to test the reliability and validity of the authorized Italian version of the CAARMS (CAARMS-ITA) in a help-seeking population. METHODS: Psychometric properties of the CAARMS-ITA were established using a sample of 223 Italian adolescents and young adults aged between 13 and 35 years, who were divided into 3 groups according to the CAARMS criteria: UHR-negative individuals (UHR [-]; n = 64), UHR-positive (UHR [+]; n = 55) and individuals with a first-episode psychosis (FEP; n = 104). The CAARMS ITA's reliability was tested measuring interrater reliability and internal consistency. Construct validity was tested comparing the Positive and Negative Syndrome Scale (PANSS) and CAARMS-ITA subscale scores across groups (ie, UHR [-], UHR [+] and FEP). For concurrent validity, we studied correlations between symptoms of the CAARMS-ITA and their equivalents in the PANSS. Finally, the predictive validity was examined by following up with UHR [+] individuals. The 12 month transition rate to psychosis was calculated. RESULTS: The CAARMS-ITA showed good interrater reliability. The PANSS "Positive Symptoms" subscale scores in UHR [+] individuals were intermediate between FEP and UHR [-] groups. The positive and negative symptoms scores of the CAARMS-ITA significantly correlated with the corresponding scores of the PANSS. After 12 months, 4 of 41 (9.8%) UHR [+] individuals had transitioned to psychosis. CONCLUSIONS: The CAARMS-ITA is a reliable and valid instrument for assessing and detecting at-risk mental states in Italian clinical settings. It also appears to be helpful in the prediction of psychosis transition. PMID- 29696796 TI - Four Natural Compounds Separated from Folium Isatidis: Crystal Structures and Antibacterial Activity. AB - Four natural compounds were obtained by concentrating, separating and purifying from the Folium isatidis. These natural compounds have been characterized by elemental analysis, IR spectrum, NMR and single-crystal X-ray diffraction analysis. The results show that these natural compounds are 4(3H)-quinazolinone (I), 2,4(1H,3H)-quinazolinedione (II), methyl 3,4-dihydro-4-oxoquinazoline-2 carboxylate (III) and ethyl 3,4-dihydro-4-oxoquinazoline-2-carboxylate (IV). The antibacterial activity experiment showed that I and II had better activity against Staphylococcus aureus, Escherichia coli, Bacillus subtilis and Salmonella than III, IV and other multiple components, because III and IV have long branches and steric hindrance effect. Compounds I and II have planar structure, which can more easily combine with these bacteria and kill them. The above results have good guiding significance for studying the antibacterial activity for single components or mixtures from natural origin. PMID- 29696797 TI - Directional Shuttling of a Stimuli-Responsive Cone-Like Macrocycle on a Single State Symmetric Dumbbell Axle. AB - Rotaxane-based molecular shuttles are often operated using low-symmetry axles and changing the states of the binding stations. A molecular shuttle capable of directional shuttling of an acid-responsive cone-like macrocycle on a single state symmetric dumbbell axle is now presented. The axle contains three binding stations: one symmetric di(quaternary ammonium) station and two nonsymmetric phenyl triazole stations arranged in opposite orientations. Upon addition of an acid, the protonated macrocycle shuttles from the di(quaternary ammonium) station to the phenyl triazole binding station closer to its butyl groups. This directional shuttling presumably originates from charge repulsion and an orientational binding preference between the cone-like cavity and the nonsymmetric phenyl triazole station. This mechanism for achieving directional shuttling by manipulating only the wheels instead of the tracks is new for artificial molecular machines. PMID- 29696798 TI - Surface Engineering of Carbon Nitride Electrode by Molecular Cobalt Species and Their Photoelectrochemical Application. AB - Graphitic carbon nitride (CN) has been widely regarded as a promising photocatalyst since the discovery of its capability for photocatalytic hydrogen evolution. Herein, we developed a functional CN film on a conductive fluorine doped tin oxide (FTO) electrode by using a microprinting-based direct growth method. Furthermore, the photoelectrochemical performance of the derived CN@FTO film was demonstrated to be enhanced by incorporating molecular cobalt species. The reduced charge transport resistance in the cobalt-modified CN@FTO films is suggested to accelerate the charge-carrier transfer rate and thus to improve the performance in photoelectrochemical application. The approach is versatile and can be further optimized by selecting a proper "ink" solution and modifier on various conductive substrates. PMID- 29696799 TI - Expanding the phenotype of congenital central hypoventilation syndrome impacts management decisions. AB - Congenital central hypoventilation syndrome (CCHS) is a neurocristopathy caused by pathogenic heterozygous variants in the gene paired-like homeobox 2b (PHOX2B). It is characterized by severe infantile alveolar hypoventilation. Individuals may also have diffuse autonomic nervous system dysfunction, Hirschsprung disease and neural crest tumors. We report three individuals with CCHS due to an 8-base pair duplication in PHOX2B; c.691_698dupGGCCCGGG (p.Gly234Alafs*78) with a predominant enteral and neural crest phenotype and a relatively mild respiratory phenotype. The attenuated respiratory phenotype reported here and elsewhere suggests an emergent genotype:phenotype correlation which challenges the current paradigm of invoking mechanical ventilation for all infants diagnosed with CCHS. Best treatment requires careful clinical judgment and ideally the assistance of a care team with expertise in CCHS. PMID- 29696800 TI - Oxoisoaporphine Alkaloids: Prospective Anti-Alzheimer's Disease, Anticancer, and Antidepressant Agents. AB - Oxoisoaporphine alkaloids are a family of oxoisoquinoline-derived alkaloids that were first isolated from the rhizome of Menispermum dauricum DC. (Menispermaceae). It has been demonstrated that oxoisoaporphine alkaloids possess various biological properties, such as cholinesterase and beta-amyloid inhibition, acting as a topoisomerase intercalator, monoamine oxidase A inhibition, and are expected to become anti-Alzheimer's disease, anticancer, and antidepressant drugs. This review provides an overview of natural sources, synthetic routes, bioactivities, structure-function relationship, and modification investigations into oxoisoaporphine alkaloids, with the aim of providing references to the structure-activity relationships for the design and development of oxoisoaporphine derivatives with higher efficacy and therapeutic potential. PMID- 29696801 TI - Probabilistic assessment of visual fatigue caused by stereoscopy using dynamic Bayesian networks. AB - PURPOSE: In this article, we develop a dynamic Bayesian network (DBN) model to measure 3D visual fatigue. As far as our information goes, this is the first adaptation of a DBN structure-based probabilistic framework for inferring the 3D viewer's state of visual fatigue. METHODS: Our measurement focuses on the interdependencies between each factor and the phenomena of visual fatigue in stereoscopy. Specifically, the implementation of DBN with using multiple features (e.g. contextual, contactless and contact physiological features) and dynamic factor provides a systematic scheme to evaluate 3D visual fatigue. RESULTS: In contrast to measurement results between the mean opinion score (MOS) and Bayesian network model (with static Bayesian network and DBN), the visual fatigue in stereoscopy at time slice t is influenced by a dynamic factor (time slice t-1). In the presence of dynamic factors (time slice t-1), our proposed measuring scheme based on DBN is more comprehensive. CONCLUSION: (i) We cover more features for inferring the visual fatigue, more reliably and accurately; (ii) at different time slices, the dynamic factor features are significant for inferring the visual fatigue state of stereoscopy. PMID- 29696802 TI - Role of fecal microbiota transplantation in inflammatory bowel disease. AB - There is increasing evidence of the key role played by altered intestinal microbiota in the pathogenesis of inflammatory bowel disease (IBD). Management strategies involving immune modulation are effective and widely used, but treatment failures and side effects occur. Fecal microbiota transplantation (FMT) provides a novel, perhaps complementary, strategy to restore the normal gut microbiota in patients with IBD. This review summarizes the available efficacy and safety data on the use of FMT in patients with IBD. Several aspects remain to be clarified about the clinical predictors of the response to FMT, its most appropriate route of administration, and the most appropriate quantity and quality of microbiota to be transplanted. Further studies focusing on long-term outcomes and safety are also warranted. PMID- 29696803 TI - X-linked intellectual disability update 2017. AB - The X-chromosome comprises only about 5% of the human genome but accounts for about 15% of the genes currently known to be associated with intellectual disability. The early progress in identifying the X-linked intellectual disability (XLID)-associated genes through linkage analysis and candidate gene sequencing has been accelerated with the use of high-throughput technologies. In the 10 years since the last update, the number of genes associated with XLID has increased by 96% from 72 to 141 and duplications of all 141 XLID genes have been described, primarily through the application of high-resolution microarrays and next generation sequencing. The progress in identifying genetic and genomic alterations associated with XLID has not been matched with insights that improve the clinician's ability to form differential diagnoses, that bring into view the possibility of curative therapies for patients, or that inform scientists of the impact of the genetic alterations on cell organization and function. PMID- 29696804 TI - Rebleeding rate and risk factors in nonsteroidal anti-inflammatory drug-induced enteropathy. AB - OBJECTIVE: Limited evidence is available on rebleeding due to nonsteroidal anti inflammatory drugs (NSAIDs)-induced enteropathy. Previous studies have primarily analyzed endoscopic findings. Therefore, there is a need to evaluate their clinical implications for patients. This study aimed to evaluate the rebleeding rate and its related risk factors in patients with NSAIDs-induced enteropathy. METHODS: Of 402 patients with obscure gastrointestinal bleeding who were evaluated with capsule endoscopy, 49 were diagnosed with NSAIDs-induced enteropathy. The clinical characteristics of the patients were retrospectively analyzed. The Charlson comorbidity index was used to stratify the comorbidities. For patients who used additional drugs that influenced their tendency to bleeding, the odds ratio was calculated and used for a quantitative comparison. RESULTS: The rebleeding rate in patients with NSAIDs-induced enteropathy was 20.4%, within a mean duration of 23.4 months. Age >=65 years (hazard ratio [HR] 8.628, 95% confidence interval [CI] 1.152-64.625), no additional use of mucoprotective agents (HR 11.712, 95% CI 1.278-76.098) and the continuation of NSAIDs after the first bleeding episode (HR 9.861, 95% CI 1.395-98.344) were independently related to rebleeding due to NSAIDs-induced enteropathy. The underlying comorbidities, drug-related rebleeding risk scores and therapeutic use of proton pump inhibitors were not significantly different (P = 0.209, 0.212 and 0.720, respectively). CONCLUSIONS: Approximately one-fifth of patients with NSAIDs-induced enteropathy showed rebleeding within 2 years. A careful long-term follow-up should be offered to elderly patients with NSAIDs-induced enteropathy who need continuous NSAID treatment without the additional use of mucoprotective medications. PMID- 29696805 TI - Visible-Light-Promoted Synthesis of Fluoroalkylated Oximes. AB - A method has been developed for the synthesis of fluoroalkylated oximes, potential fluoroalkyl building-blocks for the synthesis of various organofluorine compounds, from easily available amino substrates and fluoroalkylated alkenes. tBuONO was utilized both as a diazotizing agent and as a NO radical source for the oxime synthesis in the process, and the use of a photocatalyst under visible light irradiation increased the efficiency of the reaction. Various fluoroalkylated oximes were prepared by a tandem process of aryl radical addition to fluoroalkylated alkene and consecutive oxime generation process, albeit in moderate yields. This differentiated approach, transferring an aromatic system into an electron-deficient fluoroalkylated alkene, expands the scope of substrates where electron-poor aromatic systems could be utilized. PMID- 29696806 TI - Association of 17q24.2-q24.3 deletions with recognizable phenotype and short telomeres. AB - Microdeletions of 17q24.2-q24.3 have been described in several patients with developmental and speech delay, growth retardation, and other features. The relatively large size and limited overlap of the deletions complicate the genotype-phenotype correlation. We identified a girl with intellectual disability, growth retardation, dysmorphic features, and a de novo 2.8 Mb long deletion of 17q24.2-q24.3. Her phenotype was strikingly similar to one previously described boy with Dubowitz syndrome (MIM 223370) and a de novo 3.9 Mb long deletion encompassing the deletion of our patient. In addition, both patients had the shortest telomeres among normal age-matched controls. Our review of all 17q24.2-q24.3 deletion patients revealed additional remarkable phenotypic features shared by the patients, some of which have consequences for their management. Proposed novel genotype-phenotype correlations based on new literature information on the region include the role of PSMD12 and BPTF, the genes recently associated with syndromic neurodevelopmental disorders, and a possible role of the complex topologically associated domain structure of the region, which may explain some of the phenotypic discrepancies observed between patients with similar but not identical deletions. Nevertheless, although different diagnoses including the Dubowitz, Nijmegen breakage (MIM 251260), Silver-Russell (MIM 180860), or Myhre (MIM 139210) syndromes were originally considered in the 17q24.2-q24.3 deletion patients, they clearly belong to one diagnostic entity defined by their deletions and characterized especially by developmental delay, specific facial dysmorphism, abnormalities of extremities and other phenotypes, and possibly also short telomere length. PMID- 29696807 TI - Case report: Giant cystic lesions with a rare pulmonary diagnosis. AB - A 14-year-old male who presented with back pain was found to have giant cystic lesions on CXR and emphysematous changes on chest CT. He underwent right lobectomies and histopathology of the resected lesions demonstrated giant bullous emphysema with placental transmogrification. This has not been previously described in a pediatric patient. We describe his clinical findings, pulmonary function tests, and post-operative course. The pathogenesis of placental transmogrification remains uncertain. As this is the first reported pediatric case, we propose that giant bullous emphysema with placental transmogrification should be considered in the differential diagnosis for cystic lesions in the pediatric age group. PMID- 29696808 TI - Gas-Stabilizing Gold Nanocones for Acoustically Mediated Drug Delivery. AB - The efficient penetration of drugs into tumors is a major challenge that remains unmet. Reported herein is a strategy to promote extravasation and enhanced penetration using inertial cavitation initiated by focused ultrasound and cone shaped gold nanoparticles that entrap gas nanobubbles. The cones are capable of initiating inertial cavitation under pressures and frequencies achievable with existing clinical ultrasound systems and of promoting extravasation and delivery of a model large therapeutic molecule in an in vitro tissue mimicking flow phantom, achieving penetration depths in excess of 2 mm. Ease of functionalization and intrinsic imaging capabilities provide gold with significant advantages as a material for biomedical applications. The cones show neither cytotoxicity in Michigan Cancer Foundation (MCF)-7 cells nor hemolytic activity in human blood at clinically relevant concentrations and are found to be colloidally stable for at least 5 d at 37 degrees C and several months at 4 degrees C. PMID- 29696810 TI - Characterization of the novel HLA-C*03:02:17 allele by sequencing-based typing. AB - HLA-C*03:02:17 differs from HLA-C*03:02:02:01 by one nucleotide substitution at position 393. PMID- 29696811 TI - Development and growth trends in angiotensin II-induced murine dissecting abdominal aortic aneurysms. AB - Abdominal aortic aneurysms are pathological dilations that can suddenly rupture, causing more than 15,000 deaths in the U.S. annually. Current treatment focuses on observation until an aneurysm's size warrants surgical intervention. Thus, there is a need for therapeutic intervention to inhibit growth of smaller aneurysms. An experimental aneurysm model that infuses angiotensin II into apolipoprotein E-deficient mice is widely used to investigate underlying pathological mechanisms and potential therapeutics, but this model has two caveats: (1) aneurysms do not always form, and (2) aneurysm severity and growth is inconsistent among animals. Here we use high-frequency ultrasound to collect data from angiotensin II-induced aneurysms to develop prediction models of both aneurysm formation and growth. Baseline measurements of aortic diameter, volume/length, and strain were used with animal mass and age in a quadratic discriminant analysis and logistic regression to build two statistical models to predict disease status. Longitudinal ultrasound data were also acquired from mice with aneurysms to quantify aneurysm diameter, circumferential strain, blood flow velocity, aneurysm volume/length, and thrombus and open-false lumen volumes over 28 days. Measurements taken at aneurysm diagnosis were used with branching artery information to produce a multiple linear regression model to predict final aneurysm volume/length. All three statistical models could be useful in future aneurysm therapeutic studies to better delineate the effects of preventative and suppressive treatments from normal variations in the angiotensin II aneurysm model. PMID- 29696812 TI - Effects of aerobic and resistance exercise in older adults with rheumatoid arthritis: A randomized controlled trial. AB - OBJECTIVE: To evaluate the effect of a person-centered, moderate-to-high intensity, aerobic and resistance exercise protocol on older adults with rheumatoid arthritis (RA), through a randomized controlled multi-center trial. METHODS: Older adults (65-75 years) with RA (n=74) were randomized to either a 20 week person-centered exercise intervention at a gym (n=36) or to home-based exercise of light intensity (n=38). Assessments were performed at baseline, at 20 weeks, and at 12 months. Primary outcome was the difference in the Health Assessment Questionnaire - Disability Index (HAQ-DI), and the secondary outcomes were the differences in physical fitness assessed by a cardiopulmonary exercise test, an endurance test, Timed Up and Go, Sit To Stand test and isometric elbow flexion force. RESULTS: No significant differences between the groups were found for the primary outcome HAQ-DI. Within the intervention group there was a significant improvement of HAQ-DI when compared to baseline (p=0.022). Aerobic capacity (p<0.001) and three out of four additional performance-based tests of endurance and strength significantly improved (p<0.05) in the intervention group when compared to the control group. In the intervention group 71% rated their health as much or very much improved compared to 24% of the control group (p<0.001). At the 12-month follow-up, there were no significant difference of change between the two groups on HAQ-DI. A significant between-group difference was found for change in an endurance test (p=0.022). CONCLUSION: Person-centered aerobic and resistance exercise improved physical fitness in terms of aerobic capacity, endurance and strength in older adults with RA. This article is protected by copyright. All rights reserved. PMID- 29696813 TI - Hyaluronan-Based Nanohydrogels for Targeting Intracellular S. Aureus in Human Keratinocytes. AB - Staphylococcus aureus is one of the most significant human pathogens that is frequently isolated in a wide range of superficial and systemic infections. The ability of S. aureus to invade and survive within host cells such as keratinocytes and host immune cells has been increasingly recognized as a potential factor in persistent infections and treatment failures. The incorporation of antibiotics into hyaluronan-cholesterol nanohydrogels represents a novel paradigm in the delivery of therapeutic agents against intracellular bacteria. The work presented herein shows that NHs quickly enter human keratinocytes and accumulate into lysosomes. When used for targeting intracellular S. aureus the antimicrobial activity of loaded levofloxacin is enhanced, possibly changing the antibiotic intracellular fate from cytosol to lysosome. Indeed, gentamicin, an antibiotic that predominantly accumulates in lysosomes, shows significant and equal antibacterial activity when entrapped into NHs. These results strongly suggest that lysosomal formulations may display preferential activity toward intracellular S. aureus, opening new avenues for the use of HA-based NHs for treatment of such skin infections. PMID- 29696809 TI - A noninterventional study to monitor patients with diabetic macular oedema starting treatment with ranibizumab (POLARIS). AB - PURPOSE: Antivascular endothelial growth factor agents are increasingly used in diabetic macular oedema (DME); however, there are few studies exploring their use in DME in real-world settings. METHODS: POLARIS was a noninterventional, multicentre study to monitor 12-month outcomes in patients starting ranibizumab treatment in routine practices. The primary outcome was mean change in visual acuity (VA) from baseline to month 12 (last observation carried forward approach). Other outcomes included mean change in central retinal thickness (CRT) and resource utilization. Visual acuity (VA) outcomes were also stratified by country, baseline visual acuity score (VAS), sex, age and injection frequency. RESULTS: Outcomes were analysed from all treated patients (n = 804) and from first-year completers (patients who had a visual acuity assessment at 12 months; n = 568). The mean (SD) baseline VAS was 59.4 (15.9) letters, and the mean change in visual acuity was 4.4 letters (95% confidence interval: 3.3-5.4) at month 12 (study eye; first-year completers). The mean number of injections (study eye) was 4.9, and the mean number of all visits (any eye) was 10 (58% were injection visits) over 12 months (first-year completers). The mean (SD) baseline CRT was 410.6 (128.8) MUm, and the mean change in CRT was -115.2 MUm at month 12 (study eye; first-year completers). Visual acuity (VA) outcomes were generally comparable across most countries and subgroups and were greatest in patients with the lowest baseline VAS (<=60 letters). CONCLUSION: POLARIS showed that real world outcomes in DME patients starting treatment with ranibizumab were lower than those observed in clinical studies, in spite of extensive monitoring. PMID- 29696814 TI - Difference in prostate cancer incidence around sixty years: effects of age and metabolic diseases. AB - We examined the risk of prostate cancer in the Korean population stratified on the basis of age group and risk based on metabolic diseases, using National Health Insurance System (NHIS) data. Of the 51,827,813 people from the NHIS data in 2015, 10,879,591 men without prostate cancer who underwent a health examination were analyzed. The risk of prostate cancer was analyzed with stratification by age. Multivariate-adjusted Cox regression analysis was conducted to examine the association between prostate cancer and metabolic diseases by age groups. The risk of prostate cancer increased continuously with age and 59 years may be a point of inflection. The hazard ratio (HR) of prostate cancer development rose sharply as that age point passed. The population with metabolic diseases was more likely to develop prostate cancer than the population without any of these components. In addition, the incidence rate ratio (IRR) decreased from the youngest age group to the age group comprising 55-59 year olds. Beyond this age group, there was a plateau. The relative risk for prostate cancer associated with metabolic diseases also showed divergent associations with age. The risk of prostate cancer increased continuously with age and the peak Youden index was at 59 years. The relative risk for prostate cancer according to metabolic diseases also showed divergent associations beyond 59 years of age. Therefore, setting the age threshold at 59 years would improve the present clinical risk stratification for prostate cancer in Korea. PMID- 29696815 TI - Multicenter analysis of stereotactic radiotherapy of the resection cavity in patients with brain metastases. AB - Brain metastases show a recurrence rate of about 50% after surgical resection. Adjuvant radiotherapy can prevent progression; however, whole-brain radiotherapy (WBRT) can be associated with significant side effects. Local hypofractionated stereotactic radiotherapy (HFSRT) is a good alternative to provide local control with minimal toxicity. In this multicenter analysis, we evaluated the treatment outcome of local HFSRT after resection brain metastases in 181 patients. Patient's characteristics, treatment data as well as follow-up data were collected and analyzed with special focus on local control, locoregional control and survival. After a median follow-up of 12.6 months (range 0.3-80.2 months), the crude rate for local control was 80.5%; 1- and 2-year local recurrence-free survival rates were 75% and 70% (median not reached). Resection cavity size was a significant predictor for local recurrence (P = 0.033). The median overall survival was 16.0 months. Both graded prognostic assessment score and recursive partitioning analysis were accurate predictors of survival. HFSRT leads to excellent local control and has a high potential to consolidate results after surgery; acute and late toxicity is low. Distant intracerebral metastases occur frequently during follow-up, and therefore, a close patient monitoring needs to be warranted if whole-brain radiotherapy is omitted. PMID- 29696816 TI - Deletion of Smad4 reduces hepatic inflammation and fibrogenesis during nonalcoholic steatohepatitis progression. AB - OBJECTIVE: To explore the effects of mothers against decapentaplegic homolog family member 4 (Smad4) deletion on inflammation and fibrogenesis in nonalcoholic steatohepatitis (NASH). METHODS: Biopsied liver samples from NASH patients and normal liver tissue samples from patients who had received liver resection for trauma were collected. Smad4Co/Co and wild-type (WT) mice were used to construct the NASH model using a high-fat diet (HFD) or methionine- and choline-deficient diet (MCD). HE staining and TUNEL assay were used to observe the pathological changes and cell apoptosis, respectively. Quantitative real-time polymerase chain reaction was used to detect the expression of inflammatory, fibrogenesis and apoptosis-related genes, and immunohistochemistry to determine the protein expression of SMAD4, MCP-1 and alpha-SMA. RESULTS: SMAD4 protein expression significantly increased in NASH patients than in the control group. Compared with WT mice, HFD- and MCD-fed Smad4Co/Co mice showed decreased hepatic steatosis, inflammation, liver cell apoptosis and nonalcoholic fatty liver activity score, reduced plasma glucose, triglyceride, free fatty acids, alanine aminotransferase and aspartate aminotransferase levels but increased adiponectin. Moreover, Smad4Co/Co decreased the expression of inflammatory markers (TNF-alpha, MCP-1, IFN-gamma), fibrogenetic markers (COL1A1, alpha-SMA and TGF-beta1), lipogenic (Srebp1c, Fas and Acc) and proapoptotic genes (Bax and caspase-3), but increased the expression of beta-oxidation (Ppar-alpha, Cpt1 and Aco) and antiapoptotic genes (Bcl-2). CONCLUSION: Smad4 deletion may inhibit lipogenesis, stimulate beta oxidation, improve lipid metabolism and liver function, alleviate inflammation and fibrosis, and reduce cell apoptosis in NASH. PMID- 29696817 TI - Pediatric pulmonology year in review 2017: Part 4 (Sleep medicine). AB - Pediatric Pulmonology publishes original research, case reports and review articles on topics related to a wide range of children's respiratory disorders. In this article (Part 4 of a 5-part series), we summarize the past year's publications in sleep medicine, in the context of selected literature in this area from other journals. Articles are highlighted on topics including diagnosis and treatment of OSAS, sleep duration and position, and sleep disorders in chronic disease. PMID- 29696818 TI - Characterization of the novel HLA-B*40:01:51 allele by sequencing-based typing. AB - HLA-B*40:01:51 differs from HLA-B*40:01:01 by 2 nucleotide substitutions at position 72 and 126. PMID- 29696819 TI - CXCL10 increases in human skeletal muscle following damage but is not necessary for muscle regeneration. AB - CXCL10 is a chemokine for activated and memory T cells with many important immunological functions. We recently found that CXCL10 is upregulated in human muscle following contraction-induced damage. No information is available on the role of CXCL10 in the context of muscle damage or repair. In this study, we confirm that CXCL10 is elevated in human muscle at 2 and 3 days following damage and perform cell culture and animal studies to examine the role of CXCL10 in muscle repair. CXCL10 did not impact proliferation rates of human primary myoblasts but it did promote myogenic differentiation in vitro, suggesting a possible direct impact on muscle regeneration. To test if CXCL10 was dispensable for effective muscle regeneration in vivo, we measured functional and histological markers of muscle repair out to 14 days postmuscle injury caused by a myotoxin in wild-type (WT) mice and CXCL10 knockout (KO) mice. Between genotypes, no significant differences were found in loss or restoration of in situ muscle force, cross-sectional area of newly formed myofibers, or the number of embryonic myosin heavy chain-positive myofibers. In addition, KO animals were not deficient in T-cell accumulation in the damaged muscle following injury. Gene expression of the other two ligands (CXCL9 and 11) that bind to the same receptor as CXCL10 were also elevated in the damaged muscle of KO mice. Thus, other ligands may have compensated for the lack of CXCL10 in the KO mice. We conclude that CXCL10 is not necessary for effective muscle regeneration. PMID- 29696820 TI - Genetic correction of serum AFP level improves risk prediction of primary hepatocellular carcinoma in the Dongfeng-Tongji cohort study. AB - Serum alpha-fetoprotein (AFP) is the most commonly used tumor biomarker for screening and diagnosis of primary hepatocellular carcinoma (HCC). However, the predictive effect for HCC risk is still unsatisfactory. The aim of this prospective study was to estimate whether the individual genetic correction could improve the prediction efficiency of AFP for HCC risk. A prospective analysis with 9819 baseline HCC-free individuals based on a large population-based Chinese cohort study was performed. Two single-nucleotide polymorphisms (SNPs) associated with serum AFP level were used to calculate the genetic corrected AFP level (rs12506899 and rs2251844). Statistical analysis including logistic regression analysis and the area under the receiver operating characteristic (ROC) curve were used to assess the discriminative ability of the original and genetic corrected AFP level for HCC risk. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were presented. Fifty-seven participants were diagnosed with HCC for the first time. After adjusting AFP level with genetic effects, the participants for HCC risk increased compared to those with AFP level alone (OR = 5.34, 95% CI = 2.57-11.13; P < 0.001 vs. OR = 5.04, 95% CI = 2.46-10.30; P < 0.001). In addition, the area under the curve (AUC) for the discrimination of HCC elevated from 0.611 to 0.726. The efficiency in HCC prediction using serum AFP level can be improved by adjusting AFP level based on genetic effects. The genetic correction effect on serum AFP should be considered in the clinic application of such tumor biomarkers. PMID- 29696821 TI - A simple antegrade perfusion method for isolating viable single cardiomyocytes from neonatal to aged mice. AB - The aim of this study was to establish a simple and reproducible antegrade perfusion method for isolating single viable mouse heart cells and to determine the standard practical protocols that are appropriate for mice of various ages. Antegrade perfusion was performed by injecting perfusate from near the apex of the left ventricle of the excised heart, the aorta of which was clamped, using an infusion pump. This could thoroughly perfuse the myocardium through the coronary circulation. All procedures were carried out on a prewarmed heater mat under a microscope, which allows for the processes of injection and perfusion to be monitored. With appropriate adjustment of the size of the injection needle, the composition and amount of enzyme solution and the perfusion flow rate, this antegrade perfusion method could be applied to the hearts of neonatal to aged mice. We examined the morphological characteristics and electrophysiological properties of the isolated ventricular and atrial myocytes and found that these cells were mostly identical to those obtained with the traditional Langendorff based retrograde perfusion method. Interstitial nonmyocytes, such as cardiac progenitor cells, were also isolated simultaneously from the supernatant fraction of the centrifugation, similar to the retrograde perfusion method. The results suggest that single heart cells can be well isolated with high degree of quality by the present antegrade perfusion method, regardless of the age of the mouse. PMID- 29696822 TI - Chemical Variation in Essential Oils from the Oleo-gum Resin of Boswellia carteri: A Preliminary Investigation. AB - Frankincense, the oleo-gum resin of Boswellia species, has been an important element of traditional medicine for thousands of years. Frankincense is still used for oral hygiene, to treat wounds, and for its calming effects. Different Boswellia species show different chemical profiles, and B. carteri, in particular, has shown wide variation in essential oil composition. In order to provide insight into the chemical variability in authentic B. carteri oleoresin samples, a hierarchical cluster analysis of 42 chemical compositions of B. carteri oleo-gum resin essential oils has revealed at least three different chemotypes, i) an alpha-pinene-rich chemotype, ii) an alpha-thujene-rich chemotype, and iii) a methoxydecane-rich chemotype. PMID- 29696823 TI - A seasonal study of a passive abandoned coalmine drainage remediation system reveals three distinct zones of contaminant levels and microbial communities. AB - A passive remediation system that treats coalmine drainage was sampled to determine the impact seasonal changes had on water quality and microbial diversity. Every quarter for 1 year, water-soil slurries were collected at the influent of the 5 settling ponds and the wetlands, and the effluent of the system. The concentration of 12 metals and sulfate, as well as sequences from the V4 region of the bacterial 16S rrn genes were determined. The water quality analysis revealed high levels of iron and sulfate, and measurable levels of Al, Ba, Cu, Pb, Mn, Sr, and Zn. Iron increased 25-fold in the summer and spikes in metal concentrations were observed during several seasons in pond 3 and the wetlands. These spikes cannot be explained by abiotic chemical reactions in the neutral pH found in the pond. Based on contaminant levels and microbial community composition, our results indicate that there were 3 unique environments in the system (ponds 1 and 2; pond 3; pond 4 through the end) and that changes in contaminant levels and bacterial composition in these environments correlated with seasonal variation. Iron and sulfate are the most prevalent contaminants in the system. An examination of sequences from known iron- and sulfur-cycling bacteria demonstrated that there were more iron-reducing (IRB) bacterial sequences than iron-oxidizing (IOB) (137,912 IRB vs. 98,138 IOB), the two groups of bacteria were found mainly in the fall and winter samples, and were prevalent in different ponds. There were more sulfur/sulfide-oxidizing (SOB) bacterial sequences than sulfur/sulfate-reducing (SRB) bacterial sequences (72,978 SOB vs 30,504 SRB), they were found mainly in the fall and winter samples, and the sequences were mixed in ponds 4, 5 and the wetlands effluent. Iron is remediated in this system but sulfate is not. PMID- 29696824 TI - Comparative evaluation of acid and alkaline sulfite pretreatments for enzymatic saccharification of bagasses from three different sugarcane hybrids. AB - Sugarcane bagasses from three experimental sugarcane hybrids and a mill-reference sample were used to compare the efficiency and mode of action of acid and alkaline sulfite pretreatment processes. Varied chemical loads and reaction temperatures were used to prepare samples with distinguished characteristics regarding xylan and lignin removals, as well as sulfonation levels of residual lignins. The pretreatment with low sulfite loads (5%) under acidic conditions (pH 2) provided maximum glucose yield of 70% during enzymatic hydrolysis with cellulases (10 FPU/g) and beta-glucosidases (20 UI/g bagasse). In this case, glucan enzymatic conversion from pretreated materials was mostly associated with extensive xylan removal (70-100%) and partial delignification occurred during the pretreatment. The use of low sulfite loads under acidic conditions required pretreatment temperatures of 160 degrees C. In contrast, at a lower pretreatment temperature (120 degrees C), alkaline sulfite process achieved similar glucan digestibility, but required a higher sulfite load (7.5%). Residual xylans from acid pretreated materials were almost completely hydrolysed by commercial enzymes, contrasting with relatively lower xylan to xylose conversions observed in alkaline pretreated samples. Efficient xylan removal during acid sulfite pretreatment and during enzymatic digestion can be useful to enhance glucan accessibility and digestibility by cellulases. Alkaline sulfite process also provided substrates with high glucan digestibility, mainly associated with delignification and sulfonation of residual lignins. The results demonstrate that temperature, pH, and sulfite can be combined for reducing lignocellulose recalcitrance and achieve similar glucan conversion rates in the alkaline and acid sulfite pretreated bagasses. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:944-951, 2018. PMID- 29696825 TI - Endotracheal or tracheostomy tube occlusion during pediatric flexible bronchoscopy. PMID- 29696826 TI - Lung ultrasound compared to chest X-ray for diagnosis of pediatric pneumonia: A meta-analysis. AB - OBJECTIVE: Although a clinical diagnosis, the standard initial imaging modality for patients with concern for pediatric community acquired pneumonia (pCAP) is a chest x-ray (CXR), which has a relatively high false negative rate, exposes patients to ionizing radiation, and may not be available in resource limited settings. The primary objective of this meta-analysis is to evaluate the accuracy of lung ultrasound (LUS) compared to CXR for the diagnosis of pCAP. METHODS: Data were collected via a systematic review of PubMed, EMBASE, and Web of Science with dates up to August 2017. Keywords and search terms were generated for pneumonia, lung ultrasound, and pediatric population. Two independent investigators screened abstracts for inclusion. PRISMA was used for selecting appropriate studies. QUADAS was applied to these studies to assess quality for inclusion into the meta analysis. We collected data from included studies and calculated sensitivity, specificity, positive predictive value, and negative predictive values of CXR and LUS for the diagnosis of pCAP. RESULTS: Twelve studies including 1510 patients were selected for data extraction. LUS had a sensitivity of 95.5% (93.6-97.1) and specificity of 95.3% (91.1-98.3). CXR had a sensitivity of 86.8% (83.3-90.0) and specificity of 98.2% (95.7-99.6). Variations between the studies included ultrasound findings diagnostic of pneumonia, study setting (inpatient vs emergency department) and inclusion of CXR in the reference standard for pneumonia. CONCLUSIONS: In our meta-analysis, lung ultrasound had significantly better sensitivity with similar specificity when compared to chest x-ray for the diagnosis of pediatric community acquired pneumonia. PMID- 29696827 TI - Photoredox-Catalyzed Decarboxylative Oxidation of Arylacetic Acids. AB - A photoredox-catalyzed decarboxylative oxidation of arylacetic acids, which are privileged scaffolds in pharmaceuticals, is reported herein. The established method is operationally simple and a variety of substrates are applicable, providing rapid access to dehomologated bioisosteres of common pharmaceuticals. PMID- 29696828 TI - Contact Lenses for Color Blindness. AB - Color vision deficiency (color blindness) is an inherited genetic ocular disorder. While no cure for this disorder currently exists, several methods can be used to increase the color perception of those affected. One such method is the use of color filtering glasses which are based on Bragg filters. While these glasses are effective, they are high cost, bulky, and incompatible with other vision correction eyeglasses. In this work, a rhodamine derivative is incorporated in commercial contact lenses to filter out the specific wavelength bands (~545-575 nm) to correct color vision blindness. The biocompatibility assessment of the dyed contact lenses in human corneal fibroblasts and human corneal epithelial cells shows no toxicity and cell viability remains at 99% after 72 h. This study demonstrates the potential of the dyed contact lenses in wavelength filtering and color vision deficiency management. PMID- 29696829 TI - Perspectives of adolescent girls with cystic fibrosis and parents on disease specific sexual and reproductive health education. AB - INTRODUCTION: Adolescent girls with cystic fibrosis (CF) face significant disease specific sexual and reproductive health (SRH) concerns that are not typically addressed in routine clinical care. Additionally, there is a paucity of developmentally appropriate CF-specific SRH educational resources for this population. The goal of this study was to explore patient and parent attitudes toward SRH educational resources for adolescent girls with CF. METHODS: Adolescent girls ages 13-18 years with CF and parents of daughters ages 10-18 years with CF completed individual, semi-structured interviews regarding their experiences and preferences around CF-specific SRH education and care. To facilitate discussion, participants provided feedback on the format and design of existing SRH educational resources. Qualitative analysis was conducted using a thematic analysis approach. RESULTS: We interviewed 26 participants (14 parents and 12 patients). The majority reported they had never discussed SRH in the CF care setting. All participants preferred a comprehensive, online patient educational resource complemented by real patient stories and interactive components. Participants noted that such resources should create a sense of normalcy and community around CF and female SRH. Most desired more frequent communication around SRH between adolescent girls with CF and their healthcare providers as a way to promote SRH knowledge, decision making, and health outcomes. DISCUSSION: Adolescent girls with CF and their parents desire an online patient educational resource that normalizes SRH and enhances patient-provider communication around these topics. Creation of developmentally appropriate resources would facilitate improved health outcomes around this aspect of comprehensive care in CF. PMID- 29696830 TI - Food matrix: The influence of tools, training and policies on our nutrition practice. PMID- 29696832 TI - Progesterone administration does not acutely alter LH pulse secretion in the mid follicular phase in women. AB - It remains unclear how rapidly progesterone suppresses luteinizing hormone (LH) pulse frequency in women. Previous studies suggested that progesterone markedly increases LH pulse amplitude but does not slow LH pulse frequency within 10 h in estradiol-pretreated women studied during the late follicular phase. However, this experimental paradigm may be a model of preovulatory physiology, and progesterone may have different effects at other times of the cycle. We studied regularly cycling, nonobese women without hyperandrogenism to assess the acute effect of progesterone during the midfollicular phase and in the absence of estradiol pretreatment. The study involved two admissions in separate cycles (cycle days 5-9). For each admission, either oral micronized progesterone (100 mg) or placebo was administered at 0900 h in a randomized, double-blind fashion. Frequent blood sampling was performed between 0900 and 1900 h to define 10-h LH pulsatility. Treatment crossover (placebo exchanged for progesterone and vice versa) occurred in a subsequent cycle. After an interim futility analysis, the study was halted after 7 women completed study. Mean progesterone concentrations after placebo and progesterone administration were 0.5 +/- 0.1 (mean +/- SD) and 6.7 +/- 1.6 ng/mL, respectively. Compared to placebo, progesterone was not associated with a significant difference in 10-h LH pulse frequency (0.79 +/- 0.35 vs. 0.77 +/- 0.28 pulses/h, P = 1.0) or amplitude (3.6 +/- 2.8 vs. 4.3 +/- 2.8 IU/L, P = 0.30). This study suggests that LH pulse frequency is not rapidly influenced by progesterone administration during the midfollicular phase. PMID- 29696833 TI - Tofacitinib in Rheumatoid Arthritis: Lack of Early Change in Disease Activity Predicts a Low Probability of Achieving Low Disease Activity at Month 6. AB - OBJECTIVE: Optimal targeted treatment in rheumatoid arthritis requires early identification of failure to respond. This post-hoc analysis explored the relationship between early disease activity changes and achievement of low disease activity (LDA) and remission targets with tofacitinib. METHODS: Data were from two randomized, double-blind, Phase 3 studies. In ORAL Start (NCT01039688), methotrexate (MTX)-naive patients received tofacitinib 5 or 10 mg BID, or MTX, for 24 months. In placebo-controlled ORAL Standard (NCT00853385), MTX-inadequate responder (MTX-IR) patients received tofacitinib 5 or 10 mg BID or adalimumab 40 mg Q2W, with MTX, for 12 months. Probabilities of achieving LDA (CDAI <=10; DAS28 4[ESR] <=3.2) at months 6 and 12 were calculated, given failure to achieve threshold improvement from baseline (change in CDAI >=6; DAS28-4[ESR] >=1.2) at month 1 or 3. RESULTS: In ORAL Start, 7.2% and 5.4% of patients receiving tofacitinib 5 and 10 mg BID, respectively, failed to improve CDAI >=6 at month 3; of those who failed, 3.8% and 28.6%, respectively, achieved month 6 CDAI-defined LDA. In ORAL Standard, 18.8% and 17.5% of patients receiving tofacitinib 5 and 10 mg BID, respectively, failed to improve CDAI >=6 at month 3; of those who failed, 0% and 2.9%, respectively, achieved month 6 CDAI-defined LDA. Findings were similar when considering month 1 improvements or DAS28-4(ESR) thresholds. CONCLUSIONS: In MTX-IR patients, lack of response to tofacitinib after 1 or 3 months predicted low probability of achieving LDA at month 6. Lack of early response may be considered when deciding whether to continue treatment with tofacitinib. This article is protected by copyright. All rights reserved. PMID- 29696834 TI - How to record a 12-lead electrocardiogram. AB - RATIONALE AND KEY POINTS: This article provides a step-wise, practical approach to recording a 12-lead electrocardiogram (ECG) and explores the evidence base that supports the use of this important assessment tool in clinical practice. *A 12-lead ECG is frequently used in a variety of clinical settings, including emergency care, preoperative and post-operative assessment, and primary care. It is used to assess and diagnose patients with suspected arrhythmias, hypertension, coronary heart disease or heart failure.*Correct positioning of the electrodes using anatomical landmarks is essential to ensure an accurate and high-quality ECG recording.*Skin preparation is essential, since suboptimal electrode contact or electrodes being placed where there is a significant amount of dry or dead skin cells, grease, sweat or hair, can negatively affect the quality of the ECG recording. REFLECTIVE ACTIVITY: 'How to' articles can help to update your practice and ensure it remains evidence-based. Apply this article to your practice. Reflect on and write a short account of: 1.How this article might improve your practice when recording a 12-lead ECG.2.How you could use this information to educate your patients and colleagues on the appropriate technique for recording a 12-lead ECG. PMID- 29696835 TI - [Response of tree seedlings to altitudinal gradient and its seasonal variation in Ailao Mountain and Yulong Mountain, Yunnan Province, China.] AB - Tree seedlings under forests serve as an important part of forest ecosystem and play a role in the natural regeneration of forests. To understand the altitudinal distribution patterns of tree seedlings and the response to seasonal variation, we investigated the species composition and individual numbers of tree seedlings, and their seasonal dynamics in Ailao Mountain (subtropical region) and Yulong Mountain (subalpine region) in Yunnan Province. The results showed that the species richness of tree seedlings increased with altitude, peaked in the middle of the mountains, and followed a decline at higher altitudes, and the dominant species also changed significantly. Species richness of tree seedlings was significantly higher at the end of rainy season than that at the end of dry season, and the dominant species had obvious seasonal difference. PMID- 29696831 TI - In Vitro Tissue-Engineered Skeletal Muscle Models for Studying Muscle Physiology and Disease. AB - Healthy skeletal muscle possesses the extraordinary ability to regenerate in response to small-scale injuries; however, this self-repair capacity becomes overwhelmed with aging, genetic myopathies, and large muscle loss. The failure of small animal models to accurately replicate human muscle disease, injury and to predict clinically-relevant drug responses has driven the development of high fidelity in vitro skeletal muscle models. Herein, the progress made and challenges ahead in engineering biomimetic human skeletal muscle tissues that can recapitulate muscle development, genetic diseases, regeneration, and drug response is discussed. Bioengineering approaches used to improve engineered muscle structure and function as well as the functionality of satellite cells to allow modeling muscle regeneration in vitro are also highlighted. Next, a historical overview on the generation of skeletal muscle cells and tissues from human pluripotent stem cells, and a discussion on the potential of these approaches to model and treat genetic diseases such as Duchenne muscular dystrophy, is provided. Finally, the need to integrate multiorgan microphysiological systems to generate improved drug discovery technologies with the potential to complement or supersede current preclinical animal models of muscle disease is described. PMID- 29696836 TI - [Effect of thinning intensities on fruiting regularities of Quercus liaotungensis forests in Huang-long and Qiaoshan mountains.] AB - In order to clarify the impact of thinning intensities on fruiting regularity of Quercus liaotungensis forests, we took the Q. liaotungensis half-mature forests in Huanglong and Qiaoshan mountains on south of the Loess Plateau as the object of study, which were under close-to-natural management of different thinning intensities (CK, 10%, 20% and 30%). An analysis was made on stand density and percent of seed trees, seed number of sample tree and unit area, seed spatial distributions, seed characteristics of the Q. liaotungensis forests after 5 years of thinning. The results showed that, percent of seed trees, seed number per sample tree and percent of developed seeds of Q. liaotungensis forests increased with the increasing intensity, and showed a pattern of 30%>20%>10%>CK. Seed number per area reached the maximum number under 20% thinning, and showed a pattern of 20%>30%>CK>10%. From the seed spatial distribution in the canopy, the upper accounted for 73.6%, while the lower had 26.4%. The sunny side of canopy layer set relatively the most fruits of 65.8%, shady side only had 34.2%. Under thinning, further improving was geater under lower canopy than under upper canopy and so was on shady side than on sunny side. The seed long diameter, seed short diameter and 1000-seed mass of Q. liaotungensis forests increased with the increasing intensity, which reached the maximum under 30% thinning. 10% thinning did not significantly impact Q. liaotungensis fruiting, the thinning intensity of 20% was most conducive to the seed quantity and quality improvement of Q. liaotungensis, while the thinning intensity of 30% did not improve the fruiting, and lowered the total number of seeds. It was proposed that 20% thinning should be chosen (canopy density of 0.7) to effectively improve fruiting and quality of Q. liaotungensis. PMID- 29696837 TI - [Maximum density-size line for Larix olgensis plantations based on quantile regression.] AB - Based on 378 permanent and 415 temporary plots from Northeast China, the relationship of maximum stand density and quadratic mean diameter at breast height of treesfor Larix olgensis plantation was developed. Linear quantile regression model with different quantiles (tau=0.90, 0.95, 0.99) was used and the optimal model for the maximum density-size line model was selected. The ordinary least square (OLS) and maximum likelihood (ML) regression were also employed to develop the maximum density-size line by using the arbitrary selected data. Generalized Pareto model of extreme value theory was used to calculate the number of limited maximum trees based on the current stands so that the limited density size line was developed. The linear quantile regression model was compared with the other methods. The results showed that selecting 5 points within the whole diameter class for the maximum density-size line model development would get the satisfying prediction model. The fitting line would deviate from the maximum density-size line with the increasing points selected. The method of ML was superior to OLS in parameter estimation. The linear quantile regression model with the quantile of 0.99 achieved similar fitting results compared with ML regression and the estimation results was much stable. Traditional approach that selecting fittng data was considered arbitrary so that linear quantile regression with quantile of 0.99 was selected as the best model to construct the maximum density-size line with the estimates for the parameters as k=11.790 and beta= 1.586, and k=11.820 and beta=-1.594 for the limited density-size line model. The determined limited density-size line was above the maximum density-size line but the difference was not pronounced. The validation results by using the data of permanent sample plots showed the models were suitable to predict the maximum and limited density line of the current forest stands, which would provide basis for the sustainable management of L. olgensis plantation. PMID- 29696838 TI - [Effects of nitrogen additions on soil hydrolase and oxidase activities in Pinus elliottii plantations.] AB - We evaluated responses of hydrolase and oxidase activities in a subtropical Pinus elliottii plantation through a nitrogen (N) addition field experiment (dosage level: 0, 40, 120 kg N.hm-2.a-1). The results showed that N additions significantly decreased the carbon, nitrogen and phosphorus related hydrolase and oxidase activities. The activities of beta-1,4-glucosidase (BG), cellobiohydrolase (CBH), beta-1,4-N-acetylglucosaminidase (NAG) and peroxidase (PER) activities were decreased by 16.5%-51.1% due to N additions, and the decrease was more remarkable in the higher N addition treatment. The activities of alpha-1,4-glucosidase (aG), beta-1,4-xylosidase (BX), acid phosphatase (AP) and phenol oxidase (PPO) were decreased by 14.5%-38.6% by N additions, however, there was no significant difference among the different N addition treatments. Soil enzyme activities varied obviously in different seasons. The activities of BG, NAG, BX, CBH, AP and PPO were in the order of March > June > October, and aG and PER activities were in the order of October > March > June. Most of the soil hydrolase and oxidase activities were positively correlated with soil pH, but negatively with NO3--N content. It indicated that N additions inhibited soil hydrolase and oxidase activities by reducing soil pH and increasing soil nitrification. N additions inhibited the soil organic matter mineralization and turnover in the subtropical area, and the effects were obvious with the increasing dosage of N additions. PMID- 29696839 TI - [Response in cuttings of Taxodium hybrid 'Zhongshanshan' and their parents to drought and re-hydration.] AB - In this study, three different strains of Taxodium hybrid 'Zhongshanshan' varieties [T. hybrid 302 (T. distichum?*T. mucronatum?), T. hybrid 407 (T. mucronatum?*T. distichum?), T. hybrid 118 (T. hybrid 302 ?*T. macronatum ?)] and their parents, T. distichum and T. mucronatum, were applied to investigate the response of photosynthetic characteristics, antioxidant enzyme systems and morphological characteristics to drought stress and recovery. The results indicated that as drought days were prolonged, all plants' net photosynthetic rate (Pn) decreased, while proline accumulated. Meanwhile, the antioxidases functioned to eliminate malonaldehyde toxicity. On the 8th day, the decrease of Pn of T. distichum was the biggest, T. hybrid 118 plants showed the highest water use efficiency and the smallest MDA content, while T. macronatum plants increased the activity of superoxide dismutase and content of proline. After rewatering for 2 days, all these parameters showed signs of recovery, and the T. hybrid 118 plants showed the fastest recovery rate since their Pn and proline content had recovered for 74.4% and 60.2%, respectively. Then after recovered for 9 days, all tested parameters had almost restored to equivalent levels of CK plants. The total biomass of T. hybrid 118 plants was not affected, while the ratio of root to shoot was significantly (P<0.05) increased. The drought-resistance capacity ranged as T. macronatum>T. hybrid 118>T. hybrid 407>T. hybrid 302>T. distichum plants. In conclusion, the backcross generation T. hybrid 118 plants largely inherited the drought resistance of T. mucronatum, and the result would be instrumental in breeding and popularization of drought-resistant hybrid varieties. PMID- 29696840 TI - [Functional diversity characteristics of canopy tree species of Jianfengling tropical montane rainforest on Hainan Island, China.] AB - Based on three 1-hm2 plots of Jianfengling tropical montane rainforest on Hainan Island, 11 commom used functional traits of canopy trees were measured. After combining with topographical factors and trees census data of these three plots, we compared the impacts of weighted species abundance on two functional dispersion indices, mean pairwise distance (MPD) and mean nearest taxon distance (MNTD), by using single- and multi-dimensional traits, respectively. The relationship between functional richness of the forest canopies and species abundance was analyzed. We used a null model approach to explore the variations in standardized size effects of MPD and MNTD, which were weighted by species abundance and eliminated the influences of species richness diffe-rences among communities, and assessed functional diversity patterns of the forest canopies and their responses to local habitat heterogeneity at community's level. The results showed that variation in MPD was greatly dependent on the dimensionalities of functional traits as well as species abundance. The correlations between weighted and non-weighted MPD based on different dimensional traits were relatively weak (R=0.359-0.628). On the contrary, functional traits and species abundance had relatively weak effects on MNTD, which brought stronger correlations between weighted and non-weighted MNTD based on different dimensional traits (R=0.746-0.820). Functional dispersion of the forest canopies were generally overestimated when using non-weighted MPD and MNTD. Functional richness of the forest canopies showed an exponential relationship with species abundance (F=128.20; R2=0.632; AIC=97.72; P<0.001), which might exist a species abundance threshold value. Patterns of functional diversity of the forest canopies based on different dimensional functional traits and their habitat responses showed variations in some degree. Forest canopies in the valley usually had relatively stronger biological competition, and functional diversity was higher than expected functional diversity randomized by null model, which indicated dispersed distribution of functional traits among canopy tree species in this habitat. However, the functional diversity of the forest canopies tended to be close or lower than randomization in the other habitat types, which demonstrated random or clustered distribution of the functional traits among canopy tree species. PMID- 29696841 TI - [Effects of intensive management on soil C and N pools and soil enzyme activities in Moso bamboo plantations.] AB - In order to elucidate the effects of intensive management on soil carbon pool, nitrogen pool, enzyme activities in Moso bamboo (Phyllostachys pubescens) plantations, we collected soil samples from the soil surface (0-20 cm) and subsurface (20-40 cm) layers in the adjacent Moso bamboo plantations with extensive and intensive managements in Sankou Township, Lin'an City, Zhejiang Province. We determined different forms of C, N and soil invertase, urease, catalase and acid phosphatase activities. The results showed that long-term intensive management of Moso bamboo plantations significantly decreased the content and storage of soil organic carbon (SOC), with the SOC storage in the soil surface and subsurface layers decreased by 13.2% and 18.0%, respectively. After 15 years' intensive management of Masoo bamboo plantations, the contents of soil water soluble carbon (WSOC), hot water soluble carbon (HWSOC), microbial carbon (MBC) and readily oxidizable carbon (ROC) were significantly decreased in the soil surface and subsurface layers. The soil N storage in the soil surface and subsurface layers in intensively managed Moso bamboo plantations increased by 50.8% and 36.6%, respectively. Intensive management significantly increased the contents of nitrate-N (NO3--N) and ammonium-N (NH4+-N), but decreased the contents of water-soluble nitrogen (WSON) and microbial biomass nitrogen (MBN). After 15 years' intensive management of Masoo bamboo plantations, the soil invertase, urease, catalase and acid phosphatase activities in the soil surface layer were significantly decreased, the soil acid phosphatase activity in the soil subsurface layer were significantly decreased, and other enzyme activities in the soil subsurface layer did not change. In conclusion, long-term intensive management led to a significant decline of soil organic carbon storage, soil labile carbon and microbial activity in Moso bamboo plantations. Therefore, we should consider the use of organic fertilizer in the intensive mana-gement process for the sustainable management of Moso bamboo plantations in the future. PMID- 29696842 TI - [Effects of wind speed on drying processes of fuelbeds composed of Mongolian oak broad-leaves.] AB - Water desorption processes of fuel beds with Mongolian oak broad-leaves were observed under conditions with various wind speeds but nearly constant air temperature and humidity. The effects of wind speed on drying coefficients of fuel beds with various moisture contents were analyzed. Three phases of drying process, namely high initial moisture content (>75%) of phase 1, transition state of phase 2, and equilibrium phase III could be identified. During phase 1, water loss rate under higher wind speed was higher than that under lower wind speed. Water loss rate under higher wind speed was lower than that under lower wind speed during phase 2. During phase 3, water loss rates under different wind speeds were similar. The wind effects decreased with the decrease of fuel moisture. The drying coefficient of the Mongolian oak broad-leaves fuel beds was affected by wind speed and fuel bed compactness, and the interaction between these two factors. The coefficient increased with wind speed roughly in a monotonic cubic polynomial form. PMID- 29696843 TI - [Estimation of birch forest LAI based on single laser penetration index of airborne LiDAR data.] AB - Forest leaf area index (LAI) is an important indicator to describe the forest canopy structure and growth status of trees. In this paper, the Yigen area of Inner Mongolia was selected as the study area. Taken full account of the differences among different echo types, the LiDAR point cloud data were split into different single lasers. Then, intensity normalization was implemented for LiDAR point cloud data with the range between sensor and target. Based on the normalized intensity data, a new laser penetration index, called single laser beam penetration index (LPIs), was calculated along with the calculation of traditional LPI. These two laser penetration indexes were used to estimate the forest LAI based on the theoretical model and empirical model on four different sampling scales (5, 10, 15, and 20 m), respectively, which aimed to improve the retrieval accuracy of forest LAI through laser beam splitting. The results showed that the forest LAI estimated from mean LPIs (LPImean) was obviously better than that from traditional LPI. In addition, both of the empirical [R2=0.80, mean absolute deviation (MAD)=0.11] and theoretical models (R2=0.77, MAD=0.16) achieved the best performances with sampling scale of 15 m. The mapping of birch forest LAI for the study area was derived by integrating both the advantages of best empirical and theoretical models. PMID- 29696844 TI - [Spatial-temporal process and characteristics of vegetation recovery after Wenchuan earthquake: A case study in Longxi River basin of Dujiangyan, China.] AB - Quantitative evaluation on the vegetation recovery after the earthquake is of great scienti-fic significance for local ecological system rebuilding and regional social-economic sustainable deve-lopment. By taking the Longxi River Basin in Dujiangyan of Sichuan Province as an example, and employing the MODIS NDVI time-series data, this paper illustrated the dynamic changes of the ve getation cover rates in Longxi River basin before and after the 5.12 Wenchuan Earthquake by using Landsat data, and then time-space characters of the recovery rates of the damaged vegetation was quantified structurally by referring the factors of river-system and terrain. The results showed that the recovery of impaired vegetation coverage worked well from a holistic point of view, but the response of vegetation coverage to earthquake disaster showed a lagging phenomenon. The recovery rate of damaged vegetation was significantly correlated to its distance to surrounding river systems, elevation, slope degree, and slope aspect. This finding could provide technical supports for decision-makers to intervene the recovering process after earthquake. PMID- 29696845 TI - [Carbon sequestration in soil particle-sized fractions during reversion of desertification at Mu Us Sand land.] AB - The aim of this study was to investigate the effects of carbon sequestration in soil particle-sized fractions during reversion of desertification at Mu Us Sand Land, soil samples were collected from quicksand land, semifixed sand and fixed sand lands that were established by the shrub for 20-55 year-old and the arbor for 20-50 year-old at sand control region of Yulin in Northern Shaanxi Province. The dynamics and sequestration rate of soil organic carbon (SOC) associated with sand, silt and clay were measured by physical fractionation method. The results indicated that, compared with quicksand area, the carbon content in total SOC and all soil particle-sized fractions at bothsand-fixing sand forest lands showed a significant increasing trend, and the maximum carbon content was observed in the top layer of soils. From quicksand to fixed sand land with 55-year-old shrub and 50-year-old arbor, the annual sequestration rate of carbon stock in 0-5 cm soil depth was same in silt by 0.05 Mg.hm-2.a-1. The increase rate of carbon sequestration in sand was 0.05 and 0.08 Mg.hm-2.a-1, and in clay was 0.02 and 0.03 Mg.hm-2.a-1 at shrubs and arbors land, respectively. The increase rate of carbon sequestration in 0-20 cm soil layer for all the soil particles was averagely 2.1 times as that of 0-5 cm. At the annual increase rate of carbon, the stock of carbon in sand, silt and clay at the two fixed sand lands were increased by 6.7, 18.1 and 4.4 times after 50-55 year-old reversion of quicksand land to fixed sand. In addition, the average percentages that contributed to accumulation of total SOC by different particles in 0-20 cm soil were in the order of silt carbon (39.7%)~sand carbon (34.6%) > clay carbon (25.6%). Generally, the soil particle-sized fractions had great carbon sequestration potential during reversion of desertification in Mu Us Sand Land, and the slit and sand were the main fractions for carbon sequestration at both fixed sand lands. PMID- 29696846 TI - [Diurnal variations of grassland evapotranspiration over different periods in the Pailugou basin in the upper reach of the Heihe River, Northwest China.] AB - Evapotranspiration (ET) is an important component of water cycle, but its measurement in high altitude mountainous region is quite difficult, resulting in the poor understanding of the temporal and spatial variations of actual ET in high altitude mountainous region. In this paper, a weighing lysimeter was used to measure the hourly ET in a grassland in the Pailugou basin in the upper reach of the Heihe River, Northwest China. Based on the measured data, diurnal variations of grassland ET over different periods were analyzed. Results indicated that snow and ice sublimation appeared during the freezing period, with a very different diurnal variation pattern compared with other three periods. During the period without sunshine, the amount of snow and ice sublimation was nearly constant. When the highest global radiation and lowest relative humidity appeared in the same period, the amount of snow and ice sublimation increased a little. The early growth period was a period when snow and ice started to melt, during which snowmelt evaporation and soil evaporation occurred at the same time. The growth period had the highest ET rate. Due to continuous rainfall events, maximum and minimum ET values appeared at the same hour. ET in the late growth period mainly came from soil evaporation, producing 3 peaks in diurnal variation, which was different from only one peak in both the early growth period and the growth period. PMID- 29696847 TI - [Effect of biochar addition on soil evaporation.] AB - In order to determine the rational amount of biochar application and its effect on soil hydrological processes in arid area, soil column experiments were conducted in the laboratory using three biochar additions (5%, 10% and 15%) and four different biochar types (d<0.25 mm bamboo charcoal, 0.25 mm leaf>root; when grown on a severe saline soil, Na+ distribution followed leaf>stem~thorn>root. The distribution of Ca2+ and Mg2+ followed leaf >thorn>stem>root. With the increase of soil salt level, Na+ content in different organs of A. sparsifolia increased, while K+ content in leave decreased; meanwhile the increasing soil salt level significantly decreased the K+/Na+ ratio in both root and leave, as well as the Ca2+/Na+ and Mg2+/Na+ ratios in all organs. The selective transportation coefficients for Ca2+-Na+ and Mg2+ Na+ followed order of stem-leaf>stem-thorn>root-stem under saline habitats. Based on the integrated analysis, in order to adapt to salinity habitat, A. sparsifolia could use multiple organs to accumulate Na+, depending on soil salt level. Na+ could accumulate in stem and thorn at a relative low level, but in leaves at high levels. Besides, Ca2+ and Mg2+ could be the inorganic osmotic adjustment substances for A. sparsifolia to adapt the saline environment. PMID- 29696849 TI - [Effects of different cultivation practices on composition, carbon and nitrogen distribution of soil aggregates in farmlands.] AB - The long-term experiments were conducted at two locations with different soil fertility. There were four treatments, including super high-yielding cultivation treatment (SH), high-yielding and high efficiency cultivation treatment (HH), local farmer's practice (FP), and control (CK), respectively. The field experiments were established to study the effects of different cultivation practices on composition, carbon and nitrogen distribution of tillage layer soil aggregates in different soil fertility, with the aim of proposing technological approaches to enhance soil fertility and achieve the sustainable development of increasing yield and efficiency in wheat-maize ecosystem. The results indicated that compared with treatments in low soil fertility (LSF), same treatments in high soil ferti-lity (HSF) had the higher mean mass diameter and geometric mean diameter, contents of organic carbon and total nitrogen, and lower fractal dimension in dried soil aggregates at soil tillage layer, which was beneficial to the formation and stability of large aggregate. Optimizing application of NPK fertilizers and the application of combined chemical fertilizer with organic fertilizer could increase the diameter of soil aggregate, reduce the fractal dimension of aggregate and promote the formation and stability of large aggregates, and the effect on HSF was greater than that on LSF; also they could improve the content and distribution of organic carbon and total nitrogen in large soil aggregate, the contribution rate to >5 mm aggregate in LSF was greater than in HSF, while the contribution rate to 5-0.5 mm aggregates in HSF was greater than in LSF. PMID- 29696850 TI - [Effects of residue management and fertilizer application mode on soil organic carbon pools in an oasis cotton region.] AB - To reveal the regulation mechanisms of agricultural management practices on soil organic carbon (SOC) pools and provide scientific basis for improving soil productivity and formulating agricultural fixed carbon and reducing discharge measures, we monitored the changes of SOC pools and organic carbon fractions in an oasis cotton field under different residue management and fertilizer application modes. A split-plot experimental design was used with differing residue management including residue incorporation (S) and residue removing (NS) in the main plots and differing fertilizer application modes including no fertilizer (CK), NPK fertilizer (NPK), organic manure (OM) and NPK fertilizer plus organic manure (NPK+OM) in the subplot. The results showed that fertilization and residue incorporation significantly increased SOC pool, soil organic carbon (CT), labile carbon (CL), microbial biomass carbon (CMB), water soluble organic carbon (CWS), hot-water-soluble organic carbon (CHWS), accumulative amount of soil organic carbon mineralization (CTM) and carbon management index (CMI). The SOC pool was increased by 20.6% by residue incorporation compared to residue removing. SOC pools were increased by 7.8%, 29.5% and 37.7% in NPK, OM and NPK+OM treatments compared to CK, respectively. The contents of CT, CL, CMB, CWS and CHWS under different fertilization treatments were shown as NPK+OM>OM>NPK>CK. CTM was increased by 5.9% by residue incorporation compared to residue removing and CTM was increased by 32.7%, 59.5% and 97.3% in NPK, OM and NPK+OM treatments compared to CK, respectively. There was a significant correlation between CMI and CT, CMB, CL, CWS, CHWS, CTM, C pool and C sequestration. Therefore, we concluded that CMI is an important index for evaluating the effect of agricultural management practices on soil quality. In order to construct high-standard oasis farmland in arid region and develop cotton production, we should consider adopting reasonable agricultural management practices (i.e. combining residue incorporation with NPK fertilizer plus organic manure), which could increase the content of SOC, organic carbon fractions and soil fertility, promote soil carbon sequestration, and help the efficient use of agricultural resources and sustainable deve-lopment. PMID- 29696851 TI - [Effect of grafting on rhizosphere soil environment and its relationship with disease resistance and yield of pepper.] AB - We investigated the effect of grafting on the root rhizosphere soil microorganisms, physical properties, nutrient content, soil-borne disease and yield of pepper, using 'Weishi' (WS) and 'Buyeding' (BYD) as rootstocks, the cultivar pepper 'Xinfeng 2' (XF) as scion, and the own-root (XF/XF) pepper as the control. The results indicated that XF/WS and XF/BYD significantly increased the populations of fungi and actinomycetes and the percentage of actinomycetes. 60 days after transplanting, the activities of catalase (CAT) and peroxidase (POD) were much higher in root rhizosphere soil of grafted pepper. 90 days after transplanting, the activities of phosphatase, invertase, urease, and nitrate reductase (NR) were much higher in root rhizosphere soil of XF/WS. In addition, The XF/WS and XF/BYD also highly increased hydrocarbon compounds in soil extraction, slightly increased electric conductivity (EC) but lowered nitrogen, phosphorus and potassium contents in root rhizosphere soil. Higher pH in root rhizosphere soil was found in XF/WS but not in XF/BYD. These data indicated that grafting could optimize the rhizosphere soil environment of pepper and enhance the resistance of soil-borne diseases. The yields of XF/WS and XF/BYD were increased by 40.8% and 28.7%, respectively. PMID- 29696852 TI - [Effects of maize and pea intercropping on the total grain yield of community under different planting densities.] AB - Under plastic-film fully-mulched ridge-furrow cropping, we studied the effects of within-row-intercropping on total grain yield of community using pea plants inserted into the maize rows with spacing of 40, 50 and 60 cm, respectively, in the Loess Plateau in 2014 and 2015. The result showed that there was significant increase in total grain yield of the community when two pea plants were inserted into the maize rows with spacing of both 40 and 50 cm, while pea plants inserted into the maize row with 60 cm spacing had no significant effects on total grain yield of the community compared to maize monoculture with the same plant spacing in 2014. In 2015, in contrast, when pea plants were inserted into the maize rows with plant spacing of 40 and 50 cm, no significant effect was observed even though there was an increasing trend in total grain yield of the community, while it increased significantly when two pea plants were inserted into the rows with spacing of 60 cm. The more abundant rainfall in 2014 than in 2015 induced the varied effects of intercropping pea plants on increasing the total grain yield of the community between the two cropping seasons. Gene-rally, the total grain yield of the community reached the highest under two pea plants intercropped with spacing of 40 cm. No matter whether in monocultures only with maize or in intercropping with both maize and peas, grain yield decreased significantly with increase of maize plant spacing in current experiment. PMID- 29696853 TI - [Effects of different baynyardgrass varieties on grain yield formation of rice at different nitrogen application levels.] AB - This study aimed to investigate the effects of different barnyardgrass varieties on yield formation of rice. A Japonica rice cultivar, Nanjing 9108, was used and co-cultured with three barnyardgrass varieties from transplanting to maturity under different nitrogen (N) levels of 0, 120, 240, and 360 kg N.hm-2, taking baynyardgrass free as control. The three barnyardgrass varieties were Echinochloa crusgalli var. mitis, E. crusgali var. zelayensis and E. colonum. The results showed that, at the same N level, the plant height of the three barnyardgrass varieties was E. crusgali var. zelayensis > E. crusgalli var. mitis > E. colonum, and the growth duration was E. crusgalli var. mitis > E. crusgali var. zelayensis > E. colonum. The biomass of baynyardgrass increased with the increase of N application rates and reached a peak at the N rate of 240 kg N.hm-2, and it decreased at 360 kg N.hm-2. The biomass of either E. crusgalli var. mitis or E. crusgali var. zelayensis was significantly higher than that of E. colonum. At the 0 kg N. hm-2 level, all barnyardgrass varieties showed no significant effect on rice yield. At the 120 kg N. hm-2 level, rice yield was not significantly different among the three treatments of barnyardgrass free, co-cultured with E. crusgalli var. mitis, and co-cultured with E. colonum, but it was significantly decreased when co-cultured with E. crusgali var. zelayensis. At the 240 kg N.hm-2 level, all treatments of co-cultured with barnyardgrass significantly decreased the rice yield. At the 360 kg N.hm-2 level, rice yield was significantly decreased under the treatments of co-cultured with E. crusgali var. zelayensis or with E. crusgalli var. mitis, and showed no significant difference between barnyardgrass free and co-cultured with E. colonum. All these data indicated an interaction between barnyardgrass and N fertilizer, which mediated the formation of grain yield of rice. Furthermore, at the 120 kg N. hm-2 level, the co-cultured E. crusgali var. zelayensis treatment significantly reduced leaf nitrate reductase activity and photosynthetic rate and root oxidation activity during the grain filling period, and decreased nitrogen accumulation and dry matter accumulation at the maturity stage, but other two treatments showed no significant effect when compared with barnyardgrass free treatment. These physiological indices of rice were significantly reduced by both E. crusgalli var. mitis and E. crusgali var. zelayensis treatments at either 240 or 360 kg N.hm-2 level, and showed no significant difference among all treatments at the 0 kg N.hm-2 level. Regression analysis showed that the order of effects of barnyardgrass phenotypes on rice grain yield was biomass, plant height, growth duration and tiller number. All these results suggested that the coexistence with large biomass of barnyardgrass inhibited the leaf photosynthetic rate, nitrate reductase activity, root oxidation activity, nitrogen accumulation and dry matter accumulation of rice, and consequently, reduced the rice grain yield. PMID- 29696854 TI - [Effects of potassium on nitrogen translocation and distribution and nitrogen metabolism enzyme activities of sweet potato.] AB - A pot experiment with 15N tracing techniques was designed to study the effect of potassium application on nitrogen transfer, photosynthetic characteristics and nitrogen metabolism enzyme activities in two different growth stages of sweet potato. Results indicated that potassium application significantly increased the shoot 15N distribution rate. Compared with control, the 15N transfer rate of K3 treatment increased by 76.2% and the total accumulation of 15N increased by 92.1% in tuber formation period. Different with tuber formation period, shoot 15N distribution rate decreased from 33.7% to 24.4%, but the root 15N distribution rate increased from 5.8% to 17% with the increase of K application in tuber rapid growth stage. Especially, root 15N accumulation of K3 treatment was 3 times of the CK. During the two growth stages, nitrate reductase, glutamate dehydrogenase, glutamine synthetase, glutamate synthase and net photosynthetic rate all increased with the increase of K application. Stepwise regression analysis showed that nitrogen metabolism enzyme activities (nitrate reductase, glutamate dehydrogenase, glutamine synthetase, glutamate synthase) and Pn were the main factors to affect the 15N transfer and distribution of sweet potato (R1=0.965,R2=0.942). Path analysis showed that nitrate reductase and glutamate dehydrogenase activities were the key factors to influence 15N distribution to the shoot in tuber formation period, while glutamate dehydrogenase, glutamate synthase activities were the key factors to influence 15N distribution to the tuber in tuber rapid growth stage. PMID- 29696855 TI - [Effects of light quality on growth, secondary metabolites, and oxidative stress tolerance of Gynura bicolor.] AB - The effects of white light, red light, blue light, yellow light, red+blue light and red+blue+yellow light on the growth and quality of Gynura bicolor were investigated under the same light intensity (350+/-5 MUmol.m-2.s-1) by using light-emitting-diodes (LEDs) which could accurately regulate light quality and light intensity. The results indicated that compared with white light, red light could significantly promote the growth of G. bicolor and induce the accumulation of dry substance and soluble sugar content, but blue light inhibited the plant growth. The content of chlorophyll significantly decreased under the colored LEDs. Although the combination of red, blue and yellow light did not increase the dry substance accumulation, it resulted in significant elevation of total phenols, flavonoids and anthocyanins. The accumulation of these reduced substances could increase the tolerance to oxidative stress and the nutrient value in G. bicolor. This study provided a theoretical basis for G. bicolor diverse production regulated by light quality. PMID- 29696856 TI - [Suitability of four stomatal conductance models in agro-pastoral ecotone in North China: A case study for potato and oil sunflower.] AB - The suitability of four popular empirical and semi-empirical stomatal conductance models (Jarvis model, Ball-Berry model, Leuning model and Medlyn model) was evaluated based on para-llel observation data of leaf stomatal conductance, leaf net photosynthetic rate and meteorological factors during the vigorous growing period of potato and oil sunflower at Wuchuan experimental station in agro pastoral ecotone in North China. It was found that there was a significant linear relationship between leaf stomatal conductance and leaf net photosynthetic rate for potato, whereas the linear relationship appeared weaker for oil sunflower. The results of model evaluation showed that Ball-Berry model performed best in simulating leaf stomatal conductance of potato, followed by Leuning model and Medlyn model, while Jarvis model was the last in the performance rating. The root mean-square error (RMSE) was 0.0331, 0.0371, 0.0456 and 0.0794 mol.m-2.s-1, the normalized root-mean-square error (NRMSE) was 26.8%, 30.0%, 36.9% and 64.3%, and R-squared (R2) was 0.96, 0.61, 0.91 and 0.88 between simulated and observed leaf stomatal conductance of potato for Ball-Berry model, Leuning model, Medlyn model and Jarvis model, respectively. For leaf stomatal conductance of oil sunflower, Jarvis model performed slightly better than Leuning model, Ball-Berry model and Medlyn model. RMSE was 0.2221, 0.2534, 0.2547 and 0.2758 mol.m-2.s-1, NRMSE was 40.3%, 46.0%, 46.2% and 50.1%, and R2 was 0.38, 0.22, 0.23 and 0.20 between simulated and observed leaf stomatal conductance of oil sunflower for Jarvis model, Leuning model, Ball-Berry model and Medlyn model, respectively. The path analysis was conducted to identify effects of specific meteorological factors on leaf stomatal conductance. The diurnal variation of leaf stomatal conductance was principally affected by vapour pressure saturation deficit for both potato and oil sunflower. The model evaluation suggested that the stomatal conductance models for oil sunflower are to be improved in further research. PMID- 29696857 TI - [Effects of reducing N, straw returning and dicyandiamide application on winter wheat yield and nitrogen budgets in rain-fed region.] AB - In a 3-year field experiment, effects of reducing N fertilizer, straw returning and dicyandiamide (DCD) application on wheat yield and nitrogen budgets under wheat-fallow system were studied in rain-fed region. The experiment was carried out in Yangling of Shaanxi Province, and 4 treatments were installed including no nitrogen (CK), 220 kg N.hm-2 and no straw returning (FP), 150 kg N.hm-2 and straw returning (OPT), 150 kg N.hm-2, 7.5 kg.hm-2 DCD and straw returning (OPT+DCD). The results showed there was no remarkable difference for wheat yield between OPT and FP, but the N use efficiency of the former was 6.1% more than that of the latter, and the apparent N loss ratio was 7.2% less. OPT+DCD increased the average yield of winter wheat by 10.4% and 7.9% respectively compared to OPT and FP, the N use efficiency of winter wheat increased by 20.8% and 28.1%, and the apparent N loss ratio decreased by 8.5% and 15.1%, respectively. NH4+-N content in 0-20 cm of soil increased, accordingly the NO3--N content decreased in 40 to 45 days when DCD was applied. PMID- 29696858 TI - [Effects of temperature on leaf lettuce vernalization.] AB - To investigate the effects of different temperatures on the vernalization of leaf lettuce, and declare their type, two easy bolting leaf lettuce varieties of GB-30 and GB-31 were selected as material, which were treated by 4 C, 20 C and 25 C for 20 d respectively and afterwards treated by high temperature stress. The process of flower bud differentiation was observed by using paraffin section technology, and combined the condition of bolting and flowering to estimate whether or not it underwent vernalization, and defined its vernalization type. The results showed that, two varieties of GB-30 and GB-31 appeared bolting to different degrees at the 8th day under high temperature stress after temperature treatments in the early stage. Different temperatures in the early stage all made flower bud differentiated of two varieties. 4 C treatment did not advance the flower bud differentiation, while the high temperature in later time accelerated this progress. Furthermore, the days required for the two varieties to complete development stages differed under different temperature treatments. The effective accumulated temperature whether from pregermination to flowering or from high temperature stress to flowering of two varieties were also different. The leaf lettuce without low temperature treatment in early stage could enter into the flower bud differentiation, bolting, budding and flowering stages, and it could be considered as non-low temperature vernalization plant. The high temperature treatment in later stage could obviously promote its bolting and flowering. In addition, the effective accumulated temperature had to reach about 2500 C.d from germination to blossom. PMID- 29696859 TI - [Potential distribution of Panax ginseng and its predicted responses to climate change.] AB - This study utilized Panax ginseng as the research object. Based on BioMod2 platform, with species presence data and 22 climatic variables, the potential geographic distribution of P. ginseng under the current conditions in northeast China was simulated with ten species distribution model. And then with the receiver-operating characteristic curve (ROC) as weights, we build an ensemble model, which integrated the results of 10 models, using the ensemble model, the future distributions of P. ginseng were also projected for the periods 2050s and 2070s under the climate change scenarios of RCP 8.5, RCP 6, RCP 4.5 and RCP 2.6 emission scenarios described in the Special Report on Emissions Scenarios (SRES) of IPCC (Intergovernmental Panel on Climate Change). The results showed that for the entire region of study area, under the present climatic conditions, 10.4% of the areas were identified as suitable habitats, which were mainly located in northeast Changbai Mountains area and the southeastern region of the Xiaoxing'an Mountains. The model simulations indicated that the suitable habitats would have a relatively significant change under the different climate change scenarios, and generally the range of suitable habitats would be a certain degree of decrease. Meanwhile, the goodness-of-fit, predicted ranges, and weights of explanatory variables was various for each model. And according to the goodness-of-fit, Maxent had the highest model performance, and GAM, RF and ANN were followed, while SRE had the lowest prediction accuracy. In this study we established an ensemble model, which could improve the accuracy of the existing species distribution models, and optimization of species distribution prediction results. PMID- 29696860 TI - [Allelopathic effects of phenolic compounds of ginseng root rhizosphere on Cylindrocarpon destructans.] AB - In this study, five phenolic compounds of ginseng rhizosphere soil were identified by HPLC, including gallic acid, salicylic acid, 3-phenylpropionic acid, benzoic acid and cinnamic acid. The results show that five phenolic compounds inhibited mycelium growth and spore germination at high concentration, but promoted mycelium growth and spore germination at low concentration. Gallic acid, salicylic acid, benzoic acid of 0.5 mmol.L-1 and 3-phenylpropionic acid, cinnamic acid of 0.05 mmol.L-1 could significantly promote the spore germination, mycelium growth and disease severity of Cylindrocarpon destructans. PMID- 29696861 TI - [Effects of different amendments on contents of phenolic acids and specific microbes in rhizosphere of Pseudostellaria heterophylla.] AB - Pseudostellaria heterophylla is a perennial herbaceous plant in the family Caryophyllaceae. The tuberous roots of P. heterophylla are highly valued in traditional Chinese medicine and have a high market demand. However, extended monoculture of P. heterophylla results in a significant decline in the biomass and quality, and escalates disease and pest problems. Therefore, it is important to understand the underlying mechanism and biocontrol methods for consecutive monoculture problems. With "Zheshen 2" as an experimental material, the changes in the contents of main nutrients in soil, phenolic acids and specific microbes under monoculture and different amendments were analyzed by using high performance liquid chromatography (HPLC) and qPCR. The results showed that consecutive monoculture of P. heterophylla led to a decrease in yield by 43.5% while the microbial fertilizer treatment and the paddy-upland rotation could relieve the consecutive monoculture problems. Available nitrogen, available phosphorus, available potassium and total potassium were significantly higher in the consecutively monocultured soils than in the newly planted soils. But consecutive monoculture resulted in soil acidification. HPLC analysis showed that conse-cutive monoculture of this plant did not lead to a consistent accumulation of soil phenolic acids. At middle stage of root expansion and at harvest stage, most of phenolic acids were even higher in the newly planted soils than in the consecutively monocultured soils. Furthermore, qPCR analysis showed that the amounts of three specific pathogens identified previously (i.e. Fusarium oxysporum, Talaromyces helicus, Kosakonia sacchari) were significantly higher in the consecutively monocultured soils than in the newly planted soils. However, the microbial fertilizer treatment and the paddy-upland rotation resulted in a significant decline in the population of these specific pathogens and improved the soil environment. In conclusion, the consecutive monoculture problems of P. heterophylla may be due to the rapid proliferation of host-specific pathogens, rather than the deficiency of soil nutrients and the autotoxicity of allelochemicals in root exudates. The results in this study could provide the theoretical basis to explore the underlying mechanism of replanting disease of P. heterophylla and its biocontrol strategies. PMID- 29696862 TI - [Assessment on heat island effect based on urban regulatory planning.] AB - With the improved legal status of urban planning, regulatory detailed planning is playing an increasingly important role in guiding land leasing and regulating the spatial structure of urban construction. Understanding the effect of regulatory planning indices on urban heat island (UHI) and evaluating the heat environment performance of indices combination at the scale of regulatory planning unit and plot are of great significance for assessing the thermal environment effect of regulatory planning quantitatively and putting forward action plans to mitigate heat island impacts. In this study, we assessed impacts of main urban regulation indices and their combinations on UHI by analyzing land surface temperature (LST) data, retrieved through the thermal infrared remote sensing image (Landsat8 TIRS), using statistical and GIS spatial analysis methods. Results indicated that the indices of green ratio, plot area, building density and building height all had a significant impact on LST at regulatory planning unit level. By generating 3D models, we found the regulation index combination with round 30% of green ratio, and 2.5-3.5 of floor area ratio had the minimal impact on urban thermal environment at regulatory plot. The outcomes provided a new perspective on the rational improvement of urban regulatory planning. PMID- 29696863 TI - [Evaluation on spatial structure and rationality of city parks based on goal of disaster prevention: An application of proximal area method in Changchun, China.] AB - Urban shelter parks as one of the important urban elements are a main form of emergency shelters for a city. This study evaluated the spatial distribution of urban parks in Changchun City with the proximal area method based on disaster prevention goal. Results showed that the spatial distribution of urban shelter parks was unbalanced, with high concentration in the northwest and low concentration in the southeast. The spatial distribution of urban shelter parks of the same grade was concentrated, but the different grades were scattered. The validity of urban shelter parks was low. More than 50% of the park's per capita refuge area was insufficient. For nearly 40% of the parks, their accessibility was longer than the longest evacuation time. There were significant differences in effectiveness for urban parks of different grades. The urban shelter parks for central disaster prevention were the best, followed by the designated urban shelter parks, whereas urban shelter parks for emergency disaster prevention were the least effective. In view of the layout unreasonable situation of disaster prevention parks in Changchun City, we made following recommendations: the spatial distribution of nesting urban shelter parks with different grades should be used; standards set for urban shelter parks should evolve with population; and the construction of urban shelter parks for emergency disaster prevention should be strengthened. PMID- 29696864 TI - [Change and prediction of the land use/cover in Ebinur Lake Wetland Nature Reserve based on CA-Markov model.] AB - Taking Ebinur Lake Wetland Nature Reserve as the study area, and based on the classified result of Landsat TM images of 1998, 2006, and Landsat OLI images of 2014, this paper simulated and forecasted land use/cover types of Ebinur Lake Wetland Nature Reserve by using the CA-Markov model. In the model-building process, the transition probability matrix and the transition area matrix were obtained through the Markov model, which determined the conversion rules and iterative times of the CA model. The land use/cover pattern of the study area in 2014, 2022 and 2030 was simulated and forecasted with the CA-Markov model. Then the forecast result was compared with the actual classified data of 2014 to verify the forecast accuracy. The prediction error of land use/cover type area was not more than 6.4% in 2014, and the spatial location accuracy was 76.0%. The results showed that the forest and grassland, saline-alkali area, dry lake bed and desert had an increasing trend in 1998-2014. The saline-alkali area increased the most by 37.4% and the water body decreased by 34.8%. In 2014-2030, the areas of the forest and grassland, saline-alkali soil and desert would increase, while that of the dry lake bed, water body and other objects would decrease. This study could provide a basis for dynamic monitoring land use/cover as well as sustainable development of Ebinur Lake Wetland Nature Reserve. PMID- 29696865 TI - [Characteristics of rainfall and runoff in urban drainage based on the SWMM model.] AB - The characteristics of 235 rainfall and surface runoff events, from 2009 to 2011 in a typical urban drainage area in Shanghai were analyzed by using SWMM model. The results showed that the rainfall events in the region with high occurrence frequency were characterized by small rainfall amount and low intensity. The most probably occurred rainfall had total amount less than 10 mm, or mean intensity less than 5 mm.h-1,or peak intensity less than 10 mm.h-1, accounting for 66.4%, 88.8% and 79.6% of the total rainfall events, respectively. The study was of great significance to apply low-impact development to reduce runoff and non-point source pollution under condition of less rainfall amount or low mean rainfall intensity in the area. The runoff generally increased with the increase of rainfall. The threshold of regional occurring runoff was controlled by not only rainfall amount, but also mean rainfall intensity and rainfall duration. In general, there was no surface runoff when the rainfall amount was less than 2 mm. When the rainfall amount was between 2 to 4 mm and the mean rainfall intensity was below 1.6 mm.h-1, the runoff was less than 1 mm. When the rainfall exceeded 4 mm and the mean rainfall intensity was larger than 1.6 mm.h-1, the runoff would occur generally. Based on the results of the SWMM simulation, three regression equations that were applicable to regional runoff amount and rainfall factors were established. The adjustment R2 of the three equations were greater than 0.97. This indicated that the equations could reflect well the relationship between runoff and rainfall variables. The results provided the basis of calculations to plan low impact development and better reduce overflow pollution in local drainage area. It also could serve as a useful reference for runoff study in similar drainage areas. PMID- 29696867 TI - [Ecological fitness of transgenic GAFP cotton and its effects on the field insect community.] AB - The ecological fitness of transgenic cotton and its effects on the insect communities in cotton fields is one of the key aspects of the evaluation of the environmental safety of transgenic cotton. New transgenic GAFP (Gastrodia anti fungal protein) cotton and its parental varieties were used in this study to explore their ecological fitness and their effects on insect community infield in Anyang, Henan Province in 2013 and 2014. The results showed that there was no significant difference in dry mass for transgenic cotton leaves compared to that of parental cotton. Specific leaf areas of transgenic cotton were lowered obviously at seedling stage, while enhanced significantly at budding, flowering and bolling stages relative to parental cotton. The plant height of transgenic cotton was lowered only at seedling stage, and no significant difference was showed between the two cultivars at budding, flowering and bolling stages. No significant differences were discovered on plant branch numbers, bud numbers and falling numbers between the transgenic cotton and control material in any of the four key stages during the cotton growth. However, the number of bolls per plant for transgenic cotton was lower than that of the control cotton at the bolling stage. In the 2nd, 3rd, and 4th generation of cotton bollworm (Helicoverpa armigera), the mortality rate of cotton bollworm and beet armyworm (Spodoptera exigua) of transgenic cotton had no significant difference with parental cotton. Compared to parental cotton, total individuals of insect community, pest sub communities and enemy sub-communities in transgenic cotton field didn't show any significant difference. The above results showed that after the GAFP gene was imported into cotton, the cotton growth was enhanced significantly, while the whole yield component traits and the insect community in the field were not significantly changed. Our study on the competition of new transgenic cotton and survival of transgenic cotton insect communities in cotton field would provide the theoretical basis for the evaluation of new transgenic cotton and environmental safety, and accumulate scientific data for environmental safety evaluation of the transgenic cotton. PMID- 29696868 TI - [Effects of increased precipitation and nitrogen deposition on ground-active arthropods in an old-field of Huanghuaihai Plain.] AB - As the important driving factors of global change, changing precipitation and nitrogen (N) deposition play a key role in affecting our terrestrial ecosystem. However, most previous stu-dies focused on the aboveground plant community. The soil fauna, especially the ground-active arthropods were poorly understood. Using field manipulative experiment, this paper studied the effects of increased precipitation and N deposition on the soil ground-active arthropods in an old field ecosystem of the Huanghuihai Plain. The results showed that the increased precipitation significantly enhanced the soil arthropods population density and the number of groups by 66.9% and 27.8%, respectively. Nitrogen deposition had minor effect on soil arthropods population density and number of groups, but significantly increased the formicidae and decreased the collembolans. Our results indicated the changing precipitation was the more important factor than the N deposition to restructure the soil surface arthropod community by increasing soil moisture and stimulating plant growth in the old-field of north China plain. PMID- 29696866 TI - [Effect of Bt rice straw returning in soil on the growth and reproduction of Eisenia fetida.] AB - Bacillus thuringiensis (Bt) protein can enter the soil through Bt crops straw returning to field, which may affect the growth and reproduction of soil animals, such as earthworms. Here, Bt rice (b2B138) and conventional rice (Anfeng A) straw were returned in soil to evaluate the impact of Bt rice on Eisenia fetida. Two varieties of rice straw were added into soil to breed E. fetida at the rates of 2.5%, 5%, 7.5% and 10%. The survival rate, relative growth rate, reproduction of earthworm, the Cry1Ab content in soil-straw mixture and earthworm were detected after 7, 15, 30, 45, 60, 75, 90 d. The results showed that Bt rice straw returning at higher concentrations (7.5% and 10%) inhibited the survival rate of E. fetida. Bt rice straw returning had no adverse effect on relative growth rate (RGR) of E. fetida. Bt rice straw treatment improved the reproduction of earthworms under 5%, 7.5% and 10% straw returning in soil. Enzyme-linked immunosorbent assay (ELISA) results indicated that immunoreactive Cry1Ab was detectable in soil-straw mixture and E. fetida from Bt rice treatments, and a strong decline was observed in soil-straw mixture with the increase of treated time. Therefore, Cry1Ab released from Bt rice straw returning at 2.5% and 5% concentration had no adverse effects on the growth and reproduction of E. fetida. PMID- 29696869 TI - [Contribution of soil fauna to litter decomposition of Abies faxoniana and Rhododendron lapponicum across an alpine timberline ecotone in Western Sichuan, China.] AB - Soil fauna is an important biological factor in regulation litter decomposition. In order to quantify the contributions of soil fauna to the mass losses of litter of two dominant species fir (Abies faxoniana) and rhododendron (Rhododendron lapponicum) in the alpine timberline ecotone (coniferous forest-timberline-alpine meadow) of western Sichuan, China, a field litterbag experiment was conducted from May 2013 to November 2014. Samples of air-dried leaf litter were placed in nylon litterbags of two different mesh sizes, i.e. 3.00 mm (with the soil animals) and 0.04 mm (excluded the soil animals). The results showed that the decomposition rate of A. faxoniana (k: 0.209-0.243) was higher than that of R. lapponicum (k: 0.173-0.189) across the timberline ecotone. Soil fauna had significant contributions to litter decomposition of two species, the contributions of soil fauna to mass loss showed a decreasing trend with increasing altitude. From the coniferous forest to the alpine meadow, the mass losses caused by soil fauna for the fir litter accounted for 15.2%, 13.2% and 9.8%, respectively and that for the rhododendron litter accounted for 20.1%, 17.5% and 12.4%, respectively. Meanwhile, the daily average contributions caused by soil fauna for the fir and rhododendron litter decomposition accounted for 0.17%, 0.13%, 0.12% and 0.26%, 0.25%, 0.23%, respectively. Relatively, soil fauna had more influence on alpine rhododendron decomposition. Two-way ANOVA showed that species, altitude and their interaction had significant impact on the litter mass loss and decomposition rate caused by soil fauna. The daily average contribution caused by soil fauna for the fir and rhododendron litter decomposition accounted for 0.25% and 0.44% in the first growing season, then 0.10% and 0.19% in the second growing season, both were higher than that of snow covered season (0.07% and 0.12%). Regression analysis showed that the environmental factors (daily average temperature, freezing and thawing cycles and snow thickness) explained 42.7% and 50.9% in the mass loss as well as 43.2% and 55.6% in the contribution rate of fir and rhododendron litter decomposition. These results suggest that soil fauna contributes strongly to litter decomposition in the alpine ecosystem, and it is of great significance to thorough understanding and recognizing material cycle through the role of soil fauna in the litter decomposition. PMID- 29696870 TI - [Sublethal effects of spinetoram and azadirachtin on development and reproduction of Frankliniella occidentalis (Pergande).] AB - To evaluate the sublethal effects of spinetoram and azadirachtin on western flower thrips, Frankliniella occidentalis, leaf dipping method was used to determine their sublethal concentrations (LC25) on the 2nd instar nymph, and their influences on development and reproduction of F. occidentalis were studied. The results showed exposure of sublethal concentrations of spinetoram and azadirachtin to F. accidentalis had different degrees of effects on this insect pest. Under bisexual reproduction, the LC25 spinetoram had no significant influences on pre-oviposition period, female adult longevity and fecundity, but male adult longevity was significantly shorter than the control. The LC25 azadirachtin significantly reduced fecundity and prolonged pre-oviposition period. Under parthenogenesis, the LC25 spinetoram and azadirachtin extended the pre-oviposition duration, whereas the LC25 azadirachtin shortened the female adult longevity and significantly decreased fecundity. The LC25 spinetoram and azadirachtin had different influences on developmental duration of each stage of next generation. The immature stage in treatment group of the LC25 spinetoram was shorter than that in treatment group of the LC25 azadirachtin, under bisexual reproduction or parthenogenesis. Intrinsic rate of increase (rm) and finite rate of increase (lambda) of population treated by the LC25 spinetoram were higher than those of the control, whereas the rm, R0, and lambda of population treated by the LC25 azadirachtin were lower than those of the control. The findings indicated that the effects of the LC25 spinetoram and azadirachtin on the development and reproduction of F. accidentalis were different. The LC25 spinetoram had certain stimulating effect, whereas the LC25 azadirach-tinon had significant inhibitory effect. Two biopesticides' influences were related with the reproductive patterns of F. accidentalis. PMID- 29696871 TI - [Screening, identification and phosphate-solubilizing characteristics of phosphate-solubilizing bacteria strain D2 (Pantoea sp.)in rhizosphere of Pinus tabuliformis in iron tailings yard.] AB - Two strains of phosphate-solubilizing bacteria were isolated from the rhizosphere of Pinus tabuliformis in iron tailings vegetation restoration areas in Malan Town, Qianan City, Hebei Pro-vince. The bacterial strain D2 with strong phosphate solubilizing capacity was obtained via screening with plate and shake flask. Based on the morphology, physiology and biochemistry, and the sequence analysis of 16S rDNA, the D2 was identified as a member of Pantoea sp. A fermentation experiment was conducted to investigate the effect of carbon and nitrogen sources on the phosphate-solubilizing capacity of the strain D2; under different nitrogen sources, the organic acids in liquid culture, as well as their types and contents were determined by high performance liquid chromatography. The results showed that the strain D2 was capable of efficiently solubilizing tricalcium phosphate, and the highest value of available phosphorus was up to 392.13 mg.L-1 in liquid culture. The strain D2 displayed the strongest phosphate-solubilizing capability when glucose and ammonium sulfate were used as carbon and nitrogen sources in the culture media, respectively. Under varied nitrogen sources, the resulting organic acids and their types and contents were different. When the nitrogen source in culture media was ammonium sulfate, ammonium chloride, potassium nitrate, sodium nitrate or ammonium nitrate, all four organic acids, including oxalic acid, formic acid, acetic acid and citric acid, were produced. In addition, malic acid was uniquely produced when ammonium sulfate, ammonium chloride or ammonium nitrate was used as the nitrogen source. By Pearson's correlation analysis, a significant positive correlation between the acetic acid content and the available phosphorus content was found (r=0.886, P<0.05), suggesting that acetic acid produced by strain D2 played an important role in promoting inorganic phosphorus dissolution, which was most likely to be one of the important phosphate-solubilizing mechanisms of the strain. PMID- 29696872 TI - [Predation of Poratrioza sinica Yang Li by the adults of Coccinella septempunctata.] AB - To study predation by Coccinella septempunctata adults on 4 stages of Poratrioza sinica Yang Li, predation functional response, mutual interference, density influence and preference of C. septempunctata on P. sinica were investigated in laboratory and preying effect in field. The study indicated that functional response of adult C. septempunctata to P. sinica could be fitted by Holling 2 model, the daily maximum numbers of P. sinica eggs, 1st-2nd instar nymphs, 3rd 5th instar nymphs and adults preyed theoretically by the adult C. septempunctata were 112.6, 536, 415 and 113.9, respectively. In 30 days of adult's life cycle, density of P. sinica inside cages could be decreased by 80.1% in the field. Searching efficiency of C. septempunctata to P. sinica 1st-2nd instar nymphs was 0.9451 and processing time was 0.001865, which were better than those of other stages. The maximum rate of P. sinica 1st-2nd instar nymphs preyed was 80.2% as the prey density was 100 heads per dish, so the ratio of predator: prey was 1:100. The density had a greater impact than mutual interference on C. septempunctata. When different stages of P. sinica co-existed equally, C. septempunctata preferred P. sinica adult in 100 heads per dish while P. sinica nymphs in 300 heads per dish. The study showed that C. septempunctata has the potential to be predator of P. sinica and the newly-hatched nymphs could be controlled more effectively by C. septempunctata adult in field. PMID- 29696873 TI - [Diurnal activity pattern and seasonal variations of captive Papio hamadryas.] AB - Activity rhythms and time budgets are two important components of ecological influences on animal individual behaviors. We collected data on activity pattern using instantaneous scan sampling on captive hamadryas baboons (Papio hamadryas) in Hangzhou Wild Animal Zoo in Zhejiang, China from November 2012 to October 2013. The results showed that: 1) In the activity time allocation, the main activities (frequency percentage was more than or equal to 5%) included resting (42.5%), traveling (16.2%), playing (10.0%), feeding (9.8%), grooming (9.4%) and watching (7.3%), and the secondary activities (frequency percentage is lower than 5%) only accounted for a total of 4.8%. 2) Due to increasing in the feeding and watching time, and decreasing in the playing and grooming time in winter, their time budgets showed significant seasonal variation, but the resting and swimming time had no significant difference between the cold season and the warm season. 3) The diurnal activity rhythms of P. hamadryas showed two feeding peaks of morning and afternoon, and as the temperature gradually turned cold, feeding activity gradually increased with three feeding peaks, which might be a strategy of complementary energy against the cold season. 4) P. hamadryas only had a midday resting and grooming peak with multi peaks of traveling and playing in the warm season, and the swimming, playing and watching time rhythm had not obvious difference between the cold winter and the warm season, but there were multi peaks of resting in the cold winter. Therefore, their diurnal activity rhythm was not the same as other many primates (such as Nomascus nasutus, Propithecus verreauxi and Lagothrix sp.), the captive P. hamadryas in winter in Hangzhou area took a strategy of feeding for supplement energy to withstand cold rather than resting to reduce energy consumption. In short, Papio hamadryas reflects obvious rhythm with seasonal differences, which may be an adaptation to the influence of food and temperature changes in captivity. PMID- 29696874 TI - [Advances in research on mechanisms of seed pre-treatments.] AB - Seeds play a vital role in nature and agro-ecosystems. The success of seed germination and the establishment of a normal seedling determine the propagation and survival of a plant species, but seed vigor is often seriously damaged because of seed aging, dormancy and the deterioration of natural habitat. Thus, exploring methods for improving germination quality is of great significance to ecology and the economy. Based on the latest international reports, seed pre treatments are the most practical and effective methods for improving plant performance, increasing yields and enhancing stress resistance. This review provided a summary of the current pre-sowing treatment technologies and the physiological and biochemical responses of plants to these methods by addressing gene expression, cytological effects, enzyme system activities, material and energy metabolism, antioxidation mechanisms and signal transduction pathways. We also interpreted the mechanisms of the seed pre-treatment methods from aspects of seed germination acceleration and stress resistance enhancement. The bottleneck in seed pre-treatments at the cytological and molecular levels and the problems involved in their application were also discussed. Thus far, most studies had largely focused on the partial reaction alterations of plant biochemistry and enzyme activities, and they had generally been characterized by a lack of systematic and holistic study for applications to crop production. Finally, we proposed an outlook for further study in an attempt to provide a prospective and scientific reference for plant germplasm conservation, high-efficiency organic agriculture development and ecological environment re-construction. PMID- 29696875 TI - [Niche analysis of dominant species of forest community in Xiaowutai Mountain, China]. AB - This paper analyzed the niche breadth and niche overlap of dominant species of forest community in Xiaowutai Mountain, and fitted the response patterns of dominant species to the environment gradients by generalized additive models. The results showed that a total of 392 species of vascular plants, belonging to 222 genera, 75 families were recorded in 148 quadrats. A total of 36 dominant species were selected from the tree layer, shrub layer and herb layer by importance va lues. Betula albosinensis, Betula platyphylla, Larix principis-rupprechtii, Pinus tabuliformis at the tree layer, Spiraea pubescens, Abelia biflora, Rosa bella, Corylus mandshurica at the shrub layer, Carex breviculmis, Deyeuxia arundinacea, Sanguisorba officinalis, Carex siderosticta at the herb la-yer had higher niche breadth, and these species had greater competitiveness and stronger environmental adaptability. In the same layer, niche overlap index was high indicating that species had similar habitats, and there was competitive relationship between them. Although Acer momo and Quercus wutaishanica had high niche overlap, their competition was not strong in the condition of rich resources. There was niche overlap between B. platyphylla and a variety of mixed tree species including A. momo, Q. wutaishanica, Sorbus alnifolia, and limited resources leaded to strong competition in these communities. The adaptability of each species to environmental factors was diffe-rent. The response of most dominant species to altitude showed a single peak curve, and they distri-buted within a certain altitude range. The response of some dominant species to altitude was linearly increased or decreased, and concentrated at high altitudes or low altitudes. The response of dominant species to slope position was similar to altitude. The dominant species showed a linear change along the slope, showed significantly positive correlation with soil temperature, and showed the cha-racteristics of shade-requiring or sunny-requiring. The response of B. albosinensis, A. biflora, H. bretschneideri, C. breviculmis, C. dahurica to litter layer thickness and soil thickness showed linearly increased. The response of L. principis-rupprechtii, B. albosinensis, P. fruticosa, D. arundinacea to soil moisture showed linearly increased, while linearly decreased to soil electrical conductivity. Most dominant species to soil pH and environmental disturbance showed a single peak curve, and the others showed linearly decreased. PMID- 29696876 TI - [Fine root production and turnover of Pinus massoniana and their influencing factors in the Three Gorges Reservoir Area, China]. AB - In this study, the annual production and turnover rate of fine root of Pinus massoniana in Three Gorges Reservoir Area were calculated using sequential soil core,litterbag and compartment flux model methods, and the relationship between fine root production, turnover rate and factors was analyzed. The results showed that the annual mean biomass of <0.5, 0.5-1 and 1-2 mm fine root was 0.29, 0.59 and 0.76 t.hm-2, annual production was 0.13, 0.49, 0.37 t.hm-2, and annual turnover rate was 1.49, 1.01, 0.40 a-1, respectively. The effects of factors on production and turnover of fine roots with different diameters were different. Soil temperature and soil Ca content had significant effects on production and turnover of <0.5 mm fine roots, and soil temperature explained the variation of production and turnover by 32.8% and 25.0%, and soil Ca content explained by 65.6% and 73.1%, respectively. There was a positive relationship between fine root biomass and fine root production, and the biomass of fine root explained 41.0%, 41.1% and 54.5% of variation in fine root production for <0.5, 0.5-1 and 1 2 mm fine roots, respectively. P and K contents of fine roots correlated significantly with <0.5 mm fine root production, and explained 32.2% and 39.2% of the variation of <0.5 mm fine root production, respectively. The fine root with diameter <0.5 mm was most closely associated with soil factors, and soil temperature and soil Ca content were the main factors affecting fine root biomass. PMID- 29696877 TI - [Physiological responses of Salix rehderiana and Populus cathayana grafted seedlings to nitrogen deficiency]. AB - Morphological and physiological responses of Salix plants are different from Populus to nitrogen (N) deficiency. In this study, grafting technology was used in S. rehderiana and P. cathayana to investigate the graft compatibility of Salix and Populus, and whether grafting could improve the resistance to N deficiency in Salicaceae plants. The survival rate, growth, biomass accumulation and allocation, gas exchange parameters and non-structural carbohydrates (NSCs) were measured to evaluate the resistance to N deficiency among different grafting combinations. The results showed that the graft compatibility between S. rehderiana and P. cathayana was quite high. The survival rate was 74% and 96% in S/P (S. rehderiana was used as scions and P. cathayana as rootstocks) and P/S (P. cathayana was used as scions and S. rehderiana as rootstocks) combinations, respectively. N deficiency reduced the survival rate in all grafting combinations, which were 53.3% and 86.7% in S/P and P/S, respectively. The survival rate of S/P was lower than that of the other grafting combinations. Under control and N-deficient conditions, the height, basal diameter, biomass and net photosynthetic rate (Pn) of P/P and P/S combinations were higher than those of S/S and S/P combinations. N deficiency significantly reduced growth rate, biomass accumulation and Pn in all grafting combinations. The rate between root biomass and aboveground biomass of S. rehderiana rootstock combinations (S/S and P/S) was significantly higher than those of P. catha-yana rootstock combinations (P/P and S/P) under both control and N-deficient conditions. It indicated that more photosynthates might be allocated to belowground in S. rehderiana, while to aboveground in P. cathayana. The NSCs in roots of all grafting combinations were more sensitive to N deficiency than in stems and leaves. Except for the S/P combination, the starch, fructose, sucrose and total soluble sugar concentrations were significantly increased in roots in P/P, S/S and P/S combinations. Additionally, under N-deficient condition, the NSCs contents were significantly higher in P/P and P/S combinations than in S/S and S/P combinations. PMID- 29696878 TI - [Carbon density distribution characteristics and influencing factors in aerially seeded Pinus massoniana plantations]. AB - The distribution characteristics of carbon density under aerially seeded Pinus massoniana plantations in Ganzhou City of Jiangxi Province were studied. Total 15 factors, including site, stand, understory vegetation, litter and so on were selected to establish a relationship model between stand carbon density and influencing factors, and the main influencing factors were also screened. The results showed that the average carbon density was 98.29 t.hm-2 at stand level with soil layer (49.58 t.hm-2) > tree layer (45.25 t.hm-2) > understory vegetation layer (2.23 t.hm-2) > litter layer (1.23 t.hm-2). Significantly positive correlations were found among the tree, litter and soil layers, but not among the other layers. The main factors were tree density, avera-ge diameter at breast height (DBH), soil thickness, slope position, stand age and canopy density to affect carbon density in aerially seeded P. massoniana plantations. The partial correlation coefficients of the six main factors ranged from 0.331 to 0.434 with significance by t test. The multiple correlation coefficient of quantitative model I reached 0.796 with significance by F test (F=9.28). For stand density, the best tree density and canopy density were 1500-2100 plants.hm 2 and 0.4-0.7, respectively. The moderate density was helpful to improve ecosystem carbon sequestration. The carbon density increased with increasing stand age, DBH and soil thickness, and was higher in lower than middle and upper slope positions. PMID- 29696879 TI - [Impact of short-term grazing disturbance on nitrogen accumulation of biological soil crusts in the hilly Loess Plateau region, China]. AB - The variations of total nitrogen, available nitrogen and microbial biomass nitrogen caused by simulated grazing disturbance were investigated in the sixth and twelfth months by using field survey combined with laboratory analysis in order to reveal the sensitivity of nitrogen content in biocrustal soils to disturbance in the hilly Loess Plateau region. The results showed that nitrogen contents in biocrustal soil were sensitive to disturbance. Total nitrogen and available nitrogen in the biocrustal layers were decreased by 0.17-0.39 g.kg-1 and 1.78-5.65 mg.kg-1 during the first half-year compared to the undisturbed treatment, and they were found respectively decreased by 0.13-0.40 g.kg-1 and 11.45-32.68 mg.kg-1 one year later since disturbance. The content of microbial biomass nitrogen in the biocrustal layer was reduced by 69.99-330.97 mg.kg-1, whereas the content was increased by 25.51-352.17 mg.kg-1 in soil of 0-2 cm layer. The induction of nitrogen accumulation depended on the intensity of disturbance. Slight variation was observed in the nitrogen accumulation in biocrustal layer under 20% and 30% disturbance, while significant reduction was found in the 40% and 50% disturbance. Significant reduction was detected only in nitrogen accumulation in the biocrustal layers, whereas no significant influence was found in the top 5 cm soil layer. PMID- 29696880 TI - [Soil propagule bank of ectomycorrhizal fungi in natural forest of Pinus bungeana]. AB - To conserve and restore the forest of Pinu bungeana, we investigated the soil propagule bank of ectomycorrhizal (ECM) fungi in a severely disturbed natural forest of P. bungeana in Shaanxi Province, China. We used a seedling-bioassay method to bait the ECM fungal propagules in the soils collected from the forest site. ECM was identified by combining morph typing with ITS-PCR-sequencing. We obtained 73 unique sequences from the ECM associated with P. bungeana seedlings, and assigned them into 12 ECM fungal OTUs at the threshold of 97% based on the sequence similarity. Rarefaction curve displayed almost all ECM fungi in the propagule bank were detected. The most frequent OTU (80%) showed poor similarity (75%) with existing sequences in the online database, which suggested it might be a new species. Cenococcum geophilum, Tomentella sp., Tuber sp. were common species in the propagule bank. Although C. geophilum and Tomentella sp. were frequently detected in other soil propagule banks of pine forest, the most frequent OTU was not assigned to known genus or family, which indicated the host specif of ECM propagule banks associa-ted with P. bungeana. This result confirmed the importance of the special ECM propagule banks associated with P. bungeana for natural forest restoration. PMID- 29696882 TI - [Characteristics of soil microorganisms and soil nutrients in different sand fixation shrub plantations in Kubuqi Desert, China]. AB - Three types of sand-fixation shrub plantations, including Artemisia ordosica + Hedysarum fruticosum, Caragana korshinskii and Salix psammophila, were selected in the eastern area of Kubuqi Desert to study the changes in soil microbial biomass carbon (MBC) and microbial biomass nitrogen (MBN), quantities of soil microorganisms, contents of soil nutrients and the relations among these variables under the different plantation types and shifting sandy land. The restoration effects of each plantation type on soil quality were assessed by synthetic index method. The results showed that the contents of soil organic matter, total nitrogen and phosphorus, and available nitrogen and phosphorus under different plantations were all significantly greater than those under shifting sandy land, and the order of increase was A. ordosica + H. fruticosum > C. korshinskii > S. psammophila. The soil nutrient contents decreased with the increase of soil depth under all plantation types. The quantities of soil microorganisms and the contents of soil MBC and MBN under the plantations were higher at different degrees than those under shifting sandy land. MBC, MBN and the relative numbers of bacteria under A. ordosica+H. fruticosum plantation were higher than those under C. korshinskii plantation and S. psammophila plantation. The relative numbers of fungi and actinobacteria decreased in the order of C. korshinskii > S. psammophila > A. ordosica + H. fruticosum. The relative number of bacteria, MBC and MBN under the plantations were mainly affected by the contents of soil organic matter, total nitrogen, total phosphorus, available nitrogen, available phosphorus, as well as C/N, and the relative numbers of actinobacteria and fungi were primarily affected by the contents of soil total phosphorus, available nitrogen and available phosphorus. Soil quality was ranked in the order of A. ordosica + H. fruticosum > C. korshinskii > S. psammophila > shifting sandy land. These results demonstrated that different sand-fixation shrub plantations could improve the quality of the desert soil and the A. ordosica + H. fruticosum plantation was the best for soil restoration and quality improvement in the desert. PMID- 29696881 TI - [Effects of increased O3 concentration on growth, subcellular structure and reactive oxygen metabolism of turf-type Festuca arundinace]. AB - Taking ambient environmental O3(40 nmol.mol-1) as control, the study was conducted to assess the impact of elevated O3(80 and 160 nmol.mol-1) on the growth, subcellular structure and reactive oxygen metabolism of turf-type Festuca arundinace in open top-chambers (OTCs). The results showed that under 14-day fumigation, the height and leaf width of F. arundinace decreased significantly, and the total biomass decreased by 43.7%, and some fully expanded leaves yellowed under 80 nmol.mol-1 O3. Some visible injury symptoms, brown spots and necrosis appeared in the leaves, the total biomass decreased by 46.2%, and plasma membrane became loose from the cell wall and convoluted, chloroplast and mitochondria were damaged under 160 nmol.mol-1 O3. The rate of superoxide anion (O2-.) production, hydrogen peroxide (H2O2) content, malonaldehyde (MDA) content and the activities of antioxidant enzymes were higher under the increasing O3 concentrations (80 and 160 nmol.mol-1) compared with control. Total phenolics and the antioxidant capacity increased at first and then decreased with the rise of O3 concentration. It indicated that O3 has already affected F. arundinace growth and antioxidative metabolism before visible injury symptom appeared. F. arundinace had an adaptive response to elevated O3, but it could not protect itself from excessive O3 or long-term O3 exposure. PMID- 29696883 TI - [Characteristics of soil microbes and enzyme activities in different degraded alpine meadows]. AB - Soil microbial biomass C and N, microbial diversities and enzyme activity in 0-10 cm and 10-20 cm soil layers of different degraded grasslands (non-degradation, ND; light degradation, LD; moderate degradation, MD; sever degradation, SD; and black soil beach, ED) were measured by Biolog and other methods. The results showed that: 1) There were significant diffe-rences between 0-10 cm and 10-20 cm soil layers in soil microbial biomass, diversities and inver-tase activities in all grasslands. 2) The ratio of soil microbial biomass C to N decreased significantly with the grassland degradation. In the 0-10 cm soil layer, microbial biomass C and N in ND and LD were significantly higher than that in MD, SD and ED. Among the latter three kinds of grasslands, there was no difference for microbial biomass C, but microbial biomass N was lower in MD than in the other grasslands. The average color change rate (AWCD) and McIntosh Index (U) also decreased with grassland degradation, but only the reduction from ND to MD was significant. There were no differences among all grasslands for Shannon index (H) and Simpson Index (D). The urease activity was highest in MD and SD, and the activity of phosphatase and invertase was lowest in ED. In the 10-20 cm soil layer, microbial biomass C in ND and LD were significantly higher than that in the other grasslands. Microbial biomass N in LD and ED were significantly higher than that in the other grasslands. Carbon metabolism index in MD was significantly lower than that in LD and SD. AWCD and U index in ND and LD were significantly higher than that in ED. H index and D index showed no difference among different grasslands. The urease activity in ND and MD was significantly higher than that in the other grasslands. The phosphatase activity was highest in MD, and the invertase activity was lowest in MD. 3) The belowground biomass was significantly positively correlated with microbial biomass, carbon metabolic index and phosphatase activity, and the urease activity was negatively correlated with microbial biomass N, H index and D index. PMID- 29696884 TI - [Relation between species distribution of plant community and soil factors under grazing in alpine meadow]. AB - The research selected the alpine meadow located in the northeastern margin of the Qinghai-Tibet Plateau to study the changes of vegetation community and soil properties under different grazing intensities, as well as the quantitative relation between the distribution patterns of plant species and the physical and chemical properties of soil. The results showed that the grazing caused the differentiation of the initial vegetation community with the dominant plants, Elymus nutans and Stipa grandis. In the plots with high and low grazing intensities, the dominant plants had changed to Kobresia humilis and Melissitus ruthenica, and E. nutans and Poa crymophila, respectively. With the increase of grazing intensity, the plant richness, importance value and biomass were significantly decreased. The sequence of plant species importance value in each plot against grazing intensity could be fitted by a logarithmic model. The number of required plant species was reduced while the importance value of the remaining plant species accounted for 50% of the importance value in the whole vegetation community. The available P, available K, soil compaction, soil water content, stable infiltration rate and large aggregate index were significantly changed with grazing intensity, however, the changes were different. The CCA ordination showed that the soil compaction was the key factor affecting the distribution pattern of the plant species under grazing. The variance decomposition indicated that the soil factors together explained 30.5% of the distribution of the plant species, in particular the soil physical properties alone explained 22.8% of the distribution of the plant species, which had the highest rate of contribution to the plant species distribution. The soil physical properties affected the distribution pattern of plant species on grazed alpine meadow. PMID- 29696885 TI - [Prediction and spatial distribution of recruitment trees of natural secondary forest based on geographically weighted Poisson model]. AB - Based on the data collected from 108 permanent plots of the forest resources survey in Maoershan Experimental Forest Farm during 2004-2016, this study investigated the spatial distribution of recruitment trees in natural secondary forest by global Poisson regression and geographically weighted Poisson regression (GWPR) with four bandwidths of 2.5, 5, 10 and 15 km. The simulation effects of the 5 regressions and the factors influencing the recruitment trees in stands were analyzed, a description was given to the spatial autocorrelation of the regression residuals on global and local levels using Moran's I. The results showed that the spatial distribution of the number of natural secondary forest recruitment was significantly influenced by stands and topographic factors, especially average DBH. The GWPR model with small scale (2.5 km) had high accuracy of model fitting, a large range of model parameter estimates was generated, and the localized spatial distribution effect of the model parameters was obtained. The GWPR model at small scale (2.5 and 5 km) had produced a small range of model residuals, and the stability of the model was improved. The global spatial auto-correlation of the GWPR model residual at the small scale (2.5 km) was the lowe-st, and the local spatial auto-correlation was significantly reduced, in which an ideal spatial distribution pattern of small clusters with different observations was formed. The local model at small scale (2.5 km) was much better than the global model in the simulation effect on the spatial distribution of recruitment tree number. PMID- 29696886 TI - [Seed morphology and effects of sheep rumen digestion on seed germination of 28 Gramineae plants.] AB - An experiment was undertaken to compare the morphological characteristics of seeds of 28 Gramineae plants which widely distributed in north Xinjiang and to study their digestion in the rumen of sheep. After determining their morphological characteristics including seed length, width, height, seed shape index, 100-seed mass, and seed germination percentage, seeds were put into nylon bags and then placed in the rumen of sheep through a fistula. The bags were removed at different times to determine the morphological characteristics and seed germination rates. The results showed that 23 plant seeds were all elliptic or flat types except for Melica scabrosa, Agrostis ma-tsumurae, Poa bulbosa, Phleum pratense and Triticum aestivum. 100-seed mass of T. aestivum (3.25 g) and Avena sativa (1.69 g) were >1 g, and the 100-seed mass of the other seeds ranged from 0.01-1 g, indicating they were all medium or small type seeds. The color of seed coat was deepened, seed structure was destructed, and the lengths of seed appendages, i.e., awn, lemma and glume were decreased with increasing digestion time. Seed length, width, height, 100-seed mass were decreased with increasing digestion time, but the changes were not significant compared with the non digested seeds. The seed germination percentages were extremely decreased after sheep rumen digestion. After 6 h of sheep rumen digestion, the germination rates of the seeds of R. kamoji and A. sativa were decreased to 0, and part of the seeds of other 26 plants still had some vigor. PMID- 29696887 TI - [Effects of tillage practices on root spatial distribution and yield of spring wheat and pea in the dry land farming areas of central Gansu, China]. AB - A field experiment was conducted to explore the mechanism of cultivation measures in affecting crop yield by investigating root distribution in spring wheat-pea rotation based on a long-term conservation tillage practices in a farming region of Gansu. The results showed that with the develo-pment of growth period, the total root length, root surface area of spring wheat and pea showed a consistent trend of increase after initial decrease and reached the maximum at flowering stage. Higher root distribution was found in the 0-10 cm soil layer at seedling and 10-30 cm soil layer at flowering and maturity stages in spring wheat, while in the field pea, higher root distribution was found in the 0-10 cm soil layer at seedling and maturity, and in the 10-30 cm soil layer at flowering stages. No tillage with straw mulching and plastic mulching increased the root length and root surface area. Compared with conventional tillage in spring wheat and field pea, root length increased by 35.9% to 92.6%, and root surface area increased by 43.2% to 162.4%, respectively. No tillage with straw mulching and plastic mulching optimized spring wheat and pea root system distribution, compared with conventional tillage, increased spring wheat and field pea root length and root surface area ratio at 0-10 cm depths at the seedling stage, the root distribution at deeper depths increased significantly at flowering and maturity stages, and no tillage with straw mulching increased root length and root surface area ratio by 3.3% and 9.7% respectively, in 30-80 cm soil layer at the flowering stage. The total root length, root surface area and yield had significantly positive correlation for spring wheat in each growth period, and the total root length and pea yield also had significant positive correlation. No tillage with straw mulching and plastic mulching boosted yield of spring wheat and pea by 23.4% 38.7% compared with the conventional tillage, and the water use efficiency was increased by 13.7%-28.5%. It was concluded that no-till farming and straw mulching (plastic) could increase crop root length and root surface area, optimize the spatial distribution of roots in the soil, enhance crop root layer absorption ability, so as to improve crop yield and water utilization. PMID- 29696888 TI - [Stability of a winter wheat population with high yield and high resource use efficiency]. AB - Using the winter wheat cultivar Tainong 18 as the experimental material, we analyzed yield stability from 2012 to 2016 under three different treatments: T1(following typical local field management practices), T2(high-yield: high nitrogen and water were supplied to foster high grain yield), and T3(high-yield, high-efficiency: optimized field management including increasing plant density, reducing nitrogen input and delaying of the sowing date). Yield related phenotypic traits, including the number of ears on the main stem and tillers, leaf area index (LAI), photosynthetically active radiation (PAR) interception, dry matter accumulation and distribution, as well as grain yield, were analyzed over four seasons to determine their relationships with annual radiation, accumulated temperature and precipitation. We then determined grain yield stability for each of the three treatments. The amount and distribution of radiation, accumulated temperature, and precipitation varied greatly within each season. The ears on the main stem represented 38.9%, 58.7%, and 66.9% of the total ears, respectively, for wheat grown in the T1, T2 and T3 treatments, indicating that T1 ears originated mainly from the tillers, T2 ears from both the main stem and the tillers, and T3 ears from the main stem. The T2 and T1 treatments produced the highest and lowest amount of dry matter and grain yield, respectively. Although having relatively lower dry matter accumulation at maturity compared with T2, T3 led to higher grain yield due to high LAI, high PAR interception and utilization, high net canopy photosynthetic rate from booting (especially from 14 days after anthesis) to maturity and a higher harvest index. Among the three treatments, T3 resulted in the lowest annual range, standard deviation, and coefficient of variation for LAI, PAR interception, and dry matter accumulation. Thus, grain yield was most stable in wheat grown in the T3 treatment mainly due to stability in biological production during all four seasons. PMID- 29696889 TI - [Effects of different irrigation treatments during heading and flowering stage on cold resis-tance, yield and physiological characteristics of late rice]. AB - Taking super hybrid rice variety 'Wufengyou T025' as test material, the effects of different irrigation methods and water layer depth on physiological characteristics and yield in double-season late rice under low temperature conditions during heading and flowering stage were investigated. Three treatments were set, i.e., draining during day and containing 4-5 cm water layer during night (H1), draining during day and containing 8-10 cm water layer during night (H2), and containing 8-10 cm water layer day and night (H3), with the 0-1 cm water layer day and night was as the control (CK). The results showed that rice leaf temperature, soil layer temperature and canopy temperature under the different irrigation treatments were higher than that of CK, and the warming effect of treatment H2 was the best during the low temperature period. Leaf chlorophyll content, net photosynthetic rate, transpiration rate, leaf stomatal conductance and intercellular CO2 concentration of rice plants decreased gradually under the low temperature, while the smallest reduction occurred in H2. The increase ranges of malondialdehyde and proline content in H2 were lower, while its soluble protein content was the highest compared with other irrigation treatments. The increase ranges for the activities of superoxide dismutase and peroxidase in H2 were lower, while its decrease range for the activity of catalase was the lowest. Irrigation for heat preservation could increase the yield, and H2 performed best. Yield of H2 at the second sowing date in 2014 and 2015 encountering low temperature increased by 12.9% and 13.5% respectively compared to CK. The yield components including the effective panicle numbers per plant, panicle length, seed setting rate and 1000-grain mass were improved in all irrigation treatments compared to CK. Draining during day and containing 8-10 cm water layer during night (H2) was the most effective agronomic measure to enhance the tolerance to low temperature during heading and flowering stage for double season hybrid late rice. PMID- 29696890 TI - [Effects of nitrogen and irrigation water application on yield, water and nitrogen utilization and soil nitrate nitrogen accumulation in summer cotton]. AB - A field experiment was carried out to study the effects of nitrogen and irrigation water application on growth, yield, and water and nitrogen use efficiency of summer cotton, and to develop the optimal water and nitrogen management model for suitable yield and less nitrogen loss in summer cotton field in the Huang-Huai region. Two experimental factors were arranged in a split plot design. The main plots were used for arranging nitrogen factor which consisted of five nitrogen fertilizer le-vels(0, 60, 120, 180, 240 kg.hm-2, referred as N0, N1, N2, N3, N4), and the subplots for irrigation factor which consisted of three irrigation quota levels (30, 22.5, 15 mm, referred as I1, I2, I3). There were 15 treatments with three replications. Water was applied with drip irrigation system. Experimental results showed that both irrigation and nitrogen fertilization promoted cotton growth and yield obviously, but nitrogen fertilizer showed more important effects than irrigation and was the main factor of regulating growth and yield of summer cotton in the experimental region. With the increase of nitrogen fertilization rate and irrigation amount, the dry mater accumulation of reproductive organs, the above-ground biomass at the flowering bolling stage and seed cotton yield increased gradually, reached peak values at nitrogen fertilization rate of 180 kg.hm-2 and decreased slowly with the nitrogen fertilization rate further increased. The maximum yield of 4016 kg.hm-2 was observed in the treatment of N3I1. Increasing nitrogen fertilizer amount would improve significantly total N absorption of shoots and N content of stem and leaf, but decrease nitrogen partial factor productivity. The maximum irrigation water use efficiency of 5.40 kg.m-3 and field water use efficiency of 1.24 kg.m-3 were found in the treatments of N3I3 and N3I1, respectively. With increasing nitrogen fertilization amount, soil NO3--N content increased and the main soil NO3--N accumulation layer moved downward. By comprehensively considering above ground biomass, seed cotton yield, water and nitrogen uptake and utilization, and soil NO3--N accumulation in the soil profile, the treatment N3I1 could be recommended as the optimal water and nitrogen application pattern for summer cotton production in the experimental region. PMID- 29696891 TI - [Effects of different mulching and drip irrigation patterns on photosynthetic characteristics of maize leaves in the Hetao Irrigation District, Inner Mongolia, China]. AB - Photosynthesis controls crop growth and yield, and differences in planting methods and soil moisture can significantly affect the photosynthetic characteristics of crops. Grain filling stage and milking stage are two important stages of maize from flowering to maturity, which are essential for maize grain formation and dry matter accumulation. The effects of different mulching and drip irrigation patterns on the photosynthetic characteristics and maize yield at grain filling and milking stages were investigated in a field experiment in the Hetao Irrigation District, Inner Mongolia. Maize leaf photosynthesis during the grain filling stage was not significantly different under the different treatments. During the milking stage, photosynthetic and transpiration rates under both partial (B2) and full (Q2) film mulching with drip irrigation level 2 (350 mm) were significantly higher than those in both the partial (B1) and full (Q1) film mulching with drip irrigation level 1 (200 mm). Photosynthetic and transpiration rates, water use efficiency and stomatal conductance under the B1 and Q1 treatments were significantly higher in the grain filling stage than in the milking stage. Diurnal variations in photosynthetic and transpiration rates, stomatal conductance and water use efficiency of maize leaves during the grain filling and milking stages were synchronous and showed an upside-down "U" pattern, but the intercellular CO2 concentration showed the opposite pattern. Stepwise regression analysis showed that photosynthetically active radiation, air temperature and relative humidity were the main environmental factors influencing photosynthetic characteristics of maize leaves under the different mulching and drip irrigation treatments. In addition, maize yield was significantly higher under the B2 and the Q2 treatments than under the B1 and Q1(increase of 29.3% and 50.9%, respectively), but no significant differences were found between the B1 and Q1 treatments, indicating that drip irrigation level affects the yield of maize and its photosynthetic capacity more than mulching mode in arid regions. PMID- 29696892 TI - [Characteristics of ground-dwelling soil macro-arthropod communities in a biodiversity monitoring plot of black soil cropland, northeastern China]. AB - Agro-ecosystem is an important component of terrestrial ecosystems and it is one of the key areas of global ecological and environmental studies. A 16 hm2 permanent plot in black soil cropland was built to study the community structure of soil biodiversity in typical black soil region in Northeast China. Pitfall trap was used to investigate the ground-dwelling soil macro-arthropods from August to October 2015 in accordance with the three crop growth stages: whirling stage, silking stage, and milk stage. A total of 5284 ground-dwelling soil macro arthropods belonging to 47 species were captured sorted into 3 classes, 12 orders, 32 families. 3 dominant groups and 11 common groups were found. Phytophages and Omnivores were dominant groups. The individuals and species numbers of ground-dwelling soil macro-arthropods had significant changes with the vegetative growth period. The maximum values of the Shannon index, Margalef index, Pielou index of soil macro-arthropods all appeared in September, but the maximum dominant index appeared in August. From the variation coefficient (CV) and spatial interpolation of different species, it could be seen that there was heterogeneity in the horizontal direction of the ground-dwelling soil macro arthropod communities. Regarding the relationships between the ground-dwelling soil macro-arthropod communities and soil environmental factors including soil pH, soil organic matter, total nitrogen and soil water content, the bivariate correlation analysis showed there was no significant correlation between them. Results of canonical correspondence analysis (CCA) further indicated that the dominant and common groups were adaptable to environmental factors and widely distributed in the study area. The results showed that the species richness of ground-dwelling soil macro-arthropods was very high in cropland, and the dynamic of soil arthropod's composition and spatial distribution pattern in diffe-rent crop growth stages were significantly changed. It was indicated that biodiversity plot monitoring of black soil cropland had become important means to solve the formation and maintenance mechanism of soil fauna community through large-scale and long-term investigation. PMID- 29696893 TI - [Tasseled cap triangle (TCT)-leaf area index (LAI)model of rice fields based on PROSAIL model and its application]. AB - The tasseled cap triangle (TCT)-leaf area index (LAI) isoline is a model that reflects the distribution of LAI isoline in the spectral space constituted by reflectance of red and near-infrared (NIR) bands, and the LAI retrieval model developed on the basis of this is more accurate than the commonly used statistical relationship models. This study used ground-based measurements of the rice field, validated the applicability of PROSAIL model in simulating canopy reflectance of rice field, and calibrated the input parameters of the model. The ranges of values of PROSAIL input parameters for simulating rice canopy reflectance were determined. Based on this, the TCT-LAI isoline model of rice field was established, and a look-up table (LUT) required in remote sensing retrieval of LAI was developed. Then, the LUT was used for Landsat 8 and WorldView 3 data to retrieve LAI of rice field, respectively. The results showed that the LAI retrieved using the LUT developed from TCT-LAI isoline model had a good linear relationship with the measured LAI R2=0.76, RMSE=0.47. Compared with the LAI retrieved from Landsat 8, LAI values retrieved from WorldView 3 va-ried with wider range, and data distribution was more scattered. Resampling the Landsat 8 and WorldView 3 reflectance data to 1 km to retrieve LAI, the result of MODIS LAI product was significantly underestimated compared to that of retrieved LAI. PMID- 29696894 TI - [Effects of N application on wheat powdery mildew occurrence, nitrogen accumulation and allocation in intercropping system]. AB - The main objective of this field experiment was to study the effects of wheat and faba bean intercropping on occurrence of wheat powdery mildew, nitrogen content, accumulation and allocation of wheat plant at 4 nitrogen levels of N0(0 kg.hm-2), N1(112.5 kg.hm-2), N2(225 kg.hm-2), N3(337.5 kg.hm-2), and to explore the relationship between N content, accumulation, allocation and the occurrence of wheat powdery mildew. The results showed that both monocropped and intercropped wheat yields increased with nitrogen application, with the highest yields of monocropped and intercropped wheat being 4146 kg.hm-2 and 4679 kg.hm-2 at N2 le vel, respectively. The occurrence and development of wheat powdery mildew become more severe with the increase of N application and area under disease progression curve (AUDPC) were averagely increased by 39.6%-55.6%(calculated with disease incidence, DI) and 92.5%-217.0% (calculated with disease severity index, DSI) with N1, N2 and N3 treatments. The disease severity index was more affected by nitrogen regulation than by disease incidence. The nitrogen content and accumulation of wheat plant were significantly increased by 8.4%-51.6% and 19.7% 133.7% with nitrogen application, but there was no significant effect on N allocation ratio. Compared with monocropped wheat, yield of intercropped wheat was averagely increased by 12%, whereas, the AUDPC(DI) and AUDPC(DSI) of intercropped wheat were averagely decreased by 11.5% and 30.7%, respectively. The control effect of the disease severity index by intercropping was better than disease incidence. The nitrogen content, accumulation and nitrogen allocation ratio in intercropped wheat leaves were significantly decreased by 6.6%-12.5%, 1.4%-6.9% and 9.0%-15.5% respectively at the peak infection stage of powdery mildew. Overall findings showed that the maximum rate of nitrogen application for wheat should not exceed 225 kg.hm-2 when taking into account both disease control and yield effect. PMID- 29696895 TI - [Prediction model of meteorological grade of wheat stripe rust in winter reproductive area, Sichuan Basin, China]. AB - The winter reproductive areas of Puccinia striiformis var. striiformis in Sichuan Basin are often the places mostly affected by wheat stripe rust. With data on the meteorological condition and stripe rust situation at typical stations in the winter reproductive area in Sichuan Basin from 1999 to 2016, this paper classified the meteorological conditions inducing wheat stripe rust into 5 grades, based on the incidence area ratio of the disease. The meteorological factors which were biologically related to wheat stripe rust were determined through multiple analytical methods, and a meteorological grade model for forecasting wheat stripe rust was created. The result showed that wheat stripe rust in Sichuan Basin was significantly correlated with many meteorological factors, such as the ave-rage (maximum and minimum) temperature, precipitation and its anomaly percentage, relative humidity and its anomaly percentage, average wind speed and sunshine duration. Among these, the average temperature and the anomaly percentage of relative humidity were the determining factors. According to a historical retrospective test, the accuracy of the forecast based on the model was 64% for samples in the county-level test, and 89% for samples in the municipal-level test. In a meteorological grade forecast of wheat stripe rust in the winter reproductive areas in Sichuan Basin in 2017, the prediction was accurate for 62.8% of the samples, with 27.9% error by one grade and only 9.3% error by two or more grades. As a result, the model could deliver satisfactory forecast results, and predicate future wheat stripe rust from a meteorological point of view. PMID- 29696896 TI - [Evaluating the performance of species distribution models Biomod2 and MaxEnt using the giant panda distribution data]. AB - Species distribution models (SDMs) are widely used by researchers and conservationists. Results of prediction from different models vary significantly, which makes users feel difficult in selecting models. In this study, we evaluated the performance of two commonly used SDMs, the Biomod2 and Maximum Entropy (MaxEnt), with real presence/absence data of giant panda, and used three indicators, i.e., area under the ROC curve (AUC), true skill statistics (TSS), and Cohen's Kappa, to evaluate the accuracy of the two model predictions. The results showed that both models could produce accurate predictions with adequate occurrence inputs and simulation repeats. Comparedto MaxEnt, Biomod2 made more accurate prediction, especially when occurrence inputs were few. However, Biomod2 was more difficult to be applied, required longer running time, and had less data processing capability. To choose the right models, users should refer to the error requirements of their objectives. MaxEnt should be considered if the error requirement was clear and both models could achieve, otherwise, we recommend the use of Biomod2 as much as possible. PMID- 29696897 TI - [Assessment of ecosystem in giant panda distribution area based on entropy method and coefficient of variation]. AB - The areas of the habitat and bamboo forest, and the size of the giant panda wild population have greatly increased, while habitat fragmentation and local population isolation have also intensified in recent years. Accurate evaluation of ecosystem status of the panda in the giant panda distribution area is important for giant panda conservation. The ecosystems of the distribution area and six mountain ranges were subdivided into habitat and population subsystems based on the hie-rarchical system theory. Using the panda distribution area as the study area and the three national surveys as the time node, the evolution laws of ecosystems were studied using the entropy method, coefficient of variation, and correlation analysis. We found that with continuous improvement, some differences existed in the evolution and present situation of the ecosystems of six mountain ranges could be divided into three groups. Ecosystems classified into the same group showed many commonalities, and difference between the groups was considerable. Problems of habitat fragmentation and local population isolation became more serious, resulting in ecosystem degradation. Individuali zed ecological protection measures should be formulated and implemented in accordance with the conditions in each mountain system to achieve the best results. PMID- 29696898 TI - [Effect of soil phenolic acids on soil microbe of coal-mining depressed land after afforestation restoration by different tree species]. AB - Phenolic acids are one of the most important factors that influence microbial community structure. Investigating the dynamic changes of phenolic acids and their relationship with the microbial community structure in plantation soils with different tree species could contribute to better understanding and revealing the mechanisms of microbial community changes under afforestation restoration in coal-mining subsidence areas. In this study, plantations of three conifer and one deciduous species (Pinus koraiensis, Larix gmelinii, Pinus sylvestris var. mongolica, and Populus ussuriensis) were established on abandoned coal-mining subsidence areas in Baoshan District, Shuangyashan City. The contents of soil phenols, 11 types of phenolic acids, and microbial communities in all plots were determined. The results showed that the contents of soil complex phenol in plantations were significantly higher than that of abandoned land overall. Specifically, soils in larch and poplar plantations had higher contents of complex phenol, while soils in larch and Korean pine plantations had greater contents of total phenol. Moreover, soil in the P. koraiensis plantation had a higher content of water-soluble phenol compared with abandoned lands. The determination of 11 phenolic acids indicated that the contents of ferulic acid, abietic acid, beta-sitosterol, oleanolic acid, shikimic acid, linoleic acid, and stearic acid were higher in plantation soils. Although soil phenol contents were not related with soil microbial biomass, the individual phenolic acids showed a significant relationship with soil microbes. Ferulic acid, abietic acid, and beta sitosterol showed significant promoting effects on soil microbial biomass, and they showed positive correlations with fungi and fungi/bacteria ratio. These three phenolic acids had higher contents in the poplar plantation, suggesting that poplar affo-restation had a beneficial effect on soil quality in coal-mining subsidence areas. PMID- 29696899 TI - [Effects of land use changes on soil water conservation in Hainan Island, China]. AB - In tropical areas, a large number of natural forests have been transformed into other plantations, which affected the water conservation function of terrestrial ecosystems. In order to clari-fy the effects of land use changes on soil water conservation function, we selected four typical land use types in the central mountainous region of Hainan Island, i.e., natural forests with stand age greater than 100 years (VF), secondary forests with stand age of 10 years (SF), areca plantations with stand age of 12 years (AF) and rubber plantations with stand age of 35 years (RF). The effects of land use change on soil water holding capacity and water conservation (presented by soil water index, SWI) were assessed. The results showed that, compared with VF, the soil water holding capacity index of other land types decreased in the top soil layer (0-10 cm). AF had the lowest soil water holding capacity in all soil layers. Soil water content and maximum water holding capacity were significantly related to canopy density, soil organic matter and soil bulk density, which indicated that canopy density, soil organic matter and compactness were important factors influencing soil water holding capacity. Compared to VF, soil water conservation of SF, AF and RF were reduced by 27.7%, 54.3% and 11.5%, respectively. The change of soil water conservation was inconsistent in different soil layers. Vegetation canopy density, soil organic matter and soil bulk density explained 83.3% of the variance of soil water conservation. It was suggested that land use conversion had significantly altered soil water holding capacity and water conservation function. RF could keep the soil water better than AF in the research area. Increasing soil organic matter and reducing soil compaction would be helpful to improve soil water holding capacity and water conservation function in land management. PMID- 29696901 TI - [Spatial-temporal dynamics of rainstorm in East China based on spatial-temporal data mining technology]. AB - Based on TRMM 3B42 precipitation data, 5 time series at annual scale were constructed. Then the spatial and temporal dynamics of rainstorm in East China region from 2003 to 2015 were evaluated in the support of data mining and GIS spatial analysis technology. The results showed that, the spatial distributions of annual precipitation and annual rainstorm precipitation were similar during 2003-2015. Annual precipitation exhibited a slight increase trend while annual rainstorm ratio showed significant fluctuation. The imbalanced distribution of rainstorm in latitudinal direction was more obvious than that of longitudinal direction. Annual rainstorm frequency changed smoothly with significant spatial difference. Rainstorm showed a tendency of moving to north in the past 13 years. The changing trends of the five variables showed significant spatial differences, and most pixels showed non-significant increasing (or decreasing) trends. PMID- 29696900 TI - [Coupling effects of periodic rewatering after drought stress and nitrogen fertilizer on growth and water and nitrogen productivity of Coffea arabica]. AB - The effects of periodic rewatering after drought stress and nitrogen fertilizer on growth, yield, photosynthetic characteristics of leaves and water and nitrogen productivity of Coffea arabica (Katim P7963) were studied under different nitrogen application levels in 2.5 consecutive years. Irrigation (periodic rewatering after drought stress) and nitrogen were designed as two factors, with four modes of irrigation, namely, full irrigation (IF-F: 100%ET0+100%ET0, ET0 was reference crop evapotranspiration), rewatering after light drought stress (IL-F: 80%ET0+100%ET0), rewatering after moderate drought stress (IM-F: 60%ET0+100%ET0) and rewatering after severe drought stress (IS-F: 40%ET0+100%ET0), and three levels of nitrogen, namely, high nitrogen (NH: 750 kg N.hm-2 each time), middle nitrogen (NM: 500 kg N.hm-2 each time), low nitrogen (NL: 250 kg N.hm-2 each time), and nitrogen was equally applied for 4 times. The results showed that irrigation and nitrogen had significant effect on plant height, stem diameter, yield and water and nitrogen productivity of C. arabica, and plant height and stem diameter showed S-curve with the day ordinal number, and leaf photosynthesis decreased significantly under drought stress but most photosynthesis index recovered somewhat after rewatering. Compared with IF-F, IL-F increased dry bean yield by 6.9%, while IM-F and IS-F decreased dry bean yield by 15.2% and 38.5%, respectively; IL-F and IM-F increased water use efficiency by 18.8% and 6.0%, respectively, while IS-F decreased water use efficiency by 12.1%; IL-F increased nitrogen partial productivity by 6.1%, while IM-F and IS-F decreased nitrogen partial productivity by 14.0% and 36.0%, respectively. Compared with NH, NM increased dry bean yield and water use efficiency by 20.9% and 19.3%, while NL decreased dry bean yield and water use efficiency by 42.4% and 41.9%, respectively; NM and NL increased nitrogen partial productivity by 81.4% and 72.9%, respectively. Compared with IF-FNH, IL-FNM increased dry bean yield, water use efficiency and nitrogen partial productivity by 37.6%, 52.9% and 106.4%, respectively. Regression analysis showed that the yield of dry bean was the maximum (2362 kg.hm-2) when the irrigation amount was 318 mm and the nitrogen application amount was 583 kg.hm-2; the water use efficiency was the maximum (0.78 kg.m-3) when the irrigationamount was 295 mm and the nitrogen application amount was 584 kg.hm-2, that's to say when yield of dry bean and water use efficiency reach the maximum value at the same time, the combination was the closest to IL-FNM. Therefore, the best combination of water and nitrogen model for C. arabica was IL-FNM. PMID- 29696902 TI - [A process of aquatic ecological function regionalization: The dual tree framework and conceptual model]. AB - Aquatic ecological regionalization and aquatic ecological function regionalization are the basis of water environmental management of a river basin and rational utilization of an aquatic ecosystem, and have been studied in China for more than ten years. Regarding the common problems in this field, the relationship between aquatic ecological regionalization and aquatic ecological function regionalization was discussed in this study by systematic analysis of the aquatic ecological zoning and the types of aquatic ecological function. Based on the dual tree structure, we put forward the RFCH process and the diamond conceptual model. Taking Liaohe River basin as an example and referring to the results of existing regionalization studies, we classified the aquatic ecological function regions based on three-class aquatic ecological regionalization. This study provided a process framework for aquatic ecological function regionalization of a river basin. PMID- 29696903 TI - [Process of land use transition and its impact on regional ecological quality in the Middle Reaches of Heihe River, China]. AB - Land use transition is one of the main drivers of regional ecosystem change in arid area, which directly affects human well-being. Based on the satellite images of 1987, 2001 and 2016, the change detection assessment model and ecological response model were used to analyze the process of land use transition and response of ecological quality during 1987-2016 in the ecologically fragile middle reaches of the Heihe River. The results showed that the land use change was significant during 1987-2016 and the total change increased significantly, as well as the continuous increase of the cultivated land and construction land. There was a strong tendency of transform from grassland to cultivated land, while the tendency of transforming unused land to other land classes was not strong under a random process of gain or loss. During 1987-2016, the ecological quality of the study area displayed a decreasing trend as a whole and the ecological land decreased by 2.8%. The land use transition with the greatest impact on the ecological environment degradation was the transition of the grassland to the cultivated land and unused land. Therefore, in order to promote the sustainable use of regional land resources and to improve the regional ecological quality, it is necessary to allocate the proportion of production land and ecological land according to the regional water resources. PMID- 29696904 TI - [Dynamics of natural capital in Shenyang based on improved three-dimensional ecological footprint]. AB - Natural capital trends of Shenyang from 1995 to 2014 were analyzed using improved three-dimensional ecological footprint model. The results showed that, from 1995 to 2014, the ecological carrying capacity per capita of Shenyang fluctuated within a narrow range generally; the per capital ecological footprint, ecological deficit, footprint size and the footprint depth per capita increased along a wave like curve. The changing rates of footprint size and depth tended to stabilize gradually. The way of natural capital utilization of cultivated land changed from capital flow in 2004 to capital stock, the capital stock replaced capital flow and became a source to meet the need of na-tural resources in the regional cultivated land, the use ratios of stock-flows increased gradually. The capital flow had been used by woodland and the occupancy rates of capital flows remained unchanged. The capital stock had been used by grassland and water, and the use ratios of stock-flows increased gradually. The development of Shenyang was in an unsustainable state. Coordinating the relationship between natural capital stock consumption and the utilization of stock-flows was one of the key ways to realize the sustainable development of Shenyang. Developing new resource, rationally planning the land and improving land utilization should be to reduce the consumption of natural capi-tal, at the same time, the protection of ecological environment should be to achieve sustainable development. PMID- 29696905 TI - [Effect of influent C/N on nitrogen removal performance in tidal flow constructed wetland via CANON process]. AB - This study was conducted to explore nitrogen transformation and associated microbial characteristics in a tidal flow constructed wetland (TFCW) with the complete autotrophic nitrogen removal over nitrite (CANON) process under influent COD/TN (C/N) constraints. The influent C/N increased from 0.0 to 10.0 via the addition of glucose in the influent as a source of organics. The results showed that influent C/N significantly affected nitrogen transformation rates in the TFCW throughout the experiment. As the influent C/N increased from 0.0 to 6.0, the absolute abundance of functional genes involved in denitrification could be enriched as a consequence of the addition of organics in influent, and then the simultaneous nitrification, anammox, and denitrification (SNAD) processes occurred in the TFCW, resulting in the enhancement of nitrogen removal in the system. However, as the influent C/N was more than 6.0, the activity of aerobic ammonia-oxidizing bacteria was inhibited and its quantity reduced, leading to the deterioration in nitrogen removal of the system. When the influent C/N was 6.0, the SNAD process was enhanced most effectively in the system owing to the development of multiple and complete nitrogen removal pathways in the TFCW. The TFCW respectively had the best TN removal efficiency and removal loading rate [(93.3+/-2.3)% and (149.30+/-8.00) mg.L-1.d-1], indicating that the results had been than the maximal TN removal efficiency in a CANON process under ideal conditions. PMID- 29696906 TI - [Dynamics of habitat suitability for waterfowls from 1990 to 2015 in the ecological function zone of Sanjiang Plain, Northeast China]. AB - As a wetland of international importance, the ecological function zone of the Sanjiang Plain (EFZSP) plays an important role in maintaining waterfowl habitat. With the increasing disturbance of human beings, land use and climate changes, habitat suitability for waterfowls (HSW) has drawn greater attention of ecologists. In this study, Landsat TM/ETM+/OLI and HJ-1B images in 1990, 2000, 2010 and 2015 were used to obtain land cover classification by object-based image analysis, and the entropy and analytic hierarchy process methods were adopted to determine the factors and their weights, the factors selected in this study included water condition (lake and river density), disturbance factor (residence and road density), shelter condition (land cover type and slope), and food abundance (NDVI). Finally, the evaluation results of habitat suitability of year 1990, 2000, 2010, and 2015 were achieved based on the habitat suitability index (HSI) system, and the spatio-temporal dynamics and driving forces causing the changes were analyzed. The results showed that the excellent level of HSW mainly distributed in abundant water areas, especially along the riparian zone of the Heilongjiang River, Naoli River, Ussuri River, Muling River and Xingkai Lake. Its area decreased by 3.2% from 1990 to 2015 because of wetland reclamation. The good level of HSW concentrated in Raohe County over the past 25 years, the condition of Hulin County and Fuyuan County were improved to a good level from 2010 to 2015 due to the substantial increase of paddy field areas. The fair level of HSW distributed dispersedly, and the areas first increased from 1990 to 2000 and then decreased during 2000-2010 and 2010-2015 periods. The areas of poor le-vel increased by 6.7% from 1990 to 2000 and decreased by 3.1% from 2000 to 2015. The change of HSW level in this study area was dominated by land cover change, and both of the increasing population and economy and the drying and worming climate resulted in the decline of the HSW level, whereas the establishment of nature reserves is crucial to protect habitat for waterfowls. PMID- 29696907 TI - [Identification of key factors of marine industrial ecologization]. AB - It is extremely important to identify key factors of marine industrial ecologization and discriminate the factors that influence degrees and causal relationships for the transformation of marine industrial ecologization nowadays. Based on the conceptual model of marine industrial ecologization, this research built an evaluation system for influencing factors in regional marine industrial ecologization, which included the marine industrial structure ecologization, marine industrial organization ecologization, marine production mode ecologization and marine technological innovations ecologization. The DEMATEL method was applied to analyze the relationships between various influencing factors and drew a network diagram. The results showed that the marine production mode ecologization and marine technological innovation ecologization were in the core position of the evaluation system. They not only revealed the causes of the whole ecological evaluation dimension, but affected the marine industrial organization ecologization and marine industrial structure ecologization. Finally, on the basis of specific indicators in each dimension, some countermeasures and suggestions were put forward to improve the transformation of marine industrial ecologization. PMID- 29696908 TI - [Effects of cascading hydropower dams operation on the structure and distribution pattern of benthic macroinvertebrate assemblages in Manwan Reservoir, Southwest China]. AB - Benthic macroinvertebrate assemblages are one of the biological groups in aquatic ecosystem most sensitive to the habitat change and degradation, and can be a biological indicator for the aquatic ecosystem change and succession in cascading hydropower dam reservoir. The middle and lower reaches of the Lancang River are key spot for international biodiversity conservation and ecological studies on the effects of cascading hydropower dam exploitation. In this study, the reservoir of Manwan hydropower dam, the first dam in Lancang-Mekong river main stream, was selected as the study site. The benthic macroinvertebrate assemblages were sampled in 2011 and 2016 respectively. Meanwhile, the survey data before impounding (natural river, 1996) and early stage of single dam (1997) were collected to conduct the overall analysis for structure, distribution pattern and evolution of benthic macroinvertebrate assemblages. The results showed that the dominant biological group was gradually changed from the Oligochaeta and Insecta to the Mollusca. Along the longitudinal gradient, the density and biomass of the benthic macroinvertebrate assemblages were remarkably increased in reservoir, especially in the lacustrine zone. As for the functional feeding group, the predator and gatherer-collector changed into filter-collector predominantly in lacustrine zone. With the cascading dams operation, the biotic index indicated that the water quality of reservoir in 2016 was better than in 2011. The evolution of benthic macroinvertebrate assemblages in the Manwan Reservoir was related to the operation of Xiaowan dam in the upper reach, the hydrological regime and siltation in the reservoir, and would continue with dynamic changes with the operation of the cascading hydropower dam. PMID- 29696910 TI - [Interactive effects of temperature, CO2 concentration and precipitation on growth and yield of crops]. AB - Temperature, CO2 concentration and precipitation are the key climate factors affecting crop growth and yield. The effects of different climate factors on crops are not independent, and their interactive effects on crops have become a focus in this research field. The study of interactive effects of multiple climate factors on crops could more reliably reflect the actual situations of crop growth, which could help us to understand the crop growth and even the ecosystem response to climate change, and optimize agricultural production managements in the future. In recent years, there are a lot of reports about the effects of different climate factors on crops both in China and abroad, and thus it is quite difficult to conduct a comprehensive review for interactive effects of all climatic factors on crops. Therefore, this review only focused on the results of the interactive effects of warming, elevated CO2 concentration and changing precipitation on crop growth, photosynthetic physio-logy, and yield in recent years, and identified the knowledge gaps of the relevant studies and the key issues that urgently need to be solved in future research. This would be useful for the researches elucidating the influence of climate change on crop growth and yield. PMID- 29696909 TI - [Eco-economic thinking for developing carbon sink industry in the de-farming regions]. AB - Based on the potential and the law that plants absorb carbon dioxide, carbon sink industry means certain appropriate artificial intervention to obtain clean air, and to meet people's production and life demand for ecological environment industry. Carbon sink industry is considered as a breakthrough point and a new growth point for optimizing and upgrading of the original relatively balanced or stable agricultural industry-resources system. Among the ecosystem services in the de-farming regions, the rapid increase of the economic manifestation of carbon fixation and oxygen release function and the carbon sink potential, as well as the rise of carbon trading and carbon market both in domestic and international, have established a theoretical and practical basis for the deve lopment of carbon industry. With the development of the carbon sink industry, improving the carbon sequestration output will become the core of the carbon sink industry. The producers or marketers will form the controlling of the carbon source, the development of the path for carbon storage increasing and re-layout of agricultural industry-resources structure, and thus bring new vitality to regional sustainable development in the de-farming regions. This indicates the emphasis for the future research and development, that is, allocating the agricultural industry-resources structure and their benign coupling mechanism after integrating the carbon sink industry. PMID- 29696911 TI - [Progress in decoding the impact of abiotic stress on spikelet fertility in rice]. AB - Recent research progress in the impact of abiotic stress on florets sterility was summarized in this review to reveal key processes in determining the floret sterility resulted from abiotic stress and their coherent connections. The spikelet fertility was mainly determined by four key processes, including behavior of tapetum, anther dehiscence and pollen release, pollen germination and fertilization. Abiotic stress affected these processes and led to the spikelet sterility. Abnormal changes at the early-stage of anther growth could impact the development of germ cell and fertilization. Damages of floret fertility caused by abiotic stress could be mitigated via some practices such as spraying exogenous plant growth substances or silicon fertilizer. Some research topics were suggested for future investigation, including the interactions of multiple stress factors on fertility, morphological and physiological effects on floral organ formation, differential responses of rice varieties to abiotic stress, and molecular mechanism of abiotic stress on floral organ development. PMID- 29696912 TI - [Effect of agricultural application of municipal sewage sludge on plant-soil system: A review]. AB - Currently, reasonable disposal of municipal sewage sludge is one of the important issues in the field of resources and environmental science. Sludge is rich in large amounts of organic matter and available nutrients, promoting soil fertility, soil physical structure and biological properties. However, sludge contains a variety of heavy metals, organic contaminants and other hazardous substance, especially heavy metals, which are the bottlenecks of agricultural application of sludge. To improve the sewage sludge utilization efficiency and decrease the effect on soil, this essay made a summary on domestic and foreign studies on plant-soil interaction ecosystem with sewage sludge to provide a theoretical basis and scientific guidance for advancing sewage sludge utilization efficiency. PMID- 29696913 TI - [Progress of heterotrophic studies on symbiotic corals]. AB - Heterotrophy of zooxanthellae symbiotic corals refers to the nutrition directly coming from food absorption, not the nutrition obtained from photosynthesis. Most ex situ propagation of symbiotic corals focused on the effects of irradiation, flow rate and water quality on corals, few of them involved in the demand and supply of coral heterotrophic nutrition. This paper reviewed the significance of heterotrophic nutrient supply to symbiotic corals from the sources of coral heterotrophic nutrition, the factors affecting the supply of coral heterotrophic nutrient, and the methods of how to study the coral heterotrophy. In general, the research of coral heterotrophy is just at the beginning stage, and future studies should focus on the inherent mechanism of coral feeding selection and developing more effective research methods. PMID- 29696914 TI - [Review on enterprises'eco-innovation]. AB - Eco-innovation is an important way to realize sustainable development. It has the dual positive externality of "knowledge spillover" and "environmental spillover", which has attracted much attention from theory and practice. In order to systematically grasp the current situation of eco-innovation, this study collected the relevant foreign literatures on eco-innovation in the past ten years, and made a systematic review of the definition, characteristics and dimensions of eco-innovation. Focusing on the theory of institutional theory, stakeholder theory and resource-based view, this paper explored the antecedents of eco-innovation. Then, this paper also demonstrated the positive and negative effects of eco-innovation on corporate financial performance, and the meditating and moderating mechanisms between eco-innovation and financial performance. Finally, based on the limitations of existing research, the future research direction was put forward. PMID- 29696915 TI - [Acupuncture combined with medication for morning blood pressure of essential hypertension]. AB - OBJECTIVE: Based on the western medication, to evaluate the advantages in the morning blood pressure treated with acupuncture at Fengchi (GB 20) and Neck-Jiaji (EX-B 2) combined with acupuncture technique for activating blood circulation, eliminating wind and regulating the liver and spleen in the patients with essential hypertension. METHODS: A total of 90 patients of essential hypertension of the mild and moderate degrees were randomized into a medication group (30 cases, 3 dropping), No.1 acupuncture group (30 cases, 2 dropping) and No.2 acupuncture group (30 cases, 1 dropping). In the medication group, adalat was prescribed for oral administration, 30 mg at 7 am every day, continuously for 6 weeks. In the No.1 acupuncture group, on the basis of the treatment as the medication group, the acupuncture technique for activating blood circulation, eliminating wind and regulating the liver and spleen was applied and the acupoints were Renying (ST 9), Hegu (LI 4), Taichong (LR 3), Quchi (LI 11) and Zusanli (ST 36). In the No.2 acupuncture group, on the basis of the treatment as the No.1 acupuncture group, Fengchi (GB 20) and Neck-Jiaji (EX-B 2) were added in acupuncture. Acupuncture was given in the time zone from 8 am through 10 am every day, once a day, 5 times a week, totally for 6 weeks. Separately, before treatment and in 2, 4 and 6 weeks of treatment, the morning blood pressure, the control rate and the symptom score were observed in the patients of the three groups. The morning blood pressure was followed up in 3 and 6 months separately. RESULTS: Compared with those before treatment, in 2, 4 and 6 weeks of treatment, the levels of blood pressure reduced in the patients of the three groups (P<0.05, P<0.01). After 2-week treatment, the differences were not significant in the morning blood pressure and its control rate in the patients of the three groups (all P>0.05). In 4 and 6 weeks of treatment, the levels of the morning blood pressure in the No.2 acupuncture group were lower than those in the No.1 acupuncture group, and the results in the No.1 and No.2 acupuncture groups were all lower than those in the medication group (all P<0.05). In the follow-up visit for 3 and 6 months separately, the differences were not significant in the morning blood pressure among the three groups (all P>0.05). In 2, 4 and 6 weeks of treatment, the symptom scores reduced as compared with those before treatment in the three groups (all P<0.05). The symptom scores in the No.1 and No.2 acupuncture groups were all lower than those in the medication group (all P<0.05). The differences were not significant between the No.1 acupuncture group and the No.2 acupuncture group (all P>0.05). CONCLUSION: The comprehensive treatment of acupuncture at Fengchi (GB 20) and Neck-Jiaji (EX-B 2) combined with acupuncture technique for activating blood circulation, eliminating wind and regulating the liver and spleen achieve the effects of reducing the morning blood pressure in the patients with essential hypertension, relieving the symptoms of hypertension such as headache, vertigo and tinnitus and the effects are better than those of the acupuncture technique for activating blood circulation, eliminating wind and regulating the liver and spleen. PMID- 29696916 TI - [Adjuvant treatment of acupoint catgut embedding for essential hypertension and its effects on vascular endothelial function]. AB - OBJECTIVE: To observe the effects of acupoint catgut embedding assisting western medication and simple western medication on blood pressure and vascular endothelial function in patients with essential hypertension (EH), and to explore its mechanism. METHODS: A total of 125 cases were randomly assigned into an observation group (62 cases, 2 dropping) and a control group (63 cases, 3 dropping). Oral administration of lotensin (10 mg, once a day) was applied in the control group. Based on the treatment as the control group, acupoint catgut embedding was applied at Fengchi (GB 20), Ganshu (BL 18), Shenshu (BL 23), Quchi (LI 11), Zusanli (ST 36), Sanyinjiao (SP 6) and Taichong (LR 3) in the observation group, once every two weeks, and six treatments was taken as one session. All the patients were treated for 3 months. The blood pressure and the vascular endothelial injury markers, including endothelin-1 (ET-1), nitric oxide (NO), high sensitive C reactive protein (hsCRP) were recorded before and after treatment in the two groups. In addition, the ET-1, NO and hsCRP were collected from 60 cases of healthy participants. RESULTS: The diastolic blood pressure and systolic blood pressure reduced after treatment in the two groups (all P<0.05), which were more significant in the observation group (P<0.01, P<0.05). Before treatment, compared with those of the healthy participants, ET-1 and hsCRP were higher but NO was lower in the observation group and the control group (all P<0.05); after treatment, ET-1 and hsCRP were reduced and NO increased in the two groups (all P<0.05), which were more significant in the observation group (all P<0.05). After treatment, the differences of NO and hsCRP between the observation group and healthy participants were not significant (both P>0.05). The marked effective rate was 70.0% (42/60) in the observation group, which was superior to 33.3% (20/60) in the control group (P<0.05); the total effective rate was 96.7% (58/60) in the observation group, which was superior to 85.0% (51/60) in the control group (P<0.05). CONCLUSION: The vascular endothelial function is injured in EH patients. Based on lotensin treatment, acupoint catgut embedding could significantly improve blood pressure and vascular endothelial function. PMID- 29696917 TI - [Acupuncture combined with acupoint catgut embedding sequential therapy for mild and moderate ulcerative colitis]. AB - OBJECTIVE: To observe the efficacy of acupuncture combined with acupoint catgut embedding sequential therapy and medication for mild and moderate ulcerative colitis. METHODS: One hundred and twenty patients were randomized into an acupuncture and acupoint catgut embedding sequential therapy group (a combination group) and a mesalazine group, 60 cases in each one. Fifty-seven cases in the combination group and 55 cases in the mesalazine group were included into analysis. In the combination group, acupuncture was applied at Tianshu (ST 25), Shangjuxu (ST 37), Quchi (LI 11) during the activity period, and acupoint catgut embedding was applied at Pishu (BL 20), Zusanli (ST 36), Guanyuan (CV 4) during the alleviate period. The patients in the mesalazine group were treated with mesalazine orally. The treatment was given for 12 weeks. The scores of TCM symptoms, colonoscopy, mucosa healing rate were compared before and after treatment in the two groups. The effects, adverse reactions and the recurrent rates during 1-year follow-up were observed. RESULTS: After treatment, the scores of TCM symptoms decreased in the two groups (both P<0.05), and the result in the combination group was better than that in the mesalazine group (P<0.05). The total effective rate in the combination group was 87.7% (50/57), which was better than 70.9% (39/55) in the mesalazine group (P<0.05). The colonoscopy scores decreased after treatment in the two groups (both P<0.05). There was no significant difference between the two groups on colonoscopy score and mucosal healing rate [50.9% (29/57) vs 34.5% (19/55), both P>0.05]. The recurrent rate in the combination group was 8.5% (4/47),which was lower than 32.4% (11/34) in the mesalazine group (P<0.05). No severe adverse reaction was found during the treatment in the two groups. CONCLUSION: Acupuncture combined with acupoint catgut embedding sequential therapy can improve mild and moderate ulcerative colitis and reduce the recurrent rate. PMID- 29696918 TI - [Efficacy of acupuncture as adjunctive treatment on infertility patients with polycystic ovary syndrome]. AB - OBJECTIVE: To observe the efficacy differences between acupuncture combined with medication and medication alone for infertility patients with polycystic ovary syndrome (PCOS). METHODS: According to random number table, a total of 60 infertility patients with PCOS were randomly assigned into an observation group and a control group, 30 cases in each one. The patients in the control group were treated with diane-35 from the 3rd day into menstruation, and one menstrual cycle was taken as a session of treatment. At the same time of using diane-35, the patients in the observation group were treated with acupuncture at Guanyuan (CV 4), Qihai (CV 6), Sanyinjiao (SP 6), Zusanli (ST 36), Zigong (EX-CA 1), Shenshu (BL 23), Pishu (BL 20), Weishu (BL 21) and Ganshu (BL 18) during non-menstruation period; the acupuncture was given once every two days, three treatments per week. The patients in both groups were treated for two sessions. The basic sex hormone and body mass index (BMI) were compared between the two groups before and after treatment. After ovulation induction treatment, the endometrial thickness, amount of mature follicle, ovulation rate, clinical pregnancy rate, occurrence rate of ovarian hyperstimulation syndrome (OHSS) and the number of early spontaneous abortion were compared between the two groups during ovulation. RESULTS: After treatment, the luteinizing hormone (LH), testosterone (T) and BMI reduced in the observation group (all P<0.05), while only LH reduced in the control group (P<0.05). The reducing of estradiol (E2), T and BMI in the observation group was more significant than that in the control group (all P<0.05). The ovulation rate was 93.3% (28/30) in the observation group, which was higher than 80.0% (24/30) in the control group (P<0.05). The rate of clinical pregnancy was 43.3% (13/30) in the observation group, which was higher than 33.3% (10/30) in the control group (P<0.05). The differences of endometrial thickness, amount of mature follicle, occurrence rate of OHSS and number of early spontaneous abortion were not significant between the two groups (all P>0.05). CONCLUSION: Acupuncture as adjunctive treatment could improve BMI, reduce the levels of LH, E2 and T, increase ovulation reaction and effectively shorten reproduction cycles in infertility patients with PCOS. PMID- 29696919 TI - [Therapeutic effects of acupuncture combined with rehabilitation training on dysphagia in post-stroke pseudobulbar palsy]. AB - OBJECTIVE: To compare the therapeutic effects on dysphagia in post-stroke pseudobulbar palsy between the combined treatment with acupuncture and rehabilitation training and the combined treatment with low-frequency electrical therapy and rehabilitation training and to explore its more effective therapy, using the ultrasonographic examination. METHODS: A total of 60 patients of dysphagia in post-stroke pseudobulbar palsy were randomly assigned into an observation group and a control group, 30 cases in each one. The rehabilitation treatment was provided in the two groups. Additionally, in the observation group, acupuncture was used at the three-tongue points [Shanglianquan (Extra), located in the depression between the lingual bone and the border of lower jaw, 1 cun inferior to the midline of the jaw; and the other two points, located at 0.8 cun bilateral to Shanglianquan (Extra)], bilateral Fengchi (GB 20) and Fengfu (GV 16). After arrival of qi, the last two tongue-points were stimulated with electricity, with disperse-dense wave, periodically at 2 Hz, 10 Hz and 100 Hz, at the interval of 3 s, lasting for 30 min. Bilateral Fengchi (GB 20) was stimulated with electricity, with disperse-dense wave and the same frequency as above, lasting for 30 min. In the control group, the low-frequency electrical stimulation was adopted. The electrodes were placed on the bilateral sides of the midline of the throat, 30 min each time. The treatment was for 1 month in the two groups, once a day. The scores of the standardized swallowing assessment (SSA) and the videofluoroscopy swallowing study (VFSS) were observed and the reducing rate of the hyoid-thyroid cartilage distance was determined with ultrasound quantitative measure. RESULTS: After treatment, SSA scores of the two groups were all lower than those before treatment and VFSS scores were higher than those before treatment (all P<0.05). The above scores in the observation group were better than those in the control group (both P<0.05). The reducing rates of the hyoid-thyroid cartilage distance were higher than those before treatment in the two groups (both P<0.05). The result in the observation group was higher than that in the control group (P<0.05). CONCLUSION: The treatments with acupuncture and rehabilitation training or with the low-frequency electrical therapy and rehabilitation obtain the effects on dysphagia in post-stroke pseudobulbar palsy in the patients. The effects of the combined treatment with acupuncture and rehabilitation training are better. The ultrasonographic technology effectively and quantitatively analyzes the changes in the glossopharyngeal complex in the patients of dysphagia. PMID- 29696920 TI - [Clinical observation on idiopathic tinnitus treated with acupuncture, buzhong yiqi tang and cizhu wan]. AB - OBJECTIVE: To observe the differences in the clinical therapeutic effects on idiopathic tinnitus between the combined therapy with acupuncture and the modified formula of buzhong yiqi tang and cizhu wan and the simple administration of the modified formula of buzhong yiqi tang and cizhu wan. METHODS: A total of 60 patients were randomized into a combined treatment group and an herbal medicine group, 30 cases in each one and 2 cases dropped out in the herbal medicine group. In the combined treatment group, acupuncture was given at the local acupoints for tinnitus, such as Yifeng (TE 17), penetrating needling technique from Ermen (TE 21) to Tinggong (SI 19) and Tinghui (GB 2) combined with the scalp acupuncture [the vertigo-auditory area, Baihui (GV 20)] and the oral administration of the modified formula of buzhong yiqi tang and cizhu wan. In the herbal medicine group, the oral administration of the modified formula of buzhong yiqi tang and cizhu wan was only applied. The treatment was given once a day in each group, 5 times a week for acupuncture and 7 times a week for the oral administration of herbal medicine. Totally, the treatment for 6 weeks was required in the two groups. Before and after treatment, the tinnitus severity score (TSS) and the score of tinnitus handicap inventory (THI) were observed and the clinical therapeutic effects were compared between the two groups. RESULTS: After treatment, the TSS and THI scores reduced as compared with those before treatment in the two groups (all P<0.05). The scores in the combined treatment group were lower than those in the herbal medicine group (both P<0.05). The total effective rate in the combined treatment group was 93.3% (28/30), better than 67.9% (19/28) in the herbal medicine group (P<0.05). CONCLUSION: The combined treatment with scalp acupuncture, acupuncture around the ear and the modified formula of buzhong yiqi tang and cizhu wan achieve the superior therapeutic effects on idiopathic tinnitus as compared with the simple oral administration of the modified formula of buzhong yiqi tang and cizhu wan. PMID- 29696921 TI - [Acupuncture for female depression: a randomized controlled trial]. AB - OBJECTIVE: to observe the effect differences and safety between acupuncture and sham acupuncture for female depression on the basis of conventional western medicine therapy. METHODS: Forty-two patients with depression who met the criteria were randomly assigned into an observation group and a control group, 21 patients in each group. The basic treatment in the two groups was fluoxetine. The patients in the observation group were treated with acupuncture at Zhongwan (CV 12), Xiawan (CV 10), Qihai (CV 6), Guanyuan (CV 4) and bilateral Shangqu (KI 17). Sham acupuncture was used at the above points in the control group. The treatment was given once a day on the first 3 days and once every 3 days after that, totally for 8 weeks. The scores of self-rating depression scale (SDS) and Montgomery Asberg depression rating scale (MADRS) were compared before and after 4-week and 8-week treatment in the two groups. The effects and adverse reactions were evaluated. RESULTS: After 4-week and 8-week treatment, the SDS and MADRS scores were significantly lower than those before treatment in the two groups (all P<0.05), and the scores in the observation group were lower than those in the control group (both P<0.05). The improvements of SDS and MADRS scores in the observation group before and after treatment were better than those in the control group (both P<0.05). The total effective rates of SDS, MADRS scores were 85.7% (18/21), 90.5% (19/21) in the observation group, which were better than 38.1% (8/21), 57.1% (12/21) in the control group (both P<0.05). The adverse reactions in the observation group were significantly lower than those in the control group (P<0.05). CONCLUSION: Acupuncture combined with fluoxetine are effective and safe for female depression. PMID- 29696922 TI - [Effects on the regional homogeneity of resting-state brain function in the healthy subjects of gastric distention treated with acupuncture at the front-mu and back-shu points of the stomach, Weishu (BL 21) and Zhongwan (CV 12)]. AB - OBJECTIVE: To observe the regional homogeneity (ReHo) of resting-state brain function in the healthy subjects of gastric distention treated with acupuncture at the back-shu and front-mu points of the stomach, Weishu (BL 21) and Zhongwan (CV 12) and the correlation with gastric motility so as to explore the mechanism on the central integration of the front-mu and back-shu points of the stomach. METHODS: The crossover test design was adopted. Twenty-four healthy subjects were assigned to a Weishu group, a Zhongwan group and a combined-point group separately, 8 cases in each one in each of the three times. Totally, 24 subjects were included in each group. Under the water load condition, the subjects received acupuncture at Weishu (BL 21), Zhongwan (CV 12) and the combined Weishu (BL 21) and Zhongwan (CV 12). Before and after each acupuncture, the resting state brain functional magnetic resonance imaging (fMRI) scan and electrogastrogram (EGG) test were applied. The ReHo value was calculated in the collected fMRI imaging data. The changes in ReHo values were analyzed and compared before and after acupuncture in each group, as well as among the groups. The gastric motility was analyzed before and after acupuncture. Additionally, the correlative analysis was conducted between the gastric motility and ReHo changes before and after acupuncture. RESULTS: (1) After acupuncture, EGG amplitudes in the subjects of each group were lower remarkably as compared with those before acupuncture (all P<0.01). The EGG frequencies were not different significantly as compared with those before acupuncture (all P>0.05). The EGG amplitudes in the Weishu group and the Zhongwan group were higher than those in the combined-point group (both P<0.05). (2) As compared with the conditions before acupuncture, acupuncture at the combined front-mu and the back-shu points as well as Weishu (BL 21) and Zhongwan (CV 12) separately all induced the changes in the brain ReHo. Acupuncture at the combined front-mu and the back-shu points significantly increased Reho values in the right inferior temporal gyrus, the left thalamus, the precuneus and the posterior cingulate gyrus (all P<0.05) and remarkably reduced the ReHo values in the the middle temporal gyrus of the right temporal pole, sulcus calcarinus and precuneus (all P<0.05). Compared with the single point groups, acupuncture at the combined front-mu and the back-shu points induced the increase of ReHo value in the posterior cingulate gyrus and the decrease of ReHo in the temporal pole (all P<0.05). (3) The correlative analysis showed that the changes in the ReHo values in the posterior cingulate gyrus, the thalamus and the precuneus were positively correlated to the changes of the gastric motility amplitudes. The changes in the ReHo values in the temporal pole was negatively correlated to the changes of the gastric motility amplitudes. CONCLUSION: Acupuncture at the combined back-shu and front-mu points of the stomach, as well as acupuncture at single Weishu (BL 21) and Zhongwan (CV 12) induce the ReHo changes in the different brain regions. Acupuncture at the combined back-shu and front-mu points of the stomach may induce the ReHo changes in some new brain regions as compared with the acupuncture at the single point. The thalamus, the posterior cingulate gyrus and the precuneus may be the the important integrated brain regions for acupuncture at the back-shu and the front mu points in regulating the gastric motility. The effects of acupuncture at the back-shu and the front-mu points for the regulation of the gastric motility are closely related to the thalamus, the limbic system and the default network of the brain regions. PMID- 29696923 TI - [Exploration on the application of Qimen (LR 14) in Treatise on Febrile Diseases]. AB - In Treatise on Febrile Diseases, ZHANG Zhongjing had used Qimen (LR 14) for the most times compared with other acupoints among the limited numbers of acupuncture prescriptions. Qimen (LR 14) is the front-mu point of the liver meridian, acting on smoothing liver qi and regulating qi activity. It is commonly used to treat the disorders caused by retarded circulation of qi and blood, such as distension and pain of the hypochondriac region and masses. Based on the opening-closing pivot theory of the six meridians, the specificity of the running course of the jueyin meridian and the property of Qimen (LR 14), the mechanisms of Qimen (LR 14) were analyzed on the treatment of febrile diseases, aiming to enhance the considerations and application of this points in clinical practice and contribute to the further understanding of ZHANG Zhongjing' s academic thoughts on the syndrome differentiation in the treatment of diseases. PMID- 29696924 TI - [The theoretical basis, experimental verification and significance of revealing meridians]. AB - In this paper, scientific theory was used to prove that the meridian was the resonant channel of information energy of life, and experiment and demonstration was performed to reveal meridians to explore the significance of revealing meridian. Based on the theory of physics, biochemistry, molecular biology and information theory, the essence of meridian was demonstrated in theory. According to TCM meridian theory, acupuncture was applied at selected acupoints; the infrared thermograms of stomach meridian of foot yangming, large intestine meridian of hand yangming, small intestine meridian of hand taiyang, pericardium meridian of hand jueyin, heart meridian of hand shaoyin, triple energizer meridian of hand shaoyang, liver meridian of foot jueyin, bladder meridian of foot taiyang were recorded before and after acupuncture. As a result, thermogram recorded and showed the visual image of the meridian. It is indicated that an energy transmission network which cannot be dissected existing in the body, which was believed to be meridian. It was the resonant channel of information energy of life, and could be shown by thermogram. These experiments and theory have significance in science. PMID- 29696925 TI - [Effects of electroacupuncture at "Changqiang" (GV 1) on expression of nerve growth factor and brain derived neurotrophic factor in rats after acute spinal cord injury]. AB - OBJECTIVE: To observe the effects of electroacupuncture (EA) at"Changqiang"(GV 1) on expression of nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF) in rats after acute spinal cord injury (ASCI), and to explore the mechanism of EA at"Changqiang"(GV 1) on ASCI. METHODS: Twenty-four adult female SD rats were randomly divided into an EA group, a model group and a sham operation group, 8 rats in each one. The rats in the sham operation group were treated with laminectomy to expose the spinal cord without any strike. The rats in the model group and EA group were treated with modified Allen's method to establish ASCI model. After model was established, the rats in the EA group were treated with EA at"Changqiang"(GV 1), once a day for continuous 7 days. The rats in the sham operation group and model group were treated with immobilization, once a day, without any other interventions. The basso beattie bresnahan (BBB) was evaluated 1, 3, 5, 7 days after operation. 7 days after operation, the rats were sacrificed with perfusion and the spinal cord was embedded with paraffin. The morphological changes of spinal cord and neuron were observed by Nissl's staining method; the expressions of NGF and BDNF were detected by immune fluorescence method. RESULTS: 3 days, 5 days and 7 days after operation, the BBB scores in the EA group were higher than those in the model group (P<0.05, P<0.01). The Nissl's staining indicated the gray matter of spinal cord was butterfly-shaped with complete structure and clear boundaries between the gray and white matter; the tabby-shaped Nissl bodies were observed in cytoplasm. There were incomplete gray nucleus, big and saturate local stasis plaque. Compared with the model group, the smallerarea of blood stasis, less severity of neuron edema, better morphology of neuron and no vacuole change were observed in the EA group. The immune fluorescence results indicated the expressions of NGF and BDNF in the model group and EA group were higher than those in the sham operation group (all P<0.01); the expressions of NGF and BDNF in the EA group were higher than those in the model group (both P<0.01). CONCLUSION: EA at"Changqiang"(GV 1) could improve the expression of NGF and BDNF and increase the score of BBB in rats with ASCI, which is beneficial to the repair of ASCI. PMID- 29696926 TI - [Protective effects of electroacupuncture pretreatment on ovarian in rats with premature ovarian insufficiency]. AB - OBJECTIVE: To explore the protective effect and possible mechanism of electroacupuncture (EA) pretreatment at "Zhongliao" (BL 33) and "Tianshu" (ST 25) on ovarian in rats with premature ovarian insufficiency (POI). METHODS: A total of 32 SD female rats with regular estrus were randomly divided into a blank group, a model group, an EA group and an immobilization group, 8 rats in each one. The rats in the model group, EA group and immobilization group were treated with intraperitoneal injection of 4-vinylcyclohexene diepoxide (160 mg/kg) for 15 days to establish the model. From the beginning of model establishment, the rats in the EA group were treated with EA pretreatment at "Zhongliao" (BL 33) and "Tianshu" (ST 25), once a day for the first two weeks (5 treatments per week) and once every two days for the last two weeks (3 treatments per week). EA was given 20 min per treatment for four weeks. The rats in the immobilization group were treated with immobilization with identical duration, frequency and total amount as the EA group. No treatment was given in the blank group and model group. When model was successfully established in the model group, rats were sacrificed to test the weight of sexual gland and the sexual gland index; the ELISA method was applied to test the level of anti-mullerian hormone (AMH) and inhibin B; the radioimmunoassay method was applied to test the level of follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), progesterone (P) and testosterone (T). In addition, the morphology and the number of ovarian follicles were observed; and western blot method was applied to test the expression of B cell lymphoma-2 (Bcl-2) and Bcl-2-associated X protein (Bax) in ovarian tissue. RESULTS: Compared with the blank group, the bilateral ovary weight, ovary index, uterus weight and uterus index decreased (P<0.05, P<0.01); serum AMH, inhibin B, E2 and P reduced, while serum FSH, LH and T increased in the model group (all P<0.01); primordial follicles and primary follicles decreased, while atretic follicles increased in the model group (all P<0.01); the expression of Bax protein increased, while the expression of Bcl-2 protein decreased in the model group (both P<0.01). Compared with the model group, the bilateral ovary weight, ovary index and uterus weight increased (P<0.05, P<0.01); serum AMH, inhibin B, E2 and P increased, while serum FSH and LH reduced (P<0.05, P<0.01); primordial follicles and primary follicles increased, while atretic follicles reduced (P<0.05, P<0.01); the expression of Bax protein reduced, while the expression of Bcl-2 protein increased in the EA group (P<0.05, P<0.01). The differences of each outcome indexes were not significant between the model group and immobilization group (all P>0.05). CONCLUSION: EA pretreatment at "Zhongliao" (BL 33) and Tianshu (ST 25) for 4 weeks has certain protective effect on ovarian in POI rats, which is likely to be related with up-regulating ovarian granular cells, inhabiting the expression of Bcl-2 protein and down-regulating the expression of Bax protein. PMID- 29696927 TI - [Professor LAI Xinsheng's experience of acupuncture combined with medication for epilepsy]. AB - Professor LAI Xinsheng's experience of acupuncture combined with medication for epilepsy is summarized, which is explained from epilepsy's etiology and pathogenesis, diagnosis and treatment of acupuncture and medication, respectively. Besides, the theoretical foundation and use instruction of acupuncture technique "tong-yuan" for epilepsy are introduced. Professor LAI highly values the adherence to etiology and pathogenesis, pays attention to syndrome differentiation and searches for the primary disease cause. He proposes the wind, phlegm, stasis and deficiency are the pathogenesis of epilepsy, and points out acupuncture could be applied during attack stage and remittent stage, but electroacupuncture should be used with caution. Regulating spirit is the key for treating epilepsy. The combination of acupuncture and medication could regulate the governor vessel and guide qi to the origin, which have significant curative effect. PMID- 29696928 TI - [ZHANG Ren's experience in the treatment of cortical blindness with acupuncture: report of medical cases]. AB - ZHANG Ren's experience is introduced in the treatment of cortical blindness with the comprehensive acupuncture therapy for benefiting qi and resolving stasis. The comprehensive therapy includes acupuncture at Sishencong (EX-HN 1), Xinming No.1 (Extra), Shang Jianming, Chengqi (ST 1), Xinming No.2 (Extra), optic area and visual area (scalp acupuncture); acupoint injection applied alternatively at Qiuhou (EX-HN 7) and Taiyang (EX-HN 5); the auricular point paste stimulation at Brain Point, Shenmen (TF4), Gan (CO12), Shen (CO10), Yan (LO5), Eye No.1 and Eye No.2; as well as the tapping therapy with skin needle at Zhengguang No.1 and Zhengguang No.2. Additionally, 3 typical cases of cortical blindness are introduced. The coordination of the different acupuncture techniques is analyzed so as to explain its actions as benefiting qi, resolving stasis, promoting blood circulation and nourishment of the eyes. PMID- 29696929 TI - [Investigation and analysis on acupuncture-related contents in foreign clinical practice guidelines]. AB - OBJECTIVE: To investigate the recommendations of acupuncture therapy in foreign clinical practice guidelines (CPGs) so as to understand the situation of foreign acupuncture guidelines and provide the suggestions on the development of acupuncture CPGs. METHODS: A total of 5 website authorities were retrieved with the key words as "acupuncture" "moxibustion" "acupressure" and "electroacupuncture". RESULTS: A total of 93 papers on CPGs had been searched, of which, the most CPGs were collected in the National Guidelines Clearinghouse (NGC). 68 papers were screened according to the requirement of CPGs, with 26 diseases and symptoms included. Since 2012, CPGs on acupuncture therapies have increased remarkably. Regarding the recommendations on acupuncture, there were 35 papers recommending acupuncture, about accounting for 51.5%. Of them, 1 paper strongly recommended and 10 papers were against recommendation. There was no CPG for moxibustion recommendation. CONCLUSION: 1 The foreign recommendations are weak and brief on acupuncture. The qualities of CPGs are various among countries, which results in the limit guidance in clinical practice. The specific acupuncture CPG should be developed so as to guide the clinical strategy on acupuncture more effectively. 2 There are apparent limitations on the involved diseases between those mentioned in foreign CPGs and those in the treatment in foreign countries. Being the origin of acupuncture, China should proactively develop the advantages on acupuncture treatment and participate in the development of international CPGs. 3 The recommendation on moxibustion therapy is lack. In future research, the evaluation on the safety and effectiveness should draw attention. PMID- 29696930 TI - [Learning the new by restudying the old: discussion on "consolidating tendons when tendons involved in disorders"]. AB - In order to better understand and implement the treating principle of acupuncture as "consolidating tendons when tendons involved in disorders", the author explored the necessity of this principle in view of "the depth of disorder and depth of needle insertion" through explaining the meanings of it in the classic literature. In combination with the clinical experience, three recognitions were proposed. When treating tendon disorder, the correct recognition of disease is very important. The coordination of ashi points and the distal points enhances the therapeutic effects. Besides, the modern anatomic knowledge is assisted to the selection of acupoints. The study results enrich the connotation of this treating principle, explore the approach to the clinical treatment of the disorders of bones, joints and soft tissues and improve the therapeutic effects. PMID- 29696931 TI - [Nomenclature of Feiyang (BL 58) and its connotation exploration based on A-B Classic of Acupuncture and Moxibustion]. AB - A-B Classic of Acupuncture and Moxibustion (Zhen Jiu Jia Yi Jing) is the earliest and existed well-known work on acupuncture and moxibustion, with irreplaceable literature values and huge impacts on the later generations. Feiyang (BL 58) is the luo-connecting point of the bladder meridian and recorded 11 times in A BClassic of Acupuncture and Moxibustion. This book is the representative for the exploration on the acupoint nomenclature and clinical connotation. Through the investigation on the textual connotation of the specified terms and the alias of Feiyang (BL 58), it was discovered that the nomenclature of this acupoint was based on the main symptoms, the characters of the running course of meridian and acupuncture effects. It was proved that the unique property of this acupoint was as rising, dispersing and flying of meridian qi. In comparison of Huangdi Three Version of A-B Classic of Acupuncture and Moxibustion (Huangdi Sanbu Zhen Jiu Jia YiJing) of the printed edition of the Song Dynasty version and Meridian Collateral and Acupoints (Zhen Jiu Shu Xue Xue), it was found that the indications and connotation of Feiyang (BL 58) were more extensively richer than the records in teaching materials. Those study results contribute to the extension of the clinical application of this acupoint. PMID- 29696932 TI - [Origin and evolution of the thunder-fire moxibustion therapy]. AB - Through analyzing the origin and evolution of the thunder-fire moxibustion therapy, the mysteries and misunderstandings of it were revealed. As a result, a more objective and comprehensive recognition of this ancient therapy was displayed to the people nowadays. The thunder-fire moxibustion therapy maybe originate from the Taoism magic arts before the Yuan Dynasty and became matured in the middle of the Ming Dynasty. Two categories were divided during the long term evolution in the history. In one category, the peach twig was taken as the moxa material rather than moxa stick and the incantation of Taoism remained. Regarding the other category, the herbal medicine was mixed in the moxa stick and the herbal composition was relatively specified. The incantation was removed. The moxibustion in the first category vanished at the end of the Ming Dynasty. The latter one kept on development from the middle of the Ming Dynasty through the modern times. Additionally, the herbal composition of moxa material has been modified; the indication enlarged and the operation improved. This therapy is still developed and applied by many doctors at the present times. PMID- 29696933 TI - [Progress of fMRI-based deqi research in recent 10 years]. AB - OBJECTIVE: The research regarding the central mechanism of acupuncture deqi (arrival of qi) based on functional magnetic resonance imaging (fMRI) in recent 10 years was analyzed to summarize existing research achievements and experience. METHODS: The literature regarding fMRI-based deqi research published from January of 2007 through December of 2016 in CNKI and PubMed databases was collected. The research content and methods, including research design, inclusion criteria, acupoint selection and deqi evaluation, were analyzed. RESULTS: Totally 18 articles regarding the central mechanism of acupuncture deqi based on fMRI was included. According to research content, the literature was divided into two categories: deqi research and deqi sensation research. In deqi research, the differences of deqi and not deqi on brain functional activity were compared to summarize the central response pattern of deqi; in deqi sensation research, the differences of different sensations and intensities of deqi on central response were compared to explore the effects of different sensations and intensities of deqi on brain functional activity. In recent 10 years, the number of research gradually increased, and the type of design was various, mainly RCT and paired design. The majority of participants was healthy people, and single acupoint was the focus of researches, including Zusanli (ST 36), Waiguan (TE 5), Hegu (LI 4), etc. The evaluation of deqi was based on visual analogue scale (VAS). The research contents were mainly the effects of deqi and not deqi and different deqi sensations on brain function activities. The present studies confirmed that deqi and not deqi as well as different deqi sensations had different impacts on brain functional effects, and different acupoints had specific activated brain areas. There was a positive correlation between the degree of deqi and the intensity of the activation of brain regions. Furthermore, tingling sensation was not included to deqi sensations. CONCLUSION: The number and quality of fMRI-based deqi research need to be improved; the research content is simple, and research method is in exploratory stage. The results obtained in the literature are the phenomena of deqi in the central level, and it is imperative to summarize the essential link between deqi and the central effect through these phenomena to reveal the mechanism of deqi. The specific impact of deqi for brain function needs more clinical exploration. PMID- 29696934 TI - [Research progress of acupuncture and moxibustion for endometrial receptivity in recent 10 years]. AB - The research of acupuncture and moxibustion for endometrial receptivity in recent 10 years was reviewed. CNKI and PubMed databases were retrieved with "acupuncture" "moxibustion" and "endometrial receptivity" as key words. The retrieving time was from January of 2007 through December of 2016. As a result, 63 relevant papers were collected and 28 papers regarding clinical and experimental researches of acupuncture for endometrial receptivity were included into analysis. It was found that acupuncture and moxibustion could improve endometrial morphology (including the expression of pinopodes, endometrial thickness and the rate of endometrial type A), reduce the endometrial microcirculation (including endometrial pulsatility index, resistance index and hemodynamic index), increase the levels of estrogen and progesterone and the expressions of their receptors, and regulate the expression of molecular biological regulator (such as integrin, leukemia inhibitory factor, vascular endothelial growth factor and HOXA10). As a result, the endometrial receptivity was improved to provide good environment for embryo implantation and improve the pregnancy rate, which had significant advantage in the field of assisted reproductive technology. However, detections of pinopodes and integrin were invasive. Its application for clinical use had limitations. In addition, the evidence of acupuncture improving endometrial receptivity was still insufficient. By reviewing related research result, this paper further summarized and analyzed the action mechanism of acupuncture for endometrial receptivity to provide references for the clinical treatment. PMID- 29696936 TI - Relationship of calcification in the carotid or coronary arteries and osteoporosis in the elderly. AB - BACKGROUND: To investigate the correlation between senile osteoporosis and calcified plaques in the arteries and to study the common potential risk factors for loss of bone mass and calcified plaques in the arteries. METHODS: Eligible patients (>=60 years old) who received treatment in our hospital from January 2016 to December2016 were included in this study. Bone mineral density (BMD) was measured by dual-energy X-ray absorptiometry (DXA). Multivariate regression model was used to analyze the correlation of osteoporosis and loss of bone mass with the risk of calcified plaques in the carotid and coronary arteries. RESULTS: Compared with plaque-free group, patients in the group with calcified plaques were older with a lower bone mineral density, more cases of hypertension, diabetes and hyperlipidemia, higher levels of osteoprotegerin and leptin in serum and lower levels of serum adiponectin and 25 (OH) D. Severe loss of bone mass, osteoporosis and decreased serum level of 25 (OH) D were correlated with the occurrence of calcified plaques in the arteries after confounding factors such as age were adjusted. Severe loss of bone mass was remarkably correlative with the risk of calcified plaques and coexisting calcified plaques in the carotid and coronary arteries after confounding factors such as age were adjusted. CONCLUSIONS: Osteoporosis and severe loss of bone mass are closely related to plaques in the carotid and coronary arteries. The elderly population with severe low bone mass is the key target population for the prevention of cardiovascular events. PMID- 29696935 TI - Impaired Hippocampal Synaptic Plasticity and Enhanced Excitatory Transmission in a Novel Animal Model of Autism Spectrum Disorders with Telomerase Reverse Transcriptase Overexpression. AB - Recently, we have reported that animals with telomerase reverse transcriptase (TERT) overexpression exhibit reduced social interaction, decreased preference for novel social interaction and poor nest-building behaviors symptoms that mirror those observed in human autism spectrum disorders (ASD). Overexpression of TERT also alters the excitatory/inhibitory (E/I) ratio in the medial prefrontal cortex. However, the effects of TERT overexpression on hippocampal-dependent learning and synaptic efficacy have not been investigated. In the present study, we employed electrophysiological approaches in combination with behavioral analysis to examine hippocampal function of TERT transgenic (TERT-tg) mice and FVB controls. We found that TERT overexpression results in enhanced hippocampal excitation with no changes in inhibition and significantly impairs long-term synaptic plasticity. Interestingly, the expression levels of phosphorylated CREB and phosphory-lated CaMKIIalpha were significantly decreased while the expression level of CaMKIIalpha was slightly increased in the hippocampus of TERT overexpressing mice. Our observations highlight the importance of TERT in normal synaptic function and behavior and provide additional information on a novel animal model of ASD associated with TERT overexpression. PMID- 29696937 TI - The effects of atorvastatin on IL-6, CRP, blood lipid and myocardial protection of interventional therapy in patients with acute myocardial infarction. AB - BACKGROUND: To analyze the changes of interleukin-6 (IL-6), C-reactive protein (CRP), blood lipids and myocardial indexes after treatment of patients with acute myocardial infarction (AMI) with intensive atorvastatin and interventional therapy, and its clinical significance. METHODS: A total of 78 patients diagnosed with AMI in our hospital from March 2016 to February 2017 were selected, and divided into treatment group (n=39) and control group (n=39). Patients in treatment group were treated with intensive atorvastatin based on conventional therapy before and after percutaneous coronary intervention (PCI), while those in control group were treated with conventional therapy before and after PCI. The levels of serum IL-6, CRP, blood lipids [total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C)] and myocardial enzyme indexes [troponin T (TnT) and creatine kinase-MB (CK-MB)] at different time points were detected. The correlations among serum CRP, TC and TnT in treatment group before treatment were detected using the linear regression analysis, and changes in serum inflammatory factors, blood lipids and myocardial enzyme indexes in treatment group before and after treatment were analyzed. RESULTS: There were no statistically significant differences in general data, such as age, gender, BMI, history of hypertension, diabetes mellitus, cardiac insufficiency and smoking before treatment between treatment group and control group (P>0.05). There were no significant differences in levels of serum IL-6 and CRP before treatment between treatment group and control group, but they were decreased after treatment, and the curative effect in treatment group was significantly superior to that in control group. The differences were statistically significant (P<0.05). There were no significant differences in serum TC, TG, HDL-C and LDL-C levels before treatment between treatment group and control group. TC, TG and LDL-C were decreased but HDL-C was significantly increased after treatment compared with those before treatment. The differences were statistically significant (P<0.05). There were no significant differences in serum TnT and CK-MB levels before treatment between treatment group and control group. TnT and CK-MB were significantly increased at 24 h after treatment (P>0.05). TnT was still obviously increased, while CK MB returned to normal at 1 week after treatment. TnT and CK-MB were obviously decreased at 2 weeks after treatment. The curative effect in treatment group was superior to that in control group, and the difference was statistically significant (P<0.05). Correlation analyses of peripheral serum inflammatory factors, blood lipids and myocardial enzyme indexes showed that CRP (r=0.793, P<0.001) and TC (r=0.668, P<0.001) were positively correlated with TnT. The levels of serum inflammatory factors and blood lipids in treatment group before treatment, and at 24 h, 1 week and 2 weeks after treatment showed downward trends, and TnT was increased first and then decreased. CONCLUSIONS: The application of intensive atorvastatin for AMI patients, especially before PCI, has high safety, which can effectively reduce levels of serum inflammatory factors and blood lipids, protect myocardial cells after PCI and avoid injury. PMID- 29696938 TI - Analysis of OSAS incidence and influential factors in middle-aged and elderly patients with hypertension. AB - BACKGROUND: To investigate the detection rate and influencing factors of obstructive sleep apnea syndrome (OSAS) in middle-aged and elderly patients with hypertension. METHODS: A total of 440 patients with hypertension were selected as the research objects, all of them participated in the Berlin questionnaire survey, and the polysomnography (PSG) was performed on the patients with a high risk of OSAS. The detection rate of OSAS was analyzed, the clinical data between non-OSAS group and OSAS group were compared and stepwise linear regression and Logistic regression were used to analyze the related influencing factors to apnea hyponea index (AHI) and OSAS in hypertensive patients. RESULTS: A total of 235 patients completed PSG and 196 patients were diagnosed as OSAS with the detection rate of 83.40%. The detection rate of OSAS in male patients was higher than that in females (89.04% vs.74.16%, x2=8.025, P=0.006). The detection rates of OSAS in normal BMI group, overweight group and obesity group were 56.52%, 92.37% and 100%, respectively (x2=36.438, P<0.001). The detection rates of OSAS in normal waistline group and central obesity group were 74.42% and 88.59% (x2=7.539, P=0.016). The detection rates of OSAS in grade1, grade 2 and grade 3 hypertension groups were 57.47%, 98.23% and 100%, respectively (x2=44.623, P<0.001). BMI, systolic blood pressure (SBP), diastolic blood pressure (DBP), low density lipoprotein (LDL) and waist circumference of OSAS group were all higher than those in non-OSAS group (P<0.05). BMI, SBP and DBP were positively correlated with AHI (p<0.05), which were independent risk factors of OSAS [OR value (95%CI) = 2.548 (1.449-4.327), 1.342 (1.214-1.965) and 1.169 (1.025-1.622), respectively, P<0.05]. CONCLUSIONS: The incidence of OSAS in middle-aged and elderly patients with hypertension is high. High BMI, SBP, and DBP are independent risk factors of OSAS. PMID- 29696939 TI - Assessment of a topical product based on a mixture of polysulfated galactosaminoglycan in the topical treatment of postoperative blood extravasation (ecchymosis-hematoma) in phlebology. AB - BACKGROUND: The onset of bruising in surgery is a frequent event that can be a source of complications and delays in the patient's healing process (pigmentations, fibrosis, etc.). Having the help of an effective topical product that speeds up the resorption of blood extravasation can be an advantage in phlebological surgery and surgery in general. METHODS: Twenty-three patients both male and female (age range: 30-72 years) were enrolled. Twenty-two of them completed the study, all underwent venous surgery of the lower extremities (invagination stripping of the internal or external saphenous and Muller's ambulatory phlebectomy). The 22 patients were divided into 2 groups of 11 each and in a single blind study received topical daily therapy (every 12 hours) either in the form of a medication cream (active ingredient), or a placebo cream. All patients wore compression one-leg tights immediately after surgery, following measurement of the lower limb (Struva(r) 35 mmHg, Medi Italia, Zola Predosa, Bologna, Italy). The 30-day observational study was carried out using a standard photographic survey procedure. RESULTS: The topical application of polysulfated galactosaminoglycan showed a significantly higher rate of resorption of blood extravasations than in patients in the single blind study receiving topical therapy with the placebo (Fisher's Exact Test, dichotomous variable outcome, N.=22, with result P=0.0001<0.05). CONCLUSIONS: Topical therapy with a mixture of polysulfated galactosaminoglycans provides valid protection in the therapy of blood extravasations in phlebology and general surgery. PMID- 29696940 TI - Assessment of a topical product based on polysulfated galactosaminoglycan as an adjuvant in the treatment of acute STP and stasis dermo-hypodermitis. AB - BACKGROUND: Superficial thrombophlebitis (STP) is a relatively frequent pathology characterized by possible extension to the deep venous circulation, with notable local inflammatory reaction which is treated by subcutaneous administration of Fondaparinux. Stasis dermo-hypodermitis is characterized by cutaneous hyperpigmentation and eczema, treatment for which consists of the use of drugs targeting endothelial cells (mesoglycan, FFPM, sulodexide). In this study we evaluated the impact of local application of a mixture of semi-synthetic polysulfated galactosaminoglycans on the regression rate of STP and dermo hypodermitis in patients treated with best medical therapy (BMT). METHODS: Thirty patients (20 F and 10 M) were enrolled from May to December 2017, 20 with dermo hypodermitis due to stasis secondary to post-thrombotic syndrome (PTS) and 10 with acute STP of the great saphenous vein or its collaterals. Topical administration of the galactosaminoglycan-based product was added to the BMT of 10 pts with PTS and 5 pts with STP for 45-60 days. In all patients a Visual Analogical Scale (VAS) was used to assess the intensity of spontaneous and induced pain at 0, 15, 30, 45 and 60 days. RESULTS: With regard to PTS, VAS values at time 0 were comparable between the two groups, while at later times there was a progressive reduction in the score, with values of <=2 at 30 days for patients treated with the topical product based on galactosaminoglycans vs. 60 days for the other control subjects. With regard to STP, the values of VAS at time 0 between the two groups were comparable, while at time 15 the VAS value was lower in subjects treated with the topical product. CONCLUSIONS: This pilot study on the efficacy of a local formulation of a mixture of semi-synthetic polysulfated galactosaminoglycans highlighted the role of this product in accelerating the recovery of patients at the most advanced stages of chronic venous disease (CVD) and in the management of its complications. In the future, studies of larger series will be needed with the use of placebo to substantiate their effectiveness in these conditions and in other classes of CVD. PMID- 29696941 TI - Successful pregnancy in a woman previously suffering from beta-thalassemia following transplantation of ovarian tissue cryopreserved before puberty. AB - Ovarian tissue removed from a 9-year-old girl suffering from thalassemia was kept deep-frozen for 14 years before being transplanted back to the now adult woman. Subsequently, she conceived following IVF treatment and delivered a healthy baby where the oocyte derived from the transplanted tissue. This is the first woman worldwide to have a baby where the ovarian tissue was frozen pre-pubertally and expand the therapeutic options for rare genetic diseases like thalassemia and girls who suffer from childhood cancer. PMID- 29696943 TI - Fertility preservation in women, focusing on cancer, benign diseases and social reasons. PMID- 29696942 TI - Challenges of fertility preservation in leukemia patients. AB - An ongoing increase in survival rates among young leukemia patients is accompanied by a growing attention to possible long-term complications such as chemotherapy induced ovarian insufficiency and infertility. Therefore, an important element of the management of these patients is fertility preservation, which is challenged by considerations specific for leukemia. Such considerations include prepuberty, poor medical condition on presentation and the need for urgent chemotherapy, all of which may preclude the use of conventional assisted reproductive technologies. A restrictive approach towards utilizing cryopreserved ovarian tissue due to the risk for malignancy reintroduction on transplantation, further minimize the options that currently exist for these patients. This paper aims to provide up-to-date knowledge on gonadotoxicity associated with therapy regimens currently used in the treatment of leukemia. Different fertility preservation techniques are discussed, with an emphasis on efficacy, applicability and limitations in the context of leukemia. PMID- 29696944 TI - Endometrial cancer and hyperplasia rate in women before menopause with abnormal uterine bleeding undergoing endometrial sampling. AB - Introduction: Abnormal uterinebleeding (AUB) is the most commonsymptom of endometrial cancer (EC)and endometrial hyperplasia with(AH) or without (EH) atypia. Risk ofmalignancy and hyperplasia is significantlylower in premenopausalthan in postmenopausal women. Only10% of EC occurs before menopause.Obesity and age are well-recognizedrisk factors of endometrial cancer.Endometrial sampling is recommendedin women at high risk of endometrialmalignancy. The primary objectivewas to determine the incidenceof EC, AH and EH in premenopausalwomen undergoing dilation and curettage(D&C) because of AUB. Additionalobjective of the study wasto estimate the risk of EC and AH inoverweight and obese women withtwo types of AUB: heavy menstrualbleeding (AUB HMB) and intermenstrualbleeding (AUB-IMB), accordingto PALM-COEIN classification. Material and Methods: Retrospectivestudy in the population of womenundergoing D&C in tertiary hospitalbecause of AUB between Jan-2016and Dec-2016. The incidence of EC,AH, EH was established. The influenceof the variables: age, BMI, AUBHMB/AUB IMB on the occurrence ofabnormal histology (EC, AH, EH) wasevaluated. Finally, the model built byusing backward stepwise regressionand mechanism of v-fold cross validation,showed no statistically significantrelationship. Results: EC was detected in 2/213cases (0.9%; 95% CI 0.0003 to 0.036),AH in 3/213 cases (1.4%), giving a totalof 5/213 (2.3%) women with AH orEC. EH was detected in 16/213 (7.5%)women. High BMI raises the chance ofAH diagnosis: OR 1.16 (95% CI 1.05 1.28). The presence of HMB comparedto IMB reduces the chance of EH: OR0.24 (95% CI 0.07-0.9). IMB increasesthe chance for the diagnosis of EH 4.11 times compared toHMB (OR 4.1, 95% CI 1.1-14.9; p = 0.016). Conclusions: EC in premenopausal women with AUBundergoing D&C is rare. There is a need to search formore effective methods of selection of patients than commonlyused. Age and BMI do not seem to be factors thatshould be used to select patients. PMID- 29696945 TI - The effect of chewing-gum on dose rate of salivary gland in differentiated thyroid carcinoma patients treated with radioiodine. AB - BACKGROUND: Although, different methods have been suggested on reducing salivary gland radiation after radioiodine administration, an effective preventive or therapeutic measure is still debateful. To the best of our knowledge this is the second study that aimed to evaluate the effect of chewing-gum as a sialagogue on the radioiodine content of salivary gland, and radioiodine- induced symptoms of salivary gland dysfunction. METHODS: Twenty two patients who were referred to radioiodine therapy were randomized into chewing-gum (group A) and control (group B) groups. Anterior and posterior planar images including both head and neck were obtained 2, 6, 12, 24 and 48 hours after the administration of radioiodine in all patients and round regions of interest (ROI) were drawn for both left and right parotid glands with a rectangular ROI in the region of cerebrum as the background. All patients were followed once, 6 months after radioiodine administration via a phone call for subjective evaluation of symptoms related to salivary gland damage. RESULTS: There was no significant difference between the two groups regarding the mean age, gender and initial iodine activity. The geometric mean of background-corrected count per administrated dose and acquisition time was calculated for bilateral parotid glands. This normalized parotid count showed a significant reduction in net parotid count in both groups during the first 48 hours after the radioiodine administration. However, no significant difference was found between the groups according to the amount and pattern of dose reduction in this time period. CONCLUSIONS: This study revealed that chewing-gum had no significant effect on the radioiodine content of parotid glands during the first 48 hours after radioiodine administration. Also, no significant difference was found in the incidence of relevant symptoms after 6 months comparing both groups. PMID- 29696947 TI - The role of amino-acid PET in the light of the new WHO classification 2016 for brain tumors. AB - Since its introduction in 2016, the revision of the World Health Organization (WHO) classification of central nervous system tumors has already changed the diagnostic and therapeutic approach in glial tumors. Blurring the lines between entities formerly labelled as "high-grade" or "low-grade", molecular markers define distinct biological subtypes with different clinical course. This new classification raises the demand for non-invasive imaging methods focusing on depicting metabolic processes. We performed a review of current literature on the use of amino-acid PET (AA-PET) for obtaining diagnostic or prognostic information on glioma in the setting of the current WHO 2016 classification. So far, only a few studies have focused on combining molecular genetic information and metabolic imaging using AA-PET. The current review summarizes the information available on "molecular grading" as well as prognostic information obtained from AA-PET and delivers an insight into a possible interrelation between metabolic imaging and glioma genetics. Within the framework of molecular characterization of gliomas, metabolic imaging using AA-PET is a promising tool for non-invasive characterization of molecular features and to provide additional prognostic information. Further studies incorporating molecular and metabolic features are necessary to improve the explanatory power of AA-PET in glial tumors. PMID- 29696948 TI - Role of amino-acid PET in high-grade gliomas: limitations and perspectives. AB - Positron emission tomography (PET) using radiolabeled amino-acids was recently recommended by the Response Assessment in Neuro-Oncology (RANO) working group as an additional tool in the diagnostic assessment of brain tumors. The aim of this review is to summarize available literature data on the role of amino-acid PET imaging in high-grade gliomas (HGGs), with regard to diagnosis, treatment planning and follow-up of these tumors. Indeed, amino-acid PET applications are multiple throughout the evolution of HGGs. However, certain limitations such as lack of specificity, uncertain value for grading and prognostication or the limited data for treatment monitoring should to be taken into account, the latter of which are further developed in this review. Notwithstanding these limitations, amino-acid PET is becoming increasingly accessible in many nuclear medicine centers. Larger prospective cohort prospective studies are thus needed in order to increase the clinical value of this modality and enable its extended use to the largest number of patients. PMID- 29696946 TI - Conventional and advanced magnetic resonance imaging in patients with high-grade glioma. AB - Magnetic resonance imaging is integral to the care of patients with high-grade gliomas. Anatomic detail can be acquired with conventional structural imaging, but newer approaches also add capabilities to interrogate image-derived physiologic and molecular characteristics of central nervous system neoplasms. These advanced imaging techniques are increasingly employed to generate biomarkers that better reflect tumor burden and therapy response. The following is an overview of current strategies based on advanced magnetic resonance imaging that are used in the assessment of high-grade glioma patients with an emphasis on how novel imaging biomarkers can potentially advance patient care. PMID- 29696949 TI - Overview on current treatment standards in high-grade gliomas. AB - High-grade gliomas (HGGs) are the most common primary tumors of the central nervous system, which include anaplastic gliomas (grade III) and glioblastomas (GBM, grade IV). Surgery is the mainstay of treatment in HGGs in order to achieve a histological and molecular characterization, as well as relieve neurological symptoms and improve seizure control. Combinations of some molecular factors, such as IDH 1-2 mutations, 1p/19q codeletion and MGMT methylation status, allow to classify different subtypes of gliomas and identify patients with different outcome. The SOC in HGGs consists in a combination of radiotherapy and chemotherapy with alkylating agents. Despite this therapeutic approach, tumor recurrence occurs in HGGs, and new surgical debulking, reirradiation or second line chemotherapy are needed. Considering the poor results in terms of survival, several clinical trials have explored the efficacy and tolerability of antiangiogenic agents, targeted therapies against epidermal growth factor receptor (EGFR) and different immunotherapeutic approaches in recurrent and newly diagnosed GBM, including immune checkpoint inhibitors (ICIs), and cell- or peptide-based vaccination with unsatisfactory results in term of disease control. In this review we describe the major updates in molecular biology of HGGs according to 2016 WHO Classification, the current management in newly-diagnosed and recurrent GBM and grade III gliomas, and the results of the most relevant clinical trials on targeted agents and immunotherapy. PMID- 29696950 TI - Metformin and changes in serum lipid profile in lean patients with polycystic ovary syndrome. AB - Introduction: The aim of our studywas to assess the values of total cholesterol,high-density lipoprotein cholesterol(HDL-C), low-density lipoproteincholesterol (LDL-C) and triglyceridesbefore and after treatment with metforminin lean patients with polycysticovary syndrome (PCOS). Material and Methods: 32 patients received metformin 1500 mg per day inthree divided doses. Lipids measurementswere performed twice: beforeand after 6 months of treatment with metformin. Results: In lean patients withPCOS after treatment with metforminwe observed: statistically significantlower LDL-C levels (4.16+/-0.79 mmol/lvs 3.4+/-0.86 mmol/l, p<0.05) and triglycerideslevels (1.8+/-0.53 mmol/l vs1.12+/-0.64 mmol/l, p<0.05). We observedan increase in HDL values and a decreasein total cholesterol values, butthese changes were not statistically significant(1.5+/-0.71 mmol/l vs 1.71+/-0.69mmol/l, p=0.09; 5.87+/-0.92 mmol/l vs5.69+/-0.97 mmol/l, p=0.11). Conclusion: Our study showed thattreatment of 1500 mg metformin forabout six months among PCOS womenresults in an improvement in serumlipid profiles. We observed a significantdecrease in LDL-C and triglycerides valuesafter metformin therapy. PMID- 29696951 TI - The impact of gender on the frequency of syncope provoking factors and prodromal signs in patients with vasovagal syncope. AB - Introduction: According to theESC guidelines, syncope is a transientloss of consciousness causedby transient, general cerebral hypoperfusion,characterized by rapid onset,short duration and spontaneousrecovery. Objectives: The aim of the studywas a comparative analysis of syncopeprovoking factors and prodromalsigns in patients with vasovagalsyncope with consideration given togender. Materials and Methods: We investigated 80 patients, aged 18-74years with previously diagnosedvasovagal cause of syncope. Specialattention was paid to the frequencyof triggering factors and prodromal signs. Results: In the studied group themean age at first syncope was significantlylower in women (23.2+/-10.7)as compared to men (30.7+/-17.4).The mean total number of syncopaland presyncopal episodes was significantlyhigher in women (13.3+/-11.0vs. 7.8+/-6.6; 26.6+/-12.9 vs. 13.8+/ 6.9). Inthe group of men syncopal episodeswere more frequent after urinationand defecation. The remainingcircumstances related to syncopewere more prevalent in women, butonly the occurrence of a syncopalepisode during walking achievedstatistical significance. All the prodromalsigns that were analysed occurredmore frequently in the groupof women compared to men. Statisticalsignificance was achieved for theanalysed signs such as generalizedweakness, dyspnea, heart palpitations,cold sweats, feeling of cold orheat, visual disturbances, tinnitus,headache. Conclusions: Syncope provokingfactors and prodromal signs occurmore frequently in women. PMID- 29696952 TI - [CyberKnife for prostate cancer patients. Update of 200 patients treatment results]. AB - Introduction: This is an update regardingthe treatment results of 200prostate cancer patients' (PCP) CyberKnifebased radioablation (the firstgroup in Poland).The purpose of this study is reevaluation(after 2 years) of this treatmentmodality results of low (LR) andintermediate risk (IR) (including T2c)PCP and failure analysis. Material and Methods: 200 PCP (95LR, 86 IR, 19 T2c) 53 - 83 y.o. (mean 69)treated between 2011 and 2014. 48%used neoadjuvant ADT. The patientswere irradiated every other day witha fraction dose of 7.25 Gy to the totaldose 36.25 Gy (5 fractions in 9 days).Fiducials based tracking was performed.The patients were controlledon the treatment completion day, 1, 4,8 months later and subsequently every6 months. The PSA concentration,ADT usage, acute and late adverse effects(EORTC/RTOG) and other symptomswere evaluated. FU ranged from1 to 63.6 months (mean 32.2, median32.9). Results: The adverse effects percentagewas very low; only 1 monthafter treatment the percentage ofacute urinary reaction exceeded 40%.Only single G3 adverse effects werenoted. Over 4 months the medianPSA concentration declined from 3.75to 0.27 ng/ml. 9 failures (4.5%) werenoted - more among IR and patientswithout neoadjuvant ADT. No failurein the T2c group was found. Mediantime to failure was 32.4 months. Coxanalysis revealed that the failure riskincreases with the value of maximalPSA before treatment. Conclusions: CK based radioablation of LR andIR PCP is a safe and highly effectivetreatment modality.The main prognostic factor of failureafter this treatment is probablythe maximal PSA concentration beforetreatment.The neoadjuvant ADT in IR groupshould be considered.The lack of failures in the T2c group enables us to suggestthat even more locally advanced patients (T3) withlow PSA and maximal Gleason 3+4 could be treated withthis modality. PMID- 29696953 TI - [The assessment of factors influencing occurrence of adequate interventions of cardiac resynchronization therapy with cardioverter-defibrillator implanted in primary prevention of sudden cardiac death in dilative cardiomyopathy and percentage of biventricular pacing]. AB - : The assessment of factors influencingoccurrence of adequate interventionsof cardiac resynchronizationtherapy with cardioverter-defibrillatorimplanted in primary prevention ofsudden cardiac death in dilative cardiomyopathyand percentage of biventricularpacing. Introduction: The function of cardiacresynchronization therapy withcardioverter-defibrillator (CRT-D) isto treat heart failure (HF) and to treatventricular arrhythmia, if it occurs,with adequate intervention. Aim: The aim of the study was tofind predictors of adequate interventionsand in how many patients biventricularpacing percentage decreasesduring the follow-up. Material and methods: The studycomprised of 228 patients (178 M,mean age 66+/-10, 31-89 years) withimplanted CRTD. The following datawere analyzed: age, sex, presenceof dilative cardiomyopathy, diabetesmellitus, lowered creatinine clearance,atrial fibrillation (AF), LVEF,NYHA class, adequate interventions,number of arrhythmias, pharmacotherapymodifications, device parametersand mortality. Results: Mean ejection fraction ofthe left ventricle was 20.9+/-6.4, (10.0-35%). During the mean follow up of770+/-490 days in 84 (37%) patientsadequate interventions of the deviceoccurred. The adequate interventionsconcerned mainly patients withdiabetes mellitus (HR 2.95), in NYHAclass II, with paroxysmal atrial fibrillation(HR 2.15). In 39 patients (17%) themean percentage of biventricular pacing was below 90%,and in 18 (8%) below 85%. Conclusions: Diabetes mellitus, NYHA class II, paroxysmal atrial fibrillationhave significantly increased the risk of adequateintervention. The most common causes of loss of biventricularpacing were: inappropriate AV delay, supraventricular arrhythmiasand premature ventricular complexes.A significant correlation between low biventricularpacing percentage and the occurrence of supraventriculararrhythmias and adequate interventions was observed. PMID- 29696954 TI - [Pulmonary complications after minimally invasive aortic valve replacement surgery - a propensity score matching analysis]. AB - Instruction: To answer the questionif minimally invasive aortic valvereplacement surgery through a rightanterior minithoracotomy (RT-AVR)may result in increased incidence ofpostoperative pulmonary complicationscompared to conventional aorticvalve replacement through a mediansternotomy (AVR). Material and Methods: It was retrospectiveanalysis of 212 patientsscheduled for RT-AVR and 212 forAVR between January 2011 and December2014 selected with propensityscore matching. Respiratory systemcomplications are analysed. Results: Postoperative blooddrainage was 353+/-249 and 524+/-325ml in RT-AVR and AVR groups respectively(p<0.001). Hospital stay was5.7+/-1.6 and 8.5+/-4.3 days (p<0.001),ICU stay was 1.3+/-1.2 and 2.6+/-2.8 days(p<0.001) in RT-AVR and AVR patientsrespectively. Respiratory systemcomplications occurred in 13.7% ofRT-AVR patients and 17.0% of AVRpatients (p=0.364). Pneumonia was diagnosedin 2.4% and 0.5% of patients(p=0.129), pneumothorax in 2.0% and1.3% of patients (p=0.515), pleural effusionin 8.5% and 7.5% of patients(p =0.732) and thoracentesis wasperformed in 7.1% and 7.5% of patientsfrom RT-AVR and AVR groupsrespectively. Mediastinitis was diagnosedin 0.0% of RT-AVR and 2.8% ofAVR patients (p=0.020). Phrenic nervedysfunction was present in 3.8% ofRT-AVR and in 0.0% of AVR patients(p=0.006). COPD (OR=5.5; p<0.001)and increased postoperative bloodloss (OR=3.5; p<0.001) were risk factorsof postoperative pulmonary complications. Conclusion: Minimally invasiveRT-AVR surgery did not result in increasedrate of postoperative pulmonarycomplications compared toconventional AVR surgery througha median sternotomy. PMID- 29696955 TI - Anemia in diabetic kidney disease - underappreciated but still clinically relevant problem. AB - Anemia is the most common disorderof the blood with iron deficiencybeing the predominant cause. On theother hand, diabetes prevalence isincreasing rapidly. Over time, diabetescan damage the heart, bloodvessels, eyes, kidneys, and nerves.Diabetic kidney disease (DKD) maybe present in both types 1 and type2 diabetes mellitus. Anemia is one ofthe common feature of chronic kidneydisease. The epidemiological data onanemia prevalence are limited. In thisreview data on epidemiology, pathogenesis,complication and treatmentof anemia in diabetic kidney diseaseare presented. PMID- 29696956 TI - [An historical, sociocultural view and in the fiction literature of Bacillus anthracis cases by shaving brushes]. AB - In the period from 1915 to 1924 anthrax outbreaks were described by Bacillus anthracis due to the contamination of razor brushes that reached Europe and the United States from areas such as Japan, China or Russia. The brushes were made with badger hair, and then, to reduce the cost with horse hair and other animals. World War I supoosed that the traffics of these brushes, that passed through Europe, changed and the processes of sterilization of the same were deficient giving rise to these outbreaks, that in a percentage of 20% produced the death of the users. The impact of the fashion of wearing a beard, the presence of these cases in the press, in the society of that period, and literature are studied through the work of Agatha Christie who wrote, in 1936, the Hercules Poirot's novel Cards on the table, and where she describes the murder of one of the characters with the shaving brush contaminated with Bacillus anthracis spores. PMID- 29696957 TI - [Turicella otitidis, contributions to its role in the etiology of ear infections]. AB - OBJECTIVE: Turicella otitidis is a gram-positive bacillus coryneforme described, after 16S RNA sequencing, in 1994 by Funke et al as a microorganism involved in otitis media, and it is in health conditions a habitual colonizer of the external auditory canal. Since its description, more than twenty years ago, few cases of otitis related to or directly attributed to this microorganism have been published. METHODS: Description of a case of mastoiditis that required surgery and other cases of otic pathology in which T. otitidis was isolated, in the second semester of 2017 in our institution. They were reported only when they grew in pure culture. The identification was made by mass spectrophotometry and an antibiogram was performed. RESULTS: In our institution in the second half of 2017, 5 cases of otitis media were documented, some of them complicated, in which T. otitidis was isolated. The most of patients were children with recurrent otic pathology, and in some cases the sample was taken before the administration of antibiotics. CONCLUSIONS: Since the inclusion of new vaccines that protect against microorganisms typically causing otitis media, is possible there are a change in the etiology of this disease and that microorganisms anecdotally isolated until now have become protagonists. The improvement in the microbiological identification provided by tools such as mass spectrometry will help to clarify if there are or not a change in the etiology of these diseases. PMID- 29696958 TI - [Vitamin D - from the past antirachitic factor to new pleiotropic substance]. AB - Vitamin D is known for almost 100years. Since time of its discovery, numerousstudies on vitamin D functionin the human body were performed.Considered from the beginning asan important factor in rickets prevention,thanks to the continuous developmentof knowledge, vitamin D isregarded now as an important factorfrom the point of view of the wholebody homeostasis. Newly-find featuresof vitamin D allow to use thissubstance concentration in serumas a biomarker of general health andcreate opportunities of vitamin D usein the prevention and treatment ofmany diseases. The aim of this articleis to present basic function ofvitamin D in human body, sources ofthis substance, its metabolism andmolecular mechanism of action, takinginto account the evolution of thestate of knowledge about Vitamin D- from early researches leading to itsdiscovery, through the finding of itsbasic functions to the present studieson vitamin D mechanisms of action atmolecular and genomic level. PMID- 29696959 TI - [Cardiac complications in rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis]. AB - Connective tissue diseases area group of more than 300 separatediseases. It can affect every system oforgans, including the cardiovascularsystem. This process is particularlyhighly expressed in rheumatoid arthritis,systemic lupus erythematosusand scleroderma.Rheumatoid arthritis (RA) affects0.5-1.0% of Europeans. The mostcommon cardiac manifestation of RAis pericarditis. Its main risk factor isthe occurrence of rheumatic nodulesin people with the presence ofserum rheumatoid factor. An importanthealth problem in RA is also anincreased risk of atherosclerosis andischemic myocardial disease, the intensityof which grows independentlyof traditional risk factors and mainlydepends on the severity of inflammationand duration of the disease. Inrheumatoid arthritis also endocarditis,heart valves damage and ventriculararrhythmias can occure.Systemic lupus erythematosus(SLE) is most common in womenbetween age 16 to 55. Cardiovascularcomplications of this disease arethe third biggest cause of death ofpatients. The most common cardiacmanifestation of SLE is pericarditisoccurring in approximately 20 to 50%of the ill. Libman-Sacks non-infectiousendocarditis characterized bythickening of the heart valves and thepresence of non-bacterial vegetationis characteristic for SLE.Systemic sclerosis is characterizedby progressive fibrosis of skinand internal organs and disorders ofthe morphology and function of bloodvessels. Cardiac manifestations ofsystemic sclerosis are mainly heartfailure and arrhythmias.The European League AgainstRheumatism (EULAR) has developeda number of recommendations relatedto the prevention and therapy ofcardiovascular events in RA. Since anincreased risk of cardiovascular complicationsapplies to many rheumaticdiseases, there is a need to extend these recommendationsto other connective tissue diseases. PMID- 29696960 TI - Reversible splenial lesion in neuroleptic malignant syndrome. PMID- 29696961 TI - Socio-economic status and the clinical acuity of emergency medical admissions. PMID- 29696962 TI - Alpha1-antitrypsin deficiency: what's new after European Respiratory Society Statement. AB - Alpha-1 antitrypsin deficiency (AATD) is a clinically under-recognized inherited disorder affecting the lungs and the liver. The most common manifestations are pulmonary emphysema, bronchiectasis and liver disease. The recent publication of the European Respiratory Society statement on diagnosis and treatment of pulmonary diseases has replaced the 2003 American Thoracic Society and European Respiratory Society one. New outcome parameters have been introduced and validated by observational and randomized clinical trials, and new information about efficacy and safety of augmentation therapy have been published. In this narrative review we have commented the crucial points of the new European Respiratory Society statement on AATD, including a review of the literature on liver involvement and treatments. PMID- 29696963 TI - Inflammatory cytokines in cardiac pacing patients with atrial fibrillation and asymptomatic atrial fibrillation. AB - BACKGROUND: To investigate the changes of inflammatory cytokines in cardiac pacing patients with atrial fibrillation and asymptomatic atrial fibrillation and the effects of metoprolol on them. METHODS: A total of 92 cardiac pacing patients with atrial fibrillation and asymptomatic atrial fibrillation in our hospital from April 2015 to March 2017 were selected and randomly divided into the control group and the observation group, with 46 cases in each group. Three months after pacemaker implantation, the control group was treated with aspirin, the observation group was treated with metoprolol on the basis of aspirin, and the curative effects were compared between the two groups. After treatment, the heart rate, the frequency and duration of atrial fibrillation and the atrial fibrillation load were observed. P-wave dispersion (PD) and cardiac function of the two groups of patients at 6 months after treatment were compared. The changes of serum levels of tumor necrosis factor-alpha (TNF-alpha), high sensitive C reactive protein (Hs-CRP) and interleukin-6 (IL-6) in patients were compared before treatment and at 1, 3 and 6 months after treatment. The quality of life of the two groups of patients was observed. RESULTS: After treatment, the effective rate of treatment in the observation group was significantly higher than that in the control group (P<0.05). After treatment, the average heart rate and atrial fibrillation load in the observation group were significantly improved compared with those in the control group, and the frequency and duration of atrial fibrillation were significantly lower than those in the control group (P<0.05). After treatment, the maximum P-wave duration (Pmax), the minimum P-wave duration (Pmin) and PD in the observation group were significantly lower than those in the control group (P<0.05). The left ventricular ejection fraction (LVEF) in the observation group was significantly higher than that in the control group, and the left ventricular end-diastolic volume (LVEDV), left ventricular end-systolic volume (LVESV) and E/A in the observation group were significantly lower than those in the control group (P<0.05). After treatment, the levels of TNF-alpha, Hs CRP and IL-6 in the two groups of patients were decreased significantly, and those in the observation group were significantly lower than those in the control group (P<0.05). The quality of life score in the observation group was significantly higher than that in the control group (P<0.05). CONCLUSIONS: Metoprolol can effectively reduce the incidence of atrial fibrillation, atrial fibrillation loadand inflammatory cytokine levels in cardiac pacing patients with atrial fibrillation and asymptomatic atrial fibrillation, and improve cardiac function of the patients and their quality of life. It has an important clinical significance. PMID- 29696964 TI - Current therapies and targets for type 2 diabetes mellitus. AB - The prevalence of type 2 diabetes mellitus (T2DM) has been increasing at an alarming rate. With an increased understanding of the pathophysiology and pathogenesis of T2DM, various new therapeutic options have been developed to target different key defects in T2DM. Incremental innovations of existing therapies either through unprecedented drug combinations, modified drug molecules, or improved delivery systems are capable to nullify some of the undesirable side effects of traditional therapies as well as to enhance effectiveness. The existing administration routes include inhalation, nasal, buccal, parenteral and oral. Newer drug targets such as protein kinase B (Akt/PKB), AMP-activated protein kinase (AMPK), sirtuin (SIRT), and others are novel approaches that act via different mechanisms and possibly treating T2DM of distinct variations and aetiologies. Other therapies such as endobarrier, gene therapy, and stem cell technology utilize advanced techniques to treat T2DM, and the potential of these therapies are still being explored. Gene therapy is plausible to fix the underlying pathology of T2DM instead of using traditional reactive treatments, especially with the debut of Clustered Regularly Interspaced Short Palindromic Repeats-CRISPR associated protein9 (CRISPR-Cas9) gene editing tool. Molecular targets in T2DM are also being extensively studied as it could target the defects at the molecular level. Furthermore, antibody therapies and vaccinations are also being developed against T2DM; but the ongoing clinical trials are relatively lesser and the developmental progress is slower. Although, there are many therapies designed to cure T2DM, each of them has their own advantages and disadvantages. The preference for the treatment plan usually depends on the health status of the patient and the treatment goal. Therefore, an ideal treatment should take patient's compliance, efficacy, potency, bioavailability, and other pharmacological and non-pharmacological properties into account. PMID- 29696965 TI - Cesarean scar pregnancy - case report and review. AB - Implantation of the embryo in thecesarean section scar is a rare formof ectopic pregnancy. Such conditionposes significant threat to a woman'shealth and live, therefore, requiresaccurate diagnosis and rapid implementationof treatment. The followingarticle presents the case of a patientwith a pregnancy located in the scarafter cesarean section treated in theDepartment of Gynecology and Obstetrics,Medical University of Silesiain Katowice, Faculty of Medicine inKatowice. PMID- 29696966 TI - [Postpartum thyroiditis as the first clinical manifestation of autoimmune polyendocrine syndrome type 2 - case report]. AB - Postpartum thyroiditis is a formof autoimmune thyroiditis developingduring the first 12 months postpartumin 5-10% of women as a consequenceof the immunologic flarefollowing the immune suppressionof pregnancy. Autoimmune polyendocrinesyndromes are rarely diagnosedconditions characterized bythe association of at least two organspecificautoimmune disorders, andon the basis of their clinical picture,they may be divided into four differenttypes. The underestimation oftheir real frequency probable resultsfrom physicians' inadequate knowledgeof these clinical entities andsometimes their atypical clinical picture.Although autoimmune thyroiddisease may be a component of bothtype 2 and 3 autoimmune polyendocrinesyndromes, but the associationbetween postpartum thyroiditisand autoimmune conditions of otherendocrine organs has very rarelybeen described in literature. We reporta case of a young woman, whoafter two subsequent pregnanciesdeveloped postpartum thyroiditisof different clinical pictures. Afterher second pregnancy, postpartumthyroiditis was followed by the developmentof autoimmune adrenalfailure and premature ovarian failure,which allowed to diagnose type 2 autoimmunepolyendocrine syndrome.Our case study suggests that everyperson with postpartum thyroiditis,particularly if this disorder is accompaniedby atypical clinical manifestation,should be assessed for thepossible presence of autoimmunepolyendocrine syndrome. PMID- 29696967 TI - Enhanced Imaging of Specific Cell-Surface Glycosylation Based on Multi-FRET. AB - Cell-surface glycosylation contains abundant biological information that reflects cell physiological state, and it is of great value to image cell-surface glycosylation to elucidate its functions. Here we present a hybridization chain reaction (HCR)-based multifluorescence resonance energy transfer (multi-FRET) method for specific imaging of cell-surface glycosylation. By installing donors through metabolic glycan labeling and acceptors through aptamer-tethered nanoassemblies on the same glycoconjugate, intramolecular multi-FRET occurs due to near donor-acceptor distance. Benefiting from amplified effect and spatial flexibility of the HCR nanoassemblies, enhanced multi-FRET imaging of specific cell-surface glycosylation can be obtained. With this HCR-based multi-FRET method, we achieved obvious contrast in imaging of protein-specific GalNAcylation on 7211 cell surfaces. In addition, we demonstrated the general applicability of this method by visualizing the protein-specific sialylation on CEM cell surfaces. Furthermore, the expression changes of CEM cell-surface protein-specific sialylation under drug treatment was accurately monitored. This developed imaging method may provide a powerful tool in researching glycosylation functions, discovering biomarkers, and screening drugs. PMID- 29696968 TI - Melanosome-Targeting Near-Infrared Fluorescent Probe with Large Stokes Shift for in Situ Quantification of Tyrosinase Activity and Assessing Drug Effects on Differently Invasive Melanoma Cells. AB - Tyrosinase (TYR) plays a vital role in melanin biosynthesis and is widely regarded as a relatively specific marker for melanocytic lesions which involve vitiligo, malignant cutaneous melanoma, Parkinson's disease (PD), etc. However, the detection of TYR in living cells with fluorescent probes is usually interfered by diverse endogenous reactive oxygen species (ROS) and reactive nitrogen species (RNS). Herein, we synthesized a melanosome-targeting near infrared (NIR) fluorescent probe (HB-NP) with a large Stokes shift (195 nm), achieving a highly sensitive and selective in situ detection for intracellular TYR, by incorporating a m-hydroxybenzyl moiety that recognizes TYR specifically and the morpholine unit which facilitates the probe accumulating in the melanosome into a salicyladazine skeleton. When treated with TYR, the probe itself with weak fluorescence is lit up via an inhibited photoinduced electron transfer (PET) effect and HB-NP shows a strong fluorescence signal (nearly 48 fold enhancement) with a low detection limit of 0.5 U mL-1. HB-NP has been successfully applied in visualizing and in situ quantification of the intracellular TYR activity. Moreover, owing to the different expression levels of TYR, two human uveal melanoma cells with different invasive behaviors are distinguished by means of bioimaging and the effects of the inhibitor, kojic acid, and the up-regulating treatment, psoralen/ultraviolet A, on TYR activity of the two melanoma cells are evaluated. HB-NP is expected to be a useful tool to monitor diseases associated with the abnormal level of melanin and screen medicines for TYR disorder more effectively. PMID- 29696969 TI - Photocatalytic CO2 Reduction by Trigonal-Bipyramidal Cobalt(II) Polypyridyl Complexes: The Nature of Cobalt(I) and Cobalt(0) Complexes upon Their Reactions with CO2, CO, or Proton. AB - The cobalt complexes CoIIL1(PF6)2 (1; L1 = 2,6-bis[2-(2,2'-bipyridin-6' yl)ethyl]pyridine) and CoIIL2(PF6)2 (2; L2 = 2,6-bis[2-(4-methoxy-2,2'-bipyridin 6'-yl)ethyl]pyridine) were synthesized and used for photocatalytic CO2 reduction in acetonitrile. X-ray structures of complexes 1 and 2 reveal distorted trigonal bipyramidal geometries with all nitrogen atoms of the ligand coordinated to the Co(II) center, in contrast to the common six-coordinate cobalt complexes with pentadentate polypyridine ligands, where a monodentate solvent completes the coordination sphere. Under electrochemical conditions, the catalytic current for CO2 reduction was observed near the Co(I/0) redox couple for both complexes 1 and 2 at E1/2 = -1.77 and -1.85 V versus Ag/AgNO3 (or -1.86 and -1.94 V vs Fc+/0), respectively. Under photochemical conditions with 2 as the catalyst, [Ru(bpy)3]2+ as a photosensitizer, tri- p-tolylamine (TTA) as a reversible quencher, and triethylamine (TEA) as a sacrificial electron donor, CO and H2 were produced under visible-light irradiation, despite the endergonic reduction of Co(I) to Co(0) by the photogenerated [Ru(bpy)3]+. However, bulk electrolysis in a wet CH3CN solution resulted in the generation of formate as the major product, indicating the facile production of Co(0) and [Co-H] n+ ( n = 1 and 0) under electrochemical conditions. The one-electron-reduced complex 2 reacts with CO to produce [Co0L2(CO)] with nuCO = 1894 cm-1 together with [CoIIL2]2+ through a disproportionation reaction in acetonitrile, based on the spectroscopic and electrochemical data. Electrochemistry and time-resolved UV-vis spectroscopy indicate a slow CO binding rate with the [CoIL2]+ species, consistent with density functional theory calculations with CoL1 complexes, which predict a large structural change from trigonal-bipyramidal to distorted tetragonal geometry. The reduction of CO2 is much slower than the photochemical formation of [Ru(bpy)3]+ because of the large structural changes, spin flipping in the cobalt catalytic intermediates, and an uphill reaction for the reduction to Co(0) by the photoproduced [Ru(bpy)3]+. PMID- 29696970 TI - Desymmetrization of Cyclopropenes via the Potassium-Templated Diastereoselective 7- exo- trig Cycloaddition of Tethered Amino Alcohols toward Enantiopure Cyclopropane-Fused Oxazepanones with Antimycobacterial Activity. AB - A strain-release-driven, cation-templated intramolecular nucleophilic addition of tethered alkoxides to prochiral cyclopropenes is described. Employment of chiral beta- and gamma-amino alkoxides allowed for highly diastereoselective assembly of a small series of enantiopure cyclopropane-fused oxazepanones. It was shown that the chiral center at C-4 plays a crucial role in controlling desymmetrization of the cyclopropenyl moiety, instigated by a profound potassium-templated effect. The preliminary biological activities of the new cyclopropane-fused medium heterocycles against Gram-positive bacteria, Gram-negative bacteria, mycobacteria, cancer cells, and fungus were evaluated. PMID- 29696971 TI - Simple Chip Electrophoresis Titration of Neutralization Boundary with EDTA Photocatalysis for Distance-Based Sensing of Melamine in Dairy Products. AB - Melamine was sometimes adulterated to dairy products for false protein content increase in developing countries. However, a portable sensor has not been developed for on-spot determination of melamine in dairy products yet. Herein, a distance-based sensor was advanced for the quantification of melamine in dairy products based on chip electrophoretic titration (ET) of moving neutralization boundary (NB) and EDTA photocatalysis. In the chip sensor, EDTA, H2O2, and leucomalachite green (LMG) were added in the anode well. Under UV light, EDTA photocatalyzes H2O2 and colorless LMG as H2O and color malachite green (MG) with one positive charge. When applying an electric field, the MG in the anode well migrated into the channel and was neutralized with the base in the channel, resulting in colorless MG-OH and NB. If the melamine-content dairy sample was added into the EDTA-H2O2-LMG system, H2O2 reacts with melamine, leading to the decrease of MG. Thus, the higher the melamine content in dairy products, the shorter the distance of NB migration under the given time, implying a distance based sensor of melamine. A series of experiments manifested the validity of ET NB sensor for detection of melamine. Moreover, the results revealed the numerous merits of ET-NB sensor, such as good selectivity, high sensitivity (LOD down to 0.20 MUM for milk and 0.10 MUM for infant formula vs the FDA safety limits of 20 MUM for milk and 8.0 MUM for infant formula), good repeatability and recoveries (87-108% for milk, 90-107% for formula). Particularly, the cell phone-like sensor was portable, simple (no any pretreatment), rapid (within 15 min), as well as low cost, to evaluate the quality of dairy products. The developed sensor has great potential in on-spot detection of melamine in dairy products as well as other analytes, at which we are testing in our lab. PMID- 29696972 TI - Changes in Phenolic Compounds and Phytotoxicity of the Spanish-Style Green Olive Processing Wastewaters by Aspergillus niger B60. AB - This study systematically investigated the degradation kinetics and changes in the composition of phenolic compounds in Spanish-style Chalkidiki green olive processing wastewaters (TOPWs) during treatment using Aspergillus niger B60. The fungal growth and phenol degradation kinetics were described sufficiently by the Logistic and Edward models, respectively. The maximum specific growth rate (2.626 1/d) and the maximum degradation rate (0.690 1/h) were observed at 1500 mg/L of total polar phenols, indicating the applicability of the process in TOPWs with a high concentration of phenolic compounds. Hydroxytyrosol and the other simple phenols were depleted after 3-8 days. The newly formed secoiridoid derivatives identified by HPLC-DAD-FLD and LC-MS are likely produced by oleoside and oleuropein aglycon via the action of fungal beta-glucosidase and esterase. The treated streams were found to be less phytotoxic with reduced chemical oxygen demand by up to 76%. Findings will provide useful information for the subsequent treatment of residual contaminants. PMID- 29696973 TI - Selective Synthesis of 3-(9 H-Carbazol-2-yl)indolin-2-ones and Spiro[tetrahydrocarbazole-3,3'-oxindoles] via a HOTf Catalyzed Three-Component Reaction. AB - A HOTf catalyzed three-component reaction of indoles, acetophenones, and ( E)-3 phenacylideneoxindolinones resulted in the unexpected polysubstituted 3-(9 H carbazol-2-yl)indolin-2-ones in good yields. A similar reaction with various cyclic ketones afforded the corresponding carbocyclic fused 3-(9 H-carbazol-2 yl)indolin-2-ones. On the other hand, ( E)-3-arylideneoxindolinones in the three component reaction gave the expected spiro[tetrahydrocarbazole-3,3'-oxindoles] through a domino alkenylation/Diels-Alder reaction. The unusual different reactivity of ( E)-3-phenacylideneoxindolinones and ( E)-3-arylideneoxindolinones in the three-component reactions was believed to involve the different reaction paths caused by the existence of the carbonyl group. PMID- 29696974 TI - Molecular Oxygen Mediated Radical Dicarbofunctionalization of Olefin with Aldehyde. AB - Herein we present a metal- and peroxide-free method for the synthesis of sterically hindered amides bearing an all-carbon quaternary stereogenic center at the alpha-position via a one-pot alkylation/aryl-migration/desulfonylation radical cascade. The novel process is developed employing readily available and inexpensive aldehyde as an alkyl radical precursor and O2 as the sole oxidant. The method features a broad substrate scope, operational simplicity, convenient reagents, and scalability. A radical chain mechanism that is initiated by O2 is proposed for the process. PMID- 29696975 TI - Visualizing Carrier Transport in Metal Halide Perovskite Nanoplates via Electric Field Modulated Photoluminescence Imaging. AB - Metal halide perovskite nanostructures have recently been the focus of intense research due to their exceptional optoelectronic properties and potential applications in integrated photonics devices. Charge transport in perovskite nanostructure is a crucial process that defines efficiency of optoelectronic devices but still requires a deep understanding. Herein, we report the study of the charge transport, particularly the drift of minority carrier in both all inorganic CsPbBr3 and organic-inorganic hybrid CH3NH3PbBr3 perovskite nanoplates by electric field modulated photoluminescence (PL) imaging. Bias voltage dependent elongated PL emission patterns were observed due to the carrier drift at external electric fields. By fitting the drift length as a function of electric field, we obtained the carrier mobility of about 28 cm2 V-1 S-1 in the CsPbBr3 perovskite nanoplate. The result is consistent with the spatially resolved PL dynamics measurement, confirming the feasibility of the method. Furthermore, the electric field modulated PL imaging is successfully applied to the study of temperature-dependent carrier mobility in CsPbBr3 nanoplates. This work not only offers insights for the mobile carrier in metal halide perovskite nanostructures, which is essential for optimizing device design and performance prediction, but also provides a novel and simple method to investigate charge transport in many other optoelectronic materials. PMID- 29696976 TI - Asymmetric Arylation of 2,2,2-Trifluoroacetophenones Catalyzed by Chiral Electrostatically-Enhanced Phosphoric Acids. AB - A series of highly reactive metal-free chiral phosphoric acids possessing positively charged phosphonium ion substituents are reported and have been applied to Friedel-Crafts alkylations of indoles and 2,2,2-trifluoromethyl aryl ketones. These catalysts are orders-of-magnitude more active and have similar or better enantioselectivities than their noncharged analogues. High tolerance to a range of substrates with electron-withdrawing and electron-donating substituents was also observed. PMID- 29696977 TI - Distribution Analysis of Anthocyanins, Sugars, and Organic Acids in Strawberry Fruits Using Matrix-Assisted Laser Desorption/Ionization-Imaging Mass Spectrometry. AB - Anthocyanins, sugars, and organic acids contribute to the appearance, health benefits, and taste of strawberries. However, their spatial distribution in the ripe fruit has been fully unrevealed. Therefore, we performed matrix-assisted laser desorption/ionization, MALDI-IMS, analysis to investigate their spatial distribution in ripe strawberries. The detection sensitivity was improved by using the TM-Sprayer for matrix application. In the receptacle, pelargonidins were distributed in the skin, cortical, and pith tissues, whereas cyanidins and delphinidins were slightly localized in the skin. In the achene, mainly cyanidins were localized in the outside of the skin. Citric acid was mainly distributed in the upper and bottom side of cortical tissue. Although hexose was distributed almost equally throughout the fruits, sucrose was mainly distributed in the upper side of cortical and pith tissues. These results suggest that using the TM Sprayer in MALDI-IMS was useful for microscopic distribution analysis of anthocyanins, sugars, and organic acids in strawberries. PMID- 29696978 TI - Lipid-Polymer Hybrid Nanoparticles for Oral Delivery of Tartary Buckwheat Flavonoids. AB - Flavonoids rich in Tartary buckwheat (TBFs) are the acknowledged health-promoting substances, even with the low oral bioavailability due to its chemical instability in gastrointestinal tract and poor intestinal absorption. To obtain the enhanced oral delivery, TBFs, obtained by an environmentally friendly extraction strategy in advance with the amount of 7.66 +/- 0.47 mg rutin/g, was incorporated in biocompatible lipid-polymer hybrid nanoparticles (LPNs). Its high encapsulation efficiency of 96.4% +/- 1.1%, narrow size distribution of 61.25 +/- 1.83 nm with spherical shape, and good storage stability were observed. Compared to free TBFs, TBFs/LPNs exhibited higher antioxidant activity and significant suppression on the pro-inflammatory cytokine secretion in RAW 264.7 macrophage. Moreover, the enhanced delivery of TBFs/LPNs was also embodied in the improved transmembrane transport in Caco-2 monolayer, suggesting its better intestinal absorption, and significantly immune-enhancing efficacy in immunosuppressed mice. These results demonstrated the new perspectives of Tartary buckwheat flavonoids loaded nanosystem for pharmaceutical and nutraceutical applications. PMID- 29696979 TI - KO tBu-Promoted C4 Selective Coupling Reaction of Phenols and [60]Fullerene: One Pot Synthesis of 4-[60]Fullerephenols under Transition-Metal-Free Conditions. AB - A KO tBu-promoted direct coupling reaction of phenols and [60]fullerene was disclosed. The reaction occurs exclusively at the C4-position of phenols with high regioselectivity and provides an efficient and inexpensive manner to various 4-[60]fullerephenols in good yields. The electrochemical properties of the products render the method attractive and valuable. PMID- 29696980 TI - Enantioselective Synthesis of Thailanstatin A Methyl Ester and Evaluation of in Vitro Splicing Inhibition. AB - Thailanstatin A has been isolated recently from the fermentation broth of B. thailandensis MSMB43. We describe here an enantioselective convergent synthesis of thailanstatin A methyl ester and evaluation of its splicing activity. Synthesis of both highly functionalized tetrahydropyran rings were carried out from commercially available tri- O-acetyl-d-glucal as the key starting material. Our convergent synthesis involved the synthesis of both tetrahydropyran fragments in a highly stereoselective manner. The fragments were then coupled using cross metathesis as the key step. The synthesis of the diene subunit included a highly stereoselective Claisen rearrangement, a Cu(I)-mediated conjugate addition of MeLi to set the C-14 methyl stereochemistry, a reductive amination reaction to install the C16-amine functionality, and a Wittig olefination reaction to incorporate the diene unit. The epoxy alcohol subunit was synthesized by a highly selective anomeric allylation, a Peterson olefination, and a vanadium catalyzed epoxidation that installed the epoxide stereoselectively. Cross-metathesis of the olefins provided the methyl ester derivative of thailanstatin A. We have carried out in vitro splicing studies of the methyl ester derivative, which proved to be a potent inhibitor of the spliceosome. PMID- 29696981 TI - Oral Administration and Detection of a Near-Infrared Molecular Imaging Agent in an Orthotopic Mouse Model for Breast Cancer Screening. AB - Molecular imaging is advantageous for screening diseases such as breast cancer by providing precise spatial information on disease-associated biomarkers, something neither blood tests nor anatomical imaging can achieve. However, the high cost and risks of ionizing radiation for several molecular imaging modalities have prevented a feasible and scalable approach for screening. Clinical studies have demonstrated the ability to detect breast tumors using nonspecific probes such as indocyanine green, but the lack of molecular information and required intravenous contrast agent does not provide a significant benefit over current noninvasive imaging techniques. Here we demonstrate that negatively charged sulfate groups, commonly used to improve solubility of near-infrared fluorophores, enable sufficient oral absorption and targeting of fluorescent molecular imaging agents for completely noninvasive detection of diseased tissue such as breast cancer. These functional groups improve the pharmacokinetic properties of affinity ligands to achieve targeting efficiencies compatible with clinical imaging devices using safe, nonionizing radiation (near-infrared light). Together, this enables development of a "disease screening pill" capable of oral absorption and systemic availability, target binding, background clearance, and imaging at clinically relevant depths for breast cancer screening. This approach should be adaptable to other molecular targets and diseases for use as a new class of screening agents. PMID- 29696983 TI - Update: Heat illness, active component, U.S. Armed Forces, 2017. PMID- 29696982 TI - Coccidioidomycosis, active component, U.S. Armed Forces, 2007-2017. AB - During 2007-2017, there were 574 incident cases of coccidioidomycosis among active component service members, with an overall unadjusted incidence rate of 3.9 cases per 100,000 person-years (p-yrs). Compared to their respective counterparts, the overall rates were highest among those aged 40 years or older, Navy members, enlisted service members, and those in healthcare occupations. Overall incidence rates were similar for males and females. Within race/ethnicity groups, the overall rates of coccidioidomycosis were highest among Asian/Pacific Islanders and lowest among non-Hispanic whites. During the surveillance period, crude annual incidence rates decreased from a high of 5.2 cases per 100,000 p-yrs in 2007 to a low of 2.3 cases per 100,000 p-yrs in 2017. Of the total U.S. cases (n=547), the vast majority (85.0%) were associated with locations within states in the southwestern U.S. with Coccidioides-endemic areas, including California (47.3%), Arizona (32.5%), Texas (4.6%), and New Mexico (0.5%). Providers of health care to U.S. military members should consider coccidioidomycosis as a potential cause of febrile respiratory infectious illnesses, particularly when the individual has a history of recent travel to an endemic area (especially those who work or participate in activities where dust is generated). PMID- 29696984 TI - Update: Exertional rhabdomyolysis, active component, U.S. Armed Forces, 2013 2017. PMID- 29696985 TI - Update: Exertional hyponatremia, active component, U.S. Armed Forces, 2013-2017. PMID- 29696988 TI - Cognitive and educational outcomes of maltreated and non-maltreated youth: A birth cohort study. AB - OBJECTIVES: Previous research suggests that child maltreatment is associated with adverse outcomes, but the potential impact on cognitive and educational outcomes into adulthood has rarely been studied using a birth cohort design. The aim of this study is to investigate whether child maltreatment is associated with adverse outcomes in cognitive function, high school completion and employment by the age of 21. METHODS: Longitudinal birth cohort study commencing in the prenatal period, with mothers and infants followed up to age 21. Of the original birth cohort of 7223, 3778 (52.3%) young people participated at age 21. Child maltreatment was identified by linkage with prospectively collected data from the relevant government agency. Associations between child maltreatment (abuse and neglect) and the outcomes were adjusted for relevant sociodemographic and perinatal variables. RESULTS: After full adjustment, young people who had been notified as cases of child maltreatment had reduced performance on the Peabody Picture Vocabulary Test by over a quarter of a standard deviation (coefficient = 2.85, p = 0.004). Maltreated young people also had three times the odds of failing to complete high school (odds ratio = 3.12, p < 0.001) and more than twice the odds of not being engaged in either study or employment at age 21 (odds ratio = 2.38, p < 0.001). Both abuse and neglect were similarly associated with adverse outcomes. CONCLUSION: Child maltreatment, including both abuse and neglect, is associated with adverse cognitive, educational and employment outcomes in young adulthood. This adds further impetus to efforts to prevent child maltreatment and assist young people who have experienced it. PMID- 29696987 TI - FABP4 regulates eosinophil recruitment and activation in allergic airway inflammation. AB - Fatty acid binding protein 4 (FABP4), a member of a family of lipid-binding proteins, is known to play a role in inflammation by virtue of its ability to regulate intracellular events such as lipid fluxes and signaling. Studies have indicated a proinflammatory role for FABP4 in allergic asthma although its expression and function in eosinophils, the predominant inflammatory cells recruited to allergic airways, were not investigated. We examined expression of FABP4 in murine eosinophils and its role in regulating cell recruitment in vitro as well as in cockroach antigen (CRA)-induced allergic airway inflammation. CRA exposure led to airway recruitment of FABP4-expressing inflammatory cells, specifically eosinophils, in wild-type (WT) mice. FABP4 expression in eosinophils was induced by TNF-alpha as well as IL-4 and IL-13. FABP4-deficient eosinophils exhibited markedly decreased cell spreading/formation of leading edges on vascular cell adhesion molecule-1 and significantly decreased adhesion to intercellular adhesion molecule-1 associated with reduced beta2-integrin expression relative to WT cells. Furthermore, FABP4-deficient eosinophils exhibited decreased migration, F-actin polymerization, calcium flux, and ERK(1/2) phosphorylation in response to eotaxin-1. In vivo, CRA-challenged FABP4-deficient mice exhibited attenuated eosinophilia and significantly reduced airway inflammation (improved airway reactivity, lower IL-5, IL-13, TNF-alpha, and cysteinyl leukotriene C4 levels, decreased airway structural changes) compared with WT mice. In conclusion, expression of FABP4 in eosinophils is induced during conditions of inflammation and plays a proinflammatory role in the development of allergic asthma by promoting eosinophil adhesion and migration and contributing to the development of various aspects of airway inflammation. PMID- 29696986 TI - Fibroblast senescence in the pathology of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing interstitial pneumonia of unknown cause with a median survival of only three years. Little is known about the mechanisms that precede the excessive collagen deposition seen in IPF, but cellular senescence has been strongly implicated in disease pathology. Senescence is a state of irreversible cell-cycle arrest accompanied by an abnormal secretory profile and is thought to play a critical role in both development and wound repair. Normally, once a senescent cell has contributed to wound repair, it is promptly removed from the environment via infiltrating immune cells. However, if immune clearance fails, the persistence of senescent cells is thought to drive disease pathology through their altered secretory profile. One of the major cell types involved in wound healing is fibroblasts, and senescent fibroblasts have been identified in the lungs of patients with IPF and in fibroblast cultures from IPF lungs. The question of what is driving abnormally high numbers of fibroblasts into senescence remains unanswered. The transcription factor signal transducer and activator of transcription 3 (STAT3) plays a role in a myriad of processes, including cell-cycle progression, gene transcription, as well as mitochondrial respiration, all of which are dysregulated during senescence. Activation of STAT3 has previously been shown to correlate with IPF progression and therefore is a potential molecular target to modify early-stage senescence and restore normal fibroblast function. This review summarizes what is presently known about fibroblast senescence in IPF and how STAT3 may contribute to this phenotype. PMID- 29696989 TI - Attention-deficit hyperactivity disorder in ancient Greece: The Obtuse Man of Theophrastus. AB - We present an ancient Greek description written by the philosopher Theophrastus in his classic book ' Characters' comparable with modern attention-deficit hyperactivity disorder. The arguments are based in one chapter of this book-The Obtuse Man-presenting features of a character closely resembling the modern description of attention-deficit hyperactivity disorder. In a free comparative exercise, we compared Theophrastus descriptions with modern Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) attention-deficit hyperactivity disorder symptoms. The sentences describing The Obtuse Man written by Theophrastus are similar to several symptoms of attention-deficit hyperactivity disorder and he would probably be currently diagnosed with this disorder as an adult. To our knowledge, this is the oldest description compatible with the current conception of attention-deficit hyperactivity disorder in adults in the Western literature. Differently than the moralistic view of ancient Greece regarding those symptoms, the medical attention-deficit hyperactivity disorder conception may be advantageous to patients since it might reduce prejudice and allow individuals to seek treatment. PMID- 29696990 TI - Patient and therapist experiences of using affordable feedback-based technology in rehabilitation: a qualitative study nested in a randomized controlled trial. AB - OBJECTIVE: To explore how technologies are used and experienced in rehabilitation. DESIGN: A qualitative study using a grounded theory approach within a randomized controlled trial investigating the effectiveness of tailored, affordable technologies to improve mobility and physical activity. SETTINGS: Aged care and neurological rehabilitation wards with community follow-up. PARTICIPANTS: Twenty patients undergoing rehabilitation and randomized to the experimental arm of a trial (mean age 64 years (SD 23)) were recruited for interviews, plus 11 physiotherapists involved in technology prescription as part of the trial. METHOD: Two interviews per patient (one in hospital, one post discharge) and four focus groups with physiotherapists were conducted. Transcribed data were coded and synthesized. Memo-writing and constant comparison methods guided data analysis. RESULTS: A process of patient engagement with technology involving two stages: (1) initial patient engagement and (2) maintaining patient engagement was identified. Therapists used a series of steps and strategies to gain and maintain patient engagement. A positive first experience and continued input into patient programmes was needed. The level of patient engagement was not consistent across the duration of the trial, increasing or decreasing due to changes in the technologies prescribed or setting of use. Two conditions were key to optimizing patient engagement: sufficient support and perceived benefit from using technology. CONCLUSIONS: Patients can engage with technology during rehabilitation when prescription is tailored by a therapist. Perceiving benefit from using technology, in addition to receiving the right support to enable use appears to influence the level of patient engagement. PMID- 29696991 TI - Pressure Distribution in the Ankle and Subtalar Joint With Routine and Oversized Foot Orthoses. AB - BACKGROUND: Foot orthoses are used to treat many disorders that affect the lower limb. These assistive devices have the potential to alter the forces, load distribution, and orientation within various joints in the foot and ankle. This study attempts to quantify the effects of orthoses on the intra-articular force distribution of the ankle and subtalar joint using a cadaveric testing jig to simulate weight bearing. METHODS: Five lower-limb cadaveric specimens were placed on a custom jig, where a 334-N (75-lb) load was applied at the femoral head, and the foot was supported against a plate to simulate double-leg stance. Pressure mapping sensors were inserted into the ankle and subtalar joint. Mean pressure, peak pressure, contact area, and center of force were measured in both the ankle and subtalar joints for barefoot and 2 medial foot orthosis conditions. The 2 orthosis conditions were performed using (1) a 1.5-cm-height wedge to simulate normal orthoses and (2) a 3-cm-height wedge to simulate oversized orthoses. RESULTS: The contact area experienced in the subtalar joint significantly decreased during 3-cm orthotic posting of the medial arch, but neither orthosis had a significant effect on the spatial mean pressure or peak pressure experienced in either joint. CONCLUSION: The use of an oversized orthosis could lead to a decrease in the contact area and alterations in the distribution of pressure within the subtalar joint. CLINICAL RELEVANCE: The use of inappropriate orthoses could negatively impact the force distribution in the lower limb. PMID- 29696992 TI - Relationship of Plantar Fascia Thickness and Preoperative Pain, Function, and Quality of Life in Recalcitrant Plantar Fasciitis. AB - BACKGROUND: The measurement of plantar fascia thickness has been advocated as a diagnostic and prognostic instrument in patients with plantar fasciitis, but there are no data relative to it in recalcitrant plantar fasciitis. The aim of the study is to evaluate the correlation between plantar fascia thickness and pain, functional score, and health perception in patients with this condition. METHODS: Thirty-eight feet were studied with ultrasound and magnetic resonance imaging to measure plantar fascia thickness. The visual analogue scale (VAS), American Orthopaedic Foot & Ankle Society Hindfoot Score (AOFAS), and SF-36 were then recorded for each patient. The relationship between the fascia and these scores was analyzed to evaluate the correlation of thickness with pain, functional level, and health perception of patients. RESULTS: In patients with recalcitrant plantar fasciitis, plantar fascia thickness did not correlate with pain (VAS), AOFAS, or any item of the SF-36. CONCLUSION: The thickness of the plantar fascia in patients with recalcitrant plantar fasciitis did not correlate with its clinical impact, and thus, we believe it should not be used in treatment planning. LEVEL OF EVIDENCE: Level IV, case series. PMID- 29696993 TI - Comparison of ranibizumab and subthreshold micropulse laser in treatment of macular edema secondary to branch retinal vein occlusion. AB - PURPOSE:: To compare the effects of intravitreal ranibizumab injection and yellow (577 nm) subthreshold micropulse laser treatment in patients with macular edema following non-ischemic branch retinal vein occlusion. METHODS:: The medical records of 51 patients who underwent intravitreal ranibizumab (0.5 mg) injection or subthreshold micropulse laser for the treatment of macular edema due to branch retinal vein occlusion were retrospectively reviewed. Subthreshold micropulse laser was administered with a 10% duty cycle, 100 MUm spot diameter, 200 ms exposure time. The patients received an injection or laser treatment at baseline and were, then, retreated as needed and were followed for 12 months. The mean best corrected visual acuity changes over the follow-up and the decrease in the mean central macular thickness were evaluated. RESULTS:: A total of 27 and 24 patients were assigned to intravitreal ranibizumab and subthreshold micropulse laser subgroups, respectively. The mean number of treatment was 3.81 of intravitreal ranibizumab group and 1.5 of subthreshold micropulse laser group (p < 0.05). The subgroups were similar with regard to the mean score of best corrected visual acuity at baseline, at 1, 6, and 12 months (p > 0.05). The decrease in the mean central macular thickness was significant in both intravitreal ranibizumab and subthreshold micropulse laser groups at 1, 6, and 12 months than that of values at baseline (p < 0.05). No new ocular or systemic adverse events were observed. CONCLUSION:: Our study results showed that intravitreal ranibizumab or yellow subthreshold micropulse laser treatment for macular edema due to branch retinal vein occlusion was not found to be superior to each other for reducing macular thickness and increasing visual acuity for 1 year period. Based on these results, subthreshold micropulse laser may be a useful alternative approach in the treatment of macular edema secondary to branch retinal vein occlusion. PMID- 29696994 TI - The Impact of Musical Training on Hand Biomechanics in String Musicians. AB - BACKGROUND: The effects of musical training on the body in professional musicians remain an understudied area, particularly in reference to understanding and managing orthopedic/neuromuscular deviations and injuries in this population. The purpose of this study was to evaluate hand/finger fine motor function in musicians via physical examination as well as laboratory-based evaluations. METHODS: Thirteen healthy noninjured young elite string musicians participated in this study. Performance of musicians was compared with healthy age-matched, sex matched, and handedness-matched nonmusician controls. RESULTS: Musicians exhibited decreased intrinsic muscle strength compared with controls; however, no change in extrinsic muscle strength was found between groups. No between-group differences in overall force control were found; however, Group * Hand (right vs left) interactions were found in force control. CONCLUSIONS: These data suggest that musicians are a unique population with respect to: (1) fine motor control of the hand; and (2) exhibit changes in differential hand use. This suggests cortical reorganization of string musicians, such that this population should be studied separately from typical healthy controls with respect to hand function. PMID- 29696995 TI - The significance of supportive and undermining elements in the maternal representations of an unborn baby. AB - OBJECTIVE: The maternal representations of an unborn baby begin to develop during pregnancy. However, the factors that moderate them are not well identified. The objective of this study was to jointly explore supportive and undermining factors in the maternal representations of an unborn baby and motherhood. METHODS: Cross sectional data comprising 1646 women studied during the third trimester of pregnancy. Maternal expectations were measured using a 12-item self-report questionnaire, Mother's Representations about an Unborn Baby. Depression, anxiety, family atmosphere and adult attachment were measured using standardised questionnaires. Statistical analysis is based on multivariate linear regression analysis. RESULTS: The most powerful predictors of a mother's prenatal expectations were the mother's educational status, age, closeness in adult relationships, higher levels of depressive symptoms and family atmosphere. In accordance with our hypothesis, depression was related to the mother's more negative expectations on their relationship with the unborn baby and on regularity in the baby's sleeping and eating patterns. A positive family atmosphere and the mother's ability for closeness and dependence (i.e. confidence) in adult relationships were related to more positive expectations of the mother-unborn baby relationship. On the other hand, stress, anxiety and adverse life events were not related to the mother's expectations of her unborn baby. CONCLUSIONS: The results may be helpful in identifying families who need early professional support and call for studies where the prenatal phase is explored as a proactive phase for the development of the child-parent relationship. PMID- 29696996 TI - A technical assessment of the porcine ejaculated spermatozoa for a sperm-specific RNA-seq analysis. AB - : The study of the boar sperm transcriptome by RNA-seq can provide relevant information on sperm quality and fertility and might contribute to animal breeding strategies. However, the analysis of the spermatozoa RNA is challenging as these cells harbor very low amounts of highly fragmented RNA, and the ejaculates also contain other cell types with larger amounts of non-fragmented RNA. Here, we describe a strategy for a successful boar sperm purification, RNA extraction and RNA-seq library preparation. Using these approaches our objectives were: (i) to evaluate the sperm recovery rate (SRR) after boar spermatozoa purification by density centrifugation using the non-porcine-specific commercial reagent BoviPureTM; (ii) to assess the correlation between SRR and sperm quality characteristics; (iii) to evaluate the relationship between sperm cell RNA load and sperm quality traits and (iv) to compare different library preparation kits for both total RNA-seq (SMARTer Universal Low Input RNA and TruSeq RNA Library Prep kit) and small RNA-seq (NEBNext Small RNA and TailorMix miRNA Sample Prep v2) for high-throughput sequencing. Our results show that pig SRR (~22%) is lower than in other mammalian species and that it is not significantly dependent of the sperm quality parameters analyzed in our study. Moreover, no relationship between the RNA yield per sperm cell and sperm phenotypes was found. We compared a RNA seq library preparation kit optimized for low amounts of fragmented RNA with a standard kit designed for high amount and quality of input RNA and found that for sperm, a protocol designed to work on low-quality RNA is essential. We also compared two small RNA-seq kits and did not find substantial differences in their performance. We propose the methodological workflow described for the RNA-seq screening of the boar spermatozoa transcriptome. ABBREVIATIONS: FPKM: fragments per kilobase of transcript per million mapped reads; KRT1: keratin 1; miRNA: micro-RNA; miscRNA: miscellaneous RNA; Mt rRNA: mitochondrial ribosomal RNA; Mt tRNA: mitochondrial transference RNA; OAZ3: ornithine decarboxylase antizyme 3; ORT: osmotic resistance test; piRNA: Piwi-interacting RNA; PRM1: protamine 1; PTPRC: protein tyrosine phosphatase receptor type C; rRNA: ribosomal RNA; snoRNA: small nucleolar RNA; snRNA: small nuclear RNA; SRR: sperm recovery rate; tRNA: transfer RNA. PMID- 29696997 TI - Training and support needs of scleroderma support group facilitators: the North American Scleroderma Support Group Facilitators Survey. AB - PURPOSE: Peer-facilitated support groups are an important resource for people with scleroderma, but little is known about challenges faced by support group facilitators. The objective was to identify training and support needs of scleroderma support group facilitators to inform the development of an educational training program. METHODS: A 32-item survey assessed confidence of support group facilitators to execute tasks necessary for successfully facilitating support groups. Survey items were grouped into seven themes using content analysis. RESULTS: Eighty North American scleroderma support group facilitators completed the survey. Facilitators were generally confident in their ability to complete tasks related to: (1) Organizing, Structuring, and Facilitating the group; (2) Addressing Individual Member Needs and Diversity of the Group; (3) Helping Members Cope with Grief and Loss; and (4) Attaining and Responding to Member Feedback. They were less confident in their ability to perform tasks related to (1) Managing Difficult Group Dynamics; (2) Promoting and Sustaining the Group; and (3) Balancing Personal and Group Needs. CONCLUSION: Results suggest that a training program for scleroderma support group facilitators should address a broad range of topics, including managing difficult group interactions, promotion and maintaining the group, and balancing personal and support group needs. Implications for Rehabilitation Many patients with the rare autoimmune connective tissue disease scleroderma depend on peer-facilitated support groups for disease-related education and peer support, but the lack of training for facilitators is a barrier to forming and sustaining groups. Rehabilitation professionals can support the formation and management of local support groups by providing education and support to peer group facilitators or by referring them to national scleroderma organizations who are developing training resources. Training for support group facilitators should focus on areas where facilitators were least confident in their abilities, including managing difficult group dynamics, promoting and sustaining the group, and balancing personal and group needs. PMID- 29696998 TI - Understanding body image among adults in mid-late life: Considering romantic partners and depressive symptoms in the context of diabetes. AB - Although our bodies change as we age, there is limited research exploring body image among middle-aged and older adults. This study considered 70 adults with diabetes' ( Mage = 60.01 years) body image and revealed relatively high levels of body dissatisfaction in this sample. Furthermore, participants' own and perceptions of their partners' dissatisfaction with their bodies were moderately associated, and participants' body dissatisfaction was associated with higher levels of depressive symptoms. These findings highlight the need for further research, exploring the social and psychological correlates of body image among men and women in mid-late adulthood. PMID- 29696999 TI - Sexual well-being and diurnal cortisol after prostate cancer treatment. AB - Sexual dysfunction and psychological distress are common after prostate cancer. Research has not examined the role of neuroendocrine markers of stress (e.g. cortisol). This study examines whether sexual functioning or sexual bother is associated with diurnal cortisol. Men treated for prostate cancer completed the University of California-Los Angeles Prostate Cancer Index and provided saliva samples four times daily for cortisol assessment. Higher sexual bother, but not sexual functioning, was associated with steeper cortisol slope. Better sexual functioning, and not sexual bother, was significantly associated with the cortisol awakening response. Assessment of stress and stress-reducing interventions might be warranted in sexual rehabilitation after prostate cancer. PMID- 29697000 TI - Advancements in the management of medically less-fit and older adults with newly diagnosed acute myeloid leukemia. AB - INTRODUCTION: Treating acute myeloid leukemia (AML) in older adults remains daunting. The unique biology often renders conventional chemotherapies less effective. Accurately predicting the toxicities of treatment is another unresolved challenge. Treatment planning thus requires a good knowledge of the current trial data and familiarity with clinical tools, including formal fitness and geriatric assessments. Both obstacles - disease biology and patient fitness - might be easier overcome with specific, AML cell-targeted agents rather than traditional cytotoxic chemotherapy. This may be the future of AML therapy, but it is not our current state. Areas covered: Herein, the authors appraise the data supporting a standard induction approach, including an outline of how to predict treatment-related mortality and a review of the most up-to-date methods of geriatric assessment. They also discuss treatment expectations with less-intense therapies and highlight novel agents in development. Finally, they provide a basic approach to choosing treatment intensity. Expert opinion: In an older and/or medically less-fit patient, treatment choice should begin with a thorough disease assessment, a formal evaluation of patient fitness and frailty. There should also be a clear communication with the patient and patient's family about the risks and anticipated benefits of either an intense or nonintense treatment approach. PMID- 29697001 TI - Nestin is highly expressed in foetal spinal cord isolated from placenta previa patients and promotes inflammation by enhancing NF-kappaB activity. AB - PURPOSE: Nestin is expressed in various tissues of the embryo in patients with placenta previa, while the regulatory mechanism still unknown. MATERIALS AND METHODS: All participants terminated pregnancy. Among them, 75 patients with placenta previa were assigned to the case group and 80 healthy pregnant women with normal placenta were assigned to the control group. Expression of nestin and CDK5 in foetal spinal cord tissues was detected by Western blot and quantitative real-time RT-PCR methods. The enzyme-linked immunosorbent assay (ELISA) was used to determine the serum expression of some pro-inflammatory cytokines in placenta previa patients. The interaction between nestin and CDK5 was evaluated by immunoprecipitation and siRNA inhibition of nestin was performed to estimate its effect on NF-kappaB activity in foetal spinal cord tissues. RESULTS: Along with increased expression of nestin and CDK5 in foetal spinal cord tissues in the case group, IL-1beta, IL-6, TNF-alpha and IFN-gamma were increased in the serum of placenta previa patients. siRNA inhibition analysis indicated that nestin interacted with CDK5 and regulated NF-kappaB activity in foetal spinal cord tissues. CONCLUSIONS: Nestin is highly expressed and the interaction between nestin and CDK5 might lead to the progress of placenta previa through its regulation on NF-kappaB. PMID- 29697002 TI - Psychometric properties of the Functional Disability Inventory for assessing Pain related disability in children from the community. AB - PURPOSE: The aim of this study was to evaluate the psychometric properties of the Functional Disability Inventory for assessing pain-related disability in a community sample of children and adolescents. MATERIALS AND METHODS: Five hundred and sixty-one schoolchildren (aged 8-18 years) completed the Functional Disability Inventory. They were also administered measures assessing anxiety sensitivity, internalizing pain coping behaviors, social support seeking, and positive self-statements. A subset of 107 participants completed measures of quality of life. RESULTS: The results confirmed the two-factor structure solution for the Functional Disability Inventory items. The measure's scales scores demonstrated adequate to good internal consistencies. Convergent validity was supported by significant positive correlations between FDI scores and anxiety sensitivity and internalizing pain coping behaviors, and negative correlations with quality of life. Discriminant validity was supported by weak and non significant correlations between disability scores and the social support seeking and positive self-statements pain coping strategies scores. Differences in the disability scores between participants who did not experience pain in the last 3 months and those that experienced at least some pain provided additional evidence for construct validity. CONCLUSIONS: The findings support the Functional Disability Inventory as a reliable and valid measure for assessing pain-related disability in children and adolescents from the community. Implications for rehabilitation Chronic pain is a common health problem in youths and is associated with disability (which implies difficulties in physical, psychological, social or school functioning). The FDI is one of the most used measures to assess disability in youths with chronic pain. However, its psychometric properties have not been studied in a community sample. This study shows new and important findings demonstrating that the FDI provides reliable and valid scores when used to assess pain-related disability in a community sample of schoolchildren. These findings support the use of the FDI as a measure of the benefits of community-based pain treatments or the benefits of disability prevention programs over time. PMID- 29697003 TI - Predicting skin sensitization potential of organic compounds based on toxicity enhancement to Tetrahymena pyriformis, fathead minnow, and Daphnia magna. AB - Skin sensitization is an important occupational health problem and immunotoxicity endpoint. Considering animal welfare and time and cost savings, many alternative approaches, such as those conducted in vitro, in silico, and in chemo, have been proposed and applied to predict skin sensitization of compounds. Toxicologically, sensitizers can elicit excess toxicity at greater levels than non-sensitizers due to their capacity to react with proteins/peptides. Based on this understanding, calculated toxicity enhancements (Te) of 65 organic compounds from three in vitro bioassays, i.e. 48-hr ciliate (Tetrahymena pyriformis) growth inhibition, and both 96-hr fathead minnow and 48-hr Daphnia magna acute lethal toxicities, were employed to qualitatively and quantitatively predict skin sensitization potencies of the test agents. The sensitivity, specificity, and accuracy reaching 80% strongly suggested toxicity enhancement was an excellent parameter for predicting skin sensitization. Linear regressions of skin sensitization against toxicity enhancement were fitted for each bioassay, and they were improved after the sensitizers were categorized into different reaction mechanistic domains, which, in decreasing order of contribution from Te to sensitization, were SNAr > SN1 > MA. These results indicated that toxicity bioassays are useful tools and that Te could be a useful parameter that might be applied to predict skin sensitization. PMID- 29697004 TI - Assessment of psoriasis severity in Brazilian patients with chronic plaque psoriasis attending outpatient clinics: a multicenter, population-based cross sectional study (APPISOT). AB - PURPOSE: Data on chronic plaque psoriasis severity and its potential clinical and lifestyle implications in the Brazilian population are limited. The primary aim of this study was to assess the clinical severity of plaque psoriasis in Brazil. Further objectives included evaluating potential associations between disease severity and demographic, lifestyle, and clinical characteristics, health-related quality of life (HRQOL), and work productivity. MATERIALS AND METHODS: This observational (non-interventional) cross-sectional study was conducted in 26 dermatologic clinics across 11 Brazilian states. Psoriasis severity was assessed using investigator judgment and Finlay's Rule of Tens: a Psoriasis Area and Severity Index (PASI) score >10, a Body Surface Area (BSA) > 10%, or a Dermatology Life Quality Index (DLQI) score >10. RESULTS: Among 1125 patients, 205 (18.2%) had moderate-to-severe disease. On multiple regression analyses, psoriasis severity was significantly (directly) associated with the presence of physical inactivity and comorbid pain, anxiety, and depression; and significantly (inversely) associated with HRQOL and work productivity. LIMITATIONS: Cross sectional studies cannot assess temporal trends, and observational studies cannot conclusively determine causality or exclude biases and confounding due to unmeasured variables. CONCLUSIONS: Among Brazilian patients with moderate-to severe psoriasis, disease severity had far-reaching adverse impacts on lifestyle, comorbidities, HRQOL, and work productivity. PMID- 29697005 TI - Primary breast diffuse large B-cell lymphoma: treatment strategies and patterns of failure. AB - Treatment strategies and outcomes were assessed in 25 patients with primary breast diffuse large B-cell lymphoma (PB-DLBCL) treated between 1995 and 2016. We specifically investigated the timing of recurrence, and the roles of radiotherapy (RT) and central nervous system prophylaxis (CNS PPX). Fifty-two percent of patients received RT, and 28% received CNS PPX. Fourteen patients (56%) experienced recurrence, with 76% of relapses occurring >=24 months after diagnosis, in contrast to reports supporting the use of 24-month event-free survival as a surrogate endpoint in the general DLBCL population. Use of RT was associated with a trend toward improved progression-free survival (PFS). Twenty percent of patients experienced CNS relapse, with no clear benefit to CNS PPX. These data emphasize the importance of long-term follow-up for PB-DLBCL patients, suggest a PFS benefit with the addition of RT, and highlight high rates of CNS relapse. PMID- 29697006 TI - Toxicity of ZnO nanoparticles (NPs) with or without hydrophobic surface coating to THP-1 macrophages: interactions with BSA or oleate-BSA. AB - It is recently shown that biological macromolecules in food could interact with nanoparticles (NPs) and consequently change the biological effects of NPs. In this study, the interactions between ZnO NPs with or without hydrophobic surface coating and bovine serum albumin (BSA) or oleate (OA) complexed to BSA (OA-BSA) were assessed. Atomic force microscope (AFM) showed topographic changes of both types of NPs by BSA or OA-BSA, which could indicate the formation of protein corona. ZnO NPs showed negative Zeta potential, which was slightly decreased by BSA or OA-BSA, with OA-BSA being more effective. The UV-Vis was increased, whereas the fluorescence and synchronous fluorescence was decreased by the presence of ZnO NPs. Exposure to both types of ZnO NPs was associated with cytotoxicity to THP-1 macrophages, which was equally mitigated by BSA or OA-BSA associated with decreased cellular Zn elements. Exposure to ZnO NPs was associated with decreased release of cytokines, which was not affected by BSA or OA-BSA. In combination, the results from this study suggested that both BSA and OA-BSA could be adsorbed to ZnO NPs regardless of hydrophobic surface coating, which reduced the cytotoxicity of NPs to macrophages probably due to reduced association between NPs and cells. BSA and OA-BSA equally protected THP-1 macrophages from ZnO NP exposure, which might indicate that complexation to OA did not compromise the cytoprotective effects of BSA. These data might also indicate the complex interaction between NPs and biological macromolecules as food components, which should be considered for future nanotoxicological studies. PMID- 29697007 TI - Studies of indirect and direct effects of hypervitaminosis A on rat bone by comparing free access to food and pair-feeding. AB - BACKGROUND: The most prominent features of hypervitaminosis A in rats are spontaneous fractures and anorexia. Since caloric restriction induces alterations in bone, some effects could be secondary to loss of appetite. To clarify the mechanisms behind vitamin A-induced bone fragility it is necessary to distinguish between direct and indirect effects. MATERIALS AND METHODS: In this study we compared rats fed high doses of vitamin A both with pair-fed controls, which were fed the same amount of chow as that consumed by the vitamin A group to keep food intake the same, and to controls with free access to food. RESULTS: In contrast to the pair-fed animals, rats in the free access group fed high doses of vitamin A for 7 days had 13% lower food intake, 15% lower body weight, and 2.7% shorter femurs compared with controls. In addition, serum biomarkers of bone turnover were reduced. Peripheral quantitative computed tomography of the femurs showed that the bone mineral content, cross sectional area, and periosteal circumference were similarly reduced in the pair-fed and free access groups. However, bone mineral density (BMD) and cortical parameters were only significantly decreased in the free access group. CONCLUSIONS: Our data indicate that the major direct short-term effect of high doses of vitamin A on rat bone is a reduced bone diameter, whereas the effects on bone length, serum biomarkers of bone turnover, BMD, and bone cortex appear to be mainly indirect, caused by a systemic toxicity with loss of appetite, reduced food intake, and general effects on growth. PMID- 29697008 TI - Incorporation of p-53 mutation status and Ki-67 proliferating index in classifying Her2-neu positive gastric adenocarcinoma. AB - Her2-neu overexpression has a pathogenetic, therapeutic and a controversial prognostic role in gastric cancer. p-53 mutation status and Ki-67 proliferation index are established prognostic markers in many tumors. In this study we evaluated p-53 and Ki-67 in relation to Her2-neu positive and negative gastric adenocarcinoma (GA). This cross-sectional study was carried out at King Fahd Hospital of Imam Abdulrahman bin Faisal University. Fifty cases of GA were retrieved from pathology archives. Clinico-pathological parameters were evaluated. Immunohistochemical protein analysis for Her2-neu, Ki-67 and p-53 was carried out. Fluorescent in situ hybridization (FISH) analysis was done for Her2 neu positive cases showing 2+ immunoexpression. Frequency of Ki-67 and p-53 positivity in Her2-neu positive cases was calculated and compared with those in Her2-neu negative cases. Correlation of clinicopatological parameters with Her2 positive and negative cases, p-53 mutation status and Ki-67 proliferation index was carried out. Her2-neu overexpression was present in 12% (n = 6) cases. A high Ki-67 was seen predominantly in Her2-neu positive cases (83%, n = 5). Her2-neu negative cases (n = 44) showed moderate (31.88%, n = 14) to low (34%, n = 15) Ki 67. Diffuse p-53 positivity was seen predominantly in Her2-neu positive cases (33.33%, n = 2). Focal p-53 was seen mainly in Her2-neu negative cases 56.8% (n = 25). Negative p-53 was seen to be independent of Her2-neu status. Her2-neu positivity is strongly associated with diffuse p-53 mutation status and high Ki 67 proliferation. Her 2-neu negative status is associated with focal p-53 positivity and low to moderate Ki-67 proliferation index. Such stratifications in prognostic markers could not only be predictive in patient's prognostics but could also form a basis of molecular classification of gastric cancer. PMID- 29697009 TI - Factors associated with drinking and being satisfied with tap water in Indigenous communities in Saskatchewan, Canada. AB - Previous studies have described concerns regarding tap water in Indigenous communities, yet there is little information on participants who report drinking their tap water and being satisfied with its quality. This study undertaken with members of 8 Indigenous communities in Saskatchewan, Canada, and identified factors associated with both the decision to drink tap water at home and being satisfied with its quality. We examined the importance of factors such as individual attributes, experiences, attitudes, household and community-based variables. Less than one-quarter of participants (23.4%) drank tap water and were satisfied with its quality. Individuals who did not boil tap water (odds ratio [OR] = 5.76, 95% confidence interval [CI] = 1.68-19.8), those who did not experience tap water odour (OR = 2.38, 95% CI = 1.26-4.50) and participants living in communities away from urban centres (OR = 2.74, 95% CI = 1.63-4.51) were more likely to drink and be satisfied with their tap water. Concerns about the environment had the most impact on community members aged 55+ years. Those not reporting concerns about environmental problems affecting water (OR = 11.4, 95% CI = 3.10-42.2) were much more likely to drink and be satisfied with their tap water. Programmes to improve water quality, reduce the need for boil water advisories and increase community confidence in the environment could improve tap water satisfaction and consumption. PMID- 29697010 TI - Delayed activation of PPAR-beta/delta improves long-term survival in mouse sepsis: effects on organ inflammation and coagulation. AB - Activation of peroxisome proliferator-activated receptor (PPAR)-beta/delta reduces tissue injury in murine endotoxemia. We hypothesized that the PPAR beta/delta-agonist GW0742 improves long-term outcome after sepsis caused by cecal ligation and puncture (CLP). Fifty-one CD-1 female mice underwent CLP and received either vehicle (control), GW0742 (0.03 mg/kg/injection; five post-CLP i.v. injections), GSK0660 (PPAR-beta/delta-antagonist) or both and were monitored for 28 d. Another 20 CLP mice treated with GW0742 and vehicle were sacrificed 24 h post-CLP to assess coagulopathy. Compared to vehicle, survival of CLP-mice treated with GW0742 was higher by 35% at d 7 and by 50% at d 28. CLP mice treated with GW0742 had 60% higher IFN-gamma but circulating monocyte chemoattractant protein-1 and chemokine ligand were lower at 48 h post-CLP. Compared to vehicle, CLP mice treated with GW0742 exhibited a 50% reduction in the circulating plasminogen activator inhibitor-1 associated with an increase in platelet number at 24 h post-CLP (but no changes occurred in anti-thrombin-III, plasminogen, fibrinogen and clotting-times). CLP mice treated with GW0742 exhibited a similar increase in most of the biochemical markers of organ injury/dysfunction (lactate dehydrogenase, alanine aminotransferase, creatine kinase, creatinine, blood urea nitrogen, and triglycerides) measured. Treatment with GW0742 consistently improved long-term survival in septic CD-1 mice by partially modulating the post CLP systemic cytokine response and coagulation systems. PMID- 29697011 TI - Influence of the Vibralung Acoustical Percussor on pulmonary function and sputum expectoration in individuals with cystic fibrosis. AB - BACKGROUND: The Vibralung Acoustical Percussor is a new airway clearance therapy (ACT) utilizing intrapulmonary sound waves in addition to positive expiratory pressure (PEP). We evaluated the safety of the Vibralung and collected preliminary data on its ability to mediate sputum expectoration in individuals with cystic fibrosis (CF). METHODS: Over two separate studies, 10 and 11 mild to moderate CF patients were recruited for study I and II, respectively. Study I: Vibralung was used for 20 min with either no sound (NS: PEP only) or sound (S: PEP and sound) on randomized visits. Pulmonary function, diffusion capacity of the lungs for carbon monoxide and nitric oxide (DLCO/DLNO), symptoms, and peripheral oxygen saturation (SpO2) were measured at baseline and at 1 and 4 h post treatment. Expectorated sputum was collected over 4 h post treatment. Study II: over 5 days of in-hospital therapy, the Vibralung or vibratory vest therapy (Vest) were used for two therapy sessions per day, with sputum collected for 20 min following each therapy and pulmonary function accessed pre and post each 5 day period (days 1-5 or 7-11) in a randomized crossover design. RESULTS: Vibralung usage resulted in no change from baseline to 4 h post in pulmonary function, SpO2 or symptoms ( p > 0.05). At 4 h post therapy, the DLCO- and DLNO derived measure of alveolar-capillary unit function (DM/ VC) showed improvement (DM/ VC = 12.5 +/- 5.5 versus 7.3 +/- 18.8% change, S versus NS) with no difference between S and NS ( p = 0.74). Sputum expectoration was similar between S and NS conditions (wet sputum = 10.5 +/- 4.6 versus 9.9 +/- 3.2 g, S versus NS, p = 0.25). There were no differences in the improvement in pulmonary function between Vibralung and Vest during either 5-day period during the hospital stay. CONCLUSIONS: Vibralung was well tolerated and caused no detrimental changes in pulmonary function metrics. The Vibralung appears to be a safe ACT in individuals with CF. PMID- 29697012 TI - Heart rate variability in patients with systemic lupus erythematosus: a systematic review and methodological considerations. AB - Aim The aim of this review was to summarize current knowledge about the scientific findings and potential clinical utility of heart rate variability measures in patients with systemic lupus erythematosus. Methods PubMed, Embase and Scopus databases were searched for the terms associated with systemic lupus erythematosus and heart rate variability, including controlled vocabulary, when appropriate. Articles published in English and available in full text were considered. Finally, 11 publications were selected, according to the systematic review protocol and were analyzed. Results In general, heart rate variability, measured in the time and frequency domains, was reported to be decreased in patients with systemic lupus erythematosus compared with controls. In some systemic lupus erythematosus studies, heart rate variability was found to correlate with inflammatory markers and albumin levels. A novel heart rate variability measure, heart rate turbulence onset, was shown to be increased, while heart rate turbulence slope was decreased in systemic lupus erythematosus patients. Reports of associations of changes in heart rate variability parameters with increasing systemic lupus erythematosus activity were inconsistent, showing decreasing heart rate variability or no relationship. However, the low/high frequency ratio was, in some studies, reported to increase with increasing disease activity or to be inversely correlated with albumin levels. Conclusions Patients with systemic lupus erythematosus have abnormal heart rate variability, which reflects cardiac autonomic dysfunction and may be related to inflammatory cytokines but not necessarily to disease activity. Thus measurement of heart rate variability could be a useful clinical tool for monitoring autonomic dysfunction in systemic lupus erythematosus, and may potentially provide prognostic information. PMID- 29697013 TI - Long-term survival of kidney grafts in lupus nephritis: a Mexican cohort. AB - Kidney transplant for patients with lupus nephritis (LN) has satisfactory outcomes in studies with short-term or mid-term follow up. Nevertheless, information about long-term outcomes is scarce. We performed a retrospective matched-pair cohort study in 74 LN recipients compared with 148 non-LN controls matched by age, sex, immunosuppressive treatment, human leukocyte antigen (HLA) matches, and transplant period in order to evaluate long-term outcomes of kidney transplant in LN recipients. Matched pairs were predominantly females (83%), median age at transplant surgery of 32 years (interquartile range 23-38 years), and 66% received a graft from a living related donor. Among LN recipients, 5-, 10 , 15-, and 20-year graft survival was 81%, 79%, 57% and 51%, respectively, and it was similar to that observed in controls (89%, 78%, 64%, and 56%, respectively). Graft loss (27% vs. 21%, p = 0.24) and overall survival ( p = 0.15) were not different between LN recipients and controls. Also, there was no difference in episodes of immunological rejection, thrombosis, or infection. Only six LN recipients had biopsy-proven lupus recurrence and three of them had graft loss. In a cohort with a long follow up of kidney transplant recipients, LN recipients had similar long-term graft survival and overall outcomes compared with non-lupus recipients when predictors are matched between groups. PMID- 29697015 TI - Towards mainstream anammox: lessons learned from pilot-scale research at WWTP Dokhaven. AB - The aim of this research was to study the biological feasibility of the Partial Nitritation/Anammox (PN/A) technology to remove nitrogen from municipal mainstream wastewaters. During stable process operations at summer temperatures (23.2 +/- 1.3 degrees C), the total nitrogen removal rate was 0.223 +/- 0.029 kg N (m3 d)-1 while at winter temperatures (13.4 +/- 1.1 degrees C) the total nitrogen removal rate was 0.097 +/- 0.016 kg N (m3 d)-1. Nitrite-oxidizing bacteria (NOB) suppression was successfully achieved at the complete temperature range of municipal mainstream wastewater. Despite the presence of NOB as observed in activity tests, their activity could be successfully suppressed due to a relative low dissolved oxygen concentration. An overcapacity of ammonia-oxidizing bacteria and anammox activity was always present. Long-term stability is a focus point for future research, especially in relation to the stability of the biological oxygen demand removing step, preceding the PN/A reactor. PMID- 29697014 TI - Robust prediction of gene regulation in colorectal cancer tissues from DNA methylation profiles. AB - DNA methylation is recognized as one of several epigenetic regulators of gene expression and as potential driver of carcinogenesis through gene-silencing of tumor suppressors and activation of oncogenes. However, abnormal methylation, even of promoter regions, does not necessarily alter gene expression levels, especially if the gene is already silenced, leaving the exact mechanisms of methylation unanswered. Using a large cohort of matching DNA methylation and gene expression samples of colorectal cancer (CRC; n = 77) and normal adjacent mucosa tissues (n = 108), we investigated the regulatory role of methylation on gene expression. We show that on a subset of genes enriched in common cancer pathways, methylation is significantly associated with gene regulation through gene specific mechanisms. We built two classification models to infer gene regulation in CRC from methylation differences of tumor and normal tissues, taking into account both gene-silencing and gene-activation effects through hyper- and hypo methylation of CpGs. The classification models result in high prediction performances in both training and independent CRC testing cohorts (0.92=6.5% were categorised as having T2DM. Those with 5.7%<=HbA1c<6.5% were categorised as pre diabetics. In men, the total age-standardised prevalence of pre-diabetes (37.9% vs 31.4%) and T2DM (10.8% vs 9.5%) were higher in Sami compared with non-Sami; the ethnic difference was statistically significant for both pre-diabetes (OR 1.42, p < 0.001) and T2DM (OR 1.31, p = 0.042). In women, pre-diabetes (36.4% vs 33.5%) and T2DM (8.6% vs 7.0%) were also more common in Sami than non-Sami; the differences in both pre-diabetes (OR 1.20, p = 0.025) and T2DM (OR 1.38, p = 0.021) were also statistically significant. The observed ethnic difference in the waist-to-height ratio (WHtR) was a plausible explanation for the ethnic difference in the prevalence of pre-diabetes and T2DM. PMID- 29697017 TI - High-fat diet induces depression-like behaviour in mice associated with changes in microbiome, neuropeptide Y, and brain metabolome. AB - OBJECTIVES: The biological mechanisms linking diet-related obesity and depression remain unclear. Therefore, we examined the impact of high-fat diet (HFD) on murine behaviour, intestinal microbiome, brain metabolome, neuropeptide Y (NPY) expression, and dipeptidyl peptidase-4 (DPP-4) activity. METHODS: Male C57Bl/6J mice were fed an HFD (60 kJ% from fat) or control diet (12 kJ% from fat) for 8 weeks, followed by behavioural phenotyping. Caecal microbiome was analysed by 16S rDNA sequencing, brain metabolome by 1H nuclear magnetic resonance, NPY expression by PCR and immunoassay, and dipeptidyl peptidase-4 (DPP-4) activity by enzymatic assay. The effect of a 4-week treatment with imipramine (7 mg/kg/day) and the DPP-4 inhibitor sitagliptin (50 mg/kg/day) on HFD-induced behavioural changes was also tested. RESULTS: HFD led to a depression-like phenotype as revealed by reduced sociability and sucrose preference. In the caecum, HFD diminished the relative abundance of Bacteroidetes and increased the relative abundance of Firmicutes and Cyanobacteria. In the brain, HFD modified the metabolome of prefrontal cortex and striatum, changing the relative concentrations of molecules involved in energy metabolism (e.g. lactate) and neuronal signalling (e.g. gamma-aminobutyric acid). The expression of NPY in hypothalamus and hippocampus was decreased by HFD, whereas plasma NPY and DPP-4 like activity were increased. The HFD-induced anhedonia remained unaltered by imipramine and sitagliptin. DISCUSSION: The depression-like behaviour induced by prolonged HFD in mice is associated with distinct alterations of intestinal microbiome, brain metabolome, NPY system, and DPP-4-like activity. Importantly, the HFD-evoked behavioural disturbance remains unaltered by DPP-4 inhibition and antidepressant treatment with imipramine. PMID- 29697018 TI - A crystallographic and theoretical study of an (E)-2-Hydroxyiminoethanone derivative: prediction of cyclooxygenase inhibition selectivity of stilbenoids by MM-PBSA and the role of atomic charge. AB - We recently reported that the hydroxyiminoethanone derivative, (E)-OXM, behaves as a highly selective COX-1 inhibitor (COX-1 SI = 833), and also an interesting scaffold with unique characteristics. In the current study, a comprehensive crystallographic and computational study was performed to elucidate its conformational stability and pharmacological activity. Its conformational energy was studied at the B3LYP/6-311G** level of theory and compared to the single crystal X-ray diffraction data. In addition, computational studies of three structurally different stilbenoid derivatives used as selective COX-1 or COX-2 inhibitors were undertaken to predict their COX selectivity potentials. Flexible docking was performed for all compounds at the active site of both COX-1 and COX 2 enzymes by considering some of the key residues as flexible during the docking operation. In the next step, molecular dynamic simulation and binding free energy calculations were performed by MM-PBSA. Final results were found to be highly dependent on the atomic charges of the inhibitors and the choice of force field used to calculate the atomic charges. The binding conformation of the hydroxyiminoethanone derivative is highly correlated with the type of COX isoform inhibited. Our predictive approach can truly predict the cyclooxygenase inhibition selectivity of stilbenoid inhibitors. PMID- 29697019 TI - Frontal Lobe Cavernous Malformations in Pediatric Patients: Clinical Features and Surgical Outcomes. AB - The purpose of this study is to investigate the clinical manifestations, surgical treatment, and neurologic outcomes of frontal lobe cavernous malformations in children. A retrospective analysis of 23 pediatric frontal lobe cavernous malformation patients who underwent surgical treatment in Beijing Tiantan Hospital was performed. The case series included 16 boys and 7 girls. Gross total removal without surgical mortality was achieved in all patients. The mean follow up period after surgery was 33.1 months. Two patients who left hospital with motor deficits gradually recovered after rehabilitative treatment, and other patients were considered to be in excellent clinical condition. For symptomatic frontal lobe cavernous malformations, neurosurgical management should be the treatment of choice. Conservative treatment may be warranted in asymptomatic frontal lobe cavernous malformations, especially the deep-seated or eloquently located cases. PMID- 29697020 TI - Optimal Use of Z-Scores to Preserve the Pulmonary Valve Annulus During Repair of Tetralogy of Fallot. AB - OBJECTIVE: The size of the pulmonary annulus measured as a z-score is often used to determine when to insert a transannular patch (TAP). Multiple "cutoffs" are quoted in the literature; this could lead to inappropriate insertion. We aimed to determine whether the use of z-scores derived from different populations may have contributed to the varied "cutoffs" quoted. METHODS: PubMed was searched using the terms: "tetralogy," "Fallot," "transannular," "patch," "mortality," and "death." Studies published between January 1, 2005, and October 5, 2017, were included; studies without participants under the age of 18 years and studies that did not describe the operative procedure were excluded. RESULTS: Of 52 papers retrieved, 19 were included representing 2,500 repaired patients; 1,371 (54.8%) had a TAP. Five (26.3%) papers representing 638 patients (25.5%) quoted a z-score "cutoff" and what data set was used; "cutoffs" ranged from -2 to -4 and were derived from 2 different data sets. Three studies quoted a data set that has been shown in previous work to be problematic; the only quoted "cutoffs" of -4 were from two of these studies. CONCLUSIONS: Surprisingly few (26.3%) studies mention what pulmonary annulus size "cutoff" was used to decide when to insert a TAP. Z scores derived from different populations were used by different studies and it is possible that this may have contributed to the varied "cutoffs' quoted. Recommendations to perform valve-sparing surgery in pulmonary annuli as small as 4 may not be warranted. Future papers should record "cutoffs" employing recommended z-score data set. PMID- 29697021 TI - Successful Late Recruitment of the Occluded Left Main Coronary Artery After Initial Arterial Switch Operation. AB - We describe a surgical technique for late recruitment of the proximally occluded left main coronary artery (LMCA) after initial arterial switch operation, which had been complicated by severe left ventricular dysfunction. This technique allowed for LMCA recanalization, using the patent conal artery branching off the LMCA close to the ostium. It is particularly useful in small children, where surgical options for coronary arteries are limited and associated with a high risk of restenosis. It was successfully used in a two-month-old boy with successful revascularization confirmed by angiography. PMID- 29697022 TI - Exploring coping strategies and mental health support systems among female youth in the Northwest Territories using body mapping. AB - The mental health of young women in the Northwest Territories (NWT), Canada, is a critical public health concern; however, there is a dearth of research that examines how this population manages mental health challenges. This study explores the self-identified strategies that female youth in the NWT use to cope with mental health issues. The arts-based qualitative method of body mapping and a trauma-informed, strengths-based approach grounded in social ecological theory was used to collect data during in-depth semi-structured interviews. Forty-one participants (aged 13-17 years) attended FOXY body mapping workshops in six NWT communities in 2013 then completed interviews regarding the content of their body maps. Thematic analysis was used to identify five themes related to coping strategies: grounding via nature, strength through Indigenous cultures, connection with God and Christian beliefs, expression using the arts, and relationships with social supports. These results can be used to develop culturally relevant, strengths-based, trauma informed interventions that improve coping and resiliency among Northern youth. PMID- 29697023 TI - Comparison of vibration rolling, nonvibration rolling, and static stretching as a warm-up exercise on flexibility, joint proprioception, muscle strength, and balance in young adults. AB - Warm-up is an essential component for optimizing performance before an exercise session. This study investigated that the immediate effects of vibration rolling (VR), nonvibration rolling (NVR), and static stretching as a part of a warm-up regimen on the flexibility, knee joint proprioception, muscle strength, and dynamic balance of the lower extremity in young adults. Compared with the preintervention, VR induced the range of motion of knee flexion and extension significantly increased by 2.5% and 6%, respectively, and isokinetic peak torque and dynamic balance for muscle strength and dynamic balance increased by 33%-35% and 1.5%, respectively. In the three conditions, most outcomes between VR and NVR were comparable; however, the participants had a significantly higher knee joint reposition error after NVR than after VR, indicating that NVR would have a hampering knee joint proprioception effect. In particular, compared with static stretching, VR significantly increased the quadriceps muscle strength by 2-fold and dynamic balance by 1.8-fold. These findings suggest that athletic professionals may take VR into account for designing more efficient and effective preperformance routine to improve exercise performances. VR has high potential to translate into an on-field practical application. PMID- 29697024 TI - Historical explanation of genetic variation in the Mediterranean horseshoe bat Rhinolophus euryale (Chiroptera: Rhinolophidae) inferred from mitochondrial cytochrome-b and D-loop genes in Iran. AB - Molecular phylogeography and species distribution modelling (SDM) suggest that late Quaternary glacial cycles have portrayed a significant role in structuring current population genetic structure and diversity. Based on phylogenetic relationships using Bayesian inference and maximum likelihood of 535 bp mtDNA (D loop) and 745 bp mtDNA (Cytb) in 62 individuals of the Mediterranean Horseshoe Bat, Rhinolophus euryale, from 13 different localities in Iran we identified two subspecific populations with differing population genetic structure distributed in southern Zagros Mts. and northern Elburz Mts. Analysis of molecular variance (AMOVA) obtained from D-loop sequences indicates that 21.18% of sequence variation is distributed among populations and 10.84% within them. Moreover, a degree of genetic subdivision, mainly attributable to the existence of significant variance among the two regions is shown (thetaCT = 0.68, p = .005). The positive and significant correlation between geographic and genetic distances (R2 = 0.28, r = 0.529, p = .000) is obtained following controlling for environmental distance. Spatial distribution of haplotypes indicates that marginal population of the species in southern part of the species range have occupied this section as a glacial refugia. However, this genetic variation, in conjunction with results of the SDM shows a massive postglacial range expansion for R. euryale towards higher latitudes in Iran. PMID- 29697026 TI - Guide for Selection of Relevant Cell Lines During the Evaluation of New Anti Cancer Compounds. AB - Human cancer cell lines are valuable models for anti-cancer drug development. Although all cancer cells share common biological features, each cancer cell line has unique genotypic/ phenotypic characteristics that affect drug response. Thus, the information obtained with a specific cancer cell line cannot be easily extrapolated to other cancer cells. Consequently, cell line selection during experimental design is critical for providing proper and clinically relevant structure-activity analysis. Herein, we critically review the use of cancer cell lines as tools for activity analysis by comparing two different scenarios: i) the use of multiple cancer cell lines, with the NCI-60 Program as the most representative example; and, ii) the selection of a single cell line with specific biological characteristics that match the rationale of compound design. Considering that most laboratories evaluate the activity of new compounds using few cell lines, we provide a systematic strategy for selection based on the expression levels and genetic status of the target and the effectiveness of target inhibition or silencing. We exemplify the use of public databases for data retrieval and analysis as well as the critical comparison of such information with published results. This approach refines cell line selection, avoiding the perpetuation of published poor selection and enhancing the relevance of the results. PMID- 29697027 TI - DNA Related Enzymes as Molecular Targets for Antiviral and Antitumoral Chemotherapy. A Natural Overview of the Current Perspectives. AB - BACKGROUND: The discovery of new chemotherapeutic agents still remains a continuous goal to achieve. DNA polymerases and topoisomerases act in nucleic acids metabolism modulating different processes like replication, mitosis, damage repair, DNA topology and transcription. It has been widely documented that Polymerases serve as molecular targets for antiviral and antitumoral chemotherapy. Furthermore, telomerase is a ribonucleoprotein with exacerbated activity in most of the tumor cell lines, becoming as an emergent target in Cancer treatment. METHODS: We undertook an exhaustive search of bibliographic databases for peer-reviewed research literature related to the last decade. The characteristics of screened bibliography describe structure activity relationships and show the principal moieties involved. This work tries to summarize the investigation about natural and semi-synthetic products with natural origin with the faculty to inhibit key enzymes that play a crucial role in DNA metabolism. RESULTS: Eighty-five data references were included in this review, showing natural products widely distributed throughout the plant kingdom and their bioactive properties such as tumor growing inhibitory effects, and anti AIDS activity. CONCLUSION: The findings of this review confirm the importance to find new drugs and biologically active natural products, and their potential medicinally useful benefits. PMID- 29697028 TI - Bacterial Multidrug Efflux Proteins: A Major Mechanism of Antimicrobial Resistance AB - Antimicrobial resistance is a global challenge, for which the mechanisms of resistance arevaried and complicated. Bacterial multidrug efflux proteins are a major mechanism of antimicrobialresistance and therefore, targets for drug development. Gram-negative bacteria are intrinsically moreresistant to many antibiotics and biocides due to their cell structure and the activity of multidrug effluxproteins. These transporters actively extrude antibiotics and other xenobiotics from the cytoplasm orsurrounding membranes of cells to the external environment. Based on amino acid sequence similarity,substrate specificity and the energy source used to export their substrates, there are seven majorfamilies of distinct bacterial multidrug efflux proteins: ABC, RND, MFS, SMR, MATE, PACE,AbgT. Individual proteins may be highly specialised for one compound or highly promiscuous, transportinga broad range of structurally dissimilar substrates. Protein structural organisation in a largemajority of the families, including the number of transmembrane helices, has been confirmed by highresolutionstructure determination for at least one member. In this paper, we review the families ofbacterial multidrug efflux proteins, including basic properties, energisation, structural organisation andmolecular mechanism. Using representative proteins from each family, we also performed analyses oftransmembrane helices, amino acid composition and distribution of charged residues. Ongoing characterisationof structure-function relationships and regulation of bacterial multidrug efflux proteins arenecessary for contributing new knowledge to assist drug development and strategies that will overcomeantimicrobial resistance. PMID- 29697029 TI - Innovative Methodology in the Discovery of Novel Drug Targets in the Free-Living Amoebae. AB - Despite advances in drug discovery and modifications in the chemotherapeutic regimens, human infections caused by free-living amoebae (FLA) have high mortality rates (~95%). The FLA that cause fatal human cerebral infections include Naegleria fowleri, Balamuthia mandrillaris and Acanthamoeba spp. Novel drug-target discovery remains the only viable option to tackle these central nervous system (CNS) infection in order to lower the mortality rates caused by the FLA. Of these FLA, N. fowleri causes primary amoebic meningoencephalitis (PAM), while the A. castellanii and B. Mandrillaris are known to cause granulomatous amoebic encephalitis (GAE). The infections caused by the FLA have been treated with drugs like Rifampin, Fluconazole, Amphotericin-B and Miltefosine. Miltefosine is an anti-leishmanial agent and an experimental anti cancer drug. With only rare incidences of success, these drugs have remained unsuccessful to lower the mortality rates of the cerebral infection caused by FLA. Recently, with the help of bioinformatic computational tools and the discovered genomic data of the FLA, discovery of newer drug targets has become possible. These cellular targets are proteins that are either unique to the FLA or shared between the humans and these unicellular eukaryotes. The latter group of proteins has shown to be targets of some FDA approved drugs prescribed in non infectious diseases. This review out-lines the bioinformatics methodologies that can be used in the discovery of such novel drug-targets, their chronicle by in vitro assays done in the past and the translational value of such target discoveries in human diseases caused by FLA. PMID- 29697031 TI - TPEN exerts antitumor efficacy in murine mammary adenocarcinoma through an H2O2 signaling mechanism dependent on caspase-3. AB - BACKGROUND: Breast cancer is the second most common cancer worldwide. N, N, N', N'-Tetrakis (2-pyridylmethyl)-ethylenediamine (TPEN) is a lipid-soluble zinc metal chelator that induces apoptosis in cancer cells through oxidative stress (OS). However, the effectiveness and the mechanisms involved in TPEN-induced cell death in mammary adenocarcinoma cells in vitro and in vivo are still unclear. OBJECTIVE: This study aimed to evaluate the cytotoxic effect of TPEN in mouse embryonic fibroblasts (MEFs, as normal control cells) and mammary adenocarcinoma cancer cells (TS/A cells) in vitro and in a mammary tumor model in vivo. METHODS: Cells were treated with TPEN (0-3 uM), and changes in nuclear chromatin and DNA, mitochondrial membrane potential (DeltaPsim), and intracellular reactive oxygen species (ROS) levels were determined by both fluorescence microscopy and flow cytometry. Cell proliferation and the cell cycle were also analyzed. Cellular markers of apoptosis were evaluated by Western blot. Finally, the effect of TPEN in a mammary adenocarcinoma tumor model in vivo was determined by immunohistological analyses. RESULTS: TPEN induced apoptosis in TS/A cells in a dose-dependent manner, increasing nuclear chromatin condensation, DNA fragmentation, cell cycle arrest and DeltaPsim loss. Additionally, TPEN increased dichlorofluorescein fluorescence (DCF+) intensity, indicative of ROS production; increased DJ-1-Cys106-sulfonate expression, a marker of intracellular H2O2 stress; induced p53 and PUMA upregulation; and activated caspase-3. Moreover, TPEN induced mammary cancer cell elimination and tumor size reduction in vivo 48 h after treatment through an OS-induced apoptotic mechanism. CONCLUSION: TPEN selectively induces apoptosis in TS/A cells through an H2O2-mediated signaling pathway. Our findings support the use of TPEN as a potential treatment for breast cancer. PMID- 29697030 TI - The Role of Stem Cells for Reconstructing the Lower Urinary Tracts. AB - BACKGROUND: The urinary bladder and urethra comprise the lower urinary tracts. Pathological conditions that affect both structures necessitate reconstructive urological intervention with autologous tissue sources that cause neuromechanical and metabolic complications. Stem-cell therapies may offer an attractive alternative as they can replicate important host derived cellular functions such as mitosis, proliferation, differentiation and apoptosis. OBJECTIVE: To provide an overview on the application of stem cell therapies for regenerating the lower urinary tracts and to discuss factors that need to be addressed before stem-cells can be reliably introduced into clinical urological practice. RESULTS: Advantages of stem cells in reconstructive urology are their ability to self-renew and their durability. Mesenchymal stem cells (MSCs), embryonic stem cells (ESCs) and adult stem cells (ASCs) demonstrate excellent urological regenerative properties. Repairing defective lower urinary tract structures with various stem-cell derived therapies has been widely reported with encouraging results in vitro and in pre clinical in vivo trials. Ethical considerations, cost, regulation, manufacturing and reimbursement need to be fully transparent before stem-cells are routinely applied to urological patients. International collaboration with consensus guidelines should be considered to facilitate standards that allow safe use of stem-cell therapies in urology. CONCLUSION: Stem cells therapies in urology are developing rapidly with many important achievements to date. Despite promising in vitro and pre-clinical data; implementation of stem cells into daily urological practice is not imminent. Further investigation is required to determine whether stem-cells will provide better clinical outcomes than current urological tissue replacement strategies. PMID- 29697032 TI - Synthesis, 17alpha--hydroxylase-C17,20-lyase inhibitory and 5AR reductase activity of novel pregnenolone derivatives. AB - A series of 1,5-diaryl pyrazoline pregnenolones were synthesized and screened for 5alpha-reductase inhibitory activities. Synthesis of the analogs is multistep and proceeds in good overall yields. The key step in the synthesis of 1,5 disubstituted pyrazolinyl pregnenolones (5a-l) is the heterocyclization of bezylidine derivatives (3) in presence of phenylhydrazines (4) through the initial formation of the phenylhydrazones, which undergo concomitant cyclization to generate the stable pyrazoline derivatives. All compounds were tested for their prostate cancer cell inhibitory, 5alpha-reductase and 17alpha-hydroxylase C17,20-lyase inhibitory activities. Amongst all the compounds screened for their 5alpha-reductase inhibitory activities, compound 5c, 5e, 5g and 5l were found to be the most active. Further, compounds 5g and 5h were found to have moderate 17alpha-hydroxylase-C17,20-lyase inhibitory activities. PMID- 29697033 TI - Synthesis, Characterization and Molecular Docking Studies of Novel N (benzimidazol-1-ylmethyl)-4-chlorobenzamide Analogues for Potential Anti inflammatory and Antimicrobial Activity. AB - BACKGROUND: The benzimidazole ring is an important pharmacophore in modern drug discovery. Mannich reaction is one of the versatile reaction widely used in organic synthesis. Mannich base derivatives play an important role in medical field with diverse biological actions. OBJECTIVE: A series of N-(benzimidazol-1 ylmethyl)-4-chlorobenzamide derivatives (3a- 3m) were synthesized and evaluated for anti-inflammatory and antimicrobial potential. METHOD: Mannich reaction was used to synthesize N-(benzimidazol-1-ylmethyl)-4- chlorobenzamide analogues. The structures of novel target compounds were elucidated by spectral and analytical techniques and screened for in vivo anti-inflammatory activity and ulcerogenic activity. In addition, the prepared derivatives were also evaluated for in vitro antimicrobial activity against gram negative, gram positive and fungal strains. Further, in silico studies were carried out to define the interaction of the title compounds with COX-2 enzyme and microbial protein. RESULTS: The results revealed that out of thirteen molecules, compound 3a (containing chloromethyl substituent at 2-position of benzimidazole) showed significant antiinflammatory effect at a dose of 100 mg/kg p.o. and the experimental data was statistically significant at p<=0.05 level. Diclofenac sodium was taken as standard drug for antiinflammatory activity. Furthermore, derivative 3e (containing 2-chlorophenyl moiety at 2- position of benzimidazole scaffold) was found to be the most effective antimicrobial compound among the synthesized derivatives. Ciprofloxacin and clotrimazole were used as reference antimicrobial agents. Results from in vivo and in vitro studies of synthesized analogues were found to be in good correlation with in silico study. CONCLUSION: These results designate that N (Benzimidazol-1-ylmethyl)-4-chlorobenzamide analogues, substituted with halogen functionality, could be used as potential lead for designing more potent anti inflammatory and antimicrobial agents. PMID- 29697034 TI - Nitrocatechol Derivatives of Chalcone as Inhibitors of Monoamine Oxidase and Catechol-O-Methyltransferase. AB - INTRODUCTION: The efficacy of L-dopa in the treatment of Parkinson's disease depends on its metabolic conversion to dopamine in the brain, however extensive peripheral metabolism of L-dopa diminishes its availability for uptake into the brain. L-Dopa is extensively decarboxylated in the gastrointestinal tract and peripheral tissues by Aromatic L-Amino Acid Decarboxylase (AADC), and AADC inhibitors are thus frequently combined with L-dopa therapy. When AADC is inhibited, 3-Omethylation Catalysed by Catechol-O-Methyltransferase (COMT) becomes a dominant metabolic pathway for L-dopa, and COMT inhibitors may thus also be used as adjuncts to L-dopa in Parkinson's disease. Monoamine Oxidase (MAO), in turn, metabolises dopamine in the brain, and MAO-B inhibitors may exert a dopamine sparing effect in the brain. MATERIALS & METHODS: Based on the roles of COMT and MAO in the metabolism of L-dopa and dopamine, the present study attempts to discover novel dual inhibitors of these enzymes. For this purpose, nitrocatechol derivatives of chalcone were synthesised and evaluated as inhibitors of COMT and MAO. The chalcone class of compounds is well known to potently inhibit MAO-B, while nitrocatechol derivatives (e.g. tolcapone and entacapone) are clinically used COMT inhibitors. RESULTS: The results document that all of the derivatives are high potency in vitro inhibitors of rat liver COMT with IC50 values ranging from 0.07 to 0.29 MUM. Under these experimental conditions, tolcapone and entacapone display IC50 values of 0.26 uM and 0.25 uM, respectively. The chalcones are less potent as inhibitors of MAO with the most potent inhibitor possessing a Ki of 4.6 uM for the in vitro inhibition of human MAO-B. CONCLUSION: This study shows that nitrocatechol derivatives of chalcone may act as COMT and MAO-B inhibitors, and proposes a general strategy for further enhancing MAO-B inhibition while retaining the potent COMT inhibition activity of this class. PMID- 29697035 TI - Serum N-terminal Pro-brain Natriuretic Peptide Level is Associated with the Development of Chronic Kidney Diseases in Patients with Type 2 Diabetes. AB - BACKGROUND AND OBJECTIVE: Previous studies revealed the association between serum Nterminal pro-brain natriuretic peptide (NT-proBNP) level and chronic kidney diseases (CKD) in general population. However, little is known about the association between serum NT-proBNP level and incident CKD in patients with type 2 diabetes. Thus, we investigated the impact of serum NT-proBNP level on incident CKD in patients with type 2 diabetes. METHOD: We enrolled 211 type 2 diabetic patients without CKD in this cohort study. CKD was diagnosed as estimated glomerular filtration rate <60 ml/min/1.73 m2. We divided the patients into three groups according to the tertiles of serum NT-proBNP level. Univariates and multivariate hazard ratios (HRs) for the incident CKD were calculated by Cox regression analyses. RESULTS: Over the median follow-up period of 7 years, 56 patients developed incident CKD. Log NTproBNP was positively associated with incident CKD (HR 3.70, 95%CI 1.72-8.18, p <0.001). Compared with the lowest level of serum NT-proBNP tertile (<=36 pg/mL), the highest level of serum NTproBNP tertile (>=84 pg/mL) showed increased risk of incident CKD after adjusting age, sex, body mass index, hemoglobin A1c, creatinine, smoking, usage of hypertension drug and urinary albumin excretion at baseline examination (adjusted HR2.37, 95% CI 1.09-5.48, p = 0.028). CONCLUSION: Serum NT-proBNP level is an independent biomarker for incident CKD in patients with type 2 diabetes. PMID- 29697036 TI - Dosimetry and Radiobiology of Alpha-Particle Emitting Radionuclides. AB - BACKGROUND: Radiopharmaceutical therapy is a cancer treatment modality by which radiation is delivered directly to targeted tumor cells or to their microenvironment. This makes it possible to deliver highly potent alpha-particle radiation. The short-range and highly potent nature of alpha-particles require a dosimetry methodology that considers microscale distributions of the alpha emitting agent. The high energy deposition density along an alpha-particle track causes a spectrum of DNA lesions. The majority of these are irreparable DNA double-stranded breaks. Accordingly the biologic effects of alpha- particles are largely impervious to the adaptive and resistance mechanism that renders other therapeutics ineffectual. OBJECTIVES: In this review, the radiobiology and dosimetry of alpha-particle emitting radionuclides as related to their use in radiopharmaceutical therapy, are presented. CONCLUSION: Alpha-particle emitter radiopharmaceutical therapy is distinguished from other treatment modalities. Its safe clinical use requires an understanding of its unique dosimetry and radiobiology. PMID- 29697037 TI - Short sleep duration and poor sleep quality predict next-day suicidal ideation: an ecological momentary assessment study. AB - BACKGROUND: Sleep problems are a modifiable risk factor for suicidal thoughts and behaviors. Yet, sparse research has examined temporal relationships between sleep disturbance, suicidal ideation, and psychological factors implicated in suicide, such as entrapment. This is the first in-the-moment investigation of relationships between suicidal ideation, objective and subjective sleep parameters, and perceptions of entrapment. METHODS: Fifty-one participants with current suicidal ideation completed week-long ecological momentary assessments. An actigraph watch was worn for the duration of the study, which monitored total sleep time, sleep efficiency, and sleep latency. Daily sleep diaries captured subjective ratings of the same sleep parameters, with the addition of sleep quality. Suicidal ideation and entrapment were measured at six quasi-random time points each day. Multi-level random intercept models and moderation analyses were conducted to examine the links between sleep, entrapment, and suicidal ideation, adjusting for anxiety and depression severity. RESULTS: Analyses revealed a unidirectional relationship whereby short sleep duration (both objective and subjective measures), and poor sleep quality, predicted the higher severity of next-day suicidal ideation. However, there was no significant association between daytime suicidal ideation and sleep the following night. Sleep quality moderated the relationship between pre-sleep entrapment and awakening levels of suicidal ideation. CONCLUSIONS: This is the first study to report night-to-day relationships between sleep disturbance, suicidal ideation, and entrapment. Findings suggest that sleep quality may alter the strength of the relationship between pre-sleep entrapment and awakening suicidal ideation. Clinically, results underscore the importance of assessing and treating sleep disturbance when working with those experiencing suicidal ideation. PMID- 29697038 TI - Tree analysis modeling of the associations between PHQ-9 depressive symptoms and doctor diagnosis of depression in primary care. AB - BACKGROUND: The aim of this study was to explore the relationship between patient self-reported Patient Health Questionnaire-9 (PHQ-9) symptoms and doctor diagnosis of depression using a tree analysis approach. METHODS: This was a secondary analysis on a dataset obtained from 10 179 adult primary care patients and 59 primary care physicians (PCPs) across Hong Kong. Patients completed a waiting room survey collecting data on socio-demographics and the PHQ-9. Blinded doctors documented whether they thought the patient had depression. Data were analyzed using multiple logistic regression and conditional inference decision tree modeling. RESULTS: PCPs diagnosed 594 patients with depression. Logistic regression identified gender, age, employment status, past history of depression, family history of mental illness and recent doctor visit as factors associated with a depression diagnosis. Tree analyses revealed different pathways of association between PHQ-9 symptoms and depression diagnosis for patients with and without past depression. The PHQ-9 symptom model revealed low mood, sense of worthlessness, fatigue, sleep disturbance and functional impairment as early classifiers. The PHQ-9 total score model revealed cut-off scores of >12 and >15 were most frequently associated with depression diagnoses in patients with and without past depression. CONCLUSIONS: A past history of depression is the most significant factor associated with the diagnosis of depression. PCPs appear to utilize a hypothetical-deductive problem-solving approach incorporating pre-test probability, with different associated factors for patients with and without past depression. Diagnostic thresholds may be too low for patients with past depression and too high for those without, potentially leading to over and under diagnosis of depression. PMID- 29697039 TI - An examination of father vulnerability and coercive family process after the birth of a sibling: A spillover cascade model. AB - Fathers are a crucial source of support for children following the birth of an infant sibling. This study examined whether fathers were more vulnerable to the effects of interparental conflict than mothers, and whether there was a subsequent spillover cascade from interparental conflict to children's externalizing behavior problems. We followed 241 families after the birth of a second child. Mothers and fathers reported on interparental conflict and parental efficacy at 1 and 4 months postpartum and punitive discipline and firstborn children's externalizing behavior problems across a longitudinal investigation (prenatal and 4, 8, and 12 months postpartum). For both mothers and fathers, interparental conflict prenatally predicted decreased parental efficacy following the birth. Fathers' lower parental efficacy was significantly associated with increased punitive discipline toward the older sibling at 4 months, whereas mothers' lower parental efficacy was not. Coercive family processes were present between mothers' and fathers' punitive discipline and older siblings' externalizing behavior problems. Results were inconsistent with the father vulnerability hypothesis in that both mothers and fathers were vulnerable to interparental conflict, which in turn spilled over to create coercive family processes that exacerbated children's externalizing behavior problems in the year following the birth of a second child. PMID- 29697040 TI - Origins of mother-child reminiscing style. AB - Maternal elaborative reminiscing supports preschool children's autobiographical memory, self-concept, and emotion understanding. What are the factors contributing to mothers' elaborative style of reminiscing? In a longitudinal community sample (n = 170 at the final data point), this study explored the role of maternal depression (8-44 months), maternal sensitivity and maternal mind mindedness (8 months), as well as child factors of joint attention (15 months), attachment security (15 months), and language (26 months) for mother-child reminiscing about a positive (happy) and a negative (scared) event at 44 months. Mothers could be classed into two groups of low versus increasing depression from 8 to 44 months, yet maternal depression did not uniquely predict mother-child reminiscing after accounting for maternal sensitivity and other factors. Instead, maternal sensitivity, children's joint attention, and language uniquely predicted children's elaborations about the scared event at 44 months, and maternal sensitivity uniquely predicted mothers' elaborations about the scared event at 44 months. Mothers who are more sensitive in early interactions may later be better at engaging their children when reminiscing about negative emotions. These findings have implications for the design of interventions targeted at supporting mothers to engage in elaborative reminiscing with their preschool children. PMID- 29697041 TI - Artistic creativity and risk for schizophrenia, bipolar disorder and unipolar depression: a Swedish population-based case-control study and sib-pair analysis. AB - BACKGROUND: Many studies have addressed the question of whether mental disorder is associated with creativity, but high-quality epidemiological evidence has been lacking.AimsTo test for an association between studying a creative subject at high school or university and later mental disorder. METHOD: In a case-control study using linked population-based registries in Sweden (N = 4 454 763), we tested for associations between tertiary education in an artistic field and hospital admission with schizophrenia (N = 20 333), bipolar disorder (N = 28 293) or unipolar depression (N = 148 365). RESULTS: Compared with the general population, individuals with an artistic education had increased odds of developing schizophrenia (odds ratio = 1.90, 95% CI = [1.69; 2.12]) bipolar disorder (odds ratio = 1.62 [1.50; 1.75]) and unipolar depression (odds ratio = 1.39 [1.34; 1.44]. The results remained after adjustment for IQ and other potential confounders. CONCLUSIONS: Students of artistic subjects at university are at increased risk of developing schizophrenia, bipolar disorder and unipolar depression in adulthood.Declaration of interestNone. PMID- 29697042 TI - Dispatcher CPR Instructions Across the Age Continuum. AB - BACKGROUND: Survival rates following out-of-hospital cardiac arrest (OHCA) increase two to three times when cardiopulmonary resuscitation (CPR) is started by bystanders, as compared to starting CPR when Emergency Medical Services (EMS) arrives. Municipalities that have implemented dispatcher-assisted bystander CPR programs have seen increased rates of bystander CPR. Cardiopulmonary resuscitation instructions are given for victims of all ages, but it is unknown if offering instructions results in similar rates of EMS-documented bystander CPR across the age continuum in these municipalities. OBJECTIVES: The aim of this study was to determine if there is a difference in EMS-documented bystander CPR rates based on the age group of the OHCA victim when dispatcher CPR instructions are available in the community. METHODS: This was a three-year, retrospective chart review of OHCA patients in two municipalities within a single county that provided dispatcher-assisted CPR instructions. Bystander CPR and patient age were determined based on EMS documentation. Age was stratified into three groups: child (0-12 years), adult (13-54 years), and geriatric (>=55 years). Chi square was used to compare the rate of bystander CPR in each age group. RESULTS: During the study period, 1,993 patients were identified as being in OHCA at the time of EMS arrival. The overall bystander CPR rate was 10%. The highest rate of bystander CPR was in the child age group (19%). The lowest rate of bystander CPR was in the geriatric age group (9%). There was a statistically significant difference between age groups (P<=.01). CONCLUSIONS: The rate of EMS-documented bystander CPR was low, even though these municipalities provided dispatcher assisted CPR instructions. The highest rates of bystander CPR were observed in children (0-12 years). Future investigations should determine why this occurs and if there are opportunities to modify dispatcher coaching based on patient age so that bystander CPR rates improve. WeinmeisterKL, LernerEB, GuseCE, AteyyahKA, PirralloRG. Dispatcher CPR instructions across the age continuum. Prehosp Disaster Med. 2018;33(3):342-345. PMID- 29697043 TI - Infant feeding practices and determinant variables for early complementary feeding in the first 8 months of life: results from the Brazilian MAL-ED cohort site. AB - OBJECTIVE: The present study aimed to describe breast-feeding, complementary feeding and determining factors for early complementary feeding from birth to 8 months of age in a typical Brazilian low-income urban community. DESIGN: A birth cohort was conducted (n 233), with data collection twice weekly, allowing close observation of breast-feeding, complementary feeding introduction and description of the WHO core indicators on infant and young child feeding. Infant feeding practices were related to socio-economic status (SES), assessed by Water/sanitation, wealth measured by a set of eight Assets, Maternal education and monthly household Income (WAMI index). Two logistic regression models were constructed to evaluate risk factors associated with early complementary feeding. RESULTS: Based on twice weekly follow-up, 65 % of the children received exclusive breast-feeding in the first month of life and 5 % in the sixth month. Complementary feeding was offered in the first month: 29 % of the children received water, 15 % infant formulas, 13 % other milks and 9.4 % grain-derived foods. At 6 months, dietary diversity and minimum acceptable diet were both 47 % and these increased to 69 % at 8 months. No breast-feeding within the first hour of birth was a risk factor for the early introduction of water (adjusted OR=4.68; 95 % CI 1.33, 16.47) and low WAMI index a risk factor for the early introduction of other milks (adjusted OR=0.00; 95 % CI 0.00, 0.02). CONCLUSIONS: Data suggest local policies should promote: (i) early breast-feeding initiation; (ii) SES, considering maternal education, income and household conditions; (iii) timely introduction of complementary feeding; and (iv) dietary diversity. PMID- 29697044 TI - International Emergency Medical Teams Training Workshop Special Report. AB - The World Health Organization's (WHO; Geneva, Switzerland) Emergency Medical Team (EMT) Initiative created guidelines which define the basic procedures to be followed by personnel and teams, as well as the critical points to discuss before deploying a field hospital. However, to date, there is no formal standardized training program established for EMTs before deployment. Recognizing that the World Association of Disaster and Emergency Medicine (WADEM; Madison, Wisconsin USA) Congress brings together a diverse group of key stakeholders, a pre-Congress workshop was organized to seek out collective expertise and to identify key EMT training competencies for the future development of training programs and protocols. The future of EMT training should include standardization of curriculum and the recognition or accreditation of selected training programs. The outputs of this pre-WADEM Congress workshop provide an initial contribution to the EMT Training Working Group, as this group works on mapping training, competencies, and curriculum. Common EMT training themes that were identified as fundamental during the pre-Congress workshop include: the ability to adapt one's professional skills to low-resource settings; context-specific training, including the ability to serve the needs of the affected population in natural disasters; training together as a multi-disciplinary EMT prior to deployment; and the value of simulation in training. AlbinaA, ArcherL, BoivinM, CranmerH, JohnsonK, KrishnarajG, ManeshiA, OddyL, Redwood-CampbellL, RussellR. International Emergency Medical Teams training workshop special report. Prehosp Disaster Med. 2018;33(3):335-338. PMID- 29697045 TI - An unexpected case of post-operative superior caval vein syndrome. AB - Superior caval vein obstruction in children after congenital heart surgery has been more associated with thrombosis formation as result of single-ventricle palliation, infection, indwelling devices/catheters, or external compression. Many of these patients will present to the cardiac catheterisation laboratory for evaluation and possible intervention. We present an unusual case of superior caval vein obstruction in a patient after Tetralogy of Fallot repair. PMID- 29697046 TI - ICD-11 chapter on mental and behavioural disorders: heralding new ways of seeing old problems. PMID- 29697047 TI - Rev7 and 53BP1/Crb2 prevent RecQ helicase-dependent hyper-resection of DNA double strand breaks. AB - Poly(ADP ribose) polymerase inhibitors (PARPi) target cancer cells deficient in homology-directed repair of DNA double-strand breaks (DSBs). In preclinical models, PARPi resistance is tied to altered nucleolytic processing (resection) at the 5' ends of a DSB. For example, loss of either 53BP1 or Rev7/MAD2L2/FANCV derepresses resection to drive PARPi resistance, although the mechanisms are poorly understood. Long-range resection can be catalyzed by two machineries: the exonuclease Exo1, or the combination of a RecQ helicase and Dna2. Here, we develop a single-cell microscopy assay that allows the distinct phases and machineries of resection to be interrogated simultaneously in living S. pombe cells. Using this assay, we find that the 53BP1 orthologue and Rev7 specifically repress long-range resection through the RecQ helicase-dependent pathway, thereby preventing hyper-resection. These results suggest that 'rewiring' of BRCA1 deficient cells to employ an Exo1-independent hyper-resection pathway is a driver of PARPi resistance. PMID- 29697048 TI - A label-free approach to detect ligand binding to cell surface proteins in real time. AB - Electrophysiological recordings allow for monitoring the operation of proteins with high temporal resolution down to the single molecule level. This technique has been exploited to track either ion flow arising from channel opening or the synchronized movement of charged residues and/or ions within the membrane electric field. Here, we describe a novel type of current by using the serotonin transporter (SERT) as a model. We examined transient currents elicited on rapid application of specific SERT inhibitors. Our analysis shows that these currents originate from ligand binding and not from a long-range conformational change. The Gouy-Chapman model predicts that adsorption of charged ligands to surface proteins must produce displacement currents and related apparent changes in membrane capacitance. Here we verified these predictions with SERT. Our observations demonstrate that ligand binding to a protein can be monitored in real time and in a label-free manner by recording the membrane capacitance. PMID- 29697050 TI - Enhanced kinetics of polysulfide redox reactions on Mo2C/CNT in lithium-sulfur batteries. AB - Among different energy storage devices, the lithium-sulfur (Li-S) battery is the subject of recent attention. However, the capacity decay caused by polysulfide shuttle leading to sluggish kinetics of polysulfide redox reactions is the main hindrance for its practical application in Li-S batteries. Herein, molybdenum carbide nanoparticles anchored on carbon nanotubes (Mo2C/CNT) are reported to serve as an efficient cathode material to enhance the electrochemical kinetics of polysulfide conversion in Li-S batteries. Mo2C/CNT shows strong adsorption and activation of polar polysulfides and therefore accelerates the redox kinetics of polysulfides, reduces the energy barrier, effectively mitigates the polarization and polysulfide shuttle, thus improving the electrochemical performance. The S Mo2C/CNT composite with 70 wt% sulfur loading exhibits high specific discharge capacity (1206 mA h g-1 at 0.5 C), excellent high-rate performance, long cycle life (900 cycles), and outstanding Coulombic efficiency (~100%) at a high rate (2 C) corresponding to a capacity decay of only 0.05%. Remarkably, the S-Mo2C/CNT cathode with high areal sulfur loading of 2.5 mg cm-2 exhibits high-rate capacities and stable cycling performance over 100 cycles, offering the potential for use in high energy Li-S batteries. PMID- 29697051 TI - Fabrication of arrays of tapered silicon micro-/nano-pillars by metal-assisted chemical etching and anisotropic wet etching. AB - Fabrication of a 2D square lattice array of intentionally tapered micro-/nano silicon pillars by metal-assisted chemical etching (MACE) of silicon wafers is reported. The pillars are square rod shaped with the cross-sections in the range 0.2 * 0.2-0.9 * 0.9 MUm2 and heights 3-7 MUm. The spacing between pillars in the 2D square lattice was controlled between 0.5 and 3.0 MUm. While the pillars after MACE had the high aspect ratio ~1:5, subsequent anisotropic wet etching in potassium hydroxide solution led to 80 degrees -89.5 degrees tapers with smooth sidewalls. The resulting taper angle showed the relation with geometry of pillar structures; the spacing 0.5-3.0 MUm led to the tapering angle 89.5 degrees -80 degrees for 3 and 5 MUm tall pillars but 7 MUm tall pillars showed no dependency between the tapering angle and the inter-pillar spacing. Such an array of silicon tapered-rods with smooth sidewalls is expected to be applicable as a mold in nanoimprinting applications. PMID- 29697049 TI - Microbial eukaryotes have adapted to hypoxia by horizontal acquisitions of a gene involved in rhodoquinone biosynthesis. AB - Under hypoxic conditions, some organisms use an electron transport chain consisting of only complex I and II (CII) to generate the proton gradient essential for ATP production. In these cases, CII functions as a fumarate reductase that accepts electrons from a low electron potential quinol, rhodoquinol (RQ). To clarify the origins of RQ-mediated fumarate reduction in eukaryotes, we investigated the origin and function of rquA, a gene encoding an RQ biosynthetic enzyme. RquA is very patchily distributed across eukaryotes and bacteria adapted to hypoxia. Phylogenetic analyses suggest lateral gene transfer (LGT) of rquA from bacteria to eukaryotes occurred at least twice and the gene was transferred multiple times amongst protists. We demonstrate that RquA functions in the mitochondrion-related organelles of the anaerobic protist Pygsuia and is correlated with the presence of RQ. These analyses reveal the role of gene transfer in the evolutionary remodeling of mitochondria in adaptation to hypoxia. PMID- 29697052 TI - Resting-state functional connectivity analysis of the mouse brain using intrinsic optical signal imaging of cerebral blood volume dynamics. AB - OBJECTIVE: Resting-state functional connectivity (rsFC) of the human brain is closely related with neurological and psychiatric disorders. Mice are widely used to investigate the physiological mechanisms of such disorders, because of the applicability of invasive experimental techniques. Thus, studies on rsFC of the mouse brain are essential to link physiological mechanisms with these disorders in humans. In this study, we investigated the applicability of intrinsic optical signal imaging of cerebral blood volume (IOSI-CBV) for rsFC analysis of the mouse brain. APPROACH: Transcranial IOSI-CBV images were collected from the brains of un-anesthetized wild-type mice with a cooled-CCD camera. The time traces of all pixels were averaged to create a global signal (GS). Marginal and partial correlation analyses were performed to estimate the rsFC based on CBV signals both with and without GS removal. The consistency of the results were confirmed by comparing them with to the rsFCs data reported in the previous studies. MAIN RESULTS: We confirmed that GS correlated with heart rate fluctuation in the FC frequency band. The marginal correlation coefficient of CBV with GS removal was consistent with measurements using conventional optical imaging methods relying on oxygenated hemoglobin concentration and cerebral blood flow. SIGNIFICANCE: These results suggest the applicability and usefulness of the transcranial IOSI CBV method to estimate rsFC of the mouse brain. PMID- 29697053 TI - Porous Mn-doped cobalt oxide@C nanocomposite: a stable anode material for Li-ion rechargeable batteries. AB - Cobalt oxide is a transition metal oxide, well studied as an electrode material for energy storage applications, especially in supercapacitors and rechargeable batteries, due to its high charge storage ability. However, it suffers from low conductivity, which effectively hampers its long-term stability. In the present work, a simple strategy to enhance the conductivity of cobalt oxide is adopted to achieve stable electrochemical performance by means of carbon coating and Mn doping, via a simple and controlled, urea-assisted glycine-nitrate combustion process. Structural analysis of carbon coated Mn-doped Co3O4 (Mn-Co3O4@C) confirms the formation of nanoparticles (~50 nm) with connected morphology, exhibiting spinel structure. The Mn-Co3O4@C electrode displays superior electrochemical performance as a Li-ion battery anode, delivering a specific capacity of 1250 mAh g-1. Mn-Co3O4@C demonstrates excellent performance in terms of long-term stability, keeping charge storage ability intact even at high current rates due to the synergistic effects of fast kinetics-provided by enriched electronic conductivity, which allows ions to move freely to active sites and electrons from reaction sites to substrate during redox reactions-and high surface area combined with mesoporous architecture. The fully assembled battery device using Mn-Co3O4@C and standard LiCoO2 electrode shows 90% capacity retention over 100 cycles. PMID- 29697055 TI - Local Schottky contacts of embedded Ag nanoparticles in Al2O3/SiN x :H stacks on Si: a design to enhance field effect passivation of Si junctions. AB - This paper describes an original design leading to the field effect passivation of Si n+-p junctions. Ordered Ag nanoparticle (Ag-NP) arrays with optimal size and coverage fabricated by means of nanosphere lithography and thermal evaporation, were embedded in ultrathin-Al2O3/SiN x :H stacks on the top of implanted Si n+-p junctions, to achieve effective surface passivation. One way to characterize surface passivation is to use photocurrent, sensitive to recombination centers. We evidenced an improvement of photocurrent by a factor of 5 with the presence of Ag NPs. Finite-difference time-domain (FDTD) simulations combining with semi-quantitative calculations demonstrated that such gain was mainly due to the enhanced field effect passivation through the depleted region associated with the Ag-NPs/Si Schottky contacts. PMID- 29697054 TI - Incorporating drug delivery into an imaging-driven, mechanics-coupled reaction diffusion model for predicting the response of breast cancer to neoadjuvant chemotherapy: theory and preliminary clinical results. AB - Clinical methods for assessing tumor response to therapy are largely rudimentary, monitoring only temporal changes in tumor size. Our goal is to predict the response of breast tumors to therapy using a mathematical model that utilizes magnetic resonance imaging (MRI) data obtained non-invasively from individual patients. We extended a previously established, mechanically coupled, reaction diffusion model for predicting tumor response initialized with patient-specific diffusion weighted MRI (DW-MRI) data by including the effects of chemotherapy drug delivery, which is estimated using dynamic contrast-enhanced (DCE-) MRI data. The extended, drug incorporated, model is initialized using patient specific DW-MRI and DCE-MRI data. Data sets from five breast cancer patients were used-obtained before, after one cycle, and at mid-point of neoadjuvant chemotherapy. The DCE-MRI data was used to estimate spatiotemporal variations in tumor perfusion with the extended Kety-Tofts model. The physiological parameters derived from DCE-MRI were used to model changes in delivery of therapy drugs within the tumor for incorporation in the extended model. We simulated the original model and the extended model in both 2D and 3D and compare the results for this five-patient cohort. Preliminary results show reductions in the error of model predicted tumor cellularity and size compared to the experimentally measured results for the third MRI scan when therapy was incorporated. Comparing the two models for agreement between the predicted total cellularity and the calculated total cellularity (from the DW-MRI data) reveals an increased concordance correlation coefficient from 0.81 to 0.98 for the 2D analysis and 0.85 to 0.99 for the 3D analysis (p < 0.01 for each) when the extended model was used in place of the original model. This study demonstrates the plausibility of using DCE-MRI data as a means to estimate drug delivery on a patient-specific basis in predictive models and represents a step toward the goal of achieving individualized prediction of tumor response to therapy. PMID- 29697056 TI - Phase transition and field effect topological quantum transistor made of monolayer MoS2. AB - We study topological phase transitions and topological quantum field effect transistor in monolayer molybdenum disulfide (MoS2) using a two-band Hamiltonian model. Without considering the quadratic (q 2) diagonal term in the Hamiltonian, we show that the phase diagram includes quantum anomalous Hall effect, quantum spin Hall effect, and spin quantum anomalous Hall effect regions such that the topological Kirchhoff law is satisfied in the plane. By considering the q 2 diagonal term and including one valley, it is shown that MoS2 has a non-trivial topology, and the valley Chern number is non-zero for each spin. We show that the wave function is (is not) localized at the edges when the q 2 diagonal term is added (deleted) to (from) the spin-valley Dirac mass equation. We calculate the quantum conductance of zigzag MoS2 nanoribbons by using the nonequilibrium Green function method and show how this device works as a field effect topological quantum transistor. PMID- 29697057 TI - Monte Carlo simulation of chemistry following radiolysis with TOPAS-nBio. AB - Simulation of water radiolysis and the subsequent chemistry provides important information on the effect of ionizing radiation on biological material. The Geant4 Monte Carlo toolkit has added chemical processes via the Geant4-DNA project. The TOPAS tool simplifies the modeling of complex radiotherapy applications with Geant4 without requiring advanced computational skills, extending the pool of users. Thus, a new extension to TOPAS, TOPAS-nBio, is under development to facilitate the configuration of track-structure simulations as well as water radiolysis simulations with Geant4-DNA for radiobiological studies. In this work, radiolysis simulations were implemented in TOPAS-nBio. Users may now easily add chemical species and their reactions, and set parameters including branching ratios, dissociation schemes, diffusion coefficients, and reaction rates. In addition, parameters for the chemical stage were re-evaluated and updated from those used by default in Geant4-DNA to improve the accuracy of chemical yields. Simulation results of time-dependent and LET-dependent primary yields Gx (chemical species per 100 eV deposited) produced at neutral pH and 25 degrees C by short track-segments of charged particles were compared to published measurements. The LET range was 0.05-230 keV um-1. The calculated Gx values for electrons satisfied the material balance equation within 0.3%, similar for protons albeit with long calculation time. A smaller geometry was used to speed up proton and alpha simulations, with an acceptable difference in the balance equation of 1.3%. Available experimental data of time-dependent G-values for [Formula: see text] agreed with simulated results within 7% +/- 8% over the entire time range; for [Formula: see text] over the full time range within 3% +/ 4%; for H2O2 from 49% +/- 7% at earliest stages and 3% +/- 12% at saturation. For the LET-dependent Gx, the mean ratios to the experimental data were 1.11 +/- 0.98, 1.21 +/- 1.11, 1.05 +/- 0.52, 1.23 +/- 0.59 and 1.49 +/- 0.63 (1 standard deviation) for [Formula: see text], [Formula: see text], H2, H2O2 and [Formula: see text], respectively. In conclusion, radiolysis and subsequent chemistry with Geant4-DNA has been successfully incorporated in TOPAS nBio. Results are in reasonable agreement with published measured and simulated data. PMID- 29697058 TI - Monotropic polymorphism in a glass-forming metallic alloy. AB - This study investigates the crystallization and phase transition behavior of the amorphous metallic alloy Au70Cu5.5Ag7.5Si17. This alloy has been recently shown to exhibit a transition of a metastable to a more stable crystalline state, occurring via metastable melting under strong non-equilibrium conditions. Such behavior had so far not been observed in other metallic alloys. In this investigation fast differential scanning calorimetry (FDSC) is used to explore crystallization and the solid-liquid-solid transition upon linear heating and during isothermal annealing, as a function of the conditions under which the metastable phase is formed. It is shown that the occurrence of the solid-liquid solid transformation in FDSC depends on the initial conditions; this is explained by a history-dependent nucleation of the stable crystalline phase. The microstructure was investigated by scanning and transmission electron microscopy and x-ray diffraction. Chemical mapping was performed by energy dispersive x-ray spectrometry. The relationship between the microstructure and the phase transitions observed in FSDC is discussed with respect to the possible kinetic paths of the solid-liquid-solid transition, which is a typical phenomenon in monotropic polymorphism. PMID- 29697059 TI - Minimization of annotation work: diagnosis of mammographic masses via active learning. AB - The prerequisite for establishing an effective prediction system for mammographic diagnosis is the annotation of each mammographic image. The manual annotation work is time-consuming and laborious, which becomes a great hindrance for researchers. In this article, we propose a novel active learning algorithm that can adequately address this problem, leading to the minimization of the labeling costs on the premise of guaranteed performance. Our proposed method is different from the existing active learning methods designed for the general problem as it is specifically designed for mammographic images. Through its modified discriminant functions and improved sample query criteria, the proposed method can fully utilize the pairing of mammographic images and select the most valuable images from both the mediolateral and craniocaudal views. Moreover, in order to extend active learning to the ordinal regression problem, which has no precedent in existing studies, but is essential for mammographic diagnosis (mammographic diagnosis is not only a classification task, but also an ordinal regression task for predicting an ordinal variable, viz. the malignancy risk of lesions), multiple sample query criteria need to be taken into consideration simultaneously. We formulate it as a criteria integration problem and further present an algorithm based on self-adaptive weighted rank aggregation to achieve a good solution. The efficacy of the proposed method was demonstrated on thousands of mammographic images from the digital database for screening mammography. The labeling costs of obtaining optimal performance in the classification and ordinal regression task respectively fell to 33.8 and 19.8 percent of their original costs. The proposed method also generated 1228 wins, 369 ties and 47 losses for the classification task, and 1933 wins, 258 ties and 185 losses for the ordinal regression task compared to the other state-of-the-art active learning algorithms. By taking the particularities of mammographic images, the proposed AL method can indeed reduce the manual annotation work to a great extent without sacrificing the performance of the prediction system for mammographic diagnosis. PMID- 29697060 TI - Modifying the morphology and properties of aligned CNT foams through secondary CNT growth. AB - In this work, we report for the first time, growth of secondary carbon nanotubes (CNTs) throughout a three-dimensional assembly of CNTs. The assembly of nanotubes was in the form of aligned CNT/carbon (ACNT/C) foams. These low-density CNT foams were conformally coated with an alumina buffer layer using atomic layer deposition. Chemical vapor deposition was further used to grow new CNTs. The CNT foam's extremely high porosity allowed for growth of secondary CNTs inside the bulk of the foams. Due to the heavy growth of new nanotubes, density of the foams increased more than 2.5 times. Secondary nanotubes had the same graphitic quality as the primary CNTs. Microscopy and chemical analysis revealed that the thickness of the buffer layer affected the diameter, nucleation density as well as growth uniformity across the thickness of the foams. The effects of secondary nanotubes on the compressive mechanical properties of the foams was also investigated. PMID- 29697061 TI - Size-dependent fracture behavior of silver nanowires. AB - Silver (Ag) nanowires have great potential to be used in the flexible electronics industry for their applications in flexible, transparent conductors due to high conductivity and light reflectivity. Those applications always involve mechanical loading and deformations, which requires an in-depth understanding of their mechanical behavior and performance under loadings. However, current understanding on the mechanical properties of Ag nanowires is limited, especially on their size-dependent fracture behavior. In this work, mechanical properties of Ag nanowires with diameters ranging from 50 to 300 nm were systematically studied by in situ TEM tensile testing for the first time. The size effect was clearly found, with the increasing of the diameter of Ag nanowires, the ultimate tensile stress decreased. More importantly, the fracture behavior of Ag nanowire was studied and a brittle-to-ductile transition in fracture behavior was observed at the diameters around 100 nm which could be attributed to the dislocation activities within the geometry confinement. This work could give insights for understanding nanosized Ag wires and the design of Ag nanowire-based flexible devices and touchable panels. PMID- 29697062 TI - Spatially-controlled NiCo2O4@MnO2 core-shell nanoarray with hollow NiCo2O4 cores and MnO2 flake shells: an efficient catalyst for oxygen evolution reaction. AB - Control of structures and components of the nanoarray catalysts is very important for electrochemical energy conversion. Herein, unique NiCo2O4@MnO2 core-shell nanoarray with hollow NiCo2O4 Cores and MnO2 flake shells is in situ fabricated on carbon textile via a two-step hydrothermal treatment followed by a subsequent annealing. The as-made nanoarray is highly active and durable catalyst for oxygen evolution reaction in alkaline media attribute to the synergetic effect derived from spatially separated nanoarray with favorable NiCo2O4 and MnO2 compositions. PMID- 29697063 TI - Excitonic terahertz photoconductivity in intrinsic semiconductor nanowires. AB - Excitonic terahertz photoconductivity in intrinsic semiconductor nanowires is studied. Based on the excitonic theory, the numerical method to calculate the photoconductivity spectrum in the nanowires is developed, which can simulate optical pump terahertz-probe spectroscopy measurements on real nanowires and thereby calculate the typical photoconductivity spectrum. With the help of the energetic structure deduced from the calculated linear absorption spectrum, the numerically observed shift of the resonant peak in the photoconductivity spectrum is found to result from the dominant exciton transition between excited or continuum states to the ground state, and the quantitative analysis is in good agreement with the quantum plasmon model. Besides, the dependence of the photoconductivity on the polarization of the terahertz field is also discussed. The numerical method and supporting theoretical analysis provide a new tool for experimentalists to understand the terahertz photoconductivity in intrinsic semiconductor nanowires at low temperatures or for nanowires subjected to below bandgap photoexcitation, where excitonic effects dominate. PMID- 29697064 TI - Strong damping of the localized surface plasmon resonance of Ag nanoparticles by Ag2O. AB - By studying oxidation of AgNPs (Ag nanoparticles) and decomposition of the produced silver oxide, we demonstrate that the localized surface plasmon resonance (LSPR) of AgNPs was damped by Ag2O produced during oxygen plasma irradiation (OPI). The AgNPs were fabricated by evaporation of high pure silver under high vacuum. The oxidation was conducted in oxygen plasma generated by radio frequency glow discharging in vacuum, and the decomposition was performed by annealing the silver oxide in nitrogen ambient at temperatures ranging from room temperature to 450 degrees C. Samples were characterized by color, absorption spectra, surface enhanced Raman scattering, x-ray photoelectron spectroscopy, and field emission scanning electron microscopy. The bandgap of the silver oxide was calculated. We propose that AgNPs are only partially oxidized into silver oxide during OPI, and the LSPR of the AgNPs left without being oxidation is strongly damped by the produced silver oxide. This LSPR damping is responsible for the transparency of the sample after OPI for 2 s. PMID- 29697065 TI - Negative electron affinity from aluminium on the diamond (1 0 0) surface: a theoretical study. AB - Density functional theory calculations were performed to model the adsorption of up to 1 monolayer (ML) of aluminium on the bare and O-terminated (1 0 0) diamond surface. Large adsorption energies of up to -6.36 eV per atom are observed for the Al-adsorbed O-terminated diamond surface. Most adsorption sites give a negative electron affinity (NEA), with the largest NEAs -1.47 eV on the bare surface (1 ML coverage) and -1.36 eV on the O-terminated surface (0.25 ML coverage). The associated adsorption energies per Al atom for these sites are 4.11 eV and -5.24 eV, respectively. Thus, with suitably controlled coverage, Al on diamond shows promise as a thermally-stable surface for electron emission applications. PMID- 29697066 TI - Results of intrauterine inseminations with two pooled sequential ejaculates in cases of oligozoospermia. PMID- 29697067 TI - Eccrine syringofibroadenomatosis over the dorsa of both feet. PMID- 29697068 TI - Primary follicular mucinosis in childhood. PMID- 29697069 TI - Papillomatosis cutis lymphostatica. PMID- 29697070 TI - Hepatic caudate lobe neuroendocrine carcinoma diagnosed by EUS-guided core biopsy (with video). PMID- 29697071 TI - EUS of an atypical ectopic pancreas. PMID- 29697072 TI - Pancreatic ductal adenocarcinoma masquerading as a serous cystic tumor (with videos). PMID- 29697073 TI - Asthma and obstructive sleep apnea: More than an association! PMID- 29697074 TI - Air pollution and environmental risk factors for altered lung function among adult women of an urban slum area of Delhi: A prevalence study. AB - Background: Household and ambient air pollution are jointly responsible for about 7 million premature deaths annually. Women living in slums, with unhealthy environment, both indoors and outdoors, particularly those living close to industrial and/or vehicular pollution zones due to multiple sources of air pollution, are at the higher risk of having impaired lung function tests. Objective: The aim of this study was to estimate the prevalence of abnormal lung functions and to identify the environmental risk factors associated with them among adult women of 18-59 years. Materials and Methods: A total of 550 women aged 18-59 years were approached in a representative urban slum. Five hundred consented to participate and 299 had prebronchodilator spirometry satisfying ATS standards. House visits to assess environmental conditions were conducted to determine their association with forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC). Chi-square test was used to test the association of risk factors with lung functions. ANOVA was used to test the association of mean values of FEV1 and FVC with age. Results: Out of 299 participants with acceptable spirometric curves, 5% had reduced FEV1/FVC ratio than the normal and 26.8% and 17.4% had lower values than predicted for FVC and FEV1, respectively. Altered lung function was related to age, tobacco smoking, and history of respiratory disease. Conclusions: Both ambient and household air pollution have a deleterious pulmonary effect on long-term women residents of a representative urban slum in Delhi. PMID- 29697075 TI - Relationship of asymmetric dimethylarginine levels with disease severity and pulmonary hypertension in chronic obstructive pulmonary disease. AB - Background: Asymmetric dimethylarginine (ADMA) has emerged as a risk marker for many conditions related to pulmonary hypertension (PH); however, little is known about ADMA and symmetric dimethylarginine (SDMA) plasma concentrations in chronic obstructive pulmonary disease (COPD). Our interest centers on the role of ADMA in regulation of endothelial function in COPD and secondary PH. The aim of the present study was to evaluate the serum ADMA, SDMA, and L-arginine concentrations in COPD and its association with PH. Methods: Patients with diagnosis of COPD underwent pulmonary function tests, echocardiography, and laboratory investigations including ADMA, SDMA, and L-arginine. Results: Serum concentrations of ADMA, SDMA, and L-arginine tend to increase as COPD progresses. Patients with PH had higher concentrations of ADMA, SDMA, and L-arginine compared to cases with normal pulmonary arterial pressure (PAP); the difference was not statistically significant. Conclusions: Our results show that increased ADMA, SDMA, and L-arginine concentrations are associated with increased PAP measurements in patients with COPD, however, the relationship is not statistically significant. PMID- 29697076 TI - The levels of pro-fibrotic cytokines in pulmonary tuberculosis with minimal and extensive lesions. AB - Background: There are very few studies about the mechanism of fibrosis in tuberculosis (TB). This study aimed to determine the levels of tumor necrosis factor-alpha (TNF-alpha), insulin-like growth factor-1 (IGF-1), and transforming growth factor-beta1 (TGF-beta1) in pulmonary TB patients with minimal and extensive lesions. Materials and Methods: Cross-sectional observational study design was used to observe the pulmonary TB patients with minimal and extensive lesions, and also healthy controls, each consisting of ten patients. Results: The plasma levels of TNF-alpha, IGF-1, and TGF-beta1 in pulmonary TB groups were higher compared to the healthy controls. The TNF-alpha level in the minimal lesion of TB group was higher than the level in the extensive lesion but not significant (P = 0.741). The IGF-1 level in the minimal lesion of TB group was significantly (P = 0.007) increased compared to the extensive lesion. While the TGF-beta1 level in the minimal lesion of TB group was significantly (P = 0.005) lower than the level in the extensive lesion. Conclusion: In extensive lesion of TB group, there are differences in the levels of TNF-alpha, IGF-1, and TGF-beta1 compared to the minimal lesion of TB group as well as the healthy controls. The extent of lesions on chest radiograph also describes the state of ongoing pulmonary fibrosis which can be shown by the differences in the levels of pro fibrotic cytokines. PMID- 29697077 TI - Surgical management of stage III pediatric empyema thoracis. AB - Aim and Objective: This study aims to report 100 pediatric patients of empyema thoracis treated by open decortication, highlighting the presentation, delay in referral, operative findings, the response to surgical intervention, and follow up. Materials and Methods: All the children who underwent open decortication for stage III empyema thoracis during the study period January 2015-December 2016 were included. Preoperative workup included hemogram, serum protein, chest radiographs, and contrast-enhanced computed tomographic (CECT) scan of the chest. Results: One hundred (65 males, 35 females) (age 2 months-13 years, mean 4.5 years) were operated during a 2-year period. Among them, 90% patients were referred 3 weeks after the onset of disease. Intercostal chest drainage (ICD) had been inserted in (95) 95% cases. Thickened pleura, multiloculated pus, and lung involvement were invariably seen on CECT scan. Bronchopleural fistula was present in five patients. Decortication and removal of necrotic tissue were performed in all the patients. Mean duration of postoperative ICD was 4 days. Follow-up ranged from 1 month to 2 years (mean 12 months). There was no mortality. Five patients had proven tuberculosis. Only 10% presented within the early period of the disease. Conclusion: The duration of the disease had a direct relationship with the thickness of the pleura and injury to the underlying lung. Delayed referral causes irreversible changes in the lung prolonging recovery. Meticulous open surgical debridement gives gratifying results. The status of the lung at the end of surgery is a major prognostic factor. PMID- 29697078 TI - High-resolution computerized tomography changes in diffuse parenchymal lung disease from chronic hypersensitivity pneumonitis related to bird antigen. AB - Background: Chronic hypersensitivity pneumonitis (HP) is the most common cause of diffuse parenchymal lung disease (DPLD) in India. There is no data regarding the avian antigen exposure-associated DPLD from the country. Methods: Chronic HP from exposure to avian antigen was diagnosed when the high resolution computerized tomography (HRCT) showed features for HP and was supported by the history of exposure to pigeons, the presence of precipitin antibodies (IgG) to avian antigen in high titre with negative rheumatoid factor, antinuclear antibody, and no clinical clue for a collagen vascular disease. The HRCT changes were noted on Likert scale (0-5) in terms of affection of peripheral and/or axial involvement, reticulation, honeycombing, haze, mosaic, traction bronchiectasis, pleural reactions, features of pulmonary hypertension, and air cysts. Cardiomegaly and independent cardiac chamber enlargement were also recorded. Results: The lower lobes were predominantly (65.6%) affected with similar frequency (78.1) of peripheral and axial parenchymal affection. The parenchymal changes in HRCT were haze or ground-glass opacity (100%), mosaic appearance (93.75%), reticulations (68.75%), traction bronchiectasis (34.3%), air cysts (21.8%), and honeycombing (9.37%). Pleural reactions, though not described so far, were found in 50% of cases. Features of pulmonary hypertension (87.5%), cardiomegaly (50%), left and right atrial enlargement (81.2% and 78.1%), and right ventricular enlargement (31.2%) were the common echocardiography findings. Conclusion: Chronic HP from avian exposure shows predominantly lower lobe involvement with haze, reticulation, features of pulmonary hypertension, and pleural reactions as common HRCT findings. The likelihood of pulmonary hypertension appears high and although honeycombing is often present, the classical UIP pattern has not been found. PMID- 29697079 TI - Primary pulmonary lymphoproliferative neoplasms. AB - Pulmonary lymphoproliferative neoplasms are rare lung tumors and account for <1% of all lung tumors. Among them, primary pulmonary lymphomas (PPL) constitute the majority, which include Non-Hodgkin's lymphoma (NHL) that comprise of mucosa associated lymphoid tissue lymphoma, diffuse large B-cell lymphomas and other rare types of NHL and lymphomatoid granulomatosis. HL, which arises secondary to contiguous spread from the mediastinum, is the rarest type of PPL. Other entities described within the umbrella of pulmonary lymphoproliferative neoplasms include pleural lymphomas and posttransplant lymphoproliferative disorders (PTLD) - which occurs in the poststem cell and organ transplant patients. These neoplasms although rare, have a favorable prognosis, which does not depend on disease resectability. Moreover, with its nonspecific presentation, diagnosis is challenging, which often leads to delayed diagnosis or misdiagnosis in many cases. Therefore, knowledge of this entity is important for the practicing pulmonologist. This review article aims to describe the clinical presentation, diagnosis and management of primarily the entities within PPL, as well as pleural lymphomas and PTLD. PMID- 29697081 TI - Pasteurella multocida pneumonia in an immunocompetent patient: Case report and systematic review of literature. AB - Pasteurella multocida infection is most commonly associated with the immunocompromised, mostly in the form of soft-tissue infection, although other sites of infection are still possible and have been reported in the immunocompetent. We report a case of an immunocompetent male with a history of exposure to carrier organisms without portal of entry who developed P. multocida pneumonia with bacteremia. We undertook a focused review of literature of previously reported cases of P. multocida pneumonia in patients with chronic obstructive pulmonary disease. This literature review supports the use of penicillins as the first line of treatment over macrolides. Considering the high mortality rates with P. multocida bacteremia, it is important for clinicians to maintain a high level of suspicion for this organism in any patient with a history of carrier species exposure. PMID- 29697082 TI - Vintage meets contemporary: Use of rigid TBNA in the era of real-time imaging - first report from India. AB - In the modern era, real-time imaging-guided transbronchial needle aspiration (TBNA) has completely replaced the traditional surgical approaches to sample the mediastinal lesions for diagnosis and cancer staging. However, there is a limited role of these innovations in the presence of critical airway narrowing due to a further decrease in cross-sectional area of the airway proportionate to the outer diameters of the scope. Rigid TBNA with airway control by rigid bronchoscopy is one alternative which can be used for mediastinal sampling when modern technique is impracticable. Herein, we report the use of rigid TBNA, an underutilized old method to sample the mediastinal lesion in a patient with severe orthopnea secondary to tracheal compression by mediastinal mass. PMID- 29697080 TI - Series of rare lung diseases mimicking imaging patterns of common diffuse parenchymal lung diseases. AB - Diffuse parenchymal lung diseases (DPLDs) encompass a variety of restrictive and obstructive lung pathologies. In this article, the authors discuss a series of rare pulmonary entities and their high-resolution computed tomography imaging appearances, which can mimic more commonly encountered patterns of DPLDs. These cases highlight the importance of surgical lung biopsies in patients with imaging findings that do not show typical imaging features of usual interstitial pneumonia. PMID- 29697083 TI - Paraneoplastic syndrome associate with solitary fibrous tumor of pleura. AB - Solitary fibrous tumor (SFT) is a rare mesenchymal tumor and several paraneoplastic syndromes have been related to it. We report the case of a 60-year old male initially admitted to rule out cerebral vascular accident with the final diagnosis of SFT associated with paraneoplastic cerebellar degeneration and hypoglycemia. The diagnosis was confirmed by computed tomography-guided lung biopsy. PMID- 29697084 TI - Ectopic thyroid: The great mimicker. AB - Ectopic thyroid tissue is very rare, but its prevalence increases in those with thyroid pathology. It typically occurs due to aberrant development of the thyroid gland during its migration to the pretracheal region. In this report, there are two cases of mediastinal ectopic thyroid tissue discussed, which were initially considered to be malignancies. The hospital course, diagnostic workup, including the use of computed tomography and positron emission tomography scans, and the characteristic features of the tissue are examined here. Due to the imaging characteristics, it is important to consider ectopic thyroid tissue as a differential diagnosis for mediastinal masses as encountered in these cases. Asymptomatic ectopic thyroid tissue is usually treated medically; however, patients in both of our cases opted for surgical resection of the masses even after confirmation of the origin of the tissues. PMID- 29697085 TI - A diagnostic challenge: An incidental lung nodule in a 48-year-old nonsmoker. AB - A 43-year-old female with a medical history of renal stones, hypertension, diabetes mellitus Type 2, and depression presented to her urologist with bilateral flank pain. She complained of worsening exertional dyspnea over the last several months with recent weight gain. She also endorsed night sweats and intermittent, scant hemoptysis over the past year. She denied fever, chills, nausea, vomiting, diarrhea, constipation, hematuria, or excessive joint or muscle pain. Physical examination was unremarkable. Computed tomography scan of abdomen and pelvis demonstrated bilateral nonobstructing renal stones and a 1.8 cm * 1.7 cm nodular opacity in the right lower lobe of the lung, not present on previous scan 1 year prior. Surgical wedge resection was performed and subsequent pathologic examination demonstrated a 1.2 cm * 0.6 cm * 0.5 cm soft, gelatinous well-demarcated mass in the right lower lobe wedge specimen without gross evidence of necrosis or hemorrhage confirming colloid adenocarcinoma of the lung. PMID- 29697086 TI - Cryptococcosis with bird's eye manifestation: A case report. AB - Cryptococcosis is a menacing opportunistic infection most commonly affecting immunocompromised individuals. Its occurrence in immunocompetant individuals is uncustomary. Disseminated cryptococcosis is subtile in immunocompetent individuals. Cryptococcosis presenting with myriad of symptoms with involvement of lung, meninges, hematological system is rare. We present to you a unique case of disseminated cryptococcosis presenting as bilateral pulmonary nodular opacities with peripheral eosinophilia and meningitis along with a narration of the enthralling diagnostic process. PMID- 29697088 TI - Egg and banana sign of severe pulmonary arterial hypertension. AB - The egg and banana sign can be seen on chest computed tomography (CT) in patients with severe pulmonary arterial hypertension (PAH). It is identified by the presence of the pulmonary artery (PA) lateral to the aortic arch with the aortic arch being described as the banana and the PA as the egg. PMID- 29697087 TI - Identifying the levels of pro-fibrotic cytokines in pulmonary tuberculosis. PMID- 29697089 TI - Lung contusion. AB - Lung contusion usually follows blunt trauma to the chest. If not properly diagnosed and adequately treated, it could at times be fatal as well. This case is being presented to highlight the radiological findings of this condition. PMID- 29697090 TI - Breathless with stones! PMID- 29697091 TI - Rare cystic lung disease in patients presenting with abdominal mass. PMID- 29697092 TI - Dumbbell posterior mediastinal schwannoma invading trachea: Multidisciplinary management - weight off the chest. PMID- 29697093 TI - Seven years in the trachea. PMID- 29697094 TI - Pulmonary agenesis: A rare entity. PMID- 29697095 TI - Use of fentanyl-dexmedetomidine in conscious sedation for thoracoscopy. PMID- 29697096 TI - Catheter pinch-off syndrome. PMID- 29697097 TI - Evaluation of inhalational techniques of pressurized metered-dose inhaler with spacer in asthma patients. PMID- 29697098 TI - A Retrospective Study to Compare Five Induction Chemotherapy Regimens Prior to Radiotherapy in the Reduction of Regional Lymph Node Size in Patients with Nasopharyngeal Carcinoma. AB - BACKGROUND Combined chemotherapy and radiation therapy are used to treat nasopharyngeal carcinoma (NPC). Previous studies have shown that induction chemotherapy, given before radiotherapy, is beneficial in patients with local lymph node metastases. The aim of this study was to evaluate regional lymph node size in patients with NPC and the efficacy of five induction chemotherapy regimens given before radiotherapy. MATERIAL AND METHODS Between December 2007 and June 2011, 190 patients were included in this study, who had regionally advanced NPC (Stages II-IV). Five induction chemotherapy regimens were given prior to radiation: 98 patients (51.6%) received the TPF regimen (docetaxel, cisplatin, and fluorouracil); 56 patients (29.5%) received PF regimen (cisplatin and fluorouracil); 26 patients (13.7%) received the TP regimen (cisplatin and docetaxel); seven patients (3.7%) received combined nimotuzumab with TPF; three patients (1.6%) received a combination of the novel modified recombinant human endostatin (Endostar) with PF. The length and width of the regional lymph nodes were measured using neck B-mode (high-resolution grey scale) ultrasonography before chemotherapy and on the second day following completion of chemotherapy. Gastrointestinal tract and bone marrow suppression were also monitored during and after chemotherapy. RESULTS The TPF chemotherapy induction regimen resulted in an improved early response of lymph node size reduction, compared with the PF and TP chemotherapy induction regimens. The combined use of nimotuzumab with the TPF regimen improved efficacy by 15%. The combined use of Endostar improved the efficacy of the PF regimen by 56% (P<0.05). CONCLUSIONS In a retrospective study in patients with NPC, different induction chemotherapy regimens had different effects on lymph node size before radiation therapy. PMID- 29697100 TI - The comparative effect of wrapping solid gold nanoparticles and hollow gold nanoparticles with doxorubicin-loaded thermosensitive liposomes for cancer thermo chemotherapy. AB - Since conventional chemotherapy is a systemic treatment that affects the body globally and will not concentrate inside the tumor, it causes adverse side effects to patients. In this study, doxorubicin (DOX) together with solid gold nanoparticles (GNPs) or hollow gold nanoparticles (HGNPs), respectively, is loaded inside thermosensitive liposomes (GNPs&DOX-TLs and HGNPs&DOX-TLs), where the GNPs and HGNPs act as a "nanoswitch" for killing tumor cells directly by hyperthermia and triggering DOX release from TLs in the tumor quickly by near infrared laser (NIR) illumination. In addition, this study investigated the photothermal transformation ability, NIR triggered drug release behavior, and the intracellular uptake and cytotoxicity of breast tumor cells and the thermo chemotherapy mediated by the co-delivery of GNPs&DOX-TLs and HGNPs&DOX-TLs. GNPs and HGNPs had very different light-to-heat transduction efficiencies, while the hollow HGNPs had the advantage of NIR surface plasmon tunability, resulting in the photothermal ablation of tumors with 800 nm light penetration in tissue. The prepared HGNPs&DOX-TLs exhibited a spherical shape with a diameter of 190 nm and a xi potential of -29 mV, which were steadily dispersed for at least one month. The co-encapsulated DOX was released under hyperthermia caused by NIR-responsive HGNPs and the local drug concentration increased along with the disintegration of the liposomal membrane. This co-delivery of HGNPs&DOX-TLs produced a synergistic cytotoxicity response, thereby enhancing anticancer efficacy 8-fold and increasing the survival time compared to GNPs&DOX-TLs. This work suggested that the co-delivery of HGNPs&DOX-TLs followed by burst-release of DOX using NIR responsive HGNPs sensitized cancer cells to the chemotherapeutic compound, which provided a novel concept for the combination strategy of chemotherapy and photothermal therapy. These results suggest that the markedly improved therapeutic efficacy and decreased systemic toxicity of the NPs presented in this study hold significant potential for future cancer treatment. PMID- 29697101 TI - Selective aqueous acetylation controls the photoanomerization of alpha-cytidine 5'-phosphate. AB - Nucleic acids are central to information transfer and replication in living systems, providing the molecular foundations of Darwinian evolution. Here we report that prebiotic acetylation of the non-natural, but prebiotically plausible, ribonucleotide alpha-cytidine-5'-phosphate, selectively protects the vicinal diol moiety. Vicinal diol acetylation blocks oxazolidinone formation and prevents C2'-epimerization upon irradiation with UV-light. Consequently, acetylation enhances (4-fold) the photoanomerization of alpha-cytidine-5' phosphate to produce the natural beta-pyrimidine ribonucleotide-5'-phosphates required for RNA synthesis. PMID- 29697099 TI - Japanese encephalitis - the prospects for new treatments. AB - Japanese encephalitis is a mosquito-borne disease that occurs in Asia and is caused by Japanese encephalitis virus (JEV), a member of the genus Flavivirus. Although many flaviviruses can cause encephalitis, JEV causes particularly severe neurological manifestations. The virus causes loss of more disability-adjusted life years than any other arthropod-borne virus owing to the frequent neurological sequelae of the condition. Despite substantial advances in our understanding of Japanese encephalitis from in vitro studies and animal models, studies of pathogenesis and treatment in humans are lagging behind. Few mechanistic studies have been conducted in humans, and only four clinical trials of therapies for Japanese encephalitis have taken place in the past 10 years despite an estimated incidence of 69,000 cases per year. Previous trials for Japanese encephalitis might have been too small to detect important benefits of potential treatments. Many potential treatment targets exist for Japanese encephalitis, and pathogenesis and virological studies have uncovered mechanisms by which these drugs could work. In this Review, we summarize the epidemiology, clinical features, prevention and treatment of Japanese encephalitis and focus on potential new therapeutic strategies, based on repurposing existing compounds that are already suitable for human use and could be trialled without delay. We use our newly improved understanding of Japanese encephalitis pathogenesis to posit potential treatments and outline some of the many challenges that remain in tackling the disease in humans. PMID- 29697102 TI - Differential reorganisation of cutaneous elastic fibres: a comparison of the in vivo effects of broadband ultraviolet B versus solar simulated radiation. AB - Long-term exposure of human skin to ultraviolet radiation (UVR) in sunlight negatively impacts its appearance and function with photoaged skin having a characteristic leathery, rough appearance, with deep wrinkles. These clinical features of photodamage are thought to result from UVR-induced remodelling of the dermal extracellular matrix, particularly the elastic fibre system. There are few in vivo human data on the impact of acute UVR exposure on this fibre system and particularly solar-simulated radiation (SSR)-mediated effects. We examined the differential effect of broadband UVB and SSR on the human dermal elastic fibre system, and specifically the microfibrillar components fibrillin-1, fibulin-2 and fibulin-5. Healthy white Caucasian adults (skin type II-III) were recruited and irradiated with 3* their minimal erythema dose of broadband UVB (n = 6) or SSR (n = 6) on photoprotected buttock skin. Punch biopsies were taken 24 h after irradiation and from unirradiated control skin. Overall, histological assessment of elastic fibres revealed significantly less elastic fibre staining in broadband UVB (P = 0.004) or SSR (P = 0.04) irradiated skin compared to unirradiated control skin. Significantly less staining of fibrillin-1-positive microfibrils was also observed in the papillary dermis of UVB irradiated skin (P = 0.02) but not skin exposed to SSR. Conversely, immunohistochemistry for fibulin-5-positive microfibrils revealed significantly less expression in skin exposed to SSR (P = 0.04) but not to broadband UVB. There was no significant change in fibulin-2 positive microfibrils following either broadband UVB or SSR irradiation. Thus, broadband UVB and SSR mediate differential effects on individual components of the dermal elastic fibre network in human skin. Further human studies are required to explore the mechanisms underlying these findings and the impact of potential photoprotective agents. PMID- 29697104 TI - Facile preparation of ion-doped poly(p-phenylenediamine) nanoparticles for photothermal therapy. AB - Ion-doped poly(p-phenylenediamine) (Fe-ppd) nanoparticles were prepared at room temperature by using FeCl3 as an oxidant. Fe-ppd exhibited high photothermal conversion efficiency (39.27%) and excellent photostability. In vitro and in vivo evaluation demonstrated that Fe-ppd could be used as an ideal photothermal agent for photothermal therapy for the first time. PMID- 29697103 TI - A novel metallogel based approach to synthesize (Mn, Cu) doped ZnS quantum dots and labeling of MCF-7 cancer cells. AB - The present study aims to formulate a common synthetic strategy for preparing quantum dots (QDs) in a greener way by using combination of popular methods, viz. a colloidal method with suitable capping agent and low molecular weight gel based synthesis. Pyridine dicarboxylic acid (PDC) in presence of AlCl3 forms a stable metallogel, which serves as an excellent medium for selective ZnS QD synthesis. The aromatic pyridine moiety, well known for being a capping agent, indeed plays its part in the run up to QD synthesis. To the best of our knowledge, this is the first example of a metallogel based doped ZnS QD synthesis. Altering the doping material and its composition changes the properties of the QDs, but herein we also tried to establish how these changes affect the gel morphology and stability of both gel and QDs. We further demonstrate, by using live cell confocal microscopy, the delivery of QDs Cu ZnS and MnZnS nanomaterials in the nucleus and the cytoplasm of human breast cancer cells (MCF7), implicating the use of metallogel based QDs for bio-imaging and bio-labeling. PMID- 29697105 TI - Enhanced phosphorescence properties of a Pt-porphyrin derivative fixed on the surface of nano-porous glass. AB - The room-temperature phosphorescence chromophore, Pt(ii) coproporphyrin I (PtCP), was fixed on the surface of a 3D-network of nanoscale pores of porous glass through ion-exchange reaction. The absorption and phosphorescence spectra indicated that PtCP can be loaded while maintaining monomeric dispersion at concentrations well beyond solubility limits of PtCP in solution. The phosphorescence quantum yield of PtCP fixed on the surface was also found to have double the enhancement of solution. The extended lifetime of phosphorescence of PtCP bonded on the surface compared to that in solution clearly indicated that suppression of nonradiative deactivation plays a key role in high quantum yield and long triplet lifetime. This hybridization with nano-porous glass provides opportunities for various potential applications. PMID- 29697106 TI - Self-assembled inorganic clusters of semiconducting quantum dots for effective solar hydrogen evolution. AB - Owing to promoted electron-hole separation, the catalytic activity of semiconducting quantum dots (QDs) towards solar hydrogen (H2) production has been significantly enhanced by forming self-assembled clusters with ZnSe QDs made ex situ. Taking advantage of the favored interparticle hole transfer to ZnSe QDs, the rate of solar H2 evolution of CdSe QDs can be increased to ~30 000 MUmol h-1 g-1 with ascorbic acid as the sacrificial reagent, ~150-fold higher than that of bare CdSe QDs clusters under the same conditions. PMID- 29697107 TI - An AIEE fluorescent supramolecular cross-linked polymer network based on pillar[5]arene host-guest recognition: construction and application in explosive detection. AB - Here a novel fluorescent supramolecular cross-linked polymer network with aggregation induced enhanced emission (AIEE) properties was constructed via pillar[5]arene-based host-guest recognition. Furthermore, the supramolecular polymer network can be used for explosive detection in both solution and thin films. PMID- 29697108 TI - Dynamics of the phospholipid shell of microbubbles: a fluorescence photoselection and spectral phasor approach. AB - The lipid organization of microbubbles is important in many applications. By monitoring the photoselection and emission spectrum of the fluorescent probe Laurdan in perfluorobutane gas-filled DPPC microbubbles with a two-photon laser scanning microscope, we observed a transition to a more rigid lipid organization in 30 minutes to several hours. PMID- 29697109 TI - Critical review of the molecular design progress in non-fullerene electron acceptors towards commercially viable organic solar cells. AB - Fullerenes have formed an integral part of high performance organic solar cells over the last 20 years, however their inherent limitations in terms of synthetic flexibility, cost and stability have acted as a motivation to develop replacements; the so-called non-fullerene electron acceptors. A rapid evolution of such materials has taken place over the last few years, yielding a number of promising candidates that can exceed the device performance of fullerenes and provide opportunities to improve upon the stability and processability of organic solar cells. In this review we explore the structure-property relationships of a library of non-fullerene acceptors, highlighting the important chemical modifications that have led to progress in the field and provide an outlook for future innovations in electron acceptors for use in organic photovoltaics. PMID- 29697110 TI - Microfluidic solvent extraction of poly(vinyl alcohol) droplets: effect of polymer structure on particle and capsule formation. AB - We investigate the formation of poly(vinyl alcohol) microparticles by the selective extraction of aqueous polymer solution droplets, templated by microfluidics and subsequently immersed in a non-solvent bath. The role of polymer molecular mass (18-105 kg mol-1), degree of hydrolysis (88-99%) and thus solubility, and initial solution concentration (0.01-10% w/w) are quantified. Monodisperse droplets with radii ranging from 50 to 500 MUm were produced at a flow-focusing junction with carrier phase hexadecane and extracted into ethyl acetate. Solvent exchange and extraction result in droplet shrinkage, demixing, coarsening and phase-inversion, yielding polymer microparticles with well-defined dimensions and internal microstructure. Polymer concentration, varied from below the overlap concentration c* to above the concentrated crossover c**, as estimated by viscosity measurements, was found to have the largest impact on the final particle size and extraction timescale, while polymer mass and hydrolysis played a secondary role. These results are consistent with the observation that the average polymer concentration upon solidification greatly exceeds c**, and that the internal microparticle porosity is largely unchanged. However, reducing the initial polymer concentration to well below c* (approximately 100*) and increasing droplet size yields thin-walled (100's of nm) capsules which controllably crumple upon extraction. The symmetry of the process can be readily broken by imposing extraction conditions at an impermeable surface, yielding large, buckled, cavity morphologies. Based on these results, we establish robust design criteria for polymer capsules and particles, demonstrated here for poly(vinyl alcohol), with well-defined shape, dimensions and internal microstructure. PMID- 29697111 TI - A target-responsive liposome activated by catalytic hairpin assembly enables highly sensitive detection of tuberculosis-related cytokine. AB - Here, we propose a new fluorescence method to detect tuberculosis-related cytokine by using a target-responsive liposome activated by catalytic hairpin assembly. The method combines a DNA self-assembly based amplification process with a liposome-based signal amplification process, therefore offering a very high sensitivity. PMID- 29697112 TI - Efficient separation of C2H2 from C2H2/CO2 mixtures in an acid-base resistant metal-organic framework. AB - A novel metal-organic framework, ZJU-196, with extraordinary acid-base resistant stability has been successfully synthesized, exhibiting highly efficient separation of acetylene from C2H2/CO2 mixtures under ambient conditions. PMID- 29697113 TI - Engineering l-asparaginase for spontaneous formation of calcium phosphate bioinspired microreactors. AB - Active bioinspired materials are appealing biotechnological targets, and their study is gaining momentum. These materials, which comprise of an inorganic matrix and one or more biomolecules, are extremely variable and therefore may result difficult to characterize in their intimate structure. In this work we have prepared a hydroxyapatite-l-asparaginase composite, with the perspective of using it in acute leukemia treatment. We demonstrate that the use of electron microscopy and powder X-ray diffraction, combined with the atomic-resolution information coming from solid-state NMR, allows us to understand the topology of the material and how the different components interplay to obtain an active composite. PMID- 29697114 TI - Supported ammonia borane decomposition through enhanced homopolar B-B coupling. AB - The thermolytic decomposition of ammonia borane (AB) is known to proceed through the polymeric coupling reaction between -BH3 and -NH3 sites of multiple ammonia borane molecules, which results in the release of hydrogen and other by-products, e.g., ammonia, diborane and borazine. The formation of these by-products concomitantly pollutes the hydrogen stream, and therefore, it is necessary to remove these gases from the product stream. In the current work, a cost effective and easy to synthesize support material, aluminium phosphate (AP), is introduced in AB thermolytic decomposition. An in situ MS study reveals that the AB and AP (w/w) loading ratio of (1 * 4) is the most promising as it is able to minimise the dehydrogenation peak temperature by 18.89 degrees C compared to that of pure AB. Additionally, in the presence of support material, the by-product formation of ammonia is reduced by 70.3%, with a complete suppression in borazine and diborane release. The mechanism behind the by-product suppression of supported AB has been studied through 11B MAS NMR analysis which suggests that the release of hydrogen occurs through an intermolecular homopolar B-B bonding. The thermogravimetric and kinetic study also reveals that in the case of supported AB decomposition, hydrogen release through B-B interaction is much more efficient than a B-N interaction, thus limiting the possibility of autocatalysis during the supported decomposition reaction. PMID- 29697115 TI - Novel carbon polymorphs with cumulative double bonds in three-dimensional sp-sp2 hybrid framework. AB - A conspicuous amount of theoretical study has been published on the properties of carbon allotropes with alternate single and triple bonds, (-C[triple bond, length as m-dash]C-)n. However, theoretical characterizations of carbon allotropes with cumulative double bonds ([double bond, length as m-dash]C[double bond, length as m-dash]C[double bond, length as m-dash])n is almost non-existent in literature. Based upon first-principles calculations, two new three-dimensional (3D) microporous carbon allotropes consisting of whorl chains connected by cumulative double bonds in a sp-sp2 hybrid framework have been proposed in this study. One of these structures, namely, Trig-C9 was obtained by an evolutionary particle swarm structural search, while the other structure, denoted as Trig-C15, was obtained by inserting double bonds into Trig-C9. Both the 3D sp-sp2 hybridized carbons have a trigonal structure with 9 and 15 atoms in the hexagonal primitive cells. The calculated results demonstrate that these polymorphs are thermodynamically, mechanically, and dynamically feasible. Trig-C9 and Trig-C15 are indirect semiconductors with band gaps of 2.70 eV and 1.25 eV, respectively. Their unique frameworks render them mechanical ductility and significant elastic anisotropy. These results open up new horizons for the exploration of new carbon phases with unique structural, mechanical, and electronic properties. PMID- 29697116 TI - An in situ XAS study of the activation of precursor-dependent Pd nanoparticles. AB - The activation of precursor-dependent Pd nanoparticles was comprehensively followed by in situ X-ray absorption spectroscopy on two inorganic supports for rationalizing the final catalytic activity. Two series of Pd-based catalysts (7 wt% Pd) were prepared by impregnation of gamma-Al2O3 and activated carbon supports varying the metal precursor (Pd(NO3)2, PdCl2 and Pd(OAc)2). The most relevant physicochemical properties of the studied catalysts were determined by several techniques including ICP-OES, XRD, N2 adsorption and XAS. The results indicate that the thermal stability of the metal precursor plays an important role in the size and speciation of the formed Pd nanoparticles after the activation process. The Cl-based precursor, which presents high thermal stability, passes through a PdOxCly mixed phase when submitted to calcination on Pd/Al2O3 and leaves Cl-species after metal reduction on Pd/C (which can be detrimental to catalytic reactions). Differently, Pd(OAc)2 and Pd(NO3)2 promote the formation of larger species due to different precursor decomposition pathways. Ordered PdO is observed even before calcination when Pd(NO3)2 was used as a metallic source, which translates into large nanoparticles after reduction in H2. By using the average coordination numbers of Pd species obtained from EXAFS data of the as-reduced catalysts, a correlation was observed comparing the three precursors: PdCl2 generates smaller nanoparticles than Pd(OAc)2, which in turn generates smaller nanoparticles than Pd(NO3)2, regardless of the support used for catalyst preparation. PMID- 29697117 TI - Correction: Isolated Fe and Co dual active sites on nitrogen-doped carbon for a highly efficient oxygen reduction reaction. AB - Correction for 'Isolated Fe and Co dual active sites on nitrogen-doped carbon for a highly efficient oxygen reduction reaction' by Diyang Zhang et al., Chem. Commun., 2018, DOI: 10.1039/c8cc00988k. PMID- 29697118 TI - 209Bi quadrupole relaxation enhancement in solids as a step towards new contrast mechanisms in magnetic resonance imaging. AB - Motivated by the possibility of exploiting species containing high spin quantum number nuclei (referred to as quadrupole nuclei) as novel contrast agents for Magnetic Resonance Imaging, based on Quadrupole Relaxation Enhancement (QRE) effects, 1H spin-lattice relaxation has been investigated for tris(2 methoxyphenyl)bismuthane and tris(2,6-dimethoxyphenyl)bismuthane in powder. The relaxation experiment has been performed in the magnetic field range of 0.5 T to 3 T (the upper limit corresponds to the field used in many medical scanners). A very rich QRE pattern (several frequency specific 1H spin-lattice relaxation rate maxima) has been observed for both compounds. Complementary Nuclear Quadrupole Resonance experiments have been performed in order to determine the quadrupole parameters (quadrupole coupling constant and asymmetry parameters) for 209Bi. Knowing the parameters, the QRE pattern has been explained on the basis of a quantum-mechanical picture of the system including single and double-quantum coherences for the participating nuclei (1H and 209Bi). In this way the quantum mechanical origin of the spin transitions leading to the QRE effects has been explained. PMID- 29697119 TI - Mesocrystalline anatase nanoparticles synthesized using a simple hydrothermal approach with enhanced light harvesting for gas-phase reaction. AB - Mesocrystalline TiO2 nanoparticles were synthesized using a hydrothermal approach. A simple two-step procedure at low temperature (<140 degrees C) allowed the nucleation of primary particles sized 2-4 nm and their subsequent assembly as almost spherical aggregates sized ~20 nm. X-ray powder diffraction (XRD), Raman and X-ray photoelectron spectroscopy (XPS) studies, and HRTEM studies confirmed anatase as the unique TiO2 crystalline phase. The mesocrystalline structure of the anatase aggregates was clearly evidenced by HRTEM and SAED results. The mesocrystalline nanopowders exhibit a mesoporous structure with a surface area and pore volume of 63.5 m2 g-1 and 0.22 cm3 g-1, respectively. Ultraviolet (UV) and visible light (Vis) absorption ability were recorded. The combined high effectiveness and selectivity for the NOx abatement of the new mesocrystalline photocatalyst are reported. It is worth remarking that the maximised selectivity values reached for the NOx process are reported for the first time and could be associated with the mesoporous nature of the anatase photocatalyst. PMID- 29697120 TI - The effect of copper on the redox behaviour of iron oxide for chemical-looping hydrogen production probed by in situ X-ray absorption spectroscopy. AB - The production of high purity hydrogen with the simultaneous capture of CO2, can be achieved through a chemical looping (CL) cycle relying on an iron oxide-based oxygen carrier. Indeed, the availability of active and cyclically stable oxygen carriers is a key criterion for the practical implementation of this technology. In this regard, improving our understanding of the reduction pathway(s) of iron based oxygen carriers and the development of concepts to increase the reduction kinetics are important aspects. The aim of this work is to evaluate the effect of the addition of copper on the redox behaviour of iron oxide based oxygen carriers stabilized on ZrO2. In situ pulsed-H2 XANES (Fe K-edge) experiments allowed for the determination of the reduction pathways in these materials, viz. the reduction of both Fe2O3 and CuFe2O4 proceeded via a Fe2+ intermediate: Fe2O3 (CuFe2O4) -> Fe3O4 (Cu0) -> FeO (Cu0) -> Fe0 (Cu0). In the first step CuFe2O4 is reduced to Cu0 and Fe3O4, whereby Cu0 promotes the further reduction of iron oxide, increasing their rate of formation. In particular, the rate of reduction of FeO -> Fe0 is accelerated most dramatically by Cu0. This is an encouraging result as the FeO -> Fe0 transition is the slowest reduction reaction. PMID- 29697121 TI - Structural characterization of metal complexes in aqueous solutions: a XAS study of stannous fluoride. AB - The identity and structure of tin(ii)-fluoride complexes formed in aqueous solutions is determined by combining X-ray absorption spectroscopy, thermodynamic modeling and quantum mechanical calculations. Spectroscopic measurements confirm the presence of 3 stannous fluoride complexes, SnF+, SnF02 and SnF3-, with mean Sn-F bond distances that increase linearly, from 1.98 to about 2.04 A, as a function of the coordination number. Computational ab initio calculations indicate that the stannous fluoride complexes form localized sigmas-p bonds, with the stereochemically active lone pair of the Sn(ii) atom distorting the geometry of the complexes. In addition, the SnF3- complex exhibits loosely coordinated water, which is removed upon addition of glycerol to lower the solvent activity. Our results provide spectroscopic confirmation of the stannous fluoride complexes proposed in the literature, and explain why glycerol additions stabilize solutions of Sn(ii) against oxidation. PMID- 29697122 TI - Red-shifting and blue-shifting OH groups on metal oxide surfaces - towards a unified picture. AB - We analyse the OH vibrational signatures of 56 structurally unique water molecules and 34 structurally unique hydroxide ions in thin water films on MgO(001) and CaO(001), using DFT-generated anharmonic potential energy surfaces. We find that the OH stretching frequencies of intact water molecules on the surface are always downshifted with respect to the gas-phase species while the OH groups are either upshifted or downshifted. Despite these differences, the main characteristics of the frequency shifts for all three types of surface OH groups (OHw, OsH and OHf) can be accounted for by one unified expression involving the in situ electric field from the surrounding environment, and the gas-phase molecular properties of the vibrating species (H2O or OH-). The origin behind the different red- and blueshift behaviour can be traced back to the fact that the molecular dipole moment of a gas-phase water molecule increases when an OH bond is stretched, but the opposite is true for the hydroxide ion. We propose that familiarity with the relations presented here will help surface scientists in the interpretation of vibrational OH spectra for thin water films on ionic crystal surfaces. PMID- 29697123 TI - A new surfactant-copper(ii) complex based on 1,4-diazabicyclo[2.2.2]octane amphiphile. Crystal structure determination, self-assembly and functional activity. AB - A new surfactant-copper(ii) complex [Cu(L)Br3] (where LBr is 1-cetyl-4-aza-1 azoniabicyclo[2.2.2]octane bromide) containing a transition metal in the head group has been synthesized and characterized. Physicochemical properties, thermal stability and 3D structure were determined using X-ray diffractometry, UV-vis spectroscopy, simultaneous thermogravimetry and differential scanning calorimetry combined with mass-spectrometry of evolved vapors. The study of the self-assembly and morphological features of associated structures was performed by potentiometry using a bromide ion selective electrode and fluorescence of pyrene and 1,6-diphenyl-1,3,5-hexatriene. The influence of the metal ion embedded into the surfactant structure on critical micelle concentration, degree of counterion binding, aggregation numbers and morphology of the associates was elucidated. High solubilizing capacity and complexation ability of the metal containing micelles with respect to Orange-OT hydrophobic dye and oligonucleotide were determined. Importantly, the functional properties of this metallosurfactant complex are much better compared to those of classical cationic surfactants bearing cyclic and acyclic head groups, LBr and the LBr-CuBr2 mixture. The new cationic metallosurfactant could be recommended for investigation in gene therapy. PMID- 29697124 TI - An investigation of the roles furan versus thiophene pi-bridges play in donor-pi acceptor porphyrin based DSSCs. AB - Dye-sensitized solar cells (DSSCs) continue to attract interest due to their lower cost production compared to silicon based solar cells and their improving power conversion efficiencies. Porphyrin-based sensitizers have become an important sub-class due to their strong absorption characteristics in the visible region, convenient modulation of properties through synthetic manipulation and class-leading power conversion efficiencies. In this article, we report the synthesis and characterization of two porphyrin-based dyes and their application as sensitizers in DSSCs. A thiophene and a furan moiety have been incorporated into the push-pull architecture as a pi-bridge, allowing the systematic investigation of how these moieties influence the physical properties of the dyes and the performance of their resulting DSSCs. A significant difference in PCEs has been observed, with the furan containing dye (PorF, PCE = 4.5%) being more efficient than the thiophene-based analogue (PorT, PCE = 3.6%) in conjunction with the iodide/triiodide redox electrolyte. PMID- 29697125 TI - Neutral, closed-shell nickel bis(2-alkylthio-thiazole-4,5-dithiolate) complexes as single component molecular conductors. AB - Neutral nickel bis(dithiolene) complexes, because of their closed-shell character, are usually considered as insulating materials, unless they are formed out of highly delocalized tetrathiafulvalenedithiolate ligands. We describe here an original series of S-alkyl substituted neutral bis(thiazole-4,5-dithiolate) nickel complexes formulated as [Ni(RS-tzdt)2] (R = Me, Et), which organize in the solid state into uniform stacks and exhibit semiconducting behavior, with room temperature conductivities comparable to those reported in the prototypical [Ni(dmit)2] and [Ni(Et-thiazdt)2] neutral complexes. These findings provide new perspectives in the current search for single component molecular conductors. PMID- 29697126 TI - Multicomponent peptide assemblies. AB - Self-assembled peptide nanostructures have been increasingly exploited as functional materials for applications in biomedicine and energy. The emergent properties of these nanomaterials determine the applications for which they can be exploited. It has recently been appreciated that nanomaterials composed of multicomponent coassembled peptides often display unique emergent properties that have the potential to dramatically expand the functional utility of peptide-based materials. This review presents recent efforts in the development of multicomponent peptide assemblies. The discussion includes multicomponent assemblies derived from short low molecular weight peptides, peptide amphiphiles, coiled coil peptides, collagen, and beta-sheet peptides. The design, structure, emergent properties, and applications for these multicomponent assemblies are presented in order to illustrate the potential of these formulations as sophisticated next-generation bio-inspired materials. PMID- 29697127 TI - Controlling the charge state of supported nanoparticles in catalysis: lessons from model systems. AB - Model systems are very important to identify the working principles of real catalysts, and to develop concepts that can be used in the design of new catalytic materials. In this review we report examples of the use of model systems to better understand and control the occurrence of charge transfer at the interface between supported metal nanoparticles and oxide surfaces. In the first part of this article we concentrate on the nature of the support, and on the basic difference in metal/oxide bonding going from a wide-gap non-reducible oxide material to reducible oxide semiconductors. The roles of oxide nanostructuring, bulk and surface defectiveness, and doping with hetero-atoms are also addressed, as they are all aspects that severely affect the metal/oxide interaction. Particular attention is given to the experimental measures of the occurrence of charge transfer at the metal/oxide interface. In this respect, systems based on oxide ultrathin films are particularly important as they allow the use of scanning probe spectroscopies which, often in combination with other measurements and with first principles theoretical simulations, allow full characterization of small supported nanoparticles and their charge state. In a few selected cases, a precise count of the electrons transferred between the oxide and the supported nanoparticle has been possible. Charge transfer can occur through thin, two dimensional oxide layers also thanks to their structural flexibility. The flow of charge through the oxide film and the formation of charged adsorbates are accompanied in fact by a substantial polaronic relaxation of the film surface which can be rationalized based on electrostatic arguments. In the final part of this review the relationships between model systems and real catalysts are addressed by discussing some examples of how lessons learned from model systems have helped in rationalizing the behavior of real catalysts under working conditions. PMID- 29697128 TI - Supramolecular hydrogels for antimicrobial therapy. AB - The emergence of drug-resistant microbes has become a threat to global health, and microbial infections severely limit the use of healthcare materials. To achieve efficient antimicrobial therapy, supramolecular hydrogels demonstrate unprecedented advantages in medical applications due to the tunable and reversible nature of their supramolecular interactions and the capability of hydrogels to incorporate various therapeutic agents. Herein, antimicrobial hydrogels are categorized according to their inherent antimicrobial properties or based on their roles in encapsulating antimicrobial materials. Moreover, strategies to further enhance the antimicrobial efficacy of hydrogels are highlighted, such as the incorporation of antifouling agents or the enabling of response towards physiological cues. We envision that supramolecular hydrogels, in combination with modern medical technology and devices, will contribute to the development of efficient and safe systems for antimicrobial therapy. PMID- 29697129 TI - Metal-free oxidative decarbonylative alkylation of chromones using aliphatic aldehydes. AB - A decarbonylative alkylation of chromones via radical conjugate addition under metal-free conditions was developed using aliphatic aldehydes as alkylating reagents. A series of 2-tertiary, secondary, and even primary alkylated chromanones were obtained in moderate to excellent yields. PMID- 29697130 TI - Many-body interactions between charged particles in a polymer solution: the protein regime. AB - We study the phase behavior of charged particles in electrolyte solutions wherein non-adsorbing polymers are added to provide an attractive depletion interaction. The polymer has a radius of gyration similar to that of the particle radius, which causes significant many-body effects in the effective polymer mediated interaction between particles. We use a recently developed analytical theory, which gives a closed expression for the full depletion interaction, accounting for all orders of many-body terms in the potential of mean force. We compare with simulations of an explicit polymer model and show that the potential of mean force provides an accurate and computationally efficient description for the charged particle/polymer mixture, over a range of electrolyte concentrations. Furthermore, we demonstrate that the usual pair potential approach is highly inaccurate for these systems. A simple simulation method is used to estimate the limits of stability of the mixture. The pair approximation is shown to predict a much greater region of instability compared with the many-body treatment, due to its overestimation of the polymer depletion effect. PMID- 29697131 TI - Powering ex vivo tissue models in microfluidic systems. AB - This Frontiers review analyzes the rapidly growing microfluidic strategies that have been employed in attempts to create physio relevant 'organ-on-chip' models using primary tissue removed from a body (human or animal). Tissue harvested immediately from an organism, and cultured under artificial conditions is referred to as ex vivo tissue. The use of primary (organotypic) tissue offers unique benefits over traditional cell culture experiments, and microfluidic technology can be used to further exploit these advantages. Defining the utility of particular models, determining necessary constituents for acceptable modeling of in vivo physiology, and describing the role of microfluidic systems in tissue modeling processes is paramount to the future of organotypic models ex vivo. Virtually all tissues within the body are characterized by a large diversity of cellular composition, morphology, and blood supply (e.g., nutrient needs including oxygen). Microfluidic technology can provide a means to help maintain tissue in more physiologically relevant environments, for tissue relevant time frames (e.g., matching the natural rates of cell turnover), and at in vivo oxygen tensions that can be controlled within modern microfluidic culture systems. Models for ex vivo tissues continue to emerge and grow in efficacy as mimics of in vivo physiology. This review addresses developments in microfluidic devices for the study of tissues ex vivo that can serve as an important bridge to translational value. PMID- 29697132 TI - Isolation of EPR spectra and estimation of spin-states in two-component mixtures of paramagnets. AB - The presence of multiple paramagnetic species can lead to overlapping electron paramagnetic resonance (EPR) signals. This complication can be a critical obstacle for the use of EPR to unravel mechanisms and aid the understanding of earth abundant metal catalysis. Furthermore, redox or spin-crossover processes can result in the simultaneous presence of metal centres in different oxidation or spin states. In this contribution, pulse EPR experiments on model systems containing discrete mixtures of Cr(i) and Cr(iii) or Cu(ii) and Mn(ii) complexes demonstrate the feasibility of the separation of the EPR spectra of these species by inversion recovery filters and the identification of the relevant spin states by transient nutation experiments. We demonstrate the isolation of component spectra and identification of spin states in a mixture of catalyst precursors. The usefulness of the approach is emphasised by monitoring the fate of the chromium species upon activation of an industrially used precatalyst system. PMID- 29697133 TI - Influence of the catalyst structure in the cycloaddition of isocyanates to oxiranes promoted by tetraarylstibonium cations. AB - In the context of our work on electron deficient group 15 cations as Lewis acid catalysts, we have synthesized the triflate salts of a series of tetraarylstibonium cations of general formula [ArSbPh3]+ with Ar = Mes (4+), o (dimethylamino)phenyl (5+), and o-((dimethylamino)methyl)phenyl (6+). These new cationic antimony derivatives, along with the known [Ph4Sb]+ (1+), 1 naphthyltriphenylstibonium (2+), and [(Ant)SbPh3]+ (3+), have been evaluated as catalysts for the cycloaddition of oxiranes and isocyanates under mild conditions. While all stibonium cations favor the 3,4-oxazolidinone products, the reactivities of 5+ and 6+ are hindered by the ancillary amino donor which quenches the Lewis acidity of the antimony center. A comparison of the other stibonium cations shows that 4+ is the most selective catalyst. PMID- 29697134 TI - Plasmonic photocatalysis: complete degradation of bisphenol A by a gold nanoparticle-reduced graphene oxide composite under visible light. AB - Bisphenol A is a well-known endocrine disruptor that comes from plastic/epoxy resin-based consumer products, pollutes our environment and is responsible for various human diseases. Thus, its removal from water/food/the environment is becoming a challenging issue. Here we report the visible light photocatalytic degradation of bisphenol A using a gold nanoparticle based composite with reduced graphene oxide. The nanocomposite captures visible light and produces hydroxyl radicals that oxidize bisphenol A into smaller organic fragments such as phenol derivatives and aliphatic aldehydes/ketones. The composition of the nanocomposite has been optimized for most efficient degradation of bisphenol A under visible light and the approach may be extended for the sunlight-based removal of bisphenol A from water/food/the environment. PMID- 29697135 TI - The origin of absorptive features in the two-dimensional electronic spectra of rhodopsin. AB - In rhodopsin, the absorption of a photon causes the isomerization of the 11-cis isomer of the retinal chromophore to its all-trans isomer. This isomerization is known to occur through a conical intersection (CI) and the internal conversion through the CI is known to be vibrationally coherent. Recently measured two dimensional electronic spectra (2DES) showed dramatic absorptive spectral features at early waiting times associated with the transition through the CI. The common two-state two-mode model Hamiltonian was unable to elucidate the origin of these features. To rationalize the source of these features, we employ a three-state three-mode model Hamiltonian where the hydrogen out-of plane (HOOP) mode and a higher-lying electronic state are included. The 2DES of the retinal chromophore in rhodopsin are calculated and compared with the experiment. Our analysis shows that the source of the observed features in the measured 2DES is the excited state absorption to a higher-lying electronic state and not the HOOP mode. PMID- 29697136 TI - SPHK2 protein expression, Ki-67 index and infiltration of tumor-associated macrophages (TAMs) in human glioma. AB - INTRODUCTION: Sphingosine kinases (SPHKs), the Ki-67 index and tumor-associated macrophages (TAMs) are associated with diverse human malignancies, including glioma. SPHK2, a subtype of SPHKs, has not been assessed in glioma or correlated with the Ki-67 index or TAM infiltration. We tested the hypothesis that expression of SPHK2 correlates with the Ki-67 index and TAM infiltration in patients with glioma. MATERIALS AND METHOD: Western blot analysis was performed on protein lysates prepared from human astrocyte (HA) and glioma cell lines. Immunofluorescence was used to determine the subcellular location of SPHK2 protein in glioma cells. Next, immunohistochemistry was employed to analyze the correlations among SPHK2, Ki-67, CD68, and CD206 in 11 non-neoplastic brain tissues and 60 glioma tissues. All slides were evaluated under *400 magnification, and the ratio of positively stained cells to the total number of cells was calculated for analysis. RESULTS: SPHK2, CD68 and CD206 were all increased in glioma tissues compared to non-neoplastic brain tissues, but there were no differences between WHO grades of glioma. Ki-67 was highest in WHO grade IV tumors and lowest in non-neoplastic brain tissues, and all between-group differences were statistically significant. Moreover, SPHK2 expression was positively correlated with the Ki-67, CD68 and CD206 indexes. Finally, the CD68 and CD206 indexes were both associated with the Ki-67 index. CONCLUSION: SPHK2 protein expression, the Ki-67 index and TAM infiltration in human glioma tissue were reported in this study for the first time. SPHK2 was positively associated with TAM infiltration and glioma proliferation. Mechanistically, SPHK2 may promote glioma growth by stimulating TAMs to polarize M2-type macrophages. PMID- 29697137 TI - Covariance between predation risk and nutritional preferences confounds interpretations of giving-up density experiments. AB - Giving-up density (GUD) experiments have been a foundational method to evaluate perceived predation risk, but rely on the assumption that food preferences are absolute, so that areas with higher GUDs can be interpreted as having higher risk. However, nutritional preferences are context dependent and can change with risk. We used spiders and grasshoppers to test the hypothesis that covariance in nutritional preferences and risk may confound the interpretation of GUD experiments. We presented grasshoppers with carbohydrate-rich and protein-rich diets, in the presence and absence of spider predators. Predators reduced grasshopper preference for the protein-rich food, but increased their preference for the carbohydrate-rich food. We then measured GUDs with both food types under different levels of risk (spider density, 0-5). As expected, GUDs increased with spider density indicating increasing risk, but only when using protein-rich food. With carbohydrate-rich food, GUD was independent of predation risk. Our results demonstrate that predation risk and nutritional preferences covary and can confound interpretation of GUD experiments. PMID- 29697138 TI - Follicular flushing during oocyte retrieval in assisted reproductive techniques. AB - BACKGROUND: Follicular aspiration under transvaginal ultrasound guidance is routinely performed as part of assisted reproductive technology (ART) to retrieve oocytes for in vitro fertilisation (IVF). However, controversy as to whether follicular flushing following aspiration yields a larger number of oocytes and hence is associated with greater potential for pregnancy than aspiration only is ongoing. OBJECTIVES: To assess the safety and efficacy of follicular flushing as compared with aspiration only performed in women undergoing ART. SEARCH METHODS: We searched the following electronic databases up to 18 July 2017: Cochrane Gynaecology and Fertility Group (CGF) Specialised Register of Controlled Trials, the CENTRAL Register of Studies Online (CRSO), MEDLINE, Embase, PsycINFO, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL). We also searched the trial registries ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform to identify ongoing and registered trials up to 4 July 2017. We reviewed the reference lists of reviews and retrieved studies to identify further potentially relevant studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared follicular aspiration and flushing with aspiration alone in women undergoing ART using their own gametes. Primary outcomes were live birth rate and miscarriage rate per woman randomised. DATA COLLECTION AND ANALYSIS: Two independent review authors assessed studies against the inclusion criteria, extracted data, and assessed risk of bias. A third review author was consulted if required. We contacted study authors as required. We analysed dichotomous outcomes using Mantel-Haenszel odds ratios (ORs), 95% confidence intervals (CIs), and a fixed-effect model, and we analysed continuous outcomes using mean differences (MDs) between groups presented with 95% CIs. We examined the heterogeneity of studies via the I2 statistic. We assessed the quality of evidence by using GRADE (Grades of Recommendation, Assessment, Development and Evaluation) criteria. MAIN RESULTS: We included ten studies, with a total of 928 women. All included studies reported outcomes per woman randomised. We assessed no studies as being at low risk of bias across all domains and found that the main limitation was lack of blinding. Using the GRADE method, we determined that the quality of the evidence ranged from moderate to very low, and we identified issues arising from risk of bias, imprecision, and inconsistency.Comparing follicular flushing to aspiration alone revealed probably little or no difference in the live birth rate (OR 0.95, 95% CI 0.58 to 1.56; three RCTs; n = 303; I2 = 30%; moderate-quality evidence). This suggests that with a live birth rate of approximately 41% with aspiration alone, the equivalent live birth rate with follicular flushing is likely to lie between 29% and 52%. None of the included studies reported on the primary outcome of miscarriage rate.Data show probably little or no difference in oocyte yield (MD -0.28 oocytes, 95% CI -0.64 to 0.09; six RCTs; n = 708; I2 = 0%; moderate-quality evidence). Very low-quality evidence suggests that the duration of oocyte retrieval was longer in the follicular flushing group than in the aspiration only group (MD 166.01 seconds, 95% CI 141.96 to 190.06; six RCTs; n = 714; I2 = 88%). We found no evidence of a difference in the total number of embryos per woman randomised (MD -0.10 embryos, 95% CI -0.34 to 0.15; two RCTs; n = 160; I2 = 58%; low-quality evidence) and no evidence of a difference in the number of embryos cryopreserved (meta-analysis not possible). Data show probably little or no difference in the clinical pregnancy rate (OR 1.07, 95% CI 0.78 to 1.46; five RCTs; n = 704; I2 = 49%; moderate-quality evidence). Only two studies reported on adverse outcomes: One reported no differences in patient-reported adverse outcomes (depression, anxiety, and stress), and the other reported no differences in needle blockage, vomiting, and hypotension. No studies reported on safety. AUTHORS' CONCLUSIONS: This review suggests that follicular flushing probably has little or no effect on live birth rates compared with aspiration alone. None of the included trials reported on effects of follicular aspiration and flushing on the miscarriage rate. Data suggest little or no difference between follicular flushing and aspiration alone with respect to oocyte yield, total embryo number, or number of cryopreserved embryos. In addition, follicular flushing probably makes little or no difference in the clinical pregnancy rate. Evidence was insufficient to allow any firm conclusions with respect to adverse events or safety. PMID- 29697139 TI - Increased cardiac stiffness is associated with autonomic dysfunction in patients with temporal lobe epilepsy. AB - Autonomic dysfunction is linked to sudden death regardless of the presence of structural heart disease. The pathway from autonomic dysfunction to sudden death is not fully understood, but myocardial sympathetic stimulation leading to arrhythmia and/or cardiac fibrosis might play a role. Our goal was to evaluate cardiac stiffness by echocardiography and its association with clinical, structural, and autonomic variables in people with epilepsy (PWE) compared to healthy controls. A 12-lead electrocardiogram, treadmill testing, and transthoracic echocardiography from 30 patients with temporal lobe epilepsy (TLE) without any known cardiovascular disorders were compared to 30 individuals without epilepsy matched by sex, age, and body mass index. Distribution of cardiovascular risk factors was similar in both groups. PWE had a higher left ventricle stiffness, left ventricle filling pressure, and greater left atrial volume as well as markers of autonomic dysfunction such as impaired chronotropic index and percentage achieved of predicted peak heart rate at effort. In multiple regressions, autonomic dysfunction explained 52% of stiffness and carbamazepine treatment and polytherapy with antiepileptic drugs (AEDs) explained, additionally, 6% each. Stiffness is increased in young patients with TLE and is related to autonomic dysfunction and to a lesser extent, carbamazepine use and polytherapy with AEDs. PMID- 29697140 TI - Of mice and men - environmental temperature, body temperature, and treatment of obesity. AB - Mice are widely used for exploring obesity physiology and treatment. However, thermal biology is different between small and large mammals. In this Review, we discuss how the effect of environmental temperature must be understood to ensure applicability of mouse experiments to human obesity. At ambient environmental temperature (~ 22 degrees C), over one-third of energy expenditure in mice is devoted to maintaining core body temperature, largely by brown adipose tissue. To conserve this energy, mice can enter a regulated hypothermia, while humans do not. Since humans expend little or no energy specifically to keep warm, mice studied at thermoneutrality (~ 30 degrees C) may be a better model for human energy homeostasis. Studies indicate that environmental temperature also affects the efficacy of drugs that increase energy expenditure. In mice, dinitrophenol, a protonophore, and CL316243, a beta3-adrenergic agonist, both increase metabolic rate at thermoneutrality, but only CL316243 increases it at 22 degrees C. Furthermore, mice housed at thermoneutrality may become more obese than mice at 22 degrees C. Thus, we discuss the importance of studying mice at both thermoneutrality and at lower temperatures in obesity research. PMID- 29697141 TI - A demonstration of higher-order response class development in children. AB - We evaluated a procedure for teaching two children, one typically developing and one with autism, a higher-order generalized operant response class of unscrambling sight words. The procedures were efficacious in teaching the participants to unscramble words appearing in isolation and in the context of a sentence, with 98% of the presented discriminative stimuli novel to the participants. PMID- 29697142 TI - Comparing the effect of strontium-functionalized and fluoride-modified surfaces on early osseointegration. AB - BACKGROUND: Studies have shown that medical devices comprising strontium contribute to bone healing and osseointegration. The aim of this study was to evaluate the in vivo performance of surface-functionalized implants (Ti-Sr-O) showing predictable release characteristics of strontium and compare it to performance a commercially available fluoride-modified surface. METHODS: Ti-Sr-O functionalized, fluoride-modified, Grade 4 titanium implants were inserted in the femoral condyle of adult male New Zealand white rabbits. Atomic absorption spectrometry (AAS) was utilized to monitor strontium blood serum levels. Two weeks after insertion, histomorphometric evaluation was performed with respect to bone-to-implant contact (BIC%) and bone formation (BF%) using defined regions of interest. RESULTS: Mean values for BIC% showed a comparable degree of osseointegration for Ti-Sr-O and the fluoride-modified surface, while BF% revealed a significant difference in increased BF with Ti-Sr-O. AAS measurements did not indicate any influence of the Ti-Sr-O modified implants on the strontium blood serum concentrations. CONCLUSIONS: Within the limitations of this study, it was shown that the Ti-Sr-O coating, with sustained release characteristics of strontium, enhanced bone apposition and, thus, could find practical applications, e.g., within the field of medical implantology. PMID- 29697143 TI - Feasibility of single-port retroperitoneoscopic adrenalectomy in dogs. AB - OBJECTIVE: To evaluate the feasibility of single-port retroperitoneoscopic adrenalectomy (SPRA) in dogs. STUDY DESIGN: A pilot experimental study. ANIMALS: Eight healthy beagle dogs. METHODS: SPRA was performed on the left and right sides (4 dogs each). Resection of the adrenal gland was performed through a SILS port using a retroperitoneal approach. Operative time was defined from skin incision to the completion of skin suture. Postoperative pain was evaluated by using 3 pain scores. Integrity of the adrenal gland capsule was evaluated by histologic assessment. RESULTS: Mean time taken to complete the SPRA was 44.1 minutes (range, 37-51) and was significantly longer on the right side than on the left side (P < .05). There were no complications intraoperatively or during 14 days of postoperative monitoring. The adrenal gland capsule was found to be injured in 3 of the 8 dogs by histologic assessment. CONCLUSION: This is the first report of SPRA in the veterinary literature. With this technique it is possible to perform adrenalectomy with some risk of capsule penetration and with excellent visibility. CLINICAL SIGNIFICANCE: This study suggests that SPRA is feasible and can be used to resect small adrenal tumors with minimal complications. PMID- 29697144 TI - Penalized maximum likelihood simultaneous longitudinal PET image reconstruction with difference-image priors. AB - PURPOSE: Many clinical contexts require the acquisition of multiple positron emission tomography (PET) scans of a single subject, for example, to observe and quantitate changes in functional behaviour in tumors after treatment in oncology. Typically, the datasets from each of these scans are reconstructed individually, without exploiting the similarities between them. We have recently shown that sharing information between longitudinal PET datasets by penalizing voxel-wise differences during image reconstruction can improve reconstructed images by reducing background noise and increasing the contrast-to-noise ratio of high activity lesions. Here, we present two additional novel longitudinal difference image priors and evaluate their performance using two-dimesional (2D) simulation studies and a three-dimensional (3D) real dataset case study. METHODS: We have previously proposed a simultaneous difference-image-based penalized maximum likelihood (PML) longitudinal image reconstruction method that encourages sparse difference images (DS-PML), and in this work we propose two further novel prior terms. The priors are designed to encourage longitudinal images with corresponding differences which have (a) low entropy (DE-PML), and (b) high sparsity in their spatial gradients (DTV-PML). These two new priors and the originally proposed longitudinal prior were applied to 2D-simulated treatment response [18 F]fluorodeoxyglucose (FDG) brain tumor datasets and compared to standard maximum likelihood expectation-maximization (MLEM) reconstructions. These 2D simulation studies explored the effects of penalty strengths, tumor behaviour, and interscan coupling on reconstructed images. Finally, a real two scan longitudinal data series acquired from a head and neck cancer patient was reconstructed with the proposed methods and the results compared to standard reconstruction methods. RESULTS: Using any of the three priors with an appropriate penalty strength produced images with noise levels equivalent to those seen when using standard reconstructions with increased counts levels. In tumor regions, each method produces subtly different results in terms of preservation of tumor quantitation and reconstruction root mean-squared error (RMSE). In particular, in the two-scan simulations, the DE-PML method produced tumor means in close agreement with MLEM reconstructions, while the DTV-PML method produced the lowest errors due to noise reduction within the tumor. Across a range of tumor responses and different numbers of scans, similar results were observed, with DTV-PML producing the lowest errors of the three priors and DE-PML producing the lowest bias. Similar improvements were observed in the reconstructions of the real longitudinal datasets, although imperfect alignment of the two PET images resulted in additional changes in the difference image that affected the performance of the proposed methods. CONCLUSION: Reconstruction of longitudinal datasets by penalizing difference images between pairs of scans from a data series allows for noise reduction in all reconstructed images. An appropriate choice of penalty term and penalty strength allows for this noise reduction to be achieved while maintaining reconstruction performance in regions of change, either in terms of quantitation of mean intensity via DE-PML, or in terms of tumor RMSE via DTV-PML. Overall, improving the image quality of longitudinal datasets via simultaneous reconstruction has the potential to improve upon currently used methods, allow dose reduction, or reduce scan time while maintaining image quality at current levels. PMID- 29697145 TI - Robust quantitative contrast-enhanced dual-energy CT for radiotherapy applications. AB - PURPOSE: The purpose of this study was to develop and validate accurate methods for determining iodine content and virtual noncontrast maps of physical parameters, such as electron density, in the context of radiotherapy. METHODS: A simulation environment is developed to compare three methods allowing extracting iodine content and virtual noncontrast composition: (a) two-material decomposition, (b) three-material decomposition with the conservation of volume constraint, and (c) eigentissue decomposition. The simulation allows comparing the performance of the methods using iodine-based contrast agent contents in tissues from a reference dataset with variable density and elemental composition. The comparison is performed in two ways: (a) with a priori knowledge on the composition of the targeted tissue, and (b) without a priori knowledge on the base tissue. The three methods are tested with patient images scanned with dual energy CT and iodine-based contrast agent. An experimental calibration adapted to the presence of iodine is performed by imaging tissue equivalent materials and diluted contrast agent solutions with known atomic composition. RESULTS: Results show that in the case of known a priori on the composition of the targeted tissue, the two-material decomposition is robust to variable densities and atomic compositions without biasing the results. In the absence of a priori knowledge on the target tissue composition, the eigentissue decomposition method yields minimal bias and higher robustness to variations. Results from the experimental calibration and the images of two patients show that the extracted quantities are accurate and the bias is negligible for both methods with respect to clinical applications in their respective scope of use. For the patient imaged with a contrast agent, virtual noncontrast electron densities are found in good agreement with values extracted from the scan without contrast agent. CONCLUSION: This study identifies two accurate methods to quantify iodine-based contrast agents and virtual noncontrast composition images with dual-energy CT. One is the two-material decomposition with a priori knowledge of the constituent components focused on organ-specific applications, such as kidney or lung function assessment. The other method is the eigentissue decomposition and is useful for general radiotherapy applications, such as treatment planning where accurate dose calculations are needed in the absence of contrast agent. PMID- 29697146 TI - Red blood cell specifications for patients with hemoglobinopathies: a systematic review and guideline. AB - BACKGROUND: Red blood cell (RBC) transfusions remain essential in the treatment of patients with sickle cell disease (SCD) and beta-thalassemia. Alloimmunization, a well-documented complication of transfusion, increases the risk of delayed hemolytic transfusion reactions, complicates crossmatching and identifying compatible units, and delays provision of transfusions. Guidance is required to optimize the RBC product administered to these patients. STUDY DESIGN AND METHODS: An international, multidisciplinary team conducted a systematic review and developed, following the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology, recommendations to assist treating physicians and transfusion specialists in their decision to select RBCs for these patients. RESULTS: Eighteen studies (17 clinical studies and one cost effectiveness study) were included in the systematic review. The overall quality of the studies was very low. In total, 3696 patients were included: 1680 with beta-thalassemia and 2016 with SCD. CONCLUSION: The panel recommends that ABO D CcEe K-matched RBCs are selected for individuals with SCD and beta-thalassemia, even in the absence of alloantibodies, to reduce the risk of alloimmunization. In patients with SCD and beta-thalassemia who have developed clinically significant alloantibodies, selection of RBCs antigen negative to the alloantibody is recommended, if feasible. In these patients, selection of more extended phenotype matched RBCs will likely reduce the risk of further alloimmunization. However, given the limited availability of extended phenotype-matched units, attention should be given to ensure that a delay in transfusion does not adversely affect patient care. PMID- 29697147 TI - Gradual attenuation of a congenital extrahepatic portosystemic shunt with a self retaining polyacrylic acid-silicone device in 6 dogs. AB - OBJECTIVE: To determine the ability of a polyacrylic acid-silicone radiolucent self-retaining gradual occlusion device (PAS-OD) to attenuate congenital extrahepatic portosystemic shunts (EHPSS) in dogs. STUDY DESIGN: Prospective clinical trial. ANIMALS: Six client-owned dogs with single, congenital EHPSS. METHODS: Serum bile acids (SBA), abdominal ultrasonography, and computed tomographic angiography (CTA) were performed preoperatively and at 4 and 8 weeks postoperatively. Each dog was treated for EHPSS by placement of a PAS-OD. RESULTS: PAS-OD were placed without complication an average of 4.3 seconds (range, 3-7) after isolation of the shunt. Median surgical time was 38.5 minutes (range, 28-84) including concurrent procedures. All dogs recovered from surgery without complications. SBA were normal in 5 of 6 dogs at 4 and 8 weeks after surgery. The shunt was completely attenuated in 2 of 6 dogs at 4 weeks and in 4 of 6 dogs at 8 weeks, without evidence of acquired shunt formation in any dog. The size and velocity of the portal vasculature were improved in 5 of 6 dogs according to 8-week postoperative CTA and ultrasonography results, respectively. The remaining dog had a persistently decreased portal vasculature size but a normal velocity according to 8-week postoperative CTA and ultrasound results, respectively. CONCLUSION: The PAS-OD led to complete attenuation in 4 of 6 dogs and partial attenuation with mild residual flow of 2 EHPSS over an 8-week period in dogs. CLINICAL SIGNIFICANCE: The PAS-OD is a new option for gradual occlusion of congenital EHPSS over 8 weeks. PMID- 29697148 TI - Influence of class IV laser therapy on the outcomes of tibial plateau leveling osteotomy in dogs. AB - OBJECTIVE: To determine the effects of low-level laser therapy (LLLT) on clinical outcomes in dogs with cranial cruciate ligament disease treated with tibial plateau leveling osteotomy (TPLO). STUDY DESIGN: Randomized, placebo-controlled clinical trial. Owners and surgeons (care providers and assessors) were masked. ANIMALS: Ninety-five dogs were admitted for TPLO and assigned to 1 of 2 groups, laser group (LG; n = 51) or placebo group (PG; n = 44). METHODS: Three treatments (laser or placebo) were administered within a 4-day perioperative period. A fourth treatment was recommended and was accepted in 28.4% of cases (LG, n = 14; PG, n = 13). Dogs in the LG group received laser at wavelengths 660 nm red (100 mW) and at 800, 905 and 970 nm infrared (maximum 15 W continuous wave, 20 W peak pulsed wave), administered simultaneously. Dogs in the PG group received placebo laser (660 nm, 4 mW). Other treatments were identical. Outcomes were measured by difference in clinical metrology instruments (Liverpool Osteoarthritis in Dogs and adjusted Canine Orthopedic Index [COI]), osteotomy healing on a radiographic scale, time to cessation of nonsteroidal anti-inflammatory drug administration, and wound healing by owner questionnaire. RESULTS: The only difference detected between groups consisted of a greater improvement in the gait section of the adjusted COI (ACOI) in the LG group (median [interquartile range; IQR] = 6 [4 7.5]) compared with the PG group (median [IQR] = 4 [2-6]; P < .05). CONCLUSION: The laser protocol used in this study was associated with a greater improvement in ACOI gait in dogs treated with TPLO but did not improve any other clinical metrology instrument scores or bone healing. CLINICAL SIGNIFICANCE: This study provides some evidence that LLLT may improve the gait of dogs recovering from a TPLO, as assessed by owners. PMID- 29697149 TI - Characterization of atypical Flavobacterium columnare and identification of a new genomovar. PMID- 29697150 TI - Components of responsibility in estimating relative value units: How do dentists value their work? AB - OBJECTIVES: Responsibility weights can translate services into a common scale of work effort (relative value units). The aims were to describe the responsibility weights for main areas of dental services and assess associations of ratings of the importance of the components of responsibility with responsibility weights. METHODS: Mailed questionnaires were used to collect responsibility weights and components of responsibility from a random sample of Australian dentists who were randomly assigned into panels. Across the panels, weights were elicited for 299 service items from 9 service areas. Data were weighted to the age and sex distribution of the workforce. Ordered logit regression models assessed differences in weights by ratings of importance of the 8 components of responsibility. RESULTS: Responses were collected from 846 dentists (response rate = 37%). Adjusted models showed that, with the exception of general/miscellaneous services, all remaining service areas were associated with between 3 and 7 components. Preventive weights were associated with dexterity and mental effort but negatively with perception. Diagnostic weights were associated with knowledge, judgement, experience, perception, physical and mental effort, and negatively with dexterity. Ratings of components of responsibility were associated with responsibility weights and showed varying patterns across service areas. Mental effort, invasiveness, dexterity, experience and knowledge were associated with responsibility weights in the majority of service areas. CONCLUSIONS: The observed variation in weights across service areas showed that dentists discriminated between services in a systematic and cognizant manner and so provided broad validation of weights assigned by dentists. PMID- 29697151 TI - An updated overview with simple and practical approach for developing in vitro-in vivo correlation. AB - Preclinical Research & Development An in vitro-in vivo correlation (IVIVC) is as a predictive mathematical model that demonstrates a key role in the development, advancement, evaluation and optimization of extended release, modified release and immediate release pharmaceutical formulations. A validated IVIVC model can serve as a surrogate for bioequivalence studies and subsequently save time, effort and expenditure during pharmaceutical product development. This review discusses about different levels of correlations, general approaches to develop an IVIVC by mathematical modelling, validation, data analysis and various applications. In the current setting, the dearth of success associated with IVIVC is due to complexity of underlying scientific principles as well as the practice of fitting/matching in vivo plasma level-time data with in vitro dissolution profile. Hence, a simple, straightforward practical means to predict plasma drug levels by convolution technique and percentage drug absorbed computed from in vitro dissolution profile based on deconvolution method are illustrated. The bioavailability/bioequivalence assessment and evaluation are frequently validated by the pharmacokinetic parameters such as maximum concentration, time to reach maximum concentration, and area under the curve. The implementation of a quality by design manufacturing based on in vivo bioavailability and clinically relevant dissolution specification are recommended because corresponding design safe space will guarantee that all batches from relevant products are met with sufficient quality and bioperformance. Recently, United States Food and Drug Administration and European Medicines Agency have proposed that in silico/physiologically based pharmacokinetic modelling can be used in decision making during preclinical experiments as well as to recognize the dissolution profiles that can forecast and ensure the desired clinical performance. PMID- 29697152 TI - Migraine Burden of Disease: From the Patient's Experience to a Socio-Economic View. AB - Migraine is one of the most common diseases worldwide and, importantly, a major cause of disability. This translates into a huge clinical and economic burden to individuals and society. Despite existing data on how migraine affects populations, the disease continues to be underdiagnosed and therefore undertreated, so the scale of the public health problem may be underestimated. The impact on the daily lives of patients and their families has also been underappreciated. Clinical and regulatory guidelines are encouraging the use of patient-reported outcome tools (PROs), as these may help in disease management and facilitate physician-patient interactions. In clinical trials in migraine, PRO data are key to evaluating the effects of new therapies on patients, such as disability assessment, productivity, quality of life, and emotional and physical functioning. Digital technologies have enabled the development of ePRO tools, which may play a growing role in the collection of PRO data in the future. Here, we will consider the current view of the burden imposed by migraine on patients and society, illustrate this with two patient case studies, and examine the initiatives underway to use our knowledge to improve our management approaches for the disease. PMID- 29697153 TI - The CGRP Pathway in Migraine as a Viable Target for Therapies. AB - The neuropeptide calcitonin gene-related peptide is well established as a key player in the pathogenesis of migraine. Clinical studies show calcitonin gene related peptide levels correlate with migraine attacks, and decreases in this neuropeptide can indicate antimigraine therapy effectiveness. Research has revealed a wide distribution of expression sites for calcitonin gene-related peptide in the central and peripheral nervous system. Of these, the calcitonin gene-related peptide receptor, which binds calcitonin gene-related peptide with high affinity, has attracted growing interest as a viable target for antimigraine therapies. An incentive to pursue such research is the continuing unmet medical need of patients. Triptans have offered some clinical benefit, but many patients do not respond and these drugs have important safety considerations. Initial calcitonin gene-related peptide-focused research led to development of the "gepant" small-molecule calcitonin gene-related peptide receptor blockers. Positive efficacy reports concerning the gepants have been tempered by safety findings which led to the discontinuation of some of these agents. Currently, there is considerable excitement regarding monoclonal antibodies against calcitonin gene-related peptide (eptinezumab, galcanezumab, fremanezumab) and the calcitonin gene-related peptide receptor (erenumab). To date, these monoclonal antibodies have shown promising efficacy in clinical trials, with no major safety concerns. If ongoing long-term studies show that their efficacy can be maintained, this may herald a new era for effective antimigraine therapies. PMID- 29697154 TI - A Phase-by-Phase Review of Migraine Pathophysiology. AB - Migraine is a common, disabling neurological disorder characterized by multiple phases: premonitory, aura, headache, postdrome, and interictal. Our understanding of the pathophysiology of each phase of migraine has evolved over recent years. The premonitory phase begins as early as 3 days before the headache phase, and involves a complex interplay between various cortical and subcortical brain regions, including the hypothalamus and brainstem nuclei that modulate nociceptive signaling. The headache phase involves activation of the trigeminovascular system, a pathway that is well characterized. In one-third of patients, an aura phase may occur during some attacks and likely correlates with a cortical spreading depression-like event; a slowly propagating wave of neuronal and glial cell depolarization and hyperpolarization. Improved characterization of the pathophysiological processes involved at each stage of the migraine attack will aid the identification of new therapeutic targets for migraine prevention. This review provides an update on prevailing concepts of migraine pathophysiology. PMID- 29697155 TI - Foreword: The CGRP Pathway and Migraine Prevention: Reducing the Burden of Disease. PMID- 29697156 TI - A Review of Monoclonal Antibody Therapies and Other Preventative Treatments in Migraine. AB - Monoclonal antibodies targeting the calcitonin gene-related peptide pathway represent a new class of mechanism-specific, migraine-targeted therapies available for migraine prevention. To date, four monoclonal antibodies have demonstrated efficacy in phase II and III trials, significantly reducing migraine days per month versus placebo with rapid onset of action. While their efficacy may be considered similar to existing preventive options, their true value may lie in an improved tolerability profile, with high specificity and selectivity for the calcitonin gene-related peptide receptor or ligand reducing the potential for off-target binding and toxicity. The infrequent parenteral administration of these therapeutic proteins, and lack of requirement for dose titration, has potential to simplify treatment selection and use for clinicians and patients. However, the treatments have not yet been tested in real-world settings in patients with the range of comorbid conditions encountered in routine clinical practice, and longer-term data on safety, efficacy, and treatment persistence are required. If data from real-world settings can confirm the initial clinical trial findings, it is hoped that antibodies antagonizing the calcitonin gene-related peptide pathway will be able to improve quality of life for patients with episodic and chronic migraine, and help relieve the huge patient and societal burden of migraine. Novel treatments designed to target the specific pathophysiology of migraine could have an important place in future migraine management. PMID- 29697157 TI - Association between pancreatic fat and incidence of metabolic syndrome: a 5-year Japanese cohort study. AB - BACKGROUND AND AIM: Previous cross-sectional studies showed that pancreatic fat was associated with metabolic syndrome. However, no longitudinal study has evaluated whether people with high pancreatic fat are likely to develop future metabolic syndrome. This study investigated the association between baseline pancreatic fat and metabolic syndrome incidence. METHODS: In 2008-2009, 320 participants without metabolic syndrome underwent health checks, which included unenhanced computed tomography, and were followed up annually for 4-5 years. Baseline pancreatic fat amounts were evaluated using a histologically validated method that measured differences between pancreas and spleen attenuations on computed tomography. The participants were divided into low (reference), intermediate, and high pancreatic fat groups based on pancreas and spleen attenuation tertiles. Metabolic syndrome incidence was evaluated annually over a median follow-up period of 4.99 (interquartile range, 4.88-5.05) years, in accordance with the 2009 harmonized criteria. Risk ratios (RRs) for the association between baseline pancreatic fat amounts and metabolic syndrome incidence were estimated using Poisson regression models adjusted for age, sex, body mass index, liver fat, pre-metabolic syndrome, cigarette use, alcohol use, and physical activity. RESULTS: Metabolic syndrome incidence was 30.6% (98/320). Pancreatic fat was associated with an increased incidence of metabolic syndrome, based on a univariate analysis (RRs [95% confidence interval], 3.14 [1.74-5.67] and 3.96 [2.23-7.03] in the intermediate and high pancreatic fat groups, respectively). The association remained statistically significant in the multivariate analysis (RR [95% confidence interval], 2.04 [1.14-3.64] and 2.30 [1.28-4.14] for the same groups, respectively). CONCLUSIONS: Pancreatic fat predicts the future risk of metabolic syndrome. PMID- 29697158 TI - Safety and efficacy of antibiotics among acutely decompensated cirrhosis patients. AB - BACKGROUND AND AIM: Infection is a leading precipitant of acute-on-chronic liver failure. This study aims to determine the safety and efficacy of antibiotics within acute-on-chronic liver failure. METHODS: Retrospective study of 457 acute on-chronic liver failure patients admitted to the University of Arizona Health Network between January 1 and December 31, 2014. Eligibility criteria were as follows: at least 18 years of age and 6 months follow-up, data available to calculate systemic inflammatory response syndrome (SIRS), and acute-on-chronic liver failure. This study collected patient's clinical features and historical data. Key data points were infection, antibiotic use, and SIRS. This study used Cox proportional hazards to model the effects of clinical factors on risk of death. RESULTS: A total of 521 of 1243 met the inclusion criteria, and 64 had missing data, leaving 457 patients. Infection resulted in higher hazard (hazard ratio [HR] = 1.6, confidence interval [CI]: 1.1-1.3, P = 0.01). Patients with infections and antibiotics, compared with non-infected patients without antibiotics, had higher hazard (HR = 1.633, CI: 1.022-2.609, P = .04). Of those infected patients with antibiotics, SIRS patients experienced higher hazard (HR = 1.9, CI: 1.1-3.0, P = .007). Multivariable Cox proportional hazards associated the following with higher hazard: SIRS (HR = 1.866, CI: 1.242-2.804, P = 0.003), vancomycin (HR = 1.640, CI: 1.119-2.405, P = 0.011), Model for End-Stage Liver Disease (HR = 1.051, CI: 1.030-1.073, P < 0.001), gastrointestinal bleeding (HR = 1.727, CI: 1.180-2.527, P = 0.005), and hepatic encephalopathy (HR = 1.807, CI: 1.247-2.618, P = 0.002). CONCLUSION: Overall, treatment of infection with antibiotics did not improve survival; however, patients not meeting SIRS criteria had better outcomes, and vancomycin was associated with poorer survival among acute-on-chronic liver failure patients. PMID- 29697159 TI - Photoinduced Release of a Chemical Fuel for Acid-Base-Operated Molecular Machines. AB - Back and forth motions of the acid-base-operated molecular switch 1 are photo controlled by irradiation of a solution, which also contains the photolabile pre fuel 4. The photo-stimulated deprotection of the pre-fuel produces controlled amounts of acid 2, the base-promoted decarboxylation of which fuels the back and forth motions of the Sauvage-type [2]-catenane-based molecular switch. Because switch 1 and pre-fuel 4 do not interact in the absence of irradiation, an excess of the latter with respect to 1 can be added to the solution from the beginning. In principle, photocontrol of the back and forth motions of any molecular machine, the operation of which is guided by protonation/deprotonation, could be attained by use of pre-fuel 4, or of any other protected acid that undergoes deprotection by irradiation with light at a proper wavelength, followed by decarboxylation under conveniently mild conditions. PMID- 29697161 TI - Exchange Interactions Switch Tunneling: A Comparative Experimental and Theoretical Study on Relaxation Dynamics by Targeted Metal Ion Replacement. AB - The magnetic relaxation and magnetization blocking barriers of tailor-made homo- and heterodinuclear compounds [Dy2 (opch)2 (OAc)2 (H2 O)2 ]?MeOH (1) and [DyMn(opch)2 (OAc)(MeOH)(H2 O)2 ] (2), where H2 opch is (E)-N'-(2-hydroxy-3 methoxybenzylidene)pyrazine-2-carbohydrazide, were systematically investigated and the change in single-molecule magnet behavior originating from targeted replacement of one dysprosium site in the Dy2 compound with manganese was elucidated through a combination of experimental and theoretical studies. A detailed comparative study on these closely related model compounds revealed remarkable changes of the crystal-field splitting and anisotropy of the Dy site and the total exchange spectrum due to the replacement of Dy by Mn. The blocking barriers of these two compounds, which explain their different relaxation behaviors, were analyzed. The two Ising doublets arising from the magnetic interaction in the case of 1 are strongly uniaxial, with tunneling splittings smaller than 10-6 cm-1 , and this leads to magnetic relaxation at temperatures exceeding the exchange energy (2.14 cm-1 ), which involves transition via the excited states corresponding to local transitions on the excited doublet at the Dy site. The third and fourth exchange doublets in 2 (located at 2.16 and 3.25 cm 1 , respectively) show much larger tunneling splittings (of 10-4 and 10-3 cm-1 , respectively), and thus open an important path for magnetic relaxation. PMID- 29697160 TI - Donor-influenced Structure-Activity Correlations in Stoichiometric and Catalytic Reactions of Lithium Monoamido-Monohydrido-Dialkylaluminates. AB - A series of heteroleptic monoamido-monohydrido-dialkylaluminate complexes of general formula [iBu2 AlTMPHLi?donor] were synthesized and characterised in solution and in the solid state. Applying these complexes in catalytic hydroboration reactions with representative aldehydes and ketones reveals that all are competent, however a definite donor substituent effect is discernible. The bifunctional nature of the complexes is also probed by assessing their performance in metallation of a triazole and phenylacetylene and addition across pyrazine. These results lead to an example of phenylacetylene hydroboration, which likely proceeds via deprotonation, rather than insertion as observed with the aldehydes and ketones. Collectively, the results emphasise that reactivity is strongly influenced by both the mixed-metal constitution and mixed-ligand constitution of the new aluminates. PMID- 29697162 TI - A Cuprous/Lanthanide-Organic Framework as the Luminescent Sensor of Hypochlorite. AB - A new 3D framework {[Eu2 Cu(IN)5 (CO3 )(H2 O)] ?3 H2 O}n (1) was obtained and structurally characterized, containing CuI and an unusual lanthanide duplex chain. The luminescent explorations of compound 1 suggest that 1 could emit the characteristic emission of CuI , and 1 can act as the luminescent sensor of ClO- with the detection limit of 10-5 m. Notably, 1 represents the first example of MOF-based sensor for detecting ClO- . PMID- 29697163 TI - Shape Memory Hydrogels with Simultaneously Switchable Fluorescence Behavior. AB - Realization of shape memory process in polymeric hydrogels at ambient condition is a significant development to shape memory materials. The sound understanding of the dynamic shape memory process is fundamentally important but limited. Here, a novel shape memory hydrogel with simultaneously switchable fluorescence behavior is developed. The hydrogel is prepared by incorporating a pH-responsive fluorescent molecule, perylene tetracarboxylic acid, into chitosan-based hydrogel, and the assembly and disassembly of chitosan chains into microcrystals upon the trigger of pH are applied as reversible crosslinks to achieve shape memory effect. Therefore, the formation and disassociation of microcrystalline chitosan, and the switchable fluorescence performance happen concurrently, which bring convenience to monitoring the shape memory process by fluorescent imaging. Moreover, the erasable fluorescence behavior also gives the hydrogel potential applications in information storage. PMID- 29697164 TI - A supercritical CO2 extract of neem leaf (A. indica) and its bioactive liminoid, nimbolide, suppresses colon cancer in preclinical models by modulating pro inflammatory pathways. AB - Colorectal cancer (CRC) is the third most commonly diagnosed cancer and the second leading cause of cancer death in men and women in the United States. Anti inflammatory blockade has been proven to be a promising avenue of colorectal cancer prevention. However, NSAIDs while effective in curbing CRC risk are too toxic for long-term use in cancer prevention. The Neem tree (Azadirachta indica) is rich in liminoid terpenoids, collectively known as azadiractoids and has been shown to have anti-inflammatory effects. To explore a role of neem in CRC, human colon cancer cell lines HCT116 and HT29 cells were treated with purified Super Critical Neem Extract (SCNE) or the neem liminoid, nimbolide. SCNE treatment resulted in a dose dependent inhibition of CRC cell proliferation and an increase in apoptosis. Treatment with SCNE and nimbolide decreased the expression of transcriptional factors, STAT3 and NF-kappaB which plays a major role in gene regulation of multiple cellular processes. Protein expression of COX1, IL-6, and TNF-alpha were decreased on treatment with SCNE in CRC cells. Western blots and Zymogram assays results revealed anti-invasive effect by decreased expression of MMP2 and MMP9 proteins in CRC cells. Overall, these data confirm a potential anti cancer effect of SCNE, reducing cell proliferation, inflammation, migration, and invasion in human colon cancer cells. Confirming these indications, we found that treatment of mice bearing HT29 and HCT116 xenografted tumors exhibited striking inhibition of colon tumor growth. Clearly we must explore the effect of neem in preclinical animal models for anti-cancer therapy. PMID- 29697165 TI - Automated pixel-wise brain tissue segmentation of diffusion-weighted images via machine learning. AB - The diffusion-weighted (DW) MR signal sampled over a wide range of b-values potentially allows for tissue differentiation in terms of cellularity, microstructure, perfusion, and T2 relaxivity. This study aimed to implement a machine learning algorithm for automatic brain tissue segmentation from DW-MRI datasets, and to determine the optimal sub-set of features for accurate segmentation. DWI was performed at 3 T in eight healthy volunteers using 15 b values and 20 diffusion-encoding directions. The pixel-wise signal attenuation, as well as the trace and fractional anisotropy (FA) of the diffusion tensor, were used as features to train a support vector machine classifier for gray matter, white matter, and cerebrospinal fluid classes. The datasets of two volunteers were used for validation. For each subject, tissue classification was also performed on 3D T1 -weighted data sets with a probabilistic framework. Confusion matrices were generated for quantitative assessment of image classification accuracy in comparison with the reference method. DWI-based tissue segmentation resulted in an accuracy of 82.1% on the validation dataset and of 82.2% on the training dataset, excluding relevant model over-fitting. A mean Dice coefficient (DSC) of 0.79 +/- 0.08 was found. About 50% of the classification performance was attributable to five features (i.e. signal measured at b-values of 5/10/500/1200 s/mm2 and the FA). This reduced set of features led to almost identical performances for the validation (82.2%) and the training (81.4%) datasets (DSC = 0.79 +/- 0.08). Machine learning techniques applied to DWI data allow for accurate brain tissue segmentation based on both morphological and functional information. PMID- 29697166 TI - Supraventricular tachycardia with complete heart block. PMID- 29697167 TI - Premature ventricular extrastimulus without His or ventricular capture: An unexpected response during AV nodal reentrant tachycardia. PMID- 29697168 TI - A narrow complex tachycardia with variable R-R intervals: What is the mechanism? PMID- 29697169 TI - Cross-scale controls on carbon emissions from boreal forest megafires. AB - Climate warming and drying is associated with increased wildfire disturbance and the emergence of megafires in North American boreal forests. Changes to the fire regime are expected to strongly increase combustion emissions of carbon (C) which could alter regional C balance and positively feedback to climate warming. In order to accurately estimate C emissions and thereby better predict future climate feedbacks, there is a need to understand the major sources of heterogeneity that impact C emissions at different scales. Here, we examined 211 field plots in boreal forests dominated by black spruce (Picea mariana) or jack pine (Pinus banksiana) of the Northwest Territories (NWT), Canada after an unprecedentedly large area burned in 2014. We assessed both aboveground and soil organic layer (SOL) combustion, with the goal of determining the major drivers in total C emissions, as well as to develop a high spatial resolution model to scale emissions in a relatively understudied region of the boreal forest. On average, 3.35 kg C m-2 was combusted and almost 90% of this was from SOL combustion. Our results indicate that black spruce stands located at landscape positions with intermediate drainage contribute the most to C emissions. Indices associated with fire weather and date of burn did not impact emissions, which we attribute to the extreme fire weather over a short period of time. Using these results, we estimated a total of 94.3 Tg C emitted from 2.85 Mha of burned area across the entire 2014 NWT fire complex, which offsets almost 50% of mean annual net ecosystem production in terrestrial ecosystems of Canada. Our study also highlights the need for fine-scale estimates of burned area that represent small water bodies and regionally specific calibrations of combustion that account for spatial heterogeneity in order to accurately model emissions at the continental scale. PMID- 29697170 TI - A Persulfide Donor Responsive to Reactive Oxygen Species: Insights into Reactivity and Therapeutic Potential. AB - Persulfides (RSSH) have been hypothesized as critical components in sulfur mediated redox cycles and as potential signaling compounds, similar to hydrogen sulfide (H2 S). Hindering the study of persulfides is a lack of persulfide-donor compounds with selective triggers that release discrete persulfide species. Reported here is the synthesis and characterization of a ROS-responsive (ROS=reactive oxygen species), self-immolative persulfide donor. The donor, termed BDP-NAC, showed selectivity towards H2 O2 over other potential oxidative or nucleophilic triggers, resulting in the sustained release of the persulfide of N-acetyl cysteine (NAC) over the course of 2 h, as measured by LCMS. Exposure of H9C2 cardiomyocytes to H2 O2 revealed that BDP-NAC mitigated the effects of a highly oxidative environment in a dose-dependent manner over relevant controls and to a greater degree than common H2 S donors sodium sulfide (Na2 S) and GYY4137. BDP-NAC also rescued cells more effectively than a non-persulfide releasing control compound in concert with common H2 S donors and thiols. PMID- 29697171 TI - Cost-Minimization Analysis of Deep-Brain Stimulation Using National Database of Japanese Health Insurance Claims. AB - OBJECTIVES: A new rechargeable dual-channel deep brain stimulation (DBS) system has been introduced for the treatment of Parkinson's disease and other movement disorders. However, the clinical value of the device, which has a high cost, remains unclear. MATERIALS AND METHODS: We conducted a cost-minimization analysis using a national database of health insurance claims in Japan. DBS-related costs were compared between rechargeable and non-rechargeable devices and estimated across a 20-year period. RESULTS: Although the price of rechargeable DBS was higher than that of non-rechargeable DBS, we observed total cost-savings of 8.4 million yen across 20 years by considering costs related to implantation surgery, frequency of replacement, and risk of complications. CONCLUSIONS: In this study, real-world evidence indicated that rechargeable dual-channel DBS is a reasonable choice for saving total medical costs. Price revisions should consider cost effectiveness findings for medical devices. PMID- 29697172 TI - Peeling back of left bundle branch refractoriness facilitates mapping of a hemodynamically unstable atrial flutter. PMID- 29697173 TI - Spring phenology at different altitudes is becoming more uniform under global warming in Europe. AB - Under current global warming, high-elevation regions are expected to experience faster warming than low-elevation regions. However, due to the lack of studies based on long-term large-scale data, the relationship between tree spring phenology and the elevation-dependent warming is unclear. Using 652k records of leaf unfolding of five temperate tree species monitored during 1951-2013 in situ in Europe, we discovered a nonlinear trend in the altitudinal sensitivity (SA , shifted days per 100 m in altitude) in spring phenology. A delayed leaf unfolding (2.7 +/- 0.6 days per decade) was observed at high elevations possibly due to decreased spring forcing between 1951 and 1980. The delayed leaf unfolding at high-elevation regions was companied by a simultaneous advancing of leaf unfolding at low elevations. These divergent trends contributed to a significant increase in the SA (0.36 +/- 0.07 days 100/m per decade) during 1951-1980. Since 1980, the SA started to decline with a rate of -0.32 +/- 0.07 days 100/m per decade, possibly due to reduced chilling at low elevations and improved efficiency of spring forcing in advancing the leaf unfolding at high elevations, the latter being caused by increased chilling. Our results suggest that due to both different temperature changes at the different altitudes, and the different tree responses to these changes, the tree phenology has shifted at different rates leading to a more uniform phenology at different altitudes during recent decades. PMID- 29697174 TI - Copper-Catalyzed Heteroarylboration of 1,3-Dienes with 3-Bromopyridines: A cine Substitution. AB - A method for the heteroarylboration of 1,3-dienes is presented. The process involves an unusual cine substitution of 3-bromopyridine derivatives to deliver highly functionalized heterocyclic products. Mechanistic studies are included that clarify the details of this unusual process. PMID- 29697176 TI - In Vitro Reconstitution of OxyC Activity Enables Total Chemoenzymatic Syntheses of Vancomycin Aglycone Variants. AB - The bioactivity of vancomycin is enabled by three aromatic crosslinks, the biosynthesis of which has been an active area of investigation for two decades. Two cytochrome P450 enzymes, OxyB and OxyA, have been shown to introduce bisaryl ether linkages with the help of a so-called X-domain. The final crosslink, however, a biaryl bond thought to be installed by OxyC, has remained elusive. We report the in vitro reconstitution of the OxyC reaction and formation of the first carbon-carbon crosslink in any glycopeptide antibiotic. Using a cascade sequence, in which the peptide substrate was incubated with the Oxy enzymes in turn, we completed the chemoenzymatic synthesis of a vancomycin aglycone variant. This approach was also used to generate a new analogue carrying a thioamide linkage at residue 4, a precursor to the amidine derivative, which is effective against vancomycin-resistant pathogens. Our results set the stage for creating therapeutic vancomycin derivatives by using the native metalloenzymes. PMID- 29697175 TI - Synthesis, Structure, Bonding, and Reactivity of Metal Complexes Comprising Diborane(4) and Diborene(2): [{Cp*Mo(CO)2 }2 {MU-eta2 :eta2 -B2 H4 }] and [{Cp*M(CO)2 }2 B2 H2 M(CO)4 ], M=Mo,W. AB - The reaction of [(Cp*Mo)2 (MU-Cl)2 B2 H6 ] (1) with CO at room temperature led to the formation of the highly fluxional species [{Cp*Mo(CO)2 }2 {MU-eta2 :eta2 -B2 H4 }] (2). Compound 2, to the best of our knowledge, is the first example of a bimetallic diborane(4) conforming to a singly bridged Cs structure. Theoretical studies show that 2 mimics the Cotton dimolybdenum-alkyne complex [{CpMo(CO)2 }2 C2 H2 ]. In an attempt to replace two hydrogen atoms of diborane(4) in 2 with a 2e [W(CO)4 ] fragment, [{Cp*Mo(CO)2 }2 B2 H2 W(CO)4 ] (3) was isolated upon treatment with [W(CO)5 ?thf]. Compound 3 shows the intriguing presence of [B2 H2 ] with a short B-B length of 1.624(4) A. We isolated the tungsten analogues of 3, [{Cp*W(CO)2 }2 B2 H2 W(CO)4 ] (4) and [{Cp*W(CO)2 }2 B2 H2 Mo(CO)4 ] (5), which provided direct proof of the existence of the tungsten analogue of 2. PMID- 29697177 TI - Cascade Claisen Rearrangement: Rapid Synthesis of Polysubstituted Salicylaldehydes and Total Syntheses of Hemigossypol and Gossypol. AB - A cascade Claisen rearrangement of a well-organized maltol propargyl ether for the construction of polysubstituted salicylaldehydes is reported. This reaction features high atom economy (100 %), as well as catalyst-free and gram-scale conditions. Based on this novel methodology, the total synthesis of hemigossypol, gossypol, and their analogues has been realized. PMID- 29697178 TI - Maximizing the Number of Interfacial Sites in Single-Atom Catalysts for the Highly Selective, Solvent-Free Oxidation of Primary Alcohols. AB - The solvent-free selective oxidation of alcohols to aldehydes with molecular oxygen is highly attractive yet challenging. Interfacial sites between a metal and an oxide support are crucial in determining the activity and selectivity of such heterogeneous catalysts. Herein, we demonstrate that the use of supported single-atom catalysts (SACs) leads to high activity and selectivity in this reaction. The significantly increased number of interfacial sites, resulting from the presence of individually dispersed metal atoms on the support, renders SACs one or two orders of magnitude more active than the corresponding nanoparticle (NP) catalysts. Lattice oxygen atoms activated at interfacial sites were found to be more selective than O2 activated on metal NPs in oxidizing the alcohol substrate. This work demonstrates for the first time that the number of interfacial sites is maximized in SACs, providing a new avenue for improving catalytic performance by developing appropriate SACs for alcohol oxidation and other reactions occurring at metal-support interfacial sites. PMID- 29697179 TI - Toward understanding the contribution of waterbodies to the methane emissions of a permafrost landscape on a regional scale-A case study from the Mackenzie Delta, Canada. AB - Waterbodies in the arctic permafrost zone are considered a major source of the greenhouse gas methane (CH4 ) in addition to CH4 emissions from arctic wetlands. However, the spatio-temporal variability of CH4 fluxes from waterbodies complicates spatial extrapolation of CH4 measurements from single waterbodies. Therefore, their contribution to the CH4 budget of the arctic permafrost zone is not yet well understood. Using the example of two study areas of 1,000 km2 each in the Mackenzie Delta, Canada, we approach this issue (i) by analyzing correlations on the landscape scale between numerous waterbodies and CH4 fluxes and (ii) by analyzing the influence of the spatial resolution of CH4 flux data on the detected relationships. A CH4 flux map with a resolution of 100 m was derived from two aircraft eddy-covariance campaigns in the summers of 2012 and 2013. We combined the CH4 flux map with high spatial resolution (2.5 m) waterbody maps from the Permafrost Region Pond and Lake Database and classified the waterbody depth based on Sentinel-1 SAR backscatter data. Subsequently, we reduced the resolution of the CH4 flux map to analyze if different spatial resolutions of CH4 flux data affected the detectability of relationships between waterbody coverage, number, depth, or size and the CH4 flux. We did not find consistent correlations between waterbody characteristics and the CH4 flux in the two study areas across the different resolutions. Our results indicate that waterbodies in permafrost landscapes, even if they seem to be emission hot spots on an individual basis or contain zones of above average emissions, do currently not necessarily translate into significant CH4 emission hot spots on a regional scale, but their role might change in a warmer climate. PMID- 29697181 TI - Abundance and taxonomic affiliation of molybdenum transport and utilization genes in Tengchong hot springs, China. AB - The nitrogen, sulfur and carbon cycles all rely on critical microbial transformations that are carried out by enzymes that require molybdenum (Mo) as a cofactor. Despite Mo importance in these biogeochemical cycles, little information exists about microbial Mo utilization in extreme environments where, due to geochemical conditions, bioavailable Mo may be limited. Using metagenomic data from nine hot springs in Tengchong, Yunnan Province, China, which range in temperature from 42 degrees C to 96 degrees C and pH from 2.3 to 9, the effects of pH, temperature and spring geochemistry on the abundance and taxonomic affiliation of genes related to Mo were studied. Dissolved Mo was only detected at sites with circumneutral pH. However, processes and organisms that require Mo were detected at all sites across all temperature and pH gradients. All sites contained xanthine dehydrogenase, formate dehydrogenase, carbon-monoxide dehydrogenase, nitrate reductase, sulfite oxidase and methionine-sulfoxide reductase despite different community compositions. This suggests that different microbial communities, resulting from different physicochemical conditions, may be performing similar metabolic functions. Furthermore, the abundance and taxonomic diversity of Mo-related annotations increased with higher concentrations of Mo. This study shows that despite geochemical conditions that can limit Mo bioavailability, microbes require Mo for a variety of processes. PMID- 29697180 TI - Planar Perovskite Solar Cells with High Open-Circuit Voltage Containing a Supramolecular Iron Complex as Hole Transport Material Dopant. AB - In perovskite solar cells (PSCs), the most commonly used hole transport material (HTM) is spiro-OMeTAD, which is typically doped by metalorganic complexes, for example, based on Co, to improve charge transport properties and thereby enhance the photovoltaic performance of the device. In this study, we report a new hemicage-structured iron complex, 1,3,5-tris(5'-methyl-2,2'-bipyridin-5 yl)ethylbenzene Fe(III)-tris(bis(trifluoromethylsulfonyl)imide), as a p-type dopant for spiro-OMeTAD. The formal redox potential of this compound was measured as 1.29 V vs. the standard hydrogen electrode, which is slightly (20 mV) more positive than that of the commercial cobalt dopant FK209. Photoelectron spectroscopy measurements confirm that the iron complex acts as an efficient p dopant, as evidenced in an increase of the spiro-OMeTAD work function. When fabricating planar PSCs with the HTM spiro-OMeTAD doped by 5 mol % of the iron complex, a power conversion efficiency of 19.5 % (AM 1.5G, 100 mW cm-2 ) is achieved, compared to 19.3 % for reference devices with FK209. Open circuit voltages exceeding 1.2 V at 1 sun and reaching 1.27 V at 3 suns indicate that recombination at the perovskite/HTM interface is low when employing this iron complex. This work contributes to recent endeavors to reduce recombination losses in perovskite solar cells. PMID- 29697182 TI - Leadless pacemaker placement in a patient with chronic kidney disease: A strategy to preserve central veins. AB - Cardiac rhythm disorder is frequently encountered in hemodialysis patients and is often treated with a cardiovascular implantable electronic device (CIED). The conventional CIED requires placement of transvenous leads resulting in subclinical central venous stenosis, which can adversely affect the successful creation of a permanent dialysis vascular access. The technological advancement of a leadless pacemaker provides an opportunity to implement a strategy to preserve central veins in patients with chronic kidney disease. We report a case of successful placement of a leadless pacemaker in a dialysis patient to preserve the central veins for future vascular access creation. PMID- 29697183 TI - Genome biology of a novel lineage of planctomycetes widespread in anoxic aquatic environments. AB - Anaerobic strains affiliated with a novel order-level lineage of the Phycisphaerae class were retrieved from the suboxic zone of a hypersaline cyanobacterial mat and anoxic sediments of solar salterns. Genome sequences of five isolates were obtained and compared with metagenome-assembled genomes representing related uncultured bacteria from various anoxic aquatic environments. Gene content surveys suggest a strictly fermentative saccharolytic metabolism for members of this lineage, which could be confirmed by the phenotypic characterization of isolates. Genetic analyses indicate that the retrieved isolates do not have a canonical origin of DNA replication, but initiate chromosome replication at alternative sites possibly leading to an accelerated evolution. Further potential factors driving evolution and speciation within this clade include genome reduction by metabolic specialization and rearrangements of the genome by mobile genetic elements, which have a high prevalence in strains from hypersaline sediments and mats. Based on genetic and phenotypic data a distinct group of strictly anaerobic heterotrophic planctomycetes within the Phycisphaerae class could be assigned to a novel order that is represented by the proposed genus Sedimentisphaera gen. nov. comprising two novel species, S. salicampi gen. nov., sp. nov. and S. cyanobacteriorum gen. nov., sp. nov. PMID- 29697185 TI - Cardiac performance is influenced by rotational changes of position in the transversal plane, both in the horizontal and in the 60 head-up postures. AB - BACKGROUND: Echocardiography is usually performed with the subject/patient lying in the left lateral position (LLP), because the acoustic window is better in this than in the supine position (SP). The aim was to investigate cardiac responses to rotational changes of position in the transversal plane, from SP to LLP while horizontal, and from leaning on the back (HUT-LB) to leaning on the left side (HUT-LL) while tilted 60 degrees head-up from the horizontal. METHODS: Healthy men (n = 12) underwent 10-min HUT provocations. Cardiac variables were measured using two-dimensional echocardiography, Doppler, tissue Doppler imaging and arterial pressures using a volume-clamp method. RESULTS: In horizontal posture, cardiac volumes were smaller in SP than in LLP: end-diastolic volume (EDV) by 14%, end-systolic volume (ESV) by 13%, stroke volume (SV) by 14%, and cardiac output (CO) by 16% (P<0.03). In addition, the mitral annular plane systolic excursion (MAPSE) was 11% smaller (P = 0.001) and the left ventricle isovolumic relaxation time (IVRT) 27% longer in SP than in LLP. The ejection fraction, heart rate, arterial pressure and pulmonary ventilation were similar in SP and LLP. During HUT, EDV, SV, CO and MAPSE were smaller, and IVRT was longer, in HUT-LB than in HUT-LL, by -19%, -20%, -17%, -18% and +35%, respectively (P<0.04). CONCLUSIONS: Cardiac performance is enhanced in LLP versus SP and in HUT-LL versus HUT-LB, which can be attributed to improved venous return, conceivably, wholly or in part, due to increased hydrostatic pressure gradients between the caval veins and the heart in the LLP and HUT-LL positions. PMID- 29697184 TI - Crizotinib induces apoptosis and gene expression changes in ALK+ anaplastic large cell lymphoma cell lines; brentuximab synergizes and doxorubicin antagonizes. AB - BACKGROUND: Anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) shows 60-70% event free survival with standard treatments. Targeted therapies are being tested for increased benefit and/or reduced toxicity, but interactions with standard agents are not well known. METHODS: We exposed four ALCL cell lines to two targeted agents, crizotinib and brentuximab vedotin, and to two standard agents, doxorubicin and vinblastine. For each agent and combination, we measured apoptosis and expression of approximately 300 previously annotated genes of interest using targeted RNA-sequencing. An aurora kinase inhibitor, alisertib, was similarly tested for gene expression effects. RESULTS: Only crizotinib, alone or in combination, showed significant effects (adjusted P < 0.05) on expression and apoptosis. One hundred and nine of 277 gene expressions showed crizotinib-associated differential expression, mostly downregulation, 62 associated with apoptosis, and 28 associated with both crizotinib and apoptosis. Doxorubicin was antagonistic with crizotinib on gene expression and apoptosis. Brentuximab was synergistic with crizotinib in apoptosis, and not antagonistic in gene expression. Vinblastine also appeared synergistic with crizotinib but did not achieve statistical significance. Alisertib did not show significant expression changes. CONCLUSIONS: Our data suggest that crizotinib induces apoptosis through orderly changes in cell signaling associated with ALK inhibition. Expression effects of crizotinib and associated apoptosis are antagonized by doxorubicin, but apoptosis is synergized by brentuximab vedotin and possibly vinblastine. These findings suggest that concurrent use of crizotinib and doxorubicin may be counterproductive, while the pairing of crizotinib with brentuximab (or vinblastine) may increase efficacy. Alisertib did not induce expression changes at cytotoxic dosage. PMID- 29697186 TI - Respite care services for children with special healthcare needs: Parental perceptions. AB - PURPOSE: Parents of children with special healthcare needs may become overwhelmed with the ongoing caregiving needs of their children. Caring for a child with special healthcare needs is often challenging, requiring specialized training in many cases. As a result, parents can struggle to find qualified caregivers capable of providing them a break from the 24/7 care of their child. Respite care programs are designed to provide caregivers with a much-needed temporary break. The purpose of this study was to examine parental perceptions of utilizing a respite care program. DESIGN AND METHODS: Twenty-two parents who had a child with special healthcare needs who attended a Midwestern respite care program completed a Participant Characteristic Form addressing their experiences caring for their child with special healthcare needs and using respite care services. Parents participated in a focus group (N = 4) to explore their perceptions and experiences of respite care participation. Multistage thematic analysis and descriptive statistics were used to analyze the data. RESULTS: Themes emerging from the data included: Constant care demands; It is just so stressful; Respite is a gift, we get a break; Respite program "fit"; and Respite is their special time too. Parents emphasized the benefits of respite care for their marital relationship, as well as the benefits to the children with special healthcare needs and their siblings. Parents also described the importance of tailoring respite care to the unique needs of their family. PRACTICE IMPLICATIONS: Nurses and other healthcare professionals play a critical role in addressing the unmet respite care needs of parents of children with special healthcare needs by identifying unmet needs and making appropriate referrals to services that will meet the unique needs of the family. Healthcare professionals can also volunteer with existing programs to help expand access to respite care services and increase the availability of adequately trained respite care providers whom parents can trust to provide for the complex healthcare needs of their children. PMID- 29697187 TI - Field-evolved resistance of pink bollworm, Pectinophora gossypiella (Saunders) (Lepidoptera: Gelechiidae), to transgenic Bacillus thuringiensis (Bt) cotton expressing crystal 1Ac (Cry1Ac) and Cry2Ab in India. AB - BACKGROUND: Pink bollworm (PBW) adaptation to transgenic Bacillus thuringiensis (Bt) cotton expressing crystal 1Ac (Cry1Ac) (Bt-I) and Cry1Ac + Cry2Ab (Bt-II) was assessed in India during 2010-2017 in 38 districts of the 10 major cotton growing states. RESULTS: PBW larval incidence on Bt cotton was nil in northern India, wherein the resistance ratios (RRs) to Cry1Ac were 26-262 and those to Cry2Ab were 1-108. In central and southern India, the annual average PBW larval recovery from Bt II cotton was high at 28.85-72.49% during 2014-2017. In central and southern India, the 50% lethal concentration (LC50 ) of Cry1Ac increased from a mean of 0.330 ug mL-1 (range 0.126-0.849 ug mL-1 ) in 2013 to a mean of 6.938 ug mL-1 (range 3.52 to 10.30 ug mL-1 ) in 2017 and the RR increased from a mean of 47.12 (range 18-121) in 2013 to a mean of 1387 (704-2060) in 2017, whereas the LC50 value for Cry2Ab increased from a mean of 0.014 ug mL-1 (range 0.004-0.094 ug mL-1 ) in 2013 to a mean of 12.51 ug mL-1 (range 3.92 to 28.10 ug mL-1 ) in 2017 and the RR increased from a mean of 5.4 (range 1-31) in 2013 to a mean of 4196 (1306-9366) in 2017. CONCLUSION: High PBW larval recovery on Bt-II in conjunction with high LC50 values for Cry1Ac and Cry2Ab in major cotton-growing districts of central and southern India provides evidence of field-evolved resistance in PBW to Bt-I and Bt-II cotton. (c) 2018 Society of Chemical Industry. PMID- 29697188 TI - Biodegradable silk catheters for the delivery of therapeutics across anatomical repair sites. AB - Biodegradable silk catheters for the delivery of therapeutics are designed with a focus on creating porous gradients that can direct the release of molecules away from the implantation site. Though suitable for a range of applications, these catheters are designed for drug delivery to transplanted adipose tissue in patients having undergone a fat grafting procedure. A common complication for fat grafts is the rapid reabsorption of large volume adipose transplants. In order to prolong volume retention, biodegradable catheters can be embedded into transplanted tissue to deliver nutrients, growth factors or therapeutics to improve adipocyte viability, proliferation, and ultimately extend volume retention. Two fabrication methods are developed: a silk gel-spinning technique, which uses a novel flash-freezing step to induce high porosity throughout the bulk of the tube, and a dip-coating process using silk protein solutions doped with a water soluble porogen. Increased porosity aids in the diffusion of drug through the silk tube in a controllable way. Additionally, we interface the porous tubes with ALZET osmotic pumps for implantation into a subcutaneous nude mouse model. The work described herein will discuss the processing parameters as well as the interfacing between pump and cargo therapeutic and the resulting release profiles. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. PMID- 29697189 TI - Barriers and facilitators to sexual and reproductive health communication between pediatric oncology clinicians and adolescent and young adult patients: The clinician perspective. AB - BACKGROUND: Sexual and reproductive health (SRH) is identified by adolescent and young adult (AYA) patients with cancer as an important but often neglected aspect of their comprehensive cancer care. The purpose of this study was to investigate the attitudes and perceptions of pediatric oncology clinicians towards discussing SRH with AYAs, and to understand perceived barriers to effective communication in current practice. PROCEDURE: Pediatric oncology clinicians (physicians, certified nurse practitioners, and physician assistants) participated in semi-structured qualitative interviews investigating attitudes about SRH communication with AYAs and barriers to such conversations. Twenty-two clinicians participated from seven institutions in the Northeastern United States. Interviews were audio-recorded, transcribed, and coded using a thematic analysis approach. RESULTS: Interviews with pediatric oncology clinicians revealed the following five primary themes: the role for pediatric oncology clinicians to discuss SRH, the focus of current SRH conversations on fertility, the meaning of "sexual health" as safe sex and contraception only, clinician-reported barriers to SRH conversations, and the need for education and support. Communication barriers included lack of knowledge/experience, lack of resources/referrals, low priority, parents/family, patient discomfort, clinician discomfort, time, and lack of rapport. Clinicians identified resource and support needs, including formal education and SRH education materials for patients and families. CONCLUSIONS: Although the study participants identified a role for pediatric oncology clinicians in SRH care for AYA patients with cancer, multiple barriers interfere with such discussions taking place on a regular basis. Future efforts must focus on resource development and provider education and training in SRH to optimize the care provided to this unique patient population. PMID- 29697190 TI - Treatment of retinoblastoma in Sub-Saharan Africa: Experience of the paediatric oncology unit at Gabriel Toure Teaching Hospital and the Institute of African Tropical Ophthalmology, Bamako, Mali. AB - BACKGROUND: Retinoblastoma (Rb) is the most common intraocular primary malignancy in children. In industrialised countries, the cure rate is about 95%. We present the results of a prospective study on the management of Rb in the paediatric oncology unit of Gabriel Toure Teaching Hospital and African Institute of Tropical Ophthalmology, from November 1, 2011 to December 31, 2015. PROCEDURE: The aims of this prospective study were to evaluate the treatment of localised Rb, ocular prosthesis after enucleation, conservative management for bilateral Rb as well as survival rates in all patients. Patients with early stage Rb at diagnosis were included. The treatment was performed according to the retinoblastoma treatment guidelines of the French-African Paediatric Oncology Group. RESULTS: Eighty-eight patients were included in the study. Sex ratio was 1:1 (M = 44, F = 44). Median age at diagnosis was 3 years (range: 2 months-5 years). Unilateral intraocular Rb was predominant (n = 50; 56.8%). Conservative treatments were performed on nine eyes in nine patients. Overall survival and event-free survival of the entire cohort at the end of 4 years were 73% (95% CI 60.8-81.2%) and 59% (95% CI 47.9-69.5%), respectively, with a median follow-up of 3.7 years (0.1-5.6 years). In conclusion, early enucleation in early stage of Rb can improve outcomes in resource-limited countries. Delayed enucleation and refusal of adherence to treatment are still major concerns and remain a barrier to improving overall patient survival. PMID- 29697192 TI - Assessment of end-of-treatment transition needs for pediatric cancer and hematopoietic stem cell transplant patients and their families. AB - BACKGROUND/OBJECTIVES: The transition off active treatment is a time of significant stress for pediatric cancer patients and families. Providing information and support at this time is among the new psychosocial standards of care in pediatric oncology. This study sought to explore patient and family needs and concerns at the end of their active cancer treatment. DESIGN/METHODS: Forty nine caregiver-child dyads completed semi-structured interviews and surveys 1-2 months before ending treatment, and again 3-7 months after treatment concluded. RESULTS: Patients and caregivers reported a moderate level of understanding of follow-up care needs, late effects, and perceived preparation. Altogether, child, adolescent, and young adult cancer patients and parents identified similar priorities for information needed during the transition off active treatment. The most essential pieces of information desired by patients and families across time points included reviews of late effects, schedules for follow-up care, health and physical restrictions, communication with the patient's primary care provider, and provision of a treatment summary. At Time 2, patients and families reported a greater retrospective desire for emotional health resources. Most patients and caregivers wanted information from a variety of sources, but the desired timing to receive this information varied and was dependent on disease group. CONCLUSIONS: There are many essential components to end-of-treatment care that are not consistently provided to pediatric cancer patients and families. Formalized programs offering education and support should be provided by multidisciplinary teams prior to the end of active treatment. PMID- 29697191 TI - Treatment of refractory germ cell tumors in children with paclitaxel, ifosfamide, and carboplatin: A report from the Children's Oncology Group AGCT0521 study. AB - BACKGROUND: Paclitaxel, ifosfamide, cisplatin (TIP) is commonly used as salvage for malignant germ cell tumors (MGCT) in adults; however, additional administration of cisplatin at a young age could cause significant short- and long-term toxicities in a group of patients with high expected salvage. Because carboplatin has been shown to be effective in pediatric MGCT with less toxicity, the TIP regimen was modified by substituting carboplatin for cisplatin. METHODS: The Children's Oncology Group conducted a phase II trial between November 2007 and June 2011 evaluating "TIC" (paclitaxel 135 mg/m2 /day Day 1, ifosfamide 1,800 mg/m2 /dose Days 1-5 and carboplatin with AUC 6.5 Day 1) in children < 21 years with relapsed MGCT. The endpoint of the trial was response after two cycles, incorporating RECIST response and marker decline. RESULTS: Twenty patients (12 male, median age 13.5 years) were enrolled. Seventeen patients had tumor markers >=10 times above normal. After two cycles, by RECIST criteria, 8 patients achieved a partial response (response rate 40%), 10 had stable disease, and 2 had progressive disease. A >= 1 log reduction was achieved in 10/17 patients (58.8%) with elevated markers. By study defined criteria, combining response by RECIST and marker decline, the response rate was 44%. CONCLUSION: TIC is active in relapsed pediatric MGCT and should be considered for salvage therapy in children. In adolescents and older adults with relapse MGCT, TIP or high-dose chemotherapy with stem cell remain the standard therapy. PMID- 29697193 TI - Solid pseudopapillary and malignant pancreatic tumors in childhood: A systematic review and evidence quality assessment. AB - A systematic review of 32 studies reporting on 489 children with pancreatic tumors was performed. The most prevalent histologic subtype was solid pseudopapillary tumor (SPT) (61.3%). Pancreaticoduodenectomy was the most commonly performed operation (48%). Neoadjuvant chemo/radiotherapy was utilized in 3.9, 36.2, 25, and 27.8% of patients with SPTs, pancreatoblastomas (PBLs), neuroendocrine tumors, and exocrine carcinomas, respectively. Adjuvant chemotherapy (75.6%) and radiation (34%) were most commonly utilized in PBLs. All cause mortality was highest in exocrine carcinomas (50%). Overall, 98.8% of patients with SPTs survived. PBL exhibited the highest recurrence rate (14.7%) within a mean of 23.5 months. PMID- 29697195 TI - Conversion of phosphatidylinositol (PI) to PI4-phosphate (PI4P) and then to PI(4,5)P2 is essential for the cytosolic Ca2+ concentration under heat stress in Ganoderma lucidum. AB - How cells drive the phospholipid signal response to heat stress (HS) to maintain cellular homeostasis is a fundamental issue in biology, but the regulatory mechanism of this fundamental process is unclear. Previous quantitative analyses of lipids showed that phosphatidylinositol (PI) accumulates after HS in Ganoderma lucidum, implying the inositol phospholipid signal may be associated with HS signal transduction. Here, we found that the PI-4-kinase and PI-4-phosphate-5 kinase activities are activated and that their lipid products PI-4-phosphate and PI-4,5-bisphosphate are increased under HS. Further experimental results showed that the cytosolic Ca2+ ([Ca2+ ]c ) and ganoderic acid (GA) contents induced by HS were decreased when cells were pretreated with Li+ , an inhibitor of inositol monophosphatase, and this decrease could be rescued by PI and PI-4-phosphate. Furthermore, inhibition of PI-4-kinases resulted in a decrease in the Ca2+ and GA contents under HS that could be rescued by PI-4-phosphate but not PI. However, the decrease in the Ca2+ and GA contents by silencing of PI-4-phosphate-5-kinase could not be rescued by PI-4-phosphate. Taken together, our study reveals the essential role of the step converting PI to PI-4-phosphate and then to PI-4,5 bisphosphate in [Ca2+ ]c signalling and GA biosynthesis under HS. PMID- 29697196 TI - Abstractband anlabetalich der 26. Jahrestagung der Arbeitsgemeinschaft Dermatologische Histologie (ADH) 11.-13. Mai 2018 in Mannheim, Germany. PMID- 29697194 TI - Substrate scope of a dehydrogenase from Sphingomonas species A1 and its potential application in the synthesis of rare sugars and sugar derivatives. AB - Rare sugars and sugar derivatives that can be obtained from abundant sugars are of great interest to biochemical and pharmaceutical research. Here, we describe the substrate scope of a short-chain dehydrogenase/reductase from Sphingomonas species A1 (SpsADH) in the oxidation of aldonates and polyols. The resulting products are rare uronic acids and rare sugars respectively. We provide insight into the substrate recognition of SpsADH using kinetic analyses, which show that the configuration of the hydroxyl groups adjacent to the oxidized carbon is crucial for substrate recognition. Furthermore, the specificity is demonstrated by the oxidation of d-sorbitol leading to l-gulose as sole product instead of a mixture of d-glucose and l-gulose. Finally, we applied the enzyme to the synthesis of l-gulose from d-sorbitol in an in vitro system using a NADH oxidase for cofactor recycling. This study shows the usefulness of exploring the substrate scope of enzymes to find new enzymatic reaction pathways from renewable resources to value-added compounds. PMID- 29697197 TI - Characterization of a feruloyl esterase from Aspergillus terreus facilitates the division of fungal enzymes from Carbohydrate Esterase family 1 of the carbohydrate-active enzymes (CAZy) database. AB - Feruloyl esterases (FAEs) are accessory enzymes for plant biomass degradation, which catalyse hydrolysis of carboxylic ester linkages between hydroxycinnamic acids and plant cell-wall carbohydrates. They are a diverse group of enzymes evolved from, e.g. acetyl xylan esterases (AXEs), lipases and tannases, thus complicating their classification and prediction of function by sequence similarity. Recently, an increasing number of fungal FAEs have been biochemically characterized, owing to their potential in various biotechnological applications and multitude of candidate FAEs in fungal genomes. However, only part of the fungal FAEs are included in Carbohydrate Esterase family 1 (CE1) of the carbohydrate-active enzymes (CAZy) database. In this work, we performed a phylogenetic analysis that divided the fungal members of CE1 into five subfamilies of which three contained characterized enzymes with conserved activities. Conservation within one of the subfamilies was confirmed by characterization of an additional CE1 enzyme from Aspergillus terreus. Recombinant A. terreus FaeD (AtFaeD) showed broad specificity towards synthetic methyl and ethyl esters, and released ferulic acid from plant biomass substrates, demonstrating its true FAE activity and interesting features as potential biocatalyst. The subfamily division of the fungal CE1 members enables more efficient selection of candidate enzymes for biotechnological processes. PMID- 29697198 TI - Pathophysiology-based phenotyping in type 2 diabetes: A clinical classification tool. AB - BACKGROUND: Type 2 diabetes may be a more heterogeneous disease than previously thought. Better understanding of pathophysiological subphenotypes could lead to more individualized diabetes treatment. We examined the characteristics of different phenotypes among 5813 Danish patients with new clinically diagnosed type 2 diabetes. METHODS: We first identified all patients with rare subtypes of diabetes, latent autoimmune diabetes of adults (LADA), secondary diabetes, or glucocorticoid-associated diabetes. We then used the homeostatic assessment model to subphenotype all remaining patients into insulinopenic (high insulin sensitivity and low beta cell function), classical (low insulin sensitivity and low beta cell function), or hyperinsulinemic (low insulin sensitivity and high beta cell function) type 2 diabetes. RESULTS: Among 5813 patients diagnosed with incident type 2 diabetes in the community clinical setting, 0.4% had rare subtypes of diabetes, 2.8% had LADA, 0.7% had secondary diabetes, 2.4% had glucocorticoid-associated diabetes, and 93.7% had WHO-defined type 2 diabetes. In the latter group, 9.7% had insulinopenic, 63.1% had classical, and 27.2% had hyperinsulinemic type 2 diabetes. Classical patients were obese (median waist 105 cm), and 20.5% had cardiovascular disease (CVD) at diagnosis, while insulinopenic patients were fairly lean (waist 92 cm) and 17.5% had CVD (P = 0.14 vs classical diabetes). Hyperinsulinemic patients were severely obese (waist 112 cm), and 25.5% had CVD (P < 0.0001 vs classical diabetes). CONCLUSIONS: Patients clinically diagnosed with type 2 diabetes are a heterogeneous group. In the future, targeted treatment based on pathophysiological characteristics rather than the current "one size fits all" approach may improve patient prognosis. PMID- 29697200 TI - Global Standards to Expedite Learning From Medical Research Data. PMID- 29697199 TI - Treatments and Preventative Measures for Trauma-Induced Heterotopic Ossification: A Review. PMID- 29697201 TI - Mir-1307 regulates cisplatin resistance by targeting Mdm4 in breast cancer expressing wild type P53. AB - BACKGROUND: Many chemotherapy regimens are used to treat breast cancer; however, breast cancer cells often develop drug resistance that usually leads to relapse and poor prognosis. MicroRNAs (miRNAs) are short non-coding RNA molecules that post-transcriptionally regulate gene expression and play crucial roles in diverse biological processes, such as development, differentiation, apoptosis, and proliferation. We investigated the roles of miRNAs in the development of drug resistance in human breast cancer cells. METHODS: MiRNA expression was detected in human breast cancer cell lines MCF-7 and MDA-MB-468 via real time PCR; 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide, cell viability, colony formation, and luciferase reporter gene assays; Western blot; and immunohistochemistry. RESULTS: MiR-1307 was downregulated while MDM4 was upregulated in MCF-7/cisplatin (CDDP) and MDA-MB-468/CDDP cells compared with parental MCF-7 and MDA-MB-468 cells. in vitro drug sensitivity assay demonstrated that overexpression of miR-1307 sensitized MCF-7/CDDP cells to CDDP. Luciferase activity assay with a reporter containing sequences from the 3' untranslated region of Mdm4 in MCF-7/CDDP cells suggested that Mdm4 was the direct target gene of miR-1307. Ectopic miR-1307 expression reduced the MDM4 protein level and sensitized MCF-7/CDDP cells to CDDP-induced apoptosis. CONCLUSION: Our findings suggest, for the first time, that miR-1307 could play a role in the development of CDDP resistance in breast cancer, at least in part by modulating apoptosis by targeting Mdm4. PMID- 29697203 TI - Guanidine-sensing riboswitches: How do they work and what do they regulate? AB - After remaining an orphan for over a decade, the ykkC riboswitch family (ykkC, mini-ykkC, and ykkC-III) was recently characterized as guanidine-specific genetic regulatory elements (guanidine-I, II, and III). They respond to increased levels of intracellular guanidine by turning on genes involved in guanidine export and breakdown. Their existence suggests that regulation of intracellular guanidine levels could be an important piece of bacterial physiology which was not appreciated previously. Structural biologists moved exceptionally fast to reveal the guanidine-sensing mechanisms of these riboswitches at the atomic level. The crystal structures of all three guanidine family members have been determined. They appear to represent three independently evolved RNA sensors, with distinct tertiary folds but surprisingly similar guanidine-binding cores. A few key questions remain to be addressed: It is not known which metabolic pathway(s) may lead to guanidine accumulation and the function of close relatives to the guanidine-I riboswitch that do not respond to guanidine remains unclear. The continued characterization of these and other orphan cis-regulatory elements represents an orthogonal approach to reveal new facets of bacterial physiology. This article is categorized under: Regulatory RNAs/RNAi/Riboswitches > Riboswitches RNA Structure and Dynamics > RNA Structure, Dynamics, and Chemistry. PMID- 29697202 TI - Increased Soluble CD137 Levels and CD4+ T-Cell-Associated Expression of CD137 in Acute Atherothrombotic Stroke. AB - As a proinflammatory cytokine, CD137 (4-1BB, TNFRSF9) is present in membrane bound and soluble forms. Increased expression of CD137 was recently found in T cells in human atherosclerotic plaques. However, the exact role of CD137 in ischemic stroke is not clear. In this study we analyzed the protein levels of soluble CD137 (sCD137) and the expression of CD137 on CD4+ T cells in the peripheral blood of patients with acute atherothrombotic stroke by using the cytometry beads array (CBA) and flow cytometry. Within 24 hours of onset, the stroke patients showed elevated levels of sCD137 (2.7 pg/ml) and CD137 expression on CD4+ T cells (4.9 +/- 3.2%) compared with normal controls (1.1 pg/ml, P < 0.01; 1.3 +/- 1.0%, P < 0.01). Alterations in CD137 expression may enhance ischemia-induced inflammatory responses via bidirectional signaling and, consequently, aggravate brain injury in early stages of this disorder. PMID- 29697204 TI - Image-based management of empiric lung stereotactic body radiotherapy (SBRT) without biopsy: Predictors from a 10-year single institution experience. AB - BACKGROUND: There is emerging reliance on clinical imaging for the diagnosis, prognosis, and treatment evaluation of early stage non-small cell lung cancer (NSCLC) in patients deemed too high risk for biopsy. We report our experience of clinically diagnosed NSCLC treated empirically with stereotactic body radiotherapy (SBRT) to validate the imaging parameters used for management in this high-risk population. METHODS: We reviewed 101 empiric lung SBRT cases and profiled imaging specifics of computed tomography and positron emission tomography for diagnosis and follow-up. Secondarily, we identified potential correlates of disease progression with Cox regression multivariate analysis. RESULTS: Fifty-seven men and 43 women aged 45-94 (median 76) were treated with a median dose of 48 Gy in four fractions. The median nodule diameter was 1.6 cm (0.6-4.5 cm) and most were spiculated (n = 58), right-sided (n = 63), and in the upper lobe (n = 68). Median follow-up and survival rates were 14 and 28 months, respectively. Local control at three years was 94%. Freedom from any progression at one and three years was 85% and 69%, respectively. Toxicity >= grade 3 included two grade 3 dyspneas. A pre-treatment standard uptake value > 4.1 was the only significant predictor of disease progression. CONCLUSION: This study illustrates the instrumental role of modern clinical imaging for the effective management of presumed early stage NSCLC treated with empiric lung SBRT. As lung SBRT without tissue confirmation becomes more common, hopefully these assertions can be prospectively validated. PMID- 29697205 TI - Divergent Functionalization of N-Alkyl-2-alkenylanilines: Efficient Synthesis of Substituted Indoles and Quinolines. AB - An efficient divergent functionalization of N-alkylated ortho-alkenylanilines to substituted indoles and quinolines has been accomplished by employing rhodium catalyzed cross-dehydrogenative coupling and silver-mediated oxidative cyclization, respectively. The developed methods tolerate various functional groups and allow the synthesis of substituted indoles and quinolines in good to excellent yield. Synthetic utility is demonstrated through conversion to an indole with antimicrobial activity and C-H bond functionalization of 2 arylquinolines. Furthermore, a plausible mechanism was proposed based on preliminary mechanistic investigations. PMID- 29697206 TI - Subtyping of Magnetically Isolated Breast Cancer Cells Using Magnetic Force Microscopy. AB - Circulating tumor cell (CTC) which recently arisen as potential sources for monitoring and characterizing non-haematologic cancers and their metastatic derivatives. Immunomagnetic microbeads and magnetic nanoparticles (MNPs) have been extensively explored to isolate CTCs from blood samples. However, MNPs attached on the membrane protein are interrupted further analysis to distinguish the cancer subtype by consumption or blocking the target surface marker. Here, an MNP-mediated analysis method for surface marker expression profile by magnetic force microscopy (MFM) is described. Two MNPs, zinc ferrite and iron oxide, are showed distinct phase shift (-16.5 degrees and -3.7 degrees , respectively) signal on the MFM images. The antibody conjugated MNPs are successfully isolated target cells without giving damage to the cell. The MFM image of MNP decorated cells show clear differences between two breast cancer cell lines, MCF-7 and SK BR-3, which proof the cancer subtyping property using MFM method. To confirmation of the surface marker consumption during the cell isolation, antibody-conjugated quantum dots and drug-loaded oleosome are treated on the cells, thereby MNP decorated cells are survived. This newly developed MFM analysis method provides a new direction to utilize the MNP for the surface marker expression phenotypes. PMID- 29697207 TI - Self-descriptions on LinkedIn: Recruitment or friendship identity? AB - We used quantitative semantics to find clusters of words in LinkedIn users' self descriptions to an employer or a friend. Some of these clusters discriminated between worker and friend conditions (e.g., flexible vs. caring) and between LinkedIn users with high and low education (e.g., analytical vs. messy). PMID- 29697209 TI - Efficacy and safety of mirabegron, a beta3 -adrenoceptor agonist, in patients with detrusor hyperactivity and impaired contractility. AB - OBJECTIVE: We examined the efficacy and safety of mirabegron in elderly patients with urodynamic detrusor hyperactivity with impaired contractility (DHIC). METHODS: Patients diagnosed with DHIC received daily dose of mirabegron (25mg). Subjective symptom scores, uroflowmetry data, and adverse events (AEs) were recorded for all patients at baseline and after 1, 3, and 6 months treatment. Comparisons were made for each patient individually and between patients with detrusor overactivity (DO). RESULTS: Of the 65 patients enrolled in the study, 25 had DHIC and 40 had DO (mean [+/- SD] age 79.3 +/- 9.6 and 75.6 +/- 10.7 years, respectively). At the 6-month follow-up, significant (P < .05) improvement was seen compared with baseline in both the DHIC and DO groups in terms of OAB symptom scores (4.72 +/- 3.05 vs. 6.88 +/- 4.06 and 4.50 +/- 2.99 vs. 6.70 +/- 3.60, respectively), urgency severity score (1.90 +/- 2.00 vs. 3.35 +/- 1.13 and 1.58 +/- 1.93 vs. 3.00 +/- 1.65, respectively), and global response assessment (1.80 +/- 1.41 and 1.73 +/- 1.34, respectively). In the DHIC group, post-void residual (PVR) volume decreased from 153 +/- 52.7 mL at baseline to 85.8 +/- 90.1 mL at 6th month (P < .05) and voiding efficiency improved from 40.0 +/- 20.7% to 62.6 +/- 28.3% (P < .05). Common AEs included dry mouth and dizziness, yet 16% of DHIC patients developed PVR >180 mL. CONCLUSION: Mirabegron was an effective treatment option in elderly patients with urodynamic DO and DHIC in the present study. The AEs reported were mild and infrequent. PMID- 29697210 TI - Recombinant AroL-Catalyzed Phosphorylation for the Efficient Synthesis of Shikimic Acid 3-Phosphate. AB - Shikimic acid 3-phosphate, as a central metabolite of the shikimate pathway, is of high interest as enzyme substrate for 5-enolpyruvoyl-shikimate 3-phosphate synthase, a drug target in infectious diseases and a prime enzyme target for the herbicide glyphosate. As the important substrate shikimic acid 3-phosphate is only accessible via a chemical multi-step route, a new straightforward preparative one-step enzymatic phosphorylation of shikimate using a stable recombinant shikimate kinase has been developed for the selective phosphorylation of shikimate in the 3-position. Highly active shikimate kinase is produced by straightforward expression of a synthetic aroL gene in Escherichia coli. The time course of the shikimate kinase-catalyzed phosphorylation is investigated by 1 H- and 31 P-NMR, using the phosphoenolpyruvate/pyruvate kinase system for the regeneration of the ATP cofactor. This enables the development of a quantitative biocatalytic 3-phosphorylation of shikimic acid. After a standard workup procedure, a good yield of shikimic acid 3-phosphate, with high HPLC- and NMR purity, is obtained. This efficient biocatalytic synthesis of shikimic acid 3 phosphate is superior to any other method and has been successfully scaled up to multi-gram scale. PMID- 29697211 TI - Molecular Profiling and Clonal Tracking of Secreted Rheumatoid Factors in Primary Sjogren's Syndrome. AB - OBJECTIVE: Rheumatoid factors (RFs) are associated with systemic disease in primary Sjogren's syndrome (SS) and may be pathogenic as mixed cryoglobulins. Current detection methods cannot resolve RFs at a molecular level. This study was undertaken to perform the first proteomic and transcriptomic analysis of secreted and membrane-bound IgM-RF in primary SS and identify unique heavy-chain peptide signatures for RF clonotype tracking. METHODS: Purified heavy chains of serum RFs from 15 patients with primary SS were subjected to de novo mass spectrometric sequencing. The circulating B cell Ig repertoire was determined by massively parallel sequencing of IGH RNA from matched peripheral blood mononuclear cells (n = 7). RF-specific heavy-chain third complementarity-determining region (CDR3) peptides were identified by searching RF heavy-chain peptide sequences against the corresponding IGH RNA sequence libraries. Heavy-chain CDR3 peptides were used as biomarkers to track serum RF clonotypes using quantitative multiple reaction monitoring. RESULTS: Serum RFs were clonally restricted and composed of shared sets of IgM heavy-chain variable region (Ig VH ) 1-69, 3-15, 3-7, and 3-74 subfamilies. Cryoprecipitable RFs from patients with mixed cryoglobulinemia (MC) were distinguishable from nonprecipitating RFs by a higher frequency of amino acid substitutions and identification of stereotypic heavy-chain CDR3 transcripts. Potentially pathogenic RF clonotypes were detected in serum by multiple reaction monitoring years before patients presented with MC. Levels of Ig VH 4-34 IgM-RF decreased following immunosuppression and remission of MC. CONCLUSION: Cryoprecipitable RF clonotypes linked to vasculitis in primary SS have different molecular profiles than nonprecipitating RFs, suggesting different underlying mechanisms of production. The combined omics workflow presented herein provides molecular biomarkers for tracking and removal of pathogenic RF clones. PMID- 29697212 TI - Adaptation and validation of a nepali version of the Child-Oral Impacts on Daily Performances Index (C-OIDP). AB - : The need for culturally validated measures of Oral Health-Related Quality of Life (OHRQoL) has been increasing in recent years. OBJECTIVES: To adapt the Child Oral Impacts on Daily Performances (C-OIDP) index into the Nepali language and to validate it, to assess and compare the outcomes of self-reported oral problems, and to validate a structured questionnaire on general hygiene practices, oral hygiene practices, dietary habits, and use of tobacco. BASIC RESEARCH DESIGN: A school-based cross-sectional study on pilot and national samples. PARTICIPANTS: Nepalese schoolchildren representing WHO index age groups (5-6-year-olds, 12-year olds, and 15-year-olds). The study was conducted on a pilot sample (n=128) selected conveniently and a national sample (n=1,052), selected from 18 sampling sites on the basis of the stratified random sampling method. MAIN OUTCOME MEASURES: Adapted and validated Nepali C-OIDP Results: The Nepali C-OIDP showed excellent validation and reliability tests in both studies. The Cronbach's alpha coefficients were 0.82 and 0.71 respectively in the pilot and national study. The most common self-reported oral problem was toothache, which was statistically significantly higher in the national sample. CONCLUSIONS: The Nepali C-OIDP index is valid and reliable for measuring oral impacts on daily performance among schoolchildren of Nepal. PMID- 29697213 TI - Diagnosis and management of patients with atrial fibrillation. AB - Atrial fibrillation is a common cardiac arrhythmia and is the most frequent arrhythmia experienced by older people. It is caused by chaotic electrical activity in the atria, leading to an irregular and often rapid heart rate. Atrial fibrillation is associated with an increased risk of ischaemic stroke, resulting from the turbulent blood flow in the atria. This article details the presentation of, and risk factors associated with, developing atrial fibrillation, the importance of reducing the risk of adverse events such as stroke, and the treatment options available. It also outlines the nursing role in the care of patients with the condition, as part of a multidisciplinary team approach. PMID- 29697214 TI - Sickle cell anaemia and the experiences of young people living with the condition. AB - Sickle cell anaemia (SCA) is a life-threatening haemoglobin disorder acknowledged for its unpredictability and painful episodes. The aim of this qualitative literature review was to explore the experiences of young people living with SCA and its effect on their lives. The objective was to critically review selected primary research and make recommendations for practice, education and research. After reviewing potential articles using EBSCOhost, inclusion and exclusion criteria were devised and six appropriate studies were found with most participants in the 10-25 years age range. These studies were conducted in the UK and the United States. The Critical Appraisal Skills Programme qualitative research checklist was used to evaluate the articles. Thematic analysis identified three themes: acceptance, support and unpredictability, with sub themes of spirituality and discrimination. It was clear that SCA affected multiple areas of young people's lives. Recommendations are made for practice, education and research. PMID- 29697215 TI - Variability of activity profile during medium-sided games in professional soccer. AB - BACKGROUND: In Southern European countries it is very frequent to perform medium sized games (MSG) as last training drill. We analyzed the individual variability and changes in activity patterns during MSG throughout the preseason. METHODS: Activity profile during MSGs (10v10+goalkeepers, duration: 10-min, field length: 50 m, width: 90 m, area per player: 204.5 m2) was quantified using a GPS in 14 professional male players (6 defenders, 5 midfielders 5 and attackers). RESULTS: Inter-individual variability was higher for high-intensity (HIR), very-high speed (VHS), maximum acceleration (Accmax) and maximum deceleration (Decmax) distance (CV=25.2 to 43.3%), compared to total distance (TD), total acceleration (Acctot) and total deceleration (Dectot) distance (CV= 8.3 to 18.3 %). Defenders showed higher variability in TD, HIR, VHS, Acctot and Dectot (ES= 1.30 to 11.28) compared to the other field positions, whereas attackers showed higher variability in HIR, VHS Accmax and Decmax (ES=-4.92 to 2.07) than other the field positions. Variability in TD regularly increased (ES= -2.13 to -0.91) towards the end of the preseason, while HIR and VHS variability tended to increase over the 3rd and the 4th preseason week (ES=-0.94 to -3.05). However, the behavior of variability across the preseason period was more unpredictable for Acctot and Dectot, both decreasing in the 3rd week (ES= 0.70 to 1.20), while Decmax increased in the 4th week (ES=-0.91+/-0.59). CONCLUSIONS: During MSGs, individual variability of activity differs among field positions, and tends to increase with either speed or acceleration intensity, underlining the need of an individualized approach for training load monitoring. PMID- 29697216 TI - Chronic kidney disease AB - Chronic kidney disease has become very important issue in recent years due, among other factors, to its increasing frequency and the high costs that it generates because it is increasingly seen as a major public health problem associated with premature mortality with important social and economic implications. All this has made advisable not only its diagnosis and early detection, but also increase its degree of knowledge and coordination between different levels of care. PMID- 29697217 TI - Blood-brain barrier transport kinetics of NOTA-modified proteins: the somatropin case. AB - BACKGROUND: Chemical modifications such as PEG, polyamine and radio labeling on proteins can alter their pharmacokinetic behaviour and their blood-brain barrier (BBB) transport characteristics. NOTA, i.e. 1,4,7-triazacyclononane-1,4,7 triacetic acid, is a bifunctional chelating agent that has attracted the interest of the scientific community for its high complexation constant with metals like gallium. Until now, the comparative BBB transport characteristics of NOTA modified proteins versus unmodified proteins are not yet described. METHODS: Somatropin (i.e. recombinant human growth hormone), NOTA-conjugated somatropin and gallium-labelled NOTA-conjugated somatropin were investigated for their brain penetration characteristics (multiple time regression and capillary depletion) in an in vivo mice model to determine the blood-brain transfer properties. RESULTS: The three compounds showed comparable initial brain influx, with Kin = 0.38 +/- 0.14 MUL/(g*min), 0.36 +/- 0.16 MUL/(g*min) and 0.28 +/- 0.18 MUL/(g*min), respectively. Capillary depletion indicated that more than 80% of the influxed compounds reached the brain parenchyma. All three compounds were in vivo stable in serum and brain during the time frame of the experiments. CONCLUSIONS: Our results show that modification of NOTA as well as gallium chelation onto proteins, in casu somatropin, does not lead to a significantly changed pharmacokinetic profile at the blood-brain barrier. PMID- 29697218 TI - Total FDG lesion number on PET/CT predicts survival of esophageal carcinoma patients with recurrence following curative surgery. AB - BACKGROUND: Total lesion number is a prognostic determinant in recurrent esophageal cancer, but this requires multiple tests. Here, we investigated the prognostic value of total FDG lesion number obtained from a single PET/CT study. METHODS: Subjects were 153 esophageal squamous cell carcinoma patients with loco regional or distant recurrence following curative surgery. FDG PET/CT performed within 30 days was inspected for abnormal FDG uptake lesions using a SUVmax of 3.0 as threshold for significance. Prognostic associations were assessed by Cox proportional hazards regression and Kaplan-Meier analysis. RESULTS: PET/CT showed significant local FDG lesions in 49.0%, regional lesions in 78.4%, and distant lesions in 44.4% of patients. Among 73 patients with loco-regional recurrence, 54 had 0-3 and 19 had >=4 FDG lesions. Among 80 patients with distant recurrence, 31 had 0-3 and 49 had >=4 FDG lesions. During a median follow-up of 11.8 mo, 99 deaths occurred. Univariate variables associated with poor survival included >=4 FDG lesions and no treatment for loco-regional recurrence and no treatment for distant recurrence. Kaplan Meier analysis showed worse survival for >=4 than 0-3 FDG lesions in patients with loco-regional recurrence (15.6 vs. 32.1 mo; P = 0.009), but not in those with distant recurrence. Significant independent predictors of poor survival were >=4 FDG lesions and no treatment for loco regional recurrence and no treatment for distant recurrence. CONCLUSIONS: Total FDG lesion number assessed by PET/CT is a significant independent prognostic factor in esophageal cancer patients with loco-regional recurrence following curative surgery. PMID- 29697219 TI - 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography in primary extranodal lymphomas: treatment response evaluation and prognosis. AB - BACKGROUND: We evaluated the role of [18F]FDG PET/CT in tumor response assessment and prognosis of Primary Extranodal Lymphoma (PEL) patients. METHODS: We examined retrospectively, 56 PEL patients: 31 with aggressive diffuse large B cell lymphoma (DLBCL) and 25 with indolent lymphoma (20 mucosa-associated lymphoid tissue lymphoma-MALT and 5 follicular lymphoma). All patients had undergone [18F]FDG PET/CT at diagnosis (PET-I) and 50 of them also after therapy (PET-II). Moreover, 52 patients were subjected to a mean follow-up period of 76 months. RESULTS: PET-I was positive in 50 (89%) patients (mean SUVmax 10.3+/-6.7). In the assessment of tumor response, according to Lugano classification, 45 patients showed complete metabolic response (CMR), 4 patients had partial metabolic response (PMR) and 1 had progressive metabolic disease (PMD). Based on 66% DeltaSUVmax cut-off, among CMR patients, 41 showed a DeltaSUVmax>66% whereas among nonresponders, 4 patients showed a DeltaSUVmax<66%. At follow-up, univariate analysis showed that age, performance status, prognostic index, DeltaSUVmax and Lugano classification predicted Progression Free Survival (PFS) (p<0.05), while, performance status, prognostic index, DeltaSUVmax and Lugano classification predicted Overall Survival (OS) (p<0.05). At multivariate analysis only Lugano classification was retained in the model for prediction of both PFS (p<0.05) and OS (p<0.05). By Kaplan-Meier analysis and log- rank testing both PFS and OS were significantly better in patients in CMR as compared to patients in PMR or PMD according to Lugano classification (p<0.01). CONCLUSIONS: [18F]FDG PET/CT represents a useful tool in the detection of disease response and in the evaluation of outcome in PEL patients. PMID- 29697220 TI - Emerging topics and practical aspects for an appropriate use of amyloid PET in the current italian context. AB - In May, 2017 some representatives of the Italian nuclear medicine and neurological communities spontaneously met to discuss the issues emerged during the first two years of routine application of amyloid PET with fluorinated radiopharmaceuticals in the real world. The limitations of a binary classification of scans, the possibility to obtain early images as a surrogate marker of regional cerebral bloos flow, the need for (semi-)quantification and, thus, the opportunity of ranking brain amyloidosis, the correlation with Abeta42 levels in the cerebrospinal fluid, the occurrence and biological meaning of uncertain/boderline scans, the issue of incidental amyloidosis, the technical pittfalls leading to false negative/positive results, the position of the tool in the diagnostic flow- chart in the national reality, are the main topics that have been discussed. Also, a card to justify the examination to be filled by the dementia specialist and a card for the nuclear medicine physician to report the exam in detail have been approved and are available in the web, which should facilitate the creation of a national register, as previewed by the 2015 intersocietal recommendation on the use of amyloid PET in Italy. The content of this discussion could stimulate both public institutions and companies to support further research on these topics. PMID- 29697221 TI - Global burden of disease of chronic kidney disease in Mexico AB - The Global Burden of Disease (GBD) is a methodology that evaluates risks to the population risks when confronted with a disease or injury, such as the entirety of the effects of mortality and disability that these represent for health systems. The chronic kidney disease (CKD) is an entity with high mortality, high disability, and high health-intervention costs. The review of the data generated by the Institute for Health Metrics and Evaluation (IHME), the headquarters of the GBD Study Group, show that at worldwide level, CKD-associated mortality has increased 108% since 1990 to 2015. The main cause that generates death by CKD in Mexico is diabetes mellitus, whose impact on mortality has progressed, being found in 19th place for diabetic nephropathy in 1990 to the 3rd cause of death in 2015, representing a 670% increase. Ages with greatest mortality are situated between 45 and 75 years, generating a greater impact on disability-adjusted death in women. Mexico City has the greatest CKD-related mortality and a greatest number of DALY (Disability-Adjusted Life Years): 1,559.71 per 100 000 inhabitants. The Mexican state with the lower number of deaths is Baja California, and Quintana Roo is the state with the lower number of DALY (766.32 per 100 000 inhabitants). PMID- 29697222 TI - Economic impact of the chronic kidney disease: Perspective of the Instituto Mexicano del Seguro Social AB - In Mexico, as in other parts of the world, end-stage renal disease (ESRD) constitutes a public health problem associated with high morbidity, mortality, costs and a diminished quality of life. The Instituto Mexicano del Seguro Social (IMSS) attends to, approximately, 73% of the Mexican population requiring dialysis or transplant. In 2014, the treatment of ESRD represented 15% of the total annual expenditure of IMSS major program (Disease and Maternity Security), i.e. approximately $13 250 million Mexican pesos (MP); this expense was invested in only 0.8% of patients (those with ERSD). There are few economic evaluation studies showing the real cost of kidney replacement therapies from institution's perspective. In order to reduce the global cost of ESRD, it is necessary to implement appropriate strategies of prevention, diagnosis and treatment to reduce incidence and progression of chronic kidney disease; to intensify research studies for a better understanding of etiological factors, mechanism of kidney damage progression and identification of new therapeutic agents; to create a national kidney disease registry, and to incorporate the economic evaluation methodology in the decision-making, in order to identify improved cost-benefit or cost-effective strategies. PMID- 29697223 TI - Model of chronic kidney disease care in primary health care AB - Multidisciplinary attention models include the joined and coordinated participation of different professionals within the health team (physicians, nurses, social workers, dietitians, physical trainers, among others). A multidisciplinary approach facilitates and improves management of patients from early chronic kidney disease (CKD) in the primary health-care setting. This approach is a strategy for improving comprehensive care, initiating and maintaining healthy behaviors, promoting teamwork, eliminating barriers to achieve goals and improving the processes of care. A multidisciplinary intervention may include educational processes guided by health professional, use of self-help groups and the development of a CKD management plan. The complex and fragmented care management of patients with CKD, associated with poor outcome, enhances the importance of implementing a multidisciplinary approach in the management of this disease from the early stages. Multidisciplinary strategies should focus on the needs of patients and should be adapted to the resources and health systems; its systematic implementation can help to improve patient care and prevent/slow the progression of CKD. PMID- 29697235 TI - Biomarkers in Chronic Kidney Disease AB - Chronic kidney disease (CKD) is an important public health problem. The classification of CKD by KDOQI and KDIGO and routine reports of the estimation of the glomerular filtration rate (eGFR), have resulted in a higher frequency in the diagnosis of CKD. Identification of CKD subjects and high risk of disease progression and cardiovascular disease (CVD) development is important. In clinical practice, proteinuria is the most sensitive marker of the progression of CKD, especially when combined with eGFR, but these have limitations. Therefore, the use of other early and sensitive biomarkers is required. Promising biomarkers are now being identified for the detection of CKD progression and its associated CVD morbidity and mortality. These are sensitive biomarkers of renal function, underlying pathophysiological processes and/or cardiovascular risk. PMID- 29697236 TI - Diagnosis and clinical implications of vascular calcification of chronic kidney disease in Mexico AB - Vascular calcification (VC), it is a clinical condition highly associated to Chronic Kidney Disease (CKD), CKD patients had as a primary death cause, the cardiovascular disease (CVD), among many non-traditional factors for CKD appears VC. The pathogenesis of VC it's multifactorial and it's in short terms a change of muscle vessels cells to a bone cell; this transformation it's close related to Chronic Kidney Disease-Bone Metabolism Disorder (CKD-BMD), Vitamin D, phosphorus, calcium and parathyroid hormone are close related to VC. The diagnosis of VC can be done by different methods from Electron Beam Computed Tomography to plain X ray studies; there are many scores base on plain X ray studies that can predict mortality in patients with VC. In our setting there is scarce information regarding VC in dialysis patients, the available information show a higher frequency (~50%) and severe; predictors to the VC in our setting are: age, serum HDL and alkaline phosphatase. It is necessary in the primary care setting the evaluation of VC in order to prevent it appearing. There is not an effective treatment to VC so it's necessary search for strategies to prevent it. PMID- 29697237 TI - BNP predicts mortality of cardiovascular disease in patients with end-stage renal disease treated AB - BACKGROUND: Mortality for cardiovascular disease (CVD) in patients with chronic kidney disease (CKD) is higher. In the end-stage renal disease (ESRD) the mortality is 20 times greater in comparison with general population. Natriuretic peptides, particularly type-B natriuretic peptide (BNP) have been studied as potential markers of risk of cardiovascular (CV) mortality. The aim of this paper is to determine whether BNP acts as a prognostic marker for CV mortality in patients with ESRD. METHODS: We studied 53 patients with ESRD prevalent in peritoneal dialysis without clinical evidence of heart failure at baseline was studied. The impact of variables was performed with linear regression model. The probability of survival was estimated by Kaplan-Meir analysis and the difference between survivals between groups with log-rank test according the levels of BNP. Adjusted hazard ratios were calculated with Cox proportional hazards analysis. RESULTS: BNP strongly predicts CVD mortality. The Cox regression model showed that BNP is a predictor of death from CVD. Patients with high levels of BNP were at increased risk of death. Several pathophysiological mechanisms not well defined are involved. CONCLUSIONS: BNP predicts CVD mortality in patients with ESRD. Serum measurement of this peptide can be useful for risk stratification in these patients and adjust treatment. PMID- 29697238 TI - Multidisciplinary strategies to promote self-care in patients with early nephropathy AB - In Mexico, there is a high prevalence of early nephropathy that usually goes unnoticed and may in part be due to the acquisition of "moderns" negative habits a lifestyle from an early age like physical inactivity, unhealthy diet, smoking and alcohol intake abuse associated with the increasing prevalence of overweight and obesity, diabetes and hypertension, leading causes of chronic kidney disease (CKD) in Mexico. These behaviors are difficult to control by medical intervention alone and may be associated with lack of resources of patients to perform self care activities and the health care-model predominant in Mexico also may be insufficient to generate healthy behaviors. To improve the care of patients from early stages of CKD, is necessary to implement multidisciplinary strategies to empower the patient and develop their self-efficacy to carry out self-care actions to manage their disease, control risk factors, promotion of healthy habits and modify risk behaviors. Promoting self-care is an area of opportunity with potential benefits to reduce the progression of kidney damage and complications. The aim of this article is to review the main multidisciplinary strategies to promote self-care in patients with early nephropathy in primary health-care. PMID- 29697239 TI - Role of dietitian in prevention and treatment of early chronic kidney disease AB - Mexico occupies one of the first places worldwide in terms of incidence and prevalence of end-stage renal disease (ESRD). As renal function decreases, morbi mortality increases; therefore, early interventions could more positively influence on the evolution of disease and delay/avoid fatal outcome. Unfortunately, dietitian's participation in treatment of patients with chronic kidney disease (CKD) has been mainly focused on the late stages, when the goal of nutritional care is to manage complications, and preparation of patients to initiate dialysis. Notwithstanding, it is worthy to remark that, within the multidisciplinary team of the primary health-care, dietitian is the professional on charge of the nutritional care of patients with early CKD, or without CKD but at high risk to develop it; therefore, dietitian is responsible to promote and strength healthy eating habits. Strengthening the role of the dietitian in the prevention and treatment of early CKD must be an outstanding activity in the agenda to fight against the epidemics of ESRD in our country and the world. PMID- 29697241 TI - Simultaneous Adsorption of Anionic Surfactant and Non-Ionic Polymer Onto Griseofulvin Nanoparticles Prepared by Wet Bead Milling. PMID- 29697240 TI - Blood pressure rhythmicity in patients with end stage chronic kidney disease: bromocriptine effect AB - BACKGROUND: The aim of this paper was to characterize the blood pressure CR in patients with end stage chronic kidney disease (ESCKD) before and after treatment with bromocriptine compared to healthy volunteers. METHODS: Fifteen patients and nine healthy volunteers were included. Both groups underwent ambulatory 24 hours blood pressure (24 h ABPM). Patients received 2.5 mg every 8 hours of bromocriptine for eight weeks, at the end of the treatment 24 h ABPM was repeated; blood pressure CR was compared before and after treatment and with healthy volunteers. The CR was identified by the method of Cosinor. RESULTS: 64% of volunteers showed a 24 h CR, against 27% of patients (p < 0.05). After the treatment with bromocriptine 40% of patients showed RC 24 h. The mean arterial pressure decreased from 129 +/- 1 mmHg to 106 +/- 1 mmHg. A 12 h rhythm was identified in 45% of volunteers and 73% of patients before treatment (p < 0.05) against 60% at the end (p < 0.001), with no statistical difference with volunteers. CONCLUSIONS: The CR in blood pressure is altered in ESCKD and could be restored with bromocriptine. 12 hours rhythmicity was identified predominantly in patients with ESCKD; this rhythm was also present in the healthy volunteers. PMID- 29697242 TI - Annealing of Heavily Boron-Doped Silicon: Effect on Electrical and Thermoelectric Properties. AB - In previous studies it was shown that heavily boron-doped nanocrystalline silicon submitted to thermal treatments at temperatures >=800 degrees C is characterized by an anomalously high thermoelectric power factor. Its enhanced performances were ascribed to the formation of SiBx precipitates at grain boundary, leading to the formation of potential barriers that filter out low-energy carriers, then causing a simultaneous enhancement of the Seebeck coefficient and of the electrical conductivity. To further investigate the effect of thermal treatment on boron-doped nanocrystalline silicon, samples were submitted to a host of annealing processes or of sequences of them at temperatures between 900 and 1000 degrees C and for various amounts of time. Electrical conductivity and Hall effect measurements were carried out after each thermal treatment over the temperature range 20-300 K. They provided evidence of the formation of an impurity band, and of hopping conduction at very low temperatures. Hall resistivity data versus temperature provided therefore important insights in the electronic structure of the system, which will enable a more complete understanding of the factors ruling energy filtering in this class of materials. PMID- 29697243 TI - Energy Filtering and Thermoelectrics: Artifact or Artifice? AB - The possibility of selecting carrier energies by using suitable potential barriers has played a long-standing role in the physics of thermionic devices. It entered instead the arena of thermoelectricity only in the Nineties through the pioneering work of Rowe and Min and of Nishio and Hirano. Since then, the virtuous use of energy barrier in thermoelectricity has gone through alternating fortunes, with analyses sustaining its capacity as a tool to decouple the adverse interdependency between Seebeck coefficient and electrical conductivity; and papers disproving instead such a possibility. In spite of a yet uncomplete theoretical framework, over the last years an impressive number of papers has been published reporting unusual dependencies of thermopower and conductivity upon carrier densities, mostly in nanocomposites-and attributing them to energy filtering. Aim of this paper is to discuss to which extent and under which physical constraints energy filtering may be actually invoked to explain enhanced power factors-and which alternate possibilities of explanation may be considered instead. PMID- 29697244 TI - Investigation on Sugar-Protein Connectivity in Salmonella O-Antigen Glycoconjugate Vaccines. AB - Invasive nontyphoidal Salmonella disease, for which licensed vaccines are not available, is a leading cause of bloodstream infections in Africa. The O-antigen portion of lipopolysaccharide is a good target for protective immunity. Covalent conjugation of the O-antigen to a carrier protein increases its immunogenicity and O-antigen based glycoconjugate vaccines are currently under investigation at the preclinical stage. We developed a conjugation chemistry for linking O-antigen to CRM197 carrier protein, through sequential insertion of adipic acid dihydrazide (ADH) and adipic acid bis( N-hydroxysuccinimide) ester (SIDEA) as linkers, without impacting O-antigen chain epitopes. Here the resulting sugar protein connectivity has been investigated in detail. The core portion of the lipopolysaccharide was used as a model molecule to prepare CRM197 conjugates, making structural investigations easier. The first step of reductive amination with ADH involves the terminal 3-deoxy-d- manno-oct-2-ulosonic acid (KDO) residue of the core region. The second reaction step resulted not to be selective, as SIDEA reacted with both ADH and pyrophosphorylethanolamine (PPEtN) of the core region, independently from the pH at which the reaction was performed. Peptide mapping analysis of the deglycosylated core-CRM197 conjugates confirmed that lysine residues of CRM197 were linked to SIDEA not only through KDO-ADH but also through PPEtN. This analysis also confirmed that the conjugation chemistry is random on the protein, involving a large number of lysine residues, particularly the surface exposed ones. The method for core-CRM197 characterization was successfully extended to O-antigen-CRM197 conjugate, confirming the results obtained with the core. This study not only allowed full characterization of OAg CRM197 conjugates, but can be applied to optimize synthesis and characterization of other OAg-based glycoconjugate vaccines. Analytical methods to investigate saccharide-protein connectivity are also of fundamental importance to study the relationship between glycoconjugate structure and immune response induced. PMID- 29697245 TI - Exposure Assessment Using Secondary Data Sources in Unconventional Natural Gas Development and Health Studies. AB - Studies of unconventional natural gas development (UNGD) and health have ranked participants along a gradient of geographic information system (GIS)-based activity that incorporated the distance between participants' home addresses and unconventional natural gas wells. However, studies have used different activity metrics, making result comparisons across the studies difficult. The existing studies have only incorporated wells, without accounting for other components of development (e.g., compressors, impoundments, and flaring events), for which it is often difficult to obtain reliable data but may have relevance to health. Our aims were to (1) describe, in space and time, UNGD-related compressors, impoundments, and flaring events; (2) evaluate whether and how to incorporate these into UNGD activity assessment; and (3) evaluate associations of these different approaches with mild asthma exacerbations. We identified 361 compressor stations, 1218 impoundments, and 216 locations with flaring events. A principal component analysis identified a single component that was approximately an equal mix of the metrics for compressors, impoundments, and four phases of well development (pad preparation, drilling, stimulation, and production). However, temporal coverage for impoundments and flaring data was sparse. Ultimately, we evaluated three UNGD activity metrics, including two based on the existing studies and a novel metric that included well pad development, drilling, stimulation, production, and compressor engine aspects of UNGD. The three metrics had varying magnitudes of association with mild asthma exacerbations, although the highest category of each metric (vs the lowest) was associated with the outcome. PMID- 29697246 TI - Self-Assembly of a Stable Silver Thiolate Nanocluster Encapsulating a Lacunary Keggin Phosphotungstate Anion. AB - A polyoxometalate-templated silver(I) thiolate nanocluster has been synthesized by a one-pot reaction in high yield. This novel and stable nanocluster exhibits a core-shell structure with a Ag67S36 shell and two lacunary Keggin [PW9O34]9- cores, which is fully characterized by X-ray crystallography, X-ray photoelectron spectroscopy, UV-vis, powder X-ray diffraction, and cyclic voltammetry. PMID- 29697247 TI - Reversible Electrochemical Lithium-Ion Insertion into the Rhenium Cluster Chalcogenide-Halide Re6Se8Cl2. AB - The cluster-based material Re6Se8Cl2 is a two-dimensional ternary material with cluster-cluster bonding across the a and b axes capable of multiple electron transfer accompanied by ion insertion across the c axis. The Li/Re6Se8Cl2 system showed reversible electron transfer from 1 to 3 electron equivalents (ee) at high current densities (88 mA/g). Upon cycling to 4 ee, there was evidence of capacity degradation over 50 cycles associated with the formation of an organic solid electrolyte interface (between 1.45 and 1 V vs Li/Li+). This investigation highlights the ability of cluster-based materials with two-dimensional cluster bonding to be used in applications such as energy storage, showing structural stability and high rate capability. PMID- 29697248 TI - Tumor-Activated Water-Soluble Photosensitizers for Near-Infrared Photodynamic Cancer Therapy. AB - Current photosensitizers (PSs) for photodynamic therapy (PDT) are limited by their low water solubility and tendency to aggregate, low near-infrared (NIR) absorption, and low cancer selectivity. Here, we designed iodinated, water soluble NIR boron dipyrromethene-based PSs to achieve image-guided and efficient PDT against cancer in vivo that is enhanced by leveraging tumor-specific pH responsive activation. PEG2k5c-I and PEG2k5c-OMe-I localized to tumors and were activated by acidic pH in the tumor microenvironment to produce 1O2 and fluorescence for efficient PDT and effective cancer detection after intravenous administration. Upon NIR irradiation, these PSs exhibited strong NIR absorption at 660 and 690 nm, stable NIR emission at 692 and 742 nm, and high 1O2 quantum yields of 0.78 and 0.72 in acidic pH. PEG2k5c-I and PEG2k5c-OMe-I killed cancer cells upon irradiation of NIR light and were nontoxic without irradiation. Light activated PDT treatment of breast cancer tumors in mice resulted in suppression of tumor growth, DNA damage, and necrosis selectively in tumors. This work thus introduces a versatile method to directly synthesize modular pH-responsive water soluble PSs and provides a versatile strategy for activatable PDT against cancer. PMID- 29697249 TI - Polybrominated Diphenyl Ether (PBDE) Accumulation in Farmed Salmon Evaluated Using a Dynamic Sea-Cage Production Model. AB - Food is an important source of human exposure to hazardous chemicals. Chemical concentration in a food item depends on local environmental contamination, production conditions, and, for animal-derived foods, on feed. Here, we investigate these influences on the accumulation of individual polybrominated diphenyl ether congeners (PBDEs) in farmed Atlantic salmon ( Salmo salar). We develop a dynamic model over a full sea-cage salmon production cycle. To assess the influence of metabolic debromination on PBDE congener profiles, in vitro measurements of debromination rates in fish liver cells were extrapolated to whole-body metabolic rate constants. Model results indicate that the dominant factors governing PBDE concentration in Atlantic salmon fillet are uptake via contaminated feed and fish growth, whereas the influence of metabolic debromination is minor. PBDE concentrations in fish feed depend on several factors, including the geographic origin of fish feed ingredients, which are produced and traded globally. Human exposure to PBDE via salmon consumption is less influenced by environmental concentrations at the location of salmon farming than by environmental concentrations influencing feed components. This dependence of PBDE concentrations in salmon on the origin and composition of feed reveals the complexity of predicting contaminant concentrations in globally traded food. PMID- 29697250 TI - Effects of Nanofiber Architecture and Antimony Doping on the Performance of Lithium-Rich Layered Oxides: Enhancing Lithium Diffusivity and Lattice Oxygen Stability. AB - Li-rich layered oxides (LLOs) with high specific capacities are favorable cathode materials with high-energy density. Unfortunately, the drawbacks of LLOs such as oxygen release, low conductivity, and depressed kinetics for lithium ion transport during cycling can affect the safety and rate capability. Moreover, they suffer severe capacity and voltage fading, which are major challenges for the commercializing development. To cure these issues, herein, the synthesis of high-performance antimony-doped LLO nanofibers by an electrospinning process is put forward. On the basis of the combination of theoretical analyses and experimental approaches, it can be found that the one-dimensional porous micro /nanomorphology is in favor of lithium-ion diffusion, and the antimony doping can expand the layered phase lattice and further improve the lithium ion diffusion coefficient. Moreover, the antimony doping can decrease the band gap and contribute extra electrons to O within the Li2MnO3 phase, thereby enhancing electronic conductivity and stabilizing lattice oxygen. Benefitting from the unique architecture, reformative electronic structure, and enhanced kinetics, the antimony-doped LLO nanofibers possess a high reversible capacity (272.8 mA h g-1) and initial coulombic efficiency (87.8%) at 0.1 C. Moreover, the antimony-doped LLO nanofibers show excellent cycling performance, rate capability, and suppressed voltage fading. The capacity retention can reach 86.9% after 200 cycles at 1 C, and even cycling at a high rate of 10 C, a capacity of 172.3 mA h g-1 can still be obtained. The favorable results can assist in developing the LLO material with outstanding electrochemical properties. PMID- 29697251 TI - Supramolecular Aggregates of Tetraphenylethene-Cored AIEgen toward Mechanoluminescent and Electroluminescent Devices. AB - Luminescent materials possessing both the mechanoluminescence (MCL) and electroluminescence (EL) properties are the quest for sensing and optoelectronic applications. We report on the synthesis of a new tailor-made luminogen, 1,2 bis(4-(1-([1,1'-biphenyl]-4-yl)-2,2-diphenylvinyl)phenyl)-1,2-diphenylethene (TPE 5), using Suzuki coupling reaction with high yield. An aggregation-induced emission (AIE) active complex TPE 5 forms supramolecular spherical aggregates at the air-water interface of a Langmuir trough. As a consequence, a large enhancement of luminescence is obtained from the mono- and multilayer Langmuir Blodgett films of TPE 5 owing to the AIE effect. The luminogen TPE 5 exhibits a reversible MCL response, displaying photoluminescence switching due to change in the crystalline states under external stimuli. The unique feature of luminescence enhancement upon aggregate formation is utilized for the fabrication of light emitting diodes with low threshold voltage using supramolecular aggregates as the active layer. This work demonstrates an efficient strategy for obtaining controlled supramolecular aggregates of AIEgen with a potential in the dual applications of MCL and EL. PMID- 29697252 TI - Sculpting Nanoscale Functional Channels in Complex Oxides Using Energetic Ions and Electrons. AB - The formation of metastable phases has attracted significant attention because of their unique properties and potential functionalities. In the present study, we demonstrate the phase conversion of energetic-ion-induced amorphous nanochannels/tracks into a metastable defect fluorite in A2B2O7 structured complex oxides by electron irradiation. Through in situ electron irradiation experiments in a scanning transmission electron microscope, we observe electron induced epitaxial crystallization of the amorphous nanochannels in Yb2Ti2O7 into the defect fluorite. This energetic-electron-induced phase transformation is attributed to the coupled effect of ionization-induced electronic excitations and local heating, along with subthreshold elastic energy transfers. We also show the role of ionic radii of A-site cations (A = Yb, Gd, and Sm) and B-site cations (Ti and Zr) in facilitating the electron-beam-induced crystallization of the amorphous phase to the defect-fluorite structure. The formation of the defect fluorite structure is eased by the decrease in the difference between ionic radii of A- and B-site cations in the lattice. Molecular dynamics simulations of thermal annealing of the amorphous phase nanochannels in A2B2O7 draw parallels to the electron-irradiation-induced crystallization and confirm the role of ionic radii in lowering the barrier for crystallization. These results suggest that employing guided electron irradiation with atomic precision is a useful technique for selected area phase formation in nanoscale printed devices. PMID- 29697255 TI - Fluorescent Nanoprobes with Oriented Modified Antibodies to Improve Lateral Flow Immunoassay of Cardiac Troponin I. AB - Performance of nanoprobes can often determine the detection level of Lateral immunochromatography. Traditional probes were limited by the quantity and orientation of antibodies, immune activity of the Fab region or binding strength between protein and substrate. This study developed a new efficient and robust technology to construct fluorescent nanoprobes with oriented modified antibodies, based on specific binding of the Fc region of antibody with streptococcal protein G (SPG) on the surface of polystyrene microspheres (MS) and subsequent covalent cross-linking at binding sites to firm them. Lateral flow immunoassay using these probes was applied for the detection of cardiac troponin I (cTnI). The significantly improved detection sensitivity demonstrated that antibody orientation on MS surfaces effectively enhanced immunological activities of probes compared with random immobilizing methods. Furthermore, performance evaluation results of lateral flow test strips met clinical requirements perfectly, including limit of detection (0.032 ng/mL), linearity ( R > 0.99), repeatability (CV < 10%), correlation ( R > 0.99), and heat aging stability. This research also employed heterophilic blocking reagent (HBR) to actively block redundant binding sites of SPG for the first time in order to eliminate false positive interferences, improving the sensitivity and precision of test results further. PMID- 29697253 TI - Analysis of the Role of the Conserved Disulfide in Amyloid Formation by Human Islet Amyloid Polypeptide in Homogeneous and Heterogeneous Environments. AB - Human islet amyloid polypeptide (hIAPP) is a hormone secreted from beta-cells in the Islets of Langerhans in response to the same stimuli that lead to insulin secretion. hIAPP plays an adaptive role in glucose homeostasis but misfolds to form insoluble, fibrillar aggregates in type II diabetes that are associated with the disease. Along the misfolding pathway, hIAPP forms species that are toxic to beta-cells, resulting in reduced beta-cell mass. hIAPP contains a strictly conserved disulfide bond between residues 2 and 7, which forms a small loop at the N-terminus of the molecule. The loop is located outside of the cross beta core in all models of the hIAPP amyloid fibrils. Mutations in this region are rare, and the disulfide loop plays a role in receptor binding; however, the contribution of this region to the aggregation of hIAPP is not well understood. We define the role of the disulfide by analyzing a collection of analogues that remove the disulfide, by mutation of Cys to Ser, by reduction and modification of the Cys residues, or by deletion of the first seven residues. The cytotoxic properties of hIAPP are retained in the Cys to Ser disulfide-free mutant. Removal of the disulfide bond accelerates amyloid formation in all constructs, both in solution and in the presence of model membranes. Removal of the disulfide weakens the ability of hIAPP to induce leakage of vesicles consisting of POPS and POPC. Smaller effects are observed with vesicles that contain 40 mol % cholesterol, although N-terminal truncation still reduces the extent of leakage. PMID- 29697254 TI - Fabrication and Electrochemical Performance of Polyoxometalate-Based Three Dimensional Metal Organic Frameworks Containing Carbene Nanocages. AB - Two new polyoxometalate (POM)-based three-dimensional metal organic carbene frameworks, [Ag10(trz)4(H2O)2][HPW12O40] (POMs@MCNCs-1) and [Ag10(trz)4(H2O)6][H2SiW12O40] (POMs@MCNCs-2), were hydrothermally synthesized, in which Keggin-type polyoxoanions as templates induce the formation of two different kinds of metal-carbene nanocages (MCNCs) for the first time. Combination of the reversible multielectron redox behavior and electron storage functions of POMs with the good electrical conductivity of the single-walled carbon nanotubes (SWNTs) renders the POMs@MCNCs-1/SWNT composite excellent electrochemical performance and good stability as anode materials of lithium-ion batteries, with up to 2000 mA h g-1 for the first discharge capacity and ca. 859 mA h g-1 for the second cycle at a current density of 100 mA g-1. The successful fabrication of unprecedented MCNCs into the POM-based three-dimensional metal organic frameworks in the present work must initiate extensive research interests in diverse fields. PMID- 29697256 TI - Ruthenium-Catalyzed Decarboxylative C-H Alkenylation in Aqueous Media: Synthesis of Tetrahydropyridoindoles. AB - We disclose herein a Ru(II)-catalyzed decarboxylative and oxidative coupling of N substituted indolyl carboxylic acids with broad substrate scope in an aqueous solution. This method provides a sustainable and efficient access to synthesize various indole-fused cyclohexanyl acetic acids under mild conditions. PMID- 29697258 TI - Acid...Amide Supramolecular Synthon in Cocrystals: From Spectroscopic Detection to Property Engineering. AB - The acid...amide dimer heterosynthon in cocrystals of aromatic acids and primary amides is identified by marker peaks in the IR spectra that are characteristic of individual N-H...O and O-H...O interactions and also of the extended synthon. The O-H...O hydrogen bond is crucial to heterodimer formation in contrast to the N H...O bond. A combinatorial study, tuning the chemical nature of acid and amide functionalities, leads to 22 cocrystals out of 36 crystallization attempts. Four quadrants I-IV are defined based on acidity and basicity of the acid and amide components. The strong acid-strong base combination in quadrant I favors the planar acid...amide heterodimer in its eight cocrystals. Quadrant IV with its weak acid-weak base combination is the least favored for the planar heterosynthon and synthon diversity is observed in the eight cocrystals obtained. The strong weak and weak-strong combinations in quadrants II and III are expectedly ambivalent. This exercise highlights the effect of molecular features on supramolecular behavior. Quadrant I crystals, with their propensity for the planar acid...amide heterodimer are suitable for the engineering of crystals that can be sheared. This quadrant favors the formation of elastic crystals too. The overall result is that 57% (4 in 7) of all crystals in this quadrant are deformable, compared with 14% (1 in 7) in the three other quadrants. This work is a complete crystal engineering exercise from synthon identification to a particular desired crystal packing to property selection. One can virtually anticipate the mechanical property of a putative acid...amide cocrystal from a knowledge of just the molecular structures of the constituent acid and amide molecules. PMID- 29697257 TI - Synthesis of exo-Imidazolidin-2-one Dienes, Their Isomerization, and Selectivity in Diels-Alder Cycloadditions. AB - An efficient and alternative synthesis of exo-imidazolidin-2-one dienes is described. A condensation reaction was carried out with bis-imino derivatives, diacetyl, and triphosgene, affording symmetrically N, N-disubstituted dienes. The use of alkyl methyl alpha-diketones led to the formation of nonsymmetrical dienes, which underwent isomerization to provide more stable inner-outer-ring dienes under Lewis acid conditions. Evaluation was made of the reactivity as well as regio- and stereoselectivity of these dienes in Diels-Alder reactions. They proved to be highly reactive and selective. DFT calculations of the transition states accounted for their behavior. PMID- 29697259 TI - Nanocage-Confined Synthesis of Fluorescent Polycyclic Aromatic Hydrocarbons in Zeolite. AB - Polycyclic aromatic hydrocarbons (PAHs) attract much attention for applications to organic light-emitting diodes, field-effect transistors, and photovoltaic cells. The current synthetic approaches to PAHs involve high-temperature flash pyrolysis or complicated step-by-step organic reactions, which lead to low yields of PAHs. Herein, we report a facile and scalable synthesis of PAHs, which is carried out simply by flowing acetylene gas into zeolite under mild heating, typically at 400 degrees C and generates the products of 0.30 g g-1 zeolite. PAHs are synthesized via acetylene polymerization inside Ca2+-ion-exchanged Linde type A (LTA) zeolite, of which the alpha-cage puts a limit on the product molecular size as a confined-space nanoreactor. The resultant product after the removal of the zeolite framework exhibits brilliant white fluorescence emission in N-methylpyrrolidone solution. The product is separated into four different color emitters (violet, blue, green, and orange) by column chromatography. Detailed characterizations of the products by means of various spectroscopic methods and mainly mass spectrometric analyses indicate that coronene (C24H12) is the main component of the blue emitter, while the green emitter is a mixture of planar and curved PAHs. The orange can be attributed to curved PAHs larger than ovalene, and the violet to smaller molecules than coronene. The PAH growth mechanism inside Ca2+-exchanged LTA zeolite is proposed on the basis of mass spectral analyses and density functional theory calculations. PMID- 29697260 TI - Unravelling the Nucleophilicity of Butenolides for 1,6-Conjugate Addition to p Quinone Methides: A Direct Access to Diversely Substituted Butenolide-Derived Diarylmethanes. AB - A Lewis acid catalyzed regioselective C-C bond is constructed through beta addition of deconjugated butenolides with p-quinone methides in a 1,6-conjugate addition manner. Interestingly, Lewis acid catalyzed vinylogous Mukaiyama-Michael reaction of silyloxyfurans with p-QMs proceeds selectively through the alpha or gamma position exclusively. The reaction is mild with broad substrate scope, thus allowing easy access to a wide range of bis-arylated alpha-/beta-/gamma substituted butenolides. PMID- 29697261 TI - Enhanced Excited-State Proton Transfer via a Mixed Water-Methanol Molecular Bridge of 1-Naphthol-5-Sulfonate in Methanol-Water Mixtures. AB - We used steady-state and time-resolved fluorescence techniques to study the excited-state proton transfer (ESPT) and the nonradiative properties of two irreversible photoacids, 1-naphthol-4-sulfonate (1N4S) and 1-naphthol-5-sulfonate (1N5S). We found that the ESPT rate constant of 1N4S in water is 2.2 * 1010 s-1, whereas in methanol, it is smaller by about 3 orders of magnitude and is not observed. The ESPT process of 1N5S competes with a major nonradiative process of equal rate and kPT of 2.2 * 1010 s-1. In methanol-water mixtures of chiH2O = 0.2, the fluorescence lifetime of the ROH form of 1N5S is lower by a factor of 10 than that in pure methanol. In the steady-state fluorescence spectra of 1N5S in methanol-water mixtures, there are two iso-emissive points, one for chiH2O < 0.2 and one for chiH2O > 0.3. This large reduction in fluorescence intensity and the two iso-emissive points are explained by the existence of a mixed water-methanol bridge of about three molecules that connects the proton donor 1-OH with the 5 sulfonate in mixtures of chiH2O < 0.2. The bridge enhances both the ESPT and the nonradiative processes. For 1N4S in methanol-water mixtures at chiH2O ~0.2, the reduction in the fluorescence lifetime is only by ~30%, and only one iso-emissive point exists in the steady-state fluorescence spectra for 0 =45 years in the United States were analyzed for 1999-2015. COPD was defined by ICD-10 codes J40-J44 and J47 based either on the UCOD or up to 20 contributing causes coded. Annual age-standardized COPD death rates were computed by age, gender and race/ethnicity for those with any mention of COPD. In 2015, COPD was mentioned in 11.59% (292,572 deaths) in MCOD, compared to 11.13% (243,617 deaths) in 1999, a 4% increase. However, it was reported as the UCOD for only 5.56% and 4.97% in 2015 and 1999 respectively, an 11% increase. The most common UCOD in subjects with any mention of COPD was respiratory disorders in 49% of males and 55% of females. The relative change in death rates differed between MCOD and UCOD. For example, among non-Hispanic white females aged 65-74 years the UCOD rate per 100,000 (95% CI) decreased from 163 (160-166) to 147 (145-150), average annual percent decrease (AAPD) -0.26, while the MCOD rate decreased from 308 (304-311) to 263 (260-267), AAPD -0.87. Statistics based on UCOD understated the burden of COPD in the United States. MCOD rates were twice as high as UCOD rates. The relative change in death percent or rates differed between MCOD and UCOD. MCOD analysis should be repeated periodically to help evaluate the burden of COPD-related mortality. PMID- 29697273 TI - Impact of pathological features of brain metastases in prognosis. AB - AIM: To evaluate the prognostic value of tumor-infiltrating lymphocytes (TILs) and Ki67 in brain metastasis lesions, and the effect of adding them to variables of graded prognostic assessment score. PATIENTS & METHODS: Clinicopathological information from 111 medical charts of brain metastasis patients was obtained, and TIL distribution (n = 84), Ki67 index (n = 79) and CD3 TIL (n = 64) were prospectively evaluated. RESULTS: Most frequent TIL pattern was perivascular (67.8%), and median Ki67 and CD3 TIL percents were 30 and 4.8%, respectively. Ki67 >=15 was associated with shorter survival (p = 0.018) but CD3 TIL was not (p = 0.870). The highest graded prognostic assessment score was not associated with survival (p = 0.648), however, those with low Ki67 and high score was associated with better outcome (p = 0.007). CONCLUSION: High Ki67 index in brain metastasis carries a worse prognosis. PMID- 29697274 TI - Effect of Eicosapentaenoic Acid on Body Composition and Inflammation Markers in Patients with Head and Neck Squamous Cell Cancer from a Public Hospital in Mexico. AB - INTRODUCTION: Head and neck cancer patients are at high risk of anorexia-cachexia syndrome and literature shows that Eicosapentaenoic acid (EPA) could regulate it. We aim to determine the EPA effect on body composition and pro-inflammatory markers in patients with head neck cancer. MATERIALS AND METHODS: A randomized single-blind placebo-controlled clinical trial was conducted in patients with head and neck squamous cell cancer who received a polymeric diet with 2 g of EPA or a standard polymeric diet for six weeks before antineoplastic treatment. We assessed body composition by bioelectrical impedance analysis and determined IL 1beta, IL-6, TNF-alpha and IFN-gamma, CRP, serum proteins, and blood count at baseline and at the end of the study. RESULTS: 32 patients received EPA (2 g/day) and 32 became controls. A decrease in serum levels of IL-1beta, IL-6, TNF-alpha, and IFN-gamma was observed in the experimental group, as well as regulation of body weight (-0.3 +/- 5.9 vs. -2.1 +/- 3.7), lean body mass (-0.2 +/- 3.8 vs. 1.3 +/- 3.6), body fat mass (0.2 +/- 3.5 vs. -1.2 +/- 3.8), and quality of life (10 +/- 33 vs. 5 +/- 34). CONCLUSION: Supplementing with 2 g/day of EPA to head and neck cancer patient during antineoplastic treatment regulates serum pro inflammatory cytokines, body weight, lean body mass, and improve quality of life. PMID- 29697275 TI - Use of the National Institutes of Health Consensus Guidelines Improves the Diagnostic Sensitivity of Gastrointestinal Graft-Versus-Host Disease. AB - CONTEXT: - Graft-versus-host disease of the gastrointestinal tract is a common complication of hematopoietic stem cell transplant associated with significant morbidity and mortality. Accurate diagnosis can be difficult and is a truly clinicopathologic endeavor. OBJECTIVES: - To assess the diagnostic sensitivity of gastrointestinal graft-versus-host disease using the 2015 National Institutes of Health (NIH) histology consensus guidelines and to analyze histologic findings that support the guidelines. DESIGN: - Patients with allogeneic hematopoietic stem cell transplants were identified via a retrospective search of our electronic medical records from January 1, 2005, to January 1, 2011. Endoscopies with available histology were reviewed by 2 pathologists using the 2015 NIH guidelines. The clinical diagnosis was used as the gold standard. A nontransplant set of endoscopic biopsies was used as a control. RESULTS: - Of the 250 total endoscopies, 217 (87%) had a clinical diagnosis of gastrointestinal graft-versus host disease. Use of the NIH consensus guidelines showed a sensitivity of 86% and a specificity of 65%. Thirty-seven of 58 (64%) cases with an initial false negative histopathologic diagnosis were diagnosed as graft-versus-host disease on our review. CONCLUSIONS: - Use of the NIH histology consensus guidelines results in a high sensitivity and specificity, thereby decreasing false-negatives. Additionally, use of the NIH guidelines aids in creating uniformity and diagnostic clarity. Correlation with clinical and laboratory findings is critical in evaluating the differential diagnosis and to avoid false-positives. As expected, increased apoptosis with decreased inflammation was associated with a pathologic diagnosis of graft-versus-host disease and supports the NIH guidelines. PMID- 29697276 TI - Comparison of Cytopathologist-Performed Ultrasound-Guided Fine-Needle Aspiration With Cytopathologist-Performed Palpation-Guided Fine-Needle Aspiration: A Single Institutional Experience. AB - CONTEXT.-: Although fine-needle aspiration (FNA) practice by pathologists is now well established, it has been primarily performed by manual palpation. In recent years, pathologists have begun to venture into ultrasound-guided FNAs (UGFNAs). Reports on experiences with this relatively new technique for pathologists have shown promising results. However to date, there have been few studies in the literature comparing pathologist-performed UGFNA with the more traditional pathologist-performed palpation-guided FNA (PGFNA). OBJECTIVE.-: To compare UGFNA to PGFNA by cytopathologists at an academic medical center. DESIGN.-: A retrospective study of FNAs performed by cytopathologists within the University of California, Los Angeles (UCLA) pathology departmental FNA clinic was performed. Data collected included performance technique (UGFNA versus PGFNA), lesion site and size, adequacy status (nondiagnostic rate), and number of passes per procedure. Corresponding surgical pathology/flow cytometric/cytogenetic result follow-up was compared to FNA results. Findings between UGFNA and PGFNA cases were compared. RESULTS.-: Of 1029 FNA cases during the study period, there were 449 UGFNA cases (43.6%) and 580 PGFNA cases (56.4%). Nondiagnostic rates with UGFNA and PGFNA were 6.7% (30 of 449 cases) and 20.7% (120 of 580 cases), respectively. Nondiagnostic rate was also significantly lower with UGFNA than with PGFNA for lesions within the thyroid (6.0% versus 33.3%), head and neck (6.6% versus 21.2%), and salivary gland (6.2% versus 17.1%), and across all nodule sizes. A total of 495 of 1029 FNA cases (48.1%) had follow-up. Discordance rate was significantly lower with UGFNA than with PGFNA (5.4% versus 12.8%). CONCLUSIONS.-: This study shows improved performance characteristics of cytopathologist-performed UGFNA versus PGFNA. PMID- 29697277 TI - Urinary biomarkers reporting weakness and validation failure in Type 2 diabetic nephropathy: systematic review. AB - For better identification of novel diagnostic urinary biomarker in Type 2 diabetic nephropathy (T2DN), methodological and reporting quality is as important as validity of biomarkers. The aim of this systematic review is to find out the best-reported diagnostic urinary biomarkers study in T2DN based on STARD criteria. We also analyzed the validity of urinary markers in the selected articles those followed STARD criteria. The diagnostic accuracy of urinary biomarkers on T2DN is not conclusive because of the poor reporting quality and differences in adjustment for conventional risk factors. For a proper validation of urinary biomarkers on T2DN, in future large well-designed longitudinal studies, with specific prediction analysis and validation of the biomarkers by adjusting with possible conventional risk factors. PMID- 29697278 TI - Efficacy and metabolic effects of lurasidone versus brexpiprazole in schizophrenia: a network meta-analysis. AB - AIM: To assess the relative efficacy and metabolic effects of lurasidone and brexpiprazole in the acute treatment of schizophrenia. METHODS: Five lurasidone and three brexpiprazole trials were identified. In the absence of head-to-head trials, a Bayesian network meta-analysis comparing lurasidone and brexpiprazole was performed. RESULTS: Nonstatistically significant differences in efficacy measures were observed between lurasidone and brexpiprazole. Significant differences favoring lurasidone for weight change (-0.69 kg; 95% CrI: -1.22 to 0.15), total cholesterol (-7.60 mg/dl; 95% CrI: -13.94 to -1.22), and low-density lipoprotein (-6.58 mg/dl; 95% CrI: -12.11 to -1.04) were observed, with a trend indicating half the risk of experience >=7% weight gain. CONCLUSION: This network meta-analysis suggested that lurasidone had similar efficacy and fewer metabolic effects than brexpiprazole in patients with acute schizophrenia. PMID- 29697279 TI - Biomarkers in chimeric antigen receptor T-cell therapy. PMID- 29697280 TI - Effect of Saccharomyces Boulardii Cell Wall Extracts on Colon Cancer Prevention in Male F344 Rats Treated with 1,2-Dimethylhydrazine. AB - The effect of Saccharomyces boulardii cell wall extracts on colon cancer prevention in rats treated with 1,2-dimethylhydrazine was investigated. A crude insoluble glucan (0.5 and 1.0 mg/kg/day) and a crude mannoprotein extract (0.3 and 3.0 mg/kg/day) were administered in rats by gavage for 12 weeks along with a high fat low fiber diet whereupon rats were sacrificed and aberrant crypt foci (ACF) were counted in the colon. Moreover, NAD(P)H: quinone reductase (QR) and harmful fecal enzymes (beta-glucosidase and beta-glucuronidase) were quantified in the liver and in the caecum, respectively. Results showed a reduction in ACF counts, a decreased beta-glucuronidase activity and an increased QR activity when rats were treated only with insoluble glucan. While these enzymatic modulations may be constituted one of the mechanisms that is responsible for the reduction of ACF counts observed, the reduction of ACF counts caused by insoluble glucan should be addressed, at least, as a biomarker of their cancer-prevention properties. To our knowledge, this is the first study demonstrated that crude cell wall extract obtained from S. boulardii could have a potential role in colon cancer prevention in vivo by revealing the potential implication of QR and beta glucuronidase modulation. PMID- 29697281 TI - Enrichment of methylated molecules using enhanced-ice-co-amplification at lower denaturation temperature-PCR (E-ice-COLD-PCR) for the sensitive detection of disease-related hypermethylation. AB - AIM: The detection of specific DNA methylation patterns bears great promise as biomarker for personalized management of cancer patients. Co-amplification at lower denaturation temperature-PCR (COLD-PCR) assays are sensitive methods, but have previously only been able to analyze loss of DNA methylation. MATERIALS & METHODS: Enhanced (E)-ice-COLD-PCR reactions starting from 2 ng of bisulfite converted DNA were developed to analyze methylation patterns in two promoters with locked nucleic acid (LNA) probes blocking amplification of unmethylated CpGs. The enrichment of methylated molecules was compared to quantitative (q)PCR and quantified using serial dilutions. RESULTS: E-ice-COLD-PCR allowed the multiplexed enrichment and quantification of methylated DNA. Assays were validated in primary breast cancer specimens and circulating cell-free DNA from cancer patients. CONCLUSION: E-ice-COLD-PCR could prove a useful tool in the context of DNA methylation analysis for personalized medicine. PMID- 29697282 TI - The Role of Genetic Variants in the Association between Dietary Acrylamide and Advanced Prostate Cancer in the Netherlands Cohort Study on Diet and Cancer. AB - To investigate the association between dietary acrylanide and advanced prostate cancer, we examined acrylamide-gene interactions for advanced prostate cancer risk by using data from the Netherlands Cohort Study. Participants (n = 58,279 men) completed a baseline food frequency questionnaire (FFQ), from which daily acrylamide intake was calculated. At baseline, 2,411 men were randomly selected from the full cohort for case-cohort analysis. Fifty eight selected single nucleotide polymorphisms (SNPs) and two gene deletions in genes in acrylamide metabolism, DNA repair, sex steroid systems, and oxidative stress were analyzed. After 20.3 years of follow-up, 1,608 male subcohort members and 948 advanced prostate cancer cases were available for Cox analysis. Three SNPs showed a main association with advanced prostate cancer risk after multiple testing correction: catalase (CAT) rs511895, prostaglandin-endoperoxide synthase 2 (PTGS2) rs5275, and xeroderma pigmentosum group C (XPC) rs2228001. With respect to acrylamide gene interactions, only rs1800566 in NAD(P)H quinone dehydrogenase 1 (NQO1) and rs2301241 in thioredoxin (TXN) showed a nominally statistically significant multiplicative interaction with acrylamide intake for advanced prostate cancer risk. After multiple testing corrections, none were statistically significant. In conclusion, no clear evidence was found for interaction between acrylamide intake and selected genetic variants for advanced prostate cancer risk. PMID- 29697283 TI - Antitumoral Potency by Immunomodulation of Chloroform Extract from Leaves of Nitraria retusa, Tunisian Medicinal Plant, via its Major Compounds beta sitosterol and Palmitic Acid in BALB/c Mice Bearing Induced Tumor. AB - This study evaluated the antitumoral effect of Chloroform extract from Nitraria retusa leaves, via its major compounds beta-sitosterols and palmitic acid. BALB/c mice were subcutaneously inoculated with B16-F10 cells, then treated intra peritoneally after 7 days with the chloroform extract for 21 days. They were then euthanized, and the tumors were weighed. Lung parenchyma was analyzed. Lymphocyte and macrophages proliferation, cytotoxic T lymphocyte (CTL) activities were evaluated using the MTT assay. Macrophage phagocytosis was evaluated by measuring the lysosomal activity and nitric oxide production. Antioxidant activity was studied by cellular antioxidant activity on macrophage and splenocytes and by lipid peroxidation inhibitory activity in liver cells, kidney, and serum. beta sitosterols and palmitic acid, major compounds of chloroform extract, impeded remarkably the expansion of the transplantable tumor, protected the lung parenchyma, and increased splenocytes proliferation and both CTL activities in tumor-bearing mice. beta-sitosterols and palmitic acid were also seen to have enhanced lysosomal activity of host macrophages and antioxidant cellular activity. Also, they showed an inhibitory effect of lipid peroxidation. Our results suggest that antitumoral effect of beta-sitosterols and palmitic acid from chloroform extract is related with its immunomodulatory activity, and opens the way for a nutrition application and coprocessing phytotherapy against cancer. PMID- 29697284 TI - Biological and Immunological Aspects of Iron Deficiency Anemia in Cancer Development: A Narrative Review. AB - Iron Deficiency Anemia (IDA) is a universal health problem and a risk factor for the development of cancer. IDA changes the microenvironment of the human body by affecting both the biological and immunological systems. It increases DNA damage and genomic instability by different mechanisms. IDA is one of the leading causes of the imbalance between different antioxidant enzymes as well as enzymes involved in DNA damage and DNA repair systems of the body. It can affect the biogenesis/expression of microRNAs. IDA interrupts the oxidative phosphorylation energy metabolism and intestinal Cytochrome-P450 systems. It also disturbs multicellular signaling pathways involved in cell survival and helps in tumor angiogenesis. Moreover, IDA is also responsible for the functional deterioration of innate and adaptive immune systems that lead to immunological dysfunctions against invading pathogens. Genomic instability and immunological dysfunctions are the hallmarks of cancer development. In this review, we will review the evidence linking IDA to increased cancer risk. PMID- 29697285 TI - Grading Severity of Productive Cough Based on Symptoms and Airflow Obstruction. AB - The binary approach to the diagnosis of Chronic Bronchitis (CB) is a major barrier to the study of the disease. We investigated whether severity of productive cough can be graded using symptoms and presence of fixed airflow obstruction (FAO), and whether the severity correlates with health status, exposures injurious to the lung, biomarkers of inflammation, and measures of airway wall thickening. Findings from a cross-sectional sample of 1,422 participants from the Lovelace Smokers Cohort (LSC) were validated in 4,488 participants from the COPDGene cohort (COPDGene). Health status was based on the St. George's Respiratory Questionnaire, and Medical Outcomes Study 36-Item Short Form Health Survey. Circulating CC16 levels were quantified by ELISA (LSC), and airway wall thickening was measured using computed tomography (COPDGene). FAO was defined as postbronchodilator FEV1/FVC <0.7. The presence and duration of productive cough and presence of FAO or wheeze were graded into Healthy Smokers, Productive Cough (PC), Chronic PC, PC with Signs of Airflow Obstruction, and Chronic PC with Signs of Airflow Obstruction. In both cohorts, higher grade of severity correlated with lower health status, greater frequency of injurious exposures, greater airway wall thickening, and lower circulating CC16 levels. Further, longitudinal follow-up suggested that disease resolution can occur at every grade of severity but is more common in groups of lower severity and least common once airway remodeling develops. Therefore, severity of productive cough can be graded based on symptoms and FAO and early intervention may benefit patients by changing the natural history of disease. PMID- 29697286 TI - Vaccines for healthcare-associated infections: present, future, and expectations. AB - INTRODUCTION: In spite of the widespread implementation of preventive strategies, the prevalence of healthcare-associated infections (HAIs) remains high. HAIs are associated with multidrug resistant organisms, and in the post-antibiotic era, alternative strategies such as vaccines are needed for their management. Areas covered: Vaccines to prevent HAIs could be proposed to at-risk patients, or to healthcare workers (HCWs) to prevent cross-transmission. After searches in Pubmed and clinicaltrials.gov, existing vaccines and vaccines under clinical development are presented in this narrative review. Issues associated with the use of vaccines to prevent HAIs are discussed. Expert commentary: Future vaccines against HAIs will contribute to fight antibiotic resistance and thus reduce the burden of HAIs. At this stage, the goal of obtaining effective vaccines against S.aureus, C. difficile and gram-negative bacteria has not yet been achieved. Obtaining an efficient response to vaccines in at-risk patients for HAIs is also challenging, and future strategies of vaccination need to address this difficulty. The efficacy of vaccines for HCWs in reducing the spread of nosocomial outbreaks is counterbalanced by the lack of adherence to vaccine policies among HCWs. The acceptance of future vaccines to prevent carriage and infection with organisms involved in HAIs in HCWs will probably be a challenge. PMID- 29697287 TI - Antigens to detect the acute phase of toxoplasmosis in pregnant women: standardized comparison. AB - A key element in any diagnostic technique is the antigen (Ag), a biomarker, but this is usually a protein that has a function to the parasite. Some biological aspects of the Ags and of the Toxoplasma gondii can influence the effectiveness of the diagnosis, as well as the antibody isotype and the characteristics of the assay. A large number of papers have assessed different proteins to distinguish the phases of infection, but the 'indices of effectiveness' differ among reports. This work presents for the first time a summary of all the Ags that have been evaluated, with standardized measurements of sensitivity and specificity. These values were calculated with information presented in the papers on Ag evaluations to differentiate the infection phases. PMID- 29697288 TI - A systematic quality review of high-tech AAC interventions as an evidence-based practice. AB - Although high-tech augmentative and alternative communication (AAC) is commonly used to teach social-communication skills to people with autism spectrum disorder or intellectual disabilities who have complex communication needs, there is a critical need to evaluate the efficacy of this approach. The aim of this systematic review was to evaluate the quality of single-case experimental design research on the use of high-tech AAC to teach social-communication skills to individuals with autism spectrum disorder or intellectual disabilities who have complex communication needs, to determine if this intervention approach meets the criteria for evidence-based practices as outlined by the What Works Clearinghouse. Additionally, information on the following extended methodological standards is reported on all included studies: participant description, description of setting and materials, interventionist description, baseline and intervention description, maintenance, generalization, procedural integrity, and social validity. The results from 18 multiple-baseline or multiple-probe experiments across 17 studies indicate that using high-tech AAC to teach social communication skills to individuals with autism spectrum disorder or intellectual disabilities and complex communication needs can be considered an evidence-based practice, although the review of comparison (i.e., alternating treatment) design studies did not indicate that high-tech AAC is significantly better than low-tech AAC. PMID- 29697290 TI - Erratum. PMID- 29697292 TI - Commonly consumed beverages associate with different lifestyle and dietary intakes. AB - Sugar sweetened beverages (SSB), artificially sweetened beverages (ASB), juice, coffee and tea has been associated with risk of metabolic disease. High consumption of these beverages may be associated with certain characteristics of the overall diet that would be important to take into account when analysing beverage-disease associations. Here, we investigate five beverages and their association with lifestyle and diet in 25,112 individuals from the Malmo Diet and Cancer Cohort. We observed that high consumption of SSB was associated with lower intakes of foods perceived as healthy. However, high consumption of both tea and juice was associated with higher intakes of foods perceived as healthy. Further, high consumption of ASB was associated with higher intakes of low-fat products. High consumption of coffee was associated with higher intakes of meat and high fat margarine, and lower intake of breakfast cereals. We observe five beverages to associate with different lifestyle and dietary patterns. PMID- 29697291 TI - Vildagliptin Recruits Regulatory T Cells in Patients Undergoing Primary Percutaneous Coronary Intervention. AB - Regulatory T cells (Treg) has been documented to be protective against myocardial ischemia-reperfusion injury (MIRI). The administration of drugs which recruit Treg cells may participate in the cardioprotection of MIRI. The purpose of the present study was to investigate whether the add-on vildagliptin (vild) to standard treatment of MIRI prior to reperfusion could increase Treg recruitment, anti-inflammatory, and antioxidant effects of the standard treatment or not. Sixty diabetic patients with ST-segment elevation myocardial infarction were randomly divided into two equal groups: control group was given the standard medical treatment and vild group was given the standard medical treatment plus vild. There were no statistical differences between the mean of percentage of changes in nitric oxide, ischemia modified albumin, highly sensitive C reactive protein, and interferon-gamma levels in the studied groups. While, the percentages of changes of myeloperoxidase level, CD4+CD25+ Treg cells count, and transforming growth factor-beta1 level were significantly higher in vild group compared with control group. We concluded that addition of vild to standard medical treatment of MIRI could increase its effectiveness through recruitment of CD4+CD25+ Treg cells. PMID- 29697293 TI - Benzothiazole analogs as potential anti-TB agents: computational input and molecular dynamics. AB - Biotin is very important for the survival of Mycobacterium tuberculosis. 7,8 Diamino pelargonic acid aminotransaminase (DAPA) is a transaminase enzyme involved in the biosynthesis of biotin. The benzothiazole title compounds were investigated for their in vitro anti-tubercular activity against two tubercular strains: H37Rv (ATCC 25,177) and MDR-MTB (multidrug-resistant M. tuberculosis, resistant to isoniazid, rifampicin, and ethambutol) by an agar incorporation method. The possible binding mode and predicted affinity were computed using a molecular docking study. Among the synthesized compounds in the series, the title compound {2-(benzo[d]thiazol-2-yl-methoxy)-5-fluorophenyl}-(4-chlorophenyl) methanone was found to exhibit significant activity with minimum inhibitory concentrations of 1 MUg/mL and 2 MUg/mL against H37Rv and MDR-MTB, respectively; this compound showed the highest binding affinity (-24.75 kcal/mol) as well. PMID- 29697294 TI - Is hyponatremia associated with mortality in pulmonary arterial hypertension? AB - Hyponatremia is associated with poor prognosis in left heart failure and liver disease. Its prognostic role in pulmonary arterial hypertension (PAH) is not well defined. We investigated the association between hyponatremia and one-year mortality in two large cohorts of PAH. This study is a secondary analysis evaluating the association between hyponatremia and one-year mortality in patients treated with subcutaneous treprostinil (cohort 1). The results are validated using a PAH registry at a tertiary referral center (cohort 2). Eight hundred and twenty patients were enrolled in cohort 1 (mean age = 47 +/- 14 years) and 791 in cohort 2 (mean age = 55 +/- 15 years). Sodium level is negatively correlated with mean right atrial pressure (r = -0.09, P = 0.018; r = 0.089, P = 0.015 in cohorts 1 and 2, respectively). In unadjusted analyses of cohort 1, the sodium level (as a continuous variable) is associated with one-year mortality (hazard ratio = 0.94; P = 0.035). Hyponatremia loses its significance (as a continuous variable and when dichotomized at <= 137 mmol/L; P = 0.12) when adjusted for functional class (FC), which is identified as the variable whose presence turns the effect of sodium level into non-significant. Secondary analyses using a cut-off value of < 135 mmol/L showed similar results. These results are validated in cohort 2. Although the sample size for patients with sodium < 130 mmol/L is small (n = 31), severe hyponatremia is associated with higher overall mortality (47% versus 23%; P = 0.01), even when adjusting for age, FC, and baseline 6-min walk distance ( P < 0.001). Although baseline hyponatremia is associated with one-year mortality, it loses its significance when adjusted for FC. PMID- 29697296 TI - The physical profile of adult male basketball players: Differences between competitive levels and playing positions. AB - This study examined the physical differences in adult male basketball players of different competitive level and playing position using a large cohort. In the middle of the regular season, 129 players from four different Divisions completed a Yo-YoIR1 and, after 3-to-8 days, they performed a 6-min continuous running test (Mognoni's test), a counter-movement jump (CMJ) test and a 5-min High-intensity Intermittent running test (HIT). Magnitude-based inferences revealed that differences in HIT were very likely moderate between Division I and II and likely small between Division II and III. The differences in absolute peak power and force produced during CMJs between Division I and II and between Division II and III were possibly small. Differences in Yo-YoIR1 and Mognoni's test were very likely-to-almost certain moderate/large between Division III and VI. We observed possibly-to-likely small differences in HIT and Mognoni's test between guards and forwards and almost certainly moderate differences in absolute peak power and force during CMJs between guards and centres. The ability to sustain high intensity intermittent efforts (i.e. HIT) and strength/power characteristics can differentiate between competitive level, while strength/power characteristics discriminate guards from forwards/centres. These findings inform practitioners on the development of identification programs and training activities in basketball. PMID- 29697297 TI - Isolation of Antibacterial Hydrolysates from Hen Egg White Lysozyme and Identification of Antibacterial Peptides. AB - Native and heated hen egg white lysozyme (HEWL) hydrolysates were isolated by hydrolysis with pepsin at pH 2.0 in situ in a cation exchange membrane to isolate and identify antibacterial peptides of the HEWL hydrolysates. Native and heated HEWL was partially hydrolyzed with pepsin at pH 2.0. The fractions were eluted with 5 M ammonia to identify 23 antibacterial peptides using a tandem mass spectrometry. Then, these fractions were eluted with a solution of NaCl 1 M, and seven positively charged peptides f(23-28) YSLGNW, f(122-129) AWIRGCRL, f(123 129) WIRGCRL, f(124-129) IRGCRL, f(82-96) ALLSSDITASVNCAK, f(103-129) VAWRNRCKGTDVQAWIRGCRL, and f(97-123) KIVSDGNGMNAWVAWRNRCKGT were identified using tandem mass spectrometry. Native HEWL hydrolysate presented an enzymatic activity of 23.0%, heated HEWL hydrolysate at pH 6.0 presented a residual enzymatic activity of 22.0%, and heated HEWL hydrolysate at pH 7.0 presented an enzymatic activity of 21.33%. Native and heated HEWL hydrolysate presented antibacterial activity against Escherichia coli and Staphylococcus carnosus. Native HEWL hydrolysate presented a higher enzymatic activity than heated HEWL hydrolysates. PMID- 29697298 TI - Genetic Analysis of Victorin Sensitivity and Identification of a Causal Nucleotide-Binding Site Leucine-Rich Repeat Gene in Phaseolus vulgaris. AB - Cochliobolus victoria, the causal agent of Victoria blight, is pathogenic due to its production of a toxin called victorin. Victorin sensitivity in oats, barley, Brachypodium spp., and Arabidopsis has been associated with nucleotide-binding site leucine-rich repeat (NLR) genes, a class of genes known for conferring disease resistance. In this work, we investigated the sensitivity of Phaseolus vulgaris to victorin. We found that victorin sensivity in Phaseolus vulgaris is a developmentally regulated, quantitative trait. A single quantitative trait locus (QTL) accounted for 34% of the phenotypic variability in victorin sensitivity among Stampede * Red Hawk (S*R) recombinant inbred lines. We cloned two NLR encoding genes within this QTL and showed one, Phvul05G031200 (PvLOV), confers victorin-dependent cell death when overexpressed in Nicotiana benthamiana. Protein sequences of PvLOV from victorin-sensitive and the victorin-resistant bean parents differ by two amino acids in the leucine-rich repeat region, but both proteins confer victorin-dependent cell death when overexpressed in N. benthamiana. PMID- 29697299 TI - DNA barcoding revealed a new species of Neolissochilus Rainboth, 1985 from the Kaladan River of Mizoram, North East India. AB - Neolissochilus kaladanensis sp. nov., a new cyprinid species, is described from the Kaladan River drainage of Mizoram. It differs from all other valid Neolissochilus species in having higher number of gill rakers on the lower arm of the first gill arch (13-14 vs. 12 or below in all the species). The analysis of mitochondrial gene cytochrome c oxidase subunit I (COI) sequences separated N. kaladanensis sp. nov. from all other Neolissochilus and Tor species with an average genetic distance of 6.0%. It is further separated from the morphologically most similar species N. hendersoni and N. soroides by a genetic distance of 6.7% and 6.8%, respectively. Based on the lowest BIC and AICc scores, best fit model for COI dataset was TN93 + G + I, out of 24 different nucleotide substitution models tested. The maximum-likelihood (ML) phylogenetic tree was constructed using the COI sequences of representative Neolissochilus and Tor species. The anomalies observed among the GenBank sequences of the genera Tor and Neolissochilus are also discussed. PMID- 29697300 TI - Cooperative hydrogen bonds and mobility of the non-aromatic ring as selectivity determinants for human acetylcholinesterase to similar anti-Alzheimer's galantaminics: a computational study. AB - Galantamine (Gnt) is a natural alkaloid inhibitor of acetylcholinesterase and is presently one of the most used drugs in the treatment against Alzheimer's disease during both the initial and intermediate stages. Among several natural Gnt derivatives, sanguinine (Sng) and lycoramine (Lyc) attract attention because of the way their subtle chemical differences from Gnt lead to drastic and opposite distinctions in inhibitory effects. However, to date, there is no solved structure for these natural derivatives. In the present study, we applied computational modeling and free energy calculation methods to better elucidate the molecular basis of the subtle distinctions between these derivatives and Gnt. The results showed that differences in the mobility of the non-aromatic ring carried by the Lyc-like sp2-sp3 modification display drastic conformational, vibrational, and entropic penalties at binding compared to Gnt. Additionally, the establishment of a stronger hydrogen bond network added enthalpic advantages for the linkage of the Sng-like methoxy-hydroxy substituted ligands. These results, which suggest an affinity ranking in agreement with that found in the literature, provided insights that are helpful for future planning and development of new anti-Alzheimer's disease drugs. PMID- 29697301 TI - Outcomes of early carotid stenting and angioplasty in large-vessel anterior circulation strokes treated with mechanical thrombectomy and intravenous thrombolytics. AB - Introduction Proximal cervical internal carotid artery stenosis greater than 50% merits revascularization to mitigate the risk of stroke recurrence among large vessel anterior circulation strokes undergoing mechanical thrombectomy. Carotid artery stenting necessitates the use of antiplatelets, and there is a theoretical increased risk of hemorrhagic transformation given that such patients may already have received intravenous thrombolytics and have a significant infarct burden. We investigate the outcomes of large-vessel anterior circulation stroke patients treated with intravenous thrombolytics receiving same-day carotid stenting or selective angioplasty compared to no carotid intervention. Materials and methods The study cohort was obtained from the National (Nationwide) Inpatient Sample database between 2006 and 2014, using International Statistical Classification of Diseases, ninth revision discharge diagnosis and procedure codes. A total of 11,825 patients with large-vessel anterior circulation stroke treated with intravenous thrombolytic and mechanical thrombectomy on the same day were identified. The study population was subdivided into three subgroups: no carotid intervention, same-day carotid angioplasty without carotid stenting, and same-day carotid stenting. Outcomes were assessed with respect to mortality, significant disability at discharge, hemorrhagic transformation, and requirement of percutaneous endoscopic gastronomy tube placement, prolonged mechanical ventilation, or craniotomy. Results This study found no statistically significant difference in patient outcomes in those treated with concurrent carotid stenting compared to no carotid intervention in terms of morbidity or mortality. Conclusions If indicated, it is reasonable to consider concurrent carotid stenting and/or angioplasty for large-vessel anterior circulation stroke patients treated with mechanical thrombectomy who also receive intravenous thrombolytics. PMID- 29697303 TI - 2017 Michael Fry Award Lecture When DNA is Actually Not a Target: Radiation Epigenetics as a Tool to Understand and Control Cellular Response to Ionizing Radiation. AB - Aside from the generally accepted potential to cause DNA damage, it is becoming increasingly recognized that ionizing radiation has the capability to target the cellular epigenome. Epigenetics unifies the chemical marks and molecules that collectively facilitate the proper reading of genetic material. Among the epigenetic mechanisms of regulation, methylation of DNA is known to be the key player in the postirradiation response by controlling the expression of genetic information and activity of transposable elements. Radiation-induced alterations to DNA methylation may lead to cellular epigenetic reprogramming that, in turn, can substantially compromise the genomic integrity and has been proposed as one of the mechanisms of radiation-induced carcinogenesis. DNA methylation is strongly dependent on the one-carbon metabolism. This metabolic pathway is central to the support of DNA methylation by means of providing the donor of methyl groups, as well as for the synthesis of amino acids. To better understand the mechanisms of radiation-induced health effects, we study how exposure to radiation affects DNA methylation and one-carbon metabolism. Also, a tight interaction that exists between DNA methylation and one-carbon metabolism allows us to simultaneously manipulate both cellular epigenetic and metabolic profiles to modulate the normal and cancerous tissue response to radiotherapy. PMID- 29697305 TI - Corrigendum: Stand by Your Stroop: Standing Up Enhances Selective Attention and Cognitive Control. PMID- 29697306 TI - ELF-MF occupational exposure in die-casting and electroplating workers in Korea. AB - A 24-h exposure assessment was performed in two groups of blue-collar workers from a die-casting plant and an electroplating plant to investigate levels of exposure to extremely low-frequency magnetic fields (ELF-MFs), using an EMDEX Lite (Enertech, USA) dosimeter. ELF-MF exposure of workers from the die-casting plant (arithmetic M +/- SD 0.649 +/- 1.343 uT) is higher than in electroplating workers (0.138 +/- 0.045 uT). Higher ELF-MF exposure occurred among workers living in the same building as their workplace compared with that among other workers. This study suggests that ELF-MF exposure levels should be taken into consideration when providing dormitories for workers to minimize levels of residential ELF-MF exposure due to emissions from industrial plants. The study recommends that blue-collar workers should be made aware of measures to minimize their exposure to environmental agents such as ELF-MFs and electromagnetic fields during work, such as maintaining a safe distance between machines and avoiding undesirable behavior with equipment. PMID- 29697304 TI - Deep learning in pharmacogenomics: from gene regulation to patient stratification. AB - This Perspective provides examples of current and future applications of deep learning in pharmacogenomics, including: identification of novel regulatory variants located in noncoding domains of the genome and their function as applied to pharmacoepigenomics; patient stratification from medical records; and the mechanistic prediction of drug response, targets and their interactions. Deep learning encapsulates a family of machine learning algorithms that has transformed many important subfields of artificial intelligence over the last decade, and has demonstrated breakthrough performance improvements on a wide range of tasks in biomedicine. We anticipate that in the future, deep learning will be widely used to predict personalized drug response and optimize medication selection and dosing, using knowledge extracted from large and complex molecular, epidemiological, clinical and demographic datasets. PMID- 29697307 TI - How states exerted power to create the Millennium Development Goals and how this shaped the global health agenda: Lessons for the sustainable development goals and the future of global health. AB - Since 2000, the eight Millennium Development Goals (MDGs) provided the framework for global development efforts transforming the field now known as global health. The MDGs both reflected and contributed to shaping a normative global health agenda. In the field of global health, the role of the state is largely considered to have diminished; however, this paper reasserts states as actors in the conceptualisation and institutionalisation of the MDGs, and illustrates how states exerted power and engaged in the MDG process. States not only sanctioned the MDGs through their heads of states endorsing the Millennium Declaration, but also acted more subtly behind the scenes supporting, enabling, and/or leveraging other actors, institutions and processes to conceptualise and legitimize the MDGs. Appreciating the MDGs' role in the conceptualisation of global health is particularly relevant as the world transitions to the MDGs' successor, the Sustainable Development Goals (SDGs). The SDGs' influence, impact and importance remains to be seen; however, to understand the future of global health and how actors, particularly states, can engage to shape the field, a deeper sense of the MDGs' legacy and how actors engaged in the past is helpful. PMID- 29697308 TI - Emerging therapeutic targets in the short QT syndrome. AB - INTRODUCTION: Short QT Syndrome (SQTS) is a rare but dangerous condition characterised by abbreviated repolarisation, atrial and ventricular arrhythmias and risk of sudden death. Implantable cardioverter defibrillators (ICDs) are a first line protection against sudden death, but adjunct pharmacology is beneficial and desirable. Areas covered: The genetic basis for genotyped SQTS variants (SQT1-SQT8) and evidence for arrhythmia substrates from experimental and simulation studies are discussed. The main ion channel/transporter targets for antiarrhythmic pharmacology are considered in respect of potential genotype specific and non-specific treatments for the syndrome. Expert opinion: Potassium channel blockade is valuable for restoring repolarisation and QT interval, though genotype-specific limitations exist in the use of some K+ channel inhibitors. A combination of K+ current inhibition during the action potential plateau, with sodium channel inhibition that collectively result in delaying repolarisation and post-repolarisation refractoriness is likely to be valuable in prolonging effective refractory period and wavelength for re-entry. Genotype-specific K+ channel inhibition is limited by a lack of targeted inhibitors in clinical use, though experimentally available selective inhibitors now exist. The relatively low proportion of successfully genotyped cases justifies an exome or genome sequencing approach, to reveal new mediators and targets, as demonstrated recently for SLC4A3 in SQT8. PMID- 29697310 TI - BRUCELLA PINNIPEDIALIS IN GREY SEALS ( HALICHOERUS GRYPUS) AND HARBOR SEALS ( PHOCA VITULINA) IN THE NETHERLANDS. AB - Brucellosis is a zoonotic disease with terrestrial or marine wildlife animals as potential reservoirs for the disease in livestock and human populations. The primary aim of this study was to assess the presence of Brucella pinnipedialis in marine mammals living along the Dutch coast and to observe a possible correlation between the presence of B. pinnipedialis and accompanying pathology found in infected animals. The overall prevalence of Brucella spp. antibodies in sera from healthy wild grey seals ( Halichoerus grypus; n=11) and harbor seals ( Phoca vitulina; n=40), collected between 2007 and 2013 ranged from 25% to 43%. Additionally, tissue samples of harbor seals collected along the Dutch shores between 2009 and 2012, were tested for the presence of Brucella spp. In total, 77% (30/39) seals were found to be positive for Brucella by IS 711 real-time PCR in one or more tissue samples, including pulmonary nematodes. Viable Brucella was cultured from 40% (12/30) real-time PCR-positive seals, and was isolated from liver, lung, pulmonary lymph node, pulmonary nematode, or spleen, but not from any PCR-negative seals. Tissue samples from lung and pulmonary lymph nodes were the main source of viable Brucella bacteria. All isolates were typed as B. pinnipedialis by multiple-locus variable number of tandem repeats analysis-16 clustering and matrix-assisted laser desorption ionization-time of flight mass spectrometry, and of sequence type ST25 by multilocus sequence typing analysis. No correlation was observed between Brucella infection and pathology. This report displays the isolation and identification of B. pinnipedialis in marine mammals in the Dutch part of the Atlantic Ocean. PMID- 29697309 TI - Comprehensive identification of Vibrio vulnificus genes required for growth in human serum. AB - Vibrio vulnificus can be a highly invasive pathogen capable of spreading from an infection site to the bloodstream, causing sepsis and death. To survive and proliferate in blood, the pathogen requires mechanisms to overcome the innate immune defenses and metabolic limitations of this host niche. We created a high density transposon mutant library in YJ016, a strain representative of the most virulent V. vulnificus lineage (or phylogroup) and used transposon insertion sequencing (TIS) screens to identify loci that enable the pathogen to survive and proliferate in human serum. Initially, genes underrepresented for insertions were used to estimate the V. vulnificus essential gene set; comparisons of these genes with similar TIS-based classification of underrepresented genes in other vibrios enabled the compilation of a common Vibrio essential gene set. Analysis of the relative abundance of insertion mutants in the library after exposure to serum suggested that genes involved in capsule biogenesis are critical for YJ016 complement resistance. Notably, homologues of two genes required for YJ016 serum resistance and capsule biogenesis were not previously linked to capsule biogenesis and are largely absent from other V. vulnificus strains. The relative abundance of mutants after exposure to heat inactivated serum was compared with the findings from the serum screen. These comparisons suggest that in both conditions the pathogen relies on its Na+ transporting NADH-ubiquinone reductase (NQR) complex and type II secretion system to survive/proliferate within the metabolic constraints of serum. Collectively, our findings reveal the potency of comparative TIS screens to provide knowledge of how a pathogen overcomes the diverse limitations to growth imposed by serum. PMID- 29697311 TI - Assessment of Blood Lead, Zinc, and Mercury Concentrations and Cholinesterase Activity in Captive-reared Alligator Snapping Turtles ( Macrochelys temminckii) in Louisiana, USA. AB - The alligator snapping turtle ( Macrochelys temminckii) is a freshwater apex predator that has experienced severe population declines throughout its range due to historical overharvesting and habitat degradation. Because of its long lifespan, high trophic level, and limited home range, it is a suitable sentinel species for monitoring environmental contaminants. In Louisiana, US a pilot program aims to augment free-ranging populations by releasing captive-reared individuals. Baseline values of potential environmental contaminants were determined as part of an overall health assessment to evaluate captive-reared alligator snapping turtles for release. Blood samples from 3-yr-old ( n=23) and 4 yr-old ( n=11) captive-reared alligator snapping turtles were tested for lead (Pb), mercury (Hg), and zinc (Zn) levels by atomic absorption spectrophotometry and cholinesterase (ChE) activity (as a biomarker for organophosphate and carbamate exposure) by the modified Ellman method. Reference intervals were determined for Zn (34 to 295 MUg/dL), Hg (0 to 4.8 MUg/dL), and ChE (0.17 to 1.65 MUmole acetylthiocholine/mL per minute). Elevations of Pb, Zn, or Hg, or decreases in ChE activity levels of this cohort during recapture sampling may indicate point-source intoxications or bioaccumulation, both ultimately attributable to environmental contamination. The released animals may serve as sentinels for biomonitoring of their new habitat for the evaluated toxicants. PMID- 29697312 TI - A Mixture of Butorphanol, Azaperone, and Medetomidine for the Immobilization of American Beavers ( Castor canadensis). AB - A total of 58 American beavers ( Castor canadensis) was immobilized with butorphanol, azaperone, and medetomidine (BAM) for the purpose of health assessments, sex determination, and placement of very high-frequency tail transmitters in a subset of animals. Isoflurane gas anesthesia was available to aid with induction when needed, and all animals received supplementary oxygen. Thirty-one beavers immobilized with a mean (SD) dose of 0.65 (0.15) mg/kg butorphanol, 0.22 (0.05) mg/kg azaperone, and 0.26 (0.06) mg/kg medetomidine did not require supplemental isoflurane during induction and the mean induction time was 8 min (range: 3-21 min). This dose was equivalent to 0.024 (0.005) mL of BAM per kilogram. A total of 29 beavers that were immobilized with a mean (SD) of 0.51 (0.07) mg/kg butorphanol, 0.17 (0.02) mg/kg azaperone, and 0.2 (0.03) mg/kg medetomidine needed supplementary isoflurane at 5% and 5 L/min for <1 min to induce full anesthesia. In none of the beavers did BAM alone provide sufficient depth of anesthesia to drill a hole in the tail for transmitter placement, and supplementary isoflurane was administered to reach a sufficient level of analgesia for the procedure. The beavers were reversed with 5 mg of atipamezole per milligram of medetomidine and 1 mg of naltrexone per milligram of butorphanol. No adverse effects or mortalities were observed. Butorphanol azaperone-medetomidine can be considered safe for use in American beavers for minor procedures. PMID- 29697313 TI - Psychiatry residents' and fellows' confidence and knowledge in interpreting urine drug testing results related to opioids. AB - BACKGROUND: Prior studies have suggested that physicians and residents may not have sufficient knowledge to appropriately interpret urine drug tests (UDTs) in patients who are prescribed opioids or using illicit substances. Therefore, the aim of this study was to survey psychiatry residents and fellows about their confidence and knowledge in interpreting UDTs in patients with chronic pain or receiving office-based opioid treatment. METHODS: All psychiatry residency and fellowship program directors in the New England states were approached to recruit their trainees to participate in an anonymous online survey including a 7-item knowledge test. RESULTS: A total of 93 residents and fellows completed the survey. Only a minority (24.7%) reported any prior training in UDT interpretation. A majority (62.6%) felt confident about interpreting UDTs. The mean total score for the knowledge test was 3.5 (SD =1.1, range: 1-6). There were no significant differences in total score by confidence in UDT interpretation (3.7 vs. 3.4, t = -1.17, nonsignificant [NS]), nor by prior training in UDT interpretation (3.8 vs. 3.5, t = -1.22, NS). CONCLUSIONS: Psychiatry residents and fellows infrequently receive training in UDT interpretation, score poorly on the knowledge test, and their confidence in UDT interpretation does not reflect their knowledge. Future research should evaluate educational interventions that improve UDT interpretation among psychiatry residents and fellows. PMID- 29697314 TI - Productive aging via volunteering: Does social cohesion influence level of engagement? AB - This study investigated whether neighborhood social cohesion influenced volunteer intensity over two years. The sample was drawn from Health and Retirement Study respondents who completed the 2010 or 2012 Psychosocial and Lifestyle Questionnaire (n = 12,929). Results showed that compared to nonvolunteers, a one unit increase in neighborhood social cohesion increased the odds of moderate (OR: 1.07, p < .05) and high volunteering (OR: 1.10, p < .001). However, other productive roles, social contact, and education were significant in distinguishing high intensity from moderate volunteering while neighborhood social cohesion was not. Social workers should consider the neighborhood environment when recruiting volunteers. PMID- 29697315 TI - Erratum. PMID- 29697317 TI - LEAD the Way: Using Local Communities as Legal Laboratories to Combat Drug Addiction. PMID- 29697316 TI - A Call for National Legislation Regarding Amusement Park Safety. PMID- 29697319 TI - 2016 HLMC Best Brief. PMID- 29697318 TI - 2016-2017 Southern Illinois University National Health Law Moot Court Competition. PMID- 29697320 TI - From Dark Dens to Suburban Townhouses: Creating a Centralized System for Prescription Opiate Monitoring to Combat the Addiction Epidemic in the United States. PMID- 29697321 TI - Case Comment: Moore v. Texas. PMID- 29697323 TI - Mental Health in Prisons: Treatment or Unconstitutional Interrogation? An Introduction to the 2016 National Health Law Moot Court Competition. PMID- 29697324 TI - Why Bioethics Should Be Concerned With Medically Unexplained Symptoms. AB - Biomedical diagnostic science is a great deal less successful than we've been willing to acknowledge in bioethics, and this fact has far-reaching ethical implications. In this article I consider the surprising prevalence of medically unexplained symptoms, and the term's ambiguous meaning. Then I frame central questions that remain answered in this context with respect to informed consent, autonomy, and truth-telling. Finally, I show that while considerable attention in this area is given to making sure not to provide biological care to patients without a need, comparatively little is given to the competing, ethically central task of making sure never to obstruct access to biological care for those with diagnostically confusing biological conditions. I suggest this problem arises from confusion about the philosophical value of vagueness when it comes to the line between biological and psychosocial needs. PMID- 29697325 TI - Calibrating Confident Judgments About Medically Unexplained Symptoms. PMID- 29697326 TI - Unsolicited Diagnosis of Mental Disorder: Epistemic and Normative Perspectives. PMID- 29697327 TI - Neurologists, Psychiatrists, and the Angry Patients They Share. PMID- 29697328 TI - Tutorials, Taxonomies, and Troubles With Miracle Language in Pediatric Medicine. PMID- 29697330 TI - When a Miracle Is Expected: Allowing Space to Believe. PMID- 29697329 TI - Responding to Those Who Hope for a Miracle: Practices for Clinical Bioethicists. AB - Significant challenges arise for clinical care teams when a patient or surrogate decision-maker hopes a miracle will occur. This article answers the question, "How should clinical bioethicists respond when a medical decision-maker uses the hope for a miracle to orient her medical decisions?" We argue the ethicist must first understand the complexity of the miracle-invocation. To this end, we provide a taxonomy of miracle-invocations that assist the ethicist in analyzing the invocator's conceptions of God, community, and self. After the ethicist appreciates how these concepts influence the invocator's worldview, she can begin responding to this hope with specific practices. We discuss these practices in detail and offer concrete recommendations for a justified response to the hope for a miracle. PMID- 29697331 TI - What's in a Name? The Ethical Importance of Respecting a Patient's "Unexplained" Medical Concerns. PMID- 29697332 TI - From Frankenstein to Hawking: Which is the Real Face of Science? PMID- 29697333 TI - Consequences of the Complexity and Variety of Beliefs About Miracles. PMID- 29697334 TI - Why Bioethics Should Pay Attention to Patients Who Suffer Medically Unexplained (Physical) Symptoms-A Discussion of Uncertainty, Suffering, and Risk. PMID- 29697335 TI - Rejecting Reality and Substituting One?'s Own; Why Bioethics Should Be Concerned With Medically Unexplained Symptoms. PMID- 29697336 TI - The Need for Improved Access to Mental Health Services for Youth With Medically Unexplained Symptoms. PMID- 29697337 TI - Conversion Disorder Diagnosis and Medically Unexplained Symptoms. PMID- 29697338 TI - Schrodinger's Disease and the Ethics of (Non)Diagnosis: The Problem of Medically Unexplained Symptoms in Contemporary Medical Practice. PMID- 29697339 TI - A Feminist Bioethics Approach to Diagnostic Uncertainty. PMID- 29697340 TI - Miracles, Scarce Resources, and Fairness. PMID- 29697341 TI - Miracles for the 'Nones'. PMID- 29697342 TI - Treating Medically Unexplained Symptoms Empirically: Ethical Implications for Concurrent Diagnosis. PMID- 29697343 TI - In Search of a Place for Mystery in Clinical Bioethics. PMID- 29697345 TI - Shaken not Stirred: What Are Ethicists Licensed to Do? PMID- 29697344 TI - Medically Unexplained Symptoms and the Diagnosis of Medical Child Abuse. PMID- 29697346 TI - Fairly Allocating Space in an Immunotherapy Production Facility: Reply to Critics. PMID- 29697347 TI - Peering into the Future of Peer Review. PMID- 29697348 TI - Psychological Aspects of Hoping for a Miracle. PMID- 29697349 TI - Facts and Fetishes: When the Miracles of Medicine Fail Us. PMID- 29697350 TI - Response to Open Peer Commentaries on "Responding to Those Who Hope for a Miracle: Practices for Clinical Bioethicists". PMID- 29697351 TI - Shouldn't Chaplains Be Handling Cases With Miracle Language? PMID- 29697352 TI - Trustworthiness in Untrustworthy Times: Response to Open Peer Commentaries on Beyond Consent. PMID- 29697353 TI - Graft Failure and Repeat Penetrating Keratoplasty. AB - OBJECTIVES: In this study, we report the indications and outcomes of repeat penetrating keratoplasty and the reasons for graft failure. MATERIALS AND METHODS: We performed a retrospective data analysis of patients who had undergone 2 or more penetrating keratoplasties for the same eye between 1991 and 2016. RESULTS: Among 1613 penetrating keratoplasties, 149 regrafts of 105 eyes were reviewed. The mean follow-up time after repeat penetrating keratoplasty was 3.2 +/- 3.9 (range, 3 months to 17 years) years. The mean number of penetrating keratoplasties was 2.25 +/- 0.69 per eye (range, 2-6). The most common primary indication for repeat penetrating keratoplasty was bullous keratopathy (31.4%), which was followed by corneal dystrophy (20.0%). The mean follow-up time was 8.05 +/- 5.03 years (range, 8 mo to 24.75 y). At the last follow-up, 62 eyes (59%) had clear grafts and the mean best-corrected visual acuity was 1.26 +/- 0.99 (range, 0-3) logMAR. Endothelial failure, especially late endothelial failure (36.9%), and glaucoma-related endothelial failure (18.8%) were the most common reasons for failed grafts. Allograft rejection (17.4%) and graft infection (14.1%) constituted the next most frequent causes. CONCLUSIONS: Graft failure is a common indication among penetrating keratoplasties. Primary indications and reasons for failed grafts affect long-term outcomes. Therefore, a better understanding of the indications for risk, leading causes of failed grafts, and complications could help to determine effective preventive measures. PMID- 29697354 TI - Comparison Between Bipolar Lymphatic Vessels Cautery and Suture Ligature in Prevention of Postrenal Transplant Lymphocele Formation: A Randomized Controlled Trial. AB - OBJECTIVES: In this randomized controlled trial, our aim was to compare bipolar cautery of lymphatic vessels with standard silk-tie ligation in renal transplant procedures for prevention of lymphocele formation. MATERIALS AND METHODS: Sixty end-stage renal disease patients were enrolled in a prospective randomized controlled trial. The mean age of recipients in the suture ligature group was 41.6 years (range, 6-65 years) and 40.9 years in the bipolar cautery group. Patients were assessed by symptoms; however, ultrasonography was also used as the primary diagnostic procedure in all patients to find lymphocele collection within 5 months. RESULTS: Of 60 patients, 25 received living-donor kidney transplant and 35 received deceased-donor kidney transplant. Fifty-threeprocedures were first time kidney transplants, 6 were retransplants, and 1 was for a third-time transplant. No lymphocele collection (symptomatic or asymptomatic) was diagnosed by ultrasonography at the 5-month follow-up. Postoperative pain was not significantly different between the 2 groups (P = .245). The time for ligation or cauterization of lymphatic vessels was similar between the 2 groups. Mean duration of operative field drainage was 5.6 days in the suture ligature group and 6.07 days in the bipolar cautery group (not significantly different; P = .547). CONCLUSIONS: Bipolar cautery of lymphatic vessels to prevent lymphocele formation in kidney transplant seems to be an effective, easy, and safe method. PMID- 29697355 TI - Genetic Variation of Costimulatory Molecules, Including Cytotoxic T-Lymphocyte Antigen 4, Inducible T-Cell Costimulator, Cluster Differentiation 28, and Programmed Cell Death 1 Genes, in Iranian Patients With Leukemia. AB - OBJECTIVES: There are limited studies about the possible relationship between genetic variations of costimulatory genes and susceptibility to hematologic malignancies like leukemia and lymphoma. MATERIALS AND METHODS: This cross sectional study included 59 leukemia patients. The polymorphisms of costimulatory molecules, including the CTLA-4 gene (-318 C/T, -1722 T/C, -1661 A/G, +49 A/G), PD-1 gene (1.3 A/G, 1.9 C/T), ICOS gene (1720 C/T), and CD28 gene (17 C/T), were analyzed by polymerase chain reaction-restriction fragment length polymorphism methods. RESULTS: Our results showed that the TT genotype and T allele of the CTLA-4 -318 T/C polymorphism, the AA genotype of CTLA-4 +49 A/G polymorphism, and the CT genotype of PD-1 1.9 C/T polymorphism were significantly higher in healthy controls (P < .05). However, the AG genotype of the CTLA-4 +49 A/G, the CC genotype of the PD-1 1.9 C/T, and the CT genotype of the CD28 +17C/T polymorphism were significantly increased in patients with leukemia (P < .05). When the genotype frequency of costimulatory genes was compared between different leukemia groups, we observed that the A allele of the CTLA-4 +49 A/G and the CC genotype and C allele of the CD28 +17 C/T polymorphism were significantly higher in patients with acute leukemia than in those with chronic leukemia (P < .05). Among leukemia patients, the AA genotype of CTLA-4 +49A/G polymorphism was significantly increased in patients with acute myeloid leukemia, whereas the AG genotype was more prevalent in patients with acute lymphoblastic leukemia (P < .05). CONCLUSIONS: We show for the first time that genetic variations of costimulatory molecules CTLA-4, CD28, and PD-1 may be associated with susceptibility of Iranian patients to leukemia. PMID- 29697356 TI - Early Immune Response to Acute Gastric Fluid Aspiration in a Rat Model of Lung Transplantation. AB - OBJECTIVES: Chronic aspiration of gastric fluid contents can decrease long-term survival of pulmonary transplants due to development of obliterative bronchiolitis. However, little is known about the early immune response and the cascade of events involved in the development of obliterative bronchiolitis. MATERIALS AND METHODS: We utilized a rat orthotopic pulmonary transplant model and a single aspiration of either gastric fluid or normal saline to investigate the histologic, cellular, and cytokine changes associated with an acute gastric fluid aspiration event compared with normal saline at 2 and 10 days after aspiration. RESULTS: Our observations included a decrease in pulmonary compliance and increased airway inflammation and acute rejection of the transplanted lung, as well as increases in macrophages, granulocytes, and proinflammatory cytokines such as interleukin 1beta, transforming growth factor beta1 and beta2, and tumor necrosis factor alpha in bronchoalveolar lavage fluid from the transplanted lung of gastric fluid-aspirated rats compared with normal saline-aspirated rats. CONCLUSIONS: The acute inflammatory response observed in the present study is consistent with changes found in chronic models of aspiration-associated injury and suggests a potentially important role for mast cells in the development of obliterative bronchiolitis. PMID- 29697357 TI - EDITORIAL: Emerging Bio-inspired and Bio-Compatible Nanomaterials in 21st Century. PMID- 29697358 TI - Editorial: Nanomedicine's Multi-pronged Approach in Tackling Cancer. PMID- 29697359 TI - Editorial: Alteration of Redox Equilibrium, Inflammation and Progression of Disease. PMID- 29697360 TI - WISARD: workbench for integrated superfast association studies for related datasets. AB - BACKGROUND: A Mendelian transmission produces phenotypic and genetic relatedness between family members, giving family-based analytical methods an important role in genetic epidemiological studies-from heritability estimations to genetic association analyses. With the advance in genotyping technologies, whole-genome sequence data can be utilized for genetic epidemiological studies, and family based samples may become more useful for detecting de novo mutations. However, genetic analyses employing family-based samples usually suffer from the complexity of the computational/statistical algorithms, and certain types of family designs, such as incorporating data from extended families, have rarely been used. RESULTS: We present a Workbench for Integrated Superfast Association studies for Related Data (WISARD) programmed in C/C++. WISARD enables the fast and a comprehensive analysis of SNP-chip and next-generation sequencing data on extended families, with applications from designing genetic studies to summarizing analysis results. In addition, WISARD can automatically be run in a fully multithreaded manner, and the integration of R software for visualization makes it more accessible to non-experts. CONCLUSIONS: Comparison with existing toolsets showed that WISARD is computationally suitable for integrated analysis of related subjects, and demonstrated that WISARD outperforms existing toolsets. WISARD has also been successfully utilized to analyze the large-scale massive sequencing dataset of chronic obstructive pulmonary disease data (COPD), and we identified multiple genes associated with COPD, which demonstrates its practical value. PMID- 29697361 TI - Mut2Vec: distributed representation of cancerous mutations. AB - BACKGROUND: Embedding techniques for converting high-dimensional sparse data into low-dimensional distributed representations have been gaining popularity in various fields of research. In deep learning models, embedding is commonly used and proven to be more effective than naive binary representation. However, yet no attempt has been made to embed highly sparse mutation profiles into densely distributed representations. Since binary representation does not capture biological context, its use is limited in many applications such as discovering novel driver mutations. Additionally, training distributed representations of mutations is challenging due to a relatively small amount of available biological data compared with the large amount of text corpus data in text mining fields. METHODS: We introduce Mut2Vec, a novel computational pipeline that can be used to create a distributed representation of cancerous mutations. Mut2Vec is trained on cancer profiles using Skip-Gram since cancer can be characterized by a series of co-occurring mutations. We also augmented our pipeline with existing information in the biomedical literature and protein-protein interaction networks to compensate for the data insufficiency. RESULTS: To evaluate our models, we conducted two experiments that involved the following tasks: a) visualizing driver and passenger mutations, b) identifying novel driver mutations using a clustering method. Our visualization showed a clear distinction between passenger mutations and driver mutations. We also found driver mutation candidates and proved that these were true driver mutations based on our literature survey. The pre-trained mutation vectors and the candidate driver mutations are publicly available at http://infos.korea.ac.kr/mut2vec . CONCLUSIONS: We introduce Mut2Vec that can be utilized to generate distributed representations of mutations and experimentally validate the efficacy of the generated mutation representations. Mut2Vec can be used in various deep learning applications such as cancer classification and drug sensitivity prediction. PMID- 29697362 TI - An integrated clinical and genomic information system for cancer precision medicine. AB - BACKGROUND: Increasing affordability of next-generation sequencing (NGS) has created an opportunity for realizing genomically-informed personalized cancer therapy as a path to precision oncology. However, the complex nature of genomic information presents a huge challenge for clinicians in interpreting the patient's genomic alterations and selecting the optimum approved or investigational therapy. An elaborate and practical information system is urgently needed to support clinical decision as well as to test clinical hypotheses quickly. RESULTS: Here, we present an integrated clinical and genomic information system (CGIS) based on NGS data analyses. Major components include modules for handling clinical data, NGS data processing, variant annotation and prioritization, drug-target-pathway analysis, and population cohort explorer. We built a comprehensive knowledgebase of genes, variants, drugs by collecting annotated information from public and in-house resources. Structured reports for molecular pathology are generated using standardized terminology in order to help clinicians interpret genomic variants and utilize them for targeted cancer therapy. We also implemented many features useful for testing hypotheses to develop prognostic markers from mutation and gene expression data. CONCLUSIONS: Our CGIS software is an attempt to provide useful information for both clinicians and scientists who want to explore genomic information for precision oncology. PMID- 29697363 TI - Identifying statistically significant combinatorial markers for survival analysis. AB - BACKGROUND: Survival analysis methods have been widely applied in different areas of health and medicine, spanning over varying events of interest and target diseases. They can be utilized to provide relationships between the survival time of individuals and factors of interest, rendering them useful in searching for biomarkers in diseases such as cancer. However, some disease progression can be very unpredictable because the conventional approaches have failed to consider multiple-marker interactions. An exponential increase in the number of candidate markers requires large correction factor in the multiple-testing correction and hide the significance. METHODS: We address the issue of testing marker combinations that affect survival by adapting the recently developed Limitless Arity Multiple-testing Procedure (LAMP), a p-value correction technique for statistical tests for combination of markers. LAMP cannot handle survival data statistics, and hence we extended LAMP for the log-rank test, making it more appropriate for clinical data, with newly introduced theoretical lower bound of the p-value. RESULTS: We applied the proposed method to gene combination detection for cancer and obtained gene interactions with statistically significant log-rank p-values. Gene combinations with orders of up to 32 genes were detected by our algorithm, and effects of some genes in these combinations are also supported by existing literature. CONCLUSION: The novel approach for detecting prognostic markers presented here can identify statistically significant markers with no limitations on the order of interaction. Furthermore, it can be applied to different types of genomic data, provided that binarization is possible. PMID- 29697364 TI - IMPACT web portal: oncology database integrating molecular profiles with actionable therapeutics. AB - BACKGROUND: With the advancement of next generation sequencing technology, researchers are now able to identify important variants and structural changes in DNA and RNA in cancer patient samples. With this information, we can now correlate specific variants and/or structural changes with actionable therapeutics known to inhibit these variants. We introduce the creation of the IMPACT Web Portal, a new online resource that connects molecular profiles of tumors to approved drugs, investigational therapeutics and pharmacogenetics associated drugs. RESULTS: IMPACT Web Portal contains a total of 776 drugs connected to 1326 target genes and 435 target variants, fusion, and copy number alterations. The online IMPACT Web Portal allows users to search for various genetic alterations and connects them to three levels of actionable therapeutics. The results are categorized into 3 levels: Level 1 contains approved drugs separated into two groups; Level 1A contains approved drugs with variant specific information while Level 1B contains approved drugs with gene level information. Level 2 contains drugs currently in oncology clinical trials. Level 3 provides pharmacogenetic associations between approved drugs and genes. CONCLUSION: IMPACT Web Portal allows for sequencing data to be linked to actionable therapeutics for translational and drug repurposing research. The IMPACT Web Portal online resource allows users to query genes and variants to approved and investigational drugs. We envision that this resource will be a valuable database for personalized medicine and drug repurposing. IMPACT Web Portal is freely available for non-commercial use at http://tanlab.ucdenver.edu/IMPACT . PMID- 29697365 TI - Population-based statistical inference for temporal sequence of somatic mutations in cancer genomes. AB - BACKGROUND: It is well recognized that accumulation of somatic mutations in cancer genomes plays a role in carcinogenesis; however, the temporal sequence and evolutionary relationship of somatic mutations remain largely unknown. METHODS: In this study, we built a population-based statistical framework to infer the temporal sequence of acquisition of somatic mutations. Using the model, we analyzed the mutation profiles of 1954 tumor specimens across eight tumor types. RESULTS: As a result, we identified tumor type-specific directed networks composed of 2-15 cancer-related genes (nodes) and their mutational orders (edges). The most common ancestors identified in pairwise comparison of somatic mutations were TP53 mutations in breast, head/neck, and lung cancers. The known relationship of KRAS to TP53 mutations in colorectal cancers was identified, as well as potential ancestors of TP53 mutation such as NOTCH1, EGFR, and PTEN mutations in head/neck, lung and endometrial cancers, respectively. We also identified apoptosis-related genes enriched with ancestor mutations in lung cancers and a relationship between APC hotspot mutations and TP53 mutations in colorectal cancers. CONCLUSION: While evolutionary analysis of cancers has focused on clonal versus subclonal mutations identified in individual genomes, our analysis aims to further discriminate ancestor versus descendant mutations in population-scale mutation profiles that may help select cancer drivers with clinical relevance. PMID- 29697366 TI - Fuzzy set-based generalized multifactor dimensionality reduction analysis of gene gene interactions. AB - BACKGROUND: Gene-gene interactions (GGIs) are a known cause of missing heritability. Multifactor dimensionality reduction (MDR) is one of most commonly used methods for GGI detection. The generalized multifactor dimensionality reduction (GMDR) method is an extension of MDR method that is applicable to various types of traits, and allows covariate adjustments. Our previous Fuzzy MDR (FMDR) is another extension for overcoming simple binary classification. FMDR uses continuous member-ship values instead of binary membership values 0 and 1, improving power for detecting causal SNPs and more intuitive interpretations in real data analysis. Here, we propose the fuzzy generalized multifactor dimensionality reduction (FGMDR) method, as a combined analysis of fuzzy set based analysis and GMDR method, to detect GGIs associated with diseases using fuzzy set theory. RESULTS: Through simulation studies for different types of traits, the proposed FGMDR showed a higher detection ratio of causal SNPs, compared to GMDR. We then applied FGMDR to two real data: Crohn's disease (CD) data from the Wellcome Trust Case Control Consortium (WTCCC) with a binary phenotype and the Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) data from Korean population with a continuous phenotype. The interactions derived by our method include the pre-reported interactions associated with phenotypes. CONCLUSIONS: The proposed FGMDR performs well for GGI detection with covariate adjustments. The program written in R for FGMDR is available at http://statgen.snu.ac.kr/software/FGMDR . PMID- 29697367 TI - CAS-viewer: web-based tool for splicing-guided integrative analysis of multi omics cancer data. AB - BACKGROUND: The Cancer Genome Atlas (TCGA) project is a public resource that provides transcriptomic, DNA sequence, methylation, and clinical data for 33 cancer types. Transforming the large size and high complexity of TCGA cancer genome data into integrated knowledge can be useful to promote cancer research. Alternative splicing (AS) is a key regulatory mechanism of genes in human cancer development and in the interaction with epigenetic factors. Therefore, AS-guided integration of existing TCGA data sets will make it easier to gain insight into the genetic architecture of cancer risk and related outcomes. There are already existing tools analyzing and visualizing alternative mRNA splicing patterns for large-scale RNA-seq experiments. However, these existing web-based tools are limited to the analysis of individual TCGA data sets at a time, such as only transcriptomic information. RESULTS: We implemented CAS-viewer (integrative analysis of Cancer genome data based on Alternative Splicing), a web-based tool leveraging multi-cancer omics data from TCGA. It illustrates alternative mRNA splicing patterns along with methylation, miRNAs, and SNPs, and then provides an analysis tool to link differential transcript expression ratio to methylation, miRNA, and splicing regulatory elements for 33 cancer types. Moreover, one can analyze AS patterns with clinical data to identify potential transcripts associated with different survival outcome for each cancer. CONCLUSIONS: CAS viewer is a web-based application for transcript isoform-driven integration of multi-omics data in multiple cancer types and will aid in the visualization and possible discovery of biomarkers for cancer by integrating multi-omics data from TCGA. PMID- 29697368 TI - Exact association test for small size sequencing data. AB - BACKGROUND: Recent statistical methods for next generation sequencing (NGS) data have been successfully applied to identifying rare genetic variants associated with certain diseases. However, most commonly used methods (e.g., burden tests and variance-component tests) rely on large sample sizes. Notwithstanding, due to its-still high cost, NGS data is generally restricted to small sample sizes, that cannot be analyzed by most existing methods. METHODS: In this work, we propose a new exact association test for sequencing data that does not require a large sample approximation, which is applicable to both common and rare variants. Our method, based on the Generalized Cochran-Mantel-Haenszel (GCMH) statistic, was applied to NGS datasets from intraductal papillary mucinous neoplasm (IPMN) patients. IPMN is a unique pancreatic cancer subtype that can turn into an invasive and hard-to-treat metastatic disease. RESULTS: Application of our method to IPMN data successfully identified susceptible genes associated with progression of IPMN to pancreatic cancer. CONCLUSIONS: Our method is expected to identify disease-associated genetic variants more successfully, and corresponding signal pathways, improving our understanding of specific disease's etiology and prognosis. PMID- 29697369 TI - EAGLE: Explicit Alternative Genome Likelihood Evaluator. AB - BACKGROUND: Reliable detection of genome variations, especially insertions and deletions (indels), from single sample DNA sequencing data remains challenging, partially due to the inherent uncertainty involved in aligning sequencing reads to the reference genome. In practice a variety of ad hoc quality filtering methods are employed to produce more reliable lists of putative variants, but the resulting lists typically still include numerous false positives. Thus it would be desirable to be able to rigorously evaluate the degree to which each putative variant is supported by the data. Unfortunately, users who wish to do this, e.g. for the purpose of prioritizing validation experiments, have been faced with limited options. RESULTS: Here we present EAGLE, a method for evaluating the degree to which sequencing data supports a given candidate genome variant. EAGLE incorporates candidate variants into explicit hypotheses about the individual's genome, and then computes the probability of the observed data (the sequencing reads) under each hypothesis. In comparison with methods which rely heavily on a particular alignment of the reads to the reference genome, EAGLE readily accounts for uncertainties that may arise from multi-mapping or local misalignment and uses the entire length of each read. We compared the scores assigned by several well-known variant callers to EAGLE for the task of ranking true putative variants on both simulated data and real genome sequencing based benchmarks. For indels, EAGLE obtained marked improvement on simulated data and a whole genome sequencing benchmark, and modest but statistically significant improvement on an exome sequencing benchmark. CONCLUSIONS: EAGLE ranked true variants higher than the scores reported by the callers and can used to improve specificity in variant calling. EAGLE is freely available at https://github.com/tony-kuo/eagle . PMID- 29697370 TI - LDSplitDB: a database for studies of meiotic recombination hotspots in MHC using human genomic data. AB - BACKGROUND: Meiotic recombination happens during the process of meiosis when chromosomes inherited from two parents exchange genetic materials to generate chromosomes in the gamete cells. The recombination events tend to occur in narrow genomic regions called recombination hotspots. Its dysregulation could lead to serious human diseases such as birth defects. Although the regulatory mechanism of recombination events is still unclear, DNA sequence polymorphisms have been found to play crucial roles in the regulation of recombination hotspots. METHOD: To facilitate the studies of the underlying mechanism, we developed a database named LDSplitDB which provides an integrative and interactive data mining and visualization platform for the genome-wide association studies of recombination hotspots. It contains the pre-computed association maps of the major histocompatibility complex (MHC) region in the 1000 Genomes Project and the HapMap Phase III datasets, and a genome-scale study of the European population from the HapMap Phase II dataset. Besides the recombination profiles, related data of genes, SNPs and different types of epigenetic modifications, which could be associated with meiotic recombination, are provided for comprehensive analysis. To meet the computational requirement of the rapidly increasing population genomics data, we prepared a lookup table of 400 haplotypes for recombination rate estimation using the well-known LDhat algorithm which includes all possible two-locus haplotype configurations. CONCLUSION: To the best of our knowledge, LDSplitDB is the first large-scale database for the association analysis of human recombination hotspots with DNA sequence polymorphisms. It provides valuable resources for the discovery of the mechanism of meiotic recombination hotspots. The information about MHC in this database could help understand the roles of recombination in human immune system. DATABASE URL: http://histone.scse.ntu.edu.sg/LDSplitDB. PMID- 29697371 TI - Large-scale two-photon imaging revealed super-sparse population codes in the V1 superficial layer of awake monkeys. AB - One general principle of sensory information processing is that the brain must optimize efficiency by reducing the number of neurons that process the same information. The sparseness of the sensory representations in a population of neurons reflects the efficiency of the neural code. Here, we employ large-scale two-photon calcium imaging to examine the responses of a large population of neurons within the superficial layers of area V1 with single-cell resolution, while simultaneously presenting a large set of natural visual stimuli, to provide the first direct measure of the population sparseness in awake primates. The results show that only 0.5% of neurons respond strongly to any given natural image - indicating a ten-fold increase in the inferred sparseness over previous measurements. These population activities are nevertheless necessary and sufficient to discriminate visual stimuli with high accuracy, suggesting that the neural code in the primary visual cortex is both super-sparse and highly efficient. PMID- 29697372 TI - Coordination of robust single cell rhythms in the Arabidopsis circadian clock via spatial waves of gene expression. AB - The Arabidopsis circadian clock orchestrates gene regulation across the day/night cycle. Although a multiple feedback loop circuit has been shown to generate the 24-hr rhythm, it remains unclear how robust the clock is in individual cells, or how clock timing is coordinated across the plant. Here we examine clock activity at the single cell level across Arabidopsis seedlings over several days under constant environmental conditions. Our data reveal robust single cell oscillations, albeit desynchronised. In particular, we observe two waves of clock activity; one going down, and one up the root. We also find evidence of cell-to cell coupling of the clock, especially in the root tip. A simple model shows that cell-to-cell coupling and our measured period differences between cells can generate the observed waves. Our results reveal the spatial structure of the plant clock and suggest that unlike the centralised mammalian clock, the Arabidopsis clock has multiple coordination points. PMID- 29697374 TI - [MINIMALLY INVASIVE SURGERY OF CEREBRAL ANEURYSMS]. AB - Minimally invasive neurosurgery has significantly evolved over the last several decades. This is due to the improvement of neurodiagnostics, microneurosurgical techniques, neuroanesthesiology and intraoperative imaging. Aim - authors present the results of the use of minimally invasive surgery (MIS) in cerebral aneurysms. In the period 2013-2017, we used 4 minimally invasive approaches in 240 patients with 246 aneurysms. The choice of surgical approach was determined after a thorough evaluation of the intracranial structures and aneurysms. We retrospectively evaluated outcomes, postoperative complications and cosmetic result after MIS. On average, the catamnesis was 6-12 months. Mortality, disability or serious permanent approach-related complications in our group have not been noted. All patients had expected periorbital edema, which was not regarded as a complication. Postoperative cosmetic result was assessed by patients as excellent. Minimally invasive surgery with adequate selection of patients is a safe and effective alternative to traditional approaches in cerebral aneurysm surgery. Rapid recovery of patients and a reduction in the duration of inpatient treatment with the possibility of fast social and labor adaptation after complex neurosurgical interventions is a priority necessity today. PMID- 29697373 TI - VEGF signaling regulates the fate of obstructed capillaries in mouse cortex. AB - Cortical capillaries are prone to obstruction, which over time, could have a major impact on brain angioarchitecture and function. The mechanisms that govern the removal of these obstructions and what long-term fate awaits obstructed capillaries, remains a mystery. We estimate that ~0.12% of mouse cortical capillaries are obstructed each day (lasting >20 min), preferentially in superficial layers and lower order branches. Tracking natural or microsphere induced obstructions revealed that 75-80% of capillaries recanalized within 24 hr. Remarkably, 30% of all obstructed capillaries were pruned by 21 days, including some that had regained flow. Pruning involved regression of endothelial cells, which was not compensated for by sprouting. Using this information, we predicted capillary loss with aging that closely matched experimental estimates. Genetic knockdown or inhibition of VEGF-R2 signaling was a critical factor in promoting capillary recanalization and minimizing subsequent pruning. Our studies reveal the incidence, mechanism and long-term outcome of capillary obstructions which can also explain age-related capillary rarefaction. PMID- 29697375 TI - [URETERS INPLANTATION METHOD INTO LOW-PRESSURE SMALL INTESTINE RESERVOIR]. AB - Urine derivation after cystectomy or due to bladder functional impairment more has been a pressing problem in urology for more than a century. Various techniques of urinary derivation after cystectomy due to bladder cancer or non cancerous diseases have been suggested. In the present day, more often, the artificial reservoirs are formed from the various intestinal segments. The article describes preoperative preparation of patients, surgical technique and efficiency of the specific method of implantation of ureters into low-pressure small intestine reservoir. Statistical data of Al. Tsulukidze National Center of Urology since 1987 and postoperative results and recommendations are presented. PMID- 29697376 TI - EFFICACY OF SILODOSIN (UROREC(r)) IN THE TREATMENT OF BENIGN PROSTATIC HYPERPLASIA: THE MAXIMUM DECREASE OF BLADDER OUTLET OBSTRUCTION INDEX. AB - One of the main causes of lower urinary tract symptoms in men over the age of 40 years old is benign prostatic hyperplasia (BPH), which according to the research is detected in 26.2% of men of this age group. The purpose of this study was to evaluate the efficacy of the use of silodosin (Urorec(r)) at dosage 8 mg once a day for relief of obstructive symptoms of BPH in men over 40 years old. From September 2016 till December 2017 144 men (residents of Almaty, the Republic of Kazakhstan) aged from 56 to 81 years old (63.9 [95% CI: 63.2, 64.5]) were included into the study with a diagnosis of benign prostatic hyperplasia. Uroflowmetry (Qmax determination) was performed to all patients initially, after 7, 14, 30, 60 and 120 days from initiation of treatment. IPSS questionnaires were filled initially, after 30, 60 and 120 days from the start of treatment, and 21 men underwent a complex urodynamic study with determination of PdetQmax, Qmax and BOOI (at baseline and after 120 days). A significant decrease in bladder outlet obstruction index was observed with silodosin reception (Urorec(r)) 8 mg once daily (-28.8 [95% CI: -28.2, -29.5] or -44.5% [95% CI: -43.4%, - 45.5%] (p <0.001)), a decrease in IPSS scores after 30, 60 and 120 days from initiation of treatment (-6.3 [95% CI: -5.9, -6.7], -6.5 [95% CI: -6.1, - 6.9], -6.8 [95% CI: 6.4, -7.2] respectively (p <0.001)), an increase in Qmax after 7, 14, 30, 60 and 120 days from initiation of treatment (+1.1 mL/s [95% CI: 1.0 mL/s, 1.2 mL/s], +1.6 mL/s [95% CI: 1.5 mL/s, 1.7 mL/s], +2.4 mL/s [95% CI: 2.3 mL/s, 2.5 mL/s], +2.5 mL/s [95% CI: 2.4 mL/s, 2.6 mL/s], +2.5 mL/s [95% CI: 2.4 mL/s, 2.7 mL/s] respectively (p <0.001)). The data obtained in the study allow us to recommend silodosin (Urorec(r)) at a dosage of 8 mg once a day as a first-line drug for the pathogenetic treatment of bladder outlet obstruction due to benign prostatic hyperplasia. PMID- 29697378 TI - SURGICAL PREVENTION AND TREATMENT OF POSTOPERATIVE HYPOPARATHYROIDISM IN PATIENTS OPERATED ON THYROID GLAND. AB - The objective of the research was to develop and evaluate the algorithm of prevention and treatment of postoperative hypoparathyroidism (PHPT) based on determining parathyroid glands (PTG) viability and the use of antihypoxant antioxidant therapy in the postoperative period. The research was based on the results of a comprehensive examination and treatment of 60 patients who were operated for thyroid gland diseases. The patients underwent inpatient treatment at the surgical department of Ivano-Frankivsk Central City Clinical Hospital and Ivano-Frankivsk Regional Oncology Center from 2015 to 2017. We proposed an algorithm for surgical prevention and treatment of PHPT during thyroid gland surgeries which consisted in the following. We performed a visual assessment of PTG intraoperatively and evaluated each gland from 0 to 3 points according to the degree of its viability affection. If the gland was evaluated at 0-2 points, we left it in situ, since there was a high probability of maintaining its function. If it was evaluated at 3 points, its autotransplantation was performed. Cytoflavin drug was applied in a dose of 10 ml per 200 0.9% NaCl intravenously once a day during 7 days in the postoperative period for the purpose of antihypoxant-antioxidant therapy. 2 groups of patients were formed in order to evaluate the effectiveness of the algorithm. Each group consisted of 30 people. Patients of Group I underwent surgery on thyroid gland according to generally accepted rules. Patients of Group II underwent interventions according to the above-mentioned algorithm. The use of our proposed algorithm (intraoperative assessment of PTG viability and antihypoxant-antioxidant therapy in the postoperative period) significantly reduces the frequency of permanent PHPT justifying indications to its application. PMID- 29697377 TI - CHALLENGES AND MANAGEMENT OF CONGENITAL ABDOMINAL WALL DEFECTS (REVIEW). AB - Management of congenital abdominal wall malformations is still a challenge in paediatric surgery due to visceroabdominal disproportion, large defects of abdominal wall and immature abdominal cavity. Most of the patients treated with primary closure need artificial substitutes like patches or biomaterials for non permanent abdominal wall closure. Patches represent the source of constant infections and complications like separation of prosthesis from fascia. Removal of these patches and ventral hernia repair is essential afterwards. As for component separation technique, this method helps to restore normal anatomy of anterior abdominal wall, results in good cosmetic appearance, requires only one stage operation procedure, minimal skin flap advancement and is associated with lower infection risk. Although, while performing component separation technique, perforator branches of epigastric artery (periumbilical perforators) are damaged and puts the vascularization of the skin at the risk. Only pudendal artery branches and intercostal arteries are left to supply the skin with the blood, which from our point of view is insufficient. Accordingly, for successful treatment of congenital abdominal wall defects, further research in order to develop new operation techniques, as well as search for the ideal biomaterials for the closure of the large defects of anterior abdominal wall is essential. These biomaterials should possess unique biological properties that are important for tissue repair, including anti-inflammatory, antimicrobial, antifibrosis, antiscarring, as well as a reasonable cost and low immunogenicity. PMID- 29697379 TI - [HYPERTENSION OF PREGNANCY ASSOCIATED WITH HYPERGOMOCYSTEINEMIA OF THE FIRST TRIMESTER OF PREGNANCY]. AB - In this study, the association of high homocysteine concentrations (>10 MUmol/L) of pregnant women with hypertensive disorders during pregnancy was studied, as well as other complications of pregnancy, such as loss of pregnancy in the first half, premature birth, intrauterine growth retardation, congenital malformations development of the fetus. A single-center prospective cohort study was conducted. Depending on the concentration of homocysteine detected by the immunoenzyme assay with monoclonal antibodies Homocysteine EIA ELISA (Axis-Shield Diagnostics Ltd, Scotland), for a period of up to 14 weeks, the subjects were divided into 2 groups: with high concentrations (>10 MUmol/L) and normal levels (<10 MUmol/L). We controlled complications of pregnancy: loss of pregnancy in the first half, premature birth, delayed fetal growth, congenital malformations of the fetus, gestational hypertension, mild and severe preeclampsia, eclampsia and HELLP syndrome. The results of the study showed that at a level of homocysteine I trimester >10 MUmol/l spontaneous abortion, premature birth, gestational hypertension, mild preeclampsia develop more often. There were no differences in the groups for delaying intrauterine growth of the fetus, congenital malformations, severe preeclampsia. PMID- 29697380 TI - ACTUAL ISSUES OF ODONTOGENIC MAXILLARY SINUSITIS (REVIEW). AB - Odontogenic maxillary sinusitis has now increasing incidence in dental and otorhynolaryngological practice. Its incidence varies from 10-12 % to 50-75 %, according to different authors. Literature study showed that odontogenic maxillary sinusites are mostly unilateral, and significantly differ in complaints, clinical signs, and diagnostic and treatment measures from other types of sinusitis. This should be taken into account, because often odontogenic maxillary sinusitis is misdiagnosed with common sinusitis, and only in 77 % such patients are examined by both dental specialist and otorhynolaryngologist. Study of causes of odontogenic maxillary sinusitis revealed that now iatrogenic impact prevails over other causes, which had been previously considered as main causes of odontogenic maxillary sinusitis. Especially endodontic treatment and implantation surgery are major causes of odontogenic maxillary sinusitis in present time, due to increasing incidence of perforation and damage of sinus by filling materials, bone or tooth particles, and implants. Anatomical structure of dental-sinus border area, and volume of endodontic treatment and implanting procedures, determines last ones as causative triggers due to development of complications and inflammatory processes. Microbial flora is mostly presented by anaerobic microorganisms; at the same time aerobic and fungal organisms are found in the microscopy of histology of patients with odontogenic maxillary sinusitis. At the same time, polymicrobial associations show high resistance to wide spectrum of antimicrobial medications. In past years theory of microbial biofilms is considered leading in explanation of recurrent and persistent odontogenic sinusitis. Such polymicrobial associations are covered with complex shield of different compounds, providing protection and nutrients. This significantly complicates treatments and can cause recalcitrant and recurrent infections. PMID- 29697381 TI - [BIOSUBSTRATES AS DENTAL HEALTH INDICATORS IN SCHOOL-AGE CHILDREN]. AB - Lack of essential elements can lead to the development of general and dental diseases. To assess the level of microelements in the human body, the most informative biosubstrates are hair and dental hard tissues, in which the chemical elements are concentrated and fully reflect the quality of essential elements. We examined 34 6-12 years-old children to study the content of essential elements in biosubstrates, as in dental health indicators (in the period of formation and mineralization of most permanent teeth). The analysis was carried out by the X ray fluorescence spectroscopy method. We studied 8 essential (Ca, Zn, K, Fe, Cu, Se, Mn, Cr) and 9 conditionally essential (S, Br, Cl, Co, Ag, V, Ni, Rb, Mo, Sr, Ti ) chemical elements in hair, and in the teeth - four essential (Ca, Zn, Mn, Fe) and three conditionally essential (Rb, Ni, Sr) trace elements. According to the study, in pupils, with compensated form of caries, was found minimal lack of essential chemical elements with the norm, and in children with decompensated form of caries - significantly low level of essential elements. In particular, the analysis of hair with the X-ray-fluorescence spectrometry method in second group children showed a significant lack of: Ca (0.8 times), Zn (1.2 times), K (1.5 times) Mn (1.8 times), etc. The low content of calcium (259025 +/- 35224 ppm), iron (98.59+/-39.72 ppm), manganese (11.55+/-7.7ppm) was reported to be relatively low (p<0.05) in dental hard tissues. The exception was the zinc - its number exceeded the established norm by 28.1%, which should be explained by the fact that the zinc reduces the enamel penetration, and thus, transition of chemical elements from saliva to dental hard tissues. Thus, our study has showed that the composition of micro and macro elements in hair and dental hard tissues can be used as indicators of mineralization of dental enamel, dentine and alveolar bone. According to our results dental health changes are associated with the imbalance of chemical elements in biosubstrates. PMID- 29697382 TI - BASAL CELL CARCINOMA OF THE FOOT - TWO CASE REPORTS AND LITERATURE REVIEW. AB - Basal cell carcinoma (BCC) is considered the most common skin cancer in men. BCC of the foot, however, is very rare, and may occur on dorsal surface of the foot, foot sole or nail apparatus. Diagnosis is often delayed due to the location at an unusual site. We report on two patients: a 61-year-old female with an ulcerated BCC of the sole and dorsum of the foot on a leg with Klippel-Trenaunay syndrome and a 61-year-old male with an ulcerated BCC of the foot sole. Histologic tumor types were either metatypic or mixed solid and morphea-like with partial glandular infiltration. Perineural invasion was evident in both patients indicating the aggressive tumor behavior in the particular region. Authors also provide a review of the literature with a focus on the years 2000 through 2017. PMID- 29697383 TI - [ABNORMALITIES OF THYROID HORMONE METABOLISM DURING COMMUNITY-ACQUIRED PNEUMONIA: NONTHYROIDAL ILLNESS SYNDROME AND INTRACELLULAR IODINE DISTRIBUTION IN CHILDREN]. AB - The aim of the study - to investigate the changes of thyroid function and to reveal the relationship in between intracellular distribution of iodine in the blood with the severity of the course of pneumonia in children. We investigated 70 patients in age 6-14 years with moderate and severe CAP and 35 healthy children. The levels of free thyroxine (fT4), free triiodo-thyronine (fT3) and thyroid stimulating hormone, thyroid gland ultrasound and urinary iodine were estimated. Inorganic iodine, total and organificated iodine was investigated. The article presents that severe pneumonia in children is characterized by a transient low level of fT3 2,89 pmol/L (p?0,05). In a dynamics initially low levels of fT3 raise up to normal data. The general condition and clinical symptoms of the patients was improving after treatment of pneumonia and thyroid status was normalized. Mild iodine deficiency has been established in all children. The intracellular pool of iodine with severe pneumonia showed an inverse relationship between the levels of iodine distribution for organificated and inorganic iodine and a close connection between the levels of total and organic iodine (p<0,001). Nonthyroid illness syndrome developed for patients with severe community-acquired pneumonia. The revealed changes in indices of the intracellular pool of iodine and its distribution in the body are directly proportional to the severity of CAP. PMID- 29697384 TI - [CAUSES OF DEVELOPMENT AND CLINICAL COURSE OF RESPIRATORY TUBERCULOSIS IN ADOLESCENTS WITH AGENT DRUG RESISTANT]. AB - The aim of the study was to study the clinical manifestations and causes of the development of drug-resistant tuberculosis in adolescents. Clinical manifestations and causes of tuberculosis development were analyzed in 138 adolescents who were under care in the Aktyubinsk Regional TB Dispensary for the period 2005 - 2016. The main reasons for the development of drug-resistant tuberculosis was the presence of close contact with the patient who discharges mycobacterium tuberculosis, resistant to anti-tuberculosis drugs, lives in socially deprived families and has residual changes in the lungs. The spectrum coincidence of drug resistance with the source of tuberculosis infection was 76.2%. The marked clinical manifestations, the presence of lung tissue destruction, bacterial excretion, a high percentage of complications and damage of the bronchi are specific for drug-resistant respiratory tuberculosis. PMID- 29697385 TI - INTENSITY OF THE ANTIOXIDANT PROTECTION SYSTEM AND OXIDATIVE STRESS FACTORS IN PATIENTS WITH NON-ALCOHOLIC STEATOHEPATITIS DEPENDING ON THE FORM OF CHRONIC KIDNEY DISEASE. AB - The article presents a theoretical generalization of the research results the intensity of the antioxidant protection system and oxidative stress factors in patients with non-alcoholic steatohepatitis depending on the form of chronic kidney disease. The objective of the article - determining the pathogenetic role of the processes of antioxidant protection system in the development and interconnection mechanisms of non-alcoholic steatohepatitis (NASH) and obesity depending on the form and stage of chronic kidney disease (CKD). 177 patients were examined for this purpose, including: 35 patients with NASH with concomitant obesity of I-II degree (1st group), 36 patients with NASH with accompanying obesity of I-II degree and CKD I-II stage: Chronic bilateral pyelonephritis in the phase of exacerbation (2A group), 35 patients with NASH on the background of obesity I-II st. with CKD of the 3rd stage: Chronic bilateral peyelonephritis, exacerbation (2B group), 37 patients with NASH with obesity I-II stage and gouty nephropathy (group 3), 34 patients with NASH, which developed on the background of obesity I-II stages that developed from asymptomatic hyperuricemia (AHU) (group 4). The control group consisted of 30 practically healthy persons (PHP). For the comorbidity of NASH from CKD of the I-III stages. In the form of chronic pyelonephritis, the intensity of oxidative stress increases: the accumulation of intermediate (isolated double bonds, diene conjugates) and terminal (malonic aldehyde, ketodienes and conjugated triines) products of lipids peroxide oxidation, oxidation proteins modification (aldehyde and ketone dinitrophenyl hydrazones of the main and neutral) against the background of the disintegration of the activity of antiradical protection factors (reduction of content in erythrocytes of recovered glutathione, activity of superoxide dismutase, the growth of catalase activity, glutathion-dependent enzymes). Due to the comorbidity of non-alcoholic steatohepatitis with gouty nephropathy and in conditions of asymptomatic hyperuricemia, the degree of oxidative stress is significantly lower due to the strong antioxidant properties of uric acid, but the degree of endotoxicosis predominates in steatohepatitis without kidney damage. The uncontrolled intensification of the processes of free radical oxidation of lipids and proteins in patients with non-alcoholic steatohepatitis that developed on the background of obesity and CKD I-III stages, determines the degree of pathological process activity in the liver and the degree of endotoxicosis. PMID- 29697386 TI - USE OF CIRCULATING TUMOR DNA FOR DETECTION OF BRAF V600E MUTATION AND TREATMENT MONITORING IN MELANOMA PATIENTS. AB - Detection of BRAF V600E mutation in circulating tumor DNA may be important tool for primary diagnostic and therapeutic monitoring in patients with melanoma. For the first time in Ukraine, the sensitivity of BRAF V600E testing on circulating tumor DNA was analyzed, as well as the possibility of its application for monitoring the course of the disease. Allele-specific semi-quantitative Real-time PCR for BRAF V600E mutation was performed on DNA extracted from 28 plasma samples of 18 patients with known BRAF V600E melanoma. At baseline, BRAF V600E ctDNA was detected in 67% of all patients (n=11/17) and in 75% (n=11/15) of patients with IV stage. In 7 cases we have more than one blood sample from patient. In 2 of 3 patients with positive BRAF V600E ctDNA at the baseline, mutation became undetectable during therapy that was associated with stable disease and partial response. In 2 cases patients had stage II and after surgery BRAF V600E ctDNA was undetectable, but then mutation was detected prior to clinical disease progression (PD) in one case and simultaneously with PD in another. One patient with resected brain metastasis of melanoma with unknown primary also had negative baseline and second sample (after 5 months) but BRAF V600E was detected in third sample (after 11 months) without radiological evidence of progression. ctDNA in plasma is a good source for BRAF V600E primary testing in case of absence or low quality of FFPE tissue and potential instrument for monitoring of disease flowing. Its potential role in management of patients with malignant melanoma requires further evaluation. PMID- 29697387 TI - TREATMENT OF TOXIC THYROID ADENOMA BY THE ETHANOL DESTRUCTION METHOD. AB - The aim of study was to evaluate the long-term results and complications of percutaneous ethanol injection therapy of the thyroid gland toxic adenoma for a 10-year follow-up period. We conducted a 10-year prospective cohort study of the ethanol sclerotherapy results in 43patients with toxic adenomas of the thyroid gland aged in average 62.59 (57.95-65.73) years and a duration of the disease of 17.7 (10.8-22.20) years. As a result of the study, we found that ethanol sclerotherapy can achieve a significant reduction in the volume of adenomas based on the results of ultrasound during the 10-year observation period: the average volume after the procedure was 4.27 cm3 vs. initial - 21.12 cm3, p <0.00, and absence of the disease recurrence. The incidence of complications, including temporary local pain and transient dysphonia was 0.07+/-0.02% of cases. The patients quality of life during the 12 months of observation was significantly higher than the baseline data (Physical component: 71.96 (71.35-72.84) points after treatment versus 47.47 (47.18-47.82) (Z = -5711, p <0.00 ) Psychic component: 81.35 (78.34-85.49) points after therapy against 53.00 (52.11-54.11) points at the initial examination (Z = -5.711, p<0.00)). According to results we concluded, that the treatment of toxic thyroid adenoma by the ethanol destruction method is an effective, safe, low-cost method of therapy that has a significantly positive effect on the patients' quality of life. PMID- 29697388 TI - [TRANSFORMATION OF MYASTHENIA GRAVIS INTO AMYOTROPHIC LATERAL SCLEROSIS, OR THEIR CONCOMITANCE? (CASE REVIEW)]. AB - The authors present a case of 75-year-old male patient with typical clinical and electroneuromyographic signs of Amyotrophic Lateral Sclerosis (ALS), manifested in 4 years after a diagnosis of generalized Myasthenia Gravis (MG) had been made. The aim of the article is to assess the possibility of pathogenetic integrated comorbidity of MG and ALS, which may have resulted from a common aberrant immune process and to emphasize the importance of detailed clinical analysis and adequate diagnostic methods essential for correct diagnosis and treatment. Only several cases of coexistence of MG and ALS have been described in medical literature. Exploring the pathogenetic association between MG and ALS may lead to dysregulation of thea immune system. Deficiency of T-regulatory cells, increased activity of atrophy-related atrogenes, anomalies of neuronal nitric oxide synthase can be found in both diseases. Immunoglobulin isolated from ALS patients can affect neuromuscular junction and activate AChRs, which plays an important role in the innervation and re-innervation of muscle fibers. Immunoglobulin also changes the function of Ca2+ channels. Blood level of circulatory Heat Shock Protein 70 (HSP70) antibodies in MG patients is elevated. HSP70 maintains normal conformation of cell proteins. Conversely, HSP70 antibodies cause HSP70's dysfunction and therefore, abnormal protein synthesis, which can be the main reason of neurodegenerative diseases, such as ALS. Experimental evidence indicates, that muscle and neuromuscular junctions may be initial targets of ALS. According to the "dying-back" hypothesis, neuromuscular junction damage and failure in MG patients may precede lower and upper motor neuron loss, and thus increase risk of developing ALS. Pathogenetic mechanisms of MG and ALS are the subjects of further studies. Refining the etiology of these two diseases will answer the question whether it is a transformation or a coexistence of MG and ALS in our case. The presented case demonstrates, that in spite of meeting all diagnostic criteria it is, sometimes, impossible to make the correct diagnosis. Only a detailed clinical analysis and adequate diagnostic methods contribute to correct diagnosis and adequate therapy. PMID- 29697389 TI - [RHEOLOGICAL PROPERTIES OF BLOOD SERUM AT SYSTEMIC SCLEROSIS]. AB - Systemic sclerosis (SSc) is accompanied by severe disorders of serum component of blood rheological properties (BRP), the study indicators of which performed as the monitoring of the therapeutic interventions effectiveness. BRP changes have not been established at different forms of SSc, the connection between physicochemical serum rheological properties and morphological signs of vascular skin lesions and extracardiac implications of the disease remains unknown. The purpose and objectives of the study - to evaluate the changes of BRP serum component with clinical and morphological variants of limited and diffuse form of SSc. The study included 63 patients with SSc in age from 16 to 67 years (mean 42 years), among whom there were 11% men and 89% women. In 43% of cases there was a limited form of the disease, in 57% - diffuse. The duration of the disease was 11 years. The I level activity of the pathological process is set at 41% of patients, II - at 38%, III - at 21%, anti-topoisomerase antibodies detected in serum at 78% of cases, antibodies to native deoxyribonucleic acid - at 64%, to cardiolipin - 18%. BRP is assessed by interfacial tensiometry with the determination of surface parameters. As the control parameters studied in 52 healthy people and 42 patients with limited scleroderma. Skin microincisional biopsy was performed in 37 patients. SSc is accompanied by violations of BRP, which is manifested by increasing viscoelasticity module parameters in 8% of patients, and the surface tension in 66% on the background of reducing surface elasticity level in 37%, and the latters two parameters of interfacial tensiometry differ not only from those in healthy people as well as in patients with limited scleroderma, and changes in the viscoelastic properties of the blood are prevalent in diffuse form of the disease compared to the limited form when there are dispersive correlation BRP with the severity of skin lesions and extradermal manifestations of SSc (heart, lung, kidney disease), and the elastic and relaxation serum characteristics have predictive value, respectively, in the cases of limited and diffuse forms of the disease. SSc occurs with disorders of serum level of BRP, which is more characteristic to the diffuse form of the disease and are closely related to the severity of skin and internal organs lesions, the indicators of which can be used to improve the assessment of the clinical course severity and prognosis of the individual signs of the disease. PMID- 29697390 TI - ULTRASTRUCTURAL CHANGES OF WOUND MACROPHAGES UNDER THE INFLUENCE OF INTRAVENOUS OZONE THERAPY IN PATIENTS WITH DIABETES AND INFLAMMATORY PROCESSES OF SOFT TISSUES. AB - Investigation of ultrastructural peculiarities of morpho-functional changes of macrophages have been studied with the purpose of determining the dynamics and thrust of destructive-necrotic processes in these cells when the ischemic gangrenous form of diabetic foot syndrome develops show what under the influence of intravenous ozone therapy stimulant effect on functional activity and beneficial effect on elimination, mainly due to genetically programmed cell death (apoptosis), playing a significant role in the regulatory mechanisms of the inflammatory process. The stimulation of macrophages functional activity under the influence of ozone, as well as the presence of destructive changes in such cells without necrotizing lesions, is explained by the inclusion of the mechanism of apoptosis as a positive factor in the regulation of local homeostasis at the completion of the inflammatory (exudative) stage of the wound process. PMID- 29697391 TI - MOLECULAR BASIS OF EPIDERMAL GROWTH FACTOR RECEPTOR AND CYCLIN E EXPRESSION INTERDEPENDENCE IN BASAL-LIKE SUBTYPE OF INVASIVE BREAST CARCINOMA. AB - Aim of the study was the simultaneous assessment of EGFR and Cyclin E in "basal like" carcinoma group, in order to establish their interactivity in the aspect of the age and grade of the tumor, taking into account the common parallel HER2+ samples. The study involved postoperative and/or biopsy material (paraffin blocks) of 237 patients from archived data, who were operated due to breast cancer (National Cancer Center of Tbilisi, 2008-2012 years). In TNBC group and "basal-like" tumor subgroup expression of ESFR, Cyclin E and Cytokeratins 5/6 and 17 were shown advanced activity of processes and high dependence to patients age. Taking into account all above mentioned, the immunohistochemical profile of "basal-like" type of breast cancer is defined mostly by sensitivity to cytokeratins CK5,6/17 and EGFR. In addition, the defected synthesis and activity of the latter, which is actually observed in "basal-like" carcinoma, leads to increased malignancy grade and mitotic activity, which creates the phenotypic and group characteristics for this type of carcinomas overall. PMID- 29697392 TI - LINE-1 METHYLATION IN BLOOD AND TISSUES OF PATIENTS WITH BREAST CANCER. AB - Methylation is an epigenetic alteration proved to be involved in many disease processes including cancer. This change affects mainly gene promoters and repetitive sequences in genome. Long Interspersed Nuclear Element-1 (LINE-1) is a family of retrotransposons - repetitive elements that modify gene activity and can themselves be targeted by epigenetic mechanisms. LINE-1 methylation level is a surrogate marker for global methylation. In many conditions this parameter is found to be altered not only in affected cell groups, but also throughout other tissues. The aim of our study was to compare LINE-1 methylation pattern in DNA extracted from blood of the patients with benign and malignant breast tissue. In addition, we investigated correlation of LINE-1 methylation in blood and tissues of same patients and relationship of all variables with histopathologic and phenotypic characteristics of tumors. Patients with biopsy-proved ductal invasive carcinoma of breast and no preoperative chemo/radiotherapy were chosen for the study group. Another pool of patients with various benign breast lesions represented controls. Blood samples from both group members were collected preoperatively. Tumor tissue sections were processed for pathology report and part of remaining tissue was used for methylation study. LINE-1 methylation level was quantified using ELISA-based assay. It was analyzed in combination with histologic and phenotypic tumor parameters and compared between different tissues and different study groups. LINE-1 was found to be significantly hypomethylated in breast cancer tissue compared to blood. Blood samples of patients with malignant tumors showed slightly lower methylation level, than samples obtained from control group members. Lymphovascular invasion was the only aggressiveness determining factor that was found to be at least weakly correlated with LINE-1 hypomethylation in blood. We can conclude, that global hypomethylation measured by LINE-1 methylation level is significant in tumor tissue. But there is no significant difference between LINE-1 methylation levels in blood of patients with benign and malignant breast tumors; therefor LINE-1 hypomethylation in blood cannot be used as a marker for early tumor detection. Neither is it valid for determination of tumor behavior. PMID- 29697393 TI - POLYMORPHISM PREVALENCE OF TLR 9 TYPE GENE IN PATIENTS WITH CHRONIC FORMS OF EPSTEIN-BARR VIRUS-INFECTION. AB - The aim of the study - to determine the TLR-914 T/C gene polymorphism in patients with CVEB caused by Epstein-Barr virus. Research for the determination of polymorphism - 1486 T/C TLR-9 gene was performed in 44 patients with chronic forms of the VEB infection. DNA isolation from the specimens was performed using a kit for DNA extraction by the Miniprep Company (Siles M, Russia), using the sorption assay technique of the sorbent. Polymorphic region -1486 T/C, rs187084 of the TLR9 gene was studied by real-time PCR amplification by determining the length of the restriction fragment-PCR using restriction enzymes Ncol and oligonucleotide primers. The analysis of the results of the 1486 T/C polymorphism of the TLR-9 gene revealed three main genotypes - TT, TC, CC. Investigation of the frequency of occurrence of individual genotypes revealed the dominance of the genotype TC, compared with the homozygous genotypes of TT and CC. The study of frequency distribution of the TLR-1486 T/C gene polymorphism for different genotypes demonstrated the specificity of changes in the TC genotype in patients with HEBV and the absence of such for the genotypes of TT and CC. PMID- 29697394 TI - SPECIFICITIES OF ENDOMETRIAL PROLIFERATION/STEM CELL INDEX DISTRIBUTION IN ENDOMETRIOID CARCINOMA OF DIFFERENT GRADE OF MALIGNANCY. AB - Endometrial neoplasia is the most common malignant tumor of female genital system in developed countries. The incidence of endometrial cancer has increased in the last years and despite advances in diagnosis and treatment, the death rates have steadily been increasing over the past 20 years. Therefore aspects of endometrial cancer development, pathogenesis and effective treatment is especially urgent to this day, as much of the risk for endometrial cancer development is influenced by the environment and lifestyle. Endometrial stem cells take the special place among somatic stem cells of female reproductive system-the detection of them and identification of their location in the complex cellular hierarchy still remains challenging. Further study of endometrial stem cells will clarify their role in gynecologic pathologies associated with hyper-proliferative states of endometrium. The aim of our study was to explore the specificities of endometrial proliferative/stem cell index distribution under endometrioid carcinoma of different grade of malignancy. The study represents a retrospective research. The coded and depersonalized material data from Acad. N. Kipshidze Central University Clinic was used in the study. 3 study groups - 1st study group "Endometrioid Carcinoma Grade 1" (14 cases), 2nd study group "Endometrioid Carcinoma Grade 2" (23 cases) and 3rd study group "Endometrioid Carcinoma Grade 3" were selected from routine histopathology tissue specimens of uterus. Hematoxilyn-eosin technology and immunohistochemistry with proliferation marker ki67 and stem cell marker CD146 was performed. The proliferative/stem cell index was calculated by the ratio of Ki67-positive cell percentage value divided by CD146-positive cell percentage value. The study showed that in the 1st study group labeled as "Endometrioid Carcinoma Grade 1", the proliferative/stem cell index ranges between 21.7 and 25.5. Its mean average value in the age distribution subgroups accounts for: 1.1) reproductive age - 22.4; 1.2) menopause - 23.5; 1.3) post menopause - 24.8. Proliferative/stem cell index reaches its maximum in the samples retrieved from post-menopause age, and decreases significantly in reproductive age individuals. In the 2nd study group labeled as "Endometrioid Carcinoma Grade 2", the proliferative/stem cell index increases and ranges within the interval 23.2-27.8. Its mean average value in the age distribution subgroups accounts for: 2.1) reproductive age -23.7; 2.2) menopause - 24.2; 2.3) post menopause - 25.8. In the 3rd study group labeled as "Endometrioid Carcinoma Grade 3", the proliferative/stem cell index markedly increases and ranges within the interval 25.8-29.4. Its mean average value in the age distribution subgroups accounts for: 3.1) reproductive age - 28.4; 3.2) menopause - 28.5; 3.3) post menopause - 28.5. It was found that average value of proliferative/stem cell index in the 1st and 2nd study groups (EC Grade 1/2) keeps the same tendencies of increase in age subgroups as well as at endometrial hyperplasia conditions - in particular in both study groups increase in value of the proliferative/stem cell index in age subgroups makes about 1% (1st study group-0,97%, 2nd study group 0,96%). What about 3rd study group (EC Grade 3) average value of proliferative/stem cell index in age subgroups is almost the same. It was found that average value of proliferative/stem cell index in endometrioid carcinoma most markedly differs from the norm in post-menopause period. The study showed that average value of proliferative/stem cell index in endometrioid carcinoma cases (EC Grade 1/2) tends to increase with age like endometrial hyperplasia conditions, in contrast with the norm, where it is observed to progressively decrease with aging. The attention should be given to the fact that the mean average value of proliferative/stem cell index in endometrioid carcinoma Grade 3 is almost constant. PMID- 29697395 TI - SUBLINGUAL IMMUNOTHERAPY FOR ALLERGIC ASTHMA AND RHINITIS. AB - The purpose of our study was to perform a meta-analysis and thus, based on original randomized placebo-controlled studies, evaluate the effectiveness and safety of sublingual immunotherapy (SLIT) in children and adults suffering from allergic bronchial asthma and rhinitis. On the MEDLINE, EMBASE, LILACS and SCOPUS web pages, the corresponding experimental works were searched. After an expert evaluation, 58 case-studies were selected 38. Of these, 30 concerned the efficacy and safety of sublingual immunotherapy of allergic rhinitis, and 8 of bronchial asthma. In active groups, 347 patients with asthma and 1888 rhinitis were involved, and in the control groups, respectively, 332 and 1795 subjects studied. There were 7 different meta-analytical comparisons based on the purpose of our study. Our Meta-analytic study on the selected publications have been shown that sublingual immunotherapy in children and adults suffering from allergic bronchial asthma and rhinitis is effective and safe. However, based on the low evidentiary level and high heterogeneity of the publication that we used in the meta analysis, unambiguous recommendations regarding the advisability of using the sublingual immunotherapy method in patients with allergic rhinitis and asthma are premature. For all these reasons, the results of this analysis should be interpreted by the various selected population subgroups, following specific recommendations addressed to unified results, endpoints, time points, measurement scales and dosages, treatment distribution and power calculation. Despite our results, we believe that there are arguments indicating that SLIT may be a promising direction in the treatment of allergic rhinitis and asthma, but it should not be prescribed regularly to all patients. PMID- 29697396 TI - INFLUENCE OF TRICALCIUM SILICATE ON COURSE OF TRAUMATIC PULPITIS. AB - The use of Tricalcium Silicate (TS) as an odontotropic preparation makes it possible to create a hermetic crown restoration with a high degree of adhesion. However, the use of TS silicate by direct pulp capping remains disputable. The aim of this study was to determine the effects of TS on course of traumatic pulpitis by detection of morpho-functional peculiarities of changes in pulp tissue. We performed experimental investigation (on rabbits, males, aging three month) for study of the morpho-functional changes of the pulp tissues with modeling of traumatic pulpitis and direct pulp capping with TS preparation (8 animals, investigated group) and calcium hydroxide (Calasept, NORDISKA DENTAL) preparation (8 animals, comparison group). After 2nd and 6th weeks tissues of tooth were fixed in 10% formalin with performing routine proceeding after decalcification and making histological slides which were investigated. Manifestations of protective adaptive mechanisms have been revealed in the form of inflammatory process two weeks after the injury in the pulp tissue with its resolution six weeks after performing of direct pulp capping with TS with replacement of necrotic area by connective tissue with their delimitation from viable pulp tissue against a background of intensive formation of capillaries. Morphometric study proved dynamical changes of vascular number cross-sections per 1 mm2 from 69.31+/-4.76 (2 weeks) to 47.38+/-4.12 (6 weeks) with 49.2+/-3.47 vascular density in intact group. Cellular density of odontoblasts as changed from 3.92+/-1.03 x103 per 1 mm2 (2 weeks) to 7.49+/-1.51 x103 per 1 mm2 (6 weeks) with 8.3+/-1.02 x103 per 1 mm2 cellular density in intact group. Thus it can be argued that the use of TS as a material for direct pulp capping promotes more active regeneration processes. PMID- 29697397 TI - PATHOMORPHOLOGY OF THE MYOCARDIUM, KIDNEY AND LIVER IN SPONTANEOUSLY HYPERTENSIVE RATS TREATED WITH SHORT AND LONG-TERM USE RAMIPRIL AND CANDESARTAN. AB - Choosing a method of treating arterial hypertension remains an urgent problem today. For effective therapy, it is necessary to select hypotensive drugs that not only effectively reduce the pressure, but also contribute to the restoration of the structure of tissues sensitive to oscillations of arterial pressure. The purpose of this study was to conduct a comparative analysis of the effect of angiotensin 2-candesartan receptor antagonist and angiotensin converting factor ramipril on pathomorphological changes in the myocardium, kidney, and liver in SHR lines that received treatment for 7 days (short) and 21 days (prolonged therapy ) The study was conducted on 20 spontaneously hypertensive rats with a mass of 248.0-441.0 g. The rabbit was administered at a dose of 5 mg / kg and candesartan 4 mg / kg, respectively. The period of short-term therapy was 7 days and long-term-21 days. For the evaluation of morphological changes in the heart, kidney, liver, frozen cross sections were stained using Ramonovsky-Giemsa method (H and E). The data obtained indicate a more significant effect of candesartan on myocardium and kidney. Ramipril had a negative effect on the renal tubules, increasing the degree of atrophy. Treatment with ramipril and candesartan, especially with long-term use, reduced the hydropic swelling of hepatocytes. PMID- 29697398 TI - [SWOT-ANALYSIS OF PROFESSIONAL-PERSONAL COMPETENCE OF ECONOMISTS IN MEDICAL ORGANIZATIONS]. AB - In modern conditions, there is a tendency to replace the qualification approach of assessing economists in medical organizations - competence. The purpose of the study was to identify the professional and personal abilities of economists in medical organizations to actively participate in the management decisions of the medical organization in the transition from public administration to the right of economic management. The study was carried out in 3 stages. At the first stage, the degree of influence of the experience of the economist, the frequency of training and its burden on the profitability of the medical organization was analyzed. At the second stage - the personal evaluation of the respondents by psychodiagnostic methods (memory, attention, the level of the person's orientation, self-esteem, the level of personal claims). At the third stage, the data of professional behavior and personal evaluation were summarized in the table of SWOT-analysis factors, for determining the personnel strategy of development of economists in medical organizations. The sample size was 43 respondents, which amounted to 10.3% of the participation of medical organizations. The results of the SWOT analysis of the personal and professional qualities of medical economists in medical organizations showed the predominance of weaknesses in corporate competencies among medical economists over strong ones, while personal opportunities prevail over risks. In general, the professional-personal SWOT analysis showed the prevalence of the possibilities of medical economists (Ps=5,3) over threats (Ps = 4,9), strong (Ps = 4,4) and weak sides (Ps = 3,8). At the same time, the force of influence does not suffice: the length of work for profitability (r = -0.3, p <0.05), and the ratio of one economist to employees on the growth of the specific weight of paid services (r = 0.001, p <0.05). The revealed relationships confirm: a direct strong dependence of the training frequency of economists on the profitability of the medical organization (r = 0.7, p<0.05), i.e. The higher the frequency of training economists, the higher the profitability, showed our results in the studied medical organizations. The results of the study made it possible to identify the behavioral professional and personal capabilities of medical economists in market conditions. PMID- 29697399 TI - [LEGAL REGULATION OF TRANSPLANTOLOGY AT THE PRESENT STAGE: UKRAINIAN ISSUE AND EXPERIENCE OF FOREIGN STATES]. AB - The objective of the research is to analyze the legal regulation in the transplantology field at the present stage in Ukraine. To address identified challenges, the author investigates the foreign countries experience and suggests ways of improving certain mechanism for legal regulation in the field of organ transplantation and anatomical materials. The empiric material of the study included a wide range of legal instruments regulating this sphere of legal relationships, information regarding the problems of their application, statistics, expert analysis of Ukrainian and foreign researchers. Methodological mechanism of current research includes such methods: systematic, logical and formal, structural-functional, comparative. The research found that the most world's successful model for the organization of transplantation is in Spain. Additionally, the criteria for the reception of such a model are singled out as well as certain aspects of their application in Ukraine are analyzed. Particularly, the most important criteria are: universal and general territorial proliferation of national health systems; relevant economic resources (special attention is paid to the fact that transplantation is not a medicine of luxury, and an adequate compensation to hospitals for transplantation operations should serve as a main economic aspect); an adequate and necessary number of doctors and nurses; the availability of advanced technical options for medical mechanical ventilation (air conditioning of dead bodies). The research led to the following overall findings. Due to the rapid development of medical and biological sciences, there is an urgent need on further investigation of legal, moral and ethical, general medical aspects of transplantation with subsequent proposals for improving legislation in the field of human organs transplantation and other anatomical materials. At the same time, development of appropriate legislation by complex groups of cross-disciplinary specialists and experts (in medicine, biology, law and bioethics) is the key to legal regulation effectiveness. PMID- 29697400 TI - MEDICAL ERROR: CIVIL AND LEGAL ASPECT. AB - The scientific article is focused on the research of the notion of medical error, medical and legal aspects of this notion have been considered. The necessity of the legislative consolidation of the notion of "medical error" and criteria of its legal estimation have been grounded. In the process of writing a scientific article, we used the empirical method, general scientific and comparative legal methods. A comparison of the concept of medical error in civil and legal aspects was made from the point of view of Ukrainian, European and American scientists. It has been marked that the problem of medical errors is known since ancient times and in the whole world, in fact without regard to the level of development of medicine, there is no country, where doctors never make errors. According to the statistics, medical errors in the world are included in the first five reasons of death rate. At the same time the grant of medical services practically concerns all people. As a man and his life, health in Ukraine are acknowledged by a higher social value, medical services must be of high-quality and effective. The grant of not quality medical services causes harm to the health, and sometimes the lives of people; it may result in injury or even death. The right to the health protection is one of the fundamental human rights assured by the Constitution of Ukraine; therefore the issue of medical errors and liability for them is extremely relevant. The authors make conclusions, that the definition of the notion of "medical error" must get the legal consolidation. Besides, the legal estimation of medical errors must be based on the single principles enshrined in the legislation and confirmed by judicial practice. PMID- 29697401 TI - IMPLEMENTATION OF DRUG ADDICTS RIGHT TO HEALTH PROTECTION (SEPARATE ASPECTS). AB - The purpose of the research is to analyze specific problems of the realization of the right to protect the health of people who take narcotic drugs or psychotropic substances. To achieve this goal, statistics have been analyzed on the number of people using narcotic drugs or psychotropic substances (including drug-addicted children) placed on medical records and the number of their applications for medical care. It has been found out that people in this category often face a denial of medical care that causes extremely strong physical and mental suffering. The analysis of the understanding of the legal design of the "right to health care" in the scientific literature, national legislation and international legal documents was made. State institutions and local authorities providing "the right to health care" of people taking narcotic or psychotropic drugs are singled out. The absence of grounds for restricting the right to protect the health of people who take narcotic or psychotropic drugs who are not registered is justified. In the course of the research, it was found out that people who take narcotic drugs or psychotropic substances are more likely than other patients to need medical assistance and, when requesting the right to health care, face a number of problems that require immediate solution: incomplete provision of quality free medical care; unimplementation of rehabilitation programs for such categories of patients; the lack of the right of children who take narcotic drugs or psychotropic substances to make their own decisions at the age of 14 and apply to public health institutions for the treatment of drug addiction; violations of the continuity of SMT programs and their absence in penal institutions for drug dependent people. It was proposed to introduce a number of changes in the relevant normative legal acts. PMID- 29697402 TI - STUDY OF PHYSICAL AND TECHNOLOGICAL FEATURES AND CHEMICAL COMPOSITION OF CLAYS PREVALENT IN ADJARA REGION. AB - The Region of Adjara is one of the most interesting region by existence of mineral resources, which is not only untapped also not studied. At this stage of study, our purpose was: to research physical features and a chemical composition of biologically active substances in the clays spread in Adjara. In particular, we determined the fractional content and particle size of samples, density, humidity, fluidity, Petrographic studies and X-ray diffraction, also existence of amino and fatty acids. X-ray diffraction and petrographic studies were conducted on the base of Mining Geology Faculty of Georgian Technical University. There was used the polarization microscope Amscope PZ300T-5M and DRON-3. Determination of existence amino and fatty acids has been undertaken on the base of Tbilisi State Medical University, the method was chromatography on the thin layer. Consequently, from studying physical features we determined that mostly fractional content of our samples are from 0.5 to 1 mm. particle size. Humidity was 15%, according to density and fluidity our samples belong to middle heaviness 1100>p>600kg/m3 and high friable powders. As for X-ray diffraction and petrographic studies, there was discovered significant quantity of minerals: Ca montmorillonite, Ca-Na feldspar, quartz, calcite, dolomite, gipsy and hematite. Based on the research there was not discovered amino and fatty acids in the clay samples. PMID- 29697403 TI - [WOUND HEALING PROPERTIES OF THE RECOMBINANT HUMAN ANGIOGENIN IN THE GEL MEDICINAL FORM USED AS A TREATMENT IN THE MODEL OF PLANAL MUSCULOCUTANEOUS AND LINEAR WOUNDS]. AB - The aim of the study was to evaluate the wound healing properties of the recombinant human angiogenin drug in the gel form on the models of planar musculocutaneous wound and a linear wound. The rats were divided into 3 groups: 1st group - control animals, that did not get any treatment of wounds; 2nd group experimental, where animals' wound surface was treated with recombinant human angiogenin in a gel medicinal form; and the 3rd group - a comparison group, where animals were treated with "Solcoseryl" drug. The resulted morphology data and the time of complete epithelialization of planar wounds suggest that the human angiogenin drug in gel form has a pronounced wound healing activity. The latter surpasses the studied parameters of the reference drug "Solcoseryl", by contributing to the acceleration of healing process of planar musculocutaneous and linear wounds in rats. PMID- 29697404 TI - EXTRACTION AND CHARACTERIZATION OF HUMIC SUBSTANCES FROM SPHAGNUM PEAT PELOIDS. AB - The objective of the research was development extraction process of humic substances from sphagnum peat peloids, selection of extragent and characterization of humic substances. The objects of the research: Kolkheti peat peloids (Ispani, Anaklia, Churia, Chirukhi, Peranga) of different formation phases. Research was held using modern instrumental methods of analysis: UV spectrophotometer, Scanning Electron Microscopy, Centrifuge, Dry oven, Ultraturax. In the research extraction process of humic substances from sphagnum peat peloids was developed and composition of humic substances was studied, also E4/E6 humification coefficient was evaluated. Based on the results extraction conditions of humic substances from the peat peloids samples were determined: a) extragent with maximum yield - 1.0N NaOH; b) mixing type - KA-ULTRA TURAX-T18 - 20 000 rpm/min; c) Precipitant of humic substances -10% HCL. Composition of humic substances are studied in the samples and their relatively high content is determined in Anaklia and Churia sphagnum peat peloids. For characterization of humic substances E4/E6 humification coefficient was evaluated. Low ration of E4/E6 < 5 was established in anaklia, churia and ispani peat peloids. High ration of E4/E6 < 10 coefficient is determined in chirukhi and peranga peat peloids. PMID- 29697405 TI - Magnetization reversal in orthorhombic Sr-doped LaFe0.5Cr0.5O3-delta. AB - In this paper we studied the reversal magnetization of La1-x Sr x Fe0.5Cr0.5O3 delta (x = 0, 0.1 and 0.2) samples produced by combustion synthesis. The structural analysis was carried out by x-ray diffraction with Rietveld analysis. These analyses revealed that all samples have an orthorhombic structure with space group Pbnm (62) and that the Sr-doping induces a decrease of the lattice parameter. The x-ray photoelectron spectroscopy analysis indicates that the Sr doping favor the change of the valence states of the Fe3+ to Fe4+. The magnetization as a function of the temperature reveals an unusual magnetic behavior with a reversal of magnetization. The increase of the Sr content induces a decrease of the temperature where occurs an inversion of the magnetization and do the value of the magnetization at 5 K more negative. This effect is attributed to the increase of the concentration of Fe4+ with increasing of the Sr content. The Fe and Cr with a valence of 4+ act as paramagnetic impurities in the antiferromagnetic lattice and are responsible for the changes in the magnetic behavior. PMID- 29697406 TI - Low-energy spin dynamics of orthoferrites AFeO3 (A = Y, La, Bi). AB - YFeO3 and LaFeO3 are members of the rare-earth orthoferrites family with Pbnm space group. Using inelastic neutron scattering, the low-energy spin excitations have been measured around the magnetic Brillouin zone center. Splitting of magnon branches and finite magnon gaps (~2 meV) are observed for both compounds, where the Dzyaloshinsky-Moriya interactions account for most of this gap with some additional contribution from single-ion anisotropy. We also make comparisons with multiferroic BiFeO3 (R3c space group), in which similar behavior was observed. By taking into account all relevant local Dzyaloshinsky-Moriya interactions, our analysis allows for the precise determination of all experimentally observed parameters in the spin-Hamiltonian. We find that different properties of the Pbnm and R3c space group lead to the stabilization of a spin cycloid structure in the latter case but not in the former, which explains the difference in the levels of complexity of magnon band structures for the respective compounds. PMID- 29697407 TI - Exchange interactions in two-state systems: rare earth pyrochlores. AB - The general form of the nearest neighbour exchange interaction for rare earth pyrochlores is derived based on symmetry. Generally, the rare earth angular momentum degeneracy is lifted by the crystal electric field (CEF) into singlets and doublets. When the CEF ground state is a doublet that is well-separated from the first excited state the CEF ground state doublet can be treated as a pseudo spin of some kind. The general form of the nearest neighbour exchange interaction for pseudo-spins on the pyrochlore lattice is derived for three different types of pseudo-spins. The methodology presented in this paper can be applied to other two-state spin systems with a high space group symmetry. PMID- 29697408 TI - Quantum corrections for the phase diagram of systems with competing order. AB - We use the effective potential method of quantum field theory to obtain the quantum corrections to the zero temperature phase diagram of systems with competing order parameters. We are particularly interested in two different scenarios: regions of the phase diagram where there is a bicritical point, at which both phases vanish continuously, and the case where both phases coexist homogeneously. We consider different types of couplings between the order parameters, including a bilinear one. This kind of coupling breaks time-reversal symmetry and it is only allowed if both order parameters transform according to the same irreducible representation. This occurs in many physical systems of actual interest like competing spin density waves, different types of orbital antiferromagnetism, elastic instabilities of crystal lattices, vortices in a multigap SC and also applies to describe the unusual magnetism of the heavy fermion compound URu2Si2. Our results show that quantum corrections have an important effect on the phase diagram of systems with competing orders. PMID- 29697409 TI - Beginnings of nephrolithiasis: insights into the past, present and future of Randall's plaque formation research. AB - PURPOSE OF REVIEW: Kidney stones form as a result of heterogeneous nucleation on a calcium phosphate lesion in the renal papilla known as Randall's plaque. Stone disease has plagued humans for millennia with relatively little progress made in the realm of prevention. An understanding of the historical aspects of research into Randall's plaque is necessary to interpret novel correlative imaging discoveries. Focus for the past several decades has been on the distal papillary tip, and the overlooked Anderson-Carr-Randall progression is revitalized with novel supporting evidence. RECENT FINDINGS: Novel correlative techniques of three dimensional micro-XCT imaging combined with electron and light microscopy techniques have revealed that the earliest mineralization event in the papilla is a distinct event that occurs proximal to the region where Randall's plaque has traditionally been identified. SUMMARY: The history of Randall's plaque research and the Anderson-Carr-Randall progression is reviewed. Proximal intratubular mineral deposits in normal and Randall's plaque affected papillae may be a target for future therapeutic interventions for nephrolithiasis. Further collaboration between nephrologists and urologists is necessary to cure this debilitating disease. PMID- 29697410 TI - Role of Klotho in bone and implication for CKD. AB - PURPOSE OF REVIEW: Klotho is a transmembrane protein that acts as a co-receptor for fibroblast growth factor 23 (FGF23). Recent investigations have discovered the presence of Klotho in bone-forming osteoblasts and osteocytes. This review summarizes emerging literature on the roles of bone Klotho in mineral and bone metabolism and discusses their possible involvement in renal osteodystrophy. RECENT FINDINGS: Mouse genetic studies have demonstrated that loss of Klotho in osteocytes leads to increased bone formation and bone volume. The identification of Klotho expression in bone cells pointed to the possibility that the bone is another target organ for FGF23, providing a new basis for extending the interpretation of previous research findings. Along with this paradigm shift, recent investigations uncovered the autocrine/paracrine functions of FGF23 as a critical regulator of its own production and the Wnt-mediated bone formation. These effects may, however, be offset by down-regulation of bone Klotho in renal failure. SUMMARY: Klotho expressed in bone cells has functional roles in controlling bone formation and regulating FGF23 production. Additional studies are needed to translate these findings into the development of new therapeutic approaches for the treatment of bone fragility in patients with renal osteodystrophy and other bone diseases. PMID- 29697411 TI - A sustainable model for cochlear implantation in the developing world: perspectives from the Indian subcontinent. AB - PURPOSE OF REVIEW: The overall prevalence of deafness in India is 0.2%, but the prevalence in the southern state of Tamil Nadu is much higher (around 0.6%) because of consanguinity. Especially in India, establishing cochlear implantation as a treatment modality for hearing loss has been a daunting task, but in the last decade, the cochlear implantation program has emerged as an unqualified success in many states, with over 20 000 cochlear implantations done till date. Several states are sponsoring free implants to children under the age of 6 years and below poverty line. RECENT FINDINGS: Nearly 3000 cochlear implantations have been performed in Tamil Nadu under the Chief Minister's Comprehensive Health Insurance Scheme, with the goal to have a 'deafness free Tamil Nadu' by 2025. This scheme covers nearly 40 million people in rural areas. Valuable lessons have been learnt from this social experiment. One of the cornerstones of this scheme is the method to deliver habilitation via satellite centers in rural areas at the doorstep of the patient. The outcomes in peripheral centers were found to be statistically similar to those in the main center and correlated well with duration of habilitation. SUMMARY: Opening up satellite centers for habilitation across the state of Tamil Nadu has greatly helped to improve the attendance and outcomes. The Indian model has been hugely successful and has helped start similar cochlear implantation programs in neighboring countries such as Nepal, Sri Lanka and Bangladesh. PMID- 29697412 TI - Antineoplastic activity of linear leucine homodipeptides and their potential mechanisms of action. AB - Galaxamide is a rare cyclic homopentapeptide composed of three leucines and two N methyl leucines isolated from marine algae Galaxaura filamentosa. The strong antitumor activity of this compound makes it a promising candidate for tumor therapy. The synthesis of galaxamide, however, is a complex process, and it has poor water solubility. On the basis of its special chemical composition, we designed a series of linear leucine homopeptides. Among seven dipeptide derivatives, five compounds with terminal protection groups and methyl substitution of the hydrogen in the amido group showed remarkable inhibitory effects against various cancer cells. N-tertbutyl-D-leucine-N-methyl-D leucinebenzyl (A7), the only stereomer condensed by two D-leucines, showed the highest antineoplastic activity. A7-treated cells showed cell cycle arrest and morphological changes typical of cells undergoing apoptosis. The population of Annexin-V positive/propidium iodide-negative cells also increased, indicating the induction of early apoptosis. A7 promoted the cleavage of caspase-9 and caspase 3, as well as increased intracellular Ca levels and decreased the mitochondrial membrane potential. Collectively, certain linear leucine dipeptides derived from cyclic pentapeptide are able to inhibit tumor cell proliferation through cell cycle arrest and apoptosis induction. The N-methyl group in the side chain and the D/L conformation of the amino-acid residue are critical for their activity. PMID- 29697413 TI - Inhibition of fibroblast growth factor receptor-signaling sensitizes imatinib resistant gastrointestinal stromal tumors to low doses of topoisomerase II inhibitors. AB - The acquired resistance of gastrointestinal stromal tumors (GISTs) to the targeted-based therapy remains the driving force to identify the novel approaches that are capable of increasing the sensitivity of GISTs to the current therapeutic regimens. Our present data show that BGJ398, a selective fibroblast growth factor receptor (FGFR) inhibitor, sensitizes imatinib (IM)-resistant GIST cells with receptor tyrosine kinase (RTK) switch (loss of c-KIT/gain of pFGFR2a) to the low doses of topoisomerase II inhibitors - doxorubicin (Dox) and etoposide (Eto). Mechanistically, pretreatment of IM-resistant GIST cells with BGJ398 for 12 h markedly enhanced proapoptotic and growth-suppressive effects of Dox (or Eto). Indeed, a significant cleavage of PARP and caspase-3 was observed in GIST cells treated with a combination of FGFR and topoisomerase II inhibitor. In contrast, no signs of apoptosis were detected in IM-resistant GIST cells treated with BGJ398, whereas the low doses of Dox (Eto) exerted the minor proapoptotic effects on GISTs. The mechanism of BGJ398-induced sensitization of GIST to topoisomerase II inhibitors might be because of attenuation of DNA damage signaling and repair. Indeed, we observed a marked decrease in Rad51 expression in GIST cells treated with BGJ398 together with Dox. Similar results were obtained when an overexpressed pFGFR2a was knocked down by corresponding siRNA before Dox (Eto) exposure. Moreover, FGFR inhibition/depletion caused a loss of Rad51 foci in Dox-treated GIST cells, suggesting that FGFR-signaling plays an important regulatory role in homology-mediated DNA repair. Our data show that combined therapy (RTKs inhibitors supplemented with low doses of topoisomerase II inhibitors) might be effective for unresectable and metastatic forms of GISTs. In case of resistance to IM because of RTKs switch indicated above, FGFR inhibitors (e.g. BGJ398) might be potentially useful because of their ability to sensitize tumor cells to topoisomerase II inhibitors and induce tumor cell apoptosis by targeting DNA double-strand breaks repair. PMID- 29697414 TI - The dilemma of aneuploidy screening on low responders. AB - PURPOSE OF REVIEW: Preimplantation genetic testing for aneuploidy (PGT-A) has been demonstrated to improve implantation and pregnancy rates and decrease miscarriage rates over standard morphology-based embryo selection. However, there are limited data on its efficacy in patients with diminished ovarian reserve or a poor response to stimulation who may have fewer embryos to select amongst. RECENT FINDINGS: Early findings demonstrate that PGT-A reduces the miscarriage rate and decreases the time to delivery in poor responders. These studies highlight the importance of designing trials that compare outcomes over multiple cycles as the benefit of PGT-A in this patient population lies in eliminating the time lost to futile transfers of aneuploid embryos. Furthermore, recent studies have demonstrated that a catch-all category of 'poor responder' may need to be reevaluated as different subpopulations of patients with low response exhibit different clinical characteristics. SUMMARY: More information is needed on characterizing the physiology of ovarian aging across multiple phenotypes of diminished ovarian reserve and establishing the predictive value of aneuploid results across multiple PGT-A platforms. However, initial data suggests benefit of PGT-A in poor responders. PMID- 29697415 TI - An Update on the Clinicopathologic Features and Pathologic Diagnosis of Hepatitis E in Liver Specimens. AB - Infection with the hepatitis E virus (HEV) is globally seen a leading cause of hepatitis. Now increasingly recognized also in industrialized countries, hepatitis E constitutes a significant health problem worldwide. The patient's immune status determines the clinical course and histopathology of hepatitis E. In immunocompetent patients, hepatitis E usually follows an asymptomatic or subclinical course, but may also present with acute hepatitis. In contrast, immunocompromised patients may develop chronic hepatitis, and patients with preexisting liver diseases are at risk for liver decompensation with potentially fatal outcome. Whereas pathologists only occasionally encounter liver biopsies from immunocompetent individuals with hepatitis E, they are more likely exposed to biopsies from patients with preexisting liver disease or immunocompromised individuals. Histopathologic hallmarks of hepatitis E in immunocompetent patients comprise lobular disarray, lobular, and portal inflammation, as well as hepatocyte necrosis of varying extend and regeneration. Thus, it is similar to acute non-E viral hepatitis, yet further differential diagnoses include autoimmune hepatitis and drug-induced liver injury. Histopathologic findings of hepatitis E in preexisting liver disease are determined by the underlying pathology, but may be more severe. Histopathologic presentation of hepatitis E in immunocompromised patients is highly variable, ranging from minimal active hepatitis to chronic hepatitis with severe activity and progressive fibrosis. Taken together, the variability of the histologic features depending on the clinical context and the overlap with other liver diseases make the histopathologic diagnosis of hepatitis E challenging. Immunohistochemistry for HEV open reading frame 2 protein and molecular testing for HEV RNA are useful tissue-based ancillary tools. PMID- 29697417 TI - Chinese herbal medicines in the prevention and treatment of chemotherapy-induced nausea and vomiting. AB - PURPOSE OF REVIEW: Chemotherapy-induced nausea and vomiting (CINV) critically impact on cancer patients' quality of life, causing various complications, and increasing the risk of chemotherapeutic failure. Current treatments addressing CINV are reasonably costly and have many side effects. Chinese herbal medicines (CHMs) have been widely used in treating CINV in China. Clinical trials and modern experimental studies on CINV using CHMs are reviewed for clues that may help us to better prevent and treat CINV with CHMs, and develop safe and effective treatments. RECENT FINDINGS: Since 1985, 92 clinical trials on CINV were identified, which comprised of 3778 patients with different cancer types, chemotherapy regimens, prescriptions, treatment durations, and combinations with Western medicines. The most frequently used herbs are Pinellia Rhizoma, Glycyrrhizae Radix et Rhizoma, Poria, and Atractylodis Macrocephalae Rhizoma, aiming to regulate the flow of Qi and remove phlegm and dampness residing in the stomach and spleen. Although all of the reported trials are randomized open trials, the curative effects range from 55.81 to 100%. SUMMARY: CHMs seem effective in the prevention and treatment of CINV based on the clinical trials and some animal experiments, although the scientific validity of many clinical studies remain to be confirmed as many of them were inadequately designed. Further well designed clinical trials and more preclinical studies with reliable markers are required to confirm the usefulness of CHMs as complementary medicines for treating CINV and to use CHMs as rational prescriptions rather than based only on empirical knowledge. PMID- 29697418 TI - Recent progress in systemic treatment for lung cancer. AB - PURPOSE OF REVIEW: We intend to highlight progress made in 2017 to lung cancer molecular nosology and application of new knowledge to treatment. RECENT FINDINGS: Studies have shown that agents targeting specific molecular defects in lung cancers such as epidermal growth factor receptor(egfr) mutations, alk or ros1 gene rearrangements, are more effective than conventional combination chemotherapy as primary treatment for various lung cancer subgroups. Identification of mechanisms of drug resistance has guided development of improved agents and effective salvage regimens. Progress in reversing tumor induced immunosuppression has led to further improvements in response rates (RR) including some patients with prolonged durable remissions. SUMMARY: State-of-the art management of patients with lung cancer requires information derived from tumor molecular analysis, obtained either directly from the tumor or from tumor derived circulating DNA. Empiric combination chemotherapy is no longer uniformly the best available treatment for all patients. Therapeutic decisions should be guided by an understanding of molecular features of an individual patient's tumor. The future gains will likely emerge from finding optimal ways of combining targeted therapy, immunotherapy, and chemotherapy. PMID- 29697419 TI - Protruding Hyperkeratotic Tumor Underneath the Big Toe Nail: Challenge. PMID- 29697420 TI - Poxvirus-Induced Vascular Angiogenesis Mimicking Pyogenic Granuloma. AB - The orf virus, a member of poxvirus family, is a zoonotic parapoxvirus endemic in many countries, mostly seen among sheep, goats, oxen, and may be transmitted to humans. Orf virus infections may induce ulceration, papulonodular, pustular, or ecthyma lesions in the skin. Rarely, orf virus provokes extensive vasculoendothelial proliferation by encoding an apparent homolog of the mammalian vascular endothelial growth factor family of molecules. The vascular endothelial growth factor-like viral gene product is expressed early during infection and could be responsible for the induction of endothelial proliferation. Here, a 6 year-old male patient with poxvirus-induced widespread vascular angiogenesis is presented, which developed ten days after a thermal burn. PMID- 29697421 TI - A Case Report and Literature Review of Scrub Typhus With Acute Abdomen and Septic Shock in a Child-The Role of Leukocytoclastic Vasculitis and Granulysin. AB - : Scrub typhus is becoming a clinically important cause of acute undifferentiated febrile illness in Taiwan. The incubation period is between 6 and 21 days after exposure. It is transmitted by chiggers (larva of trombiculid mite) in long grasses and in dirt-floor homes, with infection characterized by a flu-like illness of fever, headache, and myalgia lasting approximately 1 week. It has various systemic manifestations, including GI symptoms. In some, the illness progresses to multiorgan dysfunction syndrome and death. We report on a 13-year old boy who lived in Taipei City and who had initially tentative diagnosis of acute pyrexia of unknown origin with high fever up to 40.3 degrees C for 1 week, but later had thrombocytopenia and diffuse abdominal pain with peritoneal sign suspected acute appendicitis. During the clinical course, septic shock and disseminated intravascular coagulopathy (DIC) were noted. There were skin rash in his trunk and extremities and an eschar with black crust surrounded by a scaling erythematous rim on his right buttock. In addition, we got the information of his travel history in Green Island and Orchid Island for 10 days.With the correct antibiotics, vancomycin, meropenem, and doxycycline, the patient was getting better and corresponding with high level of granulysin and tumor necrosis factor alpha. The diagnosis of scrub typhus was confirmed by the biopsy of eschar and high quantitative real-time polymerase chain reaction values of Orientia tsutsugamushi (16sRNA and 56 kDa) tested by Centers for Disease Control and Prevention, Taiwan. Histopathological findings of the eschar revealed the leukocytoclastic vasculitis, crust and thrombus formation with many gram-negative microorganisms, O. tsutsugamushi demonstrated by 47 kDa monoclonal antibody immunohistochemical stain and electromicroscopy. OUTCOMES: After the careful selection of appropriate antibiotics including meropenem, vancomycin, and doxycycline, he recovered and was subsequently discharged 7 days after admission. LESSON SUBSECTIONS: This case highlights that scrub typhus infection can mimic acute abdomen and septic shock with DIC. This rare presentation of acute abdomen and septic shock with thrombocytopenia and DIC caused by scrub typhus should remind physicians to be alert to the possibility of acute abdomen and febrile illness resulting from scrub typhus. PMID- 29697422 TI - Keratoacanthomatous Changes: Unifying the Histologic Spectrum of Actinic Granuloma. AB - Actinic granuloma (AG) manifests as annular plaques on sun-damaged skin. There remains no universal consensus on the nosology, etiology, or clinicopathologic criteria of AG as a distinct entity. Broadly, AG is characterized by granulomatous inflammation, multinucleated giant cells, elastophagocytosis, and the absence of mucin and necrobiosis. It is not uncommon, however, to encounter overlapping histological features of other granulomas, such as granuloma annulare and necrobiosis lipoidica, confounding the diagnosis of this controversial entity. Herein, we describe 2 cases of AG with features of granuloma annulare and necrobiosis lipoidica, supporting the concept of AG as a histologic spectrum. These 2 cases displayed dilated follicular infundibula and pseudoepitheliomatous hyperplasia analogous to changes in keratoacanthomas. These unique epithelial changes, in tandem with characteristic elastin alterations and clinical findings, are helpful and unifying features that permit accurate diagnosis of this controversial entity. PMID- 29697423 TI - Using Stratum Corneum Thickness and Configuration to Distinguish Lichenoid Dermatoses. AB - BACKGROUND: Clues in the stratum corneum (SC) can aide in histopathologic diagnosis of many conditions. OBJECTIVE: To determine if SC configuration and thickness could help differentiate the lichenoid dermatoses. METHODS: A retrospective study was performed. A total of 305 cases (55 lichenoid keratosis, 51 lichen planus, 7 hypertrophic lichen planus, 40 lichenoid drug eruption, 19 lichenoid graft-vs.-host disease, 14 hypertrophic lupus, 46 lichenoid actinic keratosis, 73 lentigo maligna) fulfilled the selection criteria. Cases were digitally scanned using the 40* (0.23 MUm/pixel) mode of a Hamamatsu NanoZoomer 2.0-HT Slide Scanner (Hamamatsu Photonics, Hamamatsu City, Japan), allowing for the creation of virtual (digital) slides. SC thicknesses and configuration were assessed for each case. RESULTS: Mixed SC patterns were common in cases of lichenoid keratoses. Compact parakeratosis was the most common pattern in lichenoid drug eruption. Tiered parakeratosis was the most predominant pattern in cases of lichenoid graft versus host disease and lichenoid actinic keratosis. Hypertrophic lupus had the highest average SC thickness. LIMITATIONS: The sample size for cases of hypertrophic lupus and hypertrophic lichen planus was low. CONCLUSIONS: SC thickness and configuration can be utilized to help differentiate the lichenoid dermatoses. PMID- 29697424 TI - A Case of Oral Florid Papillomatosis (Verrucous Carcinoma) With Lack of Evidence for Human Papillomavirus Involvement. PMID- 29697425 TI - Relationship Between Institutional Investment in High-Value Care (HVC) Performance Improvement and Internal Medicine Residents' Perceptions of HVC Training. AB - PURPOSE: To measure the association between institutional investment in high value care (HVC) performance improvement and resident HVC experiences. METHOD: The authors analyzed data from two 2014 surveys assessing institutions' investments in HVC performance improvement as reported by program directors (PDs) and residents' perceptions of the frequency of HVC teaching, participation in HVC focused quality improvement (QI), and views on HVC topics. The authors measured the association between institutional investment and resident-reported experiences using logistic regression, controlling for program and resident characteristics. RESULTS: The sample included 214 programs and 9,854 residents (59.3% of 361 programs, 55.2% of 17,851 residents surveyed). Most PDs (158/209; 75.6%) reported some support. Residents were more likely to report HVC discussions with faculty at least a few times weekly if they trained in programs that offered HVC-focused faculty development (odds ratio [OR] = 1.19; 95% confidence interval [CI] 1.04-1.37; P = .01), that supported such faculty development (OR = 1.21; 95% CI 1.04-1.41; P = .02), or that provided physician cost-of-care performance data (OR = 1.19; 95% CI 1.03-1.39; P = .02). Residents were more likely to report participation in HVC QI if they trained in programs with a formal HVC curriculum (OR = 1.83; 95% CI 1.48-2.27; P < .001) or with HVC focused faculty development (OR = 1.46; 95% CI 1.15-1.85; P = .002). CONCLUSIONS: Institutional investment in HVC-related faculty development and physician feedback on costs of care may increase the frequency of HVC teaching and resident participation in HVC-related QI. PMID- 29697426 TI - Does Mindfulness Training Enhance the Professional Development of Residents? A Qualitative Study. AB - PURPOSE: In addition to developing diagnostic and clinical skills, postgraduate medical education should stimulate residents' professional development. Teaching medical professionalism is challenging and is often left largely to the informal and hidden curricula. An intervention that might be beneficial for medical residents is mindfulness-based stress reduction (MBSR). The authors implemented MBSR as an optional course for residents and qualitatively explored how it influenced residents professionally. METHOD: Between 2014 and 2016, the authors conducted 19 in-depth, face-to-face interviews with residents who had participated in an MBSR course at Radboud university medical center, The Netherlands. Medical and surgical residents, across a range of disciplines, participated. The authors used the constant comparison method to analyze the data. RESULTS: The analysis of the data resulted in five themes: awareness of thoughts, emotions, bodily sensations, and behavior; increased self-reflection; acceptance and nonjudgment; increased resilience; and relating to others. Residents indicated that the MBSR training increased their awareness and self reflection at work, and they were more accepting toward themselves and toward their limitations. Furthermore, they mentioned being more resilient and better at setting priorities and limits. They improved their self-care and work-life balance. In addition, residents indicated that the training made them more aware of how they communicated. They asked for help more often and seemed to be more open toward feedback. Lastly, they indicated an increased sense of compassion for others. CONCLUSIONS: This study indicated that mindfulness training can serve as a tool to cultivate important professional competencies for residents. PMID- 29697427 TI - Postinterview Communications: Two Surveys of Internal Medicine Residency Program Directors Before and After Guideline Implementation. AB - PURPOSE: Guidelines surrounding postinterview communication (PIC) after residency interviews were issued by the National Resident Matching Program and Association of Program Directors in Internal Medicine. How they have influenced PIC and program directors' (PDs') reasons for PIC is unknown. METHOD: Annual surveys of 365 U.S. internal medicine residency PDs in 2013 and 368 in 2015 were used. Questions about frequency, intent, and usefulness of PIC and knowledge of guidelines before and after new PIC guidelines were included. Chi-square tests were used to compare data sets, and multivariate logistic regression was performed for 2015 data to identify factors predicting engagement in PIC, using program characteristics, PD characteristics, and beliefs about the benefits of PIC as independent variables. RESULTS: There were 265 (73%) respondents in 2013 and 227 (62%) in 2015. While the number of programs with a PIC policy increased 43%, the level of contact increased 7%. Few PDs indicated PIC was helpful to them; however, PDs who felt PIC helps target applicants were more likely to engage in PIC (OR 4.21, SE 1.88, P = .001). The main reason for continuing PIC (50% of PDs) was that PIC, part of their program's culture, was considered "good manners." CONCLUSIONS: New guidelines increased the number of programs with a PIC policy, but the overall rate of applicant contact did not change despite few PDs feeling PIC was helpful to recruitment. The culture surrounding PIC may be difficult to overcome via guidelines alone, and more definitive rules are necessary to implement change. PMID- 29697428 TI - Generalizability of Competency Assessment Scores Across and Within Clerkships: How Students, Assessors, and Clerkships Matter. AB - PURPOSE: Many factors influence the reliable assessment of medical students' competencies in the clerkships. The purpose of this study was to determine how many clerkship competency assessment scores were necessary to achieve an acceptable threshold of reliability. METHOD: Clerkship student assessment data were collected during the 2015-2016 academic year as part of the medical school assessment program at the University of Michigan Medical School. Faculty and residents assigned competency assessment scores for third-year core clerkship students. Generalizability (G) and decision (D) studies were conducted using balanced, stratified, and random samples to examine the extent to which overall assessment scores could reliably differentiate between students' competency levels both within and across clerkships. RESULTS: In the across-clerkship model, the residual error accounted for the largest proportion of variance (75%), whereas the variance attributed to the student and student-clerkship effects was much smaller (7% and 10.1%, respectively). D studies indicated that generalizability estimates for eight assessors within a clerkship varied across clerkships (G coefficients range = 0.000-0.795). Within clerkships, the number of assessors needed for optimal reliability varied from 4 to 17. CONCLUSIONS: Minimal reliability was found in competency assessment scores for half of clerkships. The variability in reliability estimates across clerkships may be attributable to differences in scoring processes and assessor training. Other medical schools face similar variation in assessments of clerkship students; therefore, the authors hope this study will serve as a model for other institutions that wish to examine the reliability of their clerkship assessment scores. PMID- 29697429 TI - A Guide to Reflexivity for Qualitative Researchers in Education. PMID- 29697430 TI - Why Pull the Arrow When You Cannot See the Target? Framing Professionalism Goals in Medical Education. AB - Professionalism is essential for a successful physician-patient relationship and widely acknowledged as an intrinsic and important component of medical education for learners at all levels, from medical school to residency to continuing medical education. The problem is defining the educational end points for learners and then determining how to assess these outcomes. This Invited Commentary focuses on what medical educators can and should do to refine the vision of professionalism in medical education. The authors propose a multistep process in which learners, educators, and the public are engaged in articulating clearly and definitively the end points of professionalism education. PMID- 29697431 TI - A Fine Balance: How Authors Strategize Around Journal Submission. AB - PURPOSE: Publishing in peer-reviewed journals is essential for medical education researchers. Competition remains fierce for top journals, and authors are advised to consider impact factor (IF), audience, and alignment of focus. However, little is known about how authors balance these factors when making submission decisions. The authors aimed to explore decision making around journal choice. METHOD: Using constructivist grounded theory, the authors conducted and analyzed 27 semistructured phone interviews (August-November 2016) with medical education researchers. Participants were recruited from a larger study, and all had presented abstracts at medical education meetings in 2005 or 2006. RESULTS: When deciding where to submit an article, participants weighed a journal's IF and prestige against other factors, such as a journal's vision and mission, finding the right audience, study-specific factors including perceived quality of the work, and the peer review process. The opportunity cost of aiming high and risking rejection was influenced by career stage and external pressures. Despite much higher IFs, clinical journals were viewed as less desirable for establishing legitimacy in the medical education field and were often targeted for less novel or rigorous work. Participants expressed dissatisfaction with peer review in general, citing overly critical and poorly informed reviewers. CONCLUSIONS: Authors strategize around a particular article's submission by attempting to balance many interrelated factors. Their perceptions that high-IF clinical journals are viewed as less prestigious in this field can lead to publication strategies running counter to advice given to junior faculty. This has implications for mentorship and institutional leadership. PMID- 29697432 TI - Remediation in Practicing Physicians: Current and Alternative Conceptualizations. AB - Suboptimal performance in practicing physicians is a decades-old problem. The lack of a universally accepted definition of remediation, the paucity of research on best remediation practices, and the ongoing controversy regarding the institutional responsibility for enacting and overseeing the remediation of physicians suggest that it is not merely a difficult problem to solve but a problem that the community does not grapple with meaningfully. Undoubtedly, logistical and political considerations contribute to this state of affairs; however, other underlying conceptual issues may also play a role in the medical profession's difficulties in engaging with the challenges around remediation.Through a review of the medical education and other literatures, the authors examined current conceptualizations of both reme-diation itself and the individual being remediated, as well as how the culture of medicine influences these conceptions. The authors explored how conceptualizations of remediation and the surrounding culture might affect not only the medical community's ability to support but also its willingness to engage with physicians in need of remediation.Viewing remediation as a means of supporting practice change-rather than as a means of redressing gaps in knowledge and skill-might be a useful alternative conceptualization, providing a good place to start exploring new avenues of research. However, moving forward will require more than simply a reconceptualization of remediation; it will also necessitate a change in how the community views its struggling members and a change in the medical culture that currently positions professional autonomy as the foundational premise for individual practice improvement. PMID- 29697433 TI - Ensuring Access to Quality Health Care in Vulnerable Communities. AB - For millions of Americans living in vulnerable rural and urban communities, their hospital is an important, and often their only, source of health care. As transformation in the hospital and health care field continues, some communities may be at risk of losing access to health care services and the opportunities and resources they need to improve and maintain their health. Integrated, comprehensive strategies to reform health care delivery and payment, within which vulnerable communities can make individual choices based on their needs, support structures, and preferences, are needed.In this Invited Commentary, the authors outline characteristics and parameters of vulnerable communities as well as the essential health care services that hospitals should strive to maintain locally identified by the American Hospital Association Task Force on Ensuring Access in Vulnerable Communities. They also describe four of nine emerging strategies recommended by the task force-to reform health care delivery and payment and allow hospitals to provide the essential health care services, along with implementation barriers and how to address them. While this Invited Commentary focuses on vulnerable communities, the four highlighted strategies (addressing the social determinants of health, adopting new and innovative virtual care strategies, designing global budgets, and using inpatient/outpatient transformation strategy), as well as the other five strategies, may have broader applicability for all communities. PMID- 29697434 TI - Evolution of clinical trials for rheumatoid arthritis and spondyloarthritis. AB - PURPOSE OF REVIEW: The present review presents an overview of the evolution in trial design from mainly randomized placebo-controlled efficacy trials to more strategic clinical trials in rheumatoid arthritis and spondyloarthritis. Additionally, it relates to how these differently designed trials have affected clinical practice. RECENT FINDINGS: Placebo-controlled clinical trials, comparing a new agent to placebo on a stable background, have resulted in the development of a wide array of therapeutic agents in rheumatoid arthritis and spondyloarthritis. However, these kind of trials do have some down sides as they do not provide evidence on the optimal strategy to use this multitude of treatments in daily clinical practice and the ethics concerning a placebo phase are often discussed. These and other concerns resulted in the emergence of various different types of trials in rheumatoid arthritis. A similar change of focus is now observed in spondyloarthritis clinical trials. We address literature on direct comparison ('head-to-head'), noninferiority trials, induction maintenance, discontinuation, and treat-to-target/tight control clinical trials. SUMMARY: In recent years various clinical trials have been published with a design different from placebo-controlled clinical trials. These novel trial designs aimed to provide guidance on the optimal way to use the full range of targeted treatments available and to make it possible, in some design, to leave out the placebo. In rheumatoid arthritis, some of these more strategic type of trials have had a large impact on common practice. In spondyloarthritis, the first steps toward trials with a more strategic design have been taken, and it stands to reason that more will follow. PMID- 29697435 TI - Management of herpes simplex virus epithelial keratitis. AB - PURPOSE OF REVIEW: To review recent advancements in the management of herpes simplex virus (HSV) epithelial keratitis. RECENT FINDINGS: Trifluridine eye drop, acyclovir (ACV) ointment, ganciclovir gel, and oral ACV are still the main therapeutic agents. Cryopreserved amniotic membrane has been recently used as an adjuvant treatment. Resistance to ACV has become a concerning issue. The animal models of HSV vaccine are able to reduce HSV keratitis. New antivirals are under development. SUMMARY: Current cases of HSV epithelial keratitis are manageable with available medications, but new advancements are required to decrease disease burden in the future. HSV vaccine can be revolutionary. PMID- 29697436 TI - Extended depth of focus intraocular lenses for presbyopia. AB - PURPOSE OF REVIEW: To summarize the various extended depth of focus (EDOF) intraocular lenses currently available to patients and to describe visual outcomes and patient satisfaction. RECENT FINDINGS: EDOF lenses are a relatively new option for presbyopic correction. Preliminary studies show high levels of spectacle independence and patient satisfaction. The only United States Federal Drug Administration-approved intraocular lens currently on market is the TECNIS Symfony (Johnson and Johnson Vision, Jacksonville, FL). SUMMARY: Early studies show that EDOF lenses may provide satisfactory near and intermediate vision with reduced incidence of haloes and glares often noted by patients implanted with multifocal lenses. Results are promising, but limited. PMID- 29697437 TI - Routine Use of Adjunctive p16 Immunohistochemistry Improves Diagnostic Agreement of Cervical Biopsy Interpretation: Results From the CERTAIN Study. AB - The diagnosis of squamous intraepithelial lesions in cervical tissue specimens is subject to substantial variability. Adjunctive immunohistochemical (IHC) staining for p16 has been shown to add objective biomarker information to morphologic interpretation of hematoxylin and eosin (H&E)-stained tissues. In the CERvical Tissue AdjunctIve aNalysis (CERTAIN) study, we systematically analyzed the impact of adjunctive p16 IHC on the accuracy (agreement with reference pathology results) of diagnosing cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) in the United States. Eleven hundred cervical biopsies were divided into 4 sets of 275 cases by stratified randomization. All H&E slides from each set were interpreted by 17 to 18 individual surgical pathologists, for a total of 19,250 reads by 70 surgical pathologists. After a wash-out period and blinding to original results, cases were re-read by the same pathologists using H&E+p16 stained slides. Using expert consensus diagnoses on H&E+p16 as reference, adjunctive p16 IHC use significantly improved diagnostic agreement of surgical pathologists by 4.7% (95% confidence interval [CI], 3.9, 5.4; P<0.0001). This improvement was driven by an increase of 11.5% (95% CI, 9.3, 13.5; P<0.0001) in sensitivity and an increase of 3.0% (95% CI, 2.2, 3.7; P<0.0001) in specificity. Diagnostic performance was significantly increased as well when expert consensus diagnoses established on H&E only was used as reference. Furthermore, interobserver reliability improved significantly from moderate (H&E: kappa=0.58) to substantial (H&E+p16: kappa=0.73; P<0.0001). Adjunctive use of p16 IHC provides more accurate and reproducible diagnostic results in the interpretation of cervical biopsies, ensuring that more patients are treated correctly without treating more patients. PMID- 29697438 TI - Improved Progression Prediction in Barrett's Esophagus With Low-grade Dysplasia Using Specific Histologic Criteria. AB - Risk stratification of patients with Barrett's esophagus (BE) is based on diagnosis of low-grade dysplasia (LGD). LGD has a poor interobserver agreement and a limited value for prediction of progression to high-grade dysplasia or esophageal adenocarcinoma. Specific reproducible histologic criteria may improve the predictive value of LGD. Four gastrointestinal pathologists examined 12 histologic criteria associated with LGD in 84 BE patients with LGD (15 progressors and 69 nonprogressors). The criteria with at least a moderate (kappa, 0.4 to 0.6) interobserver agreement were validated in an independent cohort of 98 BE patients with LGD (30 progressors and 68 nonprogressors). Hazard ratios (HR) were calculated by Cox proportional hazard regression analysis using time dependent covariates correcting for multiple endoscopies during follow-up. Agreement was moderate or good for 4 criteria, that is, loss of maturation, mucin depletion, nuclear enlargement, and increase of mitosis. Combination of the criteria differentiated high-risk and low-risk group amongst patients with LGD diagnosis (P<0.001). When >=2 criteria were present, a significantly higher progression rate to high-grade dysplasia or esophageal adenocarcinoma was observed (discovery set: HR, 5.47; 95% confidence interval [CI], 1.81-17; P=0.002; validation set: HR, 3.52; 95% CI, 1.56-7.97; P=0.003). Implementation of p53 immunohistochemistry and histologic criteria optimized the prediction of progression (area under the curve, 0.768; 95% CI, 0.656-0.881). We identified and validated a clinically applicable panel of 4 histologic criteria, segregating BE patients with LGD diagnosis into defined prognostic groups. This histologic panel can be used to improve clinical decision making, although additional studies are warranted. PMID- 29697439 TI - Successful Reconstruction of a Traumatic Complete Femoral Nerve Rupture with a Sural Nerve Cable Graft: A Case Report. AB - CASE: We report a rare case of complete rupture of the right femoral nerve at the pelvic level, which was caused by a self-inflicted stab wound. The nerve was surgically reconstructed with use of an autologous sural nerve cable graft. Postoperatively, the patient's sensorimotor function returned to near normal. CONCLUSION: Femoral nerve rupture caused by a laceration is very unusual. A bilateral sural nerve cable graft performed in collaboration with surgeons from other specialties achieved a good outcome in this otherwise healthy young patient. PMID- 29697440 TI - Three-Dimensionally Printed Personalized Implant Design and Reconstructive Surgery for a Bone Tumor of the Calcaneus: A Case Report. AB - CASE: A 23-year-old soldier was diagnosed with a calcaneal desmoplastic fibroma. Limb-salvage surgery using a 3-dimensionally (3D) printed personalized implant made from a titanium alloy was planned. The implant had a mesh-style surface for free tendon suture, and the joint surface was smooth to preserve the subtalar joint. The implant had 3 hollow posts in case of future transarticular immobilization. At the last follow-up, the implant was painless and stable, and the patient could walk normally without support. CONCLUSION: A 3D-printed personalized implant showed acceptable functional and anatomic outcomes for a calcaneal bone tumor. Appropriate design modification of a 3D-printed personalized implant enabled an optimal outcome in our patient. PMID- 29697441 TI - Retrospective, Multicenter Comparison of the Clinical Presentation of Patients Presenting With Diplopia From Giant Cell Arteritis vs Other Causes. AB - BACKGROUND: Although giant cell arteritis (GCA) is a well-known cause of transient and permanent vision loss, diplopia as a presenting symptom of this condition is uncommon. We compared symptoms and signs of patients presenting with diplopia from GCA to those from other causes. METHODS: This was a multicenter, retrospective study comparing the clinical characteristics of patients presenting with diplopia from GCA with age-matched controls. Demographic information, review of symptoms, ophthalmic examination, and laboratory data of biopsy-proven patients with GCA were compared with those of age-matched controls presenting with diplopia. RESULTS: A total of 27 patients presented with diplopia from GCA, 19 with constant diplopia, and 8 with transient diplopia. All patients with constant diplopia from GCA were matched with 67 control subjects who had diplopia from other etiologies. Patients with GCA were more likely to describe other accompanying visual symptoms (58% vs 25%, P = 0.008), a greater number of systemic GCA symptoms (3.5, GCA vs 0.6, controls, P < 0.001) such as headache (94% [17/18] vs 39% [23/67]; P < 0.001), jaw claudication (80% [12/15] vs 0% [0/36]; P < 0.001), and scalp tenderness (44% [7/16] vs 7% [3/43]; P < 0.001). Ocular ischemic lesions (26% vs 1%, P < 0.001) were also common in patients with diplopia from GCA. Inflammatory markers were elevated significantly in patients with GCA vs controls (erythrocyte sedimentation rate: 91% [10/11] vs 12% [3/25], P < 0.001; C-reactive protein: 89% [8/9] vs 11% [2/19], P < 0.001). CONCLUSIONS: GCA is a rare but serious cause of diplopia among older adults and must be differentiated from other more common benign etiologies. Our study suggests that most patients with diplopia from GCA have concerning systemic symptoms and/or elevated inflammatory markers that should trigger further work-up. Moreover, careful ophthalmoscopic examination should be performed to look for presence of ocular ischemic lesions in older patients presenting with acute diplopia. PMID- 29697442 TI - Relationship Between Sarcopenic Obesity and Outcomes of Hepatectomy for Hepatocellular Carcinoma. PMID- 29697444 TI - Potential Impact of "Take the Volume Pledge" on Access and Outcomes for Gastrointestinal Cancer Surgery. AB - OBJECTIVE: To quantify the number of US hospitals that would meet "Take the Volume Pledge" (TVP) volume thresholds and compare outcomes at hospitals meeting and not meeting TVP thresholds. SUMMARY BACKGROUND DATA: TVP aims to regionalize complex cancer resections to hospitals meeting established annual average volume thresholds. There is little data describing the potential impact on patient access if this initiative were broadly implemented or the relationship between these volume thresholds and quality of oncologic care. METHODS: Hospitals in the National Cancer Database (2006-2012) performing esophagectomy (n = 968), proctectomy (n = 1250), or pancreatectomy (n = 1068) were categorized based on frequency meeting TVP thresholds: always low volume (LV); low annual average and intermittently low volume (ILV); high annual average and intermittently high volume (IHV); always high volume (HV). Multivariable generalized estimating equations were used to evaluate the association between hospital TVP category, oncologic care processes, and perioperative outcomes. RESULTS: Few hospitals met annual TVP thresholds (HV or IHV)-esophagectomy 1.6%; proctectomy 19.7%; pancreatectomy 6.6%. The majority of esophagectomy (77.8%) and pancreatectomy (53.4%) and 48.1% of proctectomy patients received care at hospitals not meeting annual TVP thresholds (LV or ILV). While performance for all three procedures was generally better at ILV, IHV, and HV hospitals relative to LV hospitals, there were few differences (none of which were consistent) when comparing ILV, IHV, and HV hospitals to each other. CONCLUSIONS AND RELEVANCE: Few hospitals would meet TVP volume thresholds for complex cancer resections with little difference in outcomes between ILV, IHV, and HV hospitals. While a policy to regionalize complex surgical care may have merit, it could also compromise patient autonomy and limit access to care if patients are unable or unwilling to travel. PMID- 29697445 TI - Developing Safe Opioid Prescribing Practices Through Medical Student Education. PMID- 29697443 TI - Injury Characteristics and von Willebrand Factor for the Prediction of Acute Respiratory Distress Syndrome in Patients With Burn Injury: Development and Internal Validation. AB - OBJECTIVE: To derive and validate a prediction model for the development of ARDS in burn-injured patients. SUMMARY BACKGROUND DATA: Burn injury carries the highest incidence of acute respiratory distress syndrome (ARDS) among all predisposing conditions, but few studies exist on risk factors in these patients. Studies employing biomarkers and clinical risk factors for predicting ARDS mortality have recently been examined but none exist for onset of ARDS nor in patients with burn injury. METHODS: This was a prospective multicenter study of 113 patients with isolated burn injury or inhalation injury. Clinical variables and plasma biomarkers representative of endothelial injury, epithelial injury, or inflammation were collected within 24 hours of admission. The most parsimonious model was chosen by considering discrimination, calibration, and model fit. RESULTS: Among the biomarkers measured in patients with burn injuries, a one standard deviation increase in log-transformed levels of the A2 domain of von Willebrand factor in the first 24 hours was most strongly associated with the development of ARDS (OR 7.72; 95% CI: 1.64-36.28, P = 0.03). Of candidate models, a 3-variable model with %TBSA, inhalation injury, and von Willebrand factor-A2 had comparable discrimination to more complex models (area under the curve: 0.90; 95% CI 0.85-0.96). The 3-variable model had good model fit by Hosmer-Lemeshow test (P = 0.74) and maintained similar discrimination after accounting for performance optimism (Bootstrapped area under the curve: 0.90; 95% CI: 0.84 0.95). CONCLUSIONS: The 3-variable model with %TBSA, inhalation injury, and von Willebrand factor could be used to better identify at-risk patients for both the study and prevention of ARDS in patients with burn injury. PMID- 29697446 TI - Quality Versus Quantity: The Potential Impact of Public Reporting of Hospital Safety for Complex Cancer Surgery. AB - OBJECTIVE: To estimate the potential mortality reduction if patients chose the safest hospitals for complex cancer surgery. BACKGROUND: Mortality after complex oncologic surgery is highly variable across hospitals, and directing patients away from unsafe hospitals could potentially improve survivorship. Hospital quality measures are becoming increasingly accessible at a time when patients are more engaged in choosing providers. It is currently unclear what information to share with patients to maximally capitalize on patient-centered realignment. METHODS: The National Cancer Database was queried for adults undergoing 5 complex cancer surgeries (pulmonary lobectomy, pneumonectomy, esophagectomy, gastrectomy, and colectomy) for a primary cancer between 2008 and 2012. Risk-standardized mortality rate (RSMR) methodology, currently used by Medicare-based hospital rating systems, was used to classify hospitals as "safest" and "least safe" by procedure. Patients were modeled moving from "least safe" to "safest" hospitals and the potential number of lives saved through patient realignment determined. As surgical volume has historically been used to distinguish safe hospitals, comparisons were made to models moving patients from low-volume to high-volume hospitals. RESULTS: A total of 292,040 patients were analyzed. In an optimally modeled scenario, realignment using RSMR would result in a greater number of lives saved (3592 vs 2161, P < 0.01) and require only 15 patients to change hospitals to save a life, compared to 78 patients using volume models (P < 0.01). CONCLUSIONS: Public reporting of hospital safety, specifically based on RSMR instead of volume, has the potential to lead to meaningful reductions in surgical mortality after complex cancer surgery, even in the setting of a modest patient realignment. PMID- 29697447 TI - Long-term Outcomes of Laparoscopic Versus Open Surgery for Clinical Stage II/III Gastric Cancer: A Multicenter Cohort Study in Japan (LOC-A Study). AB - OBJECTIVE: A large-scale multicenter historical cohort study was conducted to investigate the efficacy of laparoscopic gastrectomy (LG) in comparison to open gastrectomy (OG) for locally advanced gastric cancer. BACKGROUND: LG is now practiced widely, but its applicability for advanced gastric cancer is still controversial. As oncologic outcomes of randomized trials are still pending, there is an urgent need for information that would be relevant to current practice. METHODS: Through a consensus meeting involving surgeons and biostatisticians, 30 preoperative variables possibly influencing the choice of surgical approach and associated with outcome were identified to enable rigorous estimation of propensity scores. A total of 1948 consecutive patients who underwent gastrectomy for clinical stage II/III gastric adenocarcinoma between 2008 and 2014 were identified, and their clinical data were collected from 8 participating hospitals. After propensity score matching, 610 cases (OG = 305, LG = 305) were finally selected for comparison of long-term outcomes. RESULTS: In the propensity-matched OG and LG populations, the mean observation period was 3.5 and 3.4 years, and the 5-year overall survival was 53.0% and 54.2%, respectively. The hazard ratio (LG/OG) for overall survival was 1.01 (95% confidence interval, 0.80-1.29), and noninferiority of LG was demonstrated statistically as the upper 95% confidence limit was less than the prespecified margin (1.33). The recurrence rate was 30.8% and 29.8% for OG and LG, respectively, and the hazard ratio for recurrence was 0.98 (95% confidence interval, 0.74-1.31). The patterns of recurrence in the 2 groups were similar. CONCLUSIONS: This observational study strictly adjusted for confounding factors has provided evidence to suggest that LG is oncologically comparable to OG for locally advanced gastric cancer. The validity of this result will be examined in ongoing randomized trials. PMID- 29697448 TI - No Surgical Innovation Without Evaluation: Evolution and Further Development of the IDEAL Framework and Recommendations. AB - OBJECTIVE: To update, clarify, and extend IDEAL concepts and recommendations. BACKGROUND: New surgical procedures, devices, and other complex interventions need robust evaluation for safety, efficacy, and effectiveness. Unlike new medicines, there is no internationally agreed evaluation pathway for generating and analyzing data throughout the life cycle of surgical innovations. The IDEAL Framework and Recommendations were designed to provide this pathway and they have been used increasingly since their introduction in 2009. Based on a Delphi survey, expert workshop and major discussions during IDEAL conferences held in Oxford (2016) and New York (2017), this article updates and extends the IDEAL Recommendations, identifies areas for future research, and discusses the ethical problems faced by investigators at each IDEAL stage. METHODS: The IDEAL Framework describes 5 stages of evolution for new surgical therapeutic interventions-Idea, Development, Exploration, Assessment, and Long-term Study. This comprehensive update proposes several modifications. First, a "Pre-IDEAL" stage describing preclinical studies has been added. Second we discuss potential adaptations to expand the scope of IDEAL (originally designed for surgical procedures) to accommodate therapeutic devices, through an IDEAL-D variant. Third, we explicitly recognise the value of comprehensive data collection through registries at all stages in the Framework and fourth, we examine the ethical issues that arise at each stage of IDEAL and underpin the recommendations. The Recommendations for each stage are reviewed, clarified and additional detail added. CONCLUSIONS: The intention of this article is to widen the practical use of IDEAL by clarifying the rationale for and practical details of the Recommendations. Additional research based on the experience of implementing these Recommendations is needed to further improve them. PMID- 29697449 TI - Surgical Intuition. PMID- 29697450 TI - A Statistical Model-driven Surgical Case Scheduling System Improves Multiple Measures of Operative Suite Efficiency: Findings From a Single-center, Randomized Controlled Trial. AB - OBJECTIVE: We sought to determine whether a data-driven scheduling approach improves Operative Suite (OS) efficiency. BACKGROUND: Although efficient use of the OS is a critical determinant of access to health care services, OS scheduling methodologies are simplistic and do not account for all the available characteristics of individual surgical cases. METHODS: We randomly scheduled cases in a single OS by predicting their length using either the historical mean (HM) duration of the most recent 4 years; or a regression modeling (RM) system that accounted for operative and patient characteristics. The primary endpoint was the imprecision in prediction of the end of the operative day. Secondary endpoints included measures of OS efficiency; personnel burnout captured by the Maslach Burnout Inventory; and a composite endpoint of 30-day mortality, myocardial infarction, wound infection, bleeding, amputation, or reoperation. RESULTS: Two hundred and seven operative days were allocated to scheduling with either the RM or the HM methodology. Mean imprecision in predicting the end of the operative day was higher with the HM approach (30.8 vs 7.2 minutes, P = 0.024). RM was associated with higher throughput (379 vs 356 cases scheduled over the course of the study, P = 0.04). The composite rate of adverse 30-day events was similar (2.2% vs 3.2%, P = 0.44). The mean depersonalization score was higher (3.2 vs 2.0, P = 0.044), and mean personal accomplishment score was lower during HM weeks (37.5 vs 40.5, P = 0.028). CONCLUSIONS: Compared to the HM scheduling approach, the proposed data-driven RM scheduling methodology improves multiple measures of OS efficiency and OS personnel satisfaction without adversely affecting clinical outcomes. PMID- 29697451 TI - The Challenge of Measuring Surgeon Spending for Payment Policies. AB - OBJECTIVE: Our objective was to understand the reliability of profiling surgeons on average health care spending. SUMMARY OF BACKGROUND DATA: Under its Merit based Incentive Payment System (MIPS), Medicare will measure surgeon spending and tie performance to payments. Although the intent of this cost-profiling is to reward low-cost surgeons, it is unknown whether surgeons can be accurately distinguished from their peers. METHODS: We used Michigan Medicare and commercial payer claims data to construct episodes of surgical care and to calculate average annual spending for individual surgeons. We then estimated the "reliability" (ie, the ability to distinguish surgeons from their peers) of these cost-profiles and the case-volume that surgeons would need in order to achieve high reliability [intraclass correlation coefficient (ICC) >0.8]. Finally, we calculated the reliability of 2 alternative methods of profiling surgeons (ie, using multiple years of data and grouping surgeons by hospitals). RESULTS: We found that annual cost-profiles of individual surgeons had poor reliability; the ICC ranged from <0.001 for CABG to 0.061 for cholecystectomy. We found that few surgeons in the state of Michigan have sufficient case-volume to be reliably compared; 1% had the minimum yearly case. Finally, we found that the reliability of the cost-profiles can be improved by measuring spending at the hospital-level and/or by incorporating additional years of data. CONCLUSION: These findings suggest that the Medicare program should measure surgeon spending at a group level or incorporate multiple years of data to reduce misclassification of surgeon performance in the MIPS program. PMID- 29697452 TI - Impact of Breast Surgery in Primary Metastasized Breast Cancer: Outcomes of the Prospective Randomized Phase III ABCSG-28 POSYTIVE Trial. AB - BACKGROUND: Conflicting evidence exists regarding the value of surgical resection of the primary in stage IV breast cancer patients. OBJECTIVE: The prospective randomized phase III ABCSG-28 POSYTIVE trial evaluated median survival comparing primary surgery followed by systemic therapy to primary systemic therapy in de novo stage IV breast cancer. METHODS: Between 2011 and 2015, 90 previously untreated stage IV breast cancer patients were randomly assigned to surgical resection of the primary tumor followed by systemic therapy (Arm A) or primary systemic therapy (Arm B) in Austria. Overall survival (OS) was defined as the primary study endpoint. RESULTS: The trial was stopped early due to poor recruitment. Ninety patients (45 arm A, 45 arm B) were included; median follow-up was 37.5 months. Patients in the surgery arm had more cT3 breast cancer (22.2% vs 6.7%) and more cN2 staging (15.6% vs 4.4%). Both groups were well balanced with respect to the type of first-line systemic treatment. Median survival in arm A was 34.6 months, versus 54.8 months in the nonsurgery arm [hazard ratio (HR) 0.691, 95% confidence interval (95% CI) 0.358-1.333; P = 0.267]; time to distant progression was 13.9 months in the surgery arm and 29.0 months in the nonsurgery arm (HR 0.598, 95% CI 0.343-1.043; P = 0.0668). CONCLUSION: The prospective phase III trial ABCSG-28 (POSYTIVE) could not demonstrate an OS benefit for surgical resection of the primary in breast cancer patients presenting with de novo stage IV disease. PMID- 29697453 TI - Value-based Surgical Care: Evidence for the Enigma. PMID- 29697454 TI - Objective Evidence of Reflux Control After Magnetic Sphincter Augmentation: One Year Results From a Post Approval Study. AB - OBJECTIVE: To report 1-year results from a 5-year mandated study. SUMMARY BACKGROUND DATA: In 2012, the United States Food and Drug Administration approved magnetic sphincter augmentation (MSA) with the LINX Reflux Management System (Torax Medical, Shoreview, MN), a novel device for the surgical treatment of gastroesophageal reflux disease (GERD). Continued assessment of safety and effectiveness has been monitored in a Post Approval Study. METHODS: Multicenter, prospective study of patients with pathologic acid reflux confirmed by esophageal pH testing undergoing MSA. Predefined clinical outcomes were assessed at the annual visit including a validated, disease-specific questionnaire, esophagogastricduodenoscopy and esophageal pH monitoring, and use of proton pump inhibitors. RESULTS: A total of 200 patients (102 males, 98 females) with a mean age of 48.5 years (range 19.7-71.6) were treated with MSA between March 2013 and August 2015. At 1 year, the mean total acid exposure time decreased from 10.0% at baseline to 3.6%, and 74.4% of patients had normal esophageal acid exposure time (% time pH<4 <=5.3%). GERD Health-Related Quality of Life scores improved from a median score of 26.0 at baseline to 4.0 at 1 year, with 84% of patients meeting the predefined success criteria of at least a 50% reduction in total GERD Health Related Quality of Life score compared with baseline. The device removal rate at 1 year was 2.5%. One erosion and no serious adverse events were reported. CONCLUSIONS: Safety and effectiveness of magnetic sphincter augmentation has been demonstrated outside of an investigational setting to further confirm MSA as treatment for GERD. PMID- 29697455 TI - Modified Blumgart Mattress Suture Versus Conventional Interrupted Suture in Pancreaticojejunostomy During Pancreaticoduodenectomy: Randomized Controlled Trial. AB - OBJECTIVE: This study used a randomized controlled trial (RCT) to evaluate whether mattress suture of pancreatic parenchyma and the seromuscular layer of jejunum (modified Blumgart method) during pancreaticojejunostomy (PJ) decreases the incidence of clinically relevant postoperative pancreatic fistula (POPF) after pancreaticoduodenectomy (PD). BACKGROUND: Several studies reported that mattress suture of Blumgart anastomosis in PJ could reduce POPF rate. This, however, is the first RCT. METHODS: Between June, 2013 and May, 2017, 224 patients scheduled for PD were enrolled in this study in Wakayama Medical University Hospital. Enrolled patients were randomized to either interrupted suture or modified Blumgart mattress suture. The primary endpoint was the incidence of grade B/C POPF based on the International Study Group on Pancreatic Fistula criteria. This RCT was registered with ClinicalTrials.gov (NCT01898780). RESULTS: Patients were randomized to either interrupted suture (103 patients) or modified Blumgart mattress suture (107 patients) and were analyzed by intention to-treat. Grade B/C POPF occurred in 7 patients (6.8%) in the interrupted suture group and 11 (10.3%) in the mattress suture group (P = 0.367). Mortality within 90 days was 0 in both groups. There were no significant differences in all postoperative complications between the interrupted suture group and the modified Blumgart mattress suture group. CONCLUSIONS: Mattress suture of pancreatic parenchyma and the jejunal seromuscular layer during PJ (modified Blumgart technique) did not reduce clinically relevant POPF compared with interrupted suture.This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0. PMID- 29697456 TI - Prophylactic Mesh for the Prevention of Parastomal Hernias: Need for a Deep Dive. PMID- 29697457 TI - Association of clinical and inflammatory markers with small bowel capsule endoscopy findings in Crohn's disease. AB - BACKGROUND: Mucosal healing is an established treatment endpoint in Crohn's disease (CD). Still, clinical indices and inflammatory markers are used widely in CD surveillance. AIM: The aim of this study was to investigate the diagnostic performance as well as the relationship of C-reactive protein (CRP) and Crohn's Disease Activity Index (CDAI) with small bowel capsule endoscopy's (SBCE) inflammation scoring index, the Lewis Score (LS). PATIENTS AND METHODS: CDAI, CRP, and SBCE findings of 30 CD patients with isolated small bowel disease were retrieved from our academic institution patient records and were analyzed statistically. RESULTS: SBCE showed significant mucosal inflammation [mean (SD) LS: 1599 (1380)], in nine (60.0%) of 15 patients who were in both clinical and biochemical remission. CDAI and CRP showed a weak and moderate correlation with LS (r=0.317, P=0.088 and r=0.516, P=0.004, respectively). The diagnostic performance of CDAI and CRP in predicting mucosal inflammation was as follows: sensitivity 23.8 and 52.4%; specificity 100 and 66.7%; positive predictive value 100 and 78.6%; and negative predictive value 36.0 and 37.5%. The area under the curve toward endoscopic activity prediction was 0.70 and 0.69, respectively. CONCLUSION: Both CDAI and CRP underestimated endoscopic activity as expressed by the LS in a significant proportion of patients with quiescent disease. PMID- 29697458 TI - Effects of inflammatory bowel disease treatment on the risk of nonalcoholic fatty liver disease: a meta-analysis. AB - BACKGROUND: Epidemiological studies have demonstrated an association between inflammatory bowel disease (IBD) and an increased risk for the development of nonalcoholic fatty liver disease (NAFLD). However, the risk of NAFLD in IBD patients who receive different medical treatments including glucocorticoids, immunomodulators, and tumor necrosis factor-alpha inhibitors remains unclear. We aimed to assess whether the use of certain IBD medications is associated with the development of NAFLD. MATERIALS AND METHODS: A systematic review was carried out in Medline, Embase, and Cochrane databases from inception through October 2017 to identify studies that assessed the association between the use of IBD medications and the risk of developing NAFLD. Effect estimates from the individual study were derived and combined using random-effect, generic inverse variance method of DerSimonian and Laird. RESULTS: Seven observational studies with a total of 1610 patients were enrolled. There was no significant association between the use of IBD medications and the incidence of NAFLD. The pooled odds ratios of NAFLD in patients who use biological agents, immunomodulators, methotrexate, and steroids were 0.85 [95% confidence interval (CI): 0.49-1.46], 1.19 (95% CI: 0.70-2.01), 3.62 (95% CI: 0.48-27.39), and 1.24 (95% CI: 0.85-1.82), respectively. Egger's regression asymmetry test was performed and showed no publication bias. CONCLUSION: Our study demonstrates no significant association between medications used in the treatment of IBD and the risk of developing NAFLD. The findings of our study suggest a complex, multifactorial relationship between IBD and the development of NAFLD beyond the scope of current pharmacological intervention. PMID- 29697459 TI - The effect of obesity on the rate of heparin-induced thrombocytopenia. AB - : Heparin-induced thrombocytopenia (HIT) occurs in patients receiving heparin containing products due to the formation of platelet-activating antibodies to heparin and platelet factor 4. Diagnosis includes utilization of a scoring system known as the 4-T score, and HIT laboratory assays. Recently, obesity was identified as a potential factor associated with the development of HIT. The objective of this study was to evaluate the association of HIT with obesity in ICU and general medicine patients. We performed a chart review of adult patients within the Methodist Healthcare System, and included patients who had an ELISA and serotonin release assay laboratory tests reported within same hospital admission in which they also had documented receipt of heparin. Obese patients were compared with nonobese patients (BMI < 30) for the primary outcome of HIT occurrence, and secondary outcomes including rate of thrombosis, 4-T scores, and ELISA optical density values. We also generated a 5-T score by including one additional point for those with a BMI of 30 or more to determine the predictive value of this score in identifying HIT. Obesity was confirmed to be a risk factor for HIT, and the 5-T score model was also predictive of the development of HIT. However, the 5-T score was not statistically more predictive of HIT than the 4-T score. Predicting HIT remains challenging and novel markers of HIT are needed to improve HIT recognition. Although obesity did not improve the 4-T score, it may improve the predictability of other scoring systems, and further investigation is warranted. PMID- 29697460 TI - Cardiac and pulmonary donor procurement. AB - PURPOSE OF REVIEW: Within the United States, donor heart and lung procurement varies between institutions and among surgeons within the same institution sometimes. The purpose of this article is to review the history of donor heart and lung procurement, the surgical techniques, and pitfalls. RECENT FINDINGS: The current article covers the important intraoperative evaluation of the donor heart and lungs at the procurement hospital and the surgical pitfalls that can be prevented to ensure good procurement of donor heart and lungs. SUMMARY: The current article provides a review of the history of donor procurement. The article will also provide recommendations for surgical techniques and to prevent possible complications of donor procurement at the time of surgery. PMID- 29697461 TI - Organ preservation solutions: linking pharmacology to survival for the donor organ pathway. AB - PURPOSE OF REVIEW: To provide an understanding of the scientific principles, which underpinned the development of organ preservation solutions, and to bring into context new strategies and challenges for solution development against the background of changing preservation technologies and expanded criteria donor access. RECENT FINDINGS: Improvements in organ preservation solutions continue to be made with new pharmacological approaches. New solutions have been developed for dynamic perfusion preservation and are now in clinical application. Principles defining organ preservation solution pharmacology are being applied for cold chain logistics in tissue engineering and regenerative medicine. SUMMARY: Organ preservation solutions support the donor organ pathway. The solution compositions allow additives and pharmacological agents to be delivered direct to the target organ to mitigate preservation injury. Changing preservation strategies provide further challenges and opportunities to improve organ preservation solutions. PMID- 29697462 TI - Ex-vivo machine perfusion for kidney preservation. AB - PURPOSE OF REVIEW: Machine perfusion is a novel strategy to decrease preservation injury, improve graft assessment, and increase organ acceptance for transplantation. This review summarizes the current advances in ex-vivo machine based kidney preservation technologies over the last year. RECENT FINDINGS: Ex vivo perfusion technologies, such as hypothermic and normothermic machine perfusion and controlled oxygenated rewarming, have gained high interest in the field of organ preservation. Keeping kidney grafts functionally and metabolically active during the preservation period offers a unique chance for viability assessment, reconditioning, and organ repair. Normothermic ex-vivo kidney perfusion has been recently translated into clinical practice. Preclinical results suggest that prolonged warm perfusion appears superior than a brief end ischemic reconditioning in terms of renal function and injury. An established standardized protocol for continuous warm perfusion is still not available for human grafts. SUMMARY: Ex-vivo machine perfusion represents a superior organ preservation method over static cold storage. There is still an urgent need for the optimization of the perfusion fluid and machine technology and to identify the optimal indication in kidney transplantation. Recent research is focusing on graft assessment and therapeutic strategies. PMID- 29697463 TI - Evolving challenges in thoracic transplantation. PMID- 29697464 TI - Incidence and Risk Factors for Intraoperative Seizures During Elective Craniotomy. AB - BACKGROUND: Perioperative seizures may affect 1% to 50% of patients undergoing craniotomy and adversely impact outcomes. However, data on intraoperative seizures are limited. This retrospective case-control study investigated the incidence and risk factors for intraoperative seizures during elective supratentorial craniotomy involving evoked potential monitoring. MATERIALS AND METHODS: Patients aged 18 years or above undergoing elective supratentorial craniotomy with evoked potential monitoring who experienced intraoperative seizures at our institution between December 2008 and March 2014 were compared with a control group generated using a random number generator. Six controls were used for each case from among the patients who underwent elective supratentorial craniotomy during the same calendar year. Multivariate analysis was conducted using logistic regression to identify the risk factors for intraoperative seizures. RESULTS: Among the 1916 patients who met the inclusion criteria, 45 (2.3%) had intraoperative seizures. The majority of seizures occurred during burr hole placement or craniotomy, before lesion manipulation. Timing of seizures relative to motor evoked potential runs and stimulus intensity was variable. Significant risk factors for intraoperative seizures were seizure history (odds ratio [OR], 2.18; 95% confidence interval [CI], 1.07-4.46; P=0.03), diagnosis of brain tumor (OR, 2.41; 95% CI, 1.16-4.19; P=0.02), and temporal craniotomy (OR, 5.18; 95% CI, 2.03-13.25; P=0.001). Intraoperative prophylactic use of phenytoin/fosphenytoin and levetiracetam was protective against seizure (phenytoin/fosphenytoin: OR, 0.12; 95% CI, 0.04-0.35; P<0.001 and levetiracetam: OR, 0.40; 95% CI, 0.17-0.94; P=0.04). Phenytoin/fosphenytoin was more protective than levetiracetam (OR, 0.31; 95% CI, 0.10-0.99; P=0.048). CONCLUSIONS: The overall incidence of intraoperative seizures was 2.3%. Independent risk factors for intraoperative seizures were seizure history, diagnosis of intracranial tumor, and temporal craniotomy. Intraoperative prophylactic anticonvulsant use was protective. PMID- 29697465 TI - Temporal Sensitivity Measured Shortly After Cochlear Implantation Predicts 6 Month Speech Recognition Outcome. AB - OBJECTIVES: Psychoacoustic tests assessed shortly after cochlear implantation are useful predictors of the rehabilitative speech outcome. While largely independent, both spectral and temporal resolution tests are important to provide an accurate prediction of speech recognition. However, rapid tests of temporal sensitivity are currently lacking. Here, we propose a simple amplitude modulation rate discrimination (AMRD) paradigm that is validated by predicting future speech recognition in adult cochlear implant (CI) patients. DESIGN: In 34 newly implanted patients, we used an adaptive AMRD paradigm, where broadband noise was modulated at the speech-relevant rate of ~4 Hz. In a longitudinal study, speech recognition in quiet was assessed using the closed-set Freiburger number test shortly after cochlear implantation (t0) as well as the open-set Freiburger monosyllabic word test 6 months later (t6). RESULTS: Both AMRD thresholds at t0 (r = -0.51) and speech recognition scores at t0 (r = 0.56) predicted speech recognition scores at t6. However, AMRD and speech recognition at t0 were uncorrelated, suggesting that those measures capture partially distinct perceptual abilities. A multiple regression model predicting 6-month speech recognition outcome with deafness duration and speech recognition at t0 improved from adjusted R = 0.30 to adjusted R = 0.44 when AMRD threshold was added as a predictor. CONCLUSIONS: These findings identify AMRD thresholds as a reliable, nonredundant predictor above and beyond established speech tests for CI outcome. This AMRD test could potentially be developed into a rapid clinical temporal resolution test to be integrated into the postoperative test battery to improve the reliability of speech outcome prognosis. PMID- 29697466 TI - Perioperative considerations for airway management and drug dosing in obese children. AB - PURPOSE OF REVIEW: Childhood obesity, a phenomenon that is increasing globally, holds substantial relevance for pediatric anesthesia. In particular, understanding the nuances of airway management and drug dosing in obese children can be daunting. RECENT FINDINGS: Respiratory adverse events and challenges in managing the airway may be anticipated. In addition, drug-dosing strategies for the obese child are complex and poorly understood although recent advances have clarified the optimal dosing for anesthetics in these children. SUMMARY: Theoretical knowledge, practical skills, meticulous risk stratification and optimal drug regimens are crucial to ensure the safe conduct of anesthesia for obese children. PMID- 29697467 TI - Evaluation of abnormal liver tests in the adult asymptomatic patient. AB - PURPOSE OF REVIEW: Liver blood tests, including bilirubin, aminotransferases, and alkaline phosphatase, are among the most commonly encountered tests in medicine. With roles including the investigation of symptoms, medication monitoring, assessment of chronic disease, and routine assessment, these tests serve many purposes and result in abnormality in up to 40% of patients. RECENT FINDINGS: The toll of liver disease continues to rise and abnormal liver tests offer an opportunity to identify hepatic disease early, when treatment is most effective and before patients suffer the potential downstream consequences of cirrhosis, portal hypertension, and hepatocellular carcinoma. By utilizing diagnostic strategies including detailed history gathering, alcohol use assessment, recognition of metabolic syndrome, and identifying patterns of liver test abnormalities, clinicians can develop a systematic approach to address abnormal liver tests. For these reasons, developing an evidence-based, systematic approach to handling abnormal liver tests is critically important. SUMMARY: This review seeks to synthesize key elements of the best evidence, presently available guidelines, and expert opinion in drafting a strategy to aid clinicians and patients in the timely and accurate diagnosis of liver disease for the adult asymptomatic patient with abnormal liver tests. PMID- 29697468 TI - 4'-Ethynyl-2-fluoro-2'-deoxyadenosine, MK-8591: a novel HIV-1 reverse transcriptase translocation inhibitor. AB - PURPOSE OF REVIEW: 4'-Ethynyl-2-fluoro-2'-deoxyadenosine (EFdA) is a nucleoside reverse transcriptase inhibitor (NRTI) with a novel mechanism of action, unique structure, and amongst NRTIs, unparalleled anti-HIV-1 activity. We will summarize its structure and function, antiviral activity, resistance profile, and potential as an antiretroviral for use in the treatment and preexposure prophylaxis of HIV 1 infection. RECENT FINDINGS: EFdA is active against wild-type (EC50 as low as 50 pmol/l) and most highly NRTI-resistant viruses. The active metabolite, EFdA triphosphate, has been shown to have a prolonged intracellular half-life in human and rhesus (Rh) blood cells. As a result, single drug doses tested in simian immunodeficiency virus mac251-infected Rh macaques and HIV-1-infected individuals exhibited robust antiviral activity of 7-10 days duration. Preclinical studies of EFdA as preexposure prophylaxis in the Rh macaque/simian/human immunodeficiency virus low-dose intrarectal challenge model have shown complete protection when given in clinically relevant doses. SUMMARY: EFdA is a novel antiretroviral with activity against both wild-type and NRTI-resistant viruses. As a result of the prolonged intracellular half-life of its active moiety, it is amenable to flexibility in dosing of at least daily to weekly and perhaps longer. PMID- 29697469 TI - Broadly neutralizing antibodies for treatment and prevention of HIV-1 infection. AB - PURPOSE OF REVIEW: Several anti-HIV-1 broadly neutralizing antibodies (bNAbs) with exceptional breadth and potency that target different HIV-1 envelope epitopes have been identified. bNAbs are an attractive new strategy for HIV-1 prevention and therapy, and potentially, for long-term remission or cure. Here, we discuss findings from early clinical studies that have evaluated these novel bNAbs. RECENT FINDINGS: Phase 1 studies of bNAbs targeting two distinct HIV-1 envelope epitopes have demonstrated their favorable safety and pharmacokinetic profile. Single bNAb infusions led to significant, but transient, decline in viremia with selection of escape variants. A single bNAb also delayed viral rebound in ART-treated participants who discontinued ART. Importantly, in-vivo efficacy was related to antibody potency and to the level of preexisting resistance. Studies in animal models showed that bNAbs can clear HIV-infected cells and modulate host immune responses. These findings suggest that bNAbs may target the latent HIV reservoir in humans and could contribute to long-term remission of HIV-1 infection. SUMMARY: bNAbs may offer advantages over traditional ART for both the prevention and treatment of HIV-1 infection. In addition, bNAbs may target the latent viral reservoir. bNAb combinations and bNAbs engineered for prolonged half-life and increased potency are currently undergoing clinical evaluation. PMID- 29697470 TI - Update on techniques to prevent infections associated with prostate needle biopsy. AB - PURPOSE OF REVIEW: Postbiopsy infections (PBIs) are among the most common complications associated with transrectal ultrasound-guided prostate biopsy (TRUSPB). This article discusses the pathogenesis of TRUSPB-associated infectious complications and reviews the most recent findings on techniques to prevent PBIs. RECENT FINDINGS: Risk stratification is a powerful tool for identifying TRUSPB candidates whom warrant additional preventive measures. Bowel preparation with povidone-iodine-based enemas and needle disinfection with formalin solution are simple and attractive strategies, but their effectiveness needs to be thoroughly assessed. Antibiotic prophylaxis represents the mainstay for the prevention of PBIs: the prophylactic regimen must respect the principles of antimicrobial stewardship, and local antibiotic resistance patterns among uropathogens should always be considered. Augmented and targeted antibiotic prophylaxes are powerful options, but their role in current clinical practice has yet to be clarified. The transperineal approach has shown a near-zero rate of PBIs, and should therefore be considered for the highest-risk patients. SUMMARY: Several procedures have been introduced to prevent TRUSPB-related infectious complication, but their utility and applicability in the clinical practice has yet to be elucidated. More robust evidence based on randomized control trials is needed to establish the efficacy of these tools in improving patient outcomes. PMID- 29697471 TI - Roles for active surveillance in renal cancer. AB - PURPOSE OF REVIEW: With this review, we describe the most recent advances in active surveillance as well as diagnosis and management of small renal masses (SRMs). RECENT FINDINGS: We discuss diagnosis, differentiation of solid from cystic lesions, risk prediction and treatment of the SRM. A better understanding of the disease facilitates the use of more conservatory treatments, such as active surveillance. Active surveillance has been increasingly accepted not only for SRM, but also for larger tumors and even metastatic patients. Exiting advances in risk prediction will help us define which patients can be safely managed with active surveillance and which require immediate treatment. Meanwhile, the use of renal tumor biopsies is still an important tool for these cases. SUMMARY: Active surveillance is an option for many patients with renal masses. Noninvasive methods for diagnosis and risk prediction are being developed, but meanwhile, renal tumor biopsy is a useful tool. A better understanding of the disease increases the number of patients who can undergo active surveillance fully certain of the safety of their management. PMID- 29697472 TI - Engaging telehealth to drive value-based urology. AB - PURPOSE OF REVIEW: Telehealth, or the remote delivery of healthcare services using telecommunications technology, has the potential to revolutionize the delivery of healthcare and contribute to ongoing efforts to provide high-value care. RECENT FINDINGS: We discuss several categories of telehealth that have been applied to healthcare. Several of these approaches, in particular video visits and teleconsultations, have promising early data demonstrating the significant benefits of telehealth technology with respect to the quality of care, access, cost savings, and patient experience. Nonetheless, considerable knowledge gaps still exist regarding how and for which patients and diseases telehealth modalities should be applied. Finally, we discuss the barriers to widespread adoption at the institutional, state, and federal levels. SUMMARY: Maximizing the value of healthcare is an important goal for hospitals, physicians, and policymakers. Telehealth leverages advances in technology and the widespread availability of telecommunications devices to make healthcare communication more available, more convenient, and more efficient for patients and providers. With appropriate policies and incentives, telehealth initiatives can improve the value of urologic care and smooth the transition to a value-based healthcare system. PMID- 29697473 TI - We do not know what we do not know: innovative approaches to value measurement. AB - PURPOSE OF REVIEW: Over the past several years, there has been an increasing focus on improving the 'value' of healthcare delivered, defined as the ratio of clinical outcomes to the costs incurred to achieve them. The former U.S. Secretary of Health and Human Services Sylvia Burwell announced in 2015 that the majority of healthcare payments in the Medicare and Medicaid programmes will align with value by 2018. Although this has yet to fully mature, numerous health systems have restructured with a goal of improving the value of care delivered to their populations. Nevertheless, there remain important unanswered questions regarding how we measure value in the current U.S. healthcare system. The purpose of this review is to highlight innovations that are not only making it easier to measure value but also to improve care from the patient, provider and healthcare system perspectives. RECENT FINDINGS: Behavioural start-ups and the introduction of relatively inexpensive health coaches are starting to permeate the healthcare landscape. These coaches are the consumers' advocate, acting as the quarterback of an extended care team in order to optimize health. Furthermore, time-driven activity-based costing has allowed us to understand costs on a more granular level, and novel tracking software may further automate these costing algorithms in order to better facilitate their dissemination. SUMMARY: We must all work to enable new models of care that improve value by incentivizing individuals, payers and providers to improve health, rather than treat the disease after it manifests. We must also continue to improve the efficiency of healthcare delivery largely through improvements in value measurement. PMID- 29697474 TI - Percutaneous renal biopsy: approach, diagnostic accuracy and risks. AB - PURPOSE OF REVIEW: This article provides a review of recent advances and issues regarding the controversial topic of renal mass biopsy (RMB). The purpose of this review is to provide an update on the current status of renal biopsy based on recently published literature. Here, we particularly focus on articles that have been published within the last 12 months. RECENT FINDINGS: The main topics covered in this review are the approach, diagnostic accuracy and risks related to RMB. SUMMARY: Current literature suggests that improvements in both technique and technological advancements of RMB have led to greater diagnostic accuracy and low risks to the patient. Newer technologies are leading toward innovative and harmless ways to diagnose kidney cancer, including liquid and image-based biopsy. However, it appears that the question of whether or not to instate renal biopsy as standard clinical practice has remained a highly debated controversy. PMID- 29697476 TI - A Systematic Review of the Processes Underlying the Main and the Buffering Effect of Social Support on the Experience of Pain. AB - OBJECTIVE: This review aimed to explore the processes that underlie the main and the buffering effect of social support on decreased pain experience. MATERIALS AND METHODS: The systematic review was conducted according to the PRISMA guidelines. Online databases of PubMed and PsycINFO were searched for peer reviewed articles using keywords ("social support," OR "interpersonal," OR "social presence," OR "spouse," OR "couple," OR "marriage") AND "pain"). Articles were included if they examined the cognitive or behavioral processes linking social support to any aspects of reduced pain experience. RESULTS: The database search identified 38 studies, of which 33 were cognitive-behavioral studies and 5 were neurobiological. Cognitive-behavioral studies generated a total of 57 findings of the analgesic influence of social support. This effect was further categorized as social support decreasing the adverse influence of pain-related stress (28/44 findings), reappraising pain-related stress (7/9 findings), and facilitating coping attempts (2/4 findings). Of the 5 neurobiological studies, the influence of social support on pain reduction was associated with reduced neural and physiological stress systems in response to painful stimuli. DISCUSSION: This review presents evidence that the stress-buffering effect is more often able to account for the relationship between social support and pain experience. Moreover, findings suggest the critical significance of stress appraisal and attenuated stress systems in linking social support to aspects of reduced pain experience. Findings implicate the role of integrating perceived support and intimacy in support-oriented interventional trials for chronic pain. PMID- 29697475 TI - Using Analgesics for Emotional Modulation is Associated With Increased Distress, Depression, and Risk of Opioid and Alcohol Misuse: Initial Evaluation and Component Analysis of the Reasons for Analgesic Use Measure (RAUM). AB - OBJECTIVES: It is important to identify aspects of analgesic use that are associated with harm in chronic pain. Historically, the focus has been patterns of use (eg, overuse). This study evaluated another aspect of use-rather than evaluating how analgesics were being used, the primary interest was in why they were being used. METHODS: In total, 334 analgesic using individuals with chronic pain responded to a pool of items assessing reasons for analgesic use. Measures of pain intensity, distress, depression, and opioid and alcohol misuse were also completed. RESULTS: Exploratory factor analyses indicated 3 overarching reasons for use, including taking analgesics: (1) for pain reduction/functional improvement; (2) for emotional modulation/sedation; and (3) to be compliant with prescriber instructions. Correlation and regression analyses indicated that the second factor had the strongest relations with the other measures used, such that greater endorsement of analgesic use for emotional modulation was associated with greater distress, depression, and opioid and alcohol misuse. Using analgesics for pain reduction/functional improvement was associated with greater pain-related distress and depression. Using analgesics to be compliant was not associated with any measure. This pattern of results was generally replicated when a subsample of 131 individuals taking opioids was examined. DISCUSSION: Results support the utility of examining reasons for analgesic use; use to achieve emotional modulation/sedation may be particularly associated with risk. The data also provide support for the questionnaire developed, the Reasons for Analgesic Use Measure. PMID- 29697478 TI - Clinical usefulness of noninvasively estimated central blood pressure. PMID- 29697477 TI - Utility Scores and Preferences for Surgical and Organ-Sparing Approaches for Treatment of Intermediate and High-Risk Rectal Cancer. AB - BACKGROUND: Organ-sparing approaches, including wait-and-see and local excision, are increasingly being offered to patients with rectal cancer following a good response to neoadjuvant therapy. Preferences regarding these treatment strategies are yet unknown. OBJECTIVE: This study aimed to determine the preferences and utility scores for rectal cancer treatment approaches. DESIGN: This is a cross sectional study. SETTING: This study was conducted at the Radiation-Oncology Department of the University Medical Center Utrecht. PATIENTS: Fifty-seven patients with a history of rectal cancer and 38 volunteers were included. MAIN OUTCOME MEASURES: Participants assessed 6 hypothetical treatment-outcome scenarios, including short-course radiotherapy or chemoradiation followed by abdominoperineal resection, low anterior resection, local excision, or a wait-and see approach. The hierarchy in preferences between scenarios was assessed by using ranking. Utilities were estimated with a visual analog scale and time trade off. RESULTS: Organ-sparing approaches were ranked as the first preferred treatment option by 51% of the participants. Among all scenarios, wait-and-see was most often ranked highest by patients and volunteers (36% and 50%). Meanwhile, a substantial proportion ranked wait-and-see as their lowest preference (38% in patients and 35% in volunteers). Utility scores differed significantly between scenarios. Wait-and-see received a significantly higher score on the visual analog scale than the scenarios including abdominoperineal resection and the scenario including chemoradiation with low anterior resection, and a score similar to the scenarios including local excision and short-course radiotherapy with low anterior resection. LIMITATIONS: The study population consisted of patients with a history of rectal cancer treatment and volunteers related to patients. This may have influenced preferences. CONCLUSIONS: This study suggests that there is a wide disparity in preferences concerning organ sparing approaches for rectal cancer in both patients with a history of rectal cancer and volunteers. Wait-and-see is often the highest preferred treatment, but it is also among the least preferred treatment options. These findings give insights into how patients may value the current rectal cancer treatment options. See Video Abstract at http://links.lww.com/DCR/A521. PMID- 29697479 TI - Vascular aging and target organ damage: is it predictable? PMID- 29697480 TI - Ambulatory arterial stiffness index and blood pressure response to renal denervation. PMID- 29697481 TI - Diastolic J curve, cuff artefact and low targets for SBP: a need for caution. PMID- 29697482 TI - Reply. PMID- 29697483 TI - Role of optical coherence tomography in identifying sub-optimal stent positioning and predicting major adverse cardiac events in a comparative study with angiography: a CLIO-OPCI II sub-study. AB - BACKGROUND: Quantitative coronary angiography (QCA) is the gold standard for evaluating correct stenting, despite its limitation in recognizing features indicative of suboptimal deployment. This subanalysis of the CLI-OPCI II registry addressed the role of optical coherence tomography (OCT) to verify whether suboptimal OCT deployment occurs in the presence of an optimal angiographic result. PATIENTS AND METHODS: We retrospectively analyzed 125 lesions in the 105 patients with major adverse cardiac events of the CLI-OPCI II. Every lesion was evaluated with OCT and angiography, including visual and QCA assessment. Optimal angiographic result was defined as residual stenosis of less than 30% at QCA and absence of haziness at visual angiography. The following OCT features of suboptimal stenting were considered: edge dissection (linear rim of tissue with a width >200 MUm), reference lumen narrowing (lumen area <4.5 mm in the presence of significant residual plaque adjacent to stent endings), and in-stent narrowing (minimum lumen area<4.5 mm). RESULTS: Among the 125 lesions, 105 showed an optimal angiographic result. At OCT, a suboptimal positioning was common (56%). In the group of optimal angiographic results, OCT showed a suboptimal deployment in 54% of cases. Minimum lumen area of less than 4.5 mm, distal and proximal reference narrowing, and distal edge dissections were found in 30, 25, 15, and 7% of cases, respectively. CONCLUSION: This substudy of the CLI-OPCI II showed that in patients with major adverse cardiac events, the presence of an optimal postintervention angiographic appearance with suboptimal OCT metrics is a frequent finding. Our data further support the effectiveness of OCT, which provide valuable information even in the presence of optimal poststenting angiographic results. PMID- 29697484 TI - Cohesin in haematopoiesis and leukaemia. AB - PURPOSE OF REVIEW: Disturbance of the delicate balance between self-renewal and differentiation in haematopoietic stem cells (HSCs) can lead to both leukaemia and bone marrow failure. The regulation of this balance in HSC biology has been intensely investigated in several model systems, and lately the importance of epigenetic modifications as well as the organization and architecture of chromatin has become increasingly recognized. In this review, we will focus on the role of the chromatin organizing protein complex cohesin in regulation of normal and malignant haematopoiesis. RECENT FINDINGS: Several functional studies in both mouse and human systems have implicated cohesin as a critical regulator of self-renewal and differentiation in HSCs. Together with the discovery of recurrent mutations of cohesin genes in myeloid malignancies, this points towards a direct role of perturbed cohesin function in leukemogenesis. SUMMARY: The work reviewed here provides new insights about the role of the cohesin complex and chromatin architecture in normal and malignant HSCs, and indicates how cohesin may be specifically targeted for therapeutic benefit in the future. PMID- 29697485 TI - Advances in the role of the aryl hydrocarbon receptor to regulate early hematopoietic development. AB - PURPOSE OF REVIEW: We summarize current advances to define the role the aryl hydrocarbon receptor (AHR) plays in mammalian hematopoiesis. We emphasize approaches to modulate AHR throughout human hematopoietic development in vitro to support the production of clinically relevant blood products suitable for patient care. RECENT FINDINGS: Initial data demonstrate that both pharmacologic AHR inhibition and genetic deletion from human pluripotent stem cells provide useful strategies to enhance the yield of hematopoietic stem and progenitor cells. AHR hyperactivation following the induction of CD34 megakaryocyte-erythroid progenitors skews developed toward erythroid lineages, whereas AHR inhibition supports platelet production. At the level of lymphoid specification, AHR inhibition enhances the proliferation and differentiation of functional human natural killer cells, whereas hyperactivation leads to production of Group 3 innate lymphoid cells and provides a novel platform for studying human innate lymphoid cell development. SUMMARY: Modulation of AHR in human hematopoietic cells in vitro is a promising tool to mediate development of terminal hematopoietic cell populations with significant clinical implications to generate cells suitable for antitumor immunotherapy and bone marrow transplantation. PMID- 29697486 TI - ETS transcription factor ETV2/ER71/Etsrp in haematopoietic regeneration. AB - PURPOSE OF REVIEW: Recent studies have established that haematopoietic stem cells (HSCs) remain quiescent in homeostatic conditions, and minimally contribute to haematopoietic homeostasis. However, they undergo extensive cell cycle and expansion upon bone marrow transplantation or haematopoietic injury to reestablish the haematopoietic system. Molecular basis for the HSC activation and expansion is not completely understood. Here, we review the recent study elucidating the role of the developmentally critical Ets transcription factor Etv2 in reestablishing haematopoietic system upon injury through promoting HSC regeneration. RECENT FINDINGS: We recently demonstrated that the ETS transcription factor Etv2, a critical factor for haematopoietic and vascular development, is also required for haematopoietic regeneration. Etv2, which is silent in homeostatic HSCs, was transiently activated in regenerating HSPCs and was required for the HSC expansion and regeneration following bone marrow transplantation or haematopoietic injury. As such, while Etv2 is dispensable for maintaining HSCs in steady states, it is required for emergency haematopoiesis. SUMMARY: Etv2 has been identified as a novel regulator of haematopoietic regeneration. Comprehensive understanding of the upstream regulators and downstream effectors of Etv2 in haematopoietic regeneration would be critical for fundamental understanding of haematopoietic stem cell biology, and the findings will be broadly applicable to clinical practice involving haematopoietic regenerative medicine; bone marrow transplantation, gene therapy and in-vitro HSC expansion. PMID- 29697487 TI - Family Health-related Quality of Life in Pediatric Cyclic Vomiting Syndrome. AB - OBJECTIVE: The aim of the study was to evaluate the relationship of disease characteristics and child anxiety symptoms to family health-related quality of life (FHRQoL) in youth with cyclic vomiting syndrome (CVS). METHODS: Forty-two parents of youth ages 8 to 18 years diagnosed with CVS completed the Family Impact Module of the PedsQL, a measure of the impact of the child's illness on the family. We evaluated the relationship of disease characteristics and child and parent proxy reports of anxiety symptoms on the Screen for Childhood Anxiety and Related Emotional Disorders to FHRQoL. RESULTS: Parent report of child anxiety symptoms and missed school days (mean = 11.93, standard deviation = 14.62) were the strongest predictors of FHRQoL (r = 0.33, df = 1.39, F = 8.51, P = 0.006). Other disease characteristics, including frequency, duration, chronicity of CVS episodes, and delay in initial CVS diagnosis were not significantly associated with the FHRQoL total score. Child anxiety symptoms by either parent and/or child report were associated with subscales of the FHRQoL, including family physical functioning, family communication, and family daily activities. CONCLUSIONS: HRQoL for the families assessed in this study was associated with anxiety symptoms to a greater extent than disease characteristics, indexing the importance of a biopsychosocial approach to CVS management. Screening for anxiety symptoms and support for school absences due to illness are indicated to help lessen the impact of CVS on the family as a whole. PMID- 29697488 TI - High Resolution Manometry With Multiple Rapid Swallows Confirms the Diagnosis of Type-III Achalasia in an Adolescent. PMID- 29697489 TI - The effect of Cobb angle correction on spinal length gain in patients with adolescent idiopathic scoliosis. AB - The relationship between curve correction and spinal length gain in adolescent idiopathic scoliosis was examined. A total of 102 patients who underwent posterior spinal correction and fusion alone or in combination with anterior spinal correction and fusion (ASF) were studied. The Cobb angle correction, increase in the main thoracic length, T1-L5 spinal length gain, and T1-L5 spinal length gain/Cobb angle correction were reported. The length gain/Cobb angle correction value was not significantly associated with sex, fusion approach, and the number of fused levels. Surgical T1-L5 spinal length gain (mm) equaled (70.20)-(3.51)*(degrees of Cobb angle correction)+(0.08)*(degrees of Cobb angle correction). PMID- 29697490 TI - Lower-extremity rotational profile and toe-walking in preschool children with autism spectrum disorder. AB - The aim of this study was to establish the torsional and toe-walking profiles of children with autism spectrum disorder (ASD), and to analyze the correlations between torsion, toe-walking, autism severity score, and age. In total, 79 consecutive children with autism were examined to determine their hip rotations, thigh-foot angle, degree of toe-walking, and autism severity. Femoral and tibial torsion values, of the preschool patients, were compared statistically with age matched controls. The hip rotation profile of the patients was similar to the normal group. Nearly a half of the patients with ASD present excessive external tibial torsion. The difference in the tibial torsion between patients and normal children was statistically significant. A weak correlation was found only between tibial torsion and the autism severity score, but no correlation was found between the other parameters. External tibial torsion is the cardinal and persistent orthopedic manifestation among patients with ASD. Toe-walking is the second most common such manifestation and is an independent orthopedic feature in these patients. External tibial torsion may potentially contribute toward the described gait abnormalities in patients with ASD. PMID- 29697491 TI - Preoperative Magnetic Resonance Volumetry in Predicting Myometrial Invasion, Lymphovascular Space Invasion, and Tumor Grade: Is It Valuable in International Federation of Gynecology and Obstetrics Stage I Endometrial Cancer? AB - OBJECTIVE: The aim of this retrospective single-center study was to evaluate the relationship between maximum tumor size, tumor volume, tumor volume ratio (TVR) based on preoperative magnetic resonance (MR) volumetry, and negative histological prognostic parameters (deep myometrial invasion [MI], lymphovascular space invasion, tumor histological grade, and subtype) in International Federation of Gynecology and Obstetrics stage I endometrial cancer. METHODS/MATERIALS: Preoperative pelvic MR imaging studies of 68 women with surgical-pathologic diagnosis of International Federation of Gynecology and Obstetrics stage I endometrial cancer were reviewed for assessment of MR volumetry and qualitative assessment of MI. Volume of the tumor and uterus was measured with manual tracing of each section on sagittal T2-weighted images. Tumor volume ratio was calculated according to the following formula: TVR = (total tumor volume/total uterine volume) * 100. Receiver operating characteristics curve was performed to investigate a threshold for TVR associated with MI. The Mann-Whitney U test, Kruskal-Wallis test, and linear regression analysis were applied to evaluate possible differences between tumor size, tumor volume, TVR, and negative prognostic parameters. RESULTS: Receiver operating characteristics curve analysis of TVR for prediction of deep MI was statistically significant (P = 0.013). An optimal TVR threshold of 7.3% predicted deep myometrial invasion with 85.7% sensitivity, 46.8% specificity, 41.9% positive predictive value, and 88.0% negative predictive value. Receiver operating characteristics curve analyses of TVR, tumor size, and tumor volume for prediction of tumor histological grade or lymphovascular space invasion were not significant. The concordance between radiologic and pathologic assessment for MI was almost excellent (kappa value, 0.799; P < 0.001). Addition of TVR to standard radiologic assessment of deep MI increased the sensitivity from 90.5% to 95.2%. CONCLUSIONS: Tumor volume ratio, based on preoperative MR volumetry, seems to predict deep MI independently in stage I endometrial cancer with insufficient sensitivity and specificity. Its value in clinical practice for risk stratification models in endometrial cancer has to be studied in larger cohort of patients. PMID- 29697492 TI - Acanthamoeba: An Overview of the Challenges to the Development of a Consensus Methodology of Disinfection Efficacy Testing for Contact Lens Care Products. AB - With the increasing incidence of more pathogens that can cause microbial keratitis (MK), it is necessary to periodically reassess disinfection multipurpose solutions testing requirements to ensure that relevant organisms to challenge them are being used. Current testing protocols have included common pathogens such as Pseudomonas aeruginosa, Staphylococcus aureus, Serratia marcescens, Candida albicans, and Fusarium solani but have omitted less common pathogens such as Acanthamoeba. Specifically, Acanthamoeba sp. has recently been identified as a prevalent cause of MK in certain countries. Developing an appropriate protocol for this unique organism presents a challenge, given its two distinct life stages, methods to grow the organism, encystment techniques, and many other parameters that can affect testing outcomes. Therefore, the appropriate combination of these parameters is crucial to developing a protocol that ensures consistent, accurate results. The FDA has recognized the importance of establishing a standardized testing protocol for this pathogen and embarked on research efforts to provide a recommended testing protocol for testing contact lens care products. PMID- 29697493 TI - Performance of an Automated Versus a Manual Whole-Body Magnetic Resonance Imaging Workflow. AB - OBJECTIVES: The aim of this study was to evaluate the performance of an automated workflow for whole-body magnetic resonance imaging (WB-MRI), which reduces user interaction compared with the manual WB-MRI workflow. MATERIALS AND METHODS: This prospective study was approved by the local ethics committee. Twenty patients underwent WB-MRI for myopathy evaluation on a 3 T MRI scanner. Ten patients (7 women; age, 52 +/- 13 years; body weight, 69.9 +/- 13.3 kg; height, 173 +/- 9.3 cm; body mass index, 23.2 +/- 3.0) were examined with a prototypical automated WB MRI workflow, which automatically segments the whole body, and 10 patients (6 women; age, 35.9 +/- 12.4 years; body weight, 72 +/- 21 kg; height, 169.2 +/- 10.4 cm; body mass index, 24.9 +/- 5.6) with a manual scan. Overall image quality (IQ; 5-point scale: 5, excellent; 1, poor) and coverage of the study volume were assessed by 2 readers for each sequence (coronal T2-weighted turbo inversion recovery magnitude [TIRM] and axial contrast-enhanced T1-weighted [ce-T1w] gradient dual-echo sequence). Interreader agreement was evaluated with intraclass correlation coefficients. Examination time, number of user interactions, and MR technicians' acceptance rating (1, highest; 10, lowest) was compared between both groups. RESULTS: Total examination time was significantly shorter for automated WB-MRI workflow versus manual WB-MRI workflow (30.0 +/- 4.2 vs 41.5 +/- 3.4 minutes, P < 0.0001) with significantly shorter planning time (2.5 +/- 0.8 vs 14.0 +/- 7.0 minutes, P < 0.0001). Planning took 8% of the total examination time with automated versus 34% with manual WB-MRI workflow (P < 0.0001). The number of user interactions with automated WB-MRI workflow was significantly lower compared with manual WB-MRI workflow (10.2 +/- 4.4 vs 48.2 +/- 17.2, P < 0.0001). Planning efforts were rated significantly lower by the MR technicians for the automated WB MRI workflow than for the manual WB-MRI workflow (2.20 +/- 0.92 vs 4.80 +/- 2.39, respectively; P = 0.005). Overall IQ was similar between automated and manual WB MRI workflow (TIRM: 4.00 +/- 0.94 vs 3.45 +/- 1.19, P = 0.264; ce-T1w: 4.20 +/- 0.88 vs 4.55 +/- .55, P = 0.423). Interreader agreement for overall IQ was excellent for TIRM and ce-T1w with an intraclass correlation coefficient of 0.95 (95% confidence interval, 0.86-0.98) and 0.88 (95% confidence interval, 0.70 0.95). Incomplete coverage of the thoracic compartment in the ce-T1w sequence occurred more often in the automated WB-MRI workflow (P = 0.008) for reader 2. No other significant differences in the study volume coverage were found. CONCLUSIONS: In conclusion, the automated WB-MRI scanner workflow showed a significant reduction of the examination time and the user interaction compared with the manual WB-MRI workflow. Image quality and the coverage of the study volume were comparable in both groups. PMID- 29697494 TI - Progression of Exercise Training in Early Outpatient Cardiac Rehabilitation: AN OFFICIAL STATEMENT FROM THE AMERICAN ASSOCIATION OF CARDIOVASCULAR AND PULMONARY REHABILITATION. AB - Aerobic and resistance exercise training is a cornerstone of early outpatient cardiac rehabilitation (CR) and provides impressive benefits for patients. The components of the exercise prescription for patients with cardiovascular diseases are provided in guideline documents from several professional organizations and include frequency (how many sessions per week); intensity (how hard to exercise); time (duration of the exercise training session); type (modalities of exercise training); volume (the total amount or dose of exercise); and progression (the rate of increasing the dose of exercise). The least discussed, least appreciated, and most challenging component of the exercise prescription for CR health care professionals is the rate of progression of the dose of exercise. One reason for this observation is the heterogeneity of patients who participate in CR. All components of the exercise prescription should be developed specifically for each individual patient. This statement provides an overview of the principles of exercise prescription for patients in CR with special emphasis on the rate of progression. General recommendations for progression are given and patient case examples are provided to illustrate the principles of progression in exercise training. PMID- 29697496 TI - Beyond the Audiogram: Application of Models of Auditory Fitness for Duty to Assess Communication in the Real World. AB - This manuscript provides a Commentary on a paper published in the current issue of Ear and Hearing and the companion paper published in the International Journal of Audiology (Soli et al. 2018a, 2018b). These papers report background, rationale, and results of a novel modeling approach to assess "auditory fitness for duty" or an individual's ability to perform hearing-critical tasks related to their job, based on their likelihood of effective speech communication in the listening environment in which the task is performed. PMID- 29697498 TI - Successful Cholecystectomy After Endoscopic Ultrasound Gallbladder Drainage Compared With Percutaneous Cholecystostomy, Can it Be Done? AB - BACKGROUND: Endoscopic ultrasound-guided gallbladder drainage (EGBD) with a lumen apposing metal stent is becoming a widely accepted alternative to percutaneous gallbladder drainage (PTGD) for patients who are not candidates for cholecystectomy (CCY). In some patients, medical comorbidites can improve, allowing them to undergo CCY. We compare feasibility and outcomes of interval CCY after EGBD versus PTGD. METHODS: We conducted a multicentered international cohort study of patients who underwent EGBD or PTGD and then underwent interval CCY. Baseline patient demographics, procedural details, and follow-up data were recorded and compared. RESULTS: In total, 34 patients were included. Thirteen patients underwent EGBD followed by CCY (mean age, 53.77+/-17.27, 46.15% male), and 21 patients underwent PTGD followed by CCY (mean age, 62.14+/-13.06, 61.9% male). There was no statistically significant difference in mean Charlson Comorbidity Index (P=0.12) or etiology of cholecystitis (P=0.85) between the 2 groups. All patients had a technically successful CCY. There was no difference between rates of open versus laparoscopic CCY (P=1). In addition, there was no difference in postsurgical adverse events (P=0.23). CONCLUSIONS: Surgical CCY after EGBD with lumen apposing metal stent is safe and feasible for the management of cholecystitis. If patient's underlying medical conditions improve, previous EUS-GLB drainage should not preclude patients from undergoing CCY as part of standard of care. PMID- 29697497 TI - Evidence-Based Occupational Hearing Screening I: Modeling the Effects of Real World Noise Environments on the Likelihood of Effective Speech Communication. AB - OBJECTIVES: The objectives of this study were to (1) identify essential hearing critical job tasks for public safety and law enforcement personnel; (2) determine the locations and real-world noise environments where these tasks are performed; (3) characterize each noise environment in terms of its impact on the likelihood of effective speech communication, considering the effects of different levels of vocal effort, communication distances, and repetition; and (4) use this characterization to define an objective normative reference for evaluating the ability of individuals to perform essential hearing-critical job tasks in noisy real-world environments. DESIGN: Data from five occupational hearing studies performed over a 17-year period for various public safety agencies were analyzed. In each study, job task analyses by job content experts identified essential hearing-critical tasks and the real-world noise environments where these tasks are performed. These environments were visited, and calibrated recordings of each noise environment were made. The extended speech intelligibility index (ESII) was calculated for each 4-sec interval in each recording. These data, together with the estimated ESII value required for effective speech communication by individuals with normal hearing, allowed the likelihood of effective speech communication in each noise environment for different levels of vocal effort and communication distances to be determined. These likelihoods provide an objective norm-referenced and standardized means of characterizing the predicted impact of real-world noise on the ability to perform essential hearing-critical tasks. RESULTS: A total of 16 noise environments for law enforcement personnel and eight noise environments for corrections personnel were analyzed. Effective speech communication was essential to hearing-critical tasks performed in these environments. Average noise levels, ranged from approximately 70 to 87 dBA in law enforcement environments and 64 to 80 dBA in corrections environments. The likelihood of effective speech communication at communication distances of 0.5 and 1 m was often less than 0.50 for normal vocal effort. Likelihood values often increased to 0.80 or more when raised or loud vocal effort was used. Effective speech communication at and beyond 5 m was often unlikely, regardless of vocal effort. CONCLUSIONS: ESII modeling of nonstationary real-world noise environments may prove an objective means of characterizing their impact on the likelihood of effective speech communication. The normative reference provided by these measures predicts the extent to which hearing impairments that increase the ESII value required for effective speech communication also decrease the likelihood of effective speech communication. These predictions may provide an objective evidence-based link between the essential hearing-critical job task requirements of public safety and law enforcement personnel and ESII-based hearing assessment of individuals who seek to perform these jobs. PMID- 29697499 TI - Management of Articular Cartilage Defects in the Glenohumeral Joint. AB - Articular cartilage defects are not often encountered in the glenohumeral joint. These lesions are typically found in patients with shoulder trauma, recurrent instability, or previous surgical treatment. Diagnosis can be difficult; these defects are often found incidentally during arthroscopic or open surgical management of other pathology. Initial management of isolated glenohumeral chondral defects is nonsurgical and includes physical therapy and/or corticosteroid injections. If nonsurgical treatment is unsuccessful, patients may undergo surgery. Because these lesions occur infrequently, few studies have documented surgical techniques and outcomes. Surgical strategies include arthroscopic debridement, microfracture surgery, osteochondral autograft or allograft transplantation, autologous chondrocyte implantation, and particulated juvenile allograft cartilage implantation. PMID- 29697500 TI - Heterotopic Ossification of the Inferior Pubic Ramus. AB - The hip is a common location for heterotopic ossification after surgical trauma, blunt trauma, or muscle injury. However, the region around the pubic rami is an unusual location for heterotopic bone formation. Here, we present a case of a young, active man in the Armed Forces Reserve with a large heterotopic bone involving the left inferior pubic ramus who underwent surgical excision through an unusual approach via the perineum. The patient had notable pain relief postoperatively and returned to his active duties 1 month after surgery without discomfort or functional limitation. PMID- 29697501 TI - Preregistration research training of speech and language therapists in the United Kingdom: a nationwide audit of quantity, content and delivery. AB - AIM: To carry out an audit of the quantity and content of research teaching on UK preregistration speech and language therapy (SLT) degree programmes. METHOD: Lecturers delivering research teaching from each higher education institution providing preregistration training were invited to complete an online survey. QUESTIONS INCLUDED: Amount of research teaching, content of research teaching (including final-year projects), perceived confidence by staff of graduates in research awareness, research activity and leading research. Responses were received for 14 programmes (10 undergraduate and four postgraduate), representing 73% of all undergraduate courses and 44% of all postgraduate courses in the United Kingdom. RESULTS: Fifty percent of courses included over 30 h of research teaching, with wide variability across both undergraduate and postgraduate courses in number of hours, modules and credits devoted to research. There was no association between quantity of research teaching and perception of adequacy of quantity of teaching. Critical appraisal, statistical software and finding literature were the most common topics taught. Conversely, service evaluation and audit was the least common topic covered. All institutions provided a final-year project, with 11/14 requiring empirical research. Perceived confidence of graduates was higher for research awareness than active research and leading research, but this varied across institutions. There was a strong correlation between lecturers' perceived confidence of graduates in research awareness and number of hours of research teaching. CONCLUSION: Despite the requirements for healthcare professionals to engage in evidence-based practice, the amount and nature of research training in preregistration courses for SLTs in the United Kingdom is highly variable. Levels of perceived confidence of graduates were also variable, not only for active participation in research, and for leading research, but also for research awareness. This has implications for the ability of SLTs to use and embed research in their routine clinical practice. PMID- 29697502 TI - Changes in Heart Failure Symptoms are Associated With Changes in Health-related Quality of Life Over 12 Months in Patients With Heart Failure. AB - PURPOSE: Patients with heart failure (HF) have notably poor health-related quality of life (HRQOL). A 5-point improvement in HRQOL is associated with reduction in hospitalization and mortality rates. Heart failure symptoms are associated with poor HRQOL, but little is known about whether changes in HF symptoms lead to changes in HRQOL over time. Therefore, we examined the association of changes in HF symptoms with changes in overall, physical, and emotional aspects of HRQOL over a 12-month period, controlling for typical covariates. METHODS: Data on HF symptoms and HRQOL (Minnesota Living Heart Failure questionnaire) were collected from 94 patients with HF (mean age, 58 years; 58.5% female) at baseline and 12-month follow-up. Psychosocial factors (depressive symptoms, perceived control, and social support), behavioral factors (medication adherence and sodium intake), sociodemographic and clinical factors (age, comorbidities, and body mass index), and a physical factor (functional status) were collected at baseline. Multiple and logistic regression analyses were used to analyze the data. RESULTS: In complete models, changes in HF symptoms were associated with changes in the total HRQOL (P < .001) and the physical (P < .001) and emotional (P < .001) aspects of HRQOL over 12 months, controlling for all the factors. Changes in HF symptoms were significantly associated with the likelihood of at least a 5-point improvement in HRQOL (P = .001), controlling for covariates. CONCLUSIONS: Improvement in HF symptoms was associated with improvement in HRQOL over 12 months. Thus, development and delivery of interventions that target improvement in HF symptoms may improve HRQOL. PMID- 29697503 TI - Measuring the Burden of Opioid-related Mortality in Ontario, Canada. PMID- 29697504 TI - In Response. PMID- 29697505 TI - Device-Related Error in Patient-Controlled Analgesia: Analysis of 82,698 Patients in a Tertiary Hospital. AB - BACKGROUND: Patient-controlled analgesia (PCA) is one of the most popular and effective methods for managing postoperative pain. Various types of continuous infusion pumps are available for the safe and accurate administration of analgesic drugs. Here we report the causes and clinical outcomes of device related errors in PCA. METHODS: Clinical records from January 1, 2011 to December 31, 2014 were collected by acute pain service team nurses in a 2715-bed tertiary hospital. Devices for all types of PCA, including intravenous PCA, epidural PCA, and nerve block PCA, were included for analysis. The following 4 types of infusion pumps were used during the study period: elastomeric balloon infusers, carbon dioxide-driven infusers, semielectronic disposable pumps, and electronic programmable pumps. We categorized PCA device-related errors based on the error mechanism and clinical features. RESULTS: Among 82,698 surgical patients using PCA, 610 cases (0.74%) were reported as human error, and 155 cases (0.19%) of device-related errors were noted during the 4-year study period. The most common type of device-related error was underflow, which was observed in 47 cases (30.3%). The electronic programmable pump exhibited the high incidence of errors in PCA (70 of 15,052 patients; 0.47%; 95% confidence interval, 0.36-0.59) among the 4 types of devices, and 96 of 152 (63%) patients experienced some type of adverse outcome, ranging from minor symptoms to respiratory arrest. CONCLUSIONS: The incidence of PCA device-related errors was <0.2% and significantly differed according to the infusion pump type. A total of 63% of patients with PCA device related errors suffered from adverse clinical outcomes, with no mortality. Recent technological advances may contribute to reducing the incidence and severity of PCA errors. Nonetheless, the results of this study can be used to improve patient safety and ensure quality care. PMID- 29697506 TI - Association of Neuraxial Anesthesia With Postoperative Venous Thromboembolism After Noncardiac Surgery: A Propensity-Matched Analysis of ACS-NSQIP Database. AB - BACKGROUND: Neuraxial anesthesia improves components of the Virchow's triad (hypercoagulability, venous stasis, and endothelial injury) which are key pathogenic contributors to venous thrombosis in surgical patients. However, whether neuraxial anesthesia reduces the incidence of venous thromboembolism (VTE) remain unclear. We therefore tested the primary hypothesis that neuraxial anesthesia reduces the incidence of 30-day VTE in adults recovering from orthopedic surgery. Secondarily, we tested the hypotheses that neuraxial anesthesia reduces 30-day readmission, 30-day mortality, and the duration of postoperative hospitalization. METHODS: Inpatient orthopedic surgeries from American College of Surgeons National Surgical Quality Improvement Program database (2011-2015) in adults lasting more than 1 hour with either neuraxial or general anesthesia were included. Groups were matched 1:1 by propensity score matching for appropriate confounders. Logistic regression model was used to assess the effect of neuraxial anesthesia on 30-day VTE, 30-day mortality, and readmission, while Cox proportional hazard regression model was used to assess its effect on length of stay. RESULTS: Neuraxial anesthesia decreased odds of 30 day VTE (odds ratio 0.85, 95% confidence interval, 0.78-0.95; P = .002) corresponding to number-needed-to-treat of 500. Although there was no difference in 30-day mortality, neuraxial anesthesia reduced 30-day readmission (odds ratio 0.90, 98.3% confidence interval, 0.85-0.95; P < .001) corresponding to number needed-to-treat of 250 and had a shortened hospitalization (2.87 vs 3.11; P < .001). CONCLUSIONS: Neuraxial anesthesia appears to provide only weak VTE prophylaxis, but can be offered as an adjuvant to current thromboprophylaxis in high-risk patients. PMID- 29697507 TI - Population Pharmacokinetics of Periarticular Ketorolac in Adult Patients Undergoing Total Hip or Total Knee Replacement Surgery. AB - BACKGROUND: Ketorolac tromethamine has been used for joint infiltration by the orthopedic surgeons as a part of postoperative multimodal analgesia. The objective of this study is to investigate the pharmacokinetic properties of S (-) and R (+) enantiomers of ketorolac in adult patients undergoing total hip (THA) and knee arthroplasty (TKA). METHODS: Adult patients with normal preoperative renal function received a periarticular infiltration of 30 mg of ketorolac tromethamine along with 100 mL of 0.2% ropivacaine and 1 mg of epinephrine at the end of their THA or TKA surgery. Blood samples were taken from a venous cannula at various time points after infiltration. Pharmacokinetic modeling was performed using PMetrics 1.5.0. RESULTS: From 18 participants, 104 samples were analyzed. The peak plasma concentration for S (-) ketorolac was found to be lower than that of R (+) ketorolac, for both THA (0.19-1.22 mg/L vs 0.39-1.63 mg/L, respectively) and TKA (0.28-0.60 mg/L vs 0.48-0.88 mg/L, respectively). The clearance of the S (-) ketorolac enantiomer was higher than R (+) ketorolac (4.50 +/- 2.27 vs 1.40 +/- 0.694 L/h, respectively). CONCLUSIONS: Our study demonstrates that with periarticular infiltration, S (-) ketorolac was observed to have increased clearance rate and highly variable volume of distribution and lower peak plasma concentration compared to R (+) ketorolac. PMID- 29697508 TI - In-Line Filtration Reduces Postoperative Venous Peripheral Phlebitis Associated With Cannulation: A Randomized Clinical Trial. AB - BACKGROUND: Peripheral venous cannulation is an everyday practice of care for patients undergoing anesthesia and surgery. Particles infused with intravenous fluids (eg, plastic/glass/drugs particulate) contribute to the pathogenesis of peripheral phlebitis. The aim of this study is to demonstrate the efficacy of in line filtration in reducing the incidence of postoperative phlebitis associated with peripheral short-term vascular access. METHODS: In this controlled trial, 268 surgical patients were randomly assigned to in-line filtration and standard care (NCT03193827). The incidence of phlebitis (defined as visual infusion phlebitis [VIP] score, >=2) within 48 hours was compared between the 2 groups, as well as the onset and severity of phlebitis and the reasons for removal of the cannula. The lifespan of venous cannulae was compared for the in-line filter and no-filter groups through a Kaplan-Meier curve. RESULTS: The incidence of phlebitis within 48 hours postoperatively was 2.2% and 26.9% (difference, 25% [95% confidence interval {CI}, 12%-36%]; odds ratio, 0.05 [0.01-0.15]), respectively, for the in-line filter and no-filter groups (P < .001). From 24 to 96 hours postoperatively, patients in the no-filter group had higher VIP scores than those in in-line filter group (P < .001). Venous cannulae in the in-line filter group exhibited prolonged lifespan compared to those in the no-filter group (P = .01). In particular, 64 (47.8%) of cannulae in the in-line filter group and 56 (41.8%) of those in the no-filter group were still in place at 96 hours postoperatively. At the same time point, patients with a VIP score <3 were 100% in the in-line filter group and only 50% for the no-filter group. In-line filtration was a protective factor for postoperative phlebitis (hazard ratio, 0.05 [95% CI, 0.014-0.15]; P < .0001) and cannula removal (hazard ratio, 0.7 [95% CI, 0.52-0.96]; P = .02). CONCLUSIONS: In-line filtration has a protective effect for postoperative phlebitis and prolongs cannula lifespan during peripheral venous cannulation in surgical patients. PMID- 29697509 TI - Integrative Pain Management Must Include Diet Considerations. PMID- 29697510 TI - The Incidence of Transfusion-Related Acute Lung Injury at a Large, Urban Tertiary Medical Center: A Decade's Experience. AB - BACKGROUND: While transfusion-related acute lung injury (TRALI) remains the primary cause of transfusion-related fatalities (37%), recent reports estimate the incidence of TRALI at 0.008% per unit of plasma transfused and 0.004% per all products transfused. Because blood banks have moved toward male-predominant plasma, TRALI appears, anecdotally, to have been reduced to an extremely rare event. The purpose of this study was to estimate the current incidence of TRALI at a large, urban center known for its early and aggressive use of plasma in the setting of trauma, hemorrhagic shock, and massive transfusion. METHODS: The Blood Bank Registry of our hospital was queried for all transfused patients admitted from September 2002 through March 2013. The blood bank collected and investigated all cases of clinical acute lung injury meeting the consensus definition for TRALI, as well as potential cases for which the donor product was recalled for having a high reactivity level of human leukocyte antigen antibodies (ie, the antibodies that could cause TRALI). Clinical reactions were reviewed in conjunction with independent serological testing and classified by transfusion medicine physicians as being "probable TRALI" or of "unrelated etiology." The total number of units transfused at our facility during this time period was also obtained, allowing the incidence of TRALI to be estimated. Cases were analyzed based on demographics, outcome, blood types, observed symptoms and their duration, and type of product transfused. RESULTS: Seven cases were identified at our center for the indicated time period, with only 3 of these occurring in trauma. A total of 714,757 units of blood products were transfused between September 2002 and March 2013. The incidence of TRALI was estimated to be 1 case per 100,000 units of product for the entire study period. A broad range of patients was affected. Consistent with previous descriptions, an acute duration of symptoms (average, 1.4 days) was observed and usually resolved with supportive care. Reactions were observed predominantly in plasma products, both type specific and nontype specific. CONCLUSIONS: This study demonstrates that while TRALI still occurs, clinically meaningful cases are rare. Moreover, TRALI rates remain low despite the increasingly aggressive use of plasma and platelets in the trauma setting. PMID- 29697511 TI - Establishing Radiological Screening Levels for Defense-related Uranium Mine (DRUM) Sites on BLM Land Using a Recreational Future-use Scenario. AB - Thousands of former uranium mining sites in the United States, primarily in the southwestern states of Colorado, Arizona, New Mexico, Arizona, and Utah, are being identified and evaluated to assess their potential for causing public and environmental impacts. The common radiological contaminant of concern that characterizes these sites is naturally occurring uranium ore and associated wastes that may have been left behind postmining. The majority of these sites were abandoned and in general, are referred to as abandoned uranium mines, regardless of the government authority currently managing the land or in some cases, assigned responsibility for the oversight of assessment and remediation. The U.S. Department of Energy has identified over 4,000 defense-related uranium mine sites from which uranium ore was purchased by the U.S. government for nuclear defense programs prior to 1970. U.S. Department of Energy has established a program to inventory and perform environmental screening on defense-related uranium mine sites. The focus of this paper is the approximately 2,400 defense related uranium mine sites located on federal land managed by the Bureau of Land Management and the U.S. Forest Service. This paper presents the results of an analysis to develop radiological screening criteria for U.S. Department of Energy's defense-related uranium mine sites that can be used as input to the overall ranking of these sites for prioritization of additional assessment, reclamation, or remedial actions. For these sites managed by Bureau of Land Management, public access is typically limited to short-term use, primarily for recreational purposes. This is a broad category that can cover a range of possible activities, including camping, hiking, hunting, biking, all-terrain vehicle use, and horseback riding. The radiological screening levels were developed by calculating the radiological dose to future recreational users of defense-related uranium mine sites assuming a future camper spends two weeks per year at the site engaged in recreational activities. Although a number of possible exposure pathways were included in this analysis (inhalation and ingestion of dust and soil, radon and progeny inhalation, and gamma radiation exposure from the soil), it is desirable as a practical matter to determine what gamma exposure rate would ensure that the annual acceptable exposure as determined by the regulatory authority will not be exceeded in the future. Because these sites are generally remote and located in semiarid environments, traditional exposure scenarios often applied in these types of analyses (e.g., subsistent farmers and ranchers), including exposure pathways for the ingestion of locally grown food products and water, were not considered relevant to short term recreational use. PMID- 29697513 TI - Radiation Protection for Interventional Fluoroscopy: Results of a Survey Among Dutch Hospitals. AB - A survey was conducted among 20 Dutch hospitals about radiation protection for interventional fluoroscopy. This was a follow-up of a previous study in 2007 that led to several recommendations for radiation protection for interventional fluoroscopy. The results indicate that most recommendations have been followed. However, radiation-induced complications from interventional procedures are still often not recorded in the appropriate register. Furthermore, even though professionals with appropriate training in radiation protection are usually involved in interventional procedures, this often is not the case when these procedures are carried out outside the radiology department. Although this involvement is not required by Dutch law, it is recommended to have radiation protection professionals present more often at interventional procedures. Further improvements in radiation protection for interventional fluoroscopy may come from a comparison of dose-reducing practices among hospitals, the introduction of diagnostic reference levels for interventional procedures, and a more thorough form of screening and follow-up of patients. PMID- 29697512 TI - Probability Distribution of Dose and Dose-Rate Effectiveness Factor for use in Estimating Risks of Solid Cancers From Exposure to Low-Let Radiation. AB - This paper presents an analysis to develop a subjective state-of-knowledge probability distribution of a dose and dose-rate effectiveness factor for use in estimating risks of solid cancers from exposure to low linear energy transfer radiation (photons or electrons) whenever linear dose responses from acute and chronic exposure are assumed. A dose and dose-rate effectiveness factor represents an assumption that the risk of a solid cancer per Gy at low acute doses or low dose rates of low linear energy transfer radiation, RL, differs from the risk per Gy at higher acute doses, RH; RL is estimated as RH divided by a dose and dose-rate effectiveness factor, where RH is estimated from analyses of dose responses in Japanese atomic-bomb survivors. A probability distribution to represent uncertainty in a dose and dose-rate effectiveness factor for solid cancers was developed from analyses of epidemiologic data on risks of incidence or mortality from all solid cancers as a group or all cancers excluding leukemias, including (1) analyses of possible nonlinearities in dose responses in atomic-bomb survivors, which give estimates of a low-dose effectiveness factor, and (2) comparisons of risks in radiation workers or members of the public from chronic exposure to low linear energy transfer radiation at low dose rates with risks in atomic-bomb survivors, which give estimates of a dose-rate effectiveness factor. Probability distributions of uncertain low-dose effectiveness factors and dose-rate effectiveness factors for solid cancer incidence and mortality were combined using assumptions about the relative weight that should be assigned to each estimate to represent its relevance to estimation of a dose and dose-rate effectiveness factor. The probability distribution of a dose and dose-rate effectiveness factor for solid cancers developed in this study has a median (50th percentile) and 90% subjective confidence interval of 1.3 (0.47, 3.6). The harmonic mean is 1.1, which implies that the arithmetic mean of an uncertain estimate of the risk of a solid cancer per Gy at low acute doses or low dose rates of low linear energy transfer radiation is only about 10% less than the mean risk per Gy at higher acute doses. Data were also evaluated to define a low acute dose or low dose rate of low linear energy transfer radiation, i.e., a dose or dose rate below which a dose and dose-rate effectiveness factor should be applied in estimating risks of solid cancers. PMID- 29697514 TI - Position Statement of the Health Physics Society PS009-3: Low-level Radioactive Waste Management. PMID- 29697515 TI - Estimating Fluoroscopic Peak Skin Dose Using Manual Calculations. AB - Not all healthcare providers can afford to purchase commercially available programs that can quickly and easily provide peak skin dose estimations for patients undergoing diagnostic and international fluoroscopic procedures. The air kerma reference point exposure, Ka,r, available on all equipment manufactured after 2006, may over or under estimate the patient's peak skin dose. The total air kerma reference point exposure provided at the end of a case might be on the order of 20 Gy for a patient, indicating that a Joint Commission 'sentinel event' may have occurred. An investigation to determine whether a sentinel event has occurred becomes necessary. This article will introduce information available to the investigating health physicist for data mining, how to process that information, and then how best to interpret the results. I have used this system of data mining and analysis to effectively influence how physicians performing diagnostic and interventional fluoroscopic procedures use fluoroscopic equipment. Arriving at an answer is not simple; it is time consuming, and the methodologies are imperfect. Your effort can result in improved utilization of fluoroscopic equipment at your institution which in turn will lower patient and staff doses. PMID- 29697516 TI - Performance Testing of Criticality Accident Detectors with the Godiva Burst Reactor. AB - Criticality accident detectors are required for all operations involving fissile materials in which a criticality accident can occur and cause personnel to receive unacceptable exposure to radiation (ANSI/ANS 8.3-R2012). Recently, the U.S. Department of Energy Y-12 National Security Complex tested six criticality accident detectors and eight Portable Radiation Detection Instruments (PRDIs) to verify their performance under actual criticality conditions. The tests were performed by Los Alamos National Laboratory using the Godiva critical assembly located at the National Criticality Experiments Research Center at the U.S. Department of Energy Nevada National Security Site. All six criticality accident detectors and eight Portable Radiation Detection Instruments passed the performance tests. The test results provide reasonable assurance that the Y-12 criticality accident detectors and PRDIs will detect a criticality accident and warn workers to evacuate the area to minimize their exposure to this life threatening hazard. PMID- 29697519 TI - Intraoperative combination of resuscitative endovascular balloon occlusion of the aorta and a median sternotomy in hemodynamically unstable patients with penetrating chest trauma: Is this feasible? AB - BACKGROUND: Recent evidence suggests that resuscitative endovascular balloon occlusion of the aorta (REBOA) is an effective life-saving intervention in patients with severe torso trauma. However, the deployment of REBOA in patients with isolated penetrating intrathoracic injuries remains controversial. We propose that a median sternotomy be performed in conjunction with REBOA as a feasible and effective means of hemorrhage control in patients suffering from penetrating chest trauma who present hemodynamically unstable. The objective of our study was to present our initial experience with this approach. METHODS: A prospectively collected case series of the use of REBOA (10 Fr) in conjunction with a median sternotomy from January 2015 to December 2016 at a Level I Trauma Center. We included hemodynamically unstable non-compressible torso hemorrhage patients with penetrating chest trauma who underwent intraoperative REBOA deployment plus median sternotomy. RESULTS: A total of 68 trauma-related emergent thoracic surgeries were performed at our institution during the study period. Of these, seven suffered from penetrating chest trauma and non-compressible torso hemorrhage and underwent REBOA plus median sternotomy. Six out of the seven patients suffered intrathoracic vascular injuries: two subclavian arteries, two internal mammary arteries, two aortic arch, and five major central venous injuries. Four patients had an associated lung injury with AIS >3, of which two suffered a pulmonary hilar vessel disruption. REBOA-related complications included one case of upper gastrointestinal bleeding. Six out of the seven patients survived the 30-day follow-up. No adverse neurologic outcomes or deficits were observed in survivors. CONCLUSION: The combined use of REBOA and median sternotomy could be a feasible and effective alternative to hemorrhage control in patients with non-compressible torso hemorrhage secondary to penetrating chest trauma. These findings challenge the recommendation against the use of REBOA in penetrating intrathoracic injuries. Future studies with stronger designs and larger sample sizes are required to confirm our results. LEVEL OF EVIDENCE: Therapeutic, level V. PMID- 29697520 TI - "A Drop in the Ocean": A Reflection on the Application of Cognitive Analytic Therapy Within a Prison Setting. AB - This article reflects on the application of cognitive analytic therapy (CAT) with prisoners referred to a mental health in-reach team within a U.K. prison based on the author's experience as a clinical psychologist. The extent of mental health problems in the prison population and the provision of mental health services within prisons are summarized to highlight the extent of mental health need within this setting. The central concepts and tools of CAT that provided the framework within which this author's work was undertaken within the prison are detailed, namely, reciprocal roles and reciprocal role procedures. Personal reflections on the utility of CAT within a prison setting are presented, including how CAT informed understanding of risk. The application of CAT to the role of forensic nurses within mental health in-reach teams is also considered. PMID- 29697521 TI - An Integrative Review of Nurse-Authored Research to Improve Health Equity and Human Rights for Criminal-Justice-Involved People. AB - BACKGROUND: An estimated 10 million people are incarcerated internationally, including 2.1 million people in the United States. Criminal justice involvement is a social determinant of individual and family health disparities. Health care in correctional and forensic psychiatric facilities is nurse driven. The unique contributions of nurse authors to the research literature on health equity and humane conditions for this population have not been aggregated, nor have the nursing research gaps in this area been systematically identified. This article determines the volume and country location of nurse-authored research in this area and analyzes the research by population (prisons, jails, community supervision, forensic psychiatry), clinical foci, and research methods. METHODS: We conducted an integrative review of research literature published in English between 1990 and 2017. RESULTS: Our search revealed 283 data-based articles written by 349 nurse authors, representing Asia, Australia, Europe, and North and South Americas. Most research occurred in prisons (53.3%) and focused on mental health/substance use (32.5%), infectious disease (21.6%), or correctional health services (15.6%). Almost one third of articles across clinical foci sampled nurses, not patients. IMPLICATIONS: Although there is clearly a cadre of nurse researchers working in this area, it remains a relatively small group focused most closely on mental health, infectious disease, and the correctional nursing experience. Gaps and opportunities for important nursing contributions remain, especially in reproductive health, meeting the needs of community-supervised people, and explicitly connecting this work with its human rights implications. PMID- 29697522 TI - Living With Dementia in Correctional Settings: A Case Report. AB - The prison population is aging at an alarming rate and many older persons have the potential to develop dementia while in prison. This case report aims to explore the needs of older people living with dementia in prison and discusses the interventions that exist to address these needs. As the condition progresses, persons with dementia become increasingly reliant on the support of others for their health and well-being because of the increasing complexity of physical healthcare and psychosocial needs. Very few interventions are cited in the research literature regarding the use, acceptability, and/or effectiveness of programming for people living with dementia in prison. To support the unique and complex needs of these persons, research is needed to guide the development of evidence-informed dementia programs and services as well as consideration of interdisciplinary collaboration with community organizations. PMID- 29697523 TI - Stigmatization of Overweight and Obese Women During Forensic Examinations. AB - Stigma and discrimination toward overweight and obese people pose consequences to their psychological and physical health. In the United States, overweight and obesity and affects over 34% of the population. This frequently ignored public health issue often sees overweight and obese individuals blamed for their weight, thereby justifying the bias. During a post-sexual-assault examination, sexual assault nurse examiners and other forensic examiners must be cognizant of the specific issues and challenges related to the care of these victims. Forensic nurses may need to refine their techniques such as positioning overweight and obese patients on an appropriate-sized table, obtaining equipment for better visualization, and requiring assistance during the examination (e.g., lifting the victim's pendulous skin folds for assessment and evidence collection). Moreover, they may need to recognize and reflect on their own weight related biases. Addressing these important issues may lead to decreasing stigmatization during examinations, thereby providing quality care to victims of sexual assault, regardless of their weight. PMID- 29697524 TI - Call for shift in Helicobacter pylori treatment. PMID- 29697525 TI - Night terrors associated with celiac disease. PMID- 29697526 TI - Chronic pancreatitis progression in the use of statins. PMID- 29697527 TI - Ischaemic stroke in patients with liver cirrhosis. PMID- 29697528 TI - To use entecavir, tenofovir disoproxil fumarate or tenofovir alafenamide: it's all about choosing the right patient! PMID- 29697530 TI - Using Different Expectation Mechanisms to Optimize Treatment of Patients With Medical Conditions: A Systematic Review. AB - OBJECTIVE: Patients' expectations have been shown to predict the course and treatment success of a variety of medical conditions. Therefore, expectation focused psychological interventions (EFPIs) have been developed to use these expectation effects clinically. Importantly, EFPI differ with regard to the particular expectation mechanism being addressed, i.e., expectation optimization or expectation violation. The aims of this systematic review were to give an overview of the application of these expectation interventions and to evaluate their effectiveness. METHODS: Several databases were searched to identify clinical trials or experimental studies that conducted EFPI among participants with various medical conditions. Risk of bias was evaluated using the Cochrane Risk of Bias tool. RESULTS: Eleven studies (N = 944) investigating different medical conditions (coronary heart disease, cancer, chronic pain) were included. Qualitative synthesis revealed positive effects of EFPI on clinical outcome variables in all studies. Expectation optimization approaches yielded particularly promising results. Because of the large heterogeneity of outcome measures, quantitative synthesis was not possible. CONCLUSION: This review highlights the potential of EFPI for optimizing treatment of patients with medical conditions. However, it seems that different expectation mechanisms might have different application possibilities. Therefore, we provide suggestions for further developing EFPI to tailor treatment and develop personalized psychological interventions. We argue that for this purpose, it is important to consider both disease-specific aspects and patients' personality traits. In addition, we discuss future challenges such as implementing EFPI into routine medical care. PMID- 29697532 TI - Chemokine (c-c motif) receptor 2 mediates mechanical and cold hypersensitivity in sickle cell disease mice. AB - Approximately one-third of individuals with sickle cell disease (SCD) develop chronic pain. This debilitating pain is inadequately treated because the underlying mechanisms driving the pain are poorly understood. In addition to persistent pain, patients with SCD are also in a tonically proinflammatory state. Previous studies have revealed that there are elevated plasma levels of many inflammatory mediators including chemokine (c-c motif) ligand 2 (CCL2) in individuals with SCD. Using a transgenic mouse model of SCD, we investigated the contributions of CCL2 signaling to SCD-related pain. Inhibition of chemokine receptor 2 (CCR2), but not CCR4, alleviated the behavioral mechanical and cold hypersensitivity in SCD. Furthermore, acute CCR2 blockade reversed both the behavioral and the in vitro responsiveness of sensory neurons to an agonist of TRPV1, a neuronal ion channel previously implicated in SCD pain. These results provide insight into the immune-mediated regulation of hypersensitivity in SCD and could inform future development of analgesics or therapeutic measures to prevent chronic pain. PMID- 29697531 TI - Mice lacking Kcns1 in peripheral neurons show increased basal and neuropathic pain sensitivity. AB - Voltage-gated potassium (Kv) channels are increasingly recognised as key regulators of nociceptive excitability. Kcns1 is one of the first potassium channels to be associated with neuronal hyperexcitability and mechanical sensitivity in the rat, as well as pain intensity and risk of developing chronic pain in humans. Here, we show that in mice, Kcns1 is predominantly expressed in the cell body and axons of myelinated sensory neurons positive for neurofilament 200, including Adelta-fiber nociceptors and low-threshold Abeta mechanoreceptors. In the spinal cord, Kcns1 was detected in laminae III to V of the dorsal horn where most sensory A fibers terminate, as well as large motoneurons of the ventral horn. To investigate Kcns1 function specifically in the periphery, we generated transgenic mice in which the gene is deleted in all sensory neurons but retained in the central nervous system. Kcns1 ablation resulted in a modest increase in basal mechanical pain, with no change in thermal pain processing. After neuropathic injury, Kcns1 KO mice exhibited exaggerated mechanical pain responses and hypersensitivity to both noxious and innocuous cold, consistent with increased A-fiber activity. Interestingly, Kcns1 deletion also improved locomotor performance in the rotarod test, indicative of augmented proprioceptive signalling. Our results suggest that restoring Kcns1 function in the periphery may be of some use in ameliorating mechanical and cold pain in chronic states. PMID- 29697533 TI - Interleukin-6 trans-signaling and pathological low back pain in patients with Paget disease of bone. AB - The interleukin (IL)-6 biological system plays a key role in the pathogenesis of Paget disease (PD) of bone and pathological bone pain. Bone pain, particularly in the lower back region, is the most frequent symptom in patients with PD. This case-control study aimed to evaluate the relationship between the IL-6 system and low back pain (LBP) in patients with PD. We evaluated 85 patients with PD, with the disease localized in the lumbar spine, pelvis, and/or sacrum, and classified them based on the presence or absence of LBP, before and after aminobisphosphonate treatment. We also examined 32 healthy controls without LBP. Before treatment, IL-6 levels in patients with PD were higher than those in the controls, without difference between patients with or without LBP. Patients with PD with LBP (35/85) showed higher IL-6-soluble receptor (sIL-6R) and lower soluble glycoprotein (sgp) 130 levels compared with both patients with PD without LBP and controls (sIL-6R: 46.9 +/- 7.4 vs 35.4 +/- 8.6 vs 29.9 +/- 4.2 ng/mL; sgp130: 307.2 +/- 35.4 vs 341.4 +/- 41.4 vs 417.1 +/- 58.5 ng/mL, respectively). Paget disease remission, 6 months after treatment, is associated with LBP improvement. This phenomenon is associated with reduced sIL-6R levels and increased sgp130 levels in patients with PD with LBP at the baseline. Considering the biological properties of IL-6, sIL-6R, and sgp130, the results of the study suggest that the perception of LBP in patients with PD could be linked to an enhanced transmission of IL-6 signal in the specialized neural system activated by nociceptors. PMID- 29697534 TI - Development of pain in older adults: a latent class analysis of biopsychosocial risk factors. AB - Pain significantly restricts the quality of life and well-being of older adults. With our increasingly ageing population, it is important to examine whether differing classes of biopsychosocial risk factors can predict the development of pain in older adults. Latent class analysis provides a model-based approach to identifying underlying subgroups in a population, based on some measured characteristics. In this study, latent class analysis was used to identify biopsychosocial risk classes in people aged 50 years and older, from The Irish Longitudinal Study on Ageing, who reported not often being troubled by pain at wave 1 and completed the 2-year follow-up at wave 2 (n = 4458). Four classes were identified based on 11 potential risk factors at wave 1. These classes were characterised as "Low Risk," "Physical Health Risk," "Mental Health Risk," and "High Risk." The Low-Risk class accounted for over half the sample (51.2%), whereas the High-Risk class represented 7.8% of the sample. At follow-up (wave 2), 797 (17.9%) participants reported being troubled by pain. Associations between the biopsychosocial risk classes and developing pain were examined using logistic regression, adjusting for sociodemographic variables. The High-Risk class was more likely to develop pain compared with the Low-Risk class (adjusted OR = 3.16, 95% CI = 2.40-4.16). These results add to existing data in other populations supporting the role of a range of biopsychosocial risk factors that increase the risk of developing pain. These findings have important implications for the identification, and potential moderation, of these risk factors. PMID- 29697535 TI - Reproducible and replicable pain research: a critical review. PMID- 29697536 TI - Patients with chronic pain exhibit a complex relationship triad between pain, resilience, and within- and cross-network functional connectivity of the default mode network. AB - Resilience is a psychological trait that strongly predicts chronic pain-related health outcomes. The neural correlates of both pain and trait resilience are critical to understand the brain-behaviour relationship in chronic pain; yet, neural correlates of resilience in chronic pain states are unknown. However, measures of pain perception and a wide range of psychological health measures have been linked to function of the default mode network (DMN). Thus, we aimed to determine the relationships between resilience, pain perception, and functional connectivity (FC) within the DMN and between the DMN and other brain networks. Resting-state functional magnetic resonance imaging data were acquired from 51 chronic pain patients with a form of spondylarthritis (ankylosing spondylitis) and 51 healthy control participants. Participants completed a questionnaire on their individual trait resilience (the Resilience Scale), and patients reported their clinical pain. In healthy controls, we found within-DMN FC to be stronger in less resilient individuals. In patients with chronic pain, individual resilience was negatively correlated with pain and disease activity. Cross network FC between the DMN and the sensorimotor network was abnormally high in patients with high clinical pain scores on the day of the study. Finally, there was an interaction between within-DMN FC and clinical pain report in patients: In patients reporting greater pain, the relationship between within-DMN connectivity and resilience was atypical. Thus, our findings reveal different neural representations of resilience and pain. The way in which these behavioural measures interact provides insight into understanding the neural correlates of chronic pain. PMID- 29697537 TI - Bariatric surgery and gene expression in the gut. AB - PURPOSE OF REVIEW: The current review provides an overview of recent literature on new findings related to bariatric surgery and gut gene expression. RECENT FINDINGS: Bariatric surgery modulates the expression of intestinal genes. Experimental and clinical investigations have demonstrated the association of gut rearrangement with changes in intestinal expression of genes related to glucose metabolism. Recent data suggest that bariatric surgery also affects expression of genes belonging to other pathways, including nutrient transporters and metabolism of vitamin B12, decreasing pathway-encoding genes that may contribute to vitamin B12 deficiency in the postoperative period. SUMMARY: Bariatric surgery is an effective intervention strategy against severe obesity, resulting in sustained weight loss and reduction of comorbidities. Nutritional genomic changes appear in response to bariatric surgery, possibly due to adaptive gut response. Improved understanding of the molecular pathways modulated by this intervention may facilitate weight and comorbidities management. PMID- 29697538 TI - The molecular signature of muscle stem cells is driven by nutrient availability and innate cell metabolism. AB - PURPOSE OF REVIEW: To discuss how innate muscle stem-cell metabolism and nutrient availability can provide temporal regulation of chromatin accessibility and transcription. RECENT FINDINGS: Fluorescence-activated cell sorting coupled with whole transcriptome sequencing revealed for the first time that quiescent and proliferating skeletal muscle stem cells exhibit a process of metabolic reprogramming, from fatty-acid oxidation during quiescence to glycolysis during proliferation. Using a combination of immunofluorescence and chromatin immunoprecipitation sequencing, this shift in metabolism has been linked to altered availability of key metabolites essential for histone (de)acetylation and (de)methylation, including acetyl-CoA, s-adenosylmethionine and alpha ketoglutarate. Importantly, these changes in metabolite availability have been linked to muscle stem-cell function. SUMMARY: Together, these results provide greater insight into how muscle stem cells interact with their local environment, with important implications for metabolic diseases, skeletal muscle regeneration and cell-transplantation therapies. PMID- 29697539 TI - Dietary carbohydrates and fatty liver disease: de novo lipogenesis. AB - PURPOSE OF REVIEW: To review recent evidence for the role of dietary carbohydrate in de novo lipogenesis (DNL) and nonalcoholic fatty liver disease (NAFLD). RECENT FINDINGS: A large body of evidence suggests that increased hepatic DNL is a significant pathway contributing to the development of NAFLD. Dietary carbohydrates, in particular, fructose, have been shown to stimulate DNL and increase liver fat, although it is debated whether this is due to excess energy or fructose per se. Recent dietary intervention studies conducted in energy balance show that high-fructose diets increase DNL and liver fat, whereas fructose restriction decreases DNL and liver fat. SUMMARY: The association of high-carbohydrate and high-sugar diets with NAFLD may in part be explained by the effect of sugar on increasing hepatic DNL. PMID- 29697540 TI - Ketone bodies as epigenetic modifiers. AB - PURPOSE OF REVIEW: Ketone body metabolism is a dynamic and integrated metabolic node in human physiology, whose roles include but extend beyond alternative fuel provision during carbohydrate restriction. Here we discuss the most recent observations suggesting that ketosis coordinates cellular function via epigenomic regulation. RECENT FINDINGS: Ketosis has been linked to covalent modifications, including lysine acetylation, methylation, and hydroxybutyrylation, to key histones that serve as dynamic regulators of chromatin architecture and gene transcription. Although it remains to be fully established whether these changes to the epigenome are attributable to ketone bodies themselves or other aspects of ketotic states, the regulated genes mediate classical responses to carbohydrate restriction. SUMMARY: Direct regulation of gene expression may occur in-vivo via through ketone body-mediated histone modifications during adherence to low carbohydrate diets, fasting ketosis, exogenous ketone body therapy, and diabetic ketoacidosis. Additional convergent functional genomics, metabolomics, and proteomics studies are required in both animal models and in humans to identify the molecular mechanisms through which ketosis regulates nuclear signaling events in a myriad of conditions relevant to disease, and the contexts in which the benefits of ketosis might outweigh the risks. PMID- 29697542 TI - Salt and hypertension: what do we know? AB - PURPOSE OF REVIEW: To evaluate the evidence for population-wide sodium restriction. RECENT FINDINGS: The recommendations for population-wide sodium restriction largely rely on one surrogate marker (blood pressure). However, recent evidence suggests that when looking beyond blood pressure (e.g. heart rate, aldosterone, renin, cholesterol, triglycerides, noradrenaline and adrenaline), the net effect of sodium restriction is likely harmful. Prospective studies support the notion that those consuming the lowest amounts of salt are at the highest risk of cardiovascular events and premature death. SUMMARY: There is no definitive proof that sodium restriction reduces cardiovascular events or death. It is time for the dietary guidelines to look at the totality of the evidence and reconsider the advice around population-wide sodium restriction. PMID- 29697543 TI - New diet trials and cardiovascular risk. AB - PURPOSE OF REVIEW: The prevalence of cardiovascular disease (CVD) is increasing to epidemic proportions and current management centred on treatment with drugs is not enough to stop this pandemic. CVD prevention is of paramount importance. In this context, diet and behavioural intervention programs are the first step and have the advantage of lesser cost and side effects than pharmacological approaches. In this review, we will examine the most recent evidence related to dietary prevention of CVD risk. RECENT FINDINGS: Healthy dietary patterns such as the dietary approaches to stop hypertension, the vegetarian, the low-fat high carbohydrates and mainly the Mediterranean diet have substantial evidence to be recommended for CVD prevention. SUMMARY: The evidence in this area needs to be adequately communicated to health professionals and the general public. Diet is the cornerstone of CVD prevention as well as overall health promotion. PMID- 29697544 TI - The role of the pharmacist in hypertension management. AB - PURPOSE OF REVIEW: Hypertension remains a vital, modifiable risk factor in the prevention of cardiovascular disease. However, many patients do not achieve their therapeutic goals for numerous reasons which can include poor disease insight and nonadherence. Pharmacists can be key players in controlling hypertension, given their medication knowledge and patient counseling skills, yet they remain an underutilized resource in the management of chronic disease states. Various models exist that allow pharmacists to provide direct patient-centered care but practices differ from state to state since pharmacists are not recognized nationally as healthcare providers. This article aims to provide an update on the proven methods in which pharmacists contribute to the management of hypertensive patients. RECENT FINDINGS: Several recently published studies demonstrate the positive impact of pharmacist intervention and care on patient outcomes in ambulatory and community settings. These practice models include medication therapy management, collaborative drug therapy management, telehealth and team based care. SUMMARY: The role of the pharmacist in hypertension encompasses medication management, disease state education and patient counseling and is most successful when integrated into the patient's care team. Further validation through larger, prospective trials and evaluation of long-term outcomes, such as mortality, remain viable research opportunities. PMID- 29697545 TI - Transcatheter valvular interventions in 2017: some things old, some things new! AB - PURPOSE OF REVIEW: Transcatheter valvular interventions have changed the landscape of valvular therapies. We examine some studies on transcatheter valvular interventions published in the year 2017 to better understand their implications on clinical practice and future research. RECENT FINDINGS: Findings from the SURTAVI study suggest TAVR to be a reasonable option in intermediate risk patients with aortic stenosis. Recent studies indicate that valve leaflet thrombosis is associated with poor outcomes. Data from the TVT registry on current transcatheter mitral valve repair are encouraging; alternative repair systems have been subjected to feasibility trials. TAVR for patients with bicuspid aortic valve stenosis appears to be improving. Cerebral embolic protection devices have shown promise but the population in whom they are most likely to provide benefit needs to be better defined. SUMMARY: The year 2017 has seen significant advances in the field of transcatheter valvular interventions. Strong foundations have been laid for future studies that are likely to significantly impact clinical practice. PMID- 29697546 TI - Outcomes of Transvaginal High Uterosacral Ligaments Suspension: Over 500-Patient Single-Center Study. AB - BACKGROUND: Uterosacral ligament (USL) suspension is a safe and effective procedure in terms of anatomical, functional, and subjective outcomes for primary surgical treatment of prolapse. OBJECTIVES: There has been a renewed interest toward native tissue prolapse repair by vaginal route because of low cost and lack of mesh-related complications. Uterosacral ligaments are considered safe, effective, and durable as suspending structures for primary surgical repair of the apical compartment. Our aim was to evaluate complications, anatomical, functional and subjective outcomes of high USL suspension for primary prolapse repair. METHODS: Data of patients who underwent vaginal hysterectomy followed by high USL suspension for pelvic organ prolapse were retrospectively analyzed. Operative data, as well as complications, were recorded. Anatomical recurrence was defined as descent of any compartment stage II or greater according to the Pelvic Organ Prolapse Quantification system. Functional outcomes focused on urinary, bowel, and sexual dysfunctions. International Consultation on Incontinence Questionnaire-Urinary Incontinence Short Form, Wexner, and Patient Global Impression of Improvement questionnaires were collected. RESULTS: Data of 533 women were analyzed. Mean follow-up was 32 (SD, 19) months (dropout rate, 2.6%). Most frequent complication was ureteral kinking (2.6%). Total recurrence rate was 13.7%, with anterior compartment being the most frequent (9.4%), whereas reoperation for symptomatic prolapse recurrence was required in only 1% of patients. Improvement of urinary incontinence, voiding dysfunction, constipation, and dyspareunia was observed. Overall subjective satisfaction was high (Patient Global Impression of Improvement score, 1.3), ranging from "much improved" to "very much improved." CONCLUSIONS: Uterosacral ligament suspension is a safe and effective procedure in primary surgical treatment of pelvic organ prolapse. Anatomical, functional, and subjective outcomes were very satisfactory, and reoperation rate for recurrence was only 1%. PMID- 29697548 TI - Bile Acids and the Gut Microbiome as Potential Targets for NAFLD Treatment. AB - Semisynthetic bile acid (BA) obeticholic acid, a potent farnesoid X receptor (FXR) agonist, exhibited beneficial effects on nonalcoholic fatty liver disease (NAFLD). Obeticholic acid, however, did not cause a resolution of nonalcoholic steatohepatitis. Here we discuss several prominent knowledge gaps in BA/FXR biology. Firstly, although many groups reported elevated serum BA levels, there are reports of decreased or normal serum BA levels in NAFLD, underlining the complexity of BA regulation by environmental and genetic factors. Secondly, conflicting data exist in animal studies regarding the effects of FXR signaling on obesity and associated metabolic abnormalities. Thirdly, it remains obscure how the gut microbiome and the BA pool interact and influence the pathogenesis of NAFLD. Lastly, it is not known how FXR-mediated signaling interact with G protein coupled BA receptor 1-mediated signaling. Answering these questions may lead to an improved pharmaceutical intervention for NAFLD targeting the FXR signaling pathway. PMID- 29697547 TI - AUGS Best Practice Statement: Evaluation and Counseling of Patients With Pelvic Organ Prolapse. PMID- 29697549 TI - Endoscopic Electrocautery Incisional Therapy as a Treatment for Refractory Benign Pediatric Esophageal Strictures. AB - BACKGROUND AND AIM: Refractory esophageal strictures are rare conditions in pediatrics, and are often due to anastomotic, congenital, or caustic strictures. Traditional treatment options include serial dilation and surgical stricture resection; endoscopic intralesional steroid injections, mitomycin C, and externally removable stents combined with dilation have had variable success rates. Although not as widely used, endoscopic electrocautery incisional therapy (EIT) has been reported as an alternative treatment for refractory strictures in a small number of adult series. The aim of the study was to evaluate the safety and efficacy of EIT in a pediatric population with refractory esophageal strictures. METHODS: A retrospective chart review was conducted on all patients who underwent EIT for esophageal strictures (May 2011-September 2017) at our tertiary-care referral center. A total of 57 patients underwent EIT. Procedural success was defined as no stricture resection, appropriate diameter for age, and fewer than 7 dilations within 24 months of first EIT session. This corresponded to the 90th percentile of the observed number of dilations in the data. All patients included in the study had at least 2-year follow-up. RESULTS: A total of 133 EIT sessions on 58 distinct anastomotic strictures were performed on 57 patients (24 girls). The youngest patient to have EIT was 3 months old and 4.8 kg. There were 36 strictures that met the criteria for refractory stricture and 22 non-refractory (NR) strictures. The median number of dilations before EIT therapy was 8 (interquartile range [IQR]: 6-10) in the refractory group and 3 (IQR: 0-3) in the NR group. In the refractory group, 61% of the patients met the criteria for treatment success. The median number of dilations within 2 years of EIT in the refractory group was 2 (IQR: 0-4). In the NR group, 100% of the patients met criteria for success. The median number of dilations within 2 years of EIT in the NR was 1 (IQR: 0-2). The overall adverse event rate was 5.3% (7/133), with 3 major (2.3%) and 4 minor events (3%). CONCLUSIONS: EIT shows promise as an adjunct treatment option for pediatric refractory esophageal strictures and may be considered before surgical resection even in severe cases. The complication rate, albeit low, is significant, and EIT should only be considered by experienced endoscopists in close consultation with surgery. Further prospective longitudinal studies are needed to validate this treatment. PMID- 29697551 TI - Cutting-edge Treatment for Benign Pediatric Esophageal Strictures, a Step Forward, More to Go. PMID- 29697550 TI - Use of Infliximab Biosimilar Versus Originator in a Pediatric United Kingdom Inflammatory Bowel Disease Induction Cohort. AB - OBJECTIVES: The aim of the study was to summarize short-term effectiveness, safety, and cost of using infliximab biosimilar (IFX-B) drugs, (Inflectra [Hospira] and Remsima [NAAP]) compared to originator infliximab (IFX-O) (Remicade [MSD]) in biologic naive pediatric inflammatory bowel disease in the United Kingdom. METHODS: Prospective audit of patients starting anti-tumour necrosis factor (TNF) therapy. Disease severity, response to treatment, and remission rate was measured by Pediatric Crohn's Disease Activity Index (PCDAI) and/or Physician Global Assessment. RESULTS: Between March 2015 and February 2016, 278 patients (175 IFX-O, 82 IFX-B, and 21 Adalimumab) were started on anti-TNF therapy. This was compared with collected data on 398 patients started on IFX-O from 2011 to 2015. At initiation, median PCDAI was 36 (20,48) (n = 42) in the IFX-O group and 28 (20,40) (n = 29) in the IFX-B group, (P = 0.08). Immunosuppression rates were similar: 150/175 (86%) for IFX-O and 65/82 (79%) for IFX-B (P > 0.05). Post induction, median PCDAI score was 5 (0,11) (n = 19) and 0 (0,8) (n = 15) in the IFX-O and IFX-B groups, respectively (P = 0.35). There was no difference in response to treatment using Physician Global Assessment 85% (n = 28) in IFX-O group and 86% (n = 19) in IFX-B group (P > 0.05). Adverse events at initiation and post induction were not different between both groups (P > 0.05). Using conservative calculations, L875,000 would have been saved for a 1-year period with universal adoption of biosimilars in patients who were instead treated with IFX-O. CONCLUSIONS: IFX-B is likely as effective as IFX-O in treating IBD in comparable pediatric populations. Sites should adopt infliximab biosimilar for new starts due to cost reduction with no difference in other parameters. PMID- 29697552 TI - Worldwide Variation in the Dietary Management of Eosinophilic Oesophagitis. PMID- 29697553 TI - Socioeconomic Vulnerability and Sexually Transmitted Infection Among Pregnant Haitian Women. AB - BACKGROUND: Despite evidence that education and poverty act through distinct pathways to influence sexually transmitted infection (STI), few studies have examined the unique, independent associations of these socioeconomic vulnerabilities with sexual risk behaviors and STI among women. METHODS: From August to October 2013, women at an antenatal clinic in Gressier, Haiti, were interviewed and tested for chlamydial infection, gonorrhea, and trichomoniasis (N = 200). We measured low educational attainment as less than 9 years of schooling and currently living in poverty based on crowding, defined as more than 2 people sleeping in one room. We used logistic regression to estimate independent associations between each socioeconomic indicator and outcomes of sexual behaviors and STI. RESULTS: Approximately 29% of the sample had a current STI (chlamydia, 8.0%; gonorrhea, 3.0%; trichomoniasis, 20.5%), with 2.5% testing positive for more than 1 STI. Forty percent of the sample reported low educational attainment and 40% reported current poverty. Low educational attainment was associated with early risk behaviors, including twice the odds of earlier sexual debut (adjusted odds ratio [AOR], 2.09; 95% confidence interval [CI],: 1.14-3.84). Poverty was associated with reporting the current main sexual partner to be nonmonogamous (AOR, 2.01; 95% CI, 1.00-4.01) and current STI (AOR, 2.50; 95% CI, 1.26-4.98). CONCLUSIONS: Education and poverty seem to independently influence STI behaviors and infection, with low education associated with early sexual risk and poverty associated with current risk and infection. Improving women's educational attainment may be important in improving risk awareness, thereby reducing risky sexual behaviors and preventing a trajectory of STI risk. PMID- 29697555 TI - Encourage early conversations about palliative care. PMID- 29697557 TI - Strengthening creativity in nurse educators. PMID- 29697560 TI - Chronic subdural hematoma: A common complexity. PMID- 29697558 TI - An interprofessional simulation for managing postpartum hemorrhage. PMID- 29697561 TI - Female adolescents and sexual health: "I think I'm okay, but am I?" PMID- 29697562 TI - The Affordable Care Act: Where are we now? PMID- 29697563 TI - What a patient taught me about nursing. PMID- 29697564 TI - Critical access hospitals: Meeting underserved community needs. PMID- 29697565 TI - Continuous passive motion therapy after total knee arthroplasty. PMID- 29697566 TI - Improving patient medication education. PMID- 29697567 TI - Commonly used nonopioid analgesics in adults. PMID- 29697568 TI - Video directly observed therapy: Enhancing care for patients with active tuberculosis. PMID- 29697569 TI - Trust your training. PMID- 29697570 TI - Preventing laundry detergent pod toxicity. PMID- 29697571 TI - Online mental health resources. PMID- 29697572 TI - Combination drugs for type 2 diabetes. PMID- 29697574 TI - Strategies for Fighting Medicare Fraud. AB - In 2014, the United States spent approximately $3 trillion on health care. Medicare accounted for $554 billion of these costs, and approximately $60 billion were squandered because of incorrect billing methods, abuse, and fraud. Types of fraud included kickbacks, upcoding, and organized fraudulent crimes. To reduce the financial burden associated with these activities, the United States has created various fraud prevention programs. The purpose of this study was to identify methods of Medicare fraud, examine the various programs implemented by the US government to combat fraud and abuse, and determine the effectiveness of these programs. Although fraud prevention strategies have proven to be effective, the furtherance of these strategies is imperative to continually combat rising health care expenditures in the United States. Benefits of increased fraud prevention and detection are discussed in detail. PMID- 29697575 TI - Utilization and Cost Analysis of Lung Transplantation and Survival After 10 years of Adopting the Lung Allocation Score (LAS). AB - BACKGROUND: Lungs are allocated in the United States using the Lung Allocation Score (LAS). We investigated the effect of LAS trends on lung transplant-related costs, health care utilization, and mortality. METHODS: Utilization data from Mayo Clinic (FL and MN) from 2005-2015 were obtained from the electronic health records (N=465). Costs were categorized as 1-year post or transplant episode and standardized using 2015 Medicare reimbursement and cost-to-charge ratios. Regression analysis was used to assess the relationship of LAS to length of stay (LOS), mortality, and cost of transplant. RESULTS: The mean LAS at transplant increased from 45.7 to 58.3 during the study period, while the 1-year survival improved from 88.1% to 92.5%, (p<0.0001). The proportion of patients transplanted with LAS >= 60 increased from 16.9% to 33.3%. Post-transplant, overall and ICU LOS increased with increasing LAS. Patients with higher LAS had substantially higher transplant episode costs. An increase of LAS at transplant by 10 points increased inflation-adjusted costs by 12.0% (95% CI: 9.3%-14.5%). CONCLUSIONS: The mean LAS at transplant has significantly increased over time associated with increases in LOS, resource utilization and cost. LAS has not jeopardized overall survival, but a high LAS (>60) at transplant is associated with increased mortality. PMID- 29697576 TI - Effects of Kidney Transplantation on Labor Market Outcomes in Sweden. AB - BACKGROUND: Kidney transplantation is considered a superior treatment for end stage renal disease compared with dialysis although little is known about the wider effects, especially on labor market outcomes. The objective is to estimate the treatment effect of kidney transplantation compared with dialysis on labor market outcomes, controlling for the nonrandom selection into treatment. METHODS: The average treatment effect is estimated using an inverse-probability weighting regression adjustment approach on all patients in renal replacement therapy 1995 to 2012. RESULTS: Kidney transplantation is associated with a treatment advantage over dialysis on employment, labor force participation, early retirement, and labor income. The probability of being employed 1 year after treatment is 21 (95% confidence interval, 16-25) percentage points higher for transplantation. The positive effect increases to 38 (95% confidence interval, 30-46) percentage points after 5 years, mainly due to worsening outcomes on dialysis. The effect on labor income is mainly mediated through employment probability. The productivity gains of transplantation compared to dialysis amounts to &OV0556;33 000 over 5 years. CONCLUSIONS: Transplantation is superior to dialysis in terms of potential to return to work as well as in terms of labor income and risk of early retirement, after controlling for treatment selection. This positive effect increases over time after transplantation. PMID- 29697577 TI - PRES in Pediatric HSCT: A Single-Center Experience. AB - Posterior reversible encephalopathy syndrome (PRES) has diverse etiologies and is closely linked to hematopoietic stem cell transplant (HSCT). Headache and seizures are the most common clinical presentations. Although near total recovery is seen in the majority of patients with appropriate management, the implications of its occurrence in the setting of an HSCT is much more than the residual neurological deficits. Graft rejection and occurrence of graft versus host disease has been reported. We analyzed retrospectively our data of 35 pediatric HSCT recipients over the last 2 years at our center. In total, 17% (n=6) patients developed PRES. Headache and seizures were the most common clinical presentations. All patients were on calcineurin inhibitors at the onset of symptoms. The median time after HSCT to the onset of PRES was 21 days. In total, 34% (n=2) patients developed residual neurological deficit. One patient died of acute graft versus host disease at a later date, and 50% (n=3) patients had graft rejection and return to transfusion dependence. The implications of PRES on HSCT outcomes are grave, and better immunosuppression transition protocols need to be developed. PMID- 29697578 TI - APRIL is Involved in the Proliferation and Metastasis of Acute Lymphoblastic Leukemia Cells. AB - Our previous work showed that a proliferation-inducing ligand (APRIL) was involved in the development of acute lymphoblastic leukemia (ALL) in children. However, the precise role of APRIL in ALL remains unknown. To investigate this issue, we silenced and overexpressed APRIL in Nalm-6 ALL cells using short hairpin RNA targeting the APRIL gene and recombinant human APRIL, respectively, and evaluated the effects on cell proliferation, apoptosis, and migration. APRIL mRNA and APRIL and matrix metalloproteinase-2 protein levels were evaluated by semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) and western blott, respectively. We found that APRIL expression was reduced by shRNA mediated knockdown in Nalm-6 cells; this was associated with a decrease in cell proliferation (P<0.05). APRIL knockdown increased apoptosis (P<0.01) but suppressed cell migration along with matrix metalloproteinase-2 protein level. Overexpressing recombinant human APRIL had the opposite effects in each case (P<0.05). These results demonstrate a link between APRIL expression and ALL development and suggest that APRIL is a potential therapeutic target for ALL treatment. PMID- 29697579 TI - Acid-suppressing Drugs and a Low 1 Level of Antithrombin as Risk Factors for L Asparaginase-associated Pancreatitis: A Case-control Study in the Japan Association of Childhood Leukemia Study (JACLS). AB - L-Asparaginase has significantly improved outcome for children with acute lymphoblastic leukemia and has become an essential component of multiagent chemotherapy. However, there are many adverse events due to L-asparaginase, including acute pancreatitis. The pathology of L-asparaginase-associated pancreatitis (AAP) remains unclear. We compared patients who developed AAP (n=29) and random matched controls (n=36) who had been enrolled in the Japan Association of Childhood Leukemia Study of the ALL-02 protocol. AAP and control patients were matched for age, sex, treatment, and protocol risk. We examined correlations between AAP development and clinical symptoms, laboratory data, and concomitant medication. Abdominal pain and nausea were common presenting symptoms for AAP. There was an increased risk of AAP in patients using gastric acid-suppressing agents and antithrombin (AT) supplementation. Mean fibrinogen and AT levels before the onset of AAP were lower in AAP patients than in controls. Decreased AT and fibrinogen levels resulting from the strong suppression of protein synthesis by L-asparaginase were predictive signs for AAP. Our epidemiological approach should prove clinically useful for the diagnosis the AAP as early as possible. PMID- 29697580 TI - Hepatitis-associated Aplastic Anemia: A Report of 3 Cases Associated With HAV. AB - Aplastic anemia is a rare complication of viral hepatitis. We present 3 cases of hepatitis-associated aplastic anemia after hepatitis A virus infection. One of our cases is the first reported case of hepatitis-associated aplastic anemia after fulminant hepatitis A infection. Patient characteristics were consistent with older reports with regard to age and sex. All 3 patients were male individuals under the age of 20. In addition, all 3 patients had A+ blood group. Outcomes in our series were poor because of the unavailability of antithymocyte globulin and bone marrow transplantation. PMID- 29697581 TI - Efficacy of Flu Vaccination Mail-out Reminders in Pediatric Hematology Patients for Quality Improvement: Does Snail-Mail Still Work? PMID- 29697582 TI - Cardiovascular pharmacotherapy a growing sub-speciality across all areas of cardiology: a European tradition. PMID- 29697583 TI - The Necessity for Post-Maneuver Restrictions in the Treatment of Benign Paroxysmal Positional Vertigo: An Updated Meta-Analysis of the Literature. AB - OBJECTIVE: Many studies have published conflicting results regarding the necessity of post-maneuver postural restrictions following treatment of benign paroxysmal positional vertigo (BPPV). The purpose of this meta-analysis is to complete an updated, comprehensive review to determine best practice following a repositioning maneuver (RM). DATA SOURCES: PubMed, CINAHL, and Embase were searched through July 2016. The reference lists of the selected studies were searched for studies that were not identified in the electronic database searches. STUDY SELECTION: Studies investigating the effect of post-maneuver postural restrictions on RM treatment efficacy were included. DATA EXTRACTION: The methodology, number of participants, type of RM administered, post-maneuver restrictions implemented, outcome measures, and results for each study were recorded. DATA SYNTHESIS: Following data extraction, heterogeneity and homogeneity values of included studies were determined. Risk ratios and random effects values were obtained to determine effect size. RESULTS: Eleven studies were included in the meta-analysis. The results of 739 total subjects were analyzed, 362 of which received post-maneuver postural restrictions and 377 of which did not. Meta-analysis revealed that there was not a statistically significant difference in treatment success rates between patients who received post-maneuver postural restrictions (90.3%) and those who did not (81.7%) (p = 0.095). CONCLUSIONS: There was no statistically significant difference found in treatment efficacy between subjects who received post-maneuver postural restrictions and those who did not. Based on the results of this meta-analysis, if there is any benefit from prescribing the postural restrictions, it is likely to be a small marginal improvement in outcomes. PMID- 29697584 TI - Clinical Implications of the Association Between Temporal Bone Tegmen Defects and Superior Semicircular Canal Dehiscence. AB - OBJECTIVE: To discuss the clinical implications of the association between temporal bone tegmen dehiscence (TD) necessitating surgical correction and the adjacent dehiscent superior semicircular canal (SSCD). STUDY DESIGN: Retrospective. SETTING: Tertiary referral center. PATIENTS: Sixteen patients with idiopathic TD, with or without SSCD, requiring surgical correction. INTERVENTIONS: Corrective surgery for TD. High-resolution temporal bone-targeted computed tomography. MAIN OUTCOME MEASURES: The impact of the minimal distance between TD and SSCD or the arcuate eminence on the choice of surgical approach to TD. RESULTS: The patients' median age was 58 years and 5 were males. The median body mass index was 31.8 kg/m. The average distance from the TD and the SSC was 4.9 mm (range 2.1-14.2 mm). Three of the 14 patients who were operated via a temporal craniotomy to fix a cerebrospinal fluid-leaking TD required plugging of an asymptomatic SSCD due to its close proximity (3-5 mm) to the defect, and two of them had relatively protracted vestibular recuperation. Two patients were operated via a transmastoid approach for sealing a cerebrospinal fluid-leaking TD coexisting with a bilateral asymptomatic SSCD. No patient had a hearing loss. CONCLUSION: The close proximity of a TD and an SSCD might not allow selective exposure. As a result, asymptomatic SSCD may become symptomatic during TD correction via the temporal craniotomy approach. The need to plug an asymptomatic SSCD that is proximal to a TD should be factored in planning for surgery and rehabilitation. The choice of surgical approach (middle fossa vs. transmastoid) could be influenced by this relationship, especially in cases of bilateral lesions. PMID- 29697585 TI - Longitudinal Evaluation of Bone-Anchored Hearing Aid Implant Stability Using the Advanced System for Implant Stability Testing (ASIST). AB - OBJECTIVE: This study aims to provide a clinical evaluation of the Advanced System for Implant Stability Testing (ASIST) for assessment of implant stability for bone-anchored hearing aid patients. We evaluate the longitudinal changes in implant interface stability during the first year following surgery. METHODS: ASIST measurements were collected for 39 patients selected to receive a bone anchored hearing aid for hearing loss. Measurements were collected at the time of surgery and at 3 days, 2 weeks, 1 month, 3 months, 6 months, and 12 months following surgery. Longitudinal changes in ASIST Stability Coefficient (ASC) were determined for each patient. Correlations were investigated between initial implant stability as measured by the ASC and clinical parameters such as operating surgeon, patient age at surgery, and implant type. RESULTS: ASC values ranged from 11.9 to 137.0 (31.9 +/- 18.0). On average, there was a slight decrease in ASC up to 3 months after surgery followed by an increase up to 1 year. Preliminary results presented in this study suggest that there may be differences in the initial stability between operating surgeons (p = 0.0012; p = 0.0049) and there was a trend toward possible differences between different implant types. CONCLUSION: We have shown promising results using the ASIST in a clinical setting for longitudinal evaluation of bone-implant interface integrity. Isolating the interface properties from the implant-abutment system allows for objective comparisons across patients that are not possible with other stability measurement systems. PMID- 29697586 TI - Benefits of Bimodal Hearing With Cochlear and Middle Ear Implants: Preliminary Results in Four Patients. AB - OBJECTIVE: Conventional hearing aids have some limitations in overcoming a large air-bone gap or in cases of severe high-frequency hearing loss. The authors aimed to evaluate the benefit of a new bimodal hearing configuration combining cochlear implantation (CI) and middle ear implant (MEI) in patients with severe mixed conductive and ski-slope hearing loss. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Four patients with severe to profound hearing loss, who underwent CI in one ear and MEI in the other, were enrolled. INTERVENTION: Audiological outcomes were assessed at least 6 months after the MEI/CI operation. Pure-tone audiometry (PTA) in unaided, CI-aided, and MEI-aided conditions were measured. MAIN OUTCOME MEASURES: Average threshold changes in bands of frequencies (<1 kHz, >=1 kHz) were compared between MEI-aided and HA-aided conditions. The Korean version of the Hearing-in-Noise Test (K HINT), and speech perception score in noisy and quiet conditions were evaluated in the bimodal configuration (i.e., MEI with CI). RESULTS: MEI-aided PTA was especially increased in high-frequency areas (>=1 kHz). Speech perception in noisy and quiet conditions demonstrated better scores in the bimodal configuration. K-HINT also demonstrated better scores in the bimodal configuration. CONCLUSIONS: There is an increasing number of patients with unilateral CI and residual hearing in the contralateral ear. The benefits of a new bimodal hearing configuration with CI and MEI were demonstrated in patients with severe high-frequency hearing loss or mixed conductive hearing loss in the contralateral ear. PMID- 29697587 TI - Innovative Strategies for Clinical Microscopy Instruction: Virtual Versus Light Microscopy. AB - PURPOSE: The purpose of the study was to compare virtual microscopy with light microscopy to determine differences in learning outcomes and learner attitudes in teaching clinical microscopy to physician assistant (PA) students. METHODS: A prospective, randomized, crossover design study was conducted with a convenience sample of 67 first-year PA students randomized to 2 groups. One group used light microscopes to find microscopic structures, whereas the other group used instructor-directed video streaming of microscopic elements. At the midpoint of the study, the groups switched instructional strategies. Learning outcomes were assessed via posttest after each section of the study, with comparison of final practical examination results to previous cohorts. Attitudes about the 2 educational strategies were assessed through a postcourse questionnaire with a Likert scale. RESULTS: Analysis of the first posttest demonstrated that students in the video-streamed group had significantly better learning outcomes than those in the light microscopy group (P = .004; Cohen's d = 0.74). Analysis of the posttest after crossover showed no differences between the 2 groups (P = .48). Between the 2 posttests, students first assigned to the light microscopy group scored a 6.6 mean point increase (+/-10.4 SD; p = .0011), whereas students first assigned to the virtual microscopy group scored a 1.3 mean point increase (+/-7.1 SD; p = .29). The light microscopy group improved more than the virtual microscopy group (P = .019). Analysis of practical examination data revealed higher scores for the study group compared with 5 previous cohorts of first-year students (P < .0001; Cohen's d = 0.66). Students preferred virtual microscopy to traditional light microscopy. CONCLUSION: Virtual microscopy is an effective educational strategy, and students prefer this method when learning to interpret images of clinical specimens. PMID- 29697588 TI - THE COLLABORATIVE OCULAR TUBERCULOSIS STUDY (COTS)-1: A Multinational Review of 251 Patients With Tubercular Retinal Vasculitis. AB - PURPOSE: Tubercular retinal vasculitis (TRV) is a heterogeneous disease that can be difficult to manage because of nonspecific presentation and limitations of confirmatory tests for tuberculosis. This is a big data analysis on phenotypes and treatment outcomes for TRV. METHODS: Multicentre retrospective study of patients with TRV between January 2004 and December 2014 and a minimum follow-up of 1 year. RESULTS: Two hundred and fifty-one patients with TRV with a mean age of 38.9 +/- 14.4 years (range, 9-86 years) were included. The patients were predominantly males (n = 167/251; 66.5%) of Asian ethnicity (n = 174/246; 70.7%), and geographical origin (n = 137/251; 54.6%). Most patients had features of occlusive type of RV (n = 113/185; 61.1%) except Caucasians (n = 11; 28.2%). There was no significant difference in treatment failure whether patients received antitubercular therapy (ATT) (P = 0.29), although treatment failure was less frequent in patients who received ATT (13.6%; n = 31/228) compared with those who did not (21.7%, n = 5/23). Less treatment failures were observed in patients with occlusive type RV who received ATT; however, this was not significant on survival analysis (P = 0.09). Treatment with ATT was associated with higher failure rates in patients of Hispanic and African American race and those with TRV associated with panuveitis (compared with posterior uveitis). CONCLUSION: In this multinational study of TRV, there was no significant therapeutic effect of ATT. However, a definitive conclusion about the role of ATT could not be made because of a few patients who did not receive ATT. Because this is a retrospective study with a limited 1-year follow-up, the effect of ATT may have been overestimated (or underestimated) in the duration of follow-up. PMID- 29697589 TI - DEXAMETHASONE IMPLANT FOR DIABETIC MACULAR EDEMA IN NAIVE COMPARED WITH REFRACTORY EYES: The International Retina Group Real-Life 24-Month Multicenter Study. The IRGREL-DEX Study. AB - PURPOSE: To investigate efficacy and safety of repeated dexamethasone (DEX) implants over 24 months, in diabetic macular edema (DME) eyes that were treatment naive compared with eyes refractory to anti-vascular endothelial growth factor treatment, in a real-life environment. METHODS: This multicenter international retrospective study assessed best-corrected visual acuity and central subfield thickness (CST) of naive and refractory eyes to anti-vascular endothelial growth factor injections treated with dexamethasone implants. Safety data (intraocular pressure rise and cataract surgery) were recorded. RESULTS: A total of 130 eyes from 125 patients were included. Baseline best-corrected visual acuity and CST were similar for naive (n = 71) and refractory eyes (n = 59). Both groups improved significantly in vision after 24 months (P < 0.001). However, naive eyes gained statistically significantly more vision than refractory eyes (+11.3 +/- 10.0 vs. 7.3 +/- 2.7 letters, P = 0.01) and were more likely to gain >=10 letters (OR 3.31, 95% CI 1.19-9.24, P = 0.02). At 6, 12, and 24 months, CST was significantly decreased compared with baseline in both naive and refractory eyes; however, CST was higher in refractory eyes than in naive eyes (CST 279 +/- 61 vs. 313 +/- 125 MUm, P = 0.10). CONCLUSION: Over a follow-up of 24 months, vision improved in diabetic macular edema eyes after treatment with dexamethasone implants, both in eyes that were treatment naive and eyes refractory to anti vascular endothelial growth factor treatment; however, improvement was greater in naive eyes. PMID- 29697590 TI - CLINICAL FEATURES OF LACQUER CRACKS IN EYES WITH PATHOLOGIC MYOPIA. AB - PURPOSE: To analyze the morphologic features of lacquer cracks (LCs), compare their detectability by different imaging instruments, and determine their progressive pattern. METHODS: The medical records of 47 highly myopic eyes of 33 patients with LCs were reviewed. Fundus fluorescein angiography was used as the primary method of identifying LCs, and the detection rate was compared with that by fundus autofluorescence and optical coherence tomography. RESULTS: A total of 176 LCs were detected in the 47 eyes. Lacquer cracks were detected more frequently in the temporal (44.3%) than the inferior (30.7%), superior (17.0%), and nasal (8.0%) quadrants of the retina. The detection rate of LCs was 98% in fundus photographs and 85% by fundus autofluorescence and optical coherence tomography. A progression of the LCs was observed in 22 of the 41 eyes with a follow-up period of >=1 year. The progression patterns were an increase in the number (18 of 41, including 5 eyes in which new LCs had a branching pattern), elongation (4 of 41), and progression to patchy atrophy (6 of 41). CONCLUSION: Lacquer cracks can be detected noninvasively by fundus autofluorescence and optical coherence tomography; however, improvements are necessary to detect all of the lesions. Lacquer cracks frequently progress with time, and an increase in the number of LCs was the most frequent progression pattern. PMID- 29697591 TI - OPTIMAL MANAGEMENT OF PIGMENT EPITHELIAL DETACHMENTS IN EYES WITH NEOVASCULAR AGE RELATED MACULAR DEGENERATION. AB - PURPOSE: This review aimed to determine the optimal management of retinal pigment epithelial detachments (PEDs) in neovascular age-related macular degeneration (nAMD) based on review of available evidence in the literature. METHODS: A comprehensive literature review evaluates previous retrospective and prospective studies that assessed the treatment of PEDs in nAMD. RESULTS: Studies illustrated that anti-vascular endothelial growth factor (VEGF) therapy can be effective in eyes with PED secondary to nAMD. Similar visual outcomes are associated with different anti-VEGF treatments. Higher anti-VEGF doses may improve anatomical response, without correlation with vision improvement. Fibrovascular PEDs may be difficult to treat, but even these eyes can gain vision with anti-VEGF therapy. A retinal pigment epithelial tear may develop in 15% to 20% of eyes with PEDs after anti-VEGF therapy, especially in PEDs greater than 500 um to 600 um in height; however, vision may stabilize with continued therapy. Atrophy may complicate eyes with PED and nAMD after anti-VEGF therapy, especially in association with complete PED resolution. CONCLUSION: Available literature suggests that anti-VEGF therapy is safe and efficacious for PED and nAMD. Treatment should focus on vision gains rather than PED resolution because there is no apparent correlation between anatomical and functional improvement in most eyes with PED and nAMD. PMID- 29697592 TI - Leopard-Spot Subretinal Deposits in Central Serous Chorioretinopathy. PMID- 29697593 TI - Pathways From Sexual Stigma to Inconsistent Condom Use and Condom Breakage and Slippage Among MSM in Jamaica. AB - BACKGROUND: HIV prevalence among men who have sex with men (MSM) in Jamaica, where same sex practices are criminalized, is among the Caribbean's highest. Sexual stigma, the devaluation, mistreatment, and reduced power afforded to sexual minorities, is a distal driver of HIV vulnerabilities. The mechanisms accounting for associations between sexual stigma and condom use outcomes are underexplored. We examined pathways from sexual stigma to condom use and condom breakage and/or slippage among MSM in Jamaica. METHODS: We conducted a cross sectional survey with a chain-referral sample of MSM (n = 556) in Kingston, Montego Bay, and Ocho Rios. Structural equation modeling using weighted least squares estimation methods was conducted to test the direct effects of sexual stigma on inconsistent condom use and condom breakage/slippage, and the indirect effects through depression, sexual abuse history, and condom use self-efficacy, adjusting for sociodemographic factors. RESULTS: One-fifth of participants (21%; 90/422) who had engaged in anal sex reported inconsistent condom use, and 38% (155/410) reported condom breakage/slippage during the previous 4 weeks. The relationship between sexual stigma and inconsistent condom use was mediated by the combination effect of sexual abuse history, condom use self-efficacy, and depression. The relationship between sexual stigma and condom breakage and slippage was mediated by the combination effect of condom use self-efficacy and sexual abuse history. CONCLUSIONS: Sexual stigma is associated with negative condom use outcomes in Jamaican MSM, mediated by psychosocial factors. Multilevel social ecological approaches to the HIV prevention cascade can inform interventions at individual, interpersonal, community, and systemic levels. PMID- 29697594 TI - Factors Associated With Gaps in Medicaid Enrollment Among People With HIV and the Effect of Gaps on Viral Suppression. AB - INTRODUCTION: Gaps in Medicaid enrollment may affect HIV outcomes. We evaluated factors associated with Medicaid enrollment gaps and their effect on viral suppression (VS) within the HIV Research Network. METHODS: We used a combined data set with Medicaid enrollment files from 2006 to 2010 and HIV Research Network demographic and clinical data. A gap was defined as >=1 month without Medicaid and gap length was determined. We used multivariable logistic regression to determine factors associated with a gap and multivariable logistic regression with generalized estimated equations to evaluate factors associated with VS after gap. RESULTS: Of 5836 participants, the majority were male, of black race, and aged 25-50 years. More than half had a gap in Medicaid. Factors associated with a gap included male sex [adjusted odds ratio (aOR) 1.79, (1.53, 2.08)] and younger age (aORs ranging from 1.50 to 4.13 comparing younger age groups to age >50, P < 0.05 for all). About a quarter of gaps had VS information before and after gap. Of those, 53.7% had VS both before and after gap and 25.8% were unsuppressed both before and after gap. The strongest association with VS after gap was VS before gap [aOR 15.76 (10.48, 23.69)]. Transition into Ryan White HIV/AIDS Program coverage during Medicaid gaps was common (28% of all transitions). CONCLUSIONS: Gaps in Medicaid enrollment were common and many individuals with pre-gap VS maintained VS after gap, possibly due to accessing other sources of antiretroviral therapy coverage. Implementing initiatives to maintain Medicaid enrollment and to expedite Medicaid reenrollment and having alternate resources available in gaps are important to ensure continuous antiretroviral therapy to optimize HIV outcomes. PMID- 29697595 TI - HIV Self-Testing Increases HIV Testing Frequency in High-Risk Men Who Have Sex With Men: A Randomized Controlled Trial. AB - BACKGROUND: Self-testing may increase HIV testing and decrease the time people with HIV are unaware of their status, but there is concern that absence of counseling may result in increased HIV risk. SETTING: Seattle, Washington. METHODS: We randomly assigned 230 high-risk HIV-negative men who have sex with men to have access to oral fluid HIV self-tests at no cost versus testing as usual for 15 months. The primary outcome was self-reported number of HIV tests during follow-up. To evaluate self-testing's impact on sexual behavior, we compared the following between arms: non-HIV-concordant condomless anal intercourse and number of male condomless anal intercourse partners in the last 3 months (measured at 9 and 15 months) and diagnosis with a bacterial sexually transmitted infection (STI: early syphilis, gonorrhea, and chlamydial infection) at the final study visit (15 months). A post hoc analysis compared the number of STI tests reported during follow-up. RESULTS: Men randomized to self-testing reported significantly more HIV tests during follow-up (mean = 5.3, 95% confidence interval = 4.7 to 6.0) than those randomized to testing as usual (3.6, 3.2 to 4.0; P < 0.0001), representing an average increase of 1.7 tests per participant over 15 months. Men randomized to self-testing reported using an average of 3.9 self-tests. Self-testing was noninferior with respect to all markers of HIV risk. Men in the self-testing arm reported significantly fewer STI tests during follow-up (mean = 2.3, 95% confidence interval = 1.9 to 2.7) than men in the control arm (3.2, 2.8 to 3.6; P = 0.0038). CONCLUSIONS: Access to free HIV self-testing increased testing frequency among high-risk men who have sex with men and did not impact sexual behavior or STI acquisition. PMID- 29697596 TI - Evolution of Minimally Invasive Coronary Artery Bypass Grafting: Learning Curve. AB - OBJECTIVE: Minimally invasive coronary surgery approach for coronary artery bypass grafting is a safe and reproducible procedure for multivessel revascularization. This study reviewed a single surgeon's experience with minimally invasive coronary surgery coronary artery bypass grafting, including operative time, number of bypasses, and conversion to sternotomy. METHODS: A prospective database of consecutive minimally invasive coronary surgery coronary artery bypass grafting procedures from 2005 to 2013 was reviewed. A small anterolateral left thoracotomy allowed left internal mammary artery harvest, proximal anastomoses on the ascending aorta, and distal coronary anastomoses. Early cases were compared with the later cases, focusing on grafting strategies that led to a standardized approach with Propensity Score Matching analysis. RESULTS: Seven hundred consecutive cases were divided into early (1-200) and late (201-700) groups. In the late group, the number of triple-vessel disease patients trended higher (50% vs. 57%, P = 0.0674) and the number of bypasses increased (2.3 +/- 0.8 vs. 2.7 +/- 1.0, P < 0.0001). Conversion to sternotomy significantly decreased between the groups (6% vs. 0.6%, P < 0.0001). There was no difference in rate of postoperative complications between the groups except for prolonged intubation (10% vs. 5%, P = 0.0236) and shortened length of stay (5.9 +/- 6.7 vs. 5.5 +/- 6.0, P = 0.0268). Propensity score matching analysis (n = 177) was significant for total bypass performed and time per bypass (P < 0.05). The late group was further divided into subgroups of one hundred each (subgroup 1 through 5). Operative times differed significantly (subgroup 1: 249 +/- 71.2, subgroup 2: 259 +/- 85.8, subgroup 3: 244 +/- 71.0, subgroup 4: 270 +/- 58.4, and subgroup 5: 246 +/- 47.9, P < 0.005). CONCLUSIONS: As experience with minimally invasive coronary surgery coronary artery bypass grafting increased, the ideal sequence of steps to optimize surgical outcome was defined. The number of bypassed vessels increased and the operative time and conversion to sternotomy decreased. PMID- 29697597 TI - Epicardial, Biatrial Ablation With Integrated Uni-bipolar Radiofrequency Technology in Stand-alone Persistent Atrial Fibrillation. AB - OBJECTIVE: Although minimally invasive approaches for surgical treatment of stand alone atrial fibrillation have gained popularity for the past decade, ablation technology and extensive lesion sets play a major role in the achievement of a successful procedure, especially in presence of persistent and long-standing persistent atrial fibrillation. We evaluated clinical outcomes after totally endoscopic biatrial epicardial ablation of persistent atrial fibrillation with a novel integrated uni-bipolar radiofrequency device. METHODS: Forty-nine (49) consecutive patients with stand-alone atrial fibrillation underwent right-sided monolateral thoracoscopic surgical ablation with a novel integrated uni-bipolar radiofrequency energy delivery and temperature-controlled technology. Atrial fibrillation was persistent in 13 (26.5%) of 49 and long-standing persistent in 36 (73.5%) of 49 patients. Mean +/- SD age was 60.6 +/- 10.3 years. Median duration of atrial fibrillation was 74 months. Mean +/- SD left atrial diameter was 44.7 +/- 4.0 mm. RESULTS: Epicardial en bloc isolation of all pulmonary veins (box lesion) and additional ablation of the right atrial free wall was successfully performed via minimally invasive approach without any intraoperative and postoperative major complications. Intraoperative entrance and exit block was achieved in 77.5% (38/49) and 91.8% (45/49) of patients, respectively. Mean +/- SD ablation time was 16.3 +/- 4.8 minutes. No intensive care unit stay was required. Postoperative sinus rhythm was achieved in 93.8% (30/32) patients, and no pacemaker implantation was required. At 13 months, 87.7% (43/49) of patients were in sinus rhythm; 71.4% (35/49) were free from antiarrhythmic drugs and 75.5% (37/49) from oral anticoagulation. CONCLUSIONS: Integrated uni-bipolar radiofrequency ablation technology showed to be effective for the surgical treatment of atrial fibrillation with a total endoscopic approach. A versapolar suction device with extensive right-left atrial lesion set may further improve outcomes in patients with nonparoxysmal atrial fibrillation. PMID- 29697599 TI - Significantly Elevated C-Reactive Protein Levels After Epicardial Clipping of the Left Atrial Appendage. AB - OBJECTIVE: Besides mechanical and anatomical changes of the left atrium, epicardial closure of the left atrial appendage has also possible homeostatic effects. The aim of this study was to assess whether epicardial clipping of the left atrial appendage has different biochemical effects compared with complete removal of the left atrial appendage. METHODS: Eighty-two patients were included and underwent a totally thoracoscopic AF ablation procedure. As part of the procedure, the left atrial appendage was excluded with an epicardial clip (n = 57) or the left atrial appendage was fully amputated with an endoscopic vascular stapler (n = 25). From all patients' preprocedural and postprocedural blood pressure, electrolytes and inflammatory parameters were collected. RESULTS: The mean age and left atrial volume index were comparable between the epicardial clip and stapler group (64 +/- 8 years vs. 60 +/- 9 years, P = non-significant; 44 +/- 15 mL/m vs. 40 +/- 13 mL/m, P = non-significant). Patients receiving left atrial appendage clipping had significantly elevated C-reactive protein levels compared with patients who had left atrial appendage stapling at the second, third, and fourth postoperative day (225 +/- 84 mg/L vs. 149 +/- 76 mg/L, P = 0.002, 244 +/- 78 vs. 167 +/- 76, P = 0.004, 190 +/- 74 vs. 105 +/- 48, P < 0.001, respectively). Patients had a significant decrease in sodium levels, systolic, and diastolic blood pressure at 24 and 72 hours after left atrial appendage closure. However, this was comparable for both the left atrial appendage clipping and stapling group. CONCLUSIONS: Increased activation of the inflammatory response was observed after left atrial appendage clipping compared with left atrial appendage stapling. Furthermore, a significant decrease in blood pressure was observed after surgical removal of the left atrial appendage. Whether the inflammatory response affects the outcome of arrhythmia surgery needs to be further evaluated. PMID- 29697600 TI - OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN THE DIAGNOSIS AND FOLLOW-UP OF RETINAL ARTERIAL MACROANEURYSMS. AB - PURPOSE: To describe optical coherence tomography angiography (OCTA) findings in retinal arterial macroaneurysm (RAM) associated with macular edema and to correlate OCTA findings with conventional multimodal imaging. METHODS: The clinical course, conventional multimodal imaging findings including fundus color photography, spectral domain optical coherence tomography (Spectralis; Heidelberg Engineering, Heidelberg, Germany), fluorescein angiography (Heidelberg Engineering), and OCTA (Optovue, Inc, Freemont, CA) findings at baseline and during the follow-up of two eyes (two patients) with symptomatic RAM associated with macular edema were documented. RESULTS: Two eyes of 2 patients, both women, aged 82 and 46 years, which presented with progressive visual decline, were included. On conventional multimodal imaging, exudative RAM with macular edema and lipid exudation were visible in both included eyes. On OCTA, the flow in the two RAM was detected at baseline. Case 1 was treated by focal laser photocoagulation. One month after treatment, fluorescein angiography showed RAM occlusion. Spectral domain optical coherence tomography showed a RAM and retinal thinning and a decreased central foveal thickness, resulting in visual acuity improvement. On OCTA, no flow was detectable in the RAM at 1-month follow-up. Case 2 was not treated at baseline. In this eye, no flow was detected on OCTA at 2-month follow-up. This suggests a spontaneous occlusion, which was confirmed by fluorescein angiography. CONCLUSION: Optical coherence tomography angiography is able to detect the presence or absence of flow signal within RAMs, which may both decrease the need for dye angiography in selected cases with exudative RAM and help in treatment decision making. PMID- 29697598 TI - A Phase 1 Study of a Novel Bidirectional Perfusion Cannula in Patients Undergoing Femoral Cannulation for Cardiac Surgery. AB - OBJECTIVE: Leg ischemia is a serious complication of femoral artery cannulation. The primary aim of this study was to assess the safety and efficacy of a novel bidirectional femoral arterial cannula (Sorin Group USA, a wholly owned subsidiary of LivaNova PLC, Arvada, CO USA) that provides both antegrade and retrograde flow, in patients undergoing peripheral cannulation for cardiopulmonary bypass during cardiac surgery. METHODS: Patients undergoing routine cardiac surgery requiring femoral artery cannulation for cardiopulmonary bypass were identified preoperatively. Informed written consent was obtained in all cases. Bidirectional cannula insertion used either a surgical cut-down and wire through needle approach or a percutaneous technique. Flow in the superficial femoral artery was assessed using Doppler ultrasound after commencement of cardiopulmonary bypass. Lower limb perfusion was assessed using reflectance near infrared spectroscopy to measure regional oxygen saturations in the cannulated limb during cardiopulmonary bypass. RESULTS: Fifteen patients (median age = 61.3 years, range = 26-79 years, 10 males, 5 females) underwent femoral arterial cannulation using the novel bidirectional femoral cannula between August 2016 and May 2017. Fourteen cannulae were inserted directly into the femoral artery via a surgical cut-down and wire through needle technique. One bidirectional cannula was inserted using a percutaneous insertion technique. Indications included minimally invasive mitral and aortic valve surgery, thoracic aortic aneurysm repair, and redo cardiac surgery. The median duration of cardiopulmonary bypass was 129 minutes (range = 53-228 minutes). The cannula was inserted and positioned without difficulty in 14 of 15 patients. Incorrect sizing and arterial spasm prevented correct cannula positioning in one patient. Antegrade flow in the superficial femoral artery was observed on Doppler ultrasound in 12 of 12 patients in which this was performed. Continuous stable distal perfusion was demonstrated in the cannulated limb in 14 of 15 patients. No procedural complications occurred in the immediate or convalescent postoperative period. CONCLUSIONS: This study demonstrates that in patients undergoing femoral arterial cannulation for cardiopulmonary bypass during cardiac surgery, the use of a novel bidirectional cannula is safe and easy to insert and provides stable distal perfusion of the cannulated limb. Use of the device should largely obviate the need to insert a separate downstream perfusion cannula or use other techniques to protect against lower limb ischemia. Further research on a larger scale and in different patient populations is now warranted. PMID- 29697601 TI - Lordosis Re-Creation in TLIF and PLIF: A Cadaveric Study of the Influence of Surgical Bone Resection and Cage Angle. AB - STUDY DESIGN: Controlled cadaveric study of surgical technique in Transforaminal and Posterior Lumbar Interbody Fusion (TLIF & PLIF) OBJECTIVE.: To evaluate the contribution of surgical techniques and cage variables in lordosis re-creation in posterior interbody fusion (TLIF/PLIF). SUMMARY OF BACKGROUND DATA: The major contributors to lumbar lordosis are the lordotic lower lumbar discs. The pathologies requiring treatment with segmental fusion are frequently hypolordotic or kyphotic. Current posterior based interbody techniques have a poor track record for recreating lordosis, although re-creation of lordosis with optimum anatomical alignment is associated with better outcomes and reduced adjacent segment change needing revision. It is unclear whether surgical techniques or cage parameters contribute significantly to lordosis re-creation. METHODS: Eight instrumented cadaveric motion segments were evaluated with pre and post experimental radiological assessment of lordosis. Each motion segment was instrumented with pedicle screw fixation to allow segmental stabilization. The surgical procedures were unilateral TLIF with an 18 degrees lordotic and 27 mm length cage, unilateral TLIF (18 degrees , 27 mm) with bilateral facetectomy, unilateral TLIF (18 degrees , 27 mm) with posterior column osteotomy, PLIF with bilateral cages (18 degrees , 22 mm), and PLIF with bilateral cages (24 degrees , 22 mm). Cage insertion used and 'insert and rotate' technique. RESULTS: Pooled results demonstrated a mean increase in lordosis of 2.2 degrees with each procedural step (Lordosis increase was serially 1.8 degrees , 3.5 degrees , 1.6 degrees , 2.5 degrees & 1.6 degrees through the procedures). TLIF and PLIF with posterior column osteotomy increased lordosis significantly compared with Unilateral TLIF and TLIF with bilateral facetectomy. The major contributors to lordosis re-creation were posterior column osteotomy, and PLIF with paired shorter cages rather than TLIF. CONCLUSIONS: This study demonstrates that the surgical approach to posterior interbody surgery influences lordosis gain and posterior column osteotomy optimizes lordosis gain in TLIF. The bilateral cages used in PLIF are shorter and associated with further gain in lordosis. This information has the potential to aid surgical planning when attempting to recreate lordosis to optimize outcomes. LEVEL OF EVIDENCE: N/A. PMID- 29697602 TI - A Prospective Comparison of Short-Term Outcomes of Subpectoral and Prepectoral Strattice-Based Immediate Breast Reconstruction. AB - BACKGROUND: Prepectoral acellular dermal matrix-assisted immediate implant-based breast reconstruction is gaining popularity, involving complete implant coverage with acellular dermal matrix. The authors aimed to compare pain, patient-reported outcome measures (including implant rippling), and safety of prepectoral and subpectoral Strattice-assisted implant-based breast reconstruction. METHODS: Consecutive patients were recruited prospectively, having either therapeutic or risk-reducing mastectomy. Patients scored their pain three times per day for the first 7 postoperative days on a Likert scale, and completed the BREAST-Q reconstruction module 3 months postoperatively. Clinical records and the authors' prospective complications database were used to compare the early morbidity of the two procedures. RESULTS: Forty patients were recruited into the study. There was no significant difference in pain scores between the prepectoral group (mean, 1.5) and the subpectoral cohort (mean, 1.5; p = 0.45) during the first 7 days. Thirty-one BREAST-Q questionnaires were returned; mean Q scores were similar for both prepectoral and subpectoral (72 and 71, respectively; p = 0.81) groups. Patients reported significantly more visible implant rippling in the prepectoral group than in the subpectoral group (seven of 13 versus two of 17; p = 0.02). There was no significant difference in length of stay or early morbidity, with implant loss being 4.7 percent in the prepectoral group compared with 0 percent in the subpectoral group. CONCLUSIONS: Early postoperative pain and quality of life at 3 months are equivalent between groups. Early experience of prepectoral implant placement with complete acellular dermal matrix coverage suggests this is safe and provides good quality of life for patients. Further studies are required to compare short- and long-term outcomes with the current standard forms of reconstruction. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 29697604 TI - Facebook Facts: Breast Reconstruction Patient-Reported Outcomes Using Social Media. AB - BACKGROUND: Social media are used for information sharing among patients with similar health conditions, and analysis of social media activity could inform clinical decision-making. The aim of this study was to use Facebook to evaluate a cohort of individuals' perceptions of and satisfaction with breast reconstruction. METHODS: In this observational study, the authors collected and analyzed posts pertaining to autologous and implant-based breast reconstruction from active Facebook groups. Patient satisfaction data were categorized, and a thematic analysis of posts was conducted. Qualitative posts were grouped based on common themes and quantitatively compared using frequency and chi-square analysis. RESULTS: The authors evaluated 500 posts from two Facebook groups. Two hundred sixty-four posts referenced deep inferior epigastric perforator (DIEP) flap reconstruction and 117 were related to implant-based reconstruction. Among individuals referencing DIEP flap reconstruction, 52 percent were satisfied, compared with 20 percent of individuals who referenced satisfaction with implant based reconstruction (p < 0.0001). Individuals posting about DIEP flaps reported a higher rate of unexpected side effects (p < 0.001) and numbness (p = 0.004). When referencing implant-based reconstruction, individuals reported significantly higher rates of infection, contracture, and implant failure (p < 0.001). CONCLUSIONS: Based on the authors' review of social media activity, individuals undergoing DIEP flap breast reconstruction expressed relatively high individual satisfaction despite difficult postoperative recovery. Individuals who referenced implant-based reconstruction mentioned infection and implant failure, leading to high rates of dissatisfaction. Social media appear to provide informational and emotional support to patients. Plastic surgeons can use social media to gather unbiased information of patients' experience to inform clinical conversation and guide clinical practice. PMID- 29697603 TI - Validated Outcomes in the Grafting of Autologous Fat to the Breast: The VOGUE Study. Development of a Core Outcome Set for Research and Audit. AB - BACKGROUND: Autologous fat grafting is an important part of the reconstructive surgeon's toolbox when treating women affected by breast cancer and subsequent tumor extirpation. The debate over safety and efficacy of autologous fat grafting continues within the literature. However, work performed by the authors' group has shown significant heterogeneity in outcome reporting. Core outcome sets have been shown to reduce heterogeneity in outcome reporting. The authors' goal was to develop a core outcome set for autologous fat grafting in breast reconstruction. METHODS: The authors published their protocol a priori. A Delphi consensus exercise among key stakeholders was conducted using a list of outcomes generated from their previous work. These outcomes were divided into six domains: oncologic, clinical, aesthetic and functional, patient-reported, process, and radiologic. RESULTS: In the first round, 55 of 78 participants (71 percent) completed the Delphi consensus exercise. Consensus was reached on nine of the 13 outcomes. The clarity of the results and lack of additional suggested outcomes deemed further rounds to be unnecessary. CONCLUSIONS: The VOGUE Study has led to the development of a much-needed core outcome set in the active research front and clinical area of autologous fat grafting. The authors hope that clinicians will use this core outcome set to audit their practice, and that researchers will implement these outcomes in their study design and reporting of autologous fat grafting outcomes. The authors encourage journals and surgical societies to endorse and encourage use of this core outcome set to help refine the scientific quality of the debate, the discourse, and the literature. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 29697605 TI - Evaluating Platelet-Rich Therapy for Facial Aesthetics and Alopecia: A Critical Review of the Literature. AB - BACKGROUND: Despite the growing popularity of platelet-rich plasma, existing evidence supporting its efficacy remains controversial due to the lack of large scale studies and standardized protocols for preparation and application. This article reviews its use in facial rejuvenation, fat grafting, acne scarring, and androgenic alopecia. Emphasis is placed on comparing methods of platelet-rich plasma preparation and application across studies. METHODS: A systematic review was performed for articles published between 2006 and 2015. All clinical studies and case reports that addressed platelet-rich plasma alone and/or in combination with fat grafting for facial rejuvenation, acne scarring, or androgenic alopecia were included. RESULTS: Of the 22 articles included in the analysis, seven studies used platelet-rich plasma alone for facial rejuvenation, seven in combination with fat grafting, two for treatment of acne scarring, and six for treatment of androgenic alopecia. Individual study procedures, means of evaluation, and significant results are summarized. Although the majority of studies in this review report positive results, significant variation exists in preparation protocols and in the number and frequency of clinical treatments. CONCLUSIONS: The majority of studies report positive results for all indications evaluated in this review, but the procedure is limited by the lack of a standardized method for preparation and application of platelet-rich plasma. The extent to which significant variability in platelet-rich plasma preparation and/or application methods may affect clinical outcomes is not completely clear. In the interim, we present a consolidation of platelet-rich plasma treatment techniques and outcomes currently in use to help guide physicians in their clinical practice. PMID- 29697606 TI - The Anatomy behind Adverse Events in Hand Volumizing Procedures: Retrospective Evaluations of 11 Years of Experience. AB - BACKGROUND: To retrospectively evaluate the rate of adverse events after hand volumizing procedures using a calcium hydroxylapatite product and to investigate the relationship between injector used (i.e., needle versus cannula) and technique applied (i.e., bolus, tenting, proximal-to-distal fanning, distal-to proximal single line). METHODS: Two hundred twenty individuals, including 214 women (97.3 percent) aged 52.3 +/- 11.4 years, treated bilaterally for hand rejuvenation were investigated between the years 2006 and 2017. Cadaveric dissections (n = 12), fluoroscopic (n = 4), ultrasound (n = 22), and computed tomographic (n = 4) imaging were also performed to guide conclusions. RESULTS: Thirty-two of 440 hands (7.3 percent) developed adverse events within the first 15 days, with swelling in 11 (5 percent), pain in four (1.8 percent), erythema in three (1.4 percent), and discoloration in one (0.5 percent). Using a needle (versus a cannula) was significantly related to the occurrence of adverse events (OR, 7.57; 95 percent CI, 3.76 to 15.24; p < 0.001). The proximal-to-distal fanning technique with access to the dorsal superficial lamina was identified as a safer application technique, with each of the other techniques having a significantly increased odds ratio for adverse events: bolus technique (OR, 26.9; 95 percent CI, 6.87 to 105.2; p < 0.001), tenting technique (OR, 24.73; 95 percent CI, 7.48 to 81.76; p < 0.001), and single-line technique (OR, 26.68; 95 percent CI, 7.45 to 95.48; p < 0.001). CONCLUSIONS: The results of this study support the use of cannula versus needle and the proximal-to-distal fanning technique. The underlying anatomy supports the positioning of the material into the subdermal space, which can be identified less than 1 mm deep to the skin surface, and is termed the dorsal superficial lamina. PMID- 29697607 TI - Use of Tranexamic Acid to Reduce Blood Loss in Liposuction. AB - BACKGROUND: The use of tranexamic acid for blood loss prevention has gained popularity in many specialties, including plastic surgery. However, its use in liposuction has not been studied. The authors present a prospective, double blind, nonrandomized study evaluating the efficacy of tranexamic acid in reducing perioperative blood loss during liposuction. METHODS: Twenty women undergoing liposuction were divided into two cohorts. Group 1 (n = 10) received a standard dose of 10 mg/kg of tranexamic acid intravenously in the preoperative and postoperative periods, whereas group 2 (n = 10) received a placebo. Patient hematocrit levels were evaluated preoperatively and postoperatively. Blood volume in the infranatant of the lipoaspirate was also measured; t tests were used for statistical analysis. RESULTS: Age, body mass index, and volume of lipoaspirate were comparable between the two cohorts. The volume of blood loss for every liter of lipoaspirate was 56.2 percent less in the tranexamic group compared with the control group (p < 0.001). Hematocrit levels at day 7 postoperatively were 48 percent less in group 1 compared with group 2 (p = 0.001). Furthermore, a 1 percent drop in the hematocrit level was found after liposuction of 812 +/- 432 ml in group 1 and 379 +/- 204 ml in group 2. Thus, the use of tranexamic acid could allow for aspiration of 114 percent more fat, with comparable variation in hematocrit levels. CONCLUSIONS: Tranexamic acid has been shown to be effective for minimizing perioperative blood loss in liposuction. Further large randomized controlled studies are required to corroborate this effect. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 29697608 TI - Happy and Unhappy Patients: A Quantitative Analysis of Online Plastic Surgeon Reviews for Breast Augmentation. AB - BACKGROUND: Online reviews have become modern versions of the word-of-mouth recommendation, and prospective patients are increasingly consulting them before making decisions about their surgical care. The authors' objectives were to (1) identify trends in the use of online reviews, and (2) important reasons for patient satisfaction and dissatisfaction with aesthetic surgery. The authors selected breast augmentation as the primary procedure of interest. METHODS: Reviews of the top 10 to 20 most reviewed plastic surgeons in each of six large metropolitan areas were obtained from Google, Yelp, and RealSelf. Reviews were assessed for predefined dimensions of satisfaction and dissatisfaction. RESULTS: A total of 1077 breast augmentation reviews were obtained. Ratings were distributed bimodally, with peaks at five stars and one star. The majority of reviews were positive (87.5 percent). Relative popularity of Google versus Yelp varied across geographic regions, and average rating varied by platform. Between 2011 and 2016, the number of online reviews for breast augmentation grew at an average rate of 42.6 percent per year. Aesthetic outcome was the most commonly cited dimension (69.8 percent of reviews), whereas cost was mentioned in only 7.8 percent of reviews. A substantial minority of negative Yelp (37 percent) and Google (9.4 percent) reviews were written by patients who did not actually undergo surgery. Free-text analysis of heterogeneous reviews (containing positive and negative attributes) classified dimensions as critical, redeemable, or protective. CONCLUSION: As the influence of online review platforms continues to grow, understanding drivers of positive and negative reviews may help surgeons improve patient satisfaction. PMID- 29697609 TI - Discussion: Happy and Unhappy Patients: A Quantitative Analysis of Online Plastic Surgeon Reviews for Breast Augmentation. PMID- 29697610 TI - Consequences of the U.S. Food and Drug Administration-Directed Moratorium on Silicone Gel Breast Implants: 1992 to 2006. AB - The U.S. Food and Drug Administration silicone gel breast implant moratorium occurred 25 years ago. The immediate and long-term consequences of the moratorium are reviewed and assessed. PMID- 29697611 TI - Discussion: Consequences of the U.S. Food and Drug Administration-Directed Moratorium on Silicone Gel Breast Implants: 1992 to 2006. PMID- 29697612 TI - Refinements in Upper Blepharoplasty: The Five-Step Technique. AB - Periorbital tissues are a keystone in facial beauty and a representation of youth. The aesthetically pleasing and youthful upper eyelids are full, with a defined tarsal upper lid crease and with smooth, taut pretarsal and preseptal skin. The upper blepharoplasty is a critical component of any facial rejuvenation procedure. This five-step procedure provides key steps in the correction of upper lid age-related changes and provides a reliable and reproducible method of achieving excellent results. Furthermore, the addition of fractionated fat restores volume and youthfulness of the upper lid, and also improves the skin quality of the upper lid. PMID- 29697613 TI - Discussion: Measurement of Warping Angle in Human Rib Graft: An Experimental Study. PMID- 29697614 TI - Discussion: Improved Long-Term Volume Retention of Stromal Vascular Fraction Gel Grafting with Enhanced Angiogenesis and Adipogenesis. PMID- 29697615 TI - Comparison of Patient-Reported Outcome Measurements and Objective Measurements after Cubital Tunnel Decompression. AB - BACKGROUND: The aims of this study were (1) to compare the responsiveness of disease and hand-related issues, including health status-related questions, in patients with cubital tunnel syndrome; and (2) to assess whether these tools and objective hand tests are associated with the results of nerve conduction studies after a simple cubital tunnel syndrome decompression. METHODS: Forty-seven patients with diagnosed condition were enrolled in the study. The following tools were used preoperatively and again at 3 and 6 months: the Patient-Rated Ulnar Nerve Evaluation; the Michigan Hand Outcomes Questionnaire; the Disabilities of the Arm, Shoulder, and Hand; the 12-Item Short-Form Health Survey; the pain visual analogue scale with activity; the grip and key pinch test, two-point discrimination, and the ulnar nerve conduction studies test. RESULTS: All questionnaires and pain visual analogue scale, two-point discrimination, and nerve conduction studies improved significantly at the 6-month follow-up (p < 0.05) compared with preoperative outcomes. Correlations were observed between preoperative motor conduction velocity, preoperative work of the Michigan Hand Outcomes Questionnaire (R = -0.38; p = 0.049), and pain visual analogue scale during activity (R = 0.47; p = 0.025). A correlation was found between motor conduction velocity change after 6 months and the hand function of the Michigan Hand Outcomes Questionnaire after 6 months (R = 0.57; p = 0.017). CONCLUSION: The Patient-Rated Ulnar Nerve Evaluation and the Michigan Hand Outcomes Questionnaire were more responsive for short-term recovery compared with other measures; however, only the latter correlated with motor conduction velocity. PMID- 29697616 TI - Carpal Tunnel Syndrome Management in Breast Cancer Survivors at Risk for Lymphedema: A Markov Model. AB - BACKGROUND: Breast cancer survivors that have undergone axillary lymph node dissection have an increased risk of developing same-side upper extremity lymphedema. Patients with carpal tunnel syndrome in the ipsilateral limb may not receive appropriate surgical therapy (carpal tunnel release) because of concerns that it may trigger or worsen lymphedema. METHODS: A state transition cohort model was used to evaluate the treatment options for breast cancer survivors at risk of upper extremity lymphedema presenting with carpal tunnel syndrome. The model reflected three treatment strategies: (1) early surgical intervention, (2) delayed surgical intervention, or (3) nonsurgical management. Both life-years and quality-adjusted life-years were modeled over a 30-year time horizon. RESULTS: Over a 30-year time horizon, the preferred strategy was delayed surgery, which resulted in 21.41 quality-adjusted life-years. Early surgery and nonsurgical management yielded 20.42 and 21.06 quality-adjusted life-years, respectively. The model was robust and was not sensitive to variation in any of the parameters within the clinically plausible ranges. CONCLUSIONS: Based on this decision analytic model, the optimal choice for breast cancer survivors with mild carpal tunnel syndrome who are at risk for lymphedema would be delaying surgery until severe symptoms develop. This strategy balances the potential increased risk of lymphedema following carpal tunnel release with the decreased long-term risk of severe carpal tunnel syndrome. The model comprehensively assesses a controversial area in the breast cancer and hand surgery literature to inform decision-making for patients and clinicians. PMID- 29697617 TI - Outpatient versus Inpatient Primary Cleft Lip and Palate Surgery: Analysis of Early Complications. AB - BACKGROUND: Fiscal constraints are driving shorter hospital lengths of stay. Outpatient primary cleft lip surgery has been shown to be safe, but outpatient primary cleft palate surgery remains controversial. This study evaluates outcomes following outpatient versus inpatient primary cleft lip and palate surgery. METHODS: The American College of Surgeons National Surgical Quality Improvement Program Pediatric database was used to identify patients undergoing primary cleft lip and palate surgery between 2012 and 2015. Patient clinical factors and 30-day complications were compared for outpatient versus inpatient primary cleft lip and palate surgery. Univariate and multivariate analyses were performed. RESULTS: Three thousand one hundred forty-two patients were included in the primary cleft lip surgery group and 4191 in the primary cleft palate surgery group. Patients in the cleft lip surgery group with structural pulmonary abnormalities had a significantly longer hospital length of stay (beta, 4.94; p = 0.001). Patients undergoing outpatient surgery had a significantly higher risk of superficial (OR, 1.99; p = 0.01) and deep wound dehiscence (OR, 2.22; p = 0.01), and were at a significantly lower risk of reoperation (OR, 0.36; p = 0.04) and readmission (OR, 0.52; p = 0.02). CONCLUSIONS: Outpatient primary cleft lip surgery is safe and has a complication profile similar to that of inpatient surgery. Outpatient primary cleft palate surgery is common practice in many U.S. hospitals and has a significantly higher rate of wound complications, and lower rates of reoperation and readmission. In properly selected patients, outpatient palatoplasty can be performed safely. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 29697618 TI - Discussion: Outpatient versus Inpatient Primary Cleft Lip and Palate Surgery: Analysis of Early Complications. PMID- 29697619 TI - The Skoog Lip Repair for Unilateral Cleft Lip Deformity: The Uppsala Experience. AB - BACKGROUND: The Uppsala Craniofacial Center has been treating patients with unilateral cleft lip deformity using the lip repair technique described by Tord Skoog. The aim of this study was to determine complications after lip surgery and the incidence and indications for lip revisions in all patients born with unilateral cleft lip from 1960 to 2004. METHODS: All patients who were born from 1960 to 2004 with unilateral cleft lip, cleft lip and alveolus, or cleft lip and palate and underwent lip repair were studied retrospectively. The timing, indication, complications of the primary procedure, and type of secondary surgery were recorded. Kruskal-Wallis and Fisher's exact tests were used, with Bonferroni correction. RESULTS: The study included 443 patients. The total rate of early surgical complications was 6 percent (n = 26). Secondary surgery for short upper lip was performed in 3.8 percent (n = 17), 8.4 percent (n = 37) underwent reduction of excess vermillion, 8.6 percent (n = 38) underwent scar revision, 11 percent (n = 51) underwent revision for incongruent vermillion-cutaneous border, and 10 percent (n = 45) underwent revision for other indications. Altogether, 45 percent had no secondary revisions. CONCLUSION: In conclusion, the Skoog lip repair is associated with a low total revision rate, and a short-lip deformity is rare. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 29697620 TI - Discussion: The Skoog Lip Repair for Unilateral Cleft Lip Deformity: The Uppsala Experience. PMID- 29697622 TI - Arterial Vascularization of the Mandibular Condyle and Fractures of the Condyle. AB - BACKGROUND: Despite substantial displacements, fractures of the mandibular condyle rarely lead to necrosis. This illustrates the negligible role of the inferior alveolar artery in intraosseous supply to the condyle, and led to this systematization of its arterial vascularization. METHODS: Forty-two temporomandibular joints from nonembalmed cadaveric specimens were studied following injection of latex (n = 32) or India ink (n = 10). RESULTS: The intraosseous branches of the inferior alveolar artery that lead to the condyle were inconstant and often rudimentary. In this study, the arteries that consistently led to the condyle were the superficial temporal artery, the deep posterior temporal artery, and arterial branches leading to the lateral pterygoid muscle emanating directly from the maxillary artery. These arteries, along with the transverse facial artery and the masseteric artery (when they participated in condoyle vascularization), formed a quadrangle around the mandibular condyle. After India ink injection, the pterygoid muscle was the most strongly colored muscle, thus indicating substantial vascularization. CONCLUSIONS: Although there is a lack of consensus in the literature regarding the constancy and proportions of the arteries participating in vascularization of the condyle, the superficial temporal artery, the maxillary arterial branches leading to the lateral pterygoid muscle, and the deep posterior temporal artery were constant in this study. This study shows the important role of the lateral pterygoid in the vascularization of the condyle. In case of a fracture with substantial displacement, the vascularization emanating from the superficial temporal artery and the lower alveolar artery is ruptured or compromised. PMID- 29697621 TI - Vascular Anomalies: From a Clinicohistologic to a Genetic Framework. AB - BACKGROUND: Vascular anomalies currently are classified according to their clinical and histological characteristics. Recent advances in molecular genetics have enabled the identification of somatic mutations in most types of vascular anomalies. The purpose of this study was to collate information regarding the genetic basis of vascular anomalies. METHODS: The PubMed literature was reviewed for all citations that identified a mutation in a vascular anomaly between 1994 and 2017. Search terms included "vascular anomaly," "mutation," "gene," "hemangioma," "pyogenic granuloma," "kaposiform hemangioendothelioma," "capillary malformation," "venous malformation," lymphatic malformation," "arteriovenous malformation," and "syndrome." Articles that identified both germline and somatic mutations in vascular anomalies were analyzed. Mutations were categorized by type (germline or somatic), gene, signaling pathway, and cell(s) enriched for the mutation. RESULTS: The majority of vascular anomalies had associated mutations that commonly affected tyrosine kinase receptor signaling through the RAS or PIK3CA pathways. Mutations in PIK3CA and G-protein-coupled receptors were most frequently identified. Specific types of vascular anomalies usually were associated with a single gene. However, mutations in the same gene occasionally were found in different vascular lesions, and some anomalies had a mutation in more than one gene. Mutations were most commonly enriched in endothelial cells. CONCLUSIONS: Identification of somatic mutations in vascular anomalies is changing the paradigm by which lesions are diagnosed and understood. Mutations and their pathways are providing potential targets for the development of novel pharmacotherapy. In the future, vascular anomalies will be managed based on clinical characteristics and molecular pathophysiology. PMID- 29697623 TI - Facial Reanimation in the Seventh and Eighth Decades of Life. AB - BACKGROUND: Treatment of facial paralysis in the older population is often relegated to static rather than dynamic reanimation for fear of poor outcomes. This pervasive approach lacks physiologic foundation and is not evidence based. Thus, the authors present an extensive literature review demonstrating weak evidence supporting this misguided concept, followed by detailed outcomes from three centers of the largest reported series to date of patients older than 60 years after reanimation performed using three techniques-lengthening temporalis myoplasty, free functional muscle, and nerve transfers. METHODS: A PubMed search spanning over 40 years identified all reports on reanimation in patients older than 60 years. In addition, detailed demographics, surgical techniques, and outcomes of 30 patients older than 60 years were analyzed. RESULTS: Of 629 articles, only 45 patients were identified, described in case reports or small series, lacking details or consistent long-term follow-up. In the clinical series, average age, preoperative House-Brackmann score, and comorbidities were similar among the groups. Highest excursion was observed in the free functional muscle group, followed by nerve transfer and temporalis myoplasty, averaging 10.4, 6.8, and 3.1 mm, respectively. The most notable philtral deviation correction was in the lengthening temporalis myoplasty group, followed by the free muscle and nerve transfer groups, averaging 5.6, 2.2, and 1.13 mm, respectively. Complication rates were highest in the free functional muscle group. CONCLUSIONS: Facial palsy patients should not be denied dynamic restoration based on age alone. Although surgical technique may vary based on duration of palsy, surgeon experience, and preference, with each presenting advantages and disadvantages, dynamic restoration is feasible regardless of age. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 29697624 TI - Accessory Nerves of the Forehead: A Newly Discovered Frontotemporal Neurovascular Bundle and Its Implications in the Treatment of Frontal Headache, Migraine Surgery, and Cosmetic Temple Filler Injection. AB - BACKGROUND: Surgical decompression of peripheral cranial and spinal nerves at several anatomically studied trigger sites has demonstrated significant efficacy in bringing permanent relief to migraine sufferers. In their experience performing frontal nerve decompression on migraine patients, the authors noticed a previously undescribed accessory nerve and vessel in the frontotemporal area, and report its implication in migraine surgery and cosmetic filler injection. METHODS: A retrospective review of 113 patients who underwent frontal migraine decompression surgery with the senior author at the University of Texas Southwestern Medical Center from July of 2012 to May of 2016 was performed. For the included 76 patients, measurements of this nerve had been taken intraoperatively using high-definition endoscopic assistance, and topographic measurements were correlated with endoscopic location of the nerve. RESULTS: This frontotemporal nerve (FTN) was present in 55 percent, and the bilateral incidence was 57 percent of those. An accompanying vessel was also present in 81 percent of nerve complexes. Both nerve and vessel varied in size. A large vessel was present in 8 percent of all patients, and a medium vessel was present in 20 percent. Consistently, the nerve exited a foramen in the frontal bone on average 3.4 +/- 0.47 cm superior to the lateral canthus. CONCLUSIONS: The identification and proper avulsion neurectomy of this newly described sensory FTN may lead to better surgical response rate during migraine surgery. In addition, this nerve should be considered during nerve block and botulinum toxin injections in migraine treatment. The existence of the accompanying vessel could have significant implications in the safety of filler and fat injections to this area. PMID- 29697625 TI - Morphometric Evaluation of the Frontal Migraine Trigger Site. AB - BACKGROUND: Migraine headache has been attributed to specific craniofacial peripheral nerve trigger sites. Some have postulated that hypertrophy of the corrugator muscles causes compression of the supraorbital and supratrochlear nerves, resulting in migraine headache. This study uses morphometric evaluation to determine whether corrugator anatomy differs between patients with migraine headache and control subjects. METHODS: A retrospective review identified patients with and without migraine headache who had a recent computed tomographic scan. Morphometric evaluation of the corrugator supercilii muscles was performed in a randomized and blinded fashion on 63 migraine headache and 63 gender-matched control patients using a three-dimensional image-processing program. These images were analyzed to determine whether corrugator size differed between migraine and control patients. RESULTS: There was no difference in mean corrugator volume or thickness between migraine and control patients. The mean corrugator volume was 1.01 +/- 0.26 cm compared with 1.06 +/- 0.27 cm in control patients (p = 0.258), and the mean maximum thickness was 5.36 +/- 0.86 mm in migraine patients compared with 5.50 +/- 0.91 mm in controls (p = 0.359). Similarly, subgroup analysis of 38 patients with frontal migraine and 38 control subjects demonstrated no difference in corrugator size. Further subgroup analysis of nine patients with unilateral frontal migraine showed no difference in corrugator size between the symptomatic side compared with the contralateral side. CONCLUSIONS: Muscle hypertrophy itself does not play a major role in triggering migraine headache. Instead, factors such as muscle hyperactivity or peripheral nerve sensitization may be more causative. PMID- 29697626 TI - Preoperative and Postoperative Assessment of Rectus Abdominis Muscle Size and Function following DIEP Flap Surgery. AB - BACKGROUND: Prospective evaluation of rectus abdominis muscle function after deep inferior epigastric artery perforator (DIEP) flap breast reconstruction is limited. Elimination of muscle harvest with this procedure is theoretically associated with preservation of rectus abdominis function and minimization of abdominal wall morbidity. In this study, the authors evaluate the change in rectus abdominis muscle size and function after DIEP flap surgery. METHODS: Patients undergoing unilateral DIEP flap surgery were recruited prospectively. Using computed tomography, the change in preoperative to postoperative rectus abdominis muscle size was compared between the operative side rectus abdominis muscle and the contralateral, nonoperative control rectus abdominis. Postoperative muscle integrity and contractility were evaluated using ultrasound by comparing the change in rectus abdominis muscle dimensions between contractile and relaxed states. The BREAST-Q was used to score patients' subjective satisfaction. Clinical and radiographic hernia rates were also calculated. RESULTS: Analysis of 26 paired rectus abdominis muscles revealed no significant change in muscle size from preoperative to postoperative values. Furthermore, dimensional change from contractile to relaxed states postoperatively was similar for paired operative and nonoperative rectus abdominis muscles. BREAST-Q scores indicated a high degree of satisfaction in abdominal well-being, breast satisfaction, and surgical experience domains. There were no clinical or radiographic abdominal wall hernias noted. CONCLUSIONS: The DIEP flap is an effective surgical procedure with minimal abdominal wall morbidity that is associated with no measurable loss in rectus abdominis size and contractile function postoperatively. Patients are highly satisfied with their abdominal function postoperatively using this technique. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 29697627 TI - Comparative Effectiveness of Retromuscular and Intraperitoneal Repair: What Is the Value of Posterior Sheath Reconstruction? AB - BACKGROUND: The authors hypothesize that posterior sheath reconstruction to achieve retromuscular mesh placement provides outcomes comparable to traditional retromuscular mesh placement and superior to intraperitoneal repair. METHODS: Patients were divided into three groups: (1) retromuscular mesh placement with repaired posterior sheath defects, (2) retromuscular repair with an intact posterior sheath, and (3) intraperitoneal repair. Primary outcomes included recurrence, surgical-site occurrences, and cost. RESULTS: Overall, 179 patients were included. Posterior sheath defects were repaired primarily with absorbable suture or biological mesh. Recurrence rates differed significantly between standard retromuscular repair and intraperitoneal repair groups (p < 0.009), trended toward significance between repaired posterior sheath and intraperitoneal repair groups (p < 0.058), and showed no difference between repaired posterior sheath and standard retromuscular repair (p < 0.608). Retromuscular repair was clinically protective and cost-effective. CONCLUSIONS: This analysis of posterior sheath reconstruction suggests outcomes comparable to traditional retromuscular repair and a trend toward superiority compared with intraperitoneal repair. Achieving retromuscular closure appears to demonstrate clinical and cost efficacy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 29697628 TI - Mechanical versus Hand-Sewn Venous Anastomoses in Free Flap Reconstruction: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Venous complications are the primary reason for flap loss in massive defect reconstructions; therefore, the quality and reliability of microvascular anastomoses are significant. The aim of this systematic review was to evaluate venous anastomotic time, the venous complication rate, and the flap failure rate with the mechanical anastomotic coupling device versus the hand-sewn technique in venous anastomoses of microvascular free flap operations. METHODS: Chinese and English databases were searched for eligible articles published between their inception and July of 2017. The pooled relative risk was calculated for dichotomous variables, and the weighted mean difference was calculated for continuous data. Whether to use the fixed effects or random effects model depended on the heterogeneity evaluation among the studies. RESULTS: Twelve studies were selected, including 3788 flaps (mechanical anastomotic coupling device, n = 1667; hand-sewn, n = 2121). Using the mechanical anastomotic coupling device significantly decreased venous anastomotic time (weighted mean difference, -13.50; 95 percent CI, -17.09 to -9.91; p < 0.01) and the incidence of venous complications (relative risk, 0.40; 95 percent CI, 0.25 to 0.65; p < 0.01). There was a significant difference in terms of flap failure between the groups (relative risk, 0.56; 95 percent CI, 0.32 to 0.97; p = 0.04); thus, flap survival improved with the assistance of the mechanical anastomotic coupling device. No publication bias was detected in those analyses. CONCLUSION: This meta-analysis suggests that the mechanical anastomotic coupling device contributes to reduced operative time, decreased probability of surgical reexploration, and mitigation of flap loss. PMID- 29697629 TI - Forty Years of Lower Extremity Take-Backs: Flap Type Influences Salvage Outcomes. AB - BACKGROUND: Considering that muscle has higher metabolic demand than fasciocutaneous tissue and can be more difficult to monitor clinically, the authors compared take-back salvage rates between fasciocutaneous and muscle free flaps for lower extremity trauma reconstruction. METHODS: The authors conducted a retrospective review of 806 free flaps (1979 to 2016); 481 soft-tissue flaps performed for below-knee trauma met inclusion criteria. Primary outcome measures were perioperative complications, specifically, take-backs and flap salvage rates. Univariate and multivariate regression analysis was performed where appropriate. RESULTS: Take-backs occurred in 71 flaps (muscle, n = 44; fasciocutaneous, n = 27) at an average of 3.7 +/- 5.4 days postoperatively. Indications were venous (48 percent), arterial (31 percent), unknown (10 percent), and hematoma (10 percent). Overall outcomes were complete salvage (37 percent), partial failure (25 percent), and total failure (38 percent). Take backs occurring within 48 hours postoperatively correlated with higher salvage rates (p = 0.022). Fasciocutaneous flaps demonstrated increased take-back rates compared with muscle flaps (p = 0.005) that more frequently occurred within 48 hours postoperatively (relative risk, 13.2; p = 0.012). Fasciocutaneous flaps were successfully salvaged more often than muscle-based flaps (p < 0.001). Multivariable regression strongly demonstrated higher risk of take-back failure for muscle flaps (relative risk, 9.42; p = 0.001), despite higher take-back rates among fasciocutaneous flaps (relative risk, 2.28; p = 0.004). CONCLUSIONS: Compared with muscle-based flaps, fasciocutaneous flaps demonstrated earlier and more frequent take-backs for suspected vascular compromise, with higher successful take-back salvage rates. Furthermore, muscle flaps with skin paddles also demonstrated better salvage outcomes than those without. These findings may reflect a combination of lower metabolic demand and easier visual recognition of vascular compromise in fasciocutaneous tissue. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 29697630 TI - Photoacoustic Tomography Shows the Branching Pattern of Anterolateral Thigh Perforators In Vivo. AB - : The distal branching pattern of perforators is associated with thin anterolateral thigh flap failure. The purpose of this study was to investigate the feasibility of using photoacoustic tomography as a diagnostic imaging modality to identify anterolateral thigh perforators and their branching patterns in the subcutaneous layer. Ten thighs in five healthy men were studied. The anterolateral aspect of the midthigh was examined using photoacoustic tomography. The correlation between photoacoustic tomography and ultrasound findings was evaluated. To determine the detectability of photoacoustic tomography by depth, the depth of vessels in the stem portion was compared to the depth of the deep fascia measured by ultrasound. Branching patterns of vessels in the adipose and suprafascial layers were evaluated by three-dimensional observation. A total of 18 perforators were visualized by photoacoustic tomography. Photoacoustic tomography and ultrasound had comparable diagnostic potential for the detection of perforators. Photoacoustic tomography visualized microvessels in the subcutaneous layer, especially those in oblique or horizontal orientations. The estimated mean depth of visualized vessels was 9 mm; the maximum depth was 13 mm. There was a strong correlation between the depth of visualized vessels in the stem portion and the depth of the deep fascia. Three-dimensional observation of photoacoustic tomographic images showed the branching morphology of perforators. This study showed the applicability of photoacoustic tomography to identification of the branching patterns of anterolateral thigh perforators in vivo, although limited visualization of subfascial vessels is a technical issue. The authors believe that photoacoustic tomography has the potential to be a new imaging modality for thin anterolateral thigh flap surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, IV. PMID- 29697631 TI - Facial Fractures: Pearls and Perspectives. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Describe the A-frame configuration of anterior facial buttresses, recognize the importance of restoring anterior projection in frontal sinus fractures, and describe an alternative design and donor site of pericranial flaps in frontal sinus fractures. 2. Describe the symptoms and cause of pseudo-Brown syndrome, describe the anatomy and placement of a buttress-spanning plate in nasoorbitoethmoid fractures, and identify appropriate nasal support alternatives for nasoorbitoethmoid fractures. 3. Describe the benefits and disadvantages of different lower lid approaches to the orbital floor and inferior rim, identify late exophthalmos as a complication of reconstructing the orbital floor with nonporous alloplast, and select implant type and size for correction of secondary enophthalmos. 4. Describe closed reduction of low-energy zygomatic body fractures with the Gillies approach and identify situations where internal fixation may be unnecessary, identify situations where plating the inferior orbital rim may be avoided, and select fixation points for osteosynthesis of uncomplicated displaced zygomatic fractures. 5. Understand indications and complications of use for intermaxillary screw systems, understand sequencing panfacial fractures, describe the sulcular approach to mandible fractures, and describe principles and techniques of facial reconstruction after self-inflicted firearm injuries. SUMMARY: Treating patients with facial trauma remains a core component of plastic surgery and a significant part of the value of a plastic surgeon to a health system. PMID- 29697632 TI - Addressing the Opioid Epidemic: A Review of the Role of Plastic Surgery. AB - The opioid epidemic has been a growing public health threat in the United States and Canada for the past 30 years, with alarming and steadily increasing opioid related mortality rates. Originating with well-intentioned efforts by physicians to relieve pain and suffering in their patients, the source of the opioid epidemic and much of its ammunition continues to be the sales of legally produced pharmaceutical opioids. Although surgeons are increasingly recognizing the important role they can play in mitigating this crisis, the recognition and evaluation of the opioid epidemic in plastic surgery has been lacking. The authors identified several aspects of plastic surgery that make judicious prescription of opioids in this field uniquely complex, including high variability of cases managed, large volume of ambulatory procedures, and frequent involvement in collaborative care with other surgical specialties. Additional research in plastic surgery is needed to both increase current knowledge of opioid prescribing practices and provide evidence for recommendations that can successfully combat the opioid epidemic. PMID- 29697633 TI - Evaluating the July Phenomenon in Plastic Surgery: A National Surgical Quality Improvement Program Analysis. AB - BACKGROUND: The perception that complications are more frequent earlier in the medical academic year, known as the "July phenomenon," has been studied in several specialties, with conflicting results. This phenomenon has yet to be studied in plastic surgery; therefore, this study sought to evaluate the presence of the July phenomenon within plastic surgery. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was accessed, and cases from 2005 to 2014 where "plastic surgery" was listed as the surgical specialty were identified. Only cases with trainee involvement were included for analysis. Included cases were stratified into two groups based on calendar-year quarter of admission. The quarter-3 group included 2451 cases performed during July to September of each calendar year, and the remaining-quarters group included 7131 cases performed in the remaining quarters of each calendar year. Complication rates for 24 complications of interest for quarter-3 and remaining quarters cases with trainee involvement were calculated, chi-square analysis was used to compare complication rates between groups. Multivariate regression analysis was performed to control for potential confounders. RESULTS: Comparison of complication rates within operations with trainee involvement showed a statistically significant increase in quarter-3 versus remaining-quarters groups for superficial wound infection (0.032 versus 0.023; p = 0.046) and wound dehiscence (0.010 versus 0.006; p = 0.034). No significant difference was found for the remaining 22 complications evaluated. CONCLUSION: This study of a nationwide surgical database found that for the vast majority of complications coded in the database, the rates do not increase in the beginning of the academic year. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 29697634 TI - Discussion: Evaluating the July Phenomenon in Plastic Surgery: A National Surgical Quality Improvement Program Analysis. PMID- 29697635 TI - Trends in Accreditation Council for Graduate Medical Education Accreditation for Subspecialty Fellowship Training in Plastic Surgery. AB - BACKGROUND: The purposes of this study were to (1) determine the proportion of plastic surgery residents pursuing subspecialty training relative to other surgical specialties, and (2) analyze trends in Accreditation Council for Graduate Medical Education accreditation of plastic surgery subspecialty fellowship programs. METHODS: The American Medical Association provided data on career intentions of surgical chief residents graduating from 2014 to 2016. The percentage of residents pursuing fellowship training was compared by specialty. Trends in the proportion of accredited fellowship programs in craniofacial surgery, hand surgery, and microsurgery were analyzed. The percentage of accredited programs was compared between subspecialties with added-certification options (hand surgery) and subspecialties without added-certification options (craniofacial surgery and microsurgery). RESULTS: Most integrated and independent plastic surgery residents pursued fellowship training (61.8 percent versus 49.6 percent; p = 0.014). Differences existed by specialty from a high in orthopedic surgery (90.8 percent) to a low in colon and rectal surgery (3.2 percent). From 2005 to 2015, the percentage of accredited craniofacial fellowship programs increased, but was not significant (from 27.8 percent to 33.3 percent; p = 0.386). For hand surgery, the proportion of accredited programs that were plastic surgery (p = 0.755) and orthopedic surgery (p = 0.253) was stable, whereas general surgery decreased (p = 0.010). Subspecialty areas with added certification options had more accredited fellowships than those without (100 percent versus 19.2 percent; p < 0.001). CONCLUSION: There has been slow adoption of accreditation among plastic surgery subspecialty fellowships, but added certification options appear to be highly correlated. PMID- 29697636 TI - The Evolving Presence of Women in Academic Plastic Surgery: A Study of the Past 40 Years. AB - BACKGROUND: Among surgical subspecialties, plastic surgery holds the highest percentage of women, and, the female contingent of board-certified plastic surgeons and trainees has grown steadily. However, their academic impact has been underestimated. We present the academic footprint of female plastic surgeons over the past 40 years. METHODS: A list of female plastic surgeons currently active at, and retired from, Accreditation Council for Graduate Medical Education accredited plastic surgery residency programs was compiled. Each surgeon was searched on PubMed to gather their total number of publications, journals, and topics of research after completion of training. Date of publication and 5-year impact factor for each journal were recorded. Publications were organized into 10 year periods (1976 to 1985, 1986 to 1995, 1996 to 2005, and 2006 to 2016). RESULTS: One hundred fifty-five currently active and 80 retired academic female plastic surgeons were identified, who published 2982 articles in 479 peer reviewed journals. The average 5-year impact factor was 4.093. The number of publications increased with each decade: 37 (1976 to 1985), 218 (1986 to 1995), 472 (1996 to 2005), and 2255 (2006 to 2016). The most commonly published areas were hand/nerve (22 percent), craniofacial (21 percent), and breast (20 percent). Over time, publications in hand/nerve research decreased (76, 60, 38, and 14 percent, respectively); craniofacial-related publications increased (8, 11, 18, and 23 percent, respectively); and publications in breast research increased (0, 8, 9, and 24 percent, respectively). The 2006 to 2016 period yielded the most even distribution of research topics. CONCLUSION: The academic contribution of female plastic surgeons has substantially increased in number and has become more evenly distributed across subspecialty topics. PMID- 29697637 TI - Impact of a Cleft and Craniofacial Center on an Academic Health System: Correction. PMID- 29697638 TI - Reply: Impact of Evolving Radiation Therapy Techniques on Implant-Based Breast Reconstruction. PMID- 29697639 TI - 22 Cases of Breast Implant-Associated ALCL: Awareness and Outcome Tracking from the Italian Ministry of Health. PMID- 29697640 TI - Reply: 22 Cases of Breast Implant-Associated ALCL: Awareness and Outcome Tracking from the Italian Ministry of Health. PMID- 29697641 TI - Defining the Role of Secondary Intention Healing in Full-Thickness Lid Margin Defects. PMID- 29697642 TI - Reply: Defining the Role of Secondary Intention Healing in Full-Thickness Lid Margin Defects. PMID- 29697643 TI - Vectra 3D Imaging for Quantitative Volumetric Analysis of the Upper Limb: A Feasibility Study for Tracking Outcomes of Lymphedema Treatment. PMID- 29697644 TI - Reply: Vectra 3D Imaging for Quantitative Volumetric Analysis of the Upper Limb: A Feasibility Study for Tracking Outcomes of Lymphedema Treatment. PMID- 29697645 TI - [The influence of central auditory processing on the intelligibility of the speech in the patients presenting with hearing impairment]. AB - The objective of the present study was to evaluate to what degree the function of the central auditory pathways influences the intelligibility of the speech in the patients suffering from the sensorineural loss of hearing (SNLH). The study included a total of 20 patients at the age varying from 31 to 80 years presenting with moderate to moderately severe symmetrical SNLN. All the patients were permanent hearing aid users. They underwent the standard audiological examination including pure-tone threshold and suprathreshold audimetries together with impedancemetry, the evaluation of the functional ability of the central auditory pathways with special reference to temporal resolution and differential frequency sensitivity, binaural integration, and the ability to distinguish a sound stimulus against the background noise. It has been found that the impaired intelligibility of the speech and the decreased efficiency of the hearing aids in the patients presenting with SNLH were attributable to the central auditory pathway disorders detected in 50% of the participants in the study. The strong correlation between the results of detection of the stimulus under conditions of tonal signal interference, the binaural integration test, and intelligibility of the speech in the users of hearing aids was documented. PMID- 29697646 TI - [The hearing function in the premature children following their treatment with the use of ototoxic antibiotics]. AB - The objective of the present study was the evaluation of the state of the auditory function in the premature children during the first year of life who underwent the neonatal treatment with various ototoxic antibiotics. A total of 232 newborn infants were available for the examination by the methods designed for recording distortion product optoacoustic emission (DPOAE) and short-latency auditory evoked potentials (SAEPs). The 'Statgraphics Centurion XV' program was used for the statistical treatment of the data obtained in the study. The results of recording DPOAE and SAEPs in 232 prematurely born children of different gestational age were used to evaluate their auditory function under conditions of treatment with various ototoxic antibiotics during the early neonatal period. It was shown that such treatment is likely to have an impact on the hearing function of premature children throughout the entire first year of life. Such influence can manifest itself as the enhanced threshold of the appearance of SAEPs peak V and the selective distortion of evoked responses recorded with the help of the DPOAE technique at a frequency of 4.6 kHz. It is concluded that all prematurely born children should be under observation of an otorhinolaryngologist-surdologist throughout the entire first year of life and, if appropriate, undergo the rehabilitative treatment at the earliest possible time. Moreover, the children with this condition must remain under the thorough follow-up care during at least 3 years including the yearly audiological evaluation and the comparative analysis of the results of previous observations for the timely identification of possible disturbances in the hearing function. PMID- 29697647 TI - [The role of gastroesophageal reflux disease in the development of chronic exudative otitis media in the children during the first year of life]. AB - The objective of the present study was the determination of the incidence of gastroesophageal reflux disease and the evaluation of its possible influence on the development and duration of chronic exudative otitis media in the children during the first year of life. A total of 141 infants at the age of 3 months presenting with exudative otitis media refractory to the conservative treatment throughout the first 1-1.5 months of life were available for the examination. The effectiveness of the anti-reflux therapy was estimated based on the middle ear condition (the presence or absence of exudate) within 3 and 6 months after the initiation of the treatment. The signs of aspiration of gastric chimus and gastroesophageal reflux disease were documented in 92% of the cases. The anti reflux treatment during 3 months resulted in the disappearance of the manifestations of exudative otitis media in 43% of the patients. The further prolongation of such therapy up to 6 months allowed to normalize the state of the middle ear in 69% of the children although the remaining 40% failed to respond. It is concluded that the treatment of the children presenting with exudative otitis media during first year of life should be performed taking into consideration the possible involvement of gastroesophageal reflux disease in pathogenesis of this pathological condition. PMID- 29697648 TI - [The interdisciplinary approach to the rehabilitation of the patients presenting with congenital atresia of the external auditory canal and the concomitant microtia]. AB - The objective of the present study was to develop and introduce into the clinical practice the method for the combined aesthetic and functional rehabilitation of the patients presenting with congenital atresia of the external auditory canal (CAEAC) and the concomitant microtia. A total of 8 patients at the age from 6 to 21 years with unilateral CAEAC and microtia were given the surgical treatment. During the intervention, atresia was resolved using the trans-mastoid approach, tympanoplasty of autofasciae and ossiculoplasty making use of the partial titanium prosthesis and the placement of cranial osteointegratable titanium implants. At the second stage of the surgical intervention the 3D silicone prosthesis of the auricle shaped on an individual basis were used. The long-term follow-up observations have demonstrated the stable formation of the tube of the external auditory canal, with the bone-air interval amounting to 15-20 dB. The auricular prosthesis was the mirror image of the natural ear and completely concealed the congenital defect. PMID- 29697649 TI - [The importance of the joint work of an audiologist and a teacher of the deaf and hard-of-hearing subjects for the adjustment of the cochlear implant systems]. PMID- 29697650 TI - [The rehabilitation of the children with a cochlear implant as a way to the promotion of the natural development of the auditory perception, communication, and speech]. AB - The objective of the present study was to substantiate and present the new approach to the rehabilitation of the children with cochlear implants (CI), the so-called ZP-rehabilitation, with special reference to its principal systemic differences from the 'hearing-speech' rehabilitation. The new method was tested in the course of rehabilitation of 90 deaf and dumb children having cochlear implants since the early and preschool age with the participation of 152 members of their families. As a result of the rehabilitative treatment, all the children included in the study were put on the way of the natural (normal) development of the auditory perception, communication, and speech while all the adults could communicate with the children on the natural sensory basis. It is concluded that the ZP-rehabilitation enables the child with a cochlear implant to embark on the path of the natural (normal) development and to pass (on the new natural sensory basis) through those early stages of ontogenesis that the deaf and dumb child and his relatives had gone through during the preceding period; moreover it helps to rearrange the relations between the child and his family on this new sensory basis. PMID- 29697651 TI - [The specific pathogenetic features of the development of chronic tonsillar pathology]. AB - The authors discuss the mechanisms underlying the development of chronic tonsillar pathology confirmed by the methods of histological, autoradiographic, and bacteriological diagnostics. The new aspects of vital activity of microorganisms in the parenchymal tissue of the palatine tonsils are highlighted that account for the low effectiveness of the conservative therapy of chronic tonsillitis and give evidence of the necessity of the surgical treatment of this condition. PMID- 29697652 TI - [The distribution of interleukins and cytokines in the mucous membranes of the nose and the nasopharynx in the patients presenting with the post-nasal drip syndrome]. AB - The objective of the present study was to elucidate the distribution of interleukins and cytokines in the mucous membranes of the nose and the nasopharynx in the patients presenting with the post-nasal drip syndrome. The study included 20 patients with this pathological condition and 20 volunteers who comprised the control group. The samples of the mucous membranes of the nose and the nasopharynx were examined with the use of the immunohistochemical methods to identify the protein gene product 9.5, interleukin-6, interleukin-10, the tumour necrosis factor-alpha, nuclear factor-kB, and beta-defensin. It was shown that the post-nasal drip syndrome is characterized by the enhanced content of the protein gene product 9.5, interleukin-6, interleukin-10, the tumour necrosis factor-alpha, nuclear factor-kB, and beta-defensin in the mucous membranes of the nose and the nasopharynx. PMID- 29697653 TI - [The heredity and the curvature of the nasal septum in the children]. AB - The objective of the present study was to elucidate the role of genetic and environmental factors in the development of the curvature of the nasal septum in the children by means of the twin method. A total of 171 twins were examined during the study. They included 27 pairs of monozygotic (MZ) twins and 1 triplet. There were 87 boys and 84 girls. All of them were distributed by age as follows: group 1 (3-7 years) - 97 children, group II (8-11 years) - 34 children, group III (12-15 years) - 40 adolescents. Taken together, the members of these groups accounted for 56.7%, 19.9%, and 23.4% of the participants of the study respectively. The prevalence of the nasal septum curvature among the children born after multiple pregnancies (MZ and dizygotic (DZ) twins) with such ENT pathology as the curvature of the nasal septum was estimated at 68.5% and 47.6% respectively. The intraparallel correlation analysis showed that both twins of a MZ pair presented with the curvature of the nasal septum in 12 (30.7%) pairs. The study has demonstrated the statistically significant difference in the frequency of concurrence of the nasal septum curvature between MZ and DZ twins (p=0.005). It is concluded that the results of the study give evidence that heredity and genetic factors greatly contribute to the formation of the curvature of the nasal septum in the children. PMID- 29697654 TI - [The specific features of the clinical course and the treatment strategy in the children presenting with viral sinusitis]. AB - The objective of the present study was to elucidate the peculiar features of acute viral and bacterial sinusitis in the children and to elaborate the algorithm for their treatment based on the results of the primary clinical and laboratory examination. As many as 224 children at the age varying from 1-17 years suffering from acute sinusitis were enrolled in the study. The following methods were employed for the purpose of the study; the analysis of the medical histories of the patients, general examination by an otorhinolaryngologist, diagnostic endoscopy of the nasal cavity and nasopharynx, radiological studies and computed tomography of the paranasal sinuses, echosinusoscopy, the comprehensive microbiological and virological investigation, and evaluation of the peripheral blood characteristics. The study allowed to elucidate the main clinical specific features of acute sinusitis of different etiology including the virological one. The scoring system for the estimation of the risk of development of acute bacterial sinusitis was proposed and the algorithm was developed for the treatment of the children suffering from acute sinusitis to be used in the practical work by general practitioners and otorhinolaryngologists. PMID- 29697655 TI - [About the safety of application of nasal decongestants in the practice of pediatricians]. AB - Undesirable effects of the application of the intransal vasoconstricting medications are a frequent occurrence in the pediatric practice. The objective of the present study was to evaluate the role of the intranasal vasoconstricting medications in the structure of the means and methods currently available for the treatment of toxicological pathologies based at a multi-field clinical hospital. The retrospective analysis of the medical histories of the patients admitted to the toxicological department and annual reports for the period from 2015 to 2016 was undertaken. The study has demonstrated that intoxication associated with the use of the intranasal vasoconstricting medications was the most common cause of hospitalization of the children in the toxicological departments. Intoxication of this origin accounted for 15-20% of the total number of toxicological pathologies among the children. The cases of intoxication are most frequently documented in the group of children at the age between 1 and 3 years. The risk of the undesirable serious complications is especially high after the application of naphazoline-based intranasal vasoconstricting medications (71.7-77.4% of all the cases of intoxication with these products). It is concluded that the use of intranasal vasoconstricting medications in the pediatric practice should be carried out under the strict control, with the naphazoline-based preparations being totally excluded from the application. PMID- 29697656 TI - [A case of the fracture of the temporal bone pyramid resulting in the fatal outcome]. AB - The authors report a clinical case of the fracture of the base of the skull with the concomitant damage to the sigmoid sinus, jugular vein, and internal carotid artery in the temporal bone pyramid. The injury was associated with massive bleeding from the external acoustic canal that resulted in the death of the patient. PMID- 29697657 TI - [A clinical observation of laryngeal chondrosarcoma]. PMID- 29697658 TI - [The patulous Eustachian tube syndrome: the current state of the problem and our own clinical observation. Part 1]. AB - The patulous Eustachian tube syndrome was described more than 150 years ago, but up to the present time some of its aspects continue to be a challenge for both fundamental and clinical medicine. Certain issues of etiology and pathogenesis of this condition have until recently remained unclear which probably accounts for the failure of choosing the adequate methods for its medical correction. Despite the seemingly broad spectrum of the modern tools for the purpose including first and foremost the endoscopic and radiological techniques, verification of the patulous Eustachian tube may encounter difficulties for the specialists. In connection with this, we have undertaken to summarize the views and opinions as regards the syndrome of interest available in the relevant world literature. In the first part of this communication, the authors discuss the modern concepts of etiology and pathogenesis of the patulous Eustachian tube syndrome with special reference to its clinical manifestations and methods of diagnostics. PMID- 29697659 TI - [Myoclonus of the middle ear]. AB - The objective of the present study was to overview the foreign literature concerning middle ear myoclonus (MEM) known to be the most common cause of the manifestations of objective tinnitus. The authors reports two typical clinical cases of myoclonus of the middle ear. The present article is aimed at the enhancement of the awareness of the otorhinolaryngologists, audiologists, and neurologists of the condition of interest as a way to promote the further progress in its treatment. PMID- 29697660 TI - [The topographical and anatomical characteristic of the anterior part of the external auditory passage and the tympanic cavity]. AB - The objective of the present work was to overview the currently available literature data on microtopographic anatomy of the anterior portion of the middle ear and the external auditory passage. Manipulations on these structures during miringoplasty surgery appear to be the most difficult and laborious operations because this space is anatomically very narrow and curved; moreover, it contains the important intimate structures of the middle ear and is located very close to the temporomandibular joint. The knowledge of microsurgical anatomy of the anterior part of the middle ear and the external auditory passage is paramount in the context of the improvement of the professional skills of the surgeons. The current literature data provide a basis for the conclusion that many aspects of microsurgical anatomy of the anterior part of the tympanic cavity and the external auditory passage thus far remain poorly explored. This assertion is especially true as regards the relief of the mucous membrane overlying these structure and their supply with arterial blood. Further clarification of these aspects is needed. PMID- 29697661 TI - [The immunological consequences and risks of adenoidectomy]. AB - The objective of the present review article was the analysis of the potential risks and negative consequences associated with the surgical treatment of adenoids and the comparison of the potential harm to health and effectiveness of adenoidectomy for the children. It is concluded, based on the currently available information, that adenoidectomy provides an efficient surgical method for the management of the problems associated with adenoid pathology. The application of this technique based on the proper medical indications has no adverse effects on the children's health conditions and the mechanisms of immune protection. Moreover, it contributes to the improvement of the quality of life of the patients, fosters their physical and mental development. PMID- 29697662 TI - [The peculiar features of epidemiology and clinical course of syphilis encountered in the otorhinolaryngological practice under the present-day conditions]. AB - The article was designed to report the available information about the main characteristics of epidemiology and pathomorphism of syphilis. It describes the process of development and clinical symptoms of syphilis, both classical and undergoing modification, under the present-day conditions, with special reference to the distinctive features and peculiarities of ENT organ lesions with the underlying syphilitic etiology. PMID- 29697663 TI - [Professor Abas Mekhti Ogly Talyshinsky, the founder of the Ryazan school of otorhinolaringology]. PMID- 29697664 TI - [The increasing importance of extragenital pathology in the structure of maternal mortality in Russia]. AB - OBJECTIVE: to determine the proportion of direct obstetric and indirect extragenital causes of maternal deaths in Russia in recent years. MATERIAL AND METHODS: Official statistical data on maternal mortality in Russia were analyzed according to the criteria of the 10th revision of the International Classification of Diseases and compared with those in European countries and the USA. RESULTS: In the past 10 years, Russia has registered a gradual decline in the single maternal mortality rate: 27.7 in 2005, 18.6 in 2010, 12.9 in 2013, 11.9 in 2014, 10.7 in 2015, and 8.3 in 2016 per 100,000 live births. This was mainly due to a substantial decrease in obstetric losses and to the expansion of a network of well-equipped perinatal centers. Stabilization of the proportion of extragenital causes was simultaneously found. Among them in 2014, cardiovascular diseases were a dominant cause of death (51.7%), followed by respiratory diseases (29.8%) and digestive diseases and other conditions (18.2%). The demographic, socioeconomic, and medical conditions for extragenital causes were analyzed and compared with those in European countries and the USA. Recommendations were given to improve the postmortem analysis of maternal deaths in Russia. CONCLUSION: It is necessary to improve the postmortem diagnosis of the direct and indirect causes of maternal deaths and to ensure the quality and completeness of autopsies in deceased women. PMID- 29697665 TI - [Preventability of perinatal losses by the example of the large industrial cities Chelyabinsk and Novosibirsk]. AB - : Perinatal mortality rate is an indicator that characterizes the quality of medical care, as well as the social and economic situation in the region. OBJECTIVE: to audit perinatal losses in large regional centers of the Russian Federation with a population of over 1 million inhabitants, such as Chelyabinsk and Novosibirsk. MATERIAL AND METHODS: A comprehensive postmortem examination of 309 cases of perinatal losses in 2016 was made, which was supplemented with an assessment of preventability according to the Scandinavian-Baltic classification. RESULTS: The rate of preventable deaths in Chelyabinsk and Novosibirsk amounted to 91 and 81.5% of cases, respectively; the deaths were due to stillbirths at more than 28 weeks' gestation and to dead newborns in almost half of cases. The proportion of intranatal deaths was shown to increase in Chelyabinsk; the number of neonatal deaths at more than 33 weeks' gestation rose in Novosibirsk. CONCLUSION: Supplementing the traditional clinical and postmortem analysis with an assessment of the preventability of perinatal loss makes it possible to ensure a unified approach to evaluating these conditions and the comparability of autopsy results in different subjects of the Russian Federation and to determine regional reserves for reducing perinatal mortality rates. PMID- 29697666 TI - [The clinical and anatomical aspects of preeclampsia: current features of its course]. AB - : Preeclampsia is the most menacing complication of pregnancy and childbirth worldwide and remains one of the leading causes of maternal and perinatal morbidity and mortality. It is characterized by a complex etiopathogenesis with specific clinical and laboratory changes (hypertension, proteinuria and edema), as well as by the morphological pattern of target organ damage and uteroplacental blood vascular lesions. However, the triad of clinical signs of preeclampsia is not encountered in all cases now. OBJECTIVE: to study the clinical and anatomical aspects of preeclampsia at the present stage. MATERIAL AND METHODS: 17 maternal deaths due to preeclampsia were studied at the medical institutions of the Moscow Healthcare Department from 2012 to the first half of 2017 through postmortem examination at City Clinical Hospital Thirty-One, Moscow Healthcare Department. RESULTS: This analysis showed the atypical course of preeclampsia (without substantial blood pressure elevations, with mild/moderate proteinuria, but almost always with edema). The characteristic feature is a laboratory sign, such as thrombocytopenia and liver enzyme dysfunction. Morphological examination of deceased patients showed that almost half of the cases had brain hemorrhages of different localization and size; in most cases, renal changes corresponded to the pattern of a shock kidney with endotheliosis and frequently with cortical necroses. The liver was characterized by a considerable increase in size with the development of fatty dystrophy, centrolobular necroses and hemorrhages; there were metabolic damage foci in the heart in almost half of the cases, as well as signs of disseminated intravascular coagulation with numerous hemorrhages in the organs and tissues. CONCLUSION: Characteristic uteroplacental artery morphological changes in both the surgical and autopsy material render a leading assistance in the diagnosis of preeclampsia/eclampsia. PMID- 29697667 TI - [Features of the pathogenesis of the placenta growing in the scar after cesarean section]. AB - OBJECTIVE: to investigate the structural and pathogenetic features of pathological placental attachment in the scar after cesarean section. MATERIAL AND METHODS: The investigators explored 12 uteri; 11 of which were removed with placentas at 9 to 38 weeks' gestation (one in the first trimester, three at 18-22 weeks, two at 32-35 weeks, and five at 37-38 weeks); one uterus was removed after an artificial abortion at 12 weeks' gestation in the scar, as well as the scars excised in the first trimester in non-developing (n=4) and progressive (n=2) pregnancies. For histological examination, fragments of the full-thickness uterine wall were taken from the placental bed in different areas. The sections were stained for fibrin with hematoxylin and eosin, van Gieson stain, and the Martius scarlet/blue (MSB) technique. Decidual tissue, trophoblast, vascular component, and smooth muscle tissue were identified by an immunohistochemical assay using antibodies to vimentin, pan-cytokeratin, vascular endothelium (SD31), and smooth muscle actin. RESULTS: In most cases, placental localization in the scar after cesarean section was accompanied by abnormal placental attachment: almost always placenta accreta, less frequently in combination with its ingrowth (placenta accreta/increta). The morphological substrate of placenta increta was a change in the content and ratio of normal histological components in the uterine wall, such as the mucosa, smooth muscle tissue, and vessels (the absence or thinning of decidual tissue and the myometrium, as well as its cicatricial changes). The structural criterion for placenta increta was necrosis of the walls of the large veins in the myometrium due to the replacement of their intermediate trophoblast and fibrin and to the destruction of vessel walls, leading to prolapse of the chorionic villi into the veins. CONCLUSION: In most cases, placental localization in the scar after cesarean section is accompanied by abnormal placental attachment: placenta accreta, less frequently in combination with its ingrowth (placenta accreta/increta). PMID- 29697668 TI - [Morphometric characteristics of neovascularization of carotid atherosclerotic plaques]. AB - OBJECTIVE: to identify the relationship between the magnitude of neovascularization of an atherosclerotic plaque and its other processes, such as atheromatosis, macrophage responses, hemorrhages, and calcification. MATERIAL AND METHODS: 48 carotid atherosclerotic plaques all their way underwent morphopathological examination, by assessing the magnitude of neovascularization (total vessel density per plague cm2; density of vessels of different diameters; localization in section), atheromatosis (a volume fraction), foam cells (a score of 0 to 5), hemorrhages (a score of 0 to 4), and calcification (a score of 0 to 4). The Mann-Whitney U test and the Spearman correlation coefficient with p<0.05 were used in the statistical analysis. RESULTS: There was a substantial variability in vessel diameters and densities in the plaque with a drastic predominance of vessels smaller than 20 um in diameter (69.8+/-14.3%). The vessels with a diameter as large as 20 um were more frequently located in the area of accumulation of foam cells or organizing hemorrhages (p<0.03), unlike those with a diameter of more than 40 um, which were more common in the areas of connective tissue, especially adjacent to large calcifications, and in the foci of organized hemorrhages (p<0.008). Intensified calcification was accompanied by the higher density of vessels having a diameter of more than 40 um (p<0.038) and particularly of those with a diameter of more than 60 um (p=0.006). The degree of hemorrhages and the number of foam cells were unrelated to the density of vessels, but these increased with their localization in the surface areas of a plaque (p=0.000342). With the increasing severity of atheromatosis, there was a decrease in the density of vessels larger than 20 um in diameter (p=0.00042). CONCLUSION: The number, diameter, and location of vessels in the plaque serve as a dynamic reflection of its destructive and reparative processes; and a larger number of vessels having a diameter of more than 40 um can be an indicator for the activation of reparative processes. PMID- 29697669 TI - [Trends in stroke mortality rates in Russia and the USA over a 15-year period]. AB - AIM: to comparatively analyze standardized mortality ratios (SMR) from stroke in the populations aged over 30 years in the Russian Federation and in the USA over a 15-year period. MATERIAL AND METHODS: The analysis included nontraumatic subarachnoid hemorrhage (NTSH) (a group of ICD-10 codes I60), nontraumatic intracerebral hemorrhage (NTIH) (I61), cerebral infarction (CI) (I63), and stroke, not specified as hemorrhage or infarction (SNSHI) (I64). The new European standard (European Standard Population.2013) was used for standardization. The data of the Federal State Statistics Service of the Russian Federation, those of the World Health Organization Mortality Database (WHO MD) and Human Mortality Database (HMD) for the USA were applied. RESULTS: During the considered period, 30-49-year-old Russian men showed a reduction in SMRs from NTSH (I61) by 9.0% (from 18.9 to 17.2 per 100,000 population), from SNSHI (I64) by 10 times (from 12.5 to 1.3); SMRs from CI (I63) increased by 4.3% (from 6.9 to 7.2). In men aged 50 years and older, SMRs from NTIH and SNSHI decreased by 32.3% (from 143.2 to 97.0) and by 10 times (from 580.8 to 60.6), respectively; those from CI increased by 13.8% (from 229.8 to 261.4). In the USA, 30-49-year-old men displayed 26.1% and 2-fold decreases in SMRs from NTIH (from 2.5 per 100,000 population in 1999 to 1.7 in 2013) and CI (from 1.8 to 0.9), respectively; those from SNSHI remained unchanged (1.3). In men aged 50 years and older, SMRs from NTIH, CI, and SNSHI reduced by 39.7% (from 29.0 to 17.5), by 2 times (from 1.8 to 0.9), and by 2 times (143.0 to 72.5), respectively. 30-49-year-old Russian women exhibited a 22.2% reduction in SMRs from NTIH (from 9.0 to 7.0), a 4.3% increase in those from CI (from 2.7 to 2.8), and an 11-fold decrease in those from SNSHI (from 5.5 to 0.5). Women aged 50 years and older showed changes in SMRs from the codes in the same sequence from 105.6 to 60.5, from 172.8 to 189.6, and from 466.5 to 43.7, respectively. In the USA, 30-49-year-old women displayed reductions in SMRs from NTIH by 10.0% (from 1.5 to 0.9), from CI by 33.3% (from 0.3 to 0.2), and from SNSHI by 10% (from 1.0 to 0.9). Women aged 50 years and older exhibited changes in SMRs from the codes in the same sequence from 24.0 to 14.8), n those from CI (from 20.6 to 6.7) and from SNSHI (from 6.5 to 10.3). CONCLUSION: In Russia, the reduction in mortality rates from the above causes (which is most significant from that in NTSH may be associated with both medical and socioeconomic factors, including with the improved prevention and organization of medical care. The differences in SMRs between the two countries may be related to the principles in the organization and control of coding of the causes of death. PMID- 29697670 TI - [Comparison of digital and visual methods for Ki-67 assessment in invasive breast carcinomas]. AB - AIM: to compare two methods for quantitative assessment of the proliferative activity index (PAI): a visual estimation method by several investigators and digital image analysis (DIA). The use of the Ki-67 index in the daily clinical practice of a Morbid Anatomy Department is associated with the problem of reproducibility of quantitative assessment of the Ki-67 PAI. Due to the development of digital imaging techniques in morphology, new methods for PAI evaluation using the DIA are proposed. MATERIAL AND METHODS: The Ki-67 PAI data obtained during visual assessment and digital image analysis were compared in 104 cases of grades 2-3 breast carcinoma. The histological sections were scanned using a Panoramic III scanner (3D Histech, Hungary) and digital images were obtained. DIA was carried out using the software 3D Histech QuantCenter (3D Histech, Hungary), by marking 3-10 zones. Evaluation of the obtained sections was done independently by two investigators engaged in cancer pathology. RESULTS: The level of agreement between visual and digital methods did not differ significantly (p>0.001). The authors selected a gray area in the range of 10-35% IPA, where the Ki-67 index showed a weak relationship between the analyzed groups (ICC, 0.47). The Ki67 index below 10% and above 35% showed a sufficient reproducibility in the same laboratory. CONCLUSION: The authors consider that the scanned digital form of a histological section, which can be evaluated using automated software analysis modules, is an independent and objective method to assess proliferative activity for Ki-67 index validation. PMID- 29697671 TI - [Liver disease and maternal mortality]. AB - Liver diseases associated (acute fatty liver of pregnancy) and unassociated (liver hemangioma) with pregnancy and complications due to liver failure are serious conditions and can lead to maternal death. The paper describes two maternal deaths related to liver pathology. PMID- 29697672 TI - [Intrahepatic bile duct hyperplasia in a baby with partial trisomy of the long arm of 17 chromosome]. AB - The paper describes a clinical and anatomical case of partial trisomy of the long arm of 17 chromosome in a baby aged 1 month and 4 days with the karyotype 46,XY, dup(17)(q21q24) from a dichorionic diamniotic twin born after in vitro fertilization. Intrahepatic bile duct hyperplasia was first detected in the patient with this chromosomal abnormality. Histological and immunohistochemical examinations of the liver were conducted using antibodies to Ki-67, CK-pan, CK8, CK 18, Vim, SMA, CD31, CD34, HER-2/neu. PMID- 29697673 TI - [Solitary epithelioid hemangioendothelioma concurrent with nodular parenchymal amyloidosis of the lung and Rosai-Dorfman disease]. AB - The paper describes a case of solitary epithelioid hemangioendothelioma concurrent with nodular parenchymal AL amyloidosis of the lung and Rosai-Dorfman disease in a 70-year-old woman. The core of the tumor was represented by bone tissue with dendriform ossification, as well as by amyloid that showed green apple birefringence at polarized light microscopy. The peripheral portions of the tumor and the myxohyaline stroma exhibited slit-like structures, epithelioid and fusiform cells with small cytoplasmic vacuoles. These cells expressed CD31, CD34, factor VIII, and cytokeratins 7 and 18. The Ki-67 proliferation index was 10%. S100- and CD68-positive histiocytes with the phenomenon of emperipolesis were revealed in the tumor and in the lymph nodes of the mediastinum and lung hilum. There was a positive reaction to immunoglobulin lambda light chains in the lymphocytic infiltration around amyloid clumps. The frequency of epithelioid hemangioendothelioma was less than 1 case per million people annually. We found only one case of its concurrence with pulmonary amyloidosis in the English language literature. No relationship could be revealed between this tumor and Rosai-Dorfman disease. PMID- 29697674 TI - [Pulmonary larval paragonimiasis mimicking lung cancer]. AB - Larval paragonimiasis is a parasitic disease caused by lung fluke larvae. Unlike the classic form of paragonimiasis, the larval form occurs with a large number of clinical manifestations. However, this fact only complicates the diagnosis of larval paragonimiasis, for the abundance of clinical manifestations results in the misdiagnosis of other diseases. Another feature of this form of paragonimiasis is the tendency to generalize and mimic the clinical presentation of malignant neoplasms. The performed diagnostic measures failed to give an accurate view of the nature of the disease, therefore diagnostic thoracoscopy was carried out and biopsy specimens were taken from the subpleural region of dissemination, followed by urgent histologic examination suggestive of glandular cancer. This circumstance became the reason for atypical resection of the affected portion, which was done; however, the patient died from pulmonary thromboembolism on postoperative day 2. The main diagnosis of chronic pulmonary generalized paragonimiasis (cystic and pneumosclerotic phases) with neoplastic syndrome was posthumously made. PMID- 29697675 TI - [Seventh scientific readings dedicated to the memory of Prof. Oleg Konstantinovich Khmelnitsky, Corresponding Member of the Russian Academy of Medical Sciences]. PMID- 29697676 TI - [External quality control of immunohistochemical studies in the Russian Federation. Report on pilot rounds]. PMID- 29697677 TI - [Endovascular procedures in pancreatic surgery]. AB - AIM: To evaluate an effectiveness of endovascular techniques in pancreatic surgery. MATERIAL AND METHODS: For the period 1995-2017 at Vishnevsky Institute of Surgery endovascular treatment (EVT) was applied in 51 patients with chronic pancreatitis complicated by false aneurysms (FA) and postoperative hemorrhage after pancreatectomy. Various methods of embolization and stenting were used in 24 and 11 cases respectively in order to exclude FA of celiac trunk and superior mesenteric artery from blood flow. Endovascular hemostasis for postoperative hemorrhage was carried out with embolization of damaged vessel in 11 patients. Stent-grafts were deployed in 5 patients with marginal defect of the wall of hepatic/superior mesenteric arteries. RESULTS: In all 35 patients with chronic pancreatitis complicated by false aneurysms EVT ensured thrombosis of the aneurysm's cavity. EVT was final in 14 patients with FA and absent communication with pancreatic duct. Radical surgical treatment was required after 7-10 days for FA communicated with pancreatic duct due to lysis of thrombotic masses by pancreatic enzymes. Spleen infarction was diagnosed in 3 patients. Two of them did not require treatment while 1 patient underwent splenectomy in view of splenic abscess. 1 patient died from liver cirrhosis followed by severe hepatic failure, death was not associated with bleeding. In 16 patients with post pancreatectomy bleeding hemostasis was achieved in all cases with EVT. However, recurrent bleeding occurred in 2 patients who underwent successful redo endovascular intervention. Complications after EVT were observed in 2 patients: duodenal wall necrosis followed by fistula which was closed spontaneously (n=1); advanced intestinal infarction (n=1) followed by fatal outcome; pulsating hematoma within cubital fossa that required brachial artery ligation and autovenous bypass. CONCLUSION: EVT provides thrombosis of FAs of celiac trunk and superior mesenteric artery branches in patients with chronic pancreatitis, as well as hemostasis for postoperative bleeding after pancreatectomy. PMID- 29697678 TI - [Pancreatoduodenectomy: learning curve within single multi-field center]. AB - AIM: To analyze learning curve by using of immediate results of pancreatoduodenectomy at multi-field oncology institute. MATERIAL AND METHODS: For the period 2010-2016 at Abdominal Oncology Department of Herzen Moscow Oncology Research Institute 120 pancreatoduodenal resections were consistently performed. All patients were divided into two groups: the first 60 procedures (group A) and subsequent 60 operations (group B). Herewith, first 60 operations were performed within the first 4.5 years of study period, the next 60 operations - within remaining 2.5 years. RESULTS: Learning curves showed significantly variable intraoperative blood loss (1100 ml and 725 ml), surgery time (589 min and 513 min) and postoperative hospital-stay (15 days and 13 days) in group A followed by gradual improvement of these values in group B. Incidence of negative resection margin (R0) was also significantly improved in the last 60 operations (70 and 92%, respectively). CONCLUSION: Despite pancreatoduodenectomy is one of the most difficult surgical interventions in abdominal surgery learning curve will differ from one surgeon to another. PMID- 29697679 TI - [Hybrid repair of postoperative ventral hernia]. AB - AIM: To develop new technique of abdominal wall repair for postoperative ventral hernia without disadvantages which are intrinsic for open and laparoscopic surgery. MATERIAL AND METHODS: Combined open and laparoscopic hernia repair was used in 18 patients with postoperative ventral hernia. Open stage provided safe dissection of abdominal adhesions and defect closure by autoplasty, laparoscopic procedure consisted of prosthesis deployment without separation of abdominal wall layers. Two types of composite endoprostheses with anti-adhesive coating were used for abdominal wall repair. RESULTS: There were no cases of recurrence or infectious complications in long-term period (from 3 to 106 months). CONCLUSION: Hybrid repair of postoperative ventral hernia is safe and effective procedure. Further studies are necessary to assess cost-effectiveness ratio of this method in view of expensive composite endoprostheses and laparoscopic supplies. PMID- 29697680 TI - [Specialist's training for laparoscopic surgery in Wet-lab educational operating theatre]. AB - AIM: To develop system for students training in laparoscopic surgery by using of Wet-lab educational operating theatre. MATERIAL AND METHODS: We have launched laparoscopic surgery teaching program for students of Ryazan State Medical University. This system includes several stages. At the first stage professional selection was carried out on 'dry' laparoscopic simulators among III-IV-year students of medical faculty. So, 10 people were selected. The second stage included theoretical and practical parts consisting of development of basic laparoscopic skills on 'dry' simulators. 5 students who scored the maximum points were admitted to the next stage. The third stage is working in Wet-lab operating theatre with a mentor. There were 10 sessions on 10 laboratory pigs. Final stage of our study compares two groups of participants: main group - 5 students who underwent above-described program and control group of 5 residents without experience for laparoscopic operations. RESULTS: The participants of the main group had significantly higher OSATS score compared with another group (20 vs. 10; p<0.05). Movements effectiveness estimated by measuring of movements trajectory total length was also higher in main group than in control group (6 vs. 20; p<0.05). Experts' subjective assessment according to 10-point scale was also higher for students than for interns (9 vs. 5, p<0.05). Participants in the main group required significantly less time to complete the task compared with the control group (40 vs. 90 minutes, p<0.05). CONCLUSION: Our experience has shown that training system with Wet-lab operating theatre is effective for quick and efficient training of medical students in main laparoscopic procedures. In our opinion, introduction of students into 'advanced' surgery from early age will make it possible to get finally highly professional specialists. PMID- 29697681 TI - [Minimally invasive management of biliary leakage after cholecystectomy]. AB - AIM: To analyze treatment of patients with de novo extrahepatic bile ducts lesions. MATERIAL AND METHODS: The study included 37 patients with post cholecystectomy biliary leakage which was confirmed intraoperatively and in postoperative period. Cystic duct stump failure was observed in 18 (55.3%) patients, marginal damage, complete intersection and excision of extrahepatic bile duct wall occurred in 7 (18.4%), 1 (2.6%) and 1 (2.6%) patients respectively. Injury of the duct of Lyushka was revelaed in 8 (21.1%) patients. RESULTS AND DISCUSSION: Endobiliary stenting was performed in 32 (84.2%) patients. It was final independent method in 5 (13.2%) cases and combined with other procedures in 27 patients (drainage and puncture of bile accumulations (28.9%), laparoscopic external drainage of biliary ducts (42.1%)). The greatest efficacy of these interventions was proved for cystic duct stump failure - 21 of 21 (100.0%), marginal damage of bile ducts - 7% out of 7 (100%), as well as for intersection of ducts of Lychka - 6 out of 8 (75%). CONCLUSION: Complex application of minimally invasive surgical interventions for extrahepatic bile ducts injury after cholecystectomy reduces likelihood of redo biliary surgery and may be independent treatment in some cases. PMID- 29697682 TI - [Choice of surgical tactics in patients with acute cholecystitis complicated by cholelithiasis]. AB - PURPOSE OF THE STUDY: Comparison of the methods of surgical treatment of cholelithiasis. MATERIAL AND METHODS: The work is based on the experience of treating 139 patients with acute cholecystitis complicated by choledocholithiasis from 2008 to 2016, who were on treatment of the department of acute surgical diseases of the liver and pancreas, N.V. Sklifosovsky. RESULTS: The use of percutaneous drainage of the gallbladder in an acute period can reduce complications and reduce the number of urgent video-laparoscopic cholecystectomies to 1%. PMID- 29697683 TI - [Gastroesophageal variceal bleeding in cirrhotic patients: the possibilities of effective hemostasis]. AB - AIM: To improve the results of treatment of gastroesophageal variceal bleeding (GEVB) in cirrhotic patients with thrombocytopenia. MATERIAL AND METHODS: A total experience of the clinic includes 338 GEVB patients, endoscopic variceal ligation (EVL) and transjugular intrahepatic portosystemic shunt (TIPS) were performed in 162 and 157 cases respectively. Nevertheless, just the efficacy of initial pharmacological hemostatic therapy was analyzed. RESULTS: Administration of serotonin adipinate 30-50 mg/day during 3-5 days in addition to standard initial therapy allowed us to achieve permanent hemostasis during initial treatment if EVL was impossible. Serotonin adipinate induces thrombocytes' adhesion and improves fibrin clot strength. This therapy markedly decreases mortality (33.3% vs 46.7%), incidence of recurrent bleeding (46.4% vs 60.0%). Also it contributes successful hemostasis with endoscopic ligation and effective portal decompression by TIPS procedure. PMID- 29697684 TI - [Carotid endarterectomy and stenting in patients with internal carotid artery stenosis and contralateral occlusion]. AB - AIM: To determine surgical risk factors and to compare early outcomes after carotid endarterectomy and carotid stenting in patients with internal carotid artery stenosis and contralateral occlusion. MATERIAL AND METHODS: 132 patients were enrolled. 62 and 70 patients underwent carotid endarterectomy and carotid stenting respectively. Early postoperative results were compared depending on type of surgical intervention and presence of risk factors. RESULTS: Significant difference between groups was only found for incidence of neuropathy of the cranial nerves. It was established that cardiac comorbidities are risk factors for adverse events after carotid endarterectomy. Stable (homogeneous) atherosclerotic plaque with clear contour and no ulceration is optimal for carotid stenting. PMID- 29697685 TI - [Ruptures of popliteal artery aneurysms]. AB - AIM: To improve diagnosis and surgical outcomes in patients with ruptured popliteal artery aneurysm. MATERIAL AND METHODS: Eight patients with ruptured popliteal artery aneurysm have undergone surgery for the period from 1999 to 2015 at the Vascular Surgery Department of Sklifosovsky Research Institute for Emergency Care. Incidence of rupture was 2.9% from total number of popliteal artery aneurysm. 7 patients with rupture had signs of lower limb ischemia (acute form grade I in 2 (25%) cases, grade IIA in 1 (12.5%), grade IIB in 1 (12.5%) case, chronic ischemia grade IIB in 2 (25%) patients, grade III in 1 (12.5%) patient). 1 (12,5%) patient had not lower limb ischemia. Preoperatively all patients underwent sonography of lower limb arteries and soft tissues, computed tomography of the same structures was carried out in 3 patients, 5 patients underwent subtraction digital angiography. Presence and dimensions of soft tissues hematoma, arterial perfusion proximally and distally to popliteal artery, aneurysms of contralateral limb and other localizations were assessed. RESULTS: Amputations after surgical repair were absent in 6 patients. Five patients were discharged with patent graft, completely compensated blood flow and primary healing of postoperative wound. Severe postoperative complications followed by amputation occurred in 2 patients. One patient died with reperfusion syndrome, hematoma and graft infection, sepsis. CONCLUSION: 1) Ruptured popliteal artery aneurysm is extremely rare complication, however it is a formidable event with high risk of amputation and death. 2) Early diagnosis of popliteal artery aneurysm and surgical treatment prior to embolism, thrombosis and rupture are necessary to prevent formidable complications. 3) Timely detection of aneurysms and their complications by general practitioners is extremely low due to rarity and specificity of the disease, presence of various symptoms. It is necessary to popularize knowledge about this disease among general practitioners. 4) Sonography is screening method for differential diagnosis. 5) CT-angiography or subtraction angiography are advisable to assess distal perfusion if patient's state is stable without severe ischemia. 6) Aneurysm repair with popliteal artery replacement should be performed in early period after rupture in order to reduce time of ischemia and to prevent infection of hematoma in view of ischemia and anemia. PMID- 29697686 TI - [Hardware anastomosis in stomach cancer surgery]. AB - AIM: To choose optimal technique of esophagojejunostomy in stomach cancer regarding reliability, functionality and simplicity. MATERIAL AND METHODS: 145 patients with stomach cancer grade I-IV were enrolled. They were divided into 2 groups depending on the type of the anastomosis (manual or hardware). RESULTS: There were no significant differences between groups in the incidence of anastomosis failure, anastomotic stricture and reflux-esophagitis in long-term postoperative period. At the same time, duration of reconstructive stage with hardware anastomosis was 26+/-11.3 min, whereas for manual stage - 72+/-21.9 min (p<0.0001) depending on surgeon's experience. CONCLUSION: Hardware circular anastomosis in most clinical cases is an alternative to conventional manual anastomosis with the same reliability, safety and functionality. Moreover, principles of hardware anastomosis are the same for open and endoscopic surgery that makes this technique universal and necessary for wide development. PMID- 29697687 TI - [Thoracoscopic pulmonary resection for metastatic lesion without pleural drainage: initial experience]. AB - AIM: To analyze the possibility of thoracoscopic pulmonary resection for metastatic lesion without pleural drainage. MATERIAL AND METHODS: There were 10 patients aged 53.8 years. Most of patients had solitary lung injury within 3 cm from the visceral pleura on the average. Surgical treatment was performed in standard fashion: hardware atypical pulmonary resection within healthy tissues. Pleural cavity was drained with 24 Fr tube. After that lung was inflated under visual control. Since wounds were closured residual air was evacuated by active aspiration and drainage tube was removed. Control chest X-ray was performed in 2 hours and 1 day after surgery. RESULTS: The technique was successful in all patients. Mean surgery time was 52 minutes. There was no blood loss in all patients. Pneumo- and/or hydrothorax were absent according to control chest X-ray in postoperative period. Mean length of postoperative hospital-stay was 3 days (median 2 days). There were no cases of repeated hospitalization. PMID- 29697688 TI - [Preventive therapy with mexidol in toxic damage to the heart]. AB - : The purpose of this study was to efficacy of mexidol in the prevention of toxic damage to the heart in acute pancreatitis. MATERIAL AND METHODS: The paper presents the results of experimental studies conducted on 30 adult mongrel adult dogs, which simulated acute focal pancreatic necrosis. We studied the influence of mexidol in the complex therapy for changes in the qualitative and quantitative composition of the lipid tissue structures of the heart, the intensity of processes of lipid peroxidation, antioxidant capacity, phospholipase A2 activity and morphofunctional state of the heart muscle in experimental acute focal pancreatic necrosis. Th. RESULTS AND DISCUSSION: The preventive use of antioxidant drug mexidol in complex treatment of acute focal pancreatic necrosis, which limits the development of endogenous intoxication, increased intensity of lipid peroxidation and restores antioxidant capacity, reduces leading to phospholipase activity in tissue structures of the heart, corrigiruet lipid metabolism and morphofunctional state of the heart, and, consequently, toxic damage to the heart during endotoxic. PMID- 29697689 TI - [Aspects of the importance of postoperative hepatoprotector therapy in urgent surgery]. AB - The purpose of this study was to determine the effect on the effectiveness of the correction of enteric insufficiency syndrome in patients with urgent surgical pathology included in the scheme of complex therapy Remaxol. The results of complex therapy of 227 patients (98 people with common peritonitis and 129 patients with acute intestinal obstruction) were analyzed. 128 patients of the main group in the postoperative period were included in the therapy scheme Remaxol: intravenously drip in a daily dose of 400 ml at a rate of 40 drops per minute, a course of -5 days. Patients of the control group (99 people) received standard treatment. The study is devoted to the role of postoperative hepatoprotective therapy in the treatment of patients with urgent surgical pathology. The main attention is paid to the hepatoenteric link of the pathogenesis of polyorganism insufficiency. This approach gives hope for a reduction in the risk of abdominal sepsis and a reduction in mortality among patients with acute abdominal pathology. The study found that in patients with acute abdominal pathology, an increase in the severity of enteric insufficiency syndrome due to toxic aggression and bacterial translocation can lead to hepatic dysfunction. Consequently, the implementation of hepatoprotective therapy is a pathogenetic link in the complex treatment of urgent surgical patients. The obtained results allowed to draw a number of conclusions. In particular, it has been established that the use of hepatoprotective therapy in the complex medical treatment of patients with acute abdominal pathology makes it possible to stop hepatorenal syndrome by the 5th day, and the syndrome of enteric insufficiency by the 7th day. Earlier relief of hepatic dysfunction and enteral insufficiency syndrome due to hepatoprotective therapy allowed to reduce the incidence of infectious complications to 9.7%, to reduce the lethality to 9.4% and to shorten hospitalization from 17.29 to 1.734 to 12.14+/-1.385 bed/day. PMID- 29697690 TI - [Postoperative sternomediastinitis]. PMID- 29697691 TI - [Intestinal obstruction in early postoperative period after robot-assisted prostatectomy]. PMID- 29697692 TI - [Physical minimally invasive treatment of pancreatic insulinoma]. PMID- 29697693 TI - [Multiple primary neoplasia of kidney, prostate and colon]. PMID- 29697694 TI - [Treatment of hematogenous osteomyelitis of the femur complicated by pathological fracture]. PMID- 29697695 TI - Exploring the relationship between stress and acne: a medical student's perspective. PMID- 29697696 TI - The value of near-peer teaching in the medical curriculum: a medical student's perspective. PMID- 29697697 TI - Ice Sheet Model Intercomparison Project (ISMIP6) contribution to CMIP6. AB - Reducing the uncertainty in the past, present and future contribution of ice sheets to sea-level change requires a coordinated effort between the climate and glaciology communities. The Ice Sheet Model Intercomparison Project for CMIP6 (ISMIP6) is the primary activity within the Coupled Model Intercomparison Project - phase 6 (CMIP6) focusing on the Greenland and Antarctic Ice Sheets. In this paper, we describe the framework for ISMIP6 and its relationship to other activities within CMIP6. The ISMIP6 experimental design relies on CMIP6 climate models and includes, for the first time within CMIP, coupled ice sheet - climate models as well as standalone ice sheet models. To facilitate analysis of the multi-model ensemble and to generate a set of standard climate inputs for standalone ice sheet models, ISMIP6 defines a protocol for all variables related to ice sheets. ISMIP6 will provide a basis for investigating the feedbacks, impacts, and sea-level changes associated with dynamic ice sheets and for quantifying the uncertainty in ice-sheet-sourced global sea-level change. PMID- 29697698 TI - Retraction: Curcumin-Free Turmeric Exhibits Activity against Human HCT-116 Colon Tumor Xenograft: Comparison with Curcumin and Whole Turmeric. AB - [This retracts the article on p. 871 in vol. 8, PMID: 29311914.]. PMID- 29697699 TI - Corrigendum: Unifying Speed-Accuracy Trade-Off and Cost-Benefit Trade-Off in Human Reaching Movements. AB - [This corrects the article on p. 615 in vol. 11, PMID: 29379424.]. PMID- 29697700 TI - Subcutaneous to visceral fat ratio: a possible risk factor for metabolic syndrome and cardiovascular diseases. PMID- 29697701 TI - Correction to: T cell leukemia control via Ras-Raf pathway inhibition with peptides. AB - [This corrects the article on p. 172 in vol. 10, PMID: 29075346.]. PMID- 29697702 TI - Statin on insulin and adiponectin levels: true or false prophecy? PMID- 29697703 TI - Corrigendum: Inulin-Type Fructans Modulates Pancreatic-Gut Innate Immune Responses and Gut Barrier Integrity during Experimental Acute Pancreatitis in a Chain Length-Dependent Manner. AB - [This corrects the article on p. 1209 in vol. 8, PMID: 29018453.]. PMID- 29697704 TI - An ice sheet model validation framework for the Greenland ice sheet. AB - We propose a new ice sheet model validation framework - the Cryospheric Model Comparison Tool (CmCt) - that takes advantage of ice sheet altimetry and gravimetry observations collected over the past several decades and is applied here to modeling of the Greenland ice sheet. We use realistic simulations performed with the Community Ice Sheet Model (CISM) along with two idealized, non dynamic models to demonstrate the framework and its use. Dynamic simulations with CISM are forced from 1991 to 2013 using combinations of reanalysis-based surface mass balance and observations of outlet glacier flux change. We propose and demonstrate qualitative and quantitative metrics for use in evaluating the different model simulations against the observations. We find that the altimetry observations used here are largely ambiguous in terms of their ability to distinguish one simulation from another. Based on basin- and whole-ice-sheet scale metrics, we find that simulations using both idealized conceptual models and dynamic, numerical models provide an equally reasonable representation of the ice sheet surface (mean elevation differences of <1 m). This is likely due to their short period of record, biases inherent to digital elevation models used for model initial conditions, and biases resulting from firn dynamics, which are not explicitly accounted for in the models or observations. On the other hand, we find that the gravimetry observations used here are able to unambiguously distinguish between simulations of varying complexity, and along with the CmCt, can provide a quantitative score for assessing a particular model and/or simulation. The new framework demonstrates that our proposed metrics can distinguish relatively better from relatively worse simulations and that dynamic ice sheet models, when appropriately initialized and forced with the right boundary conditions, demonstrate predictive skill with respect to observed dynamic changes occurring on Greenland over the past few decades. An extensible design will allow for continued use of the CmCt as future altimetry, gravimetry, and other remotely sensed data become available for use in ice sheet model validation. PMID- 29697705 TI - Influence of Bulk Microphysics Schemes upon Weather Research and Forecasting (WRF) Version 3.6.1 Nor'easter Simulations. AB - This study evaluated the impact of five, single- or double- moment bulk microphysics schemes (BMPSs) on Weather Research and Forecasting model (WRF) simulations of seven, intense winter time cyclones impacting the Mid-Atlantic United States. Five-day long WRF simulations were initialized roughly 24 hours prior to the onset of coastal cyclogenesis off the North Carolina coastline. In all, 35 model simulations (5 BMPSs and seven cases) were run and their associated microphysics-related storm properties (hydrometer mixing ratios, precipitation, and radar reflectivity) were evaluated against model analysis and available gridded radar and ground-based precipitation products. Inter-BMPS comparisons of column-integrated mixing ratios and mixing ratio profiles reveal little variability in non-frozen hydrometeor species due to their shared programming heritage, yet their assumptions concerning snow and graupel intercepts, ice supersaturation, snow and graupel density maps, and terminal velocities lead to considerable variability in both simulated frozen hydrometeor species and radar reflectivity. WRF-simulated precipitation fields exhibit minor spatio-temporal variability amongst BMPSs, yet their spatial extent is largely conserved. Compared to ground-based precipitation data, WRF-simulations demonstrate low-to moderate (0.217-0.414) threat scores and a rainfall distribution shifted toward higher values. Finally, an analysis of WRF and gridded radar reflectivity data via contoured frequency with altitude (CFAD) diagrams reveals notable variability amongst BMPSs, where better performing schemes favored lower graupel mixing ratios and better underlying aggregation assumptions. PMID- 29697707 TI - The importance of paying attention to relationships. PMID- 29697706 TI - Benchmarking NLDAS-2 Soil Moisture and Evapotranspiration to Separate Uncertainty Contributions. AB - Model benchmarking allows us to separate uncertainty in model predictions caused by model inputs from uncertainty due to model structural error. We extend this method with a "large-sample" approach (using data from multiple field sites) to measure prediction uncertainty caused by errors in (i) forcing data, (ii) model parameters, and (iii) model structure, and use it to compare the efficiency of soil moisture state and evapotranspiration flux predictions made by the four land surface models in the North American Land Data Assimilation System Phase 2 (NLDAS 2). Parameters dominated uncertainty in soil moisture estimates and forcing data dominated uncertainty in evapotranspiration estimates; however, the models themselves used only a fraction of the information available to them. This means that there is significant potential to improve all three components of the NLDAS 2 system. In particular, continued work toward refining the parameter maps and look-up tables, the forcing data measurement and processing, and also the land surface models themselves, has potential to result in improved estimates of surface mass and energy balances. PMID- 29697708 TI - Patient primary language in a culturally focused intervention for Latino Americans with depression. AB - BACKGROUND: This study examined whether a culturally focused psychiatric consultation program (CFP) for Latino Americans was equally effective in reducing depressive symptoms in English-speaking and Spanish-speaking patients. METHODS: The CFP utilizes the Engagement Interview Protocol (EIP), a semi-standardized protocol eliciting patient narratives about illness beliefs. The sample included 118 Latino American patients presenting with depressive symptoms. Patient preferred primary language was examined as a moderator for the effect of CFP participation vs usual care on change in depressive symptoms. RESULTS: Multiple regression analysis revealed that the interaction effect of primary language and treatment arm on depressive symptoms, as measured by the Quick Inventory of Depressive Symptomatology-Self Report was not statistically significant at 6 month follow-up (B = -2.89, t = -1.35, P = .180). CONCLUSIONS: The findings suggest that the CFP was equally effective in both Spanish and English-speaking Latino Americans. The trend in the results toward greater reduction in depressive symptoms in primary Spanish-speaking Latino Americans as compared with primary English-speaking Latino Americans suggests the importance of receiving language concordant care. PMID- 29697709 TI - Effects of nonpharmacological therapies on anxiety and cortisol: A meta-analysis. AB - BACKGROUND: Although pharmacotherapy is considered the standard of care for the treatment of anxiety, a subset of the patients remains resistant or intolerant to iatrogenic adverse effects. Nonpharmacological and nonpsychotherapeutic interventions, sometimes referred to as "complementary treatments," have emerged as possible alternatives in the treatment of anxiety. We conducted a meta analysis of placebo-controlled studies to assess the efficacy of nonpharmacological therapy on anxiety. In addition, because serum and salivary cortisol levels are elevated during anxiety, we conducted a separate meta analysis of pre- and posttreatment cortisol levels. METHODS: A search was conducted to identify randomized controlled trials published from January 2010 to May 2017 that measured the effects of nonpharmacological therapies on State Trait Anxiety Index (STAI) scores and cortisol levels before and after treatment. RESULTS: Four studies met the criteria for inclusion. Our meta-analysis reveals that participants receiving nonpharmacological therapy had a statistically significant decrease in STAI scores (d = -.340; 95% confidence interval [CI], .639, -.041; P = .026), but no statistically significant decrease in cortisol levels (d = -.085; 95% CI, -.396, .226; P = .591) after intervention. CONCLUSIONS: Our meta-analysis data suggest that "complementary" therapies improved the clinical manifestations of anxiety and thus may be useful as adjunctive approaches to drug treatment. PMID- 29697710 TI - Symptom severity and its clinical correlates in kleptomania. AB - BACKGROUND: Kleptomania (compulsive stealing) remains poorly understood, with limited data regarding its underlying pathophysiology and appropriate treatment choices. METHODS: Participants (N = 112) age 18 to 65 with a primary, current diagnosis of kleptomania were assessed for the severity of their stealing behavior and urges to steal, as well as related mental health symptoms. To identify clinical and demographic measures associated with variation in disease severity, we utilized the statistical technique of partial least squares. RESULTS: Greater kleptomania symptom severity was associated with having more frequent urges to steal, feeling excited by stealing, having a current eating disorder, and having a current diagnosis of obsessivecompulsive disorder (OCD). Worse symptom severity was associated with a shorter transition time (between first stealing and diagnosis of kleptomania), as well as with a higher chance of stealing from relatives and seeking treatment at some point. CONCLUSIONS: Feeling a sense of reward from stealing and co-occurrence of certain disorders associated with compulsivity (eg, OCD, anorexia nervosa) were strongly associated with worse illness severity in kleptomania. Treatment approaches should incorporate these disorders as possible treatment targets. These data also may support conceptualizing kleptomania as an obsessive-compulsive-related disorder rather than being allied to substance use or impulsive disorders. PMID- 29697711 TI - Age at first sexual activity: Clinical and cognitive associations. AB - BACKGROUND: Engagement in sexual activity is common among adolescents and can be considered part of adolescent development, but it carries potential life-changing consequences. METHODS: This study examined if clinical and cognitive differences existed between adolescents who engaged in voluntary sexual behavior before age 15, between ages 15 to 18, and after age 18. All participants were part of a larger study examining impulsive behavior in young adults. Participants were assessed on measures including demographics, comorbid psychiatric disorders, and clinical scales and cognitive tasks assessing impulsivity, obsessive-compulsive traits, emotion regulation, depression, anxiety, and quality of life. RESULTS: Those who engaged in voluntary sexual activity before age 15 were more likely to have increased depression and anxiety symptoms, to score higher on the Yale Brown Obsessive-Compulsive Scale for Pathologic Gambling, and to make poorer decisions on the Cambridge Gambling Task. CONCLUSIONS: The results of this study suggest that the decision to engage in sexual activity at a young age is not an act of thinking before acting or impatience, but rather a decision to engage in sensation-seeking behavior. This finding carries implications for interventions targeting healthy sexual activity in adolescents. PMID- 29697712 TI - Moral injury, posttraumatic stress disorder, and religious involvement among U.S. veterans. AB - BACKGROUND: Traumatic experiences can cause ethical conflicts. "Moral injury" (MI) has been used to describe this emotional/cognitive state, and could contribute to the development of posttraumatic stress disorder (PTSD) or block its recovery. We examine the relationship between MI and PTSD, and the impact of religious involvement (RI) on that relationship. METHODS: We conducted a study of 120 veterans enrolled at the Charlie Norwood VA Medical Center in Augusta, Georgia. Standard measures of PTSD symptoms, MI, and RI were administered. Regression models were used to examine correlates of PTSD symptoms and the moderating or mediating effects of RI. RESULTS: A strong relationship was found between MI and PTSD symptoms (r = 0.54, P <= .0001), and between MI and RI (r = .41, P <= .0001), but only a weak relationship was found between RI and PTSD symptoms (r = -.17, P = .058). RI did not mediate or moderate the relationship between MI and PTSD symptoms in the overall sample. However, among non-Middle Eastern war theater veterans, a significant buffering effect of religiosity was found. CONCLUSIONS: MI has a strong positive relationship with PTSD symptoms and an inverse relationship with RI. RI did not mediate or moderate the relationship between MI and PTSD in the overall sample, but it moderated this relationship in non-Middle Eastern war theater veterans. PMID- 29697713 TI - AlzhaTV: A nonpharmacological intervention to manage behavioral and psychological symptoms in nursing home dementia patients. AB - BACKGROUND: Currently, 5 million seniors who reside in the community or assisted living or nursing facilities are affected by Alzheimer's disease and other neurocognitive disorders. They experience various psychiatric symptoms. Also, their family members are stressed from caregiving, and may feel guilty for not doing more. METHODS: We created an innovative nonpharmacological intervention, AlzhaTV, to decrease behavioral and psychological symptoms associated with neurocognitive disorders. We offered AlzhaTV to 9 nursing home patients. RESULTS: In our retrospective examination of this case series, we found AlzhaTV was effective in reducing behavioral and psychological symptoms in patients with neurocognitive disorders. We achieved either dose reductions, discontinuation, or avoided initiating the use of antipsychotic medications and benzodiazepines in nearly all patients. CONCLUSIONS: AlzhaTV may help decrease behavioral and psychological symptoms of dementia and decrease or avoid the use of antipsychotic medications or benzodiazepines. It may help in reducing the overall cost of health care in patients with dementia or neurocognitive disorders. AlzhaTV helps patients stay connected to their families, friends, and their past while bringing them joy in the present. It also helps families and caregivers feel more connected and less helpless. PMID- 29697714 TI - Exploring Asian American attitudes regarding mental health treatment in primary care: A qualitative study. AB - BACKGROUND: In this exploratory study, we examined attitudes regarding mental health treatment among 10 Asian American patients in an urban primary care setting to better understand contextual barriers to care. METHODS: Ten semi structured telephone interviews were conducted with Asian Americans recruited from primary care practices in an urban medical center. RESULTS: The study's qualitative data suggest that focusing on specific cultural concerns is essential for increasing mental health access for Asian Americans. Although few participants initially expressed interest in a culturally focused mental health program themselves, when phrased as being part of their primary care practice, 8 expressed interest. Furthermore, most felt that the program could help family or friends. Many participants preferred to seek care initially from social systems and alternative and complementary medicine before seeking psychiatric care. CONCLUSIONS: Because Asian Americans face notable barriers to seeking mental health treatment, addressing cultural concerns by providing culturally sensitive care could help make mental health treatment more acceptable, particularly among less acculturated individuals. To our knowledge, this is the first qualitative study exploring barriers to Asian Americans accessing integrated mental health services in primary care. PMID- 29697715 TI - Catatonia in the medically ill: Etiology, diagnosis, and treatment. The Academy of Consultation-Liaison Psychiatry Evidence-Based Medicine Subcommittee Monograph. AB - BACKGROUND: Catatonia in medically ill patients is rare but often unrecognized. This monograph summarizes current knowledge on the diagnosis, epidemiology, etiology, and management of catatonia occurring in the medical setting. METHODS: PubMed searches were used to identify relevant articles from 1962 to present. RESULTS: More than 3,000 articles were obtained and reviewed for relevance, including references of articles identified by the initial search. Several areas were identified as important, including: (1) catatonia and delirium; (2) malignant catatonia; (3) pediatric catatonia; (4) catatonia associated with another medical condition (CAMC); (5) drug exposure and withdrawal syndromes associated with catatonia; and (6) treatment of catatonia in the medical setting. CONCLUSIONS: Catatonia in the medically ill appears to have numerous etiologies, although etiology does not seem to modify the general treatment approach of prompt administration of lorazepam. Delirium and catatonia are commonly comorbid in the medical setting and should not be viewed as mutually exclusive. Electroconvulsive therapy should be offered to patients who do not respond to benzodiazepines or have malignant features. Removing offending agents and treating the underlying medical condition is paramount when treating CAMC. Memantine or amantadine may be helpful adjunctive agents. There is not enough evidence to support the use of antipsychotics or stimulants in treating CAMC. PMID- 29697716 TI - Prevalence of Posterior Disc Displacement of the Temporomandibular Joint in Patients with Temporomandibular Disorders: Systematic Review and Meta-Analyses. AB - AIMS: To assess the prevalence of posterior disc displacement (PDD) in patients with temporomandibular disorders (TMD) through a systematic review of the literature and meta-analysis, as well as to assess features associated with PDD such as chief complaint, signs and symptoms, morphologic condyle and disc alterations, and PDD management. METHODS: A systematic literature search was performed in the US National Library of Medicine's PubMed/MEDLINE and Cochrane Library databases to identify all peer-reviewed, English-language manuscripts related to PDD. A critical appraisal checklist provided by the Joanna Briggs Institute for studies reporting prevalence data was used to assess the quality of the included manuscripts. A meta-analysis was conducted using software MetaXL 5.3 (EpiGear International Pty Ltd) add-in for Microsoft Excel. Pooled prevalence and 95% confidence intervals (CIs) were calculated using the software. Heterogeneity of the included studies was assessed using the Higgins I2 test and Cochran's Q (with P value; < .05 was considered significant). RESULTS: A total of 21 articles were selected for qualitative data synthesis: 2 case reports, 14 observational studies, and 5 studies that reported PDD in various conditions. Quantitative data analysis was performed for the 14 observational studies, of which 13 reported prevalence with respect to the number of joints affected and 9 reported prevalence with respect to the number of patients affected. The overall pooled prevalence of PDD for the number of joints affected was 0.7% (95% CI: 0.005 to 0.008). The pooled prevalence of PDD for the number of patients was 0.9% (95% CI: 0.007 to 0.011). PDD was found to be associated with osseous changes, including changes in the morphology of the condyle, disc, and articular eminence; osseous abnormalities (erosion, osteophytes); and joint effusion. CONCLUSION: This meta analysis showed a very low prevalence rate of PDD in TMD patients. The limited literature did not allow conclusions to be drawn about the PDD-related features. PMID- 29697717 TI - Analgesic Effects of Intranasal Ketamine in Rat Models of Facial Pain. AB - AIMS: To assess the analgesic effect of intranasal administration of S-ketamine in different rat models of facial pain. METHODS: Nociceptive responses induced by formalin injected into the upper lip and facial hyperalgesia induced by capsaicin or carrageenan injected into the upper lip were used to evaluate the analgesic effect of intranasal ketamine in acute facial pain models in rats (n = 173). The effect of intranasal ketamine on heat and mechanical hyperalgesia induced by constriction of the infraorbital nerve (CION) was also evaluated. In addition, locomotor activity in the open field test was assessed after intranasal ketamine administration. Two-way repeated measures analysis of variance followed by Bonferroni post hoc correction were used to analyze all data. RESULTS: Intranasal ketamine (0.5 mg/kg) failed to modify the first phase of the orofacial formalin test, but reduced the second phase by about 40%. Intranasal ketamine also reduced the facial heat hyperalgesia induced by capsaicin and carrageenan. In the CION model, intranasal ketamine at 0.5 mg/kg reversed the heat hyperalgesia and at 1 mg/kg attenuated the mechanical hyperalgesia 4 and 14 days after the surgery, respectively. The open field test did not reveal locomotor deficits in rats treated with intranasal ketamine. CONCLUSION: This study has demonstrated that intranasal ketamine produces analgesic effects in inflammatory and neuropathic facial pain models and may represent an adjuvant in the treatment of such conditions, especially when rapid pain relief is needed. PMID- 29697718 TI - Efficacy of Low-Level Laser Therapy in the Treatment of Temporomandibular Myofascial Pain: A Systematic Review and Meta-Analysis. AB - AIMS: To conduct a systematic review and meta-analysis to determine the efficacy of low-level laser therapy (LLLT) in treating temporomandibular myofascial pain in adults compared to laser placebo. METHODS: Randomized, placebo-controlled studies were identified by a search on March 2, 2016 and updated on February 9, 2017 in the PubMed, Web of Science, and Cochrane Library databases. Three of the authors assessed the studies for risk of bias. Outcomes included pain reduction on a visual analog scale (VAS) and interincisal opening. RESULTS: The initial search strategy yielded 142 unduplicated references assessed independently by three review authors. After evaluation, this number was reduced to eight relevant studies for inclusion in this review. Of these eight studies, four were at unclear risk of bias and four were at high risk. In a meta-analysis, pain intensity was significantly reduced after treatment in the group that received LLLT as compared to laser placebo (an average of 2.2 units on a scale of 0 to 10) (P = .005) and an average of 2.4 units 3 to 4 weeks later (P = .022). Pooled results showed a significant increase in interincisal opening at 1 month after treatment (P = .012), but not when the treatment was completed (P = .079). CONCLUSION: The findings from this systematic review showed that LLLT seems to be effective in reducing pain in patients with temporomandibular myofascial pain with moderate-quality evidence. However, due to the high heterogeneity, small number, and high risk of bias of the included studies, the results are not definitive, and further well-designed studies are needed. PMID- 29697719 TI - Changes in Type I and Type II Collagen Expression in Rat Mandibular Condylar Cartilage Associated with Aging and Dietary Loading. AB - AIMS: To evaluate the usefulness of diet board feeding as a model for temporomandibular joint (TMJ) research, characterize dietary loading-related morphometric changes in the mandibular condylar cartilage of aging rats, and investigate changes in type I and type II collagen expression in different age, sex, and diet groups. METHODS: Material was collected from a study that examined the effects of 1-year and 2-year diet board feeding on rats. In diet board feeding, rats must gnaw wood to reach their food, leading to a higher masticatory workload. The material analyzed was comprised of 150 TMJ samples from 75 Hsd:Sprague Dawley rats grouped according to feeding method (diet board [experimental group] or ad libitum [control group]), sex, and experiment length (1 or 2 years). The rats were sacrificed at the age of 15 or 26 months (15-M rats or 26-M rats). From the TMJ samples, 5-MUm-thick sections were cut parallel to the sagittal plane of the mandibular condyle. Histomorphometric analysis of the thickness of the condylar cartilage and the number of cartilage cells was performed after toluidine blue staining. Immunohistochemical staining included type I and type II collagen antigens. Differences in the thickness of the cellular layer and the number of cells in the condylar cartilage were analyzed by means of a repeated-measures analysis of variance (ANOVA) model, and differences in the type of collagen with a one-way random-effects ANOVA model. RESULTS: Condylar cartilage was significantly thicker in the 15-M diet board-fed rats than in the 15-M control rats and in the 26-M rats than in the 15-M rats. The number of cells was larger in the 26-M female rats than in the 26-M male rats. Type I collagen expression was significantly higher in the 15-M diet board-fed female rats than in the 15-M controls. Type II collagen showed increased expression in older rats compared to younger rats. CONCLUSION: Condylar cartilage is sensitive to the interplay between loading, aging, and sex of middle-aged and older rats. High loading of condylar cartilage increased the thickness of cartilage in younger rats. PMID- 29697720 TI - Pain Catastrophizing and Pain Persistence in Temporomandibular Disorder Patients. AB - AIMS: To describe pain catastrophizing in temporomandibular disorder (TMD) patients in relation to disability and pain persistence. METHODS: A total of 163 TMD patients underwent a complete TMD evaluation according to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD), including the Pain Catastrophizing Scale (PCS). Patients were divided into subgroups according to their PCS, Graded Chronic Pain Scale (GCPS), and pain persistence scores. The GCPS and pain persistence subgroups were assigned as dependent variables in a stepwise multiple logistic regression model. The ability of the DC/TMD Axis II parameters and of the PCS to discriminate between patients of low and high disability (according to the GCPS) and low and high pain persistence were examined using area under the receiver operating characteristic (ROC) curve. alpha < .05 was considered to reflect statistical significance. RESULTS: Significant differences were found between high and low pain catastrophizing patients as to socioeconomic parameter, Axis I diagnoses, pain persistence, and Axis II evaluation. The parameters with significant discriminant ability for pain persistence were pain catastrophizing, depression, and nonspecific physical symptoms, with no significant differences between them. Depression increased the odds of high disability by 1.2, while pain catastrophizing increased the odds for high pain persistence more than 6-fold. Pain catastrophizing was not significantly associated with pain disability, and depression was not significantly associated with pain persistence. CONCLUSION: High-pain catastrophizing TMD patients were similar to patients with other chronic pain conditions, but differed from TMD patients as a group. The findings of this study support the addition of an assessment for pain catastrophizing to the DC/TMD for early identification of TMD patients who might be at higher risk for developing chronic pain. PMID- 29697721 TI - In situ formation of nano-CdSe as a photocatalyst: cadmium ion-enhanced photochemical vapour generation directly from Se(vi). AB - Cadmium ion-enhanced photochemical vapour generation directly from Se(vi) has for the first time been reported here, and the key mechanism of the in situ formation of nano-CdSe as a photocatalyst has been revealed. PMID- 29697722 TI - Energy dispersive spectrometry and first principles studies on the oxidation of pentlandite. AB - Experimental and computational studies were carried out to investigate the oxidation of pentlandite (Fe4.5Ni4.5S8). The oxidation product was first analyzed by energy dispersive spectrometry to reveal the elemental distribution at the cross section. Our experimental study shows that the Fe atoms in pentlandite migrated to the surface and were preferentially oxidized to form a thin layer of Fe2O3, whereas the Ni atoms remained at the center of the grain. Furthermore, density functional theory calculations were performed to investigate the adsorption and diffusion of atomic oxygen as well as the adsorption and dissociation of molecular oxygen on the (001) and (010) surfaces of pentlandite. From the calculated adsorption energies of atomic oxygen at the different sites of the (001) and (010) surfaces, we found that oxidation of the Fe sites was preferable to that of the Ni sites when exposed to an oxidizing atmosphere. For molecular oxygen adsorption on the surfaces of pentlandite, the bridge sites (Fe Ni and Fe-Fe) were found to be the most favorable adsorption sites. The dissociative adsorption of O2 is thermodynamically more favorable than the molecular adsorption. Calculated dissociation barriers show that the oxidation is feasible during high temperature roasting. PMID- 29697723 TI - A computational exploration of CO2 reduction via CO dimerization on mixed-valence copper oxide surface. AB - The catalytic role of Cu ions in CO2 reduction on oxide-derived Cu has been elusive. In the presence of oxygen vacancy, COCO dimerization is predicted to be thermodynamically favorable with an accessible barrier on Cu4O3(202). The material's mixed valency is responsible for stabilizing the charge-separated (OC)delta+(CO)delta- intermediate. PMID- 29697724 TI - Metal alloy solid-state nanopores for single nanoparticle detection. AB - Solid-state nanopore technology for nanoparticle sensing is considered for the development of analytical tools to characterise their size, shape or zeta potential. In this field, it is crucial to understand how the nanopore inner surface influences the dynamic of nanoparticle translocation. Here, three single nanopores directly drilled in metal alloys (titanium nitride, titanium-tantalum and tantalum) are considered. The translocation of polystyrene nanoparticles coated with ssDNA is investigated by the resistive pulse method at different concentrations and voltages. The results show that the nanoparticle energy barrier for entrance into the pore decreases for nanopores that exhibits a higher surface energy and hydrophilicity, while the dwell time is found to depend on the nanopore surface state. Overall, this study demonstrates that the control of nanopore surface state must be taken into account for the resistive pulse experiments for nanoparticle detection. PMID- 29697725 TI - Ultrasonication-induced sp3 hybridization defects in Langmuir-Schaefer layers of turbostratic graphene. AB - Ultrasonic homogenization is the method of choice for producing and dispersing graphene. In this paper, we show that sp3 hybridization defects introduced by long high-power sonication cause a significant decrease in electrical conductivity. In order to show this, two turbostratic graphene (TG) dispersions were sonicated at two power settings of the tip sonifier at 20 W and 60 W, and for different periods varying from 1 min to 180 min. Afterwards, TG thin films were prepared by the Langmuir technique and transferred onto a quartz substrate by the Langmuir-Schaefer method. The thin films were investigated by electrical conductivity measurement, UV-VIS, Raman spectroscopy and scanning electron microscopy. We found that the relative performance of the TG thin films in terms of transparency and sheet resistance was higher than that for similarly prepared pristine graphene flakes, reported in our previous work. Moreover, despite the increase in transmittance, the electrical conductance significantly decreases with the time of sonication, especially for the 60 W sonication power. The results of Raman spectroscopy indicate that this particular behavior can be explained by the introduction of sp3 hybridization defects into the TG flakes during high power sonication. PMID- 29697726 TI - Mediating both valence and conduction bands of TiO2 by anionic dopants for visible- and infrared-light photocatalysis. AB - Doping is an effective way to extend the optical absorption of TiO2 to the visible range. Doping of TiO2 by carbon has been found to enhance the water splitting efficiency significantly in experiment. However, the mechanism behind this is elusive. Using the ab initio many-body Green's function theory, we find that the C2 dimer formed on the TiO2 surface produces a shallow delocalized occupied Ti 3d state just below the bottom of the conduction bands. Therefore, band-gap narrowing in carbon-doped TiO2 is caused by the opposite shifts of both valence and conduction bands simultaneously, which is in contrast to the generally accepted idea that anionic dopants can only affect the valence band of TiO2. Optical absorption in the infrared region is also increased compared to reduced TiO2. The spatially well-separated photogenerated electrons and holes might help to reduce the recombination rate of carriers, in favor of improvement in photocatalysis efficiency. This novel behavior of anionic dopants is distinct from previous understandings and may guide the engineering of TiO2. PMID- 29697727 TI - Multicomponent self-assembly as a tool to harness new properties from peptides and proteins in material design. AB - Nature is enriched with a wide variety of complex, synergistic, and highly functional protein-based multicomponent assemblies. As such, nature has served as a source of inspiration for using multicomponent self-assembly as a platform to create highly ordered, complex, and dynamic protein and peptide-based nanostructures. Such an assembly system relies on the initial interaction of distinct individual building blocks leading to the formation of a complex that subsequently assembles into supramolecular architectures. This approach not only serves as a powerful platform for gaining insight into how proteins co-assemble in nature but also offers huge opportunities to harness new properties not inherent in the individual building blocks. In the past decades, various multicomponent self-assembly strategies have been used to extract synergistic properties from proteins and peptides. This review highlights the updates in the field of multicomponent self-assembly of proteins and peptides and summarizes various strategies, including covalent conjugation, ligand-receptor interactions, templated/directed assembly and non-specific co-assembly, for driving the self assembly of multiple proteins and peptide-based building blocks into functional materials. In particular, we focus on peptide- or protein-containing multicomponent systems that, upon self-assembly, enable the emergence of new properties or phenomena. The ultimate goal of this review is to highlight the importance of multicomponent self-assembly in protein and peptide engineering, and to advocate its growth in the fields of materials science and nanotechnology. PMID- 29697729 TI - Silicon-fluorine chemistry: from the preparation of SiF2 to C-F bond activation using silylenes and its heavier congeners. AB - This feature article is intended to provide a background to the history of the isolation of silicon(ii) fluorides and the different synthetic methodologies used to generate them. Although first detected in the 1970s, the chemistry of silicon(ii) fluorides has not encountered serious research efforts for a rather long period of time. This is somewhat surprising given the fact that the chemistry of compounds with divalent silicon has undergone a renaissance during last three decades. Recently, the interest in silicon(ii) fluorides have been resparked with tremendous progress being achieved in this area, in particular, with respect to their synthesis and structural characterisation. The successful isolation of cyclic alkyl amino carbene (cAAC) stabilized silicon difluoride has completed the classic progression of SiF2, from a transient intermediate to spectroscopically detected molecule to a stable compound. The related germanium(ii), tin(ii), and lead(ii) fluoride chemistry will also be discussed. Apart from the isolation of tetrel(ii) fluorides, the use of compounds with low valent group 14 elements for the selective activation and functionalisation of C F bonds has witnessed some remarkable advances, which will also be summarized in this feature article. PMID- 29697728 TI - O-O bond cleavage via electrochemical reduction of a side-on peroxo dicopper model of hemocyanin. AB - The redox properties of the MU-eta2:eta2 peroxo complex [Cu2(H6M4h)(O2)]2+ were elucidated. This study constitutes the first full electrochemical and spectroelectrochemical characterization of a side-on peroxo Cu2:O2 bioinorganic model complex. The peroxo complex is irreversibly reduced in a two-electron process localized on the peroxo ligand triggering the cleavage of the O-O bond. PMID- 29697730 TI - Correlated energy transfer in rotationally and spin-orbit inelastic collisions of NO(X2Pi1/2, j = 1/2f) with O2(X3Sigmag-). AB - We present a combined experimental and theoretical study of state-to-state inelastic scattering of NO(X2Pi1/2, j = 1/2f) with O2(X3Sigmag-) molecules at a collision energy of 480 cm-1, focusing in particular on the observation and interpretation of correlated excitations in both NO and O2. Various final states of the NO radical, in both spin-orbit manifolds, were measured with high resolution using a crossed molecular beam apparatus which employs a combination of Stark deceleration and velocity map imaging. Velocity map imaging directly measures both the angular distribution and the radial velocity distribution of the scattered NO molecules, which probes the kinetic energy uptake or release and hence correlated excitations of NO-O2 pairs. Simultaneous excitations of NO and O2 were resolved for all studied final states of NO. In all cases, the experimental results excellently agree with the results of simulations based on quantum scattering calculations. Trends are discussed by analyzing the scattering wave functions from the calculations. PMID- 29697731 TI - Molecular dynamics simulations of the structure of mixtures of protic ionic liquids and monovalent and divalent salts at the electrochemical interface. AB - We perform molecular dynamics simulations of mixtures of a prototypical protic ionic liquid, ethylammonium nitrate, with lithium or magnesium nitrate (LiNO3/Mg(NO3)2) confined between two graphene walls. The structure of the system is analyzed by means of ionic density profiles, angular orientations of ethylammonium cations close to the wall and the lateral structure of the first layer close to the graphene wall. All these results are compared to those of the corresponding aprotic ionic liquid systems, analyzing the influence of the graphene wall charge in the structure of the protic and aprotic mixtures. Moreover, vibrational densities of states are calculated for the salt cations close to the walls. Finally, we investigate the structure of the mixture with Li salt near the interface using ab initio density functional theory, and the results are compared with those obtained by classical molecular dynamics simulations. PMID- 29697732 TI - Selective sodium intercalation into sodium nickel-manganese sulfate for dual Na Li-ion batteries. AB - Double sodium transition metal sulfates combine in themselves unique intercalation properties with eco-compatible compositions - a specific feature that makes them attractive electrode materials for lithium and sodium ion batteries. Herein, we examine the intercalation properties of novel double sodium nickel-manganese sulfate, Na2Ni1/2Mn1/2(SO4)2, having a large monoclinic unit cell, through electrochemical and ex situ diffraction and spectroscopic methods. The sulfate salt Na2Ni1/2Mn1/2(SO4)2 is prepared by thermal dehydration of the corresponding hydrate salt Na2Ni1/2Mn1/2(SO4)2.4H2O having a blodite structure. The intercalation reactions on Na2Ni1-xMnx(SO4)2 are studied in two model cells: half-ion cell versus Li metal anode and full-ion cell versus Li4Ti5O12 anode by using lithium (LiPF6 dissolved in EC/DMC) and sodium electrolytes (NaPF6 dissolved in EC:DEC). Based on ex situ XRD and TEM analysis, it is found that sodium intercalation into Na2Ni1/2Mn1/2(SO4)2 takes place via phase separation into the Ni-rich monoclinic phase and Mn-rich alluaudite phase. The redox reactions involving participation of manganese and titanium ions are monitored by ex situ EPR spectroscopy. It has been demonstrated that manganese ions from the sulfate salt are participating in the electrochemical reaction, while the nickel ions remain intact. As a result, a reversible capacity of about 65 mA h g-1 is reached. The selective intercalation properties determine sodium nickel-manganese sulfate as a new electrode material for hybrid lithium-sodium ion batteries that is thought to combine the advantages of individual lithium and sodium batteries. PMID- 29697738 TI - Stringent vaccination of cancer patients: is it that important? PMID- 29697739 TI - Sudden Unexpected Death in Parkinson's Disease (SUDPAR): a fatal event that James Parkinson did not address. PMID- 29697740 TI - Pattern recognition analysis on long noncoding RNAs: a tool for prediction in plants. AB - Motivation: Long noncoding RNAs (lncRNAs) correspond to a eukaryotic noncoding RNA class that gained great attention in the past years as a higher layer of regulation for gene expression in cells. There is, however, a lack of specific computational approaches to reliably predict lncRNA in plants, which contrast the variety of prediction tools available for mammalian lncRNAs. This distinction is not that obvious, given that biological features and mechanisms generating lncRNAs in the cell are likely different between animals and plants. Considering this, we present a machine learning analysis and a classifier approach called RNAplonc (https://github.com/TatianneNegri/RNAplonc/) to identify lncRNAs in plants. Results: Our feature selection analysis considered 5468 features, and it used only 16 features to robustly identify lncRNA with the REPTree algorithm. That was the base to create the model and train it with lncRNA and mRNA data from five plant species (thale cress, cucumber, soybean, poplar and Asian rice). After an extensive comparison with other tools largely used in plants (CPC, CPC2, CPAT and PLncPRO), we found that RNAplonc produced more reliable lncRNA predictions from plant transcripts with 87.5% of the best result in eight tests in eight species from the GreeNC database and four independent studies in monocotyledonous (Brachypodium) and eudicotyledonous (Populus and Gossypium) species. PMID- 29697741 TI - Non-epithelial ovarian cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. PMID- 29697742 TI - Prediction of lncRNAs and their interactions with nucleic acids: benchmarking bioinformatics tools. AB - The genomes of mammalian species are pervasively transcribed producing as many noncoding as protein-coding RNAs. There is a growing body of evidence supporting their functional role. Long noncoding RNA (lncRNA) can bind both nucleic acids and proteins through several mechanisms. A reliable computational prediction of the most probable mechanism of lncRNA interaction can facilitate experimental validation of its function. In this study, we benchmarked computational tools capable to discriminate lncRNA from mRNA and predict lncRNA interactions with other nucleic acids. We assessed the performance of 9 tools for distinguishing protein-coding from noncoding RNAs, as well as 19 tools for prediction of RNA-RNA and RNA-DNA interactions. Our conclusions about the considered tools were based on their performances on the entire genome/transcriptome level, as it is the most common task nowadays. We found that FEELnc and CPAT distinguish between coding and noncoding mammalian transcripts in the most accurate manner. ASSA, RIBlast and LASTAL, as well as Triplexator, turned out to be the best predictors of RNA RNA and RNA-DNA interactions, respectively. We showed that the normalization of the predicted interaction strength to the transcript length and GC content may improve the accuracy of inferring RNA interactions. Yet, all the current tools have difficulties to make accurate predictions of short-trans RNA-RNA interactions-stretches of sparse contacts. All over, there is still room for improvement in each category, especially for predictions of RNA interactions. PMID- 29697743 TI - Commentary on: A Novel Method for Lower Blepharoplasty: Repositioning of the Orbital Septum Using Inverted T-Shaped Plication. PMID- 29697744 TI - The Names Have Been Changed to Protect the . . . Humanity: Person-First Language in Correctional Health Epidemiology. AB - After objections surfaced following a call for papers on "Prisoner Health," the editors of Epidemiologic Reviews decided to rename this year's volume "Incarceration and Health." In this commentary, we trace the origins of person first language and explain why using appropriate terms in correctional health, including correctional health epidemiology, matters. We discuss the potential consequences of person-first language for justice-involved individuals and how inclusive language might affect the social, emotional, and physical well-being of individuals, families, and communities. Future directions may include measuring health outcomes when language is systematically changed. The barriers that thwart successful reentry may wane when dehumanizing language disappears. PMID- 29697745 TI - Seeking stable traits to characterize the root system architecture. Study on 60 species located at two sites in natura. AB - Background and Aims: In several disciplines, identifying relevant root traits to characterize the root system architecture of species or genotypes is a crucial step. To address this question, we analysed the inter-specific variations of root architectural traits in two contrasting environments. Methods: We sampled 60 species in natura, at two sites, each presenting homogeneous soil conditions. We estimated for each species and site a set of five traits used for the modelling of the root system architecture: extreme tip diameters (Dmin and Dmax), relative diameter range (Drange), mean inter-branch distance (IBD) and dominance slope between the diameters of parent and lateral roots (DlDm). Key Results: The five traits presented a highly significant species effect, explaining between 77 and 98 % of the total variation. Dmin, Dmax and Drange were particularly determined by the species, while DlDm and IBD exhibited a higher percentage of environmental variations. These traits make it possible to confirm two main axes of variation: 'fineness-density' (defined by Dmin and IBD) and 'dominance-heterorhizy' (DlDm and Drange), that together accounted for 84 % of the variations observed. Conclusions: We confirmed the interest of these traits in the characterization of the root system architecture in ecology and genetics, and suggest using them to enrich the 'root economic spectrum'. PMID- 29697746 TI - Effects of baicalein on pancreatic cancer stem cells via modulation of sonic Hedgehog pathway. AB - Recent studies have suggested that sonic Hedgehog (Shh) signaling pathway is aberrantly activated in cancer stem cells (CSCs). A seven-herb Chinese medicinal formula composed of Amorphophallus rivieri Durieu, Oldenlandia diffusa (Wild) Roxb, Scutellaria barbata D. Don, Gynostemma pentaphyllum (Thunb.) Mak and Amomum cardamomum L, i.e. Qingyihuaji (QYHJ) formula, has been shown to inhibit proliferation of pancreatic CSCs by inhibiting Shh signaling pathway and thereby prolong the overall survival of pancreatic cancer patients. Mass spectrometry analysis revealed that baicalein is one of the major compounds of QYHJ formula. The objective of this study was to investigate the role of Shh pathway in pancreatic cancer and to examine the molecular mechanisms of baicalein involved in pancreatic cancer treatment. We examined the effects of baicalein on pancreatic CSCs both in vivo and in vitro. The results indicated that baicalein attenuated the pluripotency of pancreatic CSCs. Then, we investigated the underlying mechanism and found that nuclear transcription factors, such as Sox-2 and Oct-4 as well as members in Shh signaling pathway, e.g. SHH, SMO, and Gli-2, were downregulated after baicalein treatment. Furthermore, silencing Gli-2 expression by small interfering RNA decreased Sox-2 expression and blocked the inhibitory effects of baicalein, suggesting that the effects of baicalein may be mediated through inhibition of Shh pathway. Our results suggested that baicalein, an active compound in QYHJ formula, could suppress the self-renewal of pancreatic CSCs through inhibition of Shh signaling pathway. PMID- 29697748 TI - Visual and hearing impairments are associated with cognitive decline in older people. AB - Introduction: highly prevalagent hearing and vision sensory impairments among older people may contribute to the risk of cognitive decline and pathological impairments including dementia. This study aims to determine whether single and dual sensory impairment (hearing and/or vision) are independently associated with cognitive decline among older adults and to describe cognitive trajectories according to their impairment pattern. Material and methods: we used data from totals of 13,123, 11,417 and 21,265 respondents aged 50+ at baseline from the Health and Retirement Study (HRS), the English Longitudinal Study of Ageing (ELSA) and the Survey of Health, Ageing and Retirement in Europe (SHARE), respectively. We performed growth curve analysis to identify cognitive trajectories, and a joint model was used to deal with attrition problems in longitudinal ageing surveys. Results: respondents with a single sensory impairment had lower episodic memory score than those without sensory impairment in HRS (beta = -0.15, P < 0.001), ELSA (beta= -0.14, P< 0.001) and SHARE (beta= 0.26, P < 0.001). The analysis further shows that older adults with dual sensory impairment in HRS (beta= -0.25, P < 0.001), ELSA (beta= -0.35, P< 0.001) and SHARE (beta= -0.68, P < 0.001) remembered fewer words compared with those with no sensory impairment. The stronger associations between sensory impairment and lower episodic memory levels were found in the joint model which accounted for attrition. Conclusions: hearing and/or vision impairments are a marker for the risk of cognitive decline that could inform preventative interventions to maximise cognitive health and longevity. Further studies are needed to investigate how sensory markers could inform strategies to improve cognitive ageing. PMID- 29697747 TI - Genetic, Psychological, and Personal Network Factors Associated With Changes in Binge Drinking Over 2 Years Among Mexican Heritage Adolescents in the USA. AB - Background: Despite prevalent binge drinking and alcohol-dependent symptoms among Hispanics, few studies have examined how multidimensional factors influence Hispanic adolescents' binge drinking. Purpose This study examines the effects of genetic, psychological, and social network factors on binge drinking over time among Mexican heritage adolescents in the USA and whether there are correlations among genetic variants that are associated with binge drinking and psychological and network characteristics. Methods: Mexican heritage adolescents (n = 731) participated in a longitudinal study, which included genetic testing at baseline, alcohol use assessments at first and second follow-ups, and questionnaires on sensation seeking, impulsivity, and peer and family network characteristics at second follow-up. Logistic regression and Spearman correlation analyses were performed. Results: After adjusting for demographic characteristics, underlying genetic clustering, and binge drinking at first follow-up, two genetic variants on tryptophan hydroxylase 2 (TPH2; rs17110451, rs7963717), sensation seeking and impulsivity, and having a greater fraction of peers who drink or encourage drinking alcohol were associated with greater risk whereas another genetic variant on TPH2 (rs11178999) and having a greater fraction of close family relationships were associated with reduced risk for binge drinking at second follow-up. Genetic variants in TPH1 (rs591556) were associated with sensation seeking and impulsivity, while genetic variants in TPH2 (rs17110451) were associated with the fraction of drinkers in family. Conclusions: Results reveal that genetic variants in the serotonin pathway, behavioral disinhibition traits, and social networks exert joint influences on binge drinking in Mexican heritage adolescents in the USA. PMID- 29697749 TI - How to talk about genome editing. AB - Background: Human genome editing is an area of growing prominence, with many potential therapeutic applications. Sources of data: A project by two UK charities, whose participants included fertility sector patients and practitioners and also people affected by genetic disease and rare disease. Scientific research into, and wider discussion of, genomics and genome editing. Areas of agreement: There is a need for improved public and professional understanding of genome editing. Areas of controversy: The way genome editing is discussed is often inconsistent and confusing. Simply defining and explaining the term 'genome' can present challenges. Growing points: There are approaches that lend themselves to achieving greater clarity and coherence in discussion of genome editing. Areas timely for developing research: People's understanding should ideally be able to withstand and evolve alongside current developments in genome editing, rather than being tied firmly to specific aspects of genome editing (which may in future be supplanted). PMID- 29697750 TI - Clinical correlation of blood culture results. PMID- 29697752 TI - BMI trajectories from childhood: the slippery slope to adult obesity and cardiovascular disease. PMID- 29697751 TI - Claims-Based Frailty Index Options. PMID- 29697754 TI - Corrigendum to: Reitan et al. Patient-assessed short-term positive response to cardiac resynchronization therapy is an independent predictor of long-term mortality. PMID- 29697753 TI - Attention, arousal and other rapid bedside screening instruments for delirium in older patients: a systematic review of test accuracy studies. AB - Objective: delirium occurs frequently in frail patients but is easily missed. Screening with a rapid, easy-to-use and highly sensitive instrument might help improve recognition. The aim of this study was to review attention, arousal and other rapid bedside screening instruments for delirium in older patients. Methods: a literature search was performed in PubMed, PsycINFO and Embase. We scrutinized forward citations in Google Scholar, and references of included articles and prior reviews. We included studies among older patients that investigated the sensitivity and specificity of delirium screening instruments that could be administered in 3 min or less, and did not require surrogate information. We extracted study characteristics, risk of bias, sensitivity and specificity. Results: we identified 27 studies among 4,766 patients in hospitals and nursing homes. They tested many different single and several combined screening instruments. Prevalence of delirium varied between 4% and 57%. Only one study scored a low risk of bias on all domains. Sensitivity varied between 17% and 100%, and specificity between 38% and 99%. Of the 22 tests with sensitivity >=90%, seven also had specificity >=80% in older patients in general. These results were approximately reproduced for the Observational Scale of Level of Arousal (OSLA) and Richmond Agitation and Sedation Scale (RASS): sensitivity and specificity were >80%. Conclusion: two arousal tests-OSLA and RASS-had reproduced high sensitivity and specificity in older patients. Nurses can administer these tests during daily interaction with patients. Test accuracy studies about rapid screening tools for delirium superimposed on dementia were scarce. PMID- 29697755 TI - The reporting of blinding in orthodontic randomized controlled trials: where do we stand? AB - Objective: To analyse in 10 orthodontic journals how many randomized controlled trials (RCTs) performed 'single-', 'double-', 'triple-', or 'outcome assessors blinding' and to evaluate, from the number of RCTs that did not conduct blinding, how many could actually have achieved it. Material and methods: Randomized controlled trials published in 10 orthodontic journals between 1 September 2012 and 28 February 2018 were included. A search was performed in PubMed and conducted for publication type 'randomized controlled trial' for each journal. Two reviewers independently analysed each RCT and registered that blinding was performed and included which specific type. It was also evaluated whether misclassifications of blinding items occurred and whether it was possible to achieve blinding among the RCTs that did not perform blinding. Results: After applying the inclusion criteria, 203 RCTs were assessed, and 61.6 per cent of them had used blinding, with the main type being 'outcome assessors blinding' (40.4%) followed by 'single-blinding' (15.3%), 'double-blinding' (2.5%), and 'triple-blinding' (3.4%). In 38.4 per cent of the trials, no blinding was performed; however, 79.4 per cent of them could have achieved blinding. Fifteen RCTs (7.3%) misclassified the blinding in relation to single-, double-, or triple blinding. Journals followed the CONSORT (AJODO, EJO, JO, OCR) published together significantly more RCTs that performed blinding than journals not following the CONSORT. Conclusions: Blinding of outcome assessors was the most frequent type, as orthodontic trials are often of intervention design and thereby difficult to mask for patients and trial staff. The misclassifications of blinding items may indicate suboptimal knowledge among researchers and peer-reviewers regarding the definitions for diverse blinding types. PMID- 29697756 TI - Erratum. PMID- 29697757 TI - Daily Temporal Associations Between Physical Activity and Symptoms in Multiple Sclerosis. AB - Background: Symptom severity is negatively associated with physical activity in multiple sclerosis (MS). However, it is unclear how physical activity and symptoms correlate on a day-to-day basis in persons with MS. Purpose: To determine the temporal within-person associations of pain, fatigue, depressed mood, and perceived cognitive function with physical activity in MS. Methods: Ambulatory adults with MS (N = 107) completed 7 days of home monitoring. Continuous physical activity data (assessed via wrist-worn accelerometer) and concurrent ecological momentary assessment (5X/day) of pain, fatigue, depressed mood, and perceived cognitive function were collected. Data were analyzed using multilevel mixed modeling. Results: Fatigue and depressed mood demonstrated bidirectional associations with physical activity, whereas pain and cognitive function did not. Higher than usual fatigue (B = -5.83, p = .001) and depressed mood (B = -4.12, p = .03) were followed by decreased physical activity. In contrast, higher than usual physical activity was associated with subsequent decline in fatigue (B = -0.001, p = .02) and depressed mood (B = -0.0007, p = .02); however, the association between physical activity and fatigue varied across the day. Conclusions: Physical activity is dynamically related to fatigue and mood on a moment-to-moment basis in MS. Efforts to increase physical activity in MS must incorporate a focus on how symptoms affect and are affected by activity. PMID- 29697758 TI - Pathways, Contributors, and Correlates of Functional Limitation across Specialties: Workshop Summary. AB - Traditional clinical care models focus on the measurement and normalization of individual organ systems and de-emphasize aspects of health related to the integration of physiologic systems. Measures of physical, cognitive and sensory, and psychosocial or emotional function predict important health outcomes like death and disability independently from the severity of a specific disease, cumulative co-morbidity, or disease severity measures. A growing number of clinical scientists in several subspecialties are exploring the utility of functional assessment to predict complication risk, indicate stress resistance, inform disease screening approaches and risk factor interpretation, and evaluate care. Because a substantial number of older adults in the community have some form of functional limitation, integrating functional assessment into clinical medicine could have a large impact. Although interest in functional implications for health and disease management is growing, the science underlying functional capacity, functional limitation, physical frailty, and functional metrics is often siloed among different clinicians and researchers, with fragmented concepts and methods. On August 25-26, 2016, participants at a trans-disciplinary workshop, supported by the National Institute on Aging and the John A. Hartford Foundation, explored what is known about the pathways, contributors, and correlates of physical, cognitive and sensory functional measures across conditions and disease states; considered social determinants and health disparities; identified knowledge gaps, and suggested priorities for future research. This paper summarizes those discussions. PMID- 29697759 TI - Novel concepts and approaches in ablation of atrial fibrillation: the role of non pulmonary vein triggers. AB - Ablation of non-pulmonary vein (PV) triggers is an important step to improve outcomes in atrial fibrillation ablation. Non-pulmonary vein triggers typically originates from predictable sites (such as the left atrial posterior wall, superior vena cava, coronary sinus, interatrial septum, and crest terminalis), and these areas can be ablated either empirically or after observing significant ectopy (with or without drug challenge). In this review, we will focus on ablation of non-PV triggers, summarizing the existing evidence and our current approach for their mapping and ablation. PMID- 29697760 TI - Insulinlike Growth Factor 1 Gene Variation in Vertebrates. AB - IGF1-a small, single-chain, secreted peptide in mammals-is essential for normal somatic growth and is involved in a variety of other physiological and pathophysiological processes. IGF1 expression appears to be controlled by several different signaling mechanisms in mammals, with GH playing a key role by activating an inducible transcriptional pathway via the Jak2 protein kinase and the Stat5b transcription factor. Here, to understand aspects of Igf1 gene regulation over a substantially longer timeline than is discernible in mammals, Igf1 genes have been examined in 21 different nonmammalian vertebrates representing five different classes and ranging over ~500 million years of evolutionary history. Parts of vertebrate Igf1 genes resemble components found in mammals. Conserved exons encoding the mature IGF1 protein are detected in all 21 species studied and are separated by a large intron, as seen in mammals; the single promoter contains putative regulatory elements that are similar to those functionally mapped in human IGF1 promoter 1. In contrast, GH-activated Stat5b binding enhancers found in mammalian IGF1 loci are completely absent, there is no homolog of promoter 2 or exon 2 in any nonmammalian vertebrate, and different types of "extra" exons not present in mammals are found in birds, reptiles, and teleosts. These data collectively define properties of Igf1 genes and IGF1 proteins that were likely present in the earliest vertebrates and support the contention that common structural and regulatory features in Igf1 genes have a long evolutionary history. PMID- 29697761 TI - Clinical Impact of a Multiplex Gastrointestinal Polymerase Chain Reaction Panel in Patients With Acute Gastroenteritis. AB - Background: Molecular syndromic diagnostic panels can enhance pathogen identification in the approximately 2-4 billion episodes of acute gastroenteritis that occur annually worldwide. However, the clinical utility of these panels has not been established. Methods: We conducted a prospective, multi-center study to investigate the impact of the BioFire FilmArray Gastrointestinal polymerase chain reaction panel on clinical diagnosis and decision-making, and compared the clinical acuity of patients with positive results obtained exclusively with the FilmArray with those detected by conventional stool culture. A total of 1887 consecutive fecal specimens were tested in parallel by FilmArray and stool culture. Laboratory and medical records were reviewed to determine rates of detection, turnaround times, clinical features, and the nature and timing of clinical decisions. Results: FilmArray detected pathogens in 35.3% of specimens, compared to 6.0% for culture. Median time from collection to result was 18 hours for FilmArray and 47 hours for culture. Median time from collection to initiation of antimicrobial therapy was 22 hours for FilmArray and 72 hours for culture. Patients diagnosed by FilmArray were more likely to receive targeted rather than empirical therapy, compared to those diagnosed by culture (P = .0148). Positive Shiga-like toxin-producing E. coli results were reported 47 hours faster with FilmArray and facilitated discontinuation of empirical antimicrobials. Patients diagnosed exclusively by FilmArray had clinical characteristics similar to those identified by culture. Conclusions: FilmArray markedly improved clinical sensitivity in patients with acute diarrhea, identified cases with clinical acuity comparable to those identified by culture, and enabled clinicians to make more timely and targeted therapeutic decisions. PMID- 29697762 TI - Longitudinal Trajectories of Brain Volume and Cortical Thickness in Treated and Untreated Primary Human Immunodeficiency Virus Infection. AB - Background: Human immunodeficiency virus (HIV) penetrates the brain in early infection. We used neuroimaging to longitudinally examine the impact of HIV and combination antiretroviral therapy (cART) on the brain in treated and untreated HIV-infected participants, starting in primary HIV infection (PHI). Methods: Sixty-five participants, enrolled during PHI, underwent longitudinal magnetic resonance imaging, 30 of whom commenced cART during follow-up. Cross-sectional data from 16 patients with chronic HIV infection (CHI) and 19 HIV-uninfected participants were included for comparison. Brain volume and cortical thickness were estimated using tensor-based morphometry and cortical modeling, respectively. Mixed-effects models longitudinally mapped structural brain changes before and after cART. The relationship between brain morphometry estimates and blood and cerebrospinal fluid (CSF) biomarkers were also tested. Region-of interest analyses were performed to compare brain morphometry estimates between the groups. Results: Prior to cART, longer duration of untreated infection in PHI correlated with volume loss in the thalamus, caudate, and cerebellum, and with cortical thinning in the frontal and temporal lobes and cingulate cortex. After cART, no further volume loss was observed. However, small increases of cortical thickness in the frontal and temporal lobe correlated with longer cART duration. No correlations were observed with blood or CSF measures. The PHI group did not have different brain morphometric measures compared to the HIV-uninfected group, but had larger volumes in the thalamus, caudate, putamen, and cortical gray matter compared with CHI participants. Conclusions: Subcortical atrophy and cortical thinning occur during untreated infection but may be arrested by cART. These findings emphasize the importance of early cART. PMID- 29697763 TI - Pathogenicity of In Vivo Generated Intestinal Th17 Lymphocytes is IFNgamma Dependent. AB - Background and Aims: T helper 17 [Th17] cells are crucially involved in the immunopathogenesis of inflammatory bowel diseases in humans. Nevertheless, pharmacological blockade of interleukin 17A [IL17A], the Th17 signature cytokine, yielded negative results in patients with Crohn's disease [CD], and attempts to elucidate the determinants of Th17 cells' pathogenicity in the gut have so far proved unsuccessful. Here, we aimed to identify and functionally validate the pathogenic determinants of intestinal IL-17-producing T cells. Methods: In vivo generated murine intestinal IL-17-producing T cells were adoptively transferred into immunodeficient Rag1-/- recipients to test their pathogenicity. Human IL-17, IFNgamma/IL-17, and IFNgamma actively secreting T cell clones were generated from lamina propria lymphocytes of CD patients. The pathogenic activity of intestinal IL-17-producing T cells against the intestinal epithelium was evaluated. Results: IL-17-producing cells with variable colitogenic activity can be generated in vivo using different experimental colitis models. The pathogenicity of IL-17-secreting cells was directly dependent on their IFNgamma secretion capacity, as demonstrated by the reduced colitogenic activity of IL-17-secreting cells isolated from IFNgamma-/- mice. Moreover, IFNgamma production is a distinguished attribute of CD-derived lamina propria Th17 cells. IFNgamma secretion by CD derived IL-17-producing intestinal clones is directly implicated in the epithelial barrier disruption through the modulation of tight junction proteins. Conclusions: Intestinal Th17 cell pathogenicity is associated with IFNgamma production, which directly affects intestinal permeability through the disruption of epithelial tight junctions. PMID- 29697764 TI - Long-term clinical outcomes of cardiac resynchronization therapy with or without defibrillation: impact of the aetiology of cardiomyopathy. AB - Aims: There is a continuing debate as to whether cardiac resynchronization therapy-defibrillation (CRT-D) is superior to CRT-pacing (CRT-P), particularly in patients with non-ischaemic cardiomyopathy (NICM). We sought to quantify the clinical outcomes after primary prevention of CRT-D and CRT-P and identify whether these differed according to the aetiology of cardiomyopathy. Methods and results: Analyses were undertaken in the total study population of patients treated with CRT-D (n = 551) or CRT-P (n = 999) and in propensity-matched samples. Device choice was governed by the clinical guidelines in the United Kingdom. In univariable analyses of the total study population, for a maximum follow-up of 16 years (median 4.7 years, interquartile range 2.4-7.1), CRT-D was associated with a lower total mortality [hazard ratio (HR) 0.72] and the composite endpoints of total mortality or heart failure (HF) hospitalization (HR 0.72) and total mortality or hospitalization for major adverse cardiac events (MACE; HR 0.71) (all P < 0.001). After propensity matching (n = 796), CRT-D was associated with a lower total mortality (HR 0.72) and the composite endpoints (all P < 0.01). When further stratified according to aetiology, CRT-D was associated with a lower total mortality (HR 0.62), total mortality or HF hospitalization (HR 0.63), and total mortality or hospitalization for MACE (HR 0.59) (all P < 0.001) in patients with ischaemic cardiomyopathy (ICM). There were no differences in outcomes between CRT-D and CRT-P in patients with NICM. Conclusion: In this study of real-world clinical practice, CRT-D was superior to CRT-P with respect to total mortality and composite endpoints, independent of known confounders. The benefit of CRT-D was evident in ICM but not in NICM. PMID- 29697765 TI - Reply to Nezic et al. PMID- 29697766 TI - Intermediate Susceptibility Dose-Dependent Breakpoints For High-Dose Rifampin, Isoniazid, and Pyrazinamide Treatment in Multidrug-Resistant Tuberculosis Programs. AB - Background: Bacterial susceptibility is categorized as susceptible, intermediate susceptible dose-dependent (ISDD), and resistant. The strategy is to use higher doses of first-line agents in the ISDD category, thereby preserving the use of these drugs. This system has not been applied to antituberculosis drugs. Pharmacokinetic/pharmacodynamic (PK/PD) target exposures, in tandem with Monte Carlo experiments, recently identified susceptibility breakpoints of 0.0312 mg/L for isoniazid, 0.0625 mg/L for rifampin, and 50 mg/L for pyrazinamide. These have been confirmed in clinical studies. Methods: Target attainment studies were carried out using Monte Carlo experiments to investigate whether rifampin, isoniazid, and pyrazinamide dose increases would achieve the PK/PD target in >90% of 10000 patients with tuberculosis caused by bacteria, revealing minimum inhibitory concentrations (MICs) between the proposed and the traditional breakpoints. Results: We found that an isoniazid dose of 900 mg/day identified a new ISDD MIC range of 0.0312-0.25 mg/L and resistance at MIC >=0.5 mg/L. Rifampin 1800 mg/day would result in an ISDD of 0.0625-0.25 mg/L and resistance at MIC >=0.5 mg/L. At a dose of pyrazinamide 4 g/day, the ISDD MIC range was 37.5-50 mg/L and resistance at MIC >=100 mg/L. Based on MIC distributions, 93% (isoniazid), 78% (rifampin), and 27% (pyrazinamide) of isolates would be within the ISDD range. Conclusions: Drug susceptibility testing at 2 concentrations delineating the ISDD range, and subsequently using higher doses, could prevent switching to a more toxic second-line treatment. Confirmatory clinical studies would provide evidence to change treatment guidelines. PMID- 29697767 TI - Acquisition of Multidrug-resistant Organisms in the Absence of Antimicrobials. AB - A nested case-control study among 137 nursing home residents who did not receive antimicrobials, of whom 44 acquired a multidrug-resistant organism, was performed. Risk factors for acquisition included gastrointestinal medications that affect the gut microbiome, number of visits from healthcare workers, pressure ulcers, and not residing in a dementia unit. PMID- 29697769 TI - Carnitine Acetyltransferase in AgRP Neurons Is Required for the Homeostatic Adaptation to Restricted Feeding in Male Mice. AB - Behavioral adaptation to periods of varying food availability is crucial for survival, and agouti-related protein (AgRP) neurons have been associated with entrainment to temporal restricted feeding. We have shown that carnitine acetyltransferase (Crat) in AgRP neurons enables metabolic flexibility and appropriate nutrient partitioning. In this study, by restricting food availability to 3 h/d during the light phase, we examined whether Crat is a component of a food-entrainable oscillator (FEO) that helps link behavior to food availability. AgRP Crat knockout (KO) mice consumed less food and regained less body weight but maintained blood glucose levels during the 25-day restricted feeding protocol. Importantly, we observed no difference in meal latency, food anticipatory activity (FAA), or brown adipose tissue temperature during the first 13 days of restricted feeding. However, as the restricted feeding paradigm progressed, we noticed an increased FAA in AgRP Crat KO mice. The delayed increase in FAA, which developed during the last 12 days of restricted feeding, corresponded with elevated plasma levels of corticosterone and nonesterified fatty acids, indicating it resulted from greater energy debt incurred by KO mice over the course of the experiment. These experiments highlight the importance of Crat in AgRP neurons in regulating feeding behavior and body weight gain during restricted feeding but not in synchronizing behavior to food availability. Thus, Crat within AgRP neurons forms a component of the homeostatic response to restricted feeding but is not likely to be a molecular component of FEO. PMID- 29697770 TI - A Therapeutic Vaccine for Recurrent Vulvovaginal Candidiasis. PMID- 29697768 TI - A Fungal Immunotherapeutic Vaccine (NDV-3A) for Treatment of Recurrent Vulvovaginal Candidiasis-A Phase 2 Randomized, Double-Blind, Placebo-Controlled Trial. AB - Background: Recurrent vulvovaginal candidiasis (RVVC) is a problematic form of mucosal Candida infection, characterized by repeated episodes per year. Candida albicans is the most common cause of RVVC. Currently, there are no immunotherapeutic treatments for RVVC. Methods: This exploratory randomized, double-blind, placebo-controlled trial evaluated an immunotherapeutic vaccine (NDV-3A) containing a recombinant C. albicans adhesin/invasin protein for prevention of RVVC. Results: The study in 188 women with RVVC (n = 178 evaluable) showed that 1 intramuscular dose of NDV-3A was safe and generated rapid and robust B- and T-cell immune responses. Post hoc exploratory analyses revealed a statistically significant increase in the percentage of symptom-free patients at 12 months after vaccination (42% vaccinated vs 22% placebo; P = .03) and a doubling in median time to first symptomatic episode (210 days vaccinated vs 105 days placebo) for the subset of patients aged <40 years (n = 137). The analysis of evaluable patients, which combined patients aged <40 years (77%) and >=40 years (23%), trended toward a positive impact of NDV-3A versus placebo (P = .099). Conclusions: In this unprecedented study of the effectiveness of a fungal vaccine in humans, NDV-3A administered to women with RVVC was safe and highly immunogenic and reduced the frequency of symptomatic episodes of vulvovaginal candidiasis for up to 12 months in women aged <40 years. These results support further development of NDV-3A vaccine and provide guidance for meaningful clinical endpoints for immunotherapeutic management of RVVC. Clinical Trials Registration: NCT01926028. PMID- 29697771 TI - Burden of disease studies in the WHO European Region-a mapping exercise. AB - Background: The World Health Organization (WHO) and the Institute for Health Metrics and Evaluation (IHME) have produced numerous global burden of disease (GBD) estimates since the 1990s, using disability-adjusted life-years (DALYs). Here we attempt to identify studies that have either independent DALY estimates or build on the work of WHO and IHME, for the WHO European Region, categorize them by scope of disease analysis and geographic coverage, and briefly compare their methodology (age weighting, discounting and disability weights). Methods: Google and Google Scholar were used with the search terms 'DALY', 'national burden of disease', Member State names and researcher's names, covering all years. Studies were categorized as: 'specific' (fewer than five disease categories or just risk factors for a single country), 'specific, multicountry' (fewer than five disease categories or just risk factors for more than one country), 'extensive' (covering five or more but not all disease categories for one country), 'full, sub country' (covering all relevant disease categories for part of one country) and 'full, country' (covering all relevant disease categories for one country). Results: A total of 198 studies were identified: 143 'specific', 26 'specific, multicountry', 7 'extensive', 10 'full, sub country' and 12 'full, country' [England (1), Estonia (2), France (1), Romania (1), Serbia (1), Spain (3), Sweden (2) and Turkey (1)]. About 5 (20%) of the 25 examinable 'extensive', 'full, sub country' and 'full, country' studies calculated DALYs using GBD 2010 methodology. Conclusions: Independent burden of diseases studies in Europe have been located, and categorized by scope of disease analysis and geographic coverage. Methodological choices varied between independent 'full, country' studies. PMID- 29697772 TI - Implementation and clinical effectiveness of a community-based non-communicable disease treatment programme in rural Mexico: a difference-in-differences analysis. AB - Non-communicable diseases (NCDs) account for the five largest contributors to burden of disease in Mexico, with diabetes representing the greatest contributor. However, evidence supporting chronic disease programmes in Mexico is limited, especially in rural communities. Companeros En Salud (CES) partnered with the Secretariat of Health of Chiapas, Mexico to implement a novel community-based NCD treatment programme. We describe the implementation of this programme and conducted a population-based, retrospective analysis, using a difference-in differences regression approach to estimate the impact of the programme. Specifically, we examined changes in diabetes and hypertension control rates between 2014 and 2016, comparing CES intervention clinics (n = 9) to care-as usual at non-CES clinics (n = 806), adjusting for differences in facility-level characteristics. In 2014, the percent of diabetes patients with this condition under control was 36.9% at non-CES facilities, compared with 41.3% at CES facilities (P > 0.05). For hypertension patients, these figures were 45.2% at non CES facilities compared with 56.2% at CES facilities (P = 0.02). From 2014 to 2016, the percent of patients with diabetes under control declined by 9.2% at non CES facilities, while improving by 11.3% at non-CES facilities where the Companeros En Salud Programa de Enfermedades Cronicas intervention was implemented (P < 0.001). Among hypertension patients, those with the condition under control increased by 21.5% at non-CES facilities between 2014 and 2016, compared with 16.2% at CES facilities (P > 0.05). Introduction of the CES model of NCD care was associated with significantly greater improvements in diabetes management between 2014 and 2016, compared with care-as-usual. Hypertension control measures were already greater at CES facilities in 2014, a difference that was maintained through 2016. These findings highlight the successful implementation of a framework for providing NCD care in rural Mexico, where a rapidly increasing NCD disease burden exists. PMID- 29697774 TI - On the Hydrodynamics of Anomalocaris Tail Fins. AB - Anomalocaris canadensis, a soft-bodied stem-group arthropod from the Burgess Shale, is considered the largest predator of the Cambrian period. Thanks to a series of lateral flexible lobes along its dorso-ventrally compressed body, it is generally regarded as an efficient swimmer, well-adapted to its predatory lifestyle. Previous theoretical hydrodynamic simulations have suggested a possible optimum in swimming performance when the lateral lobes performed as a single undulatory lateral fin, comparable to the pectoral fins in skates and rays. However, the role of the unusual fan-like tail of Anomalocaris has not been previously explored. Swimming efficiency and maneuverability deduced from direct hydrodynamic analysis are here studied in a towing tank facility using a three vane physical model designed as an abstraction of the tail fin. Through direct force measurements, it was found that the model exhibited a region of steady state lift and drag enhancement at angles of attack greater than 25 degrees when compared with a triangular-shaped reference model. This would suggest that the resultant normal force on the tail fin of Anomalocaris made it well-suited for turning maneuvers, giving it the ability to turn quickly and through small radii of curvature. These results are consistent with an active predatory lifestyle, although detailed kinematic studies integrating the full organism, including the lateral lobes, would be required to test the effect of the tail fin on overall swimming performance. This study also highlights a possible example of evolutionary convergence between the tails of Anomalocaris and birds, which, in both cases, are well-adapted to efficient turning maneuvers. PMID- 29697775 TI - Cortical Afferents of Area 10 in Cebus Monkeys: Implications for the Evolution of the Frontal Pole. AB - Area 10, located in the frontal pole, is a unique specialization of the primate cortex. We studied the cortical connections of area 10 in the New World Cebus monkey, using injections of retrograde tracers in different parts of this area. We found that injections throughout area 10 labeled neurons in a consistent set of areas in the dorsolateral, ventrolateral, orbital, and medial parts of the frontal cortex, superior temporal association cortex, and posterior cingulate/retrosplenial region. However, sites on the midline surface of area 10 received more substantial projections from the temporal lobe, including clear auditory connections, whereas those in more lateral parts received >90% of their afferents from other frontal areas. This difference in anatomical connectivity reflects functional connectivity findings in the human brain. The pattern of connections in Cebus is very similar to that observed in the Old World macaque monkey, despite >40 million years of evolutionary separation, but lacks some of the connections reported in the more closely related but smaller marmoset monkey. These findings suggest that the clearer segregation observed in the human frontal pole reflects regional differences already present in early simian primates, and that overall brain mass influences the pattern of cortico-cortical connectivity. PMID- 29697776 TI - Comparing Approaches to Measure Frailty in Medicare Data: Deficit-Accumulation Frailty Index Versus Phenotypic Frailty. PMID- 29697777 TI - On the Cutting Edge of Research to Conserve At-Risk Species: Maximizing Impact through Partnerships. AB - Today's conservation challenges are complex. Solving these challenges often requires scientific collaborations that extend beyond the scope, expertise, and capacity of any single agency, organization, or institution. Conservation efforts can benefit from interdisciplinary collaboration, scientific and technological innovations, and the leveraging of capacity and resources among partners. Here we explore a series of case studies demonstrating how collaborative scientific partnerships are furthering the mission of the US Fish and Wildlife Service (USFWS), including: (1) contaminants of emerging concern in the Great Lakes Basin, (2) Poweshiek skipperling conservation, (3) using technology to improve population survey methods for bats and monarch butterfly, and (4) Big River restoration in the Southeast Missouri lead mining district. These case studies illustrate how strategic and effective scientific collaboration is a multi-stage process that requires investment of time and resources by all participants. Early coordination and communication is crucial to aligning planned work with scientific and decision-making needs. Collaborations between USFWS and external scientists can be mutually beneficial by supporting the agency mission while also providing an avenue for innovative research to be directly applied in conservation decisions and management actions. PMID- 29697778 TI - Quality of Post-Acute Care in Skilled Nursing Facilities That Disproportionately Serve Black and Hispanic Patients. AB - Background: Understanding and addressing racial and ethnic disparities in the quality of post-acute care in skilled nursing facilities is an important health policy issue, particularly as the Medicare program initiates value-based payments for these institutions. Methods: Our final cohort included 649,187 Medicare beneficiaries in either the fee-for-service or Medicare Advantage programs, who were 65 and older and were admitted to a skilled nursing facility following an acute hospital stay, from 8,375 skilled nursing facilities. We examined the quality of care in skilled nursing facilities that disproportionately serve minority patients compared to non-Hispanic whites. Three measures, all calculated at the level of the facility, were used to assess quality of care in skilled nursing facilities: 1) 30-day rehospitalization rate; 2) successful discharge from the facility to the community; and 3) Medicare five-star quality ratings. Results: We found that African-American post-acute patients are highly concentrated in a small number of institutions, with 28% of facilities accounting for 80% of all post-acute admissions for African-American patients. Similarly, just 20% of facilities accounted for 80% of all admissions for Hispanics. Skilled nursing facilities with higher fractions of African-American patients had worse performance for three publicly-reported quality measures: rehospitalization, successful discharge to the community, and the star rating indicator. Conclusions: Efforts to address disparities should focus attention on institutions that disproportionately serve minority patients and monitor unintended consequences of value-based payments to skilled nursing facilities. PMID- 29697779 TI - Transmission of Mycobacterium tuberculosis From Patients Who Are Nucleic Acid Amplification Test Negative. AB - Background: Among adults with signs and symptoms of pulmonary tuberculosis (TB), recognition of transmissible TB has implications for airborne infection isolation and public health activities. Sputum smear-negative TB patients account for around one-fifth of tuberculosis transmission. The tuberculosis transmission risk of TB patients with negative results on nucleic acid amplification test (NAAT) of respiratory specimens has not been established. We sought to estimate the tuberculosis transmission risk of NAAT-negative TB patients. Methods: We retrospectively reviewed Maryland TB program data collected from 2004 to 2009, during which time NAAT using the Mycobacterium Tuberculosis Direct Test (MTD) was performed routinely. Patients with sputum Mycobacterium tuberculosis (M.tb) isolates having matching genotypes were assigned to clusters. Transmission sequence was approximated by collection order of individuals' first culture positive specimens. Minimum transmission risks of NAAT (MTD)-negative TB patients and of smear-negative TB patients were estimated based on individuals' positions within clusters. Results: Among 809 patients with culture-confirmed TB, M.tb genotypes were available for 782 (96.7%). For NAA-negative TB patients, the minimum transmission risk estimate was 5.1% (95% CI 0-11.4). For smear-negative TB patients, the minimum transmission risk estimate was 11.2% (95% CI 7.2-15.3). Conclusions: Minimum transmission risk of NAAT-negative TB patients was lower than that of smear-negative TB patients. However, transmission risk of NAA negative TB patients appears to not be negligible. PMID- 29697780 TI - New horizons in fall prevention. AB - Falls pose a major threat to the well-being and quality of life of older people. Falls can result in fractures and other injuries, disability and fear and can trigger a decline in physical function and loss of autonomy. This article synthesises recent published findings on fall risk and mobility assessments and fall prevention interventions and considers how this field of research may evolve in the future. Fall risk topics include the utility of remote monitoring using wearable sensors and recent work investigating brain activation and gait adaptability. New approaches for exercise for fall prevention including dual-task training, cognitive-motor training with exergames and reactive step training are discussed. Additional fall prevention strategies considered include the prevention of falls in older people with dementia and Parkinson's disease, drugs for fall prevention and safe flooring for preventing fall-related injuries. The review discusses how these new initiatives and technologies have potential for effective fall prevention and improved quality of life. It concludes by emphasising the need for a continued focus on translation of evidence into practice including robust effectiveness evaluations of so that resources can be appropriately targeted into the future. PMID- 29697781 TI - Ascending aortic aneurysm repair 44 years after Starr-Edwards caged-ball aortic valve replacement. AB - We report a case of ascending aortic aneurysm repair and redo aortic valve replacement with a bioprosthesis 44 years after aortic valve replacement with a Starr-Edwards metal caged-ball prosthesis. The patient presented with a moderately stenotic caged-ball valve and a 50-mm ascending aortic aneurysm on a routine follow-up transthoracic echocardiography. We replaced the valve with a bioprosthesis at the time of aortic repair as the patient wished to stop anticoagulation therapy. Intraoperatively, we found that the cloth covering of the cage was nearly completely destroyed. PMID- 29697773 TI - Metabolic Flexibility as an Adaptation to Energy Resources and Requirements in Health and Disease. AB - The ability to efficiently adapt metabolism by substrate sensing, trafficking, storage, and utilization, dependent on availability and requirement, is known as metabolic flexibility. In this review, we discuss the breadth and depth of metabolic flexibility and its impact on health and disease. Metabolic flexibility is essential to maintain energy homeostasis in times of either caloric excess or caloric restriction, and in times of either low or high energy demand, such as during exercise. The liver, adipose tissue, and muscle govern systemic metabolic flexibility and manage nutrient sensing, uptake, transport, storage, and expenditure by communication via endocrine cues. At a molecular level, metabolic flexibility relies on the configuration of metabolic pathways, which are regulated by key metabolic enzymes and transcription factors, many of which interact closely with the mitochondria. Disrupted metabolic flexibility, or metabolic inflexibility, however, is associated with many pathological conditions including metabolic syndrome, type 2 diabetes mellitus, and cancer. Multiple factors such as dietary composition and feeding frequency, exercise training, and use of pharmacological compounds, influence metabolic flexibility and will be discussed here. Last, we outline important advances in metabolic flexibility research and discuss medical horizons and translational aspects. PMID- 29697782 TI - The inhibitory effect of BKCa channels induced by autoantibodies against angiotensin II type 1 receptor is independent of AT1R. AB - Autoantibodies against angiotensin II Type 1 receptor (AT1-AA) are routinely detected in the serum of preeclampsia patients, which results in an increase in vascular tone and an elevation in intracellular calcium concentration of rat vascular smooth muscle (VSM). The big conductance calcium-activated potassium channels (BKCa channels) account for the dominant outward currents in VSMCs, contributing to membrane hyperpolarization and vasodilation. In the present study, we investigated the effect of AT1-AA on BKCa channels. A preeclampsia model was established by passively immunizing healthy pregnant BALB/c mice with AT1-AA extracted from hybridoma culture supernatant. Blood pressure, serum AT1-AA levels, and urinary protein were measured in the immunized mice. BKCa channel expression was detected using qRT-PCR and immunohistochemical technique. The patch-clamp technique was used to record the single currents of BKCa channels in the HEK293T cells that had been transfected. AT1-AA immunized mice exhibited elevated AT1-AA and urinary protein levels compared with mice of the vehicle group. Systolic blood pressure was also increased in the immunized group. BKCa channel beta1-subunit expression was reduced in the mesenteric arteries of immunized mice. AT1-AA could inhibit the BKCa currents and the inhibitory effects were not completely reversed following the application of valsartan, an inhibitor of AT1 receptor. In conclusion, AT1-AA could decrease BKCa expression and inhibit BKCa activity independent of AT1R. These inhibitory effects are likely to be contributory factors in the promotion of increased vascular tone caused by AT1-AA in preeclampsia. PMID- 29697783 TI - Alcohol industry corporate social responsibility initiatives and harmful drinking: a systematic review. AB - Background: There is growing awareness of the detrimental effects of alcohol industry commercial activities, and concern about possible adverse impacts of its corporate social responsibility (CSR) initiatives, on public health. The aims of this systematic review were to summarize and examine what is known about CSR initiatives undertaken by alcohol industry actors in respect of harmful drinking globally. Methods: We searched for peer-reviewed studies published since 1980 of alcohol industry CSR initiatives in seven electronic databases. The basic search strategy was organized around the three constructs of 'alcohol', 'industry' and 'corporate social responsibility'. We performed the searches on 21 July 2017. Data from included studies were analyzed inductively, according to the extent to which they addressed specified research objectives. Results: A total of 21 studies were included. We identified five types of CSR initiatives relevant to the reduction of harmful drinking: alcohol information and education provision; drink driving prevention; research involvement; policy involvement and the creation of social aspects organizations. Individual companies appear to undertake different CSR initiatives than do industry-funded social aspects organizations. There is no robust evidence that alcohol industry CSR initiatives reduce harmful drinking. There is good evidence, however, that CSR initiatives are used to influence the framing of the nature of alcohol-related issues in line with industry interests. Conclusions: This research literature is at an early stage of development. Alcohol policy measures to reduce harmful drinking are needed, and the alcohol industry CSR initiatives studied so far do not contribute to the attainment of this goal. PMID- 29697784 TI - A dose-response meta-analysis of chronic arsenic exposure and incident cardiovascular disease. PMID- 29697785 TI - Host-parasite interactions and ecology of the malaria parasite-a bioinformatics approach. AB - Malaria remains one of the highest mortality infectious diseases. Malaria is caused by parasites from the genus Plasmodium. Most deaths are caused by infections involving Plasmodium falciparum, which has a complex life cycle. Malaria parasites are extremely well adapted for interactions with their host and their host's immune system and are able to suppress the human immune system, erase immunological memory and rapidly alter exposed antigens. Owing to this rapid evolution, parasites develop drug resistance and express novel forms of antigenic proteins that are not recognized by the host immune system. There is an emerging need for novel interventions, including novel drugs and vaccines. Designing novel therapies requires knowledge about host-parasite interactions, which is still limited. However, significant progress has recently been achieved in this field through the application of bioinformatics analysis of parasite genome sequences. In this review, we describe the main achievements in 'malarial' bioinformatics and provide examples of successful applications of protein sequence analysis. These examples include the prediction of protein functions based on homology and the prediction of protein surface localization via domain and motif analysis. Additionally, we describe PlasmoDB, a database that stores accumulated experimental data. This tool allows data mining of the stored information and will play an important role in the development of malaria science. Finally, we illustrate the application of bioinformatics in the development of population genetics research on malaria parasites, an approach referred to as reverse ecology. PMID- 29697786 TI - Early and long-term outcomes of open surgery after thoracic endovascular aortic repair. AB - OBJECTIVES: This study evaluated the early and long-term outcomes of open surgery after thoracic endovascular aortic repair. METHODS: We conducted a retrospective review of 41 patients who underwent open surgery following thoracic endovascular aortic repair between October 1999 and July 2017. The mean interval from primary intervention to open surgery was 3.1 +/- 3.7 years. Indications for open repair were endoleak in 14 patients, graft infection in 10 patients, false lumen dilatation in 9 patients, retrograde dissection in 5 patients, migration in 1 patient and additional aneurysm in 2 patients. Eight patients underwent emergent surgical conversions. The mean follow-up period was 4.2 +/- 4.0 years. RESULTS: Descending aortic replacement was performed in 15 patients; thoraco-abdominal aortic repair, in 14 patients; extensive arch to descending aortic replacement, in 5 patients; and total arch replacement, in 7 patients. Six (14.6%) patients died in the hospital. The 5-year survival rate was 73.7 +/- 7.2%, and freedom from reintervention was 88.5 +/- 6.4%. CONCLUSIONS: Early outcomes of open surgical procedures after thoracic endovascular aortic repair were still suboptimal. However, hospital survivors had excellent long-term outcomes. PMID- 29697787 TI - Delayed Ileal Pouch Anal Anastomosis Has a Lower 30-Day Adverse Event Rate: Analysis From the National Surgical Quality Improvement Program. AB - Background: Ulcerative colitis (UC) patients requiring colectomy often have a staged ileal pouch anal anastomosis (IPAA). There are no prospective data comparing timing of pouch creation. We aimed to compare 30-day adverse event rates for pouch creation at the time of colectomy (PTC) with delayed pouch creation (DPC). Methods: Using prospectively collected data from 2011-2015 through the National Surgical Quality Improvement Program, we conducted a cohort study including subjects aged >=18 years with a postoperative diagnosis of UC. We assessed 30-day postoperative rates of unplanned readmissions, reoperations, and major and minor adverse events (AEs), comparing the stage of the surgery where the pouch creation took place. Using a modified Poisson regression model, we estimated risk ratios (RRs) with 95% confidence intervals (CIs) adjusting for age, sex, race, body mass index, smoking status, diabetes, albumin, and comorbidities. Results: Of 2390 IPAA procedures, 1571 were PTC and 819 were DPC. In the PTC group, 51% were on chronic immunosuppression preoperatively, compared with 15% in the DPC group (P < 0.01). After controlling for confounders, patients who had DPC were significantly less likely to have unplanned reoperations (RR, 0.42; 95% CI, 0.24-0.75), major AEs (RR, 0.72; 95% CI, 0.52-0.99), and minor AEs (RR, 0.48; 95% CI, 0.32-0.73) than PTC. Conclusions: Patients undergoing delayed pouch creation were at lower risk for unplanned reoperations and major and minor adverse events compared with patients undergoing pouch creation at the time of colectomy. 10.1093/ibd/izy082_video1izy082.video15776112442001. PMID- 29697788 TI - What Are the Targets of Inflammatory Bowel Disease Management. AB - With recent evidence suggesting that keeping the inflammatory process under tight control prevents long-term disability, the aim of treatments in inflammatory bowel disease (IBD) has shifted from symptom control toward the resolution of bowel inflammation. Mucosal healing is currently recognized as the principal treatment target to be used in a "treat to target" paradigm, whereas histologic healing and normalization of biomarkers are being evaluated as potential future targets. Although symptom relief is no longer a sufficient target, patient experience with the disease is of unquestionable importance and should be assessed in the form of patient-reported outcomes, to be used as a co-primary target with an objective measure of disease activity. IBD in is a heterogeneous disease; thus besides defining common treatment targets, every effort should be made to deliver a personalized treatment plan based on the risk factors for disease progression and individual drug metabolism to improve treatment success. PMID- 29697789 TI - Unveiling Impact Identities: A Path for Connecting Science and Society. AB - We propose a thoughtful process for scientists to develop their "impact identity", a concept that integrates scholarship in a scientific discipline with societal needs, personal preferences, capacities and skills, and one's institutional context. Approaching broader impacts from a place of integrated identity can support cascading impacts that develop over the course of a career. We argue identity is a productive driver that can improve outcomes for scientists and for society. Widespread adoption of the concept of impact identity may also have implications for the recruitment and retention of a more diverse range of scientist. PMID- 29697790 TI - Mental health interventions during ventricular assist device therapy: a scoping review. AB - OBJECTIVES: Because of the high prevalence of psychological disorders among ventricular assist device patients, mental health support is consensually recommended. No study as yet has provided an overview of recommended and reported mental health interventions. This article presents the results of a scoping review on these questions. METHODS: We searched standard databases for relevant search criteria and found 4 consensus guidelines and 13 publications with original research mentioning mental health interventions for ventricular assist device patients. These publications are synthesized and augmented with practical recommendations from our reports and from a single-centre experience of others. RESULTS: Consensus guidelines recommend mental health interventions in 4 areas: screening and diagnostics, assessment, support and treatment and education. Interventions vary across treatment phases and by device therapy strategy, as do typical sources of mental distress. A flow chart of interventions over the course of treatment summarizes these findings. CONCLUSIONS: The delivery of consensually recommended mental health support for ventricular assist device patients involves the performance of multiple, complex tasks that vary across treatment phases. Mental health professionals should have specialized skills and should interact frequently with other caregivers in care teams. PMID- 29697791 TI - Positioning Tofacitinib in the Treatment Algorithm of Moderate to Severe Ulcerative Colitis. AB - Treatment options for ulcerative colitis (UC) remain limited because conventional therapies do not succeed at controlling the disease in a considerable percentage of patients, while up to 30% of those receiving biologics are primary nonresponders and 10%-20% lose response per year, requiring an increase in the treatment dose or the use of a different drug. Recently, tofacitinib, an orally administered small molecule that inhibits the Janus kinases, was proven efficacious for inducing and maintaining remission in adult patients with moderate to severe UC. Tofacitinib may represent a therapeutic alternative for the management of UC, pending approval by the US Food and Drug Administration, the European Medicines Agency, and other international regulatory authorities. Herein, we review tofacitinib's efficacy and safety data reported from randomized controlled trials in UC populations, with the aim to define how this new molecule could be inserted into the therapeutic algorithm of patients with UC. PMID- 29697792 TI - The Natural History of Newly Diagnosed Ulcerative Colitis in Patients with Concomitant Primary Sclerosing Cholangitis. AB - Background and Aims: Primary sclerosing cholangitis (PSC) is commonly associated with ulcerative colitis (UC). Our aim was to compare the course of disease in patients with UC-PSC and UC alone in a nationwide cohort. Methods: We conducted a retrospective cohort study among nation-wide Veterans Affairs (VA) patients newly diagnosed with UC to determine the association between PSC status and clinical outcomes related to UC disease course. This study was divided into 2 groups of patients: (1) The incident UC-PSC group and (2) the incident UC-alone group. Follow-up began at the time of index colonoscopy that diagnosed UC and ended at the first occurrence of the respective outcome for the regression analysis of the following censoring events: (1) colectomy, (2) death, (3) end of follow-up, and (4 lost to follow-up. Results: The analysis included 836 UC patients without PSC and 74 UC-PSC patients. In univariate comparisons, PSC patients were more likely to have more extensive UC than those without PSC. In a multivariable Cox regression analysis adjusting for sex, age at UC diagnosis, race, severity of UC, and extent of UC, PSC status was not associated with the risk of colectomy for UC, increased risk of receiving >= 2 courses of steroids for UC, or with the risk of receiving immunomodulators for UC. Conclusion: UC-PSC patients do not have a more benign disease course than UC patients without PSC. UC-PSC patients may have a modestly increased risk for multiple courses of steroids, which may be mediated by more extensive colonic involvement. PMID- 29697794 TI - Non-coding RNAs in endometriosis: a narrative review. AB - BACKGROUND: Endometriosis is a benign gynaecological disorder, which affects 10% of reproductive-aged women and is characterized by endometrial cells from the lining of the uterus being found outside the uterine cavity. However, the pathophysiological mechanisms causing the development of this heterogeneous disease remain enigmatic, and a lack of effective biomarkers necessitates surgical intervention for diagnosis. There is international recognition that accurate non-invasive diagnostic tests and more effective therapies are urgently needed. Non-coding RNA (ncRNA) molecules, which are important regulators of cellular function, have been implicated in many chronic conditions. In endometriosis, transcriptome profiling of tissue samples and functional in vivo and in vitro studies demonstrate that ncRNAs are key contributors to the disease process. OBJECTIVE AND RATIONALE: In this review, we outline the biogenesis of various ncRNAs relevant to endometriosis and then summarize the evidence indicating their roles in regulatory pathways that govern disease establishment and progression. SEARCH METHODS: Articles from 2000 to 2016 were selected for relevance, validity and quality, from results obtained in PubMed, MEDLINE and Google Scholar using the following search terms: ncRNA and reproduction; ncRNA and endometriosis; miRNA and endometriosis; lncRNA and endometriosis; siRNA and endometriosis; endometriosis; endometrial; cervical; ovary; uterus; reproductive tract. All articles were independently screened for eligibility by the authors. OUTCOMES: This review integrates extensive information from all relevant published studies focusing on microRNAs, long ncRNAs and short inhibitory RNAs in endometriosis. We outline the biological function and synthesis of microRNAs, long ncRNAs and short inhibitory RNAs and provide detailed findings from human research as well as functional studies carried out both in vitro and in vivo, including animal models. Although variability in findings between individual studies exists, collectively, the extant literature justifies the conclusion that dysregulated ncRNAs are a significant element of the endometriosis condition. WIDER IMPLICATIONS: There is a compelling case that microRNAs, long non-coding RNAs and short inhibitory RNAs have the potential to influence endometriosis development and persistence through modulating inflammation, proliferation, angiogenesis and tissue remodelling. Rapid advances in ncRNA biomarker discovery and therapeutics relevant to endometriosis are emerging. Unravelling the significance of ncRNAs in endometriosis will pave the way for new diagnostic tests and identify new therapeutic targets and treatment approaches that have the potential to improve clinical options for women with this disabling condition. PMID- 29697793 TI - Sequence, Structure, and Expression of Opsins in the Monochromatic Stomatopod Squilla empusa. AB - Most stomatopod crustaceans have complex retinas in their compound eyes, with up to 16 spectral types of photoreceptors, but members of the superfamily Squilloidea have much simpler retinas, thought to contain a single photoreceptor spectral class. In the Atlantic stomatopod Squilla empusa, microspectrophotometry shows that all photoreceptors absorb light maximally at 517 nm, indicating that a single visual pigment is present in all photoreceptors in the retina. However, six distinct, but partial, long wavelength sensitive (LWS) opsin transcripts, which encode the protein component of the visual pigment, have been previously isolated through RT-PCR. In order to investigate the spectral and functional differences among S. empusa's opsins, we used RT-PCR to complete the 3' end of sequences for five of the six expressed opsins. The extended sequences spanned from the first transmembrane (TM1) helix to the 3' end of the coding region. Using homology-based modeling, we predicted the three-dimensional structure of the amino acid translation of the S. empusa opsins. Based on these analyses, S. empusa LWS opsins share a high sequence identity in TM regions and in amino acids within 15 A of the chromophore-binding lysine on TM helix 7 (TM7), suggesting that these opsins produce spectrally similar visual pigments in agreement with previous results. However, we propose that these spectrally similar opsins differ functionally, as there are non-conservative amino acid substitutions found in intracellular loop 2 (ICL2) and TM5/ICL3, which are critical regions for G protein binding, and substitutions in extracellular regions suggest different chromophore attachment affinities. In situ hybridization of two of the opsins (Se5 and Se6) revealed strong co-expression in all photoreceptors in both midband and peripheral regions of the retina as well as in selected ocular and cerebral ganglion neuropils. These data suggest the expression of multiple opsins-likely spectrally identical, but functionally different-in multiple types of neuronal cells in S. empusa. This suggests that the multiple opsins characteristic of other stomatopod species may have similar functional specialization. PMID- 29697795 TI - Genetic covariance components within and among linear type traits differ among contrasting beef cattle breeds. AB - Linear type traits describing the skeletal, muscular, and functional characteristics of an animal are routinely scored on live animals in both the dairy and beef cattle industries. Previous studies have demonstrated that genetic parameters for certain performance traits may differ between breeds; no study, however, has attempted to determine if differences exist in genetic parameters of linear type traits among breeds or sexes. Therefore, the objective of the present study was to determine if genetic covariance components for linear type traits differed among five contrasting cattle breeds, and to also investigate if these components differed by sex. A total of 18 linear type traits scored on 3,356 Angus (AA), 31,049 Charolais (CH), 3,004 Hereford (HE), 35,159 Limousin (LM), and 8,632 Simmental (SI) were used in the analysis. Data were analyzed using animal linear mixed models which included the fixed effects of sex of the animal (except in the investigation into the presence of sexual dimorphism), age at scoring, parity of the dam, and contemporary group of herd-date of scoring. Differences (P < 0.05) in heritability estimates, between at least two breeds, existed for 13 out of 18 linear type traits. Differences (P < 0.05) also existed between the pairwise within-breed genetic correlations among the linear type traits. Overall, the linear type traits in the continental breeds (i.e., CH, LM, SI) tended to have similar heritability estimates to each other as well as similar genetic correlations among the same pairwise traits, as did the traits in the British breeds (i.e., AA, HE). The correlation between a linear function of breeding values computed conditional on covariance parameters estimated from the CH breed with a linear function of breeding values computed conditional on covariance parameters estimated from the other breeds was estimated. Replacing the genetic covariance components estimated in the CH breed with those of the LM had least effect but the impact was considerable when the genetic covariance components of the AA were used. Genetic correlations between the same linear type traits in the two sexes were all close to unity (>=0.90) suggesting little advantage in considering these as separate traits for males and females. Results for the present study indicate the potential increase in accuracy of estimated breeding value prediction from considering, at least, the British breed traits separate to continental breed traits. PMID- 29697797 TI - Efficacy and Safety of Endoscopic Balloon Dilatation of Ileoanal Pouch Strictures. AB - Background and aims: Colectomy with ileoanal pouch is the standard of care for most patients with ulcerative colitis (UC) who require surgery. However, 5%-38% of patients with ileoanal pouch develop pouch strictures that can severely impact the functional results. We retrospectively evaluated the efficacy and safety of endoscopic balloon dilation of ileoanal pouch strictures in patients with inflammatory bowel disease (IBD). Methods: All consecutive patients with IBD that underwent endoscopic balloon dilatation of a pouch stricture at our institution between January 1, 2011, and April 31, 2016, were included. Clinical, endoscopic, and surgical variables were collected retrospectively. Stricture-related pouch failure was defined by the need for surgical management of pouch stricture including pouch excision, diversion ileostomy, or stricturoplasty. Secondary outcomes included technical success, clinical success, and safety. Results: Eighty-eight endoscopic balloon dilatations were identified in 20 patients. Sixty percent of patients were female, with a median age at ileoanal pouch of 28.6 years (interquartile range [IQR], 25.5-37.2). Ileoanal pouch was performed for UC in 95% of cases; 95% of patients underwent J pouch; and 65% had a stapled anastomosis, whereas 35% had a handsewn anastomosis. Strictures were diagnosed at a median of 4.6 years (0.2-10.6) after surgery, and half of patients were symptomatic. The most frequent location of stricture was the anal-pouch anastomosis (87%). Half of patients were found to have associated pouchitis, 4 (20%) had at least 1 fistula, and 5 (25%) had ulcerations of the pouch. At the end of follow-up, 6 patients (30%) underwent a change in diagnosis from UC to Crohn's disease (CD) of the pouch, and in 1 patient (5%) a diagnosis of ischemic stricture was made. A median of 3.5 dilatations per patient (IQR, 2.0-7.0) were performed. Technical efficacy was observed in 87 procedures (98%). Twenty-two procedures were preceded by obstructive symptoms, and a clinical improvement after endoscopic balloon dilatation was observed in 95% of cases. After a median follow-up of 3.0 years (2.1-3.5), only 1 patient had stricture-related pouch failure. After the first dilatation, 4 patients were hospitalized for obstructive symptoms. Conservative management with another endoscopic balloon dilation was clinically effective in all cases. No major complications related to dilation were observed. Conclusion: Endoscopic balloon dilatation of ileoanal pouch strictures is largely effective and safe and can be recommended as the first line strategy to treat ileoanal pouch strictures in patients with IBD. PMID- 29697796 TI - Differences in Transmission and Disease Severity Between 2 Successive Waves of Chikungunya. AB - Background: Chikungunya, an arboviral disease, caused massive epidemics in Central and South America in 2014-2016. In a prospective pediatric cohort study, we examined the introduction of chikungunya in a naive population and investigated transmission and clinical characteristics. Methods: Children presenting to the study health center with a chikungunya-like illness or undifferentiated fever were tested for chikungunya virus (CHIKV) infection by reverse transcriptase-polymerase chain reaction (RT-PCR) and serological assays. Inapparent CHIKV infections in the intervening year were determined by seroconversion in healthy blood samples collected annually. Results: A total of 4353 children participated in the cohort study from March 2014 to February 2016 during the 2 epidemic waves of chikungunya. A total of 539 cases of chikungunya were documented, for an incidence rate of 80.2 cases per 1000 person-years (95% confidence interval [CI]: 73.7, 87.2); and a total of 893 CHIKV infections were documented, for an incidence rate of 137.1 infections per 1000 person-years (95% CI: 128.4, 146.4). The seroprevalence of anti-CHIKV antibodies increased linearly with age, with seroprevalence of >45% in 14-year-old children at the end of Epidemic 2. Symptom presentation varied between the epidemics, with Epidemic 2 exhibiting both a higher symptomatic-to-inapparent ratio (1:1.20 in Epidemic 1 vs. 1:0.65 in Epidemic 2) and more severe clinical presentation among cases. The mean reproduction number was also greater in Epidemic 2 than in Epidemic 1. Conclusions: The intensity of transmission and severity of clinical presentation varied between the 2 epidemics, with higher transmission intensity associated with greater disease severity. PMID- 29697798 TI - Fifty generations of Icelanders help to explain a cause of aortic coarctation. PMID- 29697799 TI - Who wants to cross borders in the EU for healthcare? An analysis of the Eurobarometer data in 2007 and 2014. AB - Background: The European Union (EU) Directive on Patients' Rights in Cross-border Healthcare clarified the entitlements to medical care in other EU Member states. However, little is known about whether EU citizens have been travelling or are willing to travel to receive care. This study aimed to measure the determinants of cross-border patient mobility and willingness to travel to receive medical care in the EU, before and after the adoption of the Directive. Methods: We used individual data from the Eurobarometer 210 (2007) and 425 (2014). In the 2 years, 53 439 EU citizens were randomly selected. We performed a logistic regression on the cross-border patient mobility and willingness to travel to other EU countries to use healthcare services as a function of the year (2007 or 2014), adjusting for age, gender, education and country size. Results: In 2007, 3.3% of citizens reported cross-border mobility and 4.6% in 2014. The odds of cross-border patients' mobility were 11% higher in 2014, compared with 2007 [odds ratio (OR) 1.11, 95% confidence interval (CI) 1.02-1.21]. Also, mobility was 19% higher in males (OR 1.19, 95% CI 1.08-1.30) and 20% higher amongst the more educated (OR 1.20, 95% CI 1.09-1.31). However, the odds decreased 11% per decade of age (OR 0.89 per decade, 95% CI 0.85-0.93) and country size. In 2014, the willingness to travel decreased by 20% compared with 2007. Conclusions: Cross-border patient mobility is more likely amongst the younger, the more educated and those from smaller countries. The directive does not seem to have promoted mobility at a large scale among the neediest citizens. PMID- 29697800 TI - Developing Interactive Exhibits with Scientists: Three Example Collaborations from the Life Sciences Collection at the Exploratorium. AB - Science museums have made a concerted effort to work with researchers to incorporate current scientific findings and practices into informal learning opportunities for museum visitors. Many of these efforts have focused on creating opportunities and support for researchers to interact face-to-face with the public through, for example, speaker series, community forums, and engineering competitions. However, there are other means by which practicing scientists can find a voice on the museum floor-through the design and development of exhibits. Here we describe how researchers and museum professionals have worked together to create innovative exhibit experiences for an interactive science museum. For each example: scientist as (1) data providers, (2) advisors, and (3) co-developers, we highlight essential components for a successful partnership and pitfalls to avoid when collaborating on museum exhibits. Not many museums prototype and build their own exhibits like the Exploratorium. In those cases, there may be similar opportunities in more mediated offerings such as public demonstrations or lectures or in other formats that allow for direct interactions between scientists and visitors. We believe there are many opportunities for researchers to share natural phenomena, to advise on exhibit development and interpretation, to provide much needed materials, and to otherwise incorporate authentic research into the learning experiences at museums, no matter what the format. PMID- 29697801 TI - Novel mutations in PATL2 cause female infertility with oocyte germinal vesicle arrest. AB - STUDY QUESTION: Do PATL2 mutations account for female infertility with oocyte germinal vesicle (GV) arrest? SUMMARY ANSWER: Four of nine independent families with oocyte GV arrest were identified with biallelic PATL2 mutations, suggesting that these mutations may be responsible for oocyte maturation arrest in primary infertile women. WHAT IS KNOWN ALREADY: Recently, two independent studies have demonstrated that infertility in some women with oocyte maturation arrest at the GV stage was caused by biallelic mutations in PATL2. PATL2 encodes protein PAT1 homolog 2, an RNA-binding protein that may act as a translational repressor. STUDY DESIGN, SIZE, DURATION: In this study, nine unrelated primary infertile females presenting with oocyte GV arrest were recruited during the treatment of early rescue ICSI or ICSI from January 2013 to December 2016. PARTICIPANTS/MATERIALS, SETTING, METHODS: Genomic DNA was isolated from blood samples obtained from all nine affected individuals and all of their available family members. All the coding regions of PATL2 were sequenced by Sanger sequencing. The pathogenicity of the identified variants and their possible effects on the protein were evaluated in silico. MAIN RESULTS AND THE ROLE OF CHANCE: Five novel point mutations and one recurrent splicing mutation in PATL2 were identified in four of nine (44.4%) unrelated patients. We found a consanguineous family with a homozygous missense mutation in two affected sisters, and their fertile brother. There were no clear phenotypic differences in oocytes between the patient with the homozygous missense mutation, patients with nonsense mutations and undiagnosed patients. LARGE SCALE DATA: n/a. LIMITATIONS, REASONS FOR CAUTION: The function of PATL2 remains largely unknown. Both the exact pathogenic mechanism(s) of mutated PATL2 causing human oocyte maturation arrest and the strategies to overcome this condition should be further investigated in the future. WIDER IMPLICATIONS OF THE FINDINGS: According to our data, mutations in PATL2 account for 44.4% of the individuals with oocyte GV arrest. Our study further confirms that PATL2 is required for human oocyte maturation and female fertility, which indicates a potential prognostic value of testing for PATL2 mutations in primary infertile women with oocyte maturation arrest. STUDY FUNDING/COMPETING INTEREST(S): Natural Science Foundation of Anhui Province (1808085MH241), National Natural Science Foundation of China (81401251 and 81370757) and Central Guided Local Development of Science and Technology Special Fund (2016080802D114) supported this study. None of the authors have any competing interests. PMID- 29697802 TI - So You Want to Share Your Science .... Connecting to the World of Informal Science Learning. AB - Scientists can reap personal rewards through collaborations with science and natural history museums, zoos, botanical gardens, aquaria, parks, and nature preserves, and, while doing so, help to advance science literacy and broaden participation in the natural sciences. Beyond volunteer opportunities, which allow scientists to contribute their knowledge and passion within the context of existing programs and activities, there are also opportunities for scientists to bring their knowledge and resources to the design and implementation of new learning experiences for visitors to these informal science learning organizations (ISLOs). Well-designed education outreach plans that leverage the expertise and broad audiences of ISLOs can also enhance the prospects of research grant proposals made to agencies such as National Science Foundation, which encourage researchers to pay careful attention to the broader impacts of their research as well as its intellectual merit. Few scientists, however, have had the opportunity to become familiar with the pedagogy and design of informal or "free choice" science learning, and fewer still know how to go about the process of collaborating with ISLOs in developing and implementing effective programs, exhibits, and other learning experiences. This article, written by an experienced science museum professional, provides guidance for individual scientists and research groups interested in pursuing effective education outreach collaborations with science museums and other ISLOs. When prospective partners begin discussions early in the proposal development process, they increase the likelihood of successful outcomes in funding, implementation, and impact. A strategic planning worksheet is provided, along with a carefully-selected set of further resources to guide the design and planning of informal science learning experiences. PMID- 29697804 TI - Clozapine and Long-Term Mortality Risk in Patients With Schizophrenia: A Systematic Review and Meta-analysis of Studies Lasting 1.1-12.5 Years. AB - Introduction: Patients with schizophrenia have an elevated mortality risk compared to the general population, with cardiovascular-related deaths being the leading cause. The role of clozapine use in the long-term mortality risk is unclear. While clozapine treatment may increase the risk for cardiovascular mortality, it may have protective effects regarding suicidal behavior. Methods: We systematically searched EMBASE, MEDLINE, and PsycINFO and reviewed studies that used a long-term follow-up (ie, >52 weeks) and reported on mortality in adults diagnosed with schizophrenia-spectrum disorders who had received clozapine treatment. Results: Altogether, 24 studies reported on 1327 deaths from any causes during 217691 patient years in patients treated with clozapine. The unadjusted mortality rate in 22 unique samples during a follow-up of 1.1-12.5 (median = 5.4) years was 6.7 (95% confidence interval [CI] = 5.4-7.9) per 1000 patient years. Long-term, crude mortality rate ratios were not significantly lower in patients ever treated with clozapine during follow-up, but significantly lower in patients continuously treated with clozapine compared to patients with other antipsychotics (mortality rate ratio = 0.56, 95% CI = 0.36-0.85, P-value = .007). Few studies reported on rates of long-term cause-specific mortality (suicide and ischemic heart disease), which showed no significant difference in patients using clozapine compared to patients using other antipsychotics. Statistical heterogeneity was high in all analyses. Discussion: Continuous clozapine treatment in schizophrenia patients was associated with a significantly lower long-term all-cause mortality rate compared to other antipsychotic use. These findings, combined with the known efficacy of clozapine, give reason to re evaluate the hesitancy to prescribe clozapine in regular care settings. Trial registration: PROSPERO CRD42017069390. PMID- 29697803 TI - Arabidopsis HEAT SHOCK TRANSCRIPTION FACTORA1b regulates multiple developmental genes under benign and stress conditions. AB - In Arabidopsis thaliana, HEAT SHOCK TRANSCRIPTION FACTORA1b (HSFA1b) controls resistance to environmental stress and is a determinant of reproductive fitness by influencing seed yield. To understand how HSFA1b achieves this, we surveyed its genome-wide targets (ChIP-seq) and its impact on the transcriptome (RNA-seq) under non-stress (NS), heat stress (HS) in the wild type, and in HSFA1b overexpressing plants under NS. A total of 952 differentially expressed HSFA1b targeted genes were identified, of which at least 85 are development associated and were bound predominantly under NS. A further 1780 genes were differentially expressed but not bound by HSFA1b, of which 281 were classified as having development-associated functions. These genes are indirectly regulated through a hierarchical network of 27 transcription factors (TFs). Furthermore, we identified 480 natural antisense non-coding RNA (cisNAT) genes bound by HSFA1b, defining a further mode of indirect regulation. Finally, HSFA1b-targeted genomic features not only harboured heat shock elements, but also MADS box, LEAFY, and G Box promoter motifs. This revealed that HSFA1b is one of eight TFs that target a common group of stress defence and developmental genes. We propose that HSFA1b transduces environmental cues to many stress tolerance and developmental genes to allow plants to adjust their growth and development continually in a varying environment. PMID- 29697807 TI - Effects of protein supplements consumed with meals, versus between meals, on resistance training-induced body composition changes in adults: a systematic review. AB - Context: The impact of timing the consumption of protein supplements in relation to meals on resistance training-induced changes in body composition has not been evaluated systematically. Objective: The aim of this systematic review was to assess the effect of consuming protein supplements with meals, vs between meals, on resistance training-induced body composition changes in adults. Data Sources: Studies published up to 2017 were identified with the PubMed, Scopus, Cochrane, and CINAHL databases. Data Extraction: Two researchers independently screened 2077 abstracts for eligible randomized controlled trials of parallel design that prescribed a protein supplement and measured changes in body composition for a period of 6 weeks or more. Results: In total, 34 randomized controlled trials with 59 intervention groups were included and qualitatively assessed. Of the intervention groups designated as consuming protein supplements with meals (n = 16) vs between meals (n = 43), 56% vs 72% showed an increase in body mass, 94% vs 90% showed an increase in lean mass, 87% vs 59% showed a reduction in fat mass, and 100% vs 84% showed an increase in the ratio of lean mass to fat mass over time, respectively. Conclusions: Concurrently with resistance training, consuming protein supplements with meals, rather than between meals, may more effectively promote weight control and reduce fat mass without influencing improvements in lean mass. PMID- 29697806 TI - Decreasing triage time: effects of implementing a step-wise ESI algorithm in an EHR. AB - Objectives: To determine if adapting a widely-used triage scale into a computerized algorithm in an electronic health record (EHR) shortens emergency department (ED) triage time. Design: Before-and-after quasi-experimental study. Setting: Urban, tertiary care hospital ED. Participants: Consecutive adult patient visits between July 2011 and June 2013. Intervention: A step-wise algorithm, based on the Emergency Severity Index (ESI-5) was programmed into the triage module of a commercial EHR. Main Outcome Measures: Duration of triage (triage interval) for all patients and change in percentage of high acuity patients (ESI 1 and 2) completing triage within 15 min, 12 months before-and after implementation of the algorithm. Multivariable analysis adjusted for confounders; interrupted time series demonstrated effects over time. Secondary outcomes examined quality metrics and patient flow. Results: About 32 546 patient visits before and 33 032 after the intervention were included. Post-intervention patients were slightly older, census was higher and admission rate slightly increased. Median triage interval was 5.92 min (interquartile ranges, IQR 4.2 8.73) before and 2.8 min (IQR 1.88-4.23) after the intervention (P < 0.001). Adjusted mean triage interval decreased 3.4 min (95% CI: -3.6, -3.2). The proportion of high acuity patients completing triage within 15 min increased from 63.9% (95% CI 62.5, 65.2%) to 75.0% (95% CI 73.8, 76.1). Monthly time series demonstrated immediate and sustained improvement following the intervention. Return visits within 72 h and door-to-balloon time were unchanged. Total length of stay was similar. Conclusion: The computerized triage scale improved speed of triage, allowing more high acuity patients to be seen within recommended timeframes, without notable impact on quality. PMID- 29697805 TI - Single-cell analysis of [Ca2+]i signalling in sub-fertile men: characteristics and relation to fertilization outcome. AB - STUDY QUESTION: What are the characteristics of progesterone-induced (CatSper mediated) single cell [Ca2+]i signals in spermatozoa from sub-fertile men and how do they relate to fertilizing ability? SUMMARY ANSWER: Single cell analysis of progesterone-induced (CatSper-mediated) [Ca2+]i showed that reduced progesterone sensitivity is a common feature of sperm from sub-fertile patients and is correlated with fertilization rate. WHAT IS KNOWN ALREADY: Stimulation with progesterone is a widely used method for assessing [Ca2+]i mobilization by activation of CatSper in human spermatozoa. Although data are limited, sperm population studies have indicated an association of poor [Ca2+]i response to progesterone with reduced fertilization ability. STUDY DESIGN, SIZE, DURATION: This was a cohort study using semen samples from 21 donors and 101 patients attending the assisted conception unit at Ninewells Hospital Dundee who were undergoing ART treatment. Patients were recruited from January 2016 to June 2017. PARTICIPANTS/MATERIALS, SETTING, METHODS: Semen donors and patients were recruited in accordance with local ethics approval (13/ES/0091) from the East of Scotland Research Ethics Service (EoSRES) REC1. [Ca2+]i responses were examined by single cell imaging and motility parameters assessed by computer-assisted sperm analysis (CASA). MAIN RESULTS AND THE ROLE OF CHANCE: For analysis, patient samples were divided into three groups IVF(+ve) (successful fertilization; 62 samples), IVF-FF (failed fertilization; eight samples) and ICSI (21 samples). A further 10 IVF samples showed large, spontaneous [Ca2+]i oscillations and responses to progesterone could not be analysed. All patient samples loaded with the [Ca2+]i-indicator fluo4 responded to progesterone stimulation with a biphasic increase in fluorescence (transient followed by plateau) which resembled that seen in progesterone-stimulated donor samples. The mean normalized response (progesterone-induced increase in fluorescence normalized to resting level) was significantly smaller in IVF-FF and ICSI patient groups than in donors. All samples were further analysed by plotting, for each cell, the relationship between resting fluorescence intensity and the progesterone-induced fluorescence increment. In donor samples these plots overlaid closely and had a gradient of ~ 2 and plots for most IVF(+ve) samples closely resembled the donor distribution. However, in a subset (~ 10%) of IVF(+ve) samples, 3/8 IVF-FF samples and one third of ICSI samples the gradient of the plot was significantly lower, indicating that the response to progesterone of the cells in these samples was abnormally small. Examination of the relationship between gradient (regression coefficient of the plot) in IVF samples and fertilization rate showed a positive correlation. In IVF-FF and ICSI groups, the proportion of cells in which a response to progesterone could be detected was significantly lower than in donors and IVF (+ve) patients. Approximately 20% of cells in donor, IVF(+ve) and ICSI samples generated [Ca2+]i oscillations when challenged with progesterone but in IVF-FF samples only ~ 10% of cells generated oscillations and there was a significantly greater proportion of samples where no oscillations were observed. Levels of hyperactivated motility were lower in IVF(+ve) and IVF-FF groups compared to controls, IVF-FF also having lower levels than IVF(+ve). LIMITATIONS, REASONS FOR CAUTION: This is an in vitro study and caution must be taken when extrapolating these results in vivo. WIDER IMPLICATIONS OF THE FINDINGS: This study reveals important details of impaired [Ca2+]i signalling in sperm from sub fertile men that cannot be detected in population studies. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by a MRC project grant (MR/M012492/1; MR/K013343/1). Additional funding was provided by Chief Scientist Office/NHS research Scotland. PMID- 29697808 TI - A Mathematical Model of Photosynthetic Electron Transport in Response to the Light Spectrum Based on Excitation Energy Distributed to Photosystems. AB - To enable us to analyze more systematically the effects of the spectral distribution of light (i.e. light quality) on photosynthetic electron transport, we propose a simple mathematical model which describes electron transport reactions under light-limited conditions based on the excitation energy distributed to the photosystems. The model assumes that the rate-limiting photosystem performs the photochemical reaction at its maximum yield, while the yield in the other photosystem is passively down-regulated to equalize the rates of linear electron transport through the photosystems. Using intact cucumber leaves, we tested the model by comparing actual and estimated photosynthetic parameters under several combinations of photon flux densities of red and far-red lights (R and FR, respectively). Simultaneously provided R and FR yielded greater gross photosynthetic rates than the sums of the rates under only R and only FR, which is known as the 'enhancement effect'. The present model reproduced these non-additive increases in the gross photosynthetic rates in response to supplemental FR to R and provided more accurate estimates than an existing method that did not take the enhancement effect into account (root mean square errors: 0.11 and 0.21 MUmol m-2 s-1, respectively). Using the present model, the photon flux density of the supplemental FR which gives the changing point of rate limiting photosystem and the photochemical yields of the non-rate-limiting photosystems were estimated reasonably well. The present study has therefore formulated a simplified quantitative electron transport model in response to the light spectrum based on generally accepted concepts and demonstrated its validity experimentally. PMID- 29697809 TI - CD3 immunohistochemistry is helpful in the diagnosis of giant cell arteritis. AB - Objective: To evaluate whether CD3 staining performed routinely on temporal artery biopsy specimens might improve the sensitivity of temporal artery biopsy in patients with biopsy-negative GCA. Methods: Two hundred and seventy biopsies were considered for this study, stained with haematoxylin and eosin and with an anti-CD3 antibody. Results: The addition of CD3 staining modified the sensibility and the specificity of the histologic examination in 89.47 and 95.00%, respectively, with a positive and negative predictive values of 97.00 and 79.78% . Conclusion: The addition of CD3 immunostaining to the classic histologic evaluation is accompanied by a significant increase in the sensibility with a comparable specificity. PMID- 29697810 TI - Higher Infliximab Levels Are Not Associated With an Increase in Adverse Events in Inflammatory Bowel Disease. AB - Background: Patients requiring optimization of therapy for suboptimal response and/or targeting more robust outcomes may eventually reach high serum levels. Data evaluating the relationship between infliximab concentration and toxicity are limited. The aim of this study was to evaluate the frequency of adverse events (AEs) in inflammatory bowel disease (IBD) patients with infliximab higher range (HR) and lower-range (LR) trough levels. Methods: We performed a retrospective analysis of 180 patients with at least 1 measurement of serum infliximab from 2012 to 2016. The cohort was divided according to an infliximab level cutoff of 15 ug/mL (HR and LR). The primary outcome was frequency of AEs, including infections, dermatological manifestations, and infusion reactions, between the 2 groups. The secondary outcomes included frequencies of all AEs (dermatological manifestations, infusion reactions, autoimmune reactions, and opportunistic and serious infections) in both groups. AEs were also compared against observed infliximab level quartiles using logistic regression analysis. Results: A total of 53 AEs in 47 patients were reported in the overall cohort. In the LR group, there were 36 AEs recorded in 30 patients, whereas in the HR group, 17 AEs were experienced by 17 patients. Patients with HR levels did not have a higher prevalence of infections in comparison with patients with LR levels (12.2% vs 18.8%; P = 0.3). Stratification of infliximab levels by quartiles showed a comparable frequency of infection. Conclusions: Our findings indicate that higher infliximab serum concentrations are not associated with a higher frequency of infections. PMID- 29697811 TI - How have task force members determined the threshold value of EuroSCORE II for an increased surgical risk in patients undergoing aortic valve interventions? PMID- 29697812 TI - Regressed but Not Gone: Patterns of Vision Gene Loss and Retention in Subterranean Mammals. AB - Regressive evolution involves the degradation of formerly useful traits as organisms invade novel ecological niches. In animals, committing to a strict subterranean habit can lead to regression of the eyes, likely due to a limited exposure to light. Several lineages of subterranean mammals show evidence of such degeneration, which can include decreased organization of the retina, malformation of the lens, and subcutaneous positioning of the eye. Advances in DNA sequencing have revealed that this regression co-occurs with a degradation of genomic loci encoding visual functions, including protein-coding genes. Other dim light-adapted vertebrates with normal ocular anatomy, such as nocturnal and aquatic species, also demonstrate evidence of visual gene loss, but the absence of comparative studies has led to the untested assumption that subterranean mammals are special in the degree of this genomic regression. Additionally, previous studies have shown that not all vision genes have been lost in subterranean mammals, but it is unclear whether they are under relaxed selection and will ultimately be lost, are maintained due to pleiotropy or if natural selection is favoring the retention of the eye and certain critical underlying loci. Here I report that vision gene loss in subterranean mammals tends to be more extensive in quantity and differs in distribution from other dim light adapted mammals, although some committed subterranean mammals demonstrate significant overlap with nocturnal microphthalmic species. In addition, blind subterranean mammals retain functional orthologs of non-pleiotropic visual genes that are evolving at rates consistent with purifying selection. Together, these results suggest that although living underground tends to lead to major losses of visual functions, natural selection is maintaining genes that support the eye, perhaps as an organ for circadian and/or circannual entrainment. PMID- 29697813 TI - NEW DEVELOPMENTS AND APPLICATIONS OF SUPERHEATED EMULSIONS: WARHEAD VERIFICATION AND SPECIAL NUCLEAR MATERIAL INTERDICTION. AB - In recent years, neutron detection with superheated emulsions has received renewed attention thanks to improved detector manufacturing and read-out techniques, and thanks to successful applications in warhead verification and special nuclear material (SNM) interdiction. Detectors are currently manufactured with methods allowing high uniformity of the drop sizes, which in turn allows the use of optical read-out techniques based on dynamic light scattering. Small detector cartridges arranged in 2D matrices are developed for the verification of a declared warhead without revealing its design. For this application, the enabling features of the emulsions are that bubbles formed at different times cannot be distinguished from each other, while the passive nature of the detectors avoids the susceptibility to electronic snooping and tampering. Large modules of emulsions are developed to detect the presence of shielded special nuclear materials hidden in cargo containers 'interrogated' with high energy X rays. In this case, the enabling features of the emulsions are photon discrimination, a neutron detection threshold close to 3 MeV and a rate insensitive read-out. PMID- 29697814 TI - Implantable cardioverter-defibrillator therapy and device-related complications in young patients with inherited cardiomyopathies or channelopathies: a 17-year cohort study. AB - Aims: To quantify appropriate and inappropriate therapy and complications related to implantable cardioverter-defibrillator (ICD) treatment in young patients receiving an ICD for a hereditary cardiomyopathy or channelopathy. Methods and results: This was a retrospective study including 117 consecutive patients who had received an ICD at Aarhus University Hospital, Denmark from 1 January 1999 to 31 December 2015. Patients were followed from the date of ICD implantation until migration, death, heart transplantation, or end of follow-up on 1 February 2017. Mean age at implantation was 30.5 +/- 12.8 years, and the patients were followed for a mean period of 7.1 +/- 4.4 years. The cumulative incidence at 1, 5, and 10 years was 17%, 29%, and 48% for appropriate ICD therapy, 6%, 13%, and 20% for inappropriate ICD therapy, and 7%, 18%, and 33% for device-related complications, respectively. Patients with an ICD implanted for secondary prevention had a higher risk of appropriate therapy compared with patients implanted for primary prevention [adjusted hazard ratio (HR) 5.18, 95% confidence interval (CI) 2.22 12.09; P < 0.01]. There was no difference in the risk of inappropriate therapy (adjusted HR 1.58, 95% CI 0.55-4.56; P = 0.40) or device-related complications (adjusted HR 1.22, 95% CI 0.56-2.68; P = 0.62) between patients with primary and secondary preventive indication. Conclusion: We observed high absolute risk estimates for appropriate ICD therapy in young patients with an ICD indicated by a hereditary cardiomyopathy or channelopathy. Also risks for inappropriate ICD therapy and device-related complications were significant. PMID- 29697815 TI - Cannibalism of Egg and Neonate Larvae by Late Stage Conspecifics of Anopheles gambiae (Diptera: Culicidae): Implications for Ovipositional Studies. AB - Laboratory experiments intended to test the effects of a purported ovipositional deterrent pheromone of Anopheles gambiae Giles sensu stricto (Diptera: Culicidae) led instead to the finding that egg cannibalism by fourth-instar larvae explained the 'deterrent effect' rather than chemical signals from larvae. Virtually no eggs were counted from cups containing fourth-instar larvae, after oviposition. Numbers of eggs from cups containing younger, conspecific larvae, or pupae did not differ significantly from water only control. Video recording of larval behavior revealed that fourth-instar larvae consumed entire eggs in one continuous ingestive bout. Egg output in the presence of fourth-instar larvae with their mouthparts sealed was similar to the larvae-absent treatment, but nearly 100-fold greater than that counted in the presence of fourth-instar larvae that could eat freely. Thus, the huge egg reduction in eggs counted in the presence of fourth-instar larvae was due to egg cannibalism, not because presence of these larvae deterred oviposition as has been reported in previous studies. Third and especially fourth-instar larvae also cannibalized newly hatched first instar larvae. Artificial food availability did not eliminate but did reduce cannibalism during first several hours of exposure. The rate at which fourth instar larvae consumed conspecifics rose significantly and linearly with prey density, generating a non-plateauing, type I functional response curve. These results clearly show that care must be taken such that mosquito ovipositional experiments are not confounded by presence of cannibalizing larvae. PMID- 29697816 TI - Who's The Boss? A Reflective Comic. PMID- 29697818 TI - Clinical Benefit of Long-Term Adalimumab Treatment in Patients With Crohn's Disease Following Loss of Response or Intolerance to Infliximab: 96-Week Efficacy Data From GAIN/ADHERE Trials. AB - Background and Aims: In the 4-week GAIN clinical trial, adalimumab was efficacious in inducing remission in patients with moderate-to-severe Crohn's disease [CD] who had prior loss of response/intolerance to infliximab. The efficacy and safety of adalimumab in these patients are reported here for up to 96 weeks or for 3 years, respectively, in the ADHERE open-label extension study. Methods: Patients who completed GAIN could enrol in ADHERE and receive open-label adalimumab 40 mg every other week. Efficacy variables included clinical response (Crohn's Disease Activity Index [CDAI] decrease from baseline >=70/>=100 points [CR-70/CR-100]) and remission [CDAI<150], steroid discontinuation and fistula remission [absence of drainage]. Data were reported using hybrid non-responder imputation [hNRI], last observation carried forward and as-observed analysis. Subgroup analyses were performed by randomized group in GAIN and by Week 4 efficacy in GAIN. Safety was also assessed. Results: A total of 310 patients from GAIN enrolled in ADHERE. CR-70, CR-100 and remission rates at Week 96 were 39.0%, 35.5%, and 26.5% [hNRI], respectively. Of the patients with CR-70 response or remission at Week 4 of GAIN, 45.5% and 44.4% [hNRI], respectively, maintained the effect at Week 96. Steroid discontinuation and steroid-free remission rates increased from Week 12 to 96 in patients using corticosteroids at GAIN baseline. Conclusions: Long-term adalimumab maintenance therapy led to sustained clinical remission and response, and steroid discontinuation in a considerable proportion of patients with CD previously treated with infliximab. No new safety signals were observed in this patient population. PMID- 29697817 TI - Signatures of DNA Methylation across Insects Suggest Reduced DNA Methylation Levels in Holometabola. AB - It has been experimentally shown that DNA methylation is involved in the regulation of gene expression and the silencing of transposable element activity in eukaryotes. The variable levels of DNA methylation among different insect species indicate an evolutionarily flexible role of DNA methylation in insects, which due to a lack of comparative data is not yet well-substantiated. Here, we use computational methods to trace signatures of DNA methylation across insects by analyzing transcriptomic and genomic sequence data from all currently recognized insect orders. We conclude that: 1) a functional methylation system relying exclusively on DNA methyltransferase 1 is widespread across insects. 2) DNA methylation has potentially been lost or extremely reduced in species belonging to springtails (Collembola), flies and relatives (Diptera), and twisted winged parasites (Strepsiptera). 3) Holometabolous insects display signs of reduced DNA methylation levels in protein-coding sequences compared with hemimetabolous insects. 4) Evolutionarily conserved insect genes associated with housekeeping functions tend to display signs of heavier DNA methylation in comparison to the genomic/transcriptomic background. With this comparative study, we provide the much needed basis for experimental and detailed comparative analyses required to gain a deeper understanding on the evolution and function of DNA methylation in insects. PMID- 29697819 TI - Divergence of Noncoding Regulatory Elements Explains Gene-Phenotype Differences between Human and Mouse Orthologous Genes. AB - Mice have been widely used as a model organism to investigate human gene phenotype relationships based on a conjecture that orthologous genes generally perform similar functions and are associated with similar phenotypes. However, phenotypes associated with orthologous genes often turn out to be quite different between human and mouse. Herein, we devised a method to quantitatively compare phenotypes annotations associated with mouse models and human. Using semantic similarity comparisons, we identified orthologous genes with different phenotype annotations, of which the similarity score is on a par with that of random gene pairs. Analysis of sequence evolution and transcriptomic changes revealed that orthologous genes with phenotypic differences are correlated with changes in noncoding regulatory elements and tissue-specific expression profiles rather than changes in protein-coding sequences. To map accurate gene-phenotype relationships using model organisms, we propose that careful consideration of the evolutionary divergence of noncoding regulatory elements and transcriptomic profiles is essential. PMID- 29697820 TI - Introduction: Autoinflammatory Syndromes Special Issue-hidden mysteries in the corners of autoinflammation. PMID- 29697821 TI - Chemotherapy followed by gastric endoscopic submucosal dissection. PMID- 29697822 TI - Renal angiomyolipoma in patients with tuberous sclerosis complex: findings from the TuberOus SClerosis registry to increase disease Awareness. AB - Background: Renal angiomyolipoma occurs at a high frequency in patients with tuberous sclerosis complex (TSC) and is associated with potentially life threatening complications. Despite this frequency and severity, there are no large population-based cohort studies. Here we present baseline and follow-up data of the international TuberOus SClerosis registry to increase disease Awareness (TOSCA) with an aim to provide detailed clinical characteristics of renal angiomyolipoma among patients with TSC. Methods: Patients of any age with a documented clinic visit for TSC within 12 months or who were newly diagnosed with TSC before participation in the registry were eligible. Data specific to renal angiomyolipoma included physical tumour characteristics (multiple, bilateral, lesion size and growing lesions), clinical signs and symptoms, and management. The effects of age, gender and genotype on the prevalence of renal angiomyolipoma were also evaluated. Results: Renal angiomyolipoma was reported in 51.8% of patients at baseline, with higher frequency in female patients (57.8% versus 42.2%). The median age at diagnosis was 12 years. Prevalence of angiomyolipoma was higher in patients with TSC2 compared with TSC1 mutations (59.2% versus 33.3%, P < 0.01). Of the 1031 patients with angiomyolipoma at baseline, multiple lesions were reported in 88.4% and bilateral in 83.9% of patients, while the size of angiomyolipoma was >3 cm in 34.3% of patients. Most patients were asymptomatic (82%). Frequently reported angiomyolipoma-related symptoms included bleeding, pain, elevated blood pressure and impaired renal function. Embolization and mammalian target of rapamycin inhibitors were the two most common treatment modalities. Conclusions: The TOSCA registry highlights the burden of renal angiomyolipoma in patients with TSC and shows that renal manifestations are initially asymptomatic and are influenced by gender and genotype. Furthermore, the occurrence of significant problems from angiomyolipoma in a minority of younger patients suggests that surveillance should begin in infancy or at initial diagnosis. PMID- 29697823 TI - Homoeolog-specific activation of genes for heat acclimation in the allopolyploid grass Brachypodium hybridum. AB - Background: Allopolyploid plants often show wider environmental tolerances than their ancestors; this is expected to be due to the merger of multiple distinct genomes with a fixed heterozygosity. The complex homoeologous gene expression could have been evolutionarily advantageous for the adaptation of allopolyploid plants. Despite multiple previous studies reporting homoeolog-specific gene expression in allopolyploid species, there are no clear examples of homoeolog specific function in acclimation to a long-term stress condition. Results: We found that the allopolyploid grass Brachypodium hybridum and its ancestor Brachypodium stacei show long-term heat stress tolerance, unlike its other ancestor, Brachypodium distachyon. To understand the physiological traits of B. hybridum, we compared the transcriptome of the 3 Brachypodium species grown under normal and heat stress conditions. We found that the expression patterns of approximately 26% and approximately 38% of the homoeolog groups in B. hybridum changed toward nonadditive expression and nonancestral expression, respectively, under normal condition. Moreover, we found that B. distachyon showed similar expression patterns between normal and heat stress conditions, whereas B. hybridum and B. stacei significantly altered their transcriptome in response to heat after 3 days of stress exposure, and homoeologs that were inherited from B. stacei may have contributed to the transcriptional stress response to heat in B. hybridum. After 15 days of heat exposure, B. hybridum and B. stacei maintained transcriptional states similar to those under normal conditions. These results suggest that an earlier response to heat that was specific to homoeologs originating from B. stacei contributed to cellular homeostasis under long-term heat stress in B. hybridum. Conclusions: Our results provide insights into different regulatory events of the homoeo-transcriptome that are associated with stress acclimation in allopolyploid plants. PMID- 29697824 TI - Species Loss: Exploring Opportunities with Art-Science. AB - Human-induced global change has triggered the sixth major extinction event on earth with profound consequences for humans and other species. A scientifically literate public is necessary to find and implement approaches to prevent or slow species loss. Creating science-inspired art can increase public understanding of the current anthropogenic biodiversity crisis and help people connect emotionally to difficult concepts. In spite of the pressure to avoid advocacy and emotion, there is a rich history of scientists who make art, as well as art-science collaborations resulting in provocative work that engages public interest; however, such interdisciplinary partnerships can often be challenging to initiate and navigate. Here we explore the goals, impacts, cascading impacts, and lessons learned from art-science collaborations, as well as ideas for collaborative projects. Using three case studies based on Harrower's scientific research into species interactions, we illustrate the importance of artists as a primary audience and the potential for a combination of art and science presentations to influence public understanding and concern related to species loss. PMID- 29697825 TI - Development of a Novel Dry, Sticky Trap Design Incorporating Visual Cues for Drosophila suzukii (Diptera: Drosophilidae). AB - Drosophila suzukii Matsumura (Diptera: Drosophilidae) is currently one of the most serious invasive pests for berry crops and cherries worldwide. The development of an effective monitoring trap that is reliable at detecting small populations to guide management decisions is greatly needed. To develop a novel dry trapping system, D. suzukii were trapped under field conditions in cherry orchards and raspberry high tunnels using various baited dry trap designs that were compared with the currently available deli-cup style traps that utilize a liquid bait or drowning solution. In a test in cherry orchards, red panel and combination yellow panel plus red sphere traps captured significantly more flies than yellow panel traps when all were baited with a Scentry lure. In a separate test in cherry, red sphere traps with the Scentry lure captured significantly more flies than the deli-cup traps with the Scentry lure or with the yeast sugar bait, and red panel traps with the Scentry lure captured significantly more flies than deli-cup traps with the Scentry lure. In raspberry high tunnels, red sphere traps with the Scentry lure captured significantly more flies than deli-cup traps with the Scentry lure. Red traps baited with the same lure as clear deli-cup traps consistently captured more D. suzukii, demonstrating that traps integrating a visual cue in combination with an olfactory cue are superior tools for monitoring D. suzukii. A dry trap requires less labor and maintenance than cup traps containing a liquid, improving the ease of use of D. suzukii monitoring traps. PMID- 29697826 TI - Attraction of Moths of Two Noctuidae Species to Field Traps Baited With a Mixture of two to three Homologous Acetates in Poland. AB - Field trials of a series of monounsaturated straight-chain acetates, including the (Z)-5-tetradecenyl acetate, (Z)-9-tetradecenyl acetate (pheromone blend A) and (Z)-5-decenyl acetate, (Z)-7-dodecenyl acetate, (Z)-9-tetradecenyl acetate (pheromone blend B), attracted the following species from the title family: Agrotis exclamationis (Linnaeus) and Agrotis segetum (Denis & Schiffermuller), respectively. Cutworms were monitored in the 2016-2017 season with the use of white Delta-type traps and different pheromone dispensers that contained above blends. The identified pheromone components at blend A elicited maximum trap captures when combined in a Z5-14:Ac/Z9-14:Ac-mixture ratio 100:16 at dose of 350 ug. The attractiveness of dispensers with pheromone blend B combined in a Z5 10:Ac/Z7-12:Ac/Z9-14:Ac-mixture ratio 1:1:1 at dose of 200 ug was the highest. Most kinds of the dispensers tested were similar or more active to the standard lures of the Csalomon company. Pheromone component of the A. exclamationis, (Z)-5 tetradecenyl acetate, was synthesized with a new, simple, and very efficient method in high summary yield and excellent isomeric purity. PMID- 29697827 TI - Diet and Anthropometrics of Children With Inflammatory Bowel Disease: A Comparison With the General Population. AB - Background: There is a lack of knowledge regarding the diet of children with inflammatory bowel disease (IBD). Therefore, we investigated dietary intake in pediatric IBD compared to the general population and assessed anthropometrics and food avoidance. Methods: In this cross-sectional cohort study, patients younger than 18 years with IBD were included (2014-2017). Dietary intake (total energy, macro nutrients, food types) was assessed using a Food Frequency Questionnaire (FFQ) and compared with a matched reference population (n = 306). Results: There were 102 patients included (55% male, median age 15.0 years). Median height Z score was -0.39 (interquartile range [IQR]: -1.17 to 0.26). Growth failure (height Z-scores<-1.64) was present in 11% of patients. Median BMI Z-score was 0.36 (IQR: -0.70 to 0.96). Acute malnutrition (weight-for-height Z-score<-2) was present in 3% of patients. Energy intake was lower in pediatric IBD compared to the reference population (mean kilojoule/day: 8286 vs 9794, P < 0.001). Protein intake did not differ, while fat intake was higher in pediatric IBD (mean gram/day: 101 vs 91, P < 0.001), with higher intake of vegetable oils/fats. Carbohydrate intake was lower in pediatric IBD (mean gram/day: 267 vs 305, P < 0.001), with lower intake of food types high in sugar. Food avoidance was reported in 53% of patients, with frequent avoidance of spicy (46%), high-fat food (30%), and dairy (30%). Conclusions: The diet of children with IBD differs from the general pediatric population, with lower energy intake and high rates of food avoidance. Evaluation of the dietary intake alongside anthropometrics may be important to prevent nutrition deficiencies and promote health. PMID- 29697828 TI - Feasibility and efficacy of sepsis management guidelines in a pediatric intensive care unit in Saudi Arabia: a quality improvement initiative. AB - Objectives: Evaluation of feasibility and effectiveness of Surviving Sepsis Campaign (SSC) Guidelines implementation at a Pediatric Intensive Care Unit (PICU) in Saudi Arabia to reduce severe sepsis associated mortality. Design: Retrospective data analysis for a prospective quality improvement (QI) initiative. Settings: PICU at King Saud University Medical City, Saudi Arabia. Participants: Children <=14 years of age admitted to the PICU from July 2010 to March 2011 with suspected or proven sepsis. Comparisons were made to a previously admitted group of patients with sepsis from October 2009 to June 2010. Interventions: Adaptation and implementation of the Surviving Sepsis Campaign Clinical Practice Guidelines (SSC-CPGs) through AGREE instrument and ADAPTE process. Main Outcome Measures: We reported pre- and post-implementation outcome of interest for this QI initiative, annual sepsis-related mortality rate. Furthermore, we reported follow-up of annual mortality rate until December 2016. Results: Sixty-five patients was included in the study (42 in post-guidelines implementation group and 23 in pre-guidelines implementation group). Mortality was insignificantly lower in the post-implementation group (26.2% vs. 47.8%; P = 0.079). However, when adjusted for severity, identified by number of failing organs in the multivariate regression analysis, the mortality difference was favorable for the post-implementation group (P = 0.006). The lower sepsis-related mortality rate was also sustained, with an average mortality rate of 15.11% for the subsequent years (2012-16). Conclusions: Adaptation and implementation of SSC Guidelines in our setting support its feasibility and potential benefits. However, a larger study is recommended to explore detailed compliance rates. PMID- 29697829 TI - Molecular Analysis of Human Immunodeficiency Virus Type 1 (HIV-1)-Infected Individuals in a Network-Based Intervention (Transmission Reduction Intervention Project): Phylogenetics Identify HIV-1-Infected Individuals With Social Links. AB - Background: The Transmission Reduction Intervention Project (TRIP) is a network based intervention that aims at decreasing human immunodeficiency virus type 1 (HIV-1) spread. We herein explore associations between transmission links as estimated by phylogenetic analyses, and social network-based ties among persons who inject drugs (PWID) recruited in TRIP. Methods: Phylogenetic trees were inferred from HIV-1 sequences of TRIP participants. Highly supported phylogenetic clusters (transmission clusters) were those fulfilling 3 different phylogenetic confidence criteria. Social network-based ties (injecting or sexual partners, same venue engagement) were determined based on personal interviews, recruitment links, and field observation. Results: TRIP recruited 356 individuals (90.2% PWID) including HIV-negative controls; recently HIV-infected seeds; long-term HIV infected seeds; and their social network members. Of the 150 HIV-infected participants, 118 (78.7%) were phylogenetically analyzed. Phylogenetic analyses suggested the existence of 13 transmission clusters with 32 sequences. Seven of these clusters included 14 individuals (14/32 [43.8%]) who also had social ties with at least 1 member of their cluster. This proportion was significantly higher than what was expected by chance. Conclusions: Molecular methods can identify HIV infected people socially linked with another person in about half of the phylogenetic clusters. This could help public health efforts to locate individuals in networks with high transmission rates. PMID- 29697831 TI - Physical Therapists Forward Deployed on Aircraft Carriers: A Retrospective Look at a Decade of Service. AB - Introduction: Navy physical therapists (PTs) have been a part of ship's company aboard Aircraft Carriers since 2002 due to musculoskeletal injuries being the number one cause of lost duty time and disability. This article describes a decade of physical therapy services provided aboard aircraft carriers. Materials and Methods: A retrospective survey was conducted to evaluate the types of services provided, volume of workload, value of services provided, and impact of PTs on operational readiness for personnel aboard Naval aircraft carriers. Thirty four reports documenting workload from PTs stationed onboard aircraft carriers were collected during the first decade of permanent PT assignment to aircraft carriers. Results: This report quantifies a 10-yr period of physical therapy services (PT and PT Technician) in providing musculoskeletal care within the carrier strike group and adds to existing literature demonstrating a high demand for musculoskeletal care in operational platforms. A collective total of 144,211 encounters were reported during the 10-yr period. The number of initial evaluations performed by the PT averaged 1,448 per assigned tour. The average number of follow-up appointments performed by the PT per tour was 1,440. The average number of treatment appointments per tour provided by the PT and PT technician combined was 1,888. The average number of visits per patient, including the initial evaluation, was 3.3. Sixty-five percent (65%) of the workload occurred while deployed or out to sea during training periods. It was estimated that 213 medical evacuations were averted over the 10-yr period. There were no reports of adverse events or quality of care reviews related to the care provided by the PT and/or PT technician. Access to early PT intervention aboard aircraft carriers was associated with a better utilization ratio (lower average number of visits per condition) than has been reported in prior studies and suggests an effective utilization of medical personnel resources. Conclusions: The impact of Navy PTs serving afloat highlights the importance of sustaining these billets and indicates the potential benefit of additional billet establishment to support operational platforms with high volumes of musculoskeletal injury. Access to early PT intervention can prevent and rehabilitate injuries among operational forces, promote human performance optimization, increase readiness during war and peace time efforts, and accelerate rehabilitation from neuromusculoskeletal injuries. With the establishment of Electronic Health Records within all carrier medical groups a repeat study may provide additional detail related to musculoskeletal injuries to guide medical planners to staff sea-based operational platforms most effectively to care for the greatest source of battle and disease non-battle injuries and related disability in the military. PMID- 29697830 TI - Menstrual Dysfunction in Girls From the Treatment Options for Type 2 Diabetes in Adolescents and Youth (TODAY) Study. AB - Context: Little is known about reproductive function in girls with youth-onset type 2 diabetes. Objectives: To characterize girls with irregular menses and effects of glycemic treatments on menses and sex steroids in the Treatment Options for Type 2 Diabetes in Youth (TODAY) study. Design: Differences in demographic, metabolic, and hormonal characteristics between regular- vs irregular-menses groups were tested; treatment group (metformin with or without rosiglitazone, metformin plus lifestyle) effect on menses and sex steroids over time in the study was assessed. This is a secondary analysis of TODAY data. Setting: Multicenter study in an academic setting. Patients: TODAY girls not receiving hormonal contraception and those at least 1-year postmenarche were included. Irregular menses was defined as three or fewer periods in the prior 6 months. Results: Of eligible participants with serum measurement of sex steroids (n = 190; mean age, 14 years), 21% had irregular menses. Those with irregular vs regular menses had higher body mass index (BMI) (P = 0.001), aspartate aminotransferase (AST) (P = 0.001), free androgen index (P = 0.0003), and total testosterone (P = 0.01) and lower sex hormone-binding globulin (SHBG) (P = 0.004) and estradiol (P = 0.01). Differences remained after adjustment for BMI. There was no treatment group effect on menses or sex steroids at 12 or 24 months, and no association of sex steroids was seen with measures of insulin sensitivity or secretion. Conclusions: Menstrual dysfunction is common in girls with recently diagnosed type 2 diabetes and associated with alterations in sex steroids, SHBG, and AST but not with alteration in insulin sensitivity or beta-cell function and did not improve with 2 years of antihyperglycemic treatment. PMID- 29697832 TI - 2,5-dimethylfuran as a validated biomarker of smoking status. AB - Introduction: Exposure biomarkers are required in tobacco use studies to accurately assess smoking status since self-reporting usually results in misclassification estimates. This study uses breath analysis and assesses some volatile organic compounds (VOCs) as potential biomarkers of tobacco smoke exposure. Methods: Forced-expiratory breath samples were obtained from 377 volunteers (174 smokers and 203 non-smokers). Exhaled breath levels of different VOCs previously related to tobacco smoke were evaluated. The toluene-to-benzene ratio was evaluated as this ratio has been found to be different in atmospheric samples and tobacco smoke emissions. Finally, breath analyses from 64 patients attending a clinical practice were evaluated and the results were compared to their self-reporting status. Results: Univariate analysis shows that all compounds evaluated gave significant differences (p<0.001). Receiver operating characteristic (ROC) curves suggest that xylenes and toluene are not able to accurately determine smoking status, and benzene and the T/B ratio present potential utility in certain conditions. The highest discriminant capacity was obtained for 2,5-dimethylfuran (AUC=0.982, 95% CI: 0.969-0.995), with a cut-off value of 0.016 ppbv (sensibility=0.965, specificity=0.896). Drinking coffee was the only confounding parameter that can give low breath levels for this compound. The evaluation of the results obtained from the patients attending a clinical practice showed that 8% of people who claim to be non-smokers hid their real smoking status. Conclusions: The results obtained confirm that the determination of 2,5-dimethylfuran in breath samples is a good and simpler alternative to conventional blood or urine tests for assessing smoking status. Implications: Analysis of 2,5-dimethylfuran in breath samples results in a simple and fast method for the determination of the smoking status of a person. This methodology presents multiple advantages as it is neither invasive nor embarrassing for patients attending clinical practices. Moreover, analysis of biomarkers in breath samples is simpler and faster than using conventional methods based on urine or blood analysis. PMID- 29697833 TI - Sleep spindle characteristics and arousability from nighttime transportation noise exposure in healthy young and older individuals. AB - Study Objectives: Nighttime transportation noise elicits awakenings, sleep-stage changes, and electroencephalographic (EEG) arousals. Here, we investigated the potential sleep-protective role of sleep spindles on noise-induced sleep alterations. Methods: Twenty-six young (19-33 years, 12 women) and 18 older (52 70 years, 9 women) healthy volunteers underwent a repeated measures polysomnographic 6-day laboratory study. Participants spent one noise-free baseline night, followed by four transportation noise-exposure nights (road traffic or railway noise; continuous or intermittent: average sound levels of 45 dB, maximum sound levels of 50-62 dB), and one noise-free recovery night. Sleep stages were scored manually and fast sleep spindle characteristics were quantified automatically using an individual band-pass filtering approach. Results: Nighttime exposure to transportation noise significantly increased sleep EEG arousal indices. Sleep structure and continuity were not differentially affected by noise exposure in individuals with a low versus a high spindle rate. Spindle rates showed an age-related decline along with more noise-induced sleep alterations. All-night spindle rates did not predict EEG arousal or awakening probability from single railway noise events. Spindle characteristics were affected in noise-exposure nights compared to noise-free nights: we observed a reduction of the spindle amplitude in both age groups and of the spindle rate in the older group. Conclusions: We have evidence that spindle rate is more likely to represent a trait phenomenon, which does not seem to play a sleep-protective role in nighttime transportation noise-induced sleep disruptions. However, the marked reduction in spindle amplitude is most likely a sensitive index for noise induced sleep alterations. PMID- 29697834 TI - High Temperature, Oxygen, and Performance: Insights from Reptiles and Amphibians. AB - Much recent theoretical and empirical work has sought to describe the physiological mechanisms underlying thermal tolerance in animals. Leading hypotheses can be broadly divided into two categories that primarily differ in organizational scale: 1) high temperature directly reduces the function of subcellular machinery, such as enzymes and cell membranes, or 2) high temperature disrupts system-level interactions, such as mismatches in the supply and demand of oxygen, prior to having any direct negative effect on the subcellular machinery. Nonetheless, a general framework describing the contexts under which either subcellular component or organ system failure limits organisms at high temperatures remains elusive. With this commentary, we leverage decades of research on the physiology of ectothermic tetrapods (amphibians and non-avian reptiles) to address these hypotheses. Available data suggest both mechanisms are important. Thus, we expand previous work and propose the Hierarchical Mechanisms of Thermal Limitation (HMTL) hypothesis, which explains how subcellular and organ system failures interact to limit performance and set tolerance limits at high temperatures. We further integrate this framework with the thermal performance curve paradigm commonly used to predict the effects of thermal environments on performance and fitness. The HMTL framework appears to successfully explain diverse observations in reptiles and amphibians and makes numerous predictions that remain untested. We hope that this framework spurs further research in diverse taxa and facilitates mechanistic forecasts of biological responses to climate change. PMID- 29697835 TI - Socioecological Risk and Protective Factors for Smoking Among Active Duty U.S. Military Personnel. AB - Introduction: Cigarette smoking can have negative consequences in military populations including injury, reduced physical endurance, higher frequency of sick days, and reduced combat readiness. This study used the socioecological model to understand individual, interpersonal, and organizational influences on cigarette smoking among military members. Materials and Methods: The sample for this secondary analysis was drawn from personnel at 24 large U.S. military installations, six from each service branch. Analyses included 4,728 personnel who were classified as current cigarette smokers. Generalized linear mixed models were used to estimate the associations among risk and protective factors from multiple ecological levels for smoking intensity and nicotine dependence. Results: Smoking to fit in with one's unit, being in the Army, smoking as a reaction to stress, and work-related stressors were all related to increased intensity of smoking and nicotine dependence. More active coping was associated with lower nicotine dependence and reduced smoking intensity. Conclusion: Results based on the socioecological model identify influencing factors and suggest possible interventions for smoking cessation. Reducing tobacco use in the military will require coordinated interventions that address multilevel determinants of use and improve military health. This is important to the strategic alignment of policy and services across the continuum of health care needs. PMID- 29697836 TI - Aortobronchial fistula caused by an endobronchial lobar Y stent: a word of caution. AB - A 17-year-old female patient with a history of pulmonary tuberculosis was admitted with progressive dyspnoea and haemoptysis. Five months prior to admission, a left bronchial carina Y stent was implanted. Because of the already destroyed parenchyma, a pneumonectomy was planned. Intraoperatively, an aortobronchial fistula was discovered as the source of bleeding, which could be stopped by pledget-armed sutures. The formation of an aortobronchial fistula has to be considered as a potential source of endobronchial bleeding after stent implantation. PMID- 29697838 TI - Intraspecific Variation in the Information Content of an Ornament: Why Relative Dewlap Size Signals Bite Force in Some, But Not All Island Populations of Anolis sagrei. AB - In many animals, male secondary sexual traits advertise reliable information on fighting capacity in a male-male context. The iconic sexual signaling device of anole lizards, the dewlap, has been extensively studied in this respect. For several territorial anole species (experiencing strong intrasexual selection), there is evidence for a positive association between dewlap size and bite capacity, which is an important determinant of combat outcome in lizards. Intriguingly, earlier studies did not find this expected correlation (relative dewlap size-relative bite force) in the highly territorial brown anole lizard, Anolis sagrei. We hypothesize that the dewlap size-bite force relationship can differ among populations of the same species due to interpopulation variation in the degree of male-male competition. In line with this thought, we expect dewlap size to serve as a reliable predictor of bite performance only in those populations where the level of intrasexual selection is high. To tackle this hypothesis, we examined the relationship between male dewlap size and bite force on the intraspecific level in A. sagrei, using an extensive dataset encompassing information from 17 island populations distributed throughout the Caribbean. First, we assessed and compared the relationship between both variables in the 17 populations under study. Second, we linked the relative dewlap size-bite force relationship within each population to variation in the degree of intrasexual selection among populations, using sexual size dimorphism and dewlap display intensity as surrogate measures. Our results showed that absolute dewlap size is an excellent predictor of maximum bite force in nearly all A. sagrei populations. However, relative dewlap size is only an honest signal of bite performance in 4 out of the 17 populations. Surprisingly, the level of signal honesty did not correlate with the strength of intrasexual selection. We offer a number of conceptual and methodological explanations for this unexpected finding. PMID- 29697837 TI - Modeling Climate Suitability of the Western Blacklegged Tick in California. AB - Ixodes pacificus Cooley & Kohls (Acari: Ixodidae), the primary vector of Lyme disease spirochetes to humans in the far-western United States, is broadly distributed across Pacific Coast states, but its distribution is not uniform within this large, ecologically diverse region. To identify areas of suitable habitat, we assembled records of locations throughout California where two or more I. pacificus were collected from vegetation from 1980 to 2014. We then employed ensemble species distribution modeling to identify suitable climatic conditions for the tick and restricted the results to land cover classes where these ticks are typically encountered (i.e., forest, grass, scrub-shrub, riparian). Cold-season temperature and rainfall are particularly important abiotic drivers of suitability, explaining between 50 and 99% of the spatial variability across California among models. The likelihood of an area being classified as suitable increases steadily with increasing temperatures >0 degrees C during the coldest quarter of the year, and further increases when precipitation amounts range from 400 to 800 mm during the coldest quarter, indicating that areas in California with relatively warm and wet winters typically are most suitable for I. pacificus. Other consistent predictors of suitability include increasing autumn humidity, temperatures in the warmest month between 23 and 33 degrees C, and low-temperature variability throughout the year. The resultant climatic suitability maps indicate that coastal California, especially the northern coast, and the western Sierra Nevada foothills have the highest probability of I. pacificus presence. PMID- 29697840 TI - Validating the efficacy of single-stage breast-conserving therapy using multicatheter partial-breast brachytherapy based on updated ASTRO guidelines. AB - Based on the accumulating evidence for equivalent results of partial-breast irradiation (PBI) and whole-breast irradiation (WBI) in breast-conserving therapy (BCT), the American Society for Radiation Oncology (ASTRO) updated the consensus statement (CS) to expand the range of potential candidates for PBI outside clinical trials. Of the various techniques, PBI using multicatheter interstitial brachytherapy (MCB) is the oldest and has long-term data. In this study, the efficacy of single-stage BCT using MCB-PBI achieved by an intraoperative catheter placement was validated on updated ASTRO guidelines. We retrospectively examined patients undergoing BCT using MCB-PBI or WBI. The updated CS distinguished patients aged 40-49 years with ER+, tumor <=2 cm, and margin >=2 mm from unsuitable patients in the previous CS. We compared the ipsilateral breast tumor recurrence (IBTR) rate in MCB-PBI with that in WBI patients with suitable or cautionary (S/C) categories on the updated CS. Between November 2007 and September 2017, 641 patients with 647 lesions underwent BCT (MCB-PBI, 407; WBI, 240). At the median follow-up time of 54.4 months, we observed 8 (1.97%; 95% CI: 0.62-3.31%) and 7 (2.92%; 95% CI: 0.79-5.05%) IBTRs, respectively. Updating the CS increased the S/C patients receiving MCB-PBI from 232 patients (57.0%) to 319 (78.4%). Comparison of clinical outcomes at the 12-month minimum follow-up between 291 MCB-PBI and 103 WBI in S/C patients showed no significant differences in the 4-year rate of IBTR-free (100% vs 98.9%; P = 0.29) and disease-free survival (98.7% vs 95.5%; P = 0.24). Overall, single-stage BCT using MCB-PBI offered similar tumor control rates, compared with WBI, on the updated ASTRO CS. PMID- 29697839 TI - Brain-derived erythropoietin protects from intermittent hypoxia-induced cardiorespiratory dysfunction and oxidative stress in mice. AB - Study Objectives: Based on the fact that erythropoietin (Epo) administration in rodents protects against spatial learning and cognitive deficits induced by chronic intermittent hypoxia (CIH)-mediated oxidative damage, here we tested the hypothesis that Epo in the brain protects against cardiorespiratory disorders and oxidative stress induced by CIH in adult mice. Methods: Adult control and transgenic mice overexpressing Epo in the brain only (Tg21) were exposed to CIH (21%-10% O2-10 cycles/hour-8 hours/day-7 days) or room air. After CIH exposure, we used the tail cuff method to measure arterial pressure, and whole-body plethysmography to assess the frequency of apneic episodes at rest, minute ventilation, and ventilatory responses to hypoxia and hypercapnia. Finally, the activity of pro-oxidant (XO-xanthine oxidase, and NADPH) and antioxidant (super oxide dismutase) enzymes was evaluated in the cerebral cortex and brainstem. Results: Exposure of control mice to CIH significantly increased the heart rate and arterial pressure, the number of apneic events, and the ventilatory response to hypoxia and hypercapnia. Furthermore, CIH increased the ratio of pro-oxidant to antioxidant enzymes in cortex and brainstem tissues. Both physiological and molecular changes induced by CIH were prevented in transgenic Tg21 mice. Conclusions: We conclude that the neuroprotective effect of Epo prevents oxidative damage in the brain and cardiorespiratory disorders induced by CIH. Considering that Epo is used in clinics to treat chronic kidney disease and stroke, our data show convincing evidence suggesting that Epo may be a promising alternative drug to treat sleep-disorder breathing. PMID- 29697842 TI - Evaluation of the impact of a nationwide massive online open course on the appropriate use of antimicrobials. AB - Objectives: To evaluate the impact of a massive online open course (MOOC) design on the appropriate use of antimicrobial agents, to determine specific study areas with better learning outcomes and to identify weak points. Methods: A pre- and post-intervention study in the context of a training course on infectious diseases aimed at health professionals. We designed a questionnaire with 30 questions related to the management of infectious diseases in different clinical situations. Participants had to answer the questions based on their competencies and training for these situations. We analysed the scores obtained before and after the course and the resulting progress. In addition, an open response section was provided to enable a qualitative evaluation. Results: Two thousand one hundred and forty-eight health professionals were enrolled in the course. The questionnaire was completed before and after the course by 606 participants, mainly physicians (81.2%) and pharmacists (15.4%). The mean overall scores for the pre- and post-course questionnaires were 6.2 (SD 1.38) and 7.9 (SD 0.88), respectively (overall score increase = 1.8, SD 1.21, P < 0.001). A significant increase in self-assessment was detected (P < 0.001) for all the questions. Qualitative assessments were provided by 218 participants with 225 comments, most of which were very positive. Conclusions: The course with a MOOC design showed a great teaching capacity in the infectious diseases area for all the clinical situations analysed, notably in the management of severe infections with higher mortality. For future editions of this training activity, the need to include other infectious diseases, especially infections in primary care, was highlighted. PMID- 29697841 TI - Cortical region-specific sleep homeostasis in mice: effects of time of day and waking experience. AB - Sleep-wake history, wake behaviors, lighting conditions, and circadian time influence sleep, but neither their relative contribution nor the underlying mechanisms are fully understood. The dynamics of electroencephalogram (EEG) slow wave activity (SWA) during sleep can be described using the two-process model, whereby the parameters of homeostatic Process S are estimated using empirical EEG SWA (0.5-4 Hz) in nonrapid eye movement sleep (NREMS), and the 24 hr distribution of vigilance states. We hypothesized that the influence of extrinsic factors on sleep homeostasis, such as the time of day or wake behavior, would manifest in systematic deviations between empirical SWA and model predictions. To test this hypothesis, we performed parameter estimation and tested model predictions using NREMS SWA derived from continuous EEG recordings from the frontal and occipital cortex in mice. The animals showed prolonged wake periods, followed by consolidated sleep, both during the dark and light phases, and wakefulness primarily consisted of voluntary wheel running, learning a new motor skill or novel object exploration. Simulated SWA matched empirical levels well across conditions, and neither waking experience nor time of day had a significant influence on the fit between data and simulation. However, we consistently observed that Process S declined during sleep significantly faster in the frontal than in the occipital area of the neocortex. The striking resilience of the model to specific wake behaviors, lighting conditions, and time of day suggests that intrinsic factors underpinning the dynamics of Process S are robust to extrinsic influences, despite their major role in shaping the overall amount and distribution of vigilance states across 24 hr. PMID- 29697843 TI - Assessing improvement capability in healthcare organisations: a qualitative study of healthcare regulatory agencies in the UK. AB - Objectives: Healthcare regulatory agencies are increasingly concerned not just with assessing the current performance of the organisations they regulate, but with assessing their improvement capability to predict their future performance trajectory. This study examines how improvement capability is conceptualised and assessed by healthcare UK regulatory agencies. Design: Qualitative analysis of data from six UK healthcare regulatory agencies was conducted. Three data sources were analysed using an a priori framework of eight dimensions of improvement capability identified from an extensive literature review. Setting: The focus of the research study was the regulation of hospital-based care, which accounts for the majority of UK healthcare expenditure. Six UK regulatory agencies that review hospital care participated. Participants: Data sources included interviews with regulatory staff (n = 48), policy documents (n = 90) and assessment reports (n = 30). Intervention: None-this was a qualitative, observational study. Results: This research study finds that of eight dimensions of improvement capability, process improvement and learning, and strategy and governance, dominate regulatory assessment practices. The dimension of service-user focus receives the least frequency of use. It may be that dimensions which are relatively easy to 'measure', such as documents for strategy and governance, dominate assessment processes, or there may be gaps in regulatory agencies' assessment instruments, deficits of expertise in improvement capability, or practical difficulties in operationalising regulatory agency intentions to reliably assess improvement capability. Conclusions: The UK regulatory agencies seek to assess improvement capability to predict performance trajectories, but out of eight dimensions of improvement capability, two dominate assessment. Furthermore, the definition and meaning of assessment instruments requires development. This would strengthen the validity and reliability of agencies' assessment, diagnosis and prediction of performance trajectories, and support development of more appropriate regulatory performance interventions. PMID- 29697844 TI - Neighborhood socioeconomic status, sleep duration, and napping in middle-to-old aged US men and women. AB - Study Objectives: Earlier studies have linked neighborhood disadvantage with poor sleep outcomes. However, little is known about the association between changes in one's neighborhood over time and night sleep and napping. In over 300000 middle to-old aged Americans, we examined neighborhood socioeconomic status (SES) and change in neighborhood SES in relation to nocturnal sleep duration and napping. Methods: Nocturnal sleep duration and daytime napping were self-reported at baseline (1995-1996). Participants also reported baseline residential addresses, which were linked to US censuses. We derived a neighborhood SES index using census variables and calculated the baseline level and change (1990-2000) in neighborhood SES. Multinomial logistic regression was used to estimate the associations between neighborhood SES over time and nocturnal sleep and napping. Results: Lower baseline neighborhood SES was associated with short sleep, long sleep, and napping. When compared with the highest quintile of neighborhood SES, the lowest was associated with 46% and 72% increase in relative risk (RR) of reporting very short (< 5 hours) sleep, 28% and 19% higher RR of long (>=9 hours) sleep and 95% and 85% increase in long (>=1 hours) nap in men and women, respectively. Moreover, a decrease in neighborhood SES was associated with higher RR of reporting very short sleep in women; while an improvement in neighborhood SES was associated with an increase in RR of long sleep in men. Conclusions: Neighborhood disadvantage and worsening neighborhood conditions were associated with unhealthy sleep behaviors. These results reinforce a growing literature on the potential importance of neighborhood context for understanding sleep health. PMID- 29697845 TI - Novel NOD2 Mutation in Early-Onset Inflammatory Bowel Phenotype. AB - Background: Nucleotide-binding oligomerization domain 2 (NOD2) is a key intracellular protein of the innate immune system. NOD2 variants are associated with inflammatory bowel disease (IBD) and other inflammatory phenotypes. We described the case of a baby with a very early-onset IBD who is characterized by a rare homozygous variant in NOD2, found through whole-exome sequencing, Its pathogenic effect was investigated through bioinformatics and functional studies. Methods: The microbicide activity of the patient's phagocytes was analyzed using Escherichia coli. HEK293 and Caco2 cell lines were transfected with wild-type and mutated NOD2 cDNA to evaluate the NF-kB activity and the protein distribution. The functionality of the NOD2 pathway was assessed through analysis of the expression of tumor nectrosis factor alpha (TNFalpha) on monocytes. The levels of various cytokines were quantified in the patient plasma by a multiplex suspension array. Results: A missense NOD2 mutation, c.G1277A; p.R426H in homozygosis, was found. The patient's microbicide activity was comparable to that observed in controls. HEK293 cells transfected with the mutated cDNA showed a 20-fold increase of NF-kB activation in basal condition. Moreover, Caco2 immunostaining revealed a different cytoplasmic distribution of the mutated protein compared with wild-type. A higher production of TNFalpha by monocytes and elevated levels of plasmatic cytokines and chemokines were evidenced in the patient. Conclusions: This homozygous mutation is functionally relevant and shows a different NOD2 involvement in the IBD phenotype. In our patient, this mutation caused a gain of function typical of the Blau syndrome phenotype, manifesting, however, an IBD like phenotype. PMID- 29697847 TI - Corrigendum. PMID- 29697846 TI - Recent Changes in Health Insurance Coverage for Urban and Rural Veterans: Evidence from the First Year of the Affordable Care Act. AB - Introduction: Prior to the Affordable Care Act, as many as 1.3 million veterans lacked health insurance. With the passage of the Affordable Care Act, veterans now have new pathways to coverage through Medicaid expansion in those states that chose to expand Medicaid and through private coverage options offered through the Health Insurance Marketplace. We examined the impact of the ACA on health insurance coverage for veterans in expansion and non-expansion states and for urban and rural veterans. Methods: We examined changes in veterans' health insurance coverage following the first year of the ACA, focusing on whether they lived in an urban or rural area and whether they live in a Medicaid expansion state. We used data on approximately 200,000 non-elderly community-dwelling veterans, obtained from the 2013-2014 American Community Survey and estimated differences in the adjusted probability of being uninsured between 2013 and 2014 for both urban and rural areas. Adjusted probabilities were computed by fitting logistic regressions controlling for age, gender, race, marital status, poverty status, education, and employment. Results: There were an estimated 10.1 million U.S. non-elderly veterans in 2013; 82% lived in predominantly urban areas (8.3 million), and the remaining 18% (1.8 million) lived in predominately rural areas. Most veterans lived in the South (43.6%), and rural veterans were more likely to be Southerners than their urban counterparts. On every marker of economic well being, rural veterans fared worse than urban veterans. They had a statistically significant higher chance of having incomes below 138% of FPG (20.0% versus 17.0%), of being out of the labor force (29.1% versus 23.0%), and of having no more than a high school education (39.6% versus 28.8%). Rural veterans were also more likely to experience at least one functional limitation. Overall, veterans in Medicaid expansion states experienced a significantly larger increase in insurance compared to veterans living in non-expansion states. For rural veterans in Medicaid expansion states, the increase in insurance was 3.5 percentage points, compared with 1.2 percentage points in non-expansion states. Conclusion: Our analysis found a substantial 24% relative decline in the rate of uninsurance for U.S. Veterans, from 9.3 to 7.1% between 2013 and 2014. We found that coverage gains in rural areas were due to gains in Medicaid and individual market coverage. Residence in a Medicaid expansion state was particularly influential for rural veterans - the increase in the insured rate was three times larger in Medicaid expansion states versus non-expansion states. The ACA has had a positive and significant impact on the ability of U.S. Veterans to obtain health insurance coverage specifically for low-income veterans living in rural areas. The poverty rate among Veterans is rising and is particularly an issue for the more recent Gulf War veterans. Providing affordable and accessible health insurance options is part of our commitment to those who have served our country. Our analysis also presents yet another reason for the 17 non-expansion states to consider a Medicaid expansion. PMID- 29697849 TI - Chance, Finiteness, and History. AB - Importance of chance, finiteness, and history in evolution is pointed out with special reference to the neutral theory. PMID- 29697848 TI - Incidence of human brucellosis in the Kilimanjaro Region of Tanzania in the periods 2007-2008 and 2012-2014. AB - Background: Brucellosis causes substantial morbidity among humans and their livestock. There are few robust estimates of the incidence of brucellosis in sub Saharan Africa. Using cases identified through sentinel hospital surveillance and health care utilization data, we estimated the incidence of brucellosis in Moshi Urban and Moshi Rural Districts, Kilimanjaro Region, Tanzania, for the periods 2007-2008 and 2012-2014. Methods: Cases were identified among febrile patients at two sentinel hospitals and were defined as having either a 4-fold increase in Brucella microscopic agglutination test titres between acute and convalescent serum or a blood culture positive for Brucella spp. Findings from a health care utilization survey were used to estimate multipliers to account for cases not seen at sentinel hospitals. Results: Of 585 patients enrolled in the period 2007 2008, 13 (2.2%) had brucellosis. Among 1095 patients enrolled in the period 2012 2014, 32 (2.9%) had brucellosis. We estimated an incidence (range based on sensitivity analysis) of brucellosis of 35 (range 32-93) cases per 100 000 persons annually in the period 2007-2008 and 33 (range 30-89) cases per 100 000 persons annually in the period 2012-2014. Conclusions: We found a moderate incidence of brucellosis in northern Tanzania, suggesting that the disease is endemic and an important human health problem in this area. PMID- 29697851 TI - Advanced Good Cell Culture Practice for human primary, stem cell-derived and organoid models as well as microphysiological systems. AB - A major reason for the current reproducibility crisis in the life sciences is the poor implementation of quality control measures and reporting standards. Improvement is needed, especially regarding increasingly complex in vitro methods. Good Cell Culture Practice (GCCP) was an effort from 1996 to 2005 to develop such minimum quality standards also applicable in academia. This paper summarizes recent key developments in in vitro cell culture and addresses the issues resulting for GCCP, e.g. the development of induced pluripotent stem cells (iPSCs) and gene-edited cells. It further deals with human stem-cell-derived models and bioengineering of organo-typic cell cultures, including organoids, organ-on-chip and human-on-chip approaches. Commercial vendors and cell banks have made human primary cells more widely available over the last decade, increasing their use, but also requiring specific guidance as to GCCP. The characterization of cell culture systems including high-content imaging and high throughput measurement technologies increasingly combined with more complex cell and tissue cultures represent a further challenge for GCCP. The increasing use of gene editing techniques to generate and modify in vitro culture models also requires discussion of its impact on GCCP. International (often varying) legislations and market forces originating from the commercialization of cell and tissue products and technologies are further impacting on the need for the use of GCCP. This report summarizes the recommendations of the second of two workshops, held in Germany in December 2015, aiming map the challenge and organize the process or developing a revised GCCP 2.0. PMID- 29697850 TI - Depressive symptoms, pain and disability for adolescent patients with juvenile idiopathic arthritis: results from the Childhood Arthritis Prospective Study. AB - Objectives: To determine if depressive symptoms assessed near diagnosis associate with future measures of pain, disability and disease for adolescent patients diagnosed with JIA. Methods: Data were analysed from JIA patients aged 11-16 years recruited to the Childhood Arthritis Prospective Study, a UK-based inception cohort of childhood-onset arthritis. Depressive symptoms (using the Mood and Feelings Questionnaire; MFQ), active and limited joint count, disability score (Childhood Health Assessment Questionnaire), pain visual analogue scale and patient's general evaluation visual analogue scale were collected. Associations between baseline measures (first visit to paediatric rheumatologist) were analysed using multiple linear regression. Linear mixed-effect models for change in the clinical measures of disease over 48 months were estimated including MFQ as an explanatory variable. Results: Data from 102 patients were analysed. At baseline, median (IQR) age was 13.2 years (11.9-14.2 years) and 14.7% scored over the MFQ cut-off for major depressive disorder. At baseline, depressive symptoms significantly associated with all clinical measures of disease (P ? 0.01). High baseline depressive symptoms scores predicted worse pain (P ? 0.005) and disability (P ? 0.001) 12 months later but not active and limited joint counts. Conclusions: Adolescent patients with JIA and depressive symptoms had more active joints, pain and disability at the time of their first specialist appointment. The associations between baseline depression and both pain and disability continued for at least one year, however, this was not the case for active joint count. PMID- 29697852 TI - A standardized method based on pigmented epidermal models evaluates sensitivity against UV-irradiation. AB - To protect the human skin from extensive solar radiation, melanocytes produce melanin and disperse it via melanosomes to keratinocytes in the basal and suprabasal layers of the human epidermis. Moreover, melanocytes are associated with pathological skin conditions such as vitiligo and psoriasis. Thus, an in vitro skin model that comprises a defined cutaneous pigmentation system is highly relevant in cosmetic, pharmaceutical and medical research. Here, we describe how the epidermal-melanin-unit can be established in vitro. Therefore, primary human melanocytes are implemented in an open source reconstructed epidermis. Following 14 days at the air liquid interface, a differentiated epidermis was formed and melanocytes were located in the basal layer. The functionality of the epidermal melanin-unit could be shown by the transfer of melanin to the surrounding keratinocytes, and a significantly increased melanin content of models stimulated with either UV-radiation or the melanin precursor dihydroxyphenylalanine. Additionally, an UV50 assay was developed to test the protective effect of melanin. In analogy to the IC50 value in risk assessment, the UV50 value facilitates a quantitative investigation of harmful effects of natural UV radiation to the skin in vitro. Employing this test, we could demonstrate that the melanin content correlates with the resilience against simulated sunlight, which comprises 2.5 % UVB and 97.5 % UVA. Besides demonstrating the protective effect of melanin in vitro, the assay was used to determine the protective effect of a consumer product in a highly standardized setup. PMID- 29697853 TI - Injectable BMP-2 delivery system based on collagen-derived microspheres and alginate induced bone formation in a time- and dose-dependent manner. AB - The aim of the current study was to reduce the clinically used supra physiological dose of bone morphogenetic protein-2 (BMP-2) (usually 1.5 mg/mL), which carries the risk of adverse events, by using a more effective release system. A slow release system, based on an injectable hydrogel composed of BMP-2 loaded recombinant collagen-based microspheres and alginate, was previously developed. Time- and dose-dependent subcutaneous ectopic bone formation within this system and bone regeneration capacity in a calvarial defect model were investigated. BMP-2 doses of 10 ug, 3 ug and 1 ug per implant (50 ug/mL, 15 ug/mL and 5 ug/mL, respectively) successfully induced ectopic bone formation subcutaneously in rats in a time- and dose-dependent manner, as shown by micro computed tomography (uCT) and histology. In addition, the spatio-temporal control of BMP-2 retention was shown for 4 weeks in vivo by imaging of fluorescently labelled BMP-2. In the subcritical calvarial defect model, uCT revealed a higher bone volume for the 2 ug of BMP-2 per implant condition (50 ug/mL) as compared to the lower dose used (0.2 ug per implant, 5 ug/mL). Complete defect bridging was obtained with 50 ug/mL BMP-2 after 8 weeks. The BMP-2 concentration of 5 ug/mL was not sufficient to heal a calvarial defect faster than the empty defect or biomaterial control without BMP-2. Overall, this injectable BMP-2 delivery system showed promising results with 50 ug/mL BMP-2 in both the ectopic and calvarial rat defect models, underling the potential of this composite hydrogel for bone regeneration therapies. PMID- 29697854 TI - Pulmonary vascular resistance determines mortality in end-stage renal disease patients with pulmonary hypertension. AB - The multifactorial etiology of pulmonary hypertension (PH) in end-stage renal disease (ESRD) includes patients with and without elevated pulmonary vascular resistance (PVR). We explored the prognostic implication of this distinction by evaluating pretransplant ESRD patients who underwent right heart catheterization and echocardiography. Demographics, clinical data, and test results were analyzed. All-cause mortality data were obtained. Median follow-up was 4 years. Of the 150 patients evaluated, echocardiography identified 99 patients (66%) with estimated pulmonary artery (PA) systolic pressure > 36 mm Hg, which correlated poorly with mortality (HR = 1.28, 95% CI 0.72-2.27, P = .387). Right heart catheterization identified 88 (59%) patients with mean PA pressure >= 25 mm Hg. Of these, 70 had PVR <= 3 Wood units and 18 had PVR > 3 Wood units. Survival analysis demonstrated a significant prognostic effect of an elevated PVR in patients with high mean PA pressures (HR = 2.26, 95% CI 1.07-4.77, P = .03), while patients with high mean PA pressure and normal PVR had equivalent survival to those with normal PA pressure. Despite the high prevalence of PH in ESRD patients, elevated PVR is uncommon and is a determinant of prognosis in patients with PH. Patients with normal PVR had survival equivalent to those with normal PA pressures. PMID- 29697855 TI - Consensus and contentious statements on the use of probiotics in clinical practice: A south east Asian gastro-neuro motility association working team report. AB - The concept of consuming microorganisms in the treatment of a medical condition and in health maintenance has gained much attraction, giving rise to an abundance of medical claims and of health supplements. This study identified relevant clinical questions on the therapeutic use of probiotics and reviewed the literature in irritable bowel syndrome, inflammatory bowel disease, impaired intestinal immunity, liver disease, intestinal infections, and common childhood digestive disorders. Statements were developed to address these clinical questions. A panel of experienced clinicians was tasked to critically evaluate and debate the available data. Both consensus and contentious statements are presented to provide to clinicians a perspective on the potential of probiotics and importantly their limitations. PMID- 29697857 TI - Protective effects of melatonin and glucagon-like peptide-1 receptor agonist (liraglutide) on gastric ischaemia-reperfusion injury in high-fat/sucrose-fed rats. AB - Ischaemia-reperfusion (I-R) injury is a serious pathology that is often encountered with thrombotic events, during surgery when blood vessels are cross clamped, and in organs for transplantation. Increased oxidative stress is the main pathology in I-R injury, as assessed in studies on the heart, kidney, and brain with little data available on gastric I-R (GI-R). Liraglutide is a GLP-1 receptor agonist that has insulinotropic and weight reducing actions, and melatonin that has been much studied as a chronotropic hormone; have also studied as being anti-oxidative stress agents. Herein, we aimed to explore the effects of liraglutide and melatonin on GI-R injury with high-fat/sucrose diet. Rats were divided into six groups; two diet-control, two melatonin- and two liraglutide pretreated groups. All rats were subjected to 30 minutes of gastric ischaemia followed by 1 hour of reperfusion. Gastric tissues were assessed for the percentage of DNA fragmentation, myeloperoxidase activity, total oxidant status, total antioxidant capacity, oxidative stress index, BMI and histopathological examination. We showed that high-fat feeding for four weeks prior to GI-R significantly increased BMI, oxidative stress indices and decreased total antioxidant capacity, with a neutral effect on apoptosis compared to controls. Pretreatment with either melatonin (10 mg/kg per day orally) or liraglutide (25 MUg/kg per day ip) reverses these effects. Furthermore, both drugs reduced weight only in HFS-fed rats. Both liraglutide and melatonin have nearly similar protective effects on gastric I-R injury through decreasing the oxidative stress and apoptosis. PMID- 29697856 TI - Induced CNS expression of CXCL1 augments neurologic disease in a murine model of multiple sclerosis via enhanced neutrophil recruitment. AB - Increasing evidence points to an important role for neutrophils in participating in the pathogenesis of the human demyelinating disease MS and the animal model EAE. Therefore, a better understanding of the signals controlling migration of neutrophils as well as evaluating the role of these cells in demyelination is important to define cellular components that contribute to disease in MS patients. In this study, we examined the functional role of the chemokine CXCL1 in contributing to neuroinflammation and demyelination in EAE. Using transgenic mice in which expression of CXCL1 is under the control of a tetracycline inducible promoter active within glial fibrillary acidic protein-positive cells, we have shown that sustained CXCL1 expression within the CNS increased the severity of clinical and histologic disease that was independent of an increase in the frequency of encephalitogenic Th1 and Th17 cells. Rather, disease was associated with enhanced recruitment of CD11b+ Ly6G+ neutrophils into the spinal cord. Targeting neutrophils resulted in a reduction in demyelination arguing for a role for these cells in myelin damage. Collectively, these findings emphasize that CXCL1-mediated attraction of neutrophils into the CNS augments demyelination suggesting that this signaling pathway may offer new targets for therapeutic intervention. PMID- 29697858 TI - Microfluidic Devices in the Fast-Growing Domain of Single-Cell Analysis. AB - Recent advances in cellular analysis revealed that the seemingly identical cells are heterogeneous in term of functionality, compositions, and genetic performance. These differences cause difficulty in the diagnostic for a specific model of disease. Detection of biomolecules such as DNA, RNA, and protein or analysis of cell(s), detection of cell surface molecules, and secreted protein, can help us to improve the understanding of a targeted disease and development of new diagnostic and therapeutic approaches. A single-cell includes the minute quantity of these target molecules. Microfluidic devices have the ability to capture a single-cell and its lysate into a pico or femtoliter volumes droplet, or micro-well thus preventing dilution and limiting diffusion. In this review we described the advancement and limitations in microfluidic techniques used toward single-cells analysis. PMID- 29697859 TI - The effects of vitamin K1 and vitamin K2 on the proliferation, cytokine production and regulatory T-cell frequency in peripheral blood mononuclear cells of paediatric atopic dermatitis patients. AB - We estimated the pharmacological efficacy of vitamin K1 (VK1 ) and VK2 on the mitogen-activated peripheral blood mononuclear cells (PBMCs) of paediatric atopic dermatitis (AD) patients. VK2 suppressed the in vitro proliferation of T-cell mitogen-activated PBMCs of AD patients. In contrast, VK1 had little effect on the PBMC proliferation. The IL-2 production from the activated PBMCs of AD patients significantly increased (P < .05), while the production significantly decreased by 100 MUmol L-1 VK2 (P < .01). In addition, 100 MUmol L-1 VK2 reduced the percentage of CD4+ and CD4+CD25+ cells in PBMCs. These results suggest that VK2 can modulate T-cell function in PBMCs of AD patients. PMID- 29697860 TI - Mentalizing eye contact with a face on a video: Gaze direction does not influence autonomic arousal. AB - Recent research has revealed enhanced autonomic and subjective responses to eye contact only when perceiving another live person. However, these enhanced responses to eye contact are abolished if the viewer believes that the other person is not able to look back at the viewer. We purported to investigate whether this "genuine" eye contact effect can be reproduced with pre-recorded videos of stimulus persons. Autonomic responses, gaze behavior, and subjective self-assessments were measured while participants viewed pre-recorded video persons with direct or averted gaze, imagined that the video person was real, and mentalized that the person could see them or not. Pre-recorded videos did not evoke similar physiological or subjective eye contact effect as previously observed with live persons, not even when the participants were mentalizing being seen by the person. Gaze tracking results showed, however, increased attention allocation to faces with direct gaze compared to averted gaze directions. The results suggest that elicitation of the physiological arousal in response to genuine eye contact seems to require spontaneous experience of seeing and of being seen by another individual. PMID- 29697861 TI - Microglial MHC class II is dispensable for experimental autoimmune encephalomyelitis and cuprizone-induced demyelination. AB - Microglia are resident immune cells in the CNS, strategically positioned to clear dead cells and debris, and orchestrate CNS inflammation and immune defense. In steady state, these macrophages lack MHC class II (MHCII) expression, but microglia activation can be associated with MHCII induction. Whether microglial MHCII serves antigen presentation for critical local T-cell restimulation in CNS auto-immune disorders or modulates microglial signaling output remains under debate. To probe for such scenarios, we generated mice harboring an MHCII deficiency in microglia, but not peripheral myeloid cells. Using the CX3 CR1CreER -based approach we report that microglial antigen presentation is obsolete for the establishment of EAE, with disease onset, progression, and severity unaltered in mutant mice. Antigen presentation-independent roles of microglial MHCII were explored using a demyelination model induced by the copper chelator cuprizone. Absence of microglial I-Ab did not affect the extent of these chemically induced white matter alterations, nor did it affect microglial proliferation or gene expression associated with locally restricted de- and remyelination. PMID- 29697862 TI - Progress in melanoma modelling in vitro. AB - Melanoma is one of the most studied neoplasia, although laboratory techniques used for investigating this tumor are not fully reliable. Animal models may not predict the human response due to differences in skin physiology and immunity. In addition, international guidelines recommend to develop processes that contribute to the reduction, refinement and replacement of animals for experiments (3Rs). Adherent cell culture has been widely used for the study of melanoma to obtain important information regarding melanoma biology. Nonetheless, these cells grow in adhesion on the culture substrate which differs considerably from the situation in vivo. Melanoma grows in a 3D spatial conformation where cells are subjected to a heterogeneous exposure to oxygen and nutrient. In addition, cell cell and cell-matrix interaction play a crucial role in the pathobiology of the tumor as well as in the response to therapeutic agents. To better study, melanoma new techniques, including spherical models, tumorospheres and melanoma skin equivalents, have been developed. These 3D models allow to study tumors in a microenvironment that is more close to the in vivo situation and are less expensive and time-consuming than animal studies. This review will also describe the new technologies applied to skin reconstructs such as organ-on-a-chip that allows skin perfusion through microfluidic platforms. 3D in vitro models, based on the new technologies, are becoming more sophisticated, representing at a great extent the in vivo situation, the "perfect" model that will allow less involvement of animals up to their complete replacement, is still far from being achieved. PMID- 29697863 TI - Does organized sport participation during youth predict healthy habits in adulthood? A 28-year longitudinal study. AB - Health behaviors in youth can predict the same behaviors later in life, but the role of sport participation in predicting healthy lifestyle habits is unclear. This study aimed to investigate the association between participation in organized youth sport and adult healthy lifestyle habits. Data from the longitudinal Cardiovascular Risk in Young Finns Study (YFS) with a 28-year follow up were used. The participation in sport-club training sessions was self-reported by 9-18-year-olds in 1983 and 1986 (n = 1285). During 2011, participants (aged 37 43-year old) reported their smoking status, alcohol consumption, fruit and vegetable consumption, and physical activity. Odd ratios (OR) were calculated using logistic regression, to examine how participation in organized youth sport was associated with having three or four versus fewer (0-2) healthy habits in adulthood. Participants who were active in youth sport in both 1983 and 1986 had almost two times greater odds of having three or four healthy habits in adulthood than those who were not active at both time points (OR: 1.75, 95%CI: 1.11-2.76). When the analyses were stratified by sex, the findings were statistically significant among women (OR: 2.13, 95%Cl: 1.13-3.99) but not men (OR: 1.27, 95%CI: 0.63-2.58). The results suggest that participation in organized youth sport could promote healthy lifestyle choices. PMID- 29697864 TI - In Situ Synthesis of Mn3 O4 Nanoparticles on Hollow Carbon Nanofiber as High Performance Lithium-Ion Battery Anode. AB - The practical applications of Mn3 O4 in lithium-ion batteries are greatly hindered by fast capacity decay and poor rate performance as a result of significant volume changes and low electrical conductivity. It is believed that the synthesis of nanoscale Mn3 O4 combined with carbonaceous matrix will lead to a better electrochemical performance. Herein, a convenient route for the synthesis of Mn3 O4 nanoparticles grown in situ on hollow carbon nanofiber (denoted as HCF/Mn3 O4 ) is reported. The small size of Mn3 O4 particles combined with HCF can significantly alleviate volume changes and electrical conductivity; the strong chemical interactions between HCF and Mn3 O4 would improve the reversibility of the conversion reaction for MnO into Mn3 O4 and accelerate charge transfer. These features endow the HCF/Mn3 O4 composite with superior cycling stability and rate performance if used as the anode for lithium-ion batteries. The composite delivers a high discharge capacity of 835 mA h g-1 after 100 cycles at 200 mA g-1 , and 652 mA h g-1 after 240 cycles at 1000 mA g-1 . Even at 2000 mA g-1 , it still shows a high capacity of 528 mA h g-1 . The facile synthetic method and outstanding electrochemical performance of the as-prepared HCF/Mn3 O4 composite make it a promising candidate for a potential anode material for lithium-ion batteries. PMID- 29697865 TI - SjHSP60 induces CD4+ CD25+ Foxp3+ Tregs via TLR4-Mal-drived production of TGF beta in macrophages. AB - CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) play a pivotal role in limiting immunopathological damage to host organs after schistosome infection. Transforming growth factor-beta (TGF-beta) is an essential factor for the periphery conversion of CD4+ CD25- T cells into CD4+ CD25+ Foxp3+ Tregs by inducing the key transcription factor Foxp3. Antigen presenting cells (APCs), which highly express TGF-beta, are involved in parasite antigen-induced Treg conversion in peripheral. However, the mechanisms underlying high TGF-beta induction in APCs by parasite antigens remain to be clarified during schistosome infection. Here, we demonstrated that Schistosoma japonicum stress protein, heat shock protein 60 (SjHSP60), promoted TGF-beta production in macrophages (Mphi). Furthermore, we showed that activation of TLR4-Mal (MyD88 adaptor-like protein) signaling by SjHSP60 is necessary for induction of TGF-beta expression in Mphi, which subsequently promoted Treg induction. Our results not only demonstrate a novel mechanism of TGF-beta production in Mphi for inducing Tregs in mice with schistosomiasis, but also allude to the possibility of targeting parasite stress protein for potential therapeutics. PMID- 29697866 TI - Etiologies and predictors of 30-day readmissions in patients undergoing percutaneous mechanical circulatory support-assisted percutaneous coronary intervention in the United States: Insights from the Nationwide Readmissions Database. AB - BACKGROUND: Patients undergoing percutaneous mechanical circulatory support (pMCS)-assisted percutaneous coronary intervention (PCI) represent a high-risk group vulnerable to complications and readmissions. HYPOTHESIS: Thirty-day readmissions after pMCS-assisted PCI are common among patients with comorbidities and account for a significant amount of healthcare spending. METHODS: Patients undergoing PCI and pMCS (Impella, TandemHeart, or intra-aortic balloon pump) for any indication between January 1, 2012, and November 30, 2014, were selected from the Nationwide Readmissions Database. Patients were identified using appropriate ICD-9-CM codes. Clinical risk factors and complications were analyzed for association with 30-day readmission. RESULTS: Our analysis included 29 247 patients, of which 4535 (15.5%) were readmitted within 30 days. On multivariate analysis, age >= 65 years, female sex, hypertension, diabetes, chronic lung disease, heart failure, prior implantable cardioverter-defibrillator, liver disease, end-stage renal disease, and length of stay >=5 days during index hospitalization were independent predictors of 30-day readmission. Cardiac etiologies accounted for ~60% of readmissions, of which systolic or diastolic heart failure (22%), stable coronary artery disease (11.1%), acute coronary syndromes (8.9%), and nonspecific chest pain (4.0%) were the most common causes. In noncardiac causes, sepsis/septic shock (4.6%), hypotension/syncope (3.2%), gastrointestinal bleed (3.1%), and acute kidney injury (2.6%) were among the most common causes of 30-day readmissions. Mean length of stay and cost of readmissions was 4 days and $16 191, respectively. CONCLUSIONS: Thirty-day readmissions after pMCS-assisted PCI are common and are predominantly associated with increased burden of comorbidities. Reducing readmissions for common cardiac etiologies could save substantial healthcare costs. PMID- 29697867 TI - How omics technologies can enhance chemical safety regulation: perspectives from academia, government, and industry: The Perspectives column is a regular series designed to discuss and evaluate potentially competing viewpoints and research findings on current environmental issues. PMID- 29697868 TI - A chemical activity approach to exposure and risk assessment of chemicals: Focus articles are part of a regular series intended to sharpen understanding of current and emerging topics of interest to the scientific community. AB - To support the goals articulated in the vision for exposure and risk assessment in the twenty-first century, we highlight the application of a thermodynamic chemical activity approach for the exposure and risk assessment of chemicals in the environment. The present article describes the chemical activity approach, its strengths and limitations, and provides examples of how this concept may be applied to the management of single chemicals and chemical mixtures. The examples demonstrate that the chemical activity approach provides a useful framework for 1) compiling and evaluating exposure and toxicity information obtained from many different sources, 2) expressing the toxicity of single and multiple chemicals, 3) conducting hazard and risk assessments of single and multiple chemicals, 4) identifying environmental exposure pathways, and 5) reducing error and characterizing uncertainty in risk assessment. The article further illustrates that the chemical activity approach can support an adaptive management strategy for environmental stewardship of chemicals where "safe" chemical activities are established based on toxicological studies and presented as guidelines for environmental quality in various environmental media that can be monitored by passive sampling and other techniques. Environ Toxicol Chem 2018;37:1235-1251. (c) 2018 The Authors. Published by Wiley Periodicals, Inc. on behalf of SETAC. PMID- 29697869 TI - Parenting programs during adolescence: Outcomes from universal and targeted interventions offered in real-world settings. AB - The aim of this naturalistic study was to explore short and long-term outcomes of five different group-based parenting programs offered to parents of 10 to 17-year olds. Three hundred and fifteen parents (277 mothers and 38 fathers) who had enrolled in a parenting program (universal: Active Parenting, COPE; Connect; targeted: COMET; Leadership training for parents of teenagers [LFT]) answered questionnaires at three measurement waves (baseline, post-measurement, and one year follow-up). The questions concerned parenting style, parental mental health, family climate and adolescent mental health. Results revealed small to moderate changes in almost all outcome variables and in all parenting programs. Overall, parents in COMET reported the largest short and long-term changes. No substantial differences in change were seen between the other programs. The results support the general effectiveness of parenting programs for parents of adolescents. PMID- 29697871 TI - Should a smoking question be added to the Australian 2021 census? PMID- 29697870 TI - Long-term results of combined cardiac contractility modulation and subcutaneous defibrillator therapy in patients with heart failure and reduced ejection fraction. AB - BACKGROUND: Cardiac contractility modulation (CCM) is an electrical-device therapy for patients with heart failure with reduced ejection fraction (HFrEF). Patients with left ventricular ejection fraction (LVEF) <=35% also have indication for an implantable cardioverter-defibrillator (ICD), and in some cases subcutaneous ICD (S-ICD) is selected. HYPOTHESIS: CCM and S-ICD can be combined to work efficaciously and safely. METHODS: We report on 20 patients with HFrEF and LVEF <=35% who received CCM and S-ICD. To exclude device interference, patients received intraoperative crosstalk testing, S-ICD testing, and bicycle exercise testing while CCM was activated. Clinical and QOL measures before CCM activation and at last follow-up were analyzed. S-ICD performance was evaluated while both CCM and S-ICD were active. RESULTS: Mean follow-up was 34.3 months. NYHA class improved from 2.9 +/- 0.4 to 2.1 +/- 0.7 (P < 0.0001), Minnesota Living With Heart Failure Questionnaire score improved from 50.2 +/- 23.7 to 29.6 +/- 22.8 points (P < 0.0001), and LVEF improved from 24.4% +/- 8.1% to 30.9% +/- 9.6% (P = 0.002). Mean follow-up time with both devices active was 22 months. Three patients experienced a total of 6 episodes of sustained ventricular tachycardia, all successfully treated with first ICD shock. One case received an inappropriate shock unrelated to the concomitant CCM. One patient received an LVAD, so CCM and S-ICD were discontinued. CONCLUSIONS: CCM and S-ICD can be successfully combined in patients with HFrEF. S-ICD and CCM remain efficacious when used together, with no interference affecting their function. PMID- 29697872 TI - Youth perceptions of alcohol advertising: are current advertising regulations working? AB - OBJECTIVES: We investigated young people's exposure to alcohol advertising, their intentions to consume and purchase alcohol products following the viewing of advertisements, and whether they perceived the actors in the advertisements as being under the age of 25 years. METHODS: Face-to-face interviews were completed with 351 risky drinking 16-19-year-old Australians, with a sub-sample (n=68) responding to a range of alcohol advertisements in an in-depth interview. RESULTS: Participants were exposed to alcohol advertisements from an average of seven specific contexts in the past 12 months, with younger adolescents more likely to recall TV and outdoor billboards (n=351). Positive perception of advertisements was associated with increased intention to use and to purchase advertised products (n=68). A liqueur advertisement actor was perceived by 94% as being under 25 years-old, and almost 30% thought the advertisement was marketed at people younger than 18 years of age. CONCLUSIONS: Young people's perceptions of alcohol advertising are not necessarily in line with expert/industry assessment; products are sometimes marketed in a way that is highly appealing to young people. Greater appeal was associated with increased intention to consume and to purchase products. Implications for public health: These results indicate deficiencies in the effectiveness of current advertising codes in regard to protecting the health and wellbeing of adolescents. PMID- 29697873 TI - Transoral robotic resection of benign tumors of the upper aerodigestive tract: Experience of the French group of GETTEC. AB - BACKGROUND: The purpose of this study was to assess the current use of transoral robotic surgery (TORS) in benign tumors of the upper aerodigestive tract through a case series and a literature review. METHODS: This multicentric retrospective study was conducted in 6 French centers between November 2009 and July 2017. RESULTS: Twenty-one patients had a TORS resection of a tumor at varied locations with differing histopathologic characteristics. The mean postoperative hospital stay was 6.1 days. Eight patients had nasogastric tubes, which were removed after a mean of 5.6 days. Two patients had a prophylactic tracheostomy for an average of 5.5 days. A third tracheostomy was performed secondarily for postoperative bleeding. No recurrences were observed during the 2-year follow-up. CONCLUSION: This technique caused few complications and resulted in short hospitalization, with satisfactory functional and recurrence outcomes. However, the risk of bleeding and edema must be considered, and the need for a tracheostomy must be approached wisely. PMID- 29697874 TI - Coverage of Aboriginal and Torres Strait Islander nutrition in major Australian newspapers, 1996-2015. AB - OBJECTIVE: To examine the extent and nature of coverage of Aboriginal and Torres Strait Islander nutrition issues in major Australian newspapers over two decades. METHODS: Content and framing analysis of Australian newspaper articles published between 1996 and 2015 that included the terms 'Aboriginal or Indigenous' and 'nutrition or diet' in the headline and/or lead paragraph. Analysis focused on the nature of coverage, trends over time, stakeholder representation and how coverage related to policy. RESULTS: A total of 79 articles were included. Coverage of nutrition fluctuated over time, with peaks in 1998 and 2008. The majority of articles focused on remote Aboriginal communities. Both individual and structural representations of nutrition were used and dietary quality and food insecurity were the most commonly reported nutrition issues. Few articles employed positive representations of Aboriginal peoples. Six policy functions of articles were identified: highlighting problems; reporting government announcements; promoting programs; advocating solutions; critiquing government; and defending policy. CONCLUSION: The coverage of Aboriginal and Torres Strait Islander nutrition in newspapers does not reflect the diversity and strengths of Australia's First Peoples. Implications for public health: This study highlights the role of the media in policy advocacy; however, advocates should ensure that they do not perpetuate negative representations of Aboriginal and Torres Strait Islander peoples. PMID- 29697875 TI - A systematic review and meta-analysis of deep brain stimulation for depression. AB - BACKGROUND: Deep brain stimulation is increasingly being used for treatment resistant depression. Blinded, randomized controlled trials of active versus sham treatment have been limited to small numbers. METHOD: We performed a systematic review and meta-analysis on the effectiveness of deep brain stimulation (DBS) in depression. Cochrane Central Register of Controlled Trials, PubMed/Medline, Embase and PsycINFO, Chinese Biomedical Literature Service System, and China Knowledge Resource Integrated Database were searched for single- or double placebo-controlled, crossover, and parallel-group trials in which DBS was compared with sham treatment using validated scales. RESULTS: Ten papers from nine studies met inclusion criteria, all but two of which were double-blinded RCTs. The main outcome was a reduction in depressive symptoms. It was possible to combine data for 190 participants. Patients on active, as opposed to sham, treatment had a significantly higher response (OR = 5.50; 95% CI = 2.79, 10.85; p < .0001) and reductions in mean depression score (SMD = -0.42; 95% CI = -0.72, 0.12; p = .006). However, the effect was attenuated on some of the subgroup and sensitivity analyses, and there were no differences for most other outcomes. In addition, 84 participants experienced a total of 131 serious adverse effects, although not all could be directly associated with the device or surgery. Finally, publication bias was possible. CONCLUSIONS: DBS may show promise for treatment-resistant depression but remains an experimental treatment until further data are available. PMID- 29697877 TI - Emerging Applications of Bioinspired Slippery Surfaces in Biomedical Fields. AB - In this minireview, we summarize the recent development of liquid-infused slippery surfaces (LISS) for biomedical applications. The selected topics are divided into two parts: the material designs and emerging strategies to fabricate slippery surface, and their applications with strong and direct relevance to biomedical areas including antibiofouling, antithrombosis, medical device coatings and surface enhanced/assisted detection. We also describe the most critical directions in need of development to adapt this new approach to biomedical use. PMID- 29697876 TI - Osimertinib in Japanese patients with EGFR T790M mutation-positive advanced non small-cell lung cancer: AURA3 trial. AB - Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are the first-line treatment for patients with EGFR mutant non-small-cell lung cancer (NSCLC). However, most patients become resistant to these drugs, so their disease progresses. Osimertinib, a third-generation EGFR-TKI that can inhibit the kinase even when the common resistance-conferring Thr790Met (T790M) mutation is present, is a promising therapeutic option for patients whose disease has progressed after first-line EGFR-TKI treatment. AURA3 was a randomized (2:1), open-label, phase III study comparing the efficacy of osimertinib (80 mg/d) with platinum-based therapy plus pemetrexed (500 mg/m2 ) in 419 patients with advanced NSCLC with the EGFR T790M mutation in whom disease had progressed after first-line EGFR-TKI treatment. This subanalysis evaluated the safety and efficacy of osimertinib specifically in 63 Japanese patients enrolled in AURA3. The primary end-point was progression-free survival (PFS) based on investigator assessment. Improvement in PFS was clinically meaningful in the osimertinib group (n = 41) vs the platinum pemetrexed group (n = 22; hazard ratio 0.27; 95% confidence interval, 0.13-0.56). The median PFS was 12.5 and 4.3 months in the osimertinib and platinum-pemetrexed groups, respectively. Grade >=3 adverse events determined to be related to treatment occurred in 5 patients (12.2%) treated with osimertinib and 12 patients (54.5%) treated with platinum-pemetrexed. The safety and efficacy results in this subanalysis are consistent with the results of the overall AURA3 study, and support the use of osimertinib in Japanese patients with EGFR T790M mutation positive NSCLC whose disease has progressed following first-line EGFR-TKI treatment. (ClinicalTrials.gov trial registration no. NCT02151981.). PMID- 29697878 TI - Connexin 43 coupling in bovine cumulus cells, during the follicular growth phase, and its relationship to in vitro embryo outcomes. AB - Gap junctional coupling between cumulus cells is required for oocytes to reach developmental competence. Multiple connexins, which form these gap junctions, have been found within the ovarian follicles of several species including bovine. The aim of this study was to determine the role of connexin 43 (CX43) and its relationship to embryo development, after in vitro fertilization (IVF). Cumulus oocyte complexes (COCs) were obtained from abattoir sourced, mixed breed, bovine ovaries. COCs were isolated from follicles ranging from 2 to 5 mm in size, representing the preselected follicle pool. Immediately after isolation, two cumulus cell biopsies were collected and stored for analysis pending determination of developmental outcomes. Using in vitro procedures, COCs were individually matured, fertilized, and cultured to the blastocyst stage. Biopsies were grouped as originating from COCs that arrested at the two-cell stage (low developmental competence [LDC]) or having developed to the late morula/blastocyst stage (high developmental competence [HDC]), after IVF and embryo culture. The expression level of CX43 was found to be significantly higher in cumulus cells from COCs that had an HDC when compared with those that had an LDC. Moreover, the gap junctional intercellular coupling rate was significantly higher in cumulus from COCs deemed to have an HDC. Significantly higher expression of the cumulus health markers luteinizing hormone receptor and cytochrome p450 19A1 was found in the cumulus originating from oocytes with HDC, suggesting that this system may provide a mechanism for noninvasively testing for oocyte health in preselected bovine follicles. PMID- 29697879 TI - Drawing attention to a neglected injecting-related harm: a systematic review of AA amyloidosis among people who inject drugs. AB - BACKGROUND AND AIMS: Chronic skin and soft tissue infections (SSTI) among people who inject drugs (PWID) can lead to AA amyloidosis: a serious, yet neglected, multi-organ disease. We aim to synthesize findings on the epidemiology, risk factors, clinical outcomes, screening recommendations and challenges to treatment for AA amyloidosis among PWID. METHODS: A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses (PRISMA). We searched the following bibliographic databases in July 2017: CINAHL Plus, Embase, Global Health, MEDLINE, PsycEXTRA, PsycINFO and SCOPUS. Studies were included if they investigated AA amyloidosis in PWID. Studies were not restricted to location, study type, year or language of publication. Study heterogeneity precluded meta-analysis; we present a narrative review of the literature. RESULTS: Thirty-seven papers from eight countries met inclusion criteria. A total of 781 PWID are reported on, of whom 177 had AA amyloidosis. Where disease causality is established, it is attributed to chronic inflammation caused by injecting-related SSTIs. Most (88.7%) PWID with AA amyloidosis had SSTIs. The proportion of PWID with AA amyloidosis at post-mortem ranged from 1.6% (Germany) to 22.5% (Serbia). Biopsy studies reported from 5.26% (Portugal) to 50% (Germany) of AA amyloidosis in PWID with suspected or known kidney disease. Following diagnosis, the typical trajectory for PWID with AA amyloidosis was rapid deterioration of renal function requiring haemodialysis. Treatment difficulties, end-stage renal failure and premature death from sepsis were observed. Good outcomes, including reversibility of AA amyloidosis, are attributed to rapid treatment of the underlining inflammation and injecting cessation. Notably, given the population in question, no studies were published in addiction or harm reduction journals; most (92%) appeared in specialist nephrology and medical journals. CONCLUSION: There is strong evidence of an association between skin and soft tissue infections (SSTIs) and AA amyloidosis. Among people who inject drugs, injecting-related SSTIs are a significant cause of morbidity and premature mortality and there is evidence of increasing SSTI prevalence. Limitations in the literature make it difficult to estimate AA amyloidosis prevalence among people who inject drugs. PMID- 29697880 TI - Associations between socioeconomic status and psychological therapy outcomes: A systematic review and meta-analysis. AB - BACKGROUND: Socioeconomic deprivation is associated with higher prevalence of mental health problems; however, the influence of socioeconomic status (SES) on psychological therapy outcomes is as yet unclear. AIM: To review published evidence on the association between indicators of SES (income, education, employment, neighborhood deprivation, social position) and the outcomes of psychological interventions for depression and anxiety. METHODS: Systematic review and meta-analysis of outcomes research studies published in the last 10 years. RESULTS: Seventeen studies including 165,574 patients measured at least one indicator of SES and its relationship with psychological therapy outcomes. Twelve of these studies found significant relationships between SES measures and mental health outcomes. Six studies focusing on employment status offered sufficient quantitative information to conduct meta-analysis. The overall effect of employment was not significant (-0.66, confidence of interval (CI) -1.33, 0.02). A sensitivity analysis (k = 5) showed a small effect (-0.22, CI -0.36, 0.09) of employment on treatment outcomes. CONCLUSIONS: There is some evidence to indicate that socioeconomic deprivation is associated with poorer treatment outcomes, although limitations of the available data warrant treating this as a preliminary conclusion. PMID- 29697882 TI - Fluoride concentration in drinking water samples in Fiji. AB - OBJECTIVE: The main aim of this study was to determine the content of fluoride in drinking water from sources within the sampling areas for the National Oral Health Survey (NOHS) 2011 from the Central, Northern, Western and Eastern Divisions in the Fiji Islands. METHOD: Drinking water samples were collected from taps, a waterfall, wells, creeks, streams, springs, rivers, boreholes and rain water tanks in a diverse range of rural and urban areas across the Fiji Islands. A total of 223 areas were sampled between December 2014 and June 2015. Samples were analysed for fluoride using a colorimetric assay with the Zirconyl-SPADNS Reagent. The samples were pre-treated with sodium arsenite solution prior to analysis to eliminate interference from chlorine. RESULTS: Measured fluoride concentrations ranged from 0.01 to 0.35 ppm, with a mean concentration across all samples of 0.03 + 0.04 ppm. No samples achieved the optimal level for caries prevention (0.7 ppm). The Western Division had the highest fluoride levels compared to the other Divisions. The highest single fluoride concentration was found in Valase. The drinking water for this rural area located in the Western Division is from a borehole. The lowest concentrations of fluoride were in reticulated water samples from rural areas in the Central Division, which were consistently less than those recorded in the Northern, Eastern and Western Divisions. CONCLUSION: All samples had fluoride concentrations below the optimum level required to prevent dental caries. Implications for public health: This research forms part of the objectives of the 2011 National Oral Health Survey in Fiji. At present, Fiji lacks water fluoridation and therefore a baseline of the fluoride content in drinking water supplies is essential before water fluoridation is implemented. The results from this study would be beneficial in designing caries-preventive strategies through water fluoridation and for comparing those strategies with caries prevalence overtime. PMID- 29697881 TI - The DSM-5 nonsuicidal self-injury disorder among incoming college students: Prevalence and associations with 12-month mental disorders and suicidal thoughts and behaviors. AB - BACKGROUND: Approximately one in five college students report a history of nonsuicidal self-injury. However, it is unclear how many students meet criteria for the recently proposed DSM-5 nonsuicidal self-injury disorder (NSSI-D). In this study, we used full NSSI-D criteria to identify those students most in need of clinical care. METHODS: Using data from the Leuven College Surveys (n = 4,565), we examined the 12-month prevalence of DSM-5 NSSI-D in a large and representative sample of incoming college students. We also explored the optimal frequency threshold as a function of interference in functioning due to NSSI, and examined comorbidity patterns with other 12-month mental disorders (i.e., major depressive disorder, broad mania, generalized anxiety disorder, panic disorder, and alcohol dependence) and suicidal thoughts and behaviors (STB). RESULTS: Twelve-month NSSI-D prevalence was 0.8% and more common among females (1.1%) than males (0.4%). The proposed 5+ diagnostic threshold was confirmed as yielding highest discrimination between threshold and subthreshold cases in terms of distress or disability due to NSSI. A dose-response relationship was observed for NSSI recency-severity (i.e., 12-month NSSI-D, subthreshold 12-month NSSI-D, past NSSI, no history of NSSI) with number of 12-month mental disorders and STB. NSSI D occurred without comorbid disorders for one in five individuals, and remained associated with severe role impairment when controlling for the number of comorbid disorders. CONCLUSIONS: These findings offer preliminary evidence that DSM-5 NSSI-D is uncommon among incoming college students, but may help to improve the deployment of targeted resource allocation to those most in need of services. More work examining the validity of NSSI-D is required. PMID- 29697883 TI - Variation of T2 relaxation times in pediatric brain tumors and their effect on metabolite quantification. AB - BACKGROUND: Metabolite concentrations are fundamental biomarkers of disease and prognosis. Magnetic resonance spectroscopy (MRS) is a noninvasive method for measuring metabolite concentrations; however, quantitation is affected by T2 relaxation. PURPOSE: To estimate T2 relaxation times in pediatric brain tumors and assess how variation in T2 relaxation affects metabolite quantification. STUDY TYPE: Retrospective. POPULATION: Twenty-seven pediatric brain tumor patients (n = 17 pilocytic astrocytoma and n = 10 medulloblastoma) and 24 age matched normal controls. FIELD STRENGTH/SEQUENCE: Short- (30 msec) and long-echo (135 msec) single-voxel MRS acquired at 1.5T. ASSESSMENT: T2 relaxation times were estimated by fitting signal amplitudes at two echo times to a monoexponential decay function and were used to correct metabolite concentration estimates for relaxation effects. STATISTICAL TESTS: One-way analysis of variance (ANOVA) on ranks were used to analyze the mean T2 relaxation times and metabolite concentrations for each tissue group and paired Mann-Whitney U-tests were performed. RESULTS: The mean T2 relaxation of water was measured as 181 msec, 123 msec, 90 msec, and 86 msec in pilocytic astrocytomas, medulloblastomas, basal ganglia, and white matter, respectively. The T2 of water was significantly longer in both tumor groups than normal brain (P < 0.001) and in pilocytic astrocytomas compared with medulloblastomas (P < 0.01). The choline T2 relaxation time was significantly longer in medulloblastomas compared with pilocytic astrocytomas (P < 0.05), while the T2 relaxation time of NAA was significantly shorter in pilocytic astrocytomas compared with normal brain (P < 0.001). Overall, the metabolite concentrations were underestimated by ~22% when default T2 values were used compared with case-specific T2 values at short echo time. The difference was reduced to 4% when individually measured water T2 s were used. DATA CONCLUSION: Differences exist in water and metabolite T2 relaxation times for pediatric brain tumors, which lead to significant underestimation of metabolite concentrations when using default water T2 relaxation times. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 29697884 TI - Lophirones B and C halt acetaminophen hepatotoxicity by upregulating redox transcription factor Nrf-2 through Akt, PI3K, and PKC pathways. AB - We investigated the mechanism of lophirones B- and C-mediated protection against acetaminophen hepatotoxicity. Mice were pretreated with 20 mg/kg body weight lophirones B and C for 7 days and challenged with acetaminophen on day 7. Acetaminophen raised nuclear factor-kappaB (NF-kappaB) in the liver of mice but lowered protein kinase B (Akt). Although, acetaminophen produced no significant alteration on nuclear erythroid related factor-2 (Nrf-2), phosphoinositide 3 kinase (PI3K) and protein kinase C (PKC), lophirones B and C raised the level of these proteins and Akt. The acetaminophen-mediated increase in NF-kappaB was significantly reversed by lophirones B and C. Lophirones B and C prevented acetaminophen-mediated alterations in serum biomarkers of hepatic injury. Similarly, lophirones B and C lowered the biomarkers of oxidative stress in the liver of acetaminophen-treated mice. It can be inferred from this study that lophirones B and C prevent acetaminophen-induced liver injury by enhancing Nrf-2 through Akt, PI3K, and PKC pathways. PMID- 29697885 TI - Yoga for anxiety: A systematic review and meta-analysis of randomized controlled trials. AB - Yoga has become a popular approach to improve emotional health. The aim of this review was to systematically assess and meta-analyze the effectiveness and safety of yoga for anxiety. Medline/PubMed, Scopus, the Cochrane Library, PsycINFO, and IndMED were searched through October 2016 for randomized controlled trials (RCTs) of yoga for individuals with anxiety disorders or elevated levels of anxiety. The primary outcomes were anxiety and remission rates, and secondary outcomes were depression, quality of life, and safety. Risk of bias was assessed using the Cochrane tool. Eight RCTs with 319 participants (mean age: 30.0-38.5 years) were included. Risk of selection bias was unclear for most RCTs. Meta-analyses revealed evidence for small short-term effects of yoga on anxiety compared to no treatment (standardized mean difference [SMD] = -0.43; 95% confidence interval [CI] = -0.74, -0.11; P = .008), and large effects compared to active comparators (SMD = -0.86; 95% CI = -1.56, -0.15; P = .02). Small effects on depression were found compared to no treatment (SMD = -0.35; 95% CI = -0.66, -0.04; P = .03). Effects were robust against potential methodological bias. No effects were found for patients with anxiety disorders diagnosed by Diagnostic and Statistical Manual criteria, only for patients diagnosed by other methods, and for individuals with elevated levels of anxiety without a formal diagnosis. Only three RCTs reported safety-related data but these indicated that yoga was not associated with increased injuries. In conclusion, yoga might be an effective and safe intervention for individuals with elevated levels of anxiety. There was inconclusive evidence for effects of yoga in anxiety disorders. More high-quality studies are needed and are warranted given these preliminary findings and plausible mechanisms of action. PMID- 29697886 TI - Adolescent and young adult substance use in Australian Indigenous communities: a systematic review of demand control program outcomes. AB - OBJECTIVE: Identifying preventative approaches to substance use in Indigenous communities is the foundation for developing evidence-based responses. This study reports the findings of a systematic review of the published literature evaluating the impact of substance use programs on Australian Indigenous youth. METHODS: Evidence about the impact of substance use programs for Indigenous young people was identified from a systematic review of the literature conducted according to the Preferred Reporting Items for Systematic reviews and Meta Analyses guidelines. RESULTS: Only four original studies that met the inclusion criteria were identified, although a further 19 papers that described characteristics of programs that may be associated with improved outcomes were reviewed. CONCLUSIONS: Evidence relevant to the outcomes of demand control programs that target Australian Indigenous youth substance use is both weak and inconsistent. There is a need to support the type of evaluation activity required to better understand program effectiveness and build the Indigenous knowledge base. Implications for public health: These findings are discussed in relation to the development of evidence-based practice and the type of knowledge that is likely to be of most use to those seeking to address problems associated with youth substance use. PMID- 29697887 TI - An appraisal of the trustworthiness of practice guidelines for depression and anxiety in children and youth. AB - OBJECTIVE: Little is known about the trustworthiness of clinical practice guidelines (PGs) relevant to child and youth depression or anxiety. To address this gap, we used systematic review methods to identify all available relevant PGs, quality appraise them, and make recommendations regarding which PGs are trustworthy and should be used by clinicians. METHODS: Prespecified inclusion criteria identified eligible PGs. Two independent trained reviewers applied the Appraisal of Guidelines for Research and Evaluation (AGREE II) tool. Using three AGREE II domain scores (stakeholder involvement, rigor of development [clinical validity/trustworthiness], and editorial independence), PG quality was designated as (1) minimum (>=50%) and (2) high (>=70%). RESULTS: Of 25 eligible PGs, five met minimum quality criteria (depression, n = 4; anxiety, n = 1); three out of five met high-quality criteria (depression, n = 2; anxiety, n = 1). Among the five minimum quality PGs, developers included government (n = 2), independent expert groups (n = 2), and other (n = 1). No PGs developed by specialty societies achieved minimum or high-quality ratings; eight of 25 PGs were up-to-date. CONCLUSIONS: Trustworthy PGs are available to support clinical decisions about depression and anxiety in children and youth, but are few in number. Many existing PGs (up to 80%) may not be clinically valid. Clinicians who implement the high-quality PGs identified here can increase the number of children and youth who receive effective interventions for depression and anxiety, minimize harm, and avoid wasted resources. Clinicians, service planners, youth, and their families should encourage PG developers to increase the pool of high-quality PGs using internationally recognized PG development standards. PMID- 29697889 TI - Public support for bicycling and transport policies in inner Sydney, Australia: a cross-sectional survey. AB - OBJECTIVE: To describe the degree of community support - and factors associated with this support - for a number of potential transport policy options among an inner-city sample of residents in Sydney, Australia. METHODS: This study analysed data collected from a cross-sectional online survey: Wave 3 of the Sydney Transport and Health Study, conducted in September-October 2015 (n=418). RESULTS: There was a high level of overall support for policies to make public transport cheaper (85%), have more bicycle paths separated from motor vehicles (82%) and have a public bike-share program (72%), with similar levels of support across usual commute mode, age and sex. CONCLUSIONS: Despite a natural tendency for respondents to support transport policies that were of most relevance to themselves, it appeared that, in this sample, public support for public transport and bicycling policies remained strong across all respondents. Implications for public health: Policies that support public transport and active travel and achieve positive health outcomes would be well received by inner-Sydney residents. PMID- 29697888 TI - Insomnia mediates the longitudinal relationship between anxiety and depressive symptoms in a nationally representative sample of adolescents. AB - BACKGROUND: Anxiety and depression are commonly comorbid with each other, with anxiety often temporally preceding the development of depression. Although increasingly research has begun to investigate the role of sleep problems in depression, no study has examined insomnia as a mediator in the longitudinal relationship between anxiety and subsequent depression. METHODS: The current study utilizes data from Waves I, II, and IV of the National Longitudinal Study of Adolescent to Adult Health, a nationally representative prospective study conducted over a 14-year period (n = 20,745, 50.5% female, M age at Wave I = 16.20). Participants completed portions of the Center for Epidemiologic Studies Depression Scale at Waves I and IV to assess depressive symptoms, a six-item anxiety measure at Wave I, and three items assessing insomnia, sleep quality, and sleep duration at Wave II. RESULTS: Structural equation modeling indicated that insomnia and unrestful sleep significantly mediated the relationship between anxiety and subsequent depression. The relationship between anxiety and depression was not significantly mediated by sleep duration. CONCLUSIONS: Findings suggest that anxiety may increase risk for the development of later depression through insomnia. PMID- 29697891 TI - Short-term efficacy of adalimumab in a patient with pyrin-associated autoinflammation with neutrophilic dermatosis. PMID- 29697892 TI - Insights into population genetics and evolution of polyploids and their ancestors. AB - We have developed the first comprehensive simulator for polyploid genomes (PolySim) and demonstrated its value by performing large-scale simulations to examine the effect of different population parameters on the evolution of polyploids. PolySim is unlimited in terms of ploidy, population size or number of simulated loci. Our process considered the evolution of polyploids from diploid ancestors, polysomic inheritance, inbreeding, recombination rate change in polyploids and gene flow from lower to higher ploidies. We compared the number of segregating single nucleotide polymorphisms, minor allele frequency, heterozygosity, R2 and average kinship relatedness between different simulated scenarios, and to real data from polyploid species. As expected, allotetraploid populations showed no difference from their ancestral diploids when population size remained constant and there was no gene flow or multivalent (MV) pairing between subgenomes. Autotetraploid populations showed significant differences from their ancestors for most parameters and diverged from their ancestral populations faster than allotetraploids. Autotetraploids can have significantly higher heterozygosity, relatedness and extended linkage disequilibrium compared with allotetraploids. Interestingly, autotetraploids were more sensitive to increasing selfing rate and decreasing population size. MV formation can homogenize allotetraploid subgenomes, but this homogenization requires a higher MV rate than previously proposed. Our results can be considered as the first building block to understand polyploid population evolutionary dynamics. PolySim can be used to simulate a wide variety of polyploid organisms that mimic empirical populations, which, in combination with quantitative genetics tools, can be used to investigate the power of genomewide association, genomic selection or breeding programme designs in these species. PMID- 29697890 TI - Caesarean scar pregnancy in the UK: a national cohort study. AB - OBJECTIVE: To estimate the incidence of caesarean scar pregnancy (CSP) and to describe the management outcomes associated with this condition. DESIGN: A national cohort study using the UK Early Pregnancy Surveillance Service (UKEPSS). SETTING: 86 participating Early Pregnancy Units. POPULATION: All women diagnosed in the participating units with CSP between November 2013 and January 2015. METHODS: Cohort study of women identified through the UKEPSS monthly mailing system. MAIN OUTCOME MEASURES: Incidence, clinical outcomes and complications. RESULTS: 102 cases of CSP were reported, with an estimated incidence of 1.5 per 10 000 (95% CI 1.1-1.9) maternities. Full outcome data were available for 92 women. Management was expectant in 21/92 (23%), medical in 15/92 (16%) and surgical in 56/92 (61%). The success rates of expectant, medical and surgical management were 43% (9/21), 46% (7/15) and 96% (54/56), respectively. The complication rates were 15/21 (71%) with expectant, 9/15 (60%) with medical and 20/56 (36%) with surgical management. Discharge from care (median number of days) was 82 (range 37-174) with expectant, 21 (range 10-31) with medical and 11 (range 4-49) with surgical management. CONCLUSIONS: Surgical management appears to be associated with a high success rate, low complication rate and short post treatment follow up. TWEETABLE ABSTRACT: Surgery for CSP appears to be successful, with low complication rates and short post-treatment follow up. PMID- 29697893 TI - Janus Graft Block Copolymers: Design of a Polymer Architecture for Independently Tuned Nanostructures and Polymer Properties. AB - The graft-through synthesis of Janus graft block copolymers (GBCPs) from branched macromonomers composed of various combinations of homopolymers is presented. Self assembly of GBCPs resulted in ordered nanostructures with ultra-small domain sizes down to 2.8 nm (half-pitch). The grafted architecture introduces an additional parameter, the backbone length, which enables control over the thermomechanical properties and processability of the GBCPs independently of their self-assembled nanostructures. The simple synthetic route to GBCPs and the possibility of using a variety of polymer combinations contribute to the universality of this technique. PMID- 29697894 TI - A geography-aware reconciliation method to investigate diversification patterns in host/parasite interactions. AB - Cospeciation studies aim at investigating whether hosts and symbionts speciate simultaneously or whether the associations diversify through host shifts. This problem is often tackled through reconciliation analyses that map the symbiont phylogeny onto the host phylogeny by mixing different types of diversification events. These reconciliations can be difficult to interpret and are not always biologically realistic. Researchers have underlined that the biogeographic histories of both hosts and symbionts influence the probability of cospeciation and host switches, but up to now no reconciliation software integrates geographic data. We present a new functionality in the Mowgli software that bridges this gap. The user can provide geographic information on both the host and symbiont extant and ancestral taxa. Constraints in the reconciliation algorithm have been implemented to generate biologically realistic codiversification scenarios. We apply our method to the fig/fig wasp association and infer diversification scenarios that differ from reconciliations ignoring geographic information. In addition, we updated the reconciliation viewer SylvX to visualize ancestral character states on the phylogenetic trees and highlight parts of reconciliations that are geographically inconsistent when not accounting for geographic constraints. We suggest that the comparison of reconciliations obtained with and without such constraints can help solving ambiguities in the biogeographic histories of the partners. With the development of robust methods in historical biogeography, and the advent of next-generation sequencing that leads to better resolved trees, a geography-aware reconciliation method represents a substantial advance that is likely to be useful to researchers studying the evolution of biotic interactions and biogeography. PMID- 29697895 TI - Chemistry Has No Nationality. AB - "... Our job is to make absolutely sure that the needs of science are made very clear to government, and are emphasised again and again and again. Because I really believe that strong science benefits everyone. It's not just scientists who benefit: we all benefit from scientific discoveries, and a country with a strong base in science will have a strong knowledge economy ..." Read more in the Editorial by Sir John Holman and Edwin Silvester. PMID- 29697896 TI - Frontiers in Neurochemistry. PMID- 29697897 TI - Light-Induced Reversible Reconfiguration of DNA-Based Constitutional Dynamic Networks: Application to Switchable Catalysis. AB - The light-induced reversible and cyclic reconfiguration of constitutional dynamic networks, consisting of supramolecular nucleic acid structures as constituents and a photoisomerizable trans/cis-azobenzene-functionalized nucleic acid as the trigger is demonstrated. In addition, the cyclic photochemical reconfiguration of the constitutional dynamic networks guides the switchable on/off operation of an emerging hemin/G-quadruplex DNAzyme. PMID- 29697898 TI - 1,4-Iron Migration for Expedient Allene Annulations through Iron-Catalyzed C-H/N H/C-O/C-H Functionalizations. AB - C-H activation bears great potential for enabling sustainable molecular syntheses in a step- and atom-economical manner, with major advances having been realized with precious 4d and 5d transition metals. In contrast, we employed earth abundant, nontoxic iron catalysts for versatile allene annulations through a unique C-H/N-H/C-O/C-H functionalization sequence. The powerful iron catalysis occurred under external-oxidant-free conditions even at room temperature, while detailed mechanistic studies revealed an unprecedented 1,4-iron migration regime for facile C-H activations. PMID- 29697899 TI - A Two-Dimensional Ruddlesden-Popper Perovskite Nanowire Laser Array based on Ultrafast Light-Harvesting Quantum Wells. AB - Miniaturized nanowire nanolasers of 3D perovskites feature a high gain coefficient; however, room-temperature optical gain and nanowire lasers from 2D layered perovskites have not been reported to date. A biomimetic approach is presented to construct an artificial ligh-harvesting system in mixed multiple quantum wells (QWs) of 2D-RPPs of (BA)2 (FA)n-1 Pbn Br3n+1 , achieving room temperature ASE and nanowire (NW) lasing. Owing to the improvement of flexible and deformable characteristics provided by organic BA cation layers, high-density large-area NW laser arrays were fabricated with high photostability. Well controlled dimensions and uniform geometries enabled 2D-RPPs NWs functioning as high-quality Fabry-Perot (FP) lasers with almost identical optical modes, high quality (Q) factor (ca. 1800), and similarly low lasing thresholds. PMID- 29697901 TI - A German-Jewish refugee in Vichy France 1939-1941. Arno Motulsky's memoir of life in the internment camps at St. Cyprien and Gurs. PMID- 29697900 TI - [Au12 (SR)6 ]2- , As Smaller 8-Electron Gold Nanocluster Retaining an SP3 -Core. Evaluation of Bonding and Optical Properties from Relativistic DFT Calculations. AB - Exploring the versatility of atomically precise clusters is a relevant issue in the design of functional nanostructures. Superatomic clusters offer an ideal framework to gain further understanding of the different distinctive size dependent physical and chemical properties. Here, we propose [Au12 (SR)6 ]2- as a minimal 8-electron superatom related to the prototypical [Au25 (SR)18 ]- cluster, depicting half of its core-mass (2.3 kDa vs 5.0 kDa). The [Au12 (SMe)6 ]2- cluster fulfills a 1S2 1P6 electronic configuration, with a distorted tetrahedral Au8 core further viewed as an SP3 -hybridized superatom. The distinctive optical properties show a blue-shift for the first relevant 1P->1D transition, in comparison to [Au25 (SR)18 ]- . In addition, chiroptical activity is observed, denoting intrinsic core chirality. We expect that our results can shed light into the variation of the molecular properties according to the size-dependent properties, and serve as guidelines for further experimental exploration of minimal or ultrasmall nanoclusters. PMID- 29697902 TI - Simultaneous Quantification of Multiple Cancer Biomarkers in Blood Samples through DNA-Assisted Nanopore Sensing. AB - Protein biomarkers in blood have been widely used in the early diagnosis of disease. However, simultaneous detection of many biomarkers in a single sample remains challenging. Herein, we show that the combination of a sandwich assay and DNA-assisted nanopore sensing could unambiguously identify and quantify several antigens in a mixture. We use five barcode DNAs to label different gold nanoparticles that can selectively bind specific antigens. After the completion of the sandwich assay, barcode DNAs are released and subject to nanopore translocation tests. The distinct current signatures generated by each barcode DNA allow simultaneous quantification of biomarkers at picomolar level in clinical samples. This approach would be very useful for accurate and multiplexed quantification of cancer-associated biomarkers within a very small sample volume, which is critical for non-invasive early diagnosis of cancer. PMID- 29697903 TI - An Isotopic Labelling Strategy to Study Cytochrome P450 Oxidations of Terpenes. AB - The cytochrome P450 monooxygenase CYP267B1 from Sorangium cellulosum was applied for the enzymatic oxidation of the sesquiterpene alcohols T-muurolol and isodauc 8-en-11-ol. Various isotopically labelled geranyl and farnesyl diphosphates were used for product identification from micro-scale reactions, for the determination of the absolute configurations of unknown compounds, to follow the stereochemical course of a cytochrome P450-catalysed hydroxylation step, and to investigate kinetic isotope effects. Overall, this study demonstrates that isotopically labelled terpene precursors are highly useful to follow cytochrome P450 dependent oxidations of terpenes. PMID- 29697905 TI - Protein tagging in environmental microbiology: An annotated selection of World Wide Web sites relevant to the topics in environmental microbiology. PMID- 29697904 TI - A case of photodistributed multicentric reticulohistiocytosis: correlation with multiphoton microscopy imaging. PMID- 29697906 TI - The American College of Rheumatology is Launching an Open Access Journal and Seeking an Editor-in-Chief. PMID- 29697907 TI - The relationships among consumption of fruits, tooth loss and obesity. AB - OBJECTIVE: to explore whether consumption of fruits attenuates the relationship between tooth loss and obesity among adult Americans. BASIC RESEARCH DESIGN: data from the Behavioral Risk Factor Surveillance System 2012, a cross-sectional survey. PARTICIPANTS: 20,103 adults aged 18 and over who participated in the Behavioral Risk Factor Surveillance System 2012, a nationally representative survey of non-institutionalized adult American. MAIN OUTCOME MEASURES: Obesity (Body Mass Index >= 30 kg/m2). Logistic regression analysis was used to assess the association between obesity and number of missing teeth adjusting for consumption of fruits socio-demographic factors, physical activity, diabetes and self-rated general health. RESULTS: The prevalence of obesity was higher among adults with ? 6 missing teeth and among those with fruit intakes less than once a day. Individuals with ? 6 missing teeth were at higher risk of obesity with odds ratios 1.25 (95% CI: 1.04, 1.50), the relationship attenuated after adjusting for fruit consumption. CONCLUSIONS: Frequent consumption of fruits was inversely associated with each of obesity and number of missing teeth. The findings imply a mediating role of fruit consumption in the relationship between tooth loss and obesity. PMID- 29697908 TI - Thyroid disorders among dialysis patients AB - The thyroid gland and the kidney are closely related. Thyroid hormones (TH) contribute to the homeostasis of the human being through complex interactions of fluids and electrolytes, protein synthesis, etc. The effects on the kidney of TH may be pre renal or direct actions. Decreasing glomerular filtration (GF) this balance especially in advanced stages of chronic kidney disease (CKD) is altered.CKD is linked to alterations in TH levels and/or metabolism, resulting in a high prevalence of subclinical hypothyroidism and low free triiodothyronine (FT3) syndrome. These alterations are linked in micro inflammation, endothelial damage, cardiac abnormalities, and high mortality. In this study, we describe the most common thyroid abnormalities reported in CKD with dialytic stage approach. PMID- 29697909 TI - Left ventricular hypertrophy, fibrosis heart, and diastolic dysfunction in chronic kidney disease AB - Cardiovascular diseases occur 75 to 80% as causes of morbidity and mortality in patients with chronic kidney disease. In epidemiological studies the causes of cardiovascular deaths are sudden death, arrhythmias, heart failure, coronary arteries disease and myocardial infarction. Heart failure and cardiac arrhythmias are caused mainly by left ventricular hypertrophy and cardiac fibrosis. Pathophysiological factors involved in left ventricular hypertrophy ventricular hypertrophy have been divided into 3 categories: related to afterload, related to preload and not related to afterload or preload. Myocardial hypertrophy induces the activation of cellular apoptosis signals and activates metabolic pathways able to increase extracellular matrix production up to fibrosis. Fibrosis leads to progressive impairment in contractility with stiffening of myocardial wall, diastolic and systolic dysfunction and finally dilated cardiomyopathy with congestive heart failure. The main of this review is to understand the pathophysiology of left ventricular hypertrophy, cardiac fibrosis and diastolic dysfunction. PMID- 29697910 TI - Synthesis and Characterization of Bulk Nanostructured Thermoelectric Ca3Co4O9. AB - Nanostructuring has been proposed as an effective strategy for the reduction of the phonon contribution to the thermal conductivity, resulting in an increase in the figure of merit of thermoelectric materials. However, obtaining bulk samples presenting high relative density and nanometric grain size can be quite challenging, particularly in the case of ceramic phases. Only few examples have been reported and none in the case of Ca3Co4O9. In this work, we used a sol-gel synthesis coupled with ball milling to prepare powders of Ca3Co4O9 presenting a grain size as small as 4 nm. These nanopowders were then sintered at different temperature and pressures using the High-Pressure Field-Assisted Sintering Technique (HP-FAST). Relative densities up to 95 vol% where obtained while maintaining a nanometric grain size. The microstructural and electrical properties of the sintered samples have been characterized. The results show that in this oxide a reduction to the nanometric grain size produces a drastic reduction in the electrical conductivity, which cannot be compensated by the reduction in the thermal conductivity. The Seebeck effect, on the other hand, appears to be affected only marginally by the grain size and porosity. PMID- 29697911 TI - Structural and functional cardiac abnormalities during chronic kidney disease AB - Cardiovascular diseases are the leading cause of death in people with chronic kidney disease (CKD). These involve the whole structure and function of the heart, so the clinical presentation varies from chronic heart failure to arrhythmias and even sudden death, having a significant impact on the patient's quality of life and a high cost for health services. The origin of these cardiovascular alterations is ample, involving the traditional and non traditional cardiovascular risk factors, as well as systemic changes that cause the progressive loss of the glomerular filtration rate. The identification of cardiovascular alterations during the course of the CKD has become important in the clinical setting, and there is a wide field of research regarding treatment interventions, many of which have not been fully established up to date. PMID- 29697912 TI - Prevalence and risk factors of chronic kidney disease in the comprehensive care program DiabetIMSS AB - BACKGROUND: The aim of this paper is to determine prevalence and risk factors of chronic kidney disease (CKD) in the comprehensive care program DiabetIMSS. METHODS: Cross-sectional study in 488 patients with type 2 diabetes mellitus (DM2) included in the program DiabetIMSS. Sociodemographic, clinical, biochemical, and kidney function variables were collected. RESULTS: Prevalence of CKD was 32% [early nephropathy (EN) 19% and overt nephropathy (ON) 13%]. Patients with more severe nephropathy significantly (p < 0.05) had: older age [normal kidney function (NKF) 54+/-11, EN 54+/-10, ON 63+/-9, years)], cardiovascular disease (NKF 1%, EN 5%, ON 11%), hypertension (NKF 65%, EN 63%, ON 85%), longer duration of DM2 (NKF 5%, EN 5%, ON 9%,) and of hypertension (NKF 5%, EN 6%, ON 9%), glycemic lack of control (NKF 46%, EN 62%, ON 60%), hyperuricemia (NKF 7%, EN 13%, ON 23%), anemia (NKF 1%, EN 4%, ON 10%) and metabolic syndrome (NKF 79%, EN 82%, ON 93%). Uncontrolled hypertension and DM2, cardiovascular disease and hyperuricemia significantly predicted the presence of nephropathy CONCLUSIONS: A third of patients attending to DiabetIMSS had CKD and has not been previously diagnosed. Multiple risk factors are present in this high-risk population; their identification and control are extraordinarily important. Moreover, educative interventions for primary health-care professionals to improve health of this kind of patients are needed. PMID- 29697913 TI - Prazosin for Post-Traumatic Stress Disorder. PMID- 29697914 TI - Prazosin for Post-Traumatic Stress Disorder. PMID- 29697915 TI - Prazosin for Post-Traumatic Stress Disorder. PMID- 29697916 TI - Noninvasive Ablation of Ventricular Tachycardia. PMID- 29697917 TI - Noninvasive Ablation of Ventricular Tachycardia. PMID- 29697918 TI - Magnetic Resonance Imaging and Cardiac Devices. PMID- 29697919 TI - Recognizing and managing emerging infectious diseases in the emergency department. AB - With population shifts, increased travel, and climate change, the spread of emerging and re-emerging infections is increasing. Although encountering a patient with an emerging infection on any given emergency department shift is unlikely, missing a diagnosis could have profound consequences for the patient, healthcare workers, and the patient's close contacts. This review provides a framework to evaluate, diagnose, and treat a returning traveler with suspected Middle East respiratory syndrome, chikungunya virus, or Zika virus-3 recently emerged infections. All may present with nonspecific viral-like symptoms and are easily missed if an appropriate travel history is not obtained. A high level of vigilance and proper disposition will enable the emergency clinician to effectively diagnose, manage, and contain these diseases. PMID- 29697920 TI - Metastatic Prostate Cancer. PMID- 29697921 TI - Kidney Diseases Associated with Human Immunodeficiency Virus Infection. PMID- 29697922 TI - Kidney Diseases Associated with Human Immunodeficiency Virus Infection. PMID- 29697923 TI - Synthetic drug intoxication in children: recognition and management in the emergency department. AB - When children and adolescents present to the emergency department with agitation or mental status changes, intoxication from synthetic drug use should be in the differential diagnosis. Identifying the responsible compound(s) may be difficult, so asking the patient broad questions and utilizing appropriate diagnostic studies, when indicated, will aid in making the diagnosis and help identify more serious complications. This issue discusses the challenges presented by the changing chemical formulations of synthetic cannabinoids, cathinones, and phenethylamines; outlines common presentations of intoxication from these substances; and summarizes best practices for evaluating and managing patients who present with intoxication after consumption of these synthetic drugs of abuse. PMID- 29697925 TI - Ethiopian Love Song PMID- 29697924 TI - This Zoonotic World PMID- 29697926 TI - Comparison of two commercial embryo culture media (SAGE-1 step single medium vs. G1-PLUSTM/G2-PLUSTM sequential media): Influence on in vitro fertilization outcomes and human embryo quality. AB - OBJECTIVE: To compare embryo quality, fertilization, implantation, miscarriage and clinical pregnancy rates for embryos cultured in two different commercial culture media until D-2 or D-3. METHODS: In this retrospective study, we analyzed 189 cycles performed in 2016. Metaphase II oocytes were microinjected and allocated into single medium (SAGE 1-STEP, Origio) until transferred, frozen or discarded; or, if sequential media were used, the oocytes were cultured in G1 PLUSTM (Vitrolife) up to D-2 or D-3 and in G2-PLUSTM (Vitrolife) to transfer. On the following day, the oocytes were checked for normal fertilization and on D-2 and D-3 for morphological classification. Statistical analysis was performed using the chi-square and Mann-Whitney tests in PASW Statistics 18.0. RESULTS: The fertilization rates were 70.07% for single and 69.11% for sequential media (p=0.736). The mean number of embryos with high morphological quality (class A/B) was higher in the single medium than in the sequential media: D-2 [class A (190 vs. 107, p<0.001), B (133 vs. 118, p=0.018)]; D-3 [class A (40 vs. 19, p=0.048) but without differences in class B (40 vs. 49)]. Consequently, a higher number of embryos cultured in single medium were frozen: 197 (21.00%) vs. sequential: 102 (11.00%), p<0.001. No differences were found in implantation rates (30.16% vs. 25.57%, p=0.520), clinical pregnancy rates (55.88% vs. 41.05%, p=0.213), or miscarriage rates (14.29% vs. 9.52%, p=0.472). CONCLUSION: Embryo culture in single medium yields greater efficiency per cycle than in sequential media. Higher embryo quality and quantity were achieved, resulting in more frozen embryos. There were no differences in clinical pregnancy rates. PMID- 29697927 TI - Robotic excision of complex adrenal mass with retrocaval extension and encasement of renal hilum with renal preservation. AB - OBJECTIVE: The purpose of this video is to present robotic excision of a complex adrenal mass with retrocaval extension and encasement of renal hilum in a 16 year old boy. Biochemical screening was negative for metabolically active component. Computerized tomographic scan with contrast revealed a homogenous mass of approximately 10.8 cm x 6.2 cm x 4.2 cm in the suprarenal area on right side that was extend-ing behind inferior vena cava and encasing renal hilar vessels. Imaging findings were that of a classical ganglioneuroma. MATERIAL AND METHODS: Robot assisted laparoscopic adrenalectomy with sparing of renal hilar vasculature was performed. With patient in lateral position, five ports were used, including one for liver retraction. Da Vinci(r) system with four arms was docked from over the right shoulder. The displaced renal hilar structures were identified by opening Gerota's fascia. Mass was dissected completely and removed through Pfan nensteil incision. RESULTS: Duration of procedure was 345 minutes and console time was 290 minutes. Blood loss was 250 mL. Post-operative renal doppler showed normal blood flow. He was discharged on post-operative day three. Histopathologic examination of specimen revealed ganglioneuroma arising from adrenal gland. CONCLUSION: Ganglioneuroma is a rare adrenal tumor with good prognosis on surgical removal. The advent of robotic surgery has made complex surgical procedures involving vital structures like inferior vena cava be performed using minimally invasive techniques without compromising oncologic principles. PMID- 29697928 TI - Recto-urethral fistula presenting as fever of unknown origin: a rare complication of prostatic abscess. PMID- 29697929 TI - Impact of PSA density of transition zone as a potential parameter in reducing the number of unnecessary prostate biopsies in patients with psa levels between 2.6 and 10.0 ng/mL. AB - PURPOSE: To assess the accuracy of prostate-specific antigen (PSA) adjusted for the transition zone volume (PSATZ) in predicting prostate cancer by comparing the ability of several PSA parameters in predicting prostate cancer in men with intermediate PSA levels of 2.6 - 10.0 ng/mL and its ability to reduce unnecessary biopsies. MATERIALS AND METHODS: This study included 656 patients referred for prostate biopsy who had a serum PSA of 2.6 - 10.0 ng/mL. Total prostate and transition zone volumes were measured by transrectal ultrasound using the prolate ellipsoid method. The clinical values of PSA, free-to-total (F/T) ratio, PSA density (PSAD) and PSATZ for the detection of prostate cancer were calculated and statistical comparisons between biopsy-positive (cancer) and biopsy-negative (benign) were conducted. RESULTS: Cancer was detected in 172 patients (26.2%). Mean PSA, PSATZ, PSAD and F/T ratio were 7.5 ng/mL, 0.68 ng/mL/cc. 0.25 ng/mL/cc and 0.14 in patients with prostate cancer and 6.29 ng/mL, 0.30 ng/mL/cc, 0.16 ng/mL/cc and 0.22 in patients with benign biopsies, respectively. ROC curves analysis demonstrated that PSATZ had a higher area under curve (0,838) than F/T ratio (0,806) (P<0.001) and PSAD (0,806) (P<0.001). With a cut-off value of 0.22 ng/mL/cc, PSATZ had 100% of sensitivity and could have prevented 24% of unnecessary biopsies. CONCLUSIONS: PSATZ may be useful in enhancing the specificity of serum PSA. Compared to other PSA related parameters, it was better in differentiating between prostate cancer and benign prostatic enlargement. Also, PSATZ could reduce a significant number of unnecessary biopsies. PMID- 29697930 TI - The Lithocatch (TM) by Boston Scientific: how to use it and how to solve a common problem. AB - INTRODUCTION: The Lithocatch (TM) basket is a immobilization device commercialized by Boston Scientific. It allows to collect multiple stone fragments from the ureter. The ability of the basket to capture a large number of stone fragments, is however responsible for a problem connected to its usage: the entrapment of the basket inside the ureter. In this video we explain how to use it and how to solve this problem. MATERIAL AND METHODS: After positioning the Lithocatch (TM) over the fragments, the basket is opened and it is rotated through a special handle to collect stones. One frequent problem occurs when too many fragments are collected at once, preventing the extraction of the device. We research our archives to extrapolate the total number of procedures carried out with the Lithocatch (TM) in the last two years and the total number of complications occurred. RESULTS: We experienced the above mentioned complication in 16 procedures (14% of the total) of 114 surgeries performed. The way described to solve this complication was efficient and did not produce any damage to the ureter or to the basket. CONCLUSION: The Lithocatch (TM) has an excellent ability to capture small stones so it allows to reduce the length of the procedure. Paying attention to limit the amount of fragments collected, it is possible to avoid the entrapment of the basket. If this complication occurs, the problem can be solved by reducing the size of the stone fragments. The preferable type of energy is the ballistic one. PMID- 29697931 TI - Re: Endourologic strategies for a minimally invasive management of urinary tract stones in patients with urinary diversion. PMID- 29697932 TI - REPLY TO THE AUTHORS: Re: Endourologic strategies for a minimally invasive management of urinary tract stones in patients with urinary diversion. PMID- 29697933 TI - Comparison of inflammatory markers between brucella and non-brucella epididymo orchitis. AB - OBJECTIVES: Brucellosis is a multi-system infectious disease that is associated with inflammation, which causes an increase in acute phase reactants. Hematological inflammatory markers of brucellosis include mean platelet volume (MPV), red cell distribution width (RDW), neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR). In this study, we aimed to evaluate the diagnostic value of hematological inflammatory markers in Brucella epididymo orchitis (BEO), and to investigate the utility of these markers for differential diagnosis from non-Brucella epididymo-orchitis (non-BEO). MATERIALS AND METHODS: We retrospectively reviewed the records of 22 BEO and 50 non-BEO patients. Hematological parameters were recorded and compared between the two groups. The main diagnostic criteria for BEO were positive clinical findings (i.e., testicular pain, tenderness and scrotal swelling), a positive Rose Bengal test result, standard tube agglutination (STA) titer >= 1/160, and/or a positive blood culture. RESULTS: The most decisive factors in discriminating between BEO and non BEO were NLR, RDW, and MPV, in decreasing order of their strength. Regardless of other factors, NLR values < 2.3 significantly increased the odds of BEO (OR=8.080, 95% CI: 1.929- 33.843, p=0.004). After adjusting for other factors, RDW values >14.45% significantly increased the odds of BEO (OR=7.020, 95% CI: 1.749-28.176, p=0.006). Independent of the other factors, patients with MPV < 7.65 fL had a 6.336 times higher risk for BEO (95% CI: 1.393 - 28.822, p=0.017). CONCLUSION: Hematological inflammatory markers such as NLR, RDW, and MPV can aid in the differential diagnosis of BEO and non-BEO. PMID- 29697934 TI - 5-alpha Reductase Inhibitors and risk of male breast cancer: a systematic review and meta-analysis. AB - OBJECTIVE: To assess the relationship between 5alpha-reductase inhibitors (5ARIs) and the risk of male breast cancer (MBC). MATERIAL AND METHODS: We systematically searched Medline via PubMed, Embase and the Cochrane Library Central Register up to May 2017 to identify published articles related to 5ARIs and the risk of MBC. RESULTS: Summary effect estimates were calculated by a random-effect model, and tests for multivariable-unadjusted pooled risk ratios (RR) and heterogeneity, as well as the sensitivity analyses were conducted to assess publication bias. All four studies were conducted in a quality assessment according to the Newcastle Ottawa Scale system. The strength of association between 5ARIs and the prevalence of MBC was evaluated by using summarized unadjusted pooled RR with a 95% confidence interval [CI]. Four studies involving 595.776 participants, mean age range from 60 to 73.2 years old, were included in a meta-analysis, which produced a summary unadjusted RR of the risk of MBC for the treatment of 5ARIs of 1.16 (95% CI 0.85-1.58, P=0.36) and the multivariable-adjusted RR is 1.03, (95% CI 0.75-1.41, p=0.86). There was no heterogeneity among included studies (I2=0%, P=0.49). Estimates of total effects were generally consistent with the sensitivity. CONCLUSION: We did not observe a positive association between the use of 5ARIs and MBC. The small number of breast cancer cases exposed to 5ARIs and the lack of na association in our study suggest that the development of breast cancer should not influence the prescribing of 5ARIs therapy. PMID- 29697935 TI - Encrusted cystitis caused by corynebacterium urealyticum: a case report with novel treatment strategy of intravesical dimethyl sulfoxide. AB - Encrusted cystitis (EC) was first described as chronic cystitis with mucosal calcification in 1914 (1). It is a very rare chronic inflammatory disease presenting with dysuria, pelvic pain and gross hematuria. Voided urine contains mucus or calcified mucopurulent stone like particles. Urinalysis always reveals alkaline pH. It may be present in healthy individuals with no predisposing etiological factors (2-4). Etiologically, previous urological diseases, immunosuppression, urinary infection with urea splitting bacteria, or urological interventions resulting in bladder mucosa trauma may also be present (5, 6). In the present case report, we describe a novel treatment for EC with intravesical dimethyl sulfoxide. PMID- 29697936 TI - Do uroflowmetry and post - void residual urine tests necessary in children with primary nocturnal enuresis? AB - OBJECTIVES: To examine the benefits of repetitive uroflowmetry and post void residual urine (PVR) tests in children with primary nocturnal enuresis (PNE). MATERIAL AND METHODS: Children aged >=6 years with PNE who visited our clinics for management of enuresis were included for study. Patients were requested to complete a questionnaire including baseline characteristics and Dysfunctional Voiding Symptom Score (DVSS), 2-day bladder diary, and Rome III criteria for constipation. Two uroflowmetry and PVR tests were requested. Children with congenital or neurogenic genitourinary tract disorders were excluded. All children underwent urotherapy and desmopressin combined with anticholinergics or laxatives if indicated. The definition of abnormal flow patterns (>=1 abnormal), elevated PVR (>=1 abnormal), small maximal voided volume (MVV), nocturnal polyuria (NP) and response to treatment complied with the ICCS standardization document. Kaplan-Meier survival analysis and Cox proportional-hazards regression tests were used to evaluate the predictors of response. RESULTS: In total, 100 children aged 8.5+/-2.3 years were enrolled for study (M: F=66:34) with 7.3+/-7.4 months of follow-up. Poor correlation was observed between DVSS/small MVV and PVR (p>0.05). Univariate analysis revealed that elevated PVR is associated with significantly less hazard of complete response to medical treatment (HR: 0.52, p=0.03), while not significantly associated with abnormal flow patterns, NP, constipation or small MVV. Multivariate analysis revealed that only elevated PVR (HR 0.30, 95% CI 0.12-0.80) and NP (HR 2.8, 95% CI 1.10-7.28) were significant predictors for complete response. CONCLUSIONS: In managing pediatric enuresis, elevated PVR is a significant predictor for lower chance of complete response to treatment whether they had high DVSS or not. PMID- 29697952 TI - In Situ Synthesis of CdS/Graphdiyne Heterojunction for Enhanced Photocatalytic Activity of Hydrogen Production. AB - Hydrogen production through artificial photosynthesis has been regarded as a promising strategy for dealing with energy shortage and environmental problems. In this work, graphdiyne (GD) was first introduced to the visible-light catalytic system for hydrogen production, in which a CdS/GD heterojunction was prepared through a simple in situ growth process by adding Cd(AcO)2 into a dimethyl sulfoxide (DMSO) solution containing GD substrate. The as-prepared CdS/GD heterojunction exhibits much higher performance for photocatalytic hydrogen evolution compared to that of pristine GD and CdS nanoparticles. The photocatalytic performance of CdS/GD heterostructure containing 2.5 wt % of GD (GD2.5) is 2.6 times higher than that of the pristine CdS nanoparticles. The enhanced catalytic performance can be ascribed to the formation of CdS/GD heterojunction, in which the presence of GD can not only stabilize CdS nanoparticles by preventing the agglomeration of CdS nanoparticles but also act as a photogenerated hole transfer material for efficiently separating photogenerated electron-hole pairs in CdS. Accordingly, this work provides the potential of GD-derived materials for solar energy conversion and storage. PMID- 29697951 TI - Effects of N-Alkyl-4-Methylamphetamine Optical Isomers on Plasma Membrane Monoamine Transporters and Abuse-Related Behavior. AB - 4-Methylamphetamine (4-MA) is an emerging drug of abuse that acts as a substrate at plasma membrane transporters for dopamine (DAT), norepinephrine (NET), and serotonin (SERT), thereby causing nonexocytotic release of monoamine transmitters via reverse transport. Prior studies by us showed that increasing the N-alkyl chain length of N-substituted 4-MA analogues converts 4-MA from a transportable substrate (i.e., releaser) at DAT and NET to a nontransported blocker at these sites. Here, we studied the effects of the individual optical isomers of N-methyl , N-ethyl-, and N- n-propyl 4-MA on monoamine transporters and abuse-related behavior in rats because action/function might be related to stereochemistry. Uptake inhibition and release assays were conducted in rat brain synaptosomes whereas electrophysiological assessments of drug-transporter interactions were examined using cell-based biosensors. Intracranial-self-stimulation in rats was employed to assess abuse potential in vivo. The experimental evidence demonstrates that S(+) N-methyl 4-MA is a potent and efficacious releaser at DAT, NET, and SERT with the highest abuse potential among the test drugs, whereas R(-) N-methyl 4-MA is a less potent releaser with reduced abuse potential. The S(+)ethyl analogue has decreased efficacy as a releaser at DAT but retains full release activity at NET and SERT with a reduction in abuse-related effects; the R(-)ethyl analogue has a similar profile but is less potent. S(+) N-Propyl 4-MA is a nontransported blocker at DAT and NET but an efficacious releaser at SERT, whereas the R enantiomer is almost inactive. In conclusion, the S enantiomers of the N-alkyl 4-MA analogues are most potent. Lengthening the N-alkyl chain converts compounds from potent nonselective releasers showing abuse-related effects to more selective SERT releasers with no apparent abuse potential. PMID- 29697937 TI - The preoperative stratification of patients based on renal scan data is unable to predict the functional outcome after partial nephrectomy. AB - INTRODUCTION: eGFR-categories are used to predict functional outcome after partial nephrectomy (PN); no study categorized patients according to preoperative renal scan (RS) data. Aim of the study was to evaluate if stratification of patients according to RS is a reliable method to predict minor/major loss of renal function after PN. MATERIALS AND METHODS: We considered patients who underwent PN and RS pre-/post-PN for T1 tumor in our Institution (2007-2017). Demographics, perioperative and specifically functional data were analysed. On the basis of the baseline Split Renal Function (SRF), patients were stratified into risk-categories: 1) baseline operated-kidney SRF range 45-55%; 2) baseline operated-kidney SRF < 45%. Risk categories were analysed with postoperative functional outcome: postoperative operated-kidney SRF decrease below 90% of baseline was considered significant loss of function. Contingency tables and univariate/multivariate regression were analysed looking for independent factors of postoperative functional impairment. RESULTS: 224 patients were analysed, 125 (55.8%) maintained >90% of their baseline function. Worse probability of maintaining >=90 baseline renal function was found in patients with Charlson's Comorbidity Index (CCI>=3) (p=0.004) and patients with PADUA score >=8 (p=0.023). After stratification by baseline renal function, ischemia was the only independent factor: no effect on patients with poorer baseline renal function. Patients with baseline SRF 45-55% who did not experience ischemia had the highest probability to maintain >=90% baseline SRF (p=0.028). Ischemia >25 minutes was detrimental (p=0.017). CONCLUSIONS: Stratification of patients by SRF before PN is not a reliable predictor of renal functional outcome. Ischemia seems to scarcely influence patients with poorer renal function. PMID- 29697953 TI - Latent Naphthalimide Bearing Water-Soluble Nanoprobes with Catechol-Fe(III) Cores for in Vivo Fluorescence Imaging of Intracellular Thiols. AB - Here, a novel latent naphthalimide bearing water-soluble nanoprobes with catechol Fe(III) cores (Fe@LNNPs) was designed, synthesized, and evaluated for in vivo fluorescence imaging of intracellular thiols, as various diseases are associated with overexpression of cellular biothiols. The Fe@LNNPs are mainly composed of three components. The inner part constitutes pyrocatechol groups, which can coordinate with Fe(III) to form a cross-linked core for improving the stability in the complex biological environment. The naphthalimide group is linked by disulfide with the core to quench the probe fluorescence. The outer part is designed to be a hydrophilic glycol corona for prolonging blood circulation. Also, a biotin group can be easily introduced into the nanoprobe for actively targeting the HepG2 cells. The fluorescence spectra reveals that the Fe@LNNPs can be reduced explicitly by glutathione to trigger the fluorescence emission. Confocal microscopic imagings and animal experiments manifest that the Fe@LNNPs, especially with biotin groups, have much better fluorescence signal imaging compared to the reported small-molecule probe 1' both in vitro and in vivo (up to 24 h). The Fe@LNNPs thus feature great advantages such as specificity, stability, biocompatibility, and long retention time for thiol-recognition imaging and hold potential applications in clinical cancer diagnosis. PMID- 29697954 TI - Insulator-to-Metallic Spin-Filtering in 2D-Magnetic Tunnel Junctions Based on Hexagonal Boron Nitride. AB - We report on the integration of atomically thin 2D insulating hexagonal boron nitride (h-BN) tunnel barriers into magnetic tunnel junctions (2D-MTJs) by fabricating two illustrative systems (Co/h-BN/Co and Co/h-BN/Fe) and by discussing h-BN potential for metallic spin filtering. The h-BN is directly grown by chemical vapor deposition on prepatterned Co and Fe stripes. Spin-transport measurements reveal tunnel magneto-resistances in these h-BN-based MTJs as high as 12% for Co/h-BN/h-BN/Co and 50% for Co/h-BN/Fe. We analyze the spin polarizations of h-BN/Co and h-BN/Fe interfaces extracted from experimental spin signals in light of spin filtering at hybrid chemisorbed/physisorbed h-BN, with support of ab initio calculations. These experiments illustrate the strong potential of h-BN for MTJs and are expected to ignite further investigations of 2D materials for large signal spin devices. PMID- 29697955 TI - Emerging Robust Heterostructure of MoS2-rGO for High-Performance Supercapacitors. AB - The intermittent nature of renewable energy resources has led to a continuous mismatch between energy demand and supply. A possible solution to overcome this persistent problem is to design appropriate energy-storage materials. Supercapacitors based on different nanoelectrode materials have emerged as one of the promising storage devices. In this work, we investigate the supercapacitor properties of a molybdenum disulfide-reduced graphene oxide (rGO) heterostructure based binder-free electrode, which delivered a high specific capacitance (387.6 F g-1 at 1.2 A g-1) and impressive cycling stability (virtually no loss up to 1000 cycles). In addition, the possible role of rGO in the composite toward synergistically enhanced supercapacitance has been highlighted. Moreover, an attempt has been made to correlate the electrochemical impedance spectroscopy studies with the voltammetric analyses. The performance exceeds that of the reported state-of-the-art structures. PMID- 29697956 TI - Bioinspired Interfacial Chelating-like Reinforcement Strategy toward Mechanically Enhanced Lamellar Materials. AB - Many biological organisms usually derived from the ordered assembly of heterogeneous, hierarchical inorganic/organic constituents exhibit outstanding mechanical integration, but have proven to be difficult to produce the combination of excellent mechanical properties, such as strength, toughness, and light weight, by merely mimicking their component and structural characteristics. Herein, inspired by biologically strong chelating interactions of phytic acid (PA) or IP6 in many biomaterials, we present a biologically interfacial chelating like reinforcement (BICR) strategy for fabrication of a highly dense ordered "brick-and-mortar" microstructure by incorporating tiny amounts of a natural chelating agent ( e. g., PA) into the interface or the interlamination of a material ( e. g., graphene oxide (GO)), which shows joint improvement in hardness (~41.0%), strength (~124.1%), maximum Young's modulus (~134.7%), and toughness (~118.5%) in the natural environment. Besides, for different composite matrix systems and artificial chelating agents, the BICR strategy has been proven successful for greatly enhancing their mechanical properties, which is superior to many previous reinforcing approaches. This point can be mainly attributed to the stronger noncovalent cross-linking interactions such as dense hydrogen bonds between the richer phosphate (hydroxyl) groups on its cyclohexanehexol ring and active sites of GO, giving rise to the larger energy dissipation at its hybrid interfaces. It is also simple and environmentally friendly for further scale-up fabrication and can be readily extended to other material systems, which opens an advanced reinforcement route to construct structural materials with high mechanical performance in an efficient way for practical applications. PMID- 29697957 TI - Cu2- xS Nanocrystals Cross-Linked with Chlorin e6-Functionalized Polyethylenimine for Synergistic Photodynamic and Photothermal Therapy of Cancer. AB - Achieving an integrated system for combinational therapy of cancer with enhanced efficacy is always a challenge. A multifunctional system (CCeT nanoparticles (NPs)) for a synergistic photodynamic and photothermal cancer therapy was successfully developed. This system is composed of Cu2- xS nanoclusters functionalized with chlorin e6 (Ce6)-conjugated branched polyethylenimine (PEI Ce6) and mitochondria-targeting 3-(carboxypropyl)triphenylphosphonium bromide (TPP-COOH). The colocalization of the resulted CCeT NPs inside the mitochondria of cancer cells was proven. The CCeT NPs exhibited significant photodynamic therapy (PDT) efficacy due to efficient singlet oxygen (1O2) generation triggered by a 630 nm laser. This system also showed excellent photothermal conversion capability upon the irradiation of 808 nm laser for photothermal therapy (PTT). In particular, the platform achieved nearly 100% inhibitory rate of the tumor growth in vivo through combinational PDT and PTT. Thus, the CCeT NPs could efficiently inhibit the tumor growth in vitro and in vivo by combinational PDT and PTT, offering synergistic therapeutic efficiency as compared to PTT or PDT alone. PMID- 29697958 TI - Painting Supramolecular Polymers in Organic Solvents by Super-resolution Microscopy. AB - Despite the rapid development of complex functional supramolecular systems, visualization of these architectures under native conditions at high resolution has remained a challenging endeavor. Super-resolution microscopy was recently proposed as an effective tool to unveil one-dimensional nanoscale structures in aqueous media upon chemical functionalization with suitable fluorescent probes. Building upon our previous work, which enabled photoactivation localization microscopy in organic solvents, herein, we present the imaging of one-dimensional supramolecular polymers in their native environment by interface point accumulation for imaging in nanoscale topography (iPAINT). The noncovalent staining, typical of iPAINT, allows the investigation of supramolecular polymers' structure in situ without any chemical modification. The quasi-permanent adsorption of the dye to the polymer is exploited to identify block-like arrangements within supramolecular fibers, which were obtained upon mixing homopolymers that were prestained with different colors. The staining of the blocks, maintained by the lack of exchange of the dyes, permits the imaging of complex structures for multiple days. This study showcases the potential of PAINT like strategies such as iPAINT to visualize multicomponent dynamic systems in their native environment with an easy, synthesis-free approach and high spatial resolution. PMID- 29697959 TI - Inverse Stellation of CuAu-ZnO Multimetallic-Semiconductor Nanostartube for Plasmon-Enhanced Photocatalysis. AB - One-dimensional (1D) metallic nanocrystals constitute an important class of plasmonic materials for localization of light into subwavelength dimensions. Coupled with their intrinsic conductive properties and extended optical paths for light absorption, metallic nanowires are prevalent in light-harnessing applications. However, the transverse surface plasmon resonance (SPR) mode of traditional multiply twinned nanowires often suffers from weaker electric field enhancement due to its low degree of morphological curvature in comparison to other complex anisotropic nanocrystals. Herein, simultaneous anisotropic stellation and excavation of multiply twinned nanowires are demonstrated through a site-selective galvanic reaction for a pronounced manipulation of light-matter interaction. The introduction of longitudinal extrusions and cavitation along the nanowires leads to a significant enhancement in plasmon field with reduced quenching of localized surface plasmon resonance (LSPR). The as-synthesized multimetallic nanostartubes serve as a panchromatic plasmonic framework for incorporation of photocatalytic materials for plasmon-assisted solar fuel production. PMID- 29697960 TI - Oxygen-Deficient Black Titania for Synergistic/Enhanced Sonodynamic and Photoinduced Cancer Therapy at Near Infrared-II Biowindow. AB - The conventional inorganic semiconductors are not suitable for in vivo therapeutic nanomedicine because of the lack of an adequate and safe irradiation source to activate them. This work reports on the rational design of titania (TiO2)-based semiconductors for enhanced and synergistic sono-/photoinduced tumor eradication by creating an oxygen-deficient TiO2- x layer onto the surface of TiO2 nanocrystals, which can create a crystalline-disordered core/shell structure (TiO2@TiO2- x) with black color. As found in the lessons from traditional photocatalysis, such an oxygen-deficient TiO2- x layer with abundant oxygen defects facilitates and enhances the separation of electrons (e-) and holes (h+) from the energy-band structure upon external ultrasound irradiation, which can significantly improve the efficacy of sono-triggered sonocatalytic tumor therapy. Such an oxygen-deficient TiO2- x layer can also endow black titania nanoparticles with high photothermal-conversion efficiency (39.8%) at the NIR-II biowindow (1064 nm) for enhanced photothermal hyperthermia. Both in vitro cell level and systematic in vivo tumor-bearing mice xenograft evaluations have demonstrated the high synergistic efficacy of combined and enhanced sonodynamic therapy and photothermal ablation as assisted by oxygen-deficient black titania, which has achieved complete tumor eradication with high therapeutic biosafety and without obvious reoccurrence. This work not only provides the paradigm of high therapeutic efficacy of a combined sono-/photoinduced tumor-treatment protocol but also significantly broadens the nanomedical applications of semiconductor based nanoplatforms by rational design of their nanostructures and control of their physiochemical properties. PMID- 29697961 TI - Auto-optimizing Hydrogen Evolution Catalytic Activity of ReS2 through Intrinsic Charge Engineering. AB - Optimizing active electronic states responding to catalysis is of paramount importance for developing high-activity catalysts because thermodynamics itself may not favor forming an optimal electronic state. Setting the monolayer transition metal dichalcogenide (TMD) ReS2 as a model for the hydrogen evolution reaction (HER), we uncover that intrinsic charge engineering has an auto optimizing effect on enhancing catalytic activity through regulating active electronic states. The experimental and theoretical results show that intrinsic charge compensation from S to Re-Re bonds could manipulate the active electronic states, allowing hydrogen to absorb the active sites neither strongly nor weakly. Two types of S sites exhibit the optimal hydrogen adsorption free energies (Delta GH*) of 0.016 and 0.061 eV, which are the closest to zero corresponding to the highest HER activity. This auto-optimization via charge engineering is further demonstrated by higher turnover frequency per sulfur atom of 1-10 s-1 and lower overpotential of -147 mV at 10 mA cm-2 than those of other TMDs through multiscale activation and optimization. This work opens an avenue in designing extensive active catalysts through intrinsic charge engineering strategy. PMID- 29697962 TI - Synergistic Toxicity Produced by Mixtures of Biocompatible Gold Nanoparticles and Widely Used Surfactants. AB - Nanoparticle safety is usually determined using solutions of individual particles that are free of additives. However, the size-dependent properties of nanoparticles can be readily altered through interactions with other components in a mixture. In applications, nanoparticles are commonly combined with surfactants or other additives to increase dispersion or to enhance product performance. Surfactants might also influence the biological activity of nanoparticles; however, little is known about such effects. We investigated the influence of surfactants on nanoparticle biocompatibility by studying mixtures of ligand-stabilized gold nanoparticles and Polysorbate 20 in embryonic zebrafish. These mixtures produced synergistic toxicity at concentrations where the individual components were benign. We examined the structural basis for this synergy using solution-phase analytical techniques. Spectroscopic and X-ray scattering studies suggest that the Polysorbate 20 does not affect the nanoparticle core structure. DOSY NMR showed that the hydrodynamic size of the nanoparticles increased, suggesting that Polysorbate 20 assembles on the nanoparticle surfaces. Mass spectrometry showed that these assemblies have both increased uptake and increased toxicity in zebrafish, as compared to the gold nanoparticles alone. We probed the generality of this synergy by performing toxicity assays with two other common surfactants, Polysorbate 80 and sodium dodecyl sulfate. These surfactants also caused synergistic toxicity, although the extent and time frame of the response depends upon the surfactant structure. These results demonstrate a need for additional, foundational studies to understand the effects of surfactants on nanoparticle biocompatibility and challenge traditional models of nanoparticle safety where the matrix is assumed to have only additive effects on nanoparticle toxicity. PMID- 29697963 TI - Cluster-Mediated Nucleation and Growth of J- and H-Type Polymorphs of Difluoroboron Avobenzone for Organic Microribbon Lasers. AB - Controlled fabrication of organic polymorphisms with well-defined dimensions and tunable luminescent properties plays an important role in developing optoelectronic devices, sensors, and biolabeling agents but remains a challenge due to the weak intermolecular interactions among organic molecules. Herein, we developed a two-step solution self-assembly method for the controlled preparation of blue-emissive or green-emissive microribbons (MRs) of difluoroboron avobenzone (BF2AVB) by adjusting the cluster-mediated nucleation and subsequent one dimensional growth processes. We found that blue-emissive MRs belong to the monoclinic phase, in which BF2AVB molecules form slipped pi-stacks, resulting in J-aggregates with the solid-state photoluminescence efficiency phi = 68%. Meanwhile, green-emissive MRs are ascribed to the orthorhombic phase and exhibit cofacial pi-stacks, which lead to H-aggregates with phi = 24%. Furthermore, these as-prepared MRs can both act as polymorph-dependent Fabry-Perot resonators for lasing oscillators. The strategy described here might offer significant promise for the coherent light source of optoelectronic devices. PMID- 29697964 TI - Programmable In Vitro Coencapsidation of Guest Proteins for Intracellular Delivery by Virus-like Particles. AB - Bioinspired self-sorting and self-assembling systems using engineered versions of natural protein cages are being developed for biocatalysis and therapeutic delivery. The packaging and intracellular delivery of guest proteins is of particular interest for both in vitro and in vivo cell engineering. However, there is a lack of bionanotechnology platforms that combine programmable guest protein encapsidation with efficient intracellular uptake. We report a minimal peptide anchor for in vivo self-sorting of cargo-linked capsomeres of murine polyomavirus (MPyV) that enables controlled encapsidation of guest proteins by in vitro self-assembly. Using Forster resonance energy transfer, we demonstrate the flexibility in this system to support coencapsidation of multiple proteins. Complementing these ensemble measurements with single-particle analysis by super resolution microscopy shows that the stochastic nature of coencapsidation is an overriding principle. This has implications for the design and deployment of both native and engineered self-sorting encapsulation systems and for the assembly of infectious virions. Taking advantage of the encoded affinity for sialic acids ubiquitously displayed on the surface of mammalian cells, we demonstrate the ability of self-assembled MPyV virus-like particles to mediate efficient delivery of guest proteins to the cytosol of primary human cells. This platform for programmable coencapsidation and efficient cytosolic delivery of complementary biomolecules therefore has enormous potential in cell engineering. PMID- 29697965 TI - Thiazolyl-thiadiazines as Beta Site Amyloid Precursor Protein Cleaving Enzyme-1 (BACE-1) Inhibitors and Anti-inflammatory Agents: Multitarget-Directed Ligands for the Efficient Management of Alzheimer's Disease. AB - Alzheimer's disease (AD) is associated with multiple neuropathological events including beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1) inhibition and neuronal inflammation, ensuing degeneracy, and death to neuronal cells. Targeting such a complex disease via a single target directed treatment was found to be inefficacious. Hence, with an intention to incorporate multiple therapeutic effects within a single molecule, multitarget-directed ligands (MTDLs) have been evolved. Herein, for the first time, we report the discovery of novel thiazolyl-thiadiazines that can serve as MTDLs as evident from the in vitro and in vivo studies. These MTDLs exhibited BACE-1 inhibition down to micromolar range, and results from the in vivo studies demonstrated efficient anti inflammatory activity with inherent gastrointestinal safety. Moreover, compound 6d unveiled noteworthy antioxidant, antiamyloid, neuroprotective, and antiamnesic properties. Overall, results of the present study manifest the potential outcome of thiazolyl-thiadiazines for AD treatment. PMID- 29697966 TI - Interplay of Coordination Environment and Magnetic Behavior of Layered Co(II) Hydroxichlorides: A DFT+U Study. AB - In this work we present a systematic computational study of the structural and magnetic properties of a layered family of Co(II) hydroxichlorides, obeying to the general formula Co(OH)2- xCl x(H2O) y. This solid contains both octahedral and tetrahedral cobalt ions, displaying a complex magnetic order arising from the particular coupling between the two kinds of metallic centers. Here, supercells representing concentrations of 12, 20, and 40% of tetrahedral sites were modeled consistently with the compositions reported experimentally. Our simulations show that the two types of cobalt ions tend to couple antiferromagnetically, giving rise to a net magnetic moment slightly out of the plane of the layers. The band gap reaches its minimum value of 1.4 eV for the most diluted fraction of tetrahedral Co(II) sites, going up to 2.2 eV when the content is 40%. Moreover, our results suggest that the presence of interlayer water stabilizes the material and at the same time strongly modifies the electronic environment of tetrahedral Co(II), leading to a further drop of the band gap. To our knowledge, this is the first theoretical investigation of this material. PMID- 29697967 TI - Handling Different Spatial Resolutions in Image Fusion by Multivariate Curve Resolution-Alternating Least Squares for Incomplete Image Multisets. AB - Data fusion of different imaging techniques allows a comprehensive description of chemical and biological systems. Yet, joining images acquired with different spectroscopic platforms is complex because of the different sample orientation and image spatial resolution. Whereas matching sample orientation is often solved by performing suitable affine transformations of rotation, translation, and scaling among images, the main difficulty in image fusion is preserving the spatial detail of the highest spatial resolution image during multitechnique image analysis. In this work, a special variant of the unmixing algorithm Multivariate Curve Resolution Alternating Least Squares (MCR-ALS) for incomplete multisets is proposed to provide a solution for this kind of problem. This algorithm allows analyzing simultaneously images collected with different spectroscopic platforms without losing spatial resolution and ensuring spatial coherence among the images treated. The incomplete multiset structure concatenates images of the two platforms at the lowest spatial resolution with the image acquired with the highest spatial resolution. As a result, the constituents of the sample analyzed are defined by a single set of distribution maps, common to all platforms used and with the highest spatial resolution, and their related extended spectral signatures, covering the signals provided by each of the fused techniques. We demonstrate the potential of the new variant of MCR ALS for multitechnique analysis on three case studies: (i) a model example of MIR and Raman images of pharmaceutical mixture, (ii) FT-IR and Raman images of palatine tonsil tissue, and (iii) mass spectrometry and Raman images of bean tissue. PMID- 29697968 TI - Accelerating the Peroxidase-Like Activity of Gold Nanoclusters at Neutral pH for Colorimetric Detection of Heparin and Heparinase Activity. AB - The peroxidase-like catalytic activity of gold nanoclusters (Au-NCs) is quite low around physiological pH, which greatly limits their biological applications. Herein, we found heparin can greatly accelerate the peroxidase-like activity of Au-NCs at neutral pH. The catalytic activity of Au-NCs toward the peroxidase substrate 3,3',5,5'-tetramethylbenzidine (TMB) oxidation by H2O2 was 25-fold increased in the presence of heparin at pH 7. The addition of heparin not only accelerated the initial catalytic rate of Au-NCs but also prevented the Au-NCs from catalyst deactivation. This allows the sensitive colorimetric detection of heparin at neutral pH. In the presence of heparinase, heparin was hydrolyzed into small fragments, weakening the enhancement effect of catalytic activity. On the basis of this phenomenon, the colorimetric determination of heparinase in the range from 0.1 to 3 MUg.mL-1 was developed with a detection limit of 0.06 MUg.mL 1. Finally, the detection of heparin and heparinase activity in diluted serum samples was also demonstrated. PMID- 29697969 TI - Rapid Uptake/Release of Cs+ in Isostructural Redox-Active Porous Ionic Crystals with Large-Molecular-Size and Easily Reducible Dawson-Type Polyoxometalates as Building Blocks. AB - Isostructural redox-active ionic crystals were synthesized with large-molecular size and easily reducible alpha-Dawson-type polyoxometalates [alpha-P2M18O62]6- (M = Mo and W) as building blocks. The crystals possess large closed pores and show rapid (1 h) and large amounts (5.5 or 4.4 mol mol-1) of Cs+ uptake at room temperature via reduction of the polyoxometalates. The reduced compounds can be fully oxidized, and Cs+ is released within 10 min. PMID- 29697970 TI - Bronsted Catalyzed Hydrolysis of Microcystin-LR by Siderite. AB - Six naturally occurring minerals were employed to catalyze the hydrolysis of microcystin-LR (MC-LR) in water. After preliminary screening experiments, siderite stood out among these minerals due to its higher activity and selectivity. In comparison with kaolinite, which is known to act as a Lewis acid catalyst, siderite was found to act primarily as a Bronsted acid catalyst in the hydrolysis of MC-LR. More interestingly, we found that the presence of humic acid significantly inhibited catalytic efficiency of kaolinite, while the efficiency of siderite remained high (~98%). Reaction intermediates detected by LC-ESI/MS were used to indicate cleavage points in the macrocyclic ring of MC-LR, and XPS was used to characterize siderite interaction with MC-LR. Detailed analysis of the in situ ATR-FTIR absorption spectra of MC-LR indicated hydrogen bonding at the siderite-water-MC-LR interface. A metastable ring, involving hydrogen bonding, between surface bicarbonate of siderite and an amide of MC-LR was proposed to explain the higher activity and selectivity toward MC-LR. Furthermore, siderite was found to reduce the toxicity of MC-LR to mice by hydrolyzing MC-LR peptide bonds. The study demonstrates the potential of siderite, an earth-abundant and biocompatible mineral, for removing MC-LR from water. PMID- 29697971 TI - Lifetime-Encoded Infrared-Emitting Nanoparticles for in Vivo Multiplexed Imaging. AB - Advanced diagnostic procedures are required to satisfy the continuously increasing demands of modern biomedicine while also addressing the need for cost reduction in public health systems. The development of infrared luminescence based techniques for in vivo imaging as reliable alternatives to traditional imaging enables applications with simpler and more cost-effective apparatus. To further improve the information provided by in vivo luminescence images, the design and fabrication of enhanced infrared-luminescent contrast agents is required. In this work, we demonstrate how simple dopant engineering can lead to infrared-emitting rare-earth-doped nanoparticles with tunable (0.1-1.5 ms) and medium-independent luminescence lifetimes. The combination of these tunable nanostructures with time-gated infrared imaging and time domain analysis is employed to obtain multiplexed in vivo images that are used for complex biodistribution studies. PMID- 29697972 TI - Total Syntheses of a Family of Cadinane Sesquiterpenes. AB - Concise total syntheses of (-)-(1 R,6 S,7 S,10 R)-hydroxycadinan-3-en-5-one (1), (+)-(1 R,5 S,6 R,7 S,10 R)-cadinan-3-ene-1,5-diol (2), and (+)-(1 R,5 S,6 R,7 S,10 R)-cadinan-4(11)-ene-1,5-diol (3), three cadinane sesquiterpenes sharing identical trans-decalin carbon skeletons yet containing different oxidation states and substitution patterns, are reported. They were prepared from a common trans-decalin intermediate, which was readily prepared on gram scale through an aldol-Henry reaction cascade and oxidation sequence. PMID- 29697973 TI - Characterization of Metalloporphines: Iron(II) Carbonyls and Environmental Effects on nuCO. AB - The synthesis and characterization of two new iron(II) porphine complexes is described. Porphine, the simplest porphyrin derivative, has been studied less than other synthetic porphyrins owing to synthetic difficulties and solubility issues. The subjects of this study are two six-coordinate iron(II) species further coordinated by CO and an imidazole ligand (either 1-methylimidazole or 2 methylimidazole). The two species have very different CO stretching frequencies, with the 2-methylimidazole complex having a very low stretching frequency of 1923 cm-1 compared to the more usual 1957 cm-1 for the 1-methylimidazole derivative. The very low frequency is the result of environmental effects; the oxygen atom of the carbonyl forms a hydrogen bond with an adjacent coordinated imidazole with a hydrogen atom from the N-H group. The two species, with their differing C-O stretches, also display substantial differences in the values of the Fe-C and C-O bond distances, as determined by their X-ray structures. The two bond distances are strongly correlated ( R = 0.98) in the direction expected for the classical pi-backbonding model. The two bond distances are also strongly correlated with the C-O stretching frequencies. We can conclude that the Fe-C and C-O stretches are quite representative of the observed bond distances; their stretching frequencies are not affected by substantial mode mixing. PMID- 29697974 TI - Quantitative and Label-Free Detection of Protein Kinase A Activity Based on Surface-Enhanced Raman Spectroscopy with Gold Nanostars. AB - The activity of extracellular protein kinase A (PKA) is known to be a biomarker for cancer. However, conventional PKA assays based on colorimetric, radioactive, and fluorometric techniques suffer from intensive labeling-related preparations, background interference, photobleaching, and safety concerns. While surface enhanced Raman spectroscopy (SERS)-based assays have been developed for various enzymes to address these limitations, their use in probing PKA activity is limited due to subtle changes in the Raman spectrum with phosphorylation. Here, we developed a robust colloidal SERS-based scheme for label-free quantitative measurement of PKA activity using gold nanostars (AuNS) as a SERS substrate functionalized with bovine serum albumin (BSA)-kemptide (Kem) bioconjugate (AuNS BSA-Kem), where BSA conferred colloidal stability and Kem is a high-affinity peptide substrate for PKA. By performing principle component analysis (PCA) on the SERS spectrum, we identified two Raman peaks at 725 and 1395 cm-1, whose ratiometric intensity change provided a quantitative measure of Kem phosphorylation by PKA in vitro and allowed us to distinguish MDA-MB-231 and MCF 7 breast cancer cells known to overexpress extracellular PKA catalytic subunits from noncancerous human umbilical vein endothelial cells (HUVEC) based on their PKA activity in cell culture supernatant. The outcome demonstrated potential application of AuNS-BSA-Kem as a SERS probe for cancer screening based on PKA activity. PMID- 29697975 TI - Self-Assembled Coacervates of Chitosan and an Insect Cuticle Protein Containing a Rebers-Riddiford Motif. AB - The interactions among biomacromolecules within insect cuticle may offer new motifs for biomimetic material design. CPR27 is an abundant protein in the rigid cuticle of the elytron from Tribolium castaneum. CPR27 contains the Rebers Riddiford (RR) motif, which is hypothesized to bind chitin. In this study, active magnetic microrheology coupled with microscopy and protein particle analysis techniques were used to correlate alterations in the viscosity of chitosan solutions with changes in solution microstructure. Addition of CPR27 to chitosan solutions led to a 3-fold drop in viscosity. This change was accompanied by the presence of micrometer-sized coacervate particles in solution. Coacervate formation had a strong dependence on chitosan concentration. Analysis showed the existence of a critical CPR27 concentration beyond which a significant increase in particle count was observed. These effects were not observed when a non-RR cuticular protein, CP30, was tested, providing evidence of a structure-function relationship related to the RR motif. PMID- 29697976 TI - The Nature of Bonding in Bulk Tellurium Composed of One-Dimensional Helical Chains. AB - Bulk tellurium (Te) is composed of one-dimensional (1D) helical chains which have been considered to be coupled by van der Waals (vdW) interactions. However, on the basis of first-principles density functional theory calculations, we here propose a different bonding nature between neighboring chains: i.e., helical chains made of normal covalent bonds are connected together by coordinate covalent bonds. It is revealed that the lone pairs of electrons of Te atoms participate in forming coordinate covalent bonds between neighboring chains, where each Te atom behaves as both an electron donor to neighboring chains and an electron acceptor from neighboring chains. This ligand-metal-like bonding nature in bulk Te results in the same order of bulk moduli along the directions parallel and perpendicular to the chains, contrasting with the large anisotropy of bulk moduli in vdW crystals. We further find that the electron effective masses parallel and perpendicular to the chains are almost the same as each other, consistent with the observed nearly isotropic electrical resistivity. It is thus demonstrated that the normal/coordinate covalent bonds parallel/perpendicular to the chains in bulk Te lead to a minor anisotropy in structural and transport properties. PMID- 29697977 TI - Exploration and Comparison of the Geometrical and Physicochemical Properties of an alphaC Allosteric Pocket in the Structural Kinome. AB - In this work, a comprehensive analysis of the local geometrical and physicochemical properties of a type III allosteric pocket located between the regulatory alphaC helix and the activation loop of protein kinases was made by comparing available crystal structures in the structural kinome. We first explored the structural kinome to outline the possible conformations of this site. Subsequently we characterized the positions of cocrystallized ligands of the structural kinome with respect to the structural variability of the allosteric site. Then, we searched for kinase structures with similar allosteric site conformation. The search returned 26 kinases with a DFG-in/alphaC-out conformation potentially prone to bind allosteric inhibitors, as well as different scaffolds that can be useful starting points for the design of new inhibitors. These promising allosteric pockets were probed by performing molecular docking of known active compounds taken from ChEMBL. Interestingly, none of the active compounds reported in ChEMBL had a purely allosteric binding mode, and none of the ATP-competitive ligands had chemical moieties extending into the allosteric pocket in more than two-thirds of the investigated kinases, indicating that the allosteric pocket is accessible but still largely unexplored by available inhibitors. Finally, we compared the physicochemical properties of the allosteric site in the structural kinome and discussed the peculiar and conserved features. These analyses may help the design of allosteric ligands tailored toward the intended kinase(s). PMID- 29697978 TI - Investigation and Control of Single Molecular Structures of Meso- Meso Linked Long Porphyrin Arrays. AB - We have investigated conformational structures of meso- meso linked porphyrin arrays (Z n) by single molecule fluorescence spectroscopy. Modulation depths ( M values) were measured by excitation polarization fluorescence spectroscopy. The M value decreases from 0.85 to 0.46 as the number of porphyrin units increases from 3 to 128, indicating that longer arrays exhibit coiled structures. Such conformational changes depending on the length have been confirmed by coarse grained simulation. The histograms of M values and traces of centroid position of emitting sites by localization microscopy showed that the structures of longer arrays changed to more stretched after solvent vapor annealing with tetrahydrofuran. PMID- 29697979 TI - Direct Dynamics Simulation of the Thermal 3CH2 + 3O2 Reaction. Rate Constant and Product Branching Ratios. AB - The reaction of 3CH2 with 3O2 is of fundamental importance in combustion, and the reaction is complex as a result of multiple extremely exothermic product channels. In the present study, direct dynamics simulations were performed to study the reaction on both the singlet and triplet potential energy surfaces (PESs). The simulations were performed at the UM06/6-311++G(d,p) level of theory. Trajectories were calculated at a temperature of 300 K, and all reactive trajectories proceeded through the carbonyl oxide Criegee intermediate, CH2OO, on both the singlet and triplet PESs. The triplet surface leads to only one product channel, H2CO + O(3P), while the singlet surface leads to eight product channels with their relative importance as CO + H2O > CO + OH + H ~ H2CO + O(1D) > HCO + OH ~ CO2 + H2 ~ CO + H2 + O(1D) > CO2 + H + H > HCO + O(1D) + H. The reaction on the singlet PES is barrierless, consistent with experiment, and the total rate constant on the singlet surface is (0.93 +/- 0.22) * 10-12 cm3 molecule-1 s-1 in comparison to the recommended experimental rate constant of 3.3 * 10-12 cm3 molecule-1 s-1. The simulation product yields for the singlet PES are compared with experiment, and the most significant differences are for H, CO2, and H2O. The reaction on the triplet surface is also barrierless, inconsistent with experiment. A discussion is given of the need for future calculations to address (1) the barrier on the triplet PES for 3CH2 + 3O2 -> 3CH2OO, (2) the temperature dependence of the 3CH2 + 3O2 reaction rate constant and product branching ratios, and (3) the possible non-RRKM dynamics of the 1CH2OO Criegee intermediate. PMID- 29697980 TI - Inhomogeneity of Cellulose Microfibril Assembly in Plant Cell Walls Revealed with Sum Frequency Generation Microscopy. AB - Sum frequency generation (SFG) vibrational spectroscopy can selectively detect and analyze noncentrosymmetric components interspersed in amorphous matrices; this principle has been used for studies of nanoscale structure and mesoscale assembly of cellulose in plant cell walls. However, the spectral information averaged over a large area or volume cannot provide regiospecific or tissue specific information of different cells in plants. This study demonstrates spatially resolved SFG analysis and imaging by combining a broad-band SFG spectroscopy system with an optical microscope. The system was designed to irradiate both narrow-band 800 nm and broad-band tunable IR beams through a single reflective objective lens, but from opposite sides of the surface normal direction of the sample. The developed technique was used to reveal inhomogeneous distributions of cellulose microfibrils within single cell walls, such as cotton fibers and onion epidermis as well as among different tissues in Arabidopsis inflorescence stems and bamboo culms. SFG microscopy can be used for vibrational spectroscopic imaging of other biological systems in complement to conventional Fourier transform infrared spectroscopy and confocal Raman microscopy. PMID- 29697981 TI - Two-Dimensional Pulsed EPR Resolves Hyperfine Coupling Strain in Nitrogen Hydrogen Bond Donors of Semiquinone Intermediates. AB - Hydrogen bonding between semiquinone (SQ) intermediates and side-chain or backbone nitrogens in protein quinone processing sites (Q-sites) is a common motif. Previous studies on SQs from multiple protein environments have reported specific features in the 15N HYSCORE spectra not reproducible by a theory based on fixed hyperfine parameters, and the source of these lineshape distortions remained unknown. In this work, using the spectra of the SQ in the Q-sites of wild-type and mutant D75H cytochrome bo3 ubiquinol oxidase from Escherichia coli, we have explained the observed additional features as originating from a-strain of the isotropic hyperfine coupling. In two-dimensional spectra, the a-strain manifests as well-resolved lineshape distortions of the basic cross-ridges and accompanying lines of low intensity in the opposite quadrant that allow its direct analysis. We have shown that their appearance is regulated by the relative values of the strain width, Delta a, and parameter, delta = |2 a + T| - 4nu15N. alpha-strain provides a direct measure of the structural dynamics and heterogeneity of the O...H...N bond in the SQ systems. PMID- 29697982 TI - Viscoelasticity Response during Fibrillation of Amyloid beta Peptides on a Quartz Crystal-Microbalance Biosensor. AB - Unlike previous in vitro measurements where Amyloid beta (Abeta) aggregation was studied in bulk solutions, we detect the structure change of the Abeta aggregate on the surface of a wireless quartz-crystal-microbalance biosensor, which resembles more closely the aggregation process on the cell membrane. Using a 58 MHz quartz crystal, we monitored changes in the viscoelastic properties of the aggregate formed on the quartz surface from monomers to oligomers and then to fibrils, involving up to the 7th overtone mode (406 MHz). With atomic-force microscopy observations, we found a significant stiffness increase as well as thinning of the protein layer during the structure change from oligomer to fibrils at 20 h, which indicates that the stiffness of the fibril is much higher. Viscoelasticity can provide a significant index of fibrillation and can be useful for evaluating inhibitory medicines in drug development. PMID- 29697983 TI - Mesoscopic Motion of Optically Trapped Particle Synchronized with Photochromic Reactions of Diarylethene Derivatives. AB - Not only the energy but also the momentum of photons transfers to material via photoabsorption; this momentum transfer, known as radiation pressure, can induce motions of small particles. It can therefore be expected to induce mechanical motions of mesoscopic materials synchronized with the reversible change of their absorption coefficient by external stimuli. We demonstrated quantitative photomechanical motions in mesoscopic regions by combining optical tweezer and photochromic reactions of diarylethene (DAE). A microparticle including DAE was optically trapped with 532 nm laser and the absorption band of the DAE was photoswitched with UV laser, resulting in the modulation of the radiation force through the change in the complex dielectric constant of the particle. In this process, mesoscopic mechanical motions were successfully induced by the photochromic reaction. The present approach is potentially applicable in a wide variety of nano/micromechanical devices and also paves the way for monitoring the absorption of photons by molecules via photomechanical response. PMID- 29697984 TI - A Direct, Quantitative Connection between Molecular Dynamics Simulations and Vibrational Probe Line Shapes. AB - A quantitative connection between molecular dynamics simulations and vibrational spectroscopy of probe-labeled systems would enable direct translation of experimental data into structural and dynamical information. To constitute this connection, all-atom molecular dynamics (MD) simulations were performed for two SCN probe sites (solvent-exposed and buried) in a calmodulin-target peptide complex. Two frequency calculation approaches with substantial nonelectrostatic components, a quantum mechanics/molecular mechanics (QM/MM)-based technique and a solvatochromic fragment potential (SolEFP) approach, were used to simulate the infrared probe line shapes. While QM/MM results disagreed with experiment, SolEFP results matched experimental frequencies and line shapes and revealed the physical and dynamic bases for the observed spectroscopic behavior. The main determinant of the CN probe frequency is the exchange repulsion between the probe and its local structural neighbors, and there is a clear dynamic explanation for the relatively broad probe line shape observed at the "buried" probe site. This methodology should be widely applicable to vibrational probes in many environments. PMID- 29697985 TI - Unimolecular Reaction of Methyl Isocyanide to Acetonitrile: A High-Level Theoretical Study. AB - A combination of high-level coupled-cluster calculations and two-dimensional master equation approaches based on semiclassical transition state theory is used to reinvestigate the classic prototype unimolecular isomerization of methyl isocyanide (CH3NC) to acetonitrile (CH3CN). The activation energy, reaction enthalpy, and fundamental vibrational frequencies calculated from first principles agree well with experimental results. In addition, the calculated thermal rate constants adequately reproduce those of experiment over a large range of temperature and pressure in the falloff region, where experimental results are available, and are generally consistent with statistical chemical kinetics theory (such as Rice-Ramsperger-Kassel-Marcus (RRKM) and transition state theory (TST)). PMID- 29697986 TI - Selective Methylmagnesium Chloride Mediated Acetylations of Isosorbide: A Route to Powerful Nitric Oxide Donor Furoxans. AB - Isosorbide was functionalized with furoxan for the first time to give adducts that release nitric oxide up to 7.5 times faster than the commercial vasodilator, isosorbide-5-mononitrate (Is5N). The synthesis was facilitated by MeMgCl-mediated selective acetylation of isosorbide or selective deacetylation of isosorbide-2,5 diacetate, which was rationalized in terms of a more stable 5-alkoxide magnesium salt using DFT. Isosorbide-furoxans are safer to handle than Is5N due to greater thermal stability. PMID- 29697987 TI - Probing the Gelatin-Alkylammonium Salt Mixed Assemblies through Surface Tensiometry and Fluorimetry. AB - The interactions, nature of the organization, and physicochemical properties of alkyltrimethylammonium bromide (C nTAB, n = 12, 14, and 16)-gelatin mixed assemblies were investigated by UV-visible spectrometry, surface tensiometry, and fluorimetry techniques. The synergistic interaction between the surfactant and gelatin was established from the decrease in critical micellar concentration (cmc) and the increase in molecular parking area of surfactants with an increase in percentage of gelatin from 0 to 0.4%; for example, the cmc of C16TAB decreased from 0.93 mM in water to 0.44 mM in the presence of 0.4% gelatin, whereas its Amin increased from 134.98 to 325.55 A2. The fluorescence anisotropy data and polarity parameters of pyrene indicated the progressive change in the anisotropy and micropolarity of the mixed system media with gelatin percentage, respectively. The decrease in aggregation number with an increase in gelatin concentration can be attributed to the enhanced compatibility of surfactants with the bulk microenvironment. The maximum rigidity of the mixed system was also significant from the lifetime data of tyrosine. The formation of Menger micelles on gelatin segments was supported by surface tension and anisotropy data. The overall observations can be attributed to the formation of micelles via gelatin surfactant aggregates; gelatin segments are localized within the microdomain of these aggregates. PMID- 29697988 TI - Emotion regulation, mental health, and social wellbeing in a young adolescent sample: A concurrent and longitudinal investigation. AB - Previous research has established that the ability to manage emotions effectively is critical to healthy psychological and social development in adolescents. However, less research has considered the relationships between specific emotion regulation (ER) strategies, such as reappraisal and suppression, and social wellbeing in this age group. The current study investigated the concurrent and longitudinal relationships between 2 ER strategies (reappraisal and suppression) and social outcomes (peer victimization, friendship satisfaction, and family satisfaction) in young adolescents. Analyses also controlled for mental health (anxiety and depression). Given likely gender differences in these variables, key analyses were conducted in parallel for males and females. There were 232 Australian adolescents who completed measures in Grade 7 (Age Mean = 11.97, SD = .35; 64% female) and a year later in Grade 8. Zero-order correlations indicated an inverse relationship between suppression use and social wellbeing variables, although a number of these associations were no longer significant when controlling for mental health. There was limited evidence that reappraisal was uniquely related to social outcomes. However, interaction effects suggested that greater use of reappraisal might have provided some protection against the negative social effects of poorer mental health. Poorer mental and social wellbeing also appeared to be related to ER strategy use, particularly greater suppression use. The findings suggest that ER strategy use, mental health, and social outcomes all play important and interrelated roles in adolescent wellbeing. (PsycINFO Database Record PMID- 29697989 TI - Cultural orientation moderates the association between desired affect and depressed mood among Chinese international students living in the United States. AB - Culture is thought to shape an individual's ideal/desired emotions, which may in turn regulate actual emotional experiences (Tsai, Knutson, & Fung, 2006). In particular, European Americans tend to favor high-arousal positive (HAP) affect, whereas East Asians favor low-arousal positive affect. This study examined whether cultural adaptation from the East Asian to Western culture is associated with similar differences in ideal and actual affect. We recruited 150 Chinese international students enrolled in a midsize university in the United States and investigated the role of acculturation to U.S. culture in participants' ideal and actual affect as well as associated differences in depressive symptoms. Results showed that acculturation was associated with higher ideal and actual HAP affect (but not lower low-arousal positive affect). Consistent with Mauss et al. (2012), higher ideal HAP affect was directly associated with higher depressive symptoms for all participants. However, among participants with higher orientation to the U.S. culture, higher ideal HAP also had an indirect protective association with depressed mood (i.e., higher ideal HAP affect was associated with higher actual HAP affect, which in turn was associated with lower depressed mood). (PsycINFO Database Record PMID- 29697990 TI - Bored like Hell: Religiosity reduces boredom and tempers the quest for meaning. AB - Boredom involves a lack meaning. Conversely, religiosity offers people a sense of meaning. Accordingly, we proposed that by imbuing a sense of meaningfulnesss, religiosity leads people to experience less boredom. Furthermore, we hypothesized and tested that by reducing boredom, religiosity indirectly inhibits the search for meaningful engagement. In Study 1, following boring tasks, religious people experienced lower levels of boredom and were less motivated to search for meaning than nonreligious people. We found in Study 2 that religious (vs. non- or less religious) people reported higher perceived meaning in life, which was associated with a reduced tendency to feel bored, and with a reduced need to search for meaning in life. Study 3 confirmed that the meaning in life associated with religiosity was associated with reduced state boredom. Religious participants were again less inclined to search for meaning, which was explained by the relatively low levels of boredom that religious (vs. nonreligious) participants experienced. (PsycINFO Database Record PMID- 29697991 TI - Grasping at laws: Speed-accuracy trade-offs in manual prehension. AB - Most of human performance is subject to speed-accuracy trade-offs. For spatially constrained aiming, the trade-off is often said to take the specific form of Fitts' law, in which movement duration is predicted from a single factor combining target distance and target size. However, efforts to extend this law to the three-dimensional context of reaching to grasp (prehension) have had limited success. We suggest that there are potentially confounding influences in standard grasping, and we introduce a novel task to regularize the direction of approach and to eliminate the influences of nearby surfaces. In six participants, we examined speed-accuracy trade-offs for prehension, manipulating the depth (in the plane of the reach), height (orthogonal to the reach), and width (the grasped dimension) of the target object independently. We obtained lawful relationships that were consistent at the group and individual levels. It took longer to reach for more distant objects, and more time was allowed when placing the fingers on a contact surface smaller in either depth or height. More time was taken to grasp wider objects, but only beyond a critical width that varied between individuals. These speed-accuracy trade-offs showed substantial departures from Fitts' law, and were well described by a two-factor model in which reach distance and object size have separate influences on movement duration. We discuss empirical and theoretical reasons for preferring a two-factor model, and we propose that this may represent the most general form of speed-accuracy trade-off, not only for grasping but also for other spatially constrained aiming tasks. (PsycINFO Database Record PMID- 29697992 TI - A systematic review of the safety climate intervention literature: Past trends and future directions. AB - Safety climate represents the meaningfulness of safety and how safety is valued in an organization. The contributions of safety climate to organizational safety have been well documented. There is a dearth of empirical research, however, on specific safety climate interventions and their effectiveness. The present study aims at examining the trend of safety climate interventions and offering compiled information for designing and implementing evidence-based safety climate interventions. Our literature search yielded 384 titles that were inspected by three examiners. Using a stepwise process that allowed for assessment of interobserver agreement, 19 full articles were selected and reviewed. Results showed that 10 out of the 19 articles (52.6%) were based on a quasi-experimental pre- and postintervention design, whereas 42.1% (n = 8) studies were based on a mixed-design approach (including both between- and within-subject design). All interventions in these 19 studies involved either safety-/health-related communication or education/training. Improvement of safety leadership was also a common component of safety climate interventions. According to the socio technical systems classification of intervention strategies, all studies were categorized as interventions focusing on improving organizational and managerial structure as well as the personnel subsystem; four of them also aimed at improving technological aspects of work, and five of them aimed at improving the physical work subsystem. In general, a vast majority of the studies (89.5%, n = 17) showed a statistically significant improvement in safety climate across their organizations postintervention. (PsycINFO Database Record PMID- 29697993 TI - Improving everyday memory performance after acquired brain injury: An RCT on recollection and working memory training. AB - OBJECTIVE: To show the effectiveness of a combined recognition and working memory training on everyday memory performance in patients suffering from organic memory disorders. METHOD: In this double-blind, randomized controlled Study 36 patients with organic memory impairments, mainly attributable to stroke, were assigned to either the experimental or the active control group. In the experimental group a working memory training was combined with a recollection training based on the repetition-lag procedure. Patients in the active control group received the memory therapy usually provided in the rehabilitation center. Both groups received nine hours of therapy. Prior (T0) and subsequent (T1) to the therapy, patients were evaluated on an everyday memory test (EMT) as well as on a neuropsychological test battery. Based on factor analysis of the neuropsychological test scores at T0 we calculated composite scores for working memory, verbal learning and word fluency. RESULTS: After treatment, the intervention group showed a significantly greater improvement for WM performance compared with the active control group. More importantly, performance on the EMT also improved significantly in patients receiving the recollection and working memory training compared with patients with standard memory training. CONCLUSION: Our results show that combining working memory and recollection training significantly improves performance on everyday memory tasks, demonstrating far transfer effects. The present study argues in favor of a process-based approach for treating memory impairments. (PsycINFO Database Record PMID- 29697994 TI - Affective traits of psychopathy are linked to white-matter abnormalities in impulsive male offenders. AB - OBJECTIVE: Psychopathy is a personality disorder typified by lack of empathy and impulsive antisocial behavior. Psychopathic traits may partly relate to disrupted connections between brain regions. The aim of the present study was to link abnormalities in microstructural integrity of white-matter tracts to the severity of different psychopathic traits in 15 male offenders with impulse control problems and 10 without impulse control problems. METHOD: Psychopathic traits were assessed using the Psychopathy Checklist-revised (PCL-R). Diffusion-weighted MRI was used to examine white-matter tracts. Fractional anisotropy (FA), an index of white-matter integrity, was calculated for each voxel. Clusters of voxels showing a significant relationship with psychopathy severity were submitted to probabilistic tractography. RESULTS: No significant correlations between psychopathy severity and FA were present in the whole group of impulsive and nonimpulsive offenders. In impulsive offenders, interpersonal-affective traits (PCL-R Factor 1) were negatively correlated with FA in the anterior and posterior temporal lobe and orbitofrontal area. Further analyses indicated that elevated affective traits (PCL-R Facet 2) were specifically related to reduced FA in the right temporal lobe. CONCLUSIONS: Our findings suggest that white-matter abnormalities in temporal and frontotemporal tracts may be linked to the interpersonal-affective deficits of psychopathy in offenders with relatively severe impulse control problems. Our study offers novel insights into the relationships between the four facets of psychopathy and disrupted structural connectivity, and may provide new leads for further characterization of different subtypes of antisocial populations. (PsycINFO Database Record PMID- 29697995 TI - Multiple domains of new mothers' adaptation: Interrelations and roots in childhood maternal nonsupportive emotion socialization. AB - This study focused on the interrelations among different domains of maternal adaptation (i.e., emotion-regulation difficulties, depressive symptoms, and couple-relationship satisfaction) over the transition to parenthood and also their associations with mothers' recalled childhood maternal nonsupportive emotion socialization. Data were obtained from a socioeconomically and racially diverse sample of 196 primiparous mothers during the 3rd trimester of pregnancy and at 6 months postpartum. Results indicated that (a) mothers' adaptation in different domains had shared roots in their recalled childhood maternal nonsupportive emotion socialization; (b) maternal adaptation in various domains were interrelated with rather than independent of each other, and such associations were unidirectional rather than reciprocal (e.g., mothers' prenatal couple-relationship satisfaction was negatively associated with their depressive symptoms at 6 months postpartum rather than the reverse); and (c) mothers' adaptation in a given domain served as the mechanism via which their recalled childhood maternal nonsupportive emotion socialization shaped their adaptation in the other domains (e.g., mothers' recalled maternal nonsupportive emotion socialization was positively associated with their depressive symptoms at 6 months postpartum via its positive association with their prenatal emotion regulation difficulties). These associations were independent of several critical covariates (e.g., child negative affect, maternal attachment). Such findings contribute to a more nuanced understanding of the complexity inherent within maternal adaptation over the transition to parenthood and highlight potential avenues for interventions aimed at promoting mothers' successful navigation of challenges over this transition. (PsycINFO Database Record PMID- 29697996 TI - Bidirectional effects between parenting sensitivity and child behavior: A cross lagged analysis across middle childhood and adolescence. AB - Using a longitudinal, cross-lagged design, this study examined the bidirectional relations between mothers' and fathers' sensitivity and children's externalizing (EXT) and internalizing (INT) behavior from middle childhood into adolescence. The subsample comprised families (N = 578) in which the mother and father cohabitated from the study's first time point (child age = 54 months) through Age 15 in the longitudinal NICHD Study of Early Child Care and Youth Development. Study results revealed differential patterns for mother-child and father-child relations in the full sample and separately for males and females. The full cross lagged models revealed that child EXT behavior predicted maternal sensitivity, but not vice versa, and fathers' sensitivity and child behavior were reciprocally interrelated. There was a significant indirect pathway from early paternal sensitivity to later EXT in males, and from early maternal sensitivity to INT in females. The results point to the important roles that fathers play in child INT and EXT behaviors and important differences between males and females. (PsycINFO Database Record PMID- 29697997 TI - Early relational trauma and self representations: Misattributing externally derived representations as internally generated. AB - OBJECTIVE: Early relational trauma has been posited to be responsible for dysfunctional self schema as negative feedback derived from abusive close others may influence the development of self-evaluation. However, the association between early relational trauma and negative self-evaluation has proven inconsistent. In addition to the evaluative aspect, early relational trauma may impact on the procedural aspect of self schema, with a difficulty in differentiating mental representations derived from others from those generated internally by the self. METHOD: To test this hypothesis, the authors adopted a source attribution paradigm tapping on the distinction between mental representations generated by the self or derived from another person in a nonclinical sample, together with scales measuring self-evaluation and early relational experiences. RESULTS: The results showed that individuals with early relational trauma tended to attribute the representations externally derived as internally generated, although there were no associations between early relational trauma and self-evaluation. Importantly, early relational trauma had unique contribution to source misattribution independent from common covariates including early nonrelational trauma, parental dysfunction, general memory function, and negative affect states. CONCLUSIONS: Erroneously identifying information derived from other people as self-generated may be a specific sociocognitive propensity linked to early relational trauma and may impact upon the development of self schema. (PsycINFO Database Record PMID- 29697998 TI - Income gains predict cognitive functioning longitudinally throughout later childhood in poor children. AB - Alleviating disadvantage in low-income environments predicts higher cognitive abilities during early childhood. It is less established whether family income continues to predict cognitive growth in later childhood or whether there may even be bidirectional dynamics. Notably, living in poverty may moderate income cognition dynamics. In this study, we investigated longitudinal dynamics over 7 waves of data collection from 1,168 children between the ages of 4.6 and 12 years, 226 (19%) of whom lived in poverty in at least 1 wave, as part of the NICHD Study of Early Child Care and Youth Development. Two sets of dual change score models evaluated, first, whether a score predicted change from that wave to the next and, second, whether change from 1 wave to the next predicted the following score. As previous comparisons have documented, poor children had substantially lower average starting points and cognitive growth slopes through later childhood. The first set of models showed that income scores did not predict cognitive change. In reverse, child cognitive scores positively predicted income change. We speculated that parents may reduce their work investment, thus reducing income gains, when their children fall behind. Second, income changes continued to positively predict higher cognitive scores at the following wave for poor children only, which suggests that income gains and losses continue to be a leading indicator in time of poor children's cognitive performance in later childhood. This study underlined the need to look at changes in income, allow for poverty moderation, and explore bidirectional income-cognition dynamics in middle childhood. (PsycINFO Database Record PMID- 29698000 TI - Benefits and challenges of using service dogs for veterans with posttraumatic stress disorder. AB - OBJECTIVE: Veterans with posttraumatic stress disorder (PTSD) are increasingly seeking service dogs to help them manage trauma-related symptoms, yet literature describing service dog use in this population is scant. The goal of this study was to document the benefits and challenges experienced by veterans with service dogs trained to assist with PTSD-related needs. METHOD: Participants were veterans (N = 41) with service dogs, and their caregivers (n = 8), recruited through community-based service dog training agencies. We conducted in-depth interviews and observed training sessions as part of a larger study, and used thematic analysis to characterize data. RESULTS: Veterans reported that service dogs reduced hypervigilance by alerting and creating boundaries, and disrupted nightmares, improving sleep quality and duration. Dogs also helped veterans turn their attention away from invasive trauma-related thoughts. Additional reported benefits included improved emotional connections with others, increased community participation and physical activity, and reduced suicidal impulses and medication use. Demands of training, adjustment to life with a service dog, and delayed benefits were challenging for many veterans and caregivers. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Veterans report that service dogs help reduce PTSD symptoms and facilitate recovery and realization of meaningful goals. Service dogs may be a reasonable option for veterans who are reluctant to pursue or persist with traditional evidence-based treatments. Additional rigorous research on the effectiveness of service dogs for this population is warranted. (PsycINFO Database Record PMID- 29698001 TI - Initial development of the recovery-oriented services assessment: A collaboration with peer-provider consultants. AB - OBJECTIVE: The Recovery Self-Assessment (RSA) is a reliable and valid tool used to measure recovery-oriented services. Recent studies, however, suggest that the length and reading level of the RSA makes its routine use in service settings difficult. Recognizing the importance of including people with lived experience of a mental health challenge in research processes and the need to enhance the utility of tools that measure recovery-oriented services, this paper describes an innovative researcher-peer provider consultant multistep process used to revise the provider version of the RSA to create a new instrument-the Recovery-Oriented Services Assessment (ROSA). METHODS: The authors conducted an exploratory factor analysis (EFA) with principal axis factoring extraction and direct oblimin rotation to evaluate the underlying structure of the provider RSA using data from mental health employees (n = 323). To triangulate the findings of the EFA, quantitative and qualitative data were collected from peer provider consultants (n = 9) on the importance of and language of RSA items. RESULTS: EFA results indicated that a 1-factor solution provided the best fit and explained 48% of the total variance. Consultants triangulated EFA results and recommended the addition of 2 items and language revisions. These results were used to develop the ROSA-a 15-item instrument measuring recovery-oriented services with accessible language. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Two versions of the ROSA were developed: a staff version and a people-in-services version. The ROSA may provide organizations with a more accessible way to measure the extent to which their services are recovery oriented. (PsycINFO Database Record PMID- 29697999 TI - Parent depressive symptomatology moderates the etiology of externalizing behavior in childhood: An examination of gene-environment interaction effects. AB - Parent depressive symptomatology is robust risk factor for externalizing behavior in childhood (Goodman et al., 2011). Although the precise mechanisms underlying this association have yet to be fully illuminated, there is some evidence that parent depression can impact externalizing behavior via both genetic and environmental pathways. In the current study, we investigated the extent to which genetic and environmental influences on externalizing behavior are moderated by parent depressive symptoms (i.e., genotype-environment interaction) in a sample of 2,060, 6- to 11-year-old twins. Results suggest that genetic influences explain more variance in externalizing behavior as maternal depressive symptoms increase, whereas shared environmental effects decrease. These findings were specific to maternal depressive symptoms, however, and did not extend to not paternal depressive symptoms. Findings are critical for understanding the role of parental depression as a risk factor for problematic child behavior, and informing programs that seek to minimize the impact of this risk factor. (PsycINFO Database Record PMID- 29698002 TI - Is there a return on investment for training? AB - TOPIC: Funding for behavioral health service provider agencies is always limited, making it difficult to decide how and when to spend scarce resources on staff training. If evidence existed for a clear return on investment for certain training topics or techniques, agency administrators may find it easier to make the decisions about how much and what type of training to provide to staff. PURPOSE: In spite of expert opinion and some evidence that the most common training approaches are ineffective, yielding no return on investment, or a negative return (money wasted), agencies continue to provide primarily single session lecture-based training-either face-to-face or via a tedious and uninspiring online format. If this article, along with previous education and training columns, were to convince administrators to use their limited training dollars more wisely, the result is likely to be improved staff competencies and better service outcomes. SOURCES USED: Sources include the personal experience of the author and the available literature on training effectiveness and return on investment for training initiatives. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Administrators need to make informed choices about using best practices for staff development. While the well-designed studies that would clearly document return on investment for training in behavioral health services may not be possible or affordable, dialogue and consensus are needed on what measures might indicate effective training outcomes. (PsycINFO Database Record PMID- 29698003 TI - Evaluating correlations between physical activity, psychological mediators of physical activity, and negative symptoms in individuals living with psychosis and diabetes. AB - OBJECTIVE: This study examines the relationship among physical activity, psychological mediators of physical activity, and negative symptoms in people living with psychosis and prediabetes or Type II diabetes mellitus to identify which variables should be targeted in future physical activity interventions. METHOD: A total of 63 individuals were recruited and filled out questionnaires with the assistance of trained research staff. RESULTS: Spearman's correlations showed a positive significant association between physical activity and self efficacy. Negative significant associations were found between physical activity and negative symptoms of psychosis as well as perceived barriers of physical activity. There was no significant relationship between physical activity and perceived benefits of physical activity. CONCLUSION AND IMPLICATIONS FOR PRACTICE: Future physical activity interventions need to focus on enhancing the confidence individuals have being physically active and how barriers to activity can be recognized and managed. Interventions should be conducted alongside treatment of negative symptoms of psychosis. (PsycINFO Database Record PMID- 29698004 TI - Reducing perceived stigma: Work integration of people with severe mental disorders in Italian social enterprise. AB - OBJECTIVE: People with mental illnesses face stigma that hinders their full integration into society. Work is a major determinant of social inclusion, however, people with mental disorders have fewer opportunities to work. Emerging evidence suggests that social enterprises help disadvantaged people with their work integration process. The purpose of this study is to enhance our understanding about how perceptions of stigma can be decreased for people with mental disorders throughout their work experience in a social enterprise. METHOD: Using a longitudinal study design, 310 individuals with mental disorders employed in Italian social enterprises completed a battery of questionnaires on individual (e.g., severity of symptoms; occupational self-efficacy) and environmental (e.g., social support; organizational constraints) variables. Of the 223 individuals potentially eligible at the 12-month follow up, 139 completed a battery of questionnaires on social and working skills, perceived work productivity and perceived stigma. Path analyses were used to test a model delineating how people with mental disorders working in social enterprises improve social and work outcomes (i.e., motivation, skills and productivity), and reduce the perception of being stigmatized. RESULTS: Working in a social enterprise enhances working social skills, which leads to a perception of higher productivity and, consequently, the perception of being discriminated against and stigmatized is reduced. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Social enterprise provides a context in which people with mental disorders reach a sense of work-related and social competence. This sense of competence helps them to reduce perceived stigma, which is a crucial step toward social inclusion. (PsycINFO Database Record PMID- 29698005 TI - Family cohesion and enmeshment moderate associations between maternal relationship instability and children's externalizing problems. AB - This study examined the moderating roles of 2 different types of family-level closeness (i.e., family cohesion and enmeshment) in associations between maternal relationship instability and children's externalizing problems in early childhood. Participants in this longitudinal (i.e., 2 waves of data collection spaced 2 years apart), multimethod (i.e., survey, observations), multi-informant (i.e., parent, teacher, observer) study included 243 preschool children (Mage = 4.60 years) and their parents. Findings from the lagged, autoregressive tests of the predictive pathways indicated that family cohesion and enmeshment moderated associations between maternal relationship instability and increases in children's externalizing problems. Maternal relationship instability was a significantly stronger predictor of children's externalizing problems when cohesion was low or enmeshment was high. Follow-up analyses revealed that cohesion predicted decreases in externalizing problems only at higher levels of instability. Conversely, higher levels of enmeshment predicted increases in children's externalizing problems at high instability but decreases in externalizing symptoms under more stable family conditions. (PsycINFO Database Record PMID- 29698006 TI - Patterns of family management for adolescent and young adult brain tumor survivors. AB - Little is known about how families systemically incorporate the work of caring for adolescent and young adult (AYA) survivors of childhood brain tumors who often remain dependent on their families well into adulthood. The primary aim of this study was to develop a typology of family management (FM) patterns for AYA survivors. The secondary aims were to compare them with FM patterns previously described for children with chronic health conditions and to validate the patterns using quantitative and qualitative data. Guided by the Family Management Styles Framework, a sequential, mixed-methods design was used to gather quantitative data from 186 mothers (primary caregivers) and 134 AYA survivors. FM patterns (family focused; somewhat family focused; somewhat condition focused; and condition focused) were identified using cluster analysis of data from the Family Management Measure. FM patterns were found to be similar to those for children with chronic health physical conditions and were significantly related to maternal quality of life, survivor quality of life (health-related quality of life [self- and mother proxy report]), cancer-related variables (treatment intensity, medical late effects), and family functioning in theoretically meaningfully ways. Significant demographic characteristics included private insurance and AYA survivors' engagement in school or employment. Qualitative analysis of data from 45 interviews with mothers from the larger sample provided additional support for and elaborated descriptions of FM patterns. Identification of FM patterns moves the science of family caregiving forward by aggregating data into a conceptually based typology, thereby taking into account the complex intersection of the condition, the family, and condition management. (PsycINFO Database Record PMID- 29698007 TI - Effects of parent-adolescent reported family functioning discrepancy on physical activity and diet among Hispanic youth. AB - Research has shown that family functioning has been positively associated with physical activity and dietary intake, both of which are obesity-related risk factors. The most widely practiced methodological approach to assessing this construct in empirical studies relies on either parent or adolescent report. Yet, discrepancy in parent and adolescent report of family functioning may provide a fuller understanding of the effects of this construct on obesity-related health outcomes. This is especially important among Hispanics, a population that suffers from disproportionately high rates of obesity and its health-related consequences. The purpose of this study was to examine whether, and to what extent, parent-adolescent discrepancies in family functioning are associated with physical activity, and fruit and vegetable and added sugar intake. We estimated discrepancy scores between parents and adolescents (n = 280 dyads) in family functioning. Then, using structural equation modeling, we tested the effect of family functioning discrepancy on adolescent reports of physical activity, fruits and vegetables intake, and added sugar intake. After controlling for adolescent's gender and BMI, family functioning discrepancy was significantly associated with reduced physical activity (beta = -.14*, 95% CI ([-.26, -.05]) and fruits and vegetables intake (beta = -.22*, 95% CI [-.38, -.09]) such that the larger the discrepancy between parent and youth reported family functioning, the fewer days of adolescent physical activity and the poorer the fruits and vegetables intake. Our findings provide insight for the role of the family in Hispanic adolescent health outcomes and rationale for capturing rich data to better understand that role. (PsycINFO Database Record PMID- 29698008 TI - Longitudinal effects of increases and decreases in intimate partner aggression. AB - Interventions aimed at reducing interpartner aggression assume that within-couple declines in aggression enhance individual and relational outcomes, yet reductions in aggression may fail to yield these benefits when other risk-generating mechanisms remain intact. The present study evaluates this possibility by investigating whether naturally observed within-couple changes in aggression are associated with improved individual and relational outcomes in the manner assumed by intervention programs. Drawing upon 4 waves of data collected at 9-month intervals from a community sample of 431 newlywed couples (76% Hispanic) living in low-income neighborhoods, Actor-Partner-Interdependence Modeling (APIM) and Structural Equation Modeling (SEM) indicated that levels of aggression at the outset of marriage had limited associations with later outcomes. Changes in aggression, however, were associated with subsequent marital outcomes, such that decreases in aggression were beneficial and increases in aggression were costly. Individuals who experienced increases in aggression worsened in their observed communication over time and reported greater increases in stress. Reports of stress early in marriage predicted escalations in aggression over time. Thus, helping couples to contain increases in aggression might be particularly consequential for their well-being. (PsycINFO Database Record PMID- 29698009 TI - Patterns of perceived partner responsiveness and well-being in Japan and the United States. AB - Quality of marital relationships is consistently linked to personal well-being. However, almost all of the studies linking marital processes to well-being have been conducted in Western (particularly North American) countries. Growing evidence shows that perceived partner responsiveness is a central relationship process predicting well-being in Western contexts but little is known about whether this association generalizes to other countries. The present work investigated whether the predictive role of perceived partner responsiveness in well-being differs across the United States and Japan-2 contexts with contrasting views on how the self is conceptualized in relation to the social group. A large life span sample of married or long-term cohabiting adults (n = 3,079, age range = 33-83 in the United States and n = 861, age range = 30-79 in Japan) completed measures of perceived partner responsiveness, hedonic and eudaimonic well-being, and demographic (age, gender, education) and personality (extraversion and neuroticism) covariates known to predict well-being. Perceived partner responsiveness positively predicted hedonic and eudaimonic well-being both in the U.S. and in Japan. However, perceived partner responsiveness more strongly predicted both types of well-being in the United States as compared with Japan. The difference in slopes across the 2 countries was greater for eudaimonic as compared with hedonic well-being. The interaction between perceived partner responsiveness and country held even after controlling for demographic factors and personality traits. By showing that the role of perceived partner responsiveness in well-being may be influenced by cultural context, our findings contribute to achieving a more nuanced picture of the role of relationships in personal well-being. (PsycINFO Database Record PMID- 29698010 TI - Negative relationship behavior is more important than positive: Correlates of outcomes during stressful life events. AB - When people who are married or cohabiting face stressful life situations, their ability to cope may be associated with two separate dimensions of interpersonal behavior: positive and negative. These behaviors can be assessed with the Couple Resilience Inventory (CRI). It was expected that scales on this instrument would correlate with outcome variables regarding life well-being, stress, and relationship satisfaction. It was also expected that effects for negative behavior would be larger than effects for positive and that the effects might be curvilinear. Study 1 included 325 married or cohabiting people currently experiencing nonmedical major life stressors and Study 2 included 154 married or cohabiting people with current, serious medical conditions. All participants completed an online questionnaire including the CRI along with an alternate measure of couple behavior (to confirm scale validity), a measure of general coping style (to serve as a covariate), and measures of outcome variables regarding well-being, quality of life, perceived stress, and relationship satisfaction. The effects for negative behavior were larger than effects for positive in predicting most outcomes, and many effects were curvilinear. Notably, results remained significant after controlling for general coping style, and scales measuring positive and negative behavior demonstrated comparable levels of validity. (PsycINFO Database Record PMID- 29698011 TI - "Can't live with or without them:" Transitions and young adults' perceptions of sibling relationships. AB - Extant research documents how siblings' relationships develop from childhood through adolescence; yet, we know little about how sibling relationships change in young adulthood. Rooted in life course theory, this 2-wave longitudinal study investigated changes in sibling closeness and conflict, and the roles of life transitions and sibling similarity in life stage. Participants included 273 young adults from 180 families who reported on 340 sibling relationships (Time 1 M age = 24.45, SD = 5.33; Time 2 M age = 30.23, SD = 5.33). Multilevel repeated measures analysis of covariance indicated that, on average, siblings' perceptions of conflict declined over the course of young adulthood. Additionally, patterns of change in closeness and conflict were linked to life transitions surrounding coresidence, parenthood, and similarity in employment. The discussion addresses findings in regard to life course theory and similarity in life transitions. (PsycINFO Database Record PMID- 29698012 TI - Reconsidering the links between sibship size, maternal sensitivity, and child attachment: A multidimensional interactive approach. AB - Despite being a well-documented predictor of children's cognitive and social development, sibship has received remarkably little attention in the attachment and maternal sensitivity literature. The only study that has examined both sensitivity and attachment in relation to sibship found greater maternal sensitivity but no more secure attachment among first-born infants. In the current study, we sought to examine the same links while testing two related hypotheses: that sibship size relates only to some specific aspects of sensitivity, and that sibship size relates to sensitivity only among certain mothers, namely those who are at risk for suboptimal parenting because of an insecure attachment state of mind. We assessed three dimensions of maternal sensitivity at 12 months and child attachment at 15 and 25 months among 258 mother-infant dyads living in intact biparental families. Compared with mothers who had fewer children, those with more children were observed to be less accessible/available, less positive, but not less cooperative/attuned, when interacting with their infant. These links were moderated by maternal attachment state of mind, such that significant relations were observed only among mothers presenting a more insecure state of mind. Finally, sibship size was unrelated to attachment. These findings suggest that failure to consider different dimensions of sensitivity or important parental moderators may result in the erroneous conclusion that birth order and sibship size are inconsequential for parent-child relationships. (PsycINFO Database Record PMID- 29698013 TI - Disclosure and holding back: Communication, psychological adjustment, and marital satisfaction among couples coping with osteoarthritis. AB - This study examined two types of illness-related communication (disclosure and holding back) and their associations with psychological adjustment and marital satisfaction in patients with knee osteoarthritis (OA) and their spouses. A sample of 142 couples reported on disclosure and holding back of OA-related concerns, marital satisfaction, and depressive symptoms at two time points across 1 year. Results from dyadic analyses indicated that holding back was associated with decreases in one's own marital satisfaction for patients and spouses and increases in one's own depressive symptoms for spouses over 1 year. In addition, increases in disclosure were associated with increases in marital satisfaction for patients and spouses over time. Holding back and disclosure did not have significant interpersonal effects on the partner's psychological adjustment or marital satisfaction. These results provide support for the hypothesized intrapersonal effects of disclosure and holding back on marital satisfaction and psychological adjustment over time for both OA patients and their spouses, and highlight the importance of open communication for dyadic coping among couples dealing with chronic illness. (PsycINFO Database Record PMID- 29698014 TI - Longitudinal associations between family members' internalizing symptoms across middle childhood. AB - An individual's internalizing symptoms have been shown to relate to greater symptoms in family members. However, an examination of how family members' symptoms are associated with one another is needed with a model including mothers, fathers, and children. Using 633 families from the National Institutes of Child Health and Human Development Study of Early Child Care and Youth Development, the current study examines relations between different family members' internalizing symptoms over time. In the archival data set, mothers', fathers', and children's internalizing symptoms at first, third, and fifth grades were assessed during home and laboratory visits. We tested a cross-lagged path model to assess transactional associations with family income-to-needs ratio and child gender as covariates. In the model, more maternal internalizing symptoms at first and third grades were associated with greater child symptoms at third and fifth grades. More child symptoms at first and third grades were associated with greater maternal symptoms at third and fifth grades. Additionally, more child symptoms at third grade were associated with greater paternal symptoms at fifth grade. These results highlight the importance of examining how family members' internalizing symptoms are associated longitudinally in understanding family systems processes. (PsycINFO Database Record PMID- 29698015 TI - Smoking and weight loss among smokers with overweight and obesity in Look AHEAD. AB - : Smoking cessation is associated with increases in body weight, but little is known about the relationship between participation in a weight loss intervention and smoking. OBJECTIVE: To determine whether (a) weight losses at 1 year differ as a function of baseline smoking status (never smoker, current smoker, ex smoker) and (b) participation in a weight loss intervention affects smoking behavior. METHOD: This analysis addressed these questions using the publicly available database from Look AHEAD, a randomized trial comparing intensive lifestyle intervention (ILI) and diabetes support and education (DSE; control condition) among individuals with overweight/obesity and Type 2 diabetes, and included 4,387 participants who had self-reported smoking and objective weight measures available at baseline and at 1 year. RESULTS: Although participants in ILI lost a significantly greater percentage of weight than those in DSE at 1 year (ILI, M = -8.8%, SD = 6.8; DSE, M = -0.7%, SD = 4.7), there were no differences in weight loss outcomes between never smokers (n = 2,297), ex-smokers (n = 2,115), and current smokers (n = 188) within either condition. Participation in ILI was not associated with compensatory smoking or likelihood of quitting smoking or relapsing. CONCLUSIONS: Smokers in a weight loss intervention had reductions in weight that were comparable to individuals who did not smoke without any evidence of compensatory smoking to manage eating and appetite. Smokers with obesity should be encouraged to pursue weight loss without concerns regarding the impact on smoking behavior. (PsycINFO Database Record PMID- 29698016 TI - Association between posttraumatic stress disorder and lack of exercise, poor diet, obesity, and co-occuring smoking: A systematic review and meta-analysis. AB - OBJECTIVES: Research has shown that posttraumatic stress disorder (PTSD) increases the risk of development of cardiometabolic disease (CMD) including cardiovascular disease and diabetes. Whether PTSD is also associated with behavioral risk factors (e.g., diet, exercise, smoking and obesity) for CMD, is less clear. METHODS: PubMed, Web of Science, and Scopus databases were searched to obtain papers published between 1980-2016. Studies were reviewed for quality using the Quality of Cohort screen. Significance values, odds ratios (OR), 95% confidence intervals (CI), and tests of homogeneity of variance were calculated. PRINCIPAL FINDINGS: A total of 1,349 studies were identified from our search and 29 studies met all eligibility criteria. Individuals with PTSD were 5% less likely to have healthy diets (pooled adjusted OR = 0.95; 95% CI: 0.92, 0.98), 9% less likely to engage in physical activity (pooled adjusted OR = 0.91; 95% CI: 0.88, 0.93), 31% more likely to be obese (pooled adjusted OR = 1.31; 95% CI:1.25, 1.38), and about 22% more likely to be current smokers (pooled adjusted OR = 1.22; 95% CI: 1.19, 1.26), than individuals without PTSD. CONCLUSIONS: Evidence shows PTSD is associated with reduced healthy eating and physical activity, and increased obesity and smoking. The well-established association between PTSD and metabolic and cardiovascular disease may be partly due to poor diet, sedentary lifestyle, high prevalence of obesity, and co-occurring smoking in this population. The well-established association of PTSD with CMD is likely due in part to poor health behaviors in this patient population. (PsycINFO Database Record PMID- 29698017 TI - Impact of cognitive-behavioral interventions on weight loss and psychological outcomes: A meta-analysis. AB - OBJECTIVES: To examine the effects of cognitive-behavioral therapy weight loss (CBTWL) interventions on weight loss, psychological outcomes (eating behaviors [cognitive restraint, emotional/binge eating], and depressive/anxiety symptoms) in adults with overweight or obesity. METHODS: To be included, studies had to (a) be randomized controlled clinical trials of a CBTWL intervention versus a comparison intervention; (b) include weight loss and psychological outcomes; and (c) include patients who were at least overweight to obese. This review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Statement (Moher, Liberati, Tetzlaff, & Altman & the PRISMA Group, 2009). RESULTS: Twelve studies (6,805 participants) were included. The average weight loss difference between arms was -1.70 kg (95% confidence interval [CI]: -2.52 to -0.86, I2 = 1%) in favor of CBTWL. The standardized mean difference on cognitive restraint was 0.72 (95% CI: 0.33 to 1.09; I2 = 81%) and -0.32 (95% CI: -0.49 to -0.16; I2 = 0%) for emotional eating in favor of CBTWL. The reduction in depressive symptoms was not statistically different between the groups (-0.10 [95% CI: 0.21 to 0.02], I2 = 36%). Meta-analyses were not possible for anxiety and binge eating. CONCLUSIONS: In addition to weight loss, current evidence suggests that CBTWL is an efficacious therapy for increasing cognitive restraint and reducing emotional eating. However, CBTWL does not seem to be superior to other interventions for decreasing depressive symptoms. Future studies should focus on understanding how psychological factors impact weight loss and management. (PsycINFO Database Record PMID- 29698018 TI - Cognitive behavior therapy combined with exercise for adults with chronic diseases: Systematic review and meta-analysis. AB - OBJECTIVE: The present meta-analysis aimed to determine the overall effect of cognitive behavior therapy combined with physical exercise (CBTEx) interventions on depression, anxiety, fatigue, and pain in adults with chronic illness; to identify the potential moderators of efficacy; and to compare the efficacy of CBTEx versus each condition alone (CBT and physical exercise). METHOD: Relevant randomized clinical trials, published before July 2017, were identified through database searches in PubMed, PsycARTICLES, CINAHL, SportDiscus, and the Cochrane Central Register for Controlled Trials. RESULTS: A total of 30 studies were identified. CBTEx interventions yielded small to large effect sizes for depression (standardized mean change [SMC] = -0.34, 95% CI [-0.53, -0.14]), anxiety (SMC = -0.18, 95% CI [-0.34, -0.03]), and fatigue (SMC = -0.96, 95% CI [ 1.43, -0.49]). Moderation analyses revealed that longer intervention was associated with greater effect sizes for depression and anxiety outcomes. Low methodological quality was also associated with increased CBTEx efficacy for depression. When compared directly, CBTEx interventions did not show greater efficacy than CBT alone or physical exercise alone for any of the outcomes. CONCLUSION: The current literature suggests that CBTEx interventions are effective for decreasing depression, anxiety, and fatigue symptoms but not pain. However, the findings do not support an additive effect of CBT and exercise on any of the 4 outcomes compared to each condition alone. (PsycINFO Database Record PMID- 29698019 TI - Group-based physical activity for older adults (GOAL) randomized controlled trial: Exercise adherence outcomes. AB - BACKGROUND: Despite the health benefits of regular physical activity, across the globe older adults represent the least active section of society. PURPOSE: The GrOup-based physical Activity for oLder adults (GOAL) trial was a three-arm parallel randomized controlled trial (RCT) that was designed to test the efficacy of two group-based exercise programs for older adults, informed by self categorization theory (SCT), in comparison to a standard group-based exercise program. METHODS: RCT conducted in Greater Vancouver, Canada, enrolled 627 older adults (Mage = 71.57 years, SD = 5.41; 71.0% female). Participants were randomized to similar age same gender (SASG), similar age mixed gender (SAMG), or 'standard' mixed age mixed gender (MAMG) exercise group conditions. In addition to group composition, the intervention programs operationalized principles from SCT designed to foster a sense of social connectedness among participants. The primary outcome of the trial was exercise adherence behavior over 12 and 24 weeks. RESULTS: Analyses of variance revealed that older adults randomized to the SAMG (12-weeks d = .51, p < .001; 24-weeks d = .47, p < .001) and SASG (12-weeks d = .28, p = .012; 24-weeks d = .29, p = .016) conditions adhered to a greater extent than those in the MAMG comparison condition. There were no significant differences between the SAMG and SASG conditions. CONCLUSIONS: The results provide support for the efficacy of group-based physical activity programs informed by SCT. Furthermore, the results suggest that community group-based exercise programs should attempt to engage in age-targeting but not necessarily gender-targeting among older adults. (PsycINFO Database Record PMID- 29698020 TI - Longitudinal health consequences of socioeconomic disadvantage: Examining perceived discrimination as a mediator. AB - OBJECTIVE: Foundational theoretical perspectives suggest that socioeconomic disadvantage (SED) increases an individual's risk of being exposed to unfair treatment or discrimination. However, little empirical attention has been given to the role of perceived discrimination in the SED-health gradient. Addressing this knowledge gap, the current study examined the mediating role of discrimination in the longitudinal association between SED and self-rated health. METHOD: Participants in the Midlife in the United States (MIDUS) study were followed over 3 waves covering a 17- to 19-year period (N = 6,286; 53% female; 91% White; mean age at baseline = 47 years, SD = 13). SED was assessed from education, occupational prestige, income, and assets; self-rated health was measured at baseline and follow-up assessments. Two measures of discrimination perceived inequality in work and everyday discrimination-were considered as mediators. RESULTS: Both measures of discrimination emerged as important explanatory variables in the link between SED and health. SED at the baseline assessment was associated with changes in self-rated health over the 17- to 19 year period (B = -.15, p < .001). Measures of discrimination partially mediated this longitudinal association, explaining 22% of the total effect. Exposure to discrimination and its health consequences were also more pronounced at younger ages. CONCLUSION: Additional research is needed to replicate the findings of this study using objective health measures and to examine possible interventions. Challenging the ideologies and practices that underlie social class-related discrimination, or mitigating its harmful consequences, will both be important approaches to consider. (PsycINFO Database Record PMID- 29698021 TI - Impact of lower strength alcohol labeling on consumption: A randomized controlled trial. AB - OBJECTIVE: Labels indicating low/light versions of tobacco and foods are perceived as less harmful, which may encourage people to consume more. There is an absence of evidence concerning the impact on consumption of labeling alcohol products as lower in strength. The current study tests the hypothesis that labeling wine and beer as lower in alcohol increases their consumption. METHOD: Weekly wine and beer drinkers (n = 264) sampled from a representative panel of the general population of England were randomized to one of three groups to taste test drinks in a bar-laboratory varying only in the label displayed; Group 1: verbal descriptor Super Low combined with 4% alcohol by volume (ABV) for wine/1% ABV for beer; Group 2: verbal descriptor Low combined with 8% ABV for wine/3% ABV for beer; Group 3: no verbal descriptors of strength (Regular). Primary outcome was total volume (ml) of drink consumed. RESULTS: The results supported the study hypothesis: the total amount of drink consumed increased as the label on the drink denoted successively lower alcohol strength, BLin = .71, p = .015, 95% CI [0.13, 1.30]. Group contrasts showed significant differences between those offered drinks labeled as Super Low (M = 213.77) compared with Regular (M = 176.85), B = 1.43, p = .019, 95% CI [0.24, 2.61]. There was no significant difference in amount consumed between those offered drinks labeled as Low compared with Regular. CONCLUSIONS: These results suggest that labeling drinks as lower in strength increases the amount consumed. Further studies are warranted to test for replication in non-laboratory settings and to estimate whether any effects are at a level with the potential to harm health. TRIAL REGISTRATION: ISRCTN15530806. (PsycINFO Database Record PMID- 29698022 TI - Does the cortisol awakening response link childhood adversity to adult BMI? AB - OBJECTIVES: Childhood adversity is a risk factor for the development of obesity in adulthood. Dysregulated hypothalamic-pituitary-adrenal (HPA) activity, which has been associated separately with both adverse childhood experiences and obesity, has been posited as a mechanism by which stressful experiences influence body mass index (BMI); however, this mechanism has not yet been tested longitudinally. The present study uses multireporter, longitudinal data across three time points to test whether the adolescent cortisol awakening response (CAR), an index of diurnal HPA activity, mediates the association between adversity in childhood and BMI in adulthood. METHOD: Eighty-two youth, mothers, and fathers reported on adverse childhood experiences from middle childhood to late adolescence. During adolescence, youth provided saliva samples three times each morning across three days, which were assayed for cortisol to calculate CAR. During early adulthood, youth reported height and weight to calculate BMI. RESULTS: Greater adversity predicted flatter CAR and higher young adult BMI. Flatter CAR partially mediated the association between childhood adversity and young adult BMI. CONCLUSIONS: Stress-related alterations to HPA activity account in part for the childhood adversity-adult obesity link. Findings are consistent with theoretical models implicating HPA alterations as linking childhood adversity to metabolic and behavioral determinants of BMI in adulthood. (PsycINFO Database Record PMID- 29698024 TI - Experimental psychology generally, and the journal today. AB - As Editor of the Journal of Experimental Psychology: General, Cowan provides a few thoughts to help authors figure out what articles to submit, how an article will be handled, and what the journal might do for authors. (PsycINFO Database Record PMID- 29698023 TI - Individual differences and day-to-day fluctuations in goal planning and type 1 diabetes management. AB - OBJECTIVE: To examine whether individual differences and day-to-day fluctuations in diabetes goal planning are associated with Type 1 diabetes (T1D) management during late adolescence, and whether lapses in daily diabetes goal planning are more disruptive to diabetes management among those with poorer executive functioning (EF). METHOD: Late adolescents with T1D (N = 236, Mage = 17.77 years) completed survey measures assessing individual differences in levels of diabetes goal planning and adherence, as well as survey and performance-based measures of EF; glycemic control was assessed through glycated hemoglobin (HbA1c) assays. Participants then completed a 2-week daily diary, rating items measuring daily diabetes goal planning, goal effort, and adherence, and recording blood-glucose tests from their glucometer at the end of each day. RESULTS: Analyses of survey measures indicated that higher individual differences in diabetes goal planning were associated with better adherence and glycemic control. Analyses of daily data using hierarchical linear modeling indicated that adolescents displayed higher daily adherence and lower blood-glucose levels on days when they had higher-than-their-average levels of daily goal planning and daily goal effort. EF moderated the association between daily goal planning and daily adherence, indicating that lapses in daily goal planning were more disruptive for adolescents with poorer EF. CONCLUSION: Both individual differences and day-to day fluctuations in diabetes goal planning are associated with diabetes management, highlighting the challenges of managing T1D in daily life. Youth in late adolescence with poorer EF may especially benefit from planning to attain diabetes goals on a daily basis. (PsycINFO Database Record PMID- 29698025 TI - Taxing cognitive capacities reduces choice consistency rather than preference: A model-based test. AB - How do people make preferential choices in situations where their cognitive capacities are limited? Many studies link the manipulation of cognitive resources to qualitative changes in preferences. However, there is a widely overlooked alternative hypothesis, namely, that a reduction in cognitive capacities leads to an increase in choice inconsistency. We developed a mathematical model and followed a hierarchical Bayesian estimation approach to test to what extent a reduction in cognitive capacities leads to a shift in preference or an increase in choice inconsistency. Using a within-subject n-back task to manipulate cognitive load, we conducted three experiments across different choice domains: risky choice, temporal discounting, and strategic interaction. Across all three domains, results show that a reduction in cognitive capacities predominantly affected participants' level of choice consistency rather than their respective preference. These results hold on an individual and a group level. In sum, our approach and the mathematical model we used provide a rigorous and general test of how reduced cognitive capacities affect people's decision-making. (PsycINFO Database Record PMID- 29698026 TI - Causal strength induction from time series data. AB - One challenge when inferring the strength of cause-effect relations from time series data is that the cause and/or effect can exhibit temporal trends. If temporal trends are not accounted for, a learner could infer that a causal relation exists when it does not, or even infer that there is a positive causal relation when the relation is negative, or vice versa. We propose that learners use a simple heuristic to control for temporal trends-that they focus not on the states of the cause and effect at a given instant, but on how the cause and effect change from one observation to the next, which we call transitions. Six experiments were conducted to understand how people infer causal strength from time series data. We found that participants indeed use transitions in addition to states, which helps them to reach more accurate causal judgments (Experiments 1A and 1B). Participants use transitions more when the stimuli are presented in a naturalistic visual format than a numerical format (Experiment 2), and the effect of transitions is not driven by primacy or recency effects (Experiment 3). Finally, we found that participants primarily use the direction in which variables change rather than the magnitude of the change for estimating causal strength (Experiments 4 and 5). Collectively, these studies provide evidence that people often use a simple yet effective heuristic for inferring causal strength from time series data. (PsycINFO Database Record PMID- 29698027 TI - The unresponsive avenger: More evidence that disinterested third parties do not punish altruistically. AB - Many social scientists believe humans possess an evolved motivation to punish violations of norms-including norm violations that do not harm them directly. However, most empirical evidence for so-called altruistic punishment comes from experimental economics games that create experimental demand for third-party punishment, raising the possibility that the third-party punishment uncovered in these experiments has been motivated by a desire to appear concerned about social norms rather than by actual concern about upholding them. Here we present the results of five experiments in which we used an aggression paradigm to contrast second-party and third-party punishment with minimal experimental demand. We also summarize the results of these experiments meta-analytically. We found robust evidence that participants who were insulted by a stranger experienced anger and punished the insulter. To a lesser degree, participants who witnessed a friend receive an insult also became angry and punished the insulter. In contrast, we found robust evidence that participants who witnessed a stranger receive an insult did not punish the insulter, although they did experience modest amounts of anger. In only one experiment did we find any punishment on behalf of a stranger, and this result could plausibly be explained by the desire to escape the moral censure of other bystanders. Our results suggest that experimental designs that rely on demand-laden methods to test hypotheses about third-party punishment may have overstated the case for the existence of this trait. (PsycINFO Database Record PMID- 29698028 TI - Information and processes underlying semantic and episodic memory across tasks, items, and individuals. AB - The development of memory theory has been constrained by a focus on isolated tasks rather than the processes and information that are common to situations in which memory is engaged. We present results from a study in which 453 participants took part in five different memory tasks: single-item recognition, associative recognition, cued recall, free recall, and lexical decision. Using hierarchical Bayesian techniques, we jointly analyzed the correlations between tasks within individuals-reflecting the degree to which tasks rely on shared cognitive processes-and within items-reflecting the degree to which tasks rely on the same information conveyed by the item. Among other things, we find that (a) the processes involved in lexical access and episodic memory are largely separate and rely on different kinds of information, (b) access to lexical memory is driven primarily by perceptual aspects of a word, (c) all episodic memory tasks rely to an extent on a set of shared processes which make use of semantic features to encode both single words and associations between words, and (d) recall involves additional processes likely related to contextual cuing and response production. These results provide a large-scale picture of memory across different tasks which can serve to drive the development of comprehensive theories of memory. (PsycINFO Database Record PMID- 29698029 TI - Power increases the socially toxic component of narcissism among individuals with high baseline testosterone. AB - The corrosive effects of power have been noted for centuries, but the self related changes responsible for those effects have remained somewhat elusive. Narcissists tend to rise to-and abuse-positions of power, so we considered the possibility that positions of power may corrupt because they inflate narcissism. Two pathways were considered: Powerholders abuse their power because having power over others makes them feel superior (grandiosity pathway) or deserving of special treatment (entitlement pathway). Supporting the entitlement pathway, assigning participants to a position of power (vs. equal control) over a group task increased scores on the Exploitative/Entitlement component of narcissism among those with high baseline testosterone. What is more, heightened Exploitative/Entitlement scores among high-testosterone participants endowed with power (vs. equal control) statistically explained amplified self-reported willingness to misuse their power (e.g., taking fringe benefits as extra compensation). The grandiosity pathway was not well supported. The Superiority/Arrogance, Self-Absorption/Self-Admiration, and Leadership/Authority facets of narcissism did not change as a function of the power manipulation and testosterone levels. Taken together, these results suggest that people with high (but not low) testosterone may be inclined to misuse their power because having power over others makes them feel entitled to special treatment. This work identifies testosterone as a characteristic that contributes to the development of the socially toxic component of narcissism (Exploitative/Entitlement). It points to the possibility that structural positions of power and individual differences in narcissism may be mutually reinforcing, suggesting a vicious cycle with personal, relational, and societal implications. (PsycINFO Database Record PMID- 29698030 TI - Contemporary associative learning theory predicts failures to obtain blocking: Comment on Maes et al. (2016). AB - In a recent article, Maes et al. (2016) report the results from 15 experiments in the blocking effect, all of which failed to replicate the basic phenomenon. Whereas Maes et al. did not dispute the reality of the blocking effect, they concluded that the effect is more difficult to obtain than what could be assumed from the literature and that we lack insight into its boundary conditions. This conclusion is incorrect, because contemporary associative learning theory both agrees with the authors' conclusion that blocking is parameter-dependent and it makes specific predictions about the experimental parameters likely to produce a small or no blocking effect. Ten of the 15 experiments presented by Maes et al. use exactly those parameters (same-modality stimuli for the compound AX), making their results completely unsurprising in the light of contemporary associative learning theory. The results from 3 other experiments are difficult to interpret because of a floor effect. A failure to replicate blocking in only 2 experiments is unsurprising and can be explained as the result of statistical variability or changes in experimental procedure. (PsycINFO Database Record PMID- 29698032 TI - "Robust, replicable, and theoretically-grounded: A response to Brown and Coyne's (2017) commentary on the relationship between emodiversity and health": Correction to Quoidbach et al. (2018). AB - Reports an error in "Robust, replicable, and theoretically-grounded: A response to Brown and Coyne's (2017) commentary on the relationship between emodiversity and health" by Jordi Quoidbach, Moira Mikolajczak, June Gruber, Ilios Kotsou, Aleksandr Kogan and Michael I. Norton (Journal of Experimental Psychology: General, 2018[Mar], Vol 147[3], 451-458). In the article, there is an error in the byline for the first author due to a printer error. The complete, correct institutional affiliation for Jordi Quoidbach is ESADE Business School, Ramon Llull University. The online version of this article has been corrected. (The following abstract of the original article appeared in record 2018-06787-002.) In 2014 in the Journal of Experimental Psychology: General, we reported 2 studies demonstrating that the diversity of emotions that people experience-as measured by the Shannon-Wiener entropy index-was an independent predictor of mental and physical health, over and above the effect of mean levels of emotion. Brown and Coyne (2017) questioned both our use of Shannon's entropy and our analytic approach. We thank Brown and Coyne for their interest in our research; however, both their theoretical and empirical critiques do not undermine the central theoretical tenets and empirical findings of our research. We present an in-depth examination that reveals that our findings are statistically robust, replicable, and reflect a theoretically grounded phenomenon with real-world implications. (PsycINFO Database Record PMID- 29698031 TI - Failures to replicate blocking are surprising and informative-Reply to Soto (2018). AB - The blocking effect has inspired numerous associative learning theories and is widely cited in the literature. We recently reported a series of 15 experiments that failed to obtain a blocking effect in rodents. On the basis of those consistent failures, we claimed that there is a lack of insight into the boundary conditions for blocking. In his commentary, Soto (2018) argued that contemporary associative learning theory does provide a specific boundary condition for the occurrence of blocking, namely the use of same- versus different-modality stimuli. Given that in 10 of our 15 experiments same-modality stimuli were used, he claims that our failure to observe a blocking effect is unsurprising. We disagree with that claim, because of theoretical, empirical, and statistical problems with his analysis. We also address 2 other possible reasons for a lack of blocking that are referred to in Soto's (2018) analysis, related to generalization and salience, and dissect the potential importance of both. Although Soto's (2018) analyses raise a number of interesting points, we see more merit in an empirically guided analysis and call for empirical testing of boundary conditions on blocking. (PsycINFO Database Record PMID- 29698033 TI - "A combined experimental and individual-differences investigation into mind wandering during a video lecture": Correction to Kane et al. (2017). AB - Reports an error in "A combined experimental and individual-differences investigation into mind wandering during a video lecture" by Michael J. Kane, Bridget A. Smeekens, Claudia C. von Bastian, John H. Lurquin, Nicholas P. Carruth and Akira Miyake (Journal of Experimental Psychology: General, 2017[Nov], Vol 146[11], 1649-1674). In the article, the legends for Figure 2 and Figure 4 were erroneous. The correct figures are included in the errata. The online version of this article has been corrected. (The following abstract of the original article appeared in record 2017-48585-001.) A combined experimental-correlational study with a diverse sample (N = 182) from 2 research sites tested a set of 5 a priori hypotheses about mind wandering and learning, using a realistic video lecture on introductory statistics. Specifically, the study examined whether students' vulnerability to mind wandering during the lecture would predict learning from, and situational interest in, the video and also whether longhand note-taking would help reduce mind wandering, at least for some students. One half of the participants took notes during the video, and all were subsequently tested on lecture content without notes. Regression and mediation analyses indicated that (a) several individual-differences variables (e.g., pretest score, prior math interest, classroom media multitasking habits) uniquely predicted in-lecture mind wandering frequency; (b) although the note-taking manipulation did not reduce mind wandering at the group level, note-taking still reduced mind wandering for some individuals (i.e., those with lower prior knowledge and those who took notes of high quality and quantity); (c) mind wandering uniquely predicted both learning (posttest) and situational interest outcomes above and beyond all other individual-differences variables; (d) moreover, mind wandering significantly mediated the effects of several individual differences; and, finally, (e) not all types of mind wandering were problematic-in fact, off-task reflections about lecture-related topics positively predicted learning. These results, which were generally robust across the 2 sites, suggest that educationally focused cognitive research may benefit from considering attentional processes during learning as well as cognitive and noncognitive individual differences that affect attention and learning. (PsycINFO Database Record PMID- 29698034 TI - The native-language benefit for talker identification is robust in 7.5-month-old infants. AB - Adults recognize talkers better when the talkers speak a familiar language than when they speak an unfamiliar language. This language familiarity effect (LFE) demonstrates the inseparable nature of linguistic and indexical information in adult spoken language processing. Relatively little is known about children's integration of linguistic and indexical information in speech. For example, to date, only one study has explored the LFE in infants. Here, we sought to better understand the maturation of speech processing abilities in infants by replicating this earlier study using a more stringent experimental design (eliminating a potential voice-language confound), a different test population (English- rather than Dutch-learning infants), and a new language pairing (English vs. Polish rather than Dutch vs. Italian or Japanese). Furthermore, we explored the language exposure conditions required for infants to develop an LFE for a formerly unfamiliar language. We hypothesized based on previous studies (including the perceptual narrowing literature) that infants might develop an LFE more readily than would adults. Although our findings replicate those of the earlier study-demonstrating that the LFE is robust in 7.5-month-olds-we found no evidence that infants need less language exposure than do adults to develop an LFE. We concluded that both infants and adults need extensive (potentially live) exposure to an unfamiliar language before talker identification in that language improves. Moreover, our study suggests that the LFE is likely rooted in early emerging phonology rather than shared lexical knowledge and that infants already closely resemble adults in their processing of linguistic and indexical information. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29698035 TI - Cross-sensory correspondences in language: Vowel sounds can symbolize the felt heaviness of objects. AB - In sound symbolism, a word's sound induces expectations about the nature of a salient aspect of the word's referent. P. Walker (2016a) proposed that cross sensory correspondences can be the source of these expectations, and the present study assessed three implications flowing from this proposal. First, sound symbolism will embrace a wide range of referent features, including heaviness. Second, any feature of a word's sound able to symbolize one aspect of the word's referent will also be able to symbolize corresponding aspects of the referent (e.g., a sound feature symbolizing visual pointiness will also symbolize lightness in weight). Third, sound symbolism will be independent of the sensory modality through which a word's referent is encoded (e.g., whether heaviness is felt or seen). Adults judged which of two contrasting novel words was most appropriate as a name for the heavier or lighter of two otherwise identical hidden novel objects they were holding in their hands. The alternative words contrasted in their vowels and/or consonants, one or both of which were known to symbolize visual pointiness. Although the plosive or continuant nature of the consonants did not influence the judged appropriateness of a word to symbolize the heaviness of its referent, back/open vowels, compared to front/close vowels, were judged to symbolize felt heaviness. The symbolic potential of back/open vowels to represent felt heaviness, predicted on the basis of their symbolism of visual roundedness, supports the proposal that cross-sensory correspondences contribute to sound symbolism. (PsycINFO Database Record PMID- 29698036 TI - Persistent structural priming during online second-language comprehension. AB - We report 2 self-paced reading experiments investigating the longevity of structural priming effects in comprehending reduced relative clauses among adult Chinese-speaking learners of English. Experiment 1 showed that structural priming occurred both when prime and target sentences were immediately adjacent and when they were separated by 1 or 2 filler sentences of unrelated structures. Moreover, the magnitude of the priming effect held constant across different lag conditions. Experiment 2 replicated the persistent priming effect and ruled out the possibility that the effect was due to verb repetition priming. Taken together, the current results suggest that recent experience with a given structure can have relatively long-lived facilitation effect on the language processing system in second-language learners. As such, structural priming may serve as a learning mechanism for second-language speakers. (PsycINFO Database Record PMID- 29698037 TI - Effects of phrase and word frequencies in noun phrase production. AB - There is mounting evidence that the ease of producing and understanding language depends not only on the frequencies of individual words but also on the frequencies of word combinations. However, in two picture description experiments, Janssen and Barber (2012) found that French and Spanish speakers' speech onset latencies for short phrases depended exclusively on the frequencies of the phrases but not on the frequencies of the individual words. They suggested that speakers retrieved phrase-sized units from the mental lexicon. In the present study, we examined whether the time required to plan complex noun phrases in Dutch would likewise depend only on phrase frequencies. Participants described line drawings in phrases such as rode schoen [red shoe] (Experiments 1 and 2) or de rode schoen [the red shoe] (Experiment 3). Replicating Janssen and Barber's findings, utterance onset latencies depended on the frequencies of the phrases but, deviating from their findings, also depended on the frequencies of the adjectives in adjective-noun phrases and the frequencies of the nouns in determiner-adjective-noun phrases. We conclude that individual word frequencies and phrase frequencies both affect the time needed to produce noun phrases and discuss how these findings may be captured in models of the mental lexicon and of phrase production. (PsycINFO Database Record PMID- 29698038 TI - Remembering what was said and done: The activation and facilitation of memory for gesture as a consequence of retrieval. AB - The gestures that occur alongside speech provide listeners with cues that both improve and alter memory for speech. The present research investigated the interplay of gesture and speech by examining the influence of retrieval on memory for gesture. In three experiments, participants watched video clips of an actor speaking a series of statements with or without gesture before being asked to retrieve the speech portions of half of those statements. Participants were then tested on their ability to recall whether the actor had gestured during each statement and, if so, to recall the nature of the gesture that was produced. Results indicated that attempting to retrieve the speech portion of the statements enhanced participants' ability to remember the gesture portion of the statements. This result was only observed, however, for representational gestures when the speech and gesture components were meaningfully related (Experiments 1 & 2). It was not observed for beat gestures or nonsense gestures (Experiments 2 & 3). These results are consistent with the idea that gestures can be coactivated during the retrieval of speech and that such coactivation is due to the integrated representation of speech and gesture in memory. (PsycINFO Database Record PMID- 29698039 TI - Reading direction influences lateral biases in letter processing. AB - Humans have a limited capacity to identify concurrent, briefly presented targets. Recent experiments using concurrent rapid serial visual presentation of letters in horizontally displaced streams have documented a deficit specific to the stream in the right visual field. The cause of this deficit might be either prioritization of the left item based on participants' experience reading from left to right, or a right-hemisphere advantage specific to dual stimulation. Here we test the reading-experience hypothesis by using participants who have experience reading both a language written left-to-right (English) and one written right-to-left (Arabic). When tested with English letters, these participants showed a deficit, of a similar magnitude to that found previously, for reporting the item on the right. However, when the stimuli were Arabic letters the deficit was absent. This suggests that reading direction plays a large role in the second-target deficit. The pattern of participants' errors suggests where in the processing stream reading experience affects stimulus processing: Specifically, the error pattern suggests that the limited-capacity stage responsible for the deficit corresponds to a postsampling process such as consolidation into short-term memory. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29698040 TI - Children learn spurious associations in their math textbooks: Examples from fraction arithmetic. AB - Fraction arithmetic is among the most important and difficult topics children encounter in elementary and middle school mathematics. Braithwaite, Pyke, and Siegler (2017) hypothesized that difficulties learning fraction arithmetic often reflect reliance on associative knowledge-rather than understanding of mathematical concepts and procedures-to guide choices of solution strategies. They further proposed that this associative knowledge reflects distributional characteristics of the fraction arithmetic problems children encounter. To test these hypotheses, we examined textbooks and middle school children in the United States (Experiments 1 and 2) and China (Experiment 3). We asked the children to predict which arithmetic operation would accompany a specified pair of operands, to generate operands to accompany a specified arithmetic operation, and to match operands and operations. In both countries, children's responses indicated that they associated operand pairs having equal denominators with addition and subtraction, and operand pairs having a whole number and a fraction with multiplication and division. The children's associations paralleled the textbook input in both countries, which was consistent with the hypothesis that children learned the associations from the practice problems. Differences in the effects of such associative knowledge on U.S. and Chinese children's fraction arithmetic performance are discussed, as are implications of these differences for educational practice. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29698041 TI - Adaptation in pronoun resolution: Evidence from Brazilian and European Portuguese. AB - Previous research accounting for pronoun resolution as a problem of probabilistic inference has not explored the phenomenon of adaptation, whereby the processor constantly tracks and adapts, rationally, to changes in a statistical environment. We investigate whether Brazilian (BP) and European Portuguese (EP) speakers adapt to variations in the probability of occurrence of ambiguous overt and null pronouns, in two experiments assessing resolution toward subject and object referents. For each variety (BP, EP), participants were faced with either the same number of null and overt pronouns (equal distribution), or with an environment with fewer overt (than null) pronouns (unequal distribution). We find that the preference for interpreting overt pronouns as referring back to an object referent (object-biased interpretation) is higher when there are fewer overt pronouns (i.e., in the unequal, relative to the equal distribution condition). This is especially the case for BP, a variety with higher prior frequency and smaller object-biased interpretation of overt pronouns, suggesting that participants adapted incrementally and integrated prior statistical knowledge with the knowledge obtained in the experiment. We hypothesize that comprehenders adapted rationally, with the goal of maintaining, across variations in pronoun probability, the likelihood of subject and object referents. Our findings unify insights from research in pronoun resolution and in adaptation, and add to previous studies in both topics: They provide evidence for the influence of pronoun probability in pronoun resolution, and for an adaptation process whereby the language processor not only tracks statistical information, but uses it to make interpretational inferences. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29698042 TI - Sleep reduces the testing effect-but not after corrective feedback and prolonged retention interval. AB - Retrieval practice relative to restudy of learned material typically attenuates time-dependent forgetting. A recent study examining this testing effect across 12 h delays filled with nocturnal sleep versus daytime wakefulness, however, showed that sleep directly following encoding benefited recall of restudied but not of retrieval practiced items, which reduced, and even eliminated, the testing effect after sleep (Bauml, Holterman, & Abel, 2014). The present study investigated, in 4 experiments, whether this modulating role of sleep for the testing effect is influenced by two factors that have previously been shown to increase the testing effect: corrective feedback and prolonged retention intervals. Experiments 1a and 1b applied 12-h delays and showed benefits of sleep for recall after both restudy and retrieval practice with feedback, but not after retrieval practice without feedback. Experiments 2a and 2b applied 24-h or 7-day delays and failed to observe any long-lasting benefits of sleep directly after encoding, on both restudied and retrieval practiced items. These results indicate that both corrective feedback and prolonged retention intervals reduce the modulating role of sleep for the testing effect as it can be observed after 12-h delays and in the absence of corrective feedback, which suggests a fairly limited influence of sleep on the effect. (PsycINFO Database Record PMID- 29698043 TI - Flexible egocentricity: Asymmetric switch costs on a perspective-taking task. AB - We gave 40 participants a task in which they needed to select target objects from an array according to the instructions of either an informed director (who shared their perspective of the array) or an ignorant director (whose view of the array was restricted due to barriers). Importantly, sometimes only one of the directors was visible, and on some trials when both directors were present, participants were required to switch between perspectives. We found that participants were faster to select items from the informed director's perspective than the ignorant director's perspective, but that they slowed when there was a visible but inactive second director. Crucially, relative to nonswitch trials where the same perspective was taken twice consecutively, participants exhibited a significant cost of switching between perspectives when returning to take their own perspective, but not when switching to the other point of view. We interpret these results as evidence that participants inhibit their more salient perspective in order to adopt another's, and then incur an asymmetric switch cost as a result. This suggests that although we are egocentric by default, our egocentricity is effectively, albeit temporarily, eliminated if we have just adopted an alternative frame of reference. (PsycINFO Database Record PMID- 29698044 TI - Recollection is fast and slow. AB - We implemented a new approach to measuring the relative speeds of different cognitive processes, one that extends multinomial models of memory and reasoning from discrete decisions to latencies. We applied it to the dual-process prediction that familiarity is faster than recollection. Relative to prior work on this prediction, the advantages of the new approach are that it jointly measures specific retrieval processes and their latencies, provides separate sets of latency-retrieval parameters for list items and related distractors, and supplies latency parameters for bias processes as well as retrieval processes. Six experiments were conducted using a design (conjoint recognition) in which subjects make traditional old/new decisions about probes, plus two other types of decisions (New but similar to old items? Old or new but similar to old items?). The relative speeds of context recollection, target recollection, familiarity, and bias processes were measured for old list items and for related distractors. Four patterns emerged in all experiments: (a) The speed of recollection did not differ from the speed of familiarity for list items. (b) The speed ordering was context recollection > target recollection = familiarity for related distractors. (c) Bias processes were slower than recollection and familiarity for both list items and related distractors. (d) Bias processes were faster in conditions in which list items were to be accepted than in conditions in which they were to be rejected. Overall, the results suggest that the relative speeds of different retrieval and bias processes are emergent properties of the efficiency of different retrieval cues. (PsycINFO Database Record PMID- 29698045 TI - How does chunking help working memory? AB - Chunking is the recoding of smaller units of information into larger, familiar units. Chunking is often assumed to help bypassing the limited capacity of working memory (WM). We investigate how chunks are used in WM tasks, addressing three questions: (a) Does chunking reduce the load on WM? Across four experiments chunking benefits were found not only for recall of the chunked but also of other not-chunked information concurrently held in WM, supporting the assumption that chunking reduces load. (b) Is the chunking benefit independent of chunk size? The chunking benefit was independent of chunk size only if the chunks were composed of unique elements, so that each chunk could be replaced by its first element (Experiment 1), but not when several chunks consisted of overlapping sets of elements, disabling this replacement strategy (Experiments 2 and 3). The chunk size effect is not due to differences in rehearsal duration as it persisted when participants were required to perform articulatory suppression (Experiment 3). Hence, WM capacity is not limited to a fixed number of chunks regardless of their size. (c) Does the chunking benefit depend on the serial position of the chunk? Chunks in early list positions improved recall of other, not-chunked material, but chunks at the end of the list did not. We conclude that a chunk reduces the load on WM via retrieval of a compact chunk representation from long-term memory that replaces the representations of individual elements of the chunk. This frees up capacity for subsequently encoded material. (PsycINFO Database Record PMID- 29698046 TI - Simulation, false memories, and the planning of future events. AB - Three experiments investigated the relationship between future thinking and false memories. In Experiment 1, participants remembered familiar events (e.g., a holiday) from their past, imagined planning the same events in the future, or took part in a control condition in which they visualized typical events. They then rated a series of schema-related and schema-unrelated nouns for how likely they were to be encountered within those events. In a surprise recognition test, participants in the future condition falsely recognized more schema-related items than participants in the past and control conditions. No reliable effects of rating condition were observed in correct recognition. Experiment 2 found the same pattern when participants imagined unfamiliar events (e.g., taking part in a bank robbery) from past or future perspectives. Participants in Experiment 3 remembered a past or imagined a future holiday and were then instructed to generate items that someone might take on a holiday. Participants in the future condition generated more nonstudied items and fewer studied items relative to participants in the past condition. The findings of Experiments 1 and 2 indicate that simulating future events enhances the activation of related items that gives rise to false memories. The findings of Experiment 3 suggest that these activation processes play an adaptive role in guiding the planning of future events. (PsycINFO Database Record PMID- 29698047 TI - Lexical gaps and morphological decomposition: Evidence from German. AB - On the evidence of four lexical-decision tasks in German, we examine speakers' sensitivity to internal morphological composition and abstract morphological rules during the processing of derived words, real and novel. In a lexical decision task with delayed priming, speakers were presented with two-step derived nouns such as Heilung "healing" derived from the adjective heil "intact" via the verb heilen "to heal." These were compared with two sets of derived novel words, one with and the other without an intermediate verb; for example, *Spitzung "sharpening" from spitz "sharp" via spitzen "sharpen" (Experiment 1) and *Hubschung "beautifying" from hubsch "pretty" via *hubschen "beautify" (Experiment 2). The question was whether there would be a difference between the two types of novel words. Both sets were morphologically viable in terms of combinatory possibilities. Results indicated that extant and novel complex words activated their respective base forms; that is, Heilung, *Spitzung, *Hubschung all primed heil, spitz, hubsch. Both sets of novel words were then combined in a third (delayed priming) experiment, where again they primed their bases, but were nevertheless significantly different from each other. Items with real words in the intermediate position (*Spitzung) showed stronger priming effects. Controls that were only related in form or semantics did not prime; neither did structurally unviable pseudowords show priming. A final experiment (Experiment 4), comparing the two types of novel words (*Spitzung vs. *Hubschung) in a simple lexical-decision task, also revealed significant differences across these sets, suggesting that the lexical status of the intermediate derivation affects the processing of novel forms. (PsycINFO Database Record PMID- 29698048 TI - How the tracking of habitual rate influences speech perception. AB - Listeners are known to track statistical regularities in speech. Yet, which temporal cues are encoded is unclear. This study tested effects of talker specific habitual speech rate and talker-independent average speech rate (heard over a longer period of time) on the perception of the temporal Dutch vowel contrast /alpha/-/a:/. First, Experiment 1 replicated that slow local (surrounding) speech contexts induce fewer long /a:/ responses than faster contexts. Experiment 2 tested effects of long-term habitual speech rate. A high rate group listened to ambiguous vowels embedded in "neutral" speech from Talker A, intermixed with fast speech from Talker B. A low-rate group listened to the same neutral speech from Talker A, and/but to Talker B speaking at a slow rate. Between-groups comparison of the neutral trials showed that the high-rate group demonstrated a lower proportion of /a:/ responses, indicating that Talker A's habitual speech rate sounded slower when B was faster. In Experiment 3, both talkers produced speech at both rates, removing the different habitual speech rates of Talkers A and B, while maintaining the average rates differing between groups. In Experiment 3, no global rate effect was observed. Taken together, the present experiments show that a talker's habitual rate is encoded relative to the habitual rate of another talker, carrying implications for episodic and constraint-based models of speech perception. (PsycINFO Database Record PMID- 29698049 TI - Feature highlighting enhances learning of a complex natural-science category. AB - Learning naturalistic categories, which tend to have fuzzy boundaries and vary on many dimensions, can often be harder than learning well defined categories. One method for facilitating the category learning of naturalistic stimuli may be to provide explicit feature descriptions that highlight the characteristic features of each category. Although this method is commonly used in textbooks and classrooms, theoretically it remains uncertain whether feature descriptions should advantage learning complex natural-science categories. In three experiments, participants were trained on 12 categories of rocks, either without or with a brief description highlighting key features of each category. After training, they were tested on their ability to categorize both old and new rocks from each of the categories. Providing feature descriptions as a caption under a rock image failed to improve category learning relative to providing only the rock image with its category label (Experiment 1). However, when these same feature descriptions were presented such that they were explicitly linked to the relevant parts of the rock image (feature highlighting), participants showed significantly higher performance on both immediate generalization to new rocks (Experiment 2) and generalization after a 2-day delay (Experiment 3). Theoretical and practical implications are discussed. (PsycINFO Database Record PMID- 29698050 TI - Metamemory and memory for a wide range of font sizes: What is the contribution of perceptual fluency? AB - Words printed in a larger 48-point font are judged to be more memorable than words printed in a smaller 18-point font, although font size does not affect actual memory. To clarify the basis of this font size effect on metamemory and memory, 4 experiments investigated how presenting words in 48 (Experiment 1) or 4 (Experiments 2 to 4) font sizes between 6 point and 500 point affected judgments of learning (JOLs) and recall performance. Response times in lexical decision tasks were used to measure perceptual fluency. In all experiments, perceptual fluency was lower for words presented in very small and very large font sizes than for words presented in intermediate font sizes. In contrast, JOLs increased monotonically with font size, even beyond the point where a large font impaired perceptual fluency. Assessments of people's metacognitive beliefs about font size revealed that the monotonic increase in JOLs was not due to beliefs masking perceptual fluency effects (Experiment 3). Also, JOLs still increased across the whole range of font sizes when perceptual fluency was made salient at study (Experiment 4). In all experiments but Experiment 4, recall performance increased with increasing font size, although to a lesser extent than JOLs. Overall, the current study supports the idea that metacognitive beliefs underlie font size effects in metamemory. As important, it reveals that people's font size beliefs have some accuracy. (PsycINFO Database Record PMID- 29698051 TI - The variability puzzle in human memory. AB - Memory performance exhibits a high level of variability from moment to moment. Much of this variability may reflect inadequately controlled experimental variables, such as word memorability, past practice and subject fatigue. Alternatively, stochastic variability in performance may largely reflect the efficiency of endogenous neural processes that govern memory function. To help adjudicate between these competing views, the authors conducted a multisession study in which subjects completed 552 trials of a delayed free-recall task. Applying a statistical model to predict variability in each subject's recall performance uncovered modest effects of word memorability, proactive interference, and other variables. In contrast to the limited explanatory power of these experimental variables, performance on the prior list strongly predicted current list recall. These findings suggest that endogenous factors underlying successful encoding and retrieval drive variability in performance. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29698052 TI - Reward-based motor adaptation can generalize across actions. AB - Recently it has been shown that rewarded variability can be used to adapt visuomotor behavior. However, its relevance seems limited because adaptation to binary rewards has been demonstrated only when the same movement is repeated throughout the experiment. We therefore investigated whether the adaptation is action-specific and whether the amount of exploration depends on spatial complexity. Participants pointed to 3-D visual targets without seeing their hand and could use only binary reward feedback to adapt their movements. We varied the number of target positions and the number of dimensions the feedback was based on. Because the feedback was based on a 5-cm rightward shifted hand position, adaptation was needed for good performance. The participants started naive to the perturbation. If actions were made toward a single target position and the feedback was based on the lateral component of their response only, participants adapted completely within 200 trials. Having more than 1 target position or more than 1 dimension of performance resulted in considerably less adaptation but did not affect the exploration. Thus, reward-based adaptation can generalize across actions but is reduced by spatial complexity, whereas exploration is not affected by spatial complexity. (PsycINFO Database Record PMID- 29698053 TI - Comparison of Chang Run Tong and Forlaxin Treatment of Constipation in Elderly Diabetic Patients. AB - OBJECTIVE: Constipation is quite common and has impact on life quality in the elderly diabetic patients; therefore it is important to seek better treatments. The aim of this study is to evaluate the effect of Chang Run Tong (CRT) decoction on constipation in elderly diabetic patients in comparison with the effect of Macrogol 4000 powder (Forlax). DESIGN: This study was designed as a prospective study consisting of two parallel arms: CRT group and Forlax group. SETTINGS/LOCATION: The study was conducted in China-Japan Hospital. Subject interventions: Eighty elderly diabetic patients with constipation were evaluated, among them 52 patients were treated with CRT and 28 patients were treated with Forlax. OUTCOME MEASURES: The patients were interviewed for Bristol stool scale, spontaneous complete bowel movements (SCBM) and symptoms of defecation feeling, defecation weakness, feeling of incomplete evacuation, bloating, and flatulence at different time points. The changes of all above parameters from treatment for 2 and 4 weeks and follow-up for 1 and 2 months with reference to the baseline (before treatment) were compared between CRT and Forlax treatments. The treatment efficiency was evaluated and compared between two different treatments. RESULTS: For the improvement of Bristol stool scale, SCBM and feeling of incomplete evacuation, CRT was significantly better than Forlax at different time points (p < 0.01, p < 0.001). For the symptoms of defecation feeling, defecation weakness, bloating, and flatulence, CRT was significantly better than Forlax for follow-up improvement (p < 0.01, p < 0.001); whereas no difference was found at other time points of the treatment (p > 0.05). Furthermore, CRT had a significantly better treatment efficiency than Forlax (p < 0.001). CONCLUSIONS: Both CRT and Forlax treatment could effectively improve bowel habits and symptoms of constipation in elderly diabetic patients. CRT was better than Forlax to treat constipation in elderly diabetic patients and had better follow-up improvement after stopping drugs. PMID- 29698054 TI - Effects of Equine-Assisted Activities and Therapies on the Affective Network of Adolescents with Internet Gaming Disorder. AB - OBJECTIVES: Internet gaming disorder (IGD) has been suggested to be a mental health disorder. Attachment and emotional status in IGD patients are important for understanding the etiology and progression of IGD because both parameters are considered to be associated with the affective network. Equine-assisted activities and therapies (EAAT) have been reported to improve emotional status and attachment in subjects. We hypothesized that EAAT would improve attachment in IGD adolescents with insecure attachment issues and increase functional connectivity (FC) within the affective network. DESIGN: Subjects completed a demographic questionnaire, the Korean Experiences in Close Relationships Scale Revised version (K-ECRS), the Child Depression Inventory, Young's Internet Addiction Scale, the Korean Attention-Deficit Hyperactivity Disorder Rating Scale, and resting-state functional magnetic resonance imaging at baseline at the end of EAAT. SUBJECTS: Fifteen IGD adolescents with insecure attachment issues and 15 healthy comparison adolescents with secure attachment agreed to participate in this study. RESULTS: After 7 days of EAAT, K-ECRS avoidance and anxiety scores improved in all adolescents. K-ECRS avoidance scores of the IGD group showed marked improvement compared with those of the healthy group. In all participants, FC from the left amygdala to the left parahippocampal gyrus, left medial frontal gyrus, and left inferior frontal gyrus, as well as from the right amygdala to the left caudate, right claustrum, and left inferior frontal gyrus increased. In IGD adolescents, FC from the left amygdala to the left frontal orbital gyrus, as well as from the right amygdala to the right corpus callosum also increased. CONCLUSION: These findings suggested that EAAT improves attachment, which could lead to a decrease in the severity of IGD symptoms in IGD patients with insecure attachment issues. In addition, EAAT increases FC within the affective network, which was associated with attachment not only in healthy adolescents but also in adolescents with IGD. PMID- 29698055 TI - Association Between Duration of Breastfeeding and Maternal Hypertension: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: Recently, an increasing number of studies have implied that breastfeeding has a protective effect on maternal hypertension, but it remains controversial. The aim of this study is to evaluate the effect of breastfeeding on maternal hypertension through meta-analysis. MATERIALS AND METHODS: Eligible studies were searched and identified in various databases. Meta-analysis was conducted to assess the association between the duration of breastfeeding and maternal hypertension. RESULTS: Seven eligible studies that contained 444,759 participants were included in our study. Meta-analysis of these seven studies showed a significant protective effect of breastfeeding on maternal hypertension. Specifically, pooled odds ratios (ORs) of hypertension for >0-6, >6-12, and >12 months of breastfeeding were 0.92 (95% confidence interval [CI]: 0.88-0.96, I2 = 67.5%), 0.89 (95% CI: 0.86-0.92, I2 = 0), and 0.88 (95% CI: 0.84-0.93, I2 = 43.9%), respectively, compared with nonbreastfeeding mothers, and the pooled OR of hypertension was 0.93 (95% CI: 0.91-0.95, I2 = 40.8%) for women who breastfed compared with women who had not. Furthermore, the pooled hazard ratio of hypertension was 1.34 (95% CI: 1.17-1.52, I2 = 58.7%) for women who did not breastfeed compared with women who breastfed for more than 12 months for their first child. CONCLUSION: Different durations of breastfeeding have different protective effects against the development of maternal hypertension, and breastfeeding for >12 months has a better effect than <12 months. PMID- 29698056 TI - The Muc2 mucin coats murine Paneth cell granules and facilitates their content release and dispersion. AB - Paneth cells are a key subset of secretory epithelial cells found at the base of small intestinal crypts. Unlike intestinal goblet cells, which secrete the mucin Muc2, Paneth cells are best known for producing an array of antimicrobial factors. We unexpectedly identified Muc2 staining localized around Paneth cell granules. Electron microscopy (EM) confirmed an electron lucent halo around these granules, which was lost in Paneth cells from Muc2-deficient (-/-) mice. EM and immunostaining for lysozyme revealed that Muc2-/- Paneth cells contained larger, more densely packed granules within their cytoplasm, and we detected defects in the transcription of key antimicrobial genes in the ileal tissues of Muc2-/- mice. Enteroids derived from the small intestine of wild-type and Muc2-/- mice revealed phenotypic differences in Paneth cells similar to those seen in vivo. Moreover, lysozyme-containing granule release from Muc2-/- enteroid Paneth cells was shown to be impaired. Surprisingly, Paneth cells within human ileal and duodenal tissues were found to be Muc2 negative. Thus Muc2 plays an important role in murine Paneth cells, suggesting links in function with goblet cells; however human Paneth cells lack Muc2, highlighting that caution should be applied when linking murine to human Paneth cell functions. NEW & NOTEWORTHY We demonstrate for the first time that murine Paneth cell granules possess a halo comprised of the mucin Muc2. The presence of Muc2 exerts an impact on Paneth cell granule size and number and facilitates the release and dispersal of antimicrobials into the mucus layer. Interestingly, despite the importance of Muc2 in murine Paneth cell function, our analysis of Muc2 in human intestinal tissues revealed no trace of Muc2 expression by human Paneth cells. PMID- 29698057 TI - Differential associations between plasma concentrations of insulin and glucose and intestinal expression of key genes involved in chylomicron metabolism. AB - The mechanisms underlying the oversecretion of apolipoprotein (apo)B-48 containing triglyceride-rich lipoproteins (TRL) in insulin-resistance (IR) states in humans remain to be fully understood. The objective of this study was to evaluate the association between the plasma levels of insulin and glucose and the intestinal expression of key genes involved in chylomicron metabolism in a large sample of nondiabetic men displaying various degrees of IR. Duodenal biopsies were obtained by gastroduodenoscopy in 127 men free of intestinal disease. Gene expression was measured using quantitative PCR in duodenal samples. Plasma insulin and glucose concentrations were measured in the fasting state. Postprandial TRL apoB-48 kinetics were measured using a primed-constant infusion of l-[5,5,5-D3]leucine for 12 h in a subgroup of 75 subjects maintained in a constant fed state. Plasma insulin levels were negatively associated with intestinal expression of ACS1 (standard beta = -0.20, P = 0.007), DGAT1 (beta = 0.18, P = 0.001), DGAT2 (beta = -0.20, P = 0.02), and MTP (beta = -0.27, P = 0.0005), whereas glucose levels were positively associated with MTP expression (beta = 0.15, P = 0.04) independent of age, BMI, waist circumference, dietary intake, and duodenal expression of SREBP1c. Insulin levels, but not glucose concentrations, were positively correlated with postprandial TRL apoB-48 production rate ( r = 0.24, P = 0.04) and pool size ( r = 0.27, P = 0.03). In conclusion, plasma insulin and glucose levels are differentially associated with the expression of key genes involved in chylomicron metabolism. These results suggest that alterations in intestinal lipoprotein metabolism associated with IR may be regulated by plasma levels of both insulin and glucose concurrently and are therefore likely modified by the onset of insulin insufficiency. NEW & NOTEWORTHY We demonstrate that plasma insulin and glucose levels are differentially associated with the expression of key genes involved in chylomicron metabolism in men. For instance, intestinal expression of MTP is negatively associated with plasma insulin concentrations and positively associated with plasma glucose concentrations. Alterations in intestinal lipoprotein metabolism associated with insulin resistance may be regulated by plasma levels of both insulin and glucose concurrently and are therefore likely modified by the onset of insulin insufficiency. PMID- 29698058 TI - Barry Commoner and the Current Environmental Crisis. PMID- 29698059 TI - 3D printing from microfocus computed tomography (micro-CT) in human specimens: education and future implications. AB - Microfocus CT (micro-CT) is an imaging method that provides three-dimensional digital data sets with comparable resolution to light microscopy. Although it has traditionally been used for non-destructive testing in engineering, aerospace industries and in preclinical animal studies, new applications are rapidly becoming available in the clinical setting including post-mortem fetal imaging and pathological specimen analysis. Printing three-dimensional models from imaging data sets for educational purposes is well established in the medical literature, but typically using low resolution (0.7 mm voxel size) data acquired from CT or MR examinations. With higher resolution imaging (voxel sizes below 1 micron, <0.001 mm) at micro-CT, smaller structures can be better characterised, and data sets post-processed to create accurate anatomical models for review and handling. In this review, we provide examples of how three-dimensional printing of micro-CT imaged specimens can provide insight into craniofacial surgical applications, developmental cardiac anatomy, placental imaging, archaeological remains and high-resolution bone imaging. We conclude with other potential future usages of this emerging technique. PMID- 29698061 TI - Can job autonomy attenuate the effect of depression on employees' well-being? It may depend on culture. AB - BACKGROUND: Depression is one of the leading causes of work disability. Thus, it is important to explore possible ways to reduce its impact on employees. AIMS: The current research examined whether promoting job autonomy would attenuate the detrimental effect of depression on employees' well-being. METHODS: Study 1 included the data from 5974 full-time employees from China. Full-time employees living in India, a collectivistic culture, and the United States, an individualistic culture, were recruited online in Study 2. RESULTS: Study 1 revealed that job autonomy moderated the influence of depression on job strain and perceived control mediated this interaction effect. Specifically, job autonomy weakened the detrimental effect of depression on job strain via weakening the association between depression and perceived control. The data from the 258 full-time employees in Study 2 replicated the findings and found that job autonomy had a stronger attenuating effect on the influence of depression in India than it had in the United States. CONCLUSIONS: Job autonomy was found to be an effective way to reduce the negative impact of depression on employees' well being, a finding that should be considered when organizations develop their work policies. PMID- 29698060 TI - Dosimetric comparison of five different techniques for craniospinal irradiation across 15 European centers: analysis on behalf of the SIOP-E-BTG (radiotherapy working group). AB - PURPOSE: Conventional techniques (3D-CRT) for craniospinal irradiation (CSI) are still widely used. Modern techniques (IMRT, VMAT, TomoTherapy(r), proton pencil beam scanning [PBS]) are applied in a limited number of centers. For a 14-year old patient, we aimed to compare dose distributions of five CSI techniques applied across Europe and generated according to the participating institute protocols, therefore representing daily practice. MATERIAL AND METHODS: A multicenter (n = 15) dosimetric analysis of five different techniques for CSI (3D CRT, IMRT, VMAT, TomoTherapy(r), PBS; 3 centers per technique) was performed using the same patient data, set of delineations and dose prescription (36.0/1.8 Gy). Different treatment plans were optimized based on the same planning target volume margin. All participating institutes returned their best treatment plan applicable in clinic. RESULTS: The modern radiotherapy techniques investigated resulted in superior conformity/homogeneity-indices (CI/HI), particularly in the spinal part of the target (CI: 3D-CRT:0.3 vs. modern:0.6; HI: 3D-CRT:0.2 vs. modern:0.1), and demonstrated a decreased dose to the thyroid, heart, esophagus and pancreas. Dose reductions of >10.0 Gy were observed with PBS compared to modern photon techniques for parotid glands, thyroid and pancreas. Following this technique, a wide range in dosimetry among centers using the same technique was observed (e.g., thyroid mean dose: VMAT: 5.6-24.6 Gy; PBS: 0.3-10.1 Gy). CONCLUSIONS: The investigated modern radiotherapy techniques demonstrate superior dosimetric results compared to 3D-CRT. The lowest mean dose for organs at risk is obtained with proton therapy. However, for a large number of organs ranges in mean doses were wide and overlapping between techniques making it difficult to recommend one radiotherapy technique over another. PMID- 29698062 TI - Targeted deletion of T-cell S1P receptor 1 ameliorates cardiac fibrosis in streptozotocin-induced diabetic mice. AB - Infiltration of T cells is associated with patients who have diabetes at an increased risk of heart attack. T-cell sphingosine 1-phosphate receptor 1 (S1P1) mediated signaling directs T-lymphocyte trafficking. Effects of T-cell S1P1 activation on cardiac fibrosis in a murine diabetic model remain to be explored. For this purpose, conditional T-cell S1P1 knockout (TS1P1KO) mice generated by crossing S1pr1loxP/loxP mice with Lck-Cre mice were used in a model of streptozotocin-induced diabetic cardiomyopathy. The TS1P1KO mice exhibited sustained deficiency of both CD4+ and CD8+ T cells in the blood. The TS1P1KO vehicle control mouse hearts featured an altered phenotype characterized by increased myocardial fibrosis and reduced cardiac contractility under normal levels of glucose. Compared with littermate diabetic mice, TS1P1KO diabetic mice had improved cardiac function and alleviated cardiac fibrosis detected after 11 wk of diabetic induction. Our results indicate that T-cell S1P1 signaling activation plays a dual role in the pathogenesis of cardiac fibrosis with respect to the levels of glucose: T-cell S1P1 activation exerts antifibrotic effects in normoglycemia but exacerbates fibrosis under hyperglycemia.-Abdullah, C. S., Jin, Z.-Q. Targeted deletion of T-cell S1P receptor 1 ameliorates cardiac fibrosis in streptozotocin-induced diabetic mice. PMID- 29698063 TI - The experience and expression of anger in posttraumatic stress disorder: the relationship with metacognition. AB - BACKGROUND: Anger experience and expression are a common issue in those experiencing PTSD. However, it remains unclear what variables affect anger and its expression in PTSD. AIMS: To explore the relationships of synthetic forms of metacognition and metacognitive beliefs with anger experience and expression in PTSD, independent of the effects hyperarousal and depression symptoms. METHOD: Participants were 51 veterans with diagnosed with PTSD. Metacognition was assessed using the Metacognition Assessment Scale-Abbreviated (MAS-A) and the Metacognitions Questionnaire (MCQ). Depression, PTSD symptom severity, and seven domains of anger expression were also assessed. RESULTS: Correlations showed after controlling for overall levels of hyperarousal, higher MAS-A total scores were related to lower levels of State Anger, Feeling Angry, Expressing Anger Physically, and Anger Expression in. Lower MCQ scores were related to lower State anger, Expressing anger verbally, and Expressing anger physically. Higher levels of depression were related to higher levels of Trait anger, Expressing anger physically, Anger expression out, and Anger expression in. Multiple regressions suggested that the MAS-A and MCQ predicted unique portions of the variance in anger experience and expression. CONCLUSIONS: Metacognitive deficits may affect anger experience and expression in those with PTSD and may be an important treatment target. PMID- 29698065 TI - The structure of the MHC-SF in a large American sample: contributions of multidimensional scaling. AB - BACKGROUND: Multidimensional scaling (MDS) is a data reduction tool that produces a visual representation of the association between variables to facilitate the identification of underlying concepts and structures. This technique has been underused in well-being research. AIM: This study used MDS to unravel the underlying concepts and structures in the 14 items of the Mental Health Continuum Short Form (MHC-SF). METHODS: A sample of 22 606 American students was used. Two dimensional MDS plots were generated for the entire sample, and separately for each gender group. RESULTS: MDS yielded three non-overlapping clusters of the items that correspond to the three hypothesized well-being concepts measured by the MHC-SF. The results also showed that the items vary along the two underlying dimensions of personal vs. social, and hedonic vs. eudaimonic. The same general structure was found in both females and males. CONCLUSION: These results supplement and extend the findings of prior factor analytic studies on the MHC-SF by showing that the items of the scale can be distinguished along two separate continua. The results also support the tripartite model of mental well-being. PMID- 29698064 TI - Intracranial meningioma with carcinoma tumor-to-tumor metastasis: two case reports. AB - Meningiomas have been implicated as the most common primary intracranial tumor to contain tumor-to-tumor metastasis. In the following two case reports, we describe cases of adenocarcinoma and breast carcinoma that metastasized into an intracranial meningioma. The first patient was a 64-year-old man presenting to the emergency department with seizures and loss of consciousness. After a left frontal mass resection, pathology reported a heterogeneous mass consisting of a meningioma and a metastatic adenocarcinoma component. The second patient was a 63 year-old woman presenting with significant vision problems and unstable gait. After a right frontal mass resection, pathology reported a heterogeneous mass consisting of a meningioma and a metastatic breast carcinoma component. Possible explanations for the development of the tumor-to-tumor metastasis are described. PMID- 29698066 TI - A Novel Technique for Extracapsular Repair of the Intertarsal Joint in a Duck. AB - The intertarsal joint is a synovial roll-and-glide joint. Ligament damage and luxations of this joint are often the result of traumatic injury or growth deformities and result in significant functional impairment. A 9-month-old female Pekin duck ( Anas platyrhynchos domesticus) was examined because of progressive, nonweight-bearing lameness of the left leg. Moderate effusive swelling was present at the level of the left intertarsal joint, without radiographic evidence of bone involvement. The duck failed to respond to nonsteroidal anti-inflammatory medications and analgesia and was diagnosed with rupture of the medial collateral ligament. Extracapsular surgical correction using bone tunnels and circumferential nylon suture on the medial aspect of the intertarsal joint led to a complete clinical resolution with normal return to function 2 weeks after surgery. This report reviews the anatomy and function of the intertarsal joint in the duck and details a simple extracapsular repair technique useful in the correction of collateral ligament rupture in this joint of ducks. PMID- 29698067 TI - Evaluation of the Thermal Antinociceptive Effects of a Sustained-Release Buprenorphine Formulation After Intramuscular Administration to American kestrels ( Falco sparverius). AB - Previous studies have validated the clinical use of opioids with MU-receptor affinities for pain management in raptors. Buprenorphine has a longer duration of action and minimal adverse effects when compared with other opioids in American kestrels ( Falco sparverius). To evaluate the thermal antinociceptive effects, sedative effects, and duration of action of sustained-release buprenorphine given intramusculary in American kestrels, 12 adult kestrels (8 females and 4 males) were used in a randomized masked complete-crossover experimental design. Buprenorphine SR LAB (1.8 mg/kg) or a control solution were administered intramuscularly. Foot withdrawal response to a thermal stimulus was determined 1 hour before (baseline) and at 1.5, 6, 12, 24, 48, and 72 hours after treatment administration. Agitation-sedation scores were determined 3-5 minutes before each time point, and adverse effects were monitored at these times. Buprenorphine SR LAB significantly increased thermal thresholds at 6, 12, and 24 hours and resulted in mild sedation according to the mean sedation-agitation scores comparing the treatment and control groups. Depending on the severity and type of pain, adjunctive therapy, and individual response, Buprenorphine SR LAB administered at 1.8 mg/kg IM to American kestrels would require administration every 24 hours to manage pain. Further pharmacodynamic and clinical evaluations are warranted in kestrels and other Falconiformes, Accipitriformes, and Strigiformes to establish accurate dosing recommendations. PMID- 29698069 TI - Coming Meetings. PMID- 29698068 TI - Pharmacokinetics and Egg Residues of Meloxicam After Multiple Day Oral Dosing in Domestic Chickens. AB - With increased ownership of backyard poultry, veterinarians must treat these birds appropriately and take into consideration drug withdrawal times for eggs meant for consumption. Few studies have examined the pharmacokinetics or egg residues for medications commonly used in avian medicine. This study determined the pharmacokinetics of meloxicam in domestic chickens (n = 8) after oral dosing at 1 mg/kg q12h for a total of 9 doses (5 days). Additionally, the presence of meloxicam residues in eggs was determined. The terminal half-life, maximum concentration, and time to maximum concentration were 3.02 +/- 1.15 hours, 7.14 +/- 1.54 MUg/mL, and 1.6 +/- 0.52 hours, respectively. No drug was detected in yolks and whites after 8 days and 3 days, respectively. On the basis of these results, a 2-week withdrawal time should be adequate to avoid drug residues in eggs meant for consumption. PMID- 29698070 TI - What Is Your Diagnosis? PMID- 29698072 TI - Advanced Diagnostic Procedures and Surgery: What's Really Happening in Practice? PMID- 29698073 TI - Surgical Extraction of Viable Hen ( Gallus gallus domesticus) Follicles for In Vitro Fertilization. AB - Assisted reproduction techniques in birds have been developed for zootechnical purposes and have been adapted for use in conservation of wild bird species. To develop a technique for obtaining follicles in live hens, 5 Rhode Island red hens ( Gallus gallus domesticus) were anesthetized, and abdominal ultrasound was performed to confirm the presence of ovarian follicles. A left celiotomy then was performed to obtain follicles in different stages of maturation for in vitro fertilization. The follicles were located by digital exploration, then extracted by isolating each follicle with the index finger of each hand, holding it by the stigma, and then applying slight traction towards the exterior of the coelomic cavity until the follicle separated from the ovary. In total, 18 of 30 (60%) follicles obtained were suitable for in vitro fertilization, but only 3 (16%) were fertilized successfully. All birds recovered from the procedure and remained in good condition postoperatively. Perfecting assisted reproduction technique holds potential benefits for determining sex of embryos by blastomeres sexing, supporting the conservation efforts of avian species, and benefiting research areas, such as genetic and biopharmaceutical research. PMID- 29698074 TI - Use of a Compounded Poloxamer 407 Antibiotic Topical Therapy as Part of the Successful Management of Chronic Ulcerative Dermatitis in a Congo African Grey Parrot ( Psittacus erithacus). AB - A 23-year-old, 425-g male African grey parrot ( Psittacus erithacus) was evaluated for chronic ulcerative dermatitis of the axillary regions under both wings. Initial swab cultures of the sites had revealed a coagulase-positive methicillin-resistant Staphylococcus aureas (MRSA) with marked antibiotic resistance. A second swab culture obtained 8 weeks after the initial culture showed heavy growth of a coagulase-positive Staphylococcus species, which could not be speciated, but showed the same sensitivity as the previous culture. Previous treatment included systemic antibiotics and a topical antimicrobial cream, with variable response and only temporary resolution. On examination, full thickness, ulcerative, necrotic dermatitis was present under both wings with intermittent bleeding and subdermal tissue exposure. Initial treatment included wound debridement, oral antibiotics, topical therapy, analgesics, and bandages. After a relapse, a poloxamer gel containing 2% doxycycline, 1% chloramphenicol, and 0.5% mupirocin was used in combination with oral antibiotics and analgesics. On follow-up examination, the skin lesions had completely resolved and the patient was doing well and remains normal 4 years later. This report emphasizes the importance of prompt, aggressive multi-modal therapy for MRSA and other dermal bacterial infections in pet birds that may represent zoonoses or have carrier-state zoonotic potential. Preparation by a compounding pharmacy of a transdermal poloxamer gel containing antibiotics shows promise for severe, infected, ulcerative skin lesions in birds when other therapies fail to achieve a cure. PMID- 29698075 TI - Repair of a Tibiotarsal Fracture in a Pomeranian Goose ( Anser anser) With a Locking Plate. AB - A 2-year-old Pomeranian goose ( Anser anser) weighing 8.1 kg was examined because of non-weight-bearing lameness of the right limb. A closed, transverse, diaphyseal fracture of the distal third of the right tibiotarsus with a craniolateral displacement of the distal fragment was diagnosed radiographically. Surgery under general anesthesia was performed to repair the fracture with a 14 hole, 2.7-mm locking plate fixed with 6 screws in a bicortical manner. Two days later, the bird was fully weight-bearing on the leg. Radiographs performed 4 and 8 weeks after surgery showed good healing of the affected bone with an appropriate callus formation bridging the fracture line. Sixteen weeks after surgery, the patient was readmitted because of lameness exhibited while staying outside exposed to subzero ( degrees C) temperatures. On the basis of this finding, heat conduction was postulated as the possible cause of lameness because it disappeared after implant removal. To the best our knowledge, this case represents the first report of a surgical repair of a tibiotarsal fracture with a locking plate in waterfowl. PMID- 29698076 TI - Central Nervous System B-cell Lymphoma in a Bald Eagle ( Haliaeetus leucocephalus). AB - An adult bald eagle ( Haliaeetus leucocephalus) presented for nystagmus and an inability to fly. On physical examination, the eagle was open-mouth breathing and tachycardic at 200 beats per minute, had a wrinkled cere and sunken eyes, and was an estimated 10% dehydrated. Additionally, the eagle was extremely weak, with neurologic abnormalities including bilateral proprioceptive deficits, nystagmus, and no pupillary light reflex in the left eye. Despite aggressive treatment, the eagle continued to decline rapidly and subsequently died. On histologic examination, diffuse and widespread infiltration of neoplastic lymphocytes was present in the brain, optic nerves, and pecten. Immunohistochemical PAX-5 labeling confirmed B-cell lymphoma confined to the eye and nervous system. Test results for select avian retroviruses, Marek's disease, West Nile virus, avian influenza viruses, and Mycoplasma were negative. To our knowledge, this is the first report of B-cell lymphoma in a bald eagle. Although rare, this condition is a differential diagnosis in cases of neurologic or ocular diseases in birds. PMID- 29698078 TI - Outcomes of Conservatively Managed Coracoid Fractures in Wild Birds in the United Kingdom. AB - Coracoid fractures are a frequent presentation in wild birds, commonly caused by collisions with motor vehicles, windows, or other obstacles such as pylons. Despite this, there are few reports of outcomes, and those published consist of small numbers of birds with conflicting results when comparing conservative management with surgical intervention. To determine outcome success of conservative management in a larger population of wild birds, records of 232 adult wild birds in the United Kingdom (UK) with closed unilateral coracoid fractures confirmed on radiography and surviving more than 48 hours after admission were retrospectively analyzed. Conservative management had a high success rate, with 75% (n = 174/232; 95% confidence limits [CL]: 69%, 80%) of all birds successfully released back to the wild. The proportion of raptors successfully returned to the wild was even higher at 97% (n = 34/35; 95% CL: 85%, 99%). A significant difference of 26% (95% CL: 18%, 34%, Fisher exact test, P < .001) was demonstrated when comparing the outcome success of raptors (97%, n = 34/35) to nonraptors (71%, n = 140/198). The median time in captive care until released back to the wild was 30 days (95% CL: 27, 33). Conservative management of coracoid fractures in wild birds in the UK, and in particular in raptors, appears to result in good outcomes. The approach is low cost and noninvasive, in contrast to surgery, and is recommended as the first-line approach of choice in these cases. PMID- 29698079 TI - The Use of Lead Isotope Analysis to Identify Potential Sources of Lead Toxicosis in a Juvenile Bald Eagle ( Haliaeetus leucocephalus) With Ventricular Foreign Bodies. AB - A male juvenile bald eagle ( Haliaeetus leucocephalus) was admitted to the Wildlife Center of Virginia with a left humeral fracture a large quantity of anthropogenic debris in the ventriculus, a blood lead level of 0.616 ppm, and clinical signs consistent with chronic lead toxicosis. Because of the poor prognosis for recovery and release, the eagle was euthanatized. Lead isotope analysis was performed to identify potential anthropogenic sources of lead in this bird. The lead isotope ratios in the eagle's femur (0.8773), liver (0.8761), and kidneys (0.8686) were most closely related to lead paint (0.8925), leaded gasoline (0.8450), and zinc smelting (0.8240). The lead isotope ratios were dissimilar to lead ammunition (0.8179) and the anthropogenic debris in the ventriculus. This case report documents foreign body ingestion in a free-ranging bald eagle and demonstrates the clinical utility of lead isotope analysis to potentially identify or exclude anthropogenic sources of lead poisoning in wildlife patients. PMID- 29698080 TI - Superficial Chronic Ulcerative Dermatitis (SCUD) in Psittacine Birds: Review of 11 Cases (2008-2016). AB - We reviewed 11 cases of superficial chronic ulcerative dermatitis (SCUD) in psittacine birds that presented to an exotic animal practice over an 8-year period. African grey parrots ( Psittacus erithacus) were overrepresented, accounting for 55% of SCUD-affected birds. All affected birds were hand-reared pets and bonded strongly to their owners. In all cases, fungal culture results were negative. The most commonly cultured bacteria were Enterobacter cloacae (27%), followed by Escherichia coli, and Staphylococcus aureus (both 18%). An underlying cause of behavioral self-mutilation with secondary infection of dermatitis lesions by opportunistic bacteria was suspected in 10 of 11 cases. The axillae were the most common anatomic sites affected (45%). In two cases, more than one site was affected concurrently. Mean age of birds affected was 11.4 years. Two birds had suffered from SCUD previously, with 1 bird having suffered from 3 previous episodes and was euthanized as a result. All birds were treated with systemic antibiotics, topical antibacterial preparations, and systemic nonsteroidal anti-inflammatory drugs. A neck collar was applied in all cases. Median time to clinical resolution was 2 months (range, 1-21 months). Excluding the bird that was euthanized, all birds showed a positive response to treatment. PMID- 29698081 TI - Kundalini Yoga for Generalized Anxiety Disorder: An Exploration of Treatment Efficacy and Possible Mechanisms. AB - The aim of this study was to examine the efficacy of Kundalini Yoga in reducing symptoms of generalized anxiety disorder (GAD) compared to a common treatment-as usual condition using cognitive techniques. A secondary objective was to explore potential treatment mechanisms. Females aged 24 to 75 years with GAD ( n = 49) received either an 8-week Kundalini Yoga intervention ( n = 34) or an 8-week treatment-as-usual condition ( n = 15). The yoga condition resulted in lower levels of anxiety relative to the treatment-as-usual condition. Furthermore, changes in somatic symptoms mediated treatment outcome for Kundalini Yoga. Kundalini Yoga may show promise as a treatment for GAD, and this treatment might convey its effect on symptom severity by reducing somatic symptoms. PMID- 29698082 TI - Phenomenological Inquiry into Phoenix Rising Yoga Therapy. AB - There is growing recognition within psychology and other disciplines that body experience may be as important as cognitive and emotional experience. However, psychology has few psychotherapeutic interventions to support the integration of mind and body within therapy. Phoenix Rising Yoga Therapy (PRYT) is a form of mind-body therapy that uses yoga posture, touch, and psychotherapeutic dialogue to facilitate growth and healing. The current study explored the phenomenological experience of four women who each received five PRYT sessions. Research questions posed were: (1) What are the clients' experiences of the phenomena of PRYT? and (2) How does receiving PRYT sessions impact the clients' lives? The following themes emerged from the data as the essence of PRYT sessions: mindfulness, self awareness, mind-body connection, in vivo experience of new behaviors, client directed, empowerment, and life changes. These themes show significance in the mind-body connection and that it is important to consider alternative modalities such as PRYT for clients. Each participant noted greater insight into mind-body connection. They noticed the effect of cognition and emotion on the body, observed how the body can be used to improve coping through movement and breathing, and experienced different thoughts and emotions associated with different areas of their bodies. Although these results are not necessarily generalizable, they offer interesting theoretical implications for embodied interventions. PMID- 29698083 TI - Voxel-wise prostate cell density prediction using multiparametric magnetic resonance imaging and machine learning. AB - BACKGROUND: There are currently no methods to estimate cell density in the prostate. This study aimed to develop predictive models to estimate prostate cell density from multiparametric magnetic resonance imaging (mpMRI) data at a voxel level using machine learning techniques. MATERIAL AND METHODS: In vivo mpMRI data were collected from 30 patients before radical prostatectomy. Sequences included T2-weighted imaging, diffusion-weighted imaging and dynamic contrast-enhanced imaging. Ground truth cell density maps were computed from histology and co registered with mpMRI. Feature extraction and selection were performed on mpMRI data. Final models were fitted using three regression algorithms including multivariate adaptive regression spline (MARS), polynomial regression (PR) and generalised additive model (GAM). Model parameters were optimised using leave-one out cross-validation on the training data and model performance was evaluated on test data using root mean square error (RMSE) measurements. RESULTS: Predictive models to estimate voxel-wise prostate cell density were successfully trained and tested using the three algorithms. The best model (GAM) achieved a RMSE of 1.06 (+/- 0.06) * 103 cells/mm2 and a relative deviation of 13.3 +/- 0.8%. CONCLUSION: Prostate cell density can be quantitatively estimated non-invasively from mpMRI data using high-quality co-registered data at a voxel level. These cell density predictions could be used for tissue classification, treatment response evaluation and personalised radiotherapy. PMID- 29698084 TI - SLC22A16 upregulation is an independent unfavorable prognostic indicator in gastric cancer. AB - AIM: To study the expression profile of SLC22A16 in gastric cancer (GC), its prognostic value and the potential mechanisms of its upregulation. PATIENTS & METHODS: A retrospective study was performed by using data in the Human Protein Atlas and The Cancer Genome Atlas-Stomach Cancer (STAD). Results: SLC22A16 was significantly upregulated in GC tissues compared with normal stomach tissues. SLC22A16 upregulation independently predicted poor overall survival (hazard ratio [HR]: 1.424, 95% CI: 1.169-1.735; p < 0.001) and recurrence-free survival (HR: 1.658, 95% CI: 1.292-2.128; p < 0.001) in early GC and poor overall survival (HR: 1.411, 95% CI: 1.137-1.752; p = 0.002) in advanced GC. SLC22A16 DNA hypomethylation might be a compensation for DNA loss to maintain SLC22A16 elevation in GC. CONCLUSION: SLC22A16 might be a valuable prognostic marker in GC. PMID- 29698085 TI - Analysis of Corneal Astigmatism before Surgery in Chinese Congenital Ectopia Lentis Patients. AB - PURPOSE: This study aims to describe the characteristics of corneal astigmatism before surgery in congenital ectopia lentis (CEL) patients. METHODS: This retrospective study reviewed 306 CEL patients from 1st January 2006 to 31st December 2015. One eye was randomly selected from each patient when the patient had bilateral EL. The influence of sex, laterality, and Marfan syndrome on corneal astigmatism in different age subgroups was evaluated and compared. The correlation between age and corneal astigmatism was evaluated. RESULTS: Two hundred fifty-two eyes were included in this study. The mean corneal astigmatism of CEL patients was 2.00 +/- 1.28 D. There was a statistical difference in corneal astigmatism between CEL eyes with and without Marfan syndrome. However, no statistical difference was found between male and female patients, or between the EL-affected eye and the unaffected eye in monocular EL patients. There was a positive correlation between age and corneal astigmatism in CEL eyes. CONCLUSIONS: This study suggests that CEL patients' corneal astigmatism is higher in patients with Marfan syndrome, and corneal astigmatism of the CEL eye increases with age. Our results are useful for surgeons to make appropriate incision and intraocular lens (IOL) choices for patients, as well as a useful reference for designs of new IOLs. PMID- 29698086 TI - The Environmental Protection Agency in the Early Trump Administration: Prelude to Regulatory Capture. AB - We explore and contextualize changes at the Environmental Protection Agency (EPA) over the first 6 months of the Trump administration, arguing that its pro business direction is enabling a form of regulatory capture. We draw on news articles, public documents, and a rapid response, multisited interview study of current and retired EPA employees to (1) document changes associated with the new administration, (2) contextualize and compare the current pro-business makeover with previous ones, and (3) publicly convey findings in a timely manner. The lengthy, combined experience of interviewees with previous Republican and Democratic administrations made them valuable analysts for assessing recent shifts at the Scott Pruitt-led EPA and the extent to which these shifts steer the EPA away from its stated mission to "protect human and environmental health." Considering the extent of its pro-business leanings in the absence of mitigating power from the legislative branch, we conclude that its regulatory capture has become likely-more so than at similar moments in the agency's 47-year history. The public and environmental health consequences of regulatory capture of the EPA will probably be severe and far-reaching. PMID- 29698087 TI - Building a Culture of Health in Our Changing Climate. PMID- 29698088 TI - Global Climate Change and the "So What?" Issue: Reversing the Impact of Donald Trump. PMID- 29698089 TI - The Role of Health in Climate Litigation. AB - OBJECTIVES: To examine how the courts, which play a critical role in shaping public policy, consider public health in climate change and coal-fired power plant lawsuits. METHODS: We coded US local, state, and federal court decisions relating to climate change and coal-fired power plants from 1990 to 2016 (n = 873) and qualitatively investigated 139 cases in which litigants raised issues concerning the health impacts of climate change. We also conducted 78 interviews with key litigants, advocates, industry representatives, advising scientists, and legal experts. RESULTS: Health has been a critical consideration in key climate lawsuits, but in a minority of cases. Litigants have presented health arguments most frequently and effectively in terms of airborne exposures. Health impacts have typically been used to gain standing and argue that the evidence for government actions is insufficient. CONCLUSIONS: The courts represent a pivotal branch of government in shaping climate policy. Increasing inclusion of health concerns in emergent areas of litigation could help drive more effective climate policymaking. PMID- 29698090 TI - Legal Authority and State Public Health Response to Climate Change. PMID- 29698091 TI - Linking Mitigation and Adaptation to Climate Change. PMID- 29698092 TI - Are Non-US Citizens More Likely to Die From Heat Exposure? PMID- 29698093 TI - Climate Change and Human Health: Links Between History, Policy, and Science. PMID- 29698094 TI - Estimating the Health and Economic Impacts of Changes in Local Air Quality. AB - OBJECTIVES: To demonstrate the benefits-mapping software Environmental Benefits Mapping and Analysis Program-Community Edition (BenMAP-CE), which integrates local air quality data with previously published concentration-response and health-economic valuation functions to estimate the health effects of changes in air pollution levels and their economic consequences. METHODS: We illustrate a local health impact assessment of ozone changes in the 10-county nonattainment area of the Dallas-Fort Worth region of Texas, estimating the short-term effects on mortality predicted by 2 scenarios for 3 years (2008, 2011, and 2013): an incremental rollback of the daily 8-hour maximum ozone levels of all area monitors by 10 parts per billion and a rollback-to-a-standard ambient level of 65 parts per billion at only monitors above that level. RESULTS: Estimates of preventable premature deaths attributable to ozone air pollution obtained by the incremental rollback method varied little by year, whereas those obtained by the rollback-to-a-standard method varied by year and were sensitive to the choice of ordinality and the use of preloaded or imported data. CONCLUSIONS: BenMAP-CE allows local and regional public health analysts to generate timely, evidence based estimates of the health impacts and economic consequences of potential policy options in their communities. PMID- 29698095 TI - Clarifying the Connections Between Green Space, Urban Climate, and Heat-Related Mortality. PMID- 29698096 TI - National Government Denial of Climate Change and State and Local Public Health Action in a Federalist System. PMID- 29698097 TI - History of US Presidential Assaults on Modern Environmental Health Protection. AB - The Trump administration has undertaken an assault on the Environmental Protection Agency (EPA), an agency critical to environmental health. This assault has precedents in the administrations of Ronald Reagan and George W. Bush. The early Reagan administration (1981-1983) launched an overt attack on the EPA, combining deregulation with budget and staff cuts, whereas the George W. Bush administration (2001-2008) adopted a subtler approach, undermining science-based policy. The current administration combines both these strategies and operates in a political context more favorable to its designs on the EPA. The Republican Party has shifted right and now controls the executive branch and both chambers of Congress. Wealthy donors, think tanks, and fossil fuel and chemical industries have become more influential in pushing deregulation. Among the public, political polarization has increased, the environment has become a partisan issue, and science and the mainstream media are distrusted. For these reasons, the effects of today's ongoing regulatory delays, rollbacks, and staff cuts may well surpass those of the administrations of Reagan and Bush, whose impacts on environmental health were considerable. PMID- 29698098 TI - Strategies to Reduce Greenhouse Gas Emissions from Laparoscopic Surgery. AB - OBJECTIVES: To determine the carbon footprint of various sustainability interventions used for laparoscopic hysterectomy. METHODS: We designed interventions for laparoscopic hysterectomy from approaches that sustainable health care organizations advocate. We used a hybrid environmental life cycle assessment framework to estimate greenhouse gas emissions from the proposed interventions. We conducted the study from September 2015 to December 2016 at the University of Pittsburgh (Pittsburgh, Pennsylvania). RESULTS: The largest carbon footprint savings came from selecting specific anesthetic gases and minimizing the materials used in surgery. Energy-related interventions resulted in a 10% reduction in carbon footprint per case but would result in larger savings for the whole facility. Commonly implemented approaches, such as recycling surgical waste, resulted in less than a 5% reduction in greenhouse gases. CONCLUSIONS: To reduce the environmental emissions of surgeries, health care providers need to implement a combination of approaches, including minimizing materials, moving away from certain heat-trapping anesthetic gases, maximizing instrument reuse or single-use device reprocessing, and reducing off-hour energy use in the operating room. These strategies can reduce the carbon footprint of an average laparoscopic hysterectomy by up to 80%. Recycling alone does very little to reduce environmental footprint. Public Health Implications. Health care services are a major source of environmental emissions and reducing their carbon footprint would improve environmental and human health. Facilities seeking to reduce environmental footprint should take a comprehensive systems approach to find safe and effective interventions and should identify and address policy barriers to implementing more sustainable practices. PMID- 29698099 TI - The Donora Smog Revisited: 70 Years After the Event That Inspired the Clean Air Act. AB - At a storefront museum approximately 25 miles southeast of Pittsburgh, Pennsylvania, a sign reads, "Clean Air Started Here." This is not hyperbole. At the end of October 1948, the communities of Donora and Webster in Pennsylvania were visited by a smog that changed the face of environmental protection in the United States. Conservative estimates showed that 20 individuals died, while an additional 5900-43% of the population of Donora-were affected by the smog. This event led to the first large-scale epidemiological investigation of an environmental health disaster in the United States. Questions remain about the long-term effects of the smog, because higher rates of cardiovascular disease and cancer than were expected were observed in the region in the decade following the smog. Recent work has suggested that environmental contaminants from a bygone era in Donora might have an impact even today. In addition, reports regarding air pollution have indicated that levels of pollutants similar to those estimated to have occurred in Donora are currently present in some rapidly industrializing regions of China and India. Seventy years after the smog, this event still resonates. PMID- 29698100 TI - Burris Comments. PMID- 29698101 TI - Business Leadership in Global Climate Change Responses. AB - In the 2015 Paris Climate Change Agreement, 195 countries committed to reducing greenhouse gas emissions in recognition of the scientific consensus on the consequences of climate change, including substantial public health burdens. In June 2017, however, US president Donald Trump announced that the United States would not implement the Paris Agreement. We highlight the business community's backing for climate change action in the United States. Just as the US federal government is backing away from its Paris commitments, many corporate executives are recognizing the need to address the greenhouse gas emissions of their companies and the business logic of strong environmental, social, and governance practices more generally. We conclude that climate change could emerge as an issue on which the business and public health communities might align and provide leadership. PMID- 29698102 TI - Understanding Human Error in Naval Aviation Mishaps. AB - OBJECTIVE: To better understand the external factors that influence the performance and decisions of aviators involved in Naval aviation mishaps. BACKGROUND: Mishaps in complex activities, ranging from aviation to nuclear power operations, are often the result of interactions between multiple components within an organization. The Naval aviation mishap database contains relevant information, both in quantitative statistics and qualitative reports, that permits analysis of such interactions to identify how the working atmosphere influences aviator performance and judgment. METHOD: Results from 95 severe Naval aviation mishaps that occurred from 2011 through 2016 were analyzed using Bayes' theorem probability formula. Then a content analysis was performed on a subset of relevant mishap reports. RESULTS: Out of the 14 latent factors analyzed, the Bayes' application identified 6 that impacted specific aspects of aviator behavior during mishaps. Technological environment, misperceptions, and mental awareness impacted basic aviation skills. The remaining 3 factors were used to inform a content analysis of the contextual information within mishap reports. Teamwork failures were the result of plan continuation aggravated by diffused responsibility. Resource limitations and risk management deficiencies impacted judgments made by squadron commanders. CONCLUSION: The application of Bayes' theorem to historical mishap data revealed the role of latent factors within Naval aviation mishaps. Teamwork failures were seen to be considerably damaging to both aviator skill and judgment. APPLICATION: Both the methods and findings have direct application for organizations interested in understanding the relationships between external factors and human error. It presents real-world evidence to promote effective safety decisions. PMID- 29698103 TI - Otitis media with effusion after radiotherapy of the head and neck: a systematic review. AB - BACKGROUND: Otitis media (OM) and associated hearing problems may be side effects to radiotherapy of the head and neck region and affect patient quality of life. The condition is associated with the tumor location. OBJECTIVE: To perform a systematic review concerning the present knowledge of the risk of OM after radiotherapy of the head and neck. METHODS: A comprehensive search of PubMed and Embase was carried out between 1 October 2015 and 6 February 2017. The search strategy followed the PRISMA guideline for systematic reviews. RESULTS: Of 597 articles 11 fulfilled the inclusion criteria. Seven were retrospective and four prospective. There were no randomized controlled trials. Eight studies concerned nasopharyngeal cancer. One study concerned cancer of the parotid gland and two studies concerned other locations of head and neck cancer. Meta-analysis could not be done due to heterogeneity between the studies. The incidence of OM varied considerably (range 8-29%). CONCLUSIONS: The incidence of OM is high after radiotherapy of cancer of the upper head and neck area and the Eustachian tube (ET) irradiation dosage seems associated with development of OM, but the literature is poor. Research is needed to designate patients at risk of developing OM after radiotherapy. Preferably through analysis of dosage relationships between the ET and middle ear, and development of OM. Reporting of OM should be per ear and follow standardized protocols of middle ear assessment before and after radiotherapy. Furthermore, there is a need to find new ways to prevent and treat radiation-induced OME, preferably through randomized controlled trials. PMID- 29698104 TI - Bias, Operational Bias, and Generalizability in Phase II/III Trials. PMID- 29698105 TI - Radioiodine Treatment of Well-Differentiated Thyroid Cancer: Balancing Risks and Benefits. PMID- 29698106 TI - Effects of morphine on respiratory load detection, load magnitude perception, and tactile sensation in obstructive sleep apnea. AB - Pharyngeal and respiratory sensation is impaired in obstructive sleep apnea (OSA). Opioids may further diminish respiratory sensation. Thus protective pharyngeal neuromuscular and arousal responses to airway occlusion that rely on respiratory sensation could be impaired with opioids to worsen OSA severity. However, little is known about the effects of opioids on upper airway and respiratory sensation in people with OSA. This study was designed to determine the effects of 40 mg of MS-Contin on tactile sensation, respiratory load detection, and respiratory magnitude perception in people with OSA during wakefulness. A double-blind, randomized, crossover design (1 wk washout) was used. Twenty-one men with untreated OSA (apnea/hypopnea index = 26 +/- 17 events/h) recruited from a larger clinical study completed the protocol. Tactile sensation using von Frey filaments on the back of the hand, internal mucosa of the cheek, uvula, and posterior pharyngeal wall were not different between placebo and morphine [e.g., median (interquartile range) posterior wall = 0.16 (0.16, 0.4) vs. 0.4 (0.14, 1.8) g, P = 0.261]. Similarly, compared with placebo, morphine did not alter respiratory load detection thresholds for nadir mask pressure detected = -2.05 (-3.37, -1.55) vs. -2.19 (-3.36, -1.41) cmH2O, P = 0.767], or respiratory load magnitude perception [mean +/- SD Borg scores during a 5 resistive load (range: 5-126 cmH2O.l-1.s-1) protocol = 4.5 +/- 1.6 vs. 4.2 +/ 1.2, P = 0.347] but did reduce minute ventilation during quiet breathing (11.4 +/- 3.3 vs. 10.7 +/- 2.6 l/min, P < 0.01). These findings indicate that 40 mg of MS-Contin does not systematically impair tactile or respiratory sensation in men with mild to moderate, untreated OSA. This suggests that altered respiratory sensation to acute mechanical stimuli is not likely to be a mechanism that contributes to worsening of OSA with a moderate dose of morphine. NEW & NOTEWORTHY Forty milligrams of MS-Contin does not alter upper airway tactile sensation, respiratory load detection thresholds, or respiratory load magnitude perception in people with obstructive sleep apnea but does decrease breathing compared with placebo during wakefulness. Despite increasing concerns of harm with opioids, the current findings suggest that impaired respiratory sensation to acute mechanical stimuli with this dose of MS-Contin is unlikely to be a direct mechanism contributing to worsening sleep apnea severity in people with mild-to moderate disease. PMID- 29698108 TI - Capsaicin-based analgesic balm attenuates the skeletal muscle metaboreflex in healthy humans. AB - The exercise pressor reflex (EPR) is comprised of group III and IV skeletal muscle afferents and is one of the principal mediators of the cardiovascular response to exercise. In animals, capsaicin-based analgesic balm (CAP) attenuates the pressor response to muscle contraction, indicating the transient receptor potential vanilloid 1 (TRPv1) receptor (localized on the group IV afferent neuron) as an important mediator of the EPR. However, whether these findings can be extrapolated to humans remains unknown. Here, we tested the hypothesis that CAP would attenuate blood pressure (BP) and muscle sympathetic nerve activity (MSNA) responses to isolated muscle metaboreflex activation in healthy men. MSNA (microneurography) and beat-to-beat heart hate (HR, by electrocardiography), and BP (finger photoplethysmography) were continuously measured in eight healthy males (23 +/- 5 yr) at rest, during isometric handgrip exercise, and during postexercise ischemia (PEI). Trials were performed before and 30 and 60 min after the topical application of CAP (0.1%, CAPZASIN-HP) over the volar forearm of the subject's exercising arm. Isometric exercise evoked increases in mean BP (?32 +/- 4 mmHg) and MSNA (?26 +/- 5 bursts/min; ?19 +/- 5 bursts/100 heart beats). The increases in BP during handgrip were not affected by CAP, but the increase in MSNA was lower after 60 min of CAP application. During PEI, the increases in BP and MSNA were all significantly less than those before CAP (all P < 0.05). In conclusion, CAP attenuated BP and sympathetic responses evoked by PEI in humans. These data provide evidence that transient receptor potential vanilloid 1 receptors potentially contribute to the EPR in humans, via its metabolic component. NEW & NOTEWORTHY We found that topical application of capsaicin-based analgesic balm attenuates arterial blood pressure and muscle sympathetic nerve activity during isolated muscle metaboreflex activation following isometric handgrip exercise in healthy humans. These findings suggest that the transient receptor potential vanilloid 1 may contribute to the exercise pressor reflex in humans via its metabolic component. PMID- 29698107 TI - Power reserve following ramp-incremental cycling to exhaustion: implications for muscle fatigue and function. AB - In ramp-incremental cycling exercise, some individuals are capable of producing power output (PO) in excess of that produced at their limit of tolerance (LoT) whereas others cannot. This study sought to describe the 1) prevalence of a "power reserve" within a group of young men ( n = 21; mean +/- SD: age 25 +/- 4 yr; Vo2max 45 +/- 8 ml.kg-1.min-1); and 2) muscle fatigue characteristics of those with and without a power reserve. "Power reserve" (DeltaPReserve) was determined as the difference between peak PO achieved during a ramp-incremental test to exhaustion and maximal, single-leg isokinetic dynamometer power determined within 45 s of completing the ramp-incremental test. Between-group differences in pre- vs. postexercise changes in voluntary and electrically stimulated single-leg muscle force production measures (maximal voluntary contraction torque, voluntary activation, maximal isotonic velocity and isokinetic power; 1-, 10-, 50-Hz torque; and 10/50-Hz ratio), Vo2max, and constant-PO cycling time-to-exhaustion also were assessed. Frequency distribution analysis revealed a dichotomy in the prevalence of a power reserve within the sample resulting in two groups: 1) "No Reserve" (NRES: power reserve <5%; n = 10) and 2) "Reserve" (RES: power reserve >15%; n = 11). At the LoT, all participants had achieved Vo2max. Muscle fatigue was evident in both groups, although the NRES group had greater reductions ( P < 0.05) in 10-Hz peak torque (PT), 10/50 Hz ratio, and maximal velocity. Time to the LoT during the constant PO test was 22 +/- 16% greater ( P < 0.05) in RES (116 +/- 19 s; PO = 317 +/- 52 W) than in NRES (90 +/- 23 s; PO = 337 +/- 71 W), despite similar ramp-incremental exercise durations and Vo2max between groups. Compared with the RES group, the NRES group accrued greater peripheral muscle fatigue at the LoT, suggesting that the mechanisms contributing to exhaustion in a ramp-incremental protocol are not uniform. NEW & NOTEWORTHY This study demonstrates that the mechanisms associated with the limit of tolerance during ramp-incremental cycling exercise differ between those who are capable of generating power output in excess of that at exercise termination vs. those who are not. Those without a "power reserve" exhibit greater peripheral muscle fatigue and reduced muscle endurance, supporting the hypothesis that exhaustion occurs at a specific level of neuromuscular fatigue. In contrast, those with a power reserve likely are limited by other mechanisms. PMID- 29698109 TI - Kinematic patterns while walking on a slope at different speeds. AB - During walking, the elevation angles of the thigh, shank, and foot (i.e., the angle between the segment and the vertical) covary along a characteristic loop constrained on a plane. Here, we investigate how the shape of the loop and the orientation of the plane, which reflect the intersegmental coordination, change with the slope of the terrain and the speed of progression. Ten subjects walked on an inclined treadmill at different slopes (between -9 degrees and +9 degrees ) and speeds (from 0.56 to 2.22 m/s). A principal component analysis was performed on the covariance matrix of the thigh, shank, and foot elevation angles. At each slope and speed, the variance accounted for by the two principal components was >99%, indicating that the planar covariation is maintained. The two principal components can be associated to the limb orientation (PC1*) and the limb length (PC2*). At low walking speeds, changes in the intersegmental coordination across slopes are characterized mainly by a change in the orientation of the covariation plane and in PC2* and to a lesser extent, by a change in PC1*. As speed increases, changes in the intersegmental coordination across slopes are more related to a change in PC1 *, with limited changes in the orientation of the plane and in PC 2*. Our results show that the kinematic patterns highly depend on both slope and speed. NEW & NOTEWORTHY In this paper, changes in the lower-limb intersegmental coordination during walking with slope and speed are linked to changes in the trajectory of the body center of mass. Modifications in the kinematic pattern with slope depend on speed: at slow speeds, the net vertical displacement of the body during each step is related to changes in limb length and orientation. When speed increases, the vertical displacement is mostly related to a change in limb orientation. PMID- 29698110 TI - A noninterfering system to measure in-cage spontaneous physical activity in mice. AB - Due to lack of low-cost and convenient measurement procedures, uncontrolled changes in spontaneous physical activity (SPA) level often are insufficiently considered as a confounding factor in rodent studies. Nonetheless, alterations in SPA can significantly impact on a wide range of physiological measurements. Therefore, we developed an accurate, low-cost video tracking procedure to allow routine assessment of SPA in the home cage of experimental animals (i.e., mice) and in the absence of any distress that might cause alterations in SPA. SPA parameters acquired (movement distance, movement time, and movement speed) with the novel tracking system were identical to those simultaneously obtained with a high-end and well-validated movement-tracking device (mean error = 0.15 +/- 0.07%, r = 0.99, P < 0.001). To further validate the setup, we also demonstrated caffeine-induced stimulation of SPA (195% more activity compared with vehicle, P < 0.01), we adequately reproduced typical SPA fluctuations inherent to day/night cycles (146 and 702% more active during nocturnal compared with diurnal cycle for Balb/c and C57BL/6J mice, respectively, P < 0.001), and we confirmed previously documented SPA differences between animal strains (24% less activity in C57BL/6J mice compared with Balb/c mice, P < 0.05). Taken together, we provide data to prove that this novel low-cost methodology can be conveniently used in any mouse experiment where uncontrolled changes in SPA due to experimental interventions might confound data interpretation. By analogy, the system can be used to document a beneficial impact of therapeutic interventions on SPA in any disease mouse model. NEW & NOTEWORTHY We developed a low-cost procedure to routinely measure SPA in mice. The procedure maintains normal SPA because the animals continue to stay in their home cage in the absence of any external manipulation by the investigators and under habitual dark/light ambient conditions. This novel methodology can be conveniently used in any mouse experiment to quantify experimentally induced alterations in SPA or to assess natural variations in SPA that might confound data interpretation. PMID- 29698111 TI - Arachidonic acid supplementation transiently augments the acute inflammatory response to resistance exercise in trained men. AB - Strenuous exercise can result in skeletal muscle damage, leading to the systemic mobilization, activation, and intramuscular accumulation of blood leukocytes. Eicosanoid metabolites of arachidonic acid (ARA) are potent inflammatory mediators, but whether changes in dietary ARA intake influence exercise-induced inflammation is not known. This study investigated the effect of 4 wk of dietary supplementation with 1.5 g/day ARA ( n = 9, 24 +/- 1.5 yr) or corn-soy oil placebo ( n = 10, 26 +/- 1.3 yr) on systemic and intramuscular inflammatory responses to an acute bout of resistance exercise (8 sets each of leg press and extension at 80% one-repetition maximum) in previously trained men. Whole EDTA blood, serum, peripheral blood mononuclear cells (PMBCs), and skeletal muscle biopsies were collected before exercise, immediately postexercise, and at 2, 4, and 48 h of recovery. ARA supplementation resulted in higher exercise-stimulated serum creatine kinase activity [incremental area under the curve (iAUC) P = 0.046] and blood leukocyte counts (iAUC for total white cells, P < 0.001; neutrophils: P = 0.007; monocytes: P = 0.015). The exercise-induced fold change in peripheral blood mononuclear cell mRNA expression of interleukin-1beta ( IL1B), CD11b ( ITGAM), and neutrophil elastase ( ELANE), as well as muscle mRNA expression of the chemokines interleukin-8 ( CXCL8) and monocyte chemoattractant protein 1 ( CCL2) was also greater in the ARA group than placebo. Despite this, ARA supplementation did not influence the histological presence of leukocytes within muscle, perceived muscle soreness, or the extent and duration of muscle force loss. These data show that ARA supplementation transiently increased the inflammatory response to acute resistance exercise but did not impair recovery. NEW & NOTEWORTHY Daily arachidonic acid supplementation for 4 wk in trained men augmented the acute systemic and intramuscular inflammatory response to a subsequent bout of resistance exercise. Greater exercise-induced inflammatory responses in men receiving arachidonic acid supplementation were not accompanied by increased symptoms of exercise-induced muscle damage. Although increased dietary arachidonic acid intake does not appear to influence basal inflammation in humans, the acute inflammatory response to exercise stress is transiently increased following arachidonic acid supplementation. PMID- 29698112 TI - Reliability of a Categorical Scale (GOSLON) and a Continuous Scale (10-cm Visual Analog Scale) for Assessing Dental Arch Relationships Using Conventional Plaster and 3D Digital Orthodontic Study Models of Children With Complete Unilateral Cleft Lip and Palate. AB - OBJECTIVE: To assess reliability of scoring plaster models and their 3D digital copy of children with complete unilateral cleft lip and palate (CUCLP) using a continuous scale (10-cm visual analog scale [VAS]) and a categorical scale (GOSLON Yardstick). DESIGN: Reliability observational study involving 3 trained GOSLON Yardstick assessors blinded to the origin of the models. PATIENTS: Models from 35 New Zealand (NZ) and 35 Oslo CUCLP patients were standardized and randomly ordered before rating. OUTCOME MEASURES: Assessments were undertaken using the GOSLON and the VAS for both model formats. Twenty percent of sample were randomly selected and rescored at the first assessment, and whole sample was rescored 1 week later. Weighted kappa was used to assess GOSLON reliability, while correlation was used for the VAS. RESULTS: The VAS and GOSLON intra- and inter-rater agreement was similar for both model formats. Repeat measurements on the day have similar intra-rater reliability as repeat measurements at least a week part. There was no significant difference between the 2 model formats, and both the GOSLON and VAS found the NZ models were significantly worse than Oslo. CONCLUSIONS: A 10-cm VAS is a reliable method to assess dental arch relationships and appears to have good face validity when compared to GOSLON. The VAS allows for statistically robust rankings of the dental arch relationships, although more studies will be required to enable the VAS scores to have greater clinical meaning. The 3D digital models can be used for GOSLON and VAS rankings with a high degree of reliability. PMID- 29698113 TI - Nasal Obstruction in Children With Cleft Lip and Palate: Results of a Cross Sectional Study Utilizing the NOSE Scale. AB - OBJECTIVE: To characterize the epidemiology and risk factors for nasal obstruction among subjects with cleft lip and/or cleft palate (CL/P) utilizing the well-validated Nasal Obstruction Symptom Evaluation (NOSE) survey. DESIGN: Retrospective cross-sectional study. SETTING: Cleft Lip and Palate Program, Children's Hospital of Philadelphia. Patients, Subjects: One thousand twenty eight surveys obtained from 456 subjects (mean age: 10.10 (4.48) years) with CL/P evaluated between January 2015 and August 2017 with at least 1 completed NOSE survey. INTERVENTIONS: Nasal Obstruction Symptom Evaluation surveys completed at each annual visit. MAIN OUTCOME MEASURES: Composite NOSE and individual symptom scores. RESULTS: Sixty-seven percent of subjects had nasal obstruction at some point during the study period, with 49% reporting nasal obstruction at latest follow-up. subjects aged 14 years and older reported the most severe symptoms ( P = .002). Subjects with cleft lip and alveolus (CL+A) and unilateral cleft lip and palate (CLP) reported more severe nasal blockage than other phenotypes ( P = .021). subjects with a history of either posterior pharyngeal flap (PPF) or sphincter pharyngoplasty (SP) had significantly higher NOSE scores than subjects with no history of speech surgery ( P = .006). There was no significant difference ( P > .050) in NOSE scores with regard to history of primary tip rhinoplasty, nasal stent use, or nasoalveolar molding. CONCLUSIONS: There are more severe nasal obstructive symptoms among subjects older than 14 years of age, with CL+A or unilateral CLP, and with a history of PPF or SP. Future studies utilizing the NOSE are needed to evaluate and address this prevalent morbidity in the CLP population. PMID- 29698114 TI - Cleft Care of Internationally Adopted Children From China. AB - OBJECTIVE: To quantify a population of international adoptees from China with cleft lip and/or palate to assess presentations and team management practices. DESIGN: Single institution retrospective. PATIENTS: One hundred one patients with cleft lip and/or palate and history of international adoption from China. RESULTS: Forty-nine males and 52 females were adopted from 2001 to 2014. Median age at arrival was 26 months. A total of 88.1% had a combined cleft lip and palate: 59 unilateral, 30 bilateral. Only 4 patients had isolated cleft palate. A total of 85.6% had cleft lip repair before adoption; 41.6% had both cleft lip and palate repairs in China. A total of 14.9% of adoptees had no prior surgery. In China, median age at lip repair was 10 months, and palate repair was 19 months. Once in the United States, lip repair was at 24 months and palate repair at 24 months. Eighty-three revision surgeries were performed. A total of 79.2% of children demonstrated moderate to severe articulation disorders. A total of 36.6% had velopharyngeal insufficiency with hypernasal speech. Forty percent required palatal revision surgery to achieve normal resonance. Fifty seven percent of patients presented with concomitant medical issues but less than 10% with global delays or autism. CONCLUSIONS: Chinese adoptees have more complex presentations and delayed surgical care compared to their domestic counterparts. Engaging prospective families starting before adoption helps to manage expectations. Long range planning, timely surgery, aggressive therapy, and close careful follow-up can mitigate some of these differences. Speech and language problems including articulation disorders, expressive delays, and hypernasality are frequent and can persist despite interventions. PMID- 29698116 TI - Correction. PMID- 29698115 TI - Three-Dimensional Soft Tissue Nasal Changes After Nasoalveolar Molding and Primary Cheilorhinoplasty in Infants With Unilateral Cleft Lip and Palate. AB - OBJECTIVE: To quantify 3-dimensional (3D) nasal changes in infants with unilateral cleft lip with or without cleft palate (UCL+/-P) treated by nasoalveolar molding (NAM) and cheilorhinoplasty and compare to noncleft controls. DESIGN: Retrospective case series of infants treated with NAM and primary cheilorhinoplasty between September, 2012 and July, 2016. Infants were included if they had digital stereophotogrammetric records at initial presentation (T1), completion of NAM (T2), and following primary cheilorhinoplasty (T3). Images were oriented in 3dMD Vultus software, and 16 nasolabial points identified. PATIENTS: Twenty consecutively treated infants with UCL+/-P. INTERVENTIONS: Nasoalveolar molding and primary cheilorhinoplasty. MAIN OUTCOME MEASURES: Anthropometric measures of nasal symmetry and morphology were compared in the treatment group between time points using paired Student t tests. Postsurgical nasal morphology was compared to noncleft controls. RESULTS: Nasal tip protrusion increased, and at T3 was 2.64 mm greater than noncleft controls. Nasal base width decreased on the cleft side by 4.01 mm after NAM and by 6.73 mm after cheilorhinoplasty. Columellar length of the noncleft to cleft side decreased from 2:1 to 1:1 following NAM. Significant improvements in subnasale, columella, and nasal tip deviations from midsagittal plane were observed. Treatment improved symmetry of the alar morphology angle and the nasal base columella angle between cleft and noncleft sides. CONCLUSIONS: Three-dimensional analysis of UCL+/-P patients demonstrated significant improvements in nasal projection, columella length, nasal symmetry, and nasal width. Compared to noncleft controls, nasal form was generally corrected, with overcorrection of nasal tip projection, columella angle, and outer nasal widths. PMID- 29698117 TI - Mathilde Krim: Inspiring AIDS Activist and Social Justice Champion. PMID- 29698119 TI - Where Are We, a Century After the "Spanish Flu"? PMID- 29698118 TI - Our Faculty for Arts and Science The Origins of Creativity by Edward O. Wilson W. W. Norton/Liveright, New York, 2017. PMID- 29698120 TI - Use of Free/Libre Open Source Software in Sepsis "-Omics" Research: A Bibliometric, Comparative Analysis Among the United States, EU-28 Member States, and China. AB - "-Omics" systems sciences are at the epicenter of personalized medicine and public health, and drivers of knowledge-based biotechnology innovation. Bioinformatics, a core component of omics research, is one of the disciplines that first employed Free/Libre Open Source Software (FLOSS), and thus provided a fertile ground for its further development. Understanding the use and characteristics of FLOSS deployed in the omics field is valuable for future innovation strategies, policy and funding priorities. We conducted a bibliometric, longitudinal study of the use of FLOSS in sepsis omics research from 2011 to 2015 in the United States, EU-28 and China. Because sepsis is an interdisciplinary field at the intersection of multiple omics technologies and medical specialties, it was chosen as a model innovation ecosystem for this empirical analysis, which used publicly available data. Despite development of and competition from proprietary commercial software, scholars in omics continue to employ FLOSS routinely, and independent of the type of omics technology they work with. The number of articles using FLOSS increased significantly over time in the EU-28, as opposed to the United States and China (R = 0.96, p = 0.004). Furthermore, in an era where sharing of knowledge is being strongly advocated and promoted by public agencies and social institutions, we discuss possible correlations between the use of FLOSS and various funding sources in omics research. These observations and analyses provide new insights into the use of FLOSS in sepsis omics research across three (supra)national regions. Further benchmarking studies are warranted for FLOSS trends in other omics fields and geographical settings. These could, in time, lead to the development of new composite innovation and technology use metrics in omics systems sciences and bioinformatics communities. PMID- 29698121 TI - Compressed Timeline of Recent Experience in Monkey Lateral Prefrontal Cortex. AB - Cognitive theories suggest that working memory maintains not only the identity of recently presented stimuli but also a sense of the elapsed time since the stimuli were presented. Previous studies of the neural underpinnings of working memory have focused on sustained firing, which can account for maintenance of the stimulus identity, but not for representation of the elapsed time. We analyzed single-unit recordings from the lateral prefrontal cortex of macaque monkeys during performance of a delayed match-to-category task. Each sample stimulus triggered a consistent sequence of neurons, with each neuron in the sequence firing during a circumscribed period. These sequences of neurons encoded both stimulus identity and elapsed time. The encoding of elapsed time became less precise as the sample stimulus receded into the past. These findings suggest that working memory includes a compressed timeline of what happened when, consistent with long-standing cognitive theories of human memory. PMID- 29698122 TI - Clinical Study of Three Dimensional Endoscopic Technique in the Treatment of Thyroid Neoplasm. AB - OBJECTIVE: To evaluate the safety and efficacy of three-dimensional (3D) endoscopic technique in clinical practice. METHODS: A retrospective analysis of the clinical data of 180 cases of endoscopic thyroid surgery, 88 cases by umbrella 3D endoscopic technique (observation group), 92 cases with common endoscopic technique (control group), comparing two groups of patients with age, surgery related indicators, postoperative complications, recovery condition and others. RESULTS: There was no significant difference in the average age, tumor diameter, intraoperative bleeding, postoperative drainage, hospitalization time, and pain scores after surgery between the to groups (P > .05); the operation time of the observation group was shorter than the control group [(93.8 + 33.7) minutes versus (135.5 + 37.5) minutes, P < .05]. There was no hoarseness in the observation group, and 2 cases in the control group had transient hoarseness and no permanent hoarseness. CONCLUSION: The surgical application of 3D endoscopic technique can shorten the time of endoscopic thyroid surgery, reduce the risk of recurrent laryngeal nerve injury, reduce the operation difficulty and operation pressure, greatly reduce the risk of surgical patients, and increase the safety of surgery. PMID- 29698123 TI - Detection of Brucella suis, Campylobacter jejuni, and Escherichia coli Strains in Feral Pig (Sus scrofa) Communities of Georgia. AB - Feral pigs (Sus scrofa) are an environmentally destructive invasive species that act as a reservoir for zoonotic pathogens. The aim of this study was to determine the presence of Brucella suis, Campylobacter jejuni, and of Escherichia coli in feces of feral pigs from Georgia. Fecal samples were collected from 87 feral pigs from forested and agricultural regions of Georgia. DNA was extracted from the fecal samples and quantitative PCR (qPCR) was used to screen for each of the four pathogens. The qPCR assays indicated that B. suis and eaeA-containing strains of E. coli was present in about 22% and 28% of the samples, respectively. C. jejuni was undetected in any of the feral pig fecal samples. The incidence of B. suis was higher in the pigs from forested region, whereas E. coli strains possessing eaeA gene incidence was higher in the pigs from agricultural regions. In Georgia, feral pigs harbor infectious agents and are a growing threat to the transmission of pathogens to native wildlife, humans, and food crops. PMID- 29698125 TI - In Response to "Care Provider or Service Provider: What Should the Role of Radiation Oncologists Be in the Future?" PMID- 29698124 TI - Palliative Care and Hospice Interventions in Decompensated Cirrhosis and Hepatocellular Carcinoma: A Rapid Review of Literature. AB - BACKGROUND: Patients with decompensated cirrhosis (DC) and/or hepatocellular carcinoma (HCC) have a high symptom burden and mortality and may benefit from palliative care (PC) and hospice interventions. OBJECTIVE: Our aim was to search published literature to determine the impact of PC and hospice interventions for patients with DC/HCC. METHODS: We searched electronic databases for adults with DC/HCC who received PC, using a rapid review methodology. Data were extracted for study design, participant and intervention characteristics, and three main groups of outcomes: healthcare resource utilization (HRU), end-of-life care (EOLC), and patient-reported outcomes. RESULTS: Of 2466 results, eight were included in final results. There were six retrospective cohort studies, one prospective cohort, and one quality improvement study. Five of eight studies had a high risk of bias and seven studied patients with HCC. A majority found a reduction in HRU (total cost of hospitalization, number of emergency department visits, hospital, and critical care admissions). Some studies found an impact on EOLC, including location of death (less likely to die in the hospital) and resuscitation (less likely to have resuscitation). One study evaluated survival and found hospice had no impact and another showed improvement of symptom burden. CONCLUSION: Studies included suggest that PC and hospice interventions in patients with DC/HCC reduce HRU, impact EOLC, and improve symptoms. Given the few number of studies, heterogeneity of interventions and outcomes, and high risk of bias, further high-quality research is needed on PC and hospice interventions with a greater focus on DC. PMID- 29698126 TI - Whole Genome Sequencing of NDM-1-Producing ST11 Klebsiella pneumoniae Isolated in a Private Laboratory in Greece. AB - The emergence and spread of NDM-1-encoding Klebsiella pneumoniae is causing worldwide concern, whereas a second epicenter of their dissemination after the Indian subcontinent is thought to be located in the Balkans. In this study, the complete genome sequencing of an NDM-1-producing ST11 K. pneumoniae isolated in a private laboratory in Greece is presented. The genome sequencing was performed on Illumina MiniSeq. Multilocus Sequence Typing was determined using a BLAST-based approach whereas antimicrobial resistance genes and plasmid replicons were identified by ResFinder and PlasmidFinder respectively. The capsular serotype was determined by the nucleotide sequence of the wzc gene. The Rapid Annotation System Technology server v2.0 was used for genome annotation. The isolate was classified to Sequence Type 11 and to the K24 capsular serotype. Its genome consisted of 5,549,974 bp with a G + C content of 57.26%. The resistome included 16 antibiotic resistance genes, 12 located in plasmids and 4 in the chromosome. The whole genome sequence of the isolate has been deposited at GenBank to serve as future reference in the study of the epidemiology and antibiotic resistance mechanisms of carbapenemase-producing Enterobacteriaceae. PMID- 29698127 TI - Interview with Prof. Erik Fisher, Arizona State University. Dawn of Responsible Innovation. PMID- 29698128 TI - Preparation of the Secretory Recombinant ALV-J gp85 Protein Using Pichia pastoris and Its Immunoprotection as Vaccine Antigen Combining with CpG-ODN Adjuvant. AB - This study focuses on preparing the secretory recombinant J subgroup of avian leukosis virus (ALV-J) gp85 protein using Pichia pastoris and evaluating its immunoprotection as vaccine antigen combining with CpG-ODN adjuvant. The secretory recombinant plasmid pPIC9-gp85 containing ALV-J gp85 gene was designed and was transfected into the genome of P. pastoris (GS115) cells. The recombinant plasmid was expressed under the induction of methanol. The expressed products in the medium of the cells were purified and identified with endoglycosidase digestion assay and western blot mediated with monoclonal antibody (MAb) JE9. The purified product combining with CpG-ODN adjuvant was inoculated intramuscularly into 7-day-old chickens and three booster inoculations were performed on 21 days post first inoculation (dpfi), 42, and 56 dpfi. The antibody responses and cellular immune responses were detected, and the protective effects were analyzed after challenge with ALV-J. The results showed that the secretory pPIC9-gp85 plasmid was successfully constructed and could be stably expressed in GS115 cells. The expressed products were N-acetylglucosylated and could specifically combine with MAb (JE9). The secreted gp85 protein combining with CpG-ODN adjuvant could induce higher antibody response and spleen lymphocyte proliferation response and IFN-gamma-inducing response, and could protect all the inoculated chickens against the viremia and the immunosuppressive lesions caused by ALV-J challenge. The results of neutralizing test in vitro suggested that the antisera with some ALV-J antibody titers could neutralize ALV-J strain and inhibit the growth of virus in vitro. The result of IFA showed that IgG antibody in the antisera could specifically combine with ALV-J strain in cells. It can be concluded that the secretory recombinant gp85 protein, as a new acetylglucosylated gp85 protein, was successfully prepared and combining with CpG ODN adjuvant could protect the inoculated chickens against ALV-J infection. This study first reported the methods on preparing the secretory recombinant ALV-J gp85 protein using P. pastoris and evaluated its immunoprotection. PMID- 29698129 TI - A 12-month prospective cohort study of symptoms of common mental disorders among professional rugby players. AB - The primary aims were to determine the 12-month incidence (and comorbidity) of symptoms of common mental disorders (CMD) among male professional rugby players and to explore their association with potential stressors. A secondary aim was to explore the view of male professional rugby players about the consequences of symptoms of CMD and related medical support/needs. An observational prospective cohort study with three measurements over a 12-month period was conducted among male professional rugby players from several countries. Symptoms of CMD (distress, anxiety/depression, sleep disturbance, eating disorders and adverse alcohol use) and stressors (adverse life events, rugby career dissatisfaction) were assessed through validated questionnaires. A total of 595 players (mean age of 26 years; mean career duration of 6 years) were enrolled, of which 333 completed the follow-up period. The incidence of symptoms of CMD were: 11% for distress, 28% for anxiety/depression, 12% for sleep disturbance, 11% for eating disorders and 22% for adverse alcohol use (13% for two simultaneous symptoms of CMD). Professional rugby players reporting recent adverse life events or career dissatisfaction were more likely to report symptoms of CMD but statistically significant associations were not found. Around 95% of the participants stated that symptoms of CMD can negatively influence rugby performances, while 46% mentioned that specific support measures for players were not available in professional rugby. Supportive and preventive measures directed towards symptoms of CMD should be developed to improve not only awareness and psychological resilience of rugby players but also their rugby performance and quality-of-life. PMID- 29698130 TI - American Thyroid Association Guidelines and Statements: Past, Present, and Future. AB - BACKGROUND: The American Thyroid Association (ATA) is continually striving to improve the quality of its publications. The ATA Guidelines Policies and Procedures Task Force was active during 2017. It recently recommended convening a formal standing committee to review and update policies and procedures for the development of clinical practice guidelines (CPGs) and Statements on an ongoing basis. OBJECTIVE: This statement reviews the history of official ATA publications and discusses the challenges and findings identified by the Task Force. We also wish to present our "work in progress" and propose future directions for the new ATA Guidelines and Statements Committee (ATA GSC). METHODS: Our Task Force reviewed the publication record of the ATA with respect to CPGs. We also reviewed existing ATA policies for CPGs and other official statements, examined policies of other organizations, solicited input from external experts and organizations, and convened five conference calls and two in-person meetings. RESULTS: The ATA has a rich history of developing official publications that have been influential based on download and citation records as well as changes in practice trends. Key future issues to be further addressed by the ATA GSC include the following: (i) striving to improve the methodologic rigor of development of CPGs while balancing considerations of feasibility and timeliness and the role of transparently communicated expert opinion; (ii) formalizing a framework and process for development of new Statements; (iii) increasing stringency and transparency of management of competing interests of individuals being considered for CPG/Statement panel membership; (iv) encouraging consideration of equity and diversity in CPG/Statement development group composition; (v) increasing relevant stakeholder representation (including patient representatives) in development of CPGs/Statements; and (vi) expanding future guideline implementation strategies. CONCLUSIONS: As shown by the completed literature search, the ATA has a long history of producing CPGs and Statements with global impact on informing clinical management, education, and research in thyroid diseases. The ATA remains committed to a process of continual improvement of its publications and to meeting stakeholder information needs. Based on the work of our Task Force, we have identified many elements that are needed to achieve this goal and areas of challenge for our new committee. PMID- 29698131 TI - Exposure of the Bone Marrow Microenvironment to Simulated Solar and Galactic Cosmic Radiation Induces Biological Bystander Effects on Human Hematopoiesis. AB - The stem cell compartment of the hematopoietic system constitutes one of the most radiosensitive tissues of the body and leukemias represent one of the most frequent radiogenic cancers with short latency periods. As such, leukemias may pose a particular threat to astronauts during prolonged space missions. Control of hematopoiesis is tightly governed by a specialized bone marrow (BM) microenvironment/niche. As such, any environmental insult that damages cells of this niche would be expected to produce pronounced effects on the types and functionality of hematopoietic/immune cells generated. We recently reported that direct exposure of human hematopoietic stem cells (HSC) to simulated solar energetic particle (SEP) and galactic cosmic ray (GCR) radiation dramatically altered the differentiative potential of these cells, and that simulated GCR exposures can directly induce DNA damage and mutations within human HSC, which led to leukemic transformation when these cells repopulated murine recipients. In this study, we performed the first in-depth examination to define changes that occur in mesenchymal stem cells present in the human BM niche following exposure to accelerated protons and iron ions and assess the impact these changes have upon human hematopoiesis. Our data provide compelling evidence that simulated SEP/GCR exposures can also contribute to defective hematopoiesis/immunity through so-called "biological bystander effects" by damaging the stromal cells that comprise the human marrow microenvironment, thereby altering their ability to support normal hematopoiesis. PMID- 29698132 TI - Dental Age Difference in Children with ADHD. AB - OBJECTIVE: The purpose of this study was to determine if changes in dental development are associated with Attention Deficit Hyperactivity Disorder (ADHD) or ADHD medications. STUDY DESIGN: This retrospective chart review evaluated the dental age of 128 patients between 6 and 16 years of age using the Demirjian method from the following two groups a) children with ADHD b) unaffected children. The ADHD group was further stratified into four groups according to the medication type. The impact of ADHD on dental age difference (the difference between dental age and chronologic age) was analyzed using T-test and the association between medication type and dental age difference was analyzed through one way ANOVA. RESULTS: The mean difference between estimated dental age and chronologic age (dental age difference) for all subjects was 0.80 years. There was no significant dental age difference in subjects with ADHD and the control group (0.78+/-1.28vs. 0.84 +/-1.09 years respectively; P=0.75) and there was no significant difference in dental age difference and type of medication (P=0.84). CONCLUSION: No significant difference was found between children with ADHD and unaffected children with respect to dental age difference. No significant differences were found in dental age difference in the four medication groups. PMID- 29698133 TI - Viability and Reproducibility of Periodontal Ligament Cells on Avulsed Teeth Stored in Ham's F-10 Solution. AB - OBJECTIVES: The purpose of the present study was to evaluate the efficacy of Ham's F-10 in maintaining the viability and reproducibility of PDL cells on avulsed teeth. STUDY DESIGN: Sixty mature, healthy extracted premolars were used. The experimental media used were Ham's F-10, Hank's balanced salt solution (HBSS), skim milk, and tap water (n = 15 specimens each). Cell viability was tested after 1, 3, 6, and 24 h storage in medium. Cell reproducibility was assessed by methyl-thiazol-tetrazolium (MTT) assay after1, 3, and 6 h storage in Ham's F-10, HBSS, and tap water. RESULTS: The viability of PDL cells stored in Ham's F-10 and HBSS was significantly greater than that of samples stored in milk and tap water at all-time points (P<0.001). A significant difference in cell viability between samples stored in Ham's F-10 and HBSS (favoring the former) was observed only at 6h (P=0.04). MTT assay results were significantly better for samples stored in Ham's F-10 and HBSS than for those stored in tap water (P<0.001), with a significant difference between Ham's F-10 and HBSS observed only at 3h (P<0.001). CONCLUSIONS: Ham's F-10 is capable of preserving PDL cells viable and reproducible better than milk and tap water and similar to HBSS. PMID- 29698134 TI - Dental Diseases and Intestinal Dysbiosis Among Children. AB - OBJECTIVES: The goal of the present study correlates dental hard tissue mineralization, mucosal pathologies in the oral cavity and different degrees of intestinal dysbiosis. STUDY DESIGN: the study examined two groups: the study group (Group I) included 229 children and adolescents aged 1-17 (mean age 5+/ 1years) with oral pathologies (caries, acute or chronic candidiasis) and confirmed dysbiosis of varying severity and stages as well. Group II (the Control Group) was composed of 50 patients aged 1 - 16 (mean age 5+/-1years) with oral pathologies but with no detected changes in gastrointestinal (GI) flora. Dental caries were examined by DMFT-index; the extent of dental hard tissue mineralization by vital staining (2% methylene blue) and cases of oral candidiasis was investigated by taking cultures from mucosal plaques. RESULTS: on the basis of the research outcomes the correlation between the different degrees of GI dysbiosis and dental hard tissue mineralization with pathologic expressions in the oral cavity was found. Group I was divided into two subgroups: in the first subgroup that suffered from mild dysbiosis (I and II degree) moderate dental caries was revealed, whereas in the second subgroup with III and IV degree of dysbiosis-high levels of dental caries was detected. In Group II (no GI flora disturbances), the dental hard tissue demineralization indicator was minimal; in children aged 1-3 years the incidence and prevalence of caries were low and increased with age, reaching higher values during puberty (11-16 years). CONCLUSION: It may be concluded that dysbiosis of GI microflora influences on a degree of dental hard tissue demineralization, which in turn may predispose to the formation of dental caries. PMID- 29698135 TI - The Prevalence of ADHD Patients among Pediatric Dentists in Israel and Knowledge of Dental and Behavioral Aspects of Treating Them. AB - OBJECTIVE: There are no clear guidelines for managing the dental treatment of children with attention deficit hyperactivity disorder (ADHD). The use of sedation in combination with chronic ADHD medication use is also not well defined. This study surveyed the prevalence of ADHD children, management techniques and knowledge of pharmacologic therapies of these children among Israeli dentists. STUDY DESIGN: A specially designed questionnaire was distributed to all Israeli dentists attending a national conference in 2016. RESULTS: Of the 160 dentists who attended the conference, 96 completed the survey (60% response rate), and they included 46 (51%) pediatric dental specialists and 50 (49%) general dental practitioners. The medications Ritalin and Concerta were most familiar to the respondents (98.9%). Eighty-seven (91.1%) of the practitioners responded that their ADHD patients take their usual doses of any drug for treating ADHD symptoms, regardless of whether or not the dentists intended to use sedatives. The practitioners invented their own behavior management techniques with varying degrees of success. CONCLUSIONS: There are no specific guidelines for the most effective pharmacologic protocol (co administration of ADHD drugs and dental sedatives) or behavior management techniques for the provision of optimal dental care to children with ADHD. PMID- 29698136 TI - Oral Health of Portuguese Children with Type 1 Diabetes: A Multiparametric Evaluation. AB - OBJECTIVE: To perform a multiparametric evaluation of the oral health of 36 children with type 1 diabetes. STUDY DESIGN: A group of type 1 diabetic children and a sex-age-matched control group were formed. Seven parameters were evaluated: probing depth, bleeding on probing, plaque index (O'Laery index), calculus index (according to Ramfjord), dental caries (using ICDAS), salivary pH and unstimulated salivary flow rate. Statistical analysis was performed and the significance level was set at 5%. RESULTS: Both groups consisted of 36 children with a mean age of 13 years. With regard to bleeding on probing, plaque index and calculus index, higher values were obtained in the diabetic group and the differences between groups were statistically significant for all three parameters. Concerning dental caries and salivary parameters, there were no significant differences between groups. However, a statistically significant correlation between salivary parameters and metabolic control was found. CONCLUSION: This study suggests that type 1 diabetic children are associated with some risk factors related to periodontal disease and dental caries. The proven relationship between diabetes and oral health complications imposes the need for these patients to be integrated into preventive dental programs from a young age. PMID- 29698137 TI - Gender Differences in Dental Anxiety and Medical Fear in Croatian Adolescents. AB - OBJECTIVES: The aim of this study was to differentiate anxious from nonanxious adolescents and evaluate gender differences in anxiety with respect to previous negative dental and medical experiences. The purpose was also to evaluate a causative relationship between child medical fear and dental anxiety. STUDY DESIGN: This study sampled 113 Croatian adolescents from 15 to18 years of age. Children's Fear Survey Schedule - Dental Subscale (CFSS-DS) was used for the assessment of child dental anxiety regarding visits to the dentist and receiving dental treatment. A modified version of Child Medical Fear Questionnaire (CMFQ-M) was used for evaluation of child medical fear related to medical treatment and doctors in general. RESULTS AND CONCLUSION: The results showed significantly higher dental anxiety (CFSS-DS) and medical fear (CMFQ-M) in adolscent girls (p<0,001) as compared to adolescent boys. A significantly strong correlation between medical fear and dental anxiety in adolescent girls was proved by Pearson's correlation coefficient (p < 0,01). In this study, CMFQ-M and CFSS-DS questionnaires were standardized in the Croatian adolescent population and proved reliable in the estimation of anxious behaviour with respect to specific medical and dental situations. PMID- 29698138 TI - Dental Caries in Children and Adolescents During and After Antineoplastic Chemotherapy. AB - OBJECTIVE: To assess caries incidence, intensity, and treatment in children and adolescents under/after antineoplastic treatment. STUDY DESIGN: Patients with permanent and mixed dentition were divided into three groups of 60 patients each (5-18 years): CH - under chemotherapy; PCH - after chemotherapy; CG - generally healthy subjects. Caries incidence, intensity (DMFT/dmft, DMFS/dmfs), and mean numbers of teeth/surfaces with white spot lesions-WSL (D1+2/d1+2) were assessed following the ICDAS-II criteria. STATISTICAL ANALYSIS: Mann-Whitney U test, significance at p<=0.05). RESULTS: Caries incidence was significantly higher in PCH and CH (88.33% and 90%) than in CG (66.66%). Caries intensity was higher in both mixed and permanent dentition in patients under and after chemotherapy. The DMFS/DMFT correlation was the highest in PCH. Treatment indexes for primary and permanent teeth treatment were significantly lower in PCH and CH than CG. CONCLUSION: Antineoplastic chemotherapy is associated with caries development and its high incidence during/after treatment. As dental hygiene was poor in patients under and after antineoplastic treatment, dental checkups need to be more frequent and thorough. PMID- 29698139 TI - Early Childhood Caries and Risk Factors in Vietnam. AB - OBJECTIVE: To investigate caries prevalence and examine its relationship with socioeconomic status and oral health behavior of Vietnamese kindergarten children. STUDY DESIGN: The study was carried out on 1,028 children aged 2-5 years in six kindergartens in Thua Thien Hue province, Vietnam. Information about socioeconomics and oral health behaviors was collected through a self administered questionnaire, and oral health status by clinical dental examination. RESULTS: Clinical dental examination found that overall caries prevalence and mean dmft were 89.1% and 9.32. Caries prevalence and mean dmft increased greatly from two years to three years old, and gradually developed from three years to five years old. A logistic regression revealed that caries had an inverse relationship with mothers' educational level and a positive relationship with the habit of retaining food in the mouth for a long time in two-year-old children. Prolonged breastfeeding, more frequent sweets consumption, no thumb sucking habit, and higher modified debris index score were the risk factors for caries among three-to-five-year-old children. CONCLUSIONS: This study indicated a high prevalence of caries and related risk factors such as low mother's educational level and inappropriate oral health behavior among kindergarten children in Vietnam. PMID- 29698140 TI - Buccal Bifurcation Cyst: Two Case Reports and a Literature Review. AB - INTRODUCTION: A buccal bifurcation cyst (BBC) is an uncommon inflammatory odontogenic cyst associated with the permanent mandibular first or second molar in children. CASE REPORTS: These reports present two cases of BBC and describes the clinical and radiographic features leading to the diagnosis and the treatment of this lesion. Two patients complained of mandibular buccal swelling around the permanent first molar. The diagnosis of BBC in both cases was based on the clinical and radiographic features. In both cases, only enucleation was performed without extracting the involved tooth. RESULTS: There were no recurrences during follow up. All teeth remained vital and erupted normally. CONCLUSION: The most appropriate treatment is usually enucleation of the cyst without extraction of the associated tooth. Therefore, knowledge of the distinct features of BBC is important for diagnosis and appropriate treatment. PMID- 29698141 TI - Children's Preferences for Pediatric Dentist Attire: A Multicenter Study. AB - BACKGROUND: Data are conflicting regarding the effect of professional staff attire on children at pediatric dental clinics. AIM: To compare the preferences of children and their parents in three countries, regarding the gender and attire of pediatric dentists. STUDY DESIGN: A multi-centered study was conducted in pediatric dental clinics in Israel (N=100), Uruguay (N=270) and Spain (N=200). Children, aged 4-12 years, and their parents were asked to choose the pediatric dentist they preferred from 5 pictures of the same male and 5 pictures of the same female, in different attire. RESULTS: In Israeli clinics, where half of the pediatric dentists were male, and they wore white coats or casual attire, these were preferred by children, with no preference regarding the dentist's gender. In Spain, where the majority of dentists were females, wearing surgical scrubs, children preferred female dentists with this attire. In Uruguay, where female dentists wore surgical or pediatric scrubs, these were preferred by children. Parents more often selected female than male dentists; they preferred pediatric scrubs for their children's dentists more often than their children preferred such attire. CONCLUSIONS: Children's preferences for the attire of pediatric dentists reflected the common wearing apparel for dentists at the clinics they attended. PMID- 29698142 TI - Contribution of Streptococcus Mutans Virulence Factors and Saliva Agglutinating Capacity to Caries Susceptibility in Children: A Preliminary Study. AB - BACKGROUND: Many factors contribute to caries development in humans, such as diet, host factors - including different saliva components - and the presence of acidogenic bacteria in the dental biofilm, particularly Streptococcus mutans (S. mutans). Despite the influence of S. mutans in caries, this bacterium is also prevalent among healthy individuals, suggesting the contribution of genetic variation on the cariogenic potential. Based on this hypothesis, the present work investigated the influence of S. mutans virulence factors and saliva agglutinating capacity on caries susceptibility in children. STUDY DESIGN: Saliva samples of 24 children from low income families (13 caries-free and 11 caries active individuals) were collected and tested for their ability to agglutinate S. mutans. The bacteria were isolated from these samples and analyzed for the presence of the gene coding for mutacin IV (mut IV). Biofilm formation and acid tolerance were also investigated in both groups (caries-free and caries-active). RESULTS: Saliva samples from caries-free children showed an increased capacity to agglutinate S. mutans (p=0.006). Also, bacteria isolated from the caries-free group formed less biofilm when compared to the caries-active group (p=0.04). The presence of mut IV gene did not differ between bacteria isolated from caries-free and caries-active individuals, nor did the ability to tolerate an acidic environment, which was the same for the two groups. CONCLUSIONS: Altogether, the results suggest that the adhesive properties of S. mutans and the agglutinating capacity of the saliva samples correlated with the presence of caries lesions in children. PMID- 29698143 TI - Survival Rates of Stainless Steel Crowns and Multi-Surface Composite Restorations Placed by Dental Students in a Pediatric Clinic. AB - PURPOSE: This study examined survival rates of multi-surface composite restorations and stainless steel crowns (SSCs) placed by students in a pediatric dental clinic as well as the length of time it takes for restorations to be replaced with stainless steel crowns. STUDY DESIGN: Data from electronic dental records for all children with at least one 2-surface composite restorations or SSCs on a primary first or second molar from January 1, 2007 to September 30, 2015 were analyzed. The primary outcome was the time to a new restoration or SSC on the same tooth, with time to a crown as a secondary outcome. Descriptive statistics were obtained and the cumulative incidence of the event of interest was estimated using 95% confidence intervals and compared between groups using Fine-Gray regression. RESULTS: A total of 6,288 teeth from 2,044 children were analyzed. Three years after the initial procedure, 1.5% of SSCs and 21% of 2 and 3 surface composite restorations failed and needed a replacement (Hazard Ratio [HR]= 14; 95% Confidence interval [CI] 9-22, p<0.001). Also, 6.8% of composite restorations needed replacement with SSCs' (HR=4; 95% CI: 3-7). CONCLUSIONS: The study demonstrates that stainless steel crowns had a higher survival rate than multi-surface composite resins placed by students at a pediatric dental clinic in primary molars of children. PMID- 29698144 TI - Position and Eruption of Permanent Maxillary Canines in Cases of Maxillary Lateral Incisor Agenesis in Mixed Dentition. AB - OBJECTIVE: Assess whether the permanent maxillary canine (MC) has a natural tendency to erupt mesially in children with maxillary lateral incisors agenesis (MLIA), compared to children without agenesis. STUDY DESIGN: This retrospective, observational, cross-sectional study consisted of children between 5 and 12 years old divided into three groups: the first group with unilateral MLIA, in which an intraindividual analysis was performed, the second group presented bilateral MLIA, and the third group with patients without agenesis. These last two groups were matched for comparison interindividual, being pared by sex and maturation of the MC. RESULTS: The canine position in the horizontal sector showed a clear mesial positioning of the MC on the agenesis side in individuals with unilateral MLIA (group 1) when compared with the counter lateral side; and in individuals with bilateral MLIA (Group 2) compared with control Individuals without agenesis (group 3). Even with the maintenance of this deciduous tooth in the dental arch, the MC keeps its tendency to mesial eruption. CONCLUSION: There is a greater tendency for mesial angulation of the maxillary canine in patients with MLIA, regardless of the presence or absence of deciduous lateral incisor. PMID- 29698145 TI - Pre-Fabricated Myofunctional Appliance for the Treatment of Mild to Moderate Pediatric Obstructive Sleep Apnea: A Preliminary Report. AB - OBJECTIVE: The purpose of this study was to determine the efficacy of the Myobrace/MyOSA myofunctional appliance for the treatment of mild to moderate Obstructive Sleep Apnea (OSA) in children, by means of the Apnea/Hypopnea Index (AHI). STUDY DESIGN: Nine children with a diagnosis of mild to moderate OSA were included in the study. The subjects wore the Myobrace/MyOSA myofunctional appliance for a period of 90 days. The initial AHI, determined by means of a sleep test, was used as baseline (To), and a second AHI, computed at the end of the experimental period, was used as final data (T1). The differences between the AHIs at To and T1 were calculated (diff AHI) and used for statistical purposes. The level of Oxygen Saturation (SaO2) was also recorded before and after treatment, and their differences calculated as diff SaO2. Statistical analysis was performed with a paired-t- test and statistical significance was established at 95 per cent level of confidence. RESULTS: A statistical significant reduction in the AHI of the studied subjects was computed at the end of the experimental period (p = 0.0425). Although there was an improvement in the SaO2, it did not reach a statistically significant difference. CONCLUSIONS: The present results suggest that the Myobrace/MyOSA myofunctional appliance can be an alternative to treat mild to moderate OSA in children. However further studies are necessary to determine the stability of the results after treatment. PMID- 29698146 TI - Prognosis, Cost, and Occurrence of Colorectal, Lung, Breast, and Prostate Cancer in Hungary. AB - BACKGROUND: There is an increasing social debate on expenditures on the care of patients with malignant diseases, especially in Central Eastern European countries with limited health resources. OBJECTIVES: The aim of this research was to estimate the epidemiological and quality measures and resource use indicators in Hungary in four malignant conditions (breast, colorectal, lung, and prostate cancer) from the National Health Insurance Fund (NHIF) database. METHODS: Survival and cost analyses were performed on the NHIF database. Patient records containing the International Classification of Diseases (ICD) codes C50 (breast cancer), C18-C20 (colorectal cancer), C33-C34 (lung cancer), and C61 (prostate cancer) were considered eligible. Inclusion criteria were at least two consecutive ICD codes between 2000 and 2012, with a minimum of 30-day difference, or one ICD code, followed by patient death within 60 days. A total of 428,860 social insurance numbers met inclusion criteria. RESULTS: The number of new cases was 6381 for breast cancer, 8457 for colorectal cancer, 8902 for lung cancer, and 3419 for prostate cancer. The probability of 5-year overall survival from the first diagnosis was 75.2%, 41.3%, 17.1%, and 62.1%, respectively. Median time from first diagnosis to treatment initiation was less than 1 month in all conditions except for lung cancer. The annual cost of treatment was ?2585, ?3165, ?4157, and ?2834, respectively. Cost figures were compared with hemophilia as benchmark (?8284). CONCLUSIONS: The results indicated that the database of the Hungarian NHIF is suitable for real-world data analysis in the field of oncology and can support long-term evidence-based policymaking. PMID- 29698147 TI - High-Quality, Scientific Rigor, and Diversity: Value in Health Regional Issues Is Getting Its Impact. PMID- 29698148 TI - The Potential Effects of Implementing the 2013 ACC/AHA Cholesterol Guidelines on the Use of Statins in a Large Health Maintenance Organization in Israel. AB - BACKGROUND: The 2013 American College of Cardiology and American Heart Association (ACC/AHA) guidelines for the management of blood cholesterol identify candidates for statin therapy to prevent atherosclerotic cardiovascular disease (ASCVD). OBJECTIVE: The objective was to estimate the effect of adopting the ACC/AHA guidelines in Maccabi Healthcare Services (MHS), a large health maintenance organization in Israel. METHODS: This population-based study, conducted in June 2014, included all MHS members 40 years or older. We searched the computerized database of MHS to determine the number of members currently on statins, calculated the number of additional members newly eligible for statin treatment according to the new guidelines, and estimated the cost of implementing the guidelines in MHS. RESULTS: In June 2014, there were 798,076 MHS members 40 years or older. Of the 725,784 members included, 30% were receiving statin treatment at baseline. Adopting the new guidelines would increase the proportion of statin-treated members to 48% (58% and 39% among men and women, respectively). Newly eligible members were more likely to be 55 to 69 years old, men, and have a predicted 10-year ASCVD risk of 7.5% or more. The calculated incremental annual cost for medications is 54 million new Israeli shekels (US $13.5 million). The cost per cardiovascular event prevented is estimated at 82,000 new Israeli shekels (US $20,500). CONCLUSIONS: Adopting the ACC/AHA 2013 cholesterol guidelines would increase the number of MHS members 40 years or older eligible for statin therapy by 60%, with the increase mainly in primary prevention due to the predicted 10-year ASCVD risk. PMID- 29698149 TI - The Hungarian Care Managing Organization Pilot Program. AB - OBJECTIVES: The aim of this article was to provide a description of the Hungarian care managing organization (CMO) pilot program and its environment, incentive structure, and preliminary outcomes. The need to change the behavior of doctors to increase the effectiveness and cost-effectiveness of the system was the key rationale for the Hungarian CMO pilot program. METHODS: After an application process, nine CMOs were entitled to enter into the system in July 1999. By 2006, there were 14 CMOs covering 2.1 million people. The Hungarian CMO program tried to combine the advantages of both the US managed care programs and the UK general practitioner fundholding system, within the constraints and opportunities of a Central-European country committed to a single-payer health insurance system. RESULTS: The revenue of CMOs derived from a risk-adjusted capitation. The capitation formula was weighted only by age and sex. The expenditures of the CMOs included all the health expenditures on their patients that occurred in any part of the health care system. The average savings rate for all CMOs for the fiscal years 1999 to 2007 was 4.94%. The highest rates of savings were realized in chronic and acute inpatient care and medical devices. The pilot was discontinued in 2008 without a comprehensive evaluation of the experience. CONCLUSIONS: We can conclude that this pilot had a significant contribution to the modernization of the Hungarian health care system. PMID- 29698150 TI - An Investigation of the Feasibility and Cultural Appropriateness of Stated Preference Methods to Generate Health State Values in the United Arab Emirates. AB - BACKGROUND: No five-level EuroQol five-dimensional questionnaire (EQ-5D-5L) value sets are currently available in the Middle East to inform decision making in the region's health care systems. OBJECTIVES: To test the feasibility of eliciting EQ 5D-5L values from a general public sample in the United Arab Emirates (UAE) using the EuroQol Group's standardized valuation protocol. METHODS: Values were elicited in face-to-face computer-assisted personal interviews. Adult Emiratis were recruited in public places. Respondents completed 10 time trade-off tasks and 7 discrete choice experiment tasks, followed by debriefing questions about their experience of completing the valuation tasks. Descriptive analyses were used to assess the face validity of the data. RESULTS: Two hundred respondents were interviewed in December 2013. The face validity of the data appears to be reasonably high. Mean time trade-off values ranged from 0.81 for the mildest health state (21111) to 0.19 for the worst health state in the EQ-5D-5L descriptive system (55555). Health states were rarely valued as being worse than dead (6.2% of all observations; 10% of all valuations of 55555). In a rationality check discrete choice experiment task whereby a health state (55554) was compared with another that logically dominated it (55211), 99.5% of the respondents chose the dominant option. Most of the respondents stated that their religious beliefs influenced their responses to the valuation tasks. CONCLUSIONS: Our results suggest that it is feasible to generate meaningful health-state values in the UAE, though some adaptation of the methods may be required to improve their acceptability in the UAE (and other countries with predominantly Arab and/or Muslim populations). PMID- 29698151 TI - Economic Impact and Complications of Treated and Untreated Hepatitis C Virus Patients in Turkey. AB - BACKGROUND: According to the Turkish Ministry of Health's guidelines, standard double therapy, a combination of pegylated interferon-alpha and ribavirin, was the only treatment option for patients with hepatitis C virus (HCV) infection until the end of 2011. OBJECTIVE: The primary objective was to compare risk adjusted clinical and economic outcomes between treated and untreated patients with HCV infection. METHODS: Patients with HCV infection were identified from the Turkish National Health Insurance Database (2009-2011) using International Classification of Diseases, 10th Revision, Clinical Modification codes. The first prescription date was designated as the index date. Mortality and hepatocellular carcinoma (HCC) rates and health care costs of treated and untreated patients were compared using propensity score matching. Baseline demographic and clinical factors were controlled in the models. Subgroup analysis was conducted for patient groups with and without a cirrhosis diagnosis. RESULTS: Out of 12,990 patients included in the study, 1,583 were treated for HCV infection. Out of 2,467 patients who had a cirrhosis diagnosis, 231 were treated, whereas out of 10,523 patients without cirrhosis, 1,352 patients were treated. Treated patients were younger, less likely to be diagnosed with comorbid conditions, and less likely to reside in Central or Eastern Anatolia. After adjusting for baseline demographic and clinical factors, mortality (2.27% vs. 5.31%; P < 0.001) and HCC rates (0.69% vs. 1.96%; P < 0.001) were found to be lower for treated patients. Differences were more significant among patients diagnosed with cirrhosis. Treated patients incurred higher risk-adjusted annual costs (?6172 vs. ?1680; P < 0.001), mainly because of pharmaceutical costs (?4918 vs. ?583; P < 0.001). CONCLUSIONS: HCV infection treatment, although costly, significantly reduces mortality and HCC rates in Turkey. PMID- 29698152 TI - Analysis of the Financial Cost of Diabetes Mellitus in Four Cocoa Clinics of Ghana. AB - OBJECTIVE: To estimate the financial cost of managing diabetes mellitus in four Cocoa clinics of Ghana. METHODS: A descriptive cross-sectional study of diabetes management was carried out in the four Cocoa clinics of Ghana from January to December 2009. The "cost-of-illness" approach from the institutional perspective was used. A pretested data extraction form was used to review the medical records of 304 randomly selected diabetic patients. RESULTS: The patients' mean age was 55.4 +/- 9.4 years. The mean annual financial cost of managing one diabetic case at the clinics was estimated to be Ghana cedi (GHS) 540.35 (US $372.65). Service cost constituted 22% of the cost, whereas direct medical cost constituted 78% of the cost. Drug cost was 71% of the financial cost. The cost of hospitalization per patient-day at Cocoa clinics was estimated at GHS 32.78 (US $22.61). The total financial cost of diabetes management was estimated at GHS 420,087.67 (US $289,715.63). This accounted for 8% of the total expenditure for the clinics in the year 2009. The study showed that facility type, type of diabetes, and presence of complication are associated with the cost of diabetes management to Cocoa clinics. CONCLUSIONS: The mean age of detection suggests delay in diagnosis of diabetes mellitus and accompanying complications, which has cost implications. Policy that enhances early detection of diabetes in clinical practice would therefore improve management and reduce costs. The financial cost of managing diabetes can be used to forecast the economic burden of the disease in the area. PMID- 29698153 TI - Health-Related Quality-of-Life Measures: Evidence from Tunisian Population Using the SF-12 Health Survey. AB - OBJECTIVE: To explore reporting differences related to sociodemographic characteristics affecting different health status indicators to assess their impact on the measurement of self-reported health status among the Tunisian population using the Tunisian version of the 12-item Short-Form Health Survey (SF 12). METHODS: Psychometric properties of the SF-12 were validated for a random sample of individuals (N = 3864) aged 18 years and older. The SF-12 summary scores were derived using the standard US algorithm. The principal-component analysis was used to confirm the hypothesized component structure of the SF-12 items. RESULTS: "Known-subgroup" comparisons showed that the SF-12 discriminated well between groups of respondents on the basis of sex, age, education, and socioeconomic status, providing evidence of construct validity. The results suggest the existence of reporting differences related to the sociodemographic characteristics affecting the health status indicators. For a given latent health status, women and oldest people are more likely to report physical activity limitations and chronic diseases. Mental health problems are overreported by divorced people and underreported by the oldest people. In addition, highly educated and socially advantaged people more often report social activities limitations due to the problems of physical and mental health. CONCLUSIONS: The findings showed that the Tunisian version of the SF-12 is a reliable and valid measure, and suggest its potential for measuring health-related quality of life in large-scale studies, specifically when overall physical and mental health are the outcomes of interest instead of the typical eight-scale profile. PMID- 29698154 TI - Price Determinants of the Tendering Process for Pharmaceuticals in the Cyprus Market. AB - BACKGROUND: Tendering has been a promising approach for procuring pharmaceuticals. Significant price reductions have been well documented by several authors. To our knowledge, there are limited data detailing the impact of variables in the tendering process. OBJECTIVES: In this article, our objective was to evaluate the impact of potentially exploratory variables, which included innovation status, total value and volume of sales of each product, health care setting administration (hospital/outpatient), patent status (branded/generic), tendering type, and wholesale price, on price reduction in the tendering process. METHODS: Financial data of public sector sales during 2011 were analyzed. On the basis of these data, we selected 178 medicines with corresponding sales of ?49 million, out of a total market value of ?104 million. Medicines were selected according to volume, value, and therapeutic value across all therapeutic areas. We performed a beta regression for the assessment of impact of variables and applied the same methodology to different subgroups. CONCLUSIONS: The generic status of medicines is statistically significantly associated with a higher price reduction. Tendering type by alternative, high wholesale prices, and high volume are robust estimators for price reduction. Innovation status does not have any effect on price reduction. Outpatient medicines reach lower prices as compared with hospital medicines. A rather unexpected finding is the negative correlation of high sales value with price reduction. These findings will lead to better understanding of the tendering framework, enabling us to further evolve its operational capacity, aiming to generate more savings. Moreover, our study indicates areas in which a more optimized approach is needed. PMID- 29698155 TI - Project Baiterek: A Patient Access Program to Improve Clinical Outcomes and Quality of Life in Children with Type 1 Diabetes in Kazakhstan. AB - Diabetes is a key driver in the rise of noncommunicable diseases globally. It causes expensive and burdensome short- and long-term complications, with both an economic and social impact. In many countries, however, access to care and disease management in type 1 diabetes is suboptimal, increasing the risk for complications. In 2011, Project Baiterek was initiated as a collaborative effort between the Kazakhstan Ministry of Health, industry (Medtronic Plc), local physicians, and the Diabetes Association of the Republic of Kazakhstan to enhance patient access to continuous subcutaneous insulin infusion (CSII) therapy. It was the first countrywide project to provide equity and universal access to insulin pump therapy among children with type 1 diabetes, increasing pump use from zero to two-thirds of this population in less than 3 years. The project also involved instigating longitudinal data collection, and long-term clinical outcomes continue to be monitored. Here, we provide an overview of the clinical, quality of-life, and economic outcomes to date associated with providing CSII therapy to children with type 1 diabetes in Kazakhstan. Initial clinical data show that CSII therapy improved clinical outcomes and quality of life for patients entered into the program and that CSII therapy was cost-effective relative to multiple daily injection therapy. The positive outcomes of Project Baiterek provide a template for similar patient access programs in other settings, and its framework could be adapted to initiatives to change health care infrastructures and standards of care for other noncommunicable diseases. PMID- 29698156 TI - Costs of Hospital Stay in Specialized Diabetic Foot Department in Russia. AB - BACKGROUND: Diabetic foot ulcer (DFU) is considered to be one of the most common and costly diabetic complications. The approach unanimously recommended for patients with DFU is treatment by a multidisciplinary foot care team, which in Russia mainly is limited to few federal and regional hospitals. Currently, financing schemes for medical institutions are changing, thus raising the issue of setting adequate tariffs. OBJECTIVE: To identify the cost of treatment in the specialized diabetic foot department and determinants of variation in cost among individual patients with DFU in the Russian setting from the perspective of a health care organization. METHODS: We collected data on treatment cost per admission to the Diabetic Foot Department of the Endocrinology Scientific Center and information on patients' characteristics derived from medical records. Data on costs were analyzed, and descriptive statistics are reported. A standard multiple regression analysis was performed to identify the main drivers of treatment cost for patients with DFU. RESULTS: The mean treatment cost was ?3051. The mean cost of treatment for patients with DFU was significantly higher than that for diabetic patients without this complication. The most relevant predictors of the costs of treatment for patients with DFU were surgery provided and length of stay in hospital. CONCLUSIONS: The cost for treatment of DFU by a multidisciplinary team in the federal medical institution was substantially higher than basic medical insurance tariff for this disease. Because revascularization procedures appeared to be the main cost driver, our results stress the need for careful implementation of this type of treatment for patients with DFU. PMID- 29698157 TI - Patterns of Care and Treatment Target Success among Persons with Type 2 Diabetes Mellitus in Dubai: A Retrospective Cohort Study. AB - OBJECTIVES: Despite the high prevalence of type 2 diabetes mellitus (T2DM), few data exist describing its management in Dubai. This study characterized the treatment and estimated levels of glycemic, lipid, and blood pressure control among a sample with T2DM at a large Dubai Hospital. METHODS: This retrospective cohort study systematically sampled charts from adults seeking care for T2DM from October 2009 to March 2010 until the target (N = 250) was reached. Data on patient characteristics, pharmacotherapy, complications, and laboratory testing were abstracted until September 2011. The frequency of treatments and modifications over the period was calculated, and measures of glycosylated hemoglobin A1c, low-density lipoprotein, and blood pressure control were compared with guideline targets. Frequencies of complications were compared according to treatment type. RESULTS: One-third of the cohort comprised men, and the mean age was 58 years. At enrolment, the mean time from T2DM diagnosis was nearly 15 years and 74% had received insulin. During the study period, the most common regimens were insulin + oral combinations (55%) and oral combination therapy (39%). Overall, 67% received any insulin therapy during the study; and by study end, 78% had received insulin at any time. At the most recent assessment, guideline targets for glycosylated hemoglobin A1c, blood pressure, and low-density lipoprotein were met by 23%, 29%, and 71%, respectively. Complications were more frequent among those treated with combination or insulin therapies. CONCLUSIONS: This study provides baseline data from Dubai for future comparisons of the effectiveness of new treatments, and to better understand the humanistic and economic burden of T2DM and its complications. PMID- 29698158 TI - A Systematic Review of Community Pharmacists' Interventions in Reducing Major Risk Factors for Cardiovascular Disease. AB - OBJECTIVES: To conduct a systematic literature review and assess the effectiveness of community pharmacists' interventions in reducing major risk factors for cardiovascular diseases. METHODS: A comprehensive literature search from 2000 onwards was performed using MEDLINE (1946 to June 4, 2013), EMBASE (1947 to present), CINAHL, and Cochrane Library. The gray literature was also searched. Studies were classified as diabetes, hypertension, dyslipidemia, and tobacco dependence. Data abstracted from the articles included study design/participants, study duration, key components of intervention, primary outcome, and key findings. Study quality was assessed using a checklist appropriate to the study design. RESULTS: A total of 1020 citations were initially identified, with 27 meeting inclusion criteria. Eight studies were randomized controlled trials, five were cluster randomized trials, two were randomized before-after design studies, five were nonrandomized controlled before after design studies, and seven were uncontrolled before-after design studies. Interventions focused on diabetes (n = 8), hypertension (n = 9), dyslipidemia (n = 7), and tobacco dependence (n = 3). Effect sizes ranged from 7.8 to 17.7 mm Hg and from 0.2% to 2.2% reductions in systolic blood pressure and hemoglobin A1c, respectively, while reductions in total cholesterol ranged from 18.2 to 27.1 mg/dl. Study quality was generally poor. CONCLUSIONS: Available evidence suggests a potential for substantial benefit in diabetes and hypertension but clinical benefits in lipid management remain unclear. The true effect of interventions is uncertain due to poor study quality, inconsistent results, and potential for publication bias. Further well-designed studies are needed to determine the true impact of community pharmacists' interventions in reducing major risk factors for cardiovascular disease. PMID- 29698159 TI - Cost-Minimization Analysis of Direct Cost of Sevelamer Carbonate and Lanthanum Carbonate in the Treatment of Patients with Chronic Kidney Disease Not on Dialysis in Bulgaria. AB - BACKGROUND: Hyperphosphatemia is associated with significant pathophysiology in chronic kidney disease (CKD). Control of hyperphosphatemia in patients with stage 3 to 5D CKD is now regarded as a high priority. OBJECTIVE: The primary purpose of this study was to perform an economic analysis of the newly available treatments sevelamer carbonate (SC) and lanthanum carbonate (LC) for the treatment of hyperphosphatemia in patients not on dialysis in Bulgaria. METHODS: Both treatment options demonstrate equal efficacy in controlling hyperphosphatemia, as well as having a similar safety profile in regard to adverse effects. To differentiate between them, a cost-minimization analysis was performed. A time period of 4 years was chosen to perform a budget impact analysis. The robustness of the results was tested through sensitivity analysis using Tornado diagrams. RESULTS: The estimated cost per patient per year with SC and LC would be ?1441.75 and ?1569.50, respectively, at the weighted average daily dose regimen of 4000 mg SC and 2000 mg LC, whereas the cost would be ?2306.80 and ?2354.25 for 6400 mg SC and 3000 mg LC, respectively. Expected cost savings (discounted) for the 4-year period of the analysis can reach between ?1,363,601 and ?2,727,201 at 4000 mg SC and 2000 mg LC dose regimen, whereas these can reach between ?506,480 and ?1,012,961 at 6400 mg SC and 3000 mg LC, respectively. CONCLUSIONS: The equal efficacy, similar adverse effect profile, and lower cost of SC when used for the treatment of hyperphosphatemia in patients with CKD not on dialysis should make it a preferred alternative. PMID- 29698160 TI - ? AB - INTRODUCTION: Ondansetron reduces hospitalization rates for diarrhea and vomiting in children, but is not yet routinely used. OBJECTIVE: To estimate from a social perspective the relative cost-effectiveness of ondansetron for the treatment of vomiting in children with gastroenteritis and at risk of dehydration in Colombia. METHODS: Cost-effectiveness analysis from a social perspective, including direct medical costs and costs for caregivers. With a decision tree we compared costs and health outcomes of usual treatment without antiemetic to usual treatment plus ondansetron in children under 5 years with gastroenteritis and vomiting. Effectiveness of intervention was measured as reduction in hospitalization rates, and the time horizon of the model was the episode. Probabilities were obtained from clinical trials and systematic reviews, measurement of resources use was based on protocols and expert opinions, while unit costs were obtained from Colombian tariff manuals. We performed a survey to estimate indirect costs for caregivers (n=81) that included questions about wage loss, transportation, meals expenditures and other out-of-pocket payments. Deterministic and probabilistic sensitivity analyses were performed. RESULTS: Usual treatment plus ondansetron is a dominant strategy compared to usual treatment without antiemetic yielding fewer hospitalizations and saving $44.562 Colombian pesos (23,98USD) per episode. Ondansetron was dominant in 98,91% of simulations of the probabilistic analysis. CONCLUSIONS: Ondansetron is a dominant intervention that reduces hospitalization rates and costs for health system and caregivers. We recommend assessing the inclusion of this drug in the Colombian Health Benefit Plan for the treatment of gastroenteritis in children under 5 years. PMID- 29698161 TI - ? AB - OBJECTIVE: Chemotherapy is essential for the cancer treatment. Usually, in the preparation process of the chemotherapy, part of the medication must be discarded to achieve the dose prescribed by the doctor. The dose of medication discarded results in toxic waste production. The objective is to analyze the chemotherapy waste in the preparation process of the drug. METHODS: It has been conducted a cross-sectional observational study. The study data were obtained from chemotherapy's requests by oncologists linked to a health insurance plan. It has been calculated the dose of chemotherapy waste in each application, considering the dose prescribed by the doctor and the drug dosage form. RESULTS: It were analyzed 1,289 prescriptions for intravenous chemotherapy of 106 users with cancer. There were a total of 63,824mg of chemotherapy residue produced, with an average of 602mg by user and 49mg by application. The average percentage of chemotherapy waste was 11.96%, between 0 to 50%. CONCLUSION: The number of applications and the dose used in the treatment protocol, the commercial dosage forms and the no use of dose rounding of medication to the nearest vial size were factors related to increased production of chemotherapy waste. PMID- 29698162 TI - Comparacion de costos y resultados sanitarios de usuarios con neumonia adquirida en comunidad atendidos en domicilio o en hospitalizacion tradicional: estudio exploratorio de 40 casos. AB - INTRODUCTION: Economic evaluations of health technologies and health interventions are considered in many countries as the fourth barrier for adopting new services or drugs; followed by safety, efficacy and quality. The validity and reliability of the results will depend on the perspective of the study, timeframe of the analysis, discount rate, the model used and the costs involved. OBJECTIVES: This study aims to assess the cost effectiveness of home care treatment in users with diagnosis of uncomplicated community acquired pneumonia compared with traditional hospitalization at inpatient wards. The hypothesis is that home based care would be more cost effective compared to traditional hospitalization. METHODS: The study perspective was from the health provider. Microcosting was used to determine the costs of both treatment modalities in a sample of 20 users treated with each modality during 2013 at main Hospitals of Coquimbo Region, Chile. RESULTS: The main outcome of effectiveness was the number of inpatient care days saved. Additionally, number of infections associated to health care (IAHC) and type of discharge were measured. CONCLUSIONS: The study concludes that there is a better cost effectiveness relationship for the home care modality, with fewer days of treatment, at lower costs and without risk of IAHC. However, further studies are needed in order to achieve accurate results. PMID- 29698163 TI - Hospital Variation in Cesarean Delivery: A Multilevel Analysis. AB - OBJECTIVES: To assess the issue of hospital variations in Colombia and to contribute to the methodology on health care variations by using a model that clusters the variance between hospitals while accounting for individual-level reimbursement rates and objective health-status variables. METHODS: We used data on all births (N = 11,954) taking place in a contributory-regimen insurer network in Colombia during 2007. A multilevel logistic regression model was used to account for the share of unexplained variance between hospitals. In addition, an alternative variance decomposition specification was further carried out to measure the proportion of such unexplained variance due to the region effect. RESULTS: Hospitals account for 20% of the variation in performing cesarean sections, whereas region explains only one-third of such variance. Variables accounting for preferences on the demand side as well as reimbursement rates are found to predict the probability of performing cesarean sections. CONCLUSIONS: Hospital variations explain large variances within a single-payer's network. Because this insurer company is highly regarded in terms of performance and finance, these results might provide a lower bound for the scale of hospital variation in the Colombian health care market. Such lower bound provides guidance on the relevance of this issue for Colombia. Some factors such as demand-side preferences and physician reimbursement rates increase variations in health care even within a single-payer network. This is a source of inefficiencies, threatening the quality of health care and financial sustainability. The proposed methodology should be considered in further research on health care variations. PMID- 29698164 TI - Equity in access to high cost drugs in Uruguay. AB - OBJECTIVE: The aim of this study was to determine the equity in access to high cost oncology medicines reimbursed by the Uruguayan National Health System. Also, were determined the causes of access inequities. METHODS: Different levels of access were determined by crossing epidemiological and reimbursement data with geographical distribution and number of Health System users. Possible causes of inequities were determined and weighted by Delphi technique. RESULTS: Access of patients assisted in the public sector to bevacizumab for metastatic colorectal cancer, rituximab for the treatment of non-Hodgkin lymphoma and trastuzumab for advanced HER2+ breast cancer, appears to be lower compared to patients assisted in private sector.Regarding rituximab for the treatment of non-Hodgkin lymphoma and trastuzumab for advanced HER2+ breast cancer, the results seem to show less access for patients residing outside the south region compared to those living in the south region.The main barriers to get reimbursement for patients living outside southern region are the access to pathological anatomy studies, imaging and other clinical analysis. Late diagnosis appears to be the main hurdles in access to these anti-cancer drugs, for patients assisted in the public sector. CONCLUSIONS: Equitable access to high cost drugs reimbursed by the National Health System requires policy decisions to address this issue. PMID- 29698165 TI - Economic Costs Analysis of the Avoidable Mortality in Colombia 1998-2011. AB - OBJECTIVE: To estimate the economic costs of avoidable mortality (AM) in Colombia during the period 1998 to 2011, with the human capital perspective valuing the productivity lost. METHODS: The information of cases of avoidable death was identified from the Colombian official general mortality database, and we estimated the potential productivity years of life lost, assuming a productive life span between 18 years and 57 years and 18 years and 62 years in women and men, respectively. Two scenarios were built: lower loss with the minimum wage, and higher loss with the per capita gross domestic product. Total costs for the period were reported by sex and health event. Average cost per 1000 people was also estimated. All costs were adjusted and reported in 2012 US dollars. RESULTS: Sixty-eight percent of the total AM in Colombia during the period 1998 to 2011 occurred during or before the productivity age. The total AM costs were estimated to range between US $80.5 million and US $150.4 million. Higher costs of AM were incurred in men. Events from the injuries group caused the higher productivity lost. CONCLUSIONS: All the avoidable deaths in Colombia have a huge economic impact from the productivity lost perspective, equivalent to between 1.6% and 3.0% of the annual gross domestic product. The cost analyses in public health are an additional input for decision making and prioritization of intervention. PMID- 29698166 TI - Brief Latin American Update: One More ViHRI Annual Issue, and Another Exciting Biennial ISPOR Conference. PMID- 29698167 TI - Evaluating the Long-Term Health Economic Implications of Improving the Proportion of Patients with Type 2 Diabetes Meeting Treatment Targets in Mexico. AB - OBJECTIVES: To analyze the health economic implications of increasing the proportion of patients with type 2 diabetes meeting treatment targets for glycemia, blood pressure, and serum lipid levels in Mexico. METHODS: Complication rates, life expectancy, quality-adjusted life expectancy, and costs were projected over patient lifetimes using a published and validated diabetes model (with outcomes discounted at 5% annually). Baseline cohort characteristics were derived from the Mexican cohort of A1chieve. Scenarios in which 20% to 80% of the patients achieved glycemic targets (glycosylated hemoglobin [HbA1c] level of 7%) only, or blood pressure and lipid targets (based on international guidelines) in addition to glycemic targets were compared with current standard of care. RESULTS: Increasing the proportion of patients meeting Hb A1c targets was projected to increase mean life expectancy and quality-adjusted life expectancy by up to 0.60 years and 0.34 quality-adjusted life-years over current care. When patients achieved all treatment targets, clinical benefits were greater than when only the Hb A1c level was controlled. Increasing the proportion of patients reaching the glycemic target was projected to lead to cost savings over conventional treatment, reducing mean costs by up to Mexican pesos 42,389 (US $3314). Surprisingly, bringing patients to other targets, as well as the Hb A1c target, did not result in greater cost savings. This was as a result of the increased life expectancy in these simulations, leading to greater costs in the final years (survival paradox). CONCLUSIONS: Increasing the proportion of patients achieving treatment targets resulted in improved clinical outcomes and cost savings from a health care payer perspective in Mexico. PMID- 29698168 TI - Results of the Inclusion of New Medications in the Obligatory Health System Plan in Colombia, 2012-2013. AB - BACKGROUND: The Colombian health care system has had a plan with limited benefits, but since 2012, 57 drugs have been added to this plan. OBJECTIVES: The objective of this article was to describe the trends of utilization and costs of medications covered by the Agreement 029/2011 and compare them with those that were contained in the benefits plan. METHODS: This descriptive study involved a group of 3.8 million people affiliated with the Colombian health care system, in 110 cities from July 2011 until June 2013. The variables were new medications that were included, comparing them with homologous medications that were already in the plan, age, sex, dispensed quantities, and monthly billing. The study established the defined daily dosage per thousand inhabitants per day, cost per thousand inhabitants per day, cost per capita, and the rate of adoption or replacement medicines. RESULTS: The growth in the consumption of new medications was 830.0%. The defined daily dosage per thousand inhabitants per day grew from 4.3 to 42.9, with an increase of 905.5%. Medications with the highest growth were losartan/hydrochlorothiazide (15,723%), esomeprazole (4193%), atorvastatin (1402%), and sertraline (298%). There was an increase of US $16.40 in the cost per thousand inhabitants per day, which is equivalent to an increase of 61.7% and represents a rise of US $0.49 in cost per capita per month. CONCLUSIONS: The consumption behavior of new medications and the economic implications for Colombia can be demonstrated. In particular, the growth in the consumption of medications for chronic diseases can be seen, which would represent an increase of US $22.6 million per month to the entire population of the country. PMID- 29698169 TI - Cost-Effectiveness and Cost-Utility Analyses of Dabigatran Compared with Warfarin in Patients with Nonvalvular Atrial Fibrillation and Risk Factors for Stroke and Systemic Embolism within Brazilian Private and Public Health Care Systems Perspectives. AB - OBJECTIVE: To analyze the cost-effectiveness and cost-utility of dabigatran compared with warfarin in patients with nonvalvular atrial fibrillation with moderate to high risk of ischemic stroke or systemic embolism and eligible for treatment with anticoagulants. METHODS: Markov-based economic analysis was performed to estimate treatment costs and outcomes. Epidemiological and efficacy data were determined after a critical revision of the medical literature. Unit costs were taken from Brazilian official databases. Only direct medical costs were covered. Costs and benefits were discounted at a rate of 5% per year. Outcomes were expressed as life-year (LY) and quality-adjusted life-year (QALY). RESULTS: Dabigatran use is cost-effective in terms of LY and QALY considering a willingness-to-pay threshold of 3 times gross domestic product per capita of 2010 (Brazilian real 57,048/US $24,275.74) per LY and QALY saved in both analyzed perspectives (private and public health care systems). CONCLUSIONS: Dabigatran use improves patient survival and quality of life compared with warfarin. This represents the best therapeutic option in terms of cost and effectiveness in the prevention of ischemic stroke and systemic embolism in patients with nonvalvular atrial fibrillation. PMID- 29698170 TI - ? AB - Bioequivalence has become a standard request for drug commercialization in most high income countries, and significant efforts have been made to implement it in many low and middle income countries. In Chile, the requirement of bioequivalency has been gradually implemented since 2008, associated to a communicational campaign to inform the general population about its scope and importance. The objective of this study is to estimate the effect of the implementation of bioequivalence on the prices of products that have been affected by this policy. We conducted a difference in difference study in a set of 30 chronic use drugs, selected from the eighty clinical guidelines published by the Chilean Ministry of Health. The effect was assessed according to the date when the corresponding ministerial decree was published. A control drugs was selected for each analyzed medication in order to estimate the effect of implementation independently of other factors of the market. We identified three groups of drugs: (i) those which experimented a significant increment of price due to bioequivalence; (ii) those where prices decreased; and (iii) those where prices did not (significantly changed) decrease. A sensitivity analysis complemented the study results and identified the significant effect of the date when the bioequivalence was implemented. It is concluded that the implementation of bioequivalence in Chile had a significant effect on prices of some medications. However, the magnitude and direction of such effect depends on the characteristics of the particular market defined by each drug. PMID- 29698171 TI - Patient-Reported Outcomes in Latin America: Implementation in Research and Role in Emerging HTA Systems. AB - BACKGROUND: Patient-reported outcomes (PROs) are increasingly used to demonstrate the value of interventions and support health technology assessment (HTA). OBJECTIVE: The objective of this work was to analyze trends regarding PROs in Latin America (LatAm), highlight challenges in the application of PROs in this region, and suggest solutions. METHODS: A team of researchers with expertise in PROs conducted a nonsystematic PubMed literature search pertaining to the use of PROs in LatAm. The experts also drew on their experience working with PROs to assess the application of PROs in LatAm. RESULTS: The literature search yielded more than 4000 publications, with an increasing publication rate in recent years. PROs are being used in LatAm in various study types: instrument validation, phase III international clinical trials, health service research. A large Inter American Development Bank study demonstrates the growing importance of PROs in the region. The growth in local value sets for the EuroQol five-dimensional questionnaire in LatAm reflects the regional emergence of HTA systems. Operational challenges relate to ensuring the use of good-quality questionnaires that, at a minimum, have undergone appropriate cultural adaptation and ideally have established psychometric properties. CONCLUSIONS: PROs are increasingly important in LatAm. Future efforts should aim to strengthen the operational and research infrastructure around PROs in the region. Innovation should be encouraged, including studying alternative methods of eliciting health utilities for economic evaluation. A wider scope around PRO uses for decision making by HTA bodies is an international trend with potential positive prospects in LatAm. PMID- 29698172 TI - Cost-effectiveness Analysis of Viscosupplementation versus Conventional Supportive Therapy for Knee Osteoarthritis in Colombia. AB - BACKGROUND: Treatment goals for knee osteoarthritis (OA) include preservation of mobility, control of pain, and delaying total knee replacement (TKR). OBJECTIVE: To estimate the cost-effectiveness of viscosupplementation (hylan G-F 20) alone compared with conventional supportive therapy (CST) in the treatment of knee OA in Colombia. METHODS: Microsimulation in patients with knee OA, modeling of clinical outcomes (disease progression, symptom improvement, TKR), and estimation of associated costs were performed (drugs, diagnostic tests, procedures, and hospitalizations). The probabilities for disease progression and clinical events were correlated with patients' characteristics. Clinical outcome information was obtained from the literature. The costs were drawn from institutional databases from health maintenance organizations and the Colombian standard tariffs handbook (ISS 2001. Agreement No. 256 of 2001. Tariffs for the health promoter Social Security EPS-ISS. Social Insurance Board of Directors. December 19, 2001). Sensitivity analyses were performed for costs and transition probabilities. RESULTS: Monte-Carlo simulation for 1000 patients with knee OA showed that viscosupplementation with hylan G-F 20 delayed the occurrence of TKR by 3 years compared with CST. Western Ontario and McMaster Universities Arthritis Index scores indicate improvement in symptoms and function with hylan G-F 20. The incremental cost-effectiveness ratio for viscosupplementation is dominant, with reduction of US $576 in treatment cost in favor of hylan G-F 20, with more cost effectiveness per quality-adjusted life-year during the first 10 years of treatment compared with CST. CONCLUSIONS: The results of mathematical simulation indicate that in comparison to conventional support therapies, viscosupplementation with hylan G-F 20 improved disease symptoms, joint function, and quality of life, reduced direct treatment costs, delayed TKR by 3 years, and was cost-effective in Colombia. PMID- 29698173 TI - Analyses of Budget Impact Considering the Use of the Picture Archiving and Communication System. AB - OBJECTIVE: To analyze the budget impact of using the picture archiving and communication system (PACS) in comparison to the screen/film system. METHODS: The budget impact analysis was conducted on the basis of registry data from the Clinics Hospital of the Faculty of Medicine, University of Sao Paulo, Ribeirao Preto, Brazil. The budget impacts were compared between the PACS, with high- and low-cost PACS architectures, and the screen/film system by considering reference and alternative scenarios over the course of 5 years. RESULTS: The budget impact associated with the use of PACS was lower than that associated with the use of the screen/film system in all the evaluated scenarios. The low-cost PACS architecture (mini-PACS) had an even lower budget impact, especially in the scenario in which a simulation of lower numbers of medical examinations was performed. CONCLUSIONS: The screen/film system had a high budget impact in all the scenarios evaluated, wherein its costs were higher than the available budget. In contrast, the PACS (high- and low-cost architectures) showed a budget impact that allowed for savings in resources, especially the mini-PACS. Therefore, we recommend the implementation and use of the PACS in health services with any volume of examinations performed. PMID- 29698174 TI - Epidemiology of Malaria in Latin America and the Caribbean from 1990 to 2009: Systematic Review and Meta-Analysis. AB - OBJECTIVE: The objective of this study was to evaluate the burden of malaria in Latin America and the Caribbean countries through a systematic review and meta analysis of published literature, gray literature, and information from countries' public health authorities for the period 1990 to 2009. METHODS: The random-effects meta-analysis of the prospective studies, carried out in very highly endemic areas, showed an annual incidence rate of 409.0 malaria episodes/1000 person-years (95% confidence interval [CI] 263.1-554.9), considering all ages, which was 40-fold the one estimated from areas with passive surveillance only. RESULTS: Overall, the most prevalent species was Plasmodium vivax (77.5%; 95% CI 75.6-79.4) followed by Plasmodium falciparum (20.8%; 95% CI 19.0-22.6) and Plasmodium malariae (0.08%; 95% CI 0.07-0.010). Data from regional ministries of health yielded an estimated pooled crude annual mortality rate of 6 deaths/100,000 people, mainly associated with P. falciparum. CONCLUSION: This study represents the first systematic review of the burden of malaria in Latin America and the Caribbean, with data from 21 countries. PMID- 29698175 TI - Cost-Effectiveness of Canagliflozin versus Sitagliptin as Add-on to Metformin in Patients with Type 2 Diabetes Mellitus in Mexico. AB - OBJECTIVE: To assess the cost-effectiveness of canagliflozin versus sitagliptin for the treatment of type 2 diabetes mellitus (T2DM) as an add-on to metformin in Mexico. METHODS: A validated model (Economic and Health Outcomes [ECHO]-T2DM) was used to estimate the cost-effectiveness of canagliflozin 300 or 100 mg versus sitagliptin 100 mg in patients with T2DM inadequately controlled on metformin monotherapy. Data from a head-to-head, phase III clinical trial, including patients' baseline demographic characteristics, biomarker values, and treatment effects, were used to simulate outcomes and resource use over 20 years from the perspective of the Mexican health care system. Costs of complications and adverse events were tailored to the Mexican setting and discounted at 5%. Cost effectiveness was assessed using willingness-to-pay thresholds equivalent to 1 times the gross domestic product per capita (locally perceived to be "very cost effective") and 3 times the gross domestic product per capita (locally perceived to be "cost-effective") on the basis of recommendations of the Mexican government and the World Health Organization. RESULTS: Owing primarily to better glycated hemoglobin (HbA1c), body weight, and systolic blood pressure values, canagliflozin 300 and 100 mg were associated with an incremental benefit of 0.16 and 0.06 quality-adjusted life-years (QALYs) versus sitagliptin 100 mg, respectively, over 20 years. The mean differences in cost for canagliflozin 300 and 100 mg versus sitagliptin 100 mg were Mexican pesos (MXP) 1797 (US $134) and MXP 7262 (US $540), respectively, resulting in a cost per QALY gained of MXP 11,210 (US $834) and MXP 128,883 (US $9590), respectively. Both of these cost effectiveness ratios are below the very cost-effective willingness-to-pay threshold in Mexico. The general finding that canagliflozin is cost-effective versus sitagliptin in Mexico was supported by sensitivity analyses. CONCLUSION: In Mexico, both doses of canagliflozin are likely to be cost-effective versus sitagliptin in patients with T2DM who have inadequate glucose control on metformin, primarily because of better biomarker control and higher QALYs. PMID- 29698176 TI - Costing Dengue Fever Cases and Outbreaks: Recommendations from a Costing Dengue Working Group in the Americas. AB - OBJECTIVES: The overall aim of this article was to present a step-by-step guideline for determining the costs associated with dengue in dengue-endemic countries of the Latin American and the Caribbean region and to illustrate how each of these steps can be applied in dengue costing studies. METHODS: An expert panel was convened to develop standards for costing dengue so that over the next decade, decision makers will have access to improved information on the true cost of dengue in endemic countries of the Latin American and the Caribbean region. We described the outcome of the expert panel meeting, which resulted in the provision of a step-by-step dengue costing guideline that aims to provide direction to planners and program managers on how to estimate dengue economic burden studies, and provide a discussion forum of the methods used to cost dengue fever cases and outbreaks in a manner that should be accessible to persons with some familiarity with a cost study. RESULTS: The guideline includes nine sequential steps: 1) definition of the scope of the study; 2) identification of the target population; 3) description of the study perspective; 4) definition of the time horizon; 5) calculation of the sample size; 6) definition of the unit of analysis; 7) identification of the cost items; 8) measurement and valuation of the cost items; and 9) handling of uncertainty. The trade-off between accurate, patient-level cost estimates and data availability constraints is discussed. CONCLUSIONS: The current guideline is the result of constructive collaboration among a multidisciplinary research team to better ascertain the true economic burden of dengue across countries of the region. PMID- 29698177 TI - Cost-Effectiveness of Radiofrequency Ablation for Supraventricular Tachycardia in Guatemala: Patient Outcomes and Economic Analysis from a Low- to Middle-Income Country. AB - BACKGROUND: Radiofrequency ablation (RFA) is an established but expensive treatment alternative for many forms of supraventricular tachycardia (SVT). Currently, no studies exist on the cost-effectiveness of RFA compared with that of medical treatment (MT) in adult Latin American population. METHODS: Between 2007 and 2012, we identified 103 adults who underwent RFA for SVT in the National Unit of Cardiovascular Surgery (Unidad Nacional de Cirugia Cardiovascular [UNICAR]) in Guatemala. A decision tree was developed with all clinical outcome parameter estimates obtained from the Adult Electrophysiology Clinic. Cost data were obtained from UNICAR's administration. A cost-effectiveness analysis that evaluated costs and quality-adjusted life-years to compare interventions in terms of their incremental cost-effectiveness ratios was conducted. RESULTS: The first RFA had an 83% success rate, and a cumulative success rate of 94% was achieved with a second. The cost of the RFA procedure itself was $5411. RFA gained 1.46 quality-adjusted life-years and saved $7993 compared with MT for patients with SVT. This demonstrates that in Guatemala, RFA dominates MT in the management of SVT. Using assumptions based largely on the outcomes in UNICAR, we found that RFA is highly cost-effective. This is a consistent finding, even after varying assumptions about efficacy, complication rates, and quality of life. CONCLUSIONS: RFA dominates MT by improving quality of life and reducing expenditures when used to treat patients with severe symptoms of SVT in Guatemala. The robustness of these finding to variations in parameter assumptions suggests that these findings may hold in other similar settings. PMID- 29698178 TI - Medical Costs Related to Enzyme Replacement Therapy for Mucopolysaccharidosis Types I, II, and VI in Brazil: A Multicenter Study. AB - BACKGROUND: Mucopolysaccharidosis (MPS) type I (MPS I), MPS type II (MPS II), and MPS type VI (MPS VI) are lysosomal storage disorders for which enzyme replacement therapy (ERT) is available. OBJECTIVE: The objective of this study was to evaluate the frequency of medical interventions in a cohort of patients with MPS I, II, and VI on ERT to estimate the impact of direct medical costs associated with the treatment of MPS and compare its frequency with that observed among patients not on ERT. METHODS: This was a multicenter study using a retrospective design including a convenience sampling of Brazilian patients with MPS I, II, and VI. Data on the number and type of medical appointments, hospital admissions, medications used, and surgical procedures performed per patient were obtained through a review of medical records, as were data on ERT. These variables were then compared between patients undergoing ERT and those not on ERT. RESULTS: Thirty-four patients (27 on ERT) were included in the study. Overall, between group differences were found in median absolute frequencies of hospital admissions and surgical procedures per year, both of which were higher in the non ERT group. Furthermore, we observed a high rate of failure to record medication dosage regimens. CONCLUSIONS: Our findings suggest that Brazilian patients with MPS I, II, and VI who are on ERT undergo fewer medical interventions, which can lead to a reduction in direct medical costs to the publicly funded health care system. The cost of ERT, however, is extremely high and probably outweighs this reduction. PMID- 29698179 TI - Antiepileptic Drugs and Quality of Life in Patients with Epilepsy: A Tertiary Care Hospital-Based Study. AB - OBJECTIVES: The present study evaluated patterns of the use of antiepileptic drugs (AEDs) and their impact on quality of life (QOL) in patients with epilepsy. METHODS: In this cross-sectional study, patients with epilepsy (age >18 years) receiving AEDs for at least 1 year were enrolled. Demographic, clinical, and treatment parameters were recorded. QOL was measured using the modified Quality of Life in Epilepsy Inventory-10 (QOLIE-10) questionnaire for epilepsy. RESULTS: Of 200 patients, 53.5% were males and 60% were younger than 30 years. Seizures were predominantly partial (58%) and of idiopathic origin (61%). Monotherapy to polytherapy ratio was 1:1, with 70% of the patients on one new AED. Clobazam (37%) was used most frequently followed by phenytoin (25.5%), levetiracetam (23%), oxcarbazepine (21.5%), and carbamazepine (21%). Patients on polytherapy experienced a significantly more number of adverse drug reactions than did those on monotherapy (P < 0.0001). The mean QOLIE-10 score was 74.58 +/- 20.60. There was no significant difference in seizure frequency, number of adverse drug reactions, and QOLIE-10 score among patients receiving old and new AEDs. Multiple linear regression analysis identified increased seizure frequency (standardized beta -0.157; P = 0.003), more number of AEDs (standardized beta 0.107; P = 0.05) as well as adverse drug reactions (standardized beta -0.692; P = 0.0001) as significant predictors of poor QOL. CONCLUSIONS: Appropriate tools for early detection, selection of rational and safer AED treatment options, and regular monitoring for adverse effects play a crucial role in achieving seizure freedom and optimal QOL in patients with epilepsy. PMID- 29698180 TI - Supplier-Induced Demand for Chronic Disease Care in Japan: Multilevel Analysis of the Association between Physician Density and Physician-Patient Encounter Frequency. AB - BACKGROUND: There are currently large regional variations in the frequency of physician-patient encounters for the treatment of chronic lifestyle diseases in Japan. These variations may be influenced by competition among physicians, and supplier-induced demand (SID) in health care can occur when physicians manipulate their patients' demand for medical services to increase the use of health care. OBJECTIVES: To analyze patient data to investigate the presence of SID in the treatment of chronic diseases at the regional level in Japan. METHODS: We tested the hypothesis that clinic and hospital physicians in areas of high competition (high physician density) are more likely to recommend a sooner follow-up consultation than do those in areas of lower competition (lower physician density). Using random-effects multilevel models, we analyzed patient survey data and administrative claims data to estimate the effects of physician density on encounter frequency and medical charges. In the analysis of claims data, we used the mean drug administration period as a proxy for the frequency of physician initiated encounters. RESULTS: Our analysis showed that encounter frequency was significantly associated with clinic physician density, but there were no consistent associations with hospital physician density. Increases in physician density were significantly associated with increases in both clinic and hospital medical charges, and these associations were independent from encounter frequency. CONCLUSIONS: The results of our study indicate the presence of SID in Japan. Further studies should investigate whether more frequent physician-patient encounters provide clinical advantages to patients. PMID- 29698181 TI - Mapping and Analyzing Stakeholders in China's Essential Drug System by Using a Circular Model: Who We Should Deal with Next? AB - OBJECTIVES: To predict the prospects of the essential drug system by using the Stakeholder Impact Index (SII) and evaluate the current performance of each main stakeholder and suggested dangerous stakeholders and dormant stakeholders. METHODS: A Delphi method was used, involving 36 experts with experience in implementation and evaluation of the essential drug policy, to construct the circular model as well as evaluate the performance of each stakeholder. RESULTS: The central government was a dominant stakeholder of the whole essential drug system. The provincial governments were definitive stakeholders, whereas local governments and medical institutions were dependent stakeholders. Furthermore, media and drug stores were dormant stakeholders and pharmaceutical manufacturers and delivery enterprises were dangerous stakeholders. Patients, community residents, and medical insurance programs were discretionary stakeholders. The SII for the essential drug system was positive (SIIproj* = 2.72). CONCLUSIONS: The overall anticipation of the essential drug policy is optimistic. Letting definitive stakeholders (provincial governments) having more autonomy can efficiently accelerate the pace of implementation of the essential drug policy in the current situation. Central government, however, also needs to construct an experience exchange platform with the aim of building versatile methods for running the essential drug system in all provinces. Pharmaceutical manufacturers and delivery enterprises were dangerous stakeholders for the essential drug policy. Because of their potential threat to the implementation of the policy, the central government should motivate them to support the construction of the essential drug system spontaneously. In that case, provincial governments need to construct a fair, balanced, and self-stabilized bidding platform. PMID- 29698182 TI - Economic Burden of Community-Acquired Pneumonia among Adults in the Philippines: Its Equity and Policy Implications in the Case Rate Payments of the Philippine Health Insurance Corporation. AB - OBJECTIVES: To determine 1) the cost of hospitalization, the 1-week postdischarge cost, the total cost, and the economic burden of community-acquired pneumonia among patients aged 19 years or older in the Philippines and 2) the difference between the estimated costs and the Philippine Health Insurance Corporation (PhilHealth) pneumonia case rate payments. METHODS: The study involved two tertiary private hospitals in the Philippines. Using the societal perspective, both health care and non-health care costs were determined. A base-case analysis and sensitivity analyses were performed, and the economic burden of pneumonia was determined using PhilHealth claims. RESULTS: The estimated cost of hospitalization for community-acquired pneumonia-moderate risk (CAP-MR) ranged from Philippine peso (PHP) 36,153 to 113,633 (US $852-2678) and its 1-week postdischarge cost ranged from PHP1450 to 8800 (US $34-207). The cost of hospitalization for community-acquired pneumonia-high risk (CAP-HR) ranged from PHP104,544 to 249,695 (US $2464-5885) and PHP101,248 to 243, 495 (US $2386-5739) using invasive and noninvasive ventilation, respectively. The postdischarge cost for CAP-HR ranged from PHP1716 to 10,529 (US $40-248). If only health care cost was considered, the cost ranged from PHP24,403 to 89,433 for CAP-MR and PHP92,848 to 213,395 for CAP-HR. The present PhilHealth case rate payments are PHP15,000 (US $354) and PHP32,000 (US $754) for CAP-MR and CAP-HR, respectively. Based on the number of PhilHealth claims for 2012 and the estimated health care cost, the economic burden of pneumonia in 2012 was PHP8.48 billion for CAP-MR and PHP643.76 million for CAP-HR. CONCLUSIONS: The estimated health care cost of hospitalization is markedly higher than the PhilHealth case rate payments. As per the study results, the economic burden of pneumonia is, thus, significantly higher than PhilHealth estimates. PMID- 29698183 TI - Reimbursement Coverage and Pricing Systems for Single-Use Devices in Asia Pacific: Japan, Taiwan, Korea, and Australia Compared. AB - In Asia-Pacific countries, as elsewhere, medical device expenditures account for only between 3% and 6% of total health care spending per capita. Yet the contribution of medical devices is essential to delivering improved clinical and economic benefits for patients and health care systems, respectively. We briefly report a selective overview of reimbursement coverage and pricing systems for single-use devices (SUDs) in Japan, Taiwan, Korea, and Australia, major Asia Pacific markets with diverse health care systems but similar challenges. Generally speaking, all four health systems are similar in their framework for managing the coverage and reimbursement of SUDs, which are usually bundled into the overall fee designated for a surgical procedure; however, funding guidelines are unclear and decision-making processes opaque. Unfortunately, this inequitable situation encourages both the dangerous practice of reuse of devices and the imposition of additional out-of-pocket costs on patients. Reimbursement pathways in all four countries need to evolve to accommodate new methods of delivering health care, with fair decision-making processes for reimbursement coverage and pricing, which assess the overall value of medical devices, including SUDs, in terms of health outcomes and/or safety. PMID- 29698184 TI - Possessing Objectivity in Value in Health Regional Issues. PMID- 29698185 TI - Inpatient Treatment Patterns and Health Care Expenditures for Hepatocellular Carcinoma among the Population with Urban Basic Health Insurance in China. AB - OBJECTIVE: To identify inpatient treatment patterns and health care expenditures for hepatocellular carcinoma (HCC) among the population with urban basic health insurance (BHI) in China. METHODS: Hospitalizations for patients 18 years or older with discharge diagnosis of HCC from 2008 to 2011 and enrolled in the Chinese BHI plan were identified from the Chinese Health Insurance Research Association database. Treatment approaches and hospital expenditures were assessed for the full sample, and according to city level and hospital tier. Analyses were extrapolated to the national urban BHI population. RESULTS: A total of 3679 HCC hospitalizations were identified in the period 2008 to 2011, representing 615,359 hospitalizations among the urban BHI population. More than two-thirds of the patients received active treatment during hospitalization (68%, N = 418,394), most commonly with traditional Chinese medicine (51%) and/or transarterial intervention therapy (21%). Cases from larger level 1 cities and larger tier 3 hospitals reported greater use of active treatments (81% and 83%, respectively) than did those from smaller level 3 cities (46%) or tier 1 hospitals (56%). Hospital expenditures were higher in level 1 cities (mean [95% confidence interval] Chinese currency renminbi [Y] 17,119 [Y16,292-Y17,946]; US $2,506 [$2,385-$2,628]) than in level 3 cities (mean [95% confidence interval] Y7,870 [Y5,775-Y9,964]; $1,152 [$846-$1,459]). CONCLUSIONS: Most patients with HCC received active treatment during hospitalization in China. There were substantial disparities, however, in the use of HCC treatments across different economic regions, and nearly a third received only palliative care. With the recent launch of health care reform, this study provides valuable insights into current resource use and costs for HCC in China to help prioritize areas of improvement. PMID- 29698186 TI - Key Components of Increased Drug Expenditure in South Korea: Implications for the Future. AB - BACKGROUND: The cost of pharmaceuticals has increased rapidly in Korea in recent years. Expenditure is likely to grow further with the policy of expanding National Health Insurance coverage for the following four disease areas: cerebrovascular and cardiovascular disease, rare diseases, and cancer. Consequently, there is a need to analyze the different components leading to this increased expenditure as a basis for suggesting future reforms in Korea. OBJECTIVE: To quantify the impact of new and established drugs on the growth of total drug spending in South Korea in recent years, specially focusing on the differentiated components of drug spending. These include treatment expansion and drug-mix effects (switching from cheaper drugs to expensive ones and vice versa). METHODS: A model was proposed and used to assess the impact of both new and existing drugs on changes in price, quantity, and drug mix over the 5-year period in Korea from 2006 to 2010. The database used was the National Health Insurance claims data, which covers about 97% of the total population of Korea. RESULTS: Overall drug spending increased 1.43-fold from 2006 to 2010. Drug-mix effect (epsilont = 1.32) was the main factor contributing to increased drug spending, followed by increased drug utilization (Qt = 1.26). For existing drugs, treatment expansion (QI) and drug-mix effect (epsilonI) were measured at 1.28 and 1.24, respectively, while those of new drugs were 1.02 (QN) and 1.03 (epsilonN). Therefore, existing drugs have a much greater effect on drug spending than do new drugs. According to the Anatomical Therapeutic Classification, drug spending rose most significantly for the "sensory organs" class of drugs (Et = 1.78) followed by the "various" class (Et = 1.68). For existing drugs in the sensory organs class (S), drug-mix effect (epsilonI) was measured at 0.96. This implies that expensive drugs among existing drugs were replaced by cheaper ones. However, the quantity prescribed (QI) substantially increased by 1.88-fold. New drugs within this class that were more expensive than existing ones were also prescribed (epsilonN = 1.09), further increasing drug expenditure in Korea. CONCLUSIONS: We found contrasting results from previous studies. The drug-mix effect and existing drugs made the largest contribution to drug spending growth rather than new drugs. Policies targeting drug mix, such as promoting cost-effective prescription and rational use of drugs, including the use of cheaper cost generics without compromising care, should be primarily considered to help contain future drug expenditure. PMID- 29698187 TI - Reviewer Acknowledgement. PMID- 29698188 TI - How Data Packages Lacking Phase III Pivotal Trial Data Can Support Regulatory Approval and Reimbursement for Oncologics in Australia. AB - BACKGROUND: Oncology drugs lacking supportive phase III trial data have achieved Food and Drug Administration (FDA) and European Medicines Agency (EMA) regulatory approval and even European reimbursement approval where no therapeutic alternative exists and early-stage data indicate dramatic clinical benefits. OBJECTIVE: This research aimed to compare under what circumstances oncologics can obtain both regulatory and reimbursement approval in Australia on this basis. METHODS: Therapeutic Goods Administration (TGA) Australian Public Assessment Reports, EMA, FDA, and Pharmaceutical Benefits Advisory Committee (PBAC) Public Summary Documents were extracted for any oncologic indication appraised in Australia on a pivotal trial package lacking phase III data, excluding pediatric indications and new formulations. RESULTS: Australian Public Assessment Reports were available for six TGA-appraised oncologics across seven indications on such a data package: five of seven approved, one of seven restricted, and one of seven rejected. The EMA and the FDA issued recommendations on these indications an average of 1 and 2 years earlier, respectively. The PBAC appraised six oncologics across 10 indications on such a data package, with four (nilotinib, dasatinib, imatinib, and brentuximab vedotin) approved and two rejected (cetuximab and bevacizumab). Seven of the eight approved indications required multiple submissions, with inadequate clinical data frequently cited as key. Six of the eight PBAC-approved indications included economic modeling on a cost-benefit approach. CONCLUSIONS: The TGA will approve oncologics that offer potentially substantial clinical benefits on the basis of an indirect comparison of single arm trials but at a delay versus the EMA and the FDA. The PBAC reimbursement approval also requires more rigorous supportive clinical data and acceptable cost effectiveness as demonstrated on a cost-benefit or cost-quality-adjusted life year metric. PMID- 29698189 TI - Efficacy and Safety of Thrombin-Receptor Antagonist (Atopaxar and Vorapaxar) in Patients with Acute Coronary Syndrome or Coronary Artery Disease-A Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND: Meta-analysis for the efficacy and safety data of thrombin-receptor antagonist (TRA) based on patients with acute coronary syndrome (ACS) or coronary artery disease (CAD) and indirect comparisons between TRAs were not available. OBJECTIVES: We intended to synthesize the primary end points based on different patient populations (ACS or CAD) as well as perform indirect comparison between two newly invented antiplatelet agents atopaxar and vorapaxar. METHODS: A literature search was performed in MEDLINE, Embase, and Cochrane Library. Incidences of major adverse cardiovascular events (MACEs) and bleeding events according to thrombolysis in myocardial infarction were selected as primary outcomes, whereas adverse effects were considered as secondary outcomes. Corresponding results were synthesized using Revman 5.1 according to ACS or CAD cohorts. RESULTS: Among the seven included randomized controlled trials, the efficacy end points in the TRA treatment group were favorable compared with placebo. Specifically, the odds ratio (OR) of MACEs was 0.80 (95% confidence interval [CI] 0.52-1.22) for patients with ACS and 0.74 (95% CI 0.53-1.05) for the cohort with CAD. The events of bleeding were unanimously superior in the placebo arm for both cohorts. The indirect comparison showed a superior trend in favor of atopaxar over vorapaxar in occurrences of MACEs (OR 0.93; 95% CI 0.38 1.32), myocardial infarction (OR 0.52; 95% CI 0.13- 0.95), and cardiovascular death (OR 0.82; 95% CI 0.12-4.24) and caused less incidence of bleeding. CONCLUSIONS: Besides being more effective than placebo in improving the incidence of MACEs but with a higher risk of bleeding, TRAs may exert different effects in patients with ACS and CAD. Indirect comparisons also suggested that atopaxar might be better than vorapaxar in lowering the incidence of MACEs, myocardial infarction, and cardiovascular death and at the same time with lower risks of bleeding. PMID- 29698190 TI - Incidence of Intravenous Medication Errors in a Chinese Hospital. AB - OBJECTIVES: The purpose of this study was to explore intravenous (IV) medication errors in a Chinese hospital. The specific objectives were to 1) explore and measure the frequency of IV medication errors by direct observation and identify clues to their causes in Chinese hospital inpatient wards and 2) identify the clinical importance of the errors and find the potential risks in the preparation and administration processes of IV medications. METHODS: A prospective study was conducted by using the direct observational method to describe IV medication errors on two general surgery patient wards in a large teaching hospital in Beijing, China. A trained observer accompanied nurses during IV preparation rounds to detect medication errors. The difference in mean error rates between total parenteral nutrition (TPN) and non-TPN medications was tested by using the Mann-Whitney U test. RESULTS: A final total of 589 ordered IV doses plus 4 unordered IV doses as prepared and administered to the patients was observed from August 3, 2010, to August 13, 2010. The overall error rate detected on the study ward was 12.8%. The most frequent errors by category were wrong dose (5.4%), wrong time (3.7%), omission (2.7%), unordered dose (0.7%), and extra dose (0.3%). Excluding wrong time errors, the error rate was 9.1%. Non-TPN medications had significantly higher error rates than did TPN medications including wrong time errors (P = 0.0162). CONCLUSIONS: A typical inpatient in a Chinese hospital was subject to about one IV error every day. Pharmacists had a very limited role in ensuring the accuracy of IV medication preparation and administration processes. PMID- 29698191 TI - From Regulatory Approval to Subsidized Patient Access in the Asia-Pacific Region: A Comparison of Systems Across Australia, China, Japan, Korea, New Zealand, Taiwan, and Thailand. AB - OBJECTIVES: To compare processes and timings of regulatory and subsidized access systems for medicines across seven jurisdictions within the Asia-Pacific region. METHODS: A questionnaire was developed focusing on regulatory and health technology assessment-based subsidized access processes and timings in each of the seven surveyant's jurisdictions. RESULTS: Australia and Thailand are the only two jurisdictions that formally allow the subsidized access evaluation process to be conducted in parallel with the regulatory evaluation process. Australian, Japanese, Korean, New Zealand, and Taiwanese systems afford broad coverage, whereas Chinese and Thai systems provide limited coverage for medicines under patent. Subsidized access systems for all jurisdictions except Thailand have an associated patient co-payment for each medicine/prescription. The biggest disparity across the study group relates to time from regulatory submission to subsidized access of patented medicines-ranging from just over 1 year (Japan) to a minimum of 5 years (China). CONCLUSIONS: There is consistency across the seven jurisdictions studied in relation to regulatory and subsidized patient access processes-that is, regulatory approval is required before subsidized access review; subsidized access coverage is broad; and the cost of medicine subsidization is offset, in part, by patient co-payments. Although local differences will always exist in relation to budget and pricing negotiation, there may be efficiencies that can be applied across systems to improve time to subsidized access. Closer understanding of regulatory and subsidized access systems can lead to best-practice sharing and, ultimately, timely access and better health outcomes for patients. PMID- 29698192 TI - Using Dynamic Transmission Modeling to Determine Vaccination Coverage Rate Based on 5-Year Economic Burden of Infectious Disease: An Example of Pneumococcal Vaccine. AB - BACKGROUND: Vaccination can reduce the incidence and mortality of an infectious disease and thus increase the years of life and productivity for the entire society. But when determining the vaccination coverage rate, its economic burden is usually not taken into account. OBJECTIVE: This article aimed to use a dynamic transmission modeling (DTM), which is based on a susceptible-infectious-recovered model and is a system of differential equations, to find the optimal vaccination coverage rate based on the economic burden of an infectious disease. METHODS: Vaccination for pneumococcal diseases was used as an example to demonstrate the main purpose. 23-Valent pneumococcal polysaccharide vaccines (PPV23) and 13 valent pneumococcal conjugate vaccines (PCV13) have shown their cost effectiveness in elderly and children, respectively. Scenarios analysis of PPV23 to elderly aged 65+ years and of PCV13 to children aged 0 to 4 years was applied to assess the optimal vaccination coverage rate based on the 5-year economic burden. Model parameters were derived from Taiwan's National Health Insurance Research Database, government data, and published literature. Various vaccination coverage rates, the vaccine efficacy, and all epidemiologic parameters were substituted into DTM, and all differential equations were solved in R Statistical Software. RESULTS: If the coverage rate of PPV23 for the elderly and of PCV13 for the children both reach 50%, the economic burden due to pneumococcal disease will be acceptable. CONCLUSIONS: This article provided an alternative perspective from the economic burden of diseases to obtain a vaccination coverage rate using the DTM. This will provide valuable information for vaccination policy decision makers. PMID- 29698193 TI - Development and Psychometric Properties of a Tuberculosis-Specific Multidimensional Health-Related Quality-of-Life Measure for Patients with Pulmonary Tuberculosis. AB - BACKGROUND: Various generic instruments exist to assess health-related quality of life (HRQOL) in patients with tuberculosis (TB), but a psychometrically sound disease-specific instrument is lacking. OBJECTIVES: The present study aimed to develop and psychometrically validate a multidimensional TB-specific HRQOL instrument relevant to the value of patients with pulmonary TB in Iraq with an eye toward cross-cultural application. METHODS: The core general HRQOL questionnaire is composed of the Functional Assessment of Cancer Therapy-General items. A modular approach was followed for the development of the Functional Assessment of Chronic Illness Therapy-Tuberculosis (FACIT-TB) questionnaire in which a set of items assessing quality-of-life (QOL) issues not sufficiently covered by the core Functional Assessment of Cancer Therapy-General items, but considered to be relevant to the target population, was added. Moreover, principal-component analysis was used to determine the new subscale structure of the questionnaire. RESULTS: In addition to the 27 items of the core questionnaire, a set of 20 items referring to disease symptoms related to the site of infection, adverse effects, and additional QOL dimensions such as fatigue, social stigma, and economic burden of the illness was included. Factor analysis demonstrated that the FACIT-TB construct comprised five domains. CONCLUSIONS: A rigorous method was applied in the development of the FACIT-TB measure to fully understand the impact of TB on patients' QOL. The instrument is psychometrically sound and portrays multiple important dimensions of HRQOL. FACIT TB is relatively brief, is easy to administer and score, and is appropriate for use in clinical trials and practice. PMID- 29698194 TI - Does the Elderly's Number of Prescribed Medications across Months Matter? National Cohort versus Single-Center Cohort. AB - OBJECTIVES: To investigate the monthly number of prescribed medication (NPM) patterns among different elderly populations and the factors associated with monthly NPM changes. METHODS: This retrospective cohort study was conducted using the databases obtained from National Health Insurance Research Databases and a 2000-bed academic medical center in Taiwan (i.e., single-center cohort). We compared the monthly NPMs, demographic characteristics, disease states, and health care contacts among the National Health Insurance elderly cohorts in 2006 and 2007, and for those elderly in the national and single-center cohorts who had outpatient visits from November to October in 2006 to 2007 and 2007 to 2008, respectively. Generalized estimating equation analyses of repeated measures were performed for monthly NPMs. RESULTS: The average monthly NPMs among the National Health Insurance elderly cohort was 2.33 in 2006 and 4.39 in 2007, respectively. After controlling for other factors, the increment in the proportion of monthly NPMs among the older elderly patients, in certain months and for those patients with hypertension and dyslipidemia, was statistically significant among the single-center cohort but was not observed in the national elderly cohort. The proportional changes decreased significantly among patients who made visits to emergency rooms and who were hospitalized during a 1-year period. CONCLUSIONS: There was an incremental trend of monthly NPMs among the national cohort from 2006 to 2007. Although acute exacerbations and hospitalization might be the protecting factors of increasing monthly NPMs, more attention should be paid toward high-utilization patients with specific diseases during certain months for different elderly cohorts. PMID- 29698195 TI - Comparing Patient and Physician Risk Tolerance for Bleeding Events Associated with Anticoagulants in Atrial Fibrillation-evidence from the United States and Japan. AB - OBJECTIVES: Atrial fibrillation (AF) is a factor in the development of thrombi that can lead to ischemic strokes. Anticoagulants are crucial in preventing strokes among patients with AF but are associated with bleeding risks. Recent studies have shown that despite anticoagulants' efficacy in stroke prevention, many patients with AF receive subtherapeutic levels of anticoagulation because of concerns about bleeding. Of particular interest is to quantify the perceived relative importance of treatment-related benefits and risks and how these perceptions vary between patients and physicians in different countries. METHODS: Patients' and physicians' preferences were elicited using a discrete-choice experiment. We evaluated disagreements in preferences for the benefits and risks of anticoagulants. RESULTS: A total of 186 patients with AF and 107 physicians in the United States completed the survey. In Japan, 152 patients and 164 physicians completed the same survey. Japanese patients were relatively less averse than US patients to bleeding risks. Physicians in both countries did not distinguish between nondisabling and disabling strokes. US patients were less tolerant than physicians of nonmajor clinically relevant bleeding risk when this risk was a consequence of preventing nondisabling strokes. Japanese patients were generally more tolerant than physicians of bleeding risks when the risks were consequences of preventing both nondisabling and disabling strokes. CONCLUSIONS: Overall, preferences for anticoagulant benefits and risks were not statistically different between patients and physicians in the United States, nor were there differences in preferences for different stroke risks between physicians in the United States and Japan; however, preferences were different between patients and physicians in Japan. PMID- 29698196 TI - The State of Cost-Utility Analyses in Asia: A Systematic Review. AB - OBJECTIVE: To review and evaluate published cost-utility analyses (CUAs) targeting populations in Asia. METHODS: We examined data from the Tufts Medical Center Cost-Effectiveness Analysis Registry, which contains detailed information on more than 3700 English-language CUAs in peer-reviewed journals through 2012. We focused on CUAs pertaining to Asian countries (Asian CUAs), summarized study features and methodological practices, and compared them with CUAs focusing on non-Asian countries (non-Asian CUAs) from 2000 to 2012. RESULTS: We identified 175 published CUAs pertaining to Asian populations (representing 5.1% of all CUAs) from 2000 to 2012. The number has increased from 19 CUAs in the period 2000 to 2004 to 107 CUAs in the period 2009 to 2012. Roughly one-third focused on Japan (33.1%), followed by Taiwan (15.4%), China (14.9%), and Thailand (8.0%). The diseases targeted in Asian CUAs were cancer (24.6%), infectious diseases (13.7%), cardiovascular diseases (8.6%), and musculoskeletal and rheumatological diseases (5.7%). More Asian CUAs evaluated primary prevention interventions (e.g., vaccinations and screenings) compared with non-Asian CUAs (21.7% vs. 16.5%, P = 0.069). Compared with non-Asian CUAs, significantly more studies in Asia suggest that the health interventions examined provide reasonable value for money. Asian and non-Asian CUAs did not differ in adherence to good methodological practices, including clearly stating the perspective, discounting costs and quality-adjusted life-years, stating a time horizon, and correctly conducting incremental cost-effectiveness analysis. Asian CUAs, however, lagged in reporting sensitivity analyses, disclosing funding status, and currency year. CONCLUSIONS: The number of CUAs in Asia has grown steadily, with more than half focused on pharmaceuticals. The literature reveals that CUAs generally follow good methodological practices though areas for improvement exist. PMID- 29698197 TI - Economic Burden of Venous Thromboembolism in Patients Undergoing Major Abdominal Surgery. AB - BACKGROUND: Venous thromboembolism (VTE) is a serious complication that arises after major abdominal surgery. VTE poses risks of negative outcomes and health care burden. The literature on the cost of VTE in Japanese surgical patients, however, is scarce. OBJECTIVE: This study was conducted to investigate the economic consequences of VTE in Japanese patients with major abdominal surgery, using a hospital claims database. METHODS: This is a retrospective, matched cohort study. Patients who had a VTE event up to 90 days after their first major abdominal surgery and initiated warfarin or heparin within 1 day of VTE diagnosis with continued treatment for more than 4 weeks were matched with controls for surgery type, hospital, and date of surgery +/- 6 months in a 1:2 scheme. The primary outcome was 90-day costs associated with major abdominal surgery. The secondary outcomes were 6-month total costs, average length of initial inpatient stay, and cost of initial inpatient stay. RESULTS: The 90-day cumulative incidence of VTE was 4.89%. The development of a VTE event in patients undergoing major abdominal surgery resulted in a 1.5-fold increase in the length of hospitalization and a 2.8-fold increase in total costs 90 days after the surgery. Total costs further increased to 3.4-fold at 6 months. Overall, costs incurred in patients with VTE are on average much higher than in patients without VTE throughout 6-month postsurgery. CONCLUSIONS: The preventive care for VTE using more effective prophylactic treatment is recommended to reduce the economic burden associated with major abdominal surgery. PMID- 29698198 TI - Quality of life among Patients with Acute Coronary Syndrome in Malaysia. AB - OBJECTIVES: This study's objectives were to estimate the quality of life (QOL) of Malaysian patients with acute coronary syndrome (ACS) during admission and at 12 months, to explore the factors associated with the QOL, and to compare utility scores derived from tariffs from local and foreign populations. METHODS: Data collected from patients with ACS between 2008 and 2009 for a study on cardiac rehabilitation at the Sarawak General Hospital were used for this study. QOL data were obtained using a validated version of the EuroQol five-dimensional questionnaire at baseline and at 12 months. Health utility scores were calculated using visual analogue scale scores and utility tariffs from Malaysia and the United Kingdom. RESULTS: Data from 104 subjects from the earlier study was used. The mean age was 56.1 years, with 88.5% being men. The mean hospitalization duration was 6.3 days. The mean utility score was 0.75 at baseline and 0.82 at 12 months. There was a statistically significant improvement in utility from baseline to 12 months based on the Malaysian tariff (P = 0.014) but not with the UK tariff (P = 0.086). The QOL of patients was associated with sex and diagnosis of ST-segment elevation myocardial infarction. CONCLUSIONS: Our results showed that there was a significant improvement in the QOL from baseline to 12 months. Only sex and diagnosis affected the QOL score at baseline because of limited variables available for testing. It also reconfirms the importance of applying the appropriate, country-specific utility tariffs in QOL studies. Despite limitations, the study is useful toward describing QOL among a group of Malaysian patients with ACS. PMID- 29698199 TI - Cost-Minimization Analysis of Metformin and Acarbose in Treatment of Type 2 Diabetes. AB - BACKGROUND: Metformin is the first-line oral hypoglycemic agent for type 2 diabetes mellitus (T2DM) per international guidelines with proven efficacy, safety, and cost-effectiveness. However, little information comparing it with acarbose exists. OBJECTIVE: To study the cost-effectiveness of metformin and acarbose-two extensively adopted agents-in treating T2DM. METHODS: Cost minimization analysis was conducted on the assumption that metformin and acarbose have equivalent clinical effectiveness. The cost of treatment was detected and evaluated from a payer's perspective. In sensitivity analyses, several clinical scenarios were developed according to clinical practices and physicians' prescribing behaviors in China. RESULTS: Metformin can save annual treatment costs by 39.87% to 40.97% compared with acarbose. Under a wide range of assumptions on utilization profile and physician prescribing behavior, it saves costs by 19.83% to 40.97% in patients whose weight is 60 kg or less and by 39.87% to 70.49% in patients whose weight is more than 60 kg, which corroborates the results that metformin is more cost-effective than acarbose. CONCLUSIONS: Metformin appears to provide better value for money than does acarbose. Findings from this study are consistent with those from previous studies that metformin is undoubtedly the first choice in the management of T2DM, with significant glucose lowering effects and low treatment costs. PMID- 29698200 TI - Health-Related Quality of Life and Willingness to Pay per Quality-Adjusted Life Year Threshold-A Study in Patients with Epilepsy in China. AB - OBJECTIVES: To assess the health-related quality of life (HRQOL) and willingness to pay (WTP) per quality-adjusted life-year (QALY) amount of patients with epilepsy in China. METHODS: Adults with epilepsy and a healthy control were recruited in two tertiary hospitals in China. Participants completed two indirect utility elicitation instruments (Quality of Well-being Scale-self administered version and EuroQol five-dimensional questionnaire) and a WTP questionnaire. Correlations between sociodemographic or epilepsy-specific variables (age of epilepsy onset, duration of epilepsy, seizure types, types of antiepileptic drug treatment, etc.) and HRQOL or WTP/QALY were assessed to identify the candidate predictor. Multiple linear regression models were adopted to investigate the predictive performances of identified candidate predictors. Data analyses were performed on SPSS 20.0 (SPSS, Inc., Chicago, IL). RESULTS: For utilities of both the Quality of Well-being Scale-self administered version and the EuroQol five dimensional questionnaire, patients with epilepsy had statistically lower values than did the control group (P < 0.0001). In terms of the WTP/month, the percentage of WTP accounting for the monthly income and the WTP/QALY values from the epilepsy group were substantially higher than those from the control group (P < 0.0001). [Formula: see text] The multiple linear regression model identified working status (P = 0.05), seizure types (P = 0.022), income (P = 0.006), and self-rating health state (P < 0.05) as predictors of HRQOL while income (P = 0.000) and self-rating health state (P < 0.05) statistically contributed to the variations in WTP/QALY value for the epilepsy group. CONCLUSIONS: Patients with epilepsy had substantially lower HRQOL than did the healthy population. PMID- 29698201 TI - How Quality of Life as Patient-Reported Outcome Has Been Studied for Rheumatoid Arthritis in Chinese-Speaking Population. AB - OBJECTIVE: To review the use of health-related quality-of-life (HRQOL) instruments as patient-reported outcome in patients with rheumatoid arthritis (RA) in studies that have been published in Chinese-speaking populations. METHODS: Overlapping searching strategy was used using four publication databases: PubMed and EMBASE for English publications and Wanfang and CNKI for Chinese publications. Entries published between January 1, 1990, and July 31, 2014, were retrieved and then reviewed independently by two researchers. The identified studies were summarized according to information source, publishing year, study location, and study type. The validation studies were examined closely in terms of their sample sizes and psychometric properties. RESULTS: There were 99 studies from the databases selected for review. Among the studies reviewed, most studies were conducted in Mainland China. There was a clear overall increasing trend in the number of studies in recent years. Generic instruments were more frequently used by researchers outside China. Another observation was that most instruments were used without previous validation either in any Chinese-speaking population with RA or in the specific country that it was used. CONCLUSIONS: The importance of patient-reported quality of life as an outcome indicator in patients with RA is more and more realized in Chinese speaking regions during the past two decades. To facilitate the use of HRQOL for better management of patients, and improve the quality of research, there is a strong need of validating the HRQOL instruments in more locations with a larger population, more comprehensive validity, and potential cross-cultural validation in future. PMID- 29698202 TI - Progressive Hard-Mining Network for Monocular Depth Estimation. AB - Depth estimation from the monocular RGB image is a challenging task for computer vision due to no reliable cues as the prior knowledge. Most existing monocular depth estimation works including various geometric or network learning methods lack of an effective mechanism to preserve the cross-border details of depth maps, which yet is very important for the performance promotion. In this paper, we propose a novel end-to-end progressive hard-mining network (PHN) framework to address this problem. Specifically, we construct the hard-mining objective function, the intra-scale and inter-scale refinement subnetworks to accurately localize and refine those hard-mining regions. The intra-scale refining block recursively recovers details of depth maps from different semantic features in the same receptive field while the inter-scale block favors a complementary interaction among multi-scale depth cues of different receptive fields. For further reducing the uncertainty of the network, we design a difficulty-ware refinement loss function to guide the depth learning process, which can adaptively focus on mining these hard-regions where accumulated errors easily occur. All three modules collaborate together to progressively reduce the error propagation in the depth learning process, and then, boost the performance of monocular depth estimation to some extent. We conduct comprehensive evaluations on several public benchmark data sets (including NYU Depth V2, KITTI, and Make3D). The experiment results well demonstrate the superiority of our proposed PHN framework over other state of the arts for monocular depth estimation task. PMID- 29698203 TI - Too Far to See? Not Really!-Pedestrian Detection With Scale-Aware Localization Policy. AB - A major bottleneck of pedestrian detection lies on the sharp performance deterioration in the presence of small-size pedestrians that are relatively far from the camera. Motivated by the observation that pedestrians of disparate spatial scales exhibit distinct visual appearances, we propose in this paper an active pedestrian detector that explicitly operates over multiple-layer neuronal representations of the input still image. More specifically, convolutional neural nets, such as ResNet and faster R-CNNs, are exploited to provide a rich and discriminative hierarchy of feature representations, as well as initial pedestrian proposals. Here each pedestrian observation of distinct size could be best characterized in terms of the ResNet feature representation at a certain layer of the hierarchy. Meanwhile, initial pedestrian proposals are attained by the faster R-CNNs techniques, i.e., region proposal network and follow-up region of interesting pooling layer employed right after the specific ResNet convolutional layer of interest, to produce joint predictions on the bounding-box proposals' locations and categories (i.e., pedestrian or not). This is engaged as an input to our active detector, where for each initial pedestrian proposal, a sequence of coordinate transformation actions is carried out to determine its proper x-y 2D location and the layer of feature representation, or eventually terminated as being background. Empirically our approach is demonstrated to produce overall lower detection errors on widely used benchmarks, and it works particularly well with far-scale pedestrians. For example, compared with 60.51% log-average miss rate of the state-of-the-art MS-CNN for far-scale pedestrians (those below 80 pixels in bounding-box height) of the Caltech benchmark, the miss rate of our approach is 41.85%, with a notable reduction of 18.66%. PMID- 29698204 TI - Subspace Clustering via Learning an Adaptive Low-Rank Graph. AB - By using a sparse representation or low-rank representation of data, the graph based subspace clustering has recently attracted considerable attention in computer vision, given its capability and efficiency in clustering data. However, the graph weights built using the representation coefficients are not the exact ones as the traditional definition is in a deterministic way. The two steps of representation and clustering are conducted in an independent manner, thus an overall optimal result cannot be guaranteed. Furthermore, it is unclear how the clustering performance will be affected by using this graph. For example, the graph parameters, i.e., the weights on edges, have to be artificially pre specified while it is very difficult to choose the optimum. To this end, in this paper, a novel subspace clustering via learning an adaptive low-rank graph affinity matrix is proposed, where the affinity matrix and the representation coefficients are learned in a unified framework. As such, the pre-computed graph regularizer is effectively obviated and better performance can be achieved. Experimental results on several famous databases demonstrate that the proposed method performs better against the state-of-the-art approaches, in clustering. PMID- 29698205 TI - Image Segmentation for Intensity Inhomogeneity in Presence of High Noise. AB - Automated segmentation of fine objects details in a given image is becoming of crucial interest in different imaging fields. In this paper, we propose a new variational level-set model for both global and interactive?selective segmentation tasks, which can deal with intensity inhomogeneity and the presence of noise. The proposed method maintains the same performance on clean and noisy vector-valued images. The model utilizes a combination of locally computed denoising constrained surface and a denoising fidelity term to ensure a fine segmentation of local and global features of a given image. A two-phase level-set formulation has been extended to a multi-phase formulation to successfully segment medical images of the human brain. Comparative experiments with state-of the-art models show the advantages of the proposed method. PMID- 29698206 TI - PaMM: Pose-Aware Multi-Shot Matching for Improving Person Re-Identification. AB - Person re-identification is the problem of recognizing people across different images or videos with non-overlapping views. Although a significant progress has been made in person re-identification over the last decade, it remains a challenging task because the appearances of people can seem extremely different across diverse camera viewpoints and person poses. In this paper, we propose a novel framework for person re-identification by analyzing camera viewpoints and person poses called pose-aware multi-shot matching. It robustly estimates individual poses and efficiently performs multi-shot matching based on the pose information. The experimental results obtained by using public person re identification data sets show that the proposed methods outperform the current state-of-the-art methods, and are promising for accomplishing person re identification under diverse viewpoints and pose variances. PMID- 29698207 TI - Globally Variance-Constrained Sparse Representation and Its Application in Image Set Coding. AB - Sparse representation leads to an efficient way to approximately recover a signal by the linear composition of a few bases from a learnt dictionary based on which various successful applications have been achieved. However, in the scenario of data compression, its efficiency and popularity are hindered. It is because of the fact that encoding sparsely distributed coefficients may consume more bits for representing the index of nonzero coefficients. Therefore, introducing an accurate rate constraint in sparse coding and dictionary learning becomes meaningful, which has not been fully exploited in the context of sparse representation. According to the Shannon entropy inequality, the variance of Gaussian distributed data bound its entropy, indicating the actual bitrate can be well estimated by its variance. Hence, a globally variance-constrained sparse representation (GVCSR) model is proposed in this paper, where a variance constrained rate term is introduced to the optimization process. Specifically, we employ the alternating direction method of multipliers (ADMMs) to solve the non convex optimization problem for sparse coding and dictionary learning, both of them have shown the state-of-the-art rate-distortion performance for image representation. Furthermore, we investigate the potential of applying the GVCSR algorithm in the practical image set compression, where the optimized dictionary is trained to efficiently represent the images captured in similar scenarios by implicitly utilizing inter-image correlations. Experimental results have demonstrated superior rate-distortion performance against the state-of-the-art methods. PMID- 29698208 TI - Toward the Repeatability and Robustness of the Local Reference Frame for 3D Shape Matching: An Evaluation. AB - The local reference frame (LRF), as an independent coordinate system constructed on the local 3D surface, is broadly employed in 3D local feature descriptors. The benefits of the LRF include rotational invariance and full 3D spatial information, thereby greatly boosting the distinctiveness of a 3D feature descriptor. There are numerous LRF methods in the literature; however, no comprehensive study comparing their repeatability and robustness performance under different application scenarios and nuisances has been conducted. This paper evaluates eight state-of-the-art LRF proposals on six benchmarks with different data modalities (e.g., LiDAR, Kinect, and Space Time) and application contexts (e.g., shape retrieval, 3D registration, and 3D object recognition). In addition, the robustness of each LRF to a variety of nuisances, including varying support radii, Gaussian noise, outliers (shot noise), mesh resolution variation, distance to boundary, keypoint localization error, clutter, occlusion, and partial overlap, is assessed. The experimental study also measures the performance under different keypoint detectors, descriptor matching performance when using different LRFs and feature representation combinations, as well as computational efficiency. Considering the evaluation outcomes, we summarize the traits, advantages, and current limitations of the tested LRF methods. PMID- 29698209 TI - Single-Image Super-Resolution Based on Rational Fractal Interpolation. AB - This paper presents a novel single-image super-resolution (SR) procedure, which upscales a given low-resolution (LR) input image to a high-resolution image while preserving the textural and structural information. First, we construct a new type of bivariate rational fractal interpolation model and investigate its analytical properties. This model has different forms of expression with various values of the scaling factors and shape parameters; thus, it can be employed to better describe image features than current interpolation schemes. Furthermore, this model combines the advantages of rational interpolation and fractal interpolation, and its effectiveness is validated through theoretical analysis. Second, we develop a single-image SR algorithm based on the proposed model. The LR input image is divided into texture and non-texture regions, and then, the image is interpolated according to the characteristics of the local structure. Specifically, in the texture region, the scaling factor calculation is the critical step. We present a method to accurately calculate scaling factors based on local fractal analysis. Extensive experiments and comparisons with the other state-of-the-art methods show that our algorithm achieves competitive performance, with finer details and sharper edges. PMID- 29698210 TI - Video Synopsis in Complex Situations. AB - Video synopsis is an effective technique for surveillance video browsing and storage. However, most of the existing video synopsis approaches are not suitable for complex situations, especially crowded scenes. This is because these approaches heavily depend on the preprocessing results of foreground segmentation and multiple objects tracking, but the preprocessing techniques usually achieve poor performance in crowded scenes. To address this problem, we propose a comprehensive video synopsis approach which can be applied to scenes with drastically varying crowdedness. The proposed approach differs significantly from the existing methods, and has several appealing properties. First, we propose to detect the crowdedness of a given video, then, extract object tubes in sparse periods and extract video clips in crowded periods, respectively. Through such a solution, the poor performance of preprocessing techniques in crowded scenes can be avoided by extracting the whole video frames. Second, we propose a group partition algorithm which can discovers the relationships among moving objects and alleviates several segmentation and tracking errors. Third, a group-based greedy optimization algorithm is proposed to automatically determine the length of a synopsis video. Besides, we present extensive experiments that demonstrate the effectiveness and efficiency of the proposed approach. PMID- 29698211 TI - High-Order Model and Dynamic Filtering for Frame Rate Up-Conversion. AB - This paper proposes a novel frame rate up-conversion method through high-order model and dynamic filtering (HOMDF) for video pixels. Unlike the constant brightness and linear motion assumptions in traditional methods, the intensity and position of the video pixels are both modeled with high-order polynomials in terms of time. Then, the key problem of our method is to estimate the polynomial coefficients that represent the pixel's intensity variation, velocity, and acceleration. We propose to solve it with two energy objectives: one minimizes the auto-regressive prediction error of intensity variation by its past samples, and the other minimizes video frame's reconstruction error along the motion trajectory. To efficiently address the optimization problem for these coefficients, we propose the dynamic filtering solution inspired by video's temporal coherence. The optimal estimation of these coefficients is reformulated into a dynamic fusion of the prior estimate from pixel's temporal predecessor and the maximum likelihood estimate from current new observation. Finally, frame rate up-conversion is implemented using motion-compensated interpolation by pixel-wise intensity variation and motion trajectory. Benefited from the advanced model and dynamic filtering, the interpolated frame has much better visual quality. Extensive experiments on the natural and synthesized videos demonstrate the superiority of HOMDF over the state-of-the-art methods in both subjective and objective comparisons. PMID- 29698212 TI - Residual Highway Convolutional Neural Networks for in-loop Filtering in HEVC. AB - High efficiency video coding (HEVC) standard achieves half bit-rate reduction while keeping the same quality compared with AVC. However, it still cannot satisfy the demand of higher quality in real applications, especially at low bit rates. To further improve the quality of reconstructed frame while reducing the bitrates, a residual highway convolutional neural network (RHCNN) is proposed in this paper for in-loop filtering in HEVC. The RHCNN is composed of several residual highway units and convolutional layers. In the highway units, there are some paths that could allow unimpeded information across several layers. Moreover, there also exists one identity skip connection (shortcut) from the beginning to the end, which is followed by one small convolutional layer. Without conflicting with deblocking filter (DF) and sample adaptive offset (SAO) filter in HEVC, RHCNN is employed as a high-dimension filter following DF and SAO to enhance the quality of reconstructed frames. To facilitate the real application, we apply the proposed method to I frame, P frame, and B frame, respectively. For obtaining better performance, the entire quantization parameter (QP) range is divided into several QP bands, where a dedicated RHCNN is trained for each QP band. Furthermore, we adopt a progressive training scheme for the RHCNN where the QP band with lower value is used for early training and their weights are used as initial weights for QP band of higher values in a progressive manner. Experimental results demonstrate that the proposed method is able to not only raise the PSNR of reconstructed frame but also prominently reduce the bit-rate compared with HEVC reference software. PMID- 29698213 TI - What Do Germans Want to Know About Skin Cancer? A Nationwide Google Search Analysis From 2013 to 2017. AB - BACKGROUND: Experts worldwide agree that skin cancer is a global health issue, but only a few studies have reported on world populations' interest in skin cancer. Internet search data can reflect the interest of a population in different topics and thereby identify what the population wants to know. OBJECTIVE: Our aim was to assess the interest of the German population in nonmelanoma skin cancer and melanoma. METHODS: Google AdWords Keyword Planner was used to identify search terms related to nonmelanoma skin cancer and melanoma in Germany from November 2013 to October 2017. The identified search terms were assessed descriptively using SPSS version 24.0. In addition, the search terms were qualitatively categorized. RESULTS: A total of 646 skin cancer-related search terms were identified with 19,849,230 Google searches in the period under review. The search terms with the highest search volume were "skin cancer" (n=2,388,500, 12.03%), "white skin cancer" (n=2,056,900, 10.36%), "basalioma" (n=907,000, 4.57%), and "melanoma" (n=717,800, 3.62%). The most searched localizations of nonmelanoma skin cancer were "nose" (n=93,370, 38.99%) and "face" (n=53,270, 22.24%), and the most searched of melanoma were "nails" (n=46,270, 70.61%) and "eye" (n=10,480, 15.99%). The skin cancer-related category with the highest search volume was "forms of skin cancer" (n=10,162,540, 23.28%) followed by "skin alterations" (n=4,962,020, 11.36%). CONCLUSIONS: Our study provides insight into terms and fields of interest related to skin cancer relevant to the German population. Furthermore, temporal trends and courses are shown. This information could aid in the development and implementation of effective and sustainable awareness campaigns by developing information sources targeted to the population's broad interest or by implementing new Internet campaigns. PMID- 29698214 TI - Analysis of the Empathic Concern Subscale of the Emotional Response Questionnaire in a Study Evaluating the Impact of a 3D Cultural Simulation. AB - Abstract Background Empathic concern has been found to decline in health professional students. Few effective educational programs and a lack of validated scales are reported. Previous analysis of the Empathic Concern scale of the Emotional Response Questionnaire has reported both one and two latent constructs. Aim To evaluate the impact of simulation on nursing students' empathic concern and test the psychometric properties of the Empathic Concern scale. Methods The study used a one group pre-test post-test design with a convenience sample of 460 nursing students. Empathic concern was measured pre-post simulation with the Empathic Concern scale. Factor Analysis was undertaken to investigate the structure of the scale. Results There was a statistically significant increase in Empathic Concern scores between pre-simulation 5.57 (SD = 1.04) and post simulation 6.10 (SD = 0.95). Factor analysis of the Empathic Concern scale identified one latent dimension. Conclusion Immersive simulation may promote empathic concern. The Empathic Concern scale measured a single latent construct in this cohort. PMID- 29698215 TI - Study of the efficiency of moving bed biofilm reactor (MBBR) in LAS Anionic Detergent removal from hospital wastewater: determination of removing model according to response surface methodology (RSM). AB - Detergents are considered one of the important pollutants in hospital wastewater. Achieving efficient and bio-friendly methods for the removal of these pollutants is considered as a concern for environmental researchers. This study aims at studying the efficiency of a moving bed biofilm reactor (MBBR) system for removing linear alkyl benzene sulfonate (LAS) from hospital wastewater with utilization of response surface methodology (RSM). The present study was carried out on a reactor with continuous hydraulic flow using media k1 at pilot scale to remove detergent from hospital wastewater. The effect of independent variables including contact time, percentage of media filling and mixed liquor suspended solids (MLSS) concentration of 1000-3000 mg/l on the system efficiency were assessed. Methylene blue active substances (MBAS) and chemical oxygen demand (COD) 750-850 mg/l were used by closed laboratory method in order to measure the concentration of LAS. The results revealed that the removal efficiency of LAS detergent and COD using media k1, retention time of 24 hours, and MLSS concentration of around 3,000 mg/l were 92.3 and 95.8%, respectively. The results showed that the MBBR system as a bio-friendly compatible method has high efficiency in removing detergents from hospital wastewater and can achieve standard output effluent in acceptable time. PMID- 29698216 TI - Characterisation of sediments during transport of solids in circular sewer pipes. AB - This research is focused in the monitoring of sediments in circular sewer pipes with different diameters at a flume facility fed with urban wastewater. For this purpose, sediment physical and chemical characteristics, and sediment mobility were recorded. The Structure from Motion photogrammetric technique was used for the measurement of sediment bed evolution. In addition, sediment properties were determined in order to study the cohesiveness of the bed deposits. In particular, the chemical oxygen demand and the oxygen uptake rate of the sediment samples were analysed after different accumulation periods on the pipe inverts, resulting in a relation between these parameters and the mobility processes of solids. PMID- 29698217 TI - Removal of humic acid from aqueous solution using polyacrylamide/chitosan semi IPN hydrogel. AB - In this study, we provide the first documented removal of humic acid (HA) from aqueous solution using polyacrylamide/chitosan (PAAm/CS) semi-IPN hydrogel. The prepared semi-IPN hydrogel was characterized by scanning electron microscopy (SEM) and Fourier transform infrared spectroscopy (FT-IR). The factors effecting HA adsorption performance were individually tested, including initial pH, ionic strength, contact time, initial HA concentration, and temperature. The results indicated that semi-IPN hydrogel was successfully fabricated and can be applied in a wide pH range, from 3 to 9. Low ionic strength effectively enhanced the adsorption capacity. As the ionic strength increased, this enhancement was less obvious but still positive. The adsorption kinetics were fitted to a pseudo-first order kinetic model, and the adsorption isotherm was described using the Sips isotherm model. The HA adsorption capacity increased with increasing temperature. The maximum adsorption capacity has the potential to attain 166.30 mg g-1, based on the Sips isotherm at 25 degrees C. Experiments demonstrated that the HA adsorption process can be primarily attributed to electrostatic interactions, and hydrogen bonding was also involved. Facile synthesis and good adsorptive performance indicate that semi-IPN hydrogel can be used for removing HA from water. PMID- 29698218 TI - Ensembles of radar nowcasts and COSMO-DE-EPS for urban flood management. AB - Sophisticated strategies are required for flood warning in urban areas regarding convective heavy rainfall events. An approach is presented to improve short-term precipitation forecasts by combining ensembles of radar nowcasts with the high resolution numerical weather predictions COSMO-DE-EPS of the German Weather Service. The combined ensemble forecasts are evaluated and compared to deterministic precipitation forecasts of COSMO-DE. The results show a significantly improved quality of the short-term precipitation forecasts and great potential to improve flood warnings for urban catchments. The combined ensemble forecasts are produced operationally every 5 min. Applications involve the Flood Warning Service Hamburg (WaBiHa) and real-time hydrological simulations with the model KalypsoHydrology. PMID- 29698219 TI - Taguchi optimization approach for metronidazole removal from aqueous solutions by using graphene oxide functionalized beta-cyclodextrin/Ag nanocomposite. AB - Metronidazole (MNZ) is a major threat to the ecosystems and human health, due to its toxicity and carcinogenic nature. The main aim of this study was to evaluate the efficiency of graphene oxide functionalized beta-cyclodextrin/Ag nanocomposite (GO/beta-CD/Ag) for MNZ removal from aqueous solution. The effect of operational parameters such as solution pH (2-5), adsorbent dosages (0.2-1 g/L), contact time (10-80 min), initial MNZ concentrations (0.25-10 mg/L) and ionic strength (0.001-0.1 mol/L) was studied using Taguchi experimental design. The maximum removal efficiency of 93.5% was observed for optimum conditions. The optimum values of contact time, the initial MNZ concentration, the ionic strength, the adsorbent dosage and solution pH were found to be 20 min, 0.25 ppm, 0.01 mol/L, 0.4 g/L and 2, respectively. Freundlich and Dubinin-Radushkevich isotherm models were best-fitted with experimental data. Pseudo-first order and type 1 pseudo-second order kinetic models showed the maximum correlation with the experimental data. Adsorption experiments with real samples indicated that the adsorptive removal of MNZ from a hospital wastewater was 72%. Desorption studies showed maximum recovery of GO/beta-CD/Ag nanocomposite during three cycles. According to the obtained results, it can be concluded that the application of carbon adsorbents such as GO/beta-CD/Ag can be considered an efficient method for final treatment of effluents containing antibiotics. PMID- 29698220 TI - Evaluation of technology potential of Aloe arborescens biopolymer in galvanic effluent treatment. AB - Biopolymers have the ability to form gels that can be used in coagulation/flocculation processes. For this reason, the present work evaluated the application of the Aloe arborescens gel as a biopolymer in the treatment of the effluent generated in galvanic processes. The centesimal, thermogravimetric and texture profiles, as well as the functional groups and the biopolymer's performance in the treatment was analyzed. The performance results were evaluated by central composite rotational design 23. The variables biopolymer concentration, aluminum sulphate and initial pH of the effluent were significant at the confidence level of 95%. The Cr(VI) removal efficiency ranged from 6.37% to 37.74%; significant reductions in dissolved solids (89.80% to 94.13%) and suspended solids (71.06% to 90.00%) were also observed. The treated effluent still presents parameters above the regulatory limits stated by the legislation, therefore, the biopolymer could be used as initial treatment for solids removal. PMID- 29698221 TI - Modified powder activated carbon-catalyzed ozonation of humic acid: influences of chemical and textural properties. AB - A modification method that combines thermal and oxidation treatments was used to improve catalytic activity of activated carbon (AC) which catalyzed ozonation of the aquatic contaminant humic acid (HA). As a consequence of modifying virgin AC, modified AC (ACN2O2N2) had good catalytic performance for ozonation of HA. Apparent first-order rate constants (kapp) were ACN2O2N2 (7.88 * 10-3 s-1) > virgin AC (3.28 * 10-3 s-1). This change was discussed in terms of three factors: textural property, graphitization degree, and surface chemical property. From analysis results, it was deduced that the surface chemical property (the concentration of surface groups) was the main factor that influenced catalytic activity. An increase in the concentration of hydroxyl groups on AC enhanced catalytic activity of AC in ozonation of HA. Effects of phosphate (both a ligand and a strong Lewis base) further confirmed that Lewis acid sites (hydroxyl groups) were the active centers for free radical reaction in catalytic ozonation of AC. PMID- 29698222 TI - Experimental study of geysers through a vent pipe connected to flowing sewers. AB - Geysers of air-water mixtures in urban drainage systems is receiving considerable attention due to public safety concerns. However, the geyser formation process and its relation with air release from pressurized pipes are still relatively little known. A large-scale physical model, that consisted of a main tunnel with a diameter of 270 mm and a length of 25 m connecting two reservoirs and a vertical vent pipe, was established to investigate geyser evolution and pressure transients. Experimental results including dynamic pressure data and high speed videos were analysed in order to characterize geysering flow through the vent pipe. Pressure transients were observed during geysering events. Their amplitudes were found to be about three times the driving pressure head and their periods were close to the classic surge tank predictions. The influence of flow rate and vent pipe size were examined: geyser heights and pressure peaks decreased for small flow rate and large diameter vent pipe. It is suggested that geyser heights are related with the pressure head and the density of the air-water mixture. PMID- 29698223 TI - Significantly photoinduced synergy between sodium sulfite and ammonium nitrate and the mechanism study. AB - In this paper, a significantly photoinduced synergy between ammonium nitrate and sodium sulfite via dye decolorization was first found. This study mainly aims to explore the influences of several fundamental aspects on the photoinduced synergy as well as discuss the detailed mechanisms. The dye removal efficiencies of methyl orange and methylene blue of the synergistic system are much higher than that of a single one, and they reach 96.4% and 90.7% when the illumination is 6 and 14 min, respectively. The optimum mass ratio of sodium sulfite and ammonium nitrate in the reaction system is 1:1. The reaction process of photoinduced synergy follows the first-order reaction equation. Effects of different structures of dyes, amount of sodium sulfite and initial dye concentration on the synergistic effect were investigated. The changes of UV-vis spectra in the course of photoinduced synergy were also examined. The excellent synergistic effect can owe to the simultaneous photoreduction and photooxidation reaction with respect to photoinduced hydrated electrons (eaq-) and SO4*- active species, respectively. This work may provide some insight into detoxifying water contaminants in practical applications as well as developing other novel photoinduced synergistic systems with high performance. PMID- 29698224 TI - A comparative study of manhole hydraulics using stereoscopic PIV and different RANS models. AB - Flows in manholes are complex and may include swirling and recirculation flow with significant turbulence and vorticity. However, how these complex 3D flow patterns could generate different energy losses and so affect flow quantity in the wider sewer network is unknown. In this work, 2D3C stereo Particle Image Velocimetry measurements are made in a surcharged scaled circular manhole. A computational fluid dynamics (CFD) model in OpenFOAM(r) with four different Reynolds Averaged Navier Stokes (RANS) turbulence model is constructed using a volume of fluid model, to represent flows in this manhole. Velocity profiles and pressure distributions from the models are compared with the experimental data in view of finding the best modelling approach. It was found among four different RANS models that the re-normalization group (RNG) k-E and k-omega shear stress transport (SST) gave a better approximation for velocity and pressure. PMID- 29698225 TI - Inhibitory effects of Pontederia cordata on the growth of Microcystis aeruginosa. AB - This study investigated the effect of Pontederia cordata on Microcystis aeruginosa growth in three different experimental settings: (i) co-cultivation, (ii) exposure of cyanobacteria to culture water of P. cordata, and (iii) exposure of M. aeruginosa to organic extracts of P. cordata. Results showed that the growth of M. aeruginosa was significantly inhibited by co-cultivation, with the highest inhibition rate of 61.9% within 5 days. Moreover, 95% culture water with P. cordata could markedly inhibit the growth of M. aeruginosa, with inhibition rate of 98.3% on day 6, indicating that most of the algal cells died. The organic extracts of fibrous root showed stronger inhibition effect than the leaf and stalk extracts. Acetone extract of fibrous root showed the strongest inhibitory effect on M. aeruginosa. Different components of 80% acetone extracts from fibrous root exhibited varied effects on the growth of M. aeruginosa. Ethyl acetate and water components had strong inhibition effects on M. aeruginosa. By contrast, n-butyl alcohol components had weak inhibition effects, and hexane components even promoted the growth of M. aeruginosa. Allelochemicals of P. cordata were primarily released into the water through the fibrous root. Results indicated that P. cordata can be applied in environmentally friendly algal inhibition. PMID- 29698226 TI - Antibiotic resistance profile and occurrence of AmpC between Pseudomonas aeruginosa isolated from a domestic full-scale WWTP in southeast Brazil. AB - Wastewater treatment plants (WWTPs) represent an important reservoir of antibiotic resistance determinants. Although many studies have been conducted to evaluate resistance profiles in Enterobacteriaceae isolates from this setting, the dynamics of this phenomenon are poorly known to the bacterium Pseudomonas aeruginosa. Here we aimed to evaluate the resistance profiles and the production of AmpC beta-lactamase in P. aeruginosa isolates from a domestic full-scale WWTP. Samples of the raw sewage and effluent were collected and the bacterium P. aeruginosa was isolated on cetrimide agar. Susceptibility to beta-lactams, fluoroquinolones and aminoglycosides was evaluated by the disc diffusion method, and the presence of AmpC beta-lactamase was investigated phenotypically and by molecular method. We recovered 27 isolates of P. aeruginosa. Of these, 81.5% were susceptible to all antimicrobials tested. However, a considerable rate of resistance to carbapenems (11%) was found among the isolates. Twenty-two isolates were positive in the phenotypic test for inducible AmpC beta-lactamase but the blaampc gene was only identified in four isolates, suggesting the presence of other independent resistance mechanisms besides this beta-lactamase. In summary, we have shown that P. aeruginosa isolates from a domestic WWTP represents a potential reservoir of blaampC genes and other resistance determinants, including those that result in low susceptibility to carbapenems and aminoglycosides. PMID- 29698227 TI - Adsorption of Cu2+ to biomass ash and its modified product. AB - Ash produced by biomass power plants has great potential for the removal of heavy metal ions from aqueous solution. The pollution of toxic heavy metals to water is a worldwide environmental problem. Discharges containing copper, in particular, are strictly controlled because the excessive copper can cause serious harm to the environment and human health. This work aims to investigate the adsorption characteristics of copper ions in aqueous solution by biomass ash and the modified products, and to evaluate their potential application in water pollution control. The biomass ash was modified with a mesoporous siliceous material and functionalized with 3-aminopropyltriethoxysilane. The surface properties of the biomass ash and the new matrix were studied to evaluate their adsorption property for Cu2+ ions at different pHs, initial metal concentrations and the thermodynamic and kinetic were studied. The chemical and morphological properties of this modified material are analyzed; the specific surface area of the modified biomass ash was nine times that of the initial ash. Both of the two materials showed a strong affinity for Cu2+, and the Langmuir model could best represent the adsorption characteristics of Cu2+ on the two kinds of materials. The adsorption capacity of copper on the material increased with the increase of pH and pH 6 was the optimum pH. Thermodynamic analysis results showed that the adsorption of Cu2+ was spontaneous and endothermic in nature. The adsorptions of Cu2+ onto the modified biomass ash followed pseudo-second-order kinetics. PMID- 29698228 TI - Evaluation of UV/S2O8 process efficiency for removal of metronidazole (MNZ) from aqueous solutions. AB - Antibiotics are known today as emerging contaminants due to potentially adverse effects on aquatic ecosystems and the health of humans and animals, even at very low concentrations. The present study was conducted to evaluate the efficiency of the UV/S2O8 process and affecting factors (pH, initial metronidazole (MNZ) concentration, initial persulfate concentration and reaction time) in removing antibiotic MNZ. The results obtained from the experiments showed that the UV/S2O8 process efficiency is higher in acidic pH values due to production of further radical SO4- and increases with extended contact time, but the efficiency of the process is reduced by increasing the concentration of MNZ. In assessing the effect of initial persulfate concentration on the process efficiency, MNZ removal efficiency was also increased by 99.5% after contact time of 35 min with increasing the initial persulfate concentration up to 1 g/L. However, the process efficiency was decreased at higher concentrations (2 mg/L) due to reaction of sulfate radicals with each other or with persulfate and its saturation. The kinetic data fitted the pseudo-first-order kinetic model (R2 > 99%). The findings of this study clearly demonstrated the high potential of the UV/S2O8 process in the degradation of MNZ. PMID- 29698229 TI - An electrochemical sequential injection method to investigate the adsorption of selenite on Fe(III) polyhydroxy cations intercalated vermiculite. AB - A sequential injection - square wave anodic stripping voltammetry (SI-SWASV) method for determination of Se(IV) at a gold working electrode was developed to investigate the adsorption of Se(IV) onto vermiculite intercalated with Fe(III) polyhydroxy cations. The limits of detection and quantification were 0.060 and 0.20 MUmol L-1, respectively (4.7 and 15.7 MUg L-1). The linearity was up to 1.0 MUmol L-1, and the sampling throughput was 18 analyses h-1. The proposed approach is a low-cost alternative to more expensive spectrometric methods. Adsorption onto vermiculite intercalated with Fe(III) polyhydroxy cations removed 93% of Se(IV) from a 1.0 MUmol L-1 solution (250 mL) after 5 min of contact time with 625 mg of adsorbent. Adsorption isotherms (25.0 +/- 0.5 degrees C) were fitted by the Freundlich equation resulting in 1/n = 0.51 +/- 0.03 and Kf = (1.584 +/- 0.002) * 103 MUmol1-1/n g-1 L1/n (r2 = 0.995). Fitting by the Langmuir equation resulted in an adsorption constant of 0.026 +/- 0.008 L g-1 and adsorption capacity of 47 +/- 5 MUmol g-1 (3.7 +/- 0.4 mg g-1) (r2 = 0.97). This capacity was higher than that found for several other iron oxides, but lower than that obtained for oxide/hydroxide-based Fe(III) nanoparticles. PMID- 29698230 TI - Modeling the biotransformation of trimethoprim in biological nutrient removal system. AB - A pilot scale biological nutrient removal (BNR) process, batch experiments and modeling exercises were employed to investigate the removal and biotransformation of trimethoprim (TMP) in a BNR activated sludge process. The concentrations of the active microbial groups - ammonia oxidizing bacteria (AOB), ordinary heterotrophic organisms (OHOs) and polyphosphate accumulating organisms (PAOs) - in the BNR bioreactor were quantified through modeling of the pilot bioreactor. The overall TMP removal efficiency for the pilot BNR process was 64 +/- 14% while the TMP biotransformation efficiencies in the anaerobic, anoxic and aerobic zones were 22 +/- 20%, 27 +/- 8% and 36 +/- 5% respectively. Batch tests with and without nitrification inhibition showed that AOB played a role in the biotransformation of TMP in BNR activated sludge. A pseudo first order model which incorporated the contributions of PAOs, OHOs and AOB to the overall biodegradation of TMP was found to describe the biodegradation of TMP in batch tests with and without nitrification inhibition. This model showed that PAOs, OHOs and AOB contributed towards the biotransformation of TMP in aerobic BNR activated sludge with the biotransformation rate constants following the trend of kAOB > kOHOs > kPAOs. PMID- 29698231 TI - Effect of dairy wastewater on changes in COD fractions in technical-scale SBR type reactors. AB - The annual global production of milk is approximately 630,000 million litres and the volume of generated dairy wastewater accounts for 3.2 m3.m-3 product. Dairy wastewater is characterized by a high load of chemical oxygen demand (COD). In many wastewater plants dairy wastewater and municipal wastewater are co-treated. The effect of dairy wastewater contribution on COD fraction changes in municipal sewage which has been treated with a sequencing batch reactor (SBR) in three wastewater treatment plants in north-east Poland is presented. In these plants the real contribution of dairy wastewater was 10, 13 and 17%. In raw wastewater, SS fraction (readily biodegradable dissolved organic matter) was dominant and ranged from 38.3 to 62.6%. In the effluent, SS fraction was not noted, which is indicative of consumption by microorganisms. The presence of dairy wastewater in municipal sewage does not cause changes in the content of the XI fraction (insoluble fractions of non-biodegradable organic matter). SBR effluents were dominated by non-biodegradable dissolved organic matter SI, which from 57.7 to 61.7%. In raw wastewater SI ranged from 1.0 to 4.6%. Xs fraction (slowly biodegradable non-soluble organic matter) in raw wastewater ranged from 24.6 to 45.5% while in treated wastewater it ranged from 28.6 to 30.8%. In the control object (fourth wastewater plant) which does not process dairy wastewater, the SS, SI, Xs and XI fraction in inflow was 28.7, 2.4, 51.7 and 17.2% respectively. In the effluent the SS, SI, Xs and XI fraction was below 0.1, 33.6, 50.0 and 16.4% respectively. PMID- 29698232 TI - Behavior of mesoporous activated carbon used as a remover in Congo red adsorption process. AB - The adsorption characteristics of Congo red (CR) dye on activated carbon produced under optimized conditions from tomato paste waste were evaluated. The effects of adsorbent dose, initial dye concentration, contact time, ionic strength and solution temperature on adsorption were investigated. Adsorption kinetic was better described by the pseudo-first order model. Results of the intra-particle diffusion model show that the pore diffusion is not the only rate-limiting step. Adsorption isotherm was well defined by the Langmuir isotherm. The maximum adsorption capacity of the activated carbon was 435 mg g-1 at 328 K. The dimensionless separation factor RL revealed the favorable nature of the isotherm of the activated carbon-dye system. Adsorption energy was found to be 4.20-4.55 kJ mol-1 indicating that the mechanism of adsorption is physical in nature. Thermodynamic studies showed that CR adsorption onto activated carbon was feasible, spontaneous and endothermic. Desorption of the used activated carbon was studied using ethanol as solvent and desorption efficiency of 56.4% was obtained after five cycles. The findings indicated that the activated carbon is a very effective and low-cost adsorbent for removal of CR dye from aqueous solutions. PMID- 29698233 TI - MoS2/Cu/TiO2 nanoparticles: synthesis, characterization and effect on photocatalytic decomposition of methylene blue in water under visible light. AB - Photodegradation processes are of great interest in a range of applications, one of which is the photodecomposition of pollutants. For this reason, analysing nanoparticles that improve the efficiency of these processes under solar radiation are very necessary. Thus, in this study, TiO2 was doped with Mo and Cu using low-temperature hydrolysis as the method of synthesis. Pure TiO2 and x%MoS2/Cu/TiO2 nanoparticles were prepared, where x is the theoretical quantity of MoS2 added (0.0%, 1.0%, 5.5%, 10.0%), setting the nominal quantity of Cu at 0.5 wt.%. The samples obtained were characterized by X-ray diffraction, Raman spectroscopy, X-ray electron spectroscopy and UV-Vis spectroscopy in diffuse reflectance mode. The results suggest that the TiO2 structure was doped with the Mo6+ and Cu2+ ions in the position of the Ti4+. The x%MoS2/Cu/TiO2 samples presented lower band gap energy values and greater optical absorption in the visible region than the pure TiO2 sample. Lastly, the photocatalytic activity of the samples was assessed by means of the photodegradation of methylene blue under visible light. The results show that when the quantity of Mo in the co-doped samples increased (x%MoS2/Cu/TiO2) there were significant increases of up to 93% in the photocatalytic activity. PMID- 29698234 TI - Sulphate removal from mine water with chemical, biological and membrane technologies. AB - Chemical, physical and biological technologies for removal of sulphate from mine tailings pond water (8 g SO42-/L) were investigated. Sulphate concentrations of approximately 1,400, 700, 350 and 20 mg/L were obtained using gypsum precipitation, and ettringite precipitation, biological sulphate reduction or reverse osmosis (RO) after gypsum pre-treatment, respectively. Gypsum precipitation can be widely utilized as a pre-treatment method, as was shown in this study. Clearly the lowest sulphate concentrations were obtained using RO. However, RO cannot be the only water purification technology, because the concentrate needs to be treated. There would be advantages using biological sulphate reduction, when elemental sulphur could be produced as a sellable end product. Reagent and energy costs for 200 m3/h tailings pond water feed based on laboratory studies and process modelling were 1.1, 3.1, 1.2 and 2.7 MEur/year for gypsum precipitation, ettringite precipitation, RO and biological treatment after gypsum precipitation, respectively. The most appropriate technology or combination of technologies should be selected for every industrial site case by case. PMID- 29698235 TI - Multivariate frequency analysis of urban rainfall characteristics using three dimensional copulas. AB - Urban runoff is a major cause of urban flooding and is difficult to monitor in the long term. In contrast, long term continuous rainfall data are generally available for any given region. As a result, it has become customary to use design rainfall depth as a proxy for runoff in urban hydrological analyses, with an assumption of the same frequency for runoff and rainfall. However, this approach has lack of overall coordination and cannot fully reflect the variability of rainfall characteristics. To address this issue, this study presents a three-dimensional copula-based multivariate frequency analysis of rainfall characteristics based on a long term (1961-2012) rainfall data from Guangzhou, China. Firstly, continuous rainfall data were divided into individual rainfall events using the rainfall intensity method. Then the characteristic variables of rainfall (design rainfall depth, DRD; total rainfall depth, TRD; peak rainfall depth, PRD) were sampled using the annual maximum method. Finally, a copula method was used to develop the multivariate joint probability distribution and the conditional probability distribution of rainfall characteristics. The results showed that the copula-based method is easy to implement and can better reflect urban rainstorm characteristics. It can serve a scientific reference for urban flood control and drainage planning. PMID- 29698236 TI - Behaviours of direct yellow 12 adsorption on mesoporous carbons with different pore geometries. AB - Four kinds of mesoporous carbons, C1-h-w, C2-h-h, C3-s-w, and C4-s-h, with different pore geometries were prepared and characterised, and their adsorption behaviours with aqueous direct yellow 12 (DY-12) were investigated. The results of X-ray diffraction and transmission electron microscopy show that C1-h-w and C3 s-w have wormlike pore characteristics, whereas C2-h-h and C4-s-h have 2-D hexagonally arranged pores. According to the N2 adsorption/desorption results, the specific surface area of C1-h-w (1,378 m2/g) is the largest among the four carbons. The adsorption isotherms could be effectively fitted using the Langmuir model. The maximum adsorption amounts of C1-h-w, C2-h-h, C3-s-w and C4-s-h are 0.968 mmol/g, 0.726 mmol/g, 0.161 mmol/g and 0.156 mmol/g, respectively. The pseudo-second-order rate constants of C1-h-w (39.8 g/(mmol.min)) and C2-h-h (7.28 g/(mmol.min)) are substantially larger than those of C3-s-w (0.0046 g/(mmol.min)) and C4-s-h (0.014 g/(mmol.min)), indicating that an open and interconnected pore geometry is favourable for DY-12 adsorption. Furthermore, DY-12 diffusion in 2-D hexagonally ordered cylindrical pores is superior to that in wormlike pores due to the smoothness of the channels in the former. External mass transfer and intraparticle diffusion both play roles in the adsorption process. PMID- 29698237 TI - Rheology characteristics of activated sludge and thermal treated sludge at different process temperature. AB - In this paper, flow behavior for activated sludge and thermal treated sludge at different process temperature and various solids content were analyzed. Results show viscosity of activated sludge and thermal treated sludge both decreased with increasing temperature, while temperature dependence of viscosity for both types of sludge were not same at the whole study range. The relationship between viscosity and temperature could be expressed by Arrhenius equation for activated sludge, and it was interesting that this law was only suitable when certain solid content (80 g/L) for thermal treated sludge. Moreover, the logistic model was certified to be accurate in describing the functionality for thermal treated sludge. As solid content was at range of 80-100 g/L, active energy of viscosity for both kinds of sludge were similar, indicating that physicochemical properties' change of sludge after thermal hydrolysis had little effect on viscosity sensibility. Arrhenius law was also suitable for describing the relationship between storage modulus and process temperature for activated sludge. However, for thermal treated sludge, Arrhenius law was invalid. Yield stress for activated sludge was prominent, while it could be ignored for thermal treated sludge. PMID- 29698238 TI - River flood prediction using fuzzy neural networks: an investigation on automated network architecture. AB - Urban floods are one of the most devastating natural disasters globally and improved flood prediction is essential for better flood management. Today, high resolution real-time datasets for flood-related variables are widely available. These data can be used to create data-driven models for improved real-time flood prediction. However, data-driven models have uncertainty stemming from a number of issues: the selection of input data, the optimisation of model architecture, estimation of model parameters, and model output. Addressing these sources of uncertainty will improve flood prediction. In this research, a fuzzy neural network is proposed to predict peak flow in an urban river. The network uses fuzzy numbers to account for the uncertainty in the output and model parameters. An algorithm that uses possibility theory is used to train the network. An adaptation of the automated neural pathway strength feature selection (ANPSFS) method is used to select the input features. A search and optimisation algorithm is used to select the network architecture. Data for the Bow River in Calgary, Canada are used to train and test the network. PMID- 29698239 TI - Improve the biodegradability of post-hydrothermal liquefaction wastewater with ozone: conversion of phenols and N-heterocyclic compounds. AB - Hydrothermal liquefaction is a promising technology to convert wet biomass into bio-oil. However, post-hydrothermal liquefaction wastewater (PHWW) is also produced during the process. This wastewater contains a high concentration of organic compounds, including phenols and N-heterocyclic compounds which are two main inhibitors for biological treatment. Thus, proper treatment is required. In this work, ozone was used to convert phenols and N-heterocyclic compounds with a dosage range of 0-4.64 mg O3/mL PHWW. After ozone treatment, the phenols were fully converted, and acids were produced. However, N-heterocyclic compounds were found to have a low conversion rate (21.7%). The kinetic analysis for the degradation of phenols and N-heterocyclic compounds showed that the substitute played an important role in determining the priority of ozone reactions. The OH moiety in the ring compounds (phenols and pyridinol) may form hydroxyl radical, which lead to an efficient reaction. A substantial improved biodegradability of PHWW was observed after ozone treatment. The ratio of BOD5/COD was increased by about 32.36%, and reached a maximum of 0.41. The improved biodegradability of PHWW was justified by the conversion of phenols and N-heterocyclic compounds. PMID- 29698240 TI - Predicting fruit and vegetable processing wash-water quality. AB - Wastewaters from the fresh produce processing industry are high in solids and organic matter requiring adequate treatment prior to disposal or recycling. Characterization of the processing wastewater, also referred to as wash-water is challenging, as the quality is a function of the produce. Analysis of water quality parameters, such as total suspended solids, total solids, total dissolved solids, chemical oxygen demand, biochemical oxygen demand, total nitrogen, total phosphorus, ammonia, and electrical conductivity from different fruit and vegetable operations were analyzed to develop the innovative power function models and ranking system to estimate wash-water quality. The developed models take the form of Y = a(x)b, where Y, a, x, and b are estimate, scale, rank, and location parameters, respectively. The location and rank range from -0.65 to 3.18 and 0.05 (worst water quality) to 1, respectively, while the scale parameters are highly variable. Average and standard deviation estimation models show a very good fit for washing only (R2 > 73%) and washing with processing (R2 > 79%). The models and ranks highlight the degree of treatment required to address protection of surface and ground water and make the water quality conform to regulatory standards, benefiting watershed managers, government agencies, consultants, farmers, producers, processors and technology providers. PMID- 29698241 TI - Salinity and pH effects on floating and emergent macrophytes in a constructed wetland. AB - Salvinia herzogii, Pistia stratiotes and Eichhornia crassipes (floating species) were the dominant macrophytes in a constructed wetland (CW) over the first years of operation. Later, the emergent Typha domingensis displaced the floating species, becoming dominant. The industrial effluent treated at this CW showed high pH and salinity. The aim of this work was to study the tolerance of floating species and T. domingensis exposed to different pH and salinity treatments. Treatments at pH 8, 9, 10 and 11 and salinities of 2,000; 3,000; 4,000; 6,000; and 8,000 mg L-1 were performed. Floating macrophytes were unable to tolerate the studied pH and salinity ranges, while T. domingensis tolerated higher pH and salinity values. Many industrial effluents commonly show high pH and salinity. T. domingensis demonstrated to be a suitable macrophyte to treat this type of effluents. PMID- 29698242 TI - Rheology and friction loss of raw and digested sewage sludge with high TSS concentrations: a case study. AB - High total suspended solids (TSS) digestion of municipal sewage sludge reduces the required space and volume for digestion plants. However, an important consequence of high TSS is the major influence on sludge rheology. The present case study investigates the rheology of sludge from a 130 m3 high solids digestion pilot plant at Vienna's main wastewater treatment plant (4 M PE120). Raw sludge ranged from 6 to 8% TSS and digested sludge from 3.2 to 4.6%. TSS show an exponential impact on rheological parameters. Increasing raw sludge TSS from 6 to 8% at least doubles the shear stress and increases friction loss by a factor of three. However, under real operating conditions simulated at the pilot plant, there are additional impact factors. The mixing ratio between waste activated and primary sludge influences raw sludge rheology, while solids retention time and loss on ignition affects digested sludge rheology. Nevertheless, friction loss calculations based on a simple power law relationship between shear rate and shear stress proved to be applicable and sufficiently accurate for both raw and digested sludge with high TSS. Altogether, this case study underlines the relevance of comprehensive rheological considerations, measurements and calculations when designing high TSS sludge digestion. PMID- 29698243 TI - International experiences in stormwater fee. AB - Stormwater management (SWM) includes a wide range of services aimed at environmental protection, enhancement of water resources and flood control. Local governments are responsible for managing all these aspects within their jurisdiction, but they often present limitations in generating revenues. Thus, many municipalities have been seeking a dedicated funding source for these programs and practices. This publication provides a brief overview of current legal issues associated with stormwater funding focusing on the most used method: fees. It is a successful mechanism to fund legal obligations of municipalities; however, it must have a significant value to motivate the reduction of runoff. Through literature, we found stormwater fees in Australia, Brazil, Canada, Ecuador, France, Germany, Poland, South Africa and the United States (USA). France had the highest average monthly fee, but this financing experience was suspended in 2014. Brazil has the lowest fee by m2, comparable to the US fee. While in Brazil overall SWM represents low priority investments, the USA represents one of the most evolved countries in stormwater funding practices. It was noticed by reviewing the international experience that charging stormwater fees is a successful mechanism to fund the legal obligations and environmental protection. PMID- 29698244 TI - Carboxylate-functionalized sugarcane bagasse as an effective and renewable adsorbent to remove methylene blue. AB - This study prepared a carboxylate-functionalized sugarcane bagasse (CF-SCB) from sugarcane bagasse (SCB) via a simple and low-toxicity chemical modification to enhance its capacity for adsorbing methylene blue (MB) from aqueous solutions. The success of chemical modification was confirmed by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), the pore area and porosity, and zeta potential measurement analysis. The adsorption capacity of CF-SCB was investigated at different pHs, ionic strengths, temperatures, contact times and initial dye concentrations. Equilibrium data were best described by the Langmuir isotherm model, and the maximum monolayer adsorption capacity of CF-SCB (296.74 mg g-1) was greatly improved compared with SCB (77.16 mg g-1) at 30 degrees C. The thermodynamic study indicated that MB adsorption onto CF-SCB was a spontaneous, endothermic and entropy increased process. Adsorption kinetics followed a pseudo-second-order mode, and the adsorption mechanism was based on electrostatic interactions. The reusability study showed that CF-SCB had reasonably good reuse potential. All the results suggested that CF-SCB has high potential to be used as an effective and renewable adsorbent for MB removal from wastewater. PMID- 29698245 TI - Mercury (II) adsorption from aqueous solution using nitrogen and sulfur co-doped activated carbon. AB - Activated carbon (AC) was modified with urea, thioglycolic acid and thiourea to obtain nitrogen doped activated carbon (ACN), sulfur doped activated carbon (ACS) and nitrogen and sulfur co-doped activated carbon (ACNS), respectively. The AC samples were characterized by elemental analysis, N2 adsorption-desorption, determination of the pH of the point of zero charge (pHpzc) and X-ray photoelectron spectroscopy, and tested for adsorption behaviors of Hg(II) ions. The experimental data of equilibrium isotherms fitted well with the Langmuir model. ACNS showed the highest adsorption capacity of 511.78 mg/g, increasing more than 2.5 times compared to the original ACA. The adsorption process followed pseudo-second-order kinetics. The thermodynamic parameters of DeltaH degrees , DeltaS degrees , and DeltaG degrees at 30 degrees C were -20.57 kJ/mol, -0.032 kJ/mol K and -10.87 kJ/mol, respectively. It was concluded that the Hg(II) ions' adsorption on ACNS was exothermic, spontaneous and physiosorptive in nature. Finally, the adsorption capacity of ACNS reduced by just 8.13% even after the sixth cycle compared to the initial cycle. PMID- 29698246 TI - The Potential Diagnostic Accuracy of Autopsy Lung Weights, Lung-Heart Ratio, and Lung-Body Ratio in Drowning Deaths. AB - Lung weights are often increased in drowning deaths as well as in other types of deaths. Lung weights may also vary with age, sex, and body weight. A variety of methods have been proposed to utilize lung weight data to assist with the diagnosis of drowning. The present study compared lung weight, lung-heart ratio (LH), and lung-body ratio (LB) between 50 consecutive drowning and 50 nonimmersion deaths in order to assess the accuracy in diagnosing drowning. Analysis revealed both LH and LB to be statistically higher in drowning deaths (P < 0.05), with LB being the most robust measurement. However, the overall diagnostic accuracies of lung weight, LH, and LB were poor to fair, and should therefore be used only in conjunction with the other diagnostic criteria. PMID- 29698247 TI - Higher Heart Weight in New Zealand Maori and Pacific Islanders. AB - Heart weight is dependent on sex, age, height, and weight. Although previous autopsy studies showed no differences in heart weight between different ethnic groups, none have examined the New Zealand population of Maori and Pacific Islanders (Polynesians). The presented study compared heart weights between 101 European and 85 Polynesian suicide hanging deaths from New Zealand. Univariate linear regression coefficients for age, male sex, height, body weight, body mass index, and Polynesian ethnicity were positive and significant (P < 0.05). Apart from body mass index, subsequent multivariate analysis showed that all regression coefficients remained positive and significant (P < 0.05). Polynesian ethnicity seemed to be an independent predictor for increased heart weight in the study population. Apart from possible genetic factors, the higher heart weight in Polynesians may have other underlying reasons. Caution is required when interpreting heart weight in cases of sudden natural deaths, especially in this population. PMID- 29698248 TI - Simultaneous Blood Glucose Monitoring During Gastric-Emptying Scintigraphy May Identify Unsuspected Abnormalities. AB - PURPOSE: A retrospective study of 197 patients was performed to evaluate utility of simultaneous fingerstick glucose monitoring during standardized solid meal gastric-emptying scintigraphy (GES). We hypothesized the unlabeled carbohydrate components of the standardized meal often empty at different rates than the labeled egg protein component and that simultaneous glucose monitoring may identify rapid carbohydrate gastric emptying. METHODS: Patients were classified as normal, rapid, or delayed gastric emptying from the standardized solid egg meal GES criteria. Further subcategorization was made based on postprandial glycemic excursions above baseline at 30/60 minutes and was delineated as elevated (>75 mg/>85 mg/dL), normal, or diminished (<30 mg/dL) glucose excursion. RESULTS: Of the 197 patients, solid gastric-emptying rates for 105 were normal, delayed in 54, and rapid in 25 patients, and 13 patients had initially delayed emptying 1 or 2 hours with normal emptying by 4 hours. Of the 105 patients with normal gastric emptying, 58 had elevated, 47 normal, and none had diminished glucose excursions. Of the 54 patients with delayed gastric emptying, 26 had elevated, 16 had normal, and 12 had diminished glucose excursions. Nine patients with normal or delayed gastric emptying but elevated glycemic excursions returned for a liquid glucose GES. In contrast to their standardized GES results, all 9 had rapid emptying with elevated glycemic excursions. CONCLUSIONS: Simultaneous blood glucose monitoring with standardized GES protocols may provide a marker for contradictory findings of rapid gastric emptying of the unlabeled carbohydrate component in the standardized meal and may contribute to unexplained postprandial gastrointestinal symptoms. The additional insights provided by fingerstick glucose monitoring are inexpensive, easy to perform and may provide for new approaches to management of patient's gastrointestinal symptoms. PMID- 29698249 TI - Memories of Infant Pain in the Neonatal Intensive Care Unit Influence Posttraumatic Stress Symptoms in Mothers of Infants Born Preterm. AB - OBJECTIVES: The birth of a preterm infant and witnessing ones' infant in pain is remembered by parents as being one of the most stressful aspects of the neonatal intensive care unit (NICU). Elevated posttraumatic stress symptoms (PTSS) are highly prevalent among mothers of preterm infants, however, little is known about mothers' memories of invasive procedures in the NICU and how these memories may contribute to the development of PTSS. We examined the relationships between number of invasive procedures, mothers' memories of these procedures, and their PTSS at discharge from the NICU. MATERIALS AND METHODS: Participants included 36 mothers of infants born below 37 weeks gestational age recruited from a tertiary level NICU. Medical chart review was performed between birth and discharge from the NICU. At discharge, a research nurse conducted a structured memory interview with the mothers to assess their memories of their infants' invasive procedures. Mothers also completed a self-report measure of PTSS (Posttraumatic Stress Disorder Checklist for the DSM-5). RESULTS: Mothers of infants exposed to greater numbers of invasive procedures had more elevated PTSS at discharge (R=0.37). Moreover, mothers who recalled having greater anxiety about their infant's invasive procedures had greater symptoms of reexperiencing (R=0.34) and avoidance (R=0.28) at discharge from the NICU. DISCUSSION: Greater neonatal exposure to invasive procedures and mothers' recall of these procedures were related to mothers' posttraumatic stress symptomatology at discharge. Invasive procedures in the NICU represent an important target area for neonatal intervention to reduce maternal distress and improve outcomes. PMID- 29698250 TI - The Analgesic and Emotional Response to Intravenous Lidocaine Infusion in the Treatment of Postherpetic Neuralgia: A Randomized, Double-Blinded, Placebo controlled Study. AB - OBJECTIVES: This study evaluated the analgesic efficacy and emotional response to intravenous lidocaine infusion compared with placebo in patients with postherpetic neuralgia (PHN). METHODS: In this randomized, double-blinded study, patients with PHN received 5 mg/kg intravenous lidocaine infusion or placebo. The primary outcome was pain measured by Visual Analogue Scale, Von Frey, and area of allodynia. Moreover, emotional status of anxiety and depression were evaluated by Self-rating Anxiety Scale (SAS) and Self-rating Depression Scale (SDS). Quality of life was assessed by Short Form Health Survey 36. RESULTS: In total, 197 patients were enrolled and eligible data were collected from 183 of those patients. The Visual Analogue Scale scores were reduced to a minimum at 2 weeks (2.74, 2.99) after infusion, but no significant difference was found between the lidocaine and placebo groups. Similar changes were also found in mechanical pain threshold and area of allodynia. However, the lidocaine group was associated with a statistically significant reduction in consumption of analgesics with a relative risk of 6.2 (95% confidence interval [CI], 2.24-17.16). Lidocaine infusion also significantly improved the anxiety and depression status; the values of mean change in anxiety and depression were 3.89 (95% CI, 1.43-6.35) and 4.3 (95% CI, 0.63-7.98), respectively, at 2 weeks. Moreover, improvement was exhibited in Short Form Health Survey 36 health status, with the mean change of 49.81 (95% CI, 28.17-71.46) at 1 week, in particular scores on vitality, physical and emotional role functioning, and mental health. CONCLUSIONS: The analgesic response of 5 mg/kg lidocaine intravenous infusion is comparable to placebo in patients with PHN, but intravenous lidocaine infusion significantly reduced total analgesic consumption, and improved the overall emotional and health status. PMID- 29698251 TI - Effects of the Tailored Activity Program in Brazil (TAP-BR) for Persons With Dementia: A Randomized Pilot Trial. AB - OBJECTIVES: The objectives of this study were to evaluate the effects of the Tailored Activity Program-Brazilian version (TAP-BR), on behavioral symptoms and the quality of life (QOL) in persons with dementia, as well as on their caregivers, and on caregiver burden. MATERIALS AND METHODS: A 2-group randomized controlled trial with 30 dyads was conducted: the experimental group (n=15) received TAP-BR over 4 months, and a wait-list control group (n=15) received usual care. Dyads were recruited from the community of Santos City, Brazil. RESULTS: For persons with dementia, 50% were female individuals, the average age was 81.37 (+/-7.57), and the educational level was 9.97 (+/-5.32) years. For caregivers, 83.33% were female, the average age was 65.97 (+/-10.13), and the educational level was 12.10 (+/-4.44) years. At posttest, in comparison with the wait-list control group, experimental group caregivers reported greater reductions in number (P<0.001; Cohen d=0.93), frequency (P<0.001; Cohen d=1.12), and intensity (P<0.001; Cohen d=0.77) of the behavioral psychological symptoms of dementia, and caregiver distress (P<0.001; Cohen d=0.87). Caregivers also reported improvement in their own QOL (P<0.05; Cohen d=0.57) and that of the person with dementia (P<0.01; Cohen d=0.56); no differences were found in the ratings of QOL by the person with dementia themselves. CONCLUSIONS: The results provide compelling evidence that the TAP-BR is an effective strategy to support dementia caregivers in other cultures (cross-validation). PMID- 29698252 TI - Examining the Effects of an Otago-Based Home Exercise Program on Falls and Fall Risks in an Assisted Living Facility. AB - BACKGROUND AND PURPOSE: The Otago exercise program is a strengthening, balance, and walking program designed to decrease falls among community-dwelling older adults. Few studies have examined the effects of the Otago program in an assisted living environment. The purpose of the current study was to assess the effects of an Otago-based home exercise program in decreasing falls and the risk of falls among older adults living in an assisted living facility. METHODS: A retrospective chart review of 30 individuals residing at either of 2 assisted living facilities in central Florida was undertaken. Participants had a mean age of 87 years, were at risk for falls as determined by the Tinetti Performance Oriented Mobility Assessment (POMA), and were provided with an Otago-based intervention by home health physical therapy. The outcome measures were the number of falls in the previous year, the number of falls in the year following the intervention, and Tinetti POMA scores pre- and postintervention. RESULTS AND DISCUSSION: The mean number of falls significantly decreased from 1.4 (0.9) to 0.5 (0.7) fall per person per year after home health physical therapy with the tailored Otago based-exercise intervention. The intervention resulted in a statistically significant improvement in Tinetti POMA scores from 11.8 (2.5) to 17.6 (3.8). CONCLUSIONS: An Otago-based strengthening, balance, and walking home exercise program can potentially be used to decrease the number of falls and the risk of falling among older adults residing in an assisted living facility. PMID- 29698253 TI - Auditory Icon Alarms Are More Accurately and Quickly Identified than Current Standard Melodic Alarms in a Simulated Clinical Setting. AB - BACKGROUND: Current standard audible medical alarms are difficult to learn and distinguish from one another. Auditory icons represent a new type of alarm that has been shown to be easier to learn and identify in laboratory settings by lay subjects. In this study, we test the hypothesis that icon alarms are easier to learn and identify than standard alarms by anesthesia providers in a simulated clinical setting. METHODS: Twenty anesthesia providers were assigned to standard or icon groups. Experiments were conducted in a simulated intensive care unit. After a brief group-specific alarm orientation, subjects identified patient associated alarm sounds during the simulation and logged responses via a tablet computer. Each subject participated in the simulation twice and was exposed to 32 alarm annunciations. Primary outcome measures were response accuracy and response times. Secondary outcomes included assessments of perceived fatigue and task load. RESULTS: Overall accuracy rate in the standard alarm group was 43% (mean) and in the icon group was 88% (mean). Subjects in the icon group were 26.1 (odds ratio [98.75% CI, 8.4 to 81.5; P < 0.001]) times more likely to correctly identify an alarm. Response times in the icon group were shorter than in the standard alarm group (12 vs. 15 s, difference 3 s [98.75% CI ,1 to 5; P < 0.001]). CONCLUSIONS: Under our simulated conditions, anesthesia providers more correctly and quickly identified icon alarms than standard alarms. Subjects were more likely to perceive higher fatigue and task load when using current standard alarms than icon alarms. PMID- 29698256 TI - What Nurses Do. AB - Quiet thoughtfulness can be a powerful intervention. PMID- 29698255 TI - When do co-infections matter? AB - PURPOSE OF REVIEW: Advances in diagnostic methods mean that co-infections are increasingly being detected in clinical practice, yet their significance is not always obvious. In parallel, basic science studies are increasingly investigating interactions between pathogens to try to explain real-life observations and elucidate biological mechanisms. RECENT FINDINGS: Co-infections may be insignificant, detrimental, or even beneficial, and these outcomes can occur through multiple levels of interactions which include modulation of the host response, altering the performance of diagnostic tests, and drug-drug interactions during treatment. The harmful effects of chronic co-infections such as tuberculosis or Hepatitis B and C in association with HIV are well established, and recent studies have focussed on strategies to mitigate these effects. However, consequences of many acute co-infections are much less certain, and recent conflicting findings simply highlight many of the challenges of studying naturally acquired infections in humans. SUMMARY: Tackling these challenges, using animal models, or careful prospective studies in humans may prove to be worthwhile. There are already tantalizing examples where identification and treatment of relevant co-infections seems to hold promise for improved health outcomes. PMID- 29698257 TI - Adopt Zero Tolerance for Hospital Staff Bullying Nursing Students. AB - Negative clinical experiences can have a formative influence on aspiring nurses. PMID- 29698258 TI - Independent Practice by APRNs. PMID- 29698259 TI - Saving the Safety Net. PMID- 29698260 TI - Death with Dignity. PMID- 29698261 TI - Death with Dignity. PMID- 29698262 TI - Report: Nursing Homes Are Overmedicating People with Dementia. AB - Laws against such 'chemical restraints' aren't being enforced. PMID- 29698263 TI - Fighting Night-Shift Fatigue. AB - Short naps revive nurses. PMID- 29698264 TI - NewsCAP: Updates to adult and child immunization schedules are issued for 2018. PMID- 29698266 TI - NewsCAP: New AHA guidelines include extending time to treatment for ischemic stroke. PMID- 29698265 TI - Young Single Mothers Benefit from the Affordable Care Act. AB - But a study shows uneven results in birth outcomes. PMID- 29698267 TI - NSAID Users Often Exceed Recommended Dose Limits. AB - Study reveals a poor understanding of label cautions and recommendations. PMID- 29698268 TI - NewsCAP: Asymptomatic women with no known risk of ovarian cancer do not benefit from screening for the disease. PMID- 29698269 TI - NewsCAP: The FDA approves a blood test to aid assessment after head injury. PMID- 29698272 TI - Sexual Harassment in Nursing: A Long-Standing, but Rarely Studied Problem. AB - The #MeToo and #TimesUp movements have relevance for nurses. PMID- 29698273 TI - New Treatment for BRCA-Mutated Metastatic Breast Cancer. PMID- 29698274 TI - New Radiopharmaceutical Approved to Treat Rare Digestive Tract Cancer. PMID- 29698275 TI - Reports of Anaphylaxis with an Antiemetic. PMID- 29698276 TI - A Moment of Mindfulness. PMID- 29698277 TI - 1.5 CE Test Hours: Original Research: Exploring Clinicians' Perceptions About Sustaining an Evidence-Based Fall Prevention Program. PMID- 29698278 TI - 1.5 CE Test Hours: A Review of Current Practice in Transfusion Therapy. PMID- 29698279 TI - Assisted Suicide/Aid in Dying: What Is the Nurse's Role? AB - : This article presents the discussion that occurred during a policy dialogue on aid in dying (AID) presented at the American Academy of Nursing's annual conference in October 2016. Panelists explored the arguments for and against the growing state expansion of AID legislation, and the role for nurses in assisting patients who request AID. Recommendations are offered and four expert commentaries respond to the points raised. PMID- 29698280 TI - Simplified Blood Transfusion. AB - Editor's note: From its first issue in 1900 through to the present day, AJN has unparalleled archives detailing nurses' work and lives over more than a century. These articles not only chronicle nursing's growth as a profession within the context of the events of the day, but they also reveal prevailing societal attitudes about women, health care, and human rights. Today's nursing school curricula rarely include nursing's history, but it's a history worth knowing. To this end, From the AJN Archives highlights articles selected to fit today's topics and times.At one time, blood transfusions were routinely performed only in an operating room (OR). This 1937 article describes how one hospital found a way to change this practice by bringing the OR to the bedside. Author Frances A. Burgess details the contents of the sterile tray and recommends including a second sterile instrument pack in case a "cut down" might be needed for vein access. An OR nurse brings the equipment cart to the ward and assists with the transfusion.Burgess ends her article by emphasizing the benefits of the new protocol, highlighting priorities that will sound familiar to today's hospital nurses. "With this method the operating rooms are not held up by transfusions when as many as seven to nine are given in a day, and ill patients need not be moved to the operating room."For a review of blood products, current recommendations for their use, and the potential complications of transfusions, see "A Review of Current Practice in Transfusion Therapy" in this issue. PMID- 29698281 TI - Bedpans and Learning: Nursing Basics Still Matter. PMID- 29698282 TI - Low-Molecular-Weight Heparin or Heparinoids vs. Unfractionated Heparin in Acute Ischemic Stroke. AB - Editor's note: This is a summary of a nursing care-related systematic review from the Cochrane Library. For more information, see http://nursingcare.cochrane.org. PMID- 29698284 TI - Nurses at the Top. AB - Regina Cunningham and Kevin Sowers head two of the nation's leading health care institutions. PMID- 29698283 TI - AHRQ Resources for Preventing Falls in Hospitals. AB - A toolkit and a training curriculum can facilitate change. PMID- 29698285 TI - Omega-3 Fatty Acid Supplements and Risk of CHD. PMID- 29698286 TI - Medicaid Expansion Leads to Improved Breast Cancer Care. PMID- 29698287 TI - Stroke Risk Factors Unique to Women. PMID- 29698288 TI - End-Of-Life Cancer Care For Veterans Through The VA Vs. Medicare. PMID- 29698289 TI - My People, 2014. AB - A nurse with a gravely injured family member taps a hidden network of support. PMID- 29698290 TI - Wound, Ostomy, and Continence Nursing: Scope and Standards of WOC Practice, 2nd Edition: An Executive Summary. AB - Wound, ostomy, and continence (WOC) nursing was recognized as a nursing specialty by the American Nurses Association in February 2010, and the Society published the original scope and standards of WOC nursing practice in May 2010. The Wound, Ostomy, and Continence Nursing: Scope and Standards of Practice, 2nd Edition is the definitive resource promoting excellence in professional practice, quality care, and improved patient outcomes in WOC specialty practice. It can be used to articulate the value of WOC nurses to administrators, legislators, payers, patients, and others. The second edition also provides an overview of the scope of WOC nursing practice including a description of the specialty, the history and evolution of WOC nursing, characteristics of WOC nursing practice, and description of the trispecialty. The document describes various WOC nurse roles, populations served, practice settings, care coordination, and collaboration. Educational preparation, levels of practice within WOC specialty nursing, certification, mandate for continuous professional development, ethics, current trends, future considerations and challenges, and standards of WOC nursing practice and professional performance with competencies for each standard are provided. The purpose of this Executive Summary is to describe the process for developing the scope and standards document, provide an overview of the scope of WOC nursing practice, and list the standards of practice and professional performance along with the competencies for each level of WOC nurse provider. The original document is available from the WOCN Society's online book store (www.wocn.org). PMID- 29698291 TI - CSA-90 Promotes Bone Formation and Mitigates Methicillin-resistant Staphylococcus aureus Infection in a Rat Open Fracture Model. AB - BACKGROUND: Infection of open fractures remains a significant cause of morbidity and mortality to patients worldwide. Early administration of prophylactic antibiotics is known to improve outcomes; however, increasing concern regarding antimicrobial resistance makes finding new compounds for use in such cases a pressing area for further research. CSA-90, a synthetic peptidomimetic compound, has previously demonstrated promising antimicrobial action against Staphylococcus aureus in rat open fractures. However, its efficacy against antibiotic-resistant microorganisms, its potential as a therapeutic agent in addition to its prophylactic effects, and its proosteogenic properties all require further investigation. QUESTIONS/PURPOSES: (1) Does prophylactic treatment with CSA-90 reduce infection rates in a rat open fracture model inoculated with S aureus, methicillin-resistant S aureus (MRSA), and methicillin-resistant Staphylococcus epidermidis (MRSE) as measured by survival, radiographic union, and deep tissue swab cultures? (2) Does CSA-90 reduce infection rates when administered later in the management of an open fracture as measured by survival, radiographic union, and deep tissue swab cultures? (3) Does CSA-90 demonstrate a synergistic proosteogenic effect with bone morphogenetic protein 2 (BMP-2) in a noninfected rat ectopic bone formation assay as assessed by micro-CT bone volume measurement? (4) Can CSA-90 elute and retain its antimicrobial efficacy in vitro when delivered using clinically relevant agents measured using a Kirby-Bauer disc diffusion assay? METHODS: All in vivo studies were approved by the local animal ethics committee. In the open fracture studies, 12-week-old male Wistar rats underwent open midshaft femoral fractures stabilized with a 1.1-mm Kirschner wire and 10 ug BMP-2 +/- 500 ug CSA-90 was applied to the fracture site using a collagen sponge along with 1 x 10 colony-forming units of bacteria (S aureus/MRSA/MRSE; n = 10 per group). In the delayed treatment study, debridement and treatment with 500 ug CSA-90 were performed at Day 1 and Day 5 after injury and bacterial insult (S aureus). All animals were reviewed daily for signs of local infection and/or sepsis. An independent, blinded veterinarian reviewed twice-weekly radiographs, and rats showing osteolysis and/or declining overall health were culled at his instruction. The primary outcome of both fracture studies was fracture infection, incorporating survival, radiographic union, and deep tissue swab cultures. For the ectopic bone formation assay, 0 to 10 ug BMP-2 and 0 to 500 ug CSA-90 were delivered on a collagen sponge into bilateral quadriceps muscle pouches of 8-week-old rats (n = 10 per group). Micro-CT quantification of bone volume and descriptive histologic analysis were performed for all in vivo studies. Modified Kirby-Bauer disc diffusion assays were used to quantify antimicrobial activity in vitro using four different delivery methods, including bone cement. RESULTS: Infection was observed in none of the MRSA inoculated open fractures treated with CSA-90 with 10 of 10 deep tissue swab cultures negative at the time of cull. Median survival was 43 days (range, 11-43 days) in the treated group versus 11 days (range, 8-11 days) in the untreated MRSA inoculated group (p < 0.001). However, delayed debridement and treatment of open fractures with CSA-90 at either Day 1 or Day 5 did not prevent infection, resulting in early culls by Day 21 with positive swab cultures (10 of 10 for each time point). Maximal ectopic bone formation was achieved with 500 MUg CSA-90 and 10 MUg BMP-2 (mean volume, 9.58 mm; SD, 7.83), creating larger bone nodules than formed with 250 MUg CSA-90 and 10 MUg BMP-2 (mean volume, 1.7 mm; SD, 1.07; p < 0.001). Disc diffusion assays showed that CSA-90 could successfully elute from four potential delivery agents including calcium sulphate (mean zone of inhibition, 11.35 mm; SD, 0.957) and bone cement (mean, 4.67 mm; SD, 0.516). CONCLUSIONS: CSA-90 shows antimicrobial action against antibiotic-resistant Staphylococcal strains in vitro and in an in vivo model of open fracture infection. CLINICAL RELEVANCE: The antimicrobial properties of CSA-90 combined with further evidence of its proosteogenic potential make it a promising compound to develop further for orthopaedic applications. PMID- 29698292 TI - Does the Watson-Jones or Modified Smith-Petersen Approach Provide Superior Exposure for Femoral Neck Fracture Fixation? AB - BACKGROUND: A well-reduced femoral neck fracture is more likely to heal than a poorly reduced one, and increasing the quality of the surgical exposure makes it easier to achieve anatomic fracture reduction. Two open approaches are in common use for femoral neck fractures, the modified Smith-Petersen and Watson-Jones; however, to our knowledge, the quality of exposure of the femoral neck exposure provided by each approach has not been investigated. QUESTIONS/PURPOSES: (1) What is the respective area of exposed femoral neck afforded by the Watson-Jones and modified Smith-Petersen approaches? (2) Is there a difference in the ability to visualize and/or palpate important anatomic landmarks provided by the Watson Jones and modified Smith-Petersen approaches? METHODS: Ten fresh-frozen human pelvi underwent both modified Smith-Petersen (utilizing the caudal extent of the standard Smith-Petersen interval distal to the anterosuperior iliac spine and parallel to the palpable interval between the tensor fascia lata and the sartorius) and Watson-Jones approaches. Dissections were performed by three fellowship-trained orthopaedic traumatologists with extensive experience in both approaches. Exposure (in cm) was quantified with calibrated digital photographs and specialized software. Modified Smith-Petersen approaches were analyzed before and after rectus femoris tenotomy. The ability to visualize and palpate seven clinically relevant anatomic structures (the labrum, femoral head, subcapital femoral neck, basicervical femoral neck, greater trochanter, lesser trochanter, and medial femoral neck) was also recorded. The quantified area of the exposed proximal femur was utilized to compare which approach afforded the largest field of view of the femoral neck and articular surface for assessment of femoral neck fracture and associated femoral head injury. The ability to visualize and palpate surrounding structures was assessed so that we could better understand which approach afforded the ability to assess structures that are relevant to femoral neck fracture reduction and fixation. RESULTS: After controlling for age, body mass index, height, and sex, we found the modified Smith-Petersen approach provided a mean of 2.36 cm (95% confidence interval [CI], 0.45-4.28 cm; p = 0.015) additional exposure without rectus femoris tenotomy (p = 0.015) and 3.33 cm (95% CI, 1.42-5.24 cm; p = 0.001) additional exposure with a tenotomy compared with the Watson-Jones approach. The labrum, femoral head, subcapital femoral neck, basicervical femoral neck, and greater trochanter were reliably visible and palpable in both approaches. The lesser trochanter was palpable in all of the modified Smith-Petersen and none of the Watson-Jones approaches (p < 0.001). All modified Smith-Petersen approaches (10 of 10) provided visualization and palpation of the medial femoral neck, whereas visualization of the medial femoral neck was only possible in one of 10 Watson-Jones approaches (p < 0.001) and palpation was possible in eight of 10 Watson-Jones versus all 10 modified Smith Petersen approaches (p = 0.470). CONCLUSIONS: In the hands of surgeons experienced with both surgical approaches to the femoral neck, the modified Smith Petersen approach, with or without rectus femoris tenotomy, provides superior exposure of the femoral neck and articular surface as well as visualization and palpation of clinically relevant proximal femoral anatomic landmarks compared with the Watson-Jones approach. CLINICAL RELEVANCE: Open reduction and internal fixation of a femoral neck fracture is typically performed in a young patient (< 60 years old) with the objective of obtaining anatomic reduction that would not be possible by closed manipulation, thus enhancing healing potential. In the hands of surgeons experienced in both approaches, the modified Smith-Petersen approach offers improved direct access for reduction and fixation. Higher quality reductions and fixation are expected to translate to improved healing potential and outcomes. Although our experimental results are promising, further clinical studies are needed to verify if this larger exposure area imparts increased quality of reduction, healing, and improved outcomes compared with other approaches. The learning curve for the exposure is unclear, but the approach has broad applications and is frequently used in other subspecialties such as for direct anterior THA and pediatric septic hip drainage. Surgeons treating femoral neck fractures with open reduction and fixation should familiarize themselves with the modified Smith-Petersen approach. PMID- 29698293 TI - Can Shoulder Muscle Activity Be Evaluated With Ultrasound Shear Wave Elastography? AB - BACKGROUND: Quantitative assessment of rotator cuff muscle activity is important in the treatment of shoulder disorders. However, the known methods for assessing rotator cuff muscle activity thus far have been inaccurate, invasive, and inconvenient. QUESTIONS/PURPOSES: (1) Does the activity of the deltoid, supraspinatus, and infraspinatus muscles measured using ultrasound shear wave elastography have a linear correlation with muscle activity assessed using generally used methods, including isokinetic dynamometry and electromyography? (2) Does the activity of the deltoid, supraspinatus, and infraspinatus muscles measured using shear wave elastography show good intraobserver and interobserver reliability? METHODS: Twelve volunteers participated in intrasession reliability experiments. They were asked to perform isometric abduction, external rotation, and scaption contractions (defined as elevation of the arm within the plane of the scapula with neutral arm rotation) gradually increased from 0% to 75% of maximal voluntary contraction. The joint torque, electromyographic activity, and shear elastic modulus were synchronously measured in the middeltoid, supraspinatus, and infraspinatus muscles. The validity of the elastic modulus value was assessed using regression analysis between normalized torque and electromyographic root mean square values. For intraobserver and interobserver reliability measurements, repeated experiments were performed with the same protocol. RESULTS: The shear elastic modulus and normalized joint torque with isokinetic dynamometry showed a linear relationship in all muscles (deltoid, supraspinatus, and infraspinatus) and each of the ultrasonography planes (longitudinal and transverse) (mean R > 0.8 and p < 0.001 for all measurements). For the supraspinatus muscle, the mean slope of the relationship between shear elastic modulus in the longitudinal plane and the normalized joint torque during scaption contraction was 1.28 +/- 0.39 kPa/%MVC (mean R = 0.93 +/- 0.21, p < 0.001). Furthermore, similar results were obtained in relation to electromyography root mean square values (mean R > 0.8 and p < 0.001 in all measurements). For the supraspinatus muscle, the mean slope of the relationship between shear elastic modulus in the longitudinal plane and electromyographic (EMG) root mean square was 0.96 +/- 0.27 kPa/%EMG (mean R = 0.91 +/- 0.08, p < 0.001). The intraobserver and interobserver reliabilities were excellent in all positions (abduction, external rotation, and scaption) and in both the longitudinal and transverse ultrasonography planes (all intraclass correlation coefficients are > 0.85). CONCLUSIONS: Shoulder muscle activity can be noninvasively evaluated with ultrasound shear wave elastography. Clinician and scientists should consider the application of this technique in cases in which evaluation of shoulder muscle activity is required. The next step after this study will be to check the shear elastic modulus of rotator cuff muscle in patients with rotator cuff tear. We plan to evaluate the correlation between shear elastic modulus and joint torque according to tear size and fatty infiltration status of rotator cuff muscle. CLINICAL RELEVANCE: Shear wave electrography can be used to measure various tissue elasticities in both static and dynamic modes. It may be a useful tool to evaluate pre- and postoperative rotator cuff muscle activity in a relatively simple manner. Shoulder function after reverse total shoulder arthroplasty associated with deltoid muscle activity also may be evaluated. Changes in tissue tightness in shoulder disorders caused by increase soft tissue stiffness (ie, adhesive capsulitis and glenohumeral internal rotation deficit) can be evaluated. PMID- 29698294 TI - Letter to the Editor: Immune Surveillance Plays a Role in Locally Aggressive Giant Cell Lesions of Bone. PMID- 29698295 TI - Not the Last Word: A Goldwater Rule for Sports Medicine. PMID- 29698296 TI - CORR(r) International - Asia-Pacific: Poverty and its Implications on Orthopaedic Care. PMID- 29698297 TI - CORR(r) Curriculum - Orthopaedic Education: Do We Need General Orthopaedic Surgeons? PMID- 29698298 TI - Reply to the Letter to the Editor: Immune Surveillance Plays a Role in Locally Aggressive Giant Cell Lesions of Bone. PMID- 29698299 TI - CORR Insights(r): Is Platelet-rich Plasma Injection Effective for Chronic Achilles Tendinopathy? A Meta-analysis. PMID- 29698300 TI - CORR Insights(r): The 2018 Chitranjan S. Ranawat, MD Award: Developing and Implementing a Novel Institutional Guideline Strategy Reduced Postoperative Opioid Prescribing After TKA and THA. PMID- 29698301 TI - Is There an Association Between Borderline-to-mild Dysplasia and Hip Osteoarthritis? Analysis of CT Osteoabsorptiometry. AB - BACKGROUND: The definitive treatment of borderline-to-mild dysplasia remains controversial. A more comprehensive understanding of the etiology of osteoarthritis (OA) and clarification of any possible association between borderline-to-mild dysplasia and the pathogenesis of OA are essential. QUESTIONS/PURPOSES: (1) Does the distribution of acetabular subchondral bone density increase according to dysplasia severity? (2) Is there an association between borderline-to-mild dysplasia and OA pathogenesis? METHODS: We evaluated bilateral hips of patients with developmental dysplasia of the hip who underwent eccentric rotational acetabular osteotomy (ERAO) for inclusion in the dysplasia group and contralateral hips of patients with unilateral idiopathic osteonecrosis of the femoral head (ONFH) who underwent curved intertrochanteric varus osteotomy (CVO) for the control group. ERAO was performed in 46 patients and CVO was performed in 32 patients between January 2013 and August 2016 at our institution. All patients underwent bilateral hip CT. The study included 55 hips categorized according to dysplasia severity: (1) borderline-mild, 19 hips (15 degrees <= lateral center-edge angle [LCEA] < 25 degrees ); (2) moderate, 20 hips (5 degrees <= LCEA < 15 degrees ); (3) severe, 16 hips (LCEA < 5 degrees ); and (4) control, 15 hips. Thirty-seven dysplastic hips (age < 15 or > 50 years old, prior hip surgery, subluxation, aspherical femoral head, cam deformity, and radiographic OA) and 17 control hips (age < 15 or > 50 years old, bilateral ONFH, LCEA < 25 degrees or >= 35 degrees , cam deformity, and radiographic OA) were excluded. CT-osteoabsorptiometry (OAM) predicts physiologic biomechanical conditions in joints by evaluating subchondral bone density. We evaluated the distribution of subchondral bone densities in the acetabulum with CT-OAM, dividing the stress distribution map into six segments: anteromedial, anterolateral, centromedial, centrolateral, posteromedial, and posterolateral. We calculated the percentage of high-density area, which was defined as the upper 30% of Hounsfield units values in each region and compared least square means difference estimated by the random intercept model among the four groups. RESULTS: In all regions, the percentage of high-density area did not differ between the borderline-mild group and the control (eg, anterolateral, 16.2 +/- 5.6 [95% CI, 13.4 to 18.9] versus 15.5 +/- 5.7 [95% CI, 12.4 to 18.5, p = 0.984]; centrolateral, 39.1 +/- 5.7 [95% CI, 36.4 to 41.8] versus 39.5 +/- 4.7 [95% CI, 36.6 to 42.5, p = 0.995]; posterolateral, 10.9 +/- 5.2 [95% CI, 8.0 to 13.8] versus 15.1 +/- 6.8 [95% CI, 11.7 to 18.5, p = 0.389]). In the anterolateral region, a smaller percentage of high-density area was observed in the borderline mild group than in both the moderate group (16.2 +/- 5.6 [95% CI, 13.4-18.9] versus 28.2 +/- 5.1 [95% CI, 25.5-30.9], p < 0.001) and the severe group (16.2 +/ 5.6 [95% CI, 13.4-18.9] versus 22.2 +/- 6.8 [95% CI, 19.2-25.2, p = 0.026). CONCLUSIONS: Our results suggest that the cumulative hip stress distribution in borderline-to-mild dysplasia was not concentrated on the lateral side of the acetabulum, unlike severe dysplasia. CLINICAL RELEVANCE: Based on the stress distribution pattern, our results may suggest that there is no association between borderline-to-mild dysplasia and the pathogenesis of OA. Further studies are needed to evaluate the association between borderline-to-mild dysplasia and instability of the hip. PMID- 29698302 TI - Is There a Cardiotoxicity Associated With Metallic Head Hip Prostheses? A Cohort Study in the French National Health Insurance Databases. AB - BACKGROUND: There are four distinguishable types of THA devices in wide use, as defined by the femoral and acetabular bearing surfaces: metal-on-polyethylene (MoP), ceramic-on-polyethylene (CoP), metal-on-metal (MoM), and ceramic-on ceramic (CoC). Metallic head THAs (MoP and MoM) can potentially induce cardiac toxicity because cobalt species, generated at the head-neck trunnion, and in the case of MoM devices, at the articular surface as well, can be absorbed systemically. However, studies have provided inconsistent results. QUESTIONS/PURPOSES: The purpose of this study was to assess the risk of dilated cardiomyopathy (DCM) or heart failure (HF) associated with metallic head THAs using data from the French national health insurance databases. METHODS: Between 2008 and 2011 in France, 399,968 patients >= 55 years had a first THA. A total of 127,481 were excluded after we applied the exclusion criteria regarding arthroplasty and 17,137 as a result of a history of DCM/HF, recorded in the French national health insurance reimbursement databases, between January 1, 2006, and the date of inclusion. The final cohort included 255,350 individuals (43% men; mean age 72 +/- 9 years). Of them, 93,581 (37%) had been implanted with MoP, 58,095 (23%) with CoP, 11,298 (4%) with MoM, and 92,376 (36%) with CoC THAs. Patients were followed until December 2015. Patients with incident DCM/HF were identified by a new entitlement to the long-term disease scheme or a first hospitalization with a diagnosis of DCM or HF. MoP and CoP THAs are generally implanted in old patients, whereas MoM and CoC are mostly indicated in young, active male patients. Thus, to consider the specific indications of the bearing couples, analyses were separately performed in two distinct subcohorts, one comprising patients with MoP or CoP and one comprising patients with MoM or CoC THA. In each subcohort, the DCM/HF risk was compared between patients with metallic head versus nonmetallic head THAs (MoP versus CoP, MoM versus CoC). Hazard ratios (adjusted HRs) of incident DCM/HF were estimated using Cox models adjusted for baseline sex, age, THA characteristics (fixation technique with cement, use of a modular femoral neck), and comorbidities at baseline. Cox models were stratified by sex and age. RESULTS: The crude incidence of DCM/HF per 100 person-years was 2.4 in patients with MoP, 1.8 with CoP, 1.2 with MoM, and 1.1 with CoC THAs. Overall, metallic head THAs were associated with a slight increase in DCM/HF risk (MoP versus CoP: adjusted HR, 1.08; 95% confidence interval [CI], 1.05-1.12; p < 0.001; MoM versus CoC: adjusted HR, 1.11; 95% CI, 1.03-1.19; p = 0.007). In the MoM-CoC subcohort, the risk tended to be more pronounced with MoM versus CoC THAs in women (MoM versus CoC: adjusted HR, 1.20; 95% CI, 1.07-1.35; p = 0.002) and patients aged >= 75 years (MoM versus CoC: adjusted HR, 1.16; 95% CI, 1.04-1.29; p = 0.009). CONCLUSIONS: Metallic head THAs were associated with a slightly increased DCM/HF risk, especially with MoM in women and older patients. Some caveats should be mentioned: severity of DCM or HF was not available and residual confounding cannot be ruled out despite considering many covariates. Our findings suggest that cardiac function should be regularly monitored in patients with metallic head THAs. Further investigations should be planned on large international cohorts. LEVEL OF EVIDENCE: Level III, therapeutic study. PMID- 29698303 TI - Closed Reduction, Osteotomy, and Fibular Graft Are Effective in Treating Pediatric Femoral Neck Pseudarthrosis After Infection. AB - BACKGROUND: When treatment of acute septic arthritis of the hip is delayed, severe sequelae can occur. This may take the form of coxa breva, vara, or valga. Pseudoarthrosis of the femoral neck is a rare complication with only a few studies to guide treatment. QUESTION/PURPOSES: In a small series of patients with pseudarthrosis of the femoral neck after acute septic arthritis, we wanted to determine (1) whether femoral neck union can be achieved using a variety of surgical approaches; (2) whether these patients satisfied criteria outlined by Hunka and Choi, defined as a stable hip, a flexion arc >= 70 degrees and no fixed adduction or abduction contractures, fixed flexion deformity not more than 20 degrees , pain relief, and restoration of activities of daily living after surgery; and (3) any treatment-related complications if observed. METHODS: We reviewed the charts of patients who had presented to the orthopaedics outpatient department at Lady Hardinge Medical College and Associated Hospitals with the diagnosis sequelae of septic arthritis of the hip. Between 2003 and 2014, a total of 54 pediatric patients (61 hips) with sequelae of a septic hip had undergone various hip reconstructive procedures. Of these, 16 patients (30%) were diagnosed with pseudarthrosis of the femoral neck and were included in this study. All patients with this diagnosis were treated surgically. In this group, the median age at first contact with our treating team was 48 months (range, 18-96 months). The age of onset of the initial infection was 0.3 months to 84 months (median, 8 months). These 16 patients underwent a total of 24 surgical procedures to achieve union at the pseudoarthrosis site. We performed close reduction, fibula graft, and valgus osteotomy in most of the patients. Wagner's double intertrochantric osteotomy with a fibula graft was done in patients in whom there was a short femoral neck along with pseudoarthrosis. In all patients, the pseudarthrosis site was not exposed. Median followup was 6 years (range, 3-12 years). No patient was lost to followup before 3 years. Union was defined when there was complete radiologic healing at the pseudoarthrosis site. All the patients were clinically evaluated as per Choi's criteria. Parents were also asked about daily activities and pain. Other related complications were also recorded. RESULTS: Fifteen of 16 patients achieved union at the pseudarthrosis site within 6 to 24 months (median, 9 months). Ten patients underwent a single procedure to achieve union, whereas four patients underwent two surgical procedures and two patients underwent three procedures. Fifteen patients achieved Choi's criteria and one patient could not achieve this. While attempting this reconstruction, complications occurred in the form of deep infection and avascular necrosis. CONCLUSIONS: Surgical reconstruction of pseudarthrosis of the femoral neck after pyarthrosis of the hip is difficult, but a successful result may be possible in many patients. Every effort should be made to achieve pseudarthrosis repair while the femoral head remains viable on radiographs. Once union is achieved, clinical function and hip stability improve. At early followup, many patients have adequate ROM with minimal pain, an acceptable limp, and are able to do indoor and outdoor activities without support. Long-term results are unknown, and we caution that treating the sequelae of childhood hip disease is challenging. LEVEL OF EVIDENCE: Level IV, therapeutic study. PMID- 29698304 TI - Clinical Faceoff: The Role of Arthroscopic Partial Meniscectomy in the Treatment of Meniscal Tears. PMID- 29698305 TI - Pearls: How to Address Negative Online Patient Reviews. PMID- 29698306 TI - CORR Insights(r): Are Age and Patient Gender Associated With Different Rates and Magnitudes of Clinical Improvement After Reverse Shoulder Arthroplasty? PMID- 29698307 TI - Editor's Spotlight/Take 5: Body Mass Index is Associated with All-cause Mortality After THA and TKA. PMID- 29698308 TI - CORR Insights(r): Are Sonication Cultures of Antibiotic Cement Spacers Useful During Second-stage Reimplantation Surgery for Prosthetic Joint Infection? PMID- 29698309 TI - CORR Insights(r): Surgeon Personal Protection: An Underappreciated Benefit of Positive-pressure Exhaust Suits. PMID- 29698310 TI - From the archives: Challenging health disparities. PMID- 29698311 TI - 59 clicks in the EHR. PMID- 29698312 TI - Professional practice and nursing peer review. PMID- 29698313 TI - Are you prepared for a disaster? PMID- 29698314 TI - Excellence has no endpoint. PMID- 29698315 TI - Research priorities of VA nurses. PMID- 29698316 TI - Specialty certification: Nurses' perceived value and barriers. PMID- 29698317 TI - We want to hear about you!: 2018 Richard Hader Visionary Leader Award. PMID- 29698318 TI - The night-shift administrative clinical supervisor role. PMID- 29698320 TI - Developing a staffing plan to meet inpatient unit needs. PMID- 29698319 TI - Restoring joy at work. PMID- 29698321 TI - Oral hydration: does it have a role in prevention of angiography-associated acute kidney injury? PMID- 29698323 TI - Does simplification to dolutegravir-based dual regimens impact on the CD4+/CD8+ T cell ratio? PMID- 29698322 TI - Lentiviral infection of proliferating brain macrophages in HIV and simian immunodeficiency virus encephalitis despite sterile alpha motif and histidine aspartate domain-containing protein 1 expression. AB - OBJECTIVE: HIV-1 infection of the brain and related cognitive impairment remain prevalent in HIV-1-infected individuals despite combination antiretroviral therapy. Sterile alpha motif and histidine-aspartate domain-containing protein 1 (SAMHD1) is a newly identified host restriction factor that blocks the replication of HIV-1 and other retroviruses in myeloid cells. Cell cycle regulated phosphorylation at residue Thr592 and viral protein X (Vpx)-mediated degradation of SAMHD1 have been shown to bypass SAMHD1 restriction in vitro. Herein, we investigated expression and phosphorylation of SAMHD1 in vivo in relation to macrophage infection and proliferation during the neuropathogenesis of HIV-1 and simian immunodeficiency virus (SIV) encephalitis. METHODS: Using brain and other tissues from uninfected and SIV-infected macaques with or without encephalitis, we performed immunohistochemistry, multilabel fluorescence microscopy and western blot to examine the expression, localization and phosphorylation of SAMHD1. RESULTS: The number of SAMHD1 nuclei increased in encephalitic brains despite the presence of Vpx. Many of these cells were perivascular macrophages, although subsets of SAMHD1 microglia and endothelial cells were also observed. The SAMHD1 macrophages were shown to be both infected and proliferating. Moreover, the presence of cycling SAMHD1 brain macrophages was confirmed in the tissue of HIV-1-infected patients with encephalitis. Finally, western blot analysis of brain-protein extracts from SIV-infected macaques showed that SAMHD1 protein exists in the brain mainly as an inactive Thr592 phosphorylated form. CONCLUSION: The ability of SAMHD1 to act as a restriction factor for SIV/HIV in the brain is likely bypassed in proliferating brain macrophages through the phosphorylation-mediated inactivation, not Vpx-mediated degradation of SAMHD1. PMID- 29698324 TI - Please Do Not Impact Me. PMID- 29698325 TI - A Tribute to Susan Henly. PMID- 29698326 TI - Nursing and the Social Determinants of Health. PMID- 29698327 TI - Recruitment Techniques and Strategies in a Community-Based Colorectal Cancer Screening Study of Men and Women of African Ancestry. AB - BACKGROUND: Recruiting ethnically diverse Black participants to an innovative, community-based research study to reduce colorectal cancer screening disparities requires multipronged recruitment techniques. OBJECTIVES: This article describes active, passive, and snowball recruitment techniques, and challenges and lessons learned in recruiting a diverse sample of Black participants. METHODS: For each of the three recruitment techniques, data were collected on strategies, enrollment efficiency (participants enrolled/participants evaluated), and reasons for ineligibility. RESULTS: Five hundred sixty individuals were evaluated, and 330 individuals were enrolled. Active recruitment yielded the highest number of enrolled participants, followed by passive and snowball. Snowball recruitment was the most efficient technique, with enrollment efficiency of 72.4%, followed by passive (58.1%) and active (55.7%) techniques. There were significant differences in gender, education, country of origin, health insurance, and having a regular physician by recruitment technique (p < .05). DISCUSSION: Multipronged recruitment techniques should be employed to increase reach, diversity, and study participation rates among Blacks. Although each recruitment technique had a variable enrollment efficiency, the use of multipronged recruitment techniques can lead to successful enrollment of diverse Blacks into cancer prevention and control interventions. PMID- 29698328 TI - Hmong Older Adults' Perceptions of Insider and Outsider Researchers: Does It Matter for Research Participation? AB - BACKGROUND: Recruiting racial/ethnic minorities into health research is challenging. Although researchers affiliated with members of the study population (seen as insiders) may increase research participation of racial/ethnic minorities, little is known about who participants see as insiders and how they respond to insider versus outsider researchers. OBJECTIVES: The aim of the study was to examine perceptions of Hmong older adults toward insider versus outsider researchers and the influence of these perceptions on their willingness to participate in research. METHODS: Participants in a study evaluating use of a culturally and linguistically adapted audio computer-assisted self-interviewing system with helper assistance (ACASI-H) provided information about what they thought would encourage others in their community to participate in research. ACASI-H was used for collection of health data with 30 Hmong older adults. Participants rated the likelihood of participation if the researcher was Hmong and answered open-ended questions about participation when the researcher was not Hmong. Conventional content analysis was used to analyze open-ended questions. RESULTS: Sixteen (53%) participants reported that they would be "likely" to participate in the research if the researcher was Hmong. Fourteen (47%) participants reported that they would participate in research if the researcher was not Hmong. In addition to ethnic affiliation, trust in the researcher could shift the perception of the researcher toward insider status, thereby increasing willingness of Hmong adults to participate in research. Trust in the researcher and movement toward insider status could be increased by calling out a connection between the researcher and the participant or creating reciprocity. DISCUSSION: Findings suggest that increasing research participation of Hmong (and possibly other) participants, particularly when researchers do not share ethnic membership, can be achieved by building trust. This study also suggests a more nuanced perception of insider status, as a continuum, rather than a dichotomy, may be a more accurate reflection of the relationship between participants and researchers. PMID- 29698329 TI - Trends in Health Disparities, Health Inequity, and Social Determinants of Health Research: A 17-Year Analysis of NINR, NCI, NHLBI, and NIMHD Funding. AB - BACKGROUND: The theoretical landscape of health disparities research now emphasizes health inequities and the role that social determinants of health (SDOH) play in creating and perpetuating them. Whether National Institutes of Health (NIH) funding patterns reflect this theoretical shift is unknown. OBJECTIVES: The aim of this study was to examine the National Institute of Nursing Research's (NINR) funding for research focused on health disparities, health inequities, and SDOH, relative to other key NIH institutes. METHODS: Data on 32,968 projects funded by NINR, the National Cancer Institute, the National Heart, Lung, and Blood Institute, and the National Institute of Minority Health and Health Disparities (NIMHD) during the years 2000 through 2016 were downloaded from NIH RePORTER; those with health disparities, health inequity, or SDOH terms used in the abstract were identified. Descriptive statistics and a general linear model approach were used to assess differences in cumulative project counts and funding proportions, and funding trends over time. RESULTS: Overall, funding for health disparities projects was 14-19 times greater than for health inequity and SDOH projects and was more concentrated in centers and institutional training than in individual research projects. NINR's proportion of funding for disparities projects was consistently greater than that of the National Cancer Institute and the National Heart, Lung, and Blood Institute, but not for inequities and SDOH projects. NIMHD's proportion of funding for disparities, and inequities and SDOH projects (combined) was 2-30 times greater than that of other institutes. Over the 16-year period, funding for disparities, inequity, and SDOH projects each increased (all ps < .05); however, growth in inequities and SDOH funding was not evident in more recent years. DISCUSSION: Funding for projects focused on health equities and the SDOH lag behind theoretical shifts in the broader health disparities research arena. With the exception of NIMHD, there is a disconnect between funding for projects with a disparities orientation in institutional training and center projects relative to individual research projects. These trends have implications for nurse scientists seeking NIH funding to support health equity-oriented research. PMID- 29698330 TI - Inflammatory Markers and Preeclampsia: A Systematic Review. AB - BACKGROUND: Preeclampsia (PE), a serious and variable pregnancy complication affecting 5%-10% of the obstetric population, has an undetermined etiology, yet inflammation is concomitant with its development, particularly in relation to endothelial dysfunction. OBJECTIVE: The purpose of this systematic review was to examine the published evidence concerning an association between PE and inflammatory markers for their usefulness in the prediction or early identification of women with PE in antepartum clinical settings. METHODS: In this systematic review, we used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The Cumulative Index for Nursing and Allied Health and MEDLINE/OVID were the electronic databases used for identifying published articles. We placed no time limit on the publication year. RESULTS: The search generated 798 articles. After removing duplicates, screening abstracts, and conducting full-text reviews, we retained 73 articles and examined 57 unique markers. This review shows that C-reactive protein and the cytokines, specifically the proinflammatory markers IL-6, IL-8, and tumor necrosis factor alpha, garner the most support as potential inflammatory markers for clinical surveillance of PE, particularly during the second and third trimesters. DISCUSSION: Based on this review, we cannot recommend any single inflammatory marker for routine clinical use to predict/identify PE onset or progression. Research is recommended to examine a combination panel of these four inflammatory markers both with and without clinical risk factors toward the goal of translation to practice. PMID- 29698331 TI - Occurrence of Phlebitis: A Systematic Review and Meta-analysis. AB - BACKGROUND: Peripheral venous catheters (PVCs) are commonly used in clinical practice. However, varying degrees of phlebitis often occur in patients receiving intravenous injections. The relevant literature suggests that phlebitis occurrence is highly associated with the catheter gauge, insertion site, and catheterization duration. Nevertheless, no meta-analysis has been performed on the influence of these three factors on the occurrence of phlebitis. OBJECTIVE: The objective of this study was to determine whether any significant differences exist in the occurrence of phlebitis between catheters of 20 gauge or smaller and those larger than 20 gauge, between catheters inserted in the antecubital fossa and those inserted in other locations on the upper limbs, or between catheters inserted for more than 96 hours and those inserted for 96 hours or less. METHODS: Using a systematic approach, we searched for literature published between 2006 and 2017 in the Cumulative Index to Nursing and Allied Health Literature (CINAHL), PubMed, ProQuest, and Cochrane Library databases. We used Comprehensive Meta-analysis Version 2 to perform our meta-analysis. After the screening and review processes, we identified 17 studies that met our selection conditions. Among these studies, 14 contained complete data for meta-analysis. These studies involved 4,343 patients and 5,846 PVCs. RESULTS: Regarding the overall effect size in the meta-analysis, the results of the forest plot comparing catheters of 20 gauge or smaller and those larger than 20 gauge presented a risk ratio (RR) of 0.88 (95% confidence interval [0.67, 1.17], p = .380), indicating no statistically significant difference in the occurrence of phlebitis between catheters of the aforementioned gauges. The results of the forest plot comparing catheters inserted in the antecubital fossa and those inserted in other locations on the upper limbs presented an RR of 1.05 (95% confidence interval [0.82, 1.34], p = .696), indicating no statistically significant difference in the occurrence of phlebitis between catheters inserted in the aforementioned locations. The results of the forest plot comparing catheters inserted for more than 96 hours and those inserted for 96 hours or less presented an RR of 1.13 (95% confidence interval [0.49, 2.61], p = .779), indicating no statistically significant difference in the occurrence of phlebitis between catheters inserted for the aforementioned durations. DISCUSSION: The empirical results of this meta-analysis can serve as a reference for hospital management for selecting the PVC gauge, insertion site, and catheterization duration. In addition to the three factors that we analyzed, whether any other factors influence the occurrence of phlebitis in patients with catheter implantation is worth investigating in future research. PMID- 29698332 TI - Serum Proteomics in African American Female Patients With Irritable Bowel Syndrome: An Exploratory Study. AB - BACKGROUND: Sex and subtype differences within patients with irritable bowel syndrome (IBS) complicate the understanding of disorder pathogenesis and hinder the design of efficacious, therapeutic interventions. OBJECTIVES: The aims of this study were to harness the power of shotgun proteomic analysis, identify circulating proteins that differentiate African American female patients with IBS from healthy controls (HC), and gain biological insight on symptomatology. METHODS: Serum proteome analysis was performed upon a cohort of overweight, African American female participants with constipation predominant IBS symptoms (n = 5) and HC (n = 5), matched on age, sex, years of education, body mass index, and 11 physiological markers. Tandem mass tags for multiplexed proteomic analysis were performed, incorporating reverse-phase liquid chromatography and liquid chromatography-tandem mass spectrometry. RESULTS: Participants with IBS did not differ from HC in demographics, clinical characteristics, or initial proteomic analysis. Nested case control analysis of six samples (IBS: n = 3, HC: n = 3), hierarchically clustered into two main groups, with 12 out of 1,317 proteins significantly different in levels of expression: TGFbeta1, PF4V1, PF4, APP, MMP9, PPBP, CTGF, SRGN, THBS1, WRN, LTBP1 (Isoform 3), and IGLV5-48. Top associations of identified proteins in DAVID and STRING resources (upregulated in HC vs. IBS) involve platelet alpha granule lumen, platelet activation/degranulation, extracellular region, and secretion by cell. DISCUSSION: Differentially expressed proteins between participants with IBS and HC involving platelet-related associations prompt inquiry as to differences in serotonergic signaling, inflammatory or immunomodulatory mechanisms underlying IBS symptomatology. Although preliminary and requiring validation in larger cohorts, these findings bear relevance to understanding pathogenic processes of IBS and biological effects of the disorder. PMID- 29698333 TI - Nursing Research Reviewer List for 2017. PMID- 29698334 TI - The Arterial Access in Continuous Arteriovenous Hemofiltration. PMID- 29698335 TI - Pediatric Veno-Veno Extracorporeal Membrane Oxygenation Rescue From Carbon Monoxide Poisoning. AB - BACKGROUND: Carbon monoxide poisoning affects approximately 5000 children per year and can be challenging to diagnose and treat (Pediatr Emerg Med Pract. 2016;13:1-24). It is in the differential diagnosis of a patient presented with altered consciousness. Patients may look quite "pink" and well perfused, but are often in serious distress. We present the first case in the literature of carbon monoxide poisoning treated with the use of veno-veno extracorporeal membrane oxygenation (ECMO). CASE: We report the case of a 10-year-old patient who had carbon monoxide poisoning (carboxyhemoglobin of 18%). She was treated with hydroxocobalamin at 70 mg/kg and was being prepared to transfer to a facility that offered hyperbaric therapy when she suffered a cardiac arrest requiring cardiopulmonary resuscitation. After 11 minutes of resuscitation, she had return of spontaneous circulation and an echocardiogram showed reasonable cardiac function. She was judged too unstable for ambulance transport and the ECMO team was called. Veno-veno ECMO was placed via a single right internal jugular dual lumen catheter with fluoroscopy in the cardiac catheterization laboratory. There was a rapid improvement in carboxyhemoglobin level, and the ECMO therapy was weaned the next day. The patient eventually made a full recovery. CONCLUSIONS: This is the first time that veno-veno ECMO has been reported for the emergent treatment of carbon monoxide intoxication. If emergency physicians are treating such a patient and cannot administer hyperbaric oxygen therapy, ECMO represents a valuable alternative that is not commonly thought of in this situation before.This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. PMID- 29698336 TI - The Management of Pediatric Genital Injuries at a Pediatric Emergency Department in Japan. AB - OBJECTIVES: Genital injuries among children are often associated with consumer products or specific activities. There are few descriptive studies from Asia on pediatric genital injuries seen in the emergency department (ED). The aim of this study was to describe the characteristic features of accidental genital injuries among children. METHODS: A retrospective chart review of children aged 15 years or younger who visited our ED for genital injuries between March 2010 and November 2014 was conducted. Data on age, arrival time at the ED, location of the incident, mechanism of injury, objects, injured organ, consultation with specialists, emergency operation, sedation at the ED, and outcomes were collected and analyzed. RESULTS: One hundred seventy-nine patients were included in this analysis. Girls comprised 71% of the subject pool. The median age was 6 years (interquartile range, 4-9 years). Straddle injuries were the most common form of injury (56%). Male genital injuries occurred mostly outdoors (64%). Common consumer products associated with pediatric genital injuries were furniture (21%), exercise equipment (17%), and bicycles (15%). Thirty-two patients were examined by a surgeon, gynecologist, or urologist. The most commonly injured organs were the penis (55%) in boys and the labia (60%) in girls. Most patients (93%) were treated at the ED and discharged. CONCLUSIONS: The characteristics of accidental genital injuries among Japanese children were similar to those of children in other countries. The strategy for preventing genital injuries used in the West might be applicable to the East Asian context. PMID- 29698337 TI - Cold Panniculitis After Ice Therapy for Supraventricular Tachycardia. AB - A late preterm infant presenting with supraventricular tachycardia (SVT) was admitted to the pediatric intensive care unit because of poor systolic function seen on echocardiogram. The hospitalization was complicated by multiple breakthrough episodes of SVT requiring ice placed on the face during each repeat episode. The infant was later diagnosed as having cold panniculitis secondary to the application of ice to the face on multiple occasions. In children who are hemodynamically stable during SVT episodes, ice is used as first-line treatment. It is important to be aware of how often ice is being applied to the face and the duration of time to limit complications such as cold panniculitis. PMID- 29698338 TI - Physician Confidence in Dental Trauma Treatment and the Introduction of a Dental Trauma Decision-Making Pathway for the Pediatric Emergency Department. AB - OBJECTIVES: The objectives of this study were to (1) survey and report the awareness and confidence of pediatric emergency medicine physicians in the management of dental trauma and (2) determine the prevalence of dental trauma decision-making pathway utilization in the pediatric emergency department. METHODS: A survey was distributed through e-mail to the pediatric emergency medicine discussion list via Brown University LISTSERV. The survey study included 10 questions and was multiple-choice. The survey contained questions about physician confidence and their use of a dental trauma decision-making pathway. RESULTS: A total of 285 individuals responded to the survey. Somewhat confident was the most common response (61%) followed by not confident (20%) and confident (19%) by respondents in treating dental trauma. Forty-one percent of respondents felt comfortable, 39% somewhat comfortable, 19% not comfortable, and 1% not sure in replanting an avulsed tooth. Only 6% of respondents reported that their pediatric emergency department always or sometimes uses a dental trauma decision making pathway, whereas 78% of pediatric emergency departments do not. CONCLUSIONS: We believe that the adoption of a decision-making pathway will provide timely management, improve emergency physician comfort, and enhance outcomes for pediatric patients presenting with a dental trauma. A future multicenter review will aim to evaluate these goals based on the utilization of our dental trauma decision-making pathway. PMID- 29698339 TI - Disparities in Adherence to Pediatric Diabetic Ketoacidosis Management Guidelines Across a Spectrum of Emergency Departments in the State of Indiana: An Observational In Situ Simulation-Based Study. AB - BACKGROUND: Diabetic ketoacidosis (DKA) is a common presentation to an emergency department (ED), with the majority presenting to community EDs. Adherence to clinical guidelines in these EDs can reduce morbidity and mortality. Few methods to describe practice gaps for DKA management have been reported. OBJECTIVES: We hypothesized that high-fidelity in situ simulation can be used to measure and compare the quality of the care provided to pediatric patients with DKA presenting to community EDs in the state of Indiana. METHODS: This observational study examined multiprofessional teams caring for a simulated pediatric patient who presented with DKA to community EDs. The primary outcome was overall adherence to pediatric DKA guidelines as measured by a validated performance checklist. A composite adherence score (CAS) was calculated using the sum of 9 checklist performance parameters. Multivariable logistic regression was used to examine the impact of ED volume and characteristics on the scores. RESULTS: A 49 multiprofessional teams from 13 sites were enrolled. Of the 252 participants, 26 (10.3%) were physicians, 143 (56.7%) registered nurses, 25 (9.9%) respiratory therapists, and 58 (23.0%) were other. The overall CAS for all sites was 55.6% (25th, 75th interquartile range, 44.4%, 66.7%). Excessive intravenous fluid boluses were given by 53.1%, whereas 30.6% and 26.5% incorrectly administered insulin and sodium bicarbonate boluses, respectively. Only 10.2% used an appropriate intravenous fluid rate, and 57.1% performed an hourly glucose. No significant difference in the CAS was found due to pediatric ED volume or presence of an inpatient pediatric service. CONCLUSIONS: Using validated in situ simulation; we revealed high variability in adherence to the pediatric DKA management guidelines at a wide range of community EDs. A statewide education initiative focused on decreasing variation and improving adherence to pediatric DKA guidelines is necessary for patient safety. PMID- 29698340 TI - Teaching Point-of-Care Lung Ultrasound to Novice Pediatric Learners: Web-Based E Learning Versus Traditional Classroom Didactic. AB - OBJECTIVE: To assess whether Web-based teaching is at least as effective as traditional classroom didactic in improving the proficiency of pediatric novice learners in the image acquisition and interpretation of pneumothorax and pleural effusion using point-of-care ultrasound (POCUS). METHODS: We conducted a randomized controlled noninferiority study comparing the effectiveness of Web based teaching to traditional classroom didactic. The participants were randomized to either group A (live classroom lecture) or group B (Web-based lecture) and completed a survey and knowledge test. They also received hands-on training and completed an objective structured clinical examination. The participants were invited to return 2 months later to test for retention of knowledge and skills. RESULTS: There were no significant differences in the mean written test scores between the classroom group and Web group for the precourse test (absolute difference, -2.5; 95% confidence interval [CI], -12 to 6.9), postcourse test (absolute difference, 2.0; 95% CI, -1.4, 5.3), and postcourse 2 month retention test (absolute difference, -0.8; 95% CI, -9.6 to 8.1). Similarly, no significant differences were noted in the mean objective structured clinical examination scores for both intervention groups in postcourse (absolute difference, 1.9; 95% CI, -4.7 to 8.5) and 2-month retention (absolute difference, -0.6; 95% CI, -10.7 to 9.5). CONCLUSIONS: Web-based teaching is at least as effective as traditional classroom didactic in improving the proficiency of novice learners in POCUS. The usage of Web-based tutorials allows a more efficient use of time and a wider dissemination of knowledge. PMID- 29698341 TI - Early Hospital Discharge After Helicopter Transport of Pediatric Trauma Patients: Analysis of Rates of Over and Undertriage. AB - OBJECTIVES: Helicopter air ambulance (HAA) of pediatric trauma patients is a life saving intervention. Triage remains a challenge for both scene transport and interhospital transfer of injured children. We aimed to understand whether overtriage or undertriage was a feature of scene or interhospital transfer and how in or out of state transfers affected these rates. METHODS: Children (<18 years) who underwent trauma activation at a level I trauma center between 2011 and 2013 were identified and reviewed. Patients transported by HAA were compared with those transported by ground ambulance (GA). RESULTS: Of 399 pediatric patients (median age, 10.4 years; range, 0.1-17 years; 264 male [66%]), 71 (18%) were transported by HAA. Seventy-two percent of HAA patients went to the intensive care unit or the operating room from the trauma bay or suffered in hospital mortality (vs 42% GA, P < 0.001). More patients were overtriaged (HAA with injury severity score [ISS] of <15) from interhospital transfers than from the scene (25% vs 3%, P = 0.002). Undertriage (GA with ISS >15) was acceptable at 5% from the scene and 14% from interhospital transfers (P = 0.08). Overtriage of patients with ISS less than 15 to HAA was significantly lower from in-state hospitals (22%) than out-of-state hospitals (45%) (P = 0.02). Undertriage of patients with ISS greater than 15 to GA was also lower from in-state hospitals (20%) versus out-of-state hospitals (38%) (P = 0.03). CONCLUSIONS: Triage of pediatric trauma patients to HAA remains difficult. There remains potential for improvement, particularly as regards interhospital HAA overtriage, but well developed transfer protocols (such in-state protocols) may help. PMID- 29698342 TI - Unintentional Exposure of an Infant to Synthetic Cannabinoid (Bonzai) Related to the Parent's Use. AB - The increase of available synthetic cannabinoids poses an emerging public health threat worldwide. Synthetic cannabinoid use has been mainly reported in adolescent cases in pediatric practices; there are few reported cases involving infants affected by unintentional use. In this case report, we present the youngest age of synthetic cannabinoid bonzai exposure in the literature, discussing a 3-month-old child affected by exposure to the parents' use of bonzai in the home environment. Because unintentional exposure to synthetic cannabinoids like bonzai might be encountered, pediatric emergency teams should be aware of this condition and child protection teams should be informed of suspicions of child negligence and abuse as a part of the medical approach. PMID- 29698343 TI - The Effect of an Observation Unit on Pediatric Minor Head Injury. AB - OBJECTIVE: The aim of this study was to evaluate the effect of an observation unit (OU) in an emergency department on reducing unnecessary use of computed tomography (CT) for minor blunt head trauma. METHODS: This study was a retrospective before-and-after study of pediatric patients 18 years or younger with minor blunt head trauma. Patients with a Glasgow Coma Scale score of 14 or 15 who presented to the emergency department were included in the analysis. The rates of head CT use in the period before and after the institution of the OU were compared. RESULTS: In total, 4706 patients were analyzed (2344 from the period before and 2362 from period after OU institution). The median age of the patients was 3 years, and 64% were male in each period. The rates of CT use were 5.7% (95% confidence interval [CI], 4.8%-6.7%) in the period before and 4.0% (95% CI, 3.3%-4.9%) in the period after OU institution (P = 0.01). The relative risk reduction was 0.70 (95% CI, 0.54-0.91). CONCLUSIONS: The rate of CT use decreased by 30% as a result of OU institution. The OU was an effective means of avoiding an unnecessary head CT for pediatric minor head injuries. PMID- 29698344 TI - An Unlikely Cause of a Blunt Pancreatic Injury. AB - We report the case of a 17-year-old male football player with blunt abdominal trauma. Careful evaluation, including computed tomography and laboratory, revealed a pancreatic body laceration. Pancreatic injuries are relatively uncommon and associated with significant morbidity and mortality and require early diagnosis for optimal management and outcome. PMID- 29698345 TI - Presenting Signs and Symptoms of Pericardial Effusions in the Pediatric Emergency Department. AB - OBJECTIVES: The primary objective of this study was to describe the frequency of the most common presenting signs and symptoms of pericardial effusions, particularly with relation to the size of the effusion. The secondary objective was to review the final etiology of the pericardial effusion in those patients who had presented to a tertiary care pediatric emergency department. METHODS: This was a retrospective chart review of patients younger than 17 years who presented and were evaluated at the pediatric emergency department and subsequently diagnosed with a pericardial effusion during a period of 10 years. RESULTS: A total of 23 patients matched the inclusion criteria. The most common symptom was shortness of breath (65%), followed by fever (52%), fatigue (44%), and chest pain (44%). Shortness of breath (60%) and chest pain (60%) were the most frequent symptoms among patients with a small pericardial effusion. Fever (86%), cough (71%), and shortness of breath (71%) were the most frequent symptoms among patients with moderate pericardial effusion. In patients with large pericardial effusions, the most frequent symptoms were shortness of breath (63%) and abdominal pain (63%). Tachycardia (52%) and tachypnea (52%) were the most common abnormal vital signs. The most common etiology was cardiac (44%) and autoimmune disease (26%). CONCLUSIONS: This study suggests that the presence of certain symptoms should be associated with a high index of suspicion for pericardial effusion for the pediatric emergency care physician. PMID- 29698346 TI - A Mixed Presentation of Serotonin Syndrome vs Neuroleptic Malignant Syndrome in a 12-Year-Old Boy. AB - BACKGROUND: Neuroleptic malignant syndrome (NMS) and serotonin syndrome (SS) are serious medical conditions associated with commonly prescribed psychiatric medications. Although the mechanisms differ, they can be clinically difficult to distinguish. We report a case of a pediatric patient with complicated psychiatric history that developed features of both syndromes in the setting of polypharmacy. CASE: A 12-year-old boy with a history of developmental delay, attention-deficit hyperactivity disorder, and posttraumatic stress disorder presented to the emergency department with behavior changes consisting of delayed reactions, gait instability, drooling, and slowed movements. Ten days before presentation, his outpatient psychiatrist had made multiple medication changes including discontinuation of cyproheptadine (an appetite stimulant) and initiation of aripiprazole. On arrival, the patient was noted to be tachycardia and hypertensive for age. He was disoriented, intermittently agitated, and tremulous with increased tonicity, clonus in the lower extremities, and mydriasis. He was supportively treated with lorazepam and intravenous fluids while discontinuing potential offending agents. His course was complicated by hypertension and agitation managed with dexmedetomidine infusion and benzodiazepines. His mental status, tremors, and laboratory values began to improve over the next 2 days, and eventually transitioned to the inpatient psychiatric unit on hospital day 7. DISCUSSION: Diagnosis of NMS or SS can be difficult when there is overlap between syndromes, particularly in the setting of multiple potential offending agents or underlying developmental delay. In addition, pediatric patients may present atypically as compared with adult patients with the same condition. CONCLUSION: The use of antipsychotic medications for young children with behavioral problems has risen dramatically in the last decade, increasing their risk for developing SS or NMS. PMID- 29698347 TI - Trends in Imaging Findings, Interventions, and Outcomes Among Children With Isolated Head Trauma. AB - OBJECTIVE: The aim was to analyze the impact of decreased head computed tomography (CT) imaging on detection of abnormalities and outcomes for children with isolated head trauma. METHODS: The study involves a multicenter retrospective cohort of patients younger than 19 years presenting for isolated head trauma to emergency departments in the Pediatric Health Information System database from 2003 to 2015. Patients directly admitted or transferred to another facility and those with a discharge diagnosis code for child maltreatment were excluded. Outcomes were ascertained from administrative and billing data. Trends were tested using mixed effects logistic regression, accounting for clustering within hospitals and adjusted for age, sex, insurance type, race, presence of a complex chronic condition, and hospital-level case mix index. RESULTS: Between 2003 and 2015, 306,041 children presented for isolated head trauma. The proportion of children receiving head CT imaging was increasing until 2008, peaking at just under 40%, before declining to 25% by 2015. During the recent period of decreased head CT imaging, the detection of skull fractures (odds ratio [OR]/year, 0.96; 95% confidence interval [CI], 0.95-0.97) and intracranial bleeds (OR/year, 0.96; 95% CI, 0.94-0.97), hospitalization (OR/year, 0.96; 95% CI, 0.95 0.96), neurosurgery (OR/year, 0.91; 95% CI, 0.87-0.95), and revisit (OR/year, 0.98; 95% CI, 0.96-1.00) also decreased, without significant changes in mortality (OR/year, 0.93; 95% CI, 0.84-1.04) or persistent neurologic impairment (OR/year, 1.03; 95% CI, 0.92-1.15). CONCLUSIONS: The recent decline in CT scanning in children with isolated head trauma was associated with a reduction in detection of intracranial abnormalities, and a concomitant decrease in interventions, without measurable patient harm. PMID- 29698348 TI - Accuracy of Bedside Ultrasound for the Diagnosis of Skull Fractures in Children Aged 0 to 4 Years. AB - OBJECTIVES: The aim of this study was to investigate the accuracy of bedside ultrasound (US) performed by emergency physicians for diagnosing skull fractures in children 0 to 4 years old compared with the accuracy of head computed tomography (CT). We also sought to investigate characteristics and precautions associated with US. METHODS: This single-center prospective study involved children 0 to 4 years old who had a history of head trauma. Bedside US was performed by emergency medicine physicians, and the results were compared with CT scan interpretations provided by attending radiologists. The accuracy of US for the diagnosis of skull fractures was calculated, and the errors were reviewed. RESULTS: A total of 87 patients were enrolled. Skull fracture was present in 13 patients (14.9%), according to CT. Bedside US had a sensitivity and specificity of 76.9% (95% confidence interval [CI], 46.0%-93.8%) and 100% (95% CI, 93.9% 100%), respectively. Overall positive predictive value was 100% (95% CI, 65.5% 100%), and negative predictive value was 96.1% (95% CI, 88.3%-99.0%). Three false negative cases were observed. CONCLUSIONS: Bedside US performed by emergency medicine physicians with short focused US training is a useful tool for diagnosing skull fractures in children 0 to 4 years of age. However, there were 3 false-negative cases. A meticulous examination is needed in the area adjacent to the orbital wall and skull base. PMID- 29698349 TI - A Relationship Between Clinical and Laboratory Characteristics in Children With Severe Scorpion Envenomation in Cukurova, Turkey. AB - OBJECTIVE: Scorpion stings are an important health problem in many parts of the world. The aim of this study was to retrospectively examine cases of scorpion stings to evaluate their epidemiological, clinical, and laboratory features and to determine strategies that can reduce morbidity and mortality in these cases. METHODS: Scorpion stings experienced by children between 2007 and 2013 were retrospectively reviewed. The patients were categorized into groups based on severities of toxicities, and demographic, clinical, and laboratory features were compared between the groups. RESULTS: The mean +/- SD age of the 189 patients with scorpion stings was 83.43 +/- 59.62 months. There was a significant difference between the clinical stages and the age distribution of the cases (P < 0.05). White blood cell counts differed significantly between the groups (P < 0.05). There was not a significant difference in mean platelet volume and platelet distribution width between the groups, but plateletcrit and low platelet count were significantly different between stage 1 and stage 3 cases (P < 0.05). Glucose, creatinine kinase-myoglobin binding, and troponin I were also significantly different (P < 0.05). The mortality rate was 0%. CONCLUSIONS: People living in regions where scorpion stings are frequent should be informed about preventive measures against these stings, cases of scorpion stings should be monitored in appropriate centers, and staff offering care to these cases should be educated about treatment methods. In addition, treatment protocols should be determined in accordance with regions where the stings occur and studies should be performed to describe prognostic indicators. PMID- 29698350 TI - Ablative Lasers: 24 Years of Medical Malpractice Cases in the United States. PMID- 29698352 TI - To the Editor. PMID- 29698353 TI - Psychological Detachment Safer for Patient Care? A "Critical Thinking" Response. PMID- 29698354 TI - A Systematic Review of Early Warning Systems' Effects on Nurses' Clinical Performance and Adverse Events Among Deteriorating Ward Patients. AB - OBJECTIVE: Early warning systems (EWSs) are an integral part of processes that aim to improve the early identification and management of deteriorating patients in general wards. However, the widespread implementation of these systems has not generated robust data regarding nurses' clinical performance and patients' adverse events. This review aimed to determine the ability of EWSs to improve nurses' clinical performance and prevent adverse events among deteriorating ward patients. METHOD: The PubMed, CINAHL, EMBASE, and Cochrane Library databases were searched for relevant publications (January 1, 1997, to April 12, 2017). In addition, a grey literature search evaluated several guideline Web sites. The main outcome measures were nurses' clinical performance (vital sign monitoring and rapid response team notification) and patients' adverse events (in-hospital mortality, cardiac arrest, and unplanned intensive care unit [ICU] admission). RESULTS: The search identified 888 reports, although only five studies fulfilled the inclusion criteria. The findings of these studies revealed that EWSs implementation had a positive effect on nurses' clinical performance, based on their frequency of documenting vital signs that were related to the patient's clinical deterioration. In addition, postimplementation reductions were identified for cardiac arrest, unplanned ICU admission, and unexpected death. CONCLUSIONS: It seems that EWSs can improve nurses' clinical performance and prevent adverse events (e.g., in-hospital mortality, unplanned ICU admission, and cardiac arrest) among deteriorating ward patients. However, additional high quality evidence is needed to more comprehensively evaluate the effects of EWSs on these outcomes. PMID- 29698355 TI - Genital Allergic Contact Dermatitis. AB - Genital allergic contact dermatitis (ACD) is an uncommon disorder, yet it severely impairs the quality of life for both men and women. Because of cultural taboos, many patients self-treat and delay proper diagnosis before presenting to a provider. Diagnosis is further confounded by irritant contact dermatitis and other genital dermatoses, which can predispose to skin barrier dysfunction and allergen penetration. Genital ACD can present acutely with erythematous erosions and pruritus or chronically with lichenification. Patch testing helps determine the diagnosis and provide relief for the patient. Topical medications, including local anesthetics and corticosteroids, are the most common genital allergens. Other typical allergens include fragrances, preservatives, adhesives, dyes, and rubber products. Less commonly considered allergens include herbs, spices, and topical vehicle components. Here, we review the most common allergens for both men and women, discuss important patch-testing panels, and recommend safe products for patients with genital ACD. PMID- 29698356 TI - Negative Repeat Open Application Test With an Extreme Positive Occluded Patch Test for a Fragrant Lotion Preserved With a Formaldehyde Releaser. PMID- 29698357 TI - T Cells Expressing the Chemokine Receptor CXCR3 Localize to Positive Patch Test Reaction Sites. PMID- 29698358 TI - American Contact Dermatitis Society: Frontiers in Dermatitis Fall 2017 Meeting Summary. PMID- 29698359 TI - The Influence of Cultural Norms on Nickel Allergic Contact Dermatitis Prevalence Data. PMID- 29698360 TI - Piercing Metal Contact Allergy: Nothing Gold Can Stay. PMID- 29698361 TI - From the Ground Up: Improving Pregnancy and Birth Experiences Through the Provision of Extraordinary Learning Opportunities in Australia. AB - A collaborative project formally titled "Working together to improve pregnancy and birth experiences for women and provide extraordinary learning opportunities for midwifery students" was launched in April 2017, after several years of consultation and planning. The opportunity to adopt an integrated response to the needs of incarcerated pregnant women and the learning needs of midwifery students was identified and supported by the university offering a graduate-entry midwifery program, a women's correctional center, and a health service in a regional area of Australia. Incarcerated women who are pregnant require pregnancy, birth, and postnatal support distinct from their clinical care, while at the same time, midwifery students need to recruit pregnant women for continuity-of-care experiences. This article presents an overview of the implementation of the pilot project. It also discusses the project team and the challenges and successes of and unanticipated opportunities for practice modification and change. PMID- 29698362 TI - Combining Intraoral Scans, Cone Beam Computed Tomography and Face Scans: The Virtual Patient. AB - PURPOSE: The aim of this literature review was to provide an update on the current scientific knowledge in the field of 3D virtual patient science and to identify a possible easy, smart, and affordable method to combine different file formats obtained from different digital devices. METHODS: Electronic searches of the Medline database was performed, up to May 2017, for articles dealing with the construction of a 3D virtual patient; the matching of data acquired with different digital devices (cone beam computed tomography, CBCT; face scanner, FS; intraoral scanner, IOS; and desktop scanner, DS) was considered. The inclusion of studies was based on the superimposition of at least 2 different digital sources. RESULTS: Twenty-five studies were selected for subsequent examination. Only 3 studies analyzed the feasibility of superimposition of 3 different types of 3D data (CBCT + FS + IOS/DS). The most frequently used matching procedure was between CBCT and FS and CBCT and IOS/DS. CONCLUSION: The procedure of superimposition of data from CBCT, IOS, and FS is currently feasible and it is now possible to create a 3D "virtual patient" to better diagnose, plan the treatment, and communicate with patients. PMID- 29698363 TI - Relationship Between Audio-Vestibular Functional Tests and Inner Ear MRI in Meniere's Disease. AB - OBJECTIVES: Meniere's disease is an inner ear disorder generally attributed to an endolymphatic hydrops. Different electrophysiological tests and imaging techniques have been developed to improve endolymphatic hydrops diagnosis. The goal of our study was to compare the sensitivity and the specificity of delayed inner ear magnetic resonance imaging (MRI) after intravenous injection of gadolinium with extratympanic clicks electrocochleography (EcochG), phase shift of distortion product otoacoustic emissions (shift-DPOAEs), and cervical vestibular-evoked myogenic potentials (cVEMP) for the diagnosis of Meniere's disease. DESIGN: Forty-one patients, with a total of 50 affected ears, were included prospectively from April 2015 to April 2016 in our institution. Patients included had definite or possible Meniere's disease based on the latest American Academy of Otolaryngology-Head and Neck Surgery guidelines revised in 2015. All patients went through delayed inner ear MRI after intravenous injection of gadolinium (three dimension-fluid attenuated inversion recovery sequences), pure tone audiometry, extratympanic clicks EcochG, shift-DPOAEs, and cVEMP on the same day. Endolymphatic hydrops was graded on MRI using the saccule to utricle ratio inversion defined as when the saccule appeared equal or larger than the utricle. RESULTS: Abnormal EcochG and shift-DPOAEs in patients with definite Meniere's disease (DMD) were found in 68 and 64.5%, respectively. The two methods were significantly associated in DMD group. In DMD group, 25.7% had a positive MRI. The correlation between MRI versus EcochG and MRI versus shift-DPOAEs was not significant. MRI hydrops detection was correlated with hearing loss. Finally, 22.9% of DMD group had positive cVEMP. CONCLUSIONS: EcochG and shift-DPOAEs were both well correlated with clinical criteria of Meniere's disease. Inner ear MRI showed hydrops when hearing loss was higher than 35 dB. The shift-DPOAEs presented the advantage of a rapid and easy measurement if DPOAEs could be recorded (i.e., hearing threshold <60dB). In contrast, EcochG can be performed regardless of hearing loss. In combination with shift-DPOAEs, it enhances the chances to confirm the diagnosis with a better confidence. PMID- 29698365 TI - A Case of Mesh Erosion to the Sigmoid After Laparoscopic Sacrocolpopexy and a Literature Review of Mesh Related Complications. AB - Sacrocolpopexy has long been the preferred surgical procedure for the management of apical vaginal prolapse. The published literature regarding rectal mesh erosion after sacrocolpopexy includes only 6 cases in MEDLINE. We report a case of sigmoid vaginal fistula identified 4 years after laparoscopic sacrocolpopexy, along with an analysis of the follow-up of 140 patients over 12 months or more. PMID- 29698366 TI - Female Caudal Duplication Syndrome: A Surgical Case Report With 10-Year Follow-up and Review of the Literature. AB - Caudal duplication syndrome is an exceedingly rare condition that manifests as duplicative anomalies of the gastrointestinal and genitourinary systems. We present a case of an adult patient born with multiple congenital anomalies including duplicated reproductive and urinary systems. She presented to our center for initial evaluation 11 years ago largely experiencing right-sided pelvic organ prolapse and bilateral urinary tract voiding dysfunction. She underwent successful surgical management and presented several years later for recurrent symptoms. We describe her presentation and our surgical experience, including complications and outcomes, for this case. We also review caudal duplication syndrome-its etiology, clinical presentation, diagnostic workup, surgical intervention (if any), and recommendations. PMID- 29698369 TI - Current and future uses of probiotics. AB - The relationship between host and gut microbiota has been the topic of research in recent decades, with particular emphasis on various species of bacteria and their distinct role in health promotion. Early promising research led to the new term probiotic, coined to describe these beneficial bacteria. This early research has laid the foundation for various proposed mechanisms of probiotic effects on health. This article describes current areas of established probiotic use and introduces areas of current investigation, including psychobiotics, which may help patients suffering from psychiatric illness. PMID- 29698368 TI - Targeted inhibition of the BRAF pathway in a patient with stage IV melanoma. AB - This article describes the use of vemurafenib, a BRAF inhibitor, to achieve disease regression in a woman with extensive metastatic melanoma and the BRAF V600 gene mutation. Given the improved survival rates seen in these patients, clinicians need to be aware of long-term patient management and adverse reactions to the drug. PMID- 29698371 TI - Why is this patient's chronic knee pain worsening? PMID- 29698370 TI - Emergency physician evaluation of PA and NP practice patterns. AB - : The unprecedented surge in physician assistants (PAs) and NPs in the ED developed quickly in recent years, but scope of practice and practice patterns are not well described. METHODS: We conducted two cross-sectional electronic surveys of the American College of Emergency Physicians' council. Survey construction was informed by interviews and evaluated with validity and reliability studies. Univariate analyses to establish associations also were performed. RESULTS: Most councilors' departments employ PAs and NPs (72.4% of 163 responses). Supervisory requirements varied greatly among respondents for the same emergency severity index (ESI) level. Regardless of experience level, NPs were reported to use significantly more resources than PAs; chi-square(4) = 105.292, P < .001 for less-experienced PAs or NPs; chi-square(4) = 120.415, P < .001 for more experienced PAs or NPs. CONCLUSION: Councilors reported great variation in PA and NP scope of practice. The results also suggest that new graduate PAs may be more clinically prepared to practice in the ED than new graduate NPs. PMID- 29698372 TI - Hypertrophic cardiomyopathy. PMID- 29698373 TI - What is causing transaminitis in this 25-year-old patient? PMID- 29698374 TI - The championship rounds. PMID- 29698375 TI - Learning the patient experience. PMID- 29698376 TI - Perspectives on PAs as researchers. PMID- 29698377 TI - The effects of probiotics on mood and emotion. AB - Preliminary research in humans and rodents demonstrates that various probiotic formulations of Lactobacillus and Bifidobacterium have a clinical and neurochemical anxiolytic effect on the central nervous system (CNS). Further research is warranted to more extensively examine the theorized connection between the gastrointestinal tract and the CNS; however, initial evidence suggests probiotics affect various mechanisms of the gut-brain connection that modulate anxiety-like behaviors. This article describes the wider-reaching effects of probiotics, specifically related to behavior and brain function. PMID- 29698379 TI - Neogambogic Acid Suppresses Receptor Activator of Nuclear Factor kappaB Ligand (RANKL)-Induced Osteoclastogenesis by Inhibiting the JNK and NF-kappaB Pathways in Mouse Bone Marrow-Derived Monocyte/Macrophages. AB - BACKGROUND Neogambogic acid (NGA) is used in traditional Chinese medicine. The aim of this study was to investigate the effects of NGA on gene signaling pathways involved in osteoclastogenesis in mouse bone marrow-derived monocyte/macrophages (BMMs) and on bone resorption in vitro. MATERIAL AND METHODS Primary mouse BMMs were cultured with increasing concentrations of NGA. Real-time polymerase chain reaction was used to study the expression of mRNAs corresponding to gene products specific to receptor activator of NF-kappaB ligand (RANKL) induced osteoclast differentiation, including tartrate-resistant acid phosphatase (TRAP), calcitonin receptor (CTR), cathepsin K (CTSK), and nuclear factor of activated T cells c1 (NFATc1). A cell counting kit-8 assay was used to evaluate cell proliferation. Western blotting and confocal immunofluorescence microscopy were used to investigate the signaling pathways. A bone resorption model was used to quantify bone resorption. RESULTS An NGA dose of <=0.4 MUg/ml had no significant effect on the proliferation of mouse BMMs in vitro (P>0.05); concentrations of between 0.1-0.4 MUg/ml significantly inhibited RANKL-induced osteoclastogenesis (P<0.01) in a dose-dependent manner. Compared with the control group, NGA significantly reduced RANKL-induced bone resorption in vitro (P <0.01), and downregulated the expression of osteoclast-related mRNAs of TRAP, CTR, CTSK, and NFATc1. NGA suppressed the activation of JNK but not the p38 signaling pathway and significantly reduced NF-kappaB p65 phosphorylation and the nuclear transport of NF-kappaB molecules, which inhibited NFATc1 expression. CONCLUSIONS NGA suppressed RANKL-induced osteoclastogenesis by inhibiting the JNK and NF-kappaB pathways in mouse BMMs in vitro and reduced osteoclastic bone resorption. PMID- 29698380 TI - Fatal Falls Overboard in Commercial Fishing - United States, 2000-2016. AB - Commercial fishing is one of the most dangerous jobs in the United States, with a 2016 work-related fatality rate (86.0 deaths per 100,000 full-time equivalent workers) 23 times higher than that for all U.S. workers (3.6) (1). Sinking vessels cause the most fatalities in the industry; however, falling from a fishing vessel is a serious hazard responsible for the second highest number of commercial fishing-associated fatalities (2,3). CDC's National Institute for Occupational Safety and Health (NIOSH) analyzed data on unintentional fatal falls overboard in the U.S. commercial fishing industry to identify gaps in the use of primary, secondary, and tertiary prevention strategies. During 2000-2016, a total of 204 commercial fishermen died after unintentionally falling overboard. The majority of falls (121; 59.3%) were not witnessed, and 108 (89.3%) of these victims were not found. Among 83 witnessed falls overboard, 56 rescue attempts were made; 22 victims were recovered but were not successfully resuscitated. The circumstances, rescue attempts, and limited use of lifesaving and recovery equipment indicate that efforts to reduce these preventable fatalities are needed during pre-event, event, and post-event sequences of falls overboard. Vessel owners could consider strategies to prevent future fatalities, including lifeline tethers, line management, personal flotation devices (PFDs), man-overboard alarms, recovery devices, and rescue training. PMID- 29698381 TI - Three Rotavirus Outbreaks in the Postvaccine Era - California, 2017. AB - Before the introduction of rotavirus vaccine in 2006, rotavirus was the most common cause of severe diarrhea among U.S. children (1). Currently, two rotavirus vaccines are licensed for use in the United States, both of which have demonstrated good field effectiveness (78%-89%) against moderate to severe rotavirus illness (2), and the use of these vaccines has substantially reduced the prevalence of rotavirus in the United States (3). However, the most recent national vaccine coverage estimates indicate lower full rotavirus vaccine-series completion (73%) compared with receipt of at least 3 doses of vaccines containing diphtheria, tetanus, and pertussis antigens (95%), given on a similar schedule to rotavirus vaccines (4). In the postvaccine era in the United States, rotavirus activity persists in a biennial pattern (3). This report describes three rotavirus outbreaks that occurred in California in 2017. One death was reported; however, the majority of cases were associated with mild to moderate illness, and illness occurred across the age spectrum as well as among vaccinated children. Rotavirus vaccines are designed to mimic the protective effects of natural infection and are most effective against severe rotavirus illness (2). Even in populations with high vaccination coverage, some rotavirus infections and mild to moderate illnesses will occur. Rotavirus vaccination should continue to be emphasized as the best means of reducing disease prevalence in the United States. PMID- 29698383 TI - Erratum: Vol. 67, No. 10. PMID- 29698382 TI - QuickStats: Percentage* of Currently Employed? Adults Aged >=18 Years Who Received Influenza Vaccine in the Past 12 Months,S by Employment Category - National Health Interview Survey,** United States, 2012 and 2016. AB - From 2012 to 2016, the percentage of employed adults who had received an influenza vaccine in the past 12 months increased overall (32.4% versus 37.0%), among government employees (42.0% versus 45.6%), and private-sector employees (31.1% versus 36.0%), but there was no significant increase among the self employed (26.5% versus 29.8%). In both years, a higher percentage of government employees had received an influenza vaccine compared with private-sector employees, who had higher percentages than the self-employed. PMID- 29698384 TI - Adherence to CDC Recommendations for the Treatment of Uncomplicated Gonorrhea - STD Surveillance Network, United States, 2016. AB - Gonorrhea, the sexually transmitted disease (STD) caused by Neisseria gonorrhoeae, is the second most common notifiable disease in the United States after chlamydia; 468,514 cases were reported to state and local health departments in 2016, an increase of 18.5% from 2015 (1). N. gonorrhoeae has progressively developed resistance to most antimicrobials used to treat the infection (2). As a result, CDC recommends two antimicrobials (250 mg of ceftriaxone [IM] plus 1 g of azithromycin [PO]) for treating uncomplicated gonorrhea to improve treatment efficacy and, potentially, to slow the emergence and spread of antimicrobial resistance. To monitor adherence to the current CDC recommended regimen for uncomplicated gonorrhea, CDC reviewed enhanced data collected on a random sample of reported cases of gonorrhea in seven jurisdictions participating in the STD Surveillance Network (SSuN) and estimated the proportion of patients who received the CDC-recommended regimen for uncomplicated gonorrhea, by patient characteristics and diagnosing facility type. In 2016, the majority of reported patients with gonorrhea (81%) received the recommended regimen. There were no differences in the proportion of patients receiving the recommended regimen by age or race/ethnicity; however, patients diagnosed with gonorrhea in STD (91%) or family planning/reproductive health (94%) clinics were more likely to receive this regimen than were patients diagnosed in other provider settings (80%). These data document high provider adherence to CDC gonorrhea treatment recommendations in specialty STD clinics, indicating high quality of care provided in those settings. Local and state health departments should monitor adherence with recommendations in their jurisdictions and consider implementing interventions to improve provider and patient compliance with gonorrhea treatment recommendations where indicated. PMID- 29698385 TI - Notes from the Field: Identification of Tourists from Switzerland Exposed to Rabies Virus While Visiting the United States - January 2018. PMID- 29698386 TI - Non-coding RNAs as biomarkers for acute myocardial infarction. AB - Acute myocardial infarction (AMI) is a main threat to human lives worldwide. Early and accurate diagnoses warrant immediate medical care, which would reduce mortality and improve prognoses. Circulating non-coding RNAs have been demonstrated to serve as competent biomarkers for various diseases. Following the identification of cardiac-specific microRNA miR-208a in circulation, more non coding RNAs (miR-1, miR-499 and miR-133) have been identified as biomarkers not only for the diagnosis of AMI but also for prognosis post infarction. Here, we summarized recent findings on non-coding RNAs as biomarkers for early diagnosis of ST-segment elevation myocardial infarction and for disease monitoring of myocardial infarction. In addition, the prognostic potential of non-coding RNAs in patients treated with percutaneous coronary intervention was also described. We also include studies based on biobanks, and build a miRNA release spectrum after AMI, which provides quantitative and time-lapse monitoring of AMI progress. With this spectrum, we are able to customize personal medical care, which prevents further damage. By constructing a network of circulating non-coding RNAs with high specificity and sensitivity, detailed diagnostic information was provided for personalized medicine. Unveiling the roles and kinetics of circulating non-coding RNAs may lead to a revolution in clinical diagnosis. PMID- 29698388 TI - Overview of the anti-inflammatory effects, pharmacokinetic properties and clinical efficacies of arctigenin and arctiin from Arctium lappa L. AB - Arctigenin (AR) and its glycoside, arctiin, are two major active ingredients of Arctium lappa L (A lappa), a popular medicinal herb and health supplement frequently used in Asia. In the past several decades, bioactive components from A lappa have attracted the attention of researchers due to their promising therapeutic effects. In the current article, we aimed to provide an overview of the pharmacology of AR and arctiin, focusing on their anti-inflammatory effects, pharmacokinetics properties and clinical efficacies. Compared to acrtiin, AR was reported as the most potent bioactive component of A lappa in the majority of studies. AR exhibits potent anti-inflammatory activities by inhibiting inducible nitric oxide synthase (iNOS) via modulation of several cytokines. Due to its potent anti-inflammatory effects, AR may serve as a potential therapeutic compound against both acute inflammation and various chronic diseases. However, pharmacokinetic studies demonstrated the extensive glucuronidation and hydrolysis of AR in liver, intestine and plasma, which might hinder its in vivo and clinical efficacy after oral administration. Based on the reviewed pharmacological and pharmacokinetic characteristics of AR, further pharmacokinetic and pharmacodynamic studies of AR via alternative administration routes are suggested to promote its ability to serve as a therapeutic agent as well as an ideal bioactive marker for A lappa. PMID- 29698390 TI - MicroRNA expression profile and functional analysis reveal their roles in contact inhibition and its disruption switch of rat vascular smooth muscle cells. AB - Contact inhibition and its disruption of vascular smooth muscle cells (VSMCs) are important cellular events in vascular diseases. But the underlying molecular mechanisms are unclear. In this study we investigated the roles of microRNAs (miRNAs) in the contact inhibition and its disruption of VSMCs and the molecular mechanisms involved. Rat VSMCs were seeded at 30% or 90% confluence. MiRNA expression profiles in contact-inhibited confluent VSMCs (90% confluence) and non contact-inhibited low-density VSMCs (30% confluence) were determined. We found that multiple miRNAs were differentially expressed between the two groups. Among them, miR-145 was significantly increased in contact-inhibited VSMCs. Serum could disrupt the contact inhibition as shown by the elicited proliferation of confluent VSMCs. The contact inhibition disruption accompanied with a down regulation of miR-145. Serum-induced contact inhibition disruption of VSMCs was blocked by overexpression of miR-145. Moreover, downregulation of miR-145 was sufficient to disrupt the contact inhibition of VSMCs. The downregulation of miR 145 in serum-induced contact inhibition disruption was related to the activation PI3-kinase/Akt pathway, which was blocked by the PI3-kinase inhibitor LY294002. KLF5, a target gene of miR-145, was identified to be involved in miR-145-mediated effect on VSMC contact inhibition disruption, as it could be inhibited by knockdown of KLF5. In summary, our results show that multiple miRNAs are differentially expressed in contact-inhibited VSMCs and in non-contact-inhibited VSMCs. Among them, miR-145 is a critical gene in contact inhibition and its disruption of VSMCs. PI3-kinase/Akt/miR-145/KLF5 is a critical signaling pathway in serum-induced contact inhibition disruption. Targeting of miRNAs related to the contact inhibition of VSMCs may represent a novel therapeutic approach for vascular diseases. PMID- 29698391 TI - Human white matter and knowledge representation. AB - Understanding how knowledge is represented in the human brain is a fundamental challenge in neuroscience. To date, most of the work on this topic has focused on knowledge representation in cortical areas and debated whether knowledge is represented in a distributed or localized fashion. Fang and colleagues provide evidence that brain connections and the white matter supporting such connections might play a significant role. The work opens new avenues of investigation, breaking through disciplinary boundaries across network neuroscience, computational neuroscience, cognitive science, and classical lesion studies. PMID- 29698389 TI - Importance of integrating nanotechnology with pharmacology and physiology for innovative drug delivery and therapy - an illustration with firsthand examples. AB - Nanotechnology has been applied extensively in drug delivery to improve the therapeutic outcomes of various diseases. Tremendous efforts have been focused on the development of novel nanoparticles and delineation of the physicochemical properties of nanoparticles in relation to their biological fate and functions. However, in the design and evaluation of these nanotechnology-based drug delivery systems, the pharmacology of delivered drugs and the (patho-)physiology of the host have received less attention. In this review, we discuss important pharmacological mechanisms, physiological characteristics, and pathological factors that have been integrated into the design of nanotechnology-enabled drug delivery systems and therapies. Firsthand examples are presented to illustrate the principles and advantages of such integrative design strategies for cancer treatment by exploiting 1) intracellular synergistic interactions of drug-drug and drug-nanomaterial combinations to overcome multidrug-resistant cancer, 2) the blood flow direction of the circulatory system to maximize drug delivery to the tumor neovasculature and cells overexpressing integrin receptors for lung metastases, 3) endogenous lipoproteins to decorate nanocarriers and transport them across the blood-brain barrier for brain metastases, and 4) distinct pathological factors in the tumor microenvironment to develop pH- and oxidative stress-responsive hybrid manganese dioxide nanoparticles for enhanced radiotherapy. Regarding the application in diabetes management, a nanotechnology enabled closed-loop insulin delivery system was devised to provide dynamic insulin release at a physiologically relevant time scale and glucose levels. These examples, together with other research results, suggest that utilization of the interplay of pharmacology, (patho-)physiology and nanotechnology is a facile approach to develop innovative drug delivery systems and therapies with high efficiency and translational potential. PMID- 29698387 TI - Salvia miltiorrhizaBurge (Danshen): a golden herbal medicine in cardiovascular therapeutics. AB - Salvia miltiorrhiza Burge (Danshen) is an eminent medicinal herb that possesses broad cardiovascular and cerebrovascular protective actions and has been used in Asian countries for many centuries. Accumulating evidence suggests that Danshen and its components prevent vascular diseases, in particular, atherosclerosis and cardiac diseases, including myocardial infarction, myocardial ischemia/reperfusion injury, arrhythmia, cardiac hypertrophy and cardiac fibrosis. The published literature indicates that lipophilic constituents (tanshinone I, tanshinone IIa, tanshinone IIb, cryptotanshinone, dihydrotanshinone, etc) as well as hydrophilic constituents (danshensu, salvianolic acid A and B, protocatechuic aldehyde, etc) contribute to the cardiovascular protective actions of Danshen, suggesting a potential synergism among these constituents. Herein, we provide a systematic up-to-date review on the cardiovascular actions and therapeutic potential of major pharmacologically active constituents of Danshen. These bioactive compounds will serve as excellent drug candidates in small-molecule cardiovascular drug discovery. This article also provides a scientific rationale for understanding the traditional use of Danshen in cardiovascular therapeutics. PMID- 29698392 TI - Gtr/Ego-independent TORC1 activation is achieved through a glutamine-sensitive interaction with Pib2 on the vacuolar membrane. AB - TORC1 is a central regulator of cell growth in response to amino acids. The role of the evolutionarily conserved Gtr/Rag pathway in the regulation of TORC1 is well-established. Recent genetic studies suggest that an additional regulatory pathway, depending on the activity of Pib2, plays a role in TORC1 activation independently of the Gtr/Rag pathway. However, the interplay between the Pib2 pathway and the Gtr/Rag pathway remains unclear. In this study, we show that Pib2 and Gtr/Ego form distinct complexes with TORC1 in a mutually exclusive manner, implying dedicated functional relationships between TORC1 and Pib2 or Gtr/Rag in response to specific amino acids. Furthermore, simultaneous depletion of Pib2 and the Gtr/Ego system abolishes TORC1 activity and completely compromises the vacuolar localization of TORC1. Thus, the amino acid-dependent activation of TORC1 is achieved through the Pib2 and Gtr/Ego pathways alone. Finally, we show that glutamine induces a dose-dependent increase in Pib2-TORC1 complex formation, and that glutamine binds directly to the Pib2 complex. These data provide strong preliminary evidence for Pib2 functioning as a putative glutamine sensor in the regulation of TORC1. PMID- 29698393 TI - Effects of spatiotemporal HSV-2 lesion dynamics and antiviral treatment on the risk of HIV-1 acquisition. AB - Patients with Herpes Simplex Virus-2 (HSV-2) infection face a significantly higher risk of contracting HIV-1. This is thought to be due to herpetic lesions serving as entry points for HIV-1 and tissue-resident CD4+ T cell counts increasing during HSV-2 lesional events. We have created a stochastic and spatial mathematical model describing the dynamics of HSV-2 infection and immune response in the genital mucosa. Using our model, we first study the dynamics of a developing HSV-2 lesion. We then use our model to quantify the risk of infection with HIV-1 following sexual exposure in HSV-2 positive women. Untreated, we find that HSV-2 infected women are up to 8.6 times more likely to acquire HIV-1 than healthy patients. However, when including the effects of the HSV-2 antiviral drug, pritelivir, the risk of HIV-1 infection is predicted to decrease by up to 35%, depending on drug dosage. We estimate the relative importance of decreased tissue damage versus decreased CD4+ cell presence in determining the effectiveness of pritelivir in reducing HIV-1 infection. Our results suggest that clinical trials should be performed to evaluate the effectiveness of pritelivir or similar agents in preventing HIV-1 infection in HSV-2 positive women. PMID- 29698394 TI - Organization of the core respiratory network: Insights from optogenetic and modeling studies. AB - The circuit organization within the mammalian brainstem respiratory network, specifically within and between the pre-Botzinger (pre-BotC) and Botzinger (BotC) complexes, and the roles of these circuits in respiratory pattern generation are continuously debated. We address these issues with a combination of optogenetic experiments and modeling studies. We used transgenic mice expressing channelrhodopsin-2 under the VGAT-promoter to investigate perturbations of respiratory circuit activity by site-specific photostimulation of inhibitory neurons within the pre-BotC or BotC. The stimulation effects were dependent on the intensity and phase of the photostimulation. Specifically: (1) Low intensity (<= 1.0 mW) pulses delivered to the pre-BotC during inspiration did not terminate activity, whereas stronger stimulations (>= 2.0 mW) terminated inspiration. (2) When the pre-BotC stimulation ended in or was applied during expiration, rebound activation of inspiration occurred after a fixed latency. (3) Relatively weak sustained stimulation (20 Hz, 0.5-2.0 mW) of pre-BotC inhibitory neurons increased respiratory frequency, while a further increase of stimulus intensity (> 3.0 mW) reduced frequency and finally (>= 5.0 mW) terminated respiratory oscillations. (4) Single pulses (0.2-5.0 s) applied to the BotC inhibited rhythmic activity for the duration of the stimulation. (5) Sustained stimulation (20 Hz, 0.5-3.0 mW) of the BotC reduced respiratory frequency and finally led to apnea. We have revised our computational model of pre-BotC and BotC microcircuits by incorporating an additional population of post-inspiratory inhibitory neurons in the pre-BotC that interacts with other neurons in the network. This model was able to reproduce the above experimental findings as well as previously published results of optogenetic activation of pre-BotC or BotC neurons obtained by other laboratories. The proposed organization of pre-BotC and BotC circuits leads to testable predictions about their specific roles in respiratory pattern generation and provides important insights into key circuit interactions operating within brainstem respiratory networks. PMID- 29698395 TI - Personalizing physical exercise in a computational model of fuel homeostasis. AB - The beneficial effects of physical activity for the prevention and management of several chronic diseases are widely recognized. Mathematical modeling of the effects of physical exercise in body metabolism and in particular its influence on the control of glucose homeostasis is of primary importance in the development of eHealth monitoring devices for a personalized medicine. Nonetheless, to date only a few mathematical models have been aiming at this specific purpose. We have developed a whole-body computational model of the effects on metabolic homeostasis of a bout of physical exercise. Built upon an existing model, it allows to detail better both subjects' characteristics and physical exercise, thus determining to a greater extent the dynamics of the hormones and the metabolites considered. PMID- 29698396 TI - Fitness to plead: Development and validation of a standardised assessment instrument. AB - The ability of an individual to participate in courtroom proceedings is assessed by clinicians using legal 'fitness to plead' criteria. Findings of 'unfitness' are so rare that there is considerable professional unease concerning the utility of the current subjective assessment process. As a result, mentally disordered defendants may be subjected unfairly to criminal trials. The Law Commission in England and Wales has proposed legal reform, as well as the utilisation of a defined psychiatric instrument to assist in fitness to plead assessments. Similar legal reforms are occurring in other jurisdictions. Our objective was to produce and validate a standardised assessment instrument of fitness to plead employing a filmed vignette of criminal proceedings. The instrument was developed in consultation with legal and clinical professionals, and was refined using standard item reduction methods in two initial rounds of testing (n = 212). The factorial structure, test-retest reliability and convergent validity of the resultant instrument were assessed in a further round (n = 160). As a result of this iterative process a 25-item scale was produced, with an underlying two factor structure representing the foundational and decision-making abilities underpinning fitness to plead. The sub-scales demonstrate good internal consistency (factor 1: 0.76; factor 2: 0.65) and test-retest stability (0.7) as well as excellent convergent validity with scores of intelligence, executive function and mentalising abilities (p<=0.01 in all domains). Overall the standardised Fitness to Plead Assessment instrument has good psychometric properties. It has the potential to ensure that the significant numbers of mentally ill and cognitively impaired individuals who face trial are objectively assessed, and the courtroom process critically informed. PMID- 29698397 TI - Pathogen Box screening for hit identification against Mycobacterium abscessus. AB - Mycobacterium abscessus is a rapidly growing life-threatening mycobacterium with multiple drug-resistance mechanisms. However, there is no official regimen for M. abscessus therapy. In this study, we screened the Pathogen Box, which contains 400 drug-like molecules active against neglected diseases, to identify active molecules targeting Mycobacterium abscessus using resazurin live/dead assays. In this screening assay, the Z-factor was 0.7, as an indicator of the statistical confidence of the assay. A cut-off of 80% growth inhibition in the screening resulted in the identification of four different compounds at a single concentration (20 MUM). Dose-response curves identified three different hit candidates, i.e., MMV688508, MMV688844, and MMV688845, which generated good inhibitory curves. All hit candidates were expected to have different molecular targets. Among them, MMV688844 showed the best minimum inhibitory concentration value for not only wild-type M. abscessus but also for nine different R and S morphotype clinical isolates. Thus, we found that MMV688844, identified from the Pathogen Box screen, may be a promising candidate in the M. abscessus drug discovery pipeline. PMID- 29698398 TI - Predictive factors for missed adenoma on repeat colonoscopy in patients with suboptimal bowel preparation on initial colonoscopy: A KASID multicenter study. AB - Suboptimal bowel preparation can result in missed colorectal adenoma that can evolve into interval colorectal cancer. This study aims to identify the predictive factors associated with missed adenoma on repeat colonoscopy in patients with suboptimal bowel preparation at initial colonoscopy. A total of 441 patients with suboptimal bowel preparation on initial colonoscopy and who had repeat colonoscopy within two years were included from 2007 to 2014 in six tertiary hospitals. Suboptimal bowel preparation was defined as 'poor' according to the Aronchick scale or a score <= 1 in at least one segment or total score < 6 according to the Boston bowel preparation scale. Of 441 patients, mean age at initial colonoscopy was 59.1 years, and 69.2% patients were male. The mean interval from initial to repeat colonoscopy was 14.1 months. The per-patient adenoma miss rate (AMR) was 42.4% for any adenoma and 5.4% for advanced adenoma. When the association between baseline clinical characteristics and missed lesions on repeat colonoscopy was analyzed, dyslipidemia (odds ratio [OR], 5.19; 95% confidence interval [CI], 1.14-23.66; P = 0.034), and high-risk adenoma (OR, 4.45; 95% CI, 1.12-17.68; P = 0.034) on initial colonoscopy were independent risk factors for missed advanced adenoma. In patients with suboptimal bowel preparation, dyslipidemia and high-risk adenoma on initial colonoscopy were independently predictive of missed advanced adenoma on repeat colonoscopy. PMID- 29698399 TI - Total retinal detachments due to retinoblastoma: Outcomes following intra arterial chemotherapy/ophthalmic artery chemosurgery. AB - PURPOSE: To report on the rate and timing of retinal reattachment and outcomes for retinoblastoma children who have total retinal detachments at presentation to our center and were treated with intra-arterial chemotherapy (ophthalmic artery chemosurgery, OAC). PATIENTS AND METHODS: Single-center retrospective review of retinoblastoma patients who presented with total retinal detachments and were subsequently treated with OAC at MSKCC between May 2006 and July 2016. Endpoints were retinal detachment resolution, visual function, ERG amplitude, ocular survival, and patient survival from metastases. RESULTS: 87 eyes of 84 retinoblastoma patients were included. Using a survival multistate model, by 36 months of follow-up, there was a 54% cumulative probability of complete retinal reattachment and a 76% probability of partial reattachment. 24% of eyes that completely reattached received only OAC without any prior or adjuvant treatments. Eyes that completely reattached were significantly more likely to have been diagnosed at a younger age (p<0.0001) and to have greater initial ERG values (p = 0.006). At final follow-up, 14% of eyes had gained at least 25 MUV of ERG activity, and 8.0% had achieved hand motion vision or better, including one to 20/60. 13% of eyes were enucleated. No patient died from metastatic disease, and only one developed metastases. CONCLUSION: OAC can successfully treat previously considered "non-salvageable" retinoblastoma eyes with total retinal detachments, promote retinal reattachment in the majority of eyes, and preserve ocular and patient survival. PMID- 29698401 TI - Effect of population density of lettuce intercropped with rocket on productivity and land-use efficiency. AB - The objective of this study was to evaluate the influence of the spacing of lettuce rows on the production of a lettuce-rocket intercropping system over two growing seasons (11 August to 25 September 2011 and 12 January to 24 February 2012) in Jaboticabal, Sao Paulo, Brazil. We evaluated 11 treatments in each season: lettuce-rocket intercrops with five row spacings for the lettuce (0.20, 0.25, 0.30, 0.35 and 0.40 m) and the rocket planted midway between the lettuce rows, sole crops of lettuce at the same five row spacings and a sole crop of rocket. Fresh and dry masses of the lettuce and rocket and number of lettuce leaves per plant were highest with a lettuce row spacing of 0.40 m, but the productivities of the lettuce and rocket were higher with a lettuce row spacing of 0.20 m. The productivities and fresh and dry weights of the lettuce and rocket and the number of lettuce leaves per plant were highest in the sole crops, but the fresh and dry weights of the rocket were higher with intercropping. The land equivalent ratios were >1.0 in both seasons in all intercrops and were highest for the densest crop (1.41). Intercropping was therefore 41% more efficient than sole cropping for the production of lettuce and rocket. PMID- 29698400 TI - The complex association between the antioxidant defense system and clinical status in early psychosis. AB - Oxidative stress is a pathophysiological mechanism potentially involved in psychiatric disorders. The objective of this study was to assess the relationship between total antioxidant status (TAS) and the functional status of patients with a first episode of psychosis at the onset of the disease. For this purpose, a sample of 70 patients aged between 9 and 17 years with a first episode of psychosis were followed up for a period of two years. Blood samples were drawn to measure TAS levels at three time points: at baseline, at one year, and at two years. Clinical symptoms and functioning were also assessed at the same time points using various scales. Linear regression analysis was performed to investigate the relationship between TAS and clinical status at each assessment, adjusting for potential confounding factors. The distribution of clinical variables was grouped in different percentiles to assess the dose-response in the relation between clinical variables and TAS. At baseline, patient's score on Children's Global Assessment Scale (CGAS) was directly and significantly associated with TAS with a monotonic increase in percentiles, and surprising this association was reversed after one and two years of follow-up with a monotonic decrease. In summary at the onset of the illness, TAS is positively related to clinical status, whereas as the illness progresses this correlation is reversed and becomes negative. This may be the result of an adaptive response. PMID- 29698402 TI - A new method for evaluating tumor-infiltrating lymphocytes (TILs) in colorectal cancer using hematoxylin and eosin (H-E)-stained tumor sections. AB - PURPOSE: Numerous reports indicate that tumor-infiltrating lymphocytes (TILs) are a prognostic factor in various cancers and that they must be good biomarkers. However, the methods of evaluating TILs differ in each study; thus, there is not yet a standardized methodology for evaluating TILs. The purpose of this study is to evaluate the prognostic significance of tumor-infiltrating lymphocytes (TILs) in patients with colorectal cancer (CRC) using the new method proposed by the International TILs Working Group in breast cancer and to standardize the method of evaluating TILs in CRC. METHODS: We retrospectively reviewed a database of 160 patients with Stage II or III CRC. The density of TILs was assessed by measuring the area occupied by mononuclear cells over the stromal area on hematoxylin and eosin (H-E)-stained sections. We set 42% as the cut-off percentage of the area occupied by TILs according to the receiver operating characteristic curve, and we classified patients into the high-TILs and the low-TILs groups. RESULTS: The rates of relapse-free survival (RFS) and overall survival (OS) in the high-TILs group were significantly higher than those in the low-TILs group. A multivariate analysis showed that the density of TILs was independently associated with RFS and OS. Moreover, the density of TILs assessed by an observer was significantly associated with the density of TILs assessed by the automated imaging software program. CONCLUSIONS: The new method for evaluating TILs, which was recommended by the International TILs Working Group in breast cancer, might be a useful predictive factor in colorectal cancer patients. PMID- 29698403 TI - Regulation of oxidative phosphorylation is different in electrically- and cortically-stimulated skeletal muscle. AB - A computer model of the skeletal muscle bioenergetic system was used to study the regulation of oxidative phosphorylation (OXPHOS) in electrically-stimulated and cortically-stimulated skeletal muscle. Two types of the dependence of the intensity of each-step activation (ESA) of OXPHOS complexes on ATP usage activity were tested: power-type dependence and saturating-type dependence. The dependence of muscle oxygen consumption ([Formula: see text]), phosphocreatine (PCr), cytosolic ADP, ATP, inorganic phosphate (Pi), pH and taup (characteristic transition time) of the principal component of the muscle [Formula: see text] on kinetics on the ATP usage activity was simulated for both types of the ESA intensity-ATP usage activity dependence. Computer simulations involving the power type dependence predict system properties that agree well with experimental data for electrically-stimulated muscle. On the other hand, model predictions for the saturating-type dependence in the presence of the 'additional' ATP usage (postulated previously to underlie the slow component of the VO2 on-kinetics) reproduce well system properties encountered in human skeletal muscle during voluntary exercise. It is postulated that the difference between the regulation and kinetic properties of the system in electrically- and cortically-stimulated muscle is mostly due to the different muscle fibers recruitment pattern. In the former, all fiber types are recruited in parallel already at low power output (PO) values, while in the latter type I fibers (with higher ESA intensity) are stimulated at low PO values, while type II fibers (especially type II b and IIx fibers) with low ESA intensity are recruited predominantly at high PO values. PMID- 29698404 TI - Identifying seasonal mobility profiles from anonymized and aggregated mobile phone data. Application in food security. AB - We propose a framework for the systematic analysis of mobile phone data to identify relevant mobility profiles in a population. The proposed framework allows finding distinct human mobility profiles based on the digital trace of mobile phone users characterized by a Matrix of Individual Trajectories (IT Matrix). This matrix gathers a consistent and regularized description of individual trajectories that enables multi-scale representations along time and space, which can be used to extract aggregated indicators such as a dynamic multi scale population count. Unsupervised clustering of individual trajectories generates mobility profiles (clusters of similar individual trajectories) which characterize relevant group behaviors preserving optimal aggregation levels for detailed and privacy-secured mobility characterization. The application of the proposed framework is illustrated by analyzing fully anonymized data on human mobility from mobile phones in Senegal at the arrondissement level over a calendar year. The analysis of monthly mobility patterns at the livelihood zone resolution resulted in the discovery and characterization of seasonal mobility profiles related with economic activities, agricultural calendars and rainfalls. The use of these mobility profiles could support the timely identification of mobility changes in vulnerable populations in response to external shocks (such as natural disasters, civil conflicts or sudden increases of food prices) to monitor food security. PMID- 29698405 TI - Mining co-occurrence and sequence patterns from cancer diagnoses in New York State. AB - The goal of this study is to discover disease co-occurrence and sequence patterns from large scale cancer diagnosis histories in New York State. In particular, we want to identify disparities among different patient groups. Our study will provide essential knowledge for clinical researchers to further investigate comorbidities and disease progression for improving the management of multiple diseases. We used inpatient discharge and outpatient visit records from the New York State Statewide Planning and Research Cooperative System (SPARCS) from 2011 2015. We grouped each patient's visit history to generate diagnosis sequences for seven most popular cancer types. We performed frequent disease co-occurrence mining using the Apriori algorithm, and frequent disease sequence patterns discovery using the cSPADE algorithm. Different types of cancer demonstrated distinct patterns. Disparities of both disease co-occurrence and sequence patterns were observed from patients within different age groups. There were also considerable disparities in disease co-occurrence patterns with respect to different claim types (i.e., inpatient, outpatient, emergency department and ambulatory surgery). Disparities regarding genders were mostly found where the cancer types were gender specific. Supports of most patterns were usually higher for males than for females. Compared with secondary diagnosis codes, primary diagnosis codes can convey more stable results. Two disease sequences consisting of the same diagnoses but in different orders were usually with different supports. Our results suggest that the methods adopted can generate potentially interesting and clinically meaningful disease co-occurrence and sequence patterns, and identify disparities among various patient groups. These patterns could imply comorbidities and disease progressions. PMID- 29698408 TI - RIDDLE: Race and ethnicity Imputation from Disease history with Deep LEarning. AB - Anonymized electronic medical records are an increasingly popular source of research data. However, these datasets often lack race and ethnicity information. This creates problems for researchers modeling human disease, as race and ethnicity are powerful confounders for many health exposures and treatment outcomes; race and ethnicity are closely linked to population-specific genetic variation. We showed that deep neural networks generate more accurate estimates for missing racial and ethnic information than competing methods (e.g., logistic regression, random forest, support vector machines, and gradient-boosted decision trees). RIDDLE yielded significantly better classification performance across all metrics that were considered: accuracy, cross-entropy loss (error), precision, recall, and area under the curve for receiver operating characteristic plots (all p < 10-9). We made specific efforts to interpret the trained neural network models to identify, quantify, and visualize medical features which are predictive of race and ethnicity. We used these characterizations of informative features to perform a systematic comparison of differential disease patterns by race and ethnicity. The fact that clinical histories are informative for imputing race and ethnicity could reflect (1) a skewed distribution of blue- and white-collar professions across racial and ethnic groups, (2) uneven accessibility and subjective importance of prophylactic health, (3) possible variation in lifestyle, such as dietary habits, and (4) differences in background genetic variation which predispose to diseases. PMID- 29698407 TI - A novel echocardiographic hemodynamic index for predicting outcome of aortic stenosis patients following transcatheter aortic valve replacement. AB - OBJECTIVE: Transcatheter aortic valve replacement (TAVR) reduces left ventricular (LV) afterload and improves prognosis in aortic stenosis (AS) patients. However, LV afterload consists of both valvular and arterial loads, and the benefits of TAVR may be attenuated if the arterial load dominates. We proposed a new hemodynamic index, the Relative Valve Load (RVL), a ratio of mean gradient (MG) and valvuloarterial impedance (Zva), to describe the relative contribution of the valvular load to the global LV load, and examined whether RVL predicted patient outcome following TAVR. METHODS: A total of 258 patients with symptomatic severe AS (indexed aortic valve area (AVA)<0.6cm2/m2, AR<=2+) underwent successful TAVR at the University of Ottawa Heart Institute and had clinical follow-up to 1-year post-TAVR. Pre-TAVR MG, AVA, percent stroke work loss (%SWL), Zva and RVL were measured by echocardiography. The primary endpoint was all cause mortality at 1 year post TAVR. RESULTS: There were 53 deaths (20.5%) at 1-year. RVL<=7.95ml/m2 had a sensitivity of 60.4% and specificity of 75.1% for identifying all cause mortality at 1-year post-TAVR and provided better specificity than MG<40 mmHg, AVA>0.75cm2, %SWL<=25% and Zva>5mmHg/ml/m2 despite equivalent or better sensitivity. In multivariable Cox analysis, RVL<=7.95ml/m2 was an independent predictor of all cause mortality (HR 3.2, CI 1.8-5.9; p<0.0001). RVL<=7.95ml/m2 was predictive of all cause mortality in both low flow and normal flow severe AS. CONCLUSIONS: RVL is a strong predictor of all-cause mortality in severe AS patients undergoing TAVR. A pre-procedural RVL<=7.95ml/m2 identifies AS patients at increased risk of death despite TAVR and may assist with decision making on the benefits of TAVR. PMID- 29698406 TI - Generation and characterization of a bivalent protein boost for future clinical trials: HIV-1 subtypes CR01_AE and B gp120 antigens with a potent adjuvant. AB - The RV144 Phase III clinical trial with ALVAC-HIV prime and AIDSVAX B/E subtypes CRF01_AE (A244) and B (MN) gp120 boost vaccine regime in Thailand provided a foundation for the future development of improved vaccine strategies that may afford protection against the human immunodeficiency virus type 1 (HIV-1). Results from this trial showed that immune responses directed against specific regions V1V2 of the viral envelope (Env) glycoprotein gp120 of HIV-1, were inversely correlated to the risk of HIV-1 infection. Due to the low production of gp120 proteins in CHO cells (2-20 mg/L), cleavage sites in V1V2 loops (A244) and V3 loop (MN) causing heterogeneous antigen products, it was an urgent need to generate CHO cells harboring A244 gp120 with high production yields and an additional, homogenous and uncleaved subtype B gp120 protein to replace MN used in RV144 for the future clinical trials. Here we describe the generation of Chinese Hamster Ovary (CHO) cell lines stably expressing vaccine HIV-1 Env antigens for these purposes: one expressing an HIV-1 subtype CRF01_AE A244 Env gp120 protein (A244.AE) and one expressing an HIV-1 subtype B 6240 Env gp120 protein (6240.B) suitable for possible future manufacturing of Phase I clinical trial materials with cell culture expression levels of over 100 mg/L. The antigenic profiles of the molecules were elucidated by comprehensive approaches including analysis with a panel of well-characterized monoclonal antibodies recognizing critical epitopes using Biacore and ELISA, and glycosylation analysis by mass spectrometry, which confirmed previously identified glycosylation sites and revealed unknown sites of O-linked and N-linked glycosylations at non consensus motifs. Overall, the vaccines given with MF59 adjuvant induced higher and more rapid antibody (Ab) responses as well as higher Ab avidity than groups given with aluminum hydroxide. Also, bivalent proteins (A244.AE and 6240.B) formulated with MF59 elicited distinct V2-specific Abs to the epitope previously shown to correlate with decreased risk of HIV-1 infection in the RV144 trial. All together, these results provide critical information allowing the consideration of these candidate gp120 proteins for future clinical evaluations in combination with a potent adjuvant. PMID- 29698409 TI - Heparin free dialysis in critically sick children using sustained low efficiency dialysis (SLEDD-f): A new hybrid therapy for dialysis in developing world. AB - BACKGROUND: In critically sick adults, sustained low efficiency dialysis [SLED] appears to be better tolerated hemodynamically and outcomes seem to be comparable to CRRT. However, there is paucity of data in critically sick children. In children, two recent studies from Taiwan (n = 11) and India (n = 68) showed benefits of SLED in critically sick children. AIMS AND OBJECTIVES: The objective of the study was to look at the feasibility and tolerability of sustained low efficiency daily dialysis-filtration [SLEDD-f] in critically sick pediatric patients. MATERIAL AND METHODS: Design: Retrospective study Inclusion criteria: All pediatric patients who had undergone heparin free SLEDD-f from January 2012 to October 2017. Measurements: Data collected included demographic details, vital signs, PRISM III at admission, ventilator parameters (where applicable), number of inotropes, blood gas and electrolytes before, during, and on conclusion of SLED therapy. Technical information was gathered regarding SLEDD-f prescription and complications. RESULTS: Between 2012-2017, a total of 242 sessions of SLEDD-f were performed on 70 patients, out of which 40 children survived. The median age of patients in years was 12 (range 0.8-17 years), and the median weight was 39 kg (range 8.5-66 kg). The mean PRISM score at admission was 8.77+/-7.22. SLEDD-f sessions were well tolerated, with marked improvement in fluid status and acidosis. Premature terminations had to be done in 23 (9.5%) of the sessions. There were 21 sessions (8.6%) terminated due to hypotension and 2 sessions (0.8%) terminated due to circuit clotting. Post- SLEDD-f hypocalcemia occurred in 15 sessions (6.2%), post- SLEDD-f hypophosphatemia occurred in 1 session (0.4%), and post- SLEDD-f hypokalemia occurred in 17 sessions (7.0%). CONCLUSIONS: This study is the largest compiled data on pediatric SLEDD-f use in critically ill patients. Our study confirms the feasibility of heparin free SLEDD-f in a larger pediatric population, and even in children weighing <20 kg on inotropic support. PMID- 29698410 TI - Ten-year cumulative incidence of epiretinal membranes assessed on fundus photographs. The Beijing Eye Study 2001/2011. AB - PURPOSE: To assess the 10-year incidence and progression of epiretinal membranes (ERMs). METHODS: The population-based longitudinal Beijing Eye Study, which included 4439 subjects (age:40+years) in 2001, was repeated in 2011 with 2695 subjects participating (66.4% of the survivors). The study participants underwent a detailed ophthalmic examination, including retinal photography. Assessing fundus photograohs, ERMs were classified as cellophane macular reflex (CMR) without retinal folds, or as preretinal macular fibrosis (PMF) without or with retinal folds. RESULTS: Fundus photographs were available for 2476 subjects with a mean age of 69.0+/-7.8 years (range:51-93 years) and mean axial length of 23.3+/-0.9 mm (range:19.92-26.33mm). The 10-year incidence of ERMs was 8.4% (208/2476 participants; 95% confidence interval (CI):7.4,9.5). ERMs developed bilaterally in 50 (24%) individuals and unilaterally in 158 (76%) persons. The incidence of PMFs with 2.5% (95% CI: 1.9, 3.1) was lower than the incidence of CMRs with 5.9% (95% CI: 5.0, 6.9). Higher 10-year incidence of ERMs was associated with older age (P<0.001; odds ratio (OR): 1.06; 95%CI:1.04,1.09), previous cataract surgery (P = 0.003;OR:3.32;95%CI:1.51,7.29) and presence of a complete posterior vitreous detachment (P = 0.02;OR:1.84;95%CI:1.12,3.02). In the age groups of <60 years, 60-69 years, 70-79 years and 80+years, incidence of ERMs was 3.1%, 10.0%, 14.4% and 10.9%, respectively, with no significant gender difference. CONCLUSIONS: In Chinese aged 40+ years, the 10-year incidence of ERMs (8.4%) increased with older age, previous cataract surgery and complete posterior vitreous detachment. The ten-year incidence was lower for PMFs (2.5%) than for CMRs (5.9%). PMID- 29698411 TI - Hidden diversity: Phylogeography of genus Ototyphlonemertes Diesing, 1863 (Ototyphlonemertidae: Hoplonemertea) reveals cryptic species and high diversity in Chilean populations. AB - Ototyphlonemertes is a cosmopolitan genus of meiofaunal nemerteans. Their morphological characters are insufficient to reliably identify and delimit species. Consequently, some of the species are considered cosmopolitan despite anticipated low dispersion capability of the adults and a short planktonic larval phase. Indeed, recent studies show that some species actually comprise cryptic species, and populations are connected by stochastic events of long-distance dispersion. Based solely on morphological traits, a Lactea and a Pallida morph of Ototyphlonemertes are recognized here from collections at eight and five locations respectively along the Chilean coast. To assess the phylogeographic patterns of their populations, two mitochondrial markers (COI and COX3) of 162 specimens of Lactea and 25 of Pallida were sequenced. Final sequences are 605bp and 362bp for COI and COX3, respectively. Results from phylogenetic and haplotype network analyses suggest that the Lactea morph comprises up to three independent evolutionary units (one with only COX3 sequences). A COI gene tree including other previously published Ototyphlonemertes sequences groups the Chilean Lactea with other Lactea, while the Chilean Pallida is grouped with other Pallida. Different structuring and gene flow patterns found for the four groups support the hypothesis that these are four independent evolutionary entities with different ecological, dispersal and demographical characteristics. PMID- 29698412 TI - Clinical manifestations in infants and children with Mycoplasma pneumoniae infection. AB - BACKGROUND: Mycoplasma pneumoniae is a common cause of community-acquired pneumonia in older children. Pulmonary and extra-pulmonary symptoms associated with M. pneumoniae infection are reported. M. pneumoniae is mainly epidemic in Denmark with the recurrence every 4-7th year. AIMS: Retrospectively, to describe the epidemiology and clinical features, in infants and children, during the M. pneumoniae epidemic in 2010 and 2011. METHODS: All children under the age of 16 that were tested for M. pneumoniae during the period 01.02.2010-31.01.2012 were included. Medical charts, as well as radiological findings, were reviewed for all children with M. pneumoniae. A post-hoc analysis of viral co-infections was done on part of the cohort. RESULTS: 134 of 746 children were tested positive for M. pneumoniae by PCR or serology. Positive tests were found in 65% of children seven years and older, in 30% of 2-6-year-olds and 4% of infants (less than two years of age). Viral co-infection was found in 27% of the tested samples. The clinical presentation was a cough, asthma-like symptoms and low-grade fever. Extra pulmonary symptoms were common and presented as nausea/vomiting by 33% of the children and skin manifestations by 25%. 84% of the children had a chest x-ray taken, and there were positive radiological findings in 94% of these. CONCLUSION: M. pneumoniae also affected infants and young children and symptoms were similar to infections with respiratory viruses, but severe LRTI were also seen. During an up-coming epidemic, assessment of extra-pulmonary manifestations can be helpful when diagnosing M. pneumoniae infections. PMID- 29698413 TI - Proof of concept of a workflow methodology for the creation of basic canine head anatomy veterinary education tool using augmented reality. AB - Neuroanatomy can be challenging to both teach and learn within the undergraduate veterinary medicine and surgery curriculum. Traditional techniques have been used for many years, but there has now been a progression to move towards alternative digital models and interactive 3D models to engage the learner. However, digital innovations in the curriculum have typically involved the medical curriculum rather than the veterinary curriculum. Therefore, we aimed to create a simple workflow methodology to highlight the simplicity there is in creating a mobile augmented reality application of basic canine head anatomy. Using canine CT and MRI scans and widely available software programs, we demonstrate how to create an interactive model of head anatomy. This was applied to augmented reality for a popular Android mobile device to demonstrate the user-friendly interface. Here we present the processes, challenges and resolutions for the creation of a highly accurate, data based anatomical model that could potentially be used in the veterinary curriculum. This proof of concept study provides an excellent framework for the creation of augmented reality training products for veterinary education. The lack of similar resources within this field provides the ideal platform to extend this into other areas of veterinary education and beyond. PMID- 29698414 TI - CT of the paraumbilical and ensiform veins in patients with superior vena cava or left brachiocephalic vein obstruction. AB - The purpose of this study was to elaborate on the anastomoses between the paraumbilical and systemic veins, particularly the ensiform veins. The connections with the ensiform veins have received little attention in the anatomical and radiological literature, and remain incompletely described. Too small to be reliably traced in normal CT scans, the paraumbilical veins can dilate in response to increased blood flow from systemic veins in superior vena cava obstruction (SVCO), allowing a study of their arrangement and connections. Collateral paraumbilical veins were therefore analyzed retrospectively in 28 patients with SVCO using CT. We observed inferior and superior groups of collateral vessels in 23/28 (82%) and 17/28 (61%) patients, respectively. Inferior veins ascended towards the liver and drained into portal veins (19/28, 68%) or the umbilical vein (8/28, 29%); superior veins descended and drained into portal veins. The inferior veins (N = 27) could be traced to ensiform veins in almost all of the cases (26/27, 96%), and a little over half (14/27, 52%) were also traceable to subcutaneous and deep epigastric veins. They were opacified by ensiform (25/27, 93%), deep epigastric (4/27, 15%) and subcutaneous (4/27, 15%) veins. The superior veins (N = 17) were supplied by diaphragmatic (13/17, 76%) and ensiform veins (4/17, 24%); the diaphragmatic veins were branches of collateral internal thoracic, left pericardiacophrenic and anterior mediastinal veins. Collateral ensiform veins were observed in 22 patients and anastomosed with internal thoracic (19/22, 86%), superior epigastric (9/22, 41%), diaphragmatic (4/22, 18%), subcutaneous (3/22, 14%) and anterior mediastinal veins (1/22, 5%). These observations show that the paraumbilical veins communicate with ensiform, deep epigastric, subcutaneous and diaphragmatic veins, joining the liver to the properitoneal fat pad, anterior trunk, diaphragm and mediastinum. In SVCO, the most common sources of collateral flow to the paraumbilical veins are the ensiform and diaphragmatic branches of the internal thoracic veins. PMID- 29698416 TI - Effect of the 6-week home-based exercise program on physical activity level and physical fitness in colorectal cancer survivors: A randomized controlled pilot study. AB - Despite improvement in prognosis of colorectal cancer, colorectal cancer survivors often suffer from adverse effects of cancer treatment, including reduced health-related fitness level. Therefore, this study aimed to examine the feasibility and efficacy of the 6-week home-based exercise program on the level of physical activity and physical fitness in stage II to III colorectal cancer survivors. Seventy-two stage II to III colorectal cancer survivors were randomly assigned to either a home-based exercise (n = 38) or usual care (n = 34) group for 6 weeks. The goal of the home-based exercise program was to increase the level of exercise to 18 metabolic equivalent task hours per week. The primary and the secondary outcomes of this study were physical activity level and physical fitness, respectively. A total of 57 participants (79.2%) completed the trial. Intention-to-treat analysis indicated that moderate physical activity level increased significantly by 269.4 +/- 260.6 minutes per week in the exercise group (mean between-group difference, 254.6 minutes; 95% confidence interval, 172.7 434.7; p < 0.001). Physical fitness measured by using the step test (-3.9 vs. 2.6, p = 0.012) and push-up test (3.0 vs. -1.2, p = 0.012) also improved significantly in the exercise group compared to the control group. The 6-week home-based mixed aerobic and resistance exercise program was feasible and effective for increasing physical activity level and physical fitness in stage II to III colorectal cancer survivors. PMID- 29698415 TI - The influence of marital status and race/ethnicity on risk of mortality for triple negative breast cancer. AB - PURPOSE: To assess the effect of marital status and the role of race/ethnicity on breast cancer specific mortality in women with triple negative breast cancer (TNBC). METHODS: The study utilized the California Cancer Registry to identify 22,812 cases of first primary female TNBC. Unadjusted Kaplan-Meier breast cancer specific survival was computed. Cox Proportional Hazards modeling was used to compute the adjusted risk of breast cancer specific mortality for women who were single, separated, divorced, and widowed when compared with women who were married. Models were adjusted for age, stage, tumor grade, SES, and treatment with surgery, chemotherapy, hormone therapy, and radiation therapy. Hazard ratios (HR) and 95% confidence intervals (CI) were reported. RESULTS: Separated (HR: 1.45; 95% CI: 1.14-2.01) and widowed (HR: 1.39; 95%CI: 1.23-1.57) white women had a higher risk of mortality than white married women whereas single and divorced white women had the same risk of mortality. For Asian/Pacific Islanders (API), only single (HR: 1.55; 95% CI: 1.17-2.06) and divorced (HR:1.81; 95% CI:1.26 2.60) women had a higher risk of mortality than married women. Marital status had no influence on risk of mortality for either black or Hispanic women. CONCLUSIONS: The risk of mortality associated with marital status is dependent on race/ethnicity. Only white and API women with TNBC have a marital advantage. PMID- 29698417 TI - The response to selection in Glycoside Hydrolase Family 13 structures: A comparative quantitative genetics approach. AB - The Glycoside Hydrolase Family 13 (GH13) is both evolutionarily diverse and relevant to many industrial applications. Its members hydrolyze starch into smaller carbohydrates and members of the family have been bioengineered to improve catalytic function under industrial environments. We introduce a framework to analyze the response to selection of GH13 protein structures given some phylogenetic and simulated dynamic information. We find that the TIM-barrel (a conserved protein fold consisting of eight alpha-helices and eight parallel beta-strands that alternate along the peptide backbone, common to all amylases) is not selectable since it is under purifying selection. We also show a method to rank important residues with higher inferred response to selection. These residues can be altered to effect change in properties. In this work, we define fitness as inferred thermodynamic stability. We show that under the developed framework, residues 112Y, 122K, 124D, 125W, and 126P are good candidates to increase the stability of the truncated alpha-amylase protein from Geobacillus thermoleovorans (PDB code: 4E2O; alpha-1,4-glucan-4-glucanohydrolase; EC 3.2.1.1). Overall, this paper demonstrates the feasibility of a framework for the analysis of protein structures for any other fitness landscape. PMID- 29698418 TI - One-Step Nucleic Acid Amplification (OSNA): A fast molecular test based on CK19 mRNA concentration for assessment of lymph-nodes metastases in early stage endometrial cancer. AB - INTRODUCTION: The aim of the current study is to evaluate the detection rate of micro- and macro-metastases of the One-Step Nucleic Acid Amplification (OSNA) compared to frozen section examination and subsequent ultra-staging examination in early stage endometrial cancer (EC). MATERIAL AND METHODS: From March 2016 to June 2016, data of 40 consecutive FIGO stage I EC patients were prospectively collected in an electronic database. The sentinel lymph node mapping was performed in all patients. All mapped nodes were removed and processed. Sentinel lymph nodes were sectioned and alternate sections were respectively examined by OSNA and by frozen section analysis. After frozen section, the residual tissue from each block was processed with step-level sections (each step at 200 micron) including H&E and IHC slides. RESULTS: Sentinel lymph nodes mapping was successful in 29 patients (72.5%). In the remaining 11 patients (27.5%), a systematic pelvic lymphadenectomy was performed. OSNA assay sensitivity and specificity were 87.5% and 100% respectively. Positive and negative predictive values were 100% and 99% respectively, with a diagnostic accuracy of 99%. As far as frozen section examination and subsequent ultra-staging analysis was concerned, we reported sensitivity and specificity of 50% and 94.4% respectively; positive and negative predictive values were 14.3% and 99%, respectively, with an accuracy of 93.6%. In one patient, despite negative OSNA and frozen section analysis of the sentinel node, a macro-metastasis in 1 non-sentinel node was found. CONCLUSIONS: The combination of OSNA procedure with the sentinel lymph node mapping could represent an efficient intra-operative tool for the selection of early-stage EC patients to be submitted to systematic lymphadenectomy. PMID- 29698420 TI - Leaf and canopy reflectance spectrometry applied to the estimation of angular leaf spot disease severity of common bean crops. AB - This study is aimed at (i) estimating the angular leaf spot (ALS) disease severity in common beans crops in Brazil, caused by the fungus Pseudocercospora griseola, employing leaf and canopy spectral reflectance data, (ii) evaluating the informative spectral regions in the detection, and (iii) comparing the estimation accuracy when the reflectance or the first derivative reflectance (FDR) is employed. Three data sets of useful spectral reflectance measurements in the 440 to 850 nm range were employed; measurements were taken over the leaves and canopy of bean crops with different levels of disease. A system based in Principal Component Analysis (PCA) and Artificial Neural Networks (ANN) was developed to estimate the disease severity from leaf and canopy hyperspectral reflectance spectra. Levels of disease to be taken as true reference were determined from the proportion of the total leaf surface covered by necrotic lesions on RGB images. When estimating ALS disease severity in bean crops by using hyperspectral reflectance spectrometry, this study suggests that (i) successful estimations with coefficients of determination up to 0.87 can be achieved if the spectra is acquired by the spectroradiometer in contact with the leaves, (ii) unsuccessful estimations are obtained when the spectra are acquired by the spectroradiometer from one or more meters above the crop, (iii) the red to near-infrared spectral region (630-850 nm) offers the same precision in the estimation as the blue to near-infrared spectral region (440-850), and (iv) neither significant improvements nor significant detriments are achieved when the input data to the estimation processing system are the FDR spectra, instead of the reflectance spectra. PMID- 29698419 TI - Genetic susceptibility markers for a breast-colorectal cancer phenotype: Exploratory results from genome-wide association studies. AB - BACKGROUND: Clustering of breast and colorectal cancer has been observed within some families and cannot be explained by chance or known high-risk mutations in major susceptibility genes. Potential shared genetic susceptibility between breast and colorectal cancer, not explained by high-penetrance genes, has been postulated. We hypothesized that yet undiscovered genetic variants predispose to a breast-colorectal cancer phenotype. METHODS: To identify variants associated with a breast-colorectal cancer phenotype, we analyzed genome-wide association study (GWAS) data from cases and controls that met the following criteria: cases (n = 985) were women with breast cancer who had one or more first- or second degree relatives with colorectal cancer, men/women with colorectal cancer who had one or more first- or second-degree relatives with breast cancer, and women diagnosed with both breast and colorectal cancer. Controls (n = 1769), were unrelated, breast and colorectal cancer-free, and age- and sex- frequency-matched to cases. After imputation, 6,220,060 variants were analyzed using the discovery set and variants associated with the breast-colorectal cancer phenotype at P<5.0E 04 (n = 549, at 60 loci) were analyzed for replication (n = 293 cases and 2,103 controls). RESULTS: Multiple correlated SNPs in intron 1 of the ROBO1 gene were suggestively associated with the breast-colorectal cancer phenotype in the discovery and replication data (most significant; rs7430339, Pdiscovery = 1.2E 04; rs7429100, Preplication = 2.8E-03). In meta-analysis of the discovery and replication data, the most significant association remained at rs7429100 (P = 1.84E-06). CONCLUSION: The results of this exploratory analysis did not find clear evidence for a susceptibility locus with a pleiotropic effect on hereditary breast and colorectal cancer risk, although the suggestive association of genetic variation in the region of ROBO1, a potential tumor suppressor gene, merits further investigation. PMID- 29698421 TI - Prevalence of Mycoplasma genitalium in men with urethritis in a large public hospital in Brussels, Belgium: An observational, cross-sectional study. AB - BACKGROUND: Mycoplasma genitalium (MG) is a cause of urethritis. While resistance to azithromycin is increasing, routine detection of MG is not performed in Belgium, where its prevalence is unknown. The aim of this study is to determine prevalence of MG in men with urethritis. METHOD AND FINDINGS: An "in-house" amplification assay detecting MG was performed on urine of men with complaints of urethritis who consulted the emergency unit or the Sexually Transmitted Infection clinic of our public hospital in Brussels. Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) were tested on the same sample. A total of 187 men were tested. Prevalence of MG was 9% (95% Confidence Interval: 5 to 13.2%). CT was detected in 20%, NG in 22% and 56% of samples were negative for these three pathogens. Neither age, ethnic origin, sexual orientation nor HIV infection were associated with MG urethritis. CONCLUSION: M. genitalium was identified in 9% of men with complaints of urethritis indicating that amplification assay detecting MG should be implemented in routine testing for those patients. PMID- 29698422 TI - Prognostic value of diffuse splenic FDG uptake on PET/CT in patients with gastric cancer. AB - BACKGROUND: This study investigated the prognostic value of diffuse splenic uptake on F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) in gastric cancer (GC) patients. METHODS: A total of 134 pathology confirmed GC patients who underwent PET/CT for staging work-ups were enrolled. The maximal standardized uptake value (SUVmax) of primary tumor (Tmax), spleen (Smax), and spleen to liver uptake ratio (SLR) were measured. The prognostic value of PET-measured parameters in GC patients for predicting recurrence-free survival (RFS) and overall survival (OS) were assessed. And the relationships of the parameters with hematological and inflammatory parameters were also investigated. RESULTS: During follow-up period, 19 patients (14.1%) had disease recurrence and 12 (8.9%) died from GC. In univariate analysis, hematocrit (p<0.001 and p = 0.002), neutrophil to lymphocyte ratio (NLR; p = 0.021 and p = 0.040), AJCC staging (p<0.001 and p<0.001), adjuvant chemotherapy (p<0.001 and p<0.001), Tmax (p = 0.004 and p = 0.005), and SLR (p = 0.005 and p = 0.016) were significant prognostic factors for RFS and OS, whereas platelet to lymphocyte ratio (PLR; p = 0.034) was a significant prognostic factor for RFS. In multivariate analysis, only SLR was an independent prognostic factor for RFS (p = 0.018, adjusted HR = 3.011, 95% CI = 1.207-7.511). SLR were significantly associated with serum hematocrit level (r = -0.256, p = 0.002), PLR (r = 0.362, p = 0.001), and Tmax (r = 0.280, p = 0.001). CONCLUSION: Diffuse splenic uptake on FDG PET/CT was correlated with the level of hematological and inflammatory parameters and was an independent predictor for RFS in GC. PMID- 29698423 TI - Identifying artificial selection signals in the chicken genome. AB - Identifying the signals of artificial selection can contribute to further shaping economically important traits. Here, a chicken 600k SNP-array was employed to detect the signals of artificial selection using 331 individuals from 9 breeds, including Jingfen (JF), Jinghong (JH), Araucanas (AR), White Leghorn (WL), Pekin Bantam (PB), Shamo (SH), Gallus-Gallus-Spadiceus (GA), Rheinlander (RH) and Vorwerkhuhn (VO). Per the population genetic structure, 9 breeds were combined into 5 breed-pools, and a 'two-step' strategy was used to reveal the signals of artificial selection. GA, which has little artificial selection, was defined as the reference population, and a total of 204, 155, 305 and 323 potential artificial selection signals were identified in AR_VO, PB, RH_WL and JH_JF, respectively. We also found signals derived from standing and de-novo genetic variations have contributed to adaptive evolution during artificial selection. Further enrichment analysis suggests that the genomic regions of artificial selection signals harbour genes, including THSR, PTHLH and PMCH, responsible for economic traits, such as fertility, growth and immunization. Overall, this study found a series of genes that contribute to the improvement of chicken breeds and revealed the genetic mechanisms of adaptive evolution, which can be used as fundamental information in future chicken functional genomics study. PMID- 29698424 TI - Poly(3-hydroxybutyrate) production in an integrated electromicrobial setup: Investigation under stress-inducing conditions. AB - Poly(3-hydroxybutyrate) (PHB), a biodegradable polymer, can be produced by different microorganisms. The PHB belongs to the family of polyhydroxyalkanoate (PHA) that mostly accumulates as a granule in the cytoplasm of microorganisms to store carbon and energy. In this study, we established an integrated one-pot electromicrobial setup in which carbon dioxide is reduced to formate electrochemically, followed by sequential microbial conversion into PHB, using the two model strains, Methylobacterium extorquens AM1 and Cupriavidus necator H16. This setup allows to investigate the influence of different stress conditions, such as coexisting electrolysis, relatively high salinity, nutrient limitation, and starvation, on the production of PHB. The overall PHB production efficiency was analyzed in reasonably short reaction cycles typically as short as 8 h. As a result, the PHB formation was detected with C. necator H16 as a biocatalyst only when the electrolysis was operated in the same solution. The specificity of the source of PHB production is discussed, such as salinity, electricity, concurrent hydrogen production, and the possible involvement of reactive oxygen species (ROS). PMID- 29698425 TI - Complexity of type-specific 56 kDa antigen CD4 T-cell epitopes of Orientia tsutsugamushi strains causing scrub typhus in India. AB - Orientia tsutsugamushi (Ots) is an obligate, intracellular, mite-transmitted human pathogen which causes scrub typhus. Understanding the diversity of Ots antigens is essential for designing specific diagnostic assays and efficient vaccines. The protective immunodominant type-specific 56 kDa antigen (TSA) of Ots varies locally and across its geographic distribution. TSA contains four hypervariable domains. We bioinformatically analyzed 345 partial sequences of TSA available from India, most of which contain only the three variable domains (VDI III) and three spacer conserved domains (SVDI, SVDII/III, SVDIII). The total number (152) of antigenic types (amino acid variants) varied from 14-36 in the six domains of TSA that we studied. Notably, 55% (787/1435) of the predicted CD4 T-cell epitopes (TCEs) from all the six domains had high binding affinities (HBA) to at least one of the prevalent Indian human leukocyte antigen (HLA) alleles. A surprisingly high proportion (61%) of such TCEs were from spacer domains; indeed 100% of the CD4 TCEs in the SVDI were HBA. TSA sequences from India had more antigenic types (AT) than TSA from Korea. Overall, >90% of predicted CD4 TCEs from spacer domains were predicted to have HBA against one or more prevalent HLA types from Indian, Korean, Asia-Pacific region or global population data sets, while only <50% of CD4 TCEs in variable domains exhibited such HBA. The phylogenetically and immunologically important amino acids in the conserved spacer domains were identified. Our results suggest that the conserved spacer domains are predicted to be functionally more important than previously appreciated in immune responses to Ots infections. Changes occurring at the TCE level of TSA may contribute to the wide range of pathogenicity of Ots in humans and mouse models. CD4 T-cell functional experiments are needed to assess the immunological significance of these HBA spacer domains and their role in clearance of Ots from Indian patients. PMID- 29698426 TI - Surveying the spatial distribution of feral sorghum (Sorghum bicolor L.) and its sympatry with johnsongrass (S. halepense) in South Texas. AB - Sorghum (Sorghum bicolor) is an important grain and forage crop grown across the US. In some areas, sorghum can become feral along roadsides and other ruderal areas, as a result of seed spill during harvest or transport. In some of these situations, feral sorghum grows in or near established johnsongrass (S. halepense) populations. Johnsongrass, a wild relative of sorghum and an incredibly noxious weed, is capable of hybridizing with cultivated sorghum. Because commercial hybrid sorghum cultivars are produced with cytoplasmic male sterility, progeny of the hybrid crop which compose the founder feral populations also segregate for male sterility. Consequently, male sterility in feral sorghum may increase the risk of outcrossing with johnsongrass. Using field surveys and spatial modelling, the present study aimed at documenting the occurrence of feral sorghum and understanding the anthropogenic and environmental factors that influence its distribution. Further, this research documented the sympatry of feral sorghum and johnsongrass in the roadside habitat. A total of 2077 sites were visited during a systematic field survey conducted in fall 2014 in South Texas. Feral sorghum and johnsongrass were found in 360 and 939 sites, while the species co-existed at 48 sites (2.3% of all surveyed sites). The binary logistic analysis showed a significant association between the presence of feral sorghum and road type, road body-type, micro-topography of the sampling site, nearby land use, and the presence of johnsongrass, but no association with the distance to the nearest grain sorting facility. The probability of finding feral sorghum away from johnsongrass patches was generally higher than finding them co-occur in the same location. A probability map for spatial distribution of feral sorghum was developed using the nearby land use type and the regional habitat suitability for johnsongrass as two key predictors. Overall, results show that feral sorghum and johnsongrass co-occur at low frequencies in the roadside habitats of South Texas, but these low levels still present a significant opportunity for hybridization between the two species outside of cultivated fields. PMID- 29698427 TI - Intraoperative ultrasonography in laparoscopic partial nephrectomy for intrarenal tumors. AB - OBJECTIVE: To evaluate the feasibility and efficacy of intraoperative ultrasonography in laparoscopic partial nephrectomy (LPN) for intrarenal tumors. PATIENTS AND METHODS: All patients who underwent LPN for renal tumors in our institution from January 2010 to October 2016 were assessed retrospectively. Patients were divided into two groups, the first with totally intrarenal tumors (TIT group), defined as a solid renal mass with no exophytic element on both preoperative and intraoperative evaluations, and the second with exophytic tumors (control group). General information and perioperative data of the two groups were compared, including tumor characteristics, operative time, estimated blood loss, warm ischemia time and pathological findings. Intraoperative laparoscopic ultrasonography (ILUS) was used to precisely locate and delineate the TIT border, as well as seeking for other suspected lesions. RESULTS: We identified 583 patients who underwent LPN in our center, including 46 in the TIT and 537 in the control group. All patients in the TIT group were evaluated by ILUS, and all TIT procedures were successfully performed with only one conversion to open surgery. The mean tumor sizes in the TIT and control groups were 2.42 +/- 0.46 cm and 3.29 +/- 1.43 cm (p < 0.001), respectively. The TIT group's R.E.N.A.L. nephrometry score was higher than that of the control group (median 8.5 vs 6.0, p < 0.001), and their mean operation times were 127.2 +/- 16.0 min and 120.1 +/- 19.2 min, respectively. Mean estimated blood loss was higher in the TIT than in the control group (161.3 ml vs 136.6 ml, p = 0.003). Mean warm ischemia time differed in the TIT and control groups (22.2 +/- 6.4 vs 20.6 +/- 4.7 min, p = 0.105), but not significantly. Rates of open conversion and positive margins, as well as rates of major postoperative complications, pathological findings, and 1-month changes in renal function, were similar in the two groups. CONCLUSION: Intraoperative ultrasonography is technically feasible in patients undergoing LPN for TITs. This method may reduce the need for radical nephrectomy in patients with endogenic renal masses. PMID- 29698428 TI - Quantifying the impact on navigation performance in visually impaired: Auditory information loss versus information gain enabled through electronic travel aids. AB - This study's purpose was to analyze and quantify the impact of auditory information loss versus information gain provided by electronic travel aids (ETAs) on navigation performance in people with low vision. Navigation performance of ten subjects (age: 54.9+/-11.2 years) with visual acuities >1.0 LogMAR was assessed via the Graz Mobility Test (GMT). Subjects passed through a maze in three different modalities: 'Normal' with visual and auditory information available, 'Auditory Information Loss' with artificially reduced hearing (leaving only visual information), and 'ETA' with a vibrating ETA based on ultrasonic waves, thereby facilitating visual, auditory, and tactile information. Main performance measures comprised passage time and number of contacts. Additionally, head tracking was used to relate head movements to motion direction. When comparing 'Auditory Information Loss' to 'Normal', subjects needed significantly more time (p<0.001), made more contacts (p<0.001), had higher relative viewing angles (p = 0.002), and a higher percentage of orientation losses (p = 0.011). The only significant difference when comparing 'ETA' to 'Normal' was a reduced number of contacts (p<0.001). Our study provides objective, quantifiable measures of the impact of reduced hearing on the navigation performance in low vision subjects. Significant effects of 'Auditory Information Loss' were found for all measures; for example, passage time increased by 17.4%. These findings show that low vision subjects rely on auditory information for navigation. In contrast, the impact of the ETA was not significant but further analysis of head movements revealed two different coping strategies: half of the subjects used the ETA to increase speed, whereas the other half aimed at avoiding contacts. PMID- 29698429 TI - A comprehensive comparison of four species of Onchidiidae provides insights on the morphological and molecular adaptations of invertebrates from shallow seas to wetlands. AB - The Onchidiidae family is ideal for studying the evolution of marine invertebrate species from sea to wetland environments. However, comparative studies of Onchidiidae species are rare. A total of 40 samples were collected from four species (10 specimens per onchidiid), and their histological and molecular differences were systematically evaluated to elucidate the morphological foundations underlying the adaptations of these species. A histological analysis was performed to compare the structures of respiratory organs (gill, lung sac, dorsal skin) among onchidiids, and transcriptome sequencing of four representative onchidiids was performed to investigate the molecular mechanisms associated with their respective habitats. Twenty-six SNP markers of Onchidium reevesii revealed some DNA polymorphisms determining visible traits. Non-muscle myosin heavy chain II (NMHC II) and myosin heavy chain (MyHC), which play essential roles in amphibian developmental processes, were found to be differentially expressed in different onchidiids and tissues. The species with higher terrestrial ability and increased integrated expression of Os-MHC (NMHC II gene) and the MyHC gene, illustrating that the expression levels of these genes were associated with the evolutionary degree. This study provides a comprehensive analysis of the adaptions of a diverse and widespread group of invertebrates, the Onchidiidae. Some onchidiids can breathe well through gills and skin when under seawater, and some can breathe well through lung sacs and skin when in wetlands. A histological comparison of respiratory organs and the relative expression levels of two genes provided insights into the adaptions of onchidiids that allowed their transition from shallow seas to wetlands. This work provides a valuable reference and might encourage further study. PMID- 29698430 TI - Dynamic cortical participation during bilateral, cyclical ankle movements: Effects of Parkinson's disease. AB - Parkinson's disease (PD) is known to increase asymmetry and variability of bilateral movements. However, the mechanisms of such abnormalities are not fully understood. Here, we aimed to investigate whether kinematic abnormalities are related to cortical participation during bilateral, cyclical ankle movements, which required i) maintenance of a specific frequency and ii) bilateral coordination of the lower limbs in an anti-phasic manner. We analyzed electroencephalographic and electromyographic signals from nine men with PD and nine aged-matched healthy men while they sat and cyclically dorsi- and plantarflexed their feet. This movement was performed at a similar cadence to normal walking under two conditions: i) self-paced and ii) externally paced by a metronome. Participants with PD exhibited reduced range of motion and more variable bilateral coordination. However, participants with and without PD did not differ in the magnitude of corticomuscular coherence between the midline cortical areas and tibialis anterior and medial gastrocnemius muscles. This finding suggests that either the kinematic abnormalities were related to processes outside linear corticomuscular communication or PD-related changes in neural correlates maintained corticomuscular communication but not motor performance. PMID- 29698431 TI - Mapping genetic variants for cranial vault shape in humans. AB - The shape of the cranial vault, a region comprising interlocking flat bones surrounding the cerebral cortex, varies considerably in humans. Strongly influenced by brain size and shape, cranial vault morphology has both clinical and evolutionary relevance. However, little is known about the genetic basis of normal vault shape in humans. We performed a genome-wide association study (GWAS) on three vault measures (maximum cranial width [MCW], maximum cranial length [MCL], and cephalic index [CI]) in a sample of 4419 healthy individuals of European ancestry. All measures were adjusted by sex, age, and body size, then tested for association with genetic variants spanning the genome. GWAS results for the two cohorts were combined via meta-analysis. Significant associations were observed at two loci: 15p11.2 (lead SNP rs2924767, p = 2.107 * 10-8) for MCW and 17q11.2 (lead SNP rs72841279, p = 5.29 * 10-9) for MCL. Additionally, 32 suggestive loci (p < 5x10-6) were observed. Several candidate genes were located in these loci, such as NLK, MEF2A, SOX9 and SOX11. Genome-wide linkage analysis of cranial vault shape in mice (N = 433) was performed to follow-up the associated candidate loci identified in the human GWAS. Two loci, 17q11.2 (c11.loc44 in mice) and 17q25.1 (c11.loc74 in mice), associated with cranial vault size in humans, were also linked with cranial vault size in mice (LOD scores: 3.37 and 3.79 respectively). These results provide further insight into genetic pathways and mechanisms underlying normal variation in human craniofacial morphology. PMID- 29698432 TI - Intraspecies differences in natural susceptibility to amphotericine B of clinical isolates of Leishmania subgenus Viannia. AB - Amphotericin B (AmB) is a recommended medication for the treatment of cutaneous and mucosal leishmaniasis in cases of therapeutic failure with first-line medications; however, little is known about the in vitro susceptibility to AmB of clinical isolates of the subgenus Viannia, which is most prevalent in South America. This work aimed to determine the in vitro susceptibility profiles to AmB of clinical isolates of the species L. (V.) panamensis, L. (V.) guyanensis and L. (V.) braziliensis. In vitro susceptibility to AmB was evaluated for 65 isolates. Macrophages derived from the U937 cell line were infected with promastigotes and exposed to different AmB concentrations. After 96 hours, the number of intracellular amastigotes was quantified by qPCR, and median effective concentration (EC50) was determined using the PROBIT model. The controls included sensitive strains and experimentally derived less sensitive strains generated in vitro, which presented EC50 values up to 7.57-fold higher than the values of the sensitive strains. The isolates were classified into groups according to their in vitro susceptibility profiles using Ward's hierarchical method. The susceptibility to AmB differed in an intraspecies-specific manner as follows: 28.21% (11/39) of L. (V.) panamensis strains, 50% (3/6) of L. (V.) guyanensis strains and 34.61% (9/26) of L. (V.) braziliensis strains were classified as less sensitive. The latter subset featured three susceptibility groups. We identified Colombian isolates with different AmB susceptibility profiles. In addition, the capacity of species of subgenus Viannia to develop lower susceptibility to AmB was demonstrated in vitro. These new findings should be considered in the pharmacovigilance of AmB in Colombia and South America. PMID- 29698434 TI - Evaluation of a photographic food atlas as a tool for quantifying food portion size in the United Arab Emirates. AB - Although, United Arab Emirates (UAE) has one of the highest prevalence of overweight, obesity and type 2 diabetes in the world, however, validated dietary assessment aids to estimate food intake of individuals and populations in the UAE are currently lacking. We conducted two observational studies to evaluate the accuracy of a photographic food atlas which was developed as a tool for food portion size estimation in the UAE. The UAE Food Atlas presents eight portion sizes for each food. Study 1 involved portion size estimations of 13 food items consumed during the previous day. Study 2 involved portion size estimations of nine food items immediately after consumption. Differences between the food portion sizes estimated from the photographs and the weighed food portions (estimation error), as well as the percentage differences relative to the weighed food portion for each tested food item were calculated. Four of the evaluated food items were underestimated (by -8.9% to -18.4%), while nine were overestimated (by 9.5% to 90.9%) in Study 1. Moreover, there were significant differences between estimated and eaten food portions for eight food items (P<0.05). In Study 2, one food item was underestimated (-8.1%) while eight were overestimated (range 2.52% to 82.1%). Furthermore, there were significant differences between estimated and eaten food portions (P<0.05) for six food items. The limits of agreement between the estimated and consumed food portion size were wide indicating a large variability in food portion estimation errors. These reported findings highlight the need for further developments of the UAE Food Atlas to improve the accuracy of food portion size intake estimations in dietary assessments. Additionally, recalling food portions from the previous day did not seem to increase food portion estimation errors in this study. PMID- 29698433 TI - Isolation and molecular characterization of novel glucarpidases: Enzymes to improve the antibody directed enzyme pro-drug therapy for cancer treatment. AB - Repeated cycles of antibody-directed enzyme pro-drug therapy (ADEPT) and the use of glucarpidase in the detoxification of cytotoxic methotrexate (MTX) are highly desirable during cancer therapy but are hampered by the induced human antibody response to glucarpidase. Novel variants of glucarpidase (formal name: carboxypeptidase G2, CPG2) with epitopes not recognized by the immune system are likely to allow repeated cycles of ADEPT for effective cancer therapy. Towards this aim, over two thousand soil samples were collected and screened for folate hydrolyzing bacteria using folate as the sole carbon source. The work led to the isolation and the characterization of three new glucarpidase producing strains, which were designated as: Pseudomonas lubricans strain SF168, Stenotrophomonas sp SA and Xenophilus azovorans SN213. The CPG2 genes of Xenophilus azovorans SN213 (named Xen CPG2) and Stenotrophomonas sp SA (named Sten CPG2) were cloned and molecularly characterized. Both Xen CPG2 and Sten CPG2 share very close amino acid sequences (99%); we therefore, focused on the study of Xen CPG2. Finally, we demonstrated that a polyclonal antibody raised against our new CPG2, Xen CPG2, does not react with the CPG2 from Pseudomonas sp. strain RS-16 (Ps CPG2) that are currently in clinical use. The two enzymes, therefore could potentially be used consecutively in the ADEPT protocol to minimize the effect of the human antibody response that hampers current treatment with Ps CPG2. The identified novel CPG2 in this study will, therefore, pave the way for safer antibody directed enzyme pro-drug therapy for cancer treatment. PMID- 29698435 TI - Airborne transmission of invasive fusariosis in patients with hematologic malignancies. AB - From 2006 to 2013, an increasing incidence of fusariosis was observed in the hematologic patients of our University Hospital. We suspected of an environmental source, and the indoor hospital air was investigated as a potential source of the fungemia. Air samplings were performed in the hematology and bone marrow transplant (BMT) wards using an air sampler with pre-defined air volumes. To study the molecular relationship among environmental and clinical isolates, 18 Fusarium spp. recovered from blood cultures were included in the study. DNA sequencing of a partial portion of TEF1alpha gene was performed for molecular identification. Molecular typing was carried out by multi-locus sequence typing (MLST) using a four-gene scheme: TEF1alpha, rDNA, RPB1 and RPB2. One hundred four isolates were recovered from the air of the hematology (n = 76) and the BMT (n = 28) wards. Fusarium isolates from the air were from five species complexes: Fusarium fujikuroi (FFSC, n = 56), Fusarium incarnatum-equiseti (FIESC, n = 24), Fusarium solani (FSSC, n = 13), Fusarium chlamydosporum (FCSC, n = 10), and Fusarium oxysporum (FOSC, n = 1). Fifteen Fusarium isolates recovered from blood belonged to FSSC, and three to FFSC. MLST identified the same sequence type (ST) in clinical and environmental isolates. ST1 was found in 5 isolates from blood and in 7 from the air, both identified as FSSC (Fusarium petroliphilum). STn1 was found in one isolate from blood and in one from the air, both identified as FFSC (Fusarium napiforme). F. napiforme was isolated from the air of the hospital room of the patient with fungemia due to F. napiforme. These findings suggested a possible clonal origin of the Fusarium spp. recovered from air and bloodcultures. In conclusion, our study found a diversity of Fusarium species in the air of our hospital, and a possible role of the air as source of systemic fusariosis in our immunocompromised patients. PMID- 29698436 TI - Structural basis of product inhibition by arabinose and xylose of the thermostable GH43 beta-1,4-xylosidase from Geobacillus thermoleovorans IT-08. AB - Complete degradation of the xylan backbone of hemicellulosic plant cell walls requires the synergistic action of endo-xylanases and beta-1,4-xylosidases. While endo-xylanases produce xylooligosaccharides from xylan, beta-1,4-xylosidases degrade the xylooligosaccharides into xylose monomers. The glycoside hydrolase family 43 beta-1,4-xylosidase from Geobacillus thermoleovorans IT-08 is a promising, heat stable catalyst for the saccharification of hemicellulosic material into simple fermentable sugars, but it is competitively inhibited by its products arabinose and xylose. As a first step to help overcome this problem, we elucidated crystal structures of the enzyme in the unliganded form and with bound products, at 1.7-2.0 A resolution. The structures are very similar to those of other enzymes belonging to glycoside hydrolase family 43. Unexpectedly, the monosaccharides are bound in very different ways. Arabinose preferentially binds in subsite -1, while xylose exclusively interacts with subsite +1. These structures and sugar binding preferences suggest ways for improving the catalytic performance of the enzyme by rational mutational design. PMID- 29698437 TI - Predicting anti-RhD titers in donors: Boostering response and decline rates are personal. AB - BACKGROUND: Anti-RhD immunised donors provide anti-RhD immunoglobulins used for the prevention of rhesus disease. These donors are periodically hyper-immunised (boostered) to retain a high titer level of anti-RhD. STUDY DESIGN AND METHODS: We analysed anti-RhD donor records from 1998 to 2016, consisting of 30,116 anti RhD titers from 755 donors, encompassing 3,372 booster events. Various models were fit to these data to allow describing the anti-RhD titers over time. RESULTS: A random effects model with a log-linear anti-RhD titer decline over time and a saturating titer response to boostering is shown to fit the data well. This model contains two general model parameters, relating timing and maximum of the booster effect, as well as two parameters characterizing the individual donor, namely how fast the booster effect saturates with current titer and the anti-RhD decline rate. The average individual log2 decline is 0.55 per year, i.e. a 32% decline in absolute titer, with half of the donors declining between 13% and 41% per year. Their anti-RhD titer peaks around 26 days following a booster event. Boostering response reduces with higher titers at boostering; at median titer (log2 11) the mean increase per booster is log2 0.38, that is from an absolute titer of 2048 to 2665 (+30%), with half of all donors increasing between 16% and 65% in their titer. CONCLUSION: The model describes anti-RhD titer change per individual with only four parameters, two of which are donor specific. This information can be used to enhance the blood bank's immunisation programme, by deriving individualized immunization policies in which boostering is adjusted to the anticipated anti-RhD decline, effectiveness of boostering and titer levels required. PMID- 29698438 TI - Myocyte enhancer factor 2A promotes proliferation and its inhibition attenuates myogenic differentiation via myozenin 2 in bovine skeletal muscle myoblast. AB - Myocyte enhancer factor 2A (MEF2A) is widely distributed in various tissues or organs and plays crucial roles in multiple biological processes. To examine the potential effects of MEF2A on skeletal muscle myoblast, the functional role of MFE2A in myoblast proliferation and differentiation was investigated. In this study, we found that the mRNA expression level of Mef2a was dramatically increased during the myogenesis of bovine skeletal muscle primary myoblast. Overexpression of MEF2A significantly promoted myoblast proliferation, while knockdown of MEF2A inhibited the proliferation and differentiation of myoblast. RT-PCR and western blot analysis revealed that this positive effect of MEF2A on the proliferation of myoblast was carried out by triggering cell cycle progression by activating CDK2 protein expression. Besides, MEF2A was found to be an important transcription factor that bound to the myozenin 2 (MyoZ2) proximal promoter and performed upstream of MyoZ2 during myoblast differentiation. This study provides the first experimental evidence that MEF2A is a positive regulator in skeletal muscle myoblast proliferation and suggests that MEF2A regulates myoblast differentiation via regulating MyoZ2. PMID- 29698439 TI - TNF differentially regulates ganglioside biosynthesis and expression in breast cancer cell lines. AB - Gangliosides are glycosphingolipids concentrated in glycolipid-enriched membrane microdomains. Mainly restricted to the nervous system in healthy adult, complex gangliosides such as GD3 and GD2 have been shown to be involved in aggressiveness and metastasis of neuro-ectoderm derived tumors such as melanoma and neuroblastoma. GD3 synthase (GD3S), the key enzyme that controls the biosynthesis of complex gangliosides, was shown to be over-expressed in Estrogen Receptor (ER) negative breast cancer tumors, and associated with a decreased overall survival of patients. We previously demonstrated that GD3S expression in ER-negative breast cancer cells induced a proliferative phenotype and an increased tumor growth. In addition, our results clearly indicate that Tumor Necrosis Factor (TNF) induced GD3S over-expression in breast cancer cells via NFkappaB pathway. In this study, we analyzed the effect of TNF on ganglioside biosynthesis and expression in breast cancer cells from different molecular subtypes. We showed that TNF up-regulated the expression of GD3S in MCF-7 and Hs578T cells, whereas no change was observed for MDA-MB-231. We also showed that TNF induced an increased expression of complex gangliosides at the cell surface of a small proportion of MCF-7 cells. These results demonstrate that TNF differentially regulates gangliosides expression in breast cancer cell lines and establish a possible link between inflammation at the tumor site environment, expression of complex gangliosides and tumor development. PMID- 29698440 TI - Cognitive changes following multiple-modality exercise and mind-motor training in older adults with subjective cognitive complaints: The M4 study. AB - BACKGROUND: We investigated the effects of multiple-modality exercise with additional mind-motor training on cognition in community-dwelling older adults with subjective cognitive complaints. METHODS: Participants (n = 127, mean age 67.5 [7.3] years, 71% women) were randomized to receive 45 minutes of multiple modality exercise with additional 15 minutes of either mind-motor training (M4, n = 63) or control (balance, range of motion and breathing exercises [M2, n = 64]). In total, both groups exercised 60 minutes/day, 3 days/week, for 24 weeks. Standardized global cognitive functioning (GCF), concentration, reasoning, planning, and memory were assessed at 24 weeks and after a 28-week no-contact follow-up. RESULTS: There were no significant differences in the study primary outcomes. The M4 group, however, showed trends for greater improvements in GCF and memory (both, P = .07) compared to the M2 group at 24 weeks. Significant differences between group in GCF (P = .03) and memory (P = .02) were observed after the 28-week no-contact follow-up favouring the M4 group. DISCUSSION: Additional mind-motor training did not impart immediate greater benefits to cognition among the study participants. PMID- 29698441 TI - Contrasting spatial, temporal and environmental patterns in observation and specimen based species occurrence data. AB - Species occurrence data records the location and time of an encounter with a species, and is valuable for many aspects of ecological and evolutionary analyses. A key distinction within species occurrence data is between (1) collected and preserved specimens that can be taxonomically validated (i.e., natural history collections), and (2) observations, which are more error prone but richer in terms of number and spread of observations. In this study we analyse the distribution in temporal, spatial, taxonomic and environmental coverage of specimen- and observation based species occurrence data for land plants in Norway, a region with strong climatic and human population density gradients. Of 4.8 million species occurrence records, the majority (78%) were observations. However, there was a greater species richness in the specimen record (N = 4691) than in the observation record (N = 3193) and most species were recorded more as specimens than observations. Specimen data was on average older, and collected later during the year. Both record types were highly influenced by a small number of prolific contributors. The species most highly represented in the observation data set were widespread or invasive, while in the specimen records, taxonomically challenging species were overrepresented. Species occurrence records were unevenly spatially distributed. Both specimen and observation records were concentrated in regions of Norway with high human population density and with high temperatures and precipitation, but in different regions within Norway. Observation and specimen records thus differ in taxonomic, temporal, spatial and environmental coverage for a well-sampled group and study region, potentially influencing the ecological inferences made from studies utilizing species occurrence data. The distribution of observation data dominates the dataset, so inferences of species diversity and distributions do not correspond to the evolutionary or physiological knowledge of species, which is based on specimen data. We make recommendations for users of biodiversity data, and collectors to better exploit the complementary strengths of these distinct biodiversity data types. PMID- 29698442 TI - Corncob as an effective, eco-friendly, and economic biosorbent for removing the azo dye Direct Yellow 27 from aqueous solutions. AB - The corncob is an agricultural waste generated in huge quantities during corn processing. In this paper, we tested the capacity of corncob particles for water purification by removing the azo dye Direct Yellow 27 (DY27) via biosorption. The biosorption process was investigated in terms of the kinetics, equilibria, and thermodynamics. Batch biosorption studies showed that the biosorption performance has strong inverse correlations to the solution pH and the corncob particle size, and it increases quickly with increasing contact time and initial dye concentration. The pseudo-second-order kinetic model provides the best fit to the experimental data, whereas the Redlich-Peterson isotherm model is most suitable for describing the observed equilibrium biosorption. The biosorption process is exothermic, spontaneous, and physisorption in character. Fourier transform infrared (FTIR) spectroscopy and confocal scanning laser microscopy (CSLM) studies suggest that lignocellulose and proteins play key roles in the biosorption of DY27 from aqueous solutions by corncob. Furthermore, after biosorption onto the corncob, the dye can be effectively desorbed using 0.1 M NaOH solution. Therefore, the corncob can be used as a promising biosorbent to remediate DY27-contaminated water and wastewater. PMID- 29698443 TI - Representation control increases task efficiency in complex graphical representations. AB - In complex graphical representations, the relevant information for a specific task is often distributed across multiple spatial locations. In such situations, understanding the representation requires internal transformation processes in order to extract the relevant information. However, digital technology enables observers to alter the spatial arrangement of depicted information and therefore to offload the transformation processes. The objective of this study was to investigate the use of such a representation control (i.e. the users' option to decide how information should be displayed) in order to accomplish an information extraction task in terms of solution time and accuracy. In the representation control condition, the participants were allowed to reorganize the graphical representation and reduce information density. In the control condition, no interactive features were offered. We observed that participants in the representation control condition solved tasks that required reorganization of the maps faster and more accurate than participants without representation control. The present findings demonstrate how processes of cognitive offloading, spatial contiguity, and information coherence interact in knowledge media intended for broad and diverse groups of recipients. PMID- 29698444 TI - Formalin fixation increases deamination mutation signature but should not lead to false positive mutations in clinical practice. AB - Genomic analysis of cancer tissues is an essential aspect of personalized oncology treatment. Though it has been suggested that formalin fixation of patient tissues may be suboptimal for molecular studies, this tissue processing approach remains the industry standard. Therefore clinical molecular laboratories must be able to work with formalin fixed, paraffin embedded (FFPE) material. This study examines the effects of pre-analytic variables introduced by routine pathology processing on specimens used for clinical reports produced by next generation sequencing technology. Tissue resected from three colorectal cancer patients was subjected to 2, 15, 24, and 48 hour fixation times in neutral buffered formalin. DNA was extracted from all tissues twice, once with uracil-N glycosylase (UNG) treatment to counter deamination effects, and once without. Of note, deamination events at methylated cytosine, as found at CpG sites, remains unaffected by UNG. After extraction a two-step PCR targeted sequencing method was performed using the Illumina MiSeq and the data was analyzed via a custom-built bioinformatics pipeline, including filtration of reads with mapping quality <30. A larger baseline group of samples (n = 20) was examined to establish if there was a sample performance difference between the two DNA extraction methods, with/without UNG treatment. There was no statistical difference between sequencing performance of the two extraction methods when comparing read counts (raw, mapped, and filtered) and read quality (% mapped, % filtered). Analyzing mutation type, there was no significant difference between mutation calls until the 48 hour fixation treatment. At 48 hours there is a significant increase in C/G->T/A mutations that is not represented in DNA treated with UNG. This suggests these errors may be due to deamination events triggered by a longer fixation time. However the allelic frequency of these events remained below the limit of detection for reportable mutations in this assay (<2%). We do however recommend that suspected intratumoral heterogeneity events be verified by re-sequencing the same FFPE block. PMID- 29698445 TI - Evolutionary convergence in the biosyntheses of the imidazole moieties of histidine and purines. AB - BACKGROUND: The imidazole group is an ubiquitous chemical motif present in several key types of biomolecules. It is a structural moiety of purines, and plays a central role in biological catalysis as part of the side-chain of histidine, the amino acid most frequently found in the catalytic site of enzymes. Histidine biosynthesis starts with both ATP and the pentose phosphoribosyl pyrophosphate (PRPP), which is also the precursor for the de novo synthesis of purines. These two anabolic pathways are also connected by the imidazole intermediate 5-aminoimidazole-4-carboxamide ribotide (AICAR), which is synthesized in both routes but used only in purine biosynthesis. Rather surprisingly, the imidazole moieties of histidine and purines are synthesized by different, non-homologous enzymes. As discussed here, this phenomenon can be understood as a case of functional molecular convergence. RESULTS: In this work, we analyze these polyphyletic processes and argue that the independent origin of the corresponding enzymes is best explained by the differences in the function of each of the molecules to which the imidazole moiety is attached. Since the imidazole present in histidine is a catalytic moiety, its chemical arrangement allows it to act as an acid or a base. On the contrary, the de novo biosynthesis of purines starts with an activated ribose and all the successive intermediates are ribotides, with the key beta-glycosidic bondage joining the ribose and the imidazole moiety. This prevents purine ribonucleotides to exhibit any imidazole dependent catalytic activity, and may have been the critical trait for the evolution of two separate imidazole-synthesizing-enzymes. We also suggest that, in evolutionary terms, the biosynthesis of purines predated that of histidine. CONCLUSIONS: As reviewed here, other biosynthetic routes for imidazole molecules are also found in extant metabolism, including the autocatalytic cyclization that occurs during the formation of creatinine from creatine phosphate, as well as the internal cyclization of the Ala-Ser-Gly motif of some members of the ammonia lyase and aminomutase families, that lead to the MIO cofactor. The diversity of imidazole-synthesizing pathways highlights the biological significance of this key chemical group, whose biosyntheses evolved independently several times. PMID- 29698446 TI - Effects of noxious stimuli on the electroencephalogram of anaesthetised chickens (Gallus gallus domesticus). AB - The reliable assessment and management of avian pain is important in the context of animal welfare. Overtly expressed signs of pain vary substantially between and within species, strains and individuals, limiting the use of behaviour in pain studies. Similarly, physiological indices of pain can also vary and may be confounded by influence from non-painful stimuli. In mammals, changes in the frequency spectrum of the electroencephalogram (EEG) recorded under light anaesthesia (the minimal anaesthesia model; MAM) have been shown to reliably indicate cerebral responses to noxious stimuli in a range of species. The aim of the current study was to determine whether the MAM can be applied to the study of nociception in birds. Ten chickens were lightly anaesthetised with halothane and their EEG recorded using surface electrodes during the application of supramaximal mechanical, thermal and electrical noxious stimuli. Spectral analysis revealed no EEG responses to any of these stimuli. Given that birds possess the neural apparatus to detect and process pain, and that the applied noxious stimuli elicit behavioural signs of pain in conscious chickens, this lack of response probably relates to methodological limitations. Anatomical differences between the avian and mammalian brains, along with a paucity of knowledge regarding specific sites of pain processing in the avian brain, could mean that EEG recorded from the head surface is insensitive to changes in neural activity in the pain processing regions of the avian brain. Future investigations should examine alternative electrode placement sites, based on avian homologues of the mammalian brain regions involved in pain processing. PMID- 29698447 TI - Celecoxib use and circulating oxylipins in a colon polyp prevention trial. AB - Drugs that inhibit cyclooxygenase (COX)-2 and the metabolism of arachidonic acid (ARA) to prostaglandin E2 are potent anti-inflammatory agents used widely in the treatment of joint and muscle pain. Despite their benefits, daily use of these drugs has been associated with hypertension, cardiovascular and gastrointestinal toxicities. It is now recognized that ARA is metabolized to a number of bioactive oxygenated lipids (oxylipins) by cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP450) enzymes. Currently, the contribution of individual variability in ARA metabolism in response to the COX-2 inhibitors and potential adverse effects remains poorly understood. Using patient samples from the randomized, placebo-controlled phase III selenium/celecoxib (Sel/Cel) trial for the prevention of colorectal adenomatous polyps, we analyzed plasma concentrations of 74 oxylipins in a subset of participants who received celecoxib (n = 90) or placebo (n = 95). We assessed the effect of celecoxib (with and without low dose aspirin) on circulating oxylipins and systolic blood pressure (SBP). Individual CYP450- and LOX- but not COX-derived metabolites were higher with celecoxib than placebo (P<0.05) and differences were greater among non aspirin users. LOX derived 5- and 8-HETE were elevated with celecoxib and positively associated with systolic blood pressure (P = 0.011 and P = 0.019 respectively). 20-HETE, a prohypertensive androgen-sensitive CYP450 metabolite was higher with celecoxib absent aspirin and was positively associated with SBP in men (P = 0.040) but not women. Independent of celecoxib or aspirin, LOX derived metabolites from ARA were strongly associated with SBP including 5- and 8 HETE. These findings support oxylipins, particularly the ARA LOX-derived, in blood pressure control and indicate that pharmacologic inhibition of COX-2 has effects on LOX and CYP450 ARA metabolism that contribute to hypertension in some patients. PMID- 29698448 TI - Effects of arbuscular mycorrhizal fungi on growth and nitrogen uptake of Chrysanthemum morifolium under salt stress. AB - Soil salinity is a common and serious environmental problem worldwide. Arbuscular mycorrhizal fungi (AMF) are considered as bio-ameliorators of soil salinity tolerance in plants. However, few studies have addressed the possible benefits of AMF inoculation for medicinal plants under saline conditions. In this study, we examined the effects of colonization with two AMF, Funneliformis mosseae and Diversispora versiformis, alone and in combination, on the growth and nutrient uptake of the medicinal plant Chrysanthemum morifolium (Hangbaiju) in a greenhouse salt stress experiment. After 6 weeks of a non-saline pretreatment, Hangbaiju plants with and without AMF were grown for five months under salinity levels that were achieved using 0, 50 and 200 mM NaCl. Root length, shoot and root dry weight, total dry weight, and root N concentration were higher in the mycorrhizal plants than in the non-mycorrhizal plants under conditions of moderate salinity, especially with D. versiformis colonization. As salinity increased, mycorrhizal colonization and mycorrhizal dependence decreased. The enhancement of root N uptake is probably the main mechanism underlying salt tolerance in mycorrhizal plants. These results suggest that the symbiotic associations between the fungus D. versiformis and C. morifolium plants may be useful in biotechnological practice. PMID- 29698449 TI - Heterosubtypic immunity increases infectious dose required to infect Mallard ducks with Influenza A virus. AB - Previous field and experimental studies have demonstrated that heterosubtypic immunity (HSI) is a potential driver of Influenza A virus (IAV) prevalence and subtype diversity in mallards. Prior infection with IAV can reduce viral shedding during subsequent reinfection with IAV that have genetically related hemagglutinins (HA). In this experiment, we evaluated the effect of HSI conferred by an H3N8 IAV infection against increasing challenge doses of closely (H4N6) and distantly (H6N2) related IAV subtypes in mallards. Two groups of thirty 1-month old mallards each, were inoculated with 105.9 50% embryo infectious doses (EID50) of an H3N8 virus or a mock-inoculum. One month later, groups of five birds each were challenged with increasing doses of H4N6 or H6N2 virus; age-matched, single infection control ducks were included for all challenges. Results demonstrate that naive birds were infected after inoculation with 103 and 104 EID50 doses of the H4N6 or H6N2 virus, but not with 102 EID50 doses of either IAV. In contrast, with birds previously infected with H3N8 IAV, only one duck challenged with 104 EID50 of H4N6 IAV was shedding viral RNA at 2 days post-inoculation, and with H6N2 IAV, only birds challenged with the 104 EID50 dose were positive to virus isolation. Viral shedding in ducks infected with H6N2 IAV was reduced on days 2 and 3 post-inoculation compared to control birds. To explain the differences in the dose necessary to produce infection among H3-primed ducks challenged with H4N6 or H6N2 IAV, we mapped the amino acid sequence changes between H3 and H4 or H6 HA on predicted three-dimensional structures. Most of the sequence differences occurred between H3 and H6 at antigenic sites A, B, and D of the HA1 region. These findings demonstrate that the infectious dose necessary to infect mallards with IAV can increase as a result of HSI and that this effect is most pronounced when the HA of the viruses are genetically related. PMID- 29698450 TI - Stroke infarct volume estimation in fixed tissue: Comparison of diffusion kurtosis imaging to diffusion weighted imaging and histology in a rodent MCAO model. AB - Diffusion kurtosis imaging (DKI) is a new promising MRI technique with microstructural sensitivity superior to conventional diffusion tensor (DTI) based methods. In stroke, considerable mismatch exists between the infarct lesion outline obtained from the two methods, kurtosis and diffusion tensor derived metrics. We aim to investigate if this mismatch can be examined in fixed tissue. Our investigation is based on estimates of mean diffusivity (MD) and mean (of the) kurtosis tensor (MKT) obtained using recent fast DKI methods requiring only 19 images. At 24 hours post stroke, rat brains were fixed and prepared. The infarct was clearly visible in both MD and MKT maps. The MKT lesion volume was roughly 31% larger than the MD lesion volume. Subsequent histological analysis (hematoxylin) revealed similar lesion volumes to MD. Our study shows that structural components underlying the MD/MKT mismatch can be investigated in fixed tissue and therefore allows a more direct comparison between lesion volumes from MRI and histology. Additionally, the larger MKT infarct lesion indicates that MKT do provide increased sensitivity to microstructural changes in the lesion area compared to MD. PMID- 29698451 TI - Effect size and statistical power in the rodent fear conditioning literature - A systematic review. AB - Proposals to increase research reproducibility frequently call for focusing on effect sizes instead of p values, as well as for increasing the statistical power of experiments. However, it is unclear to what extent these two concepts are indeed taken into account in basic biomedical science. To study this in a real case scenario, we performed a systematic review of effect sizes and statistical power in studies on learning of rodent fear conditioning, a widely used behavioral task to evaluate memory. Our search criteria yielded 410 experiments comparing control and treated groups in 122 articles. Interventions had a mean effect size of 29.5%, and amnesia caused by memory-impairing interventions was nearly always partial. Mean statistical power to detect the average effect size observed in well-powered experiments with significant differences (37.2%) was 65%, and was lower among studies with non-significant results. Only one article reported a sample size calculation, and our estimated sample size to achieve 80% power considering typical effect sizes and variances (15 animals per group) was reached in only 12.2% of experiments. Actual effect sizes correlated with effect size inferences made by readers on the basis of textual descriptions of results only when findings were non-significant, and neither effect size nor power correlated with study quality indicators, number of citations or impact factor of the publishing journal. In summary, effect sizes and statistical power have a wide distribution in the rodent fear conditioning literature, but do not seem to have a large influence on how results are described or cited. Failure to take these concepts into consideration might limit attempts to improve reproducibility in this field of science. PMID- 29698452 TI - Iridociliary cysts do not impact on posterior phakic intraocular lens implantation for high myopia correction: A prospective cohort study in 1569 eyes. AB - PURPOSE: To investigate the clinical characters and effect of iridociliary cysts among patients who had undergone posterior phakic intraocular lens implantation. METHODS: A total 1569 eyes of 866 high myopia patients, who underwent phakic intraocular lens implantation from 1 September 2011 to 31 August 2016, was included in this prospective cohort study. These patients were followed up for more than 12 months postoperatively. RESULTS: During the study period, 218 eyes (14%) of 154 patients were diagnosed with iridociliary cysts by ultrasound biomicroscopy. There were 74.3% patients with unilateral cysts and the cysts tended to have occurred in patients ages 20 to 30 years old (22%). The location of the cysts varied with temporal position as the most (50%) and superior position as the least (9.6%). After 1 week postoperative follow-up, there were no significant differences in clinical outcomes between the cysts group and no cysts group, but the proportion of 20/20 or better uncorrected visual acuity (UCVA), best corrected visual acuity (BCVA), and the 2 types of vector astigmatism. Intraocular pressure (IOP), refraction, and vault remained stable at different time points of the follow-up period, while vault of cysts patients tend to be lower than patients without cysts at more than 12 months. CONCLUSIONS: Iridociliary cysts were more common than estimated and it had no impact on Phakic Intraocular Lens implantation because there was no clue to show significantly difference on postoperative clinical outcomes between the patients with and without iridociliary cysts in this study. PMID- 29698453 TI - Evaluating the relationship between lesion burden and aging among the skeletons of an 18th-19th century London cemetery using osteological and radiological analysis. AB - Study of disease in the past can help illuminate patterns of human health, disease, and aging in the present. As average human life expectancy and incidence of chronic disease have increased in the last century, efforts to understand this epidemiologic shift have led to more investigation of healthy aging. Using osteological and radiological methods of analysis, this study examined 212 mostly nineteenth century adult skeletons from the crypt of St. Bride's in London, in order to investigate the relationship between age-at-death, sex, and number of lesions observed in bone. Lesions were classified into macro-level categories according to the Rapid Method for Recording Human Skeletal Data, and the correlation between age group and number of lesions in each category, as well as the total number of lesions, were analyzed. Correlations between age-at-death and the number and type of lesions were compared across both methods of analysis. A greater total number of lesions and a greater number of types of lesions was observed for the osteologically analyzed data, compared to the radiologically analyzed data. Correlations between age-at-death and specific pathology groups were in general weak, though stronger for the osteologically analyzed data. For each method of analysis, there were statistically significant differences between the total number of lesions and age group, with total number of lesions increasing with age, regardless of method of analysis. Joint and metabolic lesions were the most significant predictors of age-at-death. The correlations between total lesions observed and age-at-death were similar for radiologically and osteologically analyzed data, for the same set of bones. This suggests that, for the bones analyzed, while the number of lesions recorded differed according to method of analysis, the relationship between overall observed lesion burden and age-at-death was similar for both osteological and radiological analysis. PMID- 29698454 TI - Relative importance of population size, fishing pressure and temperature on the spatial distribution of nine Northwest Atlantic groundfish stocks. AB - The spatial distribution of nine Northwest Atlantic groundfish stocks was documented using spatial indicators based on Northeast Fisheries Science Center spring and fall bottom trawl survey data, 1963-2016. We then evaluated the relative importance of population size, fishing pressure and bottom temperature on spatial distribution with an information theoretic approach. Northward movement in the spring was generally consistent with prior analyses, whereas changes in depth distribution and area occupancy were not. Only two stocks exhibited the same changes in spatiotemporal distribution in the fall as compared with the spring. Fishing pressure was the most important predictor of the center of gravity (i.e., bivariate mean location of the population) for the majority of stocks in the spring, whereas in the fall this was restricted to the east-west component. Fishing pressure was also the most important predictor of the dispersion around the center of gravity in both spring and fall. In contrast, biomass was the most important predictor of area occupancy for the majority of stocks in both seasons. The relative importance of bottom temperature was ranked highest in the fewest number of cases. This study shows that fishing pressure, in addition to the previously established role of climate, influences the spatial distribution of groundfish in the Northwest Atlantic. More broadly, this study is one of a small but growing body of literature to demonstrate that fishing pressure has an effect on the spatial distribution of marine resources. Future work must consider both fishing pressure and climate when examining mechanisms underlying fish distribution shifts. PMID- 29698455 TI - Isolation of mitochondria from Saccharomyces cerevisiae using magnetic bead affinity purification. AB - Isolated mitochondria are widely used to study the function of the organelle. Typically, mitochondria are prepared using differential centrifugation alone or in conjunction with density gradient ultracentrifugation. However, mitochondria isolated using differential centrifugation contain membrane or organelle contaminants, and further purification of crude mitochondria by density gradient ultracentrifugation requires large amounts of starting material, and is time consuming. Mitochondria have also been isolated by irreversible binding to antibody-coated magnetic beads. We developed a method to prepare mitochondria from budding yeast that overcomes many of the limitations of other methods. Mitochondria are tagged by insertion of 6 histidines (6xHis) into the TOM70 (Translocase of outer membrane 70) gene at its chromosomal locus, isolated using Ni-NTA (nickel (II) nitrilotriacetic acid) paramagnetic beads and released from the magnetic beads by washing with imidazole. Mitochondria prepared using this method contain fewer contaminants, and are similar in ultrastructure as well as protein import and cytochrome c oxidase complex activity compared to mitochondria isolated by differential centrifugation. Moreover, this isolation method is amenable to small samples, faster than purification by differential and density gradient centrifugation, and more cost-effective than purification using antibody coated magnetic beads. Importantly, this method can be applied to any cell type where the genetic modification can be introduced by CRISPR or other methods. PMID- 29698456 TI - Trypanosomal mitochondrial intermediate peptidase does not behave as a classical mitochondrial processing peptidase. AB - Upon their translocation into the mitochondrial matrix, the N-terminal pre sequence of nuclear-encoded proteins undergoes cleavage by mitochondrial processing peptidases. Some proteins require more than a single processing step, which involves several peptidases. Down-regulation of the putative Trypanosoma brucei mitochondrial intermediate peptidase (MIP) homolog by RNAi renders the cells unable to grow after 48 hours of induction. Ablation of MIP results in the accumulation of the precursor of the trypanosomatid-specific trCOIV protein, the largest nuclear-encoded subunit of the cytochrome c oxidase complex in this flagellate. However, the trCOIV precursor of the same size accumulates also in trypanosomes in which either alpha or beta subunits of the mitochondrial processing peptidase (MPP) have been depleted. Using a chimeric protein that consists of the N-terminal sequence of a putative subunit of respiratory complex I fused to a yellow fluorescent protein, we assessed the accumulation of the precursor protein in trypanosomes, in which RNAi was induced against the alpha or beta subunits of MPP or MIP. The observed accumulation of precursors indicates MIP depletion affects the activity of the cannonical MPP, or at least one of its subunits. PMID- 29698457 TI - Rapid weight reduction does not impair athletic performance of Taekwondo athletes - A pilot study. AB - In combat sports such as taekwondo (TKD), athletes rapidly reduce body weight to achieve a desired weight category. Competition takes place 16-24 h after weigh-in and thus, the recovery time is an important factor for competition performance. The purpose of this study was to investigate the impact of rapid weight reduction (RWR) on athletic performance and associated hemorheological properties considering relevant recovery time. Five male TKD athletes reduced body weight by 5% within 31/2 days. A simulated competition day (SCD) was carried out after a 16 h recovery period. Parameters were measured before RWR, at weigh-in and before and after three TKD simulation matches (SMs) at SCD. Same set-up was conducted but without RWR as control. Basal blood parameters, red blood cells (RBC) deformability and aggregation, serum glucose and fibrinogen were determined. During SMs, heart rate (HRpeak, HRmean), oxygen uptake (VO2peak, VO2mean), peak lactate (Peak La-), difference of lactate (DeltaLa) and energy systems (anaerobic alactic, -lactic and aerobic) were analyzed. Basal blood parameters remained unaltered during the interventions. RBC deformability was reduced and aggregation was increased after RWR but values returned to baseline after recovery and were not affected by the SMs. Glucose level was not affected by the interventions. Kick frequency in SMs was higher after RWR which might be responsible for higher HRpeak, VO2peak, VO2mean, Peak La-, DeltaLa- and aerobic demand. The 16 h recovery is sufficient to regenerate measured physiological and hemorheological parameters. TKD-specific performance was not negatively affected during SMs after RWR. PMID- 29698458 TI - Nitrogen narcosis induced by repetitive hyperbaric nitrogen oxygen mixture exposure impairs long-term cognitive function in newborn mice. AB - Human beings are exposed to compressed air or a nitrogen-oxygen mixture, they will produce signs and symptoms of nitrogen narcosis such as amnesia or even loss of memory, which may be disappeared once back to the normobaric environment. This study was designed to investigate the effect of nitrogen narcosis induced by repetitive hyperbaric nitrogen-oxygen mixture exposure on long-term cognitive function in newborn mice and the underlying mechanisms. The electroencephalogram frequency was decreased while the amplitude was increased in a pressure-dependent manner during 0.6, 1.2, 1.8 MPa (million pascal) nitrogen-oxygen mixture exposures in adult mice. Nitrogen narcosis in postnatal days 7-9 mice but not in adult mice induced by repetitive hyperbaric exposure prolonged the latency to find the platform and decreased the number of platform-site crossovers during Morris water maze tests, and reduced the time in the center during the open field tests. An increase in the expression of cleaved caspase-3 in the hippocampus and cortex were observed immediately on the first day after hyperbaric exposure, and this lasted for seven days. Additionally, nitrogen narcosis induced loss of the dendritic spines but not of the neurons, which may mainly account for the cognitive dysfunction. Nitrogen narcosis induced long-term cognitive and emotional dysfunction in the postnatal mice but not in the adult mice, which may result from neuronal apoptosis and especially reduction of dendritic spines of neurons. PMID- 29698459 TI - The psychometric properties of the 10-item Kessler Psychological Distress Scale (K10) in Canadian military personnel. AB - The psychometric properties of the ten-item Kessler Psychological Distress scale (K10) have been extensively explored in civilian populations. However, documentation of its psychometric properties in military populations is limited, and there is no universally accepted cut-off score on the K10 to distinguish clinical vs. sub-clinical levels of distress. The objective of this study was to examine the psychometric properties of the K10 in Canadian Armed Forces personnel. Data on 6700 Regular Forces personnel were obtained from the 2013 Canadian Forces Mental Health Survey. The internal consistency and factor structure of the K10 (range, 0-40) were examined using confirmatory factor analysis (CFA). Receiver Operating Characteristic (ROC) analysis was used to select optimal cut-offs for the K10, using the presence/absence of any of four past-month disorders as the outcome (posttraumatic stress disorder, major depressive episode, generalized anxiety disorder, and panic disorder). Cronbach's alpha (0.88) indicated a high level of internal consistency of the K10. Results from CFA indicated that a single-factor 10-item construct had an acceptable overall fit: root mean square error of approximation (RMSEA) = 0.05; 90% confidence interval (CI):0.05-0.06, comparative fit index (CFI) = 0.99, Tucker Lewis Index (TLI) = 0.99, weighted root mean square residual (WRMR) = 2.06. K10 scores were strongly associated with both the presence and recency of all four measured disorders. The area under the ROC curve was 0.92, demonstrating excellent predictive value for past-30-day disorders. A K10 score of 10 or greater was optimal for screening purposes (sensitivity = 86%; specificity = 83%), while a score of 17 or greater (sensitivity = 53%; specificity = 97%) was optimal for prevalence estimation of clinically significant psychological distress, in that it resulted in equal numbers of false positives and false negatives. Our results suggest that K10 scale has satisfactory psychometric properties for use as a measure of non-specific psychological distress in the military population. PMID- 29698460 TI - Growth differentiation factor-15 and fibroblast growth factor-23 are associated with mortality in type 2 diabetes - An observational follow-up study. AB - OBJECTIVES: Two biomarkers, growth differentiation factor 15 (GDF-15) and fibroblast growth factor 23 (FGF-23)), reflecting different aspects of renal pathophysiology, were evaluated as determinants of decline in estimated glomerular filtration rate (eGFR), incident cardiovascular disease (CVD) and all cause mortality in patients with type 2 diabetes (T2D) and microalbuminuria, but without clinical cardiac disease. MATERIALS AND METHODS: Prospective study including 200 T2D patients. The predefined endpoint of chronic kidney disease (CKD) progression: A decline in eGFR of >30% at any time point during follow-up. Hazard ratios (HR) are provided per 1 SD increment of log2-transformed values. RESULTS: Mean (+/- SD) age was 59 +/- 9 years, eGFR 91.1 +/- 18.3 ml/min/1.73m2 and median (IQR) UAER 103 (39-230) mg/24-h. During a median 6.1 years follow-up, 40 incident CVD events, 26 deaths and 42 patients reached the CKD endpoint after median 4.9 years. Higher GDF-15 was a determinant of decline in eGFR >30% and all cause mortality in adjusted models (HR 1.7 (1.1-2.5); p = 0.018 and HR 1.9 (1.2 2.9); p = 0.003, respectively). Adding GDF-15 to traditional risk factors improved risk prediction of decline in renal function (relative integrated discrimination improvement (rIDI) = 30%; p = 0.037). Higher FGF-23 was associated with all-cause mortality in adjusted models (HR 1.6 (1.1-2.2); p = 0.011) with a rIDI of 30% (p = 0.024). CONCLUSIONS: In patients with T2D and microalbuminuria, higher GDF-15 and FGF-23 were independently associated with all-cause mortality and higher GDF-15 improved risk prediction of decline in kidney function and higher FGF-23 of all-cause mortality, beyond traditional risk factors, but not independently of GDF-15. PMID- 29698461 TI - Induction of osteoarthritis by injecting monosodium iodoacetate into the patellofemoral joint of an experimental rat model. AB - This study aimed to investigate the histopathological changes in the patellofemoral joint using a rat model of osteoarthritis that was induced using monosodium iodoacetate, and to establish a novel model of patellofemoral osteoarthritis in a rat model using histopathological analysis. Sixty male rats were used. Osteoarthritis was induced through a single intra-articular injection of monosodium iodoacetate in both knee joints. Animals were equally divided into two experimental groups based on the monosodium iodoacetate dose: 0.2 mg and 1.0 mg. Histopathological changes in the articular cartilage of the patellofemoral joint and the infrapatellar fat pad were examined at 3 days, 1 week, 2 weeks, 4 weeks, 8 weeks, and 12 weeks after the monosodium iodoacetate injection. In the 1.0-mg group, the representative histopathological findings of osteoarthritis were observed in the articular cartilage of the patellofemoral joint over time. Additionally, the Osteoarthritis Research Society International scores of the patellofemoral joint increased over time. The synovitis scores of the infrapatellar fat pad in both groups were highest at 3 days, and then the values decreased over time. The fibrosis score of the infrapatellar fat pad in the 1.0 mg group increased with time, whereas the fibrosis score in the 0.2-mg group remained low. Representative histopathological findings of osteoarthritis were observed in the articular cartilage of the patellofemoral joint in a rat model of osteoarthritis induced using monosodium iodoacetate. With appropriate selection, this model may be regarded as an ideal patellofemoral osteoarthritis model. PMID- 29698462 TI - Terc is dispensable for most of the short-term HPV16 oncogene-mediated phenotypes in mice. AB - High-risk human papillomaviruses (HPVs) have been shown in vitro to impinge on telomere homeostasis in a number of ways. However, the in vivo interaction of viruses with the telomere homeostasis apparatus has not been previously explored. Since E6 and E7 are the main viral oncogenes and key for viral replication, we have explored here the short-term phenotypes of the genes in the context of defective telomere homeostasis. We examined the short-term phenotypes of E6 and E7 in a context where the Terc component of the telomerase holoenzyme was knocked out. We determined that Terc was dispensable for most oncogene-mediated phenotypes. Surprisingly, E7-mediated reduction of label retaining cells was found to be in part dependent on the presence of Terc. Under the conditions examined here, there appears to be no compelling evidence Terc is required for most short-term viral oncogene mediated phenotypes. Further studies will elucidate its role in longer-term phenotypes. PMID- 29698463 TI - Assessing the impact of environmental exposures and Cryptosporidium infection in cattle on human incidence of cryptosporidiosis in Southwestern Ontario, Canada. AB - Cryptosporidium is a waterborne parasite that causes diarrheal disease in humans and in cattle. Risk factors for human illness include contact with surface water such as lakes and rivers, exposure to contaminated municipal drinking water, as well as zoonotic transmission from livestock and agriculture. The objectives of this study are twofold: 1) to describe the temporal distribution of cryptosporidiosis in Southwestern Ontario; and 2) to determine the distribution of human cryptosporidiosis, in relation to exposures such as cryptosporidium positive cattle farms, weather events, and hydrological factors. Seasonal trends in 214 bovine and 87 human cases were assessed using regression models that predicted monthly case counts in relation to observed monthly case counts. A case crossover approach was used to evaluate acute associations between daily environmental exposures, such as weather, hydrology, the presence of Cryptosporidium positive cattle farms within the region, and the risk of human Cryptosporidium infection. Annual seasonality was found for both human cases and bovine cases with human cases peaking in mid-summer and bovine cases peaking in late winter to early spring. Bovine cases that occurred 21 days prior to human cases were associated with a three-fold increase in the odds of human case occurrence. At both 9 and 14 days prior to human case onset, the odds of a human case increased twofold per 10-degree Celsius increase in air temperature. These results provide a preliminary hypothesis for the zoonotic transmission of cryptosporidiosis from cattle to humans via the environment and suggest that the timing of environmental conditions in relation to case occurrence is biologically plausible. PMID- 29698464 TI - Shrub growth and plant diversity along an elevation gradient: Evidence of indirect effects of climate on alpine ecosystems. AB - Enhanced shrub growth and expansion are widespread responses to climate warming in many arctic and alpine ecosystems. Warmer temperatures and shrub expansion could cause major changes in plant community structure, affecting both species composition and diversity. To improve our understanding of the ongoing changes in plant communities in alpine tundra, we studied interrelations among climate, shrub growth, shrub cover and plant diversity, using an elevation gradient as a proxy for climate conditions. Specifically, we analyzed growth of bilberry (Vaccinium myrtillus L.) and its associated plant communities along an elevation gradient of ca. 600 vertical meters in the eastern European Alps. We assessed the ramet age, ring width and shoot length of V. myrtillus, and the shrub cover and plant diversity of the community. At higher elevation, ramets of V. myrtillus were younger, with shorter shoots and narrower growth rings. Shoot length was positively related to shrub cover, but shrub cover did not show a direct relationship with elevation. A greater shrub cover had a negative effect on species richness, also affecting species composition (beta-diversity), but these variables were not influenced by elevation. Our findings suggest that changes in plant diversity are driven directly by shrub cover and only indirectly by climate, here represented by changes in elevation. PMID- 29698465 TI - Barley beta-glucan improves metabolic condition via short-chain fatty acids produced by gut microbial fermentation in high fat diet fed mice. AB - Dietary intake of barley beta-glucan (BG) is known to affect energy metabolism. However, its underlying mechanism remains poorly understood because studies have presented inconsistent results, with both positive and negative effects reported in terms of satiety, energy intake, weight loss, and glycemic control. The objective of this study was to clarify the physiological role underlying the metabolic benefits of barley BG using a mouse model of high fat diet (HFD) induced obesity. Male 4-wk-old C57BL/6J mice were fed an HFD with 20% barley flour containing either high BG (HBG; 2% BG) or low BG (LBG; 0.6% BG) levels under conventional and germ-free (GF) conditions for 12 wks. In addition, mice were fed either an HFD with 5% cellulose (HFC; high fiber cellulose) or 5% barley BG (HFB; high fiber beta-glucan) for 12 wks. Then, metabolic parameters, gut microbial compositions, and the production of fecal short-chain fatty acids (SCFAs) were analyzed. The weight gain and fat mass of HBG-fed mice were lower than those of control mice at 16-wk-old. Moreover, the secretion of the gut hormones PYY and GLP-1 increased in HBG-fed mice, thereby reducing food intake and improving insulin sensitivity by changing the gut microbiota and increasing SCFAs (especially, butyrate) under conventional condition. These effects in HBG fed mice were abolished under GF conditions. Moreover, the HFB diets also increased PYY and GLP-1 secretion, and decreased food intake compared with that in HFC-fed mice. These results suggest that the beneficial metabolic effects of barley BG are primary due to the suppression of appetite and improvement of insulin sensitivity, which are induced by gut hormone secretion promoted via gut microbiota-produced SCFAs. PMID- 29698467 TI - HIV-1 genetic transmission networks among men who have sex with men in Kunming, China. AB - BACKGROUND: Yunnan has the greatest share of reported human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) cases in China. In recent years, HIV prevalence and incidence remained stubbornly high in men who have sex with men (MSM). To follow the dynamics of the HIV-1 epidemic among MSM, HIV-1 genetic characteristics and genetic transmission networks were investigated. METHODS: Blood samples from 190 newly diagnosed HIV-1 cases among MSM were continuously collected at fixed sites from January 2013 to December 2015 in Kunming City, Yunnan Province. Partial gag, pol and env genes were sequenced and used for phylogenetic and genotypic drug resistance analyses. The genetic characteristics of the predominant HIV-1 strains were analyzed by the Bayesian Markov Chain Monte Carlo (MCMC) method. The genetic transmission networks were identified with a genetic distance of 0.03 substitutions/site and 90% bootstrap support. RESULTS: Among the 190 HIV-1 positive MSM reported during 2013-2105, various genotypes were identified, including CRF01_AE (45.3%), CRF07_BC (35.8%), unique recombinant forms (URFs) (11.6%), CRF08_BC (3.2%), CRF55_01B (2.1%), subtype B (1.6%) and CRF59_01B (0.5%). The effective population sizes (EPS) for CRF01_AE and CRF07_BC increased exponentially from approximately 2001-2010 and 2005-2009, respectively. Genetic transmission networks were constructed with 308 pol sequences from MSM diagnosed during 2010-2015. Of the 308 MSM, 109 (35.4%) were identified in 38 distinct clusters. Having multiple male partners was associated with a high probability of identification in the genetic transmission networks. Of the 38 clusters, 27 (71.1%) contained individuals diagnosed in different years. Of the 109 individuals in the networks, 26 (23.9%) had >=2 potential transmission partners (>=2 links). The proportion of MSM with >=2 links was higher among those diagnosed from 2010-2012. The constituent ratios of their potential transmission partners by areas showed no significant difference among MSM from Kunming, other cities in Yunnan and other provinces. Additionally, surveillance drug resistance mutations (SDRMs) were identified in 5% of individuals. CONCLUSION: This study revealed the various HIV-a genotypes circulating among MSM in Kunming. MSM with more partners were more easily detected in transmission networks, and early-diagnosed MSM remained active in transmission networks. These findings suggested that the routine interventions should be combined with HIV testing and linkage to care and early antiretroviral therapy among HIV-positive MSM. PMID- 29698466 TI - Profiling of epidermal lipids in a mouse model of dermatitis: Identification of potential biomarkers. AB - Lipids are important structural and functional components of the skin. Alterations in the lipid composition of the epidermis are associated with inflammation and can affect the barrier function of the skin. SHARPIN-deficient cpdm mice develop a chronic dermatitis with similarities to atopic dermatitis in humans. Here, we used a recently-developed approach named multiple reaction monitoring (MRM)-profiling and single ion monitoring to rapidly identify discriminative lipid ions. Shorter fatty acyl residues and increased relative amounts of sphingosine ceramides were observed in cpdm epidermis compared to wild type mice. These changes were accompanied by downregulation of the Fasn gene which encodes fatty acid synthase. A profile of diverse lipids was generated by fast screening of over 300 transitions (ion pairs). Tentative attribution of the most significant transitions was confirmed by product ion scan (MS/MS), and the MRM-profiling linear intensity response was validated with a C17-ceramide lipid standard. Relative quantification of sphingosine ceramides CerAS(d18:1/24:0)2OH, CerAS(d18:1/16:0)2OH and CerNS(d18:1/16:0) discriminated between the two groups with 100% accuracy, while the free fatty acids cerotic acid, 16-hydroxy palmitic acid, and docosahexaenoic acid (DHA) had 96.4% of accuracy. Validation by liquid chromatography tandem mass spectrometry (LC-MS/MS) of the above-mentioned ceramides was in agreement with MRM-profiling results. Identification and rapid monitoring of these lipids represent a tool to assess therapeutic outcomes in SHARPIN-deficient mice and other mouse models of dermatitis and may have diagnostic utility in atopic dermatitis. PMID- 29698468 TI - Lack of evidence that nephrolithiasis increases the risk of sialolithiasis: A longitudinal follow-up study using a national sample cohort. AB - OBJECTIVE: The objective of this study was to evaluate the risk of sialolithiasis in nephrolithiasis patients. METHODS: Using data from the national cohort study from the Korean Health Insurance Review and Assessment Service, we selected 24,038 patients with nephrolithiasis. The control group consisted of 96,152 participants without nephrolithiasis who were matched 1:4 by age, sex, income, region of residence, diabetes, hypertension, and dyslipidemia. The incidence of sialolithiasis in the two groups was compared, with a follow-up period of up to 12 years. The crude and adjusted hazard ratio (HR) of nephrolithiasis to sialolithiasis was analyzed with a Cox-proportional hazard regression model. RESULTS: The rates of sialolithiasis in the nephrolithiasis group and the control group were not significantly different (0.08% vs. 0.1%, P = 0.447). The crude and adjusted hazard ratios of nephrolithiasis to sialolithiasis were not statistically significant (crude HR = 0.82, 95% confidence interval [CI] = 0.50 1.35, P = 0.448; adjusted HR = 0.81, 95% CI = 0.49-1.33, P = 0.399). Subgroup analyses according to age and sex also failed to reveal statistical significance. CONCLUSION: There is no evidence of an increased risk of sialolithiasis associated with nephrolithiasis. We suggest that routine evaluation for sialolithiasis in all patients with nephrolithiasis is not necessary. PMID- 29698470 TI - HIV-1 transmitted drug resistance in Slovenia and its impact on predicted treatment effectiveness: 2011-2016 update. AB - HIV-positive individuals that have a detected transmitted drug resistance (TDR) at baseline have a higher risk of virological failure with antiretroviral therapy (ART). This study offers an update on the prevalence of TDR in Slovenia, looks for onward transmission of TDR, and reassesses the need for baseline drug resistance testing. Blinded questionnaires and partial pol sequences were obtained from 54.5% (168/308) of all of the patients diagnosed with HIV-1 from 2011 to 2016. Subtype B was detected in 82.7% (139/168) of patients, followed by subtype A (8.3%), subtype C (2.4%), and CRF01_AE (1.8%). Surveillance drug resistance mutations (SDRMs) were found in four individuals (2.4%), all of them men who have sex with men (MSM) and infected with subtype B. K103N was detected in two patients and T68D and T215D in one person each, corresponding to a prevalence of 0%, 1.2%, and 1.2% of TDR to protease inhibitors (PIs), nucleoside reverse transcriptase inhibitors (NRTIs), and non-NRTIs (NNRTIs), respectively. The impact of mutations on drug susceptibility was found to be most pronounced for NNRTIs. No forward spread of TDR within the country was observed; however, phylogenetic analysis revealed several new introductions of HIV into Slovenia in recent years, possibly due to increased risky behavior by MSM. This was indirectly confirmed by a substantial increase in syphilis cases and HIV-1 non-B subtypes during the study period. A drug-resistant HIV variant with good transmission fitness is thus more likely to be imported into Slovenia in the near future, and so TDR should be closely monitored. PMID- 29698471 TI - Dose gradient curve: A new tool for evaluating dose gradient. AB - PURPOSE: Stereotactic radiotherapy, which delivers an ablative high radiation dose to a target volume for maximum local tumor control, requires a rapid dose fall-off outside the target volume to prevent extensive damage to nearby normal tissue. Currently, there is no tool to comprehensively evaluate the dose gradient near the target volume. We propose the dose gradient curve (DGC) as a new tool to evaluate the quality of a treatment plan with respect to the dose fall-off characteristics. METHODS: The average distance between two isodose surfaces was represented by the dose gradient index (DGI) estimated by a simple equation using the volume and surface area of isodose levels. The surface area was calculated by mesh generation and surface triangulation. The DGC was defined as a plot of the DGI of each dose interval as a function of the dose. Two types of DGCs, differential and cumulative, were generated. The performance of the DGC was evaluated using stereotactic radiosurgery plans for virtual targets. RESULTS: Over the range of dose distributions, the dose gradient of each dose interval was well-characterized by the DGC in an easily understandable graph format. Significant changes in the DGC were observed reflecting the differences in planning situations and various prescription doses. CONCLUSIONS: The DGC is a rational method for visualizing the dose gradient as the average distance between two isodose surfaces; the shorter the distance, the steeper the dose gradient. By combining the DGC with the dose-volume histogram (DVH) in a single plot, the DGC can be utilized to evaluate not only the dose gradient but also the target coverage in routine clinical practice. PMID- 29698469 TI - Megakaryocyte lineage development is controlled by modulation of protein acetylation. AB - Treatment with lysine deacetylase inhibitors (KDACi) for haematological malignancies, is accompanied by haematological side effects including thrombocytopenia, suggesting that modulation of protein acetylation affects normal myeloid development, and specifically megakaryocyte development. In the current study, utilising ex-vivo differentiation of human CD34+ haematopoietic progenitor cells, we investigated the effects of two functionally distinct KDACi, valproic acid (VPA), and nicotinamide (NAM), on megakaryocyte differentiation, and lineage choice decisions. Treatment with VPA increased the number of megakaryocyte/erythroid progenitors (MEP), accompanied by inhibition of megakaryocyte differentiation, whereas treatment with NAM accelerated megakaryocyte development, and stimulated polyploidisation. Treatment with both KDACi resulted in no significant effects on erythrocyte differentiation, suggesting that the effects of KDACi primarily affect megakaryocyte lineage development. H3K27Ac ChIP-sequencing analysis revealed that genes involved in myeloid development, as well as megakaryocyte/erythroid (ME)-lineage differentiation are uniquely modulated by specific KDACi treatment. Taken together, our data reveal distinct effects of specific KDACi on megakaryocyte development, and ME-lineage decisions, which can be partially explained by direct effects on promoter acetylation of genes involved in myeloid differentiation. PMID- 29698472 TI - Comparison of non-invasive assessment of liver fibrosis in patients with alpha1 antitrypsin deficiency using magnetic resonance elastography (MRE), acoustic radiation force impulse (ARFI) Quantification, and 2D-shear wave elastography (2D SWE). AB - PURPOSE: Although it has been known for decades that patients with alpha1 antitrypsin deficiency (AATD) have an increased risk of cirrhosis and hepatocellular carcinoma, limited data exist on non-invasive imaging-based methods for assessing liver fibrosis such as magnetic resonance elastography (MRE) and acoustic radiation force impulse (ARFI) quantification, and no data exist on 2D-shear wave elastography (2D-SWE). Therefore, the purpose of this study is to evaluate and compare the applicability of different elastography methods for the assessment of AATD-related liver fibrosis. METHODS: Fifteen clinically asymptomatic AATD patients (11 homozygous PiZZ, 4 heterozygous PiMZ) and 16 matched healthy volunteers were examined using MRE and ARFI quantification. Additionally, patients were examined with 2D-SWE. RESULTS: A high correlation is evident for the shear wave speed (SWS) determined with different elastography methods in AATD patients: 2D-SWE/MRE, ARFI quantification/2D-SWE, and ARFI quantification/MRE (R = 0.8587, 0.7425, and 0.6914, respectively; P<=0.0089). Four AATD patients with pathologically increased SWS were consistently identified with all three methods-MRE, ARFI quantification, and 2D SWE. CONCLUSION: The high correlation and consistent identification of patients with pathologically increased SWS using MRE, ARFI quantification, and 2D-SWE suggest that elastography has the potential to become a suitable imaging tool for the assessment of AATD-related liver fibrosis. These promising results provide motivation for further investigation of non-invasive assessment of AATD-related liver fibrosis using elastography. PMID- 29698473 TI - Transcriptome reprogramming of resistant and susceptible peach genotypes during Xanthomonas arboricola pv. pruni early leaf infection. AB - Bacterial spot caused by Xanthomonas arboricola pv. pruni (Xap) is a major threat to Prunus species worldwide. The molecular mechanisms of peach resistance to Xap during early leaf infection were investigated by RNA-Seq analysis of two Prunus persica cultivars, 'Redkist' (resistant), and 'JH Hale' (susceptible) at 30 minutes, 1 and 3 hours-post-infection (hpi). Both cultivars exhibited extensive modulation of gene expression at 30 mpi, which reduced significantly at 1 hpi, increasing again at 3 hpi. Overall, 714 differentially expressed genes (DEGs) were detected in 'Redkist' (12% at 30 mpi and 1 hpi and 88% at 3 hpi). In 'JH Hale', 821 DEGs were identified (47% at 30 mpi and 1 hpi and 53% at 3 hpi). Highly up-regulated genes (fold change > 100) at 3 hpi exhibited higher fold change values in 'Redkist' than in 'JH Hale'. RNA-Seq bioinformatics analyses were validated by RT-qPCR. In both cultivars, DEGs included genes with putative roles in perception, signal transduction, secondary metabolism, and transcription regulation, and there were defense responses in both cultivars, with enrichment for the gene ontology terms, 'immune system process', 'defense response', and 'cell death'. There were particular differences between the cultivars in the intensity and kinetics of modulation of expression of genes with putative roles in transcriptional activity, secondary metabolism, photosynthesis, and receptor and signaling processes. Analysis of differential exon usage (DEU) revealed that both cultivars initiated remodeling their transcriptomes at 30 mpi; however, 'Redkist' exhibited alternative exon usage for a greater number of genes at every time point compared with 'JH Hale'. Candidate resistance genes (WRKY-like, CRK like, Copper amine oxidase-like, and TIR-NBS-LRR-like) are of interest for further functional characterization with the aim of elucidating their role in Prunus spp. resistance to Xap. PMID- 29698474 TI - Interferon induced protein 35 exacerbates H5N1 influenza disease through the expression of IL-12p40 homodimer. AB - Pro-inflammatory cytokinemia is a hallmark of highly pathogenic H5N1 influenza virus (IAV) disease yet little is known about the role of host proteins in modulating a pathogenic innate immune response. The host Interferon Induced Protein 35 (Ifi35) has been implicated in increased susceptibility to H5N1-IAV infection. Here, we show that Ifi35 deficiency leads to reduced morbidity in mouse models of highly pathogenic H5N1- and pandemic H1N1-IAV infection. Reduced weight loss in Ifi35-/- mice following H5N1-IAV challenge was associated with reduced cellular infiltration and decreased production of specific cytokines and chemokines including IL-12p40. Expression of Ifi35 by the hematopoietic cell compartment in bone-marrow chimeric mice contributed to increased immune cell recruitment and IL-12p40 production. In addition, Ifi35 deficient primary macrophages produce less IL-12p40 following TLR-3, TLR-4, and TLR-7 stimulation in vitro. Decreased levels of IL-12p40 and its homodimer, IL-12p80, were found in bronchoalveolar lavage fluid of H5N1-IAV infected Ifi35 deficient mice. Specific antibody blockade of IL-12p80 ameliorated weight loss and reduced cellular infiltration following H5N1-IAV infection in wild-type mice; suggesting that increased levels of IL-12p80 alters the immune response to promote inflammation and IAV disease. These data establish a role for Ifi35 in modulating cytokine production and exacerbating inflammation during IAV infection. PMID- 29698475 TI - CADM1 is essential for KSHV-encoded vGPCR-and vFLIP-mediated chronic NF-kappaB activation. AB - Approximately 12% of all human cancers worldwide are caused by infections with oncogenic viruses. Kaposi's sarcoma herpesvirus/human herpesvirus 8 (KSHV/HHV8) is one of the oncogenic viruses responsible for human cancers, including Kaposi's sarcoma (KS), Primary Effusion Lymphoma (PEL), and the lymphoproliferative disorder multicentric Castleman's disease (MCD). Chronic inflammation mediated by KSHV infection plays a decisive role in the development and survival of these cancers. NF-kappaB, a family of transcription factors regulating inflammation, cell survival, and proliferation, is persistently activated in KSHV-infected cells. The KSHV latent and lytic expressing oncogenes involved in NF-kappaB activation are vFLIP/K13 and vGPCR, respectively. However, the mechanisms by which NF-kappaB is activated by vFLIP and vGPCR are poorly understood. In this study, we have found that a host molecule, Cell Adhesion Molecule 1 (CADM1), is robustly upregulated in KSHV-infected PBMCs and KSHV-associated PEL cells. Further investigation determined that both vFLIP and vGPCR interacted with CADM1. The PDZ binding motif localized at the carboxyl terminus of CADM1 is essential for both vGPCR and vFLIP to maintain chronic NF-kappaB activation. Membrane lipid raft associated CADM1 interaction with vFLIP is critical for the initiation of IKK kinase complex and NF-kappaB activation in the PEL cells. In addition, CADM1 played essential roles in the survival of KSHV-associated PEL cells. These data indicate that CADM1 plays key roles in the activation of NF-kappaB pathways during latent and lytic phases of the KSHV life cycle and the survival of KSHV infected cells. PMID- 29698476 TI - Matrix metalloproteinase inhibitors enhance the efficacy of frontline drugs against Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis (Mtb) remains a grave threat to world health with emerging drug resistant strains. One prominent feature of Mtb infection is the extensive reprogramming of host tissue at the site of infection. Here we report that inhibition of matrix metalloproteinase (MMP) activity by a panel of small molecule inhibitors enhances the in vivo potency of the frontline TB drugs isoniazid (INH) and rifampicin (RIF). Inhibition of MMP activity leads to an increase in pericyte-covered blood vessel numbers and appears to stabilize the integrity of the infected lung tissue. In treated mice, we observe an increased delivery and/or retention of frontline TB drugs in the infected lungs, resulting in enhanced drug efficacy. These findings indicate that targeting Mtb-induced host tissue remodeling can increase therapeutic efficacy and could enhance the effectiveness of current drug regimens. PMID- 29698477 TI - Characteristics of ataxic gait in familial dysautonomia patients. AB - INTRODUCTION AND OBJECTIVES: Progressive ataxic gait is a common symptom in individuals with Familial Dysautonomia (FD). At least 50% of adults with FD require assistance with walking. Our aims were to describe the medical condition of individuals with FD (ii) compare their gait characteristics to healthy individuals, and (iii) assess correlations between gait measures, presence of unstable gait pattern and frequency of falls. METHODS: Twelve subjects with FD (7 males, age 25.3+/-10.6 years) and 16 healthy participants (6 males, age 35.9+/ 11.9 years) were recruited. Gait kinematics, gait symmetry, dynamic muscle activity, and foot deep vibration sensation were recorded. RESULTS: Ataxic gait degrees were: severe (6 out of 12), moderate (4 out of 12) and low (2 out of 12). The number of falls correlated with base width asymmetry. Crouch gait was noted in 3 out of 12 of the subjects. CONCLUSIONS: In-depth quantitative gait analysis of individuals with FD revealed ataxic gait. The ataxic pattern might be a result of combined neurological deficiencies and osseous deformities. Increasing the base of support of patients with FD might increase the symmetry of the base width during gait and decrease the number of falls. Additionally, perturbation treatment and dynamic balance exercises may be recommended in order to improve compensatory strategies. Future investigation of this population should include quantification of osseous rotations of the lower limb in order to fully understand its effect on their gait pattern and falls. PMID- 29698479 TI - Finding the gap: An empirical study of the most effective shots in elite goalball. AB - This research identifies which shots types in goalball are most likely to lead to a goal and herby provides background information for improving training and competition. Therefore, we observed 117 elite level matches including 20,541 shots played in the regular situation (3 vs. 3) using notational analysis. We characterized the shots by using their target sector (A-E), technique (traditional, rotation), trajectory (flat, bounce), angle (straight, diagonal and outcome (goal, violation, out, blocked). In our data, a chi2-test showed a significantly higher goal rate for men (3.9%) compared to women (3.0%). For men, we found a significantly higher goal rate in the intersection sectors between players C (5.6%), D (4.9%), and in the outer sector A. In sector A, goal rate was higher only for straight shots (6.6%). Technique and trajectory did not affect goal rate for men, but flat shots showed a higher violation rate (3.2%) compared to bounce shouts (2.0%). In women's goalball, goal rate was higher only on sector D (4.4%). Bounce-rotation shots were the most successful (5.5%). We conclude that men should focus on shots to sectors C and D (called pocket) and straight shots to sector A, as long as there are no other tactical considerations. Women should shoot primarily towards the pocket. It might also be worth playing more bounce rotation shots and practicing them in training. PMID- 29698478 TI - Cross-sectional analysis of CD8 T cell immunity to human herpesvirus 6B. AB - Human herpesvirus 6 (HHV-6) is prevalent in healthy persons, causes disease in immunosuppressed carriers, and may be involved in autoimmune disease. Cytotoxic CD8 T cells are probably important for effective control of infection. However, the HHV-6-specific CD8 T cell repertoire is largely uncharacterized. Therefore, we undertook a virus-wide analysis of CD8 T cell responses to HHV-6. We used a simple anchor motif-based algorithm (SAMBA) to identify 299 epitope candidates potentially presented by the HLA class I molecule B*08:01. Candidates were found in 77 of 98 unique HHV-6B proteins. From peptide-expanded T cell lines, we obtained CD8 T cell clones against 20 candidates. We tested whether T cell clones recognized HHV-6-infected cells. This was the case for 16 epitopes derived from 12 proteins from all phases of the viral replication cycle. Epitopes were enriched in certain amino acids flanking the peptide. Ex vivo analysis of eight healthy donors with HLA-peptide multimers showed that the strongest responses were directed against an epitope from IE-2, with a median frequency of 0.09% of CD8 T cells. Reconstitution of T cells specific for this and other HHV-6 epitopes was also observed after allogeneic hematopoietic stem cell transplantation. We conclude that HHV-6 induces CD8 T cell responses against multiple antigens of diverse functional classes. Most antigens against which CD8 T cells can be raised are presented by infected cells. Ex vivo multimer staining can directly identify HHV-6-specific T cells. These results will advance development of immune monitoring, adoptive T cell therapy, and vaccines. PMID- 29698480 TI - Type D personality, stress, coping and performance on a novel sport task. AB - We investigated (1) the relationship between Type D personality, stress intensity appraisal of a self-selected stressor, coping, and perceived coping effectiveness and (2) the relationship between Type D personality and performance. In study one, 482 athletes completed the Type D personality questionnaire (DS14), stress thermometer and MCOPE in relation to a recently experienced sport stressor. Type D was associated with increased levels of perceived stress and selection of coping strategies (more emotion and avoidance coping) as well as perceptions of their effectiveness. In study two, 32 participants completed a rugby league circuit task and were assessed on pre-performance anxiety, post-performance affect and coping. Type D was associated with poorer performance (reduced distance; more errors), decreases in pre-performance self-confidence and more use of maladaptive resignation/withdrawal coping. Findings suggest that Type D is associated with maladaptive coping and reduced performance. Type D individuals would benefit from interventions related to mood modification or enhancing interpersonal functioning. PMID- 29698481 TI - Mechanical unfolding reveals stable 3-helix intermediates in talin and alpha catenin. AB - Mechanical stability is a key feature in the regulation of structural scaffolding proteins and their functions. Despite the abundance of alpha-helical structures among the human proteome and their undisputed importance in health and disease, the fundamental principles of their behavior under mechanical load are poorly understood. Talin and alpha-catenin are two key molecules in focal adhesions and adherens junctions, respectively. In this study, we used a combination of atomistic steered molecular dynamics (SMD) simulations, polyprotein engineering, and single-molecule atomic force microscopy (smAFM) to investigate unfolding of these proteins. SMD simulations revealed that talin rod alpha-helix bundles as well as alpha-catenin alpha-helix domains unfold through stable 3-helix intermediates. While the 5-helix bundles were found to be mechanically stable, a second stable conformation corresponding to the 3-helix state was revealed. Mechanically weaker 4-helix bundles easily unfolded into a stable 3-helix conformation. The results of smAFM experiments were in agreement with the findings of the computational simulations. The disulfide clamp mutants, designed to protect the stable state, support the 3-helix intermediate model in both experimental and computational setups. As a result, multiple discrete unfolding intermediate states in the talin and alpha-catenin unfolding pathway were discovered. Better understanding of the mechanical unfolding mechanism of alpha helix proteins is a key step towards comprehensive models describing the mechanoregulation of proteins. PMID- 29698482 TI - Determining the minimum number of protein-protein interactions required to support known protein complexes. AB - The prediction of protein complexes from protein-protein interactions (PPIs) is a well-studied problem in bioinformatics. However, the currently available PPI data is not enough to describe all known protein complexes. In this paper, we express the problem of determining the minimum number of (additional) required protein protein interactions as a graph theoretic problem under the constraint that each complex constitutes a connected component in a PPI network. For this problem, we develop two computational methods: one is based on integer linear programming (ILPMinPPI) and the other one is based on an existing greedy-type approximation algorithm (GreedyMinPPI) originally developed in the context of communication and social networks. Since the former method is only applicable to datasets of small size, we apply the latter method to a combination of the CYC2008 protein complex dataset and each of eight PPI datasets (STRING, MINT, BioGRID, IntAct, DIP, BIND, WI-PHI, iRefIndex). The results show that the minimum number of additional required PPIs ranges from 51 (STRING) to 964 (BIND), and that even the four best PPI databases, STRING (51), BioGRID (67), WI-PHI (93) and iRefIndex (85), do not include enough PPIs to form all CYC2008 protein complexes. We also demonstrate that the proposed problem framework and our solutions can enhance the prediction accuracy of existing PPI prediction methods. ILPMinPPI can be freely downloaded from http://sunflower.kuicr.kyoto-u.ac.jp/~nakajima/. PMID- 29698483 TI - Magnitude and determinants of inadequate third-trimester weight gain in rural Bangladesh. AB - OBJECTIVES: The objective of this study was to estimate the magnitude and determinants of inadequate weight gain in the third-trimester among rural women in Matlab, Bangladesh. METHODS: The study analyzed data on weight gain in the third trimester in 1,883 pregnant women in Matlab, Bangladesh. All these women were admitted to Matlab hospital of the International Centre for Diarrhoeal Disease Research, Bangladesh (icddr,b) for childbirth during 2012-2014, and they had singleton live births at term. Data were retrieved from the electronic databases of Matlab Health and Demographic Surveillance System and Matlab hospital. A multivariable logistic regression for inadequate weight gain in the third trimester (<=4 kg) was built with sociodemographic, environmental and maternal factors as predictors. RESULTS: One thousand and twenty-six (54%) pregnant women had inadequate weight gain in the third trimester. In the multivariable model, short stature turned out to be the most robust risk factor for inadequate weight gain in the third trimester (OR = 2.5; 95% CI 1.8, 3.5 for short compared to tall women). Pre-third-trimester BMI was inversely associated with insufficient weight gain (OR = 0.96; 95% CI 0.93, 0.99 for 1 unit increase in BMI). Other risk factors for inadequate weight gain in the third trimester were advanced age (OR = 1.9; 95% CI 1.2, 3.1 for >=35 years compared to <=19 years), parity (OR = 1.5; 95% CI 1.2, 1.9 for multipara compared to nulliparous women), low socioeconomic status (OR = 1.7; 95% CI 1.2, 2.3 for women in the lowest compared to women in the highest wealth quintile), low level of education (OR = 1.6; 95% CI 1.2, 2.1 for <=5 years compared to >=10 years of education), belonging to the Hindu religious community (OR = 1.8; 95% CI 1.3, 2.5), consuming arsenic-contaminated water (OR = 1.4; 95% CI 1.1, 1.9), and conceiving during monsoon or dry season compared to summer (OR = 1.4; 95% CI 1.1, 1.8). CONCLUSIONS: Among rural Bangladeshi women in Matlab, third-trimester weight gain was in general poor. Maternal characteristics such as short stature, low BMI, advanced age, parity, low level of education and socioeconomic status, being Hindu, intake of arsenic contaminated water, and conceiving during monsoon or dry season were the risk factors for inadequate weight gain in the third trimester. Special attention should be given during prenatal care to women with the risk factors identified in this study. PMID- 29698484 TI - Rapid detection of Puccinia triticina causing leaf rust of wheat by PCR and loop mediated isothermal amplification. AB - Leaf rust of wheat caused by Puccinia triticina has significant impact on wheat production worldwide. Effective and quick detection methodologies are required to mitigate yield loss and time constraints associated with monitoring and management of leaf rust of wheat. In the present study, detection of P. triticina has been simplified by developing a rapid, reliable, efficient and visual colorimetric method i.e., loop mediated isothermal amplification of DNA (LAMP). Based on in silico analysis of P. triticina genome, PTS68, a simple sequence repeat was found highly specific to leaf rust fungus. A marker (PtRA68) was developed and its specificity was validated through PCR technique which gave a unique and sharp band of 919 bp in P. triticina pathotypes only. A novel gene amplification method LAMP which enables visual detection of pathogen by naked eye was developed for leaf rust pathogen. A set of six primers was designed from specific region of P. triticina and conditions were optimised to complete the observation process in 60 minutes at 65o C. The assay developed in the study could detect presence of P. triticina on wheat at 24 hpi (pre-symptomatic stage) which was much earlier than PCR without requiring thermal cycler. Sensitivity of LAMP assay developed in the study was 100 fg which was more sensitive than conventional PCR (50 pg) and equivalent to qPCR (100 fg). The protocol developed in the study was utilized for detection of leaf rust infected samples collected from different wheat fields. LAMP based colorimetric detection assay showed sky blue color in positive reaction and violet color in negative reaction after addition of 120 MUM hydroxyl napthol blue (HNB) solution to reaction mixture. Similarly, 0.6 mg Ethidium bromide/ml was added to LAMP products, placed on transilluminator to witness full brightness in positive reaction and no such brightness could be seen in negative reaction mixture. Further, LAMP products spread in a ladder like banding pattern in gel electrophoresis. Our assay is significantly faster than the conventional methods used in the identification of P. triticina. The assay developed in the study shall be very much useful in the development of diagnostic kit for monitoring disease, creation of prediction model and efficient management of disease. PMID- 29698485 TI - High relative risk of all-cause mortality attributed to smoking in China: Guangzhou Biobank Cohort Study. AB - BACKGROUND: Prediction of disease burden in China arising from smoking based on earlier cohorts in the West and China could not reflect the disease burden at the current stage accurately. No cohort studies in China focused specifically on people born since 1950. We examined the risk of all-cause mortality attributed to smoking in adults in Guangzhou, the city with the most rapidly expanding economy in China. METHODS AND FINDINGS: This population-based prospective cohort included 21,658 women and 8,284 men aged 50+ years enrolled from 2003-2008 and followed until January 2016. During an average follow-up of 8.8 (standard deviation = 1.8) years, 2,986 (1,586 women, 1,400 men) deaths were recorded. After adjustment for confounders, the hazards ratios (95% confidence interval (CI)) of all-cause mortality in current versus never smokers increased from 1.61 (95% CI 1.45-1.80) in those born in 1920-1939 to 2.02 (95% CI 1.74-2.34), and 4.40 (95% CI 3.14 6.17), in those born in the 1940s and 1950s, respectively (P for trend 0.009). CONCLUSIONS: In smokers born after 1949 in Guangzhou and other areas which have the longest history of smoking, the mortality risk could have reached three fold that of non-smokers, as in the UK, US and Australia. If confirmed, unless China quickly and strictly complies with the WHO Framework Convention on Tobacco Control with massive smoking cessation in the population, this is a more striking warning that China will be facing an even larger disease burden from tobacco use than previous forecasts. PMID- 29698486 TI - Review of the 2017 WHO Guideline: Preventive chemotherapy to control soil transmitted helminth infections in at-risk population groups. An opportunity lost in translation. PMID- 29698487 TI - Enhanced surveillance for Rift Valley Fever in livestock during El Nino rains and threat of RVF outbreak, Kenya, 2015-2016. AB - BACKGROUND: In mid-2015, the United States' Pandemic Prediction and Forecasting Science and Technical Working Group of the National Science and Technology Council, Food and Agriculture Organization Emergency Prevention Systems, and Kenya Meteorological Department issued an alert predicting a high possibility of El-Nino rainfall and Rift Valley Fever (RVF) epidemic in Eastern Africa. METHODOLOGY/PRINCIPAL FINDINGS: In response to the alert, the Kenya Directorate of Veterinary Services (KDVS) carried out an enhanced syndromic surveillance system between November 2015 and February 2016, targeting 22 RVF high-risk counties in the country as identified previously through risk mapping. The surveillance collected data on RVF-associated syndromes in cattle, sheep, goats, and camels from >1100 farmers through 66 surveillance officers. During the 14 week surveillance period, the KDVS received 10,958 reports from participating farmers and surveillance officers, of which 362 (3.3%) had at least one syndrome. The reported syndromes included 196 (54.1%) deaths in young livestock, 133 (36.7%) abortions, and 33 (9.1%) hemorrhagic diseases, with most occurring in November and December, the period of heaviest rainfall. Of the 69 herds that met the suspect RVF herd definition (abortion in flooded area), 24 (34.8%) were defined as probable (abortions, mortalities in the young ones, and/or hemorrhagic signs) but none were confirmed. CONCLUSION/SIGNIFICANCE: This surveillance activity served as an early warning system that could detect RVF disease in animals before spillover to humans. It was also an excellent pilot for designing and implementing syndromic surveillance in animals in the country, which is now being rolled out using a mobile phone-based data reporting technology as part of the global health security system. PMID- 29698488 TI - Hepatitis B and hepatitis D virus infections in the Central African Republic, twenty-five years after a fulminant hepatitis outbreak, indicate continuing spread in asymptomatic young adults. AB - Hepatitis delta virus (HDV) increases morbidity in Hepatitis B virus (HBV) infected patients. In the mid-eighties, an outbreak of HDV fulminant hepatitis (FH) in the Central African Republic (CAR) killed 88% of patients hospitalized in Bangui. We evaluated infections with HBV and HDV among students and pregnant women, 25 years after the fulminant hepatitis (FH) outbreak to determine (i) the prevalence of HBV and HDV infection in this population, (ii) the clinical risk factors for HBV and/or HDV infections, and (iii) to characterize and compare the strains from the FH outbreak in the 1980s to the 2010 HBV-HDV strains. We performed a cross sectional study with historical comparison on FH-stored samples (n = 179) from 159 patients and dried blood-spots from volunteer students and pregnant women groups (n = 2172). We analyzed risk factors potentially associated with HBV and HDV. Previous HBV infection (presence of anti-HBc) occurred in 345/1290 students (26.7%) and 186/870 pregnant women (21.4%)(p = 0.005), including 110 students (8.8%) and 71 pregnant women (8.2%), who were also HBsAg positive (p = 0.824). HDV infection occurred more frequently in pregnant women (n = 13; 18.8%) than students (n = 6; 5.4%) (p = 0.010). Infection in childhood was probably the main HBV risk factor. The risk factors for HDV infection were age (p = 0.040), transfusion (p = 0.039), and a tendency for tattooing (p = 0.055) and absence of condom use (p = 0.049). HBV-E and HDV-1 were highly prevalent during both the FH outbreak and the 2010 screening project. For historical samples, due to storage conditions and despite several attempts, we could only obtain partial HDV amplification representing 25% of the full-length genome. The HDV-1 mid eighties FH-strains did not form a specific clade and were affiliated to two different HDV-1 African subgenotypes, one of which also includes the 2010 HDV-1 strains. In the Central African Republic, these findings indicate a high prevalence of previous and current HBV-E and HDV-1 infections both in the mid eighties fulminant hepatitis outbreak and among asymptomatic young adults in 2010, and reinforce the need for universal HBV vaccination and the prevention of HDV transmission among HBsAg-positive patients through blood or sexual routes. PMID- 29698490 TI - Fusing metabolomics data sets with heterogeneous measurement errors. AB - Combining different metabolomics platforms can contribute significantly to the discovery of complementary processes expressed under different conditions. However, analysing the fused data might be hampered by the difference in their quality. In metabolomics data, one often observes that measurement errors increase with increasing measurement level and that different platforms have different measurement error variance. In this paper we compare three different approaches to correct for the measurement error heterogeneity, by transformation of the raw data, by weighted filtering before modelling and by a modelling approach using a weighted sum of residuals. For an illustration of these different approaches we analyse data from healthy obese and diabetic obese individuals, obtained from two metabolomics platforms. Concluding, the filtering and modelling approaches that both estimate a model of the measurement error did not outperform the data transformation approaches for this application. This is probably due to the limited difference in measurement error and the fact that estimation of measurement error models is unstable due to the small number of repeats available. A transformation of the data improves the classification of the two groups. PMID- 29698489 TI - Altered distribution of ATG9A and accumulation of axonal aggregates in neurons from a mouse model of AP-4 deficiency syndrome. AB - The hereditary spastic paraplegias (HSP) are a clinically and genetically heterogeneous group of disorders characterized by progressive lower limb spasticity. Mutations in subunits of the heterotetrameric (epsilon-beta4-MU4 sigma4) adaptor protein 4 (AP-4) complex cause an autosomal recessive form of complicated HSP referred to as "AP-4 deficiency syndrome". In addition to lower limb spasticity, this syndrome features intellectual disability, microcephaly, seizures, thin corpus callosum and upper limb spasticity. The pathogenetic mechanism, however, remains poorly understood. Here we report the characterization of a knockout (KO) mouse for the AP4E1 gene encoding the epsilon subunit of AP-4. We find that AP-4 epsilon KO mice exhibit a range of neurological phenotypes, including hindlimb clasping, decreased motor coordination and weak grip strength. In addition, AP-4 epsilon KO mice display a thin corpus callosum and axonal swellings in various areas of the brain and spinal cord. Immunohistochemical analyses show that the transmembrane autophagy related protein 9A (ATG9A) is more concentrated in the trans-Golgi network (TGN) and depleted from the peripheral cytoplasm both in skin fibroblasts from patients with mutations in the MU4 subunit of AP-4 and in various neuronal types in AP-4 epsilon KO mice. ATG9A mislocalization is associated with increased tendency to accumulate mutant huntingtin (HTT) aggregates in the axons of AP-4 epsilon KO neurons. These findings indicate that the AP-4 epsilon KO mouse is a suitable animal model for AP-4 deficiency syndrome, and that defective mobilization of ATG9A from the TGN and impaired autophagic degradation of protein aggregates might contribute to neuroaxonal dystrophy in this disorder. PMID- 29698492 TI - Evaluation of cell count and classification capabilities in body fluids using a fully automated Sysmex XN equipped with high-sensitive Analysis (hsA) mode and DI 60 hematology analyzer system. AB - The XN series automated hematology analyzer has been equipped with a body fluid (BF) mode to count and differentiate leukocytes in BF samples including cerebrospinal fluid (CSF). However, its diagnostic accuracy is not reliable for CSF samples with low cell concentration at the border between normal and pathologic level. To overcome this limitation, a new flow cytometry-based technology, termed "high sensitive analysis (hsA) mode," has been developed. In addition, the XN series analyzer has been equipped with the automated digital cell imaging analyzer DI-60 to classify cell morphology including normal leukocytes differential and abnormal malignant cells detection. Using various BF samples, we evaluated the performance of the XN-hsA mode and DI-60 compared to manual microscopic examination. The reproducibility of the XN-hsA mode showed good results in samples with low cell densities (coefficient of variation; % CV: 7.8% for 6 cells/MUL). The linearity of the XN-hsA mode was established up to 938 cells/MUL. The cell number obtained using the XN-hsA mode correlated highly with the corresponding microscopic examination. Good correlation was also observed between the DI-60 analyses and manual microscopic classification for all leukocyte types, except monocytes. In conclusion, the combined use of cell counting with the XN-hsA mode and automated morphological analyses using the DI 60 mode is potentially useful for the automated analysis of BF cells. PMID- 29698491 TI - Brief exposure to obesogenic diet disrupts brain dopamine networks. AB - OBJECTIVE: We have previously demonstrated that insulin signaling, through the downstream signaling kinase Akt, is a potent modulator of dopamine transporter (DAT) activity, which fine-tunes dopamine (DA) signaling at the synapse. This suggests a mechanism by which impaired neuronal insulin receptor signaling, a hallmark of diet-induced obesity, may contribute to impaired DA transmission. We tested whether a short-term (two-week) obesogenic high-fat (HF) diet could reduce striatal Akt activity, a marker of central insulin, receptor signaling and blunt striatal and dopaminergic network responsiveness to amphetamine (AMPH). METHODS: We examined the effects of a two-week HF diet on striatal DAT activity in rats, using AMPH as a probe in a functional magnetic resonance imaging (fMRI) assay, and mapped the disruption in AMPH-evoked functional connectivity between key dopaminergic targets and their projection areas using correlation and permutation analyses. We used phosphorylation of the Akt substrate GSK3alpha in striatal extracts as a measure of insulin receptor signaling. Finally, we confirmed the impact of HF diet on striatal DA D2 receptor (D2R) availability using [18F]fallypride positron emission tomography (PET). RESULTS: We found that rats fed a HF diet for only two weeks have reductions in striatal Akt activity, a marker of decreased striatal insulin receptor signaling and blunted striatal responsiveness to AMPH. HF feeding also reduced interactions between elements of the mesolimbic (nucleus accumbens-anterior cingulate) and sensorimotor circuits (caudate/putamen-thalamus-sensorimotor cortex) implicated in hedonic feeding. D2R availability was reduced in HF-fed animals. CONCLUSION: These studies support the hypothesis that central insulin signaling and dopaminergic neurotransmission are already altered after short-term HF feeding. Because AMPH induces DA efflux and brain activation, in large part via DAT, these findings suggest that blunted central nervous system insulin receptor signaling through a HF diet can impair DA homeostasis, thereby disrupting cognitive and reward circuitry involved in the regulation of hedonic feeding. PMID- 29698493 TI - One-step estimation of networked population size: Respondent-driven capture recapture with anonymity. AB - Size estimation is particularly important for populations whose members experience disproportionate health issues or pose elevated health risks to the ambient social structures in which they are embedded. Efforts to derive size estimates are often frustrated when the population is hidden or hard-to-reach in ways that preclude conventional survey strategies, as is the case when social stigma is associated with group membership or when group members are involved in illegal activities. This paper extends prior research on the problem of network population size estimation, building on established survey/sampling methodologies commonly used with hard-to-reach groups. Three novel one-step, network-based population size estimators are presented, for use in the context of uniform random sampling, respondent-driven sampling, and when networks exhibit significant clustering effects. We give provably sufficient conditions for the consistency of these estimators in large configuration networks. Simulation experiments across a wide range of synthetic network topologies validate the performance of the estimators, which also perform well on a real-world location based social networking data set with significant clustering. Finally, the proposed schemes are extended to allow them to be used in settings where participant anonymity is required. Systematic experiments show favorable tradeoffs between anonymity guarantees and estimator performance. Taken together, we demonstrate that reasonable population size estimates are derived from anonymous respondent driven samples of 250-750 individuals, within ambient populations of 5,000-40,000. The method thus represents a novel and cost effective means for health planners and those agencies concerned with health and disease surveillance to estimate the size of hidden populations. We discuss limitations and future work in the concluding section. PMID- 29698494 TI - IncGraph: Incremental graphlet counting for topology optimisation. AB - MOTIVATION: Graphlets are small network patterns that can be counted in order to characterise the structure of a network (topology). As part of a topology optimisation process, one could use graphlet counts to iteratively modify a network and keep track of the graphlet counts, in order to achieve certain topological properties. Up until now, however, graphlets were not suited as a metric for performing topology optimisation; when millions of minor changes are made to the network structure it becomes computationally intractable to recalculate all the graphlet counts for each of the edge modifications. RESULTS: IncGraph is a method for calculating the differences in graphlet counts with respect to the network in its previous state, which is much more efficient than calculating the graphlet occurrences from scratch at every edge modification made. In comparison to static counting approaches, our findings show IncGraph reduces the execution time by several orders of magnitude. The usefulness of this approach was demonstrated by developing a graphlet-based metric to optimise gene regulatory networks. IncGraph is able to quickly quantify the topological impact of small changes to a network, which opens novel research opportunities to study changes in topologies in evolving or online networks, or develop graphlet-based criteria for topology optimisation. AVAILABILITY: IncGraph is freely available as an open-source R package on CRAN (incgraph). The development version is also available on GitHub (rcannood/incgraph). PMID- 29698495 TI - The impact of high and low-intensity exercise in adolescents with movement impairment. AB - Five to six percent of young people have movement impairment (MI) associated with reduced exercise tolerance and physical activity levels which persist into adulthood. To better understand the exercise experience in MI, we determined the physiological and perceptual responses during and following a bout of exercise performed at different intensities typically experienced during sport in youth with MI. Thirty-eight adolescents (11-18 years) categorised on the Bruininks Oseretsky Test of Motor Proficiency-2 Short-Form performed a peak oxygen uptake bike test ([Formula: see text]) test at visit 1 (V1). At visits 2 (V2) and 3 (V3), participants were randomly assigned to both low-intensity (LI) 30min exercise at 50% peak power output (PPO50%) and high-intensity (HI) 30s cycling at PPO100%, interspersed with 30s rest, for 30min protocol (matched for total work). Heart rate (HR) and rating of perceived exertion (RPE) for legs, breathing and overall was measured before, during and at 1, 3 and 7-min post-exercise (P1, P3, P7). There was a significant difference in [Formula: see text] between groups (MI:31.5+/-9.2 vs. NMI:40.0+/-9.5ml?kg-1?min-1, p<0.05). PPO was significantly lower in MI group (MI:157+/-61 vs. NMI:216+/-57 W)(p<0.05). HRavg during HI cycling was reduced in MI (140+/-18 vs. 157+/-14bpm, p<0.05), but not LI (133+/ 18 vs. 143+/-17bpm, p>0.05). Both groups experienced similar RPE for breathing and overall (MI:7.0+/-3.0 vs. NMI:6.0+/-2.0, p>0.05) at both intensities, but reported higher legs RPE towards the end (p<0.01). Significant differences were found in HRrecovery at P1 post-HI (MI:128+/-25.9 vs. NMI:154+/-20.2, p<0.05) but not for legs RPE. Perceived fatigue appears to limit exercise in youth with MI in both high and low-intensity exercise types. Our findings suggest interventions reducing perceived fatigue during exercise may improve exercise tolerance and positively impact on engagement in physical activities. PMID- 29698496 TI - Frequency of exposure of endangered Caspian seals to Canine distemper virus, Leptospira interrogans, and Toxoplasma gondii. AB - Canine distemper virus (CDV), Leptospira interrogans, and Toxoplasma gondii are potentially lethal pathogens associated with decline in marine mammal populations. The Caspian Sea is home for the endangered Caspian seal (Pusa caspica). In the late 1990s and early 2000s, CDV caused a series of mortality events involving at least several thousand Caspian seals. To assess current infection status in Caspian seals, we surveyed for antibodies to three pathogens with potential to cause mortality in marine mammals. During 2015-2017, we tested serum samples from 36, apparently healthy, Caspian seals, accidentally caught in fishing nets in the Caspian Sea off Northern Iran, for antibodies to CDV, L. interrogans, and T. gondii, by virus neutralization, microscopic agglutination, and modified agglutination, respectively. Twelve (33%), 6 (17%), and 30 (83%) samples were positive for CDV, L. interrogans and T. gondii antibodies, respectively. The highest titers of CDV, L. interrogans, and T. gondii antibodies were 16, 400, and 50, respectively. Frequencies of antibody to these pathogens were higher in seals >1 year old compared to seals <1 year old. Two serovars of L. interrogans (Pomona and Canicola) were detected. Our results suggest a need for additional studies to clarify the impact of these pathogens on Caspian seal population decline and the improvement of management programs, including systematic screening to detect and protect the remaining population from disease outbreaks. PMID- 29698497 TI - Genetic structure of South African Nguni (Zulu) sheep populations reveals admixture with exotic breeds. AB - The population of Zulu sheep is reported to have declined by 7.4% between 2007 and 2011 due to crossbreeding. There is insufficient information on the genetic diversity of the Zulu sheep populations in the different area of KwaZulu Natal where they are reared. The study investigated genetic variation and genetic structure within and among eight Zulu sheep populations using 26 microsatellite markers. In addition, Damara, Dorper and South African Merino breeds were included to assess the genetic relationship between these breeds and the Zulu sheep. The results showed that there is considerable genetic diversity among the Zulu sheep populations (expected heterozygosity ranging from 0.57 to 0.69) and the level of inbreeding was not remarkable. The structure analysis results revealed that Makhathini Research Station and UNIZULU research station share common genetic structure, while three populations (Nongoma, Ulundi and Nquthu) had some admixture with the exotic Dorper breed. Thus, there is a need for sustainable breeding and conservation programmes to control the gene flow, in order to stop possible genetic dilution of the Zulu sheep. PMID- 29698498 TI - Psychophysiological responses of junior orienteers under competitive pressure. AB - The purpose of the study was to examine psychobiosocial states, cognitive functions, endocrine responses (i.e., salivary cortisol and chromogranin A), and performance under competitive pressure in orienteering athletes. The study was grounded in the individual zones of optimal functioning (IZOF) and biopsychosocial models. Fourteen junior orienteering athletes (7 girls and 7 boys), ranging in age from 15 to 20 years (M = 16.93, SD = 1.77) took part in a two-day competitive event. To enhance competitive pressure, emphasis was placed on the importance of the competition and race outcome. Psychophysiological and performance data were collected at several points before, during, and after the races. Results showed that an increase in cortisol levels was associated with competitive pressure and reflected in higher perceived exertion (day 1, r = .32; day 2, r = .46), higher intensity of dysfunctional states (day 1, r = .59; day 2, r = .55), lower intensity of functional states (day 1, r = -.36; day 2, r = .33), and decay in memory (day 1, r = -.27; day 2, r = -.35), visual attention (day 1, r = -.56; day 2, r = -.35), and attention/mental flexibility (day 1, r = .16; day 2, r = .26) tasks. The second day we observed better performance times, lower intensity of dysfunctional states, lower cortisol levels, improved visual attention and attention/mental flexibility (p < .050). Across the two competition days, chromogranin A levels were higher (p < .050) on the most difficult loops of the race in terms of both physical and psychological demands. Findings suggest emotional, cognitive, psychophysiological, and performance variables to be related and to jointly change across different levels of cognitive and physical load. Overall results are discussed in light of the IZOF and biopsychosocial models. The procedure adopted in the study also supports the feasibility of including additional cognitive load for possible practical applications. PMID- 29698499 TI - Less screen time and more frequent vigorous physical activity is associated with lower risk of reporting negative mental health symptoms among Icelandic adolescents. AB - OBJECTIVE: Few studies have explored the potential interrelated associations of screen time and physical activity with mental health in youth, particularly using objective methods. We examined cross-sectional associations of these variables among Icelandic adolescents, using objective and subjective measurements of physical activity. METHODS: Data were collected in the spring of 2015 from 315 tenth grade students (mean age 15.8 years) in six elementary schools in metropolitan Reykjavik, Iceland. Participants reported, via questionnaire, on demographics, weekly frequency of vigorous physical activity, daily hours of screen time and mental health status (symptoms of depression, anxiety and somatic complaints, self-esteem and life satisfaction). Total physical activity was measured over one week with wrist-worn accelerometers. Body composition was determined by DXA-scanning. Poisson regression analysis was used to explore independent and interactive associations of screen time and physical activity with mental health variables, adjusting for gender, body fat percentage and maternal education. RESULTS: Less screen time (below the group median of 5.3 h/day) and more frequent vigorous physical activity (>=4x/week) were each associated with reporting fewer symptoms of depression, anxiety, low self-esteem, and life dissatisfaction. No significant associations were observed between objectively measured physical activity and mental health outcomes. Interactive regression analysis showed that the group reporting both less screen time and more frequent vigorous physical activity had the lowest risk of reporting symptoms of depression, anxiety, low self-esteem, and life dissatisfaction. CONCLUSIONS: Reports of less screen time and more frequent vigorous physical activity were associated with lower risk of reporting mental health problems among Icelandic adolescents. Those who reported a combination of engaging in less screen time and more frequent vigorous physical activity had the lowest risk, suggesting a synergistic relationship between the two behaviors on mental health outcomes. Our results support guiding youth towards more active and less sedentary/screen-based lifestyle. PMID- 29698500 TI - A fully convolutional network for weed mapping of unmanned aerial vehicle (UAV) imagery. AB - Appropriate Site Specific Weed Management (SSWM) is crucial to ensure the crop yields. Within SSWM of large-scale area, remote sensing is a key technology to provide accurate weed distribution information. Compared with satellite and piloted aircraft remote sensing, unmanned aerial vehicle (UAV) is capable of capturing high spatial resolution imagery, which will provide more detailed information for weed mapping. The objective of this paper is to generate an accurate weed cover map based on UAV imagery. The UAV RGB imagery was collected in 2017 October over the rice field located in South China. The Fully Convolutional Network (FCN) method was proposed for weed mapping of the collected imagery. Transfer learning was used to improve generalization capability, and skip architecture was applied to increase the prediction accuracy. After that, the performance of FCN architecture was compared with Patch_based CNN algorithm and Pixel_based CNN method. Experimental results showed that our FCN method outperformed others, both in terms of accuracy and efficiency. The overall accuracy of the FCN approach was up to 0.935 and the accuracy for weed recognition was 0.883, which means that this algorithm is capable of generating accurate weed cover maps for the evaluated UAV imagery. PMID- 29698501 TI - Association of Raynaud's phenomenon with a polymorphism in the NOS1 gene. AB - BACKGROUND: Raynaud's phenomenon (RP) describes the phenomenon of recurrent vasospasm of digital arteries, associated with skin colour changes: pallor, cyanosis and erythema. Twin studies have indicated a genetic predisposition for RP; however, the precise aetiology of RP remains unknown. It is thought that genetic variation in temperature-responsive or vasospastic genes might underlie RP so performed a candidate gene study in a large, population based sample. We assessed the association between RP and single nucleotide polymorphisms (SNPs) in the TRPA1, TRPM8, CALCA, CALCB and NOS1 genes. METHODS: Analysis included a total of 4276 individuals from the TwinsUK database. RP status had been determined using validated, self-administered questionnaires and was diagnosed in 640 individuals (17.6%). 66 tag SNPs across the candidate genes were tested for association with RP status using a linear regression model, accounting for covariates. Adjustment was made for multiple testing. RegulomeDB and GTEx databases were used to assess possible functional effects of the polymorphisms. RESULTS: Nominally significant associations between RP and four SNPs in NOS1 and one in CALCB were identified. After permutation testing, rs527590 SNP in NOS1 passed the significance threshold. RegulomeDB scores indicated an unlikely functional effect of this variant, while the survey of the GTEx database found the SNP and several variants in linkage disequilibrium to be cis-eQTLs in skin. CONCLUSION: Results indicate that RP is associated with variation in gene NOS1. This finding may be related to the observation that the significant SNP in NOS1 is known to exhibit functional influence on the gene expression. PMID- 29698502 TI - Factors affecting the number and type of student research products for chemistry and physics students at primarily undergraduate institutions: A case study. AB - For undergraduate students, involvement in authentic research represents scholarship that is consistent with disciplinary quality standards and provides an integrative learning experience. In conjunction with performing research, the communication of the results via presentations or publications is a measure of the level of scientific engagement. The empirical study presented here uses generalized linear mixed models with hierarchical bootstrapping to examine the factors that impact the means of dissemination of undergraduate research results. Focusing on the research experiences in physics and chemistry of undergraduates at four Primarily Undergraduate Institutions (PUIs) from 2004-2013, statistical analysis indicates that the gender of the student does not impact the number and type of research products. However, in chemistry, the rank of the faculty advisor and the venue of the presentation do impact the number of research products by undergraduate student, whereas in physics, gender match between student and advisor has an effect on the number of undergraduate research products. This study provides a baseline for future studies of discipline-based bibliometrics and factors that affect the number of research products of undergraduate students. PMID- 29698503 TI - Gene expression profiles of immune-regulatory genes in whole blood of cattle with a subclinical infection of Mycobacterium avium subsp. paratuberculosis. AB - Johne's disease is a chronic wasting disease of ruminants caused by Mycobacterium avium subsp. paratuberculosis (MAP), resulting in inflammation of intestines and persistent diarrhea. The initial host response against MAP infections is mainly regulated by the Th1 response, which is characterized by the production of IFN gamma. With the progression of disease, MAP can survive in the host through the evasion of the host's immune response by manipulating the host immune response. However, the host response during subclinical phases has not been fully understood. Immune regulatory genes, including Th17-derived cytokines, interferon regulatory factors, and calcium signaling-associated genes, are hypothesized to play an important role during subclinical phases of Johne's disease. Therefore, the present study was conducted to analyze the expression profiles of immune regulatory genes during MAP infection in whole blood. Different expression patterns of genes were identified depending on the infection stages. Downregulation of IL-17A, IL-17F, IL-22, IL-26, HMGB1, and IRF4 and upregulation of PIP5K1C indicate suppression of the Th1 response due to MAP infection and loss of granuloma integrity. In addition, increased expression of IRF5 and IRF7 suggest activation of IFN-alpha/beta signaling during subclinical stages, which induced indoleamine 2,3-dioxygenase mediated depletion of tryptophan metabolism. Increased expression of CORO1A indicate modulation of calcium signaling, which enhanced the survival of MAP. Taken together, distinct host gene expression induced by MAP infection indicates enhanced survival of MAP during subclinical stages. PMID- 29698504 TI - Addressing the most neglected diseases through an open research model: The discovery of fenarimols as novel drug candidates for eumycetoma. AB - Eumycetoma is a chronic infectious disease characterized by a large subcutaneous mass, often caused by the fungus Madurella mycetomatis. A combination of surgery and prolonged medication is needed to treat this infection with a success rate of only 30%. There is, therefore, an urgent need to find more effective drugs for the treatment of this disease. In this study, we screened 800 diverse drug-like molecules and identified 215 molecules that were active in vitro. Minimal inhibitory concentrations were determined for the 13 most active compounds. One of the most potent compounds, a fenarimol analogue for which a large analogue library is available, led to the screening of an additional 35 compounds for their in vitro activity against M. mycetomatis hyphae, rendering four further hit compounds. To assess the in vivo potency of these hit compounds, a Galleria mellonella larvae model infected with M. mycetomatis was used. Several of the compounds identified in vitro demonstrated promising efficacy in vivo in terms of prolonged larval survival and/or reduced fungal burden. The results presented in this paper are the starting point of an Open Source Mycetoma (MycetOS) approach in which members of the global scientific community are invited to participate and contribute as equal partners. We hope that this initiative, coupled with the promising new hits we have reported, will lead to progress in drug discovery for this most neglected of neglected tropical diseases. PMID- 29698505 TI - Estimation of community-level influenza-associated illness in a low resource rural setting in India. AB - OBJECTIVE: To estimate rates of community-level influenza-like-illness (ILI) and influenza-associated ILI in rural north India. METHODS: During 2011, we conducted household-based healthcare utilization surveys (HUS) for any acute medical illness (AMI) in preceding 14days among residents of 28villages of Ballabgarh, in north India. Concurrently, we conducted clinic-based surveillance (CBS) in the area for AMI episodes with illness onset <=3days and collected nasal and throat swabs for influenza virus testing using real-time polymerase chain reaction. Retrospectively, we applied ILI case definition (measured/reported fever and cough) to HUS and CBS data. We attributed 14days of risk-time per person surveyed in HUS and estimated community ILI rate by dividing the number of ILI cases in HUS by total risk-time. We used CBS data on influenza positivity and applied it to HUS-based community ILI rates by age, month, and clinic type, to estimate the community influenza-associated ILI rates. FINDINGS: The HUS of 69,369 residents during the year generated risk-time of 3945 person-years (p-y) and identified 150 (5%, 95%CI: 4-6) ILI episodes (38 ILI episodes/1,000 p-y; 95% CI 32-44). Among 1,372 ILI cases enrolled from clinics, 126 (9%; 95% CI 8-11) had laboratory confirmed influenza (A (H3N2) = 72; B = 54). After adjusting for age, month, and clinic type, overall influenza-associated ILI rate was 4.8/1,000 p-y; rates were highest among children <5 years (13; 95% CI: 4-29) and persons>=60 years (11; 95%CI: 2-30). CONCLUSION: We present a novel way to use HUS and CBS data to generate estimates of community burden of influenza. Although the confidence intervals overlapped considerably, higher point estimates for burden among young children and older adults shows the utility for exploring the value of influenza vaccination among target groups. PMID- 29698506 TI - External validation of the NOBLADS score, a risk scoring system for severe acute lower gastrointestinal bleeding. AB - BACKGROUND: We aimed to evaluate the generalizability of NOBLADS, a severe lower gastrointestinal bleeding (LGIB) prediction model which we had previously derived when working at a different institution, using an external validation cohort. NOBLADS comprises the following factors: non-steroidal anti-inflammatory drug use, no diarrhea, no abdominal tenderness, blood pressure <= 100 mmHg, antiplatelet drug use, albumin < 3.0 g/dL, disease score >= 2, and syncope. METHODS: We retrospectively analyzed 511 patients emergently hospitalized for acute LGIB at the University of Tokyo Hospital, from January 2009 to August 2016. The areas under the receiver operating characteristic curves (ROCs-AUCs) for severe bleeding (continuous and/or recurrent bleeding) were compared between the original derivation cohort and the external validation cohort. RESULTS: Severe LGIB occurred in 44% of patients. Several clinical factors were significantly different between the external and derivation cohorts (p < 0.05), including background, laboratory data, NOBLADS scores, and diagnosis. The NOBLADS score predicted the severity of LGIB with an AUC value of 0.74 in the external validation cohort and one of 0.77 in the derivation cohort. In the external validation cohort, the score predicted the risk for blood transfusion need (AUC, 0.71), but was not adequate for predicting intervention need (AUC, 0.54). The in hospital mortality rate was higher in patients with a score >= 5 than in those with a score < 5 (AUC, 0.83). CONCLUSIONS: Although the external validation cohort clinically differed from the derivation cohort in many ways, we confirmed the moderately high generalizability of NOBLADS, a clinical risk score for severe LGIB. Appropriate triage using this score may support early decision-making in various hospitals. PMID- 29698508 TI - Viewpoint on the review by Savioli and colleagues on the 2017 WHO guideline on soil-transmitted helminth infections in at-risk population groups. PMID- 29698507 TI - Altered dopaminergic regulation of the dorsal striatum is able to induce tic-like movements in juvenile rats. AB - Motor tics are sudden, repetitive, involuntary movements representing the hallmark behaviors of the neurodevelopmental disease Tourette's syndrome (TS). The primary cause of TS remains unclear. The initial observation that dopaminergic antagonists alleviate tics led to the development of a dopaminergic theory of TS etiology which is supported by post mortem and in vivo studies indicating that non-physiological activation of the striatum could generate tics. The striatum controls movement execution through the balanced activity of dopamine receptor D1 and D2-expressing medium spiny neurons of the direct and indirect pathway, respectively. Different neurotransmitters can activate or repress striatal activity and among them, dopamine plays a major role. In this study we introduced a chronic dopaminergic alteration in juvenile rats, in order to modify the delicate balance between direct and indirect pathway. This manipulation was done in the dorsal striatum, that had been associated with tic like movements generation in animal models. The results were movements resembling tics, which were categorized and scored according to a newly developed rating scale and were reduced by clonidine and riluzole treatment. Finally, post mortem analyses revealed altered RNA expression of dopaminergic receptors D1 and D2, suggesting an imbalanced dopaminergic regulation of medium spiny neuron activity as being causally related to the observed phenotype. PMID- 29698509 TI - MicroRNA-425 and microRNA-155 cooperatively regulate atrial natriuretic peptide expression and cGMP production. AB - AIMS: Atrial natriuretic peptide (ANP), secreted primarily by atrial cardiomyocytes, decreases blood pressure by raising cyclic 3',5'-guanosine monophosphate (cGMP) levels and inducing vasorelaxation, natriuresis, and diuresis. Raising the level of ANP has been shown to be an effective treatment for hypertension. To advance the future development of an anti-microRNA (miR) approach to increasing expression of ANP, we investigated the regulation of NPPA expression by two miRs: miR-425 and miR-155. We examined whether miR-425 and miR 155 have an additive effect on the expression and function of ANP. METHODS AND RESULTS: Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) were transfected with miR-425, miR-155, or a combination of the two miRs. Two days later, NPPA expression was measured using real time qPCR. Each of the miRs decreased NPPA expression over a wide range of concentrations, with a significant reduction at concentrations as low as 1 nM. The combination of miR-425 and miR 155 reduced NPPA expression to a greater extent than either miR-425 or miR-155 alone. An in vitro assay was developed to study the potential biological significance of the miR-induced decrease in NPPA expression. The cooperative effect of miR-425 and miR-155 on NPPA expression was associated with a significant decrease in cGMP levels. CONCLUSIONS: These data demonstrate that miR 425 and miR-155 regulate NPPA expression in a cooperative manner. Targeting both miRNAs with anti-miRs (possibly at submaximal concentrations) might prove to be a more effective strategy to modulate ANP levels, and thus blood pressure, than targeting either miRNA alone. PMID- 29698510 TI - ELISA method to detect alpha-synuclein oligomers in cell and animal models. AB - Soluble aggregates of alpha-synuclein, so-called oligomers, are hypothesized to act as neurotoxic species in Parkinson's disease, Lewy body dementia and multiple systems atrophy, but specific tools to detect these aggregated species are only slowly appearing. We have developed an alpha-synuclein oligomer ELISA that allows us to detect and compare alpha-synuclein oligomer levels in different in vivo and in vitro experiments. The ELISA is based on commercially available antibodies and the epitope of the capture antibody MJF14-6-4-2 is folding- and aggregate dependent and not present on monomers. PMID- 29698511 TI - Skin thickness as a potential marker of gestational age at birth despite different fetal growth profiles: A feasibility study. AB - BACKGROUND: New methodologies to estimate gestational age (GA) at birth are demanded to face the limited access to obstetric ultrasonography and imprecision of postnatal scores. The study analyzed the correlation between neonatal skin thickness and pregnancy duration. Secondarily, it investigated the influence of fetal growth profiles on tissue layer dimensions. METHODS AND FINDINGS: In a feasibility study, 222 infants selected at a term-to-preterm ratio of 1:1 were assessed. Reliable information on GA was based on the early ultrasonography-based reference. The thicknesses of the epidermal and dermal skin layers were examined using high-frequency ultrasonography. We scanned the skin over the forearm and foot plantar surface of the newborns. A multivariate regression model was adjusted to determine the correlation of GA with skin layer dimensions. The best model to correlate skin thickness with GA was fitted using the epidermal layer on the forearm site, adjusted to cofactors, as follows: Gestational age (weeks) = 28.0 + 12.8 Ln (Thickness) - 4.4 Incubator staying; R2 = 0.604 (P<0.001). In this model, the constant value for the standard of fetal growth was statistically null. The dermal layer thickness on the forearm and plantar surfaces had a negative moderate linear correlation with GA (R = -0.370, P<0.001 and R = -0.421, P<0.001, respectively). The univariate statistical analyses revealed the influence of underweight and overweight profiles on neonatal skin thickness at birth. Of the 222 infants, 53 (23.9%) had inappropriate fetal growths expected for their GA. Epidermal thickness was not fetal growth standard dependent as follows: 172.2 (19.8) MUm for adequate for GA, 171.4 (20.6) MUm for SGA, and 177.7 (15.2) MUm for LGA (P = 0.525, mean [SD] on the forearm). CONCLUSIONS: The analysis highlights a new opportunity to relate GA at birth to neonatal skin layer thickness. As this parameter was not influenced by the standard of fetal growth, skin maturity can contribute to clinical applications. PMID- 29698512 TI - Multiplexed bovine milk oligosaccharide analysis with aminoxy tandem mass tags. AB - Milk oligosaccharides (OS) are a key factor that influences the infant gut microbial composition, and their importance in promoting healthy infant development and disease prevention is becoming increasingly apparent. Investigating the structures, properties, and sources of these compounds requires a host of complementary analytical techniques. Relative compound quantification by mass spectral analysis of isobarically labeled samples is a relatively new technique that has been used mainly in the proteomics field. Glycomics applications have so far focused on analysis of protein-linked glycans, while analysis of free milk OS has previously been conducted only on analytical standards. In this paper, we extend the use of isobaric glycan tags to the analysis of bovine milk OS by presenting a method for separation of labeled OS on a porous graphitized carbon liquid chromatographic column with subsequent analysis by quadrupole time-of-flight tandem mass spectrometry. Abundances for 15 OS extracted from mature bovine milk were measured, with replicate injections providing coefficients of variation below 15% for most OS. Isobaric labeling improved ionization efficiency for low-abundance, high-molecular weight fucosylated OS, which are known to exist in bovine milk but have been only sporadically reported in the literature. We compared the abundances of four fucosylated OS in milk from Holstein and Jersey cattle and found that three of the compounds were more abundant in Jersey milk, which is in general agreement with a previous study. This novel method represents an advancement in our ability to characterize milk OS and provides the advantages associated with isobaric labeling, including reduced instrumental analysis time and increased analyte ionization efficiency. This improved ability to measure differences in bioactive OS abundances in large datasets will facilitate exploration of OS from all food sources for the purpose of developing health-guiding products for infants, immune compromised elderly, and the population at large. PMID- 29698513 TI - Complications and risk management in the use of the reaming-irrigator-aspirator (RIA) system: RIA is a safe and reliable method in harvesting autologous bone graft. AB - BACKGROUND: Autologous bone grafting (ABG) remains the gold standard for augmentation of bone defects. The RIA system has become more prevalent, but evidence regarding risk management and complications remain scarce. This study presents the risk management and complications associated with RIA in the largest single-center case series to date. METHODS: All records, operative notes, lab data and radiographs of patients receiving a RIA procedure at Heidelberg's University Hospital between 01/01/2010 and 31/12/2016 were reviewed. Multivariate logistic regression models adjusting for clinically relevant covariates were used to examine the respective relevance regarding the presence and absence of prolonged postoperative pain (PPP). RESULTS: A total of 341 RIA procedures on 306 patients were performed at our level-1 trauma center. The femur was the main donor site (98.53%; N = 336) whereas only in 1.47% (N = 5) the tibia was utilized. A total of 11 patients showed a relevant loss of hemoglobin requiring blood transfusion. A total of 22 patients suffered from PPP directly associated with the RIA procedure resulting in prevalence of 6.45%. The 6 major complications in our study were of diverse origin and all intraoperative complications took place in the early phase of the RIA procedure in our center (2010-2013). Our data revealed influence of sex (p = 0.0459) and age (p = 0.0596) on the criterion PPP. The favored model including sex and age resulted in an AUC of 66.2% (CI: 55.5%-76.9%). CONCLUSION: Perioperative blood loss remains a prevalent complication during RIA reaming. In addition, PPP occurs with a prevalence of 6.45%. This study showed a complication rate of 1.76%, emphasizing RIA's overall safety and furthermore highlighting the need for vigilance in its application and prior extensive hands-on training of surgeons. Level of Evidence: II. PMID- 29698514 TI - Medroxyprogesterone acetate, unlike norethisterone, increases HIV-1 replication in human peripheral blood mononuclear cells and an indicator cell line, via mechanisms involving the glucocorticoid receptor, increased CD4/CD8 ratios and CCR5 levels. AB - High usage of progestin-only injectable contraceptives, which include the intramuscular injectables depo-medroxyprogesterone acetate (DMPA-IM, Depo Provera) and norethisterone (NET) enanthate (NET-EN or Nur-Isterate), correlates worldwide with areas of high HIV-1 prevalence. Epidemiological data show a significant association between usage of DMPA-IM and increased HIV-1 acquisition but no such association from limited data for NET-EN. Whether MPA and NET have similar effects on HIV-1 acquisition and pathogenesis, and the relationship between these effects and the dose of MPA, are critical issues for women's health and access to suitable and safe contraceptives. We show for the first time that MPA, unlike NET, significantly increases HIV-1 replication in peripheral blood mononuclear cells (PBMCs) and a cervical cell line model. The results provide novel evidence for a biological mechanism whereby MPA, acting via the glucocorticoid receptor (GR), increases HIV-1 replication by at least in part increasing expression of the CCR5 HIV-1 coreceptor on target T-lymphocytes. MPA, unlike NET, also increases activation of T-cells and increases the CD4/CD8 ratio, suggesting that multiple mechanisms are involved in the MPA response. Our data offer strong support for different biological mechanisms for MPA versus NET, due to their differential GR activity. The dose-dependence of the MPA response suggests that significant effects are observed within the range of peak serum levels of progestins in DMPA-IM but not NET-EN users. Dose-response results further suggest that effects of contraceptives containing MPA on HIV-1 acquisition and disease progression may be critically dependent on dose, time after injection and intrinsic factors that affect serum concentrations in women. PMID- 29698515 TI - Identification and characterization of a plastidial omega-3 fatty acid desaturase EgFAD8 from oil palm (Elaeis guineensis Jacq.) and its promoter response to light and low temperature. AB - In higher plants, omega-3 fatty acid desaturases are the key enzymes in the biosynthesis of alpha-linolenic acid (18:3), which plays key roles in plant metabolism as a structural component of both storage and membrane lipids. Here, the first omega-3 fatty acid desaturase gene was identified and characterized from oil palm. The bioinformatic analysis indicated it encodes a temperature sensitive chloroplast omega-3 fatty acid desaturase, designated as EgFAD8. The expression analysis revealed that EgFAD8 is highly expressed in the oil palm leaves, when compared with the expression in the mesocarp. The heterologous expression of EgFAD8 in yeast resulted in the production of a novel fatty acid 18:3 (about 0.27%), when fed with 18:2 in the induction culture. Furthermore, to detect whether EgFAD8 could be induced by the environment stress, we detected the expression efficiency of the EgFAD8 promoter in transgenic Arabidopsis treated with low temperature and darkness, respectively. The results indicated that the promoter of EgFAD8 gene could be significantly induced by low temperature and slightly induced by darkness. These results reveal the function of EgFAD8 and the feature of its promoter from oil palm fruits, which will be useful for understanding the fuction and regulation of plastidial omega-3 fatty acid desaturases in higher plants. PMID- 29698516 TI - How to combat emerging artemisinin resistance: Lessons from "The Three Little Pigs". AB - It is rare to come across an Aesop's fable in respectable journals. It might catch scientists outside the malaria field by surprise to learn that the famous story of "The Boy Who Cried Wolf" has been repeatedly compared to the threat from artemisinin-resistant malaria parasites, including the two latest reports on the rise of a specific haplotype in Cambodia and Thailand, sensationally dubbed "Super Malaria" by the media [1, 2]. The comparison to a children's tale should not negate the fact that malaria drug resistance is one of the most pressing threats to the global public health community. Here, the findings leading to this contentious discourse will be delineated in order to provide a perspective. Possible solutions will be presented to stimulate further research and discussion to solve one of the greatest public health challenges of our lifetime. PMID- 29698517 TI - Retraction: Percutaneous Aspiration Thrombectomy for Arterial Thromboembolism during Infrainguinal Endovascular Recanalization. PMID- 29698518 TI - Practical spectrophotometric assay for the dapE-encoded N-succinyl-L,L diaminopimelic acid desuccinylase, a potential antibiotic target. AB - A new enzymatic assay for the bacterial enzyme succinyl-diaminopimelate desuccinylase (DapE, E.C. 3.5.1.18) is described. This assay employs N6-methyl-N2 succinyl-L,L-diaminopimelic acid (N6-methyl-L,L-SDAP) as the substrate with ninhydrin used to detect cleavage of the amide bond of the modified substrate, wherein N6-methylation enables selective detection of the primary amine enzymatic product. Molecular modeling supported preparation of the mono-N6-methylated-L,L SDAP as an alternate substrate for the assay, given binding in the active site of DapE predicted to be comparable to the endogenous substrate. The alternate substrate for the assay, N6-methyl-L,L-SDAP, was synthesized from the tert-butyl ester of Boc-L-glutamic acid employing a Horner-Wadsworth-Emmons olefination followed by an enantioselective reduction employing Rh(I)(COD)(S,S)-Et-DuPHOS as the chiral catalyst. Validation of the new ninhydrin assay was demonstrated with known inhibitors of DapE from Haemophilus influenza (HiDapE) including captopril (IC50 = 3.4 [+/- 0.2] MUM, 3-mercaptobenzoic acid (IC50 = 21.8 [+/-2.2] MUM, phenylboronic acid (IC50 = 316 [+/- 23.6] MUM, and 2-thiopheneboronic acid (IC50 = 111 [+/- 16] MUM. Based on these data, this assay is simple and robust, and should be amenable to high-throughput screening, which is an important step forward as it opens the door to medicinal chemistry efforts toward the discovery of DapE inhibitors that can function as a new class of antibiotics. PMID- 29698519 TI - The loss of the kinases SadA and SadB results in early neuronal apoptosis and a reduced number of progenitors. AB - The neurons that form the mammalian neocortex originate from progenitor cells in the ventricular (VZ) and subventricular zone (SVZ). Newborn neurons are multipolar but become bipolar during their migration from the germinal layers to the cortical plate (CP) by forming a leading process and an axon that extends in the intermediate zone (IZ). Once they settle in the CP, neurons assume a highly polarized morphology with a single axon and multiple dendrites. The AMPK-related kinases SadA and SadB are intrinsic factors that are essential for axon formation during neuronal development downstream of Lkb1. The knockout of both genes encoding Sad kinases (Sada and Sadb) results not only in a loss of axons but also a decrease in the size of the cortical plate. The defect in axon formation has been linked to a function of Sad kinases in the regulation of microtubule binding proteins. However, the causes for the reduced size of the cortical plate in the Sada-/-;Sadb-/- knockout remain to be analyzed in detail. Here we show that neuronal cell death is increased and the number of neural progenitors is decreased in the Sada-/-;Sadb-/- CP. The reduced number of progenitors is a non cell autonomous defect since they do not express Sad kinases. These defects are restricted to the neocortex while the hippocampus remains unaffected. PMID- 29698520 TI - Correction: An International Consensus Definition of the Wish to Hasten Death and Its Related Factors. AB - [This corrects the article DOI: 10.1371/journal.pone.0146184.]. PMID- 29698521 TI - Positive experiences of volunteers working in deployable laboratories in West Africa during the Ebola outbreak. AB - The largest outbreak of Ebola virus disease ever started in West Africa in December 2013; it created a pressing need to expand the workforce dealing with it. The aim of this study was to gain insight into the experiences of volunteers from the European Union who worked in deployable laboratories in West Africa during the outbreak. This study is part of the EMERGE project. We assessed the experiences of 251 volunteers with a 19-item online questionnaire. The questions asked about positive aspects of volunteering such as learning new skills, establishing a new path in life, and changing life values. Other questionnaire subjects were the compliance to follow-up measures, the extent to which volunteers felt these measures restricted their daily activities, the fear of stigmatization, and worries about becoming infected or infecting their families. The volunteers reported positive effects that reached far beyond their daily work, such as changes in life priorities and a greater appreciation of the value of their own lives. Although the volunteers did not feel that temperature monitoring restricted their daily activities, full compliance to temperature monitoring and reporting it to the authorities was low. The volunteers did not fear Ebola infection for themselves or their families and were not afraid of stigmatization. With respect to the burden on the families, 50% reported that their family members were worried that the volunteer would be infected with Ebola virus. Altogether, the positive experiences of the volunteers in this study far outweigh the negative implications and constitute an important argument for inspiring people who intend to join such missions and for motivating the hesitant ones. PMID- 29698522 TI - Massively parallel sequencing of micro-manipulated cells targeting a comprehensive panel of disease-causing genes: A comparative evaluation of upstream whole-genome amplification methods. AB - Single Gene Disorders (SGD) are still routinely diagnosed using PCR-based assays that need to be developed and validated for each individual disease-specific gene fragment. The TruSight One sequencing panel currently covers 12 Mb of genomic content, including 4813 genes associated with a clinical phenotype. When only a limited number of cells are available, whole genome amplification (WGA) is required prior to DNA target capture techniques such as the TruSight One panel. In this study, we compared 4 different WGA methods in combination with the TruSight One sequencing panel to perform single nucleotide polymorphism (SNP) genotyping starting from 3 micro-manipulated cells. This setting simulates clinical settings such as day-5 blastocyst biopsy for Preimplantation Genetic Testing (PGT), liquid biopsy of circulating tumor cells (CTCs) and cancer-cell profiling. Bulk cell samples were processed alongside these WGA samples to serve as a performance reference. Target coverage, coverage uniformity and SNP calling accuracy obtained using any of the WGA, is inferior to the results obtained on bulk cell samples. However, results after REPLI-g come close. Compared to the other WGA methods, the method using REPLI-g WGA results in a better coverage of the targeted genomic regions with a more uniform read depth. Consequently, this method also results in a more accurate SNP calling and could be considered for clinical genotyping of a limited number of cells. PMID- 29698523 TI - Urine mercury levels correlate with DNA methylation of imprinting gene H19 in the sperm of reproductive-aged men. AB - BACKGROUND: Mercury (Hg) is a well-recognized environmental pollutant known by its toxicity of development and neurotoxicity, which results in adverse health outcomes. However, the mechanisms underlying the teratogenic effects of Hg are not well understood. Imprinting genes are emerging regulators for fetal development subjecting to environmental pollutants impacts. In this study, we examined the association between preconceptional Hg exposure and the alteration of DNA methylation of imprinting genes H19, Meg3, and Peg3 in human sperm DNA. METHODS: A total of 616 men, aged from 22 to 59, were recruited from Reproductive Medicine Clinic of Maternal and Child Care Service Center and the Urologic Surgery Clinic of Shanxi Academy of Medical Sciences during April 2015 and March 2016. Demographic information was collected through questionnaires. Urine was collected and urinary Hg concentrations were measured using a fully-automatic double-channel hydride generation atomic fluorescence spectrometer. Methylation of imprinting genes H19, Meg3 and Peg3 of sperm DNA from 242 participants were examined by bisulfite pyrosequencing. Spearman's rank and multivariate regression analysis were used for correlation analysis between sperm DNA methylation status of imprinting genes and urinary Hg levels. RESULTS: The median concentration of Hg for 616 participants was 9.14MUg/l (IQR: 5.56-12.52 MUg/l; ranging 0.16 71.35MUg/l). A total of 42.7% of the participants are beyond normal level for non occupational exposure according to the criterion of Hg poisoning (>=10 MUg/L). Spearman's rank analysis indicated a negative correlation between urinary Hg concentrations and average DNA methylation levels of imprinted genes H19 (rs = 0.346, p <0.05), but there was no such a correlation for Peg3 and Meg3. Further, we analyzed the correlation between methylation level at individual CpG site of H19 and urinary Hg level. The results showed a negative correlation between urinary Hg concentrations and three out of seven CpG sites on H19 DMR, namely CpG2 (rs = -0.137, p <0.05), CpG4 (rs = -0.380, p <0.05) and CpG6 (rs = -0.228, p <0.05). After adjusting age, smoking, drinking, intake of aquatic products and education by multivariate regression analysis, the results have confirmed the correlation as mentioned above. CONCLUSIONS: Mercury non-occupational environmental exposure in reproductive-aged men was associated with altered DNA methylation outcomes at imprinting gene H19 in sperm, implicating the susceptibility of the developing sperm for environmental insults. PMID- 29698524 TI - Dental color measurement to predict DNA concentration in incinerated teeth for human identification. AB - Teeth exposed to thermal stress can shed light on the identification of incinerated individuals and on the circumstances of the fire. Changes in the color of burned teeth can provide information on structural changes and the temperature of exposure. The objective of this study was to correlate color modifications with the concentration of human DNA in teeth burned at different temperatures. Spectrophotometry was used to measure the color of 40 teeth heated at temperatures of 100, 200, and 400 degrees C for 60 min. DNA was extracted by phenol-chloroform extraction and quantified by real-time quantitative PCR using the Quantifier human DNA quantification kit. Preliminary results indicated an association of higher temperature with changes in colorimetric variables and a decrease in DNA concentrations. A significant positive correlation was found between luminosity values and DNA concentration (r = 0.4727, p = 0.0128) and between chromaticity a* values and DNA concentration (r = 0.4154, p = 0.0250). Spectrophotometry analysis of the color of burned teeth may predict the feasibility of extracting human DNA for identification purposes. PMID- 29698525 TI - Definition of intercultural competence (IC) in undergraduate students at a private university in the USA: A mixed-methods study. AB - INTRODUCTION: Intercultural competence (IC) is an important skill to be gained from higher education. However, it remains unclear what IC means to students and what factors might influence their definitions of IC. The aim of the current study was to qualitatively assess how students at one higher education institution in the USA define IC and to quantitatively test for relationships among IC components and various demographic characteristics, including intercultural experience and study context. A further aim was to descriptively compare the IC definitions from the US sample with the definitions obtained from another sample of university students in Germany. MATERIALS AND METHODS: A purposive sample of n = 93 undergraduate, second semester students at Dickinson College, USA, participated in the study by completing an online questionnaire. The qualitative data were content-analyzed to define the dimensions of IC. The quantitative data were cluster-analyzed to assess the multivariate relationships among the IC components and the demographic characteristics of the sample. RESULTS: The most important dimensions of IC were Knowledge, External Outcomes (interaction, communication), and Attitudes (respect, tolerance) according to the US sample. The most frequently chosen dimensions of IC differed between both samples: Knowledge was chosen by the sample in the USA while External Outcomes was chosen by the sample in Germany. Relative to the US sample, significantly more students chose Attitudes, External Outcomes, and Intrapersonal Skills in the sample in Germany. The relationships among IC components and demographic characteristics were only weak in the US sample. A person with IC was rated as Open-minded and Respectful by students who lived predominantly in the USA or Tolerant and Curious by those who lived outside the USA for at least six months. DISCUSSION: The current results suggest that students residing in two countries (USA or Germany) define IC using similar dimensions. However, IC definitions may depend on the intercultural experience and the current global discourse. Longitudinal studies with representative samples are required to assess how IC definitions change over time. PMID- 29698526 TI - Comparison of fruit organic acids and metabolism-related gene expression between Cerasus humilis (Bge.) Sok and Cerasus glandulosa (Thunb.) Lois. AB - Cerasus humilis (Bge.) Sok and Cerasus glandulosa (Thunb.) Lois are economically important fruit-producing shrubs. Although these two species have similar looking fruits, their fruit organic acid contents differ drastically. In this study, we focused on comparing the organic acid content, activity of enzymes gene expression involved in organic acid metabolism in both C. humilis and C. glandulosa fruits. To investigate the differences of organic acid metabolism in fruits of these two species, a comparative transcriptome analysis was performed. Our results showed that temporal changes of two main organic acids exhibited different trends in these two species. Transcriptome sequencing of developing C. humilis and C. glandulosa fruits systematically revealed 6,594 differentially expressed genes. Compared with C. humilis, the expression levels of 3,469 and 3,125 genes were up- and down-regulated in C. glandulosa, respectively, including one PEPC gene, 12 malic acid metabolism genes, 25 citric acid cycle genes, and 194 NAD/NADP metabolism genes. The correlation analysis and principal component analysis of gene expression, enzymatic activity and organic acid content showed that differences in the expression of genes encoding the NAD-malate dehydrogenase (NAD-MDH) and NADP-malate enzyme (NADP-ME) contributed substantially to the observed differences in organic acid accumulation of two species. Our results provide a solid foundation for future elucidation of key mechanisms regulating organic acid biosynthesis in C. humilis and C. glandulosa fruits and could lead to efficient and highly targeted generation of more commercially accepted cultivars. PMID- 29698528 TI - Correction: Microsomal prostaglandin E synthase-1 gene deletion impairs neuro immune circuitry of the cholinergic anti-inflammatory pathway in endotoxaemic mouse spleen. AB - [This corrects the article DOI: 10.1371/journal.pone.0193210.]. PMID- 29698527 TI - Effect of phenolic extracts from different extra-virgin olive oil varieties on osteoblast-like cells. AB - The reported incidence of osteoporosis is lower in countries in which the Mediterranean diet predominates, and this apparent relationship may be mediated by the phenolic compounds present in olive oil. The objective of this study was to determine the effect of phenolic extracts from different varieties of extra virgin olive oil (Picual, Arbequina, Picudo, and Hojiblanca) on the differentiation, antigenic expression, and phagocytic capacity of osteoblast-like MG-63 cells. At 24 h of treatment a significant increase in phosphatase alkaline activity and significant reductions in CD54, CD80, and HLA-DR expression and in phagocytic activity were observed in comparison to untreated controls. The in vitro study performed has demonstrated that phenolic compounds from different extra virgin olive oil varieties can modulate different parameters related to osteoblast differentiation and function. PMID- 29698529 TI - Nucleated red blood cells: Immune cell mediators of the antiviral response. PMID- 29698531 TI - Correction: Sequence, genome organization, annotation and proteomics of the thermophilic, 47.7-kb Geobacillus stearothermophilus bacteriophage TP-84 and its classification in the new Tp84virus genus. AB - [This corrects the article DOI: 10.1371/journal.pone.0195449.]. PMID- 29698532 TI - Correction: A novel encryption scheme for high-contrast image data in the Fresnelet domain. AB - [This corrects the article DOI: 10.1371/journal.pone.0194343.]. PMID- 29698530 TI - Differentially expressed microRNAs associated with changes of transcript levels in detoxification pathways and DDT-resistance in the Drosophila melanogaster strain 91-R. AB - Dichloro-diphenyl-trichloroethane (DDT) resistance among arthropod species is a model for understanding the molecular adaptations in response to insecticide exposures. Previous studies reported that DDT resistance may involve one or multiple detoxification genes, such as cytochrome P450 monooxygenases (P450s), glutathione S-transferases (GSTs), esterases, and ATP binding cassette (ABC) transporters, or changes in the voltage-sensitive sodium channel. However, the possible involvement of microRNAs (miRNAs) in the post-transcriptional regulation of genes associated with DDT resistance in the Drosophila melanogaster strain 91 R remains poorly understood. In this study, the majority of the resulting miRNAs discovered in small RNA libraries from 91-R and the susceptible control strain, 91-C, ranged from 16-25 nt, and contained 163 precursors and 256 mature forms of previously-known miRNAs along with 17 putative novel miRNAs. Quantitative analyses predicted the differential expression of ten miRNAs between 91-R and 91 C, and, based on Gene Ontology and pathway analysis, these ten miRNAs putatively target transcripts encoding proteins involved in detoxification mechanisms. RT qPCR validated an inverse correlation between levels of differentially-expressed miRNAs and their putatively targeted transcripts, which implies a role of these miRNAs in the differential regulation of detoxification pathways in 91-R compared to 91-C. This study provides evidence associating the differential expression of miRNAs in response to multigenerational DDT selection in Drosophila melanogaster and provides important clues for understanding the possible roles of miRNAs in mediating insecticide resistance traits. PMID- 29698533 TI - Classification-driven framework to predict maize hybrid field performance from metabolic profiles of young parental roots. AB - Maize (Zea mays L.) is a staple food whose production relies on seed stocks that largely comprise hybrid varieties. Therefore, knowledge about the molecular determinants of hybrid performance (HP) in the field can be used to devise better performing hybrids to address the demands for sustainable increase in yield. Here, we propose and test a classification-driven framework that uses metabolic profiles from in vitro grown young roots of parental lines from the Dent * Flint maize heterotic pattern to predict field HP. We identify parental analytes that best predict the metabolic inheritance patterns in 328 hybrids. We then demonstrate that these analytes are also predictive of field HP (0.64 >= r >= 0.79) and discriminate hybrids of good performance (accuracy of 87.50%). Therefore, our approach provides a cost-effective solution for hybrid selection programs. PMID- 29698534 TI - Impact of different biologically-adapted radiotherapy strategies on tumor control evaluated with a tumor response model. AB - Motivated by the capabilities of modern radiotherapy techniques and by the recent developments of functional imaging techniques, dose painting by numbers (DPBN) was proposed to treat tumors with heterogeneous biological characteristics. This work studies different DPBN optimization techniques for virtual head and neck tumors assessing tumor response in terms of cell survival and tumor control probability with a previously published tumor response model (TRM). Uniform doses of 2 Gy are redistributed according to the microscopic oxygen distribution and the density distribution of tumor cells in four virtual tumors with different biological characteristics. In addition, two different optimization objective functions are investigated, which: i) minimize tumor cell survival (OFsurv) or; ii) maximize the homogeneity of the density of surviving tumor cells (OFstd). Several adaptive schemes, ranging from single to daily dose optimization, are studied and the treatment response is compared to that of the uniform dose. The results show that the benefit of DPBN treatments depends on the tumor reoxygenation capability, which strongly differed among the set of virtual tumors investigated. The difference between daily (fraction by fraction) and three weekly optimizations (at the beginning of weeks 1, 3 and 4) was found to be small, and higher benefit was observed for the treatments optimized using OFsurv. This in silico study corroborates the hypothesis that DPBN may be beneficial for treatments of tumors which show reoxygenation during treatment, and that a few optimizations may be sufficient to achieve this therapeutic benefit. PMID- 29698536 TI - Correction: The development of functional mapping by three sex-related loci on the third whorl of different sex types of Carica papaya L. AB - [This corrects the article DOI: 10.1371/journal.pone.0194605.]. PMID- 29698535 TI - Biological control of potato common scab by Bacillus amyloliquefaciens Ba01. AB - Potato common scab, which is caused by soil-borne Streptomyces species, is a severe plant disease that results in a significant reduction in the economic value of potatoes worldwide. Due to the lack of efficacious pesticides, crop rotations, and resistant potato cultivars against the disease, we investigated whether biological control can serve as an alternative approach. In this study, multiple Bacillus species were isolated from healthy potato tubers, and Bacillus amyloliquefaciens Ba01 was chosen for further analyses based on its potency against the potato common scab pathogen Streptomyces scabies. Ba01 inhibited the growth and sporulation of S. scabies and secreted secondary metabolites such as surfactin, iturin A, and fengycin with potential activity against S. scabies as determined by imaging mass spectrometry. In pot assays, the disease severity of potato common scab decreased from 55.6 +/- 11.1% (inoculated with S. scabies only) to 4.2 +/- 1.4% (inoculated with S. scabies and Ba01). In the field trial, the disease severity of potato common scab was reduced from 14.4 +/- 2.9% (naturally occurring) to 5.6 +/- 1.1% after Ba01 treatment, representing evidence that Bacillus species control potato common scab in nature. PMID- 29698537 TI - Improving Teamwork and Patient Outcomes with Daily Structured Interdisciplinary Bedside Rounds: A Multimethod Evaluation. AB - BACKGROUND: Previous research has shown that interdisciplinary ward rounds have the potential to improve team functioning and patient outcomes. DESIGN: A convergent parallel multimethod approach to evaluate a hospital interdisciplinary ward round intervention and ward restructure. SETTING: An acute medical unit in a large tertiary care hospital in regional Australia. PARTICIPANTS: Thirty-two clinicians and inpatients aged 15 years and above, with acute episode of care, discharged during the year prior and the year of the intervention. INTERVENTION: A daily structured interdisciplinary bedside round combined with a ward restructure. MEASUREMENTS: Qualitative measures included contextual factors and measures of change and experiences of clinicians. Quantitative measures included length of stay (LOS), monthly "calls for clinical review," and cost of care delivery. RESULTS: Clinicians reported improved teamwork, communication, and understanding between and within the clinical professions, and between clinicians and patients, after the intervention implementation. There was no statistically significant difference between the intervention and control wards in the change in LOS over time (Wald ?2 = 1.05; degrees of freedom [df] = 1; P = .31), but a statistically significant interaction for cost of stay, with a drop in cost over time, was observed in the intervention group, and an increase was observed in the control wards (Wald ?2 = 6.34; df = 1; P = .012). The medical wards and control wards differed significantly in how the number of monthly "calls for clinical review" changed from prestructured interdisciplinary bedside round (SIBR) to during SIBR (F (1,44) = 12.18; P = .001). CONCLUSIONS: Multimethod evaluations are necessary to provide insight into the contextual factors that contribute to a successful intervention and improved clinical outcomes. PMID- 29698538 TI - Things We Do for No Reason - The "48 Hour Rule-out" for Well-Appearing Febrile Infants. PMID- 29698539 TI - Patient-Centered, Payer-Centered, or Both? The 30-Day Readmission Metric. PMID- 29698540 TI - The impact of clinical trial units on the value of clinical research in Switzerland. AB - A prominent 2014 series by The Lancet on "Increasing value, reducing waste in biomedical research" provided recommendations on how to optimise precious resources, including in clinical research. Despite being ideally placed to lead the movement in patient-oriented clinical research, academia struggles to take corresponding measures and find ways to evaluate their impact. A decade ago, Swiss stakeholders established constructive initiatives to improve the quality of clinical research, including a national Clinical Trial Unit (CTU) Network, predominantly rooted in university hospitals. At the 10th anniversary of this network (2007-2017), we reflect on the CTUs' trajectory and review whether - and how - they have been successful in improving the value of clinical research conducted in Switzerland. Anonymised surveys with involved clinical research stakeholder institutions and CTU customers at university hospitals suggest that the CTU Network has positively influenced the quality of academic clinical research. Future goals should include standardised education on Good Clinical Practice; the establishing of an audit function; the positioning of the network as an "entrance gate" for international trials; and support for young scientists launching their careers. Although stakeholder feedback has been very positive, praise does not constitute a standardised measure of the actual impact of CTU services. Beyond that, a broad understanding and practical guidance on how to increase value in academic clinical research are still lacking. We conclude with ways forward, including "INcreasing QUality In clinical Research" (INQUIRE), a comprehensive framework for the practical assessment of quality in academia developed by the CTU Basel. INQUIRE, founded on consensus across international and Swiss stakeholders, outlines six key quality dimensions to be fulfilled study wide and is available for all relevant parties involved. INQUIRE encourages academic institutions to adopt waste-reducing strategies and strives to build an evidence-based clinical research landscape in Switzerland, with national and international influence. PMID- 29698541 TI - Occupational exposure to plant protection products and health effects in Switzerland: what do we know and what do we need to do? AB - AIMS: There is currently no centralised database on workers' exposures to plant protection products (PPPs) in Switzerland, nor a national register for negative health effects linking them to occupational PPP exposure. This lack of basic data makes it difficult to implement either epidemiological research or prevention campaigns for the agricultural sector. The first objective was to understand the level of information and flow of data on occupational PPP exposures and health effects in the Canton of Vaud, Switzerland. Then, to apply this information to develop recommendations for improving a vigilance system for occupational health effects related to PPP exposure. METHODS: A mapping study and semistructured stakeholder interviews were conducted to better understand the flow of data on occupational PPP exposures and health effects. A clinical records investigation of workers occupationally exposed to PPPs was undertaken to understand the magnitude of this potential problem. Finally, a workshop brought together relevant stakeholders to discuss recommendations for the way forwards. RESULTS: A lack of data on PPP exposures and associated health effects was revealed. This highlighted important knowledge gaps at different levels of the current institutional information flow system. We found that although there were numerous stakeholders that worked efficiently in their own mandate, there was a clear need for increased collaboration and coordination in order to make use of existing data to promote safer PPP use among agricultural workers in Switzerland. CONCLUSIONS: Due to increasing evidence of an association between PPP exposure and health effects, increased collaboration between stakeholders is necessary to develop links between the data sources that already exist. Our study was the first to investigate the health effects linked to PPP exposure among the Swiss agricultural population. The recommendations presented in this paper would help promote a safer and healthier agricultural workforce in Switzerland, as well as the population at large. PMID- 29698542 TI - Point prevalence of healthcare-associated infections and antibiotic use in three large Swiss acute-care hospitals. AB - BACKGROUND: The overall burden of healthcare-associated infections (HAIs) remains high, even in high-income countries. However, the current burden of HAI in Switzerland is unknown. Prevalence surveys have a long tradition in the field of infection prevention and control for measuring both HAI and antimicrobial use. The objective of this survey was to test the point prevalence survey (PPS) methodology of the European Centre for Disease Prevention and Control (ECDC) in acute-care hospitals in Switzerland. METHODS: Two tertiary care hospitals and one secondary care hospital in central and western Switzerland participated in the survey. Patients from all wards except for emergency departments and psychiatric wards were included. Data were collected on a single day for every ward with a maximum time frame of 2 weeks for completing data collection. Methodology and definitions were based on the most recent ECDC PPS protocol. RESULTS: Data on a total of 2421 patients were analysed. One hundred thirty-six patients had 153 HAIs, corresponding to a prevalence of 5.6% (95% confidence interval [CI] 4.7 6.5%). Rapidly fatal McCabe score, hospitalisation in the intensive care unit (ICU), and having a medical device in place were independent risk factors for HAI. Lower respiratory tract infection was the most frequent HAI type (24.8%), followed by surgical site infection (22.2%), bloodstream infection (17.0%) and urinary tract infection (13.7%). The highest HAI prevalence (26.2%) was observed in the ICU. In total, 60.8% of all HAIs were microbiologically confirmed. The most common microorganism was Escherichia coli (21.1%). Six hundred sixty-nine patients (27.6%, 95% CI 25.9-29.4%) received 893 antimicrobials for 705 indications. Community-acquired infections (39.0%) were the most common indication for antimicrobial use and amoxicillin-clavulanate was the most commonly prescribed antimicrobial (18.4%). CONCLUSIONS: HAI prevalence and antimicrobial use in this survey were similar to findings of the past ECDC PPS. The ECDC methodology proved applicable to Swiss acute-care hospitals. PMID- 29698543 TI - Clinical course and prevalence of coercive measures: an observational study among involuntarily hospitalised psychiatric patients. AB - AIMS OF THE STUDY: In daily clinical work, coercion continues to be highly prevalent, with rates differing between countries and sometimes even within countries or between wards of the same hospital. Previous research found inconsistent characteristics of individuals who underwent coercive measures during psychiatric treatment. Furthermore, there continues to be a lack of knowledge on the clinical course of people after being involuntarily committed. This study aimed to describe the rate and duration of different coercive measures and characterise a cohort of involuntarily committed patients regarding sociodemographic and clinical variables. METHODS: In this observational cohort study, we analysed clinical data from the patients' medical files, the use of coercive measures (seclusion, restraint, coercive medication) and other procedural aspects in involuntarily hospitalised patients (n = 612) at the University Hospital of Psychiatry Zurich. For analysis, we used cross-tabulation with chi-square tests for categorical variables and, owing to a non-normal distribution, the Mann-Whitney U-test for interval variables. RESULTS: Coercive measures were documented in 170 patients (28% of those who were involuntarily hospitalised). The total number of seclusions was 344, with a mean duration of 9 hours per seclusion. A total of 89 patients (15%) received 159 episodes of coercive medication (oral and intramuscular). Also, 11 episodes of restraint were recorded in 7 patients (1%) with a mean duration of 12 hours per restraint. Patients subjected to coercion were significantly more often male, violent prior to admission, diagnosed with psychosis or personality disorder, and had a history of frequent hospitalisations with long durations of hospitalisation. CONCLUSIONS: The prevalence of coercive measures is still high in involuntarily hospitalised patients. Seclusion was the most frequently used coercive measure, which may be based on cultural and clinical aspects and differs from findings in other countries where restraint is more frequently used. Some sociodemographic and clinical characteristics were associated with the use of coercion. This underlines the importance of developing treatment strategies for patients at risk to prevent situations in which the use of coercion is necessary. To enable comparison between different study sites, standardised protocols should be used to document frequency and duration of coercive measures. PMID- 29698544 TI - The Swiss Cystic Fibrosis Infant Lung Development (SCILD) cohort. AB - The Swiss Cystic Fibrosis Infant Lung Development (SCILD) cohort is a prospective birth cohort study investigating the initiating events of cystic fibrosis lung disease during infancy, and their influence on the trajectory of disease progression throughout early childhood. Infants with cystic fibrosis are recruited throughout Switzerland after diagnosis by new-born screening. It is the first European population-based prospective cohort study of infants with cystic fibrosis taking advantage of a nationwide new-born screening programme. The study was established in 2011 and recruitment is ongoing. The cohort study is currently divided into three study phases (phase 1: diagnosis to age 1 year; phase 2: age 1 to 3 years; and phase 3: age 3 to 6 years). Study participants have weekly telephone interviews, weekly anterior nasal swab collection and two study visits in the first year of life. They also complete follow-up study visits at 3 and 6 years of age. Data for this study are derived from questionnaires, lung function measurements, telephone interviews, nasal swab material and magnetic resonance imaging. To date, 70 infants have been recruited into the study and 56 have completed phase 1, including a baseline study visit at 6 weeks of age, weekly surveillance and a study visit at one year of age. More than 2500 data points on respiratory health and almost 2000 nasal samples have been collected. Phases 2 and 3 will commence in 2018. The dataset of the SCILD cohort combines lung function data, the collection of environmental and sociodemographic factors, documentation of respiratory symptoms, and microbiological analyses. The design not only allows tracking of the cystic fibrosis lung disease independent of clinical status, but also surveillance of early disease prior to severe clinical symptoms. This cohort profile provides details on the study design and summarizes the first published results of the SCILD cohort. PMID- 29698545 TI - The role of molecular imaging in assessing degenerative parkinsonism - an updated review. AB - Diagnosing degenerative forms of parkinsonism still relies on a thorough clinical assessment, which in Parkinson's disease involves the presence of an asymmetric bradykinesia with rest tremor and/or rigidity that respond substantially to levodopa. Conversely, atypical forms, including multiple system atrophy, progressive supranuclear palsy and corticobasal degeneration, exhibit additional features (cerebellar or pyramidal signs, early postural instability), a poor response to dopamine replacement therapy and a bad prognosis. Consensus diagnostic criteria have excellent specificity, but lack sensitivity, and a clear diagnosis solely based on clinical evaluation is not always accurate, hence the need for diagnostic biomarkers. Nuclear medicine imaging is definitely one of them, allowing a qualitative and quantitative evaluation of in vivo functional integrity of monoaminergic (e.g., dopaminergic) pathways, brain metabolism and protein deposition and representing a unique window into these complex diseases. It has proved useful for early and accurate diagnosis, and possibly represents a valid biomarker of disease pathogenesis, progression and response to neuroprotective therapies. This review focuses on the nigrostriatal pathway dysfunctions (demonstrated with presynaptic dopamine positron emission tomography [PET] and single photon emission computed tomography [SPECT] ligands) that confirm a degenerative form of parkinsonism. In addition, 123I metaiodobenzylguanidine cardiac scintigraphy can unveil postganglionic autonomic failure specifically encountered in Parkinson's disease. Brain 18F fluorodeoxyglucose PET may also show a distinct hypometabolism for each degenerative form of parkinsonism. Since a few years ago, the proteins that aggregate in the brain of subjects with neurodegenerative diseases (tau and alpha synuclein) can be evaluated in vivo by novel radioligands. These developments open new perspectives both as diagnostic tools and to understand the regional topography and burden of protein deposition on motor impairment and cognitive decline. The last part of the review proposes a strategic workup in the practical evaluation of a patient with parkinsonism. PMID- 29698546 TI - The epidemiology of hepatitis C in Switzerland: trends in notifications, 1988 2015. AB - With an estimated antibody prevalence of 0.7% in the low-risk population, hepatitis C virus (HCV) endemicity in Switzerland is low. We reviewed data from mandatory hepatitis C surveillance for 1988-2015 in order to describe the evolution of acute HCV infections and newly reported non-acute cases, and their epidemiological features. Crude and stratified annual incidence and notification rates and rate ratios were calculated using Poisson regression. Acute HCV incidence peaked in 2002 at 1.8 cases per 100,000 population, then declined sharply, levelling at around 0.7/100,000 from 2006. Notification rates for non acute HCV cases peaked in 1999 (38.6/100,000), decreasing to 16.8/100,000 in 2015. Men constituted 65.5% of acute cases and 60.4% of non-acute cases. During the periods 1992-1995 and 2012-2015, the median age of acute cases increased from 28 to 37 and of non-acute cases from 32 to 48 years. The exposure leading to most acute (90.4%) and non-acute (71.9%) cases was presumably in Switzerland. Despite a sharp decrease since 2000, injecting drugs was the main reported exposure for both acute (63.8%) and non-acute (66.6%) cases, with a known exposure, followed by sexual contact with an infected person (18.9% and 10.3% respectively). Among all acute cases, the number of men who have sex with men increased sharply after the mid-2000s, totalling 41 during 2012-2015 (25.7%). Although the HCV epidemic peaked in 2000 - probably as a result of measures to control iatrogenic and percutaneous transmission - Switzerland must maintain prevention and surveillance. PMID- 29698547 TI - First case of Candida auris in Switzerland: discussion about preventive strategies. PMID- 29698548 TI - The place of the Ozaki procedure in the treatment of aortic valve disease. PMID- 29698549 TI - Regimen of procarbazine, lomustine, and vincristine versus temozolomide for gliomas. PMID- 29698550 TI - Anaphylaxis by exclusive allergy to swordfish and identification of a new fish allergen. PMID- 29698551 TI - Effect of near-infrared photobiomodulation therapy in a cellular wound healing model. PMID- 29698552 TI - Does cirrhosis associated with well controlled viral hepatitis confer a risk for extrahepatic cancer? PMID- 29698553 TI - Anticipating or Accommodating to Public Concern? Risk Amplification and the Politics of Precaution Reexamined. AB - Regulatory use of the precautionary principle (PP) tends to be broadly characterized either as a responsible approach for safeguarding against health and environmental risks in the face of scientific uncertainties, or as "state mismanagement" driven by undue political bias and public anxiety. However, the "anticipatory" basis upon which governments variably draw a political warrant for adopting precautionary measures often remains ambiguous. Particularly, questions arise concerning whether the PP is employed preemptively by political elites from the "top down," or follows from more conventional democratic pressures exerted by citizens and other stakeholders from the "bottom up." This article elucidates the role and impact of citizen involvement in the precautionary politics shaping policy discourse surrounding the U.K. government's "precautionary approach" to mobile telecommunications technology and health. A case study is presented that critically reexamines the basis upon which U.K. government action has been portrayed as an instance of anticipatory policy making. Findings demonstrate that the use of the PP should not be interpreted in the preemptive terms communicated by U.K. government officials alone, but also in relation to the wider social context of risk amplification and images of public concern formed adaptively in antagonistic precautionary discourse between citizens, politicians, industry, and the media, which surrounded cycles of government policy making. The article discusses the sociocultural conditions and political dynamics underpinning public influence on government anticipation and responsiveness exemplified in this case, and concludes with research and policy implications for how society subsequently comes to terms with the emergence and precautionary governance of new technologies under conflict. PMID- 29698554 TI - Long-term outcome of peanut oral immunotherapy-Real-life experience. AB - BACKGROUND: Oral immunotherapy (OIT) is currently recommended as a treatment option for peanut-allergic patients. Data regarding its long-term compliance and efficacy in real life are required. METHODS: Peanut-allergic patients aged >=4 years were enrolled in a single-center clinical OIT program. Buildup to 3000 mg peanut protein was performed. Patients reaching this dose before or after 12/2014 were instructed to consume 3000 or 1200 mg daily, respectively. Patients were followed >=6 months after reaching maintenance and rechallenged to 3000 mg. RESULTS: Of the 145 patients studied, 113 (77.9%) were fully desensitized to 3000 mg and 133 (91.7%) were desensitized to >=300 mg. 21/145 patients (14.5%) required adrenaline for home-dose reactions during buildup. Non-anaphylactic gastrointestinal symptoms, experienced by 9 patients (6.2%), reversed with dose reduction. Of the 111 patients available for analysis 6 months after reaching 3000 mg, 97 (87.4%) continued regular peanut consumption. Only 2/111 patients (1.8%) required adrenaline over the long-term (median, range; 18, 6-75 months) follow-up. Adherence to treatment was significantly higher in patients consuming 1200 mg (73/76, 96.1%) vs those consuming 3000 mg (24/35, 72.2%), (P = .001). A higher maintenance dosage and home adrenaline requirement during buildup predicted adherence cessation (OR 12.5, P = .001; and OR 7.8, P = .02, respectively). 63/64 patients (98.4%) consuming 1200 mg maintenance dose were successfully rechallenged to 3000 mg. CONCLUSIONS: This real-life experience demonstrates the efficacy of peanut OIT long-term. A lower maintenance dose minimized treatment cessation while maintaining desensitization. OIT should be performed in qualified centers given the prevalence of adverse reactions, particularly during buildup. PMID- 29698555 TI - Short-term effect of outdoor mould spore exposure on prescribed allergy medication sales in Central France. AB - BACKGROUND: Outdoor moulds are classically associated with exacerbations of asthma. OBJECTIVE: The aim of this paper was to examine nasal allergy morbidity by studying the short-term relationship between mould spore exposure and daily sales of reimbursable anti-allergic treatment in central France. METHODS: The relationship between daily changes in mould concentrations and daily sales obtained from the national healthcare database was analysed with generalized additive models, taking into account confounding factors such as air pollution, weather conditions, pollen counts, and days of the week. RESULTS: During the study, the average total yearly number of treated people was around 10 000 over approximately 230 000 surveyed. The relative risk (95% CI confidence interval) of sales of oral antihistamines with topical treatment associated with an interquartile increase in mould concentration was significant for Cladosporium 1.079 [1.019-1.142] and Aspergillus-Penicillium (Asp-Pen) 1.051 [1.021-1.082] in the whole population. When the influence of age and sex was considered, the relationship was significant only in male children aged 0-12 years and those aged between 13 and 49 years for Cladosporium: 1.256 [1.081-1.460] and 1.151 [1.063 1.245], respectively. The relationship was also significant for Asp-Pen: 1.038 [1.003-1.075] for those aged between 13 and 49 years and 1.056 [1.007-1.108] for adults over 50 years of age. CONCLUSION: The association between prescribed daily sales of oral antihistamines with topical treatment sales is associated with temporal changes to Cladosporium and Aspergillus-Penicillium in the whole population. When the influence of age and sex was considered, these two moulds contributed to prescribed medication sales only in the male general population. PMID- 29698557 TI - A simplified silver phosphate extraction method for oxygen isotope analysis of bioapatite. AB - RATIONALE: Although phosphatic materials are chemically complex and are prone to exchange oxygen isotopes with their environments, the phosphate (PO43- ) component of these materials is robust and retains its original oxygen isotopic composition. As a result, there are currently several methods for the isolation of phosphate oxygen through the precipitation of silver phosphate (Ag3 PO4 ). However, some of these techniques produce Ag3 PO4 of questionable purity, while nearly all are lengthy and/or require relatively large sample sizes. METHODS: Five milligrams of bioapatite from modern cow teeth (enamel and cementum) were pre-treated for removal of organic material prior to digestion in 2 M HF. The digested samples were titrated with silver ammine solution at 50 degrees C to precipitate Ag3 PO4 . Oxygen isotopic data were collected using a Thermal Combustion Elemental Analyzer (TC/EA) paired with a Delta VPlus isotope ratio mass spectrometer via a ConFlo III universal interface. RESULTS: The quality of Ag3 PO4 is dependent on effective removal of organic material and the volume of silver ammine solution used during titration. A two-step pre-treatment of 2.5% NaOCl, followed by a 0.125 M NaOH solution, is the most effective treatment for the removal of organic material from both enamel and cementum. Optimal yields of Ag3 PO4 were achieved using 1.8 mL of silver ammine solution. The reproducibility of the phosphate delta18 O compositions ranges from 0.3 to 0.40/00 (1sigma) for modern cow teeth. CONCLUSIONS: We present a simplified method for phosphate extraction from organic-rich phosphatic material. Our method gave reproducible delta18 O values for enamel and cementum from cows' teeth. PMID- 29698556 TI - More frequent use of health care services among distressed compared with nondistressed survivors of lymphoma and chronic lymphocytic leukemia: Results from the population-based PROFILES registry. AB - BACKGROUND: Follow-up care for a growing population of survivors of lymphoma and chronic lymphocytic leukemia (CLL) together with the adverse effects these survivors may experience as a result of their cancer and treatment have led to more pressure being placed on health care services. The objectives of the current study were to: 1) compare the use of medical care services by survivors with that of a normative population; 2) evaluate the use of medical and psychosocial care services among distressed and nondistressed survivors; and 3) identify associated sociodemographic and clinical factors. METHODS: Survivors of lymphoma and CLL diagnosed between 1999 and 2012 were selected via the population-based Netherlands Cancer Registry and completed the Hospital Anxiety and Depression Scale questionnaire and questions regarding health care. Outcomes were compared with an age-matched and sex-matched normative population. RESULTS: A total of 1444 survivors responded (69%). Survivors of lymphoma and CLL contacted their general practitioner (3.8 vs 2.3; P<.001) and medical specialist (5.7 vs 1.6; P<.001) more often within the last year compared with a normative population. In addition, psychologically distressed survivors had even more medical contacts and received psychosocial care more often compared with nondistressed survivors. In addition to psychological distress, comorbidity, female sex, and older age were found to be associated with a greater use of medical services, whereas younger age was associated with receiving psychosocial care. CONCLUSIONS: Survivors of lymphoma and CLL, especially those who are psychologically distressed, report an increased use of health care services compared with a normative population. Further studies are needed to explore whether the use of widely applicable psychosocial interventions could reduce the frequency of medical contacts. Cancer 2018;124:3016-24. (c) 2018 Netherlands Comprehensive Cancer Organisation. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. PMID- 29698558 TI - Ecological niche modeling for a cultivated plant species: a case study on taro (Colocasia esculenta) in Hawaii. AB - Under the threat of ongoing and projected climate change, communities in the Pacific Islands face challenges of adapting culture and lifestyle to accommodate a changing landscape. Few models can effectively predict how biocultural livelihoods might be impacted. Here, we examine how environmental and anthropogenic factors influence an ecological niche model (ENM) for the realized niche of cultivated taro (Colocasia esculenta) in Hawaii. We created and tuned two sets of ENMs: one using only environmental variables, and one using both environmental and cultural characteristics of Hawaii. These models were projected under two different Intergovernmental Panel on Climate Change (IPCC) Representative Concentration Pathways (RCPs) for 2070. Models were selected and evaluated using average omission rate and area under the receiver operating characteristic curve (AUC). We compared optimal model predictions by comparing the percentage of taro plots predicted present and measured ENM overlap using Schoener's D statistic. The model including only environmental variables consisted of 19 Worldclim bioclimatic variables, in addition to slope, altitude, distance to perennial streams, soil evaporation, and soil moisture. The optimal model with environmental variables plus anthropogenic features also included a road density variable (which we assumed as a proxy for urbanization) and a variable indicating agricultural lands of importance to the state of Hawaii. The model including anthropogenic features performed better than the environment-only model based on omission rate, AUC, and review of spatial projections. The two models also differed in spatial projections for taro under anticipated future climate change. Our results demonstrate how ENMs including anthropogenic features can predict which areas might be best suited to plant cultivated species in the future, and how these areas could change under various climate projections. These predictions might inform biocultural conservation priorities and initiatives. In addition, we discuss the incongruences that arise when traditional ENM theory is applied to species whose distribution has been significantly impacted by human intervention, particularly at a fine scale relevant to biocultural conservation initiatives. PMID- 29698560 TI - Review and perspectives on the applications of mass spectrometry imaging under ambient conditions. AB - Ambient mass spectrometry (AMS)-based techniques are performed under ambient conditions in which the ionization and desorption occur in the open environment allowing the direct analysis of molecules with minimal or no sample preparation. A selected group of AMS techniques demonstrate imaging capabilities that can provide information about the localization of molecules on complex sample surfaces such as biological tissues. 2D, 3D, and multimodal imaging have unlocked an array of applications to systematically address complex problems in many areas of research such as drug monitoring, natural products, forensics, and cancer diagnostics. In the present review, we summarize recent advances in the field with respect to the implementation of new ambient ionization techniques and current applications in the last 5 years. In more detail, we mainly focus on imaging applications in topics related to animal whole bodies and tissues, single cells, cancer diagnostics and biomarkers, microbial cultures and co-cultures, plant and natural product metabolomics, and forensic applications. Finally, we discuss new areas of research, future perspectives, and the overall direction that the field may take in the years to come. PMID- 29698559 TI - Tuftsin-phosphorylcholine (TPC) equally effective to methylprednisolone in ameliorating lupus nephritis in a mice model. AB - The role of helminth treatment in autoimmune diseases is growing constantly. Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease with challenging treatment options. Tuftsin-phosphorylcholine (TPC) is a novel helminth-based compound that modulates the host immune network. This study was conducted to evaluate the potential value of TPC in ameliorating lupus nephritis in a murine model and specifically to compare the efficacy of TPC to the existing first-line therapy for SLE: corticosteroids (methylprednisolone). Lupus-prone NZBxW/F1 mice were treated with TPC (5 ug/mouse), methylprednisolone (MP; 5 mg/body weight) or phosphate-buffered saline (PBS) (control) three times per week once glomerulonephritis, defined as proteinuria of grade > 100 mg/dl, was established. Levels of anti-dsDNA autoantibodies were evaluated by enzyme-linked immunosorbent assay (ELISA), splenic cytokines were measured in vitro and the kidney microscopy was analysed following staining. TPC and MP treatments improved lupus nephritis significantly and prolonged survival in NZBxW/F1 mice. TPC treated mice showed a significantly decreased level of proteinuria (P < 0.001) and anti-dsDNA antibodies (P < 0.001) compared to PBS-treated mice. Moreover, TPC and MP inhibited the production of the proinflammatory cytokines interferon IFN gamma, interleukin IL-1beta and IL-6 (P < 0.001) and enhanced expression of the anti-inflammatory cytokine IL-10 (P < 0.001). Finally, microscopy analysis of the kidneys demonstrated that TPC-treated mice maintained normal structure equally to MP-treated mice. These data indicate that the small molecule named TPC hinders lupus development in genetically lupus-prone mice equally to methylprednisolone in most of the cases. Hence, TCP may be employed as a therapeutic potential for lupus nephritis. PMID- 29698561 TI - Phenotypes of childhood wheeze in Japanese children: A group-based trajectory analysis. AB - BACKGROUND: Exploring patterns of childhood wheeze may help to clarify the etiology and prognosis of respiratory diseases. The purpose of this study was to classify phenotypes of wheezing in children up to 9 years of age in Japan and to evaluate the individual and environmental risk factors for these phenotypes. METHODS: Wheeze was evaluated at approximately 1-year intervals based on the mothers' recollection of their child's wheezing or whistling in the chest during the preceding 12 months. The children were aged 1-9 years. In total, 1116 children who had at least five measures of wheezing at all nine time points were used for identifying trajectories. Trajectories were identified with group-based trajectory analysis. A multinomial logit model was built to evaluate the relationships between phenotypes and risk factors. RESULTS: Five typical trajectories were identified. The probability of group membership was 43.7%, 32.2%, 6.2%, 8.6%, and 9.2% for the never/infrequent wheeze, transient early wheeze, school-age-onset wheeze, early-childhood-onset remitting wheeze, and persistent wheeze trajectories, respectively. Infant tobacco exposure increased the odds of membership in the transient early wheeze trajectory compared to the never/infrequent wheeze trajectory. CONCLUSIONS: Using the group-based trajectory modeling approach, we identified five trajectories of childhood wheeze development in a Japanese population. The trajectories shown here are based on formal statistical modeling rather than on subjective classification, and an assessment of its precision suggested that the model has high assignment accuracy. PMID- 29698562 TI - Association of Severe Atopic Dermatitis with month of birth in Armenian pediatric patients. PMID- 29698563 TI - C-Functionalized Cationic Diazaoxatriangulenes: Late-Stage Synthesis and Tuning of Physicochemical Properties. AB - A series of nine C-functionalized cationic diazaoxatriangulene (DAOTA) dyes have been successfully synthesized and fully characterized, including X-ray structural analysis of four derivatives. The introduction of electron-withdrawing or donating functions enables the tuning of both electro- and photochemical properties with, for instance, two consecutive (reversible) reductions or oxidations observed for nitro or amino derivatives, respectively. The substituents also impacted on the optical properties, with absorption maxima varying from lambda=528 to 640 nm and fluorescence being shifted from the yellow to the red range, up to lambda=656 nm. PMID- 29698564 TI - Spatial and trophic preferences of jumbo squid Dosidicus gigas (D'Orbigny, 1835) in the central Gulf of California: ecological inferences using stable isotopes. AB - RATIONALE: The jumbo squid Dosidicus gigas is a fishery resource of considerable economic and ecological importance in the Mexican Pacific. Studies on its habitat preferences are needed to understand recent fluctuations in the abundance and availability of the species. Stable isotope analysis allows us to infer ecological aspects such as spatial distribution and trophic preferences. METHODS: We used an isotope ratio mass spectrometer, automated for carbonate analysis, and coupled to an elemental analyzer, to determine the isotopic composition of statoliths (delta18 O and delta13 C values) and beaks (delta13 C and delta15 N values) from 219 individuals caught over two fishing seasons (2007 and 2009) off the coast of Santa Rosalia, in the central Gulf of California. We used these isotopic ratios to assess variation in spatial and trophic preferences by sex, size, and fishing season. RESULTS: In the 2009 group, we observed significant differences in statolith delta13 C values and beak delta13 C and delta15 N values between males and females. Between size groups, we observed significant differences in statolith delta18 O and delta13 C values in 2007 and in beak delta13 C and delta15 N values during both seasons. Both seasons were characterized by high overlap in delta18 O and delta13 C values between sexes and in 2009 between size groups. We observed low trophic overlap between sexes in 2009 and between size groups during both seasons. CONCLUSIONS: The isotopic ratios from statoliths and beaks indicate that D. gigas has changed its spatial and trophic preferences, a shift that is probably related to changes in the species' diet. This intraspecific variation in preferences could be related to characteristics such as size, which may influence squid distribution preferences. PMID- 29698565 TI - Automated detection of fluorescent cells in in-resin fluorescence sections for integrated light and electron microscopy. AB - Integrated array tomography combines fluorescence and electron imaging of ultrathin sections in one microscope, and enables accurate high-resolution correlation of fluorescent proteins to cell organelles and membranes. Large numbers of serial sections can be imaged sequentially to produce aligned volumes from both imaging modalities, thus producing enormous amounts of data that must be handled and processed using novel techniques. Here, we present a scheme for automated detection of fluorescent cells within thin resin sections, which could then be used to drive automated electron image acquisition from target regions via 'smart tracking'. The aim of this work is to aid in optimization of the data acquisition process through automation, freeing the operator to work on other tasks and speeding up the process, while reducing data rates by only acquiring images from regions of interest. This new method is shown to be robust against noise and able to deal with regions of low fluorescence. PMID- 29698566 TI - Role of mechanical cues in shaping neuronal morphology and connectivity. AB - Neuronal circuits, the functional building blocks of the nervous system, assemble during development through a series of dynamic processes including the migration of neurons to their final position, the growth and navigation of axons and their synaptic connection with target cells. While the role of chemical cues in guiding neuronal migration and axonal development has been extensively analysed, the contribution of mechanical inputs, such as forces and stiffness, has received far less attention. In this article, we review the in vitro and more recent in vivo studies supporting the notion that mechanical signals are critical for multiple aspects of neuronal circuit assembly, from the emergence of axons to the formation of functional synapses. By combining live imaging approaches with tools designed to measure and manipulate the mechanical environment of neurons, the emerging field of neuromechanics will add a new paradigm in our understanding of neuronal development and potentially inspire novel regenerative therapies. PMID- 29698567 TI - Ubiquitin-Specific Peptidase 10 (USP10) Inhibits Hepatic Steatosis, Insulin Resistance, and Inflammation Through Sirt6. AB - Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis, insulin resistance and inflammation, and the pathogenic mechanism of NAFLD is poorly understood. Ubiquitin-specific peptidase 10 (USP10), a member of the ubiquitin-specific protease family, is involved in environmental stress responses, tumor growth, inflammation, and cellular metabolism. However, the role of USP10 in hepatic steatosis, insulin resistance, and inflammation remains largely unexplored. USP10 expression was detected in livers of patients with NAFLD, mice with high-fat diet (HFD)-induced obesity, and genetically obese (ob/ob) mice, as well as in palmitate-induced hepatocytes. The function of USP10 in hepatic steatosis, insulin resistance, and inflammation was investigated using hepatocyte-specific USP10 deficiency or overexpression in mice induced by HFD treatment or genetic defect. The molecular mechanisms underlying USP10-regulated hepatic steatosis were further investigated in HFD-treated mice. USP10 expression was significantly decreased in the fatty livers of NAFLD patients and obese mice and in palmitate-treated hepatocytes. USP10 deficiency exacerbated the metabolic dysfunction induced by HFD treatment for 12 weeks. Conversely, USP10 overexpression significantly suppressed metabolic dysfunction in mice after HFD treatment and inhibited the development of NAFLD in ob/ob mice. Further investigation indicated that USP10 regulates hepatic steatosis by interacting with Sirt6 and inhibiting its ubiquitination and degradation. Sirt6 overexpression markedly ameliorated the effects of USP10 deficiency in hepatic steatosis, insulin resistance, and inflammation. Conversely, Sirt6 deficiency decreased the ameliorative effects of USP10 overexpression in response to HFD treatment. Conclusion: USP10 inhibits hepatic steatosis, insulin resistance, and inflammation through Sirt6. PMID- 29698568 TI - N-Acetyl Cysteine Treatment Restores Early Phase Fracture Healing in Ethanol-Fed Rats. AB - BACKGROUND: Fracture healing in alcoholics is delayed and often associated with infections resulting in prolonged rehabilitation. It has been reported that binge drinking of alcohol increases oxidative stress and delays fracture healing in rats, which is prevented by treatment with the antioxidant n-acetyl cysteine (NAC). Oxidative stress is a significant factor in pathologies of various organs resulting from chronic alcoholism. Therefore, we hypothesize that treatment with NAC reduces oxidative stress and restores fracture healing in chronic alcoholics. METHODS: Rats (10 months old) were pair-fed the Lieber-DeCarli ethanol (EtOH) diet or control diet for 16 weeks. A closed fracture was performed and rats allowed to recover for 72 hours. Rats were divided into 4 groups-control, control + NAC, EtOH, and EtOH + NAC-and injected intraperitoneally with 200 mg/kg of NAC daily for 3 days. Serum and bone fracture callus homogenates were collected and assayed for traditional markers of inflammation, oxidative stress, and bone regeneration. RESULTS: The oxidative stress marker malondialdehyde (MDA) was increased in both serum and bone tissue in EtOH-fed animals compared to controls. NAC treatment significantly (p < 0.01) reduced MDA to near normal levels and dramatically increased the index of antioxidant efficacy (catalase/MDA ratio) (p < 0.01). Inflammatory markers tumor necrosis factor-alpha, interferon-gamma, and interleukin-6 were significantly decreased in serum and callus following NAC treatment. NAC treatment reduced EtOH-induced bone resorption as evidenced by significant decreases in C-telopeptide of type-I-collagen levels (p < 0.05) and band-5 tartrate-resistant acid phosphatase levels in the tissue (p < 0.001). CONCLUSIONS: Oxidative stress and excessive inflammation are involved in the inhibition of fracture healing by EtOH. In this study, early short-term treatment of EtOH-fed animals with the antioxidant NAC reduced oxidative stress and normalized the innate immune response to fracture in the early phase of fracture healing, thereby restoring the normal onset of bone regeneration. PMID- 29698569 TI - Preemptive Activation of the Integrated Stress Response Protects Mice From Diet Induced Obesity and Insulin Resistance by Fibroblast Growth Factor 21 Induction. AB - Integrated stress response (ISR) is a signaling system in which phosphorylation of eukaryotic translation initiation factor 2alpha (eIF2alpha) by stress-specific kinases and subsequent activation of activation transcription factor (ATF) 4 help restore cellular homeostasis following exposure to environmental stresses. ISR activation has been observed in metabolic diseases, including hepatic steatosis (HS), steatohepatitis (SH), and insulin resistance (IR), but it remains unclear whether ISR contributes to disease pathogenesis or represents an innate defense mechanism against metabolic stresses. Constitutive repressor of eIF2alpha phosphorylation (CReP) is a critical regulatory subunit of the eIF2alpha phosphatase complex. Here, we show that CReP ablation causes constitutive eIF2alpha phosphorylation in the liver, which leads to activation of the ATF4 transcriptional program including increased fibroblast growth factor 21 (FGF21) production. Liver-specific CReP knockout (CRePLKO ) mice exhibited marked browning of white adipose tissue (WAT) and increased energy expenditure and insulin sensitivity in an FGF21-dependent manner. Furthermore, CRePLKO mice were protected from high-fat diet (HFD)-induced obesity, HS, and IR. Acute CReP ablation in liver of HFD-induced obese mice also reduced adiposity and improved glucose homeostasis. Conclusion: These data suggest that CReP abundance is a critical determinant for eIF2alpha phosphorylation and ensuing ISR activation in the liver. Constitutive ISR activation in the liver induces FGF21 and confers protection from HFD-induced adiposity, IR, and HS in mice. Augmenting hepatic ISR may represent a therapeutic approach to treat metabolic disorders. PMID- 29698571 TI - Low-Dose Interleukin-2 for Refractory Autoimmune Hepatitis. PMID- 29698570 TI - Interleukin 2 Promotes Hepatic Regulatory T Cell Responses and Protects From Biliary Fibrosis in Murine Sclerosing Cholangitis. AB - In the multidrug resistance protein 2 (Mdr2)-/- mouse model, low phospholipid bile instigates biliary epithelial injury, sterile inflammation, and fibrosis, thereby recapitulating disease mechanisms implicated in biliary atresia (BA) and primary sclerosing cholangitis. We hypothesize that T lymphocytes contribute to the biliary injury and fibrosis in murine sclerosing cholangitis (SC) and that they are susceptible to suppression by regulatory T cells (Tregs). In juvenile Mdr2-/- mice, intrahepatic CD8+ lymphocytes were expanded, and contraction of intrahepatic Tregs coincided with rising serum alanine transferase and alkaline phosphatase (ALP) levels between days 14-30 of life. Antibody-mediated depletion of intrahepatic CD8+ lymphocytes during that time reduced ALP levels and the expression of osteopontin (Opn), a pro-fibrogenic cytokine. Depletion of intrahepatic Tregs with anti-CD25 antibody between days 7-30 increased intrahepatic CD8+ T cells, Opn expression, and fibrosis. Conversely, expansion of intrahepatic Tregs with interleukin 2/anti-interleukin 2 immune complexes (IL-2c) downregulated hepatic expression of Opn and Tnf, reduced frequency of intrahepatic CD8+ lymphocytes, and diminished biliary injury and fibrosis. Treatment with IL-2c upregulated hepatic Treg expression of CD39, an ectonucleotidase capable of hydrolyzing pro-inflammatory adenosine triphosphate. In vitro, Tregs expressing CD39 suppressed the proliferation of hepatic CD8+ lymphocytes from Mdr2-/- mice more efficiently than those lacking CD39. In infants with BA, infiltration of interlobular bile ducts with CD8+ cells was associated with biliary expression of Opn and its transcription was negatively correlated with mRNA expression of Treg-associated genes. Conclusion: Hepatic CD8+ T lymphocytes drive biliary injury and fibrosis in murine SC. Their proliferation is controlled by hepatic Tregs through the purinergic pathway, which is responsive to IL-2c, suggesting that Treg-directed low-dose Il-2 treatment may be considered as therapy for SC. PMID- 29698572 TI - Attenuated Salmonella VNP20009 mutant (DeltahtrA) is a promising candidate for bacteria-mediated tumour therapy in hosts with TNFR1 deficiency. AB - : VNP20009 is a genetically modified strain of Salmonella typhimurium and has a good anticancer effect wildly used in tumour therapy on animal models. For its clinical application, an accurate bio-safety assessment on sensitive models is necessary. In this study, we use TNFR1 KO mice as a susceptive model to assess the virulence of bacterial VNP20009 and its derivative DeltahtrA. By intraperitoneal administration of Salmonella, the increased lethality was observed in TNFR1 KO mice infected with VNP20009, but not with DeltahtrA. We performed a systemically comparative analysis of their toxicity, and DeltahtrA shows a better bio-safety for TNFR1 KO mice. Since the macrophages with TNFR1 deficiency exhibit a reduced ability of bacteria clearance, DeltahtrA with lower survival ability in normal macrophages restores its viability in TNFR1 KO macrophages. Thus, DeltahtrA was further tested for its antitumour effect in TNFR1 KO mice bearing a B16F10 melanoma model. It displays a moderate antitumour effect, suggesting DeltahtrA instead of VNP20009 might be a promising candidate for bacteria-mediated tumour therapy specific to those with low immunity. SIGNIFICANT AND IMPACT OF THE STUDY: VNP20009 is attenuated Salmonella with a good safety widely used for tumour-targeting bacterial therapies. Little is known about its toxicity in hosts with low immunity. This study is the first systemically comparative analysis of their toxicity of VNP20009 and its mutant DeltahtrA in TNFR1-KO mice. Research on toxicity of tumour-targeting Salmonella in mice with immunodeficiency can facilitate the optimization of bacterial therapies with reduced adverse effects in future clinical trials. PMID- 29698573 TI - The prognostic impact of revascularization strategy in acute myocardial infarction and cardiogenic shock: Insights from the British Columbia Cardiac Registry. AB - BACKGROUND: In patients with acute myocardial infarction (AMI) and cardiogenic shock (CS), percutaneous coronary intervention (PCI) of the culprit vessel is associated with improved outcomes. A large majority of these patients have multivessel disease (MVD). Whether or not PCI of non-culprit disease in the acute setting improves outcomes continues to be debated. We evaluated the prognostic impact of revascularization strategy for patients presenting with AMI and CS. METHODS: We compared culprit vessel intervention (CVI) versus multivessel intervention in 649 patients with AMI, CS, and MVD enrolled in the British Columbia Cardiac Registry. We evaluated mortality at 30 days and 1 year. RESULTS: CVI was associated with lower mortality at 30 days (23.7% vs. 34.5%, P = 0.004) and 1 year (32.6% vs. 44.3%, P = 0.003). CVI was an independent predictor for survival at 30 days (HR = 0.63, 95% CI: 0.45-0.88, P = 0.009) and 1 year (HR = 0.72, 95% CI: 0.54-0.96, P = 0.027). These findings were confirmed in propensity matched cohorts. Subgroup analyses indicated that CVI was associated with lower mortality in patients aged <80 years; non-diabetics; and those presenting with ST elevation MI. When analyzing non-culprit anatomy, PCI of non-culprit LAD disease was associated with higher 1-year mortality (HR = 1.51, 95% CI: 1.13-2.01, P = 0.006), primarily with non-culprit proximal LAD disease (HR = 1.82, 95% CI: 1.20 2.76, P = 0.005). However, PCI of non-culprit non-proximal LAD, LCx, and RCA disease was not associated with mortality. CONCLUSIONS: In patients with AMI and CS, a strategy of CVI appears to be associated with lower mortality. These findings are consistent with recently published randomized-controlled trial data. PMID- 29698575 TI - Severe fire weather and intensive forest management increase fire severity in a multi-ownership landscape. AB - Many studies have examined how fuels, topography, climate, and fire weather influence fire severity. Less is known about how different forest management practices influence fire severity in multi-owner landscapes, despite costly and controversial suppression of wildfires that do not acknowledge ownership boundaries. In 2013, the Douglas Complex burned over 19,000 ha of Oregon & California Railroad (O&C) lands in Southwestern Oregon, USA. O&C lands are composed of a checkerboard of private industrial and federal forestland (Bureau of Land Management, BLM) with contrasting management objectives, providing a unique experimental landscape to understand how different management practices influence wildfire severity. Leveraging Landsat based estimates of fire severity (Relative differenced Normalized Burn Ratio, RdNBR) and geospatial data on fire progression, weather, topography, pre-fire forest conditions, and land ownership, we asked (1) what is the relative importance of different variables driving fire severity, and (2) is intensive plantation forestry associated with higher fire severity? Using Random Forest ensemble machine learning, we found daily fire weather was the most important predictor of fire severity, followed by stand age and ownership, followed by topographic features. Estimates of pre-fire forest biomass were not an important predictor of fire severity. Adjusting for all other predictor variables in a general least squares model incorporating spatial autocorrelation, mean predicted RdNBR was higher on private industrial forests (RdNBR 521.85 +/- 18.67 [mean +/- SE]) vs. BLM forests (398.87 +/- 18.23) with a much greater proportion of older forests. Our findings suggest intensive plantation forestry characterized by young forests and spatially homogenized fuels, rather than pre-fire biomass, were significant drivers of wildfire severity. This has implications for perceptions of wildfire risk, shared fire management responsibilities, and developing fire resilience for multiple objectives in multi-owner landscapes. PMID- 29698574 TI - N-glycan signatures identified in tumor interstitial fluid and serum of breast cancer patients: association with tumor biology and clinical outcome. AB - Particular N-glycan structures are known to be associated with breast malignancies by coordinating various regulatory events within the tumor and corresponding microenvironment, thus implying that N-glycan patterns may be used for cancer stratification and as predictive or prognostic biomarkers. However, the association between N-glycans secreted by breast tumor and corresponding clinical relevance remain to be elucidated. We profiled N-glycans by HILIC UPLC across a discovery dataset composed of tumor interstitial fluids (TIF, n = 85), paired normal interstitial fluids (NIF, n = 54) and serum samples (n = 28) followed by independent evaluation, with the ultimate goal of identifying tumor related N-glycan patterns in blood of patients with breast cancer. The segregation of N-linked oligosaccharides revealed 33 compositions, which exhibited differential abundances between TIF and NIF. TIFs were depleted of bisecting N-glycans, which are known to play essential roles in tumor suppression. An increased level of simple high mannose N-glycans in TIF strongly correlated with the presence of tumor infiltrating lymphocytes within tumor. At the same time, a low level of highly complex N-glycans in TIF inversely correlated with the presence of infiltrating lymphocytes within tumor. Survival analysis showed that patients exhibiting increased TIF abundance of GP24 had better outcomes, whereas low levels of GP10, GP23, GP38, and coreF were associated with poor prognosis. Levels of GP1, GP8, GP9, GP14, GP23, GP28, GP37, GP38, and coreF were significantly correlated between TIF and paired serum samples. Cross-validation analysis using an independent serum dataset supported the observed correlation between TIF and serum, for five of nine N-glycan groups: GP8, GP9, GP14, GP23, and coreF. Collectively, our results imply that profiling of N-glycans from proximal breast tumor fluids is a promising strategy for determining tumor-derived glyco-signature(s) in the blood. N-glycans structures validated in our study may serve as novel biomarkers to improve the diagnostic and prognostic stratification of patients with breast cancer. PMID- 29698576 TI - Prevalence and risk factors for HBV and HCV in prisoners in Iran: a national bio behavioural surveillance survey in 2015. AB - OBJECTIVES: To provide more accurate estimates of the prevalence of Hepatitis B (HBV) and Hepatitis C (HCV) and their contributing factors among prisoners in Iran. METHODS: Cross-sectional study of 6200 Iranian prisoners in 2015. Data were collected through questionnaires and interviews. HBV infection and HCV exposure status of the participants was determined by HBsAg and HCV antibodies blood tests using enzyme-linked immunosorbent assay (ELISA). Data were analysed in STATA-12. RESULT: Prevalence of HCV exposure was 9.48% (95% CI: 8.73-10.27), and prevalence of HBV was 2.48% (95% CI: 2.07-2.89) in the general prison population. In multivariate analysis, the most important risk factor for HBV was a history of drug use in lifetime (adjusted odds ratio, AOR: 1.8, 95% CI: 1.17-3.02). The main risk factors for HCV exposure were a history of drug use in lifetime (AOR: 4.08, CI: 2.56-6.27), age over 30 (AOR: 2.68, CI: 2.01-3.56), and having tattoos (AOR = 1.67, CI: 1.35-2.07). CONCLUSION: Although vaccination is used to control HBV among prisoners, prevalence of HCV exposure is alarming in the prison population of Iran, especially among people who inject drugs. Eliminating viral hepatitis in Iran by 2030 requires a national commitment and rapid measures for targeting this high-risk group. Given the increased efficiency of HCV treatment in recent years, prisons provide an opportunity to access patients for treatment. PMID- 29698578 TI - The Society for Cardiovascular Angiography and Interventions' 41st Annual Scientific Sessions. PMID- 29698579 TI - Regulation of Integrated Stress Response Sensitizes U87MG Glioblastoma Cells to Temozolomide Through the Mitochondrial Apoptosis Pathway. AB - Glioblastomas are the most frequently diagnosed and worst primary malignancy of the central nervous system, with very poor prognosis. The first-line antiglioma drug temozolomide shows decreasing therapeutic efficacy as treatment progresses. As the integrated stress response (ISR) may be a resistance factor and severe stress might transform the protective effect of the ISR into a damage effect, pharmacological regulation of ISR may be an effective way to sensitize glioma to temozolomide. The aim of the present study was to investigate the mechanisms of the ISR in regulating the therapeutic effect of temozolomide in the human glioblastoma multiforme cell line U87MG. Cultured U87MG cells were treated with temozolomide and PCR array was used to screen key factors in the response to treatment. Cells were co-treated with temozolomide and the eIF2alpha phosphatase inhibitor salubrinal, and cell apoptosis was measured. Combination treatment with temozolomide and salubrinal had a synergistic effect on cell viability. Salubrinal could upregulate the expression of ATF4, a key factor in the ISR, and enhance temozolomide-induced apoptosis. ATF4 transcriptionally regulated expression of the BH3-ONLY protein NOXA, thus inducing mitochondrial apoptosis. These findings suggest that ISR and ATF4 are involved in the death crosstalk between the endoplasmic reticulum and mitochondria and might be a potential target to enhance the therapeutic effect of temozolomide in patients with glioblastoma multiforme. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29698577 TI - Fatigue, Pain, and Other Physical Symptoms of Living Liver Donors in the Adult-to Adult Living Donor Liver Transplantation Cohort Study. AB - Little is known about living liver donors' perceptions of their physical well being following the procedure. We collected data on donor fatigue, pain, and other relevant physical outcomes as part of the prospective, multicenter Adult-to Adult Living Donor Liver Transplantation Cohort Study consortium. A total of 271 (91%) of 297 eligible donors were interviewed at least once before donation and 3, 6, 12, and 24 months after donation using validated measures when available. Repeated measures regression models were used to identify potential predictors of worse physical outcomes. We found that donors reported more fatigue immediately after surgery that improved by 2 years after donation, but not to predonation levels. A similar pattern was seen across a number of other physical outcomes. Abdominal or back pain and interference from their pain were rated relatively low on average at all study points. However, 21% of donors did report clinically significant pain at some point during postdonation study follow-up. Across multiple outcomes, female donors, donors whose recipients died, donors with longer hospital stays after surgery, and those whose families discouraged donation were at risk for worse physical well-being outcomes. In conclusion, although not readily modifiable, we have identified risk factors that may help identify donors at risk for worse physical outcomes for targeted intervention. Liver Transplantation 00 000-000 2018 AASLD. PMID- 29698580 TI - Clinical Implications of UCP1 mRNA Expression in Human Cervical Adipose Tissue Under Physiological Conditions. AB - OBJECTIVE: The clinical implications of human brown adipose tissue (BAT) were investigated based on the analysis of cervical adipose tissue gene expression under normal physiological conditions. METHODS: Matched-pair specimens of adipose tissue (AT) were collected from beneath the incision plane (subcutaneous AT) and from the area surrounding the carotid sheath (carotid AT) from 60 patients undergoing thyroidectomy. The mRNA expression of BAT-associated genes in these tissues was examined, and this expression was correlated with the clinical characteristics of the subjects. RESULTS: The UCP1 mRNA level was significantly higher in the carotid AT than in the subcutaneous AT. There was an inverse correlation between subject age and the ratio of UCP1 mRNA expression in the carotid AT relative to the subcutaneous AT, which is a measure of BAT activity (r = -0.459; P = 0.004), and there was a negative correlation between BMI and the ratio of UCP1 mRNA expression in subjects with higher BAT activity (r = -0.532; P = 0.016). CONCLUSIONS: UCP1 was identified as the only marker of cervical BAT in humans. There was a negative correlation between obesity and BAT activity in subjects with higher BAT activity, although BAT activity decreased with age. PMID- 29698581 TI - Segmental Analysis of the Vestibular Nerve and the Efferents of the Vestibular Complex. AB - Use of a segmental approach in the study of vestibular centers in the hindbrain improves morphological and functional understanding of this region controlled by Hox genes, among other molecular determinants. Here, we review accrued data about segmental organization of vestibular afferents and efferents. Inner ear originated vestibular fibers enter the hindbrain, together with auditory ones, through the alar plate of rhombomere 4, then branch into descending and ascending branches to reach appropriate vestibular nuclei along the vestibular column. Classical vestibular nuclei (superior, lateral, medial, and inferior) originate in eight successive rhombomeric segments, which suggests internal subdivisions correlated with distinct connections and functions. The vestibular projection neurons identified for various targets aggregate in discrete groups, which correlate topographically either with rhombomeric units, or with internal subdivisions within them. Each vestibular projection system (e.g., vestibulo spinal, vestibulo-ocular, vestibulocerebellar) has a characteristic ipsilateral/contralateral organization. Comparing them as a connective mosaic in different species shows that various aspects of this segmental connective organization are conserved throughout evolution in vertebrates. Furthermore, certain genes that control the development of the rhombomeric units in the hindbrain may determine, among other aspects, the specific properties of the different neuronal subpopulations related to their axonal navigation and synaptogenesis. Anat Rec, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29698582 TI - Power of lower extremities is most important determinant of agility among physically inactive or active adult people. AB - OBJECTIVE: The purpose of this cross-sectional study was to determine the relationships between agility, running speed, jumping height and length, body mass index, self-report pain in back and in lower extremities, personal factors as self-report health and fitness, and leisure time physical activity in physically inactive or active adult people. METHODS: Altogether, 233 healthy subjects, 149 women (43.0 +/- 7.3 years) and 84 men (44.0 +/- 7.7 years), participated into study. Outcome measures were described in the International Classification of Functioning, Disability and Health domains. RESULTS: Multiple regression analysis showed that jumping length explained 24.6% and 15.3% of the variance associated with agility in women and men (adjusted R2 = .246, p < .001; adjusted R2 = .153, p = .001, respectively). CONCLUSIONS: Jumping length was the main determinant of agility among physically inactive or active women and men. The findings of this study strengthen opinion that the Agility Test for Adults demands also other physical and cognitive characteristics as measured now and their part explaining agility results may be relatively great. We suggest that perception and decision making explain for a great part in agility. It seems that body mass index does not play important role in agility, but physical inactivity can explain or increase the decline of agility. Also, various biological mechanisms in aging process can be linked to the deterioration of capacity of agility. PMID- 29698583 TI - Tree leaf trade-offs are stronger for sub-canopy trees: leaf traits reveal little about growth rates in canopy trees. AB - Can morphological plant functional traits predict demographic rates (e.g., growth) within plant communities as diverse as tropical forests? This is one of the most important next-step questions in trait-based ecology and particularly for global reforestation efforts. Due to the diversity of tropical tree species and their longevity, it is difficult to predict their performance prior to reforestation efforts. In this study, we investigate if simple leaf traits are predictors of the more complex ecological process of plant growth in regenerating selectively logged natural forest within the Wet Tropics (WTs) bioregion of Australia. This study used a rich historical data set to quantify tree growth within plots located at Danbulla National Park and State Forest on the Atherton Tableland. Leaf traits were collected from trees that have exhibited fast or slow growth over the last ~50 yr of measurement. Leaf traits were found to be poor predictors of tree growth for trees that have entered the canopy; however, for sub-canopy trees, leaf traits had a stronger association with growth rates. Leaf phosphorus concentrations were the strongest predictor of Periodic Annual Increment (PAI) for trees growing within the sub-canopy, with trees with higher leaf phosphorus levels showing a higher PAI. Sub-canopy tree leaves also exhibited stronger trade-offs between leaf traits and adhere to theoretical predictions more so than for canopy trees. We suggest that, in order for leaf traits to be more applicable to reforestation, size dependence of traits and growth relationships need to be more carefully considered, particularly when reforestation practitioners assign mean trait values to tropical tree species from multiple canopy strata. PMID- 29698584 TI - RNA epitranscriptomics: Regulation of infection of RNA and DNA viruses by N6 methyladenosine (m6 A). AB - N6 -methyladenosine (m6 A) was discovered 4 decades ago. However, the functions of m6 A and the cellular machinery that regulates its changes have just been revealed in the last few years. m6 A is an abundant internal mRNA modification on cellular RNA and is implicated in diverse cellular functions. Recent works have demonstrated the presence of m6 A in the genomes of RNA viruses and transcripts of a DNA virus with either a proviral or antiviral role. Here, we first summarize what is known about the m6 A "writers," "erasers," "readers," and "antireaders" as well as the role of m6 A in mRNA metabolism. We then review how the replications of numerous viruses are enhanced and restricted by m6 A with emphasis on the oncogenic DNA virus, Kaposi sarcoma-associated herpesvirus (KSHV), whose m6 A epitranscriptome was recently mapped. In the context of KSHV, m6 A and the reader protein YTHDF2 acts as an antiviral mechanism during viral lytic replication. During viral latency, KSHV alters m6 A on genes that are implicated in cellular transformation and viral latency. Lastly, we discuss future studies that are important to further delineate the functions of m6 A in KSHV latent and lytic replication and KSHV-induced oncogenesis. PMID- 29698585 TI - Hv 1 Proton Channels in Dinoflagellates: Not Just for Bioluminescence? AB - Bioluminescence in dinoflagellates is controlled by HV 1 proton channels. Database searches of dinoflagellate transcriptomes and genomes yielded hits with sequence features diagnostic of all confirmed HV 1, and show that HV 1 is widely distributed in the dinoflagellate phylogeny including the basal species Oxyrrhis marina. Multiple sequence alignments followed by phylogenetic analysis revealed three major subfamilies of HV 1 that do not correlate with presence of theca, autotrophy, geographic location, or bioluminescence. These data suggest that most dinoflagellates express a HV 1 which has a function separate from bioluminescence. Sequence evidence also suggests that dinoflagellates can contain more than one HV 1 gene. PMID- 29698586 TI - Selective and context-dependent effects of chemical stress across trophic levels at the basis of marine food webs. AB - Human activities increasingly impact the functioning of marine food webs, but anthropogenic stressors are seldom included in ecological study designs. Diet quality, as distinct from just diet quantity, has moreover rarely been highlighted in food web studies in a stress context. We measured the effects of metal and pesticide stress (copper and atrazine) on the contribution of a benthic intertidal diatom community to two processes that are key to the functioning of intertidal systems: biomass (diet quantity) and lipid (diet quality) production. We then examined if stressors affected diatom functioning by selectively targeting the species contributing most to functioning (selective stress effects) or by changing the species' functional contribution (context-dependent effects). Finally, we tested if stress-induced changes in diet quality altered the energy flow to the diatoms' main grazers (harpacticoid copepods). Diatom diet quantity was reduced by metal stress but not by low pesticide levels due to the presence of an atrazine-tolerant, mixotrophic species. Selective effects of the pesticide reduced diatom diet quality by 60% and 75% at low and high pesticide levels respectively, by shifting diatom community structure from dominance by lipid-rich species toward dominance by an atrazine-tolerant, but lipid-poor, species. Context-dependent effects did not affect individual diatom lipid content at low levels of both stressors, but caused diatoms to lose 40% of their lipids at high copper stress. Stress-induced changes in diet quality predicted the energy flow from the diatoms to their copepod consumers, which lost half of their lipids when feeding on diatoms grown under low and high pesticide and high metal stress. Selective pesticide effects were a more important threat for trophic energy transfer than context-dependent effects of both stressors, with shifts in diatom community structure affecting the energy flow to their copepod grazers at stress levels where no changes in diatom lipid content were detected. PMID- 29698589 TI - ? PMID- 29698587 TI - Selective induction of cancer cell death by VDAC1-based peptides and their potential use in cancer therapy. AB - Mitochondrial VDAC1 mediates cross talk between the mitochondria and other parts of the cell by transporting anions, cations, ATP, Ca2+ , and metabolites and serves as a key player in apoptosis. As such, VDAC1 is involved in two important hallmarks of cancer development, namely energy and metabolic reprograming and apoptotic cell death evasion. We previously developed cell-penetrating VDAC1 derived peptides that interact with hexokinase (HK), Bcl-2, and Bcl-xL to prevent the anti-apoptotic activities of these proteins and induce cancer cell death, with a focus on leukemia and glioblastoma. In this study, we demonstrated the sensitivity of a panel of genetically characterized cancer cell lines, differing in origin and carried mutations, to VDAC1-based peptide-induced apoptosis. Noncancerous cell lines were less affected by the peptides. Furthermore, we constructed additional VDAC1-based peptides with the aim of improving targeting, selectivity, and cellular stability, including R-Tf-D-LP4, containing the transferrin receptor internalization sequence (Tf) that allows targeting of the peptide to cancer cells, known to overexpress the transferrin receptor. The mode of action of the VDAC1-based peptides involves HK detachment, interfering with the action of anti-apoptotic proteins, and thus activating multiple routes leading to an impairment of cell energy and metabolism homeostasis and the induction of apoptosis. Finally, in xenograft glioblastoma, lung, and breast cancer mouse models, R-Tf-D-LP4 inhibited tumor growth while inducing massive cancer cell death, including of cancer stem cells. Thus, VDAC1-based peptides offer an innovative new conceptual framework for cancer therapy. PMID- 29698590 TI - ? PMID- 29698588 TI - "Normal" Creatinine Levels Predict Persistent Kidney Injury and Waitlist Mortality in Outpatients With Cirrhosis. AB - Acute kidney injury (AKI) is a critical determinant of outcomes in hospitalized patients with cirrhosis, but little is known of the impact of AKI in the outpatient setting. We analyzed 385 adult outpatients with cirrhosis listed for liver transplant at a single center; excluded were those with severe hepatic encephalopathy, with hepatocellular carcinoma, or on hemodialysis. Baseline serum creatinine (bCr) was defined as the lowest value recorded, peak Cr as the highest value, DeltaCr as peak Cr minus bCr, AKI as a rise in serum Cr (sCr) by >=0.3 mg/dL from bCr, persistent kidney injury as elevation of sCR by >=0.3 mg/dL from bCr on each subsequent clinical assessment. Among 385 outpatients with cirrhosis, bCr was <=0.70, 0.70-0.97, and >=0.97 mg/dL in 28%, 38%, and 34%, respectively. At a median follow-up of 16 (range 8-28) months, 143 (37%) had one or more AKI episode, which increased significantly by bCr group (24% versus 37% versus 48%, P = 0.001). Of these 143 with AKI, 13% developed persistent kidney injury. A multivariable Cox regression analysis highlighted that bCr (hazard ratio [HR], 2.96) and DeltaCr (HR, 2.05) were the only factors independently associated with the development of persistent kidney injury (P < 0.001). The likelihood of death/delisting increased by bCr group (14% versus 19% versus 28%, P = 0.03). A competing risk analysis demonstrated that each 1 mg/dL increase in bCr was independently associated with a 62% higher risk of death/delisting when accounting for transplantation and adjusting for confounders. Conclusion: AKI is not only common in outpatients with cirrhosis but even "clinically normal" bCr levels significantly impact the risk of persistent kidney injury and waitlist mortality, supporting the need for a lower clinical threshold to initiate monitoring of renal function and implementation of kidney-protective strategies. PMID- 29698591 TI - ? PMID- 29698592 TI - ? PMID- 29698593 TI - ? PMID- 29698594 TI - ? PMID- 29698595 TI - ? PMID- 29698596 TI - ? PMID- 29698597 TI - ? PMID- 29698598 TI - Sequentially Moldable and Bondable Four-Dimensional Hydrogels Compatible with Cell Encapsulation. AB - Hydrogels have captivated the attention of several research and industry segments, including bioengineering, tissue engineering, implantable/wearable sensors and actuators, bioactive agent delivery, food processing, and industrial processes optimization. A common limitation of these systems is their fixed shape. The concept of hydrogel moldability is often assigned to the injectability potential of liquid precursors, and this feature is often lost right after hydrogel formation. Hydrogel modulation is a recent trend that advocates the importance of designing materials with shape fitting ability targeting on-demand responses or defect filling purposes. Here, we present a compliant and cell encapsulation-compatible hydrogel prepared from unmodified natural origin polymers with the ability to undergo extreme sequential shape alterations with high recovery of its mechanical properties. Different fragments of these hydrogels could be bonded together in spatiotemporally controlled shape- and formulation-morphing structures. This material is prepared with affordable off the-shelf polysaccharides of natural origin using a mild and safe processing strategy based solely on polyelectrolyte complexation followed by an innovative partial coacervate compaction and dehydration step. These unique hydrogels hold potential for multifield industrial and healthcare applications. In particular, they may find application as defect filling agents or highly compliant wound healing patches for cargo release and/or cell delivery for tissue regeneration and cell-based therapies. PMID- 29698599 TI - Chemo-Enzymatic Synthesis of Poly(4-piperidine lactone- b-omega-pentadecalactone) Block Copolymers as Biomaterials with Antibacterial Properties. AB - With increasing troubles in bacterial contamination and antibiotic-resistance, new materials possessing both biocompatibility and antimicrobial efficacy are supposed to be developed for future biomedical application. Herein, we demonstrated a chemo-enzymatic ring opening polymerization (ROP) approach for block copolyester, that is, poly(4-benzyl formate piperidine lactone- b-omega pentadecalactone) (PNPIL- b-PPDL), in a one-pot two-step process. Afterward, cationic poly(4-piperidine lactone- b-omega-pentadecalactone) (PPIL- b-PPDL) with pendent secondary amino groups was obtained via acidic hydrolysis of PNPIL- b PPDL. The resulting cationic block copolyester exhibited high antibacterial activity against Gram negative E. coli and Gram positive S. aureus, while showed low toxicity toward NIH-3T3 cells. Moreover, the antibacterial property, cytotoxicity and degradation behavior could be tuned simply by variation of PPIL content. Therefore, we anticipate that such cationic block copolymers could potentially be applied as biomaterials for medicine or implants. PMID- 29698600 TI - Development and Analytical Characterization of Pegunigalsidase Alfa, a Chemically Cross-Linked Plant Recombinant Human alpha-Galactosidase-A for Treatment of Fabry Disease. AB - The current treatment of Fabry disease by enzyme replacement therapy with commercially available recombinant human alpha-Galactosidase A shows a continuous deterioration of the disease patients. Human recombinant alpha-Galactosidase A is a homodimer with noncovalently bound subunits and is expressed in the ProCellEx plant cell-based protein expression platform to produce pegunigalsidase alfa. The effect of covalent bonding between two alpha-Galactosidase A subunits by PEG based cross-linkers of various lengths was evaluated in this study. The results show that cross-linking by a bifunctional PEG polymer of 2000 Da produces a more stable protein with improved pharmacokinetic and biodistribution properties. The chemical modification did not influence the tertiary protein structure but led to an increased thermal stability and showed partial masking of immune epitopes. The developed pegunigalsidase alfa is currently tested in phase III clinical trials and has a potential to show superior efficacy versus the currently used enzyme replacement therapies in the treatment of Fabry disease patients. PMID- 29698601 TI - Evaluating the Effects of Geometry and Charge Flux in Force Field Modeling. AB - We apply a model for analyzing the importance of conformational charge flux to 11 molecules with the R-(CH2) n-R structure (R = Cl, F, OH, SH, COOH, CONH2, and NH2 and n = 4-6). Atomic charges were obtained by fitting to results from density functional theory calculations using the HLY procedure, and their geometry dependence is decomposed into contributions from changes in bond lengths, bond angles, and torsional angles. The torsional degrees of freedom are the main contribution to the conformational dependence of atomic charges and molecular dipole moments, but indirect effects due to changes in bond distances and angles account for ~15% of the variations. While the magnitude of charge flux and geometry effects have been found to be independent of the number of internal degrees of freedom, the nature of the R- group has a moderate influence. The indirect effects are comparable for all of the R-groups and are approximately one half the magnitude of the corresponding effects in peptide models. However, the magnitudes are different, yet the relative importance of geometry and charge flux effects are completely similar to those of the peptide models, which suggests that modeling the charge flux effects for changes in bond lengths, bond angles, and torsional angles should be considered for developing improved force fields. PMID- 29698602 TI - One Size Does Not Fit All: The Effect of Chain Length and Charge Density of Poly(ethylene imine) Based Copolymers on Delivery of pDNA, mRNA, and RepRNA Polyplexes. AB - Nucleic acid delivery systems are commonly translated between different modalities, such as DNA and RNA of varying length and structure, despite physical differences in these molecules that yield disparate delivery efficiency with the same system. Here, we synthesized a library of poly(2-ethyl-2 oxazoline)/poly(ethylene imine) copolymers with varying molar mass and charge densities in order to probe how pDNA, mRNA, and RepRNA polyplex characteristics affect transfection efficiency. The library was utilized in a full factorial design of experiment (DoE) screening, with outputs of luciferase expression, particle size, surface charge, and particle concentration. The optimal copolymer molar mass and charge density was found as 83 kDa/100%, 72 kDa/100%, and 45 kDa/80% for pDNA, RepRNA, and mRNA, respectively. While 10 of the synthesized copolymers enhanced the transfection efficiency of pDNA and mRNA, only 2 copolymers enhanced RepRNA transfection efficiency, indicating a narrow and more stringent design space for RepRNA. These findings suggest that there is not a "one size fits all" polymer for different nucleic acid species. PMID- 29698604 TI - Cytocompatibility and Cellular Internalization of PEGylated "Clickable" Nucleic Acid Oligomers. AB - The recently developed synthetic oligonucleotides referred to as "click" nucleic acids (CNAs) are promising due to their relatively simple synthesis based on thiol-X reactions with numerous potential applications in biotechnology, biodetection, gene silencing, and drug delivery. Here, the cytocompatibility and cellular uptake of rhodamine tagged, PEGylated CNA copolymers (PEG-CNA-RHO) were evaluated. NIH 3T3 fibroblast cells treated for 1 h with 1, 10, or 100 MUg/mL PEG CNA-RHO maintained an average cell viability of 86%, which was not significantly different from the untreated control. Cellular uptake of PEG-CNA-RHO was detected within 30 s, and the amount internalized increased over the course of 1 h. Moreover, these copolymers were internalized within cells to a higher degree than controls consisting of either rhodamine tagged PEG or the rhodamine alone. Uptake was not affected by temperature (i.e., 4 or 37 degrees C), suggesting a passive uptake mechanism. Subcellular colocalization analysis failed to indicate significant correlations between the internalized PEG-CNA-RHO and the organelles examined (mitochondria, endoplasmic reticulum, endosomes and lysosomes). These results indicate that CNA copolymers are cytocompatible and are readily internalized by cells, supporting the idea that CNAs are a promising alternative to DNA in antisense therapy applications. PMID- 29698605 TI - Bioinspired Synthesis of Au Nanostructures Templated from Amyloid beta Peptide Assembly with Enhanced Catalytic Activity. AB - Peptides have been regarded as useful biomolecule templates to control the synthesis of various inorganic nanomaterials in mild conditions. Inspired by this, the easily self-assembled amyloid beta (Abeta) peptide was developed as an alternative template to prepare Au nanostructures for the enhanced catalytic activity, for instance, the reduction of 4-nitrophenol. The presence of Abeta peptide assemblies with different structures could direct the nucleation of Au to form different Au nanostructures. Using the Abeta25-35 monomers, nanoribbons, and nanofibrils prepared by the self-assembly in phosphate buffered (PB) solution at 0, 3, and 12 h, respectively, as templates could controllably prepare Au nanospheres, nanoribbons, and nanofibers, while the Abeta25-35 monomers prepared by the self-assembly in water at 0 h could direct the synthesis of Au nanoflowers. The Abeta25-35-templated Au nanostructures had different catalytic activities due to the size and structure effects, which however are significantly enhanced as compared with the template-free Au nanoparticles. PMID- 29698603 TI - Zwitterionic PEG-PC Hydrogels Modulate the Foreign Body Response in a Modulus Dependent Manner. AB - Reducing the foreign body response (FBR) to implanted biomaterials will enhance their performance in tissue engineering. Poly(ethylene glycol) (PEG) hydrogels are increasingly popular for this application due to their low cost, ease of use, and the ability to tune their compliance via molecular weight and cross-linking densities. PEG hydrogels can elicit chronic inflammation in vivo, but recent evidence has suggested that extremely hydrophilic, zwitterionic materials and particles can evade the immune system. To combine the advantages of PEG-based hydrogels with the hydrophilicity of zwitterions, we synthesized hydrogels with comonomers PEG and the zwitterion phosphorylcholine (PC). Recent evidence suggests that stiff hydrogels elicit increased immune cell adhesion to hydrogels, which we attempted to reduce by increasing hydrogel hydrophilicity. Surprisingly, hydrogels with the highest amount of zwitterionic comonomer elicited the highest FBR. Lowering the hydrogel modulus (165 to 3 kPa), or PC content (20 to 0 wt %), mitigated this effect. A high density of macrophages was found at the surface of implants associated with a high FBR, and mass spectrometry analysis of the proteins adsorbed to these gels implicated extracellular matrix, immune response, and cell adhesion protein categories as drivers of macrophage recruitment. Overall, we show that modulus regulates macrophage adhesion to zwitterionic-PEG hydrogels, and demonstrate that chemical modifications to hydrogels should be studied in parallel with their physical properties to optimize implant design. PMID- 29698606 TI - Charge Transfer Switching in Donor-Acceptor Systems Based on BN-Fused Naphthalimides. AB - Six-membered azaborine rings have been straightforwardly fused on naphthalimide based donor-acceptor systems, and a series of BN-containing heteroaromatic compounds BN1-BN3 were constructed. Electron-donating triphenylamines were functionalized in the extended direction of the 3- or/and 4-position of the naphthalimide unit. For comparison, reference BN0 without triphenylamine was also prepared. The intramolecular charge transfer (ICT) interactions in the resulting BN-fused naphthalimides (BN0-BN3) together with their precursors (N0-N3) and fluoride-coordinated analogues (FBN0-FBN3) have been systematically investigated by photophysical, electrochemical, and theoretical approaches. It is found that the fusion of the azaborine ring has a great effect on the ICT properties of the D-A systems based on BN-fused naphthalimides. For the precursors without boron, the extension of an electron donor from the 3-position of naphthalimide is superior in enhancing the D-A interactions. On the contrary, upon fusion of the azaborine ring on naphthalimide, the dominant orientation of the ICT interactions conversely converts to the extended direction of the 4-position of naphthalimide in the D-A molecules based on BN-fused naphthalimides. Most interestingly, upon coordinating the boron by a fluoride ion, the ICT interactions are dramatically enlarged and the substitution position of the triphenylamino group has a negligible effect on the ICT properties of the fluoride-coordinated analogues. PMID- 29698607 TI - Most Ligand-Based Classification Benchmarks Reward Memorization Rather than Generalization. AB - Undetected overfitting can occur when there are significant redundancies between training and validation data. We describe AVE, a new measure of training validation redundancy for ligand-based classification problems, that accounts for the similarity among inactive molecules as well as active ones. We investigated seven widely used benchmarks for virtual screening and classification, and we show that the amount of AVE bias strongly correlates with the performance of ligand-based predictive methods irrespective of the predicted property, chemical fingerprint, similarity measure, or previously applied unbiasing techniques. Therefore, it may be the case that the previously reported performance of most ligand-based methods can be explained by overfitting to benchmarks rather than good prospective accuracy. PMID- 29698609 TI - Substituent Effect in the First Excited Singlet State of Monosubstituted Benzenes. AB - sEDA, pEDA, and cSAR descriptors of the substituent effect were determined for >30 monosubstituted benzenes in the first excited singlet S1 state at the LC omegaB97XD/aug-cc-pVTZ level. It was found that in the S1 state, the sigma- and pi-valence electrons are a bit less and a bit more affected, respectively, than in the S0 state, but basically, the effect in both states remains the same. In the S0 and S1 states, the d(C-X) distances to the substituent's first atom and the ring perimeter correlate with the sEDA and pEDA in the appropriate states, respectively. The energies and the gap of the frontier orbitals in the two states are linearly correlated and for the HOMO(S1), LUMO(S1), and HOMO(S1)-LUMO(S1) gap correlate also with the pEDA(S1) and cSAR(S1) descriptors. In all studied correlations, three similar groups of substituents can be distinguished, for which correlations (i) are very good, (ii) deviate slightly, and (iii) deviate significantly. Comparison of the shape of the HOMO(S0) and HOMO(S1) orbitals shows that for case (i) HOMO orbitals exhibit almost perfect antisymmetry against the benzene plane, for case (ii) the antisymmetry of HOMO in one of the states is either perturbed or changed, and for case (iii) one HOMO state has sigma character. PMID- 29698608 TI - Maximal Unbiased Benchmarking Data Sets for Human Chemokine Receptors and Comparative Analysis. AB - Chemokine receptors (CRs) have long been druggable targets for the treatment of inflammatory diseases and HIV-1 infection. As a powerful technique, virtual screening (VS) has been widely applied to identifying small molecule leads for modern drug targets including CRs. For rational selection of a wide variety of VS approaches, ligand enrichment assessment based on a benchmarking data set has become an indispensable practice. However, the lack of versatile benchmarking sets for the whole CRs family that are able to unbiasedly evaluate every single approach including both structure- and ligand-based VS somewhat hinders modern drug discovery efforts. To address this issue, we constructed Maximal Unbiased Benchmarking Data sets for human Chemokine Receptors (MUBD-hCRs) using our recently developed tools of MUBD-DecoyMaker. The MUBD-hCRs encompasses 13 subtypes out of 20 chemokine receptors, composed of 404 ligands and 15756 decoys so far and is readily expandable in the future. It had been thoroughly validated that MUBD-hCRs ligands are chemically diverse while its decoys are maximal unbiased in terms of "artificial enrichment", "analogue bias". In addition, we studied the performance of MUBD-hCRs, in particular CXCR4 and CCR5 data sets, in ligand enrichment assessments of both structure- and ligand-based VS approaches in comparison with other benchmarking data sets available in the public domain and demonstrated that MUBD-hCRs is very capable of designating the optimal VS approach. MUBD-hCRs is a unique and maximal unbiased benchmarking set that covers major CRs subtypes so far. PMID- 29698610 TI - Optical Properties of Vibronically Coupled Cy3 Dimers on DNA Scaffolds. AB - We examine the effect of electronic coupling on the optical properties of Cy3 dimers attached to DNA duplexes as a function of base pair (bp) separation using steady-state and time-resolved spectroscopy. For close Cy3-Cy3 separations, 0 and 1 bp between dyes, intermediate to strong electronic coupling is revealed by modulation of the absorption and fluorescence properties including spectral band shape, peak wavelength, and excited-state lifetime. Using a vibronic exciton model, we estimate coupling strengths of 150 and 266 cm-1 for the 1 and 0 bp separations, respectively, which are comparable to those found in natural light harvesting complexes. For the strongest electronic coupling (0 bp separation), we observe that the absorption band shape is strongly affected by the base pairs that surround the dyes, where more strongly hydrogen-bonded G-C pairs produce a red-shifted absorption spectrum consistent with a J-type dimer. This effect is studied theoretically using molecular dynamics simulation, which predicts an in line dye configuration that is consistent with the experimental J-type spectrum. When the Cy3 dimers are in a standard aqueous buffer, the presence of relatively strong electronic coupling is accompanied by decreased fluorescence lifetime, suggesting that it promotes nonradiative relaxation in cyanine dyes. However, we show that the use of a viscous solvent can suppress this nonradiative recombination and thereby restore the dimer fluorescent emission. Ultrafast transient absorption measurements of Cy3 dimers in both standard aqueous buffer and viscous glycerol buffer suggest that sufficiently strong electronic coupling increases the probability of excited-state relaxation through a dark state that is related to Cy3 torsional motion. PMID- 29698611 TI - Selenium deficiency in mineral-rich mid-Western Australia. AB - CONTEXT: Selenium is an essential micronutrient for human beings. Selenoproteins play a role in anti-oxidation and in maintaining immunity. Selenoproteins are distributed in all tissues, the most important of which are glutathione peroxidase, thioredoxin reductase and deiodinases. The deiodinases are selenium dependent enzymes. ISSUES: An elderly man with lethargy and tiredness who had normal free thyroid hormone T4, thyroid-stimulating hormone and a low T3 with subnormal temperature and low selenium level. Selenium supplementation normalised thyroid function tests. LESSONS LEARNED: Physicians should have high level of suspicion to identify selenium deficiency as an effective replacement will cure the causative disorder. PMID- 29698612 TI - Reply to Martelli et al.: eHealth in Cystic Fibrosis: Promising, but Proof of Concept Is Still Needed. PMID- 29698613 TI - eHealth in Cystic Fibrosis: Promising, but Proof of Concept Is Still Needed. PMID- 29698614 TI - Expression and Functional Analysis of CST1 in Intractable Nasal Polyps. AB - In this study, we found Cystatin SN (CST1), a type 2 cystatin subfamily member, to be highly expressed in nasal polyps from patients with intractable chronic rhinosinusitis (CRS) with nasal polyps, using a whole-transcript analysis with next-generation sequencing. Eosinophilic CRS (ECRS) involves nasal polyps that are refractory and recur immediately after endoscopic sinus surgery. We hypothesized that CST1 may contribute to the pathogenesis of ECRS. We examined the expression of CST1 in nasal polyps from patients with ECRS by assessing mRNA expression levels using real-time PCR and immunohistochemistry. CST1 showed significantly greater expression in the epithelial cells of nasal polyps from patients with ECRS than in those from patients who did not have ECRS (non-ECRS). In particular, CST1 showed very strong expression in patients with severe ECRS. The expression of CST1 may be correlated with the recurrent and refractory nature of ECRS. We examined the function of CST1 using nasal epithelial cells and nasal fibroblasts. Stimulation by a combination of IL-4 plus double-stranded RNA plus CST1 significantly elevated mRNA expression levels and protein levels of TSLP in nasal epithelial cells. Stimulation by TSLP or IL-33 significantly elevated mRNA expression levels of CST1 in nasal epithelial cells. Stimulation of CST1 significantly elevated mRNA expression levels of CCL11 and POSTN in nasal fibroblasts. CST1 could amplify eosinophilic infiltration and T-helper cell type 2 inflammation by interacting with epithelial-derived cytokines and fibroblasts on nasal polyps. CST1 may be involved in the pathogenesis of ECRS, and may contribute to the severity and recurrence of CRS with nasal polyps after endoscopic sinus surgery. PMID- 29698615 TI - Idiopathic Pulmonary Fibrosis: Cell Death and Inflammation Revisited. PMID- 29698616 TI - Mitigating Lung Fibrosis by Targeting Dysfunctional Alveolar Epithelial Cell Lipid Metabolism. PMID- 29698617 TI - Wide coverage of the body surface by melanocyte-mediated skin pigmentation. AB - Skin pigmentation is a powerful defense against ultraviolet irradiation. Particularly in humans, the body surface needs to be widely covered by protective pigmentation, and melanocytes, a major lineage of neural crest derivatives, have evolved several maneuvers to transfer melanin pigment to the skin. Recent studies with embryonic melanocytes of chickens and mice have revealed sequential events mediated by melanocytes to maximize the skin coverage by pigmentation. These processes include the migration of melanocyte precursors in the embryo, the microscopic uniform spacing of individual melanocytes, and melanosome transfer from melanocytes to keratinocytes. In particular, in vivo/ex vivo live-imaging techniques of melanosome transfer and a quantitative method to evaluate the distribution patterns of melanocytes have greatly advanced our understanding of how a limited number of cells can implement a maximal coverage of the large surface area of a developing body. PMID- 29698618 TI - Response to 17-alpha hydroxyprogesterone caproate. PMID- 29698619 TI - Flavan enantiomers from Daphne giraldii selectively induce apoptotic cell death in p53-null hepatocarcinoma cells in vitro. AB - Hepatocellular carcinoma (HCC) is a primary malignant tumor with very poor prognosis. To search for more effective compounds for HCC treatment, two new pairs of flavan enantiomers, daphnegiranol C1/C2 (1a/1b) and daphnegiranol D1/D2 (2a/2b), were isolated from the stem bark and roots of Daphne giraldii by using chiral chromatography. MTT assay was applied to evaluate their cytotoxicity against three hepatocarcinoma cell lines (Hep3B, MHCC97H, HepG2) as well as a normal liver cell line L02. The results showed that these compounds preferred to inhibit the growth of Hep3B cells (p53 null). Among them, 2a/2b (the IC50 value was 4.87 and 3.35 MUM, respectively) exhibited a stronger cytotoxic effect than sorafenib (IC50 = 6.59 MUM) in Hep3B cells. A further study demonstrated that 2a/2b could induce apoptotic cell death with an increase in reactive oxygen species (ROS) in Hep3B cells. In addition, the IC50 values of 2a/2b in HepG2 and MHCC97H cells (both harbored p53 gene) were more than 10-folds greater when compared with Hep3B cells, indicating that 2a/2b selectively exhibited cytotoxicity in p53-null hepatocarcinoma cells. Moreover, inhibition of p53 increased the inhibitory effect in p53-wild hepatocarcinoma cells, as well as apoptotic cells and ROS generation. Taken together, flavan enantiomers 2a/2b selectively induced apoptosis in Hep3B cells because of p53 deficiency. PMID- 29698620 TI - Cytochrome P450 mediated metabolic activation of chrysophanol. AB - Chrysophanol, a major anthraquinone component occurring in many traditional Chinese herbs, is accepted as important active component with various pharmacological actions such as antibacterial and anticancer activity. Previous studies demonstrated that exposure to chrysophanol induced cytotoxicity, but the mechanisms of the toxic effects remain unknown. In the present metabolism study, three oxidative metabolites (M1-M3, aloe-emodine, 7-hydroxychrysophanol, and 2 hydroxychrysophanol) and five GSH conjugates (M4-M8) were detected in rat and human liver microsomal incubations of chrysophanol supplemented with GSH, and the formation of the metabolites was NADPH dependent except M4 and M5. M4 and M5 were directly derived from parent compound chrysophanol, M6 arose from M2, and M7 and M8 resulted from the oxidation of M4 and M5. Metabolites M5 and M6 were also observed in bile of rats after exposure to chrysophanol, M1-M3 and one NAC conjugate (M9) were detected in urine of rats administrated chrysophanol, and urinary metabolite M9 originated from the degradation of biliary GSH conjugation M6. Recombinant P450 enzyme incubation and microsome inhibition studies demonstrated that P450 1A2 was the primary enzyme responsible for the metabolic activation of chrysophanol and that P450 2B6 and P450 3A4 also participated in the generation of the oxidative metabolites. These findings helped us to understand the mechanisms of chrysophanol-induced cytotoxicity. PMID- 29698621 TI - Diagnostic and prognostic value of H-FABP in acute coronary syndrome: Still evidence to bring. AB - The assessment of chest pain patients presenting to the emergency area (EA) is still a clinical challenge, as the majority of patients are not diagnosed with acute coronary syndrome (ACS). New generation high sensitivity c-Tn (hs-cTn) assays have showed better performances compared to the standard c-Tn. However, hs Tn still presents some limitations. Hence, novel, early biomarkers are needed in this setting. Among all, heart-type fatty acid binding protein (H-FABP) has been largely investigated. This article reviews the studies evaluating H-FABP performance in diagnosing acute myocardial infarction (AMI) and stratifying chest pain patients by risk. H-FABP optimal performances in ACS have been reported by studies that used low threshold for positivity, or compared the biomarker to cTn at 3-6 h, or by studies with small sample size. Literature review allows stating that H-FABP is clearly not a reliable marker in ACS, as it is unable to diagnose AMI, neither as a stand-alone test nor combined with hs-cTn. Few evidence supports its incremental value in ruling-out AMI and its risk stratification ability for chest pain patients presenting to EA. Thus, available data may not encourage going on investigating. PMID- 29698622 TI - Editorial Comment. PMID- 29698623 TI - Reply by Authors. PMID- 29698624 TI - Correction. PMID- 29698625 TI - Sphingolipids as targets for inhalation treatment of cystic fibrosis. AB - Studies over the past several years have demonstrated the important role of sphingolipids in cystic fibrosis (CF), chronic obstructive pulmonary disease and acute lung injury. Ceramide is increased in airway epithelial cells and alveolar macrophages of CF mice and humans, while sphingosine is dramatically decreased. This increase in ceramide results in chronic inflammation, increased death of epithelial cells, release of DNA into the bronchial lumen and thereby an impairment of mucociliary clearance; while the lack of sphingosine in airway epithelial cells causes high infection susceptibility in CF mice and possibly patients. The increase in ceramide mediates an ectopic expression of beta1 integrins in the luminal membrane of CF epithelial cells, which results, via an unknown mechanism, in a down-regulation of acid ceramidase. It is predominantly this down-regulation of acid ceramidase that results in the imbalance of ceramide and sphingosine in CF cells. Correction of ceramide and sphingosine levels can be achieved by inhalation of functional acid sphingomyelinase inhibitors, recombinant acid ceramidase or by normalization of beta1-integrin expression and subsequent re-expression of endogenous acid ceramidase. These treatments correct pulmonary inflammation and prevent or treat, respectively, acute and chronic pulmonary infections in CF mice with Staphylococcus aureus and mucoid or non mucoid Pseudomonas aeruginosa. Inhalation of sphingosine corrects sphingosine levels only and seems to mainly act against the infection. Many antidepressants are functional inhibitors of the acid sphingomyelinase and were designed for systemic treatment of major depression. These drugs could be repurposed to treat CF by inhalation. PMID- 29698626 TI - Mechanistical retinal drug targets and challenges. AB - The retina is constantly exposed to light that increases reactive oxygen species in retina. Oxidative stress, inflammation and neurodegeneration are the major contributors in the most common retinal diseases, such as age-related macular degeneration (AMD), glaucoma and diabetic retinopathy (DR). Emerging developments and research for novel therapy targets and drug delivery to the posterior segment offer a promising future for the treatment of retinal diseases including rare hereditary diseases. In this review we discuss about promising mechanistical retinal drug targets. Vascular endothelial growth factor (VEGF) signaling and anti-VEGF treatments are excluded. PMID- 29698627 TI - Bronchial mucosal IFN-alpha/beta and pattern recognition receptor expression in patients with experimental rhinovirus-induced asthma exacerbations. AB - BACKGROUND: The innate immune system senses viral infection through pattern recognition receptors (PRRs), leading to type I interferon production. The role of type I interferon and PPRs in rhinovirus-induced asthma exacerbations in vivo are uncertain. OBJECTIVES: We sought to compare bronchial mucosal type I interferon and PRR expression at baseline and after rhinovirus infection in atopic asthmatic patients and control subjects. METHODS: Immunohistochemistry was used to detect expression of IFN-alpha, IFN-beta, and the PRRs: Toll-like receptor 3, melanoma differentiation-associated gene 5, and retinoic acid inducible protein I in bronchial biopsy specimens from 10 atopic asthmatic patients and 15 nonasthmatic nonatopic control subjects at baseline and on day 4 and 6 weeks after rhinovirus infection. RESULTS: We observed IFN-alpha/beta deficiency in the bronchial epithelium at 3 time points in asthmatic patients in vivo. Lower epithelial IFN-alpha/beta expression was related to greater viral load, worse airway symptoms, airway hyperresponsiveness, and reductions in lung function during rhinovirus infection. We found lower frequencies of bronchial subepithelial monocytes/macrophages expressing IFN-alpha/beta in asthmatic patients during infection. Interferon deficiency at baseline was not accompanied by deficient PRR expression in asthmatic patients. Both epithelial and subepithelial PRR expression were induced during rhinovirus infection. Rhinovirus infection-increased numbers of subepithelial interferon/PRR-expressing inflammatory cells were related to greater viral load, airway hyperresponsiveness, and reductions in lung function. CONCLUSIONS: Bronchial epithelial IFN-alpha/beta expression and numbers of subepithelial IFN-alpha/beta expressing monocytes/macrophages during infection were both deficient in asthmatic patients. Lower epithelial IFN-alpha/beta expression was associated with adverse clinical outcomes after rhinovirus infection in vivo. Increases in numbers of subepithelial cells expressing interferon/PRRs during infection were also related to greater viral load/illness severity. PMID- 29698628 TI - Dexamethasone induces omega3-derived immunoresolvents driving resolution of allergic airway inflammation. PMID- 29698629 TI - Ag-NPs induce apoptosis, mitochondrial damages and MT3/OSGIN2 expression changes in an in vitro model of human dental-pulp-stem-cells-derived neurons. AB - Silver nanoparticles (Ag-NPs) are one of the most popular nanotechnologies because of their unique antibacterial and antifungal properties. Given their increasing use in a wide range of commercial, biomedical and food products, exposure to Ag-NPs is now a reality in people's lives. However, there is a serious lack of information regarding their potential toxic effects in the central nervous system. In this study, we investigated the biocompatibility of "homemade" Ag-NPs in an in vitro model of human neurons derived from dental pulp mesenchymal stem cells. Our results showed that acute exposure to Ag-NPs cause cytotoxicity, by triggering cell apoptosis, damaging neuronal connections, affecting the mitochondrial activity and changing the mRNA expression level of MT3 and OSGIN2, two genes involved in heavy metals metabolism and cellular growth during oxidative stress conditions. Further studies are needed to understand the molecular mechanisms and the physiological consequences underlying Ag-NPs exposure. PMID- 29698630 TI - An integrated system for synchronous detection of neuron spikes and dopamine activities in the striatum of Parkinson monkey brain. AB - BACKGROUND: Synchronous detecting neuron spikes and dopamine (DA) activities in the non-human primate brain play an important role in understanding of Parkinson's disease (PD). At present, most experiments are carried out by combing of electrodes and commercial instruments, which are inconvenient, time-consuming and inefficient. NEW METHOD: Herein, this study describes a novel integrated system for monitoring neuron spikes and DA activities in non-human primate brain synchronously. This system integrates an implantable sensor, a dual-function head stage and a low noise detection instrument. METHODS: The system was developed efficiently by using the key technologies of noise reduction, interference protection and differential amplification. To demonstrate the utility of this system, synchronous recordings of electrophysiological signals and DA were in vivo performed in a monkey before and after treated as a Parkinson model monkey. RESULTS: The system typically exhibited input-referred noise levels of only ~ 3 MUVRMS, input impedance levels of up to 5.1 GOmega, and a sensitivity of 14.075 pA/MUM for DA and could detect electrophysiological signals and DA without mutual interference. In monkey experiments, lower DA concentrations in the striatum and more intensive spikes of the Parkinson model monkey than the normal one were synchronously recorded efficiently. COMPARISON WITH EXISTING METHODS: This integrated system will not only significantly simplify the experimental operation and improve the experimental efficiency, but also improve the signal quality and synchronization performance. CONCLUSIONS: This integrated system, which is practical, efficient and convenient, can be widely used for the study of PD and other neurological disorders. PMID- 29698631 TI - A constitutively expressed antifungal peptide protects Tenebrio molitor during a natural infection by the entomopathogenic fungus Beauveria bassiana. AB - Antimicrobial peptides have been well studied in the context of bacterial infections. Antifungal peptides have received comparatively less attention. Fungal pathogens of insects and their hosts represent a unique opportunity to study host-pathogen interactions due to the million of years of co-evolution they share. In this study, we investigated role of a constitutively expressed thaumatin-like peptide with antifungal activity expressed by the mealworm beetle Tenebrio molitor, named Tenecin 3, during a natural infection with the entomopathogenic fungus Beauveria bassiana. We monitored the effect of the expression of Tenecin 3 on the survival of infected hosts as well as on the progression of the fungal infection inside the host. Finally, we tested the activity of Tenecin 3 against B. bassiana. These findings could help improving biocontrol strategies and help understanding the evolution of antifungal peptides as a defense mechanism. PMID- 29698632 TI - FGIN-1-27, an agonist at translocator protein 18 kDa (TSPO), produces anti anxiety and anti-panic effects in non-mammalian models. AB - FGIN-1-27 is an agonist at the translocator protein 18 kDa (TSPO), a cholesterol transporter that is associated with neurosteroidogenesis. This protein has been identified as a peripheral binding site for benzodiazepines; in anamniotes, however, a second TSPO isoform that is absent in amniotes has been implicated in erythropoiesis. Functional conservation of the central benzodiazepine-binding site located in the GABAA receptors has been demonstrated in anamniotes and amniotes alike; however, it was not previously demonstrated for TSPO. The present investigation explored the behavioral effects of FGIN-1-27 on an anxiety test in zebrafish (Danio rerio, Family: Cyprinide) and on a mixed anxiety/panic test on wall lizards (Tropidurus oreadicus, Family: Tropiduridae). Results showed that FGIN-1-27 reduced anxiety-like behavior in the zebrafish light/dark preference test similar to diazepam, but with fewer sedative effects. Similarly, FGIN-1-27 also reduced anxiety- and fear-like behaviors in the defense test battery in wall lizards, again producing fewer sedative-like effects than diazepam; the benzodiazepine was also unable to reduce fear-like behaviors in this species. These results A) underline the functional conservation of TSPO in defensive behavior in anamniotes; B) strengthen the proposal of using anamniote behavior as models in behavioral pharmacology; and C) suggest TSPO/neurosteroidogenesis as a target in treating anxiety disorders. PMID- 29698634 TI - Function-Related Protein Expression in Fuchs Endothelial Corneal Dystrophy Cells and Tissue Models. AB - Fuchs endothelial corneal dystrophy (FECD) is a corneal pathology that affects the endothelial cell's ability to maintain deturgescence, resulting in a progressive loss of corneal transparency. In this study, we investigated the expression of function-related proteins in corneal endothelial cells using FECD or healthy corneal endothelial cells, either in a cell culture two-dimensional model or in an engineered corneal endothelium three-dimensional tissue model. No statistically significant difference in gene regulation was observed for the function-related families ATP1, SLC4, SLC16, AQP, TJP, and CDH between the FECD and the healthy cell models. Similarly, no difference in barrier integrity (transendothelial electrical resistance measurements and permeability assays) was observed in vitro between FECD and healthy cultured cells. Protein expression of the key function-related families was decreased for Na+/K+-ATPase alpha1 subunit, monocarboxylate transporters 1 and 4 in native ex vivo end-stage FECD specimens, whereas it returned to levels comparable to that of healthy tissues in the engineered FECD model. These results indicate that cell expansion and tissue engineering culture conditions can generate a corneal endothelium from pathologic FECD cells, with levels of function-related proteins similar to that of healthy tissues. Overall, these results explain why it is possible to reform a functional endothelium using corneal endothelial cells isolated from nonfunctional FECD pathologic specimens. PMID- 29698635 TI - Exosomal miR-21a-5p mediates cardioprotection by mesenchymal stem cells. AB - Though experimental, stem cell transplantation has the potential to improve the condition of the heart after myocardial infarction. It does so by reducing infarct size and inducing repair of heart muscle and its blood supply. Mesenchymal stem cells (MSC) have been found to be effective in pre-clinical animal models and clinical trials, but the mechanisms by which they induce cardioprotection and repair are still not fully understood. Small extracellular vesicles known as exosomes are now recognized to be key mediators of beneficial MSC paracrine effects, and the concept that they transfer miRNA to change gene expression in recipient cells is of current therapeutic interest. We present complete deep miRNA sequencing of MSC exosome cargo, and found that of several cardioprotective miRNAs, miR-21a-5p was the most abundant. Because miR-21a-5p is a well-known cardioprotective miRNA, we investigated the hypothesis that MSC exosomes can cardioprotect the heart by increasing the level of miR-21a-5p in recipient cardiac cells, thereby downregulating expression of the pro-apoptotic gene products PDCD4, PTEN, Peli1 and FasL in the myocardium. Using miR-21 mimic transfection and treatment with wild type and miR-21a knockout MSC exosomes, we confirmed that exosomal miR-21a-5p is transferred into myocardium and is a major cardioprotective paracrine factor produced by MSCs acting via synergistic activity on multiple pathways. The data supports that residual cardioprotective effect may be due to other ncRNA or protein cargo. In silico analyses support that MSC exosomes may also contribute to angiogenesis, cell proliferation and other aspects of cardiac repair. PMID- 29698633 TI - Neisseria gonorrhoeae molecular typing for understanding sexual networks and antimicrobial resistance transmission: A systematic review. AB - OBJECTIVES: Neisseria gonorrhoeae (NG) is a significant global public health concern due to rising diagnoses rates and antimicrobial resistance. Molecular combined with epidemiological data have been used to understand the distribution and spread of NG, as well as relationships between cases in sexual networks, but the public health value gained from these studies is unclear. We conducted a systematic review to examine how molecular epidemiological studies have informed understanding of sexual networks and NG transmission, and subsequent public health interventions. METHODS: Five research databases were systematically searched up to 31st March 2017 for studies that used sequence-based DNA typing methods, including whole genome sequencing, and linked molecular data to patient level epidemiological data. Data were extracted and summarised to identify common themes. RESULTS: Of the 49 studies included, 82% used NG Multi-antigen Sequence Typing. Gender and sexual orientation were commonly used to characterise sexual networks that were inferred using molecular clusters; clusters predominantly of one patient group often contained a small number of isolates from other patient groups. Suggested public health applications included using these data to target interventions at specific populations, confirm outbreaks, and inform partner management, but these were mainly untested. CONCLUSIONS: Combining molecular and epidemiological data has provided insight into sexual mixing patterns, and dissemination of NG, but few studies have applied these findings to design or evaluate public health interventions. Future studies should focus on the application of molecular epidemiology in public health practice to provide evidence for how to prevent and control NG. PMID- 29698636 TI - The Cellular and Molecular Basis of Direction Selectivity of Adelta-LTMRs. PMID- 29698637 TI - A mouse model of pre-pregnancy maternal obesity combined with offspring exposure to a high-fat diet resulted in cognitive impairment in male offspring. AB - BACKGROUND: Cognitive impairment is a brain dysfunction characterized by neuropsychological deficits in attention, working memory, and executive function. Maternal obesity and consumption of a high-fat diet (HFD) in the offspring has been suggested to have detrimental consequences for offspring cognitive function through its effect on the hippocampus and prefrontal cortex. Therefore, our study aimed to investigate the effects of maternal obesity and offspring HFD exposure on the brain metabolome of the offspring. METHODS: In our pilot study, a LepRdb/+ mouse model was used to model pre-pregnancy maternal obesity and the c57bl/6 wildtype was used as a control group. Offspring were fed either a HFD or a low fat control diet (LFD) after weaning (between 8 and 10 weeks). The Mirrors water maze was performed between 28 and 30 weeks to measure cognitive function. Fatty acid metabolomic profiles of the prefrontal cortex and hippocampus from the offspring at 30-32 weeks were analyzed using gas chromatography-mass spectrometry. RESULTS: The memory of male offspring from obese maternal mice, consuming a HFD post-weaning, was significantly impaired when compared to the control offspring mice. No significant differences were observed in female offspring. In male mice, the fatty acid metabolites in the prefrontal cortex were most affected by maternal obesity, whereas, the fatty acid metabolites in the hippocampus were most affected by the offspring's diet. Hexadecanoic acid and octadecanoic acid were significantly affected in both the hippocampus and pre frontal cortex, as a result of maternal obesity and a HFD in the offspring. CONCLUSION: Our findings suggest that the combination of maternal obesity and HFD in the offspring can result in spatial cognitive deficiency in the male offspring, by influencing the fatty acid metabolite profiles in the prefrontal cortex and hippocampus. Further research is needed to validate the results of our pilot study. PMID- 29698639 TI - Chronic Heart Failure and Exercise Rehabilitation: A Systematic Review and Meta Analysis. AB - OBJECTIVE: The aim of this systematic review was to identify the effect of specific exercise parameters on physical function and quality of life (QOL) in people with chronic heart failure living in the community. DATA SOURCES: A total of 5 electronic databases were searched for relevant studies published after 1994. STUDY SELECTION: The screening process was completed by 2 independent researchers, with a third independent reviewer for conflict resolution. Studies were selected if they included only chronic hHart failure participants, and the sole intervention was a structured exercise training program in an outpatient or community setting. DATA EXTRACTION: Two independent researchers completed the data extraction and qualiy assessment. Quality was assessed using the Physiotherapy Evidence Database and Grading of Recommendations Assessment, Development and Evaluation scales. DATA SYNTHESIS: In total, 40 articles (n=5411) were included in the review for meta-analysis and meta-regression, including 27 randomized control trials and 13 cohort studies. Exercise was shown to have a positive effect on QOL outcomes (standardized mean difference 1.16; 95% confidence interval [CI], 0.76-1.56) with the most commonly used measure, the Minnesota Living with Heart Failure Questionnaire, showing a clinically significant change of 8.5 points. Physical function was improved postexercise intervention in the 23 included studies (standardized mean difference 0.89; 95% CI, 0.40-1.38), with a clinically significant change of 49.8 m seen in studies using the 6-minute walk test (95% CI, 26.52-73.13). These improvements were independent of study design, study quality, participant demographics, disease severity, and exercise prescription variables. CONCLUSION: Exercise significantly improves QOL and physical function. Current evidence suggests that engagement with exercise is a more important factor in achieving improvement than how the exercise is performed. Future research should aim to identify and address barriers to engagement in exercise rehabilitation in this population. PMID- 29698640 TI - Wheelchair Breakdowns Are Associated With Pain, Pressure Injuries, Rehospitalization, and Self-Perceived Health in Full-Time Wheelchair Users With Spinal Cord Injury. AB - OBJECTIVES: To evaluate the relation between wheelchair breakdowns, their immediate consequences, and secondary health complications after spinal cord injury. "Immediate consequences" occur when part of a wheelchair breaks and leaves an individual stranded or injured, or causes him or her to miss medical appointments, work, or school. DESIGN: Survey, cross-sectional. SETTING: Spinal Cord Injury Model Systems Centers. PARTICIPANTS: Full-time wheelchair users (N=771) with SCI from 9 Spinal Cord Injury Model Systems Centers, with data collected between 2011 and 2016. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Incidence of self-reported wheelchair breakdowns within the past 6 months that did or did not result in immediate consequences (ie, injury, being stranded, missing a medical appointment, or an inability to attend school/work); self-perceived health status scale; pain severity numerical rating scale; rehospitalizations; and self-reported pressure injury development within the past 12 months. RESULTS: A total of 610 participants with complete data sets were included in the analyses. When compared to those who reported no breakdowns, participants who reported 1 or more immediate consequences had worse secondary complications: higher self-perceived health status and pain scores (partial eta2=.009-.012, P<.05), and higher odds of rehospitalization (odds ratio: 1.86, P<.05) and pressure injury development (odds ratio: 1.73, P<.05). Secondary health complications were not different in those who reported no immediate consequences compared to those who reported no breakdown. CONCLUSIONS: Wheelchair breakdowns that resulted in injury, being stranded, missing medical appointments, and/or an inability to attend work/school appear to have far-reaching impacts on health and secondary injury. Preventing wheelchair breakdowns, through either better maintenance or manufacturing, may be a means of decreasing secondary disability. PMID- 29698638 TI - Energy Impairments in Older Adults With Low Back Pain and Radiculopathy: A Matched Case-Control Study. AB - OBJECTIVES: To investigate the impact that the presence of chronic low back pain with radiculopathy (CLBPR) may have on (1) energy efficiency and (2) energy capacity among community-dwelling older adults. DESIGN: Matched case-control study. SETTING: Clinical research laboratory. PARTICIPANTS: Included in the analysis were community-dwelling older adults (N=38, 60-85 years) with and without CLBPR. Participants were matched between-groups on age (+/-5 years), sex, and diabetic status. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Energy cost of walking at self-selected speed (ie, energy efficiency) and peak volume of oxygen consumed (ie, energy capacity). RESULTS: Older adults with CLBPR had a higher energy cost of walking at self-selected speed (P=.009) and lower peak volume of oxygen consumed while walking (P=.050), compared to those without pain. CONCLUSIONS: Older adults with CLBPR may benefit from specific rehabilitative interventions that target these potentially modifiable energetic outcomes, thereby reducing the risk of mobility decline. Future studies should identify which mechanisms specifically contribute to diminished energy efficiency and capacity among older adults with CLBPR. PMID- 29698641 TI - Relationship Between Physiological and Perceived Fall Risk in People With Multiple Sclerosis: Implications for Assessment and Management. AB - OBJECTIVE: This study evaluated the relationship between physiological and perceived fall risk in people with multiple sclerosis (MS). DESIGN: Secondary analysis of data from prospective cohort studies undertaken in Australia, the United Kingdom, and the United States. SETTING: Community. PARTICIPANTS: Ambulatory people with MS (N=416) (age 51.5+/-12.0 years; 73% female; 62% relapsing-remitting MS; 13.7+/-9.9 years disease duration). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: All participants completed measures of physiological (Physiological Profile Assessment [PPA]) and perceived (Falls Efficacy Scale-international [FESi]) fall risk and prospectively recorded falls for 3 months. RESULTS: 155 (37%) of the participants were recurrent fallers (>=2 falls). Mean PPA and FESi scores were high (PPA 2.14+/-1.87, FESi 34.27+/-11.18). The PPA and the FESi independently predicted faller classification in logistic regression, which indicated that the odds of being classified as a recurrent faller significantly increased with increasing scores (PPA odds ratio [OR] 1.30 [95% CI 1.17-1.46], FESi OR 1.05 [95% CI 1.03-1.07]). Classification and regression tree analysis divided the sample into four groups based on cutoff values for the PPA: (1) low physiological/low perceived risk (PPA <2.83, FESi <27.5), (2) low physiological/high perceived risk (PPA <2.83, FESi >27.5), (3) high physiological/low perceived risk (PPA >2.83, FESi <35.5), and (4) high physiological/high perceived risk (PPA <2.83, FESi >35.5). Over 50% of participants had a disparity between perceived and physiological fall risk; most were in group 2. It is possible that physiological risk factors not detected by the PPA may also be influential. CONCLUSIONS: This study highlights the importance of considering both physiological and perceived fall risk in MS and the need for further research to explore the complex interrelationships of perceptual and physiological risk factors in this population. This study also supports the importance of developing behavioral and physical interventions that can be tailored to the individual's needs. PMID- 29698643 TI - Splitting the World with Absolute Measurements: A Call for Collaborations in Physical Biology. PMID- 29698642 TI - Obesity and Ventricular Repolarization: a Comprehensive Review. AB - Obesity is known to be a strong predictor of sudden cardiac death. For this reason, concern exists that this association may be related to delayed ventricular repolarization (VR), which has been extensively studied in overweight and obese patients. The corrected QT interval (QTc) and QT or QTc dispersion have been the most commonly-used electrocardiographic methods for assessing VR. Multiple controlled studies demonstrated that QTc and QT or QTc dispersion were significantly longer/greater in overweight and obese subjects than in normal weight controls. The preponderance of evidence indicates that weight loss in overweight and obese patients, whether achieved by diet or bariatric surgery, significantly shortens QTc and decreases QT or QTc dispersion. Several co morbidities that are commonly associated with obesity may delay VR. These include diabetes mellitus, the metabolic syndrome, systemic hypertension, left ventricular hypertrophy, heart failure, and obstructive sleep apnea. It is unclear whether overweight and obesity are independent predictors of delayed VR. It is also uncertain whether prolongation of QTc in such patients is sufficient to predispose to potentially fatal ventricular arrhythmias. PMID- 29698644 TI - Principles of Systems Biology, No. 28. AB - This month: new principles for engineering cells (Avalos/Toettcher, Li, Wang, Ellis/Stan), the daily rhythms of gene expression in a primate (Cooper/Panda), structure of the nuclear pore by an integrative approach (Rout/Akey/Sali), and scoring Mendelian disease risk using electronic medical records (Denny). PMID- 29698645 TI - The Science of Living Matter for Tomorrow. PMID- 29698646 TI - A Proteomic Connectivity Map. AB - Litichevskiy et al. describe the first large-scale use of targeted mass spectrometry to systematically investigate phospho-protein and histone modification networks across a panel of cell lines subjected to drug perturbations. PMID- 29698647 TI - Making Waves with Synthetic Oscillators. AB - New synthetic oscillator designs provide independent tuning of amplitude and frequency and flexible switching between dynamic regimes. PMID- 29698648 TI - Simultaneous Multiplexed Imaging of mRNA and Proteins with Subcellular Resolution in Breast Cancer Tissue Samples by Mass Cytometry. PMID- 29698649 TI - Autophagy during Early Virus-Host Cell Interactions. AB - Autophagy refers to the conserved, multi-step mechanism that delivers cytosolic cargoes to vesicles of the endo-lysosomal system for degradation. It maintains cellular homeostasis by ensuring the continuous degradation of misformed/senescent intracellular components and the associated recycling of nutrients. Autophagy also represents an important cell-intrinsic defense mechanism against invasion by intracellular pathogens, including viruses. Autophagy might oppose viral invasion by targeting viral particles or viral components for degradation. It can also promote the interaction of viral constituents with receptors specialized in the activation of innate immunity pathways or facilitate the activation of anti-viral adaptive immunity. In response to such pressures, viruses have evolved various sophisticated strategies to avoid anti-viral autophagic responses or to manipulate the autophagic machinery to promote their own replication. This review focuses on our current knowledge of autophagy-related events that take place at early stages during interaction of viruses with host cells as well as on their associated consequences in terms of virus replication and cell fate. PMID- 29698650 TI - Yeast Prions Compared to Functional Prions and Amyloids. AB - Saccharomyces cerevisiae is an occasional host to an array of prions, most based on self-propagating, self-templating amyloid filaments of a normally soluble protein. [URE3] is a prion of Ure2p, a regulator of nitrogen catabolism, while [PSI+] is a prion of Sup35p, a subunit of the translation termination factor Sup35p. In contrast to the functional prions, [Het-s] of Podospora anserina and [BETA] of yeast, the amyloid-based yeast prions are rare in wild strains, arise sporadically, have an array of prion variants for a single prion protein sequence, have a folded in-register parallel beta-sheet amyloid architecture, are detrimental to their hosts, arouse a stress response in the host, and are subject to curing by various host anti-prion systems. These characteristics allow a logical basis for distinction between functional amyloids/prions and prion diseases. These infectious yeast amyloidoses are outstanding models for the many common human amyloid-based diseases that are increasingly found to have some infectious characteristics. PMID- 29698651 TI - Resistance exercise modulates male factor infertility through anti-inflammatory and antioxidative mechanisms in infertile men: A RCT. AB - AIMS: Inflammation and oxidative stress appear to be involved in the pathogenesis of male factor infertility. Exercise training has been shown to strengthen antioxidant defenceses and attenuate inflammation across body fluids, organs and tissues. However, the effect of resistance exercise training upon male factor infertility is unknown. Our aim was to investigate the effects of resistance exercise training on markers of male reproduction and reproductive performance in infertile patients. MAIN METHODS: This study evaluated the changes in seminal oxidative stress status, inflammatory biomarkers, semen parameters, sperm DNA integrity and pregnancy rate following 24 weeks of resistance exercise in infertile patients. A total of 1228 sedentary infertile patient (aged 25-40 years) were screened and 430 were randomized to exercise (EX, n = 216) and non exercise (NON-EX, n = 214) groups. Semen samples were taken before, 12 and 24 weeks as well as 7 and 30 days during recovery. KEY FINDINGS: Exercise intervention favorably attenuated inflammation as indicated by seminal cytokines (IL-1beta, IL-6, IL-8 and TNF-alpha), oxidative stress (SOD, MDA and 8 isoprostane) and enhanced antioxidants (SOD and catalase) (P < 0.05), and these changes correlate with favorable improvements in semen parameters, sperm DNA integrity and pregnancy rate in this cohort of infertile patients (P < 0.05). SIGNIFICANCE: Taken together, resistance exercise training improves markers of male reproduction and reproductive performance through inflammatory and oxidative stress mechanisms in infertile patients. PMID- 29698652 TI - Diagnosis and prophylaxis for high-altitude acclimatization: Adherence to molecular rationale to evade high-altitude illnesses. AB - Lack of zero side-effect, prescription-less prophylactics and diagnostic markers of acclimatization status lead to many suffering from high altitude illnesses. Although not fully translated to the clinical setting, many strategies and interventions are being developed that are aimed at providing an objective and tangible answer regarding the acclimatization status of an individual as well as zero side-effect prophylaxis that is cost-effective and does not require medical supervision. This short review brings together the twin problems associated with high-altitude acclimatization, i.e. acclimatization status and zero side-effect, easy-to-use prophylaxis, for the reader to comprehend as cogs of the same phenomenon. We describe current research aimed at preventing all the high altitude illnesses by considering them an assault on redox and energy homeostasis at the molecular level. This review also entails some proteins capable of diagnosing either acclimatization or high-altitude illnesses. The future strategies based on bioinformatics and systems biology is also discussed. PMID- 29698653 TI - Fluctuations in Spinal Cord Perfusion Pressure: A Harbinger of Delayed Paraplegia After Thoracoabdominal Aortic Repair. AB - Delayed paraplegia (DP) following thoracoabdominal or descending thoracic aortic (TAA/DTA) repair is a dreaded complication. We reviewed our experience with the management of DP using our previously described COPS protocol (blood-pressure stabilization, cerebrospinal-fluid (CSP) draining and O2-delivery). Complete documentation of hourly CSP pressures and detailed hemodynamic variables were available since 2000. A case-control design was used to analyze the extensive hourly data in the perioperative period. Data were analyzed by contingency tables, t test, and regression analysis, as appropriate. Between 2000 and 2011, we performed 1059 TAA/DTA repairs. Of these, 47 (4.4%) had DP and 31 (2.9%) had immediate neurologic deficit. Postoperatively, renal replacement therapy and drain complications were significantly associated with DP. Variation in systolic blood pressure (SBP) was also highly predictive. Similarly, spinal-cord perfusion pressure (SCPP = SBP ? SP) showed increased risk with greater variability closer to event day (OR 1.3, P = 0.009). Fluctuation of more than 15 mmHg in SBP in a 24 hour period was associated with 3.2-fold increased odds of DP (P = 0.004). In all, 8/47 (17%) made a full recovery, whereas 19 (40%) had partial recovery by discharge. The 30-day mortality was 18/47 (38%) in DP and 7/55 (13%) in controls (P < 0.001). Long-term survival was significantly lower among DP cases (5-year survival of 28% vs. 75%, P < 0.001). DP occurs infrequently and is predictably associated with intraoperative loss of MEP, postoperative renal replacement therapy, drain complications and unstable systolic and spinal-cord perfusion pressures. Increased vigilance is recommended for patients who experience any of these events. PMID- 29698654 TI - Intercostal Nerve Blocks With Liposomal Bupivacaine: Demonstration of Safety, and Potential Benefits. AB - Liposomal bupivacaine is designed to allow drug diffusion for up to 96 hours following a single administration. Our study aimed to evaluate the safety of liposomal bupivacaine as an intercostal nerve block as part of an enhanced recovery pathway using standardized multimodality pain regimen compared with epidural analgesia in propensity score-matched patients undergoing lung resection. Patients undergoing lung resection (n?=?1737; 2010-2015) were stratified by treatment with intraoperative liposomal bupivacaine intercostal block vs epidural analgesia. We performed 2 propensity score matching analyses. In the first, propensity for treatment with liposomal bupivacaine was estimated using pretreatment variables and the patients were matched on the propensity score. The variables were age, neoadjuvant therapy, extent of resection, and the Zubrod score. In the second, the propensity score matching was performed only in patients who had a thoracotomy. Perioperative outcomes were compared between groups using paired statistical analysis techniques. In the first analysis (n?=?1236), there were more thoracotomies performed in the epidural group (P?75 years of age) with a completely resected non-small cell lung cancer. From March 2014 to April 2015, 264 patients from 22 hospitals affiliated with the National Hospital Organization in Japan were prospectively registered in the present study. The primary end point was operative morbidity (National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0). The secondary end points were operative mortality and the risk factors for operative morbidity. Preoperative comorbidities were assessed according to the Adult Comorbidity Evaluation-27 index. The mean age at the time of surgery was 79.3 years (range 75 90 years). Forty-one percent of the patients were >80 years of age. Twenty-six percent underwent sublobar resection. The incidence of morbidities of any grade was 43.2% (90% confidence interval: 38.2%-48.2%). Respiratory system-related morbidity (19.3%), followed by cardiovascular system-related morbidity (10.2%), was the most common morbidity. The in-hospital mortality rate was 1.1% (3 of 264 patients). A multivariate analysis of the risk factors for operative morbidity showed that both Adult Comorbidity Evaluation-27 grade and the blood loss volume were significant factors. The results of the present prospective multi institutional study should be used as a reference in the surgical treatment of elderly patients with lung cancer. PMID- 29698656 TI - Bilateral Pulmonary Pneumocytomas. PMID- 29698657 TI - Silicone Y-stent Placement for a Secondary Right Carina. AB - Recently, several authors have reported stenting into the right upper lobe bronchus using bifurcated stents, but little has been reported on stenting into the right middle or lower lobe bronchus. We report a case with metastatic uterine leiomyosarcoma, who was successfully treated by rigid bronchoscopic intervention, including silicone Y-stenting on the carina between the right middle lobe bronchus and the lower lobe bronchus. PMID- 29698658 TI - A novel use of infra-red spectroscopy (NIRS and ATR-FTIR) coupled with variable selection algorithms for the identification of insect species (Diptera: Sarcophagidae) of medico-legal relevance. AB - Unequivocal identification of fly specimens is an essential requirement in forensic entomology. Herein, a simple, non-destructive and rapid method based on two vibrational spectroscopy techniques [Near-Infrared Spectroscopy (NIRS) and attenuated total reflection Fourier-transform infrared (ATR-FTIR) spectroscopy] coupled with variable selection techniques such as genetic algorithm-linear discriminant analysis (GA-LDA) and successive projection algorithm-linear discriminant analysis (SPA-LDA) were applied for identifying and discriminating six species of flesh flies (Diptera: Sarcophagidae) native to Neotropical regions. This novel approach is based on the unique spectral "fingerprints" of their biochemical composition. One hundred sixty (160) NIRS and FT-IR specimens (120 male, 40 female) were acquired; different pre-processing methods such as baseline correction, derivative and Savitzky-Golay smoothing were also performed. In addition, the multivariate classification accuracy results were tested based on sensitivity, specificity, positive (or precision) and negative predictive values, Youden index, positive and negative likelihood ratios. Principal components analysis (PCA) was employed for male vs. female category using NIRS, strongly showing the separation between the classes with only three principal components and 99% explained variance. Differentiation between the genera Oxysarcodexia, Peckia and Ravinia was efficiently confirmed by both techniques. In comparison with other biological methods, this approach represents an effective choice for fast and non-destructive identification in forensic entomology. PMID- 29698659 TI - Unraveling cryptic epizootiology of equid trypanosomosis in Punjab state of India by parasitological and sero-molecular techniques. AB - To unravel equid trypanosomosis caused by Trypanosoma evansi in Punjab state of India, a cross sectional study was designed by utilizing parasitological and sero molecular tools with objective to assess the prevalence of T. evansi in association with various risk factors in all agroclimatic zones of Punjab state of India. Parasitological Romanowksy stained thin blood smears (RSTBS) to detect patent infection, molecular techniques polymerase chain reaction I (PCR I; TBR 1/2 primers; targeting minichromosomal satellite DNA of T. evansi), polymerase chain reaction II (PCR II; TR 3/4 primers; targeting variable surface glycoprotein region DNA of T. evansi) & LAMP (Loop mediated isothermal amplification) assay to detect latent infection and serological assays card agglutination test (CATT/T. evansi) & ELISA (Enzyme linked immunosorbent assay) to detect exposure status of trypanosomosis were utilized in the present study. A total 429 equid blood and serum samples from all the five agroclimatic zones of Punjab state tested by these techniques showed a prevalence of 1.39% (CL: 0 15.28) by RSTBS, 6.52% (10.94-45.09) by both TBR 1/2 PCR and LAMP assay, 5.82% (11.57-38.42) by TR 3/4 PCR, 15.15% (36.57-135.42) with CATT/T. evansi and 22.84% (17.77-840.22) with ELISA. Interpretation of various risk factors revealed that the donkey/mules population (RR = 5.46, 95% [CI] = 0.15-15.56) was found to be at higher risk of T. evansi infection predominantly at 'unorganized' farms (RR = 4.06, 95% [CI] = 0.12-4.51). Animal used for commercial purposes (RR = 3.25, 95% [CI] = 0.06-7.42), rearing of equids with other domestic animals (RR = 2.36, 95% [CI] = 0.10-17.11) and farms without application of fly repellant/insecticides/net (RR = 3.68, 95% [CI] = 0.08-5.94) made them more prone to the disease. This comprehensive report utilizing the classical, serological and molecular diagnostic tools for epidemiology of T. evansi establishes the endemic stability of this infection in all agro climatic zones of Punjab with LAMP assay to be a promisingly sensitive and specific technique for the diagnosis of T. evansi under isothermal conditions in field situations. PMID- 29698661 TI - Visual evoked potentials are similar in polysomnographically defined quiet and active sleep in healthy newborns. AB - : Morphology and late components of evoked potentials change depending on wake sleep stages in adults. Visual Evoked potentials (VEPs) have been frequently studied in newborns to identify abnormal development of visual pathways; however, large variability has been reported and there is uncertainty as to the effect of sleep stages on VEPs in neonates. OBJECTIVE: To describe the characteristics of VEPs in one month old, healthy full-term newborns during active sleep (AS) and quiet sleep (QS), defined by simultaneous polysomnography (PSG). METHODS: VEPs were obtained by monocular LEDs stimulation of each eye during AS and QS, in 20 healthy full-term newborns (gestational age 37-40 weeks) with normal birth weights and normal prenatal Doppler ultrasound indices. Latencies and amplitudes of N2, P2 and N3 components in AS and QS were compared, and their association with absolute power of EEG frequency bands, assessed. RESULTS: There were no significant differences in VEP morphology, latencies and amplitudes between sleep states. Typical wave forms were obtained in all newborns in AS; however, no VEPs could be identified clearly in 3 newborns in QS; QS VEPs were less reliable than in AS: more averaging was required; correlation was significantly lower between the VEP averages; and a larger number of babies needed more than two averages to obtain replicable responses needed for clinical purposes. CONCLUSIONS: These results indicate that changes in amplitude and latency of some VEP components observed in NREM and REM sleep in adults are not yet present in one month old newborns probably due to immaturity of cortical and sleep mechanisms. VEPs are more reliable during AS than QS in newborns. Systematic VEP recording during AS, and polysomnographic control to identify this stage, are highly recommended as methods that can increase there liability of neonatal VEPs. PMID- 29698660 TI - Enterobacteria associated with houseflies (Musca domestica) as an infection risk indicator in swine production farms. AB - Houseflies (Musca domestica) spend part of their life development on animal or human manure. Manure is high in pathogenic microbes; thus, houseflies have been known as a mechanical vector for various important zoonotic diseases. Therefore, the present study showcases captured houseflies from intensive swine production regions (which are areas of high manure concentration) in Southern Brazil, and analyses their bodies' to the presence of Escherichia coli and Salmonella sp. and the sensitivity of these bacteria to various antibiotics. Additionally, Quantitative Microbiology Risk Assessment was performed simulating the contamination of lettuce by flies' bacteria and subsequent lettuce consumption by an adult human being. Houseflies were captured in swine buildings and farm houses from five farms. E. coli quantification values ranged from 104 to 106 CFU/20 flies, and all sampling sites had positive results from bacteria presence in the collected houseflies. On the other hand, Salmonella sp. presence was observed in only three farms, where the quantification ranged from 102 to 105 CFU/20 flies. The bacteria showed to be resistant to at least two from the four tested antibiotics (ampicillin, Cefalotin, Ciprofloxacin and Norfloxacin) antibiotics used in human or veterinary medicine. Infection probability analyses showed risk of human infection by E.coli, indicating possible transmission of zoonotic pathogens through flies. In this context, it was possible to conclude that there is a need for flies control, especially in swine farms where zoonotic pathogens can be abundant, to minimize the health impact of the vectorization of enteric bacteria. PMID- 29698662 TI - Liberal Use of Delayed Sternal Closure in Children Is Not Associated With Increased Morbidity. AB - BACKGROUND: Delayed sternal closure (DSC) is often employed to optimize hemodynamics following pediatric cardiac surgery. Prior reports have suggested that DSC may be associated with increased morbidity. We sought to analyze the impact of a liberal policy of DSC on surgical outcomes at our center. METHODS: We retrospectively evaluated the clinical course of 1,000 consecutive patients between July 2005 and June 2015 whose sternum was electively left open following pediatric cardiac surgery. Data are presented as mean and standard error (parametric) or median and quartiles (nonparametric). Receiver-operating characteristic curve analysis was undertaken to identify significant points of inflection. A p less than 0.05 was considered significant. RESULTS: An a priori decision to leave the sternum open is made when complex surgery, especially in neonates and usually involving circulatory arrest, is expected to result in postoperative hemodynamic instability. Age at index surgery for the 1,000 patients was 7 (interquartile range [IQR], 3 to 19) days and weight 3.3 (IQR, 2.8 to 3.7) kg. There were 816 (82%) neonates and 569 (57%) boys. Index operations included 332 (33%) Society of Thoracic Surgeons-European Association for Cardio Thoracic Surgery (STAT) category 5, 483 (48%) STAT category 4, and 185 (19%) STAT category 3 procedures. A total of 103 (10%) patients required postoperative extracorporeal support. Following hemodynamic recovery, DSC was undertaken 3 (IQR, 2 to 4) days postoperatively and in 98.3% patients was performed in the intensive care unit. Overall, mortality was 6.3% and major Society of Thoracic Surgeons morbidity was 21.6%. There were 42 (4.2%) positive mediastinal surveillance cultures at the time of DSC, with the most common organism being coagulase-negative staphylococcus. Fifty-nine (5.9%) clinical sternal and mediastinal wound infections and a total of 117 infectious complications were encountered in 94 patients. Using Society of Thoracic Surgeons database outcome as benchmark, mortality and length of stay in our patients were comparable when analyzed by STAT categories or for the 2 most common index procedures (eg, Norwood and arterial switch operations). Receiver-operating characteristic curve analysis showed that 5 days of open sternum had a weak, but statistically significant, correlation with incidence of infectious complications (area under the curve, 0.56; p = 0.002). The need for DSC 5 or more days after the index procedure was observed in 177 (18%) patients and was not associated with increased wound infection. It was, however, independently associated on multiple regression analysis with major morbidity (odds ratio, 1.7; 95% confidence interval, 1.2 to 2.5; p = 0.002) and, in the subset of 897 patients who did not require extracorporeal support, with increased mortality (odds ratio, 2.2; 95% confidence interval, 1.3 to 3.6; p = 0.003). CONCLUSIONS: A liberal policy of DSC does not adversely affect surgical outcomes, including infectious complications and length of stay. We submit that need for DSC should not, by itself, be considered a source of morbidity. PMID- 29698663 TI - Fate of the Aortic Arch Following Surgery on the Aortic Root and Ascending Aorta in Bicuspid Aortic Valve. AB - BACKGROUND: Recent guidelines support more aggressive surgery for aneurysms of the ascending aorta and root in patients with bicuspid aortic valve. However, the fate of the arch after surgery of the root and ascending aorta is unknown. We set out to assess outcomes following root and ascending aortic surgery and subsequent growth of the arch. METHODS: Between 2005 and 2016, 536 consecutive patients underwent surgery for aneurysm of the root and ascending aorta; 168 had bicuspid aortic valve. Patients with dissection were excluded. Arch diameter was measured before and after surgery, at 6 months and then annually. RESULTS: Of 168 patients, 127 (75.6%) had aortic root replacement and 41 (24.4%) had ascending replacement. Mean age was 57 +/- 12.8 years, 82.7% were men, and 5 operations were performed during pregnancy. There was 1 (0.6%) hospital death. One (0.6%) patient had a stroke and 1 (0.6%) had resternotomy for bleeding. Median intensive care unit and hospital stays were 1 and 6 days, respectively. Follow-up was complete for 94% at a median of 5.9 years (range, 1 to 139 months). Aortic arch diameter was 2.9 cm preoperatively and 3.0 cm at follow-up. There was 97% freedom from reoperation and none of the patients required surgery on the arch. CONCLUSIONS: Prophylactic arch replacement during aortic root and ascending aortic surgery in patients with bicuspid aortic valve is not supported. Our data do not support long-term surveillance of the rest of the aorta in this population. PMID- 29698665 TI - High prevalence of multidrug resistant international clones among macrolide resistant Streptococcus pneumoniae strains in immunocompromised Patients in Tunisia. AB - Macrolide resistant Streptococcus pneumoniae (S.pneumoniae) isolates increased considerably the last decade with important geographical variations among involved phenotypes and genotypes. The aim of this study was to investigate phenotypes, genotypes, serotypes and genetic relatedness of macrolide resistant S. pneumoniae strains isolated from immunocompromised Patients Antibiotic susceptibility was studied by disk diffusion method and minimum inhibitory concentrations (MIC) of erythromycin and clindamycin were determined by Etest ((r)Biomerieux). Resistant strains were analyzed by PCR for ermB, mefA, tetM, tetO and Int-Tn1545 genes. Serotyping was done with multiplex PCRs and the Quellung reaction and molecular typing with multilocus sequence typing (MLST) technique. Macrolide resistance was observed in 41 strains (69.5%): 90.2% of strains had macrolide-lincosamide-streptogramin B (MLSB) resistance phenotype with predominance of high level MLSB inductible phenotype and harbored ermB gene. All strains with High level inductible MLSB phenotype were highly resistant to erythromycin and clindamycin. A rate of 9.8% of strains had Macrolide (M) resistance phenotype and harboured mefA gene. Erythromycin resistant strains were multidrug resistant (MDR) in 97.5% of cases and extensive drug resistant (XDR) in 12.2% of cases. Our strains belonged essentially to four serotypes: 19F, 23F, 14 and 6B. They were mainly assigned to three sequence type (ST): ST81, ST2918 and ST386. Also, 68.3% of them were grouped in three clonal complexes (CC): CC81, CC838 and CC386. Our date indicate a high prevalence of Tn1545 transposon and of three multidrug resistant international clonal contributing to the high frequency of multidrug resistance among S. pneumoniae strains isolated in our centre. PMID- 29698664 TI - Novel activities of safe-in-human broad-spectrum antiviral agents. AB - According to the WHO, there is an urgent need for better control of viral diseases. Re-positioning existing safe-in-human antiviral agents from one viral disease to another could play a pivotal role in this process. Here, we reviewed all approved, investigational and experimental antiviral agents, which are safe in man, and identified 59 compounds that target at least three viral diseases. We tested 55 of these compounds against eight different RNA and DNA viruses. We found novel activities for dalbavancin against echovirus 1, ezetimibe against human immunodeficiency virus 1 and Zika virus, as well as azacitidine, cyclosporine, minocycline, oritavancin and ritonavir against Rift valley fever virus. Thus, the spectrum of antiviral activities of existing antiviral agents could be expanded towards other viral diseases. PMID- 29698666 TI - Ovatodiolide suppresses yes-associated protein 1-modulated cancer stem cell phenotypes in highly malignant hepatocellular carcinoma and sensitizes cancer cells to chemotherapy in vitro. AB - The cancer stem cells (CSCs) theory recently became a focus of heightened attention in cancer biology, with the proposition that CSCs may constitute an important therapeutic target for effective anticancer therapy, because of their demonstrated role in tumor initiation, chemo-, and radio-resistance. Liver CSCs are a small subpopulation of poorly- or undifferentiated liver tumor cells, implicated in tumorigenesis, metastasis, resistance to therapy and disease relapse, enriched with and associated with the functional markers corresponding to the CSCs-enriched side population (SP), high aldehyde dehydrogenase (ALDH) activity, and enhanced formation of in vitro liver CSCs models, referred to herein as hepatospheres. In this study, we found YAP1 was significantly expressed in the SP cells, as well as in generated hepatospheres compared to non-SP or parental HCC cells, at transcript and/or protein levels. In addition, downregulation of YAP1 expression levels by small molecule inhibitor and siRNA transfection, in the HCC cell lines, PLC/PRF/5 and Mahlavu, were associated with marked loss of ability to form hepatospheres and increased sensitivity to sorafenib. Consistent with the above, we demonstrated that YAP1 expression positively correlated with that of Sox2, Oct4, c-Myc and GRP78, markers of stemness and drug resistance. This is suggestive of YAP1's role as a modulator of cancer stemness, ER stress and chemoresistance. For the first time, we demonstrate that Ovatodiolide significantly attenuates YAP1 expression and subsequently suppressed YAP1-modulated CSCs phenotypes and associated disease progression, consistent with our previous finding in breast cancer. Taken together, our findings suggest that YAP1, highly expressed in malignant liver tumours, contributes to hepatocellular CSCs phenotype and is a molecular target of interest for CSCs targeted therapy in liver cancer patients. PMID- 29698668 TI - FoCA: A new framework of coupled geometric active contours for segmentation of 3D cardiac magnetic resonance images. AB - In this paper, a new framework of coupled active contours (FoCA) is proposed for segmentation of the left ventricle myocardium, in cardiac magnetic resonance (CMR) images, without primary learning and user-driven segmentation. Primarily, we suggest a pair of coupled geometric active contours (GACs) for segmentation of the endo- and epicardial boundaries of the left ventricle in every CMR slice. The energy functional of each active contour includes the edge and shape terms of the STACS energy functional, regulator term of the local binary fitting (LBF), and new region and coupling terms. Two new patch-based region terms, inspired by LBF and piecewise model, are proposed to effectively handle intensity inhomogeneity of CMR images. Furthermore, a coupling energy term is added to the epicardial energy functional to avoid intersection with the endocardial curve. For 3D implementation, every 2D active contour in each slice is effectively jointed to the corresponding curves in the previous and next slices (of the same volume) by using a new coupling energy term, obtained by extending the 2D length-shortening regulator. Also, the initial contour and algorithm parameters are automatically regulated. Finally, 3D+t implementation is performed by using the sequential initialization method. Experimental results demonstrated that the proposed method provided superior solution quality compared to a large number of counterpart algorithms by using two well-known frequently-used databases. PMID- 29698667 TI - Transepidermal water loss and skin conductance as barrier integrity tests. AB - In vitro skin permeation studies are commonly used in the risk assessment of toxic compound skin exposure. The present study examined the utility of transepidermal water loss (TEWL) and electrical conductance as barrier integrity tests before skin permeation studies in vitro using a large number of skin samples and fentanyl. TEWL and conductance of the skin samples were measured before the permeation experiments in Franz diffusion cells in vitro with a vapometer and low voltage application, respectively. The data were analyzed based on the in vitro permeation results and in vivo skin absorption information from the transdermal fentanyl product labels. The results showed poor correlations between TEWL and electrical conductance for the skin samples. Weak correlations between fentanyl delivery rate (flux x area) and TEWL and skin conductance were observed. For comparison, TEWL and conductance were also examined after skin perturbation with a syringe needle, and both TEWL and conductance values of the skin samples increased after the perturbation. The data suggest that either TEWL of 10 g/m2/h or skin conductance of 0.07 mS/cm2 can be used as exclusion criteria in skin integrity testing to remove skin samples with high permeabilities under the in vitro conditions studied. PMID- 29698669 TI - Fibroblast growth factor 20 is protective towards dopaminergic neurons in vivo in a paracrine manner. AB - Neuroprotective strategies are an unmet medical need for Parkinson's disease. Fibroblast growth factor 20 (FGF20) enhances survival of cultured dopaminergic neurons but little is known about its in vivo potential. We set out to examine whether manipulation of the FGF20 system affected nigrostriatal tract integrity in rats, to identify which fibroblast growth factor receptors (FGFRs) might reside on dopaminergic neurons and to discover the source of endogenous FGF20 in the substantia nigra (SN). Male Sprague Dawley rats were subject to a partial 6 OHDA lesion alongside treatment with exogenous FGF20 or an FGFR antagonist. Behavioural readouts and tyrosine-hydroxylase (TH) immunohistochemistry were used to evaluate nigrostriatal tract integrity. Fluorescent immunohistochemistry was used to examine FGFR subtype expression on TH-positive dopamine neurons and FGF20 cellular localisation within the SN. FGF20 (2.5 MUg/day) significantly protected TH-positive cells in the SN and terminals in the striatum, while reducing the development of motor asymmetry at 5, 8 and 11 days post lesion. Conversely, the FGFR antagonist PD173074 (2 mg/kg) significantly worsened both the 6-OHDA lesion and resultant motor asymmetry. Within the SN, TH-positive cells expressed FGFR1, 3 and 4 while FGF20 co-localised with GFAP-positive astrocytes. In conclusion, FGF20 protects dopaminergic neurons in vivo, an action likely mediated through activation of FGFRs1, 3 or 4 found on these neurons. Given FGF20 is localised to astrocytes in the adult SN, endogenous FGF20 provides its protection of dopamine neurons through a paracrine action. Boosting the endogenous FGF20 production might offer potential as a future therapeutic strategy in Parkinson's disease. PMID- 29698670 TI - The pericyte secretome: Potential impact on regeneration. AB - Personalized and regenerative medicine is an emerging therapeutic strategy that is based on cell biology and biomedical engineering used to develop biological substitutes to maintain normal function or restore damaged tissues and organs. The secretory capacities of different cell types are now explored as such possible therapeutic regenerative agents in a variety of diseases. A secretome can comprise chemokines, cytokines, growth factors, but also extracellular matrix components, microvesicles and exosomes as well as genetic material and may differ depending on the tissue and the stimulus applied to the cell. With regard to clinical applications, the secretome of mesenchymal stem cells (MSC) is currently the most widely explored. However, other cell types such as pericytes may have similar properties as MSC and the potential therapeutic possibilities of these cells are only just beginning to emerge. In this review, we will summarize the currently available data describing the secretome of pericytes and its potential implications for tissue regeneration, whereby we especially focus on brain pericytes as potential new target cell for neuroregeneration and brain repair. PMID- 29698671 TI - A fluorescence polarization-based competition assay for measuring interactions between unlabeled ubiquitin chains and UCH37*RPN13. AB - Ubiquitin chains regulate distinct signaling events through cooperative interactions with effector proteins and deubiquitinases. Measuring the strength of these interactions is often challenging; either large amounts of material are required or one of the binding partners must be labeled for detection. We sought to develop a label-free method for measuring binding of ubiquitin chains to the proteasome-associated deubiquitinase UCH37 and its binding partner RPN13. The method we describe here is based on a fluorescence polarization competition (FPcomp) assay in which fluorescent monoubiquitin is competed off the UCH37*RPN13 complex by the addition of unlabeled ubiquitin chains. We show that the UCH37*RPN13 complex displays higher affinity toward chains with more than two ubiquitin subunits. Removing the ubiquitin-binding PRU domain of RPN13 does not change affinities. These results suggest UCH37*RPN13 acts to selectively recruit proteins modified with long chains (>2 subunits) to the proteasome for degradation. We also demonstrate that the FPcomp assay is suitable for high throughput screening, which is important considering both UCH37 and RPN13 are potential targets for cancer therapy. PMID- 29698672 TI - Selection and characterization, application of a DNA aptamer targeted to Streptococcus pyogenes in cooked chicken. AB - An aptamer against Streptococcus pyogenes was selected and identified, and a fluorescent method based on the reported aptamer was established to detect S. pyogenes in the cooked chicken. Through a twelve rounds of whole-bacterium SELEX (systematic evolution of ligands by exponential enrichment) selection in vitro, a set of aptamers binding to the whole cell of S. pyogenes were generated, harvesting a low-level dissociation constant (Kd) value of 44 +/- 5 nmol L-1 of aptamer S-12. Aptamer-based quantification of S. pyogenes in the cooked chicken sample was implemented in a fluorescence resonance energy transfer-based assay by using graphene oxide, resulting in a limit of detection of 70 cfu mL-1. The selected aptamer showed affinity and selectivity recognizing S. pyogenes; besides, more biosensors based on the selected aptamer as a molecular recognition element could be developed in the innovative determinations of S. pyogenes. PMID- 29698673 TI - Target-triggering multiple-cycle signal amplification strategy for ultrasensitive detection of DNA based on QCM and SPR. AB - Detection of ultralow concentrations of nucleic acid sequences is a central challenge in the early diagnosis of genetic diseases. Herein, we developed a target-triggering cascade multiple cycle amplification for ultrasensitive DNA detection using quartz crystal microbalance (QCM) and surface plasmon resonance (SPR). It was based on the exonuclease III (Exo III)-assisted signal amplification and the hybridization chain reaction (HCR). The streptavidin-coated Au-NPs (Au-NPs-SA) were assembled on the HCR products as recognition element. Upon sensing of target DNA, the duplex DNA probe triggered the Exo III cleavage process, accompanied by generating a new secondary target DNA and releasing target DNA. The released target DNA and the secondary target DNA were recycled. Simultaneously, numerous single strands were liberated and acted as the trigger of HCR to generate further signal amplification, resulting in the immobilization of abundant Au-NPs-SA on the gold substrate. The QCM sensor results were found to be comparable to that achieved using a SPR sensor platform. This method exhibited a high sensitivity toward target DNA with a detection limit of 0.70 fM. The high sensitivity and specificity make this method a great potential for detecting DNA with trace amounts in bioanalysis and clinical biomedicine. PMID- 29698674 TI - Downregulation in Helios transcription factor signaling is associated with immune dysfunction in blood leukocytes of autistic children. AB - Autism spectrum disorder (ASD) is a complex heterogeneous neurodevelopmental disorder in which immunological imbalance has been suggested to be a major etiological component. Helios, a transcription factor, has been studied extensively in the context of human T cell regulation in health and disease, yet the role of Helios signaling has not been examined in children with ASD. In the present study, we investigated the production of Helios in CD4+, CD8+, and TIM 3+, CXCR3+ cells in typically developing (TD) controls and children with ASD and in peripheral blood mononuclear cells (PBMCs). We assayed the production of IFN gamma+Helios+, IL-21+Helios+, T-bet+Helios+, and Foxp3+Helios+ cells, and determined Helios mRNA and protein expression levels in PBMCs, in TD controls and children with ASD. Our results revealed that children with ASD had lower numbers of CD4+Helios+ CD8+Helios+, TIM-3+Helios+, and CXCR3+Helios+ cells as compared to TD controls. Our results also showed that children with ASD had decreased IFN gamma+Helios+, IL-21+Helios+, T-bet+Helios+, and Helios+Foxp3+ production compared to that in TD controls. Moreover, our results indicated that children with ASD had lower Helios mRNA and protein expression levels compared to those in TD controls. These results suggest that the Helios transcription factor may be critical to immune alterations in children with ASD. Therefore, our results suggest that targeting Helios signaling might offer a strategy for developing ASD therapies. PMID- 29698675 TI - Human choroidal melanocytes express functional Toll-like receptors (TLRs). AB - Toll-like receptors (TLRs) are a class of pattern recognition receptors that sense highly conserved pathogen associated antigenic determinants, triggering an innate immune response and subsequently instructing the adaptive immune system so that together, the pathogen can be eliminated. TLRs are widely distributed in human ocular tissues and cell types, and are active players in ocular inflammation. To date, the presence and function of TLRs on human choroidal melanocytes (HCMs), the most abundant choroidal cell type, have not been characterized. The current study investigated the in vitro and in situ expression and functional status of TLRs on HCMs. HCMs were isolated and cultured from post mortem human donor eyes, and displayed characteristic melanocyte morphology and MART1 expression - a key melanocyte lineage marker up to passage 5 (P5). In vitro experiments used P1 to P4 HCMs from different donor eyes. Initial quantitative real-time PCR (qPCR) analysis revealed that HCMs (n = 3 donors) expressed specific mRNA transcripts for TLR1-10 and MYD88 (a key adaptor protein initiating the TLR signalling pathway). HCMs were stimulated with a set of synthetic TLR specific agonists and the secretion of pro-inflammatory cytokines, MCP-1 and IL 8, at 24 h measured by ELISA (n = 3 donors). The agonists Pam3CSK4 (TLR1/2), Poly I:C (TLR3), LPS (TLR4), Flagellin (TLR5), and FLS-1 (TLR2) induced a significant increase in the production of MCP-1 and IL-8, compared to untreated cells. Application of biotinylated Pam3CSK4 provided in vitro visualization of receptor agonist interactions for TLR1/2. We confirmed that cultured HCMs (n = 3 donors) expressed TLR1-6 protein using immunocytochemistry and confocal microscopy. The expression and distribution of TLR 1-6 was also studied in human choroid and retinal pigment epithelium (RPE) sections (n = 3 eyes) using immunofluorescence and confocal microscopy. Strong TLR1-6 immunolabelling that co-localized with melanocyte-dense areas (and RPE) was consistently observed; intraluminal and blood vessel-related cells (including endothelial cells) also expressed several TLRs. Taken together these observations show for the first time that HCMs constitutively express a range of functional TLRs, and as such can contribute to choroidal responses during infection and inflammation. PMID- 29698676 TI - Seroprevalence of sapovirus in dogs using baculovirus-expressed virus-like particles. AB - Caliciviruses of the Sapovirus genus have been recently detected in dogs. Canine sapoviruses (SaVs) have been identified in the stools of young or juvenile animals with gastro-enteric disease at low prevalence (2.0-2.2%), but whether they may have a role as enteric pathogens and to which extent dogs are exposed to SaVs remains unclear. Here, we report the expression in a baculovirus system of virus like-particles (VLPs) of a canine SaV strain, the prototype virus Bari/4076/2007/ITA. The recombinant antigen was used to develop an enzyme-linked immunosorbent assay (ELISA). By screening an age-stratified collection of serum samples from 516 dogs in Italy, IgG antibodies specific for the canine SaV VLPs were detected in 40.3% (208/516) of the sera. Also, as observed for SaV infection in humans, we observed a positive association between seropositivity and age, with the highest prevalence rates in dogs older than 4 years of age. PMID- 29698677 TI - Long noncoding RNA HOTTIP cooperates with CCCTC-binding factor to coordinate HOXA gene expression. AB - The spatiotemporal control of HOX gene expression is dependent on positional identity and often correlated to their genomic location within each loci. Maintenance of HOX expression patterns is under complex transcriptional and epigenetic regulation, which is not well understood. Here we demonstrate that HOTTIP, a lincRNA transcribed from the 5' edge of the HOXA locus, physically associates with the CCCTC-binding factor (CTCF) that serves as an insulator by organizing HOXA cluster into disjoint domains, to cooperatively maintain the chromatin modifications of HOXA genes and thus coordinate the transcriptional activation of distal HOXA genes in human foreskin fibroblasts. Our results reveal the functional connection of HOTTIP and CTCF, and shed light on lincRNAs in gene activation and CTCF mediated chromatin organization. PMID- 29698678 TI - Citrus bioflavonoids dipeptidyl peptidase-4 inhibition compared with gliptin antidiabetic medications. AB - This study compared dipeptidyl peptidase-4 (DPP-4) inhibitory activity of citrus bioflavonoid nutraceuticals compared with three gliptins. Citrus bioflavonoid standards and three commercially available citrus bioflavonoid supplements (Thompson's Super Bioflavonoid Complex(r)(SB), Ethical Nutrients Bioflavonoids Plus Vitamin C(r)(EN), and Country Life Citrus Bioflavonoids and Rutin(r)(CB)) were considered in this study. Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) analysis was undertaken to identify and quantitate the citrus bioflavonoids present in each supplement. The DPP-4 inhibitory activity was determined by fluorometric assay. All of the tested individual citrus flavonoids demonstrated DPP-4 inhibitory activity, with IC50 values ranging from 485 MUM (rutin) to 5700 MUM (hesperitin and eriodictyol). Similarly, the flavonoid supplements had IC50 values of 16.9 mg/mL (EN), 3.44 mg/mL (SB) and 2.72 mg/mL (CB). These values compare with gliptin IC50 values of 0.684 MUM (sitagliptin), 0.707 MUM (saxagliptin) and 2.286 MUM (vildagliptin). The supplement flavonoid content varied from 11.98% (CB) to 5.26% (EN) and 14.51% (SB) of tablet mass, corresponding to daily flavonoid doses of around 300, 150 and 400 mg, respectively, with CB and SB containing rutin at levels of 7.0% and 7.5% of tablet mass, respectively. While our data demonstrated that citrus bioflavonoid based supplements do possess DPP-4 inhibitory activity, they are several orders of magnitude less potent than gliptins. Further studies using higher concentrations of citrus bioflavonoids, as well as investigations into antioxidant properties which may add additional benefit are warranted. PMID- 29698679 TI - Glycine confers neuroprotection through PTEN/AKT signal pathway in experimental intracerebral hemorrhage. AB - Glycine has been shown to protect against ischemic stroke through various mechanisms. Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) which antagonize Akt-dependent cell survival has been linked to neuronal damage. However, whether glycine has a neuroprotective property in intracerebral hemorrhage (ICH) was unknown. This study aimed to determine the protective effect of glycine in rats ICH. Adult male Sprague-Dawley (SD) rats were subjected to left striatum infusion of autologous blood. ICH animals received glycine (0.2-3 mg/kg, icv) at 1 h after ICH with or without pre-injection of Akt Inhibitor IV (100 MUM, 2 MUl, icv) 0.5 h prior to glycine treatment. Our results showed that in the perihematomal area PTEN was up-regulated in the early stage after ICH. However, glycine treatment decreased PTEN protein level and increased the phosphorylation level of AKT (p-AKT) in the perihematomal area. With the administration of glycine, neuronal death was significantly reduced and Evans blue leakage was alleviated as well as the brain edema after ICH. Moreover, hematoma volume was decreased and neurobehavioral outcome was improved. Nevertheless, Akt Inhibitor IV abolished the neuroprotective effects of glycine after ICH. Together, our findings demonstrate, for the first time, the protective role of glycine on ICH rats, and suggest that the neuroprotective effect of glycine was mediated through PTEN/Akt signal pathway. PMID- 29698680 TI - Quercetin conjugated with silica nanoparticles inhibits tumor growth in MCF-7 breast cancer cell lines. AB - BACKGROUND: Quercetin is a plant polyphenol from the flavonoid group that plays a fundamental role in controlling homeostasis due to its potent antioxidant properties. However, quercetin has extremely low water solubility, which is a major challenge in drug absorption. METHOD: In this study, we described a simple method for the synthesis of quercetin nanoparticles. The quercetin nanoparticles had an average diameter of 82 nm and prominent yellow emission under UV irradiation. Therefore, we used an in vitro model treated with quercetin and quercetin nanoparticles to investigate the effects of quercetin nanoparticles on MCF-7 breast cancer cell line. FINDING: MCF-7 cells were cultured with different concentrations (1-100 MUM) of quercetin nanoparticles at the 24th, 48th and 72 nd hours, and cell cycle and apoptosis assays were detected by flow cytometry (FCM). In this study, we found that quercetin nanoparticles (1-100 MUM) could significantly reduce cell vitality, growth rate and colony formation of MCF-7 cells. CONCLUSION: Quercetin nanoparticles can inhibit cell growth by blocking the cell cycle and promoting apoptosis in MCF-7 cells more than quercetin. As a result, quercetin nanoparticles may be useful therapy or prevention on breast cancer. PMID- 29698681 TI - Circular RNA hsa_circRNA_103809 promotes lung cancer progression via facilitating ZNF121-dependent MYC expression by sequestering miR-4302. AB - Lung cancer characterized with malignant cell growth is the leading cause of cancer-related deaths. In recent years, several circular RNAs (circRNAs) have been reported to participate in lung cancer progression. However, the correlation between circular RNA (circRNA) and lung cancer still remains to be further investigated. In this study, we screened out a highly expressed circular RNA hsa_circRNA_103809 in lung cancer tissues. We showed hsa_circRNA_103809 could serve as a prognostic biomarker for patients with lung cancer. Furthermore, we found that hsa_circRNA_103809 knockdown significantly suppressed lung cancer cell proliferation and invasion in vitro and delayed tumor growth in vivo. In mechanism, we identified hsa_circRNA_103809 as a sponge of miR-4302 targeting ZNF121. By sequestering miR-4302, hsa_circRNA_103809 promoted the expression of ZNF121 which consequently enhanced MYC protein level in lung cancer cells. Through rescue assays, we demonstrated hsa_circRNA_103809 contributed to lung cancer cell proliferation and invasion via facilitating ZNF121-dependent MYC expression by sponging miR-4302. In conclusion, our findings illustrated a novel hsa_circRNA_103809/miR-4302/ZNF121/MYC regulatory signaling pathway in lung cancer progression. PMID- 29698682 TI - Two new 18, 19-seco Triterpenoids from Ilex asprella (Hook. et Arn.) Champ. ex Benth. AB - Two novel 18,19-seco-ursane triterpenoid saponins, ilexasprellanosides J-K (1-2, resp.), 3-O-alpha-l-Rhamnopyranosyl-(1 -> 2)-beta-d-xylopyrannosyl-19-O-beta-d glucopyranosyl-16-beta-hydroxyl-18,19-seco-13(18)-urs-ene-21, 28-lactone (1), 3-O beta-d-Xylopyrannosyl-19-O-alpha-l-rhamnopyran osyl-(1 -> 2)-alpha-l arabinopyranoside-16, 21-epoxy-18, 19-seco-13(18)-urs-ene-28-oic acid (2), five known compounds (3-7) were isolated from the leaves of Ilex asprella (Hook. et Arn.) Champ. ex Benth. (Gangmeiye). The chemical structures of these compounds were elucidated through UV, IR, ESI-MS, 1H NMR and 13C NMR analyses. In MTT and SRB assays, compounds 1-4 presented cytotoxic activities against several human cancer cell lines, namely, the HL-60 human acute promyelocytic leukaemia, Bel 7402 liver cancer, BGC-823 gastric cancer and KB human nasopharyngeal carcinoma cell lines. Compound 1 exhibited weak cytotoxic activities against the human tumour cell lines HL-60, Bel 7402 and KB with inhibition rates of 27.97%, 21.00% and 25.60%, respectively. Compound 2 exhibited weak cytotoxic activities against the human tumour cell lines HL-60, Bel 7402 and BGC-823 with inhibition rates of 19.34%, 7.50% and 4.26%. Respectively, the compounds exerted no statistically different effects on mast cell degranulation in rats. This result indicates that the compounds do not affect mast cell degranulation. PMID- 29698683 TI - Anticancer drug-induced cardiac rhythm disorders: Current knowledge and basic underlying mechanisms. AB - Significant advances in cancer treatment have resulted in decreased cancer related mortality for many malignancies with some cancer types now considered chronic diseases. Despite these improvements, there is increasing recognition that many cancer patients or cancer survivors can develop cardiovascular diseases, either due to the cancer itself or as a result of anticancer therapy. Much attention has focused on heart failure; however, other cardiotoxicities, notably cardiac rhythm disorders, can occur without underlying cardiomyopathy. Supraventricular tachycardias occur in cancer patients treated with cytotoxic chemotherapy (anthracyclines, gemcitabine, cisplatin and alkylating-agents) or kinase-inhibitors (KIs) such as ibrutinib. Ventricular arrhythmias, with a subset of them being torsades-de-pointes (TdP) favored by QTc prolongation have been reported: this may be the result of direct hERG-channel inhibition or a more recently-described mechanism of phosphoinositide-3-kinase inhibition. The major anticancer drugs responsible for QTc prolongation in this context are KIs, arsenic trioxide, anthracyclines, histone deacetylase inhibitors, and selective estrogen receptor modulators. Anticancer drug-induced cardiac rhythm disorders remain an underappreciated complication even by experienced clinicians. Moreover, the causal relationship of a particular anticancer drug with cardiac arrhythmia occurrence remains challenging due in part to patient comorbidities and complex treatment regimens. For example, any cancer patient may also be diagnosed with common diseases such as hypertension, diabetes or heart failure which increase an individual's arrhythmia susceptibility. Further, anticancer drugs are generally usually used in combination, increasing the challenge around establishing causation. Thus, arrhythmias appear to be an underappreciated adverse effect of anticancer agents and the incidence, significance and underlying mechanisms are now being investigated. PMID- 29698684 TI - Acidic pHe regulates cytoskeletal dynamics through conformational integrin beta1 activation and promotes membrane protrusion. AB - An acidic extracellular pH (pHe) in the tumor microenvironment has been suggested to facilitate tumor growth and metastasis. However, the molecular mechanisms by which tumor cells sense acidic signal to induce a transition to an aggressive phenotype remain elusive. Here, we showed that an acidic pHe (pH 6.5) stimulation resulted in protrusion and epithelial-mesenchymal transition (EMT) of cancer cells, which promoted migration and matrix degeneration. Using computational molecular dynamics simulations, we reported acidic pHe-induced opening of the Integrin dimers (alpha5beta1) headpiece which indicated the activation of integrin. Moreover, acidic pHe promoted maturation of focal adhesions, temporal activation of Rho GTPases and microfilament reorganization through integrin beta1 activated FAK signaling. Furthermore, mechanical balance of cytoskeleton (actin, tubulin and vimentin) contributed to acidic pHe-triggered protrusion and morphology change. Taken together, these findings revealed that integrin beta1 could be a novel pH-regulated sensitive molecule which confers protrusion and malignant phenotype of cancer cells. PMID- 29698685 TI - Effect of hemin, baicalein and heme oxygenase-1 (HO-1) enzyme activity inhibitors on Cd-induced accumulation of HO-1, HSPs and aggresome-like structures in Xenopus kidney epithelial cells. AB - Cadmium is a highly toxic environmental pollutant that can cause many adverse effects including cancer, neurological disease and kidney damage. Aquatic amphibians are particularly susceptible to this toxicant as it was shown to cause developmental abnormalities and genotoxic effects. In mammalian cells, the accumulation of heme oxygenase-1 (HO-1), which catalyzes the breakdown of heme into CO, free iron and biliverdin, was reported to protect cells against potentially lethal concentrations of CdCl2. In the present study, CdCl2 treatment of A6 kidney epithelial cells, derived from the frog, Xenopus laevis, induced the accumulation of HO-1, heat shock protein 70 (HSP70) and HSP30 as well as an increase in the production of aggregated protein and aggresome-like structures. Treatment of cells with inhibitors of HO-1 enzyme activity, tin protoporphyrin (SnPP) and zinc protoporphyrin (ZnPP), enhanced CdCl2-induced actin cytoskeletal disorganization and the accumulation of HO-1, HSP70, aggregated protein and aggresome-like structures. Treatment of cells with hemin and baicalein, which were previously shown to provide cytoprotection against various stresses, induced HO-1 accumulation in a concentration-dependent manner. Also, treatment of cells with hemin and baicalein suppressed CdCl2-induced actin dysregulation and the accumulation of aggregated protein and aggresome-like structures. This cytoprotective effect was inhibited by SnPP. These results suggest that HO-1 mediated protection against CdCl2 toxicity includes the maintenance of actin cytoskeletal and microtubular structure and the suppression of aggregated protein and aggresome-like structures. PMID- 29698687 TI - WHO bites back rabies pre-travel vaccination schedules - Implications for travel medicine. PMID- 29698686 TI - Structural and functional analysis of two novel somatostatin receptors identified from topmouth culter (Erythroculter ilishaeformis). AB - In the present study, we cloned and characterized two somatostatin (SS) receptors (SSTRs) from topmouth culter (Erythroculter ilishaeformis) designated as EISSTR6 and EISSTR7. Analysis of EISSTR6 and EISSTR7 signature motifs, 3D structures, and homology with the known members of the SSTR family indicated that the novel receptors had high similarity to the SSTRs of other vertebrates. EISSTR6 and EISSTR7 mRNA expression was detected in 17 topmouth culter tissues, and the highest level was observed in the pituitary. Luciferase reporter assay revealed that SS14 significantly inhibited forskolin-stimulated pCRE-luc promoter activity in HEK293 cells transiently expressing EISSTR6 and EISSTR7, indicating that the receptors can be activated by SS14. We also identified phosphorylation sites important for the functional activity of EISSTR6 and EISSTR7 by mutating Ser23, 43, 107, 196, 311 and Ser7, 29, 61, 222, 225 residues, respectively, to Ala, which significantly reduced the inhibitory effects of SS14 on the CRE promoter mediated by EISSTR6 and EISSTR7. Furthermore, treatment of juvenile topmouth culters with microcystin-LR or 17beta-estradiol significantly affected EISSTR6 and EISSTR7 transcription in the brain, liver and spleen, suggesting that these receptors may be involved in the pathogenic mechanisms induced by endocrine disruptors. Our findings should contribute to the understanding of the structure function relationship and evolution of the SSTR family. PMID- 29698688 TI - Novel thoracic glands in the ant Myopias hollandi. AB - Besides the common labial and metapleural glands, four novel exocrine glands are described in the thorax of both workers and queens of the ponerine ant Myopias hollandi. From anterior to posterior, these glands were designated as the propleural pit gland, the posterolateral pronotal gland, the anterolateral propodeal gland and the metasternal process gland. They all correspond with class 3 glands, that are made up of bicellular units that each comprise a secretory cell and a duct cell. In the propleural pit gland, the ducts are characterized by a gradually widening diameter, while in the three other glands the ducts show a portion which displays a balloon-like expansion, that on semithin sections stains very dark. For none of these novel glands the function is known as yet, although ultrastructural examination indicates that they produce a non-proteinaceous and therefore possibly pheromonal secretion. PMID- 29698689 TI - Nitric oxide induces epidermal stem cell de-adhesion by targeting integrin beta1 and Talin via the cGMP signalling pathway. AB - OBJECTIVE: Nitric oxide (NO) has emerged as a critical molecule in wound healing, but the mechanism underlying its activity is not well defined. Here, we explored the effect of NO on the de-adhesion of epidermal stem cells (ESCs) and the mechanism involved in this process. METHODS: The effects of NO on isolated human and mouse ESCs cultured in the presence of different concentrations of the NO donor S-nitroso-N-acetyl penicillamine (SNAP) were evaluated in cell de-adhesion assays mediated by integrin beta and collagen IV. Subsequently, changes in the expression of integrin beta1 and the phosphorylation of Talin in response to different doses of SNAP were detected by Western blot analysis and real-time PCR in vitro. Furthermore, the roles of various soluble guanylyl cyclase (sGC)- and protein kinase G (PKG)-specific inhibitors and agonists in the effects of NO on ESC de-adhesion, integrin beta1 expression and Talin phosphorylation were analysed. Moreover, the effects of NO on integrin beta1 expression and sGC/cGMP/PKG signalling-mediated wound healing were detected in vivo using 5 bromo-2-deoxyuridine (BrdU) label-retaining cells (LRCs) in a scald model and an excision wound healing model, respectively. RESULTS: SNAP promoted primary human and mouse ESC de-adhesion in a concentration-dependent manner in the integrin beta1-and collagen IV-mediated adhesion assay, and this effect was suppressed by the sGC and PKG inhibitors. Additionally, integrin beta1 expression and Talin phosphorylation at serine 425 (S425) were negatively correlated with SNAP levels, and this effect was blocked by the sGC and PKG inhibitors. Moreover, the roles of NO in integrin beta1 expression and cGMP signalling pathway-mediated wound healing were confirmed in vivo. CONCLUSION: Our data indicate that the stimulatory effects of NO on ESC de-adhesion related to integrin beta1 expression and Talin phosphorylation were mediated by the cGMP signalling pathway, which is likely involved in wound healing. PMID- 29698690 TI - Alzheimer's disease susceptibility genes modify the risk of Parkinson disease and Parkinson's disease-associated cognitive impairment. AB - The pathogenic mechanism underlying Parkinson's disease (PD) and PD- Cognitive impairment (CI) remains elusive. Its potential link to the risk factors in Alzheimer's disease (AD) is unclear. In this study, we analyzed 16 CE-associated single nucleotide polymorphisms (SNPs) in twelve genes in a Chinese cohort of 450 PD cases and 449 controls. Among our 298 cases clinically evaluated for CI, 113 cases did not show CI signs (PD-NC), 86 cases had mildly cognitive impairment (PD MCI) and 99 cases had dementia (PD-D). We found that the APOE epsilon4 allele is associated with a higher risk for PD-D. Gene-gene interaction analysis revealed that three significant gene-gene interactions, including BDNF and CLU, APOE and CR1, and DYRK1A and CD2AP increase the risk for PD. Because these SNPs are known genetic risk factors for AD, their contribution to PD and PD-D shown in this study suggests that PD/PD-D and AD may share convergent pathways in their pathogenesis through gene-gene interactions. PMID- 29698691 TI - Efficient vector systems for economical and rapid epitope-tagging and overexpression in Candida albicans. AB - Candida albicans is an opportunistic pathogenic fungus which causes superficial and systemic infections in immunocompromised patients. It is important to characterize the roles of genes involved in its pathogenesis, virulence, and drug resistance. Several genetic manipulation toolkits have been developed for gene function research in C. albicans. Here, we describe efficient vector systems that allow economical and rapid C-terminal and N-terminal epitope-tagging, inducible and constitutive promoter replacements, and ectopic gene overexpression in C. albicans. These systems use modularized genetic elements (conventional and non conventional selection markers, epitope tags and promoters) and universal primers. These advantages should greatly reduce laboratory work and costs of strain construction for C. albicans. PMID- 29698692 TI - Development of a flow cytometry based assay to determine the invasion of enteropathogenic Yersiniae into C2BBe1 cells. AB - A rapid method was developed to determine the invasion frequency of enteropathogenic Yersinia into intestinal C2BBe1 cells by means of flow cytometry. Bacteria are labelled with a thiol-cleavable amine-reactive biotin and subsequently incubated with the fluorochrome-labelled biotin-ligand neutravidin. After infection of the intestinal cells with the labelled bacteria, the neutravidin-coupled fluorochrome is detached by breaking up the linker through reduction of the disulphide. Despite reduced adhesion and invasion frequencies of the labelled bacteria into C2BBe1 cells this procedure offers the basis for the development of a fast single-step staining protocol for the recovery of invading bacteria in in a host-pathogen system for further transcriptome or proteome analysis. PMID- 29698693 TI - Occupational dermatitis: How to identify the exposures, make the diagnosis, and treat the disease. PMID- 29698694 TI - Maternal nicotine exposure has severe cross-generational effects on offspring behavior. AB - Our previous studies showed that paternal nicotine exposure can lead to hyperactivity in the offspring. Nevertheless, the cross-generational effects of maternal and biparental nicotine exposure remain unclear. In this study, female and male mice were exposed respectively by nicotine before pregnancy. The maternal pre-pregnancy nicotine exposure led to depression-like behaviors in the F1 offspring. However, after biparental pre-pregnancy nicotine exposure, seventy percentage of the offspring exhibited a depressive phenotype while 20% were hyperactive, and the remaining exhibited no obvious abnormal behavior. The cross generational effects appeared to be mediated via disruption of the balance between GSK3 and p-GKS3 by nicotine. These results suggested that pre-pregnancy nicotine exposure can induce alterations in the behavior of the offspring, and the cross-generational effects of maternal nicotine exposure were particularly serious. PMID- 29698695 TI - Neural mechanisms associated with treatment decision making: An fMRI study. AB - Great progress has been made in understanding how people make financial decisions. However, there is little research on how people make health and treatment choices. Our study aimed to examine how participants weigh benefits (reduction in disease progression) and probability of risk (medications' side effects) when making hypothetical treatment decisions, and to identify the neural networks implicated in this process. Fourteen healthy participants were recruited to perform a treatment decision probability discounting task using MRI. Behavioral responses and skin conductance responses (SCRs) were measured. A whole brain analysis were performed to compare activity changes between "mild" and "severe" medications' side effects conditions. Then, orbitofrontal cortex (OFC), ventral striatum (VS), amygdala and insula were chosen for effective connectivity analysis. Behavioral data showed that participants are more likely to refuse medication when side effects are high and efficacy is low. SCRs values were significantly higher when people made medication decisions in the severe compared to mild condition. Functionally, OFC and VS were activated in the mild condition and were associated with increased likehood of choosing to take medication (higher area under the curve "AUC" side effects/efficacy). These regions also demonstrated an increased effective connectivity when participants valued treatment benefits. By contrast, the OFC, insula and amygdala were activated in the severe condition and were associated with and increased likelihood to refuse treatment. These regions showed enhanced effective connectivity when participants were confronted with increased side effects severity. This is the first study to examine the behavioral and neural bases of medical decision making. PMID- 29698696 TI - The effect of adenoidectomy on cough reflex sensitivity in atopic children. AB - The aim of this study was to determine whether cough sensitivity is changed after adenoidectomy in atopic children with chronic cough. 21 Children having symptoms of chronic cough and adenoid hypertrophy verified by nasal fiberoptic endoscopy were submitted to cough sensitivity measurement before and after adenoidectomy. Their pulmonary function was within normal range. Concentrations of capsaicin causing two (C2) and five coughs (C5) were reported. Children' (14 boys and 7 girls, mean age 6,52 yrs) cough sensitivity (geometric mean, with 95% CI) for C2 was preoperatively (before adenoidectomy) 19.95 (9.95-39.98) micromol/l vs. children' C2 postoperatively 14.04 (7.16-27.55) (P = .083 for Wilcoxon paired two sample test). Children' C5 was preoperatively 86.26 (39.25-189.57) micromol/l vs. C5 postoperatively 95.23 (46.33-195.75) micromol/l (P = .794 for Wilcoxon paired two sample test). We conclude that cough sensitivity for C2 and C5 was not significantly changed after adenoidectomy in atopic children with chronic cough. PMID- 29698697 TI - A new perspective on the anterior cingulate cortex and affective pain. AB - Pain is a complex experience including sensory-discriminative and emotional affective components. Base on the intensity and chronification of pain, pain is divided into physiological and pathological pain. Anterior cingulate cortex (ACC), which is activated by noxious and contextual stimuli, is involved in pain processing, especially affective pain, the neural mechanisms of the ACC involvement in affective pain have yet to be elaborated. This review summarizes the main progresses and recent findings from our and other laboratories regarding the ACC and affective pain. Most evidence provided new insights into the neural mechanisms underlying affective pain. Excitation of ACC pyramidal neurons is necessary and sufficient for the pain-related negative emotion. We also sketched other brain regions associated with the ACC and discussed the role of these brain regions in affective pain. Actually, it is likely that the neural network between these brain regions is critical for the negative affect of pain. In particular, the important advances within the optogenetic filed provide new opportunities to deepen and expand our understanding of the affective pain. PMID- 29698698 TI - A receptor-neuron correlate for the detection of attractive plant volatiles in Helicoverpa assulta (Lepidoptera: Noctuidae). AB - Plant volatiles are vital cues in the location of hosts for feeding and oviposition for Lepidoptera moths. The noctuid Helicoverpa assulta is a typical polyphagous moth, regarded as a good model for studying the olfactory reception of plant volatiles. In this study, four full-length genes encoding odorant receptors HassOR24, HassOR40, HassOR41, and HassOR55 expressed in antenna in H. assulta were functionally characterized. The highly expressed HassOR40 was narrowly tuned to a few structurally-related plant volatiles: geranyl acetate, geraniol and nerolidol. By systematically analyzing responses of single neuron in both trichoid sensilla and basiconic sensilla using single sensillum recording, the specific neuron B in one type of short trichoid sensilla was found to be mainly activated by the same chemicals as HassOR40 with high sensitivity, and with no significant difference between male and female neurons. Thus, a clear "receptor-neuron" relationship in H. assulta was demonstrated here, suggesting that HassOR40/HassOrco are expressed in neuron B of short trichoid sensilla. The active tobacco volatile nerolidol, recognized by this receptor-neuron line, elicits significant behavioral attraction of both sexes in H. assulta adults. The results indicate that we identified a receptor-neuron route for the peripheral coding of a behaviorally relevant host volatile in H. assulta. PMID- 29698699 TI - Bim is an independent prognostic marker in intrahepatic cholangiocarcinoma. AB - Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver malignant tumor and has a poor prognosis. The prognostic factors associated with outcome remain poorly defined. In this study, we investigated the role of an important cell apoptosis initiator, Bcl-2 interacting mediator of cell death (Bim), by evaluating its expression and association with other clinicopathological features in ICCs. We analyzed 56 cases of ICC with clinical follow-up. The expression of Bim in ICC cells and other cellular components was evaluated by immunohistochemistry. Bim expression was considered up-regulated if Bim was detected in 10% or more of tumor cells. Of the 56 ICC samples, 19 (34%) had high Bim expression level, 15 (27%) were completely negative, and 22 (39%) were classified as low Bim expression (<10% positivity). Patients who had tumors with high Bim level had significantly longer overall survival than did those with low or no staining (median survival, 7.6 versus 2.6 years; hazard ratio, 0.40; P = .006). High Bim expression was also correlated with low Ki-67 index, and more importantly, none of the tumors with high Bim expression had lymph node metastases at the time of surgery. Our study demonstrates that Bim is an important and independent prognostic factor in ICC. Tumors with high Bim expression are associated with better prognosis through inhibiting tumor cell proliferation and metastatic ability. The development of new agents directly or indirectly targeting Bim may provide promising anticancer treatments. PMID- 29698700 TI - Up-regulation of long noncoding RNA M26317 correlates with tumor progression and poor prognosis in gastric cancer. AB - To investigate the expression and clinical significance of long noncoding RNA (lncRNA) in gastric cancer, we applied microarray analysis to obtain expression profiles of protein-coding genes and lncRNAs in tumor and paired adjacent nontumor tissues. We found that 41 lncRNAs were up-regulated and 31 lncRNAs were down-regulated more than 2-fold in gastric cancer versus noncancerous tissues (ratio >2.0, P < .01). We established a coexpression network of the differentially expressed lncRNAs and targeted coding genes that included 17 lncRNAs and 16 coding genes. Because the results of microarray analysis showed that lncRNA M26317 was up-regulated in gastric cancer tissues, we examined the expression level of M26317 in 103 gastric cancer tissues by reverse-transcription polymerase chain reaction and 436 gastric cancer tissues by in situ hybridization. Our data confirmed that M26317 was up-regulated in gastric cancer tissues. Moreover, expression of M26317 correlated with patient age, size of tumor, Lauren's classification, depth of invasion, lymph node and distant metastasis, TNM stage, and poor prognosis (P < .05), but was not associated with sex, location of tumor, and differentiation (P > .05). M26317 may have an important role in malignant transformation and metastasis of gastric cancer. PMID- 29698701 TI - Mucinous intrahepatic cholangiocarcinoma: a distinct variant. AB - Mucinous variant of intrahepatic cholangiocarcinoma (iCC) is rare, and its clinicopathological features and prognosis are far less clear. Six patients who had iCCs with more than 50% of mucinous component and 79 conventional iCCs were included in the study. The mean size of mucinous and conventional iCCs was 6.2 and 6.0 cm, respectively. Most patients (83%) with mucinous iCC presented at T3 stage or above compared with 28% of the conventional group (P < .01). Three patients with mucinous iCC (50%) died within 1 year. The average survival time of patients with mucinous iCCs was significantly reduced compared with that of the conventional group (9 months versus 2 years; P < .001). Immunohistochemistry was performed on 6 mucinous and 12 conventional iCCs with matched age, sex, and stage, which revealed positive immunoreactivity in MUC1 (83% versus 58%), MUC2 (33% versus 17%), MUC5AC (100% versus 42%), MUC6 (50% versus 0), CK7 (83% versus 83%), CK20 (0 versus 17%), CDX2 (17% versus 0), p53 (67% versus 67%), Smad4 (67% versus 58%), and EGFR (83% versus 42%) in mucinous and conventional iCCs, respectively. Molecular studies showed one mucinous iCC with KRAS G12C mutation and no BRAF or IDH1/2 mutations. Mucinous iCC is a unique variant that constitutes 7% of iCCs. It is more immunoreactive for MUC1, MUC2, MUC5AC, and MUC6. Unlike adenocarcinomas of colorectal primary, mucinous iCCs are often CK7+/CK20-/CDX2- and microsatellite stable. Patients with mucinous iCC likely present at advanced stage upon diagnosis with shorter survival time compared with the conventional counterparts. PMID- 29698702 TI - A dimeric form of a small-sized protein binder exhibits enhanced anti-tumor activity through prolonged blood circulation. AB - Small-sized non-antibody scaffolds have attracted considerable interest as alternatives to immunoglobulin antibodies. However, their short half-life is considered a drawback in the development of therapeutic agents. Here we demonstrate that a homo-dimeric form of a repebody enhances the anti-tumor activity than a monomeric form through prolonged blood circulation. Spytag and spycatcher were genetically fused to the C-terminus of a respective human IL-6 specific repebody, and the resulting two repebody constructs were mixed at an equimolar ratio to produce a homo-dimeric form through interaction between spytag and spycatcher. The homo-dimeric repebody was detected as a single band in the SDS-PAGE analysis with an expected molecular size (78 kDa), showing high stability and homogeneity. The dimeric repebody was shown to simultaneously accommodate two hIL-6 molecules, and its binding affinity for hIL-6 was estimated to be comparable to a monomeric repebody. The serum concentration of the dimeric repebody was observed to be about 5.5 times higher than a monomeric repebody, consequently leading to considerably higher tumor suppression effect in human tumor xenograft mice. The present approach can be effectively used for prolonging the blood half-life of small-sized protein binders, resulting in enhanced therapeutic efficacy. PMID- 29698703 TI - Predominance of ST5-II-t311 clone among healthcare-associated methicillin resistant Staphylococcus aureus isolates recovered from Zhejiang, China. AB - OBJECTIVES: To determine the molecular characteristics and antimicrobial susceptibility of healthcare-associated methicillin-resistant Staphylococcus aureus (HA-MRSA) in Zhejiang Province. METHODS: A total of 391 HA-MRSA isolates were collected from 12 hospitals in five cities of Zhejiang Province, between January 2012 and May 2013. Susceptibility to vancomycin, teicoplanin, linezolid, tigecycline, and daptomycin was determined. Resistant isolates were screened for resistance mutations. Ten isolates from each hospital were then chosen at random for molecular typing. RESULTS: The isolates showed good susceptibility to all five anti-MRSA agents; only five sporadic non-susceptible isolates were detected. CC5/ST5-MRSA-II-t311 (39/120, 32.5%) was found to be the predominant HA-MRSA clone and was spread between the different hospitals in Hangzhou. CC5/ST5-MRSA-II t002 was the most prevalent clone in Ningbo, while CC239/ST239-MRSA was epidemic only in certain hospitals in Wenzhou and Shaoxing. Fifteen ST59 isolates (15/120, 12.5%) were identified among the HA-MRSA isolates. CONCLUSIONS: CC5/ST5-MRSA-II t311 has become the predominant HA-MRSA clone in Hangzhou, Zhejiang Province. ST59 MRSA has spread into hospitals. The isolates showed good susceptibility to all five anti-MRSA agents. PMID- 29698704 TI - The cAMP-induced G protein subunits dissociation monitored in live Dictyostelium cells by BRET reveals two activation rates, a positive effect of caffeine and potential role of microtubules. AB - To study the dynamics and mechanisms controlling activation of the heterotrimeric G protein Galpha2betagamma in Dictyostelium in response to stimulation by the chemoattractant cyclic AMP (cAMP), we monitored the G protein subunit interaction in live cells using bioluminescence resonance energy transfer (BRET). We found that cAMP induces the cAR1-mediated dissociation of the G protein subunits to a similar extent in both undifferentiated and differentiated cells, suggesting that only a small number of cAR1 (as expressed in undifferentiated cells) is necessary to induce the full activation of Galpha2betagamma. In addition, we found that treating cells with caffeine increases the potency of cAMP-induced Galpha2betagamma activation; and that disrupting the microtubule network but not F-actin inhibits the cAMP-induced dissociation of Galpha2betagamma. Thus, microtubules are necessary for efficient cAR1-mediated activation of the heterotrimeric G protein. Finally, kinetics analyses of Galpha2betagamma subunit dissociation induced by different cAMP concentrations indicate that there are two distinct rates at which the heterotrimeric G protein subunits dissociate when cells are stimulated with cAMP concentrations above 500 nM versus only one rate at lower cAMP concentrations. Quantitative modeling suggests that the kinetics profile of Galpha2betagamma subunit dissociation results from the presence of both uncoupled and G protein pre-coupled cAR1 that have differential affinities for cAMP and, consequently, induce G protein subunit dissociation through different rates. We suggest that these different signaling kinetic profiles may play an important role in initial chemoattractant gradient sensing. PMID- 29698705 TI - Artificial inorganic biohybrids: The functional combination of microorganisms and cells with inorganic materials. AB - : Biohybrids can be defined as the functional combination of proteins, viable cells or microorganisms with non-biological materials. This article reviews recent findings on the encapsulation of microorganisms and eukaryotic cells in inorganic matrices such as silica gels or cements. The entrapment of biological entities into a support material is of great benefit for processing since the encapsulation matrix protects sensitive cells from shear forces, unfavourable pH changes, or cytotoxic solvents, avoids culture-washout, and simplifies the separation of formed products. After reflecting general aspects of such an immobilization as well as the chemistry of the inorganic matrices, we focused on manufacturing aspects and the application of such biohybrids in biotechnology, medicine as well as in environmental science and for civil engineering purpose. STATEMENT OF SIGNIFICANCE: The encapsulation of living cells and microorganisms became an intensively studied and rapidly expanding research field with manifold applications in medicine, bio- and environmental technology, or civil engineering. Here, the use of silica or cements as encapsulation matrices have the advantage of a higher chemical and mechanical resistance towards harsh environmental conditions during processing compared to their polymeric counterparts. In this perspective, the article gives an overview about the inorganic material systems used for cell encapsulation, followed by reviewing the most important applications. The future may lay in a combination of the currently achieved biohybrid systems with additive manufacturing techniques. In a longer perspective, this would enable the direct printing of cell loaded bioreactor components. PMID- 29698706 TI - The effect of size and polymer architecture of doxorubicin-poly(ethylene) glycol conjugate nanocarriers on breast duct retention, potency and toxicity. AB - Although systemic administration of chemotherapeutic agents is routinely used for treating invasive breast cancer, the only therapeutic options for ductal carcinoma in situ (DCIS) are surgery and radiation. Treating DCIS by delivering drugs locally to the affected milk duct offers significant advantages over systemic administration, including reduced systemic and breast toxicities, as well as a greatly reduced need for surgery and radiation. In this study, mammary gland retention and toxicity of intraductally administered poly(ethylene) glycol doxorubicin (PEG-DOX) polymeric conjugate nanocarriers of varying molecular sizes and architectures were investigated. Nanocarriers were formed by conjugating one or more copies of doxorubicin to PEG polymers, of varying molecular weights (5, 10, 20, and 40 kDa) and architectures (linear, four-arm and eight-arm). Cytotoxicity against MCF7 cells, a human breast cancer cell line, was assessed, and IC50 values were calculated. The nanocarriers were intraductally administered into the mammary glands of female retired breeder Sprague-Dawley rats. Whole body images were captured using in vivo optical imaging, and changes in ductal structure as well local inflammation were monitored. Fluorescence intensities were monitored, over time, to evaluate nanocarrier mammary gland retention half lives (t1/2). The IC50 values of PEG-DOX nanocarriers against MCF7 cells were 40 kDa PEG-(DOX)4 (1.23 MUM) < 5 kDa PEG-DOX (1.76 MUM) < 40 kDa PEG-(DOX)8 (3.49 MUM) < 10 kDa PEG-DOX (3.86 MUM) < 20 kDa PEG-DOX (8.96 MUM) < 40 kDa PEG-DOX (18.11 MUM), whereas the IC50 of free DOX was only 0.14 MUM. The t1/2 of linear 5, 20, and 40 kDa nanocarriers were 2.2 +/- 0.3, 3.6 +/- 0.6, and 13.1 +/- 3.4 h, whereas the retention t1/2 of 4- and 8-arm 40 kDa nanocarriers were 14.9 +/- 5.6 h and 11.9 +/- 2.9 h, respectively. The retention t1/2 of free doxorubicin was 2.0 +/- 0.4 h, which was significantly shorter than that of the linear and branched 40 kDa PEG-DOX nanocarriers. Increased molecular weight and decreased branching both demonstrated a strong correlation to enhanced mammary gland retention. Intraductally administered free doxorubicin resulted in ductal damage, severe inflammation and generation of atypical cell neoplasms, whereas PEG-DOX nanocarriers induced only minor and transient inflammation (i.e., damaged epithelial cells and detached cellular debris). The 40 kDa 4-arm PEG-DOX nanocarrier demonstrated the longest ductal retention half-life, the lowest IC50 (i.e., most potent), and minimal ductal damage and inflammation. The current results suggest that PEG-DOX nanocarriers with prolonged ductal retention may present the best option for intraductal treatment of DCIS, due to their low local toxicity and potential for sustained therapeutic effect. PMID- 29698707 TI - Distinct characteristics of hippocampal pathogenic TH17 cells in a mouse model of depression. AB - Increasing evidence indicates that multiple actions of the immune system are closely intertwined with the development of depression and subsequent recovery processes. One of these interactions is substantial evidence that the TH17 subtype of CD4+ T cells promotes susceptibility to depression-like behaviors in mice. Comparing subtypes of CD4+ T cells, we found that administration of TH17 cells, but not TH1 cells or TREGS, promoted susceptibility to learned helplessness depressive-like behavior and accumulated in the hippocampus of learned helpless mice. Adoptively transferred TH17 cells into Rag2-/- mice that are devoid of endogenous T cells increased susceptibility to learned helplessness, demonstrating that increased peripheral TH17 cells are capable of modulating depression-like behavior. Moreover, in wild-type mice, adoptively transferred TH17 cells accumulated in the hippocampus of learned-helpless mice and induced endogenous TH17 cell differentiation. Hippocampal TH17 cells from learned-helpless mice expressed markers of pathogenic TH17 cells (CCR6, IL-23R) and of follicular cells (CXCR5, PD-1), indicating that the hippocampal cells are TFH-17-like cells. Knockout of CCR6 blocked TH17 cells from promoting learned helplessness, which was associated with increased expression of PD-1 in CCR6 deficient TH17 cells. In summary, these results reinforce the conclusion that depression-like behaviors are selectively facilitated by TH17 cells, and revealed that these cells in the hippocampus of learned helpless mice display characteristics of TFH17-like cells, which may contribute to their pathogenic actions in promoting depression. PMID- 29698708 TI - From the head of a caterpillar: A possible treatment for neuropsychiatric sequelae of autoimmune disease. PMID- 29698709 TI - Red meat and processed meat intake and risk for cutaneous melanoma in white women and men: Two prospective cohort studies. AB - BACKGROUND: Red and processed meat consumption has been associated with increased risk for several cancers, but the association with cutaneous melanoma risk has been inconclusive. OBJECTIVE: To investigate the association between red and processed meat intake and melanoma risk. METHODS: Dietary information was assessed by using food frequency questionnaires in 2 prospective cohorts: 75,263 women from the Nurses' Health Study (1984-2010) and 48,523 men from the Health Professionals Follow-up Study (1986-2010). Melanoma cases were confirmed by reviewing pathology records. Pooled multivariable hazard ratios and 95% confidence intervals were estimated by using Cox proportional hazards models. RESULTS: A total of 679 female and 639 male melanoma cases were documented during follow-up. Red and processed meat intake was inversely associated with melanoma risk (P = .002 for trend); the pooled hazard ratios (95% confidence intervals) of the 2 cohorts were 1.00 (reference), 1.00 (0.87-1.14), 0.98 (0.86-1.13), 0.89 (0.77-1.02), and 0.81 (0.70-0.95) for increasing quintiles of intake. LIMITATIONS: Findings might have limited generalizability, considering that the cohorts were limited to white health professionals. CONCLUSION: Red and processed meat intake was inversely associated with melanoma risk in these 2 cohorts. PMID- 29698710 TI - Subcutaneous infiltration of carbon dioxide (carboxytherapy) for abdominal fat reduction: A randomized clinical trial. AB - BACKGROUND: Noninvasive fat removal is preferred because of decreased downtime and lower perceived risk. It is important to seek new noninvasive fat removal treatments that are both safe and efficacious. OBJECTIVE: To assess the extent to which carboxytherapy, which is the insufflation of carbon dioxide gas into subcutaneous fat, results in reduction of fat volume. METHODS: In this randomized, sham-controlled, split-body study, adults (body mass index, 22-29 kg/m2) were randomized to receive 5 weekly infusions of 1000 cm3 of CO2 to 1 side of the abdomen, and 5 sham treatments to the contralateral side. The primary outcome measures were ultrasound measurement of fat layer thickness and total circumference before and after treatment. RESULTS: A total of 16 participants completed the study. Ultrasound measurement indicated less fat volume on the side treated with carboxytherapy 1 week after the last treatment (P = .011), but the lower fat volume was not maintained at 28 weeks. Total circumference decreased nominally but not significantly at week 5 compared with baseline (P = .0697). Participant body weights did not change over the entire course of the study (P = 1.00). LIMITATIONS: Limitations included modest sample size and some sources of error in the measurement of circumference and fat layer. CONCLUSION: Carboxytherapy provides a transient decrease in subcutaneous fat that may not persist. Treatment is well tolerated. PMID- 29698711 TI - Bringing big data from social media reviews to quality improvement. PMID- 29698712 TI - Can trajectories of glycemic control be predicted by depression, anxiety, or diabetes-related distress in a prospective cohort of adults with newly diagnosed type 1 diabetes? Results of a five-year follow-up from the German multicenter diabetes cohort study (GMDC-Study). AB - AIMS: The longitudinal association between glycemic control with depression, anxiety or diabetes-related distress in type 1 diabetes is poorly understood. Therefore, we examined long-term trajectories of HbA1c in a new-onset cohort of adults with type 1 diabetes, and analyzed associations with depression, anxiety, and diabetes-related distress. METHODS: We included 313 newly diagnosed adults with type 1 diabetes in a prospective multicenter cohort study. Depression, anxiety, and diabetes-related distress were assessed starting with the diabetes diagnosis and at five annual surveys. HbA1c-measurements started with the one year follow-up. HbA1c trajectories were analyzed applying Growth mixture modeling, while prediction of membership in the trajectories classes was analyzed using multiple regression, and one-way ANOVA/Chi2 to identify differences between classes. RESULTS: Average HbA1c increased constantly: follow-up at 1-year 6.5% (48 mmol/mol), 2-years 6.9% (52 mmol/mol), 3-years 7.1% (54 mmol/mol), 4-years 7.1% (54 mmol/mol), and 5-years 7.4% (57 mmol/mol). HbA1c trajectories included one 'good control' and three 'poor control' (52% of patients) classes. At the five-year follow-up, mean HbA1c was 6.3% (45 mmol/mol) in the 'good control' class, and ranging from 7.9% (63 mmol/mol) to 9.0% (75 mmol/mol) in the three 'poor control' classes. Classes were neither predicable, nor differentiated by depression, anxiety, or diabetes-related distress. CONCLUSIONS: We identified distinct trajectories of glycemic control. Depression and anxiety were highly prevalent but they neither predicted 'poor'/'good' glycemic control trajectories nor were they associated with glycemic control at any assessment point. PMID- 29698713 TI - Interventions designed to reduce excessive gestational weight gain can reduce the incidence of gestational diabetes mellitus: A systematic review and meta-analysis of randomised controlled trials. AB - AIMS: To (i) evaluate the global impact of interventions designed to prevent excessive gestational weight gain (eGWG) on the incidence of gestational diabetes (GDM), and (ii) examine whether the effects differ by pre-conception body mass index (BMI) or ethnicity. METHODS: A systematic search of randomised controlled trials (RCTs) with a primary or secondary aim to reduce eGWG was conducted in seven international and three Chinese databases without date limits. Meta analysis data are reported as relative risk (RR) for GDM incidence for interventions including: diet, physical activity (PA), and lifestyle (diet and PA). RESULTS: Forty-five studies were included, 37 in the meta-analyses. Diet and PA interventions reduced GDM risk by 44% (RR: 0.56, 95% CI: 0.36-0.87) and 38% (RR: 0.62, 95% CI: 0.50-0.78), respectively. Lifestyle interventions and BMI didn't significantly alter GDM risk. PA interventions from Southern-Europe reduced GDM risk by 37% (RR: 0.63, 95% CI: 0.50-0.80). Whereas, diet and lifestyle interventions conducted in Asia reduced GDM risk by 62% (RR: 0.38, 95% CI: 0.24-0.59) and 32% (RR: 0.68, 95% CI: 0.54-0.86), respectively. CONCLUSION: Diet and PA interventions designed to reduce GWG are more effective than standard care in reducing the incidence of GDM, although the effect varies by region and BMI. The 'one size fits all' approach is not supported. PMID- 29698714 TI - pH-responsive delivery of Griffithsin from electrospun fibers. AB - Human immunodeficiency virus (HIV-1) affects over 36 million people globally. Current prevention strategies utilize antiretrovirals that have demonstrated protection, but result in antiviral resistance, adverse toxicity, and require frequent administration. A novel biologic, griffithsin (GRFT), has demonstrated outstanding safety and efficacy against laboratory and primary HIV isolates and against intravaginal murine herpes simplex virus 2 (HSV-2) challenge, making it a promising microbicide candidate. However, transient activity and instability remain concerns surrounding biologic delivery, particularly in the harsh environment of the female reproductive tract (FRT). Recently, electrospun fibers (EFs) have demonstrated promise for intravaginal delivery, with the potential to conserve active agent until release is needed. The goal of this study was to fabricate and characterize pH-responsive fibers comprised of poly(lactic-co glycolic acid) (PLGA) or methoxypolyethylene glycol-b-PLGA (mPEG-PLGA) with varying ratios of poly(n-butyl acrylate-co-acrylic acid) (PBA-co-PAA), to selectively release GRFT under pH-conditions that mimic semen introduction. Fibers comprised of mPEG-PLGA:PBA-co-PAA (90:10 w/w) demonstrated high GRFT loading that was maintained within simulated vaginal fluid (SVF), and pH dependent release upon exposure to buffered and SVF:simulated semen solutions. Moreover, GRFT fibers demonstrated potent in vitro efficacy against HIV-1 and safety in vaginal epithelial cells, suggesting their future potential for efficacious biologic delivery to the FRT. PMID- 29698715 TI - Molecular cloning and expression profiles of IGFBP-1a in common carp (Cyprinus carpio) and its expression regulation by growth hormone in hepatocytes. AB - In this study, we cloned and determined IGFBP-1a cDNA from common carp (Cyprinus carpio) liver. The 1655 bp full-length cDNA consisted of a 96 bp 5-untranslated region (UTR), a 789 bp open reading frame encoding 262 amino acid residues and a 770 bp 3-UTR containing seven mRNA instability motifs. Northern blot revealed a 1.8 kb IGFBP-1a transcript. IGFBP-1a mRNA was widely distributed in all tissues examined and predominantly expressed in the liver. During embryogenesis, IGFBP-1a mRNA was firstly observed in blastula stage, and significant increases were observed in body segment stage, lens formation stage and blood cycling stage. After hatching, its expression increased more than twenty times. Furthermore, hypoxia could significantly up-regulate IGFBP-1a expression in the liver and brain. IGFBP-1a expression increased with ovarian maturation and decreased at regressed stage. In testis, IGFBP-1a mRNA maintained relatively higher levels at recrudescing and matured stages, while it sharply declined at regressed stage. In primary cultured hepatocytes, IGFBP-1a gene was greatly down-regulated by growth hormone via the MAPK and PI3 kinase signaling pathways. These results suggest that IGFBP-1a may be involved in the IGF system regulating growth, development and reproduction in common carp. PMID- 29698716 TI - Vascular Complications and Low Delivery System Profile: The Role of Surgical Aortic Valve Replacement. PMID- 29698717 TI - Inhibition of prostatic smooth muscle contraction by the inhibitor of G protein coupled receptor kinase 2/3, CMPD101. AB - Alpha1-adrenoceptors induce prostate smooth muscle contraction, and hold a prominent role for pathophysiology and therapy of lower urinary tract symptoms in benign prostatic hyperplasia. G protein-coupled receptors are regulated by posttranslational regulation, including phosphorylation by G protein-coupled receptor kinases 2 and 3 (GRK2/3). Although posttranslational adrenoceptor regulation has been recently suggested to occur in the prostate, this is still marginally understood. With the newly developed CMPD101, a small molecule inhibitor with assumed specificity for GRK2/3 is now available. Here, we studied effects of CMPD101 on smooth muscle contraction of human prostate tissue. Electric field stimulation caused frequency-dependent contractions, which were inhibited concentration-dependently by CMPD101 (5 uM, 50 uM). 50 uM of CMPD101 did not affect myosin light chain (MCL) phosphorylation or Rho kinase activity, and did not alter contractions induced by highmolar KCl. Noradrenaline, the alpha1-adrenoceptor agonist phenylephrine, endothelin-1, and the thromboxane A2 analogue U46619 induced concentration-dependent contractions, which were inhibited by CMPD101 (50 uM). CMPD101 (50 uM) did not change phosphorylation of beta2-adrenoceptors or beta2-adrenergic relaxation of prostate strips. Molecular detection by Western blot and peroxidase staining suggested expression of GRK2 and GRK3 in human prostates. Double labeling in fluorescence staining confirmed that immunoreactivity for GRK2 and GRK3 was located to smooth muscle cells in the prostate stroma. In conclusion, CMPD101 inhibits adrenergic, neurogenic, and non adrenergic smooth muscle contractions in the human prostate. Underlying mechanisms may be independent from GRK inhibition, and from inhibition of MLC kinase and Rho kinase. This may point to unknown properties of CMPD101. PMID- 29698718 TI - Drug-Induced Sarcoidosis-Like Reactions. AB - A drug-induced sarcoidosis-like reaction (DISR) is a systemic granulomatous reaction that is indistinguishable from sarcoidosis and occurs in a temporal relationship with initiation of an offending drug. DISRs typically improve or resolve after withdrawal of the offending drug. Four common categories of drugs that have been associated with the development of a DISR are immune checkpoint inhibitors, highly active antiretroviral therapy, interferons, and tumor necrosis factor-alpha antagonists. Similar to sarcoidosis, DISRs do not necessarily require treatment because they may cause no significant symptoms, quality of life impairment, or organ dysfunction. When treatment of a DISR is required, standard antisarcoidosis regimens seem to be effective. Because a DISR tends to improve or resolve when the offending drug is discontinued, this is another effective treatment for a DISR. However, the offending drug need not be discontinued if it is useful, and antigranulomatous therapy can be added. In some situations, the development of a DISR may suggest a beneficial effect of the inducing drug. Understanding the mechanisms leading to DISRs may yield important insights into the immunopathogenesis of sarcoidosis. PMID- 29698719 TI - Serum Chloride Levels Track With Survival in Patients With Pulmonary Arterial Hypertension. AB - BACKGROUND: Serum chloride is an important homeostatic biomarker in left heart failure, with significant prognostic implications. The impact of serum chloride in the long-term survival of patients with pulmonary arterial hypertension (PAH) is unknown. We tested whether serum chloride levels are associated with long-term survival in patients with PAH. METHODS: We included patients with idiopathic or heritable PAH who had a basic metabolic panel performed at the time of their diagnostic right heart catheterization. Laboratory results were recorded both at diagnosis and 6-month follow-up. RESULTS: We included 277 patients, mean age 51 +/- 18 years and 73% women, of whom 254 had a follow-up electrolyte determination at 6 months. Serum chloride was 102.9 +/- 3.9 mM/L at diagnosis. A serum chloride <= 100 mM/L was noted in 65 (24%) and 53 (21%) patients at diagnosis and 6 months, respectively. Patients with serum chloride <= 100 mM/L at 6 months tracked with increase mortality when adjusted by age, sex, pulmonary vascular resistance, diuretics or prostacyclin analogs usage, and serum creatinine and sodium at 6 months (hazard ratio, 1.83; 95% CI, 1.11-3.00). This group of patients was older, with decreased functional capacity, had worse renal function, took more diuretics, had higher pulmonary artery wedge pressure but lower mean pulmonary artery pressure, transpulmonary gradient, and pulmonary vascular resistance. CONCLUSIONS: Serum chloride at 6 months from the PAH diagnosis is a strong and independent predictor of mortality in patients with idiopathic or heritable PAH, even after adjusting serum sodium, renal function, diuretic, and prostacyclin analog usage. PMID- 29698720 TI - Comparison of Two Lidocaine Administration Techniques on Perceived Pain From Bedside Procedures: A Randomized Clinical Trial. AB - BACKGROUND: Lidocaine is used to alleviate procedural pain but paradoxically increases pain during injection. Pain perception can be modulated by non-noxious stimuli such as temperature or touch according to the gate control theory of pain. We postulated that lidocaine dripped onto the skin prior to injection would cool or add the sensation of touch at the skin surface to reduce pain perception from the procedure. METHODS: A randomized clinical trial of patients referred to the procedure service from February 2011 through March 2015 was conducted. All patients received 1% subcutaneous lidocaine injection. Patients randomized to the intervention group had approximately 1 to 2 ml of lidocaine squirted onto the skin surface prior to subcutaneous lidocaine injection. Patients were blinded to the details of the intervention and were surveyed by a blinded investigator to document the primary outcome (severity of pain from the procedure) using a visual analog scale. RESULTS: A total of 481 patients provided consent and were randomized to treatment. There was a significant improvement in the primary outcome of procedural pain (control, 16.6 +/- 24.8 mm vs 12.2 +/- 19.4 mm; P = .03) with the intervention group as assessed by using the visual analog scale score. Pain scores were primarily improved for peripherally inserted central catheters (control, 18.8 +/- 25.6 mm vs 12.2 +/- 18.2 mm; P = .02) upon subgroup analysis. CONCLUSIONS: Bedside procedures are exceedingly common. Data regarding the severity of procedural pain and strategies to mitigate it are important for the informed consent process and patient satisfaction. Overall, pain reported from common bedside procedures is low, but pain can be further reduced with the addition of lidocaine onto the skin surface to modulate pain perception. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01330134; URL: www.clinicaltrials.gov. PMID- 29698721 TI - Fixed But Not Autoadjusting Positive Airway Pressure Attenuates the Time dependent Decline in Glomerular Filtration Rate in Patients With OSA. AB - BACKGROUND: The impact of treating OSA on renal function decline is controversial. Previous studies usually included small samples and did not consider specific effects of different CPAP modalities. The aim of this study was to evaluate the respective influence of fixed and autoadjusting CPAP modes on estimated glomerular filtration rate (eGFR) in a large sample of patients derived from the prospective European Sleep Apnea Database cohort. METHODS: In patients of the European Sleep Apnea Database, eGFR prior to and after follow-up was calculated by using the Chronic Kidney Disease-Epidemiology Collaboration equation. Three study groups were investigated: untreated patients (n = 144), patients receiving fixed CPAP (fCPAP) (n = 1,178), and patients on autoadjusting CPAP (APAP) (n = 485). RESULTS: In the whole sample, eGFR decreased over time. The rate of eGFR decline was significantly higher in the subgroup with eGFR above median (91.42 mL/min/1.73 m2) at baseline (P < .0001 for effect of baseline eGFR). This decline was attenuated or absent (P < .0001 for effect of treatment) in the subgroup of patients with OSA treated by using fCPAP. A follow-up duration exceeding the median (541 days) was associated with eGFR decline in the untreated and APAP groups but not in the fCPAP group (P < .0001 by two-way ANOVA for interaction between treatment and follow-up length). In multiple regression analysis, eGFR decline was accentuated by advanced age, female sex, cardiac failure, higher baseline eGFR, and longer follow-up duration, whereas there was a protective effect of fCPAP. CONCLUSIONS: fCPAP but not APAP may prevent eGFR decline in OSA. PMID- 29698723 TI - A segmental duplication in the common ancestor of Brassicaceae is responsible for the origin of the paralogs KCS6-KCS5, which are not shared with other angiosperms. AB - Novel morphological structures allowed adaptation to dry conditions in early land plants. The cuticle, one such novelty, plays diverse roles in tolerance to abiotic and biotic stresses and plant development. Cuticular waxes represent a major constituent of the cuticle and are comprised of an assortment of chemicals that include, among others, very long chain fatty acids (VLCFAs). Members of the beta-ketoacyl coenzyme A synthases (KCS) gene family code for enzymes that are essential for fatty acid biosynthesis. The gene KCS6 (CUT1) is known to be a key player in the production of VLCFA precursors essential for the synthesis of cuticular waxes in the model plant Arabidopsis thaliana (Brassicaceae). Despite its functional importance, relatively little is known about the evolutionary history of KCS6 or its paralog KCS5 in Brassicaceae or beyond. This lacuna becomes important when we extrapolate understanding of mechanisms gained from the model plant to its containing clades Brassicaceae, flowering plants, or beyond. The Brassicaceae, with several sequenced genomes and a known history of paleoploidy, mesopolyploidy and neopolyploidy, offer a system in which to study the evolution and diversification of the KCS6-KCS5 paralogy. Our phylogenetic analyses across green plants, combined with comparative genomic, microsynteny and evolutionary rates analyses across nine genomes of Brassicaceae, reveal that (1) the KCS6-KCS5 paralogy arose as the result of a large segmental duplication in the ancestral Brassicaceae, (2) the KCS6-KCS5 lineage is represented by a single copy in other flowering plant lineages, (3) the duplicated segments undergo different degrees of retention and loss, and (4) most of the genes in the KCS6 and KCS5 gene blocks (including KCS6 and KCS5 themselves) are under purifying selection. The last also true for most members of the KCS gene family in Brassicaceae, except for KCS8, KCS9 and KCS17, which are under positive selection and may be undergoing functional evolution, meriting further investigation. Overall, our results clearly establish that the ancestral KCS6/5 gene duplicated in the Brassicaceae lineage. It is possible that any specialized functions of KCS5 found in Brassicaceae are either part of a set of KCS6/5 gene functions in the rest of the flowering plants, or unique to Brassicaceae. PMID- 29698722 TI - Multi-tissue DNA methylation age: Molecular relationships and perspectives for advancing biomarker utility. AB - The multi-tissue DNA methylation estimator of chronological age (DNAm-age) has been associated with a wide range of exposures and health outcomes. Still, it is unclear how DNAm-age can have such broad relationships and how it can be best utilized as a biomarker. Understanding DNAm-age's molecular relationships is a promising approach to address this critical knowledge gap. In this review, we discuss the existing literature regarding DNAm-age's molecular relationships in six major categories: animal model systems, cancer processes, cellular aging processes, immune system processes, metabolic processes, and nucleic acid processes. We also present perspectives regarding the future of DNAm-age research, including the need to translate a greater number of ongoing research efforts to experimental and animal model systems. PMID- 29698724 TI - Development of Coprocessed Chitin-Calcium Carbonate as Multifunctional Tablet Excipient for Direct Compression. AB - Owing to the increasing interest in multifunctional excipients for tableting, coprocessing of individual excipients is regularly used to produce excipients of improved multifunctionality superior to individual excipients or their physical mix. The use of chitin as an excipient in tablet formulation is limited because of certain drawbacks such as poor flowability and low true density. The objective of this work is to improve these properties through coprocessing of chitin with calcium carbonate (CaCO3) by precipitating CaCO3 on chitin particles using different methods. In addition, optimization of the coprocessed chitin was carried out to improve the excipient's properties. Physicochemical (CaCO3 content, true density, X-ray diffraction, infrared spectroscopy, and scanning electron microscopy) and functional testing (swelling force, flowability, tensile strength, deformation mechanism, and disintegration time) were used to characterize the coprocessed product. Results showed that the calcite CaCO3 polymorph is precipitated on the chitin surface and that it interacts with chitin at carbonyl- and amide-group level. In addition, the coprocessed excipient has an improved true density and powder flowability, with CaCO3 forming single layer on the chitin particles surface. Tableting studies showed that the coprocessed powder exhibited an intermediate deformation behavior between CaCO3 (most brittle) and chitin (most plastic). Tablets showed acceptable tensile strength and rapid disintegration (2-4 s). These results show the potential use of coprocessed chitin-CaCO3 as a multifunctional excipient for fast disintegration of tablets produced by direct compression. PMID- 29698725 TI - Formulation Development, Optimization, and In Vitro-In Vivo Characterization of Natamycin-Loaded PEGylated Nano-Lipid Carriers for Ocular Applications. AB - The present study aimed at formulating and optimizing natamycin (NT)-loaded polyethylene glycosylated nano-lipid carriers (NT-PEG-NLCs) using Box-Behnken design and investigating their potential in ocular applications. Response surface methodology computations and plots for optimization were performed using Design Expert(r) software to obtain optimum values for response variables based on the criteria of desirability. Optimized NT-PEG-NLCs had predicted values for the dependent variables which are not significantly different from the experimental values. NT-PEG-NLCs were characterized for their physicochemical parameters; NT's rate of permeation and flux across rabbit cornea was evaluated, in vitro, and ocular tissue distribution was assessed in rabbits, in vivo. NT-PEG-NLCs were found to have optimum particle size (<300 nm), narrow polydispersity index, and high NT entrapment and NT content. In vitro transcorneal permeability and flux of NT from NT-PEG-NLCs was significantly higher than that of Natacyn(r). NT-PEG-NLC (0.3%) showed improved delivery of NT across the intact cornea and provided concentrations statistically similar to the marketed suspension (5%) in inner ocular tissues, in vivo, indicating that it could be a potential alternative to the conventional suspension during the course of fungal keratitis therapy. PMID- 29698726 TI - Development, Characterization, and In Vitro Testing of Co-Delivered Antimicrobial Dry Powder Formulation for the Treatment of Pseudomonas aeruginosa Biofilms. AB - Pseudomonas aeruginosa is an opportunistic bacteria responsible for recurrent lung infections. Previously, we demonstrated that certain materials improved the activity of tobramycin (Tob) against P. aeruginosa biofilms in vitro. We aimed to develop prototype dry powder formulations comprising Tob and a mixture of excipients and test its aerodynamic properties and antimicrobial activity. First, we evaluated different combinations of excipients with Tob in solution against P. aeruginosa biofilms. We selected the compositions with the highest activity, to prepare dry powders by spray drying. The powders were characterized by morphology, bulk density, water content, and particle size distributions. Finally, the antimicrobial activity of the powders was tested. The combinations of Tob (64 MUg/mL) with l-alanine and l-proline (at 10 and 20 mM; formulations 1 and 2, respectively) and with l-alanine and succinic acid (at 20 mM; formulation 3) showed the highest efficacies in vitro and were prepared as dry powders. Formulation 1 had the best aerodynamic performance as indicated by the fine particle fraction and the best in vitro activity against P. aeruginosa biofilms. Formulation 3 represents a good candidate for further optimization because it demonstrated good dispersibility potential and optimization of the particle size distribution may achieve high delivery efficiencies. PMID- 29698727 TI - Merits and Limitations of Dynamic Vapor Sorption Studies on the Morphology and Physicochemical State of Freeze-Dried Products. AB - The goal of the present study was to assess the applicability of dynamic vapor sorption analysis of freeze-dried products. Water vapor sorption profiles of intact and ground cakes were recorded to determine the relevance of powder handling. Grinding prior to measurements appeared to be related with a more rapid uptake of water vapor and crystallization. Crystallization may be prevented when analyzing intact cakes. More hygroscopic materials appeared to require a longer time to achieve a constant mass. The specific surface area of different freeze dried products was calculated from the sorption isotherms using water, organic solvents, and krypton. The specific surface areas calculated for mannitol with water and ethanol was in good agreement with krypton data. False high values were obtained from water vapor sorption of the investigated amorphous materials. The results were slightly improved by the application of vacuum. For trehalose and sucrose, no sorption and thus faulty results were detected with the studied organic solvents. The degree of crystallinity of mannitol within a binary formulation could not be determined by dynamic vapor sorption. Differences in sorption and crystallization tendencies of mannitol and sucrose that were freeze dried separately and in a binary mixture were considered as the root cause. PMID- 29698728 TI - Topical Application of Keratinocyte Growth Factor Conjugated Gold Nanoparticles Accelerate Wound Healing. AB - Keratinocyte growth factor (KGF) has been demonstrated to specifically stimulate the multiplication and migration of keratinocytes. However, due to rapid degradation, the results of topical application of growth factors on wounds are unsatisfactory. In this study, we cross-linked KGF to the surface of gold nanoparticles (GNPs) and explored their effects on wound healing. The as synthesized nanocomposite (KGF-GNPs) displayed good colloidal stability, decent biocompatibility as well as negligible cellular cytotoxicity. The in vitro cellular experimental results demonstrated that KGF-GNPs could effectively promote the proliferation of keratinocytes in contrast to bare GNPs or KGF. Furthermore, in animal full-thickness wound model, KGF-GNPs are more conducive to wound healing than bare GNPs or KGF. KGF-GNPs enhanced wound healing by promoting wound re-epithelialization rather than granulation. The superior biocompatibility, colloidal depressiveness and biological activity of this nanocomposite indicate that it could be utilized as a promising wound healing drug for clinical application in the future. PMID- 29698729 TI - Axonal transport proteins and depressive like behavior, following Chronic Unpredictable Mild Stress in male rat. AB - BACKGROUND: A common mood disorder, depression has long been considered a leading cause of disability worldwide. Chronic stress is involved in the development of various psychiatric diseases including major depressive disorder. Stress can induce depressive-like symptoms and initiate neurodegenerative processes in the brain. The neurodegenerative theory of depression holds impaired axonal transport as a negative factor in neural survival. Axonal transport is a critical mechanism for normal neuronal function, playing crucial roles in axon growth, neurotransmitter secretion, normal mitochondrial function and neural survival. METHODS AND MATERIALS: To investigate the effects of stress-induced depression, in the present study, we evaluated behavior by forced swimming test (FST), corticosterone plasma level by ELISA assay, hippocampal mRNA expression of three genes (NGF, kinesin and dynein) via real-time PCR and hippocamp count by Nissl staining in male Wistar rats. RESULTS: Our data demonstrated a significant decrease in the expression of NGF, kinesin and dynein genes in CUMS groups compared to the control group (non-stressed) (p < 0.05). CUMS also caused an elevation in immobility time and corticosterone plasma level in the stressed group compared to the controls (p < 0.01 and p < 0.05, respectively). CONCLUSION: The results suggested that the possibility of stress-induced depressive behavior associated with hippocampal neurodegeneration process is correlated with a low expression of kinesin and dynein, the two most important proteins in axonal transport. PMID- 29698730 TI - Critical bounds on noise and SNR for robust estimation of real-time brain activity from functional near infra-red spectroscopy. AB - The robust characterization of real-time brain activity carries potential for many applications. However, the contamination of measured signals by various instrumental, environmental, and physiological sources of noise introduces a substantial amount of signal variance and, consequently, challenges real-time estimation of contributions from underlying neuronal sources. Functional near infra-red spectroscopy (fNIRS) is an emerging imaging modality whose real-time potential is yet to be fully explored. The objectives of the current study are to (i) validate a time-dependent linear model of hemodynamic responses in fNIRS, and (ii) test the robustness of this approach against measurement noise (instrumental and physiological) and mis-specification of the hemodynamic response basis functions (amplitude, latency, and duration). We propose a linear hemodynamic model with time-varying parameters, which are estimated (adapted and tracked) using a dynamic recursive least square algorithm. Owing to the linear nature of the activation model, the problem of achieving robust convergence to an accurate estimation of the model parameters is recast as a problem of parameter error stability around the origin. We show that robust convergence of the proposed method is guaranteed in the presence of an acceptable degree of model misspecification and we derive an upper bound on noise under which reliable parameters can still be inferred. We also derived a lower bound on signal-to noise-ratio over which the reliable parameters can still be inferred from a channel/voxel. Whilst here applied to fNIRS, the proposed methodology is applicable to other hemodynamic-based imaging technologies such as functional magnetic resonance imaging. PMID- 29698731 TI - Tracking wakefulness as it fades: Micro-measures of alertness. AB - A major problem in psychology and physiology experiments is drowsiness: around a third of participants show decreased wakefulness despite being instructed to stay alert. In some non-visual experiments participants keep their eyes closed throughout the task, thus promoting the occurrence of such periods of varying alertness. These wakefulness changes contribute to systematic noise in data and measures of interest. To account for this omnipresent problem in data acquisition we defined criteria and code to allow researchers to detect and control for varying alertness in electroencephalography (EEG) experiments under eyes-closed settings. We first revise a visual-scoring method developed for detection and characterization of the sleep-onset process, and adapt the same for detection of alertness levels. Furthermore, we show the major issues preventing the practical use of this method, and overcome these issues by developing an automated method (micro-measures algorithm) based on frequency and sleep graphoelements, which are capable of detecting micro variations in alertness. The validity of the micro measures algorithm was verified by training and testing using a dataset where participants are known to fall asleep. In addition, we tested generalisability by independent validation on another dataset. The methods developed constitute a unique tool to assess micro variations in levels of alertness and control trial by-trial retrospectively or prospectively in every experiment performed with EEG in cognitive neuroscience under eyes-closed settings. PMID- 29698732 TI - Dopamine substitution alters effective connectivity of cortical prefrontal, premotor, and motor regions during complex bimanual finger movements in Parkinson's disease. AB - Bimanual coordination is impaired in Parkinson's disease (PD), affecting patients' quality of life. Besides dysfunction of the basal ganglia network, alterations of cortical oscillatory coupling, particularly between prefrontal and (pre-)motoric areas, are thought to underlie this impairment. Here, we studied 16 PD patients OFF and ON medication and age-matched healthy controls recording high resolution electroencephalography (EEG) during performance of spatially coupled and uncoupled bimanual finger movements. Dynamic causal modeling (DCM) for induced responses was used to infer task-induced effective connectivity within a network comprising bilateral prefrontal cortex (PFC), lateral premotor cortex (lPM), supplementary motor area (SMA), and primary motor cortex (M1). Performing spatially coupled movements, excitatory left-hemispheric PFC to lPM coupling was significantly stronger in controls compared to unmedicated PD patients. Levodopa induced enhancement of this connection correlated with increased movement accuracy. During performance of spatially uncoupled movements, PD patients OFF medication exhibited inhibitory connectivity from left PFC to SMA. Levodopa intake diminished these inhibitory influences and restored excitatory PFC to lPM coupling. This restoration, however, did not improve motor function. Concluding, our results indicate that lateralization of prefrontal to premotor connectivity in PD can be augmented by levodopa substitution and is of compensatory nature up to a certain extent of complexity. PMID- 29698733 TI - Evidence for degraded low frequency verbal concepts in left resected temporal lobe epilepsy patients. AB - According to a large neuropsychological and neuroimaging literature, the bilateral anterior temporal lobe (ATL) is a core region for semantic processing. It seems therefore surprising that semantic memory appears to be preserved in temporal lobe epilepsy (TLE) patients with unilateral ATL resection. However, recent work suggests that the bilateral semantic system is relatively robust against unilateral damage and semantic impairments under these circumstances only become apparent with low frequency specific concepts. In addition, neuroimaging studies have shown that the function of the left and right ATLs differ and therefore left or right ATL resection should lead to a different pattern of impairment. The current study investigated hemispheric differences in the bilateral semantic system by comparing left and right resected TLE patients during verbal semantic processing of low frequency concepts. Picture naming and semantic comprehension tasks with varying word frequencies were included to investigate the pattern of impairment. Left but not right TLE patients showed impaired semantic processing, which was particularly apparent on low frequency items. This indicates that, for verbal information, the bilateral semantic system is more sensitive to damage in the left compared to the right ATL, which is in line with theories that attribute a more prominent role to the left ATL due to connections with pre-semantic verbal regions. PMID- 29698734 TI - Metacognition of visuomotor decisions in conversion disorder. AB - Motor conversion disorder (CD) entails genuine disturbances in the subjective experience of patients who maintain they are unable to perform a motor function, despite lack of apparent neurological damage. Abilities by which individuals assess their own capacities during performance in a task are called metacognitive, and distinctive impairment of such abilities is observed in several disorders of self-awareness such as blindsight and anosognosia. In CD, previous research has focused on the recruitment of motor and emotional brain systems, generally linking symptoms to altered limbic-motor interactions; however, metacognitive function has not been studied to our knowledge. Here we tested ten CD patients and ten age-gender matched controls during a visually guided motor paradigm, previously employed in healthy controls (HC), allowing us to probe for motor awareness and metacognition. Participants had to draw straight trajectories towards a visual target while, unbeknownst to them, deviations were occasionally introduced in the reaching trajectory seen on the screen. Participants then reported both awareness of deviations and confidence in their response. Activity in premotor and cingulate cortex distinguished between conscious and unconscious movement corrections in controls better than patients. Critically, whereas controls engaged the left superior precuneus and middle temporal region during confidence judgments, CD patients recruited bilateral parahippocampal and amygdalo-hippocampal regions instead. These results reveal that distinct brain regions subserve metacognitive monitoring for HC and CD, pointing to different mechanisms and sources of information used to monitor and form confidence judgments of motor performance. While brain systems involved in sensory-motor integration and vision are more engaged in controls, CD patients may preferentially rely on memory and contextual associative processing, possibly accounting for how affect and memories can imbue current motor experience in these patients. PMID- 29698735 TI - Unconscious fearful body perception enhances discrimination of conscious anger expressions under continuous flash suppression. AB - The continuous flash suppression (CFS) paradigm is increasingly used to study unconscious visual perception. Our goal was to use CFS and to to compare the results with previous findings from patients with brain lesions, and studies of healthy participants. We used an emotion discrimination task and bilaterally presented whole-body postures expressing fear or anger, rendering the stimuli invisible in either one of the visual fields. We found that the CFS presentation did not yield the classical redundant target effect of response facilitation when the unconsciously seen stimuli had congruent emotions; instead we found a facilitation effect in reaction times by body stimuli of incongruent emotions, especially by the unconscious fearful body facilitating discrimination of conscious angry body. Our results with healthy participants showed similarities to hemianopia patients without blindsight, but not to blindsight or neglect patients, indicating that unconscious visual processing is not a single phenomenon, but is likely to involve multiple mechanisms, processes and brain regions. Further studies are necessary to validate the facilitation effect of fearful bodies on other tasks, and to study the neural substrates of this effect. PMID- 29698736 TI - Enhancement of motor-imagery ability via combined action observation and motor imagery training with proprioceptive neurofeedback. AB - Varied individual ability to control the sensory-motor rhythms may limit the potential use of motor-imagery (MI) in neurorehabilitation and neuroprosthetics. We employed neurofeedback training of MI under action observation (AO: AOMI) with proprioceptive feedback and examined whether it could enhance MI-induced event related desynchronization (ERD). Twenty-eight healthy young adults participated in the neurofeedback training. They performed MI while watching a video of hand squeezing motion from a first-person perspective. Eleven participants received correct proprioceptive feedback of the same hand motion with the video, via an exoskeleton robot attached to their hand, upon their successful generation of ERD. Another nine participants received random feedback. The training lasted for approximately 20 min per day and continued for 6 days within an interval of 2 weeks. MI-ERD power was evaluated separately, without AO, on each experimental day. The MI-ERD power of the participants receiving correct feedback, as opposed to random feedback, was significantly increased after training. An additional experiment in which the remaining eight participants were trained with auditory instead of proprioceptive feedback failed to show statistically significant increase in MI-ERD power. The significant training effect obtained in shorter training time relative to previously proposed methods suggests the superiority of AOMI training and physiologically-congruent proprioceptive feedback to enhance the MI-ERD power. The proposed neurofeedback training could help patients with motor deficits to attain better use of brain-machine interfaces for rehabilitation and/or prosthesis. PMID- 29698737 TI - Dichlorophenyl piperazines, including a recently-approved atypical antipsychotic, are potent inhibitors of DHCR7, the last enzyme in cholesterol biosynthesis. AB - While antipsychotic medications provide important relief from debilitating psychotic symptoms, they also have significant adverse side effects, which might have relevant impact on human health. Several research studies, including ours, have shown that commonly used antipsychotics such as haloperidol and aripiprazole affect cholesterol biosynthesis at the conversion of 7-dehydrocholesterol (7-DHC) to cholesterol. This transformation is promoted by the enzyme DHCR7 and its inhibition causes increases in plasma and tissue levels of 7-DHC. The inhibition of this enzymatic step by mutations in the Dhcr7 gene leads to Smith-Lemli-Opitz syndrome, a devastating human condition that can be replicated in rats by small molecule inhibitors of DHCR7. The fact that two compounds, brexpiprazole and cariprazine, that were recently approved by the FDA have substructural elements in common with the DHCR7 inhibitor aripiprazole, prompted us to evaluate the effect of brexpiprazole and cariprazine on cholesterol biosynthesis. We report that cariprazine affects levels of 7-DHC and cholesterol in cell culture incubations at concentrations as low as 5 nM. Furthermore, a common metabolite of cariprazine and aripiprazole, 2,3-(dichlorophenyl) piperazine, inhibits DHCR7 activity at concentrations comparable to those of the potent teratogen AY9944. The cell culture experiments were corroborated in mice in studies showing that treatment with cariprazine elevated 7-DHC in brain and serum. The consequences of sterol inhibition by antipsychotics in the developing nervous system and the safety of their use during pregnancy remains to be established. PMID- 29698739 TI - An ecological momentary assessment of the effect of fasting during Ramadan on disordered eating behaviors. AB - Dietary restriction contributes to disordered eating (DE) behaviors and associated cognitions. However, it is unclear how these outcomes are impacted by dietary restriction for religious purposes, such as fasting observed by Muslims during Ramadan. Using ecological momentary assessment, this study assessed the impact of Ramadan fasting on DE behaviors and correlates. Muslim participants fasting during Ramadan (n = 28) and a control group of non-fasting participants (n = 74) completed baseline measures assessing demographic characteristics and eating pathology. A mobile phone application then prompted participants six times per day for seven days to self-report on dietary restriction efforts, body satisfaction, temptation to eat unhealthily, feelings of guilt or shame following food, and DE behaviors including bingeing, vomiting, and other purging behaviors (use of laxatives, diuretics, or diet pills). After controlling for eating pathology, multilevel modeling indicated that, as expected, the Ramadan fasting group spent significantly more time restricting food intake than the non-fasting group. The Ramadan fasting group also experienced significantly greater temptation to eat unhealthily than their non-fasting counterparts. However, this difference disappeared once models were adjusted for differences in time spent restricting food intake. There were no other significant differences between the groups on any DE variables. These findings suggest that while dietary restriction for health or appearance-related reasons is a known contributor to DE, dietary restriction for religious purposes, such as that observed during the practice of Ramadan, may not confer increased risk of DE symptoms. PMID- 29698738 TI - Uranyl acetate induced DNA single strand breaks and AP sites in Chinese hamster ovary cells. AB - The aim of this study is to characterize the genotoxicity of depleted uranium (DU) in Chinese Hamster Ovary cells (CHO) with mutations in various DNA repair pathways. CHO cells were exposed to 0-300 MUM of soluble DU as uranyl acetate (UA) for 0-48 h. Intracellular UA concentrations were measured via inductively coupled mass spectrometry (ICP-MS) and visualized by transmission electron microscopy (TEM). Cytotoxicity was assessed in vitro by clonogenic survival assay. DNA damage response was assessed via Fast Micromethod(r) to determine UA induced DNA single strand breaks. Results indicate that UA is entering the CHO cells, with the highest concentration localizing in the nucleus. Clonogenic assays show that UA is cytotoxic in each cell line with the greatest cytotoxicity in the base excision repair deficient EM9 cells and the nuclear excision repair deficient UV5 cells compared to the non-homologous end joining deficient V3.3 cells and the parental AA8 cells after 48 h. This indicates that UA is producing single strand breaks and forming UA-DNA adducts rather than double strand breaks in CHO cells. Fast Micromethod(r) results indicate an increased amount of single strand breaks in the EM9 cells after 48 h UA exposure compared to the V3.3 and AA8 cells. These results indicate that DU induces DNA damage via strand breaks and uranium-DNA adducts in treated cells. These results suggest that: (1) DU is genotoxic in CHO cells, and (2) DU is inducing single strand breaks rather than double strand breaks in vitro. PMID- 29698740 TI - Current strategies to detect, manage and control carbapenemase-producing Enterobacteriaceae in NHS acute hospital trusts in the UK: time for a rethink? PMID- 29698741 TI - Prevention of 4-hydroxynonenal-induced lipolytic activation by carnosic acid is related to the induction of glutathione S-transferase in 3T3-L1 adipocytes. AB - : Induction of 4-hydroxynonenal (4-HNE), a major lipid peroxidation aldehyde, is observed in patients with obesity and type 2 diabetes mellitus. The lipolytic response by 4-HNE has been linked to insulin resistance. In this study, we investigated the effects of carnosic acid (CA) on 4-HNE-induced lipolysis and the inhibition of beta-oxidation in 3T3-L1 adipocytes. The results indicated that cells pretreated with CA reduced 4-HNE-mediated free fatty acid (FFA) release. Furthermore, CA reversed the inhibition of phosphorylation of Tyr632 of insulin receptor substrate-1 (IRS-1) and Akt and the phosphorylation of Ser307 of IRS-1. CA inhibited 4-HNE-induced phosphorylation of protein kinase A (PKA) and hormone sensitive lipase (HSL), and reversed the suppression by 4-HNE of phosphorylation of AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (p < 0.05). Pretreatment of cells with forskolin (a cAMP agonist) and compound C (an AMPK inhibitor) reversed these effects, respectively (p < 0.05). In human subcutaneous adipocytes, CA also attenuated 4-HNE-induced FFA release and the phosphorylation of PKA and HSL (p < 0.05). Moreover, CA increased the protein expression of glutathione S-transferase (GST) A and M. Pretreatment with ethacrynic acid, a GST inhibitor, prevented the 4-HNE-conjugated proteins suppression, the PKA and HSL phosphorylation reduction, and the FFA release inhibition by CA (p < 0.05). CONCLUSION: The attenuation by CA of the lipolytic response by 4-HNE is likely related to the induction of GST, which in turn reduced 4-HNE-conjugated proteins and decreased the activation of the PKA/HSL pathway. The observed effects may explain how CA improves 4-HNE-induced insulin resistance. PMID- 29698742 TI - Age and the effect of exercise, nutrition and cognitive training on oxidative stress - The Vienna Active Aging Study (VAAS), a randomized controlled trial. AB - The purpose of this study was to investigated the effect of age - over or under life-expectancy (LE) - on six months resistance training alone or combined with a nutritional supplement, and cognitive training by analyzing markers for oxidative stress and antioxidant defense in institutionalized elderly, living in Vienna. Three groups (n = 117, age = 83.1 +/- 6.1 years) - resistance training (RT), RT combined with protein and vitamin supplementation (RTS) or cognitive training (CT) - performed two guided training sessions per week for six months. Oxidative stress, antioxidant defense and DNA strand breaks were analyzed and transformed into an "antioxidant factor" to compare the total effect of the intervention. Physical fitness was assessed by the 6-min-walking, the chair-rise and the handgrip strength tests. We observed significant negative baseline correlations between 8-oxo-7.8-dihydroguanosine and handgrip strength (r = -0.350, p = 0.001), and between high sensitive troponin-T and the 6-min-walking test (r = -0.210, p = 0.035). RT and RTS groups, showed significant improvements in physical performance. Over LE, subjects of the RT group demonstrated a significant greater response in the "antioxidant factor" compared to RTS and CT (RT vs. RTS p = 0.033, RT vs. CT p = 0.028), whereas no difference was observed between the intervention groups under LE. Six months of elastic band resistance training lead to improvements in antioxidant defense, DNA stability and oxidative damage, summarized in the "antioxidant factor", however mainly in subjects over their statistical LE. Consuming a supplement containing antioxidants might inhibit optimal cellular response to exercise. The study was approved by the ethics committee of the City of Vienna (EK-11-151-0811) and registered at ClinicalTrials.gov, NCT01775111. PMID- 29698744 TI - Hyperoxia induces epigenetic changes in newborn mice lungs. AB - Supplemental oxygen exposure is a risk factor for the development of bronchopulmonary dysplasia (BPD). Reactive oxygen species may damage lung tissue, but hyperoxia also has the potential to alter genome activity via changes in DNA methylation. Understanding the epigenetic potential of hyperoxia would enable further improvement of the therapeutic strategies for BPD. Here we aimed to identify hyperoxia-related alterations in DNA methylation, which could affect the activity of crucial genetic pathways involved in the development of hyperoxic lung injury. Newborn mice (n = 24) were randomized to hyperoxia (85% O2) or normoxia groups for 14 days, followed by normoxia for the subsequent 14 days. The mice were sacrificed on day 28, and lung tissue was analyzed using microarrays developed for the assessment of genome methylation and expression profiles. The mean DNA methylation level was higher in the hyperoxia group than the normoxia group. The analysis of specific DNA fragments revealed hypermethylation of > 1000 gene promoters in the hyperoxia group, confirming the presence of the DNA hypermethylation effect of hyperoxia. Further analysis showed significant enrichment of the TGF-beta signaling pathway (p = 0.0013). The hypermethylated genes included Tgfbr1, Crebbp, and Creb1, which play central roles in the TGF beta signaling pathway and cell cycle regulation. Genome expression analysis revealed in the hyperoxia group complementary downregulation of genes that are crucial for cell cycle regulation (Crebbp, Smad2, and Smad3). These results suggest the involvement of the methylation of TGF-beta pathway genes in lung tissue reaction to hyperoxia. The data also suggest that hyperoxia may be a programming factor in newborn mice. PMID- 29698743 TI - Neurotoxicity of cytarabine (Ara-C) in dorsal root ganglion neurons originates from impediment of mtDNA synthesis and compromise of mitochondrial function. AB - Peripheral Nervous System (PNS) neurotoxicity caused by cancer drugs hinders attainment of chemotherapy goals. Due to leakiness of the blood nerve barrier, circulating chemotherapeutic drugs reach PNS neurons and adversely affect their function. Chemotherapeutic drugs are designed to target dividing cancer cells and mechanisms underlying their toxicity in postmitotic neurons remain to be fully clarified. The objective of this work was to elucidate progression of events triggered by antimitotic drugs in postmitotic neurons. For proof of mechanism study, we chose cytarabine (ara-C), an antimetabolite used in treatment of hematological cancers. Ara-C is a cytosine analog that terminates DNA synthesis. To investigate how ara-C affects postmitotic neurons, which replicate mitochondrial but not genomic DNA, we adapted a model of Dorsal Root Ganglion (DRG) neurons. We showed that DNA polymerase gamma, which is responsible for mtDNA synthesis, is inhibited by ara-C and that sublethal ara-C exposure of DRG neurons leads to reduction in mtDNA content, ROS generation, oxidative mtDNA damage formation, compromised mitochondrial respiration and diminution of NADPH and GSH stores, as well as, activation of the DNA damage response. Hence, it is plausible that in ara-C exposed DRG neurons, ROS amplified by the high mitochondrial content shifts from physiologic to pathologic levels signaling stress to the nucleus. Combined, the findings suggest that ara-C neurotoxicity in DRG neurons originates in mitochondria and that continuous mtDNA synthesis and reliance on oxidative phosphorylation for energy needs sensitize the highly metabolic neurons to injury by mtDNA synthesis terminating cancer drugs. PMID- 29698745 TI - Evolution, regulation, and function of porcine selenogenome. AB - Much less research on regulation and function of selenoproteins has been conducted in domestic pigs than in rodents or humans, although pigs are an excellent model of human nutrition and medicine and pork is a widely consumed meat in the world. Phylogenetically, the 25 identified porcine selenoproteins fell into two primitive groups, and might be further divided into three parallel branches. Despite a high similarity to that of humans and rodents, the porcine selenoproteome exhibited the closest evolutionary relationship with that of sheep and cattle among eight domestic species. Expression (mRNA, protein, and/or enzyme activity) of 2/3 of the 25 porcine selenoproteins in various tissues of pigs was affected by dietary Se intakes, and 14 of them showed responses to a high fat diet. When dietary Se deficiency mainly down-regulated the expression of selected selenoproteins, dietary Se excess exerted rather diverse effects on their expression. Overdosing pigs with dietary Se induced hyperinsulinemia, along with lipid accumulation and protein increase, in the liver and muscle by affecting key genes and(or) proteins involved in the metabolisms of glucose, lipid, and protein. In conclusion, expression of porcine selenoproteins was highly responsive to dietary Se and fat intakes, and was involved in body glucose, lipid, and protein metabolism as those of rodents and humans. PMID- 29698746 TI - Mortality, morbidity and 2-years neurodevelopmental prognosis of twin to twin transfusion syndrome after fetoscopic laser therapy: a prospective, 58 patients cohort study. AB - OBJECTIVE: To describe the morbidity and mortality and long-term neurodevelopmental outcomes in children born from a Twin-to-Twin Transfusion Syndrome (TTTS) pregnancy treated using laser fetoscopy in Toulouse. POPULATION AND METHOD: All pregnancies with TTTS treated by laser fetoscopy in our centre were included. Antenatal and postnatal morbidity and neonatal morbidity were identified in the medical records retrospectively. The neurodevelopmental outcome was studied using Ages and Stages Questionnaires (ASQ) sent to the parents, an oral interview with the parents and with the child's doctor (last objective neurological examination, rehabilitation needs, learning disabilities). RESULTS: Seventy-one pregnancies, or 144 foetuses, were included from 2008 to 2014, overall survival at 2 years was 72.9% and the survival of at least one child at 2 years was 91.5%, severe neonatal morbidity was 11.2% of the children, severe brain damage accounted for 3.6% of children admitted to the hospital unit. It was possible to study the neurodevelopmental outcome for 58 children (55.3%), with a corrected age from 24 to 95 months. Five children (8.6%) had severe neurological abnormalities and 17 (29.3%) had moderate neurological abnormalities. DISCUSSION: The mortality, neonatal morbidity and long-term neurological morbidity of our cohort are higher than those of premature infants (EPIPAGE-2 French cohort), which confirms the severity of this syndrome, and are comparable to those of the TTTS cohorts described in the literature. PMID- 29698747 TI - Neuroprotective effects of metformin on traumatic brain injury in rats associated with NF-kappaB and MAPK signaling pathway. AB - Traumatic brain injury (TBI) triggers a complex sequence of inflammatory responses that contribute to secondary injury. Metformin, a first-line drug used to treat type 2 diabetes, is reported to exhibit potent anti-inflammatory activity on diseases associated with the central nervous system (CNS). The aim of this study is to investigate the potential neuroprotective effects of metformin on acute brain injury after TBI and explore the underlying mechanisms. Male Sprague-Dawley (SD) rats were divided into four groups: sham group, TBI group, TBI + saline (NS) group and TBI + metformin group. A weight-dropping model was employed to induce TBI in rats. Modified neurological severity scores (mNSS) were employed to assess the short-term neurological deficits, neuronal degeneration and apoptosis in the brain tissues were assayed with Fluoro-Jade B and TUNEL staining, immunofluorescence was designed to investigate microglial activation. The mRNA and protein expression levels of pro-inflammatory cytokines such as necrosis factor-alpha (TNF-alpha), interleukin-beta (IL-1beta) and nterleukin-6 (IL-6) were evaluated by real-time quantitative reverse transcriptase polymerase chain reaction (QPCR) and enzyme-linked immunosorbent assay (ELISA). Western blotting analysis was engaged to examine the expression of NF-kappaB p65 and phosphorylation of ERK1/2 and p38 MAPK. Our results showed that metformin significantly ameliorated neurological deficit, cerebral edema and neuronal apoptosis in rats following TBI. Moreover, metformin administration inhibited microglial activation and decreased the production of pro-inflammatory cytokines including TNF-alpha, IL-1beta and IL-6. In addition, metformin inhibited the translocation of NF-kappaB p65 from cytoplasm into the nucleus, as well as the phosphorylation of ERK1/2 and p38 MAPK. This study suggests that metformin administration inhibits microglia activation-mediated inflammation via NF-kappaB and MAPK signaling pathway to improve neurobehavioral function following TBI, which provide a potential therapeutic benefit in treating brain injury. PMID- 29698749 TI - The Role of Ca2+ and BK Channels of Locus Coeruleus (LC) Neurons as a Brake to the CO2 Chemosensitivity Response of Rats. AB - The cellular mechanisms by which LC neurons respond to hypercapnia are usually attributed to an "accelerator" whereby hypercapnic acidosis causes an inhibition of K+ channels or activation of Na+ and Ca+2 channels to depolarize CO2-sensitive neurons. Nevertheless, it is still unknown if this "accelerator" mechanism could be controlled by a brake phenomenon. Whole-cell patch clamping, fluorescence imaging microscopy and plethysmography were used to study the chemosensitive response of the LC neurons. Hypercapnic acidosis activates L-type Ca2+ channels and large conductance Ca-activated K+ (BK) channels, which function as a "brake" on the chemosensitive response of LC neurons. Our findings indicate that both Ca2+ and BK currents develop over the first 2 weeks of postnatal life in rat LC slices and that this brake pathway may cause the developmental decrease in the chemosensitive firing rate response of LC neurons to hypercapnic acidosis. Inhibition of this brake by paxilline (BK channel inhibitor) returns the magnitude of the chemosensitive firing rate response from LC neurons in rats older than P10 to high values similar to those in LC neurons from younger rats. Inhibition of BK channels in LC neurons by bilateral injections of paxilline into the LC results in a significant increase in the hypercapnic ventilatory response of adult rats. Our findings indicate that a BK channel-based braking system helps to determine the chemosensitive respiratory drive of LC neurons and contributes to the hypercapnic ventilatory response. Perhaps, abnormalities of this braking system could result in hypercapnia-induced respiratory disorders and panic responses. PMID- 29698748 TI - Intronic antisense Alu elements have a negative splicing effect on the inclusion of adjacent downstream exons. AB - Alu elements occupy 10% of the human genome. However, although they contribute to genomic and transcriptomic diversity, their function is still not fully understood. We hypothesized that intronic Alu elements may contribute to alternative splicing. We therefore examined their effect on splicing using minigene constructs including exon 9-exon 11 inclusive of ACAT1 with truncated introns 9 and 10. These constructs contained a suboptimal splice acceptor site for intron 9. Insertion of AluY-partial AluSz6-AluSx, originally located in ACAT1 intron 5, in an antisense direction within intron 9 had a negative effect on exon 10 inclusion. This effect was additive with that of an exonic splicing enhancer mutation in exon 10, and was canceled by the substitution of G for C at the first nucleotide of exon 10 which optimized the splice acceptor site of intron 9. A sense AluY-partial AluSz6-AluSx insertion had no effect on exon 10 inclusion, and one antisense AluSx insertion had a similar effect to antisense AluY-partial AluSz6-AluSx insertion. The shorter the distance between the antisense Alu element and exon 10, the greater the negative effect on exon 10 inclusion. This distance effect was more evident for suboptimal than optimal splice sites. Based on our data, we propose that intronic antisense Alu elements contribute to alternative splicing and transcriptomic diversity in some genes, especially when splice acceptor sites are suboptimal. PMID- 29698750 TI - Low serum Kallistatin level was associated with poor neurological outcome of out of-hospital cardiac arrest survivors: Proteomics study. AB - AIM OF THE STUDY: To identify proteins of which depletion are associated with the poor 6-month neurological outcome of out-of-hospital cardiac arrest survivors. METHODS: Seven healthy volunteers and 34 out-of-hospital cardiac arrest survivors admitted to the intensive care unit (ICU) and underwent targeted-temperature management were enrolled. According to the 6-month cerebral performance category (CPC) scale, patients were divided into the good (CPC 1-2) and poor (CPC 3-5) outcome groups. Blood samples were obtained at 0, 24, and 72 h after admission to the ICU. RESULTS: With proteomic approaches, we found 23 proteins that showed group-differences between the sera pooled from 7 study groups: healthy volunteers, the good outcome groups (0, 24, and 72 h), and the poor outcome groups (0, 24, and 72 h). We selected 7 candidate proteins of which intensities were different between the good and poor outcome groups (>2-fold change) and excluded 5 proteins related to haemolysis or remaining high abundant proteins. To confirm the 2 identified proteins: retinal dehydrogenase 1 and Kallistatin, we performed enzyme-linked immunosorbent assay with individual serum. Finally, old age (odds ratio = 1.055; 95% confidence interval, 1.002-1.112; p = 0.043) and low serum kallistatin level at 0 h (odds ratio = 0.784; 95% confidence interval, 0.618-0.995; p = 0.046) were independently associated with the poor 6-month neurological outcome. CONCLUSION: The depletion of serum kallistatin at admission to the ICU was associated with the poor neurological outcome of out-of-hospital cardiac arrest survivors. PMID- 29698751 TI - Major traumatic complications after out-of-hospital cardiac arrest: Insights from the Parisian registry. AB - AIM: Due to collapse and cardiopulmonary resuscitation (CPR) maneuvers, major traumatic injuries may complicate the course of resuscitation for out-of-hospital cardiac arrest patients (OHCA). Our goals were to assess the prevalence of these injuries, to describe their characteristics and to identify predictive factors. METHODS: We conducted an observational study over a 9-year period (2007-2015) in a French cardiac arrest (CA) center. All non-traumatic OHCA patients admitted alive in the ICU were studied. Major injuries identified were ranked using a functional two-level scale of severity (life-threatening or consequential) and were classified as CPR-related injuries or collapse-related injuries, depending of the predominant mechanism. Factors associated with occurrence of a CPR-related injury and ICU survival were identified using multivariable logistic regression. RESULTS: A major traumatic injury following OHCA was observed in 91/1310 patients (6.9%, 95%CI: 5.6, 8.3%), and was classified as a life-threatening injury in 36% of cases. The traumatic injury was considered as contributing to the death in 19 (21%) cases. Injuries were related to CPR maneuvers in 65 patients (5.0%, (95%CI: 3.8, 6.1%)). In multivariable analysis, age [OR 1.02; 95%CI (1.00, 1.04); p = 0.01], male gender [OR 0.53; 95%CI (0.31, 0.91); p = 0.02] and CA occurring at home [OR 0.54; 95%CI (0.31, 0.92); p = 0.02] were significantly associated with the occurrence of a CPR-related injury. CPR-related injuries were not associated with the ICU survival [OR 0.69; 95%CI (0.36, 1.33); p = 0.27]. CONCLUSIONS: Major traumatic injuries are common after cardiopulmonary resuscitation. Further studies are necessary to evaluate the interest of a systematic traumatic check-up in resuscitated OHCA patients in order to detect these injuries. PMID- 29698752 TI - Differential effect of mild therapeutic hypothermia depending on the findings of hypoxic encephalopathy on early CT images in patients with post-cardiac arrest syndrome. AB - INTRODUCTION: The aim of this study was to evaluate the differential effects of mild therapeutic hypothermia (MTH) in post-cardiac arrest syndrome (PCAS) patients depending on the presence/absence of hypoxic encephalopathy (HE) in the early brain CT images obtained before the initiation of MTH. METHODS: We conducted a retrospective review of the data of a total of 129 patients with PCAS who were treated by MTH (34 degrees C) or normothermia treatment (NT) (35 degrees C or 36 degrees C), and had undergone brain CT examination prior to the initiation of these treatments. We divided the subjects into 4 groups, namely, the HE(-)/MTH, HE(-)/NT, HE(+)/MTH, and HE(+)/NT groups, for evaluating the interaction effect between the two variables. Then, we compared the neurological outcomes between the HE(-)/MTH and HE(-)/NT groups by multivariate logistic analysis. Good outcome was defined as a Cerebral Performance Category score of <=2 at 30 days. RESULTS: The percentages of subjects with a good outcome in the HE(-)/MTH and HE(-)/NT group were 68.9% (42/61) and 36.1% (13/36), respectively (p = .003), while those in the HE(+)/MTH and HE(+)/NT groups were lower, at 7.4% (2/27) and 20.0% (1/5), respectively (p = .410), suggesting a statistically significant interaction effect between the two variables (pinteraction = 0.002). In the HE(-) group, MTH was associated with a higher odds ratio of a good outcome as compared to NT (OR 6.80, 95% CI 1.19-38.96, p = .031). CONCLUSIONS: The effect of MTH in patients with PCAS differed depending on the presence/absence of evidence of HE on the early CT images. PMID- 29698753 TI - Resistance of pathogenic and spoilage microorganisms to disinfectants in the presence of organic matter and their residual effect on stainless steel and polypropylene. AB - OBJECTIVES: The effectiveness of disinfectants can vary according to the microorganism, type of residues and surface. The aim of this study was to determine the effectiveness of four disinfectants in the presence of organic matter and their residual effect on stainless steel grade 304 (SS) and polypropylene B (PP-B). METHODS: The effectiveness of the disinfectants in the presence of meat extract, egg yolk and whole milk was determined according to AOAC and UNE-EN 1040:2015, and the residual effect was determined according to UNE-EN 13697:2015 using approved strains. RESULTS: The effectiveness of the disinfectants was affected to different degrees depending on the organic matter present. SANICIP Q5 [400MUg/mL; fifth-generation quaternary ammonium compound (QAC)] was most effective in the presence of 10% meat extract, whilst SANICIP PAA (200MUg/mL; peracetic acid) showed better activity in the presence of 10% egg yolk and whole milk. In the evaluation of residual effect on SS and PP-B, the QAC had a better effect, reducing Listeria monocytogenes ATCC 19111 by 6 Log10 CFU/mL at 24h after its application. Conversely, the disinfectants had no residual effect against Pseudomonas aeruginosa ATCC 15442. CONCLUSIONS: The antimicrobial activity of the disinfectants tested against pathogenic and spoilage microorganisms was affected according to the type of organic matter present. SANICIP Q5 had a greater residual effect than the other disinfectants evaluated. Moreover, the residual effect of a disinfectant is greater on SS than on PP-B and is dependent on the microorganism tested. PMID- 29698754 TI - HMW-profiling using MALDI-TOF MS: A screening method for outbreaks of Clostridioides difficile. AB - Clostridioides difficile (CD), previously known as Clostridium difficile, is an anaerobic Gram-positive rod-shaped bacterium that causes mild to severe diarrhea mainly in hospitalized patients. The bacteria are easily spread between patients and can persist in hospital wards due to its ability to form spores. An outbreak of CD causes great sufferings for patients and is in many aspects very expensive for the health care organization. Continuously monitoring circulating CD isolates in the hospital as well as being able to detect possible spread between patients at an early phase would be of great benefit. Recently a new method was published by Rizzardi et al. (2015) where CD can be typed to a High Molecular Weight (HMW) profile using Matrix-Assisted Laser Desorption Ionization -Time of Flight Mass Spectrometry (MALDI-TOF MS). We analyzed 1000 isolates of toxin-positive CD with this method and compared the frequency of profiles within different hospitals as well as between two counties in the south-east part of Sweden. During the study period we could detect three outbreaks of CD in three different hospitals. One was an outbreak of CD with ribotype 027, resulting in severe consequences. The method was easily implemented at the clinical microbiology routine diagnostic laboratory and in collaboration with the hospitals Infection Control Units it is a very useful and cost-effective tool to detect outbreaks of CD at an early stage. PMID- 29698755 TI - Unresolved issues in the understanding of the pathogenesis of local tissue damage induced by snake venoms. AB - Snakebite envenoming by viperid species, and by some elapids, is characterized by a complex pattern of tissue damage at the anatomical site of venom injection. In severe cases, tissue destruction may be so extensive as to lead to permanent sequelae, with serious pathophysiological, social and psychological consequences. Significant advances have been performed in the study of venom-induced tissue damage, including identification and characterization of the toxins involved, insights into the mechanisms of action of venoms and toxins, and study of tissue responses to venom-induced injury. Nevertheless, much remains to be known and understood on the pathogenesis of these alterations. This review focuses on some of the pending issues in the topic of snake venom-induced local tissue damage. The traditional 'reductionist' approach, which has predominated in the study of snake venoms and their actions, needs to be complemented by more integrative and holistic perspectives aimed at capturing the complexity of these pathological alterations. Future advances in the study of these topics will certainly pave the way for innovative therapeutic interventions, with the goal of reducing the impact of this aspect of snakebite envenoming. PMID- 29698756 TI - First report on TTX levels of the yellow spotted pufferfish (Torquigener flavimaculosus) in the Mediterranean Sea. AB - The differences of tetrodotoxin (TTX) levels in various parts of pufferfish (Torquigener flavimaculosus) were examined in conjunction with the seasonal and sexual variations. The TTX levels in gonads, liver, intestines, skin and muscle tissue were determined using the Q-TOF LC/MS. Instrumental analysis revealed that all examined tissues from T. flavimaculosus contained high TTX concentrations. TTX levels in the gonads, liver, intestines, skin and muscle tissue of pufferfish were within the range of 5.03-100.71, 7.04-106.80, 12.59-86.30, 33.95-139.88 and 15.88-86.07 (MUg/g), respectively. It was determined that in all seasons, except for summer, female individuals had higher TTX levels than males. Among all seasons, the highest level of TTX was found in winter and the lowest in autumn. Consequently, T. flavimaculosus is a highly toxic pufferfish that is dangerous for human consumption and should not be consumed under any circumstances. PMID- 29698757 TI - Overview of the role of Shiga toxins in porcine edema disease pathogenesis. AB - Shiga toxin-producing Escherichia coli (STEC) have been implicated as the cause of enterotoxemias, such as hemolytic uremic syndrome in humans and edema disease (ED) of pigs. Stx1 and Stx2 are the most common types found in association with illness, but only Stx2e is associated with disease in the animal host. Porcine edema disease is a serious affection which can lead to dead causing great losses of weaned piglets. Stx2e is the most frequent Stx variant found in porcine feces and is considered the key virulence factor involved in the pathogenesis of porcine edema disease. Stx2e binds with higher affinity to Gb4 receptor than to Gb3 which could be due to amino acid changes in B subunit. Moreover, this subtype also binds to Forssman glycosphingolipids conferring upon Stx2e a unique promiscuous recognition feature. Manifestations of edema disease are caused by systemic effects of Stx2e with no significant morphologic changes in enterocytes. Endothelial cell necrosis in the brain is an early event in the pathogenesis of ED caused by Stx2e-producing STEC strains. Further studies are needed to generate techniques and tools which allow to understand the circulation and ecology of STEC strains in pigs even in resistant animals for diagnostic and epidemiological purposes. PMID- 29698758 TI - Characterization of truncated endo-beta-1,4-glucanases from a compost metagenomic library and their saccharification potentials. AB - A gene encoding an endo-beta-1,4-glucanase (Cel6H-f481) was cloned from a compost metagenomic library. The gene, cel6H-f481, was composed of 1446 bp to encode a fused protein of 481 amino acid residues (50,429 Da), i.e., 445 residues (Cel6H 445) from the metagenome, and 36 residues from the pUC19 vector at N-terminus. Cel6H-445 belonged to glycosyl hydrolase (GH) family 6 and showed 71% identity with Actinotalea fermentans endoglucanase with low coverage. Several active bands of truncated forms were observed by activity staining of the crude extract. Major truncated enzymes of 35 (Cel6H-p35) and 23 kDa (Cel6H-p23) were separated by HiTrap Q chromatography. The two enzymes had the same optimum temperature (50 degrees C) and pH (5.5), but Cel6H-p35 was more thermostable than Cel6H-p23 and other GH6 endoglucanases reported. Both enzymes efficiently hydrolyzed carboxymethyl-cellulose (CMC) and barley beta-glucan, but hardly hydrolyzed other substrates tested. The Vmax of Cel6H-p35 for CMC was 1.4 times greater than that of Cel6H-p23. The addition of the crude enzymes to a commercial enzyme set increased the saccharification of pretreated rice straw powder by up to 30.9%. These results suggest the N-terminal region of Cel6H-p35 contributes to thermostability and specific activity, and that the enzymes might be a useful additive for saccharification. PMID- 29698759 TI - Cloning and characterization of a new pH-stable alginate lyase with high salt tolerance from marine Vibrio sp. NJ-04. AB - Marine polysaccharide-degrading enzymes play an important role in marine algae degradation and carbon cycling, especially the alginate lyases. Although many alginate lyases have been characterized, the enzymes with industrial potential are still rather rare. A gene, encoding a new alginate lyase AlgNJ04, has been cloned from the marine bacterium Vibrio sp. NJ04. The recombinant alginate lyase was characterized followed by purification on Ni-NTA Sepharose. It exhibited an optimum activity (2416 U/mg) at pH 7.0 and 40 degrees C. Notably, the AlgNJ04 retained more than 80% of its maximum activity at a broad pH range of pH 4.0 and 10.0, which exhibited excellent pH stability. Additionally, it possessed broader substrate specificity, showing activities towards both poly beta-D-mannuronate (polyM) and poly alpha-L-guluronate (polyG). Furthermore, the Km values of AlgNJ04 towards sodium alginate (0.49 mM) and polyG (0.24 mM) were lower than that towards polyM (0.86 mM). Notably, the activity of AlgNJ-04 could be activated by NaCl with certain concentrations, which was partly caused by the removal of bound water from sodium alginate molecules or by the effects of charges in forming the alginate-enzyme complex. The ESI-MS analysis suggested that it mainly released oligosaccharides with DP of 2-5 as end products in an endolytic manner. Therefore, it may be a potent tool to produce alginate oligosaccharides with lower DPs. PMID- 29698760 TI - Statistical optimization and operational stability of Rhizomucor miehei lipase supported on magnetic chitosan/chitin nanoparticles for synthesis of pentyl valerate. AB - The chemical-catalyzed transesterification process to produce biofuels i.e. pentyl valerate (PeVa) is environmentally unfriendly, energy-intensive with tedious downstream treatment. The present work reports the use of Rhizomucor miehei lipase (RML) crosslinked onto magnetic chitosan/chitin nanoparticles (RML CS/CH/MNPs). The approach used to immobilize RML onto the CS/CH/MNPs yielded RML CS/CH/MNPs with an immobilized protein loading and specific activity of 7.6 mg/g and 5.0 U.g-1, respectively. This was confirmed by assessing data of field emission scanning electron microscopy, X-ray diffraction, thermal gravimetric analysis and Fourier transform infrared spectroscopy. A three-level-four-factor Box-Behnken design (incubation time, temperature, substrate molar ratio, and enzyme loading) was used to optimize the RML-CS/CH/MNP-catalyzed esterification synthesis of PeVa. Under optimum condition, the maximum yield of PeVa (97.8%) can be achieved in 5 h at 50 degrees C using molar ratio valeric acid:pentanol (1:2) and an enzyme load of 2 mg/mL. Consequently, operational stability experiments showed that the protocol adopted to prepare the CS/CH/MNP nanoparticles had increased the durability of RML. The RML-CS/CH/MNP could catalyze up to eight successive esterification cycles to produce PeVa. The study also demonstrated the functionality of CS/CH/MNP nanoparticles as an eco-friendly support matrix for improving enzymatic activity and operational stability of RML to produce PeVa. PMID- 29698761 TI - Overproduction and characterization of the first enzyme of a new aldoxime dehydratase family in Bradyrhizobium sp. AB - Almost 100 genes within the genus Bradyrhizobium are known to potentially encode aldoxime dehydratases (Oxds), but none of the corresponding proteins have been characterized yet. Aldoximes are natural substances involved in plant defense and auxin synthesis, and Oxds are components of enzymatic cascades enabling bacteria to transform, utilize and detoxify them. The aim of this work was to characterize a representative of the highly conserved Oxds in Bradyrhizobium spp. which include both plant symbionts and members of the soil communities. The selected oxd gene from Bradyrhizobium sp. LTSPM299 was expressed in Escherichia coli, and the corresponding gene product (OxdBr1; GenBank: WP_044589203) was obtained as an N-His6-tagged protein (monomer, 40.7 kDa) with 30-47% identity to Oxds characterized previously. OxdBr1 was most stable at pH ca. 7.0-8.0 and at up to 30 degrees C. As substrates, the enzyme acted on (aryl)aliphatic aldoximes such as E/Z-phenylacetaldoxime, E/Z-2-phenylpropionaldoxime, E/Z-3 phenylpropionaldoxime, E/Z-indole-3-acetaldoxime, E/Z-propionaldoxime, E/Z butyraldoxime, E/Z-valeraldoxime and E/Z-isovaleraldoxime. Some of the reaction products of OxdBr1 are substrates of nitrilases occurring in the same genus. Regions upstream of the oxd gene contained genes encoding a putative aliphatic nitrilase and its transcriptional activator, indicating the participation of OxdBr1 in the metabolic route from aldoximes to carboxylic acids. PMID- 29698762 TI - Lanthanum chloride-induced conformational changes of bovine liver catalase: A computational and biophysical study. AB - We have investigated the effects of lanthanum chloride (LaCl3) on catalytic activity and conformation of bovine liver catalase (BLC) in different buffer solutions in vitro at 25 degrees C. Higher concentration of the salt caused decrease in catalase activity in the following order, HEPES > MOPS > Tris > Phosphate buffer. Results obtained from circular dichroism, fluorescence and absorption spectroscopy and from computational docking studies indicate that reduction in activity of BLC by LaCl3 is due to induction of conformational changes. Lanthanum-induced reduced BLC activity in MOPS, HEPES and Tris buffer is characterized by a significant loss in native fluorescence and increase in absorbance spectra of BLC. Nevertheless, the change in secondary conformation of BLC was maximum in HEPES and MOPS followed by Tris and least in Phosphate buffer. Therefore, the significant loss of BLC activity in phosphate buffer at higher molar concentration of lanthanum is attributed to the change in buffering capacity of the buffer. The conformational transition of BLC by LaCl3 was followed as a function of concentration. Therefore, the reduced BLC activity is directly controlled by lanthanum-induced conformational change of BLC in HEPES, MOPS and Tris buffer and indirectly controlled by the change in buffering capacity of the phosphate buffer. PMID- 29698763 TI - Exploring the DNA damaging potential of chitosan and citrate-reduced gold nanoparticles: Physicochemical approach. AB - Nanomaterials offer a wide range of biomedical applications including gene/drug delivery, biosensing and bioimaging. The cytotoxic and genotoxic potential of nanoparticles need to be thoroughly investigated before their biomedical usage. This study aims to investigate and compare the nanotoxicology of chitosan (CH-Au Np) and citrate (CI-Au-Np) reduced gold nanoparticles via exploring their interaction with Calf thymus DNA (Ct-DNA) utilizing various physicochemical techniques. Structural characterization of these Nps was done using UV-Visible Spectroscopy and Transmission Electron Microscopy (TEM). Analysis of UV-Visible absorbance spectra indicates that interaction of CH-Au-Np with Ct-DNA causes destabilization of DNA by inducing significant structural and conformational changes in Ct-DNA in a concentration dependent manner, whereas there was negligible interaction between CI-Au-Np and Ct-DNA. These observations were further supported by the results of agarose gel mobility, UV-thermal melting, Circular Dichroism (CD), Dynamic Light Scattering (DLS) and TEM studies. Fluorescence spectral studies using acridine orange (AO) as a fluorescence probe and analysis of thermodynamic parameters reveal that the interactions between Ct DNA and CH-Au-Np were mainly governed by Van der Waal interactions and Hydrogen bonding. An insightful understanding of genotoxicity induced by CH-Au-Np can be advantageous, as it may provide valuable anticancer approach for cytotoxic drug designing. PMID- 29698764 TI - Efficient fructose production from plant extracts by immobilized inulinases from Kluyveromyces marxianus and Helianthus tuberosus. AB - The enzymatic hydrolysis of poly- and oligosaccharides from plants seems like an advantageous approach for sugars production. Two inulinases producing fructose from plant oligosaccharides were isolated from yeast Kluyveromyces marxianus and plant Helianthus tuberosus. Both enzymes were immobilized on polymeric carriers by using the static adsorption approach. We could save 80.4% of the initial catalytic activity of plant inulinase immobilized on KU-2 cation-exchange resin and 75.5% of yeast enzyme activity adsorbed on AV-17-2P anion-exchange resin. After immobilization, the Km values increased 1.5 and 6 times for enzymes from K. marxianus and H. tuberosus, respectively. The optimal temperatures for catalysis of both enzymes were increased from 48-50 degrees C up to 70 degrees C. The activities of both immobilized enzymes remained unchanged after the 10 cycles of 20-min hydrolysis reaction at 70 degrees C model batch reactor. Sorbents, native and immobilized enzymes did not exhibit any mutagenic or cytotoxic activity. PMID- 29698765 TI - The role of lignin on the mechanical performance of polylactic acid and jute composites. AB - The present work shows the feasibility of incorporating properly treated jute strands into a polylactic acid (PLA) thermoplastic matrix. The role of lignin in the interaction between jute strands and PLA was assessed by means of gradually decreasing the amount of lignin and producing composites. Five different lignin contents were studied and the resulting strands were incorporated into the PLA matrix at the ratio of 30 wt%. Composites were produced in a discontinuous extruder and standard specimens were injected and characterized at tensile. It was found that as the amount of lignin was decreased, the interface between the matrix and the reinforcement was properly improved, since tensile strength was increased up to 46% and FTIR analysis revealed the existence of H-bonds however they cannot be clearly related with an interaction between both phases. Both macro and micromechanical analysis showed that jute strands with a lignin content of 4% were the most suitable to be used as PLA reinforcement, mainly due to their higher intrinsic mechanical properties, better interaction with PLA and dispersion within the matrix. Overall, it was found that it is possible to obtain high-performance bio-based and presumably biodegradable composites with potential to substitute current oil-based commodities. PMID- 29698766 TI - Effects of salinity and hypoxia-induced hyperventilation on oxygen consumption and cost of osmoregulation in the estuarine red drum (Sciaenops ocellatus). AB - Understanding the physiological responses of fishes to salinity changes and aquatic hypoxia is essential for the conservation of marine species. Salinity changes affect the osmotic gradient across the gill epithelium, while hypoxia increases gill ventilation and the flow of water over the gills. Both processes affect the diffusive movement of ions and water across the gill epithelium, and the rate of active ion transport required for maintaining osmotic homeostasis. Consequently, salinity and hypoxia may affect the energetic cost of osmoregulation, and consequently the energy available for other physiological functions such as migration, growth, and reproduction. Historically, studies have assessed the costs of osmoregulation and ventilation in fishes via standard metabolic rate (SMR); however, few studies have used a multi-stressor approach that fully accounts for the osmorespiratory compromise. Here, we determined the combined effects of salinity and hypoxia on SMR, routine metabolic rate (RMR), and plasma ion concentrations in red drum (Sciaenops ocellatus) acclimated to salinities ranging from freshwater to hypersalinity. Surprisingly, there was no significant change in any parameter as a consequence of salinity or hypoxia, including the relatively extreme scenario of combined hypersalinity and hypoxia exposure. We conclude that changes in the osmotic gradient across the gill epithelium and the flow of water over the gills have a negligible effect on the whole animal energy budget of S. ocellatus, suggesting that the cost of osmoregulation is a minor component of basal metabolism regardless of oxygenation status. PMID- 29698767 TI - Regulation of neural differentiation, synaptic scaling and animal behavior by MeCP2 phophorylation. AB - Highly expressed in the mammalian brain and widely distributed across the genome, MeCP2 is a key player in recognizing modified DNA and interpreting the epigenetic information encoded in different DNA methylation/hydroxymethylation patterns. Alterations in sequence or copy number of the X-linked human MECP2 gene cause either Rett syndrome (RTT) or MECP2 duplication syndrome. Alterations in MECP2 levels have also been identified in patients with autism. To fully understand the significant role of MECP2 in regulating the development and function of the nervous system, it is important to study all aspects of MeCP2 function. Stimulus induced MeCP2 phosphorylation has been shown to influence the proliferation and differentiation of neural progenitor cells, synaptic scaling, excitatory synaptogenesis, and animal behavior. However, all of the previous functional evidence is from studying phospho-dead mutations. In addition, the relationship between phosphorylation events at multiple sites on the MeCP2 protein is not well understood. Here, we report the generation of a phospho-mimic knockin Mecp2 mouse line. At the synaptic and behavioral levels, the phospho-mimic Mecp2 mice show phenotypes opposite to those observed in phospho-dead mutation at the same phosphorylation site. Moreover, we report opposite phenotypes between phospho mutants of two sites on the MeCP2 protein. Our new data further confirm the functional significance of specific MeCP2 phosphorylation event and support the opposing regulatory role between different MeCP2 phosphorylation events. PMID- 29698768 TI - Is working memory stored along a logarithmic timeline? Converging evidence from neuroscience, behavior and models. AB - A growing body of evidence suggests that short-term memory does not only store the identity of recently experienced stimuli, but also information about when they were presented. This representation of 'what' happened 'when' constitutes a neural timeline of recent past. Behavioral results suggest that people can sequentially access memories for the recent past, as if they were stored along a timeline to which attention is sequentially directed. In the short-term judgment of recency (JOR) task, the time to choose between two probe items depends on the recency of the more recent probe but not on the recency of the more remote probe. This pattern of results suggests a backward self-terminating search model. We review recent neural evidence from the macaque lateral prefrontal cortex (lPFC) (Tiganj, Cromer, Roy, Miller, & Howard, in press) and behavioral evidence from human JOR task (Singh & Howard, 2017) bearing on this question. Notably, both lines of evidence suggest that the timeline is logarithmically compressed as predicted by Weber-Fechner scaling. Taken together, these findings provide an integrative perspective on temporal organization and neural underpinnings of short-term memory. PMID- 29698769 TI - Prevalence of human papilloma virus with risk of cervical cancer among south Indian women: A genotypic study with meta-analysis and molecular dynamics of HPV E6 oncoprotein. AB - Cervical cancer (CC) is a major fatal health problem in women with high mortality worldwide. Human Papilloma Virus (HPV) is considered as one of the causative factors for CC. The HPV prevalence and their genotype distribution among women population are essential to evaluate the deteriorating impact of HPV. A cross sectional study was performed involving 212 participants to identify the prevalence of high-risk HPV genotypes in south India using PCR and DNA Sequencing. The results obtained from cross-sectional study were used to conduct a meta-analysis of the previous published studies on HPV prevalence and genotype distribution across six geographical regions (North, Northeast, East, Central, West, and South) of India. Additionally, molecular simulation was performed using GROMACS software to determine the structural differences of E6 oncoprotein in HPV 16 and 18 genotypes, characterized from Indian subjects. Among the study participants, the HPV prevalence was found to be 81.70% in CC, 71.42% in HSIL and 61.30% in LSIL. The meta-analysis showed a high prevalence of HPV-16 in CC across the entire six regions. Of which, South and North India were found to have high HPV prevalence among Indian regions. Further, simulation of E6 oncoprotein revealed structural differences between HPV-16 and 18 which may be associated with their oncogenic nature. The HPV-16 and 18 were noticed to be highly prevalent in Indian women. Health awareness and vaccination programs are regularly needed to protect Indian women community. PMID- 29698770 TI - Surveillance and genetic characterization of rotavirus strains circulating in four states of North Indian children. AB - Acute gastroenteritis due to Rotavirus (RV) infection is a major cause of morbidity and mortality in infants and young children worldwide. In India, around 0.1 million death reported annually due to RV illness. So, to assess the disease burden continuous surveillance of the circulating genotypes is needed. This study aimed to ascertain the genetic variance of 429 rotavirus positive specimens observed during the period October 2013-September 2014 at four study centers from North India. Out of 1057 patients enrolled, 1018 stool samples were collected at four centers in four different states of North India. Children aged <5 years who showed the symptoms of severe diarrhea and needed hospitalization were enrolled. The stool samples collected were screened by Enzyme Immuno Assay (EIA), and the RV positive samples were characterized by semi-nested PCR. During the study period October 2013 through September 2014, ~42% patients were found to be rotavirus positive of 1018 collected specimen. In Delhi, Rohtak and Meerut, we observed that Rotavirus is seasonal compared to Tanda (HP). The rate of rotavirus detection was significantly higher among children aged below 2 years, and a total of 21.5% of rotavirus infections comprised children aged <6 months. Genotype G1(48.0%) was predominant and frequently circulating strain whereas G12 (16.8%) and G9 (10.0%) was second and third prevalent strain in the four states of North India. High frequency of G1 genotypes was detected under the age group of 6-11 months which is followed by G12, similarly high rate severe disease was observed due to G1 genotypes followed by P[8], P[6] and G12. The most common types of strains were G1P[8] (27.73% of strains), G12P[6] (13.28%), G9P[4] (7.23%) and G1P[6] (6.75%). The rare strain reported were G1P[9]; P[11] strain was detected in combination with G1, G2, and G12. These data emphasized G12 is the second most predominant strain circulating among Northern Indian children highlights the needs for inclusion in the future polyvalent vaccine to break the burden of rotavirus infection. PMID- 29698771 TI - Fasciola hepatica eggs in paleofaeces of the Persian onager Equus hemionus onager, a donkey from Chehrabad archaeological site, dating back to the Sassanid Empire (224-651 AD), in ancient Iran. AB - Fascioliasis is a highly pathogenic zoonotic disease caused by the liver trematodes Fasciola hepatica and F. gigantica. Within the multidisciplinary initiative against this disease, there is the aim of understanding how this disease reached a worldwide distribution, with important veterinary and medical repercussions, by elucidating the spreading steps followed by the two fasciolids from their paleobiogeograhical origins. Fasciola eggs were detected in paleofaeces of a donkey, probably the present-day endangered Persian onager Equus hemionus onager, found in the Chehrabad salt mine archaeological site, Zanjan province, northwestern Iran. The biological remains dated back to the Sassanid period, 224-651 AD. Egg characteristics allowed for their specific ascription to F. hepatica. The interest of this finding relies on the fact of being the first archaeological finding of Fasciola in Asia and the Near East. Moreover, it allows to reach many conclusions about historical, epidemiological and spreading aspects of the disease. The finding in Chehrabad indicates that, at that time, this fasciolid had already spread through the Zagros mountains eastward from the Fertile Crescent. In that region and in ancient Egypt, livestock domestication played a crucial role in facilitating the disease spread during the postdomestication period. Donkeys appear at present to be usually infected by fasciolids in countries of the Fertile Crescent - Ancient Egypt region or neighbouring that region, with prevalences from low to very high. The high pathogenicity and mortality induced by Fasciola in these equines should be considered as an additional potential factor among the causes of the extinctions of E. h. hemippus in Syria, E. h. hydruntinus in the Anatolia-Balkans area, E. h. onager in the Caucasus and maybe also its decline in Iran. Indeed, Eurasiatic wild asses were present in the region and neighbourhood of the Fertile Crescent when the domestication of the livestock reservoirs of Fasciola began. PMID- 29698772 TI - An operations-partnered evaluation of care redesign for high-risk patients in the Veterans Health Administration (VHA): Study protocol for the PACT Intensive Management (PIM) randomized quality improvement evaluation. AB - BACKGROUND: Patient-centered medical homes have made great strides providing comprehensive care for patients with chronic conditions, but may not provide sufficient support for patients at highest risk for acute care use. To address this, the Veterans Health Administration (VHA) initiated a five-site demonstration project to evaluate the effectiveness of augmenting the VA's Patient Aligned Care Team (PACT) medical home with PACT Intensive Management (PIM) teams for Veterans at highest risk for hospitalization. METHODS/DESIGN: Researchers partnered with VHA leadership to design a mixed-methods prospective multi-site evaluation that met leadership's desire for a rigorous evaluation conducted as quality improvement rather than research. We conducted a randomized QI evaluation and assigned high-risk patients to participate in PIM and compared them with high-risk Veterans receiving usual care through PACT. The summative evaluation examines whether PIM: 1) decreases VHA emergency department and hospital use; 2) increases satisfaction with VHA care; 3) decreases provider burnout; and 4) generates positive returns on investment. The formative evaluation aims to support improved care for high-risk patients at demonstration sites and to inform future initiatives for high-risk patients. The evaluation was reviewed by representatives from the VHA Office of Research and Development and the Office of Research Oversight and met criteria for quality improvement. DISCUSSION: VHA aims to function as a learning organization by rapidly implementing and rigorously testing QI innovations prior to final program or policy development. We observed challenges and opportunities in designing an evaluation consistent with QI standards and operations priorities, while also maintaining scientific rigor. TRIAL REGISTRATION: This trial was retrospectively registered at ClinicalTrials.gov on April 3, 2017: NCT03100526. Protocol v1, FY14 17. PMID- 29698773 TI - Network pharmacology-based prediction of active compounds and molecular targets in Yijin-Tang acting on hyperlipidaemia and atherosclerosis. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Yijin-Tang (YJT) is a traditional prescription for the treatment of hyperlipidaemia, atherosclerosis and other ailments related to dampness phlegm, a typical pathological symptom of abnormal body fluid metabolism in Traditional Korean Medicine. However, a holistic network pharmacology approach to understanding the therapeutic mechanisms underlying hyperlipidaemia and atherosclerosis has not been pursued. AIM OF THE STUDY: To examine the network pharmacological potential effects of YJT on hyperlipidaemia and atherosclerosis, we analysed components, performed target prediction and network analysis, and investigated interacting pathways using a network pharmacology approach. MATERIALS AND METHODS: Information on compounds in herbal medicines was obtained from public databases, and oral bioavailability and drug likeness was screened using absorption, distribution, metabolism, and excretion (ADME) criteria. Correlations between compounds and genes were linked using the STITCH database, and genes related to hyperlipidaemia and atherosclerosis were gathered using the GeneCards database. Human genes were identified and subjected to Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis. RESULTS: Network analysis identified 447 compounds in five herbal medicines that were subjected to ADME screening, and 21 compounds and 57 genes formed the main pathways linked to hyperlipidaemia and atherosclerosis. Among them, 10 compounds (naringenin, nobiletin, hesperidin, galangin, glycyrrhizin, homogentisic acid, stigmasterol, 6-gingerol, quercetin and glabridin) were linked to more than four genes, and are bioactive compounds and key chemicals. Core genes in this network were CASP3, CYP1A1, CYP1A2, MMP2 and MMP9. The compound-target gene network revealed close interactions between multiple components and multiple targets, and facilitates a better understanding of the potential therapeutic effects of YJT. CONCLUSIONS: Pharmacological network analysis can help to explain the potential effects of YJT for treating dampness phlegm-related diseases such as hyperlipidaemia and atherosclerosis. PMID- 29698774 TI - Biofilm inhibition mechanism from extract of Hymenocallis littoralis leaves. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Hymenocallis littoralis (Jacq.) Salisb. has been referred as beach spider lily and commonly known for its rich phytochemical diversity. Phytochemicals such as alkaloids, volatile constituents, phenols, flavonoids, flavonols extracted from different parts of these plants like bulbs, flowers, leaf, stem and root had been used in folk medicines from ancient times because of their excellent antimicrobial and antioxidant properties. The leaf and bulb extract of H. littoralis plant was traditionally used for wound healing. Alkaloids extracted from bulb of this plant possess anti-viral, anti-neoplastic and cytotoxic properties. However, these phytochemicals have also shown antibiofilm activity, which is considered as one of the important factor accountable for the drug resistance in microorganisms. Thus, the investigation of medicinal properties of H. littoralis could be useful to control biofilm producing pathogens. AIM OF THE STUDY: Explore antimicrobial, antibiofilm and antioxidant potentials of H. littoralis against pathogenic microorganisms using experimental and computational biology approach. MATERIALS AND METHODS: Phytochemical extraction from dried powder of H. littoralis leaves was done by solvent extraction using methanol. Antimicrobial and antibiofilm activities of leaves extract were carried out using agar well diffusion method, growth curve, minimum inhibitory concentration (MIC) and Scanning Electron Microscopy (SEM). Liquid Chromatography and Mass Spectroscopy (LCMS) technique was used for the identification of phytochemicals. Molecular docking studies of antibiofilm agents with adhesin proteins were performed using Autodock 4.2. Antioxidant activity of extract was carried out by FRAP assay. The noxious effect of extract was investigated by histological studies on rat skin. RESULTS: The preliminary phytochemical analysis of methanolic leaves extract revealed the presence of alkaloids, flavonoids, terpenoid, glycosides, terpene, terpenoids and phenolics. The various phytochemicals such as Apigenin 7-(4'', 6'' diacetylalloside)-4'- alloside, Catechin 7-O- apiofuranoside, Emodic acid, Epicatechin 3-O- beta-D glucopyranoside, 4 - Methylesculetin, Methylisoeugenol, Quercetin 5,7,3',4' tetramethyl ether 3-rutinoside, 4 - Methylumbelliferyl beta-D- glucuronide were extracted, characterized and recognized from the leaves extract of H. littoralis. The identification of these phytochemicals was performed using LC-MS. The antimicrobial property of H. littoralis leaf extract was investigated against different pathogenic microorganisms. Out of these tested microorganisms, promising antibiofilm and antimicrobial activities were confirmed against S. aureus NCIM 2654 and C. albicans NCIM 3466 by using growth curve and SEM analysis. MIC of this leaf extract was identified as 45 ug/ml and 70 ug/ml for S. aureus NCIM 2654 and C. albicans NCIM 3466 respectively. The leaves extract also showed good antioxidant activity due to presence of phenols and flavonoids. Molecular docking of these identified antibiofilm components interacts with the active site residues of adhesin proteins, Sortase A and Als3 from S. aureus and C. albicans respectively. Histological studies of extracted phytochemicals revealed non-noxious effects on rat skin. CONCLUSION: Thus, the present study revealed that the leaves extract of H. littoralis contains various phytochemicals having good extent of antimicrobial, antibiofilm and antioxidant properties. The in-vitro and in-silico results would be useful to design new lead compounds against biofilm producing pathogenic microorganisms. PMID- 29698775 TI - Anti-inflammatory and immune response regulation of Si-Ni-San in 2,4 dinitrochlorobenzene-induced atopic dermatitis-like skin dysfunction. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Si-Ni-San (SNS) is a well-known decoction in traditional Chinese medicine. Although studies have indicated that the anti inflammatory and anti-allergic properties of SNS and its components can account for their therapeutic effects, the role and mechanism of SNS in treating skin dysfunction remain unclear. AIM OF THE STUDY: Atopic dermatitis (AD), a disorder known for its prevalence in infants and adults, severely influences the quality of life of affected patients. In this study, we aimed to investigate the anti inflammatory and immune response modulations of SNS in 2,4-dinitrochlorobenzene (DNCB)-induced AD-like skin dysfunction. MATERIALS AND METHODS: Dermatitis was induced in Kunming mice by the topical application of DNCB. SNS or dexamethasone (positive control) was topically applied every day over the course of the 21-day study. The following were assessed: dermatitis severity scores; ear and dorsal skin haematoxylin and eosin staining; interleukin (IL)- 1alpha, IL-1beta, IL-2, IL-4, IL-6, and tumour necrosis factor (TNF)-alpha cytokine levels in the serum; spleen index; spleen CD4 + /CD8 + T lymphocyte ratio; and phosphorylation levels of mitogen-activated protein kinases (MAPKs- p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK)), IkappaB-alpha, and nuclear factor (NF)-kappaB (p65) in skin lesions. RESULTS: SNS significantly alleviated the symptoms of AD-like lesions induced by DNCB, decreased the infiltration of inflammatory cells in the ear and dorsal tissues, suppressed the increased cytokine levels in the serum, reduced the CD4 + /CD8 +T lymphocyte ratio in the spleen, and downregulated the activation of MAPKs, IkappaB-alpha, and NF-kappaB (p65) in the dorsal skin. The effects were similar to those of dexamethasone. CONCLUSIONS: SNS alleviated the DNCB-induced AD-like skin dysfunction in mice through anti-inflammatory and immune system modulation, indicating that SNS shows potential for AD treatment in clinical settings. PMID- 29698776 TI - Aloysia citrodora Palau (Lemon verbena): A review of phytochemistry and pharmacology. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Aloysia citrodora Palau (Lippia citriodora Kunth), commonly known as "lemon verbena" is a medicinal plant native to South America, North Africa, and South of Europe which is used by native people for several indications such as diarrhea, flatulence, insomnia, and rheumatism. AIM OF THE REVIEW: Despite the wide biological activities of lemon verbena, there is no current review summarizing medicinal properties of the plant; thus, this paper aims to discuss current state of the art regarding the phytochemistry, pharmacology, and therapeutic applications of A. citrodora considering in vitro, in vivo, and clinical studies. MATERIALS AND METHODS: Electronic databases including PubMed, Scifinder, Cochrane library, Scopus, and Science direct were searched with the scientific name of the plant and its synonyms, as well as the common name. All studies on the ethnobotany, phytochemistry, pharmacology, and clinical application of the plant until October 2017 were included in this review. RESULTS: Despite the few number of studies on the ethnopharmacology of the plant, A. citrodora is widely assessed regarding its phytochemistry and biological activities. Neral and geranial are the main ingredients of the essential oil; whereas verbascoside is the most significant component of the extract. Biological activities such as antioxidant, anxiolytic, neuroprotective, anticancer, anesthetic, antimicrobial, and sedative effects are proved in cell cultures, as well as animal studies. CONCLUSIONS: Several pharmacological activities have been reported for A. citrodora; however, the plant is not fully assessed regarding its safety and efficacy in human. Future well-designed human studies are essential to confirm the therapeutic benefits of this plant in clinical settings. PMID- 29698777 TI - Metabolic engineering to enhance heterologous production of hyaluronic acid in Bacillus subtilis. AB - Hyaluronic acid (HA) is a high-value biopolymer that is produced in large scales using attenuated strains ofgroup C streptococci. However, due to the pathogenicity and fastidious nature of these bacteria, the development of bioprocesses for HA production centered on robust 'Generally Recognized as Safe (GRAS)' organisms, such as Bacillus subtilis, is of increased interest. Here, we report metabolic engineering of novel B. subtilis strains in which the carbon flux has been partially diverted from central metabolism, i.e. the pentose phosphate pathway (PPP) and glycolysis, into HA biosynthesis. First, an improved base strain of B. subtilis was engineered for more effective HA production with less susceptibility to catabolite repression when expressing genes from a xylose inducible promoter. Subsequently, Clustered Regularly Interspaced Palindromic Repeats interference (CRISPRi) was applied to reduce the expression of individual pfkA or zwf in the base strain, leading to substantial improvements to the HA titer with a concomitant decrease in the molecular weight (MW). On the other hand, multiplexed repression of both pfkA and zwf expression resulted in increases to the HA titer of up to 108% and enhancements to the MW, compared to the base strain. Moreover, the addition of exogenous HA monomers, i.e. glucuronic acid (GlcUA) and N-acetyl-glucosamine (GlcNAc), to B. subtilis cultures markedly improved the HA MW but decreased the HA titer, providing insights into the mechanism of HA biosynthesis by streptococcal hyaluronan synthase (SeHAS) in B. subtilis. Our study demonstrates the successful application of metabolic engineering strategies to establish B. subtilis as an effective platform for high level HA production. PMID- 29698778 TI - A comparative analysis of single cell and droplet-based FACS for improving production phenotypes: Riboflavin overproduction in Yarrowia lipolytica. AB - Evolutionary approaches to strain engineering inherently require the identification of suitable selection techniques for the product and phenotype of interest. In this work, we undertake a comparative analysis of two related but functionally distinct methods of high-throughput screening: traditional single cell fluorescence activated cell sorting (single cell FACS) and microdroplet enabled FACS (droplet FACS) using water/oil/water (w/o/w) emulsions. To do so, we first engineer and evolve the non-conventional yeast Yarrowia lipolytica for high extracellular production of riboflavin (vitamin B2), an innately fluorescent product. Following mutagenesis and adaptive evolution, a direct parity-matched comparison of these two selection strategies was conducted. Both single cell FACS and droplet FACS led to significant increases in total riboflavin titer (32 and 54 fold relative to the parental PO1f strain, respectively). However, single cell FACS favored intracellular riboflavin accumulation (with only 70% of total riboflavin secreted) compared with droplet FACS that favored extracellular product accumulation (with 90% of total riboflavin secreted). We find that for the test case of riboflavin, the extent of secretion and total production were highly correlated. The resulting differences in production modes and levels clearly demonstrate the significant impact that selection approaches can exert on final evolutionary outcomes in strain engineering. Moreover, we note that these results provide a cautionary tale when intracellular read-outs of product concentration (including signals from biosensors) are used as surrogates for total production of potentially secreted products. In this regard, these results demonstrate that extracellular production is best assayed through an encapsulation technique when performing high throughput screening. PMID- 29698779 TI - Nonsurgical correction of epiblepharon using hyaluronic acid gel. AB - PURPOSE: To report a single-center experience with nonsurgical correction of epiblepharon using hyaluronic acid gel. METHODS: The medical records of consecutive patients with symptomatic epiblepharon treated over a 3-year period with hyaluronic acid gel injection were reviewed retrospectively. Hyaluronic acid gel was injected transcutaneously into the suborbicularis plane to obliterate the abnormal skin fold or evert the eyelid margin. Successful treatment was defined as eversion of the eyelid margin as assessed by lash-cornea touch. RESULTS: Ten eyelids of 8 patients (7 girls [88%]) underwent transcutaneous hyaluronic acid gel injection for correction of epiblepharon. Average age at presentation was 16.5 months (range, 1-72 months). Two patients had bilateral involvement. Of 10 eyelids, 8 had a distinct skin fold with a "valley" above it. Nine of 10 eyelids had lash-cornea touch in the primary gaze; 1 in downgaze. All 10 eyes had punctate corneal epitheliopathy on fluorescein staining. An average of 0.19 ml (range, 0.1-0.3 ml) of hyaluronic acid gel was injected per eyelid. After injection, 9 of 10 eyelids showed no lash-cornea touch in downgaze, and all 10 eyelids showed resolution of symptoms and epitheliopathy. Patients remained symptom-free for an average final follow-up of 19.1 months (range, 5-42 months). No procedure-related complications were noted. CONCLUSIONS: In our small case series, transcutaneous hyaluronic acid gel injection into the lower eyelid effectively corrected symptomatic epiblepharon; the effect was long lasting. PMID- 29698780 TI - Eye salvage in diffuse anterior retinoblastoma using systemic chemotherapy with periocular and intravitreal topotecan. AB - Diffuse anterior retinoblastoma is an infrequent presentation in which the tumor is confined to the anterior segment, and there is no retinal mass. An 18-month old Asian Indian boy presented with white spots in the left eye. There were extensive anterior segment seeds without a retinal tumor. Fine-needle aspiration biopsy confirmed the diagnosis of retinoblastoma, and the patient received intravenous chemotherapy with a combination of vincristine-carboplatin-etoposide, periocular topotecan, and intravitreal topotecan to achieve complete tumor regression. PMID- 29698781 TI - In vivo and in vitro investigation of anti-inflammatory and mucus-regulatory activities of a fixed combination of thyme and primula extracts. AB - Hypersecretion of viscous mucus is one of the hallmark symptoms of acute and chronic bronchitis and typically develops secondary to an inflammation of the airway epithelium. Bronchipret(r) TP film-coated tablets (BRO), a herbal medicinal product containing a fixed combination of thyme herb and primula root extracts, has been successfully used clinically for the treatment of acute bronchitis for more than two decades. However, the underlying pharmacological mechanisms of action have not been fully understood so far. We investigated the anti-inflammatory and mucus-regulatory effects of orally administered BRO in an animal model of pulmonary inflammation that was experimentally induced by intratracheal LPS instillation. BRO was administered once daily for up to three days following the induction of inflammation. Treatment with BRO effectively inhibited polymorphonuclear cell influx into the lung as well as the increase in mucin 5ac (MUC5AC) protein. Furthermore, the LPS-induced increase of goblet cell numbers was significantly attenuated by BRO treatment. Subsequent in vitro investigations with IL-13 stimulated human primary respiratory epithelium and the Calu-3 respiratory epithelial cell line in air-liquid-interface culture confirmed the effects on mucus production and goblet cell numbers observed in the in vivo studies. They further suggest that the reduction of MUC5AC protein secretion by BRO is associated with reduced MUC5AC mRNA expression as assessed by quantitative Real-Time PCR. Our studies provide evidence that BRO exerts both anti inflammatory and mucus-regulatory activity and that BRO's effect on mucin production is partially independent from its anti-inflammatory activity. These results contribute to the understanding of the modes of action underlying the clinical efficacy of BRO in acute bronchitis patients. PMID- 29698782 TI - Altered cytokine profile under control of the serotonergic system determines the regulation of CYP2C11 and CYP3A isoforms. AB - The aim of this study is to assess a potential mechanism by which the serotonergic system can control the expression and activity of cytochrome (CYP) 2C11 and CYP3A isoforms during liver insufficiency. A rat model of diethylnitrosamine (DEN)-induced liver insufficiency was developed by administering 50 mg/kg of DEN twice a week for 7 weeks. Dysfunction of the serotonergic system was evoked by feeding the rats with a tryptophan-free diet for three weeks. Dysfunction of the serotonergic system during liver insufficiency decreased the level of proinflammatory cytokines (TGF-beta and IL 1beta) and increased the level of an anti-inflammatory cytokine (IL-4). Simultaneously, activation of the repressive mechanism IL-4/JAK1/STAT6/SOCS1 of the JAK2/STAT5b-mediated signal transduction pathway and the pERK1/2/GR/STAT6 signal transduction pathway resulted in the suppression of the CYP2C11 and CYP3A isoforms. Moreover, dysfunction of the serotonergic system during liver insufficiency equalized the level of testosterone to the basal level, did not change the steady state of the corticosterone level and significantly enhanced the reduced level of growth hormone. An altered cytokine profile under control of the serotonergic system determines the regulation of CYP2C11 and CYP3A isoforms during liver insufficiency through mechanisms based on posttranscriptional and posttranslational processes. PMID- 29698783 TI - Potential role of nucleoside diphosphate kinase in myricetin-induced selective apoptosis in colon cancer HCT-15 cells. AB - The flavonoid myricetin (MYR) is derived from vegetables and fruits. It has been shown to exert anti-cancer effects in various cell lines; however, the exact mechanism underlying these effects is yet to be elucidated. In this study, we evaluated the anti-cancer effects induced by MYR treatment in colon cancer HCT-15 cells. To detect cell proliferation, we conducted MTT assay and real time-cell electronic sensing (RT-CES). We next performed comet assay and Annexin V and PI staining to detect cellular apoptotic features. After that, we conducted two dimensional electrophoresis (2-DE) analysis to identify apoptotic proteins. The results of this analysis revealed that eight spots were differentially expressed. Among the spots, we selected nucleoside diphosphate kinase (NDPK) for further investigation, as it has been shown to regulate cancer cell apoptosis and metastasis. After that, we conducted realtime-PCR and western blot to detect the expression of NDPK mRNA and protein and wound-healing assay to detect cell migration and invasion. Finally, we performed NDPK siRNA transfection study and the results showed that NDPK knockdown inhibited apoptosis. Based on these collective results, we suggest that MYR induces apoptosis in human colon cancer HCT-15 cells selectively by increasing the expression of NDPK and other caspase regulated apoptosis proteins. PMID- 29698784 TI - Machine learning to predict the occurrence of bisphosphonate-related osteonecrosis of the jaw associated with dental extraction: A preliminary report. AB - INTRODUCTION: The aim of this study was to build and validate five types of machine learning models that can predict the occurrence of BRONJ associated with dental extraction in patients taking bisphosphonates for the management of osteoporosis. PATIENTS & METHODS: A retrospective review of the medical records was conducted to obtain cases and controls for the study. Total 125 patients consisting of 41 cases and 84 controls were selected for the study. Five machine learning prediction algorithms including multivariable logistic regression model, decision tree, support vector machine, artificial neural network, and random forest were implemented. The outputs of these models were compared with each other and also with conventional methods, such as serum CTX level. Area under the receiver operating characteristic (ROC) curve (AUC) was used to compare the results. RESULTS: The performance of machine learning models was significantly superior to conventional statistical methods and single predictors. The random forest model yielded the best performance (AUC = 0.973), followed by artificial neural network (AUC = 0.915), support vector machine (AUC = 0.882), logistic regression (AUC = 0.844), decision tree (AUC = 0.821), drug holiday alone (AUC = 0.810), and CTX level alone (AUC = 0.630). CONCLUSIONS: Machine learning methods showed superior performance in predicting BRONJ associated with dental extraction compared to conventional statistical methods using drug holiday and serum CTX level. Machine learning can thus be applied in a wide range of clinical studies. PMID- 29698785 TI - Polyanionic holothurian glycosaminoglycans-doxorubicin nanocomplex as a delivery system for anticancer drugs. AB - A nanoscale delivery system for the anticancer drug doxorubicin (DOX) by complexation with depolymerized polyanionic holothurian glycosaminoglycans (DHG) was designed in the present studies. The physicochemical properties of the nanocomplexes were investigated by dynamic light scattering, transmission electron microscopy and zeta potential determination. DHG-DOX interaction was investigated in the presence of ethanol as a hydrogen-bond disrupting agent and NaCl as an electrostatic shielding agent. The thermal properties of nanocomplexes were ascertained by thermogravimetric analysis (TGA). The in vitro release profile was studied as well. Complexation of DHG and DOX formed spherical and smooth nanocomplexes with negative zeta potential (-46.3 mV) at a DHG/DOX (w/w) ratio of 1.0, where drug encapsulation efficiency was over 60%. The results indicated that the electrostatic and hydrogen bonds played an important role in DHG-DOX complexation. TGA confirmed that the nanocomplexes involved in the DHG as the as the coat and DOX as the content. The release profile of the nanocomplexes exhibited an initial fast release and an subsequent slow and sustained release. Furthermore, the in vitro cell cytotoxicity assays exhibited that the DOX loaded nanocomplexes could improve the cell killing ability of DOX for HepG-2, MCF-7 and A549 tumor cells and exert a sustained-release efforts in the cells. PMID- 29698786 TI - Thermal denaturation of fibrinogen visualized by single-molecule atomic force microscopy. AB - Fibrinogen denaturation is an important phenomenon in biology and medicine. It has been previously investigated with bulk methods and characterized by parameters, which refer to big protein ensembles. Here we provide a new insight into fibrinogen denaturation with a high-resolution single-molecule atomic force microscopy (AFM). The ultrastructure of individual fibrinogen molecules was studied after heating or extended contact with the highly oriented pyrolytic graphite surface (HOPG) modified with oligoglycine-hydrocarbon graphite modifier (GM). Fibrinogen heating to 65 degrees C and 90 degrees C resulted in the formation of various shapes containing fibrillar and globular structures, which were attributed to the monomers and small aggregates of fibrinogen. Fibrinogen unfolded by the extended (10 min) incubation on GM-HOPG surface in water revealed a different morphology. It contained fibrillar structures only, and their organization reflected the initial native structure of fibrinogen: typically, six polypeptide chains connected by multiple disulfide bonds were seen. A combination of two morphologies - globular aggregates with dense fibrillar networks - has been revealed for thermally denatured protein adsorbed on a GM-HOPG surface with extended (10 min) rinsing with water. The obtained results provide better understanding of fibrinogen unfolding induced by different factors and are important for improvement of biomedical applications, such as fibrinogen-based protein matrixes and carbon-based biomaterials. PMID- 29698787 TI - Bariatric surgery and burnout risks. PMID- 29698788 TI - Fixation free femoral hernia repair with a 3D dynamic responsive implant. A case series report. AB - BACKGROUND: To date, no gold standard for the surgical treatment of femoral hernia exists. Pure tissue repair as well as mesh/plug implantation, open or laparoscopic, are the most performed methods. Nevertheless, all these techniques need sutures or mesh fixation. This implies the risk of damaging sensitive structures of the femoral area, along with complications related to tissue tear and postoperative discomfort consequent to poor quality mesh incorporation. The present retrospective multicenter case series highlights the results of femoral hernia repair procedures performed with a 3D dynamic responsive implant in a cohort of 32 patients during a mean follow up of 27 months. MATERIALS AND METHODS: Aiming to simplify the surgical procedure and reduce complications, a 3D dynamic responsive implant was delivered for femoral hernia repair, in a patient cohort. After returning the hernia sack to the abdominal cavity, the implant was simply delivered into the hernia defect where it remained, thanks to its inherent centrifugal expansion, obliterating the hernia opening without need of fixation. Postoperative pain assessment was determined using the VAS score system. RESULTS: The use of the 3D prosthetic device allowed for easier and faster surgical repair in a fixation free fashion. None of the typical fixation related complications occurred in the examined patients. Postoperative pain assessment with VAS score showed a very low level of pain, allowing the return of patients to normal activities in extremely reduced times. In the late postoperative period, no discomfort or chronic pain was reported. CONCLUSIONS: Femoral hernia repair with the 3D dynamic revealed a quick and safe placement procedure. The reduced pain intensity, as well as the absence of adverse events consequent to sutures or mesh fixation, seems to be a significant benefit of the motile compliance of the device. Furthermore, this 3D prosthesis has already proven to induce an enhanced probiotic response showing ingrowth in the implant of the typical tissue components of the abdominal wall, instead of the low quality tissue ingrowth typical in conventional meshes and plugs. The highlighted features seem to represent a more physiologic and updated repair concept of femoral protrusions. PMID- 29698789 TI - Impact of preoperative transarterial embolization of carotid body tumor: A single center retrospective cohort experience. AB - OBJECTIVE: To evaluate the feasibility and efficacy of preoperative hyperselective transarterial embolization in carotid body tumor resection. METHODS: Retrospectively analyze the clinical feature, imaging examination, treatment strategy and prognosis of 29 carotid body tumor patients from January 2006 to January 2016. According to whether to carry out the pre-operative transarterial embolization, the patients were classified into embolization group and non-embolization group. The blood loss, operative time and perioperative complications were compared between the 2 groups. RESULTS: 29 carotid body tumors were resected. The median of blood loss was 80 mL in embolization group and 200 mL in non-embolization group, the difference was statistically significant (P = 0.001). The median of operative time was 120 min in embolization group and 160 min in non-embolization group, the difference was statistically significant (P = 0.006). No death, paralysis or ectopic embolism occurred in the study population. 4 patients in embolization group and 4 in non-embolization group suffered from cranial nerve injury. CONCLUSION: Surgical resection of carotid body tumor is safe and reliable, which is the first choice in the treatment of carotid body tumor. Preoperative transaterial hyperselective embolization can significantly reduce blood loss and shorten operative time, but it dose not decrease the incidence of cranial never injury. PMID- 29698790 TI - Severity of complications and long-term survival after laparoscopic total gastrectomy with D2 lymph node dissection for advanced gastric cancer: A propensity score-matched, case-control study. AB - BACKGROUND: Increasing numbers of studies have shown that postoperative complication is a negative predictor of long-term survival outcomes in various malignancies. However, the impact of severity of complications on long-term survival for patients with gastric cancer still remains unclear. This study aimed to explore the relationship between the severity of complications and long-term survival outcomes after laparoscopic total gastrectomy (LTG) for advanced gastric cancer (AGC). METHODS: The study analyzed 571 patients with AGC who underwent LTG in a single institution between April 2008 and June 2015. Patients were divided into two groups based on the occurrence or absence of postoperative complications which were recorded using the Clavien-Dindo (C-D) classification. Long-term survival outcomes were compared between groups in the propensity score-matched cohort. RESULTS: The groups were well balanced after the propensity score matched. The complication (C) group was associated with decreased 5-year cancer specific survival (CSS) (65.1% vs. 76.2%, P=0.049). Subgroup analysis showed that the severe complication (C-D grade > II) group was associated with decreased 5 year overall survival (OS) (46.3% vs. 65.9%, P = 0.042) and cancer-specific survival (CSS) (53.7% vs. 74.4%, P = 0.030). However, a comparative analysis of 5 year OS and CCS showed no significant differences between the minor complication (C-D grade II) group and matched NC group (68.9% vs. 72.2%, P = 0.578; 75.6% vs. 77.8%, P = 0.649; respectively). Multivariate analysis confirmed severe complication was an independent risk factor for decreased OS. Further analysis showed that older age, lower body mass index (BMI), and combined resection were independent risk factor for the occurrence of severe complications. CONCLUSIONS: Severe complications adversely affected long-term survival outcomes after LTG with D2 lymph node dissection for AGC. More attention should be paid to patients at high risk for severe complications in preoperative assessment and postoperative management. PMID- 29698792 TI - Genotypes and subtypes of Cryptosporidium spp. in diarrheic lambs and goat kids in northern Greece. AB - Inconsistent data exist on the distribution of zoonotic Cryptosporidium species and subtypes in sheep and goats in European countries, and few such data are available from Greece. In this study, 280 fecal specimens were collected from 132 diarrheic lambs and 148 diarrheic goat kids aged 4 to 15 days on 15 farms in northern Greece, and examined for Cryptosporidium spp. using microscopy of Ziehl Neelsen-stained fecal smears. Cryptosporidium spp. in 80 microscopy-positive fecal specimens (39 from lambs and 41 from goat kids) were genotyped by PCR-RFLP analysis of the small subunit rRNA gene and subtyped by sequence analysis the 60 kDa glycoprotein gene. Among the 33 specimens successfully genotyped, C. parvum was found in 32 and C. xiaoi in one. Seven subtypes belonging to two subtype families (IIa and IId) were identified among the 29 C. parvum specimens successfully subtyped, including IIaA14G2R1 (1/29), IIaA15G2R1 (6/29), IIaA20G1R1 (7/29), IIdA14G2 (1/29), IIdA15G1 (9/29), IIdA16G1 (3/29), and IIdA23G1 (2/29). Lambs were more commonly infected with C. parvum IIa subtypes, whereas goat kids were more with IId subtypes. The results illustrate that C. parvum is prevalent in diarrheic lambs and goat kids in northern Greece and these animals could potentially play a role in epidemiology of human cryptosporidiosis. PMID- 29698791 TI - Prognostic value of CpG island methylator phenotype among hepatocellular carcinoma patients: A systematic review and meta-analysis. AB - OBJECTIVE: CpG island methylator phenotype (CIMP), characterized by multiple genes are concurrently methylated, has been reported to be associated with the prognosis of colorectal cancer. However, current studies have not explored the relationship between CIMP status with hepatocellular carcinoma (HCC) clinicopathological features. METHODS: To assess these associations, we performed a comprehensive search of PubMed, EMBASE, and the Web of Science to identify all eligible studies. Publication bias was tested using Begg's and Egger's test. RESULTS: Seven studies that involved 568 HCC patients (379 CIMP+ and 189 CIMP-) were eligible for inclusion in our study. CIMP+ in HCC was significantly associated with distant metastasis (OR = 4.28, 95% CI = 2.57-7.10, P < 0.00001, heterogeneity = 0.888), TNM tumor stage IIII + IV (OR = 5.73, 95% CI = 3.70-8.88, P < 0.0001, heterogeneity = 0.449), cirrhosis (OR = 2.54, 95% CI = 1.33,4.83, P = 0.005, heterogeneity = 0.121) and a higher level of AFP (>300 ng/ml) than those with CIMP- (OR = 2.63, 95% CI = 1.79,3.89, P < 0.00001, heterogeneity = 0.432). Moreover, CIMP+ was associated with an unfavorable overall survival (OS) (HR = 3.02, 95% CI = 1.60-5.70, P < 0.001, heterogeneity = 0.251) and a disease-free survival (DFS) (HR = 2.80, 95% CI = 1.79-4.37, P < 0.001, heterogeneity = 0.603). CONCLUSION: CIMP is independently associated with significantly worse prognosis in HCC patients. Examination of CIMP status may be useful for identifying patients who are at higher risk for disease progression. PMID- 29698793 TI - Impact of an Additional Chromosome on the Clinical Outcomes of Hematopoietic Stem Cell Transplantation in Philadelphia Chromosome-Positive Acute Myeloid Leukemia in Adults. AB - The incidence of Philadelphia chromosome positivity (Ph+) in adults with acute myeloid leukemia (AML) is very low. Ph+ AML is considered to be high risk for failure to attain remission or for early relapse after standard chemotherapy. Because of the low incidence of the disease, it has been difficult to determine the best treatment, including the effects of tyrosine kinase inhibitors. We retrospectively analyzed 29 patients with Ph+ AML (median age, 45 years; range, 18 to 80) managed at our center between 2002 and 2016. Two patients were not treated at all, 3 received repeated low-dose cytarabine, and 24 were treated with 3 + 7 standard induction chemotherapy. All 27 treated patients also received interim imatinib 400 mg orally until the day of the next chemotherapy cycle began or as conditioning for allogeneic hematopoietic cell transplantation (HCT), which was performed in 17 patients. Of the 29 patients with Ph+ AML, 7 (24.1%) had additional inv(16), 3 of whom had therapy-related AML. In the 7 with inv(16), the median age was younger (31 versus 44 years, P = .083) and the complete remission (CR) rate was relatively higher (85.7% versus 54.5%, P = .214) than in those without inv(16). Among the 27 treated patients, 20 (74.1%) achieved CR after standard chemotherapy with interim imatinib and 2 (7.4%) achieved CR after low dose cytarabine with interim imatinib. After a median follow-up of 65.5 months (range, 13.4 to 156.6), the 5-year overall survival (OS) among all 27 treated patients was 43.1%. For the 17 patients who underwent HCT the 5-year OS of 17 patients (10 in subgroup without inv(16) and 7 in subgroup with inv(16)) treated with allogeneic HCT was 69.3%. All 7 with inv(16) were still alive at the end of the study. In contrast, all patients not treated with HCT died within a median of 6.25 months (range, .2 to 18.2). Interim imatinib combined with chemotherapy yielded an acceptable remission rate in adult patients with Ph+ AML. Allogeneic HCT as a postremission therapy provided long-term disease control in two-thirds of those who underwent the transplant. We also demonstrated that inv(16) was related to a favorable outcome in Ph+ AML, including therapy-related AML. PMID- 29698794 TI - Prognostic and therapeutic implications of vascular disease in patients with atrial fibrillation. AB - Atrial fibrillation (AF) is associated with a 5-fold increase in the risk of ischemic stroke, and AF-related stroke patients have a higher mortality and greater morbidity than patients with non-AF related stroke. AF and vascular disease share a close relationship, with the concomitant presence of both disease states leading to a dramatic rise in future cardiovascular events. Indeed, the presence of peripheral artery disease independently predicts stroke in patients with AF. Myocardial infarction (MI) is another well-established risk factor for the development of AF; however, the role of pre-existing AF in MI is less well evidenced, with recent studies showing that this population more frequently develops coronary ischaemic events and has a higher risk of mortality than sinus rhythm patients. Finally, complex aortic plaque is associated with heightened thromboembolic risk in AF patients. Recent data from clinical trials with non vitamin K antagonist oral anticoagulants (NOACs) provided new insights on the prognostic implications of vascular disease coexistence in AF patients, and randomised trials testing a combination of NOAC with antiplatelet agents are ongoing. This review article provides an overview of recent data linking adverse outcomes in concomitant AF and vascular disease and the clinical trial evidence for possible therapeutic targets. PMID- 29698795 TI - Rare Case of Tricompartmental Arachnoid Cyst Spanning Infratentorial, Supratentorial, and Extracranial Compartment and Presenting as Posterior Parietal Meningocele. AB - BACKGROUND: Arachnoid cysts constitute a mere 1% of all nontraumatic intracranialspace-occupying lesions, and only 10% of these are present in theinfratentorial compartment. We hereby report a case of a 10-month-old femalechild with a tricompartmental arachnoid cyst. CASE DESCRIPTION: The arachnoid cyst spanned both the infratentorial and supratentorialcompartment of the intracranial space. In addition, the cyst was alsoherniating into the extracranial compartment through a congenital defect in theparietal bone. The child was brought to us with a disfiguring swelling over herscalp, which was progressively increasing in size. We managed the patient byexcision of the extracranial part and placed a cystoperitoneal shunt to take care of the intracranial part. Follow-up magneticresonance imaging after 6 months of intervention showed a significant reductionin the size of the intracranial portion of the cyst with no recurrence of theextracranial part. CONCLUSIONS: This case of arachnoid cyst involves multiplestructures. But interestingly, all these structures (arachnoid, dura, veins,and bone) are of mesodermal origin. So we would like to suggest that thispathology may be a result of developmental deviation during mesodermal differentiationrather than a simple expanding arachnoid cyst. PMID- 29698796 TI - Long-Term Outcomes of a New Minimally Invasive Approach in Chiari Type 1 and 1.5 Malformations: Technical Note and Preliminary Results. AB - BACKGROUND: The treatment options for patients with Chiari malformation type 1 (CM1) and Chiari malformation type 1.5 (CM1.5) have not yet been standardized. In these malformations, the main factors include obstruction at the level of the foramen magnum and dural and ligamentous thickening. Here we present our outcomes of surgery and decompression using a minimally invasive surgery (MIS) technique. METHODS: Sixty-one patients admitted to our clinics between 2009 and 2016 due to CM1 or CM1.5 and who had undergone MIS were investigated retrospectively. All patients were followed up for a mean period of 55 months, both clinically and radiologically, and the outcomes were recorded. RESULTS: All 61 patients underwent foramen magnum decompression through a 1.5-cm mini-open incision, C1 laminectomy and C2 medial inner side tour, posterior atlanto-occipital membrane removal, external dural delamination, and widening of the internal dura with longitudinal incisions. Fifty-six patients (91.8%) were satisfied with the outcome, 4 patients (6.5%) remained the same, and 1 patient (1.6%) reported a poor outcome. Forty-five percent of the patients with syringomyelia demonstrated resolution within 2 years, and 92% demonstrated resolution in 5 years. Scoliosis was seen in 5 patients (8.1%). The rate of benefit from the surgical procedure was statistically significant (P = 0.0045), and no patient required additional surgery because of poor decompression. CONCLUSIONS: MIS is effective for uncomplicated cases of CM1 and CM1.5 due to its minimal connective and muscular tissue damage, short surgical duration, short recovery time, early mobilization, effective posterior foramen magnum widening, lack of liquor fistula development, and better clinical and radiologic improvement during long-term follow-up. PMID- 29698797 TI - Current Status of the PulseRider in the Treatment of Bifurcation Aneurysms: A Systematic Review. AB - BACKGROUND: The PulseRider is an innovative stent-like device designed for the treatment of intracranial bifurcation aneurysms. The aim of this study was to assess the current evidence on safety and effectiveness of the PulseRider. METHODS: A systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The following databases were searched: PubMed, Ovid MEDLINE, and Scopus. The search strategy consisted of "pulserider," "bifurcation aneurysm," and "endovascular" in both AND and OR combinations. Studies included were original research articles in peer reviewed journals. The manuscripts were thoroughly examined for study design, outcomes, and results. RESULTS: Three studies were identified describing use of the PulseRider device in the treatment of 63 patients with 63 bifurcation aneurysms. We identified 2 multicenter case series and 1 single-arm clinical trial. The majority of aneurysms treated were located at the basilar tip (37, 58.7%). All devices were successfully deployed, and there were 5 intraoperative complications (7.9%), including 2 intraoperative aneurysm ruptures, 1 vessel dissection, and 2 thrombus formations. Immediate complete aneurysm occlusion was achieved in 61.9% (39/63) of cases and at the 6-month imaging follow-up, 66.7% (42/63) achieved complete aneurysm occlusion. One recanalization was reported in 1 of the multicenter case series within the 6-month follow-up. CONCLUSIONS: The PulseRider is safe and probably effective for the treatment of intracranial bifurcation aneurysms, sometimes not amenable for stent-assisted coiling. However, current evidence is limited to a small sample and short follow-up. In addition, the device has not been compared with other treatment modalities. PMID- 29698798 TI - Positive effect of strong acidity on the twist of Abeta42 fibrils and the counteraction of Abeta42 N-terminus. AB - pH is a crucial factor in terms of affecting the aggregation and morphology of beta-Amyloid and hence a focus of study. In this study, structural and mechanical properties of a series of models (5, 6, ..., 30 layer) of one-fold Abeta42 fibrils at pH 1.5, 3.0 and 7.5, have been computed by using all-atom molecular dynamics simulations. 12, 14, and 15 layers are established to be the smallest realistic models for Abeta42 fibrils at pH 1.5, 3.0 and 7.5, with twist angles of 0.40 degrees , 0.34 degrees , 0.31 degrees respectively, disclosing the favorable effect of strong acidity on fibril twist. However, these angles are all lower than that (0.48 degrees ) determined for the truncated Abeta17-42 fibril at pH 7.5, indicating that the disordered N-terminal depresses greatly the fibril twist and the lower pH disfavors the depression. Three commonly used indices to measure the fibril properties, namely number of H-bonds, interstrand distance and beta-sheet content have imperceptible changes with the pH alternation, therefore changes in fibril twist can be taken as a probe to monitor fibril properties. By contrast, N-terminus is determined not only to inhibit the U-shaped fibril twist by hampering the stagger between beta1 and beta2 strands, but also to play a vital carrier role in feeling solution (i.e., pH, salt) changes. These results can help design the nextgeneration of amyloid materials for state-of-the-art bio nano-med applications by changing the solution pH or modifying chain length. PMID- 29698799 TI - Blimp-1 prolongs allograft survival without regimen via influencing T cell development in favor of regulatory T cells while suppressing Th1. AB - BACKGROUND: B lymphocyte-induced maturation protein 1 (Blimp-1) transcription factor is expressed in multiple cell lineages and in particular, T cells. However, the role of Blimp-1 in T cell-mediated allograft tolerance is still unknown. METHODS: This study is the first to investigate transplanted skin allograft survival using transgenic (Tg) mice with T cell overexpression of Blimp 1. RESULTS: Without any immunosuppression, fully MHC-mismatched skin allografts on Tg(+) mice had a significantly prolonged survival rate and partial tolerance at 90 days. Allograft lymphocytic infiltration was decreased in Tg(+) mice and a dampened donor-stimulated alloimmune response was seen. An absolute cell number ratio of inflammatory Th1 and Th17 cells against anti-inflammatory regulatory T (Treg) and IL-10-producing T cells, as well as cytolytic proteins, were significantly decreased in lymphoid organs and allograft. Blimp-1 transgenic T cells displayed an increased Treg differentiation capability and enhanced suppression of T cell proliferation. Overexpression of Blimp-1 in T cells promoted the formation of an anti-inflammatory cell-cytokine composition, both systemically and locally via transcription factor modulation such as T-bet downregulation and FoxP3 upregulation. DISCUSSION: As such, allograft survival was made possible due to Th1 suppression and Treg amplification with the creation of an 'allograft protective microenvironment'. PMID- 29698800 TI - MHC class I presented antigens from malignancies: A perspective on analytical characterization & immunogenicity. AB - : The field of cancer immunotherapy has expanded rapidly in the past few years, with many new approaches entering the clinic for T cell mediated killing of tumors. Several of these clinical approaches involve the exploitation of a CD8 + T cell response against MHC I presented tumor antigens. Here, we describe the types of tumor antigens which are considered as targets in the design of T cell based therapeutic approaches, the rationale for targeting MHC I antigens and the analytical tools commonly employed for the discovery of MHC I presented peptides. The advantages and disadvantages of each approach are discussed and a perspective on the future directions of the MHC I peptide exploration field and biotherapeutic strategies is given. SIGNIFICANCE: This work is the first time a review article has been written to summarize all the various types of tumor antigens, and the analytical tools employed to discover and characterize them. PMID- 29698801 TI - Characterization of IgG N-glycome profile in colorectal cancer progression by MALDI-TOF-MS. AB - : Colorectal cancer (CRC) has become one of the most common cancers worldwide and the fifth most prevalent cancer in China with an upward trend in incidence rates. Altered glycosylation significantly affects the structural and functional changes in immunoglobulin G (IgG) and was consequently associated with disease progression. In this study, we explored the association of glycosylation with CRC prognosis through characterizing serum IgG N-glycans derived from individuals consisting of normal, benign colorectal and CRC cohorts in discovery set. Statistical analysis showed nine of IgG N-glycans were differentially expressed in disease groups compared with controls. Additionally, five out of them were still significantly changed in CRC patients at all tumor node metastasis (TNM) stages as compared with controls. Principal component analysis (PCA) indicated obvious differentiation of benign and cancer patients from normal individuals. Further diagnostic performance of receiver operator curve (ROC) analysis demonstrated at least moderately accurate area under the curve (AUC) score with preferable sensitivity and specificity, suggesting these five IgG N-glycans were probably correlated with CRC progression. Significantly, this result has been verified in validation set. Moreover, IgG N-glycosylation analysis suggested that core-fucosylation, sialylation and sialo core-fucosylation were possibly related to the development of CRC. SIGNIFICANCE: In-depth IgG N-glycome profiling of colorectal benign patients, colorectal cancer and normal individuals reveals differentially expression levels of N-glycosylation. Differing from serum comprehensive glycomes, profiling of specific serum glycoprotein contributes to more detailed understanding of biological relevance of glycosylation alterations in disease prognosis. Additionally, the high-throughput technique, MADLI-TOF-MS could absolutely relieve manual stress from sample preparation and accelerate information acquisition as compared to another recent analytical method. Moreover, we introduced a fast and easy data processing of MS exported files based on a software solution, which had the advantage of avoiding time consuming in manually searching and calculating the interesting peaks, and automatically producing the average percentage of each glycan over usual operation with Microsoft Excel. Besides, it may be useful for large-scale study. PMID- 29698802 TI - Histology-guided proteomic analysis to investigate the molecular profiles of clear cell Renal Cell Carcinoma grades. AB - : Renal Cell Carcinoma (RCC) is the most frequent form of kidney cancer and approximately 80% of cases are defined as clear cell RCC (ccRCC). Among the histopathological factors, tumour grade represents one of the most important parameters to evaluate ccRCC progression. Nonetheless, the molecular processes associated with the grading classification haven't been deeply investigated thus far. Therefore, the aim of this study was to uncover protein alterations associated with different ccRCC grade lesions. Formalin-fixed paraffin-embedded samples from ccRCC patients were analysed by histology-guided MALDI-MSI and shotgun proteomics in order to study the biological processes implicated in ccRCC. MALDI-MSI data highlighted signals able to discriminate among different grades (AUC > 0.8). The ion at m/z 1428.92 was identified as Vimentin and was overexpressed in grade 4 lesions, whereas ions at m/z 944.71, m/z 1032.78 and m/z 1325,99 were identified as histones H2A, H3, and H4, respectively. nLC-ESI-MS/MS analysis provided a further list of proteins and their abundances, showing a difference in protein content among the four grades. Moreover, the obtained molecular profiles showed a correspondence with the different Cancer-Specific Survival rate at 10 years post-surgery, as reported in literature. SIGNIFICANCE: Despite the generally accepted role of tumour grade in ccRCC diagnosis, the proteomic processes associated with the different tumour grades has not been extensively studied and doing so may provide insights into the development of the disease. In the current study, data obtained using MALDI-MSI was integrated with that obtained using nLC-ESI-MS/MS to highlight the proteomic alterations underlying the different ccRCC grades. The combined approach identified vimentin and three histones (H2A, H3 and H4) that were able to discriminate among the four grades whilst the nLC-ESI-MS/MS analysis alone provided a further list of proteins with an altered abundance. Furthermore, there was a good correlation between the molecular profiles generated for each grade and the different Cancer Specific Survival rate at 10 years post-surgery. Such findings could be a valuable starting point for further studies aimed at clarifying the molecular events that occur during the development of ccRCC. PMID- 29698803 TI - Fasting and refeeding induces changes in the mouse hepatic lipid droplet proteome. AB - : During fasting, the liver increases lipid storage as a mean to reserve and provide energy for vital cellular functions. After re-feeding, hepatocytes rapidly decrease the amount of triacylglycerol that is stored in lipid droplets (LDs), visible as the size of hepatic LDs significantly decreases after re feeding. Little is known about the changes in the liver LD proteome that occur during the fasting/re-feeding transition. This study aimed to investigate the hepatic LD proteome in fasted and re-fed conditions in the mouse. Using label free LC-MS/MS analysis the relative abundance of 817 proteins was determined in highly purified LDs. Comparative analysis for differential protein abundance with respect to feeding states revealed 130 with higher abundance in LDs from fasted mice and 31 in LDs from re-fed mice. Among proteins observed to have higher abundance on LDs in the fasted state we found perilipin-5, and several mitochondrial and peroxisomal marker proteins, supporting the role of LDs in the provision of substrates for fatty acid oxidation. Proteins of higher abundance upon re-feeding included several peroxisomal and mitochondrial marker proteins and expand our understanding of the dynamic nature of the hepatic LD proteome according to the energetic requirements of the cell. BIOLOGICAL SIGNIFICANCE: Proteomic investigations have been revealing the complexities and dynamics of cellular LDs from a variety of cell types. As these sub-cellular structures are truly dynamic in nature, our investigations reveal that simply the feeding state of an animal leads to significant changes to the protein composition of LDs and suggest a variety of dynamic interactions with other cellular organelles, such as the mitochondria and peroxisomes. As such, the experimental design for investigations of this cellular structure must consider this dynamic baseline. Lastly our analysis on global protein abundance has revealed the unforeseen high abundance of murine major urinary proteins associated with hepatic lipid droplets, which warrants further investigations. PMID- 29698804 TI - Phenotype variability in Hajdu-Cheney syndrome. AB - Hajdu Cheney syndrome is a rare autosomal dominant skeletal dysplasia, with multi organ involvement, caused by pathogenic variants in NOTCH2. It is characterized by progressive focal bone destruction, including acro-osteolysis and generalized osteoporosis, craniofacial anomalies, hearing loss, cardiovascular involvement and polycystic kidneys. Distinct radiographic findings, such as a serpentine fibula, may aid in facilitating the diagnosis. Despite several dozens of cases described in the literature, diagnosis often remains elusive, resulting in many cases in a delay in diagnosis reaching adolescence or adulthood. We report herein two unrelated patients of Turkish/Lebanese Jewish and Ashkenazi Jewish descent, each presenting with distinct clinical challenges and subsequently distinct diagnostic odysseys leading to their molecular diagnosis. These illustrative clinical descriptions underscore the wide phenotypic variability of HCS, and further contribute to the current knowledge regarding this rare entity. PMID- 29698805 TI - Extending the clinical and genetic spectrum of ARID2 related intellectual disability. A case series of 7 patients. AB - In the last 3 years de novo sequence variants in the ARID2 (AT-rich interaction domain 2) gene, a subunit of the SWI/SNF complex, have been linked to intellectual disabilities in 3 case reports including one which describes frameshift mutations in ARID2 in 2 patients with features resembling Coffin-Siris syndrome. Coffin-Siris syndrome (CSS) is a rare congenital syndrome characterized by intellectual deficit, coarse facial features and hypoplastic or absent fifth fingernails and/or toenails among other features. Mutations in a number of different genes encoding SWI/SNF chromatin remodelling complex proteins have been described but the underlying molecular cause remains unknown in approximately 40% of patients with CSS. Here we describe 7 unrelated individuals, 2 with deletions of the ARID2 region and 5 with de novo truncating mutations in the ARID2 gene. Similarities to CSS are evident. Although hypertrichosis and hypoplasia of the fifth finger nail and distal phalanx do not appear to be common in these patients, toenail hypoplasia and the presence of Wormian bones might support the involvement of ARID2. PMID- 29698806 TI - Identification of two 14q32 deletions involving DICER1 associated with the development of DICER1-related tumors. AB - DICER1 encodes an RNase III endonuclease protein that regulates the production of small non-coding RNAs. Germline mutations in DICER1 are associated with an autosomal dominant hereditary cancer predisposition syndrome that confers an increased risk for the development of several rare childhood and adult-onset tumors, the most frequent of which include pleuropulmonary blastoma, ovarian sex cord-stromal tumors, cystic nephroma, and thyroid gland neoplasia. The majority of reported germline DICER1 mutations are truncating sequence-level alterations, suggesting that a loss-of-function type mechanism drives tumor formation in DICER1 syndrome. However, reports of patients with germline DICER1 whole gene deletions are limited, and thus far, only two have reported an association with tumor development. Here we report the clinical findings of three patients from two unrelated families with 14q32 deletions that encompass the DICER1 locus. The deletion identified in Family I is 1.4 Mb and was initially identified in a 6 year-old male referred for developmental delay, hypotonia, macrocephaly, obesity, and behavioral problems. Subsequent testing revealed that this deletion was inherited from his mother, who had a clinical history that included bilateral multinodular goiter and papillary thyroid carcinoma. The second deletion is 5.0 Mb and was identified in a 15-year-old female who presented with autism, coarse facial features, Sertoli-Leydig cell tumor, and Wilms' tumor. These findings provide additional supportive evidence that germline deletion of DICER1 confers an increased risk for DICER1-related tumor development, and provide new insight into the clinical significance of deletions involving the 14q32 region. PMID- 29698807 TI - Food-dependent cold urticaria: A new variant of physical urticaria. PMID- 29698808 TI - Rapid, highly sensitive detection of Gram-negative bacteria with lipopolysaccharide based disposable aptasensor. AB - Gram-negative bacteria are one of the most common microorganisms in the environment. Their differential detection and recognition from Gram-positive bacteria has been attracting much attention over the years. Using Escherichia coli (E. coli) as a model, we demonstrated on-site detection of Gram-negative bacteria by an AC electrokinetics-based capacitive sensing method using commercial microelectrodes functionalized with an aptamer specific to lipopolysaccharides. Dielectrophoresis effect was utilized to enrich viable bacteria to the microelectrodes rapidly, achieving a detection limit of 102 cells/mL within a 30 s' response time. The sensor showed a negligible response to Staphylococcus aureus (S. aureus), a Gram-positive species. The developed sensor showed significant advantages in sensitivity, selectivity, cost, operation simplicity, and response time. Therefore, this sensing method has shown great application potential for environmental monitoring, food safety, and real-time diagnosis. PMID- 29698809 TI - Strategies of molecular imprinting-based fluorescence sensors for chemical and biological analysis. AB - One pressing concern today is to construct sensors that can withstand various disturbances for highly selective and sensitive detecting trace analytes in complicated samples. Molecularly imprinted polymers (MIPs) with tailor-made binding sites are preferred to be recognition elements in sensors for effective targets detection, and fluorescence measurement assists in highly sensitive detection and user-friendly control. Accordingly, molecular imprinting-based fluorescence sensors (MI-FL sensors) have attracted great research interest in many fields such as chemical and biological analysis. Herein, we comprehensively review the recent advances in MI-FL sensors construction and applications, giving insights on sensing principles and signal transduction mechanisms, focusing on general construction strategies for intrinsically fluorescent or nonfluorescent analytes and improvement strategies in sensing performance, particularly in sensitivity. Construction strategies are well overviewed, mainly including the traditional indirect methods of competitive binding against pre-bound fluorescent indicators, employment of fluorescent functional monomers and embedding of fluorescence substances, and novel rational designs of hierarchical architecture (core-shell/hollow and mesoporous structures), post-imprinting modification, and ratiometric fluorescence detection. Furthermore, MI-FL sensor based microdevices are discussed, involving micromotors, test strips and microfluidics, which are more portable for rapid point-of-care detection and in-field diagnosing. Finally, the current challenges and future perspectives of MI-FL sensors are proposed. PMID- 29698810 TI - Molecularly imprinted polymers-based electrochemical DNA biosensor for the determination of BRCA-1 amplified by SiO2@Ag. AB - A novel electrochemical DNA (E-DNA) biosensing strategy was designed and used for the detection of breast cancer susceptibility gene (BRCA-1). The biosensor was based on gold nanoparticles-reduced graphene oxide (AuNPs-GO) modified glass carbon electrode (GCE) covered with the layer of molecularly imprinted polymers (MIPs) synthesized with rhodamine B (RhB) as template, methacrylic acid (MAA) as the monomer, and Nafion as additive. The signal amplification tracing tag SiO2@Ag NPs were prepared by covering AgNPs on the surface of SiO2 nanoparticles in situ, and then DNA probes were modified on AgNPs by Ag-S bond, forming the composites SiO2@Ag/DNA. In presence of target DNA (T-DNA), homogeneous hybridization was performed with SiO2@Ag/DNA and RhB labeled DNA, and the resulting SiO2@Ag/dsDNA/RhB was specifically recognized by MIPs via the interaction between imprinting cavities and RhB. Under optimal conditions, the proposed biosensor exhibited wide linear range from 10 fM to 100 nM, low detection limit of 2.53 fM (S/N = 3), excellent selectivity, reproducibility, stability, and feasibility in serum analysis. Overall, these findings suggest the promising prospects of the proposed biosensing strategy in clinical diagnostics. PMID- 29698811 TI - Red blood cells aggregability measurement of coagulating blood in extracorporeal circulation system with multiple-frequency electrical impedance spectroscopy. AB - Red blood cells (RBCs) aggregability AG of coagulating blood in extracorporeal circulation system has been investigated under the condition of pulsatile flow. Relaxation frequency fc from the multiple-frequency electrical impedance spectroscopy is utilized to obtain RBCs aggregability AG. Compared with other methods, the proposed multiple-frequency electrical impedance method is much easier to obtain non-invasive measurement with high speed and good penetrability performance in biology tissues. Experimental results show that, RBCs aggregability AG in coagulating blood falls down with the thrombus formation while that in non-coagulation blood almost keeps the same value, which has a great agreement with the activated clotting time (ACT) fibrinogen concertation (Fbg) tests. Modified Hanai formula is proposed to quantitatively analyze the influence of RBCs aggregation on multiple-frequency electrical impedance measurement. The reduction of RBCs aggregability AG is associated with blood coagulation reaction, which indicates the feasibility of the high speed, compact and cheap on-line thrombus measurement biosensors in extracorporeal circulation systems. PMID- 29698812 TI - Monitoring of bacteria biofilms forming process by in-situ impedimetric biosensor chip. AB - A biosensor chip integrated interdigital microelectrodes was proposed and applied to monitor the formation process of Salmonella and E. coli biofilms in this paper. The biosensor chip was composed of a glass substrate with interdigital microelectrodes and PDMS layer with micro cavities. The electrochemical impedance spectroscopy (EIS) of Salmonella and E. coli biofilms was measured by the biosensor chip using alternating voltage of 100 mv in the frequency range from 1 Hz to 100 kHz for 48 h. It was illustrated that the changes of impedance spectroscopy of biofilms occurred with culture time. Furthermore, impedance spectroscopy of biofilms was fitted by an equivalent circuit model including the biofilms capacitance (Cb) and the biofilms resistance (Rb) parameters. The results indicated that the Cb presented a tendency to decrease first and then rise with culture time, while the Rb was in the opposite direction. These changing trends were consistent with the formation process of biofilms that bacteria adhered to electrodes surface, and then formed mature biofilms, finally escaped from biofilms. In addition, it was also demonstrated that the changing trends of Cb and Rb with culture time were quite different between Salmonella and E. coli. The results obtained by impedance detection were in accordance with the results of using crystal violet staining to analyze biofilms formation process, under the same conditions for bacterial culture. The biosensor chip provided a promising platform for further study of biofilms owing to its unique advantages of real time, continuity, and non-invasion for bacteria biofilms detection and in situ monitoring. PMID- 29698813 TI - Neurotrophic keratopathy. AB - Neurotrophic Keratopathy (NK) refers to a condition where corneal epitheliopathy leading to frank epithelial defect with or without stromal ulceration (melting) is associated with reduced or absent corneal sensations. Sensory nerves serve nociceptor and trophic functions, which can be affected independently or simultaneously. Loss of trophic function and consequent epithelial breakdown exposes the stroma making it susceptible to enzymatic degradation. Nerve pathology can range from attrition to aberrant re-generation with corresponding symptoms from anaesthesia to hyperaesthesia/allodynia. Many systemic and ocular conditions, including surgery and preserved medications can lead to NK. NK can be mild (epithelium and tear film changes), moderate (non-healing epithelial defect) or severe (stromal melting and perforation). Moderate and severe NK can profoundly affect vision and adversely impact on the quality of life. Medical management with lubricating agents from artificial tears to serum/plasma drops, anti-inflammatory agents, antibiotics and anti-proteases all provide non-specific relief, which may be temporary. Contact lenses, punctal plugs, lid closure with botulinum toxin and surgical interventions like tarsorrhaphy, conjunctival flaps and amniotic membrane provide greater success but often at the cost of obscuring sight. Corneal surgery in a dry ocular surface with reduced sensation is at high risk of failure. The recent advent of biologicals such as biopolymers mimicking heparan sulfate; coenzyme Q10 and antisense oligonucleotide that suppress connexin 43 expression, all offer promise. Recombinant nerve growth factor (cenegermin), recently approved for human use targets the nerve pathology and has the potential of addressing the underlying deficit and becoming a specific therapy for NK. PMID- 29698814 TI - Zika and the Eye: Pieces of a Puzzle. AB - Zika virus (ZIKV) is an arbovirus mainly transmitted to humans by mosquitoes from Aedes genus. Other ways of transmission include the perinatal and sexual routes, blood transfusion, and laboratory exposure. Although the first human cases were registered in 1952 in African countries, outbreaks were only reported since 2007, when entire Pacific islands were affected. In March 2015, the first cases of ZIKV acute infection were notified in Brazil and, to date, 48 countries and territories in the Americas have confirmed local mosquito-borne transmission of ZIKV. Until 2015, ZIKV infection was thought to only cause asymptomatic or mild exanthematous febrile infections. However, after explosive ZIKV outbreaks in Polynesia and Latin American countries, it was confirmed that ZIKV could also lead to Guillain-Barre syndrome and congenital birth abnormalities. These abnormalities, which can include neurologic, ophthalmologic, audiologic, and skeletal findings, are now considered congenital Zika syndrome (CZS). Brain abnormalities in CZS include cerebral calcifications, malformations of cortical development, ventriculomegaly, lissencephaly, hypoplasia of the cerebellum and brainstem. The ocular findings, which are present in up to 70% of infants with CZS, include iris coloboma, lens subluxation, cataract, congenital glaucoma, and especially posterior segment findings. Loss of retinal pigment epithelium, the presence of a thin choroid, a perivascular choroidal inflammatory infiltrate, and atrophic changes within the optic nerve were seen in histologic analyses of eyes from deceased fetuses. To date, there is no ZIKV licensed vaccines or antiviral therapies are available for treatment. Preventive measures include individual protection from mosquito bites, control of mosquito populations and the use of barriers measures such as condoms during sexual intercourse or sexual abstinence for couples either at risk or after confirmed infection. A literature review based on studies that analyzed ocular findings in mothers and infants with CZS, with or without microcephaly, was conducted and a theoretical pathophysiologic explanation for ZIKV-ocular abnormalities was formulated. PMID- 29698815 TI - Effects of Talaromyces marneffei infection on mortality of HIV/AIDS patients in southern China: a retrospective cohort study. AB - OBJECTIVE: Talaromyces marneffei is an opportunistic infection with high morbidity among human immunodeficiency virus (HIV)/AIDS patients in Southeast Asia and southern China. Its effects on mortality in HIV/AIDS patients has not been clearly elucidated. METHODS: We conducted a retrospective cohort study of hospitalized HIV-infected individuals at the Fourth People's Hospital of Nanning, Guangxi, China during 2012-2015. Kaplan-Meier analyses were used to calculate the cumulative mortality. Cox proportional hazard models and 1:1 propensity score matching (PSM) were used to evaluate the effects of T. marneffei infection on mortality of HIV/AIDS patients. RESULTS: In total, 6791 HIV/AIDS patients were included, 1093 of them (16.1%) with documented T. marneffei co-infection. The mortality of T. marneffei-infected patients (25.0 per 100 person-months, 95% CI 21.5-26.7) was the highest among all AIDS-associated complications and was significantly higher than that of T. marneffei-uninfected HIV/AIDS patients (13.8 per 100 person-months, 95% CI 12.5-15.1; adjusted hazard ratio (AHR) 1.80, 95% CI 1.48-2.16). The results using PSM were similar (AHR 4.52 95% CI 2.43-8.42). The mortality of T. marneffei-infected patients was also significantly higher than that of patients without any complications. When stratified by demographic characteristics, T. marneffei infection has higher mortality risk in all stratifications. Co-infection with T. marneffei carries a higher mortality risk in patients at any CD4+ T-cell count. CONCLUSIONS: Talaromyces marneffei infection is commonly found in hospitalized HIV/AIDS patients in southern China and was associated with a higher mortality rate than most HIV-associated complications. These results highlight the need for improved diagnosis, treatment and prevention of infection by this neglected fungal pathogen in southern China. PMID- 29698816 TI - Common staining techniques for highlighting Acanthamoeba cysts. PMID- 29698817 TI - Genomic sequence investigation Streptococcus pyogenes clusters in England (2010 2015). AB - OBJECTIVES: To analyse genomic sequence data of referred Streptococcus pyogenes isolates and those pertaining to selected elderly/nursing care or maternity clusters from 2010 to 2015 to ascertain genomic differences between epidemiologically related isolates and unrelated isolates from outbreaks of disease. METHODS: The genomic sequences of 134 S. pyogenes isolates from 21 clusters of infection in elderly care or maternity settings from 2010 to 2015 were analysed using bioinformatics to ascertain genomic phylogeny, single nucleotide polymorphism (SNP) differences and statistical outliers from epidemiologically defined outbreaks. Analysis was undertaken within clusters and compared with sporadic isolates from geographically distinct outbreaks of S. pyogenes infection. RESULTS: Genomic sequence analysis of 21 outbreaks of S. pyogenes infection ranged in size from a single patient (with colonized healthcare worker link) to 18 patient cases of group A streptococcus (GAS) infection in a single setting. Seventeen healthcare workers were identified in 8 of 21 outbreaks with the associated outbreak strain, with multiple staff in 2 of 21 outbreaks. Genomic sequences from epidemiologically linked isolates from patients, staff and healthcare environmental settings were highly conserved, differing by 0-1 SNP in some cases and mirrored geographical data. Four of 21 outbreaks had environmental contamination with the outbreak strain, indistinguishable or of limited SNP difference to the patient isolates. Genomic SNP analysis enabled exclusion of ten isolates from epidemiological outbreaks. CONCLUSIONS: Genomic discrimination can be applied to assist outbreak investigation. It enabled confirmation or exclusion of GAS cases from epidemiologically defined outbreaks. Colonization of healthcare workers and environmental contamination with the outbreak strain was demonstrated for several outbreaks. PMID- 29698818 TI - Acinetobacter ursingii masquerading as Gram-positive cocci. PMID- 29698819 TI - Development of microemulsions of suitable viscosity for cyclosporine skin delivery. AB - Psoriasis is a widespread chronic disease affecting 2-4% of the population in Western countries. Its mild-to-moderate form, representing approximately 80% of the total cases, is treated by topical application, with corticosteroid being the standard treatment. However, in case of psoriasis, no single treatment works for every patient and optimizing topical therapy is a key aspect. A possible alternative is represented by cyclosporine, an immunosuppressant cyclic peptide administered orally in the treatment of the severe form. Its topical application could avoid the problems related to systemic immunosuppression, but the unfavourable physico-chemical properties (MW: 1202 Da; LogP ~ 3) hinder its permeation across the stratum corneum. The aim of the paper was the preparation, characterization and ex-vivo evaluation of cyclosporine loaded microemulsions using oleic acid as oil phase, either Tween(r)80 or a soluble derivative of vitamin E (TPGS) as surfactants and either Transcutol(r), propylene glycol or 1,3 propanediol as co-surfactants. The issue of formulation viscosity was also addressed 1) by evaluating the thickening of Tween(r)80-based microemulsions by direct addition of different rheological modifiers, 2) by building pseudo-ternary phase diagrams using TPGS, to identify the water/oil/surfactants proportions resulting in viscous self-gelifying systems. Nine formulations (five Tween(r)80 based and four TPGS-based) were selected, characterized in terms of droplets size (low viscosity systems) or rheological properties (high viscosity systems), loaded with 6 mg/g cyclosporine and applied ex-vivo on porcine skin for 22 h. A relevant skin accumulation was obtained either with a low-viscosity Tween(r)80 based microemulsion (9.78 +/- 3.86 ug/cm2), or with a high viscosity TPGS-based microemulsion (18.3 +/- 5.69 ug/cm2), with an increase of about 3 and 6 times respectively for comparison with a control cyclosporine solution in propylene glycol. The role of water content, surfactant, co-surfactant and viscosity was also addressed and discussed. The kinetic of skin uptake from the best performing formulation was finally evaluated, highlighting a relatively quick skin uptake and the achievement, after 2 h of contact, of potentially therapeutic cyclosporine skin concentrations. PMID- 29698820 TI - Design of PEI-conjugated bio-reducible polymer for efficient gene delivery. AB - The poly(cystaminebis(acrylamide)-diaminohexane) (poly(CBA-DAH)) was designed previously as a bio-reducible efficient gene delivery carrier. However, the high weight ratio required to form the polyplexes between poly(CBA-DAH) with pDNA is still a problem that needs to be addressed. To solve this problem and increase the transfection efficiency, poly(ethylenimine) (PEI, 1.8 kDa) was conjugated to poly(CBA-DAH) via disulfide bond. The PEI conjugated poly(CBA-DAH) (PCDP) can bind with pDNA at a very low weight ratio of 0.5 and above, like PEI 25 kDa, and form the polyplexes with nano-size (102-128 nm) and positive surface charge (27 34 mV). PCDP and PCDP polyplexes had negligible cytotoxicity and indicated similar or better cellular uptake than the comparison groups such as PEI 25 kDa and Lipofectamine(r) polyplexes. To confirm the transfection efficiency, the plasmid DNA (pDNA) encoded with the luciferase reporter gene (gWiz-Luc) and green fluorescent protein reporter gene (GFP) were used and treated with PCDP into the A549, Huh-7, and Mia PaCa-2 cells. PCDP/pDNA polyplexes showed highest transfection efficiency in all tested cell lines. In the luciferase assay, PCDP polyplexes showed 10.2 times higher gene transfection efficiency than Lipofectamine(r) polyplexes in mimic in vivo conditions (30% FBS, A549 cells). The VEGF siRNA expressing plasmid (pshVEGF), which is constructed as a therapeutic gene by our previous work, was delivered by PCDP into the cancer cells. The VEGF gene expression of PCDP/pshVEGF polyplexes was dramatically lower than control and the VEGF gene silencing efficiencies of PCDP/pshVEGF (w/w; 10/1) polyplexes were 54% (A549 cells), 77% (Huh-7 cells), and 66% (Mia PaCa-2 cells). In addition, PCDP/pshVEGF had reduced cell viability rates of about 31% (A549 cells), 39% (Huh-7 cells), and 42% (Mia PaCa-2 cells) and showed better results than all comparison groups. In the transfection efficiency and VEGF silencing assay, PCDP polyplexes showed better results than poly(CBA-DAH) at 4-fold lower weight ratio. The data of all experiments demonstrate that the synthesized PCDP could be used for efficient gene delivery and could be widely applied. PMID- 29698821 TI - Determination of permeation pathways of hydrophilic or hydrophobic dyes through the mammary papilla. AB - The transport pathways and permeation kinetics of lipophilic and hydrophilic fluorescent dyes through porcine mammary papillae were visualized and quantified. Porcine mammary papillae, removed from full-thickness abdominal tissue, were positioned in a Franz diffusion cell for passive diffusion studies. Solutions containing the fluorescent dyes were applied topically for time periods ranging from 30 min to 48 h. Dye concentrations in tissue and Franz diffusion compartments were analyzed using fluorescence microscopy and fluorimetry. Fluorescence micrographs elucidated two permeation pathways, transepidermal and transductal. Hydrophilic sulforhodamine B predominantly penetrated via the transepidermal route, while lipophilic nile red diffused mainly by the transductal route. An almost 4-fold higher amount of sulforhodamine B was retained within the nipple over time compared to nile red, despite both dyes permeating through the tissue at similar rates. Diffusion through the porcine nipple was 500-fold higher than through adjacent skin for both dyes, likely attributable to the two mammary ducts which provide an entry point and transport route through the tissue. These results, generated from both qualitative and quantitative evidence at a micro and macro scale, demonstrate that the mammary ducts provide a direct pathway that contributes significantly to passive transport through the nipple, particularly for lipophilic molecules. PMID- 29698822 TI - Design and evaluation of clickable gelatin-oleic nanoparticles using fattigation platform for cancer therapy. AB - The principles of bioorthogonal click chemistry and metabolic glycoengineering were applied to produce targeted anti-cancer drug delivery via fattigation platform-based gelatin-oleic nanoparticles. A sialic acid precursor (Ac4ManNAz) was introduced to the cell surface. Gelatin and oleic acid were conjugated by 1 (3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride/N-hydroxysuccinimide (EDC/NHS) chemistry with the subsequent covalent attachment of dibenzocyclooctyne (DBCO) in a click reaction on the cell surface. The physicochemical properties, drug release, in vitro cytotoxicity, and cellular uptake of DBCO-conjugated gelatin oleic nanoparticles (GON-DBCO; particle size, ~240 nm; zeta potential, 6 mV) were evaluated. Doxorubicin (DOX) was used as a model drug and compared with the reference product, Caelyx(r). A549 and MCF-7 cell lines were used for the in vitro studies. GON-DBCO showed high DOX loading and encapsulation efficiencies. In A549 cells, the IC50 value for GON-DBCO-DOX (1.29 ug/ml) was six times lower than that of Caelyx(r) (10.54 ug/ml); in MCF-7 cells, the IC50 values were 1.78 ug/ml and 2.84 ug/ml, respectively. Confocal microscopy confirmed the click reaction between GON-DBCO and Ac4ManNAz on the cell surface. Flow cytometry data revealed that the intracellular uptake of GON-DBCO-DOX was approximately two times greater than that of GON-DOX and Caelyx(r). Thus, the newly designed GON DBCO-DOX provided a safe and efficient drug delivery system to actively target the anticancer agents. PMID- 29698823 TI - Hydrogels in three-dimensional dendritic cell (MUTZ-3) culture as a scaffold to mimic human immuno competent subcutaneous tissue. AB - The objective of this study was to develop a 3D cell culture model of the human subcutaneous tissue, allowing the prediction of the immunogenicity of subcutaneously injected therapeutic proteins. Several hydrogels were evaluated as scaffolds to mimic the human subcutaneous tissue in vitro. Cytocompatibility of the hydrogels with the human myelomonocytic cell line (MUTZ-3) was investigated, as well as their influence on cellular phenotype changes. Elastic Young's moduli in compression of the hydrogels were measured by a texture analyser and compared to ex vivo human samples. MUTZ-3 cells were differentiated into dendritic cells before embedding in hydrogels. Agarose at various concentrations (0.5%, 0.35% and 0.25% w/v), Geltrex(r) matrix and HyStemTM scaffold (1% w/v) displayed a wide range of elastic Young's moduli from 560 kPa to 49 kPa, compared to the reference value of 23 kPa obtained for human tissue. With the exception of HyStemTM, good cytocompatibility of hydrogels was shown at the concentrations tested. An optimal combination of MUTZ-3 cells with 0.25% agarose or Geltrex(r) is suggested. PMID- 29698824 TI - A brief facial morphing intervention to reduce skin cancer risk behaviors: Results from a randomized controlled trial. AB - The current study was designed to test the efficacy of an appearance-based facial morphing program to reduce intentional UV exposure among individuals at risk for skin cancer. A three-arm randomized controlled trial was employed (N = 219) comparing facial morphing + health information to: (1) mindfulness + health information; and (2) health information only. Participants were young adults with a history of recent intentional tanning and future intentions to tan. Primary outcomes were indoor and outdoor tanning frequency and tanning intentions, with secondary outcomes of tanning attitudes, body image, and affect. Facial morphing participants reported less frequent tanning, compared to mindfulness and control participants at 1-month follow-up. Facial morphing participants also generally reported lower intentions to tan at immediate follow-up, although the magnitude of these effects weakened at 1-month follow-up. Facial morphing programs may offer a brief, efficacious, and scalable augmentation to standard of care in reducing intentional UV exposure. This trial is registered with clinicaltrials.gov (NCT03237013). PMID- 29698826 TI - Emergence of a multi host biofilm forming opportunistic pathogen Staphylococcus sciuri D26 in coral Favites abdita. AB - Corals are hotspots of ocean microbial diversity and imbalance in the composition of coral associated microbes has been mostly correlated with the emergence of climate change driven diseases which affect the overall stability of the reef ecosystem. Coral sampling was performed by SCUBA diving at Palk Bay (latitude 9.271580, longitude 79.132203) south Indian coast. Among the 54 bacterial isolates, an isolate MGL-D26 showed comparatively high biofilm formation and was identified as Staphylococcus sciuri based on phylogenetic analysis. The production of exopolysaccharide (EPS) confirmed the formation of a slimy EPS matrix associated with the biofilm. The biofilm formation in S. sciuri D26 was induced significantly by UV exposure followed by other stress factors including pollution, agitation, and salinity. The strain inhibited innate immune factors of corals such as melanin synthesis and phenoloxidase. Challenge experiments in a model organism Aiptasia sp. showed pathogenicity of S. sciuri. Histopathological analysis revealed tissue invasion by S. sciuri which was a predisposing factor leading to mortality in challenged Aiptasia sp. However, specific disease condition of corals infected by S. sciuri requires continuous field monitoring and further investigation. Based on the findings, S. sciuri was a first reported multi-host opportunistic pathogen which has emerged in corals under environmental stress. PMID- 29698825 TI - Experimental bovine rotavirus-A (RV-A)infection causes intestinal and extra intestinal pathology in suckling mice. AB - We describe here the intestinal and extra-intestinal spread of the species A rotavirus (RV-A) and associated lesions thereof in Swiss albino suckling mice pups, inoculated with a bovine-origin RV-A strain. In total, 35 suckling pups were used, wherein 20 pups received cell culture isolated RV-A @ 160 MUL (TCID50/ml, 5 * 106.5) per pup [oral 80 MUL and intra peritoneal (IP) 80 MUL] and served as an infected group, while 15 pups were kept in the control group and inoculated the same volume of phosphate buffered saline (PBS) of neutral pH orally and IP. Four pups from the infected group and 3 from control group were sacrificed at 3, 5, 7, 9 and 12 day post infection (DPI). Of note, infected pups exhibited signs of dullness and restlessness till 5DPI, but none showed diarrhea at any point of time. No appreciable gross lesions were evident in any of the organs, except for mild congestion of the small intestine and yellowish catarrhal smearing over the luminal surface. However, light microscopic lesions in hematoxylin and eosin (H&E) stained sections of jejunum and ileum revealed vacuolation and pyknosis of nuclei of the mature enterocytes, their lysis and detachment, constriction and detachment of villi, mild mononuclear cells (MNCs) infiltration in the lamina propria and mildcell depletion of Peyer's patches and mesenteric lymph nodes (MLN). The extra-intestinal lesions of the cellular degeneration and mild MNCs infiltration were identified in the liver and kidneys from 3 to 7 DPI, but no lesion was seen in the brain. Interstitial thickening with MNCs of lung parenchyma was visible from 3 to 7 DPI. The lesions in the intestine, lymphoid tissues and lungs resolved after 7 DPI. The presence of viral nucleic acid was seen in the intestinal contents from 3 to 5 DPI by using a RV-A specific reverse-transcription polymerase chain reaction (RT-PCR), while in the MLNs and the lungs it could be detected till 5 DPI by both the RT-PCR and direct fluorescent antigen test (dFAT). However, liver, spleen and brain were tested negative for the presence of RV-A by any of these tests. Nonetheless, the persistence of the RV-A was seen in the MLNs even after the absence of virus from the small intestines. Findings here conclusively indicates that heterologous host origin RV-A has an affinity not only to the intestine but also to extra intestinal tissues like MLNs and lung tissues. PMID- 29698827 TI - Performance evaluation of duplex constructed wetlands for the treatment of diesel contaminated wastewater. AB - A duplex constructed wetland (duplex-CW) is a hybrid system that combines a vertical flow (VF) CW as a first stage with a horizontal flow filter (HFF) as a second stage for a more efficient wastewater treatment as compared to traditional constructed wetlands. This study evaluated the potential of the hybrid CW system to treat influent wastewater containing diesel range organic compounds varying from C7 - C40 using a series of 12-week practical and numerical experiments under controlled conditions in a greenhouse (pH was kept at 7.0 +/- 0.2, temperature between 20 and 23 degrees C and light intensity between 85 and 100-MUmol photons m-2 sec-1 for 16 h d-1). The VF CWs were planted with Phragmites australis and were spiked with different concentrations of NH4+-N (10, 30 and 60 mg/L) and PO43 -P (3, 6 and 12 mg/L) to analyse their effects on the degradation of the supplied petroleum hydrocarbons. The removal rate of the diesel range organics considering the different NH4+-N and PO43--P concentrations were simulated using Monod degradation kinetics. The simulated results compared well with the observed database. The results showed that the model can effectively be used to predict biochemical transformation and degradation of diesel range organic compounds along with nutrient amendment in duplex constructed wetlands. PMID- 29698828 TI - Combined application of EDDS and EDTA for removal of potentially toxic elements under multiple soil washing schemes. AB - Chelant-enhanced soil washing, such as EDTA (ethylenediaminetetraacetic acid) and biodegradable EDDS ([S,S]-ethylene-diamine-disuccinic acid), has been widely studied, however, EDTA is persistent under natural conditions while EDDS has a low efficiency for Pb extraction. Therefore, we investigated the efficacy of mixed chelants (EDDS and EDTA mixture at 1:1 M ratio) for the removal of Cu, Zn, and Pb from a field-contaminated soil using various washing schemes (multi-pulse, step-gradient chelant, and continuous washing schemes). Speciation modelling of the target metals, mineral elements, and EDDS/EDTA was performed, while the leachability and bioaccessibility of residual metals in the treated soils were also assessed. Our results suggested that the combined use of EDDS and EDTA reached equivalent extraction efficiency of the target metals as EDTA, i.e., 50% reduction in the dosage of EDTA was made possible. This was accomplished by selective extraction of Cu by EDDS and Pb by EDTA, which was supported by the results of speciation calculation. Multi-pulse washing scheme with intermittent water rinsing steps removed entrapped metal-chelant complexes and free chelants, therefore reducing the leachability and bioaccessibility of residual metals in the treated soils. Step-gradient chelant washing with the maximum dosage of chelants in the first washing step only achieved marginal improvement but undesirably promoted Pb bioaccessibility. Continuous washing for 24 h enhanced metal extraction but promoted mineral dissolution, together with a large amount of uncomplexed chelants and increase in Cu leachability. Thus the combined use of EDDS and EDTA in multi-pulse washing is recommended for further studies. PMID- 29698829 TI - Influence of soil conditions on the distribution coefficients of 226Ra in natural soils. AB - In order to clarify some of the assumptions and approximations about the use of the distribution coefficient Kd for 226Ra in soils, a systematic study has been performed using centrifugation to extract the soil solution. The separated fractions of the soil solution have different kinetics with respect to the sorption process in the soil, which may in turn condition the final chemical composition and even the speciation of the radionuclides in solution. In the experimental design of this study three factors were considered: the moisture level in the incubation process, incubation time and the speed of centrifugation. Also, three levels were chosen for each factor. In order to analyze the influence of the structural characteristics of the soil, this study was performed with three textural fractions: coarse sand, fine sand, and silt and clay, obtained from an only soil. Also, the soil was naturally enriched with radionuclides of the 238U series. An analysis of variance (ANOVA) was performed in order to assess the influence of the factors studied on the distribution coefficient of 226Ra. The results indicate that different behaviors can be observed depending on the structural characteristic of the soil. In the case of particle size, the soil with the largest grain size showed that the incubation process parameters influence the equilibrium level achieved, while in the case of the smallest edaphic particles, radium is not homogeneously distributed in the soil solution and the Kd value is dependent on the speed of centrifugation. PMID- 29698830 TI - 7Be spatial and temporal pattern in southwest of Europe (Spain): Evaluation of a predictive model. AB - This study presents a comprehensive statistical analysis of the cosmogenic radioisotope 7Be measured in surface air in ten stations over Spain for a 9 years period (from January 2006 to December 2014). Besides the analysis of 7Be seasonal and inter-annual variability, 7Be frequency distributions and its correlations with meteorological variables observed in the 10 sampling sites were investigated. The second part of this paper focuses on a feasibility study for the application of the Artificial Neural Networks (ANNs) to predict monthly 7Be activity concentrations using meteorological variables, PM10 concentrations and the sunspot number as input parameters. Notwithstanding the low correlations found between 7Be and input parameter, the performance of the ANNs, as evaluated by the relevant statistical parameters, demonstrates their capability to correctly predict 7Be monthly activities in the 10 Spanish sampling sites. PMID- 29698831 TI - In situ, one step removal of ammonia from onshore and offshore formation water of petroleum production fields. AB - Fish, crustaceans and other living organisms are threatened due to disposal of harmful contaminants in sea water. Ammonia is considered one of harmful contaminants due to industrial activities of oil companies, where excess ammonia in the formation water is discharged into sea water. Electrochemical treatment (EC) was used in one step for total removal of ammonia and remediation of other contaminants. Three working electrodes were examined EC cell, aluminum, iron and modified electrode (Ti/IrO2). Graphite electrode was used as counter electrode in all processes of binary system. Both ionized and unionized ammonia of onshore (5.54 mg L-1) and off shore (110 mg L-1) were totally undetected after one step using all types of electrodes. The study was extended also to check the removal efficiency of other contaminants, where the analysis indicated the alleviation of them. Total suspended solid (TSS) of both onshore 64 mg L-1 and offshore 228 mg L 1 samples was reduced to 4 mg L-1. Total dissolved solids (TDS), chemical oxygen demand (COD) and biological oxygen demand (BOD) of high values, 232,000, 8500 and 2442 mg L-1 were also reduced to lower levels 18,400, 4000 and 1600 mg L-1, respectively. The formed sludge after EC treatment was also investigated using XRD. PMID- 29698832 TI - Effect of exposition to chlorpyrifos upon plasmatic cholinesterases, hematology and blood biochemistry values in Bothrops asper (Serpentes: Viperidae). AB - The terciopelo (Bothrops asper), is one of the most important venomous snakes in Costa Rica and common on agriculture where insecticides are frequently used for pest control. To assess the exposure to organophosphates on captive B. asper, an experiment using chlorpyrifos and butyrylcholinesterase (BChE), as a biomarker was conducted. In addition to BChE, hematology, aspartate aminotransferase (AST), total proteins (TP) and albumin were measured after exposure. Different concentrations of chlorpyrifos were used in Group A (0.1%) and B (1%), while the Control Group received distilled water; each group was composed of 5 snakes. Values of BChE, AST, TP, and albumin were measured before exposure, and at 6, 12, 24, 196, 360 and 528 h post-exposure. Hematology values were measured after 24 h post-exposure. As result, an important variation between subjects in all groups before exposure was obtained. Moreover, BChE activity showed 37% inhibition of Group A when compared to Control Group at 12 h post-exposure, and a higher inhibition of Group B (97%) related to Control Group, at 6 h post-exposure. Recovery of BChE occurred towards 528 h, never reaching initial values. Despite some variation in the rest of parameters used, a marked relative lymphopenia and monocytosis occurred at 24 h, assuming stress as the main cause. PMID- 29698833 TI - Electrochemical degradation of antibiotic levofloxacin by PbO2 electrode: Kinetics, energy demands and reaction pathways. AB - In this work, the electrochemical degradation of antibiotic levofloxacin (LFX) has been studied using a novel rare earth La, Y co-doped PbO2 electrode. The effect of applied current density, pH value and initial LFX concentration on the degradation performance were systematically evaluated. The results demonstrated that electrochemical oxidation of LFX over the La-Y-PbO2 electrode was highly effective and the reaction followed an apparent first-order kinetic model. Considering the degradation efficiency and energy efficiency, the relative optimal conditions are identified as current density 30 mA cm-2, pH 3 and initial LFX concentration 800 mg L-1. According to the identified products, a reaction mechanism has been proposed and the products were further oxidized to CO2, H2O, NH4+, NO3- and F-. A total of four aromatic intermediate products of LFX degradation were identified and the different structural changes to the LFX molecule included pepiperazinyl hydroxylation, decarboxylation and defluorination. PMID- 29698835 TI - Suppression of Wild-Type Amplification by Selectivity Enhancing Agents in PCR Assays that Utilize SuperSelective Primers for the Detection of Rare Somatic Mutations. AB - In PCR assays designed to detect rare somatic mutations, SuperSelective primers, by virtue of their short 3'-foot sequences, selectively initiate synthesis on mutant DNA target fragments, while suppressing the synthesis of related wild-type fragments, and the resulting threshold cycle reflects the quantity of mutant targets present. However, when there are <=10 mutant target fragments in a sample, the threshold cycle that is observed occurs so late that it can be confused with the threshold cycle that arises from samples that contain only abundant related wild-type fragments. We report here that the inclusion of the selectivity enhancing agents tetramethylammonium chloride or bis tetramethylammonium oxalate in SuperSelective PCR assays substantially suppresses the amplification of related wild-type fragments. As a result of this selective suppression, assay sensitivity is increased to such an extent that multiplex PCR assays can be performed in which it is highly unlikely that there will be a false positive or false-negative result. This advance provides a foundation for the development of rapid, low-cost, multiplex PCR assays for noninvasively assessing the presence of relevant mutations in cancer patients, thereby enabling individually appropriate therapy. PMID- 29698834 TI - Role of lncRNAs in ovarian cancer: defining new biomarkers for therapeutic purposes. AB - Long noncoding RNAs (lncRNAs) are a class of noncoding RNA, involved in regulation of diverse physiological and pathological processes. Ovarian cancer is the leading cause of death among all gynecological malignancies in the world and its underlying mechanism is still unclear. LncRNAs exhibit multiple biological functions in various stages of ovarian cancer development. We will discuss and summarize the new and important lncRNAs and their involvement in disease, which might represent promising therapeutic targets. Therapeutic intervention based on silencing or functional inhibition of target lncRNAs will be beneficial for ovarian cancer patients. PMID- 29698836 TI - System for Informatics in the Molecular Pathology Laboratory: An Open-Source End to-End Solution for Next-Generation Sequencing Clinical Data Management. AB - Next-generation sequencing (NGS) diagnostic assays increasingly are becoming the standard of care in oncology practice. As the scale of an NGS laboratory grows, management of these assays requires organizing large amounts of information, including patient data, laboratory processes, genomic data, as well as variant interpretation and reporting. Although several Laboratory Information Systems and/or Laboratory Information Management Systems are commercially available, they may not meet all of the needs of a given laboratory, in addition to being frequently cost-prohibitive. Herein, we present the System for Informatics in the Molecular Pathology Laboratory (SIMPL), a free and open-source Laboratory Information System/Laboratory Information Management System for academic and nonprofit molecular pathology NGS laboratories, developed at the Genomic and Molecular Pathology Division at the University of Chicago Medicine. SIMPL was designed as a modular end-to-end information system to handle all stages of the NGS laboratory workload from test order to reporting. We describe the features of SIMPL, its clinical validation at University of Chicago Medicine, and its installation and testing within a different academic center laboratory (University of Colorado), and we propose a platform for future community co development and interlaboratory data sharing. PMID- 29698837 TI - Chemo-enzymatic synthesis of furfuralcohol from chestnut shell hydrolysate by a sequential acid-catalyzed dehydration under microwave and Escherichia coli CCZU Y10 whole-cells conversion. AB - In this study, chemo-enzymatic synthesis of furfuralcohol from biomass-derived xylose was successfully demonstrated by a sequential acid-catalyzed dehydration under microwave and whole-cells reduction. After dry dewaxed chestnut shells (CNS, 75 g/L) was acid-hydrolyzed with dilute oxalic acid (0.5 wt%) at 140 degrees C for 40 min, the obtained CNS-derived xylose (17.9 g/L xylose) could be converted to furfural at 78.8% yield with solid acid SO42-/SnO2-Attapulgite (2.0 wt% catalyst loading) in the dibutyl phthalate-water (1:1, v:v) under microwave (600 W) at 180 degrees C for 10 min. In the dibutyl phthalate-water (1:1, v/v) media at 30 degrees C and pH 6.5, the furfural liquor (47.0 mM furfural) was biologically converted to furfuralcohol by recombinant Escherichia coli CCZU-Y10 whole-cells harboring an NADH-dependent reductase (PgCR) without extra addition of NAD+ and glucose, and furfural was completely converted to furfuralcohol after 2.5 h. Clearly, this one-pot synthesis strategy can be effectively used for furfuralcohol production. PMID- 29698838 TI - Kinetic modeling and microbial community analysis for high-rate biohydrogen production using a dynamic membrane. AB - This study investigated the kinetic parameters of high-rate continuous performance and biofilm layer formation in a H2-producing dynamic membrane bioreactor, composed of a continuously stirred tank reactor along with an external module containing polyester mesh with a pore size of 100 um. A maximum H2 production rate of 48.9 L/L-day and hydrogen yield of 2.8 mol/mol glucoseadded were attained at a hydraulic retention time of 3 h. The maximum specific growth rate and Monod constant were estimated as 14.92 d-1 and 1.02 g COD/L, respectively. During the entire operation without backwashing, the transmembrane pressure remained below 1.7 kPa, while tightly bound extracellular polymeric substances increased as the dynamic membrane was developed. Fluorescent in situ hybridization and quantitative polymerase chain reaction assays revealed that Clostridium butyricum was dominant in all samples; however, the biofilm had a higher proportion of Prevotella spp. than the fermentation liquor. PMID- 29698839 TI - Microbial nitrate removal in biologically enhanced treated coal gasification wastewater of low COD to nitrate ratio by coupling biological denitrification with iron and carbon micro-electrolysis. AB - Mixotrophic denitrification coupled biological denitrification with iron and carbon micro-electrolysis (IC-ME) is a promising emerging bioprocess for nitrate removal of biologically enhanced treated coal gasification wastewater (BECGW) with low COD to nitrate ratio. TN removal efficiency in R1 with IC-ME assisted was 16.64% higher than R2 with scrap zero valent iron addition, 23.05% higher than R3 with active carbon assisted, 30.51% higher than R4 with only active sludge addition, 80.85% higher than R5 utilizing single IC-ME as control. Fe2+ generated from IC-ME decreased the production of N2O and enriched more Nitrate reducing Fe(II) oxidation bacteria (NRFOB) Acidovorax and Thiobacillus, which could convert nitrate to nitrogen gas. And the presence of Fe3+, as the Fe2+ oxidation product, could stimulate the growth of Fe(III)-reducing strain (FRB) that indicated by redundancy analysis. Microbial network analysis demonstrated FRB Geothrix had a co-occurrence relationship with other bacteria, revealing its dominant involvement in nitrate removal of BECGW. PMID- 29698840 TI - Optimization of lutein production with a two-stage mixotrophic cultivation system with Chlorella sorokiniana MB-1. AB - The major purpose of this study was to investigate the effects of operational factors and bioprocess strategies on the mixotrophic cultivation of a microalgae Chlorella sorokiniana MB-1 for lutein production. Aeration with CO2 showed the highest biomass productivity and lutein productivity of 0.89 g/L/d and 3.49 mg/L/d, respectively. Semi-batch operation performed with 80% medium replacement ratio resulted in the highest biomass productivity and lutein productivity of 1.55 g/L/d and 5.51 mg/L/d, respectively. A two-stage strategy was developed to enhance the biomass production of the MB-1 strain in stage 1 with semi-batch mixotrophic culture and to optimize lutein accumulation in stage 2 under photoautotrophic conditions. The maximum biomass productivity and lutein productivity was 1.98 g/L/d and 7.62 mg/L/d, respectively, with a medium replacement ratio of 80% in stage 1. Compared with batch cultivation, the lutein productivity was enhanced by 32.7% for semi-batch operation alone and 85.9% for the semi-batch-integrated two-stage process. PMID- 29698841 TI - Role of Ca-bentonite to improve the humification, enzymatic activities, nutrient transformation and end product quality during sewage sludge composting. AB - This study was aimed to examine the response of Ca-bentonite (CB) amendment to improve the sewage sludge (SS) composting along with wheat straw (WS) as bulking agent. Five treatments (SS + WS) were mixed with or without blending of discrepant concentration of CB (2%, 4%, 6%, and 10%), respectively, and without CB added treatment applied as the control. The results showed that compared to control and 2%CB blended treatments, while the 6-10%CB -amended treatment indicated maximum enzymatic activities with the composting progress and highest organic matter degradation and loss. The amendment of 6-10%CB increased the humic acid, HA/FA ratio, DON, NH4+-N, NO3 and DOC but reduced the fulvic acids content and the maturity period by 2 weeks as compared to control. In addition, maturity parameters also confirmed that the highest seed germination was observed with the 10%CB applied compost followed by 6%CB, 4%CB and 2%CB applied treatments, respectively. PMID- 29698842 TI - The transformation of nitrogen during pressurized entrained-flow pyrolysis of Chlorella vulgaris. AB - The transformation of nitrogen in microalgae during entrained-flow pyrolysis of Chlorella vulgaris was systematically investigated at the temperatures of 600-900 degrees C and pressures of 0.1-4.0 MPa. It was found that pressure had a profound impact on the transformation of nitrogen during pyrolysis. The nitrogen retention in bio-char and its content in bio-oil reached a maximum value at 1.0 MPa. The highest conversion of nitrogen (50.25 wt%) into bio-oil was achieved at 1.0 MPa and 800 degrees C, which was about 7 wt% higher than that at atmospheric pressure. Higher pressures promoted the formation of pyrrolic-N (N-5) and quaternary-N (N-Q) compounds in bio-oil at the expense of nitrile-N and pyridinic N (N-6) compounds. The X-Ray photoelectron spectroscopy (XPS) and Fourier transform infrared spectroscopy (FTIR) results on bio-chars clearly evidenced the transformation of N-5 structures into N-6 and N-Q structures at elevated pressures. The nitrogen transformation pathways during pyrolysis of microalgae were proposed and discussed. PMID- 29698843 TI - Creatinine downregulates TNF-alpha in macrophage and T cell lines. AB - Creatinine is the breakdown product of creatine, a key participant in the generation of ATP and is traditionally considered to be a biologically inert waste product. Based on our earlier work, we analyzed the effects of creatinine hydrochloride on the expression of tumor necrosis factor-alpha (TNF-alpha), a pro inflammatory cytokine, in a human T cell line, as well as human and mouse macrophage cell lines. Exposing cells to creatinine hydrochloride significantly reduced TNF-alpha mRNA and protein levels compared to control-treated cultures in all cell lines tested. Lipopolysaccharide (LPS), a potent inducer of inflammation, was employed with in mouse macrophage cell lines to induce high levels of TNF-alpha in order to determine whether creatinine hydrochloride could reduce preexisting inflammation. Cells treated with LPS and creatinine hydrochloride had significantly reduced TNF-alpha levels compared to cells treated with LPS alone. As the NF-kappaB signaling pathway represents a major mechanism of TNF-alpha generation, nuclear extracts were examined for NF-kappaB pathway activation. Cells exposed to CRN had significantly lower levels of NF kappaB in the nucleus compared to control-treated cells. Together, these results support the hypothesis that CRN can alter anti-inflammatory responses by interfering with the activation of the NF-kappaB pathway. PMID- 29698844 TI - Increased practice of a standing motor sequence task in healthy young and healthy elders: Short communication. AB - BACKGROUND: Sequence-specific learning (SSL); the ability to implicitly integrate repeated sequences compared to random sequences during a motor sequence paradigm, is impaired in healthy elders (HE) compared to healthy young (HY). Prior studies have provided limited practice (small repetitions and only 1 to 3 days). RESEARCH QUESTION: Using a standing, postural control task we sought to assess if more practice (7 days) would remediate the differences observed in SSL for HE. METHODS: We used a continuous tracking task following a sinusoidal path of randomly presented random and repeated patterns. Root mean square error (RMSE) was the primary dependent variable, and the difference in RMSE between the random and repeated sequences was calculated to determine if SSL occurred. RESULTS: Improvement in SSL was documented as a decreasing value of the mean repeated sequence and less or no change in the random sequence. Eight HY and 8 HE practiced the repeated sequences 420 times over 7 days. No differences were observed between the groups on cognition, balance, and mobility. HE did not demonstrate the ability to integrate the repeated sequence on day 1, but with increased practice, they integrated the repeated sequence similar to HY by the end of practice. The results of this study suggest that sustained practice over 7 days remediated differences in performance of a standing, implicit, sequence specific task between HY and HE. SIGNIFICANCE: Clinically, it is important to provide individuals with sufficient practice amount to achieve integration of a standing task. Results suggest that older adults need more practice to demonstrate SSL. PMID- 29698845 TI - The effect of CSF drainage on ambulatory center of mass movement in idiopathic normal pressure hydrocephalus. AB - BACKGROUND: Although gait and balance disturbances are core symptoms of idiopathic normal pressure hydrocephalus (iNPH), the ambulatory center of mass (COM) movements in patients with iNPH remain unclear. We aimed to clarify the ambulatory COM movements using an accelerometer on the patients' lower torsos and to investigate the changes in COM movement after cerebrospinal fluid tap tests (TT) and shunt surgeries (SS). METHODS: Twenty-three patients with iNPH and 18 age-matched healthy controls (HCs) were recruited. A triaxial accelerometer was fixed with a belt onto each participant's torso at the L3 vertebra level. We assessed each patient's 10-m gait before TT, 3 days after TT, and 1 week after SS. RESULTS: Compared to the HCs, the patients exhibited decreased gait velocities, increased step numbers, and increased step times. Their movement trajectory amplitudes (i.e., the COM movements) were increased in the medial/lateral direction and decreased in the vertical direction. They also exhibited greater variability (measured as coefficients of variation) in step time and movement trajectory amplitude in both the medial/lateral and vertical directions. The patients' gait parameters were significantly improved after TT and SS. SIGNIFICANCE: Our results suggest that iNPH-associated gait disturbances could cause abnormal ambulatory COM movements and that these disturbances are mitigated by TT and SS. PMID- 29698846 TI - Expert monitoring and verbal feedback as sources of performance pressure. AB - The influence of monitoring-pressure and verbal feedback on the performance of the intrinsically stable bimanual coordination patterns of in-phase and anti phase was examined. The two bimanual patterns were produced under three conditions: 1) no-monitoring, 2) monitoring-pressure (viewed by experts), and 3) monitoring-pressure (viewed by experts) combined with verbal feedback emphasizing poor performance. The bimanual patterns were produced at self-paced movement frequencies. Anti-phase coordination was always less stable than in-phase coordination across all three conditions. When performed under conditions 2 and 3, both bimanual patterns were performed with less variability in relative phase across a wide range of self-paced movement frequencies compared to the no monitoring condition. Thus, monitoring-pressure resulted in performance stabilization rather than degradation and the presence of verbal feedback had no impact on the influence of monitoring pressure. The current findings are inconsistent with the predictions of explicit monitoring theory; however, the findings are consistent with studies that have revealed increased stability for the system's intrinsic dynamics as a result of attentional focus and intentional control. The results are discussed within the contexts of the dynamic pattern theory of coordination, explicit monitoring theory, and action-focused theories as explanations for choking under pressure. PMID- 29698847 TI - The universal and automatic association between brightness and positivity. AB - The present study investigates the hypothesis that brightness of colors is associated with positivity, postulating that this is an automatic and universal effect. The Implicit Association Test (IAT; Greenwald, McGhee, & Schwartz, 1998) was used in all studies. Study 1 used color patches varying on brightness, Study 2 used achromatic stimuli to eliminate the potential confounding effects of hue and saturation. Study 3 replicated Study 2 in a different cultural context (Japan vs. Austria), both studies also included a measure of explicit association. All studies confirmed the hypothesis that brightness is associated with positivity, at a significance level of p < .001 and Cohen's D varying from 0.90 to 3.99. Study 1-3 provided support for the notion that this is an automatic effect. Additionally, Study 2 and Study 3 showed that people also have an explicit association of brightness with positivity. However, as expected, our results also show that the implicit association was stronger than the explicit association. Study 3 shows clear support for the universality of our effects. In sum, our results support the idea that brightness is associated with positivity and that these associations are automatic and universal. PMID- 29698848 TI - Motor command inhibition and the representation of response mode during motor imagery. AB - Research on motor imagery proposes that overt actions during motor imagery can be avoided by proactively signaling subthreshold motor commands to the effectors and by invoking motor-command inhibition. A recent study by Rieger, Dahm, and Koch (2017) found evidence in support of motor command inhibition, which indicates that MI cannot be completed on the sole basis of subthreshold motor commands. However, during motor imagery, participants know in advance when a covert response is to be made and it is thus surprising such additional motor-command inhibition is needed. Accordingly, the present study tested whether the demand to perform an action covertly can be proactively integrated by investigating the formation of task-specific action rules during motor imagery. These task-specific action rules relate the decision rules of a task to the mode in which these rules need to be applied (e.g., if smaller than 5, press the left key covertly). To this end, an experiment was designed in which participants had to switch between two numerical judgement tasks and two response modes: covert responding and overt responding. First, we observed markers of motor command inhibition and replicated the findings of Rieger and colleagues. Second, we observed evidence suggesting that task-specific action rules are created for the overt response mode (e.g., if smaller than 5, press the left key). In contrast, for the covert response mode, no task-specific action rules are formed and decision rules do not include mode specific information (e.g., if smaller than 5, left). PMID- 29698849 TI - Synthesis of glyceryl glycosides related to A-type prymnesin toxins. AB - A suite of glycosylated glycerol derivatives representing various fragments of the glycosylated ichthyotoxins called prymnesins were chemically synthesised. Glycerol was used to represent a small fragment of the prymnesin backbone, and was glycosylated at the 2 degrees position with the sugars currently reported to be present on prymnesin toxins. Neighbouring group participation was utilised to synthesise 1,2-trans-glycosides. SnCl2-promoted glycosylation with furanosyl fluorides gave 1,2-cis-furanosides with moderate stereocontrol, whilst TMSOTf promoted glycosylation with a furanosyl imidate gave a 1,2-cis-furanoside with good stereocontrol. The chemical synthesis of two larger glyceryl diglycoside fragments of prymnesin-1, glycosylated with alpha-L-arabinopyranose and alpha-? ribofuranose, is also described. As the stereochemistry of the prymnesin backbones at this region is undefined, both the 2R- and 2S- glycerol isomers were synthesised. The separated diastereoisomers were distinguished by comparing NOESY NMR with computational models. PMID- 29698851 TI - Transfemoral amputee intact limb loading and compensatory gait mechanics during down slope ambulation and the effect of prosthetic knee mechanisms. AB - BACKGROUND: Intact limb knee osteoarthritis is a prevalent secondary disability in transfemoral amputees. Walking down a ramp may increase this risk due to excessive limb loading. We sought to determine whether intact limb loading differed between transfemoral amputees and controls during down slope ambulation, and the compensatory strategies transfemoral amputees used to modify intact limb loading. Secondarily, we sought to determine the effect of prosthetic knee type. METHODS: Five unilateral transfemoral amputees and five non-amputee controls walked down a ramp and the following outcome measures were compared between amputees and controls and across prosthetic knee type (C-leg versus Power Knee): step length, walking speed, leading limb ground reaction forces, and trailing and leading limb ankle and knee energy absorption. Linear mixed effects regression was used to test for association between gait variables and limb. FINDINGS: There were no significant differences in intact limb loading between amputees and controls or between prosthetic knee types. Transfemoral amputees walked slower (C leg - control = -0.29 m/s; P = 0.008, Power Knee - control = -0.38 m/s; P < 0.001) with a shorter intact limb step length (C-leg - control = -0.12 m/s; P < 0.001, Power Knee - control = -0.16 m/s; P < 0.001). The prosthetic trailing limb ankle absorbed less energy throughout stance than the trailing limb in controls (C-leg-control = -0.22 J/kg; P < 0.001, Power Knee - control = -0.22 J/kg; P < 0.001). INTERPRETATION: Intact limb loading in transfemoral amputees is equivalent to controls during down ramp ambulation, in spite of reduced prosthetic trailing limb energy absorption. The primary compensatory strategies include a reduced ambulation speed and intact limb step length, which reduces center of mass velocity at heel contact. PMID- 29698850 TI - Structural elements of stromal interaction molecule function. AB - Stromal interaction molecule (STIM)-1 and -2 are multi-domain, single-pass transmembrane proteins involved in sensing changes in compartmentalized calcium (Ca2+) levels and transducing this cellular signal to Orai1 channel proteins. Our understanding of the molecular mechanisms underlying STIM signaling has been dramatically improved through available X-ray crystal and solution NMR structures. This high-resolution structural data has revealed that intricate intramolecular and intermolecular protein-protein interactions are involved in converting STIMs from the quiescent to activation-competent states. This review article summarizes the current high resolution structural data on specific EF hand, sterile alpha motif and coiled-coil interactions which drive STIM function in the activation of Orai1 channels. Further, the work discusses the effects of post-translational modifications on the structure and function of STIMs. Future structural studies on larger STIM:Orai complexes will be critical to fully defining the molecular bases for STIM function and how post-translational modifications influence these mechanisms. PMID- 29698852 TI - The trabecular effect: A population-based longitudinal study on age and sex differences in bone mineral density and vertebral load bearing capacity. AB - BACKGROUND: Approximately 16-24% of postmenopausal women are affected by vertebral fractures, negatively affecting their quality of life. Trabecular and cortical bones in vertebrae decline differently with age, thus having a distinct impact on vertebral failure loads. The purpose of this study was to investigate the effect of trabecular and cortical volumetric bone mineral density loss over time on estimated failure loads; and to evaluate the effect of sex and age. METHOD: Fracture properties from a cohort of 82 patients were evaluated for L1-L3 vertebrae at baseline and 6th year using an image-based method that implements axial rigidity analysis. Cortical and trabecular volumetric bone mineral density were obtained, as well as their individual contribution to total failure load. Regression analyses were performed to determine the effect of age and sex on volumetric bone mineral density and failure loads. FINDINGS: Decline in trabecular and cortical volumetric bone mineral density, and failure load was sex dependent (p <= 0.0095). Cortical and trabecular volumetric bone mineral density reduced 2.08 (g/cm3)/year and 2.02 (g/cm3)/year, respectively. A 1012 N difference in failure load, ~70% attributed to trabecular bone, was found between men and women of similar age. Over 6 years, this difference increased by 287 N. Areal bone mineral density measured by dual X-ray absorptiometry explained ~60% of the vertebral failure load. INTERPRETATION: Trabecular bone has a significantly greater effect than cortical bone on the structural integrity and load bearing capacity of vertebrae. This might lead to a higher incidence of fragility fractures in osteoporotic women. Our non-invasive, quantitative computed tomography image-based approach may improve prevention, monitoring, and management of fractures. PMID- 29698853 TI - Upper-limb biomechanical analysis of wheelchair transfer techniques in two toilet configurations. AB - BACKGROUND: Using proper technique is important for minimizing upper limb kinetics during wheelchair transfers. The objective of the study was to 1) evaluate the transfer techniques used during toilet transfers and 2) determine the impact of technique on upper limb joint loading for two different toilet configurations. METHODS: Twenty-six manual wheelchair users (23 men and 3 women) performed transfers in a side and front wheelchair-toilet orientation while their habitual transfer techniques were evaluated using the Transfer Assessment Instrument. A motion analysis system and force sensors were used to record biomechanical data during the transfers. FINDINGS: More than 20% of the participants failed to complete five transfer skills in the side setup compared to three skills in the front setup. Higher quality skills overall were associated with lower peak forces and moments in both toilet configurations (-0.68 < r < 0.40, p < 0.05). In the side setup, participants who properly placed their hands in a stable position and used proper leading handgrips had lower shoulder resultant joint forces and moments than participants who did not perform these skills correctly (p <= 0.04). In the front setup, positioning the wheelchair within three inches of the transfer target was associated with reduced peak trailing forces and moments across all three upper limb joints (p = 0.02). INTERPRETATION: Transfer skills training, making toilet seats level with the wheelchair seat, positioning the wheelchair closer to the toilet and mounting grab bars in a more ideal location for persons who do sitting pivot transfers may facilitate better quality toilet transfers. PMID- 29698854 TI - Avian leukosis virus subgroup J promotes cell proliferation and cell cycle progression through miR-221 by targeting CDKN1B. AB - Avian leukosis virus subgroup J (ALV-J), a highly oncogenic retrovirus, causes leukemia-like proliferative diseases in chickens. microRNAs post transcriptionally suppress targets and are involved in the development of various tumors. We previously showed that miR-221 is upregulated in ALV-J-induced tumors. In this study, we analyzed the possible function of miR-221 in ALV-J tumorigenesis. The target validation system showed that CDKN1B is a target of miR 221 and is downregulated in ALV-J infection. As CDKN1B arrests the cell cycle and regulates its progression, we analyzed the proliferation of ALV-J-infected DF-1 cells. ALV-J-infection-induced DF1 cell derepression of G1/S transition and overproliferation required high miR-221 expression followed by CDKN1B downregulation. Cell cycle pathway analysis showed that ALV-J infection induced DF-1 cell overproliferation via the CDKN1B-CDK2/CDK6 pathway. Thus, miR-221 may play an important role in ALV-J-induced aggressive growth of DF-1 cells; these findings have expanded our insights into the mechanism underlying ALV-J infection and tumorigenesis. PMID- 29698855 TI - Use of gamma radiation for inactivating Salmonella spp., Escherichia coli O157:H7 and Listeria monocytogenes in tahini halva. AB - Tahini halva is a traditional sweet product that is consumed with bread in different countries. It is a low water activity (aw) product basically made by mixing and cooking tahini, sugar, citric acid and Saponaria officinalis root extract together. Tahini halva maybe contaminated with foodborne pathogens during any stage of production from tahini and other raw ingredients, workers, environment or contact surfaces. The objectives of the study were to i) investigate the efficacy of gamma radiation to inactivate Salmonella spp., Escherichia coli O157:H7 and Listeria monocytogenes in tahini halva, ii) evaluate the effect of pre-irradiation storage (0, 7 and 30 days at 21 degrees C) of tahini halva on the sensitivity of these microorganisms toward gamma radiation, and iii) evaluate the effect of post-irradiation storage of tahini halva for up to 6 months on the their survival characteristics. Tahini halva samples were inoculated with Salmonella spp., E. coli O157:H7 and L. monocytogenes separately then stored at 21 degrees C for 0, 7 and 30 days prior to irradiation at 0-4 KGy and for up to 6 months after irradiation at 4 KGy. Salmonella spp. were the most irradiation resistance among the tested microorganisms. Irradiation (0.8-4.0 KGy) reduced the bacteria in samples stored for 0, 7 and 30 days pre-irradiation in the range of 0.43-2.11, 0.45-2.68 and 0.52-2.7 log10 CFU/g for Salmonella spp., 0.55-3.08, 0.66-3.00 and 0.60-2.80 log10 CFU/g for E. coli O157:H7, and 0.69 2.96, 0.86-4.30, 0.62-3.29 log10 CFU/g for L. monocytogenes, respectively. The D10-value, the irradiation dose needed to inactivate 1 log10 of pathogen, was 1.83, 1.47 and 1.50 KGy for Salmonella spp., 1.28, 1.32 and 1.48 KGy for E. coli O157:H7, and 1.33, 0.94 and 1.27 KGy for L. monocytogenes in pre-irradiation stored samples for 0, 7 and 30 days, respectively. Post-irradiation storage was efficient in decreasing the levels of the microorganisms ca. >=2 log10 CFU/g in the first month and to undetected level after the second month of storage but enrichment results showed that Salmonella spp. and L. monocytogenes were detected in the samples until of the end of storage period. The study demonstrates that gamma radiation can be applied to inactivate of foodborne pathogens in tahini halva. Irradiation dose at 4 KGy can reduce Salmonella spp., E. coli O157:H7 and L. monocytogenes in tahini halva by 2-3 log10 CFU/g. Storage of tahini halva before or after irradiation may reduce the risk of foodborne pathogens in the product. PMID- 29698856 TI - A meta-barcoding approach to assess and compare the storage temperature-dependent bacterial diversity of gilt-head sea bream (Sparus aurata) originating from fish farms from two geographically distinct areas of Greece. AB - Bacterial diversity of whole gilt-head sea bream (Sparus aurata L. 1758) originating from Ionian and Aegean Sea aquaculture farms and stored at 0 (ice), 4 and 8 degrees C was determined by 16S rRNA gene amplicon sequencing method using the Illumina's MiSeq platform. The composition of Aerobic Plate Counts (APC) was also monitored by 16S rRNA gene sequencing. The rejection time point of sea bream from either area, as determined by sensory evaluation, was about 14, 6 and 3 days at 0, 4 and 8 degrees C, respectively. APC was approximately 4.5 log cfu/g at day 0 and ranged from 7.5 to 8.5 log cfu/g at sensory rejection. Culture-depended analysis showed that Pseudomonas and Shewanella were the most abundant microorganisms grown on plates for both seas. Moreover, culture-independent analysis of DNA extracted directly from fish flesh showed that sea bream originating from different geographical areas exhibited different bacterial diversity. Pseudomonas and Psychrobacter were the dominant microorganisms of chill-stored fish from Ionian (apart from 8 degrees C, where Carnobacterium dominated) and Aegean Sea, respectively. In addition, small changes of storage temperature greatly affected bacterial microbiota of stored fish. Various bacterial species, not detected by conventional microbiological methods, were also revealed through 16S amplicon sequencing. In conclusion, the use of NGS approach is a promising methodology for assessing bacterial diversity of sea bream originating from different geographical areas and stored at various temperatures. PMID- 29698857 TI - Research on the enhancement of biological nitrogen removal at low temperatures from ammonium-rich wastewater by the bio-electrocoagulation technology in lab scale systems, pilot-scale systems and a full-scale industrial wastewater treatment plant. AB - In cold areas, nitrogen removal performance of wastewater treatment plants (WWTP) declines greatly in winter. This paper systematically describes the enhancement effect of a periodic reverse electrocoagulation technology on biological nitrogen removal at low temperatures. The study showed that in the lab-scale systems, the electrocoagulation technology improved the biomass amount, enzyme activity and the amount of nitrogen removal bacteria (Nitrosomonas, Nitrobacter, Paracoccus, Thauera and Enterobacter). This enhanced nitrification and denitrification of activated sludge at low temperatures. In the pilot-scale systems, the electrocoagulation technology increased the relative abundance of cold-adapted microorganisms (Luteimonas and Trueperaceae) at low temperatures. In a full-scale industrial WWTP, comparison of data from winter 2015 and winter 2016 showed that effluent chemical oxygen demand (COD), NH4+-N, and NO3--N reduced by 10.37, 3.84, and 136.43 t, respectively, throughout the winter, after installation of electrocoagulation devices. These results suggest that the electrocoagulation technology is able to improve the performance of activated sludge under low temperature conditions. This technology provides a new way for upgrading of the performance of WWTPs in cold areas. PMID- 29698858 TI - Cell membrane-bound CD200 signals both via an extracellular domain and following nuclear translocation of a cytoplasmic fragment. AB - In previous studies we had reported that the immunosuppressive cell membrane bound molecule CD200 is released from the cell following cleavage by matrix metalloproteases, with the released soluble CD200 acting as an immunosuppressant following binding to, and signaling through, its cognate receptor CD200R expressed on target cells. We now show that although the intracellular cytoplasmic tail (CD200C-tail) of CD200 has no consensus sites for adapter molecules which might signal the CD200+ cell directly, cleavage of the CD200C tail from the membrane region of CD200 by a consensus gamma-secretase, leads to nuclear translocation and DNA binding (identified by chromatin immunoprecipitation followed by sequencing, Chip-sequencing) of the CD200C-tail. Subsequently there occurs an altered expression of a limited number of genes, many of which are transcription factors (TFs) known to be associated with regulation of cell proliferation. Altered expression of these TFs was also prominent following transfection of CD200+ B cell lines and fresh patient CLL cells with a vector construct containing the CD200C-tail. Artificial transfection of non CD200+ Hek293 cells with this CD200C-tail construct resulted in altered expression of most of these same genes. Introduction of a siRNA for one of these TFs, POTEA, reversed CD200C-tail regulation of altered cell proliferation. PMID- 29698859 TI - Design, synthesis and pharmacological evaluation of ALK and Hsp90 dual inhibitors bearing resorcinol and 2,4-diaminopyrimidine motifs. AB - Rather than by directly focusing on the ever-changing ALK mutants, here we report an alternative strategy to overcome the drug resistance caused by treatment of ALK inhibitors by developing ALK and Hsp90 dual targeting inhibitors. Since Hsp90 is a molecular chaperone that regulates the maturation, activation and stability of numerous "client proteins" including ALK, dual targeting ALK and Hsp90 may bring more benefits and efficacy against drug resistance of ALK inhibitors. By using our previously developed ALK inhibitor 6 and the clinical Hsp90 inhibitors AUY922 or AT13387 as the templates, we developed several series of resorcinol tethered 2,4-diaminopyrimidines as ALK/Hsp90 dual inhibitors bearing various linkers at different linking sites. Compound 10h and 10j showed high potency against ALK (17.3 vs 9.8 nM) and Hsp90alpha (100 vs 40 nM). They also have high potency against ALK resistant mutants, especially the gatekeeper mutation ALKL1196M. Both compounds showed strong antiproliferative activity against the ALK-addictive H3122 cells (11 vs 13 nM). The dual functioning mechanism is further confirmed by their down-regulation of the Hsp90 clients ALK and AKT, and up-regulation of the chaperone protein Hsp70 in H3122 cells. PMID- 29698860 TI - Design, synthesis and anthelmintic activity of 7-keto-sempervirol analogues. AB - The plant-derived, diterpenoid 7-keto-sempervirol was recently reported to display moderate activity against larval stages of Schistosoma mansoni (IC50 = 19.1 MUM) and Fasciola hepatica (IC50 = 17.7 MUM), two related parasitic blood and liver flukes responsible for the neglected tropical diseases schistosomiasis and fascioliasis, respectively. Here, we aimed to increase the potency of 7-keto sempervirol by total synthesis of 30 structural analogues. Subsequent screening of these new diterpenoids against juvenile and adult lifecycle stages of both parasites as well as the human HepG2 liver cell line and the bovine MDBK kidney cell line revealed structure-activity relationship trends. The most active analogue, 7d, displayed improved dual anthelmintic activity over 7-keto sempervirol (IC50 ~ 6 MUM for larval blood flukes; IC50 ~ 3 MUM for juvenile liver flukes) and moderate selectivity (SI ~ 4-5 for blood flukes, 8-13 for liver flukes compared to HepG2 and MDBK cells, respectively). Phenotypic studies using scanning electron microscopy revealed substantial tegumental alterations in both helminth species, supporting the hypothesis that the parasite surface is one of the main targets of this family of molecules. Further modifications of 7d could lead to greater potency and selectivity metrics resulting in a new class of broad spectrum anthelmintic. PMID- 29698861 TI - LC-MS based urinary metabolomics study of the intervention effect of aloe-emodin on hyperlipidemia rats. AB - Hyperlipidemia has been highlighted to be one of the most prominent and global chronic condition nowadays. Daming capsule (DMC), a traditional Chinese medicine (TCM) preparation, has treated hyperlipidemia on clinic in China for decades. Our recent study showed that aloe-emodin (AE) is one of the main bioactive components in DMC. Therefore, the present study aims to further investigate the lipid lowering effect by serum biochemistry and histopathological examination, and reveal the underlying mechanisms by urinary metabolomics approach. After oral administration of AE for 6 weeks, the total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-c) levels in 50 and 100 mg/kg AE groups were both decreased significantly (P < 0.05 and P < 0.001). An ultra-performance liquid chromatography/electrospray ionization quadruple time-of-flight mass spectrometry (UPLC-ESI-QTOF-MS) followed by principal components analysis (PCA), partial least squares- discriminant analysis (PLS-DA), orthogonal partial least squares discriminant analysis (OPLS-DA), correlation analysis, heat map, and KEGG pathways was employed to identify 26 potential biomarkers. Twenty three among them were restored by AE including L-citrulline, 6-methylaminopurine, imidazoleacetic acid riboside, N-acetylhistamine, 3-methyladenine, 1 methyladenosine, dopamine, N1-methyl-4-pyridone-3-carboxamide, formylanthranilic acid, 4-pyridoxate, cAMP, salsolinol, isethionate, d-ribonic acid, 3-sulfolactic acid, vitamin C, mesaconic acid, sulfosalicylic acid, salicyluric acid, N acetylanthranilic acid, 4,6- Dihydroxyquinoline, sebacic acid and hyocholic Acid. The related metabolic pathways include TCA cycle, the metabolism of amino acids, taurine, B vitamins, purines and pyrimidines. The results indicate that AE has a favorable therapeutic effect on HFD-induced hyperlipidemia by adjusting the metabolic disorders. Notably, urinary metabolomics combined with pattern recognition analysis provides a powerful and reliable approach into the research and development of TCM and phytochemicals. PMID- 29698862 TI - Magnetic solid-phase extraction based on Fe3O4/graphene nanocomposites for enantioselective determination of representative profens in the environmental water samples and molecular docking study on adsorption mechanism of graphene. AB - In this work, a nanocomposite, Fe3O4/graphene was prepared and characterized. Five profens (including ibuprofen, flurbiprofen, pranoprofen, indoprofen and loxoprofen sodium) were extracted from three environmental water samples by using the synthetic Fe3O4/graphene, followed by simultaneous determination of the enantiomers on a Chiralcel OJ-RH column coupled with a triple quadrupole mass spectrometry. Factors affecting the extraction efficiency, such as amount of adsorbents, solution pH, ionic strength, type and volume of desorption solvent, as well as elution time were thoroughly investigated. Method validation showed high sensitivity with method quantification limits in the range of 8.49-26.3 ng/L. Satisfactory recovery (73.6-90.2%), good intra-day precision (RSD 3.2-9.7%) and inter-day precision (RSD 5.2-10%) were also obtained. Furthermore, possible interactions between analyte and graphene, such as electrostatic attraction, charge-pi interaction, hydrophobic interaction and pi-pi stacking were discussed by combining the experiment results and molecular docking study, which provided a new insight into the adsorption mechanism of graphene. PMID- 29698863 TI - Development and validation of a sensitive LC MS/MS method for the measurement of the checkpoint kinase 1 inhibitor prexasertib and its application in a cerebral microdialysis study. AB - LC MS/MS methods to measure prexasertib in mouse plasma and Ringer's solution containing 0.5% BSA (Ringer's/BSA) were developed and validated. Liquid-liquid extraction with tert-butyl methyl ether was used to extract prexasertib from mouse plasma and Ringer's/BSA. Reverse phase chromatography with gradient elution was performed to separate prexasertib from the endogenous interference in the matrix, followed by MS detection using positive ion MRM mode. The initial calibration curve for mouse plasma samples ranged from 1 to 500 ng/ml, and after validation of that curve and use in a preliminary study another calibration curve (0.2-200 ng/ml) was created to enable the quantitation of prexasertib at lower concentrations. The method described was precise and accurate with %CV in precision studies of <= 6.7% and accuracies within 95.0-110% of nominal target concentration across all concentrations tested for both matrices. This validated method was successfully applied in the analysis of prexasertib in mouse plasma and dialysate samples collected during a cerebral microdialysis study. PMID- 29698864 TI - Cost-Effectiveness Analysis of the Introduction of HPV Vaccination of 9-Year-Old Girls in Iran. AB - OBJECTIVES: To estimate the cost effectiveness of introducing the quadrivalent human papillomavirus (HPV) vaccine into the national immunization program of Iran. METHODS: The CERVIVAC cost-effectiveness model was used to calculate incremental cost per averted disability-adjusted life-year by vaccination compared with no vaccination from both governmental and societal perspectives. Calculations were based on epidemiologic parameters from the Iran National Cancer Registry and other national data sources as well as from literature review. We estimated all direct and indirect costs of cervical cancer treatment and vaccination program. All future costs and benefits were discounted at 3% per year and deterministic sensitivity analysis was used. RESULTS: During a 10-year period, HPV vaccination was estimated to avert 182 cervical cancer cases and 20 deaths at a total vaccination cost of US $23,459,897; total health service cost prevented because of HPV vaccination was estimated to be US $378,646 and US $691,741 from the governmental and societal perspective, respectively. Incremental cost per disability-adjusted life-year averted within 10 years was estimated to be US $15,205 and US $14,999 from the governmental and societal perspective, respectively, and both are higher than 3 times the gross domestic product per capita of Iran (US $14,289). Sensitivity analysis showed variation in vaccine price, and the number of doses has the greatest volatility on the incremental cost-effectiveness ratio. Using a two-dose vaccination program could be cost-effective from the societal perspective (incremental cost-effectiveness ratio = US $11,849). CONCLUSIONS: Introducing a three-dose HPV vaccination program is currently not cost-effective in Iran. Because vaccine supplies cost is the most important parameter in this evaluation, considering a two-dose schedule or reducing vaccine prices has an impact on final conclusions. PMID- 29698865 TI - MOPEDS: The high cost of cheap and poorly legislated transportation for negligent drivers. AB - INTRODUCTION: This study evaluates the impact of moped crashes in North Carolina, a state with lenient moped legislation by(1) describing the characteristics of moped crashes and (2) estimating the cost burden of moped-related injuries. METHODS: Health and public records of moped crash subjects treated at our hospital were reviewed. Direct costs were billed hospital charges. Indirect costs based on age and outcomes were calculated. RESULTS: Between 2008-2013, 368 subjects were involved in 373 moped crashes. 52% of drivers were intoxicated. 38% of drivers had prior DWIs and 26% had prior revoked licenses. Hospitalized subjects (n = 305) had a combined 2687 hospital days, 695 ICU days and 449 trips to the operating room for treatment of their injuries. Average hospital charges were $70,561 per subject. Total direct and indirect costs of moped injuries were over $26 million and $81 million respectively. Medicaid absorbed most of the direct cost ($13.7 M). Estimated direct cost of moped crashes across the state totaled $133 million. CONCLUSION: Healthcare and financial ramifications of moped collisions are substantial. Laws governing moped drivers and stricter penalties for intoxicated drivers are needed. PMID- 29698866 TI - Wrong-way driving crashes: A random-parameters ordered probit analysis of injury severity. AB - In the context of traffic safety, whenever a motorized road user moves against the proper flow of vehicle movement on physically divided highways or access ramps, this is referred to as wrong-way driving (WWD). WWD is notorious for its severity rather than frequency. Based on data from the U.S. National Highway Traffic Safety Administration, an average of 355 deaths occur in the U.S. each year due to WWD. This total translates to 1.34 fatalities per fatal WWD crashes, whereas the same rate for other crash types is 1.10. Given these sobering statistics, WWD crashes, and specifically their severity, must be meticulously analyzed using the appropriate tools to develop sound and effective countermeasures. The objectives of this study were to use a random-parameters ordered probit model to determine the features that best describe WWD crashes and to evaluate the severity of injuries in WWD crashes. This approach takes into account unobserved effects that may be associated with roadway, environmental, vehicle, crash, and driver characteristics. To that end and given the rareness of WWD events, 15 years of crash data from the states of Alabama and Illinois were obtained and compiled. Based on this data, a series of contributing factors including responsible driver characteristics, temporal variables, vehicle characteristics, and crash variables are determined, and their impacts on the severity of injuries are explored. An elasticity analysis was also performed to accurately quantify the effect of significant variables on injury severity outcomes. According to the obtained results, factors such as driver age, driver condition, roadway surface conditions, and lighting conditions significantly contribute to the injury severity of WWD crashes. PMID- 29698867 TI - Polymeric nano-shielded islets with heparin-polyethylene glycol in a non-human primate model. AB - Intraportal pancreatic islet transplantation incurs huge cell losses during its early stages due to instant blood-mediated inflammatory reactions (IBMIRs), which may also drive regulation of the adaptive immune system. Therefore, a method that evades IBMIR will improve clinical islet transplantation. We used a layer-by layer approach to shield non-human primate (NHP) islets with polyethylene glycol (nano-shielded islets, NSIs) and polyethylene glycol plus heparin (heparin nano shielded islets; HNSIs). Islets ranging from 10,000 to 20,000 IEQ/kg body weight were transplanted into 19 cynomolgus monkeys (n = 4, control; n = 5, NSI; and n = 10, HNSI). The mean C-peptide positive graft survival times were 68.5, 64 and 108 days for the control, NSI and HNSI groups, respectively (P = 0.012). HNSI also reduced the factors responsible for IBMIR in vitro. Based on these data, HNSIs in conjunction with clinically established immunosuppressive drug regimens will result in superior outcomes compared to those achieved with the current protocol for clinical islet transplantation. PMID- 29698868 TI - Combinational strategy for high-performance cancer chemotherapy. AB - The clinical outcomes of conventional mono-chemotherapy of cancers are usually far from satisfactory due to some issues such as tumor heterogeneity and resistance to chemotherapeutic drugs. With the increasing knowledge of molecular signal pathways and pathological mechanisms involved in the initiation and progression of cancers, collaborative strategies have been elaborated to optimize therapeutic outcomes. This review surveys the most recent advances in combination therapy including combination chemotherapy, chemotherapy plus gene therapy, chemotherapy plus phototherapy, as well as chemotherapy plus immunotherapy. Additionally, chemotherapy-involved multiple therapy that merges various therapeutic modalities is also presented. We try to elicit the rationales of applying these combinational formulations for cancer chemotherapy, which might provide new guidelines for high-performance cancer treatments. PMID- 29698869 TI - Highly enhanced cancer immunotherapy by combining nanovaccine with hyaluronidase. AB - Tumor vaccine has been one of the research hotspots for cancer immunotherapy in recent years. By introducing tumor antigens into the body, the patient's own immune system will be specifically activated to induce effective immune responses for controlling or eliminating the malignant tumor cells. In this study, a simple nanovaccine was developed to induce antigen-specific anti-tumor immune responses. Polycationic polyethylenimine (PEI) was utilized to co-deliver the antigen ovalbumin (OVA) and the adjuvant unmethylated cytosine-phosphate-guanine (CpG) by electrostatic binding. The positively charged PEI could be beneficial to augment the PEI/CpG/OVA nanovaccine uptake in dendritic cells (DCs) and facilitate the endosomal escape of the nanovaccine for antigen delivering into the cytoplasm. The nanovaccine showed significant stimulation on DCs' maturation in vitro, and it was further applied for in vivo anti-tumor immunotherapy. To enhance the tumor infiltration of the nanovaccine-generated tumor-specific T cells, hyaluronidase (HAase) was employed to increase the permeability of the tumor tissues by breaking down the hyaluronan (HA) in the extracellular matrix (ECM) of tumors. Highly enhanced in vivo anti-tumor therapeutic efficiency was achieved by combining the PEI/CpG/OVA nanovaccine with HAase, which was attributed to the increased quantity of OVA-specific T cells in tumor tissues. The combination of nanovaccine with HAase has offered a simple and efficient strategy for inducing powerful anti-tumor effect in cancer immunotherapy. PMID- 29698870 TI - Measuring patient respect in the intensive care unit: Validation of the ICU RESPECT instrument. AB - PURPOSE: To validate a brief index of patient and family experiences of respect in the intensive care unit. MATERIAL AND METHODS: A survey including the 10-item ICU-RESPECT scale was administered to patients and family members in one ICU at a large west coast academic medical center. Confirmatory psychometric analyses were conducted. RESULTS: Based on 142 completed surveys, factor analysis confirmed a unidimensional scale with an alpha of 0.90, an Eigen value of 4.9, and factor loadings from 0.50 to 0.86. The mean total score was 7.59 (SD = 3.06) out of a maximum of 10. Among the 106 surveys that included demographics, overall scores did not differ by type of respondent (patient or family) or by gender. There were modest differences in overall scores by patient race. Two individual items differed by type of respondent. CONCLUSIONS: The ICU-RESPECT index demonstrates reliability and concurrent validity in a different ICU setting from the one where the index was developed. Future research should assess the scale's predictive validity, and factors associated with variation in scores. As hospitals address patient experience more broadly in response to national metrics, the index could identify particular behaviors or ICUs that would benefit from interventions to enhance respectful treatment. PMID- 29698871 TI - Peer victimization and substance use: Understanding the indirect effect of depressive symptomatology across gender. AB - OBJECTIVE: Peer victimization in school is common, with emerging literature suggesting that it may also increase risk for substance abuse. Yet, little is known about the underlying mechanisms within this risk pathway. The objective of this study is to use a prospective 3-wave design to examine the mediating role of depressive symptomatology on the relationship between peer victimization and substance use, as well as examine if the pathway varies based on gender. METHOD: 801 youth between 6th and 12th grade completed surveys across three years, which included measures on school peer victimization, depression symptomatology and substance use. Models tested the mediational pathway between victimization, depressive symptoms, and substance use. Models were stratified by gender. RESULTS: Controlling for grade and the effect of each variable across waves, a significant indirect effect of peer victimization on substance use through depressive symptoms was found for females, with a non-significant indirect effect for males. CONCLUSION: Results suggest that female youth who are victimized by peers engage in substance use behaviors, at least in part, due to increases in depressive symptoms. Given its effect on depression, female victims may therefore benefit from coping skills training that targets emotion regulation and distress tolerance skills in order to combat increased risk for substance use behaviors as a coping response to their victimization. Further research is warranted to better understand the risk pathway for male youth who also experience peer victimization. PMID- 29698872 TI - A nested case-control study of polychlorinated biphenyls, organochlorine pesticides, and thyroid cancer in the Janus Serum Bank cohort. AB - BACKGROUND: Polychlorinated biphenyls (PCBs) and organochlorine pesticides have been associated with altered thyroid hormone levels in humans, but their relationship with thyroid cancer is unknown. METHODS: We conducted a nested case control study of thyroid cancer in the Norwegian Janus Serum Bank cohort using pre-diagnostic blood samples from 1972 to 1985. Incident thyroid cancer (n = 108) was ascertained through 2008. Controls were matched 2:1 by age, date of blood draw, gender, and county. We used gas chromatography/mass spectrometry to quantify 36 PCB congeners and metabolites of pesticides DDT, chlordane, hexachlorocyclohexane, and hexachlorobenzene. PCBs and pesticide metabolites were evaluated individually and summed by degree of chlorination and parent compound, respectively. Odds ratios (OR) and 95% confidence intervals (CI) were computed using conditional logistic regression per specified increase in lipid-adjusted concentration. We additionally stratified analyses by birth cohort (1923-1932, 1933-1942, 1943-1957). RESULTS: Increasing concentration of DDT metabolites (ORper 1000 ng/g = 0.80, 95%CI = 0.66-0.98) was inversely associated with thyroid cancer. Associations for PCBs were null or in inverse direction. We observed interactions for total PCBs, moderately-chlorinated PCBs, and chlordane metabolites with birth cohort (p <= 0.04). Among participants born 1943-1957, total PCBs (ORper 100 ng/g = 1.25, 95%CI = 1.00-1.56), moderately-chlorinated PCBs (ORper 100 ng/g = 1.31, 95%CI = 1.01-1.70), and chlordane metabolites (ORper 10 ng/g = 1.78, 95%CI = 1.09-2.93) were positively associated with thyroid cancer. For individuals born before 1943, associations were generally null or in the inverse direction. CONCLUSIONS: Emissions of PCBs and OC pesticides varied over time. Different risk patterns by birth cohort suggest the potential importance of timing of exposure in thyroid cancer risk. Further evaluation of these associations is warranted. PMID- 29698873 TI - Clinical significance of IgM and IgA class anti-NMDAR antibodies in herpes simplex encephalitis. AB - BACKGROUND: Herpes simplex encephalitis (HSE) is a devastating disease, often leaving patients with severe disabilities. It has been shown that IgG anti-N methyl-d-aspartate receptor (NMDAR) antibodies appear in approximately 25% of HSE patients and could be associated with impaired recovery of cognitive performance. OBJECTIVES: To characterize the prevalence of IgM and IgA anti-NMDAR antibodies in HSE patients, in relation to subsequent development of IgG anti-NMDAR and correlation to cognitive performance. STUDY DESIGN: A total of 48 subjects were included from a previously described cohort of patients with HSE verified by HSV 1 PCR. Cerebrospinal fluid (CSF) and serum samples drawn close to onset of disease, after 14-21 days of iv aciclovir treatment and after 90 days of follow up, were analyzed for the presence of IgM and IgA anti-NMDAR, and related to IgG anti-NMDAR. Antibody levels were correlated to the recovery of cognitive performance, as estimated by the Mattis Dementia Rating Scale (MDRS), for a total of 24 months. RESULTS: In total, 27 of 48 (56%) study subjects were anti-NMDAR positive, defined as the presence of IgG (12/48, 25%), IgM (14/48, 29%) or IgA (13/48, 27%) antibodies in CSF and/or serum. IgM or IgA anti-NMDAR did not predict subsequent IgG autoimmunization and did not correlate to cognitive outcome. IgG anti-NMDAR serostatus, but not antibody titers, correlated to impaired recovery of cognitive performance. CONCLUSIONS: A majority of HSE patients develop IgG, IgM or IgA anti-NMDAR antibodies. However, the predictive value and clinical relevance of non-IgG isotypes remains to be shown in this setting. PMID- 29698874 TI - Assessing the competences associated with a nursing Bachelor thesis by means of rubrics. AB - BACKGROUND: Writing a Bachelor thesis is the last step in obtaining a university degree. The thesis may be job- or research-orientated, but it must demonstrate certain degree-level competences. Rubrics are a useful way of unifying the assessment criteria. OBJECTIVES: To design a system of rubrics for assessing the competences associated with the Bachelor thesis of a nursing degree, to examine the system's reliability and validity and to analyse results in relation to the final thesis mark. DESIGN: Cross-sectional and psychometric study conducted between 2012 and 2014. SETTINGS: Nursing degree at a Spanish university. PARTICIPANTS: Twelve tutors who designed the system of rubrics. Students (n = 76) who wrote their Bachelor thesis during the 2013-2014 academic year. METHODS: After deciding which aspects would be assessed, who would assess them and when, the tutors developed seven rubrics (drafting process, assessment of the written thesis by the supervisor and by a panel, student self-assessment, peer assessment, tutor evaluation of the peer assessment and panel assessment of the viva). We analysed the reliability (inter-rater and internal consistency) and validity (convergent and discriminant) of the rubrics, and also the relationship between the competences assessed and the final thesis mark. RESULTS: All the rubrics had internal consistency coefficients >0.80. The rubric for oral communication skills (viva) yielded inter-rater reliability of 0.95. Factor analysis indicated a unidimensional structure for all but one of the rubrics, the exception being the rubric for peer assessment, which had a two-factor structure. The main competences associated with a good quality Bachelor thesis were written communication skills and the ability to work independently. CONCLUSION: The assessment system based on seven rubrics is shown to be valid and reliable. Writing a Bachelor thesis requires a range of degree-level competences and it offers nursing students the opportunity to develop their evidence-based practice skills. PMID- 29698875 TI - Costs of helping only influence children's intention to help ethnic out-group peers. AB - Studies show that children are often inclined to help less when the costs of helping increase. However, these studies do not take into account who children are helping. Yet, developmental intergroup research has shown that the intergroup context influences children's reasoning about helping behavior. Two experimental vignette studies are presented that examined the influence of the costs of helping on children's (8-13 years) intention to help in an ethnic intergroup context. Study 1 (N = 320) showed that the costs of helping reduce children's willingness to help ethnic out-group peers but do not influence children's intention to help ethnic in-group peers. Study 2 (N = 166) replicated the results of Study 1 for a different ethnic out-group context. Moreover, children's reduced willingness to help ethnic out-group peers when costs increase was not contingent on their ethnic in-group or out-group evaluation or their age. Taken together, this research shows, for the first time, that the costs of helping reduce children's willingness to help ethnic out-group peers but not ethnic in-group peers. PMID- 29698876 TI - Childhood sexual abuse, mental health, and religion across the Jewish community. AB - Current estimates of childhood sexual abuse among Jews in the United States are only available for females and do not include a spectrum of religiosity. We examined sexual abuse, mental health, and religion, in a religiously diverse sample of male and female Jewish adults from North America, using a novel methodology to minimize sampling/response biases. A total of 372 diversely religious Jews participated. Prevalence of any form of childhood sexual abuse was statistically equivalent to national rates, except that females reported less involuntary penetration (OR = 0.53). All Jewish religious groups reported equivalent levels of sexual abuse, except that history of involuntary penetration was greater among formerly (but not presently) Orthodox Jews (OR = 3.00). Across our sample, sexual abuse was associated with increased likelihood of psychiatric diagnosis (OR = 1.34), greater mental distress (F ranging from 2.99 to 9.08, p < .05 for all analyses), lower religious observance (F = 4.53, p = .03), and lower intrinsic religiosity (F = 4.85, p = .03). Further, across our sample we observed a moderate buffering effect of spiritual/religious factors against mental distress (DeltaR2 values ranging from 0.028 to 0.045, p <.01 for all analyses). Thus, we found childhood sexual abuse to occur across the spectrum of Jewish religious affiliation and greater prevalence among formerly Orthodox individuals. Furthermore, history of childhood sexual abuse was associated with greater risk for psychiatric distress and less religious involvement, however spiritual/religious engagement and belief appeared to facilitate resilience in the context of abuse. PMID- 29698877 TI - Higher torque and muscle fibre conduction velocity of the Biceps Brachii in karate practitioners during isokinetic contractions. AB - PURPOSE: Although upper limb techniques are largely utilized during karate combat competitions scarce information regarding their NM control is available. This study aims at investigating the effect of karate practice on the NM control of Biceps and Triceps Brachii during isokinetic contractions to enhance current knowledge on neuromuscular control adaptations and training methodologies in combat sports. METHODS: Torque and surface electromyograms (sEMG) of Biceps Brachii Caput Longum (BB) and Triceps Brachii Lateral Head (TB) were recorded in eight karate practitioners (KA) and eight age-matched sedentary individuals (CO) during isokinetic elbow flexion-extensions (0-240 degrees /s-1). BB and TB sEMG amplitude (Root Mean Square - RMS) and frequency (Median Frequency - MDF) were computed during agonist and antagonist activity. Moreover, muscle fibre conduction velocity (MFCV) of the BB was computed. RESULTS: During the isokinetic contractions, KA group demonstrated higher peak torque and higher MFCV in the BB with respect to CO. KA and CO presented comparable activation of agonist and antagonist muscles and comparable frequency content in both BB and TB. CONCLUSIONS: The greater torque observed in KA should be interpreted in the light of a different motor unit recruitment strategy as suggested by the higher MFCV. Karate and combat sport practitioners should consider including in their training programmes methodologies emphasising neural rather than morphological adaptations. PMID- 29698878 TI - Educating new graduate nurses in their first year of practice: The perspective and experiences of the new graduate nurses and the director of nursing. AB - New graduate nurses are the future of nursing and the education they receive as they transition into the workforce as a newly registered nurse is critical for building a suitably qualified nursing workforce that will adequately serve the future population. Variation exists in education programmes for new graduate nurses in their first year of practice which is known to impact on transition experience. A qualitative study using focus groups and semi-structured interviews was undertaken to explore the experiences and perceptions of New Graduate Nurses undertaking a new graduate programme and Directors of Nursing supporting them to complete the programme which may or may not have been inclusive of a postgraduate course (Masters Level). The findings of this study are in line with previous research and support the value of new graduate programmes but did reveal a lack of consensus in regards to the structure and content of such programmes. This study revealed some commonalities and challenges between the differing programmes but has identified the need for further research to establish the impact of postgraduate education in the first year of practice and how this impacts on nursing practice and patient care. There are numerous terms in the literature with reference to new graduate programmes; transition to practice programme, nurse entry to practice programme, first year of clinical practice programme, new graduate programme and early career nursing programme. For the purpose of this article the term Nurse Entry to Practice (NETP) will be used in reference to any form of new graduate programme. PMID- 29698879 TI - Use of PipelineTM embolization device for the treatment of traumatic intracranial pseudoaneurysms: Case series and review of cases from literature. AB - OBJECTIVE: Intracranial traumatic pseudoaneurysms (PSA) are a rare but dangerous subtype of cerebral aneurysm. Reports documenting use of flow-diverting stents to treat traumatic intracranial PSAs are few and lack long-term follow-up. To our knowledge, this is the largest case-series to date demonstrating use of Pipeline Endovascular Device (PED) for traumatic intracranial PSAs. PATIENTS AND METHODS: Retrospective review of 8 intracranial traumatic PSAs in 7 patients treated using only PED placement. Patients were followed clinically and angiographically for at least 6 months. RESULTS: Seven patients with a mean age of 37 years were treated for 8 intracranial pseudo-aneurysms between 2011-2015. Six aneurysms were the result of blunt trauma; 2 were from iatrogenic injury during transsphenoidal surgery. Mean clinical and angiographic follow-up in surviving patients was 15.2 months. In patients with angiographic follow-up, complete occlusion was achieved in all but one patient, who demonstrated near-complete occlusion. No ischemic events or stent-related stenosis were observed. One patient developed a carotid cavernous fistula after PED, which was successfully retreated with placement of a second PED. There were two mortalities. One was due to suspected microwire perforation remote from the target aneurysm resulting in SAH/IPH. The other was due to a traumatic SDH and brainstem hemorrhage from an unrelated fall during follow-up interval. CONCLUSIONS: Use of PED for treatment of intracerebral PSAs following trauma or iatrogenic injury showed good persistent occlusion, and acceptable complication rate for this high-risk pathology. Risks of this procedure and necessary antiplatelet therapy require appropriate patient selection. Larger prospective studies are warranted. PMID- 29698881 TI - Goblet cell carcinoid of the appendix: Case report of a high grade tumor in a 20 year-old. AB - INTRODUCTION: Goblet cell carcinoid (GCC) is an extraordinarily rare appendiceal tumor that is usually an incidental diagnosis on post-operative histology. It typically presents in the fifth or sixth decade of life. Our patient is the only reported case study of GCC in a pediatric-young adult. Due to its potentially poor prognosis, GCC is surgically treated as an adenocarcinoma, with right hemicolectomy as the mainstay of treatment. PRESENTATION OF CASE: The patient was a 20-year-old male who presented with a history, physical exam, and work up consistent with acute appendicitis. He underwent an uneventful laparoscopic appendectomy and was diagnosed with a high grade GCC post-operatively. DISCUSSION: GCC is a rare tumor of the appendix with unique histological features including small rosettes with crescentic nuclei distended with mucin. It is often retroactively diagnosed with histology after a majority of patients present with acute appendicitis symptoms. The behavior of this tumor in pediatric-young adults is very poorly understood. CONCLUSION: We review the literature for GCC of the appendix and illustrate a case report of a young, otherwise healthy 20-year-old who presented as appendicitis. Although rare, neoplasm must be kept in mind while offering non-operative management for acute appendicitis. PMID- 29698882 TI - Neural and genetic basis of dexterous hand movements. AB - An ability to control dexterous hand movements is considered to parallel the evolutionary development of the corticospinal tract and the appearance of direct connections between corticospinal neurons and motoneurons (the corticomotoneuronal (CM) pathway), which developed uniquely in higher primates. However, recent studies have revealed that some non-primate animal species have higher levels of dexterity than previously supposed, and in higher primates, various indirect non-CM descending pathways have been shown to participate in the control of dexterous movements. More recently, the CM pathway was shown to exist in rodents during early development, suggesting that rodents and primates diverged in their reliance on the CM pathway at some point in evolution, thus challenging the traditional view of the sequential development of hand control from rodents to primates. PMID- 29698880 TI - Performance of the Japanese version of the Patient Health Questionnaire-9 (J-PHQ 9) for depression in primary care. AB - OBJECTIVE: To assess the performance of the Japanese version of the Patient Health Questionnaire-9 (J-PHQ-9) for depression in primary care. METHODS: Participants in both phases completed the J-PHQ-9, while patients in the second phase also completed the SF-8 (the short form for the health-related QOL scale SF 36). Subjects (n = 284; male = 107, female = 177) had to return the questionnaires to their health care professional within 48 hours and undergo a diagnostic evaluation interview based on the Japanese version of M.I.N.I-Plus. RESULTS: 93 patients were diagnosed as having major depressive disorder (MDD). In the J-PHQ-9, the optimal cutpoint >= 10 had sensitivity of 90.5% and specificity of 76.6%. As for the categorical algorithms, the sensitivity was 80.6%; specificity was 89.5%, and a positive likelihood ratio of 7.7. The Stratum specific likelihood ratios (SSLRs) of the J-PHQ-9 scores of 0-9, 10-14, 15-19, and 20-27 for major depression were 0.10 (95% CI: 0.05-0.20), 1.67 (95% CI: 1.02 2.76), 5.41 (95% CI: 2.87-10.22), and 11.98 (95% CI: 5.39-26.63), respectively. The relationship between the severity of J-PHQ-9 and the MCS of SF-8 was significant (chi 2 = 85.72, df = 4, P <= 0.0001). CONCLUSIONS: This study has validated the J-PHQ-9 as a useful tool for the assessment of MDD in primary care in Japan. PMID- 29698883 TI - A role for TLR10 in obesity and adipose tissue morphology. AB - Toll like receptors (TLRs) are expressed in adipose tissue and promote adipose tissue inflammation during obesity. Recently, anti-inflammatory properties have been attributed to TLR10 in myeloid cells, the only member of the TLR family with inhibitory activity. In order to assess whether TLR10-induced inhibition of inflammation may be protective during the development of obesity and metabolic abnormalities we used transgenic human TLR10 mice (hTLR10tg) and wild type (WT) controls on a C57B6J background. HFD-feeding enhanced TLR10 expression in the adipose tissue, and HFD-fed hTLR10tg mice displayed reduced adipocyte size, adipose tissue weight, and a trend toward lower plasma insulin levels compared to WT mice. In humans, obese individuals with polymorphisms in the TLR10 gene displayed reduced macrophage infiltration in the adipose tissue accompanied by a trend to lower leptin levels and higher adiponectin levels in plasma. In healthy individuals with the same polymorphisms in the TLR10 gene we did not observe any difference in plasma concentrations of leptin and adiponectin. We conclude that TLR10 impacts adipose tissue morphology in obesity. Larger studies in humans are warranted to assess its potential value as therapeutic target in metabolic syndrome and type 2 diabetes. PMID- 29698884 TI - Primary intrahepatic mesotheliomas: A case presentation and literature review. AB - INTRODUCTION: Primary Intrahepatic mesotheliomas are malignant tumors arising from the mesothelial cell layer covering Glisson's capsule of the liver. They are exceedingly rare with only fourteen cases reported in the literature. They have nonspecific signs and symptoms and need a high index of suspicion and an extensive workup prior to surgery. Surgery remains the mainstay of treatment. PRESENTATION OF CASE: 48 year old male presented with a 3 months history of abdominal pain, productive cough, anemia and weight loss. He had no history of asbestos exposure. A computed tomography scan and magnetic resonance study demonstrated a heterogeneous subscapular mass within the dome of the right hepatic lobe measuring 11.3 * 6.1 cm involving the diaphragm. Combined resection of the liver and diaphragm was performed to achieve negative margins. Pathology demonstrated an epithelioid necrotic intrahepatic mesothelioma that stained positive for calretinin, CK AE1/AE3, WT-1, D2-40 and CK7. DISCUSSION: Primary intrahepatic mesotheliomas originate from the mesothelial cells lining Glisson's capsule of the liver. They predominantly invade the liver but may also abut or involve the diaphragm. Surgery should include a diagnostic laparoscopy to rule out occult disease or diffuse peritoneal mesothelioma. Complete resection with negative margins should be attempted while maintaining an adequate future liver remnant. Attempts at dissecting the tumor off the involved diaphragm will result in excessive bleeding and may leave residual disease behind. CONCLUSION: Intrahepatic mesotheliomas are rare peripherally-located malignant tumors of the liver. They require a high index of suspicion and a comprehensive workup prior to operative intervention. PMID- 29698885 TI - The use of a NHS-PEG coated, collagen-based sealant in a patient undergoing Associating Liver Partition and Portal vein Ligation for Staged hepatectomy (ALPPS). AB - INTRODUCTION: ALPPS (Associating Liver Partition and Portal vein Ligation for Staged hepatectomy) is a new two-stage hepatectomy for patients in whom conventional treatment is not feasible due to insufficient future liver remnant (FLR). During stage one of ALPPS, accelerated growth of the FLR is induced by ligation of the portal vein and in situ split of the liver, which prevents interlobar collateral portal circulation and attributes to the accelerated hypertrophy response. This can present a risk for postoperative haemorrhage. Furthermore, adhesion of the adjacent resection surfaces might complicate the second stage of the procedure. Hemopatch(r) is a flexible, NHS-PEG coated, absorbable collagen-based sealant that provides haemostasis. This paper illustrates the use of Hemopatch during ALPPS for hemostasis and prevention of adhesions between the cut-surfaces of the liver. PRESENTATION OF CASE: An 81-year old patient requiring right hemihepatectomy for synchronous liver metastases underwent ALPPS. During stage one, Hemopatch was applied according to the manufacturer's instructions to the hepatic resection surfaces. Stage-2 was performed uneventfully, with no adhesions observed in the resection plane 18days after the first stage. The patient was discharged without any major complications. DISCUSSION: Hemopatch is a useful tool in prevention of postoperative haemorrhage in patients undergoing ALPPS procedure as well as in the prevention of adhesions between the cut-surfaces after transection. This facilitates stage-2 of the procedure which potentially improves postoperative outcomes. CONCLUSION: Topic haemostatic agents to cover the transection surface during stage one of ALPPS could help to prevent adverse interstage events. PMID- 29698886 TI - Presence and function of kisspeptin/KISS1R system in swine ovarian follicles. AB - Kisspeptin and its receptor KISS1R are involved in the neuroendocrine regulation of mammalian reproduction and their role on follicular development and function can be hypothesized. The present work was designed to confirm the immunopresence of kisspeptin and its receptor in the ovary of swine and to study the effects of kisspeptin 10 and its antagonist, kisspeptin 234, on main functional parameters of granulosa cells (i.e. cell proliferation, steroid production, and redox status) as well as their modulatory action on angiogenesis. The immunopresence of kisspeptin and KISS1R were detected in granulosa cells. Kisspeptin 10 stimulated progesterone in vitro production, thus indirectly suggesting that it can have a role in the luteinization process of granulosa cells. Kisspeptin 10 displayed potentiating effects on non-enzymatic scavenging activity, thus supporting its involvement in the control of the antioxidant defense system of ovarian follicles. In addition, results from the angiogenesis bioassay suggest that kisspeptin may have a role in the physiological development of new ovarian vessels. Additional studies are needed to confirm the functional significance of the kisspeptin/KISS1R system within the swine ovary. PMID- 29698887 TI - Hypoxia-dependent accumulation of hypoxia-inducible factor-1 alpha induces transient cell cycle arrest in porcine trophectoderm cells. AB - In the uterine environment, the pre-implantation embryo adapts to low oxygen concentrations through intracellular responses including modification of gene expression, progression via the cell cycle and metabolism. In this study, we determined mechanisms underlying the adaptation of pig embryos to oxygen deficiency in the maternal-conceptus microenvironment in in vitro experiments using our established porcine trophectoderm (pTr) cells in culture. The transition from G1 to S phase in pTr cells was reduced in response to 2% oxygen during a short period (<24 h), and the hypoxia-induced G1 arrest was reversible during prolonged hypoxia exposure. Acute hypoxia up-regulated expression of transcription factors p21 and p27 and down-regulated cell cycle regulators associated with the G1/S phase transition including cyclin D1, cyclin E1 and E2F1 mRNAs and proteins. Furthermore, hypoxia exposure for 24 h markedly increased the abundance of HIF-1alpha protein. Even under acute hypoxia, by HIF-1alpha silencing reduced the hypoxia-induced transient G1 arrest and expression of p21 and p27 genes was restored. Contrary to acute hypoxia, the accumulation of HIF 1alpha protein decreased as the length of the hypoxic period increased. Overall results of the present study suggest that increases in HIF-1alpha are responsible for initial response to hypoxia that results in a transient cell cycle arrest in pTr cells and cell cycle progression is restored by increasing degradation of HIF 1alpha during prolonged hypoxia. These findings advance understating of cellular adaptation of developing pre-implantation porcine conceptuses to hypoxic stress. PMID- 29698888 TI - Comparison of measured and simulated concentrations of 133Xe in the shallow subsurface. AB - Radioactive isotopes of the noble gases xenon and argon are considered primary indicators of an underground nuclear explosion. However, high atmospheric concentrations from other anthropogenic sources may lead to an elevation in the underground levels of these gases, particularly in times of increasing atmospheric pressure. In 2014, a week long sampling campaign near Canadian Nuclear Laboratories in the Ottawa River Valley resulted in first of their kind measurements of atmospheric 133Xe that had been pressed into the subsurface. In an effort to better understand this imprinting process, a second follow-up sampling campaign was conducted in the same location in 2016. The results of the second sampling campaign, where samples were collected at depths of 1 m and 2 m over a 14 day period and measured for their 133Xe concentration, are presented here. Gas transport and sample concentrations were predicted using the Subsurface Transport over Multiple Phases (STOMP) simulator. These results are examined and compared to the corresponding experimental results. PMID- 29698890 TI - A simple respirogram-based approach for the management of effluent from an activated sludge system. AB - Managing wastewater treatment plant (WWTP) based on respirometric analysis is a new and promising field. In this study, a multi-dimensional respirogram space was constructed, and an important index Res/t (ratio of in-situ respiration rate to maximum respiration rate) was derived as an alarm signal for the effluent quality control. A smaller Res/t value suggests better effluent. The critical R'es/t value used for determining whether the effluent meets the regulation depends on operational conditions, which were characterized by temperature and biomass ratio of heterotrophs to autotrophs. With given operational conditions, the critical R'es/t value can be calculated from the respirogram space and effluent conditions required by the discharge regulation, with no requirement for calibration of parameters or any additional measurements. Since it is simple, easy to use, and can be readily implemented online, this approach holds a great promise for applications. PMID- 29698889 TI - Acetylation of oxidized base repair-initiating NEIL1 DNA glycosylase required for chromatin-bound repair complex formation in the human genome increases cellular resistance to oxidative stress. AB - Posttranslational modifications of DNA repair proteins have been linked to their function. However, it is not clear if posttranslational acetylation affects subcellular localization of these enzymes. Here, we show that the human DNA glycosylase NEIL1, which is involved in repair of both endo- and exogenously generated oxidized bases via the base excision repair (BER) pathway, is acetylated by histone acetyltransferase p300. Acetylation occurs predominantly at Lys residues 296, 297 and 298 located in NEIL1's disordered C-terminal domain. NEIL1 mutant having the substitution of Lys 296-298 with neutral Ala loses nuclear localization, whereas Lys > Arg substitution (in 3KR mutant) at the same sites does not affect NEIL1's nuclear localization or chromatin binding, presumably due to retention of the positive charge. Although non-acetylated NEIL1 can bind to chromatin, acetylated NEIL1 is exclusively chromatin-bound. NEIL1 acetylation while dispensable for its glycosylase activity enhances it due to increased product release. The acetylation-defective 3KR mutant forms less stable complexes with various chromatin proteins, including histone chaperones and BER/single-strand break repair partners, than the wild-type (WT) NEIL1. We also showed that the repair complex with WT NEIL1 has significantly higher BER activity than the 3KR mutant complex. This is consistent with reduced resistance of non-acetylable mutant NEIL1 expressing cells to oxidative stress relative to cells expressing the acetylable WT enzyme. We thus conclude that the major role of acetylable Lys residues in NEIL1 is to stabilize the formation of chromatin bound repair complexes which protect cells from oxidative stress. PMID- 29698891 TI - Paper waste extracted alpha-cellulose fibers super-magnetized and chitosan functionalized for covalent laccase immobilization. AB - Enormous disposal of paper wastes (PW) causing number of environmental problems. PW is efficiently used to extract multifunctional alpha-cellulose fibers (alphaCFs). Thus, alphaCFs extraction from PW, and functionalization with Fe3O4 and chitosan were successfully performed for immobilization of laccase. Therefore, in this investigation, PW extracted alphaCFs were tuned with supermagnetic Fe3O4 (M) and functionalized with chitosan (CTA) (M-PW-alphaCF CTA). Furthermore, M-PW-alphaCF-CTA was glutaraldehyde cross-linked for covalent laccase immobilization. The synthesized materials were characterized by FT-IR, TGA, FE-SEM, FE-HR-TEM and VSM analyzes. M-PW-alphaCF-CTA exhibited magnetic saturation value of 14.72 emu/g. Laccase immobilized on M-PW-alphaCF-CTA (M-PW alphaCF-CTA-Lac) gave 92% of activity recovery and loading capacity of 73.30 mg/g. M-PW-alphaCF-CTA-Lac showed excellent pH, temperature, and storage stabilities with the exceptional reusability potential. Moreover, M-PW-alphaCF CTA-Lac was applied for repeated removal of carcinogenic Direct Red 28 (DR28). Therefore, M-PW-alphaCF-CTA-Lac is green and economical biocatalyst with extraordinary separation potential can be enforced for environmental pollutants reclamation. PMID- 29698892 TI - 3H-pyrazolo[4,3-f]quinoline haspin kinase inhibitors and anticancer properties. AB - Histone modification, a post-translational modification of histones and involving various covalent tags, such as methyl, phosphate and acetate groups, affects gene expression and hence modulates various cellular events, including growth and proliferation. Consequently histone-modifying proteins have become targets for the development of anticancer agents. Thus far, compounds that inhibit the methylation or acetylation of histones have advanced in the clinic, but inhibitors of histone phosphorylation have lagged behind. Haspin is a kinase that phosphorylates histone H3 and is a promising anticancer target. Thus far only a handful of haspin inhibitors have been reported. Using a one-flask Doebner/Povarov reaction, we synthesized a library of compounds that potently inhibit haspin with IC50 values as low as 14 nM. Some of these compounds also inhibited the proliferation of cancer cell lines HCT116, HeLa and A375. The ease of synthesis of the new haspin inhibitors, coupled with their anticancer activities make these compounds interesting leads to develop into therapeutics. PMID- 29698893 TI - Norditerpenoid alkaloids of Delphinium denudatum as cholinesterase inhibitors. AB - Three new norditerpenoids alkaloids, 1beta-hydroxy,14beta-acetyl condelphine (1), jadwarine-A (2), jadwarine-B (3) along with two known alkaloids isotalatizidine hydrate (4) and dihydropentagynine (5) were isolated from medicinal plant Delphinium denudatum. The structures of natural products 1-5 were established on the basis of HR-EIMS, 1H and 13C NMR (1D & 2D) spectroscopic data as well as by comparison from literature data. The structures of compound 1 and 4 were also confirmed by single crystal X-ray diffraction studies. In-vitro AChE and BChE enzyme inhibitory activities of compounds 1-5 and molecular docking studies were performed to investigate the possible molecular inhibitory mechanism of the isolated natural products. Compound 2, 4 and 5 showed competitive inhibitory effects by inhibiting AChE and BChE, respectively, while 1 and 3 showed non competitive inhibition. This work is the first report that provides a supporting evidence about the use of constituents of Delphinium denudatum in cerebral dementia and Alzheimer diseases. PMID- 29698894 TI - Biological correlates of self-reported new and continued abstinence in cannabis cessation treatment clinical trials. AB - BACKGROUND: The agreement between self-reported cannabis abstinence with urine cannabinoid concentrations in a clinical trials setting is not well characterized. We assessed the agreement between various cannabinoid cutoffs and self-reported abstinence across three clinical trials, one including contingency management for abstinence. METHODS: Three cannabis cessation clinical trials where participants reported use and provided weekly urine samples for cannabis and creatinine concentration measurements were included. Bootstrapped data were assessed for agreement between self-reported 7+ day abstinence and urine cannabinoid tests using generalized linear mixed effects models for clustered binary outcomes. One study implemented contingency management for cannabis abstinence. Four hundred and seventy-three participants with 3787 valid urine specimens were included. Urine was analyzed for 11-nor-9-carboxy-Delta9 tetrahydrocannabinol and creatinine using immunoassay methods Biological cutoffs of 50, 100, and 200 ng/ml, as well as changes in CN normalized THCCOOH (25%/50% decrease), were assessed for agreement with self-reported abstinence during the three clinical trials. RESULTS: Agreement between measured THCCOOH and self reported abstinence increases with increasing cutoff concentrations, while the agreement with self-reported non-abstinence decreases with increasing cutoff concentrations. Combining THCCOOH cutoffs with recent changes in CN-THCCOOH provides a better agreement in those self-reporting abstinence. Participants in the studies that received CM for abstinence had a lower agreement between self reported abstinence and returned to use than those in studies that did not have a contingency management component. CONCLUSION: Using combinations of biological measurements and self-reported abstinence, confirmation of study related abstinence may be verifiable earlier and with greater accuracy than relying on a single measurement. PMID- 29698895 TI - Drinking patterns and adherence to "low-risk" guidelines among community-residing older adults. AB - BACKGROUND: Older adults constitute a rapidly expanding proportion of the U.S. POPULATION: Contemporary studies note the increasing prevalence of alcohol consumption in this group. Thus, understanding alcohol effects, consumption patterns, and associated risks in aging populations constitute critical areas of study with increasing public health relevance. METHODS: Participants (n = 643; 292 women; ages 21-70) were community residing adult volunteers. Primary measures of interest included four patterns of alcohol consumption (average [oz./day]; typical quantity [oz./occasion]; frequency [% drinking days]; and maximal quantity [oz.]). Regression analyses explored associations between these measures, age, and relevant covariates. Subsequent between-group analyses investigated differences between two groups of older adults and a comparator group of younger adults, their adherance to "low-risk" guidelines, and whether alcohol-associated risks differed by age and adherence pattern. RESULTS: Average consumption did not vary by age or differ between age groups. In contrast, markedly higher frequencies and lower quantities of consumption were observed with increasing age. These differences persisted across adherence categories and were evident even in the oldest age group. Exceeding "low-risk" guidelines was associated with greater risk for alcohol-related problems among the older groups. CONCLUSIONS: These results emphasize the utility of considering underlying constituent patterns of consumption in older drinkers. Findings highlight difficulties in identifying problem drinking among older adults and contribute to the few characterizations of "risky" drinking patterns in this group. Taken together, our data contribute to literatures of import for the design and enhancement of screening, prevention, and education initiatives directed toward aging adults. PMID- 29698896 TI - Perfluoroalkyl substances in umbilical cord serum and gestational and postnatal growth in a Chinese birth cohort. AB - Although animal studies have found that perfluoroalkyl substances (PFASs) affect gestational and postnatal growth, the epidemiological findings are limited and not in agreement. We explored the associations of PFAS concentrations in umbilical cord blood with gestational and postnatal growth in China. Three hundred thirty-seven singleton newborns and their mothers were recruited from November 2013 to December 2015 in Zhoukou City, China. Umbilical cord blood was collected to measure eleven PFASs by liquid chromatography-mass spectrometry. The index of gestational and postnatal growth contained fetal weight, length, and head circumference. These were obtained at birth and at the follow-up investigation (mean 19 months). Exposed to higher perfluorooctanoic acid (PFOA) were connected with reduced length at birth (p for trend = 0.01) and decreased postnatal weight (beta = -429.2 g; 95% CI: -858.4, -0.121 for 2nd VS. 1st). Exposed to perfluoroundecanoic acid (PFUdA) were positively associated with indications of gestational growth and postnatal growth (p for trend = 0.02 for birth length; p for trend = 0.04 for postnatal length). Exposed to higher perfluorododecanoic acid (PFDoA) were associated with lower birth weight (beta = 122.9 g, 95% CI: -244.7 to -1.2 for 2nd VS. 1st), but higher postnatal length (p for trend = 0.03). Neonates in the highest exposure group of per fluorohexanesulfonate (PFHxS) showed decreased birth length (beta = -0.33 cm, 95% CI: -0.68 to -0.01, for 2nd VS. 1st), but increased postnatal head circumference (p for trend = 0.04). Increased PFOA concentrations was associated with shorter birth length only in girls (p for trend = 0.04), suggesting that the effect of PFASs on gestational growth were different between boys and girls. In utero exposure to PFASs may affect gestational and postnatal growth. PMID- 29698897 TI - Perfluoroalkyl and polyfluoroalkyl substances in matched parental and cord serum in Shandong, China. AB - BACKGROUND: Perfluoroalkyl and polyfluoroalkyl substances (PFASs) have been widely detected in different populations. However, limited data is available about exposure among family members. OBJECTIVES: To investigate the PFASs levels in parents and their newborns and to understand their correlation and health implications of in utero exposure to PFASs. METHODS: Ten PFASs were measured in matched parental and cord serum (N = 369 families) from a birth cohort in Shandong, one of the regions seriously polluted by PFASs in China. The correlation of PFASs levels within families was examined. A questionnaire survey on maternal factors and risk assessment using the hazard quotients (HQs) approach based on maternal PFASs levels was conducted. RESULTS: Within a family, the father had the highest levels of all PFASs. Among the 10 PFASs, perfluorooctanoic acid (PFOA) was the highest, with 103.38, 42.83, and 34.67 ng/ml in paternal, maternal and cord serum, respectively. PFASs levels were positively correlated among family members (r = 0.14-0.91, p < 0.01). Maternal age, body mass index (BMI); smoking history; and intake of fish, milk, poultry, vegetables and tap water were significantly related to PFASs concentrations in cord serum. Twenty seven (7.3%) HQ values exceeded 1 for both PFOA and the sum of PFOA and perfluorooctane sulfonate (PFOS), indicating potential concern for developmental toxicity in the local newborns. CONCLUSIONS: PFASs, and especially PFOA levels were extremely high and positively correlated between parents, indicating heavy pollution in this region and common sources of exposure. In utero exposure to PFASs might pose potential concern for developmental toxicity in the local newborns. PMID- 29698899 TI - The abundance and diversity of antibiotic resistance genes in the atmospheric environment of composting plants. AB - Composting is considered to reduce the introduction of antimicrobial resistance genes (ARGs) into the environment through land application of manure; however, the possible pollution of ARGs in the atmospheric environment of composting plants is unknown. In this study, 29 air samples including up- and downwind, composting, packaging, and office areas from 4 composting plants were collected. Dynamic concentrations of 22 subtypes of ARGs, class 1 integron (intl1), and 2 potential human pathogenic bacteria (HPB), and bacterial communities were investigated using droplet digital PCR and 16S rRNA gene sequencing, respectively. In this study, intl1 and 22 subtypes of ARGs (except tetQ) were detected in air of composting, packaging, office, and downwind areas. The highest concentration of 15 out of 22 subtypes of ARGs was detected in the packaging areas, and intl1 also had the maximum average concentration of 104 copies/m3, with up to (1.78 +/- 0.49) * 10-2 copies/16S rRNA copy. Non-metric multi dimensional scaling of ARGs, potential HPBs, and bacterial components all indicated that the bioaerosol pollutant pattern in packaging areas was most similar to that in composting areas, followed by office, downwind, and upwind areas. The co-occurrence between ARGs and bacterial taxa assessed by Procrustes test, mantel test, and network analysis implied that aerosolized ARG fragments from composting and packaging areas contributed to the compositions of ARG aerosols in office and downwind areas. The results presented here show that atmoshperic environments of composting plants harbor abundant and diverse ARGs, which highlight the urgent need for comprehensive evaluation of potential human health and ecological risks of composts during both production as well as land application. PMID- 29698898 TI - Carbon nanotube and nanofiber exposure and sputum and blood biomarkers of early effect among U.S. workers. AB - BACKGROUND: Carbon nanotubes and nanofibers (CNT/F) are increasingly used for diverse applications. Although animal studies suggest CNT/F exposure may cause deleterious health effects, human epidemiological studies have typically been small, confined to single workplaces, and limited in exposure assessment. OBJECTIVES: We conducted an industrywide cross-sectional epidemiological study of 108 workers from 12 U.S. sites to evaluate associations between occupational CNT/F exposure and sputum and blood biomarkers of early effect. METHODS: We assessed CNT/F exposure via personal breathing zone, filter-based air sampling to measure background-corrected elemental carbon (EC) (a CNT/F marker) mass and microscopy-based CNT/F structure count concentrations. We measured 36 sputum and 37 blood biomarkers. We used factor analyses with varimax rotation to derive factors among sputum and blood biomarkers separately. We used linear, Tobit, and unconditional logistic regression models to adjust for potential confounders and evaluate associations between CNT/F exposure and individual biomarkers and derived factors. RESULTS: We derived three sputum and nine blood biomarker factors that explained 78% and 67%, respectively, of the variation. After adjusting for potential confounders, inhalable EC and total inhalable CNT/F structures were associated with the most sputum and blood biomarkers, respectively. Biomarkers associated with at least three CNT/F metrics were 72 kDa type IV collagenase/matrix metalloproteinase-2 (MMP-2), interleukin-18, glutathione peroxidase (GPx), myeloperoxidase, and superoxide dismutase (SOD) in sputum and MMP-2, matrix metalloproteinase-9, metalloproteinase inhibitor 1/tissue inhibitor of metalloproteinases 1, 8-hydroxy-2'-deoxyguanosine, GPx, SOD, endothelin-1, fibrinogen, intercellular adhesion molecule 1, vascular cell adhesion protein 1, and von Willebrand factor in blood, although directions of associations were not always as expected. CONCLUSIONS: Inhalable rather than respirable CNT/F was more consistently associated with fibrosis, inflammation, oxidative stress, and cardiovascular biomarkers. PMID- 29698900 TI - Outdoor air pollution and mosaic loss of chromosome Y in older men from the Cardiovascular Health Study. AB - BACKGROUND: Mosaic loss of chromosome Y (mLOY) can occur in a fraction of cells as men age, which is potentially linked to increased mortality risk. Smoking is related to mLOY; however, the contribution of air pollution is unclear. OBJECTIVE: We investigated whether exposure to outdoor air pollution, age, and smoking were associated with mLOY. METHODS: We analyzed baseline (1989-1993) blood samples from 933 men >=65 years of age from the prospective Cardiovascular Health Study. Particulate matter <=10 MUm (PM10), carbon monoxide, nitrogen dioxide, sulfur dioxide, and ozone data were obtained from the U.S. EPA Aerometric Information Retrieval System for the year prior to baseline. Inverse distance weighted air monitor data were used to estimate each participants' monthly residential exposure. mLOY was detected with standard methods using signal intensity (median log-R ratio (mLRR)) of the male-specific chromosome Y regions from Illumina array data. Linear regression models were used to evaluate relations between mean exposure in the prior year, age, smoking and continuous mLRR. RESULTS: Increased PM10 was associated with mLOY, namely decreased mLRR (p trend = 0.03). Compared with the lowest tertile (<=28.5 MUg/m3), the middle (28.5 31.0 MUg/m3; beta = -0.0044, p = 0.09) and highest (>=31 MUg/m3; beta = -0.0054, p = 0.04) tertiles had decreased mLRR, adjusted for age, clinic, race/cohort, smoking status and pack-years. Additionally, increasing age (beta = -0.00035, p = 0.06) and smoking pack-years (beta = -0.00011, p = 1.4E-3) were associated with decreased mLRR, adjusted for each other and race/cohort. No significant associations were found for other pollutants. CONCLUSIONS: PM10 may increase leukocyte mLOY, a marker of genomic instability. The sample size was modest and replication is warranted. PMID- 29698902 TI - Patient outcomes associated with primary care behavioral health services: A systematic review. AB - OBJECTIVE: This systematic review focused on Primary Care Behavioral Health (PCBH) services delivered under normal clinic conditions that included the patient outcomes of: 1) access/utilization of behavioral health services, 2) health status, and 3) satisfaction. METHOD: Following PRISMA guidelines, comprehensive database searches and rigorous coding procedures rendered 36 articles meeting inclusion criteria. The principle summary measures of odd ratios or Cohen's d effect sizes were reported. RESULTS: Due to significant limitations in the methodological rigor of reviewed studies, robust findings only emerged for healthcare utilization: PCBH is associated with shorter wait-times for treatment, higher likelihood of engaging in care, and attending a greater number of visits. Several small, uncontrolled studies report emerging evidence that functioning, depression, and anxiety improve overtime. There was no evidence of greater improvement in patient health status when PCBH was compared to other active treatments. The limited available evidence supports that patient satisfaction with PCBH services is high. CONCLUSIONS: The implementation of PCBH services is ahead of the science supporting the usefulness of these services. Patient outcomes for PCBH are weaker than outcomes for Collaborative Care. More rigorous investigations of patient outcomes associated with PCBH are needed to allow for optimization of services. PMID- 29698901 TI - Prenatal exposure to organophosphates and associations with birthweight and gestational length. AB - Organophosphate esters (OPEs) are often used as flame retardants and plasticizers. Animal data suggest exposure to OPEs could impact children's growth and development, yet impacts on human birth outcomes are understudied. We evaluate impacts of OPE exposure on the timing of delivery and infant's birthweight in the Pregnancy Infection and Nutrition Study (PIN). North Carolina women enrolled in PIN in early pregnancy and participated in follow-up through delivery. Analyses were limited to mothers recruited from 2002 to 2005, whose children participated in additional follow-up in early childhood (n = 349). Mothers collected urine samples in which OPE metabolites were assessed and birth outcomes were abstracted from medical records. Bis(1,3-dichloro-2-propyl) phosphate (BDCIPP), diphenyl phosphate (DPHP), isopropyl-phenyl phenyl phosphate (ip-PPP), bis(1-chloro-2-propyl) 1-hydroxy-2-propyl phosphate (BCIPHIPP) were detected in >80% of samples. Average birthweight and gestational age were 3326 g and 39.1 weeks, respectively. As data suggest that the mechanisms of action by which OPEs impact birth outcomes may be fetal sex dependent, we conducted sex stratified statistical analyses. Women with the highest ip-PPP concentrations delivered girls 1 week earlier than women with lower levels (95% Confidence Interval (CI): -1.85, -0.15). Women with BDCIPP levels above the median had 3.99 (95% CI: 1.08, 14.78) times the odds of delivering their daughters preterm. Similarly, higher ip-PPP levels were associated with lower birthweight, but not after standardizing for gestational age. Among males, maternal ip-PPP was associated with decreased odds of preterm birth (OR = 0.21, 95% CI: 0.06, 0.68). DPHP and BCIPHIPP levels were not associated with outcomes in either sex. Results indicate that prenatal OPE exposure may impact timing of birth, though results are imprecise. Given widespread OPE exposure and the urgent need to identify and mitigate causes of preterm birth, further investigation is warranted. PMID- 29698903 TI - Fucoidan suppresses excessive phagocytic capacity of porcine peripheral blood polymorphonuclear cells by modulating production of tumor necrosis factor-alpha by lipopolysaccharide-stimulated peripheral blood mononuclear cells. AB - We examined the effect of fucoidan, an immune modulator, on the phagocytic capacity of porcine peripheral blood polymorphonuclear cells (PMNs) exposed to culture supernatant from lipopolysaccharide (LPS)-stimulated peripheral blood mononuclear cells (PBMCs). For this purpose, we evaluated the phagocytic capacity of porcine PMNs by flow cytometry and measured levels of tumor necrosis factor alpha (TNF-alpha) protein and mRNA in porcine PBMCs by enzyme-linked immunosorbent assay (ELISA) and real time-polymerase chain reaction (PCR), respectively. Fucoidan or LPS alone did not affect the phagocytic capacity of PMNs, but phagocytosis by these cells was increased by exposure to culture supernatant from PBMCs treated with fucoidan or LPS. In particular, the culture supernatant from PBMCs treated with LPS revealed excessive phagocytosis of PMNs. This excessive phagocytic capacity was diminished by co-treatment LPS with fucoidan. Production of TNF-alpha mRNA and protein increased upon treatment of PBMCs with either fucoidan or LPS, but this effect was also diminished by co treatment LPS with fucoidan. The ability of culture supernatant from PBMCs treated with LPS and/or fucoidan to increase the phagocytic capacity of PMNs was inhibited by anti-recombinant porcine TNF-alpha polyclonal antibody. These results suggested that fucoidan suppresses the phagocytic capacity of PMNs by modulating TNF-alpha production by LPS-stimulated PBMCs. PMID- 29698904 TI - Fe1-xZnxS ternary solid solution as an efficient Fenton-like catalyst for ultrafast degradation of phenol. AB - Heterogeneous Fenton-like system has been proved to be an promising alternative to Fenton system due to its easy separation. However, it's a challenge to design heterogeneous Fenton-like catalysts with high activity and great durability. Here, ternary solid solution Fe1-xZnxS were prepared via hydrothermal synthesis as heterogeneous Fenton-like catalysts. The Fe0.7Zn0.3S sample exhibited state of the art activity for yielding OH by H2O2 decomposition, and the ultrafast degradation of phenol was achieved in 4 min at initial acidic condition under room temperature. The phenol degradation rate constant of Fe0.7Zn0.3S was 99 and 70 times of ZnS and FeS, respectively. Further, we show that the unique structural configuration of iron atoms, the formation of FeS2-pyrite with (200) plane, are responsible for the excellent activity. The intermediate products were identified by LC-MS and a possible pathway was accordingly proposed to elucidate the mechanism of phenol degradation by OH. Overall, this work provides an idea for the rational design of the relevant heterogeneous Fenton-like catalysts. PMID- 29698905 TI - Hungry children age faster. AB - We analyze how childhood hunger affects human aging for a panel of European individuals. For this purpose, we use six waves of the Survey of Health, Aging, and Retirement in Europe (SHARE) dataset and construct a health deficit index. Results from log-linear regressions suggest that, on average, elderly European men and women developed about 20 percent more health deficits when they experienced a hunger episode in their childhood. The effect becomes larger when the hunger episode is experienced earlier in childhood. In non-linear regressions (akin to the Gompertz-Makeham law), we obtain greater effects suggesting that health deficits in old age are up to 40 percent higher for children suffering from hunger. The difference of health deficits between hungry and non-hungry individuals increases absolutely and relatively with age. This implies that individuals who suffered from hunger as children age faster. PMID- 29698907 TI - Using an emotional saccade task to characterize executive functioning and emotion processing in attention-deficit hyperactivity disorder and bipolar disorder. AB - Despite distinct diagnostic criteria, attention-deficit hyperactivity disorder (ADHD) and bipolar disorder (BD) share cognitive and emotion processing deficits that complicate diagnoses. The goal of this study was to use an emotional saccade task to characterize executive functioning and emotion processing in adult ADHD and BD. Participants (21 control, 20 ADHD, 20 BD) performed an interleaved pro/antisaccade task (look toward vs. look away from a visual target, respectively) in which the sex of emotional face stimuli acted as the cue to perform either the pro- or antisaccade. Both patient groups made more direction (erroneous prosaccades on antisaccade trials) and anticipatory (saccades made before cue processing) errors than controls. Controls exhibited lower microsaccade rates preceding correct anti- vs. prosaccade initiation, but this task-related modulation was absent in both patient groups. Regarding emotion processing, the ADHD group performed worse than controls on neutral face trials, while the BD group performed worse than controls on trials presenting faces of all valence. These findings support the role of fronto-striatal circuitry in mediating response inhibition deficits in both ADHD and BD, and suggest that such deficits are exacerbated in BD during emotion processing, presumably via dysregulated limbic system circuitry involving the anterior cingulate and orbitofrontal cortex. PMID- 29698906 TI - Contrasting effects of biochar nanoparticles on the retention and transport of phosphorus in acidic and alkaline soils. AB - Land application of biomass-derived biochar has been increasingly recommended as a beneficial soil amendment for nutrients (such as N, P) retention. However, the small-scale biochar particles, especially those in the nano-scale range, may carry nutrients downward the soil profile, reducing nutrition retention and posing a potential risk to the groundwater. In this study, column experiments were conducted to investigate the retention and transport of phosphorus (P) in two acidic and two alkaline soils as affected by wood chip-derived biochar nanoparticles (NPs). In acidic paddy and red soils, biochar NPs facilitated the retention of P, increasing by about 24% and 16%, respectively, compared to the biochar absence. It is because biochar NPs stabilize soil Fe/Al oxides and dissolved organic carbon (DOC), thereby reducing the release of Fe/Al oxides- and DOC-associated P. In contrast, in alkaline huangmian and chao soils, retention of P was reduced in the presence of biochar NPs, decreasing by about 23% and 18%, respectively. It was mainly due to the increased transport of Fe/Al oxides associated P in effluents. Moreover, biochar NPs could also act as a P carrier, mediating the retention of P. The diffusive gradients in thin films provided in suit measurement of labile P in soil profiles, showing much lower labile P from retained P in acidic soils than that from alkaline soils though the labile P with biochar NPs presence was increased in all soils. Our findings indicate that biochar NPs have contrasting effects on the retention of P in acidic and alkaline soils, implying the cautious land applications of biochar for nutrients retention in soils with different acidities. PMID- 29698908 TI - The expression of autophagy-related proteins within the corpus luteum lifespan in pigs. AB - Autophagy is a cellular process that involves the degradation of intracellular components. Recent studies suggested a role for autophagy in corpus luteum (CL) regression; however, a complete understanding of its contribution to CL function remains unclear. The present research using porcine CLs obtained from gilts at the early (CL1, n = 5), middle (CL2, n = 5), and late (CL3, n = 5) luteal phase of the estrous cycle aimed to assess the incidence of autophagy during CL development. The stages of collected CLs were verified through morphological analysis and intraluteal progesterone concentration. The presence of autophagosomes was assessed using transmission electron microscopy, and the expression of autophagic markers was examined at mRNA (BECN1 and Lamp1) and protein (Beclin 1, LC3-II, and Lamp 1) levels. Lamp 1 immunolocalization was also performed in luteal tissue. Double-membrane autophagosomes and autophagy-related proteins were found in all examined CLs. Interestingly, there was a greater expression of Beclin 1 (P = 0.005 and P = 0.025) and Lamp 1 (P = 0.009 and P = 0.032) protein in CL3 as compared with CL1 and CL2. In addition, the presence of autolysosomes in CL3 indicated advanced autophagy at that developmental stage. Overall, the occurrence of autophagy throughout CL development and regression suggests it has a role in the regulation of CL lifespan in pigs. In the early and mature CL, autophagy is proposed to promote luteal formation and function, whereas in the late CL, it may participate in luteal regression. PMID- 29698909 TI - Development and application of an exchange model for anisotropic water diffusion in the microporous MOF aluminum fumarate. AB - Diffusion of water in aluminum fumarate was studied by means of pulsed field gradient (PFG) nuclear magnetic resonance (NMR). Due to water molecules exchanging between the intracrystalline anisotropic pore space and the isotropic intercrystalline void space the model of intracrystalline anisotropic diffusion fails to describe the experimental PFG NMR data at high observation times. Therefore, the two-site exchange model developed by Karger is extended to the case of exchange between an anisotropic and an isotropic site. This extended exchange model is solved by numerical integration. It describes the experimental data very well and yields values for the intracrystalline diffusion coefficient and the mean residence times of the respective sites. Further PFG NMR studies were performed with coatings consisting of small aluminum fumarate crystals, which are used in adsorptive heat transformation applications. The diffusion coefficients of water in the small crystal coating are compared to the values expected from the extended two-site exchange model and from the model of long range diffusion. PMID- 29698910 TI - Tomato plants ectopically expressing Arabidopsis GRF9 show enhanced resistance to phosphate deficiency and improved fruit production in the field. AB - Agronomic performance of transgenic tomato overexpressing functional genes has rarely been investigated in the field. In an attempt to improve low-phosphate (P) stress tolerance of tomato (Solanum lycopersicum) plants and promote tomato fruit production in the field, an expression vector containing cDNA to an Arabidopsis 14-3-3 protein, General Regulatory Factor 9 (GRF9), driven by a cauliflower mosaic virus 35S promoter, was transferred into tomato plants. Transgenic expression of GRF9 was ascertained by quantitative real-time PCR analysis. The degree of low-P tolerance in transgenic plants was found to be significantly greater than that in wild-type plants, and reflected in improved root development and enhanced P content under hydroponic conditions. For transgenic tomato, roots had higher P uptake, as evidenced by tissue P content and relative expression of the genes LePT1 and LePT2 in both normal and low-P hydroponic solutions. GRF9 overexpressors had greatly enhanced proton extrusion from roots and heightened activity of the plasma-membrane H+-ATPase (PM H+-ATPase) in roots under low-P hydroponic conditions. Thus, in addition to enhanced root development, higher expression of genes coding for phosphate transporters and improved capacity for acidification in the rhizosphere emerged as key mechanisms underpinning improved P acquisition in transgenic tomato plants in soil. Subsequent field trials measuring tomato fruit production at two P levels, indicated that GRF9 can indeed improve total tomato production and may play a role in early fruit maturity. Our results suggest that the heterologous Arabidopsis GRF9 gene can confer resistance to P deficiency in transgenic tomato plants and promote fruit production. PMID- 29698911 TI - Chloroplastic ATP synthase plays an important role in the regulation of proton motive force in fluctuating light. AB - The proton motive force (pmf) across the thylakoid membranes plays a key role for photosynthesis in fluctuating light. However, the mechanisms underlying the regulation of pmf in fluctuating light are not well known. In this study, we aimed to identify the roles of chloroplastic ATP synthase and cyclic electron flow (CEF) around photosystem I (PSI) in the regulation of the pmf in fluctuating light. To do this, we measured chlorophyll fluorescence, P700 parameters, and the electrochromic shift signal in the fluctuating light alternating between 918 (high light) and 89 (low light) MUmol photons m-2 s-1 every 5 min. We found that the activity of chloroplastic ATP synthase (gH+), pmf, CEF activity, non photochemical quenching (NPQ), and the P700 redox state changed rapidly in fluctuating light. During transition from low to high light, the decreased gH+ and the stimulation of CEF both contributed to the rapid formation of pmf, activating NPQ and optimizing the redox state of P700 in PSI. During the low light phases, gH+ rapidly increased and the pmf declined sharply, leading to the relaxation of NPQ and down-regulation of photosynthetic control. These findings indicate that in fluctuating light the gH+ and CEF are finely regulated to modulate the pmf formation, avoiding the over-accumulation of reactive intermediates and maximizing energy use efficiency. PMID- 29698912 TI - The varied ability of grains to synthesize and catabolize ABA is one of the factors affecting dormancy and its release by after-ripening in imbibed triticale grains of cultivars with different pre-harvest sprouting susceptibilities. AB - Abscisic acid (ABA) is a phytohormone involved in the acquisition of primary dormancy during seeds maturation as well as dormancy maintenance in imbibed seeds. After imbibition, the ABA content decreased to a much lower level in embryos of freshly harvested triticale grains of the Leontino cultivar, which is more susceptible to pre-harvest sprouting (PHS) than embryos of the Fredro cultivar. Lower ABA content in the Leontino cultivar resulted from increased expression of TsABA8'OH1 and TsABA8'OH2, which encode ABA 8'-hydroxylase and are involved in ABA catabolism. Higher ABA content and maintenance of dormancy in Fredro grains were correlated with intensified ABA biosynthesis, which resulted from higher expression of TsNCED1, which encodes 9-cis-epoxycarotenoid dioxygenase. These results suggest that grains of triticale cultivars with different resistance to PHS vary in their ability to metabolize ABA after imbibition. After-ripening did not affect the ABA content in embryos of dry grains of either triticale cultivar. However, after-ripening caused dormancy release in Fredro grains and significantly affected the ABA content and the rate of its metabolism after imbibition. A more rapid decline in ABA content in imbibed Fredro grains was accompanied by decreased transcript levels of TsNCED1 as well as increased expression of TsABA8'OH1 and TsABA8'OH2. Thus, after ripening may affect dormancy of grains through reduction of the ABA biosynthesis rate and intensified ABA catabolism. Overexpression of TsNCED1 in tobacco increases ABA content and delays germination, while overexpression of TsABA8'OH2 decreases ABA content, accelerates germination, and reduces the sensitivity to ABA of transgenic seeds compared to seeds of wild-type plants. Therefore, these genes might play an important role in the regulation of triticale grain dormancy, thus affecting susceptibility to PHS. PMID- 29698913 TI - The sequence specificity of UV-induced DNA damage in a systematically altered DNA sequence. AB - The sequence specificity of UV-induced DNA damage was investigated in a specifically designed DNA plasmid using two procedures: end-labelling and linear amplification. Absorption of UV photons by DNA leads to dimerisation of pyrimidine bases and produces two major photoproducts, cyclobutane pyrimidine dimers (CPDs) and pyrimidine(6-4)pyrimidone photoproducts (6-4PPs). A previous study had determined that two hexanucleotide sequences, 5'-GCTC*AC and 5' TATT*AA, were high intensity UV-induced DNA damage sites. The UV clone plasmid was constructed by systematically altering each nucleotide of these two hexanucleotide sequences. One of the main goals of this study was to determine the influence of single nucleotide alterations on the intensity of UV-induced DNA damage. The sequence 5'-GCTC*AC was designed to examine the sequence specificity of 6-4PPs and the highest intensity 6-4PP damage sites were found at 5'-GTTC*CC nucleotides. The sequence 5'-TATT*AA was devised to investigate the sequence specificity of CPDs and the highest intensity CPD damage sites were found at 5' TTTT*CG nucleotides. It was proposed that the tetranucleotide DNA sequence, 5' YTC*Y (where Y is T or C), was the consensus sequence for the highest intensity UV-induced 6-4PP adduct sites; while it was 5'-YTT*C for the highest intensity UV induced CPD damage sites. These consensus tetranucleotides are composed entirely of consecutive pyrimidines and must have a DNA conformation that is highly productive for the absorption of UV photons. PMID- 29698915 TI - Forensic facial comparison in South Africa: State of the science. AB - Forensic facial comparison (FFC) is a scientific technique used to link suspects to a crime scene based on the analysis of photos or video recordings from that scene. While basic guidelines on practice and training are provided by the Facial Identification Scientific Working Group, details of how these are applied across the world are scarce. FFC is frequently used in South Africa, with more than 700 comparisons conducted in the last two years alone. In this paper the standards of practice are outlined, with new proposed levels of agreement/conclusions. We outline three levels of training that were established, with training in facial anatomy, terminology, principles of image comparison, image science, facial recognition and computer skills being aimed at developing general competency. Training in generating court charts and understanding court case proceedings are being specifically developed for the South African context. Various shortcomings still exist, specifically with regard to knowledge of the reliability of the technique. These need to be addressed in future research. PMID- 29698914 TI - Error quantification of osteometric data in forensic anthropology. AB - This study evaluates the reliability of osteometric data commonly used in forensic case analyses, with specific reference to the measurements in Data Collection Procedures 2.0 (DCP 2.0). Four observers took a set of 99 measurements four times on a sample of 50 skeletons (each measurement was taken 200 times by each observer). Two-way mixed ANOVAs and repeated measures ANOVAs with pairwise comparisons were used to examine interobserver (between-subjects) and intraobserver (within-subjects) variability. Relative technical error of measurement (TEM) was calculated for measurements with significant ANOVA results to examine the error among a single observer repeating a measurement multiple times (e.g. repeatability or intraobserver error), as well as the variability between multiple observers (interobserver error). Two general trends emerged from these analyses: (1) maximum lengths and breadths have the lowest error across the board (TEM<0.5), and (2) maximum and minimum diameters at midshaft are more reliable than their positionally-dependent counterparts (i.e. sagittal, vertical, transverse, dorso-volar). Therefore, maxima and minima are specified for all midshaft measurements in DCP 2.0. Twenty-two measurements were flagged for excessive variability (either interobserver, intraobserver, or both); 15 of these measurements were part of the standard set of measurements in Data Collection Procedures for Forensic Skeletal Material, 3rd edition. Each measurement was examined carefully to determine the likely source of the error (e.g. data input, instrumentation, observer's method, or measurement definition). For several measurements (e.g. anterior sacral breadth, distal epiphyseal breadth of the tibia) only one observer differed significantly from the remaining observers, indicating a likely problem with the measurement definition as interpreted by that observer; these definitions were clarified in DCP 2.0 to eliminate this confusion. Other measurements were taken from landmarks that are difficult to locate consistently (e.g. pubis length, ischium length); these measurements were omitted from DCP 2.0. This manual is available for free download online (https://fac.utk.edu/wp-content/uploads/2016/03/DCP20_webversion.pdf), along with an accompanying instructional video (https://www.youtube.com/watch?v=BtkLFl3vim4). PMID- 29698916 TI - Microbial community composition of a multi-stage moving bed biofilm reactor and its interaction with kinetic model parameters estimation. AB - Microbial community diversity determines the function of each chamber of multi stage moving bed biofilm reactor (MBBR) systems. How the microbial community data can be further used to serve wastewater treatment process modelling and optimization has been rarely studied. In this study, a MBBR system was set up to investigate the microbial community diversity of biofilm in each functional chamber. The compositions of microbial community of biofilm from different chambers of MBBR were quantified by high-throughput sequencing. Significantly higher proportion of autotrophs were found in the second aerobic chamber (15.4%), while 4.3% autotrophs were found in the first aerobic chamber. Autotrophs in anoxic chamber were negligible. Moreover, ratios of active heterotrophic biomass and autotrophic biomass (XH/XA) were obtained by performing respiration tests. By setting heterotroph/autotroph ratios obtained from sequencing analysis equal to XH/XA, a novel approach for kinetic model parameters estimation was developed. This work not only investigated microbial community of MBBR system, but also it provided an approach to make further use of molecular microbiology analysis results. PMID- 29698917 TI - A mania-related memory bias is associated with risk for relapse in bipolar disorder. AB - OBJECTIVE: Previous work has shown that neuropsychological performance can predict outcome of psychotherapy. The present paper explores whether an affective bias in verbal memory is associated with recurrence of mood episodes in patients with Bipolar Disorder (BD). METHOD: 76 euthymic adult patients with BD were randomly assigned to either 9 months of Cognitive Behavioral Therapy (CBT) or Support Therapy (ST), and followed up for 2 years after completing therapy. At baseline, affective learning memory (Emotional Auditory Verbal Learning Test; EMO AVLT) and other measures were assessed. Recurrence of a mood episode was the primary outcome. RESULTS: The survival analyses revealed that the interaction between therapy condition, more specifically ST, and a recognition bias in favor of mania-related, but not depression-related words predicted recurrence of mania. Recurrence of depression was predicted by neither affective memory bias nor their interaction with treatment. CONCLUSIONS: A mania-related memory bias emerged as a predictor of mania recurrence, specifically in an unstructured setting such as ST. Perhaps mania-related schemata are more salient or more easily activated in those at high risk for recurrence. Interventions targeting patients' insight into their internal states as potential indicators of prodromal manic symptoms could be the key to improve the outcome of psychological interventions in BD. Additional research in the role of cognitive factors in relapse prevention is warranted. PMID- 29698918 TI - Work intensity in men and work-related emotional demands in women are associated with increased suicidality among persons attending primary care. AB - BACKGROUND: A large proportion of persons died by suicide are employed at the time of death and work-related factors partly contribute to suicide risk. Our aim was to examine the association between multiple aspects of work organization and suicidal ideation in a study conducted in primary care. METHODS: Data came from a study of 2027 working patients attending a GP representative of patients in the Nord Pas-de-Calais region in France (April-August 2014). Suicidality was assessed using the MINI (Mini International Neuropsychiatric Interview). Six emergent worked-related factors were explored (work intensity, emotional demands, autonomy, social relationships at work, conflict of values, insecurity of work). Several covariates were considered: patient's and GP's characteristics, and area level data (material and social deprivation, psychiatrist and GPs' density, suicide attempts and suicide rates). RESULTS: 8.0% of participants reported suicidal ideation in the preceding month (7.5% of men and 8.6% of women, p = .03). In multivariate analyses adjusted for covariates, suicidality was significantly associated with work intensity (OR = 1.65; 95%CI [1.18-2.31]) in men and with work-related emotional demands (OR = 1.35; 95%CI [1.01-1.80]) in women. Area-level data were not associated. LIMITATIONS: Our cross-sectional study cannot assess the direction of the relationships under study. CONCLUSION: Our results emphasise a central role for GPs in suicide prevention among workers and highlight the importance of work-related factors with regard to suicidality in primary care. PMID- 29698919 TI - The evolving role of lymphatics in cancer metastasis. AB - While the link between the lymphatic system and the metastatic spread of cancer is centuries old, understanding of the underlying mechanisms is still evolving. Lymphatic vessels provide a route for tumour cells to reach regional lymph nodes (LNs), which is prognostic of distant organ metastasis and poor survival. However, genomic analyses of metastatic cancer now reveal complex patterns of dissemination. The lymphatic endothelial cells lining lymphatics respond to molecular cues from the tumour microenvironment, mediating growth and remodelling of lymphatic vessels at the primary tumour, draining LNs and distant premetastatic niches. Recent studies emphasise that this not only supports metastasis but also influences antitumour immunity. Understanding the complex interactions between tumour cells, the immune system and lymphatics will be essential to inform developing therapeutic and prognostic approaches to cancer. PMID- 29698920 TI - A vibrational entropy term for DNA docking with autodock. AB - DNA interacts with small molecules, from water to endogenous reactive oxygen and nitrogen species, environmental mutagens and carcinogens, and pharmaceutical anticancer molecules. Understanding and predicting the physical interactions of small molecules with DNA via docking is key not only for the comprehension of molecular-level events that lead to carcinogenesis and other diseases, but also for the rational design of drugs that target DNA. We recently validated AutoDock, a popular docking method that includes a physics-based scoring function and a Lamarckian Genetic Algorithm, for the prediction of small molecule geometries upon physical binding to DNA. In this work, we added a vibrational entropy term based on the docking frequency to the scoring function in order to improve the accuracy of the best (lowest) score geometry. We found that in four small molecule-DNA systems the inclusion of the vibrational entropy term decreased the root-mean-square-deviation from the experimental crystallographic structure. Including the entropy term also preserved the successful prediction of the binding geometry compared to the crystallographic structure for the rest of the small molecule-DNA systems. We also improved the method of creating clusters of docking geometries and emphasized the importance of the length of the search process for similar vibrational entropy terms. PMID- 29698922 TI - Suicidal ideation and behavior in US veterans with schizophrenia or bipolar disorder. AB - OBJECTIVE: Using data from a Department of Veterans Affairs study of schizophrenia (SZ) and bipolar I disorder (BP), we evaluated lifetime risks for suicidal ideation and behavior. We were interested in the prevalence and correlates of these outcomes, in populations of patients with severe mental illness (SMI), who have not been compared directly in previous studies despite data on high risk in each group separately. METHOD: Data were collected on demographic factors, medical and psychiatric comorbidity, cognitive and functional status, and lifetime suicidal ideation or behavior in a study of veterans with SZ (N = 3942) or BP (N = 5414). In-person diagnosis and evaluation, including performance-based assessments of cognition and functional skills, make this study unique compared to studies of completed suicide. Multinomial logistic regression examined how risk factors, including major depression and negative symptoms in SCZ patients, correlated with ideation and behavior. RESULTS: A lifetime history of suicidal ideation or behavior was reported by a majority of Veterans with SZ (69.9%) or BP (82.3%). Lower risk was found for patients with SZ vs. BP (odds ratio [OR] = 0.82 for ideation; OR = 0.81 for behavior). The highest risk was found for patients with multiple psychiatric comorbidities (OR = 2.61 for ideation; OR = 3.82 for behavior). Clinical factors (e.g., psychiatric comorbidity) contributed more of the variance in the predictive model than demographic factors. CONCLUSIONS: A history of suicidal ideation or behavior is common among US Veterans with SZ or BP, and specific demographic and clinical attributes correlate with variation in risk. These findings underscore the need for continuous monitoring for suicidal ideation and behavior in veteran populations with SMI, as well as the development of better risk predictions, including genomic factors. Although PTSD is a major current focus in veteran populations, the large number of veterans with SZ or BP and their high suicide risk suggests a greater clinical focus may be warranted. PMID- 29698921 TI - Design, synthesis and evaluation of novel sulfonamides as potential anticancer agents. AB - Based on modern literature data about biological activity of E7010 derivatives, a series of new sulfonamides as potential anticancer drugs were rationally designed by QSAR modeling methods Slassification learning QSAR models to predict the tubulin polymerization inhibition activity of novel sulfonamides as potential anticancer agents were created using the Online Chemical Modeling Environment (OCHEM) and are freely available online on OCHEM server at https://ochem.eu/article/107790. A series of sulfonamides with predicted activity were synthesized and tested against 60 human cancer cell lines with growth inhibition percent values. The highest antiproliferative activity against leukemia (cell lines K-562 and MOLT-4), non-small cell lung cancer (cell line NCI H522), colon cancer (cell lines NT29 and SW-620), melanoma (cell lines MALME-3M and UACC-257), ovarian cancer (cell lines IGROV1 and OVCAR-3), renal cancer (cell lines ACHN and UO-31), breast cancer (cell line T-47D) was found for compounds 4 9. According to the docking results the compounds 4-9 induce cytotoxicity by the disruption of the microtubule dynamics by inhibiting tubulin polymerization via effective binding into colchicine domain, similar the E7010. PMID- 29698923 TI - Anti-inflammatory effects of alpha-linolenic acid in M1-like macrophages are associated with enhanced production of oxylipins from alpha-linolenic and linoleic acid. AB - Chronic inflammation, mediated in large part by proinflammatory macrophage populations, contributes directly to the induction and perpetuation of metabolic diseases, including obesity, insulin resistance and type 2 diabetes. Polyunsaturated fatty acids (PUFAs) can have profound effects on inflammation through the formation of bioactive oxygenated metabolites called oxylipins. The objective of this study was to determine if exposure to the dietary omega-3 PUFA alpha-linolenic acid (ALA) can dampen the inflammatory properties of classically activated (M1-like) macrophages derived from the human THP-1 cell line and to examine the accompanying alterations in oxylipin secretion. We find that ALA treatment leads to a reduction in lipopolysaccharide (LPS)-induced interleukin (IL)-1beta, IL-6 and tumor necrosis factor-alpha production. Although ALA is known to be converted to longer-chain PUFAs eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), DHA oxylipins were reduced overall by ALA treatment, as was LPS-induced secretion of EPA oxylipins. In contrast, we observed profound increases in oxylipins directly derived from ALA. Lipoxygenase products of linoleic acid were also dramatically increased, and LPS-induced production of AA oxylipins, particularly prostaglandin D2, was reduced. These results suggest that ALA may act to dampen the inflammatory phenotype of M1-like macrophages by a unique set of mechanisms distinct from those used by the long-chain omega-3 fatty acids EPA and DHA. Thus, there is strong rationale for investigating the functions of ALA oxylipins and lesser-known LA oxylipins since they hold promise as anti-inflammatory agents. PMID- 29698925 TI - Highly significant improvement in guideline adherence, relapse-free and overall survival in breast cancer patients when treated at certified breast cancer centres: An evaluation of 8323 patients. AB - OBJECTIVES: Certified multi-disciplinary breast cancer centres (CBCs) have been established worldwide. Development of CBCs, guideline-adherent systemic therapy and surgical management should now show an impact on outcomes. This analysis aimed to investigate whether guideline adherence (GA) rates, relapse-free survival (RFS) and overall survival (OS) have significantly improved at CBCs compared to the pre-certification period. MATERIALS AND METHODS: 8323 patients with primary breast cancer were treated in 17 German CBCs, which had been certified between 2003 and 2007 [2003 (n = 1), 2004 (n = 6), 2005 (n = 3), 2006 (n = 6) and 2007 (n = 1)]. 3544 patients (42.6%) were treated before certification and 4779 patients (57.4%) after certification. RESULTS AND CONCLUSION: A highly significant (p < 0.001) difference in 100%-GA was found between the various hospitals before certification (min 25.0%; max 54.6%). In 2008, when all participating hospitals were certified, the GA rate was 61.8% (min 39.5%, max 74.4%) and 69.2% (min 45.9%, max 86.4%) for patients <75 y (n = 6675). The difference between pre-certification 100%-GA (46.9%) and post-certification (57.2%) was highly significant (p < 0.001). RFS and OS were both significantly better after certification compared to the pre-certification period (RFS: HR = 0.79; 95% CI: 0.68-0.92; p = 0.003; OS: HR = 0.75; 95% CI: 0.65-0.85; p < 0.001). 5-year RFS (OS) of patients <75 y was 89.6% (85.4%) pre-certification and 91.4% (89.5%) post-certification. Since improvement in GA and outcomes correlated as well, GA remains a highly significant prognostic factor for RFS and OS regardless of NPI, intrinsic subtype and adjuvant systemic therapy. This suggests that the certification process is strongly associated with improvements in outcome. PMID- 29698926 TI - Outcomes of systemic therapy for advanced triple-negative breast cancer: A single centre experience. AB - BACKGROUND: Prognosis is worse for advanced triple-negative breast cancer (aTNBC) compared to other disease subtypes. Trials describe treatment outcomes in single specified lines of therapy; but few data describe treatment outcomes across the whole treatment pathway, which is critical in determining when patients should be referred for trials and to inform discussion. We evaluated treatment outcomes for aTNBC (overall response rate [ORR], median progression-free survival [mPFS] and median overall survival [mOS]) in patients treated largely outside of clinical trials. METHODS: We retrospectively identified 268 patients diagnosed with aTNBC from 01/12/2011 to 30/11/2016 from our electronic records and recorded patients' and tumour characteristics and treatment outcomes. Chi-squared/Fishers exact test and Kaplan-Meier statistical methods were utilised. RESULTS: 186 patients treated with >=1 line of systemic treatment were eligible and had median age of 55 (range 26-91). 53.8% had ECOG Performance Status 0 and 69.9% visceral involvement. 38.6% had disease-free interval (DFI)<=12 months following surgery or adjuvant chemotherapy completion and 14.0% had de-novo advanced disease. 11.4% carried a BRCA mutation. 64.5% received two lines of therapy, 37.6% three and 21.5% four. ORR and mPFS were 43.9% and 3.7 months for first-line therapy, 40.2% and 3.5 months for second-line, 28.8% and 2.5 months for third-line and 25.0% and 2.1 months for fourth-line. In first line, DFI>12 months was associated with higher ORR and longer PFS compared DFI <=12 months. CONCLUSIONS: The observed response rates are consistent with literature. However, PFS is short, and early consideration of clinical trials can be justified in these patients. PMID- 29698924 TI - Integrative metabolomics and transcriptomics signatures of clinical tolerance to Plasmodium vivax reveal activation of innate cell immunity and T cell signaling. AB - Almost invariably, humans become ill during primary infections with malaria parasites which is a pathology associated with oxidative stress and perturbations in metabolism. Importantly, repetitive exposure to Plasmodium results in asymptomatic infections, which is a condition defined as clinical tolerance. Integration of transcriptomics and metabolomics data provides a powerful way to investigate complex disease processes involving oxidative stress, energy metabolism and immune cell activation. We used metabolomics and transcriptomics to investigate the different clinical outcomes in a P. vivax controlled human malaria infection trial. At baseline, the naive and semi-immune subjects differed in the expression of interferon related genes, neutrophil and B cell signatures that progressed with distinct kinetics after infection. Metabolomics data indicated differences in amino acid pathways and lipid metabolism between the two groups. Top pathways during the course of infection included methionine and cysteine metabolism, fatty acid metabolism and urea cycle. There is also evidence for the activation of lipoxygenase, cyclooxygenase and non-specific lipid peroxidation products in the semi-immune group. The integration of transcriptomics and metabolomics revealed concerted molecular events triggered by the infection, notably involving platelet activation, innate immunity and T cell signaling. Additional experiment confirmed that the metabolites associated with platelet activation genes were indeed enriched in the platelet metabolome. PMID- 29698927 TI - A randomized phase II trial of trastuzumab plus capecitabine versus lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer previously treated with trastuzumab and taxanes: WJOG6110B/ELTOP. AB - BACKGROUND: For human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) with progression on trastuzumab-based therapy, continuing trastuzumab beyond progression and switching to lapatinib combined with chemotherapy are both valid options. We conducted an open-label, randomized phase II trial to compare the efficacy of these strategies. PATIENTS AND METHODS: Women with HER2-positive MBC previously treated with trastuzumab and taxanes were randomly assigned to receive trastuzumab plus capecitabine (HX) or lapatinib plus capecitabine (LX). The primary endpoint was progression-free survival (PFS) and the secondary endpoints included overall survival (OS) and the objective response rate (ORR). To explore the predictive value of the differential benefit of anti HER2 drugs, PIK3CA mutations were assessed using circulating tumor DNA. RESULTS: Eighty-six patients (43 in each arm) were enrolled. The median PFS was 6.1 months in the HX arm and 7.1 months in the LX arm (hazard ratio, 0.81; 90% CI, 0.55 1.21; p = 0.39); the median OS was 31.0 months in the HX arm and was not reached in the LX arm (hazard ratio, 0.58; 95% CI, 0.26-1.31; p = 0.18). The ORR was 40% in the HX arm and 41% in the LX arm. PIK3CA mutations were detected in 23% of the 35 analyzed patients, and in patients without PIK3CA mutations, LX yielded relatively longer PFS and OS than HX. CONCLUSION: In women with HER2-positive MBC previously treated with trastuzumab and taxanes, no significant differences in PFS and OS were observed between patients treated with LX and HX. TRIAL REGISTRATION NUMBER: UMIN000005219. PMID- 29698928 TI - Identifying pathologic complete response of the breast after neoadjuvant systemic therapy with ultrasound guided biopsy to eventually omit surgery: Study design and feasibility of the MICRA trial (Minimally Invasive Complete Response Assessment). AB - PURPOSE: Improvements in neoadjuvant systemic therapy (NST) for breast cancer patients have led to increasing rates of pathologic complete response (pCR). The MICRA trial (NTR6120) aims at identifying pCR with post-NST biopsies. Here, we report the study design and feasibility. METHODS: The MICRA-trial is a multi center prospective cohort study. Patients with a pre-NST placed marker and radiologic complete (rCR) or partial response on MRI after NST are eligible for inclusion. Ultrasound guided biopsy of the original tumor area is performed. Pathology results of the biopsies and surgery specimens are compared. The primary endpoint is false-negative rate of biopsies in identifying pCR. RESULTS: During the first year of the trial 58 patients with rCR were included. One patient was a screening failure and excluded for analysis. Twenty-one percent had hormone receptor (HR)+/HER2- tumors, 21% HR+/HER2+ tumors, 18% HR-/HER2+ tumors and 40% TN tumors. Overall pCR was 68%. In seven patients biopsies could not be obtained: in 6 patients, the marker could not be identified on ultrasound in the OR and in 1 patient there were technical difficulties. A median of eight biopsies was obtained (range 4-9). The median of histopathological representative biopsies was 4 (range 1-8). CONCLUSION: Ultrasound guided biopsy of the breast in patients with excellent response on MRI after NST is feasible. Accuracy results of the MICRA trial will be presented after inclusion of 525 patients to determine if ultrasound guided biopsy is an accurate alternative to surgical resection for assessment of pCR after NST. PMID- 29698929 TI - Characterisation of human urethral rupture thresholds for urinary catheter inflation related injuries. AB - Data on urethral catheter related injuries is sparse. In this study we aimed to characterise urethral diametric strain and urinary catheter inflation pressure thresholds that precede human urethral trauma during urethral catheterisation (UC). Human urethras were obtained from patients undergoing male to female gender reassignment surgery [(n = 9; age 40 +/- 13.13 (range: 18-58)) years]. 12Fr urinary catheters were secured in the bulbar urethra and the catheter's anchoring balloon was inflated with a syringe pump apparatus. Urethral diametric strain and balloon pressure were characterised with video extensometry and a pressure transducer respectively. Immunohistochemistry, Masson's trichrome and Verhoeff Van Gieson stains evaluated urethral trauma microscopically. Morphological characterisation of the urethral lumen was performed by examining non-traumatised histological sections of urethra and recording luminal area, perimeter and major/minor axis length. Tearing (n = 3) and rupture (n = 3) of the urethra were observed following catheter balloon inflation. The threshold for human urethral rupture occurred at an external urethral diametric strain >= 27% and balloon inflation pressure >= 120kPa. Significant relationships were identified between urethral wall thickness and the level of trauma induced during catheter balloon inflation (p = 0.001) and between the pressure required to inflate the catheter balloon and the length of the major axis of the urethral lumen (p = 0.004). Ruptured urethras demonstrated complete transection of collagen, elastin and muscle fibres. In conclusion, urethral rupture occurs at an external urethral diametric strain >= 27% or with balloon inflation pressures >= 120 kPa. Incorporation of these parameters may be useful for designing a safety mechanism for preventing catheter inflation related urethral injuries. PMID- 29698930 TI - Role of porosity and matrix behavior on compressive fracture of Haversian bone using random spring network model. AB - Haversian remodeling is known to result in improved resistance to compressive fracture in healthy cortical bone. Here, we examine the individual roles of the mean porosity, structure of the network of pores and remodeled bone matrix properties in the fracture behavior of Haversian bone. The detailed structure of porosity network is obtained both pre- and post-testing of dry cubical bone samples using micro-Computed Tomography. Based on the periodicity in the features of porosity along tangential direction, we develop a two dimensional porosity based random spring network model for Haversian bone. The model is shown to capture well the macroscopic response and reproduce the avalanche statistics similar to recently reported experiments on porcine bone. The predictions suggest that at the millimeter scale, the remodeled bone matrix of Haversian bone is less stiff but tougher than that of plexiform/primary bone. PMID- 29698931 TI - The impact of a public health department's expansion from a one-step to a two step refugee screening process on the detection and initiation of treatment of latent tuberculosis. AB - OBJECTIVES: To determine, subsequent to the expansion of a county health department's refugee screening process from a one-step to a two-step process, the change in early loss to follow-up and time to initiation of treatment of new refugees with latent tuberculosis infection (LTBI). STUDY DESIGN: Quasi experimental, quantitative. METHODS: Review of patient medical records. RESULTS: Among 384 refugees who met the case definition of LTBI without prior tuberculosis (TB) classification, the number of cases lost to early follow-up fell from 12.5% to 0% after expansion to a two-step screening process. The average interval between in-country arrival and initiation of LTBI treatment was shortened by 41.4%. DISCUSSION: The addition of a second step to the refugee screening process was correlated with significant improvements in the county's success in tracking and treating cases of LTBI in refugees. Given the disproportionate importance of foreign-born cases of LTBI to the incidence of TB disease in low-incidence countries, these improvements could have a substantial impact on overall TB control, and the process described could serve as a model for other local health department refugee screening programs. PMID- 29698932 TI - A new look at the International Duration Evaluation of Adjuvant therapy (IDEA) classification-Defining novel predictive and prognostic markers in stage III colon cancer. AB - BACKGROUND: The International Duration Evaluation of Adjuvant therapy (IDEA) pooled analysis compared 3 to 6 months of adjuvant chemotherapy for stage III colon cancer. The overarching goal was to reduce chemotherapy-related toxicity, mainly oxaliplatin-induced neuropathy. Patients were classified into low-risk and high-risk groups, suggesting that low-risk patients may be offered only 3 months of treatment. We aimed to evaluate the benefit of monotherapy versus doublet chemotherapy in low and high IDEA risk groups. METHODS: Using the National Cancer Database (2004-2014), we identified 56,728 low-risk and 47,557 high-risk individuals with stage III colon cancer, according to the IDEA classification. We used multivariate Cox regression to evaluate the magnitude of survival differences between IDEA risk groups, according to treatment intensity (doublet versus monotherapy). In a secondary analysis, we examined the prognostic and predictive value of subgroups of age, tumour sidedness and lymph node ratio (LNR). RESULTS: Low and high IDEA risk groups derived similar benefit from doublet adjuvant chemotherapy as compared with monotherapy, with hazard ratios (HRs) of 0.83 (95% confidence interval [CI] 0.79-0.86) and 0.80 (95% CI 0.78 0.83), respectively. The only subpopulations that did not benefit from doublet chemotherapy were low-risk patients older than 72 years (HR = 0.95, 95% CI 0.90 1.01) and high-risk patients older than 85 years (HR = 0.90, 95% CI 0.77-1.05). LNR and tumour sidedness were shown as additional prognostic, but not predictive, factors within the IDEA risk groups. CONCLUSIONS: IDEA risk classification per se does not predict for treatment benefit from doublet chemotherapy in stage III colon cancer. However, omission of oxaliplatin can be considered in IDEA low-risk patients older than 72 years. PMID- 29698933 TI - Detection of immune-related adverse events by medical imaging in patients treated with anti-programmed cell death 1. AB - BACKGROUND: Programmed death receptor-1 blocking antibodies (anti-PD1) are a new standard of care in many cancer types. Patients benefit from improved survival but have the risk of immune-related adverse events (irAE). We evaluated if medical imaging procedures, used for anti-tumour response assessment, can detect irAEs. MATERIALS AND METHODS: All consecutive patients treated with anti-PD1 and with a medical imaging acquisition performed within 2 weeks with irAEs >=2 were retrospectively included. Data were gathered from June 2014 to February 2017, and a central review was performed. The primary and secondary end-points were i) to evaluate the overall detection rate of irAEs by medical imaging and ii) to provide a comprehensive radiological description of irAEs. RESULTS: Fifty-three patients (31 women, 22 men; average age: 61 years) were included. The primary tumour was melanoma (n = 32), lung cancer (n = 18) and other (n = 3). Patients were treated with nivolumab (n = 27) or pembrolizumab (n = 26). Of 74 medical imaging procedures analysed (ratio = 1.4 medical imaging per patient), 55 irAE were detected. The detection rate was overall: 74% (95 confidence interval: 63 84%), positron emission tomography with 18F-fludeoxyglucose integrated with computed tomography (18F-FDG PET/CT): 83% (n = 10/12), magnetic resonance imaging: 83% (n = 5/6), computed tomography scan: 79% (n = 19/24), ultrasonography: 70% (n = 19/27), standard X-rays: 40% (n = 2/5), lung/mediastinum: 100% (n = 7/7), enterocolitis: 100% (n = 8/8), hypophysitis: 100% (n = 3/3), thyroiditis: 75% (n = 15/20), hepatitis: 67% (n = 2/3), arthralgia or arthritis: 40% (n = 2/5) and pancreas: 28% (n = 2/7). CONCLUSION: Medical imaging detected 74% of irAE in patients treated with anti-PD1. Beyond response assessment, medical imaging can detect irAE and guide towards specific management. We described the most frequent sites and patterns of imaging findings. PMID- 29698934 TI - A Review of Clinical Radioprotection and Chemoprotection for Oral Mucositis. AB - The first tenet of medicine, "primum non nocere" or "first, do no harm", is not always compatible with oncological interventions e.g., chemotherapy, targeted therapy and radiation, since they commonly result in significant toxicities. One of the more frequent and serious treatment-induced toxicities is mucositis and particularly oral mucositis (OM) described as inflammation, atrophy and breakdown of the mucosa or lining of the oral cavity. The sequelae of oral mucositis (OM), which include pain, odynodysphagia, dysgeusia, decreased oral intake and systemic infection, frequently require treatment delays, interruptions and discontinuations that not only negatively impact quality of life but also tumor control and survivorship. One potential strategy to reduce or prevent the development of mucositis, for which no effective therapies exist only best supportive empirical care measures, is the administration of agents referred to as radioprotectors and/or chemoprotectors, which are intended to differentially protect normal but not malignant tissue from cytotoxicity. This limited-scope review briefly summarizes the incidence, pathogenesis, symptoms and impact on patients of OM as well as the background and mechanisms of four clinical stage radioprotectors/chemoprotectors, amifostine, palifermin, GC4419 and RRx-001, with the proven or theoretical potential to minimize the development of mucositis particularly in the treatment of head and neck cancers. PMID- 29698935 TI - High Serum Level of Soluble Programmed Death Ligand 1 is Associated With a Poor Prognosis in Hodgkin Lymphoma. AB - Blockade of the programmed cell death 1-programmed cell death ligand 1 pathway is a new and promising therapeutic approach in Hodgkin lymphoma (HL). To our knowledge, the impact of soluble programmed cell death ligand 1 (sPD-L1) serum levels on HL patient prognosis has not yet been investigated. In this study, the prognostic value of sPD-L1 was assessed in patients with HL. We measured serum sPD-L1 levels and identified their prognostic value in 108 newly diagnosed HL patients using an enzyme-linked immunosorbent assay (ELISA). We found higher serum sPD-L1 concentrations in HL patients than in healthy controls. The best sPD L1 cutoff value for predicting disease progression risk was 25.1674 ng/ml. The 4 year progression-free survival (PFS) rates for the high-sPD-L1 and low-sPD-L1 groups were 78.8% and 93.3%, respectively. Multivariate survival analysis showed that advanced stage and higher sPD-L1 levels (>25.1674 ng/ml) were independent prognostic factors for shorter PFS. In addition, higher sPD-L1 levels were positively correlated with advanced stage and negatively correlated with peripheral blood monocyte number. The serum sPD-L1 level is an independent prognostic factor for PFS in HL patients and may allow identification of a subgroup of patients who require more intensive therapy and who may benefit from anti-PD-1 agents. PMID- 29698936 TI - Response Predictors to Calcineurin Inhibitors in Patients with Primary Membranous Nephropathy. AB - BACKGROUND: Currently, there is an urgent need to find ways of identifying primary membranous nephropathy (PMN) patients who are likely to benefit from calcineurin inhibitors (CNI) or who are resistant to them. In this study, we employed nano-HPLC-MS/MS analysis to identify serum biomarkers that predict the clinical response to CNI therapy in PMN patients. METHODS: The endpoint was complete remission (CR) after CNI treatment. PMN patients were grouped into no remission (NR) or CR groups to screen predictive candidates using the nano-HPLC MS/MS analysis. RESULTS: Compared with NR patients, 3 upregulated proteins and 5 downregulated proteins were found to present a twofold change in CR patients' serum. Serum amyloid A1 protein (SAA1) was further validated by ELISA; it was decreased in patients in the NR group compared with patients in the CR group, but SAA1 in patients in these groups was lower than in healthy controls and minimal change disease patients. The area under the receiver operating characteristic (ROC) curve of SAA1 was used to distinguish PMN NR patients from those in remission and was 0.901, with a sensitivity of 78.3% and specificity of 86.8%, similar to that of the phospholipase A2 receptor (PLA2R) antibody. Combining SAA1 with the PLA2R antibody, the area under the ROC curve was 0.956, which was higher than that of SAA1 or the PLA2R antibody alone. CONCLUSIONS: Serum SAA1 may be a candidate PMN biomarker that can be used to discriminate CNI NR cases from remission patients. The combination of SAA1 and the PLA2R antibody increases the accuracy of diagnosis. PMID- 29698937 TI - Differences in Race and Ethnicity in Muscular Dystrophy Mortality Rates for Males under 40 Years of Age, 2006-2015. AB - BACKGROUND/AIMS: Duchenne Muscular Dystrophy (DMD) has childhood onset, primarily affects males, and is usually fatal before the age of 40 years. Previous studies have indicated that this X-linked condition is more prevalent in whites than in blacks, but those were based on active surveillance, and limited to smaller populations and younger ages. METHODS: US death data were used to calculate mortality rates by race and ethnicity, with MD as either the underlying or multiple cause of death (MCD). Poisson approximation was used for confidence intervals; chi-square was used to compare rates. RESULTS: From 2006 to 2015, there were 3,256 deaths in males <40 years with MD as MCD, and 71% of these were aged 15-29 years. For whites, the average annual death rate was 0.43/100,000, which was significantly higher (p < 0.0001) that that of blacks (0.28), American Indian/Alaska Natives (0.20), and Asian/Pacific Islanders (0.21). The rate for non-Hispanic whites (0.46) was significantly higher (p < 0.0001) than the rates for Hispanic whites (0.31), Hispanic blacks (0.07), and non-Hispanic blacks (0.29). CONCLUSION: Since DMD is the primary cause of deaths in young males with MD, mortality rates are a reasonable proxy for the relative difference in racial prevalence. It appears that DMD is significantly more common in white males than in males of other races. PMID- 29698938 TI - Clinicopathological Features and Prognosis of Gastrointestinal Stromal Tumor Located in the Jejunum and Ileum. AB - BACKGROUND: Data about the clinicopathological features and prognosis of gastrointestinal stromal tumors (GISTs) located in jejunum and ileum are lacking. The present study aims to investigate the features and prognosis of jejunal and ileal GISTs based on the Surveillance, Epidemiology, and End Results (SEER) database. PATIENTS AND METHODS: Cases of jejunal and ileal GISTs were extracted from SEER database. Clinicopathological characteristics and survival data of patients were recorded. The clinicopathological features and prognosis of patients were analyzed. RESULTS: There were 399 male (56.8%) and 303 female (43.2%). The median age was 60 years (17-96). Four hundred and seventy-two tumors were located in the jejunum (67.2%) and 230 tumors in the ileum (32.8%). The median tumor size was 7.0 cm (0.5-90). The 5-, 10-, and 20-year disease specific survival (DSS) was 84.4, 71.2, and 54.2% respectively. Clinicopathological features were comparable between tumors located in the jejunum and ileum (all p > 0.05) except gender and tumor size (both p < 0.05). Jejunal GISTs, rather than ileal GISTs (p = 0.043), were commonly found in the males. The tumor size of jejunal GISTs was smaller than that of ileal GISTs (p = 0.010). The DSS of jejunal GISTs was comparable to that of ileal GISTs (p = 0.269). CONCLUSIONS: Jejunal GISTs were more common than ileal GISTs. The prognosis was comparable between jejunal and ileal GISTs. PMID- 29698939 TI - Synergistic Strategies to Promote Stroke Research. PMID- 29698940 TI - Corticosteroid Therapy Improves the Outcome of Autoimmune Hepatitis-Induced Acute Liver Failure. AB - BACKGROUND/AIMS: Autoimmune hepatitis (AIH) is a relatively rare cause of liver dysfunction and may lead in some cases to acute liver failure (ALF). The aim of our study was to evaluate the clinical course and outcome of patients with AIH induced ALF. METHODS: We retrospectively enrolled 32 patients with AIH-induced ALF and 93 age- and sex-matched patients with chronic AIH (cAIH) who were enrolled at the University Clinic Essen from 1988 to 2014. All ALF patients were treated with corticosteroids after diagnosis. RESULTS: Overweight, higher gamma globulin levels, the absence of anti-smooth muscle antibodies and human leukocyte antigen (HLA) B8 and the presence of anti-mitochondrial antibodies and HLA DR7 were risk factors for an ALF vs chronic hepatitis manifestation of AIH. Liver histology was significantly more often typical for AIH in an ALF setting than in cAIH. The spontaneous survival rate was 91% and 97% in ALF and cAIH patients, respectively, at 6 months after diagnosis and only 1 patient in the ALF group developed sepsis under therapy. CONCLUSION: Liver biopsy in an AIH-mediated ALF setting was both safe and effective in diagnosing AIH. Corticosteroid therapy was not associated with high mortality or sepsis. Our findings suggest that corticosteroid treatment of AIH-mediated ALF may improve the outcome. PMID- 29698941 TI - Computer-Assisted Quantitative Assessment of Prostatic Calcifications in Patients with Chronic Prostatitis. AB - BACKGROUND: The aim of this study was the development of quantitative assessment of prostatic calcifications at prostatic ultrasound examination by the use of an image analyzer. MATERIALS AND METHODS: A group of 82 patients was evaluated by medical history, physical, and transrectal ultrasound examination. Patients had a urethral swab, a 4-specimen study and culture of the seminal fluid. Patients were classified according to National Institute of Diabetes and Digestive and Kidney Diseases/National Institutes of Health. Subjective symptoms were scored by Chronic Prostatitis Symptom Index (CPSI) questionnaire. Ultrasound images were analyzed by the digital processing software Image J to quantitatively assess the presence of calcifications. RESULTS: Computer-assessed calcified areas were significantly higher in chronic bacterial prostatitis (n = 18; group II; 6.76 +/- 8.09%) than in the chronic pelvic pain syndrome group IIIa (n = 26; 2.07 +/- 1.01%) and IIIb (n = 38; 2.31 +/- 2.18%). The area of calcification of the prostate was significantly related to the CPSI score for domains of micturition (r = 0.278, p = 0.023), Prostatic Specific Antigen values (r = 0341, p = 0.005), postvoiding residual urine (r = 0.262, p = 0.032), total prostate volume (r = 0.592, p = 0.000), and adenoma volume (r = 0.593; p = 0.000). CONCLUSIONS: The presence of calcifications is more frequently observed in patients with chronic bacterial prostatitis and is related to urinary symptoms. PMID- 29698942 TI - Diagnostic Accuracy of Latex Agglutination Turbidimetric Immunoassay in Screening Adolescents for Helicobacter pylori Infection in Japan. AB - BACKGROUND/AIMS: Serologic tests are commonly used for screening Helicobacter pylori infection because they not only provide quick results but also are inexpensive. A new latex agglutination serum antibody assay (LZ test) has been developed and it is expected to be as effective as conventional assays. This study aimed to calculate a reliable cutoff value for the LZ test and to estimate the sensitivity and specificity of the cutoff value in screening adolescents for H. pylori infection in Japan. METHODS: We screened junior high school students in Akita Prefecture, Japan, for H. pylori infection. We used the data of 213 such students who underwent H. pylori stool antigen (HpSA) tests in 2016. The students who had positive results with HpSA tests were diagnosed with H. pylori infection. Of the 213 students, 209 underwent the LZ test. RESULTS: The prevalence rate of H. pylori infection was 3.8% (8/209). The area under the curve for the LZ test was 0.88. The cutoff value of the LZ test was determined to be 3.1 U/mL. At this value, the sensitivity and specificity were 87.5 and 91.5%, respectively. CONCLUSION: The accuracy of the LZ test in adolescents was well balanced for sensitivity and specificity as well as for tolerable results. PMID- 29698943 TI - The Concentration of Iodine in Perigastric Adipose Tissue: A Novel Index for the Assessment of Serosal Invasion in Patients with Gastric Cancer after Neoadjuvant Chemotherapy. AB - OBJECTIVE: This study aims to explore the association between iodine concentration (IC) in perigastric adipose tissue (PAT), quantified by dual-energy computed tomography (DECT) and serosal invasion (SI) in patients with gastric cancer post-neoadjuvant chemotherapy (NAC). METHODS: Forty-three patients with T4 staged gastric cancer were enrolled. IC and standardized IC in PAT (ICPAT and SICPAT) were quantified by DECT pre and post NAC. A postoperative pathologic examination was performed to stage gastric cancer. RESULTS: After NAC, a total of 43 participants were assigned to group A with 13 patients and group B with 30 patients according to the results of the postoperative pathologic examination. The accuracy of conventional CT in identifying SI was 74.42%. Differences of variations between pre- and post- NAC ICPAT, SICPAT, ?ICPAT, and ?SICPAT were observed respectively (p < 0.05). Intragroup ICPAT and SICPAT also changed significantly after NAC (p < 0.05). The area under the ROC curve was 0.929, with the threshold of ?SICPAT reaching 0.095. The sensitivity, specificity, and accuracy of SICPAT in identifying post-NAC SI were 92.30, 86.70, and 88.37% respectively. Moreover, the 2 measurements in the same patient maintain a high level of consistency. CONCLUSION: These results showed that SICPAT is a reliable index for identifying post-NAC SI. PMID- 29698944 TI - Mucosally Expressed Cytokines are Associated with the Esophageal Motility Function. AB - BACKGROUND AND AIM: Although basic research has shown that certain cytokines affect gastrointestinal motility, the clinical evidence is lacking. The objective of this study was to explore the association between mucosally expressed cytokines and the esophageal motility function in humans. METHODS: We enrolled a total of 57 patients with suspected esophageal motility disorders (EMDs) who underwent high-resolution manometry. RESULTS: The diagnoses of the patients were as follows: normal esophageal motility (n = 25), ineffective esophageal motility (n = 5), esophagogastric junction outflow obstruction (EGJOO; n = 10), distal esophageal spasm (n = 5), achalasia (n = 10), absent contractility (n = 1), and jackhammer esophagus (n = 1). The expression of tumor necrosis factor (TNF)-alpha in the esophagogastric junction (EGJ) was significantly higher in EGJOO (14.6, 14.0-15.8, n = 10) than in normal esophageal motility (13.3, 12.8-14.1, n = 25); however, there was no difference in the expression of TNF-alpha between achalasia (13.4, 13.0-14.1, n = 10) and normal esophageal motility (13.3, 12.8-14.1, n = 25). EGJOO was discriminated from achalasia/normal by a linear discriminant analysis (AUC = 0.917). A multivariable regression analysis revealed that interleukin (IL)-13 and IL-23A were predictive of the distal contractile integral, whereas TNF-alpha and IL-6 were predictive of the basal EGJ pressure. CONCLUSIONS: The esophageal motility was associated with mucosally expressed cytokines in humans; these cytokines could be useful targets for the diagnosis and treatment of EMDs. PMID- 29698945 TI - Comparison of Small Bowel Lesions Using Capsule Endoscopy in Ulcerative Colitis and Crohn's Disease: A Single-Center Retrospective Analysis. AB - BACKGROUND: Capsule endoscopy (CE) has allowed the characterization of small bowel lesions. However, small bowel lesions in ulcerative colitis (UC) have not been elucidated and no studies have compared between UC and Crohn's disease (CD). AIM: The objective of this study was to investigate the small bowel lesions in UC, and to characterize UC lesions by comparison with CD. METHODS: Subjects comprised 54 UC patients and 39 CD patients who underwent CE. We retrospectively investigated characteristics of small bowel lesions in UC. We also compared endoscopic findings and degree of inflammation between UC and CD. RESULTS: The incidence of small bowel lesions in UC was 27.8%. The group with small bowel lesions exhibited higher endoscopic activity in the colon than without small bowel lesions (p = 0.002). Comparing small bowel lesions between UC and CD, significantly more ulcerative lesions, notched appearance, longitudinal tendency of lesions, and cobblestone appearance were seen in CD. The Lewis score was significantly higher in CD than UC in the second and third tertiles (205 +/- 379 vs. 73 +/- 223, p = 0.01; 358 +/- 449 vs. 105 +/- 333, p < 0.001). CONCLUSIONS: Small bowel lesions in UC were linked to colonic activity. UC and CD differ in terms of the morphology and distribution of small bowel lesions. PMID- 29698946 TI - Automatic Change Detection in Older and Younger Women: A Visual Mismatch Negativity Study. AB - BACKGROUND: In comparison to controlled (attentional) processing, relatively little is known about the age-related changes of the earlier (preattentive) processes. An event-related potential (ERP) index of preattentive (automatic) visual processing, the visual mismatch negativity (vMMN) is a good candidate for analyzing age-related differences in the automatic processing of visual events. OBJECTIVE: So far results concerning age-related changes in vMMN have been equivocal. Our aim was to develop a method resulting in a reliable vMMN in a paradigm short enough to use in the applied field. METHODS: We investigated an older (mean age: 66.4 years, n = 15) and a younger (mean age: 22.4 years, n = 15) group of healthy women. ERPs were obtained for checkerboard onset patterns in a passive oddball condition (during which participants performed a tracking task). One of the checkerboards was frequent (standard; p = 0.8), and the other was rare (deviant; p = 0.2). RESULTS: vMMN emerged over posterior locations in the latency range of 100-300 ms in both age groups. The amplitude of the earlier part of the vMMN was similar in the older and the younger participants, but latency was longer in the older group. The later part of the vMMN was slightly diminished in the elderly. CONCLUSION: Automatic detection of violated sequential regularities, reflected by the vMMN, emerged in the two age groups (earlier vMMN). However, detection of stimulus change, a preattentive visual process delayed in the elderly, and identification of the specific change was compromised in the older participants. PMID- 29698948 TI - The Role of Clinical Engineers in Dialysis Therapy in Japan. PMID- 29698947 TI - Real-Time Elastography: Noninvasive Diagnostic Tool in the Evaluation of Liver Stiffness in Patients with Chronic Viral Hepatitis, Correlation with Histological Examination. AB - PURPOSE: To determine the value of real-time elastography (RTE) in the assessment of liver stiffness in patients with chronic viral hepatitis, correlating RTE data with the extent of fibrosis based on biopsy findings (Ishak score). METHODS: We evaluated 98 patients (45-75 years) with chronic viral hepatitis (51 HCV, 47 HBV) by using ultrasonography (US) study combined with RTE analysis. In the RTE images, relative tissue stiffness is expressed, according to color scale, with soft areas represented in green/red colors and hard areas in blue. We divided the patients into 2 groups based on the fibrosis degree: soft degree (D1, corresponding to F1-F3 Ishak score) and hard degree (D2, corresponding to F4-F6). Before RTE, all patients underwent a US-guided percutaneous liver biopsy (right lobe). RESULTS: Quantitative RTE data were compared with liver biopsy by using the Spearman correlation coefficient in order to assess the correlation between the RTE (D) and fibrosis, according to Ishak score (F) at histology. At RTE, out of 98 patients 55 had degree D1 and 43 had degree D2; at histological analysis, we observed the following: 15 patients with F1, 28 with F2, 17 with F3, 16 with F4, 12 with F5, and 10 with F6. The Spearman's coefficient showed significant correlation between D and F degree, obtaining rho = 0.573, p = 0.003. CONCLUSIONS: RTE analysis showed high diagnostic accuracy in the assessment of fibrosis, and it appears to be a useful diagnostic tool for noninvasive quantification of fibrosis in patients with chronic viral hepatitis. PMID- 29698949 TI - Salivary and Serum Antioxidant and Oxidative Stress Markers in Dental Caries. AB - Dental caries is the most common, chronic, noncommunicable, preventable oral disease worldwide. Oxidation may play an important role in dental caries initiation and progression. Antioxidants in body fluids protect cells. The aim of this study was to evaluate salivary and serum total antioxidant capacity (TAC) and malondialdehyde (MDA) levels in dental caries. A total of 118 healthy caries free and caries-active male and female students participated. Caries was detected clinically. Unstimulated whole-saliva samples and blood samples were obtained. Sialochemical analysis was carried out by spectrophotometric assay. Data were analyzed with the Student t test using STATA 11. Salivary and serum TAC levels in the case and control groups did not show any significant differences. Mean salivary MDA levels in the case and control groups were 0.71 +/- 0.1 and 0.35 +/- 0.06 nmol/mL, respectively. The results showed significantly higher levels of salivary and serum MDA in the case group compared to the healthy control group. The oxidative stress marker was significantly higher in the caries group compared to the healthy control group. Antioxidants were not significantly different between the two groups. MDA can be produced by dental caries, resulting in a decrease in antioxidant levels, causing disease progression. Further studies are necessary to determine whether MDA is the cause or effect of the disease. PMID- 29698950 TI - The Influence of Reactive Oxygen Species and Glucocorticoids on Dry Skin in a Mouse Model of Arthritis. AB - BACKGROUND: Dry skin induced by rheumatoid arthritis (RA) causes itching, which negatively influences a patient's quality of life. We previously reported that mast cells are related to dry skin in arthritic mice. However, the mechanism of mast cell activation is unclear. In this study, we examined the mechanism underlying the formation of dry skin induced by mast cells in arthritis that involves thymic stromal lymphopoietin (TSLP), neutrophils, reactive oxygen species (ROS), and glucocorticoids. METHODS: Mice with DBA/1JJmsSlc collagen induced arthritis were treated with inhibitors or neutralizing antibodies. We measured transepidermal water loss (TEWL) to examine the modulating signal of mast cells. RESULTS: TEWL, the number of mast cells, and the plasma levels of TSLP, ROS, and corticosterone in the arthritic mice were increased when compared with the control mice. However, the mice treated with TSLP- and neutrophil neutralizing antibodies and ROS and glucocorticoid receptor inhibitors (N-acetyl L-cysteine [NAC] and RU-486, respectively) experienced an improvement. The ameliorating effect was most remarkable following treatment with NAC + RU-486. CONCLUSION: This study suggested that inhibiting ROS and glucocorticoids is important to ameliorate dry skin in arthritis, which may provide a novel treatment option for dry skin in RA patients. PMID- 29698951 TI - Usefulness of Fecoflowgram for Assessment of Defecation after Intersphincteric Resection. AB - AIM: We have developed an imaging functional assessment of defecation after partial intersphincteric resection (ISR) by fecoflowgram obtained by defecography. PATIENTS AND METHODS: Between January 2012 and December 2014, 6 patients with temporary ileostomy who underwent partial ISR for lower rectal cancer at our hospital were enrolled in this study. Defecography was performed 2 weeks after closure of the ileostomy. The defecation of all patients was evaluated by defecography and a fecoflowgram calculated from defecography. During the same period, the control group was comprised of 2 male and 2 female healthy volunteers. RESULTS: The descent of the perineum and linearization of the anorectal angle was observed relative to normal defecation in the healthy volunteers. All barium was discharged by a single abdominal pressure within 5 s in the controls. In patients after partial ISR, all barium could not be discharged by a single abdominal pressure. The time course of pressure distribution after ISR was lower than that of healthy volunteers, which could not be evaluated by defecography. Defecation time in patients following ISR was longer than that of healthy volunteers. CONCLUSION: Fecoflowgrams calculated from defecography seem to be useful for functional assessment of defecation after rectal resection. PMID- 29698953 TI - Developments in the Role of Clinical Engineers in Blood Purification Therapy. PMID- 29698952 TI - Combined Systemic Chemotherapy and CT-Guided High-Dose-Rate Brachytherapy for Isolated Local Manifestation of Pancreatic Cancer after Surgical Resection. AB - BACKGROUND: Prospective data on the optimal management of patients with pancreatic ductal adenocarcinoma (PDA) and isolated local manifestation (ILM) after surgery are lacking. Hence, no statements with respect to this entity have been released from most international guidelines including European Society for Medical Oncology, National Comprehensive Cancer Network, and American Society for Clinical Oncology. METHODS: We report for the first time a case-series of 3 patients with PDA and ILM receiving combined systemic chemotherapy and CT-guided high-dose-rate interstitial brachytherapy (CT-HDRBT). RESULTS: CT-HDRBT allowed in all patients with pronounced chemotherapy-induced side effects either a pause of cytostatic treatment or de-escalation to a "maintenance" therapy (dose reduction, interval prolongation, scheme modification with withdrawal of most toxic drugs). CONCLUSION: Combining CT-HDRBT to systemic chemotherapy in patients with PDA and ILM is feasible and safe. As for patients with PDA and ILM no standard of care exists, designing an appropriate randomized prospective trial for this highly selected group of patients is challenging. PMID- 29698954 TI - Giant Thoracolumbar Dumbbell Ganglioneuroma. PMID- 29698955 TI - Serum Uromodulin: A Biomarker of Long-Term Kidney Allograft Failure. AB - BACKGROUND: Uromodulin is a kidney-derived glycoprotein and putative tubular function index. Lower serum uromodulin was recently associated with increased risk for kidney allograft failure in a preliminary, longitudinal single-center European study involving 91 kidney transplant recipients (KTRs). METHODS: The Folic Acid for Vascular Outcome Reduction in Transplantation (FAVORIT) trial is a completed, large, multiethnic controlled clinical trial cohort, which studied chronic, stable KTRs. We conducted a case cohort analysis using a randomly selected subset of patients (random subcohort, n = 433), and all individuals who developed kidney allograft failure (cases, n = 226) during follow-up. Serum uromodulin was determined in this total of n = 613 FAVORIT trial participants at randomization. Death-censored kidney allograft failure was the study outcome. RESULTS: The 226 kidney allograft failures occurred during a median surveillance of 3.2 years. Unadjusted, weighted Cox proportional hazards modeling revealed that lower serum uromodulin, tertile 1 vs. tertile 3, was associated with a threefold greater risk for kidney allograft failure (hazards ratio [HR], 95% CI 3.20 [2.05-5.01]). This association was attenuated but persisted at twofold greater risk for allograft failure, after adjustment for age, sex, smoking, allograft type and vintage, prevalent diabetes mellitus and cardiovascular disease (CVD), total/high-density lipoprotein cholesterol ratio, systolic blood pressure, estimated glomerular filtration rate, and natural log urinary albumin/creatinine: HR 2.00, 95% CI (1.06-3.77). CONCLUSIONS: Lower serum uromodulin, a possible indicator of less well-preserved renal tubular function, remained associated with greater risk for kidney allograft failure, after adjustment for major, established clinical kidney allograft failure and CVD risk factors, in a large, multiethnic cohort of long-term, stable KTRs. PMID- 29698956 TI - Long-Term Hearing Outcomes following Stapedotomy in Patients with Otosclerosis and Preoperative Small Air-Bone Gap. AB - OBJECTIVES: To assess the long-term effectiveness of stapedotomies performed on patients with otosclerosis and preoperative small air-bone gaps (ABGs). METHODS: Retrospective study comparing the 10-year postoperative hearing outcomes after primary stapedotomies in patients with small (<=20 dB) and large ABGs (> 20 dB). Ninety out of 175 stapedotomies (22 and 68 in the small and large ABG groups, respectively) were monitored with long-term follow-ups. RESULTS: Ten years after the operation, hearing measurements were similar for both groups, although a significant decline of bone conduction thresholds was evident (p = 0.007 and p < 0.001, respectively). An improvement of >=10 dB in the postoperative ABG (clinical improvement) was achieved only in the large ABG group. CONCLUSIONS: Even though long-term hearing levels will evolve similarly in patients with <=20 and > 20 dB preoperative ABGs, the lack of clinical improvement found in the small ABG group is not in favor of an early surgery. PMID- 29698957 TI - Smoking History as a Predictor of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Patients with Non-Small Cell Lung Cancer Harboring EGFR Mutations. AB - BACKGROUND: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKIs) therapy has been recognized as the standard treatment for patients with non-small cell lung cancer (NSCLC) harboring EGFR mutations. However, resistance to EGFR-TKIs has been observed in certain subpopulations of these patients. We aimed to evaluate the impact of smoking history on the efficacy of EGFR-TKIs. METHODS: The records of patients (n = 248) with NSCLC harboring activating EGFR mutations who were treated with gefitinib or erlotinib at our institution between March 2010 and June 2016 were retrospectively reviewed, and the treatment outcomes were evaluated. RESULTS: The overall response rate and median progression-free survival (PFS) were 59.7% and 10.7 months, respectively. The overall response rate was significantly higher in the ex- and nonsmokers than in the current smokers (64.6 vs. 51.1%, p = 0.038). PFS also differed significantly between the current smokers and the ex- and nonsmokers (12.4 vs. 7.4 months, p = 0.016). Multivariate analysis identified smoking history as an independent predictor of PFS and overall survival. CONCLUSION: The clinical data obtained in this study provide a valuable rationale for considering smoking history as a predictor of the efficacy of EGFR-TKI in NSCLC patients harboring activating EGFR mutations. PMID- 29698958 TI - Vibrant Soundbridge Implantation: Floating Mass Transducer Coupled with the Stapes Head and Embedded in Fat. AB - Subtotal petrosectomy may be performed for refractory chronic middle ear diseases, such as massive cholesteatoma or recurrent otitis media. It involves permanent obliteration of the operative cavity, thus precluding the chance to restore conductive hearing via traditional inertial ossicular prostheses. The Vibrant Soundbridge (VSB) is an alternative option for hearing rehabilitation. Vibrant energy is delivered into the inner ear via a floating mass transducer (FMT), which can be coupled with any part of the middle ear acoustic transmission structure. To restore the hearing of a young woman with cholesteatoma, we combined subtotal petrosectomy with obliteration of the cavity and VSB implantation with an FMT coupled to the stapes head. Two years of follow-up demonstrated excellent auditory rehabilitation, improved sound source localization ability, and a lower speech recognition threshold. This study showed that the FMT works well in an obliterated cavity, and the experience acquired through this successful exploration is worth disseminating. PMID- 29698959 TI - Lectin Affinity Plasmapheresis for Middle East Respiratory Syndrome-Coronavirus and Marburg Virus Glycoprotein Elimination. AB - BACKGROUND/AIMS: Middle East respiratory syndrome coronavirus (MERS-CoV) and Marburg virus (MARV) are among the World Health Organization's top 8 emerging pathogens. Both zoonoses share nonspecific early symptoms, a high lethality rate, and a reduced number of specific treatment options. Therefore, we evaluated extracorporeal virus and glycoprotein (GP) elimination by lectin affinity plasmapheresis (LAP). METHODS: For both MERS-CoV (pseudovirus) as well as MARV (GPs), 4 LAP devices (Mini Hemopurifiers, Aethlon Medical, San Diego, CA, USA) and 4 negative controls were tested. Samples were collected every 30 min and analyzed for reduction in virus infectivity by a flow cytometry-based infectivity assay (MERS-CoV) and in soluble GP content (MARV) by an immunoassay. RESULTS: The experiments show a time-dependent clearance of MERS-CoV of up to 80% within 3 h (pseudovirus). Up to 70% of MARV-soluble GPs were eliminated at the same time. Substantial saturation of the binding resins was detected within the first treatment hour. CONCLUSION: MERS-CoV (pseudovirus) and MARV soluble GPs are eliminated by LAP in vitro. Considering the high lethality and missing established treatment options, LAP should be evaluated in vivo. Especially early initiation, continuous therapy, and timed cartridge exchanges could be of importance. PMID- 29698961 TI - Impact of Serum Vancomycin Trough Levels in the Treatment of Central Nervous System Shunt Infections Caused by Coagulase-Negative Staphylococci. AB - Coagulase-negative staphylococci (CoNS) are a common cause of pediatric ventricular shunt infections. The Infectious Diseases Society of America recommends vancomycin serum troughs of 15-20 ug/mL when treating CoNS shunt infections in adult patients. We report a series of pediatric cases of CoNS shunt infections in which clinical cure was obtained with troughs < 15 ug/mL. These findings question the relevance of this recommendation in pediatric patients. PMID- 29698960 TI - Protective Effects of Fucoidan on Epithelial-Mesenchymal Transition of Retinal Pigment Epithelial Cells and Progression of Proliferative Vitreoretinopathy. AB - BACKGROUND/AIMS: Proliferative vitreoretinopathy (PVR) is a severe blinding complication of rhegmatogenous retinal detachment. Epithelial-mesenchymal transition (EMT) of retinal pigment epithelial (RPE) cells is thought to play a pivotal role in the pathogenesis of PVR. Fucoidan, a marine extract, reportedly has many benefits effects in a variety of tissues and organs such as anti inflammation, anti-oxidative stress, and anti-carcinogenesis. In this study, we investigated the potential role of fucoidan on EMT in RPE cells and its effect on the development of PVR. METHODS: MTS, Transwell, and collagen gel contraction assays were employed to measure the viability, migration, and contraction of RPE cells, respectively. mRNA and protein expression were evaluated via real-time quantitative PCR and western blot analysis, respectively. In vivo, a pigmented rabbit model of PVR was established to examine the anti-PVR effect of fucoidan. RESULTS: Fucoidan reversed the transforming growth factor (TGF)-beta1-induced EMT of RPE cells, including the increased expression of alpha-smooth muscle actin (alpha-SMA) and fibronectin and down-regulation of E-cadherin in human primary RPE cells. Moreover, the upregulation of phosphorylated Smad2/3 induced by TGF beta1 was suppressed by fucoidan. Fucoidan also inhibited the migration and contraction of RPE cells induced by TGF-beta1. In vivo, fucoidan inhibited the progression of experimental PVR in rabbit eyes. Histological findings showed that fucoidan suppressed the formation of alpha-SMA-positive epiretinal membranes. CONCLUSION: Our findings regarding the protective effects of fucoidan on the EMT of RPE cells and experimental PVR suggest the potential clinical application of fucoidan as an anti-PVR agent. PMID- 29698962 TI - Subacute Combined Degeneration: A Retrospective Study of 68 Cases with Short-Term Follow-Up. AB - PURPOSE: The study aimed to analyze the clinical characteristics, laboratory test results, neuroimaging findings, and outcomes in patients diagnosed with subacute combined degeneration (SCD). MATERIALS AND METHODS: A total of 68 patients with SCD who had been appropriately treated for no less than 6 months were included in our study. Histories, results of routine blood tests, biochemical indices, serum vitamin B12 levels, and spinal magnetic resonance imaging (MRI) findings from the patients were studied and analyzed. Clinical signs and symptoms, graded using a functional disability rating scale, were scored at the time of admission and 3 and 6 months after admission. RESULTS: Limb numbness, limb weakness, and gait disturbances were the most common symptoms in patients with SCD. All patients showed clinical improvement to different degrees at the follow-up visits after vitamin B12 treatment. No differences in rating score were found in patients grouped by sex, hemoglobin level, serum vitamin B12, or MRI manifestations at the time of admission or at the follow-up visits. Younger patients and those with shorter disease courses had better rating scores at the short-term follow-up visits. CONCLUSION: Anemia, low levels of serum vitamin B12, and MRI abnormalities in the spinal cord are not expected to be associated with worse clinical manifestations. The age of onset and course of disease are important in evaluating the short-term prognosis of patients with SCD. PMID- 29698963 TI - Effects of a Voice Therapy Program for Patients with Muscle Tension Dysphonia. AB - OBJECTIVE: This study aimed to verify the effects of a voice therapy program focusing on patients with muscle tension dysphonia (MTD). PATIENTS AND METHODS: The sample comprised 30 participants diagnosed with MTD, 8 men and 22 women, none of whom was a voice professional. The assessments and reassessments employed the perceptual-auditory protocol GRBASI, measures of maximum phonation times, s/z ratio, and acoustic voice analysis. The voice therapy program included indirect and direct therapy approaches. RESULTS: All parameters assessed using the GRBASI protocol improved following treatment, particularly in regard to lowering voice strain, which is important when treating MTD. The average overall maximum phonation times increased from 8.15 to 10.8 s, while the average s/z ratio did not significantly change. Among the various acoustic parameters, a positive difference was observed for vocal jitter and shimmer. CONCLUSIONS: The therapeutic approach adopted in this study proved effective in the treatment of primary and secondary MTD. Speech therapy favored lower phonation effort, lowered vocal strain, and adequacy of adjustment of laryngeal muscles. PMID- 29698964 TI - Announcing a New Affiliated Society Member of Blood Purification: The Japan Association for Clinical Engineers. PMID- 29698965 TI - Lack of Change in the Adaptation Ability of the Bladder for the Urine Production Rate in Aged Men with Nocturia. AB - INTRODUCTION: To investigate the association between bladder capacity and the urine production rate in aged men with or without nocturia using a frequency volume chart (FVC). MATERIALS AND METHODS: One-hundred and thirty-eight men aged 65-80 years were enrolled. After the International Prostate Symptom Score (IPSS) and 3 consecutive days FVC were evaluated, men were divided into 2 groups: Nocturia group, with any total IPSS, and >=1.5 micturition on average at night; and Control group, with total IPSS < 8 and < 1.5 micturition on average at night. Each parameter was compared between the 2 groups using unpaired t tests. Linear and multiple regression analyses were performed between the urine production rate and volume/voids. RESULTS: Men numbering 45 and 21 were assigned to the Nocturia and Control groups respectively. There were no differences in background factors between the 2 groups. Volume/voids positively correlated with the urine production rate in both groups for day and night. A multivariate regression model also showed the same results. In the Control group, the degree of slope at night was higher than that during the day. However, in the Nocturia group, there were no differences in the degree of slope between day and night. CONCLUSIONS: This novel finding has led to a possibility for resolving nocturia. PMID- 29698966 TI - Diamine Oxidase Supplementation in Chronic Spontaneous Urticaria: A Randomized, Double-Blind Placebo-Controlled Study. AB - INTRODUCTION: Diamine oxidase (DAO) catabolizes and inactivates histamine, a key player in a wide range of invalidating conditions, such as migraine and chronic spontaneous urticaria (CSU). The highest expression of DAO occurs in the gastrointestinal tract, possibly to control the burden of histamine intake from food. METHODS: Here, we tested the hypothesis that a 30-day oral supplementation with DAO (1 capsule b.i.d., 15 min before a meal) could reduce the severity of CSU as estimated by the 7-Day Urticaria Activity Score (UAS-7). The study was designed as a double-blind, placebo-controlled, crossover investigation of 22 patients with CSU incompletely controlled by first-line antihistamine therapy. RESULTS: Twenty patients completed the study. Supplemental therapy with DAO caused a 3.8 +/- 1.2 point mean +/- SEM UAS-7 score reduction in patients with low serum DAO levels at time 0 (p = 0.041 compared to placebo). The degree of UAS 7 improvement was inversely correlated with the levels of basal DAO (p = 0.019). Patients receiving DAO supplementation were able to slightly reduce their daily antihistamine dose (p = 0.049). CONCLUSION: These data suggest that DAO may be involved in the pathogenic cascade of CSU and that DAO supplementation could be effective for symptom relief in patients with low DAO levels in serum. PMID- 29698967 TI - Motorized Spiral Enteroscopy for Occult Bleeding. AB - Small-bowel disorders remain a diagnostic and therapeutic challenge due to intestinal length. Their management was revolutionized by the emergence of deep enteroscopy. In comparison with video capsule endoscopy, deep enteroscopy allows diagnostic and therapeutic interventions. Spiral enteroscopy (Spirus Medical Endo Ease Overtube) achieves progression by gentle push and manual clockwise rotation inducing pleating of the small bowel on the endoscope. It has the advantage of shorter examination time and more stability during withdrawal but requires two operators. The Novel Motorized Spiral Enteroscope (Olympus Corp.) incorporates a user-controlled motor contained in the handle of the endoscope. This would offer the possibility to accelerate the procedure, facilitate insertion, and simplify the technique with a single operator. PMID- 29698968 TI - Gamma Knife Stereotactic Radiosurgery for the Treatment of Brain Metastases from Primary Tumors of the Urinary Bladder. AB - BACKGROUND/AIMS: Brain metastases from bladder cancer are rare and published outcomes data are sparse. To date, no institutions have reported a series of patients with brain metastases from bladder cancer treated with stereotactic radiosurgery (SRS). Our aim was to identify patients with brain metastases from bladder primaries treated with SRS with or without surgical resection and report the clinical outcomes. METHODS: Patients meeting eligibility criteria at our institution between 2000 and 2017 were included. The clinical variables of interest, including overall survival (OS), local recurrence, V12, distant brain failure (DBF), and initial brain metastases velocity, were calculated. Cox proportional hazards analysis was performed to identify predictors of time-to event outcomes. RESULTS: A total of 14 patients were included. The median OS from the time of treatment was 2.1 months. Factors predictive of OS include intracranial resection (HR 0.21, p = 0.03). The cumulative incidence of local failure was 21% at 6 months and 30% at 12 months. The cumulative incidence of DBF at 6 and 12 months was 23 and 31%, respectively. CONCLUSIONS: The prognosis in this patient population remains guarded. Factors associated with improved survival include intracranial resection. Future, prospective work is needed to further define optimal management. PMID- 29698969 TI - Endoscopic Ultrasound Features of Multiple Endocrine Neoplasia Type 1-Related versus Sporadic Pancreatic Neuroendocrine Tumors: A Single-Center Retrospective Study. AB - AIM: Pancreatic neuroendocrine tumors (pNETs) can occur in patients with a familial syndrome either as multiple endocrine neoplasia type 1 (MEN-1) or as sporadic tumors. Endoscopic ultrasound (EUS) has become one of the first-line investigations for pNET characterization. The ultrasonographic features of pNETs may differ depending on the familial versus sporadic pathogenesis of the tumor. Therefore, the EUS findings could help and direct the definition of a pNET with an impact on the most appropriate diagnostic and therapeutic patient management. METHODS: In this single-center retrospective study, we reviewed the EUS features of 94 pNETs from 37 MEN-1 patients and 15 pNETs from 11 sporadic disease patients at the time of their first EUS assessment. We analyzed the most relevant morphological and ultrasonographic characteristics of the tumors and compared the findings between the 2 patient groups. RESULTS: Patients with MEN-1 more likely present with multiple pNETs than patients with sporadic disease. Sporadic pNETs are usually much bigger than those due to MEN-1. Moreover, pNETs are more heterogeneous in patients with sporadic disease than in those with MEN-1. No statistical difference with regard to definition of the margins, morphology, and vascularization of the pNETs appears between the 2 groups. CONCLUSIONS: Patients with sporadic disease usually present with bigger and more heterogeneous pNETs than patients with MEN-1, who tend to present with a higher number of lesions. EUS can facilitate the precise characterization of a pNET, and the ultrasonographic features of the lesion can help and distinguish MEN-1-related versus sporadic disease. PMID- 29698970 TI - Apparent Treatment Resistant Hypertension, Blood Pressure Control and the Progression of Chronic Kidney Disease in Patients with Type 2 Diabetes. AB - BACKGROUND/AIMS: Apparent treatment resistant hypertension (aTRH) is highly prevalent in patients with type 2 diabetes (T2D) and chronic kidney disease (CKD). The impact of aTRH and achievement of recommended blood pressure (BP) values on the rate of glomerular filtration rate (eGFR) loss in CKD patients is poorly known. To assess the role of aTRH and time-updated BP control (BPC) on the progression of CKD in patients with T2D and hypertension (HT) in real life clinical practice. METHODS: Clinical records from a total of 2,778 diabetic patients with HT and stage 3 CKD (i.e. baseline eGFR values between 30 and 60 ml/min) and regular visits during a four-year follow-up were analyzed. The association between BPC (i.e. 75% of visits with BP <140/90 mmHg) and eGFR loss (i.e. a >30% reduction from baseline) or worsening of albuminuria status over time was assessed. RESULTS: At baseline 33% of patients had aTRH. Over the 4-year follow-up, 20% had a >30% eGFR reduction. Patients with aTRH had an increased risk of eGFR loss >30% (OR 1.31; P<0.007). In patients with aTRH, BPC was associated with a 79% (P=0.029) greater risk of eGFR reduction despite a 58% (P=0.001) lower risk of albuminuria status worsening. In non-aTRH, no association was found between BPC and renal outcome. CONCLUSION: In patients with stage 3 CKD the presence of aTRH entails a faster loss of eGFR. More effective prevention of aTRH should be implemented as this condition is associated with a burden of risk not modifiable by tight BP reduction. PMID- 29698971 TI - Effectiveness of Wound-Edge Protectors for Preventing Surgical Site Infections after Open Surgery for Colorectal Disease: A Prospective Cohort Study with Two Parallel Study Groups. AB - BACKGROUND: Standard procedures to reduce the surgical site infection (SSI) rate after colorectal surgery have not been established. A prospective cohort study with 2 parallel study groups was performed to clarify the SSI rate after open surgery with and without a wound-edge protector (WEP) for colorectal disease. METHODS: A total of 102 patients who underwent elective open surgery for colorectal disease between October 2012 and August 2014 were randomly assigned to a WEP group and a WEP (-) group. The primary endpoint was the SSI rate in both groups. RESULTS: Fifty-one patients were assigned to the WEP group and 51 to the WEP (-) group. Two patients were excluded from this study. The rate of SSI with and without a WEP was 16 and 36% respectively (p = 0.021). Older age (p = 0.0073) and no WEP (p = 0.021) were risk factors for SSI after open surgery for colorectal diseases on univariate analysis. On multivariate analysis, both older age (p = 0.016) and no WEP (p = 0.012) were independent risk factors for SSI. CONCLUSION: The present randomized, phase II trial found an SSI rate of 16% with use of a WEP. The SSI rate was lower in the WEP group than in the WEP (-) group. A WEP may reduce the SSI rate after open surgery for colorectal disease in Japanese patients. PMID- 29698972 TI - Icariin Restores Bone Structure and Strength in a Rat Model of Chronic High-Dose Alcohol-Induced Osteopenia. AB - BACKGROUND/AIMS: Chronic alcohol abuse is an important risk factor for osteopenia. However, few studies have focused on the efficacy and mechanism of action of icariin on alcohol-induced osteopenia. The aim of this study was to investigate the efficacy and underlying mechanism of action of icariin in the treatment of chronic high-dose alcohol-induced osteopenia in a rat model. METHODS: Thirty-six adult male Sprague-Dawley rats were randomly divided into four groups: sham, alcohol, and low-dose and high-dose icariin groups. Bone volume fraction (BV/TV), bone mineral density (BMD), bone biomechanical properties, and bone morphology were assessed after 16 weeks. Reverse transcription PCR was used to detect mRNA expression levels of alkaline phosphatase (ALP), collagen type I (Col I), osteocalcin (OC), runt-related transcription factor 2 (Runx2), bone morphogenetic protein-2 (BMP-2), and osteoprotegerin (OPG). RESULTS: Bone metabolic markers and biomechanical properties in the alcohol group were decreased significantly compared with the sham group. BV/TV, BMD, mineral apposition rate (MAR), percent trabecular area (%Tb.Ar), and bone biomechanical properties were elevated in the low-dose and high-dose icariin groups relative to the alcohol group. ALP, Col I, OC, Runx2, BMP-2, and OPG mRNA levels in the icariin group were significantly elevated in comparison with the alcohol group. CONCLUSION: Icariin can prevent overall progression of chronic high-dose alcohol-induced osteopenia in a rat model, in a dose-dependent manner. Icariin promotes bone formation and inhibits bone loss, and effectively restores bone structure and strength in chronic high-dose alcohol induced osteopenic rats. Bone metabolism reversal is evidenced by increased BV/TV, BMD, MAR, %Tb.Ar, and biomechanical properties and elevated ALP, Col I, OC, Runx2, BMP-2, and OPG mRNA levels. PMID- 29698973 TI - The Novel Biomarker of Germ Cell Tumours, Micro-RNA-371a-3p, Has a Very Rapid Decay in Patients with Clinical Stage 1. AB - BACKGROUND: Accumulating evidence suggests serum levels of microRNA (miR)-371a-3p to be a novel tumour marker of testicular germ cell tumours (GCTs). Presently, there is only limited information regarding the velocity of decline of serum levels in response to treatment. PATIENTS AND METHODS: Twenty-four patients with testicular GCT (20 seminoma, 4 nonseminoma, median age 40 years) with clinical stage 1 had measurements of serum levels of miR-371a-3p preoperatively and repeatedly on the following 3 days. Three had additional tests done within 24 h after surgery. Measurement results were analysed using descriptive statistical methods. RESULTS: Serum levels dropped to 2.62, 1.27, and 0.47% of the preoperative level within 1, 2, and 3 days, respectively. The computed half-life amounts to 3.7-7 h. The velocity of decay is significantly associated with tumour size. CONCLUSIONS: Serum-levels of miR-371a-3p have a short half-life of less than 12 h. The rapid decay after treatment represents a valuable feature confirming the usefulness of miR-371a-3p as a valuable serum biomarker of GCT. PMID- 29698974 TI - HOXD3 Plays a Critical Role in Breast Cancer Stemness and Drug Resistance. AB - BACKGROUND/AIMS: Homeobox D3 (HOXD3) is a member of the homeobox family of genes that is known primarily for its transcriptional regulation of morphogenesis in all multicellular organisms. In this study, we sought to explore the role that HOXD3 plays in the stem-like capacity, or stemness, and drug resistance of breast cancer cells. METHODS: Expression of HOXD3 in clinical breast samples were examined by RT-PCR and immunohistochemistry. HOXD3 expression in breast cancer cell lines were analyzed by RT-PCR and western blot. Ability of drug resistance in breast cancer cells were elevated by MTT cell viability and colony formation assays. We examined stemness using cell fluorescent staining, RT-PCR and western blot for stem cell marker expression. Finally, activity of wnt signaling was analyzed by FOPflash luciferase assays. RT-PCR and western blot were performed for downstream genes of wnt signaling. RESULTS: We demonstrated that HOXD3 is overexpressed in breast cancer tissue as compared to normal breast tissue. HOXD3 overexpression enhances breast cancer cell drug resistance. Furthermore, HOXD3 upregulation in the same cell lines increased sphere formation as well as the expression levels of stem cell biomarkers, suggesting that HOXD3 does indeed increase breast cancer cell stemness. Because we had previously shown that HOXD3 expression is closely associated with integrin beta3 expression in breast cancer patients, we hypothesized that HOXD3 may regulate breast cancer cell stemness and drug resistance through integrin beta 3. Cell viability assays showed that integrin beta 3 knockdown increased cell viability and that HOXD3 could not restore cancer cell stemness or drug resistance. Given integrin beta 3's relationship with Wnt/beta-catenin signaling, we determine whether HOXD3 regulates integrin beta 3 activity through Wnt/beta-catenin signaling. We found that, even though HOXD3 increased the expression of Wnt/beta-catenin downstream genes, it did not restore Wnt/beta-catenin signaling activity, which was inhibited in integrin beta3 knockdown breast cancer cells. CONCLUSION: We demonstrate that HOXD3 plays a critical role in breast cancer stemness and drug resistance via integrin beta3-mediated Wnt/beta-catenin signaling. Our findings open the possibility for improving the current standard of care for breast cancer patients by designing targeted molecular therapies that overcome the barriers of cancer cell stemness and drug resistance. PMID- 29698975 TI - Intrarenal Arterial Lesions Are Associated with Higher Blood Pressure, Reduced Renal Function and Poorer Renal Outcomes in Patients with IgA Nephropathy. AB - BACKGROUND/AIMS: Arterial fibrotic intimal thickening and arteriolar hyaline are considered common pathological features in immunoglobulin A nephropathy (IgAN), whereas little is known about the acute pathological manifestations of endothelial cell injury. The aim of this study was to investigate characteristics of intrarenal arterial lesions and to estimate their prognostic values in patients with IgAN. The primary renal endpoint was a 50% reduction in estimated glomerular filtration rate (eGFR) or end-stage renal disease (ESRD). METHODS: Various renal arterial lesions (arterial fibrotic intimal thickening, arteriolar hyaline, arteriolar endotheliocyte swelling, arteriolar inflammatory cell infiltration, and arteriolar thrombosis) in 1683 patients with IgAN were reviewed and reclassified using a semi-quantitative scoring system. Their correlations with clinical features, pathological characteristics, and renal outcomes were evaluated. RESULTS: The prevalence of intrarenal arterial lesions was up to 72.2% in IgAN patients. There were 978 patients (58.1%) with arterial fibrotic intimal thickening, 350 patients (20.8%) with arteriolar hyaline, 432 patients (25.7%) with arteriolar endotheliocyte swelling, 356 patients (21.2%) with arteriolar inflammatory cell infiltration and 43 patients (2.6%) with arteriolar thrombosis. Arterial fibrotic intimal thickening and arteriolar hyaline were strongly associated with higher mean arterial pressure (MAP) and reduced eGFR (P < 0.001) but were not related to proteinuria at the time of renal biopsy. In contrast, arteriolar endotheliocyte swelling and arteriolar thrombosis were correlated with heavier proteinuria as well as higher MAP and reduced eGFR. During follow-up, patients with vascular lesions received more renin-angiotensin system (RAS) blockade and less glucocorticoid and showed poorer renal outcomes. Univariate Cox model showed that the presence of renal vascular lesions [hazard ratio (HR) = 25.01, 95% confidence interval (CI): 6.19 to 101.03, P < 0.001] was a risk factor for renal outcomes. However, in multivariable Cox analysis, which included clinical factors and the Oxford-MEST-C, vascular lesions were not significantly associated with an increased risk of renal failure. Remarkably, the impact of vascular lesions on the survival from ESRD or 50% reduction in renal function was eliminated by the use of RAS blockade after adjustment for eGFR, proteinuria, and MAP. CONCLUSION: Our study demonstrates the high prevalence of vascular lesions, including the chronic and acute arterial pathological changes, in patients with IgAN. The presence of vascular lesions is associated with higher MAP, reduced eGFR and poorer renal outcomes, which could be influenced by the RAS blockade treatment. PMID- 29698981 TI - Partial Hemiresurfacing of Osteochondral Defects of the Talus? Surgical Technique and Preliminary Report from Four Patients. AB - BACKGROUND: Osteochondral lesions of the medial talus (OLT) frequently lead to chronic ankle pain and osteoarthritis. Arthroscopic debridement, subchondral bone stimulation by drilling, and microfracturing are options for primary therapy in small lesions. In larger lesions, restoration of the talar dome contour seems to be a mandatory course of action. METHODS: In a case series, we followed up four patients being treated with a focal resurfacing prosthetic due to large osteochondral talar lesions. In contrast to other studies, we can report on an off-label application to restore defects of the lateral talar dome with two patients for the first time. At follow-up, three patients reported a remarkable reduction in pain and were able to return to sports activities. One patient developed pseudarthrosis of the medial malleolar osteosynthesis. CONCLUSIONS: With selected patients, focal resurfacing appears to be an option for large osteochondral defects of the talus. PMID- 29698982 TI - A Fast Track to Hypoalgesia - The Anaerobic Exercise Effect on Pain Sensitivity. AB - Maximal anaerobic exercise, is a short high intensity effort, involves activation of the hypothalamus-pituitary-adrenal axis, and may suggest hypoalgesic effects. In addition, this exercise-induced muscle pain may contribute to hypoalgesia via the pain inhibits pain phenomenon, which is related to the diffuse noxious inhibitory control (DNIC) mechanism. We aimed to investigate whether: 1) a single bout of 30 s maximal anaerobic exercise has an analgesic effect on experimental pain sensitivity; 2) DNIC is the underlying mechanism of anaerobic exercise induced hypoalgesia (EIH). Fifty healthy subjects participated. The experimental group performed the 'Wingate Anaerobic Test' (WAT) and controls set on the bikes without exercising. Psychophysical tests, performed before and after the intervention, in local and remote areas, included: heat (HPT) and pressure pain thresholds (PPT); suprathreshold heat and cold pain stimulation; the conditioned pain modulation (CPM) paradigm testing the DNIC mechanism. Following WAT, PPT and HPT increased (p<0.001) , pain ratings in response to heat and cold stimuli (p<0.001) and CPM (p=0.029) decreased compared with controls. No correlation was found between muscle pain, blood lactate level and EIH. To conclude WAT induces local and remote analgesic effects. The involvement of central pain modulatory processes with DNIC probably not the underline mechanism of EIH. PMID- 29698983 TI - microRNAs in High and Low Responders to Resistance Training in Breast Cancer Survivors. AB - Accounting for one in three cancer diagnoses, breast cancer is the second most commonly diagnosed cancer in women. Exercise has a well-accepted role in the multi-disciplinary approach to rehabilitating breast cancer survivors. Despite the many known benefits of resistance training on women recovering from breast cancer, the molecular mechanisms are poorly understood. MicroRNAs are small non coding RNAs that have crucial roles in growth and development. Here, we analysed the abundance of 9 miRNAs, with known roles in muscle physiology and some linked to cancer, in serum samples from 24 breast cancer survivors before and after a 16 week resistance training or usual care intervention. The resistance training group completed supervised thrice-weekly training. miRNA abundance was assessed before and after the intervention period using qPCR. There were no statistically significant changes in any of the miRNAs between groups after the intervention period (all p>0.05). After assessing miRNA abundance in context with high and low responders to resistance training, we observed that relative to low responders, high responders exhibited increased miR-133a-3p and a borderline statistically significant increase in miR-370-3p. Findings from our controlled study indicate the diverse interindividual miRNA responses to resistance training and reveal a discordant regulation between high and low responders. PMID- 29698984 TI - Antiprotozoal Diterpenes from Perovskia abrotanoides. AB - As part of a screening for new antiparasitic natural products from Iranian plants, n-hexane and ethyl acetate extracts from the aerial parts of Perovskia abrotanoides were found to exhibit strong inhibitory activity against Trypanosoma brucei rhodesiense and Leishmania donovani. The activity was tracked by high performance liquid chromatography (HPLC)-based activity profiling. Preparative isolation by a combination of silica gel column chromatography and HPLC afforded 17 diterpenoids (1: -17: ), including 14 abietane-, two icetexane-, and one isopimarane-type derivatives. Among these, (5R,10S)-11-hydroxy-12-methoxy-20 norabieta-8,11,13-triene (2: ), 12-hydroxy-norabieta-1(10),8,11,13-tetraene-1,11 furan (6: ), and 12-methoxybarbatusol (9: ) were new compounds, the structure of which was established by comprehensive spectroscopic data analysis (one- and two dimensional nuclear magnetic resonance, high-resolution electrospray ionization mass spectrometry, electronic circular dichroism). The antiprotozoal activity of the isolated compounds was evaluated against T. b. rhodesiense, Trypanosoma cruzi, L. donovani, and Plasmodium falciparum. Selectivity indexes (SI) were calculated in comparison to cytotoxicity on rat myoblast (L6) cells. Particularly active were 7alpha-ethoxyrosmanol (4: ) with an IC50 of 0.8 uM against T. b. rhodesiense (SI 14.9) and an IC50 of 1.8 uM (SI 6.9) against L. donovani, ferruginol (8: ) with an IC50 of 2.9 uM (SI 19.2) against P. falciparum, and miltiodiol (10: ) with an IC50 of 0.5 uM (SI 10.5) against T. b. rhodesiense. None of the compounds exhibited selective toxicity against T. cruzi (SI <= 1.6). PMID- 29698985 TI - [Juvenile Dermatomyositis]. PMID- 29698986 TI - [Analysis of Late AMNOG Benefit Assessments]. AB - OBJECTIVE: Since 2011, new drugs are assessed at the time of launch in Germany (AMNOG). Based on this early benefit assessment (EBA), drug prices are negotiated. At this time, the evidence base might be weak. A later benefit assessment (LBA) is not done on a regular basis except for selected drugs. Our objective was to analyze the impact of LBAs of drugs for the same indication. METHODS: Analysis of all completed LBAs between 2011 and 2016. RESULTS: 228 benefit assessments have been performed since 2011. 26 drugs were assessed twice for the same indication. Oncology and diabetes were the most common therapeutic areas in LBA and more pronounced than in EBA. 15 LBAs were due to the EBAs having a time limitation because of insufficient evidence base partially based on conditional approval. Time between EBA and LBA was 2.6 years. All 15 drugs had added benefit in the EBA, 4 got a better, 5 a worse assessment in the LBA. Seven drugs without added benefit in the EBA were assessed at the request of the manufacturer because of new data after 1.7 years. Three drugs could show added benefit in the LBA. Finally, 4 orphan drugs were reassessed according to the AMNOG regulation after achieving annual sales of 50 million euros. One got a better, 2 got a worse benefit assessment. Average improvement of benefit was +1.5 on a scale between - 3 (worst negative benefit) and +9 (highest positive benefit). Average deterioration of added benefit was - 1.4. Negotiated prices were significantly correlated with the change in the benefit assessment. CONCLUSIONS: LBA on a broader evidence base did not result in a significantly changed outcome. A general LBA for all drugs does not appear to be necessary because of the limited effect on the benefit assessment and the price when considering cost and administrative burden of the AMNOG benefit assessment. The selective approach of LBA for specific drugs is sufficient in cases in which the evidence base was limited at launch. PMID- 29698987 TI - Quality Control of Herbal Drugs and Preparations. PMID- 29698988 TI - Correction: The size, morphology, site, and access score predicts critical outcomes of endoscopic mucosal resection in the colon. PMID- 29698989 TI - Digital pancreatoscopy in the evaluation of main duct intraductal papillary mucinous neoplasm: a multicenter study. AB - BACKGROUND: The aim of this study was to investigate the outcomes of digital pancreatoscopy in main duct intraductal papillary mucinous neoplasm (MD-IPMN). METHODS: This was a multicenter retrospective study. Outcomes analyzed were safety, incremental pathology yield compared with previous cross sectional/endoscopic ultrasound (EUS) imaging, and whether the surgical procedure was dictated by the pancreatoscopy. RESULTS: A total of 31 patients were enrolled from six tertiary care centers. Overall, 42 % of cases had findings on pancreatoscopy that were not seen on cross-sectional imaging or EUS. Digital pancreatoscopy dictated the type of surgery performed in 13 patients (42 %) who underwent surgery. However, in patients with a diffusely dilated pancreatic duct (> 10 mm), the pancreatoscopy dictated the type of surgery in 77 % of cases vs. 17 % of cases in the focally dilated pancreatic duct group (10/13 vs. 3/18; P = 0.001). CONCLUSION: Digital pancreatoscopy should be considered in the diagnostic algorithm of MD-IPMN in patients with a diffusely dilated pancreatic duct and without any focal lesions seen on cross-sectional imaging or EUS. PMID- 29698990 TI - Effect of Endocuff-assisted colonoscopy on adenoma detection rate: meta-analysis of randomized controlled trials. AB - BACKGROUND: Yield of Endocuff-assisted colonoscopy (EAC) compared with standard colonoscopy is conflicting in terms of adenoma detection rate (ADR). A meta analysis of randomized controlled trials (RCTs) appears necessary. METHODS: PubMed and Google Scholar were searched in December 2017. Abstracts from Digestive Disease Week and United European Gastroenterology Week meetings were also searched to 2017. All RCTs comparing EAC with standard colonoscopy were included. Analysis was conducted by using the Mantel-Haenszel models. Heterogeneity was quantified using the I2 test. RESULTS: Of the 265 articles reviewed, 12 RCTs were included, with a total of 8376 patients (EAC group 4225; standard colonoscopy group 4151). In the meta-analysis, ADR was significantly increased in the EAC group vs. the standard colonoscopy group (41.3 % vs. 34.2 %; risk ratio [RR] = 1.20, 95 % confidence interval [CI] 1.06 to 1.36; P = 0.003; I2 = 79 %), especially for operators with low-to-moderate ADRs (< 35 %): RR = 1.51, 95 %CI 1.35 to 1.69; P < 0.001; I2 = 43 %). In contrast, this benefit was not reached for operators with high ADRs (> 45 %): RR = 1.01, 95 %CI 0.93 to 1.09; P = 0.87; I2 = 0.0 %). The mean number of adenomas per patient tended to be higher with EAC (mean difference = 0.11 adenomas/patient, 95 %CI - 0.17 to 0.38). Similar results were shown for polyp detection rates (61.6 % vs. 51.4 %; RR = 1.20, 95 %CI 1.06 to 1.36; P = 0.004). Use of the Endocuff did not impact the cecal intubation rate (95.1 % vs. 95.7 %; P = 0.08), or the procedure time compared with standard colonoscopy. Adverse events related to Endocuff were rare and exclusively mild mucosal erosion (4.0 %; 95 %CI 2.0 % to 8.0 %). CONCLUSION: With moderate-quality evidence, this study showed an improvement in ADR with EAC without major adverse events, especially for operators with low-to-moderate ADRs. PMID- 29698991 TI - The Battle Ground between Two Giants: Toe Transfer and Hand Allotransplantation. AB - A few severe hand injuries represent a gray zone for the reconstructive surgeon, for which autologous tissue transfer and allotransplantation can yield satisfactory results, but not without downsides or morbidity.This article is written to address the dilemma of application of both techniques in those selected cases. PMID- 29698992 TI - ? PMID- 29698993 TI - Evolution of Keratoconus: From Diagnosis to Therapeutics. AB - This review describes the evolution of the diagnosis and treatment of keratoconus from the earliest written description to present day. The first description was provided in 1736 by Benedict Duddell who described the prominent corneas of a fourteen-year-old boy. Throughout the 19th century, a variety of surgical procedures were proposed to manage the disease, such as surgically repositioning the pupil away from the cone, iris incarceration to produce a slit-like pupil, cauterization of the cone to produce a scar, and full thickness elliptical excision of the cone. Despite the ingenuity of these procedures, many led to serious complications. In 1936, Ramon Castroviejo revolutionized surgical management by performing the first corneal transplant for keratoconus. The advent of refractive surgery in the 1990s brought about a sudden and critical need for better understanding of keratoconus and corneal ectatic disease. Topographic analysis allowed for earlier detection of keratoconus, prior to clinical signs and symptoms. Tomographic analysis provided analysis of the anterior and posterior surfaces of the cornea and allowed for even earlier detection. The Belin/Ambrosio Enhanced Ectasia Display on the Pentacam incorporates anterior and posterior elevation, pachymetric map, best fit sphere and enhanced reference surface to provide an overall "D" value that is predictive of ectatic disease. This display allows refractive providers to quickly and accurately screen potential refractive surgery candidates to identify those at risk for ectasia and early subclinical keratoconus. Corneal crosslinking was revolutionary in the treatment of keratoconus. There have been several randomized controlled trials that have found it to be safe and effective to halt ectatic progression. Crosslinking was recently approved by the FDA for progressive keratoconus. Currently, there is no clear definition of ectasia progression. Providers must be able to clearly, objectively and consistently diagnose progressive disease to institute timely treatment in the population with the greatest potential benefit. The new Belin ABCD grading system and progression analysis incorporated into the Oculus Pentacam software provides an objective way of assessing progression over time. Keratoconus diagnosis and management have grown tremendously since the first description in 1736, but there is still much to learn about keratoconus and its management. PMID- 29698994 TI - Validity of a basketball-specific complex test in female professional players. AB - The purpose of this study was to assess the validity of a new basketball-specific complex test (BBCT) based on the ascertained match performance.Fourteen female professional basketball players (ages: 23.4 +/- 1.8 years) performed the BBCT and a treadmill test (TT) at the beginning of pre-season training. Lactate, heart rate (HR), time, shooting precision and number of errors were measured during the four test sequences of the BBCT (short distance sprinting with direction changes, with and without a ball; fast break; lay-up parcours; sprint endurance test). In addition, lactate threshold (LT) and HR were assessed at selected times throughout the TT and the BBCT and over 6 (TT) or 10 (BBCT) minutes after the tests. The match performance score (mps) was calculated on specific parameters (e. g. points) collected during all matches during the subsequent season (22 matches). The mps served as the "gold standard" within the validation process for the BBCT and the TT.TT parameters demonstrated an explained variance (EV) between 0 % (HR recovery) and 11 % (running speed at 6 mmol/l LT). The EV from the BBCT was higher and ranged from 0 % (HR recovery 6 minutes after end of exercise) to 28 % (sprint endurance test after 8 of 10 sprints). Ten out of 21 BBCT parameters (48 %) and 2 out of 5 TT parameters (40 %) demonstrated an EV higher than 10 %. Average EV for all parameters was 12 % (BBCT) and 6 % (TT), respectively. The BBCT had a higher validity than the TT for predicting match performance. These findings suggest that coaches and scientists should consider using the BBCT testing protocol to estimate the match performance abilities of elite female players. PMID- 29698996 TI - Alina Surmacka Szczesniak. PMID- 29698995 TI - [Burn wound treatment through enzymatic debridement: First experience in Switzerland]. AB - INTRODUCTION: Thermal injuries are frequent and can be associated with relevant morbidity and mortality in severe cases. Excisional debridement followed by autografting is the standard of care for deep burns, but is associated with serious potential complications. Clinical results of a novel enzymatic debridement based on Bromelain raw material extracted from the pineapple plant (NexobridTM) were published in 2014. At the Center for Burns at the University Hospital Zurich enzymatic debridement was introduced in 2016. Our experience and interpretation of the first 12 cases are reported. PATIENTS AND METHODS: Patients of at least 18 years of age with second and third degree burns were included in this study. Pregnant or breast feeding women were excluded. After so-called "pre soaking" with saline solution, the NexobridTM gel was applied for 4 hours with occlusive sealing. After abrasion of the debris, "post-soaking" with Prontosan(r) followed and definite wound dressings were applied. RESULTS: The mean age of the patients was 51 (19-78) years, the length of hospital stay was 38 (1-92) days. The amount of burns was 25 (1-67) % of the total body surface area (TBSA). On average, 11 (1-18) % of the TBSA was debrided with NexobridTM after 7 (1-19) days. In 8 patients, the defects completely healed without scarring after NexobridTM treatment. In 4 patients additional surgical measures were necessary to complete the debridement as well as to cover the defect. The treatment with NexobridTM was efficient in difficult treatment areas such as back, hands and feet, where preservation of the demis prevented joint contracture through scarring. CONCLUSION: Treatment with NexobridTM extends the armamentarium to treat partial second-degree thermal injuries with good long-term results. It can be applied in analgosedation in an intensive care setting and reduces the need for surgical treatment. PMID- 29698997 TI - Commemorative issue for Alina Szczesniak and Malcolm Bourne. PMID- 29698998 TI - Malcolm Bourne. PMID- 29698999 TI - Metamorphosis of Ichthyophonus Schizonts Transiting the Gastrointestinal Tract of Experimentally Exposed Rainbow Trout. AB - Other than the initial infectious cell, schizonts are the only stage of the parasite Ichthyophonus sp. that has been identified in the tissues of a living host, and they are known to initiate new infections when ingested by a suitable host. However, after feeding Ichthyophonus-infected tissue to Rainbow Trout Oncorhynchus mykiss, we observed that once infection was initiated, some schizonts proceeded to develop into several other morphologic forms indistinguishable from those previously described from recently deceased hosts, decomposing infected corpses, and in vitro culture. It appeared that not all schizonts participated in the infection process; some initiated infection, as expected, while others passed into the intestines, where they morphed into multiple cell types (e.g., schizonts, some with partially digested or ruptured capsules, ameboid plasmodia, merozoites, hyphenated cells, and empty capsules). Some of these cells were viable when cultured, but none was infectious to naive Rainbow Trout when administered by gavage. We posit that (1) not all tissue schizonts are programmed to perform the same function or (2) not all respond similarly to their environment. After consumption by a piscivore, those schizonts that do not initiate an infection do not die but rather metamorphose into different cell types as they transit the gastrointestinal tract and are ultimately released back into the aquatic environment through defecation. The fate of these cells after exiting the host is presently unknown, but they likely represent a segment of the Ichthyophonus life cycle. PMID- 29699000 TI - Spermidine prevents high glucose-induced senescence in HT-22 cells by upregulation of CB1 receptor. AB - Hyperglycaemia-induced neurotoxicity involved in the pathogenesis of diabetic encephalopathy and neuronal senescence is one of the worst effects of hyperglyceamic neurotoxicity. Cannabinoid receptor type 1 (CB1) has neuroprotective function in a series of neuropathy. Spermidine (Spd) has anti aging function in many tissues. However, the role of Spd in hyperglyceamia induced neuronal senescence remains unexplored. Therefore, we used high glucose (HG)-treated HT-22 cell as vitro model to investigate whether Spd protects neurons against hyperglyceamia-induced senescence and the mediatory role of CB1 receptor. The HT-22 cells were cultured in HG condition in the presence of different dose of Spd. Then, the viability of cells was measured by Cell Counting Kit-8 (CCK-8) assay. The senescence of cells was detected by Senescence associated beta-galactosidase (SA-beta-Gal) staining. The expressions of p16INK4a , p21CIP1 and CB1 receptor were measured by western blot. We found that Spd inhibited HG-induced neurotoxicity (the loss of cell viability) and senescence (the increase of SA-beta-Gal positive cells, the upregulation of p16INK4a and p21CIP1 ) in HT-22 cells. Also, Spd prevented HG-induced downregulation of CB1 receptor in HT-22 cells. Furthermore, we demonstrated that AM251 (a specific inhibitor of the CB1 receptor) reversed the protective effects of Spd on HG induced neurotoxicity and senescence. These results indicated that Spd prevents HG-induced neurotoxicity and senescence via the upregulation of CB1 receptor. Our findings provide a promising future of Spd-based preventions and therapies for diabetic encephalopathy. PMID- 29699002 TI - [The impact of social psychological fators on the health of modern professional women and countermeasurs]. PMID- 29699001 TI - National implementation of multi-parametric magnetic resonance imaging for prostate cancer detection - recommendations from a UK consensus meeting. AB - OBJECTIVES: To identify areas of agreement and disagreement in the implementation of multi-parametric magnetic resonance imaging (mpMRI) of the prostate in the diagnostic pathway. MATERIALS AND METHODS: Fifteen UK experts in prostate mpMRI and/or prostate cancer management across the UK (involving nine NHS centres to provide for geographical spread) participated in a consensus meeting following the Research and Development Corporation and University of California-Los Angeles (UCLA-RAND) Appropriateness Method, and were moderated by an independent chair. The experts considered 354 items pertaining to who can request an mpMRI, prostate mpMRI protocol, reporting guidelines, training, quality assurance (QA) and patient management based on mpMRI levels of suspicion for cancer. Each item was rated for agreement on a 9-point scale. A panel median score of >=7 constituted 'agreement' for an item; for an item to reach 'consensus', a panel majority scoring was required. RESULTS: Consensus was reached on 59% of items (208/354); these were used to provide recommendations for the implementation of prostate mpMRI in the UK. Key findings include prostate mpMRI requests should be made in consultation with the urological team; mpMRI scanners should undergo QA checks to guarantee consistently high diagnostic quality scans; scans should only be reported by trained and experienced radiologists to ensure that men with unsuspicious prostate mpMRI might consider avoiding an immediate biopsy. CONCLUSIONS: Our consensus statements demonstrate a set of criteria that are required for the practical dissemination of consistently high-quality prostate mpMRI as a diagnostic test before biopsy in men at risk. PMID- 29699003 TI - [The comparison of neurobehavioral changes and impaired locations between the mouse model of manganism and Parkinson's disease]. AB - Objective: To investigate the effect of manganese chloride (MnCl(2)) or 1-methyl 4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) on the neurobehavioral and histopathology in C57BL/6 mice and provide evidence for the diagnosis, treatment and prevention of manganism. Methods: Adult male C57BL/6 mice were treated with MnCl(2) and MPTP respectively by intraperitoneal injection at the doses of 5, 10, 20mg Mn/kg and 30mg MPTP/kg. Controls were injected equivalent normal saline. All animals were administrated 5 times a week for 4 consecutive weeks and sacrificed after behavior tests on the fifth week. Balance ability, anxiety and depression level and cognitive function were tested respectively by vertical pole test, open field locomotion test and Morris swim task. The neuron pathological changes of striatum and substantia nigra were examined through HE-staining pathological section by using optical microscope. Results: Compared with the control group, the high dose of MnCl(2) reduced body weight obviously (P<0.01) . The results of vertical pole test showed that MnCl(2) and MPTP lengthened the pole-climbing time and turnaround time. Open field locomotion test showed that movement distance, stand-up time and central field time were decreased after the exposure of MnCl(2) or MPTP. In the Morris swim task, the escape latency time increased and the target quadrant activity time decreased significantly after the injection of MPTP as well as high-dose MnCl(2), comparing with controls (P<0.05) . Moreover, the escape latency time of high dose MnCl(2) prolonged prominently comparing with MPTP grou (P<0.05) . The results of histopathology showed that acidophilic changes elevated in MnCl(2) and MPTP group, comparing with controls. Furthermore, in striatum the oxyphil cells number increased in MnCl(2) high-dose group comparing with MPTP group (P<0.01) . On the contrary, there were more oxyphil cells in MPTP group comparing with MnCl(2) groups in substantia nigra (P<0.01) . Conclusion: Both manganese and MPTP can induce the impairment of dopaminergic neural system, but the symptons and injured location of manganism are inconsistent with PD models induced by MPTP. PMID- 29699004 TI - [Effect of low-dose ionizing radiation exposure on thyroid function in a medical occupational population]. AB - Objective: We evaluated the effect of low-dose of ionizing radiation on thyroid function of medical occupational group with long-term exposure; furthermore; we analyzed the relationship between the thyroid hormones and the risk factors; such as exposure length; department. Ultimately; providing the scientific basis for setting the ionizing radiation protection standards. Methods: The population who engaged radiodiagnosis and radiotherapy in a tertiary-A hospital were set up as occupational exposure; 724 medical professionals as the research object. We figured out the basic information and general condition of the groups by face-to face questionnaire survey; By means of the thyroid hormone testing; we analyzed the thyroid hormone levels with different population; occupational exposure factors. Then; obtained the prevalence of thyroid nodules by the thyroid ultrasound. Besides; we used the logistic regression model to analyze the risk factors related to thyroid nodule. Applying Epidata,Excel in data management. All the data was analyzed by statistical software package Stata12.0. Descriptive statistics; single factor analysis of variance and other statistical methods were used for data analysis. Test standard: alpha=0.05,P<0.05 statistical significant. Results: 1. Based on the work experience; we divided the study population into four groups; such as 1-9; 10-19; 20-29; and>30 years. The difference of the TSH level among the four groups was statistically significant (P<0.05) . 2. The multiple logistic regression showed that sex and seniority were the independent risk factors for the abnormal rate of thyroid nodules. Conclusion: Long-term exposure to low-dose ionizing radiatiom could induce the thyroid damage of medical occupational population; which should be broader concerned. PMID- 29699005 TI - [Investingation on abnovral lmenstration and ddvesse pregnancy outume of fenial workers in netallurgical industiry]. PMID- 29699006 TI - [An investigation of lanthanum and other metals levels in blood, urine and hair among residents in the rare earth mining area of a city in China]. AB - Objective: To investigate the levels of lanthanum, cerium, praseodymium, and neodymium in the blood, urine, and hair samples from residents in the rare earth mining area of a city in China, and to provide a scientific basis for the control of rare earth pollution and the protection of population health. Methods: A total of 147 residents who had lived in the rare earth mining area of a city for a long time were selected as the exposure group, and 108 residents in Guyang County of this city who lived 91 km away from the rare earth mining area were selected as the control group. Blood, urine, and hair samples were collected from the residents in both groups. Inductively coupled plasma mass spectrometry was used to determine the content of lanthanum, cerium, praseodymium, and neodymium in blood, urine, and hair samples. Results: In the exposure group, the median levels of lanthanum, cerium, praseodymium, and neodymium were 0.854, 1.724, 0.132, and 0.839 MUg/L, respectively, in blood samples, 0.420, 0.920, 0.055, and 0.337 MUg/L, respectively, in urine samples, and 0.052, 0.106, 0.012, and 0.045 MUg/g, respectively, in hair samples. The exposure group had significantly higher levels of the four rare earth elements in blood, urine, and hair samples than the control group (P<0.01) . Conclusion: The residents in the rare earth mining area of this city have higher content of lanthanum, cerium, praseodymium, and neodymium in blood, urine, and hair than those in the non-mining area; the content of cerium is highest, followed by lanthanum, neodymium, and praseodymium. PMID- 29699007 TI - [Mental health status in railway female workers and its occupational influencing factors]. AB - Objective: To investigate the mental health status of railway female workers and related influencing factors, and to provide a scientific strategy for labor protection regulations in railway female workers. Methods: Cluster sampling was used to select 5033 female workers from Jinan, Nanning, Qinghai-Tibet, and Wuhan railway systems in China from January to August, 2016. A uniform reproductive health questionnaire, as well as the Symptom Checklist-90 (SCL-90) , was used to investigate their general information (age, marital status, education level, and family income) , work type (day shift, night shift, or work on shift) , work position, and the presence or absence of exposure to occupational hazardous factors. The score on each factor of SCL-90 and the positive rate of mental health status were calculated. Results: The positive rate of mental health status was 10.6% in railway female workers. The workers exposed to occupational hazardous factors had a significantly higher positive rate of mental health status than those not exposed to occupational hazardous factors (14.20% vs 8.02%, P<0.01) . There were significant differences in the positive rate of mental health status between workers with different ages, marital status, education levels, histories of abortion, or annual family income levels (P<0.01) . The scores of somatization (1.54+/-0.62) and horror (1.28+/-0.47) in SCL-90 were significantly higher than the Chinese adult norm (P<0.01) . The multivariate logistic regression analysis showed that exposure to occupational hazardous factors, night shift, overwork, and carrying heavy objects were associated with mental health problems (OR=1.797, 95%CI: 1.393-2.318; OR=0.641, 95%CI: 0.498 0.827; OR=0.586, 95%CI: 0.439-0.783; OR=0.580, 95%CI: 0.378-0.890) . Conclusion: Railway female workers have lower levels of mental health than the general population and are under significant occupational stress. Exposure to occupational hazardous factors, night shift, overwork, and carrying heavy objects are associated with the development of mental health problems in railway female workers. PMID- 29699008 TI - [Epidemiolgy and analysis of resk foutors associated with acute renal injury dure to bee wasp stiny]. PMID- 29699009 TI - [An analysis of mental health status of female migrant workers in a city]. AB - Objective: To investigate the mental health status of female migrant workers in a city. Methods: From August to December, 2016, cluster random sampling was used to select female migrant workers aged 16-60 years from 10 districts of this city, and Symptom Checklist-90 (SCL-90) and a questionnaire on general status were used. Results: Among these female migrant workers, the detection rates of obsessive-compulsion, hostility, and depression were 6.62%, 4.18%, and 4.10%, respectively. There was a significant difference in the detection rate of mental health issues between the female migrant workers from different districts, with different occupations, or with different education levels (P<0.05) . Districts, occupation, and education level were associated with mental health issues, after adjustment for age (P<0.05) . Conclusion: Although female migrant workers in this city have a high mental health level, the issues such as obsessive-compulsion, hostility, and depression should be taken seriously. Targeted mental health surveys and comprehensive interventions should be implemented to improve the mental health level of female migrant workers. PMID- 29699010 TI - [Analyzing the mental health status and its impact factors among female nurses in China]. AB - Objective: To analyze the mental health status and its impact factors among nurses, finding ways to improve the mental health of nurses. Methods: A total of 13 425 female healthcare workers aged from 18 to 65 were selected as study objects. The survey was conducted with unified design questionnaire. The survey included the basic situation of the individuals and SCL-90 questionnaire. Comparing the female doctors, the mental health status and its impact factors of nurses were analyzed. Results: The income, age, education and occupation, which include shift work, heavy work load and overtime work are different between nurses and doctors. The main mental health problems of nurses were obsessive compulsive symptoms, depressive symptoms and somatization. The results of univariate analysis indicated that shift work, overtime work, and heavy work load affected the positive rate of each factor. The results of multivariate analysis showed that occupation, shift work, overtime work, and heavy work load have significant adverse effects on the positive rate of the total score in female healthcare workers (P<0.01) . The positive rate of each dimension of SCL-90 in nurses is significantly higher than that of doctors. Conclusion: The mental health problems of nurses are significantly higher than doctors. The main reasons are low occupational level and adverse workstyles which include shift work, heavy workload and so on. Health administration and hospital management departments should pay much more attention to the mental health of nurses, improving their mental health through a variety of ways. PMID- 29699011 TI - [Prevalence of reproductive system diseases among female workers in a city and related occupational influencing factors: an analysis of 9944 cases]. AB - Objective: To investigate the prevalence of reproductive system diseases among female workers in a city and related occupational influencing factors. Methods: From June to September, 2016, a cross-sectional survey was used to select 9 944 female workers from six districts of Beijing and then a face-to-face questionnaire survey was performed. Univariate analysis using chi-square test and multivariate logistic regression analysis were used to investigate the risk factors for reproductive system diseases. Results: The age of 9944 female workers ranged from 18 to 65 years (mean 35.53+/-9.52 years) , and among them, 7 351 (73.92%) were married. The overall prevalence rate of reproductive system diseases among these 9944 female workers during the past three months was 28.29%, and the prevalence rates of hyperplasia of mammary glands, vaginitis, and hysteromyoma were 15.54%, 11.25%, and 6.77%, respectively. After adjustment for age, marital status, education level, and annual family income, the multivariate logistic regression analysis showed that frequent overtime work (odds ratio[OR]=1.119, 95% confidence interval[CI]: 1.070-1.343) , frequent night shifts (OR=1.198, 95%CI: 1.054-1.361) , standing for a long time (OR=1.197, 95%CI: 1.063-1.347) , sitting for a long time (OR=1.327, 95%CI: 1.191-1.479) , heavy workload (OR=1.429, 95%CI: 1.262-1.615) , exposure to lead (OR=1.696, 95%CI: 1.307-2.201) , exposure to mercury (OR=1.452, 95%CI: 1.086-1.940) , and exposure to ionizing radiation (OR=1.679, 95%CI: 1.424-1.980) were associated with reproductive system diseases. Conclusion: The prevalence of reproductive system diseases among female workers in Beijing is not optimistic. Reproductive system diseases are associated with frequent overtime work, frequent night shifts, standing for a long time, sitting for a long time, heavy workload, and exposure to lead, mercury, and ionizing radiation. PMID- 29699012 TI - [Mental health problems among female staff in a provincial maternal and child health hospital: an investigation of 647 individuals]. AB - Objective: To investigate the current status of depression and anxiety among female staff in a maternal and child health hospital, and to provide a basis for developing related prevention and intervention measures and promoting the mental health of female staff. Methods: The female staff from a provincial maternal and child health hospital completed a psycho-health questionnaire survey on Internet from June to October, 2016. The questionnaires used in the survey consisted of Patient Health Questionnaire (PHQ-9) , Generalized Anxiety Disorder Scale (GAD-7) , and Symptom Checklist-90 (SCL-90) . The distribution features of mental health problems such as depression and anxiety were analyzed according to the results: of the questionnaire survey. Results Of all female staff surveyed, 42.04% showed depression symptoms, 28.90% showed anxiety symptoms, and 26.12% showed comorbid symptoms of depression and anxiety. Moderate or severe depression (anxiety) was mainly distributed among the female staff with comorbid symptoms (90.63% and 97.01%, respectively) . There were significant differences in the distribution of moderate or severe anxiety symptoms between the medical staff and nursing staff (chi(2)= 5.81, P=0.05) and between those with intermediate and junior professional titles (chi(2)=7.99, P=0.018) . As for SCL-90 results, the total score, total average score, and scores on factors of somatization, compulsion, interpersonal sensitivity, depression, and anxiety in the female staff with comorbid symptoms, moderate or severe depression, and moderate or severe anxiety were significantly higher than the national norm (P<0.01) , while the scores on paranoid and psychotic factors were significantly lower than the national norm (P<0.01) . The numbers of cases of positive factors were significantly higher in the female staff with comorbid symptoms than in the female staff with a single symptom and asymptomatic female staff (both P<0.01) , and positive cases were mainly distributed in depression, interpersonal sensitivity, compulsion, anxiety, and somatic factors. Conclusion: The prevalence of depression and anxiety is high among female staff in the maternal and child health hospital, mainly characterized by comorbid symptoms of moderate or severe depression and anxiety. Comorbidity is accompanied by mental health problems such as interpersonal sensitivity, obsessive compulsion, and physical discomfort. Corresponding measures are needed for the prevention and intervention of mental health problems among female staff in the maternal and child health hospital. PMID- 29699013 TI - [Investigation and Analysis on shift work female workers' and the impact on reproductive health]. AB - Objective: To investigate the distribution of shift work of female workers in different industries and the relationship between shift work and reproductive health, then provide reference for the female workers' labor protection. Methods: From June to September 2016, cluster sampling questionnaire survey was performed among female workers from 11 industries including electronics, medicine and health, pharmacy. To investigate the general information, shift-work information, reproductive health and childbearing history of these female workers. Results: A total of 63 711 usable questionnaires were collected, resulting in a response rate of 96.94%.A total of 13 546 workers worked in shifts, accounting for 21.26%, the highest proportion was in the medical industry 30.61%, metallurgy 30.81%, petrochemical engineerin 26.78% respectively. Compared with the workers who did not work in shifts, those who worked in shifts had significantly higher rate of abnormal menstruation, rate of reproductive system infection in married workers, the rate of infertility (chi(2)=19.108,10.673,21.510, P<0.05) ; Compared with the workers who did not work in nightshifts, those who worked in nightshifts had significantly higher rate of abnormal menstruation, rate of reproductive system infection among married workers and rate of infertility (chi(2)=140.043,71.901,29.024, P<0.01) . Conclusion: The highest rate of shift work was in the medical industry, metallurgy, petrochemical engineering industry. Workers who worked in shifts have serious reproductive health issues, the occurrence of abnormal menstruation, reproductive system infection and infertility may associated with shift work. PMID- 29699015 TI - [Occupational exposure investigation and protective measures in a tertiary infectious disease hospital]. AB - Objective: To investigate the cause of occupational exposure among 136 nurses in a tertiary infectious disease hospital, and puts forward the prevention strategy. Methods: A total of 136 nurses exposed to occupational exposure between 2014 and 2016 were included in the study. Analysis was conducted from the years of work of nurses, exposure routes, and the pathogens. Results: The nurses suffer from the highest risk of occupational exposures (73.91%) .Nurses working for less than 5 years and interns are most likely to suffer occupational exposure (45.59% and 35.29% respectively) . Occupational exposure was mainly caused by needle injuries, in which infusion was the main route of occupational exposure (36.76%) . The improper treatment of needle pulling after infusion is the main link of needle puncture (36.76%) . Occupational exposure pathogens were mainly HBV (63.24%) . Conclusion: Nursing staff is the high-risk group of occupational exposure. Irregular operation, lack of awareness of protection, improper disposal after the needle withdrawal and poor safety assessment of the operating environment are the main causes of occupational exposure. It is suggested to strengthen the training of occupational safety and protection, enhance clinical nurses occupational safety protection consciousness, standardize medical operation, so as to prevent the occurrence of occupational exposure. PMID- 29699014 TI - [A meta-analysis of Symptom Checklist-90 assessment results in Chinese nurses]. AB - Objective: To investigate the application of Symptom Checklist-90 (SCL-90) in Chinese nurses. Methods: We performed a literature search for articles in Chinese on the mental health of nurses investigated using the SCL-90 that were published from January 2007 to December 2016. A total of 129 articles were included, involving 178 groups of valid samples as well as 36316 subjects in 27 provinces or cities in China. The metafor package of R 3.2.1 software and Excel were used for meta-analysis and data statistics. Results: Heterogeneity was identified for the nine factors included in the literature data (Q test: P<0.05; I(2) test >40%) , so a random effects model was used. For all factors except interpersonal relationship factor, the 95% confidence intervals of the pooled effect sizes did not include 0. For all factors except interpersonal relationship factor (Egger test: P<0.05) , no significant asymmetry or incompleteness appeared in the funnel plots. The fail-safe number of each factor was much larger than 5k+10. The merger scores and mean values of nine factors were higher than the national norm. Conclusion: The SCL-90 is widely used in the study of mental status of Chinese nurses, but the SCL-90 norm for nurses is lacking. PMID- 29699016 TI - [The study on behaviour of protective equipment utilization of workers exposed to benzene and factors based on Planned Behavior Theory]. AB - Objective: To investigate and predict the behavioral intention and mode of the protective equipment utilization selection of the workers who used Benzene, the Theory of Planned Behavior (TPB) was applied to establish the behavioral model to enhance the theoretical foundation for long-term intervention. Methods: Questionnaires were used to survey the 707 workers, and all the behaviors of using protective equipment were investigated. Evaluate the relationships between each variable and obtain the influence affects by structural equation model. Results: The investigation showed that 38.47% of the total workers (272 cases) used whole body protection, 13.58% used partially, and 16.69% didn't use any body protection. There were significant difference between the varying degrees in the four dimensions (behavioral attitude, perceived behavior control, subjective norm, and behavioral intention) (P<0.01) . The results of structural equation model revealed that perceived behavior control was the most important influencing factor, subjective norm, positive attitude, negative attitude were the other three respects in sequence. The path co-efficient were 0.600,0.215,0.141 and 0.046 respectively. Conclusion: The study show that the theory of planned behavior can effectively explain the behavioral intention and behavior of protective equipment utilization. Therefore, combining the subjective initiative of individuals with the supervision of enterprises, In order to effectively enhance the protective equipment utilization of benzene workers. PMID- 29699017 TI - [Influencing factors for reproductive health of female workers in petrochemical industry]. AB - Objective: To investigate the reproductive health status of female workers in petrochemical industry, and to provide a reference for improving reproductive health status and developing preventive and control measures for female workers in petrochemical industry. Methods: A face-to-face questionnaire survey was performed from January to October, 2016. The Questionnaire on Women's Reproductive Health was used to investigate the reproductive health of female workers in petrochemical industry. The multivariate logistic regression model was used to identify the influencing factors for reproductive health of female workers in petrochemical industry. Results: Among the 7485 female workers, 1 268 (40.9%) had abnormal menstrual period, 1 437 (46.4%) had abnormal menstrual volume, 177 (28.5%) had hyperplasia of mammary glands, and 1 807 (24.6%) had gynecological inflammation. The reproductive system diseases in female workers in petrochemical industry were associated with the factors including age, marital status, education level, unhealthy living habits, abortion, overtime work, work shift, workload, video operation, occupational exposure, positive events, and negative events, and among these factors, negative events (odds ratio[OR]= 1.856) , unhealthy living habits (OR=1.542) , and positive events (OR=1.516) had greater impact on reproductive system diseases. Conclusion: Many chemical substances in the occupational environment of petrochemical industry can cause damage to the reproductive system, which not only affects the health of the female workers, but also poses potential threats to the health of their offspring. Occupational exposure, unhealthy living habits, overtime work, and work shift have great influence on reproductive system diseases in female workers. PMID- 29699018 TI - [Investigation on occupational stress, social support and job burnout of the staffs in sport goods chain stores]. AB - Objective: To understand the relationship between occupational stress, social support and job burnout, and to explore the moderating role of social support for occupational stress and job burnout. Methods: 256 employees were conveniently chosen to engage in a survey, including occupational stress indicator (OSI) , social support rating scale (SSRS) as well as maslach burnout inventory-general survey (MBI-GS) from March to June in 2017. Results: The occupational stress score of the stafls in sport goods Chain stores was 55.5+/-11.7, the score of social support was 28.2+/-7.6, and the score of job burnaut was 41.3+/-11.6. Occupational stress was positively correlated with job burnout (r=0.425, P<0.001) , however, occupational stress was negatively related to objective support, subjective support and support utilization (r values were-0.182, -0.227, and 0.208, P<0.05) , and job burnout was also negatively related to them, (r values were-0.324, -0.201, and-0.171, P<0.05) . The interaction between occupational stress and subjective support and support utilization were statistically significant (beta values were-0.069 and-0.077, P<0.05) . Conclusion: Social support is the effective moderating for occupational stress and job burnout, especially in subjective support and support utilization. PMID- 29699019 TI - [Effects of ethylbenzene on cell injury and mitochondrial membrane potential of CPCs]. AB - Objective: To investigate the effects of ethylbenzene on growth morphology,proliferation ability and mitochondrial membrane potential (MMP) of cochlear progenitor cells (CPCs) , and to lay a foundation for the mechanism of hearing loss induced by ethylbenzene. Methods: We can use the fluorescence microscopy to identify the original CPCs isolated from the newborn rats, and followed by the addition of different concentrations of ethylbenzene (0, 15, 30, 45 MUmol/L) for 24 hours. The morphological changes of cell injury were observed by inverted optical microscope. The proliferation ability of cells was detected by MTT colorimetry, and the change of MMP was detected by fluorescent probe JC-1. Results: The results of CPCs identification showed the expression of Myosin VIIa and Epsin positive; The results observed by inverted optical microscope showed all groups of CPCs morphological changes compared with the control group; MTT results showed that the decreased significantly proliferation ability of CPCs groups compared with the control group and a dose effect relationship with statistically significant difference (P<0.05) ; JC-1 test results showed the decreased significantly mitochondrial membrane potential in the treated group compared with the control group, and there was a statistically significant difference (P<0.05) . Conclusion: Ethylbenzene may cause damage to CPCs, inhibition of cell proliferation and decrease of MMP in rats. PMID- 29699020 TI - [Construction of cochlear progenitor cells with recombinant short-hairpin RNA lentiviral vector inhibiting the expression of the beta-catenin gene]. AB - Objective: To construct a recombinant short-hairpin RNA (shRNA) lentiviral vector targeting the beta-catenin gene in cochlear precursor cells (CPCs) in mice, and to investigate its inhibitory effect. Methods: PCR was used for the multiplication of the beta-catenin gene, and shRNA oligo was designed based on the beta-catenin gene to construct an interference vector. Gateway Technology was used to construct shRNA lentiviral vector which carried the beta-catenin gene, and then 293FT cells were transfected with the constructed lentiviral vector and helper plasmids pLV/helper-SL3, pLV/helper-SL4, and pLV/helper-SL5. The virus supernatant was collected to obtain viral particles, and then mouse CPCs were transiently infected with the recombinant lentivirus with four different concentrations (0, 5, 10, and 20 MUl) . The shRNA control group was established. Quantitative real-time PCR and Western blot were used to investigate the inhibitory effect of shRNA beta-catenin lentiviral vector on beta-catenin. Results: The recombinant shRNA beta-catenin lentiviral vector was successfully constructed, and the virus titers of shbeta-catenin and shbeta-catenin-control were 5.05*10(7) and 4.34*10(7), respectively. The results of in vitro experiments showed that in CPCs transfected with four different concentrations of recombinant lentivirus, the content of beta-catenin protein gradually decreased with the increase in concentration, and there was a significant difference between groups (P<0.05) ; the CPCs transfected with shbeta-catenin had significantly lower mRNA expression of beta-catenin than those in the shbeta-catenin-control group (P<0.05) . Conclusion: The constructed lentiviral vector targeting the beta catenin gene has a high infection efficiency, and the successful construction of lentiviral vectors provides a technical support for analyzing the role of beta catenin in the differentiation of CPCs into auditory hair cells. PMID- 29699021 TI - [Effect of ulinastatin on myocardial injury in patients with acute severe carbon monoxide poisoning]. AB - Objective: To observe the effect of ulinastatin on myocardial injury in patients with acute severe carbon monoxide poisoning (ASCOP) . Methods: By using the prospective study method, 123 cases of ASCOP patients admitted to our hospital, were randomly divided into two groups. There were no significantly different between the two groups in the abnormal rates of ECG, brain natriuretic peptide (BNP) , troponin I (cTNI) , creatine phosphokinase (CK-MB) and creatine phosphokinase (CK) . The control group according to the patients need to be treated with hyperbaric oxygen and routine medical treatment; the observation group was treated with ulinastatin 100 thousand u intravenous injection based on routine treatment measures on Q8 h, the two groups were 7 d for the 1 course of treatment. Compared two groups of patients after 3 days, 7 days of electrocardiogram, brain natriuretic peptide (BNP) , troponin I (cTNI) , creatine kinase isoenzyme (CK-MB) , creatine kinase (CK) , the case fatality rate within 14 days, and the abnormality rate of BNP, cTNI, CK-MB and Ck. Results: the observation group for 3 days, 7 days, 14 days were abnormal, brain natriuretic peptide (BNP) , cardiac troponin I (cTNI) , creatine kinase isoenzyme (CK-MB) , creatine kinase (CK) the average results were significantly lower than those in the control group (P<0.05) ; The 14 d BNP in the observation group was significantly lower than the control group (P<0. 05) ; the case fatality rateof observation group was lower than the control group within 14 days (1.2% vs 3.3%) . Conclusion: Ulinastatin can significantly improve the ASCOP to reduce the damage to the heart, reduce the case fatality rateand improve the prognosis. PMID- 29699022 TI - [An intramuscular injection of sodium dimer captopropane sulfonate induced epidermal necrolysis type drug eruption in 1 case]. PMID- 29699023 TI - [Quantitative EEG and event-related potential P300 analysis oxiracetam injection curative effect in the treatment of delayed encephalopathy after acutecarbon monoxide poisoning]. AB - Objective: oevaluateclinical curative effect of oxiracetam injection in the treatment of delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) . Methods: Methods 52 patients with DEACMP were randomly divided into the observation group and the control group, 27 cases in the observation group and 25 cases in the control group. The 2 groups were adopted the treatment to improve the cerebral microcirculation and other symptomatic, the observation group on the basis of treatment for the treatment of oxiracetam Injection. Quantitative electroencephalogram (QEEG) and event-related potential P300 were used to evaluate the therapeutic effects of the 2 groups before and after treatment. Results: After treatment, QEEG value and event related potential P300 in observation group were decreased with statistically significant, respectively (P<0.05) , compared with the control group after treatment, the observation group excepted the occipital lobe, left parietal lobe, left around central and other indicators, QEEG and P300 oflatent period was shortened while the bank widens with statistical significance (P<0.05) . Conclusion: Olathe injection of DEACMP patients recovery have certain curative effect. PMID- 29699024 TI - [Implementing the strategy of 'Healthy China' and strengthening the setting-up of National Demonstration Areas, for Comprehensive Prevention and Control of Non communicable Diseases]. AB - The former Ministry of Health launched a project regarding National Demonstration Areas for Comprehensive Prevention and Control of Non-communicable Diseases (NCDs) in 2010. This study combined quantitative and qualitative methods, using epidemiological, anthropological and sociological methods to carry out process assessment, effectiveness and case study to evaluate the outcomes of the Demonstration Areas in China. A government leading body, under multi-sectoral cooperation pattern set for prevention and control of NCDs in the Demonstration Areas, was established. All the health related indicators of the residents from the NCDs appeared better than the national average level, showing the fact that the first phase goal on the establishment of Demonstration Areas was materialized. Papers that included in this issue "Evaluation on China National Demonstration Areas for NCDs Prevention and Control" elaborated the implementation status and effectiveness of the Demonstration Areas. It was our hope to provide reference for scaling up the Demonstration Areas and dynamic management in the future. PMID- 29699025 TI - [Study on the effectiveness of implementation: the National Demonstration Areas for Comprehensive Prevention and Control of Non-communicable Diseases]. AB - Objective: To assess the implementation and impact of programs carried out by the National Demonstration Areas for Comprehensive Prevention and Control of Non communicable Diseases. Methods: Both sociological and epidemiological methods were used to collect qualitative and quantitative data in November and December, 2016 in order to conduct on process and outcome evaluation of the above mentioned objective. In the meantime, case study was also conducted. Results: All the National Demonstration Areas for Comprehensive Prevention and Control of Non communicable Diseases were found well implemented across the country, with health education and health promotion, surveillance and safeguard measures in particular. A government-led and inter-sector coordination and communication mechanism had been well established, with more than 16 non-health departments actively involved. 28.7% of the residents living in the National Demonstration Areas for Comprehensive Prevention and Control of Non-communicable Diseases were aware of the key messages related to chronic diseases. Among the residents, 72.1% of them consumed vegetables and 53.6% consumed fruits daily, with another 86.9% walked at least 10 minutes per day. Over 70% of the patients with hypertension or diabetes reported that they were taken care of by the Community Health Centers, and above 50% of them were under standardized management. Residents, living in the National Demonstration Areas under higher ranking of implementation scores, were more likely to be aware of relevant knowledge on chronic disease control and prevention (OR=6.591, 95%CI: 5.188-8.373), salt reduction (OR=1.352, 95%CI: 1.151 1.589), oil reduction (OR=1.477, 95%CI: 1.249-1.746) and recommendation on physical activities (OR=1.975, 95%CI: 1.623- 2.403). Conclusion: The implementation of programs carried out by the National Demonstration Areas for Comprehensive Prevention and Control of Non-communicable Diseases had served a local platform for the control and prevention of non-communicable diseases, and thus become an important 'carrier' for chronic disease prevention and control programs in China. PMID- 29699026 TI - [Current status on prevalence, treatment and management of hypertension among Chinese adults in the National Demonstration Areas for Comprehensive Prevention and Control of Non-communicable Diseases]. AB - Objective: To investigate the current status of prevalence, treatment, and management on hypertension among Chinese adults from the National Demonstration Areas for Comprehensive Prevention and Control of Non-communicable Diseases. Methods: We selected a total of 4 000 residents aged >=18 years for this questionnaire-based survey by multi-stage clustering sampling in 10 National Demonstration Areas between November and December, 2016. Results: There were 3 891 effective questionnaires. The self-reported prevalence of hypertension among aged >=35 years was 31.47% (1 011/3 213). For the past two weeks, the self reported treatment of hypertension was 86.75%(877/1 011), with the rates of guidance as 56.87% (575/1 011) on physical activity, 40.95% (414/1 011) on diet, 38.33% (385/1 011) on weight management, and 22.75% (228/1 011) on smoking cessation. For the past 12 months, 74.68% (755/1 011) of the residents aged >=35 years were under the proper management and 62.12% (628/1 011) of them were under the standardized management programs. The follow-up program lasted for 4 (P(25) P(75): 4-12) times per year, with 15 (P(25)-P(75): 10-20) minutes per each visit. Hypertensive patients would mainly visit the outpatient clinics (53.51%), followed by home visits (22.91%) and telephone calls (13.64%). Rate of satisfaction on management services was 94.83% (716/755) from the hypertensive patients. Multivariate analysis showed that the rate of self-reported treatment (OR=1.986, 95%CI: 1.222-3.228) and self-reported standardized management (OR=2.204, 95%CI: 1.519-3.199) on hypertension were higher in the Demonstration Areas with higher implementation scores of self-reported non-communicable diseases management. Conclusions: Prevention and management on hypertension in the Demonstration Areas had met the requirement set for the Demonstration Areas during the "12th Five-Year Plan" . Projects on setting up the National Non communicable Diseases Demonstration Areas had played an active role in promoting the standardized management program on hypertension. PMID- 29699027 TI - [Management programs on diabetes among Chinese adults in the National Demonstration Areas for Comprehensive Prevention and Control of Non-communicable Diseases]. AB - Objective: To understand the current situation on management of diabetes mellitus patients aged 35 and above in the National Demonstration Areas for Comprehensive Prevention and Control of Non-communicable Diseases, in China. Methods: Local residents, aged 18 years and above were randomly selected by a complex, multistage, probability sampling method. Face-to-face questionnaire survey was carried out between November and December 2016. Rates regarding prevalence, treatment and management of diabetes were calculated, and influencing factors of diabetes were analyzed by using the non-conditional logistic regression model. Results: A total of 3 213 residents aged >=35 years were included in this study, of which 11.48% (369/3 213) reported that they had ever been informed by a doctor or other health worker that their blood sugar level was high or being diabetic. The rate of self-reported treatment among the diabetic patients was 83.20% (307/369). Rates on overall management and standardized management were 69.92% (258/369) and 53.66% (198/369), respectively. Higher rates were seen in residents aged 55 to 64 years, 76.32% for overall management and 59.65% for standardized management. Through multiple logistic regression analysis, we found that standardized management for diabetes was much higher in the Demonstration Areas located in the eastern areas (OR=2.942, 95%CI: 1.547-5.594), or patients with characteristics including high implementation score (OR=3.499, 95%CI: 1.865 6.563), already signed family doctors (OR=5.661, 95%CI: 3.237-9.899), or without hypertension (OR=1.717, 95%CI: 1.010- 2.920). Residents who were living in the first and second batch areas of implementation or responding to the NCDs with positive attitude were more likely to accept standardized management. Conclusion: Prevention and management programs on diabetes had met the requirements set for the Demonstration Areas which had promoted the specific implementation and further development of standardized management on diabetes. PMID- 29699028 TI - [Study on consumption of vegetables and fruits and related influencing factors among residents from the National Demonstration Areas for Comprehensive Prevention and Control of Non-communicable Diseases]. AB - Objective: To investigate the consumption of vegetables and fruits and related influencing factors among residents from the National Demonstration Areas of Comprehensive Prevention and Control of Non-communicable Diseases. Methods: From November to December, 2016, a total of 4 000 residents, aged 18 or above, from ten Demonstration Areas, were selected as participants for this study by multi stage cluster random sampling method. Information on vegetables, fruits consumption and related influencing factors was collected via questionnaire. Results: A total of 3 891 residents were involved in the final analysis. Daily consumption of vegetables and fruits accounted for 72.1% and 53.6% of the residents under study. The residents who were aware of the National Demonstration Areas activities were more willing to have adequate intake of vegetables (OR=3.017, 95%CI: 2.426-3.753) and fruits (OR=1.261, 95%CI: 1.007-1.580). Residents with higher degree of participation activities of the demonstration areas were more likely to have adequate fruits intake (high degree: OR=1.431, 95%CI: 1.210-1.694; medium degree: OR=1.573, 95%CI: 1.315- 1.882). Conclusions: The implementation of the National Demonstration Areas for Comprehensive Prevention and Control of Non-communicable Diseases has improved the adequate vegetables and fruits intake among residents. Relevant activities carried out in the Demonstration Areas appeared conducive to the healthy lifestyle of the residents. PMID- 29699029 TI - [Study on the overall implementation status of the National Demonstration Areas for Comprehensive Prevention and Control of Non-communicable Diseases]. AB - Objective: To understand the current overall status of implementation on the National Demonstration Areas of Comprehensive Prevention and Control of Non communicable Diseases. Methods: According to the scheme design of the questionnaires, all the National Demonstration Areas were involved in this study. For each National Demonstration Areas, eight departments were selected to complete a total of 12 questionnaires. Results: Scores related to the implementation of the National Demonstration Areas accounted for 71.8% of the total 170 points. Based on the scores gathered from this study, the 23-items index-system that represented the status of project implementation was classified into seven categories. Categories with higher percentile scores would include: monitoring (88.0%), safeguard measures (75.0%), health education and health promotion (75.0%). Categories with lower percentile scores would include: the national health lifestyle actions (67.7%), community diagnosis (66.7%), discovery and intervention of high-risk groups (64.7%), and patient management (60.9%). There were significant differences noticed among the eastern, central and western areas on items as safeguard measures, health education/promotion, discovery and intervention of high-risk groups. In all, the implementation programs in the eastern Demonstration Areas seemed better than in the central or western regions. As for the 23 items, five of the highest scores appeared on policy support, mortality surveillance, tumor registration, reporting system on cardiovascular/cerebrovascular events, and on tobacco control, respectively. However, the lowest five scores fell on healthy diet, patient self-management program, oral hygiene, setting up the demonstration units and promotion on basic public health services, respectively. The overall scores in the eastern region was higher than that in the central or the western regions. The scores in the central and western regions showed basically the same. Conclusions: The overall status of implementation on the National Demonstration Areas was satisfactory. Future attention should be focusing on patient management as well as discovery and intervention of high-risk groups, which also presented the lowest scores, in this survey. PMID- 29699030 TI - [Levels of calcaneus bone mineral density in adults from 10 regions of China]. AB - Objective: To describe the regional and population-related differences in calcaneus bone mineral density (BMD) across ten regions of China. Methods: Based on the results: from the second Re-survey of China Kadoorie Biobank project, in which 5% of the surviving participants were interviewed during 2013-2014 and 24 677 participants aged 38-87 years were included in the study. We excluded those people with missing data for BMD and important variables. Calcaneus BMD was measured using the quantitative ultrasound bone densitometer. We analyzed four indexes, including broadband ultrasound attenuation (BUA), speed of sound (SOS), stiffness index (SI), and T score. Results The average calcaneus BMDs of the present population were: BUA (109.7+/-12.6) dB/MHz, SOS (1 554.7+/-45.6) m/s, SI (88.3+/-18.8), T score (-0.74+/-1.28). Urban residents showed higher calcaneus BMD, so as in men. The calcaneus BMD decreased by age, with a larger decline seen in women. Current smokers and postmenopausal women presented lower calcaneus BMD, while in those who frequently drank milk or yogurt or being physically more active, had higher calcaneus BMD. Conclusion: Calcaneus BMD varied greatly among people from the ten regions of CKB study and among participants having different demographic characteristics, lifestyle behaviors or health conditions. PMID- 29699031 TI - [Association between high-sensitivity C-reactive protein and both cardiovascular, total mortality events in middle-aged Chinese adults]. AB - Objective: To estimate the association between high-sensitivity C-reactive protein (hs-CRP) and cardiovascular events as well as all-cause mortality events. Methods: During 2009- 2010, out of the 11 623 individuals, 1 000 participants aged 35-64 years, were recruited and divided into 12 age-groups, to have received a study on CVD risk factors. Information on the risk factors of cardiovascular diseases was also collected. Fasting blood sample was gathered for all the participants, with hs-CRP tested. Participants in 7 out of the 12 sites were followed, with 6.21 years (36 075 person-years) as the median follow-up period. Cardiovascular and all-cause mortality events were collected. A total of 6 177 participants had been followed after excluding participants who had baseline infections, or did not take hs-CRP test/physical examination at the baseline. Finally, 5 984 participants were included for analysis. Participants were categorized into three groups based on the hs-CRP (mg/L) values: <1, 1-3 and >3, respectively. Cox proportional hazards regression model was used to analyze the relationships between hs-CRP with cardiovascular events or all-cause mortality events, after adjusting for confounding factors. Results: Mean age of the participants was 50.2 years. The incidence rates of cardiovascular disease events were 3.6/1 000 person-years, 7.1/1 000 person-years,and 10.4/1 000 person-years among three groups and 3.0/1 000 person-years, 5.7/1 000 person-years, 9.1/1 000 person-years for all-cause mortality events, respectively. After adjusting for confounding factors, the hazard risks (HR) for cardiovascular events were 1.33 (95%CI: 0.95-1.84) in the hs-CRP 1-3 mg/L group and 1.76 (95%CI: 1.20-2.60) in the hs-CRP>3 mg/L group when comparing with the hs-CRP<1 mg/L group (trend test P=0.003). The HRs for all-cause mortality events were 1.76 (95%CI: 1.23-2.54) and 2.64 (95%CI: 1.74-4.01) (trend test P<0.001), respectively. Conclusion: Hs-CRP appeared an independent predictor for cardiovascular events and all-cause mortality events. PMID- 29699032 TI - [Relations between cigarette smoking and chronic diseases of Chinese adults in 2013]. AB - Objective: To explore the relations between the prevalence of multiple chronic diseases and cigarette smoking behavior in the Chinese adults. Methods: Based on the results: from the 2013 Chronic Disease Risk Factor Surveillance (NCD Surveillance), 176 534 Chinese residents aged 18 years and above, covering 298 counties (districts) in 31 provinces, was randomly recruited, using the multi stage stratified clustering sampling method. Information on demographics, cigarette smoking (status, quantity and period) was obtained through face-to-face interviews and questionnaires. Anthropometric data and blood samples were collected and properly stored for analysis. Results In total, 175 386 adults were included for statistical analyses, with 42.7% as males and 57.3% as females. The prevalence rates of hypertension, high total cholesterol and high triglycerides were 30.4%, 7.2% and 18.0% in male smokers, 35.6%, 14.0%, 10.3% and 15.9% in female smokers respectively, which were all higher than those in the respective non-smokers. Male smokers were found under lower risk on hypertension, but 19% higher on total glycerides when compared with non-smokers of the same sex(OR=1.19, 95%CI:1.10-1.30), when multiple risk factors were under control. Male current smokers with more than 20 cigarettes per day have 41% (OR=1.41, 95%CI: 1.28-1.55) higher risk of high TG than non-smokers. Female smokers presented 40% (OR=1.40, 95%CI: 1.15-1.70) higher risk in high glycerides than the non-smokers. Specifically, women smoking longer than 20 years have 60% (OR=1.60, 95%CI: 1.31-1.95) higher risk of high TG than women smoking less than 20 years. Conclusions: Prevalence rates of certain chronic diseases were seen higher in smokers of both genders. People with longer history of smoking or being heavier smokers, appeared at advanced risk on developing chronic diseases. PMID- 29699033 TI - [Current status of falls and related injuries among Chinese elderly in 2013]. AB - Objective: To investigate the demographic characteristics of falls and fall related injuries in Chinese elderly population. Methods: In 2013, the 4(th) round Chronic Non-communicable Disease and Risk Factor Surveillance in China was conducted in 31 provinces. A stratified multi-stage cluster sampling was used to select the samples. A total number of 98 629 community-based adults aged 60 years and older received a set of standardized questionnaires with a face to face interview. The prevalence rates of falls and consequent injuries were compared between different genders, age groups, levels of education and areas of residency. Results: The overall prevalence of falls among elderly in the previous 6 months was 8.0%(95%CI: 7.5%-8.5%). The prevalence was increasing with age and decreasing with the levels of education, and higher in females (9.1%) than in males (6.8%), with differences statistically significant (chi(2)=74.1, P<0.01). Prevalence rates were also seen higher in rural (8.6%), in widowed (11.0%) residents and in farmers or house workers than those in urban areas (7.2%), in non-widowed (7.0%), or having other jobs, with differences all statistically significant (chi(2)=7.7, P<0.01, chi(2)=128.0, P<0.01). 52.6% of the elderly got injured when fell. The proportion of injury was greater in females (54.8%) than that in males (49.6%), with differences statistically significant (chi(2)=10.2, P<0.01). Proportion of most frequent types of injuries were hip fractures (7.3%), hand/arm fractures (12.5%), head injury (8.0%) and bruise (53.6%) respectively. The proportion of hip fractures was 12.4% in elderly over 80 year of age, also was the highest. Conclusions: Results from the present study showed that elderly suffered high prevalence of falls.Statistically significant differences were seen in residents with different groups as genders, age, education levels, marital status, urban/rural areas or jobs. Group-based comprehensive prevention and intervention on falls should be strengthened. PMID- 29699034 TI - [Association between obesity and DNA methylation among the 7-16 year-old twins]. AB - Objective: On whole-genome scale, we tried to explore the correlation between obesity-related traits and DNA methylation sites, based on discordant monozygotic twin pairs. Methods: A total of 90 pairs of 6-17 year-old twins were recruited in Chaoyang district, Yanqing district and Fangshan district in Beijing in 2016. Information on twins was gathered through a self-designed questionnaire and results: from physical examination, including height, weight and waist circumference of the subjects under study. DNA methylation detection was chosen on the Illumina Human Methylation EPIC BeadChip. R 3.3.1 language was used to read the DNA methylation signal under quality control on samples and probes. Ebayes function of empirical Bayes paired moderated t-test was used to identify the differential methylated CpG sites (DMCs). VarFit function of empirical Bayes paired moderated Levene test was used to identify the differentially variables CpG sits (DVCs) in obese and normal groups. Results According to the obesity discordance criteria, we collected 23 pairs of twins (age range 7 to 16 years), including 12 male pairs. A total of 817 471 qualified CpG loci were included in the genome-wide correlation analysis. According to the significance level of FDR set as <0.05, no positive sites would meet this standard. When DMC CpG site cg05684382, with the smallest P value (1.26E-06) as on chromosome 12, the DVC CpG site cg26188191 with the smallest P value (6.44E-06) appeared in CMIP gene on chromosome 16. Conclusions: In this study, we analyzed the genome-wide DNA methylation and its correlation with obesity traits. After multiple testing corrections, no positive sites were found to have associated with obesity. However, results from the correlation analysis demonstrated sites cg05684382 (chr: 12) and cg26188191 (chr: 16) might have played a role in the development of obesity. This study provides a methodologic reference for the studies on discordance twins related problems. PMID- 29699035 TI - [Effect of docosahexenoic acid supplementation on infant's growth and body mass index during maternal pregnancy]. AB - Objective: To investigate the effects of docosahexenoic acid (DHA) supplementation on infant's growth and BMI during pregnancy. Methods: A total of 1 516 healthy pregnant women delivered their babies in two maternal and child health care hospitals in Beijing and were chosen as the subjects in this cohort study from May to October 2015. Self-developed questionnaires were used to gather general information of the subjects, including age, height, weight, weight gain during pregnancy, delivery mode, DHA supplementation etc., before giving birth. Information on body length, weight, head circumference and BMI at birth and 6 months postnatal, of the infants were recorded. Breast milk was collected to test the fatty acid profiles by using the gas chromatography (GC) method at one to three months postnatally. Results: The overall rate of DHA supplementation was 47.76% among the pregnant women, in which introduction of DHA from the early and second stage of the pregnancy accounted for 49.31% and 39.64% respectively. When DHA supplementation began from the early pregnant stage, the DHA concentration showed an increase in the milk (P<0.05), whereas the supplementation began from the second and third stages did not affect the milk DHA concentration (P>0.05). Higher height and lower BMI were seen in the infants at birth and 6 months in the supplementation group when comparing to the non-supplementary group (P<0.05), with the greatest effects noticed in the earliest supplementation group. Specifically, the head circumference appeared larger from the early pregnant stage in the DHA supplementary group, than that in the non-supplement group (P=0.001). The increment of head circumference was larger than that in the other groups when the infants were 6-month old (P<0.01). Results from the partial regression analysis showed that during pregnancy, there were positive correlations between DHA supplementation and height (r=0.324, r=0.216), head circumference (r=0.221, r=0.302) as well as the increment of head circumference (r=0.276) at birth and 6 months (P<0.05). Whereas, a negative correlation was shown between DHA and the infants' BMI (r=-0.310, r=-0.371) (P<0.05) when supplementation was given during maternal pregnancy. Conclusions: When DHA supplementation program was carried out during maternal pregnancy, it could increase the height and head circumference and inhibit the rapid increase of BMI in the infants BMI. Our findings seemed helpful in promoting brain development and preventing the childhood obesity. PMID- 29699036 TI - [A prospective cohort study on the relationship between maternal prenatal depressive symptoms and children's behavioral problems at 2 years old]. AB - Objective: To explore the associations between maternal and prenatal depressive symptoms and children's behavioral problems at 2 years old. Methods: In the present study, a total of 491 mother-child pairs were selected from the Shanghai Minhang Birth Cohort Study (S-MBCS) which was conducted in Maternal and Child Health Hospital of Minhang District in Shanghai between April and December, 2012. Data from the Center for Epidemiologic Studies on Depression was gathered to assess the maternal depressive symptoms in the second and third trimester of pregnancy, as well as at 6 months and 12 months postpartum. Neurodevelopment at 2 years was assessed, using the Child Behavior Checklist. We used generalized linear models with a log-link function and a Binomial distribution to estimate the risk ratios (RRs) and 95%CIs, on children's behavioral problems at 2 years of age. Sensitivity analyses were performed among participants without postpartum depressive symptoms. Results: After adjustment on factors as maternal age, gestation week, average monthly income per person, parental education and children's gender etc., maternal depression in second trimester of pregnancy was found associated with higher risk of both developing emotional (RR=2.61, 95%CI: 1.36-4.99) and internalizing problems (RR=1.94, 95%CI: 1.22-3.08). However, maternal depression in third trimester was found to be associated with higher risks of developing emotional (RR=6.46, 95%CI: 3.09-13.53), withdrawn (RR=2.42, 95%CI: 1.16-5.02), aggressive (RR=2.93, 95%CI: 1.45-5.94), internalizing (RR=1.79, 95%CI: 1.01-3.16) or externalizing problems (RR=2.56, 95%CI:1.49-4.42). In sensitivity analysis, antenatal maternal depression was found positively associated with children's emotional, internalizing and externalizing problems and the differences all statistically significant. Conclusions: Maternal depression during pregnancy might increase the risks of children's behavioral problems. In order to decrease the incidence of children's behavioral problems and promoting both maternal and child health status, monitoring program regarding maternal mental health care should be strengthened. PMID- 29699037 TI - [Study on sleep quality and related determinants among centenarians in Hainan province]. AB - Objective: To investigate the sleep quality and related determinants among centenarians in Hainan. Methods: A cross-sectional study of centenarians from 16 cities/counties was carried out in Hainan province between June 2014 and June 2016. Data related to demography, chronic diseases and lifestyles of the centenarians were collected. Pittsburg sleep quality index (PSQI) was used to assess the quality of sleep while multivariable logistic Regression model was used to determine the risk factors on the quality of sleep. Results: Of the 730 centenarians in this study, 225 suffered from sleep disorders (30.8%). The average score of PSQI was (6.44+/-3.05), with the top three problems related to sleep as sleep inefficiency (48.5%), sleep latency (35.5%), and daytime dysfuntion (20.6%) among the centenarians. Results from the multivariate logistic analysis showed that incontinence, cardiovascular disease and chronic pain were risk factors, while habitual afternoon nap, and regular diet appeared as protective factors (P<0.05), related to sleep disorder. Conclusions: Quality of sleep had been a problem to the centenarians in Hainan. Intervention on risk factors of sleep disorder should be helpful on these centenarians. PMID- 29699038 TI - [Potential interaction effect on attention-deficit/hyperactivity disorder between mother's educational level and preschoolers' dietary pattern]. AB - Objective: To explore the interaction effect between mother's educational level and preschoolers' dietary pattern on attention-deficit/hyperactivity disorder (ADHD). Methods: In 2014, there were 16 439 children aged 3-6 years old from 91 kindergartens in Ma'anshan municipality of China. A semi-quantitative food frequency questionnaire and the 10-item Chinese version of the Conners' Abbreviated Symptom Questionnaire (C-ASQ) were administered to assess the usual dietary intake and symptoms on ADHD. Social-demographic information was collected through questionnaires. Unconditional logistic regression was used to analyze the multiplication interaction effect between mother's educational level and preschoolers' dietary pattern on ADHD. Excel software was used to analyze the additive interaction effect of mother's educational level and preschoolers'dietary pattern on ADHD. Results: Results showed that factors as: mother's low educational level[aOR=1.31 (1.13-1.52)], scores related to preschoolers in the top quintile of "food processing" [aOR=1.31 (1.16-1.48)] and "snack" [aOR=1.45 (1.29-1.63)]patterns showed greater odds while preschoolers in the top quintile of "vegetarian" [aOR=0.80 (0.71-0.90)]showed less odds for having ADHD symptoms. Both multiplication and additive interactions were observed between mothers with less education. The processed dietary patterns (OR=1.17, 95%CI: 1.11-1.25), relative excess risk of interaction (RERI), attributable proportion (AP) and the interaction index (SI) appeared as 0.21, 0.13 and 1.47, respectively. Multiplication interaction was observed between levels of mother's low education and the snack dietary pattern (OR=1.21, 95%CI: 1.14-1.29), with RERI, AP and SI as 0.49, 0.26 and 2.36, respectively. However, neither multiplication interaction or additive interaction was noticed between levels of mother's low education and the vegetarian dietary pattern (OR=0.97, 95%CI: 0.92 1.03), with RERI, AP and SI as 0.09, 0.05 and 1.15, respectively. Conclusions: Levels of mother's low education presented a risk factor for ADHD symptoms in preschool children. Both multiplication interaction and additive interaction were observed between mother's low education levels and the processed dietary pattern. Multiplication interaction was noticed between mother's education levels and the snack dietary pattern but not with the vegetarian dietary pattern. PMID- 29699039 TI - [Correlation between both neck/shoulder and low back pain and daily behavioral habits among middle school students in Shenzhen]. AB - Objective: To study the relations between neck/shoulder or low back pain and their daily behavioral habits among middle school students in Shenzhen. Methods: We randomly chose 3 952 students from 10 high schools in Shenzhen to complete the questionnaires. Data was gathered and analyzed, using the IBM SPSS 23.0. Results: Of the 3 952 participants, 20.3% had neck/shoulder pain and 15.2% had low back pain. Among students experienced neck/shoulder pain, female (25.3%), high school (24.5%) and boarding students (24.4%) experienced higher rates of neck/shoulder pain (P<0.05). Female students (17.9%) also had higher rate of low back pain (P<0.05). Results from logistic regression analysis showed that factors as: gender, type of school, taking naps on the desk, staying up late, self-perceived stress from learning, overloading homework, time spent on mobile phone and TV, spending long time on computer etc. were related to the neck/shoulder pain (P<0.05). Factors as: gender, naps on the desk, stay up late, self-perceived stress, overloading homework, time spent on mobile phone and TV etc., were related to low back pain (P<0.05). Conclusion: Neck/shoulder pain and low back pain were both commonly seen while high self-perceived stress, sedentary behaviors and poor sleeping habits were associated with both neck/shoulder and low back pain in high school students in Shenzhen. PMID- 29699040 TI - [Epidemiology related to soil-borne nematode disease in Danzhou city, Hainan province]. AB - Objective: To understand the prevalence, trend and related factors on soil-borne nematode in Danzhou city to provide information for prevention and control of the disease. Methods: According to the guidelines set by the National National soil borne nematode technical solutions, one village was randomly chosen from every township as the monitoring location, in the east, west, south and north parts of Danzhou city. A total of 200 residents aged 3 years and over were randomly selected in each monitoring site, with modified Kato thick smear and Cellophane tape anal swab used for microscopy. Results: In this survey, we retrospectively analyzed the rates on soil borne nematode infection in five monitoring locations of Danzhou city and the results showed that the overall positive rates of infection was 19.5% (195/1 000). Comparing with the previous surveys, rates on soil-borne parasites infection were decreasing. The main types of soil-borne nematode infection appeared as roundworm, whipworm, hookworm and pinworm in Danzhou city, with rate of hookworm-egg infection ranking the highest (42.5%, 85/200) in Dacheng. The infection rate was seen significantly higher in females than males. People aged over 60 and between 3-10, had a higher rates of infection. Rate on multiple infections reached 16.9%, including 5 triple infection cases. Conclusion: Rates of infection on soil-borne nematodes in Danzhou city showed a decreasing trend from 2013 to 2016 with hookworm and whipworm as the major ones. PMID- 29699041 TI - [Characteristics and influencing factors regarding social relations among men who have sex with men]. AB - Objective: To study the characteristics of social relations and relative factors among MSM in Guangzhou. Methods: Data was collected through a cross-sectional study in Guangzhou from November 2016 to May 2017. Sample size was estimated and participants were recruited from the voluntary counseling and testing services (VCT) which were set for MSM population, by nongovernmental organizations (NGOs) and the Centers for Disease Control and Prevention (CDC). Social ties and demographic characteristics of the respondents and their sexual partners were analyzed through both Chi square test and generalized estimating equations (GEE). Results: A total of 1 073 MSM, together with their nominated 4 301 partners were successfully recruited and involved in this study. Age (OR=1.2, P=0.01) and non internet based intercourse (OR=1.65, P<0.01) were easy to form close relation with strong ties. Compared with MSM traditional venues (chess and cards room, tea room bathhouse, club), general public venue (bars, KTV, parks, shopping malls, schools, restaurants) (OR=1.46-3.12, P<0.01) showed close relation with strong ties. Our finding showed that MSM at the age of 18-25 preferred to build weak ties with the older MSM, while the 26-30-year-olds and 31-40-year-olds prefer to establish weak ties with younger partners but the 41-50-year-olds preferred to develop weak ties with one that were ten years younger. Conclusions: Clusters were noticed in the MSM populations when grouping and making friends with ones at different age. Characteristics regarding the relationship between sexual partners in choosing venues and ways of dating were different. Targeted intervention programs need to be explored innovatively. PMID- 29699042 TI - [Knowledge, related behavior and on AIDS/HIV infection among rural adults with Derung minority, in Yunnan province, 2016]. AB - Objective: To understand the related risk behaviors, knowledge and status of HIV/AIDS infection among rural adults of Derung minority, to provide relevant messages for the development of HIV/AIDS intervention strategy in this minority group. Methods: We used system sampling method to conduct a cross-sectional survey in 6 administration villages of Derung Township, Gongshan Derung and Nu Autonomous County in Nujiang Lisu Autonomous Prefecture of Yunnan Province, with a sample size estimated as 383. Adult residents with Derung minority in six villages of Gongshan County were involved, with relevant information collected through door-to-door visit. HIV antibody was tested and SPSS 17.0 was used for statistical analysis. Results: Information on 394 valid respondents was collected, with age as between 18 and 65 (34.39+/-9.74), 80.7% (318/394) as married, 54.0% (213/394) having had primary school education, 13.2% (52/394) as migrant workers. In this population, the overall HIV infection rate appeared as 0.5% (2/400), mainly through sexually transmission. The rate of awareness on HIV/AIDS was 69.8% (275/394), mainly through free publicized materials 50.0% (197/394). Rates on premarital sexual behavior on multiple sexual partners in the past year, on temporary sexual partners in the past year, having commercial sexual experiences in the past year and ever used condoms when engaging in casual sex, were 6.4% (60/366), 18.0%(66/366), 5.7%(21/366), 1.9%(7/366) and 8.0%(25/311), respectively. Conclusions: Few numbers of HIV infections were identified among the migrating workers with Derung minority, with sexual transmission as the major route, along with the increased number of rural migrant workers and the low rates both on AIDS knowledge and condom use, accompanied by the high risk sexual behavior appeared in this rural adult residents of Derung minority. Relative strategies on HIV/AIDS intervention and control should be developed. PMID- 29699043 TI - [Dynamic variations of BMI and influencing factors among HIV/AIDS patients receiving highly active antiretroviral therapy in Liuzhou, Guangxi Zhuang Autonomous Region, 2013-2014]. AB - Objective: To understand the dynamic variation of BMI and influencing factors among HIV/AIDS patients receiving highly active anti-retroviral therapy (HAART) in Liuzhou, Guangxi Zhuang Autonomous Region (Guangxi). Methods: HIV/AIDS patients receiving HAART for the first time since 1 January 2013 were selected. Data on BMI was analyzed among patients receiving HAART at baseline,6 months and 12 months after treatment. By using the general linear model repeated measures of analysis of variance, BMI dynamic variations and influencing factors were described and analyzed. Results: The average BMI of 2 871 patients at baseline, 6th months and 12th months appeared as (20.65+/-3.32), (20.87+/-3.22) and (21.18+/-3.20), respectively, with differences all statistically significant (F=18.86, P<0.001). BMI were increasing over time with treatments (F=37.25, P<0.001). Main influencing factors were noticed as: age, sex, marital status, baseline data of CD(4)(+)T cells and the WHO classification on clinical stages. Conclusions: Higher proportion of BMI malnutrition counts was seen among patients before receiving HAART in Liuzhou. BMI of the patients that were on HAART seemed being influenced by many factors. It is necessary to select appropriate treatment protocols on different patients so as to improve the nutritional status of the patients. PMID- 29699044 TI - [Differences on geographic distribution of rabies virus lineages in China]. AB - Objective: To study the lineages of rabies virus and the epidemic characteristics in different provincial populations of China, to provide information for the development of control and prevention measures in each respective provinces. Methods: Full length N and G genes and full-genome of epidemic strains of rabies virus collected in China were downloaded from GenBank and combined with newly sequenced strains by our lab. Each strain was classified under six lineages of China rabies by constructing phylogenetic trees based on the N or G sequences. Numbers of strains and lineages in each province were counted and compared. Results: Six lineages (China I-VI) were prevalent in China, with 4 found in Yunnan and Hunan. In 6 provinces, including Henan and Fujian, 3 lineages were found. In 8 provinces, including Shanghai and Jiangxi, 2 lineages were found Only 1 lineage, were found in Beijing, Tianjin and other 12 provinces. the China I, was the dominant one in 25 provinces. In recent years, China III had been found in wild animals and spread over livestock in Inner Mongolia and Xinjiang areas. Qinghai and Tibet had been influenced by China IV, which also been found in wild animals of Inner Mongolia and Heilongjiang. Conclusion: There had been obvious differences in lineages and strain numbers of rabies virus identified in different provinces in China. PMID- 29699045 TI - [Situation and reasons for missed follow-up services among newly reported HIV/AIDS cases transmitted by homosexual behavior in China, 2008-2015]. AB - Objective: To determine the prevalence and relative factors on those who missed the follow-up service among newly reported HIV/AIDS cases that were infected by homosexual behavior. Methods: Data were extracted from both HIV/AIDS case reporting and follow-up cards on HIV/AIDS in the Comprehensive Response Information Management System, between December 2008 and December 2015. Data was analyzed, using the generalized estimating equations (GEE) to explore the relative factors of influence. Results: Among the newly reported HIV infection among MSM, the proportion of those who missed the follow-up services was 5.06% (6 037/119 358), and decreased dramatically, from 37.57% (1 261/3 356) to 0.84% (267/31 935) (trend chi(2)=103.43, P<0.01). In MSM population, the younger than 20-year olds (OR=1.30, 95%CI: 1.11-1.52), 20-year olds (OR=1.52, 95%CI: 1.36 1.69), 30-year olds (OR=1.22, 95%CI: 1.12-1.34), 40-year olds (OR=1.10, 95%CI: 1.01-1.20) were receiving less follow-up services than those 50-year olds. Those who had received either junior (OR=1.52, 95%CI: 1.37-1.69) or senior high school education (OR=1.35, 95%CI: 1.23-1.49) were receiving less follow-up service than those who were more educated. MSM with the following characteristics as unspecified occupation (OR=2.06, 95%CI: 1.49-2.87),unemployed (OR=1.54, 95%CI: 1.30-1.83), working in commercial service (OR=1.31, 95%CI: 1.15-1.49) or being student (OR=1.34, 95%CI: 1.18-1.52) were more difficult to be traced or followed than the cadres. Cases being identified on site (OR=2.99, 95%CI: 2.26-3.95) or under special investigation (OR=1.43, 95%CI: 1.29-1.59) had received less follow up service than those being identified through voluntary counsel testing service. Floating population (OR=1.46, 95%CI: 1.28-1.66) were getting less follow-up service than local residents. Conclusions: The prevalence of those who had missed the follow-up services in the newly discovered MSM HIV cases declined dramatically. Among the MSM HIV cases, those having the following characteristics as: younger than 50-year old, with less school education, with unspecified occupation or unemployment, working in commercial service, being student, having history of incarceration, recruited from special investigation, and floating population were prone to miss the follow-up program, suggesting that the follow up service should be targeting on these patients. PMID- 29699046 TI - [Data analysis on hepatitis B through pilot surveillance reporting system in Henan province, 2012-2016]. AB - Objective: To standardize the reporting system on hepatitis B in order to improve the quality of monitoring program in Henan province. Methods: A total of 6 sites of Hepatitis B pilot surveillance were selected in Xinzheng of Zhengzhou city, Linzhou of Anyang city, Shanyang district of Jiaozuo city, Shaoling district of Luohe city, Yongcheng of Shangqiu city, Pingqiao district of Xinyang city in Henan province. Subjects under study were those reported hepatitis B cases, from 2012 to 2016. Cases diagnosed in 2011 were chosen as controls. Data on classification of hepatitis B, time that HBsAg became positive and ALT value of the cases were analyzed annually. 5 ml venous blood was collected and anti-HBc IgM confirmed test was made for those suspected acute cases on hepatitis B. Based on the 2016 data from the monitoring system, the incidence of acute hepatitis B in Henan province was estimated. Results: The number of reported hepatitis B cases had declined in 6 sites of Hepatitis B pilot surveillance substantially. A total of 17 436 hepatitis B reported in 2011 but only 2 632 cases were reported in 2016, with a reduction of 84.90%(14 804/17 436) in these six monitoring sites. The number of unclassified hepatitis B cases also dropped sharply. In 2011, 36.87% of the cases were unclassified, but the figure reduced to 0.08% in 2016, from the six sites. The rate on ALT detection also gradually improved. The rate of misdiagnosis on HBV carrier from hepatitis B almost disappeared. From 2013 to 2016, 777 blood samples were collected from six pilot sites. 29.34% (228/777) of the blood samples were tested positive for anti-HBc IgM after confirmed by the hepatitis laboratory of the China Center for Disease Control and Prevention. Conclusions: Since the development of the pilot surveillance program, the quality of reporting system on hepatitis B had been improved, as well as the accuracy of diagnosis. Rate on the accuracy of reporting on hepatitis B and the methods of testing should be improved at the monitoring sites. PMID- 29699047 TI - [Study on the current status of smoking, intention of tobacco concession and related risk factors among 18-65-year olds patients with chronic diseases in Beijing]. AB - Objective: To understand the status, attitude and related risk factors on smoking among 18-65 years old patients with hypertension, diabetes, dyslipidemia, chronic obstructive pulmonary disease (COPD) or asthma in Beijing. Methods: Data was gathered from the 2014 Beijing Non-communicable and Chronic Disease Surveillance Program. Multiple classified cluster sampling method was used and 19 815 participants aged 18-65 were sampled from 16 districts in Beijing. Results: Among all the 18 405 participants, male hypertensive patients showed a higher rate on current smoking than the other groups (chi(2)=17.695, P<0.001). Male patients with dyslipidemia had higher current smoking rate than the other groups (chi(2)=39.292, P<0.001). However, female patients with COPD or with asthma showed higher rate on current smoking than the other groups (chi(2)=6.276, P=0.012), (chi(2)=8.245, P=0.004). Among the smokers, hypertensive patients presented lower rate (chi(2)=20.487, P<0.001) on intention of smoking concession, than the other groups. Patients with COPD showed greater intention in quitting smoking (chi(2)=6.085, P=0.048), than the other groups. Male patients with diabetes (chi(2)=9.219, P=0.010) or dyslipidemia (chi(2)=13.513, P=0.001) who had stopped smoking tobacco appeared having higher rates in keeping the current status. Results from logistic regression analyses showed that smoking was the risk factor for hypertension (OR=1.17), dyslipidemia (OR=1.25), COPD (OR=1.78), and asthma (OR=1.57). Conclusions: Patients with certain kinds of chronic diseases showed higher rate of current smoking and lower rate of quitting. Cigarette consumption appeared an important risk factor for patients with hypertension, dyslipidemia, COPD, or asthma in Beijing. PMID- 29699048 TI - [Trend on mortality/incidence ratio of acute myocardial infarction in Tianjin from 2007 to 2015]. AB - Objective: To explore the variation for mortality/incidence (MI) ratio on acute myocardial infarction (AMI) in Tianjin from 2007 to 2015. Methods: Data from both disease and death surveillance systems on AMI in Tianjin from 2007 to 2015, were collected. Incidence and mortality for AMI of people over 35 years old were calculated and fitted by using the exponential model. Annual MI ratios by gender and different age groups were calculated. Join-point regression was used for sensitivity analysis of the ratio. Results: Other than 2007, 2010, 2014 and 2015, the ratios in rest of the years were all bigger than one. From 2007 to 2015, the ratios were ranging from 0.80 to 1.60, with 0.90 to 1.80 for females, and 0.80 to 1.40 for males, respectively. Conclusion: The MI ratio on AMI changed relatively stable in Tianjin from 2007 to 2015, but the AMI incidence data in Tianjin seemed underreported, especially for people over 75 years old, indicating that some elderly AMI cases were not reported to the disease surveillance system. PMID- 29699049 TI - [Cloning expression and serological evaluation on Mycobacterium tuberculosis four new antigens]. AB - Objective: To evaluate the serological diagnostic value of Mycobacterium (M.) tuberculosis four new antigens Rv0432, Rv0674, Rv1566c and Rv1547. Methods:Rv0432, Rv0674, Rv1566c and Rv1547 were amplified from M. tuberculosis strain H37Rv genomic DNA by using PCR, among which Rv1547 was divided into two segments for amplification (Rv1547-1 and Rv1547-2). The segments were cloned into expression vector PET-32a while the recombinant proteins were purified by affinity chromatography. Serums were incubated with BL21 (DE3) proteins. Antibodies IgG against M. tuberculosis were tested with 151 serum samples (41 healthy people and 110 TB patients) by using ELISA. The diagnostic efficiency of antigens was analyzed by means of receiver operating characteristic curve. Difference of the objective proteins in TB patients and healthy controls was compared by t-test. Results: Recombinant antigens Rv0432, Rv0674, Rv1566c, Rv1547 1 and Rv1547-2 were successfully expressed and purified. Results from ELISA showed that the sensitivity, specificity, positive predictive value, negative predictive value, Youden index and area under the curve of Rv0432, Rv0674, Rv1566c, Rv1547-1 and Rv1547-2, as 43.64%-92.73%, 80.49%-92.68%, 0.92-0.94, 0.38 0.80, 0.363-0.732 and 0.649-0.915. All the objective proteins showed significantly higher antibody levels in TB patients, when compared to the healthy controls (P<0.000 1). Conclusion: The newly identified antigens Rv0432, Rv0674, Rv1566c, Rv1547-1 and Rv1547-2 all performed well when being used for TB serological diagnosis, thus were expected to be new candidate antigens used for TB diagnosis. PMID- 29699050 TI - [Realization of design regarding experimental research in the clinical real-world research]. AB - Real world study (RWS), a further verification and supplement for explanatory randomized controlled trial to evaluate the effectiveness of intervention measures in real clinical environment, has increasingly become the focus in the field of research on medical and health care services. However, some people mistakenly equate real world study with observational research, and argue that intervention and randomization cannot be carried out in real world study. In fact, both observational and experimental design are the basic designs in real world study, while the latter usually refers to pragmatic randomized controlled trial and registry-based randomized controlled trial. Other nonrandomized controlled and adaptive designs can also be adopted in the RWS. PMID- 29699051 TI - [Risk on bias assessment: (6) A Revised Tool for the Quality Assessment on Diagnostic Accuracy Studies (QUADAS-2)]. AB - This paper introduced the Revised Tool for the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2), including the development and comparison with the original QUADAS, and illustrated the application of QUADAS-2 in a published paper related to the study on diagnostic accuracy which was included in systematic review and Meta-analysis. QUADAS-2 presented considerable improvement over the original tool. Confused items that included in QUADAS had disappeared and the quality assessment of the original study replaced by the rating of risk on bias and applicability. This was implemented through the description on the four main domains with minimal overlapping and answering the signal questions in each domain. The risk of bias and applicability with 'high','low' or 'unclear' was in line with the risk of bias assessment of intervention studies in Cochrane, so to replace the total score of quality assessment in QUADAS. Meanwhile, QUADAS-2 was also applicable to assess the diagnostic accuracy studies in which follow-up without prognosis was involved in golden standard. It was useful to assess the overall methodological quality of the study despite more time consuming than the original QUADAS. However, QUADAS-2 needs to be modified to apply in comparative studies on diagnostic accuracy and we hope the users would follow the updates and give their feedbacks on line. PMID- 29699052 TI - [Progress of research on the association between air pollution and prevalence of major cancers]. AB - Being an undisputed risk factor of cancer, air pollution is posing a huge threat to the health on human beings. In this article, we introduced the composition of air pollution, and the standards on air quality which was set by both World Health Organization and the Chinese government. We also summarized the most recent research findings on the association between air pollution and the risk of lung, breast, bladder and other major cancers. PMID- 29699053 TI - [Current situation on new psychoactive substances abuse among methadone maintenance treatment patients in China]. AB - Methadone maintenance treatment (MMT) greatly contributed to the successful outcomes of prevention and control on both AIDS and drug abuse in China. However, the features on drug abuse changed in the past decades, and the prevalence of new psychoactive substances abuse potentially somehow offset the achievement of MMT. This paper concised the information on research and surveys of this issue that targeting on the current situation, characteristics, related factors and relevant public health problem on new psychoactive substances abuse, among patients who have been on MMT, in China. PMID- 29699054 TI - Prevalence, Cognitive and Socio-Demographic Determinants of Prostate Cancer Screening AB - Screening may be effective for reducing deaths due to prostate cancer. The aim of this study was determine theprevalence and determinants influencing prostate cancer early detection behaviors based on the theory planned behavior(TPB). In this cross-sectional study, conducted in the west of Iran, a total of 250 men aged 50 to 70 years old wererandomly selected to participate. Of these, 200 (80%) signed the consent form and voluntarily agreed to take part. Astructured questionnaire based on TPB constructs was applied for collecting data by interview. Analyses were conductedwith SPSS version 16 using bivariate correlations, and logistic and linear regression. Some 26.5% of the participantsdemonstrated prostate cancer early detection behavior. Age higher than 60 (OR: 5.969), academic education (OR: 2.904),number of family members more than four (OR: 3.144), and knowledge about prostate cancer (OR: 3.693) were themost influential predictive factors for early detection behavior. Furthermore, among the TPB constructs, attitude(OR=1.090) and subjective norms (OR=1.280) were the most influential predictors. Attitude, subjective norms, andperceived behavioral control accounted for 43% of the variation in the outcome measure of the intention to screenfor prostate cancer (adjusted R squared= 0.43, F= 49.270 and P < 0.001). Designing and implementation programs toincrease positive attitudes and encourage subjective norms towards prostate cancer screening behavior may be usefulfor promotion of early detection. PMID- 29699055 TI - Symptoms in Advanced Cancer Patients in a Greek Hospital: a Descriptive Study AB - Background: Advanced cancer patients experience several physical or psychological symptoms which requirepalliative care for alleviation. Purpose: To assess the prevalence and intensity of symptoms among cancer patientsreceiving palliative care in a Greek hospital and to examine the association between reported symptoms and socialclinical and demographic characteristics. Material-methods: This descriptive research was conducted during a sixmonthperiod using a convenient sample of 123 advanced cancer patients. All participants were assessed for theirsymptoms using the Edmonton Symptom Assessment System (ESAS) with a questionnaire covering demographicand clinical characteristics. Results: The mean age was 63.8+/- 10.8 years, with lung and breast (58.5% and 11.4%,respectively) as the most common primary cancer types. The most severe symptoms were fatigue, sleep disturbance,dyspnea, depression and anxiety. Negative correlations were revealed between age and the following symptoms: pain(r = -0.354, p = 0.001), fatigue (r = -0.280, p = 0.002), nausea (r = -0.178, p = 0.049), anorexia (r = 0.188, p = 0.038),dyspnea (r = -0.251, p = 0.005), and depression (r = -0.223, p = 0.013). Advanced breast cancer patients scored higherin pain, fatigue and dyspnea compared to those with other cancers. Conclusions: Hospitalized cancer patients in Greeceexperience several symptoms during the last months of their life. These are influenced by demographic characteristics.Appropriate interventions are strongly advised with appropriate recognition and evaluation of symptoms by healthprofessionals. PMID- 29699056 TI - Circulating MicroRNA-21 Expression as a Novel Serum Biomarker for Oral Sub-Mucous Fibrosis and Oral Squamous Cell Carcinoma AB - Background: Circulating miRNAs (miRs) in the biofluids such as serum and plasma act as potential biomarkersfor early diagnosis, treatment and prognosis. In the present study, an attempt made to see the expression of miR-21in serum of 20 cases of Oral sub-mucous fibrosis (OSMF), 20 cases of Oral squamous cell carcinoma and 40 healthyvolunteers. The expression of miR-21 was evaluated in relation to different demographical and clinicopathologicalfeatures such as sex, tobacco, pan-masala, alcohol, smoking and clinical staging respectively with an aim to identifycorrelation with oral pre-cancer and cancer stages. Materials and Methods: The relative expression level of miR-21was determined by quantitative real-time RT-PCR (qRT-PCR) in the sera of 20 OSCC, 20 OSMF patients and 40healthy subjects as a control. Association between expression of miR-21 and OSCC clinical stages and demographicalparameters such as sex, pan-masala, tobacco, smoking, alcohol have also been analyzed in detail. Results: The resultsobtained by t-test revealed significant increase in the expression level of miR-21 in OSCC as compared to OSMF. Thestudy also revealed the positive correlation between higher miR-21 expression and pan-masala chewers as shown byt-test. The statistical test, ANOVA has also indicated a positive correlation between up-regulation of miR-21 in theclinical stages of the OSCC. Conclusion: The results of present study indicated up-regulation of circulating miR-21 inserum of OSCC as compared to OSMF (p=0.001), this study also elucidated the positive correlation between miR 21expression in OSCC/OSMF patients, only one demographical parameter (Pan-masala) and negative correlation forother parameters such as sex, tobacco, smoking, alcohol etc. Other findings suggested a significant increase (p=0.000)in the expression of miR-21 in clinical staging (I-IV) of oral cancer. More studies are needed to validate it as potentialdiagnostic and prognostic biomarker for OSMF and OSCC for better management. PMID- 29699057 TI - Significant Association of the MDM2 T309G Polymorphism with Breast Cancer Risk in a Turkish Population AB - Background: Breast cancer is a leading cause of death in women worldwide. Genetic polymorphisms have beenreported to be important etiological factors. Murine double minute 2 (MDM2) T309G interacts with p53 and mutationsin p53 are present in approximately 50% of all cancers. However, it has been reported that effect of the polymorphismon breast cancer risk may vary in different populations. Here, we therefore investigated whether there is an associationbetween MDM2 T309G (rs2279744) polymorphism and breast cancer in a Turkish population. Materials and Methods:We analysed 110 patients with breast cancer and 138 matched? controls. For genotyping, polymerase chain reactionand restriction length fragment polymorphism methods were used. Results: A significant difference was observedbetween case and control groups with regard to the distribution of the MDM2 T309G polymorphism (p<0.05). Therewas a significantly higher frequency of the TT genotype in the control group (p=0.028; OR, 2.42; 95% CI, 1.09 5.37).However, we did not find any relationships among tumor grade and metastasis status and this polymorphism. Conclusion:This study indicates that the MDM2 T309G polymorphism GG genotype and the TG+GG combination may be riskfactors for breast cancer in our Turkish population. PMID- 29699058 TI - Psychological Limbo as a Barrier to Spiritual Care for Parents of Children with Cancer: A Qualitative Study AB - Background: Pediatric cancer causes reduced life quality and psychological problems for parents. It is necessaryto pay attention to spirituality, which plays a significant role in increasing the life quality of these parents and theirpatient children and managing the conditions associated with the disease. This study was performed to determinefactors predisposing to spiritual care in parents of children suffering from cancer. Methods: This qualitative study wasconducted by conventional content analysis. Fifteen parents of children with cancer hospitalized in the oncology andhematology wards of governmental hospitals in Iran were selected using a purposive sampling method and underwentsemi structured deep interviews from 2015.1.10 until 2017.3.10. Results: On data analysis, 12 subcategories emergedleading to extraction of three : "projection", "mental concern", and "psychological pains". The final result was a focuson the theme "psychological limbo". Conclusion: Our findings showed that cancer induces psychological problemsin parents, which may serve as factors that drive them towards spiritual affairs. Hence, attention should be paid topredisposing factors of spiritual care to facilitate tranquility and an ability to adapt to their circumstances in affectedparents. PMID- 29699059 TI - Measuring Intrahepatic Vascular Changes Using Contrast-Enhanced Ultrasonography to Predict the Prognosis of Alcoholic Hepatitis Combined with Cirrhosis: A Prospective Pilot Study. AB - Background/Aims: Acute hepatic dysfunction combined with alcoholic hepatitis (AH) in alcoholic cirrhosis is related to hepatic hypo-perfusion secondary to intrahepatic necroinflammation, neoangiogenesis, and shunt. The hepatic vein arrival time (HVAT) assessed by microbubble contrast-enhanced ultrasonography (CEUS) is closely correlated with the severity of intrahepatic changes. We investigated the usefulness of HVAT to predict short-term mortality of AH in cirrhosis. Methods: Thirty-nine patients with alcoholic cirrhosis (27 males) and AH were prospectively enrolled. HVAT study was performed within 3 days after admission using ultrasonic contrast (SonoVue(r)). The primary outcome was 12-week mortality. Results: Twelve-week mortality developed in nine patients. HVAT was significantly different between the mortality and survival groups (9.3+/-2.0 seconds vs 12.6+/-3.5 seconds, p=0.002). The odds ratio of a shortened HVAT for 12-week mortality was 1.481 (95% confidence interval, 1.050-2.090; p=0.025). The area under the receiver operating characteristic curve of HVAT for 12-week mortality was 0.787 (p=0.010). The combination of MDF and HVAT >=11.0 seconds resulted in an 87.5% survival rate even if the MDF score >=32; however, HVAT <11.0 seconds was related with mortality despite a MDF score<32. Conclusions: HVAT using microbubble CEUS could be a useful additional index to predict short term mortality in patients with AH and cirrhosis. PMID- 29699060 TI - Contrast-Enhanced Endoscopic Ultrasound for Differentially Diagnosing Autoimmune Pancreatitis and Pancreatic Cancer. AB - Background/Aims: Differentially diagnosing focal-type autoimmune pancreatitis (f AIP) and pancreatic cancer (PC) is challenging. Contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) may provide information for differentiating pancreatic masses. In this study, we evaluated the usefulness of CEH-EUS in differentiating f-AIP from PC. Methods: Data were collected prospectively and analyzed on patients who underwent CEH-EUS between May 2014 and May 2015. Eighty consecutive patients were diagnosed with f-AIP or PC. PC and f-AIP were compared for enhancement intensity, contrast agent distribution, and internal vasculature. Results: The study group comprised 53 PC patients and 27 f-AIP patients (17 with type-1 AIP [15 definite and two probable], two with probable type-2 AIP, and eight with AIP, not otherwise specified). Hyper- to iso-enhancement in the arterial phase (f-AIP, 89% vs PC, 13%; p<0.05), homogeneous contrast agent distribution (f-AIP, 81% vs PC, 17%; p<0.05), and absent irregular internal vessels (f-AIP, 85% vs PC, 30%; p<0.05) were observed more frequently in the f AIP group. The combination of CEH-EUS and enhancement intensity, absent irregular internal vessels improved the specificity (94%) in differentiating f-AIP from PC. Conclusions: CEH-EUS may be a useful noninvasive modality for differentially diagnosing f-AIP and PC. Combined CEH-EUS findings could improve the specificity of CEH-EUS in differentiating f-AIP from PC. PMID- 29699061 TI - Expression of Fibroblast Growth Factor 21 and beta-Klotho Regulates Hepatic Fibrosis through the Nuclear Factor-kappaB and c-Jun N-Terminal Kinase Pathways. AB - Background/Aims: Fibroblast growth factor (FGF) 21 is associated with hepatic inflammation and fibrosis. However, little is known regarding the effects of inflammation and fibrosis on the beta-Klotho and FGF21 pathway in the liver. Methods: Enrolled patients had biopsy-confirmed viral or alcoholic hepatitis. FGF19, FGF21 and beta-Klotho levels were evaluated using enzyme-linked immunosorbent assay, real-time polymerase chain reaction, and Western blotting. Furthermore, we explored the underlying mechanisms for this process by evaluating nuclear factor-kappaB (NF-kappaB) and c-Jun N-terminal kinase (JNK) pathway involvement in Huh-7 cells. Results: We observed that the FGF19 and FGF21 serum and mRNA levels in the biopsied liver tissue gradually increased and were correlated with fibrosis stage. Inflammatory markers (interleukin 1beta [IL 1beta], IL-6, and tumor necrosis factor-alpha) were positively correlated, while beta-Klotho expression was negatively correlated with the degree of fibrosis. In Huh-7 cells, IL-1beta increased FGF21 levels and decreased beta-Klotho levels. NF kappaB and JNK inhibitors abolished the effect of IL-1beta on both FGF21 and beta Klotho expression. FGF21 protected IL-1beta-induced growth retardation in Huh-7 cells. Conclusions: These results indicate that the inflammatory response during fibrogenesis increases FGF21 levels and suppresses beta-Klotho via the NF-kappaB and JNK pathway. In addition, FGF21 likely protects hepatocytes from hepatic inflammation and fibrosis. PMID- 29699062 TI - Patient Response to Endoscopic Therapy for Gastroesophageal Varices Based on Endoscopic Ultrasound Findings. AB - Background/Aims: Gastroesophageal variceal hemorrhage is a common complication of portal hypertension. Endoscopic therapy is currently recommended for preventing gastroesophageal variceal rebleed. However, the rate of variceal rebleed and its associated mortality remain concerning. This study is aimed at differentiating patient response to endoscopic therapy based on endoscopic ultrasound (EUS) findings. Methods: One-hundred seventy patients previously treated with repeat endoscopic therapy for secondary prophylaxis were enrolled and classified into two groups based on treatment response. Prior to consolidation therapy, all patients received an EUS examination to observe for extraluminal phenomena. All available follow-up endoscopic examination records were retrieved to validate study results. Results: Of the 170 subjects, 106 were poor responders, while 64 were good responders. The presence of para-gastric, gastric perforating, and esophageal perforating veins was associated with poor patient response (p<0.001). The odds ratio for para-gastric veins was 5.374. Follow-up endoscopic findings for poor responders with incomplete variceal obliteration was closely correlated with the presence of para-gastric veins (p=0.002). Conclusions: The presence of para-gastric veins is a characteristic of poor response to endoscopic therapy for treating gastroesophageal varices. Early identification of this subgroup necessitates a change in course of treatment to improve overall patient outcome. PMID- 29699063 TI - Clinical Impact of Recombinant Soluble Thrombomodulin for Disseminated Intravascular Coagulation Associated with Severe Acute Cholangitis. AB - Background/Aims: Recently, recombinant human soluble thrombomodulin (rTM) has been developed as a new drug for disseminated intravascular coagulation (DIC). This study aims to evaluate the clinical benefit of rTM in patients with sepsis induced DIC caused by acute cholangitis who underwent biliary drainage. Methods: Patients were divided into two groups: the rTM therapy group and the non-rTM therapy group. The primary outcome was the DIC resolution rate at 7 days, and the secondary outcome was 28-day mortality rate. Results: Thirty-five patients were treated by rTM, and 36 patients were treated without rTM for DIC. The rate of resolution of DIC at day 7 was significantly higher in the rTM group than in the non-rTM group (82.9% vs 55.6%, p=0.0012). Compared with the non-rTM group, the 28 day survival rate of the r-TM group was significantly higher (rTM vs non-rTM, 91.4% vs 69.4%, p=0.014). According to multivariate analysis, non-rTM (hazard ratio [HR], 2.681) and CRP (HR, 2.370) were factors related to decreased survival. Conclusions: rTM treatment may have a positive impact on improving DIC and survival rates in patients with severe acute cholangitis. PMID- 29699064 TI - Inverse Association between Glucose-6-Phosphate Dehydrogenase Deficiency and Hepatocellular Carcinoma AB - Background: Studies in experimental models and humans suggest that glucose-6 phosphate dehydrogenase(G6PD) deficiency, an inherited condition, may be inversely related to hepatocellular carcinoma (HCC). We testedthis hypothesis in a large cohort of Sardinian patients. Methods: A case-control study was performed using datafrom 11,143 records of patients who underwent upper endoscopy between 2002 and 2017. Gender, age, G6PD statusand information regarding the presence of HCC, were recorded. Cases (HCC positive) and controls (HCC negative)were compared for the presence of G6PD deficiency adjusting for major HCC risk factors using logistic regression.Results: Overall, 114 HCC cases and 11,029 controls were identified. G6PD deficiency was detected in 11.5% ofstudy participants, and was associated with a reduced risk of HCC [odds ratio (OR); 0.451; 95% confidence interval(CI), 0.207-0.982] after adjusting for all covariates. Factors significantly associated with HCC were cirrhosis (OR,23.30; 95% CI, 11.48-47.25), diabetes (OR, 2.396; 95% CI, 1.449-3.963), among infection hepatitis HBV with anOR of 2.326, age >=65 years (OR, 1.941; 95% CI, 1.234-2.581) and male gender (OR, 1.611; 95% CI, 1.006-3.081).Conclusions: Our study revealed a significant inverse association between G6PD deficiency and risk of HCC. Thesefindings need to be confirmed in further studies. PMID- 29699065 TI - Evaluation of Collagen in Leukoplakia, Oral Submucous Fibrosis and Oral Squamous Cell Carcinomas Using Polarizing Microscopy and Immunohistochemistry AB - Objectives: Picrosirius red and MMP are capable of degrading extracellular matrix proteins, expressed in lesions suchas squamous cell carcinomas. The present study was undertaken with an aim to analyze and compare changes in collagenusing Picrosirius red staining under polarizing microscopy and immunohistochemical staining using anti MMP-13 insamples of oral leukoplakia, oral submucous fibrosis and oral squamous cell carcinoma. Materials and Methods:A total of 70 slides were prepared and divided into 3 groups. Group I comprised 10 slides of normal gingival tissue,Group II 40 slides of potentially malignant disorders and Group III 20 slides of well differentiated oral squamous cellcarcinoma. Half the slides for each group were stained with Picrosirius red stain and the remainder with antibodies toMMP-13. Rerults: In Group II, MMP-13 connective tissue expression was greater in OSMF as compared to leukoplakia.Group III showed elevated expression among 70% of cases. Picrosirius red staining in Group II cases, showed higherstaining Yellow-Orange andGreen-Yellow mature fibers in OSMF than leukoplakia cases while in Group III, 50%OSCC cases showed Green-yellow stained immature thin fibers. Conclusion: In future, therapeutic measures targetedagainst MMP-13 may inhibit collagenolysis to some extent and delay spread of tumors. An easy and reliable methodto determine the state of the stroma in such cases may be Picrosirius red staining with polarizing microscopy. PMID- 29699066 TI - Advances in the cryopreservation of mammalian oocytes and embryos: Development of ultrarapid vitrification. AB - The cryopreservation of embryos has become a powerful tool in assisted reproduction in several mammalian species. Embryos are cryopreserved by slow freezing or by vitrification. However, consistently high survival has not been obtained in most oocytes and in some embryos. The main reasons for the low survival would be sensitivity to low temperatures, which leads to chilling injury, and low permeability of the cell membrane, which leads to the formation of intracellular ice. As a strategy aiming to overcome these injuries, modified vitrification methods have been devised in which the cooling and warming rate is markedly increased by minimizing the volume of the solution and the container. The modified methods use electron microscope grids, open-pulled straws, cryoloops, or container-less microdrops. In this article, recent developments in the ultrarapid vitrification of mammalian oocytes and embryos are reviewed based on the understanding of the mechanisms of cell injury in cryopreservation. (Reprod Med Biol 2002; 1: 1-9). PMID- 29699067 TI - Measurement of intracavernosal catecholamine during a prostaglandin E1 test. AB - Background : Erectile dysfunction (ED) can be a cause of male infertility among young men. The prostaglandin E1 (PGE1) intracavernous injection test, an erectile function test, is known as an objective method of examining the penile vasculature system. However, some ED patients fail to sufficiently maintain an erection because of the stress load upon them during the test. Thus, we measured changes in catecholamine levels by stress loading when we performed dynamic infusion cavernosometry (DIC). Methods : Among the 221 ED patients undergoing a PGE1 test, 10 were selected as the subjects for the present study. These 10 patients were 25-56 years of age, with a mean of 32.8 years, whose maximal penile rigidity was normal, but in whom penile erection could not be maintained sufficiently in the PGE1 test. Stress loading via vibratory sensory measurement during the PGE1 test suppressed penile rigidity strongly. Catecholamine levels were measured by using blood samples obtained from the corpus cavernosum and the cubital vein when erection was suppressed by stress loading, pain caused by needle insertion, and also when erection recovered from the suppression. Dynamic infusion cavernosometry was performed after each blood sampling time, to check corporeal veno-occlusive function and cavernosal arterial flow. Results : Penile norepinephrine levels were 0.20 +/- 0.06 ng/mL during a suppressed erection and 0.15 +/- 0.03 ng/mL during an erection, showing a significantly higher level (Student's t-test, P = 0.0309) during suppressed erection. The results of the DIC measurement indicated a normal corporeal veno-occlusive function and cavernosal artery in all cases. Conclusion : The results of the present study revealed that corporeal veno-occlusive function and cavernosal arterial flow are normal in men who have normal maximum penile rigidity, but cannot sufficiently maintain the erection in the PGE1 test, suggesting the involvement of stress-induced penile norepinephrine in the suppression of erection maintenance. (Reprod Med Biol 2002; 1: 11-15). PMID- 29699068 TI - Influence of endometrial thickness and pattern on pregnancy rates in in vitro fertilization-embryo transfer. AB - Aim : Our aim was to investigate the role of endometrial thickness and pattern in the pregnancy rate during an in vitro fertilization-embryo transfer (IVF-ET) cycle. Methods : Records of patients who underwent IVF-ET at the Jichi Medical School Hospital during May 1995-December 1999 were evaluated retrospectively. Only cycles, in which endometrial thickness and pattern on the day of human chorionic gonadotrophin (HCG) administration were recorded, were analyzed in this study. Endometrial thickness was divided into three categories (A: < 10 mm, B: 10 14 mm, C: > 14 mm), and endometrial pattern was divided into two categories: triple line and non-triple line. A total of 156 IVF-ET cycles from 120 patients was evaluated. Results : There were no significant differences for both the endometrial thickness and pattern in the pregnancy rate during the IVF-ET cycle (P > 0.05). Among the study groups, the triple-line endometrial pattern was found to be 58.7% in group A, 84.0% in group B and 70% in group C. We found that in the triple-line endometrial pattern, there was a significant difference between group A and group B (P < 0.01). Triple-line endometrial pattern appeared significantly in younger women (33 +/- 5.4 years) than in non-triple-line endometrial pattern (36 +/- 5.2 years; P = 0.047). The minimum and maximum endometrial thickness where pregnancy occurred was 6.5 mm (two pregnancies) and 19 mm (one pregnancy), respectively. Conclusion : Endometrial thickness and pattern have no influence on the pregnancy rates in an IVF-ET cycle, but patients with triple-line endometrial pattern and group B endometrial thickness showed a better pregnancy outcome in the IVF-ET treatment. (Reprod Med Biol 2002; 1: 17-21). PMID- 29699069 TI - Establishment and application of criteria for the elective transfer of two good quality embryos to reduce high-order multiple pregnancies. AB - Aim : This study was carried out to establish criteria for the elective transfer of two good-quality embryos to reduce high-order multiple pregnancy rates. The pregnancy and multiple pregnancy rates per transfer were retrospectively analyzed in 128 in vitro fertilization and embryo transfer (IVF-ET) cycles. Results : The analysis revealed that the pregnancy and multiple pregnancy rates were 26.6% (34 of 128) and 23.5% (eight of 34), respectively. Five twin and three triplet pregnancies were included. The pregnancy rates in women 29 years old and younger, 30-34 years, 35-39 years, and 40 years and older were 21.2 (seven of 33), 37.0 (17 of 46), 25.8 (eight of 31), and 11.1% (two of 18), respectively. There was a significant difference of the pregnancy rates between 30 and 34-year-old and 40 year-old and older women (P < 0.05). The multiple-pregnancy rate in women 40 years and older was 0%. Three triplet pregnancies were established only in the first attempt of IVF-ET. The pregnancy rates in women, to whom good-quality embryos (0-4) were transferred, were 0% (none of 12) for 0, 17.2% (five of 29) for one, 41.2% (seven of 17) for two, 30.8% (12 of 39) for three, and 32.3% (10 of 31) for four and more embryos, respectively. The multiple pregnancy rates in women who had good-quality embryos of one, two, three, and four and more transferred were 0% (none of five), 23.5% (four of seven), 16.7% (two of 12), and 20.0% (two of 10), respectively. Conclusion : The criteria for the elective transfer of two good-quality embryos were established as follows: age < 40 years, a first treatment cycle, and more than three good-quality embryos available for transfer. After the application of the established criteria, the overall pregnancy and multiple pregnancy rates were 30.4% (14 of 46) and 14.3% (two of 14), respectively, which was satisfactory as compared with those in the 128 IVF ET cycles before application of the criteria. An elective transfer of two good quality embryos can be highly recommended to avoid high-order multiple pregnancies in subjects with the established criteria. (Reprod Med Biol 2002; 1: 23-29). PMID- 29699070 TI - Testicular sperm extraction using microdissection for non-obstructive azoospermia. AB - Background : Men presenting with non-obstructive azoospermia (NOA) caused by germinal failure can now be treated in some cases using testicular sperm extraction (TESE) and intracytoplasmic sperm injection (ICSI). However, TESE is a blind procedure that does not identify the focal sperm-producing areas until excision of the testicular tissue. Microdissection TESE, which is the only method available for obtaining excised dilated seminiferous tubules under the operating microscope, improves sperm yield with minimal tissue excision in NOA patients. Methods and Results : We performed this procedure on 16 NOA patients. All subjects underwent a microdissection TESE on the right testis, and triple biopsy on the left testis in consecutive fashion in order to compare the efficacy of microdissection TESE with that of a standard biopsy. Although dilated seminiferous tubules were presented in all patients, spermatozoa were retrieved in only a single patient by microdissection TESE. Furthermore, spermatozoa could not be identified by standard biopsies. Conclusion : In this series, microdissection TESE did not contribute to spermatozoa recovery in NOA patients. Further study is needed in order to arrive at a reliable assessment of microdissection TESE relative to a standard multiple biopsy in cases of NOA. (Reprod Med Biol 2002; 1: 31-34). PMID- 29699071 TI - Fertility reduced by immunization with p84: A human sperm-coating antigen in the mouse. AB - Background : p84 is an 84-kDa protein with the ABO (H) antigenic epitope, and it is also a member of the family of sperm-coating antigens. In order to investigate whether the antibodies against p84 reduce fertility in mice, p84 and lactotransferrin (Lf), whose N-terminal sequence is similar to that of p84, were injected into female mice. Results : When p84 was used as the immunogen, the fertilization ratio was 37.5% lower than that of female mice immunized with no antigen (control group; P < 0.01). When Lf was used as the immunogen, there was no significant difference in the fertilization ratio between the Lf and control groups. Sera from female mice immunized with these antigens showed no agglutination against human erythrocytes, suggesting that the ABO(H) determinant site on p84 is not the factor reducing fertility. Although the titer of antibody (IgG) against p84 in serum from female mice immunized with p84 was generally higher than that against Lf, the titer was not related to the reduction of fertility. Conclusion : We conclude that an injection of p84 can reduce the fertility of female mice by inducing antibodies against p84. Our results suggest that the antibodies may act to inhibit the sperm-egg interaction, and that the binding site is the carbohydrate chain of p84, excluding the ABO (H) antigenic epitope, rather than the p84 protein itself. (Reprod Med Biol 2002; 1: 35-39). PMID- 29699072 TI - Spermatozoon and mitochondrial DNA. AB - In eukaryotic cells, mitochondria are the major site of ATP production, which is achieved through the electron-transport chain and oxidative phosphorylation, according to the energy demand. Mitochondria contain their own genome (mitochondrial DNA, mtDNA) on which a limited number of genes are encoded. In the human sperm, mitochondria helically wrap the midpiece of the tail and supply the energy for the driving force of motility. While various mutations in mtDNA in somatic cells are found to be associated with a wide spectrum of diseases, it is also reported that the abnormal mtDNA causes astenozoospermia and male infertility. At fertilization, the paternal mitochondria and mtDNA are rapidly degraded early in embryogenesis, thus, only maternal mtDNA is transmitted to the descendant. We briefly review here the basic characteristics of mtDNA and its maternal transmission during fertilization, as well as male infertility. (Reprod Med Biol 2002; 1: 41-47). PMID- 29699073 TI - Relationships between circulating leptin concentrations and other hormonal parameters in obese and non-obese women with polycystic ovary syndrome. AB - Aim: To clarify the role of leptin in women with polycystic ovary syndrome (PCOS), we analyzed whether serum leptin levels correlate with other hormonal parameters in obese and non-obese women with PCOS. Methods: We studied 20 obese (body mass index, BM >=25 kg/m2) and 20 non-obese (BMI <25 kg/m2) women with PCOS diagnosed by the existence of menstrual disturbance, elevated serum level of luteinizing hormone (LH) with normal follicle-stimulating hormone (FSH) and the characteristic polycystic appearance of the ovaries on transvaginal ultrasound images. Blood samples for LH, FSH, estradiol, testosterone (T), androstenedione (Delta4) and leptin were obtained, and the relationships between variables were examined by calculating Spearman correlation coefficients. Results: Mean levels of leptin, T and Delta4 in obese PCOS women were significantly higher than those in non-obese PCOS women, but this was not the case for BMI, bodyweight and waist to hip ratio. In all the 40 PCOS women considered together, there were significant positive correlations of leptin with BMI, waist to hip ratio, and Delta4 levels. However, in each group separately, serum leptin levels in obese PCOS women correlated only with BMI and bodyweight, whereas serum leptin levels in non-obese PCOS women correlated with serum A4 levels. Conclusion: Although further study is needed to assess the role of leptin on ovarian function in non obese women with PCOS, present findings do not support the fact that leptin is involved in the development of hormonal abnormalities in obese women with PCOS. (Reprod Med Biol 2002; 1: 49-54). PMID- 29699074 TI - Oxidative state and zona-binding ability in mouse spermatozoa treated with reduced glutathione. AB - Background and Aims: Nuclear proteins in mature mammalian spermatozoa nuclei are oxidized to form numerous disulfide bonds. Reduced glutathione (GSH) in the oocyte has been linked to spermatozoan nuclear decondensation after fertilization. In this study, we analyzed whether GSH reduced protamines in sperm nuclei in vitro, and examined the zona-binding ability of treated nuclei. Methods: Three groups of mouse cauda epididymal spermatozoa were prepared. The first group was cultured in Chatot-Tasca-Ziomek (CZB; control group), the second in 10 mmol/L GSH (GSH group), and the third group was the GSH group re-cultured in CZB (re-cultured group). Each sperm was stained with acridine orange, and the oxidative and reductive state of nuclei was analyzed by using fluorescence microscopy. Furthermore, we examined the zona-binding ability for each group by insemination to mouse oocytes after exposure to hyaluronidase. Results: All sperm nuclei from the control group displayed an oxidized pattern (green), and those from the GSH group displayed a reduced pattern (red), attributable to reduced protamines. Sperm nuclei from the re-cultured group displayed the oxidized pattern. Although the zona-binding ability of the GSH group was deteriorated compared with the control group sperm, no significant differences were observed between the control and re-cultured groups. Conclusion: From these results, in vitro reduced sperm were shown to be oxidized in CZB. A reduction of mouse spermatozoa in vitro by GSH is, therefore, reversible, and the oxidative state of sperm nuclei exerts an effect on zona-binding ability. (Reprod Med Biol 2002; 1: 55-58). PMID- 29699075 TI - Evaluation of testicular microlithiasis in varicoceles. AB - Background: Testicular microlithiasis is said to be characterized by calcific concretions within the seminiferous tubules. There have been reports suggesting a link between testicular microlithiasis and testicular dysfunction and tumors. Methods: In this study, we assessed subjects with varicoceles detected by using testicular ultrasound, and evaluated the cases of testicular microlithiasis in terms of age, seminalysis findings, and endocrinological parameters (testosterone, follicular stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL)). The subjects comprised 224 patients with varicoceles diagnosed by using testicular ultrasound, who attended this institution as outpatients between January 1998 and August 2000. Results: Testicular microlithiasis was detected in 15 out of 224 subjects (6.7%), bilateral in all cases. No significant differences were seen between the group with testicular microlithiasis and the group without testicular microlithiasis, in terms of age, seminalysis findings, and/or endocrinological parameters (testosterone, FSH, LH, prolactin). The incidence of testicular microlithiasis in outpatients undergoing testicular ultrasound varies between reports, but is of the order of 0.6-2.0%. Conclusion: In this study, we found a high proportion of testicular microlithiasis at 6.7%, strongly suggesting a link with male infertility. (Reprod Med Biol 2002; 1: 75-79). PMID- 29699076 TI - The function of bone morphogenetic proteins in the human ovary. AB - The gonadotropins, follicle-stimulating hormone (FSH), and luteinizing hormone (LH), are of particular importance in ovarian physiology. However, FSH receptors and LH receptors are not expressed until the secondary follicle stage, indicating that initiation of follicular growth is independent of the gonadotropins. Among many intra-ovarian growth factors, many studies have shown that bone morphogenetic proteins (BMPs) play pivotal roles in regulating the early phases of follicular growth. The BMP system induces the gonadotropin system by modulating gonadotropin receptors in early-stage follicles. Interestingly, the BMP system also prevents precocious maturation of the follicle by suppressing luteinization. Signals provoked by the preovulatory LH surge eliminate BMPs, enabling luteinization to progress. Thus, the BMP system and the gonadotropin system seem to cooperate in regulating follicular development, maturation, and luteinization. PMID- 29699077 TI - Serum anti-Mullerian hormone level as a predictor of poor ovarian response in in vitro fertilization patients. AB - Purpose: To evaluate the clinical value of day 3 serum anti-Mullerian hormone (AMH) compared with day 3 serum follicle-stimulating hormone (FSH) and human chorionic gonadotropin (hCG) day estradiol (E2) levels and antral follicle count (AFC) in the prediction of poor ovarian response in controlled ovarian hyperstimulation (COH). Methods: AMH, FSH and AFC on day 3 as well as hCG day E2 levels were determined in 164 subjects. Receiver operating curve analyses and area under curves (AUC) of the study parameters were performed. Predictive values of the levels of day 3 AMH, FSH, AFC, and hCG day E2 as clinical parameters of ovarian response to COH were studied. Results: Thirty-eight women were defined as poor responders. The day 3 AMH and hCG day E2 levels and AFC of normal responders were significantly higher than those of the poor responders. In predicting poor response, the AUC of day 3 AMH level was significantly higher than that of day 3 FSH level but was similar to the hCG day E2 level. Day 3 AMH, FSH and hCG day E2 levels and AFC were found to predict a poor response. Day 3 AMH and hCG day E2 levels were more predictive compared with day 3 FSH level and AFC. The cut-off level of AMH was <=2 with a sensitivity of 78.9% and a specificity of 73.8%. Conclusion: Day 3 AMH has the ability to predict a poor response to COH and it is more predictive than day 3 FSH and AFC. PMID- 29699078 TI - The role of blood in early endometrial-peritoneal interactions in a syngeneic mouse model of endometriosis. AB - Purpose: The aim of this study was to clarify the role of blood in the early stage of development of endometriotic lesions by developing a syngeneic transplantation model using immunocompetent mice. Methods: Endometriotic lesions were induced in C57BL/6 mice by an intraperitoneal injection of endometrial fragments plus saline or endometrial fragments plus blood. Some endometrial fragments plus blood were injected with heparin, hirudin or tissue plasminogen activator (tPA). Endometriotic lesions on days 1, 3 and 5 were evaluated by gross and microscopic findings. Results: The areas of endometriotic lesions in the blood group (6.4 +/- 1.7 mm2) were significantly larger than those in the saline group (0.5 +/- 0.3 mm2). The areas of endometriotic lesions were significantly reduced by the addition of heparin, hirudin or tPA. On day 1, endometriotic lesions in the blood group were observed on the peritoneum in five of the six mice. Endometriotic lesions on days 3 and 5 were significantly larger than those on day 1. On day 5, endometriotic lesions appeared cystic in all the mice. Conclusions: Blood accelerates the early stage of development of endometriotic lesions when endometrial fragments plus blood are injected. Blood property might be involved in early endometrial-peritoneal interactions. PMID- 29699079 TI - Effect of bovine cumulus-oocyte complexes-conditioned medium on in-vitro maturation of canine oocytes. AB - Purpose: To investigate the ability of medium conditioned with bovine cumulus oocyte complexes (COCs) to support nuclear maturation of canine oocytes recovered from domestic dog ovaries. Methods: Cumulus-oocyte complexes were obtained from ovaries of domestic bitches (8 months old to 7 years old), and in-vitro maturation was evaluated in TCM-199 supplemented with different concentrations (0, 20, 30 or 50%) of bovine COCs-conditioned medium (BCM). The canine COCs were cultured for 72 or 96 h at 38.5 degrees C in 5% CO2, 5% O2 and 90% N2. The bovine COCs-conditioned medium was obtained from culture of bovine COCs with TCM-199 supplemented with 5% FCS for 22 h at 38.5 degrees C in 2% CO2, 98% air. Results: The proportion of germinal vesicle breakdown (GVBD) after 72 h was significantly higher (P < 0.05) in medium supplemented with 30% BCM (20.7%) compared with the control group (13.4%). The rates of GVBD-MII stage were significantly higher (P < 0.05) when oocytes were matured with BCM at concentration of 30% (41.5%) compared with control (26.6%) after 72 h in-vitro culture. After 96 h in-vitro culture, the oocytes matured in medium supplemented with 30% BCM (5.5%) showed a significant increase (P < 0.05) in the proportion of MII compared with control (0.7%). However, increasing the cultivation time from 72 to 96 h resulted in an increase in oocyte degeneration rate. Conclusions: The results suggested that bovine COCs-conditioned medium supplementation significantly increased nuclear maturation of canine oocytes. PMID- 29699080 TI - Two cases of ectopic ovary and one case of potential ectopic ovary. AB - Ectopic ovary is a rare gynecologic entity. A variety of synonymous terms such as ectopic ovary, supernumerary ovary, accessory ovary, and autoamputation of the ovary have been used to describe this condition. The etiology for ectopic ovary has not been elucidated, but several mechanisms have been proposed. They are categorized as either congenital (embryologically derived) or acquired. This report presents two cases of ectopic ovary resulting from different causes and one case of potential ectopic ovary. PMID- 29699081 TI - Normal delivery following resection of an androgen-secreting adrenal carcinoma. AB - A 31-year-old female presented to a gynecological clinic complaining of amenorrhea and virilism over a 2-month period. Blood tests revealed high serum total testosterone and free testosterone levels. A left adrenal tumor was identified following computed tomography and she was referred to our clinic where a laparoscopic left adrenalectomy was performed. The tumor weighed 98 g and the pathological diagnosis according to Weiss' criteria was adrenocortical carcinoma. The post-operative course was uneventful; her serum free testosterone level normalized and regular menstruation was observed 1 month post-operatively. The patient became pregnant 1 year later, resulting in the normal delivery of a girl. PMID- 29699082 TI - Sexual quality of life for localized prostate cancer: a cross-cultural study between Japanese and American men. AB - Introduction: Race and ethnicity are important factors in health-related quality of life (QOL) because of racial differences in preferences for, and trust in, health systems. Such factors are likely to affect QOL and patient satisfaction with care. Results: Using a self-reported questionnaire, Japanese men with prostate cancer reported lower sexual function scores at baseline. In detail, Japanese men were more likely than American men to report poor sexual desire, poor erection ability, poor overall ability to function sexually, poor ability to attain orgasm, poor quality of erections, infrequency of erections, infrequency of morning erections, and intercourse in the previous 4 weeks. However, Japanese men were less likely than American men to be concerned about their sexual function. Two years after surgery, American patients were more likely than Japanese patients to regain their baseline sexual function. The use of phosphodiesterase-5 (PDE-5) inhibitors has been widely publicized as the solution to erectile dysfunction after prostate cancer treatment. Although PDE-5 inhibitors have been available in Japan since 1999, it is striking that Japanese men with localized prostate cancer are much less likely (only 10%) to use PDE-5 inhibitors than American men. Conclusion: Japanese patients with localized prostate cancer report worse sexual function but are less concerned about their reduced function. In the absence of a biological explanation for such differences, however, we suspect that cultural differences may explain the differences between QOL survey results from Japanese or American men with prostate cancer. PMID- 29699083 TI - Structural and functional changes linked to, and factors promoting, cytoplasmic maturation in mammalian oocytes. AB - In most mammals, oocyte maturation is the final process of oogenesis, from the prophase of the first meiosis (germinal vesicle stage) to the metaphase of the second meiosis (MII), during which the oocyte acquires fertilizable competence as well as post-fertilization development competence. The nuclear and cytoplasmic maturation processes occur in synchrony but independently. Cytoplasmic maturation entails biochemical and structural changes in the cytoplasm, which give rise to oocytes capable of being fertilized and developing into embryos. Herein we review the literature and results from our own experiments on the structural and molecular events regulating cytoplasmic maturation in oocytes, concentrating on (1) the appropriate reorganization of active mitochondria and the endoplasmic reticulum, a structural and functional feature of cytoplasmic maturation, and (2) factors involved in regulatory mechanisms such as cumulus cell-oocyte gap junctional signaling, cumulus cell-oocyte bidirectional paracrine signaling, and the complex interactions of these signaling processes and follicular fluid constituents in the follicle environment. PMID- 29699085 TI - Effect of H89 on the meiotic resumption of pig oocytes. AB - Purpose: We studied the effect of H89, an inhibitor of protein kinase A (PKA), on the meiotic resumption of pig oocytes. Methods: Pig cumulus-oocyte complexes (COCs) and denuded oocytes (DOs) were cultured for 27 h to induce meiotic resumption. COCs and DOs were exposed to H89 for different periods. Oocyte PKA activity was assessed by in vitro kinase assay and immunocytochemistry using an antibody against fully active PKA catalytic subunits. Oocyte serine/threonine (Ser/Thr)-phosphorylated proteins were detected by Western blotting and immunocytochemistry using an anti-pSer/pThr PKA substrate antibody. Results: H89 suppressed germinal vesicle break down (GVBD) in COCs and DOs. To determine whether the suppression was due to inhibition of oocyte PKA, we analyzed oocyte PKA. Kinase assay showed that both types of oocytes possessed PKA activity throughout the culture period. Immunocytochemistry showed that fully active PKA catalytic subunits and Ser/Thr phosphorylated proteins were present in the oocytes at the GV stage and after GVBD. Western blotting indicated that both types of oocytes contained Ser/Thr phosphorylated proteins at the GV stage, and that several proteins became phosphorylated after GVBD. Conclusions: Pig oocytes contain active PKA during the occurrence of GVBD, and H89 suppresses the GVBD. PMID- 29699084 TI - Anticancer chemotherapeutic agents and testicular dysfunction. AB - The improvement of the survival rates of various cancer patients has resulted in increased focus on the long-term complications of treatment. Most anticancer chemotherapeutic agents are gonadotoxic, and sterility is therefore one of the most common complications for cancer survivors. The degree of gonadal dysfunction induced by anticancer chemotherapeutic agents seems to be drug specific and dose related. Following the development of new chemotherapeutic agents that have high benefit-to-risk ratios, sufficient sperm can be acquired by collection of ejaculated semen after the treatment in relatively many cases, and assisted reproductive techniques enable conceptions with even severe spermatogenesis dysfunction. However, anticancer chemotherapeutic agents have consistently exhibited the potential to induce permanent azoospermia. Cryopreservation of semen, which is currently the only proven successful option for future fertility preservation in male cancer patients, should certainly be recommended before cancer therapy. However, to date, no established effective methods have shown the capability to protect gonadal function from anticancer treatment in prepubertal cancer patients. PMID- 29699086 TI - Reprogramming of adult human testicular cells by four transcription factors (OCT4, SOX2, KLF4, and C-MYC). AB - Purpose: Induced pluripotent stem (iPS) cells have been generated from mouse and human fibroblasts by several groups; however, transplanted mouse iPS cells can cause teratomas, depending on their tissue of origin. Therefore, human iPS cells are preferable, and various tissues are being evaluated for their potential to generate human iPS cells. Methods: We examined whether adult human testicular tissue had undergone reprogramming by introducing four transcription factors, OCT4, SOX2, KLF4, and C-MYC, using lentiviral vectors. Results: We obtained embryonic stem (ES)-like cells derived from human testicular tissue by introducing four cDNAs, encoding the transcription factors OCT4, SOX2, KLF4, and C-MYC, using lentiviral vectors. We showed that DAZL and VASA were expressed in testicular cells but down-regulated in ES-like cells, indicating that the cells had undergone reprogramming. ES-like cells could develop tumors, which is a hallmark of pluripotency, when SCID mice were injected with these cells. Conclusions: We induced iPS cells from adult human testicular tissue by introducing four transcription factors, OCT4, SOX2, KLF4, and C-MYC, using lentiviral vectors. Future studies on these cells may elucidate the causes of male infertility, and eventually lead to treatments with autologous testicular tissue-derived iPS cells. PMID- 29699087 TI - Serum anti-mullerian hormone concentrations in reproductive age women with and without polycystic ovary syndrome: the influence of body mass index. AB - Purpose: To evaluate the correlation between anti-mullerian hormone (AMH) and body mass index (BMI) in patients with and without polycystic ovarian syndrome (PCOS). Methods: Serum AMH levels of 332 women in their reproductive period and below 45 years of age who were admitted to our reproductive endocrinology clinic with infertility were investigated in a cross-sectional study. Patients were divided into two groups as BMI under and equal or over 25 kg/m2. Both groups were divided into two subgroups as PCOS and non-PCOS. AMH levels of patients were analyzed for each group. Results: Mean AMH values of BMI <25 and >=25 kg/m2 groups were 3.87 +/- 2.95 and 3.58 +/- 2.93 ng/mL, respectively (P > 0.05) in all patients. Means of AMH were not significantly different in BMI quartiles (r = 0.008401, P = 0.96). Among 107 patients with PCOS, means of AMH were 6.85 +/- 2.95 ng/mL in 56 patients with BMI <25 kg/m2 and 6.66 +/- 3.18 ng/mL in 51 patients with BMI >=25 kg/m2 (P > 0.05). In the group of 225 non-PCOS patients, means of AMH were 2.27 +/- 1.12 ng/mL in 104 patients with BMI <25 kg/m2 and 2.28 +/- 1.49 ng/mL in 121 patients with BMI >=25 kg/m2 (P > 0.05). Conclusions: Body mass index does not seem to have an effect on serum AMH levels in reproductive age women both with and without PCOS. PMID- 29699088 TI - Advances in the study of the peripheral nervous system for erection in animals and humans. AB - Introduction: Since Walsh first emphasized the importance of preserving the neurovascular bundle n to protect the cavernous nerve during pelvic surgery, patients' sexual life quality has dramatically improved. Today, nerve-sparing radical prostatectomy is the established gold standard for organ-confined prostate cancer patients. Recent technical advances in functional assessment such as intraoperative electrical stimulation have unveiled new anatomical features and physiological roles. Basic research has advanced understanding of cavernous nerve function, while molecular biology has uncovered the crucial role of neuronal nitric oxide in mediating erection, and has led to new treatments such as phosphodiesterase type-5 inhibitors. A recent focus in cavernous nerve research concerns the nerve distribution external to the neurovascular bundle. The cavernous nerves in humans appear to be distributed more widely beneath the lateral pelvic fascia than in other animals, and electrical stimulation studies suggest possible involvement of these nerves in erection. These findings have prompted new surgical techniques such as the "veil of Aphrodite", or "intrafascial nerve-sparing" procedures. Materials and Methods: These recent anatomical and physiological studies in humans and animals and their impact are reviewed in this article. Conclusions: Further investigation should stimulate future advances in strategies to preserve erectile function in RP patients. PMID- 29699089 TI - Hematospermia: etiology, diagnosis, and treatment. AB - Hematospermia is a relatively frequent, distressing, and frightening symptom for the majority of men. Although the differential diagnosis list is extensive, it is usually a benign, self-limiting disorder, including inflammatory and infective pathologies, resolving in several weeks. However, in some cases, hematospermia is the harbinger of more serious pathological lesions that should not be missed. In younger patients below 40 years of age, infection of the urogenital tract is the most common etiology. Simple routine laboratory studies should identify the pathological factors. In patients 40 years or older, or those with persistent or recurrent conditions or associated symptoms, it is necessary to exclude urogenital malignant disorders. Patients should also undergo medical history taking, physical examination including temperature and blood pressure assessment, digital rectal palpation, and laboratory blood, urine, and semen tests. If the diagnosis is still unclear, further investigations involve transrectal ultrasonography, magnetic resonance imaging, urethrocystoscopy, and histological confirmation by biopsy. Treatment for hematospermia depends on the underlying pathological lesions, but often involves only minimal examinations and simple reassurance in most cases. Hematospermia caused by genitourinary infections is effectively treated with appropriate antiviral, antibiotic, or antiparasitic agents. Hematospermia due to malignant disorders including prostate, testis, and seminal vesicle cancers resolves with definitive treatment of the primary lesions. PMID- 29699090 TI - Cryopreservation of female germ cells and ovarian tissues for fertility preservation. AB - To preserve the fertility of patients who undergo chemotherapy and/or radiotherapy, procedures for cryopreservation of female germ cells have been investigated. Cyropreservation methods differ according to follicle stage because the mammalian ovary contains a large number of oocytes at different growth stages. Follicles at very early stages, for example the primordial and primary stages, are usually cryopreserved within ovarian cortical tissue because they need surrounding somatic cells for subsequent development. In contrast, fully grown oocytes in Graafian follicles are cryopreserved without any other cells at the metaphase II stage. Recently, ultra-rapid cooling was incorporated into cryopreservation procedures for human ovaries. In this review, we describe oocyte freezing, the development of ultra-rapid cooling systems for ovarian tissues, freezing of human ovaries, and ovarian transplantation. PMID- 29699091 TI - Stem cell research for male infertility. AB - Stem cells have the ability both to differentiate into numerous tissues and to self-renew. Because of these unique properties, stem cells are promising candidates for use in regenerative medicine. Among stem cell types, embryonic stem (ES) cells have been the most studied; however, alternatives such as induced pluripotent stem cells or other adult stem cells are now being established. In this review, we focus on stem cell research that may have applications in treating male infertility. Stem cells with ES-like properties have been generated from adult human testis tissue. We expect that breakthroughs in stem cell research will increase our understanding of male infertility and lead to treatments in the near future. PMID- 29699092 TI - Spermatogonial stem cells and in vitro spermatogenesis. AB - Spermatogonial stem cells (SSCs) provide the basis for the life-long production of enormous numbers of sperm. The nature of these mysterious cells is being clarified. Although they were regarded to be mostly dormant, dividing rarely and remaining static in a niche, their rather dynamic behavior in the seminiferous tubules has been disclosed. The territories of each colony of SSCs can also quickly change in size. The development of a culture method for SSCs also shed light on their stable, but at the same time, fragile characteristics. In addition, an in vitro system for spermatogenesis was developed which can produce functional sperm from SSCs. These new developments will contribute to reproductive medicine. PMID- 29699093 TI - Vitrified-warmed ovarian tissue autotransplantation into ovariectomized mice restores sufficient ovarian function to support full-term pregnancy. AB - Purpose: Our previous study demonstrated that heterotopic autotransplantation of fresh ovarian tissue followed by transfer of blastocysts supported full-term pregnancy in the mouse. In the present study, to address whether vitrified-warmed ovarian tissue has the potential to support uterine preparation for implantation and subsequent pregnancy to full term, we examined vitrified-warmed ovarian tissue autotransplantation (VOAT) in mice. Methods: VOAT into kidney capsules was performed for sexual cycle-ceased mice after 7 days of ovariectomy. Uterine potential of decidualization was examined by oil infusion on day 4 of pseudopregnancy. Immunohistochemical analysis was performed to examine the potential in VOAT ovarian tissues. Blastocysts were transferred into uteri on day 4 of pseudopregnancy. Results: In VOAT mice, uterine decidualization on day 8 of pseudopregnancy was the same as that in intact mice. Blastocyst transfer into the pseudopregnant VOAT mice showed the same rates of pregnancy and live birth pups as intact mice, while less steroidogenesis in the corpus luteum was detected in VOAT mice. Conclusions: The autotransplantation of vitrified-warmed ovarian tissues after 7 days of ovariectomy restored their sexual cycle and then supported their pregnancy and production of offspring. PMID- 29699094 TI - Successful infertility treatment following fertility-sparing surgery and chemotherapy for ovarian immature teratoma: a case report and a literature review. AB - Introduction: Malignant ovarian germ cell tumors (MOGCTs) are highly chemosensitive tumors most commonly found in adolescent girls and young women. However, patients with advanced disease can now be successfully cured with fertility-sparing surgery and adjuvant chemotherapy, resulting in childbearing. Case: A 24-year-old nulliparous Japanese woman was diagnosed as having a stage IIIc immature teratoma. After fertility-sparing surgery, she received four cycles of chemotherapy consisting of cisplatin, etoposide, and pepleomycin. She married at the age of 34, but did not conceive due to sexual dysfunction of her husband. At the age of 38, intrauterine insemination was performed following ovulation induction with clomid and human menopausal gonadotrophin, which resulted in a singleton pregnancy. A healthy female infant was delivered at 38 weeks' gestation. Conclusion: Treatment might sometimes be needed for infertile women with a history of MOGCTs, but further studies are needed to determine whether infertility treatment, including ovulation induction, is appropriate. PMID- 29699095 TI - Chromosomal integrity and DNA damage in freeze-dried spermatozoa. AB - Freeze-drying technology may one day be used to preserve mammalian spermatozoa indefinitely without cryopreservation. Freeze-dried mouse spermatozoa stored below 4 degrees C for up to 1 year have maintained the ability to fertilize oocytes and support normal development. The maximum storage period for spermatozoa increases at lower storage temperatures. Freeze-drying, per se, may reduce the integrity of chromosomes in freeze-dried mouse spermatozoa, but induction of chromosomal damage is suppressed if spermatozoa are incubated with divalent cation chelating agents prior to freeze-drying. Nevertheless, chromosomal damage does accumulate in spermatozoa stored at temperatures above 4 degrees C. Currently, no established methods or strategies can prevent or reduce damage accumulation, and damage accumulation during storage is a serious obstacle to advances in freeze-drying technology. Chromosomal integrity of freeze-dried human spermatozoa have roughly background levels of chromosomal damage after storage at 4 degrees C for 1 month, but whether these spermatozoa can produce healthy newborns is unknown. The safety of using freeze-dried human spermatozoa must be evaluated based on the risks of heritable chromosome and DNA damage that accumulates during storage. PMID- 29699096 TI - Physiological function of hyaluronan in mammalian oocyte maturation. AB - Despite its structural simplicity, hyaluronan exhibits a broad spectrum of biological activities. Cumulus expansion observed during oocyte maturation in mammals is also induced by hyaluronan accumulation in cumulus-oocyte complexes. It has been demonstrated that this volumetric change in cumulus-oocyte complexes correlates with the progression of oocyte maturation. We have investigated the molecular mechanism of oocyte maturation in mammals, focusing on hyaluronan accumulation in cumulus-oocyte complexes during cumulus expansion. In this review, we describe the physiological function of hyaluronan, emphasizing the progression of oocyte maturation in mammals based on our previous findings. PMID- 29699097 TI - Embryonic stem (ES) cells and induced pluripotent stem (iPS) cells in rats. AB - Over the past 25 years, the reverse genetic approach including precise and conditional replacement or loss of gene function at a specific locus was considered possible only in mice due to the absence of embryonic stem (ES) or induced pluripotent stem (iPS) cell lines in other species. Recently, however, stem cell technology in rats has become available for biomedical research. In this paper we overview the recent progress of rat ES and iPS cell technology. Starting from the establishment of rat ES cells, the use of ES cells for foreign gene transfer and endogenous gene knock-out is discussed, followed by the successful establishment of rat iPS cells and the generation of an iPS cell derived organ via interspecific blastocyst complementation. Finally, the possible contribution of rat stem cell technology to reproductive medicine is described. PMID- 29699099 TI - Effect of graft site and gonadotrophin treatment on follicular development of canine ovarian grafts transplanted to NOD-SCID mice. AB - Purpose: To investigate the effect of graft site and gonadotrophins administration on the number and survival rate of follicles of canine ovarian grafts transplanted to NOD-severe combined immune deficiency (SCID) mice. Methods: Fresh ovarian cortex slices obtained from immature bitches were grafted subcutaneously (SC), under kidney capsule (KC) or into ovarian bursa (OB) in NOD SCID mice. Two months after surgery, the mice allocated into non-treated and treated gonadotrophins groups that injected with porcine follicle stimulating hormone during 7 days and human chorionic gonadotrophin 48 h later. Ovarian grafts were collected after 10 h of last injection and processed for histology. Results: The number of transitional and preantral follicles under KC and into OB was significantly higher in gonadotrophins-treated mice than those who received saline. Furthermore, the survival rates of primary, transitional and preantral follicles under KC and into OB grafts were significantly higher than those placed SC in the treated gonadotrophins group, and in the non-treated gonadotrophins group; the proportion of primary and preantral follicle survival was significantly higher under KC and into OB than SC grafts. Conclusions: In canine ovarian xenografting, administration of gonadotrophin could be effective for improvement of survival of transplanted ovary. Furthermore, the grafting into OB appeared to be better than grafting under KC, which in turn is better than SC. PMID- 29699100 TI - Heterotopic triplet pregnancy: report of a patient with remnant tubal ectopic and intrauterine twin pregnancy after frozen-thawed embryo transfer. AB - A case of heterotopic triplet pregnancy after frozen-thawed embryo transfer is presented. The patient conceived after transfer of three frozen-thawed embryos at a fertility clinic where she had previously undergone laparoscopic left salpingectomy due to pyosalpinx. Approximately 4 weeks after the embryo transfer, she presented with a complaint of abnormal genital bleeding and was diagnosed by ultrasound as having a dichorionic twin pregnancy. One week later, she was referred to our hospital because of lower abdominal pain. Hematoperitoneum was suspected based on findings of low blood pressure and tachycardia. Diagnostic emergent laparoscopy demonstrated an ectopic pregnancy in the remnant isthmic portion of the left tube. Laparoscopic excision of the remnant fallopian tube was performed, but the procedure resulted in early-pregnancy loss of one of the twins. The risk of heterotopic pregnancy is not small under assisted reproductive technology. Attention should be paid to the risk of tubal pregnancy after transferring more than two embryos or controlled ovarian hyperstimulation, even after salpingectomy has been performed. PMID- 29699098 TI - Cellular and molecular mechanisms of various types of oocyte aging. AB - It is well established that age-related decline of a woman's fertility is related to the poor developmental potential of her gametes. The age-associated decline in female fertility is largely attributable to the oocyte aging caused by ovarian aging. Age-associated oocyte aging results in a decrease in oocyte quality. In contrast to ovarian aging, there is a concept of postovulatory oocyte aging. Postovulatory aging of oocytes, not being fertilized for a prolonged time after ovulation, is known to significantly affect the development of oocytes. Both categories of oocyte aging have similar phenotypes of reproductive failure. However, the mechanisms of the decline in oocyte quality are not necessarily equivalent. An age-dependent increase in aneuploidy is a key determinant of oocyte quality. The reduced expression of molecules regulating cell cycle control during meiosis might be involved in the age-dependent increase in aneuploidy. The mechanism of age-associated oocyte aging might be involved in mitochondrial dysfunction, whose etiologies are still unknown. Alternatively, the mechanism of postovulatory oocyte aging might be involved in reactive oxygen species-induced mitochondrial injury pathways followed by abnormal intracellular Ca2+ regulation of the endoplasmic reticulum. We suggest that future research into the mechanism of oocyte aging will be necessary to develop a method to rescue the poor developmental potential of aged oocytes. PMID- 29699101 TI - Oocyte growth in vitro: potential model for studies of oocyte-granulosa cell interactions. AB - Various factors such as gonadotrophins, growth factors, and steroid hormones play important roles in the regulation of oocyte/follicular growth in mammalian ovaries. In addition to these factors, there is a bidirectional interaction between oocytes and granulosa cells that is essential for achieving optimal oocyte developmental competence. Oocytes play a key role in this interaction by secreting paracrine factors that alter the activities of neighboring cumulus cells, such as the expression of a specific amino acid transporter, cholesterol biosynthesis, and levels of glycolysis in the cumulus cells. Among the known oocyte-derived factors, growth differentiation factor 9 (GDF9) is the dominant factor mediating the regulation by oocytes leading to cumulus expansion and granulosa cell proliferation. GDF9 frequently interacts with other oocyte-derived factors in a synergistic manner. It seems reasonable to speculate that oocytes growing in vitro require interactions similar to those in vivo. Some of the oocyte-mediated regulations have been confirmed in vitro, providing evidence of the usefulness of culture systems as a strong tool for such studies. This review discusses in vitro culture of growing oocytes in terms of oocyte-granulosa cell interactions. PMID- 29699102 TI - Gonadotropin stimulation: past, present and future. AB - Gonadotropin therapy is so central to infertility treatment that it is easy to overlook the considerable discovery and research that preceded production of the effective and safe products available today. The history underpinning this development spans over 300 years and provides a splendid example of how basic animal experimentation and technological advances have progressed to clinical application. Following the discovery of germ cells in 1677 and realizing, in 1870, that fertilization involved the merging of two cell nuclei, one from the egg and one from sperm, it took another 40 years to discover the interplay between hypothalamus, pituitary and gonads. The potential roles of gonadotropin regulation were discovered in 1927. Gonadotropin, such as pregnant mare serum gonadotropin (PMSG), was first introduced for ovarian stimulation in 1930. However, use of PMSG leads to antibody formation, and had to be withdrawn. Following withdrawal of PMSG, human pituitary gonadotropin (HPG) and urinary menopausal gonadotropin (hMG) appeared on the market, and 50 years ago the first child was delivered by our group in 1961 and opened the path to controlled ovarian stimulation. HPG produced good results, but its use came to an end in the late 1980s when it was linked to the development of Creutzfeldt-Jakob disease (CJD). HMG preparations containing a high percentage of unknown urinary proteins, making quality control almost impossible, were then the only gonadotropins remaining on the market. With the availability of hMG, clomiphene citrate, ergot derivatives, GnRH agonists and antagonists, as well as metformin, algorithms were developed for their optimal utilization and were used for the next four decades. Following the first human IVF baby in 1978 and ICSI in 1991, such procedures became standard practice. The main agents for controlled ovarian stimulation for IVF were gonadotropins and GnRH analogues, with batch to batch consistent gonadotropic preparations; methods could be developed to predict and select the correct dose and the optimal protocol for each patient. We are now seeing the appearance of gonadotropin with sustained action and orally active GnRH analogues as well as orally active molecules capable to stimulate follicle growth and inducing ovulation. These new developments may one day remove the need for the classical gonadotropin in clinical work. PMID- 29699103 TI - Mechanism of maternal vascular remodeling during human pregnancy. AB - Remodeling of maternal spiral arteries by invasion of extravillous trophoblast (EVT) is crucial for an adequate blood supply to the fetus. EVT cells that migrate through the decidual tissue destroy the arterial muscular lining from the outside (interstitial invasion), and those that migrate along the arterial lumen displace the endothelium from the inside (endovascular invasion). Numerous factors including cytokines/growth factors, chemokines, cell adhesion molecules, extracellular matrix-degrading enzymes, and environmental oxygen have been proposed to stimulate or inhibit the differentiation/invasion of EVT. Nevertheless, it is still difficult to depict overall pictures of the mechanism controlling perivascular and endovascular invasion. Potential factors that direct interstitial trophoblast towards maternal spiral artery are relatively high oxygen tension in the spiral artery, maternal platelets, vascular smooth muscle cells, and Eph/ephrin system. On the other hand, very little is understood about endovascular invasion except for the involvement of endothelial apoptosis in this process. Only small numbers of molecules such as polysialylated neural cell adhesion molecules and CCR1 have been suggested as specific markers for the endovascular trophoblast. Therefore, an initial step to approach the mechanisms for endovascular invasion could be more detailed molecular characterization of the endovascular trophoblast. PMID- 29699105 TI - Usefulness of statistics for establishing evidence-based reproductive medicine. AB - During the last decade, evidence-based medicine has been described as a paradigm shift in clinical practice, and as "the conscientious, explicit, and judicious use of current best evidence in making decisions about the care of individual patients". Appropriate statistical methods for analyzing data are critical for the correct interpretation of the results in proof of the evidence. However, in the medical literature, these statistical methods are often incorrectly interpreted or misinterpreted, leading to serious methodological errors and misinterpretations. This review highlights several important aspects related to the design and statistical analysis for evidence-based reproductive medicine. First, we clarify the distinction between ratios, proportions, and rates, and then provide a definition of pregnancy rate. Second, we focus on a special type of bias called 'confounding bias', which occurs when a factor is associated with both the exposure and the disease but is not part of the causal pathway. Finally, we present concerns regarding misuse of statistical software or application of inappropriate statistical methods, especially in medical research. PMID- 29699104 TI - Heat stress on reproductive function and fertility in mammals. AB - In most mammalian species including cattle, heat stress has deleterious effects on nutritional, physiological and reproductive functions. Exposure of animals to a hot environment causes an increase in body temperature in mammals, including domestic animals. High ambient temperature also causes a decrease in the length and intensity of estrus by disturbing ovarian function as well as decreasing pregnancy rate after artificial insemination. Therefore, it is important to understand the effects of heat stress on reproductive function in order to improve the production of domestic animals. Heat stress decreases appetite, weight gain, and milk yield in dairy cattle. It also adversely affects the reproductive performance of both sexes. In males, it reduces spermatogenic activity, while in females it adversely impacts oogenesis, oocyte maturation, fertilization development and implantation rate. Detection and evaluation of the deteriorating effects of heat stress on reproductive organs and cells can help to design measures to prevent them and improve reproductive functions. In this review, we discuss the impacts of heat stress on reproductive functions. PMID- 29699106 TI - Ejaculatory dysfunction as a cause of infertility. AB - Ejaculatory dysfunction (EjD), the most prevalent male sexual disorder, is clearly different from erectile dysfunction (ED). EjD is divided into 4 categories: premature ejaculation, delayed ejaculation, retrograde ejaculation and anejaculation. EjD-related infertility is one of the most serious problems in young patients. If sexual intercourse is achieved successfully without any ejaculate sexual partners/wives will not be able to conceive. Therefore, establishment of management of EjD as well as ED is increasingly crucial for couples wishing for a baby. The therapeutic approach of EjD-related infertility is based upon two scenarios: (1) if EjD alone is the reason for having no children, adequate treatment for EjD alone is required, or (2) if EjD is not the only reason and is combined with a worsening of semen quality, total management for male infertility (including EjD treatment) is needed. In this article, the background of EjD-related infertility is presented briefly, followed by a review of treatment modalities. PMID- 29699107 TI - Changes in cervical neutrophil elastase levels during the menstrual cycle. AB - Purpose: Cervical mucus plays an important role in host defense mechanisms and is involved in the ascendance of sperm. To determine the change of neutrophil mediators contained in cervical mucus, we measured total neutrophil elastase (NE) levels throughout the menstrual cycle. Methods: Cervical NE concentrations in 31 healthy women having regular ovulatory cycles were measured during the follicular, ovulatory and luteal phases. Results: The cervical NE levels during the follicular, ovulatory and luteal phases were 0.73 +/- 0.57 (mean +/- SD), 0.29 +/- 0.33 and 1.32 +/- 1.24 MUg/ml, respectively. The NE concentrations during the ovulatory phase were significantly lower than the other phases. Conclusions: The decrease in total cervical NE level during the ovulatory phase suggests that neutrophil activity in cervical mucus is depressed around ovulation. The decreased cervical NE levels and the depressed neutrophil activity in cervical mucus at ovulation may be suitable for sperm passage through the cervical canal. PMID- 29699108 TI - Alternative strategies to in vitro fertilization/intracytoplasmic sperm injection treatment for aged infertile women. AB - Purpose: This study aimed to maximize the chance of pregnancy and provide an optimal protocol for infertile female patients of advanced reproductive age as an alternative to in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI) treatment. Methods: We retrospectively analyzed medical records of 432 infertile women aged >=38 at the beginning of the treatment. Stepwise non IVF/ICSI treatments using timed intercourse or intrauterine insemination, with or without controlled ovarian stimulation, were adopted for all patients. In this population, we extracted 8 representative infertility factors and examined these effects on fertility rate by calculating clinical pregnancy rate. Results: The prognosis for infertile women possessing at least one of the three factors, 'advanced female age (>=42 years)', 'endometriosis/adenomyosis', and 'tubal infertility' was apparently poor because only 5 out of 155 women were able to conceive (1.02% per cycle). In contrast, 95 patients without the four factors, 'advanced female age', 'endometriosis/adenomyosis', 'tubal infertility', and 'male infertility', were more likely to conceive (9.14% per cycle). Conclusions: Fertility centers can offer appropriate protocols for non-IVF/ICSI treatment and establish guidelines for aged infertile patients by examining infertility factors and considering their combinations. PMID- 29699109 TI - Mechanism of mammalian germ cell development: toward assisted new reproductive technologies. AB - Approximately 10% of Japanese couples who want to have children experience infertility, and the majority of these individuals have either abnormal egg cell or abnormal sperm development. In addition, currently, there is a low birth rate in many parts of the developed world; therefore, it is critical to elucidate the mechanisms of germ cell development. Thus, the study of assisted reproductive technologies has scientific significance, and is a key to solving infertility problems. This review summarizes the development of mouse germ cells, particularly focusing on the role of Nanos genes, which are essential for the development of mouse germ cells and have been identified as genes that are involved in human infertility. We also briefly introduce a study in which this information is applied to assisted reproductive technologies. PMID- 29699110 TI - Comparison between the gonadotropin-releasing hormone antagonist protocol and the gonadotropin-releasing hormone agonist long protocol for controlled ovarian hyperstimulation in the first in vitro fertilization-embryo transfer cycle in an unspecified population of infertile couples. AB - Purpose: We aimed to compare the efficacy of a gonadotropin-releasing hormone (GnRH) antagonist protocol and a GnRH agonist long protocol used in the first in vitro fertilization-embryo transfer (IVF-ET) cycle in an unspecified population of infertile couples. Methods: Fifty and 34 patients were treated with a GnRH agonist long protocol (agonist group) and GnRH antagonist protocol (antagonist group), respectively, in the first treatment cycle. The primary and secondary outcome measures were cumulative live birth rates after fresh and cryopreserved thawed ETs and incidence of grades II and III ovarian hyperstimulation syndrome (OHSS), respectively. Results: No significant differences were observed in clinical pregnancy rates (38.0 vs. 32.4%) and live birth rates (22.0 vs. 23.5%), which included both fresh and cryopreserved-thawed ETs, between the 2 groups. However, the incidence of grade III OHSS was significantly lower with the GnRH antagonist protocol than the GnRH agonist long protocol. Conclusions: Used in the first IVF-ET cycle in an unspecified population of infertile patients, the GnRH antagonist protocol showed the same clinical outcome as the GnRH agonist long protocol. PMID- 29699111 TI - A programmed schedule of oocyte retrieval using mild ovarian stimulation (clomiphene citrate and recombinant follicle-stimulating hormone). AB - Purpose: The purpose was to establish a mild ovarian stimulation protocol that would help assisted reproductive technology (ART) units to avoid scheduling on weekends. Methods: This protocol directed patients to take 50 mg/day of clomiphene citrate between days 3 and 7 of the menstrual cycle: 225 IU of recombinant follicle-stimulating hormone (rec-FSH) were administered on days 3, 5 and 7; human chorionic gonadotropin (hCG) was administered on day 9; and, oocyte pick-up (OPU) was planned for day 11. From October 2008 through October 2009, 514 women underwent ART treatment with mild stimulation at the Sugiyama Clinic, and we evaluated whether OPU was accomplished on the planned day. Results: Of all the treatment cycles, 419 (81.5%) underwent OPU on day 11 (scheduled group). Additional rec-FSH administration was needed in 83 cycles, in which case OPU was performed on day 12 or later. In 12 cycles, OPU was canceled. The unscheduled group (n = 95) consisted of delayed OPU cycles and canceled cycles. Of all treatment cycles, 332 cycles in the scheduled group and 68 cycles in the unscheduled group underwent embryo transfer, with 81 and 16, respectively, resulting in pregnancies. Conclusions: Using this protocol, OPU was performed on the scheduled day in about 80% of the cycles. Most weekend scheduling of OPU can be avoided using this mild stimulation. PMID- 29699112 TI - The origin of progesterone in blood when a bacterial solution is infused into the uterus of rats. AB - Purpose: The infusion of a bacterial solution into the uterus of rats raises the progesterone (P4) concentration in serum and extends diestrus. To understand the origin of the P4, we investigated the change in the P4 concentration of seven groups of rats for 5 days after the infusion of a bacterial solution. Methods: The rats were divided into 7 treatment groups as follows: OvxBac, AdxBac, Ovx, Adx, LapBac, Lap, and Cont. In OvxBac, rats received both ovariectomy and bacterial inoculation into their uterus. In AdxBac, rats received both adrenalectomy and bacterial inoculation into their uterus. In Ovx, rats received only ovariectomy. In Adx, rats received only adrenalectomy. In LapBac, rats received only bacterial inoculation into their uterus. In Lap, rats received only laparotomy. In Cont, rats did not receive any treatment and acted as controls. Results: The P4 concentration in all treatment groups was higher than in Cont on day 1 (the day following operation) and day 2. In Lap and LapBac, the P4 concentration was high on day 1 (>30 ng/mL) and maintained that value until day 2. In Adx and AdxBac, the P4 concentration was average on day 1 (approximately 25 ng/mL) and increased on day 2 to a value close to that of LapBac and Lap. In OvxBac, although the P4 concentration increased slightly on day 1 and day 2, it reached 22.5 +/- 7.5 ng/mL on day 4. In AdxBac and LapBac, the P4 concentration on day 4 tended to be high. Conclusion: These results suggest that P4 is initially secreted from the ovaries and the adrenals in response to the surgical stress of laparotomy, and is later secreted from the adrenals due to the inflammatory reaction of the uterus. PMID- 29699113 TI - Use of magnetic resonance analysis for clinical evaluation of the peripheral area of gestational sac in bleeding and non-bleeding ectopic pregnancy cases. AB - Purpose: To evaluate preoperative magnetic resonance (MR) imaging features of bleeding and non-bleeding ectopic pregnancy (EP) by comparison with surgical findings. Methods: Eighteen suspected EP cases underwent preoperative MR imaging. We classified 8 cases as the bleeding group and 7 cases as the non-bleeding group with or without intra-abdominal bleeding and/or hematoma at the site of EP, and compared, retrospectively, gestational sac (GS)-like structure, particularly the peripheral area of the GS via MR analysis. Excluded were 3 cases that were insufficient for assessing extrauterine GS-like structure: ruptured tubal pregnancy and uterine horn pregnancy. Results: GS-like structures were typically observed as low intensity on T1-weighted image (T1WI) and as high intensity on T2 weighted image (T2WI). In non-bleeding cases, most peripheral areas of the GS were of intermediate intensity on T1WI and high intensity on T2WI. Most bleeding cases were of high intensity on T1WI and low to high intensity on T2WI. Furthermore, the peripheral area of the GS was of higher intensity on T1WI with fat suppression than on T1WI. Conclusions: It is clear that MR imaging is effective for diagnosis of cases of suspected EP. EP conditions may be predicted by signal intensity of the peripheral area of the GS via MR analysis. PMID- 29699114 TI - Effects of pantothenic acid supplement on secretion of steroids by the adrenal cortex in female rats. AB - Purpose: The effect of pantothenic acid (PaA) supplementation on adrenal secretion of corticosterone and progesterone in female rats was investigated. Methods: An in-vitro primary adrenal cell culture system was used. Pregnant rats were given 0.03% PaA in their drinking water throughout pregnancy and the period of lactation. In the first experiment, after weaning, female rats continued to receive 0.03% PaA treatment until 10 weeks of age. The animals were then decapitated and adrenal cells were cultured in the absence or presence of rat adrenocorticotropic hormone (ACTH) for 4 h. In the second experiment, adrenal cells from lactating rats on day 5 of lactation were cultured in the absence or presence of rat ACTH for 4 h. Results: The effect of ACTH at 10-10 m on corticosterone and progesterone release was greater for PaA-treated cyclic rats than for control cyclic rats. The effect of ACTH at 10-10 m on corticosterone release was greater for PaA-treated lactating rats than for control lactating rats. Circulating ACTH and corticosterone levels in PaA-treated and control cyclic and lactating rats were no different. Conclusions: These results indicate that PaA supplementation induced hyperresponsiveness to ACTH stimulation in cyclic and lactating female rats. These results clearly demonstrated that PaA is an essential factor in adrenal steroidogenesis of female rats. PMID- 29699115 TI - A case of placental polyp treated with an intraoperative injection of prostaglandin F2alpha followed by hysteroscopic resection. AB - A 27-year-old woman had massive genital bleeding after an artificial abortion. Color Doppler ultrasonography showed a hypervascular mass. Hysteroscopy revealed a placental polyp. Serum hemoglobin level was decreased to 7.7 g/dl. Although uterine artery embolization (UAE) followed by hysteroscopic resection has been used for treatment of a placental polyp, UAE may not be an ideal option for patients with intent for future pregnancy because of the risk of ovarian function failure. This report presents a case of a placental polyp managed successfully with intracervical injection of prostaglandin F2alpha, as an alternative UAE, followed by hysteroscopic resection. PMID- 29699117 TI - Extended uterine receptivity for blastocyst implantation and full-term fetal development in mice with vitrified-warmed ovarian tissue autotransplantation. AB - Purpose: Our previous study demonstrated that vitrified-warmed ovarian tissue autotransplantation (VOAT) into estrus cycle-ceased ovariectomized mice restored fertility to achieve full-term fetal development for transferred embryos, while less steroidogenesis in the corpus luteum was observed in VOAT mice. It has been reported that the window of uterine receptivity for blastocyst implantation is extended at lower estrogen levels. Therefore, we hypothesized that duration of the window in VOAT mice could be extended. Methods: Blastocysts were transferred into VOAT mice on day 5 of pseudopregnancy. Immunohistochemical analysis was performed to examine the potential in VOAT ovarian tissues. Results: The rate of live birth pups from embryos transferred on day 5 of pseudopregnant VOAT mice was not different from that of embryos transferred on day 4 of pseudopregnancy in VOAT mice, while embryo transfer on day 5 into intact mice showed no pregnancy. Immunohistochemical analysis of the corpus luteum of day 8 pseudopregnant VOAT mice with uteri having decidualization induced on day 5 showed less steroidogenesis and blood vessel formation as compared to intact mice. Conclusions: Uterine receptivity was extended in VOAT mice. Less steroidogenesis and blood vessel formation in the transferred ovarian tissues may be associated with the extended uterine receptivity. PMID- 29699116 TI - Functions of interferon tau as an immunological regulator for establishment of pregnancy. AB - The establishment of a successful pregnancy requires a "fine quality embryo", "maternal recognition of pregnancy", and a "receptive uterus" during the period of conceptus implantation to the uterine endometrium. In ruminants, a conceptus cytokine, interferon tau (IFNT), a major cytokine produced by the peri implantation trophectoderm, is known as a key factor for maternal recognition of pregnancy. IFNT can be considered one of the main factors in conceptus-uterus cross-talk, resulting in the rescue of ovarian corpus luteum (CL), induction of endometrial gene expressions, activation of residual immune cells, and recruitment of immune cells. Much research on IFNT has focused on the CL life span (pregnancy recognition) and uterine gene expression through IFNT and related genes; however, immunological acceptance of the conceptus by the mother has not been well characterized. In this review, we will discuss the progress in IFNT and implantation research made by us and others for over 10 years, and relate this progress to pregnancy in mammalian species other than ruminants. PMID- 29699118 TI - Combination of recombinant follicle stimulating hormone with human menopausal gonadotrophin or recombinant luteinizing hormone in a long gonadotrophin releasing hormone agonist protocol: a retrospective study. AB - Purpose: To assess the effect of supplementation with recombinant human luteinizing hormone (rhLH) for patients treated either with recombinant follicle stimulating hormone (rFSH) plus rhLH or with rFSH plus human menopausal gonadotrophin (HMG) in a long gonadotrophin-releasing hormone (GnRH) agonist stimulation protocol. Methods: A single-centre, retrospective analysis of patients with hypo responsiveness to a long GnRH agonist protocol (n = 174), with consecutive in-vitro fertilization or intracytoplasmic sperm injection cycles, compared the outcomes of long luteal GnRH agonist ovarian stimulation using rFSH combined with HMG (n = 100) versus rFSH combined with rhLH (n = 74). The endpoints included clinical pregnancy, number of oocytes retrieved, and total gonadotrophin dose. Results: Significantly more clinical pregnancies were achieved after stimulation with rFSH and rhLH than after stimulation with rFSH and HMG (35.1 vs. 19%, p < 0.01). More oocytes were recovered (13.1 vs. 11.3, p = 0.024) with less FSH utilized in the rFSH and rhLH group than in the rFSH and HMG group (2706.4 vs. 4134.2 U, p < 0.001). Conclusions: Use of rFSH combined with rhLH in long GnRH agonist assisted reproductive technology (ART) cycles was associated with more clinical pregnancies, recovery of more oocytes, and reduction in gonadotrophin use, suggesting that the superior purity and consistency of rFSH and rhLH may result in better clinical outcomes. PMID- 29699119 TI - Effects of exogenous 17beta-estradiol on follicular development in the neonatal and immature mouse in vivo. AB - Purpose: The study was aimed to examine the effects of exogenous 17beta-estradiol (E2) on oocyte nest breakdown and follicular growth in the ovary of neonatal and immature mice. Methods: The effect of E2 on primordial follicle formation and differentiation were examined by treating neonatal mice with E2 in mineral oil at a dose of 10 mg/kg by sc injection each day from postnatal days 1 (PND1) to 10 (PND10). This investigation was conducted by using histological observation and immunohistochemical staining of proliferating cell nuclear antigen (PCNA); the numbers of follicles at each stage were examined to assess the follicular development. Results: The results indicated that such dose of E2 inhibited oocyte nest breakdown from PND1 to PND10 significantly and enhanced the oocyte staining intensity of PCNA in the ovary by PND3, 5 and 10. PCNA staining was mainly detected on growing follicles (stages later than primary follicle). Our results also revealed that E2 decreased the size of the reproductive tract at PD10. Conclusions: This dose of E2 treatment inhibits oocyte nest breakdown and primordial follicle assembly, and causes follicle losses after PND5. Effects of exogenous E2 on follicular development in the neonatal and immature mouse may through a PCNA-dependent pathway. PMID- 29699120 TI - Singleton pregnancy outcomes after assisted and non-assisted reproductive technology in infertile patients. AB - Purpose: Singleton pregnancy after assisted reproductive technology (ART) has been associated with higher risks of adverse pregnancy outcome than naturally conceived singleton pregnancy. This study was to elucidate whether the ART procedure is responsible for abnormal pregnancy outcome comparing those after ART and non-ART in infertile patients. Methods: We compare the singleton pregnancy outcome of infertile patients in our university hospital between 2000 and 2008 following ART (351 pregnancies) and non-ART (213 pregnancies) procedures. Pregnancy outcome parameters were incidence of pregnancy induced hypertension, placenta previa, placental abruption, cesarean delivery, preterm birth, very preterm birth, stillbirth, low birth weight and very low birth weight. Results: Most of the pregnancy outcome parameters were not significantly different between the ART group and the non-ART group. Only placenta previa was significantly higher in the ART group than in the non-ART group (odds ratio 4.0; 95 % CI 1.2 13.7). Conclusions: ART procedure may itself be a risk factor for the development of placenta previa. Some of the abnormal perinatal outcomes that had been previously attributed to ART, however, may be due to the baseline characteristics of infertile patients. PMID- 29699121 TI - Successful delivery following intracytoplasmic sperm injection with calcium ionophore A23187 oocyte activation in a partially globozoospermic patient. AB - Purpose: To describe a successful pregnancy outcome following intracytoplasmic sperm injection (ICSI) with assisted oocyte activation (AOA) in a case of partial globozoospermia. Methods: AOA was accomplished with calcium ionophore A23187. Sperm morphology was observed via light, fluorescent and electron microscopy following a Diff-Quik stain and fluorescein isothiocyanate-labeled peanut agglutinin (FITC-PNA) staining. An activation ability test was employed using a mouse oocyte exposed to strontium chloride. Results: Via light microscopy, it was found that a large number of sperm possessed deficient acrosomes and a sharply rounded head; however, we observed both normal and the aforementioned abnormal sperm via FITC-PNA staining of a semen specimen. Mouse oocyte activation was 87.5 % via natural activation without AOA. With AOA after ICSI, 100 % oocyte activation was observed. Five oocytes were retrieved, and AOA with A23187 after ICSI resulted in a high fertilization rate (4 of 5, 80 %). Two embryos developed and the patient subsequently delivered a healthy female infant without any congenital abnormalities. Conclusions: We report a successful pregnancy outcome using an early stage embryo, which developed following ICSI using sperm from a partially globozoospermic patient who possessed temporary potential oocyte activation. PMID- 29699122 TI - Superovulation, in vitro fertilization (IVF) and in vitro development (IVD) protocols for inbred BALB/cJ mice in comparison with outbred NMRI mice. AB - Purpose: To study assisted reproductive technology (ART) protocols including superovulation, in vitro fertilization (IVF) and in vitro development (IVD) for BALB/cJ mice in comparison with a common ART protocol for NMRI mice. Methods: Adult NMRI and BALB/cJ mice were superovulated using a 48 h G-interval. In order to find a more suitable G-interval for the BALB/cJ strain, G-intervals including 44, 46 and 50 h were also examined. Superovulation rates were recorded in all groups. IVF rate of BALB/c oocytes in T6 and mHTF media were compared. IVD rates of BALB/cJ zygotes in mHTF, T6 and G1V5/G2V5 media were compared. In addition, IVF and IVD rates of BALB/cJ and NMRI oocytes were compared in T6 medium during IVF-IVD procedures. Results: In BALB/cJ mice the highest superovulation rates were observed with 44-46 h G-intervals. However, with a 48 h G-interval, superovulation rates were significantly lower in BALB/cJ compared to NMRI mice (p < 0.05). mHTF medium significantly increased in vitro fertilization of BALB/cJ oocytes compared to T6 medium (p < 0.05). Fertilization rate of NMRI oocytes was significantly higher than BALB/cJ oocytes in T6 medium (p < 0.05). The BALB/cJ embryo IVD was significantly higher in G1/G2 medium compared to mHTF and T6 media (p < 0.01). Conclusions: Superovulation with 48 h G-interval and using T6 during all in vitro procedures produces embryos more efficiently for NMRI mice than for BALB/cJ mice. For BALB/cJ mice, a protocol including superovulation with a 44-46 h G-interval, using mHTF during IVF and G1V5/G2V5 medium during IVD, may improve in vitro embryo production. PMID- 29699123 TI - Foxo3 negatively regulates the activation of mouse primordial oocytes. AB - Purpose: The objective of this study is to know the role of Foxo3, a forkhead transcription factor, in the growth initiation of primordial oocytes in neonatal mice. Methods: We studied the expression of Foxo3 in 0-, 1-, 2-, 7- and 21-day old mouse ovaries by immunohistochemistry. Ovaries from 1-day-old mice were treated with Foxo3 siRNAs (small interfering RNAs) and subsequently organ cultured for 6 days, and the oocyte growth was examined histologically. Results: Expression of Foxo3 was low in newborn mouse ovaries. In 1-day-old ovaries, Foxo3 was expressed in the nuclei of 20 +/- 7 % primordial oocytes. The percentage of Foxo3-positive primordial oocytes was increased to 48 +/- 8, 37 +/- 2 and 47 +/- 4 in 2-, 7- and 21-day-old mice, respectively. After treatment of ovaries with Foxo3 siRNAs, higher proportion of oocytes entered the growth phase in cultured ovaries than that in control. Conclusions: These results suggest that Foxo3 negatively regulates the growth initiation of primordial oocytes and knockdown of Foxo3 leads primordial oocytes to the growth phase in vitro. PMID- 29699124 TI - Severe oligozoospermia in a patient with myxedema coma. AB - A case of severe oligozoospermia with myxedema coma is herein presented. The patient was referred to a male infertility clinic with a 5-year history of primary infertility. Decreased serum testosterone and elevated serum prolactin without abnormal MRI findings in the hypothalamus, and decreased semen volume and sperm motility were noted. A GnRH test revealed a decreased luteinizing hormone response, whereas the HCG test showed a normal testosterone increase. Because a urinalysis after ejaculation indicated retrograde ejaculation, imipramine administration was started. However, the semen quality deteriorated, so the patient was referred to an ART clinic. Twenty-one months from the initial visit, the patient developed a loss of consciousness and edema due to myxedema coma, a life-threatening state of hypothyroidism. The patient recovered after 1 month of thyroid hormone replacement therapy (HRT) with corticosteroids. Three months after the myxedema coma, a semen analysis showed a decreased semen volume (0.2 mL) and severe oligozoospermia (two spermatozoa/ejaculate). Elevated prolactin and decreased testosterone levels were still present. These parameters gradually improved after restoration of euthyroidism by HRT. In conclusion, physicians should confirm the thyroid function in the management of male infertility, especially in patients with elevated prolactin levels. PMID- 29699126 TI - Toward standardization of the cut-off value for the direct immunobead test using the postcoital test in immunologically infertile males. AB - Purpose: There is a need to improve our understanding of the cut-off value of the direct immunobead test (D-IBT). Methods: The subjects were 26 D-IBT-positive and 140 D-IBT-negative males. The results of post coital tests (PCTs) for each subject were examined. Results: A significant difference was observed in abnormal PCTs between values <20 % and those >=20 % (P = 0.02). However, there was no significant difference in abnormal PCTs between values <50 % and those >=50 % (P = 0.084). Conclusions: A cut-off value of 20 % was correlated with the possibility of conception on treatment with IUI. The D-IBT is a screening test, and the value of 20 % initially suggested by Bronson et al. seems to be more appropriate than that of 50 % in the criteria defined by the World Health Organization. PMID- 29699127 TI - Progesterone-enhanced sperm hyperactivation through IP3-PKC and PKA signals. AB - Propose: The present study examined whether regulation of progesterone-enhanced hyperactivation of spermatozoa is associated with the production of inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) by phospholipase C (PLC) and cyclic adenosine monophosphate (cAMP) by adenylate cyclase (AC), as well as activation of protein kinase C (PKC) and protein kinase A (PKA). Methods: Hamster spermatozoa were hyperactivated by incubation for 4 h in modified Tyrode's albumin lactate pyruvate (mTALP) medium. In order to examine the effects of IP3 receptor (IP3R), PKC and PKA on progesterone-enhanced hyperactivation, their inhibitors (xestospongin C, bisindolylmaleimide 1 and H-89) were used. Results: Progesterone-enhanced hyperactivation was significantly suppressed by the inhibitors of IP3R, PKC and PKA. Conclusions: The results suggest that progesterone-enhanced sperm hyperactivation occurs through two signal pathways. One is an intracellular Ca2+ signal through production of IP3 and DAG by PLC, binding of IP3 to IP3R and activation of PKC by DAG and Ca2+. The other is a cAMP PKA signal through production of cAMP by AC and activation of PKA by cAMP. PMID- 29699125 TI - Cell-intrinsic reprogramming capability: gain or loss of pluripotency in germ cells. AB - In multicellular organisms, germ cells are an extremely specialized cell type with the vital function of transmitting genetic information across generations. In this respect, they are responsible for the perpetuity of species, and are separated from somatic lineages at each generation. Interestingly, in the past two decades research has shown that germ cells have the potential to proceed along two distinct pathways: gametogenesis or pluripotency. Unequivocally, the primary role of germ cells is to produce gametes, the sperm or oocyte, to produce offspring. However, under specific conditions germ cells can become pluripotent, as shown by teratoma formation in vivo or cell culture-induced reprogramming in vitro. This phenomenon seems to be a general propensity of germ cells, irrespective of developmental phase. Recent attempts at cellular reprogramming have resulted in the generation of induced pluripotent stem cells (iPSCs). In iPSCs, the intracellular molecular networks instructing pluripotency have been activated and override the exclusively somatic cell programs that existed. Because the generation of iPSCs is highly artificial and depends on gene transduction, whether the resulting machinery reflects any physiological cell intrinsic programs is open to question. In contrast, germ cells can spontaneously shift their fate to pluripotency during in-vitro culture. Here, we review the two fates of germ cells, i.e., differentiation and reprogramming. Understanding the molecular mechanisms regulating differentiation versus reprogramming would provide invaluable insight into understanding the mechanisms of cellular reprogramming that generate iPSCs. PMID- 29699128 TI - Pregnancy despite ovarian insufficiency in a patient with breast cancer. AB - Future fertility is a concern for many young breast cancer survivors. Secondary amenorrhea occurs frequently during or soon after oncologic treatment. Return of menstruation and serum biomarkers are not absolute predictors of future fertility. We report a case of a 28 year old gravida 0 with recurrent Stage IIB invasive ductal breast carcinoma who managed to conceive twice despite showing clinical and biochemical signs of decreased ovarian reserve following treatment with chemotherapy and radiation. This case illustrates the potential for fertility in a patient with breast cancer despite chemotherapy-related amenorrhea and undetectable anti-Mullerian hormone levels. It exemplifies the imprecise nature of all clinical tests used to predict future fertility in breast cancer patients post-treatment. It should remind all providers to be careful in basing recommendations for childbearing on these surrogate endpoints. PMID- 29699129 TI - Induced pluripotent stem cells in reproductive medicine. AB - Despite recent advances in reproductive medicine, there are still no effective treatments for severe infertility caused by congenital absence of germ cells or gonadotoxic treatments during prepubertal childhood. However, the development of technologies for germ cell formation from stem cells in vitro, induction of pluripotency from somatic cells, and production of patient-specific pluripotent stem cells may provide new solutions for treating these severe fertility problems. It may be possible to produce germ cells in vitro from our own somatic cells that can be used to restore fertility. In addition, these technologies may also bring about novel therapies by helping to elucidate the mechanisms of human germ cell development. In this review, we describe the current approaches for obtaining germ cells from pluripotent stem cells, and provide basic information about induction of pluripotency and germ cell development. PMID- 29699130 TI - Mitochondrial DNA transmission and confounding mitochondrial influences in cloned cattle and pigs. AB - Although somatic cell nuclear transfer (SCNT) is a powerful tool for production of cloned animals, SCNT embryos generally have low developmental competency and many abnormalities. The interaction between the donor nucleus and the enucleated ooplasm plays an important role in early embryonic development, but the underlying mechanisms that negatively impact developmental competency remain unclear. Mitochondria have a broad range of critical functions in cellular energy supply, cell signaling, and programmed cell death; thus, affect embryonic and fetal development. This review focuses on mitochondrial considerations influencing SCNT techniques in farm animals. Donor somatic cell mitochondrial DNA (mtDNA) can be transmitted through what has been considered a "bottleneck" in mitochondrial genetics via the SCNT maternal lineage. This indicates that donor somatic cell mitochondria have a role in the reconstructed cytoplasm. However, foreign somatic cell mitochondria may affect the early development of SCNT embryos. Nuclear-mitochondrial interactions in interspecies/intergeneric SCNT (iSCNT) result in severe problems. A major biological selective pressure exists against survival of exogenous mtDNA in iSCNT. Yet, mtDNA differences in SCNT animals did not reflect transfer of proteomic components following proteomic analysis. Further study of nuclear-cytoplasmic interactions is needed to illuminate key developmental characteristics of SCNT animals associated with mitochondrial biology. PMID- 29699132 TI - Treatment with an equine chorionic gonadotrophin single dose restored spermatozoa production in an azoospermic pampas deer (Ozotoceros bezoarticus) male: a case report. AB - Azoospermy was diagnosed after semen extraction in a pampas deer male, an endangered species. To determine the reproductive status, testicular fine needle aspiration cytology (FNAC), followed by a gonadotrophin-releasing hormone (GnRH) challenge (8.4 MUg of buserelin acetate) was performed. Blood samples were obtained to measure luteinizing hormone (LH) and testosterone by radioimmunoanalysis. No spermatozoa was visible in the cytology examination. LH and testosterone surges were observed after the GnRH challenge. Thereafter, 5,000 IU of equine chorionic gonadotrophin (eCG) were injected intramuscularly. A second FNAC was performed 2 months later, and semen was extracted 4 months after eCG administration. Spermatozoa were observed both in the smear and in the semen sample. In summary, although limited in number, after a single dose of 5,000 IU of eCG, spermatozoa production was restored. This opens an interesting therapeutical option to stimulate testicular activity. PMID- 29699131 TI - The effect of intra-peritoneal administration of Papaver bracteatum Lindl. extract on development of NMRI mice oocytes treated with Doxorubicin. AB - Purpose: The effect of water-alcohol Papaver bracteatum Lindl. extract on development of mice oocytes treated with Doxorubicin (dox) was examined in this study. Methods: The mice were classified into four groups. Control group, mice injected intraperitoneally (IP) with saline. Extract group alone, mice treated with 200 mg/kg of body weight (bw), IP, twelve consecutive days. Dox group alone, mice were given dox, IP, 10 mg/kg bw. Experimental group treated with extract and dox together. Effect of the extract on the development of mice oocytes treated with dox were evaluated through assisted reproductive technology techniques (ARTs). Results: Developmental rate and blastocyst formation was improved by using the extract. A significant increase in in vitro developmental competence in comparison with dox group (P < 0.05) was observed. Conclusions: The results of this study indicated that P. bracteatum Lindl. extract could prevent dox toxicity of dox affecting both follicle or oocytes, and therefore it can result in improved embryo development which was observed in mice treated with dox plus P. bracteatum Lindl. compared to mice treated with dox alone. PMID- 29699133 TI - Pregnancy after in vitro fertilization in a liver transplant patient. AB - We present the case of a liver transplant patient who conceived following assisted reproduction and experienced a normal pregnancy with a good outcome. This case illustrates that, in select cases and with multidisciplinary effort, women may undergo ovarian hyperstimulation and egg retrieval following liver transplant without undue risk or complications. PMID- 29699134 TI - Glycodelin in reproduction. AB - To achieve a successful pregnancy in humans, sperm is required for capacitation, followed by binding to and entry into an oocyte. Maternal endometrial epithelial cells (EECs) prepare the appropriate implantation environment through regulation of immune cells and endometrial cells. After acquiring endometrial receptivity, a successful pregnancy consists of complex and finely regulated steps involving apposition, adhesion, invasion, and penetration. Glycodelin is a secretory glycoprotein that affects cell proliferation, differentiation, adhesion, and motility. Glycodelin has four glycoforms (glycodelin-A, -S, -F. and -C); differences in glycosylation affect each characteristic function. Glycodelin has a unique temporospatial pattern of expression, primarily in the reproductive tract where glycodelin is mid-secretory phase-dominant. Recent studies have demonstrated that glycodelin protein has the potential to regulate various processes, including immunosuppression, fertilization, and implantation. This review details the orchestrated regulation of successful pregnancy by glycodelin as well as a discussion of the basic characteristics of glycodelin. PMID- 29699135 TI - Crude bark extract of Dysozylum alliarium induces alteration in histological structures and VEGF-C expression in uterus during days 4-7 of gestation in albino rat. AB - Purpose: Crude bark extract (CBE) of Dysoxylum alliarium was tested in vivo for its effects on rat uterus during estrus and day 4-7 of gestation. The purpose is to study the effects of CBE on embryo implantation and VEGF-C expression during peri-implantation period to find out possible role of VEGF-C and embryo implantation. Methods: Threshold was determined by multiple-dose administration of CBE. CBE prepared in methanol was orally administered in a dose of 500 mg/kg/day to female rats during day 1-7 of gestation. Routine H&E histology of uteri was studied during estrus phase and days 4-7 of gestation. The vascular endothelial growth factor (VEGF-C) was studied immunohistochemically and via western blot using VEGF-C antibody. Results: The crude bark extract induced the structural aberration of uterine histology in cyclic stage and during peri implantation. Cellular degeneration of embryo and supporting maternal tissue caused loss of embryo minimizing the litter size. Expression of VEGF-C was drastically reduced in the CBE treated females' uteri than that of the controls. Conclusions: CBE contains potential compounds capable of fertility control as post-coital contraceptive. Effects of CBE on embryo and foetal-maternal interface either mediated through reduced VEGF-C expression or vice versa. PMID- 29699136 TI - Difference in mitochondrial gene expression in granulosa cells between recombinant FSH and hMG cycles under in vitro fertilization and transfer. AB - Purpose: Examination of the mitochondrial mRNA expression in granulosa cells from an unspecified population of infertile patients to evaluate whether recombinant follicle stimulating hormone (recFSH) is more effective in producing higher quality embryo rates compared with human menopausal gonadotropin (hMG). Method: Thirty-nine patients who underwent the in vitro fertilization and embryo transfer program were retrospectively examined. Patients were administered recFSH (n = 18) or hMG (n = 20) in a long protocol where GnRH agonist was used. Granulosa cells were obtained during oocyte retrieval and examined for mitochondria mRNA expression ratio against GAPDH. Expressions of mitochondria mRNA were evaluated by real-time PCR analysis. Results: The high-quality embryo rate in the hMG cycle was higher than in the recFSH cycle, and the total dose of hMG showed a positive correlation with the expression level of mitochondrial genes in granulosa cells. Moreover, mitochondria mRNA expression was higher in the hMG cycle than in the recFSH cycle. Conclusions: Compared with recFSH, hMG induces a higher mitochondrial gene expression ratio in granulosa cells at the time of oocyte retrieval and, therefore, may lead to higher quality embryo rates. PMID- 29699137 TI - Using a mild stimulation protocol combined with clomiphene citrate and recombinant follicle-stimulating hormone to determine the optimal number of oocytes needed to achieve pregnancy and reduce the concerns of patients. AB - Purpose: The purpose of this study was to investigate how many oocytes are needed to achieve an adequate pregnancy rate per 1 oocyte retrieval cycle in mild ovarian stimulation. Methods: This protocol consisted of clomiphene citrate and recombinant-follicle-stimulating hormone injection without a gonadotropin releasing hormone-antagonist. From January 2009 through December 2010, there were 1,227 women who underwent assisted reproductive technologies treatment with mild stimulation at the Sugiyama Clinic. The overall pregnancy rate per single oocyte retrieval cycle was evaluated using both fresh and cryopreserved-and-thawed embryos according to the retrieved oocyte number. Results: According to the retrieved oocyte number, a total of 1,227 cycles were divided into 4 groups: group A (the oocyte number <4; 433 cycles), group B (the oocyte number = 4, 5; 317 cycles), group C (the oocyte number = 6, 7; 206 cycles), and group D (the oocyte number >=8; 271 cycles). The overall pregnancy rates for groups A, B, C, and D were 22.2, 42.9, 52.4, and 56.0 %, respectively, the rates for groups C and D were significantly higher than that for group A (p < 0.01). Conclusions: The optimal number of retrieved oocytes proved to be between 6 and 7 for the patients who received our milder stimulation protocol and experienced no reduction in their overall pregnancy rate. PMID- 29699138 TI - A case of empty follicle syndrome who conceived after aspiration of an endometrial cyst. AB - Empty follicle syndrome (EFS) has been defined as a condition where no oocytes can be retrieved for in vitro fertilization (IVF) even though ultrasound findings and estradiol (E2) levels suggest the presence of potential follicles. The EFS is a rare condition with an incidence of 0.5-7 % of women undergoing IVF treatments. Although there are many hypotheses as to the cause of EFS, including advanced ovarian age, drug-related problems, and dysfunctional folliculogenesis, its cause remains unknown. A 37-year-old woman with endometriosis and a 5-year history of primary infertility underwent IVF treatment for 4 cycles. No oocytes were retrieved in 2 cycles and no fertilized eggs were obtained in the other 2 cycles. We assumed that endometriosis adversely affected folliculogenesis and fertilization. Aspiration of an endometrial cyst in the right ovary and subsequent administration of oral contraceptives resulted in successful folliculogenesis and fertilization. Thereafter, she conceived and delivered a 2,662 g female infant at 38 weeks of gestation. Here, we report a case of EFS who conceived in the 5th IVF cycle after aspiration of an endometrial cyst. We assumed that endometriosis might have been involved in the dysfunction of folliculogenesis and EFS. PMID- 29699139 TI - Critical role of exosomes in sperm-egg fusion and virus-induced cell-cell fusion. AB - In mammals, two integral membrane proteins, sperm IZUMO1 and egg CD9, regulate sperm-egg fusion, and their roles are critical, but yet unclear. Recent studies, however, indicate interesting connections between the sperm-egg fusion and virus induced cell-cell fusion. First, CD9-containing exosome-like vesicles, which are released from wild-type eggs, can induce the fusion between sperm and CD9 deficient egg, even though CD9-deficient eggs are highly refractory to the fusion with sperm. This finding provides strong evidence for the involvement of CD9 containing, fusion-facilitating vesicles in the sperm-egg fusion. Secondly, there are similarities between the generation of retroviruses in the host cells and the formation of small cellular vesicles, termed exosomes, in mammalian cells. The exosomes are involved in intercellular communication through transfer of proteins and ribonucleic acids (RNAs) including mRNAs and microRNAs. These collective studies provide an insight into the molecular mechanism of membrane fusion events. PMID- 29699140 TI - Uterine receptivity and embryo-uterine interactions in embryo implantation: lessons from mice. AB - Implantation is a process of the first feto-maternal encounter in the uterus. A competent blastocyst and a receptive uterus are critical for successful implantation. For an acquisition of uterine receptivity, the following conditions need to be satisfied in the uterine environments: the endometrial preparation with stromal proliferation and epithelial differentiation in the pre-receptive phase and proper interactions between the uterus and blastocyst later in the phase. Focusing on these points and primarily referring to the mouse in vivo evidence, this review article has shown detailed molecular mechanisms for successful implantation. PMID- 29699141 TI - What are the risks of the assisted reproductive technologies (ART) and how can they be minimized? AB - Although assisted reproductive technologies (ART) have become established procedures performed around the world, there are still many unanswered questions regarding safety. Possible risks associated with infertility and ART include (1) those inherent to pregnancy, delivery, and childhood; (2) those associated with the infertility itself and its causes; and (3) risks iatrogenic to ART. Although there are many potential risks associated with ART, it has become clear that the major risk is multiple pregnancy and its consequences. Major efforts are warranted to reduce the risk of multiple gestations with IVF, but it is also clear that single-embryo transfer is not the solution in all cases. Moreover, several studies have now documented that perinatal outcomes are somewhat poorer in IVF singleton infants than in spontaneously conceived singletons, but it is not clear if this increased risk is due to the ART or the infertility. Concerns about the impact of abnormalities in genomic imprinting persist at this time, as do risks associated with the culture conditions and even our environment. Only time will tell if children born following ART are at any increased risk of developing certain chronic diseases as they age. In any case, the risks to IVF children and mothers are likely to remain higher than those for children and mothers conceived spontaneously without medical assistance. However, since there have been over 5 million births after ART worldwide, and the vast majority of pregnancies and children have been essentially "normal", it is obvious that any excess risk must be relatively small. The normality of most pregnancies mandates that extreme care be exercised in making any changes to current practice. PMID- 29699142 TI - Effect of long-term caffeine administration to mice on in vitro fertilization and embryo development using oocytes. AB - Purpose: To evaluate the effect of long-term caffeine administration to mice on in vitro fertilization (IVF) of oocytes. Methods: Mice were injected with different dosages (0, 0.1, and 1.0 mg/mouse/converted day) of caffeine for one month. Subsequently, the fertilization rate and embryo development to blastocyst stage were evaluated in IVF using oocytes from the mice. Results: The retrieved average oocyte rate was significantly lower (27.4) in mice injected with 1.0 mg caffeine than in the control group (36.5; P < 0.05); the fertilization rate was significantly different between the 0 mg (317/401; 79.1 %) and 1.0 mg group (199/301; 66.1 %) (P < 0.05). At 96 h after insemination, the blastocyst formation rate was significantly decreased in the 1.0 mg group (94/199; 47.2 %) compared with the control (0 mg) group (237/317; 74.8 %) and 0.1 mg group (226/323; 70 %) (P < 0.05). When 1.0 mg caffeine was administered for two weeks, embryo development was significantly impacted. Conclusions: Our findings suggest that caffeine administration negatively impacts oocytogenesis and embryonic development after IVF. PMID- 29699143 TI - Alterations of the ovarian histomorphometry at pre-puberty in rat offspring from diabetic mothers. AB - Purpose: Maternal diabetes leads to increased blood glucose concentration in the mother and consequently in the foetus, causing various neonatal problems. This study was conducted to evaluate the effects of maternal diabetes on foetal ovarian structure. Methods: Sixteen adult female rats were allocated into two equal groups. Diabetes was induced in one group by alloxan. Both groups became pregnant by natural mating. Thirty days after birth, the female offspring were terminated, the body weight and blood glucose of the animals measured and their ovaries removed. Various histological and cellular parameters were determined using histological and electron microscopy techniques. Results: Results revealed a significant increase in body weight and blood glucose in the offspring of the diabetic mothers (ODM) compared to that of the controls. The weight, volume and diameter of the ovary and the ovarian capsule thickness were inclined to decrease in ODM compared to that of controls. The number and diameter of primary, pre antral and antral follicles were decreased in ovaries in the ODM. The electro micrographs have demonstrated the organelle alterations in oocytes and granulosa cells that suggest the apoptosis progress and oxidative stress. Conclusions: Maternal hyperglycaemia exhibited deleterious effects on the female reproductive system in the offspring. PMID- 29699144 TI - Cysteamine supplementation during in vitro maturation (IVM) of rabbit oocyte improves the developmental capacity after intracytoplasmic sperm injection. AB - Purpose: Current approaches to in vitro maturation (IVM) may result in low efficiency and inadequate quality of the oocytes due to insufficient cytoplasmic maturation. Although positive effects of the cysteamine supplementation in IVM medium for oocyte nuclear maturation or male pronuclear formation have been confirmed, it is still controversial whether the cysteamine addition affects embryo development after IVM. We aimed here to confirm the effect of cysteamine addition into IVM medium for subsequent embryo development in vitro. Methods: We administered the cysteamine to the IVM culture of rabbit immature oocytes at various concentrations and observed the developmental rate, speed to reach blastocyst stage and cell numbers at the blastocyst stage. Results: Cysteamine supplementation improved developmental rate to blastocyst stage of the IVM oocytes. On the other hand, addition of glutathione (GSH) inhibitor buthionine sulfoximine inhibited GSH accumulation in the oocytes and subsequent embryo development to the blastocyst stage. Conclusions: Controlling the GSH quantity of IVM oocytes may be an important factor for success of embryo development, and it is quite probable that a cysteamine supplementation can contribute to an increase of GSH content in oocyte. PMID- 29699145 TI - A live birth from vitrified-warmed oocytes in a Philadelphia chromosome-positive acute lymphoid leukemia patient 5 years following allogenic bone marrow transplantation and after a magnitude 9.0 earthquake in Japan. AB - Purpose: To report a live birth from vitrified-warmed oocytes for a Philadelphia chromosome-positive acute lymphoid leukemia (Ph-ALL) patient. Methods: A 20-year old single woman with Ph-ALL requested oocyte cryopreservation at a private fertility clinic using assisted reproduction technology (ART). In cases of leukemia, there is a very short time before chemotherapy, follwed shortly by total body irradiation (TBI), and although she had already received the chemotherapy, ten oocytes were vitrified and stored for 59 months before warming. Soon after the oocyte cryopreservation, she received TBI and bone marrow transplant (BMT). During the storage, a magnitude 9.0 earthquake occurred making oocyte transport necessary. The embryo transfer was planned in a hormone replacement cycle, and intracytoplasmic sperm injection (ICSI) was performed on the vitrified-warmed oocytes. On day 3, two embryos were transferred. Results: The patient became pregnant and delivered a healthy girl after ICSI using vitrified-warmed oocytes. Conclusions: Oocyte cryopreservation is the best option for fertility preservation of young single women with leukemia. Oncologists and gynecologists who conduct ART should cooperate to improve the quality of life of cancer patients. PMID- 29699146 TI - Patients with 47, XXX karyotype who experienced premature ovarian failure (POF): two case reports. AB - Purpose: Pubertal onset and sexual development are usually normal in 47, XXX individuals; however, we report two cases of premature ovarian failure (POF) in infertile women with trisomy X. Methods: Chromosome analysis was conducted with G banding and fluorescence in situ hybridization using X- and Y-bearing probe. Hormonal administration was primarily Kaufmann's treatment or long-term estradiol treatment, followed by withdrawal bleeding from estrogen and progesterone. Results: Two patients with trisomy X, aged 31 (patient 1) and 27 years (patient 2), were diagnosed with POF due to hypergonadotropic hypogonadism. Their ovaries were small. Patient 1 had a FSH level of 44.6 mIU/ml and patient 2 had a FSH level of 74.6 mIU/ml. In patient 1, with Kaufmann's treatment, the FSH decreased to 13.5 mIU/ml; however, follicle growth did not occur following HMG stimulation. In patient 2, FSH did not decrease despite Kaufmann's treatment; therefore, she was given a GnRH agonist and her FSH level decreased to 7.1 mIU/ml. However, her ovaries never responded to HMG stimulation. Conclusion: We report on two patients with a 47, XXX karyotype who became infertile due to POF. We recommend that when a patient is diagnosed with trisomy X, the possibility of POF must be strongly considered. PMID- 29699148 TI - Simple, sensitive and reliable in vivo assays to evaluate the estrogenic activity of endocrine disruptors. AB - Purpose: We compared three in vivo assays, determining changes of body weight, and uterotropic and vaginal cytology assays, for the evaluation of estrogenic activity of an estrogen disrupting compound, Pueraria mirifica (PM), in comparison with 17beta-estradiol (E). Methods: Female rats were ovariectomized and gavaged with distilled water, 0.01, 0.1, 1, 10 and 20 mg/kg BW/day of E and 100 and 1,000 mg/kg BW/day of PM for 14 days. Body weights were measured weekly, and vaginal epithelium cells were monitored daily. The uterus was dissected at the end of the treatment period, weighed and examined for histomorphometry. Results: There were a decrease in body weight and an increase in uterine weight, uterine, endometrium and myometrium areas, uterine gland numbers, and percent of cornified cell which were dependent on doses of E and PM treatments. Conclusions: Of the three assays proposed, although all are reliable and had critical read out, measurements of body and uterine weights is likely convenient and simple, but the uterotropic assay needs to kill the animals. Vaginal cytology assay appears most promising for sensitivity and shortening the duration of the assay. Compared to those of E, the estrogenic activity of PM at concentrations of 100 and 1,000 mg/kg BW was in the range of 14 to >20 mg/kg BW. PMID- 29699147 TI - Infertility and Immunocontraception based on zona pellucida. AB - The zona pellucida (ZP) is an extracellular matrix surrounding ovarian oocytes, ovulated eggs and preimplantation embryos. It plays several important roles at different stages of reproduction. Its constituent glycoproteins are expressed specifically in the ovary. It is thus possible to produce autoantibodies to ZP proteins that interfere with reproductive functions including folliculogenesis, fertilization and implantation. First, this article describes the history of anti ZP antibodies detected in women with idiopathic infertility. Second, the current relationship between anti-ZP antibodies and infertility is discussed in relation to assisted reproductive medicine. Third, we introduce the latest studies of animal experiments involving the ZP. Finally, immunocontraceptive vaccine development using various ZP antigens is reviewed. PMID- 29699149 TI - Evaluation of oxygen consumption in human vitrified and warmed pre-antral follicles after prolonged low temperatures. AB - Purpose: The purpose of this study was to evaluate the effect of transportation at prolonged low temperatures on the survival of pre-antral follicles. Methods: Ovarian tissue was removed from six women with gender identity disorder. Tissues were stored in an icebox at 4 degrees C for 6 or 18 h prior to vitrification. After warming, ovarian tissues were cultured for 24 h and follicle survival was assessed via a viability/cytotoxicity kit. Morphological features and oxygen consumption rate (OCR) were evaluated by scanning electrochemical microscopy (SECM). Results: Survival rate of isolated primordial follicles was 95.7 and 100 %, and that of primary follicles was 91.7 and 81.8 % in the 6- and 18-h groups respectively. There was no difference in morphology between the 6- and 18-h storage groups. In comparison with OCR of vitrified-warmed follicles and OCR of 24-h culture after vitrified-warmed follicles, OCR of 24-h culture after vitrified-warmed primordial follicles was significantly higher in both 6-hour (0.02 +/- 0.02 vs 0.07 +/- 0.04, P < 0.05) and 18-h groups (0.02 +/- 0.02 vs 0.11 +/- 0.10, P < 0.05). Conclusions: This strongly suggests that prolonged transportation of ovarian tissue at low temperatures is useful when there are no available local systems for fertility preservation. PMID- 29699150 TI - Roles of epigenome in mammalian spermatogenesis. AB - Mammalian spermatogenesis is a successive process consisting of spermatogonial proliferation, spermatocytic meiosis, and spermiogenesis, representing the maturation of haploid spermatids. During the process, 25-75 % of the expected sperm yield is thought to be lost through apoptosis. In addition, spermatogenesis is considered to be a process undergoing successive heterochromatinization, finally reaching a complete condensed form in the sperm head. Thus, cell proliferation, differentiation and death may be strictly regulated by epigenetic factors in this process. This review describes the current understanding of the role of epigenome in spermatogenesis, especially focusing on the following aspects; DNA methylation, modification of histones, and small RNA function. These epigenetic factors affect each other and play a central role in events essential for spermatogenesis, fertilization and embryogenesis, through the regulation of gene expression, transposon activities, meiotic sex chromosome inactivation, histone remodeling and genome imprinting. Finally, a brief discussion of future avenues of study is highlighted. PMID- 29699151 TI - Oxidative stress and redox regulation of gametogenesis, fertilization, and embryonic development. AB - Oxidative stress caused by elevated reactive oxygen species (ROS) is one of the predominant causes of both male and female infertility. Oxidative stress conditions cause either cell death or senescence by oxidation of cellular molecules including nucleic acid, proteins, and lipids. It is particularly important to minimize oxidative stress when in vitro fertilization is performed for the purpose of assisted reproduction. The problems associated with assisted reproductive technology are becoming evident, and it is now the time to clarify its mechanisms and cope with them. On the other hand, the beneficial roles of ROS, such as intracellular signaling, have become evident. The antithetical functions of ROS make it more difficult to overcome the problems caused by oxidative stress. Despite the difficulty in understanding mammalian reproduction, the mechanisms and problems can be gradually unveiled by advanced technology such as genetic modification of animals. PMID- 29699152 TI - Abnormal lysine acetylation with postovulatory oocyte aging. AB - Background: A postovulatory mammalian oocyte decreases developmental potential with in vivo aging in the oviduct or in vitro aging in the culture dish. The mechanism underlying oocyte aging still largely remains an enigma. Accumulating data suggest that the epigenetic alterations such as histone acetylation are also associated with postovulatory aging. Objective: To perform a review evaluating a new aspect of oocyte aging in terms of the epigenetic alterations focusing on lysine acetylation. Methods: In addition to a search of the literature in Pubmed, we introduced our recent published data. Results: Histone acetylation in the mouse oocyte increases during aging, potentially impacting gene regulation in the subsequent embryonic development. Oocyte aging results in increased acetylation of alpha-tubulin, a non-histone protein, and nicotinamide, an inhibitor of class III HDAC, partially prevents some of oocyte aging phenotypes. Conclusion: Abnormal regulation of protein acetylation itself is suggested in oocyte aging and could contribute to the aging phenotypes. PMID- 29699153 TI - Sperm DNA fragmentation assay by sperm chromatin dispersion (SCD): correlation between DNA fragmentation and outcome of intracytoplasmic sperm injection. AB - Purpose: The aim of the present study was to investigate the relationship between sperm DNA fragmentation index (sDFI) and outcome of intracytoplasmic sperm injection (ICSI). Methods: All the patients were divided into two groups based on sperm DNA fragmentation analysis by the sperm chromatin dispersion (SCD) method. A total of 237 patients were in the DNA fragmentation normal group (sDFI <= 30 %), and 140 patients were in the DNA fragmentation abnormal group (sDFI >= 30 %). The relationship of sDFI with the outcome of ICSI was analyzed. Results: A significant difference in semen parameters was observed between the DNA fragmentation normal and abnormal groups [count, motility and morphology (p < 0.05)]. However, no significant difference was seen between the number of oocytes retrieved and fertilization rates between the two groups, whereas the number of embryos progressed to day 3 and the blastocyst formation rate in the remaining embryos after transfer were significantly more in the DNA fragmentation normal group (p < 0.05). A significant negative correlation was noted between DFI values of more than 30 % and number of pregnancies and deliveries (p < 0.05). A higher DFI was also associated with increased abortion rates. Conclusions: In the present study, sperm with DNA fragmentation showed a negative correlation with semen parameters. Further, sperm with damaged DNA have potential adverse effects on embryo progression, clinical pregnancy rate, and ongoing pregnancies. PMID- 29699154 TI - Male infertility and androgen replacement therapy for subjects with bilateral testicular tumors. AB - Purpose: The purpose of this study was to investigate andrological aspects, including male infertility and androgen deficiency, after treatments of bilateral testicular tumors. Methods: Five subjects with bilateral testicular cancer were clinically analyzed between April 1996 and March 2013. Results: The mean age at initial treatment was 29.4 +/- 3.3 years old. In the 4 metachronous cases, a contralateral tumor occurred after 79.0 +/- 50.0 months. Histologically, bilateral seminoma occurred in 3 cases and seminoma and nonseminoma was combined in 2 cases. All subjects underwent bilateral orchiectomy, with additional chemotherapy, radiation therapy, and surgery for metastasis. No tumor recurrence was observed in the 5-34 years following initial treatment. Two subjects married following bilateral orchiectomy after receiving informed consent from their wives. One had two children before contralateral testicular treatment. The other was single and had undergone micro-testicular sperm extraction at contralateral orchiectomy, although no sperm was found. The other one was unknown because long term followup failed. Androgen replacement therapy (ART) was applied for 4 subjects, and relieved physical and psychological symptoms due to testosterone deficiency without adverse reactions. Conclusions: ART safely and effectively relieves symptoms in subjects with bilateral testicular tumors. However, male infertility treatment is insufficient, and more aggressive management may be required. PMID- 29699155 TI - Progressing management of non-obstructive azoospermia in the era of microdissection testicular sperm extraction. AB - Previously, it was absolutely impossible for azoospermic men to reproduce except in some obstructive azoospermic cases for whom reconstruction of the seminal pathway was successful. However, nowadays, intracytoplasmic sperm injection and microdissection testicular sperm extraction have brought about chances of biological paternity in some non-obstructive azoospermic men. It is almost 15 years since the first trials of testicular sperm retrieval using surgical microscopy for non-obstructive azoospermia were reported. In this manuscript, the progress and outcomes of these novel techniques since then are reviewed, the controversial points are discussed and the latest research to achieve pregnancies in tough non-obstructive azoospermic couples are introduced. Not only the bright side of the renovations, but the underlying concerns are also discussed. PMID- 29699156 TI - Changes in expression levels of oxidative stress-related genes in mouse epididymides by neonatal exposure to low-dose decabromodiphenyl ether. AB - Decabromodiphenyl ether (decaBDE), one of the polybrominated diphenyl ethers (PBDEs), is the most well-known flame retardant and is used worldwide. In a previous study, we identified adverse effects of neonatal decaBDE exposure on mouse epididymides, such as decreased epididymal weight. On the other hand, neonatal exposure to diethylstilbestrol (DES), an artificial estrogenic compound, also causes several adverse effects on epididymides. DES exposure results in decreased epididymal weight, morphological abnormalities, and permanent alterations in the expression levels of several genes. The molecular mechanisms underlying the harmful effects of decaBDE exposure remain unclear. Many studies have reported that PBDEs have estrogenic activity, which may contribute to the induction of the adverse effects of decaBDE exposure. We aimed to examine the effects of neonatal decaBDE exposure on epididymides. Our data showed that (1) no histological change was observed on epididymal tissues from neonatal decaBDE exposure, unlike the effect of DES, (2) decaBDE exposure did not induce the alterations in gene expression observed with DES exposure; instead alterations in gene expression of certain oxidative stress-related genes were observed, and (3) the expression of ubiquitin C increased in decaBDE-exposed mouse epididymides. Our present data suggest the possibility that increased oxidative stress plays a role in the harmful effects observed in mouse epididymides after decaBDE exposure. PMID- 29699158 TI - Regulation and disruption of hamster sperm hyperactivation by progesterone, 17beta-estradiol and diethylstilbestrol. AB - Purpose: Hyperactivation of hamster sperm is dose-dependently enhanced by progesterone (P) and 17beta-estradiol (E). In the first part of the present study, enhancement of hyperactivation in response to the concentrations of P and E was examined in detail and in the second part, it was examined whether enhancement of hyperactivation by P and E was disrupted by diethylstilbestrol (DES). Methods: Hamster spermatozoa were hyperactivated by incubation in modified Tyrode's albumin lactate pyruvate medium with P, E and/or DES. After spermatozoa were recorded using a video-microscope, observations were quantified by manually counting the numbers of total, motile and hyperactivated spermatozoa. Results: Hyperactivation was enhanced in response to the concentrations of P and E. When spermatozoa were exposed to DES with E, moreover, DES significantly and strongly suppressed P-enhanced hyperactivation by accelerating the effect of E, but DES itself only weakly suppressed P-enhanced hyperactivation. Conclusions: Enhancement of hyperactivation was regulated by the concentrations of P and E, suggesting that in vivo hamster spermatozoa are hyperactivated through "monitoring" these concentrations in the oviduct. DES in combination with E suppressed P-enhanced hyperactivation, suggesting that DES significantly disrupts hyperactivation by acting as an accelerator of the effect of E. PMID- 29699157 TI - Nicotine and endometrial decidual growth in pseudopregnant rats. AB - Purpose: The present study aims to investigate the effects of nicotine on the endometrial decidual growth and levels of estrogen and progesterone in pseudopregnant rats. Methods: Pseudopregnancy (pc) was induced in cyclic Sprague Dawley rats by sterile mating. Subcutaneous injection of nicotine tartrate (7.5 mg/kg/day) was scheduled from day 1 through day 5, day 5 through day 9 or day 1 through day 9 of pc. In another group of pseudopregnant rats, concomitant treatment of nicotine tartrate concurrently with progesterone (2 mg/day) was scheduled from day 1 through day 9 pc. Control groups received subcutaneous injections of vehicle only. Endometrial decidualization was induced on day 5 pc. On day 10 pc, animals were sacrificed.The degree of decidual growth and circulating levels of estrogen and progesterone were measured. Results: The decidual growth in all the first three nicotine-treated groups of animals was significantly reduced, particularly in the animals treated with nicotine from day 1 through day 9 pc. Plasma estrogen levels were significantly elevated in animals treated with nicotine from day 1 through day 9 pc. Conversely, levels of plasma progesterone were found to be significantly attenuated in the same group of nicotine-treated animals compared to controls. Exogenous replacement of progesterone, however, caused a higher degree of endometrial decidualization compared to the nicotine-treated group but it was slightly less than when compared to control. Conclusions: In conclusion, nicotine-induced progesterone deficiency with a corresponding elevation of estrogen may possibly attenuate the degree of endometrial decidualization in pseudopregnant rats. PMID- 29699159 TI - The association of physiological cortisol and IVF treatment outcomes: a systematic review. AB - Purpose: A systematic review was conducted to (1) collate and synthesise the available evidence for the role of cortisol in relation to IVF treatment outcomes; (2) to establish the strength of an association between cortisol and IVF; and (3) to assess the overall quality of the studies and guide future research in this area. Methods: Seven electronic databases, including the reference lists of published papers, were searched. Inclusion criteria qualified any prospective/observational cohort study that reported original data. Quality assessment of eligible studies was conducted using the STROBE statement, which was used to assess the risk of bias and the quality of observational studies included in this review. Results: A total of eight studies reported a significant association between cortisol and IVF outcomes. Three studies found that higher cortisol may be associated with more favourable IVF outcomes, whereas five studies found that lower cortisol levels may be conducive to IVF success. Eleven of all studies included in this review were regarded as low quality publications. Conclusions: Study findings were that the evidence for the role of cortisol in relation to IVF outcomes is currently mixed. Future researchers are encouraged to consider the methodological limitations highlighted in this review and to utilise more robust assessment methods when examining the influence that chronic, rather than acute, stress may have on IVF outcomes. PMID- 29699160 TI - Role of varicocele repair for male infertility in the era of assisted reproductive technologies. AB - Varicocele is an abnormal condition characterized by dilatation of the pampiniform plexus veins draining the testis and is present in 15 % of men. Varicoceles have an adverse effect on spermatogenesis and are the most common cause of male infertility. Approximately 35 % of infertile men and more than 70 % of men with secondary infertility were reported to have varicoceles. Although data on methods of varicocele repair are accumulating, there remains controversy regarding the indications and techniques for varicocele repair. In addition, the role of varicocele repair in this era of assisted reproductive technologies continues to be debated. In this study, we performed a comprehensive PubMed search in order to review the current status of varicocele repair for male infertility. We reviewed English-language studies published from 1992 through 2013. After reviewing the articles, we identified a recent meta-analysis of four randomized controlled trials, which found that varicocele repair for oligozoospermic men was associated with better pregnancy rates as compared with observation. Our review of prospective studies showed that all semen parameters, including sperm concentration, motility, and progressive motility, were significantly improved after varicocele repair. We also summarize the findings of recent studies reporting beneficial effects of varicocele repair, i.e., decreased oxidative stress and sperm DNA fragmentation after varicocele repair and superior cost effectiveness versus in vitro fertilization/intracytoplasmic sperm injection alone, which may be important in the era of assisted reproductive technologies. Varicocele repair is a widespread, well-established procedure that can improve semen parameters in men with infertility. The effect of such treatment on the pregnancy rate is unclear because evidence is limited due to difficulties in recruiting patients for studies. Among the repair techniques, microsurgical repair using a subinguinal approach is potentially the best practice, although this procedure requires training in microsurgery. All these topics require further research in studies with sufficient patient enrollment and follow-up. PMID- 29699161 TI - Time-lapse observations to analyze the effects of assisted hatching. AB - Purpose: Assisted hatching (AH) is an artificial disruption of the zona pellucida with the aim of facilitating embryo implantation. We used time-lapse observations of mouse embryos to examine the effect of AH in mouse blastocysts. Methods: AH techniques were performed with acid Tyrode's solution. We compared the rates of blastocyst formation and blastocyst attachment to Ishikawa cells between the control (n = 28) and the AH group (n = 24). To analyze the effects of AH, 8-cell mice embryos were cultured under time-lapse observations (every 15 min). The time required for hatching, the hatching rates, the frequency of contraction, and the contraction rates in the blastocysts were analyzed. Results: There were no significant differences between the two groups in hatching rate or attachment rate. The times required for hatching were 286 +/- 22 min in the AH group and 990 +/- 437 min in the control group (P = 0.018). The contraction frequencies in blastocysts were 3.5 +/- 0.7 times in the AH group and 7.5 +/- 2.5 times in the control group (P = 0.020). Conclusions: From the time-lapse observations we found that the time required for hatching and the frequency of contraction in blastocysts were both reduced by AH, although blastocyst formation and attachment were not affected. PMID- 29699163 TI - Low dose gonadotropin-releasing hormone agonist treatments with early discontinuation for controlled ovarian hyperstimulation in an in vitro fertilization program. AB - Aim: The purpose of the present study was to investigate the applicability of a protocol for controlled ovarian hyperstimulation (COH) featuring early discontinuation of low dose gonadotropin-releasing hormone agonist (GnRHa) for ovulation induction for in vitro fertilization (IVF). Methods: Four hundred and eighty-seven women undergoing 555 IVF cycles were recruited into the study. Controlled ovarian hyperstimulation was achieved by using either a short protocol of low dose GnRHa (for 5 days only; groups 1 and 2) or a modified long protocol with early discontinuation of GnRHa (groups 3 and 4). Groups 1 and 3 received urinary follicle-stimulating hormone (FSH) and groups 2 and 4 received recombinant FSH. Oocyte retrieval was performed 34 to 36 h after human chorionic gonadotropin (hCG) injection, followed by embryo transfer 3 days later. Results: Luteinizing hormone (LH) levels on the hCG injection day were lower with the modified long protocol (groups 3 and 4) than with the short 5-day treatment (groups 1 and 2). There were higher LH levels in group 1 than in groups 2, 3 and 4, resulting in a worse fertilization rate and clinical pregnancy rate. There were no statistically significant differences between groups 2, 3 and 4 in the rates of fertilization, clinical pregnancy and delivery. A higher estradiol (E2) level in group 3 than in groups 1, 2 and 4 resulted in a worse implantation rate. Conclusion: Early cessation of GnRHa may not induce a premature LH surge in controlled ovarian hyperstimulation, while a low dose also offers a useful alternative to a long protocol of IVF. Ovarian stimulation with recombinant follicle-stimulating hormone (rFSH) is considered to be favorable in this low dose GnRHa treatment. (Reprod Med Biol 2003; 2: 25-30). PMID- 29699164 TI - Application of transvaginal hydrolaparoscopy for ovarian drilling using Nd:YAG laser in infertile women with polycystic ovary syndrome. AB - Since transvaginal hydrolaparoscopy (THL) was introduced as the first-line procedure in the early stage of the exploration of the tubo-ovarian structures in infertile women, it has been shown that THL is a less traumatic and a more suitable outpatient procedure than diagnostic laparoscopy. In the present study, a minimally invasive surgery was carried out in infertile women with polycystic ovary syndrome (PCOS) by THL. Ovarian drilling using Nd:YAG laser vaporization by THL was performed in two clomiphen citrate-resistant infertile women with PCOS. After ovarian drilling with THL, a patient recovered an ovulatory cycle. These findings suggest that ovarian drilling by THL seems to be a safe procedure in infertile women with PCOS. However, further investigations are required to evaluate the effectiveness and risks of this minimally invasive operation. (Reprod Med Biol 2003; 2: 37-40). PMID- 29699165 TI - Two cases of dizygotic triplet pregnancy following conventional in vitro fertilization. AB - The mechanism of monozygotic multifetal pregnancy and its association with assisted reproductive technology are uncertain. This report presents two cases of dizygotic triplet pregnancy after the transfer of three embryos in utero. The incidence of monozygotic twinning following assisted conception procedures is higher than in the general population. Zonal manipulation may be a major factor in the increased incidence of monozygotic twinning. As both cases followed the conventional in vitro fertilization (IVF), the reason for these monozygotic twinnings might be because of the changes in the zona pellucida in in vitro conditions. In one case, fetuses developed into severe twin-to-twin transfusion syndrome (TTTS), resulting in one intrauterine fetal death at 26 weeks gestation. (Reprod Med Biol 2003; 2: 41-44). PMID- 29699162 TI - Insulin-like growth factors and their binding proteins: Potential relevance to reproductive physiology. AB - Cyclic ovarian follicular development is a complex process that involves proliferation, differentiation, and death of follicle cells. Gonadotropins produced by the pituitary gland have a central role in the regulation of these processes. In addition, a wide range of paracrine and autocrine factors produced in the reproductive organs have been proposed as regulators of reproductive functions. Components of the insulin-like growth factors (IGF) system are widely expressed in the female reproductive tract. The IGFs and their binding proteins play a significant role in several processes of reproductive physiology, including ovarian follicular development, oogenesis and oocyte maturation, ovulation, luteal function, follicular atresia, and testicular function. The majority of these physiological actions of the IGFs are believed to occur via activation of the IGF-I receptor, although the IGF-I effects are modulated by IGF binding proteins (IGFBPs). As much of the data obtained to date have been in the rodent reproductive organs, it may not be possible to directly extrapolate the results to the primate organs. There is a distinct species-difference in the gene expression and functional roles of the IGF-IGFBP system in reproductive organs. However, the disturbance of the IGF-IGFBP system in human reproductive physiology may lead to anovulation, disorders of androgen excess, infertility associated with implantation failure, and male infertility. Further research is needed in domestic animals to determine if manipulation of the IGF-IGFBP system may result in improved reproductive efficiency. As our understanding of the IGF-IGFBP system increases, the uses of human recombinant IGF peptides and IGFBPs as clinical therapy for disease states is becoming a reality. (Reprod Med Biol 2003; 2: 1 24). PMID- 29699166 TI - Studies on the effects of initial injection doses of follicle stimulating hormone on the pregnancy and the ovarian hyperstimulation syndrome incidence in polycystic ovarian syndrome patients. AB - Background: Patients with polycystic ovarian syndrome (PCOS) are often resistant to clomiphene citrate, which causes the need for subsequent gonadotropin treatment. However, careful administration is required because of the potential side-effects, that is, ovarian hyperstimulation syndrome (OHSS) and multiple pregnancy. Methods: Forty-three cycles in 22 patients with PCOS were enrolled in this study. Ovarian stimulation was initiated on day 7 of the menstrual cycle with 150 IU/day of follicle stimulating hormone (FSH; 150 IU course), 100 IU/day (100 IU course), and 75 IU/day (75 IU course), successively. If follicles over 12 mm in diameter did not develop after 1 week, the dose was increased. In each treatment course, the number of developed follicles, the serum estradiol level before ovulation, total FSH dosage and duration of administration, the incidence of OHSS, and pregnancy rate were examined. Results and Conclusion: The largest number of developed follicles and the highest serum estradiol level were found in the 150 IU course. In contrast, the total FSH dosage and duration of administration were highest and longest in the 75 IU course. The incidence of OHSS and pregnancy rate were highest in the 150 IU course and in the 75 IU course, respectively. The present study indicates that 100 IU or 75 IU of FSH is recommended as an initial injection dose for PCOS patients. (Reprod Med Biol 2003; 2: 63-67). PMID- 29699167 TI - Detection of mitomycin C-induced testicular toxicity by micronucleus assay in mice. AB - Background, Aims and Methods: Mitomycin C is a promising cancer agent that has been shown to inhibit DNA synthesis. Our previous study showed that mitomycin C induces spermatogenic cell apoptosis in the mouse testis. By using TdT-mediated dUTP-biotin nick-end labeling in the study, we confirmed that apoptotic cell death was most commonly found in the spermatogonia and less frequently found in spermatocytes in mitomycin C-treated mice. We therefore hypothesized that the spermatogenic cell apoptosis induced by mitomycin C occurred as the result of a mechanism to eliminate male germ cells with DNA damage or chromosomal aberrations. To test our hypothesis, we used a micronucleus assay for the detection of chromosomal damage induced in the spermatogonia or spermatocyte stages. Results and Conclusions: The frequency of micronuclei was clearly increased in the mitomycin C-treated animals, and the number of micronuclei was greater at the spermatogonia or early spermatocyte stage than at the secondary spermatocyte stage. These results revealed that apoptosis and chromosomal aberration in the mouse testis after mitomycin C treatment occurred in the same cell types, that is, spermatogonia and spermatocytes. These findings indicate that chromosomal aberration of the spermatogenic cells induced by mitomycin C may have caused the spermatogenic cell apoptosis. (Reprod Med Biol 2003; 2: 69-73). PMID- 29699168 TI - Changes in the activity of sperm nitric oxide synthase in the oviductal reservoir during ovulation. AB - Background: The oviductal isthmus is known to act as a sperm reservoir in several mammalian species including mice, but it is still unclear how sperm are released from the reservoir after ovulation. Recently, nitric oxide (NO) was reported to have important roles as a mediator in various sperm functions, including hyperactivation and capacitation. Therefore, we have investigated the change of the activity of nitric oxide synthase (NOS) of sperm of the isthmus in relation to ovulation under in vivo fertilization conditions. Methods and Results: The sperm were collected from the isthmus and uterus of the female mated before or after ovulation. The NOS activity change was evaluated by using the beta-nicotinamide adenine dinucleotide phosphate-diaphorase staining method, and sperm NOS activity was quantified by using NIH image software. The results showed that, in the reservoir, the peak intensity of sperm NOS activity was higher after ovulation (135.5 +/- 22.4) than before ovulation (102.7 +/- 15.5; P <= 0.05). After ovulation, the number of free sperm in the isthmus increased, and these sperm expressed strong NOS activity. Conclusion: The change of sperm NOS activity is related to their release from the epithelium of the oviductal reservoir. (Reprod Med Biol 2003; 2: 75-81). PMID- 29699169 TI - Delivery of a healthy newborn using vitrified zygotes that developed from in vitro matured oocytes retrieved from a patient with polycystic ovarian syndrome. AB - The aim of this study is to evaluate vitrified zygotes, which were developed from in vitro matured oocytes that were retrieved from a patient with polycystic ovarian syndrome. Oocyte retrieval was performed on day 15 following withdrawal bleeding. The oocytes were incubated for 24 h in human tissue culture medium (TCM)-199 maturation medium supplemented with 20% filtrated-mixed patients follicle fluid, follicle stimulating hormone (FSH), and human chorionic gonadotropin (hCG). A total of four immature oocytes were collected. Two of the four oocytes (50.0%) developed to the metaphase-II stage and, subsequently, two fertilized oocytes were vitrified at the pronuclear stage because a very thin endometrium was not conducive for transfer. One of the two vitrified zygotes was thawed and developed to a 4-cell cleavage stage embryo within 24 h. Subsequent to the embryo transfer, a healthy newborn was delivered. A successful delivery was ensued by using vitrified zygotes from an anovulatory woman with polycystic ovarian syndrome. (Reprod Med Biol 2003; 2: 87-90). PMID- 29699170 TI - G2/M transition of pig oocytes: How do oocytes initiate maturation? AB - In the ovary, mammalian oocytes resume meiosis and mature to the second metaphase when they are stimulated with gonadotrophins. Similarly, oocytes can mature in vitro when they are liberated from ovarian follicles and cultured under appropriate conditions. Early in the process of maturation, oocytes undergo dramatic but well-ordered changes at the G2/M transition in the cell cycle including: (i) chromosome condensation; (ii) nucleolus disassembly; (iii) germinal vesicle breakdown (GVBD); and (iv) spindle formation in the first metaphase (MI-spindle). These events have been thought to be induced by MPF (maturation-promoting factor or M-phase promoting factor), now known as Cdc2 kinase or Cdk1 kinase, which consists of a catalytic subunit, Cdc2, and a cyclin B regulatory subunit. In fact, nuclear lamins are phosphorylated by Cdc2 kinase, and nuclear membrane breakdown occurs concomitantly with the activation of Cdc2 kinase in the M-phase of both somatic cells and oocytes. Based on the classical and recent studies of the pig oocyte, however, the chromosomes start to condense and the nucleolus disassembles before full activation of Cdc2 kinase, and the MI spindle is formed after activation of both Cdc2 kinase and MAP kinase; another kinase known to become activated during oocyte maturation. These findings suggest that chromosome condensation and nucleolus disassembly in oocytes are induced by either some kinase(s) other than Cdc2 kinase and MAP kinase or some phosphatase(s). The accumulation of new results regarding the molecular nature of oocyte maturation is important for improving the reproductive technologies in domestic animals as well as in humans. (Reprod Med Biol 2003; 2: 91-99). PMID- 29699171 TI - Clinical experience of vasoepididymostomy using a triangulation technique. AB - Background: Although the number of patients receiving vasoepididymostomies is gradually increasing, these individuals are limited in the recent advanced assisted reproductive technology (ART) era. A novel technique involving vasoepididymostomy with epididymal tubular invagination has been reported. We attempted to define the results of this method and to compare them with the conventional end-to-side technique in patients with suspected epididymal obstruction and no previous history of vasectomy. Methods and Results: Eight eligible triangulation end-to-side vasoepididymostomy procedures performed on five azoospermic patients exhibiting either unilateral or bilateral epididymal obstruction are described. The overall patency rate following operation was 100% (five of five). Two pregnancies were achieved by natural intercourse and one was accomplished via artificial insemination. A single pregnancy was obtained with an intracytoplasmic sperm injection using frozen-thawed sperm collected during the operation. Conclusion: Vasoepididymostomy, using the triangulation technique for epididymal obstruction, resulted in an earlier patency in all patients. This method may afford advantages when compared with the conventional end-to-side approach; however, larger subject populations are required in order to assess further the efficacy of this procedure. In addition, long-term follow up is necessary. (Reprod Med Biol 2003; 2: 101-104). PMID- 29699172 TI - Infertile women without sensitization to an appropriate amount of sperm do not produce sperm-immobilizing antibodies in their sera. AB - Background and Aim: The factors that affect sperm immobilizing antibody production in some women are not fully understood. This study was performed to investigate if production of sperm immobilizing antibodies in women is associated with their husbands' sperm count. Methods: The sperm immobilization test (SIT) was performed on 221 infertile women whose husbands had normal semen characteristics according to the criteria by WHO; 160 patients were treated by intracytoplasmic sperm injection (ICSI) because of poor semen characteristics, and 1013 virgin female children acted as the controls. Results: A significant difference of the incidence in SIT was observed between the virgin female children and the women whose husbands had a normal sperm count (P < 0.0001). There was also a significant difference of the incidence in SIT between the women treated by intracytoplasmic sperm injection (ICSI) because of a severe male factor and those whose husbands had a normal sperm count (P < 0.05). Conclusions: These results indicate that production of sperm immobilizing antibodies in women begins after they have been exposed to a large enough amount of sperm. However, the precise amount of sperm required to produce the antibodies is not clarified by the present study. (Reprod Med Biol 2003; 2: 105-108). PMID- 29699173 TI - Association of testicular undescent induced by prenatal flutamide treatment with thickening of the cremaster muscle in rats. AB - Background and Aims: Previously, in cryptorchid rats, which were induced by prenatal exposure to flutamide, we found a thickening of the cremaster muscle. This study was undertaken to quantify the increase of the cremaster muscle thickness in the cryptorchid rats, and to examine its possible relationship with the proliferation of muscle cells. Methods: To obtain cryptorchid rats, pregnant Wistar rats were subcutaneously injected with flutamide (100 mg/kg per day) during gestational days 16-17. Serial sections of the scrotum, containing the testis and cremaster muscle, were prepared from the control and cryptorchid rats that were 2-6 weeks of age, and stained with hematoxylin-eosin for morphometry, or stained with antibody against the proliferating cell nuclear antigen (PCNA) to analyze the cell proliferation ability. Results: The thickened cremaster muscle was always associated with cryptorchid testis and, in the case of unilateral cryptorchidism, the cremaster muscle of the contralateral (descended testis) side exhibited normal thickness. The average thickness of the affected cremaster muscle was 0.80 and 1.89 mm at 4 and 6 weeks of age, respectively, although that of the normal muscle was 0.28 and 0.33 mm at the same time period, respectively. Conclusion: Our results showed that the cremaster muscle of the cryptorchid rats was significantly thicker than that of the control rats. The immunohistochemical analysis revealed that a thickened cremaster muscle contained many PCNA-positive nuclei even at 4 weeks of age, in contrast to the control, which had only a few positive nuclei. Our present study indicates that continuous proliferation of the muscle cells associated with cryptorchid testis increases the thickness of cremaster cells in rats exposed to flutamide prenatally. (Reprod Med Biol 2003; 2: 109-113). PMID- 29699174 TI - Activation of protein kinase C inhibits the secretion of platelet-activating factor acetylhydrolase by human decidual macrophages. AB - Background and Aims: Platelet activating factor (PAF), a potent phospholipid mediator, has been implicated in a number of reproductive processes through ovulation to parturition. To clarify the regulatory mechanism of PAF metabolism in the decidua, we have investigated the effect of activation of protein kinase C (PKC) on the secretion of PAF-acetylhydrolase (PAF-AH), a PAF-inactivating enzyme, by human decidual macrophages. Methods: Decidual macrophage populations were isolated from human decidua by using enzymic digestion, Ficoll-Paque centrifugation, or flow cytometric sorting. The cells were treated with a PKC activator (TPA), H-7, dibutyryl cyclic adenosine monophosphate (AMP), Bis-(o aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, tetra (acetoxymethyl)-ester (BAPTA/AM) and/or nifedipine. The activity of PAF-AH secreted in the culture medium was assayed. Results: The PKC activator, TPA, inhibited the PAF-AH secretion by decidual cells in a dose-dependent manner. The TPA also decreased the enzyme secretion by flow cytometrically purified macrophages. The inhibitory effect of TPA was blocked by a PKC inhibitor, H-7. Protein kinase A (PKA) activation by dibutyryl cyclic AMP was without effect on the enzyme secretion. Calcium channel blockers, BAPTA/AM and nifedipine had no effect on the PAF-AH secretion. Conclusion: It is suggested that the TPA-induced inhibition of PAF-AH secretion may be mediated, in part, by a PKC-dependent signal transduction, and that activation of PKC may result in the increase in the local concentration of PAF in the decidua because of its inhibitory effect on the PAF-AH secretion by decidual macrophages. (Reprod Med Biol 2003; 2: 121-126). PMID- 29699175 TI - Enhancing the fertility of poor responders by treatment with estrogen rebound combined with a short protocol. AB - Aim: To assess the efficacy of estrogen rebound (ER) plus flare-up by gonadotropin releasing hormone agonist (GnRH-a) in poor responders who failed to become pregnant prior to a long protocol treatment. Methods: The patients comprised of thirty-one infertile patients with oocyte retrieval levels of less than five, who had undergone several long protocol treatment cycles. The efficacy of treatment with the ER plus flare-up from GnRH-a was compared with the prior long protocol treatment. The main outcome measures are: confirmation of ER, maximal serum E2 levels prior to human chorionic gonadotropin (hCG) administration, follicular development, dose, and duration of gonadotrophins in a clinical setting. Results: The ER was confirmed by estrogen levels; FSH increased with ER plus flare-up from GnRH-a. Although the 31 patients included in the study had undergone frequent prior treatment cycles, including the long protocol, the pregnancy rate per embryo transfer following ER plus flare-up by GnRH-a was 37.5% (nine of 24). The number of follicles, number of oocytes retrieved, and the E2 level was higher than those found in prior treatment cycles. Conclusion: Exogenous estrogen administration with PremarinR plus flare up by GnRH-a may represent an alternative and effective protocol for poor responder patients who had previously undergone several prior long protocol treatments. (Reprod Med Biol 2003; 2: 127-131). PMID- 29699176 TI - Two-step consecutive transfer of early embryos and blastocysts. AB - Aim: To evaluate and confirm the merit of two consecutive transfer attempts of early embryos and blastocysts. Methods: A total of 685 patients underwent routine in vitro fertilization (IVF) cycles. The study population consisted of three groups: (i) Group 1, early stage embryos were transferred (460 patients; 567 cycles); (ii) group 2, blastocysts were transferred (88 patients; 105 cycles); and (iii) group 3, a two-step (consecutive) transfer was performed on 137 women (141 cycles). Specifically, a standard embryo transfer was performed on day 3, together with a two-step (consecutive) transfer of blastocysts. After the early embryo transfer, an extended culture of supernumerary embryos was conducted, followed by a second transfer of blastocyst(s). Results: No significant differences were found in the three groups with regards to either pregnancy or implantation rates for groups 1, 2, or 3; pregnancy: 34.6, 29.9, and 33.6%, respectively; implantation: 18.6, 15.9, and 15.1%, respectively. The miscarriage rate for each group was also not significant; 20.4, 30.8 and 28.6% for groups 1, 2 and 3, respectively. The multiple pregnancy rate of the three groups was 30.4, 30.8 and 35.7%, respectively, and these were not found to be significant results. Conclusion: No significant difference was found between the three groups with regards to the pregnancy, implantation, multiple pregnancy and miscarriage rates. The multiple pregnancy rate was highest in the two-step (consecutive) transfer group. This difference was not regarded to be highly significant. (Reprod Med Biol 2003; 2: 133-137). PMID- 29699177 TI - Melatonin as a new drug for improving oocyte quality. AB - Background: Although recent technical advances have benefited infertile couples, inadequate embryo development as a result of poor quality oocytes still contributes to infertility. The purpose of the present study was to evaluate melatonin as a drug for improving oocyte quality in such cases. Methods: Twenty seven women from whom fewer than three fertilized embryos were grown and who failed to fall pregnant in previous treatment cycles were enrolled in the current prospective clinical study. Subjects took 1 mg or 3 mg tablets of melatonin orally at 22:00 h from the fifth day of the previous menstrual cycle to the day they were injected with human chorionic gonadotropin. The numbers of mature follicles, retrieved oocytes, degenerate oocytes, and fertilized embryos were compared to their previous data without melatonin (the control cycle). Results: Intrafollicular melatonin concentrations were significantly increased, and intrafollicular lipid peroxide concentrations showed a tendency towards lower levels in the 3 mg melatonin treatment cycles compared with the control cycles. The number of degenerate oocytes was significantly reduced, and the number of fertilized embryos showed a tendency towards an increase in the 3 mg cycle compared to the control cycle. Three women succeeded in falling pregnant. Conclusion: Melatonin is likely to become the drug of choice for improving oocyte quality in women who cannot fall pregnant because of poor quality oocytes. (Reprod Med Biol 2003; 2: 139-144). PMID- 29699178 TI - Accuracy of sperm velocity assessment using the Sperm Quality Analyzer V. AB - Aim: The correct diagnosis of the functional capacity of human sperm is limited. The Sperm Quality Analyzer (SQA) with the visualization system (SQA V, Medical Electronic System, Hatavorzo, Israel), an upgraded version of SQA, was recently developed to provide a rapid and low-cost quantitative evaluation of sperm quality as well as sperm velocity assessment. The aim of the present study was to evaluate whether the SQA V's new parameters correlate with computer-aided sperm analysis (CASA) estimates. Methods: Semen quality analysis of 66 fresh samples was determined using SQA V and CASA. Results: There were significant correlations of total sperm concentration (P < 0.001), sperm motility (P = 0.145), and percentage of progressive motile sperm (P = 0.001), between the SQA V variables and the CASA estimates. The sperm velocity assessed by SQA V was significantly correlated with some of the CASA estimates, including sperm motility (P = 0.001), the percentage of progressively motile sperm (P < 0.001), straight-line velocity (P < 0.001), curvilinear velocity (P < 0.001) and average path velocity (P < 0.001). However, it did not correlate with amplitude of lateral head displacement, beat cross frequency, straightness, or linearity, assessed by CASA. Conclusion: Assessment of sperm motility has been shown as one of the important factors to predict the functional capacity of human sperm. On the basis of the present study, SQA V is considered useful for screening sperm quality in the management of male infertility. (Reprod Med Biol 2003; 2: 151 157). PMID- 29699179 TI - Relationship between follicular fluid hormone levels, embryo quality, and maternal age during in vitro fertilization after the short or long protocol with a gonadotropin releasing hormone agonist. AB - Purpose: To examine the relationship between embryo quality and follicular fluid hormonal level in short and long protocol gonadotrophin releasing hormone agonist treatment cycles. Methods: A total of 90 patients had non-polycystic ovary syndrome (non-PCOS) and 10 had PCOS. A total of 100 subjects underwent in vitro fertilization (IVF). Thirty-six subjects underwent conventional IVF and 64 subjects underwent intracytoplasmic sperm injection (ICSI). The dominant follicles were initially retrieved and a hormonal assay was done. A total of 32 patients underwent a short protocol and 66 patients were treated with the long protocol. Estradiol (E2), progesterone (P4), total testosterone (TTE) and androstenedione (ASG) levels in follicular fluid (FF) were compared in the two treatment groups (short and long protocol), in regard to maternal age and oocyte/embryo quality. Results: The retrieval FF volume was not significantly different between the PCOS and non-PCOS patients; however, P4 was significantly lower with PCOS (P < 0.01). Analysis of four different hormone levels was not significantly different between the short and long protocol groups. No significant relationship was found between four hormone levels in regard to oocyte morphology and embryo quality. The levels of P4 of younger women was significantly lower than that of older women; furthermore, a significantly higher TTE and ASG were found in the younger women. Progesterone was found to statistically significantly increase with FF volume. Conclusion: Follicular fluid P4 from the younger group was significantly lower, and TTE and ASG was significantly higher when compared to the older group. Analysis of four different hormone levels revealed no significant difference between the short and long protocol groups. No significant relationship was found between four hormone levels, oocyte morphology, and embryo quality. (Reprod Med Biol 2003; 2: 165 169). PMID- 29699180 TI - Correlations between steroids concentration in follicular fluid, pronuclear morphology and embryo qualities in in vitro fertilization. AB - Background: Several parameters of early embryo development are known as predictors of implantation success. Recently, zygote or embryo morphological assessments are thought to be a major method of selection in embryo transfer. We expected that the concentrations of the steroids in follicular fluid (FF) were associated with oocyte maturation and embryo quality. In the present paper, we evaluated the relationship of several parameters. Methods: We investigated 105 samples of FF from 22 subjects by in vitro fertilization (IVF). We evaluated the correlations between the FF concentrations of estradiol (E2) and progesterone (P4), the diameter of the ovarian follicles, fertilization, and zygote assessment based on pronuclear morphology and day 3 embryo qualities (i.e. number of blastomeres and fragmentation rate). Results: There was a positive correlation between the E2 concentrations in FF and serum (r = 0.273, P < 0.01), but there was no correlation between follicular diameter and the FF concentration of each steroid. The concentration of E2 in FF containing fertilized oocytes was not significantly different from that in FF containing unfertilized oocytes. At the pronuclear stage, the concentration of either steroid in FF did not differ among the morphological groups. The concentration of P4 in FF was significantly lower in the group in which pronuclei were detected at 20 h after insemination than in the group in which pronuclei were not detected. The concentration of E2 in FF was significantly related to the number of blastomeres (r = 0.271, P < 0.05) and furthermore, was significantly higher in FF from which morphologically good embryos were obtained at day 3 (P < 0.05). Conclusions: The FF concentrations of the steroids did not affect the pronuclear pattern, but P4 production may play a role in reducing the potential of the oocyte to develop pronuclei and the concentration of E2 may predict the cleavage capability of the oocyte. (Reprod Med Biol 2003; 2: 171-176). PMID- 29699181 TI - Surgery results using different uterine wall incision directions in laparoscopic myomectomy of the intramural myoma. AB - Objective: To study clinical outcomes for different uterine wall incision directions, comparing vertical incision and transverse incision in laparoscopic myomectomy of the intramural myoma. Methods: Laparoscopic myomectomies were performed on 50 women with intramural myomas. Using a table of random numbers, they were randomly divided into a vertical incision group (25 women) and a transverse incision group (25 women) according to the direction of incisions in the uterine wall. The numbers of enucleated myoma, operation duration, amount of bleeding, and numbers of sutures were compared. The Mann-Whitney U-test was used for analysis. Results: For the transverse incision group, the amount of bleeding (137.6 +/- 88.1 mL) was a significantly lower value (P = 0.0426) than for the vertical incision group (235.8 +/- 169.4 mL). In addition, in cases where the maximum myoma nucleus diameter was 7 cm or larger, operation duration (129.0 +/- 32.5 min) and amount of bleeding (158.9 +/- 87.1 mL) showed significantly lower values (P = 0.0067 and P = 0.0002, respectively) for the transverse incision group than did operation duration (362.3 +/- 147.3 min) and amount of bleeding (362.3 +/- 147.3 mL) for the vertical incision group. Conclusion: Transverse incision of the uterine wall is useful to reduce the amount of bleeding in the laparoscopic myomectomy of the intramural myoma. Transverse incision also shortens operation duration in cases where the myoma nuclei are large. (Reprod Med Biol 2004; 3: 33-37). PMID- 29699182 TI - A successful pregnancy and delivery outcome for a 46-year-old woman following in vitro fertilization. AB - Background: Decreased conception rate with advanced maternal age has been well demonstrated. Although this decline becomes apparent at 35 years of age, and accelerates rapidly in women over 40 years of age, we are able to report pregnancy and delivery case for a 46-year-old with in vitro fertilization and embryo transfer (IVF-ET). We report a rare case of a successful delivery of a healthy infant by a 46-year-old women following IVF-ET. Methods: She tried three times with conventional IVF and two times cryopreserved embryo transfer, but she failed to conceive. Low-dose dexamethasone was co-treated the last two times with IVF on the first day of the beginning menstrual cycle daily and continued until retrieval day. We obtained good quality embryos and she became pregnant at the sixth time of IVF which was carried out at the morula and early blastocyst stage. Result: She finally conceived following co-treatment with low-dose dexamethasone. She delivered vaginally a single male infant with no congenital abnormalities at 40 weeks' (3416 g; 46, XY). Conclusion: We have demonstrated a successful pregnancy due to obtaining quality embryos using co-treatment low-dose dexamethasone and delivery outcome for a 46-year-old woman using IVF. (Reprod Med Biol 2004; 3: 39-42). PMID- 29699183 TI - Laminin and fibronectin concentrations of the follicular fluid correlate with granulosa cell luteinization and oocyte quality. AB - Background and Aims: Progesterone production of human cultured luteinizing granulosa cells was reported to be modified by extracellular matrix, suggesting that extracellular matrix regulates luteinization of granulosa cells after ovulation. In the present study, the relationship among laminin, fibronectin, progesterone and estradiol in follicular fluid along with oocyte quality was analyzed to estimate the physiological role of extracellular matrix in follicular luteinization and oocyte quality during ovulation. Methods and Results: Follicular fluid was collected at oocyte pick-up from the patients undergoing in vitro fertilization treatment and intracytoplasmic sperm injection. The concentrations of laminin, fibronectin, progesterone and estradiol in the follicular fluid were measured by enzyme immunoassay and radioimmunoassay. The morphology of oocytes were also assessed during the procedure of intracytoplasmic sperm injection and was classified into normal and abnormal groups. The fibronectin concentration was higher in the normal ooplasm group than in the abnormal group, but it did not correlate with estradiol or progesterone concentration. However, laminin concentration significantly correlated with that of progesterone, but not with cytoplasm morphology of oocytes. There was no difference in estradiol or progesterone concentration between the normal and abnormal groups. Conclusion: These findings suggest that extracellular matrix plays some roles in regulating human granulosa cell luteinization and oocyte quality during ovulation. (Reprod Med Biol 2004; 3: 43-49). PMID- 29699184 TI - High-risk group and high-risk life stage: Key issues in adverse effects of environmental agents on human health. AB - Our previous studies analyzing umbilical cords show that human fetuses are exposed to multiple environmental agents. Fetuses are at a high-risk life stage in human life and our results revealed that there is a presence of potential high risk group in Japanese babies. It suggests the necessity to develop a new method of evaluating health risk factors to human fetuses of the possible long-term effects caused by prenatal exposure to multiple environmental agents. Its main goal is to find the potential high-risk group in the next generation and to prevent the long-term effects caused by fetal exposure to multiple chemicals. Recently, we introduced our attempts to apply toxicogenomic analysis of gene expressions in umbilical cords using DNA microarray to the future health risk assessment. Our trial showed that it could be used as an effective newborn screening to detect potential high-risk groups focusing on the exposure level and the susceptibility. To improve future children's health, it is necessary to develop a risk reduction method, in addition to the establishment of the new risk assessment, to avoid multiple chemical exposures and to reduce the concentration level of persistent chemicals in the human body. Worldwide cooperation is urgently required focusing on the high-risk group and high-risk life stage. (Reprod Med Biol 2004; 3: 51-58). PMID- 29699185 TI - Reproductive toxicity of 2,5-hexanedione in male rats. AB - Background, Aims and Method: 2,5-Hexanedione is an industrial solvent which causes peripheral neuropathy. In the current study, the effect of 2,5-hexanedione on testicular histology of adult rats as well as sperm concentration, motility, and morphology were studied by administering 100 mg, 200 mg, 400 mg/kg per day for 12 weeks. Results: No sperm motility was observed in the 200 mg and 400 mg/kg per day treatment groups and significantly reduced motility was observed in the 100 mg/kg per day group. The morphology were also significantly reduced in the 200 mg and 400 mg/kg per day groups compared to the control group, but the sperm concentration was significantly reduced only in the 400 mg/kg per day group. Histological examination of the testes in the 400 mg/kg per day group revealed that two-thirds of the testes had Sertoli cell only syndrome, whereas in the 200 mg/kg per day group half of the testes showed maturation arrest and sperm as well as spermatids were observed in 83% of the testes. Conclusions: In conclusion, we have shown that 2,5-hexanedione severely affected sperm motility even at low doses, whereas high doses adversely affected all the sperm parameters as well as causing testicular injury. (Reprod Med Biol 2004; 3: 59-62). PMID- 29699186 TI - Physical and mental development of children after in vitro fertilization and embryo transfer. AB - Objective: To evaluate the physical and mental development of children after in vitro fertilization (IVF) and frozen embryo transfer (FET). Methods: Between July 1995 and November 2003, 506 patients delivered 658 babies after IVF and ET treatment at our clinic (intracytoplasmic sperm injection (ICSI), 418; conventional IVF, (C-IVF) 125; FET, 115). A survey of the physical and mental developmental of the children was conducted by mailing questionnaires to parents. Comparisons were made between three treatment procedures, and development of singleton, twin and triplet delivery. Results: The response rate was 73.4% (483/658) for 324 children born after ICSI, 78 born after C-IVF, and 81 born after FET. The height and weight of assisted reproductive technology (ART) children at birth were significantly lower than that of naturally conceived babies (ART children: natural delivery; 46.8 cm, 49.0 cm and 2524 g, 3040 g, respectively). However, there was no significant difference between the singletons alone and naturally conceived children irrespective of the ART method. In addition, mental development was the same between singletons and naturally conceived children. The ART group tended to delay body development such as 'holding their head up', 'sitting up', 'crawl' to moving growth in multiple births. Conclusion: The physical and mental development of twins or triplets was significantly more delayed than that of naturally conceived babies, but had improved to a similar extent of the singletons after the age of 6 months. (Reprod Med Biol 2004; 3: 63-67). PMID- 29699187 TI - Pregnancy complicated by adenomyosis resulted in miscarriage in three cases of in vitro fertilization-embryo transfer. AB - Three women with adenomyosis conceived by in vitro fertilization-embryo transfer (IVF-ET), but miscarried in the second trimester. The uterus in each case was inflamed post-partum and one patient underwent total abdominal hysterectomy as treatment for the severe inflammation. Although the mechanism of the miscarriages is unclear, these cases strongly suggest that it is related to the inflammation of the myometrium associated with adenomyosis, and that such pregnancies have a high risk of not continuing to term. Preventing inflammation could result in a live birth. (Reprod Med Biol 2004; 3: 95-98). PMID- 29699188 TI - Randomized study comparing day 2 versus day 3 elective transfer of two good quality embryos. AB - Objective: The number of embryos transferred is very important to avoid multiple pregnancies without compromising pregnancy rates in in vitro fertilization (IVF)/intracytoplasmic sperm injection (ICSI)-embryo transfer (ET). We established criteria for the elective transfer of two embryos (age <40, first treatment cycle, good-quality embryos >=3) to avoid high-order multiple pregnancies, and reported their usefulness. In the current study, we compared the clinical outcome of day 2 versus day 3 elective transfer of two good-quality embryos, in order to investigate the day of preferential transfer. Methods: A total of 228 cycles were treated with IVF/ICSI-ET from August 1999 to August 2002. From this total, 114 patients who were less than 40 years old and also had a first treatment cycle were enrolled in the present study (50.0%). The elective transfer of two good-quality embryos was carried out in 36 cycles (31.6%). Patients were randomized for transfer on either day 2 or day 3 after oocyte retrieval. Results: The pregnancy rate of women who received two good-quality embryos was 44.4% (16 out of 36). The multiple pregnancy rate was 12.5% (two out of 16) and all pregnancies outcomes were twins. There were no significant differences between day 2 and day 3 ET for the following criteria: the number of cycles (24, 12); age (32.8 +/- 3.4 years, 32.5 +/- 2.7 years); number of oocytes retrieved (10.0 +/- 3.3, 9.0 +/- 6.0); number of embryos developed (7.6 +/- 3.5, 6.9 +/- 3.7); and number of good-quality embryos cryopreserved (3.5 +/- 2.7, 3.6 +/- 2.1). Higher pregnancy and implantation rates were obtained in day 3 ET than day 2 ET (37.5 and 20.8% in day 2 ET vs 58.3 and 33.3% in day 3 ET); however, there were no significant differences. Conclusion: Day 3 ET appears to be preferable to achieve more viable embryos than day 2 ET. (Reprod Med Biol 2004; 3: 99-104). PMID- 29699189 TI - Current problems of food intake in young women in Japan: Their influence on female reproductive function. AB - Accumulating evidence suggests that food customs are associated with quality of life in women of the reproductive age. In Japan, dietary limitation for cosmetic purposes, skipping food intake, intake of processed foods and the shift from Japanese to Westernized style food have increased among young women. These changes in food habits can cause inadequate intake of calories, micronutrients, unsaturated fat, phytestrogens and fiber as well as increasing environmental toxins. Furthermore, these food habits increase risk as a result of intake of food additives, anti-oxidants, processing agents and sweeteners, which have been demonstrated to be harmful to human health. These factors are speculated to not only influence the present lifestyle, but also to induce gynecologic disorders such as dysmenorrhea and irregular menstruation. The adverse effects of these dietary habits on pregnancy outcome and carcinogenesis of breast and ovarian cancers have also been demonstrated. In addition, latent development of organic diseases such as endometriosis, which are accompanied by dysmenorrhea, is a concern under the current nutritional environment in young women. Thus, it is an urgent issue to evaluate the present situation of eating habits in young Japanese women and estimate the influence of these habits on the quality of life including reproductive functions. (Reprod Med Biol 2004; 3: 107-114). PMID- 29699191 TI - Effect of oocyte transportation time on the clinical results of transport in vitro fertilization/intracytoplasmic sperm injection-embryo transfer. AB - Background and Aims: In transport assisted reproductive technology (ART), the time taken to transport oocytes to the main center differs greatly among the satellite facilities and may influence the clinical results. Methods: For the conventional in vitro fertilization (IVF) groups in which oocytes were collected at the satellite facilities and transported to the main ART center for insemination and embryo transfer, there were 29 cycles in 27 patients with a transportation time within 60 min (short time transport IVF (ST-IVF)), 78 cycles in 62 patients with a time between 60 and 120 min (long time transport IVF (LT IVF)), and there were 141 cycles in 110 patients at the main ART center (center IVF (C-IVF)). For the intracytoplasmic sperm injection (ICSI) group, there were 65 ST-ICSI cycles in 42 patients, 146 LT-ICSI cycles in 97 patients, and 326 cycles in 238 patients at the main ART center (C-ICSI). Results: The morphologically favorable embryo rate was lower in the ST-ICSI group (33.8%, P < 0.05) than in the C-ICSI group (38.1%), and the morphologically poor embryo rate in the LT-IVF group (38.6%, P < 0.0001) was higher than in the C-IVF group (26.7%). The rate of embryo transfers resulting in pregnancies was 16.7% in the ST-ICSI group (P < 0.01) and 17.3% in the LT-ICSI group (P < 0.001), both less than that of 35.2% for the C-ICSI group. Conclusions: To improve both the morphologically favorable embryo rate and the pregnancy rate in transport ART, it is essential to improve the total quality control at the satellite facilities. (Reprod Med Biol 2004; 3: 123-131). PMID- 29699190 TI - Epigenetic alteration by the chemical substances, food and environmental factors. AB - Epigenetic alteration is one of the most important mechanisms for gene regulation; however, it is not changes in gene function with DNA sequence changes. Recently, epigenetics were studied in the wide ranging fields of research. In the present review, we introduce recent studies on epigenetic alteration, especially DNA methylation, by chemical exposure, food intake and environmental factors. In addition, we introduced our results on alteration of DNA methylation by transient exposure of neonatal mice to diethylstilbestrol. As these data suggest that chemical exposure, food intake and environmental factors are responsible for epigenetic alteration, we insist the necessity of the new risk assessment focusing on epigenetic alteration. (Reprod Med Biol 2004; 3: 115 121). PMID- 29699193 TI - Histological analysis of the 'critical point' in follicular development in mice. AB - Aim: To histologically examine ovarian follicular development in cycling mice. Methods: Mice were observed at 13:00 h at each stage of the estrous cycle. The ovaries were cut into complete serial sections. All sections were observed, and the size of each follicle was measured by using a micrometer. Follicles with advanced atresia were excluded and non-atretic healthy follicles were differentiated from atretic follicles. Results: The measurement of the number of follicles in each stage of the estrous cycle, with reference to their size, showed that in each mouse, the number of small healthy follicles (100-249 um in average diameter) was approximately 100 for all stages and the number of medium sized healthy follicles (250-349 um) was close to 20 in only the metestrus and diestrus stages. In contrast, large healthy follicles (>=350 um) showed marked changes throughout the estrous stage. Many healthy large follicles were observed in the proestrus stage, but they disappeared in the estrus stage, which suggests that they have ovulated. This was supported by observations of oocytes resuming meiosis in large healthy follicles. Conclusion: As follicular atresia was frequently observed in follicles of 250-399 um diameter, this size range may be a 'critical point' for atresia. The results suggest that there is a 'critical point' in follicular development, and that only follicles that pass this point will ovulate, while those that do not will become atretic follicles. (Reprod Medical Biol 2004; 3: 141-145). PMID- 29699192 TI - Identification of 66 kDa phosphoprotein associated with motility initiation of hamster spermatozoa. AB - Background and Aims: Sperm motility is regulated by protein phosphorylation. The 66 kDa protein obtained from hamster sperm flagella was phosphorylated at serine residues associated with the motility initiation. In order to understand the regulatory mechanism of sperm motility, the 66 kDa protein was identified in the present study. Methods: The 66 kDa protein was purified by 2-D gel electrophoresis and identified by matrix-assisted laser desorption ionization mass spectrometry, liquid chromatography-tandem mass spectrometry and peptide sequencer. Results: The 66 kDa protein was tubulin beta chain. Conclusion: The 66 kDa protein is one of the tubulin beta chain isoforms and phosphorylated in relation to the motility initiation. (Reprod Med Biol 2004; 3: 133-139). PMID- 29699194 TI - Chromosome analysis of human spermatozoa with morphologically abnormal heads by injection into mouse oocytes. AB - Aim: The risk of chromosome aberrations in human spermatozoa with an abnormal head shape was examined using intracytoplasmic sperm injection into mouse oocytes. Methods: Human spermatozoa with small, large, pointed or elongated head shape from a fertile donor were injected into mouse oocytes, and the hybrid oocytes were cytogenetically analyzed at the first cleavage metaphase. Results: The oocyte activation rate was significantly lower in hybrid oocytes injected with pointed (90.2%) or elongated spermatozoa (94.1%) than with normal spermatozoa (99.0%). However, the frequency of intracytoplasmic sperm injection oocytes at the first cleavage metaphase did not differ among the sperm groups (71.8-77.2%). No difference in the incidences of aneuploidy (1.8, 2.6 and 1.4%), diploidy (0, 0 and 0%) and structural chromosome aberrations (6.3, 10.4 and 8.6%) was observed between small or pointed spermatozoa and normal spermatozoa. Only a small population of large spermatozoa (3.7%) was diploidy. Elongated spermatozoa showed significantly frequent structural chromosome aberrations (33.3%) as compared with normal spermatozoa. Conclusion: The results reveal some interesting details of the mechanism of sperm nuclear condensation: small sperm size is attributed to the problem of nuclear condensation, not a decrease in chromosomes. Diploidy prevents sperm nucleus from condensing, resulting in a large sperm head. Elongation of sperm nucleus causes DNA lesions leading to structural chromosome aberrations. (Reprod Med Biol 2004; 3: 147-152). PMID- 29699195 TI - Effect of repeated administration of clomiphene citrate at two different times on the endometrium in patients undergoing intrauterine insemination. AB - Background, Aims and Methods: Clomiphene citrate (CC) has been widely used for induction of ovulation; however, despite the high rate of ovulation, the pregnancy rate is only 30%. The anti-estrogenic effect of CC on the endometrium is one explanation for this finding. It is well known that repeated administration of CC enhances its anti-estrogenic effect. To overcome this adverse affect, a number of techniques have been used. One technique is the early administration of CC, in an attempt to decrease the anti-estrogenic effects of CC on the endometrium. The aim of the present study was to retrospectively evaluate if repeated administration of CC at varying times may affect the endometrium during preovulatory period; pregnancy rates were compiled for patients with unexplained infertility undergoing intrauterine insemination (IUI). The patients were divided into four groups based on the number of repeat administrations and the time of CC administration. Results: The endometrial thickness at the day of human chorionic gonadotropin administration was greater in early administration within three consecutive CC cycles than the others. Conclusion: When the endometrium is thin during classical administration of CC, it is worth attempting the early administration of CC in the CC/IUI treatment for patients with unexplained infertility. However, this effect disappeared over the duration of the three consecutive CC cycles. (Reprod Med Biol 2004; 3: 153-157). PMID- 29699196 TI - Costs of maternal and neonatal medical care for triplet and quadruplet pregnancies in Japan. AB - Aims: It is well documented that maternal morbidity and neonatal morbidity and mortality increase alike in high-order multiple (HOM) births. There have, however, been few reports concerning the costs of maternal and neonatal medical care associated with HOM births. This is the first such report on the situation in Japan. Materials and methods: All triplet and quadruplet pregnancies managed at this institution from before 16 weeks' gestation, and delivered at no earlier than 22 weeks' gestation, between 1997 and 2002 were included. Prophylactic cervical ligature, hospitalization to prevent premature labor from 23 weeks' gestation until delivery, and delivery by cesarean section, were all routine for HOM pregnancies. All women with singleton and twin pregnancies, who underwent in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) and also delivered their babies at no earlier than 22 weeks' gestation at this institution, between 1997 and 2002, were also examined as controls. Prophylactic cervical ligature, preventive hospitalization, and cesarean section were not routine in the control group. Results: The average gestational ages at delivery in singleton (n = 58), twin (n = 21), triplet (n = 14) and quadruplet (n = 1) pregnancies, were 39.4, 35.6, 31.9 and 25.1 weeks, respectively (P < 0.001 by anova). Birthweights were 2886 +/- 425 g, 2117 +/- 623 g, 1430 +/- 373 g, and 633 +/- 77 g (mean +/- SD), respectively (P < 0.001). The average inpatient medical care cost for mother and child(ren), from maternal admissions after 12 weeks' gestation to the discharge of all family members from hospital, was Y703 279 yen (~US$5861), Y4 903 270 (~US$40 861), Y11 810 327 (~US$98 419), and Y44 961 000 (~US$374 675), respectively (P < 0.001). Conclusion: The present study outlined the high costs of medical care for HOM pregnancies. Not only from a medical viewpoint, but also from the viewpoint of medical costs, it is important to avoid HOM pregnancies as a result of infertility treatment. (Reprod Med Biol 2004; 3: 159-164). PMID- 29699198 TI - Follicular development and induction of ovulation with human chorionic gonadotropin in the pregnant rat. AB - Aims: The number of ovarian follicles and ovulations after human chorionic gonadotrophin (hCG) was given at various doses during pregnancy were investigated in rats. Methods: On designated days of pregnancy, rats were injected with hCG at 13.00 hours and the number of ova were observed. The same rats were then killed at 13.00 hours the next day. The ovaries were cut into complete sections. All sections were observed and the size of each follicle was measured. Results: The number of large (>=550 um), healthy, non-atretic follicles (Graafian follicles) ranged from 1.5 to 11 during pregnancy. Ovulation was induced in rats at any stage of pregnancy with intramuscular injections of 40 or 50 IU hCG, but 10 IU had no effect and 20 or 30 IU had an incomplete effect. The number of ovulations after 40 IU hCG was 2-12 and there was not a significant difference between the number of ovulations and the number of large, healthy follicles at any point in the pregnancy. Conclusion: Graafian follicles existed through the pregnancy. Results suggest that although hCG induces ovulation in large ovarian follicles (>=550 um) during pregnancy, the responsiveness to hCG is lower than in recurrent estrus-stage rats. (Reprod Med Biol 2004; 3: 201-204). PMID- 29699199 TI - Comparison of sperm counts in two groups of men presenting for infertility investigations 20 years apart. AB - Aims: To compare sperm counts for two groups of men who had presented for infertility investigations approximately 20 years apart. Methods: The study compared results for 309 men tested between 1977 and 1981 with those of 559 men tested between 1997 and 1998 using identical methodology. In order to approximate the normal population, only those men with counts above 5 million/mL were included in the final analysis. Bias, due to repeated testing after an initial abnormal result, was minimized by including only the patient's first test results. In addition, to allow for time-dependent changes in the requirements for semen samples, results were included only if a complete sample was produced by masturbation after 3-5 days abstinence. Results: There was a small, but statistically significant drop in ejaculate volume (3.9-3.6 mL, P = 0.015) and a significant increase in the patient's mean age (32.18 vs 35.08, P < 0.001). Both groups had median abstinence of 3 days and no difference in sperm counts with a mean (median) count for the early group of 87.9 (75) versus 92.0 (76) for the recent group (P > 0.80). The significant drop in ejaculate volume was not reflected in a difference (P = 0.45) in total sperm numbers in the ejaculate with 320.7 (255) versus 313.1 (234). Conclusion: This study found no evidence of a decrease in sperm counts or total sperm output in men (excluding those with severe oligospermia) presenting for infertility investigations in Melbourne, Australia, over the last two decades of the twentieth century. (Reprod Med Biol 2004; 3: 211-216). PMID- 29699200 TI - Successful pregnancy following conservative treatment of massive ascites associated with acute Chlamydia trachomatis peritonitis. AB - It is well known that Chlamydia trachomatis causes acute and chronic pelvic inflammatory disease including salpingitis. We describe a case of successful pregnancy following conservative treatment of massive ascites associated with acute Chlamydia trachomatis peritonitis. In this present case, we conservatively treated a woman with acute chlamydial salpingitis accompanied with marked ascites and an adnexal mass that simulated a malignant neoplasm. Elevated CA125 and CA19 9 also suggested a malignancy at the time of diagnosis, however following treatment they decreased to below the cut-off value, and were useful in identifying the efficacy of medical treatment. The patient subsequently became pregnant after infertility treatment and underwent a normal vaginal delivery. We conclude that the possibility of Chlamydia trachomatis peritonitis should be considered when a patient presents with ascites and an adnexal mass in sexually active women. (Reprod Med Biol 2004; 3: 217-221). PMID- 29699201 TI - Changes in the amount of cytoplasmic inclusions in mouse oocytes during meiotic maturation in vivo and in vitro. AB - Background and aims: The changes in cytoplasmic inclusions during meiotic maturation have only been examined in porcine oocytes. In the present study, the amount and the number of cytoplasmic inclusions (glycogen granules, lipid droplets and fibrous structures) were examined in mouse oocytes in the process of in vivo and in vitro maturation. For those inclusions that changed in amount during maturation, we also examined their content in oocytes treated with olomoucine, an inhibitor of cyclin-dependent kinase, in order to clarify the relationship between nuclear maturation and changes in the inclusions. Methods: Nuclear maturation in the oocytes cultured for various periods and those collected from antral follicles and oviducts was examined after staining with aceto-orcein. For the demonstration of glycogen granules and lipid droplets, oocytes were stained with periodic acid-Schiff or Sudan IV. Fibrous structures in the oocytes were observed under an electron microscope. Results: The amount of glycogen granules, Sudanophilic lipid droplets and fibrous structures did not change in the oocytes matured in vivo and in vitro, whereas the number of the lipid droplets increased during maturation. In the oocytes treated with olomoucine, the resumption of nuclear maturation was inhibited, whereas the increase in the number of Sudanophilic lipid droplets was not inhibited. Conclusion: Present findings suggest that the increase in the number of Sudanophilic lipid droplets occurs in the cytoplasm of mouse oocytes during maturation, regardless of in vivo or in vitro maturation, and that such the change in the inclusion is not related to nuclear maturation. (Reprod Med Biol 2004; 3: 231-236). PMID- 29699197 TI - Role of reactive oxygen species in gynecologic diseases. AB - Free radicals derived from molecular oxygen and nitrogen are highly reactive metabolites called reactive oxygen species (ROS). Cells continuously produce free radicals and ROS as part of the metabolic process. They are involved in the various functions of the reproductive system. Antioxidants are enzymes or compounds that scavenge and reduce the presence of free radicals. Normally, a balance exists between concentrations of reactive oxygen species and antioxidant scavenging systems. The disruption of the delicate balance between pro- and antioxidants results in oxidative stress. Oxidative stress has been implicated in embryo fragmentation, DNA damage, apoptosis and poor pregnancy outcome. It has also been implicated in a large number of gynecologic diseases, such as endometriosis, pre-eclampsia and maternal diabetes. The use of antioxidants may be beneficial in combating the harmful effects of oxidative stress in many of these diseases. The present review outlines the importance of these species in the pathology of various gynecologic diseases. (Reprod Med Biol 2004; 3: 177 - 199). PMID- 29699202 TI - The human transcript induced in spermatogenesis 50. AB - Background and Aims: Recently, a number of genes that are expressed specifically in the testis have been identified in rat and mouse. In 2002, 80 transcript induced in spermatogenesis (Tisp) genes with this specific expression were isolated in mice. In the human, however, the number of such genes isolated is much lower. The aim of this study therefore was the isolation of human genes specifically expressed in testis. Methods: We searched for human genome region with homology to the mouse Tisp gene family at the amino acid level using GenBank. The primers were made in human homologous regions, and polymerase chain reaction analysis was performed with templates using cDNA libraries of a range of human tissues. The cDNA specifically expressed in testis were isolated and detailed expression analysis was performed. Results: The 28 human TISP related genes were analyzed. Five of these genes were not expressed in testis and only three, TISP50, TISP15 and TISP43 related gene, were expressed specifically in testis. The cDNA of these three genes were isolated. Conclusion: Expression analysis demonstrated that there is some discrepancy between human and mouse for the TISP gene family. From expression patterns and amino acid sequences, it is suggested that the human TISP50, TISP15 and TISP43 related genes play some critical roles in spermatogenesis. (Reprod Med Biol 2004; 3: 237 - 243). PMID- 29699206 TI - Cardiovascular consequences of hormone therapy in postmenopausal women: Messages to clinicians. AB - Results from the recent randomized clinical trials indicating that hormone therapy (HT) does not provide cardiovascular protection, but potentially harm are in profound disagreement with the sound evidence from numerous observational and experimental studies. While the observational studies have mainly assessed symptomatic recently menopausal women, the randomized trials have studied symptomless elderly postmenopausal women with established coronary heart disease or various risk factors for cardiovascular disease. Therefore, the recent trials have only revealed that HT does not provide secondary cardiovascular benefits. Since primary cardiovascular benefits of HT are rational but not yet proven in clinical trials, new studies are in demand. Until more data from recently menopausal symptomatic women are available, we need to base our decisions on existing evidence and good clinical practice. Although the potential of HT to provide cardiovascular benefits is decreased by advancing age and time since menopause, this should not preclude the use of individualized HT in younger postmenopausal women. (Reprod Med Biol 2005; 4: 1- 6). PMID- 29699209 TI - New insights into possible factors contributing to male subfertility. AB - Male subfertility contributes significantly to fertility problems in couples. Although semen analysis may identify abnormalities in sperm numbers, morphology and/or motility that might contribute to subfertility, in other instances the semen parameters may appear to be normal, but the spermatozoa might be dysfunctional. A number of endogenous and exogenous factors have now been identified that can significantly affect sperm function in vitro and it is possible that they may have similar effects in vivo. Some endogenous factors maintain the spermatozoa in a non-fertilizing state, to avoid them 'burning out' and losing fertility before they reach an oocyte, while others stimulate spermatozoa to become fertile and then hold them in a state of readiness to fertilize. Exogenous environmental molecules, referred to as xenobiotics, have been shown to continuously stimulate spermatozoa so that they become fertile quickly, but then 'burn out'. Defects relating to the endogenous molecules could result in spermatozoa either never becoming fertile or becoming fertile too quickly and so losing fertilizing potential. By understanding the mechanisms involved in promoting sperm fertilizing ability, it may be possible to develop new therapeutic treatments to overcome such defects. (Reprod Med Biol 2005; 4: 45 53). PMID- 29699207 TI - Sperm function and assisted reproduction technology. AB - The evaluation of different functional sperm parameters has become a tool in andrological diagnosis. These assays determine the sperm's capability to fertilize an oocyte. It also appears that sperm functions and semen parameters are interrelated and interdependent. Therefore, the question arose whether a given laboratory test or a battery of tests can predict the outcome in in vitro fertilization (IVF). One-hundred and sixty-one patients who underwent an IVF treatment were selected from a database of 4178 patients who had been examined for male infertility 3 months before or after IVF. Sperm concentration, motility, acrosin activity, acrosome reaction, sperm morphology, maternal age, number of transferred embryos, embryo score, fertilization rate and pregnancy rate were determined. In addition, logistic regression models to describe fertilization rate and pregnancy were developed. All the parameters in the models were dichotomized and intra- and interindividual variability of the parameters were assessed. Although the sperm parameters showed good correlations with IVF when correlated separately, the only essential parameter in the multivariate model was morphology. The enormous intra- and interindividual variability of the values was striking. In conclusion, our data indicate that the andrological status at the end of the respective treatment does not necessarily represent the status at the time of IVF. Despite a relatively low correlation coefficient in the logistic regression model, it appears that among the parameters tested, the most reliable parameter to predict fertilization is normal sperm morphology. (Reprod Med Biol 2005; 4: 7-30). PMID- 29699208 TI - Reactive oxygen species in ovarian physiology. AB - Cells living under aerobic conditions always face oxygen paradox. Oxygen is necessary for cells to maintain their lives. However, reactive oxygen species such as superoxide radical ( ), hydroxyl radical (OH-) and hydrogen peroxide (H2O2) are generated from oxygen and damage cells. Oxidative stress occurs as a consequence of excessive production of reactive oxygen species and impaired antioxidant defense systems. Antioxidant enzymes include: superoxide dismutase (SOD), which is a specific enzyme to scavenge superoxide radicals; copper-zinc SOD, located in the cytosol; and manganese SOD, located in the mitochondria. Both types of SOD belong to the first enzymatic step to scavenge superoxide radicals. It has been reported that a number of local factors such as cytokines, growth factors and eicosanoids are involved in the regulation of ovarian function, in addition to gonadotropins and ovarian steroid hormones. Since reactive oxygen species are generated and SOD is expressed in the ovary, there is a possibility that reactive oxygen species and SOD work as local regulators of ovarian function. The present review reports that reactive oxygen species and their scavenging systems play important roles in several processes of reproductive physiology, including follicular development, oocyte maturation, ovulation, corpus luteum function and follicular atresia. (Reprod Med Biol 2005; 4: 31- 45). PMID- 29699210 TI - Five cases of dizygotic triplet pregnancy following assisted reproductive techniques. AB - Of 816 patients who became clinically pregnant by assisted reproductive techniques between September 2000 and August 2004, we experienced 10 cases (1.2%) of monozygotic twinning, and in five of these 10 cases, implantation of another embryo resulted in dizygotic triplets. Here, we report these five cases of dizygotic triplets. Fresh embryo transfer was performed in all five cases. Intracytoplasmic sperm injection or assisted hatching was not carried out in these cases. Blastocyst transfer was performed in three cases. Three embryos were transferred in case 1 (40-year-old female). While only two embryos were transferred in the other four cases so as to avoid triplet pregnancy, triplet pregnancies were confirmed. Triplet pregnancy was maintained in three cases, but in the other two cases, monochorionic twinning resulted in miscarriage during the first trimester. For the three patients who delivered the triplets, while the postnatal growth has been normal for all nine babies, the mothers were hospitalized for a long period of time, and an emergency cesarean section was performed on two patients. Because triplet pregnancy could not be completely prevented even when only two embryos were transferred, physicians should be sure to obtain informed consent in similar cases. (Reprod Med Biol 2005; 4: 59-64). PMID- 29699211 TI - An experimental trial to establish risk communication as a tool to decrease the risk by exposure to multiple chemicals for the future generations. AB - Background: Recently, it has become clear that fetuses are exposed to multiple chemicals and environmental contaminants. However, it has been reported that allergies among young children have been increasing rapidly in the last few decades, and some congenital anomalies are also increasing. There is no evidence to connect these facts directly, however if adverse health effects are caused by environmental reasons, it could be prevented by early education or risk communication. Methods: The authors gave lectures to students at a high school and universities, and carried out a questionnaire survey before and after the lectures to see the change of the students' knowledge, attitude and behavior. The total number of high-school students and university students was 47 and 605, respectively. Results: It became clear that all the levels of knowledge, attitude and behavior were elevated, and they were more elevated among high school students than university students. It was suggested that risk communication at a younger age is important to elevate people's attention and motivate them, and eventually prevent their future health risk from environmental contaminants. Conclusion: Risk communication at a young age would be more effective in increasing students' knowledge, attitude and behavior. (Reprod Med Biol 2005; 4: 65-70). PMID- 29699212 TI - Body fat distribution and leptin correlation in women with polycystic ovary syndrome: Endocrine and biochemical evaluation in south Indian population. AB - Aims: Obesity is associated with the increased prevalence of infertility and is also an independent risk factor in women with polycystic ovary syndrome (PCOS). The aim of this study was to examine the extent to which the ob gene product, leptin, alone or in combination with other metabolic and endocrinal parameters, may be correlated to infertility with the incidence of PCOS. Methods: Serum leptin levels were measured in both PCOS and non-PCOS subjects of the following categories, such as thin, overweight, obese and morbidly obese, and compared with normal weight women. Female infertility is associated with body mass index, percentage of body fat, body fat distribution, and other biochemical and endocrinal parameters parameters. Results: Women with PCOS and normally menstruating control women were analyzed by univariate analysis for body fat distribution. Serum leptin was positively correlated with body mass index, percentage of body fat, serum levels of dehydroepiandrosterone sulfate, testosterone, free testosterone, luteinizing hormone and prolactin. Serum leptin was inversely correlated with serum sex hormone-binding globulin concentration and androstenedione. Conclusions: We report, for the first time in the Indian population, that leptin levels are different in thin and morbidly obese PCOS patients than in regularly menstruating normal weight subjects, and leptin could be a novel, independent risk factor for PCOS. (Reprod Med Biol 2005; 4: 71-78). PMID- 29699213 TI - Ovarian follicular development in the unilateral ovariectomized rat. AB - Background and Aims: Following unilateral ovariectomy, the contralateral ovary underwent hypertrophy and the number of ovulations remained unchanged. The aim of the present study was to elucidate the mechanism, which occurred by this compensation, through examination of ovarian follicular development in operated rats. Methods: Rats were examined 1-8 weeks post unilateral operation. The ovaries were serially sectioned. All sections were examined and the size of each follicle was measured. Results: Large follicles soon recovered after surgery, but it took 5 weeks for small and medium-sized follicles to recover. The rate of atresia at the 'critical point' was 31.1% in unilateral ovariectomized animals and 73.9% in the sham-operated rats. Conclusions: These findings showed that in operated rats, the recovery of the number of follicles varied depending on the size of the follicle. Compared with the control animals, approximately twice as many large healthy follicles were saved from atresia at the 'critical point', producing a compensatory increase in the ovulation number (P < 0.01). (Reprod Med Biol 2005; 4: 89-93). PMID- 29699214 TI - Matrix remodeling and endometriosis. AB - The physiological changes in endometriosis involving multiple steps of matrix remodeling include abnormal tissue growth, invasion, and adhesion formation. Endometriosis-associated abnormal matrix remodeling is affected by several molecular factors including proteolytic enzymes and their inhibitors, which mediate tissue turnover throughout the reproductive tract to maintain the integrity of the endometrium, and ovarian steroids, which normally regulate reconstruction and breakdown of endometrium in the menstrual cycle. In addition, various growth factors, such as platelet-derived growth factor, transform growth factor beta, and epidermal growth factor, direct modulation of growth, activation, and chemotaxis which may facilitate endometrial cell adhesion onto the peritoneal mesothelium during the development of endometriosis. Furthermore, cell adhesion molecules are believed to be critically involved in most cellular level processes including cellular differentiation, motility, and attachment with the extracellular matrix. The present review focuses on the abnormal matrix remodeling process and its possible regulatory mechanism in association with endometriosis development. As a greater understanding of the cause of endometriosis is achieved, better treatment of the disease and its prevention become possible. (Reprod Med Biol 2005; 4: 93-99). PMID- 29699215 TI - Activation of motility and chemotaxis in the spermatozoa: From invertebrates to humans. AB - Activation of the sperm motility and chemotactic behavior of sperm toward eggs are the first communication between spermatozoa and eggs at fertilization, and understanding of the phenomena is a prerequisite for progress of not only basic biology, but also clinical aspects. The nature of molecules derived from eggs by which sperm are activated and attracted towards the eggs and the molecular mechanisms underlying the sperm activation and chemotaxis have been investigated in only a few invertebrate species, sea urchins, ascidians and herring fish. However, knowledge on this phenomena has been ignored in mammalian species including humans. The current review first introduces the studies on the activation and chemotaxis of sperm in marine invertebrates, and the same phenomena in mammals including humans, are described. (Reprod Med Biol 2005; 4: 101-115). PMID- 29699217 TI - Survival of mouse ovarian tissue transplanted into the uterine horn of post partum rats nursing pups of various numbers and sizes. AB - Aim and background: To investigate the effect of the number of pups being nursed on the survival of mouse ovarian tissue transplanted into the post-partum rat uterus. Methods: Mouse ovarian tissue was transplanted into the uterine horn of post-partum rats. The number of pups nursed by each recipient rat was adjusted in a manner predetermined. Examinations were undertaken at 1-11 weeks after transplantation. Ovarian tissue containing healthy follicles was considered to have taken successfully. Results: In rats with 12 pups, ovarian tissue remained viable at 11 weeks post-transplantation. No viable ovarian tissue remained when there were one or two pups. Viability improved as the number of pups increased. Conclusion: When mouse ovarian tissue is transplanted into post-partum lactating rats, viability improves as the number of pups increases. We concluded that these findings may be explained in terms of progesterone levels in the recipient rats. (Reprod Med Biol 2005; 4: 149-152). PMID- 29699216 TI - Diagnosis and treatment of immunologically infertile males with antisperm antibodies. AB - The presence of antisperm antibodies (ASA) can reduce fecundity in both males and females. The present review describes a strategy, established by investigations of the diverse inhibitory effects of ASA on fertility, for the appropriate diagnosis and treatment of infertile males with ASA. For infertile males with ASA, diagnosis using the direct-immunobead test (D-IBT), the postcoital test (PCT) and the hemizona assay (HZA) should be carried out as the basis for decision-making. If the patient with ASA has an abnormal hemizona index, it seems reasonable to advise selecting intracytoplasmic sperm injection-embryo transfer (ICSI-ET) as a primary treatment. However, it has been shown that some immunologically infertile males with normal fertilizing ability established pregnancy by timed intercourse (TI) or intrauterine insemination (IUI). In such patients with ASA having normal hemizona index, TI or IUI can be selected based on the PCT result. Therefore, the treatment strategy for males with ASA is similar to that for infertile males with oligozoospermia or asthenozoospermia. In conclusion, it should be emphasized that a diversity of ASA exists and their effects on fertility in infertile males. Although there is an argument that routine testing for ASA in males is not always necessary, one should be aware that in some cases of failed IUI or IVF, ICSI is selected afterward because of the diagnosis of ASA. (Reprod Med Biol 2005; 4: 133-141). PMID- 29699218 TI - Pregnancy rate, multiple pregnancy rate, and embryo quality: Clues for single blastocyst transfer from double blastocyst transfer in an unselected population. AB - Objective: Minimizing multiple pregnancy is a priority in assisted reproduction. As implantation rates are critical to success and reduce multiple pregnancy, we investigated whether blastocyst grade determined implantation rate following double blastocyst transfer in unselected cases. Materials and Methods: We studied 69 three-cleavage stage embryo transfers and 64 two-blastocyst transfers. Two blastocysts, or one when two blastocysts were not available, were transfered after evaluating the grade of blastocysts. The difference in pregnancy and implantation rates to patient age, the number of retrieved oocytes and grade of blastocysts were analyzed. Results: Blastocyst and grade 3AA rates per fertilized egg were 50.3% and 26.0%, respectively. Following two-blastocyst transfer, pregnancy rate per transfer, implantation rate per embryo, and multiple pregnancy rate per pregnancy were 39.1%, 26.5%, and 24.0%, respectively. Two blastocyst transfer achieved implantation more often than three-cleavage-stage embryo transfer, but did not reduce multiple pregnancy. Pregnancy, implantation, and multiple pregnancy rates did not reflect maternal age. Higher pregnancy and implantation rates per transfer were attained for with six or more oocytes retrieved or transfer of two-blastocyst graded 3AA or higher especially when two or more blastocysts graded 3AA or higher are available, but the latter showed a high multiple pregnancy rate (38.5%). Conclusions: Single embryo transfer could be carried out when two or more blastocysts of grade 3AA or higher have been developed. (Reprod Med Biol 2005; 4: 153-160). PMID- 29699219 TI - Human sperm motility in a microgravity environment. AB - Background and Aims: We carried out clinostat and parabolic flight experiments to examine the effects of a microgravity (uG) environment on human sperm motility. Methods: Semen samples were obtained manually from 18 healthy men (aged 27.4 +/- 5.4 years) who had given their informed consent. In clinostat experiments, samples that were left stationary were used as a stationary control. Samples rotated vertically and horizontally were used as a rotation control and a clinostat rotation, respectively. In parabolic flight experiments using a jet plane, sperm motility was compared for each parameter at uG, 1G and 2G. The state of 1G during the flight was used as a control. Sperm motility was determined using an automatic motility analyzer HT-M2030 in a microgravity environment. Results: All parameters of sperm motility tended to be lower in clinostat rotation compared with rotation control at both low-speed and high-speed, but the differences were not statistically significant. In parabolic flight, sperm motility and parameters of linear movement were decreased (P < 0.05). There was no significant difference between uG and 2G, but sperm motility was significantly decreased at uG than at 1G. Conclusions: Our findings suggest that sperm motility is reduced under uG. (Reprod Med Biol 2005; 4: 161-168). PMID- 29699220 TI - Microtubule organization during rabbit fertilization by intracytoplasmic sperm injection with and without sperm centrosome. AB - Aim: In most mammalian fertilization, the sperm introduces the centrosome, which acts as a microtubule organizing center (MTOC) and is essential for pronuclear movement. In rabbit fertilization, biparental centrosomal contribution in microtubule organization has been suggested. Methods: To reveal the function and inheritance of the centrosome during rabbit fertilization, we compared microtubule organization and early embryonal development following intracytoplasmic sperm injection (ICSI) with and without sperm centrosome. Sperm centrosome was removed by sonication, and the isolated sperm head was injected by a Piezo-driven micromanipulator. Samples were studied by light microscope after immunocytological stain. Results: The sperm aster formation was observed 2-3 h after ICSI with intact sperm. In contrast, microtubules were organized between the male and female pronucleus without a nucleation site in the eggs after ICSI with an isolated sperm head. In the late pronuclear stage following ICSI with an isolated sperm head, microtubule organization was the same as in late pronuclear stage eggs after intact sperm injection. The first mitotic spindle was organized in eggs following ICSI with an isolated sperm head, as observed in eggs following ICSI with an intact sperm. Conclusions: These results indicate that the MTOC is in oocyte cytoplasm during fertilization and fulfils the function when the sperm centrosome is absent. (Reprod Med Biol 2005; 4: 169-178). PMID- 29699221 TI - Cytoskeletal dynamics during mammalian gametegenesis and fertilization: Implications for human reproduction. AB - From gamete to neonate, human fertilization is a series of cell motilities (motion and morphological changes). Cytoskeletons play a role in cell motility as they work as a field worker in the cell. The present study is a review of dynamic motility of cytoskeletons (microfilaments and microtubules) during mammalian gamategenesis and fertilization. Dynamic and proper organization of cytoskeletons is crucial for the completion of oocyte maturation and spermatogenesis. By intracytoplasmic sperm injection, some difficulties in fertilization by sperm entry into the egg cytoplasm are overcome. However, the goal of fertilization is the union of the male and female genome, and sperm incorporation into an oocyte is nothing but the beginning of fertilization. Sperm centrosomal function, which introduces microtubule organization and promotes pronuclear apposition and first mitotic spindle formation, plays the leading role in the 'motility' of post intracytoplasmic sperm injection events in fertilization. The present review introduces novel challenges in functional assessment of the human sperm centrosome. Furthermore, microtubule organization during development without the sperm centrosome (e.g. parthenogenesis) is mentioned. (Reprod Med Biol 2005; 4: 179-187). PMID- 29699222 TI - New regulatory mechanisms for human extravillous trophoblast invasion. AB - Human extravillous trophoblasts (EVT) invade maternal deciduas and reconstructed maternal spiral arteries during early placentation. However, the precise regulatory mechanisms to induce EVT invasion toward arteries and/or to protect EVT from further invasion have not been well understood. Recently, it was found that EVT that had already ceased their invasion, specifically expressed cluster of differentiation (CD9) and dipeptidyl peptidase IV (DPPIV) on their cell surface. In addition, EVT migrating to maternal spiral arteries expressed CC chemokine receptor type-1 (CCR-1), which is a chemokine receptor for regulated on activation normal T cell expressed and secreted (RANTES) and so on. CD9 is associated with integrin molecules on the cell surface and is considered to modulate integrin function. In contrast, DPPIV is a cell surface peptidase that can metabolize RANTES at extracellular sites before its accessing to the chemokine receptors. In vitro functional assay showed that CD9, DPPIV and RANTES are involved in the regulation for EVT invasion. From these findings, it can be proposed that CD9 and DPPIV, including chemokines, are new regulatory factors for human extravillous trophoblasts. (Reprod Med Biol 2005; 4: 189-195). PMID- 29699223 TI - Elective single embryo transfer: Comparison of blastocyst and cleavage-stage embryo transfer. AB - Objective: Blastocysts are reportedly suitable for preventing multiple pregnancies as a result of the high implantation rate per embryo. The present study compared clinical results for elective single embryo transfer (ET) between blastocysts and cleavage-stage embryos in order to ascertain the usefulness of blastocyst culturing in single ET. Methods: Between January 2002 and December 2004, conventional in vitro fertilization ET and/or intracytoplasmic sperm injection was carried out for single ET in 86 cycles, to prevent multiple pregnancies (for medical reasons or because of patient wishes). Results: Among the 80 cycles in which a fresh embryo was transferred, pregnancy/implantation rates per ET were 35.3% for day 2/3 ET and 50.0% for day 5 ET, and pregnancy/implantation rates per oocyte retrieval were 35.3% for day 2/3 ET and 44.2% for day 5 ET. Ongoing pregnancy/delivery rates per oocyte retrieval were 32.4% for day 2/3 ET and 38.5% for day 5 ET. Monozygotic twinning occurred in one case of day 5 ET. Conclusions: Pregnancy rates per single ET tended to be higher for day 5 ET than for day 2/3 ET. However, no marked differences were identified in ongoing pregnancy/delivery rates per oocyte retrieval between groups. (Reprod Med Biol 2005; 4: 197-201). PMID- 29699224 TI - In vitro fertilization outcome in severe ovarian hyperstimulation syndrome: An age-matched contemporaneous control study. AB - Aim: Ovarian hyperstimulation syndrome (OHSS) is a potentially life threatening, iatrogenic complication of assisted reproduction and has been associated with poor in vitro fertilization outcome. The aim of the present study was to evaluate the pregnancy rate and outcome following severe OHSS, at a single center over a three-year period. Methods: The incidence of severe OHSS at the IVF Center, National University of Singapore, in Singapore, was 4% (48 cases over 1200 cycles) during the period of 1997-2000. The present retrospective study compared 48 cases of severe OHSS to 144 age-matched, contemporaneous controls without OHSS. Results: The total gonadotropin required for severe OHSS group was found to be lower than for that of controls (2664.06 +/- 768.29 IU vs 3349.58 +/- 2003.73 IU), although duration of stimulation was similar. The OHSS group was associated with a fivefold increase (OR 5.293, 95% CI: 2.116-13.238) in pregnancy rate compared to controls (87.5% vs 56.9%; P < 0.05). Late OHSS was more common (38/48 cases) and had a pregnancy rate of 97% per embryo transfer. There was no significant difference in the multiple pregnancy (54% vs 48%; P > 0.05) and miscarriage rates (14% vs 7.3%; P > 0.05) between the groups. Conclusion: Severe OHSS at our center were mostly late onset. The pregnancy rate was significantly higher, but multiple pregnancy and miscarriage rates were not significantly increased when compared to the age-matched contemporaneous controls. (Reprod Med Biol 2005; 4: 207-211). PMID- 29699225 TI - Sperm flagella protein components: Human meichroacidin constructed by the membrane occupation and recognition nexus motif. AB - Background and Aims: In a previous study, the authors of the present study cloned mouse meichroacidin (MCA), which is expressed in stages of spermatogenesis from pachytene spermatocytes through round spermatid germ cells. MCA protein contains the membrane occupation and recognition nexus (MORN) motif and localizes to a male meiotic metaphase chromosome. Recently, a MCA homolog of carp (Cyprinus carpio), MORN motif-containing sperm-specific axonemal protein (MSAP), was reportedly identified and localized in sperm flagella. Present knowledge of human spermiogenesis requires the identification of proteins in human sperm. The present study identified the human orthologue of MCA. Methods: Colony hybridization using a human testis plasmid cDNA library was carried out to clone human MCA (h-MCA) cDNA. Northern blot, Western blot, and immunohistochemical analyses were carried out. Results: h-MCA was found to be specifically expressed in the testes. The h-MCA amino acid sequence shared 79.8% identity with mouse MCA and contained MORN motifs. h-MCA localized in the sperm flagellum and basal body, as does MSAP in carp. Conclusion: Expression and localization analyses showed that h-MCA is a component of the sperm flagellum and basal body and might play an important role in the development of the sperm flagellum in humans. (Reprod Med Biol 2005; 4: 213-219). PMID- 29699227 TI - Cytokines and leptin correlation in patients with polycystic ovary syndrome: Biochemical evaluation in south Indian population. AB - Background: In polycystic ovary syndrome (PCOS), the leptin (OB protein) is related to reproductive function and inflammatory response. Leptin and cytokines have been thought to be putative local regulators in PCOS. Methods: To examine the relationship between serum leptin and serum interleukin-6 (IL-6), interleukin 8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) levels in underweight, overweight, obese and morbidly obese PCOS and non-PCOS subjects compared with normal weight, regularly menstruating women. Results: Leptin levels are highly correlated with TNF-alpha, IL-6 and IL-8. There is a significant dependent increase with the degree of obesity, but in underweight PCOS subjects, leptin levels are elevated irrespective of the body mass index. Conclusion: The present study showed that leptin levels were elevated in underweight and morbidly obese PCOS subjects. This could be the result of impaired expression of leptin in PCOS, leading to leptin resistance. As a result of this regulation, TNF-alpha, IL-6 and IL-8 were also elevated in morbidly obese and underweight PCOS subjects. In obese subjects, where there was an increase in adipose mass, increased levels of leptin were observed and this was attributed to the inflammatory properties while increasing the adipose mass. Serum IL-6 and IL-8 circulate at high levels and are more important systemically. They are, perhaps, the hormonal factors that induce leptin and insulin resistance in underweight PCOS subjects. Therefore, leptin and inflammatory markers were acting at paracrine and endocrine levels in PCOS subjects. (Reprod Med Biol 2005; 4: 247-254). PMID- 29699228 TI - New plication technique for the treatment of congenital penile curvature. AB - Introduction: Conditions that cause curvature of the erect penis also lead to difficulties with intercourse. The present study presents an effective surgical treatment for congenital penile curvature. Methods: Between March 1996 and August 2004, 49 patients were diagnosed with congenital penile curvature at the Toho University Omori Hospital Reproduction Center, Tokyo. Of these, 27 eligible patients underwent surgical treatment. The operative technique used involved the tunica albuginea being exposed and a number of vertical incisions were made through its superficial layers. The superficial layer of the tunica albuginea was then resected using scissors. Inverted plication sutures were then placed in the raw surface of the corpus cavernosum using 2-0 nylon. In addition, 2-0 polyglactic acid (Vicryl) sutures were placed on either side of each nylon suture knot. Results: Of a total of 49 patients, 27 eligible patients underwent surgical treatment with no serious postoperative complications. All 27 patients were able to sustain intercourse. There were no new cases of erectile dysfunction, penile pain or penile shortening. There were no recurrences of penile curvature. Conclusions: This new partial thickness shaving, inverted sutures reinforced with dissolving sutures plication method is an extremely effective surgical treatment for congenital penile curvature, with a superior safety profile. (Reprod Med Biol 2005; 4: 255-258). PMID- 29699226 TI - Phytoestrogens and reproductive biology. AB - Phytoestrogens are naturally occurring plant substances that can either mimic or antagonize the action of endogenous estrogens. This is because of the similarity of the functional structure of phytoestrogens and endogenous estrogens. In premenopausal women, phytoestrogen intake might induce a decrease in luteinizing hormone, follicle-stimulating hormone and estradiol (E2), which are associated with a longer follicular phase. The circulating transport protein, sex hormone binding globulin, is increased, resulting in less cellular availability of E2. Phytoestrogens inhibit the activities of E2 synthetic enzymes through adenylate cyclase and tyrosine kinase cascades. This might decrease of risk of hormone dependent cancers. A phytoestrogen-rich diet might reproduce normal body composition, affecting the course of polycystic ovary syndrome (PCOS). Some herbs used in traditional Japanese medicine contain phytoestrogens that influence endogenous hormone levels to directly regulate the pituitary-ovarian system, in particular, the chemotactic effects on ovaries. (Reprod Med Biol 2005; 4: 225 229). PMID- 29699229 TI - Transferrin and inhibin mRNA in mature pig Sertoli cells. AB - Aims: There is increasing concern about the effect of environmental toxins and endocrine disrupters on human spermatogenesis but ethical considerations prohibit direct research. Therefore, we developed a method of isolating mature pig Sertoli cells and studying the levels of mRNA of transferrin and inhibin, markers of Sertoli cell function, using real-time polymerase chain reaction analysis. Methods: Sertoli cells from mature Meishan boars were isolated and cultured. The mRNA was isolated from the cells after 3 days of treatment with follicle stimulating hormone (FSH), testosterone and beta-estradiol. The amounts of transferrin and inhibin mRNA were analyzed by real-time polymerase chain reaction and the relative level of mRNA was calculated. Results: FSH tended to increase the levels of transferrin and inhibin mRNA, as did the combinations of FSH and the steroids. The effect of testosterone and beta-estradiol alone on the level of mRNA was less than that of FSH. Beta-estradiol treatment resulted in a dose dependent decrease in mRNA. Conclusion: The Sertoli cell culture used in the present study appears to have a normal secretory function because the mRNA levels of both markers increased after FSH treatment. The suppressive effect of beta estradiol on inhibin mRNA level suggests that beta-estradiol has an effect on the function of Sertoli cells. (Reprod Med Biol 2005; 4: 259 -264). PMID- 29699230 TI - Severe ovarian hyperstimulation syndrome in a 42-year-old woman with successful pregnancy after intracytoplasmic sperm injection embryo transfer. AB - Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic complication of ovulation induction for infertile women. It has been shown that patients suffering from OHSS are generally young because OHSS depends on the patient's ovarian reserve. Therefore, women >=40 years of age seldom suffer from the severe form of OHSS. In the present study, we report a case of severe OHSS that occurred in a 42-year-old woman with a successful pregnancy after intracytoplasmic sperm injection (ICSI)-embryo transfer. She had been diagnosed as having polycystic ovary syndrome (PCOS). After 5 cycles of unsuccessful treatment with gonadotropins plus intrauterine insemination for her husband's asthenozoospermia, the treatment with assisted reproductive technology (ART) was indicated. In the third ART attempt, the patient was treated by ICSI-embryo transfer (ET) and she developed severe OHSS at 4 weeks' gestation. On admission, marked hemoconcentration, oligouria and hypo-albuminemia were diagnosed. A continuous autotransfusion system of ascites, which was developed to expand circulating plasma volume without exogenous albumin, was carried out for 5 h at a rate of 100 200 mL/h once a day for a total of 5 days. The course of the pregnancy was uneventful. At 37 weeks' gestation, a healthy baby boy weighing 3336 g was born by cesarean section when the patient was 43 years of age. The postoperative course was also uneventful. To the best of our knowledge, the present report describes the oldest woman showing severe OHSS. (Reprod Med Biol 2005; 4: 265 269). PMID- 29699231 TI - Direct gene delivery to murine testis as a possible means of transfection of mature sperm and epithelial cells lining epididymal ducts. AB - The use of a sperm cell to introduce exogenous DNA into an oocyte at the time of fertilization is of interest for the simple production of transgenic mice, and is now called 'sperm-mediated gene transfer (SMGT)'. In vivo transfection of sperm cells has been developed as an alternative method for SMGT and can be carried out by direct gene delivery into an interstitial space in a testis (now called 'testis-mediated gene transfer [TMGT]'), into the vas deferens, or into seminiferous tubules. This review summarizes what has been achieved in the field of in vivo gene transfer using sperm cells. (Reprod Med Biol 2006; 5: 1-7). PMID- 29699233 TI - Reproductive outcome after laparoscopic myomectomy for intramural myomas in infertile women with or without associated infertility factors. AB - Aims: To evaluate reproductive outcome after laparoscopic myomectomy for intramural myomas in infertile women with or without associated infertility factors. Methods: A retrospective study was carried out in 30 infertile women with intramural myomas measuring >=50 mm in diameter and treated using laparoscopy. Results: The overall rate of spontaneous intrauterine pregnancy was 50.0% (15 patients). Of 13 patients with infertility factors associated with the uterine myomas, three (23.1%) became pregnant, whereas 12 of 17 patients (70.6%) with no other associated infertility factor became pregnant. No uterine ruptures were observed. All pregnancies were spontaneous and 13 occurred within 1 year of the operation. In the 10 patients who gave birth by Cesarean section, no adhesions were found on the myomectomy scar. Conclusions: On the basis of these results, laparoscopic surgery for myomas appears to offer comparable results to laparotomy. In infertile patients with intramural myoma, pregnancy rates are affected by the presence of other infertility factors associated with the uterine myomas. (Reprod Med Biol 2006; 5: 31-35). PMID- 29699232 TI - Immune cells contribute to systemic cross-talk between the embryo and mother during early pregnancy in cooperation with the endocrine system. AB - In early pregnancy, human chorionic gonadotropin (HCG) stimulates the corpus luteum to produce progesterone that in turn maintains human embryo implantation in the uterus. This inevitable communication through blood circulation can be called 'systemic cross-talk between the embryo and mother'. Despite considerable evidence suggesting that the human corpus luteum cannot be maintained by HCG alone, no other responsible soluble factors have been proposed. We found that peripheral blood mononuclear cells (PBMC) derived from pregnant women promoted progesterone production by human luteal cells and propose that both hormones and immune cells participate in this systemic cross-talk. This systemic cross-talk by immune cells is believed to operate in embryo implantation. Splenocytes derived from pregnant mice promoted endometrial differentiation and embryo implantation in vivo. Human PBMC derived from women early in pregnancy promoted invasion of murine embryos in vitro. In addition, recombinant HCG increased the effects of human PBMC on murine embryo invasion. Human chorionic gonadotropin also increased chemokine production by human PBMC through a lectin-glycan interaction, which is a primitive pathway in the immune system. Furthermore, chemokines were shown to induce human trophoblast invasion. These findings suggest that the immune system positively contributes to systemic cross-talk between the embryo and mother in cooperation with the endocrine system. (Reprod Med Biol 2006; 5: 19-29). PMID- 29699235 TI - Strain difference in tolerance to low-temperature treatment of fertilized mouse oocytes. AB - Background and Aims: The aim of this study was to determine which mouse strains exhibit tolerance to cooling when fertilized oocytes have been stored at 4 degrees C. Methods: In-vitro-fertilization-derived oocytes of eight mouse strains were incubated at 4 degrees C in 20 mmol/L Hepes-potassium modified simplex optimized medium (KSOM) medium for 0, 24, 48, 60 or 72 h, and then returned to normal culture conditions at 37 degrees C in KSOM medium. The rates of development of cultured oocytes into blastocysts and cell numbers of blastocysts were examined. In some cases, a Comet assay was carried out to evaluate DNA damage. In addition, the effects of beta-mercaptoethanol on the development of the 4 degrees C-treated oocytes were assessed. Results: Of the eight strains tested, BDF1, B6C3F1 and FVB/N strains exhibited relatively higher degrees of tolerance to 4 degrees C treatment and approximately 90%, 83% and 78% of oocytes treated at 4 degrees C for 48 h developed to morphologically normal blastocysts, respectively. Comet assay revealed no clear DNA damage in oocytes treated at 4 degrees C. Treatment with beta-mercaptoethanol failed to improve the in vitro survival rate of low-temperature-treated oocytes. Conclusion: Strain differences were observed in tolerance to cooling treatment when fertilized oocytes were temporarily treated with 4 degrees C, although the reasons for this remain unclear. (Reprod Med Biol 2006; 5: 43-50). PMID- 29699234 TI - Serum testosterone levels using the radioimmunoassay method in healthy Japanese male volunteers. AB - Aim: The objective of the present study was to measure serum free and total testosterone values using the radioimmunoassay (RIA) method in healthy Japanese male volunteers with no current diseases. Methods: Two hundred and fifty-one healthy men who had no medical illness and received no current medical treatment were selected from 405 male volunteers. Free and total testosterone were measured in blood samples using the RIA method. Results: Free but not total testosterone significantly decreased with age. Mean free testosterone values from morning blood samples for each age decade from the 20s to the 70s were 17.0, 14.6, 12.5, 10.6, 8.9 and 8.5 pg/mL, respectively. Mean total testosterone values from morning blood samples for each age decade from the 20s to the 70s were 4.7, 4.2, 4.4, 4.2, 4.2, 4.0 and 4.0 ng/mL, respectively. The rates of healthy volunteers that fell within the standard reference ranges for free and total testosterone were 97% and 97%, respectively. However, 19% of the total testosterone values were considered to indicate hypogonadism according to the International Society for the Study of the Aging Male (ISSAM) criteria (<3.17 ng/mL). Conclusions: Our data corresponded to the standard reference ranges of Japanese men but not the ISSAM criteria. It may be more appropriate to establish a standard reference range for serum testosterone for individual countries. (Reprod Med Biol 2006; 5: 37-41). PMID- 29699236 TI - Laparoscopy for the treatment of unexplained infertility. AB - Aim: To determine the best treatment for unexplained infertility. Methods: A retrospective study was used to examine Japanese women with unexplained infertility that had undergone laparoscopy. The main outcome measure of the study was the rate of pregnancy after laparoscopy. Results: One hundred and thirty eight women diagnosed with unexplained infertility received laparoscopy and as a result 55 women had their diagnosis of unexplained infertility confirmed. There were no statistically significant differences between the women who became pregnant after laparoscopy in terms of duration of infertility, duration of treatment or age. The pregnancy rate of women with unexplained infertility was 56.4%, with 90% of these pregnancies achieved within the first 6 months. There were 64 women with minor endometriosis considered to be suffering from unexplained infertility before laparoscopy. The characteristics of the patients in the unexplained infertility group and in the minor endometriosis group were similar, but patients with minor endometriosis were found to have a lower pregnancy rate compared to those with unexplained infertility (35.9%vs 56.4%; P = 0.02). Conclusions: The effective period after laparoscopy appears to be 6 months. Assisted reproductive technology should be considered after that time. Pregnancy rates were low in women with minor endometriosis compared with unexplained infertility. It is important to clarify the cause of infertility using laparoscopy. (Reprod Med Biol 2006; 5: 59-64). PMID- 29699237 TI - Comparison of the number of spermatogonia and Sertoli cells in fetal and neonatal testes autopsied between 1958-1964 and 1989-1998 in Tokyo. AB - Background: Studies in several countries have reported a decline in human sperm quality similar to that observed in wild animals. To quantify whether the number of sperm in humans has decreased and whether humans are affected by similar environmental influences, we compared the number of spermatogonia and Sertoli cells in human fetal and neonatal testes autopsied at two institutions in Tokyo between 1958-1964 (term A) and 1989-1998 (term B), with special attention to chronological changes during gestation. Methods: We used an immunohistochemical method with antibody against neuron-specific enolase to determine the percentage of seminiferous tubules containing spermatogonia in the formalin-fixed tissue samples, and a morphometrical method using a dissector to count the number of spermatogonia. Results: There were no significant statistical differences between the two time periods in the regression parameters compared for the number of spermatogonia and Sertoli cells, nor was there a remarkable difference in the estimated number of Leydig cells. Conclusion: The results indicate that even if there has been a deterioration in human semen quality, it is not necessarily caused by endocrine disruption of fetal testicular development. (Reprod Med Biol 2006; 5: 65-70). PMID- 29699238 TI - Folliculogenesis following syngeneic transplantation of young murine ovaries into the testes. AB - Background and Aim: To examine the effects of intratesticular transplantation on the growth and maturation of young murine ovaries. Methods: Two-week-old ovaries from transgenic mice with enhanced green fluorescent protein expression were transplanted under the testicular capsule of 4-week-old non-transgenic mice. Results: Two months after transplantation all successfully grafted ovaries had survived, based on the presence of bright green fluorescence. The grafts showed various stages of folliculogenesis, including expanded follicles. The neighboring seminiferous tubules had a normal structure and mature sperm in their lumens, indicating active spermatogenesis, and all the recipient males were fertile. There was no evidence of extensive cell migration from the grafted ovaries into the testis. Similar findings were obtained for the grafted ovaries 6 months after surgery, although cell death (as evidenced by yellowish or pale fluorescence) was more frequent. Conclusion: Young murine ovaries can grow and mature autonomously for at least 6 months unaffected by the male hormonal environment. (Reprod Med Biol 2006; 5: 71-77). PMID- 29699239 TI - Uterine angiogenesis during implantation and decidualization in mice. AB - Increased uterine vascular permeability and angiogenesis are hallmarks of implantation and placentation. These events are profoundly influenced by vascular endothelial growth factor (VEGF). Although VEGF and its receptor Flk-1 are primarily important for uterine vascular permeability and angiogenesis before and during the attachment phase of the implantation process, VEGF together with the angiopoietins and their receptor Tie-2 directs angiogenesis during decidualization after implantation. Uterine expression of HIF and ARNT follows the localization of VEGF expression with increasing angiogenesis during the postimplantation period, although their expression does not correlate with VEGF expression during the pre-implantation period. Upstream of VEGF, estrogen promotes uterine vascular permeability but inhibits angiogenesis, whereas progesterone stimulates angiogenesis with little effect on vascular permeability. Furthermore, COX-2-derived prostaglandins participate in uterine vascular permeability and angiogenesis during implantation and decidualization. (Reprod Med Biol 2006; 5: 81-86). PMID- 29699240 TI - The involvement of immunoglobulin superfamily proteins in spermatogenesis and sperm-egg interaction. AB - The immunoglobulin superfamily (IgSF) proteins are expressed on the plasma membrane between Sertoli cells and germ cells in the testis. IgSF proteins are specifically present at the apical Sertoli-germ cell junction, that is, ectoplasmic specialization and are involved in germ cell differentiation. Some IgSF proteins are present on the surface of germ cells and undergo further biochemical modifications during sperm maturation. These IgSF proteins undergo final modifications during capacitation and/or the acrosome reaction. The function and expression of IgSF proteins in the testis and spermatozoa, as they relate to spermatogenesis and sperm-egg interaction, are discussed. (Reprod Med Biol 2006; 5: 87-93). PMID- 29699241 TI - Sperm-zona pellucida interaction and immunological infertility. AB - Immune reactions against gametes appear to be physiologically important for the maintenance of homeostasis in reproduction. In contrast, aberration of the immune homeostasis might give rise to 'immunological infertility'. Antisperm antibodies cause infertility by blocking fertilization. The mechanism can be explained as inhibiting the acrosome reaction of sperm by their blocking effect on capacitation through inhibiting an increase of fluidity of the sperm membrane. Autoantibodies against zona pellucida also cause infertility by blocking sperm zona pellucida interaction, though the definitive mechanism has not been elucidated. Pretreatment of spermatozoa with D-mannnose completely inhibited sperm penetration through, but not binding to, the zona pellucida. Furthermore, very rapid kinetics between sperm extracts and D-mannnose by a BIAcore apparatus suggest that a D-mannose ligand of the sperm surface is easy to bind to and dissociate from a D-mannose residue in the sperm receptor site on the zona pellucida. Thus, D-mannnose on the human zona pellucida might be an essential molecule acting as a second sperm receptor, through which sperm penetrate into the zona pellucida. Because these antibodies appear to not cause any deleterious clinical symptoms, sperm and zona pellucida antigens are promising candidates in the development of an immunocontraceptive. (Reprod Med Biol 2006; 5: 95-104). PMID- 29699242 TI - Concentration of lactoferrin and interleukin-6 in cervical mucus from patients being treated for infertility. AB - Background: The concentrations of the iron-binding protein lactoferrin (LF) and interleukin-6 (IL-6) were measured in the cervical mucus of patients being treated for infertility throughout the menstrual cycle. Methods: A total of 251 cervical mucus samples were obtained from the patients throughout the menstrual cycle. One hundred and fifty samples were from primary infertility patients with unexplained infertility and 101 samples were from secondary infertility patients as a control. The concentrations of LF and IL-6 were measured by enzyme immunoassays. The standard curve of LF concentrations ranged from 1.6 to 50 ng/mL. Results: The mean LF and IL-6 concentrations in the cervical mucus of primary infertility patients were higher than that of the control patients (P= 0.04, P= 0.032, respectively) The LF and IL-6 concentrations were highly correlated (P < 0.0001). Conclusion: Elevated levels of IL-6 and LF in the cervical mucus were obtained from primary infertility patients. We speculate that LF might also be one of the causes of infertility and might play an important role in reproductive processes in the cervix. (Reprod Med Biol 2006; 5: 105-109). PMID- 29699243 TI - Determinants of oral contraceptive pill use and its discontinuation among rural women in Bangladesh. AB - Oral contraceptive pills (OCP) contribute a major share in the current method-mix in Bangladesh. However, multiple studies show high discontinuation rates of OCP. The present study examines the behavior and attitude towards OCP use, and investigates the determinants of its discontinuation among the rural married women of Bangladesh. The present study is based on critical analyses of the data from 24 focus group discussions and 135 in-depth-interviews with women, their husbands and key informants conducted over the period of 1 year. The present study shows that more than two-thirds of married women have at one time or another used OCP as a method of family planning. However, many women did not take the pills regularly and about one-quarter of ever users had taken, at one stage or another, a 'short break' from OCP use. Although nearly half of them took a break because of side effects, interestingly, 16% took a break as the result of fear of health problems that were related to 'folk stories' and other misconceptions. The individual assessment by users of the national family planning service delivery, perceived side effects, misconceptions about continuous use of pills, quality of counseling and information, and contraceptive behavior of the OCP users considerably influenced the decisions on contraceptive use or non-use. (Reprod Med Biol 2006; 5: 111-121). PMID- 29699244 TI - Profiling of proteins phosphorylated or dephosphorylated during hyperactivation via activation on hamster spermatozoa. AB - Background and Aims: It has been widely accepted that sperm hyperactivation is regulated by protein phosphorylations. But, the sperm hyperactivation phosphorylation pathway is not well understood yet because several different proteins have been detected in other studies. In order to understand the phosphorylation pathway that regulates hyperactivation, we established how to extract sperm protein completely and detected proteins that were phosphorylated during hyperactivation. Methods: Protein phosphorylation of hamster spermatozoa was detected by western blotting using antiphospho-amino acid monoclonal antibodies or the SELDI ProteinChip system with IMAC-Ga(III). Results: We detected 75 protein/peptide phosphoryations using the method established in the present study. Tyrosine phosphorylations occurred during hyperactivation. Serine or threonine phosphorylations occurred for 30 min. Furthermore, four of the serine or threonine phosphorations were phosphorylated by A-kinase. As for peptides, 15 peptides were dephosphorylated for 30 min. Other peptides were phosphorylated during hyperactivation. Conclusions: Because most of the proteins detected in the present study have been described previously, we could detect comprehensive protein phosphorylations. Moreover, we also detected many novel phosphopeptides. Although we did not understand the role of peptide, it was likely that motility was basically regulated by serine/threonine phosphorylations and hyperactivation was mainly regulated by tyrosine phosphorylations. (Reprod Med Biol 2006; 5: 123-135). PMID- 29699245 TI - Effect of L-ascorbic acid supplementation on testicular oxidative stress and endocrine disorders in mature male rats exposed to intensive swimming exercise. AB - In order to investigate the ameliorative potential of L-ascorbic acid on intensive swimming exercise induced testicular oxidative stress, 18 Wistar male rats (age: 3 months, weight: 127.5 +/- 5.3 g) were randomly divided into the following groups: (i) control group (CG, n = 6); (ii) experimental group (EG, n = 6); and (iii) supplemented group (SG, n = 6). An exercise protocol of 3 h swimming per day, five days per week was followed for 6 weeks in EG and SG with no exercise in CG. In SG, L-ascorbic acid was supplied orally at a dose of 25 mg/kg of bodyweight each day for 6 weeks. A significant decrease (P < 0.05) was noted in paired testicular weights, epididymal sperm count, testicular Delta5, 3beta-hydroxyseroid dehydrogenase, 17beta-hydroxyseroid dehydrogenase, plasma levels of testosterone luteinizing hormone, follicle stimulating hormone, prolactin, the numbers of preleptotine spermatocytes, midpachytene spermatocytes and stage 7 spermatids of stage VII seminiferous epithelium cycle in EG when compared with CG. A significant elevation (P < 0.05) in plasma corticosterone and testicular content of malondialdehyde along with a significant reduction (P < 0.05) in glutathione, ascorbic acid, alpha-tocopherol, superoxide dismutase, catalase and glutathione-peroxidase, and glutathione-S-transferase were noted in testes of EG compared with CG. No significant change was noted in final bodyweight or numbers of spermatogonia-A among the groups. Furthermore, L ascorbic acid supplementation restored the above parameters to the control level. Conclusion: It can be concluded that intensive swimming exercise induced oxidative stress causes dysfunctions in the male reproductive system, which can be protected by L-ascorbic acid. (Reprod Med Biol 2006; 5: 145-153). PMID- 29699246 TI - Polygonum hydropiper crude root extract mimics estrogenic properties in females: Evidence of uterine protein profiles studied by sodium dodecyl sulfate polyacrylamide gel electrophoresis. AB - Polygonum hydropiper is a widely grown weed in the north-eastern states of India. In the present study, estrogenic effects of the crude root extract (CRE) of Polygonum hydropiper on uterine protein was tested in ovary-intact and ovariectomized (OVX) female albino rats. The methanolic crude extract of Polygonum hydropiper was given to adult ovary-intact and OVX female albino rat in a dose of 1000 mg/kg bodyweight per day. Oral administration of the CRE was carried out for a period of 12 days from the onset of proestrus and for a similar period of time for the OVX female. To study the estrogenic effect, OVX females were subcutaneously injected with 0.1 ug of estradiol-17beta (E2). E2 was injected at the interval of 24 h for a total period of 72 h. The uterine protein of ovary-intact and OVX females was studied by single dimensional sodium dodecyl sulfate polyacrylamide gel electrophoresis. The results showed similar protein bands in OVX females treated with E2 and CRE. In addition, treatment with CRE stimulated expression of more proteins in the uterus. The results showed that CRE of Polygonum hydropiper mimics the effect of estradiol-17beta in the uterine protein profiles of adult female albino rats. (Reprod Med Biol 2006; 5: 155-160). PMID- 29699247 TI - Role of mammalian sperm nuclear structure in fertilization and embryo development. AB - Although intact spermatozoon is successfully collected from infertile patients, repeated implantation failure or pregnancy loss are often experienced. Sperm nuclear defects have been thought to be one of the most important reasons for repeated assisted reproductive technology failure. In comparison with other mammalians, characteristic heterogeneity has been found in each mature human sperm nuclei, therefore it is necessary to investigate the significance between fertilization failure, developmental disability and structural abnormality of human sperm nuclei. Furthermore, if close relationships between the heterogeneity of human ejaculated sperm nuclei and DNA fragmentation are defined by analyzing sperm nucleoproteins, it would be clearly shown that impaired sperm chromatin leads to failure of embryo development in vitro or in vivo, so called late paternal effect on embryo development. It will be necessary in the near future to study the strategy for more novel methodology than those previously reported in terms of sperm selection. The present report reviews the roles of mammalian sperm nuclear structure, especially in humans, in fertilization and embryo development after the insemination procedure. (Reprod Med Biol 2006; 5: 161-168). PMID- 29699248 TI - Cumulus cells affect distribution and function of the cytoskeleton and organelles in porcine oocytes. AB - Mammalian oocytes grow and undergo meiosis within ovarian follicles. Oocytes are arrested at the first meiotic prophase, being controlled or influenced by follicular somatic cells. Under the influence of gonadotropins, immature oocytes resume meiosis. During meiotic progression, some cytoplasmic changes occur, so called cytoplasmic maturation. However, porcine follicular oocytes vary greatly in developmental competence. The present review summarizes recent studies highlighting the importance of cumulus cells in maintaining the developmental ability and in reorganizing the cytoskeleton and organelles of porcine oocytes. Factors affecting wide variation of the nuclear and cytoplasmic maturation observed in the porcine oocytes are discussed. (Reprod Med Biol 2006; 5: 183 194). PMID- 29699249 TI - Impact of the malaria parasite on reproductive indices of male mice. AB - Aim: To investigate the impact and possible mechanism of action of the rodent malarial parasite on reproduction. Methods: Male albino mice were infected with 15, 30 and 45%Plasmodium berghei berghei through inoculation with 107 parasitized red blood cells. Each experiment had its own control that was not infected with P. berghei berghei. Mice infected with 15%P. berghei berghei were killed on days 0, 5, 10 and 15; those infected with 30%P. berghei berghei were killed on days 0, 3, 6 and 10; and those infected with 45%P. berghei berghei were killed on days 1 7 after infection. Caudal epididymal sperm motility, counts and morphology, body and wet organ weights and hematological indices were determined. Results: The results showed a progressive duration dependent decrease in sperm motility, sperm count and viability (P < 0.01) in parasitized mice. There were significant decreases in serum testosterone and increases in cortisol levels (P < 0.05) in the infected mice compared with the controls. There was also a progressive decrease (P < 0.05) in red blood cell count and packed cell volume. However, there was a progressive increase (P < 0.01) in white blood cell count and weight of the spleen and liver. There was no significant change in weight of the testis and epididymides. Conclusion: The results suggest that the malaria parasite could depress male fertility indices. (Reprod Med Biol 2006; 5: 201-209). PMID- 29699250 TI - Effect of relaxin on motility, acrosome reaction and viability of cryopreserved boar spermatozoa. AB - Background and Aims: Relaxin has an important role in stimulating motility and the acrosome reaction (AR) of fresh boar spermatozoa. The objective of the present study was to determine whether relaxin can improve the motility, AR and viability of cryopreserved boar spermatozoa. Methods: Cryopreserved boar spermatozoa were thawed, washed and incubated at 37 degrees C for 4 h in modified Beltsville thawing solution supplemented with 0, 20 or 40 ng/mL relaxin. Sperm motility, AR, viability, and incorporation and oxidation of 14C-glucose were evaluated during 0-4 h of incubation. Results: The results show that the supplementation of relaxin (especially at 20 ng/mL) in the thawing solution improved sperm motility significantly (P < 0.05) at 1-3 h of incubation. The percentage of acrosome reacted live spermatozoa was improved significantly (P < 0.05) when the spermatozoa were treated with 20 ng/mL relaxin. Viability was not significantly (P > 0.05) improved by supplementation with relaxin. The rates of incorporation and oxidation of 14C-glucose were increased in correlation with AR up to 4 h of incubation. Conclusion: We conclude that relaxin can improve the sperm motility and AR, and enhance the glucose metabolism of cryopreserved boar spermatozoa. (Reprod Med Biol 2006; 5: 215-220). PMID- 29699251 TI - Assisted hatching using a 1.48-um diode laser: Evaluation of zona opening and zona thinning techniques in human embryos. AB - Aim: We assessed the effectiveness of assisted hatching using a 1.48-um diode laser in human embryos, comparing zona opening and zona thinning techniques. Methods: A total of 56 day 3 embryos were assigned randomly to a zona opening group, a zona thinning group, or a control group. We then carried out assisted hatching using the OCTAX Laser Shot system (MTG Medical Technology, Altdorf, Germany) in the first two groups. In the zona opening group, the inner membrane of the zona pellucida was broken to create a full-thickness opening. In the zona thinning group, the inner membrane of the zona pellucida was not breached. After the laser procedure, embryos were cultured to the hatched blastocyst stage. Results: Blastocyst development rates did not differ significantly between the three groups. In the zona opening group, blastocysts were significantly more likely to hatch than those in the control group (P <= 0.05) and no arrested hatching of blastocysts was observed. Conclusions: Assisted hatching using a 1.48-um diode laser in the zona opening technique increases the likelihood of blastocyst hatching in human embryos and does not adversely effect subsequent embryo development. (Reprod Med Biol 2006; 5: 221-226). PMID- 29699252 TI - Significance of matrix metalloproteinases in the pathophysiology of the ovary and uterus. AB - Matrix metalloproteinases (MMP) are capable of degrading a variety of extracellular matrix (ECM) proteins and are also involved in the processing of a number of bioactive molecules. Our findings indicate that the functions of MMP in the ovary and uterus are organ-specific and time-dependently vary during the reproductive cycle. Prolactin induces structural luteolysis indicated by loss of luteal weight, protein and DNA within 36 h after pretreatment with ergot alkaloid. MMP activation appears crucial for the selective depletion of protein during luteal involution, which entails loss of ECM accompanied by apoptosis. During GnRHagonist-induced luteolysis, this response was also associated with marked increases in MMP-2, which degraded collagen type IV, and MT1-MMP, which in addition to activating MMP-2 also degrades collagen type I, III and V. We also found that the level of MT1-MMP and MMP-2 expression in the human CL is greater during the late luteal phase than during either the early mid luteal phases or during gestation, respectively. That dehydroepiandrosterone (DHEA) treatment caused the formation of cysts from antral follicles in the ovaries of immature rats while depressing MMP-2 collagenolytic activity and enhancing lysyl oxidase expression highlights the importance of collagen degradation in the process of ovulation and suggests that changes in the activities of these enzymes play a key role in ovarian cystogenesis in polycystic ovary syndrome patients. Furthermore, immunohistochemical analyses showed that MT1-MMP and FasL co-localize with TdT mediated dUTP-biotin nick end-labeling (TUNEL)-positive apoptotic granulosa cells in rats treated with DHEA, that the Fas/FasL/Caspase-8 (death receptor-dependent) pathway is pivotal for follicular atresia and that increased levels of MT1-MMP likely play an important role in tissue remodeling during follicular atresia. After parturition, the uterus undergoes involution, a conspicuous feature characterized by a rapid reduction in the collagen content mediated by degradation of extracellular collagen bundles. Our findings strongly suggest that MT1-MMP, MMP-2 and MMP-9 are each time-dependently regulated and play important roles in tissue remodeling during postpartum uterine involution. (Reprod Med Biol 2006; 5: 235-243). PMID- 29699253 TI - BMP-15 regulation of ovulation quota in mammals. AB - Naturally occurring mutations in the oocyte-specific factor, bone morphogenetic protein-15 (BMP-15), cause infertility in women and in ewes. In contrast to these monoovulatory mammals, the targeted deletion of BMP-15 in polyovulatory mice results in subfertility with only minimal defects in the ovulation process. Given the established role of BMP-15 in governing the progression of folliculogenesis, it is hypothesized that species-specific differences in the BMP-15 system are involved in species-specific determination of ovulation quota and litter size. Recent data using in vitro cell transfection methodology indicate that, in contrast to human BMP-15 which is successfully processed and secreted, the mouse BMP-15 proprotein is resistant to proteolytic cleavage. Thus, no functional mature BMP-15 is secreted in vitro. Further studies have shown that the functional mature form of BMP-15 is barely detectable in mouse oocytes in vivo until just before ovulation, when it is markedly increased. The general hypothesis to emerge from these observations is that the species-specific differences in the defects caused by mutations in the bmp15 gene between monoovulatory ewes and women and polyovulatory mice might be attributed to the timing of the production of BMP-15 mature protein. (Reprod Med Biol 2006; 5: 245 248). PMID- 29699254 TI - The improvement in fertilizing ability of cryopreserved mouse spermatozoa using laser-microdissected oocytes. AB - Aim: The C57BL/6 mouse strain is now commonly used for producing transgenic/knockout strains. However, the fertilizing ability of these spermatozoa decreases as a result of cryopreservaion. Although the micromanipulation technique has been established to increase their fertilizing ability, it requires a considerable degree of technical skill. In the present report, we investigate the simple microdissection of zona pellucida by laser to increase the fertilizing ability of cryopreserved spermatozoa. Methods: C57BL/6J spermatozoa were cryopreserved using a solution consisting of 18% raffinose/3% skim milk. Oocytes of the same strain were placed in PB1 medium containing 0, 0.25, 0.50 or 0.75 mol sucrose. The zona pellucida of oocytes was microdissected by laser with different pulse lengths selected from 0.45 to 0.65 ms. Microdissected oocytes were then fertilized with cryopreserved spermatozoa, and the subsequent development of embryos was assessed. Results: When oocytes were microdissected in PB1 medium without sucrose, 81.5% of the oocytes were fertilized. The fertilization rates increased significantly as the pulse length was lengthened when compared with oocytes with intact zona pellucida. Furthermore, normal offspring were obtained in all experiments. Conclusion: The fertilizing ability of cryopreserved spermatozoa is improved when oocytes with their zona pellucida microdissected by laser were used. (Reprod Med Biol 2006; 5: 249-253). PMID- 29699255 TI - Chemical removal of zona pellucida versus laser assisted hatching after repeated failures of assisted reproductive technology. AB - Background and Aims: To evaluate outcomes after zona pellucida removal by pronase or laser assisted hatching in women with repeated assisted reproduction failures. Methods: Of 389 procedures (January 2004 to November 2005), 203 control cycles had an intact zona, 116 cycles had chemical removal of the zona and 70 cycles had laser assisted hatching. Rates of pregnancy, implantation and abortion were compared, and pregnancy rate was secondarily evaluated for fresh or frozen-thawed blastocysts. Results: Pregnancy rates were 33.5% (68/203) for controls, 29.3% (34/116) for chemical removal and 30.0% (21/70) for laser. Implantation rates were 24.8% (68/274) for controls, 21.8% (34/156) for chemical removal and 30.0% (21/105) for laser. There were no significant differences among groups. Abortion rates were 15.6% (10/64) for controls, 13.9% (5/36) for chemical removal and 14.3% (3/21) for laser. No difference was observed by blastocyst type for control or laser assisted hatching cycles. In the chemical removal group, both pregnancy and implantation rates were higher for frozen-thawed blastocysts than for fresh blastocysts. (41.5%vs 13.2% and 30.7%vs 11.1%, respectively). Conclusions: Assisted hatching did not show a significant benefit. Chemical zona pellucida removal might increase pregnancy rates for frozen-thawed blastocysts. (Reprod Med Biol 2006; 5: 263-267). PMID- 29699256 TI - Effects of orchids (Orchis anatolica) on reproductive function and fertility in adult male mice. AB - Aims: The aim of the present study was to determine the effect of orchid bulbs on the reproductive system of male albino mice. Methods: Orchid bulb extract was fed to 20 male albino mice (5 g/mouse/day) for 35 days and compared with a similar number of mice as controls. Total testicular germ cell population, histometrical parameters, serum blood biochemistry and hormonal assay were determined. Results: The ingestion of orchid bulb by mice induced a significant increase in the following parameters: (i) testes and seminal vesicle weights; (ii) number of different testicular germ cell population including interstitial Leydig cells and fibroblasts; and (iii) testicular cell linage dynamics obtained from testes and cauda epidydimides. An important finding was that the ingestion of the orchid diet by male mice increased their fertility. This was indicated by an elevation in the number of impregnated females when allowed to mate with treated mice, an increase in the impregnation sites, and an increase in the number of viable fetuses and the offspring's male/female ratio. A slight significant increase in the testosterone and follicular stimulating hormone titers in the treated mice were found in their blood serum. In contrast, a decrease in the number of degenerating cells was observed. Conclusions: Orchid bulb treatment might play an important role in improving male reproductive potential and fertility. (Reprod Med Biol 2006; 5: 269-276). PMID- 29699257 TI - Comprehensive assessment of the effect of Sphenocentrum jollyanum root extract on male reproductive activity in albino rats. AB - Aim: To evaluate the effect of methanol extract from the Sphenocentrum jollyanum root on male reproductive activity. Methods: Male albino rats were treated orally with distilled water (vehicle for the extract; control) and 50, 100 and 150 mg kg-1 body weight of Sphenocentrum jollyanum root extract for 8 weeks. Each group had its own recovery. Rats were killed 24 h after the last treatment. Caudal epididymal sperm count, motility, viability, morphology and organ weights were determined. Hematological indices, serum proteins, enzymes, testicular superoxide dismutase (SOD) activity, and testicular and epididymal histology were determined. Results: Compared with the control, the extract caused a dose dependent significant (P < 0.05) reduction in progressive motility of spermatozoa, viability and total sperm counts. The number of abnormal spermatozoa and epididymal volume were not statistically significant. There was a significant increase (P < 0.05) in serum testosterone levels in rats treated with 50 (P < 0.01) and 100 mg kg-1 (P < 0.05) of Sphenocentrum jollyanum. There was a significant (P < 0.05) increase in red blood cell count, packed cell volume and hemoglobin concentration, whereas there was no change in white blood cell count, mean total serum protein, albumin and globulin in the sera of Sphenocentrum jollyanum treated rats when compared with the control. The extract caused a significant decrease (P < 0.05) in serum aspartate and alanine aminotransferase activities with a significant increase (P < 0.05) in testicular SOD activity at a dose of 50 mg kg-1 bodyweight. Testicular cytoarchitecture of the extract treated rats showed degeneration of seminiferous tubules, whereas regeneration of germinal epithelium and restructuring of the germinal interstitium occurred in the recovery rats. No lesions were observed in the epididymis of the rats. Conclusion: The results suggest that methanol extract of the Sphenocentrum jollyanum root could produce harmful effects on reproductive functions in male albino rats which can be attributed to poor sperm quantity (epididymal sperm count), quality (sperm motility, viability and morphology) and testicular degeneration. The steroidogenic potential of the plant could explain its use as an aphrodisiac agent. (Reprod Med Biol 2006; 5: 283-292). PMID- 29699260 TI - Molecular biological features of male germ cell differentiation. AB - Somatic cell differentiation is required throughout the life of a multicellular organism to maintain homeostasis. In contrast, germ cells have only one specific function; to preserve the species by conveying the parental genes to the next generation. Recent studies of the development and molecular biology of the male germ cell have identified many genes, or isoforms, that are specifically expressed in the male germ cell. In the present review, we consider the unique features of male germ cell differentiation. (Reprod Med Biol 2007; 6: 1-9). PMID- 29699261 TI - Androgen receptor functions in male and female reproduction. AB - The androgen receptor (AR) is a ligand-dependent transcription factor involved in the regulation of many different physiological processes. Dysfunction of AR causes diverse clinical conditions, such as testicular feminization mutation (Tfm) syndrome and prostate cancer. However, the molecular basis of the AR in these disorders largely remains unknown, as a result of a lack of genetic models. Using conditional targeting technique with Cre-loxP system, we successfully generated null AR mutant (ARKO) mice. The ARKO males grew healthily, but they showed typical Tfm abnormalities. The ARKO males exhibited late onset of obesity with impaired bone metabolism and sexual behaviors. No overt abnormality was found in female ARKO mice, but a premature ovarian failure-like phenotype was found with impaired folliculogenesis. Thus, andorogen/AR system supports normal reproduction as well as normal female reproduction. (Reprod Med Biol 2007; 6: 11 17). PMID- 29699262 TI - Ovarian stimulation length, number of follicles higher than 17 mm and estradiol on the day of human chorionic gonadotropin administration are risk factors for multiple pregnancy in intrauterine insemination. AB - Aim: The aim of the present study was to identify the risk factors, their prognostic value on multiple pregnancies (MP) prediction and their thresholds in women undergoing controlled ovarian hyperstimulation (COH) with follicle stimulating hormone (FSH) and intrauterine insemination (IUI). Methods: A case control study was carried out by identifying in our database all the pregnancies reached by donor and conjugal IUI (DIUI and CIUI, respectively), and compared cycle features, patients' characteristics and sperm analysis results between women achieving single pregnancy (SP) versus MP. The number of gestational sacs, follicular sizes and estradiol levels on the human chorionic gonadotropin (hCG) administration day, COH length and semen parameters were obtained from each cycle and compared. Student's t-tests for mean comparisons, receiver-operator curve (ROC) analysis to determine the predictive value of each parameter on MP achievement and multiple regression analysis to determine single parameter influence were carried out. Results: Women with MP in IUI stimulated cycles reached the adequate size of the dominant follicle (17 mm) significantly earlier than those achieving SP. Also, the mean follicles number, and estradiol levels on the hCG day were higher in the CIUI and DIUI MP group. Nevertheless, only ROC curve analysis revealed good prognostic value for estradiol and follicles higher than 17 mm. Multiple regression analysis confirmed these results. No feature of the basic sperm analysis, either in the ejaculate or in the prepared sample, was different or predictive of MP. When using donor sperm, different thresholds of follicle number, stimulation length and estradiol in the prediction of MP were noted, in comparison with CIUI. Conclusions: MP in stimulated IUI cycles are closely associated to stimulation length, number of developed follicles higher than 17 mm on the day of hCG administration and estradiol levels. Also, estradiol has a good predictive value over MP in IUI stimulated cycles. The establishment of clinical thresholds will certainly help in the management of these couples to avoid undesired multiple pregnancies by canceling cycles or converting them into in vitro fertilization procedures. (Reprod Med Biol 2007; 6: 19-26). PMID- 29699263 TI - Antisperm antibodies in infertile men and their correlation with seminal parameters. AB - Aim: Antisperm antibodies (ASA) in males cause the autoimmune disease 'immune infertility'. The present study intended to detect the presence of ASA and their incidence in men with unexplained infertility, as well as to evaluate the correlation between the presence of ASA and semen parameter alterations. Methods: Blood and sperm assessment were collected to carry out a direct and indirect mixed antiglobulin reaction (MAR) test and semen analysis in infertile and fertile men from the University Hospital of the Faculty of Medicine, Sao Paulo State University, Sao Paulo. Results: In the MAR test, 18.18% of infertile men were positive for ASA. In fertile men, no positivity was found. A significant correlation between the presence of ASA with an increased white blood cell count plus a decreased hypoosmotic swelling test result was observed. Conclusions: The results indicate that ASA are involved in reduced fertility. It is not ASA detection per se that provides conclusive information about the occurrence of damage to fertility. The correlation between infertility and altered seminal parameters reinforce the ASA participation in this pathology. (Reprod Med Biol 2007; 6: 33-38). PMID- 29699264 TI - Estrogen to progesterone ratio affects hormonal and lipid follicular fluid profiles in dairy cows. AB - Aim: The present study described hormonal and lipids concentrations of follicles that develop under high progesterone plasmatic levels, mimicking the second follicular wave. Methods: All follicles were removed by aspiration in order to generate a new follicular wave. Follicular fluid was then obtained from either 3 day old follicles (F3) or 6 day old follicles (F6). This experimental protocol was carried out at 20 days and 90 days post-partum on Frisian dairy cows that had already returned to cyclicity. Results: Estrogen active follicles (ratio of estrogen to progesterone in follicular fluid higher than 1) have higher levels of VEGF, IGF-I and linoleic acid, and have lower levels of NEFA, oleic and arachidonic acid. Non-estrogen active follicular fluid concentrations of IGF-I and NEFA were similar to plasma concentrations. In contrast, estrogen active follicles showed higher IGF-I and lower NEFA levels than plasmatic ones that could be used to sustain follicular growth. Conclusions: The results show that estrogen active follicles might have their own metabolism. (Reprod Med Biol 2007; 6: 45-51). PMID- 29699265 TI - Clinical outcomes of two different endometrial preparation methods for cryopreserved-thawed embryo transfer in patients with a normal menstrual cycle. AB - Aim: To compare the clinical outcomes of cryopreserved-thawed embryo transfer among patients with a normal menstrual cycle who had natural or hormone replacement cycles. Methods: From January 2004 to June 2006, cryopreserved embryos following conventional in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) were thawed and transferred in a total of 720 natural cycles and 136 hormone-replacement cycles. Results: Cryopreserved-thawed embryo transfer in patients who had a natural or hormone-replacement cycle resulted in clinical pregnancy in 43.1% and 40.4%, respectively; a rate of miscarriage of 14.5% and 23.6%, respectively; and a rate of ongoing pregnancy and delivery of 36.5% and 30.9%, respectively. None of these differences were statistically significant. Conclusions: Patients with a normal menstrual cycle who have natural or hormone-replacement cycles can be expected to have comparable clinical outcomes with cryopreserved-thawed embryo transfer. (Reprod Med Biol 2007; 6: 53 57). PMID- 29699266 TI - Cryopreservation and in vitro maturation of germinal vesicle stage oocytes of animals for application in assisted reproductive technology. AB - Cryopreservation, in vitro maturation, fertilization and culture can be applied to various processes across a wide range of species, that is, for the breeding and reproduction of farm animals, preservation of genetic variants in laboratory animals, and the conservation of wild species. In particular, the storage of oocytes by cryopreservation and IVM following cryopreservation, might become effective alternative assisted reproduction treatments for infertile patients. For example, in a clinical context, these techniques might be important for patients who are at risk of losing their ovarian function because of extirpative therapy, chemotherapy or radiation. Thus, it is important for assisted reproductive technology to improve IVM and cryopreservation techniques. In the present review, we introduce our recent studies on vitrification and IVM of germinal vesicle stage oocytes in animals. PMID- 29699267 TI - In vitro growth and maturation of mouse oocyte-granulosa cell complex from cryopreserved ovaries and achievement of pup birth. AB - Ovarian tissue banking is a feasible strategy for fertility preservation for young women after cancer treatments. Ovarian tissue, after thawing, is used for several options; orthotopic grafting (normal site), autologous heterotopic grafting and collection of ovarian follicles for culture. Recent reports of live birth encouraged clinicians and researchers to apply this technology to premature ovarian failure (POF) resulting from strong cancer therapy. Grafting, however, carries a risk of malignant cell recurrence. For safety, development of a culture method is necessary but optimum culturing conditions for less-developed follicles abundant in the ovary are not well known. In the present article, the current status of ovarian tissue cryopreservation, and in vitro oocyte growth and maturation from the preserved ovaries are reviewed. PMID- 29699268 TI - Successful pregnancy in ovariectomized mice using a combination of heterotopic autotransplantation of ovarian tissues and embryo transfer. AB - Aim: The present report is the first to show that, after ovariectomy, female mice with autotransplanted ovarian sections can maintain pregnancy after embryo transfer (ET) independent of the transplantation site. Methods: Three-month-old ICR females were ovariectomized, and sections from their own ovaries were transplanted either under their kidney capsule (KC group) or into a subcutaneous space (SC group) just after ovariectomy. In vitro fertilized blastocysts were transferred into uterine horns of the pseudopregnant mice that had received the transplanted ovarian tissues. Cesarean sections were carried out 17 days after ET to deliver any live fetuses that were present, and the numbers of implantation sites and fetuses were noted. Transplanted ovarian sections were removed and fixed for histological analysis. Results: Of the 10 mice in the KC group that received 107 blastocysts, two females (20%) became pregnant; they showed 12 implantation sites (11.2%) and produced four pups (3.7%). In the SC group, 101 blastocysts were transferred to eight females, and three females (37.5%) became pregnant; there were seven implantation sites (6.9%), and three pups (3.0%) were born. There were no statistically significant differences between the two groups in any of the parameters evaluated. On histological examination, luteinization and vascularization of the ovarian sections that were transplanted in the pregnant SC and KC females were noted. Conclusion: The pregnancy and full-term fetal development were obtained in ovariectomized mice using a combination of heterotopic ovarian tissue autotransplantation and transfer of embryos produced by in vitro fertilization. PMID- 29699269 TI - Effect of protopanaxatriol saponin on spermatogenic stem cell survival in busulfan-treated male mice. AB - Background and aims: Panax ginseng C.A. Meyer is a medicinal herb widely used in Asian countries. Many of its pharmacological actions are attributed to ginsenosides (saponin). However, the pharmacological effects or functions of ginsenosides on mammalian spermatogenesis are unclear. Methods: In the present study study, we investigated the therapeutic and prophylactic effects of protopanaxatriol saponin (PT) on testicular organ weight and morphology, testicular germ cells, proliferation, differentiation and spermatogenesis after induction of toxicity by a chemotherapeutic agent, busulfan, in male mice. Results: Intraperitoneally (IP) busulfan treatment markedly decreased the organ weight of testis, caput and cauda epididymis. After the treatment, the testes had collapsed seminiferous tubules with incomplete spermatogenesis. However, a single dose of busulfan treatment followed by PT injection showed milder damage on seminiferous tubules than busulfan alone. Conclusion: These results suggest that PT is effective in recovery of the male reproductive organ, and induced an increase in the number and viability of germ cells overcoming busulfan toxicity. PT might have applications in the recovery of male infertility arising from azoospermia and oligospermia. PMID- 29699270 TI - Possible correlation of leptin with body fat distribution and adiposity: Evaluation of serum leptin in South Indian population. AB - Background: Leptin, an adipocyte-derived hormone, is known to play an important role in body fat. Gender, age, degree of obesity and sex steroids are expressed differentially in men and women. Methods: We measured serum leptin, testosterone and beta-estradiol concentration by radioimmunoassay in 300 subjects (60 normal weight, 60 underweight, 60 overweight, 60 obese and 60 morbidly obese) by age group (18-40 years and 41-62 years), using full-length recombinant human leptin as a standard. Results: The present study found that morbidly obese and obese men and women older than 50 years had 50-70% higher body mass index (BMI) adjusted leptin levels than younger subjects. In addition, obese and underweight subjects showed a tendency towards lower BMI-adjusted leptin levels in younger than older, in both men and women subjects. Multiple regression analysis showed that age was positively correlated with leptin in both genders, even if the slope of rise was twice as high in women than in men. Together, these results indicate that in both genders, most prominently in females, aging is associated with increased leptin production that is independent from the amount of fat and/or the role of sex hormones. Conclusion: In conclusion, our data show that serum leptin concentrations in men and women gradually increase during aging, being higher in women than in men, but they are independent from BMI and other hormones. The inclusion of several hormones in our regression model showed that only testosterone in men, and estradiol and androstenedione in women were independent contributions to serum leptin levels, possibly accounting for part of the leptin sexual dimorphism in a south Indian population. PMID- 29699271 TI - Cryopreservation of human sperm in patients with malignancy: First 2 years' experience. AB - Background: Patients with malignancy (n = 130) participated in the sperm cryopreservation program. Methods: After washing and concentrating, sperm was cryopreserved using KS-VIm cryoprotectant medium. Participant background factors such as age, marital status, underlying disease, presence or absence of previous treatment and semen findings (concentration, motility and morphology) were analyzed to determine parameters associated with the program. Results: Patients in their 20s were most common (64 cases) and 94 cases were unmarried at the first visit. The main underlying diseases were testicular tumor (53 cases), leukemia (43 cases) and malignant lymphoma (13 cases). The program was completed for 118 cases. For leukemia, all semen parameters were closer to normal in patients without previous treatment (untreated group, UG) compared with the treated group (TG). When semen findings in the UG were classified according to underlying disease, sperm concentration was lower in patients with testicular tumor compared with those who had leukemia or malignant lymphoma. Four couples underwent reproductive therapies with the cryopreserved sperm through assisted reproductive technology, and three babies were born to two couples. Conclusion: Sperm cryopreservation liberates patients with malignancy from iatrogenic infertility as a consequence of intensive therapy, allowing them to retain reproductive ability. PMID- 29699272 TI - Elimination of HIV-1 from semen and application of the processed semen to assisted reproductive technology. AB - As HIV infection is becoming a controllable chronic infection after the introduction of the highly active antiretroviral therapy (HAART), patients with this infection are now able to make plans for the future. Numerous serodiscordant (HIV-positive men and HIV-negative women) couples seek medical assistance to have a child with minimum risk to the HIV-negative female partner and the child using processed (washed) sperm. HIV-1 elimination from the semen using density gradient centrifugation and the swim-up procedure, which is a standard processing procedure, depends on both sperm motility and the physical properties of the virus-containing particles. To establish a simple method for recovering sperm from poor quality semen, we developed the tilted-tube rotation method to generate a continuous density gradient, and using this continuous density gradient we have succeeded in recovering motile sperm, even from the semen of seropositive males with severe male factors. This review aims to summarize the recent progress in the underlying principles and technical aspects of semen processing for elimination of HIV-1. (Reprod Med Biol 2007; 6: 151-156). PMID- 29699273 TI - Effect of amino acids and dipeptides on accumulation of ammonia in the medium during in vitro maturation and fertilization of porcine oocytes. AB - Aim: The present study was designed to investigate the effect of amino acids and their dipeptides on the accumulation of ammonia in the medium during in vitro maturation (IVM) and in vitro fertilization (IVF) of porcine oocytes. Methods: The IVM and IVF media were modified North Carolina State University-37 solution and modified Tyrode's albumin lactate pyruvate, respectively. Porcine oocytes were matured in IVM medium containing 75-2400 umol ammonia. Amino acids (1.0 mmol) or their dipeptides (2.0 mmol) related to the urea cycle were added individually to the IVM and IVF media containing 300 umol ammonia. Oocyte maturation and fertilization were assessed using acetic-orcein staining, and the accumulation of ammonia in the media was measured using the indophenol method. Results: Percentages of metaphase II (MII) were adversely affected (P < 0.05) by >=300 umol concentrations of ammonia in the IVM medium. In the presence of 300 umol ammonia in the IVM and IVF media, glutamic acid, l-alanyl-L-glutamine (AlaGln), l-glycyl-L-glutamine (GlyGln) and AlaGln + GlyGln showed the highest rate (P < 0.05) of MII, monospermic fertilization, and the lowest rate (P < 0.05) of ammonia accumulation in the media. Conclusion: AlaGln and GlyGln in IVM and IVF media were more stable and effective than the individual amino acids in reducing the accumulation of ammonia, and increased the rate of porcine oocyte MII and monospermic fertilization in vitro. (Reprod Med Biol 2007; 6: 165-170). PMID- 29699274 TI - Sperm retention site and its influence on pronucleus stage evaluation following intracytoplasmic sperm injection. AB - Aim: It has been suggested that the position of the sperm after intracytoplasmic sperm injection (ICSI) has an effect on the development and quality of the embryo. In this study, we retrospectively examined whether pronucleus stage evaluation used through clinical studies in recent years has relevance with regard to sperm location. Methods: From 2003 to 2005, 1285 oocytes from 459 patients (average age: 36 years) were retrospectively analyzed. The 459 patients underwent ICSI because of fertilization disorders and oligozoospermia. Follicle stimulation was via either Clomid or the long protocol. Human chorionic gonadotropin was administered to induce ovulation and oocyte retrieval was conducted 35 h later. After confirming the presence of a polar body, we immobilized the ovum at the 6 o'clock position, introduced the injection pipette at the 3 o'clock position and carried out ICSI. Results: When a sperm was located at a position that was opposite to the polar body, both classifications of Scott and Tesarik regarding embryo quality were distinctly low. Furthermore, a good embryo classification ensued when the sperm was located adjacent to the polar body. Conclusion: The zone in which the sperm was located did not always correlate with embryo quality; however, our study suggested that sperm location affects the synchronization of the nucleolus. When carrying out ICSI, it is important to take into consideration the insertion point of the sperm. (Reprod Med Biol 2007; 6: 171-174). PMID- 29699275 TI - Uterine rupture during pregnancy soon after a laparoscopic adenomyomectomy. AB - Although laparoscopic adenomyomectomy may be a possible risk factor for uterine rupture in subsequent pregnancy, few reports have described it. A 35-year-old woman became pregnant 1 month after laparoscopic adenomyomectomy. At the 28th week, uterine contraction occurred, leading to intravenous ritodrine infusion. Severe abdominal pain and a non-reassuring fetal heart rate occurred abruptly and an emergency cesarean section was carried out. The uterus ruptured at the site of previous surgery of the uterine body, which was reconstructed. The mother and the infant did well postoperatively. We report the second case of uterine rupture during pregnancy subsequent to laparoscopic adenomyomectomy. A history of adenomyomectomy and a short interval to subsequent pregnancy may be risk factors for uterine rupture. (Reprod Med Biol 2007; 6: 175-177). PMID- 29699276 TI - Short-term exposure of female rats to industrial metal salts: Effect on implantation and pregnancy. AB - Aim: The objective of this study was to characterize the adverse effects of industrial metal salts during the early stages of pregnancy. Methods: Successfully mated female rats were exposed to the following metal salts via intragastric intubation; manganese sulfate, lead acetate, aluminum chloride, ferrous chloride and ferric chloride in doses of 50 mg/kg body weight and chromium chloride and potassium dichromate in doses of 25 mg/kg body weight on days l-3 or 4-6 of pregnancy. Female rats were killed on day 20 of gestation and the pregnancy outcome was determined. Results: The administration of manganese sulfate, chromium chloride, potassium dichromate and ferric chloride to female rats on days 1-3 of pregnancy caused pregnancy failure. However, the administration of manganese sulfate and potassium dichromate reduced the number of implantations. The administration of manganese sulfate, potassium dichromate and ferric chloride reduced the number of viable fetuses. The total number of resorptions increased in the lead acetate, aluminum chloride, ferrous chloride and ferric chloride exposed groups. In contrast, the administration of manganese sulfate, aluminum chloride and ferric chloride on days 4-6 of pregnancy caused pregnancy failure. However, the administration of ferric chloride reduced the number of implantations. The administration of manganese sulfate, aluminum chloride, potassium dichromate, ferrous chloride and ferric chloride reduced the number of viable fetuses. The total number of resorptions increased in the manganese sulfate, lead acetate, aluminum chloride, potassium dichromate, ferrous chloride and ferric chloride exposed groups. Conclusion: This work demonstrates that the short-term exposure of female rats to industrial metal salts during the early stages of gestation would cause failure of pregnancy and produce fetotoxic or fetal resorptive potentials. (Reprod Med Biol 2007; 6: 179-183). PMID- 29699278 TI - Recombinant human albumin supports mouse blastocyst development, suppresses apoptosis in blastocysts and improves fetal development. AB - Aim: Human serum albumin (HSA) is usually added to human in vitro fertilization culture medium to support embryo development, but carries some risk of contamination with various other compounds. Recombinant human albumin (rHA) has been shown to be a chemically defined protein. We evaluated the effect of rHA on mouse embryo development. Methods: B6D2F1 pronuclear oocytes were cultured in protein-free potassium simplex optimized medium with non-essential and essential amino acids supplemented with rHA, HSA (1 mg/mL) or polyvinyl alcohol (PVA; 0.1 mg/mL) for 96 h. The incidence of apoptosis and the generation of nitric oxide (NO) in blastocysts and fetal development after embryo transfer were examined. Results: Blastocyst development was equal in the three supplements. The incidence of apoptosis and the generation of NO in blastocysts developed in rHA was significantly (P < 0.05) lower than in HSA or PVA. After transfer of blastocysts developed in rHA, the percentage of fetal development was significantly (P < 0.05) higher than in HSA or PVA (75.8 +/- 2.2%vs 46.8 +/- 7.5% or 42.4 +/- 3.9%, respectively). Conclusions: Supplementing culture medium with rHA resulted in decreased apoptosis and increased fetal development after embryo transfer. The results show that the presence of rHA in the culture medium is beneficial for producing high-quality blastocysts. (Reprod Med Biol 2007; 6: 195 201). PMID- 29699277 TI - Semen quality of Asian men. AB - After the controversial report by Carlsen et al. in 1992 showing a possible decline in human semen quality over the past 50 years, many laboratories investigated their own records of semen findings that had been kept for the past decades, and a significant decrease in sperm quality was reported from some laboratories, but not others. At the beginning of the 21st century, a definitive interpretation of this issue has not yet been offered; however, it seems plausible that there are large regional differences in semen quality. Decreases in semen quality have been reported from various regions around the world, and a concurrent rise in the incidence of other reproductive problems, such as testicular cancer and genital abnormalities, has been observed in many regions. However, most of the reports showing regional differences were from Western or Western-derived countries, despite the fact that Asia is the region with the highest population on earth. Recently we undertook a cross-sectional study on fertile men in Japan to describe the current status of semen quality of Japanese men. We took confounders into consideration to allow a comparison with a previous European study. Japanese fertile men proved to have a semen quality at the level of Danish men, who were reported to have the lowest level among the men examined in the European study. This low level of sperm concentration in fertile Japanese men may result from differences in lifestyle or other environmental factors, but we cannot rule out the possibility of ethnic differences caused by different genetic variation or combination. To address this issue we need more information on the reproductive function in Asian men, who have been reported to have certain differences in reproductive characteristics from Caucasian men. This article is an attempt to review our present knowledge concerning the current status of semen quality in healthy Asian men on the basis of the limited publications from Asia. (Reprod Med Biol 2007; 6: 185-193). PMID- 29699279 TI - Collection and culture of primordial germ cells from cynomolgus monkeys (Macaca fascicularis). AB - Aim: To clarify the location of primordial germ cells (PGC) in an embryo of target-age and to examine the culture environment of the PCG. Methods: The days of ovulation and fertilization were estimated by measuring the serum concentration of estrogen. Pregnancy was confirmed by measurement of the serum concentration of the beta subunit of macaque chorionic gonadotropin and by ultrasonography. We also examined the location of PGC in the embryo at the time of retrieval. Results: Results showed that PGC in an embryo were in the hindguts at day 30 postfertilization, arrived at the genital ridges via mesenteries at approximately day 33 postfertilization, and colonized the gonads by day 36 postfertilization. Conclusions: In conclusion, embryos collected on day 33 postfertilization are more suitable for obtaining PGC from cynomolgus monkeys. The PGC collected from cynomolgus monkey fetuses were cultured under conditions for the derivation and culture of human embryonic germ cells; enzymatically dispersed single cells were cultured on a SIM thioguanine-resistant ouabain resistant cells (STO) feeder layer with recombinant human leukemia inhibitory factor, recombinant human basic fibroblast growth factor and forskolin. The cells from genital ridges and mesenteries at day 33 postfertilization had alkaline phosphatase (ALP) activity in vitro for a maximum of 13 days. In contrast, ALP activity had been held for 2 months under the same culture condition when the cells were derived from the gonads at day 66 postfertilization. Derivation of an embryonic germ cell from a cynomolgus monkey was not achieved from these cultures. (Reprod Med Biol 2007; 6: 203-210). PMID- 29699280 TI - Hormonal and histological study on irregular genital bleeding in patients with endometriosis during treatment with dienogest, a novel progestational therapeutic agent. AB - Aim: Dienogest, a novel progestational 19-norsteroid, has been shown to have a therapeutic effect on endometriosis with its major side-effect being irregular genital bleeding. This study aimed to investigate the mechanism responsible for the bleeding seen during dienogest therapy. Methods: For this multicenter, single-dose, open-label study, dienogest at a daily oral dose of 2 mg was administered for 16 weeks to nine patients with endometriosis showing regular menstrual cycles. Weekly determinations of serum endocrine hormone levels during the course of the treatment period and histological endometrial biopsies at the onset of genital bleeding were undertaken. Results: All cases showed genital bleeding irregularly during the treatment period. Endometrial histological findings at the time of presentation of the bleeding revealed a secretory, inert or atrophic appearance of the epithelium, pseudo-decidualization in the stroma, and local hemorrhage around the regions of desquamation of epithelium and lysis in the subepithelial stromal tissue, which are characteristics of breakthrough bleeding known to occur with progestational agents. In contrast, no association with the course of genital bleeding was found with respect to changes in serum estradiol, progesterone, follicle stimulating hormone and luteinizing hormone concentrations, plasma dienogest concentration, endometrial thickness or follicular diameter. Conclusion: These results suggest that the genital bleeding seen in the period of medication with dienogest originated from breakthrough bleeding from the pseudodecidua, which reflects a direct progestational effect of dienogest on the endometrium. (Reprod Med Biol 2007; 6: 223-228). PMID- 29699281 TI - Effect of fatty acids on boar sperm motility, viability and acrosome reaction. AB - Aim: The present study was undertaken to determine which fatty acids improve motility, viability, and increase acrosome reaction (AR) in boar spermatozoa. Methods: Boar spermatozoa were washed, swum-up and incubated at 37 degrees C for 4 h in TALP medium supplemented with myristic, palmitic, stearic, lignoceric, oleic, linoleic, arachidonic, docosahexaenoic and palmitoleic acid. Sperm motility, viability and AR were evaluated during 4 h of incubation. Results: Results show that oleic and linoleic acid significantly improved (P < 0.05) the motility and viability of boar spermatozoa. The AR was significantly improved (P < 0.05) by oleic and arachidonic acid in almost all incubation periods. When combinations of oleic, linoleic and arachidonic acid were studied for motility, viability and AR, it was found that oleic plus linoleic acid significantly increased (P < 0.05) motility, whereas arachidonic plus oleic acid significantly increased (P < 0.05) AR. Conclusion: Unsaturated fatty acids, especially arachidonic acid, can improve boar sperm motility and AR. A combination of arachidonic and oleic acid is important for inducing boar sperm AR. (Reprod Med Biol 2007; 6: 235-239). PMID- 29699284 TI - Preservation of female fertility during cancer treatment. AB - Improvements in the success of cancer treatments have resulted in increased awareness of the long-term effects of treatment, of which gonadal failure is the most significant. Thus, preservation of fertility potential has become a major goal and could be realized by preventing ovarian toxicity or by cryopreservation of reproductive cells/tissues. This review aimed to critically discuss the current protocols for the management of chemotherapy-inducced/radiotherapy induced premature ovarian failure (POF). A medical approach using the gonadotropin-releasing hormone analog (GnRHa) may act to protect the gonads during radiation and/or chemotherapy by preferentially steering cells into cell cycle arrest with a decline in responsibility to the chemotherapeutic agents. Ovarian protection by GnRHa cotreatment against chemotherapy can enable the preservation of future fertility in survivors and prevent the bone demineralization and osteoporosis associated with hypestrogenism and POF. In vitro fertilization of retrieved oocytes could enable embryo freezing in some patients. Embryo cryopreservation is considered standard practice and widely available, but may seldom be used because of a lack of a male partner, the need to postpone cancer therapy for a few weeks and the possibility that an estrogen rise may be undesirable in sensitive cancer patients. Improvement in oocyte cryopreservation may offer additional possibilities; the prolonged culture of primordial and primary follicles in vitro is still unfeasible. Currently, the cryopreservation of ovarian cortex, which hosts thousands of immature follicles, is an investigational method, but has the advantage of requiring neither a sperm donor nor ovarian stimulation. Fertility preservation is often possible in women undergoing cancer treatment. To preserve the full range of options, fertility preservation procedures should be considered as early as possible during therapy planning. (Reprod Med Biol 2008; 7: 17-27). PMID- 29699285 TI - Effects of relaxin and IGF-I on capacitation, acrosome reaction, cholesterol efflux and utilization of labeled and unlabeled glucose in porcine spermatozoa. AB - Aim: Relaxin and insulin-like growth factor (IGF)-I have pronounced effects on the male and female reproductive tracts. The aim of this study was to investigate the effects of relaxin and IGF-I on the motility, capacitation, acrosome reaction, cholesterol efflux and utilization of glucose in porcine spermatozoa. Methods: Swim-up separated spermatozoa that had been washed twice were incubated at 37 degrees C for 1 or 4 h in modified Tyrode's albumin lactate pyruvate (mTALP) medium supplemented without (control) or with relaxin (20 ng/mL) or IGF-I (20 ng/mL) or both (10 + 10 ng/mL). Results: Progressive motility and the induction rate of capacitation and acrosome reaction were increased (P < 0.05) by relaxin and IGF-I alone or in combination, especially after 4 h of incubation. Relaxin alone or combined with IGF-I enhanced (P < 0.05) the cholesterol efflux after 4 h, whereas IGF-I alone did not show any significant effect on the cholesterol efflux compared with the control at any time point. The utilization rates of labeled and unlabeled glucose increased (P < 0.05) in spermatozoa incubated with relaxin or IGF-I alone or in combination compared with the control. Conclusion: Thus, supplementation of relaxin alone or combined with IGF I into the medium possibly plays a beneficial role in porcine spermatozoal prefertilization events in vitro. (Reprod Med Biol 2008; 7: 29-36). PMID- 29699286 TI - Growth of follicles of various animals following ovarian grafting under the kidney capsules of immunodeficient mice. AB - Aim: Various researchers have studied xenografting ovarian tissues into immunodeficient mice to accelerate the follicular growth of several mammalian species. In this study, the authors focused on the following three points in growing follicles in transplanted ovarian tissues under kidney capsules: the effects of the storage conditions of the donor ovarian tissues, the effects of donor age on the survival rates of grafted mouse ovaries, and the methods used to grow the follicles of xenografted bovine ovaries. Methods and Results: When ovaries stored for 0, 6, 12 or 24 h at 4 degrees C and at room temperature were transplanted under the kidney capsules of immunodeficient mice, fewer mouse and rabbit grafts survived following 24 h storage. The survival rates of bovine grafts were relatively low for all storage times. When mouse ovaries were held for 24 h at 4 degrees C or at room temperature, low-temperature storage effectively improved the survival rates of the grafts. Although the survival rates of grafted genital ridges containing premeiotic germ cells from fetuses and grafted ovaries from mice 0, 10, 20, 40 and 80 days after birth were similar among donors of different ages, the cleavage rate of oocytes following insemination was significantly lower in the grafts from the ovaries of 80-day-old mice. Antral follicles formed in surviving bovine ovarian grafts. Cumulus-oocyte complexes were collected from the grafted ovaries of fetuses and calves, and the oocytes reached the metaphase II stage following culture, but they did not develop to the pronuclear stage after in vitro fertilization. Conclusion: Our findings provide basic data on xenografting ovarian tissues into immunodeficient mice to accelerate the growth of follicles. (Reprod Med Biol 2008; 7: 45-54). PMID- 29699287 TI - Regulation of hyperactivation of hamster spermatozoa by progesterone. AB - Aim: Although it is accepted that progesterone (P) induces acrosome reaction through non-genomic regulation, it is not well known if P also affects hyperactivation of sperm. Methods: Hamster spermatozoa were hyperactivated by incubation for 4 h on modified Tyrode's albumin lactate pyruvate medium and recorded on a DVD via a charge-coupled device camera attached to a microscope with phase-contrast illumination and a small CO2 incubator. Phosphorylation of proteins was detected by western blotting using antiphosphotyrosine antibodies. Results: Sperm hyperactivation was significantly increased and accelerated by a non-genomic signal of P. Although acceleration of motility of hyperactivated sperm occurred with 10, 20 and 40 ng/mL P, the most effective concentration was 20 ng/mL. Progesterone also significantly increased 80-kDa tyrosine phosphorylation of sperm proteins. Both extracellular Ca2+ and albumin were essential for sperm hyperactivation, and the former was also essential for maintaining sperm flagellar movement. Moreover, phospholipase C (PLC) was associated with the regulation of hyperactivation by P. Conclusion: It is likely that P regulates sperm hyperactivation by a non-genomic signal in relation to tyrosine phosphorylation and PLC. (Reprod Med Biol 2008; 7: 63-74). PMID- 29699288 TI - Mild stimulation with clomiphene citrate in combination with recombinant follicle stimulating hormone and gonadotropin-releasing hormone antagonist and its influence on serum estradiol level and pregnancy rate. AB - Aim: The mild ovarian stimulation protocol for in vitro fertilization (IVF) is carried out to minimize adverse side-effects as well as cost. While performing mild ovarian stimulation with a gonadotropin-releasing hormone (GnRH) antagonist, the pregnancy rate was examined in cases that exhibited a serum estradiol (E2) drop down. Methods: In this study, 174 patients who requested mild ovarian stimulation for IVF began clomiphene citrate on day 3 and recombinant follicle stimulating hormone (FSH) on day 5 of their menstrual cycles. A GnRH antagonist was administered when the dominant follicle reached a diameter of 14 mm. Serum luteinizing hormone and estradiol were measured at the time of GnRH antagonist administration and at the time of human chorionic gonadotropin (hCG) injection. Pregnancy rates and implantation rates were compared between 24 cycles in which the E2 level fell at the time of hCG injection and 150 cycles in which it did not fall. Results: The pregnancy rate in the cases in which the E2 level fell (25% decrease) at the time of hCG injection was significantly lower than it was in the cases in which it did not fall (16.7 vs 41.0%). The implantation rate for the cases in which the E2 level fell was also lower than that of the control group (7.0 vs 31.0%). There was no significant difference in the number of good-quality embryos between the two groups. Conclusion: When performing the mild ovarian stimulation protocol, serum E2 should be followed. It is prudent to avoid embryo transfer in the same cycle in cases that exhibit E2 drop down. (Reprod Med Biol 2008; 7: 85-89). PMID- 29699290 TI - Large-scale questionnaire survey of erectile dysfunction drugs in Japanese men. AB - Aim: The aim of the present study was to investigate the assessment of currently prescribed drugs and approaches to overall erectile dysfunction (ED) therapy. Methods: A large-scale questionnaire survey was conducted in patients with ED who had taken an ED drug in the past 2 months. Results: Of the 308 patients surveyed, 23% became aware of having ED more than 3 years ago. In the early stages, the patients frequently experienced 'anxiety and a sense of loss' and 'irritation and powerlessness'. The ED drugs taken were sildenafil and vardenafil in 65 and 31% of the patients, respectively. Although their efficacy was generally high, approximately 80% of the patients (younger patients in particular) experienced some problems with these medications. As negative assessments, the difficulty in finding a good time to take the drug and the strange sensation of the drug forcing the patient to have an erection were pointed out. Conclusion: Use of an ED drug such as tadalafil, which produces long-lasting effects and allows more spontaneity in sexual activity, will improve ED symptoms in a favorable manner, and will not only improve the self-image of the ED patients, leading to activation and fulfillment of their lives as a whole, but will also enhance the satisfaction and security of their partners. (Reprod Med Biol 2008; 7: 105-114). PMID- 29699289 TI - Angiogenesis in the human corpus luteum. AB - Angiogenesis is important for the formation and development of the corpus luteum and for maintenance of luteal function. Blood vessel regression is an important physiological phenomenon in the corpus luteum, which is associated with tissue involution during structural luteolysis. Angiogenesis actively occurs during the early luteal phase and is completed by the mid-luteal phase. Perivascular cells (pericytes) increase in number from the early luteal phase to the mid-luteal phase, suggesting that blood vessels are gradually stabilized until the mid luteal phase. In the corpus luteum undergoing luteolysis, blood vessels and pericytes decrease in number, which is related to structural involution. In the corpus luteum of early pregnancy, the number of blood vessels with pericytes increases, suggesting that angiogenesis occurs again, accompanied by blood vessel stabilization. These changes in vasculature of the corpus luteum are regulated by the collaboration with vascular endothelial growth factor, which is involved in proliferation of vascular endothelial cells, and angiopoietins, which are involved in stabilization of blood vessels. This review focuses on angiogenesis, blood vessel stabilization and blood vessel regression during the divergent phases of luteal formation, luteal regression and luteal rescue by pregnancy. (Reprod Med Biol 2008; 7: 91-103). PMID- 29699291 TI - Retrograde vasal sperm aspiration in anejaculatory patients with spinal cord injury. AB - Aim: This paper describes our experience with retrograde vasal sperm aspiration (ReVSA) in anejaculatory patients with spinal cord injury. Methods: We performed 11 vasal sperm aspiration procedures on eight patients presenting with neurogenic anejaculation associated with spinal cord injury at our institute between 2004 and 2007. This procedure was conducted under local anesthesia with a spermatic block. A 24G needle was inserted into the vas in a retrograde fashion. Sperm washing medium was gently injected into the proximal vas several times and collected. Aspirated sperm was cryopreserved for intracytoplasmic sperm injection. Results: Adequate motile sperm was obtained from all patients. All couples underwent intracytoplasmic sperm injection; clinical pregnancies were achieved in eight cases (two ongoing pregnancies and the births of six healthy babies). Conclusion: Retrograde vasal sperm aspiration is a reliable method for the consistent recovery of sperm of sufficient quality to afford a high pregnancy rate and in sufficient quantity to permit cryopreservation of excess sperm for future use. (Reprod Med Biol 2008; 7: 115-118). PMID- 29699292 TI - Successful pregnancy after artificial insemination in a case of human seminal plasma allergy. AB - Human seminal plasma allergy in women is uncommon, but causes a variety of serious reactions, including urticaria, dyspnea and vomiting, in those that are affected. Semen barriers, such as condoms, are the most widely advocated method for avoiding these reactions. However, this is not acceptable to couples who wish to have children. We present a case of a woman with human seminal plasma allergy who became pregnant after the eighth cycle of artificial insemination using washed sperm from her spouse. (Reprod Med Biol 2008; 7: 119-122). PMID- 29699293 TI - Effect of amino acids and dipeptides on the acrosome reaction and accumulation of ammonia in porcine spermatozoa. AB - Aim: The present study was designed to investigate the effect of amino acids and their dipeptides in the medium related to the urea cycle on the motility, viability, acrosome reaction (AR) and accumulation of ammonia in the medium over different incubation periods in porcine spermatozoa and to assess the utilization of glucose. Methods: Porcine spermatozoa were washed, swim-up and incubated at 37 degrees C for 0-4 h in mTALP medium supplemented with 75-600 umol/L ammonia. Amino acids (1.0 mmol) or their dipeptides (2.0 mmol) were added individually to the mTALP medium containing either no ammonia or 300 umol/L of ammonia. The viability and AR of porcine spermatozoa were assessed using the triple-staining technique and the accumulation of ammonia in the medium was measured using the indophenol method. Results: The motility, viability and AR were adversely affected (P < 0.05) by concentrations of ammonia >=300 umol/L compared with the control. Supplementation of l-alanyl-l-glutamine (AlaGln), l-glycyl-l-glutamine (GlyGln) and AlaGln + GlyGln in the presence of 300 umol/L ammonia significantly increase (P < 0.05) the rate of motility, viability, AR, incorporation, accumulation of ammonia and oxidation of 14C(U)-glucose compared with the ammonia supplement control. Conclusion: AlaGln and GlyGln in mTALP medium were more stable and effective than the individual amino acids in reducing the accumulation of ammonia, and subsequently increasing the rate of AR and the utilization of glucose in porcine spermatozoa. (Reprod Med Biol 2008; 7: 123-131). PMID- 29699294 TI - The present status of artificial oocyte activation in assisted reproductive technology. AB - Intracytoplasmic sperm injection (ICSI) is the most effective treatment for achieving fertilization in assisted reproductive technology (ART). However, fertilization failure occurs. The incidence of fertilization failure after ICSI is 1-5%. Approximately 50% of fertilization failure cases could be attributed to the abnormality of sperm factor. As the fertilization fails after ICSI using mature sperm, round spermatids and globozoospermia, artificial oocyte activation may provide a means of improving fertilization rates in such cases. The oocyte activation treatments used in clinical research include calcium (Ca) ionophore treatment, electrostimulation and strontium treatment. In terms of the efficiency of oocyte activation, electrostimulation and Ca ionophore gave better outcomes than strontium treatment. Strontium treatment causes Ca2+ oscillations in mice, so it has been viewed favorably. However, in human oocytes calcium oscillation has not been observed. The fertilization rate after ICSI was low in the case of globozoospermia and wiht round spermatids. Some cases of pregnancy were achieved by ICSI alone and oocyte activation methods were not essential in these cases. Among the various oocyte activation methods currently used, it should be noted that issues of genetic safety have not been addressed for the combined use of these oocyte activation methods. (Reprod Med Biol 2008; 7: 133-142). PMID- 29699296 TI - Attitudes toward oocyte donation among medical and nursing students and couples who have recently become parents: A Swedish study. AB - Aim: The aim of the present study was to investigate attitudes toward oocyte donation and receiving oocytes in relation to gender, demographic variables and other factors that could influence these attitudes, such as anonymity of the donor and financial compensation. Methods: The study population consisted of 595 subjects divided into two groups; one group contained men and women who had recently become parents and the other group consisted of medical and nursing students. All subjects were asked to answer a study-specific questionnaire. Results: The proportions of respondents positive toward oocyte donation were 32% in the student group and 37% in the parental group. Of the respondents in the student group, 87% were positive toward donating organs other than oocytes compared with 78% in the parental group (P < 0.05). In the parental group, the respondents that were positive toward organ donation in general were also more positive toward donating/partner donating and receiving/partner receiving oocytes (P < 0.001 and P < 0.01, respectively). The majority of the respondents stated that their attitudes were not affected by anonymity of the donation, financial compensation or knowing the outcome of the donation. Conclusion: Respondents' attitudes were unaffected by anonymity of the donation, financial compensation and knowing the outcome of the donation. However, the data suggest that respondents who were positive toward organ donation in general were also more positive toward donating/partner donating and receiving/partner receiving oocytes. (Reprod Med Biol 2008; 7: 161-168). PMID- 29699295 TI - Increase in the concentration of cytosolic-free calcium induced by human follicular fluid was decreased in single human spermatozoon with abnormal morphology. AB - Aim: The increase in the concentration of cytosolic-free calcium ([Ca2+]i) induced by follicular fluid or progesterone has been reported to promote an acrosome reaction and alternation in several motion parameters in human sperm (hyperactivation). We previously reported that populations of sperm in cell suspension obtained from infertile men with abnormal morphology exhibited lower mean peak progesterone-evoked [Ca2+]i compared with morphologically normal sperm using cell-suspension methods. In the present study, the change in [Ca2+]i in individual normally and abnormally shaped spermatozoa was compared. Methods: The change in [Ca2+]i induced by human follicular fluid in individual spermatozoa with normal and abnormal morphology was compared using the fluorescent calcium sensitive dye fluo-3/AM. The spatial distribution of the increase in [Ca2+]i in single sperm was also investigated. Results: The [Ca2+]i of normally shaped spermatozoa increased rapidly after the administration of human follicular fluid. The response reached a peak within 2-3 s and then slowly declined to a plateau phase. The baseline and peak fluorescence in spermatozoa with abnormal morphology was lower when compared with normal spermatozoa. The follicular-fluid-induced increase in [Ca2+]i (expressed as a percentage increase in [Ca2+]i over basal) in morphologically abnormal sperm was 39.2 +/- 5.3% (n = 107, mean +/- standard error), which was smaller than that of morphologically normal sperm (61.6 +/- 5.7%, n = 100, P < 0.005) from seven healthy donors. The follicular-fluid-induced [Ca2+]i increases observed in sperm with morphologically abnormal mid-pieces (20.9 +/- 4.3%, n = 12, P < 0.05) or tails (40.7 +/- 6.0%, n = 92, P < 0.05) were lower than those of morphologically normal spermatozoa (61.6 +/- 5.3%, n = 101). The follicular-fluid-induced [Ca2+]i increase of morphologically normal spermatozoa from infertile couples (35.1 +/- 6.3%, n = 25, P < 0.05) was also found to be lower than that of morphologically normal spermatozoa from healthy donors. Conclusion: The present study shows that spermatozoa with abnormal morphology in healthy donors have disorders of signal transduction, as do normally shaped sperm in men from infertile couples. (Reprod Med Biol 2008; 7: 143-149). PMID- 29699297 TI - Different regulation of tissue inhibitors of metalloproteinases-1, -2 and -3 in human endometrial stromal cells during decidualization in vitro. AB - Aim: Endometrial tissue inhibitors of metalloproteinases (TIMPs) appear to play an essential role during early implantation by modulating the invasiveness of the trophoblast. The expression of TIMP-1, TIMP-2 and TIMP-3 in human endometrial stromal cells (ESC) was investigated during decidualization in vitro. Methods: Endometrial stromal cells were isolated from hysterectomy specimens from premenopausal women undergoing surgery for benign reasons. Decidualization in vitro was induced by the application of 1 umol/L progesterone and 30 nmol/L 17beta-estradiol over 9 days. The expression of TIMP-1, TIMP-2 and TIMP-3 in ESC was measured by semiquantitative real-time reverse transcription polymerase chain reaction and enzyme-linked immunosorbent assay over intervals of 3 days. Results: Decidualization in vitro was confirmed by a significant increase in prolactin expression. TIMP-1 and TIMP-2 mRNA and secreted protein showed no significant changes over the time-course of decidualization. In contrast, TIMP-3 was upregulated during the first 3 days of decidualization. An eightfold upregulation was observed until day 6, and the effect was less pronounced by day 9. Conclusion: These results suggest a regulatory role of the TIMP system for endometrial differentiation in the second half of the menstrual cycle and in early implantation. The expression pattern of endometrial TIMP-3 might be important for the regulation of trophoblast invasion. (Reprod Med Biol 2008; 7: 169-175). PMID- 29699300 TI - A new stage and a new partner for RMB. PMID- 29699301 TI - Inhibition of apoptosis by ascorbic and dehydroascorbic acids in Xenopus egg extracts. AB - Purpose: The viability of mammalian eggs after ovulation is reported to be improved by the presence of ascorbic acid in the culture medium. However, the pro survival mechanisms of ascorbic acid are poorly understood. The molecular pathways of apoptosis are evolutionarily conserved among animal species, and Xenopus eggs are technically and ethically more suitable for biochemical analyses than mammalian eggs. We used Xenopus egg cytoplasmic extracts to examine the direct intracellular effects of ascorbic acid. Methods: Incubation of egg extracts for more than 4 h induces the spontaneous release of cytochrome c from mitochondria. This event triggers the activation of caspases, cleavage of substrate proteins, and execution of apoptosis. Multiple signal transduction pathways including proteolysis and protein phosphorylation are also involved in this process. We examined whether any of these events might be inhibited by the addition of ascorbic acid. Results: Ascorbic acid showed no effect against cytochrome c release, but prevented caspase activation and substrate cleavage. Ascorbic acid also blocked the proteolysis of apoptosis inhibitor proteins and the dephosphorylation of p42 MAP kinase. However, dehydroascorbic acid (oxidized form of ascorbic acid) and acetate (unrelated acid) were equally effective, indicating that these effects were primarily due to their acidity. In addition, dehydroascorbic acid inhibited caspase activities directly in vitro. Conclusions: The anti-apoptotic effect of ascorbic acid in Xenopus egg extracts is mainly due to cytoplasmic acidification rather than its intracellular antioxidant activity. Instead, oxidative conversion of ascorbic acid into dehydroascorbic acid may inhibit apoptosis through the inhibition of caspases. PMID- 29699302 TI - Effect of glutathione on the development of rat embryos following microinsemination. AB - Purpose: The present study was carried out to evaluate the role of glutathione on rat embryo developmental potential after ICSI. We observed the effects of glutathione on the development of non-treated rat embryos, ICSI embryos and embryos with sham injection treatment. The development of glutathione microinjected embryos was also observed. Methods: Oocytes and fertilized embryos were obtained from superovulated Wistar-Imamichi rats and cultured in mR1ECM medium. Oocytes and embryos were then allowed to develop to assess the effect of glutathione on the development rate in intact embryos, micro-injected embryos and ICSI embryos. Results: (1) In the intact embryo, the proportion of blastocyst stage development increased when 0.01 mM GSH was added to the medium compared to the control. (2) Microinjection of glutathione (GSSG, GSH) into the embryo increased development at each stage, and the addition of 0.2 nM GSSG or GSH significantly increased blastocyst development, in comparison to that of the control (P < 0.05). (3) Compared to the control, all the GSSG and GSH concentrations improved damaged blastocyst development, where 0.01 mM GSH improved significantly (P < 0.05). (4) The addition of glutathione in the medium increased the rate of blastocyst development after ICSI. A significantly higher number of TE and total cells were obtained in the micro-injected embryo with both of the 0.02 mM GSSG and GSH treatments (P < 0.05). Conclusions: The addition of glutathione into the culture media can improve early embryo development and is capable of repairing the damage of ICSI rat embryos. PMID- 29699303 TI - The beneficial effect of fructose and glucose on in vitro maturation and the fertilization of porcine oocytes. AB - Purpose: This study was conducted to investigate the effects of supplementing fructose in the culture medium on in vitro maturation (IVM), in vitro fertilization (IVF), and metabolism of porcine oocytes. Methods: Porcine oocytes were matured in vitro in modified North Carolina State University 37 medium (NCSU 37) and then supplemented with either glucose (5.5 mM), fructose (5.5 mM), or glucose (2.75 mM) plus fructose (2.75 mM). The maturation and fertilization of oocytes, and the incorporation and oxidation of 14C-glucose, 14C-fructose, and 14C-methionine in oocytes at different stages of development were examined. Results: The supplementation of glucose plus fructose significantly promoted (P < 0.05) oocytes germinal vesicle break down (GVBD), maturation to metaphase II (MII), penetration by spermatozoa, and male pronuclear formation compared with glucose. The incorporation and oxidation of 14C-methionine into the oocyte significantly increased (P < 0.05) with glucose plus fructose supplementation than glucose. A significantly higher (P < 0.05) rate of incorporation and oxidation was achieved with 14C-fructose compared to 14C-glucose. Conclusions: Glucose plus fructose supplementation improved maturation, penetration by spermatozoa, male pronuclear formation, and energy metabolism by porcine oocytes. PMID- 29699304 TI - Assessment of fertility by sperm mechanical energy using computer-assisted sperm analysis system. AB - Purpose: It is known that the energy distribution of sperm obeys the following equations and the total mechanical energy in a sperm population is expressed as nKlambda * a constant. nKlambda/102 is defined as the sperm energy index (SEI). [Formula: see text] Here, P is the existing probability density of sperm, t is the square of amplitude of lateral head displacement, lambda is the mean of t, n is the number of motile sperm in semen in a measurement field, and K is a constant determined for each semen sample. These values can be obtained with the use of computer-assisted sperm analysis (CASA). Methods: Sperm motility parameters were measured using CASA in 163 ejaculated semen samples from 47 infertile men (infertility group), and 162 ejaculated semen samples from 45 fertile men (natural pregnancy group). Klambda is defined for the present investigation as the mean energy index (MEI). SEI and MEI were obtained according to the methods described in sperm energy theory. Results: There were no natural pregnancy subjects with SEI < 0.5. All subjects with MEI > 2.0 and SEI > 1.0 were in the natural pregnancy group. Conclusions: An assessment of fertility was possible by using the sperm energy index. PMID- 29699305 TI - The dilemma faced by patients who undergo single embryo transfer. AB - Purpose: The aim of this study was to identify the factors that contribute to the decision to choose single embryo transfer (SET). Methods: Two hundred and nine patients who underwent ART treatment in our clinics between April 2006 and May 2007 were enrolled in this study. All patients had elected to undergo SET before the start of each treatment cycle; a questionnaire was administered to all patients prior to the SET procedure. Results: The mean age of the patients was 34.6 years old (range: 24-45 years). The mean number of redundant embryos was 3.7 (range: 1-17), and the pregnancy rate per embryo transfer was 25.7%. A total of 121 patients (57.9%) who underwent SET returned their questionnaires. Based on the results of questionnaire, 56.2% of patients who received SET waived their right to choose between single and double embryo transfer. Among patients who selected SET, 67.6% believed that the pregnancy rate resulting from double embryo transfer (DET) is significantly greater than that associated with SET, and 25% of patients wanted to have twins. The majority of patients (80.9%) who underwent SET understood that multi-fetal pregnancy increases the risk of complications during gestation and delivery. Among all patients who completed the questionnaire, 72.8% believed that the number of transferred embryos should not be controlled by law. Conclusions: The results of the present study show that greater than one-half of patients who underwent SET were faced with a dilemma--the difficult choice between their own desires and their clinician's recommendation. PMID- 29699306 TI - Effect of relaxin and IGF-I on the pre-implantation development of Mongolian gerbil (Meriones unguiculatus) embryos in vitro. AB - Purpose: Both relaxin and insulin-like growth factor (IGF) are members of the insulin super family. This study aimed to investigate the effect of relaxin and IGF-I on the pre-implantation of Mongolian gerbil of blastocyst development in vitro. Methods: Blastocysts and eight-cell stage embryos were collected from female gerbils. Eight-cell embryos and blastocysts were cultured in mM16 medium supplemented with or without relaxin or IGF-I for 24 h. Blastocysts were counted for total, inner cell mass (ICM) and trophectoderm (TE) cell numbers, and assessed apoptosis incidence. In addition, to measure incorporation of 3H methionine, blastocysts were cultured for 3 h with relaxin or IGF-I, washed with trichloroacetic acid and measured by liquid scintiration counter. Results: Relaxin (200 ng/ml) increased total, TE and ICM cell numbers of blastocyst (P < 0.05) when it was compared with the control. IGF-I (150 ng/ml) also has influence on total and ICM cell numbers of blastocyst when compared with control. Apoptosis incidence was relatively low, and a significant difference was not observed between each group. The effect of relaxin on incorporation of 3H-methionine was higher than the control group (P < 0.05). Relaxin increased the developmental rate from the eight-cell stage to blastocyst (P < 0.05). Conclusions: In conclusion, relaxin and IGF-I stimulated protein synthesis and increased cell numbers of blastocysts, promoting development of the gerbil embryo in vitro culture. PMID- 29699307 TI - Non-genomic regulation of mammalian sperm hyperactivation. AB - Although it has been suggested that the acrosome reaction is induced through non genomic regulation in a ligand-dependent manner, it is not known whether hyperactivation is similarly regulated. Progesterone and melatonin have been identified as ligands that regulate hyperactivation, the former through non genomic regulation with phospholipase C and the latter most likely through a reactive oxygen species-mitogen activated protein kinase cascade. Both may be involved in spontaneous regulation of hyperactivation via tyrosine phosphorylation. The concentration of many hormones changes according to environmental conditions and biological rhythms, which will modulate ligand dependent regulation of hyperactivation. PMID- 29699308 TI - Time-dependent changes in cardiovascular function during copulation in male rats. AB - Purpose: Sudden cardiac death after ejaculation has been reported in humans and highlights the important relationship between sexual behavior and the heart. The rat is an extremely useful animal model for investigating reproductive function in male mammals. In this study, we examined the relationship between autonomic nervous system activity and the circulatory system during sexual behavior in male rats. Methods: Male Wistar-Imamichi rats were exposed to female rats in estrous and heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), and plasma noradrenaline (NA) and adrenaline (Ad) concentrations were measured by telemetry during copulation. Results: The resting HR was 365.5 +/- 18.4 beats/min (mean +/- SE), which increased to 531.2 +/- 21.1 beats/min at ejaculation and decreased to 404.6 +/- 30.7 beats/min 1 min after ejaculation. At rest, SBP and DBP were 123.8 +/- 6.6 and 81.5 +/- 4.1 mmHg, respectively, which increased to 154.5 +/- 5.9 and 112.1 +/- 7.3 mmHg at ejaculation. Baseline plasma Ad and NA concentrations were 151.6 +/- 32.0 and 248.5 +/- 22.5 pg/ml, respectively, and these increased to 393.8 +/- 89.9 and 792.7 +/- 154.0 pg/ml at ejaculation, after which they decreased to resting levels. The rate of increase in NA at ejaculation differed significantly from that of Ad. Conclusions: The load on the circulatory and autonomic nervous systems is controlled by a rapid decrease in HR and NA concentration immediately after ejaculation, such that the male rat is prepared for the next copulation. PMID- 29699309 TI - Embryo development after intracytoplasmic sperm injection can be predicted by assessment of sperm nuclear chromatin. AB - Purpose: To assess the influence of structural differences in sperm nuclei on embryo development in intracytoplasmic sperm injection (ICSI). Methods: Semen obtained from forty-four infertile patients who underwent ICSI was examined. In assessing blastocyst development, only those patients who had successfully obtained over five fertilized eggs were included to exclude any oocyte factors (n = 22). Spermatozoa were assessed using excitation fluorescence flow cytometry with acridine orange and the sperm chromatin dispersion (SCD) test. Results: There was a significant positive correlation between the COMP values obtained from flow cytometry and blastocyst formation. (r = 0.477, p = 0.025). There was a significant negative correlation between the SCD values representing DNA fragmentation and blastocyst formation. (r = 0.796, p < 0.001). COMP values and SCD values were independent parameters to assess sperm nuclear quality regarding embryo development in vitro (r = 0.224, p = 0.080). Conclusion: Results suggest that injection of spermatozoa with fewer disulfide bonds and less nuclear DNA fragmentation could achieve better blastocyst formation in human ICSI. Assessment of sperm chromatin should help to predict embryo development after ICSI. PMID- 29699310 TI - Thy-1+ cells isolated from adult human testicular tissues express human embryonic stem cell genes OCT3/4 and NANOG and may include spermatogonial stem cells. AB - Purpose: Spermatogonial stem cells (SSCs) are self-renewing cells whose progeny are committed to differentiate into spermatozoa; this is a life-long process in male mammals. There are several methods for obtaining enriched populations of mouse SSCs, and immunological separation using surface antigens is a commonly used technique. The study of human SSCs is much less advanced. Methods: We used biopsied human testicular tissues [obstructive azoospermia patients (n = 5) and patients who underwent a testis biopsy as part of an evaluation for infertility (n = 7)] to obtain Thy-1+ cells. Thy-1-a glycosyl phosphatidylinositol-anchored surface antigen-is a marker uniquely expressed on SSCs that is used to isolate SSC-enriched cell populations in mice. The Thy-1+ cells from human testicular tissues were cultured in a basic system consisting of serum-free medium and mitotically inactivated STO (SIM mouse embryo-derived thioguanine- and ouabain resistant) cell feeders with added growth factors: glial cell line-derived neurotrophic factor (GDNF), basic fibroblast growth factor (bFGF), and GDNF family receptor alpha1 (GFRalpha-1). Results: The Thy-1+ cells were maintained in vitro using this system for 1 week. The Thy-1+ cells expressed OCT3/4 and alkaline phosphatase, like mouse SSCs. They also expressed NANOG. Thy-1+ cells injected into nude mice did not cause tumor formation over a period of at least 6 months. Conclusions: These results support the possibility that the Thy-1+ cell population included human SSCs, and that Thy-1 may be a marker for human SSCs. PMID- 29699311 TI - A postpartum separation induces c-Fos expression in the supramammillary nucleus of lactating rats. AB - Aim: Elucidation of the neural mechanism of maternal behaviors is a medically and biologically important research task. The rat is the laboratory animal most extensively analyzed for maternal behaviors. However, the neural mechanism that maintains the motivation of postpartum rats for maternal behaviors has not yet been elucidated. In this study, we aimed to identify brain regions involved in the maintenance of motivation for maternal behaviors by detecting brain regions that exhibit changes in nerve activity when the mother rat is separated from her pups. Methods: Lactating mother rats were separated from their pups on postpartum day 3 and kept away from the pups for a certain period of time, and brain regions that exhibited changes in nerve activity when the rats were separated from their pups and those that exhibited changes in nerve activity when the pups are returned were detected by immunohistochemistry using anti-c-Fos antibody, a marker for increased nerve activity. Results: Rats that were separated from their pups and with the pups returned later showed increases in the number of c-Fos immunoreactive (c-Fos-IR) cells in the medial preoptic area (MPA), the bed nucleus of the stria terminalis (BST), the caudal portion of posterior hypothalamic area (PH) and the supramamillary nucleus (SUM). In mother rats permanently separated from their pups, only the PH and SUM exhibited an increase in the number of c-Fos-IR cells. Conclusion: In rats, the SUM is involved in aversive memory and changes in the postpartum anxiety level. The observed increase in the number of c-Fos-IR cells in the SUM of mother rats separated from their pups suggests that the nerve activity change in the SUM, which is involved in aversive memory and anxiety, is involved in the maintenance of maternal behaviors. PMID- 29699312 TI - Laparoscopically-assisted transabdominal oocyte retrieval in an infertility patient with ovarian malposition. AB - Infertility patients with malpositioned ovaries have considerable difficulty conceiving naturally because of extended fallopian tubes and ovarian malposition; such patients turn for help to assisted reproductive technology (ART) treatment. For most of these patients, ovarian malposition prevents transvaginal oocyte retrieval, so the transabdominal approach for oocyte retrieval is required. One of our infertility patients presented with ovarian malposition, and laparoscopy assisted transabdominal oocyte retrieval was performed. We performed a Gonadotropin-releasing hormone agonist (GnRH-a) long protocol with human menopausal gonadotropin (hMG) ovarian stimulation, and used a standard transvaginal probe through the anterior abdominal wall for ovarian imaging and monitoring of the growing follicles. The patient underwent laparoscopically assisted transabdominal oocyte retrieval-9 oocytes were recovered, and 5 were fertilized, and 2 embryos were transferred to the patient's uterus. The patient became pregnant and a gestational sac was detectable by transvaginal ultrasonography, but she spontaneously miscarried. The patient then received several laparoscopically-assisted transabdominal oocyte retrievals and finally became pregnant following a thawed embryo transfer during a hormone replacement cycle, and now her pregnancy is going well. PMID- 29699313 TI - Possible causal factors of structural chromosome aberrations in intracytoplasmic sperm injection of the mouse. AB - Incidence of structural chromosome aberrations in mouse one-cell embryos produced by intracytoplasmic sperm injection (ICSI) with mature epididymal spermatozoa were influenced by sperm incubation medium and time. When spermatozoa were incubated in bicarbonate-buffered TYH for <=0.5 h, the embryo aberration rates were significantly higher than in vitro fertilization (IVF) embryos. However, after the incubation of spermatozoa in the same medium for >=2 h, the aberration rates were close to the IVF embryo level. When spermatozoa were incubated in bicarbonate-buffered mCZB, hepes-buffered H-TYH and H-mCZB, and phosphate buffered PB1, the increased incidences of aberrations were observed at any incubation time. In the case of sperm incubation in H-TYH, H-mCZB and PB1, the aberration rates increased in a time-dependent manner. Chromosome aberrations generated by ICSI were transmissible to offspring. On the other hand, the aberration rate in embryos derived from testicular spermatozoa was independent of the medium type and incubation time. Thus, the incubation media appears to have no effect on sperm chromatin. TYH can effectively induce capacitation and acrosome reaction, while H-TYH, H-mCZB and PB1 never induce these spermatozoal events. It is probable that the cholesterol-rich plasma membrane and intact acrosome injected into the ooplasm affect sperm chromatin remodeling, thus resulting in the generation of chromosome damage in ICSI embryos. PMID- 29699315 TI - Chromosome analysis of human refrozen embryos following fluorescence in situ hybridization. AB - Purpose: Several recent reports have discussed refrozen and thawed embryo transfer; however, the process may cause a degree of chromosomal damage and subtle genomic mutation. In view of this possibility, the purpose of this study was to investigate the incidence of aneuploidy in refrozen embryos. Methods: In order to investigate the incidence of aneuploidy and mosaicism observed in chromosome 1, fluorescent in situ hybridization (FISH) was used on surviving embryos that first underwent one freeze-thaw cycle, then were allowed to develop to the blastocyst stage, and subsequently survived a second freeze-thaw cycle. Results: Of 1,132 blastomeric nuclei analyzed from 15 refrozen embryos, disomy was found in 82.9%. In contrast, for the 11 blastocysts subjected to only one freeze-thaw cycle, disomy was noted in 78.4%. Of the 197 blastomeric nuclei analyzed in all arrested embryos, disomy was found in 51.8%. Conclusions: The refreezing process did not increase aneuploidy. The good and fair morphology groups demonstrated a higher percentage of disomy than the poor morphology group regardless of whether they were frozen once or twice. PMID- 29699314 TI - Antireproductive effect of calcium channel blockers on male rats. AB - Introduction: Drugs have been shown to adversely affect male fertility and recently anti-hypertensive drugs were added to the list. The anti-fertility effects of nifedipine and similar calcium channel blockers are well-illustrated in in vitro experiments but not in vivo. Purpose: The present study was designed to experimentally elucidate the sub-chronic effect of nifedipine, verapamil and diltiazem on sperm functions and reproductive hormone levels in vivo. Methods: Male rats (150-200 g) were divided into four groups of ten rats each. Group 1 (control) received distilled water; Group 2 received nifedipine 0.57 mg/kg BW; Group 3 were given verapamil 3.40 mg/kg BW and Group 4 were given diltiazem 2.57 mg/kg BW. Each drug-treated group had its own recovery group from which treatment was discontinued for 30 days before the animals were sacrificed. Blood samples were collected for hormonal assay of FSH, LH and testosterone. Semen evaluation was done and the testes, seminal vesicle, epididymis and prostate were removed, and weighed immediately. Results: Nifedipine, verapamil and diltiazem significantly decreased (P < 0.05) sperm count and motility in drug treated groups. The weight of the epididymis was significantly reduced (P < 0.05) in the drug treated rats. Semen parameters and other associated changes were restored after 30 days of drug withdrawal. Conclusion: Calcium channel blockers appear to have a reversible anti-fertility effect on male rats which does not occur through inhibition of the pituitary-gonadal axis. PMID- 29699316 TI - The impact of endometriosis, endometrioma and ovarian cystectomy on assisted reproductive technology. AB - Purpose: To assess outcomes in assisted reproductive technology (ART) in infertile women with endometriosis with respect to their concomitant endometrioma status and surgical history in our department. Methods: This is a retrospective case control study which analyzes informational data obtained at a university hospital. The study drew from a patient pool of 332 cases (877 cIVF/ICSI cycles) that took place in our department from 2006 to 2008. Sixty-one cases (97 cycles) had major indications for cIVF/ICSI with endometriosis. We classified groups from these 61 cases as follows: an unoperated endometrioma group (A) with 31 cycles, a postoperative endometrioma group (B) with 51 cycles, and a no endometrioma group (C) with 15 cycles. We analyzed and compared these three groups and also included a non-endometriosis tubal infertility group (D) with 27 cycles. Results: In the control group (D), serum FSH levels and the cancellation rates were significantly lower than those of other groups, and the number of developing follicles was higher. E2 levels before oocyte aspiration in the postoperative endometrioma group (B) was lower. Implantation, pregnancy, delivery and miscarriage rates were not significantly different among the four groups. Conclusion: The results suggest that endometriosis causes a decrease in endocrinologic ovarian function whether or not an endometrioma is also present. As for E2 level before oocyte aspiration, our results suggest that ovarian reserves might be reduced by endometrioma excision, but this is difficult to evaluate. In the endometriosis groups, cancellation rates were significantly higher, although when embryos were transferred the pregnancy rates were not significantly different when compared with the non-endometriosis group. As for infertile women with endometriomas, our results suggest that preexisting ovarian reserve is reduced by the presence of endometriosis, and ovarian reserve might also be reduced by excision of endometriomas. PMID- 29699317 TI - Retrospective analysis of laparoscopic salpingostomy and conservative expectant management of tubal ectopic pregnancy. AB - Purpose: To identify predictive factors for successful expectant management of ectopic pregnancy and to evaluate the prognosis for fertility after expectant management and laparoscopic salpingostomy. Methods: Forty-six cases of expectant management and eighty cases of laparoscopic salpingostomy for tubal ectopic pregnancy were retrospectively analyzed. Subjects were classified in three groups: those who underwent laparoscopic salpingostomy, those treated by expectant management only, and those treated by expectant management but requiring additional treatment. Results: The rates of tubal patency, intrauterine pregnancy and repeated ectopic pregnancy in the laparoscopic salpingostomy group were 75, 40, and 16%. The rates in the expectant management group were not significantly different: 72, 42 and 15%. Finally, the rates in the extra treatment group were 75, 39 and 15%. Success rate of expectant management was 54%. In 93% of cases expectant management was successfully completed when the initial levels of urinal hCG were less than 3000 mIU/ml and the levels of hCG 48 h later were less than 80% of the initial levels. However, expectant management alone was insufficient and required extra treatment in 90% of cases when the initial levels of hCG were 3000 mIU/ml and above or when the levels of hCG level 48 h later was 80% of initial levels and above. Conclusions: Expectant management in combination with salpingostomy is not only minimally invasive but also a useful way to preserve fertility. Initial urine hCG levels and their variation over time can help predict whether expectant management will succeed. PMID- 29699318 TI - Diagnosis and treatment methods for recurrent miscarriage cases. AB - Recurrent miscarriage is classically defined as three or more consecutive pregnancy losses. Established causes of recurrent miscarriage are antiphospholipid antibodies, uterine anomalies and abnormal chromosomes in either partner, particularly translocations. Embryonic aneuploidy is the most important cause of miscarriage before 10 weeks' gestation. It can be speculated that about 51% of patients with a history of three miscarriages experienced these because of abnormal embryonic karyotypes. It is not necessary to give any medication for such cases caused by an abnormal embryonic karyotype. Psychological tender loving care might be the most important requirement to continue conceiving till live birth results. PMID- 29699319 TI - Predictive factors of successful pregnancy after assisted reproductive technology in women aged 40 years and older. AB - Purpose: This study aimed to investigate the factors that predict successful pregnancy (live birth) in assisted reproductive technology (ART) for infertile women aged 40 and older. Methods: Patients who underwent first ART treatments at the age of 40 and older at our institution were enrolled. Several factors which can be evaluated before the first treatments were retrospectively compared among those patients who did and did not achieve live birth. Results: Nineteen of 119 patients delivered healthy babies. There was no significant difference of live birth rate among age groups of 40, 41 and 42. No women who underwent the first treatment at age 43 or older achieved live birth. In the successful group, significantly more women held FSH levels under 12 mIU/ml and had regular menstrual cycles (26-32 days) than unsuccessful women of the same age group. In addition, significantly fewer women in the successful group had prior ovarian surgery. Conclusions: Our results show that low FSH levels, regular menstrual cycles and absence of prior ovarian surgery were related to high live-birth rates and they are good prognostic factors in patients between 40 and 42 years of age. On the other hand, none of these parameters were correlated with success in women aged 43 and older. PMID- 29699320 TI - Aggravating effect of natural sand dust on male reproductive function in mice. AB - Purpose: Although adverse health effects of environment (such as cadmium, pesticides, diesel exhaust, etc.) on the male reproductive system have been suggested, there is little experimental evidence of such an effect of atmospheric sand dust. In the present study, the effects of sand dust (mineral particles) were investigated on the male reproductive system of mice. Methods: Two types of sand dusts (Asian sand dust and Arizona sand dust) were intratracheally administered (0.1 mg/mouse 4 times every other week) to ICR male mice and then male reproductive organ weight, daily sperm production (DSP), histological analysis and serum testosterone level were measured. Results: Histological examination showed that interstitial edema was produced by both sand dust types, and partial vacuolation of the seminiferous tubules was detected in the exposed mice. Moreover, exposure to these natural sand dusts significantly decreased DSP. On the other hand, there was no significant differences in serum testosterone concentration. Conclusions: These results suggest that natural sand dust-exposure produced adverse effects on mouse male reproductive function. PMID- 29699321 TI - Low fertility in vivo resulting from female factors causes small litter size in 129 inbred mice. AB - Purpose: 129 inbred mice show poor reproductive ability, as evidenced by small litters; however, the exact cause of this is unknown. In the present in vivo study we examined fertility and subsequent post-implantation development in an attempt to clarify the cause of small litter size in 129 mice. Methods: 129 or C57BL/6J females that displayed vaginal plugs 1 day after mating with males of the same strain were examined for the presence of fertilized eggs. Reciprocal matings were also performed between 129 and C57BL/6J mice. Subsequent post implantation development of fertilized eggs was examined by dissecting females 18 19 days after the vaginal plugs were found. Results: Mean numbers of recovered eggs were 7.9 and 8.0 in 129 and C57BL/6J mice, respectively. Half of the recovered eggs were unfertilized in 129 mice, whereas all were fertilized in C57BL/6J mice. Mean numbers of live fetuses 18-19 days after mating were significantly lower in 129 mice (4.7) than in C57BL/6J mice (7.3). In different types of pairings using both strains of mice, the fertility was significantly lower whenever 129 females were used. Conclusions: The small litter size in 129 mice is caused by low fertility resulting from female factors. PMID- 29699322 TI - Effect of relaxin on the decidual cell reaction in the Mongolian gerbil (Meriones unguiculatus). AB - Purpose: Differentiation of endometrial stromal cells into decidual cells occurs during embryo implantation and pregnancy. Recently, it has been reported that relaxin affects the decidualization of cultured human endometrial cells in vitro; however, there has been no study on the decidualization of the Mongolian gerbil (Meriones unguiculatus). The authors demonstrated artificially induced decidualization, and the effect of relaxin on decidualization in gerbils. Methods: Ten-to-twelve-week-old female Mongolian gerbils were ovariectomized, treated with estradiol, progesterone, and relaxin, and the uterine horn was stimulated. On day 10, uterine horns were measured for weight, protein concentration, and the incorporation of 14C-methionine; tissue sections were examined. Interleukin-11 (IL-11) primers were used for RT-PCR to confirm decidualization. Results: Decidualization can be induced artificially in gerbils. In general, the histological observations of gerbil decidual cells were very similar to those of rats. The uterine horn weight, protein content, and protein synthesis from 14C-methionine significantly increased in the relaxin-treated gerbils (P< 0.05). Mast cells in the relaxin-treated uterus had proliferated more than those of the non-relaxin-treated group, which was confirmed by IL-11 expression. Conclusions: We conclude that decidualization can be induced artificially, and relaxin increased weight of uterine horn, protein concentration, protein synthesis and IL-11 expression in gerbils. PMID- 29699323 TI - Differentiation of human round spermatids into motile spermatozoa through in vitro coculture with Vero cells. AB - Purpose: This study was undertaken to examine whether human early round spermatids will differentiate in an in vitro coculture with Vero cells. Methods: A total of 1450 and 400 isolated early round spermatids mechanically collected from two non-obstructive and three obstructive azoospermic men with a normal karyotype were cocultured on Vero cell monolayers in minimum essential medium plus 10% fetal bovine serum, with or without 50 or 100 IU/L FSH and 1 or 10 MUmol/L testosterone, at 32.5 degrees C, in an environment of 5% CO2 in air. Morphological changes of the spermatids were observed microscopically. Results: After 7 days of coculture, almost half (40-50%) of the round spermatids from both non-obstructive and obstructive azoospermic men resumed spermiogenesis in vitro. Only cells from the latter patients gave rise to spermatozoa, a few of which had a motile flagellum. Low concentrations of FSH and testosterone increased the percentage of in vitro spermiogenesis. Conclusions: Isolated round spermatids can resume spermiogenesis in vitro when cocultured on a Vero cell monolayer. PMID- 29699324 TI - Spontaneous ectopic pregnancy occurring in the remnant tube after ipsilateral salpingectomy: a report of 2 cases. AB - Ectopic pregnancy occurring in the remnant tube after ipsilateral salpingectomy is assumed to be rare. We report 2 cases of spontaneous ectopic pregnancy occurring in the remnant tube that were treated surgically. Even in spontaneous pregnancy, attention should be paid to the remnant tube so as not to miss an ectopic pregnancy after previous salpingectomy. PMID- 29699325 TI - Current concepts of the pathogenesis of endometriosis. AB - Endometriosis is a disease that causes the health of women of reproductive age to deteriorate. The implantation theory is the most widely accepted pathogenesis of the disease, although many points remain poorly understood concerning this theory. According to this theory, regurgitated endometrial debris has to go through various sequential events for the disease to develop. Recent studies have elucidated several aspects of these events. A remarkably reduced gene expression of GnRH II and an increase in uterine contraction-induced IL-8 secretion are suggested to be pathogenic changes in the eutopic endometrium of women with endometriosis. An increased level of osteoprotegerin in the peritoneal fluid of women with endometriosis is suggested to impede tumor necrosis factor (TNF) related apoptosis-inducing ligand (TRAIL)-induced apoptosis of endometriotic cells. An increase in the concentration of hepatocyte growth factor and a decrease in the concentration of interferon gamma-inducible protein-10 in the peritoneal fluid of women with endometriosis may stimulate the angiogenesis and development of endometriosis. Midkine, the concentration of which is very high in the follicular fluid of the ovary, may stimulate the growth of endometriosis at the time of ovulation. Immune cells, such as macrophages, lymphocytes, mast cells, and neutrophils, in endometriotic lesions are suggested to play important roles in the progression of the disease. For example, IL-4 from Th2 cells, IL-17 from Th17 cells, tryptase from mast cells, and some serine proteases from neutrophils have been shown to stimulate endometriotic stromal cells, suggesting their specific roles in endometriosis. Interestingly, adiponectin, a key factor in metabolism, also appears to be involved in the pathogenesis of endometriosis. These novel findings sustain the current understanding of the pathogenesis of endometriosis. PMID- 29699326 TI - Stem/progenitor cells and the regeneration potentials in the human uterus. AB - The human uterus is unique in that it possesses the tremendous regenerative capacity required for cyclical regeneration and remodeling throughout a woman's reproductive life. Not only must the uterus rapidly enlarge to accommodate the developing fetus, the endometrium must also regenerate with each menstrual cycle. This plasticity of the reproductive system has recently been highlighted. My research group and collaborators showed that functional endometrial tissue could be regenerated from only a small number of singly dispersed human endometrial cells, transplanted beneath the kidney capsule of severely immunodeficient mice. This artificially generated endometrium resembles the natural endometrium, and contains human blood vessels that invade the mouse kidney parenchyma. Additionally, it mimics normal hormone-dependent changes including proliferation, differentiation, and tissue breakdown (menstruation). The regenerative capacity of endometrial cells makes them ideal candidates for tissue reconstitution, angiogenesis, and human-mouse chimeric vessel formation. The smooth muscle cells of the uterus (myometrium) share the plasticity of the endometrium. This is evidenced by their capacity for dramatic, repeatable, pregnancy-induced enlargement. Regeneration and remodeling in the female reproductive tract allude to the existence of endometrial and myometrial stem cell systems. We have recently isolated candidate populations of adult stem cells from both the human endometrium and myometrium. Characterization of these endometrial and myometrial cells, along with the study of the mechanisms controlling their regeneration, will improve the understanding of the physiology and pathophysiology of the female reproductive tract. Furthermore, myometrial and endometrial stem-like cells might also represent a novel source of biological material that could be used for the reconstruction of not only the human uterus but other organs as well. PMID- 29699327 TI - Screening, epidemiology, molecular biology, and treatment strategies for endometriosis-associated ovarian cancer. AB - Objectives: This article reviews recent data on the biology, pathogenesis and pathophysiology of the different entity of epithelial ovarian cancer (EOC). Study design: The present article reviews the English language literature for screening, epidemiology, clinical diagnosis, natural history, preclinical and clinical trials, and promising molecular targets on EOC, particularly for clear cell EOC (cEOC) based on the gene expression profiling studies. Results: Prospective ovarian cancer screening trials in Japan showed that (1) serous-type EOC (sEOC) may exhibit a rapid progression possibly through de novo carcinogenesis, (2) the EOC risk was elevated significantly among patients with ovarian endometrioma (SIR = 8.95), (3) advancing age (>40 years) and the diameter of endometriomas (>9 cm) were independent predictors of development of EOC, (4) the benign-appearing ovarian masses are present several years before the EOC diagnosis in patients with endometriosis-associated EOC, and (5) the slightly elevated CA125 level is also typically present many years (>3 years) before the diagnosis in these patients. Upregulation of HNF-1beta and PLK-Emi1 genes were specifically detected in cEOC. In addition, the therapy currently used in renal cell carcinoma (RCC) should be considered as an attractive therapeutic option for cEOC. Conclusions: Ovarian endometrioma could be viewed as a neoplastic process, particularly in perimenopausal women. Understanding the mechanisms of endometriosis development and elucidating its pathogenesis and pathophysiology are intrinsic to prevention and the search for effective therapies of endometriosis-associated EOC. PMID- 29699328 TI - Metabolism of exogenous fatty acids, fatty acid-mediated cholesterol efflux, PKA and PKC pathways in boar sperm acrosome reaction. AB - Purpose: For understanding the roles of fatty acids on the induction of acrosome reaction which occurs under association of cholesterol efflux and PKA or PKC pathways in boar spermatozoa, metabolic fate of alone and combined radiolabeled 14C-oleic acid and 3H-linoleic acid incorporated in the sperm was compared, and behavior of cholesterol and effects of PKA and PKC inhibitors upon fatty acid induced acrosome reaction were examined. Methods: Semen was collected from a Duroc boar, and the metabolic activities of fatty acids in the spermatozoa were measured using radioactive compounds and thin layer chromatography. Cholesterol efflux was measured with a cholesterol determination assay kit. Participation of fatty acids on the AR through PKA and PKC pathways was evaluated using a specific inhibitor of these enzymes. Results: Incorporation rate of 14C-oleic acid into the sperm lipids was significantly higher than that of 3H-linoleic acid (P < 0.05). The oxidation of 14C-oleic acid was higher in combined radiolabeling rather than in one. The highest amounts of 3H-linoleic acid and 14C-oleic acid were recovered mainly in the triglycerides and phospholipids fraction, and 14C oleic acid distribution was higher than the 3H-linoleic acid in both labeled (P < 0.05) sperm lipids. In the 3H-linoleic and 14C-oleic acid combined radiolabeling, the incorporation rate of the radioactive fatty acids in all the lipid fractions increased 15 times more than the alone radiolabeling. Boar sperm utilize oleic acid to generate energy for hyperactivation (P < 0.05). Supplementation of arachidonic acid significantly increased (P < 0.05) cholesterol efflux in sperm. When spermatozoa were incubated with PKA or PKC inhibitors, there was a significant reduction of arachidonic acid-induced acrosome reaction (AR) (P < 0.05), and inhibition by PKA inhibitor is stronger than that by PKC inhibitor. Conclusions: Incorporation of unsaturated fatty acids, especially oleic acid, into triglycerides and phospholipids provides prerequisite energy for AR. Cholesterol efflux by arachidonic acid triggers AR. Arachidonic acid activated PKA and PKC pathway participate in induction of the AR. PMID- 29699329 TI - Down-regulation of murine testicular 17beta-HSD3 and hepatic CYP1A2 enzymes by a bovine testes extract. AB - Purpose: We investigated the effects of a bovine testes extract (BTE), which was developed as an alternative product for andropausal men, on expression of testicular enzymes responsible for sex hormone synthesis genes and a carcinogen activation related gene. Methods: Expression of testicular CYP1A2, CYP11A1, CYP17, 3beta-HSD, and 17beta-HSD3 mRNAs as well as hepatic CYP1A2 mRNA were semi quantitatively determined by RT-PCR. In addition, expression of hepatic CYP1A2 protein and methoxyresorufin O-demethylase activity were carried out. Results: Bovine testes extract did not alter the testicular expression of CYP11A1, CYP17, and 3beta-HSD mRNAs, while that of CYP11A1 was significantly down-regulated by testosterone. Interestingly, administration of BTE for 3 weeks significantly suppressed testicular 17beta-HSD3 and hepatic CYP1A2 mRNA. Correspondingly, methoxyresorufin O-demethylase (MROD) activity and expression of hepatic CYP1A2 protein were significantly decreased. Conclusions: These findings strongly suggested considering risks versus benefits and raised concerns regarding the use of BTE as an alternative medication or health supplement in andropausal men due to its potential for suppressing expression of both 17beta-HSD3 and CYP1A2 mRNAs, testicular enzymes responsible for sex hormone gene synthesis. PMID- 29699330 TI - A successful conception by a shift from human menopausal gonadotropin therapy to therapy with recombinant human follicular-stimulating hormone for the treatment of male hypogonadotropic hypogonadism. AB - Stimulatory therapy with gonadotropins effectively induces spermatogenesis and increases the chances of successful reproduction. However, the optimal treatment modality and schedule, and required duration of treatment have not been determined. A 27-year-old man presented with erectile and ejaculatory disorder. Endocrinological examinations revealed isolated luteinizing hormone-releasing hormone (LHRH) deficiency of the hypothalamus, resulting in hypogonadotropic hypogonadism. No causative abnormality was detected in imaging studies. Having a diagnosis of adult-onset hypogonadotropic hypogonadism, the patient received pulsatile subcutaneous human chorionic gonadotropin (hCG) and human menopausal gonadotropin (hMG). Hypogonadism did not improve with hCG/hMG combination therapy. He was successfully treated with the replacement therapy from hMG into recombinant human follicular-stimulating hormone (rhFSH) for induction of spermatogenesis, along with pregnancy in the female partner. PMID- 29699332 TI - Effect of selenium and vitamin E on acrosome reaction in porcine spermatozoa. AB - Purpose: Selenium (Se) and vitamin E (Vit-E), as an integral part of antioxidant systems, play an important role in the motility and acrosome reaction (AR) of mammalian spermatozoa. The purpose of this study was to investigate the effect of Se and Vit-E on motility, viability, AR and accumulation of ammonia in the culture medium during different incubation periods in porcine sperm. Methods: Sperm samples were washed, swum-up and incubated at 37 degrees C for 1 and 3 h in Sp-TALP medium supplemented with sodium selenite (SS), seleon l-methionine (SeMet) and Vit-E in the presence or absence of ammonia. Sperm motility was determined on the basis of movement quality examined by phase microscopy. Viability and AR of spermatozoa were assessed by Hoechst 33258 and chlortetracycline (CTC) staining technique, and accumulation of ammonia was measured by the indophenol method. The incorporation of 14C(U)-glucose was assessed with a liquid scintillation counter. Results: In experiment 1, the sperm motility, viability, AR and incorporation of 14C(U)-glucose increased significantly (P < 0.05) in SS, SeMet and Vit-E (5, 5 MUg/l and 1.0 mM, respectively) compared with the control. In experiment 2, treatment of the sperm with SeMet and SeMet + Vit-E in the presence of 300 MUM ammonia also resulted in a significant increase (P < 0.05) in the rate of motility, viability, AR and incorporation of 14C(U)-glucose. In contrast, the accumulation of ammonia was reduced by SeMet and SeMet + Vit-E compared with the other treatments. Conclusions: These findings indicate that SeMet and SeMet + Vit-E may play an important role in reducing the accumulation of ammonia and subsequently in increasing the rate of AR and the utilization of glucose in porcine spermatozoa. PMID- 29699333 TI - Recombinant follicle-stimulating hormone (follitropin alfa) versus purified urinary follicle-stimulating hormone in a low-dose step-up regimen to induce ovulation in Japanese women with anti-estrogen-ineffective oligo- or anovulatory infertility: results of a single-blind Phase III study. AB - Purpose: We aimed to compare the efficacy and safety of recombinant human follicle-stimulating hormone (follitropin alfa) and purified urinary human follicle-stimulating hormone (urofollitropin) for ovulation induction in Japanese women with anovulatory infertility;also to verify the noninferiority (in terms of ovulation rate) of follitropin alfa versus urofollitropin. Methods: In a Phase III, multicenter, single-blind, parallel-group study, we enrolled 265 Japanese women aged 20-39 years. The patients were menstruating without apparent ovulation or were amenorrheic (with a positive progestin challenge test), and had failed to conceive with anti-estrogen ovulation-induction therapy. The patients underwent a low-dose step-up regimen using follitropin alfa or urofollitropin with a starting dose of 75 IU. The primary endpoint was the proportion of patients who ovulated (mid-luteal serum progesterone >=5 ng/mL and/or confirmed clinical pregnancy). Secondary endpoints included the proportion of patients with a dominant follicle (>=18 mm) and the duration of stimulation. Results: Ovulation occurred in 79.1% and 82.6% of the patients who received follitropin alfa and urofollitropin, respectively, in the full-analysis set (n = 261), and in 79.2% and 82.5% of the per-protocol set (n = 251). The predefined noninferiority criteria for the primary endpoint were achieved. No significant differences were observed in any secondary endpoint. Treatment-emergent adverse events were reported by a similar proportion of patients in each group (follitropin alfa, 53.5%; urofollitropin, 50.0%). Conclusions: No significant difference in the primary efficacy endpoint (rate of ovulation) was observed between follitropin alfa and purified urofollitropin in women with anovulatory infertility who were menstruating or had progestin-positive amenorrhea. The use of treatment holidays in this study prevents comparison of the data with previous trials that utilized consecutive daily doses. PMID- 29699331 TI - Vaccines for immunological control of fertility. AB - Vaccines have been proposed as one of the strategies for population control. Immunocontraceptive vaccines can be designed to inhibit: (1) production of gametes (sperm and egg); (2) functions of gametes, leading to blocking of fertilization; and (3) gamete outcome (pregnancy). Immunization with gonadotropin releasing hormone coupled to different carriers has shown curtailment in the production of sperm with concomitant infertility in various species. Immunization of nonhuman primates and men with ovine follicle stimulating hormone has also resulted in reduced sperm output. Various spermatozoa-specific proteins such as FA1, PH-20, LDH-C4, SP-10, SP-17, sp56, SPAG9, and Izumo have been proposed as candidate antigens to develop contraceptive vaccines, which have shown efficacy in inhibiting fertility in different animal models. Immunization with zona pellucida glycoproteins-based immunogens also results in curtailment of fertility in a variety of species. However, ways to overcome the observed oophoritis associated with zona proteins immunization have yet to be discovered, a necessary step before their proposal for control of human population. Nonetheless, this is a very promising approach to control wildlife animal population. Phase II clinical trials of beta-human chorionic gonadotropin-based vaccine in women have established the proof of principle that it is possible to inhibit fertility without any untoward side-effects by vaccination. Further scientific inputs are required to increase the efficacy of contraceptive vaccines and establish their safety beyond doubt, before they can become applicable for control of fertility in humans. PMID- 29699334 TI - Current concepts of human azoospermia and its causes. AB - Infertility is a serious social problem in advanced nations today. One of the most important causes is the male factor. Striking progress has been achieved in recent years in elucidating the mechanisms of spermatogenesis in mice by experimental methods represented by the knockout mouse. Although many factors associated with male infertility are known in mice, the translation of this information to people has been slow. This is because the knockout mouse phenotype cannot necessarily be reproduced faithfully in humans. However, it is known that environmental factors, chromosomal defects and several specific gene mutations result in human male infertility. In this review, we first discuss the environmental factors considered likely to be involved in male infertility, and secondly we describe the Y chromosome and several important genes on the Y chromosome that play critical roles in spermatogenesis in humans. Then, we demonstrate the three critical genes identified in our laboratory in autosomes involved in human spermatogenesis, the SYCP3, MEI1 and PARP-2. Finally, we explain the future directionality and possibilities of research in this field. PMID- 29699335 TI - Azoospermia factor and male infertility. AB - Recently, work has shown that azoospermia factor (AZF) microdeletions result from homologous recombination between almost identical blocks in this gene region. These microdeletions in the Y chromosome are a common molecular genetic cause of spermatogenetic failure leading to male infertility. After completion of the sequencing of the Y chromosome, the classical definition of AZFa, AZFb, and AZFc was modified to five regions, namely AZFa, P5/proximal-P1, P5/distal-P1, P4/distal-P1, and AZFc, as a result of the determination of Y chromosomal structure. Moreover, partial AZFc deletions have also been reported, resulting from recombination in their sub-ampliconic identical pair sequences. These deletions are also implicated in a possible association with Y chromosome haplogroups. In this review, we address Y chromosomal complexity and the modified categories of the AZF deletions. Recognition of the association of Y deletions with male infertility has implications for the diagnosis, treatment, and genetic counseling of infertile men, in particular candidates for intracytoplasmic sperm injection. PMID- 29699336 TI - Duration of sexual intercourse related to satisfaction: survey of Japanese married couples. AB - Purpose: Inappropriate intromission time causes sexual problems for couples, and therefore it is important for the couple to set treatment targets. Methods: We investigated appropriate intromission times by conducting a questionnaire survey of the interval from initiation of insertion to just before ejaculation in Japanese married couples. A questionnaire survey of 300 married couples was conducted by mail. Results: The estimated mean intromission times were 14.5 min (median: 10 min) for male subjects and 13.6 min (median: 10 min) for female subjects. The mean desired intromission time for female subjects was 15.7 min (median: 15 min). Regarding the difference between the actual and desired intromission times, the desired time was longer, the same, and shorter for 43.0%, 38.7%, and 18.3% of all the female subjects. Conclusions: It seems that female subjects may consider a wide variety of intravaginal insertion times to be desirable. Accordingly, married couples need to improve communication regarding the desired duration of intromission and other related issues. PMID- 29699337 TI - Infertility support sought from local government: preliminary survey of needs among people who attended public lecture. AB - Purpose: Support both from medical centers and from local government is indispensable to the growing number of infertile couples who are seeking treatment after advances in medical technology. Methods: A self-administered questionnaire survey of the demand for infertility support was conducted among those who attended a public lecture offered by Aichi Prefecture, asking specifically about their requests for Aichi Prefectural government aid. Results: The survey results indicated that information was obtained about financial support by administrative and infertility support programs in Aichi Prefecture. Because most people usually received this information at medical institutions, local government coordinated with medical institutions. Men and women were found to have different demands for infertility support-while women typically sought psychological support, for example counseling, men usually sought learning opportunities in study groups. In particular, women sought opportunities to interact with interested parties, which suggested that the establishment of peer activities would be a helpful form of support. Conclusions: We need collaboration of government services with medical institutions, support, and investigation to form an infertility network that accepts sex differences. PMID- 29699338 TI - Anti-Mupsilonllerian hormone and 3D-power Doppler histogram: markers of ovarian function with in vitro fertilization treatment. AB - Purpose: To investigate the ability of three-dimensional (3D) ultrasonography and anti-Mupsilonllerian hormone (AMH) to predict successful embryo development in patients undergoing in vitro fertilization (IVF) treatment. Methods: We prospectively studied 28 patients undergoing IVF treatment, using 3D ultrasound Sono automatic volume calculation (AVC) and a 3D-power Doppler volume histogram. Sono AVC was used to automatically measure the number and volume of follicles. The volume histogram was used to measure the vascularization index (VI), flow index, and vascularization flow index in the ovaries. Serum AMH (S-AMH) was determined by enzyme immunoassay (ng/ml). Results: The number of embryos isolated was 3.3 +/- 2.8. The S-AMH of the patients who were under 35 years of age (0.570 +/- 0.216 ng/ml) was higher than that in the patients over 40 years of age (0.377 +/- 0.071 ng/ml; p = 0.0003). Principal component analyses determined that the quality of the embryo depended on the patients's age, S-AMH, and VI of the ovary. The receiver operating characteristic (ROC) curve showed that the cutoff for the S-AMH was 0.2855 ng/ml, and the optimal age of the patient was 32.5 years, when implanted with an embryo on day 16. Conclusions: We demonstrated that investigating the relationships between the number of the embryo and ovarian function, using a combination of AMH with a volume histogram, might be useful to predict the response to IVF treatment. PMID- 29699339 TI - Sex-discordant twins despite single embryo transfer: a report of two cases. AB - We report two extremely rare cases in which the patients delivered male and female infants that were dizygotic twins (DZT) despite single embryo transfer. Case 1: The patient was a 35-year-old woman with a 9-year history of unexplained infertility. In an oocyte retrieval cycle, one blastocyst was transferred; at 26 weeks of gestation, she delivered a 704-g female infant and a 420-g male infant by cesarean section. Because both infants were of extremely low birth weight, they were placed in the neonatal intensive care unit. Congenital anomalies were not found in either infant. Case 2: The patient was a 30-year-old woman with a 1 year history of infertility. Hysterosalpingogram revealed bilateral tubal occlusion. In a frozen/thawed cycle one blastocyst was transferred during her natural ovulation cycle. She achieved a pregnancy and delivered a 2,877-g female infant and a 2,544-g male infant at 36 weeks of gestation by cesarean section. The female infant was diagnosed with a neural tube defect. No congenital anomalies were detected in the male infant. We hypothesize that the DZTs might have been the result of concurrent embryo transfer and natural ovulation and intercourse. PMID- 29699340 TI - Successful pregnancy after intracytoplasmic sperm injection with testicular spermatozoa transported only under refrigeration. AB - Purpose: This case report describes two successful pregnancies after intracytoplasmic sperm injection (ICSI) with testicular spermatozoa that were transported under refrigeration. Methods: Two first-time couples consulted our clinic concerned about their primary infertility. No sperm were present in the semen samples from either of the husbands and they were referred to the urology department (UD) of a neighbouring hospital. At the UD, seminiferous tubules were obtained by testicular sperm extraction. The tissue samples were put in a centrifuge tube with phosphate-buffered saline at 6 degrees C and placed with refrigerant in a cushioned styrofoam box that was then transported to our clinic. Immediately upon arrival at our clinic, testicular spermatozoa were extracted. On the same day, ovum pickup was performed and mature oocytes were extracted that were then inseminated by conventional ICSI. Fertilized eggs were cultured for 2 days, and then cleaved embryos were cryopreserved. In one case after 4 months and in the other case after 2 months of cryopreservation, the frozen-thawed embryos were transferred. Result: Both patients became pregnant and normal, healthy babies were born. Conclusions: These results suggest that cases of obstructive azoospermia can be treated with ICSI by refrigerated transport of the seminiferous tubules, in cooperation with a UD, in a small single departmental obstetrics and gynecology clinic. PMID- 29699341 TI - Fertility preservation for boys with cancer. AB - Childhood cancer is a curable disease due to the development of chemo- and radiation therapies, but long-term survivors suffer late side-effects including infertility. Cytotoxic agents and radiation impair spermatogenesis and cause oligospermia or azoospermia as well as genetic damage in sperm. To date, the only established option to preserve fertility is cryopreservation of sperm before treatment and artificial reproduction techniques, if men with cancer can ejaculate, but only a quarter of men have banked sperm. Lack of information is the most common reason for failing to bank sperm. However, prepubertal patients who have only spermatogonia and spermatocytes in their testes do not benefit from cryopreservation of their sperm and assisted reproductive techniques. Thus, the only available option is to harvest testicular tissues before treatment for cryopreservation, from which immature germ cells can somehow be maturated. Autotransplantation of germ cells into the testis holds promise for fertility restoration, but contamination by malignant cells may induce relapse. Fluorescence-activated cell sorting (FACS) with two surface markers could exclude contaminated leukemic cells from murine germ cells, and transplantation of sorted germ cells successfully restored fertility without transmission of leukemia. Human germ cells could be also isolated from human leukemia and lymphoma cell lines by FACS using surface markers. Before autotransplantation can be applied clinically, some issues, including the risk of contamination by malignant cells and in vitro propagation of spermatogonial stem cells, should be resolved. PMID- 29699342 TI - Insulin resistance/hyperinsulinemia and reproductive disorders in infertile women. AB - Obesity, which disturbs lipid and glucose metabolism, is a recent medical concern. It threatens human health and also has adverse effects on reproductive functions by causing insulin resistance/hyperinsulinemia, especially in women with polycystic ovary syndrome (PCOS). For PCOS patients to prevent these adverse effects, it is important to take into account improving their lifestyles by exercise and proper diets. The relationship between insulin resistance/hyperinsulinemia and reproductive disorders should be understood as fully as possible in order to provide effective treatment. It is well known that insulin resistance and compensatory hyperinsulinemia can be triggered by obesity with visceral fat accumulation. Hyperinsulinemia affects granulosa cells in small follicles and theca cells. This condition induces early response to luteinizing hormones on granulosa cells of small follicles and causes premature differentiation of these cells, which eventually results in anovulation. For improvement of anovulation because of hyperinsulinemia, insulin-sensitizing agents (biguanide and thiazolidinedione derivatives) are useful. Hyperinsulinemia may adversely affect the endometrial functions and environment, and evoke implantation disturbance. Treatment with an insulin-sensitizing agent (metformin) improves the levels of glycodelin, insulin-like growth factor binding protein 1, and blood flow in spiral arteries during the peri-implantation period. It supports endometrial function, improves the endometrial environment, and facilitates embryo implantation. The rate of early pregnancy loss during the first trimester is 30-50% in women with PCOS, which is threefold higher than for normal women. Metformin treatment improves the levels of insulin, the homeostasis model assessment for insulin resistance, and plasminogen activator inhibitor activity, and decreases early pregnancy loss. It goes without saying that lifestyle change is fundamental for improving reproductive performance in addition to treatment with insulin-sensitizing agents. PMID- 29699343 TI - Effects of Saireito on the ovarian function of patients with polycystic ovary syndrome. AB - Purposes: It is sometimes difficult to restore a regular ovulatory cycle in women with polycystic ovary syndrome (PCOS) using classic agents such as clomiphene citrate or gonadotropins. Saireito, a herbal medicine, is believed to have an effect similar to corticosteroids. We examined the effect of Saireito on ovulatory induction and endocrine status in women with PCOS. Methods: Twenty-four women with PCOS were treated with Saireito for 3 months. Serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), prolactin (PRL), testosterone (T), estradiol (E2), adrenocorticotropic hormone (ACTH), and cortisol were measured before and after treatment, and ovulation was assessed. We compared serum LH levels between ovulation (n = 21) and anovulation (n = 3) groups, and compared ovulation rate and serum LH levels between obese (n = 6) and nonobese (n = 18) groups. Results: Ovulation was restored in 21 (87.5%) of the 24 PCOS patients following administration of Saireito for 3 months. LH levels were significantly decreased 1 month after medication in ovulatory group (P < 0.001), but only slightly decreased in anovulatory group. Ovulation rate in the nonobese group (94.4%) was higher than in the obese group (66.7%). Serum LH levels were significantly reduced in the nonobese group, but only slightly reduced in the obese group. Conclusions: Saireito reduced serum LH levels and increased ovulatory rate, particularly in nonobese women. PMID- 29699344 TI - Cryopreservation of ovarian tissue after pretreatment with a gonadotropin releasing hormone agonist. AB - Purpose: The purpose of this study was to investigate whether slow-rate freezing or vitrification is better for cryopreservation of ovary tissues pretreated with gonadotropin-releasing hormone agonist. Methods: In this nonclinical study performed in rats, leuprorelin acetate was administered to female Wistar rats, aged 6-8 weeks. After confirming arrest of the estrous cycle by examination of vaginal smears, ovarian tissue was cryopreserved by vitrification and slow-rate freezing prior to thawing and autotransplantation. The time required for estrous cycle recovery was assessed from vaginal smears in each group starting from day 1 of transplantation. Estradiol levels were also monitored after transplantation. Results: The estrous cycle recovered after transplantation of ovarian tissue frozen by either method, but recovery was significantly faster after transplantation of vitrified tissue. The estradiol level also recovered by 10 days after transplantation. Conclusions: Ovarian function was restored after transplantation of tissue preserved by either vitrification or slow-rate freezing after pretreatment with leuprorelin acetate. This method may be applicable for patients scheduled to undergo cryopreservation of ovarian tissue before chemotherapy. PMID- 29699345 TI - Plasma prolactin concentrations and copulatory behavior after salsolinol injection in male rats. AB - Purpose: The dopamine-derived endogenous compound, R-salsolinol (SAL), was recently identified as a putative endogenous prolactin (PRL)-releasing factor. However, how SAL influences copulatory behavior is unknown. In this study, we examined the relationship between SAL and copulatory behavior in male rats. Methods: Male Sprague-Dawley rats administered SAL were exposed to female rats in estrus, the plasma PRL concentration was measured, and the behavioral frequency and time during copulatory behavior were noted. Results: In the control and SAL groups, plasma PRL concentrations at 15 min before exposure to the female were 7.3 +/- 2.0 and 8.0 +/- 1.5 ng/ml, respectively. Moreover, plasma PRL concentrations in males immediately after exposure to the female were 7.4 +/- 1.2 and 68.0 +/- 5.9 ng/ml, respectively (P < 0.05). All (8/8) of the control animals ejaculated in the presence of the female, whereas only 33% (2/6) of the SAL group ejaculated. An increasing tendency for mount latency and intromission latency and a decreasing tendency for intromission frequency were observed in the SAL group. Conclusions: Copulatory behavior was inhibited in male rats after SAL injection, suggesting that SAL is a copulatory behavior inhibiting factor. PMID- 29699346 TI - Effect of Papaver rhoeas extract on in vitro maturation and developmental competence of immature mouse oocytes. AB - Purpose: This experiment examined the effect of Papaver rhoeas L. extract on in vitro maturation, in vitro fertilization (IVF) and subsequent developmental competence of mouse oocytes. Materials and methods: Cumulus oocyte complexes (COCs) at germinal vesicle stage were collected from female Naval Medical Research Institute (NMRI) mouse ovaries. The COCs were transferred to maturation medium supplemented with different concentrations of P. rhoeas extract. Two trials were carried out to examine the effect of low concentrations (0, 10, 15, 20, 25 MUg/ml) and high concentrations (0, 50, 100, 200 MUg/ml) of the extract. The maturation rate was recorded. After IVF, embryos were cultured and their developmental process was monitored for 96 h. Results: Maturation rate and blastocyst formation improved by using low concentrations of the extract; however, no significant increase was observed when compared to the control group. In addition no significant differences were observed in the fertilization rates of oocytes treated with both low and high concentrations compared to the control group. However, among higher concentrations, 100 MUg/ml, P. rhoeas extract significantly increased both the in vitro maturation rate and in vitro developmental (IVD) competence when compared to the control group (P < 0.05). Conclusions: It was concluded that natural extracts increase the IVD competence of oocytes. The improved effect on oocyte maturation was dependent on the addition of optimum concentrations of P. rhoeas extract to the maturation medium. PMID- 29699347 TI - Intravenous immunoglobulin therapy for aspirin-heparinoid-resistant antiphospholipid syndrome. AB - We encountered a woman who had a history of repeated fetal losses and positive tests for lupus anticoagulant, phosphatidylserine-dependent antiprothrombin (aPS/PT) IgG, IgM and kininogen-dependent antiphosphatidylethanolamine (aPE) IgG, IgM. Her previous pregnancy had ended in intrauterine fetal death at 24 weeks of gestation despite a therapy of low-dose aspirin, prednisolone and danaparoid. During the present pregnancy, she was treated with repeated intravenous infusions of immunoglobulin (IVIg) together with low-dose aspirin, prednisolone and heparin. When thrombocytopenia developed, she delivered a female baby weighing 2,152 g at 34 weeks of gestation by cesarean section. Titers of aPS/PT IgM and aPE IgM were reduced or maintained at low levels by repeated IVIg therapies. The IVIg therapy might be effective for aspirin-heparinoid-resistant antiphospholipid syndrome. PMID- 29699348 TI - Serum Resistin Level and Its Receptor Gene Expression in Liver Biopsy as Predictors for the Severity of Nonalcoholic Fatty Liver Disease. AB - Background: Liver histology remains the gold standard for assessing nonalcoholic fatty liver disease (NAFLD). Noninvasive serological markers have been developed to evaluate steatosis to avoid biopsy. In NAFLD patients, serum resistin was higher than those in control lean and obese patients. Objective of the study: To investigate serum resistin and its receptor gene expression in liver biopsy as predictors for NAFLD severity. Patients and methods: This study was conducted on 54 obese patients, with suspected fatty liver by ultrasound (excluding diabetic, alcoholic, hepatitis C virus antibody (HCVAb) or hepatitis B surface antigen (HBsAg) positive patients). They were subjected to anthropometric measurements, laboratory studies including serum resistin, abdominal ultrasonography (US) and liver biopsy. The 15 lean subjects were included as a control group. According to biopsy results, patients were subdivided into nonalcoholic steatohepatitis (NASH) group (46 patients) and non-NASH group (8 patients). Results: Significantly higher levels of resistin were detected in NAFLD patients compared to control subjects (p = 0.0001). Also, higher levels of resistin were recorded in NASH group compared to the non-NASH group; however, the difference was not statistically significant (p = 0.584). Serum alanine aspirate aminotransferase (AST), alanine aminotransferase (ALT) and gamma-glutamyl transpeptidase (GGT) were higher in NASH patients than non-NASH group (p = 0.223, p = 0.005 and p = 0.006 respectively). Abdominal US showed high sensitivity in NAFLD diagnosis (sensitivity of sonar in detecting steatosis grade compared to biopsy was 61% in grade 1, 25% in grade 2 and 75% in grade 3). Conclusion: Serum resistin can be combined with other noninvasive markers to predict the presence of NASH as an alternative to liver biopsy.How to cite this article: Hegazy M, Abo-Elfadl S, Mostafa A, Ibrahim M, Rashed L, Salman A. Serum Resistin Level and Its Receptor Gene Expression in Liver Biopsy as Predictors for the Severity of Nonalcoholic Fatty Liver Disease. Euroasian J Hepato-Gastroenterol 2014;4(2):59-62. PMID- 29699349 TI - Sequential Therapy vs Quadruple Therapy for Helicobacter pylori Eradication in South West of Iran. AB - Aim: To compare the efficacy of quadruple and sequential therapy in eradication of Helicobocter pylori (H. pylori) in a randomized study. Method: Three hundred H. pylori positive patients were enrolled into the study. These patients were randomly divided into two groups: group I (n = 150) received quadruple therapy (20 mg omeprazole bid, 240 mg bismuth subcitrate bid, 1,000 mg tetracycline bid and 500 mg metronidazole bid) for 14 days, group II (n = 150) received sequential therapy (20 mg omeprazole bid, 1,000 mg amoxicillin bid for 5 days, followed by 20 mg omeprazole bid, 500 mg metronidazole bid, 500 mg clarithromycin for the other 5 days). H. pylori status was assessed by histology and rapid urease test at baseline. Follow-up breath test by 14C urea breath test (UBT) was performed 4 weeks after completion of treatment. Eradication was defined as negative results on UBT. Results: Successful eradication was achieved in 245 patients. In each group, five patients did not tolerate the regimen and were excluded from analysis. About 29 (20%) patients who received sequential therapy and 21 (14.5%) of the quadruple group tolerated mild side effects (p = 0.21).Per-protocol analysis demonstrated eradication rates of 86.9% for sequential therapy and 82.7% for quadruple therapy (p = 0.26). Results according to the intention to treat analysis were 84 and 79.5% in the sequential and quadruple group respectively. Eradication rate differences were not significant. Conclusion: The success rate of sequential therapy is comparable with quadruple therapy. Sequential therapy due to the short duration and lesser drug usage is a good alternative for eradication of H. pylori in the country.How to cite this article: Masjedizadeh AR, Hajiani E, Hashemi SJ, Alavinejad P, Dalvand H. Sequential Therapy vi Quadruple Therapy for Helicobocter pylori Eradication in South West of Iran. Euroasian J Hepato-Gastroenterol 2014;4(2):63-66. PMID- 29699350 TI - Platelet Number and Indexes during Acute Pancreatitis. AB - Aim: Acute pancreatitis (AP) is an inflammatory disorder, the incidence of which has been increasing over recent years. Mean platelet volume (MPV) is an index of platelet activation and influenced by inflammation. The objective of the present study is to assess whether MPV would be convenient parameters for predictor factor of patients with AP. Materials and methods: A total of 140 AP patients (male/female: 63/77) and 70 healthy subjects (male/female: 23/47) were enrolled in this study. The following data were extracted from the hospital medical records, including age, sex, platelet count, MPV, were recorded at the time of admission and as well as at the 1st day of remission of the disease. Results: Mean platelet volume levels at onset and remission of AP were 7.8 +/- 1.6 and 7.7 +/- 0.9 respectively, and there was no statistically significant difference between these groups. Platelet count at onset and remission of AP and control subjects was 203 +/- 74 * 103/MUl, 234 +/- 76 * 103/MUl and 251 +/- 87 * 103/MUl, respectively, and there was statistically significant difference between these groups. Platelet count at onset and remission of AP was statistically lower than control subjects. Conclusion: Some studies in literature suggest that MPV might be a useful parameter to be used as an indicator for AP and a prognostic factor for AP, but, in this study, it was revealed that MPV values do not change at AP compared with controls. Therefore, further prospective studies investigating the factors affecting the platelet size are required to determine whether MPV has a clinical implication and for predictor value of patients with AP.How to cite this article: Kefeli A, Basyigit S, Yeniova AO, Kucukazman M, Nazligul Y, Aktas B. Platelet Number and Indexes during Acute Pancreatitis. Euroasian J Hepato Gastroenterol 2014;4(2):67-69. PMID- 29699351 TI - Optimization of a Therapeutic Vaccine Candidate by Studying Routes, Immunization Schedules and Antigen Doses in HBsAg-positive Transgenic Mice. AB - Hepatitis B core antigens (HBcAg) and hepatitis B surface antigens (HBsAg) are the main structural antigens of hepatitis B virus (HBV). Both antigens are potent immunogens for experimental animals as well as in acutely infected patients. A novel formulation based on the combination of HBsAg and HBcAg has been developed as a therapeutic vaccine candidate, aimed at inducing an immune response capable of controlling the infection. An immunization schedule was conducted to evaluate the immunogenicity of this formulation after simultaneous immunization by the intranasal and parenteral routes using different schedules and doses. Humoral and cellular immune responses generated in blood and spleen were evaluated by engyme linked immunosorbent assay (ELISA) and enzyme-liked immunospot (ELISPOT) assays respectively. A first experiment evaluated two groups of mice simultaneously immunized by intranasal (IN) and subcutaneous (SC) routes, one including alum by SC route and, in the other, the formulation was injected without adjuvant. As a result, alum adjuvant did not increase the immunogenicity under the studied conditions. In fact, the group without alum induced the most potent immune response. The immune response was enhanced by combining IN and SC immunization compared to the SC route alone. In a second experiment, mice were immunized by different mucosal routes at the same time, and compared to the simultaneously (IN/SC) immunized groups. It was demonstrated that there is no improvement on the resulting immune response by using multiple routes of immunizations simultaneously; however, the increase of the antigen dose induced a superior immune response. Interestingly, the increase of antigen dose only by SC route did not favor the resulting immunogenicity. In conclusion, the use of HBsAg transgenic mice has proven useful to optimize the formulation, avoiding the unnecessary use of alum as adjuvant as well as provided information of the role of different mucosal immunization routes and antigen dose on the resulting immune response. How to cite this article: Trujillo H, Blanco A, Garcia D, Freyre F, Aguiar J, Lobaina Y, Aguilar JC. Optimization of a Therapeutic Vaccine Candidate by Studying Routes, Immunization Schedules and Antigen Doses in HBsAg-positive Transgenic Mice. Euroasian J Hepato-Gastroenterol 2014;4(2):70-78. PMID- 29699352 TI - Prevalence of Blood-Borne Viral Infections among Blood Donors of Tripura. AB - Background: Blood-borne viral infections, like hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV), are most common during blood transfusion. Morbidity and mortality resulting from the transfusion of infected blood have far reaching consequences not only for the recipients themselves but also for their families, communities and the wider society. Aims: The study was designed to determine the prevalence of HBV, HCV and HIV among voluntary and replacement blood donors of Tripura, India, and to study the trends of HBV, HCV and HIV infections in the population. Materials and methods: This study is a retrospective cross-sectional study. The data was collected for consecutive 8 years from 2005 to 2013. Analyses were done in respect of total blood collection and HBV, HCV and HIV infections among the donors. Results: Among all donors, 91.8% was voluntary donors and 8.2% was replacement donors. The average HBV, HCV and HIV positivity was 1.2% (95% CI: 1.155-1.255), 0.109% (95% CI: 0.0950.125) and 0.093% (95% CI: 0.080-0.108) respectively. Among these, HBV seropositivity was 1.19% among voluntary donors and 1.33% among replacement donors and, in case of HCV and HIV, the seropositivity among voluntary and replacement donors were 0.109%, 0.11% and 0.089%, 0.145% respectively. HBV positivity was reduced in 8 years, whereas those of HCV and HIV remain unchanged. Conclusion: The most important observation of this study is gradual decrease in prevalence of HBV (p = 0.0018), whereas change in prevalence of HCV and HIV was not statistically significant. This might be due to mass hepatitis B vaccination program in Tripura.How to cite this article: Bhaumik P, Debnath K. Prevalence of Blood-Borne Viral Infections among Blood Donors of Tripura. Euroasian J Hepato Gastroenterol 2014;4(2):79-82. PMID- 29699353 TI - Influence of Mesenchymal Stem Cells Transplantation on Regeneration Activity of Cirrhotic Liver. AB - The efficacy of mesenchymal stem cells transplantation on regeneration activity of cirrhotic liver was evaluated in an animal model of cirrhotic liver. Autologous stem cells were obtained from bone marrow. Transplantation was performed 1 week after surgery by introducing stem cells into the liver. Immunohistochemical staining (proliferative activity, myofibroblast activation and sinusoidal capillarization) was evaluated to assess the efficacy of transplantation. It was found that, 2 months after stem cell transplantation, the severity of perisinusoidal fibrosis, inflammation of the liver and the number of myofibroblasts were reduced. Stem cell transplantation may be one of the new treatment modalities for cirrhotic liver. How to cite this article: Maksud AR, Gennadiyevich PA, Elkhan JR. Influence of Mesenchymal Stem Cells Transplantation on Regeneration Activity of Cirrhotic Liver. Euroasian J Hepato-Gastroenterol 2014;4(2):83-86. PMID- 29699354 TI - Nucleoside Analog-treated Chronic Hepatitis B Patients showed Reduced Expression of PECAM-1 Gene in Peripheral Blood Mononuclear Cells in Bangladesh. AB - Background and aim: Assessment of therapeutic response is important for monitoring the prognosis and to take decision for cessation of nucleoside analogues therapy in chronic hepatitis B patients. In addition to serum alanine aminotransferase (ALT), hepatitis B virus (HBV) deoxyribonucleic acid (DNA) load and HBeAg status, identification of molecular markers associated with host immune response would be essential to assess therapeutic response. In this regard the current study was performed with the aim to detect expression of platelet endothelial cell adhesion molecule (PECAM)-I gene in peripheral blood monocytes (PBMCs) of treated chronic hepatitis B patients and also to correlate expression of this gene with serum HBV DNA load and serum ALT levels. Materials and methods: The study analyzed 60 chronic hepatitis B (CHB) patients, including 30 untreated and 30 nucleoside analogs treated and 10 healthy controls. PECAM-1 gene expression/ transcripts were detected by conventional RT-PCR. Results: The expression PECAM-1 mRNA in the PBMCs of CHB patients was significantly higher in untreated (3.17 +/- 0.75) than the treated patients (1.64 +/- 0.29) (p < 0.01). Expression of PECAM-1 was positively correlated with serum ALT levels of both untreated (r = 0.580) and treated (r = 0.566) CHB patients. Moreover, in both untreated and treated groups, these gene expressions were positively correlated to serum HBV DNA load with the correlation coefficient r = 0.545 and r = 0.591 respectively. Conclusion: PECAM-1 may be used as a biomarker for assessment of inflammatory activity as well as therapeutic response in CHB patients.How to cite this article: Sultana N, Tabassum S, Munshi SU, Hossain M, Imam A. Nucleoside Analog-treated Chronic Hepatitis B Patients showed Reduced Expression of PECAM-1 Gene in Peripheral Blood Mononuclear Cells in Bangladesh. Euroasian J Hepato Gastroenterol 2014;4(2):87-91. PMID- 29699355 TI - Immunotherapy for Chronic Hepatitis B using HBsAg-based Vaccine Formulations: From Preventive Commercial Vaccines to Therapeutic Approach Julio Cesar Aguilar. AB - Despite the existence of effective prophylactic vaccines, hepatitis B virus (HBV) infections remain a major public health problem. It has been estimated that about 370 million people are chronically infected with this virus worldwide. These individuals act as a reservoir for viral spread and chronic infection also increases the risk of liver diseases, such as cirrhosis and hepatocellular carcinoma. Current antiviral therapies fail to control viral replication in the long term in most patients. Viral persistence has been associated with a defect in the development of HBV-specific cellular immunity. The limitations of the current available therapies underline the need for alternative therapies. Specific immunotherapeutic strategies target not only the induction or stimulation of CD4(+) and CD8(+) T-cell responses but also the induction of proinflammatory cytokines capable of controlling viral replication. Therapeutic vaccination has been extensively studied in chronic hepatitis B (CHB) based in the properties of hepatitis B surface antigen (HBsAg) and taking advantage of its previous use in preventive vaccination. In this sense, pioneer studies were carried out employing HBsAg-based vaccines, including prophylactic commercial vaccines and HBsAg-based formulations with novel adjuvants. The results and general knowledge coming from these studies are discussed in the present review. The decision on developing new generations of vaccines including new antigens or formulations should take into account the experience with HBsAg-based vaccine formulations in order to decide about changing the vaccine antigen or adding new antigens to improve the composition. How to cite this article: Aguilar JC, Lobaina Y. Immunotherapy for Chronic Hepatitis B using HBsAg-based Vaccine Formulations: From Preventive Commercial Vaccines to Therapeutic Approach. Euroasian J Hepato-Gastroenterol 2014;4(2):92-97. PMID- 29699356 TI - Esophageal Leiomyoma in Patients with Megaloblastic Anemia. AB - Esophageal leiomyoma is the most common benign intramural tumor of esophagus. Although its incidence is not exactly known, it is very rare (0.006%-0.1% in autopsy series). It is generally asymptomatic and detected incidentally. Here, we present a rare case report describing coexistence of megaloblastic anemia and esophageal leiomyoma. How to cite this article: Coskun A, Unubol M, Yukselen O, Yukselen V, Aydin A, Sen S, Karaoglu AO. Esophageal Leiomyoma in Patients with Megaloblastic Anemia. Euroasian J Hepato-Gastroenterol 2014;4(2):98-100. PMID- 29699357 TI - A Rare Spontaneous Gastrobiliary Fistula. AB - We report the case of a 69-year-old man with a spontaneous gastrobiliary fistula. Internal biliary fistulas are usually the result of longstanding, untreated choledocholithiasis, cholecystolithiasis, peptic ulcers or rarely neoplasia. This patient's unspecific clinical picture led to a late diagnosis, which was made during surgery. How to cite this article: Chwiesko A, Jurkowska G, Kedra B, Okulczyk B, Kamocki Z, Dabrowski A. A Rare Spontaneous Gastrobiliary Fistula. Euroasian J Hepato-Gastroenterol 2014;4(2):101-103. PMID- 29699358 TI - A Case of Breast Cancer Following Infliximab Treatment for Treatment-Refractory Crohn's Disease. AB - : Crohn's disease is a chronic, or long lasting inflammatory disease in the gastrointestinal (GI) tract. Most commonly, Crohn's disease affects the small intestine and the beginning of the large intestine. Treatment for Crohn's disease usually involves drug therapy or, in certain cases, surgery. Several side effects develop from the use of drugs. A case with Crohn's disease refractory to 5-ASA, corticosteroid and azathioprine treatments who developed breast carcinoma following infliximab treatment is being presented in this report. CASE: SE, aged 44 years, presented to our polyclinic with weight loss, abdominal pain and flatulence. The patient had no response to mesalazine, steroid and azathioprine therapy. Upon identifying inflammatory stricture with abdominal MR, the medicines the patient has been using was discontinued and anti-TNF alpha (infliximab) treatment was initiated after receiving the consent of the patient. At 3rd month of treatment, the patient detected a small mass at the left breast. Mastectomy was performed and axillary lymph nodes were resected. Because breast cancer was detected following infliximab treatment in this case, we believe that a breast examination (physical examination, mammary USG) must be performed in female patients prior to infliximab therapy. How to cite this article: Goral V, Unsal B, Sivrikoz ON. A Case of Breast Cancer Following Infliximab Treatment for Treatment Refractory Crohn's Disease. Euroasian J Hepato-Gastroenterol 2014;4(2): 104-106. PMID- 29699360 TI - Postoperative Sigmoid Apoplexy: A Rare Entity in Pediatric Gastroenterology. AB - An 11-year-old boy underwent ligation of sac for left congenital hydrocele. In the immediate postoperative period, he developed bleeding per rectum and obstructive features. Intramural hematoma of sigmoid colon was detected in diagnostic laparoscopy and confirmed by laparotomy. Sigmoidectomy with colorectal anastomosis was done. Postoperative period was uneventful. How to cite this article: Jagannathan M, Krishnamurthy G. Postoperative Sigmoid Apoplexy: A Rare Entity in Pediatric Gastroenterology. Euroasian J Hepato-Gastroenterol 2014;4(2):110-112. PMID- 29699359 TI - Primary Amyloidosis with Gastric Involvement. AB - Amyloidosis can involve all the segments of the gastrointestinal system (GIS) from mouth to anal canal. We present a case of amyloidosis that is detected by gastric biopsy taken in esophagogas-troduodenoscopy (EGD) performed to investigate the etiology of weight loss, nausea and vomiting. It is worth emphasizing that random gastric biopsy is important in gastric evaluations. How to cite this article: Borazan S, Coskun A, Yavasoglu I, Yenicerioglu Y, Meteoglu i, Yasa MH, Karaoglu AOO. Primary Amyloidosis with Gastric Involvement. Euroasian J Hepato-Gastroenterol 2014;4(2):107-109. PMID- 29699361 TI - Low Grade Appendiceal Mucinous Neoplasm with Pseudomyxoma Peritonei: An Enigma for Pathologist. AB - Malignant mucinous neoplasms of the appendix is an infrequently encountered entity. Extra-appendiceal spread of these tumor is one of the commonest etiology of pseudomyxoma peritonei, which demands a hightened vigilance in their early diagnosis. Although low-grade appendiceal mucinous neoplasms (LAMNs) largely stay confined to the appendix, but they can spread to the peritoneum as pseudomyxoma peritonei leading to an unpredictable outcome. Due to the rare occurrence of low grade appendiceal neoplasm only tenuous and limited information is present in the medical literature. We report a case of LAMN with pseudomyxoma peritonei in a 45 year-old male, who presented with the complaints of abdominal distension associated with abdominal pain and constipation. Clinical examinations and computed tomography (CT) scan were suggestive of pseudomyxoma peritonei. Peroperative findings and histopathological examination rendered a conclusive diagnosis of low-grade appendiceal neoplasm. How to cite this article: Qadri S, Alam K, Alam F, Maheshwari V. Low Grade Appendiceal Muci-nous Neoplasm with Pseudomyxoma Peritonei: An Enigma for Pathologist. Euroasian J Hepato Gastroenterol 2014;4(2):113-116. PMID- 29699362 TI - Childhood Hepatitis in Osh Province of Southern Kyrgyzstan. AB - Abbreviations: CHC: Chronic hepatitis C; HCV: Hepatitis C virus; LC: Liver cirrhosis. How to cite this article: Toichuev R, Leybman E, Omorbekova C, Rakhimova G, Zhumabek Kyzy B, Nikolaeva L. Childhood Hepatitis in Osh Province of Southern Kyrgyzstan. Euroasian J Hepato-Gastroenterol 2014;4(2):117-118. PMID- 29699363 TI - An Unusual Cause of Gastrointestinal Bleeding in a Patient with Enteral Feeding. AB - Abbreviations: NG: Nasogastric; PEG: Percutaneous gastrostomy. How to cite this article: Ozturk O, Aksoy EK, Dadakci YC, Basar O. An Unusual Cause of Gastrointestinal Bleeding in a Patient with Enteral Feeding. Euroasian J Hepato Gastroenterol 2014;4(2):119. PMID- 29699364 TI - Editorial. PMID- 29699365 TI - Erratum. AB - [This corrects the article DOI: 10.1111/j.1447-0578.2007.00199.x.]. PMID- 29699366 TI - Erratum to: The impact of endometriosis, endometrioma and ovarian cystectomy on assisted reproductive technology. AB - [This corrects the article DOI: 10.1007/s12522-009-0021-1.]. PMID- 29699367 TI - Erratum: ERRTAUM. AB - [This corrects the article on p. 36 in vol. 4, PMID: 29264317.]. PMID- 29699368 TI - Tobacco Cessation Scenarios Among Healthcare Profession Students: A Multidisciplinary Study AB - Background: It is acknowledged that the most effective means to contain the tobacco epidemic is to involvehealthcare providers across various disciplines. The present study was undertaken to gain a comprehensive insightinto various factors that determine the efficacy of multidisciplinary approaches in tobacco control. Methods: A crosssectional study design using a structured, pretested and self-administered questionnaire was employed in the present study,conducted among medical and dental interns and final year nursing students. Respondent demographics, knowledge,attitude, behaviour, perceived effectiveness and barriers, and willingness to participate in tobacco cessation were assessed.Results: A total of 268 subjects participated, with mean knowledge, attitude, behaviour, perceived effectiveness andbarrier scores of 69. 7%, 89.0%, 72.0%, 80.6% and 88.6% respectively. There were significant differences among themean scores of the study domains across the 3 disciplines. The majority (92.91%) of the respondents were willing toparticipate in tobacco cessation activities, but only 14.2% had previously received relevant training. Regression analysisrevealed that the significant predictors of behaviour scores were gender, course, attitude and perceived effectiveness;those for willingness to undertake tobacco cessation activities were course, attitude, behaviour and perceived barriers.Conclusions: The study highlighted the willingness but low previous training among the participants and also identifiedfactors that determine t behaviour and willingness to undertake tobacco cessation activities. The study emphasizes theneed for modification in the policies pertaining to curricula of medical, dental and nursing training programs. PMID- 29699369 TI - Early Detection of Breast Cancer and Barrier to Screening Programmes amongst Thai Migrant Women in Australia: A Qualitative Study AB - Background: Breast cancer screening programme is seen as the best practice to detect breast cancer early. However,there are circumstances that can prevent immigrant women from attending screening programmes. Little is knownabout Thai migrants and the barriers to their seeking breast cancer screening when living in a new homeland. This paperaimed to discuss the barriers to attending screening services among Thai migrant women living in Australia. Methods:This study adopted qualitative approach. Semi-structured in-depth interviewing and drawing methods were employedas data collection technique with 25 Thai migrant women who had not experienced breast cancer and were living inMetropolitan Melbourne, Australia. Thematic analysis method was employed to analyse the data. Results: Basing onthe Health Belief Model, most Thai migrant women did not perceive that they were at risk of breast cancer. Despiteseeing a breast cancer screening programme as important, the women rarely paid attention to breast cancer screeningand used the mammography services provided by the Australian health care system. The barriers included the locationof the services, unfamiliar patterns of health care provision, and language difficulties. Conclusions: There are manybarriers that that they encountered in Australia that prevent Thai migrant women living in Melbourne Australia to payattention to mammographic screening service provided by Australia health system. Our findings suggest that healthservices and interventions need to be designed more sensitive to the needs and socio-cultural context of migrant womenin general and Thai migrant women in particular. PMID- 29699370 TI - Exploring Spatial Patterns of Colorectal Cancer in Tehran City, Iran AB - Objectives: Colorectal cancer (CRC) may now be the second most common cancer in the world. The aim of thisstudy was to determine whether clusters of high and low risk of CRC might exist at the neighborhood level in Tehrancity. Methods: In this study, new cases of CRC provided from Cancer Registry Data of the Management Center ofMinistry of Health and Medical Education of Iran in the period from March 2008 to March 2011 were analyzed. Rawstandardized incidence rates (SIRs) were calculated for CRC in each neighborhood, along with ratios of observed toexpected cases. The York and Mollie (BYM) spatial model was used for smoothing of the estimated raw SIRs. Todiscover clusters of high and low CRC incidence a purely spatial scan statistic was applied. Results: A total of 2,815new cases of CRC were identified and after removal of duplicate cases, 2,491 were geocoded to neighborhoods. Thelocations with higher than expected incidence of CRC were northern and central districts of Tehran city. An observedto expected ratio of 2.57 (p<0.001) was found for districts of 2, 6 and 11, whereas, the lowest ratio of 0.23 (p<0.001)was apparent for northeast and south areas of the city, including district 4. Conclusions: This study showed that thereis a significant spatial variation in patterns of incidence of CRC at the neighborhood level in Tehran city. Identificationof such spatial patterns and assessment of underlying risk factors can provide valuable information for policymakersresponsible for equitable distribution of healthcare resources. PMID- 29699371 TI - Knowledge, Perception, and Acceptance of HPV Vaccination and Screening for Cervical Cancer among Women in YogyakartaProvince, Indonesia AB - Objective: To determine knowledge, perception, and acceptance related to cervical cancer, HPV vaccination andscreening for cervical cancer among Indonesian women, particularly in Yogyakarta province. Methods: A conveniencesample of 392 women consists of 192 young women, 100 mothers of girls aged 12 - 15 years, and 100 adult womenin Yogyakarta province, Indonesia was participated in this study. A self-administered paper-based questionnaire wasused to determine demographics characteristics of respondents, as well as their knowledge - perception - acceptancerelated to cervical cancer, HPV vaccination, and screening for cervical cancer. Data collection were conducted duringDecember 2013 to March 2014. Descriptive statistics was used to analyze description of demographics characteristics,knowledge, perception, and acceptance; while crosstab analysis using Chi-Square was used to analyze the relationshipbetween demographics characteristics versus knowledge, perception, and acceptance. Results: This study found thatknowledge and perception regarding cervical cancer, HPV vaccination, and screening for cervical cancer among womenin Indonesia, particularly in Yogyakarta Province were still insufficient, however the acceptance was good. Among femaleyoung women, 64% had good knowledge, 62% had positive perception of cervical cancer and HPV vaccination, and92% tended to accept HPV vaccination. Among mothers of girls aged 12 - 15 years, 44% had good knowledge, 46%had positive perception of cervical cancer and HPV vaccination, and 91% tended to accept HPV vaccination for theirdaughters. Among adult women, 68% had good knowledge, 57% had positive perception of cervical cancer and screeningfor cervical cancer, and 90% tended to accept cervical cancer screening. In general, demographics characteristics ofhaving experience and exposure to information had significant relationship with knowledge, perception, and acceptanceof HPV vaccination and screening for cervical cancer. Conclusions: Either knowledge or perception of cervical cancerand strategies toward it among Indonesian women particularly in Yogyakarta province were still unsatisfied. Effortsshould be improved for supporting cervical cancer prevention and control in Indonesia through such as education oncervical cancer disease and strategies toward it. PMID- 29699372 TI - Prognostic Factors for Hormone Sensitive Metastatic Prostate Cancer: Impact of Disease Volume AB - Background and Aim: The optimal management of metastatic hormone-sensitive prostate cancer has beencontroversial in recent years with introduction of upfront chemohormonal treatment based on results of several Westernstudies. This changing landscape has renewed interest in the concept "disease volume", the focus of the present studyis the Egyptian patients. Methods: Patients with hormone sensitive metastatic prostate cancer presenting at MenoufiaUniversity Hospital, Egypt, during the period from June 2013 to May 2016, were enrolled. All received hormonaltreatment. Radiologic images were evaluated and patients were stratified according to their disease volume into high orlow, other clinical and pathological data that could affect survival also being collected and analyzed. Results: A totalof 128 patients were included, with a median age of 70 years (53.9% >=70). About 46% had co-morbidities, 62% havinghigh volume disease. During the median follow up period of 28 months about half of the patients progressed and onethird received chemotherapy. On univariate analysis, disease volume, performance status (PS), prostate specific antigenlevel (PSA) and presence of pain at presentation were identified as factors influencing overall survival. Multivariateanalysis revealed the independent predictor factors for survival to be PS, PSA and disease volume. The median overallsurvival with 27 months was high volume versus 49 with low volume disease (hazard ratio 2.1; 95% CI 1.2 - 4.4;P=0.02). Median progression free survival was 19 months in the high volume, as compared with 48 months in the lowvolume disease patients (hazard ratio, 2.44; 95% CI, 1.42 - 7.4; P=0.009). Conclusions: Disease volume is a reliablepredictor of survival which should be incorporated with other important factors as; patient performance status andcomorbidities in treatment decision-making. PMID- 29699373 TI - Evaluating the Oncogenic and Tumor Suppressor Role of XPO5 in Different Tissue Tumor Types AB - The miRNAs nuclear export protein XPO5 has been previously studied in several individual malignancies. In ourrecent study we have demonstrated that excess levels of XPO5 enhanced the proliferation of prostate cancer cells.Similarly, there are studies to support the inhibitory role of XPO5 in cancers. In order to evaluate discrepancies in theexpression levels of XPO5 in differential tumor types, we quantified the expression of XPO5 using gene expressionRNA-seq data for several tumor types which were independently confirmed by immunohistochemistry in multipleorgans cancer tissue microarray (TMAs) experiment. We found that while some tumors (Breast, Bladder, Lymph-node,Lung, Esophagus and Ovary) showed higher differences between normal and malignant tumors in XPO5 expression,there were tissues (Kidney and Brain) that have a significantly lower XPO5 expression in malignant tumors. We furtherstudies these observations of overexpression and down regulation of XPO5 in breast and kidney cancer cell lines andfound that XPO5 might have a dual role in promoting or inhibiting tumor growth in different cancer tissue types. PMID- 29699374 TI - Inhibitory Effects of Arsenic Trioxide and Thalidomide on Angiogenesis and Vascular Endothelial Growth Factor Expression in Leukemia Cells AB - Acute myeloid leukemia (AML) is a blood disorder characterized by uncontrolled proliferation of myeloidprogenitors and decrease in the apoptosis rate. The vascular endothelial growth factor (VEGF) promotes blood vesselregeneration which might play important roles in development and progression of neoplasia. Our previous studiesfocused on cytotoxicity and anticancer effects of arsenic trioxide (ATO) and thalidomide (THAL) as an anti-VEGFcompound in the AML cell model. ATO also affects regulatory genes involved in cell proliferation and apoptosis. Theaim of present study was to examine the effects of ATO and THAL alone and in combination on U937 and KG-1 cells, with attention to mRNA expression for VEGF isoforms. Growth inhibitory effects was assessed by MTT assay andapoptosis induction was determined by Annexin/PI staining. mRNA expression levels were evaluated by real-timePCR. Our data indicated that ATO (1.618MUM and 1MUM in KG-1 and U937 cell lines respectively), THAL (80MUM and60MUM) and their combination inhibited proliferation and induced apoptosis in our cell lines. mRNA expression ofVEGF (A, B) decreased while C and D isoforms did not show any significant changes. Taken together, according tothe obtained results, the VEGF autocrine loop could be a target as a therapeutic strategy for cases of AML. PMID- 29699375 TI - Potential Impact of Vascular Endothelial Growth Factor Gene Variation (-2578C>A) on Breast Cancer Susceptibility in Saudi Arabia: a Case-Control Study AB - Aim: VEGF gene polymorphisms can induce either increase or inhibition of VEGF secretion, with altered promoteractivity. The VEGF rs699947 SNP is located in the promoter region and is associated with susceptibility to breastcarcinoma development. Here, we investigated the association of the -2578C>A polymorphism in the VEGF genewith breast cancer risk in Saudi women. Methodology: Genotyping of the VEGF-gene variation (-2578A>C) wasperformed using the amplification refractory mutation system PCR. We investigated the association of VEGF genevariants with different clinicopathological features of breast cancer patients. Results: A significant difference wasobserved in genotype distribution among the breast cancer cases and sex matched healthy controls (p=0.03). Thefrequencies of the three genotypes CC, CA, AA found in the patient samples were 37%, 45% and 18% and in the healthycontrols were 54%,37% ,and 09% respectively. An increased risk of developing breast cancer in Saudi women wasassociated with the VEGF -2578 AA genotype (OR = 2.91, 95 % CI, 1.18-7.20; p = 0.01; RR 1.78 (1.01-3.11 p=0.01),the VEGF -2578 A allele (OR = 1.79, 95 % CI, 1.17-2.73; p = 0.004: RR 1.35 1.07-1.71) and the VEGFR-(CA+AA) (OR 1.99 1.13 3.51; RR 1.401.0-1.85). Thus the A allele increased the risk of BC when compared with C allele.When we stratified groups of patients according to the status of tumor markers, stage, age and metastasis, statisticallysignificant associations with -2578 C/A SNP were revealed. Conclusion: Our data showed a significant associationof the VEGF -2578C>A polymorphism with BC susceptibility in Saudi women. The VEGF -2578AA homozygotesignificantly increases the risk and can be useful as a predisposing genetic marker. Further studies with larger samplesizes are necessary to confirm our findings. PMID- 29699376 TI - Digital Cervicography by Simply Portable Device as an Alternative Test for Cervical Cancer Screening in Rural Area of Thailand AB - Objective: Various screening methods for cervical cancer are proved to be effective in reducing such type of cancer.We aims to introduce a new portable device as an alternative method for cervical cancer screening. The performanceof device was tested on the assessment of cervical lesions using cervicograph score with the cervical cytology.Methods: 325 non-pregnant women were tested from March 2013 to August 2015. The cervical and vaginal cellsfrom the sample were collected for cytology, then all of them received the digital cervicography conducted with ournew device and scored using cervicograph score. Small pieces of cervical tissues were also collected for histologicexamination. SPSS software version 18.0 was used for the statistical analysis. Results: We grouped cytology resultsand cervicograph scores to 2 subgroups, <= ASC-US and >= LSIL, and 0-3 points and 4-6 points, respectively. The datathen correlated with histology results which sub grouped to <= CIN 1 and >= CIN 2. The accuracy, sensitivity, specificity,and positive predictive value (PPV) of cervicograph scores 4-6 points to detect CIN 2+ were 92%, 72.41%, 97%, and84%, respectively which were not inferior to Pap smear did. Conclusion: The digital cervicography device providessimilar accuracy to Pap cytology screening and is suitable to use in the area that lacks cytoscreeners. Large scale useand generalization are required for this new device PMID- 29699377 TI - A practical guide to the feeding of organic farm animals: pigs, poultry, cattle, sheep and goats. PMID- 29699378 TI - Use of Vitamin D in Children and Adults: Frequently Asked Questions AB - In recent years, the increase in interest and use of vitamin D has been attributed mainly to the extra-skeletal effects of vitamin D and confusion about normal reference values for serum 25-hydroxy vitamin D (25-OHD). However, The Institute of Medicine, which determines daily intake of nutrients, vitamins and minerals in the United States, emphasizes that there is no additional benefit of having a 25-OHD level above 20 ng/mL in terms of parathyroid hormone suppression, calcium absorption and "fall risk". Taking into consideration that there has not been a significant increase in vitamin D deficiency and related conditions in Turkey over the past five years, it is not hard to suppose that this increased interest is due to doctors, using mass media platforms, who have made claims that vitamin D is a "panacea". This paper aims to answer some frequently asked questions such as the threshold values recommended for the evaluation of vitamin D status, the clinical indications for measuring 25-OHD and suggestions on the use of lifelong vitamin D starting from pregnancy. PMID- 29699379 TI - Endoscopic Features of Mucous Cap Polyps: A Way to Predict Serrated Polyps. AB - BACKGROUND/AIMS: The aims of the study were to identify whether a mucous-cap predicts the presence of serrated polyps, and to determine whether additional endoscopic findings predict the presence of a sessile serrated adenomas/polyp (SSA/P). METHODS: We analyzed 147 mucous-capped polyps with corresponding histology, during 2011-2014. Eight endoscopic features (presence of borders, elevation, rim of debris, location in the colon, size >=10 mm, varicose vessels, nodularity, and alteration in mucosal folds) of mucous-capped polyps were examined to see if they can predict SSA/Ps. RESULTS: A total of 86% (n=126) of mucous-capped polyps were from the right sided serrated pathway (right-sided hyperplastic [n=83], SSA/Ps [n=43], traditional serrated adenoma [n=1]), 10% (n=15) were left-sided hyperplastic polyps, and 3% (n=5) were from the adenoma carcinoma sequence. The presence of a mucous cap combined with varicose vessels was the only significant predictor for SSA/Ps. The other seven characteristics were not found to be statistically significant for SSA/Ps, although location in the colon and the presence of nodularity trended towards significance. CONCLUSIONS: Our study suggests that mucous-capped polyps have high predictability for being a part of the serrated pathway. Gastroenterologists should be alert for a mucous-capped polyp with varicose veins, as these lesions have a higher risk of SSA/P. PMID- 29699380 TI - Therapeutic Efficacy of Mesenchymal Stem Cells and Mesenchymal Stem Cells-derived Neural Progenitors in Experimental Autoimmune Encephalomyelitis. AB - Background and Objectives: The goal of treatment for MS is to reduce the inflammation and induce the regeneration of degenerated axons. Considering the anti-inflammatory and regenerative capacity of mesenchymal stem cell (MSCs), in this study the therapeutic efficacy of allogeneic MSCs and MSCs-derived neural progenitor cells (MSCs-NPs) was investigated in cellular therapy of chronic experimental autoimmune encephalomyelitis (EAE). Methods and Results: MSCs, MSCs NPs and MSCs+MSCs-NP were administered intravenously to EAE mice on days 22, 29, and 36 post immunization. The levels of cytokines and PGE2 in sera or supernatant of in vitro cultured splenocytes derived from treated mice were measured by ELISA. The results of this study showed that in comparison to MSCs monotherapy, MSCs-NPs administration had a more profound capability of inhibiting the proliferation of pathogenic MOG35-55-specific T cells, decreasing IFN-gamma production and increasing anti-inflammatory IL-10 cytokine production. These findings could be explained by higher ability of in vitro cultured MSCs-NPs in production of PGE2 compared to MSCs. In line with these findings, while the administration of MSCs and MSCs-NPs significantly decreased the clinical scores of EAE in comparison with the untreated EAE group, MSCs-NPs were significantly more efficient in reducing clinical score compared to MSCs. Of interest, combined therapy with MSCs and MSCs-NPs did not provide any benefit over monotherapy with MSCs-NPs. Conclusions: In comparison to MSCs, allogenic MSCs-NPs are more potent in the attenuation of EAE. PMID- 29699381 TI - Improvement of Cell Cycle Lifespan and Genetic Damage Susceptibility of Human Mesenchymal Stem Cells by Hypoxic Priming. AB - Hypoxic culture is widely recognized as a method to efficiently expand human mesenchymal stem cells (MSCs) without loss of stem cell properties. However, the molecular basis of how hypoxia priming benefits MSC expansion remains unclear. We report that hypoxic priming markedly extends the cell cycle lifespan rather than augmenting the multipotency of MSC differentiation lineage. Hypoxic priming does not affect to chromosome damage but significantly attenuates the susceptibility of chromosome damage. Our results provide important evidence that multipotency of human MSCs by hypoxic priming is determined by cell cycle lifespan. PMID- 29699382 TI - Transcriptional Profiling of Mesenchymal Stem Cells Identifies Distinct Neuroimmune Pathways Altered by CNS Disease. AB - Background and Objectives: Bone marrow mesenchymal stem cells (BM-MSCs) are an attractive cell based therapy in the treatment of CNS demyelinating diseases such as multiple sclerosis (MS). Preclinical studies demonstrate that BM-MSCs can effectively reduce clinical burden and enhance recovery in experimental autoimmune encephalomyelitis (EAE), a commonly used animal model of MS. However, a number of recent clinical trials have not shown significant functional benefit following BM-MSC infusion into MS patients. One possibility for the discrepancy between animal and human studies is the source of the cells, as recent studies suggest BM-MSCs from MS patients or animals with EAE lack reparative efficacy compared to naive cells. We sought to define important transcriptional and functional differences between diseased and naive MSCs. Methods and Results: We utilized RNA Sequencing (RNA-Seq) to assess changes in gene expression between BM MSCs derived from EAE animals and those derived from healthy controls. We show that EAE alters the expression of a large number of genes in BM-MSCs and changes in gene expression are more pronounced in chronic versus acute disease. Bioinformatic analysis revealed extensive perturbations in BM-MSCs in pathways related to inflammation and the regulation of neural cell development. These changes suggest that signals from EAE derived BM-MSCs inhibit rather than enhance remyelination, and in-vitro studies showed that conditioned medium from EAE MSCs fails to support the development of mature oligodendrocytes, the myelinating cells of the CNS. Conclusions: These data provide insight into the failure of autologous BM-MSCs to promote recovery in MS and support the concept of utilizing non-autologous MSCs in future clinical trials. PMID- 29699383 TI - Human Embryonic Stem Cell Derived from Early Stage Fertilized Ovum: Non Immunogenic and Universal, Neuronal and Non-neuronal Cell Lines. AB - Background: Human embryonic stem cells (hESCs) have the potential to treat various human disorders currently labeled as incurable and/or terminal illness. However, the fear that the patients' immune system would recognize them as non self and lead to an immune rejection has hampered their use. The main cause for immune rejection is usually the incompatibility of both donor and recipient's major histocompatibility complex (MHC). Methods: We describe a hESC line developed through a patented technology that does not lead to immune reaction upon transplantation. We have transplanted these cells in >1,400 patients with chronic/terminal conditions and did not observe any immune reaction. No immunosuppressant were administered to these patients. We analyzed the expression levels of MHC-I and MHC-II on the surface of these hESCs using microarray technology. The gene targets for miRNA were analyzed using Gene ontology and DAVID database and pathways for these genes were determined using Reactome and Panther databases. Results: Our results showed that the levels of expression of MHC-I and MHC-II on hESCs is almost negligible and thus the hESCs are less susceptible to an immune rejection. Conclusions: The hESCs cultured at our facility expresses low levels of MHC-I and do not produce an immune reaction. These can be administered universally and need no cross matching before transplantation. PMID- 29699384 TI - TGF-beta induces Smad2 Phosphorylation, ARE Induction, and Trophoblast Differentiation. AB - Background: Transforming growth factor beta (TGF-beta) signaling has been shown to control a large number of critical cellular actions such as cell death, differentiation, and development and has been implicated as a major regulator of placental function. SM10 cells are a mouse placental progenitor cell line, which has been previously shown to differentiate into nutrient transporting, labyrinthine-like cells upon treatment with TGF-beta. However, the signal transduction pathway activated by TGF-beta to induce SM10 progenitor differentiation has yet to be fully investigated. Materials and Methods: In this study the SM10 labyrinthine progenitor cell line was used to investigate TGF-beta induced differentiation. Activation of the TGF-beta pathway and the ability of TGF-beta to induce differentiation were investigated by light microscopy, luciferase assays, and Western blot analysis. Results and Conclusions: In this report, we show that three isoforms of TGF-beta have the ability to terminally differentiate SM10 cells, whereas other predominant members of the TGF-beta superfamily, Nodal and Activin A, do not. Additionally, we have determined that TGF-beta induced Smad2 phosphorylation can be mediated via the ALK-5 receptor with subsequent transactivation of the Activin response element. Our studies identify an important regulatory signaling pathway in SM10 progenitor cells that is involved in labyrinthine trophoblast differentiation. PMID- 29699385 TI - Local Mesenchymal Stem Cell Therapy in Experimentally Induced Colitis in the Rat. AB - Background: Multipotent mesenchymal stem cells (MSCs) have been used in inflammatory bowel diseases because of their immunomodulatory and regenerative properties. We investigated their local use in an experimental model of colitis in the rat. Materials and Methods: Colitis was induced into 20 Wistar rats with local TNBS instillation. Allogeneic stem cells were derived from rat adipose tissue and labeled with PKH2 linker dye with creation of a control and a second group treated by a local injection into the rectal wall of 2*106 allogeneic adipose tissue-derived stem cells (ADSCs). The thicknesses of different components of the rectum were measured with comparisons made in different parts of the colon of the Hunter inflammatory score. PKH2-dyed ADSCs were detected by fluorescence microscopy. Results and Conclusions: Total colitis was induced in 19/20 rats with homing of fluorescent ADSCs. to the crypt base and perivascular space of the submucosa. There were no differences in component rectal wall thicknesses with a higher Hunter score in the treated group compared with the controls, in the rectum (3.8+/-2.74 vs. 1.5+/-2.37, respectively; p=0.017) and in right colon (2.5+/-1.08 vs. 0.20+/-0.42, respectively; p=0.0001). Local colonic injection of allogeneic adipose stem cells. in experimental colitis is feasible and safe. There is demonstrable homing of cells in chemically-induced colitis both to the treated region and parts of the colon distant to the MSC treatment site. Such cells readily proliferate in vitro and could potentially be a source for future treatment of resistant disease. PMID- 29699386 TI - The Effect of Umbilical Cord-derived Mesenchymal Stem Cell Transplantation in a Patient with Cerebral Palsy: A Case Report. AB - Background: Cerebral Palsy (CP) is the most common motor disability reason of childhood that occurs secondarily to non-progressive damage in the brain whose development is still ongoing. Methods: 6-year-old dystonic-spastic male CP patient received allogenic mesenchymal stem cells treatment four times as 1*106/kg in intrathecal and intravenous administration of Umbilical Cord-derived mesenchymal stem cells (UC-MSCs) ways. Before and after the treatment, the patient was followed-up with FIM (Functional Independent Measurement), GMFCS (Gross Motor Function Classification System 88), Tardieu Scale, TCMS (Trunk Control Measurement Scale), MACS (Manual Ability Classification Scale), CFSS (Communication Function Classification System) for 18 months and received intensive rehabilitation. Results: Improvements were observed especially in functional scales except for the Tardieu Scale, and no adverse effects were detected aside from a slight pain in the back. Conclusion: Wider future case studies on UC-MSCs will enable us to assess the efficacy of UC-MSCs which have positive impacts especially on functional scales. PMID- 29699387 TI - The Bromodomain Inhibitor JQ1 Enhances the Responses to All-trans Retinoic Acid in HL-60 and MV4-11 Leukemia Cells. AB - All-trans retinoic acid (ATRA) is a highly effective treatment for acute promyelocytic leukemia (APL), a cytogenetically distinct subtype of acute myeloid leukemia (AML). However, ATRA-based treatment is not effective in other subtypes of AML. In non-APL AML, ATRA signaling pathway is impaired or downmodulated, and consequently fails to respond to pharmacological doses of ATRA. Therefore, complementary treatment strategies are needed to improve ATRA responsiveness in non-APL AML. In this study, we investigated the combined effect of ATRA and bromodomain inhibitor JQ1, proven to have potent anti-cancer activity mainly through inhibition of c-Myc. We showed that the combination of ATRA with JQ1 synergistically inhibited proliferation of AML cells. The synergistic growth inhibition was resulted from differentiation or apoptosis depending on the kind of AML cells. Concomitantly, the combined treatment of ATRA and JQ1 caused greater depletion of c-Myc and hTERT expression than each agent alone in AML cells. Taken together, these findings support the rationale for the use of the combination of ATRA and JQ1 as a therapeutic strategy for the treatment of AML. PMID- 29699388 TI - Enhancement of Replication and Differentiation Potential of Human Bone Marrow Stem Cells by Nicotinamide Treatment. AB - Background and Objectives: Therapies using mesenchymal stem cells (MSCs) generally require substantial expansion of cell populations. However, the replicative life span of MSCs is limited and their multipotency declines over continued passages, imposing a limitation on their application especially in aged individuals. In an effort to increase MSC life span, we tested the effects of nicotinamide (NAM), a precursor of NAD+ that has been shown to reduce reactive oxygen species generation and delay the onset of replicative senescence in fibroblasts. Methods: Bone marrow stem cells (BMSCs) from healthy donors were cultivated in the presence of 5 mM NAM until the end of their life span. The levels of proliferation and differentiation to osteogenic, adipogenic, and chondrogenic lineages of BMSCs were compared between populations incubated in the absence or presence of NAM. Results: The replicative life span was substantially increased with a significant delay in the onset of senescence, and differentiation to all tested lineages was increased. Furthermore, differentiation was sustained and the adipogenic switch from osteogenesis to adipogenesis was attenuated in late-passage BMSCs. Conclusions: NAM could be considered as an important biological agent to expand and sustain the multipotency of BMSCs and thus broaden the application of stem cells in cell therapies. PMID- 29699390 TI - Selenium Dioxide As an Alternative Reagent for the Direct alpha-Selenoamidation of Aryl Methyl Ketones. AB - A general strategy for the preparation of N, N-dialkyl-2-oxo-2 arylethaneselenoamides is described. The single step method involves direct coupling of aryl methyl ketones with secondary amines and selenium dioxide in DMSO. The reactions proceeded smoothly at room temperature to provide a number of the alpha-oxo-selenoamides in good to excellent yields. PMID- 29699389 TI - A Synopsis of Current Practice in the Diagnosis and Management of Patients with Turner Syndrome in Turkey: A Survey of 18 Pediatric Endocrinology Centers AB - Objective: A comprehensive survey was conducted to evaluate the shortcomings of clinical care in patients with Turner syndrome (TS) in Turkey. Methods: A structured questionnaire prepared by the Turner study group in Turkey, which covered relevant aspects of patient care in TS was sent to 44 pediatric endocrinology centers. Results: Eighteen centers (41%) responded to the questionnaire. In the majority of the centers, diagnostic genetic testing, screening for Y chromosomal material, protocols regarding the timing and posology of growth hormone (GH) and estrogen, thrombophilia screening, fertility information and screening for glucose intolerance, thyroid, and coeliac diseases in patients with TS were in line with the current consensus. Thirteen centers (72.2%) performed GH stimulation tests. Only four centers (22.2%) used oxandrolone in patients with TS with very short stature. The majority of the centers relied on bone age and breast development to assess estrogen adequacy, though together with variable combinations of oestrogen surrogates. Two centers (11.1%) reported performing serum estradiol measurements. Eight centers (44.4%) routinely conducted cardiac/thoracic aorta magnetic resonance imaging. Screening for hearing, dental and ophthalmologic problems were performed by thirteen (72.2%), six (33.3%) and ten (55.6%) centers, respectively. Psychiatric assessments were made by four centers (22.2%) at diagnosis, with only one center (5.6%) requiring annual reassessments. Conclusion: Although we found some conformity between the current consensus and practice of the participating centers in Turkey regarding TS, further improvements are mandatory in the multi disciplinary approach to address co-morbidities, which if unrecognized, may be associated with reduced quality of life and even mortality. PMID- 29699391 TI - Protecting-Group-Free Site-Selective Reactions in a Metal-Organic Framework Reaction Vessel. AB - Site-selective organic transformations are commonly required in the synthesis of complex molecules. By employing a bespoke metal-organic framework (MOF, 1.[Mn(CO)3N3]), in which coordinated azide anions are precisely positioned within 1D channels, we present a strategy for the site-selective transformation of dialkynes into alkyne-functionalized triazoles. As an illustration of this approach, 1,7-octadiyne-3,6-dione stoichiometrically furnishes the mono-"click" product N-methyl-4-hex-5'-ynl-1',4'-dione-1,2,3-triazole with only trace bis triazole side-product. Stepwise insights into conversions of the MOF reaction vessel were obtained by X-ray crystallography, demonstrating that the reactive sites are "isolated" from one another. Single-crystal to single-crystal transformations of the Mn(I)-metalated material 1.[Mn(CO)3(H2O)]Br to the corresponding azide species 1.[Mn(CO)3N3] with sodium azide, followed by a series of [3+2] azide-alkyne cycloaddition reactions, are reported. The final liberation of the "click" products from the porous material is achieved by N-alkylation with MeBr, which regenerates starting MOF 1.[Mn(CO)3(H2O)]Br and releases the organic products, as characterized by NMR spectroscopy and mass spectrometry. Once the dialkyne length exceeds the azide separation, site selectivity is lost, confirming the critical importance of isolated azide moieties for this strategy. We postulate that carefully designed MOFs can act as physical protecting groups to facilitate other site-selective and chemoselective transformations. PMID- 29699392 TI - Nanoscale Imaging of Light-Matter Coupling Inside Metal-Coated Cavities with a Pulsed Electron Beam. AB - Many applications in (quantum) nanophotonics rely on controlling light-matter interaction through strong, nanoscale modification of the local density of states (LDOS). All-optical techniques probing emission dynamics in active media are commonly used to measure the LDOS and benchmark experimental performance against theoretical predictions. However, metal coatings needed to obtain strong LDOS modifications in, for instance, nanocavities, are incompatible with all-optical characterization. So far, no reliable method exists to validate theoretical predictions. Here, we use subnanosecond pulses of focused electrons to penetrate the metal and excite a buried active medium at precisely defined locations inside subwavelength resonant nanocavities. We reveal the spatial layout of the spontaneous-emission decay dynamics inside the cavities with deep-subwavelength detail, directly mapping the LDOS. We show that emission enhancement converts to inhibition despite an increased number of modes, emphasizing the critical role of optimal emitter location. Our approach yields fundamental insight in dynamics at deep-subwavelength scales for a wide range of nano-optical systems. PMID- 29699393 TI - Lead-Free, Two-Dimensional Mixed Germanium and Tin Perovskites. AB - Hybrid two-dimensional (2D) organic-inorganic perovskites continue to draw increased attention in view of their outstanding performance in optoelectronic devices such as solar cells and light-emitting devices. Herein, for the first time, we report the synthesis and characterization of lead-free, 2D mixed Ge-Sn halide perovskites, (PEA)2Ge1- xSn xI4 (where PEA = C6H5CH2CH2NH3+), and demonstrate that the bandgaps decrease linearly with increasing Sn content. Most importantly, among them, (PEA)2Ge0.5Sn0.5I4 possesses the smallest bandgap of 1.95 eV. Density functional theory calculations confirm that Sn substitution induces a smaller bandgap and more dispersed band structure, which are desirable characteristics of light-absorbing materials. In addition, conductivity and stability of (PEA)2Ge0.5Sn0.5I4 have also been assessed. PMID- 29699394 TI - Colloidal Nanobioconjugate with Complementary Surface Chemistry for Cellular and Subcellular Targeting. AB - Chemically and biochemically functionalized colloidal nanoparticles with appropriate surface chemistry are essential for various biomedical applications. Although a variety of approaches are now available in making such functional nanoparticles and nanobioconjugates, the lack of complementary surface chemistry often leads to poor performance with respect to intended biomedical applications. This feature article will focus on our efforts to make colloidal nanobioconjugates with appropriate/complementary surface chemistry for better performance of a designed nanoprobe with respect to cellular and subcellular targeting applications. In particular, we emphasize polyacrylate-based coating chemistry followed by a conjugation strategy for transforming <10 nm inorganic nanoparticle to colloidal nanoprobe of 20-50 nm hydrodynamic size. We show that a colloidal nanoprobe can be chemically designed to control the cell-nanoparticle interaction, cellular endocytosis, and targeting/labeling of subcellular compartments. Further study should be directed to adapt this surface chemistry to different nanoparticles, fine tune the surface chemistry for targeting/imaging on the subcellular/molecular length scale, and develop a delivery nanocarrier for subcellular compartments. PMID- 29699395 TI - Incorporation Modes of Iodate in Calcite. AB - Iodate (IO3-) incorporation in calcite (CaCO3) is a potential sequestration pathway for environmental remediation of radioiodine-contaminated sites (e.g., Hanford Site, WA), but the incorporation mechanisms have not been fully elucidated. Ab initio molecular dynamics (AIMD) simulations and extended X-ray absorption fine structure spectroscopy (EXAFS) were combined to determine the local coordination environment of iodate in calcite, the associated charge compensation schemes (CCS), and any tendency for surface segregation. IO3- substituted for CO32- and charge compensation was achieved by substitution of Ca2+ by Na+ or H+. CCS that minimized the I-Na/H distance or placed IO3- at the surface were predicted by density functional theory to be energetically favored, with the exception of HIO3, which was found to be metastable relative to the formation of HCO3-. Iodine K-edge EXAFS spectra were calculated from AIMD trajectories and used to fit the experimental spectrum. The best-fit combination consisted of a significant proportion of surface-segregated IO3- and charge compensation was predominantly by H+. Important implications are therefore that pH should strongly affect the extent of IO3- incorporation and that IO3- accumulated at the surface of CaCO3 particles may undergo mobilization under conditions that promote calcite dissolution. These impacts need to be considered in calcite-based iodate remediation strategies. PMID- 29699396 TI - DBU-Promoted [4 + 4] Domino Cycloaddition of Ynones with Benzylidenepyrazolones To Access Eight-Membered Cyclic Ethers. AB - An efficient DBU-promoted [4 + 4] domino annulation reactions of ynones and benzylidenepyrazolones has been developed. This process resulted finally in the formation of eight-membered cyclic ethers in moderate to good yields. The easy availability of starting materials and the simple cyclization procedure make this approach suitable for the preparation of a wide range of useful oxocino [2,3- c] pyrazoles. PMID- 29699401 TI - What Are the Basic Elements of a Novel Sensor Paper? PMID- 29699397 TI - Defect Patterns from Controlled Heterogeneous Nucleations by Polygonal Confinements. AB - Defects are often observed in crystalline structures. To regulate the formation or annihilation of defects presents an interesting question. In this work, we propose a method to fabricate defect patterns composed of regularly distributed steady "programmed defects", which is proceeded via the heterogeneous nucleation of a hexagonal pattern from a homogeneous state. The nucleation process occurring in a model system of AB-diblock/C-homopolymer blends under polygonal confinement is modeled by the time-dependent Ginzburg-Landau theory and is simulated by the cell dynamics simulations. Specifically, we demonstrate the validity of this method by means of three polygonal confinements including square, pentagon, and octagon, which have mismatched angles with the hexagonal lattice. Each corner or side of the polygons induces a nucleation event separately. Two nucleated domain grains by two neighboring corners or sides exhibit incommensurate orientations, and thus their merging leads to a radial line of clustered defects in the form of five-seven pairs. As a result, these radial lines constitute a radial pattern of defects, and their number is equal to the side number of the polygon. The distance of five-seven defect pairs is dictated by the incommensurate angle between two neighboring grains, which is similar to that of defects in hard crystals. This method can be extended to fabricate diverse defect patterns by programming the nucleation agents beyond simple polygonal confinements. PMID- 29699402 TI - Systemic sclerosis and sarcoidosis: a rare case of chronic intestinal pseudo obstruction. AB - The coexistence of systemic sclerosis (SSc) and sarcoidosis is an extremely rare phenomenon; some studies question its existence. We report the case of a male with a diagnosis of sarcoidosis that was admitted due to abdominal distension and pain. After a thorough investigation, he was diagnosed with severe chronic intestinal pseudo-obstruction as a manifestation of SSc. PMID- 29699403 TI - Ten years of follow-up of the Spanish cohort of the European PreventCD study: the lessons learned. AB - AIM: to evaluate the influence of gluten consumption on celiac disease development and to describe its natural history in the Spanish cohort of the European PreventCD study. METHODS: prospective multi-center double blind study of 225 children that were followed up from birth. All cases were HLA-DQ2/HLA-DQ8 positive with a 1st degree relative with celiac disease and were followed up in three centers from Madrid, Reus and Valencia. Gluten intake was determined between four and ten months according to the protocol. Gluten intake was ad libitum between eleven and 36 months and was prospectively quantified by means of dietary records. Clinical visits and specific antibody analysis for celiac disease were performed periodically. RESULTS: twenty-six cases were diagnosed, all had a positive biopsy and serology; 21 had gastrointestinal symptoms and five were asymptomatic. In addition, 2,565 food records were analyzed and statistically significant differences (p < 0.001) were found with regard to gluten consumption among the three centers, although not between celiac and non celiac children (p = 0.025). The HLA-DQ2.5/DQ2.5 and DQ2.5/DQ2.2 genotypes had a relative risk of 4.7 (95% CI: 0.80-27.55; p = 0.08), which was higher than for the rest of genotypes. Female gender also had a relative risk that was five times higher than that for males. CONCLUSIONS: the amount of gluten intake between 11 and 36 months or the duration of breast feeding were not risk factors for the development of CD in the Spanish population. The HLA genotype and gender were the most relevant associated factors. In this at-risk group, the disease presented before two years of age in the majority of the cases with a weak clinical expression. PMID- 29699404 TI - HLA-DQ distribution and risk assessment of celiac disease in a Spanish center. AB - AIMS: celiac disease is a multisystem immune-mediated disease triggered by gluten in genetically susceptible individuals. The HLA-DQ2 and/or HLA-DQ8 heterodimers are encoded by the main genetic predisposing factors and their presence is required for the development of the immunological response that leads to the disease. However, the HLA-conferred risk can differ within different countries. The aim of the study was to analyze the risk of Spanish children to develop celiac disease according to their HLA-DQ genotype. METHODS: a retrospective observational case-control study was performed using a sample of 475 celiac patients and 628 controls. RESULTS: children carrying the HLA-DQ2.5 had the highest disease risk, especially those with two HLA-DQB1*02 alleles. A similar high risk was observed in HLA-DQ8 homozygous individuals. A risk conferred by HLA DQ8 in heterozygosity and HLA-DQ2.2 was also found and two patients with celiac disease carried the HLA-DQ7.5 haplotype as the only HLA risk factor. CONCLUSIONS: there are four genetic risk categories according to the HLA-DQ genotype. The HLA DQ7.5 genotype does not confer risk but should not be used to rule out celiac disease when a high suspicion of the disease exists. These findings could be relevant to determine when to perform serological screening in asymptomatic subjects at risk of celiac disease. PMID- 29699405 TI - Generational health improvement or decline? Exploring generational differences of British ethnic minorities in six physical health outcomes. AB - OBJECTIVES: To explore ethnic and generational differences in six physical health outcomes and whether these differences can be explained by health-related behaviors and socio-economic status. DESIGN: Multivariate analyses using nationally representative data in 2010-2011 on self-assessed general health, activity-limiting illness, doctor-diagnosed diabetes, doctor-diagnosed high blood pressure, doctor-diagnosed asthma and body mass index from 21,651 White British, 997 Pakistanis, 695 Bangladeshis, 1,126 Indians, 573 Black Caribbeans and 873 Black Africans, adjusted for age, gender, health-related behaviors and socio economic status. RESULTS: While ethnicity is of great importance in patterning health differences, we find that ethnic differences in activity-limiting illness, diabetes, asthma and body mass index vary across generations. Health-related behaviors and socio-economic status are shown to partly explain ethnic and generational differences in some health outcomes. CONCLUSIONS: This study enables a better understanding of more nuanced patterns of ethnic and generational differences in health, highlighting the need to understand ethnicity as a fluid and changing characteristic, and the importance of socio-economic status and health-related behaviors in shaping ethnic differences in certain health outcomes. PMID- 29699406 TI - Nature-based interventions in institutional and organisational settings: a scoping review. AB - The objective of this review was to scope the literature on nature-based interventions that could be conducted in institutional settings where people reside full-time for care or rehabilitation purposes. Systematic searches were conducted across CINAHL, Medline, Criminal Justice Abstracts, PsycINFO, Scopus, Social Care Online and Cochrane CENTRAL. A total of 85 studies (reported in 86 articles) were included. Four intervention modalities were identified: Gardening/therapeutic horticulture; animal-assisted therapies; care farming and virtual reality-based simulations of natural environments. The interventions were conducted across a range of settings, including inpatient wards, care homes, prisons and women's shelters. Generally, favourable impacts were seen across intervention types, although the reported effects varied widely. There is a growing body of literature on nature-based interventions that could be applied to a variety of institutional settings. Within most intervention types, there is sufficient research data available to perform full systematic reviews. Recommendations for future systematic reviews are offered. PMID- 29699407 TI - The current landscape of early drug development for patients with sarcoma in the immunotherapy era. AB - Immunotherapy has changed the treatment paradigm of melanoma and other malignancies. Recently, trials of checkpoint inhibition in sarcomas have been far from outstanding, although specific sarcoma subtypes appear to benefit from these novel therapies. The next steps involve combining immune checkpoint inhibition with classic cancer therapies in order to increase immunogenicity and also potentially complex immunotherapy techniques such as adoptive cell therapy. Currently, numerous clinical trials are exploring different immunotherapies in the sarcomas. Herein, we describe some of the preclinical and clinical data that have laid the groundwork for the use of immunotherapies in sarcomas, as well as the current and future studies that could make immunotherapy a therapeutic option for patients with sarcoma. PMID- 29699408 TI - A qualitative analysis of trainer/coach experiences of changing care home practice in the Well-being and Health in Dementia randomised control trial. AB - Objectives This study explored the experiences of a range of health and social care professionals employed in the role of trainer/coaches to support care home staff to implement a psychosocial intervention for residents living with dementia. It aimed to identify the factors which are pertinent to these roles, in the context of a cascade model of training. Method A focus group was convened involving dementia trainer/coaches and supervisors who had worked on Well-being and Health for people with Dementia randomised control trial. Twelve participants explored their preparedness for and experiences of their role as 'Well-being and Health for people with Dementia therapists'. They reflected on their perceptions of the resources and support required. The data were transcribed verbatim and subjected to inductive thematic analysis. Results Three main themes emerged from the data. Within the theme of 'skills in relationship building' were two subthemes of developing trust and getting to know individual staff and each care home. In the second main theme of 'making use of tangible resources' two subthemes relating to using the Well-being and Health for people with Dementia manuals and the supervision of the therapists arose. The third theme, 'being an agent for change' contained three subthemes: effective training methods, creating opportunities for Dementia Champions to reflect and therapists' perceived rewards of their role. Conclusion The findings provide new insights into the trainer/coach role applicable to the practices of services recruiting, training and providing ongoing professional support to practitioners in-reaching into care homes. PMID- 29699409 TI - A systematic meta-review of self-management support for people with dementia. AB - Self-management support for people with dementia is important to help them and their family caregivers to cope with challenges in daily live. Insight into the effects of self-management support interventions on people with dementia is however lacking, despite existing relevant systematic reviews. We therefore conducted a meta-review of relevant systematic reviews, following the PRISMA statement. Systematic literature searches were conducted in PubMed, CINAHL, the Cochrane Library, Embase and PsycINFO. The searches were done in December 2015, and all relevant references until then were taken into consideration. No conclusions about the effects of self-management support interventions on people with dementia could be drawn. Recommendations for future research and practice include that self-management support interventions and effect measurements should be wider in scope than psychological well-being. PMID- 29699410 TI - Using normalisation process theory to understand barriers and facilitators to implementing mindfulness-based stress reduction for people with multiple sclerosis. AB - Objectives To study barriers and facilitators to implementation of mindfulness based stress reduction for people with multiple sclerosis. Methods Qualitative interviews were used to explore barriers and facilitators to implementation of mindfulness-based stress reduction, including 33 people with multiple sclerosis, 6 multiple sclerosis clinicians and 2 course instructors. Normalisation process theory provided the underpinning conceptual framework. Data were analysed deductively using normalisation process theory constructs (coherence, cognitive participation, collective action and reflexive monitoring). Results Key barriers included mismatched stakeholder expectations, lack of knowledge about mindfulness based stress reduction, high levels of comorbidity and disability and skepticism about embedding mindfulness-based stress reduction in routine multiple sclerosis care. Facilitators to implementation included introducing a pre-course orientation session; adaptations to mindfulness-based stress reduction to accommodate comorbidity and disability and participants suggested smaller, shorter classes, shortened practices, exclusion of mindful-walking and more time with peers. Post-mindfulness-based stress reduction booster sessions may be required, and objective and subjective reports of benefit would increase clinician confidence in mindfulness-based stress reduction. Discussion Multiple sclerosis patients and clinicians know little about mindfulness-based stress reduction. Mismatched expectations are a barrier to participation, as is rigid application of mindfulness-based stress reduction in the context of disability. Course adaptations in response to patient needs would facilitate uptake and utilisation. Rendering access to mindfulness-based stress reduction rapid and flexible could facilitate implementation. Embedded outcome assessment is desirable. PMID- 29699411 TI - Characteristics of Cats Admitted to Czech Shelters. AB - The aim of this study was to describe the numbers and characteristics of cats entering Czech shelters. Records of sheltered cats were collected from three cat shelters situated in different regions of the Czech Republic from 2011 to 2015. A total of 2170 cat admissions were analyzed in this study. Significantly (p < .001) greater numbers of females (56%) were admitted. Most cats (60%) were admitted when they were aged younger than six months. Cats with dark coat colors prevailed (73%), cats with medium-shade colors followed (20%), and light-colored cats were the rarest (7%). The greatest numbers of cats were admitted in summer (36%), followed by autumn (33%). The fewest cats were admitted in winter (14%). Adoption was the most common outcome for admitted cats (65%), followed by unassisted death (22%) and euthanasia (11%) due to health reasons. Only 2% of cats were reclaimed from the shelters by their original caretakers. The length of stay ranged from 0 days to 1736 days with a median of 45 days. These findings may help shelter operators define optimal strategies and operational plans. PMID- 29699413 TI - Australia's proactive approach to radiation protection of the environment: how integrated is it with radiation protection of humans? AB - Australia's regulatory framework has evolved over the past decade from the assumption that protection of humans implies protection of the environment to the situation now where radiological impacts on non-human species (wildlife) are considered in their own right. In an Australian context, there was a recognised need for specific national guidance on protection of non-human species, for which the uranium mining industry provides the major backdrop. National guidance supported by publications of the Australian Radiation Protection and Nuclear Safety Agency (Radiation Protection Series) provides clear and consistent advice to operators and regulators on protection of non-human species, including advice on specific assessment methods and models, and how these might be applied in an Australian context. These approaches and the supporting assessment tools provide a mechanism for industry to assess and demonstrate compliance with the environmental protection objectives of relevant legislation, and to meet stakeholder expectations that radiological protection of the environment is taken into consideration in accordance with international best practice. Experiences from the past 5-10 years, and examples of where the approach to radiation protection of the environment has been well integrated or presented some challenges will be discussed. Future challenges in addressing protection of the environment in existing exposure situations will also be discussed. PMID- 29699412 TI - Are Financial Incentives for Lifestyle Behavior Change Informed or Inspired by Behavioral Economics? A Mapping Review. AB - OBJECTIVE: To identify the behavioral economics (BE) conceptual underpinnings of lifestyle financial incentive (FI) interventions. DATA SOURCE: A mapping review of peer-reviewed literature was conducted by searching electronic databases. STUDY INCLUSION AND EXCLUSION CRITERIA: Inclusion criteria were real-world FI interventions explicitly mentioning BE, targeting individuals, or populations with lifestyle-related behavioral outcomes. Exclusion criteria were hypothetical studies, health professional focus, clinically oriented interventions. DATA EXTRACTION: Study characteristics were tabulated according to purpose, categorization of BE concepts and FI types, design, outcome measures, study quality, and findings. Data Synthesis and Analysis: Financial incentives were categorized according to type and payment structure. Behavioral economics concepts explicitly used in the intervention design were grouped based on common patterns of thinking. The interplay between FI types, BE concepts, and outcome was assessed. RESULTS: Seventeen studies were identified from 1452 unique records. Analysis showed 76.5% (n = 13) of studies explicitly incorporated BE concepts. Six studies provided clear theoretical justification for the inclusion of BE. No pattern in the type of FI and BE concepts used was apparent. CONCLUSIONS: Not all FI interventions claiming BE inclusion did so. For interventions that explicitly included BE, the degree to which this was portrayed and woven into the design varied. This review identified BE concepts common to FI interventions, a first step in providing emergent and pragmatic information to public health and health promotion program planners. PMID- 29699414 TI - Personality risk factors of occurrence of female breast cancer: a case-control study in China. AB - To investigate the association of personality traits with breast cancer risk, a case-control study was conducted from May 2014 to February 2017, in which the case group consisted of 262 women with breast cancer and 262 without (control group). The Eysenck Personality Questionnaire (EPQ) (88-question Adult Edition) and another self-assessment questionnaire that contained open questions to obtain more specific character traits were used to complete this survey. The results of the E scale showed that 121 women (46.18%) in the case group and 94 women (35.88%) in the control group were extroverted. The results of the N scale showed that 150 women (57.25%) in the case group and 86 women (32.82%) in the control group had unstable personality. Adjusting for other confounding factors, extroversion and unstable personality were risk factors for breast cancer (E scale: OR = 1.70, 95% CI = 1.28-2.15; N scale: OR = 3.18, 95% CI = 1.77-4.91). Personality instability was a higher risk factor than extroversion was. People with unstable personalities were 3.18 times more likely to have breast cancer than were those who had stable personalities. The results of the self-assessment questionnaire suggested that the more frequent character traits mentioned were being concerned over everything, irritable, and perfectionistic, seeking to prevail over others, and being manipulative and oversensitive. PMID- 29699415 TI - Automated Needle Targeting with X-ray (ANT-X) - Robot-assisted device for percutaneous nephrolithotomy (PCNL) with its first successful use in human. AB - INTRODUCTION: To make percutaneous access easier in PCNL, we developed Automated Needle Targeting with X-ray (ANT-X) Method: ANT-X uses an image registration software with a closed loop feedback system to autoalign the puncture needle to the desired calyx using the bullseye technique. We tried percutaneous punctures on a live pig model and compared the results with free-hand technique. We then performed our first PCNL in a human subject with the aid of ANT-X. Our patient was a 48 year-old gentleman with a 1.4cm left lower pole stone. RESULTS: Initial results for live animal trial showed radiation exposure for robot-assisted arm during puncture was reduced by 26% compared to the free-hand technique (8.2mGy vs 11.2mGy). In the human trial, obtaining percutaneous access was successful at first attempt. CONCLUSION: ANT-X system can potentially help surgeons feel confident and potentially reduce complications, hence enabling more surgeons to adopt this procedure. PMID- 29699416 TI - [Bill C-14: Important Modifications to the Criminal Code. Example of the First Case in Canada]. PMID- 29699417 TI - Physical Exercise: An Evaluation of a New Clinical Biomarker of Survival in Hospice Patients. AB - PURPOSE: Survival analysis is an important issue in palliative care. However, there is a lack of quality clinical biomarkers for assessing survival, especially in bedridden patients. Recent research supports the benefit of physiotherapy in palliative care, as majority of hospice patients are able to perform physical therapy. We propose the hypothesis that the difference in activity during physical exercise can be used as a biomarker of survival in hospice care. METHODS: We examined 536 consecutive patients who performed physical exercises in our hospice from March 2013 to July 2017. Univariate, multivariate, and Kaplan Meier analysis were performed to explore the association between the level of physical exercise activity and survival. RESULTS: Physical exercises were performed by almost 70% of our hospice patients. The patients who initially performed active exercises lived longer, on average, compared to patients who only managed passive exercises (15 days vs 6 days, hazard ratio 0.60, 0.49-0.74). Surprisingly, the difference in survival based on the level of physical activity remained consistent regardless of the patient performance score, emphasizing its usefulness as an independent survival biomarker in a hospice setting. This tool also gave us an option to recognize a significant proportion of bedridden patients performing active exercises (30%), previously unrecognized using standard performance scales, exhibiting longer survival compared to others with the same performance score. CONCLUSION: Patients' level of activity during physical exercises has the potential to be a valuable new clinical biomarker in palliative care, whether used individually or combined with commonly used performance scales. PMID- 29699418 TI - Role of Early Palliative Care Interventions in Hematological Malignancies and Bone Marrow Transplant Patients: Barriers and Potential Solutions. AB - INTRODUCTION: Despite advances in palliative care management of physical, psychological, and emotional symptoms along the spectrum of chronic conditions, early palliative care interventions are not used frequently and comprehensively in bone marrow transplant units. METHODS: The literature review of PubMed articles in English published until December 2017. RESULTS: Patients with hematologic malignancies and bone marrow transplant interventions are a heterogeneous group. The majority experience symptoms associated with induction or condition regimens. Curative intent of treatment is the norm. Pain, mucositis, nausea and vomiting, diarrhea, psychological, spiritual, and emotional concerns may not be properly and comprehensively tackled by primary oncology and bone marrow transplant teams. Quality of life may be decreased due to the presence of these symptoms. Obstacles to early palliative care interventions include overestimation of survival, focus on curative intent with underestimation of palliative care needs, lack of a comprehensive understanding of hematologic malignancies and bone marrow transplant process on the side of palliative care providers, and logistical restrictions. Potential interventions include education of oncologists, palliative care providers, patients, integration of models of care pre- and posttreatment and bone marrow transplantation, development of guidelines, institutional commitment and leadership in creating new initiatives, clinical research activities to measure outcomes, and community-based participatory research. CONCLUSIONS: Early palliative care interventions are beneficial for patients with hematologic malignancies and bone marrow transplant processes. Better understanding of barriers to its implementation and development of creative initiatives is of paramount importance. New research endeavors should focus on providers' attitudes toward patients and communities. PMID- 29699419 TI - Integrated protection of humans and the environment: a view from Japan. AB - Six and a half years after the accident at Fukushima Daiichi nuclear power plant, an area of existing exposure situation remains. One of the main concerns of people is the higher level of ionising radiation than before the accident, although this is not expected to have any discernible health effect. Since the accident, several 'abnormalities' in environmental organisms have been reported. It is still not clear if these abnormalities were induced by radiation. It appears that the impact of the released radioactivity has not been sufficient to threaten the maintenance of biological diversity, the conservation of species, or the health and status of natural habitats, which are the focus in environmental protection. This highlights a difference between the protection of humans and protection of the environment (individuals for humans and populations/species for the environment). The system for protection of the environment has been developed with a similar approach as the system for protection of humans. Reference Animals and Plants (RAPs) were introduced to connect exposure and doses in a way similar to that for Reference Male and Reference Female. RAPs can also be used as a tool to associate the level of radiation (dose rate) with the biological effects on an organism. A difference between the protection of humans and that of the environment was identified: an effect on humans is measured in terms of dose, and an effect on the environment is measured in terms of dose rate. In other words, protection criteria for humans are expressed in term of dose (as dose limits, dose constraints, and reference levels), whereas those for the environment are expressed in terms of dose rate (as derived consideration reference levels). PMID- 29699420 TI - Analysis of preventability of hypertensive disorder in pregnancy-related maternal death using the nationwide registration system of maternal deaths in Japan. AB - OBJECTIVE: Hypertensive disorder of pregnancy (HDP) is a major cause of maternal death. The goal of this study was to investigate factors associated with maternal death due to HDP. STUDY DESIGN: HDP-related maternal deaths in Japan reported to the Committee of the Ministry of Health, Labor and Welfare from 2010 to 2015 were examined. RESULTS: Out of 47 cases of HDP, 30 were identified as the major cause of maternal death. The median maternal age was 34 years (range 24-45) and the mortality in women aged >=40 years was seven times higher that than in women aged <34 years. The etiologies were intracerebral hemorrhage (n = 22), subarachnoid hemorrhage (n = 3), subcapsular hematoma of the liver (n = 2), peripartum cardiomyopathy (n = 2), and eclampsia (n = 1), and 19 cases were deemed preventable. The most frequent antepartum problems were delays in hospitalization, maternal transfer, and termination of pregnancy. In four cases, diagnosis of HELLP syndrome was too late because laboratory data were not checked, despite the patient reporting epigastric pain or showing elevation of blood pressure (BP). Treatment for lowering of BP was improper in 2/3 intrapartum cases, even though BP was elevated during pregnancy (144 versus 188 mmHg, p < .001). There was inadequate lowering of BP and lack of use of magnesium sulfate in 7/11 postpartum cases (64%), despite aspartate aminotransferase (AST) (p < .005), alanine aminotransferase (ALT) (p < .01), lactate dehydrogenase (LDH) (p < .005), and platelet count (PLT) (p < .01) all significantly worsening after delivery. CONCLUSION: HDP accounts for 11% of maternal deaths in Japan. Mothers aged >=40 years are most at risk for HDP-related maternal death. Major concerns for preventabilities were late hospitalization, maternal transportation, and termination of pregnancy for term or near-term HDP. Regular vital checks and prompt lowering of BP were lacked during labor in most cases. HELLP syndrome should be managed at a general hospital with sufficient medical resources. PMID- 29699421 TI - Work and Home Neighborhood Design and Physical Activity. AB - PURPOSE:: To investigate relations of perceived worksite neighborhood environments to total physical activity and active transportation, over and above home neighborhood built environments. DESIGN:: Observational epidemiologic study. SETTING:: Baltimore, Maryland-Washington, DC, and Seattle-King County, Washington metropolitan areas. PARTICIPANTS:: One thousand eighty-five adults (mean age = 45.0 [10.2]; 46% women) recruited from 32 neighborhoods stratified by high/low neighborhood income and walkability. MEASURES:: The Neighborhood Environment Walkability Survey assessed perceptions of worksite and home neighborhood environments. Accelerometers assessed total moderate-to-vigorous physical activity (MVPA). The International Physical Activity Questionnaire assessed total active transportation and active transportation to and around work. ANALYSIS:: Mixed-effects regression tested relations of home and worksite neighborhood environments to each physical activity outcome, adjusted for demographics. RESULTS:: Home and worksite mixed land use and street connectivity had the most consistent positive associations with physical activity outcomes. Worksite traffic and pedestrian safety were also associated with multiple physical activity outcomes. The worksite neighborhood explained additional variance in physical activity outcomes than explained by the home neighborhood. Worksite and home neighborhood environments interacted in explaining active transportation to work, with the greatest impacts occurring when both neighborhoods were activity supportive. CONCLUSION:: Both worksite and home neighborhood environments were independently related to total MVPA and active transportation. Community design policies should target improving the physical activity supportiveness of worksite neighborhood environments and integrating commercial and residential development. PMID- 29699422 TI - Availability and Use of Workplace Supports for Health Promotion Among Employees of Small and Large Businesses. AB - PURPOSE: To explore the availability and utilization of workplace health supports by employees of small and large-sized employers. DESIGN: Cross-sectional, telephone-based interviews collected on 16 workplace health supports for physical activity and diet. SETTING: Participants selected by random-digit-dialing from 4 metropolitan areas of Missouri employees from 2012 to 2013. PARTICIPANTS: Two thousand fifteen working adults. METHODS: We explored the availability and use of supports by employer size (<100 employees vs >=100 employees), accounting for industry and personal factors. ANALYSIS: We examined distributions and Poisson regression models of availability for supports by employer size and by industry and use of supports by employer size and personal factors. RESULTS: One-fifth of the 1796 employees were employed by small-sized employers. Large employers offered more supports than small (mean: 6 vs 3), but a higher proportion of employees of small-sized employers used supports when available (59% vs 47%). The differences in offered supports between industries were not due to size alone. In regard to the determinants of participation, the personal factors of gender, age, weight, and income were associated with participation in 10 of the supports. Employer size was also associated with participation in 10 supports. No associations were found between personal factors or workplace size and participation for 3 supports. CONCLUSION: A higher proportion of employees working for smaller businesses use available supports than employees of larger businesses. Supports offered by employers should target the needs and interests of the workforce, particularly for the higher risk low-income employees. PMID- 29699423 TI - Single-Family Housing Value Resilience of Walkable Versus Unwalkable Neighborhoods During a Market Downturn: Causal Evidence and Policy Implications. AB - OBJECTIVES:: This study investigated the resilience of single-family housing values in walkable versus unwalkable neighborhoods during the economic downturn from 2008 to 2012 in Dallas, Texas. METHODS:: Using propensity score matching and difference in differences methods, this study established a natural experimental design to compare before-and-after value changes of single-family (SF) homes in walkable neighborhoods with unwalkable neighborhoods during the Great Recession. Two thousand seven hundred ninety-nine SF homes within 18 Tax Increment Financing (TIF) districts were categorized into walkable (Walk Score >=50) and unwalkable (<50) groups. Six hundred twenty-four dwellings in walkable neighborhoods were matched with the most identical ones in the unwalkable neighborhoods by controlling for the selected structural and residential location variables. Relative average treatment effects were examined for SF values in walkable and unwalkable neighborhoods. RESULTS:: On average, the SF homes in walkable neighborhoods held $4566 (2.08%) more value than their how walkable counterparts. CONCLUSIONS:: This study aims to help planners and decision-makers by documenting the unmet demand for walkable communities and their sustained economic benefit. Increased awareness of the sustained value of walkable communities can be used by lenders who finance and by policy makers who regulate placemaking. Results from this study can be integrated with research that demonstrates health-care cost savings of walkable environments to create an even more comprehensive set of evidence-based interventions to increase their supply. PMID- 29699424 TI - Particle Accumulation in Ureteral Stents Is Governed by Fluid Dynamics: In Vitro Study Using a "Stent-on-Chip" Model. AB - OBJECTIVE: To investigate the correlation between fluid dynamic processes and deposition of encrusting particles in ureteral stents. MATERIALS AND METHODS: Microfluidic models (referred to as "stent-on-chip" or SOC) were developed to replicate relevant hydrodynamic regions of a stented ureter, including drainage holes and the cavity formed by a ureteral obstruction. Computational fluid dynamic simulations were performed to determine the wall shear stress (WSS) field over the solid surfaces of the model, and the computational flow field was validated experimentally. Artificial urine was conveyed through the SOCs to measure the temporal evolution of encrustation through optical microscopy. RESULTS: It was revealed that drainage holes located well downstream of the obstruction had almost stagnant flow and low WSS (average 0.01 Pa, at 1 mL/min), and thus suffered from higher encrustation rates. On the contrary, higher levels of WSS in holes proximal to the obstruction (average ~0.04 Pa, at 1 mL/min) resulted in lower encrustation rates in these regions. The cavity located nearby the obstruction was characterized by high levels of encrustation, because of the low WSS (average 1.6 * 10-4 Pa, at 1 mL/min) and the presence of flow vortices. Increasing the drainage flow rate from 1 to 10 mL/min resulted in significantly lower deposition of encrusting crystals. CONCLUSION: This study demonstrated an inverse correlation between deposition of encrusting bodies and the local WSS in a stented ureter model. Critical regions with low WSS and susceptible to encrustation were identified, including "inactive" side holes (i.e., with minimal or absent flow exchange between stent and ureter) and the cavity formed by a ureteral occlusion. Findings from this study can open new avenues for improving the stent's design through fluid dynamic optimization. PMID- 29699425 TI - Evaluation of a Portable Urinary pH Meter and Reagent Strips. AB - OBJECTIVE: To evaluate a portable electronic pH meter and to put its accuracy in perspective with reagent strips read by a layperson, a healthcare professional, and an electronic reading device. MATERIALS AND METHODS: Based on a preanalysis on 20 patients, a sample size of 77 urine aliquots from healthy volunteers was necessary to obtain sufficient study power. Measurements of urinary pH were obtained by use of reagent strips, a portable pH meter and a laboratory pH meter (gold standard). Reagents strips were read by a professional experienced in interpreting strips, a layperson, and an electronic strip reader. The mean matched pair difference between measurement methods was analyzed by the paired t test. The degree of correlation and agreement were evaluated by the Pearson's correlation coefficient and Bland-Altman plots, respectively. RESULTS: The mean matched pair difference between the gold standard and all other pH measurement methods was the smallest with the portable electronic pH meter (bias 0.01, 95% confidence interval [CI] -0.07 to 0.08; p = 0.89), followed by strips read by a professional (bias -0.09, 95% CI -0.21 to 0.02; p = 0.10), layperson (bias -0.17, 95% CI -0.31 to -0.04; p = 0.015), and electronic strip reader (bias -0.29, 95% CI -0.41 to -0.16; p < 0.001). The portable electronic pH meter achieved the highest Pearson's correlation coefficient and narrowest 95% limits of agreement, followed by strip interpretation by a professional, electronic strip reader, and layperson. To quantify the ability of pH measurement methods to correctly classify values within a predefined urinary pH target range, we performed classification tests for several stones. The portable electronic pH meter outperformed all other measurement methods for negative predictive values. CONCLUSIONS: Findings of this study support that the portable electronic pH meter is a reliable pH measuring device. It appears to be more accurate compared to reagent strips readings. PMID- 29699426 TI - Familial aggregation of first degree relatives of children with essential hypertension. AB - PURPOSE: Determining familial aggregation is an important first step in narrowing the search for disease-causing genes and hence we determined the familial aggregation of EH among first degree relatives of children with EH. MATERIALS AND METHODS: We prospectively enrolled children with EH along with their first degree relatives from a tertiary pediatric hypertension clinic in a large ambulatory care center. We utilized rigorous methodology for blood pressure (BP) measurements and diagnoses of EH to reduce the heterogeneity in the phenotype. For those enrolled, parental BP status was confirmed by in-clinic direct BP measurements. We also enrolled control children without EH along with their first degree relatives from the same pediatric ambulatory center. RESULTS: In our case control study of 153 families, the odds of having familial EH was more than 3 times higher among the cases than in controls (OR: 3.63, 95% CI: 1.85-7.12) with 71% of the cases and 41% of the controls reporting familial EH. One parent with EH was seen in 88% of the cases and 52% of the controls (OR: 6.92, 95% CI: 2.68 17.84). The odds of at least one parent (compared to neither) with EH was almost 7-fold higher, and odds of having two parents with EH was 14-fold higher among cases versus controls. The risk of EH did not go back from the first degree relative to the second degree relatives. CONCLUSIONS: We identified familial aggregation with an increased liability of childhood onset EH with parental EH. The risk of childhood onset EH is more than doubled in the presence of EH in both parents versus in a single parent. Prediction for childhood-onset EH is improved by obtaining a family history of EH in the first degree relatives. PMID- 29699427 TI - Promoting a Culture of Health Through Cross-Sector Collaborations. AB - In this study, we explore the experiences of innovative nurses who have developed cross-sector collaborations toward promoting a culture of health, with the aim of identifying lessons that can inform similar efforts of other health care professionals. We used a mixed-methods approach based on data from both an online survey and telephone interviews. A majority of the participants had significant collaborations with health care providers and non-health care providers. Strong partners included mental health providers, specialists, and primary care providers on the health side, and for non-health partners, the strongest collaborations were with community leaders, research institutions, and local businesses. Themes that emerged for successful collaborations included having to be embedded in both the community and in institutions of power, ensuring that a shared vision and language with all partners are established, and leading with strength and tenacity. A focus on building a culture of health will grow as payment policy moves away from fee-for-service toward models that focus on incentivizing population health. Effective efforts to promote a culture of health require cross-sector collaborations that draw on long-term, trusting relationships among leaders. Health care practitioners can be important leaders and "bridgers" in collaborations, but they must possess or develop the knowledge, attitudes, and skills of "bilingual" facilitators, partners, and "relationship builders." PMID- 29699428 TI - Prostate cancer with cribriform morphology: diagnosis, aggressiveness, molecular pathology and possible relationships with intraductal carcinoma. AB - INTRODUCTION: The Gleason grading system is one of the most important prognostic factors in prostate cancer (PCa). From the 2005 to the 2014 conference organized by the International Society of Urological Pathology (ISUP), the histological criteria for the Gleason patterns were improved, resulting in the shrinkage of the Gleason pattern (GP) 3 and expansion of the GP 4. Areas Covered: Cribriform, fused, ill-defined and glomeruloid glands are part of the morphologic spectrum of the current GP 4. Cribriform, derived from the Latin word cribrum (i.e. sieve), was introduced by Gleason to describe glands composed of a solid sheet with perforations or lumina. Cribriform morphology has a worse prognosis compared with the other, non-cribriform, GP4 morphologies. A practical implication is that a cribriform growth precludes a patient from selecting an active surveillance (AS) protocol. Expert commentary: The presence of these four growth patterns should be incorporated into the current Grade Group (GG) system. Enhancing our understanding of cribriform tumor behavior will lead to correctly identifying and treating those patients that will die because of PCa, while sparing treatment in those who do not require it. PMID- 29699430 TI - Current evidence of peripheral vestibular symptoms secondary to otitis media. AB - BACKGROUND: The association between otitis media and vestibular symptoms has been hypothesized in the past. Thus, in this study, we aimed to critically analyze (based in a systematic review of the literature) whether patients who have otitis media are at greater risk of developing vestibular impairment or not. METHODS: We performed a systematic review of the literature and identified potentially relevant articles reporting vestibular symptoms and results of vestibular function tests in patients with otitis media through searches of the PubMED, Web of Science, Scopus, and Google Scholar databases. The quality of the final set of records was assessed using the "Newcaste-Ottawa Scale". RESULTS: Of the 2334 records searched, 43 met our inclusion and exclusion criteria, and those included 2250 patients. The records comprised 20 longitudinal studies, 21 cross-sectional studies, and 2 case reports. Regarding the type of otitis media studied, 25 examined vestibular impairment in otitis media with effusion, 6 acute otitis media, and 12 chronic otitis media. Results of anamnesis, clinical exams, and several vestibular function tests are reported and critically discussed. CONCLUSION: Most studies evaluating the association between otitis media and vestibular symptoms have potential methodological flaws. Clinical evidence suggests that patients with otitis media have increased chances for having vestibular symptoms, delayed acquisition of developmental milestones, and abnormalities in several vestibular function tests as compared with controls. Future studies with rigorous methodology aiming to assess the clinical significance (and prognostic factors) of the association between otitis media and vestibular impairment are warranted. Key message Several studies demonstrated long-term sequelae secondary to otitis media. However, the evidence supporting those assumptions are based in low-quality evidence. Thus, better structured studies are warranted to better understand the clinical relevance of such association. PMID- 29699431 TI - Examining inventions, shaping property: The savants and the French patent system. AB - In 1791, the Loi relative aux decouvertes utiles instituted a new patent system in France. Because patents were seen as the expression of the natural right of inventors, prior examination was abolished. However, only a few years after the law was passed, an unofficial examination was reinstated, and it was entrusted to the Comite Consultatif des Arts et Manufactures - a consultative body composed of prominent scientists. I analyze the political significance of the involvement of the savants in the patent system, and based on the archives of the Comite, I study the scope and practicalities of the examination process, paying close attention to the ways through which the savants of the Comite directly intervened in the writing and drawing of specifications. I show how a distinct regime of intellectual property emerged in France and how it was constructed by the interests and norms of scientists, eager as they were to distinguish 'science' from 'industry' and establish the superiority of the former over the latter. PMID- 29699432 TI - Vaginal antiseptics reduce the risk of perinatal infection with group B streptococci. AB - OBJECTIVE: To evaluate the efficacy and safety of dequalinium chloride (DQC; 10 mg vaginal tablets), administered shortly prior to delivery in women with group B streptococcus (GBS) infection. METHODS: This observational, longitudinal, and prospective study involved 201 pregnant women at term, potentially carriers of GBS bacteria, scheduled for induction with oxytocin and with no premature rupture of amniotic membranes. RESULTS: A total of 163 women (81.09%) tested positive for GBS in their first vaginal swab (pre-DQC administration). In their second swab, post-DQC administration, 48 women were positive (23.88%) and 153 (76.12%) were negative. The number of GBS-colonized women after the administration of DQC was reduced by 57.21%. In the third swab, postpartum, 57 women were positive (28.35%). None of the newborns were positive for GBS in the oropharynx swab. The median DQC exposure time was 9.98 hours. Adverse events associated with the prophylactic treatment were reported in five women (vulvovaginal irritation). CONCLUSIONS: The administration of a single vaginal tablet of 10 mg DQC the day before induction reduced the number of GBS-colonized women by 57.21%, causing no maternal and perinatal adverse events. PMID- 29699433 TI - Prescription Drug Misuse and Child Maltreatment Among High-Risk Families. AB - Prescription drug misuse is increasingly common in the United States. To date, little is known about how prescription drug misuse relates to negative parenting behaviors like child maltreatment, even though use of illicit drugs increases rates of both child neglect and physical abuse. This study used secondary data from the Fragile Families and Child Well-Being Study (FFCWS), a clustered national sample of families at high risk for both prescription drug misuse and child maltreatment ( n = 2,917). Data from mothers who participated in the 9-year follow-up of this study were used to create logistic regression models examining prescription drug misuse and physically aggressive and neglectful parenting, while controlling for demographic and psychosocial variables. Black, non-Hispanic mothers and mothers in worse health had higher odds of physically aggressive parenting. Mothers in worse health and those who used other illicit drugs had greater odds of neglectful parenting. There were no relationships between prescription drug misuse and either parenting outcome. The findings do not provide evidence that prescription drug misuse is a risk factor for child maltreatment. Further research examining this issue and potential progression from prescription drug misuse to other illicit drug use could help clarify whether this behavior is related to negative outcomes for children. PMID- 29699435 TI - Fetal cerebral and cardiac hemodynamics in postdate pregnancy. AB - OBJECTIVE: We aimed to determine the fetal cerebro-placental Doppler indices and modified myocardial performance index (Mod-myocardial performance index (MPI)) in this homogenous group of postdated pregnancies. METHODS: A total of 92 singleton pregnant women were included in this prospective study. The study involved three groups; full term control (Group 1, n = 42, 39 0/7 to 40 6/7 week' gestation), late term (Group 2, n = 34, 41 0/7 to 41 6/7 week' gestation) and post term (Group 3, n = 16, >= 42 0/7 weeks' gestation). Each participant underwent a Doppler assessment of the fetal umbilical artery (UA), middle cerebral artery (MCA), Mod-MPI. We determined the correlation of the Doppler indices and mod-MPI in patients with unfavorable outcome. RESULTS: MCA pulcatility indices (PI), cerebroplacental ratio (CPR) values were significantly higher in the control group than those in the late-term and post-term groups (Group 1: 1.63 +/- 0.3, Group 2: 1.27 +/- 0.51, Group 3: 1.13 +/- 0.22, respectively, p < .001). The Mod MPI was significantly higher in the late-term and post-term groups than in the control group (Group 1:0.38 +/- 0.1, Group 2: 0.59 +/- 0.09, Group 3: 0.60 +/- 0.08, respectively, p < .001. MCA PI and CPR were only significantly lower in patients with unfavorable outcome). The threshold value for CPR levels for predicting unfavorable outcome in postdate pregnancies was calculated as 1.11 (area under curve [AUC] 0.762, confidence interval [CI] 0.575-0.95) with 72.7% sensitivity and 71.8% specificity. CONCLUSIONS: Fetal Mod-MPI does not differ in postdate pregnancies with favorable and unfavorable outcome. The monitorization of fetal well-being with CPR may help to clinicians to select patient for expectant management in postdate pregnancies. PMID- 29699434 TI - The combined use of an aspiration catheter and balloon angioplasty for acute atherosclerotic occlusion of the middle cerebral artery. AB - Stent-retriever thrombectomy for atherosclerotic acute occlusion of cerebral arteries is difficult. We experienced three patients with middle cerebral artery atherosclerotic occlusion who achieved successful recanalization with the combined use of aspiration thrombectomy devices and cerebral angioplasty balloons. The combination is feasible in terms of smooth delivery of the balloon catheter. PMID- 29699436 TI - The association of different progesterone preparations with preterm birth prevention. AB - OBJECTIVE: We aimed to compare the efficacy of commonly available progesterone preparations for preterm birth prevention. METHODS: A retrospective cohort study of all women treated with progesterone to prevent preterm birth and delivered in a single university-affiliated tertiary medical-center. Four progesterone preparations were compared: vaginal Endometrin 100 mg twice daily, vaginal Crinone 8% gel 90 mg daily, vaginal Utrogestan 200 mg daily, and intramuscular 17alpha-hydroxyprogesterone caproate (17-OHPC) 250 mg weekly. All women were considered at risk for preterm birth according to: prior preterm birth or cervical length below 25 mm measured during the second trimester. Significant maternal morbidity, pregnancy achieved by artificial reproductive technique and cerclage placement were excluded. Primary outcome was the rate of preterm birth prior to 37 weeks of gestation. RESULTS: Overall, 422 women were allocated to four study groups according to progesterone preparation: Endometrin 175 (41.5%), Crinone 73 (17.3%), Utrogestan 154 (36.5%), and 17-OHPC 20 (4.7%). Rates of preterm birth prior to 37 gestational weeks were lowest on the Endometrin treatment group (12.6 versus 20.5, 17.5, and 35% in the rest, p = .05). Multivariate analysis revealed that the progesterone preparation was associated with preterm birth prior to 37 gestational weeks (LR = 8.3, p = .004). The need for maternal red blood cells transfusion was significantly higher in the Endometrin subgroup (4% versus 0 in all others, p = .018). This finding remained significant after adjustment to potential confounders (LR 16.44, p < .001). Neonatal outcomes did not differ between groups. CONCLUSIONS: Different progesterone preparations prescribed to women at risk, may possess different efficacy in preventing preterm delivery prior to 37 weeks of gestation. PMID- 29699437 TI - A fragmentation study of isoflavones by IT-TOF-MS using biosynthesized isotopes. AB - To aid in the identification and quantification of biologically and agriculturally significant natural products, tandem mass spectrometry can provide accurate structural information with high selectivity and sensitivity. In this study, diagnostic fragmentation patterns of isoflavonoids were examined by liquid chromatography-ion trap-time of flight-mass spectrometry (LC-IT-TOF-MS). The fragmentation scheme for [M+H-2CO]+ ions derived from isoflavones and [M+H-B-ring CO]+ ions derived from 5-hydroxyisoflavones, were investigated using different isotopically labeled isoflavones, specifically [1',2',3',4',5',6',2,3,4-13C9] and [2',3',5',6',2-D5] isoflavones. Specific isotopically labeled isoflavones were prepared through the biosynthetic incorporation of pharmacologically applied 13C- and D-labelled L-phenylalanine precursors in soybean plants following the application of insect elicitors. Using this approach, we empirically demonstrate that the [M+H-2CO]+ ion is generated by an intramolecular proton rearrangement during fragmentation. Furthermore, [M+H-B-ring-CO]+ ion is demonstrated to contain a C2H moiety derived from C-ring of 5-hydroxyisoflavones. A mechanistic understanding of characteristic isoflavone fragmentation patterns contributes to the efficacy and confidence in identifying related isoflavones by LC-MSn. PMID- 29699438 TI - A novel thiamine-derived pigment, pyrizepine, formed by the Maillard reaction. AB - To find a Maillard pigment derived from thiamine, a solution containing glucose and thiamine was heated and analyzed with high-performance liquid chromatography equipped with diode-array detection. As a result, a unique peak showing an absorption maximum at 380 nm was detected. This peak was then isolated from a reaction solution containing glucose, lysine and thiamine, and was identified as 1-(2-methyl-6,9-dihydro-5H-pyrimido[4,5-e][1,4]diazepin-7-yl)ethan-1-one using instrumental analyses. This compound, named pyrizepine, was a novel yellow pigment having a fused ring consisting of pyrimidine and diazepine. Pyrizepine was a major low-molecular-weight pigment in the reaction solution. The structure suggests that pyrizepine is formed by condensation reaction between a degradation product of thiamine and a tetrosone derivative formed from glucose by the Maillard reaction. PMID- 29699439 TI - Synthesis of fisetin and 2',4',6'-trihydroxydihyrochalcone 4'-O-beta neohesperidoside based on site-selective deacetylation and deoxygenation. AB - Fisetin and 2',4',6'-trihydroxydihyrochalcone 4'-O-beta-neohesperidoside were synthesized from commercially available quercetin and naringin in five steps. The key steps are site-selective deacetylation and subsequent deoxygenation. The target molecules were obtained in 37% and 23% yields from the starting materials, respectively. PMID- 29699440 TI - Corrigendum to "A North American perspective of content and quality of websites in the English language on childhood-onset lupus erythematosus". AB - Corrigendum to A North American perspective of content and quality of websites in the English language on childhood-onset lupus erythematosus by C Cutler et al. Published in Lupus (2018) 27, 762-770. DOI: 10.1177/0961203317746246 . The authors wish to highlight the following correction. The subheading in Table 5 should read Content criteria and not DISCERN criteria. As well, the numbering of the table should read 1-15. [Table: see text]. PMID- 29699441 TI - Simvastatin reduces antiphospholipid antibodies formation in patients with systemic lupus erythematosus: a preliminary study. PMID- 29699442 TI - Bioinspired nanocarriers for an effective chemotherapy of hepatocellular carcinoma. AB - Drug-loaded nanoparticles have been widely researched in the antitumor. However, some of them are unsatisfactory in the long blood circulation and controlled drug release. Red blood cell (RBC) membrane vesicles (RV)-coated nanoparticles have gained more and more attention in drug delivery for their many unique advantages, such as excellent stability, long blood circulation, and reduced the macrophage cells uptake. Herein, by utilizing the advantages of RV, we fabricated RV-coated poly(lactide- co-glycolide) (PLGA)-docetaxel (RV/PLGA/DTX) nanoparticles to enhance the antitumor efficiency in vivo. The RV/PLGA/DTX showed spherical morphology with particle size of about 100 nm and zeta potential at -12.63 mV, which could maintain stability for a long time. The RV/PLGA/DTX significantly enhanced cellular uptake of DTX compared to PLGA/DTX in HepG2 cells. Moreover, RV/PLGA/DTX showed the strongest antitumor effect in vitro. Prolonged blood circulation and enhanced DTX accumulation at the tumor site through enhanced permeability and retention (EPR) effect were achieved by RV/PLGA/DTX, which eventually obtained satisfactory antitumor effect and depressed system toxicity on mice bearing HepG2 xenografts mouse models when compared with free DTX. The hematoxylin and eosin (H&E) and immunofluorescence assays further proved the advantages of RV/PLGA/DTX in vivo antitumor. These RV-coated nanoparticles provide a mimetic therapy, completely inhibited the growth of the HepG2 cells, and with simple compositions, suggesting it to be an ideal strategy for improving the antitumor effect of drug-loaded nanoparticles. PMID- 29699443 TI - Leveraging the Social Role of Dad to Change Gender Stereotypes of Men. AB - Trait stereotypes of men tend to be more fixed and negative than those of women. The current studies test whether stereotypes of men can be shifted through leveraging their social role as fathers. Trait attributes perceived to characterize women and moms were highly redundant, but those of men and dads were less so; moreover, men were perceived more negatively than dads, women, and moms (Study 1). Perceivers for whom the social role father was made salient rated men more similarly to dads, and no less similarly to men, and rated men more positively relative to a control condition (Study 2). Finally, among men, a threat to the category men resulted in greater opposition to benevolent social policies, but not if the social role father was primed (Study 3). Discussion focuses on positive consequences of increasing the psychological connection between men and fatherhood. PMID- 29699446 TI - Learning in the Target Prevalence Effect. AB - Rare or low prevalence targets are detected less well than counterparts that occur with higher probability. It stands to reason, though, that before such a deficit is apparent, information about a given target's probability of occurrence must be apprehended. In this study, we investigated how much target experience is necessary for target probabilities to be fully acquired and established within mental task representations. A central finding was that different target probability values required approximately the same amount of target sampling to learn. This was true whether learning about target probabilities from a naive start-point (Experiment 1) or when recalibrating from one probability value to another (Experiment 2). We discuss these findings in relation to how mental task representations are modified when new task-relevant information is received and the attentional consequences of such changes. PMID- 29699444 TI - Lithium Improves Dopamine Neurotransmission and Increases Dopaminergic Protein Abundance in the Striatum after Traumatic Brain Injury. AB - Experimental models of traumatic brain injury (TBI) recapitulate secondary injury sequela and cognitive dysfunction reported in patients afflicted with a TBI. Impairments in neurotransmission are reported in multiple brain regions in the weeks following experimental TBI and may contribute to behavioral dysfunction. Formation of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex is an important mechanism for neurotransmitter exocytosis. We previously showed that lithium treatment attenuated hippocampal decreases in alpha-synuclein and VAMP2, enhanced SNARE complex formation, and improved cognitive performance after TBI. However, the effect of TBI on striatal SNARE complex formation is not known. We hypothesized lithium treatment would attenuate TBI-induced impairments in evoked dopamine release and increase the abundance of synaptic proteins associated with dopamine neurotransmission. The current study evaluated the effect of lithium (1 mmol/kg/day) administration on striatal evoked dopamine neurotransmission, SNARE complex formation, and proposed actions of lithium, including inhibition of GSK3beta, assessment of synaptic marker protein abundance, and synaptic proteins important for dopamine synthesis and transport following controlled cortical impact (CCI). Sprague-Dawley rats were subjected to CCI or sham injury and treated daily with lithium chloride or vehicle for 7 days post-injury. We provide novel evidence that CCI reduces SNARE protein and SNARE complex abundance in the striatum at 1 week post-injury. Lithium administration improved evoked dopamine release and increased the abundance of alpha-synuclein, D2 receptor, and phosphorylated tyrosine hydroxylase in striatal synaptosomes post-injury. These findings show that lithium treatment attenuated dopamine neurotransmission deficits and increased the abundance of synaptic proteins important for dopamine signaling after TBI. PMID- 29699447 TI - Nuisance Compounds, PAINS Filters, and Dark Chemical Matter in the GSK HTS Collection. AB - High-throughput screening (HTS) hits include compounds with undesirable properties. Many filters have been described to identify such hits. Notably, pan assay interference compounds (PAINS) has been adopted by the community as the standard term to refer to such filters, and very useful guidelines have been adopted by the American Chemical Society (ACS) and subsequently triggered a healthy scientific debate about the pitfalls of draconian use of filters. Using an inhibitory frequency index, we have analyzed in detail the promiscuity profile of the whole GlaxoSmithKline (GSK) HTS collection comprising more than 2 million unique compounds that have been tested in hundreds of screening assays. We provide a comprehensive analysis of many previously published filters and newly described classes of nuisance structures that may serve as a useful source of empirical information to guide the design or growth of HTS collections and hit triaging strategies. PMID- 29699448 TI - Comparative study of polyethylene polyamines as activator molecules for a structurally unstable group I ribozyme. AB - Polyamines are a promising class of molecules that can modulate RNA enzyme activities. To analyze the effects of the number of amine moieties systematically, we employed four polyamines sharing dimethylene units to connect amine moieties. As a model RNA enzyme, we used a structurally unstable group I ribozyme, which was activated most and least efficiently by tetraethylenepentamine and diethylenetriamine respectively. PMID- 29699449 TI - The femoral vein diameter and its correlation with sex, age and body mass index - An anatomical parameter with clinical relevance. AB - Background The femoral vein diameter is a critical factor when assessing endoprosthetic valve size for the treatment of chronic venous insufficiency. To examine the previously stated correlation between body mass index and femoral vein diameter and to re-assess the anatomical and physiological demands for a valve implant for chronic venous insufficiency treatment, we measured the femoral vein diameter in 82 subjects. Method Femoral vein diameters (164 legs) were measured with B-mode sonography both in supine position at rest and in upright position during Valsalva maneuver. Result The mean femoral vein diameter differed significantly between supine position (13.6 +/- 3.0 mm) and upright position (16.4 +/- 2.6 mm). Males possessed a significant bigger diameter than females. A significant positive correlation between femoral vein diameter and body mass index was observed. Conclusion Assuming an increased femoral vein diameter due to obesity would further impair valve functionality by increasing distance between both valve cusps. For the development of artificial venous valves, it is crucial to consider patient- and condition-dependent vein dilation. PMID- 29699450 TI - Child Temperament, Maternal Feeding Practices, and Parenting Styles and Their Influence on Obesogenic Behaviors in Hispanic Preschool Children. AB - Although obesogenic behaviors (physical activity and/or sedentary behavior and dietary intake) are known predictors of childhood weight status, little is known about mother and child behaviors contributing to obesogenic behaviors and obesity in Hispanic preschool children, whose obesity rate is higher than in non-Hispanic Whites and non-Hispanic Blacks. The purpose of this cross-sectional, descriptive study was to examine relationships among child temperament, maternal behaviors (feeding practices and parenting style), child obesogenic behaviors, and child weight status in 100 Hispanic preschool children. Results showed that higher scores on the negative affectivity dimension of child temperament were associated with higher scores on the dimension of permissive parenting, and permissive parenting was associated with less time spent in sedentary behaviors ( B = -3.53, confidence interval [-7.52, -0.90]). Findings can guide school nurses in developing interventions that consider child temperament and parenting style to promote nonobesogenic behavior in Hispanic preschoolers. PMID- 29699451 TI - An Explore Transplant Group Randomized Controlled Education Trial to Increase Dialysis Patients' Decision-Making and Pursuit of Transplantation. AB - INTRODUCTION: Dialysis centers must provide transplant education to patients but often do not address the risks and benefits of living and deceased donor transplant. RESEARCH QUESTIONS: In a group randomized controlled trial of 20 dialysis centers and 253 patients, we assessed whether the Explore Transplant education program increased patients' readiness to pursue transplant, transplant knowledge, informed transplant decision-making, discussions about transplant with potential living donors, pursuit and receipt of living or deceased donor transplant, and whether these effects varied by race. METHODS: Patients at participating dialysis centers were randomized to receive either (1) a 4-module Explore Transplant education program, including videos, printed materials, and transplant educator discussions or (2) standard-of-care transplant education provided by dialysis centers. The trial had 3 phases: (1) pre- and postsurveying and dialysis center education (2007-2008), (2) follow-up to determine whether patients restarted or began transplant evaluation (2008-2010), and (3) assessment of participants' receipt of a renal transplant (2012-2015). RESULTS: Compared to patients in standard-of-care dialysis centers, patients who received the intervention were more likely to increase in their stage of readiness for living donor transplantation (odds ratio: 2.50; 95% confidence interval: 1.10-5.66), had greater increases in their transplant knowledge ( P < .001), and were more likely to call to restart/begin transplant evaluation (38% vs 24%, P = .006). When analyses were stratified by race, black patients were more likely to take several steps toward transplant in comparison to whites. DISCUSSION: The Explore Transplant helps dialysis patients make informed decisions and increases their pursuit of transplant, particularly among black patients. PMID- 29699452 TI - The African spiny mouse ( Acomys spp.) as an emerging model for development and regeneration. AB - The African spiny mouse ( Acomys spp.) is an emerging animal model with remarkable biological characteristics that make it a subject of interest for a broad range of research fields. Typically a desert species adapted to a low calorie diet, spiny mice develop diabetes-related symptoms when switched to high energy diets. Spiny mice undergo relatively long gestation periods and have small litters of highly developed pups, making them an adequate model for late organogenesis and perinatal biology. Recently, they have been shown to have remarkable healing and regeneration capabilities, which make them unique among mammals. In this work, we describe our experience in housing a colony of African spiny mice and cover all basic aspects of feeding, maintenance and breeding for research purposes. PMID- 29699453 TI - Factors affecting conscience-based nursing practices: A qualitative study. AB - BACKGROUND: Conscience is a guiding factor in nursing practice for delivering the ultimate care. In order to expand the concept of conscience-based care, factors affecting conscience in nursing practice need to be identified. OBJECTIVES: The current study assessed nurses' experiences to explore factors affecting conscience in nursing practice. RESEARCH DESIGN: This qualitative content analysis study employed purposive sampling to reach 14 nurses working at educational hospitals in Tabriz and Urmia, Iran. Data were analyzed using inductive and conventional analysis. Ethical considerations: This research was approved by the Ethics Committee of Urmia University of Medical Science. Voluntary participation, anonymity, and confidentiality were considered. FINDING: Two themes emerged from our analysis for enhancing conscience in nursing practices, including environment of professional performance and personal factors. DISCUSSION: The two important factors for enhancing conscience in nursing practice are environment and personal factors. CONCLUSION: It is necessary to emphasize on religious beliefs, professional commitment, and communication skills in educational training structure. Also, establishing appropriate management systems will help nurses to provide moral care. PMID- 29699454 TI - Reporting Fatal Neglect in Child Death Review. AB - Child death reviews are conducted with the aim of preventing child deaths however, definitions, inclusion criteria for the review of child deaths and reporting practices vary across Child Death Review Teams (CDRTs). This article aims to identify a common context and understanding of fatal neglect reporting by reviewing definitional issues of fatal neglect and comparing reporting practice across a number of CDRTs. Providing a consistent context for identifying and reporting neglect-related deaths may improve the understanding of the impact of fatal neglect and the risk factors associated with it and therefore, improve the potential of CDRT review to inform prevention programs, policies, and procedures. PMID- 29699455 TI - Perspectives on Adolescent Sexual Relations With Older Persons: A Systematic Review of the Literature. AB - Relations between minors under the age of consent and older persons are legally prohibited in many countries. However, the nature of these relationships, their impact on the lives of minors involved, and how they should be dealt by law enforcement and welfare systems are highly controversial. The differences between the way these relations are perceived by the minors involved and the public are also unclear. This literature review examines them as perceived by youths or young adults who had experienced sexual relations with a person at least 2 years older during their adolescence as well as by students and other adult members of the public. A systematic search of 977 studies initially identified as relevant yielded 16 studies that fit the inclusion criteria. Most (13) research samples were located in the United States, and the remainder were in the United Kingdom (2) and Australia (1). All were published in English. Four main themes emerged from the analysis of these studies: adolescent motives for sexual relations with older persons (two studies); characteristics of sexual relations between adolescents and older persons (6); contextual factors affecting the way such relations are perceived, including the partners' ages and genders (11); and perspectives on the legal framing of such relations (6). The studies' findings are discussed and implications for future research, policy, and practice are suggested, highlighting the complexity and ambiguity of the phenomenon and calling on intervention programs to focus on strengthening the family unit and social network of these youth and for policies to address teen sexuality as defined both normatively and legally. PMID- 29699456 TI - Global Posttrauma Symptoms: A Systematic Review of Qualitative Literature. AB - Exposure to potentially traumatic events is a global health problem, especially in low- and middle-income countries. Assessments for symptoms resulting from trauma exposure rely heavily on the Diagnostic and Statistical Manual of Mental Disorders, fifth edition (DSM-5) criteria for post-traumatic stress disorder (PTSD), which may not be relevant in all regions of the globe. We examined posttrauma symptoms that were not limited to Western constructs of mental health (i.e., PTSD). In a systematic review, we searched nine databases to identify posttrauma symptoms arising in qualitative literature published before July 17, 2017. A total of 17,938 records were identified and 392 met inclusion criteria. The 392 studies represented data on 400 study populations from 71 different nationalities/ethnicities. The presence and frequency of posttrauma symptoms were examined across all regions. Fisher's exact tests were also conducted to compare frequencies in posttrauma symptoms across region and gender. Based on a weighted analysis across regions, a list of global posttrauma symptoms ( N = 85) was compiled into an item bank. We found that the majority of DSM-5 PTSD symptoms were mentioned across regions (with the exception of inability to recall specific aspects of the trauma and blame of self or others for the event). Across all regions, we also found a number of symptoms mentioned that were not part of PTSD and its associated features. Findings suggest that assessing posttrauma symptoms solely based on PTSD may be limiting to global populations. Research, policy, and practice implications are discussed. PMID- 29699457 TI - A review of epidemiological research on stroke and dementia and exposure to air pollution. AB - Background Outdoor air pollution is now a well-known risk factor for morbidity and mortality, and is increasingly being identified as a major risk factor for stroke. Methods A narrative literature review of the effects of short and long term exposure to air pollution on stroke and dementia risk and cognitive functioning. Results Ten papers on stroke and 17 on dementia were selected. Air pollution, and in particular small particulate matter, contributes to about one third of the global stroke burden and about one-fifth of the global burden of dementia. It particularly affects vulnerable patients with other vascular risk factors or a prior history of stroke in low- and medium-income countries. New pathophysiological mechanisms of the cause-effect associations are suggested. Conclusion Air pollution should be considered as a new modifiable cerebrovascular and neurodegenerative risk factor. This massive worldwide public health problem requires environmental health policies able to reduce air pollution and thus the stroke and dementia burden. PMID- 29699459 TI - Re: Clinical haematology and biochemistry profiles of cattle naturally infected with Theileria orientalis Ikeda type in New Zealand. PMID- 29699458 TI - Pancreatic Effects of a Bruton's Tyrosine Kinase Small-molecule Inhibitor in Rats Are Strain-dependent. AB - Inhibitors of Bruton's tyrosine kinase (BTK) are under development as potential therapies for various autoimmune diseases. In repeat-dose toxicity studies, small molecule BTK inhibitors (BTKi) have been reported to cause a constellation of histologic effects at the pancreatic endocrine-exocrine interface in male rats; however, similar findings were not reported in other species. Since the BTKi induced pancreatic effect is morphologically similar to well-documented spontaneous changes (predominantly characterized by insular/peri-insular hemorrhage, pigment deposition, chronic inflammation, and fibrosis) that are known to vary by rat strain, we investigated potential strain-dependent differences in the pancreatic effects of a small-molecule BTKi, LY3337641. Following 13 weeks of LY3337641 treatment, Crl:CD(SD) rats were most sensitive, Crl:WI(Han) rats were of intermediate sensitivity, and Hsd:SD rats were least sensitive. These strain differences appear to be related to differences in rate of weight gain across strains and sexes; however, a definitive mechanism was not determined. This study demonstrated that BTKi-induced pancreatic effects were highly dependent on rat strain and correlated with differences in the incidence and severity of the spontaneous background change. When considered with the lack of pancreas effects in nonrat species, these changes in rats are unlikely predictive of similar changes in humans administered a BTK inhibitor. PMID- 29699461 TI - New metabolites, sarcopodinols A and B, isolated from deep-sea derived fungal strain Sarcopodium sp. FKJ-0025. AB - Fungal strain FKJ-0025 was isolated from deep-sea sediment collected at the Wakamiko Caldera in Kagoshima Bay (water depth: 200 m). The fungal strain FKJ 0025 was identified as the genus Sarcopodium based on its morphology and internal transcribed spacer (ITS) sequence. Two new compounds, designated sarcopodinols A (1) and B (2), were isolated together with the known compound SF-227 (3). PMID- 29699462 TI - Illness Perception as a Predictor of Foot Care Behavior Among People With Type 2 Diabetes Mellitus in Indonesia. AB - INTRODUCTION: Illness perception may contribute to foot care behavior because people with type 2 diabetes mellitus (T2DM) in Indonesia may have different beliefs that influence their foot care behaviors. This study aimed to determine the relationships among foot care knowledge, illness perception, local beliefs, and foot care behaviors in people with T2DM in Indonesia. METHODS: Cross sectional study with a convenience sampling technique was used to recruit 200 people with T2DM from the Outpatient Department of Islamic Hospital. The Foot Care Knowledge, Brief Illness Perception, Local Beliefs, and Foot Self-Care Behavior questionnaires were administered. RESULTS: The predictors of foot care were having a family member or friend with diabetic foot ulcer ( p = .001), diabetes mellitus duration ( p = .026), foot care knowledge ( p < .001), consequences ( p < .001), treatment control ( p < .001), and local beliefs ( p = .017). DISCUSSION: Health care providers may cultivate a spiritual approach, providing success stories to create positive images of the disease's outcomes and increase patients' confidence to control the disease. PMID- 29699463 TI - Humility: A Concept in Cultural Sensitivity. PMID- 29699464 TI - 'Unless you come with your partner you will be sent back home': strategies used to promote male involvement in antenatal care in Southern Tanzania. AB - BACKGROUND: Male involvement in pregnancy and childbirth has been shown to improve maternal and child health. Many countries have used different strategies to promote participation of men in antenatal care services. While many strategies have been employed to promote male participation in antenatal care, few have been evaluated to provide much-needed lessons to support wider adoption. OBJECTIVE: This study aimed at describing strategies that were used by health providers and the community to promote male participation in antenatal care services and challenges associated with the implementation of these interventions in Southern Tanzania. METHODS: We used qualitative data and analytical methods to answer the research questions. The study relied on semi-structured interviews with health providers, men and women, village and community leaders and traditional birth attendants. Data were analysed using a thematic approach. RESULTS: The findings of this study revealed that different strategies were employed by health providers and the community in promoting participation of men in antenatal care services. These strategies included: health providers denying services to women attending antenatal care without their partners, fast-tracking service to men attending antenatal care with their partners, and providing education and community sensitisation. The implementation of these strategies was reported to have both positive and unintended consequences. CONCLUSIONS: This study concludes that despite the importance of male involvement in pregnancy and childbirth related services, the use and promotion of the male escort policy should not inadvertently affect access to antenatal care services by pregnant women. In addition, programmes aiming for men's involvement should be implemented in ways that respect, promote and facilitate women's choices and autonomy and ensure their safety. Furthermore, there is a need for sensitisation of health providers and policymakers on what works best for involving men in pregnancy and childbirth. PMID- 29699465 TI - Alterations of Brain Gray Matter Density and Olfactory Bulb Volume in Patients with Olfactory Loss after Traumatic Brain Injury. AB - Olfactory loss and traumatic brain injury (TBI) both lead to anatomical brain alterations in humans. Little research has been done on the structural brain changes for TBI patients with olfactory loss. Using voxel-based morphometry, the gray matter (GM) density was examined for 22 TBI patients with hyposmia, 24 TBI patients with anosmia, and 22 age-matched controls. Olfactory bulb (OB) volumes were measured by manual segmentation of acquired T2-weighted coronal slices using a standardized protocol. Brain lesions in the olfactory-relevant areas also were examined for TBI patients. Results showed that patients with anosmia have more frequent lesions in the OB, orbitofrontal cortex (OFC), and the temporal lobe pole, compared with patients with hyposmia. GM density in the primary olfactory area was decreased in both groups of patients. In addition, compared with controls, patients with anosmia showed GM density reduction in several secondary olfactory eloquent regions, including the gyrus rectus, medial OFC, anterior cingulate cortex, insula, and cerebellum. However, patients with hyposmia showed a lesser degree of GM reduction, compared with healthy controls. Smaller OB volumes were found for patients with olfactory loss, compared with controls. TBI patients with anosmia had the smallest OB volumes, which were caused by the lesions for OB. In addition, post-TBI duration was negatively correlated with GM density in the secondary olfactory areas in patients with hyposmia, but was positively correlated with GM density in the frontal and temporal gyrus in patients with anosmia. The GM density and OB volume reduction among TBI patients with olfactory loss was largely dependent on the location and severity of brain lesions in olfactory-relevant regions. Longer post-TBI duration had an impact on brain GM density changes, which indicate a decreased olfactory function in patients with hyposmia and possible compensatory mechanisms in patients with anosmia. PMID- 29699466 TI - Delayed Subclavian Artery Aneurysm Following Fixation of a Clavicular Fracture. AB - Aneurysms of the subclavian artery are rare phenomena that have the potential for limb and life-threatening complications. Delayed diagnosis increases the risk of life-threatening complications or at the very least may result in a detrimental effect to both functional capacity and quality of life; primary care offers a vital opportunity to screen for such rare vascular complications and should be a consideration in all patients with evolving peripheral nerve or vascular symptoms with a history of localized clavicular trauma. We present the case of a left subclavian artery aneurysm with radial artery thrombotic sequelae following an injury and screw-plate fixation of his left clavicle. This required a 2-stage surgical approach to treatment and provides useful learning considerations for identifying rare vascular anomalies early in a primary care setting. PMID- 29699467 TI - Nonpharmacologic and Medication Minimization Strategies for the Prevention and Treatment of ICU Delirium: A Narrative Review. AB - Delirium is a multifactorial entity, and its understanding continues to evolve. Delirium has been associated with increased morbidity, mortality, length of stay, and cost for hospitalized patients, especially for patients in the intensive care unit (ICU). Recent literature on delirium focuses on specific pharmacologic risk factors and pharmacologic interventions to minimize course and severity of delirium. While medication management clearly plays a role in delirium management, there are a variety of nonpharmacologic interventions, pharmacologic minimization strategies, and protocols that have been recently described. A PubMed search was performed to review the evidence for nonpharmacologic management, pharmacologic minimization strategies, and prevention of delirium for patients in the ICU. Recent approaches were condensed into 10 actionable steps to manage delirium and minimize medications for ICU patients and are presented in this review. PMID- 29699468 TI - Lower Respiratory Tract Infection and Short-Term Outcome in Patients With Acute Respiratory Distress Syndrome. AB - OBJECTIVE: To assess whether ventilator-associated lower respiratory tract infections (VA-LRTIs) are associated with mortality in critically ill patients with acute respiratory distress syndrome (ARDS). MATERIALS AND METHODS: Post hoc analysis of prospective cohort study including mechanically ventilated patients from a multicenter prospective observational study (TAVeM study); VA-LRTI was defined as either ventilator-associated tracheobronchitis (VAT) or ventilator associated pneumonia (VAP) based on clinical criteria and microbiological confirmation. Association between intensive care unit (ICU) mortality in patients having ARDS with and without VA-LRTI was assessed through logistic regression controlling for relevant confounders. Association between VA-LRTI and duration of mechanical ventilation and ICU stay was assessed through competing risk analysis. Contribution of VA-LRTI to a mortality model over time was assessed through sequential random forest models. RESULTS: The cohort included 2960 patients of which 524 fulfilled criteria for ARDS; 21% had VA-LRTI (VAT = 10.3% and VAP = 10.7%). After controlling for illness severity and baseline health status, we could not find an association between VA-LRTI and ICU mortality (odds ratio: 1.07; 95% confidence interval: 0.62-1.83; P = .796); VA-LRTI was also not associated with prolonged ICU length of stay or duration of mechanical ventilation. The relative contribution of VA-LRTI to the random forest mortality model remained constant during time. The attributable VA-LRTI mortality for ARDS was higher than the attributable mortality for VA-LRTI alone. CONCLUSION: After controlling for relevant confounders, we could not find an association between occurrence of VA-LRTI and ICU mortality in patients with ARDS. PMID- 29699469 TI - Social Media Engagement and the Critical Care Medicine Community. AB - Over the last decade, social media has transformed how we communicate in the medical community. Microblogging through platforms such as Twitter has made social media a vehicle for succinct, targeted, and innovative dissemination of content in critical care medicine. Common uses of social media in medicine include dissemination of information, knowledge acquisition, professional networking, and patient advocacy. Social media engagement at conferences represents all of these categories and is often the first time health-care providers are introduced to Twitter. Most of the major critical care medicine conferences, journals, and societies leverage social media for education, research, and advocacy, and social media users can tailor the inflow of content based on their own interests. From these interactions, networks and communities are built within critical care medicine and beyond, overcoming the barriers of physical proximity. In this review, we summarize the history and current status of health-care social media as it relates to critical care medicine and provide a primer for those new to health-care social media with a focus on Twitter, one of the most popular microblogging platforms. PMID- 29699470 TI - Stressful Life Events and Depressive Symptomatology Among Basque Adolescents: The Mediating Role of Attachment Representations. AB - The occurrence of stressful life events is a risk factor for psychopathology in adolescence. Depression is a problem of notable clinical importance that has a negative psychosocial impact on adolescents and which has considerable social, educational, and economic costs. The aim of this study was to examine the relationship between stressful life events and depressive symptomatology in adolescence, taking into account the effect that attachment representations may have on this relation. Participants were 1653 adolescents (951 girls) aged between 13 and 18 years. The sample was selected by means of a random sampling procedure based on the availability of schools to participate. Data were collected at two time points: attachment and stressful life events were assessed first, and symptoms of depression were evaluated eight to nine months later. Two time points were used in order to better analyze the mediating role of attachment security. Stressful life events were recorded using the Inventory of Stressful Life Events, attachment was evaluated by the Inventory of Parent and Peer Attachment (mother, father, and peer versions), and depressive symptomatology was assessed through the Children's Depression Scale. In all cases, the Basque version of these scales was used. The results indicated that attachment to parents was a mediating variable in the relationship between stressful life events and depressive symptomatology. Contrary to what we expected, the results indicate that stressful life events did not have a negative effect on peer attachment, and neither did the latter variable act as a mediator of the relationship between stressful life events and depressive symptoms. It can be concluded that attachment-based interventions may be especially useful for reducing depression symptoms among adolescents. The findings also suggest a role for interventions that target parent-child attachment relationships. PMID- 29699471 TI - The Impact of Constructive and Destructive Leadership on Soldier's Job Satisfaction. AB - The aim of this study was to investigate whether constructive or destructive leadership behaviors are the best predictors of soldiers' experienced meaningfulness of work and general job satisfaction. Data were collected among 300 employed soldiers using a questionnaire. The questionnaire contained questions about the immediate leader's constructive and destructive leadership, meaningfulness of work and general job satisfaction. The results show that the constructive leadership factor inspiration and motivation was the best predictor of both experienced meaningfulness of work and general job satisfaction. None of the destructive leadership factors gave a significant contribution to the models although both the passive and active forms of destructive leadership showed a weak to moderate significant, negative correlation with experienced meaningfulness of work and general job satisfaction. PMID- 29699472 TI - Increases in Emotional Intelligence After an Online Training Program Are Associated With Better Decision-Making on the Iowa Gambling Task. AB - Higher levels of emotional intelligence have been associated with better inter and intrapersonal functioning. In the present study, 59 healthy men and women were randomized into either a three-week online training program targeted to improve emotional intelligence ( n = 29), or a placebo control training program targeted to improve awareness of nonemotional aspects of the environment ( n = 30). Compared to placebo, participants in the emotional intelligence training group showed increased performance on the total emotional intelligence score of the Mayer-Salovey-Caruso Emotional Intelligence Test, a performance measure of emotional intelligence, as well as subscales of perceiving emotions and facilitating thought. Moreover, after emotional intelligence training, but not after placebo training, individuals displayed the ability to arrive at optimal performance faster (i.e., they showed a faster learning rate) during an emotion guided decision-making task (i.e., the Iowa Gambling Task). More specifically, although both groups showed similar performance at the start of the Iowa Gambling Task from pre- to posttraining, the participants in the emotional intelligence training group learned to choose more advantageous than disadvantageous decks than those in the placebo training group by the time they reached the "hunch" period of the task (i.e., the point in the task when implicit task learning is thought to have occurred). Greater total improvements in performance on the Iowa Gambling Task from pre- to posttraining in the emotional intelligence training group were also positively correlated with pre- to posttraining changes in Mayer Salovey-Caruso Emotional Intelligence Test scores, in particular with changes in the ability to perceive emotions. The present study provides preliminary evidence that emotional intelligence can be trained with the help of an online training program targeted at adults; it also suggests that changes in emotional intelligence, as a result of such a program, can lead to improved emotion-guided decision-making. PMID- 29699473 TI - Black American College Students Report Higher Memory of Love for Mothers in Childhood Than White Students. AB - Cultural differences between Black and White individuals in the South are connected to the inequitable history of the United States. We wondered if these cultural differences would translate to a particularly precious aspect of life: memories of love felt in childhood toward one's parents. Some past studies have shown that Whites score higher on parental attachment measures to parents than Blacks, while other studies show no significant differences. However, no previous study has ever measured memory of feelings of love in relation to differences between ethnicities. In this study, Black ( n = 124) and White ( n = 125) undergraduates self-reported the strength and frequency of their past feelings of love toward their mother and father in first, sixth, and ninth grade as well as their current feelings of love. Results suggested that Black students reported feeling more love for their mothers in first, sixth, and ninth grades compared to White students. These findings were not explained when we statistically adjusted for age, gender, socioeconomic status, education levels, income, number of years spent living with mother or father, stress, or personality. Therefore, this relationship may be explained by unmeasured or unmeasurable cultural differences. The direction of this effect was in the opposite direction from what we expected based on past attachment research. Given the inequities in U.S. history and the current discussions around ethnicity and race in the United States, the finding that Blacks reported higher remembered feelings of love for their mothers in childhood is intriguing and worthy of dissemination and discussion. PMID- 29699474 TI - Stable knockdown of ZBTB7A promotes cell proliferation and progression in nasopharyngeal carcinoma. AB - AIMS: Although high expression of ZBTB7A is positively relative to metastasis in nasopharyngeal carcinoma (NPC) patients, the association between its low expression and metastasis of NPC remains unclear. The present study aimed to definitely identify the association. METHODS: The level of ZBTB7A was effectively knocked down by stable transfection of short hair RNA plasmid in NPC cell lines CNE2 and 5-8F (shRNA-CNE2 and shRNA-5-8F), compared with the cells that stably transfected empty plasmid (NC-CNE2 and NC-5-8F). The levels of ZBTB7A were assessed by real-time polymerase chain reaction and Western blot in the cell lines. MTT assay, colorimetric focus-formation assay, flow cytometry, wound healing assay, transwell assays, and xenograft model were performed to analyze cell vitality, proliferation, cell cycle, migration, invasion, and tumorigenicity. RESULTS: The levels of ZBTB7A were effectively reduced in shRNA CNE2 and shRNA-5-8F. Their carcinogenicity was stronger separately than the abilities of NC-CNE2 and NC-5-8F. NC-CNE2 and shRNA-CNE2 were selected to establish the xenograft model because of their stronger tumorigenicity than NC-6 10B and shRNA-5-8F. The assay showed that shRNA-CNE2 had stronger tumorigenicity than NC-CNE2. CONCLUSIONS: The results demonstrated the reverse association between the expression of ZBTB7A and the tumorigenicity of NPC. We postulate that some oncogenic pathways, which are suppressed by ZBTB7A, will vicariously promote the proliferation and progression of NPC when ZBTB7A is decreased. PMID- 29699475 TI - Diabetes in South African older adults: prevalence and impact on quality of life and functional disability - as assessed using SAGE Wave 1 data. AB - BACKGROUND: Diabetes is a chronic disease with severe late complications. It is known to impact the quality of life and cause disability, which may affect an individual's capacity to manage and maintain longer-term health and well-being. OBJECTIVES: To examine the prevalence of self-report diabetes, and association between diabetes and each of health-related quality of life and disability amongst South Africa's older adults. To study both the direct relationship between diabetes and these two measures, as well as moderation effects, i.e. whether associations between other factors and these measures of well-being differed between individuals with diabetes and those without. METHODS: Secondary analyses of data on participants aged 50 years and older from the Study on global AGEing and adult health (SAGE) in South Africa Wave 1 (2007-2008) were conducted. Prevalence of self-reported diabetes was assessed. Multivariable regressions describe the relationships between each of quality of life (WHOQoL) and disability (WHODAS), and diabetes, while controlling for selected socio demographic characteristics, health risk behaviours and co-morbid conditions. In the regression models, we also investigated whether diabetes moderates the relationships between these additional factors and WHOQoL/WHODAS. RESULTS: Self reported diabetes prevalence was 9.2% (95% CI: 7.8,10.9) and increased with age. Having diabetes was associated with poorer WHOQoL scores (additive effect: -4.2; 95% CI: -9.2,0.9; p-value <0.001) and greater disability (multiplicative effect: 2.1; 95% CI: 1.5,2.9; p-value <0.001). Lower quality of life and greater disability were both related to not being in a relationship, lower education, less wealth, lower physical activity and a larger number of chronic conditions. CONCLUSIONS: Diabetes is associated with lower quality of life and greater disability amongst older South Africans. Attention needs to be given to enhancing the capacity of health systems to meet the changing needs of ageing populations with diabetes in SA as well as facilitating social support networks in communities. PMID- 29699476 TI - An improved approach to infer protein-protein interaction based on a hierarchical vector space model. AB - BACKGROUND: Comparing and classifying functions of gene products are important in today's biomedical research. The semantic similarity derived from the Gene Ontology (GO) annotation has been regarded as one of the most widely used indicators for protein interaction. Among the various approaches proposed, those based on the vector space model are relatively simple, but their effectiveness is far from satisfying. RESULTS: We propose a Hierarchical Vector Space Model (HVSM) for computing semantic similarity between different genes or their products, which enhances the basic vector space model by introducing the relation between GO terms. Besides the directly annotated terms, HVSM also takes their ancestors and descendants related by "is_a" and "part_of" relations into account. Moreover, HVSM introduces the concept of a Certainty Factor to calibrate the semantic similarity based on the number of terms annotated to genes. To assess the performance of our method, we applied HVSM to Homo sapiens and Saccharomyces cerevisiae protein-protein interaction datasets. Compared with TCSS, Resnik, and other classic similarity measures, HVSM achieved significant improvement for distinguishing positive from negative protein interactions. We also tested its correlation with sequence, EC, and Pfam similarity using online tool CESSM. CONCLUSIONS: HVSM showed an improvement of up to 4% compared to TCSS, 8% compared to IntelliGO, 12% compared to basic VSM, 6% compared to Resnik, 8% compared to Lin, 11% compared to Jiang, 8% compared to Schlicker, and 11% compared to SimGIC using AUC scores. CESSM test showed HVSM was comparable to SimGIC, and superior to all other similarity measures in CESSM as well as TCSS. Supplementary information and the software are available at https://github.com/kejia1215/HVSM . PMID- 29699477 TI - Effects of bacterial translocation on hemodynamic and coagulation parameters during living-donor liver transplant. AB - BACKGROUND: Bacterial translocation (BT) has been proposed as a trigger for stimulation of the immune system with consequent hemodynamic alteration in patients with liver cirrhosis. However, no information is available regarding its hemodynamic and coagulation consequences during liver transplantation. METHODS: We screened 30 consecutive adult patients undergoing living-donor liver transplant for the presence of BT. Bacterial DNA, Anti factor Xa (aFXa), thromboelastometry, tumor necrosis factor-alpha TNF-alpha, and interleukin-17 (IL 17) values were measured in sera before induction of anesthesia. Systemic hemodynamic data were recorded throughout the procedures. RESULTS: Bacterial DNA was detected in 10 patients (33%) (bactDNA(+)). Demographic, clinical, and hemodynamic data were similar in patients with presence or absence of bacterial DNA. BactDNA(+) patients showed significantly higher circulating values of TNF alpha and IL-17, and had significantly higher clotting times and clot formation times as well as significantly lower alpha angle and maximal clot firmness than bactDNA(-) patients, P < 0.05. We found no statistically significant difference in aFXa between the groups, P = 0.4. Additionally, 4 patients in each group needed vasopressor agents, P = 0.2. And, the amount of transfused blood and blood products used were similar between both groups. CONCLUSION: Bacterial translocation was found in one-third of patients at the time of transplantation and was largely associated with increased markers of inflammation along with decreased activity of coagulation factors. TRIAL REGISTRATION: Trial Registration Number: NCT03230214 . (Retrospective registered). Initial registration date was 20/7/2017. PMID- 29699478 TI - Thrombus aspiration in patients with ST-elevation myocardial infarction: results of a national registry of interventional cardiology. AB - BACKGROUND: We aimed to evaluate the impact of thrombus aspiration (TA) during primary percutaneous coronary intervention (P-PCI) in 'real-world' settings. METHODS: We performed a retrospective study, using data from the National Registry of Interventional Cardiology (RNCI 2006-2012, Portugal) with ST elevation myocardial infarction (STEMI) patients treated with P-PCI. The primary outcome, in-hospital mortality, was analysed through adjusted odds ratio (aOR) and 95% confidence intervals (95%CI). RESULTS: We assessed data for 9458 STEMI patients that undergone P-PCI (35% treated with TA). The risk of in-hospital mortality with TA (aOR 0.93, 95%CI:0.54-1.60) was not significantly decreased. After matching patients through the propensity score, TA reduced significantly the risk of in-hospital mortality (OR 0.58, 95%CI:0.35-0.98; 3500 patients). CONCLUSIONS: The whole cohort data does not support the routine use of TA in P PCI, but the results of the propensity-score matched cohort suggests that the use of selective TA may improve the short-term risks of STEMI. PMID- 29699479 TI - Repeat propofol anesthesia does not exacerbate plaque deposition or synapse loss in APP/PS1 Alzheimer's disease mice. AB - BACKGROUND: There is increasing interest in whether anesthetic agents affect the risk or progression of Alzheimer's disease (AD). To mitigate many of the methodological issues encountered in human retrospective cohort studies we have used a transgenic model of AD to investigate the effect of propofol on AD pathology. METHODS: Six month-old amyloid precursor protein/presenilin 1 (APP/PS1) transgenic AD mice and control mice were exposed to 3 doses of propofol (200 mg/kg) or vehicle, delivered at monthly intervals. RESULTS: There was no difference in the extent of beta-amyloid (Abeta) immunolabeled plaque deposition in APP/PS1 mice in vehicle versus propofol treatment groups. We also detected no difference in plaque-associated synapse loss in APP/PS1 mice following repeat propofol exposure relative to vehicle. Western blotting indicated that there was no difference in post-synaptic density protein 95, synaptophysin or glutamic acid decarboxylase 65/67 expression in control or APP/PS1 mice subjected to repeat propofol treatment relative to vehicle. CONCLUSIONS: These data suggest that repeat propofol anesthesia may not exacerbate plaque deposition or associated synapse loss in AD. Interestingly, this data also provides some of the first evidence suggesting that repeat propofol exposure in adult wild-type mice does not result in robust long-term alterations in the levels of key excitatory and inhibitory synaptic markers. PMID- 29699480 TI - Enhanced JBrowse plugins for epigenomics data visualization. AB - BACKGROUND: New sequencing techniques require new visualization strategies, as is the case for epigenomics data such as DNA base modifications, small non-coding RNAs, and histone modifications. RESULTS: We present a set of plugins for the genome browser JBrowse that are targeted for epigenomics visualizations. Specifically, we have focused on visualizing DNA base modifications, small non coding RNAs, stranded read coverage, and sequence motif density. Additionally, we present several plugins for improved user experience such as configurable, high quality screenshots. CONCLUSIONS: In visualizing epigenomics with traditional genomics data, we see these plugins improving scientific communication and leading to discoveries within the field of epigenomics. PMID- 29699481 TI - Computer simulations of the signalling network in FLT3 +-acute myeloid leukaemia indications for an optimal dosage of inhibitors against FLT3 and CDK6. AB - BACKGROUND: Mutations in the FMS-like tyrosine kinase 3 (FLT3) are associated with uncontrolled cellular functions that contribute to the development of acute myeloid leukaemia (AML). We performed computer simulations of the FLT3-dependent signalling network in order to study the pathways that are involved in AML development and resistance to targeted therapies. RESULTS: Analysis of the simulations revealed the presence of alternative pathways through phosphoinositide 3 kinase (PI3K) and SH2-containing sequence proteins (SHC), that could overcome inhibition of FLT3. Inhibition of cyclin dependent kinase 6 (CDK6), a related molecular target, was also tested in the simulation but was not found to yield sufficient benefits alone. CONCLUSIONS: The PI3K pathway provided a basis for resistance to treatments. Alternative signalling pathways could not, however, restore cancer growth signals (proliferation and loss of apoptosis) to the same levels as prior to treatment, which may explain why FLT3 resistance mutations are the most common resistance mechanism. Finally, sensitivity analysis suggested the existence of optimal doses of FLT3 and CDK6 inhibitors in terms of efficacy and toxicity. PMID- 29699482 TI - Structural disorder of plasmid-encoded proteins in Bacteria and Archaea. AB - BACKGROUND: In the last decade and a half it has been firmly established that a large number of proteins do not adopt a well-defined (ordered) structure under physiological conditions. Such intrinsically disordered proteins (IDPs) and intrinsically disordered (protein) regions (IDRs) are involved in essential cell processes through two basic mechanisms: the entropic chain mechanism which is responsible for rapid fluctuations among many alternative conformations, and molecular recognition via short recognition elements that bind to other molecules. IDPs possess a high adaptive potential and there is special interest in investigating their involvement in organism evolution. RESULTS: We analyzed 2554 Bacterial and 139 Archaeal proteomes, with a total of 8,455,194 proteins for disorder content and its implications for adaptation of organisms, using three disorder predictors and three measures. Along with other findings, we revealed that for all three predictors and all three measures (1) Bacteria exhibit significantly more disorder than Archaea; (2) plasmid-encoded proteins contain considerably more IDRs than proteins encoded on chromosomes (or whole genomes) in both prokaryote superkingdoms; (3) plasmid proteins are significantly more disordered than chromosomal proteins only in the group of proteins with no COG category assigned; (4) antitoxin proteins in comparison to other proteins, are the most disordered (almost double) in both Bacterial and Archaeal proteomes; (5) plasmidal proteins are more disordered than chromosomal proteins in Bacterial antitoxins and toxin-unclassified proteins, but have almost the same disorder content in toxin proteins. CONCLUSION: Our results suggest that while disorder content depends on genome and proteome characteristics, it is more influenced by functional engagements than by gene location (on chromosome or plasmid). PMID- 29699483 TI - Emergence of the Asian lineage dengue virus type 3 genotype III in Malaysia. AB - BACKGROUND: Dengue virus type 3 genotype III (DENV3/III) is associated with increased number of severe infections when it emerged in the Americas and Asia. We had previously demonstrated that the DENV3/III was introduced into Malaysia in the late 2000s. We investigated the genetic diversity of DENV3/III strains recovered from Malaysia and examined their phylogenetic relationships against other DENV3/III strains isolated globally. RESULTS: Phylogenetic analysis revealed at least four distinct DENV3/III lineages. Two of the lineages (DENV3/III-B and DENV3/III-C) are current actively circulating whereas the DENV3/III-A and DENV3/III-D were no longer recovered since the 1980s. Selection pressure analysis revealed strong evidence of positive selection on a number of amino acid sites in PrM, E, NS1, NS2a, NS2b, NS3, NS4a, and NS5. The Malaysian DENV3/III isolates recovered in the 1980s (MY.59538/1987) clustered into DENV3/III-B, which was the lineage with cosmopolitan distribution consisting of strains actively circulating in the Americas, Africa, and Asia. The Malaysian isolates recovered after the 2000s clustered within DENV3/III-C. This DENV3/III-C lineage displayed a more restricted geographical distribution and consisted of isolates recovered from Asia, denoted as the Asian lineage. Amino acid variation sites in NS5 (NS5-553I/M, NS5-629 T, and NS5-820E) differentiated the DENV3/III-C from other DENV3 viruses. The codon 629 of NS5 was identified as a positively selected site. While the NS5-698R was identified as unique to the genome of DENV3/III-C3. Phylogeographic results suggested that the recent Malaysian DENV3/III-C was likely to have been introduced from Singapore in 2008 and became endemic. From Malaysia, the virus subsequently spread into Taiwan and Thailand in the early part of the 2010s and later reintroduced into Singapore in 2013. CONCLUSIONS: Distinct clustering of the Malaysian old and new DENV3/III isolates suggests that the currently circulating DENV3/III in Malaysia did not descend directly from the strains recovered during the 1980s. Phylogenetic analyses and common genetic traits in the genome of the strains and those from the neighboring countries suggest that the Malaysian DENV3/III is likely to have been introduced from the neighboring regions. Malaysia, however, serves as one of the sources of the recent regional spread of DENV3/III-C3 within the Asia region. PMID- 29699484 TI - PDZscape: a comprehensive PDZ-protein database. AB - PDZ-containing proteins comprise one of the most widely distributed protein families playing major role in localization and membrane receptor clustering. They are hence important regulators of signal transduction in cellular pathways. Although knowledge on these proteins has increased exponentially, the existing database 'PDZBase' is limited by presence of only 339 proteins as it dates back to 2004 when very little data was available. Thus, lack of exclusive information on this protein family led us to develop PDZscape. 'PDZscape' encompasses the complete available information on 58,648 PDZ-containing proteins with their known and putative binding partners on one platform. It has a user-friendly web interface that can be easily queried with external protein identifiers. With unique integration of prominent databases including NCBI, UniProtKB, Swiss-Prot, Pubmed, PDB, STRING, IntAct, KEGG, Pfam and Protein Mutant Database, it provides detailed information on PDZ interactome apart from the customized BLAST option. Most importantly, this database encompasses the mutations and diseases associated with PDZ containing proteins manually curated by our group, thus making it a comprehensive compilation. It also features tools to query the database using sequence (PDZ-Blast) and to find if protein of interest is a PDZ-binding protein. PDZscape is freely available at http://www.actrec.gov.in:8080/pdzscape . PMID- 29699485 TI - Chromosomal evolution and phylogeny in the Nullicauda group (Chiroptera, Phyllostomidae): evidence from multidirectional chromosome painting. AB - BACKGROUND: The family Phyllostomidae (Chiroptera) shows wide morphological, molecular and cytogenetic variation; many disagreements regarding its phylogeny and taxonomy remains to be resolved. In this study, we use chromosome painting with whole chromosome probes from the Phyllostomidae Phyllostomus hastatus and Carollia brevicauda to determine the rearrangements among several genera of the Nullicauda group (subfamilies Gliphonycterinae, Carolliinae, Rhinophyllinae and Stenodermatinae). RESULTS: These data, when compared with previously published chromosome homology maps, allow the construction of a phylogeny comparable to those previously obtained by morphological and molecular analysis. Our phylogeny is largely in agreement with that proposed with molecular data, both on relationships between the subfamilies and among genera; it confirms, for instance, that Carollia and Rhinophylla, previously considered as part of the same subfamily are, in fact, distant genera. CONCLUSIONS: The occurrence of the karyotype considered ancestral for this family in several different branches suggests that the diversification of Phyllostomidae into many subfamilies has occurred in a short period of time. Finally, the comparison with published maps using human whole chromosome probes allows us to track some syntenic associations prior to the emergence of this family. PMID- 29699486 TI - Integrative analysis and machine learning on cancer genomics data using the Cancer Systems Biology Database (CancerSysDB). AB - BACKGROUND: Recent cancer genome studies on many human cancer types have relied on multiple molecular high-throughput technologies. Given the vast amount of data that has been generated, there are surprisingly few databases which facilitate access to these data and make them available for flexible analysis queries in the broad research community. If used in their entirety and provided at a high structural level, these data can be directed into constantly increasing databases which bear an enormous potential to serve as a basis for machine learning technologies with the goal to support research and healthcare with predictions of clinically relevant traits. RESULTS: We have developed the Cancer Systems Biology Database (CancerSysDB), a resource for highly flexible queries and analysis of cancer-related data across multiple data types and multiple studies. The CancerSysDB can be adopted by any center for the organization of their locally acquired data and its integration with publicly available data from multiple studies. A publicly available main instance of the CancerSysDB can be used to obtain highly flexible queries across multiple data types as shown by highly relevant use cases. In addition, we demonstrate how the CancerSysDB can be used for predictive cancer classification based on whole-exome data from 9091 patients in The Cancer Genome Atlas (TCGA) research network. CONCLUSIONS: Our database bears the potential to be used for large-scale integrative queries and predictive analytics of clinically relevant traits. PMID- 29699487 TI - The parthenocarpic gene Pat-k is generated by a natural mutation of SlAGL6 affecting fruit development in tomato (Solanum lycopersicum L.). AB - BACKGROUND: Parthenocarpy is a desired trait in tomato because it can overcome problems with fruit setting under unfavorable environmental conditions. A parthenocarpic tomato cultivar, 'MPK-1', with a parthenocarpic gene, Pat-k, exhibits stable parthenocarpy that produces few seeds. Because 'MPK-1' produces few seeds, seedlings are propagated inefficiently via cuttings. It was reported that Pat-k is located on chromosome 1. However, the gene had not been isolated and the relationship between the parthenocarpy and low seed set in 'MPK-1' remained unclear. In this study, we isolated Pat-k to clarify the relationship between parthenocarpy and low seed set in 'MPK-1'. RESULTS: Using quantitative trait locus (QTL) analysis for parthenocarpy and seed production, we detected a major QTL for each trait on nearly the same region of the Pat-k locus on chromosome 1. To isolate Pat-k, we performed fine mapping using an F4 population following the cross between a non-parthenocarpic cultivar, 'Micro-Tom' and 'MPK 1'. The results showed that Pat-k was located in the 529 kb interval between two markers, where 60 genes exist. By using data from a whole genome re-sequencing and genome sequence analysis of 'MPK-1', we could identify that the SlAGAMOUS LIKE 6 (SlAGL6) gene of 'MPK-1' was mutated by a retrotransposon insertion. The transcript level of SlAGL6 was significantly lower in ovaries of 'MPK-1' than a non-parthenocarpic cultivar. From these results, we could conclude that Pat-k is SlAGL6, and its down-regulation in 'MPK-1' causes parthenocarpy and low seed set. In addition, we observed abnormal micropyles only in plants homozygous for the 'MPK-1' allele at the Pat-k/SlAGL6 locus. This result suggests that Pat-k/SlAGL6 is also related to ovule formation and that the low seed set in 'MPK-1' is likely caused by abnormal ovule formation through down-regulation of Pat-k/SlAGL6. CONCLUSIONS: Pat-k is identical to SlAGL6, and its down-regulation causes parthenocarpy and low seed set in 'MPK-1'. Moreover, down-regulation of Pat k/SlAGL6 could cause abnormal ovule formation, leading to a reduction in the number of seeds. PMID- 29699488 TI - Patterns of geographic variation of thermal adapted candidate genes in Drosophila subobscura sex chromosome arrangements. AB - BACKGROUND: The role of chromosomal arrangements in adaptation is supported by the repeatable clinal variation in inversion frequencies across continents in colonizing species such as Drosophila subobscura. However, there is a lack of knowledge on the genetic variation in genes within inversions, possibly targets of climatic selection, across a geographic latitudinal gradient. In the present study we analysed four candidate loci for thermal adaptation, located close to the breakpoints, in two chromosomal arrangements of the sex (A) chromosome of Drosophila subobscura with different thermal preferences. Individual chromosomes with A2 (the inverted arrangement considered warm adapted) or AST (the standard ancestral arrangement considered cold adapted) were sequenced across four European localities at varying latitudes, up to ~ 2500 Kms apart. RESULTS: Importantly, we found very low differentiation for each specific arrangement across populations as well as no clinal patterns of genomic variation. This suggests wide gene exchange along the cline. Differentiation between the sex chromosome arrangements was significant in the two more proximal regions relative to the AST orientation but not in the distal ones, independently of their location inside or outside the inversion. This can be possibly due to variation in the levels of gene flux and/or selection acting in these regions. CONCLUSIONS: Gene flow appears to have homogenized the genetic content within-arrangement at a wide geographical scale, despite the expected diverse selective pressures in the specific natural environments of the different populations sampled. It is thus likely that the inversion frequency clines in this species are being maintained by local adaptation in face of gene flow. The differences between arrangements at non-coding regions might be associated with the previously observed differential gene expression in different thermal regimes. Higher resolution genomic scans for individual chromosomal arrangements performed over a large environmental gradient are needed to find the targets of selection and further elucidate the adaptive mechanisms maintaining chromosomal inversion polymorphisms. PMID- 29699489 TI - Adaptations in energy metabolism and gene family expansions revealed by comparative transcriptomics of three Chagas disease triatomine vectors. AB - BACKGROUND: Chagas disease is a parasitic infection caused by Trypanosoma cruzi. It is an important public health problem affecting around seven to eight million people in the Americas. A large number of hematophagous triatomine insect species, occupying diverse natural and human-modified ecological niches transmit this disease. Triatomines are long-living hemipterans that have evolved to explode different habitats to associate with their vertebrate hosts. Understanding the molecular basis of the extreme physiological conditions including starvation tolerance and longevity could provide insights for developing novel control strategies. We describe the normalized cDNA, full body transcriptome analysis of three main vectors in North, Central and South America, Triatoma pallidipennis, T. dimidiata and T. infestans. RESULTS: Two-thirds of the de novo assembled transcriptomes map to the Rhodnius prolixus genome and proteome. A Triatoma expansion of the calycin family and two types of protease inhibitors, pacifastins and cystatins were identified. A high number of transcriptionally active class I transposable elements was documented in T. infestans, compared with T. dimidiata and T. pallidipennis. Sequence identity in Triatoma-R. prolixus 1:1 orthologs revealed high sequence divergence in four enzymes participating in gluconeogenesis, glycogen synthesis and the pentose phosphate pathway, indicating high evolutionary rates of these genes. Also, molecular evidence suggesting positive selection was found for several genes of the oxidative phosphorylation I, III and V complexes. CONCLUSIONS: Protease inhibitors and calycin-coding gene expansions provide insights into rapidly evolving processes of protease regulation and haematophagy. Higher evolutionary rates in enzymes that exert metabolic flux control towards anabolism and evidence for positive selection in oxidative phosphorylation complexes might represent genetic adaptations, possibly related to prolonged starvation, oxidative stress tolerance, longevity, and hematophagy and flight reduction. Overall, this work generated novel hypothesis related to biological adaptations to extreme physiological conditions and diverse ecological niches that sustain Chagas disease transmission. PMID- 29699490 TI - The magnitude of antibiotic resistance to Helicobacter pylori in Africa and identified mutations which confer resistance to antibiotics: systematic review and meta-analysis. AB - BACKGROUND: Worldwide Helicobacter pylori (H.pylori) treatment is of great challenge due to increased antibiotic resistance. The burden of H. pylori antibiotic resistance in Africa is high with unclear information regarding the real magnitude. This systematic review and meta-analysis was conducted to investigate the magnitude of H.pylori antibiotic resistance in Africa to gain insight of the extent of the problem among H.pylori naive treatment patients. METHOD: The search was performed in the academic databases, Embase, PubMed, Web of Science and Africa Wide Information. ProQuest Dissertation and Theses, Scopus, Ethos, Africa Index Medicus (WHO), BioMed Central Proceedings, BASE, British Library, Open grey, Library of Congress and the New York Academy of Grey Literature Report were additionally searched for grey literature. Published articles from Africa on H.pylori antibiotic resistance between 1986 and June 2017 were systematically reviewed to estimate the H. pylori extent of resistance to macrolides, quinolones, amoxicillin, tetracycline and metronidazole. RESULTS: In 26 articles a total of 2085 isolates were tested for metronidazole, 1530 for amoxicillin, 1277 for tetracycline, 1752 for clarithromycin and 823 for quinolones.The overall pooled proportion of H.pylori resistance to quinolones, clarithromycin, tetracycline, metronidazole and amoxicillin were: (17.4%, 95%CI 12.8 - 21.9), (29.2%, 95%CI:26.7-31.8), (48.7%, 95%CI: 44.5-52.9), (75.8%, 95% CI: 74.1-.77.4) and (72.6%, 95% CI: 68.6-76.6), respectively. The commonest mutation detected were A2143G (49/97) for clarithromycin, RdxA (41/56) for metronidazole and D87I (16/40) for quinolones. CONCLUSION: Prevalence of metronidazole, clarithromycin, and amoxicillin resistance is high in developing world including Africa. This could impair the first line triple therapy of the H.pylori infection. There is a need of conducting surveillance of H.pylori susceptibility pattern in Africa for dual and triple resistance which can be used for the empirical treatment. PMID- 29699492 TI - Are low and high utilization related to the way GPs manage their practices? An observational study. AB - BACKGROUND: General practice care plays a key role in keeping healthcare effective and cost-efficient. However, variation in the utilization rates of practices may reveal variation in practice performance. Our research goal is to investigate whether the socio-demographic profile of the patients' area of residence and practice organization characteristics influence the low or high utilization of general practice care. METHODS: Data on the utilization of general practice care were derived from the electronic health records of 232 general practices participating in the NIVEL Primary Care Database for the year 2013. Census data for the year 2013 were matched with the postal code of the patients. A small area estimation (SAE) technique was used to calculate the estimated utilization rate for general practice care per practice based on the socio demographic profile of the patients' area of residence. Subsequently, the actual utilization rates were compared to the estimated rates per practice. Linear regression analysis was used to link the differences between the actual and estimated utilization rates to practice organization characteristics. RESULTS: The socio-demographic profile of the patients' area of residence accounted for 25.7% of the estimated utilization rates per practice. Practice organization characteristics accounted for 19.3% of the difference between the actual utilization rates and the estimated rates. Practices had higher utilization rates than estimated when a practice was a dual practice, when it employed female GPs, when it employed other healthcare providers and/or when it offered more services related to a disease management programme. CONCLUSION: We found that utilization rates of general practice care can be partially explained by the socio demographic profile of the patients' area of residence, but also by practice organization characteristics. Insight into these factors provides both GPs and the other stakeholders involved in the organization of general practice care with information to help reflect on the utilization of care. PMID- 29699491 TI - Live attenuated Salmonella typhimurium vaccines delivering SaEsxA and SaEsxB via type III secretion system confer protection against Staphylococcus aureus infection. AB - BACKGROUND: Staphylococcus aureus (S. aureus) causes a wide range of infectious diseases in human and animals. The emergence of antibiotic-resistant strains demands novel strategies for prophylactic vaccine development. In this study, live attenuated S. enterica subsp. enterica serotype Typhimurium (S. Typhimurium) vaccine against S. aureus infection was developed, in which Salmonella Pathogenesis Island-1 Type 3 Secretion System (SPI-1 T3SS) was employed to deliver SaEsxA and SaEsxB, two of ESAT-6-like (Early Secreted Antigenic Target-6) virulence factors of S. aureus. METHODS: Antigens SaEsxA and SaEsxB were fused with the N-terminal secretion and translocation domain of SPI-1 effector SipA. And cytosolic delivery of Staphylococcal antigens into macrophages was examined by western blot. BALB/c mice were orally immunized with S. Typhimurium-SaEsxA and S. Typhimurium-SaEsxB vaccines. Antigen-specific humoral and Th1/Th17 immune responses were examined by ELISA and ELISPOT assays 7-9 days after the 2nd booster. For ELISPOT assays, the statistical significance was determined by Student's t test. The vaccine efficacy was evaluated by lethal challenge with two S. aureus clinical isolates Newman strain and USA 300 strain. Statistical significance was determined by Log rank (Mantel-Cox) analysis. And a P value of < 0.05 was considered statistically significant. RESULTS: Oral administration of S. Typhimurium-SaEsxA and S. Typhimurium-SaEsxB vaccines induced antigen-specific humoral and Th1/Th17 immune responses, which increased the survival rate for vaccinated mice when challenged with S. aureus strains. CONCLUSIONS: The newly developed S. Typhimurium-based vaccines delivering SaEsxA and SaEsxB by SPI-1 T3SS could confer protection against S. aureus infection. This study provides evidence that translocation of foreign antigens via Salmonella SPI-1 T3SS into the cytosol of antigen presenting cells (APCs) could induce potent immune responses against pathogens. PMID- 29699493 TI - Effects of age, comorbidity and adherence to current antimicrobial guidelines on mortality in hospitalized elderly patients with community-acquired pneumonia. AB - BACKGROUND: Limited information exists on the clinical characteristics predictive of mortality in patients aged >=65 years in many countries. The impact of adherence to current antimicrobial guidelines on the mortality of hospitalized elderly patients with community-acquired pneumonia (CAP) has never been assessed. METHODS: A total of 3131 patients aged >=65 years were enrolled from a multi center, retrospective, observational study initiated by the CAP-China network. Risk factors for death were screened with multivariable logistic regression analysis, with emphasis on the evaluation of age, comorbidities and antimicrobial treatment regimen with regard to the current Chinese CAP guidelines. RESULTS: The mean age of the study population was 77.4 +/- 7.4 years. Overall in-hospital and 60-day mortality were 5.7% and 7.6%, respectively; these rates were three-fold higher in those aged >=85 years than in the 65-74 group (11.9% versus 3.2% for in hospital mortality and 14.1% versus 4.7% for 60-day mortality, respectively). The mortality was significantly higher among patients with comorbidities compared with those who were otherwise healthy. According to the 2016 Chinese CAP guidelines, 62.1% of patients (1907/3073) received non-adherent treatment. For general-ward patients without risk factors for Pseudomonas aeruginosa (PA) infection (n = 2258), 52.3% (1094/2090) were over-treated, characterized by monotherapy with an anti-pseudomonal beta-lactam or combination with fluoroquinolone + beta-lactam; while 71.4% of intensive care unit (ICU) patients (120/168) were undertreated, without coverage of atypical bacteria. Among patients with risk factors for PA infection (n = 815), 22.9% (165/722) of those in the general ward and 74.2% of those in the ICU (69/93) were undertreated, using regimens without anti-pseudomonal activity. The independent predictors of 60-day mortality were age, long-term bedridden status, congestive heart failure, CURB-65, glucose, heart rate, arterial oxygen saturation (SaO2) and albumin levels. CONCLUSIONS: Overtreatment in general-ward patients and undertreatment in ICU patients were critical problems. Compliance with Chinese guidelines will require fundamental changes in standard-of-care treatment patterns. The data included herein may facilitate early identification of patients at increased risk of mortality. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov ( NCT02489578 ). PMID- 29699494 TI - Endoscopic ultrasound-guided transmural drainage for subphrenic abscess: report of two cases and a literature review. AB - BACKGROUND: An intra-abdominal abscess can sometimes become serious and difficult to treat. The current standard treatment strategy for intra-abdominal abscess is percutaneous imaging-guided drainage. However, in cases of subphrenic abscess, it is important to avoid passing the drainage route through the thoracic cavity, as this can lead to respiratory complications. The spread of intervention techniques involving endoscopic ultrasonography (EUS) has made it possible to perform drainage via the transmural route. CASE PRESENTATION: We describe two cases of subphrenic abscess that occurred after intra-abdominal surgery. Both were treated successfully by EUS-guided transmural drainage (EUS-TD) without severe complications. Our experience of these cases and a review of the literature suggest that the drainage catheters should be placed both internally and externally together into the abscess cavity. In previous cases there were no adverse events except for one case of mediastinitis and pneumothorax resulting from transesophageal drainage. Therefore, we consider that the transesophageal route should be avoided if possible. CONCLUSIONS: Although further studies are necessary, our present two cases and a literature review suggest that EUS-TD is feasible and effective for subphrenic abscess, and not inferior to other treatments. We anticipate that this report will be of help to physicians when considering the drainage procedure for this condition. As there have been no comparative studies to date, a prospective study involving a large number of patients will be necessary to determine the therapeutic options for such cases. PMID- 29699495 TI - Association between the gait pattern characteristics of older people and their two-step test scores. AB - BACKGROUND: The Two-Step test is one of three official tests authorized by the Japanese Orthopedic Association to evaluate the risk of locomotive syndrome (a condition of reduced mobility caused by an impairment of the locomotive organs). It has been reported that the Two-Step test score has a good correlation with one's walking ability; however, its association with the gait pattern of older people during normal walking is still unknown. Therefore, this study aims to clarify the associations between the gait patterns of older people observed during normal walking and their Two-Step test scores. METHODS: We analyzed the whole waveforms obtained from the lower-extremity joint angles and joint moments of 26 older people in various stages of locomotive syndrome using principal component analysis (PCA). The PCA was conducted using a 260 * 2424 input matrix constructed from the participants' time-normalized pelvic and right-lower-limb joint angles along three axes (ten trials of 26 participants, 101 time points, 4 angles, 3 axes, and 2 variable types per trial). RESULTS: The Pearson product moment correlation coefficient between the scores of the principal component vectors (PCVs) and the scores of the Two-Step test revealed that only one PCV (PCV 2) among the 61 obtained relevant PCVs is significantly related to the score of the Two-Step test. CONCLUSIONS: We therefore concluded that the joint angles and joint moments related to PCV 2-ankle plantar-flexion, ankle plantar-flexor moments during the late stance phase, ranges of motion and moments on the hip, knee, and ankle joints in the sagittal plane during the entire stance phase-are the motions associated with the Two-Step test. PMID- 29699496 TI - Co-sequencing and novel delayed anti-correlation identify function for pancreatic enriched microRNA biomarkers in a rat model of acute pancreatic injury. AB - BACKGROUND: Co-sequencing of messenger ribonucleic acid (mRNA) and micro ribonucleic acid (miRNA) across a time series (1, 3, 6, 24, and 48 h post injury) was used to identify potential miRNA-gene interactions during pancreatic injury, associate serum and tissue levels of candidate miRNA biomarkers of pancreatic injury, and functionally link these candidate miRNA biomarkers to observed histopathology. RNAs were derived from pancreatic tissues obtained in experiments characterizing the serum levels of candidate miRNA biomarkers in response to acute pancreatic injury in rats. RESULTS: No correlation was discovered between tissue and serum levels of the miRNAs. A combination of differential gene expression, novel delayed anti-correlation analysis and experimental database interrogation was used to identify messenger RNAs and miRNAs that experienced significant expression change across the time series, that were negatively correlated, that were complementary in sequence, and that had experimentally supported relationships. This approach yielded a complex signaling network for future investigation and a link for the specific candidate miRNA biomarkers, miR 216a-5p and miR-217-5p, to cellular processes that were in fact the prominent histopathology observations in the same experimental samples. RNA quality bias by treatment was observed in the study samples and a statistical correction was applied. The relevance and impact of that correction on significant results is discussed. CONCLUSION: The described approach allowed extraction of miRNA function from genomic data and defined a mechanistic anchor for these miRNAs as biomarkers. Functional and mechanistic conclusions are supported by histopathology findings. PMID- 29699497 TI - Ioncopy: an R Shiny app to call copy number alterations in targeted NGS data. AB - BACKGROUND: Somatic copy number alterations (CNAs) contribute to the clinically targetable aberrations in the tumor genome. For both routine diagnostics and biomarkers research, CNA analysis in a single assay together with somatic mutations is highly desirable. RESULTS: Ioncopy is a validated method and easy-to use software for CNA calling from targeted NGS data. Copy number and significance of CNA are estimated for each gene in each sample. Copy number gains and losses are called after multiple testing corrections controlling FWER or FDR. CONCLUSIONS: Ioncopy facilitates calling of CNAs in a cohort of tumors tissues with or without using normal (germline) DNA controls. PMID- 29699498 TI - Prediction of clinical outcome in patients treated with cardiac resynchronization therapy - the role of NT-ProBNP and a combined response score. AB - BACKGROUND: Cardiac resynchronization therapy (CRT) is an established therapy for appropriately selected patients with heart failure. Response to CRT has been heterogeneously defined using both clinical and echocardiographic measures, with poor correlation between the two. METHODS: The study cohort was comprised of 202 CRT-treated patients and CRT response was defined at 6 months post-implant. Echocardiographic response (E+) was defined as a reduction in LVESV >= 15%, clinical response as an improvement of >= 1 NYHA class (C+), and biomarker response as a >= 25% reduction in NT-proBNP(B+). The association of response measures (E+, B+, C+; response score range 0-3) and clinical endpoints at 3 years was assessed in landmarked Cox models. RESULTS: Echo and clinical responders demonstrated greater declines in NT-proBNP than non-responders (median [E+/B+]: 52%, [E+]: -27%, [C+]: -39% and [E-/C-]: -13%; p = 0.01 for trend). Biomarker (HR 0.43 [95% CI: 0.22-0.86], p = 0.02) and clinical (HR 0.40 [0.23-0.70] p = 0.001) response were associated with a significantly reduced risk of the primary endpoint. When integrating each response measure into a composite score, each 1 point increase was associated with a 31% decreased risk for a composite endpoint of mortality, LVAD, transplant and HF hospitalization (HR 0.69 [95% CI: 0.50 0.96], p = 0.03), and a 52% decreased risk of all-cause mortality (HR 0.48 [95% CI: 0.26-0.89], p = 0.02). CONCLUSION: Serial changes in NT-proBNP are associated with clinical outcomes following CRT implant. Integration of biomarker, clinical, and echocardiographic response may discriminate CRT responders versus non responders in a clinically meaningful way, and with higher accuracy. TRIAL REGISTRATION: The cohort was combined from study NCT01949246 and the study based on local review board approval 2011/550 in Lund, Sweden. PMID- 29699499 TI - Factors influencing dialysis withdrawal: a scoping review. AB - BACKGROUND: Research on factors associated with dialysis withdrawal is scarce. This study examined the predictors that might influence rate of dialysis withdrawal. Existing literature is summarized, analyzed and synthesized to identify gaps in the literature with regard to the factors associated with dialysis withdrawal. METHODS: This scoping review used a systematic search to synthesize research findings related to dialysis withdrawal and identified gaps in the literature. The search strategy was developed and applied using PubMed, EMBASE and CINHAL databases. The selection criteria included articles written in English and published between 1997 and 2016 that examined dialysis withdrawal and associated factors in patients with any modality of renal dialysis.. Case reports and studies only including renal transplant patients were excluded. Fifteen articles were selected in accordance with these selection criteria. RESULTS: The literature review revealed a scarcity of research on dialysis withdrawal and associated factors. Furthermore, the study findings were inconsistent and inconclusive. Authors have defined dialysis withdrawal in terms of dialysis discontinuation, withholding, death, withdrawal, treatment refusal/cessation, or technique failure. Authors have selected homogeneous patient population on either hemodialysis (HD) or peritoneal dialysis (PD) patients, thus making comparisons of studies and generalization of findings difficult. CONCLUSION: Future studies should explore the influence of both HD and PD on patient-elected dialysis withdrawal using a large a priori calculated sample size. PMID- 29699500 TI - In-flight angina pectoris; an unusual presentation. AB - BACKGROUND: An unusual case of typical angina which occurred on a long haul flight is presented. This case is notable as this was the index presentation, with no previous symptoms prior to this. Physiological changes at altitude can be marked, and include hypoxia, tachycardia and an increase in cardiac output. These changes were enough to expose underlying angina in our patient. CASE PRESENTATION: A 68 year old man presented with typical cardiac chest pain on a long haul flight. His symptoms first started 10-15 min after take-off and resolved on landing. This was his index presentation, and there were no similar symptoms in the past. Background history included hypercholesterolaemia and benign prostatic hypertrophy only. He led a rather sedentary lifestyle. A CT coronary angiogram showed significant disease in the proximal left anterior descending artery and proximal right coronary artery. He went on to have a coronary angiogram with invasive physiological measurements, which determined both lesions were physiologically significant. Both arteries were treated with drug eluting stents. Since treatment, he once again embarked on a long haul flight, and was completely asymptomatic. CONCLUSION: The presentation of symptoms in this individual was rather unusual, but clearly caused by significant coronary artery disease. Potentially his sedentary lifestyle was not enough in day-to-day activities to promote anginal symptoms. When his cardiovascular system was physiologically stressed during flight, brought about by hypoxia, raised sympathetic tone and increased cardiac output, symptoms emerged. In turn, when landing, with atmospheric conditions normalised, physiological stress was removed, and symptoms resolved. Clinically therefore, one should not exclude symptoms that occur with differing physiological states, such as stress and altitude, as they are also potential triggers for myocardial ischaemia, despite absence of day-to-day symptoms. PMID- 29699501 TI - Urinary excretion of uric acid is negatively associated with albuminuria in patients with chronic kidney disease: a cross-sectional study. AB - BACKGROUND: Increasing evidence has shown that albuminuria is related to serum uric acid. Little is known about whether this association may be interrelated via renal handling of uric acid. Therefore, we aim to study urinary uric acid excretion and its association with albuminuria in patients with chronic kidney disease (CKD). METHODS: A cross-sectional study of 200 Chinese CKD patients recruited from department of nephrology of Huadong hospital was conducted. Levels of 24 h urinary excretion of uric acid (24-h Uur), fractional excretion of uric acid (FEur) and uric acid clearance rate (Cur) according to gender, CKD stages, hypertension and albuminuria status were compared by a multivariate analysis. Pearson and Spearman correlation and multiple regression analyses were used to study the correlation of 24-h Uur, FEur and Cur with urinary albumin to creatinine ratio (UACR). RESULTS: The multivariate analysis showed that 24-h Uur and Cur were lower and FEur was higher in the hypertension group, stage 3-5 CKD and macro-albuminuria group (UACR> 30 mg/mmol) than those in the normotensive group, stage 1 CKD group and the normo-albuminuria group (UACR< 3 mg/mmol) (all P < 0.05). Moreover, males had higher 24-h Uur and lower FEur than females (both P < 0.05). Multiple linear regression analysis showed that UACR was negatively associated with 24-h Uur and Cur (P = 0.021, P = 0.007, respectively), but not with FEur (P = 0.759), after adjusting for multiple confounding factors. CONCLUSIONS: Our findings suggested that urinary excretion of uric acid is negatively associated with albuminuria in patients with CKD. This phenomenon may help to explain the association between albuminuria and serum uric acid. PMID- 29699502 TI - Admixture, evolution, and variation in reproductive isolation in the Boechera puberula clade. AB - BACKGROUND: Hybridization is very common in plants, and the incorporation of new alleles into existing lineages (i.e. admixture) can blur species boundaries. However, admixture also has the potential to increase standing genetic variation. With new sequencing methods, we can now study admixture and reproductive isolation at a much finer scale than in the past. The genus Boechera is an extraordinary example of admixture, with over 400 hybrid derivates of varying ploidy levels. Yet, few studies have assessed admixture in this genus on a genomic scale. RESULTS: In this study, we used Genotyping-by-Sequencing (GBS) to clarify the evolution of the Boechera puberula clade, whose six members are scattered across the western United States. We further assessed patterns of admixture and reproductive isolation within the group, including two additional species (B. stricta and B. retrofracta) that are widespread across North America. Based on 14,815 common genetic variants, we found evidence for some cases of hybridization. We find evidence of both recent and more ancient admixture, and that levels of admixture vary across species. CONCLUSIONS: We present evidence for a monophyletic origin of the B. puberula group, and a split of B. puberula into two subspecies. Further, when inferring reproductive isolation on the basis of presence and absence of admixture, we found that the accumulation of reproductive isolation between species does not seem to occur linearly with time since divergence in this system. We discuss our results in the context of sexuality and asexuality in Boechera. PMID- 29699503 TI - Comparison of the incidence, clinical features and outcomes of invasive candidiasis in children and neonates. AB - BACKGROUND: Invasive candidiasis differs greatly between children and neonates. We aimed to investigate the different therapeutic approaches and their effects on treatment outcomes of these two groups. METHODS: Episodes of neonatal invasive candidiasis were compared with non-neonatal pediatric episodes during a 12-year cohort study. Clinical isolates were documented by matrix-assisted laser desorption/ionization-time of flight mass spectrometry and DNA sequencing, and antifungal susceptibility testing was performed. RESULTS: A total of 342 episodes of invasive candidiasis (113 neonatal and 229 non-neonatal pediatric episodes) in 281 pediatric patients (96 neonates and 185 children) were identified. Candida albicans was the most common pathogen causing invasive candidiasis in neonates and children (47.8% vs. 44.1%). The antifungal susceptibility profiles were not significantly different between neonates and children. More neonates received amphotericin B as therapy, whereas more children received fluconazole or caspofungin. Compared with children, neonates had a significantly longer duration of fungemia, higher rates of septic shock (34.5% vs. 21.8%; P = 0.013), sepsis attributable mortality (28.3% vs. 17.5%; P = 0.024) and in-hospital mortality (42.7% vs. 25.4%; P = 0.004) than children. Independent risk factors for treatment failure of invasive candidiasis were septic shock (odds ration [OR] 16.01; 95% confidence interval [CI] 7.64-33.56; P < 0.001), delayed removal of intravenous catheter (OR 6.78; 95% CI 2.80-17.41; P < 0.001), renal failure (OR 5.38; 95% CI 1.99-14.57; P = 0.001), and breakthrough invasive candidiasis (OR 2.99; 95% CI 1.04-8.67; P = 0.043). CONCLUSIONS: Neonatal invasive candidiasis has worse outcomes than non-neonatal pediatric candidiasis. Neonatologists and pediatricians must consider age-specific differences when developing treatment and prevention guidelines, or when interpreting studies of other age groups. PMID- 29699504 TI - Host genotype and environment affect the trade-off between horizontal and vertical transmission of the parasite Edhazardia aedis. AB - BACKGROUND: If a parasite is able to transmit horizontally or vertically, which transmission mode will it choose? We investigated how the growth conditions and the genotype of the mosquito Aedes aegypti affect the transmission mode of the parasite Edhazardia aedis. RESULTS: In poor conditions the parasites were more likely to be transmitted horizontally, whereas in favourable conditions they were more likely to be transmitted vertically. Unfavourable conditions delayed emergence, giving the parasite more time to produce its horizontally transmitted stage; in more favourable conditions mosquitoes have greater reproductive success, increasing the effectiveness of vertical transmission. In addition, the parasite's ability to transmit vertically was influenced by the genetic background of the host (i.e., its full-sib family), giving a genetic correlation between the host's life-history and which of the parasite's transmission mode it enables. In particular, genotypes with large bodies (and therefore high fecundity) were more likely to enable vertical transmission than genotypes with small bodies. This led to a trade-off among the host's families (which can be interpreted as a genetic correlation) for the parasite's transmission mode. CONCLUSIONS: Since horizontal transmission is linked to higher virulence than vertical transmission, the host's contribution to transmission mode has important consequences for the evolution of parasites with mixed-mode transmission. PMID- 29699505 TI - Relationship between Helicobacter pylori infection and bone mineral density: a retrospective cross-sectional study. AB - BACKGROUND: Helicobacter pylori (H. pylori) infection can induce individual inflammatory and immune reactions which associated with extra-digestive disorders. Our aim is to investigate the association between H. pylori infection and bone mineral density. METHODS: This retrospective cross-sectional study was performed by using the data from the health examination database in a medical center of southern Taiwan in 2013. We investigated the relationship between sex, age, body mass index (BMI), waist circumstance, lipid profile, H. pylori infection, the findings of upper gastrointestinal endoscopy and bone mineral density (BMD). Because of nonrandomized assignment and strong confounding effect of age on BMD, the 1:1 propensity score match was applied for age adjustment. The simple and multiple stepwise logistic regression analysis were performed to assess the risk factors of decreased BMD in these well-balanced pairs of participants. RESULTS: Of the 867 subjects in final analysis with the mean age of 55.9 +/- 11.3 years, 381 (43.9%) subjects had H. pylori infection, and 556 (64.1%) subjects had decreased BMD. In decreased BMD group, the portion of woman was higher than a normal BMD group (37.2% versus 29.6%, P = 0.023), the age was significantly older (59.4 +/- 9.8 versus 49.8 +/- 11.3, p < 0.001) and BMI was significantly lower (24.7 +/- 3.5 versus 25.4 +/- 3.7, p = 0.006) than the normal BMD group. The prevalence of H. pylori infection was 39.9% and 46.2% in the normal BMD group and the decreased BMD group respectively (P = 0.071). The multivariate analysis which was used for these possible risk factors showed that only advanced age (OR 1.09, 95% CI 1.08-1.11, P < 0.001), and low BMI (OR 0.91, 95% CI 0.87-0.95, P < 0.001) were independently significantly associated with decreased BMD in this nonrandomized study. In the propensity score-matched participants, the multiple stepwise logistic regression analysis revealed H. pylori infection (OR 1.62, 95% CI 1.12-2.35, P = 0.011) and low BMI (OR 0.92, 95% CI 0.87-0.97, P = 0.001) were independently significantly associated with decreased BMD. CONCLUSIONS: H. pylori infection and low BMI were independently significantly associated with decreased BMD in selected propensity score-matched populations after age adjustment. PMID- 29699506 TI - Correction to: The Ferumoxytol for Anemia of CKD Trial (FACT)-a randomized controlled trial of repeated doses of ferumoxytol or iron sucrose in patients on hemodialysis: background and rationale. AB - Following publication of the original article [1], the authors reported that one of the authors' name is spelled incorrectly. In this Erratum the incorrect and correct author name are shown. The original publication of this article has been corrected. PMID- 29699507 TI - High resolution magnetic resonance imaging in pathogenesis diagnosis of single lenticulostriate infarction with nonstenotic middle cerebral artery, a retrospective study. AB - BACKGROUND: It is usually difficult to identify stroke pathogenesis for single lenticulostriate infarction with nonstenotic middle cerebral artery (MCA). Our aim is to differentiate the two pathogeneses, non-branch atheromatous small vessel disease and branch atheromatous disease (BAD) by high-resolution magnetic resonance imaging (HR-MRI). METHODS: Thirty-two single lenticulostriate infarction patients with nonstenotic MCA admitted to the China-Japan Friendship Hospital from December 2014 to August 2017 were enrolled for retrospective analysis. National Institutes of Health Stroke Scale (NIHSS), modified Rankin Scale (mRS), atherosclerotic risk factors, imaging features, and the characteristic of MCA vessel wall in HR-MRI were evaluated. RESULTS: MCA plaques were detected in 15(46.9%) patients which implied BAD and 8 of 15 (53.3%) patients had plaques location in upper dorsal side of the vessel wall. Patients with HR-MRI identified plaques had a significantly larger infarction lesion length (1.95 +/- 0.86 cm versus 1.38 +/- 0.55 cm; P = 0.031) and larger lesion volume (2.95 +/- 3.94 cm3 versus 0.90 +/- 0.94 cm3; P = 0.027) than patients without plaques. Patients with HR-MRI identified plaques had a significant higher percentage of proximal lesions than patients without plaques (P = 0.055). However, according to the location of MCA plaques, there were no significant differences in terms of imaging features, NIHSS and mRS. CONCLUSION: We demonstrated high frequency of MCA atheromatous plaques visualized in single lenticulostriate infarction patients with nonstenotic MCA by using HR-MRI. Patients with HR-MRI identified plaque presented larger infarction lesions and more proximal lesions than patients without plaque, which were consistent with imaging features of BAD. HR-MRI is an important and effective tool for identifying stroke etiology in patients with nonstenotic MCA. PMID- 29699508 TI - Factors associated with congenital anomalies in Addis Ababa and the Amhara Region, Ethiopia: a case-control study. AB - BACKGROUND: The early stage of embryo development is extremely vulnerable to various teratogenic factors, leading to congenital anomalies. In Ethiopia, a significant number of babies are born with congenital anomalies, but the risk factors for the anomalies have never been studied. Understanding the specific risk factors for congenital anomalies is very essential to provide health education that aims at creating awareness and establishing preventive strategic plan/s. The main objective of this study was to assess the risk factors associated with congenital anomalies in Addis Ababa and the Amhara Region, Ethiopia. METHODS: A case-control study was conducted from January 1- June 30, 2015. The participants were recruited at the purposively selected hospitals in Addis Ababa and the Amhara Region. A total of 207 cases and 207 controls were included in the study. Cases were neonates, infants, and children 0-11 months of age with external and internal major congenital anomalies diagnosed by pediatricians. Controls were neonates, infants, and children 0-11 months of age without external and internal anomalies. Data on sociodemographic characteristics, exposure to risk factors, and reproductive history were collected by face to face interviews with children's mothers/caregivers using a structured questionnaire. Binary logistic regression was employed to explore risk factors associated with the occurrence of the problems. RESULTS: About 87.4% of the children were below 6 months, and 12.6% were between 6 and 11 months. The majority (59.9%) of the children were male, with the M: F sex ratio of 1.49. The mean age of the mothers was 26 years (16-45 years). Unidentified medication use during early pregnancy (AOR = 4.595; 95% CI: 1.868-11.301, P-value = 0.001), maternal alcohol drinking (AOR = 2.394; 95% CI: 1.212-4.726, P-value = 0.012), and exposure to chemicals (AOR = 9.964; 95% CI = 1.238-80.193, P-value = 0.031) were significantly associated with the occurrence of congenital anomalies. Iron folate use (AOR = 0.051; 95% CI: 0.010-0.260, P-value = < 0.001) before and during early pregnancy had a protective effect on congenital anomaly. CONCLUSION: Unidentified medication use, alcohol drinking during early pregnancy, and exposure to chemicals had a significant association with the occurrence of congenital anomalies, whereas iron folate use before and during early pregnancy had a protective effect from congenital anomalies. PMID- 29699509 TI - The effects of short-term fasting on quality of life and tolerance to chemotherapy in patients with breast and ovarian cancer: a randomized cross-over pilot study. AB - BACKGROUND: This pilot trial aimed to study the feasibility and effects on quality of life (QOL) and well-being of short-term fasting (STF) during chemotherapy in patients with gynecological cancer. METHODS: In an individually randomized cross-over trial patients with gynecological cancer, 4 to 6 planned chemotherapy cycles were included. Thirty-four patients were randomized to STF in the first half of chemotherapies followed by normocaloric diet (group A;n = 18) or vice versa (group B;n = 16). Fasting started 36 h before and ended 24 h after chemotherapy (60 h-fasting period). QOL was assessed by the FACIT-measurement system. RESULTS: The chemotherapy-induced reduction of QOL was less than the Minimally Important Difference (MID; FACT-G = 5) with STF but greater than the MID for non-fasted periods. The mean chemotherapy-induced deterioration of total FACIT-F was 10.4 +/- 5.3 for fasted and 27.0 +/- 6.3 for non-fasted cycles in group A and 14.1 +/- 5.6 for non-fasted and 11.0 +/- 5.6 for fasted cycles in group B. There were no serious adverse effects. CONCLUSION: STF during chemotherapy is well tolerated and appears to improve QOL and fatigue during chemotherapy. Larger studies should prove the effect of STF as an adjunct to chemotherapy. TRIAL REGISTRATION: This trial was registered at clinicaltrials.gov: NCT01954836 . PMID- 29699510 TI - Putative cancer stem cells may be the key target to inhibit cancer cell repopulation between the intervals of chemoradiation in murine mesothelioma. AB - BACKGROUND: Cancer cell repopulation during chemotherapy or radiotherapy is a major factor limiting the efficacy of treatment. Cancer stem cells (CSC) may play critical roles during this process. We aim to demonstrate the role of mesothelioma stem cells (MSC) in treatment failure and eventually to design specific target therapies against MSC to improve the efficacy of treatment in malignant mesothelioma. METHODS: Murine mesothelioma AB12 and RN5 cells were used to compare tumorigenicity in mice. The expression of CSC-associated genes was evaluated by quantitative real-time PCR in both cell lines treated with chemo radiation. Stemness properties of MSC-enriched RN5-EOS-Puro2 cells were characterized with flow cytometry and immunostaining. A MSC-specific gene profile was screened by microarray assay and confirmed thereafter. Gene Ontology analysis of the selected genes was performed by GOMiner. RESULTS: Tumor growth delay of murine mesothelioma AB12 cells was achieved after each cycle of cisplatin treatment, however, tumors grew back rapidly due to cancer cell repopulation between courses of chemotherapy. Strikingly, a 10-times lower number of irradiated cells in both cell lines led to a similar tumor incidence and growth rate as with untreated cells. The expression of CSC-associated genes such as CD24, CD133, CD90 and uPAR was dramatically up-regulated, while others did not change significantly after chemoradiation. Highly enriched MSC after selection with puromycin displayed an increasing GFP-positive population and showed typical properties of stemness. Comparatively, the proportion of MSC significantly increased after RN5-EOS parental cells were treated with either chemotherapy, gamma-ray radiation, or a combination of the two, while MSC showed more resistance to the above treatments. A group of identified genes are most likely MSC-specific, and major pathways related to regulation of cell growth or apoptosis are involved. Upregulation of the gene transcripts Tnfsf18, Serpinb9b, Ly6a, and Nppb were confirmed. CONCLUSION: Putative MSC possess the property of stemness showing more resistance to chemoradiation, suggesting that MSC may play critical roles in cancer cell repopulation. Further identification of selected genes may be used to design novel target therapies against MSC, so as to eliminate cancer cell repopulation in mesothelioma. PMID- 29699511 TI - Genes and functions from breast cancer signatures. AB - BACKGROUND: Breast cancer is a heterogeneous disease and personalized medicine is the hope for the improvement of the clinical outcome. Multi-gene signatures for breast cancer stratification have been extensively studied in the past decades and more than 30 different signatures have been reported. A major concern is the minimal overlap of genes among the reported signatures. We investigated the breast cancer signature genes to address our hypothesis that the genes of different signature may share common functions, as well as to use these previously reported signature genes to build better prognostic models. METHODS: A total of 33 signatures and the corresponding gene lists were investigated. We first examined the gene frequency and the gene overlap in these signatures. Then the gene functions of each signature gene list were analysed and compared by the KEGG pathways and gene ontology (GO) terms. A classifier built using the common genes was tested using the METABRIC (Molecular Taxonomy of Breast Cancer International Consortium) data. The common genes were also tested for building the Yin Yang gene mean expression ratio (YMR) signature using public datasets (GSE1456 and GSE2034). RESULTS: Among a total of 2239 genes collected from the 33 breast cancer signatures, only 238 genes overlapped in at least two signatures; while from a total of 1979 function terms enriched in the 33 signature gene lists, 429 terms were common in at least two signatures. Most of the common function terms were involved in cell cycle processes. While there is almost no common overlapping genes between signatures developed for ER-positive (e.g. 21 gene signature) and those developed for ER-negative (e.g. basal signatures) tumours, they have common function terms such as cell death, regulation of cell proliferation. We used the 62 genes that were common in at least three signatures as a classifier and subtyped 1141 METABRIC cases including 144 normal samples into nine subgroups. These subgroups showed different clinical outcome. Among the 238 common genes, we selected those genes that are more highly expressed in normal breast tissue than in tumours as Yang genes and those more highly expressed in tumours than in normal as Yin genes and built a YMR model signature. This YMR showed significance in risk stratification in two datasets (GSE1456 and GSE2034). CONCLUSIONS: The lack of significant numbers of overlapping genes among most breast cancer signatures can be partially explained by our discovery that these signature genes represent groups with similar functions. The genes collected from these previously reported signatures are valuable resources for new model development. The subtype classifier and YMR signature built from the common genes showed promising results. PMID- 29699513 TI - Case of convulsive seizure developing during electroretinographic recordings: a case report. AB - BACKGROUND: To present our findings in a case of convulsive seizures and loss of consciousness that developed during recording electroretinograms (ERG). CASE PRESENTATION: A 34-year-old man had reduced vision in his left eye for about 15 years, and night blindness for about two years. His visual acuity was 20/15 in the right eye and 20/50 in the left eye. The fundus was normal but the sensitivity in the macular region of the left eye was decreased. Optical coherence tomography (OCT) showed partial loss of the interdigitation zone. Upon completion of the flicker ERG recording, a paralysis developed in both upper limbs, then convulsions of the lower limbs followed by a loss of consciousness. The convulsions disappeared after an intravenous injection of diazepam. After that incident, he reported that he had had previous conscious-loss seizures. CONCLUSIONS: Photosensitive epileptic seizures can occur with the light stimuli used for conventional ERG recordings. We recommended that clinicians request information on any prior seizure episodes of the patients and their family members before ERG recordings. PMID- 29699514 TI - Pleocytosis in a patient with relapsing polychondritis accompanied by meningoencephalitis: a case report. AB - BACKGROUND: Relapsing polychondritis (RP) is an uncommon immune-related disease with unknown causes. It is characterized by inflammation of cartilaginous or non cartilaginous structures, such as the ears, nose, respiratory tract, eyes, and joints. Neurological involvement is rare in RP. CASE PRESENTATION: We report a case of pleocytosis in a 64-year-old man diagnosed as having RP with meningoencephalitis. The patient's condition markedly improved following methylprednisolone treatment. CONCLUSIONS: To our knowledge, this is the first report of recurrent pleocytosis in a patient with RP accompanied by meningoencephalitis. Steroid pulse therapy is effective in most cases, and early diagnosis is of importance. PMID- 29699512 TI - Regulation of calretinin in malignant mesothelioma is mediated by septin 7 binding to the CALB2 promoter. AB - BACKGROUND: The calcium-binding protein calretinin (gene name: CALB2) is currently considered as the most sensitive and specific marker for the diagnosis of malignant mesothelioma (MM). MM is a very aggressive tumor strongly linked to asbestos exposure and with no existing cure so far. The mechanisms of calretinin regulation, as well as its distinct function in MM are still poorly understood. METHODS: We searched for transcription factors binding to the CALB2 promoter and modulating calretinin expression. For this, DNA-binding assays followed by peptide shotgun-mass spectroscopy analyses were used. CALB2 promoter activity was assessed by dual-luciferase reporter assays. Furthermore, we analyzed the effects of CALB2 promoter-binding proteins by lentiviral-mediated overexpression or down regulation of identified proteins in MM cells. The modulation of expression of such proteins by butyrate was determined by subsequent Western blot analysis. Immunohistochemical analysis of embryonic mouse lung tissue served to verify the simultaneous co-expression of calretinin and proteins interacting with the CALB2 promoter during early development. Finally, direct interactions of calretinin with target proteins were evidenced by co-immunoprecipitation experiments. RESULTS: Septin 7 was identified as a butyrate-dependent transcription factor binding to a CALB2 promoter region containing butyrate-responsive elements (BRE) resulting in decreased calretinin expression. Accordingly, septin 7 overexpression decreased calretinin expression levels in MM cells. The regulation was found to operate bi-directionally, i.e. calretinin overexpression also decreased septin 7 levels. During murine embryonic development calretinin and septin 7 were found to be co-expressed in embryonic mesenchyme and undifferentiated mesothelial cells. In MM cells, calretinin and septin 7 colocalized during cytokinesis in distinct regions of the cleavage furrow and in the midbody region of mitotic cells. Co-immunoprecipitation experiments revealed this co-localization to be the result of a direct interaction between calretinin and septin 7. CONCLUSIONS: Our results demonstrate septin 7 not only serving as a "cytoskeletal" protein, but also as a transcription factor repressing calretinin expression. The negative regulation of calretinin by septin 7 and vice versa sheds new light on mechanisms possibly implicated in MM formation and identifies these proteins as transcriptional regulators and putative targets for MM therapy. PMID- 29699515 TI - Creutzfeldt-Jakob disease with Alzheimer pathology, presenting with status epilepticus following repeated partial seizures: a case report and literature review. AB - BACKGROUND: Creutzfeldt-Jakob disease (CJD) is a fatal neurodegenerative disease. Common first symptoms are dementia, cerebellar ataxia, visual disturbance, and psychiatric symptoms. Seizure as the first symptom of CJD is a very rare finding. CASE PRESENTATION: We experienced an elderly woman who presented initially with status epilepticus following repeated partial seizures in the course of Alzheimer disease (AD) dementia. Anti-convulsive therapy had no effect. Autopsy revealed definite CJD with AD pathology. COCLUSIONS: This is the first reported CJD case presenting with status epilepticus in the course of AD dementia. PMID- 29699516 TI - Reduction of MHC-I expression limits T-lymphocyte-mediated killing of Cancer initiating cells. AB - BACKGROUND: It has been proposed that cancer establishment, maintenance, and recurrence may be attributed to a unique population of tumor cells termed cancer initiating cells (CICs) that may include characteristics of putative cancer stem cell-like cells. Studies in lung cancer have shown that such cells can be enriched and propagated in vitro by culturing tumor cells in serum-free suspension as tumorspheres. CICs have been characterized for their phenotype, stem cell-like qualities, and their role in establishing tumor and maintaining tumor growth. Less is known about the interaction of CICs with the immune system. METHODS: We established CIC-enriched tumorspheres from murine TC-1 lung cancer cells, expressing human papillomavirus 16 (HPV-16) E6/E7 antigens, and evaluated their susceptibility to antitumor immune responses both in vitro and in vivo. RESULTS: TC-1 CICs demonstrated reduced expression of surface major histocompatibility complex (MHC)-I molecules compared to non-CICs. We similarly determined decreased MHC-I expression in five of six human lung cancer cell lines cultured under conditions enriching for CICs. In vivo, TC-1 cells enriched for CICs were resistant to human papillomavirus 16 E6/E7 peptide vaccine-mediated killing. We found that vaccinated mice challenged with CIC enriched tumorspheres demonstrated shorter survivals and showed significantly fewer CD8+ tumor infiltrating lymphocytes compared to CIC non-enriched challenged mice. Furthermore, cultured cytotoxic T lymphocytes (CTLs) from vaccinated mice demonstrated reduced capacity to lyse TC-1 cells enriched for CICs compared to non-enriched TC-1 cells. Following treatment with IFN-gamma, both CIC enriched and non-enriched TC-1 cells expressed similar levels of MHC-I, and the increased MHC-I expression on CICs resulted in greater CTL-mediated tumor lysis and improved tumor-free survival in mice. CONCLUSIONS: These results suggest that the attenuated expression of MHC-I molecules by CICs represents a potential strategy of CICs to escape immune recognition, and that the development of successful immunotherapy strategies targeting CICs may decrease their resistance to T cell mediated immune detection by enhancing CIC MHC-I expression. PMID- 29699517 TI - Effect of childhood BMI on asthma: a systematic review and meta-analysis of case control studies. AB - BACKGROUND: Asthma is a multifactorial syndrome that threatens the health of children. Body mass index (BMI) might be one of the potential factors but the evidence is controversial. The aim of this study is to perform a comprehensive meta-analysis to investigate the association between asthma and BMI. METHODS: Electronic databases including, Web of Science, Pubmed, Scopus, Science Direct, ProQuest, up to April 2017, were searched by two researchers independently. The keywords "asthma, body mass index, obesity, overweight, childhood and adolescence" were used. Random and fixed effects models were applied to obtain the overall odds ratios (ORs) and standardized mean difference (SMD). Heterogeneity between the studies was examined using I2 and Cochrane Q statistics. RESULTS: After reviewing 2511 articles, 16 studies were eligible for meta-analysis according to inclusion/exclusion criteria. A meta-analysis from 11 case-control studies revealed OR of asthma and overweight as OR = 1.64; (95% Confidence Interval (CI): 1.13-2.38) and from 14 case-control studies, OR for asthma and obesity was OR = 1.92 (95% CI: 1.39-2.65), which indicated that risk of asthma in overweight and obese children and adolescence was significantly higher (1.64 and 1.92 times) than that of individuals with (p-value < 0.01 for underweight/normal weight in both cases). Furthermore, there was a significant relationship between asthma and BMI > 85 percentile according to SMD SMD = 0.21; (95%CI: 0.03-0.38; p-value = 0.021). CONCLUSIONS: The results showed a significant relationship between BMI (obesity/overweight) and asthma among children and adolescents. It is important to study the confounding factors that affect the relationship between asthma and BMI in future epidemiological researches. PMID- 29699518 TI - Comparison of two techniques for toric intraocular lens implantation: hydroimplantation versus ophthalmic viscosurgical devices. AB - BACKGROUND: To compare the results between hydroimplantation of a single-piece, acrylic foldable toric intraocular lens (IOLs) and conventional implantation using an ophthalmic viscosurgical device (OVD). METHODS: In this study, 60 eyes with cataract and preexisting regular corneal astigmatism of 1.0 to 3.0 diopters (D) underwent the implantation of the AcrySof toric IOLs (Alcon Laboratories, Inc.). The patients were randomly assigned to a conventional implantation technique with an OVD or a hydroimplantation technique. Comparison of preoperative and postoperative parameters was performed using paired Student t tests, and independent Student t test was used to compare between the two groups. RESULTS: Three months postoperatively, the mean subjective astigmatism was 0.45 D +/- 0.24 (SD) in the OVD group and 0.49 +/- 0.29 D in the hydroimplantation group (P = 0.492). The mean endothelial cell density (ECD) loss was 7.54% +/- 0.82% and 7.32% +/- 0.59%, respectively (P = 0.117). The mean absolute IOL rotation was 4.77 +/- 2.32 degrees and 4.70 +/- 1.95 degrees, respectively (P = 0.334). The mean time for IOL implantation was 71.50 +/- 8.10 s and 37.60 +/- 3.90 s, respectively (P < 0.001). Two hours, 1 day, 1 week, 1 month, and 3 months postoperatively, there was no significant difference in IOP between the two groups (P > 0.05), although IOP two hours postoperatively seemed to be a little higher in the OVD group. CONCLUSIONS: Compared with the use of OVDs for toric IOLs implantation, the hydroimplantation technique provided advantages of increased efficiency, reduced surgical time and cost, and no concerns of OVD induced elevated IOP. TRIAL REGISTRATION: Current Controlled Trials ISRCTN55696872 , Retrospectively registered (Date of registration: 25 March 2018). PMID- 29699519 TI - Comprehensive gene expression analysis of canine invasive urothelial bladder carcinoma by RNA-Seq. AB - BACKGROUND: Invasive urothelial carcinoma (iUC) is a major cause of death in humans, and approximately 165,000 individuals succumb to this cancer annually worldwide. Comparative oncology using relevant animal models is necessary to improve our understanding of progression, diagnosis, and treatment of iUC. Companion canines are a preferred animal model of iUC due to spontaneous tumor development and similarity to human disease in terms of histopathology, metastatic behavior, and treatment response. However, the comprehensive molecular characterization of canine iUC is not well documented. In this study, we performed transcriptome analysis of tissue samples from canine iUC and normal bladders using an RNA sequencing (RNA-Seq) approach to identify key molecular pathways in canine iUC. METHODS: Total RNA was extracted from bladder tissues of 11 dogs with iUC and five healthy dogs, and RNA-Seq was conducted. Ingenuity Pathway Analysis (IPA) was used to assign differentially expressed genes to known upstream regulators and functional networks. RESULTS: Differential gene expression analysis of the RNA-Seq data revealed 2531 differentially expressed genes, comprising 1007 upregulated and 1524 downregulated genes, in canine iUC. IPA revealed that the most activated upstream regulator was PTGER2 (encoding the prostaglandin E2 receptor EP2), which is consistent with the therapeutic efficiency of cyclooxygenase inhibitors in canine iUC. Similar to human iUC, canine iUC exhibited upregulated ERBB2 and downregulated TP53 pathways. Biological functions associated with cancer, cell proliferation, and leukocyte migration were predicted to be activated, while muscle functions were predicted to be inhibited, indicating muscle-invasive tumor property. CONCLUSIONS: Our data confirmed similarities in gene expression patterns between canine and human iUC and identified potential therapeutic targets (PTGER2, ERBB2, CCND1, Vegf, and EGFR), suggesting the value of naturally occurring canine iUC as a relevant animal model for human iUC. PMID- 29699520 TI - A methodological framework for the evaluation of syndromic surveillance systems: a case study of England. AB - BACKGROUND: Syndromic surveillance complements traditional public health surveillance by collecting and analysing health indicators in near real time. The rationale of syndromic surveillance is that it may detect health threats faster than traditional surveillance systems permitting more timely, and hence potentially more effective public health action. The effectiveness of syndromic surveillance largely relies on the methods used to detect aberrations. Very few studies have evaluated the performance of syndromic surveillance systems and consequently little is known about the types of events that such systems can and cannot detect. METHODS: We introduce a framework for the evaluation of syndromic surveillance systems that can be used in any setting based upon the use of simulated scenarios. For a range of scenarios this allows the time and probability of detection to be determined and uncertainty is fully incorporated. In addition, we demonstrate how such a framework can model the benefits of increases in the number of centres reporting syndromic data and also determine the minimum size of outbreaks that can or cannot be detected. Here, we demonstrate its utility using simulations of national influenza outbreaks and localised outbreaks of cryptosporidiosis. RESULTS: Influenza outbreaks are consistently detected with larger outbreaks being detected in a more timely manner. Small cryptosporidiosis outbreaks (<1000 symptomatic individuals) are unlikely to be detected. We also demonstrate the advantages of having multiple syndromic data streams (e.g. emergency attendance data, telephone helpline data, general practice consultation data) as different streams are able to detect different outbreak types with different efficacy (e.g. emergency attendance data are useful for the detection of pandemic influenza but not for outbreaks of cryptosporidiosis). We also highlight that for any one disease, the utility of data streams may vary geographically, and that the detection ability of syndromic surveillance varies seasonally (e.g. an influenza outbreak starting in July is detected sooner than one starting later in the year). We argue that our framework constitutes a useful tool for public health emergency preparedness in multiple settings. CONCLUSIONS: The proposed framework allows the exhaustive evaluation of any syndromic surveillance system and constitutes a useful tool for emergency preparedness and response. PMID- 29699521 TI - Mediating effects of burden on quality of life for caregivers of first-time stroke patients discharged from the hospital within one year. AB - BACKGROUND: Caregiver burden may be either a predictor or an outcome of caregiver quality of life (QoL). Patient or caregiver factors that directly affect caregiver QoL, predictors that are simultaneously shared with caregiver burden and QoL, and factors that affect caregiver QoL through caregiver burden are not well understood. This study explored predictors of caregiver QoL and identified whether caregiver burden is a mediator for caregivers of first-time stroke patients. METHODS: This is a cross-sectional study. We recruited first-time stroke patients who had been discharged from the hospital within 1 year. We screened caregivers with two major inclusion criteria: age > 20 years old and being the family member who provides the most patient-care hours out of all family caregivers. Caregiver burden (Caregiver Strain Index, CSI), QoL (Caregiver Quality of Life Index, CQLI), and patient and caregiver characteristics were assessed with structured questionnaires. Multiple-regression and bootstrap analysis were conducted for data analysis. RESULTS: A total of 126 caregivers completed the questionnaires. Higher caregiver burdens, lower caregiver education level, lower self-rated health, lower monthly family income, and spouses who were responsible for medical fees were significant predictors of lower caregiver QoL. Poor self-rated health and monthly family income of $ 666 USD or below were the strongest predictors of caregiver QoL. Spouses who were responsible for medical fees and lower monthly family income had direct negative effects on caregiver QoL, but these factors exhibited no indirect mediating effect between caregiver characteristics and QoL through caregiver burden as a mediator. Caregiver education level at or below elementary school and poor or fair self-rated-health had direct negative effects on caregiver QoL, which were mediated by caregiver burden. CONCLUSIONS: Our study indicated predictors of caregiver QoL and the relationships with caregiver burden among first-time stroke survivors in the early stage. Caregivers' financial factors affected caregiver QoL directly. Caregivers' poor self-rated health and lower education level negatively affected caregiver QoL indirectly through caregiver burden as a mediator. Interventions to make appropriate policies for financial subsidies, to enhance caregivers' health and to provide tailored stroke-related education through multidisciplinary cooperation may effectively promote caregiver QoL. PMID- 29699522 TI - Psychometric properties and measurement invariance of the Beck hopelessness scale (BHS): results from a German representative population sample. AB - BACKGROUND: The Beck Hopelessness Scale (BHS) has been the most frequently used instrument for the measurement of hopelessness in the past 40 years. Only recently has it officially been translated into German. The psychometric properties and factor structure of the BHS have been cause for intensive debate in the past. METHODS: Based on a representative sample of the German population (N = 2450) item analysis including item sensitivity, item-total correlation and item difficulty was performed. Confirmatory factor analyses (CFA) for several factor solutions from the literature were performed. Multiple group factor analysis was performed to assess measurement invariance. Construct validity was assessed via the replication of well-established correlations with concurrently assessed measures. RESULTS: Most items exhibited adequate properties. Items #4, #8 and #13 exhibited poor item characteristics- each of these items had previously received negative evaluations in international studies. A one dimensional factor solution, favorable for the calculation and interpretation of a sum score, was regarded as adequate. A bi-factor model with one content factor and two method factors (defined by positive/negative item coding) resulted in an excellent model fit. Cronbach's alpha in the current sample was .87. Hopelessness, as measured by the BHS, significantly correlated in the expected direction with suicidal ideation (r = .36), depression (r = .53) and life satisfaction (r = -.53). Strict measurement invariance could be established regarding gender and depression status. Due to limited research regarding the interpretation of fit indices with dichotomous data, interpretation of CFA results needs to remain tentative. CONCLUSION: The BHS is a valid measure of hopelessness in various subgroups of the general population. Future research could aim at replicating these findings using item response theory and cross cultural samples. A one-dimensional bi-factor model seems appropriate even in a non-clinical population. PMID- 29699523 TI - Accuracy of risk scales for predicting repeat self-harm and suicide: a multicentre, population-level cohort study using routine clinical data. AB - BACKGROUND: Risk scales are used widely in the management of patients presenting to hospital following self-harm. However, there is evidence that their diagnostic accuracy in predicting repeat self-harm is limited. Their predictive accuracy in population settings, and in identifying those at highest risk of suicide is not known. METHOD: We compared the predictive accuracy of the Manchester Self-Harm Rule (MSHR), ReACT Self-Harm Rule (ReACT), SAD PERSONS Scale (SPS) and Modified SAD PERSONS Scale (MSPS) in an unselected sample of patients attending hospital following self-harm. Data on 4000 episodes of self-harm presenting to Emergency Departments (ED) between 2010 and 2012 were obtained from four established monitoring systems in England. Episodes were assigned a risk category for each scale and followed up for 6 months. RESULTS: The episode-based repeat rate was 28% (1133/4000) and the incidence of suicide was 0.5% (18/3962). The MSHR and ReACT performed with high sensitivity (98% and 94% respectively) and low specificity (15% and 23%). The SPS and the MSPS performed with relatively low sensitivity (24-29% and 9-12% respectively) and high specificity (76-77% and 90%). The area under the curve was 71% for both MSHR and ReACT, 51% for SPS and 49% for MSPS. Differences in predictive accuracy by subgroup were small. The scales were less accurate at predicting suicide than repeat self-harm. CONCLUSIONS: The scales failed to accurately predict repeat self-harm and suicide. The findings support existing clinical guidance not to use risk classification scales alone to determine treatment or predict future risk. PMID- 29699524 TI - Epidemiological study of child and adolescent psychiatric disorders in Lithuania. AB - BACKGROUND: From the public health perspective, epidemiological data of child mental health and psychosocial correlates were necessary and very lacking in Lithuanian society that has been undergoing rapid socio-economic change since the past decades. Together with determining the prevalence rates of disorders and assessing the needs for the services, this study has also shifted attention from the highly selective samples of children attending children and adolescent mental health services towards less severe cases of psychopathology as well as different attitudes of parents and teachers. The aim of the first epidemiological study in Lithuania was to identify the prevalence of psychiatric disorders in the community sample of children. METHODS: Child psychiatric disorders were investigated in a representative sample of 3309 children aged 7-16 years (1162 7 10-year-olds and 2147 11-16-year-olds), using a two-phase design with the Lithuanian version of the Strengths and Difficulties Questionnaire (SDQ) in the first screening phase, and the Development and Well-Being Assessment (DAWBA) in the second diagnostic phase. RESULTS: The estimated point prevalence of ICD-10 psychiatric disorders was 13.1% for the total sample (14.0% for the child sample and 12.1% for adolescent sample). The most common groups of disorders were Conduct disorders 6.6% (7.1% for child sample and 6.0% for adolescent sample), Anxiety disorders 5.0% (5.9% for child sample and 6.0% for adolescent sample), with Hyperkinesis being less common 2.0% (2.7% for child sample and 1.2% for adolescent sample). Potential risk factors were related to individual characteristics of the child (gender, poor general health, and stressful life experiences), and the family (single parenthood, foster care, unfavourable family climate, disciplining difficulties, worries related to TV or computer use). CONCLUSIONS: The overall prevalence of youth psychiatric disorders was relatively high in this representative Lithuanian sample compared to Western European countries. The SDQ and DAWBA measures appear useful for the further research and clinical practice in this society. PMID- 29699525 TI - Risk factors for carriage of Streptococcus pneumoniae in children. AB - BACKGROUND: During the past decades Streptococcus pneumoniae has developed significant resistance to many classes of antimicrobial drugs. Potential risk factors for colonization of the nasopharynx by Streptococcus pneumoniae in children and for carriage of drug resistant strains were examined. METHODS: Between 2007 and 2008 nasopharyngeal swabs were collected from 402 children 6 months to 5 years old visiting the public sector immunization centers and outpatient departments as well as offices of paediatricians from private practice in Nicosia district in Cyprus. Information on demographic characteristics and potential risk factors of participating children were collected using a standardized questionnaire distributed to parents. RESULTS: In multivariable analyses we found that attendance at day care center, having siblings in the family and having both parents originating from Cyprus, statistically increased the risk of pneumococcal colonization. Full immunization with PCV7 appears to be a protective factor against colonization by pneumococcus. Previous administration of antimicrobials during the last month prior to specimen collection appeared to be the most consistent risk factor for carrying a non susceptible strain of Streptococcus pneumoniae to either penicillin or erythromycin. Factors such as age, nationality, previous or current breastfeeding, passive exposure to cigarette smoke and attendance in a day care center do not appear as independent risk factors for colonization by non susceptible strains. CONCLUSIONS: Prudent use of antibiotics especially for upper respiratory tract infections in children as well as increased vaccination coverage by the pneumococcal conjugate vaccines could prove effective in reducing levels of colonization by drug resistant pneumococcal strains. PMID- 29699526 TI - Computerized tomography findings in calcified signet-ring gastric cancer receiving chemotherapy: a case report. AB - BACKGROUND: Calcification in primary gastric cancer is very rare. In this report, we describe the computerized tomography (CT) changes in calcification in a patient with locally advanced signet-ring gastric cancer treated with chemotherapy. CASE PRESENTATION: A 49-year-old man presented with 5 months' history of abdominal pain, anorexia, and rapid weight loss. He had undergone Billroth-II subtotal gastrectomy for a bleeding gastric ulcer 30 years ago. Abdominal CT showed irregular thickening of the gastric wall and miliary calcifications. Histologic examination of specimen obtained by endoscopic biopsy showed poorly differentiated calcified signet-ring gastric cancer. The patient was clinically staged T4N2M0 and treated with docetaxel, cisplatin, and fluorouracil (DCF)/oxaliplatin and S-1 (XLOX)/S-1. After five cycles of chemotherapy, the general condition of the patient improved and tumor markers (CEA, CA125, CA199) decreased. However, follow-up CT scans showed continuing increase in the calcification. CONCLUSIONS: To conclude, in this case report we have described the dynamic changes in calcification in a gastric cancer patient receiving chemotherapy. One explanation for the observed increase in calcifications could be that the ischemic necrosis resulting from chemotherapy creates an alkaline environment, which promotes deposition of calcium salts. Our theory needs to be confirmed with histological evidence from a large series of patients. Nevertheless, we hope that these findings will improve understanding of the mechanism of calcification in gastric cancer. PMID- 29699527 TI - Collaborative, individualised lifestyle interventions are acceptable to people with first episode psychosis; a qualitative study. AB - BACKGROUND: The adverse impact of unhealthy lifestyle choices and the prescription of antipsychotic medications contribute to weight gain, poor cardiovascular health and reduced life expectancy for people with psychosis. The present study aimed to explore the acceptability and perceived outcomes of a lifestyle intervention designed to prevent or reduce weight gain in people with first-episode psychosis. METHODS: This was a qualitative study using a data driven approach. People recovering from first-episode psychosis recruited from UK early intervention services and taking part in the active arm of a randomised controlled trial of a lifestyle intervention (the InterACT trial), were interviewed using a semi-structured interview schedule. Interviews were transcribed verbatim and analysed using Framework Analysis. RESULTS: Participants valued the collaborative and individualised approach taken by the intervention deliverers, and formed high quality relationships with them. Aspects of the intervention that were positively appraised included goal setting, social opportunities, and progress monitoring. Benefits of the intervention, including increased levels of exercise; improved diet and physical health; increased psychological wellbeing (e.g. confidence, self-esteem); and improved social relationships, were identified by participants, independent of actual weight loss. CONCLUSIONS: Future interventions should ensure that workers have the skills to form high quality relationships with users, and to individualise the intervention according to users' needs and preferences. Future trials that test healthy living interventions should consider supplementing physical outcome measures with wider psychosocial outcome assessments, in particular social relationship quality, psychological wellbeing, self-esteem and self-efficacy. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN22581937 . Date of registration: 27 October 2010 (retrospectively registered). PMID- 29699528 TI - FOLFOX activity in a rare case of metastatic colonic adenocarcinoma of the tongue: a case report. AB - BACKGROUND: Adenocarcinomas of the oral cavity are rare neoplasms, and only four cases of primary colonic adenocarcinoma of the tongue have ever been described in literature. Very few information about chemotherapy sensitiveness of this type of neoplasia is available, with only one regimen that showed some activity in a metastatic patient. CASE PRESENTATION: We describe the case of a patient bearing a metastatic colonic adenocarcinoma of the tongue submitted to a first-line chemotherapy with oxaliplatin, 5-fluorouracil and folinic acid (FOLFOX regimen). After chemotherapy the patient obtained the complete disappearance of the primitive neoplasia located in the body of the tongue, and a tumor size reduction > 50% of liver and lung metastases. CONCLUSIONS: This case demonstrated the activity of the combination of oxaliplatin and 5-fluorouracil in this very rare neoplasia. The FOLFOX regimen might be considered either in advanced and especially in the neoadjuvant setting, when the reduction of the primary tumor is highly needed. PMID- 29699529 TI - Substance use and suicidal ideation and behaviour in low- and middle-income countries: a systematic review. AB - BACKGROUND: Understanding relationships between substance use and suicidal ideation and behaviour (SIB) has important public health implications for suicide prevention in low- and middle-income countries (LMICs), where 75% of suicides occur. This systematic review explored the associations between substance use and SIB in LMICs. METHODS: We searched five databases using a combination of keywords for substance use, SIB and LMICs to identify English-written quantitative studies published between January 2006 and February 2016. Data were extracted to provide an overview of what is known about the topic, highlight gaps in the literature, and explore the implications of current knowledge for suicide prevention. Studies included in the review were assessed for methodological quality using the Scottish Intercollegiate Guidelines Network checklist. RESULTS: Analysis of included studies (N = 108) demonstrated a consistent positive association between substance use and SIB across all substances (i.e. alcohol, tobacco, cannabis, illicit drugs, non-medical use of prescription drugs), all substance use dimensions (i.e. intoxication, use, and pathological use) and all SIB dimensions (i.e. suicidal ideation, non-fatal suicidal behaviour, and suicide). Most of the available research evidence comes from upper-middle-income countries, only 22% comes from lower-middle-income and low-income countries. Most studies focused on alcohol and tobacco, while neglecting substances such as cannabis, opioids, sedatives, stimulants, misuse of prescription medication, inhalants, and hallucinogens. Most of the studies employed a cross-sectional design, were conducted within a risk-factor paradigm, and provided little information about the potential interaction between variables. CONCLUSIONS: Public health suicide prevention policy and research in LMICs should take account of the fact that: substance use is a potentially modifiable risk factor; assessment and management of substance use is integral to the care of at-risk patients; reducing consumption and hazardous use of substances in LMICs is important for suicide prevention; and research needs to be expanded to include more theory driven research that focuses on all substance use dimensions and SIB dimensions, while employing more sophisticated statistical methods. PMID- 29699530 TI - Associations between degree and sub-dimensions of depression and metabolic syndrome (MetS) in the community: results from the Gutenberg Health Study (GHS). AB - BACKGROUND: A growing number of studies have associated metabolic syndrome (MetS) and depression, both retrospectively and prospectively. However, it has remained unclear, which degrees, or sub-dimensions of depression are related to MetS and if comorbid depression affects health care utilization. The purpose of the study was to determine the associations of a) somatic and cognitive-affective symptoms to MetS and b) depression and MetS to health care utilization. METHODS: In a population-based, representative survey of 14.499 participants we studied the associations of the two dimensions of depression with MetS and health care utilization. Depressive symptoms were assessed by the Patient Health Questionnaire (PHQ-9). RESULTS: MetS and its components were associated with the degree of depression, particularly with moderately severe/ severe depressive symptoms (PHQ-9 > = 15). There were clear positive associations of somatic affective depressive symptoms with the presence of MetS and its components. Cognitive-affective symptoms were negatively associated with MetS. At the single item level, disorders of sleep and appetite as well as exhaustion were positively, while trouble concentrating was negatively associated with MetS. Symptoms of depression were related to higher consultations of somatic and mental health care, while the presence of MetS was related to somatic health care utilization. There was an additional interaction of depressive symptoms and MetS with mental health care. CONCLUSIONS: Somatic affective symptoms of depression are positively associated, while cognitive-affective symptoms are negatively associated with MetS. PMID- 29699531 TI - Correction to: Optima nutrition: an allocative efficiency tool to reduce childhood stunting by better targeting of nutrition-related interventions. AB - It has been highlighted that the original manuscript [1] contains a typesetting error in the name of Meera Shekar. This had been incorrectly captured as Meera Shekhar in the original article which has since been updated. PMID- 29699532 TI - The impact of completing upper secondary education - a multi-state model for work, education and health in young men. AB - BACKGROUND: Completing upper secondary education is associated with higher work participation and less health-related absence from work. Although these outcomes are closely interrelated, most studies focus on single outcomes, using cross sectional designs or short follow-up periods. As such, there is limited knowledge of the long-term outcomes, and how paths for completers and non-completers unfold over time. In this paper, we use multi-state models for time-to-event data to assess the long-term effects of completing upper secondary education on employment, tertiary education, sick leave, and disability pension over twelve and a half years for young men. METHODS: Baseline covariates and twelve and a half years of follow-up data on employment, tertiary education, sick leave and disability pension were obtained from national registries for all males born in Norway between 1971 and 1976 (n =184951). The effects of completing upper secondary education (by age 23) were analysed in a multi-state framework, adjusting for both individual and family level confounders. All analyses were done separately for general studies and vocational tracks. RESULTS: Completers do better on a range of outcomes compared to non-completers, for both fields of upper secondary education, but effects of completion change over time. The largest changes are for tertiary education and work, with the probability of work increasing reciprocally to the probability of education. Vocational students are quicker to transfer to the labour market, but tend to have more unemployment, sick leave and disability, and the absolute effects of completion on these outcomes are largest for vocational tracks. However, the relative effects of completion are larger for general studies. CONCLUSION: Completing upper secondary education increases long-term work participation and lowers health-related absence for young men, but effects diminish over time. Studies that have used shorter follow-up periods could be overstating the negative effects of dropout on labour market participation. Multi-state models are well suited to analyse data on work, education and health-related absence, and can be useful in understanding the dynamic aspects of these outcomes. PMID- 29699533 TI - Process evaluation of two home-based bimanual training programs in children with unilateral cerebral palsy (the COAD-study): protocol for a mixed methods study. AB - BACKGROUND: As part of the COAD-study two home-based bimanual training programs for young children with unilateral Cerebral Palsy (uCP) have been developed, both consisting of a preparation phase and a home-based training phase. Parents are coached to use either an explicit or implicit motor learning approach while teaching bimanual activities to their child. A process evaluation of these complex interventions is crucial in order to draw accurate conclusions and provide recommendations for implementation in clinical practice and further research. The aim of the process evaluation is to systematically assess fidelity of the home-based training programs, to examine the mechanisms that contribute to their effects on child-related and parent-related outcomes, and to explore the influence of contextual factors. METHODS: A mixed methods embedded design is used that emerges from a pragmatism paradigm. The qualitative strand involves a generic qualitative approach. The process evaluation components fidelity (quality), dose delivered (completeness), dose received (exposure and satisfaction), recruitment and context will be investigated. Data collection includes registration of attendance of therapists and remedial educationalists to a course regarding the home-based training programs; a questionnaire to evaluate this course by the instructor; a report form concerning the preparation phase to be completed by the therapist; registration and video analyses of the home-based training; interviews with parents and questionnaires to be filled out by the therapist and remedial educationalist regarding the process of training; and focus groups with therapists and remedial educationalists as well as registration of drop-out rates and reasons, to evaluate the overall home-based training programs. Inductive thematic analysis will be used to analyse qualitative data. Qualitative and quantitative findings are merged through meta-inference. DISCUSSION: So far, effects of home-based training programs in paediatric rehabilitation have been studied without an extensive process evaluation. The findings of this process evaluation will have implications for clinical practice and further research regarding development and application of home-based bimanual training programs, executed by parents and aimed at improving activity performance and participation of children with uCP. PMID- 29699534 TI - High prevalence of hepatitis B infections in Burkina Faso (1996-2017): a systematic review with meta-analysis of epidemiological studies. AB - BACKGROUND: Hepatitis B virus (HBV) infection was long considered an important public health concern in Burkina Faso and still represents a major cause of liver cancer and cirrhosis in the active population. To counter the problem, a national strategic plan was developed and adopted in July 2017 to coordinate viral hepatitis elimination's efforts. However evidence to support its implementation remains scanty and scattered. The main purpose of this study was to summarize available information from per-reviewed articles published over the last two decades to accurately estimate the prevalence of HBV infection in Burkina Faso. METHODS: We conducted a systematic search with meta-analysis of scientific articles using Science-Direct, Web-of-Science, PubMed/Medline, and Google Scholar. We systematically assessed all relevant publications that measured the prevalence of hepatitis B surface antigen and which were published between 1996 and 2017. We estimated the national HBV prevalence and its 95% confident interval. We subsequently adjusted the meta-analysis to possible sources of heterogeneity. RESULTS: We retrieved and analyzed a total of 22 full text papers including 99,672 participants. The overall prevalence was 11.21%. The prevalence after adjustment were 9.41%, 11.11%, 11.73% and 12.61% in the general population, pregnant women, blood donors and HIV-positive persons respectively. The prevalence was higher before implementation of HBV universal vaccination and decreased from 12.80% between 1996 and 2001 to 11.11% between 2012 and 2017. The prevalence was also higher in rural area 17.35% than urban area 11.11%. The western regions were more affected with 12.69% than the central regions 10.57%. The prevalence was 14.66% in the boucle of Mouhoun region and 14.59 in the center west region. Aggregate data were not available for the other regions. CONCLUSIONS: HBV has clearly an important burden in Burkina Faso as described by its high prevalence and this problem significantly challenges the national health care system. There is an urgent need for effective public health interventions to eliminate the problem. However, higher quality data are needed to produce reliable epidemiological estimates that will guide control efforts towards the achievement of the national strategic plan's goals. PMID- 29699535 TI - Factors associated with unmet need for contraception in Mexico: evidence from the National Survey of Demographic Dynamics 2014. AB - BACKGROUND: Worldwide, the importance of contraception to control fertility has been recognized. A useful indicator of the gap between reproductive preferences and the provision of contraception is "unmet need for contraception". The aims of this paper are to estimate the levels of unmet need for contraception among married and single women, and to explore factors associated with unmet need for contraception for spacing and limiting births in Mexico. METHODS: We used the Mexican National Survey of Demographic Dynamics 2014, using a sub-sample of 56,797 sexually active women aged 15-49 years who were either currently in union or who had never been in union to estimate the prevalence of unmet need for spacing and limiting births. We applied multivariable binary logistic regressions to examine the relationship between unmet need for spacing and limiting considering associated factors. RESULTS: Unmet need for contraception was estimated at 11.5% among women in union (6.4% limiting; 5.1% spacing), and 28.9% for women never in union (8% limiting; 20.9% spacing). In the logistic regression for unmet need for spacing, the likelihood was statistically significant associated with younger women (OR = 6.8; CI = 2.95-15.48); women never in union (OR = 1.6; CI = 1.40-1.79); low levels of education (OR = 1.4; CI = 1.26-1.56); and residing in poor regions (OR = 1.9; CI = 1.52-2.49). Those with full access to public services were significantly less likely to have unmet need for spacing (OR = 0.8; CI = 0.66-0.88). In the logistic regression for unmet need for limiting, being younger (OR = 6.3; CI = 4.73-8.27), never in union and sexually active (OR = 3.0; CI = 2.47-3.54); with less schooling (OR 1.13; CI: 1.02-1.26); rural residence (OR = 1.2; CI = 1.07-1.32); and residing in poor regions (OR = 1.5; CI = 1.23-1.93) were factors positively associated with this unmet need. Women with private health services were the least likely to have unmet need for limiting (OR = 0.5; CI = 0.37-0.77). CONCLUSIONS: Younger women currently in union and never in union had the highest unmet needs of contraception for spacing and limiting. The results from this study suggest that in Mexico family planning services must prioritize the contraception needs of all young women, both in union and not in union, with appropriate and suitable services to cover their needs. PMID- 29699536 TI - Prevalence and associated factors of dysmenorrhea among secondary and preparatory school students in Debremarkos town, North-West Ethiopia. AB - BACKGROUND: Dysmenorrhea is one of the most common gynecologic disorders and a frequently observed cause of anxiety and discomfort among female adolescents. Its prevalence varies between 16% and 91% in women of reproductive age. Its population statistics are too scant in Ethiopia. This study was aimed to determine the prevalence and associated factors of dysmenorrhea among secondary and preparatory school students in Debremarkos town, 2016. METHODS: Institutional based cross-sectional study was employed from Sept.26 to Oct.17, 2016 among secondary and preparatory school students in Debremarkos town. Self-administered questionnaire was used to collect data from 539 individuals selected by simple random sampling technique. Data were checked, coded and entered into Epi-data version 3.1 and exported to SPSS version 20 for analysis. Univariate, bivariate and multivariable analysis were carried out. Binary logistic regression model was computed and P value < 0.05 was considered as significant. All ethical procedures were considered. RESULTS: The prevalence of dysmenorrhea was 69.3%. Age, AOR (95% CI) =1.38(1.15, 1.65), family history of dysmenorrhea, AOR (95% CI) = 9.79(4.99, 19.20), physical activity, AOR (95% CI) =0.39(0.13, 0.82), sugar intake, AOR (95% CI) =2.94 (1.54, 5.61), early menarche AOR (95% CI) =4.10(1.21,13.09), late menarche AOR (95% CI) =0.50 (0.27, 0.91), heavy menstrual periods AOR (95% CI) =2.91(1.59, 5.35) and sexual intercourse AOR (95% CI) =0.24 (0.10.0.55) had statistically significant association with the occurrence of dysmenorrhea. CONCLUSIONS: Age, positive family history of dysmenorrhea, physical activity, excessive sugar intake, early menarche, late menarche, sexual intercourse and heavy menstrual periods had a statistically significant association with the occurrence of dysmenorrhea. PMID- 29699537 TI - Performance of centralized versus decentralized tuberculosis treatment services in Southern Brazil, 2006-2015. AB - BACKGROUND: Tuberculosis (TB) control programs face the challenges of decreasing incidence, mortality rates, and drug resistance while increasing treatment adherence. The Brazilian TB control program recommended the decentralization of patient care as a strategy for combating the disease. This study evaluated the performance of this policy in an area with high default rates, comparing epidemiological and operational indicators between two similar municipalities. METHODS: This study analyzed epidemiological and operational indicators on new cases of pulmonary tuberculosis reported in the Brazilian Notifiable Diseases Information System between 2006 and 2015. In addition, to characterize differences between the populations of the two studied municipalities, a prospective cohort study was conducted between 2014 and 2015, in which patients with new cases of culture-confirmed pulmonary tuberculosis were interviewed and monitored until the disease outcome. A descriptive analysis, the chi-square test, and a Poisson regression model were employed to compare TB treatment outcomes and health care indicators between the municipalities. RESULTS: Two thousand three hundred nine cases were evaluated, of which 207 patients were interviewed. Over the 2006-2015 period, TB incidence per 100,000 population in the municipality with decentralized care was significantly higher (39%, 95% CI 27-49%) in comparison to that of the municipality with centralized care. TB treatment default rate (45%, 95% CI 12-90%) was also higher in the municipality with decentralized care. During the two-year follow-up, significant differences were found between patients in centralized care and those in decentralized care regarding treatment success (84.5 vs. 66.1%), treatment default (10.7 vs. 25.8%), illicit drug use (27.7 vs. 45.9%), and homelessness (3.6 vs. 12.9%). The operational indicators revealed that the proportion of control smear tests, medical imaging, and HIV tests were all significantly higher in the centralized care. However, a significantly higher proportion of patients started treatment in the early stages of the disease in the municipality with decentralized care. CONCLUSIONS: These data showed a low success rate in TB treatment in both municipalities. Decentralization of TB care, alone, did not improve the main epidemiological and operational indicators related to disease control when compared to centralized care. Full implementation of strategies already recommended is needed to improve TB treatment success rates. PMID- 29699538 TI - Impact of infection prevention and control training on health facilities during the Ebola virus disease outbreak in Guinea. AB - BACKGROUND: In 2014-2016, West Africa faced the most deadly Ebola Virus Disease (EVD) outbreak in history. A key strategy to overcome this outbreak was continual staff training in Infection Prevention and Control (IPC), with a focus on Ebola. This research aimed to evaluate the impact of IPC training and the quality of IPC performance in health care facilities of one municipality of Conakry, Guinea. METHODS: This study was conducted in February 2016. All health facilities within Ratoma municipality, Conakry, Guinea, were evaluated based on IPC performance standards developed by the Guinean Ministry of Health. The IPC performance of healthcare facilities was categorised into high or low IPC scores based on the median IPC score of the sample. The Mantel-Haenzsel method and logistic regression were used for statistical analysis. RESULTS: Twenty-five percent of health centres had one IPC-trained worker, 53% had at least two IPC-trained workers, and 22% of health centres had no IPC-trained workers. An IPC score above median was positively associated with the number of trained staff; health centres with two or more IPC-trained workers were eight times as likely to have an IPC score above median, while those with one IPC-trained worker were four times as likely, compared to centres with no trained workers. Health centres that implemented IPC cascade training to untrained medical staff were five times as likely to have an IPC score above median. CONCLUSIONS: This research highlights the importance of training healthcare staff in IPC and organising regular cascade trainings. IPC strategies implemented during the outbreak should continue to be reinforced for the better health of patients and medical staff, and be considered a key factor in any outbreak response. PMID- 29699539 TI - Collection of social determinants of health in the community clinic setting: a cross-sectional study. AB - BACKGROUND: Addressing social and behavioral determinants of health (SBDs) may help improve health outcomes of community clinic patients. This cross-sectional study explored how assessing SBDs can be used to complement health data collection strategies and provide clinicians with a more in-depth understanding of their patients. METHODS: Adult patients, ages 18 and older, at an urban community health care clinic in Tennessee, U.S.A., were asked to complete a questionnaire regarding health status, health history and SBDs while waiting for their clinic appointment. The SBD component included items from the National Academy of Medicine, the Protocol for Responding to and Assessing Patient Assets, Risks, and Experiences instrument, and the Survey of Household Economics and Decisionmaking. Data collection and analysis occurred in 2017. RESULTS: One hundred participants completed the study. The questionnaire took approximately 11 min to complete, and the response rate was 90% or higher for all items except annual household income (unanswered by 40 participants). The median number of negative SBDs was 4 (IQR 2.75-7.0), 96 participants had at least one unmet need, and the most common negative SBD was physical activity (75%; 75/100). CONCLUSIONS: The hybrid questionnaire provided insight into a community clinic population's SBDs and allowed for a more complete understanding than a single questionnaire alone. The brief questionnaire administration time and low non response rate support the questionnaire's feasibility in the community clinic setting, and results can be used by clinicians to further the personalization goals of precision medicine. Next steps include evaluating how to connect patients with appropriate resources for addressing their SBDs. PMID- 29699540 TI - Insomnia and risk of chronic musculoskeletal complaints: longitudinal data from the HUNT study, Norway. AB - BACKGROUND: The aim of this study was to investigate the prospective association between insomnia and risk of chronic musculoskeletal complaints (CMSC) and chronic widespread musculoskeletal complaints (CWMSC). A second aim was to evaluate the association between insomnia and number of body regions with CMSC at follow-up. METHODS: We used data from the second (HUNT2, 1995-1997) and third (HUNT3, 2006-2008) wave of the Nord-Trondelag Health Study (the HUNT Study). The population-at-risk included 13,429 people aged 20-70 years who reported no CMSC at baseline in HUNT2 and who answered the questionnaires on insomnia in HUNT2 and CMSC in HUNT3. Insomnia was defined according to the 4th edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) with minor modification, whereas CMSC was assessed for nine different body regions. CWMSC was defined according to the 1990 criteria by the American College of Rheumatology. We used Poisson regression to estimate adjusted risk ratios (RRs) for CMSC and CWMSC at 11 years follow-up. Precision of the estimates was assessed by a 95% confidence interval (CIs). RESULTS: Insomnia at baseline was associated with increased risk of any CMSC (RR 1.16, 95% CI 1.03-1.32) and CWMSC (RR 1.58, 95% CI 1.26-1.98) at follow-up. RR for CMSC for specific body regions ranged from 1.34 (95% CI 1.05-1.73) for the knees and 1.34 (1.10-1.63) for the neck to 1.60 (95% CI 1.19-2.14) for the ankles/ft. Further, insomnia was associated with increased risk of CMSC in 3-4 regions (RR 1.36, 95% CI 1.05-1.77), and 5 or more regions (RR 1.93, 95% CI 1.40-2.66), but not 1-2 regions (RR 0.99, 95% CI 0.80 1.24). CONCLUSIONS: Insomnia is associated with increased risk of CMSC, CWMSC, and CMSC located in 3 or more body regions. PMID- 29699541 TI - Factors associated with asthma control: MOSAR study (Multicenter Observational Study of Asthma in Rabat-Morocco). AB - BACKGROUND: The purpose of the study is to describe the profile of patients with asthma and to identify the signifiant risks and the protective factors associated with asthma control. METHODS: A prospective epidemiological study was conducted in three hospitals of Rabat-Morocco and included 396 patients with asthma. Differences in characteristics across the levels of asthma control were compared by the one-way analysis of variance for continuous variables, and chi-square test was used for categorical variables. The risk and protective factors associated with the asthma control levels were determined by Proportional Odds Model (POM) for bivariate and multivariate ordinal logistic regression, also expressed as Odds Ratios (OR) and 95% Confidence Intervals (95% CI). RESULTS: From 7440 patients screened by 28 physicians, 396 were included in study. 53% of the particiants sufferd controlled, 18% had partly controlled and 29% had uncontrolled asthma symptoms. A multivariate ordinal logistic regression analysis showed that having respiratory infections (AOR = 5.71), suffering from concomitant diseases (AOR = 3.36) and being allergic to animals (AOR = 2.76) were positively associated with poor control of asthma. However, adherence to treatement (AOR = 0.07), possession of health insurance (AOR = 0.41) and having more than 2 children (AOR = 0.47) were associated with good asthma control. CONCLUSION: The study established a clinical-epidemiological profile of asthmatic patients in Rabat region in Morocco. By ordinal logistic regression we found that 6 factors - respiratory infections, concomitant diseases, animals allergy, adherence to treatment, health insurance and having more than two children - were associated with asthma control. PMID- 29699542 TI - Improved heart hemodynamics after draining large-volume pleural effusion: a prospective cohort study. AB - BACKGROUND: Pleural effusion (PE) drainage can relieve the symptoms of dyspnea; however, details of the resulting hemodynamic changes remain undefined. METHODS: Subjects older than 12 years with massive PE requiring pleural drainage were included in this study. Hemodynamic parameters were collected using transthoracic echocardiography at pre-drainage, immediately post-drainage, and 24 h after drainage. RESULTS: We enrolled 47subjects in this prospective study from June 9, 2015 to September 18, 2016 in Beijing Chaoyang Hospital and 28 subjects were analyzed finally. Draining large-volume PE led to a progressive increase in left ventricular end-diastolic volume index, left atrial volume index, right ventricular area, right atrial area, left ventricular ejection fraction, stroke volume, and tricuspid annular plane systolic excursion, both immediately (P < 0.05) and 24 h after drainage (P < 0.05). The cardiac diastolic measurement ratios of early-transmitral flow velocity to diastolic mitral annular velocity and myocardial performance index decreased significantly following drainage (P < 0.05). More parameters were influenced by left-sided PE drainage. The correlation between effusion volume and changes in echocardiographic measurements was not statistically significant. CONCLUSIONS: Improved preload, and systolic and diastolic function is pivotal for hemodynamic change after draining large PE volumes. Subjects experienced improved cardiac hemodynamics following PE drainage, underlining the beneficial therapeutic and subjective effects. PMID- 29699543 TI - What predicts emotional response in men awaiting prostate biopsy? AB - BACKGROUND: Incidence of prostate cancer is increasing as opportunistic screening becomes widespread and life expectancy rises. Despite screening availability, research reveals conflicting results on medical outcomes, for example, disease specific mortality. However the gold standard in early diagnosis of potentially curable organ confined prostate cancer is transrectal ultrasound-guided systematic prostate biopsy (TRUS-BX). While focus has been given to medical sequalae there is a paucity of research on the psychological impact of biopsy. Awaiting biopsy may be inherently stressful but no studies to date, have assessed men's perception of stress and its impact on emotional response. This study, therefore, examines the role of stress and also personal resources namely, self efficacy and sense of coherence in emotional adjustment in men awaiting a prostate biopsy. METHODS: Men attending a Rapid Access Prostate Cancer Clinic for a transrectal prostate biopsy (N = 114) participated in the study. They completed self report questionnaires on perceived stress (PSS), generalised self-efficacy (GSES), and sense of coherence (SOC). Adjustment was measured by the Profile of Mood States (POMS-B) which assesses tension, depression, anger, fatigue, confusion and vigour. RESULTS: Hierarchical regression analyses demonstrated that the set of predictors accounted for 17%-34% of variance across six mood states and predicted 46% of total mood disturbance. Perceived stress explained variance on all domains (11%-26%) with high stress linked to poor functioning. CONCLUSION: Perceived stress was the strongest and most consistent predictor of emotional adjustment. This is an important finding as stress appraisal has not been examined previously in this context and suggests that stress management is an important target to enhance emotional wellbeing of men attending for a prostate biopsy. PMID- 29699544 TI - Longitudinal association between change in the neighbourhood built environment and the wellbeing of local residents in deprived areas: an observational study. AB - BACKGROUND: Features of the urban neighbourhood influence the physical, social and mental wellbeing of residents and communities. We explored the longitudinal association between change to the neighbourhood built environment and the wellbeing of local residents in deprived areas of Glasgow, Scotland. METHODS: A cohort of residents (n = 365; mean age 50 years; 44% male; 4.1% of the 9000 mailed surveys at baseline) responded to a postal survey in 2005 and 2013. Wellbeing was assessed with the mental (MCS-8) and physical (PCS-8) components of the SF-8 scale. We developed software to aid identification of visible changes in satellite imagery occurring over time. We then used a Geographical Information System to calculate the percentage change in the built environment occurring within an 800 m buffer of each participant's home. RESULTS: The median change in the neighbourhood built environment was 3% (interquartile range 6%). In the whole sample, physical wellbeing declined by 1.5 units on average, and mental wellbeing increased by 0.9 units, over time. In multivariable linear regression analyses, participants living in neighbourhoods with a greater amount of change in the built environment (unit change = 1%) experienced significantly reduced physical (PCS-8: -0.13, 95% CI -0.26 to 0.00) and mental (MCS-8: -0.16, 95% CI -0.31 to - 0.02) wellbeing over time compared to those living in neighbourhoods with less change. For mental wellbeing, a significant interaction by baseline perception of financial strain indicated a larger reduction in those experiencing greater financial strain (MCS-8: -0.22, 95% CI -0.39 to - 0.06). However, this relationship was reversed in those experiencing lower financial strain, whereby living in neighbourhoods with a greater amount of change was associated with significantly improved mental wellbeing over time (MCS-8: 0.38, 95% CI 0.04 to 0.72). CONCLUSIONS: Overall, we found some evidence that living in neighbourhoods experiencing higher levels of physical change worsened wellbeing in local residents. However, we found a stronger negative relationship in those with lower financial security and a positive relationship in those with higher financial security. This is one of few studies exploring the longitudinal relationship between the environment and health. PMID- 29699545 TI - Inequalities in oral health among adolescents in Gangneung, South Korea. AB - BACKGROUND: This study aims to evaluate inequality in oral health among adolescents and to explain the mechanisms of such inequalities in Gangneung, South Korea. METHODS: One thousand two hundred sixty-seven students in their first year from four vocational and three general schools participated in the baseline survey of 2011, and 84.7% of them were surveyed again in 2013. Oral examinations by the same dentist and a self-administered questionnaire were repeated during both waves. Outcome measure for oral health was the existence of untreated dental caries (DT). As socioeconomic position (SEP) indicators, school type (general vs. vocational), father's and mother's education, perceived economic status, and Family Affluence Scale (FAS) were measured. Variables measuring oral health related behaviours included tooth brushing frequency, frequency of eating snacks and drinking sodas, smoking, and annual visits to dental clinics. Chi-square tests and panel logistic regression were adopted to examine the associations between dental caries and SEP indicators by STATA version 15.1. RESULTS: Having a less educated father and attending a vocational school were significant predictors for untreated caries after controlling for SEP indicators. However, students from general schools, higher SEP by father's education, perceived economic status, or FAS, or having non-smoking experience or annual visits to dental clinics were more likely to stay caries-free. CONCLUSIONS: There were socioeconomic inequalities in oral health on an adolescent panel. Given that oral health status during adolescents can persist throughout the course of a person's life, intervention to tackle such inequalities and school environments are required. PMID- 29699547 TI - Managers' experience of success criteria and barriers to implementing mobile radiography services in nursing homes in Norway: a qualitative study. AB - BACKGROUND: In order to meet the future challenges posed by ageing populations, new technology, telemedicine and a more personalized healthcare system are needed. Earlier research has shown mobile radiography services to be highly beneficial for nursing home residents in addition to being cost-effective. Despite the benefits, mobile radiography services are uncommon in Europe and Norway. The purpose of this study was to explore success criteria and barriers in the process of implementing mobile radiography services, from the point of view of the hospital and municipal managers. METHODS: Eleven semi-structured interviews were conducted with managers from five hospitals and six municipalities in Norway where mobile radiography services had been implemented. Core issues in the interview guide were barriers and facilitators in the different phases of implementation. The framework method for thematic analysis was used for analysing the data inductively in a research team. RESULTS: Five main categories were developed through the success criteria and barriers experienced by the participants: national health policy, regional and municipal policy and conditions, inter-organizational implementation projects, experienced outcome, and professional skills and personal characteristics. The categories were allocated into three higher-order classifications: macro, meso and micro levels. The main barriers experienced by the managers were financial, procedural and structural. In particular, the reimbursement system, lack of management across healthcare levels and the lack of compatible information systems acted as barriers. The main facilitators were external funding, enthusiastic individuals in the organizations and good collaboration between hospitals and municipalities. CONCLUSIONS: The managers experienced financial, structural and procedural barriers. The main success criteria in the process were external funding, and the support and engagement from the individuals in the organizations. This commitment was mainly facilitated by the intuitive appeal of mobile radiography. Changes in healthcare management and in the financial system might facilitate services across healthcare levels. In addition, compatible information systems across healthcare levels are needed in order to facilitate the use of new technology and mobile services. PMID- 29699546 TI - Elevated urinary excretion of free pyridinoline in Friesian horses suggests a breed-specific increase in collagen degradation. AB - BACKGROUND: Friesian horses are known for their high inbreeding rate resulting in several genetic diseases such as hydrocephaly and dwarfism. This last decade, several studies focused on two other presumed hereditary traits in Friesian horses: megaoesophagus and aortic rupture. The pathogenesis of these diseases remains obscure but an important role of collagen has been hypothesized. The purpose of this study was to examine possible breed-related differences in collagen catabolism. Urinary specimens from Friesian (n = 17, median age 10 years old) and Warmblood horses (n = 17, median age 10 years old) were assessed for mature collagen cross-links, i.e. pyridinoline (PYD) (=hydroxylysylpyridinoline/HP) and deoxypyridinoline (DPD) (lysylpyridinoline /LP). Solid-phase extraction was performed, followed by reversed-phase ion-paired liquid chromatography prior to tandem mass spectrometry (MS/MS) detection. RESULTS: Mean urinary concentrations of free PYD, expressed as fPYD/creatinine ratio, were significantly higher in Friesian horses compared to Warmblood horses (28.5 +/- 5.2 versus 22.2 +/- 9.6 nmol/mmol, p = 0.02) while mean fDPD/creatinine ratios were similar in both horse breeds (3.0 +/- 0.7 versus 4.6 +/- 3.7 nmol/mmol, p = 0.09). CONCLUSIONS: Since DPD is considered a specific bone degradation marker and PYD is more widely distributed in connective tissues, the significant elevation in the mean PYD/DPD ratio in Friesian versus Warmblood horses (9.6 +/- 1.6 versus 5.7 +/- 1.8, p < 0.0001) suggests a soft tissue origin for the increased fPYD levels. Considering that a previous study found no differences in total collagen content between Friesian and Warmblood horses for tendon and aortic tissue, this indicates a higher rate of collagen degradation. The latter might, at least in part, explain the predisposition of Friesians to connective tissue disorders. PMID- 29699548 TI - Unfulfilled need for contraception among women with unmet need but with the intention to use contraception in Rakai, Uganda: a longitudinal study. AB - BACKGROUND: Longitudinal data from a rural Ugandan cohort was used to estimate rates of unfulfilled need for contraception, defined as having unmet need and intent to use contraception at baseline but having an unintended pregnancy or with persistent unmet need for contraception at follow up. METHODS: Between 2002 and 2009 (5 survey rounds), a total of 2610 sexually active non-pregnant women with unmet need for contraception at the start of an inter-survey period were asked whether they intended to use any method of contraception until they desired a child. Modified Poisson multivariate regression was used to estimate unadjusted and adjusted prevalence ratios (PR) and 95% CI of unfulfilled need for contraception. RESULTS: The proportion of women with unmet need at the start of an interval who intended to use contraception significantly increased from 61 to 69.1% (p < 0.05). However the majority of women who said they intended to use contraception had unfulfilled need for contraception at the subsequent survey (64.8 to 56.8%). In the adjusted analysis, significant predictors of unfulfilled need for contraception included age 40-49 years (PR = 1.34; 95% CI 1.04-1.74) and those with unknown HIV status (PR = 1.16; 95% CI 1.06-1.26). CONCLUSIONS: There is a significant discrepancy between women's intent to use contraception (> 60%) and subsequent initiation of use (< 30%) with many having unintended pregnancies which might explain the persistent high fertility in Uganda. Future research needs to address unfulfilled need for contraception among women at risk of unintended pregnancies. PMID- 29699549 TI - Evaluation of human-papillomavirus testing and visual inspection for cervical cancer screening in Rwanda. AB - BACKGROUND: A pilot screening campaign in Rwanda, based on careHPV-testing followed by visual inspection with acetic acid triage (careHPV+VIA triage), was evaluated against other WHO-recommended screening options, namely HPV screen-and treat and VIA screen-and-treat. METHODS: 764 women aged 30-69 underwent at visit 1: i) VIA, and cervical cell collection for ii) careHPV in Rwanda, and iii) liquid-based cytology and GP5+/6+ HR-HPV PCR in The Netherlands. All 177 women positive by VIA, careHPV and/or PCR were recalled, of whom 84% attended. At visit 2, VIA was again used to triage screen-positive women for treatment and to obtain biopsies from all women either from visible lesions or at 12 o'clock of the squamocolumnar junction. Cross-sectional screening indices were estimated primarily against histological high-grade squamous intraepithelial lesions or worse (hHSIL+), after imputation of missing histology data, based on 1-visit or 2 visit approaches. RESULTS: In a 1-visit screen-and-treat approach, VIA had sensitivity and specificity of 41% and 96%, respectively, versus 71% and 88% for careHPV, and 88% and 86% for PCR. In a 2-visit approach (in which hHSIL+ imputed among women without visit 2 were considered untreated) careHPV sensitivity dropped to 59% due to loss of 13% of hHSIL+. For careHPV+VIA triage, sensitivity dropped further to 35%, as another 24% of hHSIL+ were triaged to no treatment. CONCLUSIONS: CareHPV was not as sensitive as gold-standard PCR, but detected considerably more hHSIL+ than VIA. However, due to careHPV-positive hHSIL+ women being lost to follow-up and/or triaged to no treatment, 2-visit careHPV+VIA triage did not perform better than VIA screen-and-treat. PMID- 29699551 TI - Carlsberg alibi marketing in the UEFA euro 2016 football finals: implications of Probably inappropriate alcohol advertising. AB - BACKGROUND: Alcohol advertising is a key driver of alcohol consumption, and is prohibited in France by the Loi Evin. In 2016 the Danish brewer Carlsberg sponsored the UEFA Euro 2016 finals, held in France, and used the alibis 'Probably' and '...the best in the world' in place of Carlsberg in pitch-side advertising. We have quantified the advertising exposure achieved during the final seven games in the UEFA Euro 2016 championship. METHODS: Appearances of the Carlsberg alibis 'Probably' and 'the best in the world' were counted and timed to the nearest second during all active play in live coverage of quarter final, semi final and final matches broadcast in the UK. We used census data and viewing figures from Kantar Media to estimate gross and per capita impressions of these advertisements in the UK population. RESULTS: In 796 min, 29 s of active play there were 746 alibi appearances, totalling 68 min 35 s duration and representing 8.6% of active playing time. Appearances were particularly frequent at the end of normal time, extra time and penalties. The seven matches delivered up to 7.43 billion Carlsberg alibi impressions to UK adults and 163.3 million to children. In the only match involving a second country with laws prohibiting alcohol advertising (France versus Iceland), exposure occurred for only 1.8% of playing time. CONCLUSIONS: Alibi marketing achieved significant advertising coverage during the final seven EURO 2016 championship games, particularly to children. Since 'Probably' is registered by Carlsberg as a wordmark this advertising appears to contravene the Loi Evin, though Carlsberg have defended their marketing actions. PMID- 29699550 TI - Evaluating clinical effectiveness of 13-valent pneumococcal conjugate vaccination against pneumonia among middle-aged and older adults in Catalonia: results from the EPIVAC cohort study. AB - BACKGROUND: Benefits using the 13-valent pneumococcal conjugate vaccine (PCV13) in adults are controversial. This study investigated clinical effectiveness of PCV13 vaccination in preventing hospitalisation from pneumonia among middle-aged and older adults. METHODS: Population-based cohort study involving 2,025,730 individuals >=50 years in Catalonia, Spain, who were prospectively followed from 01/01/2015 to 31/12/2015. Primary outcomes were hospitalisation for pneumococcal or all-cause pneumonia and death from any cause. Cox regression models were used to evaluate the association between PCV13 vaccination and the risk of each outcome, adjusting for age, sex and major comorbidities/underlying risk conditions. RESULTS: Cohort members were observed for a total of 1,990,701 person years, of which 6912 person-years were PCV13 vaccinated. Overall, crude incidence rates (per 100,000 person-years) were 82.8 (95% confidence interval [CI]: 77.7 88.1) for pneumococcal pneumonia, 637.9 (95% CI: 599.0-678.7) for all-cause pneumonia and 2367.2 (95% CI: 2222.8-2518.7) for all-cause death. After multivariable adjustments we found that the PCV13 vaccination did not alter significantly the risk of pneumococcal pneumonia (multivariable-adjusted hazard ratio [mHR]: 1.17; 95% CI: 0.75-1.83; p = 0.493) and all-cause death (mHR: 1.07; 95% CI: 0.97-1.18; p = 0.190), although it remained significantly associated with an increased risk of all-cause pneumonia (mHR: 1.69; 95% CI: 1.48-1.94; p < 0.001). In stratified analyses focused on middle-aged or elderly persons and immunocompromised or immunocompetent subjects, PCV13 vaccination did not appear effective either. CONCLUSION: Our data does not support clinical benefits of PCV13 vaccination against pneumonia among adults in Catalonia. It must be closely monitored in future studies involving more vaccinated person-time at-observation. PMID- 29699552 TI - Rationing elective surgery for smokers and obese patients: responsibility or prognosis? AB - BACKGROUND: In the United Kingdom (UK), a number of National Health Service (NHS) Clinical Commissioning Groups (CCG) have proposed controversial measures to restrict elective surgery for patients who either smoke or are obese. Whilst the nature of these measures varies between NHS authorities, typically, patients above a certain Body Mass Index (BMI) and smokers are required to lose weight and quit smoking prior to being considered eligible for elective surgery. Patients will be supported and monitored throughout this mandatory period to ensure their clinical needs are appropriately met. Controversy regarding such measures has primarily centred on the perceived unfairness of targeting certain health states and lifestyle choices to save public money. Concerns have also been raised in response to rhetoric from certain NHS authorities, which may be taken to imply that such measures punitively hold people responsible for behaviours affecting their health states, or simply for being in a particular health state. MAIN BODY: In this paper, we examine the various elective surgery rationing measures presented by NHS authorities. We argue that, where obesity and smoking have significant implications for elective surgical outcomes, bearing on effectiveness, the rationing of this surgery can be justified on prognostic grounds. It is permissible to aim to maximise the benefit provided by limited resources, especially for interventions that are not urgently required. However, we identify gaps in the empirical evidence needed to conclusively demonstrate these prognostic grounds, particularly for obese patients. Furthermore, we argue that appeals to personal responsibility, both in the prospective and retrospective sense, are insufficient in justifying this particular policy. CONCLUSION: Given the strength of an alternative justification grounded in clinical effectiveness, rhetoric from NHS authorities should avoid explicit statements, which suggest that personal responsibility is the key justificatory basis of proposed rationing measures. PMID- 29699553 TI - Assessment of oral health and cost of care for a group of refugees in Germany: a cross-sectional study. AB - BACKGROUND: There is a research gap concerning the evaluation of the oral healthcare of refugees. Therefore, the aim of this study was to evaluate the oral health of refugees and to estimate the costs of oral care. METHODS: The study was conceptualized as a pilot study. The study participants were refugees who lived either in collective living quarters or at a reception center in a region of the federal state of Schleswig-Holstein, Germany. The cross-sectional design was complemented by dental screening. Data were collected from August 2016 until July 2017. The basic condition of the teeth was evaluated using a convenience sample by a single dentist. The assessment of caries was carried out visually in accordance with the International Caries Detection and Assessment System from code 3 and higher. The DMF-T (decayed, (D), missing, (M), filled (F), teeth (T)) index was calculated. The costs of oral care were analyzed for conservative treatment (filling or extraction) and for prosthetic treatment (missing teeth) in the form of a bridge or crown. RESULTS: The dental screening was attended by 102 refugees, with a mean age of 28 years. A total of 49% of the study sample suffered from toothache, and the DMF-T index had a mean of 6.89. For 92% of the study sample, treatment was indicated, and a cost estimate of the treatment could be calculated. The average cost of conservative treatment was estimated to be 205.86 EUR, and the average cost of prosthetic treatment was estimated to be 588.0 EUR. The oral healthcare costs of the different treatment procedures were higher for refugees that presented with toothache than for those without toothache, with the exception of prosthetic treatment procedures. CONCLUSIONS: There is a lack of population-based data that survey the oral health status of refugees. Therefore, the current study presents an initial overview regarding the oral health status and the potential costs of oral healthcare of refugees. PMID- 29699554 TI - Would changing the selection process for GP trainees stem the workforce crisis? A cohort study using multiple-imputation and simulation. AB - BACKGROUND: There is currently a shortage of qualified GPs in the UK and not all of the training posts available each year are filled. Changing the way in which GP trainees are selected could help increase the training post fill rate and the number of new entrants to the GP Register. The aim of this study was to model the impact of changing the selection process for GP training on the number of trainees obtaining GP Registration, either with or without extensions. METHOD: This was a cohort study using UK applications for GP training in 2011-14. Application data were linked using GMC numbers to training outcome data where available, and imputed using multiple imputation where missing. The number of trainees appointed and GP Registrations within three and five years' full-time equivalent were estimated for four different selection processes. RESULTS: The cut scores used in the actual 2015 selection process makes it impossible to fill all training posts. Random selection is the worst option, but the difference between this and other processes modelled falls as more trainees are selected. There are large marginal effects on outcomes: those with the highest selection scores are more likely to obtain GP Registration than those with the lowest scores. CONCLUSIONS: Changing the selection process alone would have a small impact on the number of GP Registrations; reducing/removing cut scores would have a much larger impact. This would also increase the number of trainees requiring extensions and being released from training which would have adverse consequences for the profession. PMID- 29699555 TI - Association between maternal acculturation and health beliefs related to oral health of Latino children. AB - BACKGROUND: This report is presenting the association of maternal acculturation, measured by preferred language, and oral health-related psychosocial measures in an urban Latino population. METHODS: A cross-sectional survey was conducted with 100 mother-child dyads from the Dental Center at the Children's Hospital Colorado, the University of Colorado. A portion of Basic Research Factors Questionnaire capturing information about parental dental knowledge, attitudes, behavior and psychosocial measures was used to collect data from the participating mothers. Descriptive statistics were calculated for demographics and psychosocial measures by acculturation. A univariate linear regression model was performed for each measure by preferred language for primary analysis followed by adjusted model adjusting for parent's education. RESULTS: The mean age of the children was 3.99 years (SD = 1.11), and that of the mother was 29.54 years (SD = 9.62). Dental caries, measured as dmfs, was significantly higher in children of Spanish-speaking mothers compared to children of English-speaking mothers. English-speaking mothers had higher mean scores of oral health knowledge, oral health behaviors, knowledge on dental utilization, self-efficacy, and Oral Health Locus of Control as compared to Spanish-speaking mothers. Univariate analysis demonstrated significant association for preference for Spanish language with knowledge on dental utilization, maternal self-efficacy, perceived susceptibility and perceived barriers. The effect of language was attenuated, but significant, for each of these variables after adjusting for parent's education. CONCLUSION: This study reported that higher acculturation measured by a preference for the English language had a positive association with oral health outcomes in children. Spanish-speaking mothers perceived that their children were less susceptible to caries. Additionally, they perceived barriers in visiting the dentist for preventive visits. PMID- 29699556 TI - The struggle against perceived negligence. A qualitative study of patients' experiences of adverse events in Norwegian hospitals. AB - BACKGROUND: Every year, 14 % of patients in Norwegian hospitals experience adverse events, which often have health-damaging consequences. The government, hospital management and health personnel attempt to minimize such events. Limited research on the first-hand experience of the patients affected is available. The aim of this study is to present patients' perspectives of the occurrence of, disclosure of, and healthcare organizations' responses to adverse events. Findings are discussed within a social constructivist framework and with reference to principles of open disclosure policy. METHODS: This qualitative study with an explorative descriptive design included fifteen in-depth interviews with former patients recruited by the Health and Social Services ombudsmen in the two northernmost counties of Norway. Inclusion criteria were as follows: 1) experience of adverse events in connection with surgical, orthopedic or medical treatment in general hospitals; 2) men and women; 3) aged 20-70; and 4) a minimum of one year since the event occurred. Transcribed audio-recorded interviews were analyzed through qualitative content analysis. RESULTS: The analysis revealed three main topics regarding patients' experiences of adverse events: 1) ignored concerns or signs of complications; 2) lack of responsibility and error correction; and 3) lack of support, loyalty and learning opportunities. Patients had to struggle to demonstrate the error that had occurred and to receive the necessary treatment and monitoring in the aftermath of the events. CONCLUSIONS: Patient narratives reveal a lack of openness, care and responsibility in connection with adverse events. Conflicting power structures, attitudes and established procedures may inhibit prevention, learning and patient safety work in spite of major efforts and good intentions. Attitudes in day-to-day patient care and organizational procedures should be challenged to invite patients into open disclosure processes and include them in health and safety work to a greater extent. The study's small sample of self-selected participants limits the generalizability of the findings, and future studies should include a larger number of patients as well as professional perspectives. PMID- 29699557 TI - Emotional violence and maternal mental health: a qualitative study among women in northern Vietnam. AB - BACKGROUND: Worldwide, intimate partner violence (IPV) during pregnancy is a pressing and prevalent public health problem. Existing research has found close associations between IPV and perinatal mental health, yet little is known about women's own perceptions of these associations. This study aimed to explore Vietnamese women's experiences of emotional partner violence and their perceptions of the implications of such violence for their mental health. METHODS: The data were collected through in-depth interviews with 20 women living in Hanoi, Vietnam who had reported exposure to emotional partner violence and attained high depression scores in a prospective cohort study. Ten women were pregnant and ten had recently given birth. The data were analysed by qualitative content analysis. RESULTS: The women described emotional partner violence as a major life stressor. Their accounts pointed to three particularly significant dimensions of emotional violence: being ignored by the husband; being denied support; and being exposed to controlling behaviours. These experiences affected the women's sense of wellbeing profoundly, causing sadness and distress. The women's accounts indicated that experiences of emotional violence were significantly shaped by dominant kinship arrangements: practices of patrilocal residence and principles of patrilineal descent tended to aggravate women's vulnerabilities to partner violence. CONCLUSIONS: This qualitative study from Vietnam documents close associations between emotional partner violence and perinatal distress, while also pointing to kinship arrangements as particularly significant structural contexts shaping women's experiences of partner violence. The study findings suggest that effective policies and programs to decrease women's vulnerability to intimate partner violence must take into account the kinship arrangements that prevail in a given society. PMID- 29699558 TI - Tween-20 transiently changes the surface morphology of PK-15 cells and improves PCV2 infection. AB - BACKGROUND: Low concentrations of nonionic surfactants can change the physical properties of cell membranes, and thus and in turn increase drug permeability. Porcine circovirus 2 (PCV2) is an extremely slow-growing virus, and PCV2 infection of PK-15 cells yields very low viral titers. The present study investigates the effect of various nonionic surfactants, namely, Tween-20, Tween 28, Tween-40, Tween-80, Brij-30, Brij-35, NP-40, and Triton X-100 on PCV2 infection and yield in PK-15 cells. RESULT: Significantly increased PCV2 infection was observed in cells treated with Tween-20 compared to those treated with Tween-28, Tween-40, Brij-30, Brij-35, NP-40, and Triton X-100 (p < 0.01). Furthermore, 24 h incubation with 0.03% Tween-20 has shown to induce significant cellular morphologic changes (cell membrane underwent slight intumescence and bulged into a balloon, and the number of microvilli decreased), as well as to increase caspase-3 activity and to decrease cell viability in PCV2-infected PK-15 cells cmpared to control group; all these changes were restored to normal after Tween-20 has been washed out from the plate. CONCLUSION: Our data demonstrate that Tween-20 transiently changes the surface morphology of PK-15 cells and improves PCV2 infection. The findings of the present study may be utilized in the development of a PCV2 vaccine. PMID- 29699559 TI - 'Screening audit' as a quality assurance tool in good clinical practice compliant research environments. AB - BACKGROUND: With the growing amount of clinical research, regulations and research ethics are becoming more stringent. This trend introduces a need for quality assurance measures for ensuring adherence to research ethics and human research protection beyond Institutional Review Board approval. Audits, one of the most effective tools for assessing quality assurance, are measures used to evaluate Good Clinical Practice (GCP) and protocol compliance in clinical research. However, they are laborious, time consuming, and require expertise. Therefore, we developed a simple auditing process (a screening audit) and evaluated its feasibility and effectiveness. METHODS: The screening audit was developed using a routine audit checklist based on the Severance Hospital's Human Research Protection Program policies and procedures. The measure includes 20 questions, and results are summarized in five categories of audit findings. We analyzed 462 studies that were reviewed by the Severance Hospital Human Research Protection Center between 2013 and 2017. We retrospectively analyzed research characteristics, reply rate, audit findings, associated factors and post screening audit compliance, etc. RESULTS: Investigator reply rates gradually increased, except for the first year (73% -> 26% -> 53% -> 49% -> 55%). The studies were graded as "critical," "major," "minor," and "not a finding" (11.9, 39.0, 42.9, and 6.3%, respectively), based on findings and number of deficiencies. The auditors' decisions showed fair agreement with weighted kappa values of 0.316, 0.339, and 0.373. Low-risk level studies, single center studies, and non-phase clinical research showed more prevalent frequencies of being "major" or "critical" (p = 0.002, < 0.0001, < 0.0001, respectively). Inappropriateness of documents, failure to obtain informed consent, inappropriateness of informed consent process, and failure to protect participants' personal information were associated with higher audit grade (p < 0.0001, p = 0.0001, p < 0.0001, p = 0.003). We were able to observe critical GCP violations in the routine internal audit results of post-screening audit compliance checks in "non-responding" and "critical" studies upon applying the screening audit. CONCLUSIONS: Our screening audit is a simple and effective way to assess overall GCP compliance by institutions and to ensure medical ethics. The tool also provides useful selection criteria for conducting routine audits. PMID- 29699560 TI - Alcohol exposure decreases osteopontin expression during fracture healing and osteopontin-mediated mesenchymal stem cell migration in vitro. AB - BACKGROUND: Alcohol consumption is a risk factor for impaired fracture healing, though the mechanism(s) by which this occurs are not well understood. Our laboratory has previously shown that episodic alcohol exposure of rodents negatively affects fracture callus development, callus biomechanics, and cellular signaling which regulates stem cell differentiation. Here, we examine whether alcohol alters chemokine expression and/or signaling activity in the mouse fracture callus during early fracture healing. METHODS: A mouse model for alcohol impaired tibia fracture healing was utilized. Early fracture callus was examined for alcohol-effects on tissue composition, expression of chemokines involved in MSC migration to the fracture site, and biomechanics. The effects of alcohol on MSC migration and cell adhesion receptors were examined in an in vitro system. RESULTS: Mice exposed to alcohol showed decreased evidence of external callus formation, decreased callus-related osteopontin (OPN) expression levels, and decreased biomechanical stiffness. Alcohol exposure decreased rOPN-mediated MSC migration and integrin beta1 receptor expression in vitro. CONCLUSIONS: The effects of alcohol exposure demonstrated here on fracture callus-associated OPN expression, rOPN-mediated MSC migration in vitro, and MSC integrin beta1 receptor expression in vitro have not been previously reported. Understanding the effects of alcohol exposure on the early stages of fracture repair may allow timely initiation of treatment to mitigate the long-term complications of delayed healing and/or fracture non-union. PMID- 29699562 TI - The trend of feminization of doctors' workforce in Oman: is it a phenomenon that could rouse the health system? AB - BACKGROUND: Participation of women in the medical profession over several countries worldwide was increased over the past decades. This paper is a part of ongoing studies aiming at addressing the issue of health workforce feminization among doctors in the Sultanate of Oman as well as exploring the health system readiness in dealing with this phenomenon. METHODS: Literature in addition to reports and records of the Ministry of Health, Oman (MoH), Sultan Qaboos University (SQU) and Oman Medical Specialty Board were reviewed regarding the gender of the doctors and the medical students. RESULTS: Findings regarding the medical students at the SQU showed higher number of females compared to males (64% females in 2015 compared to 54% in 2009). A similar trend was observed regarding the postgraduates as 61.5% of the graduated residents doctors were females. As for active workforce, the MoH 2015 report revealed that female doctors represent 42% of the total doctors compared to 27% in 1990. It increased 4% from 1990 to 2000, doubled to 8% from 2000 to 2010. The proportion of specialized female doctors reached 31% in 2015 compared to 21% in 1990. There were also gender variations among specialities. The proportion of female general practitioners reached 50% in 2015 compared to 30% in 1990 (4% increase every 5 years). CONCLUSIONS: The feminization phenomenon in Oman is increasing and requires more attention in order to assess the health system readiness of meeting the needs and accommodating the females as the main care providers. The trend is expected to have important consequences on future planning, given that women doctors differ from men in how they participate in the workforce. It may also potentially contribute to a shortage in supply due to difference in preferences and consequently affect the skill-mix and productivity. The cultural, social context and dimensions need to be explored and feasible options to be provided for better planning. PMID- 29699561 TI - Docosahexaenoic acid (DHA) effects on proliferation and steroidogenesis of bovine granulosa cells. AB - BACKGROUND: Docosahexaenoic acid (DHA) is a n-3 polyunsaturated fatty acid (PUFA) belonging to a family of biologically active fatty acids (FA), which are known to have numerous health benefits. N-3 PUFAs affect reproduction in cattle, and notably directly affect follicular cells. In terms of reproduction in cattle, n-3 PUFA-enriched diets lead to increased follicle size or numbers. METHODS: The objective of the present study was to analyze the effects of DHA (1, 10, 20 and 50 MUM) on proliferation and steroidogenesis (parametric and/or non parametric (permutational) ANOVA) of bovine granulosa cells in vitro and mechanisms of action through protein expression (Kruskal-Wallis) and signaling pathways (non parametric ANOVA) and to investigate whether DHA could exert part of its action through the free fatty acid receptor 4 (FFAR4). RESULTS: DHA (10 and 50 MUM) increased granulosa cell proliferation and DHA 10 MUM led to a corresponding increase in proliferating cell nuclear antigen (PCNA) expression level. DHA also increased progesterone secretion at 1, 20 and 50 MUM, and estradiol secretion at 1, 10 and 20 MUM. Consistent increases in protein levels were also reported for the steroidogenic enzymes, cytochrome P450 family 11 subfamily A member 1 (CYP11A1) and hydroxy-delta-5-steroid dehydrogenase, 3 beta- and steroid delta isomerase 1 (HSD3B1), and of the cholesterol transporter steroidogenic acute regulatory protein (StAR), which are necessary for production of progesterone or androstenedione. FFAR4 was expressed in all cellular types of bovine ovarian follicles, and in granulosa cells it was localized close to the cellular membrane. TUG-891 treatment (1 and 50 MUM), a FFAR4 agonist, increased granulosa cell proliferation and MAPK14 phosphorylation in a similar way to that observed with DHA treatment. However, TUG-891 treatment (1, 10 and 50 MUM) showed no effect on progesterone or estradiol secretion. CONCLUSIONS: These data show that DHA stimulated proliferation and steroidogenesis of bovine granulosa cells and led to MAPK14 phosphorylation. FFAR4 involvement in DHA effects requires further investigation, even if our data might suggest FFAR4 role in DHA effects on granulosa cell proliferation. Other mechanisms of DHA action should be investigated as the steroidogenic effects seemed to be independent of FFAR4 activation. PMID- 29699563 TI - Adverse events profile of oral corticosteroids among asthma patients in the UK: cohort study with a nested case-control analysis. AB - BACKGROUND: To evaluate the adverse events profile of oral prednisolone among adult asthma patients in the UK. METHODS: Using data from the UK-based Clinical Practice Research Datalink, we conducted a series of cohort studies to quantify incidence rates and incidence rate ratios, and a series of nested case-control analyses to estimate crude and adjusted odds ratios, of 11 different potential corticosteroid-related adverse events (bone-related conditions, hypertension, peptic ulcer, severe infections, herpes zoster, diabetes mellitus type 2, cataract, glaucoma, chronic kidney disease, affective disorders, and cardiovascular events). RESULTS: Between 165,900 and 269,368 asthma patients were included in each of the 11 cohorts, of whom between 836 and 16,192 developed an outcome of interest. Incidence rates per 1000 person-years of potential corticosteroid-related adverse events in patients with new current use of oral prednisolone ranged from 1.4 (95% confidence interval [CI], 1.0-1.8) for peptic ulcer to 78.0 (95% CI, 74.8-81.2) for severe infections. After adjusting for confounding, current oral prednisolone use was most strongly associated with an increased risk of severe infection, compared with non-use of prednisolone; OR 2.16 (95% CI, 2.05-2.27). There were smaller elevated risks of peptic ulcer, affective disorders, and cataract at higher doses, and marginally increased risks of herpes zoster, cardiovascular events, diabetes mellitus type 2, and bone related conditions, compared with non-use of prednisolone. We did not observe an association between oral prednisolone use and glaucoma, chronic kidney disease, or hypertension. CONCLUSION: Oral prednisolone use is associated with infections, gastrointestinal, neuropsychiatric, ocular, cardiovascular, metabolic, and bone related complications among adult asthma patients. PMID- 29699564 TI - Cirrhosis is not a contraindication to cytoreductive surgery and hyperthermic intraperitoneal chemotherapy in highly selected patients. AB - BACKGROUND: Patient selection for cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is critically important to optimizing outcomes. There is currently no literature regarding the safety of CRS/HIPEC in patients with cirrhosis. The aim of this case series is to report the outcomes of three patients with well-compensated cirrhosis who underwent CRS/HIPEC. METHODS: Patients were identified from a prospectively maintained peritoneal surface malignancy database. Patient, tumor, and operative-related details were recorded as short-term postoperative outcomes. Results were analyzed using descriptive statistics. RESULTS: All patients had well-compensated (Child-Pugh Class A) cirrhosis and Eastern Cooperative Oncology Group (ECOG) performance status of 0. One patient had preoperative evidence of portal hypertension. All safely underwent CRS/HIPEC with completeness of cytoreduction (CC) scores of 0. The postoperative morbidity profile was unique, but all complications were manageable and resulted in full recovery to preoperative baseline status. CONCLUSIONS: Patient selection for CRS/HIPEC is critical for optimization of short- and long term outcomes. This small series suggests that well-compensated cirrhosis should not be an absolute contraindication to CRS/HIPEC. PMID- 29699566 TI - Novel oncolytic chimeric orthopoxvirus causes regression of pancreatic cancer xenografts and exhibits abscopal effect at a single low dose. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) has been increasing by 0.5% per year in the United States. PDAC portends a dismal prognosis and novel therapies are needed. This study describes the generation and characterization of a novel oncolytic chimeric orthopoxvirus for the treatment of pancreatic cancer. METHODS: After chimerization and high-throughput screening, CF33 was chosen from 100 new chimeric orthopoxvirus isolates for its ability to kill pancreatic cancer cells. In vitro cytotoxicity was assayed in six pancreatic cancer cell lines. In vivo efficacy and toxicity were evaluated in PANC-1 and MIA PaCa-2 xenograft models. RESULTS: CF33 caused rapid killing of six pancreatic cancer cells lines in vitro, releasing damage-associated molecular patterns, and regression of PANC 1 injected and non-injected distant xenografts in vivo after a single low intratumoral dose of 103 plaque-forming units. Using luciferase imaging, CF33 was noted to preferentially replicate in tumors which corresponds to the low viral titers found in solid organs. CONCLUSION: The low dose of CF33 required to treat pancreatic cancer in this preclinical study may ease the manufacturing and dosing challenges currently facing oncolytic viral therapy. PMID- 29699565 TI - In vitro quality control analysis after processing and during storage of feline packed red blood cells units. AB - BACKGROUND: During the storage of packed red blood cells (pRBC), packed cell volume (PCV), bacterial contamination and percentage of haemolysis [percentage of free haemoglobin (HGB) in relation to the total HGB] are important quality parameters. Both PCV and haemolysis are indicators of the cellular integrity of stored units. There are no published experimental studies that evaluated these parameters during storage of feline pRBC using SAGM (adenine, dextrose, mannitol and sodium chloride) as the additive solution. The present study aims to (1) evaluate the quality of feline pRBCs stored in SAGM; (2) test for the semi-closed system's suitability for use and risk of bacterial contamination; (3) establish the maximum storage time that may be appropriate to meet the criteria established by the United States Food and Drug Administration (US-FDA) guidelines for human blood banking; and (4) evaluate the need to calculate the percentage of haemolysis prior to the administration of units stored for more than 4 weeks. Four hundred eighty nine feline pRBC units were analyzed. Bacterial culture, PCV and percentage of haemolysis were determined within 6 h after processing (t0). One hundred and eighty units were re-tested for haemolysis and PCV after 29-35 days of storage (t1) and 118 units after 36-42 days (t2). RESULTS: Bacterial contamination was not detected in any pRBC unit. Mean PCV at t0 was 52.25% (SD: +/-5.27) and decreased significantly (p < 0.001) during storage to 48.15% (SD: +/ 3.79) at t1 and to 49.34% (SD: +/-4.45) at t2. Mean percentage of haemolysis at t0 was 0.07% (SD: +/-0.06) and increased significantly (p < 0.001) to 0.69% (SD: +/-0.40) at t1 and to 0.81% (SD: +/-0.47) at t2. In addition, 13.88% and 19.49% of pRBC units exceeded 1% haemolysis at t1 and t2, respectively. CONCLUSIONS: According to the US-FDA guidelines for human blood banking that recommend a maximum of 1% haemolysis, the results of this study show that all feline pRBC units with less than 24 h of shelf life have low levels of haemolysis. However, units preserved up to 28 days can only be administered if tested for haemolysis before use, since 13.88% units exceeded the 1% limit. The semi-closed system was considered safe for use as bacterial contamination was not detected in any pRBC unit. PMID- 29699567 TI - Anti-high mobility group box 1 antibody suppresses local inflammatory reaction and facilitates olfactory nerve recovery following injury. AB - BACKGROUND: Refractory olfactory dysfunction is a common finding in head trauma due to olfactory nerve injury. Anti-inflammatory treatment using steroids is known to contribute to functional recovery of the central and peripheral nervous systems in injury models, while there is a concern that steroids can induce side effects. The present study examines if the inhibition of proinflammatory cytokine, high mobility group box 1 (HMGB1), can facilitate olfactory functional recovery following injury. METHODS: Olfactory nerve transection (NTx) was performed in OMP-tau-lacZ mice to establish injury models. We measured HMGB1 gene expression in the olfactory bulb using semi-quantitative polymerase chain reaction (PCR) assays and examined HMGB1 protein localization in the olfactory bulb using immunohistochemical staining. Anti-HMGB1 antibody was intraperitoneally injected immediately after the NTx and histological assessment of recovery within the olfactory bulb was performed at 5, 14, 42, and 100 days after the drug injection. X-gal staining labeled OMP in the degenerating and regenerating olfactory nerve fibers, and immunohistochemical staining detected the presence of reactive astrocytes and macrophages/microglia. Olfactory function was assessed using both an olfactory avoidance behavioral test and evoked potential recording. RESULTS: HMGB1 gene and protein were significantly expressed in the olfactory bulb 12 h after NTx. Anti-HMGB1 antibody-injected mice showed significantly smaller areas of injury-associated tissue, fewer astrocytes and macrophages/microglia and an increase in regenerating nerve fibers. Both an olfactory avoidance behavioral test and evoked potential recordings showed improved functional recovery in the anti-HMGB1 antibody-injected mice. CONCLUSIONS: These findings suggest that inhibition of HMGB1 could provide a new therapeutic strategy for the treatment of olfactory dysfunction following head injuries. PMID- 29699568 TI - Retraction Note: SNPs in genes implicated in radiation response are associated with radiotoxicity and evoke roles as predictive and prognostic biomarkers. AB - The authors are retracting this article [1] because the data have already been published in [2] making this a redundant publication. Ghazi Alsbeih, Najla Al Harbi, Khaled Al-Hadyan, Mohamed Shoukri and Nasser Al-Rajhi agree with this retraction. Medhat El-Sebaie did not respond to our correspondence. PMID- 29699570 TI - Patenting human genes: Chinese academic articles' portrayal of gene patents. AB - BACKGROUND: The patenting of human genes has been the subject of debate for decades. While China has gradually come to play an important role in the global genomics-based testing and treatment market, little is known about Chinese scholars' perspectives on patent protection for human genes. METHODS: A content analysis of academic literature was conducted to identify Chinese scholars' concerns regarding gene patents, including benefits and risks of patenting human genes, attitudes that researchers hold towards gene patenting, and any legal and policy recommendations offered for the gene patent regime in China. RESULTS: 57.2% of articles were written by law professors, but scholars from health sciences, liberal arts, and ethics also participated in discussions on gene patent issues. While discussions of benefits and risks were relatively balanced in the articles, 63.5% of the articles favored gene patenting in general and, of the articles (n = 41) that explored gene patents in the Chinese context, 90.2% supported patent protections for human genes in China. The patentability of human genes was discussed in 33 articles, and 75.8% of these articles reached the conclusion that human genes are patentable. CONCLUSION: Chinese scholars view the patent regime as an important legal tool to protect the interests of inventors and inventions as well as the genetic resources of China. As such, many scholars support a gene patent system in China. These attitudes towards gene patents remain unchanged following the court ruling in the Myriad case in 2013, but arguments have been raised about the scope of gene patents, in particular that the increasing numbers of gene patents may negatively impact public health in China. PMID- 29699569 TI - Prion infectivity is encoded exclusively within the structure of proteinase K resistant fragments of synthetically generated recombinant PrPSc. AB - Transmissible spongiform encephalopathies, also known as prion diseases, are a group of fatal neurodegenerative disorders affecting both humans and animals. The central pathogenic event in prion disease is the misfolding of normal prion protein (PrPC) into the pathogenic conformer, PrPSc, which self-replicates by converting PrPC to more of itself. The biochemical hallmark of PrPSc is its C terminal resistance to proteinase K (PK) digestion, which has been historically used to define PrPSc and is still the most widely used characteristic for prion detection. We used PK-resistance as a biochemical measure for the generation of recombinant prion from bacterially expressed recombinant PrP. However, the existence of both PK- resistant and -sensitive PrPSc forms in animal and human prion disease led to the question of whether the in vitro-generated recombinant prion infectivity is due to the PK-resistant or -sensitive recombinant PrP forms. In this study, we compared undigested and PK-digested recombinant prions for their infectivity using both the classical rodent bioassay and the cell-based prion infectivity assay. Similar levels of infectivity were detected in PK digested and -undigested samples by both assays. A time course study of recombinant prion propagation showed that the increased capability to seed the conversion of endogenous PrP in cultured cells coincided with an increase of the PK-resistant form of recombinant PrP. Moreover, prion infectivity diminished when recombinant prion was subjected to an extremely harsh PK digestion. These results demonstrated that the infectivity of recombinant prion is encoded within the structure of the PK-resistant PrP fragments. This characteristic of recombinant prion, that a simple PK digestion is able to eliminate all PK-sensitive (non infectious) PrP species, makes possible a more homogenous material that will be ideal for dissecting the molecular basis of prion infectivity. PMID- 29699571 TI - Safety and efficacy of dehydrated ethanol soaking of the operative field in the treatment of spontaneous hepatocellular carcinoma rupture. AB - BACKGROUND: The aim of our study was to evaluate the clinical safety and value of ethanol surgical field infiltration (ESFI), combined with distilled water peritoneal lavage (DWPL), after hepatectomy in patients with hepatocellular carcinoma (HCC) rupture. METHODS: Rat liver tissue samples were soaked in dehydrated ethanol for different soaking times, and 18 rats were assigned to three groups that underwent different soaking methods of the hepatectomy cut surface. We retrospectively reviewed 45 patients who underwent hepatectomy for treatment of ruptured HCC. Among these, EFSI combined with DWPL was used in 21 patients (DAW group), with only DWPL used in the other 24 patients (DW group). Clinical outcomes were compared between the two groups. RESULTS: For in vitro experiments, the depth of coagulation degeneration and necrosis increased with the duration of soaking. For in vivo experiments, rats in all three groups survived until postoperative day 7 without significant postoperative complication. In patients, the rate of post-operation complication was comparable between the two groups (P = 0.398), with no between-group differences in liver function levels. The incidence of peritoneal dissemination was significantly higher for DW than DAW group (P = 0.037). Kaplan-Meier test identified dehydrated ethanol treatment as a significant factor of disease-free survival (DFS) (P = 0.036). On univariate analysis, dehydrated ethanol treatment was associated with better prognostic outcomes, although it was not retained as an independent factor of patient outcome. CONCLUSIONS: Dehydrated ethanol soaking of the cut surface of the hepatectomy could potentially lower the risk of metastasis and improve the effect of hepatectomy for ruptured HCC as well as showed potential therapeutic value for intraoperative iatrogenic rupture of HCC. PMID- 29699572 TI - Ischemic stroke is associated with the pro-inflammatory potential of N glycosylated immunoglobulin G. AB - BACKGROUND: Glycosylation significantly affects protein structure and function and thus participates in multiple physiologic and pathologic processes. Studies demonstrated that immunoglobulin G (IgG) N-glycosylation associates with the risk factors of ischemic stroke (IS), such as aging, obesity, dyslipidemia, type 2 diabetes, and hypertension. METHODS: The study aimed to investigate the association between IgG N-glycosylation and IS in a Chinese population. IgG glycome composition in patients with IS (n = 78) and cerebral arterial stenosis (CAS) (n = 75) and controls (n = 77) were analyzed by ultra-performance liquid chromatography. RESULTS: Eleven initial glycans and 10 derived glycans in IgG glycome representing galactosylation, sialylation, and bisecting GlcNAc significantly differed between IS patients and CAS and healthy controls after controlling for gender, age, obesity, diabetes, hypertension, and dyslipidemia. Logistic regression models incorporating IgG glycan traits were able to distinguish IS from CAS (area under receiver-operator characteristic curves (AUC), 0.802; 95% confidence interval (CI), 0.732-0.872) and controls (AUC, 0.740; 95% CI, 0.661-0.819). The canonical correlation analysis indicated that initial N-glycan structures are significantly correlated with inflammation markers (r = 0.566, p < 0.001). CONCLUSION: Our findings indicated that loss of galactose and sialic acid, as well as addition of bisecting GlcNAc, might involve in pro- or anti-inflammatory IgG functionality and further contribute to the pathogenesis of IS. IgG glycan profiles may be developed as clinical useful biomarkers for chronic disease in the future. PMID- 29699573 TI - Responses to dietary levels of methionine in broilers medicated or vaccinated against coccidia under Eimeria tenella-challenged condition. AB - BACKGROUND: Coccidiosis is a prevalent problem in chicken production. Dietary addition of coccidiostats and vaccination are two approaches used to suppress coccidia in the practical production. Methionine (Met) is usually the first limiting amino acid that plays important roles in protein metabolism and immune functions in chickens. The present study is aimed to investigate whether increasing dietary Met levels will improve the anticoccidial effects in broilers medicated or vaccinated against coccidia under Eimeria (E.) tenella-challenged condition. Two thousand male Partridge Shank broiler chicks were obtained from a hatchery. After hatch, birds were weighed, color-marked and allocated equally into two anticoccidial treatments, namely medicated and vaccinated groups. Chicks were either fed, from 1 d of age, diets containing coccidiostat (narasin) or diets without the coccidiostat but were inoculated with an anticoccidial vaccine at 3 d of age. At 22 d of age, 1080 chicks among them were randomly allocated evenly into 6 groups under a 2 * 3 treatment with 2 anticoccidial programs and 3 dietary methionine (Met) levels. Chicks medicated or vaccinated against coccidia were fed diets containing 0.45%, 0.56% or 0.68% of Met from 22 to 42 d of age. All chicks were orally introduced with an amount of 5 * 104 sporulated oocysts of E. tenella at 24 d of age. The growth performance, serum anti-oxidative indexes, intestinal morphology, cecal lesion scores, fecal oocyst counts and immune parameters were measured. RESULTS: The results showed increasing dietary Met level from 0.45% to 0.56% and 0.68% improved weight gain and feed conversion of broilers medicated against coccidia. In contrast, higher dietary levels of Met did not improve growth performance of the vaccinated chickens. Higher Met levels helped the medicated chickens resist E. tenella infection, as indicated by improved intestinal morphology and immune functions as well as decreased cecal lesion and fecal oocyst counts. CONCLUSIONS: Anticoccidial vaccination is a better strategy for controlling coccidiosis than feeding narasin, due to not only greater growth performance, but also the lower Met supplementation. Furthermore, higher dietary Met levels improved growth performance of chickens medicated rather than vaccinated against coccidia under E. tenella-challenged condition. PMID- 29699574 TI - A longitudinal study on how implicit attitudes and explicit cognitions synergistically influence physical activity intention and behavior. AB - BACKGROUND: Strategies to promote physical activity (PA) focus mainly on changing or fostering explicit cognitions and are only modestly effective. Contemporary studies suggest that, as well as explicit cognitions, implicit cognitions influence health behavior, such as PA, and that implicit processes interact with the intention to be active. Relatively little is known about whether implicit processes interact with other explicit cognitions which determine PA intention and behavior, i.e. self-efficacy. The aim of the current study was to investigate the direct effects of explicit cognitions and implicit attitudes on PA behavior as well as interactions between them regarding intention and behavior prediction. METHODS: In a longitudinal study, participants (N = 340) completed self-report measures of explicit cognitions (perceived pros, perceived cons, social norms, social modeling, self-efficacy, intention) and activity levels, as well as a Single-Category Implicit Association Task to measure implicit attitudes towards PA at baseline (T0), and at one (T1) and 3 months thereafter (T2). RESULTS: Hierarchical multiple regressions revealed that T0-positive implicit attitudes moderated the relationship between T0 self-efficacy and T1 PA. Similarly, T0 neutral implicit attitudes were associated with the relationship between T0 intention and T1 PA. Negative implicit attitudes strengthened the negative relationship between perceived cons and intention at baseline; neutral or positive implicit attitudes strengthened the positive relationship between self efficacy and intention. At the follow-ups, the relationship between social modeling and intention was strengthened by negative implicit attitudes. CONCLUSION: This study revealed important insights into how implicit attitudes and explicit cognitions synergistically predict PA intention and behavior. As well as targeting explicit cognitions, steering a person's implicit attitude towards a more positive one, i.e. by implicit cognitive trainings, could help to increase both PA intention and behavior. PMID- 29699575 TI - Sex differences in relationships between metabolic syndrome components and factors associated with health-related quality of life in middle-aged adults living in the community: a cross-sectional study in Taiwan. AB - BACKGROUND: Metabolic syndrome (MetS) is a widespread condition with important effects on public health, in general. There is a lack of relevant research on possible sex differences in the relationship between MetS and health-related quality of life (HRQoL) and also the sex differences in factors associated with HRQoL. The aims of this study were to identify: 1) whether women exhibit greater negative impacts on physical domain HRQoL from MetS compared with men; 2) whether women exhibit greater mental domain impacts compared with men; and 3) whether factors associated with HRQoL scores are different for men and women. METHODS: This cross-sectional study was conducted in Taipei, Taiwan. Using random sampling, a total of 906 participants aged 35-55 years were recruited. MetS was defined according to the MetS criteria for the Taiwanese population, and HRQoL were assessed using physical component summary (PCS) and mental component summary (MCS) scores of the Short Form Health Survey (SF-36), Taiwan version. Demographics, physical activity, medical history, and blood tests as covariates were recorded and checked. The associations were assessed by multiple linear regression. RESULTS: After adjusting for covariates, women but not men with more components of MetS had significantly lower PCS scores (beta = - 0.542, p = 0.036). The number of components of MetS was not a significant factor in MCS score differences between the sexes. Furthermore, there were sex differences regarding age, education level, physical activity, and smoking status in association with PCS scores. For MCS scores, sex differences were found in education level, marital status, and habits of smoking and alcohol consumption. CONCLUSIONS: There were sex differences in the relationships between metabolic syndrome components and factors associated with HRQoL among middle-aged adults living in the community in Taiwan. Further research should be conducted to investigate mechanisms of these sex differences. PMID- 29699576 TI - Ethnobotanical investigation on medicinal plants in Algoz area (South Kordofan), Sudan. AB - BACKGROUND: The inhabitants of western Sudan use traditional medicine for the treatment of various ailments due to lack of medical doctors and unaffordable prices of pharmaceutical products. The present study is the first documentation of the traditional plant knowledge on medicinal uses of plants by healers in Algoz (South Kordofan), Sudan. METHOD: Ethnobotanical data were collected over a period from March to November 2015 using semi-structured interviews with 30 healers (24 male and 6 female) living in the investigated area. Quantitative indices such as use categories, use value (UV) and informant consensus factor (ICF) were intended to evaluate the importance of medicinal plant species. RESULTS: A total of 94 medicinal plants, which belong to 45 families and 81 genera, were recorded in the study area. The most represented families are Leguminosae with 20 species followed by Combretaceae (6 species), Rubiaceae (5 species) and Asteraceae (4 species). The reported species were belonging to herbs (43%), trees (28%), shrubs (22%), climbers (4%) and parasites (3%). Root and stem (21% each) were the most plant parts used. A majority of remedies are administered orally (67%) where infusion (36%) and maceration (32%) are the most used methods. The highest ICF (0.87) was reported for poisonous animal bites followed by urinary system diseases (0.89), blood system disorders (0.88) and gynaecological diseases (0.87). Anastatica hierochuntica, Ctenolepis cerasiformis, Echinops longifolius, Cleome gynandra, Maerua pseudopetalosa, Martynia annua, Oldenlandia uniflora, Opuntia ficus-indica, Solanum dubium, Sonchus cornutus, Tribulus terrestris and Drimia maritima were reported for the first time in this study. CONCLUSION: The number of medicinal plants reported in this paper reflects evidence that Algoz area had a high diversity of medicinal plants which will continue to play an important role in the healthcare system in the study area. PMID- 29699577 TI - The detection of 3 ambiguous type 2 vaccine-derived polioviruses (VDPV2s) in Uganda. AB - BACKGROUND: The Oral Polio Vaccine (OPV or Sabin) is genetically unstable and may mutate to form vaccine-derived polioviruses (VDPVs). METHODS: In 2014, two VDPVs type 2 were identified during routine surveillance of acute flaccid paralysis (AFP) cases. Consequently, a retrospective VDPV survey was conducted to ensure that there was no circulating VDPV in the country. All Sabin poliovirus isolates identified in Uganda 6 months before and 6 months after were re-screened; Sabin 1 and 3 polioviruses were re-screened for Sabin 2 and Sabin 2 polioviruses were re screened for VDPVs type 2. The Poliovirus rRT-PCR ITD/VDPV 4.0 assay and sequencing were used respectively. RESULTS: The first two VDPVs type2 were identified in Eastern Uganda and the third was identified during the survey from South-western Uganda. These regions had low OPV coverage and poor AFP surveillance indicators. CONCLUSION: The retrospective VDPV survey was a useful strategy to screen for VDPVs more exhaustively. Supplementary surveillance methods need to be encouraged. PMID- 29699578 TI - Targeting the Hsp90-Cdc37-client protein interaction to disrupt Hsp90 chaperone machinery. AB - Heat shock protein 90 (Hsp90) is a critical molecular chaperone protein that regulates the folding, maturation, and stability of a wide variety of proteins. In recent years, the development of Hsp90-directed inhibitors has grown rapidly, and many of these inhibitors have entered clinical trials. In parallel, the functional dissection of the Hsp90 chaperone machinery has highlighted the activity disruption of Hsp90 co-chaperone as a potential target. With the roles of Hsp90 co-chaperones being elucidated, cell division cycle 37 (Cdc37), a ubiquitous co-chaperone of Hsp90 that directs the selective client proteins into the Hsp90 chaperone cycle, shows great promise. Moreover, the Hsp90-Cdc37-client interaction contributes to the regulation of cellular response and cellular growth and is more essential to tumor tissues than normal tissues. Herein, we discuss the current understanding of the clients of Hsp90-Cdc37, the interaction of Hsp90-Cdc37-client protein, and the therapeutic possibilities of targeting Hsp90-Cdc37-client protein interaction as a strategy to inhibit Hsp90 chaperone machinery to present new insights on alternative ways of inhibiting Hsp90 chaperone machinery. PMID- 29699580 TI - Genetic deletion of muscle RANK or selective inhibition of RANKL is not as effective as full-length OPG-fc in mitigating muscular dystrophy. AB - Although there is a strong association between osteoporosis and skeletal muscle atrophy/dysfunction, the functional relevance of a particular biological pathway that regulates synchronously bone and skeletal muscle physiopathology is still elusive. Receptor-activator of nuclear factor kappaB (RANK), its ligand RANKL and the soluble decoy receptor osteoprotegerin (OPG) are the key regulators of osteoclast differentiation and bone remodelling. We thus hypothesized that RANK/RANKL/OPG, which is a key pathway for bone regulation, is involved in Duchenne muscular dystrophy (DMD) physiopathology. Our results show that muscle specific RANK deletion (mdx-RANK mko ) in dystrophin deficient mdx mice improves significantly specific force [54% gain in force] of EDL muscles with no protective effect against eccentric contraction-induced muscle dysfunction. In contrast, full-length OPG-Fc injections restore the force of dystrophic EDL muscles [162% gain in force], protect against eccentric contraction-induced muscle dysfunction ex vivo and significantly improve functional performance on downhill treadmill and post-exercise physical activity. Since OPG serves a soluble receptor for RANKL and as a decoy receptor for TRAIL, mdx mice were injected with anti-RANKL and anti-TRAIL antibodies to decipher the dual function of OPG. Injections of anti-RANKL and/or anti-TRAIL increase significantly the force of dystrophic EDL muscle [45% and 17% gains in force, respectively]. In agreement, truncated OPG-Fc that contains only RANKL domains produces similar gains, in terms of force production, than anti-RANKL treatments. To corroborate that full-length OPG-Fc also acts independently of RANK/RANKL pathway, dystrophin/RANK double-deficient mice were treated with full-length OPG-Fc for 10 days. Dystrophic EDL muscles exhibited a significant gain in force relative to untreated dystrophin/RANK double-deficient mice, indicating that the effect of full-length OPG-Fc is in part independent of the RANKL/RANK interaction. The sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) activity is significantly depressed in dysfunctional and dystrophic muscles and full-length OPG-Fc treatment increased SERCA activity and SERCA-2a expression. These findings demonstrate the superiority of full-length OPG-Fc treatment relative to truncated OPG-Fc, anti-RANKL, anti-TRAIL or muscle RANK deletion in improving dystrophic muscle function, integrity and protection against eccentric contractions. In conclusion, full-length OPG-Fc represents an efficient alternative in the development of new treatments for muscular dystrophy in which a single therapeutic approach may be foreseeable to maintain both bone and skeletal muscle functions. PMID- 29699581 TI - Genotypic characterization of rotavirus in children under 5 years circulating in Cote D'Ivoire from 2010 to 2013. AB - BACKGROUND: Rotavirus infection is the most common cause of severe gastroenteritis in children under five years of age in both developed and developing countries. The World Health Organisation (WHO) recommends the surveillance of rotavirus strains prior to vaccine introduction in all applicable countries. The objective of this study was to describe the epidemiological characteristics as well as to determine the circulating genotypes of rotaviruses in Cote d'Ivoire prior to vaccine introduction. METHODS: The study included children under five years of age who met the inclusion criteria after informed consent had been sort from their parents or guardians. Rotavirus VP6 antigens were detected for each stool sample using Enzyme Immunoassay (EIA). Genotyping of positive EIA samples was performed by reverse-transcriptase-PCR (RT-PCR) assays. RESULTS: A total of 684 children were recruited. Children aged between 6 and 11 months were the most represented with 34%. Rotavirus VP6 antigens were found in 27.1% (186/684) of samples tested. Commonly detected G genotypes included G12 (46.6% (82/176) and G1 (13.1% (23/176) whilst P[8] (49.8% (91/183) was the most predominant P genotype. Rotavirus G12P[8] was the most predominant strain circulating in Cote d'Ivoire within the period of study and constituted 26.6% of all strains detected. CONCLUSION: The monitoring of circulating strains will help guide decision-makers in the choice of vaccine. Genotypic variability of circulating rotavirus strains over the years implies there is a need for continuous rotavirus strain surveillance even after vaccine introduction. PMID- 29699579 TI - Urinary biomarkers predict advanced acute kidney injury after cardiovascular surgery. AB - BACKGROUND: Acute kidney injury (AKI) after cardiovascular surgery is a serious complication. Little is known about the ability of novel biomarkers in combination with clinical risk scores for prediction of advanced AKI. METHODS: In this prospectively conducted multicenter study, urine samples were collected from 149 adults at 0, 3, 6, 12 and 24 h after cardiovascular surgery. We measured urinary hemojuvelin (uHJV), kidney injury molecule-1 (uKIM-1), neutrophil gelatinase-associated lipocalin (uNGAL), alpha-glutathione S-transferase (ualpha GST) and pi-glutathione S-transferase (upi-GST). The primary outcome was advanced AKI, under the definition of Kidney Disease: Improving Global Outcomes (KDIGO) stage 2, 3 and composite outcomes were KDIGO stage 2, 3 or 90-day mortality after hospital discharge. RESULTS: Patients with advanced AKI had significantly higher levels of uHJV and uKIM-1 at 3, 6 and 12 h after surgery. When normalized by urinary creatinine level, uKIM-1 in combination with uHJV at 3 h post-surgery had a high predictive ability for advanced AKI and composite outcome (AUC = 0.898 and 0.905, respectively). The combination of this biomarker panel (normalized uKIM-1, uHJV at 3 h post-operation) and Liano's score was superior in predicting advanced AKI (AUC = 0.931, category-free net reclassification improvement of 1.149, and p < 0.001). CONCLUSIONS: When added to Liano's score, normalized uHJV and uKIM-1 levels at 3 h after cardiovascular surgery enhanced the identification of patients at higher risk of progression to advanced AKI and composite outcomes. PMID- 29699582 TI - Effects of megavoltage computed tomographic scan methodology on setup verification and adaptive dose calculation in helical TomoTherapy. AB - BACKGROUND: To evaluate the effect of pretreatment megavoltage computed tomographic (MVCT) scan methodology on setup verification and adaptive dose calculation in helical TomoTherapy. METHODS: Both anthropomorphic heterogeneous chest and pelvic phantoms were planned with virtual targets by TomoTherapy Physicist Station and were scanned with TomoTherapy megavoltage image-guided radiotherapy (IGRT) system consisted of six groups of options: three different acquisition pitches (APs) of 'fine', 'normal' and 'coarse' were implemented by multiplying 2 different corresponding reconstruction intervals (RIs). In order to mimic patient setup variations, each phantom was shifted 5 mm away manually in three orthogonal directions respectively. The effect of MVCT scan options was analyzed in image quality (CT number and noise), adaptive dose calculation deviations and positional correction variations. RESULTS: MVCT scanning time with pitch of 'fine' was approximately twice of 'normal' and 3 times more than 'coarse' setting, all which will not be affected by different RIs. MVCT with different APs delivered almost identical CT numbers and image noise inside 7 selected regions with various densities. DVH curves from adaptive dose calculation with serial MVCT images acquired by varied pitches overlapped together, where as there are no significant difference in all p values of intercept & slope of emulational spinal cord (p = 0.761 & 0.277), heart (p = 0.984 & 0.978), lungs (p = 0.992 & 0.980), soft tissue (p = 0.319 & 0.951) and bony structures (p = 0.960 & 0.929) between the most elaborated and the roughest serials of MVCT. Furthermore, gamma index analysis shown that, compared to the dose distribution calculated on MVCT of 'fine', only 0.2% or 1.1% of the points analyzed on MVCT of 'normal' or 'coarse' do not meet the defined gamma criterion. On chest phantom, all registration errors larger than 1 mm appeared at superior inferior axis, which cannot be avoided with the smallest AP and RI. On pelvic phantom, craniocaudal errors are much smaller than chest, however, AP of 'coarse' presents larger registration errors which can be reduced from 2.90 mm to 0.22 mm by registration technique of 'full image'. CONCLUSIONS: AP of 'coarse' with RI of 6 mm is recommended in adaptive radiotherapy (ART) planning to provide craniocaudal longer and faster MVCT scan, while registration technique of 'full image' should be used to avoid large residual error. Considering the trade-off between IGRT and ART, AP of 'normal' with RI of 2 mm was highly recommended in daily practice. PMID- 29699583 TI - Recurrent upper lumbar disc herniation treated via the transforaminal approach using microendoscopy-assisted lumbar discectomy: a case report. AB - BACKGROUND: Although microendoscopy-assisted lumbar discectomy for lateral or extraforaminal lumbar disc herniations via the lateral approach has previously been reported, microendoscopy-assisted lumbar discectomy for central or paramedian disc herniations via the lateral approach has not been reported. We report the first case of recurrent upper lumbar disc herniation (L2-L3) treated with microendoscopy-assisted lumbar discectomy via the transforaminal approach. No microendoscopy-assisted lumbar discectomy for recurrent upper lumbar disc herniation via the transforaminal approach has previously been reported. Percutaneous endoscopic lumbar discectomy via the transforaminal approach is very useful as a minimally invasive surgery for disc herniations. We applied percutaneous endoscopic lumbar discectomy via the transforaminal approach, and invented a new microendoscopy-assisted lumbar discectomy via the transforaminal approach. CASE PRESENTATION: A 79-year-old Japanese man was operatively managed for recurrent L2-L3 herniation. An 18 mm skin incision was made approximately 70 mm from the midline to the lateral side to allow a sufficiently angled trajectory to the extraforaminal space. The transforaminal approach was used. The exiting nerve root was identified along its course inferior to the pedicle. The lateral portion of the pars interarticularis and the facet joint was removed using a high speed drill under the guidance of an endoscope. The tip of the endoscope was set at the lateral side of the dura mater. The dura mater was retracted medially and gently, and the herniated disc fragments were removed safely. All symptoms were relieved postoperatively. Postoperative magnetic resonance imaging demonstrated disappearance of all herniated disc fragments. A postoperative three-dimensional computed tomographic scan demonstrated the complete preservation of the facet joint. CONCLUSIONS: This is the first report of a case of recurrent upper lumbar disc herniation treated with microendoscopy-assisted lumbar discectomy via the transforaminal approach. This procedure allows for the use of a nerve retractor and other instruments to detach adhesions from the dura mater. This procedure has the advantages of clear visualization of the dura mater, exiting nerve root, and traversing nerve root, and diminished risk of nerve injury, and complete preservation of the articular surface of the facet joint. PMID- 29699584 TI - Androgen receptor and heat shock protein 27 co-regulate the malignant potential of molecular apocrine breast cancer. AB - BACKGROUND: The most striking feature of molecular apocrine breast cancer (MABC) is the expression of androgen receptor (AR). We report here the mechanism of the AR in regulating the behavior of MABC. METHODS: The MABC cell line, MDA-MB-453, and the nonMABC cell line, MCF7, were used in this study. The effect of dihydrotestosterone (DHT) and heat shock protein 27 (HSP27) on cell proliferation was quantified using the cell counter kit-8 (CCK8) and clonogenic assays in vitro and by a xenograft tumor model in vivo. The expression of the AR and HSP27 was analyzed using western blot, qPCR, and immunofluorescence assays. Complexes of the AR and HSP27 were detected by co-immunoprecipitation (Co-IP). RESULTS: In MDA MB-453 cells, DHT promoted cell proliferation and stimulated AR and HSP27 translocation from the cytoplasm to the nucleus, whereas, it inhibited MCF7 cell growth, and only the AR translocated into the nucleus. HSP27 knock-down decreased the proliferative ability of MDA-MB-453 cells, which could be rescued by DHT, while HSP27 and DHT had synergistic effects on MCF7 cells. HSP27 phosphorylation was a prerequisite for AR translocation into the nucleus, especially phosphorylation on serine 82. In addition, DHT stimulated the tumorigenic and metastatic capacities of MDA-MB-453 cells, while HSP27 knock-down decreased the rate of tumor formation and induced apoptosis in cells. CONCLUSIONS: The results suggest that HSP27 assists the AR in regulating the malignant behavior of MABC, and these findings might be helpful in the treatment of MABC. PMID- 29699585 TI - Primary pulmonary amebic abscess in a patient with pulmonary adenocarcinoma: a case report. AB - BACKGROUND: Primary pulmonary amoeba is very rare and here we report a case of a 68-year-old man presenting with primary pulmonary amoeba after undergoing chemotherapy for lung adenocarcinoma. CASE PRESENTATION: In October 2016, the man aged 68 was admitted to our hospital because of repeated cough for 8 months and hemoptysis for 1 month. He was diagnosed lung adenocarcinoma and underwent surgery in 2012 without receiving chemotherapy. In March 2016, the patients suffered recurrence of cancer and was treated with chemotherapy. After 2 months of chemotherapy, the patient had consistent cough with white sputum, and chest CT showed a local lung nodule. The physicians suspected that the patient had pulmonary infectious diseases, and he was treated with empirical antibacterial treatment. However, his symptom wasn't relieved and later the percutaneous lung biopsy found trophozites of Entamoeba histolytica. After administration of metronidazole, the symptoms of the patient were markedly relieved and the lesions were absorbed. CONCLUSIONS: In such cases where patients with pulmonary nodules were in immunodeficiency state and had adequate but ineffective anti-bacterial treatment, Entamoeba histolytica infection could be one of the rare causes. Percutaneous lung biopsy should be recommended and specific dying for parasites should be done when necessary. PMID- 29699586 TI - Intussusception caused by an inverted colonic diverticulum: a case report. AB - BACKGROUND: Intussusception is an unusual disorder among the complications of diverticula in adults. This study aimed to report intussusception due to an inverted colonic diverticulum. Such a large inverted colonic diverticulum has rarely been reported. CASE PRESENTATION: A 62-year-old Chinese woman presented to the First Hospital of Jilin University with abdominal pain, vomiting, and bloody stool. Preoperative computed tomography imaging indicated intussusception. The intraoperative diagnosis was consistent with postoperative pathology. Our patient was diagnosed as having an inverted colonic diverticulum near the ileocecal valve with intussusception and intestinal necrosis. CONCLUSION: Although inverted colonic diverticulum is extremely rare, it should also be considered among the causative factors of intussusception. PMID- 29699587 TI - The association between insurance coverage for insulin pen needles and healthcare resource utilization among insulin-dependent patients with diabetes in China. AB - BACKGROUND: Pen needles are an important component of insulin delivery among patients with diabetes, but are not universally covered in China. We compared clinical and economic characteristics of insulin-dependent patients in China who have some level of pen needle (PN) reimbursement to those with no PN reimbursement. METHODS: A cross-sectional study was conducted among 400 insulin users with Type 1 or Type 2 diabetes treated in outpatient endocrinology units of four large tertiary care hospitals in Nanjing, Chongqing, Beijing and Zhengzhou. Demographics, medical history, healthcare resource utilization (RU), out-of pocket costs, insurance and PN reimbursement status were surveyed. Unit costs were assigned to healthcare RU and compared using descriptive statistics and multivariate regression models. RESULTS: A total of 400 patients were analyzed; 142 (35.5%) with some level of PN coverage/reimbursement and 258 (64.5%) without. Patients without PN reimbursement had a higher prevalence of lipohypertrophy (59.3% vs. 40.7%, p = 0.0007), greater median PN reuse (12 vs. 7 times per needle, p < 0.0001), greater 6-month insulin costs (1591 vs. 1328 Renminbi [RMB], p = 0.0025) and total unadjusted 6-month expenditures (6433 vs. 4432 RMB, p < 0.0001), respectively. After controlling for clinical and demographic characteristics, patients without PN reimbursement had 4.6 times greater odds of high costs compared to those with PN reimbursement. CONCLUSIONS: Insulin users without PN reimbursement may pose a greater economic burden to China compared to those with PN reimbursement. Expansion of insurance coverage for insulin PNs can improve the quality of care and potentially help reduce the economic burden in this population. PMID- 29699588 TI - Burden of disease attributable to suboptimal diet, metabolic risks and low physical activity in Ethiopia and comparison with Eastern sub-Saharan African countries, 1990-2015: findings from the Global Burden of Disease Study 2015. AB - BACKGROUND: Twelve of the 17 Sustainable Development Goals (SDGs) are related to malnutrition (both under- and overnutrition), other behavioral, and metabolic risk factors. However, comparative evidence on the impact of behavioral and metabolic risk factors on disease burden is limited in sub-Saharan Africa (SSA), including Ethiopia. Using data from the Global Burden of Disease (GBD) Study, we assessed mortality and disability-adjusted life years (DALYs) attributable to child and maternal undernutrition (CMU), dietary risks, metabolic risks and low physical activity for Ethiopia. The results were compared with 14 other Eastern SSA countries. METHODS: Databases from GBD 2015, that consist of data from 1990 to 2015, were used. A comparative risk assessment approach was utilized to estimate the burden of disease attributable to CMU, dietary risks, metabolic risks and low physical activity. Exposure levels of the risk factors were estimated using spatiotemporal Gaussian process regression (ST-GPR) and Bayesian meta-regression models. RESULTS: In 2015, there were 58,783 [95% uncertainty interval (UI): 43,653-76,020] or 8.9% [95% UI: 6.1-12.5] estimated all-cause deaths attributable to CMU, 66,269 [95% UI: 39,367-106,512] or 9.7% [95% UI: 7.4 12.3] to dietary risks, 105,057 [95% UI: 66,167-157,071] or 15.4% [95% UI: 12.8 17.6] to metabolic risks and 5808 [95% UI: 3449-9359] or 0.9% [95% UI: 0.6-1.1] to low physical activity in Ethiopia. While the age-adjusted proportion of all cause mortality attributable to CMU decreased significantly between 1990 and 2015, it increased from 10.8% [95% UI: 8.8-13.3] to 14.5% [95% UI: 11.7-18.0] for dietary risks and from 17.0% [95% UI: 15.4-18.7] to 24.2% [95% UI: 22.2-26.1] for metabolic risks. In 2015, Ethiopia ranked among the top four countries (of 15 Eastern SSA countries) in terms of mortality and DALYs based on the age standardized proportion of disease attributable to dietary and metabolic risks. CONCLUSIONS: In Ethiopia, while there was a decline in mortality and DALYs attributable to CMU over the last two and half decades, the burden attributable to dietary and metabolic risks have increased during the same period. Lifestyle and metabolic risks of NCDs require more attention by the primary health care system of the country. PMID- 29699589 TI - Suicidal patients presenting to secondary and tertiary emergency departments and referral to a psychiatrist: a population-based descriptive study from Japan. AB - BACKGROUND: In Japan, although many suicidal studies were previously conducted in tertiary emergency department (ED) settings, no published studies have reported on suicidal patients presenting to the secondary EDs. The aim of the study was to describe the characteristics of suicidal patients and the referral rates to a psychiatrist overall and by type of facility. METHODS: Questionnaires were sent to all secondary and tertiary EDs in Tochigi prefecture, Japan. Data were collected for cases who presented in September 2009. Chi-square, Fisher's exact, and t-tests compared the results by gender and type of ED. RESULTS: All 74 EDs responded to the survey. There were 81 patients who attempted or died by suicide (36 men and 45 women). The most common method of suicide attempt was drug overdose (57%) followed by stabbing (17%). About a half used prescription drugs to attempt or die by suicide. The majority had a history of psychiatric disorders, and 35% had previous suicide attempt. About a half were admitted to medical or surgical unit; 33% were discharged home; and 9% died. After excluding those who died, 53% were referred to a psychiatrist, but 47% were not referred to a psychiatrist. The referral rate was lower for cases seen at secondary EDs (38%) compared to tertiary EDs (67%). CONCLUSION: Although professional organizations suggest that suicidal patients are seen by a psychiatrist, many were not, especially at secondary EDs. Further research is needed to assure that suicidal patients presenting to EDs receive appropriate psychiatric assessment and follow up after discharge. PMID- 29699590 TI - Attenuation of TGFBR2 expression and tumour progression in prostate cancer involve diverse hypoxia-regulated pathways. AB - BACKGROUND: Dysregulation of transforming growth factor beta (TGF-beta) signaling and hypoxic microenvironment have respectively been reported to be involved in disease progression in malignancies of prostate. Emerging evidence indicates that downregulation of TGFBR2, a pivotal regulator of TGF-beta signaling, may contribute to carcinogenesis and progression of prostate cancer (PCa). However, the biological function and regulatory mechanism of TGFBR2 in PCa remain poorly understood. In this study, we propose to investigate the crosstalk of hypoxia and TGF-beta signaling and provide insight into the molecular mechanism underlying the regulatory pathways in PCa. METHODS: Prostate cancer cell lines were cultured in hypoxia or normoxia to evaluate the effect of hypoxia on TGFBR2 expression. Methylation specific polymerase chain reaction (MSP) and demethylation agents was used to evaluate the methylation regulation of TGFBR2 promoter. Besides, silencing of EZH2 via specific siRNAs or chemical inhibitor was used to validate the regulatory effect of EZH2 on TGFBR2. Moreover, we conducted PCR, western blot, and luciferase assays which studied the relationship of miR-93 and TGFBR2 in PCa cell lines and specimens. We also detected the impacts of hypoxia on EZH2 and miR-93, and further examined the tumorigenic functions of miR-93 on proliferation and epithelial-mesenchymal transition via a series of experiments. RESULTS: TGFBR2 expression was attenuated under hypoxia. Hypoxia-induced EZH2 promoted H3K27me3 which caused TGFBR2 promoter hypermethylation and contributed to its epigenetic silencing in PCa. Besides, miR-93 was significantly upregulated in PCa tissues and cell lines, and negatively correlated with the expression of TGFBR2. Ectopic expression of miR-93 promoted cell proliferation, migration and invasion in PCa, and its expression could also be induced by hypoxia. In addition, TGFBR2 was identified as a bona fide target of miR-93. CONCLUSIONS: Our findings elucidate diverse hypoxia-regulated pathways including EZH2-mediated hypermethylation and miR-93-induced silencing contribute to attenuation of TGFBR2 expression and promote cancer progression in prostate cancer. PMID- 29699591 TI - New perspectives: systems medicine in cardiovascular disease. AB - BACKGROUND: Cardiovascular diseases (CVD) represent one of the most important causes of morbidity and mortality worldwide. Innovative approaches to increase the understanding of the underpinnings of CVD promise to enhance CVD risk assessment and might pave the way to tailored therapies. Within the last years, systems medicine has emerged as a novel tool to study the genetic, molecular and physiological interactions. CONCLUSION: In this review, we provide an overview of the current molecular-experimental, epidemiological and bioinformatical tools applied in systems medicine in the cardiovascular field. We will discuss the status and challenges in implementing interdisciplinary systems medicine approaches in CVD. PMID- 29699592 TI - Effects of feet warming using bed socks on sleep quality and thermoregulatory responses in a cool environment. AB - BACKGROUND: As a way of helping to sleep in winter, methods of warming the feet through footbaths or heating pads before bedtime are tried. In particular, bed socks are popular during winter sleeping in Korea, but scientific evidence about the physiological effects of bed socks on sleep quality is rarely reported. The purpose of this study was to evaluate the effect of feet warming using bed socks on sleep quality and thermoregulatory responses during sleep in a cool environment. METHODS: Six young males (22.7 +/- 2.0 years in age, 175.6 +/- 3.5 cm in height, and 73.1 +/- 8.5 kg in body weight) participated in two experimental conditions (with and without feet warming) in a random order. The following variables on sleep quality using a wrist actigraphy were measured during a 7-h sleep at an air temperature of 23 degrees C with 50% RH: sleep onset latency, sleep efficiency, total sleep time, number of awakenings, wake after sleep onset, average awakening length, movement index, and fragmentation index. Heart rate and rectal and skin temperatures were monitored during the 7-h sleep. Questionnaire on sleep quality was obtained after awakening in the morning. RESULTS: The results showed that sleep-onset latency was on average 7.5 min shorter, total sleep time was 32 min longer, the number of awakenings was 7.5 times smaller, and sleep efficiency was 7.6% higher for those wearing feet warming bed socks during a 7-h sleep than control (no bed socks) (all P < 0.05). Also, their foot temperature was maintained on average 1.3 degrees C higher and the value in the distal-proximal skin temperature gradient was higher for those wearing feet warming bed socks when compared to the control condition (P < 0.05). However, there were no significant differences in heart rate, rectal and mean skin temperature, or in the questionnaire-based subjective evaluations between the two conditions. CONCLUSIONS: Feet warming using bed socks during sleep in a cool environment had positive effects on sleep quality by shortened sleep onset, lengthened sleep time, and lessened awakenings during sleep but had no significant influence on core body temperature. These results imply that sleep quality could be improved by manipulation of the foot temperature throughout sleeping. PMID- 29699593 TI - Can elearning be used to teach palliative care? - medical students' acceptance, knowledge, and self-estimation of competence in palliative care after elearning. AB - BACKGROUND: Undergraduate palliative care education (UPCE) was mandatorily incorporated in medical education in Germany in 2009. Implementation of the new cross-sectional examination subject of palliative care (QB13) continues to be a major challenge for medical schools. It is clear that there is a need among students for more UPCE. On the other hand, there is a lack of teaching resources and patient availabilities for the practical lessons. Digital media and elearning might be one solution to this problem. The primary objective of this study is to evaluate the elearning course Palliative Care Basics, with regard to students' acceptance of this teaching method and their performance in the written examination on the topic of palliative care. In addition, students' self estimation in competence in palliative care was assessed. METHODS: To investigate students' acceptance of the elearning course Palliative Care Basics, we conducted a cross-sectional study that is appropriate for proof-of-concept evaluation. The sample consisted of three cohorts of medical students of Heinrich Heine University Dusseldorf (N = 670). The acceptance of the elearning approach was investigated by means of the standard evaluation of Heinrich Heine University. The effect of elearning on students' self-estimation in palliative care competencies was measured by means of the German revised version of the Program in Palliative Care Education and Practice Questionnaire (PCEP-GR). RESULTS: The elearning course Palliative Care Basics was well-received by medical students. The data yielded no significant effects of the elearning course on students' self estimation in palliative care competencies. There was a trend of the elearning course having a positive effect on the mark in written exam. CONCLUSIONS: Elearning is a promising approach in UPCE and well-accepted by medical students. It may be able to increase students' knowledge in palliative care. However, it is likely that there are other approaches needed to change students' self-estimation in palliative care competencies. It seems plausible that experience-based learning and encounters with dying patients and their relatives are required to increases students' self-estimation in palliative care competencies. TRIAL REGISTRATION: Heinrich Heine University Medical School Clinical Trial Registry No. 4876 (date of approval 26.11.2014). PMID- 29699594 TI - Beneficial effects of curcumin and capsaicin on cyclophosphamide-induced premature ovarian failure in a rat model. AB - BACKGROUND: In recent years, cancer rates have been rising among reproductive-age women. Thus, chemotherapy exposure has become an important cause of premature ovarian failure (POF). There has been growing interest regarding the preservation and restoration of ovarian function before and after oncological treatment because of the reproductive risk of chemotherapeutics and improved long-term survival of cancer patients. In this study, we sought to analyze the effects of curcumin (CRC) and capsaicin (CPS) on cyclophosphamide-induced POF in a rat model. METHODS: POF in rats was induced by intraperitoneal injection of 200 mg/kg cyclophosphamide on day 1 and then 8 mg/kg/day for the following 14 days. After 14 days of cyclophosphamide administration, rats were randomly divided into three groups as follows (n = 10/group): POF, POF + CRC (100 mg/kg/day), and POF + CPS (0.5 mg/kg/day) to determine the effects of CRC and CPS on the cyclophosphamide induced POF rat model. Biochemical, hormonal, and histopathological evaluations were performed on blood and tissue samples 14 days after the CRC and CPS treatments. RESULTS: Malonaldehyde levels were significantly reduced, and glutathione levels and superoxide dismutase activity were significantly increased, in ovarian tissues in the POF + CRC and POF + CPS groups compared with the POF group. In the POF group, we observed hemorrhage and prominent mononuclear cell infiltration beneath the germinative epithelium, vascular congestion in ovarian stroma, hemorrhage around the corpus luteum, and atresia in ovarian follicles. This histopathological damage was significantly improved by treatment with CRC and CPS. There was a significant reduction in serum follicle-stimulating hormone and luteinizing hormone levels in rats treated with CRC and CPS compared with the POF group. Moreover, the levels of estradiol and anti-mullerian hormone in rats treated with CRC and CPS were significantly increased compared with the control group. CONCLUSIONS: In conclusion, CRC and CPS treatment of rats with cyclophosphamide-induced POF had a beneficial effect on reducing ovarian damage by improving tissue oxidative stress marker levels, ovarian reserve marker levels, and histopathological parameters. The significant improvements in ovarian tissue histopathological damage and hormonal levels detected in this study indicate that treatment with CRC or CPS might be a conservative treatment approach for cyclophosphamide-induced POF. PMID- 29699596 TI - Nano-Cathodoluminescence Measurement of Asymmetric Carrier Trapping and Radiative Recombination in GaN and InGaN Quantum Disks. AB - The ability to characterize recombination and carrier trapping processes in group III nitride-based nanowires is vital to further improvements in their overall efficiencies. While advances in scanning transmission electron microscope (STEM) based cathodoluminescence (CL) have offered some insight into nanowire behavior, inconsistencies in nanowire emission along with CL detector limitations have resulted in the incomplete understanding in nanowire emission processes. Here, two nanowire heterostructures were explored with STEM-CL: a polarization-graded AlGaN nanowire light-emitting diode (LED) with a GaN quantum disk and a polarization-graded AlGaN nanowire with three different InGaN quantum disks. Most nanowires explored in this study did not emit. For the wires that did emit in both structures, they exhibited asymmetrical emission consistent with the polarization-induced electric fields in the barrier regions of the nano-LEDs. In the AlGaN/InGaN sample, two of the quantum disks exhibited no emission potentially due to the three-dimensional landscape of the sample or due to limitations in the CL detection. PMID- 29699595 TI - Skills and Core Competencies of Pharmacists in Humanitarian Assistance. AB - BACKGROUND: Pharmacists' participation in health care within multi-disciplinary teams in Humanitarian Assistance (HA) shall be encouraged. Limited literature exists on their role in the humanitarian context. The objective of this paper is to evidence the skill-specific, comprehensive core competencies that pharmacists must demonstrate working in humanitarian interventions. METHODS: The literature search laid the groundwork for the development of interview guides and further analysis of the data. Semi-structured interviews were conducted with expatriate pharmacists and medical coordinators, all of whom have worked in the field of HA. The interviews were recorded, transcribed, and analyzed using a content analysis methodology. RESULTS: Three pharmacists and three medical coordinators were interviewed, who had worked in a combined 32 humanitarian missions. The main functions of pharmacists were focused on stock management and supply of medicinal products. However, pharmacists in HA did not perform many functions related to the provision of effective medication therapy management (MTM). A core competency framework for pharmacists working in the humanitarian field was created, which reflects the personal and technical competencies that are essential to work in HA. CONCLUSION: Self-management in a pressured and changing environment, the ability to adapt to changing situations, and planning, prioritizing, and performing tasks well under pressure are the skills required for pharmacists and for any other humanitarian health worker. The results highlight great efforts being dedicated to pharmaceutical product supply and management by pharmacists working in HA. VardanyanH, MoseguiGBG, MirandaES. Skills and core competencies of pharmacists in humanitarian assistance. Prehosp Disaster Med. 2018;33(3):266-272. PMID- 29699597 TI - Scanning Electron Microscopy (SEM) Energy Dispersive X-ray Spectroscopy (EDS) Mapping and In-situ Observation of Carbonization of Culms of Bambusa Multiplex. AB - Green culms of bamboo and charcoal of Bambusa multiplex were investigated by scanning electron microscopy (SEM) and energy dispersive X-ray spectroscopy (EDS) mapping. A dynamic observation of the initial stage of carbonization was also performed in-situ by heating a radial longitudinal section of the bamboo culm at a rate of 20 degrees C/min up to 500 degrees C. EDS mapping of the green bamboo culms detected Si signals in the harder cells such as the epidermis (Ep), cortex (Cor) and vascular bundle sheath (Bs) and between these cells as silicon oxide particles. Appreciable morphological change of the cells occurred in a temperature range of about 300-400 degrees C due to the decomposition of cellulose that is the main component of the bamboo cells. The charcoal of the bamboo culm has a skin layer which originates from the Ep and Cor and the main central cylinder with many openings that originate from the expanded xylem and phloem holes. During carbonization, the Si atoms in the Ep and Cor were segregated as thin silicon oxide layers onto both the sides of the skin layer and the Si included in the Bs fibers and parenchyma cells accumulated near the walls of the openings. PMID- 29699598 TI - The Accuracy of Al and Cu Film Thickness Determinations and the Implications for Electron Probe Microanalysis. AB - The accuracy to which Cu and Al coatings can be determined, and the effect this has on the quantification of the substrate, is investigated. Cu and Al coatings of nominally 5, 10, 15, and 20 nm were sputter coated onto polished Bi using two configurations of coater: One with the film thickness monitor (FTM) sensor colocated with the samples, and one where the sensor is located to one side. The FTM thicknesses are compared against those calculated from measured Cu Lalpha and Al Kalpha k-ratios using PENEPMA, GMRFilm, and DTSA-II. Selected samples were also cross-sectioned using focused ion beam. Both systems produced repeatable coatings, the thickest coating being approximately four times the thinnest coating. The side-located FTM sensor indicated thicknesses less than half those of the software modeled results, propagating on to 70% errors in substrate quantification at 5 kV. The colocated FTM sensor produced errors in film thickness and substrate quantification of 10-20%. Over the range of film thicknesses and accelerating voltages modeled both the substrate and coating k ratios can be approximated by linear trends as functions of film thickness. The Al films were found to have a reduced density of ~2 g/cm2. PMID- 29699599 TI - In Situ Scanning Electron Microscope (SEM) Observations of Damage and Crack Growth of Shale. AB - To better understand the formation and evolution of hierarchical crack networks in shales, observations of microscopic damage, and crack growth were conducted using an in situ tensile apparatus inside a scanning electron microscope. An arched specimen with an artificial notch incised into the curved edge was shown to afford effective observation of the damage and crack growth process that occurs during the brittle fracturing of shale. Because this arched specimen design can induce a squeezing effect, reducing the tensile stress concentration at the crack tip, and preventing the brittle shale from unstable fracturing to some extent. Both induced and natural pores and cracks were observed at different scales around the main crack path or on fractured surfaces. Observations indicate that the crack initiation zone develops around the crack tip where tensile stresses are concentrated and micro/nanoscale cracks nucleate. Crack advancement generally occurs by the continuous generation and coalescence of damage zones having intermittent en echelon microscopic cracks located ahead of the crack tips. Mineral anisotropy and pressure build-up around crack tips causes crack kinking, deflection, and branching. Crack growth is often accompanied by the cessation or closure of former branch cracks due to elastic recovery and induced compressive stress. The branching and interactions of cracks form a three dimensional hierarchical network that includes induced branch cracks having similar paths, as well as natural structures such as nanopores, bedding planes, and microscopic cracks. PMID- 29699603 TI - Multimycotoxin Analysis by LC-MS/MS in Cereal Food and Feed: Comparison of Different Approaches for Extraction, Purification, and Calibration. AB - Twelve different approaches commonly used for the simultaneous LC tandem MS (MS/MS) determination of mycotoxins (deoxynivalenol, aflatoxins, ochratoxin A, T 2 and HT-2 toxins, fumonisins, and zearalenone) were tested in cereals and feed materials. They comprised different extraction solvents, types of cleanup [solid phase extraction, QuEChERS, and immunoaffinity (IMA)], and calibration approaches (external or matrix-matched). The percentage of mycotoxins with acceptable recovery, according to Regulation (EC) No. 401/2006, ranged from 9 to 100%. The approach giving the highest percentage of acceptable results was selected and further tested for corn, rice, and feed spiked at three different mycotoxin levels (low, medium, and high). The method is based on extraction with MeOH-water (70 + 30, v/v) and cleanup with two multiantibody IMA columns. For corn and rice spiked at low mycotoxin levels, a significant matrix effect was observed and was compensated by using 13C calibration. At higher mycotoxin levels (medium and high), matrix effects were negligible as no significant differences were observed for the majority of recovery results calculated by 13C calibration and external calibration. Although the proposed method still needs improvement in terms of accuracy and, to a lesser extent, precision, it was successfully tested with four proficiency tests in buckwheat, corn, rice, and feed, giving acceptable z-scores for 97% (34 out of 35) of results. PMID- 29699605 TI - Chitinase 3-like-1, a novel regulator of Th1/CTL responses, as a therapeutic target for increasing anti-tumor immunity. AB - Chitinase-Like Proteins (CLPs) are an evolutionarily conserved protein which lose their enzymatic activity for degrading chitin macromolecules. Chitinase-3-like-1 (Chi3l1) is a type of CLP that is highly expressed in epithelial cells, macrophages, etc., and is known to have correlations with type 2 inflammation and cancer. Although the increased level of Chi3l1 in the blood was reported in various disease patients, the function of Chi3l1 in adaptive immunity has been totally unknown. Recently, we found that Chi3l1 is expressed in T cells and has a negative regulatory role in T-cell activation and proliferation. A genetic ablation study of Chi3l1 in T cells showed hyperresponsiveness to TcR stimulation, which increased proliferation and Th1 differentiation. A significant increase of IFNgamma signaling in Chi3l1-deficient T cells synergistically increased Th1 and CTL functions against melanoma cells in vitro and in vivo. In addition, targeted knockdown by Chi3l1 siRNA complexed with the cell-penetrating peptide dNP2, which showed decreased pulmonary melanoma metastasis with increased infiltration of Th1 and CTL in the lung. This study first suggests that Chi3l1 is a novel regulator of Th1/CTL responses and could be a target for treating cancer to increase tumor immunity. [BMB Reports 2018; 51(5): 207-208]. PMID- 29699604 TI - Hindsiipropane B alleviates HIV-1 Tat-induced inflammatory responses by suppressing HDAC6-NADPH oxidase-ROS axis in astrocytes. AB - Human immunodeficiency virus-1 (HIV-1) transactivator of transcription (Tat) is an important viral factor in neuroinflammation. Hindsiipropane B, present in Celastrus hindsii, possesses various biological mechanisms including antiinflammatory activity. In this report, we explored the regulatory activity of hindsiipropane B on HIV-1 Tat-mediated chemokine production and its mode of action in astrocytes. Hindsiipropane B significantly alleviated HIV-1 Tat mediated production of inflammatory chemokines, CCL2, CXCL8, and CXCL10. Hindsiipropane B inhibited expression of HDAC6, which is important regulator in HIV-1 Tat-mediated chemokine production. Hindsiipropane B diminished HIV-1 Tat mediated reactive oxygen species (ROS) generation and NADPH oxidase activation/expression. Furthermore, hindsiipropane B inhibited HIV-1 Tat-mediated signaling cascades including MAPK, NF-kappaB, and AP-1. These data suggest that hindsiipropane B exerts its inhibitory effects on HIV-1 Tat-mediated chemokine production via down-regulating the HDAC6-NADPH oxidase-MAPK-NF-kappaB/AP-1 signaling axis, and could serve as a therapeutic lead compound against HIV-1 Tat associated neuroinflammation. [BMB Reports 2018; 51(8): 394-399]. PMID- 29699606 TI - Insulin receptor substrate 2: a bridge between Hippo and AKT pathways. AB - NAFLD induces the development of advanced liver diseases such as NASH and liver cancer. Therefore, understanding the mechanism of NAFLD development is critical for its prevention and treatment. Ablation of PTEN or Hippo pathway components induces liver cancer in a murine model by hyperactive AKT or YAP/TAZ, respectively. Although the regulation of these two pathways occurs in the same hepatocyte, the details of crosstalk between Hippo-YAP/TAZ and PTEN-AKT pathways in liver homeostasis and tumorigenesis still remain unclear. Here, we found that depletion of both PTEN and SAV1 in liver promotes spontaneous NAFLD and liver cancer through hyperactive AKT via YAP/TAZmediated up-regulation of IRS2 transcription. Conversely, NAFLD is rescued by both ablation of YAP/TAZ and activation of the Hippo pathway. Furthermore, human HCC patients with NAFLD showed strong correlation between YAP/TAZ and IRS2 or phospho-AKT expression. Finally, the inhibition of AKT by MK-2206 treatment attenuates NAFLD development and tumorigenesis. Our findings indicate that Hippo pathway interacts with AKT signaling during the intervention with IRS2 to prevent NAFLD and liver cancer. [BMB Reports 2018; 51(5): 209-210]. PMID- 29699607 TI - ? PMID- 29699608 TI - ? PMID- 29699610 TI - Transcatheter Mitral Valve Replacement for Severe Mitral Annular Calcification: Is it Ready for Prime Time? PMID- 29699612 TI - Dangers and Long-Term Outcomes in Metabolically Healthy Obesity: The Impact of the Missing Fitness Component. PMID- 29699611 TI - Metabolically Healthy Obesity, Transition to Metabolic Syndrome, and Cardiovascular Risk. AB - BACKGROUND: Debate over the cardiometabolic risk associated with metabolically healthy obesity (MHO) continues. Many studies have investigated this relationship by examining MHO at baseline with longitudinal follow-up, with inconsistent results. OBJECTIVES: The authors hypothesized that MHO at baseline is transient and that transition to metabolic syndrome (MetS) and duration of MetS explains heterogeneity in incident cardiovascular disease (CVD) and all-cause mortality. METHODS: Among 6,809 participants of the MESA (Multi-Ethnic Study of Atherosclerosis) the authors used Cox proportional hazards and logistic regression models to investigate the joint association of obesity (>=30 kg/m2) and MetS (International Diabetes Federation consensus definition) with CVD and mortality across a median of 12.2 years. We tested for interaction and conducted sensitivity analyses for a number of conditions. RESULTS: Compared with metabolically healthy normal weight, baseline MHO was not significantly associated with incident CVD; however, almost one-half of those participants developed MetS during follow-up (unstable MHO). Those who had unstable MHO had increased odds of CVD (odds ratio [OR]: 1.60; 95% confidence interval [CI]: 1.14 to 2.25), compared with those with stable MHO or healthy normal weight. Dose response for duration of MetS was significantly and linearly associated with CVD (1 visit with MetS OR: 1.62; 95% CI: 1.27 to 2.07; 2 visits, OR: 1.92; 95% CI: 1.48 to 2.49; 3+ visits, OR: 2.33; 95% CI: 1.89 to 2.87; p value for trend <0.001) and MetS mediated approximately 62% (44% to 100%) of the relationship between obesity at any point during follow-up and CVD. CONCLUSIONS: Metabolically healthy obesity is not a stable or reliable indicator of future risk for CVD. Weight loss and lifestyle management for CVD risk factors should be recommended to all individuals with obesity. PMID- 29699609 TI - 1-Year Outcomes of Transcatheter Mitral Valve Replacement in Patients With Severe Mitral Annular Calcification. AB - BACKGROUND: The risk of surgical mitral valve replacement in patients with severe mitral annular calcification (MAC) is high. Several patients worldwide with severe MAC have been treated successfully with transcatheter mitral valve replacement (TMVR) using balloon-expandable aortic transcatheter valves. The TMVR in MAC Global Registry is a multicenter registry that collects data on outcomes of these procedures. OBJECTIVES: The goal of this study was to evaluate 1-year outcomes in this registry. METHODS: This study was a multicenter retrospective review of clinical outcomes. RESULTS: A total of 116 extreme surgical risk patients with severe MAC underwent TMVR; 106 had a procedure date >1 year before data-lock and were included in the analysis. Their mean age was 73 +/- 12 years, and 68% were female. The mean Society of Thoracic Surgeons score was 15.3 +/- 11.6%, and 90% were in New York Heart Association functional class III or IV. Thirty-day and 1-year all-cause mortality was 25% and 53.7%, respectively. Most patients who survived 30 days were alive at 1 year (49 of 77 [63.6%]), and the majority (71.8%) were in New York Heart Association functional class I or II. Echocardiography data at 1 year were available in 34 patients. Mean left ventricular ejection fraction was 58.6 +/- 11.2%, mean mitral valve area was 1.9 +/- 0.5 cm2, mean mitral gradient was 5.8 +/- 2.2 mm Hg, and 75% had zero or trace mitral regurgitation. CONCLUSIONS: TMVR with balloon-expandable aortic valves in extreme surgical risk patients with severe MAC is feasible but associated with high 30-day and 1-year mortality. Most patients who survive the 30-day post-procedural period are alive at 1 year and have sustained improvement of symptoms and transcatheter valve performance. The role of TMVR in patients with MAC requires further evaluation in clinical trials. PMID- 29699613 TI - Pharmacogenomic Testing to Select Antiplatelet Therapy. PMID- 29699615 TI - Long-Term Assessment of Bioresorbable Coronary Scaffolds: Disappearing Stents, Reappearing Atherosclerosis. PMID- 29699614 TI - Neoatherosclerosis 5 Years After Bioresorbable Vascular Scaffold Implantation. AB - BACKGROUND: Data regarding neoatherosclerosis after everolimus-eluting bioresorbable vascular scaffold (BVS) (ABSORB BVS Rev. 1.1, Abbott Vascular, Santa Clara, California) implantation are limited. OBJECTIVES: This study investigated the findings of neoatherosclerosis at 5 years after BVS 1.1 implantation by using multi-imaging modalities, including optical coherence tomography (OCT). METHODS: Patients included in the ABSORB EXTEND (ABSORB EXTEND Clinical Investigation) trial at Shonan Kamakura General Hospital underwent OCT at baseline after the index procedure and at 1 and 5 years. Intimal plaque distributions in the in-scaffold and out-scaffold segments were analyzed. RESULTS: Twenty patients (22 lesions) with stable angina pectoris were enrolled. The median follow-up duration was 67 months (interquartile range: 65 to 69 months), and the mean age was 69 +/- 8 years. Patients with diabetes mellitus (25%) were included. Based on the baseline angiogram, 10 (46%) lesions were type B2/C lesions. At 1 and 5 years of follow-up, significant differences in the prevalence of in-scaffold lipid-laden neointima (17% vs. 61%; p = 0.04), calcification (28% vs. 94%; p < 0.01), neovascularization (6% vs. 78%; p < 0.01), and thin-cap fibroatheroma (0% vs. 22%; p = 0.02) were found. In the out-scaffold segments, no significant difference in the plaque prevalence between 1 and 5 years was noted. CONCLUSIONS: The occurrence and progression of in-scaffold neoatherosclerosis with luminal narrowing was observed at 5 years after BVS 1.1 implantation. The small size of the current study warrants confirmation in larger study. (ABSORB EXTEND Clinical Investigation [ABSORB EXTEND]; NCT01023789). PMID- 29699617 TI - Why Is Propranolol Better Than Metoprolol in Acute Treatment of Electrical Storm? PMID- 29699616 TI - Propranolol Versus Metoprolol for Treatment of Electrical Storm in Patients With Implantable Cardioverter-Defibrillator. AB - BACKGROUND: Electrical storm (ES), characterized by unrelenting recurrences of ventricular arrhythmias, is observed in approximately 30% of patients with implantable cardioverter-defibrillators (ICDs) and is associated with high mortality rates. OBJECTIVES: Sympathetic blockade with beta-blockers, usually in combination with intravenous (IV) amiodarone, have proved highly effective in the suppression of ES. In this study, we compared the efficacy of a nonselective beta blocker (propranolol) versus a beta1-selective blocker (metoprolol) in the management of ES. METHODS: Between 2011 and 2016, 60 ICD patients (45 men, mean age 65.0 +/- 8.5 years) with ES developed within 24 h from admission were randomly assigned to therapy with either propranolol (160 mg/24 h, Group A) or metoprolol (200 mg/24 h, Group B), combined with IV amiodarone for 48 h. RESULTS: Patients under propranolol therapy in comparison with metoprolol-treated individuals presented a 2.67 times decreased incidence rate (incidence rate ratio: 0.375; 95% confidence interval: 0.207 to 0.678; p = 0.001) of ventricular arrhythmic events (tachycardia or fibrillation) and a 2.34 times decreased rate of ICD discharges (incidence rate ratio: 0.428; 95% CI: 0.227 to 0.892; p = 0.004) during the intensive care unit (ICU) stay, after adjusting for age, sex, ejection fraction, New York Heart Association functional class, heart failure type, arrhythmia type, and arrhythmic events before ICU admission. At the end of the first 24-h treatment period, 27 of 30 (90.0%) patients in group A, while only 16 of 30 (53.3%) patients in group B were free of arrhythmic events (p = 0.03). The termination of arrhythmic events was 77.5% less likely in Group B compared with Group A (hazard ratio: 0.225; 95% CI: 0.112 to 0.453; p < 0.001). Time to arrhythmia termination and length of hospital stay were significantly shorter in the propranolol group (p < 0.05 for both). CONCLUSIONS: The combination of IV amiodarone and oral propranolol is safe, effective, and superior to the combination of IV amiodarone and oral metoprolol in the management of ES in ICD patients. PMID- 29699618 TI - Cerebrovascular Events After Cardiovascular Procedures: Risk Factors, Recognition, and Prevention Strategies. AB - Stroke has long been a devastating complication of any cardiovascular procedure that unfavorably affects survival and quality of life. Over time, strategies have been developed to substantially reduce the incidence of stroke after traditional cardiovascular procedures such as coronary artery bypass grafting, isolated valve surgery, and carotid endarterectomy. Subsequently, with the advent of minimally invasive technologies including percutaneous coronary intervention, carotid artery stenting, and transcatheter valve therapies, operators were faced with a new host of procedural risk factors, and efforts again turned toward identifying novel ways to reduce the risk of stroke. Fortunately, by understanding the procedural factors unique to these new techniques and applying many of the lessons learned from prior experiences, we are seeing significant improvements in the safety of these new technologies. In this review, the authors: 1) carefully analyze data from different cardiac procedural experiences ranging from traditional open heart surgery to percutaneous coronary intervention and transcatheter valve therapies; 2) explore the unique risk factors for stroke in each of these areas; and 3) describe how these risks can be mitigated with improved patient selection, adjuvant pharmacotherapy, procedural improvements, and novel technological advancements. PMID- 29699619 TI - Domain Management Approach to Heart Failure in the Geriatric Patient: Present and Future. AB - Heart failure (HF) is a quintessential geriatric cardiovascular condition, with more than 50% of hospitalizations occurring in adults age 75 years or older. In older patients, HF is closely linked to processes inherent to aging, which include cellular and structural changes to the myocardium, vasculature, and skeletal muscle. In addition, HF cannot be considered in isolation of physical functioning, or without the social, psychological, and behavioral dimensions of illness. The role of frailty, depression, cognitive impairment, nutrition, and goals of care are each uniquely relevant to the implementation and success of medical therapy. In this paper, we discuss a model of caring for older adults with HF through a 4-domain framework that can address the unique multidimensional needs and vulnerabilities of this population. We believe that clinicians who embrace this approach can improve health outcomes for older adults with HF. PMID- 29699620 TI - Prior Authorization Reform for Better Patient Care. PMID- 29699621 TI - JACC: Basic to Translational Science: The Apple That Falls Closely to the JACC Family Tree. PMID- 29699622 TI - Reply: The Case of Dynamic CHA2DS2-VASc Score: Beyond Risk Prediction. PMID- 29699623 TI - The Case of Dynamic CHA2DS2-VASc Score: Beyond Risk Prediction. PMID- 29699624 TI - Left Bundle Branch Block-Associated Cardiomyopathies and Early Cardiac Resynchronization Therapy: Conceptualizing a Tailored Approach. PMID- 29699625 TI - Dyssynchrony-Induced Cardiomyopathy. PMID- 29699626 TI - Reply: Early Cardiac Resynchronization Therapy for Left Bundle Branch Block Associated Cardiomyopathies. PMID- 29699627 TI - Reinventing the Interventional Cardiology Fellowship: Aligning the Incentives. PMID- 29699628 TI - ? PMID- 29699629 TI - ? PMID- 29699630 TI - ? PMID- 29699631 TI - ? PMID- 29699632 TI - Mulberry anthocyanins improves thyroid cancer progression mainly by inducing apoptosis and autophagy cell death. AB - Dietary anthocyanin compounds have multiple biological effects, including antioxidant, anti-inflammatory, and anti-atherosclerotic characteristics. The present study evaluated the anti-tumor capacity of mulberry anthocyanins (MA) in thyroid cancer cells. Our data showed that MA suppressed SW1736 and HTh-7 cell proliferation in a time- and dose-dependent manner. Meanwhile, flow cytometry results indicated that MA significantly increased SW1736 and HTh-7 cell apoptosis. We additionally observed that SW1736 and HTh-7 cell autophagy was markedly enhanced after MA treatment. Importantly, anthocyanin-induced cell death was largely abolished by 3-methyladenine (3-MA) or chloroquine diphosphate salt (CQ) treatment, suggesting that MA-induced SW1736 and HTh-7 cell death was partially dependent on autophagy. In addition, activation of protein kinase B (Akt), mammalian target of rapamycin (mTOR), and ribosomal protein S6 (S6) were significantly suppressed by anthocyanin exposure. In summary, MA may serve as an adjunctive therapy for thyroid cancer patients through induction of apoptosis and autophagy-dependent cell death. PMID- 29699634 TI - Alteration in CD8+ T cell subsets in enterovirus-infected patients: An alarming factor for type 1 diabetes mellitus. AB - Type 1 diabetes is a multi-factorial disease that can develop due to the combination of genetic and environmental factors. Viruses, particularly enteroviruses, are major environmental candidates in the pathogenesis of type 1 diabetes, even though the mechanisms of pathogenicity of these viruses and their effects on the immune system have not been understood very well yet. Previous studies show that any imbalance in the population of different lymphocyte subsets could develop autoimmune diseases. Our theory is that enteroviral infection causes an impairment in the distribution of lymphocyte subtypes and consequently results in the diabetes onset in some individuals. Therefore, in this project, we evaluated the distribution of T CD8+ lymphocytes and their subsets in type 1 diabetes patients. This study was conducted to investigate the relationship between enteroviral infection and type 1 diabetes mellitus in an Iranian population, and suggestion a predicting approach for susceptible subjects. PMID- 29699633 TI - miR-17-92 ameliorates renal ischemia reperfusion injury. AB - There is limited information on the role of miR-17-92 in renal tubular pathophysiology. Therefore, the present study was performed to determine whether miR-17-92 plays a role in ischemia-reperfusion injury (IRI)-induced acute kidney injury. We originally demonstrated that miR-17-92 is up-regulated following IRI in vivo. To explore the roles of miR-17-92 in the IRI process, we first generated a renal proximal tubule-specific miR-17-92 deletion (PT-miR-17-92-/-) knockout mouse model with Cre driven by the Kap promoter. We found that PT-deficient miR 17-92 mice had more severe renal dysfunction and renal structures than their littermates. Compared with sham-operated mice, both wide-type (WT) mice and PT miR-17-92-/- mice showed increased serum levels of creatinine and urea. However, the levels of serum urea and creatinine in PT-miR-17-92-/- mice after the IRI operation were significantly higher than the levels in WT mice. In addition, PT miR-17-92-/- mice showed higher levels of serum potassium and phosphonium after the IRI operation. Histological analysis revealed that PT-miR-17-92-/- mice had substantial histopathologic changes, such as tubular dilation and tubular necrosis. Overexpression of miR-17-92 could partially reverse the side-effects of IRI on the proximal tubules in vivo. Furthermore, we employed a quantitative proteomic strategy and identified 16 proteins as potential targets of miR-17-92. Taken together, our findings suggested that miR-17-92 may ameliorates IRI-induced acute kidney injury. Our results indicate that pharmacologic modulation of these miRNAs may have therapeutic potential for acute kidney injury. PMID- 29699635 TI - Definite intensity-modulated radiotherapy with concurrent chemotherapy more than 4 cycles improved survival for patients with locally-advanced or inoperable esophageal squamous cell carcinoma. AB - We investigated which prognostic factor could improve survival for esophageal cancer patients who received definite concurrent chemoradiation (CCRT). Eighty patients with age >=18, Karnofsky Performance Scale (KPS) >= 60, and clinical stage T1-4N0-3M0 esophageal squamous cell carcinoma were enrolled from July 2004 to December 2015. They underwent definite intensity-modulated radiotherapy (IMRT) with or without simultaneous integrated boost to the primary tumor, and reception of concurrent chemotherapy >= 1 cycle. The primary endpoints were overall survival (OS), locoregional progression-free survival (LRPFS) and distant metastasis-free survival (DMFS). The median follow-up duration for alive patients was 21.5 months. The rates of 2-, 3- and 5-year OS/LRPFS/DMFS were 23.8%/53.5%/49.3%, 19.1%/44.6%/49.3%, and 13.0%/44.6%/43.9%, respectively. Only the non-clinical complete response (non-cCR) after CCRT was an independent poor prognostic factor in OS (HR 3.101, 95% CI 1.535-6.265, p = 0.0016). Radiation dose >50.4 Gy and chemotherapy >=4 cycles significantly predicted better LRPFS (p = 0.0361 and 0.0163, respectively). Poorly differentiated tumor and stage III disease have poor DMFS (p = 0.0336 and 0.0411, respectively), and chemotherapy >= 4 cycles was a better predictor (p = 0.0004). In subgroup analysis, patients who received radiation dose <=50.4 Gy with concurrent chemotherapy >=4 cycles had the best survival outcome with 1-, 2-, 3- and 5-year survival rates of 73.7%, 39.4%, 31.5% and 17.5%, respectively. In conclusion, definite radiotherapy with concurrent chemotherapy >=4 cycles improved the survival for patients with inoperable or locally-advanced esophageal squamous cell carcinoma. PMID- 29699636 TI - Conservative surgery of diffuse adenomyosis with TOUA: Single surgeon experience of one hundred sixteen cases and report of fertility outcomes. AB - The aim of this study is to evaluate the clinical outcomes of conservative adenomyomectomy with TOUA for diffuse uterine adenomyosis and to determine the feasibility and safety. One hundred and sixteen patients with symptomatic diffuse uterine adenomyosis underwent adenomyomectomy with TOUA by a single surgeon at Ulsan University Hospital between May 2011 and March 2016. Surgical outcomes included operative time, intraoperative injury and operative blood loss. We assessed the degree of improvement in dysmenorrhea and menorrhagia at the 7-month follow-up visit after the operation. The mean age of patients was 37.49 years (range: 26-49). The mean total surgical time was 116.12 min (range: 60-300, SD: 37.27). The mean estimated blood loss was 207.22 mL (range: 30-1200, SD: 161.08) and there were no cases of injury to the uterine arteries or pelvic nerves. The mean duration of hospital stay was 5.05 days (range: 4-7, SD: 0.68) and the mean follow-up period of 16.67 months (range: 6-49, SD: 12.77). At the 7-month follow up after adenomyomectomy with TOUA, dysmenorrhea and menorrhagia were improved in 100% and 89% of the patients, respectively. In patients with diffuse uterine adenomyosis, even when the whole uterus is involved, for relief of severe adenomyosis-related symptoms, adenomyomectomy with TOUA could be a safe and effective surgical treatment option for those who want to preserve their fertility. PMID- 29699638 TI - Increased frequency of AMP-activated protein kinase-positive spinal motor neurons after sciatic nerve injury in a mouse model. AB - The role of AMP-activated protein kinase (AMPK) in the regulation of energy metabolism and the control of skeletal muscle regeneration post injury has been described previously. It remains unknown whether this metabolic sensor plays a role in the mechanism of axonal regeneration post injury. In this study, we used a sciatic nerve crushed mouse model to detect the expression of AMPK in sciatic nerve and spinal motor neurons at 1 week, 2 weeks and 3 weeks after injury by immunofluorescence staining. Electrophysiological and histopathological studies were used to confirm the nerve injury and regeneration. Our results showed that frequency of AMPK-positive spinal motor neurons was significantly higher on day 7 after sciatic nerve crush (SNC) and peaked on day 14. No expression of AMPK was detected in axons of the sciatic nerve before and after the injury. Taken together, our study suggested a possible role of AMPK in the mechanism of motor nerve regeneration after injury. PMID- 29699637 TI - Risk factors for nasal bleeding in patients undergoing transnasal gastrointestinal endoscopy. AB - Transnasal endoscopy is widely used in screening for upper gastrointestinal lesions because of less associated pain. Nasal bleeding is the most severe adverse effect, but specific risk factors have not been identified. The aim of this study is to identify risk factors for nasal bleeding during transnasal endoscopy. Nasal bleeding occurred in 160/3035 (5.3%) of patients undergoing transnasal endoscopy as part of health checkups. Patient data were retrospectively evaluated including anthropometric, medical, and life-style parameters with multiple logistic regression analysis. Multiple logistic regression revealed that nasal bleeding was significantly associated with age in decades [odds ratio/10 years 0.78, 95% confidence interval (CI) 0.63-0.97, p = 0.027], female gender (2.15, 95% CI 1.48-3.12, p < 0.001), a history of previous upper gastrointestinal endoscopy (0.55, 95% CI 0.36-0.82, p = 0.004), and chronic/allergic rhinitis (0.60, 95% CI 0.36-0.98, p = 0.043). Other factors including the use of antiplatelet and/or anticoagulant drugs were not significantly associated with nasal bleeding. Female and young patients are significantly associated with an increased risk of bleeding from transnasal endoscopy, but antiplatelet and/or anticoagulant medications and a history of chronic/allergic rhinitis may not be associated. PMID- 29699639 TI - Rapid progression and mortality of necrotizing fasciitis caused by Aeromonas hydrophila in a patient with type I open tibial fracture. PMID- 29699640 TI - Eruptive vellus hair cysts in an unusual location with atypical pathological features. PMID- 29699642 TI - Editorial for JIP special issue on insect nutritional homeostasis. PMID- 29699641 TI - The Cellular Response to Transcription-Blocking DNA Damage. AB - In response to transcription-blocking DNA lesions such as those generated by UV irradiation, cells activate a multipronged DNA damage response. This response encompasses repair of the lesions that stall RNA polymerase (RNAP) but also a poorly understood, genome-wide shutdown of transcription, even of genes that are not damaged. Over the past few years, a number of new results have shed light on this intriguing DNA damage response at the structural, biochemical, cell biological, and systems biology level. In this review we summarize the most important findings. PMID- 29699643 TI - Admission, discharge and triage guidelines for paediatric intensive care units in Spain. AB - A paediatric intensive care unit (PICU) is a separate physical facility or unit specifically designed for the treatment of paediatric patients who, because of the severity of illness or other life-threatening conditions, require comprehensive and continuous inten-sive care by a medical team with special skills in paediatric intensive care medicine. Timely and personal intervention in intensive care reduces mortality, reduces length of stay, and decreases cost of care. With the aim of defending the right of the child to receive the highest attainable standard of health and the facilities for the treatment of illness and rehabilitation, as well as ensuring the quality of care and the safety of critically ill paediatric patients, the Spanish Association of Paediatrics (AEP), Spanish Society of Paediatric Intensive Care (SECIP) and Spanish Society of Critical Care (SEMICYUC) have approved the guidelines for the admission, discharge and triage for Spanish PICUs. By using these guidelines, the performance of Spanish paediatric intensive care units can be optimised and paediatric patients can receive the appropriate level of care for their clinical condition. PMID- 29699644 TI - Patient Health Questionnaire-9 in Patients With Broad-Spectrum Traumatic Brain Injury. PMID- 29699645 TI - The Authors Respond. PMID- 29699646 TI - Questionable Conclusions About Locomotor Training. PMID- 29699647 TI - Response to Letter to the Editor. PMID- 29699648 TI - Dysphagia (Trouble Swallowing) in People With Head and Neck Cancer. PMID- 29699649 TI - Structural characteristics and rheological properties of ovalbumin-gum arabic complex coacervates. AB - After formation of the ovalbumin (OVA)-gum arabic (GA) complex coacervates, a more ordered crystal structure was obtained, and the protein denaturation temperature increased from 72 to 96 degrees C. GA can reduce the pH-induced conformational perturbations of ovalbumin. The presence of GA improved the stability of the alpha-helix and beta-turn regions against pH, but showed less influence on the random coil and beta-sheet domains. The complex coacervates showed the highest viscosity value at pH 3.7 compared with the other pH values tested (4.0, 3.4, 3.0, 2.7) due to the stronger interactions of OVA and GA. A large thixotropic loop was observed for the coacervate obtained at pH 3.7 compared with that obtained at pH 4.0. Moreover, the salt concentration and OVA:GA ratio influenced the rheological properties by affecting the structure and composition of the complexes. A stronger interaction between OVA and GA led to greater viscoelastic properties. PMID- 29699651 TI - Effect of high pressure and thermal processing on shelf life and quality of strawberry puree and juice. AB - The purpose of the study was to determine the effects of high pressure processing (HPP; 400-600 MPa, 20 degrees C, 1.5 or 3 min) and heat treatment (HT; 85 degrees C for 2 min) of strawberry puree and juice made from the same raw material. Microbiological and enzymatic inactivation, Brix, pH, anthocyanins, vitamin C, colour and sensory properties were analysed after processing and cold storage. The microbiological shelf life of the products was at least 49 days when processed at 500 or 600 MPa. Anthocyanins, vitamin C and colour were well preserved after HPP and HT. During storage, anthocyanins, vitamin C and sensory quality were better conserved in HT than in HPP purees, while there were minor differences between HT and HPP juices. This was probably due to higher enzyme activity in HPP purees, and indicates that raw materials with lower initial enzyme activity, like juices, are more suited for HPP than e.g. purees. PMID- 29699650 TI - Extruded flour improves batter pick-up, coating crispness and aroma profile. AB - Fried battered foods are widely consumed worldwide. In this study, the influence of the replacement of native wheat flour by extruded flours (7.5 and 15%) subjected to different extrusion severities on chicken nuggets was assessed. Microstructure, pick-up, moisture and fat content, texture, colour, volatile profile, and consumer acceptability were evaluated. Extruded flour replacement resulted in batters with improved pick-up with increasing percentage and severity of extrusion treatment. Extruded flour also contributed to a moisture increase, while oil remained practically unchanged. Textural properties highlighted a higher crispness of batters made with high-severity treatment extruded flours. Volatile compounds analyses revealed lower amount of lipid oxidation (lower rancidity notes) and higher furfuryl alcohol content (pleasant aroma and darker crust) in fried batters containing extruded flour. Consumers testing showed that batters made with intermediate-severity treatment extruded flour presented the best acceptability. These results confirm that extruded flour inclusion improves the quality of deep-fried batters. PMID- 29699652 TI - A comparative metabolomics study of flavonoids in sweet potato with different flesh colors (Ipomoea batatas (L.) Lam). AB - To study the diversity and cultivar-specific of phytochemicals in sweet potato, Liquid Chromatography-Electrospray Ionization-Mass Spectrometry was used to analyze the metabolic profiles of five sweet potato cultivars exhibiting different flesh colors: purple, yellow/orange, and white. A total of 213 metabolites, including 29 flavonoids and 27 phenolic acids, were characterized. The flavonoid profiles of the five different cultivars were distinguished using PCA, the results suggested the flesh color accounted for the observed metabolic differences. In addition to anthocyanins, quinic acids and ferulic acids were the prominent phenolic acids, O-hexoside of quercetin, chrysoeriol were the prominent flavonoids in sweet potato tubers, and they were all higher in the OFSP and PFSP than WFSP. The main differential metabolic pathways between the OFSP, PFSP and the WFSP included those relating to phenylpropanoid and flavonoid biosynthesis. This study provides new insights into the differences in metabolite profiles among sweet potatoes with different flesh colors. PMID- 29699653 TI - Carbon dots based dual-emission silica nanoparticles as ratiometric fluorescent probe for nitrite determination in food samples. AB - In this work, a simple and effective strategy for designing a ratiometric fluorescent nanosensor was described. A carbon dots (CDs) based dual-emission nanosensor for nitrite was prepared by coating the CDs on to dye-doped silica nanoparticles. Dual-emission silica nanoparticles fluorescence was quenched in sulfuric acid using potassium bromate (KBrO3). The nitrite present catalyzed the KBrO3 oxidation, resulting in ratiometric fluorescence response of the dual emission silica nanoparticles. Several important parameters affecting the performance of the nanosensor were investigated. Under optimized conditions, the limit of detection was 1.0 ng mL-1 and the linear range 10-160 ng mL-1. Furthermore, the sensor was suitable for nitrite determination in different food samples. PMID- 29699654 TI - Effect of antioxidant compounds from seaweeds on storage stability of C20-22 polyunsaturated fatty acid concentrate prepared from dogfish liver oil. AB - Ethyl acetate extracts of seaweeds were chromatographically fractionated to yield 14-methyl pentyl tetrahydro-8-hydroxy-10-methylnaphthalene-8-carboxylate (1) and tetrahydro-4-isopropyl-9-(9, 14-dimethyldec-9-enyl)-pyran-1-one (2) from Sargassum ilicifolium, whereas Padina gymnospora afforded dihydro-2-(10 (hydroxymethyl)-7,15-dimethyl-9-oxoundec-11-enyl)-2-methyl-2H-pyran-1(4H)-one (3) and 1-(decahydro-1-hydroxy-7-methyl-8-vinylnaphthalen-2-yl)ethanone (4) as major constituents. Compound 1 displayed significantly higher antioxidant activity (IC50 < 1 mg/mL, p < 0.05) comparable to other analogues (IC50 > 1 mg/mL). The C20-22 polyunsaturated fatty acid (C20-22 PUFA) concentrate (CFA) prepared from the deep-sea dogfish liver oil was added with the studied compounds and physiochemical properties and fatty acid composition during an accelerated storage were evaluated. No significant reduction in C20-22 PUFAs (~6%) in the CFA treated with 1 as compared to that with the control (~35%) was recorded. A greater induction time was observed for the CFA supplemented with 1 (6.8 h) than other compounds (<=6 h) and control (~1.6 h), maintaining the oxidation indices of the CFA within desirable limits. PMID- 29699656 TI - Determination of drying kinetics and quality parameters of grape pomace dried with a heat pump dryer. AB - Pomace of Hamburg Muscat was dried at temperature of drying air 45 degrees C and different air velocity (1.5, 2.0 and 2.5 m/s) in open-loop heat pump (HP) and laboratory-type closed-loop dryer (as a control). In the HP dryer, it was concluded that drying air velocity was slightly effective on drying time however there is no significant effect on the power consumption of the change in the drying air velocity at the same temperature. When comparing the energy consumption of the HP dryer and convective dryer, the energy consumption was reduced by up to 51%. In HP drying, the increase of air velocity from 1.5 m/s to 2.5 m/s caused a reduction in drying time by 69%. It was observed that part of the bioactive properties was lost in pomace samples but there were fewer losses in all bioactive properties than the others except the total anthocyanin at 2 m/s. PMID- 29699655 TI - Emulsion droplet crystallinity attenuates early in vitro digestive lipolysis and beta-carotene bioaccessibility. AB - The impacts of lipid crystallinity on in vitro digestive lipolysis and bioaccessibility of encapsulated (0.1 wt%) beta-carotene (BC) were investigated for a 15 wt% cocoa butter emulsion prepared as crystalline (i.e. solid emulsions, SE & SE-BC) or undercooled (liquid emulsions, LE & LE-BC) droplets at 25 degrees C. Particle size distributions (D4,3 ~0.7 MUm), morphology (spherical), polymorphism (beta-V), thermal behavior (peak melting ~30 degrees C), zeta potential (~-44 mV) and BC degradation under accelerated lighting conditions were similarly extensive. Following exposure to simulated gastric conditions, duodenal hydrolysis and BC bioaccessibility were lower for SE-BC up to 2 h (P < 0.05). Ultimately, samples with both solid and liquid droplets were hydrolyzed extensively and BC bioaccessibility did not differ (P > 0.05). Therefore, for compositionally equivalent emulsions, lipid droplet solid state delayed digestive lipolysis and bioactive solubilization. These results help to clarify the role of lipid physical state on dietary lipid digestion and bioactive release. PMID- 29699657 TI - Qualitative and quantitative assessment of DNA quality of frozen beef based on DNA yield, gel electrophoresis and PCR amplification and their correlations to beef quality. AB - Freezing is a practical method for meat preservation but the quality of frozen meat can deteriorate with storage time. This research investigated the effect of frozen storage time (up to 66 months) on changes in DNA yield, purity and integrity in beef, and further analyzed the correlation between beef quality (moisture content, protein content, TVB-N value and pH value) and DNA quality in an attempt to establish a reliable, high-throughput method for meat quality control. Results showed that frozen storage time influenced the yield and integrity of DNA significantly (p < 0.05). The DNA yield decreased as frozen storage time increased due to DNA degradation. The half-life (t1/2 = ln2/0.015) was calculated as 46 months. The DNA quality degraded dramatically with the increased storage time based on gel electrophoresis results. Polymerase chain reaction (PCR) products from both mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) were observed in all frozen beef samples. Using real-time PCR for quantitative assessment of DNA and meat quality revealed that correlations could be established successfully with mathematical models to evaluate frozen beef quality. PMID- 29699658 TI - Two types of phenoloxidases contribute to hemolymph PO activity in spiny Lobster. AB - Phenoloxidases (POs) play a crucial role in melanization of crustaceans. There are at least two types of POs characterized in crustaceans: the conventional type (POalpha here) that is expressed in hemocytes and PObeta, a secreted protein synthesized in the hepatopancreas. We investigated the source of PO activity in the hemolymph of a lobster and determined the kinetic parameters of mono- and di PO activities. In the lobster hemolymph, POalpha, which formed a hexamer similar to both PObeta and hemocyanin, contributed to PO activity, whereas the amount of PObeta was low. Kinetic analyses using purified prophenoloxidase of crustaceans showed that lobster POalpha has a higher rate constant, while shrimp PObeta has higher specificity in both mono- and di-PO reactions, when tyramine and dopamine were employed as substrates. There should be at least two types of PO molecules in crustacean hemolymph, but the dominant PO molecule type varies among species. PMID- 29699659 TI - Air-assisted liquid-liquid microextraction integrated with QuEChERS for determining endocrine-disrupting compounds in fish by high-performance liquid chromatography-tandem mass spectrometry. AB - A new, sensitive, and rapid method based on the Quick, Easy, Cheap, Effective, Rugged and Safe (QuEChERS) approach and air-assisted liquid-liquid microextraction (AALLME) technology was developed for the determination of 20 endocrine-disrupting compounds (EDCs) in fish by high-performance liquid chromatography-tandem mass spectrometry. The method first integrates AALLME into QuEChERS to achieve clean-up and enrichment of the EDCs in one step. A self-made glass tube was enfolded with plasticine to withstand the high centrifugal force. The established method was developed by optimization of the parameters. High linearities (R2 > 0.9924) and recoveries (78.2-118.6%) at three spiked levels (5, 10, and 20 ng g-1), and low relative standard deviation values (1.1-14.5%) and limits of detection (0.03-0.80 ng g-1) were obtained. The method comparison shows that the proposed method is superior as it involves less organic solvent usage, simple operation and high efficiency. This method was successfully applied to different fishes for analyzing EDCs. PMID- 29699660 TI - Characterization and antioxidant activity of the complexes of tertiary butylhydroquinone with beta-cyclodextrin and its derivatives. AB - Tertiary butylhydroquinone (TBHQ) is a water-insoluble antioxidant. In this study, three cyclodextrin inclusion complexes were prepared to improve the water solubility of TBHQ and expand its range of application. Analysis of phase solubility indicated that TBHQ can form 1:1 inclusion complex with hydroxypropyl beta-cyclodextrin (HP-beta-CD) and dimethyl-beta-cyclodextrin (DM-beta-CD) and 1:2 inclusion complex with beta-cyclodextrin (beta-CD). The possible inclusion configuration between TBHQ and CDs was determined through FT-IR, PXRD, DSC, NMR, and SEM analyses. Results were validated by theoretical study of AutoDock molecular docking. The scavenging effects of the inclusion complexes were not effective on DPPH radical but higher on hydroxyl, superoxide and ABTS+ radicals than that of TBHQ monomer. Moreover, the water solubility of TBHQ increased after complexation with HP-beta-CD and DM-beta-CD. The stability of TBHQ is related to the type of storage materials used, and the stability can be improved by complexation with CDs. PMID- 29699661 TI - Fast and direct analysis of Cr, Cd and Pb in brown sugar by GF AAS. AB - A simple and fast analytical method for the determination of Cr, Pb and Cd in brown sugar by GF AAS using slurry sampling was developed and in house validated for the first time. Analytical curves were prepared by external standardization for Cr, and by matrix simulation for Pb and Cd and they were linear. Low limits of quantification for Cr (32.8 ng g-1), Pb (49.3 ng g-1) and Cd (4.5 ng g-1) were found. Repeatability and intermediate precision estimates (<10% and <15%, respectively) and recovery rates (95-103%) demonstrated a good precision and accuracy. The levels in brown sugar samples ranged from <32.8 to 160 ng g-1 for Cr, from <49.3 to 211.0 ng g-1 for Pb and from <4.5 to 7.0 ng g-1 for Cd and they may be assigned to anthropogenic activities and the adoption of inadequate practices of production and processing. PMID- 29699662 TI - Ruminant meat and milk contain delta-valerobetaine, another precursor of trimethylamine N-oxide (TMAO) like gamma-butyrobetaine. AB - Quaternary ammonium compounds containing N-trimethylamino moiety, such as choline derivatives and carnitine, abundant in meat and dairy products, are metabolic precursors of trimethylamine (TMA). A similar fate is reported for Nepsilon trimethyllysine and gamma-butyrobetaine. With the aim at investigating the metabolic profile of such metabolites in most employed animal dietary sources, HPLC-ESI-MS/MS analyses on ruminant and non-ruminant milk and meat were performed. Results demonstrate, for the first time, the presence of delta valerobetaine, occurring at levels higher than gamma-butyrobetaine in all ruminant samples compared to non-ruminants. Demonstration of delta-valerobetaine metabolic origin, surprisingly, showed that it originates from rumen through the transformation of dietary Nepsilon-trimethyllysine. These results highlight our previous findings showing the ubiquity of free Nepsilon-trimethyllysine in vegetable kingdom. Furthermore, delta-valerobetaine, similarly to gamma butyrobetaine, can be degraded by host gut microbiota producing TMA, precursor of the proatherogenic trimethylamine N-oxide (TMAO), unveiling its possible role in the biosynthetic route of TMAO. PMID- 29699663 TI - Development and stability evaluation of water-in-edible oils emulsions formulated with the incorporation of hydrophilic Hibiscus sabdariffa extract. AB - New functional oils (extra virgin olive oil, EVOO and sunflower oil, SO) containing antioxidants from Hibiscus sabdariffa extract were developed by W/O emulsion. Their physical and chemical stability was measured over time. The lowest coalescence rate was obtained with 8 and 12 wt% surfactant amount for EVOO and SO emulsions, respectively. Before the evaluation of the oxidative stability, an optimization of phenolic compounds extraction from emulsions by multi-response surface methodology was performed. EVOO emulsions were chemically more stable over time than SO emulsions in terms of total phenolic content (TPC), antioxidant activity and chemical composition measured by HPLC-ESI.TOF-MS. TPC significantly increased (from 2.02 +/- 0.07 to 2.71 +/- 0.06 mg Eq GAE/g extract) and the antioxidant activity measured by TEAC remained constant for 1 month of storage. Thus, W/O emulsion technology has proven to be a potential method to vehiculize and stabilize bioactive compounds from H. sabdariffa into edible oils. PMID- 29699664 TI - Aptamer-mediated colorimetric method for rapid and sensitive detection of chloramphenicol in food. AB - We report an aptamer-mediated colorimetric method for sensitive detection of chloramphenicol (CAP). The aptamer of CAP is immobilized by the hybridization with pre-immobilized capture probe in the microtiter plate. The horseradish peroxidase (HRP) is covalently attached to the aptamer by the biotin-streptavidin system for signal production. CAP will preferably bind with aptamer due to the high binding affinity, which attributes to the release of aptamer and HRP and thus, affects the optical signal intensity. Quantitative determination of CAP is successfully achieved in the wide range from 0.001 to 1000 ng/mL with detection limit of 0.0031 ng/mL, which is more sensitive than traditional immunoassays. This method is further validated by measuring the recovery of CAP spiked in two different food matrices (honey and fish). The aptamer-mediated colorimetric method can be a useful protocol for rapid and sensitive screening of CAP, and may be used as an alternative means for traditional immunoassays. PMID- 29699665 TI - Quantification of folpet and phthalimide in food by gas chromatography and mass spectrometry: Overcoming potential analytical artefacts. AB - Accurate quantification of folpet is problematic because it degrades into phthalimide during sample preparation and analysis by gas chromatography (GC). Thus, EU regulation was recently modified to include phthalimide in the folpet residue definition. However, recent studies have shown that phthalimide could also be generated from different sources, which could lead to an overestimation of the phthalimide content and therefore to false positives. GC coupled with either negative chemical ionisation and single quadrupole mass spectrometry, or electron ionisation with triple quadrupole mass spectrometry (GC-EI-MS/MS), were evaluated for the determination of folpet and phthalimide in food. Both methods were validated in 4 different matrices namely apple puree, rice flour, raspberry puree and infant formula. Better selectivity and precision were obtained with GC EI-MS/MS. Negligible amounts of phthalimide was found in blank matrices, and validation results met the SANTE/11813/2017 criteria in all matrices at the LOQ concentration levels by using GC-EI-MS/MS. PMID- 29699667 TI - Effect of degree of milling on physicochemical, structural, pasting and cooking properties of short and long grain Indica rice cultivars. AB - The effects of degree of milling (DOM) between 0 and 8% on physico-chemical, structural, pasting and cooking properties of short and long grain Indica rice cultivars were studied. Ash, protein, lipids and minerals decreased while blue value and crystallinity increased with increase in DOM. The colour parameters (a*, b*) and cooking time (CT) decreased while L*(lightness) increased with increase in DOM. Elongation ratio (ER), gruel solid loss (GSL), length/breadth (L/B) and paste viscosities during cooking increased with increase in DOM. Short grain rice contained lower ash, protein, lipids, Mn, K, Ca, CT and GSL than long grain while the later showed higher crystallinity, Mn, P, K, Ca and ER. Paste and dough characteristics measured using Rheometer and Mixolab, respectively correlated well and differed with cultivar and DOM. Short and long grain cultivars showed variation in loss of different chemical constituents during varied DOM causing variation in cooking characteristics. PMID- 29699666 TI - Molecular insight into the inclusion of the dietary plant flavonol fisetin and its chromophore within a chemically modified gamma-cyclodextrin: Multi spectroscopic, molecular docking and solubility studies. AB - We explored the encapsulation of dietary plant flavonols fisetin and its chromophore 3-hydroxyflavone, within 2-hydroxypropyl-gamma-cyclodextrin (HPgamma CDx) nano-cavity in aqueous solution using multi-spectroscopic approaches and molecular docking. Upon addition of HPgamma-CDx, dramatic changes occur in the intrinsic 'two color' fluorescence behavior of the fluorophores. This is manifested by significant increase in the steady state fluorescence intensities, anisotropies, average fluorescence lifetimes and rotational correlation times. Furthermore, in the CDx environment, intrinsically achiral flavonols exhibit prominent induced circular dichroism bands. These findings indicate that the flavonol molecules spontaneously enter the relatively hydrophobic, chiral environment of the HPgamma-CDx nano-cavities. Molecular docking computations corroborate the spectroscopic findings, and predict selectivity in orientation of the encapsulated flavonols. HPgamma-CDx inclusion increases the aqueous solubility of individual flavonols ~100-1000 times. The present study demonstrates that the hydroxypropyl substituent in gamma-CDx controls the inclusion mode of the flavonols, leading to their enhanced solubilization and altered spectral signatures. PMID- 29699668 TI - Polyphenolic profile of butterhead lettuce cultivar by ultrahigh performance liquid chromatography coupled online to UV-visible spectrophotometry and quadrupole time-of-flight mass spectrometry. AB - In the present study, the butterhead lettuce cultivar was analyzed by ultrahigh performance liquid chromatography (UHPLC) coupled online to diode array detection (DAD), electrospray ionization (ESI) and quadrupole time-of-flight mass spectrometry (QToF/MS) in the positive and negative ion mode in order to characterize its polyphenolic profile for the first time. The instrument acquisition mode MSE was used to collect automatic and simultaneous information of exact mass at high and low collision energies of precursor ions as well as other ions produced as a result of their fragmentation. One hundred eleven phenolic compounds were identified in the acidified hydromethanolic extract of freeze-dried leaves of butterhead lettuce cultivar: 40 hydroxycinnamic acid derivatives, 21 hydroxybenzoic acid derivatives, 2 hydroxyphenylacetic acid derivatives, 18 flavonols, 9 flavones, one flavanone, 7 coumarins, one hydrolysable tannin and 12 lignans. Forty-seven of these compounds have been tentatively identified for the first time in lettuce. PMID- 29699669 TI - Antityrosinase and antioxidant properties of mung bean seed proanthocyanidins: Novel insights into the inhibitory mechanism. AB - This study investigated the structure, antioxidant activity, antityrosinase activity and mechanism of proanthocyanidins from mung bean seed [Vigna radiata (L.) Wilczek]. The structural composition were characterized by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), electrospray ionization-full-mass spectrometry (ESI-Full-MS), and high-pressure liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-MS) techniques. The mung bean seed proanthocyanidins were composed of procyanidins, prodelphinidins, and their rhamnosides. According to enzyme kinetic analysis, these compounds were potent, reversible, and mixed-type inhibitors of tyrosinase. They inhibited the enzyme activity by interacting with enzyme as well as substrates. The results of molecular docking showed that the interaction between mung bean seed proanthocyanidins and tyrosinase was driven by hydrogen bond, hydrophobic and electrostatic interactions. In addition, mung bean seed proanthocyanidins were demonstrated as powerful antioxidants. Therefore, this study confirmed a novel tyrosinase inhibitor and would lay a scientific foundation for their utilization in pharmaceutical and food industries. PMID- 29699671 TI - Determination of l-cysteine origin on the basis of its delta15N values. AB - The majority of l-cysteine is obtained industrially by hydrolysis of animal materials, such as poultry feathers. Despite widespread belief, there is little evidence that human hair is used as a source material and its use is explicitly banned in the European Union (2000/63/EC decision). We developed an isotope ratio mass spectrometric (EA-IRMS) method to determine carbon and nitrogen isotopic ratio in cysteine preparations and related compounds, e.g. cystine and carbocysteine. A threshold relying on the 15N/14N was established to differentiate between hair and feathers; a value below 6.60/00 indicates a poultry feathers origin. Global uncertainty of measurement was found to be 0.10/00 for delta15N (sample size of 0.5-1.8 mg). PMID- 29699670 TI - Chlorogenic acid induces resistance against Penicillium expansum in peach fruit by activating the salicylic acid signaling pathway. AB - The objective of this study was to investigate the effect of chlorogenic acid (CGA) treatment on induction of resistance against pathogens in peach fruit. Treatment with CGA at 25-150 mg L-1 was effective at reducing lesion diameter and decay index of peach fruit during storage at 25 degrees C after Penicillium expansum infection. CGA treatment had also significant beneficial effects on fruit quality parameters including firmness, soluble solids contents, pH value, and titratable acidity. Activities of main defense-related enzymes and expression of key genes involved in the salicylic acid (SA) signaling pathway, such as PAL, ICS, WRKY, NPR1, PR1, CHI, GLU, PR5, and POD, were enhanced by CGA treatment. These findings suggest that CGA treatment is a promising approach to controlling postharvest blue mold rot in peach fruit, and activation of the SA signaling pathway may play a potential role in mechanisms involving CGA-induced plant disease resistance. PMID- 29699672 TI - Essential oils (EOs), pressurized liquid extracts (PLE) and carbon dioxide supercritical fluid extracts (SFE-CO2) from Algerian Thymus munbyanus as valuable sources of antioxidants to be used on an industrial level. AB - The aim of this study was to demonstrate the potential of extracts from Algerian Thymus munbyanus as a valuable source of antioxidants for use on an industrial level. To this end, a study was conducted on the composition and antioxidant activities of essential oils (EOs), pressurized liquid extracts (PLE) and supercritical fluid extracts (SFE-CO2) obtained from Thymus munbyanus subsp. coloratus (TMC) and subsp. munbyanus (TMM). EOs and SFE-CO2 extracts were analysed by GC-FID and GC*GC-TOFMS revealing significant differences. A successive extraction of the solid SFE-CO2 residue by PLE extraction with solvents of increasing polarity such as acetone, ethanol and water, was carried out. The extracts were evaluated for total phenolic content by Folin-Ciocalteu assay, while the antioxidant power was assessed by DPPH, FRAP, and ORAC assays. SFE-CO2 extracts were also analysed for their tocopherol content. The antioxidant activity of PLE extracts was found to be higher than that of SFE-CO2 extracts, and this increased with solvent polarity (water > ethanol > acetone). Overall, these results support the use of T. munbyanus as a valuable source of substances to be used on an industrial level as preservative agents. PMID- 29699673 TI - Phosphoesterification of soybean and peanut proteins with sodium trimetaphosphate (STMP): Changes in structure to improve functionality for food applications. AB - Soybean and peanut protein isolates underwent phosphorylation using sodium trimetaphosphate (STMP). Changes in functional properties and the influence of STMP (1, 2 or 3% w/w), pH (11.5 or 12.5), temperature (35 or 55 degrees C) and time (3 or 5 h) were evaluated. The highest degree of phosphorylation was achieved at 2% of STMP and pH 12.5. The best specific conditions varied according to the raw material: in soybean, 25% phosphorylation was achieved at 55 degrees C and 5 h whereas in peanut, 30% was reached at 35 degrees C and 3 h. The modified proteins showed an improved emulsifying activity (27.3% for soybean and 6.6% for peanut), whereas NSI for soybean increased more than three times and for peanut decreased by half. In vitro digestibility improved in both isolates around 1.5%. These results showed that phosphorylation with STMP of peanut and soybean proteins yielded isolates with a wide array of potential applications in food systems. PMID- 29699674 TI - Mechanistic insight into the relationship between triacylglycerol and crystallization of lipase-catalyzed interesterified blend of palm stearin and vegetable oil. AB - To give a deep insight into the relationship between triacylglycerol and crystallization of interesterified fat, the blends of palm stearin and various vegetable oil were catalyzed by two different immobilized lipases in this study. After interesterification, the blends had wider plastic range indicated by the SFC results and more beta' crystal. The improved physicochemical characteristics of interesterified blends were attributed to their changed TAG profiles. The statistical analysis showed that the interesterified blends were more likely to form beta' crystal with the increase of SU2-type TAG content and the decrease of SSS-type TAG content (p < 0.01). In addition, the decrease of ECN 42- and ECN 48 type TAGs and the increase of ECN 50-type TAGs also significantly enhanced the formation of beta' crystal (p < 0.05). Furthermore, the sn-1,3-specific Lipozyme TL IM-catalyzed interesterified blends were favorable for the formation of beta' crystal than the non-specific Novozym 435-catalyzed interesterified blends. PMID- 29699675 TI - Comparative study on the chemical composition, anthocyanins, tocopherols and carotenoids of selected legumes. AB - Twenty-nine legumes were assessed for their nutritional and phytochemical compositions. Soybean and black soybean had the highest protein contents (34.05 42.65 g/100 g DW, dry weight of legumes), particularly being a rich source of lysine (1.78-2.23 g/100 g DW. Soybean and black soybean had the highest fat contents (14.13-22.19 g/100 g DW). Broad beans had the highest unsaturated fatty acids (83.57-89.01 g/100 g fatty acid), particularly rich in alpha-linolenic and linoleic acid. The highest and the lowest dietary fiber were found in red kidney beans (35.36 g/100 g DW) and mung beans (22.77 g/100 g DW), respectively. Except for soybean and white kidney bean, 6 major anthocyanins in the legumes samples were identified. The soybean contained the highest total tocopherols content (90.40-120.96 MUg/g dry weight of beans), followed by black soybean (66.13-100.76 MUg/g DW). The highest carotenoids were found in lentils (4.53-21.34 MUg/g DW) and red kidney beans (8.29-20.95 MUg/g DW). PMID- 29699676 TI - Effects of season and industrial processes on volatile 4-alkyl-branched chain fatty acids in sheep milk. AB - 4-alkyl-branched-chain fatty acids (vBCFAs) are responsible for the goaty-sheepy flavour of sheep and goat milk. The levels of vBCFAs were investigated in sheep, goat and cow milk powders. The effect of season and industrial processes on the levels of vBCFAs in sheep milk was also evaluated. Sheep milk powders contained lower amounts of 4-Me-8:0 and 4-Et-8:0 (143-176 and 1.2-10.7 ug/g milk fat) than goat milk powders (335-481 and 73.1-105 ug/g milk fat), while 4-Me-9:0 was low in both sheep and goat milk powders (<8 ug/g milk fat). Odour activity values (OAVs) of sheep milk powders (17-393) were 6-fold lower than the values of goat milk powders (882-1323). Higher levels of vBCFAs were found in sheep milk produced in spring than in summer. Thermisation had little impact on vBCFAs; however, spray drying led to dramatic increases in free vBCFAs, particularly towards late lactation, which resulted in higher OAVs in sheep milk powder compared to raw milk. PMID- 29699678 TI - Effect-directed classification of biological, biochemical and chemical profiles of 50 German beers. AB - Biological and biochemical fingerprints were investigated for the first time for the feasibility of effect-directed classification, and thus, to allow the choice of a distinct beer with regard to beneficial health effects. A high-performance thin-layer chromatography method was newly developed and combined with in situ effect-directed analysis for profiling 50 German beers for multipotent active compounds, and thus, their health-related potential. Discovered multipotent active zones were online eluted and characterized by high resolution mass spectrometry. For example, isoxanthohumol, iso-alpha-ad/n-humulone or its isomers, desdimethyl-octahydro-isocohumulone and ad/n-humulone were proven as antimicrobial compounds, isoxanthohumol as an acetylcholinesterase inhibitor, and isoxanthohumol and iso-alpha-ad/n-humulone or its isomers as radical scavengers. Investigating multivariate data analysis of effect-directed fingerprints for the first time, the pattern recognition and classification results showed the power of clustering non-alcoholic beers from other types of beer, or it showed the differentiation of dark and non-alcoholic beers. PMID- 29699677 TI - Simultaneous determination of multi-residue and multi-class antibiotics in aquaculture shrimps by UPLC-MS/MS. AB - An accurate, reliable and fast multi-residue, multi-class method using ultra performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) was developed and validated for simultaneous determination and quantification of 24 pharmacologically active substances of three different classes (Quinolones including fluoroquinolones, sulphonamides and tetracyclines) in aquaculture shrimps. Sample preparation involves extraction with acetonitrile containing 0.1% formic acid and followed by clean up with n-hexane and 0.1% methanol in water by UPLC-MS/MS within 8 min. The method was validated according to European Commission Decision 2002/657. Acceptable values were obtained for linearity (5 200 MUg kg-1), specificity, Limit of Quantification (5-10 MUg kg-1), recovery (between 83 and 100%), repeatability (RSD < 9%), within lab reproducibility (RSD < 15%), reproducibility (RSD <= 22%), decision limit (105-116 MUg kg-1) and detection capability (110-132 MUg kg-1). The validated method was applied to aquaculture shrimp samples from India. PMID- 29699679 TI - Impact of oligomeric procyanidins on wheat gluten microstructure and physicochemical properties. AB - We found that oligomeric procyanidins improve the physicochemical properties of wheat flour, and that a more compact and denser gluten microstructure is formed when an increasing amount of oligomeric procyanidins is incorporated. Further, we found that oligomeric procyanidins alter the rheological properties, molecular weight distribution, secondary structure, and thermal stability of gluten, and that oligomeric procyanidins alleviate the loss of extensibility and viscosity after the dough is exposed to high temperatures. Collectively, these results imply that oligomeric procyanidins improve the rheological properties of flour based foods, likely by (1) regulating sulfhydryl/disulfide redox reactions in the gluten network and impairing the formation of large polymers, and by (2) binding to hydrophobic sites in gluten proteins and altering their conformation. PMID- 29699680 TI - Acrylamide content in French fries prepared in households: A pilot study in Spanish homes. AB - An observational cross-sectional pilot study in 73 Spanish households was conducted to evaluate the impact of consumer practices on the formation of acrylamide during the preparation of French fries from fresh potatoes applying one stage frying. 45.2% of samples presented acrylamide concentrations above the benchmark level for French fries (500 ug/kg). 6.9% of samples exceeded 2000 ug/kg and the 95th percentile was 2028 ug/kg. The median and average values were significantly higher than the EFSA report for this food category, suggesting that the total exposure to acrylamide by the population could be underestimated. In this randomised scenario of cooking practices, the content of reducing sugar and asparagine did not explain the acrylamide levels. However, the chromatic parameter a* of the fried potato was a powerful tool to classify the samples according to the acrylamide benchmark level regardless of the agronomical characteristics of the potato or the consumer practices. PMID- 29699682 TI - Gold-nanoparticle-based fluorescent "turn-on" sensor for selective and sensitive detection of dimethoate. AB - A simple approach to fabricate a highly selective and sensitive dimethoate probe was developed based on Rhodamine B (RB)-functionalized gold nanoparticles (AuNPs). The quenching of RB fluorescence in the presence of AuNPs in the solution, mediated by fluorescence resonance energy transfer, was observed. In the presence of dimethoate, the fluorescence intensity of the RB-AuNP solution is gradually recovered when dimethoate molecules displace RB molecules on the surface of the AuNPs, which significantly increased the fluorescence intensity of RB. Fluorescence is proportional to the dimethoate concentration in the range of 0.005-1.0 ppm (R2 = 0.989), and the LOD was 0.004 ppm. The recoveries of dimethoate in water and fruit samples were 86-116% with a good RSD (< 9.3%). Because of its high sensitivity, excellent selectivity, and convenient fabrication process, this method is a promising candidate for dimethoate screening. PMID- 29699681 TI - Dipping probe electrospray ionization/mass spectrometry for direct on-site and low-invasive food analysis. AB - Rapid, direct, on-site and noninvasive food analysis is strongly needed for quality control of food. To satisfy this demand, the technique of dipping probe electrospray ionization/mass spectrometry (dPESI/MS) was developed. The sample surface was pricked with a fine acupuncture needle and a sample of ~200 pL was captured at the needle tip. After drying the sample, the needle tip was dipped into the solvent for ~50 ms and was moved upward. A high-voltage was applied to the needle to generate electrospray when the needle reached the highest position, and mass spectra were measured with a time-of-flight mass spectrometer. For evaluation of the method, the technique was used to analyze foods such as vegetables, salmon flesh, cow's milk, yogurt, and soy-bean milk. The detected major ions for cow's milk and yogurt were [(Lac)n + Ca]2+ with n = 1-6 (where (Lac) is lactose), indicating that Ca2+ is tightly bound by Lac molecules. PMID- 29699684 TI - Characterization of food additive-potato starch complexes by FTIR and X-ray diffraction. AB - Fourier-transform infrared spectroscopy (FTIR) and X-ray diffraction (XRD) techniques were used to study the effect of four food additives, agar, alginate, lecithin and glycerol, at three different concentrations, 0.5, 1 and 1.5%, on the molecular structure of potato puree prepared from commercial potato powder. Vibrational spectra revealed that the amylose-amylopectin skeleton present in the raw potato starch was missing in the potato powder but could be fully recovered upon water addition when the potato puree was prepared. FTIR peaks corresponding to water were clearly present in the potato powder, indicating the important structural role of water molecules in the recovery of the initial molecular conformation. None of the studied puree samples presented a crystalline structure or strong internal order. A comparison of the FTIR and XRD results revealed that the additives exerted some effects, mainly on the long-range order of the starch structure via interacting with and changing -OH and hydrogen bond interactions. PMID- 29699683 TI - Residue dissipation and risk assessment of tebuconazole, thiophanate-methyl and its metabolite in table grape by liquid chromatography-tandem mass spectrometry. AB - An efficient method was developed and validated for simultaneous determination of tebuconazole, thiophanate-methyl and its metabolite carbendazim in grape and soil using QuEChERS procedure and liquid chromatography-tandem mass spectrometry. The average recoveries of the method were 83.2%-105.4%, the limit of detection (LOD) ranged from 2.1 * 10-5 to 8.7 * 10-4 mg L-1, and the limit of quantitation (LOQ) was 0.1 mg kg-1. The field results showed that tebuconazole and thiophanate methyl in soil and grape were rapidly dissipated with half-lives less than 24.7 days. The terminal residues of all analytes in grape were lower than the maximum residue limit (MRL) set by China (2 mg kg-1 for tebuconazole; 3 mg kg-1 for both thiophanate-methyl and carbendazim). Risk assessment showed that tebuconazole, thiophanate-methyl and its metabolite would be unlikely to cause health problems. However, carbendazim, the higher active metabolites of thiophanate-methyl, should receive more concerns. PMID- 29699685 TI - Evaluation of the physicochemical stability and digestibility of microencapsulated esterified astaxanthins using in vitro and in vivo models. AB - Esterified astaxanthins are used as functional nutraceuticals in many food products. Unfortunately, their utilization is currently limited owing to their poor water solubility, chemical instability, and low bioavailability. In this study, esterified astaxanthin microcapsules were fabricated through electrostatic complexation of whey protein and gum arabic by adjusting the pH to 4.0. After their encapsulation, the stability of the esterified astaxanthins was effectively better than that of the oleoresin. In vitro tests revealed a 26% rate of astaxanthin release from the microcapsules, which was significantly higher than the 14.6% rate from the oleoresin (P < 0.05). In vivo experiments showed that the AUC0-t value after oral gavage of the microcapsules (8.23 +/- 1.33 h.MUg.mL-1) was approximately 2-fold higher than that after gavage of the oleoresin (3.72 +/- 0.98 h.MUg.mL-1). In conclusion, the bioavailability of esterified astaxanthins can be significantly improved by microencapsulation. PMID- 29699686 TI - Physiological and proteomic analyses of coix seed aging during storage. AB - Although a series of physio-biochemical changes of coix seed occur during the storage, the underlying mechanism remains unknown. The present study aimed to investigate the aging mechanism of coix seed during storage. Proteome patterns of coix seed stored for 1-month, 5-month and 10-month at room temperature were compared using 2-dimensional gel electrophoresis (2-DE) and mass spectra. Thirty one differentially expressed proteins (DEPs) were detected, which involved seven pathways including starch and sucrose metabolism, carbon metabolism, RNA transport, proteasome, protein processing in endoplasmic reticulum, ribosome, and RNA degradation. Sucrose synthase 1 was associated with sucrose metabolism and affected the sucrose content during the storage. Increased ambient temperature enhanced respiration of coix after 5-month storage, and overexpression of aconitate hydratase 2 promoted the generation of energy. In addition, the proteins involved in the antioxidant system and resistance stimulus of coix seed were mostly up-regulated during storage. PMID- 29699687 TI - Effect of gallic acid/chitosan coating on fresh pork quality in modified atmosphere packaging. AB - Fresh meat safety and quality is a major concern of consumers in the current food market. The objective of this research was to investigate a newly developed gallic acid/chitosan edible coating on the preservation of fresh pork quality in modified atmosphere package (MAP) stored at 4 degrees C. The pork loins were coated with 2% chitosan (CHI), 0.2% gallic acid in 2% chitosan (CHI/0.2G), or 0.4% gallic acid in 2% chitosan (CHI/0.4G). Results showed that the antimicrobial activity of the chitosan coating was increased with the incorporation of gallic acid. The CHI/0.2G and CHI/0.4G pork loins also had lower lipid oxidation and myoglobin oxidation. However, the CHI/0.4G sample exhibited a pro-protein oxidation effect, suggesting an optimal concentration of gallic acid should be incorporated. This research provides a practical method in application of gallic acid/chitosan coatings on preservation of fresh pork to improve the safety and quality in MAP environment. PMID- 29699688 TI - Propolis wax nanostructured lipid carrier for delivery of beta sitosterol: Effect of formulation variables on physicochemical properties. AB - Preparation and characterization of novel functional nanostructured lipid carriers containing beta sitosterol has been studied. The nanostructured lipid carrires (NLCs) were formulated with propolis wax (PW) alone or in mixture (1:1 w/w) with glyceryl behenate (GB), and pomegranate seed oil (PSO) and produced by a hot melt emulsification method. Response surface methodology was used to optimize formulations with respect to beta sitosterol concentration, liquid lipid content and solid lipid composition. The NLCs formulated with less oil and higher drug content showed higher size and lower encapsulation efficiency. Solid state analysis exhibited lower crystallinity of optimal formulations compared to raw lipids and a drug amorphization into the NLC matrix. The compatibility between drug and encapsulating materials was confirmed by Fourier transform infrared spectroscopy. Transmission electron microscopy showed spherical particles ranged around 100 nm confirming the applicability of such formulations for the production of functional foods. PMID- 29699689 TI - Follicle-Stimulating Hormone Receptor: Advances and Remaining Challenges. AB - Follicle-stimulating hormone (FSH) is produced in the pituitary and is essential for reproduction. It specifically binds to a membrane receptor (FSHR) expressed in somatic cells of the gonads. The FSH/FSHR system presents many peculiarities compared to classical G protein-coupled receptors (GPCRs). FSH is a large naturally heterogeneous heterodimeric glycoprotein. The FSHR is characterized by a very large NH2-terminal extracellular domain, which binds FSH and participates to the activation/inactivation switch of the receptor. Once activated, the FSHR couples to Galphas and, in some instances, to other Galpha-subunits. GPCR kinases and beta-arrestins are also recruited to the FSHR and account for its desensitization, the control of its trafficking and its intracellular signaling. Of note, the FSHR internalization and recycling are very fast and involve very early endosomes (EE) instead of EE. All the transduction mechanisms triggered upon FSH stimulation lead to the activation of a complex signaling network that controls gene expression by acting at multiple levels. The integration of these mechanisms not only leads to context-adapted responses from the target gonadal cells but also indirectly affects the fate of germ cells. Depending on the physiological/developmental stage, FSH elicits proliferation, differentiation, or apoptosis in order to maintain the homeostasis of the reproductive system. Pharmacological tools targeting FSHR recently came to the fore and open promising prospects both for basic research and therapeutic applications. This chapter provides an updated review of the most salient aspects and peculiarities of FSHR biology and pharmacology. PMID- 29699690 TI - Spatiotemporal Modulation of ERK Activation by GPCRs. AB - ERK1/2 (extracellular signal-regulated protein kinases) are the nodal proteins that regulate diverse cellular functions primarily in response to activation from receptor tyrosine kinases (RTKs). Not only is ERK activated through a variety of RTKs, but noncanonical signaling through GPCRs also activates them. Such multimodal activation allows appropriate integration of many inputs to critical cell fate decisions such as proliferation and differentiation that MAP kinases typically regulate. MAP kinases also regulate many polar responses such as apoptosis and proliferation, dedifferentiation-differentiation, and the diversity in the outcomes though the same terminal molecule can be explained based on differences in the activation dynamics and rates. However, two processes have now been established as drivers for most of the diversity recorded in the outcomes of MAP kinase signaling. These parameters are cellular compartmentalization, i.e., spatial confinement of the molecules participating in a pathway and changes in the kinetics of the activation-deactivation, i.e., temporal regulation. While phosphorylation is the key to activating responses, specifically for ERK, the terminal MAP kinase, it is the spatiotemporal dynamics that governs the outcome generated by it. This chapter reviews our present understanding of the spatial and temporal regulation of MAP kinase cascade and the ERK activity, specifically through GPCRs. PMID- 29699691 TI - The Dynamics of GPCR Oligomerization and Their Functional Consequences. AB - The functional importance of G protein-coupled receptor (GPCR) oligomerization remains controversial. Although obligate dimers of class C GPCRs are well accepted, the generalizability of this phenomenon is still strongly debated with respect to other classes of GPCRs. In this review, we focus on understanding the organization and dynamics between receptor equivalents and their signaling partners in oligomeric receptor complexes, with a view toward integrating disparate viewpoints into a unified understanding. We discuss the nature of functional oligomeric entities, and how asymmetries in receptor structure and function created by oligomers might have implications for receptor function as allosteric machines and for future drug discovery. PMID- 29699692 TI - Melatonin Receptor Signaling: Impact of Receptor Oligomerization on Receptor Function. AB - The melatonin receptor subfamily is composed of three members, MT1 and MT2, which are binding to melatonin, and GPR50, which shows high sequence homology to MT1 and MT2 but does not bind to melatonin or any other known ligand. An interesting feature of these receptors is their capacity to form homo- and heteromers between each other and also with other GPCRs. The following heteromers have been described: MT1/MT2, MT1/GPR50, and heteromers composed of MT2 and the serotonin 5 HT2c receptor or the orphan GPR61, GPR62, and GPR135 receptors. These heteromers represent novel pharmacological entities as they exhibit functional properties that are different from those of the corresponding homomers. Formation of several of these heteromers has been confirmed in tissues. MT2/5-HT2c heteromers are targeted by the clinically relevant antidepressant agomelatine, and MT1/MT2 heteromers regulate nocturnal retinal light sensitivity. Here, we resume our current knowledge on melatonin receptor heteromerization and discuss how it contributes to the diversification of the function of melatonin receptors. PMID- 29699693 TI - ERK Activation Pathways Downstream of GPCRs. AB - GPCRs, the 7-TM receptors, represent a class of cell surface receptors which modulate a variety of physiological responses. The serpentine structure in addition to contributing the diversity of stimuli these receptors can sense also provides flexibility to the extracellular and intracellular regions where other proteins can interact with and can form functionally active multimeric entities. The range in signaling and physiological responses generated by these receptors can be attributed to a large repertoire of the receptor subtypes as well as their differential coupling to various classes of G-protein subunits and other proteins which facilitate multistate activation. A multistate GPCR can engage diverse signaling molecules, thereby modulating not only the canonical cellular responses but also noncanonical responses typically associated with activation of other cascades such as RTK and MAPK/ERK signaling. Given the crucial involvement of MAP kinase/ERK signaling in cell fate determination specially with respect to regulating cell proliferation, cellular apoptosis, and survival, GPCR-mediated cross-activation of MAPK has been explored in various systems and shown to involve functional integration of multiple pathways. This review describes the present knowledge of the different mechanisms of ERK activation downstream of GPCRs and our present understanding of receptor-dependent and -independent MAPK activation cascades. PMID- 29699694 TI - Multi-disciplinary clinical protocol for the diagnosis of bulbar amyotrophic lateral sclerosis. AB - INTRODUCTION AND OBJECTIVES: The objective of this study was to examine the role of different specialists in the diagnosis of amyotrophic lateral sclerosis (ALS), to understand changes in verbal expression and phonation, respiratory dynamics and swallowing that occurred rapidly over a short period of time. MATERIALS AND METHODS: 22 patients with bulbar ALS were submitted for voice assessment, ENT evaluation, Multi-Dimensional Voice Program (MDVP), spectrogram, electroglottography, fiberoptic endoscopic evaluation of swallowing. RESULTS: In the early stage of the disease, the oral tract and velopharyngeal port were involved. Three months after the initial symptoms, most of the patients presented hoarseness, breathy voice, dysarthria, pitch modulation problems and difficulties in pronunciation of explosive, velar and lingual consonants. Values of MDVP were altered. Spectrogram showed an additional formant, due to nasal resonance. Electroglottography showed periodic oscillation of the vocal folds only during short vocal cycle. Swallowing was characterized by weakness and incoordination of oro-pharyngeal muscles with penetration or aspiration. CONCLUSIONS: A specific multidisciplinary clinical protocol was designed to report vocal parameters and swallowing disorders that changed more quickly in bulbar ALS patients. Furthermore, the patients were stratified according to involvement of pharyngeal structures, and severity index. PMID- 29699695 TI - Results of a national survey about perioperative care in gastric resection surgery. AB - INTRODUCTION: Enhanced recovery after surgery programs in abdominal surgery are being established progressively. The aim of this study is to evaluate the application of different perioperative care measures in gastric surgery by Spanish surgeons. METHODS: A descriptive study of 162 surveys answered from September to December 2017 about the management and perioperative care in non bariatric gastric resection surgery. RESULTS: Antibiotic and antithrombotic prophylaxis are always used by 96.9 and 99.4%, respectively; 62.7% recommend a fasting time for liquids greater than 6hours and only 3% use preoperative carbohydrate drinks. Only 32.4 and 13.3% of subtotal and total gastrectomies are performed laparoscopically; 56.8% use epidural analgesia and drains are always placed by 53.8% in total gastrectomy. Nasogastric tubes are used selectively by 34.6% and always by 11.3%. Bladder catheters are removed during the first 48hours by 77.2%. In the first 24 postoperative hours, less than 20% indicate oral intake and 15.4% mobilize their patients; 49.3% indicate walking after the first 24hours; 30.4% apply a clinical pathway for the care of these patients and only 15.2% used an enhanced recovery after surgery protocol. CONCLUSIONS: The implementation of enhanced recovery after surgery measures in non-bariatric gastric resection surgery is not widespread in our country. PMID- 29699696 TI - Adaptive nonsingular fast terminal sliding-mode control for the tracking problem of uncertain dynamical systems. AB - In this paper, robust and adaptive nonsingular fast terminal sliding-mode (NFTSM) control schemes for the trajectory tracking problem are proposed with known or unknown upper bound of the system uncertainty and external disturbances. The developed controllers take the advantage of the NFTSM theory to ensure fast convergence rate, singularity avoidance, and robustness against uncertainties and external disturbances. First, a robust NFTSM controller is proposed which guarantees that sliding surface and equilibrium point can be reached in a short finite-time from any initial state. Then, in order to cope with the unknown upper bound of the system uncertainty which may be occurring in practical applications, a new adaptive NFTSM algorithm is developed. One feature of the proposed control law is their adaptation techniques where the prior knowledge of parameters uncertainty and disturbances is not needed. However, the adaptive tuning law can estimate the upper bound of these uncertainties using only position and velocity measurements. Moreover, the proposed controller eliminates the chattering effect without losing the robustness property and the precision. Stability analysis is performed using the Lyapunov stability theory, and simulation studies are conducted to verify the effectiveness of the developed control schemes. PMID- 29699697 TI - The reliability of operative rating tool evaluations: How late is too late to provide operative performance feedback? AB - BACKGROUND: Operative rating tools can enhance performance assessment in surgical training. However, assessments completed late may have questionable reliability. We evaluated the reliability of assessments according to evaluation time-to completion. METHODS: We stratified assessments from MileMarker'sTM Operative Entrustability Assessment by evaluation time-to-completion, using concordance correlation coefficient (CCC) between self-assessment and evaluator scores as a measure of reliability. RESULTS: Overall, self-assessment and evaluator scores were strongly correlated (CCC = 0.72; p < 0.001) though self-assessments were slightly higher (p = 0.048). Reliability remained stable for evaluations completed within 0 days (CCC = 0.77; p < 0.001), 1-3 days (CCC = 0.73; p < 0.001), and 4-13 days after surgery (CCC = 0.69; p < 0.001), but dropped for evaluations completed within 14-38 days (CCC = 0.60; p < 0.001) and over 38 days (CCC = 0.54; p < 0.001) after surgery. There was strong evidence for an interaction between time-to-completion and reliability (p < 0.001). CONCLUSIONS: Our data support the reliability of assessments completed until 2 weeks after surgery. This finding may help refine the interpretation of evaluation scores as surgical specialties move toward competency-based accreditation. PMID- 29699698 TI - Is functional gallbladder disease truly increasing? Results from the Rochester Epidemiology Project. AB - INTRODUCTION: Reports from US administrative databases showed an increase in cholecystectomy rate for functional gallbladder disorder (FGBD), a disease is not well recognized elsewhere. We aimed to identify the incidence and cholecystectomy rate for FGBD in an epidemiologically well-defined and prospectively studied population and compare results to published data. METHODS: After IRB approval, we extracted data from the NIH funded Rochester Epidemiology Project. We used ICD-9 codes (575.8) and (575.9) to identify patients with FGBD from 2000 to 2014. RESULTS: Between 2000 and 2014 we identified 253 patients with specified ICD-9 codes and no stones among a population of 135,000. Based on their medical records, 24 patients had confirmed FGBD, the incidence was 1.77/10,000 and cholecystectomy rate was for these patients was 70%. CONCLUSION: The incidence of FGBD was much lower than State data with similar cholecystectomy rate. Additional investigation may be needed to understand if cholecystectomy rate is truly increasing. PMID- 29699699 TI - Reply. PMID- 29699700 TI - The effects of cognitive-behavior therapy for depression on repetitive negative thinking: A meta-analysis. AB - It is not clear if treatments for depression targeting repetitive negative thinking (RNT: rumination, worry and content-independent perseverative thinking) have a specific effect on RNT resulting in better outcomes than treatments that do not specifically target rumination. We conducted a systematic search of PsycINFO, PubMed, Embase and the Cochrane library for randomized trials in adolescents, adults and older adults comparing CBT treatments for (previous) depression with control groups or with other treatments and reporting outcomes on RNT. Inclusion criteria were met by 36 studies with a total of 3307 participants. At post-test we found a medium-sized effect of any treatment compared to control groups on RNT (g = 0.48; 95% CI: 0.37-0.59). Rumination-focused CBT: g = 0.76, <0.01; Cognitive Control Training: g = 0.62, p < .01; CBT: g = 0.57, p < .01; Concreteness training: g = 0.53, p < .05; and Mindfulness-based Cognitive Therapy: g = 0.42, p < .05 had medium sized and significantly larger effect sizes than other types of treatment (i.e., anti-depressant medication, light therapy, engagement counseling, life review, expressive writing, yoga) (g = 0.14) compared to control groups. Effects on RNT at post-test were strongly associated with the effects on depression severity and this association was only significant in RNT focused CBT. Our results suggest that in particular RNT-focused CBT may have a more pronounced effect on RNT than other types of interventions. Further mediation and mechanistic studies to test the predictive value of reductions in RNT following RNT-focused CBT for subsequent depression outcomes are called for. PMID- 29699701 TI - AIBP decreases atherogenesis by augmenting cholesterol efflux. PMID- 29699702 TI - Corrigendum to "On-line confidence monitoring during decision making" [Cognition 171 (2018) 112-121]. PMID- 29699703 TI - Where are we with haemolytic uremic syndrome? AB - Haemolytic uremic syndrome (HUS) is characterised by microangiopathic haemolytic anaemia with acute kidney injury. It is currently classified into two main categories: Shiga-toxin producing E. coli-hemolytic uremic syndrome (STEC-HUS) and atypical haemolytic uremic syndrome (aHUS). Endothelial cell damage is the common pathway in HUS to developing thrombotic microangiopathy. Atypical HUS includes primary, secondary and aHUS due to metabolic diseases. In the majority of aHUS cases, hyperactivity of the alternative complement pathway plays a central role. Therefore, treatment is based on complement inhibitors like eculizumab, a drug that has revolutionised the natural history of the disease. Relapses are frequent after kidney transplant and thus confer a poor prognosis. PMID- 29699704 TI - Knowledge translation strategies to improve health care. PMID- 29699705 TI - Assessment of ecological and human health risks of metals in urban road dust based on geochemical fractionation and potential bioavailability. AB - Metals are one of the primary pollutants in the urban environment that pose adverse ecological and human health impacts. Therefore, the accurate quantification of the risk posed by metals is essential for developing effective risk management strategies to safeguard the urban environment. This study assessed the ecological and human health risks of six metals, commonly present in road dust by improving the original risk indices based on their potential bioavailability characteristics. The bioavailability of metals was determined by considering their distribution between the different geochemical phases of exchangeable, reducible, oxidisable and residual. The results of the modified risk analysis indicated that the road dust poses a low ecological risk in most of the study sites. According to the present situation, the non-cancer risk of individual metals for both, children and adults followed the decreasing trend of Pb > Cu > Cr > Zn > Ni > Cd. This study also found that depending on the particle size ranges, the potential of multiple metals being able to cause non-cancer health risk was low at most study sites. In terms of cancer health risk, Cr present at most of the study sites was found to be within the cancer threshold limit, even though the Cr content and the bioavailable fractions were relatively low. PMID- 29699706 TI - Heart failure self-management and normalizing symptoms: an exploration of decision making in the community. AB - OBJECTIVE: To explore the decision making processes undertaken by community dwelling individuals with heart failure as they experience symptom changes. BACKGROUND: Heart failure patients are responsible for daily self-management that includes responding to symptom fluctuations between exacerbations. Despite education, some patients fail to seek timely medical intervention when symptoms change. METHODS: Semi-structured interviews were conducted with homecare patients after receiving self-management education. Grounded theory methods and qualitative software were used to collect and analyze the data. RESULTS: Five themes were identified: perceiving symptoms, alleviating actions and control, normalizing symptoms, absence of help seeking behaviors, and decreased functional capacity. Normalizing symptoms included actions taken by participants to mitigate symptom fluctuations. Daily fluctuations were assimilated into normal life resulting in desensitization of symptom recognition and decreased functional capacity. CONCLUSIONS: Findings support the need to educate on early symptom recognition, the benefits of safe physical activity, and building a system to support self-management patient-physician collaboration. PMID- 29699707 TI - Anaesthetic management of a paediatric patient with congenital fibre type disproportion myopathy. AB - Congenital fibre type disproportion (CFTD) is a rare type of myopathy that is characterised by muscle weakness and hypotonia during childhood. Clinical features include motor delay, feeding difficulties, limb weakness, joint contractures, and scoliosis. A report is presented of the anaesthetic management of a 3-year-old girl with CFTD myopathy associated with a mutation of the TPM3 gene, scheduled for adenotonsillectomy because of obstructive sleep apnoea hypopnoea syndrome (OSAHS). The main concerns were the possible susceptibility to malignant hyperthermia, the risk of anaesthesia-induced rhabdomyolysis, a greater sensitivity to non-depolarising muscle relaxants, and the presence of OSAHS. Total intravenous anaesthesia with propofol and the use of rocuronium/sugammadex appear to be safe options. Given the high risk of respiratory compromise and other complications, patients should be closely monitored in the post-operative period. PMID- 29699708 TI - The Effects of Reflux on the Elderly: The Problems with Medications and Interventions. AB - Reflux-related complaints are a frequent cause for otolaryngology consultation, and with the aging population the concerns specific to the elderly reflux patient are critical. The elderly patient is less likely to present with typical laryngopharyngeal reflux (LPR) or gastroesophageal reflux disease (GERD) symptoms. Importantly, elderly patients typically have objective findings more severe than the level of the symptoms. Therefore, upfront invasive esophageal testing as opposed to an initial medical therapy trial is the recommended management strategy. For all patients irrespective of age, lifestyle and diet modifications continue to represent the cornerstone of medical management for LPR and GERD. PMID- 29699709 TI - Endocrine Surgery in the Geriatric Population. AB - Age must be a factor when considering endocrine surgery. Age itself is a risk factor for complications after thyroidectomy, specifically pulmonary, infectious, and cardiac complications. For this reason, in patients with nodular thyroid disease or thyroid microcarcinoma, length of observation must be measured against age and surgical risk. Outcomes of thyroid surgery in geriatric patients can be improved with several measures, including careful preoperative risk stratification based on comorbidities and frailty. In this population subset, it is imperative to have an earnest discussion with patients, their families, and any surrogate decision maker regarding potential outcomes of treatment versus observation. PMID- 29699710 TI - [Understanding the distrust towards the assessment of medicines. Beyond conflict of interests]. AB - This article aims at analyzing mechanisms leading to a situation of mistrust about the scientific evaluation of the medicinal product, beyond issues related to links of interests. The assumption is that conflicts of interest are only one component of this mistrust. It doesn't explain all social controversies affecting this sector, in particular the credibility of drug evaluation systems. We explore here how, during the six stages of certification that characterize the trajectory of the drug and its evaluation - the functioning of scientific production and collective representations contribute to this mistrust. Without any analyses on the precise mechanisms of this mistrust, the loss of legitimacy of institutions and of scientific evaluation will increase. This goes hand in hand with a potential risk to public health. PMID- 29699711 TI - The utility of dual-energy CT for metal artifact reduction from intracranial clipping and coiling. AB - OBJECTIVE: To assess the ability of dual-energy CT (DECT) to reduce metal-related artifacts in patients with clips and coils in head CT angiography, and to analyze the differences in this reduction between both type of devices. MATERIALS AND METHODS: Thirteen patients (6 clips, 7 coils) were selected and retrospectively analized. Virtual monoenergetic images (MEI) with photon energies from 40 to 150 keV were obtained. Noise was measured at the area of maximum artifact. Subjective evaluation of streak artifact was performed by two radiologists independently. Differences between noise values in all groups were tested by using the ANOVA test. Mann-Whitney U test was used to compare the differences between clips and coils. Cohens kappa statistic was used to determine interobserver agreement. RESULTS: The lowest noise value was observed at high energy levels (p<0,05). Noise was higher in the coil group than in the clip group (p<0.001). Interobserver agreement was good (kappa=0.72). CONCLUSIONS: TCED with MEI helps to minimize the artifact from clips ands coils in patients who undergo head CT angiography. The reduction of the artifact is greater in patients with surgical clipping than in patients with endovascular coiling. PMID- 29699712 TI - Foetoplacental epigenetic changes associated with maternal metabolic dysfunction. AB - Metabolic-related diseases are attributed to a sedentary lifestyle and eating habits, and there is now an increased awareness regarding pregnancy as a preponderant window in the programming of adulthood health and disease. The developing foetus is susceptible to the maternal environment; hence, any unfavourable condition will result in foetal physiological adaptations that could have a permanent impact on its health. Some of these alterations are maintained via epigenetic modifications capable of modifying gene expression in metabolism related genes. Children born to mothers with dyslipidaemia, pregestational or gestational obesity, and gestational diabetes mellitus, have a predisposition to develop metabolic alterations during adulthood. CpG methylation-associated alterations to the expression of several genes in the human placenta play a crucial role in the mother-to-foetus transfer of nutrients and macromolecules. Identification of epigenetic modifications in metabolism-related tissues of offspring from metabolic-altered pregnancies is essential to obtain insights into foetal programming controlling newborn, childhood, and adult metabolism. This review points out the importance of the foetal milieu in the programming and development of human disease and provides evidence of this being the underlying mechanism for the development of adulthood metabolic disorders in maternal dyslipidaemia, pregestational or gestational obesity, and gestational diabetes mellitus. PMID- 29699713 TI - The glyceraldehyde-3-phosphate dehydrogenase of the shrimp Litopenaeus vannamei: Molecular cloning, characterization and expression during hypoxia. AB - Some marine crustaceans like the white shrimp Litopenaeus vannamei are tolerant to environmental hypoxia. Under oxygen deprivation, shrimp tissues obtain energy by enhancing anaerobic glycolysis. In mammals, hypoxia increases the expression of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH), which has been shown a "moonlighting" role in cells. However, the effect of hypoxia on the GAPDH expression has not been studied in crustaceans. In the present work, we obtained a 2744 bp gene sequence with a 999 bp ORF split by a single intron. The deduced protein is 332 amino acids and corresponds to the L. vannamei GAPDH (LvGAPDH), which is highly similar in sequence and structure to other animal GAPDHs. During hypoxia, LvGAPDH expression is significantly induced in gills but not in hepatopancreas, suggesting that it may play a role in the molecular and cellular response of shrimp to hypoxia. PMID- 29699716 TI - Pedunculated Lesion at the Entrance of Left Main Bronchus Causing Dyspnea. PMID- 29699715 TI - Atherosclerosis and clonal hematopoyesis: A new risk factor. AB - Recent research has revealed that clonal hematopoyesis of indeterminate potential (CHIP) characterized by the acquisition of somatic mutations in hematopoietic stem cells, is not only a common age-related disorder and a premalignant condition, but it is also associated with the development of atherosclerotic vascular diseases. Mutations in DNMT3A, TET2 and ASXL1 were each individually associated with coronary heart disease, stroke and coronary calcification. Therefore, CHIP emerges as a new risk factor for atherosclerotic vascular pathologies and its detection may be relevant as a new therapeutic target in order to modify the natural course of the disease. PMID- 29699714 TI - The red cell distribution width as a prognostic indicator in upper aerodigestive tract (UADT) cancer: A systematic review and meta-analysis. AB - PURPOSE: The aim of this systematic review and meta-analysis was to investigate the relationship between the Red Cell Distribution Width (RDW) and prognosis in upper aerodigestive tract (UADT) cancer. METHODS: PubMed (via the web), Embase, Scopus, and the Cochrane Library were searched. A systematic review and meta analysis was done to generate the pooled hazard ratios (HR) for overall survival (OS), disease specific survival (DSS), and recurrence free survival (RFS). RESULTS: Our analysis included the results of 4200 patients in 8 cohorts. The pooled data demonstrated that an elevated RDW was associated with significantly poorer OS (HR: 1.44, 95% CI: 1.13-1.83), RFS (HR: 1.43, 95%CI: 1.13-1.82). The DSS result had high heterogeneity and 95% CI was not pooled. CONCLUSIONS: An elevated RDW may be an indicator of poor prognosis in UADT cancers in certain populations. Further research is needed to confirm this effect. PMID- 29699717 TI - [Effectiveness of a new model of telephone derivation shared between primary care and hospital care]. AB - AIM: The purpose of this study is to find out whether telephone referral from Primary Health Care to Internal Medicine Consult manages to reduce waiting days as compared to traditional referral. This study also aims to know how acceptable is the telephone referral to general practitioners and their patients. DESIGN: No blind randomized controlled clinical trial. SETTING: Northern Huelva Health District. PARTICIPANTS: 154 patients. INTERVENTIONS: Patients referrals from intervention clinicians were sent via telephone consultation, whereas patients referrals from control clinicians were sent by traditional via. MEASUREMENTS: Number of days from referral request to Internal Medicine Consult. Number of telephone and traditional referrals. Number of doctors and patients denied. Denial reasons. RESULTS: A statistically significant difference was found between groups, with an average of 27 (21-34) days. Among General Practitioners, 8 of the first 58 total doctors after randomization and, subsequently, 6 of the 20 doctors of the test group refused to engage in the trial because they considered "excessive time and effort consuming". 50% of patients referred by the 14 General Practitioners finally randomized to the intervention group were denied referral by telephone due to patient's complexity. CONCLUSIONS: Telephone referral significantly reduces waiting days for Internal Medicine consult. This type of referral did not mean an "excessive time and effort consuming" to General Practitioners and was not all that beneficial to complex patients. PMID- 29699718 TI - A Novel Technique for the Standardized Application of Shock Waves in Experimental Research: The Diver Box. AB - The Diver Box is designed to prevent impedance differences, energy loss or damage to neighboring structures caused by the use of shock waves with application gels. The Diver Box is an acrylic glass container filled with tempered water and includes a coupling membrane to prevent the impedance jump from air to water and to avoid the continuous propagation of shock waves into the tissue, maintaining wave dynamics. Different modes of extracorporeal shock waves can be applied to a mouse skin wound without energy loss and protected from harmful phase-reversed waves. Macroscopic changes were seen in only 5% to 12% of tested specimens. Hazardous phase reversal, back reflection and mechanical tissue damage can be avoided by use of the Diver Box, ensuring standardized extracorporeal shock wave application. PMID- 29699719 TI - Three-dimensional biomimetic head model as a platform for thermal testing of protective goggles for prevention of eye injuries. AB - BACKGROUND: The rate of eye injury is steadily rising during military conflicts of the century, with thermal burns being the most common type of injury to the eyes. The present study focuses on assessing the heat resistance properties of military protective goggles using three-dimensional (3D) finite element head modeling fitted with the tested protective gear. METHODS: A computational thermal impact was applied onto a 3D biomimetic human head model fitted with two goggle models - sports (Type 1) and square (Type 2). The resultant temperature of the eye tissues and the thermal injury thresholds were calculated by using the modeling, hence allowing to determine the protective efficacy of the goggles objectively, in a standardized, quantitative and cost-effective manner. FINDINGS: Both types of goggles had a dramatic protective effect on the eyes. The specific goggle geometry had no notable effect on the level of protection to the inner tissues against the thermal insult. At the skin level goggles reduced temperatures by ~64% under the impact zone, with only a mild difference (10 degrees C) between the goggles. INTERPRETATION: Little limitations on the shape and geometry of goggles were observed and any structure of goggles can provide an adequate protection against a thermal insult (per se) to inner cranial tissues, assuming the lenses are wide and thick enough to block direct skin contact of the heat insult. It was shown that our 3D biomimetic human head model provides a practical and cost-effective tool for determining the performance level of goggles with different attributed (i.e., shapes and thermal properties). PMID- 29699720 TI - Getting Inside the Expert's Head: An Analysis of Physician Cognitive Processes During Trauma Resuscitations. AB - STUDY OBJECTIVE: Crisis resource management skills are integral to leading the resuscitation of a critically ill patient. Despite their importance, crisis resource management skills (and their associated cognitive processes) have traditionally been difficult to study in the real world. The objective of this study was to derive key cognitive processes underpinning expert performance in resuscitation medicine, using a new eye-tracking-based video capture method during clinical cases. METHODS: During an 18-month period, a sample of 10 trauma resuscitations led by 4 expert trauma team leaders was analyzed. The physician team leaders were outfitted with mobile eye-tracking glasses for each case. After each resuscitation, participants were debriefed with a modified cognitive task analysis, based on a cued-recall protocol, augmented by viewing their own first person perspective eye-tracking video from the clinical encounter. RESULTS: Eye tracking technology was successfully applied as a tool to aid in the qualitative analysis of expert performance in a clinical setting. All participants stated that using these methods helped uncover previously unconscious aspects of their cognition. Overall, 5 major themes were derived from the interviews: logistic awareness, managing uncertainty, visual fixation behaviors, selective attendance to information, and anticipatory behaviors. CONCLUSION: The novel approach of cognitive task analysis augmented by eye tracking allowed the derivation of 5 unique cognitive processes underpinning expert performance in leading a resuscitation. An understanding of these cognitive processes has the potential to enhance educational methods and to create new assessment modalities of these previously tacit aspects of expertise in this field. PMID- 29699721 TI - Genetic analysis of TIA1 gene in Chinese patients with amyotrophic lateral sclerosis. AB - Mutations in the low-complexity domain (LCD) of T cell-restricted intracellular antigen-1 (TIA1) was recently identified to be associated with amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in non-Hispanic white populations. We sequenced the TIA1 exons 11-13 encoding LCD in a series of 588 Chinese ALS/ALS-FTD patients (Familial ALS = 29; Sporadic ALS = 546; ALS-FTD = 13) and 500 neurologically normal control subjects. We found a novel heterozygous missense mutation (c.973A>G, p.N325D) in a sporadic ALS patient, which suggests that TIA1 LCD mutations are not common in Chinese ALS/ALS-FTD. PMID- 29699722 TI - Reduction of Peripartum Racial and Ethnic Disparities: A Conceptual Framework and Maternal Safety Consensus Bundle. AB - Racial and ethnic disparities exist in both perinatal outcomes and health care quality. For example, Black women are three to four times more likely to die from pregnancy-related causes and have more than a twofold greater risk of severe maternal morbidity than White women. In an effort to achieve health equity in maternal morbidity and mortality, a multidisciplinary workgroup of the National Partnership for Maternal Safety, within the Council on Patient Safety in Women's Health Care, developed a concept article for the bundle on reduction of peripartum disparities. We aimed to provide health care providers and health systems with insight into racial and ethnic disparities in maternal outcomes, the etiologies that are modifiable within a health care system, and resources that can be used to address these etiologies and achieve the desired end of safe and equitable health care for all childbearing women. PMID- 29699723 TI - Delayed increase of thrombocyte levels after a single sub-anesthetic dose of ketamine - A randomized trial. AB - Recently, ketamine has been investigated as a potential antidepressant option for treatment resistant depression. Unlike traditional drugs, it yields immediate effects, most likely via increased glutamatergic transmission and synaptic plasticity. However, ketamine administration in humans is systemic and its long term impact on blood parameters has not yet been described in clinical studies. Here we investigated potential sustained effects of ketamine administration (0.5 mg/kg ketamine racemate) on hematological and biochemical values in plasma and serum in a randomized double-blinded study. 80 healthy young participants were included and whole blood samples were collected 5 days before, and 14 days after the infusion. To assess the group effect, repeated measure analyses of co variance (rmANCOVA) were conducted for the following blood parameters: levels of sodium, potassium, calcium, hemoglobin and number of erythrocytes, lymphocytes, and thrombocytes. RmANCOVA revealed a significant time by treatment effect on thrombocyte levels (F1, 74 = 13.54, p < 0.001, eta = 0.155), driven by an increase in the ketamine group (paired t-test, t = -3.51, df = 38, p = 0.001). Specificity of thrombocyte effect was confirmed by logistic regression, and in addition, no other coagulation parameters showed significant interaction. Moreover, the relative increase in the ketamine group was stable across sexes and not predicted by age, BMI, smoking, alcohol or drug use, and contraception. Our results describe aftereffects of sub-anesthetic ketamine administration on blood coagulation parameters, which should be considered especially when targeting psychiatric populations with relevant clinical comorbidities. PMID- 29699724 TI - Erectile dysfunction: Imbalance between pro-angiogenic and anti-angiogenic factors in systemic sclerosis. PMID- 29699725 TI - Trajectories of cognitive development in toddlers with language delays. AB - BACKGROUND: Toddlers with early language delays (LD) are at risk for developmental difficulties, including autism spectrum disorder (ASD). However, little is known about early cognitive skill acquisition in this population. AIMS: To explore heterogeneity in cognitive development in toddlers with significant LD (n = 30) or typical development (n = 61), and how this relates to 36-month outcomes (ASD, non-ASD delays, or no delays). METHODS: Growth mixture modeling of nonverbal and verbal mental age (NVMA, VMA) scores from the Mullen Scales of Early Learning was conducted with data from 18, 24 and 36 months. RESULTS: A two class NVMA solution was selected (Age Appropriate, 82%, Delayed, 18%); class membership was related to the no delay outcome, and although the proportion of toddlers with ASD in the Age-Expected class was 17% compared to 50% of toddlers with non-ASD delays, this difference was not statistically significant. The best fitting model for VMA included three classes: Age Appropriate (66%), Delay Catch Up (23%), Delayed (11%); class assignment differed by outcome. Children in the Delay Catch-Up class were more likely to have non-ASD delays compared to ASD, while the reverse was true in the Delayed class. CONCLUSIONS: Cognitive development in toddlers with LD is heterogeneous, and delayed verbal trajectories relate to later ASD diagnosis. PMID- 29699726 TI - Evaluation of maifanite and silage as amendments for green waste composting. AB - Composting is a popular method for recycling organic solid wastes including agricultural and forestry residues. However, traditional composting method is time consuming, generates foul smells, and produces an immature product. The effects of maifanite (MF; at 0%, 8.5%, and 13.5%) and/or silage (SG; at 0%, 25%, and 45%) as amendments on an innovative, two-stage method for composting green waste (GW) were investigated. The combined addition of MF and SG greatly improved composting conditions, reduced composting time, and enhanced compost quality in terms of composting temperature, bulk density, water-holding capacity, void ratio, pH, cation exchange capacity, ammonia nitrogen content, dissolved organic carbon content, crude fibre degradation, microbial numbers, enzyme activities, nutrient contents, and phytotoxicity. The two-stage composting of GW with 8.5% MF and 45% SG generated the highest quality and the most mature compost product and did so in only 21 days. With the optimized composting, the degradation rate of cellulose and hemicellulose reached 46.3 and 82.3%, respectively, and the germination index of Chinese cabbage and lucerne was 153 and 172%, respectively, which were all far higher than values obtained with the control. The combined effects of MF and SG on GW composting have not been previously explored, and this study therefore provided new and practical information. The comprehensive analyses of compost properties during and at the end of the process provided insight into underlying mechanisms. The optimized two-stage composting method may be a viable and sustainable alternative for GW management in that it converts the waste into a useful product. PMID- 29699727 TI - (Bio)degradable polymeric materials for a sustainable future - part 1. Organic recycling of PLA/PBAT blends in the form of prototype packages with long shelf life. AB - Prediction studies of advanced (bio)degradable polymeric materials are crucial when their potential applications as compostable products with long shelf-life is considered for today's market. The aim of this study was to determine the effect of the polylactide (PLA) content in the blends of PLA and poly(butylene adipate co-terephthalate) (PBAT); specifically how the material's thickness corresponded to changes that occurred in products during the degradation process. Additionally, the influence of talc on the degradation profile of all samples in all environments was investigated. It was found that, differences in the degradation rate of materials tested with a similar content of the PLA component could be caused by differences in their thickness, the presence of commercial additives used during processing or a combination of both. The obtained results indicated that the presence of talc may interfere with materials behavior towards water and consequently alter their degradation profile. PMID- 29699728 TI - Comprehensive nutritional and metabolic assessment in patients with spinal muscular atrophy: Opportunity for an individualized approach. AB - Optimal nutrition support is recommended for patients with spinal muscular atrophy (SMA). In a prospective study, we performed comprehensive nutritional assessments with the aim to guide best nutritional strategies for patients with SMA types II and III. We recorded a) anthropometry; b) macro- and micronutrient intakes; c) measured resting energy expenditure by indirect calorimetry; and d) body composition including dual X-ray absorptiometry. We enrolled a cohort of 21 patients aged 3 to 36 years of which 13 were female; 19 had SMA type II and 2 had SMA type III. The body mass index z-score ranged from -3 to 2.4. Forty-five percent of the cohort was either underfed or overfed, based on the difference between actual energy intake and measured resting energy expenditure. Vitamin D, E, K, folate and calcium intakes were low in a majority of the cohort. Forty-five percent of the cohort was either hypometabolic or hypermetabolic. Fat mass index (kg/m2) was significantly higher and lean body mass index (kg/m2) was significantly lower in the study cohort compared to population normalized values. Bone mineral density was low in 13 of 17 patients. In summary, we have described the prevalence of malnutrition, suboptimal feeding and alterations in body composition in children with SMA. A comprehensive nutritional assessment could guide individualized nutrition therapy in this vulnerable population. PMID- 29699729 TI - PACAP and VIP regulate hypoxia-inducible factors in neuroblastoma cells exposed to hypoxia. AB - Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two related peptides acting as neurotransmitters/neuromodulators in central and peripheral nervous system. They are also involved in cancer showing a controversial role. Particulary, they are implicated in neuroblastoma differentiation (NB). This pediatric tumor can evolve to a malignant metastatic disease or spontaneously regress towards a benign form, known as ganglioneuroblastoma/ganglioneuroma. A negative hallmark of neoplasia progression is represented by hypoxic microenvironment. Low oxygen tension induces activation of hypoxia-inducible factors (HIFs) promoting cells proliferation and metastasis formation. Moreover, HIFs trigger vascular endothelial growth factor (VEGF) release favouring high-risk NB phenotype development. In the present work, we have investigated for the first time, if PACAP and VIP interfere with NB differentiation through modulation of hypoxic/angiogenic process. To this end, we analyzed their effect in malignant undifferentiated and all-trans retinoic acid (RA) differentiated SH-SY5Y cells, representing the benign form of this tumor. Our results have suggested tha both peptides, but predominantly VIP, induce NB differentiation into benign form by regulating HIFs, VEGF and VEGFRs expression and distribution. All these data give new insight regarding PACAP/VIP regulatory role in NB progression. PMID- 29699730 TI - Defining degree of aortic occlusion for partial-REBOA: A computed tomography study on large animals. AB - INTRODUCTION: Partial resuscitative endovascular balloon occlusion of the aorta (P-REBOA) is a modified REBOA technique designed to help ameliorate ischemia reperfusion injury. The balloon is partially deflated, allowing a proportion of aortic flow distal to the balloon. The aim of this study is to use an ovine model of haemorrhagic shock to correlate the degree of occlusion to several hemodynamic indices. MATERIALS AND METHODS: Six sheep weighing 35-46 kg underwent a controlled venous haemorrhage inside a CT scanner until the systolic arterial pressure (AP) dropped to <90 mmHg. A balloon positioned in an aortic zone I was incrementally filled with 1 mL of saline, with serial measurement of the proximal (carotid artery) and distal (femoral artery) mean APs (MAP) and intra-balloon pressure (IBP), along with CT imaging, following each inflation, until full occlusion was achieved. RESULTS: A diameter of the aorta at zone I was 16.0 (15.7 17.2) mm, with a cross-sectional area of 212 (194-233) mm2. Median volume of saline injected into the balloon until total occlusion was 7.0 (6.3-8.5) mL. During gradual balloon inflation, proximal MAP increased and distal MAP decreased proportionate to the degree of occlusion, in a linear fashion (proximal: r2 = 0.85, p < 0.001; distal: r2 = 0.95, p < 0.001). The femoral/carotid (F/C) pressure gradient also demonstrated a linear trend (r2 = 0.90, p < 0.001). The relationship between percentage occlusion and IBP was sigmoid. MAP values became significantly different at 40-49% occlusion and more (p < 0.01). Furthermore, a drop in the distal pulse pressure from 7.0 (5.5-16.5) to 2.0 (1.5-5.0) mmHg was observed at 80% occlusion. All animals had femoral pulse pressure <5 mmHg at 80% of occlusion and more, which also coincided with the observed loss of pulsatility of the femoral wave-form. CONCLUSION: Serial CT angiography at an ovine model of haemorrhagic shock demonstrates a correlation between the femoral MAP, F/C pressure gradient and degree of zone I P-REBOA during the staged partial aortic occlusion. These parameters should be considered potential parameters to define the degree of P-REBOA during animal research and clinical practice. PMID- 29699731 TI - Epidemiology and social costs of hip fracture. AB - Hip fracture is an important and debilitating condition in older people, particularly in women. The epidemiological data varies between countries, but it is globally estimated that hip fractures will affect around 18% of women and 6% of men. Although the age-standardised incidence is gradually falling in many countries, this is far outweighed by the ageing of the population. Thus, the global number of hip fractures is expected to increase from 1.26 million in 1990 to 4.5 million by the year 2050. The direct costs associated with this condition are enormous since it requires a long period of hospitalisation and subsequent rehabilitation. Furthermore, hip fracture is associated with the development of other negative consequences, such as disability, depression, and cardiovascular diseases, with additional costs for society. In this review, we show the most recent epidemiological data regarding hip fracture, indicating the well-known risk factors and conditions that seem relevant for determining this condition. A specific part is dedicated to the social costs due to hip fracture. Although the costs of hip fracture are probably comparable to other common diseases with a high hospitalisation rate (e.g. cardiovascular disease), the other social costs (due to onset of new co-morbidities, sarcopenia, poor quality of life, disability and mortality) are probably greater. PMID- 29699732 TI - Vertebral Fragility Fractures (VFF)-Who, when and how to operate. AB - Vertebral Fragility Fractures (VFF) are common and lead to pain, long term disability and increased mortality. Most patients will have mild to moderate pain symptoms and can be managed conservatively. However, patients with severe pain who have minimal or no pain relief with potent analgesia, or who only achieve adequate pain relief with high doses of morphine based analgesia which results in significant adverse events, should be considered for vertebral augmentation. Ideally, for vertebral augmentation, patients should present within four months of the fracture (onset of acute pain) and have at least 3 weeks of failure of conservative treatment although early intervention may be more appropriate for hospitalised patients, who tend to be older, more frail and likely to be less tolerant to the adverse effects of conservative treatment. The Cardiovascular and Interventional Radiological Society of Europe (CIRSE) recommends Percutaneous Vertebroplasty as the first line surgical augmentation technique for VFF in older people, which has been shown to improve pain symptoms, allow early restoration of functional mobility and may reduce the risk of further vertebral collapse. CIRSE recommends percutaneous Balloon Kyphoplasty as second line treatment in VFF, although the optimal indication is for acute traumatic vertebral fractures (less than 7-10 days) in younger people. Assessment and treatment of underlying osteoporosis is important to reduce the risk of further fractures in older people with VFF. PMID- 29699734 TI - Trials and tribulations. PMID- 29699733 TI - Acute Compartment Syndrome: Do guidelines for diagnosis and management make a difference? AB - BACKGROUND: The best outcomes following Acute Compartment Syndrome (ACS) are attributed to early diagnosis and treatment. National guidelines were issued in the United Kingdom in 2014 (BOAST 10) to standardise and improve management. We analysed standards of diagnosis and management before and after the introduction of the guidelines. METHODS: We retrospectively reviewed the data of all patients with ACS requiring fasciotomy between March 2010 and May 2015 across four Major Trauma Centres (MTCs) in the Northwest of England. We analysed the pooled data for variations between the centres and the effect of BOAST10 implementation. RESULTS: 75 fasciotomies were recorded, with trauma being the cause in 42 cases (56%). The commonest site was the leg (44, 59%) followed by the forearm (15, 20%). The median time from decision to operate to fasciotomy was 2 h (range 0-6) and thereafter a median of 2 days (1-7) until a second visit. The practice across the four centres was similar up to diagnosis and treatment, but there was significant variation in practice after fasciotomy. The BOAST guidelines did not improve the time to surgery, time to second visit nor the recording of clinical signs. 21 patients had severe complications, including one death and 4 amputations. CONCLUSIONS: There continues to be significant variability in the definitive management of ACS. National guidelines do not appear to make a discernible impact on practice, and additional methods of ensuring safe management of this critical condition seem warranted. PMID- 29699735 TI - Improving outcomes in schizophrenia by preventing early relapses. PMID- 29699736 TI - Mental rehabilitation in China: the clubhouse model. PMID- 29699737 TI - Randomised controlled trials for multisystemic therapy: when is enough, enough? PMID- 29699738 TI - Randomised controlled trials for multisystemic therapy: when is enough, enough? - Authors' reply. PMID- 29699741 TI - Emily Holmes: a snapshot of a mental health scientist. PMID- 29699739 TI - Mental health of incarcerated people: a global call to action. PMID- 29699742 TI - The end of over-the-counter codeine in Australia. PMID- 29699743 TI - Art, power, and the asylum: Adamson, healing, and the Collection. PMID- 29699744 TI - Stairway to heaven-Jacob's Ladder. PMID- 29699745 TI - Preserve Enduring Personality Changes After Catastrophic Events (EPCACE) as a diagnostic resource. PMID- 29699746 TI - Characteristics, Management, and Outcome of Transient ST-elevation Versus Persistent ST-elevation and Non-ST-elevation Myocardial Infarction. AB - Patients with acute myocardial infarctions (AMIs) present as persistent ST elevation myocardial infarction (STEMI) or as non-ST-segment elevation myocardial infarction (NSTEMI). In some patients with STEMI, ST elevations are transient and resolve before coronary intervention (transient ST-elevation myocardial infarction [TSTEMI]). We analyzed our registry comprising all consecutive patients with AMI admitted during 2009 to 2014, and compared the characteristics, management, and outcome of patients with TSTEMI with those of patients with STEMI and NSTEMI. Of 1,847 patients with AMI included in the registry, 1,073 patients sustained a STEMI (58%), 649 had a NSTEMI (35%), and 126 presented with TSTEMI (6.9%). Patients with TSTEMI were younger than patients with NSTEMI and STEMI (56.5 vs 62.8, p <0.001, and 59.5 years, p <0.02, respectively), smoked more (77.8 vs 54.0, p <0.001, and 62.1%, p <0.0005), and fewer were hypertensive (52.4 vs 74.2% and 58.8%, both p <0.001) and diabetic (26.2% vs 47.7%, p <0.0001, and 36.9%, p <0.02). The extent of coronary artery disease in patients with TSTEMI was similar to that of patients with STEMI except for less involvement of the left anterior descending artery (p <0.001), but less extensive than in NSTEMI patients. TSTEMI involved less myocardial damage by troponin-T level (p <0.005) with better cardiac function (LVEF 61% vs 55% and 49%, both p <0.0001). Mortality was lower among TSTEMI both in-hospital (0 vs 2.3% [p = NS] and 4.2% [p <0.01]) and long-term (4.8% vs 14.7% and 14.2%, both p <0.003) at a median of 36 months. In conclusion, TSTEMI is an acute coronary syndrome distinct from NSTEMI and STEMI, characterized by fewer risk factors, a similar extent of coronary artery disease to STEMI, but is associated with less myocardial damage and portends a better outcome. PMID- 29699747 TI - Meta-Analysis Comparing Outcomes After Everolimus-Eluting Bioresorbable Vascular Scaffolds Versus Everolimus-Eluting Metallic Stents in Patients with Acute Coronary Syndromes. AB - Acute coronary syndromes (ACS) may represent an intriguing clinical scenario for implantation of bioresorbable vascular scaffold (BRS). Nevertheless, the knowledge about the performance of these devices in patients with ACS is limited. Therefore, we performed a meta-analysis of clinical studies aiming to assess the safety and efficacy of everolimus-eluting-BRS versus everolimus-eluting-metallic stents (EES) in ACS patients undergoing percutaneous coronary intervention. Six studies enrolling 2,318 patients were included and analyzed for the risk of primary safety outcome (stent or scaffold thrombosis [ST/ScT]), primary efficacy outcome (target lesion revascularisation [TLR]), and secondary outcomes (myocardial infarction, cardiac death, all-cause death). Median follow-up was 9.5 (6 to 19.5) months. Patients treated with BRS had a significantly higher risk of definite ST/ScT compared with those receiving EES (2.3% vs 1.08%, odds ratio [OR] 2.22, 95% confidence interval [CI] 1.10 to 4.45, p = 0.03, I2 = 0%). Similarly, the risk of TLR was significantly higher in the BRS compared with EES group (3.5% vs 2.5%, OR 1.79, 95% CI 1.02 to 3.16, p = 0.04, I2 = 0%). When TLRs due to thrombosis were excluded, the difference in risk estimates between the 2 groups was no longer significant (OR 1.19, 95% CI 0.48 to 2.98, p = 0.71, I2 = 25%). Risk for secondary endpoints did not differ between the 2 groups. Results were confirmed when clinical and procedural variables were tested as potential effect modifiers in the meta-regression analysis for both primary endpoints. In conclusion, compared with those receiving EES, patients with ACS treated with BRS had increased risk of definite device thrombosis and TLR at mid-term follow-up. PMID- 29699748 TI - A Randomized Double-Blind Placebo-Controlled Study Comparing Intracoronary Versus Intravenous Abciximab in Patients With ST-Elevation Myocardial Infarction Undergoing Transradial Rescue Percutaneous Coronary Intervention After Failed Thrombolysis. AB - The risk and benefit ratio of glycoprotein IIb/IIIa inhibitors with dual oral antiplatelet therapy after failed thrombolysis and rescue percutaneous coronary intervention (PCI) is unclear. Using a randomized placebo-controlled, double blind design, we compared intravenous (IV) and intracoronary (IC) abciximab delivery in 74 patients referred for rescue transradial PCI. The primary angiographic end points were the final thrombolysis in myocardial infarction flow and myocardial blush grades. Secondary end points included acute and 6-month outcomes using angiographic parameters, platelet aggregation parameters, cardiac biomarkers, cardiac magnetic resonance measurements (CMR) and clinical end points. After rescue PCI, normal thrombolysis in myocardial infarction 3 flows were obtained in 70% in the IC group, 48% in the IV group, and 71% in the placebo group, respectively (p = 0.056). Final myocardial blush grades 2 and 3 were obtained in 43% and 39% in the IC group, 48% and 26% in the IV group, and 46% and 42% in the placebo group (p = 0.67), respectively. Acutely, peak release of cardiac biomarkers, necrosis size, myocardial perfusion and no-reflow as assessed by CMR, and clinical end points were similar between the groups and did not suggest a benefit for IC or IV abciximab compared with placebo. There was no increase in bleeding or access site-related complications with abciximab compared with placebo. Clinical, angiographic, and CMR outcomes at 6 months remained comparable between the groups. In patients with ST-elevation myocardial infarction presenting with failed thrombolysis undergoing transradial rescue PCI, IC or IV abciximab had no significant clinical impact. PMID- 29699749 TI - Response to "Re: Management of Atherosclerotic Carotid and Vertebral Artery Disease: 2017 Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS)". PMID- 29699750 TI - Hypersexuality: Fact or Fiction? PMID- 29699751 TI - Plaque Incision and Grafting for Peyronie's Disease. Dead or Alive? PMID- 29699752 TI - Deciding Which Testosterone Therapy to Prescribe. PMID- 29699753 TI - De-Pathologization of Consensual BDSM. PMID- 29699754 TI - Topically Applied Curcumin-Loaded Nanoparticles Treat Erectile Dysfunction in a Rat Model of Type-2 Diabetes. AB - BACKGROUND: Curcumin, a naturally occurring anti-inflammatory compound, has shown promise in pre-clinical studies to treat erectile dysfunction (ED) associated with type-1 diabetes. However, poor bioavailability following oral administration limits its efficacy. The present study evaluated the potential of topical application of curcumin-loaded nanoparticles (curc-np) to treat ED in a rat model of type-2 diabetes (T2D). AIM: Determine if topical application of curc-np treats ED in a T2D rat model and modulates expression of inflammatory markers. METHODS: Curc-np (4 mg curcumin) or blank nanoparticles were applied every 2 days for 2 weeks to the shaved abdomen of 20-week-old Zucker diabetic fatty male rats (N = 5 per group). Lean Zucker diabetic fatty male rat controls were treated with blank nanoparticles (N = 5). Penetration of nanoparticles and curcumin release were confirmed by 2-photon fluorescence microscopy and histology. Erectile function was determined by measuring intracorporal pressure (ICP) normalized to systemic blood pressure (ICP/BP) following cavernous nerve stimulation. Corporal tissue was excised and reverse transcription and quantitative polymerase chain reaction used to determine expression of the following markers: nuclear factor (NF) kappabeta, NF-kappabeta-activating protein (Nkap), NF erythroid 2-related factor 2, Kelch-like enoyl-CoA hydratase-associated protein-1, heme oxygenase-1 (HO-1), variable coding sequence-A1, phosphodiesterase-5, endothelial and neuronal nitric oxide synthase, Ras homolog gene family member A, and Rho-associated coiled-coil containing protein kinases-1 and -2. OUTCOMES: Erectile function by determination of ICP/BP and expression of molecular markers in corporal tissue by RT-qPCR. RESULTS: Nanoparticles penetrated the abdominal epidermis and persisted in hair follicles for 24 hours. Curc-np-treated animals exhibited higher average ICP/BP than animals treated with blank nanoparticles at all levels of stimulation and this was statistically significant (P < .05) at 0.75 mA. In corporal tissue, Nkap expression decreased 60% and heme oxygenase-1 expression increased 60% in curc-np compared to blank nanoparticle-treated animals. ICP/BP values inversely correlated with Nkap and directly correlated with HO-1 expression levels. CLINICAL TRANSLATION: These studies demonstrate the potential for topical application of curc-np as a treatment for ED in T2D patients. CONCLUSIONS: The T2D animal model of ED represents a more prevalent disease than the more commonly studied type-1 diabetes model. Although there is improved erectile response in curc-np-treated animals, only at the lower levels of stimulation (0.75 mA) was this significant compared to the blank nanoparticle-treated animals, suggesting more studies are needed to optimize protocols and evaluate toxicity. Topical application of curc-np to a rat model of T2D can systemically deliver curcumin, treat ED, and modulate corporal expression of inflammatory markers. Draganski A, Tar MT, Villegas G, et al. Topically Applied Curcumin-Loaded Nanoparticles Treat Erectile Dysfunction in a Rat Model of Type-2 Diabetes. J Sex Med 2018;15:645 653. PMID- 29699755 TI - Characteristics of Genital Dissatisfaction Among a Nationally Representative Sample of U.S. Women. AB - BACKGROUND: Female genital self-image is an important aspect of psychosocial and sexual health. The Female Genital Self-Image Scale (FGSIS) is a validated instrument that has been used to characterize women's level of genital dissatisfaction. AIM: In this report, we assess genital dissatisfaction using the FGSIS in a nationally representative sample of U.S. women. METHODS: We conducted a nationally representative survey of non-institutionalized adults aged 18-65 years residing in the United States. The survey included questions about demographics, sexual behavior, and the FGSIS. OUTCOMES: Demographic characteristics were found to significantly correlate to women's perceived genital dissatisfaction. RESULTS: In total, 3,372 women completed the survey and 3,143 (93.2%) completed the FGSIS. The mean age was 46 years, and there was broad representation across the United States in terms of age, education, and location. On bivariate analysis, women's genital dissatisfaction was significantly correlated to their age, race, location, and education. Women who were sexually active were less likely to report genital dissatisfaction than women who were not sexually active (76% vs 62%, respectively, P < .001). The frequency of sexual activity was negatively correlated with genital dissatisfaction (P = .002). Women who reported genital dissatisfaction were less likely than those who reported satisfaction to engage in receptive vaginal sex (83% vs 88%, respectively, P = .03). There were no other significant associations between genital dissatisfaction and types of sexual activity. On multivariate analysis, women were less likely to report genital dissatisfaction if they were older, of black race, had an education level of high school or above, and/or lived in the Northeastern or Midwestern United States. There was no association between genital dissatisfaction and relationship status or gender of sexual partner. CLINICAL TRANSLATION: Female genital dissatisfaction may be related to age, race, education, and geography. CONCLUSIONS: This is the first nationally representative sample of U.S. women focusing on genital and self-image and dissatisfaction. These data may not apply outside the United States. These data may help providers who provide information for women and manage concerns related to genital self-image. Rowen TS, Gaither TW, Shindel AW, et al. Characteristics of Genital Dissatisfaction Among a Nationally Representative Sample of U.S. Women. J Sex Med 2018;15:698-704. PMID- 29699756 TI - Predictive Factors of Patients' and Their Partners' Sexual Function Improvement After Collagenase Clostridium Histolyticum Injection for Peyronie's Disease: Results From a Multi-Center Single-Arm Study. AB - BACKGROUND: Collagenase Clostridium histolyticum (CCH; Xiapex) injections represent the only licensed medical treatment for Peyronie's disease (PD). AIM: To evaluate the efficacy and safety of CCH injections in men with stable PD, using a modified treatment protocol and to assess partners' bother improvement in a large cohort of White-European sexually active heterosexual men treated in a single tertiary-referral center. METHODS: All the 135 patients enrolled underwent a thorough assessment, which included history taking, physical examination, and pharmacologically induced artificial erection test (intra-cavernous injection) to assess the degree of penile curvature (PC) at baseline and after the completion of the treatment. Patients with calcified plaque and/or ventral curvature were excluded. All patients underwent a modified treatment protocol, which consisted of 3 intra-lesional injections of 0.9 mg of CCH performed at 4-week intervals at the point of maximum curvature. After each injection, patients were instructed to follow a strict routine involving daily penile stretching in the intervals between injections. OUTCOMES: International Index of Erectile Function (IIEF)-15, Global Assessment of PD, PD questionnaires (PDQ), and Female Sexual Function Index (FSFI) questionnaire were performed at baseline and at the end of treatment. RESULTS: Overall, 135 patients completed the study protocol. Before treatment, 18 (13.33%) partners showed a degree of sexual dysfunction. Baseline median IIEF-15, FSFI, and PDQ scores were, respectively, 59.0, 35.0, and 23.0. Overall, both IIEF-total and all domains significantly improved after treatment (all P < .01). A PC mean change of 19.07 (P = .00) was measured. At the univariate linear regression analysis, IIEF-15, IIEF-erectile function, IIEF sexual desire, and IIEF-intercourse satisfaction were positively associated with FSFI (all P <= .03); conversely, PDQ-penile pain, PDQ-symptom bother, and post treament penile curvature (P <= .04) were associated with a decreased FSFI score. Furthermore, median change of PC was significantly associated with median change of FSFI (r = 0.25; 95% CI 0.02-0.11; P = .004). Global satisfaction after treatment was 89.6% (121/135). CLINICAL TRANSLATION: This modified CCH treatment protocol could improve both patients' and partner's sexual function. STRENGTH AND LIMITATIONS: This was an open-label, single-arm clinical study, without placebo. where only heterosexual couples in stable relationships were included. Furthermore, no real assessment of female sexual distress was carried out and long-term sexual function in both patients and female partners were not taken into account. CONCLUSIONS: The modified treatment schedule with CCH injections for stable PD has a positive impact on both patients' and partners' sexual function in heterosexual couples with a stable sexual relationship. Cocci A, Russo GI, Salonia A, et al. Predictive Factors of Patients' and Their Partners' Sexual Function Improvement After Collagenase Clostridium Histolyticum Injection for Peyronie's Disease: Results From a Multi-Center Single-Arm Study. J Sex Med 2018;15:716-721. PMID- 29699757 TI - Psychometric Properties of the Sexual Event Diary in a Sample of Dutch Women With Female Sexual Interest/Arousal Disorder. AB - BACKGROUND: Efficacy of on-demand drugs for women with hypoactive sexual desire disorder or female sexual interest/arousal disorder (FSIAD) should be assessed using a validated instrument that assesses the discrete sexual events during which the on-demand drug is taken, because this type of assessment is more proximate to an on-demand drug's efficacy compared to instruments that assess sexual function over longer periods of time. AIM: The aim of this study was to assess the psychometric properties of the Dutch translation of the previously validated 11-item Sexual Event Diary (SED) for measuring sexual satisfaction and sexual functioning during discrete sexual events. METHODS: Psychometric assessment was performed on data of 1,840 SEDs from 139 women with hypoactive sexual desire disorder/FSIAD, collected during a randomized clinical cross-over trial conducted in the Netherlands. OUTCOMES: Item scores of the SED at the event level, and at subject level, summarized item scores during the placebo run-in period (PRI) and active treatment period, and score changes from PRI to active treatment period. RESULTS: Reliability and convergent validity were confirmed. All item scores showed the ability to discriminate between known groups. Larger mean score changes from PRI were observed in groups with known benefit from the medication, as compared to those with no benefit. Guyatt effect sizes ranged from 0.51-1.02, thereby demonstrating ability to detect change. CLINICAL TRANSLATION: The Dutch version of the SED is an excellent instrument for assessing female sexual functioning and sexual satisfaction during discrete sexual events and for assessing these concepts over longer periods of time. CONCLUSIONS: Data were collected in a randomized, well-controlled trial. The large number of data points gave high statistical power, and the results confirmed previous findings. However, care is needed when generalizing the SED's validity to other areas of research, eg, recreational drug use and sexual risky behaviors, since the current validation study has not used such data. Consistent with the US-English version, the Dutch version of the SED is a reliable, valid, and responsive instrument, and suitable for use in evaluating effects of on-demand drugs in women with FSIAD. van Nes Y, Bloemers J, Kessels R, et al. Psychometric Properties of the Sexual Event Diary in a Sample of Dutch Women With Female Sexual Interest/Arousal Disorder. J Sex Med 2018;15:722-731. PMID- 29699758 TI - Enriching the Interpretation of the Erectile Dysfunction Inventory of Treatment Satisfaction: Characterizing Success in Treatment Satisfaction. AB - BACKGROUND: Patient-reported outcomes, such as the Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) index, are essential for successful evaluation and treatment of patients with erectile dysfunction. AIM: To enrich interpretation of the EDITS index score and to complement the existing 0 to 100 scoring. METHODS: This supplemental analysis evaluated EDITS questionnaire data (11 items; index score range = 0-100; higher scores indicate more treatment satisfaction) after completion of an 8-week double-blinded trial of 279 men 18 to 65 years old with erectile dysfunction randomized to sildenafil 100 mg, sildenafil 50 mg, or placebo. Response options for each EDITS item were grouped into "success" (the 2 most satisfied or favorable responses) and "no success" (the remaining 3 responses). The binary response (success or no success) for each item was expressed as a function of overall EDITS score in a simple logistic regression model with all treatments combined. OUTCOMES: Odds ratios and success probabilities (using Wald chi2 tests) were calculated for specified point differences and total EDITS index scores, respectively. RESULTS: EDITS index score increases corresponded with significant increases in odds of success in different EDITS aspects (P < .0001 for all comparisons). For instance, a 10-point EDITS index score difference was associated with odds ratios of 11.3, 42.0, 17.7, and 6.8 for overall treatment satisfaction, treatment meeting expectations, satisfaction with treatment quickness, and satisfaction with how long treatment lasts, respectively. For a given EDITS index score, likelihood of success was determined for different aspects of treatment satisfaction. For example, a mean EDITS index score of 78 (sildenafil 100 mg; SD = 18) corresponded to 96%, 88%, 94%, and 88% chances of success for the 4 EDITS items referenced earlier, respectively. Corresponding probabilities for a mean EDITS index score of 50 (placebo; SD = 18) were 3%, less than 0.1%, 1%, and 4%, respectively. CLINICAL IMPLICATIONS: Interpretation of the EDITS index score can be augmented using key aspects of treatment satisfaction as reported by the patient. STRENGTHS AND LIMITATIONS: This analysis used a well-established anchor-based approach to interpret EDITS index scores. The methodology used and corresponding results are appropriate for clinical practice and clinical trial settings. Limitations include data evaluation only for the Patient EDITS and not the complementary Partner EDITS and use of data from a clinical trial enrolling a well-defined patient population only in stable relationships. CONCLUSION: These results enable a meaningful interpretation of EDITS index scores, facilitating decision making by stakeholders for better-informed health care choices. Cappelleri JC, Tseng L J, Stecher V, Goldstein I. Enriching the Interpretation of the Erectile Dysfunction Inventory of Treatment Satisfaction: Characterizing Success in Treatment Satisfaction. J Sex Med 2018;15:732-740. PMID- 29699759 TI - Declining Sexual Activity and Desire in Men-Findings From Representative German Surveys, 2005 and 2016. AB - BACKGROUND: Surveys have indicated an increase of sexual activity in aging men; recently, however, a decrease of sexual activity has been reported in young men. AIM: To assess (i) sexual activity and desire and their determinants across the age range in a population-based male sample and (ii) their changes over 11 years. METHODS: A representative survey of men (N = 1,095) 18 to 93 years old from 2016 was compared with a survey from 2005 (N = 1,106 men) with the same age range. Samples were drawn from the German population at random using standardized sampling procedures. Questions were filled out by participants in the presence of a trained interviewer. Sexual activity was compared using logistic regression with the factors survey (2005 vs 2016), living with a partner (yes vs no), and age. Frequency of sexual desire was compared using analysis of covariance with the factors survey (2005 vs 2016), living with a partner (yes vs no), and the covariate age. OUTCOMES: Sexual activity was assessed as having been intimate with someone in the past year; frequency of sexual desire was evaluated within the past 4 weeks. RESULTS: The great majority of men cohabiting with a partner in 2016 was sexually active and indicated sexual desire until 70 years of age; half did so at an older age. Across the age range, men living without a partner reported considerably less sexual activity and desire. Compared with 2005, fewer men reported living with a partner. The overall proportion of men reporting sexual activity deceased from 81% to 73% in 2016 and absent sexual desire increased from 8% to 13%. CLINICAL TRANSLATION: The findings highlight the relevance of living with a partner for sexual activity and desire. We advocate using a measure of sexual activity that encompasses many variants of intimate behavior. STRENGTHS AND LIMITATIONS: Large and methodologically comparable population-based samples were compared. However, interpretations are limited by the absence of longitudinal data. We did not assess the effect of having a partner living elsewhere. CONCLUSION: Sexual activity and desire decreased, especially in the young and middle-age groups. The decrease of men living with a partner contributed to this decreased sexual activity and desire. There was a generation effect, with younger and middle-age men living without a partner becoming less sexually active and experiencing less desire compared with the previous survey. The findings unveil changes in sexual activity and desire in a short time span. Beutel ME, Burghardt J, Tibubos AN, et al. Declining Sexual Activity and Desire in Men-Findings From Representative German Surveys, 2005 and 2016. J Sex Med 2018;15:750-756. PMID- 29699760 TI - Desire to Have Children Among Transgender People in Germany: A Cross-Sectional Multi-Center Study. AB - BACKGROUND: Many trans individuals undergo medical interventions that result in irreversible loss of fertility. Little is known about their desire to have children and attitudes toward fertility preservation options. AIM: To study how the desire for children and the use of fertility preservation options varies among trans women and trans men in different transitioning stages in Germany. METHODS: In this cross-sectional multi-center study, N = 99 trans women and N = 90 trans men were included. Of these, 26 of each sex were just about to start medical treatment. OUTCOMES: Outcome parameter were the prevalence and determinants of a desire to have children in trans persons. RESULTS: Before treatment, a desire for children was significantly higher in trans men compared to trans women (P = .016). In contrast, in those who had already started treatment, a current desire to have children was equally present in about one fourth of participants of both genders while the interest in having children in the future was significantly higher in trans women (69.9%) than in trans men (46.9%; P = .034). Although 76.1% of trans women and 76.6% of trans men indicated that they had at least thought about preserving germ cells before starting medical transition, only 9.6% of trans women and 3.1% of trans men had put this idea into practice. Most trans men in both groups indicated that insemination of a female partner with sperm from an unrelated donor was a suitable option to fulfill their child wish, potentially explaining their low interest in preserving their own germ cells. Finally, a logistic regression analysis accounting for potential confounders revealed that overall trans women were more than twice as likely to have a current desire to have children (odds ratio 2.58), and this wish was on average 5.3% lower with each year of increasing age. CLINICAL TRANSLATION: A low level of fertility preservation among trans persons is contrasted by a high level of desire for children. This highlights the importance of counseling trans individuals regarding fertility preservation options. CONCLUSIONS: To our knowledge, this is the first study that addresses desire to have children in a clinical sample of trans women. It is also the first that investigates this issue among trans men who have not started medical treatment, and the first comparison of both genders. A limitation for the generalization of our results is the special legal context in Germany that forbids oocyte donation for reciprocal in vitro fertilization. Reproductive desire is high among trans individuals, but the use of reproductive options is surprisingly low. Auer MK, Fuss J, Nieder TO, et al. Desire to Have Children Among Transgender People in Germany: A Cross Sectional Multi-Center Study. J Sex Med 2018;15:757-767. PMID- 29699761 TI - Prospective Evaluation of Self-Reported Aggression in Transgender Persons. AB - BACKGROUND: Although research on the relation between testosterone and aggression in humans is inconclusive, guidelines (including the World Professional Association for Transgender Health Standards of Care, edition 7) have warned for an increase in aggression in transgender men taking testosterone treatment. AIMS: To investigate the association between levels of testosterone and aggression in treatment-seeking transgender people and explore the role of mental health psychopathology (anxiety and depressive symptoms) and social support in aggression in this population. METHODS: Every transgender person invited for assessment at a national transgender health clinic in the United Kingdom during a 3-year period (2012-2015) completed self-report measures for interpersonal problems, including levels of aggression (Inventory of Interpersonal Problems [IIP-32]), symptoms of anxiety and depression (Hospital Anxiety and Depression Scale [HADS]), social support (Multidimensional Scale of Perceived Social Support), and experiences of transphobia before and 1 year after the initiation of gender-affirming hormonal therapy. Correlations between prospective scores for the IIP-32 factor "too aggressive" and prospective levels of sex steroids, prospective psychological (HADS), and baseline psychosocial measurements were tested. OUTCOMES: Prospective scores for the factor "too aggressive" were not correlated to prospective serum testosterone levels. RESULTS: Results of 140 people (56 transgender men, 84 transgender women) were analyzed. A prospective increase in scores for the factor "too aggressive" of the IIP-32 in transgender men 1 year after being treated with testosterone treatment or a decrease of the IIP-32 aggression scores in transgender women 1 year after gender-affirming hormonal therapy was not found. However, a positive correlation was found between increasing HADS anxiety scores and increasing scores for the IIP-32 "too aggressive" score in the entire study population and a positive correlation with lower support from friends in transgender women. CLINICAL IMPLICATIONS: Hormone prescribing physicians can be reassured that the long-term administration of testosterone in transgender men does not increase aggressive behavior. STRENGTHS AND LIMITATIONS: This is the 1st prospective study to assess the effect of gender affirming hormonal care on aggression. Limitations included the use of different laboratories, the use of a patient-reported outcome measure, and the lack of aggression subtypes. CONCLUSIONS: Testosterone therapy was not associated with an increase in levels of aggression in transgender men or a decrease in aggressive behavior in transgender women on antiandrogen and estrogen therapy, but other psychological and/or social factors, such as anxiety levels, appear to contribute to self-reported aggression in transgender people. Defreyne J, T'Sjoen G, Bouman WP, et al. Prospective Evaluation of Self-Reported Aggression in Transgender Persons. J Sex Med 2018;15:768-776. PMID- 29699762 TI - The G-Spot Anatomical Structure Spotted. PMID- 29699763 TI - Response and Rebuttal to the Letter to the Editor Re: "The G-Spot Anatomical Structure Spotted". PMID- 29699764 TI - Erratum. PMID- 29699765 TI - Gay and Gray Session: An Interdisciplinary Approach to Transgender Aging. AB - With the overarching goals of improving the healthcare of older transgender individuals and of inspiring pertinent clinical research, a session at the 2017 American Association for Geriatric Psychiatry Annual Meeting focused on an interdisciplinary approach to transgender aging. The older the transgender adult, the more likely the individual grew up in a historical context when there was greater social stigma towards their gender identity, even among mental health professionals. In order to provide optimal healthcare to transgender adults, mental health care providers should become familiar with the basic terminology presented in this article. Transgender older adults face greater risks of poor physical health, disability, anxiety and depressive symptoms, victimization, and stigma, and higher rates of smoking, excessive alcohol use, and risky sexual behavior compared with non-transgender older adults. In spite of notable health disparities, some evidence points to resilience among transgender older adults. The mental health professional often serves as the first contact for a patient who is struggling with gender identity. The role of a mental health professional can be divided into five categories: 1) assessment of gender dysphoria; 2) psychoeducation of patients and family members about the diversity of gender identities and various options for alleviating gender dysphoria; 3) referral to and collaboration with other healthcare professionals; 4) treatment of coexisting mental health concerns; 5) advocating for transgender patients and for the transgender community. Recently, the criteria for medical and surgical transition have been simplified. End-of-life preparations are especially important for transgender individuals. PMID- 29699766 TI - Factors associated with preservation of C-peptide levels at the diagnosis of type 1 diabetes. AB - AIMS: The level of C-peptide can identify individuals most likely to respond to immune interventions carried out to prevent pancreatic beta-cell damage. The aim of the study was to evaluate factors associated with C-peptide levels at type 1 diabetes (T1D) diagnosis. METHODS: This study included 1098 children aged 2-17 with newly recognized T1D. Data were collected from seven Polish hospitals. The following variables were analyzed: date of birth, fasting C-peptide, HbA1c, sex, weight, height, pH at diabetes onset. RESULTS: A correlation was observed between fasting C-peptide level and BMI-SDS (p = 0.0001), age (p = 0.0001), and HbA1c (p = 0.0001). The logistic regression model revealed that fasting C-peptide >=0.7 ng/ml at diabetes diagnosis was dependent on weight, HbA1c, pH and sex (p < 0.0001). Overweight and obese children (n = 124) had higher fasting C-peptide (p = 0.0001) and lower HbA1c (p = 0.0008) levels than other subjects. Girls had higher fasting C-peptide (p = 0.036) and higher HbA1c (p = 0.026) levels than boys. CONCLUSION: Obese and overweight children are diagnosed with diabetes at an early stage with largely preserved C-peptide levels. Increased awareness of T1D symptoms as well as improved screening and diagnostic tools are important to preserve C-peptide levels. There are noticeable gender differences in the course of diabetes already at T1D diagnosis. PMID- 29699767 TI - Psychosocial and behavioural factors in the regulation of weight: Self regulation, self-efficacy and locus control. AB - OBJECTIVE: To identify the relationship and behaviour of the variables of self control, self-efficacy and locus control in weight regulation of obese, overweight and normal weight adults. METHOD: Transversal study undertaken in the Health Centre of El Coto (Gijon) from 1st April to 30th July 2015. PARTICIPANTS: Subjects between 18-65 years of age with a body mass index recording within the last two years. EXCLUSIONS: serious medical illness, eating disorders or pregnant women. MAIN MEASUREMENTS: Behavioural variables: self-regulation of body weight (Inventory of self-control of body weight), perceived self-efficacy in weight regulation (Inventory of perceived self-efficacy in weight regulation) and locus control in weight regulation (Inventory of locus control in weight regulation). Anthropometric variables: weight (kg) and height (m), body mass index. RESULTS: One hundred and six participants were included: 32 were obese, 28 overweight and 46 normal weight. Significant differences were found between the 3 study groups for total scale of self-efficacy (F=61.77; p<.01), total scale of self-regulation (F=45.97; p<.01), internal locus control (F=13.92; p=.019), other weighty influences of locus control (F=9.21; p<.01) and random locus control (F=3.50; p=.011). CONCLUSIONS: The relationship between body mass index and behavioural variables of self-efficacy, self-regulation and locus control, suggests the need for healthcare professionals to include psychological factors of behaviour in any preventive action and intervention directed at weight control. PMID- 29699768 TI - Dilated Cardiomyopathy in a Child with Recessive Dystrophic Epidermolysis Bullosa. PMID- 29699769 TI - Papulopustular Rosacea: Response to Treatment with Oral Azithromycin. AB - INTRODUCTION: Oral tetracyclines and topical antibiotics have been used to treat papulopustular rosacea (PPR) for years, but it is not uncommon to find patients who do not respond to this standard treatment. In such refractory cases, oral azithromycin has proven to be an effective option. MATERIAL AND METHOD: We conducted a prospective pilot study of 16 patients with PPR who were treated with oral azithromycin after a lack of response to oral doxycycline and metronidazole gel. At the first visit, the patients were assessed for baseline severity of PPR on a 4-point clinical scale and started on oral azithromycin. At the second visit, response to treatment in terms of improvement from baseline was evaluated on a 3-point scale. Patients were then scheduled for follow-up visits every 12 weeks to assess long-term effectiveness. RESULTS: All 16 patients experienced an improvement in their PPR following treatment with oral azithromycin. Eight weeks after completion of treatment, 14 patients (87.5%) showed complete or almost complete recovery (slight or no residual redness and complete clearance of papules and pustules). Only 2 patients experienced a new episode of inflammatory PPR lesions during follow-up. CONCLUSIONS: The findings of this pilot study suggest that oral azithromycin could be a very effective short-term and long-term treatment for RPP resistant to conventional treatment. PMID- 29699771 TI - Propofol induced diverse and subtype-specific translocation of PKC families. AB - Propofol is the most commonly used anesthetic. Immunohistochemical studies have reported that propofol translocated protein kinase Cs (PKCs) in cardiomyocyte in a subtype-specific manner; however detailed features of the propofol-induced translocation of PKCs remain unknown. In this study, we performed real-time observation of propofol-induced PKC translocation in SH-SY5Y cells expressing PKCs fused with a fluorescent protein. Propofol unidirectionally translocated gammaPKC-GFP, a conventional PKC, and zetaPKC-GFP, an atypical PKC, to the plasma membrane and nucleus, respectively, whereas the propofol-induced translocation of novel PKCs was diverse and subtype-specific among deltaPKC, epsilonPKC and etaPKC. The propofol-induced translocation of epsilonPKC-GFP was especially complicated and diverse, that is, 200 MUM propofol first translocated epsilonPKC GFP to the perinuclear region. Thereafter, epsilonPKC was translocated to the nucleus, followed by translocation to the plasma membrane. Analysis using a mutant epsilonPKC in which the C1 domain was deleted demonstrated that the C1b domain of epsilonPKC was indispensable for its translocation to the perinuclear region and plasma membrane, but not for its nuclear translocation. An in vitro kinase assay revealed that propofol increased the activities of the PKCs activities at the concentration that triggered the translocation. These results suggest that propofol could translocate PKCs to their appropriate target sites in a subtype-specific manner and concomitantly activated PKCs at these sites, contributing to its beneficial or adverse effects. PMID- 29699773 TI - Pragmatic clinical trials at the National Institute of Nursing Research. AB - BACKGROUND: Pragmatic clinical trials are used to test the efficacy of interventions in a real-world clinical practice setting. PURPOSE: The purpose of this article was to summarize the presentation given at the Council on Advancement of Nursing Science 2017 Meeting. METHODS: Key science focus areas of the National Institute of Nursing Research (NINR) and the National Institutes of Health (NIH) guidelines relevant to pragmatic clinical trials were reviewed. DISCUSSION: The NIH supports some large-scale pragmatic trials and NINR participates in two of them. Generally, the NINR supports small-scale pragmatic trials that are a mission fit with the NINR. Now pragmatic trials are subject to the new NIH clinical trial requirements. CONCLUSION: Investigators must respond to a specific clinical trial announcement and use the new clinical trial application forms. The NINR program staff are a valuable resource to answer questions that investigators may have regarding their pragmatic clinical trial proposal. PMID- 29699772 TI - Review and application of the National Academies of Sciences, Engineering, and Medicine bullying or cyberbullying recommendations for screening and lesbian, gay, bisexual, and transgender youth. AB - Bullying has been long seen as a natural part of childhood and adolescence. However, a growing body of evidence suggests bullying and now cyberbullying may inflict harm or distress on targeted youth including physical, psychological, social, or educational harm. The purpose of this paper is to endorse the National Academies of Sciences, Engineering, and Medicine statement, summarize the report, and apply the recommendations to screening lesbian, gay, bisexual and transgender youth related to bullying and cyberbullying; line 11 change exemplified to discussed. Screening for bullying against youth; lesbian, gay, bisexual, and transgender youth as a high-risk group for bullying victimization; and implications to address bullying against youth are exemplified. Nurses need to promote policies that foster inclusive, supportive, safe, and healthy schools and environments for youth. PMID- 29699774 TI - What are the preferences of patients attending a memory clinic for disclosure of Alzheimer's disease? AB - BACKGROUND/AIMS: This report shares and discusses the collected personal preferences of patients attending a memory clinic for disclosure of a potential Alzheimer's disease (AD) diagnosis. METHODS: In this prospective study of outpatients attending a single memory clinic over a 6-year period (March 2004 October 2010), doctors collected their patients' wishes (willingness to be informed, motivation, presence of the family) through a standardized procedure. RESULTS: Of the 1005 patients questioned throughout the study period-with a final diagnosis of dementia for 480 of them-858 (85.3%) wished to be informed of an AD diagnosis, whereas 72 (7.2%) did not and 75 (7.5%) were not sure. Older age and reduced cognitive functioning were independently associated with a preference to not be informed of a potential AD diagnosis. CONCLUSION: Our study provides evidence of the willingness of most patients to know the truth vis-a-vis AD and also offers some insight into their motivations. PMID- 29699775 TI - Metronidazole-induced encephalopathy. PMID- 29699776 TI - Communication networks of medication management in an ambulatory care setting. AB - BACKGROUND: Systems approaches in healthcare address complexities of care related to medication safety. Adverse drug events can be prevented by communication between providers. Thus, methods that depict the structures and processes of communications are foundational for prevention efforts. Social network analysis is a methodology applied in healthcare settings to describe and quantify communication patterns. Knowledge of the structures and processes surrounding medication management communications will be useful to explain and intervene on related quality or safety outcomes. OBJECTIVES: The aim of this study was to use social network analysis as a tool to describe the communication structures and processes of medication management for patients on warfarin therapy in an ambulatory care setting. METHOD: A longitudinal, roster-based assessment was used for the social network analysis. Data were collected from electronic medical records and coded using a fixed-list format. Information was collected regarding who was involved as well as frequency and type of communications. The analysis followed 16 subjects at one internal medicine clinic over six months. RESULTS: Structurally, communications were unidirectional and most often connected actors from different groups. Most communications were directed from nursing staff to patients. Central actors were a pharmacist, several nursing staff and one prescriber. Difference in processes were identified by characterizing communications according to level of impact on patient safety. Moderate impact communications corresponded to focused connections between providers. Further, the pharmacist was measured as the most prominent gatekeeper in moderate impact communications compared to an advanced registered nurse practitioner for low impact communications. CONCLUSIONS: Medication management reflected a unidirectional and interdisciplinary communication structure that maintained process variation according to the potential impact on patient safety. The level of influence of the pharmacist as a connector in the network rose in conjunction with the level of potential impact the communication had on patient safety. PMID- 29699778 TI - [Lower limit of normal vs. fixed ratio for the diagnosis of COPD: Is it that important?] PMID- 29699777 TI - [Can PFTs still be interpreted based on fixed limits of normality?] PMID- 29699779 TI - The Psychosocial Effects of Perioperative Complications After Bariatric Surgery. AB - BACKGROUND: Bariatric surgery is an effective weight loss tool that results in sustained weight loss, improvement in obesity-related comorbidities, and positive psychosocial outcomes. However, bariatric procedures also present with risks, as surgical complications are not uncommon. OBJECTIVE: This study aims to better understand the effect of postoperative complications from bariatric surgeries on patients' psychosocial well-being. MATERIALS AND METHODS: Surgical data on postoperative complications were matched with results from self-administered psychosocial questionnaires. Depression, anxiety, and quality of life (QOL) were assessed preoperatively, and at 1-year postoperatively. RESULTS: A total of 365 patients were included. Overall, the complication rate was 15.3% (n = 56), with 31 (8.5%) patients experiencing complications within 30 days of surgery, and 25 (6.8%) experiencing late complications. All patients achieved significant weight loss at 1-year postoperatively. Patients with uncomplicated recoveries showed significant improvement in depression (P < 0.001), anxiety (P < 0.001), mental QOL (P < 0.001), and physical QOL (P < 0.001) at 1-year postsurgery. Patients who experienced postoperative complications showed significant improvement in depression (P < 0.001), anxiety (P = 0.04) and physical QOL (P < 0.001), but not in mental QOL (P = 0.210). Despite improved psychosocial outcomes from baseline, patients experiencing complications showed higher postoperative depression scores (P < 0.01) and lower physical QOL (P < 0.01) than patients without complication. Comparison between those with early and late complications did not show significant difference in outcomes. CONCLUSIONS: Complications following bariatric surgery can hinder improvements in patient's psychological well-being and QOL. Bariatric centers should provide more support for patients who have experienced complications. PMID- 29699780 TI - JMT-1: a novel, spherical lytic halotolerant phage isolated from Yuncheng saline lake. AB - This work described a novel halotolerant phage, JMT-1, with a spherical morphology. JMT-1, which was isolated from a hypersaline lake, could produce clear plaques on Chromohalobacter sp. LY7-3. The purified virions are spherical, have no visible tail, and are about 30-50nm in diameter. JMT-1 has a wide host range, and this study showed that the phage can infect at least five halophilic bacteria. The proteins of JMT-1 were analyzed using sodium dodecyl sulfate polyacrylamide gel electrophoresis, and six proteins were detected. Results show that JMT-1 is a bacteriophage with a linear double-stranded DNA. Meanwhile, the genome is approximately 23kb in length and is sensitive to the restriction endonucleases Bam I, EcoR I, Hind III and Kpa I. JMT-1 has a high titer, approaching 1.5*109pfu/mL after dilution to 10-6pfu/mL. The phage is also sensitive to chloroform but not to temperature, pH, and lowered salt concentration. JMT-1 is a spherical lytic halotolerant phage with a wide host range and has the tolerance to specific extreme environments. These data could provide references for studying phage resources in extreme environments and would also provide the useful methods for isolation and identification of other valuable phage in the salt lake environment. PMID- 29699781 TI - Long-term follow-up for pilonidal sinus surgery: A review of literature with metanalysis. AB - BACKGROUND: Sacrococcygeal pilonidal sinus disease (PSD) is a common chronic inflammation of the natal cleft and presents as an abscess or a chronically discharging, painful sinus tract. The management of chronic PSD is variable, contentious, and problematic. Although many surgical procedures have been tried, the best surgical method remains controversial. The aim of this systematic review with meta-analysis of literature is to provide surgeons an objective instrument of decision through an analysis of recurrence rate of various surgical techniques in a long-term follow-up. METHODS: Systematic literature searches were performed to identify all available studies. According to the pre-specified protocol, all studies reporting a surgical approach to PSD with a minimum follow-up of 5 years were included. RESULTS: Fifteen studies were included in the analysis. The number of patients varied from 50 to 1165 with a mean follow-up from 58.36 to 240 months. The overall incidence of recurrence was of 0.138; the resulting incidence of open healing, midline closure and out-midline closure were of 17.9%, 16.8% and 10% respectively. CONCLUSIONS: Interestingly, our data reveal a rate of relapsing disease higher than the one defined in previous studies both for the overall PSD and for each surgical procedure. A long-term follow-up of at least 5 years, should be considered the gold standard in pilonidal sinus surgery benchmarking. From our results, we can state that open healing and midline closure should not be considered effective for their high frequency of relapse disease and midline primary closure should be preferred. PMID- 29699783 TI - Is it really risky for postpartum stress urinary incontinence in the first year postpartum? PMID- 29699782 TI - A systematic review of mechanical thromboprophylaxis in the lithotomy position. AB - BACKGROUND: Venous thrombosis and compartment syndrome are potentially serious complications of prolonged, lithotomy position surgery. It is unclear whether mechanical thromboprophylaxis in this group of patients modifies the risk of compartment syndrome. This qualitative systematic review examines the evidence base to guide clinical practice. METHOD: A systematic review was performed guided by Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) criteria, to identify studies reporting relationships between lithotomy position, compartment syndrome and mechanical thromboprophylaxis. The aim was to determine if mechanical thromboprophylaxis influenced compartment syndrome risk in the lithotomy position. RESULTS: Sixteen studies were identified: eight case reports or case series (12 patients), two completed audit cycles (approximately 2000 patients), four reviews and two volunteer case control studies (33 subjects). There were no randomised studies. Nine studies associated mechanical thromboprophylaxis with compartment syndrome risk but in each case a causative relationship was speculative. In contrast, five papers, including an experimental, cohort study and two observational, population studies recommended intermittent pneumatic compression as prevention against compartment syndrome in lithotomy position. One review and one case report were unable to make a recommendation. CONCLUSIONS: The level of evidence addressing the interaction between the lithotomy position, compartment syndrome and mechanical thromboprophylaxis is weak. There is no conclusive evidence that mechanical thromboprophylaxis causes compartment syndrome in the lithotomy position. There is limited evidence to suggest intermittent pneumatic compression may be a safe method of mechanical thromboprophylaxis if accompanied by strict adherence to other measures to reduce the chance of compartment syndrome. However further studies are required. PMID- 29699784 TI - Smartphone app uses loyalty point incentives and push notifications to encourage influenza vaccine uptake. AB - PURPOSE: Carrot Rewards is a free, incentive-based, smartphone health app available in participating provinces in Canada. One feature of Carrot was designed to incentivize influenza vaccine education messages and encourage vaccine uptake for users in the province of British Columbia. This study aimed to evaluate the uptake of the Carrot Flu Campaign educational quiz and to determine if mobile "push" notifications, plus loyalty point incentives, resulted in users visiting a sponsored pharmacy to discuss and receive the influenza vaccine. METHODS: The Carrot Flu Campaign delivered an in-app quiz, educating users on the importance of the influenza vaccine. Push notifications were then sent to users when they came within 200 m of a sponsored pharmacy. Those who visited the pharmacy collected bonus points and completed a follow up quiz tracking influenza vaccine behaviour. A sub-sample of users completed the Flu Campaign between their baseline and follow up Health Risk Assessment (HRA), a survey which asked about influenza vaccine uptake behaviour. Descriptive statistics were summarized. RESULTS: A total of 38.1% (30,538/80,228) registered Carrot users completed the Flu Campaign quiz. Of those in participating cities (n = 21,469), 41% clicked on the map to show the nearest sponsored pharmacy and 78% enabled their smartphone's "locations" feature, allowing them to receive the push notifications. A small number of users spoke to a pharmacist (n = 96) and less than half reported receiving the influenza vaccine (38/96; 39.6%). From the HRA sub-sample (n = 3693), approximately 5% more users reported receiving the influenza vaccine during the 2017 influenza season compared to the previous year. CONCLUSIONS: Carrot Rewards used a novel delivery method to educate the general population and showed geolocation could be used to facilitate influenza vaccine uptake. Future iterations could tailor content to target those most at risk and should consider more robust evaluation methods to determine the app's effectiveness. PMID- 29699785 TI - Where girls are less likely to be fully vaccinated than boys: Evidence from a rural area in Bangladesh. AB - BACKGROUND: Immunization is one of the most successful and effective health intervention to reduce vaccine preventable diseases for children. Recently, Bangladesh has made huge progress in immunization coverage. In this study, we compared the recent immunization coverage between boys and girls in a rural area of Bangladesh. SETTING: The study is based on data from Chakaria Health and Demographic Surveillance System (HDSS) of icddr,b, which covers a population of 90,000 individuals living in 16,000 households in 49 villages. METHODS: We calculated the coverage of fully immunized children (FIC) for 4584 children aged 12-23 months of age between January 9, 2012 and January 19, 2016. We analyzed immunization coverage using crude FIC coverage ratio (FCR) and adjusted FCR (aFCR) from binary regression models. The dynamic of gender inequality was examined across sociodemographic and economic conditions. MAIN OUTCOME MEASURE: The adjusted female/male (F/M) FIC coverage ratios in various sociodemographic and economic categories. RESULTS: Among children who lived below the lower poverty line, the F/M aFCR was 0.89 (0.84-0.94) compared to 0.98 (0.95-1.00) for children from the households above lower poverty line (p = 0.003, test for interaction). For children of mothers with no high school education, the F/M aFCR was 0.94 (0.91-0.97), whereas it was 1.00 (0.96-1.04) for children of mothers who attended high school (p = 0.04, test for interaction). The F/M aFCR was 1.01 (0.96-1.06) for first born children but 0.95 (0.93-0.98) for second or higher birth order children (p = 0.04, test for interaction). CONCLUSIONS: Fewer girls than boys were completely vaccinated by their first birthday due to girls' lower coverage for measles vaccine. The tendency was most marked for children living below the poverty line, for children whose mothers did not attend high school, and for children of birth order two or higher. In the study setting and similar areas, sex differentials in coverage should be taken into account in ongoing immunization programmes. PMID- 29699786 TI - Comparison of reproductive protection against bovine viral diarrhea virus provided by multivalent viral vaccines containing inactivated fractions of bovine viral diarrhea virus 1 and 2. AB - Bovine viral diarrhea virus (BVDV) is an important viral cause of reproductive disease, immune suppression and clinical disease in cattle. The objective of this study was to compare reproductive protection in cattle against the impacts of bovine viral diarrhea virus (BVDV) provided by three different multivalent vaccines containing inactivated BVDV. BVDV negative beef heifers and cows (n = 122) were randomly assigned to one of four groups. Groups A-C (n = 34/group) received two pre-breeding doses of one of three commercially available multivalent vaccines containing inactivated fractions of BVDV 1 and BVDV 2, and Group D (n = 20) served as negative control and received two doses of saline prior to breeding. Animals were bred, and following pregnancy diagnosis, 110 cattle [Group A (n = 31); Group B (n = 32); Group C (n = 31); Group D (n = 16)] were subjected to a 28-day exposure to cattle persistently infected (PI) with BVDV (1a, 1b and 2a). Of the 110 pregnancies, 6 pregnancies resulted in fetal resorption with no material for testing. From the resultant 104 pregnancies, BVDV transplacental infections were demonstrated in 73 pregnancies. The BVDV fetal infection rate (FI) was calculated at 13/30 (43%) for Group A cows, 27/29 (93%) for Group B cows, 18/30 (60%) for Group C cows, and 15/15 (100%) for Group D cows. Statistical differences were observed between groups with respect to post vaccination antibody titers, presence and duration of viremia in pregnant cattle, and fetal infection rates in offspring from BVDV-exposed cows. Group A vaccination resulted in significant protection against BVDV infection as compared to all other groups based upon outcome measurements, while Group B vaccination did not differ in protection against BVDV infection from control Group D. Ability of inactivated BVDV vaccines to provide protection against BVDV fetal infection varies significantly among commercially available products; however, in this challenge model, the inactivated vaccines provided unacceptable levels of BVDV FI protection. PMID- 29699787 TI - The impact of time since vaccination and study design on validity in parental recall of childhood vaccination status in the All Our Families cohort. AB - INTRODUCTION: Parental reporting of childhood vaccination status is often used for policy and program evaluation and research purposes. Many factors can bias parental reporting of childhood vaccination status, however, to our knowledge, no analysis has assessed whether time since vaccination impacts reporting accuracy. Therefore, using the Calgary electronic vaccine registry (PHANTIM) as the gold standard, we aimed to test the accuracy of parental reporting of childhood vaccination status at three different time-points since vaccination. METHODS: The All Our Families (AOF) cohort study asked parents to report their child's 2, 4, 6, 12 and 18 month vaccines (vaccination time-point) on questionnaires given when the child was 1, 2 and 3 years of age (survey time-point). We linked the AOF parental reporting of vaccination status to the PHANTIM registry and calculated the percent agreement and difference in coverage estimates between PHANTIM and AOF at each vaccination and survey time-point combination. Furthermore, we measured the sensitivity and specificity, and negative (NPV) and positive predictive values (PPV) of parental vaccine recall across time. RESULTS: AOF parent reports of coverage rates were consistently higher than the PHANTIM estimates. While we saw significant differences in percent agreement for certain vaccination time-points, we saw no consistent directional difference by survey time-point, suggesting that parental accuracy did not change with time. We found a uniformly high sensitivity across all vaccination and survey time-points, and no consistent patterns in the specificity, PPV and NPV results. CONCLUSION: Time since vaccination may not be the most important consideration when designing and implementing a vaccination survey. Other factors that may contribute to the bias associated with parental reporting of vaccination status include the complexity of the vaccine schedule, schedule changes over time, and the wording and structure of the questionnaires. PMID- 29699788 TI - The influence of incomplete case ascertainment on measures of vaccine efficacy. AB - BACKGROUND: Motivated by the unexplained variation in the performance of some vaccines across different settings, we extend previous theoretical work to consider the potential impact of incomplete case ascertainment on measures of vaccine efficacy (VE), which is more likely in subclinical or clinically unimportant infections, such as rotavirus gastroenteritis. METHODS: By simulating the measurement of VE under outbreak conditions using a discrete time stochastic SIR model, we compare three commonly used measures, VERisk, VERate, and VEHazard, calculated respectively based on risk ratio, rate ratio and hazard ratio of disease. We investigate how these measures are influenced by factors such as biological activity, action mechanism of vaccine, proportion of cases ascertained, and underlying force of infection. RESULTS: Under plausibly low levels of ascertainment, the group with the most infections, and therefore the most missed cases, has the most falsely inflated denominator, producing similar rates in the control and intervention groups. As a result, VERate and VEHazard will underestimate the true VE compared to high case ascertainment scenarios. Furthermore, the extent of underestimation is greater for leaky vaccine models with lower biological protective effects and under conditions which are conducive to high transmission. CONCLUSIONS: This study demonstrates that a biologically active vaccine may produce a low measured VE under a range of epidemiological, vaccine-related and logistical conditions. Low case ascertainment may partly explain the observed heterogeneity in the performance of rotavirus vaccine across different settings, and should be considered in the design and interpretation of future field trials. PMID- 29699789 TI - VaxArray for hemagglutinin and neuraminidase potency testing of influenza vaccines. AB - Practical methods to measure the potency of influenza vaccines are needed as alternatives for the standard single radial immunodiffusion (SRID) assay. VaxArray assays for influenza hemagglutinin (HA) and neuraminidase (NA) have been developed to address this need. In this report, we evaluate the use of these assays to assess the potency of HA and NA of an A/H3N2 subunit vaccine by determining the correlation between the amounts measured by VaxArray and the immunogenicity in mice. The antibody response after one and two doses of five formulations of the vaccine ranging from 5 ug/mL to 80 ug/mL of HA, was measured by hemagglutination inhibition (HAI) and neuraminidase inhibition (NAI) assays. For hemagglutinin, vaccine potency determined by VaxArray was equivalent to potency measured SRID and these amounts were predictive of immunogenicity, with excellent correlation between potency measured by VaxArray and the HAI geometric mean titers (GMT). Likewise, the amount of NA measured by VaxArray was predictive of the NAI GMT. The VaxArray NA assay reported non-detectable levels of intact NA for a sample that had been heat degraded at 56 degrees C for 20 h, demonstrating that the assay measures the native, active form of NA. Similarly, the HA potency measured by VaxArray in this heat-treated sample was very low when a monoclonal antibody was used to detect the amount of antigen bound. Importantly, the force degraded sample induced low HAI titers and the NAI titers were not measurable, supporting the conclusion that the VaxArray HA and NA assays measure the immunogenic forms of these A/H3N2 antigens. This study indicates that VaxArray assays can be used to assess the potency of HA and NA components in influenza vaccines as a proxy for immunogenicity. PMID- 29699790 TI - Immunological and physical evaluation of the multistage tuberculosis subunit vaccine candidate H56/CAF01 formulated as a spray-dried powder. AB - Liquid vaccine dosage forms have limited stability and require refrigeration during their manufacture, distribution and storage. In contrast, solid vaccine dosage forms, produced by for example spray drying, offer improved storage stability and reduced dependence on cold-chain facilities. This is advantageous for mass immunization campaigns for global public health threats, e.g., tuberculosis (TB), and offers cheaper vaccine distribution. The multistage subunit vaccine antigen H56, which is a fusion protein of the Mycobacterium tuberculosis (Mtb) antigens Ag85B, ESAT-6, and Rv2660, has been shown to confer protective efficacy against active TB before and after Mtb exposure in preclinical models, and it is currently undergoing clinical phase 2a testing. In several studies, including a recent study comparing multiple clinically relevant vaccine adjuvants, the T helper type 1 (Th1)/Th17-inducing adjuvant CAF01 was the most efficacious adjuvant for H56 to stimulate protective immunity against Mtb. With the long-term goal of designing a thermostable and self-administrable dry powder vaccine based on H56 and CAF01 for inhalation, we compared H56 spray-dried with CAF01 with the non-spray-dried H56/CAF01 vaccine with respect to their ability to induce systemic Th1, Th17 and humoral responses after subcutaneous immunization. Here we show that spray drying of the H56/CAF01 vaccine results in preserved antigenic epitope recognition and adjuvant activity of CAF01, and the spray-dried, reconstituted vaccine induces antigen-specific Th1, Th17 and humoral immune responses, which are comparable to those stimulated by the non-spray-dried H56/CAF01 vaccine. In addition, the spray-dried and reconstituted H56/CAF01 vaccine promotes similar polyfunctional CD4+ T-cell responses as the non-spray dried vaccine. Thus, our study provides proof-of-concept that spray drying of the subunit vaccine H56/CAF01 preserves vaccine-induced humoral and cell-mediated immune responses. These results support our ongoing efforts to develop a thermostable, dry powder-based TB vaccine. PMID- 29699791 TI - Epidemiology, clinical presentation, risk factors, intensive care admission and outcomes of invasive meningococcal disease in England, 2010-2015. AB - The epidemiology of invasive meningococcal disease (IMD) is constantly changing as new strains are introduced into a population and older strains are removed through vaccination, population immunity or natural trends. Consequently, the clinical disease associated with circulating strains may also change over time. In England, IMD incidence has declined from 1.8/100,000 in 2010/2011 to 1.1/100,000 in 2013/2014, with a small increase in 2014/2015 to 1.3/100,000. Between 01 January 2011 and 30 June 2015, MenB was responsible for 73.0% (n = 2489) of 3411 laboratory-confirmed IMD cases, followed by MenW (n = 371, 10.9%), MenY (n = 373, 10.9%) and MenC (n = 129, 3.8%); other capsular groups were rare (n = 49, 1.4%). Detailed questionnaires were completed for all 3411 laboratory confirmed cases. Clinical presentation varied by capsular group and age. Atypical presentations were uncommon (244/3411; 7.2%), increasing from 1.2% (41/3411) in children to 3.5% (120/3411) in older adults. Known IMD risk factors were rare (18/3411; 0.5%) and included complement deficiency (n = 11), asplenia (n = 6) or both (n = 1). Nearly a third of cases required intensive care (1069/3411; 31.3%), with rates highest in adults. The 28-day CFR was 6.9% (n = 237), with the lowest rates in 0-14 year-olds (85/1885, 4.5%) and highest among 85+ year-olds (30/94, 31.9%). These observations provide a useful baseline for the current burden of IMD in a European country with enhanced national surveillance. PMID- 29699792 TI - Long-term immunogenicity of a quadrivalent human papillomavirus vaccine in systemic lupus erythematosus. AB - OBJECTIVES: To evaluate the 5-year immunogenicity of a quadrivalent human papillomavirus (HPV) vaccine (GARDASIL) in patients with systemic lupus erythematosus (SLE). METHODS: Female SLE patients and controls, aged 18-35 years, who received GARDASIL in 2011 and sero-converted 12 months post-vaccination were followed for persistence of immunogenicity. Antibody measurement to HPV serotypes 6, 11, 16, 18 was repeated at 5 years. The rate of sero-reversion was compared between patients and controls, and factors associated with sero-reversion of the anti-HPV antibodies were studied. RESULTS: 50 SLE patients and 50 controls were vaccinated with GARDASIL. Among subjects who sero-converted at 1 year and consented for this study, antibodies to HPV serotypes 6, 11, 16 and 18 at 5 years were persistent in 24/27 (89%), 26/31 (84%), 32/34 (94%) and 24/25 (96%) of the SLE patients; and 32/33 (97%), 32/33 (97%), 32/32 (100%) and 23/24 (96%) of the controls, respectively. Antibody titers to HPV-6 and 16 were significantly lower in patients than controls. Seven (21%) SLE patients had sero-reversion of >=1 anti-HPV antibodies. Sero-reverted patients experienced significantly more SLE flares, particularly renal, and had received significantly higher cumulative doses of prednisolone, mycophenolate mofetil and tacrolimus than those with persistent immunogenicity. The cumulative doses of prednisolone correlated inversely and significantly with the anti-HPV 6, 11, and 16 titers at 5 years. CONCLUSIONS: Immunogenicity of the quadrivalent HPV vaccine was retained in a high proportion of SLE patients at 5 year. Patients with more SLE renal flares and had received more immunosuppression were more likely to have sero-reversion of the anti-HPV antibodies. CLINICAL TRIAL REGISTRATION NUMBER: US ClinicalTrials.gov (NCT00911521 & NCT02477254). PMID- 29699793 TI - Serum interleukin 15 levels in patients with seropositive myasthenia gravis do not correlate with disease severity. AB - AIM: To assess interleukin 15 (IL-15) serum levels in patients with seropositive myasthenia gravis (MG); searching for potential relationship between IL-15 levels and clinical features such as gender, age at onset, clinical presentation or treatment received. BACKGROUND: IL-15 plays pivotal role in T-cell dependent autoimmunity. Increased IL-15 serum levels have been reported in several autoimmune diseases including MG patients from Japan. PATIENTS AND METHODS: Sera of 42 seropositive MG patients (66.7% women), mean age 50.6+/-23.7 years) have been tested by ELISA for IL-15 levels. RESULTS: There were no statistically significant differences between IL-15 serum levels in MG patients in comparison with controls as well as between subgroups of MG patients (early vs. late onset and thymoma MG). Mean/median IL-15 serum levels were similar in MG patients treated with corticosteroids (CS) and CS naive. Outliers (very high values) were seen only in untreated generalized MG patients. CONCLUSIONS: Serum interleukin 15 levels in patients with seropositive myasthenia gravis do not correlate with disease severity. PMID- 29699794 TI - Community engagement in the Aboriginal Families Study: Strategies to promote participation. AB - BACKGROUND: Aboriginal women and families are under-represented in Australian research on pregnancy and childbirth. The Aboriginal Families Study aimed to investigate the views and experiences of a representative sample of women giving birth to an Aboriginal baby in South Australia between July 2011 and June 2013, using methods designed to respect Aboriginal culture and communities. METHODS: A team of 12 Aboriginal researchers facilitated community engagement and recruitment of Aboriginal and non-Aboriginal mothers of Aboriginal infants in urban, regional and remote areas of South Australia over a two-year period. RESULTS: A total of 344 women took part, around a quarter of all Aboriginal women giving birth in South Australia in the study period (39% urban, 35% regional and 25% from remote areas). Participants were representative in relation to maternal age (mean age of 25 years, range=15-43 years). Over half of women (56%) first heard about the study via a member of the fieldwork team making contact with them through community connections. Other major sources of recruitment were: Aboriginal health services/programs (20%) and public maternity hospitals (16%). Almost all of the women (95%) recruited via community networks of the fieldwork team completed the questionnaire. In contrast, 51% of women recruited via public hospitals completed the questionnaire (odds ratio=0.1, 95% confidence interval 0.0-0.1, p<0.001). CONCLUSIONS: Aboriginal researchers' community knowledge and leadership is critical to the conduct of successful Aboriginal health research. High levels of participation in research by 'harder to reach' populations are achievable when researchers take time to build relationships and work in partnership with communities. PMID- 29699795 TI - Brain Hydatid in a Child. PMID- 29699797 TI - Deficiencies in the conduct and reporting of pediatric clinical trials. PMID- 29699796 TI - Prevalence of Nephrocalcinosis in Pseudohypoparathyroidism: Is Screening Necessary? AB - The prevalence of nephrocalcinosis in persons with pseudohypoparathyroidism has not been systematically examined. We conducted a retrospective study of renal imaging and biochemical results in 19 patients with pseudohypoparathyroidism with 49 imaging assessments. No cases of nephrocalcinosis were identified. Routine screening for nephrocalcinosis in pseudohypoparathyroidism may not be necessary. PMID- 29699798 TI - Whither the Jones Criteria? PMID- 29699799 TI - Critical issues underlying expenditures for adolescent idiopathic scoliosis surgery: questioning the surgical treatment motivation. PMID- 29699800 TI - Dosimetric effects of bolus and lens shielding in treating ocular lymphomas with low-energy electrons. AB - Radiation therapy is an effective treatment for primary orbital lymphomas. Lens shielding with electrons can reduce the risk of high-grade cataracts in patients undergoing treatment for superficial tumors. This work evaluates the dosimetric effects of a suspended eye shield, placement of bolus, and varying electron energies. Film (GafChromic EBT3) dosimetry and relative output factors were measured for 6, 8, and 10 MeV electron energies. A customized 5-cm diameter circle electron orbital cutout was constructed for a 6 * 6-cm applicator with a suspended lens shield (8-mm diameter Cerrobend cylinder, 2.2-cm length). Point doses were measured using a scanning electron diode in a solid water phantom at depths representative of the anterior and posterior lens. Depth dose profiles were compared for 0-mm, 3-mm, and 5-mm bolus thicknesses. At 5 mm (the approximate distance of the anterior lens from the surface of the cornea), the percent depth dose under the suspended lens shield was reduced to 15%, 15%, and 14% for electron energies 6, 8, and 10 MeV, respectively. Applying bolus reduced the benefit of lens shielding by increasing the estimated doses under the block to 27% for 3-mm and 44% for 5-mm bolus for a 6 MeV incident electron beam. This effect is minimized with 8 MeV electron beams where the corresponding values were 15.5% and 18% for 3-mm and 5-mm bolus. Introduction of a 7-mm hole in 5-mm bolus to stabilize eye motion during treatment altered lens doses by about 1%. Careful selection of electron energy and consideration of bolus effects are needed to account for electron scatter under a lens shield. PMID- 29699802 TI - Clinical trial methodology in rare gynecologic tumor research: Strategies for success. AB - BACKGROUND: Performing clinical trials in rare gynecologic cancers presents specific challenges. Strategies for improving accrual and modifications in clinical trial design are outlined. METHODS: The literature was reviewed in order to present statistical designs pertinent to the study of rare gynecologic cancers. The experience of the Gynecologic Oncology Group/NRG Oncology is outlined as it relates to rare gynecologic cancer clinical trial development. RESULTS: Significant progress has been made in studying rare tumors, both nationally and in gynecologic oncology, but challenges inherent to the study of uncommon diseases remain. Important components of these trials include establishing the standard of care, utilizing the appropriate clinical trial design to effectively answer the question in the trial, accurately estimating sample size, choosing modified and realistic endpoints, and avoiding pitfalls specific to rare tumors. Adaptive trial design and statistical modifications are important components of clinical trial design in rare tumors. CONCLUSION: Strategies for effective study of rare gynecologic cancers must be implemented when designing clinical trials for these patients. PMID- 29699803 TI - [Bilateral nuclear cataract]. PMID- 29699801 TI - Expression and role of autophagy-associated p62 (SQSTM1) in multidrug resistant ovarian cancer. AB - OBJECTIVE: Multidrug resistance is the major cause of treatment failure in ovarian cancer. p62 (SQSTM1) is a multifunctional protein involved in multiple cellular processes including proliferation, drug sensitivity and autophagy associated cancer cell growth. However, the role of p62 in drug resistance remains controversial. METHODS: In this study, we examined p62 expression by immunohistochemistry in a unique ovarian cancer tissue microarray (TMA), which was constructed with paired primary, metastatic, and recurrent tumor tissues. The expression levels of p62 and autophagy related proteins were evaluated in two panels of human cancer cell lines by western blot. Cell viabilities were determined by MTT assay after exposure ovarian cancer cells to different concentrations of paclitaxel alone or in combination with autophagy inhibitors. RESULTS: Both the metastatic and recurrent tumor tissues expressed less p62 than the patient-matched primary tumor. A significant inverse correlation has been found between p62 expression and both the disease-free survival and overall survival. Additionally, multidrug resistant cancer cell lines expressed lower levels of p62 as compared with their parental drug sensitive cell lines. Importantly, inhibition of autophagy enhanced paclitaxel sensitivity in drug resistant ovarian cancer cells. Furthermore, the wound healing assay exhibited that the inhibition of autophagy significantly decreased resistant ovarian cancer cell migration in vitro. CONCLUSION: Our findings highlight the potential of p62 as a new prognostic marker for ovarian cancer patients and p62's associated autophagy pathway may be a promising therapeutic target to prevent metastasis, recurrence and to reverse drug resistance in ovarian cancer. PMID- 29699804 TI - Preoperative localization modalities in primary hyperparathyroidism: Correlation with postoperative cure. AB - BACKGROUND: Accurate preoperative localization is critical to the success of minimally invasive parathyroidectomy. This investigation aimed to assess the correlation among preoperative imaging results, intraoperative findings, and postoperative cure rates in patients undergoing operation for primary hyperparathyroidism. METHODS: A retrospective review of all patients who underwent operation for primary hyperparathyroidism between June 2010 and March 2016 was performed. RESULTS: During the study period, 398 patients underwent parathyroidectomy. The overall cure rate was 97.5%. The ultrasonography performed by the surgeon was superior to the ultrasonography performed by the radiologist and to the sestamibi scan in lateralizing the adenoma correctly (80% vs 62% vs 70%, P < .001, respectively), and had the greatest sensitivity (93%) and accuracy (80%) among all tests (P < .001). Age >=65 was found to be associated with lesser cure rates (94% vs 99.2%, P = .003). The number of positive preoperative studies correlated with cure rate, ranging from 80% for patients with 0 positive studies, to 100% in those with 4 positive studies (P = .0004). In patients with a negative sestamibi and an ultrasonography performed by the radiologist, there was no significant difference in the cure rates among those with no preoperative computed tomography, a positive preoperative computed tomography, or a negative preoperative computed tomography. CONCLUSION: An ultrasonography performed by an experienced surgeon is an extremely valuable preoperative localization modality. The cure rate obtained is proportional to the number of positive imaging studies. In patients with negative ultrasonography performed by a nonexperienced radiologist and a negative sestamibi scan, the performance of computed tomography does not seem to increase cure rate. Patients with no positive preoperative scans represent a challenging subgroup, with cure rates of approximately 80%. PMID- 29699805 TI - Minimally invasive versus full sternotomy aortic valve replacement in low-risk patients: Which will stand against transcatheter aortic valve replacement? AB - BACKGROUND: Minimally invasive aortic valve replacement using upper hemisternotomy has been associated with improved results compared to full sternotomy aortic valve replacement. Given the likely expansion of transcatheter aortic valve replacement to low-risk patients, we examine contemporary outcomes after full sternotomy and minimally invasive aortic valve replacement in low-risk patients using our 15-year experience. METHODS: Two thousand ninety-five low-risk patients (Society of Thoracic Surgeons Predicted Risk of Mortality score <4) underwent elective isolated aortic valve replacement, including 1,029 (49%) minimally invasive and 1,066 (51%) full sternotomy, from 2002 to 2015. RESULTS: Compared to minimally invasive aortic valve replacement patients, full sternotomy aortic valve replacement patients had a greater burden of comorbidities, including diabetes, stroke, congestive heart failure, and predicted risk of mortality (all P <= .05). Operative mortality, stroke, and reoperation rates for bleeding were similar. There was a clinical trend toward shorter median intensive care unit stay and significantly shorter hospital length of stay among minimally invasive aortic valve replacement patients. Adjusted survival analysis identified age, chronic kidney disease, prior sternotomy, and congestive heart failure as predictors of decreased survival (all P <= .05), while type of intervention approach was nonsignificantly different. CONCLUSION: In low-risk patients, minimally invasive aortic valve replacement results in similar mortality, stroke, reoperation rates for bleeding, and midterm survival (after adjusting for confounders), but shorter hospital length of stay and a trend (P = .075) toward shorter intensive care unit stay, compared to full sternotomy aortic valve replacement. Therefore, minimally invasive aortic valve replacement should stand as a benchmark against transcatheter aortic valve replacement in these patients. PMID- 29699806 TI - Corticosteroid response predicts success of laparoscopic splenectomy in treating immune thrombocytopenia. AB - BACKGROUND: Laparoscopic splenectomy is a second-line therapy for immune thrombocytopenia with a sustained success rate of 66%. In a climate of new available medical therapies for immune thrombocytopenia, the comparative safety and efficacy of laparoscopic splenectomy are worthy of attention. The purpose of this study is to identify factors predictive of laparoscopic splenectomy success that will enable preoperative prognostication. METHODS: A retrospective cohort study was conducted of patients undergoing laparoscopic splenectomy for immune thrombocytopenia. The data collected evaluated response to medical and surgical therapy, which was defined on a platelet level of 50 * 109/L with no bleeding events. Univariate and multivariate analyses were conducted to evaluate factors predictive of laparoscopic splenectomy success, with an additional subanalysis planned to assess for laparoscopic splenectomy safety in individuals >=65 years. RESULTS: One hundred forty-one patients were reviewed. Operative outcomes showed a 3.6% conversion rate and 8.5% complication rate. Disease remission was achieved in 78.7% of patients. Response to initial corticosteroid therapy was associated with a laparoscopic splenectomy success rate of 90% and increased odds of surgical success by 5.58 over individuals with no response to corticosteroids. Age did not confer an increased risk of failure or complications. CONCLUSION: Laparoscopic splenectomy is a safe and effective intervention for immune thrombocytopenia regardless of age. Initial response to corticosteroids is associated with laparoscopic splenectomy success rate of 90% and improved odds of surgical success. Laparoscopic splenectomy should be the standard second-line therapy for immune thrombocytopenia, especially in patients responding to corticosteroids. PMID- 29699807 TI - Weight-based enoxaparin dosing and deep vein thrombosis in hospitalized trauma patients: A double-blind, randomized, pilot study. AB - BACKGROUND: Venous thromboembolism is a cause of morbidity and mortality in trauma patients. Chemoprophylaxis with low-molecular-weight heparin at a standardized dose is recommended. Conventional chemoprophylaxis may be inadequate. We hypothesized that a weight-adjusted enoxaparin prophylaxis regimen would reduce the frequency of venous thromboembolism in hospitalized trauma patients and at 90-day follow-up. METHODS: This prospective, randomized pilot study enrolled adult patients admitted to a level 1 trauma center between July 2013 and January 2015. Subjects were randomized to receive either standard (30 mg subcutaneously every 12 hours) or weight-based (0.5mg/kg subcutaneously every 12 hours) enoxaparin. Surveillance duplex ultrasound for lower extremity deep vein thrombosis was performed on hospital days 1, 3, and 7, and weekly thereafter. The primary outcome was deep vein thrombosis during hospitalization. Secondary outcomes included venous thromboembolism at 90 days and significant bleeding events. RESULTS: Two hundred thirty-four (124 standard, 110 weight-based) subjects were enrolled. There was no difference between standard and weight-based regarding age, body mass index, percentage female gender, injury severity score, or percentage that had surgery. There was a trend toward less in-hospital deep vein thrombosis in weight-based (12 [9.7%] standard vs 4 [3.6%] weight-based, P = .075). At 90 days, there was no difference in venous thromboembolism (12 [9.7%] standard vs 6 [5.5%] weight-based, P =.34). There was 1 bleeding event, which occurred in a standard subject. CONCLUSION: Weight-based enoxaparin dosing for venous thromboembolism chemoprophylaxis in trauma patients may provide better protection against venous thromboembolism than standard. A definitive study is necessary to determine whether weight-based dosing is superior to standard. PMID- 29699808 TI - Vitamin A and Retinoic Acid Exhibit Protective Effects on Necrotizing Enterocolitis by Regulating Intestinal Flora and Enhancing the Intestinal Epithelial Barrier. AB - BACKGROUND: Exaggerated inflammation that characterizes necrotizing enterocolitis (NEC) is caused by the invasion of pathogens through an immature intestinal barrier. Vitamin A (VA) and retinoic acid (RA) play important roles in the growth of epithelial tissue and in modulating immune function. OBJECTIVE: To investigate the roles of VA and RA in the development of NEC. METHODS: Levels of serum retinol in patients and in a NEC mouse model were detected with high-performance liquid chromatography. Bacterial communities of NEC mice treated with VA or PBS were detected by high-throughput sequencing. In vitro and in vivo, levels of inflammatory factors were measured by ELISA and RT-PCR, and expression levels of claudin-1, occludin, and ZO-1 were detected by Western blotting. Transepithelial electrical resistance (TEER) was measured in Caco-2 cell monolayers. RESULTS: The level of VA in the NEC patients was lower than in the control patients. In the NEC mice that were treated with VA versus PBS, the proportion of Escherichia Shigella was lower, while the abundance of Bacteroides was markedly higher. Both in vivo and in vitro, the levels of inflammatory factors were significantly reduced, while the expression levels of claudin-1, occludin, and ZO-1 were increased, after the VA and RA treatments. Meanwhile, TEER was increased and lipopolysaccharide-induced damage was reduced in Caco-2 cell monolayers after RA treatment. CONCLUSIONS: These results suggest that VA may regulate intestinal flora, alleviate inflammatory reactions, and enhance the intestinal epithelial barrier in NEC. Thus, VA may be an effective drug for providing protection against NEC in newborns. PMID- 29699809 TI - Serum Paraoxonase-1 Concentration as a Potential Predictor of Urinary Bladder Cancer Recurrence. A Five Year Follow-Up Study. AB - This study provides preliminary information on the usefulness of measuring serum paraoxonase-1 (PON1) concentration and activity (and other inflammatory markers) to predict tumor recurrence in patients with urinary bladder cancer. We studied a total of 39 hospitalized patients in whom the diagnosis of urinary bladder cancer was confirmed by transurethral resection. After five years of follow-up, 29 patients presented with tumor recurrence. As control subjects, we also studied 61 healthy subjects and a further 132 hospitalized patients who had a urinary catheter-related infection due to causes other than cancer. Results showed that urinary bladder patients had lower serum PON1 concentration and activity, and higher chemokine (C-C motif) ligand 2, C-reactive protein, and procalcitonin concentrations than the control individuals. Patients with tumor recurrence had significantly lower serum PON1 concentration than patients without tumor recurrence. The mean area under the curve of the receiver operating characteristics plot for serum PON1 concentration in discriminating patients with and those without tumor recurrence was 0.755 and the best combination of sensitivity and specificity was obtained at PON1 = 100 mg/L (0.72 and 0.80, respectively). Establishing this value as a cut-off, positive predictive value was = 0.91, and negative predictive value was = 0.50. These results suggest that the measurement of serum PON1 concentration may be a high-sensitivity marker of tumor recurrence in urinary bladder cancer patients. PMID- 29699810 TI - Characterization of Folic Acid Surface-Coated Selenium Nanoparticles and Corresponding In Vitro and In Vivo Effects Against Breast Cancer. AB - BACKGROUNDS AND AIMS: Selenium nanoparticles (SeNPs) have been reported to exhibit an inhibitory effect on cancer cells. In the present study, we aimed to compare the in vitro and in vivo effects of SeNPs and folic acid surface-coated selenium nanoparticles (FA@SeNPs) on breast cancer. METHODS: FA@SeNPs and SeNPs were chemically synthesized and characterized with different instrumental techniques. The cytotoxicity of both nanomaterials was evaluated against 4T1 cells. In addition, the intravenous administration effect of these nanomaterials (300 MUg/week) on the lifespan and tumor size of cancer-bearing mice was investigated. RESULTS: Although the SeNPs showed an antiproliferative effect against the cell line, the cytotoxicity of the FA@SeNPs was higher than that of the SeNPs. A low concentration of FA@SeNPs (25 MUg/mL corresponding to 8.75 MUg/mL of elemental SeNPs) caused approximately 68% cell mortality. In the in vivo study, the nanomaterials decreased the tumor growth rate in cancerous mice in relation to the control group. FA@SeNPs were more effective than SeNPs. CONCLUSIONS: The combination of SeNPs and FA has a potent antiproliferative effect against 4T1 cells, significantly increases the lifespan, and prevents tumor growth. PMID- 29699811 TI - Healthcare waste management from the point of view of circular economy. PMID- 29699812 TI - A short-term increase in dietary cholesterol and fat intake affects high-density lipoprotein composition in healthy subjects. AB - BACKGROUND AND AIMS: High-cholesterol and high-fat diets alter biochemical composition and anti-oxidant properties of high-density lipoproteins (HDL) in animals. Whether this occurs in humans is unknown. Therefore, we examined the effect of a short-term elevation in dietary cholesterol and fat intake on HDL composition in healthy subjects. METHODS AND RESULTS: In a randomized, crossover clinical trial, 14 healthy young volunteers followed a 14-day low-cholesterol/low fat diet (LChF) and a 14-day isocaloric high-cholesterol/high-fat diet (HChF) in a random order. After each diet, we measured HDL concentrations of hydroxyeicosatetraenoic acids (HETE), hydroxyoctadecadienoic acids (HODE), and haptoglobin, as well as serum amyloid A (SAA) and paroxonase-1 activity (PON-1). HDL concentrations of 15-HETE (+254%, p = 0.002), 5-HETE (+116%, p = 0.004), 13 HODE (+102%, p = 0.049), and SAA levels (+75%, p = 0.007) were significantly higher after the HChF than after the LChF. Furthermore, haptoglobin was marginally increased (+32%, p = 0.091) while PON-1 activity was unaffected (-16%, p = 0.366) by the HChF. CONCLUSION: In healthy subjects, a short-term elevation in dietary cholesterol and fat intake increases HDL lipid hydroperoxide content (15-HETE, 5-HETE, 13-HODE) and SAA levels, which are key features of dysfunctional HDL. This is the first study showing that a physiologic manipulation of dietary cholesterol and fat intake affects HDL lipidome and proteome in healthy subjects independently of weight changes. CLINICAL TRIAL REGISTRATION: NCT02549144. PMID- 29699813 TI - BMI correlates with pulse pressure in offspring of patients with type 2 diabetes and albuminuria. PMID- 29699814 TI - DXA-measured visceral fat mass and lean body mass reflect abnormal metabolic phenotypes among some obese and nonobese Chinese children and adolescents. AB - BACKGROUND AND AIM: The exact constellation of body composition characteristics among metabolically unhealthy obese (MUO) and nonobese (MUNO) children and adolescents remains unclear. The purpose of this study was to identify the major body composition determinants of metabolically unhealthy phenotypes among Chinese children and adolescents. METHODS AND RESULTS: We used data from a cross sectional survey in 2015 that included 1983 children and adolescents aged 6-18 years. Subjects were classified into two phenotypes based on a combination of body mass index (BMI) and metabolic syndrome components. Body composition was measured by dual-energy X-ray absorptiometry (DXA). Among all boys and among adolescent boys, those with MUNO phenotypes displayed significantly higher indices of body composition except for fat mass (FM) percentage and trunk-to-legs FM ratio compared with the metabolically healthy nonobese phenotype (all P < 0.05). MUO individuals had higher arm FM, lean body mass (LBM), and trunk lean mass compared to metabolically healthy obese individuals (all P < 0.05). Visceral fat mass (VFM) and BMI were the major independent determinants of MUNO (VFM, 6- to 9-year-old boys, OR = 1.02, 95% CI = 1.00-1.03, P = 0.021; BMI, 6- to 9-year old girls, OR = 1.90, 95% CI = 1.31-2.84, P = 0.001; and adolescent boys, OR = 1.34, 95% CI = 1.23-1.44, P < 0.001). LBM was the major independent predictor of MUO among adolescent boys (OR = 1.90, 95% CI = 1.03-1.17, P = 0.003). CONCLUSIONS: Among children and adolescents, the metabolically unhealthy phenotype was associated with excess of body composition, but with significant differences observed based on age and sex. VFM and LBM derived by DXA can predict the metabolically unhealthy phenotype effectively in specific sex and age groups. PMID- 29699815 TI - Associations between persistent organic pollutants and metabolic syndrome in morbidly obese individuals. AB - BACKGROUND AND AIMS: Persons with "metabolically healthy" obesity may develop cardiometabolic complications at a lower rate than equally obese persons with evident metabolic syndrome. Even morbidly obese individuals vary in risk profile. Persistent organic pollutants (POPs) are widespread environmental chemicals that impair metabolic homeostasis. We explored whether prevalence of metabolic syndrome in morbidly obese individuals is associated with serum concentrations of POPs. METHODS AND RESULTS: A cross-sectional study among 161 men and 270 women with BMI >35 kg/m2 and comorbidity, or >40 kg/m2. Circulating concentrations of 15 POPs were stratified by number of metabolic syndrome components. In multiple logistic regression analysis odds ratios between top quartile POPs and metabolic risk factors versus POPs below the top quartile were calculated adjusting for age, gender, body mass index, smoking status, alcohol consumption and cholesterol concentrations. Age-adjusted concentrations of trans-nonachlor and dioxin-like and non-dioxin-like polychlorinated biphenyls (PCBs) increased with number of metabolic syndrome components in both genders (p < 0.001), while the organochlorine pesticides HCB, beta-HCH and p,p'DDE increased only in women (p < 0.008). Organochlorine pesticides in the top quartile were associated with metabolic syndrome as were dioxin-like and non-dioxin-like PCBs (OR 2.3 [95% CI 1.3-4.0]; OR 2.5 [95% CI 1.3-4.8] and 2.0 [95% CI 1.1-3.8], respectively). Organochlorine pesticides were associated with HDL cholesterol and glucose (OR = 2.0 [95% CI = 1.1-3.4]; 2.4 [95% CI = 1.4-4.0], respectively). Dioxin-like PCBs were associated with diastolic blood pressure, glucose and homeostatic model assessment-insulin resistance index (OR = 2.0 [95% CI = 1.1-3.6], 2.1 [95% CI = 1.2-3.6] and 2.1 [95% CI = 1.0-4.3], respectively). CONCLUSION: In subjects with morbid obesity, metabolic syndrome was related to circulating levels of organochlorine pesticides and PCBs suggesting that these compounds aggravate clinically relevant complications of obesity. PMID- 29699817 TI - Molecular evidence that cellulolytic bacterial genus Cohnella is widespread among Neotropical Nasutitermitinae from NE Argentina. AB - Cohnella is a highly cellulolytic bacterial genus, which can be found in a variety of habitats. The aim of this study was to assess its presence in the digestive tract of termite species collected in North-eastern Argentina: Nasutitermes aquilinus, N. corniger and Cortaritermes fulviceps. Gut homogenates were incubated with cellulosic substrate for bacterial growth. Bacterial 16S rDNA was partially amplified using new primers for Cohnella spp. and cloned. Sequences obtained showed highest similarity (97.2-99.9%) with those of Cohnella spp. previously reported from diverse environments. Phylogenetic analysis tended to group the clones according to their host species and sampling sites. These results indicate the association of Cohnella-related intestinal symbionts with three common Neotropical termites. Their potential industrial application encourages further research. PMID- 29699816 TI - Weight gain prevention buffers the impact of CETP rs3764261 on high density lipoprotein cholesterol in young adulthood: The Study of Novel Approaches to Weight Gain Prevention (SNAP). AB - BACKGROUND AND AIMS: Two weight gain prevention strategies, one targeting small changes to diet and physical activity and a second targeting large changes, significantly reduced weight gain in young adulthood. We examined whether weight gain prevention blunts genetic risk for body weight increase and/or high density lipoprotein cholesterol (HDL-C) lowering over two years. METHODS AND RESULTS: Participants were 524 male and female young adults (mean age = 28.2, SD = 4.3; mean BMI = 25.5, SD = 2.6). Obesity-related SNPs accounting for >= 0.04% of the variance were genotyped and combined into a genetic risk score. For HDL-C, SNPs within CETP, LIPC and FADS2 were genotyped. The obesity-related genetic risk score did not predict change in BMI independently or in interaction with treatment arm. However, consistent with the prior literature, each copy of the HDL-C risk, C, allele at CETP rs3764261 was associated with lower HDL-C at baseline. Moreover, significant interaction between SNP and treatment arm for change in HDL-C was observed (p = 0.02). In the control group, HDL-C change was dependent upon rs3764261 (p = 0.004) with C allele carriers showing a continued reduction in HDL-C. In contrast, within the two intervention groups, HDL-C increased on average with no differential effect of rs3764261 (p > 0.24). Notably, even among carriers of the CC genotype, small and large change arms were associated with increased HDL-C and the control arm a reduction (p = 0.013). CONCLUSIONS: The C allele at CETP rs3764261 is a strong risk factor for low HDL-C in young adulthood but weight gain prevention may mitigate this risk. CLINICAL TRIAL REGISTRY NUMBER AND WEBSITE: clinicaltrials.gov Identifier: NCT01183689, https://clinicaltrials.gov/. PMID- 29699818 TI - Identification of remission in adult-onset asthma. PMID- 29699819 TI - Lung cancer immunotherapy biomarkers: refine not reject. PMID- 29699820 TI - Erratum to "Ultrasound features of retroareolar breast carcinoma" [Diagn. Interv. Imaging 98 (2017) 409-413]. PMID- 29699821 TI - Atlas of optimal coil orientation and position for TMS: A computational study. AB - BACKGROUND: Transcranial magnetic stimulation (TMS) activates target brain structures in a non-invasive manner. The optimal orientation of the TMS coil for the motor cortex is well known and can be estimated using motor evoked potentials. However, there are no easily measurable responses for activation of other cortical areas and the optimal orientation for these areas is currently unknown. OBJECTIVE: This study investigated the electric field strength, optimal coil orientation, and relative locations to optimally stimulate the target cortex based on computed electric field distributions. METHODS: A total of 518,616 stimulation scenarios were studied using realistic head models (2401 coil locations * 12 coil angles * 18 head models). Inter-subject registration methods were used to generate an atlas of optimized TMS coil orientations on locations on the standard brain. RESULTS: We found that the maximum electric field strength is greater in primary somatosensory cortex and primary motor cortex than in other cortical areas. Additionally, a universal optimal coil orientation applicable to most subjects is more feasible at the primary somatosensory cortex and primary motor cortex. We confirmed that optimal coil angle follows the anatomical shape of the hand motor area to realize personalized optimization of TMS. Finally, on average, the optimal coil positions for TMS on the scalp deviated 5.5 mm from the scalp points with minimum cortex-scalp distance. This deviation was minimal at the premotor cortex and primary motor cortex. CONCLUSION: Personalized optimal coil orientation is preferable for obtaining the most effective stimulation. PMID- 29699822 TI - Finite element modeling of the human kidney for probabilistic occupant models: Statistical shape analysis and mesh morphing. AB - Statistical shape analysis was conducted on 15 pairs (left and right) of human kidneys. It was shown that the left and right kidney were significantly different in size and shape. In addition, several common modes of kidney variation were identified using statistical shape analysis. Semi-automatic mesh morphing techniques have been developed to efficiently create subject specific meshes from a template mesh with a similar geometry. Subject specific meshes as well as probabilistic kidney meshes were created from a template mesh. Mesh quality remained about the same as the template mesh while only taking a fraction of the time to create the mesh from scratch or morph with manually identified landmarks. This technique can help enhance the quality of information gathered from experimental testing with subject specific meshes as well as help to more efficiently predict injury by creating models with the mean shape as well as models at the extremes for each principal component. PMID- 29699823 TI - Accelerometer-based prediction of running injury in National Collegiate Athletic Association track athletes. AB - Running-related injuries (RRI) may result from accumulated microtrauma caused by combinations of high load magnitudes (vertical ground reaction forces; vGRFs) and numbers (strides). Yet relationships between vGRF and RRI remain unclear - potentially because previous research has largely been constrained to collecting vGRFs in laboratory settings and ignoring relationships between RRI and stride number. In this preliminary proof-of-concept study, we addressed these constraints: Over a 60-day period, each time collegiate athletes (n = 9) ran they wore a hip-mounted activity monitor that collected accelerations throughout the entire run. Accelerations were used to estimate peak vGRF, number of strides, and weighted cumulative loading (sum of peak vGRFs weighted to the 9th power) across the entirety of each run. Runners also reported their post-training pain/fatigue and any RRI that prevented training. Across 419 runs and >2.1 million strides, injured (n = 3) and uninjured (n = 6) participants did not report significantly different pain/fatigue (p = 0.56) or mean number of strides per run (p = 0.91). Injured participants did, however, have significantly greater peak vGRFs (p = 0.01) and weighted cumulative loading per run (p < 0.01). Results from this small but extensively studied sample of elite runners demonstrate that loading profiles (load magnitude-number combinations) quantified with activity monitors can provide valuable information that may prove essential for: (1) testing hypotheses regarding overuse injury mechanisms, (2) developing injury-prediction models, and (3) designing and adjusting athlete- and loading-specific training programs and feedback. PMID- 29699824 TI - Fitness effects of interspecific competition between two species of desert rodents. AB - Many factors affect individual fitness, but while some factors, such as resource availability, have received strong experimental support, others including interspecific competition have rarely been quantified. Nevertheless, interspecific competition is commonly mentioned in the context of reproductive success and fitness. In general, when reproduction is likely to fail, reproductive suppression may occur. We studied the golden spiny mouse (Acomys russatus) and the common spiny mouse (A. cahirinus; however, recent molecular analysis in spiny mice from Jordan and Sinai suggests this species is A. dimidiatus (Frynta et al., 2010), as a model for the effect of competition on reproduction in four field enclosures: two populated only by A. russatus individuals, and two populated by individuals of both species. In presence of A. cahirinus, fitness of A. russatus was lower: the number of A. rusatus offspring was significantly lower; more males had regressed testes (indicating reproductive depression); more A. russatus young had damaged tails. However, no clear effect was evident in A. russatus female vaginal smear cytology. We conclude that the presence of A. cahirinus impairs fitness and reproductive success of A. russatus. While various direct and/or indirect mechanisms may be responsible for the effect of competition on reproduction, a plausible mechanism is increased use of torpor induced by the presence of A. cahirinus previously documented in A. russatus. PMID- 29699825 TI - Chronic Obstructive Pulmonary Disease Is Associated With Short-Term Complications Following Total Knee Arthroplasty. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major global health issue and a leading cause of morbidity and mortality. Patients with COPD are at increased risk of complications following surgery. The purpose of this study is to evaluate the postoperative total knee arthroplasty (TKA) outcomes in these patients in comparison to a non-COPD matching cohort. Specifically, we asked the following questions: (1) "Is COPD associated with adverse perioperative outcomes?" and (2) "Does COPD increase the risk of short-term complications following TKA?" METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was used to identify 111,168 patients who underwent TKA between 2008 and 2014. A total of 3975 patients with COPD were identified. Both COPD and non-COPD cohorts were compared in terms of the following outcomes: hospital length of stay, discharge disposition, and 30-day postoperative complications. RESULTS: COPD was a predictor for a prolonged length of stay and a discharge to an extended care facility (P < .001). They were at significantly increased risk of any complication including increased mortality, pneumonia, reintubation, use of a mechanical ventilator for >48 hours, cardiac arrest, progressive renal insufficiency, deep infection, return to operating room, and a readmission within 30 days postoperatively. CONCLUSION: Patients with COPD are more likely to experience postoperative complications following TKA when compared to non-COPD patients. Pulmonary evaluation and optimization are crucial to minimize adverse events from occurring in this difficult-to-treat population. PMID- 29699826 TI - The Safety of Tranexamic Acid in Total Joint Arthroplasty: A Direct Meta Analysis. AB - BACKGROUND: Tranexamic acid (TXA) is effective in reducing blood loss in total joint arthroplasty (TJA), but concerns still remain regarding the drug's safety. The purpose of this direct meta-analysis was to evaluate and establish a basis for the safety recommendations of the combined clinical practice guidelines on the use of TXA in primary TJA. METHODS: A search was completed for studies published before July 2017 on TXA in primary TJA. We performed qualitative and quantitative homogeneity testing and a direct comparison meta-analysis. We used the American Society of Anesthesiologists (ASA) score of 3 or greater as a proxy for patients at higher risk for complications in general and performed a meta regression analysis to investigate the influence of comorbidity burden on the risk of arterial thromboembolic event and venous thromboembolic event (VTE). RESULTS: Topical, intravenous, and oral TXA were not associated with an increased risk of VTE after TJA. In addition, meta-regression demonstrated that TXA use in patients with an ASA status of 3 or greater was not associated with an increased risk of VTE after total knee arthroplasty. CONCLUSION: Although most studies included in our analysis excluded patients with a history of prior thromboembolic events, our findings support the lack of evidence of harm from TXA administration in patients undergoing TJA. Moderate evidence supports the safety of TXA in patients undergoing total knee arthroplasty with an ASA score of 3 or greater. The benefits of using TXA appear to outweigh the potential risks of thromboembolic events even in patients with a higher comorbidity. PMID- 29699828 TI - Wear Kinetics of Highly Cross-Linked and Conventional Polyethylene Are Similar at Medium-term Follow-Up After Primary Total Hip Arthroplasty. AB - BACKGROUND: Wear debris is a major factor in aseptic loosening of total hip arthroplasty. Ultra high molecular weight polyethylene inlays are known for significant wear, and the following generation, highly cross-linked polyethylene (HCLPE), has shown promising in vitro and short-term in vivo results. This study aimed to investigate wear debris of HCLPE liners with ceramic heads after 9 years to reveal the in vivo wear kinetics of this common bearing combination. METHODS: Fifty-seven patients (72 hips; 46.5 +/- 15.5 years; range 16-76 years) who underwent hip arthroplasty with an HCLPE liner (28- or 32-mm Biolox forte ceramic head) were followed up (mean 9.1 +/- 2.4 years; range 3.9-13.8 years). Conventional anteroposterior X-rays were analyzed using Hip Analysis Suite software. RESULTS: Volumetric wear had a mean of 38.67 +/- 22.09 mm3/year, 333.08 +/- 183.93 mm3 overall, and linear wear was 0.063 +/- 0.03 mm/year and 0.546 +/- 0.27 mm overall. Male patients had a significantly higher wear rate (46.42 +/- 27.68 mm3/year) and total wear (400.71 +/- 235.21 mm3). Larger femoral heads had a significantly higher wear rate (43.10 +/- 23.93 mm3/year) and total wear (364.23 +/- 203.68 mm3). Regression analysis showed a significant cubic relationship (R2 = 0.307) with increasing yearly wear after approximately 108 months postoperatively. CONCLUSIONS: HCLPE liners show significant in vivo wear after 9 years. While the total wear compared to ultra high molecular weight polyethylene liners was decreased, the wear kinetics show a comparable course. The increase in wear rate after only 108 months postoperatively is especially alarming. Longer term follow-up is needed to distinguish the long-term superiority of HCLPE liners in polyethylene-ceramic paired hip arthroplasty. PMID- 29699827 TI - Iatrogenic Bone and Soft Tissue Trauma in Robotic-Arm Assisted Total Knee Arthroplasty Compared With Conventional Jig-Based Total Knee Arthroplasty: A Prospective Cohort Study and Validation of a New Classification System. AB - BACKGROUND: The objective of this study was to compare macroscopic bone and soft tissue injury between robotic-arm assisted total knee arthroplasty (RA-TKA) and conventional jig-based total knee arthroplasty (CJ-TKA) and create a validated classification system for reporting iatrogenic bone and periarticular soft tissue injury after TKA. METHODS: This study included 30 consecutive CJ-TKAs followed by 30 consecutive RA-TKAs performed by a single surgeon. Intraoperative photographs of the femur, tibia, and periarticular soft tissues were taken before implantation of prostheses. Using these outcomes, the macroscopic soft tissue injury (MASTI) classification system was developed to grade iatrogenic bone and soft tissue injuries. Interobserver and Intraobserver validity of the proposed classification system was assessed. RESULTS: Patients undergoing RA-TKA had reduced medial soft tissue injury in both passively correctible (P < .05) and noncorrectible varus deformities (P < .05); more pristine femoral (P < .05) and tibial (P < .05) bone resection cuts; and improved MASTI scores compared to CJ TKA (P < .05). There was high interobserver (intraclass correlation coefficient 0.92 [95% confidence interval: 0.88-0.96], P < .05) and intraobserver agreement (intraclass correlation coefficient 0.94 [95% confidence interval: 0.92-0.97], P < .05) of the proposed MASTI classification system. CONCLUSION: There is reduced bone and periarticular soft tissue injury in patients undergoing RA-TKA compared to CJ-TKA. The proposed MASTI classification system is a reproducible grading scheme for describing iatrogenic bone and soft tissue injury in TKA. CLINICAL RELEVANCE: RA-TKA is associated with reduced bone and soft tissue injury compared with conventional jig-based TKA. The proposed MASTI classification may facilitate further research correlating macroscopic soft tissue injury during TKA to long term clinical and functional outcomes. PMID- 29699829 TI - [Depression among patients affected by the human immunodeficiency virus]. PMID- 29699830 TI - Prevalence and risk factors for low bone mineral density in antiretroviral therapy-naive HIV-infected young men. AB - OBJECTIVE: We aimed to investigate the prevalence of low bone mineral density (BMD) and associated factors in antiretroviral therapy (ART)-naive HIV-infected young men. METHODS: In this cross-sectional study, dual-energy X-ray absorptiometry (DXA) was used to measure BMD. BMD at the lumbar spine, total hip and femoral neck sites was expressed as a Z-score (number of standard deviations away from the mean in an age, race and sex-matched reference population). Low BMD was defined as Z-scores<=-2 at any of the three sites. The prevalence of low BMD was evaluated at the lumbar spine, total hip and femoral neck sites, as were risk factors associated with Z-scores. RESULTS: The study cohort comprised 49 men, of whom 87.8% were white. Mean age was 31.6 (+/-7.7) years and mean BMI was 22.7 (+/ 4.0)kg/m2. Half of patients (51.0%) were current smokers. The prevalence of low BMD was 24.5% [95% CI, 13.3-38.9]. Low estradiol levels and low BMI were associated with low Z-scores at each skeletal site, whereas current smoking and high IGF1 levels were associated with low Z-scores at the lumbar spine site. Among the HIV-related factors, low CD4+ cell count was associated with low Z scores at the lumbar spine site. CONCLUSIONS: We observed a high prevalence of low BMD in our ART-naive cohort of young men. Risk factors associated with low Z scores were those usually observed in HIV-infected individuals (low BMI, current smoking and CD4+ cell count) or linked to endocrine hormone levels (estradiol, IGF-1). PMID- 29699831 TI - Breeding Soundness Examination of the Bitch. AB - A breeding soundness examination is a vital part of any breeding program. These examinations are not performed as frequently in the bitch as they are in the male dog. They allow clinicians to identify any problems at an early stage in a bitch's breeding career and to screen for any genetic abnormalities. A thorough physical examination and accurate history guide the choice of which diagnostics tests are most useful. Ultrasound, culture, cytology, and biopsies (surgical and nonsurgical techniques) are discussed. Knowing which stage of the cycle to perform these diagnostics yields the most information and increases the chance of a successful outcome. PMID- 29699832 TI - Adaptive radiotherapy for head and neck cancers: Fact or fallacy to improve therapeutic ratio? AB - Modern standards of precision radiotherapy, primarily driven by the technological advances of intensity modulation and image guidance, have led to increased versatility in radiotherapy planning and delivery. The ability to shape doses around critical normal organs, while simultaneously "painting" boost doses to the tumor have translated to substantial therapeutic gains in head and neck cancer patients. Recently, dose adaptation (or adaptive radiotherapy) has been proposed as a novel concept to enhance the therapeutic ratio of head and neck radiotherapy, facilitated in part by the onset of molecular and functional imaging. These contemporary imaging techniques have enabled visualisation of the spatial molecular architecture of the tumor. Daily cone-beam imaging, besides improving treatment accuracy, offers another unique angle to explore radiomics - a novel high throughput feature extraction and selection workflow, for adapting radiotherapy based on real-time tumor changes. Here, we review the existing evidence of molecular and functional imaging in head and neck cancers, as well as the current application of adaptive radiotherapy in the treatment of this tumor type. We propose that adaptive radiotherapy can be further exploited through a systematic application of molecular and functional imaging, including radiomics, at the different phases of planning and treatment. PMID- 29699833 TI - A novel voxel based homogeneity index: Rationale and clinical implications for whole-brain radiation therapy. AB - PURPOSE OR OBJECTIVE: A homogeneity index (HI) measures the uniformity of a dose distribution within a given target volume. Traditional HIs only use a limited number of dose-volume histogram data-points for calculation. A voxel-based homogeneity index (VHI) is proposed which utilizes the entire information of the three-dimensional dose distribution. We compared the VHI with existing HIs and analyzed if VHI results were associated with treatment outcomes in patients who underwent therapeutic WBRT. MATERIAL AND METHODS: The VHI analyzes deviations from the prescribed dose in each voxel of the target volume. We retrospectively analyzed WBRT treatment plans. Overall survival (OS), CNS progression-free survival (CNS PFS) and hazard rates were compared for tertile-split levels of the VHI using the Kaplan-Meier methods and multivariable Cox-regression analysis. RESULTS: WBRT treatment plans (n = 770) were used for HIs comparison. OS and CNS PFS were assessed for 430 patients. The VHI showed a higher sensitivity for dose inhomogeneities. Lower OS and CNS PFS were observed for higher levels of VHIUnderdosage, particularly in patients with good performance status (KPS >70%) (OS: Log-rank P = .007, HR = 1.37 95%CI [1.09, 1.72]). CONCLUSION: Higher sensitivity and feasibility to assess treatment plan quality using the VHI were demonstrated. First clinical implications were found in terms of compromised OS/CNS PFS for WBRT with radiation underdosage. PMID- 29699834 TI - Respiratory muscle strength and state of consciousness values measured prior to the decanulation in different levels of complexity. A longitudinal prospective case series study. AB - OBJECTIVE: To describe the variables related to effective cough capacity and the state of consciousness measured prior to decannulation and compare their measured values between the different areas of care such as the Intensive Care Unit (ICU), General ward and Mechanical Ventilation Weaning and Rehabilitation Centers (MVWRC). Secondarily analyze the evolution of patients once decannulated. DESIGN: Case series, longitudinal and prospective. SCOPE: Multicentric 31 ICUs (polyvalent) and 5 MVWRC. PATIENTS: Tracheostomized adults prior to decannulation. MEASUREMENTS: Maximum expiratory pressure, peak expiratory flow coughed (PEFC), Glasgow Coma Scale (GCS). RESULTS: Two hundred and seven decannulated patients, 124 (60%) in ICU, 59 (28%) General ward and 24 (12%) in MVWRC. The PEFC presented differences between the patients (ICU 110 - 190 l/min versus MVWRC 167.5 - 232.5 l/min, p <.01). The GCS was different between General ward (9 -15) versus ICU (10-15) and MVWRC (12-15); p <.01 and p <.01, respectively. There were differences in the days of hospitalization (p <.01), days with tracheostomy (<0.01) and the number of patients referred at home (p =.02) between the different scenarios. CONCLUSION: There are differences in the values of PEFC and GCS observed when decannulating between different areas. A considerable number of patients are decannulated with values of PEFC and maximum expiratory pressure below the suggested cut-off points as predictors of failure in the literature. No patient in our series was decanulated with an GCS <8, this reflects the importance that the treating team gives to the state of consciousness prior to decannulation. PMID- 29699835 TI - Intensive care in cancer patients in the age of the multidisciplinary approach of cancer treatments: The radiotherapy perspective. PMID- 29699836 TI - Automatic notification and infectious diseases consultation for patients with Staphylococcus aureus bacteremia. AB - Observational studies suggest that Infectious Diseases (ID) consultation is associated with improved outcomes for patients with Staphylococcus aureus bacteremia (SAB), but few studies have sought to standardize timely ID consultation through automatic notification by the Microbiology laboratory. In this 3-year quasi-experimental evaluation, introduction of this change resulted in increased ID consultation for SAB (70% versus 100%, P < 0.001) and decreased time to consultation (14.5 versus 4 h, P < 0.0001). Adherence to Quality of Care Indicators (QCIs) increased (45% versus 87%, P < 0.0002), transfer to intensive care unit decreased (38% versus 16%, P = 0.03), while decrease in 30-day readmission or death did not reach statistical significance (33% versus 27%, P = 0.5). Automatic notification and ID consultation for patients with SAB are a feasible system for ensuring improved adherence to established QCIs. PMID- 29699837 TI - Drug-related police encounters across the globe: How do they compare? AB - BACKGROUND: Drug law enforcement subsumes the majority of drug policy expenditure across the globe. Fuelled by knowledge that much of this investment is ineffective or counter-productive there have been increasing calls for cross national comparisons to identify where policing approaches differ and what types of approaches may be more effective. Yet, to date cross-national comparison of drug law enforcement has proven a methodologically hazardous affair. Using a new drug policing module added to the 2017 Global Drug Survey, this study seeks to provide the first cross-national comparison of the incidence, nature and intensity of illicit drug-related police encounters amongst people who use drugs. METHODS: The Global Drug Survey was administered in late 2016. Across 26 countries including Australia, Germany, Italy, Mexico, Switzerland, the UK and the USA a total of 45,942 people who had recently used drugs completed the drug policing module. Key variables assessed included the incidence and frequency of drug-related police encounters in the last 12 months that involved: a) being stopped and searched; b) encountering a drug detection dog; c) being given a caution or warning; d) being charged and arrested; and e) paying a bribe. Multi level models were used to control for pre-existing national differences in drug use prevalence and non-drug specific policing (including the total number of police personnel in each country). RESULTS: Drug-related police encounters were most commonly reported in Italy and Scotland. Conversely, police encounters were most likely to lead to arrest in Norway, Finland and Sweden. The type and locations of encounters further differed across countries, with for example stop and search most reported in Greece and Colombia, and encounters with drug detection dogs most reported in Scotland, Italy, UK and Australia. Multi-level models showed that the incidence of reported policing encounters continued to differ significantly across countries after controlling for pre-existing national differences in drug use prevalence and policing, and that drug policing encounters were 4 to 14 times more common in some nations than others. CONCLUSION: The findings unearth significant cross-national differences in the incidence and nature of drug-related policing of people who use drugs. This suggests that there may be opportunities for countries to learn from each other about how and why they differ, and the potential benefits of switching to lower intensity modes of drug policing. PMID- 29699838 TI - Perioperative and mid-term oncologic outcomes of robotic assisted radical cystectomy with totally intracorporeal neobladder: Results of a propensity score matched comparison with open cohort from a single-centre series. AB - AIM: In this study, we compared perioperative and oncologic outcomes of patients treated with either open or robot-assisted radical cystectomy and intracorporeal neobladder at a tertiary care center. METHODS: The institutional prospective bladder cancer database was queried for "cystectomy with curative intent" and "neobladder". All patients underwent robot-assisted radical cystectomy and intracorporeal neobladder or open radical cystectomy and orthotopic neobladder for high-grade non-muscle invasive bladder cancer or muscle invasive bladder cancer with a follow-up length >=2 years were included. A 1:1 propensity score matching analysis was used. Kaplan-Meier method was performed to compare oncologic outcomes of selected cohorts. Survival rates were computed at 1,2,3 and 4 years after surgery and the log rank test was applied to assess statistical significance between the matched groups. RESULTS: Overall, 363 patients (299 open and 64 robotic) were included. Open radical cystectomy patients were more frequently male (p = 0.08), with higher pT stages (p = 0.003), lower incidence of urothelial histologies (p = 0.05) and lesser adoption of neoadjuvant chemotherapy (<0.001). After applying the propensity score matching, 64 robot-assisted radical cystectomy patients were matched with 46 open radical cystectomy cases (all p >= 0.22). Open cohort showed a higher rate of perioperative overall complications (91.3% vs 42.2%, p 0.001). At Kaplan-Meier analysis robotic and open cohorts displayed comparable disease-free survival (log-rank p = 0.746), cancer-specific survival (p = 0.753) and overall-survival rates (p = 0.909). CONCLUSIONS: Robot assisted radical cystectomy and intracorporeal neobladder provides comparable oncologic outcomes of open radical cystectomy and orthotopic neobladder at intermediate term survival analysis. PMID- 29699839 TI - The hepatic bridge. AB - BACKGROUND: The hepatic bridge forms a tunnel of liver parenchyma that may obscure peritoneal metastases associated with the round ligament. Visualization and then resection of nodules associated with this structure is necessary. MATERIALS AND METHODS: The incidence of a hepatic bridge and the extent that it covered the round ligament was determined in consecutive patients. Extent of coverage of the round ligament by the hepatic bridge was determined: Class 1 indicates up to one-third of the round ligament obscured, Class 2 up to two thirds and Class 3 more than two-thirds. RESULTS: In 102 patients in whom the round ligament of the liver could be completely visualized, 50 had a hepatic bridge. Class 1 was 22 (44%) of the bridges, Class 2 was 16 (32%) and Class 3 was 12 (24%). A hepatic bridge was more frequently present in 28 of 45 male patients (62%) vs. 22 of 57 female patients (38%). CONCLUSIONS: Approximately one-half of our patients having cytoreductive surgery for peritoneal metastases were observed to have a hepatic bridge. Up to 56% of these patients have Class 2 or 3 hepatic bridge and may require division of the hepatic bridge to completely visualize the contents of the tunnel created by this structure. PMID- 29699840 TI - Iron toxicity - Its effect on the bone marrow. AB - Excess iron can be extremely toxic for the body and may cause organ damage in the absence of iron chelation therapy. Preclinical studies on the role of free iron on bone marrow function have shown that iron toxicity leads to the accumulation of reactive oxygen species, affects the expression of genes coding for proteins that regulate hematopoiesis, and disrupts hematopoiesis. These effects could be partially attenuated by iron-chelation treatment with deferasirox, suggesting iron toxicity may have a negative impact on the hematopoietic microenvironment. Iron toxicity is of concern in transfusion-dependent patients. Importantly, iron chelation with deferasirox can cause the loss of transfusion dependency and may induce hematological responses, although the mechanisms through which deferasirox exerts this action are currently unknown. This review will focus on the possible mechanisms of toxicity of free iron at the bone marrow level and in the bone marrow microenvironment. PMID- 29699841 TI - Lateral meniscus allograft transplantation with platelet-rich plasma injections: A minimum two-year follow-up study. AB - BACKGROUND: The aim of this study was to report the short-term clinical and imaging outcomes of lateral meniscus allograft transplantations (LMAT) combined with intra-articular platelet-rich plasma (PRP) injection. METHODS: Thirty-three patients who had undergone LMAT combined with intra-articular PRP injection were evaluated. The Lysholm, International Knee Documentation Committee (IKDC), Western Ontario and McMaster Universities Osteoarthritis Index, Tegner activity level scale and visual analog scale for pain scores were used to evaluate the outcomes. Magnetic resonance imaging scans were performed postoperatively to assess graft position and chondral degeneration/damage. RESULTS: A total of 31 of the original 33 patients were evaluated over a mean follow-up period of 37.0months. Patients demonstrated statistically significant improvements in all scoring data from the pre-operative to two-year follow-up period. The mean postoperative extrusion was 1.59+/-1.20mm (range 0-3.9mm). There were no significant differences in the distribution of the grade of chondral damage between the pre-operative and two-year follow-up periods. Three patients (9.7%) showed no improvements or had lower evaluation scores. One patient underwent matrix-induced autologous chondrocyte implantation at one year after LMAT. CONCLUSION: Lateral meniscus allograft transplantation combined with intra articular PRP injection resulted in statistically significant improvements in all functions and pain scores, and clinical improvements in Tegner, IKDC, and Lysholm values during short-term follow-up. A further case-control study with a larger sample size and longer follow-up is required to obtain an overall assessment of the benefits of PRP on MAT patients. Level of evidence IV. PMID- 29699842 TI - Effects of appraisal training on responses to a distressing autobiographical event. AB - Dysfunctional appraisals are a key factor suggested to be involved in the development and maintenance of PTSD. Research has shown that experimental induction of a positive or negative appraisal style following a laboratory stressor affects analogue posttraumatic stress symptoms. This supports a causal role of appraisal in the development of traumatic stress symptoms and the therapeutic promise of modifying appraisals to reduce PTSD symptoms. The present study aimed to extend previous findings by investigating the effects of experimentally induced appraisals on reactions to a naturally occurring analogue trauma and by examining effects on both explicit and implicit appraisals. Participants who had experienced a distressing life event were asked to imagine themselves in the most distressing moment of that event and then received either a positive or negative Cognitive Bias Modification training targeting appraisals (CBM-App). The CBM-App training induced training-congruent appraisals, but group differences in changes in appraisal over training were only seen for explicit and not implicit appraisals. However, participants trained positively reported less intrusion distress over the subsequent week than those trained negatively, and lower levels of overall posttraumatic stress symptoms. These data support the causal relationship between appraisals and trauma distress, and further illuminate the mechanisms linking the two. PMID- 29699843 TI - Novel mathematic models for quantitative transitivity of quality-markers in extraction process of the Buyanghuanwu decoction. AB - BACKGROUND: Nowadays, to research and formulate an efficiency extraction system for Chinese herbal medicine, scientists have always been facing a great challenge for quality management, so that the transitivity of Q-markers in quantitative analysis of TCM was proposed by Prof. Liu recently. In order to improve the quality of extraction from raw medicinal materials for clinical preparations, a series of integrated mathematic models for transitivity of Q-markers in quantitative analysis of TCM were established. Buyanghuanwu decoction (BYHWD) was a commonly TCMs prescription, which was used to prevent and treat the ischemic heart and brain diseases. In this paper, we selected BYHWD as an extraction experimental subject to study the quantitative transitivity of TCM. STUDY DESIGN: Based on theory of Fick's Rule and Noyes-Whitney equation, novel kinetic models were established for extraction of active components. Meanwhile, fitting out kinetic equations of extracted models and then calculating the inherent parameters in material piece and Q-marker quantitative transfer coefficients, which were considered as indexes to evaluate transitivity of Q-markers in quantitative analysis of the extraction process of BYHWD. METHODS: HPLC was applied to screen and analyze the potential Q-markers in the extraction process. Fick's Rule and Noyes-Whitney equation were adopted for mathematically modeling extraction process. Kinetic parameters were fitted and calculated by the Statistical Program for Social Sciences 20.0 software. The transferable efficiency was described and evaluated by potential Q-markers transfer trajectory via transitivity availability AUC, extraction ratio P, and decomposition ratio D respectively. The Q-marker was identified with AUC, P, D. RESULTS: Astragaloside IV, laetrile, paeoniflorin, and ferulic acid were studied as potential Q-markers from BYHWD. The relative technologic parameters were presented by mathematic models, which could adequately illustrate the inherent properties of raw materials preparation and affection of Q-markers transitivity in equilibrium processing. AUC, P, D for potential Q-markers of AST-IV, laetrile, paeoniflorin, and FA were obtained, with the results of 289.9 mAu s, 46.24%, 22.35%; 1730 mAu s, 84.48%, 1.963%; 5600 mAu s, 70.22%, 0.4752%; 7810 mAu s, 24.29%, 4.235%, respectively. CONCLUSION: The results showed that the suitable Q-markers were laetrile and paeoniflorin in our study, which exhibited acceptable traceability and transitivity in the extraction process of TCMs. Therefore, these novel mathematic models might be developed as a new standard to control TCMs quality process from raw medicinal materials to product manufacturing. PMID- 29699844 TI - Research on Q-markers of Qiliqiangxin capsule for chronic heart failure treatment based on pharmacokinetics and pharmacodynamics association. AB - BACKGROUND: Qiliqiangxin capsule (QLQX), composed of 11 herbs, is an effective traditional Chinese medicine (TCM) that has been widely used for treatment of chronic heart failure (CHF) in China. In the Chinese pharmacopoeia (Ch.P.) only astragaloside was described as the marker component to control the quality of QLQX, which could not reflect the overall effectiveness. PURPOSE: The aim of this work was to investigate the quality markers (Q-markers) of QLQX based on the association of the pharmacodynamics (PD) of inhibitory effect on activated renin angiotensin-aldosterone system (RAAS) and the pharmacokinetics (PK) of bioactive compounds according to the Q-marker theory. METHODS: The contents of astragaloside, calycosin-7-glucoside, sinapine, ginsenoside Rb1, ginsenoside Rb2, ginsenoside Rg1, salvianolic acid A, salvianolic acid B, danshensu, rosmarinic acid, formononetin, aconitine, mesaconitine, hypaconitine, benzoylaconine, benzoylmesaconine and benzoylhypacoitine were determined by an HPLC-MS/MS method both in QLQX preparation and in the plasma of CHF rats administered intragastrically with QLQX. The effect of lowering angiotensin II (Ang II) production by QLQX was assayed by ELISA. The association between PK and PD was explored and the bioactive compounds with higher content in vitro and better exposure in vivo, which were closely related to the inhibitory effect on the activated RAAS, were identified as Q-markers of QLQX for CHF treatment. RESULTS: The contents of 17 constituents were in the order of salvianolic acid B > danshensu > ginsenoside Rb1 > sinapine > benzoylmesaconine > astragaloside > benzoylhypacoitine > ginsenoside Rb2 > salvianolic acid A > ginsenoside Rg1 > calycosin-7-glucoside > rosmarinic acid > formononetin > benzoylaconine > hypaconitine > aconitine > mesaconitine in QLQX preparation. PK and PD association study of 14 bioactive compounds of QLQX showed the maximum effect (Emax) of astragaloside, calycosin-7-glucoside, sinapine and ginsenoside Rg1 and their peak concentration (Cmax) appeared at the same time; while the time of Emax of ginsenoside Rb1, ginsenoside Rb2, salvianolic acid A, salvianolic acid B, danshensu, rosmarinic acid, formononetin, benzoylaconine, benzoylmesaconine and benzoylhypacoitine was delayed from the time of their Cmax. CONCLUSIONS: Astragaloside, calycosin-7-glucoside, sinapine and ginsenoside Rg1 are suitable as the Q-markers of QLQX for CHF treatment, which have higher content in vitro, finer exposure in vivo and a direct correlation with the inhibitory effect on activated RAAS. PMID- 29699845 TI - Transcatheter Aortic Valve Replacement for Left Ventricular Assist Device-Induced Aortic Insufficiency. PMID- 29699846 TI - Selected 2017 Highlights in Congenital Cardiac Anesthesia. PMID- 29699847 TI - Perioperative Hyperlactemia Is a Poor Predictor of Outcome in Patients Undergoing Surgery for Acute Type-A Aortic Dissection. AB - OBJECTIVE: In patients presenting with acute type-A aortic dissection (aTAAD), lactic acid measurement is a frequently used analysis for diagnosis of acute ischemia, which may have a dismal prognosis. The aim of the current study was to determine the performance of perioperative arterial lactic acid measurements in predicting outcome in aTAAD patients. DESIGN: Retrospective, observational study. SETTING: Cardiothoracic surgery unit at a tertiary-level hospital. PARTICIPANTS: The study involved 285 consecutive patients undergoing surgery for aTAAD. INTERVENTIONS: Preoperative and postoperative lactic acid levels were measured and evaluated together with clinical data related to outcome, including in hospital and 1-year mortality. MEASUREMENTS AND MAIN RESULTS: Altogether, 37 patients (13%) died during the index hospital admission, and survival was 84.4 +/ 2.2 at 1 year. Preoperative cardiac malperfusion (odds ratio [OR] 3.1; 95% confidence interval [CI] 1.3-7.3) and cerebral malperfusion (OR 2.6; 95% CI 1.2 5.6) were associated significantly with poorer 1-year survival. The area under the curve (AUC) for in-hospital and 1-year mortality in relation to preoperative lactic acid levels was 0.684 and 0.673, respectively, corresponding to a lactic acid cut-off for in-hospital mortality of 2.75 mmol/L (sensitivity 56%; specificity 72%) and a cut-off for 1-year mortality of 2.85 mmol/L (sensitivity 48%; specificity 74%). The AUC for in-hospital and 1-year mortality in relation to lactic acid levels measured postoperatively on arrival at the intensive care unit was 0.582 and 0.498, respectively. CONCLUSION: Although hyperlactemia in aTAAD indicates an increased risk of postoperative mortality, the sole use of lactic acid levels as a tool for accurate assessment of postoperative mortality is inadvisable due to its poor discriminatory performance. PMID- 29699848 TI - Phosphorylation of Wat1, human Lst8 homolog is critical for the regulation of TORC2 -Gad8 dependent pathway in fission yeast Schizosacchromyces pombe. AB - Mammalian Lst8 interacts with the kinase domain of mTOR and stabilizes its interaction with Raptor regulating cell growth through the mTOR-S6K1 signalling pathway. Fission yeast Wat1, an ortholog of mammalian Lst8 is also an essential component of TOR complex 1 (TORC1) and TOR Complex 2 (TORC2) that control protein kinases essential for metabolic pathways. Here, we show that in response to osmotic stress, the Wat1 protein undergoes hyper-phosphorylation at S116 position. Wat1 interacts with the C-terminal region of Tor1 that also contain kinase domain. Co-immunoprecipitation and molecular modelling studies suggest that Wat1-Tor1 interaction is stabilized by FATC domain of Tor1 protein present at the C-terminal region. We have also demonstrated a physical interaction of Wat1 with Gad8, an AGC family protein kinase that is dependent on phosphorylation of Wat1 at S116 residue. Wat1 phosphorylation is required for the maintenance of vacuolar integrity and sexual differentiation. Collectively, our study reveals Wat1 phosphorylation regulates Gad8 function in a manner dependent on Tor1 interaction. PMID- 29699849 TI - Masseter-to-facial nerve transfer: Technique and outcomes utilizing a fibrin sealant for coaptation. PMID- 29699850 TI - Donor predicted heart mass as predictor of primary graft dysfunction. AB - BACKGROUND: Concern over the hazards associated with undersized donor hearts has impeded the utilization of otherwise viable allografts for transplantation. Previous studies have indicated predicted heart mass (PHM) may provide better size matching in cardiac transplantation than total body weight (TBW). We investigated whether size-matching donor hearts by PHM is a better predictor of primary graft dysfunction (PGD) than matching by TBW. METHODS: Records of consecutive adult cardiac transplants performed between 2012 and 2016 at a single center academic hospital were reviewed. We compared patients implanted with hearts undersized by >=30% with those implanted with donor hearts matched for size (within 30%), and performed the analysis both for undersizing by PHM and for undersizing by TBW. The primary outcome was moderate/severe PGD within 24 hours, according to the 2014 International Society for Heart and Lung Transplantation consensus. Secondary outcome was 1-year survival. RESULTS: Of 253 patients, 21 (8%) and 30 (12%) received hearts undersized by TBW and PHM, respectively. The overall rate of moderate/severe PGD was 13% (33 patients). PGD was associated with undersizing if performed by PHM (p = 0.007), but not if performed by TBW (p = 0.49). One-year survival was not different between groups (log-rank, p > 0.8). Multivariate analysis confirmed that undersizing donor hearts by PHM, but not by TBW, was predictive of moderate/severe PGD (OR 3.3, 95% CI 1.3 to 8.6). CONCLUSIONS: Undersized donor hearts by >=30% by PHM may increase rates of PGD after transplantation, confirming that PHM provides more clinically appropriate size matching than TBW. Better size matching may ultimately allow for expanding the donor pool. PMID- 29699851 TI - Blockade of adhesion molecule lymphocyte function-associated antigen-1 improves long-term heart allograft survival in mixed chimeras. AB - BACKGROUND: The mixed chimerism approach for intentional induction of donor specific tolerance was shown to be successful in various models from mice to humans. For transplant patients, the approach would obviate the need for long term immunosuppression and associated side effects; moreover, it would preclude the risk of late graft loss due to chronic rejection. Widespread clinical application is hindered by toxicities related to recipient pre-conditioning. Herein we aimed to investigate a clinically relevant protocol for tolerance induction to cardiac allografts, sparing CD40 blockade or T-cell depletion. METHODS: B6 mice were conditioned with non-myeloablative total body irradiation, fully mismatched BALB/c bone marrow cells, and short-term therapy, based on either anti- lymphocyte function-associated antigen-1 (anti-LFA-1) or anti-CD40L. Multilineage chimerism was followed by flow-cytometric analysis, tolerance was assessed with skin and heart allografts from fully or major histocompatibility complex-mismatched donors. Mechanisms of tolerance were investigated by analysis of donor-specific antibodies (DSAs), mixed lymphocyte reaction (MLR) assays, and deletion of donor-reactive T cells. RESULTS: We found that the combination of cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA4Ig) and rapamycin with LFA 1 blockade enhanced bone marrow engraftment and led to more efficient T-cell engraftment and subsequent tolerization. Although fully mismatched skin grafts were chronically rejected, primarily vascularized heart allografts survived indefinitely and without signs of chronic rejection, independent of minor antigen mismatches. CONCLUSIONS: We have demonstarted a robust protocol for the induction of tolerance for cardiac allografts in the absence of CD40 blockade. Our findings demonstrate the potential of a clinically relevant minimal conditioning protocol designed to induce lifelong immunologic tolerance toward cardiac allografts. PMID- 29699852 TI - Relative Bioavailability of a Single 4-mg Dose of Somatropin Administered by Subcutaneous Injection or by Needle-free Device and Coadministered With the Growth Hormone Inhibitor Octreotide Acetate in Healthy Adult Subjects. AB - PURPOSE: Somatropin, used to treat growth hormone deficiency, has been traditionally administered by subcutaneous (SC) injection with needle and syringe. Needle-free devices offer ease of administration and may improve adherence and outcomes. This study evaluated the relative bioavailability of somatropin delivered with a needle-free device compared with traditional SC injection. METHODS: In this randomized, single-dose, crossover study, healthy adults aged 18 to 35 years received single 4-mg doses of somatropin via a needle free device or SC injection, along with octreotide to suppress endogenous growth hormone production. Blood samples were analyzed for serum somatropin and insulin like growth factor-1 (IGF-1) concentrations over 24 hours after somatropin dosing. Pharmacokinetic and pharmacodynamic parameters were evaluated by using noncompartmental methods, and bioequivalence was determined based on ln transformation of the AUC0-24, AUC0-infinity, Cmax, area under the effect-time curve from time 0 to 24 hours (AUEC0-24), and maximum effect concentration (Emax). Bioequivalence was concluded if the 90% CIs of the needle-free device compared with the SC injection, constructed by using the two 1-sided hypotheses at the alpha = 0.05 level, for these pharmacokinetic/pharmacodynamic parameters fell within the 80.00% to125.00% regulatory acceptance range. FINDINGS: A total of 57 subjects completed both study periods and were included in the pharmacokinetic analyses. Point estimates (90% CIs) of the geometric mean ratio (needle-free device/SC injection) based on serum somatropin were 1.013 (0.987 1.040) for AUC0-24, 1.012 (0.986-1.038) for AUC0-infinity, and 1.200 (1.137 1.267) for Cmax. For IGF-1, baseline-corrected point estimates (90% CIs) were 0.901 (0.818-0.993) for AUEC0-24 and 0.867 (0.795-0.946) for Emax. Non-baseline corrected values were 0.978 (0.953-1.004) for AUEC0-24 and 0.953 (0.923-0.984) for Emax. Both treatments were well tolerated; blood glucose levels increased in nearly all subjects (98.3%). All adverse events were mild and resolved spontaneously within 24 hours. IMPLICATIONS: Bioequivalence was shown for a single 4-mg dose of somatropin delivered by using a needle-free device compared with SC injection based on ln-transformed AUC0-24 and AUC0-infinity but not ln transformed Cmax. PMID- 29699853 TI - Monoclonal Antibody Biosimilars in Oncology: Critical Appraisal of Available Data on Switching. AB - PURPOSE: With the introduction of biosimilars of anticancer monoclonal antibodies (mAbs) in oncology, physicians are potentially confronted with the question whether it is clinically adequate to switch patients who are clinically stable on treatment with the reference product to a newly available biosimilar (or vice versa/from 1 biosimilar to another). For a proper impact assessment of switching, robust, product-specific, and clinically relevant evidence should be required, ideally including data from appropriately designed switching studies. In this article, we assess the current body of switching data available for approved or proposed biosimilars of anticancer mAbs. METHODS: PubMed was systematically searched and ClinicalTrials.gov and abstract databases of selected congresses were hand-searched to identify all switching studies including biosimilars of anticancer mAbs. FINDINGS: We identified 8 switching studies with biosimilars of rituximab (CT-P10, GP2013, PF-05280586, and BCD-020) and trastuzumab (ABP 980). Two were performed in oncology indications and the other 6 in rheumatoid arthritis (RA). Key elements of a well-designed switching study, such as randomization and blinding, were contained in several of the studies, but significant limitations were also present. The most frequent limitations were low statistical power because of small patient numbers, lack of an appropriate control arm, short follow-up, chosen outcome measures, and (for studies performed in RA) the concern whether switching data can be extrapolated to oncology indications. Accordingly, the data from these studies need to be interpreted with caution. Of note, all identified studies included a single switch only, whereas multiple switches may occur in the real-world setting. The scientific need to evaluate the impact of repeated switching has been recognized by the US Food and Drug Administration, who incorporated such a requirement in its draft guidance on interchangeability. IMPLICATIONS: From the scarce data available, the consequences of switching between reference product mAbs and their biosimilar(s) in the oncology setting are as yet unknown. Additional clinical evidence from well-designed switching studies is needed to guide switching decisions. PMID- 29699854 TI - Use of software applications to improve medication adherence and achieve more integrated disease management in heart failure. AB - The treatment and management of heart failure is associated with high mortality rates and treatment costs. Poor medication adherence is a major barrier to improving care and traditional interventions addressing non-adherence have not consistently demonstrated improvement in health care outcomes like readmission. The reasons for non-adherence are complicated and illustrate the broader challenges patients face when managing a complex disease like heart failure. In this review, a digitally enabled heart failure management platform consisting of medical digital tools and software solutions that are designed to be patient facing and continuously accessed is explored as a way to integrate the multiple components of heart failure care and deliver personalized patient management tools. PMID- 29699855 TI - [Original strategy for prevention of recurrent symptomatic urinary tract infections in patients with neurogenic bladder: Bacterial interference, state of the art]. AB - PURPOSE: Urinary tract infection (UTI) is the most common complication in patients with neurogenic bladder. The long-term use of antibiotic drugs induces an increase in antimicrobial resistance and adverse drug reactions. Bacterial interference is a new concept to prevent recurrent UTI which consists in a bladder colonization with low virulence bacteria. We performed a literature review on this emerging therapy. MATERIALS AND METHODS: Literature review of bacterial interference to prevent symptomatic urinary tract infection in neurological population. RESULTS: Seven prospectives study including 3 randomized, double-blind and placebo controlled trial were analyzed. The neurological population was spinal cord injured in most cases. The bladder colonization was performed with 2 non-pathogen strains of Escherichia coli: HU 2117 and 83972. At 1 month, 38 to 83% of patients were colonized. Mean duration of colonization was 48.5 days to 12.3 months. All studies showed that colonization might reduce the number of urinary tract infections and is safe with absence of serious side effects. CONCLUSION: Bacterial interference is a promising alternative therapy for the prevention of recurrent symptomatic urinary tract infections in neurogenic patients. This therapy should have developments for a daily use practice and for a long-term efficacy. PMID- 29699856 TI - Nephron sparing surgery in tumours greater than 7cm. AB - INTRODUCTION: Partial nephrectomy (PN) is the gold standard treatment for renal cell carcinomas under 4cm. No robust data exists to recommend PN for tumours>7cm (cT2). The objective of this work is to evaluate the results of PN for cT2 tumours. PATIENTS AND METHODS: All patients who underwent PN or radical nephrectomy (RN) for cT2 tumours between 2000 and 2013 at our institution have been included. Patient demographics, postoperative data including renal function, morbidity, mortality and oncologic outcomes were reviewed retrospectively and compared using chi2 test, Mann-Whitney test, Kaplan-Meier method and log rank test. RESULTS: We included 130 patients, 49 (38%) in the PN group and 81 (62%) in the RN group, with a median follow-up of 42 months [19-69]. Variation of postoperative renal function at day 5 and last recorded value was significantly different between the groups (P=0.03 and P<0.001). The PN group had a significantly higher complication rate as compared with RN group (37% versus 14%, P=0.002). There were no significant differences between the two groups for overall, recurrence free and specific survival (P=0.55, P=0.55, P=0.24, respectively). In univariate analysis, the type of surgery (PN versus RN) was not associated with a significant difference of oncologic outcome (margins, survival). CONCLUSION: PN can be offered for cT2 tumours with oncological outcomes similar to RN. Despite an increased morbidity, it remains acceptable with the demonstrated advantage of preservation of renal function. LEVEL OF EVIDENCE: 4. PMID- 29699857 TI - Prevalence and significance of notched T-waves in elite professional cyclists. AB - OBJECTIVES: To identify the frequency and significance of notched T-waves (NTW) in elite endurance athletes. METHODS: Professional cyclists were followed for 4 years with a clinical, electrocardiographic and echocardiographic assessment. Electrocardiograms were classified according to the presence or absence of NTWs; clinical and echocardiographic correlates were assessed. RESULTS: 42 Caucasian male cyclists were included. NTW were detected in 8 (19%) cyclists who showed significantly longer QT (461 +/- 15 vs 422 +/- 33 ms, p < 0.01) and QTc intervals (434 +/- 19 vs 383 +/- 21 ms, p < 0.01), a larger left ventricular end-diastolic volume (163 +/- 27 vs 137 +/- 23 mL, p = 0.014), end-diastolic volume index (84 +/- 13 vs 73 +/- 11 mL, p = 0.037) and end-diastolic apex-to-base length (9.9 +/- 0.7 vs 9.3 +/- 0.5 mm. p = 0.035). There were no detected arrhythmic events, and echocardiography did not reveal any abnormalities. CONCLUSIONS: This is to our knowledge the first study reporting a high prevalence of NTW in athletes. In our small cohort of cyclists NTW were associated with QT interval prolongation and left ventricular changes. This may be indicative of underlying inhomogeneity of repolarisation. Expanding on this research could reveal a role for NTW in identifying ventricular morphological changes. PMID- 29699858 TI - Efficacy and Tolerability of Mirabegron Compared with Antimuscarinic Monotherapy or Combination Therapies for Overactive Bladder: A Systematic Review and Network Meta-analysis. AB - BACKGROUND: Mirabegron is an established treatment alternative to antimuscarinic therapy for patients with overactive bladder (OAB), as shown by efficacy and tolerability data from phase III trials. OBJECTIVE: To assess efficacy and tolerability of mirabegron 50mg versus antimuscarinic monotherapies and combination therapies. DESIGN, SETTING, AND PARTICIPANTS: Systematic literature review and network meta-analysis of randomised controlled trials (2000-2017) assessing eligible treatments for OAB. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Efficacy assessments included micturition frequency, urgency urinary incontinence, dry rate, and 50% reduction in incontinence. Tolerability assessments included dry mouth, constipation, blurred vision, and hypertension. RESULTS AND LIMITATIONS: A total of 64 studies (n=46 666) were included in the network meta-analysis. Mirabegron 50mg was significantly more efficacious than placebo for all efficacy endpoints. Comparable overall efficacy was observed for mirabegron 50mg versus most active treatments, but solifenacin 10mg monotherapy and solifenacin 5mg plus mirabegron 25 or 50mg in combination were more efficacious for some/all outcomes. Mirabegron 50mg was significantly better tolerated regarding dry mouth, constipation, and urinary retention than 21/22, 9/20, and 7/10 active comparators, respectively; similar overall tolerability was observed between mirabegron 50mg and all treatments (including placebo) for the remaining endpoints. Limitations of the study included between-trial variations in the definition of certain endpoints and heterogeneity of the available data (eg, number of studies and patients assessed) for comparator treatments across different endpoints. CONCLUSIONS: The relief of key OAB symptoms produced by mirabegron 50mg is significantly better than placebo, and similar to a range of common antimuscarinics, with the benefit of significantly fewer bothersome anticholinergic side effects such as dry mouth. Combination treatment of solifenacin 5mg plus mirabegron 25 or 50mg appears to provide an efficacy benefit compared with mirabegron 50mg, with the expected side effects of individual antimuscarinics. PATIENT SUMMARY: This study assessed the efficacy and tolerability of different drug treatments for OAB. Mirabegron 50mg was as effective as antimuscarinic therapy, with fewer common, bothersome side effects such as dry mouth, constipation, and urinary retention. Combination treatment of solifenacin 5mg plus mirabegron 25 or 50mg was more effective than mirabegron 50mg alone, but with more anticholinergic side effects. PMID- 29699859 TI - Clinical significance of macroscopic no-margin hepatectomy for hepatocellular carcinoma. AB - BACKGROUND: Hepatectomy with a sufficient margin is often impossible for hepatocellular carcinomas that are close to the large intrahepatic vascular structures, and macroscopically complete resection along the tumor capsule is the only choice. The aim of this retrospective study was to evaluate the clinical significance of macroscopic no-margin hepatectomy (MNMH). METHODS: Among patients undergoing macroscopically curative resection for untreated hepatocellular carcinoma, outcomes were compared between patients undergoing MNMH (n = 87) and those undergoing hepatectomy with a macroscopic margin (n = 192). RESULTS: MNMH was significantly associated with a longer operation time (P < 0.001), greater intraoperative blood loss (P < 0.001), a greater need for blood transfusion (P = 0.018), a higher incidence of major postoperative complications (P = 0.031), multiple tumors (P = 0.015), tumor capsule formation (P = 0.030), and a microscopically positive surgical margin (P = 0.021). There was no significant difference between the groups in terms of recurrence-free survival (P = 0.946) and overall survival (P = 0.259). DISCUSSION: MNMH is technically demanding and results more frequently in a microscopically positive surgical margin, however, it can yield a long-term outcome comparable to hepatectomy with a macroscopic margin even in patients with otherwise unresectable hepatocellular carcinoma. PMID- 29699860 TI - Summary of the National Institute of Standards and Technology and US Food And Drug Administration cell counting workshop: Sharing practices in cell counting measurements. AB - The emergence of cell-based therapeutics has increased the need for high-quality, robust and validated measurements for cell characterization. Cell count, being one of the most fundamental measures for cell-based therapeutics, now requires increased levels of measurement confidence. The National Institute of Standards and Technology (NIST) and the US Food and Drug Administration (FDA) jointly hosted a workshop focused on cell counting in April 2017 entitled "NIST-FDA Cell Counting Workshop: Sharing Practices in Cell Counting Measurements." The focus of the workshop was on approaches for selecting, designing and validating cell counting methods and overcoming gaps in obtaining sufficient measurement assurance for cell counting. Key workshop discussion points, representing approximately 50 subject matter experts from industry, academia and government agencies, are summarized here. A key conclusion is the need to design the most appropriate cell counting method, including control/measurement assurance strategies, for a specific counting purposes. There remains a need for documentary standards for streamlining the process to develop, qualify and validate cell counting measurements as well as community-driven efforts to develop new or improved biological and non-biological reference materials. PMID- 29699861 TI - Knowledge and practice regarding the German and the EASL-EASD-EASO NAFLD guidelines among members of the German Obesity Society. PMID- 29699862 TI - Effect of nonoperative concomitant intraarticular pathologies on the outcome of arthroscopic capsular release for adhesive capsulitis of the shoulder. AB - OBJECTIVE: The aim of this study was to investigate whether coexistent intraarticular lesions are negative prognostic factors for the results of arthroscopic capsular release in frozen shoulder patients. METHODS: Seventy-two patients who met inclusion criteria and underwent arthroscopic capsular release between March 2011 and August 2015 for the frozen shoulder were retrospectively evaluated. The patients were divided into two groups according to existence of concomitant intraarticular pathologies detected during arthroscopy. Preoperative and postoperative functional results were assessed with Constant score and shoulder ranges of motion; and the amount of pain was evaluated using visual analog scale (VAS). RESULTS: Group I consisted of 46 patients (mean age 47.2 years and mean follow-up 26 months) without concomitant shoulder pathologies and group II consisted of 26 patients (mean age 48.6 years and mean follow-up 15 months) with coexistent lesions (SLAP lesions, n = 8; SLAP and partial rupture of the RC, n = 4; SLAP, partial rupture of RC and impingement, n = 10; SLAP and impingement, n = 2; and AC arthritis and impingement, n = 2). Preoperatively, the mean ranges of forward flexion (p = 0.221), abduction (p = 0.065), internal rotation (p = 0.564), Constant (p = 0.148) and VAS (p = 0.365) scores were similar between the groups. After a minimum 12 months of follow-up, all patients significantly improved but no statistically significant difference was detected in the mean ranges of forward flexion (152 vs 150; p = 0.902), abduction (137 vs 129; p = 0.095), external rotation (45 vs 40; p = 0.866), internal rotation (5 vs 5 point; p = 0.474), Constant (82 vs 82.3; p = 0.685) and VAS (1.2 vs 1.2; p = 0.634) scores between the groups. CONCLUSION: The presence of concomitant shoulder pathologies does not appear to affect the clinical outcomes in patients undergoing arthroscopic capsular release for frozen shoulder. LEVEL OF EVIDENCE: Level III, Therapeutic study. PMID- 29699863 TI - Two Japanese cases of epileptic encephalopathy associated with an FGF12 mutation. AB - A heterozygous mutation in the fibroblast growth factor 12 (FGF12) gene, which elevates the voltage dependence of neuronal sodium channel fast inactivation, was recently identified in some patients with epileptic encephalopathy. Here we report 1 Japanese patient diagnosed with early infantile epileptic encephalopathy (EIEE) and another diagnosed with epilepsy of infancy with migrating focal seizures (EIMFS). These 2 patients had an identical heterozygous missense mutation [c.341G>A:p.(Arg114His)] in FGF12 , which was identified with whole exome sequencing. This mutation is identical to previously reported mutations in cases with early onset epileptic encephalopathy. One of our cases exhibited EIMFS, and this case responded to phenytoin and high-dose phenobarbital (PB). FGF12-related epileptic encephalopathy may exhibit diverse phenotypes and may respond to sodium channel blockers or high-dose PB. PMID- 29699864 TI - Adult Human Hippocampal Neurogenesis: Controversy and Evidence. AB - The hippocampus has been described as one of the few sites in the mammalian brain capable of generating new cells continuously throughout life. Two recent studies that report contradicting findings on adult human hippocampal neurogenesis, however, reminds us of the caveats and challenges of studying this phenomenon in postmortem tissues. PMID- 29699865 TI - Color-coded Digital Subtraction Angiography for Assessing Acute Skeletal Muscle Ischemia-Reperfusion Injury in a Rabbit Model. AB - RATIONALE AND OBJECTIVES: This paper describes an ongoing investigation of imaging and characterization of ischemia-reperfusion (IR) and investigated the use of color-coded digital subtraction angiography (DSA) to assess reperfusion injury or potential injury. METHODS: New Zealand white rabbits were subjected to right hindlimb ischemia (IR, n = 24) or sham operation (control, n = 6). After 3 hours, the IR rabbits underwent reperfusion and were assessed at 0, 6, 12, or 24 hours (n = 6 each). DSA of the bilateral vastus lateralis muscle of each animal was performed. The maximum contrast enhancement value of a consistent region of interest in the right and left hind limbs (peak enhancement-R/L) was determined. Associations between the relative ratio of the peak right limb to the peak left limb (peak-R/L) and the following blood indicators of IR injury were analyzed: lactic dehydrogenase (LDH), creatine kinase (CK), malondialdehyde (MDA), and superoxide dismutase (SOD). RESULTS: Serum LDH, CK, and MDA values in each IR group were significantly higher than those of the control group and were positively associated with the IR interval, whereas SOD was significantly lower and negatively associated. The mean peak-R/L decreased linearly with the IR interval from 1.07 +/- 0.01 in the control group, and 0.93 +/- 0.06, 0.79 +/- 0.05, 0.65 +/- 0.04, and 0.47 +/- 0.04 at 0, 6, 12, and 24 hours in the IR groups. The coefficients of correlation between the peak-R/L and LDH, CK, MDA, SOD serum levels were -0.885, -0.908, -0.541, and 0.832, respectively. CONCLUSIONS: Color-coded DSA may be used for monitoring the dynamics of skeletal muscle IR injury. PMID- 29699866 TI - Effects of practice on visual finger-force control in children at risk of developmental coordination disorder. AB - BACKGROUND: The production of finger force control is essential for a large number of daily activities. There is evidence that deficits in the mechanisms of accuracy and control of finger force tasks are associated with children's motor difficulties. OBJECTIVE: To compare the effect of practice of an isometric finger force/torque task between children with significant movement difficulty and those with no difficulty movement. METHODS: Twenty-four children aged between 9 and 10 years (12 at risk of developmental coordination disorder and 12 with no movement difficulty - typically developing children) were asked to produce finger force/torque control in a continuous and constant 25% of maximum voluntary torque with visual feedback during 15s. Practice was given during five consecutive days with 15 trials per day. After the practice with visual feedback, children were asked to perform five trials without visual feedback. In these trials, feedback was removed 5s after the start of the trial. RESULTS: Typically developing children were consistently more accurate in maintaining finger force/torque control than those children at risk of developmental coordination disorder. Children from both groups improved the performance in the task according to practice sessions. Also, children at risk of developmental coordination disorder poorly performed the task without visual feedback as they did when visual feedback was available. CONCLUSION: The present study give support to the idea that movement difficulty is associated with finger force/torque control and children at risk of developmental coordination disorder can improve finger force/torque control with practice when visual feedback is available. PMID- 29699867 TI - Precision medicine in the management of type 2 diabetes. AB - The study of type 2 diabetes has been driven by advances in human genetics, epigenetics, biomarkers, mechanistic studies, and large clinical trials, enabling new insights into disease susceptibility, pathophysiology, progression, and development of complications. Simultaneously, several new drug classes with different mechanisms of action have been introduced over the past two decades, accompanied by data about cardiovascular safety and non-glycaemic outcomes. In this Review, we critically examine the progress and integration of this new science into clinical practice, and review opportunities for enabling the use of precision medicine in the diagnosis and treatment of type 2 diabetes. We contrast the success in delivering personalised medicine for monogenic diabetes with the greater challenge of providing a precision medicine approach for type 2 diabetes, highlighting gaps, limitations, and areas requiring further study. PMID- 29699868 TI - The shaping, making and baking of a pancreatologist. AB - The European Pancreatic Club Lifetime Achievement award is a distinction awarded for research on the pancreas. It comes with the obligation to submit a review article to the society's journal, Pancreatology. Since the research topics of my group have recently been covered in reviews and book chapters I want to use this opportunity to appraise the stations of my clinical and research education, the projects that I pursued and abandoned, the lessons I have learned from them, and the women and men who influenced my training and development as a physician scientist. Some crossed my path, some become collaborators and friends, and some turned into role models and had a lasting impact on my life. PMID- 29699869 TI - Analysis of microRNA and modified oligonucleotides with the use of ultra high performance liquid chromatography coupled with mass spectrometry. AB - The present study highlights the application of ultra high performance liquid chromatography coupled with mass spectrometry for the selective separation and sensitive quantification of microRNAs and modified phosphorothioate oligonucleotide. The Central Composite Design was used for comprehensive optimization of mass spectrometer parameters (for tandem mass spectrometer and quadrupole-time-of-flight mass spectrometer). Ion pair chromatography was used in order to separate the studied compounds. Furthermore, the optimization of concentration of ion pair reagents in the mobile phase was done with respect to mass spectrometry sensitivity and liquid chromatography separation. The greatest sensitivity for studied compounds was determined for the mixture of 100 mM hexafluoroisopropanol, 5 mM N,N-dimethylbutylamine and methanol. This mobile phase also provided the best separation results in the shortest time for two of the four columns used in the study. Finally, the Hypersil GOLD aQ was selected for routine analysis of microRNA and modified phosphorothioate oligonucleotide in serum samples. These compounds were extracted from the sample with the use of combined liquid-liquid and solid phase extraction. The method developed during the study was then applied for the qualitative and quantitative analysis with limits od quantification equal to 49-63 nM. PMID- 29699870 TI - Quantitative determination of major alkaloids in Cinchona bark by Supercritical Fluid Chromatography. AB - Chinoline alkaloids found in Cinchona bark still play an important role in medicine, for example as antimalarial and antiarrhythmic drugs. For the first time Supercritical Fluid Chromatography has been utilized for their separation. Six respective derivatives (dihydroquinidine, dihydroquinine, quinidine, quinine, cinchonine and cinchonidine) could be resolved in less than 7 min, and three of them quantified in crude plant extracts. The optimum stationary phase showed to be an Acquity UPC2 Torus DEA 1.7 MUm column, the mobile phase comprised of CO2, acetonitrile, methanol and diethylamine. Method validation confirmed that the procedure is selective, accurate (recovery rates from 97.2% to 103.7%), precise (intra-day <=2.2%, inter-day <=3.0%) and linear (R2 >= 0.999); at 275 nm the observed detection limits were always below 2.5 MUg/ml. In all of the samples analyzed cinchonine dominated (1.87%-2.30%), followed by quinine and cinchonidine. Their total content ranged from 4.75% to 5.20%. These values are in good agreement with published data, so that due to unmatched speed and environmental friendly character SFC is definitely an excellent alternative for the analysis of these important natural products. PMID- 29699871 TI - Countercurrent separation assisted identification of two mammalian steroid hormones in Vitex negundo. AB - Countercurrent separation (CCS) has been widely used for the separation of high abundance compounds. However, the identification of low abundance compounds, such as mammalian steroid hormones, from natural sources is still a challenging task. A mixture of 14 human steroid hormone reference compounds was prepared for the development of a CCS enrichment strategy. The TLC-based GUESS (Generally Useful Estimate of Solvent Systems) method along with partitioning experiments were implemented to develop a process for the enrichment of these low abundance compounds with CCS. The application of CCS to the steroid hormone enrichment of Vitex negundo extracts was demonstrated by the identification of progesterone and estriol. This method provides a CCS-driven strategy to mine plant sources for low abundance compounds. PMID- 29699872 TI - Methods in endogenous steroid profiling - A comparison of gas chromatography mass spectrometry (GC-MS) with supercritical fluid chromatography tandem mass spectrometry (SFC-MS/MS). AB - In various fields of endocrinology, the determination of steroid hormones synthesised by the human body plays an important role. Research on central neurosteroids has been intensified within the last years, as they are discussed as biomarkers for various cognitive disorders. Their concentrations in cerebrospinal fluid (CSF) are considered to be regulated independently from peripheral fluids. For that reason, the challenging matrix CSF becomes a very interesting specimen for analysis. Concentrations are expected to be very low and available amount of CSF is limited. Thus, a comprehensive method for very sensitive quantification of a set of analytes as large as possible in one analytical aliquot is desired. However, high structural similarities of the selected panel of 51 steroids and steroid sulfates, including numerous isomers, challenges achievement of chromatographic selectivity. Since decades the analysis of endogenous steroids in various body fluids is mainly performed by gas chromatography (GC) coupled to (tandem) mass spectrometry (MS(/MS)). Due to the structure of the steroids of interest, derivatisation is performed to meet the analytical requirements for GC-MS(/MS). Most of the laboratories use a two-step derivatisation in multi-analyte assays that was already published in the 1980s. However, for some steroids this elaborate procedure yields multiple isomeric derivatives. Thus, some laboratories utilize (ultra) high performance liquid chromatography ((U)HPLC)-MS/MS as alternative but, even UHPLC is not able to separate some of the isomeric pairs. Supercritical fluid chromatography (SFC) as an orthogonal separation technique to GC and (U)HPLC may help to overcome these issues. Within this project the two most promising methods for endogenous steroid profiling were investigated and compared: the "gold standard" GC-MS and the orthogonal separation technique SFC-MS/MS. Different derivatisation procedures for gas chromatographic detection were explored and the formation of multiple derivatives described and confirmed. Taken together, none of the investigated derivatisation procedures provided acceptable results for further method development to meet the requirements of this project. SFC with its unique selectivity was able to overcome these issues and to distinguish all selected steroids, including (pro-)gestagens, androgens, corticoids, estrogens, and steroid sulfates with appropriate selectivity. Valued especially in the separation of enantiomeric analytes, SFC has shown its potential as alternative to GC. The successful separation of 51 steroids and steroid sulfates on different columns is presented to demonstrate the potential of SFC in endogenous steroid profiling. PMID- 29699873 TI - Report of a unique case of myoepithelial carcinoma of left parotid gland with metachronous bilateral cavernous sinus metastasis. AB - Myoepithelial carcinoma (MC) is a rare, locally aggressive malignant neoplasm of the salivary glands. Only few evidences on its metastatic behavior are available in the literature. We herein present a unique case of MC of left parotid gland which metastasized to bilateral cavernous sinuses. The patient was successfully treated with palliative radiotherapy and chemotherapy. PMID- 29699874 TI - Aortic Arch Reconstruction: Are Hybrid Debranching Procedures a Good Choice? AB - INTRODUCTION: Conventional open total arch replacement is the treatment of choice for surgical aortic arch pathologies. However, it is an invasive procedure, requiring cardiopulmonary bypass and deep hypothermic circulatory arrest leading to significant morbidity and mortality rates. Hybrid aortic arch debranching procedures without (type I) or with (type II) ascending aorta replacement seek to limit operative, bypass, and circulatory arrest times by making the arch repair procedure simpler and shorter. MATERIAL AND METHODS: A meta-analysis and detailed review of the literature published from January 2013 until December 2016, concerning hybrid aortic arch debranching procedures was conducted and data for morbidity and mortality rates were extracted. RESULTS: As far as type I hybrid aortic arch reconstruction is concerned, among the 122 patients included, the pooled endoleak rate was 10.78% (95%CI=1.94-23.40), 30-day or in-hospital mortality was 3.89% (95%CI=0.324-9.78), stroke rate was 3.79% (95%CI=0.25-9.77) and weighted permanent paraplegia rate was 2.4%. In terms of type II hybrid approach, among 40 patients, endoleak rate was 12.5%, 30-day or in-hospital mortality rate was 5.3%, stroke rate was 2.5%, no permanent paraplegia was noticed and late mortality rate was 12.5%. CONCLUSIONS: Hybrid aortic arch debranching procedures are a safe alternative to open repair with acceptable short- and mid-term results. They extend the envelope of intervention in aortic arch pathologies, particularly in high-risk patients who are suboptimal candidates for open surgery. PMID- 29699875 TI - Stroke and (or) myocardial infarction attributable to modifiable risk factors in Henan, China. AB - Estimating population attributable risks of potential modifiable risk factors for stroke and (or) myocardial infarction may be useful for planning cardiovascular disease (CVD) preventive strategies. A population of 17,292 adults aged 18 years and older from a cross-sectional survey was included in the study. The binary logistic regression was used to evaluate the association between risk factors with disease events, then population attributable fraction according to prevalence and odds ratios were calculated to identify and compare the effects at different subpopulations. We found that the main risk factor for CVD events was hypertension with about 50% of population attributable fraction; prehypertension (22.24%) only acts at rural older females; the efficiency of low- and moderate level physical activities were higher in males (over 20%) than females (under 20%); ever smoked contributed to CVDs in rural older populations (males, 19.25%; females, 5.57%) and urban younger males (54.52%); while as for high body mass index, overweight (12.59%) only made contribution to rural males over 60 years. In conclusion, hypertension control in the whole population, physical activity increasing in males and older females, smoking prevention in rural elders and urban younger males, and slimming in rural elder males might be effective to reduce the burden of CVDs in Henan. PMID- 29699876 TI - Therapeutic Injury and Tumor Regrowth: Tumor Resection and Radiation Establish the Recurrent Glioblastoma Microenvironment. PMID- 29699877 TI - Diagnostic accuracy of neuropathy tests in obese population remains elusive. PMID- 29699878 TI - The role of red cell distribution width in the locoregional recurrence of laryngeal cancer. AB - INTRODUCTION: Although the red cell distribution width has been reported as a reliable predictor of prognosis in several types of cancer, to our knowledge few reports have focused on the prognostic value of red cell distribution width in laryngeal carcinoma. OBJECTIVE: We aimed to explore whether the pretreatment red cell distribution width predicted recurrence in laryngeal cancer patients is a simple, reproducible, and inexpensive prognostic biomarker. METHODS: All laryngeal cancer patients who underwent curative surgery (n=132) over a 7 year study period were evaluated. Data on demographics, primary tumor site, T-stage, N stage, histological features (differentiation; the presence of perineural/perivascular invasion), treatment group (total laryngectomy or partial laryngectomy) or adjuvant therapy (chemotherapy/radiotherapy); laboratory parameters (complete blood count, including the pre-operative red cell distribution width), and disease-free survival rates were retrospectively reviewed. All cases were divided into three groups by the red cell distribution width tertile [<13% (25th percentile) (n=31), 13-14.4% (50th percentile) (n=72), and >14.4% (75th percentile) (n=29)]. RESULTS: High-red cell distribution width group included more patients of advanced age, and more of those with recurrent and metastatic tumors (p=0.005, 0.048, and 0.043, respectively). Individuals with red cell distribution width >14.4% (75th percentile) had lower disease free survival rates than did those with red cell distribution width <13% (25th percentile) (p=0.014). Patients with red cell distribution width >14.4% at diagnosis were at a higher risk of locoregional recurrence (hazard ratio=5.818, 95% confidence interval (95% CI) 1.25-26.97; p=0.024) than patients with a normal red cell distribution width (<13%). CONCLUSION: We found that the pretreatment red cell distribution width was independently prognostic of disease free survival rate in patients with laryngeal cancer and may serve as a new, accurate, and reproducible means of identifying early-stage laryngeal cancer patients with poorer prognoses. PMID- 29699880 TI - Association between facial nerve second genu angle and facial canal dehiscence in patients with cholesteatoma: evaluation with temporal multidetector computed tomography and surgical findings. AB - INTRODUCTION: Otitis media, mastoiditis or the pressure effect of tumorous lesions such as cholesteatoma can be the cause of facial canal dehiscence and facial nerve paralysis. The most common segment involved in dehiscence is the tympanic segment and the second most common is the lateral aspect of the facial canal in the oval window area. OBJECTIVE: To determine the prevalence of the facial canal dehiscence and the relationship between the angle at the second genu of the facial nerve and facial canal dehiscence. METHODS: We evaluated the surgical findings in 113 patients who underwent surgery for cholesteatoma. Facial canal dehiscence was detected in 62 of the 113 patients. Patients were divided into two groups: Group 1, with dehiscence of the facial canal and Group 2, without dehiscence of the facial canal. RESULTS: The mean angles at the second genu of the facial nerve in Groups 1 and 2 were 117.8 degrees +/-9.63 degrees and 114 degrees +/-9.9 degrees , respectively. There was a statistically significant difference between the mean angles at the second genu for the two groups (p=0.04). CONCLUSION: In patients with dehiscence of the facial canal, the angle at the second genu was found to be wider than those without dehiscence. PMID- 29699879 TI - Treatment of post-intubation laryngeal granulomas: systematic review and proportional meta-analysis. AB - INTRODUCTION: Laryngeal granulomas post intubation are benign but recurrent lesions. There is no consensus for its treatment. OBJECTIVE: To describe the effectiveness of different treatment modalities for primary or recurrent laryngeal granulomas resulting from endotracheal intubation. METHODS: Systematic review and proportional meta-analysis. Eligibility criteria - experimental or observational studies with at least five subjects. Outcomes studied - granuloma resolution, recurrence, and time for resolution. Databases used - Pubmed, Embase, Lilacs, and Cochrane. The Stats Direct 3.0.121 program was used. RESULTS: Six studies were selected, with 85 patients. The treatments registered were: antireflux therapy, speech therapy, anti-inflammatory drugs, steroids, antibiotics, zinc sulfate and surgery. 85 patients from six studies had primary treatment: surgery+/-associations (41 patients), resolution chance 75% (95% CI: 0.3-100%, I2=90%), absolute relapse risk 25% (95% CI: 0.2-71%); medical treatment (44 patients), resolution chance 86% (95% CI: 67-97%); and absolute relapse risk 14% (95% CI: 3-33%). There was no significant difference between groups. Three studies, encompassing 19 patients, analyzed secondary treatment (failure or recurrence after primary treatment); three subjects presented new recurrence. The time needed to resolve the lesions varied from immediate, after surgery, to 23 months, for inhaled steroid. CONCLUSION: There is no evidence of high quality that proves the efficacy of any treatment for laryngeal granulomas resulting from endotracheal intubation. PMID- 29699881 TI - The process of preparing the chapter on mental and behavioural disorders of the ICD 11. PMID- 29699882 TI - Radical robot-assisted laparoscopic nephrectomy with thrombectomy in the vena cava. AB - BACKGROUND: Renal cell carcinoma has a natural tendency to extend through the renal vein. When the thrombus reaches the vena cava, thrombectomy and the necessary reconstruction of the vena cava are typically performed by open pathway. Robot-assisted technology provides advantages for performing this complex technique, using a minimally invasive access. MATERIAL AND METHODS: We present the technique we employed in the first case performed in our department. After performing renal artery embolisation, we conducted the surgery with the Vinci S robotic system. The main steps of the surgery are as follows: detachment and Kocher manoeuvre; release of the lower renal pole; clamping and sectioning of the renal artery; endocavitary ultrasound to locate the thrombus; placement of tourniquets in the vena cava below and above the renal veins and in the left renal vein; closure of the 3 tourniquets; opening of the vena cava; resection and extraction of the thrombus; suture of the vena cava; opening of the tourniquets; complete release of the kidney; bagging and extraction of the specimen. RESULTS: The surgery was performed without complications. The patient required a transfusion of 2 units of packed red blood cells and was discharged with modest renal failure (creatinine level of 1.60mg/dl). CONCLUSIONS: Radical nephrectomy with thrombectomy in the vena cava is a technique susceptible to severe complications and has, to date, been performed in few centres. We believe that the technique is reproducible and has clear advantages for our patients. PMID- 29699883 TI - Expanding indication of padeliporfin (WST11) vascular-targeted photodynamic therapy: results of prostate cancer Latin-American multicenter study. AB - OBJECTIVES: To explore the proportion of patients with higher risk localized prostate cancer (PCa) that would become safely biopsy negative 12 months after non-thermal focal therapy with padeliporfin vascular-targeted photodynamic therapy (VTP). METHODS: Multicenter study in a scenario of prostate-specific antigen (PSA) <=20ng/ml and variable PCa target volumes Gleason pattern 3 or low volume secondary Gleason pattern 4, all patients received VTP, consisting of intravenous 4mg/kg padeliporfin activated by light-diffusing fibers in the prostate. The prostate was biopsied at baseline, months 6 and 12, PSA, patient reported functional outcomes and quality of life (QoL) questionnaires were recorded at baseline, months 3, 6, and 12 and adverse events (AE) throughout the study. RESULTS: In the intention-to-treat population (n=81), the proportion of patients with negative biopsies at month 12 was 74% (60/81 patients; 95% CI: 63.1%,83.2%). In the per-protocol population, the proportion was 79% (58/73 patients; 95% CI: 68.4%,88.0%). Questionnaire results indicated a slight improvement in urinary function and limited deterioration in sexual function. No difference in QoL was observed over time. A total of 42/81 (52%) patients reported mild or moderate and 4 of 81 (4.9%) experienced serious AE, all resolved without sequelae. No phototoxicity, cardiovascular event, fistula or prolonged urinary incontinence, secondary cancer or death was reported. CONCLUSIONS: Results support the efficacy, safety, and QoL associated with padeliporfin focal treatment for low/intermediate risk localized PCa. PMID- 29699884 TI - Impact of Telehealth Interventions on Processes and Quality of Care for Patients With ESRD. AB - Caring for patients with end-stage renal disease (ESRD) requiring dialysis is intensive and expensive. Telehealth may improve the access and efficiency of ESRD care. For this perspective, we systematically reviewed studies that examined the effectiveness of telehealth versus or in addition to usual care for ESRD management. 10 studies were identified, including 7 randomized trials and 3 cohort studies. Study populations, modes of delivery (including telephone, telemetry, or videoconferencing), and the outcomes evaluated varied substantially between studies. Two studies examined telehealth interventions versus standard ESRD care and demonstrated mixed results on processes of care, no differences in laboratory surrogate markers of ESRD care, and reduced or similar rates of hospitalization. Eight studies evaluated the addition of telehealth to usual care and demonstrated no significant improvements in processes of care or surrogate laboratory measures, variable impacts on hospitalization rates, and mixed impacts on some domains of quality of life, including improvement in mental health. Although potential benefits of telehealth in ESRD care have been reported, optimal designs for delivery and elements of care that may be improved through telehealth remain uncertain. PMID- 29699885 TI - Impact of a Primary Care CKD Registry in a US Public Safety-Net Health Care Delivery System: A Pragmatic Randomized Trial. AB - BACKGROUND: Many individuals with chronic kidney disease (CKD) do not receive guideline-concordant care. We examined the impact of a team-based primary care CKD registry on clinical measures and processes of care among patients with CKD cared for in a public safety-net health care delivery system. STUDY DESIGN: Pragmatic trial of a CKD registry versus a usual-care registry for 1 year. SETTING & PARTICIPANTS: Primary care providers (PCPs) and their patients with CKD in a safety-net primary care setting in San Francisco. INTERVENTION: The CKD registry identified at point of care all patients with CKD, those with blood pressure (BP)>140/90mmHg, those without angiotensin-converting enzyme (ACE) inhibitor/angiotensin receptor blocker (ARB) prescription, and those without albuminuria quantification in the past year. It also provided quarterly feedback pertinent to these metrics to promote "outreach" to patients with CKD. The usual care registry provided point-of-care cancer screening and immunization data. OUTCOMES: Changes in systolic BP at 12 months (primary outcome), proportion of patients with BP control, prescription of ACE inhibitors/ARBs, quantification of albuminuria, severity of albuminuria, and estimated glomerular filtration rate. RESULTS: The patient population (n=746) had a mean age of 56.7+/-12.1 (standard deviation) years, was 53% women, and was diverse (8% non-Hispanic white, 35.7% black, 24.5% Hispanic, and 24.4% Asian). Randomization to the CKD registry (30 PCPs, 285 patients) versus the usual-care registry (49 PCPs, 461 patients) was associated with 2-fold greater odds of ACE inhibitor/ARB prescription (adjusted OR, 2.25; 95% CI, 1.45-3.49) and albuminuria quantification (adjusted OR, 2.44; 95% CI, 1.38-4.29) during the 1-year study period. Randomization to the CKD registry was not associated with changes in systolic BP, proportion of patients with uncontrolled BP, or degree of albuminuria or estimated glomerular filtration rate. LIMITATIONS: Potential misclassification of CKD; missing baseline medication data; limited to study of a public safety-net health care system. CONCLUSIONS: A team-based safety-net primary care CKD registry did not improve BP parameters, but led to greater albuminuria quantification and more ACE inhibitor/ARB prescriptions after 1 year. Adoption of team-based CKD registries may represent an important step in translating evidence into practice for CKD management. PMID- 29699886 TI - Blood Lead Levels and Decreased Kidney Function in a Population-Based Cohort. AB - BACKGROUND: Environmental lead exposure has been associated with decreased kidney function, but evidence from large prospective cohort studies examining low exposure levels is scarce. We assessed the association of low levels of lead exposure with kidney function and kidney disease. STUDY DESIGN: Prospective population-based cohort. SETTING & PARTICIPANTS: 4,341 individuals aged 46 to 67 years enrolled into the Malmo Diet and Cancer Study-Cardiovascular Cohort (1991 1994) and 2,567 individuals subsequently followed up (2007-2012). PREDICTOR: Blood lead concentrations in quartiles (Q1-Q4) at baseline. OUTCOMES: Change in estimated glomerular filtration rate (eGFR) between the baseline and follow-up visit based on serum creatinine level alone or in combination with cystatin C level. Chronic kidney disease (CKD) incidence (185 cases) through 2013 detected using a national registry. MEASUREMENTS: Multivariable-adjusted linear regression models to assess associations between lead levels and eGFRs at baseline and follow-up and change in eGFRs over time. Cox regression was used to examine associations between lead levels and CKD incidence. Validation of 100 randomly selected CKD cases showed very good agreement between registry data and medical records and laboratory data. RESULTS: At baseline, 60% of study participants were women, mean age was 57 years, and median lead level was 25 (range, 1.5-258) MUg/L. After a mean of 16 years of follow-up, eGFR decreased on average by 6mL/min/1.73m2 (based on creatinine) and 24mL/min/1.73m2 (based on a combined creatinine and cystatin C equation). eGFR change was higher in Q3 and Q4 of blood lead levels compared with Q1 (P for trend = 0.001). The HR for incident CKD in Q4 was 1.49 (95% CI, 1.07-2.08) compared with Q1 to Q3 combined. LIMITATIONS: Lead level measured only at baseline, moderate number of CKD cases, potential unmeasured confounding. CONCLUSIONS: Low-level lead exposure was associated with decreased kidney function and incident CKD. Our findings suggest lead nephrotoxicity even at low levels of exposure. PMID- 29699887 TI - Repetitive transcranial magnetic stimulation accuracy as a spinal cord stimulation outcome predictor in patients with neuropathic pain. AB - OBJECT: Spinal cord stimulation (SCS) is an effective albeit invasive and relatively expensive treatment of neuropathic pain. Repetitive transcranial magnetic stimulation (rTMS) over the primary motor cortex (M1) is a non-invasive treatment of neuropathic pain. The aim of the current study was to investigate whether rTMS can predict the successful outcome of SCS. METHODS: The study population consisted of 22 patients with neuropathic pain who had undergone SCS and rTMS. We conducted statistical analyses to identify the factors that predict pain reduction following SCS. RESULTS: Multiple regression analyses showed that only degree of pain relief following rTMS was statistically correlated with success in SCS; on the other hand, age, sex, lesion location, pain duration and laterality, and targeted extremities were not correlated. Using receiver operating characteristic (ROC) curve analyses of the pain relief following rTMS, the diagnostic sensitivity for successful SCS was 0.60 and the specificity was 0.83. CONCLUSIONS: The degree of pain relief following rTMS over M1 is a significant prognostic factor of SCS outcome in patients with intractable neuropathic pain. SIGNIFICANCE: The current study provides evidence showing that rTMS, a non-invasive and relatively easy to administer procedure, may aid in the selection of suitable candidates for SCS treatment. PMID- 29699888 TI - Lingual sulcus and cerebral polyopia. PMID- 29699889 TI - Genetic testing for CYP2D6 and CYP2C19 suggests improved outcome for antidepressant and antipsychotic medication. AB - Individuals carrying genetic variants that result in non-extensive CYP2D6 and CYP2C19 enzyme activity seem to be more prone to non-response and side-effects of psychotropic medications. Therefore, tailoring prescriptions using genetic information may improve patient outcomes. This study examined treatment outcome in psychiatric care after CYP2D6 and CYP2C19 genetic information was provided to patients and physicians. CYP2D6 and CYP2C19 genotyping, assessment of side effects and medical histories were obtained from 80 subjects who were prescribed either antidepressant or antipsychotic medications. Our measure of outcome was mainly physicians' opinions however UKU side effects scores were also used. For CYP2D6, we calculated an activity score based on genotype and psychiatric medications. Correlation analysis was performed for CYP2D6 activity scores and UKU scores. Overall, we received supportive responses from physicians who enrolled patients in our study. Notably, while almost every fourth physician reported improvement in patient outcome, not a single physician indicated that their patient's symptoms worsened after they had used a pharmacogenetic report to guide treatment. We did not observe statistically significant differences in side effects. Overall, our results suggest improved patient outcome following pharmacogenetic testing; nonetheless, more research is required to assess the exact benefit of pharmacogenetics in clinical practice. PMID- 29699890 TI - Separation of electrocardiographic from electromyographic signals using dynamic filtration. AB - Trunk muscle electromyographic (EMG) signals are often contaminated by the electrical activity of the heart. During low or moderate muscle force, these electrocardiographic (ECG) signals disturb the estimation of muscle activity. Butterworth high-pass filters with cut-off frequency of up to 60 Hz are often used to suppress the ECG signal. Such filters disturb the EMG signal in both frequency and time domain. A new method based on the dynamic application of Savitzky-Golay filter is proposed. EMG signals of three left trunk muscles and pure ECG signal were recorded during different motor tasks. The efficiency of the method was tested and verified both with the experimental EMG signals and with modeled signals obtained by summing the pure ECG signal with EMG signals at different levels of signal-to-noise ratio. The results were compared with those obtained by application of high-pass, 4th order Butterworth filter with cut-off frequency of 30 Hz. The suggested method is separating the EMG signal from the ECG signal without EMG signal distortion across its entire frequency range regardless of amplitudes. Butterworth filter suppresses the signals in the 0-30 Hz range thus preventing the low-frequency analysis of the EMG signal. An additional disadvantage is that it passes high-frequency ECG signal components which is apparent at equal and higher amplitudes of the ECG signal as compared to the EMG signal. The new method was also successfully verified with abnormal ECG signals. PMID- 29699891 TI - Electrohysterographic characterization of the uterine myoelectrical response to labor induction drugs. AB - Labor induction is a common practice to promote uterine contractions and labor onset. Uterine electrohysterogram (EHG) has proved its suitability for characterizing the uterus electrophysiological condition in women with spontaneous labor. The aim of this study was to characterize and compare uterine myoelectrical activity during the first 4 h in response to labor induction drugs, Misoprostol (G1) and Dinoprostone (G2), by analyzing the differences between women who achieved active phase of labor and those who did not (successful and failed inductions). A set of temporal, spectral and complexity parameters were computed from the EHG-bursts. As for successful inductions, statistical significant and sustained increases with respect to basal period were obtained for EHG amplitude, mean frequency, uterine activity index (UAI) and Teager, after 60' for the G1 group; duration, amplitude, number of contractions and UAI for the G2 group, after 120'. Moreover, Teager showed statistical significant and sustained differences between successful and failed inductions (1.43 +/- 1.45 uV2.Hz2.105 vs. 0.40 +/- 0.26 uV2.Hz2.105 after 240') for the G1 group, but not in the G2 group, probably due to the slower pharmacokinetics of this drug. These results revealed that EHG could be useful for successful induction prediction in the early stages of induction, especially when using Misoprostol. PMID- 29699892 TI - Primary Mutational Landscape Linked with Pre-Docetaxel Lactate Dehydrogenase Levels Predicts Docetaxel Response in Metastatic Castrate-Resistant Prostate Cancer. AB - BACKGROUND: Docetaxel chemotherapy is a standard of care for metastatic castrate resistant prostate cancer (mCRPC): 40-50% of patients achieve a biochemical response. However, there is a lack of response predictive biomarkers. OBJECTIVE: To assess lactate dehydrogenase (LDH) as a docetaxel response biomarker in mCRPC and to examine the association of LDH with genomic alterations in primary diagnostic biopsies. DESIGN, SETTING, AND PARTICIPANTS: Clinical and associated primary tumour-targeted next-generation sequencing data from matched training (n=150) and test (n=120) cohorts of progressive mCRPC patients receiving docetaxel therapy were analysed. Data were correlated with large-scale prostate cancer genomic datasets. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Prostate specific antigen (PSA) response, radiographic response, biochemical progression free survival (PFS), overall survival (OS), genomic analysis of primary biopsies, and genomic datasets (Memorial Sloan Kettering Cancer Center [MSKCC] and SU2C/PCF). RESULTS AND LIMITATIONS: Serum LDH >=450U/l is a reliable prognostic biomarker (area under the curve: 0.757 [standard deviation 0.054, 95% confidence interval [CI] 0.650-0.864, p<0.001]) in progressive mCRPC, predicting PFS at 3 mo. Patients with LDH >=450U/l were poorer PSA responders, with shorter PFS (213 vs 372 d, hazard ratio [HR] 1.876, 95% CI 1.289-2.7300) and OS (362 vs 563 d, HR 1.630, 95% CI 1.127-2.357). High LDH is an independent surrogate marker for survival following docetaxel and predicts a poor radiological response (p=0.043). Of the 14 patients with LDH >=450U/l available for next-generation sequencing, nine (64.3%) were more likely to have DNA repair gene mutation(s) (BRCA1/2, ATM, CHEK2, Fanconi anaemia gene) in their primary biopsy. Cross correlation with MSKCC and SU2C/PCF databases revealed a positive correlation between LDHA, PARP1 (r=0.667, p<0.01), and other DNA repair genes. CONCLUSIONS: Genomic abnormalities of LDHA and DNA repair in primary biopsies link to high pretreatment LDH and poor response to docetaxel in mCRPC. PATIENT SUMMARY: The presence of mutations of the lactate dehydrogenase and DNA repair pathways are associated with aggressive prostate cancer and poor response to chemotherapy later in the disease. PMID- 29699893 TI - Resource requirements and reduction in cardiac mortality from deep inspiration breath hold (DIBH) radiation therapy for left sided breast cancer patients: A prospective service development analysis. AB - INTRODUCTION: Use of deep inspiration breath hold (DIBH) radiation therapy may reduce long-term cardiac mortality. The resource and time commitments associated with DIBH are impediments to its widespread adoption. We report the dosimetric benefits, workforce requirements, and potential reduction in cardiac mortality when DIBH is used for left-sided breast cancers. METHODS AND MATERIALS: Data regarding the time consumed for planning and treating 50 patients with left-sided breast cancer with DIBH and 20 patients treated with free breathing (FB) radiation therapy were compiled prospectively for all personnel (regarding person hours [PH]). A second plan was generated for all DIBH patients in the FB planning scan, which was then compared with the DIBH plan. Mortality reduction from use of DIBH was calculated using the years of life lost resulting from ischemic heart disease for Indians and the postulated reduction in risk of major cardiac events resulting from reduced cardiac dose. RESULTS: The median reduction in mean heart dose between the DIBH and FB plans was 166.7 cGy (interquartile range, 62.7 257.4). An extra 6.76 PH were required when implementing DIBH as compared with FB treatments. Approximately 3.57 PH were necessary per Gy of reduction in mean heart dose. The excess years of life lost from ischemic heart disease if DIBH was not done in was 0.95 per 100 patients, which translates into a saving of 12.8 hours of life saved per PH of work required for implementing DIBH. DIBH was cost effective with cost for implementation of DIBH for all left-sided breast cancers at 2.3 times the annual per capita gross domestic product. CONCLUSION: Although routine implementation of DIBH requires significant resource commitments, it seems to be worthwhile regarding the projected reductions in cardiac mortality. PMID- 29699894 TI - Durable response of early-stage breast cancer to bilateral definitive SBRT in a medically inoperable patient. PMID- 29699895 TI - Association between increased serum d-serine and cognitive gains induced by intensive cognitive training in schizophrenia. AB - Neuroscience-guided cognitive training induces significant improvement in cognition in schizophrenia subjects, but the biological mechanisms associated with these changes are unknown. In animals, intensive cognitive activity induces increased brain levels of the NMDA-receptor co-agonist d-serine, a molecular system that plays a role in learning-induced neuroplasticity and that may be hypoactive in schizophrenia. Here, we investigated whether training-induced gains in cognition were associated with increases in serum d-serine in outpatients with schizophrenia. Ninety patients with schizophrenia and 53 healthy controls were assessed on baseline serum d-serine, l-serine, and glycine. Schizophrenia subjects performed neurocognitive tests and were assigned to 50 h of either cognitive training of auditory processing systems (N = 47) or a computer games control condition (N = 43), followed by reassessment of cognition and serum amino acids. At study entry, the mean serum d-serine level was significantly lower in schizophrenia subjects vs. healthy subjects, while the glycine levels were significantly higher. There were no significant changes in these measures at a group level after the intervention. However, in the active training group, increased d-serine was significantly and positively correlated with improvements in global cognition and in Verbal Learning. No such associations were observed in the computer games control subjects, and no such associations were found for glycine. d-Serine may be involved in the neurophysiologic changes induced by cognitive training in schizophrenia. Pharmacologic strategies that target d serine co-agonism of NMDA-receptor functioning may provide a mechanism for enhancing the behavioral effects of intensive cognitive training. PMID- 29699896 TI - Corrigendum to "Neuroanatomical correlates of perceptual aberrations in psychosis" [Schizophr. Res. 179 (2017) 125-131]. PMID- 29699897 TI - Development of regional extracorporeal life support system: The importance of innovative simulation training. AB - BACKGROUND: Despite advances in mechanical ventilation, severe acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality rates ranging from 30% to 60%. Extracorporeal Membrane Oxygenation (ECMO) can be used as a "bridge to recovery". ECMO is a complex network that provides oxygenation and ventilation and allows the lungs to rest and recover from respiratory failure, while minimizing iatrogenic ventilator-induced lung injury. In the critical care settings, ECMO is shown to improve survival rates and outcomes in patients with severe ARDS. The primary objective was to present an innovative approach for using high-fidelity medical simulation before setting ECMO program for reversible respiratory failure (RRF) in Poland's first unique regional program "ECMO for Greater Poland", covering a total population of 3.5 million inhabitants in the Greater Poland region (Wielkopolska). AIM AND METHODS: Because this organizational model is complex and expensive, we use advanced high-fidelity medical simulation to prepare for the real-life implementation. The algorithm was proposed for respiratory treatment by veno-venous (VV) Extracorporeal Membrane Oxygenation (ECMO). The scenario includes all critical stages: hospital identification (Regional Department of Intensive Care) - inclusion and exclusion criteria matching using an authorship protocol; ECMO team transport; therapy confirmation; veno-venous cannulation of mannequin's artificial vessels and implementation of perfusion therapy and transport with ECMO to another hospital in a provincial city (Clinical Department of Intensive Care), where the VV ECMO therapy was performed in the next 48 h, as training platform. RESULTS: The total time, by definition, means the time from the first contact with the mannequin to the cannulation of artificial vessels and starting VV perfusion on ECMO, did not exceed 3 h - including 75 min of transport (the total time of simulation with first call from provincial hospital to admission to the Clinical Intensive Care department was 5 h). The next 48 h for perfusion simulation "in situ" generated a specific learning platform for intensive care personnel. Shortly after this simulation, we performed, the first in the region: ECMO used for RRF treatment. The transport was successful and exceeded 120 km. During first year of Program duration we performed 6 successful ECMO transports (5 adult and 1 paediatric) with 60% of adult patient survival of ECMO therapies. Three patients in good condition were discharged to home. Two years old patient was successfully disconnected from ECMO and in stabile condition is treated in Paediatric Department. CONCLUSIONS: We discovered the important role of medical simulation, not only as an examination for testing the medical professional's skills, but also as a mechanism for creating non-existent procedures. During debriefing, it was found that the previous simulation-based training allowed to build a successful procedural chain, to eliminate errors at the stage of identification, notification, transportation and providing ECMO perfusion therapy. PMID- 29699898 TI - An evaluation of single question delirium screening tools in older emergency department patients. AB - OBJECTIVES: To determine the diagnostic performances of several single question delirium screens. To the patient we asked: "Have you had any difficulty thinking clearly lately?" To the patient's surrogate, we asked: "Is the patient at his or her baseline mental status?" and "Have you noticed the patient's mental status fluctuate throughout the course of the day?" METHODS: This was a prospective observational study that enrolled English speaking patients 65 years or older. A research assistant (RA) and emergency physician (EP) independently asked the patient and surrogate the single question delirium screens. The reference standard for delirium was a consultation-liaison psychiatrist's assessment using Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria. All assessments were performed within 3 h and were all blinded to each other. RESULTS: Of the 406 patients enrolled, 50 (12%) were delirious. A patient who was unable to answer the question "Have you had any difficulty thinking clearly lately?" was 99.7% (95% CI: 98.0%-99.9%) specific, but only 24.0% (95% CI: 14.3%-37.4%) sensitive for delirium when asked by the RA. The baseline mental status surrogate question was 77.1% (95% CI: 61.0%-87.9%) sensitive and 87.5% (95% CI: 82.8%-91.1%) specific for delirium when asked by the RA. The fluctuating course surrogate question was 77.1% (95% CI: 61.0%-87.9%) sensitive and 80.2% (95% CI: 74.8%-84.7%) specific. When asked by the EP, the single question delirium screens' diagnostic performances were similar. CONCLUSIONS: The patient and surrogate single question delirium assessments may be useful for delirium screening in the ED. PMID- 29699899 TI - Acute renal infarction: A diagnostic challenge. AB - Acute renal infarction is a relatively rare and scarcely reported condition. Contrast enhanced CT scan is essential for diagnosing this condition. The most common etiology of this condition is cardioembolic, however up to 59% of cases could be classified as idiopathic acute renal infarction. Here we present a case of a 41 year-old male who was admitted for acute onset right flank pain with fevers and rigors. A CT abdomen with contrast showed findings concerning for right pyelonephritis or renal infarction. Urinalysis was negative for infection. He did not respond to treatment with intravenous antibiotics and was thus diagnosed with acute renal infarction. Work-up for common etiologies was negative and the renal infarction was presumed to be idiopathic. He was discharged home on Enoxaparin. In conclusion, acute renal infarction is a rare condition which should be suspected in patients presenting with acute flank/abdominal pain in whom the more common etiologies have been ruled out. PMID- 29699900 TI - Apneic oxygenation reduces hypoxemia during endotracheal intubation in the pediatric emergency department. AB - BACKGROUND: Apneic oxygenation (AO) has been evaluated in adult patients as a means of reducing hypoxemia during endotracheal intubation (ETI). While less studied in pediatric patients, its practice has been largely adopted. OBJECTIVE: Determine association between AO and hypoxemia in pediatric patients undergoing ETI. METHODS: Observational study at an urban, tertiary children's hospital emergency department. Pediatric patients undergoing ETI were examined during eras without (January 2011-June 2011) and with (August 2014-March 2017) apneic oxygenation. The primary outcome was hypoxemia, defined as pulse oximetry (SpO2) < 90%. The chi2 and Wilcoxon rank-sum tests examined differences between cohorts. Multivariable regression models examined adjusted associations between covariates and hypoxemia. RESULTS: 149 patients were included. Cohorts were similar except for greater incidence of altered mental status in those receiving AO (26% vs. 7%, p = 0.03). Nearly 50% of the pre-AO cohort experienced hypoxemia during ETI, versus <25% in the AO cohort. Median [IQR] lowest SpO2 during ETI was 93 (69, 99) for pre-AO and 100 [95, 100] for the AO cohort (p < 0.001). In a multivariable logistic regression model, hypoxemia during ETI was associated with AO (aOR 0.3, 95% confidence interval [CI] 0.1-0.8), increased age (for 1 year, aOR 0.8, 95% CI 0.7-1.0), lowest SpO2 before ETI (for 1% increase, aOR 0.9, 95% CI 0.8-1.0), and each additional intubation attempt (aOR 4.0, 95% CI 2.2-7.2). CONCLUSIONS: Apneic oxygenation is an easily-applied intervention associated with decreases in hypoxemia during pediatric ETI. Nearly 50% of children not receiving AO experienced hypoxemia. PMID- 29699901 TI - INSPIRED: Instruction of sonographic placement of IVs by registered nurses in the emergency department. PMID- 29699902 TI - Intravenous leiomyomatosis of the uterus: A clinicopathologic analysis of 13 cases with an emphasis on histogenesis. AB - The object of this study is to investigate the prognosis and potential histologic origin of uterine intravenous leiomyomatosis (IVL). We retrospectively analyzed the clinicopathologic and immunohistochemical features of 13 cases of IVL from a single institute. The patients underwent hysterectomy (3 with bilateral salpingo oophorectomy, and 8 with excision of the broad ligaments and/or parametrium). They survived with no evidence of disease for 6-90 months. Intravascular worm like plugs were macroscopically identified in the myometrium in 10 of 13 cases (76.9%). Six patients (46.1%) had extra-uterine involvement. Histopathologically, the intravascular tumor foci were covered with endothelium. We found the presence of congested vessels in the tumor and the surrounding myometrium in 9 of 13 cases (69.2%). The concurrent entities included seven uterine leiomyomas, one leiomyoma with adenomyosis, one adenomyosis, and one pulmonary benign metastasizing leiomyoma. Estrogen receptor and desmin were positive in IVL, and negative in the vascular wall. We conclude that IVL confined to the uterus may have a favorable prognosis, and we believe IVL is likely to originate from contiguous leiomyoma or myometrium. PMID- 29699903 TI - Evaluation of specific modified histones in lip carcinogenesis. AB - OBJECTIVE: Histones regulate chromatin density and therefore influence gene expression and cellular proliferation. These properties are modified by methylation, acetylation and phosphorylation of histones. The aim of this study was to investigate the variation of specific modified histones in actinic cheilitis (AC) and squamous cell carcinoma of the lip (SCCL). METHODS: Samples of non-neoplastic tissue of the lip (NNTL, n = 9), AC (n = 33), and SCCL (n = 27) were submitted to immunohistochemistry to detect the modified histones H3K36me3, H3K9ac, H4K12ac, and H3S10 ph. RESULTS: Reactivity for all of the modified histones was significantly decreased from NNTL to AC, but not from AC to SCCL. Dysplasia in AC or histological grade in SCCL were not related to the reactivity of any modified histones. CONCLUSIONS: Histone modifications are related to initial actinic damage, but not to malignant transformation in the lip. PMID- 29699904 TI - Tumorigenic role of YAP in hepatocellular carcinogenesis is involved in SHP2 whose function is different in vitro and in vivo. AB - Yes-associated protein (YAP) is a nuclear effector of the cell-density sensing Hippo pathway and interacts with Src homology phosphotyrosine phosphatase 2 (SHP2), which controls cell proliferation and survival. The tumor promoting/suppressing activities of YAP and SHP2 during liver tumorigenesis remain controversial. This study aimed to investigate the tumorigenic roles of YAP and SHP2 in hepatocellular carcinogenesis. Cell density associated subcellular distributions of YAP and SHP2 in normal human hepatocytes (THLE-2) and hepatocellular carcinoma (HCC) cells (SK-Hep1, SNU-182) were investigated by Western blotting and cell block immunohistochemistry. The effects of YAP knockdown on proliferation, migration and invasion were studied using YAP specific siRNAs. The prognostic significance of YAP and SHP2 expressions was investigated immunohistochemically using a tissue microarray (TMA) from 50 HCC cases. High-cell density decreased the nuclear expression of YAP and SHP2 in normal hepatocytes as compared with low-cell density. However, in HCC cells, nuclear YAP and SHP2 were observed regardless of cell density. Nuclear YAP influenced SHP2 expression and cell proliferation. In particular, YAP knockdown impacted nuclear levels of SHP2 protein in SK-Hep1 cells. In HCC tissues, nuclear YAP expression was elevated and cytoplasmic SHP2 expression was diminished as compared with adjacent non-tumor tissues. Notably, these expressions were found to be significantly associated with poor recurrence-free and overall survival rate in patients with HCC. Consequently, the tumor promoting role of YAP is involved in SHP2 which functions as a tumor promoter in vitro but as a tumor suppressor in vivo. YAP and SHP2 can be unfavorable prognostic markers in HCC. PMID- 29699905 TI - Tibia-hindfoot turn-up rotationplasty in uncontrollable infection after total femoral resection: Report of two cases. PMID- 29699906 TI - Comparisons of direct costs, outcomes, and cost-utility of decompression surgery with fusion versus decompression alone for degenerative lumbar spondylolisthesis. AB - BACKGROUND: Cost-utility analysis of surgery for degenerative lumber spondylolisthesis (DS) is essential for healthcare providers and patients to select appropriate treatment. The purpose of this study was to review the cost utility of decompression alone versus decompression with fusion for DS. METHODS: A retrospective review of 99 consecutive patients who were treated for Meyerding grade 1 DS at two representative spine centers was performed. Patients with significant spinal instability were treated by decompression with fusion (F group, 40 patients); all others were treated by decompression surgery alone (D group, 59 patients). All patients were followed for three years. Demographic and radiographic data, health-related quality of life (HRQoL), and the direct cost for surgery were analyzed, and the incremental cost-effectiveness ratio (ICER) was determined using cost/quality-adjusted life years (QALY). RESULTS: There were no differences between the groups in baseline demographics (D vs. F: age 68 +/- 9 vs. 66 +/- 7 years; 37% vs. 40% female) or HRQoL (ODI: D, 41 +/- 16 vs. F, 46 +/- 13%). The F group had a higher initial-surgery cost ($18,992 +/- 2932) but lower reoperation frequency (7%) than the D group ($7660 +/- 2182 and 12%, respectively). The three-year total direct cost was higher for F than for D ($19,222 +/- 3332 vs. $9668 +/- 6,168, p = .01). ICER was higher for F at one year ($136,408 +/- 187,911 vs. $237,844 +/- 212,049, p < .01), but was comparable for F and D at three years (D, $41,923 +/- 44,503 vs. F, $51,313 +/- 32,849, p = .17). CONCLUSION: At the three-year follow-up, the two methods had comparable cost-utility. Both methods were cost-effective (defined as an ICER within three times the per-capita gross domestic product). PMID- 29699908 TI - Uukuniemi virus, Czech Republic. AB - Following the identification of severe fever with thrombocytopenia syndrome and Heartland viruses, the interest on tick-borne phleboviruses has increased rapidly. Uukuniemi virus has been proposed as a model for tick-borne phleboviruses. However, the number of available sequences is limited. In the current study we performed whole-genome sequencing on two Uukuniemi viral strains isolated in 2000 and 2004 from Ixodes ricinus ticks in the Czech Republic. Both strains cluster together with Potepli63 strain isolated in the country in 1963. Although the Czech strains were isolated many years apart, a high identity was seen at the nucleotide and amino acid levels, suggesting that UUKV has a relatively stable genome. PMID- 29699907 TI - Post-Traumatic Stress Disorder, Neighborhood Residency and Satisfaction, and Social Network Characteristics among Underserved Women in Baltimore, Maryland. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) prevalence is high, but not well-understood, among women living in urban, impoverished areas. Although previous studies have established social support as an important factor in PTSD development and maintenance, little is known about how perceptions of neighborhood are linked to PTSD. This study examined the relationship between PTSD and social network and neighborhood factors among women with a low socioeconomic status. METHODS: We analyzed cross-sectional data collected from a human immunodeficiency virus/sexually transmitted infection peer network study in Baltimore, Maryland (n = 438). We used bivariate analyses to examine the associations between PTSD and social network characteristics and time in neighborhood and satisfaction. We then constructed multivariable regression models that controlled for the following with PTSD: homelessness, cocaine/heroin use, and unemployment. MAIN FINDINGS: Overall, 30% of women had PTSD symptom severity consistent with a clinical diagnosis. In the multivariable model, dissatisfaction with neighborhood block (odds ratio [OR], 1.80; p = .03) and living in one's neighborhood for more than 5 years (OR, 1.69; p = .03) were associated with PTSD. Social network factors that were significantly associated with PTSD included a higher number of network members in conflict with the participant (OR, 1.28; p = .02), presence of a network member who would let the participant stay with them (OR, 0.4; p = .004), and the number of network members with whom the participant socialized (OR, 0.6; p = .04). CONCLUSIONS: In this sample of impoverished urban women with a high prevalence of PTSD, duration of residency, satisfaction with neighborhood, and network characteristics were found to be strongly associated with PTSD symptom severity. PMID- 29699909 TI - Osteoblastic differentiation on hydrogels fabricated from Ca2+-responsive self assembling peptides functionalized with bioactive peptides. AB - We recently developed an amphiphilic peptide, E1Y9 (Ac-E-YEYKYEYKY-NH2), that self-assembles into nanofibers and forms a hydrogel in the presence of Ca2+ ion. Four E1Y9-derivatives (E1Y9-ALK, E1Y9-DGR, E1Y9-PRG and E1Y9-RGD) were designed as conjugates of E1Y9 with bioactive peptide sequences named as ALK (ALKRQGRTLYGF), DGR (DGRDSVAYG), PRG (PRGDSGYRGDS) and RGD (RGDS), respectively, and stimulated osteoblast cells growth as well as differentiation. In this study, E1Y9/E1Y9-derivative mixed hydrogels were constructed to serve as scaffolds for osteoblastic differentiation of MC3T3-E1 cells. E1Y9 and E1Y9-derivatives co assembled into networked nanofibers and formed hydrogels in response to Ca2+ ion. The pre-osteoblast cell line MC3T3-E1 was cultured and differentiated on mixed hydrogels. An E1Y9/E1Y9-ALK mixed hydrogel exhibited the highest cell proliferation and differentiation activity among the peptide hydrogels. The peptide sequence ALK promoted expression of RUNX2 and osteopontin, a key transcription factor and bone tissue matrix protein, respectively, during the differentiation stage. During the later stage, localization of RUNX2 and osteopontin was regulated in the cytosol and extracellularly, respectively, indicating that the E1Y9/E1Y9-ALK mixed hydrogel controlled the differentiation of MC3T3-E1 cells. Thus, the E1Y9/E1Y9-ALK mixed hydrogel developed in this study showed potential for the culture and regulation of differentiation of osteoblast cells for bone regeneration. PMID- 29699910 TI - Investigation of novel pyrazole carboxamides as new apoptosis inducers on neuronal cells in Helicoverpa zea. AB - Novel pyrazole carboxamides with a diarylamine-modified scaffold were modified based on the bixafen (Bayer) fungicide, which has excellent activity against Rhizoctonia solani, Rhizoctonia cerealis and Sclerotinia sclerotiorum. To discover the potential insecticidal activity of these novel pyrazole carboxamides, the present study explored their possible cytoactivity on the insect neuronal cells (RP-HzVNC-AW1) in Helicoverpa zea. The preliminary bioassays showed that some of the target compounds exhibited good cytoactivity against AW1 cells. Among them, compounds a5 and b4-b7 showed good activity in vitro with IC50 values of 11.28, 10.46, 9.04, 11.72 and 12.19 MUM, respectively. Notably, the IC50 value of compound b5 was better than 11.81 MUM for fipronil. We subsequently attempted to illustrate the mechanism of b5. Intracellular biochemical assays showed that b5 induced AW1 cell apoptosis with a decrease in themitochondrial membrane potential, as well as a significantly increased intracellular calcium ion concentration and caspase-3 activity. A significant decrease in Bcl-2 levels and a marked augmentation of cytochrome-c and Bax were also detected. These results indicate that a mitochondrially dependent intrinsic pathway contributes to compound b5-induced apoptosis in AW1 cells. This study suggests that b5 may act as a potential insecticide that can be used for further optimization. PMID- 29699911 TI - Novel amidrazone derivatives: Design, synthesis and activity evaluation. AB - A series of new 6-styryl-naphthalene-2-amidrazone derivatives were synthesized and evaluated as potential ASIC1a inhibitors. Among them, compound 5e showed the most activity to inhibit [Ca2+]i. elevation in acid-induced articular chondrocytes. Together with the important role of ASIC1a in the pathogenesis of tissue acidification diseases including rheumatoid arthritis, these results might provide a meaningful hint or inspiration in developing drugs targeting at tissue acidification diseases. PMID- 29699912 TI - Preferences of patients' family regarding family-witnessed cardiopulmonary resuscitation: A qualitative perspective of intensive care patients' family members. AB - OBJECTIVES: To describe preferences of intensive care patients' family members regarding the idea of an inpatient family-witnessed cardiopulmonary resuscitation. RESEARCH METHODOLOGY/DESIGN: A descriptive qualitative design was used in this study. Twelve family members of intensive care patients took part in individual semi-structured interviews. Data were analysed using thematic analysis. SETTING: A population of Finnish and Polish former intensive care adult patients' relatives. FINDINGS: The thematic analysis resulted in two main themes with four subthemes each: (Theme 1) Being more involved and engaged in patient's care in case of cardiopulmonary resuscitation, with subthemes: (a) Having an option to decide, (b) Being in physical proximity to the patient, (c) Feeling like having more control and impact and (d) Having a better idea about the situation. (Theme 2) Being cared for and treated respectfully during possible cardiopulmonary resuscitation, with subthemes: (a) Need for more support and understanding from the staff, (b) Uniqueness of the family - patient relationship, (c) Need for staff to be more humane and less mechanical and (d) Professional and highly qualified staff. CONCLUSION: Results of this study suggest a possible gap in family-centred care delivery in intensive care settings. System changes are necessary in order to increase nurses' awareness of patients' families' preferences, and successfully implement recommended family witnessed cardiopulmonary resuscitation. PMID- 29699914 TI - Risk factors for non-motor symptoms in Parkinson's disease. AB - Non-motor symptoms (NMS) of Parkinson's disease can be predominant as the disease advances, thereby constituting a major source of disease burden for patients and caregivers. However, current understanding of NMS is incomplete, particularly as a result of the absence of standardisation of outcome definitions and the heterogeneity of the risk factors that are assessed. The best data on risk factors for NMS in Parkinson's disease come from longitudinal studies, with the strongest evidence identifying factors for cognitive impairment and dementia, hallucinations, depression, apathy, excessive daytime sleepiness, insomnia, and impulse-control disorders. Cognitive impairment, hallucinations, and depression have several common risk factors, and many other NMS share a few risk factors, showing the interdependence between NMS with advancing Parkinson's disease. Disease severity, sex, age, and antiparkinsonian medication might have roles in the development of different NMS, although only antiparkinsonian medication is potentially modifiable. Until disease-modifying therapies are developed, increased knowledge of risk factors could ameliorate early identification of patients who are at an increased risk of developing specific NMS and potentially allow improvement of symptom management or prevention of specific NMS. PMID- 29699913 TI - Prenatal exposure to environmental pollutants and child development trajectories through 7 years. AB - BACKGROUND: Prenatal exposure to environmental pollutants such as mold, lead, pesticides, tobacco, and air pollutants has been suggested to impair cognitive development. Evidence is needed from longitudinal studies to understand their joint impact on child development across time. OBJECTIVE: To study associations between exposure to indoor environmental pollutants or outdoor air pollution during pregnancy and offspring cognitive development trajectories through 7 years. METHODS: We included 718 Mexican mother-child pairs. Prenatal exposure to indoor environmental pollutants (mold, ventilation, pesticides, tobacco smoke, and use of vidiartred clay pots) was self-reported by the mothers and integrated into an index, or objectively measured in the case of outdoor air pollutants (nitrogen oxides, benzene, toluene, and xylene). Child global cognitive development was measured at 12, 18, 60, or 84 months. Using Latent Class Growth Analysis, we identified three developmental trajectories (positive = 108, average = 362, low = 248). We used multinomial logistic models to test associations between environmental pollutant score (EPS) or outdoor air pollutants, and cognitive development trajectories. RESULTS: After adjustment for sociodemographic covariates, EPS was associated with the average (OR = 1.26 95%CI = 1.01, 1.55) and low (OR = 1.41 95%CI = 1.11, 1.79) trajectories compared to positive; where a unit increase in EPS means an additional prenatal exposure to a pollutant. There was no association between outdoor air pollutants and cognitive development trajectories. CONCLUSION: Children of women who reported higher exposure to indoor environmental pollutants during pregnancy were more likely to follow worse developmental trajectories through 7 years. These results support the development and testing of interventions to reduce exposure to environmental pollutants during pregnancy and early childhood as a potential strategy to improve long-term cognitive development. PMID- 29699915 TI - Dyslipidemia is associated with pediatric nonalcoholic fatty liver disease. AB - BACKGROUND: With the increasing prevalence of childhood obesity, nonalcoholic fatty liver disease (NAFLD) has emerged as the most common cause of pediatric chronic liver disorder. Factors underlying the pathophysiology of NAFLD remain poorly defined. OBJECTIVE: This study aimed to describe the metabolic characteristics of children with NAFLD differing in race/ethnicity and to test associations between dyslipidemia and NAFLD. METHODS: A retrospective chart review was conducted at a tertiary referral university hospital among 309 children with a diagnosis of NAFLD. RESULTS: Participants (mean age 12.5 +/- 3.4 years) were 64% male, 63% white, 23% Hispanic, and 14% black. Hispanic children were diagnosed with NAFLD at a significantly younger age (10.6 +/- 3.1 years, P < .0001) and lower body mass index (31.5 +/- 6.8 kg/m2, P < .0001) than their white and black counterparts. For the entire cohort, prevalence of systolic hypertension was 41%, diabetes 14%, elevated cholesterol 42%, elevated non-high density lipoprotein cholesterol (non-HDL-C) 58%, elevated low-density lipoprotein cholesterol 36%, elevated triglycerides (TG) 88%, and low high-density lipoprotein cholesterol 77%. Whites had elevated non-HDL-C, low-density lipoprotein cholesterol, and TG compared to blacks or Hispanics. Serum TG and non HDL-C were significantly correlated to alanine aminotransferase (r = 0.18, P = .01; r = 0.16, P = .02), respectively, and persisted after adjusting for age and body mass index. CONCLUSION: Cardiometabolic derangements, especially dyslipidemia, are highly prevalent in children with NAFLD and differ based on race/ethnicity. Serum TG and non-HDL-C may play an important role in the pathophysiology of pediatric NAFLD. PMID- 29699916 TI - Posttranslational modification of proprotein convertase subtilisin/kexin type 9 is differentially regulated in response to distinct cardiometabolic treatments as revealed by targeted proteomics. AB - BACKGROUND: The proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that interacts with the low-density lipoprotein (LDL) receptor at the surface of hepatocytes to regulate circulating LDL cholesterol levels. High circulating PCSK9 levels have been associated with elevated LDL cholesterol. Recently, the Food and Drug Administration of the United States approved new LDL cholesterol-lowering drugs that specifically target the inhibition of PCSK9. Similar to most human proteins, PCSK9 exists in multiple forms as it is the target of posttranslational modifications (PTMs) such as proteolytic cleavage, phosphorylation, and others, which can affect its biological activity. However, commercially available assays, such as enzyme-linked immunosorbent assays, do not discriminate between these forms. OBJECTIVE: To investigate, in 2 patient cohorts, the relationships between circulating levels of multiple forms of PCSK9 and cardiometabolic interventions or treatments known to reduce LDL cholesterol levels. METHODS: PCSK9 forms were measured in plasma: (1) in 20 patients before and 6 months after bariatric surgery and (2) in 132 patients before and 12 months after daily statin treatment. A series of specific peptides used as surrogates for various PCSK9 forms were quantified by a novel semiautomated proteomic assay termed protein affinity capture coupled to quantitative mass spectrometry. RESULTS: Bariatric surgery resulted in a decrease in the plasma level of PCSK9 prodomain (P < .05), but did not result in a significant change in other measured PCSK9 forms. Statin treatment resulted in an increase in all measured plasma PCSK9 peptides (P < .001), but a 25% decrease in the phosphorylated state of PCSK9 at S688 (P < .05). CONCLUSIONS: These unexpected findings indicate that measuring the circulating levels of the various domains and PTMs of PCSK9 provides more in depth information than total PCSK9 and that the prodomain and the phosphorylated state of S688 may represent novel biomarkers to explore in cardiometabolic diseases and response to treatment. In addition, our data generated new hypotheses on the function of PCSK9 PTMs in health and disease. PMID- 29699917 TI - High-density lipoprotein cholesterol and causes of death in chronic kidney disease. AB - BACKGROUND: Recent data suggest a U-shaped association between high-density lipoprotein cholesterol (HDL-c) and death in chronic kidney disease (CKD). However, whether the increased mortality in patients with extreme levels is explained by specific causes of death remains unclear. OBJECTIVES: We studied the associations between HDL-c and cause-specific deaths in CKD. METHODS: We included 38,377 patients with estimated glomerular filtration rate 15-59 mL/min/1.73 m2. We classified deaths into 3 major categories: (1) cardiovascular; (2) malignant; and (3) noncardiovascular/nonmalignant causes. We fitted Cox regression models for overall mortality and separate competing risk models for each major cause of death category to evaluate their respective associations with categories of HDL-c (<=30, 31-40, 41-50 [referent], 51-60, >60 mg/dL). Separate analyses were conducted for men and women. RESULTS: During a median follow-up of 4.5 years, 9665 patients died. After adjusting for relevant covariates, in both sexes, HDL-c 31 to 40 mg/dL and <=30 mg/dL were associated with higher risk of all-cause mortality, cardiovascular mortality, malignancy-related deaths, and noncardiovascular/nonmalignancy-related deaths. HDL-c >60 mg/dL was associated with lower all-cause (hazard ratio: 0.75, 95% confidence interval: 0.69, 0.81), cardiovascular, malignancy-related, and noncardiovascular/nonmalignancy-related deaths among women but not in men. Similar results were noted when HDL-c was examined as a continuous measure. CONCLUSIONS: In a non-dialysis-dependent CKD population, HDL-c <=40 mg/dL was associated with risk of higher all-cause, cardiovascular, malignant, and noncardiovascular/nonmalignant mortality in men and women. HDL >60 mg/dL was associated with lower risk of all-cause, cardiovascular, malignant, and noncardiovascular/nonmalignant mortality in women but not in men. PMID- 29699918 TI - Cyclodextrins or cholesterol-loaded-cyclodextrins? A better choice for improved cryosurvival of chicken spermatozoa. AB - This study was designed to test if treating chicken sperm with i) the cyclodextrins 2-hydroxypropyl-beta-cyclodextrin (HBCD) and methyl-beta cyclodextrin (MBCD) alone improve fresh, liquid-stored and cryopreserved semen quality, or ii) cholesterol-loaded cyclodextrins (CLCs): 2-hydroxypropyl-beta cyclodextrin loaded with cholesterol (HCLC) and methyl-beta-cyclodextrin loaded with cholesterol (MCLC) enhance chicken semen quality for application to assisted reproductive technologies. Three consecutive experiments were performed with different concentrations of additives: Exp. 1: 1, 2, 4 mg of HBCD and MBCD in fresh and liquid stored semen; Exp. 2: 1, 2, 4 mg of HCLC and MCLC in fresh and liquid stored semen; and Exp. 3: 1, 2 mg of HBCD, HCLC, 1 mg MBCD, MCLC in cryopreserved and post-thaw storage semen. Sperm motility parameters were assessed by CASA system and comprehensive sperm characteristics were evaluated by flow cytometry. Supplementation with 4 mg HBCD, MBCD, HCLC and MCLC resulted in the lowest motility and functional parameters of fresh and stored spermatozoa for 24 h at 5 degrees C. After cryopreservation, spermatozoa stored with CLCs showed significantly lower progressive motility and velocity of movement, and exhibited the lowest percentage of cells with intact plasma membranes and acrosomes, mitochondrial activity and cells without apoptosis. These results indicated that CLCs did not improve chicken sperm viability after cryopreservation. However, spermatozoa treated with 2 mg HBCD showed higher proportion of motile sperm (28%; P < 0.01) together with higher proportion of sperm cells with high mitochondrial potential (25%; P < 0.05) compared to the control (18%; 21%, respectively) after 3 h of post-thaw storage. CLC, especially with methyl-beta-cyclodextrin, appeared to be detrimental to chicken spermatozoa, causing apoptosis, impairment of mitochondrial potential, and damaged acrosomes and sperm plasma membranes. PMID- 29699919 TI - Effect of cooling rate on sperm quality of cryopreserved Andalusian donkey spermatozoa. AB - The aim of this study was to evaluate the effect of different cooling rates on post-thaw quality of cryopreserved donkey spermatozoa. Eighteen ejaculates from six adult Andalusian donkeys (three ejaculates per donkey) were collected using an artificial vagina. Pooled semen samples (two ejaculates per pool) were divided into three aliquots, and frozen in Gent freezing extender using three different cryopreservation protocols (P): P1 (conventional slow freezing, as control): semen pre-cooled in an Equitainer for 2 h and frozen in liquid nitrogen (LN2) vapour; P2 (controlled pre-freeze cooling rate): semen pre-cooled at a controlled rate for 73 min and frozen in LN2 vapour; and P3 (rapid freezing) semen frozen immediately in LN2 vapour. After thawing at 37 degrees C for 30 s, semen samples were assessed for motility, morphology, acrosome and plasma membrane integrity; spermatozoa were also tested for DNA integrity. Significant (P < 0.01) differences were found between the cryopreservation protocols for all sperm parameters evaluated, except for DNA integrity. Semen samples frozen using P2 showed significantly (P < 0.01) higher values for sperm motility, morphology, sperm membrane integrity, and acrosome integrity. On the contrary, P3 reduced sperm motility (P < 0.01) and increased the percentage of spermatozoa with damaged plasma membrane (P < 0.001). In our study, we demonstrated that the sperm of Andalusian donkey is particularly sensitive to the cooling rate used before freezing. Furthermore, Andalusian donkey semen can be successfully cryopreserved using controlled cooling rates combined with freezing in LN2 vapour. PMID- 29699920 TI - Effect of cholesterol loaded cyclodextrin on semen cryopreservation of Aksaray Malakli shepherd dogs of different ages. AB - The objective of the study was to determine the effect of cholesterol-loaded cyclodextrin (CLC) on the quality parameters of semen from Aksaray Malakli Shepherd dogs of different age groups. Forty-eight male dogs were divided into 3 groupings according to their ages (young age (Y): <=3 years, n: 20; middle age (M): 4-6 years, n: 20; old age (O): >=7 years; n: 8). The sperm-rich portion of the ejaculate from each dog was divided into four aliquots and extended with either tris as a control (C) or tris loaded with 0.5, 1.0, and 1.5 mg/120 * 106 CLC as low (L), intermediate (I), and high (H) doses, respectively. Following equilibration for at least half an hour, the straws were frozen in nitrogen vapor and then stored in liquid nitrogen at least for 48 h. Later, the frozen straws were thawed in a water bath for spermatological evaluation. Significant differences were observed between different age groups in terms of the spermatological parameters (p < 0.05). The evidence suggests that increasing age is associated with poor in-vitro spermatological parameters and CLC was able to protect the acrosome integrity from cryo-damage during the freeze-thawing process. Better semen freezability characteristics were obtained at young ages, considering the overall parameters. PMID- 29699921 TI - Monte Carlo study of out-of-field exposure in carbon-ion radiotherapy with a passive beam: Organ doses in prostate cancer treatment. AB - PURPOSE: The aim of this work was to estimate typical dose equivalents to out-of field organs during carbon-ion radiotherapy (CIRT) with a passive beam for prostate cancer treatment. Additionally, sensitivity analyses of organ doses for various beam parameters and phantom sizes were performed. METHODS: Because the CIRT out-of-field dose depends on the beam parameters, the typical values of those parameters were determined from statistical data on the target properties of patients who received CIRT at the Heavy-Ion Medical Accelerator in Chiba (HIMAC). Using these typical beam-parameter values, out-of-field organ dose equivalents during CIRT for typical prostate treatment were estimated by Monte Carlo simulations using the Particle and Heavy-Ion Transport Code System (PHITS) and the ICRP reference phantom. RESULTS: The results showed that the dose decreased with distance from the target, ranging from 116 mSv in the testes to 7 mSv in the brain. The organ dose equivalents per treatment dose were lower than those either in 6-MV intensity-modulated radiotherapy or in brachytherapy with an Ir-192 source for organs within 40 cm of the target. Sensitivity analyses established that the differences from typical values were within ~30% for all organs, except the sigmoid colon. CONCLUSIONS: The typical out-of-field organ dose equivalents during passive-beam CIRT were shown. The low sensitivity of the dose equivalent in organs farther than 20 cm from the target indicated that individual dose assessments required for retrospective epidemiological studies may be limited to organs around the target in cases of passive-beam CIRT for prostate cancer. PMID- 29699922 TI - Hit discovery of Mycobacterium tuberculosis inosine 5'-monophosphate dehydrogenase, GuaB2, inhibitors. AB - Tuberculosis remains a global concern. There is an urgent need of newer antitubercular drugs due to the development of resistant forms of Mycobacterium tuberculosis (Mtb). Inosine 5'-monophosphate dehydrogenase (IMPDH), guaB2, of Mtb, required for guanine nucleotide biosynthesis, is an attractive target for drug development. In this study, we screened a focused library of 73 drug-like molecules with desirable calculated/predicted physicochemical properties, for growth inhibitory activity against drug-sensitive MtbH37Rv. The eight hits and mycophenolic acid, a prototype IMPDH inhibitor, were further evaluated for activity on purified Mtb-GuaB2 enzyme, target selectivity using a conditional knockdown mutant of guaB2 in Mtb, followed by cross-resistance to IMPDH inhibitor resistant SRMV2.6 strain of Mtb, and activity on human IMPDH2 isoform. One of the hits, 13, a 5-amidophthalide derivative, has shown growth inhibitory potential and target specificity against the Mtb-GuaB2 enzyme. The hit, 13, is a promising molecule with potential for further development as an antitubercular agent. PMID- 29699923 TI - Discovery of dimethyl pent-4-ynoic acid derivatives, as potent and orally bioavailable DGAT1 inhibitors that suppress body weight in diet-induced mouse obesity model. AB - Diacylglycerol acyltransferase (DGAT) is expressed abundantly in intestine, liver, and adipose tissues. DGAT1 is the crucial and rate-limiting enzyme that mediates the final step in triacylglycerol (TAG) resynthesis during dietary fat absorption. However, too much triacylglycerol (TAG) reserve will lead to genetic obesity (Hubert et al., 2000). DGAT1 knockout mice could survive and displayed a reduction in the postprandial rise of plasma TG, and increased sensitivity of insulin and leptin. Here we report the discovery and characterization of a novel selective DGAT1 inhibitor 29 to potentially treat obesity. Compound 29 showed lipid lowering effect in mouse lipid tolerance test (LTT) and also reduced body weight in DIO mice without observable liver damage. PMID- 29699924 TI - Design, synthesis and biological evaluation of substituted (+)-SG-1 derivatives as novel anti-HIV agents. AB - SG-1 was previously identified as a potent Non-nucleoside reverse transcriptase inhibitors (NNRTI) which works through inhibition of reverse transcriptase (RT) RNA-dependent DNA polymerase activity via a direct binding event. To further investigate the relationship between its structure and activity, four series of novel analogues were designed and synthesized with 12 of them inhibiting HIV-1 replication with IC50s in the range 0.09-6.71 MUM. Compound 4b, 4c, 4f, 2 and 6b were further tested on two NNRTI-resistant HIV-1 strains and one NNRTI-resistant superbug. The result showed that RT- E138K/M184V mutant virus conferred 4.7-9.1 fold resistance to 4c, 4f, 2 and 6b, but only showed slight resistance to 4b (2 fold) which was better than SG-1. PMID- 29699925 TI - Discovery of d-amino acid oxidase inhibitors based on virtual screening against the lid-open enzyme conformation. AB - d-Amino acid oxidase (DAAO) inhibitors are typically small polar compounds with often suboptimal pharmacokinetic properties. Features of the native binding site limit the operational freedom of further medicinal chemistry efforts. We therefore initiated a structure based virtual screening campaign based on the X ray structures of DAAO complexes where larger ligands shifted the loop (lid opening) covering the native binding site. The virtual screening of our in-house collection followed by the in vitro test of the best ranked compounds led to the identification of a new scaffold with micromolar IC50. Subsequent SAR explorations enabled us to identify submicromolar inhibitors. Docking studies supported by in vitro activity measurements suggest that compounds bind to the active site with a salt-bridge characteristic to DAAO inhibitor binding. In addition, displacement of and interaction with the loop covering the active site contributes significantly to the activity of the most potent compounds. PMID- 29699926 TI - [Spanish Society of Hypertension position statement on the 2017 ACC/AHA hypertension guidelines]. AB - The American College of Cardiology (ACC) and the American Heart Association (AHA) have recently published their guidelines for the prevention, detection, evaluation, and management of hypertension in adults. The most controversial issue is the classification threshold at 130/80mmHg, which will allow a large number of patients to be diagnosed as hypertensive who were previously considered normotensive. Blood pressure (BP) is considered normal (<120mmHg systolic and <80mmHg diastolic), elevated (120-129 and <80mmHg), stage 1 (130-139 or 80 89mmHg), and stage 2 (>=140 or >=90mmHg). Out-of-office BP measurements are recommended to confirm the diagnosis of hypertension and for titration of BP lowering medication. In management, cardiovascular risk would be determinant since those with grade 1 hypertension and an estimated 10-year risk of atherosclerotic cardiovascular disease >=10%, and those with cardiovascular disease, chronic kidney disease and/or diabetes will require pharmacological treatment, the rest being susceptible to non-pharmacological treatment up to the 140/90mmHg threshold. These recommendations would allow patients with level 1 hypertension and high atherosclerotic cardiovascular disease to benefit from pharmacological therapies and all patients could also benefit from improved non pharmacological therapies. However, this approach should be cautious because inadequate BP measurement and/or lack of systematic atherosclerotic cardiovascular disease calculation could lead to overestimation in diagnosing hypertension and to overtreatment. Guidelines are recommendations, not impositions, and the management of hypertension should be individualized, based on clinical decisions, preferences of the patients, and an adequate balance between benefits and risks. PMID- 29699927 TI - mTORC1-dependent increase in oxidative metabolism in POMC neurons regulates food intake and action of leptin. AB - OBJECTIVE: Nutrient availability modulates reactive oxygen species (ROS) production in the hypothalamus. In turn, ROS regulate hypothalamic neuronal activity and feeding behavior. The mechanistic target of rapamycin complex 1 (mTORC1) pathway is an important cellular integrator of the action of nutrients and hormones. Here we tested the hypothesis that modulation of mTORC1 activity, particularly in Proopiomelanocortin (POMC)-expressing neurons, mediates the cellular and behavioral effects of ROS. METHODS: C57BL/6J mice or controls and their knockout (KO) littermates deficient either for the mTORC1 downstream target 70-kDa ribosomal protein S6 kinase 1 (S6K1) or for the mTORC1 component Rptor specifically in POMC neurons (POMC-rptor-KO) were treated with an intracerebroventricular (icv) injection of the ROS hydrogen peroxide (H2O2) or the ROS scavenger honokiol, alone or, respectively, in combination with the mTORC1 inhibitor rapamycin or the mTORC1 activator leptin. Oxidant-related signal in POMC neurons was assessed using dihydroethidium (DHE) fluorescence. RESULTS: Icv administration of H2O2 decreased food intake, while co-administration of rapamycin, whole-body deletion of S6K1, or deletion of rptor in POMC neurons impeded the anorectic action of H2O2. H2O2 also increased oxidant levels in POMC neurons, an effect that hinged on functional mTORC1 in these neurons. Finally, scavenging ROS prevented the hypophagic action of leptin, which in turn required mTORC1 to increase oxidant levels in POMC neurons and to inhibit food intake. CONCLUSIONS: Our results demonstrate that ROS and leptin require mTORC1 pathway activity in POMC neurons to increase oxidant levels in POMC neurons and consequently decrease food intake. PMID- 29699928 TI - Female sex hormones are necessary for the metabolic effects mediated by loss of Interleukin 18 signaling. AB - OBJECTIVE: Interleukin (IL)-18 plays a crucial role in maintaining metabolic homeostasis and levels of this cytokine are influenced by gender, age, and sex hormones. The role of gender on IL-18 signaling, however, is unclear. We hypothesized that the presence of female sex hormone could preserve the metabolic phenotype of the IL-18R-/- animals. METHODS: We studied female mice with a global deletion of the alpha isoform of the IL-18 receptor (IL-18R-/-) and littermates control. Three studies were done: 1) animals fed a high fat diet (HFD) for 16 weeks; 2) animals fed chow diet for 72 weeks and 3) animals (3 weeks-old) randomized to either bilateral ovariectomy (OVX) or control surgery (SHAM) and followed for 16 weeks. RESULTS: Female IL-18R-/- mice gained less weight and maintained glucose homeostasis on a chow diet compared with HFD, but no differences between genotypes were observed. The maintenance of body weight and glucose homeostasis in IL-18R-/- mice was lost with aging. By 72 weeks of age, IL 18R-/- mice became heavier compared with WT mice due to an increase in both visceral and subcutaneous adiposity and displayed glucose intolerance. OVX did not affect body weight in IL-18R-/- mice but exacerbated glucose intolerance and impaired liver insulin signaling when compared with SHAM mice. CONCLUSIONS: Female mice harboring a global deletion of the IL-18R, only present the same phenotype as reported in male IL-18R-/- mice if they are aged or have undergone OVX, in which circulating estrogen is likely to be blunted. The role of estrogen signaling in the protection against altered metabolic homeostasis in IL-18R-/- mice appears to be mediated by liver insulin signaling. We therefore suggest that the metabolic effects mediated by loss of IL-18 signaling are only present in a female sex hormone free environment. PMID- 29699929 TI - Is There an Influence of Surgeon's Experience on the Clinical Course in Patients With a Proximal Femoral Fracture? AB - OBJECTIVES: Teaching of surgical procedures is of paramount importance. However, it can affect patients outcome. The aim of this study was to evaluate if teaching of hip fracture surgery is an independent predictor for negative in-hospital outcome. DESIGN AND SETTING: Retrospectively, we analyzed all hip fracture patients between 2008 and 2013 recorded in a national quality measurement database (AQC). Inclusion criteria were proximal femoral fracture (ICD-10 diagnostic codes S72.00-S72.11), surgical care of those fracture and a documented teaching status of the intervention. Variables were sought in bivariate and multivariate analyses. Teaching status was entered in multiple regression analysis models for in-hospital death, complications and length of stay while controlling for confounders. PARTICIPANTS: In the 6-year study period, a total of 4397 patients at a mean age of 80 years met the inclusion criteria. Totally, 48% (n = 2107) of the procedures were conducted as teaching interventions. The rest of our examined cases (n = 2290) were conducted as nonteaching procedures. RESULTS: There was no association between teaching and mortality, but complications (odds ratio = 1.3; 95% CI: 1.04-1.5; p = 0.018) and prolonged hospitalization (standardized beta = 0.045, p = 0.002) were more likely to occur in the teaching group while controlling for confounders. CONCLUSIONS: There appears to be no effect of the educational status on the in-hospital death in patients with a proximal femoral fracture. However, teaching was an independent predictor of complications and longer length of stay. Although the differences were significant, the clinical outcome was comparable in both groups, thus justifying the benefits of resident teaching. PMID- 29699930 TI - Barriers to Completion of Research Projects Among Orthopaedic Trainees. AB - INTRODUCTION & AIM: It is a requirement of the Australian Orthopaedic Association (AOA) training program that surgical education training (SET) trainees demonstrate competency in clinical or basic science research as part of their teaching curriculum. The aim of this study is to identify barriers in completing research by the Victorian and Tasmanian Region AOA SET trainees. METHODS: We designed a short qualitative survey which was distributed to all Victorian and Tasmanian orthopaedic trainees through the AOA. The survey consisted of 18 questions most of which were based on a 5-point Likert scale with options to add comments based on individual experience. RESULTS: Thirty-two (61%) orthopaedic trainees responded to the survey. Two did not give consent for their data to be used. Trainees were more likely to abandon their research projects if they had insufficient time to complete a project (p = 0.01), had fewer opportunities to take part in research (p = 0.011), were unable to complete a research project within their hospital rotation (p = 0.024), and did not have access to funding (p = 0.025). CONCLUSION: A large amount of research is abandoned by trainees. The barriers to research completion are similar to those found in the literature, however, not all barriers identified in the literature were found to be barriers to the Victorian and Tasmanian Orthopaedic trainees. By identifying barriers to research completion within training programs, we hope to assist efficiency and help improve the likelihood of project completion as well as assist mentors in their guidance of trainees while conducting research. PMID- 29699931 TI - A Video-Based Coaching Intervention to Improve Surgical Skill in Fourth-Year Medical Students. AB - OBJECTIVE: For senior medical students pursuing careers in surgery, specific technical feedback is critical for developing foundational skills in preparation for residency. This pilot study seeks to assess the feasibility of a video-based coaching intervention to improve the suturing skills of fourth-year medical students. DESIGN: Fourth-year medical students pursuing careers in surgery were randomized to intervention vs. control groups and completed 2 video recorded suture tasks. Students in the intervention group received a structured coaching session between consecutive suturing tasks, whereas students in the control group did not. Each coaching session consisted of a video review of the students' first suture task with a faculty member that provided directed feedback regarding technique. Following each suturing task, students were asked to self-assess their performance and provide feedback regarding the utility of the coaching session. All videos were deidentified and graded by independent faculty members for evaluation of suture technique. SETTING: The University of Michigan Medical School in Ann Arbor, Michigan. PARTICIPANTS: All fourth-year medical students pursuing careers in surgical specialties were contacted via e-mail for voluntary participation. In all, 16 students completed both baseline and follow up suture tasks. RESULTS: All students who completed the coaching session would definitely recommend the session for other students. A total of 94% of the students strongly agreed that the exercise was a beneficial experience, and 75% strongly agreed that it improved their technical skills. Based on faculty grading, students in the intervention group demonstrated greater average improvements in bimanual dexterity compared to students in the control group; whereas students in the control group demonstrated greater average improvements in domains of efficiency and tissue handling compared to the intervention group. Based on student self assessments, those in the intervention group had greater subjective improvements in all scored domains of bimanual dexterity, efficiency, tissue handling, and consistency compared to the control group. Subjective, free-response comments centered on themes of becoming more aware of hand movements when viewing their suturing from a new perspective, and the usefulness of the coaching advice. CONCLUSIONS: This pilot study demonstrates the feasibility of a video-based coaching intervention for senior medical students. Students who participated in the coaching arm of the intervention noticed improvements in all domains of technical skill and noted that the experience was overwhelmingly positive. In summary, video-based review shows promise as an educational tool in medical education as a means to provide specific technical feedback. PMID- 29699932 TI - Assessing the carcinogenic potential of E-cigarette. PMID- 29699933 TI - H*(10) due to scattered radiation on the cancer-patient bodies treated with Tomotherapy. AB - The ambient dose equivalent has been measured on the walls of a bunker with a 6 MV TomoLINAC, which was designed to have a conventional 18 MV LINAC. The ambient dose equivalent is due to scattered photons on patient bodies during cancer treatment. Measurements were carried out with thermoluminescent dosimeters that were fixed, at the isocentre plane, on the primary and secondary barriers, the maze, and on the TomoLINAC surface. Measurements were repeated three times, in each time dosimeters were on place during seven working days, where approximately 50 patients were treated per day. Ambient dose equivalent at each location was normalized to the total dose applied during the measuring time. The primary and secondary concrete barriers are thick enough to reduce the dose to safe values. PMID- 29699934 TI - [Rumination syndrome: Diagnostic and therapeutic difficulties of a not so infrequent disorder]. PMID- 29699935 TI - Development of eosinophilic esophagitis following sublingual immunotherapy with cedar pollen extract: A case report. PMID- 29699937 TI - Molecular regulations and therapeutic targets of Gaucher disease. AB - Gaucher disease (GD) is the most common lysosomal storage disease caused by deficiency of beta-glucocerebrosidase (GCase) resulting in lysosomal accumulation of its glycolipid substrate glucosylceramide. The activity of GCase depends on many factors such as proper folding and lysosomal localization, which are influenced by mutations in GCase encoding gene, and regulated by various GCase binding partners including Saposin C, progranulin and heat shock proteins. In addition, proinflammatory molecules also contribute to pathogenicity of GD. In this review, we summarize the molecules that are known to be important for the pathogenesis of GD, particularly those modulating GCase lysosomal appearance and activity. In addition, small molecules that inhibit inflammatory mediators, calcium ion channels and other factors associated with GD are also described. Discovery and characterization of novel molecules that impact GD are not only important for deciphering the pathogenic mechanisms of the disease, but they also provide new targets for drug development to treat the disease. PMID- 29699936 TI - IL-6 family cytokines: Key inflammatory mediators as biomarkers and potential therapeutic targets. AB - IL-6 is a critical cytokine in acute phase response and involved in the pathogenesis of several chronic inflammatory diseases including cancer. Studies have highlighted that levels of IL-6 and its family members can be useful for diagnosis, prognosis of relapse-free survival and recurrence. IL-6 family cytokines have been identified as cancer biomarkers through screening of inflammatory mediators in different fluids including saliva, serum, and bronchoalveolar lavage fluid (BALF). IL-6 can be modulated by chemopreventive drugs, small molecules, monoclonal antibodies and immune checkpoint inhibitors. Unveiling the different sources of IL-6, the interaction between IL-6 and its cellular targets, the IL-6-dependent tumor resistance mechanisms, and the identification of novel regulators of IL-6 are some of the highly complex topics included in this review and their understanding could aid cancer biomarkers and therapy development. PMID- 29699938 TI - Black-white disparity in physical performance among older women with newly diagnosed non-metastatic breast cancer: Exploring the role of inflammation and physical activity. AB - OBJECTIVE: To examine racial differences in physical performance among older women with newly diagnosed non-metastatic breast cancer and identify clinical, behavioral and biological factors that might contribute to such disparities. METHODS: This is a cross-sectional study of women aged >=65 years with newly diagnosed stage I-III breast cancer recruited from ambulatory oncology clinics at an academic center, between September 2010 and August 2015. Participants completed a Comprehensive Geriatric Assessment and laboratory testing for biomarkers of inflammation [interleukin-6 (IL6)] prior to receiving systemic treatment for cancer. The primary outcome was poor physical performance, defined as scoring <=7 on the Short Physical Performance Battery, Yes or No. Logistic regression analyses were undertaken. RESULTS: Among 135 women with mean age of 74.8 years (SD = 6.9), 31% were African-American (AA), and 33% had poor physical performance. Controlling for age, education, comorbidities and geriatric syndromes, participants with poor physical performance were more likely to be AA [versus (vs.) Non-Hispanic Whites (NHW)], odds ratio (OR) = 3.10, 95% confidence interval (CI) = 1.18-8.15. Controlling further for physical activity (PA) attenuated the racial disparity in physical performance (OR = 2.50, CI = 0.91 6.84). Lastly, controlling for IL6 further diminished the racial disparity in physical performance (OR = 1.93, CI = 0.67-5.56). In adjusted models, PA and IL6 explained 29% and 38%, respectively, of the racial disparity in poor physical performance. CONCLUSION: Among older women with newly diagnosed non-metastatic breast cancer, poor physical performance was prevalent and AA were disproportionately affected. Less engagement in physical activity and subclinical inflammation partly contributed to this disparity. PMID- 29699939 TI - Chemotherapy-Induced Long Non-coding RNA 1 Promotes Metastasis and Chemo Resistance of TSCC via the Wnt/beta-Catenin Signaling Pathway. AB - Increasing evidence has shown that chemo-resistance is related to the process of epithelial-mesenchymal transition (EMT) and increased invasiveness by tongue squamous cell carcinoma (TSCC) cells. Long non-coding RNAs (lncRNAs) play pivotal roles in tumor metastasis and progression. However, the roles and mechanisms of lncRNAs in cisplatin-resistance-induced EMT and metastasis are not well understood. In this study, a chemotherapy-induced lncRNA 1 (CILA1) was discovered by using microarrays and was functionally identified as a regulator of chemo sensitivity in TSCC cells. Upregulation of CILA1 promotes EMT, invasiveness, and chemo-resistance in TSCC cells, whereas the inhibition of CILA1 expression induces mesenchymal-epithelial transition (MET) and chemo-sensitivity, and inhibits the invasiveness of cisplatin-resistant cells both in vitro and in vivo. We also found that CILA1 exerts its functions via the activation of the Wnt/beta catenin signaling pathway. High CILA1 expression levels and low levels of phosphorylated beta-catenin were closely associated with cisplatin resistance and advanced disease stage, and were predictors of poor prognosis in TSCC patients. These findings provided a new biomarker for the chemo-sensitivity of TSCC tumors and a therapeutic target for TSCC treatment. PMID- 29699940 TI - Hydrophobicity of Lipid-Conjugated siRNAs Predicts Productive Loading to Small Extracellular Vesicles. AB - Small extracellular vesicles (sEVs) show promise as natural nano-devices for delivery of therapeutic RNA, but efficient loading of therapeutic RNA remains a challenge. We have recently shown that the attachment of cholesterol to small interfering RNAs (siRNAs) enables efficient and productive loading into sEVs. Here, we systematically explore the ability of lipid conjugates-fatty acids, sterols, and vitamins-to load siRNAs into sEVs and support gene silencing in primary neurons. Hydrophobicity of the conjugated siRNAs defined loading efficiency and the silencing activity of siRNA-sEVs complexes. Vitamin-E conjugated siRNA supported the best loading into sEVs and productive RNA delivery to neurons. PMID- 29699942 TI - Daidzein reductase of Eggerthella sp. YY7918, its octameric subunit structure containing FMN/FAD/4Fe-4S, and its enantioselective production of R dihydroisoflavones. AB - S-Equol is a metabolite of daidzein, a type of soy isoflavone, and three reductases are involved in the conversion of daidzein by specific intestinal bacteria. S-Equol is thought to prevent hormone-dependent diseases. We previously identified the equol producing gene cluster (eqlABC) of Eggerthella sp. YY7918. Daidzein reductase (DZNR), encoded by eqlA, catalyzes the reduction of daidzein to dihydrodaidzein (the first step of equol synthesis), which was confirmed using a recombinant enzyme produced in Escherichia coli. Here, we purified recombinant DZNR to homogeneity and analyzed its enzymological properties. DZNR contained FMN, FAD, and one 4Fe-4S cluster per 70-kDa subunit as enzymatic cofactors. DZNR reduced the CC bond between the C-2 and C-3 positions of daidzein, genistein, glycitein, and formononetin in the presence of NADPH. R-Dihydrodaidzein and R dihydrogenistein were highly stereo-selectively produced from daidzein and genistein. The Km and kcat for daidzein were 11.9 MUM and 6.7 s-1, and these values for genistein were 74.1 MUM and 28.3 s-1, respectively. This enzyme showed similar kinetic parameters and wide substrate specificity for isoflavone molecules. Thus, this enzyme appears to be an isoflavone reductase. Gel filtration chromatography and chemical cross-linking analysis of the active form of DZNR suggested that the enzyme consists of an octameric subunit structure. We confirmed this by small-angle X-ray scattering and transmission electron microscopy at a magnification of *200,000. DZNR formed a globular four-petal cloverleaf structure with a central vertical hole. The maximum particle size was 173 A. PMID- 29699941 TI - Pluripotent Stem Cell-Derived Cardiomyocytes as a Platform for Cell Therapy Applications: Progress and Hurdles for Clinical Translation. AB - Cardiovascular diseases are the leading cause of morbidity and mortality worldwide. Regenerative therapy has been applied to restore lost cardiac muscle and cardiac performance. Induced pluripotent stem cells (iPSCs) can provide an unlimited source of cardiomyocytes and therefore play a key role in cardiac regeneration. Despite initial encouraging results from pre-clinical studies, progress toward clinical applications has been hampered by issues such as tumorigenesis, arrhythmogenesis, immune rejection, scalability, low graft-cell survival, and poor engraftment. Here, we review recent developments in iPSC research on regenerating injured heart tissue, including novel advances in cell therapy and potential strategies to overcome current obstacles in the field. PMID- 29699943 TI - Characterization of the 3-methyl-4-nitrophenol degradation pathway and genes of Pseudomonas sp. strain TSN1. AB - 3-Methyl-4-nitrophenol (3M4NP) is formed in soil as a hydrolysis product of fenitrothion, one of the major organophosphorus pesticides. A Pseudomonas strain was isolated as a 3M4NP degrader from a crop soil and designated TSN1. This strain utilized 3M4NP as a sole carbon and energy source. To elucidate the biodegradation pathway, we performed transposon mutagenesis with pCro2a (mini Tn5495) and obtained three mutants accumulating a dark pink compound(s) from 3M4NP. Rescue cloning and sequence analysis revealed that in all mutants, the transposon disrupted an identical aromatic compound meta-cleaving dioxygenase gene, and a monooxygenase gene was located just downstream of the dioxygenase gene. These two genes were designated mnpC and mnpB, respectively. The gene products showed high identity with the methylhydroquinone (MHQ) monooxygenase (58%) and the 3-methylcatechol 2,3-dioxygenase (54%) of a different 3M4NP degrader Burkholderia sp. NF100. The transposon mutants converted 3M4NP or MHQ into two identical metabolites, one of which was identified as 2-hydroxy-5-methyl 1,4-benzoquinone (2H5MBQ) by GC/MS analysis. Furthermore, two additional genes (named mnpA1 and mnpA2), almost identical to the p-nitrophenol monooxygenase and the p-benzoquinone reductase genes of Pseudomonas sp. WBC-3, were isolated from the total DNA of strain TSN1. Disruption of mnpA1 resulted in the complete loss of the 3M4NP degradation activity, demonstrating that mnpA1 encodes the initial monooxygenase for 3M4NP degradation. The purified mnpA2 gene product could efficiently reduce methyl p-benzoquinone (MBQ) into MHQ. These results suggest that strain TSN1 degrades 3M4NP via MBQ, MHQ, and 2H5MBQ in combination with mnpA1A2 and mnpCB, existing at different loci on the genome. PMID- 29699944 TI - Antagonistics of Lactobacillus plantarum ZDY2013 against Helicobacter pylori SS1 and its infection in vitro in human gastric epithelial AGS cells. AB - In this study, the anti-Helicobacterpylori activity of Lactobacillusplantarum ZDY2013 was investigated and Lactobacillusrhamnosus GG was used as a positive control. The anti-H. pylori mechanism in vitro was also examined. Results revealed that either the viable cells or supernatant of L. plantarum ZDY2013 could suppress the growth or urease activity of H. pylori. The inhibitory effects of L. plantarum ZDY2013 were relatively higher than those of L. rhamnosus GG (P < 0.05), and such effects might be a result of their lactic acid production (e.g., 51.105 +/- 0.097 mmol/L for L. plantarum ZDY2013 and 33.113 +/- 0.063 mmol/L for L. rhamnosus GG). The anti-adhesion capacity of L. plantarum ZDY2013 against H. pylori was also stronger than that of L. rhamnosus GG in terms of inhibition, competition, and displacement. Among these inhibitory strategies, competition exhibited the best performance, with an inhibition ratio of 92.65%. Upon inhibition and anti-adhesion, the cells and supernatant of L. plantarum ZDY2013 significantly strengthened the expression of the anti-inflammatory cytokine IL 10, but attenuated the expression of the pro-inflammatory cytokine TNF-alpha in AGS cells induced by H. pylori SS1. Remarkably, the supernatant of ZDY2013 achieved a relatively higher anti-inflammatory effect than that exerted by its cells. With excellent lactic acid yield and antagonistic and anti-inflammatory effects against H. pylori SS1 infection, L. plantarum ZDY2013 shows potential to be used as a probiotics candidate. PMID- 29699945 TI - Special focus issue on potentially premalignant oral epithelial lesions: introduction and perspective. PMID- 29699946 TI - Corrigendum to "Clinical and pathological analyses of tuberculosis in the oral cavity: report of 11 cases" [Oral Surgery oral medicine oral pathology oral radiology 2018;125: 44-51]. PMID- 29699947 TI - Evaluation of the diagnostic value of immunoglobulin clonal gene rearrangements in patients with parotid gland MALT lymphoma using BIOMED-2 protocol. AB - OBJECTIVES: The aim of this study was to evaluate the diagnostic value of immunoglobulin (Ig) clonal gene rearrangements for mucosa-associated lymphoid tissue (MALT) lymphoma of the parotid gland. STUDY DESIGN: We collected and retrospectively analyzed clinical data of 21 patients referred to our institution between 2009 and 2017. Eight patients had been primarily diagnosed MALT lymphoma of the parotid gland and the remaining patients with lymphoepithelial lesion. Paraffin-embedded tissues were chosen for extracting genomic DNA and multiplex primer polymerase chain reaction amplification by using BIOMED-2 primers. Polymerase chain reaction amplification products were analyzed by heteroduplex analysis. RESULTS: Generally, 17 patients were identified to have parotid gland MALT lymphoma; 47.06% of them had Sjogren syndrome. The sensitivity of IGH VH-JH FR1, FR2, FR3, IGK Vkappa-Jkappa, and IGK (Vkappa-Kde and intron-Kde) as targets was 76.47%, 82.35%, 88.24%, 29.41%, and 35.29%, respectively. The sensitivity of combined application of the above-mentioned 3 IGH primers as targets was 100%. The sensitivity of combined application of the above two IGK primers as targets was 58.82%. CONCLUSIONS: Ig clonal gene rearrangements assays using BIOMED-2 protocol can be a highly reliable diagnostic method for parotid gland MALT lymphoma. For patients with Sjogren syndrome along with histologically benign lymphoepithelial lesion, identification of Ig clonal gene rearrangements is important for routine differential diagnosis. PMID- 29699949 TI - Risk factors of gestational diabetes mellitus using results of a prospective population-based study in Iranian pregnant women. AB - AIMS: Early identification of at-risk groups is an important step in preventing gestational diabetes and its subsequent side effects. This study aimed to evaluate the risk factors of gestational diabetes based on the International Association of Diabetes and Pregnancy Study Groups criteria in Ahvaz. MATERIAL AND METHODS: In a cross-sectional case control study, 520 pregnant women involving life after gestational diabetes Ahvaz cohort study (LAGAs) were investigated for risk factors of gestational diabetes mellitus. RESULT: The prevalence of overweight and obesity were 40% and25.8% in the GMD group and in 35.8% and 16.2% in the control group respectively (p = 0.002). According to NCEP ATP III criteria, 16.9% of women with GDM and 6.9% of mothers in the control group had metabolic syndrome in first visit of pregnancy (p < 0.001. Logistic regression showed that there is a significant relationship between maternal age[OR = 1.05(95% CI, 1.01-1.10)] (p = 0.01), previous GDM [OR = 5.60(95% CI, 2.21-14.18)] (p = 0.001), positive family history of diabetes[OR = 1.86(95% CI, 1.19-2.94)] (p = 0.006), pre-pregnancy BMI [OR = 1.05(95% CI, 1.007-1.11)] (p = 0.04) and metabolic syndrome in first visit of pregnancy[OR = 2.34 (95% CI, 1.038 5.30)] (p = 0.04) with GDM. CONCLUSION: Factors including maternal age, previous GDM, family history of diabetes, pre-pregnancy BMI reported in previous studies around the world. A significant association between metabolic syndrome in the first visit of pregnancy and GDM is novel finding of this study. Therefore screening of pre-pregnancy metabolic syndrome in women at risk of gestational diabetes is recommended. PMID- 29699948 TI - Immediate effect of a tear enhancer and meibomian gland expression on the corneal surface and whole eye higher order aberrations. AB - PURPOSE: To investigate changes in higher order ocular aberrations (HOA) induced by the administration of 0.15% sodium hyaluronate tear enhancer (TE) and meibomian gland expression (ME) on the tear film of normal subjects. METHODS: HOA values were obtained from the corneal surface (CS) and whole eye (WE), using a corneal topographer and Shack-Hartmann aberrometer, from both eyes of 50 subjects (25 females, mean age+/-sd 32.5+/-11.0 years, and 25 males, 33.88+/-11.2 years) for two pupil sizes (3 and 6mm) in a dark environment. One drop of Blink ContactsTM (Abbott Medical Optics) was instilled into the right eye and HOA measurements repeated after 30s. After 1h, the meibomian glands of the left lower eyelid were gently squeezed and HOA measurements repeated after 30s. RESULTS: There was no significant difference for CS and WE root mean square (RMS) HOAs between right and left eyes before (both pupil sizes) and after TE use or ME (3mm pupil). For 6mm pupil, TE use significantly reduced the WE RMS HOA (p<0.05, mean+/-sd) for Z40 (0.297+/-0.136 to 0.053+/-0.069), and Z55 (0.221+/-0.372 to 0.098+/-0.121) while ME significantly increased CS RMS HOA (p<0.05, mean+/-sd) for Z3-3 (0.799+/-1.178 to 1.302+/-1.991) and Z44 (0.594+/-1.184 to 0.988+/ 1.463). In general, the change in HOA was significantly correlated with the initial value before TE use or ME (p<0.05). CONCLUSION: There were no detectable differences between right and left eyes. For the 6mm pupil, the tear enhancer tended to improve optical performance of the WE and meibomian gland expression tended to reduce the optical performance at the CS. PMID- 29699950 TI - Low-density lipoprotein cholesterol and risk of type 2 diabetes: The Isfahan diabetes prevention study. AB - BACKGROUND: Studies reported that lipid-lowering treatment may increase the risk of diabetes, support the hypothesis that low-density lipoprotein cholesterol (LDLC) may be associated with type 2 diabetes (T2D). OBJECTIVE: The aim of this study was to assess the association between the LDLC levels and the incidence of T2D in an Iranian high-risk population not treated with lipid-lowering medications. METHODS: Mean 10-year follow-up data (1819) in non-diabetic first degree relatives (FDR) of consecutive patients with T2D 30-70 years old, who were not treated with lipid-lowering drugs at baseline were examined. The diagnosis of T2D based on serial oral glucose tolerance test was the primary outcome. Cox proportional hazard model was used to estimate the hazard ratio (HR) for the incidence of T2D within tertiles of LDLC. RESULTS: A higher LDLC concentration was significantly associated with higher risk of T2D. Compared with the first tertile, the adjusted risk of T2D increased for the second (HR 1.20, 95% CI: 1.07, 1.35, P < 0.01) and third (HR 1.22, 95% CI: 1.08, 1.37, P < 0.01), tertiles of LDLC. CONCLUSIONS: While these results await confirmation, a higher LDLC level was significantly associated with higher risk of T2D, independent of age, gender, fasting plasma glucose, waist circumference or blood pressure, in high-risk individuals in Iran. PMID- 29699951 TI - PPARalpha receptor expression in patients with metabolic syndrome. AB - BACKGROUND: Metabolic syndrome (MS) is considered one of the major worldwide epidemics. It accounts for billions of cardiovascular disease events and deaths. Till now, major basics of MS are not fully clarified. Peroxisome Proliferator Activated Receptor-alpha (PPARalpha) displays a ligand-activated transcription factor. It is involved in the regulation of many metabolic processes including inflammation, lipid, and glucose metabolism. Therefore, this study investigated the leucocytic expression of PPARalpha in a metabolic patient in comparison to healthy controls. METHODS: 100 subjects with MS were recruited, in addition to 100 subjects without any obvious metabolic disorders as healthy controls. Expression of PPARalpha and CD 36 were analyzed on different leucocytic populations using optimized flow-cytometric analysis. Correlations of the expression of both indexes with different clinical and laboratory parameters were analyzed. RESULTS: The eosinophilic expression of PPARalpha was found to be lower in subjects with MS in comparison to the healthy controls (p value 0.001). Also, PPARalpha expression, on most of the leucocytic populations, was inversely correlated with waist circumferences among the study populations. CONCLUSION: Circulated eosinophilic expression of PPARalpha protein is reduced in MS subjects. This conclusion may explain the endothelial dysfunction and obesity associated with MS, as well as it may help in the management of this worldwide health problem. PMID- 29699952 TI - Associations of vitamin D status with markers of metabolic health: A community based study in Shanghai, China. AB - AIMS: This study investigated the associations of vitamin D status (i.e., serum 25(OH)D concentration) with markers of metabolic health and metabolic syndrome (MS), as well as possible gender differences in these associations, with metabolic syndrome (MS) for a sample from Shanghai, China. METHODS: Demographic and anthropometric data, as well as 25-hydroxyvitamin D (serum 25(OH)D), blood glucose, and lipid concentrations were obtained for 508 urban residents aged 19 70 years. After grouping into tertiles according to their serum 25(OH)D concentrations, linear and logistic regressions were used to evaluate associations between serum 25(OH)D concentration and risk factors for MS across tertiles. RESULTS: A 1 ng/mL increase in 25(OH)D was associated with a significant decrease in total cholesterol by 0.25 mmol/L [95% CI: (-0.44, -0.05); P = 0.014] for the third tertile, with reference to the first tertile. Also, 1 ng/mL increase in 25(OH)D was associated with a significant decrease in LDL by 0.18 mmol/L [95% CI: (-0.35, -0.02); P = 0.026] for the third tertile. In addition, participants in the third tertile had a 54% reduction in the OR for MS [95% CI: (-1.10,- 0.02), P = 0.041]. Lastly, while there was no gender difference in vitamin D deficiency status, the non-MS women had significantly higher 25(OH)D level than those with MS (30.1 +/- 5.8 vs. 28.5 +/- 5.9 ng/mL, P = 0.035), while no such difference was observed for men. CONCLUSIONS: Higher serum 25(OH)D concentration was associated with a better metabolic profile and thus a lower risk for developing MS in urban Shanghai residents of China. PMID- 29699953 TI - The role of metabolic syndrome variant in the malignant tumors progression. AB - Metabolic syndrome (MS) is one of the leading risk factors for the development of some common cancers (endometrial cancer, postmenopausal breast cancer, colorectal cancer). Currently, a drug-induced metabolic syndrome related with androgen deprivation therapy in patients with prostate cancer represents a serious medical problem. Not only MS, or its individual components, but MS variants with different levels of leptin, adiponectin, visfatin, resistin are associated with tumor invasion, metastasis and survival rates in patients with MS-associated malignancies. PMID- 29699954 TI - The National Medical Commission - More of the same. AB - The Cabinet chaired by the Prime Minister has accepted six amendments to the National Medical Commission Bill suggested by the Department-related Parliamentary Standing Committee (1). These amendments are: the proposed National Licentiate Examination has been replaced by a countrywide final MBBS examination called the National Exit Test (NEXT); the bridge course to train practitioners from AYUSH (Ayurveda, Unani, Siddha and Homeopathy) in modern medicine has been removed, and it has been left to individual states to take a decision about this; the percentage of seats in private medical training institutions under fee regulation has been increased from 40% to 50%; the number of nominees from the states and Union territories who are members of the Commission has been increased from three to six; the penalties for non-compliance with educational norms for colleges has been modified; and the punishment for practising modern medicine without qualification has been made imprisonment up to one year and a fine of Rs 5 lakh. PMID- 29699955 TI - Medical case reports published in PubMed-indexed Indian journals in 2015: Adherence to 2013 CARE guidelines. AB - In 2013, an independent group of researchers developed the CARE guidelines, a checklist to standardise reporting of case reports. This study assesses adherence to CARE guidelines among PubMed-indexed Indian medical journals in 2015 and the extent of endorsement of these guidelines by the journals. Case reports published in 2015 in journals indexed by PubMed, belonging to the medical stream, currently active, and that had an impact factor were included for analysis. Case series and journals that were published from India but for another country were excluded. Total adherence score and classification of adherence as "excellent", "very good", "good", and "poor" as also adherence to individual components of the checklist were the outcome measures. A total of 162 journals were identified by the search strategy, of which 36 satisfied the selection criteria. In these 36 journals, 1178 case reports were published. We tested the association between the type of journal and impact factor with adherence by using the chi-squared test and generated crude odds ratios. All analyses were done at 5% significance. Based on the total percent score, no case report had excellent adherence, and 19% had good, 70.7% average, and 10% poor adherence, respectively. Among the sub-items, the best adherence was seen in the clinical findings [97.9%], followed by keywords [88.5%], and introduction [71.5%]. The items with extremely poor adherence were patient perspective [0%], informed consent [2.8%], and timeline [4.6%]. Journals with an impact factor of more than 1 had better adherence, relative to those with an impact factor lower than 1. Only one journal's website mentioned the CARE guidelines. Greater awareness needs to be created among authors, peer reviewers, and editors about using these guidelines. As informed consent is a metric of autonomy, all stakeholders must ensure its reporting. PMID- 29699956 TI - Outcomes of robotic, laparoscopic, and open hysterectomy for benign conditions in obese patients AB - OBJECTIVE: To compare outcomes of robotic-assisted (RAH), total laparoscopic hysterectomy (LH), and total abdominal hysterectomy (TAH) for benign conditions in obese patients. MATERIAL AND METHODS: Retrospective cohort (Class II-2) analysis. All obese patients who underwent RAH, LH or TAH for benign conditions by a single surgeon at the University of Texas Medical Branch between January 2009 and December 2011 were identified and their charts reviewed. The patients' characteristics, operative data, and post-operative outcomes were collected and statistically analyzed. RESULTS: A total of 208 patients who underwent RAH (n=51), LH (n=24) or TAH (n=133) were analyzed. There were no significant differences among the groups in demographic characteristics, indications for surgery or pathologic findings. RAH and LH were associated with lower estimated blood loss (EBL) (p<0.001) and shorter length of hospital stay (LOS) (p<0.001) compared with TAH. In addition, RAH and LH had lower intraoperative and early postoperative (<=6 weeks) complications compared with TAH (p=0.002). However, the procedure time was longer in RAH and LH (p<0.001). No significant differences were noted among the groups for late post-operative complications (after 6 weeks) or unscheduled post-operative visits. CONCLUSION: Minimally invasive hysterectomy appears to be safe in obese patients with the advantages of less EBL, fewer intraoperative complications, and shorter LOS. PMID- 29699957 TI - Iodine deficiency in pregnant women at first trimester in Ankara. AB - OBJECTIVE: Iodine deficiency in pregnant woman in Ankara was shown in previous studies. We aimed to conduct a study in a tertiary center to investigate for the need for iodine replacement in our population. MATERIAL AND METHODS: This was a single tertiary center, non-interventional, retrospective, cross-sectional study. Data were retrieved retrospectively from 440 women who had been in first trimester in gestational age. Maternal iodine status, TSH levels, T4 levels were examined. Urinary iodine concentration (UIC) was calculated based on Sandell Kolthoff reaction which is a colorimetric method. We excluded patients with previous thyroid disease or current thyroid disease. Thyroid hormones and TSH were measured by chemiluminescence immunoassays. RESULTS: Iodine deficiency prevalence (UI <150 MUg/L) was 84.7% in first trimester of pregnancy in our population. The median UIC was 81.6 (1-450) MUg/L, indicating iodine insufficiency. All the patients declared iodized salt use. None of the patients were taking iodine replacement. The mean TSH level was 1.53+/-1.27 mIU/l, (0.01 mIU/l-14.74 mIU/l) and mean T4 levels was 12.51+/-5.01 mIU/l, (7.09 mIU/l, -23.7 mIU/l,). TSH levels of 56 patients were higher than 2.5 mIU/l. According to these results 12.72% of the patients had subclinical hypothyroidism based on serum TSH and Free T4 levels. Isolated hypothyroxinemia was present in one patient. CONCLUSION: Our study demonstrated that pregnant women still suffer from iodine deficiency in Ankara despite of mandatory iodine salt use. Iodized salt use does not provide enough iodine supplement especially in pregnant women. Iodine supplementation is shown to enhance neurological development and psychomotor performance. We suggest that iodine should be a part of routine laboratory evaluation at the first prenatal visit for its importance in early pregnancy. Also, iodized salt use education should be provided to the women to eradicate iodine deficiency. Iodine supplements should be recommended to all pregnant women in addition to iodized salt. PMID- 29699958 TI - The assessment of thyroid autoantibody levels in euthyroid patients with polycystic ovary syndrome AB - Objective: Thyroid hormone abnormalities are commonly seen in polycystic ovary syndrome (PCOS) and have considerable effects on comorbidities. The association with PCOS and thyroid autoimmunity which lead to thyroid pathologies are not revealed clearly. We targeted to commentate anti-thyroid peroxidase (anti-TPO), anti-thyroglobulin (anti-TG) antibody levels and thyroid autoimmunity in PCOS. Material and Methods: One hundred eighty four patients who got the diagnosis of PCOS regard to the revised 2003 Rotterdam criteria were embodied in this study. One hundred six age-matched female volunteers were included in the control group. Characteristics, biochemical parameters, thyroid hormone and autoantibody levels of groups were investigated. Results: Although; we did not find out a statistically significant difference in TSH and sT4 levels between two groups (p>0.05), anti-TPO and anti-TG antibody levels were determined higher in PCOS group significantly (p<0.001). Anti-TPO Ab and anti-TG Ab positivity prevalence of PCOS patients were significantly higher as against to controls (p<0.001; p=0.01). Conclusion: Not only thyroid hormone levels but also thyroid autoantibody levels should be screened during the investigation of PCOS and the patients with positive results need to be followed up carefully in the long run. PMID- 29699960 TI - Is corona mortis a historical myth? A perspective from a gynecologic oncologist PMID- 29699959 TI - Current management of gynecologic cancer in pregnancy AB - Cancer during pregnancy is a particularly challenging complication. The incidence has increased in recent years due to childbearing at advanced maternal ages due to career choices and/or the development of reproductive technology. Approximately two thirds of cancer cases during pregnancy comprise invasive cervical cancers and breast cancer. Cancer during gestation is characterized by a need for specialized treatment due to major changes in the hormonal profile (estrogen-progesterone), metabolism (enhancement of anabolism), hemodynamic changes (hyperdynamic circulation), immunologic changes (cell-mediated and humoral immunity), and increased angiogenesis (increased blood flow towards the uterus). Moreover, the management of such patients is based on the trimester of pregnancy, type and stage of cancer, and informed consent of the mother based on her wishes. The optimal treatment of cancer during pregnancy remains elusive because there are limited data from retrospective studies with small samples. As a result, it is crucial that data regarding survival of the women and long-term follow-up of the children from different cancer centers and registries are shared. This need is dictated by the fact that the incidence of cancer during pregnancy will continue to rise as child-bearing age continues to increase. PMID- 29699961 TI - The Development of a Social Networking-Based Relatedness Intervention Among Young, First-Time Blood Donors: Pilot Study. AB - BACKGROUND: Increasing repeat blood donation behavior is a critical public health goal. According to self-determination theory, the process of developing internal motivation to give blood and an associated self-identity as a blood donor may be promoted by feelings of "relatedness" or a connection to other donors, which may be enhanced through social relations and interactions. OBJECTIVE: The purpose of this report it to describe the development and pilot testing of a social networking-based (Facebook) intervention condition designed to increase feelings of relatedness via virtual social interaction and support. METHODS: To develop the intervention condition content, images, text, polls, and video content were assembled. Ohio University college students (N=127) rated the content (82 images/text) presented by computer in random order using a scale of one to five on various dimensions of relatedness. Mean ratings were calculated and analyses of variance were conducted to assess associations among the dimensions. Based on these results, the relatedness intervention was adapted and evaluated for feasibility, acceptability, and preliminary efficacy among 24 first-time donors, aged 18 to 24 years, in a 30-day pilot trial. Paired t-tests were conducted to examine change over time in relatedness and connectedness. RESULTS: The intervention condition that was developed was acceptable and feasible. Results of the uncontrolled, preintervention, and postintervention evaluation revealed that feelings of individual-level relatedness increased significantly after the intervention. CONCLUSIONS: By promoting first-time blood donor relatedness, our goal is to enhance internal motivation for donating and the integration of the blood donor identity, thus increasing the likelihood of future repeat donation. TRIAL REGISTRATION: ClinicalTrials.gov NCT02717338; https://clinicaltrials.gov/ct2/show/NCT02717338 (Archived by WebCite at http://www.webcitation.org/6ymHRBCwu) PMID- 29699962 TI - A Neuroimaging Web Services Interface as a Cyber Physical System for Medical Imaging and Data Management in Brain Research: Design Study. AB - BACKGROUND: Structural and functional brain images are essential imaging modalities for medical experts to study brain anatomy. These images are typically visually inspected by experts. To analyze images without any bias, they must be first converted to numeric values. Many software packages are available to process the images, but they are complex and difficult to use. The software packages are also hardware intensive. The results obtained after processing vary depending on the native operating system used and its associated software libraries; data processed in one system cannot typically be combined with data on another system. OBJECTIVE: The aim of this study was to fulfill the neuroimaging community's need for a common platform to store, process, explore, and visualize their neuroimaging data and results using Neuroimaging Web Services Interface: a series of processing pipelines designed as a cyber physical system for neuroimaging and clinical data in brain research. METHODS: Neuroimaging Web Services Interface accepts magnetic resonance imaging, positron emission tomography, diffusion tensor imaging, and functional magnetic resonance imaging. These images are processed using existing and custom software packages. The output is then stored as image files, tabulated files, and MySQL tables. The system, made up of a series of interconnected servers, is password-protected and is securely accessible through a Web interface and allows (1) visualization of results and (2) downloading of tabulated data. RESULTS: All results were obtained using our processing servers in order to maintain data validity and consistency. The design is responsive and scalable. The processing pipeline started from a FreeSurfer reconstruction of Structural magnetic resonance imaging images. The FreeSurfer and regional standardized uptake value ratio calculations were validated using Alzheimer's Disease Neuroimaging Initiative input images, and the results were posted at the Laboratory of Neuro Imaging data archive. Notable leading researchers in the field of Alzheimer's Disease and epilepsy have used the interface to access and process the data and visualize the results. Tabulated results with unique visualization mechanisms help guide more informed diagnosis and expert rating, providing a truly unique multimodal imaging platform that combines magnetic resonance imaging, positron emission tomography, diffusion tensor imaging, and resting state functional magnetic resonance imaging. A quality control component was reinforced through expert visual rating involving at least 2 experts. CONCLUSIONS: To our knowledge, there is no validated Web based system offering all the services that Neuroimaging Web Services Interface offers. The intent of Neuroimaging Web Services Interface is to create a tool for clinicians and researchers with keen interest on multimodal neuroimaging. More importantly, Neuroimaging Web Services Interface significantly augments the Alzheimer's Disease Neuroimaging Initiative data, especially since our data contain a large cohort of Hispanic normal controls and Alzheimer's Disease patients. The obtained results could be scrutinized visually or through the tabulated forms, informing researchers on subtle changes that characterize the different stages of the disease. PMID- 29699963 TI - The Efficacy of Electronic Health-Supported Home Exercise Interventions for Patients With Osteoarthritis of the Knee: Systematic Review. AB - BACKGROUND: Osteoarthritis of the knee is the most common cause for disability and limited mobility in the elderly, with considerable individual suffering and high direct and indirect disease-related costs. Nonsurgical interventions such as exercise, enhanced physical activity, and self-management have shown beneficial effects for pain reduction, physical function, and quality of life (QoL), but access to these treatments may be limited. Therefore, home therapy is strongly recommended. However, adherence to these programs is low. Patients report lack of motivation, feedback, and personal interaction as the main barriers to home therapy adherence. To overcome these barriers, electronic health (eHealth) is seen as a promising opportunity. Although beneficial effects have been shown in the literature for other chronic diseases such as chronic pain, cardiovascular disease, and diabetes, a systematic literature review on the efficacy of eHealth interventions for patients with osteoarthritis of knee is missing so far. OBJECTIVE: The aim of this study was to compare the efficacy of eHealth-supported home exercise interventions with no or other interventions regarding pain, physical function, and health-related QoL in patients with osteoarthritis of the knee. METHODS: MEDLINE, CENTRAL, CINAHL, and PEDro were systematically searched using the keywords osteoarthritis knee, eHealth, and exercise. An inverse variance random-effects meta-analysis was carried out pooling standardized mean differences (SMDs) of individual studies. The Cochrane tool was used to assess risk of bias in individual studies, and the quality of evidence across studies was evaluated following the Grading of Recommendations, Assessment, Development, and Evaluation approach. RESULTS: The literature search yielded a total of 648 results. After screening of titles, abstracts, and full-texts, seven randomized controlled trials were included. Pooling the data of individual studies demonstrated beneficial short-term (pain SMD=-0.31, 95% CI -0.58 to -0.04, low quality; QoL SMD=0.24, 95% CI 0.05-0.43, moderate quality) and long-term effects (pain -0.30, 95% CI -0.07 to -0.53, moderate quality; physical function 0.41, 95% CI 0.17-0.64, high quality; and QoL SMD=0.27, 95% CI 0.06-0.47, high quality). CONCLUSIONS: eHealth-supported exercise interventions resulted in less pain, improved physical function, and health-related QoL compared with no or other interventions; however, these improvements were small (SMD<0.5) and may not make a meaningful difference for individual patients. Low adherence is seen as one limiting factor of eHealth interventions. Future research should focus on participatory development of eHealth technology integrating evidence-based principles of exercise science and ways of increasing patient motivation and adherence. PMID- 29699965 TI - Public Awareness of Uterine Power Morcellation Through US Food and Drug Administration Communications: Analysis of Google Trends Search Term Patterns. AB - BACKGROUND: Uterine power morcellation, where the uterus is shred into smaller pieces, is a widely used technique for removal of uterine specimens in patients undergoing minimally invasive abdominal hysterectomy or myomectomy. Complications related to power morcellation of uterine specimens led to US Food and Drug Administration (FDA) communications in 2014 ultimately recommending against the use of power morcellation for women undergoing minimally invasive hysterectomy. Subsequently, practitioners drastically decreased the use of morcellation. OBJECTIVE: We aimed to determine the effect of increased patient awareness on the decrease in use of the morcellator. Google Trends is a public tool that provides data on temporal patterns of search terms, and we correlated this data with the timing of the FDA communication. METHODS: Weekly relative search volume (RSV) was obtained from Google Trends using the term "morcellation." Higher RSV corresponds to increases in weekly search volume. Search volumes were divided into 3 groups: the 2 years prior to the FDA communication, a 1-year period following, and thereafter, with the distribution of the weekly RSV over the 3 periods tested using 1-way analysis of variance. Additionally, we analyzed the total number of websites containing the term "morcellation" over this time. RESULTS: The mean RSV prior to the FDA communication was 12.0 (SD 15.8), with the RSV being 60.3 (SD 24.7) in the 1-year after and 19.3 (SD 5.2) thereafter (P<.001). The mean number of webpages containing the term "morcellation" in 2011 was 10,800, rising to 18,800 during 2014 and 36,200 in 2017. CONCLUSIONS: Google search activity about morcellation of uterine specimens increased significantly after the FDA communications. This trend indicates an increased public awareness regarding morcellation and its complications. More extensive preoperative counseling and alteration of surgical technique and clinician practice may be necessary. PMID- 29699966 TI - Safer Prescribing and Care for the Elderly (SPACE): Protocol of a Cluster Randomized Controlled Trial in Primary Care. AB - BACKGROUND: High-risk prescribing, adverse drug events, and avoidable adverse drug event hospitalizations are common. The single greatest risk factor for high risk prescribing and adverse drug events is the number of medications a person is taking. More people are living longer and taking more medications for multiple long-term conditions. Most on-going prescribing occurs in primary care. The most effective, cost-effective, and practical approach to safer prescribing in primary care is not yet known. OBJECTIVE: To test the effect of the Safer Prescribing And Care for the Elderly (SPACE) intervention on high-risk prescribing of nonsteroidal anti-inflammatory and antiplatelet medicines, and related adverse drug event hospitalizations. METHODS: This is a protocol of a cluster randomized controlled trial. The clusters will be primary care practices. Data collection and analysis will be at the level of patient. RESULTS: Recruitment started in 2018. Six-month data collection will be in 2018. CONCLUSIONS: This study addresses an important translational gap, testing an intervention designed to prompt medicines review and support safer prescribing in routine primary care practice. TRIAL REGISTRATIONgeneral practice: Australian New Zealand Clinical Trials Registry: ACTRN12618000034235 http://www.ANZCTR.org.au/ACTRN12618000034235.aspx (Archived with Webcite at http://www.webcitation.org/6yj9RImDf) PMID- 29699964 TI - A Single-Session, Web-Based Parenting Intervention to Prevent Adolescent Depression and Anxiety Disorders: Randomized Controlled Trial. AB - BACKGROUND: Depression and anxiety disorders are significant contributors to burden of disease in young people, highlighting the need to focus preventive efforts early in life. Despite substantial evidence for the role of parents in the prevention of adolescent depression and anxiety disorders, there remains a need for translation of this evidence into preventive parenting interventions. To address this gap, we developed a single-session, Web-based, tailored psychoeducation intervention that aims to improve parenting practices known to influence the development of adolescent depression and anxiety disorders. OBJECTIVE: The aim of this study was to evaluate the short-term effects of the intervention on parenting risk and protective factors and symptoms of depression and anxiety in adolescent participants. METHODS: We conducted a single-blind, parallel group, superiority randomized controlled trial comparing the intervention with a 3-month waitlist control. The intervention is fully automated and consists of two components: (1) completion of an online self-assessment of current parenting practices against evidence-based parenting recommendations for the prevention of adolescent depression and anxiety disorders and (2) an individually tailored feedback report highlighting each parent's strengths and areas for improvement based on responses to the self-assessment. A community sample of 349 parents, together with 327 adolescents (aged 12-15 years), were randomized to either the intervention or waitlist control condition. Parents and adolescents completed online self-reported assessments of parenting and adolescent symptoms of depression and anxiety at baseline, 1-month (parent-report of parenting only), and 3-month follow-up. RESULTS: Compared with controls, intervention group parents showed significantly greater improvement in parenting risk and protective factors from baseline to 1-month and 3-month follow-up (F2,331.22=16.36, P<.001), with a small to medium effect size at 3-month follow up (d=0.33). There were no significant effects of the intervention on adolescent report of parenting or symptoms of depression or anxiety in the adolescents (all P>.05). CONCLUSIONS: Findings suggest that a single-session, individually tailored, Web-based parenting intervention can improve parenting factors that are known to influence the development of depression and anxiety in adolescents. However, our results do not support the effectiveness of the intervention in improving adolescent depression or anxiety symptoms in the short-term. Long-term studies are required to adequately assess the relationship between improving parenting factors and adolescent depression and anxiety outcomes. Nonetheless, this is a promising avenue for the translation of research into a low-cost, sustainable, universal prevention approach. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12615000247572; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=1261500024757 (Archived by WebCite at http://www.webcitation.org/6v1ha19XG) PMID- 29699967 TI - Patients Using an Online Forum for Reporting Progress When Engaging With a Six Week Exercise Program for Knee Conditioning: Feasibility Study. AB - BACKGROUND: The use of electronic health (eHealth) and Web-based resources for patients with knee pain is expanding. Padlet is an online noticeboard that can facilitate patient interaction by posting virtual "sticky notes." OBJECTIVE: The primary aim of this study was to determine feasibility of patients in a 6-week knee exercise program using Padlet as an online forum for self-reporting on outcome progression. METHODS: Undergraduate manual therapy students were recruited as part of a 6-week study into knee conditioning. Participants were encouraged to post maximum effort readings from quadriceps and gluteal home exercises captured from standard bathroom scales on a bespoke Padlet. Experience and progression reporting were encouraged. Posted data were analyzed for association between engagement, entry frequency, and participant characteristics. Individual data facilitated single-subject, multiple-baseline analysis using statistical process control. Experiential narrative was analyzed thematically. RESULTS: Nineteen participants were recruited (47%, 9/19 female); ages ranged from 19 to 53 years. Twelve individuals (63%) opted to engage with the forum (range 4-40 entries), with five (42%) reporting across all 6 weeks. Gender did not influence reporting (odds ratio [OR] 0.76, 95% CI 0.06-6.93). No significant difference manifested between body mass index and engagement P=.46); age and entry frequency did not correlate (R2=.054, 95% CI -0.42 to 0.51, P=.83). Statistically significant conditioning profiles arose in single participants. Themes of pain, mitigation, and response were inducted from the experiences posted. CONCLUSIONS: Patients will engage with an online forum for reporting progress when undertaking exercise programs. In contrast to related literature, no significant association was found with reporting and gender, age, or body mass index. Individual posted data allowed multiple-baseline analysis and experiential induction from participants. Conditioning responses were evident on visual inspection. The importance of individualized visual data to patients and the role of forums in monitoring patients' progress in symptomatic knee pain populations need further consideration. PMID- 29699968 TI - Guided Web-Based Cognitive Behavior Therapy for Perfectionism: Results From Two Different Randomized Controlled Trials. AB - BACKGROUND: Perfectionism can become a debilitating condition that may negatively affect functioning in multiple areas, including mental health. Prior research has indicated that internet-based cognitive behavioral therapy can be beneficial, but few studies have included follow-up data. OBJECTIVE: The objective of this study was to explore the outcomes at follow-up of internet-based cognitive behavioral therapy with guided self-help, delivered as 2 separate randomized controlled trials conducted in Sweden and the United Kingdom. METHODS: In total, 120 participants randomly assigned to internet-based cognitive behavioral therapy were included in both intention-to-treat and completer analyses: 78 in the Swedish trial and 62 in the UK trial. The primary outcome measure was the Frost Multidimensional Perfectionism Scale, Concern over Mistakes subscale (FMPS CM). Secondary outcome measures varied between the trials and consisted of the Clinical Perfectionism Questionnaire (CPQ; both trials), the 9-item Patient Health Questionnaire (PHQ-9; Swedish trial), the 7-item Generalized Anxiety Disorder scale (GAD-7; Swedish trial), and the 21-item Depression Anxiety Stress Scale (DASS-21; UK trial). Follow-up occurred after 6 months for the UK trial and after 12 months for the Swedish trial. RESULTS: Analysis of covariance revealed a significant difference between pretreatment and follow-up in both studies. Intention-to-treat within-group Cohen d effect sizes were 1.21 (Swedish trial; 95% CI 0.86-1.54) and 1.24 (UK trial; 95% CI 0.85-1.62) for the FMPS CM. Furthermore, 29 (59%; Swedish trial) and 15 (43%; UK trial) of the participants met the criteria for recovery on the FMPS CM. Improvements were also significant for the CPQ, with effect sizes of 1.32 (Swedish trial; 95% CI 0.97 1.66) and 1.49 (UK trial; 95% CI 1.09-1.88); the PHQ-9, effect size 0.60 (95% CI 0.28-0.92); the GAD-7, effect size 0.67 (95% CI 0.34-0.99); and the DASS-21, effect size 0.50 (95% CI 0.13-0.85). CONCLUSIONS: The results are promising for the use of internet-based cognitive behavioral therapy as a way of targeting perfectionism, but the findings need to be replicated and include a comparison condition. PMID- 29699969 TI - Enhancing Home Health Mobile Phone App Usability Through General Smartphone Training: Usability and Learnability Case Study. AB - BACKGROUND: Each year, millions of older adults fall, with more than 1 out of 4 older people experiencing a fall annually, thereby causing a major social and economic impact. Falling once doubles one's chances of falling again, making fall prediction an important aspect of preventative strategies. In this study, 22 older adults aged between 65 and 85 years were trained in the use of a smartphone based fall prediction system. The system is designed to continuously assess fall risk by measuring various gait and balance parameters using a smart insole and smartphone, and is also designed to detect falls. The use case of the fall prediction system in question required the users to interact with the smartphone via an app for device syncing, data uploads, and checking system status. OBJECTIVE: The objective of this study was to observe the effect that basic smartphone training could have on the user experience of a group that is not technically proficient with smartphones when using a new connected health system. It was expected that even short rudimentary training could have a large effect on user experience and therefore increase the chances of the group accepting the new technology. METHODS: All participants received training on how to use the system smartphone app; half of the participants (training group) also received extra training on how to use basic functions of the smartphone, such as making calls and sending text messages, whereas the other half did not receive this extra training (no extra training group). Comparison of training group and no extra training group was carried out using metrics such as satisfaction rating, time taken to complete tasks, cues required to complete tasks, and errors made during tasks. RESULTS: The training group fared better in the first 3 days of using the system. There were significant recorded differences in number of cues required and errors committed between the two groups. By the fourth and fifth day of use, both groups were performing at the same level when using the system. CONCLUSIONS: Supplementary basic smartphone training may be critical in trials where a smartphone app-based system for health intervention purposes is being introduced to a population that is not proficient with technology. This training could prevent early technology rejection and increase the engagement of older participants and their overall user experience with the system. PMID- 29699970 TI - Consensus on Quality Indicators of Postgraduate Medical E-Learning: Delphi Study. AB - BACKGROUND: The progressive use of e-learning in postgraduate medical education calls for useful quality indicators. Many evaluation tools exist. However, these are diversely used and their empirical foundation is often lacking. OBJECTIVE: We aimed to identify an empirically founded set of quality indicators to set the bar for "good enough" e-learning. METHODS: We performed a Delphi procedure with a group of 13 international education experts and 10 experienced users of e learning. The questionnaire started with 57 items. These items were the result of a previous literature review and focus group study performed with experts and users. Consensus was met when a rate of agreement of more than two-thirds was achieved. RESULTS: In the first round, the participants accepted 37 items of the 57 as important, reached no consensus on 20, and added 15 new items. In the second round, we added the comments from the first round to the items on which there was no consensus and added the 15 new items. After this round, a total of 72 items were addressed and, of these, 37 items were accepted and 34 were rejected due to lack of consensus. CONCLUSIONS: This study produced a list of 37 items that can form the basis of an evaluation tool to evaluate postgraduate medical e-learning. This is, to our knowledge, the first time that quality indicators for postgraduate medical e-learning have been defined and validated. The next step is to create and validate an e-learning evaluation tool from these items. PMID- 29699971 TI - Prevalence, Demographic Correlates, and Perceived Impacts of Mobile Health App Use Amongst Chinese Adults: Cross-Sectional Survey Study. AB - BACKGROUND: Mobile health apps have changed the way people obtain health information and services and advance their understanding and management of their health. Although many health apps are available, little is known about the prevalence of their use for different purposes, whether such use is associated with demographic characteristics, and the impacts of their use on health knowledge and management. OBJECTIVE: The main objectives of this study were to examine the prevalence, extent, and demographic correlates of health app use and the perceived impacts of health app use on increased health knowledge and improved health condition management. METHODS: We conducted a cross-sectional questionnaire survey of 633 Chinese adults randomly drawn from the general population in Hong Kong. RESULTS: Of the 633 participants, 612 (96.7%) reported using mobile devices. Of them, 235 (38.4%) reported using multiple types of health apps. The most-used type of health app was about healthy living information (197/612, 32.2%), followed by measuring/recording vital signs (80/612, 13.1%), health and medical reminders (64/612, 10.5%), recovery and rehabilitation information (42/612, 6.9%), diagnosis assistance (28/612, 4.6%), emergency services (16/612, 2.6%), telehealth (11/612, 1.8%), and "other" (19/612, 3.1%). Multivariate logistic regression analysis found that health app users were more likely to be women (odds ratio [OR] 1.68, 95% CI 1.14-2.48, P=.01) of a higher self-rated social class (OR 3.66, 95% CI 1.11-12.11, P=.03). Participants who worked in education/culture/academia (OR 2.31, 95% CI 1.16-4.59, P=.02) or disciplinary forces (OR 5.07, 95% CI 1.25-20.62, p=.02) were more likely to believe that using health apps could increase their health knowledge; participants working in education/culture/academia were also more likely to believe that using health apps could improve the effectiveness of health condition management (OR 2.18, 95% CI 1.10-4.34, P=.03). CONCLUSIONS: Effort should be made to promote health app use, especially to demographic groups that are currently less likely to use health apps (eg, males, individuals from lower social classes). From the public health perspective, guidelines could be developed to help individuals identify quality health apps that meet their needs. Moreover, app developers could improve the usability of health apps to promote health app use. PMID- 29699972 TI - Ultrasonographic findings of multiple intussusception in an extremely preterm infant. PMID- 29699973 TI - Association of Total and Differential Leukocyte Counts With Cardiovascular Disease and Mortality in the UK Biobank. AB - OBJECTIVE: Elevated white blood cell count is associated with a higher risk of cardiovascular disease (CVD). We aimed to investigate whether specific leukocyte subpopulations, which may more closely indicate a specific inflammatory pathway, are specifically associated with CVD. APPROACH AND RESULTS: Participants (478 259) from UK Biobank with data for white blood cell count were included. Death because of CVD (n=1377) and non-CVD causes (n=8987) occurred during median follow up time of 7.0 years (interquartile range, 6.3-7.6). In Cox models, deciles of leukocyte counts (lymphocytes, monocytes, neutrophils, eosinophils, and basophils) were examined using the fifth decile as the referent group. Models were stratified by sex and adjusted for a range of classical risk factors. A sensitivity analysis excluded participants with baseline comorbidites and the first 2 years of follow-up. Men (hazard ratio [HR], 1.59; 95% confidence interval, 1.22-2.08) and women (HR, 2.15; 95% confidence interval, 1.38-3.35) in the highest decile of neutrophil count were at higher risk of CVD mortality and nonfatal CVD (men HR, 1.28; 95% confidence interval, 1.16-1.42 and women HR, 1.21; 95% confidence interval, 1.06-1.38). In the sensitivity analysis, the power to investigate CVD mortality was limited, but for both sexes combined, the linear HRs for a 1*109/L cell count increase in white blood cell count and neutrophils, respectively, was 1.05 (1.03-1.07) and 1.07 (1.04-1.11). CONCLUSIONS: Among circulating leukocyte subpopulations, neutrophil count in men was most consistently associated with fatal and nonfatal CVD. Further studies of interventions that lower circulating neutrophils, such as canakinumab, are required to investigate causality. PMID- 29699975 TI - Author's reply to Williams and Rowe. PMID- 29699974 TI - Lifetime risk of atrial fibrillation according to optimal, borderline, or elevated levels of risk factors: cohort study based on longitudinal data from the Framingham Heart Study. AB - OBJECTIVE: To examine the association between risk factor burdens-categorized as optimal, borderline, or elevated-and the lifetime risk of atrial fibrillation. DESIGN: Community based cohort study. SETTING: Longitudinal data from the Framingham Heart Study. PARTICIPANTS: Individuals free of atrial fibrillation at index ages 55, 65, and 75 years were assessed. Smoking, alcohol consumption, body mass index, blood pressure, diabetes, and history of heart failure or myocardial infarction were assessed as being optimal (that is, all risk factors were optimal), borderline (presence of borderline risk factors and absence of any elevated risk factor), or elevated (presence of at least one elevated risk factor) at index age. MAIN OUTCOME MEASURE: Lifetime risk of atrial fibrillation at index age up to 95 years, accounting for the competing risk of death. RESULTS: At index age 55 years, the study sample comprised 5338 participants (2531 (47.4%) men). In this group, 247 (4.6%) had an optimal risk profile, 1415 (26.5%) had a borderline risk profile, and 3676 (68.9%) an elevated risk profile. The prevalence of elevated risk factors increased gradually when the index ages rose. For index age of 55 years, the lifetime risk of atrial fibrillation was 37.0% (95% confidence interval 34.3% to 39.6%). The lifetime risk of atrial fibrillation was 23.4% (12.8% to 34.5%) with an optimal risk profile, 33.4% (27.9% to 38.9%) with a borderline risk profile, and 38.4% (35.5% to 41.4%) with an elevated risk profile. Overall, participants with at least one elevated risk factor were associated with at least 37.8% lifetime risk of atrial fibrillation. The gradient in lifetime risk across risk factor burden was similar at index ages 65 and 75 years. CONCLUSIONS: Regardless of index ages at 55, 65, or 75 years, an optimal risk factor profile was associated with a lifetime risk of atrial fibrillation of about one in five; this risk rose to more than one in three a third in individuals with at least one elevated risk factor. PMID- 29699976 TI - NHS hospital drug costs are set to surpass spending in primary care. PMID- 29699977 TI - UK will explore net zero carbon emissions policy by 2050, says minister. PMID- 29699978 TI - Diagnostic value of ganglion cell-inner plexiform layer for early detection of ethambutol-induced optic neuropathy. AB - AIM: To evaluate the diagnostic value of macular ganglion cell-inner plexiform layer (mGCIPL) thickness versus peripapillary retinal nerve fibre layer (pRNFL) thickness for the early detection of ethambutol-induced optic neuropathy (EON). METHODS: Twenty-eight eyes of 15 patients in the EON group and 100 eyes of 53 healthy subjects in the control group were included. All patients with EON demonstrated the onset of visual symptoms within 3 weeks. Diagnostic power for pRNFL and mGCIPL thicknesses measured by Cirrus spectral-domain optical coherence tomography was assessed by area under the receiver operating characteristic (AUROC) curves and sensitivity. RESULTS: All of the mGCIPL thickness measurements were thinner in the EON group than in the control group in early EON (p<0.001). All of pRNFL thicknesses except inferior RNFL showed AUROC curves above 0.5, and all of the mGCIPL thicknesses showed AUROC curves above 0.5. The AUROC of the average mGCIPL (0.812) thickness was significantly greater than that of the average pRNFL (0.507) thickness (p<0.001). Of all the mGCIPL-related parameters considered, the minimum thickness showed the greatest AUROC value (0.863). The average mGCIPL thickness showed a weak correlation with visual field pattern standard deviations (r2=0.158, p<0.001). CONCLUSIONS: In challenging cases of EON, the mGCIPL thickness has better diagnostic performance in detecting early onset EON as compared with using pRNFL thickness. Among the early detection ability of mGCIPL thickness, minimum GCIPL thickness has high diagnostic ability. PMID- 29699979 TI - Changes in retinal ischaemic index correlate with recalcitrant macular oedema in retinal vein occlusion: WAVE study. AB - AIM: To evaluate changes in the ischaemic index (ISI) after targeted retinal photocoagulation (TRP) and to investigate the correlation between these changes and macular oedema (ME). METHOD: Twenty-four eyes of 24 patients with retinal vein occlusion (RVO) with recurrent ME were included. Ultra-widefield fluorescein angiography (UWFFA; Optos 200Tx) was obtained at baseline and every 4 months. The regions of retinal non-perfusion and the total gradable retina were manually segmented on UWFFA images for calculating the global ISI. ISI was also computed for specific regions defined by a standardised grid: perimacular area (PMA), near peripheral area (NPA), mid-peripheral area (MPA) and far-peripheral area (FPA). Global and regional ISIs and change in ISI over time were correlated with central macular thickness (CMT). RESULTS: The ISIs of entire retina, PMA, NPA, MPA and FPA at baseline were 30.5%+/-23.3, 17.7%+/-20.6, 21.9%+/-19.0, 33.0%+/-27.9 and 48.0%+/-32.9, respectively. The ISIs at final follow-up were 23.5%+/-19.9, 15.7%+/-22.2, 16.5%+/-16.7, 24.7%+/-24.7 and 24.7%+/-24.7, respectively. A significant correlation was found between CMT and global ISI during follow-up (r=0.22, p=0.03). Among the different retinal zones, PMA showed a correlation with CMT (r=0.27, p=0.007). The change in ISI for the total retina (Deltatotal), PMA (DeltaPMA) and NPA (DeltaNPA) retinal regions was positively correlated with the change in CMT (DeltaCMT) (r=0.45, 0.42 and 0.50, respectively, p=0.006, 0.009 and 0.002, respectively). CONCLUSION: The severity of ME was correlated with the ISIs of the entire retina and the PMA. The reduction in ME was correlated with the reduction in ISI of the entire retina as well as the ISIs for the NPA and PMA following TRP. The role of TRP, particularly to these regions (NPA, PMA), warrants further investigation in recalcitrant RVO-associated ME. PMID- 29699980 TI - Neuro-ophthalmological manifestations of Behcet's disease. AB - BACKGROUND: The neuro-ophthalmological manifestations of Behcet's disease (BD) are rare, and data regarding their characteristics and outcome are lacking. OBJECTIVE: To report prevalence, main characteristics and outcome of neuro ophthalmological manifestations in BD. PATIENTS AND METHODS: This is a retrospective monocentric study of 217 patients diagnosed with neuro-Behcet's disease (NBD), of whom 29 (13.3%) patients presented with neuro-ophthalmological manifestations (55% of men and mean+/-SD age of 26+/-8 years). All patients underwent a detailed ophthalmological examination and were followed up in the internal medicine and the ophthalmology departments. RESULTS: Neuro ophthalmological manifestations were the first presentation of BD in 45% of patients and developed later in the course of the disease in 55% of patients. They are divided into parenchymal (PM) and non-parenchymal (NPM)-related manifestations in, respectively, 13 patients (45%) and 16 patients (55%). PM included papillitis in seven patients (53.8%), retrobulbar optic neuritis in four patients (30.8%) and third cranial nerve palsy in two patients (15.4%). NPM included papilloedema related to cerebral venous thrombosis in all 16 patients, of whom 6 patients (37.5%) had sixth cranial nerve palsy. At initial examination, 93.1% of patients had visual alterations, including mainly decreased visual acuity visual field defects and/or diplopia. All patients were treated with corticosteroids and 79% of patients received immunosuppressive agents. After treatment, the visual outcome improved or stabilised in 66.7% of patients while it worsened in 33.3. The mean+/-SD logarithm of the minimum angle of resolution visual acuity improved from 0.4+/-0.3 at diagnosis to 0.2+/-0.3 after therapy. 10.3% and 3.4% of patients were legally blind at diagnosis and after therapy, respectively. CONCLUSION: Neuro-ophthalmological manifestations of BD represented 13% of NBD. They could be potentially severe and disabling. Prompt treatment is the key factor in improving visual outcome. PMID- 29699981 TI - Microaneurysm turnover is a predictor of diabetic retinopathy progression. AB - AIM: To analyse retinopathy phenotypes and microaneurysm (MA) turnover in mild non-proliferative diabetic retinopathy (NPDR) as predictors of progression to diabetic central-involved macular oedema (CIMO) in patients with type 2 diabetes mellitus (DM) in two different ethnic populations. METHODS: 205 patients with type 2 DM and mild NPDR were followed in a prospective observational study for 2 years or until development of CIMO, in two centres from different regions of the world. Ophthalmological examinations, including best-corrected visual acuity (BCVA), fundus photography with RetmarkerDR analysis, and optical coherence tomography (OCT), were performed at baseline and 6 12 and 24 months. RESULTS: 158 eyes/patients reached either the study endpoint, CIMO (24) or performed the last study visit (24-month visit) without developing CIMO (134). From the eyes/patients in analysis, 27 eyes (17.1%) progressed to more advanced ETDRS (Early Treatment Diabetic Retinopathy Study) levels: 6 progressed to mild NPDR (level 35), 15 progressed to moderate NPDR (level 43), 5 progressed to moderately severe NPDR (level 47) and 1 progressed to high risk PDR (level 71). Worsening in ETDRS level is associated with phenotype C (p=0.005). From the 130 eyes/patients with a low MA turnover, 18 (13.8%) eyes/patients had an increase in ETDRS level, and from the 19 eyes/patients with a high MA turnover, 9 (47.4%) had an increase in ETDRS level (p<0.001). CONCLUSION: Eyes in the initial stages of diabetic retinopathy show different phenotypes with different risks for progression to CIMO. In phenotype C, MA turnover correlates with ETDRS grading worsening and development of CIMO. PMID- 29699982 TI - Atypical epiretinal tissue in full-thickness macular holes: pathogenic and prognostic significance. AB - BACKGROUND: To elucidate the clinical characteristics of a full-thickness macular hole (FTMH) with atypical epiretinal tissue (AET), and expand the spectrum of pathogenesis of MH. METHODS: This study involved 225 consecutive eyes of 211 patients who underwent surgery for an idiopathic FTMH. Eyes were divided into two groups according to the presence of AET. Tomographic features at baseline, closure rate of the MH and visual outcomes were compared between the two groups. RESULTS: AET was detected in 26 (11.6%) among 225 eyes. Overall closure of the MH was noted in 92.3% of eyes with AET and 99.5% of eyes without AET at 12 months postoperatively (p=0.003). At 12 months postoperatively, the mean logarithm of the minimum angle of resolution visual acuity in eyes with and without AET was 0.38 and 0.21, respectively (p=0.046). At baseline, eyes with AET more frequently had splitting of the inner retina but fewer intact photoreceptors compared with eyes without AET (19.2% vs 2.5%, and 57.7% vs 89.9%, p<0.001, respectively). CONCLUSIONS: The presence of AET in an FTMH was related to poorer anatomical success and less visual recovery after surgery, suggesting that AET reflects a chronic pathogenic process involving more severe damage to the foveal tissue. PMID- 29699983 TI - Correspondence between retinotopic cortical mapping and conventional functional and morphological assessment of retinal disease. AB - PURPOSE: The present study describes retinotopic mapping of the primary visual cortex using functional MRI (fMRI) in patients with retinal disease. It addresses the relationship between fMRI data and data obtained by conventional assessment including microperimetry (MP) and structural imaging. METHODS: Initial testing involved eight patients with central retinal disease (Stargardt disease, STGD) and eight with peripheral retinal disease (retinitis pigmentosa, RP), who were examined using fMRI and MP (Nidek MP-1). All had a secure clinical diagnosis supported by electrophysiological data. fMRI used population-receptive field (pRF) mapping to provide retinotopic data that were then compared with the results of MP, optical coherence tomography and fundus autofluorescence imaging. RESULTS: Full analysis, following assessment of fMRI data reliability criteria, was performed in five patients with STGD and seven patients with RP; unstable fixation was responsible for unreliable pRF measurements in three patients excluded from final analysis. The macular regions in patients with STGD with central visual field defects and outer retinal atrophy (ORA) at the macula correlated well with pRF coverage maps showing reduced density of activated voxels at the occipital pole. Patients with RP exhibited peripheral ORA and concentric visual field defects both on MP and pRF mapping. Anterior V1 voxels, corresponding to peripheral regions, showed no significant activation. Correspondence between MP and pRF mapping was quantified by calculating the simple matching coefficient. CONCLUSION: Retinotopic maps acquired by fMRI provide a valuable adjunct in the assessment of retinal dysfunction. The addition of microperimetric data to pRF maps allowed better assessment of macular function than MP alone. Unlike MP, pRF mapping provides objective data independent of psychophysical perception from the patient. PMID- 29699984 TI - Prevalence of glaucoma in the Australian National Eye Health Survey. AB - AIM: To estimate the prevalence of glaucoma in Australia. METHODS: This was a population-based study of 3098 non-Indigenous Australians (50-98 years) and 1738 Indigenous Australians (40-92 years) stratified by remoteness. Each participant underwent a standard examination that included visual field assessment, tonometry and non-mydriatic fundus photography. Two fellowship-trained glaucoma specialists independently assessed relevant case notes (past ocular history, best-corrected visual acuity, frequency doubling technology visual fields, Van Herick grade, intraocular pressure and optic disc-centred photographs) and assigned a diagnosis ranked on a scale of certainty: none, possible, probable or definite glaucoma. RESULTS: A total of 4792 (99.1%, 3062 non-Indigenous and 1730 Indigenous) participants had retinal photographs in at least one eye that were gradable for glaucoma. The weighted prevalence of glaucoma (definite) in non-Indigenous Australians and Indigenous Australians was 1.5% (95% CI 1.0 to 2.2) and 0.6% (95% CI 0.4 to 1.1), respectively. When definite and probable cases of glaucoma were combined, rates were 3.4% (95% CI 2.7 to 4.3) among non-Indigenous and 1.6% (95% CI 1.1 to 2.3) in Indigenous Australians. Only 52.4% of non-Indigenous Australians and 28.0% of Indigenous Australians with glaucoma self-reported a known history of glaucoma. CONCLUSION: We estimate that 198 923 non-Indigenous Australians aged 50 years and over and 2139 Indigenous Australians aged 40 years and over have glaucoma. Given the high rates of undiagnosed glaucoma coupled with a significant ageing of the Australian population, improvements in case detection and access to low vision rehabilitation services may be required to cope with the growing burden of glaucoma. PMID- 29699985 TI - Global prevalence of visual impairment associated with myopic macular degeneration and temporal trends from 2000 through 2050: systematic review, meta analysis and modelling. AB - PURPOSE: We used systematic review and meta-analysis to identify and assimilate evidence quantifying blindness and visual impairment (VI) associated with myopic macular degeneration (MMD), then derived models to predict global patterns. The models were used to estimate the global prevalence of blindness and VI associated with MMD from 2000 to 2050. METHODS: The systematic review identified 17 papers with prevalence data for MMD VI fitting our inclusion criteria. Data from six papers with age-specific data were scaled to relative age-dependent risk and meta analysed at VI and blindness levels. We analysed variance in all MMD VI and blindness data as a proportion of high myopia against variables from the place and year of data collection, with a model based on health expenditure providing the best correlation. We used this model to estimate the prevalence and number of people with MMD VI in each country in each decade. RESULTS: We included data from 17 studies comprising 137 514 participants. We estimated 10.0 million people had VI from MMD in 2015 (prevalence 0.13%, 95% CI 5.5 to 23.7 million, 0.07% to 0.34%), 3.3 million of whom were blind (0.04%, 1.8 to 7.8 million, 0.03% to 0.10%). We estimate that by 2050, without changing current interventions, VI from MMD will grow to 55.7 million people (0.57%, 29.0 to 119.7 million, 0.33% to 1.11%), 18.5 million of whom will be blind (0.19%, 9.6 to 39.7 million, 0.11% to 0.37%). CONCLUSION: The burden of MMD blindness and VI will rise significantly without efforts to reduce the development and progression of myopia and improve the management of MMD. PMID- 29699986 TI - Resting nailfold capillary blood flow in primary open-angle glaucoma. AB - BACKGROUND/AIMS: An altered haemodynamic profile for various ocular posterior segment capillary beds has been documented in primary open-angle glaucoma (POAG). POAG may also involve abnormal non-ocular blood flow, and the nailfold capillaries, which are not affected by elevated intraocular pressure (IOP), are readily assessable. METHODS: We measured resting nailfold capillary blood flow in 67 POAG and 63 control subjects using video capillaroscopy. Masked readers tracked blood column voids between consecutive, registered image sequence frames, measured vessel diameter and calculated blood flow. We used multiple logistic regression to investigate the relation between nailfold capillary blood flow and POAG. In secondary analyses, we stratified cases by maximum IOP and concurrent topical beta-blocker use. RESULTS: Mean (+/-SD) blood flow in picolitres per second was 26.8+/-17.6 for POAG cases and 50.1+/-24.2 for controls (p<0.0001). After adjustment for demographic and clinical factors including blood pressure and pulse, every picolitre per second increase in resting nailfold blood flow was associated with a 6% (95% CI 0.92 to 0.96) reduced odds of POAG (p<0.0001). Similar relations between nailfold capillary blood flow and POAG were found for cases stratified by maximum known IOP and for cases stratified by concurrent topical beta-blocker use. CONCLUSION: Reduced resting nailfold capillary blood flow is present in POAG independent of covariates such as blood pressure, pulse and IOP. PMID- 29699988 TI - Lords condemn "wholly inadequate" delivery of government's life sciences strategy. PMID- 29699987 TI - Decreased expression of A20 is associated with ocular Behcet's disease (BD) but not with Vogt-Koyanagi-Harada (VKH) disease. AB - PURPOSE: A20 is a ubiquitously expressed and inducible cytosolic protein, which plays an important role in the negative regulation of inflammation and immunity. In this study, we investigated the role of A20 in Behcet's disease (BD) and Vogt Koyanagi-Harada (VKH) disease. METHODS: The levels of A20 in peripheral blood mononuclear cells (PBMCs) and dendritic cells (DCs) were detected in BD patients with active and inactive uveitis, VKH patients with active and inactive uveitis, and normal subjects, respectively, by real-time PCR. The effect of A20 silencing was performed by transduction of DCs with adenovirus containing an A20 shRNA vector. The effect of A20 silencing on the maturation of DCs was measured by flow cytometry. The effect of A20 silencing of DCs on cytokine production by DCs and CD4+ T cells was analysed by ELISA. The phosphorylation levels of JNK, p38 and ERK1/2 were detected by flow cytometry. RESULTS: The expression of A20 was markedly decreased in PBMCs and DCs obtained from BD patients with active uveitis, but not in patients with VKH disease as compared with normal controls. Silencing of A20 significantly increased the levels of interleukin (IL)-1beta and IL-6 and suppressed the expression of the anti-inflammatory cytokines IL-10 and IL-27. Downregulation of A20 also led to an increase in IL-17 production by CD4+ T cells. However, downregulation of A20 in DCs did not have an effect on cell surface markers such as CD40, CD80, CD83, CD86 and HLA-DR. Silencing of A20 caused an increased expression of phospho-JNK and phospho-MAPK p38 but not phospho-ERK1/2. CONCLUSIONS: This study showed that the expression of A20 was decreased in BD patients with active uveitis but not in VKH disease. Decreased expression of A20 may lead to an enhanced activation of proinflammatory Th17 cells, causing a reactivation of BD. PMID- 29699989 TI - Allogeneic hematopoietic stem cell transplantation for T-cell lymphomas. AB - Mature T- and natural killer (NK)-cell neoplasms comprise a group of morphologically, immunophenotypically, molecularly, and clinically heterogeneous disorders with generally unfavorable outcome. Results of first-line chemotherapy are unsatisfactory for the most common T-cell lymphomas (peripheral T-cell lymphoma, not otherwise specified; angioimmunoblastic T-cell lymphoma; anaplastic large cell lymphomas; anaplastic lymphoma tyrosine kinase-negative) as well as for many other entities. High-dose therapy followed by autologous hematopoietic stem cell transplantation (HSCT) is widely recommended for consolidation after a complete or partial remission is achieved. However, about one-third of patients never reach transplantation because of early relapse or refractoriness. Targeted therapies have recently been developed; combinations with chemotherapy may improve outcomes, but long-term results from prospective studies are largely missing. In this situation, allogeneic HSCT remains a valuable treatment option inducing long-lived remissions in about 30% to 50% of patients with relapsed and refractory T-cell lymphoma able to proceed to transplantation. Results of allogeneic transplantation for consolidation in first remission are less defined and its indications remain controversial. With growing evidence that haploidentical HSCT also works in lymphoma, more patients can be brought to transplantation. Decreasing the morbidity and mortality of allogeneic transplantation is a continuous challenge. Integrating new drugs into transplant concepts and setting up prospective studies involving allogeneic transplantation remain unmet needs that warrant urgent study in a group of disorders in which classical chemotherapy and new drugs have generated results, which are far from optimal until today. PMID- 29699991 TI - UK needs over 700 more paediatric consultants, says Royal College. PMID- 29699992 TI - Myo1f is critical for neutrophil migration in vivo. PMID- 29699993 TI - Ibrutinib: coming of age? PMID- 29699990 TI - TRAIL mediates and sustains constitutive NF-kappaB activation in LGL leukemia. AB - Large granular lymphocyte (LGL) leukemia results from clonal expansion of CD3+ cytotoxic T lymphocytes or CD3- natural killer (NK) cells. Chronic antigen stimulation is postulated to promote long-term survival of LGL leukemia cells through constitutive activation of multiple survival pathways, resulting in global dysregulation of apoptosis and resistance to activation-induced cell death. We reported previously that nuclear factor kappaB (NF-kappaB) is a central regulator of the survival network for leukemic LGL. However, the mechanisms that trigger constitutive activation of NF-kappaB in LGL leukemia remain undefined. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is known to induce apoptosis in tumor cells but can also activate NF-kappaB through interaction with TRAIL receptors 1, 2, and 4 (also known as DR4, DR5, and DcR2, respectively). The role of TRAIL has not been studied in LGL leukemia. In this study, we hypothesized that TRAIL interaction with DcR2 contributes to NF-kappaB activation in LGL leukemia. We observed upregulated TRAIL messenger RNA and protein expression in LGL leukemia cells with elevated levels of soluble TRAIL protein in LGL leukemia patient sera. We also found that DcR2 is the predominant TRAIL receptor in LGL leukemia cells. We demonstrated that TRAIL-induced activation of DcR2 led to increased NF-kappaB activation in leukemic LGL. Conversely, interruption of TRAIL-DcR2 signaling led to decreased NF-kappaB activation. Finally, a potential therapeutic application of proteasome inhibitors (bortezomib and ixazomib), which are known to inhibit NF-kappaB, was identified through their ability to decrease proliferation and increase apoptosis in LGL leukemia cell lines and primary patient cells. PMID- 29699994 TI - Ibrutinib and fungus: an invasive concern. PMID- 29699996 TI - EBV+ mucocutaneous ulcer: a new entity of WHO 2017. PMID- 29699997 TI - Plasma cell leukemia presenting as "lymphocytosis". PMID- 29699995 TI - A chance to cut (the genome) is a chance to cure. PMID- 29699998 TI - Data chart: what do trainees do after completing foundation training? PMID- 29699999 TI - Reducing outpatient activity does not cut costs. PMID- 29700000 TI - Restoring biomedical literature with RIAT. PMID- 29700001 TI - MVisAGe Identifies Concordant and Discordant Genomic Alterations of Driver Genes in Squamous Tumors. AB - Integrated analyses of multiple genomic datatypes are now common in cancer profiling studies. Such data present opportunities for numerous computational experiments, yet analytic pipelines are limited. Tools such as the cBioPortal and Regulome Explorer, although useful, are not easy to access programmatically or to implement locally. Here, we introduce the MVisAGe R package, which allows users to quantify gene-level associations between two genomic datatypes to investigate the effect of genomic alterations (e.g., DNA copy number changes on gene expression). Visualizing Pearson/Spearman correlation coefficients according to the genomic positions of the underlying genes provides a powerful yet novel tool for conducting exploratory analyses. We demonstrate its utility by analyzing three publicly available cancer datasets. Our approach highlights canonical oncogenes in chr11q13 that displayed the strongest associations between expression and copy number, including CCND1 and CTTN, genes not identified by copy number analysis in the primary reports. We demonstrate highly concordant usage of shared oncogenes on chr3q, yet strikingly diverse oncogene usage on chr11q as a function of HPV infection status. Regions of chr19 that display remarkable associations between methylation and gene expression were identified, as were previously unreported miRNA-gene expression associations that may contribute to the epithelial-to-mesenchymal transition.Significance: This study presents an important bioinformatics tool that will enable integrated analyses of multiple genomic datatypes. Cancer Res; 78(12); 3375-85. (c)2018 AACR. PMID- 29700002 TI - Zika Virus Selectively Kills Aggressive Human Embryonal CNS Tumor Cells In Vitro and In Vivo. AB - Zika virus (ZIKV) is largely known for causing brain abnormalities due to its ability to infect neural progenitor stem cells during early development. Here, we show that ZIKV is also capable of infecting and destroying stem-like cancer cells from aggressive human embryonal tumors of the central nervous system (CNS). When evaluating the oncolytic properties of Brazilian Zika virus strain (ZIKVBR) against human breast, prostate, colorectal, and embryonal CNS tumor cell lines, we verified a selective infection of CNS tumor cells followed by massive tumor cell death. ZIKVBR was more efficient in destroying embryonal CNS tumorspheres than normal stem cell neurospheres. A single intracerebroventricular injection of ZIKVBR in BALB/c nude mice bearing orthotopic human embryonal CNS tumor xenografts resulted in a significantly longer survival, decreased tumor burden, fewer metastasis, and complete remission in some animals. Tumor cells closely resembling neural stem cells at the molecular level with activated Wnt signaling were more susceptible to the oncolytic effects of ZIKVBR Furthermore, modulation of Wnt signaling pathway significantly affected ZIKVBR-induced tumor cell death and viral shedding. Altogether, these preclinical findings indicate that ZIKVBR could be an efficient agent to treat aggressive forms of embryonal CNS tumors and could provide mechanistic insights regarding its oncolytic effects.Significance: Brazilian Zika virus strain kills aggressive metastatic forms of human CNS tumors and could be a potential oncolytic agent for cancer therapy. Cancer Res; 78(12); 3363-74. (c)2018 AACR. PMID- 29700003 TI - Inhibition of the Wnt/beta-Catenin Pathway Overcomes Resistance to Enzalutamide in Castration-Resistant Prostate Cancer. AB - Enzalutamide is a second-generation nonsteroidal antiandrogen clinically approved for the treatment of castration-resistant prostate cancer (CRPC), yet resistance to endocrine therapy has limited its success in this setting. Although the androgen receptor (AR) has been associated with therapy failure, the mechanisms underlying this failure have not been elucidated. Bioinformatics analysis predicted that activation of the Wnt/beta-catenin pathway and its interaction with AR play a major role in acquisition of enzalutamide resistance. To validate the finding, we show upregulation of beta-catenin and AR in enzalutamide resistant cells, partially due to reduction of beta-TrCP-mediated ubiquitination. Although activation of the Wnt/beta-catenin pathway in enzalutamide-sensitive cells led to drug resistance, combination of beta-catenin inhibitor ICG001 with enzalutamide inhibited expression of stem-like markers, cell proliferation, and tumor growth synergistically in various models. Analysis of clinical datasets revealed a molecule pattern shift in different stages of prostate cancer, where we detected a significant correlation between AR and beta-catenin expression. These data identify activation of the Wnt/beta-catenin pathway as a major mechanism contributing to enzalutamide resistance and demonstrate the potential to stratify patients with high risk of said resistance.Significance: Wnt/beta catenin inhibition resensitizes prostate cancer cells to enzalutamide. Cancer Res; 78(12); 3147-62. (c)2018 AACR. PMID- 29700005 TI - Indole Propionic Acid: a Small Molecule Links between Gut Microbiota and Tuberculosis. PMID- 29700004 TI - PHF5A Epigenetically Inhibits Apoptosis to Promote Breast Cancer Progression. AB - Alternative splicing (AS) and its regulation play critical roles in cancer, yet the dysregulation of AS and its molecular bases in breast cancer development have not yet been elucidated. Using an in vivo CRISPR screen targeting RNA-binding proteins, we identified PHD finger protein 5A (PHF5A) as a key splicing factor involved in tumor progression. PHF5A expression was frequently upregulated in breast cancer and correlated with poor survival, and knockdown of PHF5A significantly suppressed cell proliferation, migration, and tumor formation. PHF5A was required for SF3b spliceosome stability and linked the complex to histones, and the PHF5A-SF3b complex modulated AS changes in apoptotic signaling. In addition, expression of a short truncated FAS-activated serine/threonine kinase (FASTK) protein was increased after PHF5A ablation and facilitated Fas mediated apoptosis. This PHF5A-modulated FASTK-AS axis was widely present in breast cancer specimens, particularly those of the triple-negative subtype. Taken together, our findings reveal that PHF5A serves as an epigenetic suppressor of apoptosis and thus provides a mechanistic basis for breast cancer progression and may be a valuable therapeutic target.Significance: This study provides an epigenetic mechanistic basis for the aggressive biology of breast cancer and identifies a translatable therapeutic target. Cancer Res; 78(12); 3190-206. (c)2018 AACR. PMID- 29700006 TI - Erratum for Fang et al., "High Genetic Plasticity in Multidrug-Resistant Sequence Type 3-IncHI2 Plasmids Revealed by Sequence Comparison and Phylogenetic Analysis". PMID- 29700007 TI - Abnormal clotting of the intrinsic/contact pathway in Alzheimer disease patients is related to cognitive ability. AB - Alzheimer disease (AD) is a neurodegenerative disorder characterized by extracellular beta-amyloid (Abeta) deposition. Although peripheral inflammation and cerebrovascular pathology are reported in AD, there is a lack of plasma biomarkers in this field. Because the contact system is triggered in patient plasma, we hypothesized that the hemostasis profile could be a novel biomarker in AD. Here, we assessed the clotting profile in plasma from AD patients and age matched controls. Utilizing clinically relevant assays, thromboelastography and activated partial thromboplastin time, we found impaired clot initiation and formation rate in AD patient plasma. These coagulation end points correlated with cerebrospinal fluid neurofilament-light levels and cognition and were more profound in younger AD patients. Ex vivo intrinsic clotting of plasma from AD mice expressing human amyloid precursor protein (APP) was also delayed in an age dependent manner, suggesting that this phenotype is related to APP, the parent protein of Abeta. Further analysis of coagulation factors in human plasma indicated that endogenous inhibitor(s) of factors XII and XI in AD plasma contribute to this delayed clotting. Together, these data suggest that delayed clotting in young AD patients is a novel biomarker and that therapies aimed to correct this phenotype might be beneficial in this patient population. Follow-up studies in additional AD patient cohorts are warranted to further evaluate these findings. PMID- 29700008 TI - Smoking and Prostate Cancer-Specific Mortality after Diagnosis in a Large Prospective Cohort. AB - Background: Prior studies of prostate cancer survivors suggest that smoking might be associated with higher prostate cancer-specific mortality (PCSM) after diagnosis with prostate cancer. However, most of these studies were small, and questions remain regarding this association's strength and whether it persists after adjustment for stage and Gleason score.Methods: This analysis included men diagnosed with nonmetastatic prostate cancer between enrollment in the Cancer Prevention Study II Nutrition Cohort in 1992-1993 and June 2013. Cigarette smoking was self-reported at enrollment and updated in 1997 and every 2 years thereafter. Analyses of pre-diagnosis and post-diagnosis smoking included 9,781 and 9,111 prostate cancer cases, respectively, with vital status follow-up through 2014.Results: There were 672 deaths from prostate cancer in analyses of pre-diagnosis smoking and 554 in analyses of post-diagnosis smoking. In multivariable-adjusted Cox proportional hazards regression models including stage and Gleason score, both current smoking before diagnosis [HR = 1.50; 95% confidence interval (CI), 1.06-2.13] and current smoking after diagnosis (HR = 1.71; 95% CI, 1.09-2.67) were associated with higher PCSM compared to never smoking. Prostate cancer survivors who quit smoking <20 years before diagnosis were also at significantly higher risk of PCSM (HR = 1.29; 95% CI, 1.04 1.61).Conclusions: This large prospective study suggests that current smoking both before and after diagnosis of prostate cancer is associated with higher PCSM, even after accounting for stage and Gleason score.Impact: Our results provide evidence that smoking is a relevant prognostic factor for prostate cancer patients and that prostate cancer may be among the causes of death attributable to smoking. Cancer Epidemiol Biomarkers Prev; 27(6); 665-72. (c)2018 AACR. PMID- 29700009 TI - Human Papillomavirus Seroprevalence and Association with Anal HPV Infection and Squamous Intraepithelial Lesions in Australian Gay and Bisexual Men. AB - Background: Gay and bisexual men (GBM) are at disproportionately high risk of anal cancer. The precursor lesions, high-grade squamous intraepithelial lesions (HSIL), are very common and it is evident that not all HSIL progresses to cancer. The serologic response to anal human papillomavirus (HPV) in GBM has not been well characterized.Methods: The Study of the Prevention of Anal Cancer is an ongoing cohort study of GBM ages 35 years and older. At six visits over three years, anal samples are collected for cytology, HPV DNA testing, and histology. Baseline serum was tested for HPV L1, E6, and E7 antibodies for 10 HPV types. Seroprevalence and associated predictors were analyzed.Results: A total of 588 of 617 participants were included in this analysis. A total of 436 (74.2%) were seropositive for at least one of the 10 HPV types. Almost half had L1 antibodies to HPV6 (48.5%), over a third to HPV11 (36.4%) and HPV16 (34.5%). HIV-positive men were more likely to be HPV L1 seropositive. HSIL detection was highest among participants who were HPV serology and DNA positive. There was a borderline significant association between presence of HPV16 E6 antibodies and prevalent HSIL (OR = 2.97; 95% confidence interval, 0.92-9.60; P = 0.068).Conclusions: HPV L1 seropositivity was common in this cohort of older GBM. These results suggest that HPV L1 seropositivity, in conjunction with anal HPV DNA detection, predicts concurrent HSIL. The apparent association between HPV16 E6 antibodies and prevalent HSIL is a finding with potential clinical significance that needs further exploration.Impact: HPV seropositivity with concurrent DNA detection predicted anal HSIL detection. Cancer Epidemiol Biomarkers Prev; 27(7); 768-75. (c)2018 AACR. PMID- 29700010 TI - Elevated Hemoglobin A1c Is Associated With Incident Diabetes Within 4 Years Among Normoglycemic, Working-Age Individuals in an Employee Wellness Program. PMID- 29700011 TI - An Investigation of Drug-Drug Interaction Alert Overrides at a Pediatric Hospital. AB - OBJECTIVES: Drug-drug interactions (DDIs) can result in patient harm. DDI alerts are intended to help prevent harm; when the majority of alerts presented to providers are being overridden, their value is diminished. Our objective was to evaluate the overall rates of DDI alert overrides and how rates varied by specialty, clinician type, and patient complexity. METHODS: A retrospective study of DDI alert overrides that occurred during 2012 and 2013 within the inpatient setting described at the medication-, hospital-, provider-, and patient encounter specific levels was performed at an urban, quaternary-care, pediatric hospital. RESULTS: There were >41 000 DDI alerts presented to clinicians; ~90% were overridden. The 5 DDI pairs that were most frequently presented and overridden included the following: potassium chloride-spironolactone, methadone-ondansetron, ketorolac-ibuprofen, cyclosporine-fluconazole, and potassium chloride-enalapril, each with an alert override rate of >=0.89. Override rates across provider groups ranged between 0.84 and 0.97. In general, patients with high complexity had a higher frequency of alert overrides, but the rates of alert overrides for each DDI pairing did not differ significantly. CONCLUSIONS: High rates of DDI alert overrides occur across medications, provider groups, and patient encounters. Methods to decrease DDI alerts which are likely to be overridden exist, but it is also clear that more robust and intelligent tools are needed. Characteristics exist at the medication, hospital, provider, and patient levels that can be used to help specialize and enhance information transmission. PMID- 29700014 TI - Seven days in medicine: 18-24 April 2018. PMID- 29700012 TI - Cellular kinetics of MED12-mutant uterine leiomyoma growth and regression in vivo. AB - Cellular mechanisms of uterine leiomyoma (LM) formation have been studied primarily utilizing in vitro models. However, recent studies established that the cells growing in the primary cultures of MED12-mutant LM (MED12-LM) do not carry causal mutations. To improve the accuracy of LM research, we addressed the cellular mechanisms of LM growth and regression utilizing a patient-derived xenograft (PDX) model, which faithfully replicates the patient tumors in situ The growth and maintenance of MED12-LMs depend on 17beta-estradiol (E2) and progesterone (P4). We determined E2 and P4-activated MAPK and PI3K pathways in PDXs with upregulation of IGF1 and IGF2, suggesting that the hormone actions on MED12-LM are mediated by the IGF pathway. When hormones were removed, MED12-LM PDXs lost approximately 60% of volume within 3 days through reduction in cell size. However, in contrast to general belief, the survival of LM cells was independent of E2 and/or P4, and apoptosis was not involved in the tumor regression. Furthermore, it was postulated that abnormal collagen fibers promote the growth of LMs. However, collagen fibers of actively growing PDXs were well aligned. The disruption of collagen fibers, as found in human LM specimens, occurred only when the volume of PDXs had grown to over 20 times the volume of unstimulated PDXs, indicating disruption is the result of growth not the cause. Hence, this study revises generally accepted theories on the growth and regression of LMs. PMID- 29700013 TI - Dynamic human immune and tumour cells cross-talk in PDX-humanised mice warrants checkpoint inhibitor cancer immunotherapies assessment. PMID- 29700015 TI - Getting It. PMID- 29700016 TI - The discipline of general practice: recognition and teaching. PMID- 29700017 TI - Safety netting: now doctors need it too. PMID- 29700018 TI - A new model of undergraduate clinical education? PMID- 29700019 TI - GPs: working harder than ever. PMID- 29700020 TI - Cancer and the heart. PMID- 29700021 TI - Information flow to enable integrated health care: integration or interoperability. PMID- 29700023 TI - Heart age woes: unnecessarily testing. PMID- 29700022 TI - Making technology-enabled health care work in general practice. PMID- 29700024 TI - Screening for thyroid dysfunction in patients with diabetes. PMID- 29700025 TI - Dare to think rare: diagnostic delay and rare diseases. PMID- 29700026 TI - Bad Medicine. PMID- 29700027 TI - Evidence-based physical examination and point-of-care testing to improve patient care and avoid unnecessary hospital admission. PMID- 29700028 TI - Viewpoint: Primary care in Iran needs a paradigm shift. PMID- 29700029 TI - Interview: Sir Terence Stephenson; paediatrician and Chair of the GMC. PMID- 29700030 TI - Yonder: Chronic pain, asthma, obstructive sleep apnoea, and methadone prescribing. PMID- 29700031 TI - The health needs of asylum-seeking children. PMID- 29700032 TI - Bad Medicine: Reassurance? PMID- 29700033 TI - Books: Blinded by Science: The Social Implications of Epigenetics and Neuroscience: Perfecting People. PMID- 29700034 TI - Books: More Harm than Good? The Moral Maze of Complementary and Alternative Medicine: A Drop in the Ocean. PMID- 29700035 TI - Two tasks. PMID- 29700036 TI - Polycystic ovarian syndrome: overdiagnosed and overtreated? PMID- 29700037 TI - Polycystic ovarian syndrome: an under-recognised problem? PMID- 29700038 TI - The GP workforce pipeline: increasing the flow and plugging the leaks. PMID- 29700039 TI - Nose and sinus tumours: red flags and referral. PMID- 29700040 TI - Idiopathic pulmonary fibrosis: a clinical update. PMID- 29700041 TI - Electronic Cigarette Prevalence and Patterns of Use in Adults with a History of Cardiovascular Disease in the United States. AB - BACKGROUND: Characterizing electronic cigarette (e-cigarette) use patterns is important for guiding tobacco regulatory policy and projecting the future burden of tobacco-related diseases. Few studies have examined patterns of e-cigarette use in individuals with cardiovascular disease (CVD). METHODS AND RESULTS: We examined e-cigarette use in adults aged 18 to 89 years with a history of CVD, using data from the 2014 National Health Interview Survey. We investigated associations between ever and current e-cigarette use and smoking with multivariable logistic regression. In a secondary analysis, we modeled the association between e-cigarette use and a quit attempt over the past year. Former smokers with CVD who quit smoking within the past year showed 1.85 (95% confidence interval, 1.03, 3.33) times the odds of having ever used e-cigarettes as compared with those who reported being "some days" current smokers. Current smokers who attempted to quit smoking within the past year showed significantly increased odds of ever having used e-cigarettes (odds ratio, 1.70; 95% confidence interval, 1.25, 2.30) and currently using e-cigarettes (odds ratio, 1.97; 95% confidence interval, 1.32, 2.95) as compared with smokers who had not attempted to quit over the past year. CONCLUSIONS: Individuals with CVD who recently quit smoking or reported a recent quit attempt were significantly more likely to use e cigarettes than current smokers and those who did not report a quit attempt. Our findings may indicate that this population is using e-cigarettes as an aid to smoking cessation. Characterizing emerging e-cigarette use behaviors in adults with CVD may help to inform outreach activities aimed at this high-risk population. PMID- 29700042 TI - Long-Term Effects of Ambient Particulate Matter (With an Aerodynamic Diameter <=2.5 MUm) on Hypertension and Blood Pressure and Attributable Risk Among Reproductive-Age Adults in China. AB - BACKGROUND: Epidemiological evidence on the association between long-term exposure to ambient fine particulate matter (with an aerodynamic diameter <=2.5 MUm; PM2.5) and hypertension is mixed. We investigated the long-term association between ambient fine particles and hypertension in reproductive-age adults. METHODS AND RESULTS: This analysis included 39 348 119 reproductive-age (20-49 years) participants from the National Free Preconception Health Examination Project from April 22, 2010 to December 31, 2015 across China. The estimation of annual average ambient PM2.5 concentrations for each community was realized through using satellite-based spatial statistical models. Linear mixed models and 2-level logistic regressions adjusted for potential confounders with natural cubic splines were used to investigate the shape of PM2.5-blood pressure and PM2.5-hypertension, respectively. The effect modification by sex, obesity, smoking status, age, diabetes mellitus, urbanity, race, and region was also taken into account. The concentration-response relationship between PM2.5 and hypertension was nonlinear, with a threshold concentration of 47.9 MUg/m3. The odds ratio of hypertension related to a 10-MUg/m3 increase in PM2.5 above threshold was 1.010 (95% confidence interval, 1.007-1.012). A 10-MUg/m3 increase in PM2.5 above threshold corresponded to a 0.569 (95% confidence interval, 0.564 0.573) mm Hg elevation in systolic blood pressure and a 0.384 (95% confidence interval, 0.381-0.388) mm Hg elevation in diastolic blood pressure. There were 2.3% (95% confidence interval, 2.2%-2.4%) of the hypertension cases that could be attributed to PM2.5 exposures in reproductive-age adult populations. CONCLUSIONS: Long-term exposures to PM2.5 above certain levels might increase population risk for hypertension and might be responsible for China's avoidable hypertension burden in reproductive-age adults. PMID- 29700043 TI - Enhancement of red blood cell transfusion compatibility using CRISPR-mediated erythroblast gene editing. AB - Regular blood transfusion is the cornerstone of care for patients with red blood cell (RBC) disorders such as thalassaemia or sickle-cell disease. With repeated transfusion, alloimmunisation often occurs due to incompatibility at the level of minor blood group antigens. We use CRISPR-mediated genome editing of an immortalised human erythroblast cell line (BEL-A) to generate multiple enucleation competent cell lines deficient in individual blood groups. Edits are combined to generate a single cell line deficient in multiple antigens responsible for the most common transfusion incompatibilities: ABO (Bombay phenotype), Rh (Rhnull), Kell (K0), Duffy (Fynull), GPB (S-s-U-). These cells can be differentiated to generate deformable reticulocytes, illustrating the capacity for coexistence of multiple rare blood group antigen null phenotypes. This study provides the first proof-of-principle demonstration of combinatorial CRISPR mediated blood group gene editing to generate customisable or multi-compatible RBCs for diagnostic reagents or recipients with complicated matching requirements. PMID- 29700044 TI - Dark Rims: Novel Sequence Enhances Diagnostic Specificity in Multiple Sclerosis. AB - BACKGROUND AND PURPOSE: The 2010 McDonald criteria are designed to sensitively detect MS; however, the low specificity of these criteria can occasionally lead to the misdiagnosis of MS. The purpose of this study was to determine whether a novel double inversion recovery MR imaging technique has the potential to increase the specificity of diagnostic criteria distinguishing MS from non-MS white matter lesions. MATERIALS AND METHODS: This was a cross-sectional observational study. MR imaging data were acquired between 2011 and 2016. A novel double inversion recovery sequence that suppresses CSF and GM signal was used (GM double inversion recovery). We compared WM lesions in a group of patients with multiple sclerosis and in a second group of positive controls with white matter lesions who did not have a diagnosis of MS. The presence of a rim on the GM double inversion recovery MR imaging sequence was combined with the 2001 and 2010 McDonald disseminated-in-space criteria. Multiple MR imaging markers, including lesion location, size, and the presence of a rim, were compared between groups as well as a quantitative measure of lesion T1 hypointensity. RESULTS: MR images from 107 patients with relapsing-remitting MS (median age, 32 years) and 36 positive control (median age, 39 years) subjects were analyzed. No significant differences were found in age and sex. In patients with MS, 1120/3211 lesions (35%) had a rim on GM-double inversion recovery; the positive control group had only 9/893 rim lesions (1%). Rims were associated with a decrease in the lesion T1 ratio. Using the 2010 MR imaging criteria plus the presence of rims on GM double inversion recovery, we achieved 78% and 97% specificity in subjects with >=1 and >=2 rim lesions, respectively. CONCLUSIONS: The addition of a novel GM double inversion recovery technique enhanced specificity for diagnosing MS compared with established MR imaging criteria. PMID- 29700045 TI - Diffusion-Weighted Zonal Oblique Multislice-EPI Enhances the Detection of Small Lesions with Diffusion Restriction in the Brain Stem and Hippocampus: A Clinical Report of Selected Cases. AB - Diffusion restriction is the morphologic hallmark of acute ischemic infarcts and excitotoxic brain injury in various cerebral pathologies. Diffusion restriction is visible as hyperintensity on DWI and as hypointensity on ADC maps. Due to the vicinity of multiple anatomic structures in the brain stem and hippocampus, very small lesions with diffusion restriction may result in severe clinical symptomatology, but these small lesions easily go undetected on standard cerebral DWI due to insufficient spatial resolution, T2* blurring, and image artifacts caused by susceptibility-related image distortions. Diffusion-weighted zonal oblique multislice-EPI with reduced FOV acquisition permits a considerable increase in spatial resolution and enhances the visualization of very small pathologic lesions in the brain stem and hippocampus. Improved performance in the depiction of different pathologic lesions with diffusion restriction in the brain stem and hippocampus using this sequence compared with standard DWI in selected cases is presented. PMID- 29700046 TI - Common Origin of Brachiocephalic and Left Common Carotid Arteries: Proposal of New Terminology. PMID- 29700047 TI - Multicentric Experience in Distal-to-Proximal Revascularization of Tandem Occlusion Stroke Related to Internal Carotid Artery Dissection. AB - BACKGROUND AND PURPOSE: Internal carotid dissection is a frequent cause of ischemic stroke in young adults. It may cause tandem occlusions in which cervical carotid obstruction is associated with intracranial proximal vessel occlusion. To date, no consensus has emerged concerning endovascular treatment strategy. Our aim was to evaluate our endovascular "distal-to-proximal" strategy in the treatment of this stroke subtype in the first large multicentric cohort. MATERIALS AND METHODS: Prospectively managed stroke data bases from 2 separate centers were retrospectively studied between 2009 and 2014 for records of tandem occlusions related to internal carotid dissection. Atheromatous tandem occlusions were excluded. The first step in the revascularization procedure was intracranial thrombectomy. Then, cervical carotid stent placement was performed depending on the functionality of the circle of Willis and the persistence of residual cervical ICA occlusion, severe stenosis, or thrombus apposition. Efficiency, complications, and radiologic and clinical outcomes were recorded. RESULTS: Thirty-four patients presenting with tandem occlusion stroke secondary to internal carotid dissection were treated during the study period. The mean age was 52.5 years, the mean initial NIHSS score was 17.29 +/- 6.23, and the mean delay between onset and groin puncture was 3.58 +/- 1.1 hours. Recanalization TICI 2b/3 was obtained in 21 cases (62%). Fifteen patients underwent cervical carotid stent placement. There was no recurrence of ipsilateral stroke in the nonstented subgroup. Twenty-one patients (67.65%) had a favorable clinical outcome after 3 months. CONCLUSIONS: Endovascular treatment of internal carotid dissection-related tandem occlusion stroke using the distal-to-proximal recanalization strategy appears to be feasible, with low complication rates and considerable rates of successful recanalization. PMID- 29700048 TI - Segmentation of the Globus Pallidus Internus Using Probabilistic Diffusion Tractography for Deep Brain Stimulation Targeting in Parkinson Disease. AB - BACKGROUND AND PURPOSE: Although globus pallidus internus deep brain stimulation is a widely accepted treatment for Parkinson disease, there is persistent variability in outcomes that is not yet fully understood. In this pilot study, we aimed to investigate the potential role of globus pallidus internus segmentation using probabilistic tractography as a supplement to traditional targeting methods. MATERIALS AND METHODS: Eleven patients undergoing globus pallidus internus deep brain stimulation were included in this retrospective analysis. Using multidirection diffusion-weighted MR imaging, we performed probabilistic tractography at all individual globus pallidus internus voxels. Each globus pallidus internus voxel was then assigned to the 1 ROI with the greatest number of propagated paths. On the basis of deep brain stimulation programming settings, the volume of tissue activated was generated for each patient using a finite element method solution. For each patient, the volume of tissue activated within each of the 10 segmented globus pallidus internus regions was calculated and examined for association with a change in the Unified Parkinson Disease Rating Scale, Part III score before and after treatment. RESULTS: Increasing volume of tissue activated was most strongly correlated with a change in the Unified Parkinson Disease Rating Scale, Part III score for the primary motor region (Spearman r = 0.74, P = .010), followed by the supplementary motor area/premotor cortex (Spearman r = 0.47, P = .15). CONCLUSIONS: In this pilot study, we assessed a novel method of segmentation of the globus pallidus internus based on probabilistic tractography as a supplement to traditional targeting methods. Our results suggest that our method may be an independent predictor of deep brain stimulation outcome, and evaluation of a larger cohort or prospective study is warranted to validate these findings. PMID- 29700049 TI - Consensus Needed for Noncontrast CT Markers in Intracerebral Hemorrhage. PMID- 29700050 TI - REPLY. PMID- 29700051 TI - Is Gd-DTPA Necessary in Clinical Practice for Peripheral Nerve Injury? PMID- 29700052 TI - Changes in recreational drug use, drug use associated with chemsex, and HIV related behaviours, among HIV-negative men who have sex with men in London and Brighton, 2013-2016. AB - OBJECTIVES: The objective of this study was to compare the prevalence of polydrug use, use of drugs associated with chemsex, specific drug use, and HIV-related behaviours, between two time periods, using two groups of HIV-negative men who have sex with men (MSM) attending the same sexual health clinics in London and Brighton, in two consecutive periods of time from 2013 to 2016. METHODS: Data from MSM in the cross-sectional Attitudes to and Understanding Risk of Acquisition of HIV (AURAH) study (June 2013 to September 2014) were compared with baseline data from different MSM in the prospective cohort study Attitudes to and Understanding Risk of Acquisition of HIV over Time (AURAH2) (November 2014 to April 2016). Prevalence of polydrug use, drug use associated with chemsex and specific drug use, and 10 measures of HIV-related behaviours including condomless sex, post-exposure prophylaxis (PEP) use, pre-exposure prophylaxis (PrEP) use, and HIV testing, were compared. Prevalence ratios (PRs) for the association of the study (time period) with drug use and HIV-related behaviour measures were estimated using modified Poisson regression analysis, unadjusted and adjusted for sociodemographic factors. RESULTS: In total, 991 MSM were included from AURAH and 1031 MSM from AURAH2. After adjustment for sociodemographic factors, use of drugs associated with chemsex had increased (adjusted PR (aPR) 1.30, 95% CI 1.11 to 1.53) and there were prominent increases in specific drug use; in particular, mephedrone (aPR 1.32, 95% CI 1.10 to 1.57), gamma-hydroxybutyric/gamma butryolactone (aPR 1.47, 95% CI 1.15 to 1.87) and methamphetamine (aPR 1.42, 95% CI 1.01 to 2.01). Use of ketamine had decreased (aPR 0.54, 95% CI 0.38 to 0.78). Certain measures of HIV-related behaviours had also increased, most notably PEP use (aPR 1.50, 95% CI 1.21 to 1.88) and number of self-reported bacterial STI diagnoses (aPR 1.24, 95% CI 1.08 to 1.43). CONCLUSIONS: There have been significant increases in drug use associated with chemsex and some measures of HIV-related behaviours among HIV-negative MSM in the last few years. Changing patterns of drug use and associated behaviours should be monitored to enable sexual health services to plan for the increasingly complex needs of some clients. PMID- 29700053 TI - TK Inhibitor Pazopanib Primes DCs by Downregulation of the beta-Catenin Pathway. AB - Tyrosine kinase inhibitors (TKIs) target angiogenesis by affecting, for example, the VEGF receptors in tumors and have improved outcomes for patients with metastatic renal cell carcinoma (mRCC). Immune checkpoint inhibitors (ICIs) have also been proposed for treatment of mRCC with encouraging results. A better understanding of the activity of immune cells in mRCC, the immunomodulatory effects of TKIs, and the characteristics defining patients most likely to benefit from various therapies will help optimize immunotherapeutic approaches. In this study, we investigated the influence of the TKI pazopanib on dendritic cell (DC) performance and immune priming. Pazopanib improved DC differentiation and performance by promoting upregulation of the maturation markers HLA-DR, CD40, and CCR7; decreasing IL10 production and endocytosis; and increasing T-cell proliferation. PD-L1 expression was also downregulated. Our results demonstrate that pazopanib inhibits the Erk/beta-catenin pathway, suggesting this pathway might be involved in increased DC activation. Similar results were confirmed in DCs differentiated from mRCC patients during pazopanib treatment. In treated patients pazopanib appeared to enhance a circulating CD4+ T-cell population that expresses CD137 (4-1BB). These results suggest that a potentially exploitable immunomodulatory effect induced by pazopanib could improve responses of patients with mRCC in customized protocols combining TKIs with ICI immunotherapy. Cancer Immunol Res; 6(6); 711-22. (c)2018 AACR. PMID- 29700054 TI - Ventricular Electrical Delay Measured From Body Surface ECGs Is Associated With Cardiac Resynchronization Therapy Response in Left Bundle Branch Block Patients From the MADIT-CRT Trial (Multicenter Automatic Defibrillator Implantation Cardiac Resynchronization Therapy). AB - BACKGROUND: Although cardiac resynchronization therapy (CRT) is beneficial in heart failure patients with left bundle branch block, 30% of these patients do not respond to the therapy. Identifying these patients before implantation of the device is one of the current challenges in clinical cardiology. METHODS: We verified the diagnostic contribution and an optimized computerized approach to measuring ventricular electrical activation delay (VED) from body surface 12-lead ECGs. We applied the method to ECGs acquired before implantation (baseline) in the MADIT-CRT trial (Multicenter Automatic Defibrillator Implantation-Cardiac Resynchronization Therapy). VED values were dichotomized using its quartiles, and we tested the association of VED values with the MADIT-CRT primary end point of heart failure or death. Multivariate Cox proportional models were used to estimate the risk of study end points. In addition, the association between VED values and hemodynamic changes after CRT-D implantation was examined using 1-year follow-up echocardiograms. RESULTS: Our results showed that left bundle branch block patients with baseline VED <31.2 ms had a 35% risk of MADIT-CRT end points, whereas patients with VED >=31.2 ms had a 14% risk (P<0.001). The hazard ratio for predicting primary end points in patients with low VED was 2.34 (95% confidence interval, 1.53-3.57; P<0.001). Higher VED values were also associated with beneficial hemodynamic changes. These strong VED associations were not found in the right bundle branch block and intraventricular conduction delay cohorts of the MADIT-CRT trial. CONCLUSIONS: Left bundle branch block patients with a high baseline VED value benefited most from CRT, whereas left bundle branch block patients with low VED did not show CRT benefits. PMID- 29700055 TI - Hot Balloon Versus Cryoballoon Ablation for Atrial Fibrillation: Lesion Characteristics and Middle-Term Outcomes. AB - BACKGROUND: Hot balloon ablation (HBA) and cryoballoon ablation (CBA) were developed to simplify ablation for atrial fibrillation. Because the lesion characteristics and efficacy of these balloon modalities have not been clarified, we compared lesion characteristics and outcomes of HBA and CBA. METHODS: Of 165 consecutive patients who underwent initial catheter ablation for atrial fibrillation, 74 propensity scorematched (37 HBA and 37 CBA) patients were included in our study. RESULTS: Patients' clinical characteristics, including age, sex, body mass index, atrial fibrillation subtype, CHA2DS2-VASc score, and left atrial dimension, were similar between the 2 groups. Touch-up radiofrequency ablation was required for residual/dormant pulmonary vein conduction in 52% of the patients with HBA versus 24% of the patients with CBA (P=0.02) and often in the anterior aspect of the left superior pulmonary vein after HBA (41%) versus the inferior aspect of the inferior pulmonary veins after CBA (22%). HBA lesions were smaller than CBA lesions (23.8+/-7.9 versus 33.5+/-14.5 cm2; P=0.0007). Similar results were observed when lesions in each pulmonary vein were compared between groups. Twentyfour hours after the procedure, serum levels of the cardiac biomarkers, including troponin-T, creatine kinase, and creatine kinase-MB, were higher in the HBA group than in the CBA group. Atrial fibrillation recurrence did not differ between the groups within 6 (3% versus 11%; P=0.36) or 12 months (16% versus 16%; P=1.00). CONCLUSIONS: Although HBA lesions appear to be smaller than CBA lesions, middle-term outcomes are not statistically different between these balloon modalities. PMID- 29700056 TI - Ablation of the Ligament of Marshall and Left Stellate Ganglion Similarly Reduces Ventricular Arrhythmias During Acute Myocardial Infarction. AB - BACKGROUND: Sympathetic denervation exerts protective effects against ventricular arrhythmias (VAs) induced by acute myocardial infarction. The results of a previous study indicated that the distal part of the ligament of Marshall (LOMLSPV) might be a sympathetic conduit between the left stellate ganglion (LSG) and the ventricles. The present study was designed to compare the effects between LSG and LOMLSPV ablation on ischemia-induced VAs. METHODS: Twenty-nine dogs were randomly divided into sham ablation group (group 1, n=9), LOMLSPV ablation group (group 2, n=10), and LSG ablation group (group 3, n=10). Ablation was performed before occlusion of the left anterior coronary artery. Changes in the heart rate variability, serum norepinephrine, ventricular effective refractory period, and blood pressure induced by LSG stimulation were observed, and the occurrence of VAs was recorded. Immunostaining examinations of LOMLSPV were performed in dogs without ablation. RESULTS: In group 2, LOMLSPV ablation evidently attenuated blood pressure elevation induced by LSG stimulation. Both LOMLSPV ablation and LSG ablation similarly prolonged ventricular effective refractory period and reduced the concentration of serum norepinephrine, the sympathetic index of heart rate variability, and the incidence of VAs compared with sham ablation. Abundant sympathetic nerve fibers were observed in LOMLSPV. CONCLUSIONS: LOMLSPV ablation prevented acute myocardial infarction-induced VAs with the same efficiency as LSG ablation, potentially by blocking the sympathetic pathway from the LSG to the heart. PMID- 29700057 TI - How Accurate Is Inverse Electrocardiographic Mapping? A Systematic In Vivo Evaluation. AB - BACKGROUND: Inverse electrocardiographic mapping reconstructs cardiac electrical activity from recorded body surface potentials. This noninvasive technique has been used to identify potential ablation targets. Despite this, there has been little systematic evaluation of its reliability. METHODS: Torso and ventricular epicardial potentials were recorded simultaneously in anesthetized, closed-chest pigs (n=5), during sinus rhythm, epicardial, and endocardial ventricular pacing (70 records in total). Body surface and cardiac electrode positions were determined and registered using magnetic resonance imaging. Epicardial potentials were reconstructed during ventricular activation using experiment-specific magnetic resonance imaging-based thorax models, with homogeneous or inhomogeneous (lungs, skeletal muscle, fat) electrical properties. Coupled finite/boundary element methods and a meshless approach based on the method of fundamental solutions were compared. Inverse mapping underestimated epicardial potentials >2 fold (P<0.0001). RESULTS: Mean correlation coefficients for reconstructed epicardial potential distributions ranged from 0.60+/-0.08 to 0.64+/-0.07 across all methods. Epicardial electrograms were recovered with reasonable fidelity at ~50% of sites (median correlation coefficient, 0.69-0.72), but variation was substantial. General activation spread was reproduced (median correlation coefficient, 0.72-0.78 for activation time maps after spatio-temporal smoothing). Epicardial foci were identified with a median location error ~16 mm (interquartile range, 9-29 mm). Inverse mapping with meshless method of fundamental solutions was better than with finite/boundary element methods, and the latter were not improved by inclusion of inhomogeneous torso electrical properties. CONCLUSIONS: Inverse potential mapping provides useful information on the origin and spread of epicardial activation. However the spatio-temporal variability of recovered electrograms limit resolution and must constrain the accuracy with which arrhythmia circuits can be identified independently using this approach. PMID- 29700058 TI - Impact of Female Sex on Clinical Outcomes in the FIRE AND ICE Trial of Catheter Ablation for Atrial Fibrillation. AB - BACKGROUND: Data on predictors of long-term clinical outcomes after catheter ablation of atrial fibrillation (AF) are limited. We sought to assess the association of baseline covariates with clinical outcomes in the 750 patients with drug-refractory paroxysmal AF enrolled in FIRE AND ICE. METHODS: In a 2-part analysis, univariate and multivariable Cox regression models were first used to identify baseline patient characteristics predictive of catheter ablation efficacy determined by the clinical end points of (1) atrial arrhythmia recurrence (primary efficacy failure), (2) cardiovascular rehospitalization, and (3) repeat ablation. Propensity score stratification methods were then used to account for differences in baseline characteristics between sexes. RESULTS: Female sex (hazard ratio [HR], 1.37; 95% confidence interval [CI], 1.08-1.73; P=0.010) and prior direct current cardioversion (HR, 1.40; 95% CI, 1.07-1.82; P=0.013) were independently associated with atrial arrhythmia recurrence. Female sex (HR, 1.36; 95% CI, 1.02-1.80; P=0.035) and hypertension (HR, 1.48; 95% CI, 1.09-2.00; P=0.013) independently predicted cardiovascular rehospitalization. A longer history of AF (HR, 1.03; 95% CI, 1.00-1.06; P=0.039) increased the rate of repeat ablation. Women continued to have higher rates of primary efficacy failure and cardiovascular rehospitalization after propensity score adjustment, with adjusted HRs of 1.51 (95% CI, 1.16-2.18; P<0.05) and 1.40 (95% CI, 1.15-2.17; P<0.05), respectively. CONCLUSIONS: After catheter ablation of paroxysmal AF, female sex was associated with an almost 40% increase in the risks of primary efficacy failure and cardiovascular rehospitalization. Primary efficacy failure was also adversely impacted by a history of direct current cardioversion, whereas hypertension had a negative impact on cardiovascular rehospitalization. History of AF was the only predictor of repeat ablation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01490814. PMID- 29700059 TI - Ventricular Electrical Activation Delay and High-Frequency Electrocardiograms: Hype or Hope? PMID- 29700060 TI - Growth hormone transgenesis in coho salmon disrupts muscle immune function impacting cross-talk with growth systems. AB - Suppression of growth during infection may aid resource allocation towards effective immune function. Past work supporting this hypothesis in salmonid fish revealed an immune-responsive regulation of the insulin-like growth factor (IGF) system - an endocrine pathway downstream of growth hormone (GH). Skeletal muscle is the main target for growth and energetic storage in fish, yet little is known about how its growth is regulated during an immune response. We addressed this knowledge gap by characterising muscle immune responses in size-matched coho salmon (Oncorhynchus kisutch) achieving different growth rates. We compared a wild-type strain with two GH transgenic groups from the same genetic background achieving either maximal or suppressed growth - a design separating GH's direct effects from its influence on growth rate and nutritional state. Fish were sampled 30 h post-injection with phosphate-buffered saline (control) or mimics of bacterial or viral infection. We quantified mRNA expression levels for genes from the GH, GH receptor, IGF hormone, IGF1 receptor and IGF-binding protein families, along with immune genes involved in inflammatory or antiviral responses and muscle growth status marker genes. We demonstrate dampened immune function in GH transgenics compared with wild-type. The muscle of GH transgenics achieving rapid growth showed no detectable antiviral response, coupled with evidence of a constitutive inflammatory state. GH and IGF system gene expression was strongly altered by GH transgenesis and fast growth, both for baseline expression and responses to immune stimulation. Thus, GH transgenesis strongly disrupts muscle immune status and normal GH and IGF system expression responses to immune stimulation. PMID- 29700061 TI - Alteration of size perception: serotonin has opposite effects on the aggressiveness of crayfish confronting either a smaller or a larger rival. AB - We injected serotonin (5-HT) into adult male crayfish before pairing them with size-matched non-injected competitors, and observed dyadic agonistic interactions. Paradoxically, 5-HT elicited opposite behavioral responses if the injected animal was opposed by a smaller or larger rival: the level of aggressiveness of the injected crayfish was higher when facing a larger rival but lower when facing a smaller rival. Our results indicate that the effects of 5-HT on aggressiveness are dependent on the perception of the relative size difference of the opponent. In both cases, however, 5-HT significantly delayed the decision to retreat. We conclude that 5-HT does not primarily act on aggressiveness but rather on the brain centers that integrate risk assessment and/or decision making, which then modulate the aggressive response. Our findings support a reinterpretation of the role of 5-HT in crustacean agonistic behavior that may be of interest for studies of other animals. PMID- 29700062 TI - Combination of ibuprofen and acetaminophen is no different than low-dose opioid analgesic preparations in relieving short-term acute extremity pain. PMID- 29700063 TI - Omics, Big Data, and Precision Medicine in Cardiovascular Sciences. PMID- 29700064 TI - Personal Omics for Precision Health. PMID- 29700065 TI - A New Approach to an Old Problem: One Brave Idea. PMID- 29700067 TI - Epigenomics: Technologies and Applications. AB - The advent of high-throughput epigenome mapping technologies has ushered in a new era of multiomics where powerful tools can now delineate and record different layers of genomic output. Integrating various components of the epigenome from these multiomics measurements allows the interrogation of cellular heterogeneity in addition to the discovery of molecular connectivity maps between the genome and its functional output. Mapping of chromatin accessibility dynamics and higher order chromatin structure has enabled new levels of understanding of cell fate decisions, identity, and function in normal development, physiology, and disease. We provide a perspective on the progress of the epigenomics field and applications and anticipate an even greater revolution in our understanding of the human epigenome for years to come. PMID- 29700068 TI - Advances in Transcriptomics: Investigating Cardiovascular Disease at Unprecedented Resolution. AB - Whole-genome transcriptional profiling has become a standard genomic approach to investigate biological processes. RNA sequencing (RNAseq) in particular has witnessed myriad applications in genetics and various biomedical fields. RNAseq involves a relatively simple experimental protocol of RNA extraction and cDNA library preparation and, because of decreasing next-generation sequencing cost and lower computational burden for data processing, has obtained a central role in the modern biology. The recent application of RNAseq methodology to single cell transcriptional profiling has enabled the more precise characterization of cell lineage and cell state genetic profiles. The development of bioinformatic and statistical tools has provided for differential gene expression analysis, RNA isoform analysis, haplotype-specific analysis of gene expression (allele-specific expression), and analysis of expression quantitative trait loci. We give an overview of these and recent developments in RNAseq methodology with emphasis on quality control, read mapping, feature counting, differential gene expression, allele-specific expression and expression quantitative trait loci analysis, and fusion transcript detection. We describe utilization of RNAseq as a diagnostic tool in Mendelian diseases, complex phenotypes, and cancer and give an overview of long read RNAseq technology. Furthermore, we discuss in detail the recent revolution in single-cell transcriptomics that is reshaping modern biology. PMID- 29700066 TI - Opportunities and Challenges in Cardiovascular Pharmacogenomics: From Discovery to Implementation. AB - This review will provide an overview of the principles of pharmacogenomics from basic discovery to implementation, encompassing application of tools of contemporary genome science to the field (including areas of apparent divergence from disease-based genomics), a summary of lessons learned from the extensively studied drugs clopidogrel and warfarin, the current status of implementing pharmacogenetic testing in practice, the role of genomics and related tools in the drug development process, and a summary of future opportunities and challenges. PMID- 29700071 TI - Defining the Human Envirome: An Omics Approach for Assessing the Environmental Risk of Cardiovascular Disease. AB - Both genetic and environmental factors contribute to the development of cardiovascular disease, but in comparison with genetics, environmental factors have received less attention. Evaluation of environmental determinants of cardiovascular disease is limited by the lack of comprehensive omics approaches for integrating multiple environmental exposures. Hence, to understand the effects of the environment as a whole (envirome), it is important to delineate specific domains of the environment and to assess how, individually and collectively; these domains affect cardiovascular health. In this review, we present a hierarchical model of the envirome; defined by 3 consecutively nested domains, consisting of natural, social, and personal environments. Extensive evidence suggests that features of the natural environment such as sunlight, altitude, diurnal rhythms, vegetation, and biodiversity affect cardiovascular health. However, the effects of the natural environment are moderated by the social environment comprised of built environments, agricultural and industrial activities, pollutants and contaminants, as well as culture, economic activities, and social networks that affect health by influencing access to healthcare, social cohesion, and socioeconomic status. From resources available within society, individuals create personal environments, characterized by private income, wealth and education, and populated by behavioral and lifestyle choices relating to nutrition, physical activity, sleep, the use of recreational drugs, and smoking. An understanding of the interactions between different domains of the envirome and their integrated effects on cardiovascular health could lead to the development of new prevention strategies and deeper insights into etiologic processes that contribute to cardiovascular disease risk and susceptibility. PMID- 29700069 TI - Precision Profiling of the Cardiovascular Post-Translationally Modified Proteome: Where There Is a Will, There Is a Way. AB - There is an exponential increase in biological complexity as initial gene transcripts are spliced, translated into amino acid sequence, and post translationally modified. Each protein can exist as multiple chemical or sequence specific proteoforms, and each has the potential to be a critical mediator of a physiological or pathophysiological signaling cascade. Here, we provide an overview of how different proteoforms come about in biological systems and how they are most commonly measured using mass spectrometry-based proteomics and bioinformatics. Our goal is to present this information at a level accessible to every scientist interested in mass spectrometry and its application to proteome profiling. We will specifically discuss recent data linking various protein post translational modifications to cardiovascular disease and conclude with a discussion for enablement and democratization of proteomics across the cardiovascular and scientific community. The aim is to inform and inspire the readership to explore a larger breadth of proteoform, particularity post translational modifications, related to their particular areas of expertise in cardiovascular physiology. PMID- 29700070 TI - Cardiovascular Metabolomics. AB - Disturbances in cardiac metabolism underlie most cardiovascular diseases. Metabolomics, one of the newer omics technologies, has emerged as a powerful tool for defining changes in both global and cardiac-specific metabolism that occur across a spectrum of cardiovascular disease states. Findings from metabolomics studies have contributed to better understanding of the metabolic changes that occur in heart failure and ischemic heart disease and have identified new cardiovascular disease biomarkers. As technologies advance, the metabolomics field continues to evolve rapidly. In this review, we will discuss the current state of metabolomics technologies, including consideration of various metabolomics platforms and elements of study design; the emerging utility of stable isotopes for metabolic flux studies; and the use of metabolomics to better understand specific cardiovascular diseases, with an emphasis on recent advances in the field. PMID- 29700072 TI - Taking Systems Medicine to Heart. AB - Systems medicine is a holistic approach to deciphering the complexity of human physiology in health and disease. In essence, a living body is constituted of networks of dynamically interacting units (molecules, cells, organs, etc) that underlie its collective functions. Declining resilience because of aging and other chronic environmental exposures drives the system to transition from a health state to a disease state; these transitions, triggered by acute perturbations or chronic disturbance, manifest as qualitative shifts in the interactions and dynamics of the disease-perturbed networks. Understanding health to-disease transitions poses a high-dimensional nonlinear reconstruction problem that requires deep understanding of biology and innovation in study design, technology, and data analysis. With a focus on the principles of systems medicine, this Review discusses approaches for deciphering this biological complexity from a novel perspective, namely, understanding how disease-perturbed networks function; their study provides insights into fundamental disease mechanisms. The immediate goals for systems medicine are to identify early transitions to cardiovascular (and other chronic) diseases and to accelerate the translation of new preventive, diagnostic, or therapeutic targets into clinical practice, a critical step in the development of personalized, predictive, preventive, and participatory (P4) medicine. PMID- 29700073 TI - Biomedical Informatics on the Cloud: A Treasure Hunt for Advancing Cardiovascular Medicine. AB - In the digital age of cardiovascular medicine, the rate of biomedical discovery can be greatly accelerated by the guidance and resources required to unearth potential collections of knowledge. A unified computational platform leverages metadata to not only provide direction but also empower researchers to mine a wealth of biomedical information and forge novel mechanistic insights. This review takes the opportunity to present an overview of the cloud-based computational environment, including the functional roles of metadata, the architecture schema of indexing and search, and the practical scenarios of machine learning-supported molecular signature extraction. By introducing several established resources and state-of-the-art workflows, we share with our readers a broadly defined informatics framework to phenotype cardiovascular health and disease. PMID- 29700075 TI - Trial Design Innovations to Accelerate Therapeutic Advances in Chronic Kidney Disease: Moving from Single Trials to an Ongoing Platform. PMID- 29700074 TI - Emerging Role of Precision Medicine in Cardiovascular Disease. AB - Precision medicine is an integrative approach to cardiovascular disease prevention and treatment that considers an individual's genetics, lifestyle, and exposures as determinants of their cardiovascular health and disease phenotypes. This focus overcomes the limitations of reductionism in medicine, which presumes that all patients with the same signs of disease share a common pathophenotype and, therefore, should be treated similarly. Precision medicine incorporates standard clinical and health record data with advanced panomics (ie, transcriptomics, epigenomics, proteomics, metabolomics, and microbiomics) for deep phenotyping. These phenotypic data can then be analyzed within the framework of molecular interaction (interactome) networks to uncover previously unrecognized disease phenotypes and relationships between diseases, and to select pharmacotherapeutics or identify potential protein-drug or drug-drug interactions. In this review, we discuss the current spectrum of cardiovascular health and disease, population averages and the response of extreme phenotypes to interventions, and population-based versus high-risk treatment strategies as a pretext to understanding a precision medicine approach to cardiovascular disease prevention and therapeutic interventions. We also consider the search for resilience and Mendelian disease genes and argue against the theory of a single causal gene/gene product as a mediator of the cardiovascular disease phenotype, as well as an Erlichian magic bullet to solve cardiovascular disease. Finally, we detail the importance of deep phenotyping and interactome networks and the use of this information for rational polypharmacy. These topics highlight the urgent need for precise phenotyping to advance precision medicine as a strategy to improve cardiovascular health and prevent disease. PMID- 29700077 TI - Meet the First Authors. PMID- 29700076 TI - Computer-aided biochemical programming of synthetic microreactors as diagnostic devices. AB - Biological systems have evolved efficient sensing and decision-making mechanisms to maximize fitness in changing molecular environments. Synthetic biologists have exploited these capabilities to engineer control on information and energy processing in living cells. While engineered organisms pose important technological and ethical challenges, de novo assembly of non-living biomolecular devices could offer promising avenues toward various real-world applications. However, assembling biochemical parts into functional information processing systems has remained challenging due to extensive multidimensional parameter spaces that must be sampled comprehensively in order to identify robust, specification compliant molecular implementations. We introduce a systematic methodology based on automated computational design and microfluidics enabling the programming of synthetic cell-like microreactors embedding biochemical logic circuits, or protosensors, to perform accurate biosensing and biocomputing operations in vitro according to temporal logic specifications. We show that proof-of-concept protosensors integrating diagnostic algorithms detect specific patterns of biomarkers in human clinical samples. Protosensors may enable novel approaches to medicine and represent a step toward autonomous micromachines capable of precise interfacing of human physiology or other complex biological environments, ecosystems, or industrial bioprocesses. PMID- 29700078 TI - RCAN1-Calcineurin Axis and the Set-Point for Myocardial Damage During Ischemia Reperfusion. PMID- 29700079 TI - Aging and Protein Kinase Activation: Is It the Missing Link Between Age and Atrial Fibrillation? PMID- 29700080 TI - A New Player in Circulatory Adaptation to Orthostatism: Better to Play With Than Without Him. PMID- 29700082 TI - Rotimi Mesubi: Time Well Spent. PMID- 29700081 TI - Refining the Risk Prediction of Cardiorespiratory Fitness With Network Analysis: A Welcome and Needed Line of Inquiry. PMID- 29700083 TI - Watching Small Vessel Disease Grow. PMID- 29700085 TI - Valproate: life-saving, life-changing. AB - Antiepileptic medications, and valproate principally, are commonly prescribed teratogens. There is significant concern that we are not doing enough to educate clinicians and potential parents about the risks of valproate in pregnancy. There is clear advice from the Medicines and Healthcare products Regulatory Agency and the International League Against Epilepsy about the risks of valproate exposure in utero Reviews and guidelines that are focused on fetal risk, however, fall short in being able to fully replicate the complexity of a real clinical decision. Valproate is certainly life-changing if your child is one of the 10% with a major malformation or 30-40% with a neurodevelopmental disorder, but valproate is also potentially life-saving in the context of ensuring the best possible seizure control for some mothers with epilepsy. There are significant knowledge gaps regarding the risks to mothers who elect to take another drug, or to mother and baby if she comes off medication entirely. We also should be doing more to reduce rates of sudden unexpected death in epilepsy (SUDEP), which is recognised as a key target when evaluating all maternal deaths. PMID- 29700086 TI - Hyperacute management of intracerebral haemorrhage. AB - Intracerebral haemorrhage causes 1 in 10 strokes, but has the worst overall outcomes of all stroke subtypes. Baseline haematoma volume is a key prognostic factor and early complications - such as haematoma expansion, obstructive hydrocephalus and perihaematomal oedema - may worsen outcome. There is evidence that withdrawal of care may occur more often in intracerebral haemorrhage than ischaemic stroke independent of premorbid health and stroke severity. However, recent evidence shows that reversal of anticoagulants, intensive blood pressure lowering and surgery in carefully selected cases may improve outcomes. Ongoing research may also provide evidence for new medical treatments and minimally invasive approaches to surgery. Effective implementation of evidence-based care to intracerebral haemorrhage patients can be difficult but quality improvement methodology can help to achieve maximal benefit. PMID- 29700088 TI - Sudden cardiac death in the young: a genetic destiny? PMID- 29700087 TI - What is new in stroke imaging and intervention? AB - Recent updates to guidelines around brain imaging in stroke and transient ischaemic attack are reviewed. A more detailed examination of advanced brain imaging in acute stroke is presented. The recent evidence for endovascular mechanical thrombectomy in acute stroke is reviewed. The implications of delivering thrombectomy are discussed. PMID- 29700089 TI - Heart failure with preserved ejection fraction. AB - Heart failure with preserved ejection fraction (HFpEF) represents a heterogeneous collection of conditions that are unified by the presence of a left ventricular ejection fraction >=50%, evidence of impaired diastolic function and elevated natriuretic peptide levels, all within the context of typical heart failure signs and symptoms. However, while HFpEF is steadily becoming the predominant form of heart failure, disease-modifying treatment options for this population remain sparse. This review provides an overview of the diagnosis, management and prevention of HFpEF for general physicians. PMID- 29700090 TI - Cardiac amyloidosis. AB - Systemic amyloidosis comprises an uncommon group of disorders caused by the extracellular deposition of misfolded proteins in various organs. Cardiac amyloid deposition, causing an infiltrative/restrictive cardiomyopathy, is a frequent feature of amyloidosis and a major determinant of survival. It may be the presenting feature of the disease or may be identified while investigating a patient presenting with other organ involvement. The need for a high index of suspicion and the critical importance of precise biochemical typing of the amyloid deposits is paramount in light of recent therapeutic advances that can significantly improve prognosis. Most cases of cardiac amyloidosis are of either transthyretin type, which may be acquired in older individuals or inherited in younger patients, or acquired monoclonal immunoglobulin light chain (AL) type. This article aims to review recent developments in diagnosis and management of cardiac amyloidosis. PMID- 29700091 TI - Diagnosis and treatment of severe asthma: a phenotype-based approach. AB - Severe asthma is a heterogeneous and often difficult to treat condition that results in a disproportionate cost to healthcare systems. Appropriate diagnosis and management of severe asthma is critical, as most asthma deaths have been retrospectively identified as having poorly recognised severe asthma. With multiple biologic agents becoming available, it is crucial to correctly phenotype patients in order to identify those that will respond to these high-cost treatments. We provide an overview of the assessment, phenotyping and management of severe asthma in primary and secondary care. PMID- 29700092 TI - Recent advances in the management of lung cancer. AB - Historically, the prognosis for individuals diagnosed with lung cancer has been bleak. However, the past 10 years have seen important advances in treatment and diagnosis which have translated into the first improvements seen in lung cancer survival. This review highlights the major advances in treatments with curative intent, systemic targeted therapies, palliative care and early diagnosis in lung cancer. We discuss the pivotal research that underpins these new technologies/strategies and their current position in clinical practice. PMID- 29700093 TI - From genomics to targeted treatment in haematological malignancies: a focus on acute myeloid leukaemia. AB - The haematological malignancies are a heterogeneous group of neoplastic disorders, which lead to almost 10,000 deaths annually in the UK. Over the past 2 decades, there has been significant progress in our understanding of the pathological mechanisms underlying these cancers, accompanied by improvements in outcomes for some patients. In particular, advances in next-generation sequencing now make it possible to define the genetic lesions present in each patient, which has led to improved disease classification, risk stratification and identification of new therapeutic targets. Here we discuss recent advances in the genomic classification and targeted treatment of haematological malignancies, focusing on acute myeloid leukaemia. Multiple novel drug classes are now on the horizon, including agents that target overactive signalling pathways, differentiation therapies and immunotherapies. By combining molecular diagnostics with targeted therapy, the management of these diseases is set to change radically over the coming years. PMID- 29700084 TI - Reactive Oxygen Species in Metabolic and Inflammatory Signaling. AB - Reactive oxygen species (ROS) are well known for their role in mediating both physiological and pathophysiological signal transduction. Enzymes and subcellular compartments that typically produce ROS are associated with metabolic regulation, and diseases associated with metabolic dysfunction may be influenced by changes in redox balance. In this review, we summarize the current literature surrounding ROS and their role in metabolic and inflammatory regulation, focusing on ROS signal transduction and its relationship to disease progression. In particular, we examine ROS production in compartments such as the cytoplasm, mitochondria, peroxisome, and endoplasmic reticulum and discuss how ROS influence metabolic processes such as proteasome function, autophagy, and general inflammatory signaling. We also summarize and highlight the role of ROS in the regulation metabolic/inflammatory diseases including atherosclerosis, diabetes mellitus, and stroke. In order to develop therapies that target oxidative signaling, it is vital to understand the balance ROS signaling plays in both physiology and pathophysiology, and how manipulation of this balance and the identity of the ROS may influence cellular and tissue homeostasis. An increased understanding of specific sources of ROS production and an appreciation for how ROS influence cellular metabolism may help guide us in the effort to treat cardiovascular diseases. PMID- 29700094 TI - Genetics of alcoholic liver disease and non-alcoholic steatohepatitis. AB - Alcohol-related liver disease (ARLD) and non-alcoholic fatty liver disease (NAFLD) are leading causes of chronic liver disease globally. Both ARLD and NAFLD are multifactorial and refer to a spectrum of disease severity, ranging from steatosis through steatohepatitis to fibrosis and cirrhosis. Both diseases exhibit substantial inter-patient variation in long-term outcomes and are best considered complex disease traits where genetic and environmental factors interact to mediate disease severity and progression. Here, we briefly review the current literature describing the best validated genetic modifiers that influence severity of these liver conditions, including variants of the genes PNPLA3, TM6SF2 and MBOAT7, which have also been implicated in lipid dysregulation. PMID- 29700095 TI - Management of decompensated cirrhosis. AB - Decompensated cirrhosis is a common reason for admission to the acute medical unit, and such patients typically have complex medical needs and are at high risk of in-hospital death. It is therefore vital that these patients receive appropriate investigations and management as early as possible in their patient journey. Typical presenting clinical features include jaundice, ascites, hepatic encephalopathy, hepato-renal syndrome or variceal haemorrhage. A careful history, examination and investigations can help identify the precipitating cause (infections, gastrointestinal bleeding, high alcohol intake / alcohol-related hepatitis or drug-induced liver injury), so appropriate treatment can be given. A 'care bundle' that has been endorsed by the British Society of Gastroenterology is available to help guide the management of patients with decompensated cirrhosis for the first 24 hours and ensure all aspects are addressed. Specific management of complications, such as infections, gastrointestinal bleeding, hepatic encephalopathy and hepatorenal syndrome, are discussed. PMID- 29700096 TI - Surveillance for hepatocellular cancer. AB - Hepatocellular carcinoma (HCC) is a common complication of cirrhosis. The incidence of HCC is rising and HCC-related mortality is rising in parallel such that there were more than 1,700 deaths in the UK in 2015. Since cirrhosis is a known risk factor for the development of HCC and early diagnosis is associated with improved outcomes, surveillance for the development of HCC using regular ultrasound scans is recommended by many expert bodies including the National Institute for Health and Care Excellence (NICE). This surveillance is not supported by high-quality evidence and there is an increasing appreciation of the associated harms. In this review the likely benefits of surveillance are discussed together with recommendations to increase the effectiveness of surveillance overall. PMID- 29700097 TI - Prostaglandin E2 receptor 3 signaling is induced in placentas with unexplained recurrent pregnancy losses. AB - Although an inflammatory microenvironment is required for successful implantation, an inflammatory overreaction is one of the causes of unexplained recurrent pregnancy losses (uRPL). Prostaglandin E2 (PGE2) plays a pivotal role in regulating immune balance during early pregnancy, and it can stimulate inflammatory reactions via prostaglandin E2 receptor 3 (EP3). However, the role of PGE2 receptor signaling in the uRPL remains unknown. We aimed to investigate whether EP3 signaling is involved in the mechanism of uRPL. Via immunohistochemistry we could show that the expression of cyclooxygenase-2, EP3 and G protein alpha inhibitor 1 (Gi1) was enhanced in the decidua of the uRPL group in comparison to the control group in first-trimester placentas. In vitro, we demonstrated that sulprostone (an EP1/EP3 agonist) inhibited the secretion of beta-hCG and progesterone in JEG-3 cells and the secretion of beta-hCG in HTR 8/SVneo cells while it induced the expression of plasminogen activator inhibitor type 1 in JEG-3 cells. In addition, PGE2/sulprostone was able to stimulate the expression of Gi1, phosphorylated-extracellular signal-regulated kinases 1/2 (p ERK1/2) and p53. L-798,106 (an EP3-specific antagonist) suppressed the expression of EP3 and p-ERK1/2 without affecting the secretion of beta-hCG. Elevated activation of EP3 signaling in first-trimester placentas plays an important role in regulating the inflammatory microenvironment, the hormone secretion of extravillous trophoblasts and the remodeling of extracellular matrix in the fetal maternal interface. L-798,106 might be a 'potential therapeutic candidate' for the treatment of uRPL. PMID- 29700098 TI - High prevalence of iodine deficiency in pregnant women living in adequate iodine area. AB - OBJECTIVES: Iodine deficiency during pregnancy is associated with obstetric and neonatal adverse outcomes. Serum thyroglobulin (sTg) and thyroid volume (TV) are optional tools to urinary iodine concentration (UIC) for defining iodine status. This cross-sectional study aims to evaluate the iodine status of pregnant women living in iodine-adequate area by spot UIC and correlation with sTg, TV and thyroid function. METHODS: Two hundred and seventy-three pregnant women were evaluated at three trimesters. All had no previous thyroid disease, no iodine supplementation and negative thyroperoxidase and thyroglobulin antibodies. Thyroid function and sTg were measured using electrochemiluminescence immunoassays. TV was determined by ultrasonography; UIC was determined using a modified Sandell-Kolthoff method. RESULTS: Median UIC was 146 ug/L, being 52% iodine deficient and only 4% excessive. TSH values were 1.50 +/- 0.92, 1.50 +/- 0.92 and 1.91 +/- 0.96 mIU/L, respectively, in each trimester (P = 0.001). sTg did not change significantly during trimesters with median 11.2 ng/mL and only 3.3% had above 40 ng/mL. Mean TV was 9.3 +/- 3.4 mL, which positively correlated with body mass index, but not with sTg. Only 4.5% presented with goitre.When pregnant women were categorized as iodine deficient (UIC < 150 ug/L), adequate (>=150 and <250 ug/L) and excessive (>=250 ug/L), sTg, thyroid hormones and TV at each trimester showed no statistical differences. CONCLUSIONS: Iodine deficiency was detected frequently in pregnant women living in iodine-adequate area. sTg concentration and TV did not correlate to UIC. Our observation also demonstrated that the Brazilian salt-iodization programme prevents deficiency, but does not maintain iodine status within adequate and recommended ranges for pregnant women. PMID- 29700099 TI - Effect of A549 neuroendocrine differentiation on cytotoxic immune response. AB - The present study was designed to determine the effects of factors secreted by the lung adenocarcinoma cell line with the neuroendocrine phenotype, A549NED, on cytotoxic T lymphocytes (CTLs) activity in vitro A perspective that integrates the nervous, endocrine and immune system in cancer research is essential to understand the complexity of dynamic interactions in tumours. Extensive clinical research suggests that neuroendocrine differentiation (NED) is correlated with worse patient outcomes; however, little is known regarding the effects of neuroendocrine factors on the communication between the immune system and neoplastic cells. The human lung cancer cell line A549 was induced to NED (A549NED) using cAMP-elevating agents. The A549NED cells showed changes in cell morphology, an inhibition of proliferation, an overexpression of chromogranin and a differential pattern of biogenic amine production (decreased dopamine and increased serotonin [5-HT] levels). Using co-cultures to determine the cytolytic CTLs activity on target cells, we showed that the acquisition of NED inhibits the decrease in the viability of the target cells and release of fluorescence. Additionally, the conditioned medium of A549NED and 5-HT considerably decreased the viability and proliferation of the Jurkat cells after 24 h. Thus, our study successfully generated a neuroendocrine phenotype from the A549 cell line. In co cultures with CTLs, the pattern of secretion by A549NED impaired the proliferation and cytotoxic activity of CTLs, which might be partly explained by the increased release of 5-HT. PMID- 29700100 TI - Are sweet snacks more sensitive to price increases than sugar-sweetened beverages: analysis of British food purchase data. AB - OBJECTIVES: Taxing sugar-sweetened beverages (SSBs) is now advocated, and implemented, in many countries as a measure to reduce the purchase and consumption of sugar to tackle obesity. To date, there has been little consideration of the potential impact that such a measure could have if extended to other sweet foods, such as confectionery, cakes and biscuits that contribute more sugar to the diet than SSBs. The objective of this study is to compare changes in the demand for sweet snacks and SSBs arising from potential price increases. SETTING: Secondary data on household itemised purchases of all foods and beverages from 2012 to 2013. PARTICIPANTS: Representative sample of 32 249 households in Great Britain. PRIMARY AND SECONDARY OUTCOME MEASURES: Change in food and beverage purchases due to changes in their own price and the price of other foods or beverages measured as price elasticity of demand for the full sample and by income groups. RESULTS: Chocolate and confectionery, cakes and biscuits have similar price sensitivity as SSBs, across all income groups. Unlike the case of SSBs, price increases in these categories are also likely to prompt reductions in the purchase of other sweet snacks and SSBs, which magnify the overall impact. The effects of price increases are greatest in the low-income group. CONCLUSIONS: Policies that lead to increases in the price of chocolate and confectionery, cakes and biscuits may lead to additional and greater health gains than similar increases in the price of SSBs through direct reductions in the purchases of these foods and possible positive multiplier effects that reduce demand for other products. Although some uncertainty remains, the associations found in this analysis are sufficiently robust to suggest that policies-and research-concerning the use of fiscal measures should consider a broader range of products than is currently the case. PMID- 29700101 TI - Evaluation of a decision aid for incidental genomic results, the Genomics ADvISER: protocol for a mixed methods randomised controlled trial. AB - INTRODUCTION: Genome sequencing, a novel genetic diagnostic technology that analyses the billions of base pairs of DNA, promises to optimise healthcare through personalised diagnosis and treatment. However, implementation of genome sequencing faces challenges including the lack of consensus on disclosure of incidental results, gene changes unrelated to the disease under investigation, but of potential clinical significance to the patient and their provider. Current recommendations encourage clinicians to return medically actionable incidental results and stress the importance of education and informed consent. Given the shortage of genetics professionals and genomics expertise among healthcare providers, decision aids (DAs) can help fill a critical gap in the clinical delivery of genome sequencing. We aim to assess the effectiveness of an interactive DA developed for selection of incidental results. METHODS AND ANALYSIS: We will compare the DA in combination with a brief Q&A session with a genetic counsellor to genetic counselling alone in a mixed-methods randomised controlled trial. Patients who received negative standard cancer genetic results for their personal and family history of cancer and are thus eligible for sequencing will be recruited from cancer genetics clinics in Toronto. Our primary outcome is decisional conflict. Secondary outcomes are knowledge, satisfaction, preparation for decision-making, anxiety and length of session with the genetic counsellor. A subset of participants will complete a qualitative interview about preferences for incidental results. ETHICS AND DISSEMINATION: This study has been approved by research ethics boards of St. Michael's Hospital, Mount Sinai Hospital and Sunnybrook Health Sciences Centre. This research poses no significant risk to participants. This study evaluates the effectiveness of a novel patient-centred tool to support clinical delivery of incidental results. Results will be shared through national and international conferences, and at a stakeholder workshop to develop a consensus statement to optimise implementation of the DA in practice. TRIAL REGISTRATION NUMBER: NCT03244202; Pre-results. PMID- 29700102 TI - In vitro, in silico and in vivo study challenges the impact of bronchial thermoplasty on acute airway smooth muscle mass loss. AB - Bronchial thermoplasty is a treatment for asthma. It is currently unclear whether its histopathological impact is sufficiently explained by the proportion of airway wall that is exposed to temperatures necessary to affect cell survival.Airway smooth muscle and bronchial epithelial cells were exposed to media (37-70 degrees C) for 10 s to mimic thermoplasty. In silico we developed a mathematical model of airway heat distribution post-thermoplasty. In vivo we determined airway smooth muscle mass and epithelial integrity pre- and post thermoplasty in 14 patients with severe asthma.In vitro airway smooth muscle and epithelial cell number decreased significantly following the addition of media heated to >=65 degrees C. In silico simulations showed a heterogeneous heat distribution that was amplified in larger airways, with <10% of the airway wall heated to >60 degrees C in airways with an inner radius of ~4 mm. In vivo at 6 weeks post-thermoplasty, there was an improvement in asthma control (measured via Asthma Control Questionnaire-6; mean difference 0.7, 95% CI 0.1-1.3; p=0.03), airway smooth muscle mass decreased (absolute median reduction 5%, interquartile range (IQR) 0-10; p=0.03) and epithelial integrity increased (14%, IQR 6-29; p=0.007). Neither of the latter two outcomes was related to improved asthma control.Integrated in vitro and in silico modelling suggest that the reduction in airway smooth muscle post-thermoplasty cannot be fully explained by acute heating, and nor did this reduction confer a greater improvement in asthma control. PMID- 29700103 TI - Maximal exercise capacity in patients with obstructive sleep apnoea syndrome: a systematic review and meta-analysis. AB - Maximal aerobic capacity is a strong health predictor and peak oxygen consumption (V'O2peak) is considered a reflection of total body health. No systematic reviews or meta-analyses to date have synthesised the existing data regarding V'O2peak in patients with obstructive sleep apnoea (OSA).A systematic review of English and French articles using PubMed/MEDLINE and Embase included studies assessing V'O2peak in OSA patients either in mL.kg-1.min-1 compared with controls or in % predicted. Two independent reviewers analysed the studies, extracted the data and assessed the quality of evidence.Mean V'O2peak expressed in mL.kg-1.min-1 was significantly lower in patients with OSA than in controls (mean difference -2.7 mL.kg-1.min-1; p<0.001; n=850). This reduction in V'O2peak was found to be larger in non-obese patients (body mass index <30 kg.m-2). Mean V'O2peak % pred was 89.9% in OSA patients (n=643).OSA patients have reduced maximal aerobic capacity, which can be associated with increased cardiovascular risks and reduced survival in certain patient subgroups. Maximal exercise testing can be useful to characterise functional limitation and to evaluate health status in OSA patients. PMID- 29700104 TI - Nocturnal cerebral hypoxia in obstructive sleep apnoea: a randomised controlled trial. AB - Cerebral hypoxia may promote cerebral damage in patients with obstructive sleep apnoea (OSA). We investigated whether OSA patients experience nocturnal cerebral hypoxia that is prevented by continuous positive airway pressure (CPAP).OSA patients using CPAP underwent sleep studies including pulse oximetry (arterial oxygen saturation (SpO2 )) and near-infrared spectroscopy to monitor cerebral tissue oxygenation (CTO) at baseline and after 2 weeks on either subtherapeutic or therapeutic CPAP according to randomised allocation. Changes in oxygenation at end of the 2-week intervention were compared between groups.Among 21 patients (mean apnoea/hypopnoea index 50.3 events.h-1), OSA recurred in all nine patients using subtherapeutic CPAP and in none of the patients using therapeutic CPAP: mean (95% CI) between-group differences in changes of oxygen desaturation index from baseline to 2 weeks +40.7 (31.1-50.4) events.h-1 for SpO2 and +37.0 (25.3 48.7) events.h-1 for CTO (both p<0.001). Mean nocturnal SpO2 and CTO decreased more in patients using subtherapeutic versus therapeutic CPAP: -2.4 (-3.4--1.1)% and -3.8 (-7.4--0.1)%, respectively; both p<0.03. Severe CTO drops >=13% associated with cerebral dysfunction in previous studies occurred in four out of nine patients using subtherapeutic CPAP, but in none out of 12 patients using therapeutic CPAP (p=0.01).In patients with OSA, CPAP withdrawal resulted in nocturnal cerebral deoxygenation, suggesting a role of cerebral hypoxia in predisposing untreated OSA patients to cerebral damage. PMID- 29700105 TI - Lung cancer staging: a concise update. AB - Diagnosis and clinical staging of lung cancer are fundamental to planning therapy. The techniques for clinical staging, i.e anatomic and metabolic imaging, endoscopies and minimally invasive surgical procedures, should be performed sequentially and with an increasing degree of invasiveness. Intraoperative staging, assessing the magnitude of the primary tumour, the involved structures, and the loco-regional lymphatic spread by means of systematic nodal dissection, is essential in order to achieve a complete resection. In resected tumours, pathological staging, with the systematic study of the resected specimens, is the strongest prognostic indicator and is essential to make further decisions on therapy. In the present decade, the guidelines on lung cancer staging of the American College of Chest Physicians and the European Society of Thoracic Surgeons are based on the best available evidence and are widely followed. Recent advances in the classification of the adenocarcinoma of the lung, with the definition of adenocarcinoma in situ, minimally invasive adenocarcinoma and lepidic predominant adenocarcinoma, and the publication of the eighth edition of the tumour, node and metastasis classification of lung cancer, have to be integrated into the staging process. The present review complements the latest guidelines on lung cancer staging by providing an update of all these issues. PMID- 29700106 TI - Long-term bedaquiline-related treatment outcomes in patients with extensively drug-resistant tuberculosis from South Africa. AB - Optimal treatment regimens for patients with extensively drug-resistant tuberculosis (XDR-TB) remain unclear. Long-term prospective outcome data comparing XDR-TB regimens with and without bedaquiline from an endemic setting are lacking.We prospectively followed-up 272 South African patients (49.3% HIV infected; median CD4 count 169 cells.uL-1) with newly diagnosed XDR-TB between 2008 and 2017. Outcomes were compared between those who had not received bedaquiline (pre-2013; n=204) and those who had (post-2013; n=68; 80.9% received linezolid in addition).The 24-month favourable outcome rate was substantially better in the bedaquiline versus the non-bedaquiline group (66.2% (45 out of 68) versus 13.2% (27 out of 204); p<0.001). In addition, the bedaquiline group exhibited reduced 24-month rates of treatment failure (5.9% versus 26.0%; p<0.001) and default (1.5% versus 15.2%; p<0.001). However, linezolid was withdrawn in 32.7% (18 out of 55) of patients in the bedaquiline group because of adverse events. Admission weight >50 kg, an increasing number of anti-TB drugs and bedaquiline were independent predictors of survival (the bedaquiline survival effect remained significant in HIV-infected persons, irrespective of CD4 count).XDR-TB patients receiving a backbone of bedaquiline and linezolid had substantially better favourable outcomes compared to those not using these drugs. These data inform the selection of XDR-TB treatment regimens and roll-out of newer drugs in TB-endemic countries. PMID- 29700107 TI - Mesenchymal stromal cells and macrophages in sepsis: new insights. PMID- 29700108 TI - NETs in pneumonia: is just enough the right amount? PMID- 29700109 TI - A high-content screen for small-molecule regulators of epithelial cell-adhesion molecule (EpCAM) cleavage yields a robust inhibitor. AB - Epithelial cell-adhesion molecule (EpCAM) is a transmembrane protein that regulates cell cycle progression and differentiation and is overexpressed in many carcinomas. The EpCAM-induced mitogenic cascade is activated via regulated intramembrane proteolysis (RIP) of EpCAM by ADAM and gamma-secretases, generating the signaling-active intracellular domain EpICD. Because of its expression pattern and molecular function, EpCAM is a valuable target in prognostic and therapeutic approaches for various carcinomas. So far, several immunotherapeutic strategies have targeted the extracellular domain of EpCAM. However, targeting the intracellular signaling cascade of EpCAM holds promise for specifically interfering with EpCAM's proliferation-stimulating signaling cascade. Here, using a yellow fluorescence protein-tagged version of the C-terminal fragment of EpCAM, we established a high-content screening (HCS) of a small-molecule compound library (n = 27,280) and characterized validated hits that target EpCAM signaling. In total, 128 potential inhibitors were initially identified, of which one compound with robust inhibitory effects on RIP of EpCAM was analyzed in greater detail. In summary, our study demonstrates that the development of an HCS for small-molecule inhibitors of the EpCAM signaling pathway is feasible. We propose that this approach may also be useful for identifying chemical compounds targeting other disorders involving membrane cleavage-dependent signaling pathways. PMID- 29700110 TI - Homo- and hetero-oligomerization of hydrophobic pulmonary surfactant proteins SP B and SP-C in surfactant phospholipid membranes. AB - Pulmonary surfactant is a lipid/protein mixture that reduces surface tension at the respiratory air-water interface in lungs. Among its nonlipidic components are pulmonary surfactant-associated proteins B and C (SP-B and SP-C, respectively). These highly hydrophobic proteins are required for normal pulmonary surfactant function, and whereas past literature works have suggested possible SP-B/SP-C interactions and a reciprocal modulation effect, no direct evidence has been yet identified. In this work, we report an extensive fluorescence spectroscopy study of both intramolecular and intermolecular SP-B and SP-C interactions, using a combination of quenching and FRET steady-state and time-resolved methodologies. These proteins are compartmentalized in full surfactant membranes but not in pure 1-palmitoyl-2-oleoylphosphatidylcholine (POPC) vesicles, in accordance with their previously described preference for liquid disordered phases. From the observed static self-quenching and homo-FRET of BODIPY-FL labeled SP-B, we conclude that this protein forms homoaggregates at low concentration (lipid:protein ratio, 1:1000). Increases in polarization of BODIPY-FL SP-B and steady-state intensity of WT SP-B were observed upon incorporation of under-stoichiometric amounts of WT SP-C. Conversely, Marina Blue-labeled SP-C is quenched by over-stoichiometric amounts of WT SP-B, whereas under-stoichiometric concentrations of the latter actually increase SP-C emission. Time-resolved hetero-FRET from Marina Blue SP-C to BODIPY-FL SP-B confirm distinct protein aggregation behaviors with varying SP B concentration. Based on these multiple observations, we propose a model for SP B/SP-C interactions, where SP-C might induce conformational changes on SP-B complexes, affecting its aggregation state. The conclusions inferred from the present work shed light on the synergic functionality of both proteins in the pulmonary surfactant system. PMID- 29700111 TI - Disruption of an oligomeric interface prevents allosteric inhibition of Escherichia coli class Ia ribonucleotide reductase. AB - Ribonucleotide reductases (RNRs) convert ribonucleotides to deoxynucleotides, a process essential for DNA biosynthesis and repair. Class Ia RNRs require two dimeric subunits for activity: an alpha2 subunit that houses the active site and allosteric regulatory sites and a beta2 subunit that houses the diferric tyrosyl radical cofactor. Ribonucleotide reduction requires that both subunits form a compact alpha2beta2 state allowing for radical transfer from beta2 to alpha2 RNR activity is regulated allosterically by dATP, which inhibits RNR, and by ATP, which restores activity. For the well-studied Escherichia coli class Ia RNR, dATP binding to an allosteric site on alpha promotes formation of an alpha4beta4 ring like state. Here, we investigate whether the alpha4beta4 formation causes or results from RNR inhibition. We demonstrate that substitutions at the alpha-beta interface (S37D/S39A-alpha2, S39R-alpha2, S39F-alpha2, E42K-alpha2, or L43Q alpha2) that disrupt the alpha4beta4 oligomer abrogate dATP-mediated inhibition, consistent with the idea that alpha4beta4 formation is required for dATP's allosteric inhibition of RNR. Our results further reveal that the alpha-beta interface in the inhibited state is highly sensitive to manipulation, with a single substitution interfering with complex formation. We also discover that residues at the alpha-beta interface whose substitution has previously been shown to cause a mutator phenotype in Escherichia coli (i.e. S39F-alpha2 or E42K alpha2) are impaired only in their activity regulation, thus linking this phenotype with the inability to allosterically down-regulate RNR. Whereas the cytotoxicity of RNR inhibition is well-established, these data emphasize the importance of down-regulation of RNR activity. PMID- 29700112 TI - RhoA, Rac1, and Cdc42 differentially regulate alphaSMA and collagen I expression in mesenchymal stem cells. AB - Mesenchymal stem cells (MSC) are suggested to be important progenitors of myofibroblasts in fibrosis. To understand the role of Rho GTPase signaling in TGFbeta-induced myofibroblast differentiation of MSC, we generated a novel MSC line and its descendants lacking functional Rho GTPases and Rho GTPase signaling components. Unexpectedly, our data revealed that Rho GTPase signaling is required for TGFbeta-induced expression of alpha-smooth muscle actin (alphaSMA) but not of collagen I alpha1 (col1a1). Whereas loss of RhoA and Cdc42 reduced alphaSMA expression, ablation of the Rac1 gene had the opposite effect. Although actin polymerization and MRTFa were crucial for TGFbeta-induced alphaSMA expression, neither Arp2/3-dependent actin polymerization nor cofilin-dependent severing and depolymerization of F-actin were required. Instead, F-actin levels were dependent on cell contraction, and TGFbeta-induced actin polymerization correlated with increased cell contraction mediated by RhoA and Cdc42. Finally, we observed impaired collagen I secretion in MSC lacking RhoA or Cdc42. These data give novel molecular insights into the role of Rho GTPases in TGFbeta signaling and have implications for our understanding of MSC function in fibrosis. PMID- 29700114 TI - Disruption of protein kinase A localization induces acrosomal exocytosis in capacitated mouse sperm. AB - Protein kinase A (PKA) is a broad-spectrum Ser/Thr kinase involved in the regulation of several cellular activities. Thus, its precise activation relies on being localized at specific subcellular places known as discrete PKA signalosomes. A-Kinase anchoring proteins (AKAPs) form scaffolding assemblies that play a pivotal role in PKA regulation by restricting its activity to specific microdomains. Because one of the first signaling events observed during mammalian sperm capacitation is PKA activation, understanding how PKA activity is restricted in space and time is crucial to decipher the critical steps of sperm capacitation. Here, we demonstrate that the anchoring of PKA to AKAP is not only necessary but also actively regulated during sperm capacitation. However, we find that once capacitated, the release of PKA from AKAP promotes a sudden Ca2+ influx through the sperm-specific Ca2+ channel CatSper, starting a tail-to-head Ca2+ propagation that triggers the acrosome reaction. Three-dimensional super resolution imaging confirmed a redistribution of PKA within the flagellar structure throughout the capacitation process, which depends on anchoring to AKAP. These results represent a new signaling event that involves CatSper Ca2+ channels in the acrosome reaction, sensitive to PKA stimulation upon release from AKAP. PMID- 29700113 TI - Autophagy regulates exosomal release of prions in neuronal cells. AB - Prions are protein-based infectious agents that autocatalytically convert the cellular prion protein PrPC to its pathological isoform PrPSc Subsequent aggregation and accumulation of PrPSc in nervous tissues causes several invariably fatal neurodegenerative diseases in humans and animals. Prions can infect recipient cells when packaged into endosome-derived nanoparticles called exosomes, which are present in biological fluids such as blood, urine, and saliva. Autophagy is a basic cellular degradation and recycling machinery that also affects exosomal processing, but whether autophagy controls release of prions in exosomes is unclear. Our work investigated the effect of autophagy modulation on exosomal release of prions and how this interplay affects cellular prion infection. Exosomes isolated from cultured murine central neuronal cells (CAD5) and peripheral neuronal cells (N2a) contained prions as shown by immunoblotting for PrPSc, prion-conversion activity, and cell culture infection. We observed that autophagy stimulation with the mTOR inhibitor rapamycin strongly inhibited exosomal prion release. In contrast, inhibition of autophagy by wortmannin or CRISPR/Cas9-mediated knockout of the autophagy protein Atg5 (autophagy-related 5) greatly increased the release of exosomes and exosome associated prions. We also show that a difference in exosomal prion release between CAD5 and N2a cells is related to differences at the level of basal autophagy. Taken together, our results indicate that autophagy modulation can control lateral transfer of prions by interfering with their exosomal release. We describe a novel role of autophagy in the prion life cycle, an understanding that may provide useful targets for containing prion diseases. PMID- 29700115 TI - COX-2 expression mediated by calcium-TonEBP signaling axis under hyperosmotic conditions serves osmoprotective function in nucleus pulposus cells. AB - The nucleus pulposus (NP) of intervertebral discs experiences dynamic changes in tissue osmolarity because of diurnal loading of the spine. TonEBP/NFAT5 is a transcription factor that is critical in osmoregulation as well as survival of NP cells in the hyperosmotic milieu. The goal of this study was to investigate whether cyclooxygenase-2 (COX-2) expression is osmoresponsive and dependent on TonEBP, and whether it serves an osmoprotective role. NP cells up-regulated COX-2 expression in hyperosmotic media. The induction of COX-2 depended on elevation of intracellular calcium levels and p38 MAPK pathway, but independent of calcineurin signaling as well as MEK/ERK and JNK pathways. Under hyperosmotic conditions, both COX-2 mRNA stability and its proximal promoter activity were increased. The proximal COX-2 promoter (-1840/+123 bp) contained predicted binding sites for TonEBP, AP-1, NF-kappaB, and C/EBP-beta. While COX-2 promoter activity was positively regulated by both AP-1 and NF-kappaB, AP-1 had no effect and NF-kappaB negatively regulated COX-2 protein levels under hyperosmotic conditions. On the other hand, TonEBP was necessary for both COX-2 promoter activity and protein up regulation in response to hyperosmotic stimuli. Ex vivo disc organ culture studies using hypomorphic TonEBP+/- mice confirmed that TonEBP is required for hyperosmotic induction of COX-2. Importantly, the inhibition of COX-2 activity under hyperosmotic conditions resulted in decreased cell viability, suggesting that COX-2 plays a cytoprotective and homeostatic role in NP cells for their adaptation to dynamically loaded hyperosmotic niches. PMID- 29700116 TI - Comparative analysis of Parkinson's disease-associated genes in mice reveals altered survival and bioenergetics of Parkin-deficient dopamine neurons. AB - Many mutations in genes encoding proteins such as Parkin, PTEN-induced putative kinase 1 (PINK1), protein deglycase DJ-1 (DJ-1 or PARK7), leucine-rich repeat kinase 2 (LRRK2), and alpha-synuclein have been linked to familial forms of Parkinson's disease (PD). The consequences of these mutations, such as altered mitochondrial function and pathological protein aggregation, are starting to be better understood. However, little is known about the mechanisms explaining why alterations in such diverse cellular processes lead to the selective loss of dopamine (DA) neurons in the substantia nigra (SNc) in the brain of individuals with PD. Recent work has shown that one of the reasons for the high vulnerability of SNc DA neurons is their high basal rate of mitochondrial oxidative phosphorylation (OXPHOS), resulting from their highly complex axonal arborization. Here, we examined whether axonal growth and basal mitochondrial function are altered in SNc DA neurons from Parkin-, Pink1-, or DJ-1-KO mice. We provide evidence for increased basal OXPHOS in Parkin-KO DA neurons and for reduced survival of DA neurons that have a complex axonal arbor. The surviving smaller neurons exhibited reduced vulnerability to the DA neurotoxin and mitochondrial complex I inhibitor MPP+, and this reduction was associated with reduced expression of the DA transporter. Finally, we found that glial cells play a role in the reduced resilience of DA neurons in these mice and that WT Parkin overexpression rescues this phenotype. Our results provide critical insights into the complex relationship between mitochondrial function, axonal growth, and genetic risk factors for PD. PMID- 29700118 TI - The 3' mRNA I-shaped structure of maize necrotic streak virus binds to eukaryotic translation factors for eIF4F-mediated translation initiation. AB - Unlike the mRNAs of their eukaryotic hosts, many RNAs of viruses lack a 5' m7GpppN cap and the 3' polyadenosine tail, and yet they are translated efficiently. Plant RNA viruses, in particular, have complex structures within their mRNA UTRs that allow them to bypass some cellular translation control steps. In the 3' UTR of maize necrotic streak virus (MNeSV), an I-shaped RNA structure (ISS) has been shown to bind eukaryotic initiation factor (eIF)4F and to mediate viral translation initiation. A 5'-3' RNA "kissing-loop" interaction is required for optimal translation. However, the details of how the 3' ISS mediates translation initiation are not well understood. Here, we studied the binding of the 3' ISS with eIFs. The eIF4A-eIF4B complex was found to increase binding affinity of eIF4F with the 3' ISS by 4-fold (from KD = 173 +/- 34 nm to KD = 48 +/- 11 nm). Pre-steady-state analysis indicated that the eIF4A-eIF4B complex increased the RNA association rate and decreased the dissociation rate in an ATP-independent manner. Furthermore, our findings suggest that eIF4F could promote binding of the 3' ISS with the MNeSV 5'UTR, enhancing the long-distance kissing-loop interaction. However, the association of the 5'UTR with the 3' ISS eIF4F complex did not increase 40S ribosomal subunit binding affinity. These quantitative results suggest a stepwise model in which the first committed step is eIF4F binding to the 3' ISS, followed by an interaction with the 5'UTR and subsequent 40S ribosomal subunit binding. PMID- 29700117 TI - Sterol carrier protein-2 deficiency attenuates diet-induced dyslipidemia and atherosclerosis in mice. AB - Intracellular cholesterol transport proteins move cholesterol to different subcellular compartments and thereby regulate its final metabolic fate. In hepatocytes, for example, delivery of high-density lipoprotein (HDL)-associated cholesterol for bile acid synthesis or secretion into bile facilitates cholesterol elimination from the body (anti-atherogenic effect), whereas delivery for esterification and subsequent incorporation into apolipoprotein B-containing atherogenic lipoproteins (e.g. very-low-density lipoprotein (VLDL)) enhances cholesterol secretion into the systemic circulation (pro-atherogenic effect). Intracellular cholesterol transport proteins such as sterol carrier protein-2 (SCP2) should, therefore, play a role in regulating these pro- or anti atherosclerotic processes. Here, we sought to evaluate the effects of SCP2 deficiency on the development of diet-induced atherosclerosis. We generated LDLR /- mice deficient in SCP2/SCPx (LS) and examined the effects of this deficiency on Western diet-induced atherosclerosis. SCP2/SCPx deficiency attenuated atherosclerosis in LS mice by >80% and significantly reduced plasma cholesterol and triglyceride levels. Investigation of the likely underlying mechanisms revealed a significant reduction in intestinal cholesterol absorption (given as an oral gavage) in SCP2/SCPx-deficient mice. Consistently, siRNA-mediated knockdown of SCP2 in intestinal cells significantly reduced cholesterol uptake. Furthermore, hepatic triglyceride/VLDL secretion from the liver or hepatocytes isolated from SCP2/SCPx-deficient mice was significantly reduced. These results indicate an important regulatory role for SCP2 deficiency in attenuating diet induced atherosclerosis by limiting intestinal cholesterol absorption and decreasing hepatic triglyceride/VLDL secretion. These findings suggest targeted inhibition of SCP2 as a potential therapeutic strategy to reduce Western diet induced dyslipidemia and atherosclerosis. PMID- 29700119 TI - Assembly of human C-terminal binding protein (CtBP) into tetramers. AB - C-terminal binding protein 1 (CtBP1) and CtBP2 are transcriptional coregulators that repress numerous cellular processes, such as apoptosis, by binding transcription factors and recruiting chromatin-remodeling enzymes to gene promoters. The NAD(H)-linked oligomerization of human CtBP is coupled to its co transcriptional activity, which is implicated in cancer progression. However, the biologically relevant level of CtBP assembly has not been firmly established; nor has the stereochemical arrangement of the subunits above that of a dimer. Here, multi-angle light scattering (MALS) data established the NAD+- and NADH-dependent assembly of CtBP1 and CtBP2 into tetramers. An examination of subunit interactions within CtBP1 and CtBP2 crystal lattices revealed that both share a very similar tetrameric arrangement resulting from assembly of two dimeric pairs, with specific interactions probably being sensitive to NAD(H) binding. Creating a series of mutants of both CtBP1 and CtBP2, we tested the hypothesis that the crystallographically observed interdimer pairing stabilizes the solution tetramer. MALS data confirmed that these mutants disrupt both CtBP1 and CtBP2 tetramers, with the dimer generally remaining intact, providing the first stereochemical models for tetrameric assemblies of CtBP1 and CtBP2. The crystal structure of a subtle destabilizing mutant suggested that small structural perturbations of the hinge region linking the substrate- and NAD-binding domains are sufficient to weaken the CtBP1 tetramer. These results strongly suggest that the tetramer is important in CtBP function, and the series of CtBP mutants reported here can be used to investigate the physiological role of the tetramer. PMID- 29700120 TI - Protease-Activated Receptor-2 Plays a Critical Role in Vascular Inflammation and Atherosclerosis in Apolipoprotein E-Deficient Mice. AB - BACKGROUND: The coagulation system is closely linked with vascular inflammation, although the underlying mechanisms are still obscure. Recent studies show that protease-activated receptor (PAR)-2, a major receptor of activated factor X, is expressed in both vascular cells and leukocytes, suggesting that PAR-2 may contribute to the pathogenesis of inflammatory diseases. Here we investigated the role of PAR-2 in vascular inflammation and atherogenesis. METHODS: We generated apolipoprotein E-deficient ( ApoE-/-) mice lacking systemic PAR-2 expression ( PAR-2-/- ApoE-/-). ApoE-/- mice, which lack or express PAR-2 only in bone marrow (BM) cells, were also generated by BM transplantation. Atherosclerotic lesions were investigated after 20 weeks on a Western-type diet by histological analyses, quantitative reverse transcription polymerase chain reaction, and Western blotting. In vitro experiments using BM-derived macrophages were performed to confirm the proinflammatory roles of PAR-2. The association between plasma activated factor X level and the severity of coronary atherosclerosis was also examined in humans who underwent coronary intervention. RESULTS: PAR-2-/- ApoE-/- mice showed reduced atherosclerotic lesions in the aortic arch ( P<0.05) along with features of stabilized atherosclerotic plaques, such as less lipid deposition ( P<0.05), collagen loss ( P<0.01), macrophage accumulation ( P<0.05), and inflammatory molecule expression ( P<0.05) compared with ApoE-/- mice. Systemic PAR2 deletion in ApoE-/-mice significantly decreased the expression of inflammatory molecules in the aorta. The results of BM transplantation experiments demonstrated that PAR-2 in hematopoietic cells contributed to atherogenesis in ApoE-/- mice. PAR-2 deletion did not alter metabolic parameters. In vitro experiments demonstrated that activated factor X or a specific peptide agonist of PAR-2 significantly increased the expression of inflammatory molecules and lipid uptake in BM-derived macrophages from wild-type mice compared with those from PAR-2-deficient mice. Activation of nuclear factor-kappaB signaling was involved in PAR-2-associated vascular inflammation and macrophage activation. In humans who underwent coronary intervention, plasma activated factor X level independently correlated with the severity of coronary atherosclerosis as determined by Gensini score ( P<0.05) and plaque volume ( P<0.01). CONCLUSIONS: PAR-2 signaling activates macrophages and promotes vascular inflammation, increasing atherosclerosis in ApoE-/- mice. This signaling pathway may also participate in atherogenesis in humans. PMID- 29700121 TI - Genetic Lineage Tracing of Nonmyocyte Population by Dual Recombinases. AB - BACKGROUND: Whether the adult mammalian heart harbors cardiac stem cells for regeneration of cardiomyocytes is an important yet contentious topic in the field of cardiovascular regeneration. The putative myocyte stem cell populations recognized without specific cell markers, such as the cardiosphere-derived cells, or with markers such as Sca1+, Bmi1+, Isl1+, or Abcg2+ cardiac stem cells have been reported. Moreover, it remains unclear whether putative cardiac stem cells with unknown or unidentified markers exist and give rise to de novo cardiomyocytes in the adult heart. METHODS: To address this question without relying on a particular stem cell marker, we developed a new genetic lineage tracing system to label all nonmyocyte populations that contain putative cardiac stem cells. Using dual lineage tracing system, we assessed whether nonmyocytes generated any new myocytes during embryonic development, during adult homeostasis, and after myocardial infarction. Skeletal muscle was also examined after injury for internal control of new myocyte generation from nonmyocytes. RESULTS: By this stem cell marker-free and dual recombinases-mediated cell tracking approach, our fate mapping data show that new myocytes arise from nonmyocytes in the embryonic heart, but not in the adult heart during homeostasis or after myocardial infarction. As positive control, our lineage tracing system detected new myocytes derived from nonmyocytes in the skeletal muscle after injury. CONCLUSIONS: This study provides in vivo genetic evidence for nonmyocyte to myocyte conversion in embryonic but not adult heart, arguing again the myogenic potential of putative stem cell populations for cardiac regeneration in the adult stage. This study also provides a new genetic strategy to identify endogenous stem cells, if any, in other organ systems for tissue repair and regeneration. PMID- 29700122 TI - COSCA (Core Outcome Set for Cardiac Arrest) in Adults: An Advisory Statement From the International Liaison Committee on Resuscitation. AB - Cardiac arrest effectiveness trials have traditionally reported outcomes that focus on survival. A lack of consistency in outcome reporting between trials limits the opportunities to pool results for meta-analysis. The COSCA initiative (Core Outcome Set for Cardiac Arrest), a partnership between patients, their partners, clinicians, research scientists, and the International Liaison Committee on Resuscitation, sought to develop a consensus core outcome set for cardiac arrest for effectiveness trials. Core outcome sets are primarily intended for large, randomized clinical effectiveness trials (sometimes referred to as pragmatic trials or phase III/IV trials) rather than for pilot or efficacy studies. A systematic review of the literature combined with qualitative interviews among cardiac arrest survivors was used to generate a list of potential outcome domains. This list was prioritized through a Delphi process, which involved clinicians, patients, and their relatives/partners. An international advisory panel narrowed these down to 3 core domains by debate that led to consensus. The writing group refined recommendations for when these outcomes should be measured and further characterized relevant measurement tools. Consensus emerged that a core outcome set for reporting on effectiveness studies of cardiac arrest (COSCA) in adults should include survival, neurological function, and health-related quality of life. This should be reported as survival status and modified Rankin scale score at hospital discharge, at 30 days, or both. Health-related quality of life should be measured with >=1 tools from Health Utilities Index version 3, Short-Form 36-Item Health Survey, and EuroQol 5D-5L at 90 days and at periodic intervals up to 1 year after cardiac arrest, if resources allow. PMID- 29700123 TI - ILCOR Scientific Knowledge Gaps and Clinical Research Priorities for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care: A Consensus Statement. AB - Despite significant advances in the field of resuscitation science, important knowledge gaps persist. Current guidelines for resuscitation are based on the International Liaison Committee on Resuscitation 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations, which includes treatment recommendations supported by the available evidence. The writing group developed this consensus statement with the goal of focusing future research by addressing the knowledge gaps identified during and after the 2015 International Liaison Committee on Resuscitation evidence evaluation process. Key publications since the 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations are referenced, along with known ongoing clinical trials that are likely to affect future guidelines. PMID- 29700124 TI - Biodistribution and Radiation Dosimetry of 124I-DPA-713, a PET Radiotracer for Macrophage-Associated Inflammation. AB - Whole-body PET/CT was performed using 124I-DPA-713, a radioligand for the 18-kDa translocator protein (TSPO), to determine biodistribution and radiation dosimetry. Methods: Healthy subjects aged 18-65 y underwent whole-body PET/CT either at 4, 24, and 48 h or at 24, 48, and 72 h after intravenous injection of 124I-DPA-713. Time-activity curves were generated and used to calculate organ time-integrated activity coefficients for each subject. The resulting time integrated activity coefficients provided input data for calculation of organ absorbed doses and effective dose for each subject using OLINDA. Subjects were genotyped for the TSPO polymorphism rs6971, and plasma protein binding of 124I DPA-713 was measured. Results: Three male and 3 female adults with a mean age of 40 +/- 19 y were imaged. The mean administered activity and mass were 70.5 +/- 5.1 MBq (range, 62.4-78.1 MBq) and 469 +/- 34 ng (range, 416-520 ng), respectively. There were no adverse or clinically detectable pharmacologic effects in any of the 6 subjects. No changes in vital signs, laboratory values, or electrocardiograms were observed. 124I-DPA-713 cleared rapidly (4 h after injection) from the lungs, with hepatic elimination and localization to the gastrointestinal tract. The mean effective dose over the 6 subjects was 0.459 +/- 0.127 mSv/MBq, with the liver being the dose-limiting organ (0.924 +/- 0.501 mGy/MBq). The percentage of free radiotracer in blood was approximately 30% at 30 and 60 min after injection. Conclusion: 124I-DPA-713 clears rapidly from the lungs, with predominantly hepatic elimination, and is safe and well tolerated in healthy adults. PMID- 29700125 TI - 18F-FAC PET Selectively Images Liver-Infiltrating CD4 and CD8 T Cells in a Mouse Model of Autoimmune Hepatitis. AB - Immune cell-mediated attack on the liver is a defining feature of autoimmune hepatitis and hepatic allograft rejection. Despite an assortment of diagnostic tools, invasive biopsies remain the only method for identifying immune cells in the liver. We evaluated whether PET imaging with radiotracers that quantify immune activation (18F-FDG and 18F-1-(2'-deoxy-2'-fluoro arabinofuranosyl)cytosine [18F-FAC]) and hepatocyte biology (18F-2-deoxy-2 fluoroarabinose [18F-DFA]) can visualize and quantify liver-infiltrating immune cells and hepatocyte inflammation, respectively, in a preclinical model of autoimmune hepatitis. Methods: Mice treated with concanavalin A (ConA) to induce a model of autoimmune hepatitis or vehicle were imaged with 18F-FDG, 18F-FAC, and 18F-DFA PET. Immunohistochemistry, digital autoradiography, and ex vivo accumulation assays were used to localize areas of altered radiotracer accumulation in the liver. For comparison, mice treated with an adenovirus to induce a viral hepatitis were imaged with 18F-FDG, 18F-FAC, and 18F-DFA PET. 18F FAC PET was performed on mice treated with ConA and vehicle or with ConA and dexamethasone. Biopsy samples of patients with autoimmune hepatitis were immunostained for deoxycytidine kinase. Results: Hepatic accumulation of 18F-FDG and 18F-FAC was 173% and 61% higher, respectively, and hepatic accumulation of 18F-DFA was 41% lower, in a mouse model of autoimmune hepatitis than in control mice. Increased hepatic 18F-FDG accumulation was localized to infiltrating leukocytes and inflamed sinusoidal endothelial cells, increased hepatic 18F-FAC accumulation was concentrated in infiltrating CD4 and CD8 cells, and decreased hepatic 18F-DFA accumulation was apparent in hepatocytes throughout the liver. In contrast, viral hepatitis increased hepatic 18F-FDG accumulation by 109% and decreased hepatic 18F-DFA accumulation by 20% but had no effect on hepatic 18F FAC accumulation (nonsignificant 2% decrease). 18F-FAC PET provided a noninvasive biomarker of the efficacy of dexamethasone for treating the autoimmune hepatitis model. Infiltrating leukocytes in liver biopsy samples from patients with autoimmune hepatitis express high levels of deoxycytidine kinase, a rate-limiting enzyme in the accumulation of 18F-FAC. Conclusion: Our data suggest that PET can be used to noninvasively visualize activated leukocytes and inflamed hepatocytes in a mouse model of autoimmune hepatitis. PMID- 29700126 TI - Imaging Melphalan Therapy Response in Preclinical Extramedullary Multiple Myeloma with 18F-FDOPA and 18F-FDG PET. AB - Multiple myeloma (MM) is a debilitating neoplasm of terminally differentiated plasma B cells that resulted in over 13,000 deaths in 2017 alone. Combination therapies involving melphalan, a small-molecule DNA alkylating agent, are commonly prescribed to patients with relapsed or refractory MM, necessitating the stratification of responding patients to minimize toxicities and improve quality of life. Here, we evaluated the use of 3,4-dihydroxy-6-18F-fluoro-l-phenylalanine (18F-FDOPA), a clinically available PET radiotracer with specificity to the L type amino acid transporter 1 (LAT1), which also mediates melphalan uptake, for imaging melphalan therapy response in a preclinical immunocompetent model of MM. Methods: C57BL/KaLwRij mice were implanted subcutaneously with unilateral murine green fluorescent protein-expressing 5TGM1 tumors and divided into 3 independent groups: untreated, treated beginning week 2 after tumor implantation, and treated beginning week 3 after tumor implantation. The untreated and week 2 treated groups were imaged with preclinical MRI and dynamic 18F-FDG and 18F-FDOPA PET/CT at week 4 on separate, contiguous days, whereas the week 3 treated group was longitudinally imaged weekly for 3 wk. Metabolic tumor volume, total lesion avidity, SUVmax, and total uptake were calculated for both tracers. Immunohistochemistry was performed on representative tissue from all groups for LAT1 and glucose transporter 1 (GLUT1) expression. Results: Melphalan therapy induced a statistically significant reduction in lesion avidity and uptake for both 18F-FDG and 18F-FDOPA. There was no visible effect on GLUT1 expression, but LAT1 density increased in the week 2 treated group. Longitudinal imaging of the week 3 treated group showed variable changes in 18F-FDG and 18F-FDOPA uptake, with an increase in 18F-FDOPA lesion avidity in the second week relative to baseline. LAT1 and GLUT1 surface density in the untreated and week 3 treated groups were qualitatively similar. Conclusion: 18F-FDOPA PET/CT complemented 18F FDG PET/CT in imaging melphalan therapy response in preclinical extramedullary MM. 18F-FDOPA uptake was linked to LAT1 expression and melphalan response, with longitudinal imaging suggesting stabilization of LAT1 levels and melphalan tumor cytotoxicity. Future work will explore additional MM cell lines with heterogeneous LAT1 expression and response to melphalan therapy. PMID- 29700127 TI - 18F-Alfatide II PET/CT for Identification of Breast Cancer: A Preliminary Clinical Study. AB - 18F-alfatide II has been proven to have excellent clinical translational potential. In this study, we investigated 18F-alfatide II for identifying breast cancer and compared the performances between 18F-alfatide II and 18F-FDG. Methods: Forty-four female patients with suspected primary breast cancer were recruited. PET/CT images using 18F-alfatide II and 18F-FDG were acquired within 7 d. Tracer uptake in breast lesions was evaluated by visual analysis, and semiquantitative analysis with SUVmax and SUVmean Results: Forty-two breast cancer lesions and 11 benign breast lesions were confirmed by histopathology in 44 patients. Both 18F-alfatide II and 18F-FDG had higher uptake in breast cancer lesions than in benign breast lesions (P < 0.05 for 18F-alfatide II, P < 0.05 for 18F-FDG). The area under the curve of 18F-alfatide II was slightly less than that of 18F-FDG. Both 18F-alfatide II and 18F-FDG had high sensitivity (88.1% vs. 90.5%), high positive predictive value (88.1% vs. 88.4%), moderate specificity (54.5% vs. 54.5%), and moderate negative predictive value (54.5% vs. 60.0%) for differentiating breast cancer from benign breast lesions. By combining 18F alfatide II and 18F-FDG, the sensitivity and negative predictive value significantly increased to 97.6% and 85.7%, respectively, with positive predictive value slightly increased to 89.1% and no change to the specificity (54.5%). The uptake of 18F-alfatide II (SUVmax: 3.77 +/- 1.78) was significantly lower than that of 18F-FDG (SUVmax: 7.37 +/- 4.48) in breast cancer lesions (P < 0.05). 18F-alfatide II uptake in triple-negative subtype was significantly lower than that in luminal A and luminal B subtypes. By contrast, human epidermal growth factor receptor-2 (HER-2)-overexpressing subtype had higher 18F-FDG uptake than the other 3 subtypes. There were 8 breast cancer lesions with higher 18F alfatide II uptake than 18F-FDG uptake, which all had a common characteristic that HER-2 expression was negative and estrogen receptor expression was strongly positive. Conclusion: 18F-alfatide II is suitable for clinical use in breast cancer patients. 18F-alfatide II is of good performance, but not superior to 18F FDG in identifying breast cancer. 18F-alfatide II may have superiority to 18F-FDG in detecting breast cancer with strongly positive estrogen receptor expression and negative HER-2 expression. PMID- 29700128 TI - Neurometabolic Resting-State Networks Derived from Seed-Based Functional Connectivity Analysis. PMID- 29700129 TI - Regional Myocardial Perfusion Disturbance in Experimental Chronic Chagas Cardiomyopathy. AB - Altered myocardial perfusion is a common finding in chronic Chagas cardiomyopathy (CCC), but its underlying histologic changes have not been elucidated. We investigated the occurrence of myocardial perfusion defects (MPDs) and the correlated regional changes to histology in an experimental model of CCC in hamsters. Methods: Female Syrian hamsters (n = 34) were infected with 3.5 * 104 to 105 trypomastigote forms of Trypanosoma cruzi, Y strain, and 6-10 mo afterward underwent in vivo imaging including resting 99mTc-sestamibi SPECT, segmental and global left ventricular function assessment using 2-dimensional echocardiography, and 18F-FDG PET for evaluation of myocardial viability. Histologic analysis included quantification of fibrosis, inflammatory infiltration, and the diameter and density of myocardial microcirculation. Results: MPDs were present in 17 (50%) of the infected animals. Histologic analysis revealed no transmural scar in segments with an MPD, and normal or mildly reduced 18F-FDG uptake, indicating viable myocardium. Infected animals with an MPD, in comparison to infected animals without an MPD and control animals, showed a lower left ventricular ejection fraction (P = 0.012), a higher wall motion score index (P = 0.004), and a higher extent of inflammatory infiltration (P = 0.018) but a similar extent of fibrosis (P = 0.15) and similar microvascular diameter and density (P > 0.05). Segments with an MPD (n = 65), as compared with normally perfused regions in the same animal (n = 156), showed a higher wall motion score index (P = 0.005) but a similar extent of inflammatory infiltration, a similar extent of fibrosis, and a similar microvascular diameter and density. Conclusion: Resting MPDs are frequent in experimental CCC and are associated with myocardial inflammation but do not designate scar tissue, corresponding to regions with metabolically viable myocardium. PMID- 29700130 TI - Embrace Progress. PMID- 29700131 TI - Complete Genome Sequences of Two Novel Staphylococcus aureus Podoviruses of Potential Therapeutic Use, vB_SauP_phiAGO1.3 and vB_SauP_phiAGO1.9. AB - Here, we report the genome sequences of two Staphylococcus aureus phages belonging to the family Podoviridae and subfamily Picovirinae, vB_SauP_phiAGO1.3 and vB_SauP_phiAGO1.9, which were isolated from Warsaw sewage. Analysis of their genomes provides valuable information about the diversity of phages belonging to the genus Rosenblumvirus and their genes that undergo evolutionary adaptation to cells of different host strains. PMID- 29700132 TI - Draft Genome Sequence of the Phytopathogenic Fungus Ganoderma boninense, the Causal Agent of Basal Stem Rot Disease on Oil Palm. AB - Ganoderma boninense is the dominant fungal pathogen of basal stem rot (BSR) disease on Elaeis guineensis We sequenced the nuclear genome of mycelia using both Illumina and Pacific Biosciences platforms for assembly of scaffolds. The draft genome comprised 79.24 Mb, 495 scaffolds, and 26,226 predicted coding sequences. PMID- 29700133 TI - Draft Genome Sequence of Novosphingobium sp. Strain HII-3, a Bacterium Capable of Degrading the Cembranoid alpha(beta)-2,7,11-Cembratriene-4,6-Diol to Farnesal. AB - Novosphingobium sp. HII-3, the first bacterium confirmed to degrade the cembranoid alpha(beta)-2,7,11-cembratriene-4,6-diol to farnesal, was isolated from cured tobacco leaf in Henan, China. Here, we report the annotated draft genome sequence of strain HII-3, which has an estimated size of 4.45 Mb and comprises 4,072 coding sequences. PMID- 29700134 TI - Draft Genome Sequence of Paucibacter aquatile CR182T, a Strain with Antimicrobial Activity Isolated from Freshwater of Nakdong River in South Korea. AB - This report details a draft genome sequence of Paucibacter aquatile CR182T, isolated from river water, which contains 5,523,543 bp, has a G+C content of 66.3%, and harbors 4,544 protein-coding genes in 4 contigs. These genome data provide insights into the genetic basis of this strain's antibacterial activity and adaptive mechanisms. PMID- 29700135 TI - Draft Genome Sequence of Multidrug-Resistant Escherichia coli NIVEDI-P44, Isolated from a Chicken Fecal Sample in Northeast India. AB - We report here the draft genome sequence of a multidrug-resistant Escherichia coli strain (NIVEDI-P44) isolated from a chicken fecal sample. The estimated genome size is 4.76 Mb, with a G+C content of 50.65%. The genome harbors multiple antibiotic resistance genes, blaDHA-1, mph(A), strA, strB, dfrA14, sul-2, tet(A), and qnrS1. PMID- 29700136 TI - Genome Sequence of the Brown Rot Fungal Pathogen Monilinia laxa. AB - Monilinia laxa (phylum Ascomycota) is a plant pathogen responsible for the brown rot blossom blight disease in stone fruit trees of the Rosaceae family, such as apricots. We report here the genome sequence of strain 8L of this species, which was assembled into 618 scaffolds, having a total size of 40.799 Mb and encoding 9,567 unique protein-coding genes. PMID- 29700137 TI - Draft Genome Sequence of the Extremely Desiccation-Tolerant Cyanobacterium Gloeocapsopsis sp. Strain AAB1. AB - Gloeocapsopsis sp. strain AAB1 is an extremely desiccation-tolerant cyanobacterium isolated from translucent quartz stones from the Atacama Desert (Chile). Here, we report its draft genome sequence, which consists of 137 contigs with an ~5.4-Mb genome size. The annotation revealed 5,641 coding DNA sequences, 38 tRNA genes, and 5 rRNA genes. PMID- 29700138 TI - Complete Sequence of the Intronless Mitochondrial Genome of the Saccharomyces cerevisiae Strain CW252. AB - The mitochondrial genomes of Saccharomyces cerevisiae strains contain up to 13 introns. An intronless recombinant genome introduced into the nuclear background of S. cerevisiae strain W303 gave the S. cerevisiae CW252 strain, which is used to model mitochondrial respiratory pathologies. The complete sequence of this mitochondrial genome was obtained using a hybrid assembling methodology. PMID- 29700139 TI - Complete Chromosome and Plasmid Sequences of Two Plant Pathogens, Dickeya solani Strains D s0432-1 and PPO 9019. AB - Dickeya solani species are emerging bacterial pathogens of Solanum tuberosum Here, we announce the complete genome sequences of two strains, Dickeya solani D s0432-1 and PPO 9019. Strain PPO 9019 represents the first described member of the genus Dickeya with an extrachromosomal genetic element. PMID- 29700140 TI - Complete Genome Sequences of Six Human Bocavirus Strains from Patients with Acute Gastroenteritis in the North Region of Brazil. AB - Human bocavirus (HBoV) is commonly associated with acute respiratory tract illness and gastroenteritis. We report six complete genomic sequences of HBoV strains from patients with gastroenteritis in Belem do Para and Tocantins in the North Region of Brazil. Phylogenetic analysis indicated that the six HBoV strains belong to genotypes 1, 2, and 3. PMID- 29700141 TI - Complete Genome Sequencing of a Novel Type of Omikronpapillomavirus 1 in Indian River Lagoon Bottlenose Dolphins (Tursiops truncatus). AB - The genome sequence of a papillomavirus was determined from fecal samples collected from bottlenose dolphins in the Indian River Lagoon, FL. The genome was 7,772 bp and displayed a typical papillomavirus genome organization. Phylogenetic analysis supported the bottlenose dolphin papillomavirus as being a novel type of Omikronpapillomavirus1. PMID- 29700142 TI - Complete Genome Sequence of Multiple-Antibiotic-Resistant Streptococcus parauberis Strain SPOF3K, Isolated from Diseased Olive Flounder (Paralichthys olivaceus). AB - Here, we report the complete genome sequence of multiple-antibiotic-resistant Streptococcus parauberis strain SPOF3K, isolated from the kidney of a diseased olive flounder in South Korea in 2013. Sequencing using a PacBio platform yielded a circular chromosome of 2,128,740 bp and a plasmid of 23,538 bp, harboring 2,123 and 24 protein-coding genes, respectively. PMID- 29700143 TI - Complete Genome Sequence of Sphingobium sp. Strain YG1, a Lignin Model Dimer Metabolizing Bacterium Isolated from Sediment in Kagoshima Bay, Japan. AB - Sphingobium sp. strain YG1 is a lignin model dimer-metabolizing bacterium newly isolated from sediment in Kagoshima, Japan, at a depth of 102 m. Here, we report the complete genome nucleotide sequence of strain YG1. PMID- 29700144 TI - Complete Genome Sequence of Methylomonas denitrificans Strain FJG1, an Obligate Aerobic Methanotroph That Can Couple Methane Oxidation with Denitrification. AB - Methylomonas denitrificans strain FJG1 is a member of the gammaproteobacterial methanotrophs. The sequenced genome of FJG1 reveals the presence of genes that encode methane, methanol, formaldehyde, and formate oxidation. It also contains genes that encode enzymes for nitrate reduction to nitrous oxide, consistent with the ability of FJG1 to couple denitrification with methane oxidation. PMID- 29700145 TI - Complete Genome Sequence of a Novel Porcine Circovirus Type 3 Strain, CH/GX/1776D/2017, Isolated from Guangxi, China. AB - Porcine circovirus type 3 (PCV3) was first described in 2016 in U.S. swine herds as a pathogenic agent for pigs. To date, PCV3 has been reported to be widely circulating in the United States, China, South Korea, Brazil, Italy, and Poland. Here, we report the genome sequence of a PCV3 strain (CH/GX/1776D/2017) isolated from Guangxi Province in southern China. The sequence data presented in this study will help us better understand the molecular characteristics and genetic diversity of PCV3 in China. PMID- 29700146 TI - Whole-Genome Sequences of 18 Bovine Alphaherpesvirus 1 Field Isolates from Pennsylvania and Minnesota. AB - Bovine alphaherpesvirus 1 (BHV-1), a member of the Herpesviridae family, causes respiratory and reproductive tract infections in cattle. Here, we report complete genome sequences of 18 field isolates of BHV-1 from Pennsylvania and Minnesota. PMID- 29700147 TI - Draft Genome Sequence of Plant Growth-Promoting Burkholderia sp. Strain BE12, Isolated from the Rhizosphere of Maize. AB - Burkholderia sp. strain BE12, isolated from a French agricultural soil, possesses antifungal activity against a set of phytopathogenic fungi and has friendly interactions with grapevine. Here, we present the draft genome sequence of BE12, along with genes related to plant growth-promoting traits and siderophores that this strain contains, supporting its plant growth and antifungal activities. PMID- 29700148 TI - Reevaluation of the Complete Genome Sequence of Magnetospirillum gryphiswaldense MSR-1 with Single-Molecule Real-Time Sequencing Data. AB - Magnetospirillum gryphiswaldense is a key organism for understanding magnetosome formation and magnetotaxis. As earlier studies suggested a high genomic plasticity, we (re)sequenced the type strain MSR-1 and the laboratory strain R3/S1. Both sequences differ by only 11 point mutations, but organization of the magnetosome island deviates from that of previous genome sequences. PMID- 29700149 TI - Complete Genome Sequence of the Freshwater Bacterium Beggiatoa leptomitoformis Strain D-401. AB - Here, we report the complete closed genome sequence and methylome analysis of Beggiatoa leptomitoformis strain D-401 (DSM 14945, UNIQEMU 779), which is quite different from the previously described Beggiatoa leptomitoformis neotype strain D-402T (DSM 14946, UNIQEM U 779) with regard to morphology and lithotrophic growth in the presence of thiosulfate. PMID- 29700150 TI - Draft Genome Sequence of the Putative Marine Pathogen Aquimarina sp. Strain I32.4. AB - Aquimarina sp. strain I32.4 (formerly Aquimarina sp. 'homaria') is a putative pathogen involved in epizootic shell disease in the American lobster (Homarus americanus). We report here the draft genome sequence for Aquimarina sp. strain I32.4 and describe virulence factors that may provide insight into its mechanism of pathogenicity. PMID- 29700151 TI - Genome Sequences of RIGVIR Oncolytic Virotherapy Virus and Five Other Echovirus 7 Isolates. AB - We report here the nearly complete Illumina-sequenced consensus genome sequences of six isolates of echovirus 7 (E7), including oncolytic virotherapy virus RIGVIR and the Wallace prototype. Amino acid identities within the coding region were highly conserved across all isolates, ranging from 95.31% to 99.73%. PMID- 29700152 TI - Discovery of Four Novel Circular Single-Stranded DNA Viruses in Fungus-Farming Termites. AB - Here, we describe four novel circular single-stranded DNA viruses discovered in fungus-farming termites (Odontotermes sp.). The viruses, named termite-associated circular virus 1 (TaCV-1) through TaCV-4, are most similar to members of the family Genomoviridae and were widely detected in African termite mounds. PMID- 29700153 TI - Genome Sequence of Australian Indigenous Wine Yeast Torulaspora delbrueckii COFT1 Using Nanopore Sequencing. AB - Here, we report the first sequenced genome of an indigenous Australian wine isolate of Torulaspora delbrueckii using the Oxford Nanopore MinION and Illumina HiSeq sequencing platforms. The genome size is 9.4 Mb and contains 4,831 genes. PMID- 29700154 TI - Draft Genome Sequence of Bacillus sp. Strain M21, Isolated from the Arid Area of Matmata, Tunisia. AB - Bacillus sp. strain M21 was isolated from an environmental sample. In antibacterial screenings, the strain inhibited growth of Gram-positive and Gram negative test strains. The genome was assembled into 69 contigs with a total size of 5.178 Mb. The strain contains at least nine biosynthetic gene clusters for the production of specialized metabolites. PMID- 29700156 TI - Complete Genome Sequence of a VIM-1-Producing Salmonella enterica subsp. enterica Serovar Infantis Isolate Derived from Minced Pork Meat. AB - Carbapenems are considered last-resort antibiotics used to treat human infections caused by multidrug-resistant bacteria. In 2011, VIM-1 carbapenemase-producing Salmonella enterica subsp. enterica serovar Infantis strains were isolated from livestock for the first time in Germany. Here, we announce the complete genome sequence of the first German blaVIM-1-harboring Salmonella Infantis isolate (15 SA01028) originating from food. PMID- 29700155 TI - Draft Genome Sequences of the Obligatory Marine Myxobacterial Strains Enhygromyxa salina SWB005 and SWB007. AB - The two marine myxobacterial strains Enhygromyxa salina SWB005 and SWB007 were isolated from coastal soil samples using Escherichia coli as bait for these predatory strains. These strains produce unique specialized metabolites. Genomes were assembled into 312 contigs for E. salina SWB005 (9.0 Mbp) and 192 contigs for E. salina SWB007 (10.6 Mbp). PMID- 29700157 TI - Draft Genome Sequence of the First South Korean Clinical Isolate of Burkholderia pseudomallei, H0901. AB - We report here the draft genome sequence of Burkholderia pseudomallei H0901. This strain was isolated in 2003 from the first melioidosis patient in South Korea. PMID- 29700158 TI - First Insights into the Genome Sequence of Clostridium thermopalmarium DSM 5974, a Butyrate-Producing Bacterium Isolated from Palm Wine. AB - Clostridium thermopalmarium is a moderate thermophilic, rod-shaped, and endospore forming bacterium, which was isolated from palm wine in Senegal. Butyrate is produced from a broad variety of sugar substrates. Here, we present the draft genome sequence of C. thermopalmarium DSM 5974 (2.822 Mb) containing 2,665 predicted protein-encoding genes. PMID- 29700159 TI - Draft Genome Sequence of the Interspecies Hybrid Saccharomyces pastorianus Strain HA2560, Isolated from a Municipal Wastewater Treatment Plant. AB - Saccharomyces pastorianus is an industrially relevant yeast frequently isolated from brewing environments. Here, we report the draft genome sequence of the S. pastorianus HA2560 strain isolated from a municipal wastewater treatment plant. PMID- 29700160 TI - Complete Genome Sequence of a Porcine Polyomavirus from Nasal Swabs of Pigs with Respiratory Disease. AB - Metagenomic sequencing of pooled nasal swabs from pigs with unexplained respiratory disease identified a large number of reads mapping to a previously uncharacterized porcine polyomavirus. Sus scrofa polyomavirus 2 was most closely related to betapolyomaviruses frequently detected in mammalian respiratory samples. PMID- 29700161 TI - Draft Genome Sequence of Burkholderia cepacia ATCC 17759, a Polyhydroxybutyrate Co-Valerate Copolymer-Producing Bacterium. AB - Burkholderia cepacia ATCC 17759, isolated from forest soils in Trinidad, accumulates large amounts of polyhydroxyalkanoate copolymers when grown on xylose, mannose, arabinose, other carbohydrates, and organic acid cosubstrates. This 8.72-Mb draft genome sequence of B. cepacia ATCC 17759 will provide better insight into this organism's utility in lignocellulose bioconversion. PMID- 29700162 TI - Draft Genome Sequence of the Thermophilic Acetogen Moorella humiferrea DSM 23265. AB - Moorella humiferrea is an endospore-forming, anaerobic, and thermophilic bacterium which was isolated from a terrestrial hydrothermal spring. M. humiferrea is able to use humic acid or 10-anthraquinone-2,6-disulfonate as an electron-shuttling compound for growth and Fe(III) reduction. The genome has a size of 2.629 Mb and contains 2,668 predicted protein-coding genes. PMID- 29700163 TI - Whole-Genome Sequence of Infectious Pancreatic Necrosis Virus Isolated from Farmed Brook Trout (Salvelinus fontinalis) in Pennsylvania. AB - Infectious pancreatic necrosis (IPN) is an acute contagious systemic disease affecting several fish species and a critical disease in the salmonid fish farming industry. Here, we report the complete genome sequence of IPN virus (IPNV) RNA segments A and B, isolated from a farmed brook trout in Pennsylvania. PMID- 29700164 TI - Draft Genome Sequence of Mycobacterium virginiense Strain GF75, Isolated from the Mud of a Swine Farm in Japan. AB - Mycobacterium virginiense, a newly described species of the Mycobacterium terrae complex, is a cause of tenosynovitis and osteomyelitis in the United States. Here, we report the 4,849,424-bp draft genome sequence of M. virginiense strain GF75, isolated from a mud sample taken from a Japanese swine farm. PMID- 29700165 TI - Complete Genome Sequences of Two Bacillus pumilus Strains from Cuatrocienegas, Coahuila, Mexico. AB - We assembled the complete genome sequences of Bacillus pumilus strains 145 and 150a from Cuatrocienegas, Mexico. We detected genes codifying for proteins potentially involved in antagonism (bacteriocins) and defense mechanisms (abortive infection bacteriophage proteins and 4-azaleucine resistance). Both strains harbored prophage sequences. Our results provide insights into understanding the establishment of microbial interactions. PMID- 29700167 TI - Moral narcissism and moral complicity in global health and humanitarian aid. PMID- 29700166 TI - Recurrent haemoptysis in a child with advanced cystic fibrosis lung disease. PMID- 29700168 TI - Phase I study of the heparanase inhibitor roneparstat: an innovative approach for ultiple myeloma therapy. PMID- 29700169 TI - Stability of fetal hemoglobin levels in patients receiving metformin therapy. PMID- 29700170 TI - Real-world treatment and outcomes among older adults with chronic lymphocytic leukemia before the novel agents era. PMID- 29700171 TI - Short-hairpin RNA against aberrant HBBIVSI-110(G>A) mRNA restores beta-globin levels in a novel cell model and acts as mono- and combination therapy for beta thalassemia in primary hematopoietic stem cells. PMID- 29700172 TI - The early expansion of anergic NKG2Apos/CD56dim/CD16neg natural killer represents a therapeutic target in haploidentical hematopoietic stem cell transplantation. AB - Natural killer cells are the first lymphocyte population to reconstitute early after non-myeloablative and T cell-replete haploidentical hematopoietic stem cell transplantation with post-transplant infusion of cyclophosphamide. The study herein characterizes the transient and predominant expansion starting from the second week following haploidentical hematopoietic stem cell transplantation of a donor-derived unconventional subset of NKp46neg-low/CD56dim/CD16neg natural killer cells expressing remarkably high levels of CD94/NKG2A. Both transcription and phenotypic profiles indicated that unconventional NKp46neg low/CD56dim/CD16neg cells are a distinct natural killer cell subpopulation with features of late stage differentiation, yet retaining proliferative capability and functional plasticity to generate conventional NKp46pos/CD56bright/CD16neg low cells in response to interleukin-15 plus interleukin-18. While present at low frequency in healthy donors, unconventional NKp46neg-low/CD56dim/CD16neg cells are greatly expanded in the seven weeks following haploidentical hematopoietic stem cell transplantation, and express high levels of the activating receptors NKG2D and NKp30 as well as of the lytic granules Granzyme-B and Perforin. Nonetheless, NKp46neg-low/CD56dim/CD16neg cells displayed a markedly defective cytotoxicity that could be reversed by blocking the inhibitory receptor CD94/NKG2A. These data open new and important perspectives to better understand the ontogenesis/homeostasis of human natural killer cells and to develop a novel immune-therapeutic approach that targets the inhibitory NKG2A check-point, thus unleashing natural killer cell alloreactivity early after haploidentical hematopoietic stem cell transplantation. PMID- 29700173 TI - The mutational landscape of 18 investigated genes clearly separates four subtypes of myelodysplastic/myeloproliferative neoplasms. PMID- 29700174 TI - Ceasing the use of the highest priority critically important antimicrobials does not adversely affect production, health or welfare parameters in dairy cows. AB - Due to scientific, public and political concern regarding antimicrobial resistance (AMR), several EU countries have already taken steps to reduce antimicrobial (AM) usage in production animal medicine, particularly that of the highest priority critically important AMs (HP-CIAs). While veterinarians are aware of issues surrounding AMR, potential barriers to change such as concerns of reduced animal health, welfare or production may inhibit progress towards more responsible AM prescribing. Farmers from seven dairy farms in South West England engaged in changing AM use through an active process of education and herd health planning meetings. Prescribing data were collected from veterinary sales records; production and health data were accessed via milk recording and farm-recorded data. This study demonstrates that cattle health and welfare-as measured by production parameters, fertility, udder health and mobility data and culling rates-can be maintained and even improved alongside a complete cessation in the use of HP-CIAs as well as an overall reduction of AM use on dairy farms. This study also identified a need to consider different metrics when analysing AM use data, including dose-based metrics as well as those of total quantities to allow better representation of the direction and magnitude of changes in AM use. PMID- 29700175 TI - Preliminary assessment of cognitive impairments in canine idiopathic epilepsy. AB - In humans, epilepsy can induce or accelerate cognitive impairment (CI). There is emerging evidence of CI in dogs with idiopathic epilepsy (IE) from recent epidemiological studies. The aim of our study was to assess CI in dogs with IE using two tests of cognitive dysfunction designed for use in a clinical setting. Dogs with IE (n=17) were compared against controls (n=18) in their performance in two tasks; a spatial working memory task and a problem-solving task. In addition, owners completed the Canine Cognitive Dysfunction Rating (CCDR) scale for their dog. The groups did not differ statistically with respect to age and breed. Dogs with IE performed significantly worse than controls on the spatial working memory task (P=0.016), but not on the problem solving task (P=0.683). CCDR scores were significantly higher in the IE group (P=0.016); however, no dogs reach the recommended threshold score for CCD diagnosis. Our preliminary data suggest that dogs with IE exhibit impairments in a spatial working memory task. Further research is required to explore the effect of IE on other cognitive abilities in dogs with a larger sample, characterising the age of onset, nature and progression of any impairments and the impact of anti-epileptic drugs. PMID- 29700176 TI - ECG in hyperkalaemia. PMID- 29700177 TI - Homeopathy - need it get so personal? PMID- 29700178 TI - Heating up: homeopathy debate turns 'nasty'. PMID- 29700179 TI - Government must act now on sentience. PMID- 29700180 TI - Vets criticise government on TB proposals. PMID- 29700182 TI - Remembering 'a colossus of the profession'. PMID- 29700183 TI - State-of-the-art camel care. AB - An international team of vets is providing expert care in the world's first dedicated camel hospital, explains Daniel Gillett. PMID- 29700184 TI - Wearing PPE: a culture change for vets. PMID- 29700186 TI - Johne's disease control: a challenging yet achievable goal. PMID- 29700187 TI - Understanding feline idiopathic cystitis. PMID- 29700189 TI - Behaviour survey of small animal vets and owners. PMID- 29700190 TI - Banning the use of electric shock collars. PMID- 29700192 TI - Brachyspira hyodysenteriae in apparently healthy pig herds. PMID- 29700191 TI - Support for Defra's position on homeopathy. PMID- 29700193 TI - Employers need to take ownership. PMID- 29700195 TI - N. C. Craig Sharp. AB - A vet whose journey took him from veterinary physiology, through pathology to sports science, a field in which he was world-renowned. PMID- 29700198 TI - Contrast thresholds reveal different visual masking functions in humans and praying mantises. AB - Recently, we showed a novel property of the Hassenstein-Reichardt detector, namely that insect motion detection can be masked by 'undetectable' noise, i.e. visual noise presented at spatial frequencies at which coherently moving gratings do not elicit a response (Tarawneh et al., 2017). That study compared the responses of human and insect motion detectors using different ways of quantifying masking (contrast threshold in humans and masking tuning function in insects). In addition, some adjustments in experimental procedure, such as presenting the stimulus at a short viewing distance, were necessary to elicit a response in insects. These differences offer alternative explanations for the observed difference between human and insect responses to visual motion noise. Here, we report the results of new masking experiments in which we test whether differences in experimental paradigm and stimulus presentation between humans and insects can account for the undetectable noise effect reported earlier. We obtained contrast thresholds at two signal and two noise frequencies in both humans and praying mantises (Sphodromantis lineola), and compared contrast threshold differences when noise has the same versus different spatial frequency as the signal. Furthermore, we investigated whether differences in viewing geometry had any qualitative impact on the results. Consistent with our earlier finding, differences in contrast threshold show that visual noise masks much more effectively when presented at signal spatial frequency in humans (compared to a lower or higher spatial frequency), while in insects, noise is roughly equivalently effective when presented at either the signal spatial frequency or lower (compared to a higher spatial frequency). The characteristic difference between human and insect responses was unaffected by correcting for the stimulus distortion caused by short viewing distances in insects. These findings constitute stronger evidence that the undetectable noise effect reported earlier is a genuine difference between human and insect motion processing, and not an artefact caused by differences in experimental paradigms. PMID- 29700199 TI - Functional characterization of DYRK1A missense variants associated with a syndromic form of intellectual deficiency and autism. AB - Haploinsufficiency of DYRK1A is a cause of a neurodevelopmental syndrome termed mental retardation autosomal dominant 7 (MRD7). Several truncation mutations, microdeletions and missense variants have been identified and result in a recognizable phenotypic profile, including microcephaly, intellectual disability, epileptic seizures, autism spectrum disorder and language delay. DYRK1A is an evolutionary conserved protein kinase which achieves full catalytic activity through tyrosine autophosphorylation. We used a heterologous mammalian expression system to explore the functional characteristics of pathogenic missense variants that affect the catalytic domain of DYRK1A. Four of the substitutions eliminated tyrosine autophosphorylation (L245R, F308V, S311F, S346P), indicating that these variants lacked kinase activity. Tyrosine phosphorylation of DYRK1A-L295F in mammalian cells was comparable to wild type, although the mutant showed lower catalytic activity and reduced thermodynamic stability in cellular thermal shift assays. In addition, we observed that one variant (DYRK1A-T588N) with a mutation outside the catalytic domain did not differ from wild-type DYRK1A in tyrosine autophosphorylation, catalytic activity or subcellular localization. These results suggest that the pathogenic missense variants in the catalytic domain of DYRK1A impair enzymatic function by affecting catalytic residues or by compromising the structural integrity of the kinase domain.This article has an associated First Person interview with the first author of the paper. PMID- 29700200 TI - External Validation of the PediBIRN Clinical Prediction Rule for Abusive Head Trauma. AB - BACKGROUND AND OBJECTIVES: A 4-variable abusive head trauma (AHT) clinical prediction rule (CPR) for use in the PICU was derived and validated for children <3 years of age by the Pediatric Brain Injury Research Network (PediBIRN). We aimed to externally validate PediBIRN as designed (PICU only) as well as using broader inclusion criteria (admitted children with head injuries). METHODS: This was a secondary analysis of a prospective multicenter study of pediatric head injuries at 5 Australian and New Zealand tertiary pediatric centers. Possible AHT was identified by clinician suspicion, epidemiology codes, or a high-risk group (<3 years of age, admitted, abnormal neuroimaging results). At 1 center, we additionally reviewed head injuries in the forensic database. We designated patients as positive for AHT, negative for AHT, or having indeterminate outcome after multidisciplinary review and applied the PediBIRN CPR, blinded to outcome, to PICU admissions only, and any head injury admissions. CPR accuracy was calculated by using 95% confidence intervals. RESULTS: One hundred and forty-one patients were admitted with abnormal neuroimaging results. Twenty-eight (20%) were positive for AHT, 94 (67%) were negative for AHT, and 19 (13%) had indeterminate outcome. Excluding indeterminate cases, in the PICU (n = 28), the CPR was 100% (75%-100%) sensitive and 11% (0%-48%) specific; in all admitted patients (n = 141), sensitivity was 96% (82%-100%) and specificity of 43% (32% 53%). CONCLUSIONS: This validation revealed high sensitivity and low specificity for PICU patients. Specificity was improved but moderate in a broader group of admitted head injury patients. PMID- 29700202 TI - A systematic survey of conformational states in beta1 and beta4 integrins using negative-stain electron microscopy. AB - Structural analyses of beta2 and beta3 integrins have revealed that they generally assume a compact bent conformation in the resting state and undergo a global conformational transition involving extension during upregulation of ligand affinity, collectively called the 'switchblade model'. This hypothesis, however, has not been extensively tested for other classes of integrins. We prepared a set of recombinant integrin ectodomain fragments including alphavbeta3, alpha2beta1, alpha3beta1, alpha5beta1, alpha6beta1 and alpha6beta4, and used negative-stain electron microscopy to examine their structures under various conditions. In contrast to alphavbeta3 integrin, which exhibited a severely bent conformation in low-affinity 5 mM Ca2+ conditions, all beta1 integrin heterodimers displayed a mixed population of half-bent to fully extended conformations. Moreover, they did not undergo significant conformational change upon activation by Mn2+ Integrin alpha6beta4 was even more resistant to conformational regulation, showing a completely extended structure regardless of the buffer conditions. These results suggest that the mechanisms of conformational regulation of integrins are more diverse and complex than previously thought, requiring more experimental scrutiny for each integrin subfamily member. PMID- 29700201 TI - Antibiotic Allergy in Pediatrics. AB - The overlabeling of pediatric antibiotic allergy represents a huge burden in society. Given that up to 10% of the US population is labeled as penicillin allergic, it can be estimated that at least 5 million children in this country are labeled with penicillin allergy. We now understand that most of the cutaneous symptoms that are interpreted as drug allergy are likely viral induced or due to a drug-virus interaction, and they usually do not represent a long-lasting, drug specific, adaptive immune response to the antibiotic that a child received. Because most antibiotic allergy labels acquired in childhood are carried into adulthood, the overlabeling of antibiotic allergy is a liability that leads to unnecessary long-term health care risks, costs, and antibiotic resistance. Fortunately, awareness of this growing burden is increasing and leading to more emphasis on antibiotic allergy delabeling strategies in the adult population. There is growing literature that is used to support the safe and efficacious use of tools such as skin testing and drug challenge to evaluate and manage children with antibiotic allergy labels. In addition, there is an increasing understanding of antibiotic reactivity within classes and side-chain reactions. In summary, a better overall understanding of the current tools available for the diagnosis and management of adverse drug reactions is likely to change how pediatric primary care providers evaluate and treat patients with such diagnoses and prevent the unnecessary avoidance of antibiotics, particularly penicillins. PMID- 29700204 TI - SunRiSE - measuring translation elongation at single-cell resolution by means of flow cytometry. AB - The rate at which ribosomes translate mRNAs regulates protein expression by controlling co-translational protein folding and mRNA stability. Many factors regulate translation elongation, including tRNA levels, codon usage and phosphorylation of eukaryotic elongation factor 2 (eEF2). Current methods to measure translation elongation lack single-cell resolution, require expression of multiple transgenes and have never been successfully applied ex vivo Here, we show, by using a combination of puromycilation detection and flow cytometry (a method we call 'SunRiSE'), that translation elongation can be measured accurately in primary cells in pure or heterogenous populations isolated from blood or tissues. This method allows for the simultaneous monitoring of multiple parameters, such as mTOR or S6K1/2 signaling activity, the cell cycle stage and phosphorylation of translation factors in single cells, without elaborated, costly and lengthy purification procedures. We took advantage of SunRiSE to demonstrate that, in mouse embryonic fibroblasts, eEF2 phosphorylation by eEF2 kinase (eEF2K) mostly affects translation engagement, but has a surprisingly small effect on elongation, except after proteotoxic stress induction.This article has an associated First Person interview with the first author of the paper. PMID- 29700203 TI - Multiple roles of epithelial heparan sulfate in stomach morphogenesis. AB - Heparan sulfate proteoglycans (HSPGs) have been shown to regulate various developmental processes. However, the function of heparan sulfate (HS) during the development of mammalian stomach has not been characterized yet. Here, we investigate the role of epithelial HS in embryonic stomach by examining mice deficient in the glycosyltransferase gene Ext1 We show that HS exhibits a specific and dynamic expression pattern in mouse embryonic stomach. Depletion of the epithelial HS leads to stomach hypoplasia, with phenotypic differences in the gastric mucosa between the forestomach and hindstomach. In the posterior stomach, HS depletion disrupts glandular stomach patterning and cytodifferentiation via attenuation of Fgf signaling activity. Inhibition of Fgf signaling in vitro recapitulates the patterning defect. Ligand and carbohydrate engagement assay (LACE) reveals a diminished assembly of Fgf10 and Fgfr2b in the mutant. In the anterior stomach, loss of epithelial HS leads to stratification and differentiation defects of the multilayered squamous epithelium, along with reduced Hh and Bmp signaling activity. Our data demonstrate that epithelial HS plays multiple roles in regulating mammalian stomach morphogenesis in a regional specific manner. PMID- 29700205 TI - Laboratory-Based Biomarkers and Liver Metastases in Metastatic Castration Resistant Prostate Cancer. AB - BACKGROUND: Metastatic castrate-resistant prostate cancer (mCRPC) patients with liver metastases have a poor prognosis. No large studies have investigated the clinical and biochemical parameters associated with liver metastases in this population. MATERIALS AND METHODS: Patient data made available via Project Data Sphere were collected from 1,281 men with mCRPC who were enrolled on to three phase III clinical trials for the treatment of their disease. Multiple logistic regression was performed on eight clinical and biochemical baseline variables to test their association with the presence of liver metastases on baseline radiographic imaging. Variables of interest included prior docetaxel exposure, Eastern Cooperative Oncology Group performance status, albumin, alkaline phosphatase, alanine transaminase, aspartate transaminase (AST), hemoglobin (HGB), lactate dehydrogenase (LDH), prostate-specific antigen, and total bilirubin. Final models were compared when treating the variables as either continuous or categorized. RESULTS: Multiple variable analysis demonstrated that an increasing serum AST or LDH or a decreasing HGB was associated with an increased probability of having documented radiographic liver metastases (p < .0001). The area under the curve for the continuous model was 0.6842 and 0.6890 for the categorical one, with the latter model containing a dichotomized AST and LDH based on the upper limit of normal and tertile ranges of HGB based on the distribution of the outcome. CONCLUSION: Our analysis demonstrated a significant association between the presence of liver metastases and laboratory levels of AST, LDH, and HGB. These have implications for patient management. More research is needed to validate these biomarkers and prospectively determine their application in the clinical setting. IMPLICATIONS FOR PRACTICE: The purpose of this study was to evaluate biochemical and clinical biomarkers associated with the presence of liver metastases in men diagnosed with metastatic castrate resistant prostate cancer. The results indicate that quantitative assessments of aspartate transaminase, lactate dehydrogenase, and hemoglobin are significantly associated with an increased probability of having documented radiographic liver metastases. Analysis of these simple variables can alert clinicians to those at high risk for prostate cancer that has spread to the liver, a finding of clear importance for clinical management. PMID- 29700206 TI - Clinical Utility of Analyzing Circulating Tumor DNA in Patients with Metastatic Colorectal Cancer. AB - Multiple genomic changes caused by clonal evolution induced by therapeutic pressure and corresponding intratumoral heterogeneity have posed great challenges for personalized therapy against metastatic colorectal cancer (mCRC) in the past decade. Liquid biopsy has emerged as an excellent molecular diagnostic tool for assessing predominant spatial and temporal intratumoral heterogeneity with minimal invasiveness.Previous studies have revealed that genomic alterations in RAS, BRAF, ERBB2, and MET, as well as other cancer-related genes associated with resistance to anti-epidermal growth factor receptor (EGFR) therapy, can be analyzed with high diagnostic accuracy by circulating tumor DNA (ctDNA) analysis. Furthermore, by longitudinally monitoring ctDNAs during anti-EGFR therapy, the emergence of genomic alterations can be detected as acquired resistance mechanisms in specific genes, mainly those associated with the mitogen-activated protein kinase signaling pathway. Analysis of ctDNA can also identify predictive biomarkers to immune checkpoint inhibitors, such as mutations in mismatch repair genes, microsatellite instability-high phenotype, and tumor mutation burden. Some prospective clinical trials evaluating targeted agents for genomic alterations in ctDNA or exploring resistance biomarkers by monitoring of ctDNA are ongoing.To determine the value of ctDNA analysis for decision-making by more accurate molecular marker-based selection of patients and identification of resistance mechanisms to targeted therapies or sensitive biomarkers for immune checkpoint inhibitors, clinical trials must be refined to evaluate the efficacy of study treatment in patients with targetable genomic alterations confirmed by ctDNA analysis, and resistance biomarkers should be explored by monitoring ctDNA in large-scale clinical trials. In the near future, ctDNA analysis will play an important role in precision medicine for mCRC. IMPLICATIONS FOR PRACTICE: Treatment strategies for metastatic colorectal cancer (mCRC) are determined according to the molecular profile, which is confirmed by analyzing tumor tissue. Analysis of circulating tumor DNA (ctDNA) may overcome the limitations of tissue based analysis by capturing spatial and temporal intratumoral heterogeneity of mCRC. Clinical trials must be refined to test the value of ctDNA analysis in patient selection and identification of biomarkers. This review describes ctDNA analysis, which will have an important role in precision medicine for mCRC. PMID- 29700207 TI - Representation of Minorities and Elderly Patients in Multiple Myeloma Clinical Trials. AB - Multiple myeloma (MM) occurs in all races, but the incidence in non-Hispanic black patients (NHBs) is two to three times higher than in non-Hispanic white patients (NHWs). We determined the representation of minorities and elderly patients in MM clinical trials. Enrollment data from all therapeutic trials reported in ClinicalTrials.gov from 2000 to 2016 were analyzed. Enrollment fraction (EF) was defined as the number of trial enrollees divided by the 2014 MM prevalence. Participation in MM clinical trials varied significantly across racial and ethnic groups; NHWs were more likely to be enrolled in clinical trials (EF 0.18%) than NHBs (EF 0.06%, p < .0001) and Hispanic patients (EF 0.04%, p < .0001). The median age of trial participants was 62 years, with 7,956 participants (66%) being less than 65 years of age. Collaborations between investigators, sponsors, and the community are necessary to increase access to clinical trials to our minority and elderly patients. PMID- 29700208 TI - Comprehensive Molecular Characterization of Young Chinese Patients with Lung Adenocarcinoma Identified a Distinctive Genetic Profile. AB - BACKGROUND: Occurrence at a younger age has been demonstrated to be associated with a distinct biology in non-small cell lung cancer. However, genomics and clinical characteristics among younger patients with lung adenocarcinoma remain to be determined. Here we studied the potentially targetable genetic alterations by next-generation sequencing (NGS) assay in young Chinese patients with lung adenocarcinoma. MATERIALS AND METHODS: Seventy-one surgically resected lung adenocarcinoma tissue samples from patients aged less than 45 years were collected with informed consent from all patients. Targeted NGS assays were used to identify actionable genetic alterations in the cancer tissues. Additionally, the genomic and clinicopathologic characteristics of 106 patients with lung adenocarcinoma who received NGS testing over the same period were analyzed retrospectively. RESULTS: The frequencies of targetable genetic alterations in 177 patients with lung adenocarcinoma were analyzed by defined age categories, which unveiled a distinctive molecular profile in the younger group, aged less than 45 years. Notably, higher frequency of ALK and HER2 genetic alterations were associated with young age. However, a reverse trend was observed for KRAS, STK11 and EGFR exon 20 mutations, which were more frequently identified in the older group, aged more than 46 years. Furthermore, concurrent EGFR/TP53 mutations were much more prevalent in the younger patients (81.6% vs. 46.8%), which might have a poor response to treatment with epidermal growth factor receptor tyrosine kinase inhibitor. CONCLUSION: In this study, NGS assay revealed a distinctive genetic profile in younger patients with adenocarcinoma. High frequency of concurrent EGFR/TP53 mutations was found in the younger patients, which especially warranted personalized treatment in this population. IMPLICATIONS FOR PRACTICE: Further investigation is needed to understand the genomics and clinical characteristics of young patients with lung adenocarcinoma. In the present study, hybrid capture based next-generation sequencing assays were used to identify targeted genetic alterations in young lung adenocarcinoma patients. Young patients with lung adenocarcinoma, aged less than 45 years, harbored a higher frequency of ALK and HER2 genetic alterations compared with patients aged more than 46 years. Dramatically, concurrent EGFR/TP53 mutations were much more prevalent in younger patients, which had a poor response to treatment with epidermal growth factor receptor kinase inhibitor. These results reveal a distinctive genetic profile in younger patients with adenocarcinoma, which might improve the treatment of this subpopulation. PMID- 29700209 TI - At What Cost to Clinical Trial Enrollment? A Retrospective Study of Patient Travel Burden in Cancer Clinical Trials. AB - BACKGROUND: Recent literature suggests that living in a rural setting may be associated with adverse cancer outcomes. This study examines the burden of travel from home to cancer center for clinical trial (CT) enrollees. MATERIALS AND METHODS: Patients from the University of California San Francisco Clinical Trial Management System database who enrolled in a cancer CT for a breast, genitourinary, or gastrointestinal malignancy between 1993 and 2014 were included. Cancer type, household zip code, race/ethnicity, phase of study, study sponsor, and year of signed consent were exported. Distance traveled from home to center was calculated using a GoogleMaps application programming interface. The relationships of distance with phase of CT, household income, and race/ethnicity were examined. RESULTS: A total of 1,600 patients were enrolled in breast (55.8%), genitourinary (29.4%), or gastrointestinal (14.9%) cancer CTs. The overall median unidirectional distance traveled from home to study site was 25.8 miles (interquartile range [IQR] 11.5-75.3). Of the trial sponsors examined, principal investigator (56.4%), industry (22.2%), cooperative group (11.6%), and National Institutes of Health (NIH; 9.8%), the longest distance traveled was for NIH-sponsored trials, with a median of 39.4 miles (p < .001). Phase I (8.4%) studies had the longest distance traveled, with a median of 41.2 miles (IQR 14.5 101.0 miles; p = .001). White patients (83%) traveled longer compared with black patients (4.4%), with median distances of 29.9 and 13.9 miles, respectively (p < .001). Patients from lower-income areas (n = 799) traveled longer distances compared with patients from higher-income areas (n = 773; 58.3 vs. 17.8 miles, respectively; p < .001). A multivariable linear model where log10 (distance) was the outcome and adjusting for the exported variables and income revealed that cancer type, year of consent, race/ethnicity, and income were significantly associated with distance traveled. CONCLUSION: This study found that the burden of travel is highest among patients enrolled in NIH-sponsored trials, phase I studies, or living in low-income areas. These data suggest that travel burden for cancer CT participants may be significant. IMPLICATIONS FOR PRACTICE: This study is one of the first to measure travel distance for patients in cancer clinical trials using a real-world GoogleMaps calculator. Out-of-pocket expenses such as travel are not typically covered by health care payers; therefore, patients may face considerable cost to attend each study visit. Using a single-center clinical trials enrollment database, this study found that the burden of travel is highest for patients enrolled in National Institutes of Health-sponsored trials and phase I studies, as well as for patients living in low-income areas. Results suggest that a significant proportion of patients enrolled in clinical trials face a substantial travel burden. PMID- 29700210 TI - Genomic Profiling of HER2-Positive Gastric Cancer: PI3K/Akt/mTOR Pathway as Predictor of Outcomes in HER2-Positive Advanced Gastric Cancer Treated with Trastuzumab. AB - BACKGROUND: HER2-positive gastric cancer (GC) affects 7%-34% of patients with GC. Trastuzumab-based first-line treatment has become the standard of care for HER2 positive advanced gastric cancer (AGC). However, there are no clinically validated biomarkers for resistance to HER2-targeted therapies. Upregulation of PI3K pathway and tyrosine kinase receptor (TKR) alterations have been noted as molecular mechanisms of resistance in breast cancer. Our study aimed to perform a molecular characterization of HER2-positive AGC and investigate the role of PI3K/Akt/mTOR signaling pathway activation and TKR gene copy number (GCN) gains as predictive biomarkers in HER2-positive AGC treated with trastuzumab. PATIENTS AND METHODS: Forty-two HER2-positive GC samples from patients treated with trastuzumab-based first-line chemotherapy were selected. DNA samples were sequenced. PTEN and MET immunohistochemistry were also performed. RESULTS: Concurrent genetic alterations were detected in 97.1% of HER2-positive AGC. We found activation of PI3K/Akt/mTOR pathway in 52.4% of patients and TKR GCN gains in 38.1%. TKR GCN gains did not correlate with overall survival (OS) or progression-free survival (PFS). Multivariate Cox models showed that PI3K/Akt/mTOR activation negatively affects the effectiveness of trastuzumab based chemotherapy in terms of OS and PFS. CONCLUSION: Our results provide for the first time a detailed molecular profile of concurrent genetic alterations in HER2-positive AGC. PI3K pathway activation could be used as a predictive marker of worse outcome in this patient population. In addition, gains in copy number of other TKR genes in this subgroup may also influence the survival benefit obtained with trastuzumab. IMPLICATIONS FOR PRACTICE: This article reports, for the first time, a detailed molecular profile of genomic alterations in patients with HER2 positive advanced gastric cancer (AGC). PI3K/Akt/mTOR signaling pathway activation seems to have a differentially negative effect on overall survival and progression-free survival in AGC treated with trastuzumab-based chemotherapy. Combining different targeted agents could be a successful therapeutic strategy to improve the prognosis of HER2-positive AGC. PMID- 29700211 TI - Monoclonal Antibodies and Multiple Myeloma: All in All It's Just Another Brick in the Wall? PMID- 29700212 TI - Neonatal maternal deprivation impairs localized de novo activity-induced protein translation at the synapse in the rat hippocampus. AB - Neonatal neuropsychiatric stress induces alterations in neurodevelopment that can lead to irreversible damage to neuronal physiology, and social, behavioral, and cognitive skills. In addition, this culminates to an elevated vulnerability to stress and anxiety later in life. Developmental deficits in hippocampal synaptic function and plasticity are among the primary contributors of detrimental alterations in brain function induced by early-life stress. However, the underlying molecular mechanisms are not completely understood. Localized protein translation, occurring at the synapse and triggered by neuronal activity, is critical for synapse function, maintenance, and plasticity. We used a rodent model of chronic maternal deprivation to characterize the effects of early-life neuropsychiatric stress on localized de novo protein translation at synaptic connections between neurons. Synaptoneurosomal preparations isolated biochemically from the hippocampi of rat pups that were subjected to maternal deprivation were deficient in depolarization-induced activity-dependent protein translation when compared with littermate controls. Conversely, basal unstimulated protein translation was not affected. Moreover, deficits in activity driven synaptic protein translation were significantly correlated with a reduction in phosphorylated cell survival protein kinase protein B or Akt (p473 Ser and p308 Thr), but not phosphorylated extracellular signal-regulated kinase. PMID- 29700213 TI - MiR-382 functions as tumor suppressor and chemosensitizer in colorectal cancer. AB - Increasing evidence suggests that microRNAs (miRNAs) play a critical role in tumorigenesis. Decreased expression of miR-382 has been observed in various types of cancers. However, the biological function of miRNA-382 in colorectal cancer (CRC) is still largely unknown. Here, we found that miR-382 was down regulated in human colorectal cancer tissues and cell lines associated with it. MiR-382 inhibited colorectal cancer cell proliferation, migration, invasion and enhance chemo sensitivity. Furthermore, we identified krueppel-like factor 12 (KLF12) and homeodomain-interacting protein kinase 3 (HIPK3) as the target of miR-382, miR 382 rescued the promotion effect of KFL12 on migration and enhance chemosensitivity in colorectal cancer cell lines. Collectively, these findings revealed that miR-382 inhibits migration,enhance chemosensitivity by targeting KLF12 and HIPK3 in colorectal cancer. These found might serve as a tumor suppressor in CRC. PMID- 29700214 TI - Silencing SUMO2 promotes protection against degradation and apoptosis of nucleus pulposus cells through p53 signaling pathway in intervertebral disc degeneration. AB - OBJECTIVE: Intervertebral disc degeneration (IDD), as a common cause of back pain, is related to the promotion of cellular senescence and reduction in proliferation. Based on recent studies, small ubiquitin-related modifier (SUMO) proteins have been implicated in various biological functions. Therefore, in the present study, we investigated the effects of SUMO2 on proliferation and senescence of nucleus pulposus cells (NPCs) via mediation of p53 signaling pathway in rat models of IDD. METHODS: After the establishment of rat models of IDD for the measurement of positive expression of SUMO2/3 protein, the mRNA and protein levels of SUMO2, molecular phenotype [matrix metalloproteinase-2 (MMP-2) and hypoxia-inducible factor-1alpha (HIF-1alpha)] and p53 signaling pathway related genes [p21, murine double minute-2 (MDM2), growth arrest and DNA-damage inducible protein 45 alpha (GADD45alpha), cyclin-dependent kinase 2/4 (CDK2/4), and CyclinB1] were determined, followed by the detection of cell proliferation, cell cycle, apoptosis, and cell senescence. RESULTS: The rat models of IDD were successfully constructed. The results obtained showed that there was a higher positive expression of SUMO2/3 protein in IDD rats. Moreover, the silencing of the SUMO2 gene decreases the levels of SUMO2, p53, p21, MDM2, GADD45alpha, MMP-2, and HIF-1alpha expressions and p53 phosphorylation level while it increases the levels of CDK2/4 and CyclinB1 expressions. In addition, SUMO2 gene silencing enhances proliferation and suppresses apoptosis and cell senescence of NPCs. CONCLUSION: In conclusion, SUMO2 gene silencing promotes proliferation, and inhibits the apoptosis and senescence of NPCs in rats with IDD through the down regulation of the p53 signaling pathway. Thus, SUMO2 is a potential target in the treatment of IDD. PMID- 29700215 TI - circFADS2 regulates lung cancer cells proliferation and invasion via acting as a sponge of miR-498. AB - CircRNAs could play critical functions in tumor progression. However, the expression and underlying mechanism of circRNAs in lung cancer progression remain poorly defined. In the present study, high-throughput microarray assay revealed that hsa_circRNA_100833 (identified as circFADS2) was markedly evaluated in lung cancer tissues, and it was further validated by qRT-PCR. High expression of circFADS2 was correlated with advanced TNM stage, lymph node metastasis, poor differentiation, and shorter overall survival of NSCLC patients. In vitro assays results showed that circFADS2 inhibition suppressed lung cancer cells proliferation and invasion ability. Bioinformatics analysis showed that miR-498 contained the complementary binding region of circFADS2, which was confirmed by Dual-luciferase reporter assay. In addition, the expression of miR-498 was down regulated and negatively associated with circFADS2 expression in nonsmall cell lung cancer. Furthermore, rescue assays showed that miR-498 inhibitors abolished the effects of circFADS2 inhibition on lung cancer cells progression. Taken together, our findings indicated that circFADS2 was an effective tumor promoter in lung cancer progression, and its functions were performed by regulating the expression of miR-498. These data suggested that circFADS2 could act as a target for lung cancer treatment. PMID- 29700216 TI - In vivo imaging of hepatic neutrophil migration in severe alcoholic hepatitis with 111In-radiolabelled leucocytes. AB - The study's aim was to image severe alcoholic hepatitis (SAH) using 111In labelled leucocytes with two objectives in mind: firstly for non-invasive diagnosis and secondly to provide a platform for experimental therapies aiming to inhibit intrahepatic neutrophil migration. 111In-leucocyte scintigraphy was performed 30 min and 24 h post-injection in 19 patients with SAH, 14 abstinent patients with alcohol-related cirrhosis and 11 normal controls. Eleven with SAH and seven with cirrhosis also had 99mTc-nanocolloid scintigraphy. Change in hepatic 111In radioactivity was expressed as decay-corrected 24 h:30 min count ratio and, in SAH, compared with histological grading of steatohepatitis and expression of granulocyte marker, CD15. Hepatic microautoradiography on biopsy specimens obtained 24 h post-injection of 111In-leucocytes was performed in one patient. Median 24 h:30 min hepatic 111In activity ratio was higher in SAH (2.5 (interquartile range (IQR): 1.7-4.0) compared with cirrhotics and normal controls (1.0 (0.8-1.1) and 0.8 (0.7-0.9) respectively, P<0.0001). In SAH, it correlated with CD15 expression (r = 0.62, P=0.023) and was higher in marked compared with mild/moderate steatohepatitis (4.0 (3.0-4.6) compared with 1.8 (1.5-2.6), P=0.006). Hepatic-to-splenic 99mTc count rate ratio was reduced in SAH (0.5 (0.4 1.4)) compared with cirrhotics (2.3( 0.6-3.0)) and three historic normal controls (4.2 (3.8-5.0); P=0.003), consistent with impaired hepatic reticuloendothelial function. Scintigraphic findings in SAH included prominent lung radioactivity at 30 min, likely the result of neutrophil primimg. Microautoradiography demonstrated cell-associated 111In in areas of parenchymal neutrophil infiltration. In conclusion, 111In-leucocyte scintigraphy can non-invasively diagnose SAH and could provide a platform for evaluation of novel treatments aiming to inhibit intrahepatic neutrophil migration. PMID- 29700217 TI - A novel combined approach using a Penumbra catheter and balloon catheter for cerebral venous sinus thrombosis. AB - Cerebral venous sinus thrombosis is sometimes fatal. We describe a case of sinus thrombosis in a 43-year-old woman presenting with generalized seizure, delirium, and a 2 week history of headache and nausea. The patient underwent mechanical thrombectomy using a novel combined approach, in which a Shouryu HR balloon catheter (Kaneka) was anchored in the right transverse sinus (TS), sigmoid sinus (SS), and superior sagittal sinus (SSS), while a Penumbra 5 MAX ACE (Penumbra) catheter was moved back and forth between the right TS, SS, and SSS. Additionally, back and forth movement of the inflated balloon with aspiration-the so-called 'dental floss technique'-was performed. Partial recanalization was eventually obtained. Follow-up angiography on postoperative day 7 showed a dramatic improvement in venous outflow. The patient was transferred to a rehabilitation hospital on postoperative day 42. We describe our combined approach using aspiration, and Penumbra and balloon catheters, to achieve mechanical thrombectomy for sinus thrombosis. PMID- 29700218 TI - Psychosis, creativity and recovery: exploring the relationship in a patient. AB - Relation between mental illness and creativity is intricate. While many creative people show signs of mental illness, persons with severe mental illness occasionally have creative output beyond the ordinary. We are presenting a patient with psychotic illness whose creative potential took a positive turn during the illness phase and grew further following symptomatic improvement and helped in her recovery process. Observing the contrast related to creative productivity pre and post psychotic phase raises the probability of whether psychotic illness or process might enhance creative potential. The case additionally illustrates how creativity can be a useful method supporting recovery from severe mental illnesses. PMID- 29700219 TI - Isolated solitary recurrent skull metastasis in papillary thyroid carcinoma. PMID- 29700220 TI - Intensive care management of severe hypernatraemia in the context of group A streptococcal septicaemia. AB - This case describes a 54-year-old woman with exudative eczema, who was admitted to the intensive care unit with a serum sodium concentration of 191 mmol/L, secondary to profound dehydration in the context of group A streptococcal septicaemia. Successful rehydration and electrolyte normalisation was achieved with continuous venovenous haemodiafiltration (CVVHDF), the replacement fluid of which was infused with hypertonic saline to limit the rate of sodium reduction. This case report comments on three areas of interest. First, hypernatraemia of this level is unusual. Second, the infusion of hypertonic saline into the replacement fluid of the CVVHDF filter is not common practice but successfully ensured a controlled reduction in serum sodium concentration while aggressively replacing a 9 L water deficit. Third, the notable physiological reserve demonstrated by the patient: despite an extraordinary serum sodium concentration in the context of overwhelming streptococcal septicaemia, she has made a full cognitive recovery. PMID- 29700221 TI - Fungating breast mass in a developed country. PMID- 29700222 TI - Cardiac CT confirmation of normal prosthetic mechanical aortic valve function in patient with presyncope and significantly increased Doppler velocities. PMID- 29700223 TI - Fatal case of commercial moisture absorber ingestion. PMID- 29700224 TI - Assessing whether the 2017 Mw 5.4 Pohang earthquake in South Korea was an induced event. AB - The moment magnitude (Mw) 5.4 Pohang earthquake, the most damaging event in South Korea since instrumental seismic observation began in 1905, occurred beneath the Pohang geothermal power plant in 2017. Geological and geophysical data suggest that the Pohang earthquake was induced by fluid from an enhanced geothermal system (EGS) site, which was injected directly into a near-critically stressed subsurface fault zone. The magnitude of the mainshock makes it the largest known induced earthquake at an EGS site. PMID- 29700226 TI - The November 2017 Mw 5.5 Pohang earthquake: A possible case of induced seismicity in South Korea. AB - The moment magnitude (Mw) 5.5 earthquake that struck South Korea in November 2017 was one of the largest and most damaging events in that country over the past century. Its proximity to an enhanced geothermal system site, where high-pressure hydraulic injection had been performed during the previous 2 years, raises the possibility that this earthquake was anthropogenic. We have combined seismological and geodetic analyses to characterize the mainshock and its largest aftershocks, constrain the geometry of this seismic sequence, and shed light on its causal factors. According to our analysis, it seems plausible that the occurrence of this earthquake was influenced by the aforementioned industrial activities. Finally, we found that the earthquake transferred static stress to larger nearby faults, potentially increasing the seismic hazard in the area. PMID- 29700225 TI - Single-cell reconstruction of developmental trajectories during zebrafish embryogenesis. AB - During embryogenesis, cells acquire distinct fates by transitioning through transcriptional states. To uncover these transcriptional trajectories during zebrafish embryogenesis, we sequenced 38,731 cells and developed URD, a simulated diffusion-based computational reconstruction method. URD identified the trajectories of 25 cell types through early somitogenesis, gene expression along them, and their spatial origin in the blastula. Analysis of Nodal signaling mutants revealed that their transcriptomes were canalized into a subset of wild type transcriptional trajectories. Some wild-type developmental branch points contained cells that express genes characteristic of multiple fates. These cells appeared to trans-specify from one fate to another. These findings reconstruct the transcriptional trajectories of a vertebrate embryo, highlight the concurrent canalization and plasticity of embryonic specification, and provide a framework with which to reconstruct complex developmental trees from single-cell transcriptomes. PMID- 29700227 TI - The dynamics of gene expression in vertebrate embryogenesis at single-cell resolution. AB - Time series of single-cell transcriptome measurements can reveal dynamic features of cell differentiation pathways. From measurements of whole frog embryos spanning zygotic genome activation through early organogenesis, we derived a detailed catalog of cell states in vertebrate development and a map of differentiation across all lineages over time. The inferred map recapitulates most if not all developmental relationships and associates new regulators and marker genes with each cell state. We find that many embryonic cell states appear earlier than previously appreciated. We also assess conflicting models of neural crest development. Incorporating a matched time series of zebrafish development from a companion paper, we reveal conserved and divergent features of vertebrate early developmental gene expression programs. PMID- 29700229 TI - Single-cell mapping of gene expression landscapes and lineage in the zebrafish embryo. AB - High-throughput mapping of cellular differentiation hierarchies from single-cell data promises to empower systematic interrogations of vertebrate development and disease. Here we applied single-cell RNA sequencing to >92,000 cells from zebrafish embryos during the first day of development. Using a graph-based approach, we mapped a cell-state landscape that describes axis patterning, germ layer formation, and organogenesis. We tested how clonally related cells traverse this landscape by developing a transposon-based barcoding approach (TracerSeq) for reconstructing single-cell lineage histories. Clonally related cells were often restricted by the state landscape, including a case in which two independent lineages converge on similar fates. Cell fates remained restricted to this landscape in embryos lacking the chordin gene. We provide web-based resources for further analysis of the single-cell data. PMID- 29700231 TI - Use of Subcutaneous and Intraperitoneal Administration Methods to Facilitate Cassette Dosing in Microdialysis Studies in Rats. AB - Microdialysis is a powerful technique allowing for real-time measurement of unbound drug concentrations in brain interstitial fluid in conscious animals. Use of microdialysis in drug discovery is limited by high resource requirement and low throughput, but this may be improved by cassette dosing. Administering multiple compounds intravenously of diverse physiochemical properties, it is often very challenging and time consuming to identify a vehicle that can dissolve all of the compounds. To overcome this limitation, the present study explores the possibility of administering a cassette dose of nine diverse compounds (carbamazepine, citalopram, desmethylclozapine, diphenhydramine, gabapentin, metoclopramide, naltrexone, quinidine, and risperidone) in suspension, rather than in solution, by intraperitoneal and subcutaneous routes, and determining if this is a viable option for assessing blood-brain barrier penetration in microdialysis studies. Repeated hourly subcutaneous dosing during the 6-hour microdialysis study allowed for the best attainment of distributional equilibrium between brain and plasma, resulting in less than a 2-fold difference in the unbound brain to unbound plasma concentration ratio for the cassette dosing method versus discrete dosing. Both subcutaneous and intraperitoneal repeated dosing can provide a more practical substitute for intravenous dosing in determining brain penetration of a cassette of diverse compounds in brain microdialysis studies. The results from the present study demonstrate that dosing compounds in suspension represents a practical approach to eliminating the technical challenge and labor-intensive step of preparation of solutions of a mixture of compounds and will enable the use of the cassette brain microdialysis method in a central nervous system drug discovery setting. PMID- 29700228 TI - NUFIP1 is a ribosome receptor for starvation-induced ribophagy. AB - The lysosome degrades and recycles macromolecules, signals to the master growth regulator mTORC1 [mechanistic target of rapamycin (mTOR) complex 1], and is associated with human disease. We performed quantitative proteomic analyses of rapidly isolated lysosomes and found that nutrient levels and mTOR dynamically modulate the lysosomal proteome. Upon mTORC1 inhibition, NUFIP1 (nuclear fragile X mental retardation-interacting protein 1) redistributes from the nucleus to autophagosomes and lysosomes. Upon these conditions, NUFIP1 interacts with ribosomes and delivers them to autophagosomes by directly binding to microtubule associated proteins 1A/1B light chain 3B (LC3B). The starvation-induced degradation of ribosomes via autophagy (ribophagy) depends on the capacity of NUFIP1 to bind LC3B and promotes cell survival. We propose that NUFIP1 is a receptor for the selective autophagy of ribosomes. PMID- 29700232 TI - 3,4-Dihydroxyphenylacetaldehyde-Induced Protein Modifications and Their Mitigation by N-Acetylcysteine. AB - The catecholaldehyde hypothesis posits that 3,4-dihydroxyphenylacetaldehyde (DOPAL), an obligate intermediary metabolite of dopamine, is an autotoxin that challenges neuronal homeostasis in catecholaminergic neurons. DOPAL toxicity may involve protein modifications, such as oligomerization of alpha-synuclein (AS). Potential interactions between DOPAL and other proteins related to catecholaminergic neurodegeneration, however, have not been systemically explored. This study examined DOPAL-induced protein-quinone adduct formation ("quinonization") and protein oligomerization, ubiquitination, and aggregation in cultured MO3.13 human oligodendrocytes and PC12 rat pheochromocytoma cells and in test tube experiments. Using near-infrared fluorescence spectroscopy, we detected spontaneous DOPAL oxidation to DOPAL-quinone, DOPAL-induced quinonization of intracellular proteins in both cell lines, and DOPAL-induced quinonization of several proteins related to catecholaminergic neurodegeneration, including AS, the type 2 vesicular monoamine transporter, glucocerebrosidase, ubiquitin, and l aromatic-amino-acid decarboxylase (LAAAD). DOPAL also oligomerized AS, ubiquitin, and LAAAD; inactivated LAAAD (IC50 54 MUM); evoked substantial intracellular protein ubiquitination; and aggregated intracellular AS. Remarkably, N acetylcysteine, which decreases DOPAL-quinone formation, attenuated or prevented all of these protein modifications and functional changes. The results fit with the proposal that treatments based on decreasing the formation and oxidation of DOPAL may slow or prevent catecholaminergic neurodegeneration. PMID- 29700233 TI - Aurora A Kinase Function at Kinetochores. AB - One of the most important regulatory aspects of chromosome segregation is the ability of kinetochores to precisely control their attachment strength to spindle microtubules. Central to this regulation is Aurora B, a mitotic kinase that phosphorylates kinetochore substrates to promote microtubule turnover. A critical target of Aurora B is the kinetochore protein Ndc80/Hec1, which is a component of the NDC80 complex, the primary force-transducing link between kinetochores and microtubules. Although Aurora B is regarded as the "master regulator" of kinetochore-microtubule attachment, it is becoming clear that this kinase is not solely responsible for phosphorylating Hec1 and other kinetochore substrates to facilitate microtubule turnover. In particular, there is growing evidence that Aurora A kinase, whose activities at spindle poles have been extensively described, has additional roles at kinetochores in regulating the kinetochore microtubule interface. PMID- 29700234 TI - A Conversation with Arshad Desai. PMID- 29700236 TI - A Conversation with Aaron Straight. PMID- 29700235 TI - A Conversation with Yukiko Yamashita. PMID- 29700237 TI - The principles of cascading power limits in small, fast biological and engineered systems. AB - Mechanical power limitations emerge from the physical trade-off between force and velocity. Many biological systems incorporate power-enhancing mechanisms enabling extraordinary accelerations at small sizes. We establish how power enhancement emerges through the dynamic coupling of motors, springs, and latches and reveal how each displays its own force-velocity behavior. We mathematically demonstrate a tunable performance space for spring-actuated movement that is applicable to biological and synthetic systems. Incorporating nonideal spring behavior and parameterizing latch dynamics allows the identification of critical transitions in mass and trade-offs in spring scaling, both of which offer explanations for long-observed scaling patterns in biological systems. This analysis defines the cascading challenges of power enhancement, explores their emergent effects in biological and engineered systems, and charts a pathway for higher-level analysis and synthesis of power-amplified systems. PMID- 29700239 TI - Evidence for opportunity. PMID- 29700238 TI - Asymmetric distribution and spatial switching of dynein activity generates ciliary motility. AB - Motile cilia and flagella are essential, highly conserved organelles, and their motility is driven by the coordinated activities of multiple dynein isoforms. The prevailing "switch-point" hypothesis posits that dyneins are asymmetrically activated to drive flagellar bending. To test this model, we applied cryo electron tomography to visualize activity states of individual dyneins relative to their locations along beating flagella of sea urchin sperm cells. As predicted, bending was generated by the asymmetric distribution of dynein activity on opposite sides of the flagellum. However, contrary to predictions, most dyneins were in their active state, and the smaller population of conformationally inactive dyneins switched flagellar sides relative to the bending direction. Thus, our data suggest a "switch-inhibition" mechanism in which force imbalance is generated by inhibiting, rather than activating, dyneins on alternating sides of the flagellum. PMID- 29700240 TI - News at a glance. PMID- 29700241 TI - Searching for a Stone Age Odysseus. PMID- 29700242 TI - Data trove helps pin down the shape of the Milky Way. PMID- 29700243 TI - Siberian sculpture is among the oldest monumental art. PMID- 29700244 TI - Is genome-guided cancer treatment hyped? PMID- 29700245 TI - Robotic weather balloon launchers spread in Alaska. PMID- 29700246 TI - Chronicling embryos, cell by cell, gene by gene. PMID- 29700247 TI - Peace dividend. PMID- 29700248 TI - Cleaning up the killing fields. PMID- 29700249 TI - Regenerating tissues. PMID- 29700250 TI - Split, but still attached. PMID- 29700251 TI - Disrupting metabolism to treat autoimmunity. PMID- 29700252 TI - Weighing one protein with light. PMID- 29700253 TI - Plastics recycling with a difference. PMID- 29700254 TI - Next-generation diagnostics with CRISPR. PMID- 29700255 TI - Gunter Blobel (1936-2018). PMID- 29700256 TI - Advancing the ethics of paleogenomics. PMID- 29700257 TI - Bee conservation: Key role of managed bees. PMID- 29700258 TI - Bee conservation: Inclusive solutions. PMID- 29700259 TI - Response-"Bee conservation: Key role of managed bees" and "Bee conservation: Inclusive solutions". PMID- 29700260 TI - A synthetic polymer system with repeatable chemical recyclability. AB - The development of chemically recyclable polymers offers a solution to the end-of use issue of polymeric materials and provides a closed-loop approach toward a circular materials economy. However, polymers that can be easily and selectively depolymerized back to monomers typically require low-temperature polymerization methods and also lack physical properties and mechanical strengths required for practical uses. We introduce a polymer system based on gamma-butyrolactone (GBL) with a trans-ring fusion at the alpha and beta positions. Such trans-ring fusion renders the commonly considered as nonpolymerizable GBL ring readily polymerizable at room temperature under solvent-free conditions to yield a high molecular weight polymer. The polymer has enhanced thermostability and can be repeatedly and quantitatively recycled back to its monomer by thermolysis or chemolysis. Mixing of the two enantiomers of the polymer generates a highly crystalline supramolecular stereocomplex. PMID- 29700261 TI - Spatial entanglement patterns and Einstein-Podolsky-Rosen steering in Bose Einstein condensates. AB - Many-particle entanglement is a fundamental concept of quantum physics that still presents conceptual challenges. Although nonclassical states of atomic ensembles were used to enhance measurement precision in quantum metrology, the notion of entanglement in these systems was debated because the correlations among the indistinguishable atoms were witnessed by collective measurements only. Here, we use high-resolution imaging to directly measure the spin correlations between spatially separated parts of a spin-squeezed Bose-Einstein condensate. We observe entanglement that is strong enough for Einstein-Podolsky-Rosen steering: We can predict measurement outcomes for noncommuting observables in one spatial region on the basis of corresponding measurements in another region with an inferred uncertainty product below the Heisenberg uncertainty bound. This method could be exploited for entanglement-enhanced imaging of electromagnetic field distributions and quantum information tasks. PMID- 29700262 TI - Spatially distributed multipartite entanglement enables EPR steering of atomic clouds. AB - A key resource for distributed quantum-enhanced protocols is entanglement between spatially separated modes. However, the robust generation and detection of entanglement between spatially separated regions of an ultracold atomic system remain a challenge. We used spin mixing in a tightly confined Bose-Einstein condensate to generate an entangled state of indistinguishable particles in a single spatial mode. We show experimentally that this entanglement can be spatially distributed by self-similar expansion of the atomic cloud. We used spatially resolved spin read-out to reveal a particularly strong form of quantum correlations known as Einstein-Podolsky-Rosen (EPR) steering between distinct parts of the expanded cloud. Based on the strength of EPR steering, we constructed a witness, which confirmed genuine 5-partite entanglement. PMID- 29700263 TI - Entanglement between two spatially separated atomic modes. AB - Modern quantum technologies in the fields of quantum computing, quantum simulation, and quantum metrology require the creation and control of large ensembles of entangled particles. In ultracold ensembles of neutral atoms, nonclassical states have been generated with mutual entanglement among thousands of particles. The entanglement generation relies on the fundamental particle exchange symmetry in ensembles of identical particles, which lacks the standard notion of entanglement between clearly definable subsystems. Here, we present the generation of entanglement between two spatially separated clouds by splitting an ensemble of ultracold identical particles prepared in a twin Fock state. Because the clouds can be addressed individually, our experiments open a path to exploit the available entangled states of indistinguishable particles for quantum information applications. PMID- 29700264 TI - Quantitative mass imaging of single biological macromolecules. AB - The cellular processes underpinning life are orchestrated by proteins and their interactions. The associated structural and dynamic heterogeneity, despite being key to function, poses a fundamental challenge to existing analytical and structural methodologies. We used interferometric scattering microscopy to quantify the mass of single biomolecules in solution with 2% sequence mass accuracy, up to 19-kilodalton resolution, and 1-kilodalton precision. We resolved oligomeric distributions at high dynamic range, detected small-molecule binding, and mass-imaged proteins with associated lipids and sugars. These capabilities enabled us to characterize the molecular dynamics of processes as diverse as glycoprotein cross-linking, amyloidogenic protein aggregation, and actin polymerization. Interferometric scattering mass spectrometry allows spatiotemporally resolved measurement of a broad range of biomolecular interactions, one molecule at a time. PMID- 29700265 TI - Interregional synaptic maps among engram cells underlie memory formation. AB - Memory resides in engram cells distributed across the brain. However, the site specific substrate within these engram cells remains theoretical, even though it is generally accepted that synaptic plasticity encodes memories. We developed the dual-eGRASP (green fluorescent protein reconstitution across synaptic partners) technique to examine synapses between engram cells to identify the specific neuronal site for memory storage. We found an increased number and size of spines on CA1 engram cells receiving input from CA3 engram cells. In contextual fear conditioning, this enhanced connectivity between engram cells encoded memory strength. CA3 engram to CA1 engram projections strongly occluded long-term potentiation. These results indicate that enhanced structural and functional connectivity between engram cells across two directly connected brain regions forms the synaptic correlate for memory formation. PMID- 29700267 TI - My second coming out. PMID- 29700268 TI - Heartbeat: Focus on valvular heart disease. PMID- 29700266 TI - Field-deployable viral diagnostics using CRISPR-Cas13. AB - Mitigating global infectious disease requires diagnostic tools that are sensitive, specific, and rapidly field deployable. In this study, we demonstrate that the Cas13-based SHERLOCK (specific high-sensitivity enzymatic reporter unlocking) platform can detect Zika virus (ZIKV) and dengue virus (DENV) in patient samples at concentrations as low as 1 copy per microliter. We developed HUDSON (heating unextracted diagnostic samples to obliterate nucleases), a protocol that pairs with SHERLOCK for viral detection directly from bodily fluids, enabling instrument-free DENV detection directly from patient samples in <2 hours. We further demonstrate that SHERLOCK can distinguish the four DENV serotypes, as well as region-specific strains of ZIKV from the 2015-2016 pandemic. Finally, we report the rapid (<1 week) design and testing of instrument free assays to detect clinically relevant viral single-nucleotide polymorphisms. PMID- 29700269 TI - Association mapping and favourable QTL alleles for fibre quality traits in Upland cotton (Gossypium hirsutum L.). AB - Improving cotton fibre quality is a major breeding goal for Upland cotton in China.To investigate the genetic mechanisms of fibre quality, a diverse panel of 403 Upland cotton accessions was grown, and the fibre quality traits were measured in six different environments. Genotyping was performed with genomewide simple sequence repeats. A total of 201 markers were polymorphic and generated 394 allele loci, and 403 accessions were arranged into two subgroups using Structure software. Of the marker loci, 18.94% showed significant linkage disequilibrium (P < 0.05). A mixed linear model in association mapping showed that 51 associations were significant between 39 polymorphic loci and five fibre quality traits, according to best linear unbiased prediction, and in at least three of six environments. Of the 39 associated marker loci, 12 were coincident with previous studies. There were 41 typical accessions identified as containing favourable allele loci related to fibre quality traits. The identified favourable QTL alleles and typical accessions for fibre quality are excellent genetic resources for future cotton breeding in China. PMID- 29700270 TI - Characterization of 108 novel expressed sequence tag-derived single-nucleotide polymorphism markers in the blood clam Tegillarca granosa using a transcriptome database. PMID- 29700271 TI - Isolation and characterization of microsatellite markers in the spiny lobster, Panulirus echinatus Smith, 1869 (Decapoda: Palinuridae) by Illumina MiSeq sequencing. PMID- 29700272 TI - A new set of mulberry-specific SSR markers for application in cultivar identification and DUS testing. PMID- 29700273 TI - Identification of novel microsatellite markers in okra (Abelmoschus esculentus (L.) Moench) through next-generation sequencing and their utilization in analysis of genetic relatedness studies and cross-species transferability. PMID- 29700274 TI - Development and diversity of a novel panel of short tandem repeat markers encompassing the SCN5Agene in Iranian population. PMID- 29700275 TI - Anesthesia Management of Modified Ex Vivo Liver Resection and Autotransplantation. AB - BACKGROUND Ex situ liver surgery allows liver resection and vascular reconstruction in patients who have liver tumors located in critical sites. Only a small series of studies about ex situ liver surgery is available in the literature. No anesthesia management experience has been previously published. The aim of the currents study was to summarize our experience with anesthetic management of patients during ex vivo liver surgery. MATERIAL AND METHODS The first 43 patients who received ex vivo liver surgery between January 2007 and April 2012 were included. A pulmonary artery catheter (PAC), transesophageal echocardiography (TEE), and pulse indicator continuous cardiac output (PiCCO) were used intraoperatively in the patients to monitor the hemodynamic changes. Thromboelastogram and the plasma coagulation test were used to monitor the coagulation changes. RESULTS All patients received general anesthesia with rapid sequence induction. The data obtained by PAC, TEE, and PiCOO in these cases showed large changes in hemodynamics during the stages of the first or second vessel reconstruction. The CI decreased about 59%/63% and the MPAP decreased about 49%/37% during the first/second vessel reconstruction. Accurate judgment of the dosage of active drug for vascular support is the key for the stabilization of hemodynamics as quickly as possible. However, a high incidence (35.5%) of prophase fibrinolysis in a long anhepatic phase should be monitored and managed. CONCLUSIONS Ex vivo liver surgery is no longer experimental and is a therapeutic option for patients with liver cancer in critical sites. Good anesthesia support is an essential element of liver autotransplantation. PMID- 29700276 TI - Endometrial Metastasis from Ductal Breast Carcinoma: A Case Report with Literature Review. AB - BACKGROUND There are few reports of breast cancer cases with uterine metastases; among them, myometrium is more frequently involved than endometrium. The majority of breast cancer metastases to endometrium are lobular type, and there have been only 5 reported cases of ductal type since 1984. Here, we describe a new case of invasive ductal carcinoma with metastases to endometrium and isolated presentation of abnormal uterine bleeding, in addition to reviewing the existing literature on other similar cases. CASE REPORT The patient was a 51-year-old Persian woman with no remarkable past medical or family history of cancer, who presented with a 6-month complaint of menorrhagia to our gynecology clinic. Diagnostic studies including trans-vaginal ultrasonography, pathological examination of endometrial curettage specimen, immunohistochemistry findings, and X-plane and magnetic resonance mammography, and breast core-needle biopsy revealed invasive ductal breast carcinoma as the origin of the endometrial metastasis. CONCLUSIONS Abnormal uterine bleeding in a premenopausal patient should alert clinicians to the possibility of secondary as well as primary neoplasms. It is necessary to differentiate a metastatic tumor from a primary one, since the treatment and prognosis are completely different. PMID- 29700277 TI - Prophylactic Anticonvulsants in Patients Undergoing Craniotomy: A Single-Center Experience. AB - BACKGROUND There is no consensus on the efficacy of seizure prophylaxis in patients undergoing craniotomy. Some studies show that antiepileptic use decreases the risk of seizures, but other studies do not support this. The present study investigated the role of antiepileptic drugs in patient undergoing craniotomy due to various intracranial pathologies. MATERIAL AND METHODS A retrospective review was performed in adult patients undergoing craniotomy between January 2013 and June 2017. Results of 282 patients who did not have a history of seizures and had craniotomies for various reasons were included. In all patients with craniotomy planned, prophylactic AEDs were initiated pre operatively. RESULTS The incidence of postoperative seizures was 17.7% when all craniotomized patients were considered. The most commonly used anticonvulsant agent was phenytoin (75.2%). No serious antiepileptic drug reaction occurred requiring cessation of treatment. CONCLUSIONS Prophylactic antiepileptic treatment of patients undergoing craniotomy should not be continued beyond the first perioperative week if there is no serious brain injury. The intra- or extra axial placement of the tumor affects the prophylaxis. Further randomized controlled studies are warranted in the future to investigate the efficacy of these medications. PMID- 29700279 TI - Using tyrosinase as a tri-modality reporter gene to monitor transplanted stem cells in acute myocardial infarction. AB - The study aimed to investigate the feasibility of noninvasive monitoring of bone marrow mesenchymal stem cells (MSCs) transduced with the tyrosinase reporter gene for acute myocardial infarction (AMI) with photoacoustic imaging (PAI), magnetic resonance imaging (MRI), and positron emission tomography (PET) in vitro and in vivo. MSCs were transduced with a lentivirus carrying a tyrosinase reporter gene. After transduction, the rate of 18F-5-fluoro-N-(2 [diethylamino]ethyl)picolinamide (18F-5-FPN) uptake was measured. PAI and MRI of stable cell lines expressing tyrosinase (TYR-MSCs) were performed in vitro. An AMI model was induced and verified. TYR-MSCs and MSCs were injected into the margins of the infarcted areas, and PAI, MRI, and PET images were acquired 1, 7, 14, 21, and 28 days after cell injection. Sham-operated models without injection were used as the control group. TYR-MSCs showed noticeably higher uptake of 18F-5 FPN and stronger signals in T1-weighted MRI and PAI than non-transduced MSCs. In vivo studies revealed prominent signals in the injected area of the infarcted myocardium on PAI/MRI/PET images, whereas no signal could be seen in rats injected with non-transduced MSCs or sham-operated rats. The uptake values of 18F 5-FPN in vivo showed a slight decrease over 28 days, whereas MRI and PAI signal intensity decreased dramatically. MSCs stably transduced with the tyrosinase reporter gene could be monitored in vivo in myocardial infarction models by PET, MRI, and PAI, providing a feasible and reliable method for checking the viability, location, and dwell time of transplanted stem cells. PMID- 29700278 TI - Targeting of epigenetic regulators in neuroblastoma. AB - Approximately 15,000 new cases of pediatric cancer are diagnosed yearly in Europe, with 8-10% corresponding to neuroblastoma, a rare disease with an incidence of 8-9 cases per million children <15 years of age. Although the survival rate for low-risk and intermediate-risk patients is excellent, half of children with high-risk, refractory, or relapsed tumors will be cured, and two thirds of the other half will suffer major side effects and life-long disabilities. Epigenetic therapies aimed at reversing the oncogenic alterations in chromatin structure and function are an emerging alternative against aggressive tumors that are or will become resistant to conventional treatments. This approach proposes targeting epigenetic regulators, which are proteins that are involved in the creation, detection, and interpretation of epigenetic signals, such as methylation or histone post-translational modifications. In this review, we focused on the most promising epigenetic regulators for targeting and current drugs that have already reached clinical trials. PMID- 29700281 TI - Smad proteins differentially regulate obesity-induced glucose and lipid abnormalities and inflammation via class-specific control of AMPK-related kinase MPK38/MELK activity. AB - Smad proteins have been implicated in metabolic processes, but little is known about how they regulate metabolism. Because Smad 2, 3, 4, and 7 have previously been shown to interact with murine protein serine-threonine kinase 38 (MPK38), an AMP-activated protein kinase (AMPK)-related kinase that has been implicated in obesity-associated metabolic defects, we investigated whether Smad proteins regulate metabolic processes via MPK38. Smads2/3/4 increased, but Smad7 decreased, MPK38-mediated apoptosis signal-regulating kinase-1 (ASK1)/transforming growth factor-beta (TGF-beta)/p53 signaling. However, MPK38 mediated phosphorylation-defective Smad mutants (Smad2 S245A, Smad3 S204A, Smad4 S343A, and Smad7 T96A) had no such effect. In addition, Smads2/3/4 increased, but Smad7 decreased, the stability of MPK38. Consistent with this, Smads2/3/4 attenuated complex formation between MPK38 and its negative regulator thioredoxin (Trx), whereas Smad7 increased this complex formation. However, an opposite effect was observed on complex formation between MPK38 and its positive regulator zinc-finger-like protein 9 (ZPR9). When Smads were overexpressed in high-fat diet (HFD)-fed obese mice using an adenoviral delivery system, Smads2/3/4 improved, but Smad7 worsened, obesity-associated metabolic parameters and inflammation in a MPK38 phosphorylation-dependent manner. These findings suggest that Smad proteins have class-specific impacts on obesity-associated metabolism by differentially regulating MPK38 activity in diet-induced obese mice. PMID- 29700280 TI - Altered AKAP12 expression in portal fibroblasts and liver sinusoids mediates transition from hepatic fibrogenesis to fibrosis resolution. AB - Liver fibrosis can be reversed by removing its causative injuries; however, the molecular mechanisms mediating the resolution of liver fibrogenesis are poorly understood. We investigate the role of a scaffold protein, A-Kinase Anchoring Protein 12 (AKAP12), during liver fibrosis onset, and resolution. Biliary fibrogenesis and fibrosis resolution was induced in wild-type (WT) or AKAP12 deficient C57BL/6 mice through different feeding regimens with 0.1% 3,5 diethoxycarbonyl-1,4-dihydrocollidine (DDC)-containing chow. AKAP12 expression in portal fibroblasts (PFs) and liver sinusoidal endothelial cells (LSECs) gradually decreased as fibrosis progressed but was restored after cessation of the fibrotic challenge. Histological analysis of human liver specimens with varying degrees of fibrosis of different etiologies revealed that AKAP12 expression diminishes in hepatic fibrosis from its early stages onward. AKAP12 KO mice displayed reduced fibrosis resolution in a DDC-induced biliary fibrosis model, which was accompanied by impaired normalization of myofibroblasts and capillarized sinusoids. RNA sequencing of the liver transcriptome revealed that genes related to ECM accumulation and vascular remodeling were mostly elevated in AKAP12 KO samples. Gene ontology (GO) and bioinformatic pathway analyses identified that the differentially expressed genes were significantly enriched in GO categories and pathways, such as the adenosine 3',5'-cyclic monophosphate (cAMP) pathway. Knockdown of the AKAP12 gene in cultured primary PFs revealed that AKAP12 inhibited PF activation in association with the adenosine 3',5'-cyclic monophosphate (cAMP) pathway. Moreover, AKAP12 knockdown in LSECs led to enhanced angiogenesis, endothelin-1 expression and alterations in laminin composition. Collectively, this study demonstrates that AKAP12-mediated regulation of PFs and LSECs has a central role in resolving hepatic fibrosis. PMID- 29700282 TI - LincRNA 1700020I14Rik alleviates cell proliferation and fibrosis in diabetic nephropathy via miR-34a-5p/Sirt1/HIF-1alpha signaling. AB - Long intergenic noncoding RNAs (lincRNAs) have been gradually identified to be functional in a variety of different mechanisms associating with development and epigenetic regulation of cellular homeostasis. However, the study of lincRNAs in diabetic nephropathy (DN) is still in its infancy. Here, we have found dysexpressed long noncoding RNAs (lncRNAs) in renal tissues of db/db DN mice compared with db/m mice by RNA sequencing. In this study, 5 lincRNAs were confirmed to express in a consistent trend among these DN-related lncRNAs both in vivo and in vitro. Particularly, 1700020I14Rik was the downregulated one. Moreover, our data showed overexpression or knockdown of 1700020I14Rik could regulate cell proliferation and fibrosis in mouse mesangial cells (MCs). Furthermore, 1700020I14Rik was found to interact with miR-34a-5p via both the directly targeting way by bioinformatic investigation and luciferase assay and the Ago2-dependent manner by RIP assay. Results also displayed that overexpression of 1700020I14Rik inhibited cell proliferation and expressions of renal fibrosis markers through miR-34a-5p/Sirt1/HIF-1alpha pathway in MCs under high glucose condition, while knockdown of 1700020I14Rik could increase cell proliferation and expressions of renal fibrosis markers. In conclusion, these results provide new insights into the regulation between 1700020I14Rik and miR 34a-5p/Sirt1/HIF-1alpha signaling pathway during the progression of DN. PMID- 29700283 TI - Optically-controlled bacterial metabolite for cancer therapy. AB - Bacteria preferentially accumulating in tumor microenvironments can be utilized as natural vehicles for tumor targeting. However, neither current chemical nor genetic approaches alone can fully satisfy the requirements on both stability and high efficiency. Here, we propose a strategy of "charging" bacteria with a nano photocatalyst to strengthen their metabolic activities. Carbon nitride (C3N4) is combined with Escherichia coli (E. coli) carrying nitric oxide (NO) generation enzymes for photo-controlled bacterial metabolite therapy (PMT). Under light irradiation, photoelectrons produced by C3N4 can be transferred to E. coli to promote the enzymatic reduction of endogenous NO3- to cytotoxic NO with a 37-fold increase. In a mouse model, C3N4 loaded bacteria are perfectly accumulated throughout the tumor and the PMT treatment results in around 80% inhibition of tumor growth. Thus, synthetic materials-remodeled microorganism may be used to regulate focal microenvironments and increase therapeutic efficiency. PMID- 29700284 TI - Mutation of IPO13 causes recessive ocular coloboma, microphthalmia, and cataract. AB - Ocular coloboma is a developmental structural defect of the eye that often occurs as complex ocular anomalies. However, its genetic etiology remains largely unexplored. Here we report the identification of mutation (c.331C>T, p.R111C) in the IPO13 gene in a consanguineous family with ocular coloboma, microphthalmia, and cataract by a combination of whole-exome sequencing and homozygosity mapping. IPO13 encodes an importin-B family protein and has been proven to be associated with the pathogenesis of coloboma and microphthalmia. We found that Ipo13 was expressed in the cornea, sclera, lens, and retina in mice. Additionally, the mRNA expression level of Ipo13 decreased significantly in the patient compared with its expression in a healthy individual. Morpholino-oligonucleotide-induced knockdown of ipo13 in zebrafish caused dose-dependent microphthalmia and coloboma, which is highly similar to the ocular phenotypes in the patient. Moreover, both visual motor response and optokinetic response were impaired severely. Notably, these ocular phenotypes in ipo13-deficient zebrafish could be rescued remarkably by full-length ipo13 mRNA, suggesting that the phenotypes observed in zebrafish were due to insufficient ipo13 function. Altogether, our findings demonstrate, for the first time, a new role of IPO13 in eye morphogenesis and that loss of function of IPO13 could lead to ocular coloboma, microphthalmia, and cataract in humans and zebrafish. PMID- 29700285 TI - HOXA4, down-regulated in lung cancer, inhibits the growth, motility and invasion of lung cancer cells. AB - The involvement of HOXA4 in colorectal cancer and epithelial ovarian cancer has been reported. Although it has been reported that the Hoxa4 gene is involved in the patterning of the mouse lung during embryonic development, little is known about the biological functions of HOXA4 in lung cancer. In the current study, HOXA4 expression was down-regulated in lung cancer tissues when compared with non cancerous tissues. HOXA4 expression was associated with tumor size, TNM stage, lymph node metastasis and prognosis. Bioinformatics analysis revealed that HOXA4 expression was negatively correlated with cell cycle, metastasis, and the Wnt signaling pathway. Moreover, HOXA4 overexpression in lung cancer cell lines suppressed cell proliferation, migration, and invasion. HOXA4 decreased the protein expression levels of beta-catenin, Cyclin D1, c-Myc and Survivin, indicating the inhibition of Wnt signaling. HOXA4 significantly increased the protein and mRNA levels of glycogen synthase kinase-3beta (GSK3beta) by promoting its transcription. Furthermore, inhibition of GSK3beta by LiCl abolished the suppression of cell growth, migration, and invasion mediated by HOXA4. Overexpression of HOXA4 in xenograft tumors also decreased tumor growth and Wnt signaling. Collectively, these data suggest that HOXA4 is a potential diagnostic and prognostic marker in lung cancer, and its overexpression could inhibit lung cancer progression in part by promoting GSK3beta transcription. PMID- 29700286 TI - c-MYC and reactive oxygen species play roles in tetrandrine-induced leukemia differentiation. AB - Tetrandrine is a broadly used bisbenzylisoquinoline alkaloid component of traditional Chinese medicine that has antitumor effects in some cancer types. In this study, we investigated the effects of tetrandrine on leukemia in vitro and in vivo. The results showed that tetrandrine effectively induced differentiation and autophagy in leukemia cells. In addition, tetrandrine treatment activated the accumulation of reactive oxygen species (ROS) and inhibited c-MYC protein expression. Further, we found that treatment with the ROS scavengers N-acetyl-L cysteine (NAC) and Tiron as well as overexpression of c-MYC reduced tetrandrine induced autophagy and differentiation. Moreover, a small molecular c-MYC inhibitor, 10058-F4, enhanced the tetrandrine-induced differentiation of leukemia cells. These results suggest that ROS generation and c-MYC suppression play important roles in tetrandrine-induced autophagy and differentiation, and the results from in vivo experiments were consistent with those from in vitro studies. Therefore, our data suggest that tetrandrine may be a promising agent for the treatment of leukemia. PMID- 29700287 TI - MiR-125a-5p ameliorates monocrotaline-induced pulmonary arterial hypertension by targeting the TGF-beta1 and IL-6/STAT3 signaling pathways. AB - Pulmonary vascular remodeling due to excessive proliferation and resistance to apoptosis of pulmonary artery smooth muscle cells (PASMCs) is the hallmark feature of pulmonary arterial hypertension (PAH). Recent evidence suggests that miR-125a-5p plays a role in a rat model of monocrotaline-induced PAH (MCT-PAH); however, the underlying mechanism is currently unknown. Here, we examined the expression profile of miR-125a-5p in MCT-PAH rats and investigated the putative therapeutic effect of miR-125a-5p using the miR-125a-5p agomir. In addition, the miR-125a-5p agomir or antagomir was transfected into rat PASMCs, and proliferation and apoptosis were measured. Activity of the miR-125a-5p target STAT3 was measured using a luciferase reporter assay, and the expression of downstream molecules was measured using RT-qPCR and/or western blot analysis. Importantly, inducing miR-125a-5p expression in vivo slowed the progression of MCT-PAH by reducing systolic pulmonary arterial pressure, the Fulton index, and pulmonary vascular remodeling. Moreover, overexpressing miR-125a-5p inhibited the proliferation and promoted the apoptosis of PASMCs. In addition, stimulating PASMCs with TGF-beta1 or IL-6 upregulated miR-125a-5p expression, whereas overexpressing miR-125a-5p reduced TGF-beta1 and IL-6 production, as well as the expression of their downstream targets STAT3 and Smad2/3; in contrast, downregulating miR-125a-5p increased TGF-beta1 and IL-6 production. Finally, a dual-luciferase reporter assay revealed that miR-125a-5p targets the 3'-UTR of STAT3, suppressing the downstream molecules PCNA, Bcl-2, and Survivin. Taken together, these findings suggest that miR-125a-5p ameliorates MCT-PAH in rats, has a negative feedback regulation with TGF-beta1 and IL-6, and regulates the proliferation and apoptosis of PASMCs by directly targeting STAT3. PMID- 29700288 TI - ATP depletion during mitotic arrest induces mitotic slippage and APC/CCdh1 dependent cyclin B1 degradation. AB - ATP depletion inhibits cell cycle progression, especially during the G1 phase and the G2 to M transition. However, the effect of ATP depletion on mitotic progression remains unclear. We observed that the reduction of ATP after prometaphase by simultaneous treatment with 2-deoxyglucose and NaN3 did not arrest mitotic progression. Interestingly, ATP depletion during nocodazole induced prometaphase arrest resulted in mitotic slippage, as indicated by a reduction in mitotic cells, APC/C-dependent degradation of cyclin B1, increased cell attachment, and increased nuclear membrane reassembly. Additionally, cells successfully progressed through the cell cycle after mitotic slippage, as indicated by EdU incorporation and time-lapse imaging. Although degradation of cyclin B during normal mitotic progression is primarily regulated by APC/CCdc20, we observed an unexpected decrease in Cdc20 prior to degradation of cyclin B during mitotic slippage. This decrease in Cdc20 was followed by a change in the binding partner preference of APC/C from Cdc20 to Cdh1; consequently, APC/CCdh1, but not APC/CCdc20, facilitated cyclin B degradation following ATP depletion. Pulse-chase analysis revealed that ATP depletion significantly abrogated global translation, including the translation of Cdc20 and Cdh1. Additionally, the half life of Cdh1 was much longer than that of Cdc20. These data suggest that ATP depletion during mitotic arrest induces mitotic slippage facilitated by APC/CCdh1 dependent cyclin B degradation, which follows a decrease in Cdc20 resulting from reduced global translation and the differences in the half-lives of the Cdc20 and Cdh1 proteins. PMID- 29700289 TI - RCP induces FAK phosphorylation and ovarian cancer cell invasion with inhibition by curcumin. AB - Rab coupling protein (RCP) aggravates cancer cell metastasis and has been implicated in various cancer patient outcomes. Recently, we showed that RCP induces Slug expression and cancer cell invasion by stabilizing the beta1 integrin protein. In the present study, we demonstrated that FAK is implicated in RCP-induced EGFR phosphorylation and ovarian cancer cell invasion with inhibition by curcumin. Ectopic expression of RCP induced FAK phosphorylation, which links beta1 integrin with EGFR and participates in a positive regulation loop with EGFR. Interestingly, we observed for the first time that curcumin attenuates RCP induced ovarian cancer cell invasion by blocking stabilization of beta1 integrin and consequently inhibiting FAK and EGFR activation, providing potential biomarkers for ovarian cancer and therapeutic approaches for this deadly disease. PMID- 29700292 TI - Enhancement of 5-HT2A receptor function and blockade of Kv1.5 by MK801 and ketamine: implications for PCP derivative-induced disease models. AB - MK801 and ketamine, which are phencyclidine (PCP) derivative N-methyl-d-aspartate receptor (NMDAr) blockers, reportedly enhance the function of 5-hydroxytryptamine (HT)-2A receptors (5-HT2ARs). Both are believed to directly affect the pathogenesis of schizophrenia, as well as hypertension. 5-HT2AR signaling involves the inhibition of Kv conductance. This study investigated the interaction of these drugs with Kv1.5, which plays important roles in 5-HT2AR signaling and in regulating the excitability of the cardiovascular and nervous system, and the potential role of this interaction in the enhancement of the 5 HT2AR-mediated response. Using isometric organ bath experiments with arterial rings and conventional whole-cell patch-clamp recording of Chinese hamster ovary (CHO) cells ectopically overexpressing Kv1.5, we examined the effect of ketamine and MK801 on 5-HT2AR-mediated vasocontraction and Kv1.5 channels. Both ketamine and MK801 potentiated 5-HT2AR-mediated vasocontraction. This potentiation of 5 HT2AR function occurred in a membrane potential-dependent manner, indicating the involvement of ion channel(s). Both ketamine and MK801 rapidly and directly inhibited Kv1.5 channels from the extracellular side independently of NMDArs. The potencies of MK801 in facilitating the 5-HT2AR-mediated response and blocking Kv1.5 were higher than those of ketamine. Our data demonstrated the direct inhibition of Kv1.5 channels by MK801/ketamine and indicated that this inhibition may potentiate the functions of 5-HT2ARs. We suggest that 5-HT2AR-Kv1.5 may serve as a receptor-effector module in response to 5-HT and is a promising target in the pathogenesis of MK801-/ketamine-induced disease states such as hypertension and schizophrenia. PMID- 29700291 TI - Protectin DX increases alveolar fluid clearance in rats with lipopolysaccharide induced acute lung injury. AB - Acute respiratory distress syndrome is a life-threatening critical syndrome resulting largely from the accumulation of and the inability to clear pulmonary edema. Protectin DX, an endogenously produced lipid mediator, is believed to exert anti-inflammatory and pro-resolution effects. Protectin DX (5 ug/kg) was injected i.v. 8 h after LPS (14 mg/kg) administration, and alveolar fluid clearance was measured in live rats (n = 8). In primary rat ATII epithelial cells, protectin DX (3.605 * 10-3 mg/l) was added to the culture medium with LPS for 6 h. Protectin DX improved alveolar fluid clearance (9.65 +/- 1.60 vs. 15.85 +/- 1.49, p < 0.0001) and decreased pulmonary edema and lung injury in LPS induced lung injury in rats. Protectin DX markedly regulated alveolar fluid clearance by upregulating sodium channel and Na, K-ATPase protein expression levels in vivo and in vitro. Protectin DX also increased the activity of Na, K ATPase and upregulated P-Akt via inhibiting Nedd4-2 in vivo. In addition, protectin DX enhanced the subcellular distribution of sodium channels and Na, K ATPase, which were specifically localized to the apical and basal membranes of primary rat ATII cells. Furthermore, BOC-2, Rp-cAMP, and LY294002 blocked the increased alveolar fluid clearance in response to protectin DX. Protectin DX stimulates alveolar fluid clearance through a mechanism partly dependent on alveolar epithelial sodium channel and Na, K-ATPase activation via the ALX/PI3K/Nedd4-2 signaling pathway. PMID- 29700290 TI - Brain region-specific disruption of Shank3 in mice reveals a dissociation for cortical and striatal circuits in autism-related behaviors. AB - We previously reported a new line of Shank3 mutant mice which led to a complete loss of Shank3 by deleting exons 4-22 (Deltae4-22) globally. Deltae4-22 mice display robust ASD-like behaviors including impaired social interaction and communication, increased stereotypical behavior and excessive grooming, and a profound deficit in instrumental learning. However, the anatomical and neural circuitry underlying these behaviors are unknown. We generated mice with Shank3 selectively deleted in forebrain, striatum, and striatal D1 and D2 cells. These mice were used to interrogate the circuit/brain-region and cell-type specific role of Shank3 in the expression of autism-related behaviors. Whole-cell patch recording and biochemical analyses were used to study the synaptic function and molecular changes in specific brain regions. We found perseverative exploratory behaviors in mice with deletion of Shank3 in striatal inhibitory neurons. Conversely, self-grooming induced lesions were observed in mice with deletion of Shank3 in excitatory neurons of forebrain. However, social, communicative, and instrumental learning behaviors were largely unaffected in these mice, unlike what is seen in global Deltae4-22 mice. We discovered unique patterns of change for the biochemical and electrophysiological findings in respective brain regions that reflect the complex nature of transcriptional regulation of Shank3. Reductions in Homer1b/c and membrane hyper-excitability were observed in striatal loss of Shank3. By comparison, Shank3 deletion in hippocampal neurons resulted in increased NMDAR-currents and GluN2B-containing NMDARs. These results together suggest that Shank3 may differentially regulate neural circuits that control behavior. Our study supports a dissociation of Shank3 functions in cortical and striatal neurons in ASD-related behaviors, and it illustrates the complexity of neural circuit mechanisms underlying these behaviors. PMID- 29700293 TI - DNA methylation, through DNMT1, has an essential role in the development of gastrointestinal smooth muscle cells and disease. AB - DNA methylation is a key epigenetic modification that can regulate gene expression. Genomic DNA hypomethylation is commonly found in many gastrointestinal (GI) diseases. Dysregulated gene expression in GI smooth muscle cells (GI-SMCs) can lead to motility disorders. However, the consequences of genomic DNA hypomethylation within GI-SMCs are still elusive. Utilizing a Cre-lox murine model, we have generated SMC-restricted DNA methyltransferase 1 (Dnmt1) knockout (KO) mice and analyzed the effects of Dnmt1 deficiency. Dnmt1-KO pups are born smaller than their wild-type littermates, have shortened GI tracts, and lose peristaltic movement due to loss of the tunica muscularis in their intestine, causing massive intestinal dilation, and death around postnatal day 21. Within smooth muscle tissue, significant CpG hypomethylation occurs across the genome at promoters, introns, and exons. Additionally, there is a marked loss of differentiated SMC markers (Srf, Myh11, miR-133, miR-143/145), an increase in pro-apoptotic markers (Nr4a1, Gadd45g), loss of cellular connectivity, and an accumulation of coated vesicles within SMC. Interestingly, we observed consistent abnormal expression patterns of enzymes involved in DNA methylation between both Dnmt1-KO mice and diseased human GI tissue. These data demonstrate that DNA hypomethylation in embryonic SMC, via congenital Dnmt1 deficiency, contributes to massive dysregulation of gene expression and is lethal to GI-SMC. These results suggest that Dnmt1 has a necessary role in the embryonic, primary development process of SMC with consistent patterns being found in human GI diseased tissue. PMID- 29700294 TI - Reduction of Endoplasmic Reticulum Stress Improves Angiogenic Progenitor Cell function in a Mouse Model of Type 1 Diabetes. AB - Persistent vascular injury and degeneration in diabetes are attributed in part to defective reparatory function of angiogenic cells. Our recent work implicates endoplasmic reticulum (ER) stress in high-glucose-induced bone marrow (BM) progenitor dysfunction. Herein, we investigated the in vivo role of ER stress in angiogenic abnormalities of streptozotocin-induced diabetic mice. Our data demonstrate that ER stress markers and inflammatory gene expression in BM mononuclear cells and hematopoietic progenitor cells increase dynamically with disease progression. Increased CHOP and cleaved caspase- 3 levels were observed in BM--derived early outgrowth cells (EOCs) after 3 months of diabetes. Inhibition of ER stress by ex vivo or in vivo chemical chaperone treatment significantly improved the generation and migration of diabetic EOCs while reducing apoptosis of these cells. Chemical chaperone treatment also increased the number of circulating angiogenic cells in peripheral blood, alleviated BM pathology, and enhanced retinal vascular repair following ischemia/reperfusion in diabetic mice. Mechanistically, knockdown of CHOP alleviated high-glucose-induced EOC dysfunction and mitigated apoptosis, suggesting a pivotal role of CHOP in mediating ER stress-associated angiogenic cell injury in diabetes. Together, our study suggests that targeting ER signaling may provide a promising and novel approach to enhancing angiogenic function in diabetes. PMID- 29700295 TI - Emerging two-dimensional ferromagnetism in silicene materials. AB - The appeal of ultra-compact spintronics drives intense research on magnetism in low-dimensional materials. Recent years have witnessed remarkable progress in engineering two-dimensional (2D) magnetism via defects, edges, adatoms, and magnetic proximity. However, intrinsic 2D ferromagnetism remained elusive until recent discovery of out-of-plane magneto-optical response in Cr-based layers, stimulating the search for 2D magnets with tunable and diverse properties. Here we employ a bottom-up approach to produce layered structures of silicene (a Si counterpart of graphene) functionalized by rare-earth atoms, ranging from the bulk down to one monolayer. We track the evolution from the antiferromagnetism of the bulk to intrinsic 2D in-plane ferromagnetism of ultrathin layers, with its characteristic dependence of the transition temperature on low magnetic fields. The emerging ferromagnetism manifests itself in the electron transport. The discovery of a class of robust 2D magnets, compatible with the mature Si technology, is instrumental for engineering new devices and understanding spin phenomena. PMID- 29700296 TI - High frequency temperature variability reduces the risk of coral bleaching. AB - Coral bleaching is the detrimental expulsion of algal symbionts from their cnidarian hosts, and predominantly occurs when corals are exposed to thermal stress. The incidence and severity of bleaching is often spatially heterogeneous within reef-scales (<1 km), and is therefore not predictable using conventional remote sensing products. Here, we systematically assess the relationship between in situ measurements of 20 environmental variables, along with seven remotely sensed SST thermal stress metrics, and 81 observed bleaching events at coral reef locations spanning five major reef regions globally. We find that high-frequency temperature variability (i.e., daily temperature range) was the most influential factor in predicting bleaching prevalence and had a mitigating effect, such that a 1 degrees C increase in daily temperature range would reduce the odds of more severe bleaching by a factor of 33. Our findings suggest that reefs with greater high-frequency temperature variability may represent particularly important opportunities to conserve coral ecosystems against the major threat posed by warming ocean temperatures. PMID- 29700297 TI - Experimental search for high-temperature ferroelectric perovskites guided by two step machine learning. AB - Experimental search for high-temperature ferroelectric perovskites is a challenging task due to the vast chemical space and lack of predictive guidelines. Here, we demonstrate a two-step machine learning approach to guide experiments in search of xBi[Formula: see text]O3-(1 - x)PbTiO3-based perovskites with high ferroelectric Curie temperature. These involve classification learning to screen for compositions in the perovskite structures, and regression coupled to active learning to identify promising perovskites for synthesis and feedback. The problem is challenging because the search space is vast, spanning ~61,500 compositions and only 167 are experimentally studied. Furthermore, not every composition can be synthesized in the perovskite phase. In this work, we predict x, y, Me', and Me" such that the resulting compositions have both high Curie temperature and form in the perovskite structure. Outcomes from both successful and failed experiments then iteratively refine the machine learning models via an active learning loop. Our approach finds six perovskites out of ten compositions synthesized, including three previously unexplored {Me'Me"} pairs, with 0.2Bi(Fe0.12Co0.88)O3-0.8PbTiO3 showing the highest measured Curie temperature of 898 K among them. PMID- 29700298 TI - RNA-guided transcriptional silencing in vivo with S. aureus CRISPR-Cas9 repressors. AB - CRISPR-Cas9 transcriptional repressors have emerged as robust tools for disrupting gene regulation in vitro but have not yet been adapted for systemic delivery in adult animal models. Here we describe a Staphylococcus aureus Cas9 based repressor (dSaCas9KRAB) compatible with adeno-associated viral (AAV) delivery. To evaluate dSaCas9KRAB efficacy for gene silencing in vivo, we silenced transcription of Pcsk9, a regulator of cholesterol levels, in the liver of adult mice. Systemic administration of a dual-vector AAV8 system expressing dSaCas9KRAB and a Pcsk9-targeting guide RNA (gRNA) results in significant reductions of serum Pcsk9 and cholesterol levels. Despite a moderate host response to dSaCas9KRAB expression, Pcsk9 repression is maintained for 24 weeks after a single treatment, demonstrating the potential for long-term gene silencing in post-mitotic tissues with dSaCas9KRAB. In vivo programmable gene silencing enables studies that link gene regulation to complex phenotypes and expands the CRISPR-Cas9 perturbation toolbox for basic research and gene therapy applications. PMID- 29700299 TI - Epigenetic reprogramming using 5-azacytidine promotes an anti-cancer response in pancreatic adenocarcinoma cells. AB - Curative management of pancreatic adenocarcinoma is limited because this malignancy remains resistant to most chemotherapeutic drugs. Strategies that reverse epigenetic alterations offer a unique opportunity for cancer cell reprogramming, which is valuable for development of new treatments. The aim of this work was to reprogram pancreatic ductal adenocarcinoma (PDAC) cells toward a less aggressive and drug-responsive phenotype. The process applied is called "epigenetic reprogramming". To evaluate the efficiency of PDAC epigenetic reprogramming, we assessed tumor growth and drug response in PANC-1 cells after exposure to non-cytotoxic doses of the demethylating agent 5-azacytidine (5-AZA). Here, we showed that an epigenetic regimen using 5-AZA promoted an anti-cancer response by inhibiting PDAC tumor growth in vivo after the engraftment of treated cells. Remarkably, the subsequent addition of gemcitabine (GEM) to the 5-AZA mediated reprogramming resulted in a marked growth inhibition effect in GEM resistant pancreatic cancer cells. We observed that various characteristic peptides expressed in the pancreas, which included the antiproliferative hormone somatostatin (SST) and the SST receptor 2 (SSTR2), were significantly upregulated in the epigenetically reprogrammed PDAC cells. The inhibitory effect of octreotide (OCT), an SST analog, was tested on PDAC cells and found to be improved after cell reprogramming. Furthermore, we found that SST gene expression restoration following 5-AZA treatment or following knockdown of the DNA methyltransferase (DNMT) 1 enzyme was associated with the reversion of SST epigenetic silencing through regional CpG demethylation. Lastly, we confirmed the efficacy of 5-AZA-based epigenetic reprogramming in vivo using a PDAC tumor growth model. In conclusion, this study demonstrates that epigenetic reprogramming using the demethylating compound 5-AZA shows anti-cancer effects in PANC-1 cells and is potentially attractive for the treatment of solid tumors. PMID- 29700300 TI - Aerodynamic generation of electric fields in turbulence laden with charged inertial particles. AB - Self-induced electricity, including lightning, is often observed in dusty atmospheres. However, the physical mechanisms leading to this phenomenon remain elusive as they are remarkably challenging to determine due to the high complexity of the multi-phase turbulent flows involved. Using a fast multi-pole method in direct numerical simulations of homogeneous turbulence laden with hundreds of millions of inertial particles, here we show that mesoscopic electric fields can be aerodynamically created in bi-disperse suspensions of oppositely charged particles. The generation mechanism is self-regulating and relies on turbulence preferentially concentrating particles of one sign in clouds while dispersing the others more uniformly. The resulting electric field varies over much larger length scales than both the mean inter-particle spacing and the size of the smallest eddies. Scaling analyses suggest that low ambient pressures, such as those prevailing in the atmosphere of Mars, increase the dynamical relevance of this aerodynamic mechanism for electrical breakdown. PMID- 29700301 TI - Publisher Correction: Optimal compressed representation of high throughput sequence data via light assembly. AB - The original version of this Article contained errors in the affiliations of the authors Ibrahim Numanagic and Thomas A. Courtade, which were incorrectly given as 'Department of Electrical Engineering and Computer Sciences, University of California, Berkeley, CA 94720, USA' and 'Computer Science & Artificial Intelligence Laboratory, Massachusetts Institute of Technology, Cambridge, MA 02139, USA', respectively. Also, the hyperlink for the source code in the Data Availability section was incorrectly given as https://github.iu.edu/kzhu/assembltrie , which links to a page that is not publicly accessible. The source code is publicly accessible at https://github.com/kyzhu/assembltrie . Furthermore, in the PDF version of the Article, the right-hand side of Figure 3 was inadvertently cropped. These errors have now been corrected in both the PDF and HTML versions of the Article. PMID- 29700302 TI - Bcl11b is essential for licensing Th2 differentiation during helminth infection and allergic asthma. AB - During helminth infection and allergic asthma, naive CD4+ T-cells differentiate into cytokine-producing Type-2 helper (Th2) cells that resolve the infection or induce asthma-associated pathology. Mechanisms regulating the Th2 differentiation in vivo remain poorly understood. Here we report that mice lacking Bcl11b in mature T-cells have a diminished capacity to mount Th2 responses during helminth infection and allergic asthma, showing reduced Th2 cytokines and Gata3, and elevated Runx3. We provide evidence that Bcl11b is required to maintain chromatin accessibility at Th2-cytokine promoters and locus-control regions, and binds the Il4 HS IV silencer, reducing its accessibility. Bcl11b also binds Gata3-intronic and downstream-noncoding sites, sustaining the Gata3 expression. In addition, Bcl11b binds and deactivates upstream enhancers at Runx3 locus, restricting the Runx3 expression and its availability to act at the Il4 HS IV silencer. Thus, our results establish novel roles for Bcl11b in the regulatory loop that licenses Th2 program in vivo. PMID- 29700303 TI - Neuro-computational account of how mood fluctuations arise and affect decision making. AB - The influence of mood on choices is a well-established but poorly understood phenomenon. Here, we suggest a three-fold neuro-computational account: (1) the integration of positive and negative events over time induce mood fluctuations, (2) which are underpinned by variations in the baseline activities of critical brain valuation regions, (3) which in turn modulate the relative weights assigned to key dimensions of choice options. We validate this model in healthy participants, using feedback in a quiz task to induce mood fluctuations, and a choice task (accepting vs. declining a motor challenge) to reveal their effects. Using fMRI, we demonstrate the pivotal role of the ventromedial prefrontal cortex and anterior insula, in which baseline activities respectively increase and decrease with theoretical mood level and respectively enhance the weighting of potential gains and losses during decision making. The same mechanisms might explain how decisions are biased in mood disorders at longer timescales. PMID- 29700304 TI - Dysregulation of mitochondrial dynamics proteins are a targetable feature of human tumors. AB - Altered mitochondrial dynamics can broadly impact tumor cell physiology. Using genetic and pharmacological profiling of cancer cell lines and human tumors, we here establish that perturbations to the mitochondrial dynamics network also result in specific therapeutic vulnerabilities. In particular, through distinct mechanisms, tumors with increased mitochondrial fragmentation or connectivity are hypersensitive to SMAC mimetics, a class of compounds that induce apoptosis through inhibition of IAPs and for which robust sensitivity biomarkers remain to be identified. Further, because driver oncogenes exert dominant control over mitochondrial dynamics, oncogene-targeted therapies can be used to sensitize tumors to SMAC mimetics via their effects on fission/fusion dynamics. Collectively, these data demonstrate that perturbations to the mitochondrial dynamics network induce targetable vulnerabilities across diverse human tumors and, more broadly, suggest that the altered structures, activities, and trafficking of cellular organelles may facilitate additional cancer therapeutic opportunities. PMID- 29700305 TI - The therapeutic effect of miR-125b is enhanced by the prostaglandin endoperoxide synthase 2/cyclooxygenase 2 blockade and hampers ETS1 in the context of the microenvironment of bone metastasis. AB - Bone is the most common site for breast cancer spread. In the pro-metastatic cell line 1833, derived from MDA-MB-231 breast adenocarcinoma cells, both hypoxia and hepatocyte growth factor (HGF) influence the effect of miR-125b on ETS proto oncogene 1 transcription factor (ETS1). The effect of hypoxia inducible factor 1 alpha subunit (HIF1A), known to promote metastatic spread by upregulating prostaglandin endoperoxide synthase 2 (PTGS2), may be dampened by miR-125b targeting PTGS2. Here, we investigated whether miR-125b plays a role in breast cancer metastasis by measuring its activity in response to the chemotherapeutic agent NS-398 in a xenograft model. NS-398 is typically used in the clinic to target PTGS2. We also aimed to describe the molecular mechanisms in vitro, since the enhancement of epithelial properties may favor the efficacy of therapies. We report that in the xenograft model, miR-125b reduced metastasis to the bone. We also report suppression of PTGS2 enhanced survival by decreasing HIF1A in cells within the bone marrow. In 1833 cells transfected with a miR-125b mimic we observed several phenotypic changes including enhancement of the epithelial marker E-cadherin, a reduction of mesenchymal-associated genes and a reduction of WNT-associated stem cell signaling. Our findings suggest that in vivo, key players of the bone microenvironment promoting breast cancer spread are regulated by miR-125b. In future, biological molecules imitating miR-125b may enhance the sensitivity of chemotherapeutic agents used to counteract bone metastases. PMID- 29700306 TI - circRNA disease: a manually curated database of experimentally supported circRNA disease associations. PMID- 29700307 TI - ZBTB20 regulates EGFR expression and hepatocyte proliferation in mouse liver regeneration. AB - Liver has a unique regenerative capacity, however, its regulatory mechanism is not fully defined. We have established the zinc-finger protein ZBTB20 as a key transcriptional repressor for alpha-fetoprotein (AFP) gene in liver. As a marker of hepatic differentiation, AFP expression is closely associated with hepatocyte proliferation. Unexpectedly, here we showed that ZBTB20 acts as a positive regulator of hepatic replication and is required for efficient liver regeneration. The mice specifically lacking ZBTB20 in hepatocytes exhibited a remarkable defect in liver regeneration after partial hepatectomy, which was characterized by impaired hepatocyte proliferation along with delayed cyclin D1 induction and diminished AKT activation. Furthermore, we found that epithelial growth factor receptor (EGFR) expression was dramatically reduced in the liver in the absence of ZBTB20, thereby substantially attenuating the activation of EGFR signaling pathway in regenerating liver. Adenovirus-mediated EGFR overexpression in ZBTB20-deficient hepatocytes could largely restore AKT activation in response to EGFR ligands in vitro, as well as hepatocyte replication in liver regeneration. Furthermore, ZBTB20 overexpression could significantly restore hepatic EGFR expression and cell proliferation after hepatectomy in ZBTB20 deficient liver. Taken together, our data point to ZBTB20 as a critical regulator of EGFR expression and hepatocyte proliferation in mouse liver regeneration, and may serve as a potential therapeutic target in clinical settings of liver regeneration. PMID- 29700309 TI - Publisher Correction: A new antagonist for CCR4 attenuates allergic lung inflammation in a mouse model of asthma. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29700308 TI - FoxM1 drives ADAM17/EGFR activation loop to promote mesenchymal transition in glioblastoma. AB - Mesenchymal transition (MES transition) is a hallmark of glioblastoma multiforme (GBM), however, the mechanism regulating the process remains to be elucidated. Here we report that FoxM1 drives ADAM17/EGFR activation loop to promote MES transition in GBM. Firstly, FoxM1 expression was positively associated with ADAM17 expression, and their expression was correlated with the mesenchymal features and overall patient survival of GBM. Overexpressing FoxM1 or ADAM17 increased the mesenchymal phenotype of glioma cells, which could be reversed by silencing FoxM1 or ADAM17. Importantly, FoxM1 bound to the ADAM17 promoter to transcriptionally upregulate its expression. Using gain- and loss-of-function studies, we showed that FoxM1/ADAM17 axis promoted the MES transition in glioma cells. Moreover, tissue microarray analysis and orthotopic xenograft model further confirmed that FoxM1/ADAM17 axis played key roles in malignancy of GBM. Mechanistically, FoxM1/ADAM17 axis activated the EGFR/AKT/GSK3beta signaling pathway and ADAM17/EGFR/GSK3beta axis could maintain FoxM1 stability in glioma cells. Taken together, our study demonstrated that FoxM1/ADAM17 feedback loop controlled the MES transition and regulated the progression of GBM, raising the possibility that deregulation of this loop might improve the durability of therapies in GBM. PMID- 29700310 TI - Focused Ultrasound-enabled Brain Tumor Liquid Biopsy. AB - Although blood-based liquid biopsies have emerged as a promising non-invasive method to detect biomarkers in various cancers, limited progress has been made for brain tumors. One major obstacle is the blood-brain barrier (BBB), which hinders efficient passage of tumor biomarkers into the peripheral circulation. The objective of this study was to determine whether FUS in combination with microbubbles can enhance the release of biomarkers from the brain tumor to the blood circulation. Two glioblastoma tumor models (U87 and GL261), developed by intracranial injection of respective enhanced green fluorescent protein (eGFP) transduced glioblastoma cells, were treated by FUS in the presence of systemically injected microbubbles. Effect of FUS on plasma eGFP mRNA levels was determined using quantitative polymerase chain reaction. eGFP mRNA were only detectable in the FUS-treated U87 mice and undetectable in the untreated U87 mice (maximum cycle number set to 40). This finding was replicated in GL261 mice across three different acoustic pressures. The circulating levels of eGFP mRNA were 1,500-4,800 fold higher in the FUS-treated GL261 mice than that of the untreated mice for the three acoustic pressures. This study demonstrated the feasibility of FUS-enabled brain tumor liquid biopsies in two different murine glioma models across different acoustic pressures. PMID- 29700311 TI - Increased transforming growth factor beta (TGF-beta) and pSMAD3 signaling in a Murine Model for Contrast Induced Kidney Injury. AB - We tested the hypothesis that post-contrast acute kidney injury (PC-AKI) occurs due to increase in transforming growth factor beta (Tgf-beta) and pSMAD3 signaling in a murine model of PC-AKI. Mice had nephrectomy performed and twenty eight days later, 100-MUL of radio-contrast (Vispaque 320) or saline was administered via the jugular vein. Animals were sacrificed at 2, 7, and 28 days later and the serum BUN, creatinine, urine protein levels, and kidney weights were assessed. In human kidney-2 (HK-2) cells, gene and protein expression with cellular function was assessed following inhibition of TGFbetaR-1 plus contrast exposure. After contrast administration, the average serum creatinine is significantly elevated at all time points. The average gene expression of connective tissue growth factor (Ctgf), Tgfbeta-1, matrix metalloproteinase-9 (Mmp-9), and collagen IVa (Col IVa) are significantly increased at 2 days after contrast administration (P < 0.05). Cellular proliferation is decreased and there is increased apoptosis with tubulointerstitial fibrosis. Contrast administered to HK-2 cells results in increased pSMAD3 levels and gene expression of Ctgf, Tgfbeta-1, Tgfbeta-2, Col IVa, Mmp-9, and caspase/7 activity with a decrease in proliferation (all, P < 0.05). TGFbetaR-1 inhibition decreased the expression of contrast mediated pro-fibrotic genes in HK-2 cells with no change in the proliferation and apoptosis. PMID- 29700312 TI - Action and object words are differentially anchored in the sensory motor system - A perspective on cognitive embodiment. AB - Embodied and grounded cognition theories have assumed that the sensorimotor system is causally involved in processing motor-related language content. Although a causal proof on a single-cell basis is ethically not possible today, the present fMRI study provides confirmation of this longstanding speculation, as far as it is possible with recent methods, employing a new computational approach. More specifically, we were looking for common activation of nouns and objects, and actions and verbs, representing the canonical and mirror neuron system, respectively. Using multivariate pattern analysis, a resulting linear classifier indeed successfully generalized from distinguishing actions from objects in pictures to distinguishing the respective verbs from nouns in written words. Further, these action-related pattern responses were detailed by recently introduced predictive pattern decomposition into the constituent activity atoms and their relative contributions. The findings support the concept of canonical neurons and mirror neurons implementing embodied processes with separate roles in distinguishing objects from actions, and nouns from verbs, respectively. This example of neuronal recycling processing algorithms is consistent with a multimodal brain signature of human action and object concepts. Embodied language theory is thus merged with actual neurobiological implementation. PMID- 29700313 TI - Extraction of cage-like sporopollenin exine capsules from dandelion pollen grains. AB - Pollen-based microcapsules such as hollow sporopollenin exine capsules (SECs) have emerged as excellent drug delivery and microencapsulation vehicles. To date, SECs have been extracted primarily from a wide range of natural pollen species possessing largely spherical geometries and uniform surface features. Nonetheless, exploring pollen species with more diverse architectural features could lead to new application possibilities. One promising class of candidates is dandelion pollen grains, which possess architecturally intricate, cage-like microstructures composed of robust sporopollenin biopolymers. Here, we report the successful extraction and macromolecular loading of dandelion SECs. Preservation of SEC morphology and successful removal of proteinaceous materials was evaluated using scanning electron microscopy (SEM), matrix-assisted laser desorption/ionization-time of flight (MALDI-TOF) mass spectrometry, elemental CHN analysis, dynamic image particle analysis (DIPA) and confocal laser scanning microscopy (CLSM). Among the tested processing schemes, acidolysis using 85% (v/v) phosphoric acid refluxed at 70 degrees C for 5 hours yielded an optimal balance of intact particle yield, protein removal, and preservation of cage-like microstructure. For proof-of-concept loading, bovine serum albumin (BSA) was encapsulated within the dandelion SECs with high efficiency (32.23 +/- 0.33%). Overall, our findings highlight how hollow microcapsules with diverse architectural features can be readily prepared and utilized from plant-based materials. PMID- 29700314 TI - Simulating SIR processes on networks using weighted shortest paths. AB - We present a framework to simulate SIR processes on networks using weighted shortest paths. Our framework maps the SIR dynamics to weights assigned to the edges of the network, which can be done for Markovian and non-Markovian processes alike. The weights represent the propagation time between the adjacent nodes for a particular realization. We simulate the dynamics by constructing an ensemble of such realizations, which can be done by using a Markov Chain Monte Carlo method or by direct sampling. The former provides a runtime advantage when realizations from all possible sources are computed as the weighted shortest paths can be re calculated more efficiently. We apply our framework to three empirical networks and analyze the expected propagation time between all pairs of nodes. Furthermore, we have employed our framework to perform efficient source detection and to improve strategies for time-critical vaccination. PMID- 29700315 TI - The delta neutrophil index (DNI) as a prognostic marker for mortality in adults with sepsis: a systematic review and meta-analysis. AB - We performed a meta-analysis to seek evidence for the usefulness of the delta neutrophil index (DNI) as a prognostic blood biomarker for mortality in the early stage of sepsis in adults. A literature search was performed using criteria set forth in a predefined protocol. Studies of adults with sepsis that provided a DNI measurement and that had mortality as the outcome, were included. Review articles, editorials, and non-human studies were excluded. The methodological quality of identified studies was assessed independently by two authors using the Quality in Prognosis Studies (QUIPS) tool. A total of 1,822 patients from eleven studies were ultimately included. Standardized mean differences between non survivors and survivors were compared. An elevated DNI was associated with mortality in patients with sepsis (standardized mean difference [SMD] 1.22; 95% confidence interval 0.73-1.71; I2 = 91%). After excluding two studies-one that included paediatric patients and one with a disproportionately low mortality rate heterogeneity was minimized (SMD 0.74, 95% confidence interval 0.53-0.94; I2 = 43%). Overall, the findings suggest that high DNI values are associated with mortality in septic patients. PMID- 29700316 TI - Polarization noise places severe constraints on coherence of all-normal dispersion femtosecond supercontinuum generation. AB - Supercontinuum (SC) generated with all-normal dispersion (ANDi) fibers has been of special interest in recent years due to its potentially superior coherence properties when compared to anomalous dispersion-pumped SC. However, care must be taken in the design of such sources since too long pump pulses and fiber length has been demonstrated to degrade the coherence. To assess the noise performance of ANDi fiber SC generation numerically, a scalar single-polarization model has so far been used, thereby excluding important sources of noise, such as polarization modulational instability (PMI). In this work we numerically study the influence of pump power, pulse length and fiber length on coherence and relative intensity noise (RIN), taking into account both polarization components in a standard ANDi fiber for SC generation pumped at 1064 nm. We demonstrate that the PMI introduces a power dependence not found in a scalar model, which means that even with short ~120 fs pump pulses the coherence of ANDi SC can be degraded at reasonable power levels above ~40 kW. We further demonstrate how the PMI significantly decreases the pump pulse length and fiber length at which the coherence of the ANDi SC is degraded. The numerical predictions are confirmed by RIN measurements of fs-pumped ANDi fiber SC. PMID- 29700317 TI - PGC1alpha promotes cholangiocarcinoma metastasis by upregulating PDHA1 and MPC1 expression to reverse the Warburg effect. AB - PGC1alpha acts as a central regulator of mitochondrial metabolism, whose role in cancer progression has been highlighted but remains largely undefined. Especially, it is completely unknown about the effect of PGC1alpha on cholangiocarcinoma (CCA). Here we showed that PGC1alpha overexpression had no impact on CCA growth despite the decreased expression of PGC1alpha in CCA compared with adjacent normal tissue. Instead, PGC1alpha overexpression-promoted CCA metastasis both in vitro and in vivo. Mechanistically, for the first time, we illuminated that PGC1alpha reversed the Warburg effect by upregulating the expression of pyruvate dehydrogenase E1 alpha 1 subunit and mitochondrial pyruvate carrier 1 to increase pyruvate flux into the mitochondria for oxidation, whereas simultaneously promoting mitochondrial biogenesis and fusion to mediate the metabolic switch to oxidative phosphorylation. On the one hand, enhanced mitochondrial oxidation metabolism correlated with elevated reactive oxygen species (ROS) production; on the other hand, increased PGC1alpha expression upregulated the expression levels of mRNA for several ROS-detoxifying enzymes. To this end, the ROS levels, which were elevated but below a critical threshold, did not inhibit CCA cells proliferation. And the moderately increased ROS facilitated metastatic dissemination of CCA cells, which can be abrogated by antioxidants. Our study suggests the potential utility of developing the PGC1alpha-targeted therapies or blocking PGC1alpha signaling axis for inhibiting CCA metastasis. PMID- 29700318 TI - Iron deficiency is associated with Hypothyroxinemia and Hypotriiodothyroninemia in the Spanish general adult population: Di@bet.es study. AB - Previous studies have suggested that iron deficiency (ID) may impair thyroid hormone metabolism, however replication in wide samples of the general adult population has not been performed. We studied 3846 individuals free of thyroid disease, participants in a national, cross sectional, population based study representative of the Spanish adult population. Thyroid stimulating hormone (TSH), free thyroxin (FT4) and free triiodothyronine (FT3) were analyzed by electrochemiluminescence (E170, Roche Diagnostics). Serum ferritin was analyzed by immunochemiluminescence (Architect I2000, Abbott Laboratories). As ferritin levels decreased (>100, 30-100, 15-30, <15 ug/L) the adjusted mean concentrations of FT4 (p < 0.001) and FT3 (p < 0.001) descended, whereas TSH levels remained unchanged (p = 0.451). In multivariate logistic regression models adjusted for age, sex, UI, BMI and smoking status, subjects with ferritin levels <30 ug/L were more likely to present hypothyroxinemia (FT4 < 12.0 pmol/L p5): OR 1.5 [1.1-2.2] p = 0.024, and hypotriiodothyroninemia (FT3 < 3.9 pmol/L p5): OR 1.8 [1.3-2.6] p = 0.001 than the reference category with ferritin >=30 ug/L. There was no significant heterogeneity of the results between men, pre-menopausal and post menopausal women or according to the iodine nutrition status. Our results confirm an association between ID and hypothyroxinemia and hypotriiodothyroninemia in the general adult population without changes in TSH. PMID- 29700319 TI - Elovl6 is a negative clinical predictor for liver cancer and knockdown of Elovl6 reduces murine liver cancer progression. AB - The elongation of long-chain fatty acids family member 6 (Elovl6) is a key enzyme in lipogenesis that catalyzes the elongation of saturated and monounsaturated fatty acids. Insulin resistance involves upregulation of Elovl6, which has been linked to obesity-related malignancies, including hepatocellular carcinoma (HCC). However, the role of Elovl6 in cancer progression remains unknown. In this study, we analyzed the expression of Elovl6 in 61 clinical HCC specimens. Patients with Elovl6 high-expressing tumors were associated with shorter disease-free survival and overall survival compared to those with Elovl6 low-expressing tumors. Knockdown of Elovl6 in HCC cells reduced cell proliferation and Akt activation, as well as sensitivity to fatty acids. Inhibition of Elovl6 reduced tumor growth and prolonged survival in mice bearing tumors. Taken together, our results indicate that Elovl6 enhances oncogenic activity in liver cancer and is associated with poor prognosis in patients with HCC. Elovl6 may be a therapeutic target for HCC; thus, further studies to confirm this strategy are warranted. PMID- 29700320 TI - Evaluation of subconjunctival liposomal steroids for the treatment of experimental uveitis. AB - Non-infectious anterior uveitis (AU) is a potentially sight threatening inflammatory condition. The current gold standard for treatment is topical steroids, but low ocular bioavailability and compliance issues with the intensive dosing regimen limit the efficacy of this treatment. Liposomes as a drug delivery system may help to overcome these problems. We studied the efficacy of a PEG liposomal formulation of liposomal steroids, administered as a single subconjunctival dose, in the treatment of experimental uveitis in rabbit eyes. Rabbits that received subconjunctival liposomal triamcinolone acetonide phosphate (LTAP) or liposomal prednisolone phosphate (LPP) had significantly lower mean inflammatory scores than untreated controls on Day 4 after induction of uveitis (LPP vs controls, p = 0.049) and 8 (LPP vs controls, p = 0.007; LTAP vs controls, p = 0.019), and lower scores than rabbits given topical PredForte1% 4 times a day on Day 8 (p = 0.03). After antigen rechallenge, the subconjunctival liposomal steroid groups continued to have greater suppression of inflammation than untreated controls on Day 11 (p = 0.02). Localization of liposomes in inflamed ocular tissue was confirmed by histology and immunostaining, and persisted in the eye for at least one month. Our study demonstrates that a single subconjunctival injection of liposomal steroids induces effective and sustained anti-inflammatory action. PMID- 29700321 TI - A compendium of long non-coding RNAs transcriptional fingerprint in multiple myeloma. AB - Multiple myeloma (MM) is a clonal proliferation of bone marrow plasma cells characterized by highly heterogeneous genetic background and clinical course, whose pathogenesis remains largely unknown. Long ncRNAs (lncRNAs) are a large class of non-protein-coding RNA, involved in many physiological cellular and genomic processes as well as in carcinogenesis and tumor evolution. Although still in its infancy, the role of lncRNAs in MM is progressively expanding. Besides studies on selected candidates, lncRNAs expression at genome-wide transcriptome level is confined to microarray technologies, thus investigating a limited collection of transcripts. In the present study investigating a cohort of 30 MM patients, a deep RNA-sequencing analysis overwhelmed previous array studies and allowed the most accurate definition of lncRNA transcripts structure and expression, ultimately providing a comprehensive catalogue of lncRNAs specifically associated with the main MM molecular subgroups and genetic alterations. Despite the small number of analyzed samples, the high accuracy of RNA-sequencing approach for complex transcriptome processing led to the identification of 391 deregulated lncRNAs, 67% of which were also detectable and validated by whole-transcript microarrays. In addition, we identified a list of lncRNAs, with potential relevance in MM, co-expressed and in close proximity to genes that might undergo a cis-regulatory relationship. PMID- 29700322 TI - Phenotypic variability between Social Dominance Ranks in laboratory mice. AB - The laboratory mouse is the most prevalent animal used in experimental procedures in the biomedical and behavioural sciences. Yet, many scientists fail to consider the animals' social context. Within a cage, mice may differ in their behaviour and physiology depending on their dominance relationships. Therefore, dominance relationships may be a confounding factor in animal experiments. The current study housed male and female C57BL/6ByJ mice in same-sex groups of 5 in standard laboratory conditions and investigated whether dominance hierarchies were present and stable across three weeks, and whether mice of different dominance ranks varied consistently in behaviour and physiology. We found that dominance ranks of most mice changed with time, but were most stable between the 2nd and 3rd week of testing. Phenotypic measures were also highly variable, and we found no relation between dominance rank and phenotype. Further, we found limited evidence that variation in measures of phenotype was associated with cage assignment for either males or females. Taken together, these findings do not lend support to the general assumption that individual variation among mice is larger between cages than within cages. PMID- 29700323 TI - HIV antiretroviral exposure in pregnancy induces detrimental placenta vascular changes that are rescued by progesterone supplementation. AB - Adverse birth outcomes are common in HIV-positive pregnant women receiving combination antiretroviral therapy (cART), especially when cART is initiated in early pregnancy. The mechanisms remain poorly understood. Using a mouse model we demonstrate that protease inhibitor based-cART exposure beginning on day 1 of pregnancy was associated with a pro-angiogenic/pro-branching shift in the placenta driven by lower Flt-1 levels and higher Gcm-1 expression. Micro-CT imaging revealed an increase in the number of arterioles in cART-treated placentas, which correlated with fetal growth restriction. Delaying initiation of cART, or supplementing cART-treated mice with progesterone, prevented the pro angiogenic/pro-branching shift and the associated placenta vascular changes. In agreement with our mouse findings, we observed an increase in the number of terminal-villi capillaries in placentas from HIV-positive cART-exposed women compared to HIV-negative controls. Capillary number was inversely correlated to maternal progesterone levels. Our study provides evidence that cART exposure during pregnancy influences placenta vascular formation that may in turn contribute to fetal growth restriction. Our findings highlight the need for closer investigation of the placenta in HIV-positive pregnancies, particularly for pregnancies exposed to cART from conception, and suggest that progesterone supplementation could be investigated as a possible intervention to improve placenta function in HIV-positive pregnant women. PMID- 29700324 TI - Self-homodimerization of an actinoporin by disulfide bridging reveals implications for their structure and pore formation. AB - The Trp111 to Cys mutant of sticholysin I, an actinoporin from Stichodactyla helianthus sea anemone, forms a homodimer via a disulfide bridge. The purified dimer is 193 times less hemolytic than the monomer. Ultracentrifugation, dynamic light scattering and size-exclusion chromatography demonstrate that monomers and dimers are the only independent oligomeric states encountered. Indeed, circular dichroism and fluorescence spectroscopies showed that Trp/Tyr residues participate in homodimerization and that the dimer is less thermostable than the monomer. A homodimer three-dimensional model was constructed and indicates that Trp147/Tyr137 are at the homodimer interface. Spectroscopy results validated the 3D-model and assigned 85 degrees to the disulfide bridge dihedral angle responsible for dimerization. The homodimer model suggests that alterations in the membrane/carbohydrate-binding sites in one of the monomers, as result of dimerization, could explain the decrease in the homodimer ability to form pores. PMID- 29700325 TI - KH176 Safeguards Mitochondrial Diseased Cells from Redox Stress-Induced Cell Death by Interacting with the Thioredoxin System/Peroxiredoxin Enzyme Machinery. AB - A deficient activity of one or more of the mitochondrial oxidative phosphorylation (OXPHOS) enzyme complexes leads to devastating diseases, with high unmet medical needs. Mitochondria, and more specifically the OXPHOS system, are the main cellular production sites of Reactive Oxygen Species (ROS). Increased ROS production, ultimately leading to irreversible oxidative damage of macromolecules or to more selective and reversible redox modulation of cell signalling, is a causative hallmark of mitochondrial diseases. Here we report on the development of a new clinical-stage drug KH176 acting as a ROS-Redox modulator. Patient-derived primary skin fibroblasts were used to assess the potency of a new library of chromanyl-based compounds to reduce ROS levels and protect cells against redox-stress. The lead compound KH176 was studied in cell based and enzymatic assays and in silico. Additionally, the metabolism, pharmacokinetics and toxicokinetics of KH176 were assessed in vivo in different animal species. We demonstrate that KH176 can effectively reduce increased cellular ROS levels and protect OXPHOS deficient primary cells against redox perturbation by targeting the Thioredoxin/Peroxiredoxin system. Due to its dual activity as antioxidant and redox modulator, KH176 offers a novel approach to the treatment of mitochondrial (-related) diseases. KH176 efficacy and safety are currently being evaluated in a Phase 2 clinical trial. PMID- 29700326 TI - Author Correction: Nitrogen-rich organic soils under warm well-drained conditions are global nitrous oxide emission hotspots. AB - The original version of this Article contained an error in the first sentence of the Acknowledgements section, which incorrectly referred to the Estonian Research Council grant identifier as "PUTJD618". The correct version replaces the grant identifier with "PUTJD619". This has been corrected in both the PDF and HTML versions of the Article. PMID- 29700327 TI - Class I histone deacetylase (HDAC) inhibitor CI-994 promotes functional recovery following spinal cord injury. AB - Spinal cord injury (SCI) induces severe and long-lasting neurological disability. Accumulating evidence has suggested that histone deacetylase (HDAC) inhibitors exert neuroprotective effects against various insults and deficits in the central nervous system. In the present study, we assessed the effect of the class I HDAC inhibitor CI-994 in a mouse model of SCI. Following SCI, mice were treated with either dimethyl sulfoxide (control vehicle) or 1, 10, or 30 mg/kg CI-994. Level of acetylated histone H3 expression was increased in the motor cortex and spinal cord of 10 mg/kg CCI-994-treated mice after SCI. CI-994 increased histone H3 acetylation in the myeloperoxidase-positive neutrophils and CD68-positive microglia/macrophages in the spinal cord. Although it did not appear to contribute to corticospinal tract axonal reorganization, intraperitoneal injection of CI-994 promoted behavioral recovery following SCI. Furthermore, administration of CI-994 suppressed neutrophil accumulation, inflammatory cytokine expressions, and neuronal loss as early as 3 days following injury. Thus, our findings indicate that HDAC inhibitors may improve functional recovery following SCI, especially during the early stages of the disease. PMID- 29700328 TI - YAP1 contributes to NSCLC invasion and migration by promoting Slug transcription via the transcription co-factor TEAD. AB - Yes-associated protein 1 (YAP1) contributes to the development of multiple tumors, but the mechanism underlying YAP1 deregulation in non-small cell lung cancer (NSCLC) remains unclear. By performing immunohistochemistry (IHC) assays, we found that YAP1 was significantly upregulated in NSCLC compared with adjacent tissues; therefore, we sought to elucidate whether the upregulation of YAP1 contributes to NSCLC progression. MTT and transwell assays showed that YAP1 overexpression promoted proliferation, migration, and invasion in the NSCLC cell lines A549 and H460; YAP1 overexpression also promoted the significant differential expression of epithelial-mesenchymal transition (EMT)-related markers. Nevertheless, YAP1 knockdown alleviated TGF-beta1-induced EMT and proliferation, migration, and invasion in NSCLC. Furthermore, western blotting showed that the co-transcription complex YAP1/TEAD was impaired by YAPS94A (a YAP1 mutant without the TEAD binding site), and verteporfin (a small molecular inhibitor of YAP1) inhibited A549 and H460 cell metastasis and EMT-related markers expression, indicating that TEAD mediated the NSCLC aggressiveness induced by YAP1. Moreover, sequence analysis and ChIP and luciferase assays confirmed that YAP1 transcriptionally activated Slug expression by binding to TEAD. Importantly, silencing YAP1 inhibited A549 cell tumorigenesis and EMT and downregulated Slug expression in vivo. Overall, our findings revealed that YAP1 is a driver of NSCLC metastasis because YAP1 promoted the EMT program by inducing Slug transcription. PMID- 29700329 TI - Atomic optical stimulated amplifier with optical filtering of ultra-narrow bandwidth. AB - Taking advantages of ultra-narrow bandwidth and high noise rejection performance of the Faraday anomalous dispersion optical filter (FADOF), simultaneously with the coherent amplification of atomic stimulated emission, we propose a stimulated amplified Faraday anomalous dispersion optical filter (SAFADOF) at cesium 1470 nm. The SAFADOF is able to significantly amplify very weak laser signals and reject noise in order to obtain clean signals in strong background. We show that for a weak signal of 50 pW, the gain factor can be larger than 25000 (44 dB) within a bandwidth as narrow as 13 MHz. Having the ability to amplify weak signals with low background contribution, the SAFADOF finds outstanding potential applications in weak signal detections. PMID- 29700330 TI - Prion protein modulates glucose homeostasis by altering intracellular iron. AB - The prion protein (PrPC), a mainly neuronal protein, is known to modulate glucose homeostasis in mouse models. We explored the underlying mechanism in mouse models and the human pancreatic beta-cell line 1.1B4. We report expression of PrPC on mouse pancreatic beta-cells, where it promoted uptake of iron through divalent metal-transporters. Accordingly, pancreatic iron stores in PrP knockout mice (PrP /-) were significantly lower than wild type (PrP+/+) controls. Silencing of PrPC in 1.1B4 cells resulted in significant depletion of intracellular (IC) iron, and remarkably, upregulation of glucose transporter GLUT2 and insulin. Iron overloading, on the other hand, resulted in downregulation of GLUT2 and insulin in a PrPC-dependent manner. Similar observations were noted in the brain, liver, and neuroretina of iron overloaded PrP+/+ but not PrP-/- mice, indicating PrPC mediated modulation of insulin and glucose homeostasis through iron. Peripheral challenge with glucose and insulin revealed blunting of the response in iron overloaded PrP+/+ relative to PrP-/- mice, suggesting that PrPC-mediated modulation of IC iron influences both secretion and sensitivity of peripheral organs to insulin. These observations have implications for Alzheimer's disease and diabetic retinopathy, known complications of type-2-diabetes associated with brain and ocular iron-dyshomeostasis. PMID- 29700331 TI - High throughput evaluation of macrocyclization strategies for conformer stabilization. AB - While macrocyclization of a linear compound to stabilize a known bioactive conformation can be a useful strategy to increase binding potency, the difficulty of macrocycle synthesis can limit the throughput of such strategies. Thus computational techniques may offer the higher throughput required to screen large numbers of compounds. Here we introduce a method for evaluating the propensity of a macrocyclic compound to adopt a conformation similar that of a known active linear compound in the binding site. This method can be used as a fast screening tool for prioritizing macrocycles by leveraging the assumption that the propensity for the known bioactive substructural conformation relates to the affinity. While this method cannot to identify new interactions not present in the known linear compound, it could quickly differentiate compounds where the three dimensional geometries imposed by the macrocyclization prevent adoption of conformations with the same contacts as the linear compound in their conserved region. Here we report the implementation of this method using an RMSD-based structural descriptor and a Boltzmann-weighted propensity calculation and apply it retrospectively to three macrocycle linker optimization design projects. We found the method performs well in terms of prioritizing more potent compounds. PMID- 29700332 TI - MitoQ supplementation prevent long-term impact of maternal smoking on renal development, oxidative stress and mitochondrial density in male mice offspring. AB - To investigate the effect of maternal MitoQ treatment on renal disorders caused by maternal cigarette smoke exposure (SE). We have demonstrated that maternal SE during pregnancy increases the risk of developing chronic kidney disease (CKD) in adult offspring. Mitochondrial oxidative damage contributes to the adverse effects of maternal smoking on renal disorders. MitoQ is a mitochondria-targeted antioxidant that has been shown to protect against oxidative damage-related pathologies in many diseases. Female Balb/c mice (8 weeks) were divided into Sham (exposed to air), SE (exposed to cigarette smoke) and SEMQ (exposed to cigarette smoke with MitoQ supplemented from mating) groups. Kidneys from the mothers were collected when the pups weaned and those from the offspring were collected at 13 weeks. Maternal MitoQ supplementation during gestation and lactation significantly reversed the adverse impact of maternal SE on offspring's body weight, kidney mass and renal pathology. MitoQ administration also significantly reversed the impact of SE on the renal cellular mitochondrial density and renal total reactive oxygen species in both the mothers and their offspring in adulthood. Our results suggested that MitoQ supplementation can mitigate the adverse impact of maternal SE on offspring's renal pathology, renal oxidative stress and mitochondrial density in mice offspring. PMID- 29700333 TI - Transient elevation of cytoplasmic calcium ion concentration at a single cell level precedes morphological changes of epidermal keratinocytes during cornification. AB - Epidermal keratinocytes achieve sequential differentiation from basal to granular layers, and undergo a specific programmed cell death, cornification, to form an indispensable barrier of the body. Although elevation of the cytoplasmic calcium ion concentration ([Ca2+]i) is one of the factors predicted to regulate cornification, the dynamics of [Ca2+]i in epidermal keratinocytes is largely unknown. Here using intravital imaging, we captured the dynamics of [Ca2+]i in mouse skin. [Ca2+]i was elevated in basal cells on the second time scale in three spatiotemporally distinct patterns. The transient elevation of [Ca2+]i also occurred at the most apical granular layer at a single cell level, and lasted for approximately 40 min. The transient elevation of [Ca2+]i at the granular layer was followed by cornification, which was completed within 10 min. This study demonstrates the tightly regulated elevation of [Ca2+]i preceding the cornification of epidermal keratinocytes, providing possible clues to the mechanisms of cornification. PMID- 29700335 TI - Controllable interlayer space effects of layered potassium triniobate nanoflakes on enhanced pH dependent adsorption-photocatalysis behaviors. AB - Despite the extensive study of two-dimensional layered KNb3O8 (KN), there still remains some vital problems need to be clarified for future applications in environmental purification. Here we demonstrated the successful preparation of interlayer-controlled KN nanoflakes using alkaline hydrothermal conditions by adjusting the amount of thiourea in the reaction. This process resulted in KN nanoflakes with a larger specific surface area than previously reported. Moreover, the initial pH of dye solution and discrepant preferential orientation of interlayer peak have been proved to significantly influence the adsorption and photocatalysis performances of KN. In addition, relevant photocatalysis mechanisms have been expounded, by combined the first-principles calculation. The present work could be helpful in revealing the intrinsic adsorption photocatalysis features of KN and other similar niobates. PMID- 29700334 TI - 3D Reconstruction of Lipid Droplets in the Seed of Brassica napus. AB - Rapeseed is one of the most important and widely cultured oilseed crops for food and nonfood purposes worldwide. Neutral lipids are stored in lipid droplets (LDs) as fuel for germination and subsequent seedling growth. Most of the LD detection in seeds was still in 2D levels, and some of the details might have been lost in previous studies. In the present work, the configuration of LDs in seeds was obtained by confocal imaging combined with 3D reconstruction technology in Brassica napus. The size and shape of LDs, LD numbers, cell interval spaces and cell size were observed and compared at 3D levels in the seeds of different materials with high and low oil content. It was also revealed that different cells located in the same tissue exhibited various oil contents according to the construction at the 3D level, which was not previously reported in B. napus. The present work provides a new way to understand the differential in cell populations and enhance the seed oil content at the single cell level within seeds. PMID- 29700336 TI - Nanocrystalline Iron Monosulfides Near Stoichiometry. AB - Solids composed of iron and sulfur are earth abundant and nontoxic, and can exhibit interesting and technologically important optical, electronic, and magnetic phenomena. However, the iron-sulfur (Fe-S) phase diagram is congested in regions of slight non-stoichiometric iron vacancies, and even when the iron atomic composition changes by even a few percent at standard temperature and pressure, there are myriad stable crystal phases that form with qualitatively different electronic properties. Here, we synthesized and characterized nanocrystals of the pyrrhotite-4M structure (Fe7S8) in an anhydrous oleylamine solvent. Upon heating from 140 degrees C to 180 degrees C, the solid sequentially transformed into two kinetically trapped FeS intermediate phases before reaching the pyrrhotite-4M final product. Finally, we assessed the effects of iron vacancies using the stoichiometric end-member, troilite, as a reference system. Density functional theory calculations show that iron vacancies in troilite shift the structure from hexagonal FeS to a monoclinic structure, similar to crystal structures of pyrrhotites, and suggest that this iron deficient troilite may be a stable intermediate between the two crystal structures. The calculations predict that defects also close the band gap in iron deficient troilite. PMID- 29700337 TI - Nanofabrication of Conductive Metallic Structures on Elastomeric Materials. AB - Existing techniques for patterning metallic structures on elastomers are limited in terms of resolution, yield and scalability. The primary constraint is the incompatibility of their physical properties with conventional cleanroom techniques. We demonstrate a reliable fabrication strategy to transfer high resolution metallic structures of <500 nm in dimension on elastomers. The proposed method consists of producing a metallic pattern using conventional lithographic techniques on silicon coated with a thin sacrificial aluminium layer. Subsequent wet etching of the sacrificial layer releases the elastomer with the embedded metallic pattern. Using this method, a nano-resistor with minimum feature size of 400 nm is fabricated on polydimethylsiloxane (PDMS) and applied in gas sensing. Adsorption of solvents in the PDMS causes swelling and increases the device resistance, which therefore enables the detection of volatile organic compounds (VOCs). Sensitivity to chloroform and toluene vapor with a rapid response (~30 s) and recovery (~200 s) is demonstrated using this PDMS nano-resistor at room temperature. PMID- 29700338 TI - Novel analysis of the Harderian gland transcriptome response to Newcastle disease virus in two inbred chicken lines. AB - Behind each eye of the chicken resides a unique lymph tissue, the Harderian gland, for which RNA sequencing (RNA-seq) analysis is novel. We characterized the response of this tissue to Newcastle disease virus (NDV) in two inbred lines with different susceptibility to NDV across three time points. Three-week-old relatively resistant (Fayoumi) and relatively susceptible (Leghorn) birds were inoculated with a high-titered (107EID50) La Sota strain of NDV via an oculonasal route. At 2, 6, and 10 days post infection (dpi) Harderian glands were collected and analyzed via RNA-seq. The Fayoumi had significantly more detectable viral transcripts in the Harderian gland at 2 dpi than the Leghorn, but cleared the virus by 6 dpi. At all three time points, few genes were declared differentially expressed (DE) between the challenged and nonchallenged birds, except for the Leghorns at 6 dpi, and these DE genes were predicted to activate an adaptive immune response. Relative to the Leghorn, the Fayoumi was predicted to activate more immune pathways in both challenged and nonchallenged birds suggesting a more elevated immune system in the Fayoumis under homeostatic conditions. Overall, this study helped characterize the function of this important tissue and its response to NDV. PMID- 29700339 TI - Mutational profiling can identify laryngeal dysplasia at risk of progression to invasive carcinoma. AB - Early diagnosis of laryngeal squamous cell carcinoma (LSCC) at the stage of dysplasia could greatly improve the outcome of affected patients. For the first time we compared the mutational landscape of non-progressing dysplasia (NPD; n = 42) with progressing dysplasia (PD; n = 24), along with patient-matched LSCC biopsies; a total of 90 samples. Using targeted next-generation sequencing identified non-synonymous mutations in six genes (PIK3CA, FGFR3, TP53, JAK3, MET, FBXW7), and mutations were validated by Sanger sequencing and/or qPCR. Analysis was extended in silico to 530 head and neck (HNSCC) cases using TCGA data. Mutations in PIK3CA and FGFR3 were detected in PD and LSCC cases, as well as other HNSCC cases, but absent in NPD cases. In contrast, mutations in JAK3, MET and FBXW7 were found in NPD cases but not PD, LSCC or other HNSCC cases. TP53 was the most frequently mutated gene in both PD and NPD cases. With the exception of R248W, mutations were mutually exclusive. Moreover, five of seven PD mutations were located in motif H2 of p53, whereas none of the NPD mutations were. In summary, we propose that the mutational profile of laryngeal dysplasia has utility for the early detection of patients at risk of progression. PMID- 29700340 TI - A unique hybrid-structured surface produced by rapid electrochemical anodization enhances bio-corrosion resistance and bone cell responses of beta-type Ti-24Nb 4Zr-8Sn alloy. AB - Ti-24Nb-4Zr-8Sn (Ti2448), a new beta-type Ti alloy, consists of nontoxic elements and exhibits a low uniaxial tensile elastic modulus of approximately 45 GPa for biomedical implant applications. Nevertheless, the bio-corrosion resistance and biocompatibility of Ti2448 alloys must be improved for long-term clinical use. In this study, a rapid electrochemical anodization treatment was used on Ti2448 alloys to enhance the bio-corrosion resistance and bone cell responses by altering the surface characteristics. The proposed anodization process produces a unique hybrid oxide layer (thickness 50-120 nm) comprising a mesoporous outer section and a dense inner section. Experiment results show that the dense inner section enhances the bio-corrosion resistance. Moreover, the mesoporous surface topography, which is on a similar scale as various biological species, improves the wettability, protein adsorption, focal adhesion complex formation and bone cell differentiation. Outside-in signals can be triggered through the interaction of integrins with the mesoporous topography to form the focal adhesion complex and to further induce osteogenic differentiation pathway. These results demonstrate that the proposed electrochemical anodization process for Ti2448 alloys with a low uniaxial tensile elastic modulus has the potential for biomedical implant applications. PMID- 29700341 TI - ABO Antigens Active Tri- and Disaccharides Microarray to Evaluate C-type Lectin Receptor Binding Preferences. AB - Understanding blood group antigen binding preferences for C-type lectin receptors holds promise for modulating immune responses, since several Gram-negative bacteria express blood group antigens as molecular mimicry to evade immune responses. Herein, we report the synthesis of ABO blood group antigen active tri and disaccharides to investigate the binding specificity with various C-type lectin receptors using glycan microarray. The results of binding preferences show that distinct glycosylation on the galactose and fucose motifs are key for C-type lectin receptor binding and that these interactions occur in a Ca2+-dependent fashion. PMID- 29700342 TI - Affimer proteins for F-actin: novel affinity reagents that label F-actin in live and fixed cells. AB - Imaging the actin cytoskeleton in cells uses a wide range of approaches. Typically, a fluorescent derivative of the small cyclic peptide phalloidin is used to image F-actin in fixed cells. Lifeact and F-tractin are popular for imaging the cytoskeleton in live cells. Here we characterised novel affinity reagents called Affimers that specifically bind to F-actin in vitro to determine if they are suitable alternatives as eGFP-fusion proteins, to label actin in live cells, or for labeling F-actin in fixed cells. In vitro experiments showed that 3 out of the 4 Affimers (Affimers 6, 14 and 24) tested bind tightly to purified F actin, and appear to have overlapping binding sites. As eGFP-fusion proteins, the same 3 Affimers label F-actin in live cells. FRAP experiments suggest that eGFP Affimer 6 behaves most similarly to F-tractin and Lifeact. However, it does not colocalise with mCherry-actin in dynamic ruffles, and may preferentially bind stable actin filaments. All 4 Affimers label F-actin in methanol fixed cells, while only Affimer 14 labels F-actin after paraformaldehyde fixation. eGFP Affimer 6 has potential for use in selectively imaging the stable actin cytoskeleton in live cells, while all 4 Affimers are strong alternatives to phalloidin for labelling F-actin in fixed cells. PMID- 29700343 TI - A closer look at cross-validation for assessing the accuracy of gene regulatory networks and models. AB - Cross-validation (CV) is a technique to assess the generalizability of a model to unseen data. This technique relies on assumptions that may not be satisfied when studying genomics datasets. For example, random CV (RCV) assumes that a randomly selected set of samples, the test set, well represents unseen data. This assumption doesn't hold true where samples are obtained from different experimental conditions, and the goal is to learn regulatory relationships among the genes that generalize beyond the observed conditions. In this study, we investigated how the CV procedure affects the assessment of supervised learning methods used to learn gene regulatory networks (or in other applications). We compared the performance of a regression-based method for gene expression prediction estimated using RCV with that estimated using a clustering-based CV (CCV) procedure. Our analysis illustrates that RCV can produce over-optimistic estimates of the model's generalizability compared to CCV. Next, we defined the 'distinctness' of test set from training set and showed that this measure is predictive of performance of the regression method. Finally, we introduced a simulated annealing method to construct partitions with gradually increasing distinctness and showed that performance of different gene expression prediction methods can be better evaluated using this method. PMID- 29700344 TI - Analysis of natural female post-mating responses of Anopheles gambiae and Anopheles coluzzii unravels similarities and differences in their reproductive ecology. AB - Anopheles gambiae and An. coluzzii, the two most important malaria vectors in sub Saharan Africa, are recently radiated sibling species that are reproductively isolated even in areas of sympatry. In females from these species, sexual transfer of male accessory gland products, including the steroid hormone 20 hydroxyecdysone (20E), induces vast behavioral, physiological, and transcriptional changes that profoundly shape their post-mating ecology, and that may have contributed to the insurgence of post-mating, prezygotic reproductive barriers. As these barriers can be detected by studying transcriptional changes induced by mating, we set out to analyze the post-mating response of An. gambiae and An. coluzzii females captured in natural mating swarms in Burkina Faso. While the molecular pathways shaping short- and long-term mating-induced changes are largely conserved in females from the two species, we unravel significant inter specific differences that suggest divergent regulation of key reproductive processes such as egg development, processing of seminal secretion, and mating behavior, that may have played a role in reproductive isolation. Interestingly, a number of these changes occur in genes previously shown to be regulated by the sexual transfer of 20E and may be due to divergent utilization of this steroid hormone in the two species. PMID- 29700345 TI - 3D bio-printed scaffold-free nerve constructs with human gingiva-derived mesenchymal stem cells promote rat facial nerve regeneration. AB - Despite the promising neuro-regenerative capacities of stem cells, there is currently no licensed stem cell-based product in the repair and regeneration of peripheral nerve injuries. Here, we explored the potential use of human gingiva derived mesenchymal stem cells (GMSCs) as the only cellular component in 3D bio printed scaffold-free neural constructs that were transplantable to bridge facial nerve defects in rats. We showed that GMSCs have the propensity to aggregate into compact 3D-spheroids that could produce their own matrix. When cultured under either 2D- or 3D-collagen scaffolds, GMSC spheroids were found to be more capable of differentiating into both neuronal and Schwann-like cells than their adherent counterparts. Using a scaffold-free 3D bio-printer system, nerve constructs were printed from GMSC spheroids in the absence of exogenous scaffolds and allowed to mature in a bioreactor. In vivo transplantation of the GMSC-laden nerve constructs promoted regeneration and functional recovery when used to bridge segmental defects in rat facial nerves. Our findings suggest that GMSCs represent an easily accessible source of MSCs for 3D bio-printing of scaffold-free nervous tissue constructs with promising potential application for repair and regeneration of peripheral nerve defects. PMID- 29700346 TI - Germination heterochrony in annual plants of Salsola L.: an effective survival strategy in changing environments. AB - Germination heterochrony refers to germination of seeds dispersed in a single growing season, which is different from delayed germination. We studied two year's demographic characteristics, characteristics of fruit heteromorphism, the relationship between fruit heteromorphism and germination heterochrony, effects of moisture and temperature on germination characteristics, as well as seed longevity of four annual Salsola L. species to analyze the adaptive significance and causes of germination heterochrony. We found that the number of individuals of all populations changed drastically in one year. Approximately 41.6-100% of seedlings germinated in spring died. The number of fruit types varied with interspecies and intraspecies. Despite the wide range of germination temperature of different fruit types (0-35 degrees C), the germination percentage at 0-15 degrees C was the highest. When the soil moisture content was 20%, the germination percentage was the highest, reaching 50% within the shortest time. The contrary was the case with the decreasing of soil moisture. The seed longevity of the four species was one year. Fruit heteromorphism had no direct relationship to germination heterochrony. Germination heterochrony was caused by precipitation characteristics and short seed longevity of annual Salsola L., which was an effective survival strategy for plant to adapt to the changing environments in arid area. PMID- 29700347 TI - Charge Carrier Scattering in Polymers: A New Neutral Coupled Soliton Channel. AB - The dynamical scattering of two oppositely charged bipolarons in non-degenerate organic semiconducting lattices is numerically investigated in the framework of a one-dimensional tight-biding-Hubbard model that includes lattice relaxation. Our findings show that it is possible for the bipolaron pair to merge into a state composed of a confined soliton-antisoliton pair, which is characterized by the appearance of states within less than 0.1 eV from the Fermi level. This compound is in a narrow analogy to a meson confining a quark-antiquark pair. Interestingly, solitons are quasi-particles theoretically predicted to arise only in polymer lattices with degenerate ground state: in the general case of non degenerate ground state polymers, isolated solitons are not allowed. PMID- 29700348 TI - RTS,S/AS01 malaria vaccine mismatch observed among Plasmodium falciparum isolates from southern and central Africa and globally. AB - The RTS,S/AS01 malaria vaccine encompasses the central repeats and C-terminal of Plasmodium falciparum circumsporozoite protein (PfCSP). Although no Phase II clinical trial studies observed evidence of strain-specific immunity, recent studies show a decrease in vaccine efficacy against non-vaccine strain parasites. In light of goals to reduce malaria morbidity, anticipating the effectiveness of RTS,S/AS01 is critical to planning widespread vaccine introduction. We deep sequenced C-terminal Pfcsp from 77 individuals living along the international border in Luapula Province, Zambia and Haut-Katanga Province, the Democratic Republic of the Congo (DRC) and compared translated amino acid haplotypes to the 3D7 vaccine strain. Only 5.2% of the 193 PfCSP sequences from the Zambia-DRC border region matched 3D7 at all 84 amino acids. To further contextualize the genetic diversity sampled in this study with global PfCSP diversity, we analyzed an additional 3,809 Pfcsp sequences from the Pf3k database and constructed a haplotype network representing 15 countries from Africa and Asia. The diversity observed in our samples was similar to the diversity observed in the global haplotype network. These observations underscore the need for additional research assessing genetic diversity in P. falciparum and the impact of PfCSP diversity on RTS,S/AS01 efficacy. PMID- 29700349 TI - Integrative metabolic and microbial profiling on patients with Spleen-yang deficiency syndrome. AB - Gut microbiota is recognized as an indispensable "metabolic organ" that plays crucial roles in maintaining human health or initiating diseases. Spleen-yang deficiency syndrome (SYDS) is a common syndrome of Traditional Chinese Medicine (TCM) clinic. It is a complex phenotype reflecting the overall changes of metabolism which are mainly caused by digestive disorders. However, little is known about the changes of gut microbiota and metabolism in patients with SYDS, as well as the crosstalk between gut microbiota and host metabolism. In the current study, an integrative metabolic and microbial profiling was performed on plasma, urine and feces from recruited SYDS and healthy individuals by using a LC QTOFMS-based metabolomic and 16 s rRNA sequencing approaches. Our results showed a potentially significant contribution of gut dysbiosis to the metabolic disorders in SYDS. By integrating the differential gut bacteria with the metabolites, the results revealed some active bacterium of norank_f_CFT112H7, f_lachnospiraceae and bacteroides were closely involved in host mucosal integrity, bile acid metabolism and polysaccharides decomposition. Therefore, our results indicated the probable involvement of gut microbiota in mediating the metabolic changes, which warrants a further investigation on the role of gut microbiota in modulating the pathogenesis of SYDS. PMID- 29700350 TI - Mindfulness-Based Stress Reduction (MBSR) or Psychoeducation for the Reduction of Menopausal Symptoms: A Randomized, Controlled Clinical Trial. AB - Psychological and behavioural interventions may be effective in reducing menopause-related symptoms. This randomized controlled trial aimed to evaluate the effectiveness of Mindfulness-based Stress Reduction (MBSR) in reducing menopause-related symptoms by comparing with an active control group, the menopause education control (MEC). Symptomatic peri-menopausal and post menopausal women with mild to moderate symptoms were recruited. The primary outcome was overall menopausal symptoms measured by modified Greene Climacteric Scale (GCS). Secondary outcomes include subscales of the GCS perceived stress, mindfulness and health related Quality of Life. All outcome measures were collected at baseline, 2 months (immediately post intervention), 5 and 8 months (3 and 6 months post intervention respectively). Both MBSR (n = 98) and MEC (n = 99) groups reported a reduction in total GCS score at 8 months. Between group analysis show significant symptom score reduction in MBSR group on Anxiety and Depression subscales of GCS. No differences were found between groups on other GCS subscales and majority of the secondary outcome measures. The findings show that menopausal symptoms in both MBSR and MEC significantly reduced over the study period. MBSR show a greater reduction of psychological symptoms of depression and anxiety above active controls but do not reduce other somatic, urogenital and vasomotor symptoms. PMID- 29700351 TI - Cytokine storms are primarily responsible for the rapid death of ducklings infected with duck hepatitis A virus type 1. AB - Duck hepatitis A virus type 1 (DHAV-1) is one of the most harmful pathogens in the duck industry. The infection of adult ducks with DHAV-1 was previously shown to result in transient cytokine storms in their kidneys. To understand how DHAV-1 infection impacts the host liver, we conducted animal experiments with the virulent CH DHAV-1 strain and the attenuated CH60 commercial vaccine strain. Visual observation and standard hematoxylin and eosin staining were performed to detect pathological damage in the liver, and viral copy numbers and cytokine expression in the liver were evaluated by quantitative PCR. The CH strain (108.4 copies/mg) had higher viral titers than the CH60 strain (104.9 copies/mg) in the liver and caused ecchymotic hemorrhaging on the liver surface. Additionally, livers from ducklings inoculated with the CH strain were significantly infiltrated by numerous red blood cells, accompanied by severe cytokine storms, but similar signs were not observed in the livers of ducklings inoculated with the CH60 strain. In conclusion, the severe cytokine storm caused by the CH strain apparently induces hemorrhagic lesions in the liver, which might be a key factor in the rapid death of ducklings. PMID- 29700352 TI - Epidemics of HIV, HCV and syphilis infection among synthetic drugs only users, heroin-only users and poly-drug users in Southwest China. AB - The number of poly-drug users who mix use heroin and synthetic drugs (SD) is increasing worldwide. The objective of this study is to measure the risk factors for being infected with hepatitis C (HCV), human immunodeficiency virus (HIV) and syphilis among SD-only users, heroin-only users and poly-drug users. A cross sectional study was conducted in 2015 from a national HIV surveillance site in Southwest China, 447 poly-drug, 526 SD-only and 318 heroin-only users were recruited. Poly-drug users have higher drug-use frequency, higher rates of drug sharing and unsafe sexual acts than other users (p < 0.05). About a third (36.7%) of poly-drug users experienced sexual arousal due to drug effects, which is higher than the rate among other drug users. Poly-drug users had the highest prevalence of HIV (10.5%) and syphilis (3.6%), but heroin-only users had the highest prevalence of HCV (66.0%) (all p < 0.05) among three groups. Logistic regression shows among poly-drug users, having sex following drug consumption and using drugs >=1/day were the major risk factors for both HIV (Adjusted odds ratio (AOR) = 2.4, 95% CI [1.8-3.4]; 2.3, [1.6-3.1]) and syphilis infection (AOR = 4.1, [2.1-6.9]; 3.9, [1.8-5.4]). Elevated risk of both HIV and syphilis infection have been established among poly-drug users. PMID- 29700353 TI - The origin, type and hydrocarbon generation potential of organic matter in a marine-continental transitional facies shale succession (Qaidam Basin, China). AB - This organic-rich shale was analyzed to determine the type, origin, maturity and depositional environment of the organic matter and to evaluate the hydrocarbon generation potential of the shale. This study is based on geochemical (total carbon content, Rock-Eval pyrolysis and the molecular composition of hydrocarbons) and whole-rock petrographic (maceral composition) analyses. The petrographic analyses show that the shale penetrated by the Chaiye 2 well contains large amounts of vitrinite and sapropelinite and that the organic matter within these rocks is type III and highly mature. The geochemical analyses show that these rocks are characterized by high total organic carbon contents and that the organic matter is derived from a mix of terrestrial and marine sources and highly mature. These geochemical characteristics are consistent with the results of the petrographic analyses. The large amounts of organic matter in the Carboniferous shale succession penetrated by the Chaiye 2 well may be due to good preservation under hypersaline lacustrine and anoxic marine conditions. Consequently, the studied shale possesses very good hydrocarbon generation potential because of the presence of large amounts of highly mature type III organic matter. PMID- 29700354 TI - Survey and evaluation of mutations in the human KLF1 transcription unit. AB - Erythroid Kruppel-like Factor (EKLF/KLF1) is an erythroid-enriched transcription factor that plays a global role in all aspects of erythropoiesis, including cell cycle control and differentiation. We queried whether its mutation might play a role in red cell malignancies by genomic sequencing of the KLF1 transcription unit in cell lines, erythroid neoplasms, dysplastic disorders, and leukemia. In addition, we queried published databases from a number of varied sources. In all cases we only found changes in commonly notated SNPs. Our results suggest that if there are mutations in KLF1 associated with erythroid malignancies, they are exceedingly rare. PMID- 29700355 TI - Claudin 11 regulates bone homeostasis via bidirectional EphB4-EphrinB2 signaling. AB - Claudins (Cldns) are well-established components of tight junctions (TJs) that play a pivotal role in the modulation of paracellular permeability. Several studies have explored the physiologic aspects of Cldn family members in bone metabolism. However, the effect of Cldn11, a major component of central nervous system myelin, on bone homeostasis has not been reported. In this study, we demonstrate that Cldn11 is a potential target for bone disease therapeutics as a dual modulator of osteogenesis enhancement and osteoclastogenesis inhibition. We found that Cldn11 played a negative role in the receptor activator of nuclear factor kappa B ligand-induced osteoclast (OC) differentiation and function by downregulating the phosphorylated form of extracellular signal-regulated kinase (ERK), Bruton's tyrosine kinase, and phospholipase C gamma 2, in turn impeding c Fos and nuclear factor in activated T cell c1 expression. The enhancement of osteoblast (OB) differentiation by positive feedback of Cldn11 was achieved through the phosphorylation of Smad1/5/8, ERK, and c-Jun amino-terminal kinase. Importantly, this Cldn11-dependent dual event in bone metabolism arose from targeting EphrinB2 ligand reverse signaling in OC and EphB4 receptor forward signaling in OB. In agreement with these in vitro effects, subcutaneous injection of Cldn11 recombinant protein exerted anti-resorbing effects in a lipopolysaccharide-induced calvarial bone loss mouse model and increased osteogenic activity in a calvarial bone formation model. These findings suggest that Cldn11 is a novel regulator in bone homeostasis. PMID- 29700356 TI - Incidence and predictors of readmission within 30 days of transurethral resection of the prostate: a single center European experience. AB - Hospital readmission rates have been analyzed due to their contribution to increasing medical costs. Little is known about readmission rates after urological procedures. We aimed to assess the incidence and predictors of 30-day readmission after discharge in patients treated with transurethral resection of the prostate (TURP). Data from 160 consecutive patients who underwent TURP from January 2015 to December 2016 were analysed. Intra hospitalization characteristics included length of stay (LOS), catheterization time (CT) and complications. Comorbidities were scored with the Charlson Comorbidity Index (CCI). Mean (SD) age was 70.1 (8.1) yrs and mean prostate volume was 80 (20.1) ml. Mean LOS and CT were 4.9 (2.5) days and 3.3 (1.6) days, respectively. The overall 30-day readmission rate was 14.4%, but only 7 (4.4%) patients required hospitalization. The most frequent reasons for readmission were haematuria (6.8%), fever/urinary tract infections (4.3%) and acute urinary retention (3.1%). Multivariable logistic regression analysis revealed age, CCI and CT to be independent predictors of readmission. However, when analysed according to age at the time of surgery, a beneficial effect from longer CT was observed only for patients older than 75 years. These parameters should be taken in account at the time of discharge after TURP. PMID- 29700357 TI - Comparative analyses and structural insights of the novel cytochrome P450 fusion protein family CYP5619 in Oomycetes. AB - Phylogenetic and structural analysis of P450 proteins fused to peroxidase/dioxygenase has not been reported yet. We present phylogenetic and in silico structural analysis of the novel P450 fusion family CYP5619 from the deadliest fish pathogenic oomycete, Saprolegnia diclina. Data-mining and annotation of CYP5619 members revealed their unique presence in oomycetes. CYP5619 members have the highest number of conserved amino acids among eukaryotic P450s. The highest number of conserved amino acids (78%) occurred in the peroxidase/dioxygenase domain compared to the P450 domain (22%). In silico structural analysis using a high-quality CYP5619A1 model revealed that CYP5619A1 has characteristic P450 structural motifs including EXXR and CXG. However, the heme-binding domain (CXG) in CYP5619 members was found to be highly degenerated. The in silico substrate binding pattern revealed that CYP5619A1 have a high affinity to medium chain fatty acids. Interestingly, the controlling agent of S. diclina malachite green was predicted to have the highest binding affinity, along with linoleic acid. However, unlike fatty acids, none of the active site amino acids formed hydrogen bonds with malachite green. The study's results will pave the way for assessing CYP5619A1's role in S. diclina physiology, including the nature of malachite green binding. PMID- 29700358 TI - Premyogenic progenitors derived from human pluripotent stem cells expand in floating culture and differentiate into transplantable myogenic progenitors. AB - Human induced pluripotent stem cells (hiPSCs) are a potential source for cell therapy of Duchenne muscular dystrophy. To reliably obtain skeletal muscle progenitors from hiPSCs, we treated hiPS cells with a Wnt activator, CHIR-99021 and a BMP receptor inhibitor, LDN-193189, and then induced skeletal muscle cells using a previously reported sphere-based culture. This protocol greatly improved sphere formation efficiency and stably induced the differentiation of myogenic cells from hiPS cells generated from both healthy donors and a patient with congenital myasthenic syndrome. hiPSC-derived myogenic progenitors were enriched in the CD57(-) CD108(-) CD271(+) ERBB3(+) cell fraction, and their differentiation was greatly promoted by TGF-beta inhibitors. TGF-beta inhibitors down-regulated the NFIX transcription factor, and NFIX short hairpin RNA (shRNA) improved the differentiation of iPS cell-derived myogenic progenitors. These results suggest that NFIX inhibited differentiation of myogenic progenitors. hiPSC-derived myogenic cells differentiated into myofibers in muscles of NSG-mdx 4Cv mice after direct transplantation. Our results indicate that our new muscle induction protocol is useful for cell therapy of muscular dystrophies. PMID- 29700359 TI - Quantitative correlation between the void morphology of niobium-tin wires and their irreversible critical current degradation upon mechanical loading. AB - Understanding the critical current performance variation of Nb3Sn superconducting wires under mechanical loading is a crucial issue for the design of next generation accelerator and fusion magnets. In these applications, the mechanical properties of the conductors may become a limiting factor due to the strong electro-magnetic forces resulting from the combination of large magnets and intense magnetic fields. In particular, the presence of voids in the superconducting filament structure, which are formed during the fabrication and the reaction heat treatment, determines localized stress concentrations and possibly the formation of cracks. In this work, we demonstrate a quantitative correlation between the void morphology and the electro-mechanical limits measured on different Bronze route Nb3Sn wires. Hot Isostatic Pressing (HIP) prior to the reaction heat treatment is utilized to partially eliminate the voids. The wires' void distributions - with and without HIP treatment - are detected and statistically analyzed using high energy X-ray micro tomography. The stress concentration due to the shape and distribution of the voids as well as their impact on the electro-mechanical properties are determined through finite element method modeling. Finally, the results are quantitatively correlated with the experimentally determined limits of the irreversible critical current degradation upon mechanical loading. PMID- 29700360 TI - Endometrial Mesenchymal Stem/Stromal Cells Modulate the Macrophage Response to Implanted Polyamide/Gelatin Composite Mesh in Immunocompromised and Immunocompetent Mice. AB - The immunomodulatory properties of human endometrial mesenchymal stem cells (eMSC) have not been well characterised. Initial studies showed that eMSC modulated the chronic inflammatory response to a non-degradable polyamide/gelatin mesh in a xenogeneic rat skin wound repair model, but the mechanism remains unclear. In this study, we investigated the immunomodulatory effect of eMSC on the macrophage response to polyamide/gelatin composite mesh in an abdominal subcutaneous wound repair model in C57BL6 immunocompetent and NSG (NOD-Scid IL2Rgamma null ) immunocompromised mice to determine whether responses differed in the absence of an adaptive immune system and NK cells. mCherry lentivirus labelled eMSC persisted longer in NSG mice, inducing longer term paracrine effects. Inclusion of eMSC in the mesh reduced inflammatory cytokine (Il-1beta, Tnfalpha) secretion, and in C57BL6 mice reduced CCR7+ M1 macrophages surrounding the mesh on day 3 and increased M2 macrophage marker mRNA (Arg1, Mrc1, Il10) expression at days 3 and 7. In NSG mice, these effects were delayed and only observed at days 7 and 30 in comparison with controls implanted with mesh alone. These results show that the differences in the immune status in the two animals directly affect the survival of xenogeneic eMSC which leads to differences in the short-term and long-term macrophage responses to implanted meshes. PMID- 29700361 TI - Human limbal niche cells are a powerful regenerative source for the prevention of limbal stem cell deficiency in a rabbit model. AB - In this article, human limbal niche cells (LNC) or bone marrow derived mesenchymal stem cells (BMMSC) were used to prevent limbal stem cell deficiency (LSCD) in an alkali burn rabbit model and their results were compared. The epithelial cell defect area, corneal neovascularization, and the print cell cytometry were quantified to grade the severity of LSCD. Three months after the alkali burn, a partial LSCD was observed in the control group (no treatment) indicated by chronic corneal epithelial defects, positive corneal fluorescein staining, neovascularization and goblet cell migration. In contrast, the severity of LSCD in both the LNC and BMMSC transplantation groups was dramatically reduced as shown by smaller epithelial cell defects, decreased fluorescein sodium staining, decreased neovascularization and decreased goblet cell density. Interestingly, the LNC group was shown to more effectively prevent LSCD than the BMMSC group. Further analysis indicated subconjunctivally transplanted LNCs were more powerful than BMMSCs to prevent LSCD, at least partially, due to increased activation of SCF-c-Kit signal. We conclude that LNCs are a more powerful resource than BMMSCs to prevent LSCD in an alkali burn rabbit model, at least partially due to increased activation of SCF signaling. PMID- 29700362 TI - Local Moment Instability of Os in Honeycomb Li2.15Os0.85O3. AB - Compounds with honeycomb structures occupied by strong spin orbit coupled (SOC) moments are considered to be candidate Kitaev quantum spin liquids. Here we present the first example of Os on a honeycomb structure, Li2.15(3)Os0.85(3)O3 (C2/c, a = 5.09 A, b = 8.81 A, c = 9.83 A, beta = 99.3 degrees ). Neutron diffraction shows large site disorder in the honeycomb layer and X-ray absorption spectroscopy indicates a valence state of Os (4.7 +/- 0.2), consistent with the nominal concentration. We observe a transport band gap of Delta = 243 +/- 23 meV, a large van Vleck susceptibility, and an effective moment of 0.85 MUB, much lower than expected from 70% Os(+5). No evidence of long range order is found above 0.10 K but a spin glass-like peak in ac-susceptibility is observed at 0.5 K. The specific heat displays an impurity spin contribution in addition to a power law ?T(0.63+/-0.06). Applied density functional theory (DFT) leads to a reduced moment, suggesting incipient itineracy of the valence electrons, and finding evidence that Li over stoichiometry leads to Os(4+)-Os(5+) mixed valence. This local picture is discussed in light of the site disorder and a possible underlying quantum spin liquid state. PMID- 29700363 TI - Deep winter convection and phytoplankton dynamics in the NW Mediterranean Sea under present climate and future (horizon 2030) scenarios. AB - Deep water convection (DC) in winter is one of the major processes driving open ocean primary productivity in the Northwestern Mediterranean Sea. DC is highly variable in time, depending on the specific conditions (stratification, circulation and ocean-atmosphere interactions) of each specific winter. This variability also drives the interannual oscillations of open-ocean primary productivity in this important region for many commercially-important fish species. We use a coupled model system to 1) understand to what extent DC impacts phytoplankton seasonality in the present-day and 2) to explore potential changes in future scenarios (~2030). Our model represents quite accurately the present day characteristics of DC and its importance for open-ocean phytoplankton blooms. However, for the future scenarios the importance of deep nutrients in fertilizing the euphotic layer of the NW Mediterranean decreases. The model simulates changes in surface density and on the levels of kinetic energy that make mesoscale activity associated with horizontal currents to become a more important fertilization mechanism, inducing subsequently phenological changes in seasonal plankton cycles. Because of our focus on the open-sea, an exact quantification of the impact of those changes on the overall biological production of the NW Mediterranean cannot be made at the moment. PMID- 29700364 TI - Publisher Correction: Polarized electron beams elastically scattered by atoms as a tool for testing fundamental predictions of quantum mechanics. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29700365 TI - Author Correction: Variation in salinity tolerance between and within anadromous subpopulations of pike (Esox lucius). AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29700366 TI - Dissociating the effect of disruptive colouration on localisation and identification of camouflaged targets. AB - Disruptive camouflage features contrasting areas of pigmentation across the animals' surface that form false edges which disguise the shape of the body and impede detection. In many taxa these false edges feature local contrast enhancement or edge enhancement, light areas have lighter edges and dark areas have darker edges. This additional quality is often overlooked in existing research. Here we ask whether disruptive camouflage can have benefits above and beyond concealing location. Using a novel paradigm, we dissociate the time courses of localisation and identification of a target in a single experiment. We measured the display times required for a stimulus to be located or identified (the critical duration). Targets featured either uniform, disruptive or edge enhanced disruptive colouration. Critical durations were longer for identifying targets with edge enhanced disruptive colouration camouflage even when presented against a contrasting background, such that all target types were located equally quickly. For the first time, we establish empirically that disruptive camouflage not only conceals location, but also disguises identity. This shows that this form of camouflage can be useful even when animals are not hidden. Our findings offer insights into how edge enhanced disruptive colouration undermines visual perception by disrupting object recognition. PMID- 29700368 TI - Publisher Correction: Cerebral ischemia induces the aggregation of proteins linked to neurodegenerative diseases. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29700367 TI - Differential Interaction of Platelet-Derived Extracellular Vesicles with Leukocyte Subsets in Human Whole Blood. AB - Secretion and exchange of biomolecules via extracellular vesicles (EVs) are crucial mechanisms in intercellular communication, and the roles of EVs in infection, inflammation, or thrombosis have been increasingly recognized. EVs have emerged as central players in immune regulation and can enhance or suppress the immune response, depending on the state of donor and recipient cells. We investigated the interaction of blood cell-derived EVs with leukocyte subpopulations (monocytes and their subsets, granulocytes, B cells, T cells, and NK cells) directly in whole blood using a combination of flow cytometry, imaging flow cytometry, cell sorting, and high resolution confocal microscopy. Platelet derived EVs constituted the majority of circulating EVs and were preferentially associated with granulocytes and monocytes, while they scarcely interacted with lymphocytes. Further flow cytometric differentiation of monocyte subsets provided clear indications for a preferential association of platelet-derived EVs with intermediate (CD14++CD16+) monocytes in whole blood. PMID- 29700369 TI - Action-effect related motor adaptation in interactions with everyday devices. AB - Human action planning relies on integrated representations of motor acts and the associated consequences, which implies that changing the set of effects associated to a motor act might directly influence action planning and control. The present study investigated the hypothesis that action-effect manipulations also affected the motor components of the actions even when only a single action option was available. Participants performed simple everyday actions (pinched a plastic sheet, pressed a button, tapped on a table) in two conditions. In the motor-auditory condition actions resulted in the presentation of a tone, whereas no tones were presented in the motor condition. The applied force was softer in the motor-auditory than in the motor condition for all three types of actions. The temporal characteristics of force application showed that action-effect related motor adaptation occurred during action planning, but possibly also during action execution. This demonstrates that even in simple, well-defined interactions with everyday devices we take all (even seemingly task-irrelevant) action-effects into account during action planning, which affects the motor component of the action. The results also imply that in experiments manipulating contingent action effects, one cannot rely on the assumption that the motor part of the action is invariant between conditions. PMID- 29700370 TI - Human-Pathogenic Enterocytozoon bieneusi in Captive Giant Pandas (Ailuropoda melanoleuca) in China. AB - Human and animal infections of Enterocytozoon bieneusi (E. bieneusi) have consistently been reported worldwide, garnering public attention; however, the molecular epidemiology of E. bieneusi in the giant panda remains limited. We surveyed captive giant pandas in China for the presence of E. bieneusi by using PCR and sequence analysis of the ribosomal internal transcribed spacer (ITS) revealing a 34.5% positive rate, with seven known genotypes (SC02, EpbC, CHB1, SC01, D, F, and Peru 6) and five novel genotypes (SC04, SC05, SC06, SC07, and SC08) identified. We similarly analyzed water samples, and E. bieneusi was detected in two samples, with genotype SC02 identified. Phylogenetic analysis revealed that CHB1 did not cluster with any recognized group, while the remaining genotypes belonged to group 1. The predominance of zoonotic group 1 genotypes indicates a public health threat that giant pandas could spread E. bieneusi to humans. The identification of E. bieneusi in water samples suggests giant pandas could contribute to water contamination. Effective control measures are therefore needed to minimize the contamination of the water and prevent a human microsporidiosis outbreak. PMID- 29700371 TI - Unhealthy behaviours and risk of visual impairment: The CONSTANCES population based cohort. AB - Unhealthy behaviours are linked to a higher risk of eye diseases, but their combined effect on visual function is unknown. We aimed to examine the individual and combined associations of diet, physical activity, smoking and alcohol consumption with visual impairment among French adults. 38 903 participants aged 18-73 years from the CONSTANCES nationwide cohort (2012-2016) with visual acuity measured and who completed, lifestyle, medical and food frequency questionnaires were included. Visual impairment was defined as a presenting visual acuity <20/40 in the better eye. After full multivariate adjustment, the odds for visual impairment increased with decreasing diet quality (p for trend = 0.04), decreasing physical activity (p for trend = 0.02) and increasing smoking pack years (p for trend = 0.03), whereas no statistically significant association with alcohol consumption was found. Combination of several unhealthy behaviours was associated with increasing odds for visual impairment (p for trend = 0.0002), with a fully-adjusted odds ratio of 1.81 (95% CI 1.18 to 2.79) for participants reporting 2 unhealthy behaviours and 2.92 (95% CI 1.60 to 5.32) for those reporting 3 unhealthy behaviours. An unhealthy lifestyle including low/intermediate diet quality, low physical activity and heavy smoking was associated with visual impairment in this large population-based study. PMID- 29700372 TI - Tilted grating phase-contrast computed tomography using statistical iterative reconstruction. AB - Grating-based phase-contrast computed tomography (GBPC-CT) enables increased soft tissue differentiation, but often suffers from streak artifacts when performing high-sensitivity GBPC-CT of biomedical samples. Current GBPC-CT setups consist of one-dimensional gratings and hence allow to measure only the differential phase contrast (DPC) signal perpendicular to the direction of the grating lines. Having access to the full two-dimensional DPC signal can strongly reduce streak artefacts showing up as characteristic horizontal lines in the reconstructed images. GBPC-CT with gratings tilted by 45 degrees around the optical axis, combining opposed projections, and reconstructing with filtered backprojection is one method to retrieve the full three-dimensional DPC signal. This approach improves the quality of the tomographic data as already demonstrated at a synchrotron facility. However, additional processing and interpolation is necessary, and the approach fails when dealing with cone-beam geometry setups. In this work, we employ the tilted grating configuration with a laboratory GBPC-CT setup with cone-beam geometry and use statistical iterative reconstruction (SIR) with a forward model accounting for diagonal grating alignment. Our results show a strong reduction of streak artefacts and significant increase in image quality. In contrast to the prior approach our proposed method can be used in a laboratory environment due to its cone-beam compatibility. PMID- 29700373 TI - Optimized microwave extraction, characterization and antioxidant capacity of biological polysaccharides from Eucommia ulmoides Oliver leaf. AB - Microwave-induced technique was combined with response surface methodology for optimizing the isolation of polysaccharides from Eucommia ulmoides Oliver leaf. The maximum polysaccharides yield of 12.31% was achieved by microwave extraction at 74 degrees C for 15 min with a solid to liquid ratio of 1:29 g/mL, which agreed with the predicted value and was 2.9-fold higher than that of the conventional heat-reflux extraction method. The dominant bioactive constituent in extracts was chlorogenic acid (1.3-1.9%), followed by geniposidic acid (1.0 1.7%). The polysaccharides from the optimized extraction had a high molecular weight and polydispersity (Mw 38,830 g/mol, Mw/Mn 2.19), as compared to the fraction prepared in the absence of microwave (Mw 12,055 g/mol, Mw/Mn 1.26). Glucose was the dominant sugar component (38.2-39.1%) of heterogeneous polysaccharides which belonged to a structure of beta-type acidic heteropolysaccharides with a glucan group and highly branched degree. The polysaccharides showed a higher DPPH radical scavenging index (0.87-1.22) than BHT (0.41) but lower than BHA (3.56), which can act as a favorable antioxidant in functional food. PMID- 29700374 TI - Exotic grass invasion alters microsite conditions limiting woody recruitment potential in an Australian savanna. AB - Andropogon gayanus Kunth. is a large African tussock grass invading Australia's tropical savannas. Invasion results in more intense fires which increases the mortality rate of adult woody plants. Invasion may also affect community structure by altering the recruitment potential of woody plants. We investigated the effects of A. gayanus invasion on ground-level microclimate, and the carbon assimilation potential and recruitment potential of two Eucalyptus species. We compared microclimatic variables from the early wet-season and into the mid-dry season to coincide with the period of growth of A. gayanus. We assessed Eucalyptus recruitment by monitoring seedling establishment, growth and survival of experimentally sown seed, and estimating seedling density resulting from natural recruitment. A. gayanus invasion was associated with increased grass canopy height, biomass and cover. Following invasion, the understorey microclimate had significantly reduced levels of photon flux density, increased air temperatures and vapour pressure deficit. The conditions were less favourable for woody seedling with aboveground biomass of seedlings reduced by 26% in invaded plots. We estimated that invasion reduced daily carbon assimilation of woody seedlings by ~30% and reduced survivorship of Eucalyptus seedlings. Therefore, A. gayanus invasion reduces recruitment potential, contributing to the transformation of savanna to a grassland ecosystem. PMID- 29700375 TI - JIB-04, A Small Molecule Histone Demethylase Inhibitor, Selectively Targets Colorectal Cancer Stem Cells by Inhibiting the Wnt/beta-Catenin Signaling Pathway. AB - Although several epigenetic modulating drugs are suggested to target cancer stem cells (CSCs), additional identification of anti-CSC drugs is still necessary. Here we showed that JIB-04, a pan-selective inhibitor of histone demethylase(s), was identified as a small molecule that selectively target colorectal CSCs. Our data showed that JIB-04 is capable of reducing self-renewal and stemness of colorectal CSCs in three different colorectal cancer cell lines. JIB-04 significantly attenuated CSC tumorsphere formation, growth/relapse, invasion, and migration in vitro. Furthermore, JIB-04-treated colorectal cancer cells showed reduced tumorigenic activity in vivo. RNA sequencing analysis revealed that JIB 04 affected various cancer-related signaling pathways, especially Wnt/beta catenin signaling, which is crucial for the proliferation and maintenance of colorectal cancer cells. qRT-PCR and TOP/FOP flash luciferase assays showed that JIB-04 down-regulated the expression of Wnt/beta-catenin-regulated target genes associated with colorectal CSC function. Overall, the effects of JIB-04 were equal to or greater than those of salinomycin, a known anti-colorectal CSC drug, despite the lower concentration of JIB-04 compared with that of salinomycin. Our results strongly suggest that JIB-04 is a promising drug candidate for colorectal cancer therapy. PMID- 29700376 TI - Day length is associated with physical activity and sedentary behavior among older women. AB - Physical activity may be influenced by one's physical environment, including day length and weather. Studies of physical activity, day length, and weather have primarily used self-reported activity, broad meteorological categorization, and limited geographic regions. We aim to examine the association of day length and physical activity in a large cohort of older women, covering a wide geographic range. Participants (N = 16,741; mean (SD) age = 72.0 (SD = 5.7) years) were drawn from the Women's Health Study and lived throughout the United States. Physical activity was assessed by accelerometer (ActiGraph GT3X+) between 2011 and 2015. Day length and weather information were obtained by matching weather stations to the participants' location using National Oceanic and Atmospheric Administration databases. Women who experienced day lengths greater than 14 hours had 5.5% more steps, 9.4% more moderate-to-vigorous physical activity, and 1.6% less sedentary behavior, compared to women who experienced day lengths less than 10 hours, after adjusting for age, accelerometer wear, temperature, and precipitation. Day length is associated with physical activity and sedentary behavior in older women, and needs to be considered in programs promoting physical activity as well as in the analyses of accelerometer data covering wide geographic regions. PMID- 29700378 TI - How to eliminate gastric cancer-related death worldwide? PMID- 29700379 TI - Neoadjuvant PD-1 blockade in NSCLC. PMID- 29700377 TI - Knowledge acquisition is governed by striatal prediction errors. AB - Discrepancies between expectations and outcomes, or prediction errors, are central to trial-and-error learning based on reward and punishment, and their neurobiological basis is well characterized. It is not known, however, whether the same principles apply to declarative memory systems, such as those supporting semantic learning. Here, we demonstrate with fMRI that the brain parametrically encodes the degree to which new factual information violates expectations based on prior knowledge and beliefs-most prominently in the ventral striatum, and cortical regions supporting declarative memory encoding. These semantic prediction errors determine the extent to which information is incorporated into long-term memory, such that learning is superior when incoming information counters strong incorrect recollections, thereby eliciting large prediction errors. Paradoxically, by the same account, strong accurate recollections are more amenable to being supplanted by misinformation, engendering false memories. These findings highlight a commonality in brain mechanisms and computational rules that govern declarative and nondeclarative learning, traditionally deemed dissociable. PMID- 29700380 TI - Tracing the steps of cancer evolution. PMID- 29700381 TI - Author Correction: Evaluation of Weight Loss Indicators and Laparoscopic One Anastomosis Gastric Bypass Outcomes. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29700383 TI - Role for S. aureus in insulin resistance. PMID- 29700382 TI - Reconstructing the Neanderthal brain using computational anatomy. AB - The present study attempted to reconstruct 3D brain shape of Neanderthals and early Homo sapiens based on computational neuroanatomy. We found that early Homo sapiens had relatively larger cerebellar hemispheres but a smaller occipital region in the cerebrum than Neanderthals long before the time that Neanderthals disappeared. Further, using behavioural and structural imaging data of living humans, the abilities such as cognitive flexibility, attention, the language processing, episodic and working memory capacity were positively correlated with size-adjusted cerebellar volume. As the cerebellar hemispheres are structured as a large array of uniform neural modules, a larger cerebellum may possess a larger capacity for cognitive information processing. Such a neuroanatomical difference in the cerebellum may have caused important differences in cognitive and social abilities between the two species and might have contributed to the replacement of Neanderthals by early Homo sapiens. PMID- 29700385 TI - Design of Metamaterial Absorber using Eight-Resistive-Arm Cell for Simultaneous Broadband and Wide-Incidence-Angle Absorption. AB - In this paper, a broadband metamaterial (MM) absorber is presented for X-band applications. A novel eight-resistive-arm (ERA) cell is proposed as an MM unit cell to achieve both broadband absorption and wide incidence angles. The proposed ERA cell is designed using equivalent circuit model and full-wave analysis in order to achieve an absorption ratio higher than 90% in the range of 8.2-13.4 GHz. The experimental results indicate that the absorptivity was greater than 90% in the range of 8-13 GHz for all polarization angles under normal incidence. Under oblique incidence, the measured absorptivity was greater than 90% in the range of 8.2-12.2 GHz up to 60 degrees and in the range of 9.2-12 GHz up to 65 degrees in the transverse electric (TE) mode. In the transverse magnetic (TM) mode, the measured absorptivity was higher than 90% in the range of 9.5-12.4 GHz when the incidence angle was varied from 0 degrees to 60 degrees and remaining a 90% absorption bandwidth in the range of 10-12 GHz up to 65 degrees . Compared to other broadband MM absorbers, the proposed MM absorber exhibited the widest incidence angles in both TE and TM modes. PMID- 29700384 TI - A Temporal Examination of Platelet Counts as a Predictor of Prognosis in Lung, Prostate, and Colon Cancer Patients. AB - Platelets, components of hemostasis, when present in excess (>400 K/MUL, thrombocytosis) have also been associated with worse outcomes in lung, ovarian, breast, renal, and colorectal cancer patients. Associations between thrombocytosis and cancer outcomes have been made mostly from single-time-point studies, often at the time of diagnosis. Using laboratory data from the Department of Veterans Affairs (VA), we examined the potential benefits of using longitudinal platelet counts in improving patient prognosis predictions. Ten features (summary statistics and engineered features) were derived to describe the platelet counts of 10,000+ VA lung, prostate, and colon cancer patients and incorporated into an age-adjusted LASSO regression analysis to determine feature importance, and predict overall or relapse-free survival, which was compared to the previously used approach of monitoring for thrombocytosis near diagnosis (Postdiag AG400 model). Temporal features describing acute platelet count increases/decreases were found to be important in cancer survival and relapse survival that helped stratify good and bad outcomes of cancer patient groups. Predictions of overall and relapse-free survival were improved by up to 30% compared to the Postdiag AG400 model. Our study indicates the association of temporally derived platelet count features with a patients' prognosis predictions. PMID- 29700386 TI - Minimal residual disease analysis in chronic lymphocytic leukemia: a way for achieving more personalized treatments. AB - Therapeutic approaches for chronic lymphocytic leukemia (CLL) have dramatically changed over the recent past. In parallel, quantification of minimal residual disease (MRD) proved to be an independent prognostic factor for progression-free and overall survival. The European Research Initiative on CLL (ERIC) in collaboration with American and Australasian partners developed harmonised assays that could be applied reproducibly to compare the efficacy of different treatments. The potential for MRD analysis to identify the most effective treatments prior to reaching survival endpoints was recognised by regulatory agencies and approved as an intermediate endpoint for licensure in randomized studies, in Europe. More recently treatment approaches have evolved, in particular with BCL2-pathway inhibitors, so that MRD analysis may be informative for most patients and clinical trials, potentially becoming a tool for managing CLL patients in clinical practice. In the recent past the importance of the type of MRD assay used, the most appropriate timing and compartment to assess for different treatment types have been learnt as we move towards eradicating residual disease beyond the guideline threshold of one cell in ten thousand. Nowadays, MRD assessment in CLL has quickly become an indispensable tool for clinical research and development that promise to change the way we manage our patients in the future. PMID- 29700387 TI - Multivalent exposure of trastuzumab on iron oxide nanoparticles improves antitumor potential and reduces resistance in HER2-positive breast cancer cells. AB - Targeted therapies have profoundly changed the clinical prospect in human epidermal growth factor receptor 2 (HER2)-positive breast cancer. In particular, the anti-HER2 monoclonal antibody trastuzumab represents the gold standard for the treatment of HER2+ breast cancer patients. Its contribution in dampening cancer progression is mainly attributed to the antibody-dependent cell-mediated cytotoxicity (ADCC) rather than HER2 blockade. Here, multiple half chains of trastuzumab were conjugated onto magnetic iron oxide nanoparticles (MNP-HC) to develop target-specific and biologically active nanosystems to enhance anti-HER2 therapeutic potential. HER2 targeting was assessed in different human breast cancer cell lines, where nanoparticles triggered site-specific phosphorylation in the catalytic domain of the receptor and cellular uptake by endocytosis. MNP-HC induced remarkable antiproliferative effect in HER2+ breast cancer cells, exhibiting enhanced activity compared to free drug. Accordingly, nanoparticles induced p27kip1 expression and cell cycle arrest in G1 phase, without loosing capability to prime ADCC. Finally, MNP-HC affected viability of trastuzumab resistant cells, suggesting interference with the resistance machinery. Our findings indicate that multiple arrangement of trastuzumab half chain on the nanoparticle surface enhances anticancer efficacy in HER2+ breast cancer cells. Powerful inhibition of HER2 signaling could promote responsiveness of resistant cells, thus suggesting ways for drug sensitization. PMID- 29700389 TI - Does the association of prostate cancer with night-shift work differ according to rotating vs. fixed schedule? A systematic review and meta-analysis. AB - BACKGROUND: Recent studies suggested that the relation between night-shift work and prostate cancer may differ between rotating and fixed schedules. OBJECTIVES: We aimed to quantify the independent association between night-shift work and prostate cancer, for rotating and fixed schedules. METHODS: We searched MEDLINE for studies assessing the association of night-shift work, by rotating or fixed schedules, with prostate cancer. We computed summary relative risk (RR) estimates with 95% confidence intervals (95% CI) using the inverse variance method and quantified heterogeneity using the I2 statistic. Meta-regression analysis was used to compare the summary RR estimates for rotating and fixed schedules, while reducing heterogeneity. RESULTS: A total of nine studies assessed the effect of rotating and, in addition, four of them provided the effect of fixed night-shift work, in relation to daytime workers. Rotating night-shift work was associated with a significantly increased risk of prostate cancer (RR = 1.06, 95% CI of 1.01 to 1.12; I2 = 50%), but not fixed night-shift work (RR of 1.01, 95% CI of 0.81 to 1.26; I2 = 33%). In meta-regression model including study design, type of population, and control of confounding, the summary RR was 20% higher for rotating vs. fixed schedule, with heterogeneity fully explained by these variables. CONCLUSIONS: This is the first meta-analysis suggesting that an increased risk of prostate cancer may be restricted to workers with rotating night shifts. However, the association was weak and additional studies are needed to further clarify this relation before it can be translated into measures for risk reduction in occupational settings. PMID- 29700388 TI - Changes in cerebral metabolic activity in men undergoing androgen deprivation therapy for non-metastatic prostate cancer. AB - OBJECTIVE: Androgen deprivation therapy (ADT) is a common treatment option for men with biochemical relapse from prostate cancer. ADT is associated with changes in mood, cognition, and quality of life, and most recently with increased risk for Alzheimer's disease (AD). This study examined changes in brain metabolism using positron emission tomography (PET) in men undergoing intermittent ADT. METHODS: Nine men with prostate cancer and a rising PSA (biochemical recurrence) without evidence of metastases were treated with intermittent ADT consisting of 9 months of complete androgen blockade achieved with combined leuprolide acetate and flutamide. Patients underwent resting [Fuorine-18] fluorodeoxyglucose PET (18F-FDGPET) at baseline (before treatment) and again after 9 months of ADT. RESULTS: Whole-brain mapping analysis after 9 months of androgen deprivation compared to pretreatment baseline revealed decreased regional cerebral glucose metabolism in the cerebellum, posterior cingulate, and medial thalamus bilaterally. Associations of brain metabolism with measurements of cognition and mood while on androgen deprivation revealed positive correlations between the posterior cingulate, left inferior parietal lobule (BA40), and left mid temporal gyrus (BA39) and spatial reasoning and a negative correlation between left inferior parietal lobule and verbal memory. Several mood indices were negatively correlated with hypothalamus and brainstem. CONCLUSION: These findings suggest that complete androgen deprivation may result in changes in regional brain metabolism associated with variation in mood, verbal memory, and spatial performance. Brain regions that were impacted from ADT are similar and overlap with brain regions with metabolic decline found in early AD and diabetes, suggesting possible common mechanisms. PMID- 29700390 TI - Using a genetic test result in the care of family members: how does the duty of confidentiality apply? AB - The use of genetic and genomic testing is becoming more widespread in healthcare and more inherited explanations for family history of diseases or conditions are being uncovered. Currently, relevant genetic information is not always used in the care of family members who might benefit from it, because of health professionals' fears of inappropriately breaching another family member's confidence. Such examples are likely to increase as testing possibilities expand. Here we present the case for use of familial information in the care and treatment of family members. We argue that whilst a clinical diagnosis in person A is confidential, the discovery of a familial factor that led to this diagnosis should be available for use in depersonalised form by health professionals to inform the testing and clinical care of other family members. The possibility of such use should be made clear in clinical practice at the time of initial testing, but should not require consent from the person in whom the familial factor was first identified. We call for further debate on these questions in the wake of high profile non-disclosure of genetic information cases, and forthcoming Data Protection legislation changes. PMID- 29700391 TI - Effects of autozygosity and schizophrenia polygenic risk on cognitive and brain developmental trajectories. AB - Cognitive and brain development are determined by dynamic interactions between genes and environment across the lifespan. Aside from marker-by-marker analyses of polymorphisms, biologically meaningful features of the whole genome (derived from the combined effect of individual markers) have been postulated to inform on human phenotypes including cognitive traits and their underlying biological substrate. Here, estimates of inbreeding and genetic susceptibility for schizophrenia calculated from genome-wide data-runs of homozygosity (ROH) and schizophrenia polygenic risk score (PGRS)-are analyzed in relation to cognitive abilities (n = 4183) and brain structure (n = 516) in a general-population sample of European-ancestry participants aged 8-22, from the Philadelphia Neurodevelopmental Cohort. The findings suggest that a higher ROH burden and higher schizophrenia PGRS are associated with higher intelligence. Cognition-ROH and cognition-PGRS associations obtained in this cohort may, respectively, evidence that assortative mating influences intelligence, and that individuals with high schizophrenia genetic risk who do not transition to disease status are cognitively resilient. Neuroanatomical data showed that the effects of schizophrenia PGRS on cognition could be modulated by brain structure, although larger imaging datasets are needed to accurately disentangle the underlying neural mechanisms linking IQ with both inbreeding and the genetic burden for schizophrenia. PMID- 29700393 TI - Shieldin the ends for 53BP1. PMID- 29700392 TI - EPHB6 augments both development and drug sensitivity of triple-negative breast cancer tumours. AB - Triple-negative breast cancer (TNBC) tumours that lack expression of oestrogen, and progesterone receptors, and do not overexpress the HER2 receptor represent the most aggressive breast cancer subtype, which is characterised by the resistance to therapy in frequently relapsing tumours and a high rate of patient mortality. This is likely due to the resistance of slowly proliferating tumour initiating cells (TICs), and understanding molecular mechanisms that control TICs behaviour is crucial for the development of effective therapeutic approaches. Here, we present our novel findings, indicating that an intrinsically catalytically inactive member of the Eph group of receptor tyrosine kinases, EPHB6, partially suppresses the epithelial-mesenchymal transition in TNBC cells, while also promoting expansion of TICs. Our work reveals that EPHB6 interacts with the GRB2 adapter protein and that its effect on enhancing cell proliferation is mediated by the activation of the RAS-ERK pathway, which allows it to elevate the expression of the TIC-related transcription factor, OCT4. Consistent with this, suppression of either ERK or OCT4 activities blocks EPHB6-induced pro proliferative responses. In line with its ability to trigger propagation of TICs, EPHB6 accelerates tumour growth, potentiates tumour initiation and increases TIC populations in xenograft models of TNBC. Remarkably, EPHB6 also suppresses tumour drug resistance to DNA-damaging therapy, probably by forcing TICs into a more proliferative, drug-sensitive state. In agreement, patients with higher EPHB6 expression in their tumours have a better chance for recurrence-free survival. These observations describe an entirely new mechanism that governs TNBC and suggest that it may be beneficial to enhance EPHB6 action concurrent with applying a conventional DNA-damaging treatment, as it would decrease drug resistance and improve tumour elimination. PMID- 29700395 TI - Theoretical prediction and atomic kinetic Monte Carlo simulations of void superlattice self-organization under irradiation. AB - Nano-structured superlattices may have novel physical properties and irradiation is a powerful mean to drive their self-organization. However, the formation mechanism of superlattice under irradiation is still open for debate. Here we use atomic kinetic Monte Carlo simulations in conjunction with a theoretical analysis to understand and predict the self-organization of nano-void superlattices under irradiation, which have been observed in various types of materials for more than 40 years but yet to be well understood. The superlattice is found to be a result of spontaneous precipitation of voids from the matrix, a process similar to phase separation in regular solid solution, with the symmetry dictated by anisotropic materials properties such as one-dimensional interstitial atom diffusion. This discovery challenges the widely accepted empirical rule of the coherency between the superlattice and host matrix crystal lattice. The atomic scale perspective has enabled a new theoretical analysis to successfully predict the superlattice parameters, which are in good agreement with independent experiments. The theory developed in this work can provide guidelines for designing target experiments to tailor desired microstructure under irradiation. It may also be generalized for situations beyond irradiation, such as spontaneous phase separation with reaction. PMID- 29700394 TI - Stage-specific Effects of Bioactive Lipids on Human iPSC Cardiac Differentiation and Cardiomyocyte Proliferation. AB - Bioactive lipids such as sphingosine-1-phosphate (S1P) and lysophosphatidic acid (LPA) regulate diverse processes including cell proliferation, differentiation, and migration. However, their roles in cardiac differentiation and cardiomyocyte proliferation have not been explored. Using a 96-well differentiation platform for generating human induced pluripotent stem cell-derived cardiomyocytes (hiPSC CMs) we found that S1P and LPA can independently enhance cardiomyocyte generation when administered at an early stage of differentiation. We showed that the combined S1P and LPA treatment of undifferentiated hiPSCs resulted in increased nuclear accumulation of beta-catenin, the canonical Wnt signaling pathway mediator, and synergized with CHIR99021, a glycogen synthase kinase 3 beta inhibitor, to enhance mesodermal induction and subsequent cardiac differentiation. At later stages of cardiac differentiation, the addition of S1P and LPA resulted in cell cycle initiation in hiPSC-CMs, an effect mediated through increased ERK signaling. Although the addition of S1P and LPA alone was insufficient to induce cell division, it was able to enhance beta-catenin mediated hiPSC-CM proliferation. In summary, we demonstrated a developmental stage-specific effect of bioactive lipids to enhance hiPSC-CM differentiation and proliferation via modulating the effect of canonical Wnt/beta-catenin and ERK signaling. These findings may improve hiPSC-CM generation for cardiac disease modeling, precision medicine, and regenerative therapies. PMID- 29700396 TI - A history of exploring cancer in context. AB - The concept that progression of cancer is regulated by interactions of cancer cells with their microenvironment was postulated by Stephen Paget over a century ago. Contemporary tumour microenvironment (TME) research focuses on the identification of tumour-interacting microenvironmental constituents, such as resident or infiltrating non-tumour cells, soluble factors and extracellular matrix components, and the large variety of mechanisms by which these constituents regulate and shape the malignant phenotype of tumour cells. In this Timeline article, we review the developmental phases of the TME paradigm since its initial description. While illuminating controversies, we discuss the importance of interactions between various microenvironmental components and tumour cells and provide an overview and assessment of therapeutic opportunities and modalities by which the TME can be targeted. PMID- 29700397 TI - Organoid diversity. PMID- 29700399 TI - Breast cancer therapy and cardiac mortality. PMID- 29700398 TI - Structure and solvents effects on the optical properties of sugar-derived carbon nanodots. AB - Carbon nanodots are a new and intriguing class of fluorescent carbon nanomaterials and are considered a promising low cost, nontoxic alternative to traditional inorganic quantum dots in applications such as bioimaging, solar cells, photocatalysis, sensors and others. Despite the abundant available literature, a clear formation mechanism for carbon nanodots prepared hydrothermally from biomass precursors along with the origins of the light emission are still under debate. In this paper, we investigate the relationships between the chemical structure and optical properties of carbon nanodots prepared by the hydrothermal treatment of glucose. Our major finding is that the widely reported excitation-dependent emission originates from solvents used to suspend the as-prepared carbon nanodots, while emission from dry samples shows no excitation-dependence. Another important highlight is that the hydrothermal conversion of biomass-derivatives under subcritical conditions leads to a heterogeneous mixture of amorphous-like nanoparticles, carbon onion-type and crystalline carbons composed of at least three different phases. The potential chemical reaction pathways involved in the formation of these hydrothermal carbon products along with a comprehensive structural and optical characterization of these systems is also provided. PMID- 29700400 TI - Young women have worse outcomes after STEMI. PMID- 29700401 TI - Fitness ameliorates genetic risk of heart disease. PMID- 29700402 TI - Selenoprotein P - a new player in PAH. PMID- 29700403 TI - Quantifying population exposure to air pollution using individual mobility patterns inferred from mobile phone data. AB - A critical question in environmental epidemiology is whether air pollution exposures of large populations can be refined using individual mobile-device based mobility patterns. Cellular network data has become an essential tool for understanding the movements of human populations. As such, through inferring the daily home and work locations of 407,435 mobile phone users whose positions are determined, we assess exposure to PM2.5. Spatiotemporal PM2.5 concentrations are predicted using an Aerosol Optical Depth- and Land Use Regression-combined model. Air pollution exposures of subjects are assigned considering modeled PM2.5 levels at both their home and work locations. These exposures are then compared to residence-only exposure metric, which does not consider daily mobility. In our study, we demonstrate that individual air pollution exposures can be quantified using mobile device data, for populations of unprecedented size. In examining mean annual PM2.5 exposures determined, bias for the residence-based exposures was 0.91, relative to the exposure metric considering the work location. Thus, we find that ignoring daily mobility potentially contributes to misclassification in health effect estimates. Our framework for understanding population exposure to environmental pollution could play a key role in prospective environmental epidemiological studies. PMID- 29700404 TI - Preservation of rat limbs by hyperbaric carbon monoxide and oxygen. AB - Cold ischemia times ranging from <6 h to as long as 24 h are generally quoted as the limits for attempting the replantation of amputated extremities. In this study, we aimed to assess the effect of hyperbaric carbon monoxide (CO) and oxygen (O2) on rat limb preservation. Donor rat limbs were preserved in a chamber filled with hyperbaric CO and O2 for 3 days (CO + O2 3 days) or 7 days (CO + O2 7 days). Positive and negative control groups were created by using non-preserved limbs (NP) and limbs wrapped in saline-moistened gauze for 3 days (SMG 3 days), respectively. The survival rate of transplanted limbs at postoperative day 90 was 88% in the NP and 86% in the CO + O2 3 days. The corresponding survival rate was 50% in the CO + O2 7 days at postoperative day 90 but was 0% in the SMG 3 days at postoperative day 3. Muscle mass decreased in the CO + O2 3 days and CO + O2 7 days compared with the NP, but sciatic-tibial nerve conduction velocities did not differ. These results indicate that amputated extremities preservation with hyperbaric CO and O2 could extend the time limits of preservation, maintaining their viability for replantation. PMID- 29700405 TI - Integrated analysis of microRNA and mRNA expression profiles in rats with selenium deficiency and identification of associated miRNA-mRNA network. AB - Selenium deficiency is closely related with various type of cardiovascular disease. However, the miRNA-mRNA regulatory network in Selenium deficiency related cardiac change remains to be understand. In the present study, a reliable Selenium deficiency rat model was established and confirmed by pathological and biochemical examination. The mRNA and miRNA expression profiles were conducted by microarray technology. Gene Ontology (GO) Analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) Pathway Analysis was performed to investigate the function of targeted genes, and the relationship between miRNA and mRNA was studied by network analysis. A total of 4931 mRNAs and 119 miRNAs was differentially expressed between any two groups (control group, low-selenium group and selenium supplementation group). GO and KEGG pathway analysis of selected miRNAs target genes found that selenium deficiency was related to several different biological processes. Furthermore, a miRNA-mRNA regulatory network was conducted to illustrate the interaction of miRNAs and these targeted genes. In conclusion, our present study provides a new insight that potential molecular mechanism of Selenium deficiency was a multiply miRNAs and mRNA caused biological change. PMID- 29700406 TI - Sub-noxious Intravesical Lipopolysaccharide Triggers Bladder Inflammation and Symptom Onset in A Transgenic Autoimmune Cystitis Model: A MAPP Network Animal Study. AB - Patients with interstitial cystitis/bladder pain syndrome (IC/BPS) can potentially develop symptom flares after exposure to minor bladder irritants such as subclinical bacterial infection. To reproduce this symptom onset, we intravesically instilled a sub-noxious dose of uropathogenic E. coli component lipopolysaccharide (LPS) in young URO-OVA/OT-I mice, a transgenic autoimmune cystitis model that spontaneously develops bladder inflammation at >=10 weeks of age. Female URO-OVA/OT-I mice (6-weeks old) were treated intravesically with phosphate-buffered saline (PBS) or PBS containing a sub-noxious dose (1 MUg) of LPS. Mice were evaluated for bladder inflammation, pelvic pain, and voiding dysfunction at days 1, 7, and 14 post-treatment. Mice treated with LPS but not PBS developed early bladder inflammation with increased macrophage infiltration. Accordingly, the inflamed bladders expressed increased levels of mRNA for proinflammatory cytokines (IL-1beta and IL-6) and pain mediator (substance P precursor). In addition, LPS-treated mice exhibited pelvic pain and voiding dysfunction such as increased urinary frequency and reduced bladder capacity. These functional changes sustained up to day 14 tested. Our results indicate that a single sub-noxious dose of intravesical LPS triggers early bladder inflammation and symptom onset in URO-OVA/OT-I mice, providing a useful model for IC/BPS symptom flare study. PMID- 29700407 TI - Ineffectiveness of tactile gating shows cortical basis of nociceptive signaling in the Thermal Grill Illusion. AB - Painful burning sensations can be elicited by a spatially-alternating pattern of warm and cold stimuli applied on the skin, the so called "Thermal Grill Illusion" (TGI). Here we investigated whether the TGI percept originates spinally or centrally. Since the inhibition of nociceptive input by concomitant non nociceptive somatosensory input has a strong spinal component, we reasoned that, if the afferent input underlying the TGI originates at spinal level, then the TGI should be inhibited by a concomitant non-nociceptive somatosensory input. Conversely, if TGI is the result of supraspinal processing, then no effect of touch on TGI would be expected. We elicited TGI sensations in a purely thermal condition without tactile input, and found no evidence that tactile input affected the TGI. These results provide further evidence against a spinal mechanism generating the afferent input producing the TGI, and indicate that the peculiar burning sensation of the TGI results from supraspinal interactions between thermoceptive and nociceptive systems. PMID- 29700409 TI - Author Correction: Diversity and evolution of sex determination systems in terrestrial isopods. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29700410 TI - Internalization of CD239 highly expressed in breast cancer cells: a potential antigen for antibody-drug conjugates. AB - Antibody-drug conjugates (ADCs) are attractive in cancer therapy because they can directly bind to cancer cells and provide anticancer activity. To kill cancer cells with ADCs, the target antigens are required not only to be highly and/or selectively expressed on cancer cells but also internalized by the cells. CD239, also known as the Lutheran blood group glycoprotein (Lu) or basal cell adhesion molecule (B-CAM), is a specific receptor for laminin alpha5, a major component of basement membranes. Here, we show that CD239 is strongly expressed in a subset of breast cancer cells and internalized into the cells. We also produced a human single-chain variable fragment (scFv) specific to CD239 fused with human IgG1 Fc, called C7-Fc. The binding affinity of the C7-Fc antibody is similar to that of mouse monoclonal antibodies. Although the C7-Fc antibody alone does not influence cellular functions, when conjugated with a fragment of diphtheria toxin lacking the receptor-binding domain (fDT), it can selectively kill breast cancer cells. Interestingly, fDT-bound C7-Fc shows anticancer activity in CD239-highly positive SKBR3 cells, but not in weakly positive cells. Our results show that CD239 is a promising antigen for ADC-based breast cancer therapy. PMID- 29700408 TI - E-cadherin breast tumor expression, risk factors and survival: Pooled analysis of 5,933 cases from 12 studies in the Breast Cancer Association Consortium. AB - E-cadherin (CDH1) is a putative tumor suppressor gene implicated in breast carcinogenesis. Yet, whether risk factors or survival differ by E-cadherin tumor expression is unclear. We evaluated E-cadherin tumor immunohistochemistry expression using tissue microarrays of 5,933 female invasive breast cancers from 12 studies from the Breast Cancer Consortium. H-scores were calculated and case case odds ratios (OR) and 95% confidence intervals (CIs) were estimated using logistic regression. Survival analyses were performed using Cox regression models. All analyses were stratified by estrogen receptor (ER) status and histologic subtype. E-cadherin low cases (N = 1191, 20%) were more frequently of lobular histology, low grade, >2 cm, and HER2-negative. Loss of E-cadherin expression (score < 100) was associated with menopausal hormone use among ER positive tumors (ever compared to never users, OR = 1.24, 95% CI = 0.97-1.59), which was stronger when we evaluated complete loss of E-cadherin (i.e. H-score = 0), OR = 1.57, 95% CI = 1.06-2.33. Breast cancer specific mortality was unrelated to E-cadherin expression in multivariable models. E-cadherin low expression is associated with lobular histology, tumor characteristics and menopausal hormone use, with no evidence of an association with breast cancer specific survival. These data support loss of E-cadherin expression as an important marker of tumor subtypes. PMID- 29700412 TI - Feeding young infants with their head in upright position reduces respiratory and ear morbidity. AB - The influence of feeding position of the infant in the pathogenesis of ear and airway diseases has not been well established. We investigated the influence of instructing mothers to feed their 3-month old infants with their head in an upright position on ear and respiratory morbidity during a one-year follow-up. Mothers of 88 infants were instructed by trained nurses to feed their infants with their head in upright position (intervention group). The control group consisted of 75 mothers of infants of similar socioeconomic background who fed their infants without special instructions. Both groups were followed at Maternal Child-Health clinics. Feeding position was evaluated at the beginning and the end of the twelve-month study, and parent reported morbidity data of both groups were evaluated at every 3-month's follow-up meeting. Infants from the intervention group were fed at a more upright head position. Parameters of parent reported morbidity evaluated as area under the curve were significantly lower in infants from the intervention group concerning ear diseases, respiratory diseases, prolonged fever episodes, need of bronchodilator inhalations and antibiotic courses compared to the control group. Instructing mothers to feed infants with their head in upright position was accompanied with less morbidity and treatment burden. PMID- 29700411 TI - A dualistic model of primary anal canal adenocarcinoma with distinct cellular origins, etiologies, inflammatory microenvironments and mutational signatures: implications for personalised medicine. AB - BACKGROUND: Primary adenocarcinoma of the anal canal is a rare and aggressive gastrointestinal disease with unclear pathogenesis. Because of its rarity, no clear clinical practice guideline has been defined and a targeted therapeutic armamentarium has yet to be developed. The present article aimed at addressing this information gap by in-depth characterising the anal glandular neoplasms at the histologic, immunologic, genomic and epidemiologic levels. METHODS: In this multi-institutional study, we first examined the histological features displayed by each collected tumour (n = 74) and analysed their etiological relationship with human papillomavirus (HPV) infection. The intratumoural immune cell subsets (CD4, CD8, Foxp3), the expression of immune checkpoints (PD-1, PD-L1), the defect in mismatch repair proteins and the mutation analysis of multiple clinically relevant genes in the gastrointestinal cancer setting were also determined. Finally, the prognostic significance of each clinicopathological variable was assessed. RESULTS: Phenotypic analysis revealed two region-specific subtypes of anal canal adenocarcinoma. The significant differences in the HPV status, density of tumour-infiltrating lymphocytes, expression of immune checkpoints and mutational profile of several targetable genes further supported the separation of these latter neoplasms into two distinct entities. Importantly, anal gland/transitional-type cancers, which poorly respond to standard treatments, displayed less mutations in downstream effectors of the EGFR signalling pathway (i.e., KRAS and NRAS) and demonstrated a significantly higher expression of the immune inhibitory ligand-receptor pair PD-1/PD-L1 compared to their counterparts arising from the colorectal mucosa. CONCLUSIONS: Taken together, the findings reported in the present article reveal, for the first time, that glandular neoplasms of the anal canal arise by HPV-dependent or independent pathways. These etiological differences leads to both individual immune profiles and mutational landscapes that can be targeted for therapeutic benefits. PMID- 29700413 TI - Identification of the allosteric P2X7 receptor antagonist [11C]SMW139 as a PET tracer of microglial activation. AB - The P2X7 receptor plays a significant role in microglial activation, and as a potential drug target, the P2X7 receptor is also an interesting target in positron emission tomography. The current study aimed at the development and evaluation of a potent tracer targeting the P2X7 receptor, to which end four adamantanyl benzamide analogues with high affinity for the human P2X7 receptor were labelled with carbon-11. All four analogues could be obtained in excellent radiochemical yield and high radiochemical purity and molar activity, and all analogues entered the rat brain. [11C]SMW139 showed the highest metabolic stability in rat plasma, and showed high binding to the hP2X7 receptor in vivo in a hP2X7 receptor overexpressing rat model. Although no significant difference in binding of [11C]SMW139 was observed between post mortem brain tissue of Alzheimer's disease patients and that of healthy controls in in vitro autoradiography experiments, [11C]SMW139 could be a promising tracer for P2X7 receptor imaging using positron emission tomography, due to high receptor binding in vivo in the hP2X7 receptor overexpressing rat model. However, further investigation of both P2X7 receptor expression and binding of [11C]SMW139 in other neurological diseases involving microglial activation is warranted. PMID- 29700414 TI - Boosting Terahertz Photoconductive Antenna Performance with Optimised Plasmonic Nanostructures. AB - Advanced nanophotonics penetrates into other areas of science and technology, ranging from applied physics to biology, which results in many fascinating cross disciplinary applications. It has been recently demonstrated that suitably engineered light-matter interactions at the nanoscale can overcome the limitations of today's terahertz (THz) photoconductive antennas, making them one step closer to many practical implications. Here, we push forward this concept by comprehensive numerical optimization and experimental investigation of a log periodic THz photoconductive antenna coupled to a silver nanoantenna array. We shed light on the operation principles of the resulting hybrid THz antenna, providing an approach to boost its performance. By tailoring the size of silver nanoantennas and their arrangement, we obtain an enhancement of optical-to-THz conversion efficiency 2-fold larger compared with previously reported results for similar structures, and the strongest enhancement is around 1 THz, a frequency range barely achievable by other compact THz sources. We also propose a cost effective fabrication procedure to realize such hybrid THz antennas with optimized plasmonic nanostructures via thermal dewetting process, which does not require any post processing and makes the proposed solution very attractive for applications. PMID- 29700417 TI - Progression and regression of fibrosis in viral hepatitis in the treatment era: the Beijing classification. AB - In this new era of successful long term suppression of hepatitis B viral replication and consistent eradication of hepatitis C virus the necessity for routine pre-treatment biopsies has often been eliminated. Thus, whether there is utility to perform liver biopsy in chronic viral hepatitis is undergoing re examination. In response to these changing needs, we have developed a new staging system, the Beijing Classification, for assessment of biopsy specimens from patients with chronic viral hepatitis. The most important novelty of the Beijing Classification is that it includes not only extent (stage) of fibrosis, but the quality of fibrosis, namely if the specimen shows predominantly regressive vs. progressive features (or is indeterminantly balanced between the two), the P-I-R score. This histologic distinction between regressive and progressive fibrosis, while invoked in this particular setting of chronic viral hepatitis, may have applicability to all forms of chronic liver disease. Thus, the review contains a description of the concepts of regression and progression with the aim of empowering pathologists to apply them in histopathologic-clinical correlation research as well as in the specific clinical setting for which it was developed. Also, in light of changing clinical needs, grading of necroinflammatory activity and staging of fibrosis are simplified into three point scales. These simplifications should aid the general diagnostic pathologist in being comfortable and confident in assessing biopsy specimens as the criteria for their distinction are far more precise, with significantly reduced "gray zones" of prior grading/staging systems. PMID- 29700416 TI - Synthesis and conformational analysis of linear homo- and heterooligomers from novel 2-C-branched sugar amino acids (SAAs). AB - Sugar amino acids (SAAs), as biologically interesting structures bearing both amino and carboxylic acid functional groups represent an important class of multifunctional building blocks. In this study, we develop an easy access to novel SAAs in only three steps starting from nitro compounds in high yields in analytically pure form, easily available by ceric (IV) mediated radical additions. Such novel SAAs have been applied in the assembly of total nine carbopeptoids with the form of linear homo- and heterooligomers for the structural investigations employing circular dichroism (CD) spectroscopy, which suggest that the carbopeptoids emerge a well-extended, left (or right)-handed conformation similar to polyproline II (PPII) helices. NMR studies also clearly demonstrated the presence of ordered secondary structural elements. 2D-ROESY spectra were acquired to identify i+1 NH <-> i C 1 H, i C 2 H correlations which support the conformational analysis of tetramers by CD spectroscopy. These findings provide interesting information of SAAs and their oligomers as potential scaffolds for discovering new drugs and materials. PMID- 29700415 TI - Comparative systems analysis of the secretome of the opportunistic pathogen Aspergillus fumigatus and other Aspergillus species. AB - Aspergillus fumigatus and multiple other Aspergillus species cause a wide range of lung infections, collectively termed aspergillosis. Aspergilli are ubiquitous in environment with healthy immune systems routinely eliminating inhaled conidia, however, Aspergilli can become an opportunistic pathogen in immune-compromised patients. The aspergillosis mortality rate and emergence of drug-resistance reveals an urgent need to identify novel targets. Secreted and cell membrane proteins play a critical role in fungal-host interactions and pathogenesis. Using a computational pipeline integrating data from high-throughput experiments and bioinformatic predictions, we have identified secreted and cell membrane proteins in ten Aspergillus species known to cause aspergillosis. Small secreted and effector-like proteins similar to agents of fungal-plant pathogenesis were also identified within each secretome. A comparison with humans revealed that at least 70% of Aspergillus secretomes have no sequence similarity with the human proteome. An analysis of antigenic qualities of Aspergillus proteins revealed that the secretome is significantly more antigenic than cell membrane proteins or the complete proteome. Finally, overlaying an expression dataset, four A. fumigatus proteins upregulated during infection and with available structures, were found to be structurally similar to known drug target proteins in other organisms, and were able to dock in silico with the respective drug. PMID- 29700418 TI - SMARCA4-deficient undifferentiated uterine sarcoma (malignant rhabdoid tumor of the uterus): a clinicopathologic entity distinct from undifferentiated carcinoma. AB - Small cell carcinoma of the ovary, hypercalcemic type is a rare, aggressive malignancy which usually occurs in young women and is characterized by mutations in SMARCA4, with few other alterations. We recently encountered uterine tumors with morphologic, immunohistochemical, and genetic similarities to small cell carcinoma of the ovary, hypercalcemic type. Herein we report the clinicopathologic and molecular features (using a targeted massively parallel sequencing [MPS] assay) of these tumors. The cases were diagnosed on cervical and endometrial biopsies (n = 2, 34, and 29 years) or hysterectomy and bilateral salpingo-oophorectomy (n = 3, 25, 33, and 58 years). The tumors were composed of sheets of large atypical epithelioid cells with prominent rhabdoid morphology, indistinguishable from the "large cell" variant of small cell carcinoma of the ovary, hypercalcemic type. In three cases, the ovaries were pathologically examined to exclude a primary ovarian malignancy. Immunohistochemically, four of four cases showed SMARCA4 loss, and were negative or only focally positive for keratins, EMA, and claudin-4. One of three cases was positive for WT-1. Targeted MPS was successfully performed on 4 of 5 tumors, and showed recurrent mutations in SMARCA4, with few other alterations. Of the cases diagnosed on hysterectomy, all had extensive lymphovascular invasion, extra-uterine spread, and marked infiltrative growth. These tumors were uniformly aggressive; all patients died of disease (median survival 7 months, range 1-43 months). We propose this entity be called "SMARCA4-deficient undifferentiated uterine sarcoma (malignant rhabdoid tumor of the uterus)", a term which describes both the tumor's underlying molecular abnormality and its morphology. Its unique clinicopathologic and molecular features differentiate it from other related malignancies, including undifferentiated endometrial carcinoma, small cell carcinoma of the ovary (hypercalcemic type), and epithelioid sarcoma. We review and discuss previously reported "rhabdoid tumors of the uterus;" while they are a heterogenous group of tumors, some of them are likely examples of this entity. Correctly identifying cases of SMARCA4-deficient uterine sarcoma from histologic mimics is important as it may have prognostic, predictive, and germline implications. PMID- 29700419 TI - The Correlation Between the Immune and Epithelial-Mesenchymal Transition Signatures Suggests Potential Therapeutic Targets and Prognosis Prediction Approaches in Kidney Cancer. AB - Both epithelial-mesenchymal transition (EMT) and immune regulation are important biological process in malignant tumours. The current research aims to comprehensively explore the potential association between the epithelial mesenchymal transition (EMT) signature and immune checkpoint signature and its role in predicting the prognosis of clear-cell renal cell carcinoma (ccRCC) patients. EMT-related genes were collected from an experiment-based study and then were investigated using data from the Cancer Genome Atlas. A total of 357 genes were included, and 23 of them that were upregulated and correlated with prognosis were analysed further as core EMT genes in ccRCC. Interestingly, the emerging immune checkpoints CD276, OX40 and TGFB1 were found to be significantly co-expressed with core EMT genes, and TGFB1, CXCR4, IL10, and IL6 were the most important molecules potentially interacting with EMT molecules in our model, as determined from mRNA co-expression and protein-protein interaction network analysis. Additionally, an integrated scoring model based on FOXM1, TIMP1 and IL6 was successfully established to distinguish ccRCC patients with different clinical risks. Our results identified core genes in the EMT-immunophenotyping correlation and evaluated their risk assessment capabilities, providing more potential therapeutic targets and prediction approaches regarding the translational research of treatment and prognosis in ccRCC. PMID- 29700420 TI - Exposure to toxic metals triggers unique responses from the rat gut microbiota. AB - Our understanding of the interaction between the gut microbiota and host health has recently improved dramatically. However, the effects of toxic metal exposure on the gut microbiota remain poorly characterized. As this microbiota creates a critical interface between the external environment and the host's cells, it may play an important role in host outcomes during exposure. We therefore used 16S ribosomal RNA (rRNA) gene sequencing to track changes in the gut microbiota composition of rats exposed to heavy metals. Rats were exposed daily for five days to arsenic, cadmium, cobalt, chromium, nickel, or a vehicle control. Significant changes to microbiota composition were observed in response to high doses of chromium and cobalt, and significant dose-dependent changes were observed in response to arsenic, cadmium and nickel. Many of these perturbations were not uniform across metals. However, bacteria with higher numbers of iron importing gene orthologs were overly represented after exposure to arsenic and nickel, suggesting some possibility of a shared response. These findings support the utility of the microbiota as a pre-clinical tool for identifying exposures to specific heavy metals. It is also clear that characterizing changes to the functional capabilities of microbiota is critical to understanding responses to metal exposure. PMID- 29700421 TI - Ultra-slow mechanical stimulation of olfactory epithelium modulates consciousness by slowing cerebral rhythms in humans. AB - The coupling between respiration and neural activity within olfactory areas and hippocampus has recently been unambiguously demonstrated, its neurophysiological basis sustained by the well-assessed mechanical sensitivity of the olfactory epithelium. We herein hypothesize that this coupling reverberates to the whole brain, possibly modulating the subject's behavior and state of consciousness. The olfactory epithelium of 12 healthy subjects was stimulated with periodical odorless air-delivery (frequency 0.05 Hz, 8 s on, 12 off). Cortical electrical activity (High Density-EEG) and perceived state of consciousness have been studied. The stimulation induced i) an enhancement of delta-theta EEG activity over the whole cortex mainly involving the Limbic System and Default Mode Network structures, ii) a reversal of the overall information flow directionality from wake-like postero-anterior to NREM sleep-like antero-posterior, iii) the perception of having experienced an Altered State of Consciousness. These findings could shed further light via a neurophenomenological approach on the links between respiration, cerebral activity and subjective experience, suggesting a plausible neurophysiological basis for interpreting altered states of consciousness induced by respiration-based meditative practices. PMID- 29700423 TI - Anti-inflammatory phomalichenones from an endolichenic fungus Phoma sp. AB - Four new compounds, phomalichenones A-D (1-4), and seven known compounds (5-11) were isolated from the cultures of an endolichenic fungus Phoma sp. EL002650. Their structures were determined by the analysis of their spectroscopic data (NMR and MS). Compounds 1 and 6 inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. In addition, compound 1 diminished the protein expression levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2), and decreased the mRNA expression levels of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin(IL)-1beta, and IL-6. PMID- 29700422 TI - Structure of the receptor-activated human TRPC6 and TRPC3 ion channels. AB - TRPC6 and TRPC3 are receptor-activated nonselective cation channels that belong to the family of canonical transient receptor potential (TRPC) channels. They are activated by diacylglycerol, a lipid second messenger. TRPC6 and TRPC3 are involved in many physiological processes and implicated in human genetic diseases. Here we present the structure of human TRPC6 homotetramer in complex with a newly identified high-affinity inhibitor BTDM solved by single-particle cryo-electron microscopy to 3.8 A resolution. We also present the structure of human TRPC3 at 4.4 A resolution. These structures show two-layer architectures in which the bell-shaped cytosolic layer holds the transmembrane layer. Extensive inter-subunit interactions of cytosolic domains, including the N-terminal ankyrin repeats and the C-terminal coiled-coil, contribute to the tetramer assembly. The high-affinity inhibitor BTDM wedges between the S5-S6 pore domain and voltage sensor-like domain to inhibit channel opening. Our structures uncover the molecular architecture of TRPC channels and provide a structural basis for understanding the mechanism of these channels. PMID- 29700424 TI - Cyclo(Pro-DOPA), a third identified bioactive metabolite produced by Streptomyces sp. 8812. AB - A new metabolite, cyclic dipeptide, cis-(3S,8aS)-3-(3,4 dihydroxybenzyl)hexahydropyrrolo[1,2-a]pyrazine-1,4-dione, named JS-3 was isolated from Streptomyces sp. 8812 fermentation broth. Its chemical structure was established by means of spectroscopic analysis. A wide-range-screening study, which included inhibition assay of DD-carboxypeptidase/transpeptidase activity, determination of antibacterial, antifungal, and antiproliferative activities as well as free-radical scavenging was performed. To authors knowledge, this is the first isolation of such compound from natural sources and the first one from bacteria, Streptomyces. PMID- 29700425 TI - Isolation of a jadomycin incorporating L-ornithine, analysis of antimicrobial activity and jadomycin reactive oxygen species (ROS) generation in MDA-MB-231 breast cancer cells. AB - Herein, we report the characterization and antimicrobial activity of a previously unreported jadomycin (1) obtained from a culture of S. venezuelae ISP5230 with L ornithine (Orn). 1 arises from the rearrangement of a putative five-membered ring containing jadomycin incorporating Orn, whereby intramolecular attack of the E ring carbonyl from the delta-NH2 group of the Orn side chain results in collapse of the oxazolone ring and formation of a stable six-membered lactam. This rearrangement produces a jadomycin with a 3a hemiaminal position that is susceptible to solvolysis. A structure-activity relationship is discussed based on the antimicrobial activity of 1 compared to previously reported jadomycins, providing evidence that the presence of a 3a hemiaminal enhances activity against Gram-positive bacteria. Additionally, assays to quantify reactive oxygen species (ROS) generation and cell viability were performed using a series of nine jadomycins. Compound 1 was found to produce the highest ROS activity and to possess the greatest cytotoxicity against MDA-MB-231 breast cancer cells. PMID- 29700426 TI - Diversity, structure and sources of bacterial communities in earthworm cocoons. AB - Animals start interactions with the bacteria that will constitute their microbiomes at embryonic stage. After mating, earthworms produce cocoons externally which will be colonized with bacteria from their parents and the environment. Due to the key role bacterial symbionts play on earthworm fitness, it is important to study bacterial colonization during cocoon formation. Here we describe the cocoon microbiome of the earthworms Eisenia andrei and E. fetida, which included 275 and 176 bacterial species, respectively. They were dominated by three vertically-transmitted symbionts, Microbacteriaceae, Verminephrobacter and Ca. Nephrothrix, which accounted for 88% and 66% of the sequences respectively. Verminephrobacter and Ca. Nephrothrix showed a high rate of sequence variation, suggesting that they could be biparentally acquired during mating. The other bacterial species inhabiting the cocoons came from the bedding, where they accounted for a small fraction of the diversity (27% and 7% of bacterial species for E. andrei and E. fetida bedding). Hence, earthworm cocoon microbiome includes a large fraction of the vertically-transmitted symbionts and a minor fraction, but more diverse, horizontally and non-randomly acquired from the environment. These data suggest that horizontally-transmitted bacteria to cocoons may play an important role in the adaptation of earthworms to new environments or diets. PMID- 29700427 TI - An improved deep learning approach for detection of thyroid papillary cancer in ultrasound images. AB - Unlike daily routine images, ultrasound images are usually monochrome and low resolution. In ultrasound images, the cancer regions are usually blurred, vague margin and irregular in shape. Moreover, the features of cancer region are very similar to normal or benign tissues. Therefore, training ultrasound images with original Convolutional Neural Network (CNN) directly is not satisfactory. In our study, inspired by state-of-the-art object detection network Faster R-CNN, we develop a detector which is more suitable for thyroid papillary carcinoma detection in ultrasound images. In order to improve the accuracy of the detection, we add a spatial constrained layer to CNN so that the detector can extract the features of surrounding region in which the cancer regions are residing. In addition, by concatenating the shallow and deep layers of the CNN, the detector can detect blurrier or smaller cancer regions. The experiments demonstrate that the potential of this new methodology can reduce the workload for pathologists and increase the objectivity of diagnoses. We find that 93:5% of papillary thyroid carcinoma regions could be detected automatically while 81:5% of benign and normal tissue could be excluded without the use of any additional immunohistochemical markers or human intervention. PMID- 29700428 TI - Effects of meaningfulness on perception: Alpha-band oscillations carry perceptual expectations and influence early visual responses. AB - Perceptual experience results from a complex interplay of bottom-up input and prior knowledge about the world, yet the extent to which knowledge affects perception, the neural mechanisms underlying these effects, and the stages of processing at which these two sources of information converge, are still unclear. In several experiments we show that language, in the form of verbal labels, both aids recognition of ambiguous "Mooney" images and improves objective visual discrimination performance in a match/non-match task. We then used electroencephalography (EEG) to better understand the mechanisms of this effect. The improved discrimination of images previously labeled was accompanied by a larger occipital-parietal P1 evoked response to the meaningful versus meaningless target stimuli. Time-frequency analysis of the interval between the cue and the target stimulus revealed increases in the power of posterior alpha-band (8-14 Hz) oscillations when the meaning of the stimuli to be compared was trained. The magnitude of the pre-target alpha difference and the P1 amplitude difference were positively correlated across individuals. These results suggest that prior knowledge prepares the brain for upcoming perception via the modulation of alpha band oscillations, and that this preparatory state influences early (~120 ms) stages of visual processing. PMID- 29700430 TI - Sustainable aspirator tubes. PMID- 29700432 TI - Upholstery that stays looking good. PMID- 29700431 TI - Total care means total transparency. PMID- 29700429 TI - A thin ice layer segregates two distinct fungal communities in Antarctic brines from Tarn Flat (Northern Victoria Land). AB - Brines are hypersaline solutions which have been found within the Antarctic permafrost from the Tarn Flat area (Northern Victoria Land). Here, an investigation on the possible presence and diversity of fungal life within those peculiar ecosystems has been carried out for the first time. Brines samples were collected at 4- and 5-meter depths (TF1 and TF2, respectively), from two brines separated by a thin ice layer. The samples were analyzed via Illumina MiSeq targeting the ITS region specific for both yeasts and filamentous fungi. An unexpected high alpha diversity was found. Beta diversity analysis revealed that the two brines were inhabited by two phylogenetically diverse fungal communities (Unifrac value: 0.56, p value < 0.01; Martin's P-test p-value < 0.001) characterized by several specialist taxa. The most abundant fungal genera were Candida sp., Leucosporidium sp., Naganishia sp. and Sporobolomyces sp. in TF1, and Leucosporidium sp., Malassezia sp., Naganishia sp. and Sporobolomyces sp. in TF2. A few hypotheses on such differentiation have been done: i) the different chemical and physical composition of the brines; ii) the presence in situ of a thin layer of ice, acting as a physical barrier; and iii) the diverse geological origin of the brines. PMID- 29700434 TI - Oral health set to improve in Powys. PMID- 29700433 TI - Every ten minutes a child has a rotten tooth removed. PMID- 29700435 TI - A systematic approach. PMID- 29700436 TI - Volunteers help refugees understand the importance of oral health. PMID- 29700437 TI - Correction. AB - This corrects the article DOI: 10.1038/sj.bdj.2012.989. PMID- 29700438 TI - SOFT DRINKS LEVY: Sugar tax now in place. PMID- 29700441 TI - Healthy, fresh and odour-free mouths. PMID- 29700440 TI - Durable, colour-stable hybrid ceramics. PMID- 29700442 TI - Evidence-based knowledge on the aesthetic and maintenance of peri-implant soft tissues: Osteology Foundation Consensus Report Part 3 - Aesthetics of peri implant soft tissues. AB - For single-tooth implants, the papilla height between an implant and a tooth is predominantly dependent on the clinical attachment level of the tooth. In cases with two adjacent implants, it is not possible to define the optimal horizontal distance between two adjacent implants restored with fixed dental prostheses. et al. 2018; 29 (Suppl 15): 14-17. PMID- 29700444 TI - Webinar highlights the impact of modern diets and lifestyle on dentition. PMID- 29700443 TI - OMFS: Sialolith infection. PMID- 29700445 TI - The healthcare system and the provision of oral healthcare in European Union member states. Part 9: Sweden. AB - Equally accessible and affordable dental services for all population groups have been a political goal in Sweden for almost a century. All political parties have shared the idea that a person's social background should not have consequences for his or her dental status. Strategic tools to achieve this ambitious goal have been the wide use of publicly provided oral healthcare services, covering even sparsely populated areas, focusing on preventive care and significant subsidies for necessary treatments. Besides free care for children and young adults, oral healthcare is reimbursed from public funds. The public subsidy was particularly generous in 1975-1999 when a 'full clearance' of adults' dentitions was undertaken both by the public and private providers under fixed prices and high reimbursement levels for all treatment measures. Today, preventive oral healthcare for the elderly is given higher priority as most Swedes have been able to keep their natural teeth. PMID- 29700447 TI - Self-medication for dental pain is a major cause of accidental overdose. PMID- 29700446 TI - Social media: is it 'so yesterday'? PMID- 29700449 TI - The first biotech dental product. PMID- 29700448 TI - Help inform future pay awards. PMID- 29700450 TI - Albert Adeline. PMID- 29700451 TI - Open evenings for postgraduate implantology course. PMID- 29700452 TI - DIY dentistry: Clip-on veneer. PMID- 29700453 TI - DENTISTS ON FILM: Melinda and Melinda. PMID- 29700455 TI - 'Johnny' Dennis Vero. PMID- 29700454 TI - Masquerading as periodontal disease. PMID- 29700456 TI - CONFERENCE REPORT: National Health Careers Conference. PMID- 29700457 TI - Preparing for enhanced data protection. PMID- 29700458 TI - Effect of nonextraction and extraction orthodontic treatments on smile esthetics for different malocclusions. AB - Extraction subjects with >4 mm overjet were rated higher than the non-extraction subjects , . 2018; 153: 81-86. PMID- 29700459 TI - Cause of osteonecrosis. PMID- 29700460 TI - Dentists need to relinquish work to DCPs. PMID- 29700461 TI - Spotlight on the British Dental Conference and Dentistry Show. PMID- 29700462 TI - Your one stop dental shop. PMID- 29700463 TI - An infection control show-stopper. PMID- 29700464 TI - In-office dental bleaching with light vs. without light: A systematic review and meta-analysis. AB - Activation of in-office bleaching gel with light does not improve colour change nor affect tooth sensitivity. et al. 2018; 70: 1-13. PMID- 29700466 TI - Straws in a haystack. PMID- 29700467 TI - Digestion-ligation-only Hi-C is an efficient and cost-effective method for chromosome conformation capture. AB - Chromosome conformation capture (3C) technologies can be used to investigate 3D genomic structures. However, high background noise, high costs, and a lack of straightforward noise evaluation in current methods impede the advancement of 3D genomic research. Here we developed a simple digestion-ligation-only Hi-C (DLO Hi C) technology to explore the 3D landscape of the genome. This method requires only two rounds of digestion and ligation, without the need for biotin labeling and pulldown. Non-ligated DNA was efficiently removed in a cost-effective step by purifying specific linker-ligated DNA fragments. Notably, random ligation could be quickly evaluated in an early quality-control step before sequencing. Moreover, an in situ version of DLO Hi-C using a four-cutter restriction enzyme has been developed. We applied DLO Hi-C to delineate the genomic architecture of THP-1 and K562 cells and uncovered chromosomal translocations. This technology may facilitate investigation of genomic organization, gene regulation, and (meta)genome assembly. PMID- 29700468 TI - Sizing up whole-genome sequencing studies of common diseases. PMID- 29700469 TI - Expanding the toolbox for 3D genomics. PMID- 29700470 TI - No evidence for unknown archaic ancestry in South Asia. PMID- 29700471 TI - Telobox motifs recruit CLF/SWN-PRC2 for H3K27me3 deposition via TRB factors in Arabidopsis. AB - Polycomb repressive complexes (PRCs) control organismic development in higher eukaryotes through epigenetic gene repression1-4. PRC proteins do not contain DNA binding domains, thus prompting questions regarding how PRCs find their target loci 5 . Here we present genome-wide evidence of PRC2 recruitment by telomere repeat-binding factors (TRBs) through telobox-related motifs in Arabidopsis. A triple trb1-2, trb2-1, and trb3-2 (trb1/2/3) mutant with a developmental phenotype and a transcriptome strikingly similar to those of strong PRC2 mutants showed redistribution of trimethyl histone H3 Lys27 (H3K27me3) marks and lower H3K27me3 levels, which were correlated with derepression of TRB1-target genes. TRB1-3 physically interacted with the PRC2 proteins CLF and SWN. A SEP3 reporter gene with a telobox mutation showed ectopic expression, which was correlated with H3K27me3 depletion, whereas tethering TRB1 to the mutated cis element partially restored repression. We propose that telobox-related motifs recruit PRC2 through the interaction between TRBs and CLF/SWN, a mechanism essential for H3K27me3 deposition at a subset of target genes. PMID- 29700472 TI - Inferring parsimonious migration histories for metastatic cancers. AB - Metastasis is the migration of cancerous cells from a primary tumor to other anatomical sites. Although metastasis was long thought to result from monoclonal seeding, or single cellular migrations, recent phylogenetic analyses of metastatic cancers have reported complex patterns of cellular migrations between sites, including polyclonal migrations and reseeding. However, accurate determination of migration patterns from somatic mutation data is complicated by intratumor heterogeneity and discordance between clonal lineage and cellular migration. We introduce MACHINA, a multi-objective optimization algorithm that jointly infers clonal lineages and parsimonious migration histories of metastatic cancers from DNA sequencing data. MACHINA analysis of data from multiple cancers shows that migration patterns are often not uniquely determined from sequencing data alone and that complicated migration patterns among primary tumors and metastases may be less prevalent than previously reported. MACHINA's rigorous analysis of migration histories will aid in studies of the drivers of metastasis. PMID- 29700474 TI - Comparison of methods that use whole genome data to estimate the heritability and genetic architecture of complex traits. AB - Multiple methods have been developed to estimate narrow-sense heritability, h2, using single nucleotide polymorphisms (SNPs) in unrelated individuals. However, a comprehensive evaluation of these methods has not yet been performed, leading to confusion and discrepancy in the literature. We present the most thorough and realistic comparison of these methods to date. We used thousands of real whole genome sequences to simulate phenotypes under varying genetic architectures and confounding variables, and we used array, imputed, or whole genome sequence SNPs to obtain 'SNP-heritability' estimates. We show that SNP-heritability can be highly sensitive to assumptions about the frequencies, effect sizes, and levels of linkage disequilibrium of underlying causal variants, but that methods that bin SNPs according to minor allele frequency and linkage disequilibrium are less sensitive to these assumptions across a wide range of genetic architectures and possible confounding factors. These findings provide guidance for best practices and proper interpretation of published estimates. PMID- 29700473 TI - An analytical framework for whole-genome sequence association studies and its implications for autism spectrum disorder. AB - Genomic association studies of common or rare protein-coding variation have established robust statistical approaches to account for multiple testing. Here we present a comparable framework to evaluate rare and de novo noncoding single nucleotide variants, insertion/deletions, and all classes of structural variation from whole-genome sequencing (WGS). Integrating genomic annotations at the level of nucleotides, genes, and regulatory regions, we define 51,801 annotation categories. Analyses of 519 autism spectrum disorder families did not identify association with any categories after correction for 4,123 effective tests. Without appropriate correction, biologically plausible associations are observed in both cases and controls. Despite excluding previously identified gene disrupting mutations, coding regions still exhibited the strongest associations. Thus, in autism, the contribution of de novo noncoding variation is probably modest in comparison to that of de novo coding variants. Robust results from future WGS studies will require large cohorts and comprehensive analytical strategies that consider the substantial multiple-testing burden. PMID- 29700476 TI - Quality of life, burden and satisfaction with care in caregivers of patients with a spinal cord injury during and after rehabilitation. AB - STUDY DESIGN: Longitudinal, prospective cohort study. OBJECTIVES: To examine the course that burden, quality of life (QoL) and satisfaction with care taken in Dutch caregivers of patients with a SCI. SETTING: Adelante Rehabilitation Centre and Dutch community, the Netherlands METHODS: Caregiver Strain index (CSI), Short Form36 (SF-36) and Caregivers' Satisfaction with (Stroke) Care Questionnaire (C SASC) were administered to caregivers (n = 37) of patients with a recently acquired SCI at the start of rehabilitation (T1), discharge from rehabilitation (T2) and at 8 weeks (T3), 6 months (T4) and 18 months after discharge (T5). RESULTS: During rehabilitation, 20 caregivers (54%) experienced high levels of burden (cutoff >6). CSI scores significantly decreased during follow-up (median CSI score T1:7 IQR[5,10], T5:4 IQR[1,7], p = 0.010), at T5 5 caregivers (24%) scored >6 on burden. Initial low scores on QoL improved significantly in the SF 36 domains 'social-functioning', 'emotional-role-functioning', 'mental health' and 'vitality'. Overall satisfaction with care of caregivers was good (C-SASC: median 3, IQR[3,4]) and stable over time. Moderate strongly negative correlations were found between total CSI-score and 'social-functioning' (T2-T3-T4), 'emotional-role-functioning' (all time points), 'mental health' (all time points) and 'vitality' (all time points) with p values < 0.041. CONCLUSIONS: This study demonstrates the high burden and a low QoL on the 'the Mental Health Component' domains (or MHC) of caregivers during inpatient rehabilitation. During the early home phase, we found a significant improvement in burden and MHC. Clinicians working with both SCI-patients and caregivers should be aware of the possible high burden and low QoL of caregivers during rehabilitation. PMID- 29700478 TI - Safety of nintedanib for treatment of fibrotic lung disease after allogeneic hematopoietic stem cell transplantation. PMID- 29700479 TI - Refractory cytomegalovirus DNAemia after allogeneic hematopoietic stem cell transplantation: when should genotypic drug resistance testing be requested? PMID- 29700477 TI - Lower extremity outcome measures: considerations for clinical trials in spinal cord injury. AB - STUDY DESIGN: This is a focused review article. OBJECTIVES: To identify important concepts in lower extremity (LE) assessment with a focus on locomotor outcomes and provide guidance on how existing outcome measurement tools may be best used to assess experimental therapies in spinal cord injury (SCI). The emphasis lies on LE outcomes in individuals with complete and incomplete SCI in Phase II-III trials. METHODS: This review includes a summary of topics discussed during a workshop focusing on LE function in SCI, conceptual discussion of corresponding outcome measures and additional focused literature review. RESULTS: There are a number of sensitive, accurate, and responsive outcome tools measuring both quantitative and qualitative aspects of LE function. However, in trials with individuals with very acute injuries, a baseline assessment of the primary (or secondary) LE outcome measure is often not feasible. CONCLUSION: There is no single outcome measure to assess all individuals with SCI that can be used to monitor changes in LE function regardless of severity and level of injury. Surrogate markers have to be used to assess LE function in individuals with severe SCI. However, it is generally agreed that a direct measurement of the performance for an appropriate functional activity supersedes any surrogate marker. LE assessments have to be refined so they can be used across all time points after SCI, regardless of the level or severity of spinal injury. SPONSORS: Craig H. Neilsen Foundation, Spinal Cord Outcomes Partnership Endeavor. PMID- 29700480 TI - Long-Term Effects of Omitting Antibiotics in Uncomplicated Acute Diverticulitis. AB - BACKGROUND: Traditionally uncomplicated acute diverticulitis was routinely treated with antibiotics, although evidence for this strategy was lacking. Recently, two randomized clinical trials (AVOD trial and DIABOLO trial) published short-term results of omitting antibiotics compared to routine antibiotic treatment. Both showed no significant differences regarding recovery from the initial episode, as well as rates of complicated or recurrent diverticulitis and sigmoid resection. However, both studies showed a trend of higher rates of sigmoid resection in the observational groups. Here, the long-term effects of omitting antibiotics in first episode uncomplicated acute diverticulitis were assessed. METHODS: A total of 528 patients with CT-proven, primary, left-sided, uncomplicated acute diverticulitis were randomized to either an observational or an antibiotic treatment strategy (DIABOLO trial). Outcome measures were complicated diverticulitis, recurrent diverticulitis and sigmoid resection at 24 months' follow up. Differences between the groups were explored and risk factors were identified using multivariable logistic regression. RESULTS: Complete case analyses showed no difference in rates of recurrent diverticulitis (15.4% in the observational group versus 14.9% in the antibiotic group; p = 0.885), complicated diverticulitis (4.8% versus 3.3%; p = 0.403) and sigmoid resection (9.0% versus. 5.0%; p = 0.085). Young patients (<50 years) and patients with a pain score at presentation of 8 or higher on a visual analogue pain scale were at risk for complicated or recurrent diverticulitis. In this multivariable analysis, treatment type (with or without antibiotics) was not an independent predictor for complicated or recurrent diverticulitis. CONCLUSION: Omitting antibiotics in the treatment of uncomplicated acute diverticulitis did not result in more complicated diverticulitis, recurrent diverticulitis or sigmoid resections at long-term follow up. As the DIABOLO trial was not powered for these secondary outcome measures, some uncertainty remains whether (small) non-significant differences could be true associations. PMID- 29700481 TI - The natural course of eosinophilic esophagitis and long-term consequences of undiagnosed disease in a large cohort. AB - BACKGROUND: Eosinophilic esophagitis (EoE) is a chronic esophageal inflammation that may lead to stricture formation. This narrowing can cause major complications including food impactions. Despite increasing interest in EoE accurate data on its natural course is scarce. Therefore, we aimed to investigate the natural course of EoE and to evaluate the association between undiagnosed disease and the occurrence of complications over two decades in a large cohort. METHODS: We retrospectively analyzed charts of patients diagnosed with EoE between 1996 and 2015, collected from 15 hospitals throughout the Netherlands. Histologic, clinical, and endoscopic characteristics were identified and stratified by age and diagnostic delay. RESULTS: We included 721 patients (524 males, 117 children (<=18 years)). Dysphagia and food impactions were more common in adults whereas children more often presented with vomiting and abdominal pain (all p < 0.001). The prevalence of fibrotic endoscopic features was higher in adults (76%) than in children (39%) (p < 0.001). As time with undiagnosed disease progressed the percentage of patients with strictures and food impactions increased from 19% and 24% (diagnostic delay <= 2 years) to 52% and 57% (diagnostic delay >= 21 years) (p < 0.001), respectively. In a multivariate logistic regression model, diagnostic delay (odds ratio (OR) = 1.09; 95% confidence interval (CI) = 1.05-1.13) and male gender (OR = 2.69, 95% CI = 1.61 4.50) were the major risk factors for stricture presence. CONCLUSION: During the natural course of EoE, progression from an inflammatory to a fibrostenotic phenotype occurs. With each additional year of undiagnosed EoE the risk of stricture presence increases with 9%. PMID- 29700482 TI - Charles D. Surh, PhD: 1961-2017. PMID- 29700483 TI - Identifying key membrane protein lipid interactions using mass spectrometry. AB - With the recent success in determining membrane protein structures, further detailed understanding of the identity and function of the bound lipidome is essential. Using an approach that combines high-energy native mass spectrometry (HE-nMS) and solution-phase lipid profiling, this protocol can be used to determine the identity of the endogenous lipids that directly interact with a protein. Furthermore, this method can identify systems in which such lipid binding has a major role in regulating the oligomeric assembly of membrane proteins. The protocol begins with recording of the native mass spectrum of the protein of interest, under successive delipidation conditions, to determine whether delipidation leads to disruption of the oligomeric state. Subsequently, we propose using a bipronged strategy: first, an HE-nMS platform is used that allows dissociation of the detergent micelle at the front end of the instrument. This allows for isolation of the protein-lipid complex at the quadrupole and successive fragmentation at the collision cell, which leads to identification of the bound lipid masses. Next, simultaneous coupling of this with in-solution LC MS/MS-based identification of extracted lipids reveals the complete identity of the interacting lipidome that copurifies with the proteins. Assimilation of the results of these two sets of experiments divulges the complete identity of the set of lipids that directly interact with the membrane protein of interest, and can further delineate its role in maintaining the oligomeric state of the protein. The entire procedure takes 2 d to complete. PMID- 29700484 TI - Computational 3D genome modeling using Chrom3D. AB - Chrom3D is a computational platform for 3D genome modeling that simulates the spatial positioning of chromosome domains relative to each other and relative to the nuclear periphery. In Chrom3D, chromosomes are modeled as chains of contiguous beads, in which each bead represents a genomic domain. In this protocol, a bead represents a topologically associated domain (TAD) mapped from ensemble Hi-C data. Chrom3D takes as input data significant pairwise TAD-TAD interactions determined from a Hi-C contact matrix, and TAD interactions with the nuclear periphery, determined by ChIP-sequencing of nuclear lamins to define lamina-associated domains (LADs). Chrom3D is based on Monte Carlo simulations initiated from a starting random bead configuration. During the optimization process, TAD-TAD interactions constrain bead positions relative to each other, whereas LAD information constrains the corresponding bead toward the nuclear periphery. Optimization can be repeated many times to generate an ensemble of 3D genome models. Analyses of the models enable estimations of the radial positioning of genomic sites in the nucleus across cells in a population. Chrom3D provides opportunities to reveal spatial relationships between TADs and LADs. More generally, predictions from Chrom3D models can be experimentally tested in the laboratory. We describe the entire Chrom3D protocol for modeling a 3D diploid human genome, from the creation of input files to the final rendering of 3D genome structures. The procedure takes ~18 h. Chrom3D is freely available on GitHub. PMID- 29700475 TI - Genome-wide association analyses identify 44 risk variants and refine the genetic architecture of major depression. AB - Major depressive disorder (MDD) is a common illness accompanied by considerable morbidity, mortality, costs, and heightened risk of suicide. We conducted a genome-wide association meta-analysis based in 135,458 cases and 344,901 controls and identified 44 independent and significant loci. The genetic findings were associated with clinical features of major depression and implicated brain regions exhibiting anatomical differences in cases. Targets of antidepressant medications and genes involved in gene splicing were enriched for smaller association signal. We found important relationships of genetic risk for major depression with educational attainment, body mass, and schizophrenia: lower educational attainment and higher body mass were putatively causal, whereas major depression and schizophrenia reflected a partly shared biological etiology. All humans carry lesser or greater numbers of genetic risk factors for major depression. These findings help refine the basis of major depression and imply that a continuous measure of risk underlies the clinical phenotype. PMID- 29700485 TI - Near-infrared light-controlled systems for gene transcription regulation, protein targeting and spectral multiplexing. AB - Near-infrared (NIR, 740-780 nm) optogenetic systems are well-suited to spectral multiplexing with blue-light-controlled tools. Here, we present two protocols, one for regulation of gene transcription and another for control of protein localization, that use a NIR-responsive bacterial phytochrome BphP1-QPAS1 optogenetic pair. In the first protocol, cells are transfected with the optogenetic constructs for independently controlling gene transcription by NIR (BphP1-QPAS1) and blue (LightOn) light. The NIR and blue-light-controlled gene transcription systems show minimal spectral crosstalk and induce a 35- to 40-fold increase in reporter gene expression. In the second protocol, the BphP1-QPAS1 pair is combined with a light-oxygen-voltage-sensing (LOV) domain-based construct into a single optogenetic tool, termed iRIS. This dual-light-controllable protein localization tool allows tridirectional protein translocation among the cytoplasm, nucleus and plasma membrane. Both procedures can be performed within 3 5 d. Use of NIR light-controlled optogenetic systems should advance basic and biomedical research. PMID- 29700487 TI - Is ciliary Hedgehog signalling dispensable in the kidneys? PMID- 29700486 TI - Identification and characterization of nucleobase-modified aptamers by click SELEX. AB - Aptamers are single-stranded oligonucleotides that are in vitro-selected to recognize their target molecule with high affinity and specificity. As they consist of the four canonical nucleobases, their chemical diversity is limited, which in turn limits the addressable target spectrum. Introducing chemical modifications into nucleic acid libraries increases the interaction capabilities of the DNA and thereby the target spectrum. Here, we describe a protocol to select nucleobase-modified aptamers by using click chemistry (CuAAC) to introduce the preferred chemical modification. The use of click chemistry to modify the DNA library enables the introduction of a wide range of possible functionalities, which can be customized to the requirements of the target molecule and the desired application. This protocol yields modified DNA aptamers with extended interaction properties that are not accessible with the canonical set of nucleotides. After synthesis of the starting library containing a commercially available, alkyne-modified uridine (5-ethynyl-deoxyuridine (EdU)) instead of thymidine, the library is functionalized with the modification of choice by CuAAC. The thus-modified DNA is incubated with the target molecule and the best binding sequences are recovered. The chemical modification is removed during the amplification process. Therefore, this protocol is compatible with conventional amplification procedures and avoids enzymatic incompatibility problems associated with more extensive nucleobase modifications. After single-strand generation, the modification is reintroduced into the enriched library, which can then be subjected to the subsequent selection cycle. The duration of each selection cycle as outlined in the protocol is ~1 d. PMID- 29700490 TI - IDO takes a blow. PMID- 29700488 TI - Diagnosis and management of resistant hypertension: state of the art. AB - Resistant hypertension is defined as a lack of ambulatory blood pressure response to optimized medical treatment after exclusion of secondary hypertension in patients who are fully adherent to antihypertensive therapy. Patients with resistant hypertension are at high risk of complications, particularly cardiovascular events, and optimization of medical treatment remains the cornerstone of their management. Such optimization should be based on simple algorithms and include the use of aldosterone antagonists. The available data from clinical trials do not support the use of device-based approaches such as renal denervation, baroreflex activation therapy or arteriovenous anastomosis for the treatment of resistant hypertension in the majority of patients. Therefore, device treatment remains a last-resort for patients with truly resistant hypertension in the context of clinical research in highly skilled tertiary referral centres. Future research should focus on improving understanding of the intrinsic (physiological and psychological factors) and extrinsic (environmental stressors) mechanisms that contribute to a lack of response to blood-pressure lowering drugs in adherent patients. The use of biomarkers to identify patients with early target organ damage and new technologies, such as renal nerve stimulation, to predict blood pressure responses to renal denervation could aid the selection of patients who might benefit from device therapies. PMID- 29700492 TI - Type 2 diabetes: Targeting glutamine metabolism. PMID- 29700491 TI - Anticancer drugs: Flipping the switch for selective GSK3 inhibition. PMID- 29700493 TI - Malaria: Clues to vaccine design. PMID- 29700494 TI - Neurodegeneration: New strategy for SBMA therapy. PMID- 29700495 TI - Microglia-targeted candidates push the Alzheimer drug envelope. PMID- 29700496 TI - Cashing in with off-the-shelf CAR Ts. PMID- 29700497 TI - Anja Konig. PMID- 29700498 TI - Industry embraces virtual trial platforms. PMID- 29700499 TI - Novartis grows its gene therapy ambitions. PMID- 29700500 TI - Regulatory watch: FDA new drug approvals in Q1 2018. PMID- 29700502 TI - Outcomes of therapeutic TMD interventions on oral health related quality of life: A qualitative systematic review. AB - OBJECTIVES: This systematic review aims to determine the impact of temporomandibular disorder (TMD) therapeutic interventions on patients' oral health related quality of life (OHRQoL) and to recommend approaches that improve QoL. DATA SOURCES: A systematic search of the literature was performed between January 2007 and October 2017 to identify articles on TMD interventions and OHRQoL. Randomized controlled trials, and retrospective and prospective cohort studies that mentioned dedicated tools for measurement of OHRQoL changes in TMD patients after therapeutic interventions were included. Abstracts of studies that did not mention any form of measurement of OHRQoL in their treatment outcome were excluded. The initial screening yielded 171 articles. After evaluation of abstracts and full text articles, five articles fulfilled all selection criteria and were included. Most TMD treatment interventions seem to improve QoL to some extent, but no single treatment modality can be advocated as the sole approach to managing TMD. CONCLUSION: Psychotherapy, occlusal appliance therapy, arthrocentesis, and orthodontics/orthognathic surgery (in subjects with severe malocclusion) appear to improve OHRQoL of TMD patients. Recommendation on the best TMD intervention for improving QoL could not be made due to the diverse TMD subtypes and non-disease specific OHRQoL instruments employed. More studies incorporating TMD-specific OHRQoL measures and targeting explicit TMD subtypes based on internationally accepted diagnostic criteria are warranted in this area of research. PMID- 29700503 TI - The efficacy of air polishing devices in supportive periodontal therapy: A systematic review and meta-analysis. AB - OBJECTIVE: This systematic review analyzes existing literature on the clinical efficacy of air polishing devices (APDs), discussing the evidence-based data available for justifying their use as an alternative to conventional periodontal debridement in supportive periodontal therapy. The main objective of the review was to assess whether APD was as equally efficient or superior in obtaining successful treatment outcomes when compared with conventional methods. DATA SOURCES: Following PRISMA guidelines, a systematic literature search of articles in English, up to December 2016, was conducted using PubMed, Cochrane, and Medline. Relevant articles were selected based on specific criteria. Seven studies were selected for the final assessment. One more study was added after a manual search of the literature. Due to considerable heterogeneity in study designs and outcome variables measured, only clinical parameters (probing depth, bleeding on probing, and clinical attachment level) were selected for meta analysis. CONCLUSION: The studies selected for this systematic review provide some evidence that APDs as monotherapy could be an alternative to conventional debridement of single- and multi-rooted teeth with no furcation involvement, during supportive periodontal therapy. Comparing clinical and microbiologic outcomes, APDs seem to be as effective as conventional treatments. The primary advantage for the use of APDs in supportive periodontal therapy seems to be their ability to efficiently remove biofilm, without causing damage to the periodontal soft tissues or tooth and root structure. There may also be an advantage regarding patient comfort and time consumed. PMID- 29700504 TI - An efficient non-fullerene acceptor based on central and peripheral naphthalene diimides. AB - Through the coupling of central and terminal naphthalene diimide functionalities, a unique non-fullerene electron acceptor, coded as N10, was designed, synthesized, characterized and applied in solution-processable bulk heterojunction devices. The target N10 displayed good solubility, excellent thermal stability and energy levels complementing those of the conventional donor polymer poly(3-hexyl thiophene) (P3HT). An excellent power conversion efficiency of 7.65% was obtained in simple BHJ devices (P3HT : N10 1 : 1.2), which is the highest observed so far for NDI core-based non-fullerene acceptors. PMID- 29700505 TI - Modifications in gut microbiota and fermentation metabolites in the hindgut of rats after the consumption of galactooligosaccharide glycated with a fish peptide. AB - The aim of this research was to investigate the impact of a diet containing galactooligosaccharide (GOS)-fish peptide (FP) conjugates prepared via Maillard reaction on the colonic fermentation properties and the composition of gut microbiota in Sprague-Dawley rats. The rats were fed the GOS diet, FP diet, GOS and FP mixture (GOS/FP) diet, GOS glycated with FP (80 degrees C for 120 min, G GOS/FP) diet, or control (CK) diet for three weeks. Compared to the GOS/FP diet, the G-GOS/FP diet greatly changed the pattern of SCFA production in the hindgut of rats, by increasing the total SCFA (44%), butyrate (55%) and propionate (1.23 fold) levels in the proximal colon, and the butyrate levels (74%) in the distal colon, and decreased the production of ammonia in feces (P < 0.05). The G-GOS/FP altered the colonic microbiota by increasing (P < 0.05) the relative abundance of Anaerovibrio (7.43-fold) and Prevotella-9 (2.47-fold), and by decreasing (P < 0.05) the relative abundance of Alloprevotella (0.57-fold) and Holdemanella (0.64 fold), and showed a similar relative abundance of Bifidobacterium, when compared with GOS/FP. The GOS/FP diet increased the number of Lactobacillus and the intensity of fermentation in the cecum, but the G-GOS/FP diet and GOS diet did not have these effects, showing that the glycation clearly altered the fermentability of the fish peptide. It is concluded that the glycation-induced modification of GOS by mild thermal treatments showed its fermentation persistence in the colon of the host, and improved some prebiotic activities of GOS. These results may provide new strategies for oligosaccharides in combination with peptides to modulate the intestinal environment to promote human health. PMID- 29700506 TI - Scaffold-free three-dimensional cell culturing using magnetic levitation. AB - Three-dimensional (3D) cell culture has emerged as a pioneering methodology and is increasingly utilized for tissue engineering, 3D bioprinting, cancer model studies and drug development studies. The 3D cell culture methodology provides artificial and functional cellular constructs serving as a modular playground prior to animal model studies, which saves substantial efforts, time and experimental costs. The major drawback of current 3D cell culture methods is their dependency on biocompatible scaffolds, which often require tedious syntheses and fabrication steps. Herein, we report an easy-to-use methodology for the formation of scaffold-free 3D cell culture and cellular assembly via magnetic levitation in the presence of paramagnetic agents. To paramagnetize the cell culture environment, three different Gadolinium(iii) chelates were utilized, which led to levitation and assembly of cells at a certain levitation height. The assembly and close interaction of cells at the levitation height where the magnetic force was equilibrated with gravitational force triggered the formation of complex 3D cellular structures. It was shown that Gd(iii) chelates provided an optimal levitation that induced intercellular interactions in scaffold-free format without compromising cell viability. NIH 3T3 mouse fibroblasts and HCC827 non-small-cell lung cancer cells were evaluated via the magnetic levitation system, and the formation of 3D cell culture models was validated for both cell lines. Hereby, the developed magnetic levitation system holds promises for complex cellular assemblies and 3D cell culture studies. PMID- 29700507 TI - A caged metabolic precursor for DT-diaphorase-responsive cell labeling. AB - In this study, we report incorporation of a covalent linker at the anomeric position of N-azidoacetylmannosamine (ManNAz) for caging its metabolic process. We synthesized a DT-diaphorase-responsive metabolic precursor, HQ-NN-AAM, using an optimized linker. The caged metabolite showed responsiveness to DT-diaphorase in vitro, resulting in metabolic incorporation of an azido sugar into the cell surface in multiple cell lines. PMID- 29700508 TI - Ligand induced shape transformation of thorium dioxide nanocrystals. AB - Nanocrystals (NCs) with size and shape dependent properties are a thriving research field. Remarkable progress has been made in the controlled synthesis of NCs of stable elements in the past two decades; however, the knowledge of the NCs of actinide compounds has been considerably limited due the difficulties in handling them both experimentally and theoretically. Actinide compounds, especially actinide oxides, play a critical role in many stages of the nuclear fuel cycle. Recently, a non-aqueous surfactant assisted approach has been developed for the synthesis of actinide oxide NCs with different morphologies, but an understanding of its control factors is still missing to date. Herein we present a comprehensive study on the low index surfaces of thorium dioxide (ThO2) and their interactions with relevant surfactant ligands using density functional calculations. A systematic picture on the thermodynamic stability of ThO2 NCs of different sizes and shapes is obtained employing empirical models based on the calculated surface energies. It is found that bare ThO2 NCs prefer the octahedral shape terminated by (111) surfaces. Oleic acid displays selective adsorption on the (110) surface, leading to the shape transformation from octahedrons to nanorods. Other ligands such as acetylacetone, oleylamine, and trioctylphosphine oxide do not modify the equilibrium shape of ThO2 NCs. This work provides atomic level insights into the anisotropic growth of ThO2 NCs that was recently observed in experiments, and thus may contribute to the controlled synthesis of actinide oxide NCs with well-defined size and shape for future applications. PMID- 29700501 TI - The expanding role of prodrugs in contemporary drug design and development. AB - Prodrugs are molecules with little or no pharmacological activity that are converted to the active parent drug in vivo by enzymatic or chemical reactions or by a combination of the two. Prodrugs have evolved from being serendipitously discovered or used as a salvage effort to being intentionally designed. Such efforts can avoid drug development challenges that limit formulation options or result in unacceptable biopharmaceutical or pharmacokinetic performance, or poor targeting. In the past 10 years, the US Food and Drug Administration has approved at least 30 prodrugs, which accounts for more than 12% of all approved small molecule new chemical entities. In this Review, we highlight prodrug design strategies for improved formulation and pharmacokinetic and targeting properties, with a focus on the most recently marketed prodrugs. We also discuss preclinical and clinical challenges and considerations in prodrug design and development. PMID- 29700509 TI - Site-selectivity in the halogenation of titanium-functionalized polyoxovanadate alkoxide clusters. AB - Herein, we report the synthesis and characterization of a dititanium functionalized polyoxovanadate-alkoxide cluster. The incorporation of a second heterometal within the cluster core results in striking differences in reactivity of the multimetallic complex. Chlorination of the metal oxide cluster is reported, revealing the directing role of titanium in M-O bond cleavage. PMID- 29700510 TI - Phosphorus anionic redox activity revealed by operando P K-edge X-ray absorption spectroscopy on diphosphonate-based conversion materials in Li-ion batteries. AB - When cycling diphosphonate-based organic-inorganic hybrid materials as negative battery electrodes, specific charges exceeding the maximum for a metal redox reaction are recorded. Classical explanations are electrolyte reduction and solid electrolyte interphase (SEI) oxidation. Using operando X-ray absorption spectroscopy (XAS) at the P K-edge experiment, we demonstrate an additional contribution of reversible ligand co-cycling based on the P-atoms of the diphosphonate ligands, upon delithiation occurring during the first potential plateau, which matches perfectly to previous investigations using Fe K-edge XAS. We thus investigate experimentally an anionic redox process in situ. Thereby we could demonstrate a possible methodology to measure P K-edge XANES on Li-ion battery active materials under operando conditions, which could be applied to verify the predicted P co-cycling of other conversion-type negative electrode materials. PMID- 29700511 TI - Synthesis of 2-arylbenzofuran-3-carbaldehydes via an organocatalytic [3+2] annulation/oxidative aromatization reaction. AB - A novel organocatalytic [3+2] annulation/oxidative aromatization reaction of enals with 2-halophenols or beta-naphthols is reported. This process enables chemo- and regioselective access to 2-arylbenzofuran-3-carbaldehydes without the use of transition metals or strong oxidants. Preliminary mechanistic studies reveal that an unprecedented, organocatalytic, direct alpha-arylation pathway is involved. PMID- 29700512 TI - Thermal decomposition of FC(O)OCH3 and FC(O)OCH2CH3. AB - The thermal decomposition of methyl and ethyl formates has been extensively studied due to their importance in the oxidation of several fuels, pesticidal properties and their presence in interstellar space. We hitherto present the study of the thermal decomposition of methyl and ethyl fluoroformates, which could help in the elucidation of the reaction mechanisms. The reaction mechanisms were studied using FTIR spectroscopy in the temperature range of 453-733 K in the presence of different pressures of N2 as bath gas. For FC(O)OCH3 two different channels were observed; the unimolecular decomposition which is favored at higher temperatures and has a rate constant kFC(O)OCH3 = (5.3 +/- 0.5) * 1015 exp[-(246 +/- 10 kJ mol-1/RT)] (in units of s-1) and a bimolecular channel with a rate constant kFC(O)OCH3 = (1.6 +/- 0.5) * 1011 exp[-(148 +/- 10 kJ mol-1/RT)] (in units of s-1 (mol L)-1). However for ethyl formate, only direct elimination of CO2, HF and ethylene operates. The rate constants of the homogeneous first-order process fit the Arrhenius equation kFC(O)OCH2CH3 = (2.06 +/- 0.09) * 1013 exp[ (169 +/- 6 kJ mol-1/RT)] (in units of s-1). The difference between the mechanisms of the two fluoroformates relies on the stabilization of a six-centered transition state that only exists for ethyl formate. First principles calculations for the different channels were carried out to understand the dynamics of the decomposition. PMID- 29700513 TI - Selectively targeting bacteria by tuning the molecular design of membrane-active peptidomimetic amphiphiles. AB - Here we report the design of membrane-active peptidomimetic molecules with a tunable arrangement of hydrophobic and polar groups. In spite of having the same chemical composition, the effective hydrophobicities of the compounds were different as a consequence of their chemical structure and conformational properties. The compound with lower effective hydrophobicity demonstrated antibacterial activity that was highly selective towards bacteria over mammalian cells. This study, highlighting the role in membrane selectivity of the specific arrangement of the different moieties in the molecular structure, provides useful indications for developing non-toxic antibacterial agents. PMID- 29700514 TI - Advanced bi-functional CoPi co-catalyst-decorated g-C3N4 nanosheets coupled with ZnO nanorod arrays as integrated photoanodes. AB - In this work, a CoPi-decorated type II heterojunction composed of one-dimensional (1D) ZnO nanorod arrays (NRAs) coated with two-dimensional (2D) carbon nitride (g C3N4) was successfully prepared and used as photoanode. CoPi has been speculated to be a mixture of amorphous compound and two cobalt-based compounds: Co3(PO3)6.14H2O and Co(H2PO2)2.6H2O. The advanced bi-functional CoPi acts like a shelter, effectively inhibiting the photocorrosion of CNNS/ZnO NRAs and providing a faster hole transfer channel. Synergistic effects at the interface of the heterojunction efficiently improve the separation of charge carriers from photoexcited g-C3N4 nanosheets to the ZnO nanorods. Photocurrent density is also greatly enhanced by loading CoPi on CNNS/ZnO NRAs heterojunction. The maximum photocurrent density (2.45 mA cm-2 at 1.23 V vs. RHE) generated from CoPi(10) CNNS(600)/ZnO nanorods is about 10.2 times greater than that of pristine ZnO nanorods (0.24 mA cm-2 at 1.23 V vs. RHE) and 2.5 times higher than that of CNNS(800)/ZnO (0.95 mA cm-2 at 1.23 V vs. RHE). The further increase of photoelectrocatalytic performance may be attributed to CoPi relieving the charge accumulation at the semiconductor/electrolyte, which decreases the electron-hole recombination rate. PMID- 29700515 TI - Engineering TiO2 supported Pt sub-nanoclusters via introducing variable valence Co ion in high-temperature flame for CO oxidation. AB - As a typical catalytic reaction model, CO catalytic oxidation has many practical applications in gas purification. TiO2 supported Pt sub-nanoclusters have been prepared by introducing variable valence Co ions into a one step flame spray pyrolysis process. Co2+ was oxidized to Co3+ in the high-temperature flame, and the released electrons were transferred to the surface of Pt and suppressed the aggregation of Pt nanoclusters supported on TiO2. As a result, the average size of Pt nanoclusters reduced from 2.47 nm to 0.72 nm with only 1% Co2+ ion doping. Moreover, due to the presence of Co, surface oxygen species were also affected, and these changes also led to a significant increase in the catalytic activity of CO oxidation. The temperature at 100% conversion was decreased from 120 degrees C to 70 degrees C, and the TOF increased by an order of magnitude. In addition, in situ DRIFTS was also used to investigate the cause of the significant increase in activity, and it was shown that adsorbed CO species on Pt could be desorbed more easily because of the electron transfer between Pt and Co species. PMID- 29700516 TI - Factors impacting the aggregation/agglomeration and photocatalytic activity of highly crystalline spheroid- and rod-shaped TiO2 nanoparticles in aqueous solutions. AB - We investigate the characteristics, fate and photocatalytic activity of spheroid- and rod-shaped TiO2 nano-crystals in aqueous solutions to better understand their behaviour in media of biological and environmental interest. For this purpose, the potential of a solvothermal method in synthesizing highly crystalline nanoparticles and tuning their sizes/shapes is explored. Spheroid- and rod-shaped nanoparticles are successfully obtained with different aspect ratios, while keeping their structures as well as their cross-sectional areas identical. The aggregation/agglomeration of these nanostructures in aqueous solutions shows an obvious shape effect, revealing critical coagulation concentrations (CCCs) significantly lower for the rods compared to the spheroids (aspect ratio ~ 2-3). This trend is observed in both NaCl and CaCl2 electrolytes at pH values above and below the pHPZC of TiO2 nanoparticles. The photocatalytic activity of the spheroids is unexpectedly superior to that of the rods at NaCl and CaCl2 concentrations over a range of 2 to 100 and 1 to 50 mM, respectively. Our results show that an increase in the chloride concentration leads to an inhibition of the photocatalytic activity rate, with a more pronounced impact for the rods. In contrast, the size of aggregates/agglomerates has only a little effect on the photocatalytic properties of both nano-crystals. PMID- 29700517 TI - Insight into the mechanism of methanol assistance with syngas conversion over partially hydroxylated gamma-Al2O3(110D) surface in slurry bed. AB - Despite numerous studies devoted to the various properties of gamma-Al2O3, the explorations of its catalytic activity remain scarce. In this study, density functional theory calculations are performed to study the elementary adsorption and reaction mechanisms for syngas conversion on partially hydroxylated gamma Al2O3(110D) surface in liquid paraffin. It is found that the partially hydroxylated gamma-Al2O3(110D) surface with the hydroxyl coverage of 8.9 OH nm-2 is formed by two dissociative adsorptions of H2O on the dry gamma-Al2O3(110D) surface. The hydroxyl coverage conditions play a key role in determining the dominant reaction mechanism on account of the existence of strong hydrogen bonds. The preferential pathway for syngas conversion with assistance of methanol over the partially hydroxylated gamma-Al2O3(110D) surface in liquid paraffin has been proven to be CH3OH -> CH3O + H -> CH3 + OH, CH3 + CO -> CH3CO. C2H5OH is then formed by successive hydrogenation via the pathway CH3CO + 3H -> CH3CHO + 2H -> CH3CH2O + H -> C2H5OH. Here, CH3CHO formation by CH3CO hydrogenation is not inhibited. Actually, with the assistance of partially hydroxylated gamma-Al2O3, CH3CHO has been synthesized with high selectivity in our previous experiment by the reaction of methanol and syngas, which provides favorable evidence for our results. The rate-limiting step is the formation of CH3O from CH3OH dehydrogenation with an activation barrier of 122.2 kJ mol-1. Moreover, the reaction barrier of CO insertion into the adsorbed CH3 group is at least 89.4 kJ mol-1, lower than those of CH4, C2H6, and CH3OCH3 formations. ADCH charge and ESP analyses indicate that the typical (Al, O) Lewis acid-base pair may have a significant effect upon the initial C-C chain formation. Thus, the present study provides a new approach for the rational tailoring and designing of new catalysts with superior reactivity involved in syngas conversion. PMID- 29700521 TI - Superconductivity in two-dimensional phosphorus carbide (beta0-PC). AB - Two-dimensional (2D) boron has been predicted to show superconductivity. However, intrinsic 2D carbon and phosphorus have not been reported to be superconductors, which has inspired us to study the superconductivity of their mixture. Here we performed first-principles calculations for the electronic structure, phonon dispersion, and electron-phonon coupling of the metallic phosphorus carbide monolayer, beta0-PC. The results show that it is an intrinsic phonon-mediated superconductor, with an estimated superconducting temperature Tc of ~13 K. The main contribution to the electron-phonon coupling is from the out-of-plane vibrations of phosphorus. A Kohn anomaly on the first acoustic branch is observed. The superconducting related physical quantities are found to be tunable by applying strain or by carrier doping. PMID- 29700522 TI - Crystallization of silica promoted by residual hydrogen bonding interactions at high temperature. AB - A novel approach to prepare crystalline silica through calcination of the composite of silica and highly fluorinated graphene at a relatively low temperature is demonstrated. Silica and its composites with graphene and its derivatives (graphene, graphene oxide and graphene with various degrees of fluorination) were synthesized and then calcined at 900 degrees C in an air atmosphere. The results of X-ray-diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy reveal that cristobalite was produced through calcining composites of silica and highly fluorinated graphene under ambient air at a relatively low temperature (900 degrees C), while for the composites of silica and graphene and its derivatives, the calcined products are all amorphous. Thermal gravimetric analysis results indicate that the maximum decomposition temperature of functional groups in highly fluorinated graphene at air temperature is 457 degrees C, which is higher than that in medium fluorinated graphene, lower fluorinated graphene and graphene oxide (411.3 degrees C, 313.4 degrees C and 238.9 degrees C). A high degradation temperature of highly fluorinated graphene contributes to strong residual hydrogen bonding interactions at high temperature. FTIR results further illustrate that many residual hydrogen bonding interactions in composites of silica and highly fluorinated graphene at higher temperature result in enough linear structures. As a consequence, stronger residual hydrogen bonding interactions at high temperature in composites of silica and highly fluorinated graphene restrain the self-condensation of Si-OH groups and promote the formation of crystalline structures. PMID- 29700523 TI - Hydrogen bonds of the imidazolium rings of ionic liquids with DMSO studied by NMR, soft X-ray spectroscopy, and SANS. AB - The hydrogen bonds of the imidazolium-ring H atoms of ionic liquids (ILs), 1 alkyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amides ([Cnmim][TFSA], n = 2 to 12 where n represents the alkyl chain length), with the O atom of dimethyl sulfoxide (DMSO) have been elucidated using 1H, 13C, and 15N NMR spectroscopy and soft X-ray absorption and emission spectroscopy (XAS and XES). Density functional theory (DFT) calculations have been performed on an isolated DMSO molecule and two cluster models of [Cnmim]+-DMSO by hydrogen bonding to interpret the XES spectra for the [Cnmim][TFSA]-DMSO solutions. The 1H and 13C NMR chemical shifts of the imidazolium ring showed that deshielding of the ring H and C atoms is moderate as the DMSO mole fraction xDMSO increases to ~0.8; however, it becomes more significant with further increase of xDMSO. This finding suggests that the hydrogen bonds of the three ring H atoms with the DMSO O atoms are saturated in solutions with xDMSO increased to ~0.8. The 1H and 13C chemical shifts of the alkyl chains revealed that the electron densities of the chain H and C atoms gradually decrease with increasing xDMSO, except for the N1-bound carbon atom C7 of the chain. The 15N NMR chemical shifts showed that the imidazolium-ring N1 atom which is bound to the alkyl chain is shielded with increasing xDMSO in the range from 0 to 0.8 and is then deshielded with further increase of xDMSO. In contrast, the imidazolium ring N3 atom is simply deshielded with increasing xDMSO. Thus, the electron densities of the alkyl chain may be condensed at the C7 and N1 atoms of [Cnmim]+ by the hydrogen bonding of the ring H atoms with DMSO. The hydrogen bonding of DMSO with the ring results in low-energy shifts of the XES peaks of the O K-edge of DMSO. Small-angle neutron scattering experiments showed that [Cnmim][TFSA] and DMSO are homogeneously mixed with each other on the mesoscopic scale. This results from the strong hydrogen bonds of DMSO with the imidazolium-ring H atoms. PMID- 29700524 TI - Excitation-wavelength-dependent photoluminescence of silicon nanoparticles enabled by adjustment of surface ligands. AB - We herein present pioneering studies to reveal that excitation-wavelength dependent photoluminescence properties of fluorescent silicon nanoparticles (SiNPs) can be realized by rationally designing surface ligands, i.e., several kinds of oxidized indole derivatives. The resultant ligand-decorated SiNPs exhibit strong fluorescence, with significant excitation-wavelength-dependent emissive shifting from ~420 nm to ~550 nm. Taking advantage of their unique optical merits, we further exploit the resultant ligand-decorated SiNPs as novel fluorescent labels for anti-counterfeiting and cell imaging. PMID- 29700525 TI - Size-dependent magnetic and inductive heating properties of Fe3O4 nanoparticles: scaling laws across the superparamagnetic size. AB - An efficient heat activating mediator with an enhanced specific absorption rate (SAR) value is attained via control of the iron oxide (Fe3O4) nanoparticle size from 3 to 32 nm. Monodispersed Fe3O4 nanoparticles are synthesized via a seed less thermolysis technique using oleylamine and oleic acid as the multifunctionalizing agents (surfactant, solvent and reducing agent). The inductive heating properties as a function of particle size reveal a strong increase in the SAR values with increasing particle size up to 28 nm. In particular, the SAR values of ferromagnetic nanoparticles (>16 nm) are strongly enhanced with the increase of ac magnetic field amplitude than that for the superparamagnetic (3-16 nm) nanoparticles. The enhanced SAR values in the ferromagnetic regime are attributed to the synergistic contribution from the hysteresis and susceptibility loss. Specifically, the 28 nm Fe3O4 nanoparticles exhibit an enhanced SAR value of 801 W g-1 which is nearly an order higher than that of the commercially available nanoparticles. PMID- 29700529 TI - 2-Chloromalonaldehyde, a model system of resonance-assisted hydrogen bonding: vibrational investigation. AB - The chelated enol isomer of 2-chloromalonaldehyde (2-ClMA) is experimentally characterized for the first time by IR and Raman spectroscopies. The spectra are obtained by trapping the molecule in cryogenic matrices and analyzed with the assistance of theoretical calculations. Experiments were performed in argon, neon and para-hydrogen matrices. The results highlight puzzling matrix effects, beyond site effects, which are interpreted as due to a tunneling splitting of the vibrational levels related to the proton transfer along the internal hydrogen bond (IHB). 2-ClMA is thus one of the very few molecules in which the H tunneling has been observed in cryogenic matrices. The comparison with its parent molecule (malonaldehyde) shows experimentally and theoretically the weakening of the IHB upon chlorination, with a reduced cooperative effect in the resonance assisted hydrogen bond. In addition, the Cl substitution induces an important stabilization of two open enol conformers. These two open forms appear in the spectra of as-deposited samples, meaning that, in contrast with other well studied molecules of the same family (beta-dialdehydes and beta-diketones), they are present in the gas phase at room temperature. PMID- 29700530 TI - Facile preparation of a nano-imprinted polymer on magnetite nanoparticles for the rapid separation of lead ions from aqueous solution. AB - A novel nanostructured magnetic ion-imprinted polymer (IIP) was synthesized for the selective adsorption of Pb(ii) from aqueous solution. The IIP was prepared on functional Fe3O4@SiO2 core/shell nanoparticles as a support. Monomer units in the polymer featured the typical bidentate ligand itaconic acid. We used ethylene glycol dimethacrylate and 2,2-azoisobisbutyronitrile as a cross-linker and an initiator, respectively. Monomers with different acid-base properties and different proportions of cross-linker were investigated to obtain high performance adsorbents. Our results showed that the IIP prepared from itaconic acid had a high adsorption capacity owing to the strong binding between the monomer and Pb(ii) template ion. The IIPs were characterized using Fourier transform infrared spectroscopy, Brunauer-Emmett-Teller surface area analysis, thermogravimetric analysis, and transmission electron microscopy. We confirmed the formation of a nano-imprinted shell layer on the surface of Fe3O4@SiO2. The adsorption rate was fast, conforming to a pseudo-second-order kinetic and Langmuir adsorption model; the adsorption mechanism was deemed to be chemisorption as a single molecular layer. The maximum adsorption capacity of the IIP (51.2 mg g-1) was approximately three times as large as that of the non imprinted polymer (17.9 mg g-1). The selectivity factors for Pb(ii) in mixed solutions of Pb(ii)/Co(ii), Pb(ii)/Cu(ii), and Pb(ii)/Zn(ii) were 45.6, 6.45, and 8.3, respectively. Pb-IIP exhibited a high selectivity towards Pb(ii), which enabled the enrichment of Pb(ii) in aqueous solution. PMID- 29700531 TI - Laser-induced surface deformation microscope for the study of the dynamic viscoelasticity of plasma membrane in a living cell. AB - A laser-induced surface deformation (LISD) microscope is developed and applied to measurement of the dynamic relaxation responses of the plasma membrane in a living cell. A laser beam is tightly focused on an optional area of cell surface and the focused light induces microscopic deformation on the surface via radiation pressure. The LISD microscope not only allows non-contact and destruction-free measurement but provides power spectra of the surface responses depending on the frequency of the intensity of the laser beam. An optical system for the LISD is equipped via a microscope, allowing us to measure the relaxation responses in sub-cellular-sized regions of the plasma membrane. In addition, the forced oscillation caused by the radiation pressure for surface deformation extends the upper limit of the frequency range in the obtained power spectra to 106 Hz, which enables us to measure relaxation responses in local regions within the plasma membrane. From differences in power-law exponents at higher frequencies, it is realized that a cancerous cell obeys a weaker single power-law than a normal fibroblast cell. Furthermore, the power spectrum of a keratinocyte cell obeys a power-law with two exponents, indicating that alternative mechanical models to a conventional soft glassy rheology model (where single power-laws explain cells' responses below about 103 Hz) are needed for the understanding over a wider frequency range. The LISD microscope would contribute to investigation of microscopic cell rheology, which is important for clarifying the mechanisms of cell migration and tissue construction. PMID- 29700532 TI - Modeling TADF in organic emitters requires a careful consideration of the environment and going beyond the Franck-Condon approximation. AB - The origin of the thermally-activated delayed fluorescence (TADF) of three organic emitters is investigated, focusing on the nature of the lowest excited states, their transition properties, as well as the role of the environment. For this purpose, the algebraic-diagrammatic construction for the polarization propagator at second order of perturbation theory [ADC(2)], time-dependent density-functional theory in the Tamm-Dancoff approximation (TDA) and unrestricted Kohn-Sham DFT in combination with the maximum-overlap method (DeltaDFT) are employed. The influence of the dielectric environment is rigorously included using different variants of the polarizable continuum model. The calculations reveal the lowest excited singlet and triplet states of all studied emitters to be dominated by charge-transfer (CT) character already in the most apolar environment corresponding to cyclo-hexane. The dielectric stabilization entails a drastic reduction of the singlet-triplet gaps, increasing the calculated TADF rates by several orders of magnitude. Another ingredient for accurate TADF rates is hidden in the excited-state potential-energy surfaces along the donor-acceptor twisting angle. A presence of large, shallow plateaus in apolar environments causes the transition properties to be governed by thermal fluctuations rather than the minimum-energy geometries. This leads to a large increase of the oscillator strengths, as well as a breakdown of the Franck-Condon approximation. The last ingredient is a small but significant spin-orbit coupling (SOC) between the singlet and triplet CT states, which is traced back to a delocalization of the excitation hole or excited electron of the triplet CT state. Taking into account all of these effects, a reasonable agreement with experimental TADF and fluorescence lifetimes is obtained. For this, it proves to be sufficient to consider only the lowest lying singlet and triplet excited states. PMID- 29700533 TI - Liquid worm-like and proto-micelles: water solubilization in amphiphile-oil solutions. AB - Noncovalent interactions determine the structure-property relationship of materials. Self-assembly originating from weak noncovalent interactions represents a broad variety of solution-based transformations spanning micellization and crystallization, which, nevertheless, conforms to neither colloid nor solution sciences. Here, we investigate the weak self-assembly in water-amphiphile-oil solutions to understand the connection between the amphiphilic molecular structure and water solubilization in oil. X-ray and neutron scattering, converged with large-scale atomistic molecular dynamics simulations, support the fact that the amphiphiles assemble into liquid worm-like micelles and loose inverted proto-micelles. The inverted proto-micelles are energetically ready to accommodate a higher amount of water. These structures arise from a balance of intermolecular interactions controlled by the amphiphile tail-group structures. Thus, by linking the aggregate morphology to the molecular structure, this work provides insights on the molecular design for control of water solubility and dispersion in oil. PMID- 29700534 TI - Computational screening of a single transition metal atom supported on the C2N monolayer for electrochemical ammonia synthesis. AB - The nitrogen reduction reaction (NRR) under ambient conditions using renewable energy is a green and sustainable strategy for the synthesis of NH3, which is one of the most important chemicals and carbon-free carriers. Thus, the search for low-cost, highly efficient, and stable NRR electrocatalysts is critical to achieve this goal. Herein, using comprehensive density functional theory (DFT) computations, we design a new class of NRR electrocatalysts based on a single transition metal (TM) atom supported on the experimentally feasible two dimensional C2N monolayer (TM@C2N). Based on the computed free energies of each elementary pathway, Mo@C2N is predicted to exhibit the best catalytic activity among the TM@C2N, in which the proton-coupled electron transfer of the NH2* species to NH3(g) is the potential-determining step. Especially, the computed onset potential of the NRR on Mo@C2N is -0.17 V, which is even lower than that for the well-established stepped Ru(0001) surface (-0.43 V). Furthermore, the NRR catalytic performance of these TM@C2N can be well explained by their adsorption strength with N2H* species. Our findings open a new avenue for optimizing the TM catalytic performance for the NRR with the lowest number of metal atoms on porous low-dimensional materials. PMID- 29700535 TI - A reversible conductivity modulation of azobenzene-based ionic liquids in aqueous solutions using UV/vis light. AB - Photo-induced conductivity modulation of stimuli-responsive materials is of great importance from the viewpoint of fundamental research and technology. In this work, 5 new kinds of azobenzene-based photo-responsive ionic liquids were synthesized and characterized, and UV/vis light modulation of their conductivity was investigated in an aqueous solution. The factors affecting the conductivity modulation of the photo-responsive fluids, such as photo-isomerization efficiency, photo-regulation aggregation, concentration and chemical structure of the ionic liquids, were examined systematically. It was found that the conductivity of the ionic liquids in water exhibited a significant increase upon UV light irradiation and the ionic liquids with a shorter alkyl spacer in the cation showed a more remarkable photo-induced conductivity enhancement with a maximum increase of 150%. In addition, the solution conductivity was restored (or very close) to the initial value upon an alternative irradiation with visible light. Thus, the solution conductivity can be modulated using alternative irradiation with UV and visible light. Although the reversible photo isomerization of the azobenzene group under UV/vis irradiation is the origin of the conductivity modulation, the photo-regulated aggregation of the ionic liquid in water is indispensable for the maximum degree of conductivity modulation because UV irradiation can weaken, even break the aggregated cis-isomers of the ionic liquids in an aqueous solution. PMID- 29700536 TI - The amplified electrochemiluminescence response signal promoted by the Ir(iii) containing polymer complex. AB - A novel Ir(iii)-containing polymer complex (P2) as an electrochemiluminescence (ECL) emitter was prepared by the coordination reaction of the N-containing bidentate ligand (-CH[double bond, length as m-dash]N-CH2-CH2-N[double bond, length as m-dash]CH-) in the conjugated polymer P1 with [Ir2(2-ppy)4(MU-Cl)2] (M3). Despite a rather low Ir(iii) content in P2, it can emit a greatly enhanced ECL signal compared with its polymer ligand P1 and the Ir(iii) model complex using TPrA as a co-reactant in CH3CN solution due to the effective intramolecular metal-ligand charge transfer (MLCT) from the Ir(iii)-complex centre to the polymer backbone. PMID- 29700537 TI - Exploring function activated chlorins using MCD spectroscopy and DFT methods: design of a chlorin with a remarkably intense, red Q band. AB - The electronic structures of three previously synthesized Ni-coordinated chlorins with beta-substituents of thioketone, fluorene, and ketone were investigated using magnetic circular dichroism spectroscopy (MCD) and density functional theory (DFT) for potential application as sensitizers for dye-sensitized solar cells (DSSCs). Computational studies on modeled Zn-coordinated chlorins allowed identification of charge transfer and d-d transitions of the Ni2+ coordinated chlorins. Two fictive Zn chlorins, M1 and M2, were designed with thiophene units based on the fluorene substituted chlorin. Substitution with thiophene altered the typical arrangement of the four Gouterman molecular orbitals (MOs) and red shifted and greatly intensified the lowest energy absorption band (the Q band). The introduction of the thiophene-based MO as the LUMO below the usual Gouterman LUMO is predicted to increase the efficiency of electron transfer from the dye to the conduction band of the semiconductor in DSSCs. The addition of a donor group on the opposite pyrrole (M2) red-shifted the Q band further and introduced a donor-based MO between the typical Gouterman HOMO and HOMO-1. Despite the relatively small DeltaHOMO, M1 and M2 exhibited remarkably intense Q bands. M2 would be a possible candidate for application in DSSCs due to its panchromatic absorption, intense and red-shifted Q band, and the presence of the substituent based MO properties. Another indicator of a successful dye is the alignment of the ground state and excited state oxidation potentials (GSOP and ESOP, respectively) with respect to the conduction band of the semiconductor. The GSOP for M2 lies 0.55 eV below the I-/I3- redox potential and the ESOP lies 0.48 eV above the TiO2 conduction band. The impact of the thiophene dominance in the LUMO also supports the prediction of efficient sensitization properties. The remarkably intense Q band of M2 predicted to be at 777 nm with a DeltaHOMO of just 1.04 eV provides a synthetic route to tetrapyrroles with extremely intense, red Q bands without the need for aza nitrogens of the phthalocyanines. This study illustrates the value of guided synthesis using MCD spectral analysis and computational methods for optimizing the design of porphyrin dyes. PMID- 29700538 TI - Highly negative Poisson's ratio in a flexible two-dimensional tungsten carbide monolayer. AB - Auxetic materials have numerous promising engineering applications such as fracture resistance and energy storage due to their negative Poisson's ratios (NPRs). However, compared to materials possessing positive Poisson's ratios (PPRs), auxetic materials are rare. In this paper, by employing first principles calculations, we found a high NPR two-dimensional (2D) material, tungsten carbide (W2C), in the transition metal carbides (MXenes). Our results of the relatively moderate Young's modulus and fracture strength as well as the critical strain showed that the 2D monolayer W2C is an extraordinary flexible material. Our DFT results also demonstrated that W2C possesses high NPRs while Hf2C and Ta2C have PPRs. Furthermore, the mechanically induced deformation mechanism and the NPR formation mechanism of W2C have been proposed. Such an intrinsic NPR in W2C is attributed to the strong coupling between the C-p and W-d orbitals in the pyramid structural unit. The mechanically induced deformation mechanism and the PPR formation mechanism of Hf2C have also been determined. The intrinsic NPR for W2C transforms to PPR upon the surface functionalization induced. The behavior occurs due to the W-C interaction weakening. The excellent NPR in the 2D MXene material combined with other outstanding properties such as the metallic state would bring about its promising engineering prospects, ranging from the metal-ion battery, to automobiles and aircraft. PMID- 29700539 TI - Ultrafast photochemistry of free-base porphyrin: a theoretical investigation of B -> Q internal conversion mediated by dark states. AB - We examine the mechanism of ultrafast internal conversion between the B band (Soret band) and the Q band in porphine (H2P), the prototypical free-base porphyrin, using electronic structure studies and on-the-fly surface-hopping nonadiabatic dynamics. Our study highlights the crucial role of dark states within the N band which are found to mediate B/Q state transfer, necessitating a treatment beyond Gouterman's classic four-orbital model. The sequential B -> N -> Q pathway dominates largely over the direct B -> Q pathway which is found to be energetically unfavorable. Potential energy surface cuts and conical intersections between excited states are determined by TDDFT and validated by CASSCF/CASPT2 and XMCQDPT2 calculations. Both the static analysis and on-the-fly surface-hopping calculations suggest a pathway which involves minor structural deformations via in-plane vibrations. The B -> N conversion is a barrierless adiabatic process occurring within ~20 fs, while the subsequent N -> Q conversion occurs via a conical intersection within ~100 fs, in agreement with time-resolved experiments for porphine and related free base porphyrins. Furthermore, evidence for both sequential and direct transfer to the Qx and Qy states is obtained. PMID- 29700540 TI - 2D nanomaterials: graphene and transition metal dichalcogenides. PMID- 29700541 TI - Micromechanical characterization of soft, biopolymeric hydrogels: stiffness, resilience, and failure. AB - Detailed understanding of the local structure-property relationships in soft biopolymeric hydrogels can be instrumental for applications in regenerative tissue engineering. Resilin-like polypeptide (RLP) hydrogels have been previously demonstrated as useful biomaterials with a unique combination of low elastic moduli, excellent resilience, and cell-adhesive properties. However, comprehensive mechanical characterization of RLP hydrogels under both low-strain and high-strain conditions has not yet been conducted, despite the unique information such measurements can provide about the local structure and macromolecular behavior underpinning mechanical properties. In this study, mechanical properties (elastic modulus, resilience, and fracture initiation toughness) of equilibrium swollen resilin-based hydrogels were characterized via oscillatory shear rheology, small-strain microindentation, and large-strain puncture tests as a function of polypeptide concentration. These methods allowed characterization, for the first time, of the resilience and failure in hydrogels with low polypeptide concentrations (<20 wt%), as the employed methods obviate the handling difficulties inherent in the characterization of such soft materials via standard mechanical techniques, allowing characterization without any special sample preparation and requiring minimal volumes (as low as 50 MUL). Elastic moduli measured from small-strain microindentation showed good correlation with elastic storage moduli obtained from oscillatory shear rheology at a comparable applied strain rate, and evaluation of multiple loading-unloading cycles revealed decreased resilience values at lower hydrogel concentrations. In addition, large strain indentation-to-failure (or puncture) tests were performed to measure large strain mechanical response and fracture toughness on length scales similar to biological cells (~10-50 MUm) at various polypeptide concentrations, indicating very high fracture initiation toughness for high-concentration hydrogels. Our results establish the utility of employing microscale mechanical methods for the characterization of the local mechanical properties of biopolymeric hydrogels of low concentrations (<20 wt%), and show how the combination of small and large strain measurements can provide unique insight into structure-property relationships for biopolymeric elastomers. Overall, this study provides new insight into the effects on local mechanical properties of polypeptide concentration near the overlap polymer concentration c* for resilin-based hydrogels, confirming their unique elastomeric features for applications in regenerative medicine. PMID- 29700542 TI - Facet-selective deposition of Au and Pt on Ag nanocubes for the fabrication of bifunctional Ag@Au-Pt nanocubes and trimetallic nanoboxes. AB - We report a facile route to the synthesis of Ag@Au-Pt trimetallic nanocubes in which the Ag, Au, and Pt atoms are exposed at the corners, side faces, and edges, respectively. Our success relies on the use of Ag@Au nanocubes, with Ag2O patches at the corners and Au on the side faces and edges, as seeds for the site selective deposition of Pt on the edges only in a reaction system containing ascorbic acid (H2Asc) and poly(vinylpyrrolidone). At an initial pH of 3.2, H2Asc can dissolve the Ag2O patches, exposing the Ag atoms at the corners of a nanocube. Upon the injection of the H2PtCl6 precursor, the Pt atoms derived from the reduction by both H2Asc and Ag are preferentially deposited on the edges, leading to the formation of Ag@Au-Pt trimetallic nanocubes. We demonstrate the use of 2,6-dimethylphenyl isocyanide as a molecular probe to confirm and monitor the deposition of Pt atoms on the edges of nanocubes through surface-enhanced Raman scattering (SERS). We further explore the use of these bifunctional trimetallic nanoparticles with integrated plasmonic and catalytic properties for in situ SERS monitoring the reduction of 4-nitrothiophenol by NaBH4. Upon the removal of Ag via H2O2 etching, the Ag@Au-Pt nanocubes evolve into trimetallic nanoboxes with a wall thickness of about 2 nm and well-defined openings at the corners. The trimetallic nanoboxes embrace plasmon resonance peaks in the near infrared region with potential in biomedical applications. PMID- 29700543 TI - Physical foundation of the fluid particle dynamics method for colloid dynamics simulation. AB - Colloid dynamics is significantly influenced by many-body hydrodynamic interactions mediated by a suspending fluid. However, theoretical and numerical treatments of such interactions are extremely difficult. To overcome this situation, we developed a fluid particle dynamics (FPD) method [H. Tanaka and T. Araki, Phys. Rev. Lett., 2000, 35, 3523], which is based on two key approximations: (i) a colloidal particle is treated as a highly viscous particle and (ii) the viscosity profile is described by a smooth interfacial profile function. Approximation (i) makes our method free from the solid-fluid boundary condition, significantly simplifying the treatment of many-body hydrodynamic interactions while satisfying the incompressible condition without the Stokes approximation. Approximation (ii) allows us to incorporate an extra degree of freedom in a fluid, e.g., orientational order and concentration, as an additional field variable. Here, we consider two fundamental problems associated with these approximations. One is the introduction of thermal noise and the other is the incorporation of coupling of the colloid surface with an order parameter introduced into a fluid component, which is crucial when considering colloidal particles suspended in a complex fluid. Here, we show that our FPD method makes it possible to simulate colloid dynamics properly while including full hydrodynamic interactions, inertia effects, incompressibility, thermal noise, and additional degrees of freedom of a fluid, which may be relevant for wide applications in colloidal and soft matter science. PMID- 29700544 TI - A cation size effect on the framework structures in ABi2SeO3F5 (A = K and Rb): first examples of alkali metal bismuth selenite fluorides. AB - Two new centric alkali metal bismuth selenite fluorides, ABi2SeO3F5 (A = K and Rb), have been synthesized through a soft hydrothermal method. KBi2SeO3F5 crystallizes in an orthorhombic crystal system with the centric space group Pbcm possessing a three-dimensional (3D) network made up of SeO3 trigonal pyramids and asymmetric BiO3F5 polyhedra. As regards compound RbBi2SeO3F5, it crystallizes in a triclinic crystal system with a centric space group of P1[combining macron], which contains alternant two-dimensional (2D) [Bi2SeO3F5]infinity1- layers separated by Rb+ cations. In terms of structure, the differences between KBi2SeO3F5 and RbBi2SeO3F5 originate from the size of alkali metal cations, which has a great influence on the framework geometry and the dimensionalities of crystals. The UV-vis diffuse reflectance spectroscopy study of powder samples indicates that the band gaps of KBi2SeO3F5 and RbBi2SeO3F5 are approximately 4.08 and 4.18 eV, respectively, which are the largest ones among the known bismuth selenites owing to the existence of alkali metal cations as well as fluorine anions in crystals. Furthermore, theoretical calculations show that the optical absorption of two compounds is mainly attributed to the contribution of BiOxFy polyhedra and [SeO3]2- anionic groups. PMID- 29700545 TI - Molecular dynamics simulation of potentiometric sensor response: the effect of biomolecules, surface morphology and surface charge. AB - The silica-water interface is critical to many modern technologies in chemical engineering and biosensing. One technology used commonly in biosensors, the potentiometric sensor, operates by measuring the changes in electric potential due to changes in the interfacial electric field. Predictive modelling of this response caused by surface binding of biomolecules remains highly challenging. In this work, through the most extensive molecular dynamics simulation of the silica water interfacial potential and electric field to date, we report a novel prediction and explanation of the effects of nano-morphology on sensor response. Amorphous silica demonstrated a larger potentiometric response than an equivalent crystalline silica model due to increased sodium adsorption, in agreement with experiments showing improved sensor response with nano-texturing. We provide proof-of-concept that molecular dynamics can be used as a complementary tool for potentiometric biosensor response prediction. Effects that are conventionally neglected, such as surface morphology, water polarisation, biomolecule dynamics and finite-size effects, are explicitly modelled. PMID- 29700546 TI - Luminescent magnetic nanoparticles encapsulated in MOFs for highly selective and sensitive detection of ClO-/SCN- and anti-counterfeiting. AB - It is well-known that ClO- and SCN- can cause adverse effects on the environment and organisms; therefore, development of new strategies for detecting ClO- and SCN-, especially in water, are highly desirable. Here, we present luminous Eu(iii) complex-functionalized Fe3O4 nanoparticles encapsulated into zeolitic imidazolate framework materials (nano-ZIF-8) and successfully employ this nano MOF as a fluorescence probe for selective and sensitive detection of ClO- and SCN . The introduction of ClO- into nano-ZIF-8 solution induced a significant decrease in the characteristic fluorescence emission of Eu3+ at 613 nm. However, strong fluorescence emission was again observed when SCN- was successively injected into the prepared nano-ZIF-8-ClO-. Thus, a novel fluorescence system for simultaneous detection of free ClO- and SCN- was established. On the basis of the superior adsorption performance of nano-MOF materials, free residual ClO- and SCN in water was rapidly, sensitively and selectively detected with a detection limit of 0.133 nM and 0.204 nM, respectively. Moreover, nano-ZIF-8 was successfully used for monitoring the concentration levels of ClO- and SCN- in specimens of tap water and Yellow River water. Furthermore, the reversibility and regeneration of nano-ZIF-8 in sensing ClO- and SCN- is advantageous for applications of nano-ZIF-8 in solid-state sensing and anti-counterfeiting. As far as we know, this is the first time that nano-MOFs have been used as a selective fluorescence probe for ClO-/SCN- detection and anti-counterfeiting. PMID- 29700547 TI - Gold nanocages entering into the realm of high-contrast photoacoustic ocular imaging. AB - Bioinert gold nanoparticles of various shapes and functionalities are widely accepted as contrast agents (CAs) for several modalities of imaging, viz., electron microscopy, computerized tomography (CT), X-ray and photoacoustic (PA) imaging. However, testing of novel compact-imaging probes for ocular diagnostic imaging is always challenging. Here, ultra-fast microwave oven synthesized gold nanocages (AuNcgs) were successfully demonstrated for high-contrast PA ocular imaging for the first time. Methods are described for the synthesis, characterization and application of quickly synthesized AuNcgs in diagnostic ocular imaging. PA and ultrasound (US) images were acquired using a commercial US imaging scanner integrated with a tunable nanosecond pulsed laser. This integrated hybrid-modality system is a combined PA and US platform for imaging which enabled acquiring of complementary structural and optical absorption-based information simultaneously. Initial experiments were conducted using tubings filled with solutions of different concentrations of quickly synthesized AuNcgs. Biological PA and US imagings were demonstrated using enucleated porcine eye samples. Based on the acquired results, it is envisaged that AuNcgs can be employed as a high strength PA CA to potentially diagnose ocular disease like uveal melanoma in the near future. PMID- 29700548 TI - Molecular dynamics simulation of charged colloids confined between hard walls: pre-melting and pre-freezing across the BCC-fluid coexistence. AB - Molecular dynamics (MD) computer simulations are used to study the structure of hard-core Yukawa systems confined between two parallel hard walls. States around the coexistence between a fluid and a body-centered cubic (BCC) crystal are considered. In all cases a pronounced layering in the vicinity of the walls is observed. Using a thermodynamic integration scheme, we determine the wall-fluid interfacial free energy gamma which is negative and monotonically decreasing with increasing bulk density of the fluid. In the case of the fluid, the layers next to the walls undergo a transition from a fluid to a hexagonal structure. This pre freezing transition occurs well below the coexistence bulk density of the fluid. The confined BCC crystal in (111) orientation shows melted regions between crystalline face-centered cubic (FCC) layers close to the wall and the BCC bulk region. PMID- 29700549 TI - Adsorption of phospholipids at oil/water interfaces during emulsification is controlled by stress relaxation and diffusion. AB - Adsorption of phosphatidylcholines at oil/water interfaces strongly deviates from spread monolayers at air/water surfaces. Understanding its nature and consequences could vastly improve applications in medical nanoemulsions and biotechnologies. Adsorption kinetics at interfaces of water with different oil phases were measured by profile analysis tensiometry. Adsorption kinetics for 2 different phospholipids, DPPC and POPC, as well as 2 organic phases, squalene and squalane, show that formation of interfacial monolayers is initially dominated by stress-relaxation in the first minutes. Diffusion only gradually contributes to a decrease in interfacial tension at later stages of time and higher film pressures. The results can be applied for the optimization of emulsification protocols using mechanical treatments. Emulsions using phospholipids with unsaturated fatty acids are dominated much more strongly by stress-relaxation and cover interfaces very fast compared to those with saturated fatty acids. In contrast, phospholipid layers consisting of saturated fatty acids converge faster towards the equilibrium than those with unsaturated fatty acids. PMID- 29700550 TI - Correction: Soft modes and strain redistribution in continuous models of amorphous plasticity: the Eshelby paradigm, and beyond? AB - Correction for 'Soft modes and strain redistribution in continuous models of amorphous plasticity: the Eshelby paradigm, and beyond?' by Xiangyu Cao et al., Soft Matter, 2018, DOI: 10.1039/c7sm02510f. PMID- 29700551 TI - Factors influencing the adoption of telemedicine for treatment of military veterans with post-traumatic stress disorder. AB - BACKGROUND: Military veterans returning from a combat zone often face mental health challenges as a result of traumatic experiences. The veteran in the United States has been underdiagnosed and underserved. Since its advancement in the 1990s, telemedicine has become a more prevalent means of delivering services for post-traumatic stress disorder among veterans in the United States, but its adoption is not ubiquitous. OBJECTIVE: To clarify the association of telemedicine and the treatment of veterans with post-traumatic stress disorder through identification of facilitators and barriers to the adoption of the modality. METHODS: Reviewers analysed articles from CINAHL and PubMed databases, using relative key words, selecting the 28 most germane to the study objective. RESULTS: The most common adoption facilitators were: improving access to rural populations of veterans (22%), effective treatment outcomes (16%), and decreased costs related to care (13%). The most prevalent barriers were: veterans lacking access to necessary modalities (25%), availability of physicians competent in post-traumatic stress disorder treatment (20%), and complications with technology (20%). Five themes surfaced for facilitators: accessibility, effectiveness, cost reduction, positive patient perception, and supportive community; and 5 themes for barriers: access to technology, technical complications, physician availability, negative patient perception, and uninformed patients. CONCLUSION: This literature review identifies cost and outcomes-effectiveness. The association of telemedicine with the treatment of veterans with post-traumatic stress disorder is feasible, beneficial and effective. PMID- 29700552 TI - [Environmental burden of disease in Germany]. AB - BACKGROUND: Environmental risk factors can have a substantial impact on population health. With the environmental burden of disease (EBD) approach, the health losses attributable to environmental risk factors can be quantified using disability-adjusted life years (DALY). OBJECTIVES: The aim of this article is to present and discuss available EBD estimates with a focus on Germany. MATERIALS: Using current EBD studies, the share of the burden of disease attributable to environmental risk factors globally and DALYs for Germany are presented. Ambient particulate matter (PM), water-related risks and environmental noise are used as examples to emphasize the importance of availability and quality of input data for burden of disease assessments. RESULTS: The share of the global burden of disease attributable to environmental risk factors varies according to the available studies and lies between 13 and 22%. For Germany, EBD estimates are available for 12 environmental risk factors. Most estimates are available for particulate matter in ambient air, however, the estimated burden differs greatly. Nonetheless, according to current knowledge, particulate matter pollution is the environmental risk factor with the highest burden of disease in Germany. CONCLUSIONS: Differences in the estimated burden of disease for the considered risk factors are due to varying underlying assumptions, e. g. for life expectancy or counterfactual value and the input data used. PMID- 29700554 TI - Platelet-rich plasma as an additional therapeutic option for infected wounds with multi-drug resistant bacteria: in vitro antibacterial activity study. AB - PURPOSE: Infected wounds, such as diabetic foot infections, are mostly polymicrobial and microorganisms have high resistance rates to antimicrobials. Infected wounds in diabetic patients have high cost, morbidity, and mortality rates. Based on these facts, there is a need for supportive localized treatment options such as platelet-rich plasma (PRP) implementations. Demonstrating the in vitro antimicrobial effect, our aim was to lead up to clinical trials of localized PRP implementations in infected wounds such as diabetic foot infections. In this study, we aimed to demonstrate the in vitro antibacterial activity of PRP against methicilin-resistant Staphylococcus aureus (MRSA) and three more multi-drug resistant bacteria species that are important and hard-to treat in wound infections. MATERIALS AND METHODS: In vitro antimicrobial activity of autologous PRP, platelet-poor plasma (PPP), and phosphate-buffered saline (PBS) on methicillin-resistant Staphylococcus aureus, vancomycin-resistant Enterococcus spp., extended spectrum beta lactamase producing Klebsiella pneumoniae, and carbapenem-resistant Pseudomonas aeruginosa was compared by assessment of bacterial growth on agar plates and antimicrobial susceptibility test results. RESULTS: When compared to control group, PRP and PPP significantly suppressed bacterial growth of MRSA, K. pneumoniae, and P. aeruginosa at 1st, 2nd, 5th, and 10th hours of incubation (p < 0.05). VRE was the only bacteria that PRP and PPP showed limited activity against. When compared to PPP, PRP showed higher activity against MRSA, K. pneumoniae, and P. aeruginosa. However, the differences between PRP and PPP were statistically significant only against MRSA and P. aeruginosa at the first hour of incubation. CONCLUSIONS: Emerging PRP and other platelet-derived products seem to be promising alternative tools besides antibiotic treatment, debridement, negative pressure wound therapy, hyperbaric oxygen therapy, and other treatment options for treating diabetic foot infections. PMID- 29700555 TI - From basic research to applied veterinary sciences: current status, challenges and perspectives. PMID- 29700553 TI - Functional characterisation of naturally occurring mutations in human melanopsin. AB - Melanopsin is a blue light-sensitive opsin photopigment involved in a range of non-image forming behaviours, including circadian photoentrainment and the pupil light response. Many naturally occurring genetic variants exist within the human melanopsin gene (OPN4), yet it remains unclear how these variants affect melanopsin protein function and downstream physiological responses to light. Here, we have used bioinformatic analysis and in vitro expression systems to determine the functional phenotypes of missense human OPN4 variants. From 1242 human OPN4 variants collated in the NCBI Short Genetic Variation database (dbSNP), we identified 96 that lead to non-synonymous amino acid substitutions. These 96 missense mutations were screened using sequence alignment and comparative approaches to select 16 potentially deleterious variants for functional characterisation using calcium imaging of melanopsin-driven light responses in HEK293T cells. We identify several previously uncharacterised OPN4 mutations with altered functional properties, including attenuated or abolished light responses, as well as variants demonstrating abnormal response kinetics. These data provide valuable insight into the structure-function relationships of human melanopsin, including several key functional residues of the melanopsin protein. The identification of melanopsin variants with significantly altered function may serve to detect individuals with disrupted melanopsin-based light perception, and potentially highlight those at increased risk of sleep disturbance, circadian dysfunction, and visual abnormalities. PMID- 29700556 TI - Diagnostic value of novel biomarkers for heart failure : A meta-analysis. AB - BACKGROUND: The present meta-analysis examined the diagnostic value of novel biomarkers for heart failure (HF), including copeptin, galectin-3, hs-cTnT, MR proANP, MR-proADM, and ST2. METHODS: English (EMBASE, Cochrane, and PubMed) and Chinese (Wanfang data, CNKI, SinoMed) databases were searched to identify suitable studies that were published before 1 December 2016. Data were extracted using standard forms. Pooled diagnostic statistics were calculated using DerSimonian-Laird random-effects models. RESULTS: The analysis comprised 45 studies. The pooled sensitivities of all biomarkers were 0.80-0.86, along with pooled specificities of 0.60-0.82, positive predictive values (PPVs) of 0.52 0.80, and negative predictive values (NPVs) of 0.70-0.87. Among them, hs-cTnT had the highest sensitivity (0.86 [95% CI: 0.84-0.88]), specificity (0.82 [95% CI: 0.79-0.84]), PPV (0.80 [95% CI: 0.77-0.83]), and NPV (0.87 [95% CI: 0.85-0.89]), while MR-proADM had the lowest sensitivity (0.80 [95% CI: 0.75-0.84]), specificity (0.60 [95% CI: 0.56-0.64]), and PPV (0.52 [95% CI: 0.47-0.56]). Copeptin had the lowest NPV (0.70 [95% CI: 0.66-0.74]). The positive likelihood ratio (LR+) of all biomarkers ranged from 1.97 to 3.21, and the negative likelihood ratio (LR-) from 0.20 to 0.36. MR-proADM had the lowest LR+ and highest LR-; galectin-3 had the highest LR+ and MR-proANP had the lowest LR-. The area under the curve (AUC) was as low as 0.68 for MR-proADM, while AUCs for the other biomarkers ranged from 0.83 to 0.89. CONCLUSION: The overall diagnostic accuracy of copeptin, galectin-3, hs-cTnT, MR-proANP, and ST2 was relatively good. MR-proADM had a poor capacity to confirm or exclude HF. Improving the diagnostic accuracy of HF by a combination of biomarkers could be considered in the future. PMID- 29700557 TI - Ambient desorption/ionization mass spectrometry: evolution from rapid qualitative screening to accurate quantification tool. AB - In this article, some recent trends and developments in ambient desorption/ionization mass spectrometry (ADI-MS) are reviewed, with a special focus on quantitative analyses with direct, open-air sampling. Accurate quantification with ADI-MS is still not routinely performed, but this aspect is considered of utmost importance for the advancement of the field. In fact, several research groups are devoted to the development of novel and optimized ADI MS approaches. Some key trends include novel sample introduction strategies for improved reproducibility, tailored sample preparation protocols for removing the matrix and matrix effects, and multimode ionization sources. In addition, there is significant interest in quantitative mass spectrometry imaging. Graphical abstract Conceptual diagram of the ambient desorption/ionization mass spectrometry approach with different desorption/ionization probes. PMID- 29700558 TI - Differential Expression Profiles of Circular RNAs During Osteogenic Differentiation of Mouse Adipose-Derived Stromal Cells. AB - Osteogenesis is a complex and tightly regulated process. Circular RNAs (circRNAs) are covalently closed RNA molecules which are thought to play a significant role in bone metabolism. The purpose of this study was to investigate the expression and putative function of circRNAs during the osteogenic differentiation of mouse adipose-derived stromal cells (mADSCs). circRNA microarrays were used to determine differential circRNAs expression at different stages during osteogenesis of mADSCs. The most frequent differentially expressed circRNAs were selected by Venn analysis and clustered among the three induced groups. In addition, bioinformatic analyses (gene ontology, pathway, and co-expression network analysis) were used to further investigate these differentially expressed circRNAs. A total of 14,236 circRNAs were detected, of which 43 circRNAs (40 upregulated) were consistently altered at indicated time points during osteogenic differentiation of mADSCs. The exonic circRNAs represented a significantly larger proportion among the differentially expressed circRNAs compared to other types of circRNAs. Gene ontology and Kyoto Encyclopedia of Genes and Genomes biological pathway analysis were performed to evaluate the functions of differentially expressed circRNAs during the osteogenic process. Our circRNA-miRNA co-expression network showed that miR-338-3p was correlated with upregulation of two circRNAs (mmu_circRNA_013422, mmu_circRNA_22566). Our data on circRNA expression profiles may provide valuable insight into circRNA function during osteogenic differentiation of mADSCs. Additionally, the circRNA-miRNA-mRNA pathways may provide information on novel mechanisms and targets for clinical investigations on bone formation and regeneration. PMID- 29700559 TI - [Primary sclerosing cholangitis : Current diagnostics and treatment]. AB - Primary sclerosing cholangitis (PSC) is a chronic cholestatic liver disease of unknown etiology. Characteristic features are multifocal strictures and dilatations of the bile ducts. In 60-80 % of cases the PSC is strongly associated with chronic inflammatory bowel disease, mostly in the form of pancolitis. The diagnosis is established based on detection of typical cholangiographic lesions of the bile ducts and exclusion of secondary causes of sclerosing cholangitis. There is no approved medical treatment, but in Germany ursodeoxycholic acid is frequently used. Clinically relevant stenoses can be successfully treated by interventional endoscopy. Patients with PSC suffer from a greatly increased risk of hepatobiliary malignancies, especially with respect to cholangiocarcinoma and colorectal cancer and therefore require regular surveillance and screening. Liver transplantation is currently the only curative treatment option. PMID- 29700561 TI - Correction to: Epidemiology of diabetes and diabetic complications in China. AB - Unfortunately, the reference given in the legend to Fig. 2 was incorrect. The legend should have stated that Fig. 2 was drawn based on data from reference [49]. PMID- 29700560 TI - Greater fear of reinjury is related to stiffened jump-landing biomechanics and muscle activation in women after ACL reconstruction. AB - PURPOSE: Fear of reinjury is an important factor in determining who returns to sport following anterior cruciate ligament reconstruction (ACLR). Evidence from other musculoskeletal injuries indicates fear of reinjury may be related to stiffened movement patterns observed in individuals following ACLR. The relationship between fear of reinjury and performance on dynamic tasks, however, has not been investigated. Therefore, the purpose of this study was to investigate the relationship between fear of reinjury and jump-landing biomechanics. METHODS: Thirty-six females (height = 168.7 +/- 6.5 cm, body mass = 67.2 +/- 10.0 kg, age = 18.9 +/- 1.5 years) with a history of ACLR (time from surgery = 26.1 +/- 13.3 months) participated in the study. Each participant performed five trials of a standard jump-landing task. 3D motion capture and surface electromyography was used to record peak kinematics and lower extremity muscle activation on the injured limb during the jump landings. Spearman's rank correlations established the relationship between TSK-11 scores and each biomechanical variable of interest. RESULTS: There was a significant, negative relationship between fear of reinjury (TSK-11: 19.9 +/- 4.5) and knee (p = 0.006), hip (p = 0.003), and trunk flexion (p = 0.013). There was also a significant, positive relationship between hip adduction (p = 0.007), and gluteus maximus preparatory activation (p = 0.001). CONCLUSIONS: The results of this study indicate that higher fear of reinjury is associated with stiffened movement patterns that are associated with increased risk of a second ACL injury. Similar movement patterns have been observed in patients with low back pain. Clinicians should evaluate psychological and emotional consequences of injury in addition to the physical consequences as they appear to be related. LEVEL OF EVIDENCE: III. PMID- 29700564 TI - Gulliver's travels in the intensive care unit. PMID- 29700562 TI - Evaluation of anti-insulin receptor antibodies as potential novel therapies for human insulin receptoropathy using cell culture models. AB - AIMS/HYPOTHESIS: Bi-allelic loss-of-function mutations in the INSR gene (encoding the insulin receptor [INSR]) commonly cause extreme insulin resistance and early mortality. Therapeutic options are limited, but anti-INSR antibodies have been shown to activate two mutant receptors, S323L and F382V. This study evaluates four well-characterised murine anti-INSR monoclonal antibodies recognising distinct epitopes (83-7, 83-14, 18-44, 18-146) as surrogate agonists for potential targeted treatment of severe insulin resistance arising from insulin receptoropathies. METHODS: Ten naturally occurring mutant human INSRs with defects affecting different aspects of receptor function were modelled and assessed for response to insulin and anti-INSR antibodies. A novel 3T3-L1 adipocyte model of insulin receptoropathy was generated, permitting conditional knockdown of endogenous mouse Insr by lentiviral expression of species-specific short hairpin (sh)RNAs with simultaneous expression of human mutant INSR transgenes. RESULTS: All expressed mutant INSR bound to all antibodies tested. Eight mutants showed antibody-induced autophosphorylation, while co-treatment with antibody and insulin increased maximal phosphorylation compared with insulin alone. After knockdown of mouse Insr and expression of mutant INSR in 3T3-L1 adipocytes, two antibodies (83-7 and 83-14) activated signalling via protein kinase B (Akt) preferentially over signalling via extracellular signal-regulated kinase 1/2 (ERK1/2) for seven mutants. These antibodies stimulated glucose uptake via P193L, S323L, F382V and D707A mutant INSRs, with antibody response greater than insulin response for D707A. CONCLUSIONS/INTERPRETATION: Anti-INSR monoclonal antibodies can activate selected naturally occurring mutant human insulin receptors, bringing closer the prospect of novel therapy for severe insulin resistance caused by recessive mutations. PMID- 29700563 TI - What's new in cardiorenal syndrome? PMID- 29700565 TI - Peri-hippocampal developmental venous anomalies and memory loss: more than a normal variant? PMID- 29700566 TI - Microeconomic Benefit of Corneal Transplantation in a Developing Country via Public-Private Partnership Model. AB - BACKGROUND: We measured the microeconomic benefit, QOL, DALYs averted and clinical outcomes of corneal transplant surgery via a public-private partnership in Guyana. Corneas were obtained, ex gratia, from US eye banks, and the work was done at no cost to the patient or the Governments of USA or Guyana. METHODS: We obtained qualitative data using a "semi-structured interview technique" to question 60 recent recipients of corneal transplants in Guyana. Our questions covered schooling in children, training for job, and type and income of job, both before and after surgery. We also discussed improvement in family income and quality of life (QOL) using a Likert scale of 1 lowest to 5 highest. RESULTS: Our data came from five humanitarian missions from July 2014 to July 2017. All school going children (n = 6) were able to return to school and participate in educational activities. Young adults (n = 13), were able to acquire new jobs (50%) or training positions (50%) with higher income. Patients in the middle-age adult group (n = 20) re-acquired their employment positions (25%) or found new work (75%). Elderly patients (n = 21) after transplant were able to perform odd jobs to increase the family income. A consistent theme across all age groups was a dramatic improvement in the QOL. Two hundred and sixty DALYs (4.3 per patient) were averted. In this cohort of 62 surgery cases, mean preoperative visual acuity was 0.03 and postoperative mean visual acuity was 0.20. CONCLUSIONS: We have shown microeconomic benefits and improved QOL of corneal transplantation in a low income country. PMID- 29700567 TI - Risk Factors for Surgical Complications in Ventral Hernia Repair. AB - BACKGROUND: The aim of this study was to identify risk factors for an adverse event, i.e. early surgical complication, need for ICU care and readmission, following ventral hernia repair. Our hypothesis was that there is an association between an increased complication rate following ventral hernia repair and specific factors, including hernia size, BMI > 35, concomitant bowel surgery, ASA class, age, gender and method of hernia repair. METHODS: Data from a hernia database with prospectively entered data on 408 patients operated for ventral hernia between 2007 and 2014 at two Swedish university hospitals were analysed. A 3-month follow-up of complications, need for intensive care and readmission, was performed by reviewing the medical records. RESULTS: Eighty-one of 408 patients (20%) had a registered complication. Fifty-eight (14%) of these were classed as Clavien I-IIIa, and in 19 cases a Clavien IIIb-IV complication was reported. Large hernia size was associated with increased risk for early complication. A Kendall Tau test analysis revealed a proportional relationship between hernia size and modified Clavien outcome class (p < 0.001). Morbid obesity, ASA-class, method, hernia recurrence, age and concomitant bowel surgery were not statistically significant predictors of adverse events. CONCLUSIONS: Assessment of hernia aperture size is of great importance in the preoperative evaluation of ventral hernia patients to consider risk for post-operative complications. These results suggest a careful attitude when applying watchful waiting concepts and when postponing hernia surgery to achieve weight loss. A delaying attitude may result in increased risk of complications caused by increasing hernia size. PMID- 29700568 TI - Response to "Immune-mediated cholangitis: is it always nivolumab's fault?" PMID- 29700570 TI - [The new S3 guideline "Prevention of cervical carcinoma" : What is important for pathology?] AB - Of the numerous aspects involved in the diagnosis, treatment, and follow-up of cervical uterine precursor lesions, epidemiology, virology, cytology, human papillomavirus (HPV) testing, and diagnostic algorithms for equivocal and HPV positive findings are important for pathologists. Cytology will continue to be used as a preventive medical check-up in young women, while HPV-based screening is suggested for older women. HPV screening has yielded a significant reduction in cancer precursors and invasive cervical carcinoma in numerous studies. In contrast to the sensitivity, the specificity of the HPV test is inferior to that of cytology and the morphological biomarker p16/Ki-67, so that they are suitable as methods in the triage of HPV-positive findings. Cytological abnormalities and mildly dysplastic changes could be further clarified by an HPV test or the p16/Ki 67 test. The HPV test should also be used in the follow-up of patients after conization. PMID- 29700569 TI - Enzyme oxidation of plant galactomannans yielding biomaterials with novel properties and applications, including as delivery systems. AB - New biomaterials from renewable sources and the development of "functionalized biopolymers" are fields of growing industrial interest. Plant polysaccharides represent a valid alternative to traditional synthetic polymers, which are obtained from monomers of fossil, non-renewable origin. Several polysaccharides, either in their natural or chemically/biochemically modified forms, are currently employed in the biomedical, food and feed, and industrial fields, including packaging. Sustainable biochemical reactions, such as enzyme modifications of polysaccharides, open further possibilities for new product and process innovation. In the present review, we summarize the recent progress on enzyme oxidation of galactomannans (GM) from few leguminous plants (performed either with galactose oxidase or laccase) and we focus on the versatile and easily accessible laccase/TEMPO oxidative reaction. The latter causes a steep viscosity increase of GM water solutions and a transition of the gels from a viscous to an elastic form, due to formation of emiacetalic bonds and thus of internal cross linking of the polymers. Following lyophilization of these hydrogels, stable aerogels can be obtained, which were shown to have good potential as delivery systems (DS) of actives. The active molecules tested and herewith described are polymyxin B, an antibiotic; nisin, an antimicrobial peptide; the enzymes lysozyme, protease and lipase; the mixture of the industrial microbiocides 5 chloro-2-methyl-4-isothiazolin-3-one (CIT) and 2-methyl-4-isothiazolin-3-one (MIT). The advantages of such aerogel systems and the possibilities they open for future developments, including as DS, are described. PMID- 29700571 TI - Sleep disorders in children with brain tumors: a pilot study based on a sleep disorder questionnaire. AB - PURPOSE: The aim of this study is to compare the prevalence of sleep disorders (SD) between children treated for brain tumors and healthy children, and to define the type of SD. METHODS: A case-control study was performed from October 2014 to April 2015. Inclusion criteria were patients between 2 and 16 years with "cases" defined as children affected by central nervous system tumors at least 3 months after the end of treatment (surgery and/or radiotherapy and/or chemotherapy) at the time of evaluation and "controls" as healthy children. Children's sleep quality was assessed with a questionnaire administered to parents (Child's Sleep Habits Questionnaire, CSHQ). A total score greater than 41 is suggestive for the presence of disturbed sleep. The risk of SD was estimated by the odds ratio (OR) and their 95% confidence intervals (95% CI) through logistic regression models. RESULTS: Twenty-nine cases and 87 controls (in a 1:3 model) were enrolled, for a total of 116 subjects. The prevalence of SD resulted of 82.8% among cases and 64.4% in controls. A statistically significant difference between the two groups (OR 2.65; 95% CI 0.92-7.65) was not reached. Analyzing singular disturbances, parasomnias and night awakenings showed a statistically significant difference between the two groups (OR 4.32; 95% CI 1.08 17.34). CONCLUSIONS: Our study revealed a trend toward SD in children with brain tumor when compared to healthy population. Hovewer, analyzing specific subtypes of SD some significant differences were obtained. A significant difference was obtained only for specific subtypes of SD. Further investigations could better define the real burden of SD. PMID- 29700572 TI - Long-term effects of anatrophic nephrolithotomy on selective renal function. AB - To evaluate the long-term changes of selective renal function after anatrophic nephrolithotomy (ANL). A retrospective study was conducted for patients who underwent ANL between January 1995 and December 2016. Inclusion criteria were availability of preoperative and follow-up (1 year or more) radio-isotopic renal scans. Stone-free status was evaluated after 1 month with KUB and ultrasonography or NCCT. Renal isotope scans using 99mTc MAG3 were performed to measure the changes in selective function of the affected kidney (GFR%). Eligible patients were classified into two groups, group 1 patients with stable or improved function and group 2 patients with deteriorated function (> 5% decrease in GFR%). Univariate and multivariate analyses were performed to determine risk factors for deterioration of renal function. The cutoff value for any significant variable was determined using ROC curve. The study included 50 patients with mean age 43.8 + 13.9 years. Complications developed in 26 patients (52%), and stone-free status was documented in 42 patients (84%). After a median follow-up of 2.7 years (range 1-11), mean GFR% of all cases significantly decreased from preoperative value of 52.7% + SD 20 to 45.4% + SD 25% during follow-up (P < 0.001). Deterioration of GFR% was documented in 21 kidneys (42%). Cold ischemia time with a cutoff value 50 min was the independent risk factor (RR 3.986, 95% CI 1.069-14.869, P 0.039). The results of this study support limiting ANL to a selected group of patients and taking all the possible efforts to minimize cold ischemia time below 50 min. PMID- 29700573 TI - Gamma probe and ultrasound-guided fine needle aspiration cytology of the sentinel node (GULF) trial. AB - PURPOSE: Sentinel lymph node biopsy (SLNB) was introduced as a minimally invasive technique for nodal staging. Since associated morbidity is not negligible, it is highly relevant to pursue a more minimally invasive alternative. The purpose of this study was to prospectively evaluate the sensitivity of fine needle aspiration cytology (FNAC) with combined gamma probe and ultrasound (US) guidance in comparison with the gold standard histology of the sentinel node (SN) after SLNB for detecting metastasis. METHODS: The study was designed as a prospective, multicentre, open-label, single-arm trial enrolling patients with newly diagnosed cutaneous melanoma or breast cancer between May 2015 and August 2017. Sample radioactivity was measured using a Mini 900 scintillation monitor. After FNAC, all patients underwent SLNB. Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were estimated. RESULTS: Accrual was terminated early following an unplanned interim analysis indicating that a FNAC sensitivity of at least 80% could not be achieved. In total 58 patients of the originally planned 116 patients underwent FNAC with gamma probe and US guidance. There were no true-positive FNAC results, 14 false-negative results and one false positive result, and thus the sensitivity, specificity, PPV and NPV of FNAC were 0%, 98%, 0% and 75%, respectively. At least 75% of the FNAC samples had a radioactivity signal higher than the background signal. CONCLUSION: FNAC with gamma probe and US guidance is not able to correctly detect metastases in the SN and is therefore not able to replace SLNB. Gamma probe-guided US is a highly accurate method for correctly identifying the SN, which offers possibilities for future research. PMID- 29700574 TI - Serum brain-derived neurotrophic factor level and exercise tolerance complement each other in predicting the prognosis of patients with heart failure. AB - Brain-derived neurotropic factor (BDNF) is a myokine that plays a key role in regulating survival, growth, and maintenance of neurons. We investigated whether the serum BDNF level at discharge could predict the prognosis in patients with heart failure (HF). Furthermore, we aimed to examine the relationship between this myokine and exercise tolerance. We prospectively enrolled 94 patients who were hospitalized for worsening HF and had cardiac rehabilitation. At discharge, the serum BDNF level of all patients was measured using a commercial ELISA kit and they underwent a cardiopulmonary exercise test to measure peak oxygen uptake (peak VO2). Correlation was not observed between BDNF and peak VO2. Kaplan-Meier analysis demonstrated that cardiac death or rehospitalization owing to worsening HF was significantly higher in the low BDNF group (p = 0.023). The combination of peak VO2 and BDNF levels led to the identification of subgroups with significantly different probabilities of events (p = 0.005). In particular, in the low BDNF and low peak VO2 group, the frequency of rehospitalization within half a year after discharge was much higher than that in other groups. Multivariate analysis found BDNF as an independent factor of adverse events (hazard ratio 0.956; 95% confidence interval 0.911-0.999; p = 0.046). The serum BDNF level at discharge may be a useful biomarker of the prognosis in patients with HF. Furthermore, combining BDNF and peak VO2 may be useful for predicting early cardiac events. PMID- 29700575 TI - Comparison of tumor size assessments in tumor growth inhibition-overall survival models with second-line colorectal cancer data from the VELOUR study. AB - PURPOSE: To compare lesion-level and volumetric measures of tumor burden with sum of the longest dimensions (SLD) of target lesions on overall survival (OS) predictions using time-to-growth (TTG) as predictor. METHODS: Tumor burden and OS data from a phase 3 randomized study of second-line FOLFIRI +/- aflibercept in metastatic colorectal cancer were available for 918 patients out of 1216 treated (75%). A TGI model that estimates TTG was fit to the longitudinal tumor size data (nonlinear mixed effect modeling) to estimate TTG with: SLD, sum of the measured lesion volumes (SV), individual lesion diameters (ILD), or individual lesion volumes (ILV). A parametric OS model was built with TTG estimates and assessed for prediction of the hazard ratio (HR) for survival. RESULTS: Individual lesions had consistent dynamics within individuals. Between-lesion variability in rate constants was lower (typically < 27% CV) than inter-patient variability (typically > 50% CV). Estimates of TTG were consistent (around 12 weeks) across tumor size assessments. TTG was highly significant in a log-logistic parametric model of OS (median over 12 months). When individual lesions were considered, TTG of the fastest progressing lesions best predicted OS. TTG obtained from the lesion-level analyses were slightly better predictors of OS than estimates from the sums, with ILV marginally better than ILD. All models predicted VELOUR HR equally well and all predicted study success. CONCLUSION: This analysis revealed consistent TGI profiles across all tumor size assessments considered. TTG predicted VELOUR HR when based on any of the tumor size measures. PMID- 29700576 TI - Targeted overexpression of CRH receptor subtype 1 in central amygdala neurons: effect on alcohol-seeking behavior. AB - RATIONALE: The corticotropin-releasing hormone (CRH) system is a key mediator of stress-induced responses in alcohol-seeking behavior. Recent research has identified the central nucleus of the amygdala (CeA), a brain region involved in the regulation of fear and stress-induced responses that is especially rich in CRH-positive neurons, as a key player in mediating excessive alcohol seeking. However, detailed characterization of the specific influences that local neuronal populations exert in mediating alcohol responses is hampered by current limitations in pharmacological and immunohistochemical tools for targeting CRH receptor subtype 1 (CRHR1). OBJECTIVE: In this study, we investigated the effect of cell- and region-specific overexpression of CRHR1 in the CeA using a novel transgenic tool. METHODS: Co-expression of CRHR1 in calcium-calmodulin-dependent kinase II (alphaCaMKII) neurons of the amygdala was demonstrated by double immunohistochemistry using a Crhr1-GFP reporter mouse line. A Cre-inducible Crhr1 expressing adeno-associated virus (AAV) was site-specifically injected into the CeA of alphaCaMKII-CreERT2 transgenic rats to analyze the role of CRHR1 in alphaCaMKII neurons on alcohol self-administration and reinstatement behavior. RESULTS: Forty-eight percent of CRHR1-containing cells showed co-expression of alphaCaMKII in the CeA. AAV-mediated gene transfer in alphaCaMKII neurons induced a 24-fold increase of Crhr1 mRNA in the CeA which had no effect on locomotor activity, alcohol self-administration, or cue-induced reinstatement. However, rats overexpressing Crhr1 in the CeA increased responding in the stress-induced reinstatement task with yohimbine serving as a pharmacological stressor. CONCLUSION: We demonstrate that CRHR1 overexpression in CeA-alphaCaMKII neurons is sufficient to mediate increased vulnerability to stress-triggered relapse into alcohol seeking. PMID- 29700577 TI - Audiovisual integration in depth: multisensory binding and gain as a function of distance. AB - The integration of information across sensory modalities is dependent on the spatiotemporal characteristics of the stimuli that are paired. Despite large variation in the distance over which events occur in our environment, relatively little is known regarding how stimulus-observer distance affects multisensory integration. Prior work has suggested that exteroceptive stimuli are integrated over larger temporal intervals in near relative to far space, and that larger multisensory facilitations are evident in far relative to near space. Here, we sought to examine the interrelationship between these previously established distance-related features of multisensory processing. Participants performed an audiovisual simultaneity judgment and redundant target task in near and far space, while audiovisual stimuli were presented at a range of temporal delays (i.e., stimulus onset asynchronies). In line with the previous findings, temporal acuity was poorer in near relative to far space. Furthermore, reaction time to asynchronously presented audiovisual targets suggested a temporal window for fast detection-a range of stimuli asynchronies that was also larger in near as compared to far space. However, the range of reaction times over which multisensory response enhancement was observed was limited to a restricted range of relatively small (i.e., 150 ms) asynchronies, and did not differ significantly between near and far space. Furthermore, for synchronous presentations, these distance-related (i.e., near vs. far) modulations in temporal acuity and multisensory gain correlated negatively at an individual subject level. Thus, the findings support the conclusion that multisensory temporal binding and gain are asymmetrically modulated as a function of distance from the observer, and specifies that this relationship is specific for temporally synchronous audiovisual stimulus presentations. PMID- 29700578 TI - Specialised DNA polymerases in Escherichia coli: roles within multiple pathways. AB - In many bacterial species, DNA damage triggers the SOS response; a pathway that regulates the production of DNA repair and damage tolerance proteins, including error-prone DNA polymerases. These specialised polymerases are capable of bypassing lesions in the template DNA, a process known as translesion synthesis (TLS). Specificity for lesion types varies considerably between the different types of TLS polymerases. TLS polymerases are mainly described as working in the context of replisomes that are stalled at lesions or in lesion-containing gaps left behind the replisome. Recently, a series of single-molecule fluorescence microscopy studies have revealed that two TLS polymerases, pol IV and pol V, rarely colocalise with replisomes in Escherichia coli cells, suggesting that most TLS activity happens in a non-replisomal context. In this review, we re-visit the evidence for the involvement of TLS polymerases in other pathways. A series of genetic and biochemical studies indicates that TLS polymerases could participate in nucleotide excision repair, homologous recombination and transcription. In addition, oxidation of the nucleotide pool, which is known to be induced by multiple stressors, including many antibiotics, appears to favour TLS polymerase activity and thus increases mutation rates. Ultimately, participation of TLS polymerases within non-replisomal pathways may represent a major source of mutations in bacterial cells and calls for more extensive investigation. PMID- 29700579 TI - A Cdc42 homolog in Colletotrichum gloeosporioides regulates morphological development and is required for ROS-mediated plant infection. AB - The Rho GTPase Cdc42 is conserved in fungi and plays a key role in regulating polarity establishment, morphogenesis and differentiation. In this study, we identified an ortholog of Cdc42, CgCdc42, and functionally characterized it to determine the role of Cdc42 in the development and pathogenicity of Colletotrichum gloeosporioides, a causal agent of poplar anthracnose. Targeted deletion of CgCdc42 resulted in reduced vegetative growth and dramatic morphological defects, including the formation of elongated conidia and abnormally shaped appressoria. Moreover, CgCdc42 deletion mutants were less virulent on poplar leaves than were wild type. Appressoria formed by DeltaCgCdc42 mutants were morphologically abnormal and present in lower numbers on poplar leaves than were those formed by wild type. However, an ROS scavenging assay indicated that the DeltaCgCdc42 mutants maintained wild type pathogenicity in the absence of ROS despite having fewer appressoria than wild type, suggesting that the DeltaCgCdc42 mutants were deficient in their tolerance of ROS. Additionally, we also found that the distribution of ROS was different after the deletion of CgCdc42, the DeltaCgCdc42 mutants were hypersensitive to H2O2, and transcriptional analysis revealed that CgCdc42 is involved in the regulation of ROS-related genes. Furthermore, loss of CgCdc42 caused defects in cell wall integrity and an uneven distribution of chitin. These data collectively suggest that CgCdc42 plays an important role in the regulation of vegetative growth, morphological development, cell wall integrity and ROS-mediated plant infection in C. gloeosporioides. PMID- 29700580 TI - Temporal Variation of Phthalic Acid Esters (PAEs) in Ambient Atmosphere of Delhi. AB - Phthalic acid esters (PAEs) are a group of chemical species, ubiquitously present in the environment and pose a serious risk to humans. In the present study, the average concentrations of PAEs in PM10 (particulate matter <= 10 um) are reported at a densely populated site in Delhi. The average concentration of PAEs was reported to be 703.1 +/- 36.2 ng m-3 with slightly higher concentrations in winter than in summer; suggesting that sources are relatively stable over the whole year. The average concentration of PAEs was 35.7 +/- 30.5 ng m-3 in winter, 35.4 +/- 27.0 ng m-3 in summer, 3.4 +/- 1.5 ng m-3 in monsoon and 7.5 +/- 5.2 ng m-3 in post-monsoon. Principal component analysis was performed, which suggested that emissions were mainly due to plasticizers, cosmetics and personal care products, municipal solid waste, thermal power stations, industrial wastewater, cement plants and coke ovens. PMID- 29700581 TI - Toxicological Assessment of Heavy Metal Bioaccumulation and Oxidative Stress Biomarkers In Clarias gariepinus from Igbokoda River of South Western Nigeria. AB - This study evaluated the environmental safety of Igbokoda River, a popular fishing hub in an oil producing area in Nigeria. Biomarkers of oxidative stress and heavy metals were determined in the liver and muscle of Clarias gariepinus from Igbokoda River and also in fish samples from a clean fish farm (control). Water samples from both sites were analysed for physicochemical parameters, heavy metals and bacterial contamination. There was significant increase in the level of heavy metals in water samples and in the organs of fish from Igbokoda River. A significant increase in malondialdehyde level as well as alterations in antioxidant status was observed in the organs of fish samples from Igbokoda River compared with control. Coliforms and salmonella were also visible in Igbokoda River alongside particulate matter. These results show that Igbokoda River is polluted; consumption of aquatic organisms from the River may be unsafe for people in that community. PMID- 29700583 TI - The correlation of sagittal osteotomy inclination and the anteroposterior translation in medial open-wedge high tibial osteotomy-one of the causes affecting the patellofemoral joint? AB - PURPOSE: For opening-wedge high tibial osteotomy, previous studies have shown that most osteotomies were anterior-inclined. The purpose of this study was to determine the effect of sagittal osteotomy inclination on the anteroposterior translation of osteomized fragments and discuss its possible impact on the patellofemoral joint. METHODS: We retrospectively measured the angle between the joint line and the sagittal osteotomy line. We also evaluated the anteroposterior translation of osteomized fragments by measuring the distance from the most posterior point of the tibial plateau to the tibial tuberosity and the anterior cortical line. Correlation between the sagittal osteotomy inclination and the anteroposterior translation of fragments was analyzed. RESULTS: The mean sagittal osteotomy inclination was 6.3 +/- 8.4 degrees anteriorly to the joint line and 82% of osteotomies were anterior-inclined. The anteroposterior translation of the osteomized fragments was moderately correlated to the sagittal inclination. Anterior-inclined osteotomy tends to result in the anterior translation of the proximal fragment. CONCLUSION: High rates of anterior-inclined osteotomy have been described previously as well as in this study. Anterior-inclined osteotomy tends to result in the anterior translation of the proximal fragment. This may result in increased vertical vector force onto the patellofemoral joint, which further accelerates patellofemoral joint degeneration. Therefore, surgeons should attempt to perform parallel osteotomy or avoid anterior displacement of the proximal fragment if there is concern of anterior-inclined osteotomy. PMID- 29700582 TI - Delay of total hip arthroplasty to advanced stage worsens post-operative hip motion in patients with femoral head osteonecrosis. AB - PURPOSE: Osteonecrosis of the femoral head (ONFH) is commonly detected in young patients and most surgeons tend to delay total hip arthroplasty (THA) until the end stage of the disease. We hypothesised that post-operative range of motion (ROM) of the hip as well as baseline ROM at the time of surgery decreases with the disease progression. The purpose of this study was to determine whether patients, who were operated at an advanced stage, have pre- and post-operative hip ROM similar to ROM of patients, who were operated at earlier stages. METHODS: Eight hundred and fifty patients (850 hips) treated with THA for ONFH were classified according to pre-operative stages of Association Research Circulation Osseous (ARCO). Fifty-six patients were operated at stage 2, 458 at stage 3, and 336 at stage 4. Pre-operative and one year post-operative ROM was compared among the stages. RESULTS: Pre-operative sum of hip ROM decreased with the progression of ARCO stage (P < 0.001) and correlated with the post-operative sum of hip ROM (correlation coefficient 0.661). Although hip ROM improved after THA in all stages, post-operative ROM in patients with lower pre-operative ROM did not improve to the same level as in those with a higher pre-operative ROM (P < 0.001). CONCLUSIONS: The progression of ONFH negatively affected post-operative hip ROM as well as baseline hip ROM at the time of THA. Surgeons should consider a delay of THA negatively affects the hip ROM after the arthroplasty, when they determine the treatment modality for ONFH patients. PMID- 29700585 TI - Location of the femoral tunnel aperture during single-bundle posterior cruciate ligament reconstruction: outside-in versus inside-out techniques. AB - PURPOSE: Placement of the femoral tunnel is critical to graft function after posterior cruciate ligament (PCL) reconstruction. To date, however, the location of the femoral tunnel aperture has not been compared by in vivo 3-dimensional computed tomography (3D-CT) during PCL reconstruction with the outside-in (OI) and inside-out (IO) techniques. This study used 3D-CT analysis to compare the location of the femoral tunnel aperture in patients who underwent PCL reconstruction with the OI and IO techniques. METHODS: A total of 77 patients underwent single-bundle PCL reconstruction using the OI (n = 46) or IO (n = 31) technique. The location of the femoral tunnel aperture was assessed by 3D-CT and measured by the anatomic coordinate axis method to construct 3D surface models. RESULTS: The mean location of the femoral tunnel aperture in the low-to-high direction did not differ significantly in the OI and IO groups (75.0 vs. 75.2%, P = 0.869). However, in the deep-to-shallow direction, the femoral tunnel aperture was positioned more shallowly in the IO than in the OI group (75.7 vs. 81.1%, P < 0.001). CONCLUSION: The IO technique of single-bundle PCL reconstruction yielded a shallower femoral tunnel in the deep-to-shallow direction than did the OI technique. However, femoral tunnel location in the low-to-high direction was similar using the two techniques. PMID- 29700584 TI - MicroRNA-mediated interacting circuits predict hypoxia and inhibited osteogenesis of stem cells, and dysregulated angiogenesis are involved in osteonecrosis of the femoral head. AB - PURPOSE: MicroRNAs (miRNAs) are associated with various pathologic conditions and can serve as diagnostic or therapeutic biomarkers. This study tried to identify the differentially expressed miRNAs to predict the possible pathomechanisms involved in osteonecrosis of the femoral head (ONFH). METHODS: We compared the peripheral blood miRNAs in 46 patients with ONFH and 85 healthy controls by microarray and droplet digital polymerase chain reaction (ddPCR). Putative interacted networks between the differentially responded miRNAs were analyzed by web-based bioinformatics prediction tools. RESULTS: Microarray identified 51 differentially expressed miRNAs with at least twofold change (upregulation in 34 and downregulation in 17), and the results were validated by ddPCR using six selected miRNAs. Bioinformatics genetic network analysis focusing on the six miRNAs found the upregulated miR-18a and miR-19a are associated with angiogenesis after induction of ischemia; the upregulated miR-138-1 can inhibit osteogenic differentiation of mesenchymal stem cells; the most targeted genes, p53 and SERBP1, are associated with hypoxia and hypofibrinolysis. CONCLUSIONS: This study combined the miRNA analysis with the bioinformatics and predicts that hypoxia, inhibited osteogenesis of stem cells, and dysregulated angiogenesis might be orchestrated through the miRNA interacting circuits in the pathogenesis of ONFH. PMID- 29700586 TI - Current treatment and outcomes of traumatic sternal fractures-a systematic review. AB - PURPOSE: Traumatic sternal fractures are rare injuries. The most common mechanism of injury is direct blunt trauma to the anterior chest wall. Most (> 95%) sternal fractures are treated conservatively. Surgical fixation is indicated in case of fracture instability, displacement or non-union. However, limited research has been performed on treatment outcomes. This study aimed to provide an overview of the current treatment practices and outcomes of traumatic sternal fractures and dislocations. METHODS: A systematic review of literature published from 1990 to June 2017 was conducted. Original studies on traumatic sternal fractures, reporting sternal healing or sternal stability were included. Studies on non traumatic sternal fractures or not reporting sternal healing outcomes, as well as case reports (n = 1), were excluded. RESULTS: Sixteen studies were included in this review, which reported treatment outcomes for 191 patients. Most included studies were case series of poor quality. All patients showed sternal healing and 98% reported pain relief. Treatment complications occurred in 2% of patients. CONCLUSIONS: Treatment of traumatic sternal fractures and dislocations is an underexposed topic. Although all patients in this review displayed sternal healing, results should be interpreted with caution since most included studies were of poor quality. PMID- 29700588 TI - Comet-tail artifact in adenomyomatosis. PMID- 29700587 TI - Bone combined cement grafting in giant cell tumor around the knee reduces mechanical failure. AB - OBJECTIVES: The aims of our study are (1) to explore the risk factors of mechanical failure (MF), (2) to figure out an index to evaluate this risk, and (3) to select an optimal reconstruction strategy to reduce this risk. METHODS: We retrospectively reviewed 104 patients from Dec. 2008 to Mar. 2016, undergone extensive knee curettages in our institution. Radiographs and post-operative interviews were used to classified cases of MF. Relative factors (age, tumor location, the invaded area, etc.) were also collected and analyzed by SPSS software. RESULTS: Thick subchondral bony layer (p = 0.006) and combined grafting of the cement and bone (p = 0.006) had lower risk of mechanical failure. Mechanical failure appeared to happen in the femur (p = 0.012) more easily. The ROC curve (AUC = 0.722) reveals that less post-operative bony layer (<= 3.3 mm) is more likely to cause mechanical failure. The Kaplan-Meier survival curve showing increased survival in those patients after a combination grafting surgery (HR, 3.799; p = 0.006). CONCLUSION: Based on our study results, combined grafting of the cement and bone reduced the risk of mechanical failure in the knee due to the thin subchondral bone layer (SCB), especially in the femur. PMID- 29700589 TI - Gut signature sign in enteric duplication cysts. PMID- 29700590 TI - Precision analysis of a quantitative CT liver surface nodularity score. AB - PURPOSE: To evaluate precision of a software-based liver surface nodularity (LSN) score derived from CT images. METHODS: An anthropomorphic CT phantom was constructed with simulated liver containing smooth and nodular segments at the surface and simulated visceral and subcutaneous fat components. The phantom was scanned multiple times on a single CT scanner with adjustment of image acquisition and reconstruction parameters (N = 34) and on 22 different CT scanners from 4 manufacturers at 12 imaging centers. LSN scores were obtained using a software-based method. Repeatability and reproducibility were evaluated by intraclass correlation (ICC) and coefficient of variation. Using abdominal CT images from 68 patients with various stages of chronic liver disease, inter observer agreement and test-retest repeatability among 12 readers assessing LSN by software- vs. visual-based scoring methods were evaluated by ICC. RESULTS: There was excellent repeatability of LSN scores (ICC:0.79-0.99) using the CT phantom and routine image acquisition and reconstruction parameters (kVp 100-140, mA 200-400, and auto-mA, section thickness 1.25-5.0 mm, field of view 35-50 cm, and smooth or standard kernels). There was excellent reproducibility (smooth ICC: 0.97; 95% CI 0.95, 0.99; CV: 7%; nodular ICC: 0.94; 95% CI 0.89, 0.97; CV: 8%) for LSN scores derived from CT images from 22 different scanners. Inter-observer agreement for the software-based LSN scoring method was excellent (ICC: 0.84; 95% CI 0.79, 0.88; CV: 28%) vs. good for the visual-based method (ICC: 0.61; 95% CI 0.51, 0.69; CV: 43%). Test-retest repeatability for the software-based LSN scoring method was excellent (ICC: 0.82; 95% CI 0.79, 0.84; CV: 12%). CONCLUSION: The software-based LSN score is a quantitative CT imaging biomarker with excellent repeatability, reproducibility, inter-observer agreement, and test retest repeatability. PMID- 29700591 TI - The role of MR imaging in the assessment of renal allograft vasculature. AB - Renal allograft dysfunction after transplantation is a relatively common occurrence with various potential etiologies. Vascular etiologies are of particular importance as early surgical or minimally invasive intervention can, in some cases, salvage the graft. Diagnosis of vascular pathology resulting in allograft dysfunction requires a thorough workup, of which imaging is a key component. Generally, ultrasound is the first-line imaging modality. More recently, MRI has been shown to be an effective and safe modality for diagnosis of vascular pathology after renal transplantation, particularly for diagnosis of transplant renal artery stenosis. This review will summarize imaging modalities that are most commonly used in evaluating vascular pathology after renal transplantation, with a focus on the various contrast- and non-contrast-enhanced MR techniques described in the literature and used at our institution. Of particular interest is the relatively recent utilization of the non-gadolinium containing iron-based contrast agent, ferumoxytol, in time-resolved contrast enhanced MR angiography. PMID- 29700592 TI - Three-dimensional CT enterography versus barium follow-through examination in measurement of remnant small intestinal length in short bowel syndrome patients. AB - PURPOSE: To evaluate the feasibility and accuracy of remnant small intestinal length measured by barium follow-through (BaFT) examination and three-dimensional CT enterography (CTe). MATERIALS AND METHODS: Twenty-nine consecutive short bowel syndrome patients (SBS) who underwent BaFT, CTe, and prior surgical measurements of small intestine were included. Measurements of total remnant small intestinal length on BaFT and CTe were compared to surgical measurements using Spearman's rank correlation coefficients, Bland-Altman plots, and paired t test. RESULTS: The average remnant intestinal length was 73.1 +/- 37.2 cm according to surgical measurement. There was a significant positive correlation between CTe and surgical measurement (r2 = 0.99; p < 0.0001), and a relatively weaker correlation between BaFT and surgical measurement (r2 = 0.71; p < 0.001). Compared with surgical measurement, the percentage differences of CTe and BaFT were 5.71 +/- 6.71% and 27.14 +/- 18.41% (mean +/- SD), respectively. Furthermore, Bland-Altman plots showed good agreement between CTe and surgical measurement, whereas relatively poor agreement between BaFT and surgical measurement. However, significant difference was found among the three measurement methods by paired t test (p < 0.0001). CONCLUSIONS: Assessment of remnant small intestinal length by CTe is accurate and acceptable for clinical application, whereas BaFT is less accurate although BaFT is more convenient and cheaper for clinical application. And CTe can provide a cost-effective and noninvasive determination of remnant small intestinal length in planning surgical and nutritional intervention in SBS patients. PMID- 29700593 TI - Neurovascular and tendon injuries due to ankle arthroscopy portals: a meta analysis of interventional cadaveric studies. AB - Neurovascular and tendon structures are considered at risk when performing ankle arthroscopy. Injury rate and distance from portals to such structures varied in the literature. The aim of this meta-analysis is to evaluate the injury risk of these structures in terms of proximity and injury prevalence. Thirteen studies including 184 cadaveric ankle arthroscopy procedures met the inclusion criteria. The antero-central portal exhibited the highest frequencies of nerve/vessel proximity and nerve/vessel missed injuries. Weighted mean distances were as follows: 2.76 +/- 2.37 mm for the superficial fibular nerve (SFN) to the antero lateral portal, 8.13 +/- 2.45 mm for the saphenous nerve to the antero-medial portal, 2.1 +/- 1.7 mm for the dorsalis pedis artery (DPA) to the antero-central (AC) portal, 6.84 +/- 2.59 mm for the sural nerve to the postero-lateral portal. Distances to the postero-medial portal were 7.82 +/- 2.98 and 11.03 +/- 3.2 mm for the posterior tibial nerve and the posterior tibial artery, respectively. A total of 14 (10.3%) nerve injuries and 17 (12.5%) missed nerve injuries with a cumulative frequency of 22.8% of nerve structure at high risk. The SFN was the most vulnerable (10.3% of injury/missed injury), and it was the closest nerve to a portal. Vascular involvement consisted of 2 (1.5%) injuries and 12 (8.8%) missed injuries with the DPA being the most vulnerable (20%) through the AC portal. Tendon injuries were found in 8.7% procedure acts. The injury rates of extra-articular structures were found to be higher than previously reported in clinical literature. Apart from clinical studies, distance to portals and missed injuries of these structures could be evaluated. This cadaveric meta-analysis yielded more accurate results over the proximity and potential injury risk of ankle noble structure and should incite surgeons for more attention during portal placement. Such anatomical meta-analyses could offer an excellent statistical model of evidence synthesis when assessing injury risk in mini-invasive surgeries. PMID- 29700594 TI - Spatial orientation of the adult cochlea: rotation, tilt, and angle theta 3. AB - OBJECTIVE: Quantitative description in adult crania of (1) angular orientation of the basal turn of the cochlea relative to the sagittal (termed "rotation") and Frankfort horizontal (termed "tilt") planes, and angle theta 3 [angular relationship of the line defined by the cochlea's spiral center and cochlear (round) window, to the cochlear window]; (2) orientation of the cochlea relative to the plane defined by the horizontal and vertical portions of the facial nerve; (3) orientation of the basal turn of the cochlea relative to the plane of the posterior semicircular canal; and (4) the association of these orientations with the extent of mastoid pneumatization. METHODS: Postmortem material analysis. From 41 bequeathed anatomical ear-normal cadaveric cranial, high-resolution CT scans were performed of the five crania with the largest and the five with the smallest mastoids. Eleven points in three-dimensional Cartesian space were appointed and studied with the software program FIJI. RESULTS: The median angle values (and ranges) for right ears were: "rotation" 52 degrees (range 47-61); and, "tilt" 84 degrees (79-89). The planes of the cochlear basal turn and facial nerve approximated superimposition: median 15 degrees (2-19). Angle theta 3 for right ears was median 40 degrees (28-44). Bilateral symmetry was found for the relationships between the planes. However, no association of any planar relationship with mastoid pneumatization was suggested. CONCLUSION: Considering the range of angles found in clinically normal adult specimens, spatial orientation of the cochlea may explain some of the difficulties in implantation. PMID- 29700595 TI - Ultrasonographic reference values for the median nerve at the level of pronator teres muscle. AB - PURPOSE: The purpose of this study was to investigate the ultrasonographic reference values for diameters and cross-sectional area (CSA) of the median nerve between the two heads of the pronator teres muscle in healthy population as well as to correlate the findings with height, weight, sex and age. METHODS: Fifty five healthy Caucasian volunteers (110 median nerves) were included in this study. The reference range (mean +/- 2 standard deviations; 2.5th-97.5th quintiles) and the upper limit of side-to-side difference of the median nerve between the two heads of the pronator teres muscle were investigated using high frequency ultrasound. The effects of age, sex, height, handedness, and body mass index (BMI) were examined. RESULTS: The mean age was 39.4 +/- 10.6 years (range 18-75 years). The mean +/- 2SD of the median CSA was 4.9-12.9 mm2. The upper limit of normal side-to-side difference was 3.0 mm2. The differences between genders and between the dominant and non-dominant hands were not significant. The mean antero-posterior and transverse diameters were 7.2 +/- 1.5 and 10.7 +/- 2.4 mm, respectively. Significant correlations were observed between the dominant side CSA and BMI (r = 0.33; p = 0.01) and age (r = 0.31; p = 0.02). The correlation between the CSA and height (r = 0.19; p = 0.16) was not significant. CONCLUSIONS: The measurements obtained in this study are of importance for examining median nerve entrapments in the forearm using high-frequency ultrasound. Age and BMI showed to be correlated with median nerve CSA; while gender and height were not. PMID- 29700596 TI - Modeling and analysis of a new locomotion control neural networks. AB - Experimental data have shown that inherent bursting of the neuron plays an important role in the generation of rhythmic movements in spinal networks. Based on the mechanism that the spinal neurons of a lamprey generate this inherent bursting, this paper builds a simplified inherent bursting neuron model. A new locomotion control neural network is built that takes advantage of this neuron model and its performance is analyzed mathematically and by numerical simulation. From these analyses, it is found that the new control networks have no restriction on their topological structure for generating the oscillatory outputs. If a network is used to control the motion of bionic robots or build the model of the vertebrate spinal circuitry, its topological structure can be constructed using the unit burst generator model proposed by Grillner. The networks can also be easily switched between oscillatory and non-oscillatory output. Additionally, inactivity and saturation properties of the new networks can also be developed, which will be helpful to increase the motor flexibility and environmental adaptability of bionic robots. PMID- 29700597 TI - Cerebrospinal fluid neurogranin concentration in neurodegeneration: relation to clinical phenotypes and neuropathology. AB - Neurogranin (Ng) is a post-synaptic protein that previously has been shown to be a biomarker for synaptic function when measured in cerebrospinal fluid (CSF). The CSF concentration of Ng is increased in Alzheimer's disease dementia (ADD), and even in the pre-dementia stage. In this prospective study, we used an enzyme linked immunosorbent assay that quantifies Ng in CSF to test the performance of Ng as a marker of synaptic function. In 915 patients, CSF Ng was evaluated across several different neurodegenerative diseases. Of these 915 patients, 116 had a neuropathologically confirmed definitive diagnosis and the relation between CSF Ng and topographical distribution of different pathologies in the brain was evaluated. CSF Ng was specifically increased in ADD compared to eight other neurodegenerative diseases, including Parkinson's disease (p < 0.0001), frontotemporal dementia (p < 0.0001), and amyotrophic lateral sclerosis (p = 0.0002). Similar results were obtained in neuropathologically confirmed cases. Using a biomarker index to evaluate whether CSF Ng contributed diagnostic information to the core AD CSF biomarkers (amyloid beta (Abeta), t-tau, and p tau), we show that Ng significantly increased the discrimination between AD and several other disorders. Higher CSF Ng levels were positively associated with greater Abeta neuritic plaque (Consortium to Establish a Registry for Alzheimer's Disease (CERAD) neuritic plaque score, p = 0.0002) and tau tangle pathology (Braak neurofibrillary tangles staging, p = 0.0007) scores. In the hippocampus and amygdala, two brain regions heavily affected in ADD with high expression of Ng, CSF Ng was associated with plaque (p = 0.0006 and p < 0.0001), but not with tangle, alpha-synuclein, or TAR DNA-binding protein 43 loads. These data support that CSF Ng is increased specifically in ADD, that high CSF Ng concentrations likely reflect synaptic dysfunction and that CSF Ng is associated with beta amyloid plaque pathology. PMID- 29700600 TI - Fetal overgrowth in pregnancies complicated by diabetes: development of a clinical prediction index. AB - PURPOSE: To develop an index to predict fetal overgrowth in pregnancies complicated by diabetes. METHODS: Data were derived from a cohort of 275 women with singleton gestations in a collaborative diabetes in pregnancy program. Regression analysis incorporated clinical factors available in the first 20-30 weeks of pregnancy that were assigned beta-coefficient-based weights, the sum of which yielded a fetal overgrowth index (composite score). RESULTS: Fifty-one (18.5%) pregnancies were complicated by fetal overgrowth. The derived index included five clinical factors: age <= 30, history of macrosomia, excessive gestational weight gain, enlarged fetal abdominal circumference, and fasting hyperglycemia. Area under the curve (AUC) for the index is 0.88 [95% confidence interval (CI) 0.82-0.92]. Cut-points were selected to identify "high-risk" and "low-risk" ranges (>= 8 and <= 3) that have positive and negative predictive values of 84% (95% CI 70-98%) and 95% (95% CI 92-98%), respectively. The majority of women in our cohort (n = 182, 66%) had a "low-risk" index while 9% (n = 25) had a "high-risk" index. Sub-analyses of nulliparous women and women with gestational and pre-gestational diabetes revealed that the overgrowth index was equally or more predictive when applied separately to each of these groups. CONCLUSION: This fetal overgrowth index that incorporates five clinical factors provides a means of predicting fetal overgrowth and thereby serves as a tool for targeting the allocation of healthcare resources and treatment individualization. PMID- 29700598 TI - Mammalian cold TRP channels: impact on thermoregulation and energy homeostasis. AB - Body temperature regulation is a fundamental homeostatic function in homeothermic animals. It is governed by the central nervous system that integrates temperature signals from internal body structures and the skin and provides efferent responses to adjust heat-exchange rates with the environment. Thermoregulation has a major influence on energy balance by regulating food intake as well as heat production and energy expenditure. Surprisingly, although almost 50% of our energy expenditure is dedicated to maintaining homeothermy, very little is yet known about the molecular aspects and the neural wiring involved in the intimate interrelationship between these two critical homeostatic systems. Some non selective cation channels of the transient receptor potential (TRP) family work as molecular thermal sensors in sensory neurons and other cells. In this review, we discuss recent advances in our understanding of the basic mechanisms responsible for thermoregulation in the cold. We have focused our attention on the role of two cold-activated TRP channels (transient receptor potential melastatin 8 and transient receptor potential ankyrin 1) in body temperature regulation as well as their impact on energy balance and metabolism. A better understanding of the mechanisms coupling thermoregulation to energy homeostasis, including the involvement of thermosensitive TRPs, may uncover additional mechanisms underlying the pathogenesis of obesity and its metabolic consequences in humans, opening new strategies for the diagnosis, treatment, and prevention of this disease. PMID- 29700601 TI - Attitude towards ovarian tissue and oocyte cryopreservation for non-medical reasons: a cross-sectional study. AB - PURPOSE: To assess the attitude towards ovarian tissue and oocyte cryopreservation for non-medical reasons. METHODS: Cross-sectional electronic survey in 248 Swiss women aged 15-35 years, nationally representative for educational level. RESULTS: Most women did not worry about an age-related fertility decline. Two-thirds of women would consider using hormone therapy (HT) for menopausal symptom relief although concerns about side effects and risks were still high. Acceptance of cryopreservation of oocytes (19%) or ovarian tissue (13%) for postponing fertility or menopause was generally low, but increased (37%) if both goals could be achieved with one surgery. Cryopreservation of ovarian tissue for postponing menopause was acceptable for 22% of women. Not having a suitable partner until age 35 increased the likelihood of considering postponing fertility by cryopreservation (p < 0.001) and had a stronger impact on that decision than the factor "pursuing a career" (p < 0.001). CONCLUSION: More education on age-related fertility decline, menopause and HT (benefit-risk ratio) is needed. Furthermore, the political and socioeconomic discussion should focus on women's needs, especially on compatibility of career and family. PMID- 29700599 TI - Pilot study on probe-based confocal laser endomicroscopy for colorectal neoplasms: an initial experience in Japan. AB - BACKGROUND: The aim of this pilot study is to investigate the diagnostic yield of probe-based confocal laser endomicroscopy (pCLE) in the evaluation of depth of invasion in colorectal lesions. METHODS: Patients with colorectal lesions eligible for either endoscopic treatment or surgery were enrolled in the study. Tumor's depth of invasion was classified as mucosal or slight submucosal (M-SM1) and deep submucosal invasion or deeper (SM2 or deeper). White light endoscopy (WLE), magnifying narrow band imaging (M-NBI), and magnifying chromoendoscopy (M CE) were used to assess colorectal lesions, and pCLE was used to identify tumor's features related to SM2 or deeper. The diagnostic classification of depth of invasion was obtained by correlating pCLE findings with histology results (on site diagnosis). All colorectal lesions were stratified by a second endoscopist who was blinded to any clinical and histological information with the use of WLE, M-NBI, M-CE, and pCLE (off-line review). RESULTS: A total of 22 colorectal lesions were analyzed: seven were adenoma, ten intramucosal cancer, and five SM2 or deeper cancer. With respect to pCLE findings, loss of crypt structure was seen in all SM2 or deeper cancers and only in one M-SM1 lesion. Sensitivity, specificity, and accuracy of WLE, M-NBI, and M-CE in off-line review were 60/94/86, 60/94/86, and 80/94/91%, respectively. Sensitivity/specificity/accuracy of pCLE in off-line review were 80/94/91%, respectively. The inter-observer agreement of pCLE between on-site diagnosis and off-line review was 0.64 (95%CI 0.27-1.0). CONCLUSIONS: pCLE may represent a useful tool to evaluate the depth of invasion in colorectal lesions. PMID- 29700603 TI - Gamarada debralockiae gen. nov. sp. nov.-the genome of the most widespread Australian ericoid mycorrhizal fungus. AB - This study describes a novel ericoid mycorrhizal fungus (ErMF), Gamarada debralockiae Midgley and Tran-Dinh gen. nov. sp. nov. Additionally, catabolism was explored from a genomic perspective. The nuclear and mitochondrial genomes of G. debralockiae were sequenced. Morphological characteristics were assessed on various media. Catabolic genes of G. debralockiae were explored using SignalP and dbCAN. Phylogenetic comparisons were undertaken using Phylogeny.fr. The 58.5-Mbp draft genome of G. debralockiae contained 17,075 putative genes. The complete mitochondrial genome was 28,168 bp in length. In culture, G. debralockiae produces slow-growing non-sporulating colonies. Gamarada debralockiae has many putative secreted catabolic enzymes. Phylogeny indicated G. debralockiae was distinct from known ascomycetous ErMF: Pezoloma ericae, Meliniomyces spp., Oidiodendron spp., and Cairneyella variabilis. It is closely related to many undescribed plant root-associated fungi and its nearest described relative is Hyphodiscus brevicollaris. Gamarada debralockiae has been recovered from virtually all Australian ericoid mycorrhizal studies and biogeographic data suggests the taxon is widespread in Australia. Gamarada debralockiae has similar catabolic potential to C. variabilis and co-occurs with C. variabilis at Australian sites. Plants that host multiple ErMF may benefit from subtle differences in catabolism that improve access to nitrogen and phosphorus from within recalcitrant organic matter. PMID- 29700604 TI - Fragility fractures of the sacrum occur in elderly patients with severe loss of sacral bone mass. AB - INTRODUCTION: Patients suffering from osteoporosis-associated fragility fractures of the sacrum (FFS; also termed sacral insufficiency fractures) are increasingly observed. They have typical fracture patterns with fracture lines located in the sacral ala. When treating these patients operatively, iliosacral screw loosening is not uncommon. We aimed to study the sacral bone mass in patients presenting with a FFS using 3D statistical models. MATERIALS AND METHODS: 3D models of averaged Hounsfield units (HU) were generated based on CT scans from 13 patients with a unilateral FFS (mean age 79.6 years; 11 females, 2 males). The control group without fractures consisted of 28 males and 32 females (mean age of 68.3 years). A virtual bone probe along the trans-sacral corridors S1 and S2 was taken. RESULTS: The bone mass distribution in the fractured sacra was similar to the control group, however, with overall lower HU. Large zones of negative HU were located in the sacral ala. In the fractured sacra, the HU in the sacral ala was significantly lower on the non-injured side when comparing to the fractured side (p < 0.001) as well as compared to the non-fractured group (p < 0.001). Low bone mass was observed in sacral body S1 (40 HU) and S2 (20 HU). CONCLUSIONS: The extensive area of negative HU may explain the fracture location in the sacral ala. The low HU in the sacral bodies advocates the use of trans-sacral implants or augmented iliosacral screws to enhance the strength of fracture fixation. The increased HU in the fractured ala could be explained by fracture-asssociated hemorrhage and can be used as a diagnostic tool. PMID- 29700605 TI - Blind method regarding the effect of dexmedetomidine on CRBD. PMID- 29700602 TI - Influence of sphingosine-1-phosphate signaling on HCMV replication in human embryonal lung fibroblasts. AB - The human cytomegalovirus (HCMV) is a common pathogen, which causes severe or even deadly diseases in immunocompromised patients. In addition, congenital HCMV infection represents a major health concern affecting especially the lung tissue of the susceptible individuals. Antivirals are a useful strategy to treat HCMV caused diseases. However, all approved drugs target viral proteins but significant toxicity and an increasing resistance against these compounds have been observed. In infected cells, numerous host molecules have been identified to play important roles during HCMV replication. Among others, HCMV infection depends on the presence of bioactive sphingolipids. In this study, the role of sphingosine-1-phosphate (S1P) signaling in HCMV-infected human embryonal lung fibroblasts (HELF) was analyzed. Viral replication depended on the functional activity of sphingosine kinases (SK). During SK inhibition, addition of extracellular S1P restored HCMV replication. Moreover, neutralization of extracellular S1P by anti-S1P antibodies decreased HCMV replication as well. While the application of FTY720 as an functional antagonist of S1P receptor (S1PR)1,3-5 signaling did not reduce HCMV replication significantly, JTE-013, an inhibitor of S1PR2, decreased viral replication. Furthermore, inhibition of Rac-1 activity reduced HCMV replication, whereas inhibition of the Rac-1 effector protein Rac-1-activated kinase 1 (PAK1) had no influence. In general, targeting S1P-induced pathways, which are essential for a successful HCMV replication, may represent a valuable strategy to develop new antiviral drugs. PMID- 29700606 TI - Correction to: Assessing size of pituitary adenomas: a comparison of qualitative and quantitative methods on MR. AB - We have incorrectly described the ellipsoid equation as being calculated using maximal diameters. It is in fact calculated using half the maximal diameter, i.e. the maximal radii. The diameter is initially recorded on the MRI images (as per Fig. 1), as the lesions do not have a defined midpoint. PMID- 29700607 TI - Cerebrovascular inflammation is associated with tau pathology in Guam parkinsonism dementia. AB - Parkinsonism-dementia complex of Guam (Guam PDC) is a neurodegenerative disease with parkinsonism and early onset Alzheimer-like dementia. Guam PDC belongs to the family of neurodegenerative disorders, known as tauopathies, which are histopathologically characterized by abnormal deposition of microtubule associated protein tau. While changes in the blood-brain barrier (BBB) in Alzheimer's disease are increasingly recognized, dysfunction of BBB in Guam PDC has not been extensively studied. In this study, we characterized cerebrovascular changes in the patients with Guam PDC. The brain tissue from ten post-mortem Guam PDC patients and six non-demented controls were assessed for structural and functional changes in BBB. Entorhinal cortex sections were immunostained for the markers of brain endothelial cells (claudin-5, occludin, and collagen IV) and inflammation (VCAM-1, ICAM-1, P-Selectin, and E-Selectin). The ultrastructure of brain capillaries was investigated by confocal microscopy and morphological changes and intensity alterations were evaluated. We found a significant decrease of tight junction proteins and the upregulation of adhesion molecules that correlated with the presence of neurofibrillary tangles. In addition, we showed the presence of CD3+-positive cells in the brain areas affected by pathological lesions. Our findings indicate that pathological lesions in Guam PDC are associated with inflammatory changes of brain capillaries and could mediate transmigration of cells to the brain parenchyma. PMID- 29700609 TI - Potential of Cationic Liposomes as Adjuvants/Delivery Systems for Tuberculosis Subunit Vaccines. AB - The weakness of the BCG vaccine and its highly variable protective efficacy in controlling tuberculosis (TB) in different age groups as well as in different geographic areas has led to intense efforts towards the development and design of novel vaccines. Currently, there are several strategies to develop novel TB vaccines. Each strategy has its advantages and disadvantages. However, the most important of these strategies is the development of subunit vaccines. In recent years, the use of cationic liposome-based vaccines has been considered due to their capacity to elicit strong humoral and cellular immune responses against TB infections. In this review, we aim to evaluate the potential for cationic liposomes to be used as adjuvants/delivery systems for eliciting immune responses against TB subunit vaccines. The present review shows that cationic liposomes have extensive applications either as adjuvants or delivery systems, to promote immune responses against Mycobacterium tuberculosis (Mtb) subunit vaccines. To overcome several limitations of these particles, they were used in combination with other immunostimulatory factors such as TDB, MPL, TDM, and Poly I:C. Cationic liposomes can provide long-term storage of subunit TB vaccines at the injection site, confer strong electrostatic interactions with APCs, potentiate both humoral and cellular (CD4 and CD8) immune responses, and induce a strong memory response by the immune system. Therefore, cationic liposomes can increase the potential of different TB subunit vaccines by serving as adjuvants/delivery systems. These properties suggest the use of cationic liposomes to produce an efficient vaccine against TB infections. PMID- 29700608 TI - Person-related factors associated with work participation in employees with health problems: a systematic review. AB - PURPOSE: The objective of this systematic review was to explore and provide systematically assessed information about the association between person-related factors and work participation of people with health problems. The research question was: what is the association between selected person-related factors and work participation of workers with health problems? METHODS: A systematic review was carried out in PubMed and PsycINFO to search for original papers published between January 2007 and February 2017. The risk of bias of the studies included was assessed using quality assessment tools from the Joanna Briggs Institute. The quality of evidence was assessed using the GRADE framework for prognostic studies. RESULTS: In total, 113 studies were included, all of which addressed the association between person-related factors and work participation. The factors positively associated with work participation were positive expectations regarding recovery or return to work, optimism, self-efficacy, motivation, feelings of control, and perceived health. The factors negatively associated with work participation were fear-avoidance beliefs, perceived work-relatedness of the health problem, and catastrophizing. Different coping strategies had a negative or a positive relationship with work participation. CONCLUSIONS: The results of this review provide more insight into the associations between different cognitions and perceptions and work participation. The results of this study suggest that person-related factors should be considered by occupational- and insurance physicians when they diagnose, evaluate or provide treatment to employees. Further research is required to determine how these physicians could obtain and apply such information and whether its application leads to a better quality of care. PMID- 29700610 TI - Methylboronic acid fertilization alleviates boron deficiency symptoms in Arabidopsis thaliana. AB - MAIN CONCLUSION: Our results showed that methylboronic acid is capable of alleviating boron deficiency, enhancing plant growth, and is less toxic than boric acid at higher concentrations. Boron is an essential plant micronutrient and its deficiency occurs in several regions globally, resulting in impaired plant growth. Boron fertilization is a common agricultural practice, but the action range of boron is narrow, sharply transitioning from deficiency to toxicity. Boric acid (BA) is the most common chemical form used in agriculture. In this work, we describe that methylboronic acid (MBA) is capable of alleviating boron deficiency in Arabidopsis. MBA is a boronic acid, but does not naturally occur in soils, necessitating synthesis. Other boronic acids have been described as boron competitors in plants, inhibiting auxin biosynthesis and root development. MBA is more water-soluble than BA and delivers the same amount of boron per molecule. We observed that Arabidopsis seedlings grown in the presence of MBA presented higher numbers of lateral roots and greater main root length compared to plants grown in BA. In addition, root hair length and leaf surface area were increased using MBA as a boron fertilizer. Finally, MBA was less toxic than BA at high concentrations, producing a slight reduction in the main root length but no decrease in total chlorophyll. Our results open a new opportunity to explore the use of a synthetic form of boron in agriculture, providing a tool for future research for plant nutrition. PMID- 29700612 TI - Pigmented villonodular synovitis managed by total synovectomy and cementless total hip arthroplasty. AB - BACKGROUND: Pigmented villonodular synovitis or PVNS is a benign proliferating disease of the synovium; it behaves much as a neoplastic process does. METHODS: This retrospective clinical study included 11 consecutive cases who underwent for total synovectomy combined with cementless total hip arthroplasty of PVNS of the hip joint. RESULTS: The mean patient preoperative hip score of Harris was 46.1 points (range 30-70 points) improved to 94.3 points (range 90-100 points) at the last follow-up visits. No clinical or radiological evidence of recurrent PVNS or osteolysis or loosening had been detected in our patients. CONCLUSION: Total synovectomy combined with total arthroplasty (THA) could be considered as the ideal treatment in the case of pigmented villonodular synovitis with major osteoarticular destruction and provided good results, as reported in the current series. LEVEL OF EVIDENCE: IV, case series. PMID- 29700611 TI - A member of cation diffusion facilitator family, MTP11, is required for manganese tolerance and high fertility in rice. AB - MAIN CONCLUSION: Rice MTP11 is the trans-Golgi-localized transporter that is involved in Mn tolerance with MTP8.1, and it is required for normal fertility. Rice (Oryza sativa L.) is one of the most manganese (Mn)-tolerant species, and it is able to accumulate high levels of this metal in the leaves without showing toxic symptoms. The metal tolerance protein 8.1 (MTP8.1), a member of the Mn cation diffusion facilitator (CDF) family, has been shown to play a central role in high Mn tolerance by sequestering Mn into vacuoles. Recently, rice MTP11 was identified as an Mn transporter that is localized to Golgi-associated compartments, but its exact role in Mn tolerance in planta has not yet been understood. Here, we investigated the role of MTP11 in rice Mn tolerance using knockout lines. Old leaves presented higher levels of constitutively expressed MTP11 than other tissues and MTP11 expression was also found in reproductive organs. Fused MTP11:green fluorescent protein was co-localized to trans-Golgi markers and differentiated from other Golgi-associated markers. Knockout of MTP11 in wild-type rice did not affect tolerance and accumulation of Mn and other heavy metals, but knockout in the mtp8.1 mutant showed exacerbated Mn sensitivity at the vegetative growth stage. Knockout of MTP11 alone resulted in decreased grain yield and fertility at the reproductive stage. Thus, MTP11 is a trans-Golgi localized transporter for Mn, which plays a role in Mn tolerance through intracellular Mn compartmentalization. It is also required for maintaining high fertility in rice. PMID- 29700613 TI - MR arthrography is slightly more accurate than conventional MRI in detecting TFCC lesions of the wrist. AB - INTRODUCTION: In case of clinical suspicion of triangular fibrocartilage complex (TFCC) injury, different imaging techniques are used. The aim of this study was to determine whether MRA is superior to MRI and whether 3.0 T is better than 1.5 T (expresses in sensitivity, specificity and accuracy) in detecting TFCC injury, using arthroscopy as the gold standard. MATERIALS AND METHODS: The arthroscopic and MR findings of 150 patients who underwent arthroscopy for ulnar-sided wrist pain between January 2009 and November 2016 were retrospectively reviewed. RESULTS: MRA was slightly more accurate compared to conventional MRI, and 1.5 T was slightly more accurate than 3.0 T. 1.5 T wrist MRA had a sensitivity of 80%, a specificity of 100% and accuracy of 90%; 3.0 T wrist MRA 73, 100 and 86%, resp. Conventional 1.5 T wrist MRI had a sensitivity of 71%, a specificity of 75% and accuracy of 73%. For 3.0 T conventional MRI, this was 73, 67 and 70%, resp. CONCLUSIONS: MRA seems slightly superior to conventional MRI, but one could question whether this difference in diagnostic accuracy outweighs the burden and risks of an invasive procedure for patients with its additional costs. Furthermore, we could not confirm the superiority of 3 T compared to 1.5 T. PMID- 29700614 TI - Bioactive glass-ceramic bone repair associated or not with autogenous bone: a study of organic bone matrix organization in a rabbit critical-sized calvarial model. AB - OBJECTIVE: The aim of the study was to analyze bone matrix (BMX) organization after bone grafting and repair using a new bioactive glass-ceramic (Biosilicate(r)) associated or not with particulate autogenous bone graft. MATERIAL AND METHODS: Thirty rabbits underwent surgical bilateral parietal defects and divided into groups according to the materials used: (C) control blood clot, (BG) particulate autogenous bone, (BS) bioactive glass-ceramic, and BG + BS. After 7, 14, and 30 days post-surgery, a fragment of each specimen was fixed in - 80 degrees C liquid nitrogen for zymographic evaluation, while the remaining was fixed in 10% formalin for histological birefringence analysis. RESULTS: The results of this study demonstrated that matrix organization in experimental groups was significantly improved compared to C considering collagenous organization. Zymographic analysis revealed pro-MMP-2, pro-MMP-9, and active (a)-MMP-2 in all groups, showing gradual decrease of total gelatinolytic activity during the periods. At day 7, BG presented more prominent gelatinolytic activity for pro-MMP-2 and 9 and a-MMP-2, when compared to the other groups. In addition, at day 7, a 53% activation ratio (active form/[active form + latent form]) was evident in C group, 33% in BS group, and 31% in BG group. CONCLUSION: In general, BS allowed the production of a BMX similar to BG, with organized collagen deposition and MMP-2 and MMP-9 disponibility, permitting satisfactory bone remodeling at the late period. CLINICAL RELEVANCE: The evaluation of new bone substitute, with favorable biological properties, opens the possibility for its use as a viable and efficient alternative to autologous bone graft. PMID- 29700615 TI - Sociodemographic differences in 10-year time trends of emotional and behavioural problems among adolescents attending secondary schools in Amsterdam, The Netherlands. AB - Societal change in western societies may impact emotional and behavioural problems of adolescents. Firm epidemiological evidence of changes in emotional and behavioural problems during the last decade is lacking. Insight into secular changes in emotional and behavioural problems among adolescents from various sociodemographic groups is crucial for adequate and targeted policy making. Therefore, the purpose of this study was to examine 10-year time trends in emotional and behavioural problems among adolescents, and potential differences in time trends between sociodemographic groups. Analyses were based on annually repeated cross-sectional data including 56,159 multi-ethnic students (13-14 years old) in the second year of various levels of secondary education in Amsterdam, The Netherlands, using the internationally validated Strengths and Difficulties Questionnaire. In general, emotional and behavioural problems increased over a 10 year time period (i.e., relative increase of total difficulties by 19%). This increase was mainly due to an increase in hyperactivity/inattention problems, while peer-relationship problems decreased. Time trends differed somewhat by sex: total difficulties and emotional problems increased in girls but remained fairly stable in boys. In Amsterdam, emotional and behavioural problems in adolescents seemingly increased over time, especially hyperactivity/inattention problems. Further research is needed to clarify the underlying causes. We cannot totally exclude potential confounders underlying our findings. Our findings can inform policies to target health programs at sociodemographic groups at increased risk. PMID- 29700616 TI - Chronic inflammatory demyelinating polyneuropathy: evaluation of the vestibular system with cervical and ocular vestibular evoked myogenic potentials. AB - PURPOSE: To investigate the possibility of vestibular damage in a group of patients suffering from chronic inflammatory demyelinating polyneuropathy (CIDP) using a diagnostic protocol including the caloric test, C-VEMPs and O-VEMPs. METHODS: Twenty patients suffering from CIDP (mean age 58.5 years, range 33-80 years; 4 women and 16 men) were investigated. To assess any eventual audio vestibular involvement, all patients of the study underwent pure tone audiometry, Fitzgerald-Hallpike caloric vestibular test, C-VEMPs and O-VEMPs. RESULTS: In 11 patients with CIDP values of both O-VEMPs and C-VEMPs were either absent or abnormal. An absent trace at O-VEMPs testing occurred in 36% of these pathological patients, whereas an increase of n10 latency and amplitude was present in the other 64% . CONCLUSIONS: A specific diagnostic protocol including the caloric test, C-VEMPS, O-VEMPS, could be useful when employed for identifying vestibular damage in CIDP patients. PMID- 29700617 TI - The role of the vitreous body in effective IOL positioning. AB - PURPOSE: To compare the effective lens position (ELP) after phaco surgery alone and after combined phacovitrectomy surgery. METHODS: Twenty patients who were scheduled for elective surgery in both eyes were included. In one eye, phacovitrectomy surgery was performed (without any tamponade), and in the fellow eye, only phaco surgery was performed using the same IOL type. Pre- and postoperative biometric measurements were performed using laser interference biometry. The postoperative anterior chamber depth (ACD) was measured to determine the ELP. The primary outcome measure was the difference in the postoperative ACD between both eyes. RESULTS: The postoperative ACD following phacovitrectomy showed a statistically significant increase compared with that following phaco surgery alone, indicating a more posterior position of the IOL. CONCLUSIONS: An adjusted ELP parameter to optimize IOL calculation may be useful in eyes undergoing combined phacovitrectomy sugergy. PMID- 29700619 TI - Analysis of radiological parameters associated with decreased fractional anisotropy values on diffusion tensor imaging in patients with lumbar spinal stenosis. AB - PURPOSE: Previous studies have indicated that decreased fractional anisotropy (FA) values on diffusion tensor imaging (DTI) are well correlated with the symptoms of nerve root compression. The aim of our study is to determine primary radiological parameters associated with decreased FA values in patients with lumbar spinal stenosis involving single L5 nerve root. METHODS: Patients confirmed with single L5 nerve root compression by transforaminal nerve root blocks were included in this study. FA values of L5 nerve roots on both symptomatic and asymptomatic side were obtained. Conventional radiological parameters, such as disc height, degenerative scoliosis, dural sac cross sectional area (DSCSA), foraminal height (FH), hypertrophic facet joint degeneration (HFJD), sagittal rotation (SR), sedimentation sign, sagittal translation and traction spur were measured. Correlation and regression analyses were performed between the radiological parameters and FA values of the symptomatic L5 nerve roots. A predictive regression equation was established. RESULTS: Twenty-one patients were included in this study. FA values were significantly lower at the symptomatic side comparing to the asymptomatic side (0.263 +/- 0.069 vs. 0.334 +/- 0.080, P = 0.038). DSCSA, FH, HFJD, and SR were significantly correlated with the decreased FA values, with r = 0.518, 0.443, 0.472 and - 0.910, respectively (P < 0.05). DSCSA and SR were found to be the primary radiological parameters related to the decreased FA values, and the regression equation is FA = - 0.012 * SR + 0.002 * DSCSA. CONCLUSIONS: DSCSA and SR were primary contributors to decreased FA values in LSS patients involving single L5 nerve root, indicating that central canal decompression and segmental stability should be the first considerations in preoperative planning of these patients. These slides can be retrieved under Electronic Supplementary Material. PMID- 29700620 TI - Dual Receptor Targeting Cell Penetrating Peptide Modified Liposome for Glioma and Breast Cancer Postoperative Recurrence Therapy. AB - PURPOSE: Cell penetrating peptides (CPPs) were widely used as motifs for drug delivery to tumor. In former study, an RGD reverse sequence dGR was used to develop active-targeting liposome R8dGR-Lip, which showed well penetrating ability and treatment efficiency on glioma model. However, recurrence after tumor resection caused by post-operative residual cancer cells was a huge obstacle in tumor treatment. In consideration of the effective anti-cancer effect of PTX R8dGR-Lip when treating glioma in former study, we decide to evaluate its pharmacodynamics on tumor resection models, which were more invasive and resistant. METHOD: In vitro, the effectiveness of PTX-R8dGR-Lip in reducing tumor initiating cell (TIC) was investigated using mammosphere formation. In vivo, the inhibition efficiency of PTX-R8dGR-Lip on C6 glioma recurrence and 4 T1 breast cancer recurrence model were evaluated, including tumor bioluminescence imaging, survival rate and immumohistochemical staining, etc.. RESULTS: C6 mammosphere formation rate of PTX-R8dGR-Lip group was 48.06 +/- 2.72%, and 4 T1 mammosphere formation rate of PTX-R8dGR-Lip group was 39.51 +/- 4.02% when PBS group was set as 100%. C6 and 4 T1 bioluminescent tumor resected model were established, then effectiveness of different PTX-loaded preparations were evaluated on these two models. PTX-R8dGR-Lip could obviously inhibit tumor recurrence, prolong survival rate and reduce tumor tissue invasion. CONCLUSION: PTX-R8dGR-Lip could reduce post-operative recurrence rate, prolong survival time, and decrease the proliferation of residual cancer cells through regulating the expression of recurrence-related cytokines. PMID- 29700621 TI - Molecular insights into the antifungal mechanism of bacilysin. AB - Bacilysin is one of the simplest antimicrobial peptides and has drawn great attention for its excellent performance against Candida albicans. In this study, the antifungal mechanism of bacilysin was investigated. The target enzyme glucosamine-6-phosphate synthase (GFA) was expressed heterologously in Escherichia coli and its inhibition by bacilysin and derivatives was studied. It was concluded that bacilysin could be hydrolyzed by a proteinase of C. albicans, and that the released product, anticapsin, then inhibited the aminotransferase activity of GFA. This result was verified by molecular simulation, and the interaction mode of anticapsin with GFA was detailed, which provides data for the development of novel antifungal drugs. Transport of bacilysin into fungal cells was also simulated and it was shown that bacilysin is more readily transported into cells than anticapsin. Thus, our findings support a mechanism whereby bacilysin is transported into fungal pathogens, hydrolyzed to anticapsin, which then inhibits GFA. PMID- 29700622 TI - Assessment of Complement Activation by Nanoparticles: Development of a SPR Based Method and Comparison with Current High Throughput Methods. AB - PURPOSE: A Surface Plasmon Resonance chip (SPR) was developed to study the activation of complement system triggered by nanomaterials in contact with human serum, which is an important concern today to warrant safety of nanomedicines. METHODS: The developed chip was tested for its specificity in complex medium and its longevity of use. It was then employed to assess the release of complement fragments upon incubation of nanoparticles in serum. A comparison was made with other current methods assessing complement activation (MUC-IE, ELISA). RESULTS: The SPR chip was found to give a consistent response for C3a release upon activation by nanoparticles. Results were similar to those obtained by MUC-IE. However, ELISA detection of iC3b fragments showed an explained high non-specific background. The impact of sample preparation preceding the analysis was assessed with the newly develop SPR method. The removal of nanoparticles before analysis showed an important modification in the obtained response, possibly leading to false negative results. CONCLUSION: The SPR chip developed in this work allows for an automated assessment of complement activation triggered by nanoparticles with possibility of multiplexed analysis. The design of the chip proved to give consistent results of complement activation by nanoparticles. PMID- 29700624 TI - Insight into the molecular mechanism of the sulfur oxidation process by reverse sulfite reductase (rSiR) from sulfur oxidizer Allochromatium vinosum. AB - Sulfur metabolism is one of the oldest known biochemical processes. Chemotrophic or phototrophic proteobacteria, through the dissimilatory pathway, use sulfate, sulfide, sulfite, thiosulfate or elementary sulfur by either reductive or oxidative mechanisms. During anoxygenic photosynthesis, anaerobic sulfur oxidizer Allochromatium vinosum forms sulfur globules that are further oxidized by dsr operon. One of the key redox enzymes in reductive or oxidative sulfur metabolic pathways is the DsrAB protein complex. However, there are practically no reports to elucidate the molecular mechanism of the sulfur oxidation process by the DsrAB protein complex from sulfur oxidizer Allochromatium vinosum. In the present context, we tried to analyze the structural details of the DsrAB protein complex from sulfur oxidizer Allochromatium vinosum by molecular dynamics simulations. The molecular dynamics simulation results revealed the various types of molecular interactions between DsrA and DsrB proteins during the formation of DsrAB protein complex. We, for the first time, predicted the mode of binding interactions between the co-factor and DsrAB protein complex from Allochromatium vinosum. We also compared the binding interfaces of DsrAB from sulfur oxidizer Allochromatium vinosum and sulfate reducer Desulfovibrio vulgaris. This study is the first to provide a comparative aspect of binding modes of sulfur oxidizer Allochromatium vinosum and sulfate reducer Desulfovibrio vulgaris. PMID- 29700623 TI - A fluorescent nanoprobe for real-time monitoring of intracellular singlet oxygen during photodynamic therapy. AB - Sensing of intracellular singlet oxygen (1O2) is required in order to optimize photodynamic therapy (PDT). An optical nanoprobe is reported here for the optical determination of intracellular 1O2. The probe consists of a porous particle core doped with the commercial 1O2 probe 1,3-diphenylisobenzofuran (DPBF) and a layer of poly-L-lysine. The nanoparticle probes have a particle size of ~80 nm in diameter, exhibit good biocompatibility, improved photostability and high sensitivity for 1O2 in both absorbance (peak at 420 nm) and fluorescence (with excitation/emission peaks at 405/458 nm). Nanoprobes doped with 20% of DPBF are best suited even though they suffer from concentration quenching of fluorescence. In comparison with the commercial fluorescent 1O2 probe SOSG, 20%-doped DPBF-NPs (aged) shows higher sensitivity for 1O2 generated at an early stage. The best nanoprobes were used to real-time monitor the PDT-triggered generation of 1O2 inside live cells, and the generation rate is found to depend on the supply of intracellular oxygen. Graphical abstract A fluorescent nanoprobe featured with refined selectivity and improved sensitivity towards 1O2 was prepared from the absorption-based probe DBPF and used to real-time monitoring of the generation of intracellular 1O2 produced during PDT. PMID- 29700625 TI - Carbon dioxide capture using covalent organic frameworks (COFs) type material-a theoretical investigation. AB - The present work deals with a density functional theory (DFT) study of porous organic framework materials containing - groups for CO2 capture. In this study, first principle calculations were performed for CO2 adsorption using N-containing covalent organic framework (COFs) models. Ab initio and DFT-based methods were used to characterize the N-containing porous model system based on their interaction energies upon complexing with CO2 and nitrogen gas. Binding energies (BEs) of CO2 and N2 molecules with the polymer framework were calculated with DFT methods. Hybrid B3LYP and second order MP2 methods combined with of Pople 6 31G(d,p) and correlation consistent basis sets cc-pVDZ, cc-pVTZ and aug-ccVDZ were used to calculate BEs. The effect of linker groups in the designed covalent organic framework model system on the CO2 and N2 interactions was studied using quantum calculations. PMID- 29700626 TI - The Use of Smartphones in Different Phases of Medical School and its Relationship to Internet Addiction and Learning Approaches. AB - The use of smartphones is revolutionizing the way information is acquired, leading to profound modifications in teaching medicine. Nevertheless, inadvertent use can negatively affect student learning. The present study aims to evaluate smartphone use in the educational context as well as Internet addiction and its repercussions on surface and deep learning and to compare them during the different phases of medical students' education. This is a cross-sectional study involving medical students in all phases of education. Sociodemographic data, type and frequency of smartphone use, degree of digital addiction (Internet Addiction Test - IAT), and surface and deep approaches to learning (Biggs) were analyzed. A total of 710 students were included. Almost all students had a smartphone and a total of 96.8% used it during lectures, classes, and meetings. Less than half of the students (47.3%) reported using a smartphone for more than 10 min for educational purposes, a usage that is higher among clerkship students. At least 95% reported using a smartphone in the classroom for activities not related to medicine (social media and searching for general information) and 68.2% were considered problematic Internet users according to the IAT. The most common reasons for noneducational use were that the class was uninteresting, students needed to receive or make an important call, and the educational strategy was not stimulating. The "frequency of smartphone use" and higher "internet addiction" were correlated to both higher levels of surface learning and lower levels of deep learning. Educators should advise and educate their students about conscientious use of this tool to avoid detrimental impact on the learning process. PMID- 29700627 TI - The Preservation of Lyophilized Human Growth Hormone Activity: how Do Buffers and Sugars Interact? AB - PURPOSE: One of the most common classes of excipients used in protein formulations are buffers. The aim of this work is to investigate the effect of buffers on protein stabilization given by sugars during freeze drying. METHODS: Molecular Dynamics simulations of human growth hormone (hGH) in the presence of sucrose and trehalose were performed, and the impact of phosphate and citrate buffers on their protective action was analyzed. RESULTS: We found that buffers broke the hydrogen bonding network formed by excipients, and the consequences of this disruption of structure ordering were different in sucrose-based or trehalose-based formulations. More specifically, we observed that buffers increased protein recovery in the presence of excipients, such as sucrose, that exert their action mainly by preferential exclusion. By contrast, the opposite effect was sometimes noted in the case of excipients, such as trehalose, whose protective action is related to the formation of a highly structured matrix. CONCLUSIONS: We found that buffers have important properties, other than the control of pH, that can contribute to the overall stability of proteins. Some of these properties are related to their interaction with the other components of the formulation. PMID- 29700628 TI - Extension of coarse-grained UNRES force field to treat carbon nanotubes. AB - Carbon nanotubes (CNTs) have recently received considerable attention because of their possible applications in various branches of nanotechnology. For their cogent application, knowledge of their interactions with biological macromolecules, especially proteins, is essential and computer simulations are very useful for such studies. Classical all-atom force fields limit simulation time scale and size of the systems significantly. Therefore, in this work, we implemented CNTs into the coarse-grained UNited RESidue (UNRES) force field. A CNT is represented as a rigid infinite-length cylinder which interacts with a protein through the Kihara potential. Energy conservation in microcanonical coarse-grained molecular dynamics simulations and temperature conservation in canonical simulations with UNRES containing the CNT component have been verified. Subsequently, studies of three proteins, bovine serum albumin (BSA), soybean peroxidase (SBP), and alpha-chymotrypsin (CT), with and without CNTs, were performed to examine the influence of CNTs on the structure and dynamics of these proteins. It was found that nanotubes bind to these proteins and influence their structure. Our results show that the UNRES force field can be used for further studies of CNT-protein systems with 3-4 order of magnitude larger timescale than using regular all-atom force fields. Graphical abstract Bovine serum albumin (BSA), soybean peroxidase (SBP), and alpha-chymotrypsin (CT), with and without CNTs?. PMID- 29700630 TI - Tumorcode : A framework to simulate vascularized tumors. AB - During the past years our group published several articles using computer simulations to address the complex interaction of tumors and the vasculature as underlying transport network. Advances in imaging and lab techniques pushed in vitro research of tumor spheroids forward and animal models as well as clinical studies provided more insights to single processes taking part in tumor growth, however, an overall picture is still missing. Computer simulations are a non invasive option to cumulate current knowledge and form a quasi in vivo system. In our software, several known models were assembled into a multi-scale approach which allows to study length scales relevant for clinical applications. We release our code to the public domain, together with a detailed description of the implementation and several examples, with the hope of usage and futher development by the community. A justification for the included algorithms and the biological models was obtained in previous publications, here we summarize the technical aspects following the workflow of a typical simulation procedure. PMID- 29700629 TI - An analysis of the influence of the local effects of climatic and hydrological factors affecting new malaria cases in riverine areas along the Rio Negro and surrounding Puraquequara Lake, Amazonas, Brazil. AB - A study was conducted at three sampling regions along the Rio Negro and surrounding Puraquequara Lake, Amazonas, Brazil. The aim was to determine the influence of the local effects of climatic and hydrological variables on new malaria cases. Data was gathered on the river level, precipitation, air temperature, and the number of new cases of autochthonous malaria between January 2003 and December 2013. Monthly averages, time series decompositions, cross correlations, and multiple regressions revealed different relationships at each location. The sampling region in the upper Rio Negro indicated no statistically significant results. However, monthly averages suggest that precipitation and air temperature correlate positively with the occurrence of new cases of malaria. In the mid Rio Negro and Puraquequara Lake, the river level positively correlated, and temperature negatively correlated with new transmissions, while precipitation correlated negatively in the mid Rio Negro and positively on the lake. Overall, the river level is a key variable affecting the formation of breeding sites, while precipitation may either develop or damage them. A negative temperature correlation is associated with the occurrence of new annual post-peak cases of malaria, when the monthly average exceeds 28.5 degrees C. This suggests that several factors contribute to the occurrence of new malaria cases as higher temperatures are reached at the same time as precipitation and the river levels are lowest. Differences between signals and correlation lags indicate that local characteristics have an impact on how different variables influence the disease vector's life cycle, pathogens, and consequently, new cases of malaria. PMID- 29700631 TI - Strong fluctuations in aboveground population size do not limit genetic diversity in populations of an endangered biennial species. AB - Assessing genetic diversity within populations of rare species and understanding its determinants are crucial for effective species protection. While a lot is known about the relationships between genetic diversity, fitness, and current population size, very few studies explored the effects of past population size. Knowledge of past population size may, however, improve our ability to predict future population fates. We studied Gentianella praecox subsp. bohemica, a biennial species with extensive seed bank. We tested the effect of current, past minimal and maximal population size, and harmonic mean of population sizes within the last 15 years on genetic diversity and fitness. Maximum population size over the last 15 years was the best predictor of expected heterozygosity of the populations and was significantly related to current population size and management. Plant fitness was significantly related to current as well as maximum population size and expected heterozygosity. The results suggested that information on past population size may improve our understanding of contemporary genetic diversity across populations. They demonstrated that despite the strong fluctuations in population size, large reductions in population size do not result in immediate loss of genetic diversity and reduction of fitness within the populations. This is likely due to the seed bank of the species serving as reservoir of the genetic diversity of the populations. From a conservation point of view, this suggests that the restoration of small populations of short-lived species with permanent seed bank is possible as these populations may still be genetically diverse. PMID- 29700632 TI - Limited dietary overlap amongst resident Arctic herbivores in winter: complementary insights from complementary methods. AB - Snow may prevent Arctic herbivores from accessing their forage in winter, forcing them to aggregate in the few patches with limited snow. In High Arctic Greenland, Arctic hare and rock ptarmigan often forage in muskox feeding craters. We therefore hypothesized that due to limited availability of forage, the dietary niches of these resident herbivores overlap considerably, and that the overlap increases as winter progresses. To test this, we analyzed fecal samples collected in early and late winter. We used molecular analysis to identify the plant taxa consumed, and stable isotope ratios of carbon and nitrogen to quantify the dietary niche breadth and dietary overlap. The plant taxa found indicated only limited dietary differentiation between the herbivores. As expected, dietary niches exhibited a strong contraction from early to late winter, especially for rock ptarmigan. This may indicate increasing reliance on particular plant resources as winter progresses. In early winter, the diet of rock ptarmigan overlapped slightly with that of muskox and Arctic hare. Contrary to our expectations, no inter-specific dietary niche overlap was observed in late winter. This overall pattern was specifically revealed by combined analysis of molecular data and stable isotope contents. Hence, despite foraging in the same areas and generally feeding on the same plant taxa, the quantitative dietary overlap between the three herbivores was limited. This may be attributable to species-specific consumption rates of plant taxa. Yet, Arctic hare and rock ptarmigan may benefit from muskox opening up the snow pack, thereby allowing them to access the plants. PMID- 29700633 TI - Determinants of food resource assimilation by stream insects along a tropical elevation gradient. AB - Food resource availability varies along gradients of elevation where riparian vegetative cover exerts control on the relative availability of allochthonous and autochthonous resources in streams. Still, little is known about how elevation gradients can alter the availability and quality of resources and how stream food webs respond. We sampled habitat characteristics, stable isotope signatures (delta13C, delta15N, delta2Eta) and the carbon, nitrogen and phosphorus composition of basal food resources and insects in 11 streams of similar size along an elevation gradient from 1260 to 4045 m on the northeastern slope of the Ecuadorian Andean-Amazon region. Algal-based (autochthonous) food resources primarily supported insects occurring at higher elevations, but at low elevations there was a shift to greater allochthony, corresponding with lower light availability and reduced epilithon resource abundance. Additionally, percent phosphorus (%P) of both autochthonous and allochthonous food resources and of body tissue for some abundant insect taxa (stonefly Anacroneuria and mayfly Andesiops) declined with increasing elevation, despite the greater autochthony at high elevation. Allochthonous food resources were always a lower quality food resource, as indicated by higher C:N, N:P, and lower %P, across elevation in comparison to autochthonous resources, but autochthonous resources had higher %P than allochthonous resources across all elevations and comprised a greater portion of high-elevation insect resource assimilation. Aquatic insects may be able to compensate for the lower quality of both resource types at high elevations through altered body stoichiometry, even though higher quality autochthonous-based foods are in high abundance at high elevations. PMID- 29700635 TI - Favorable long-term outcomes of one-year adjuvant S-1 monotherapy for pathological stage II or III gastric cancer treated at a high-volume center. AB - BACKGROUND: One-year adjuvant S-1 monotherapy following D2 gastrectomy has been the Japanese treatment standard for pathological stage II or III gastric cancer since the Adjuvant Chemotherapy Trial of S-1 for Gastric Cancer (ACTS-GC) was concluded in 2007. Trial patients were selected according to the 13th edition of the Japanese classification (JC-13). The JC-13 and the TNM classification underwent major revisions in 2010 (JC-14/TNM-7). However, neither the recent therapeutic results for patients with stage II/III disease defined by the current system nor comparisons with the ACTS-GC-results have been reported. METHODS: The 390 study patients had pathological stage II/III gastric cancer defined by the JC 14/TNM-7 and treated with S-1 following D2 gastrectomy between 2008 and 2012. The completion rate of 1-year S-1, first relapse site, and stage-specific survival according to the JC-14/TNM-7, JC-13, and TNM-6 were examined and the results compared with those of the ACTS-GC. RESULTS: The completion rate for 1-year S-1 (69.5%) was slightly higher than in the ACTS-GC. The recurrence pattern was almost identical. The 5-year overall survival rates of pathological IIA, IIB, IIIA, IIIB, and IIIC in the JC-14/TNM-7 were 96.0, 85.5, 81.8, 72.0, and 51.1%, respectively. Their 5-year overall and relapse-free survival rates by the JC-13 and TNM-6 systems were favorable as compared to those of ACTS-GC patients for all substages. CONCLUSIONS: Survival outcome shown in this study of patients treated with 1-year adjuvant S-1 after D2 gastrectomy at a high-volume cancer hospital will provide a reference for future adjuvant trials targeting JC-14/TNM-7 stage II/III disease. PMID- 29700634 TI - Frequency of pathogenic germline mutations in cancer susceptibility genes in breast cancer patients. AB - In this study, we evaluated the incidence of pathogenic germline mutations in 30 breast cancer susceptibility genes in breast cancer patients. Our aim was to understand the involvement of the inherited mutations in these genes in a breast cancer cohort. Two hundred ninety-six female breast cancer patients including 4.5% of familial breast cancer cases were included in the study. 200 ng of genomic DNA was used to evaluate the pathogenic mutations, detected using Global Screening Array (GSA) microchip (Illumina Inc.) according to the manufacturer's instructions. The pathogenic frameshift and nonsense mutations were observed in BRCA2 (10.9%), MLH1 (58.6%), MTHFR (50%), MSH2 (14.2%), and CYTB (52%) genes. Familial breast cancer patients (4.5%) had variations in BRCA2, MLH1, MSH2, and CYTB genes. 28% of patients with metastasis, recurrence, and death harbored mono/biallelic alterations in MSH2, MLH1, and BRCA2 genes. The results of this study can guide to develop a panel to test the breast cancer patients for pathogenic mutations, from Malwa region of Punjab. The screening of MSH2, MLH1, and BRCA2 should be carried in individuals with or without family history of breast cancer as these genes have been reported to increase the cancer risk by tenfold. PMID- 29700636 TI - Results of a phase II trial for high-risk neuroblastoma treatment protocol JN-H 07: a report from the Japan Childhood Cancer Group Neuroblastoma Committee (JNBSG). AB - BACKGROUND: The Japanese Children's Cancer Group (JCCG) Neuroblastoma Committee (JNBSG) conducted a phase II clinical trial for high-risk neuroblastoma treatment. We report the result of the protocol treatment and associated genomic aberration studies. METHODS: JN-H-07 was a single-arm, late phase II trial for high-risk neuroblastoma treatment with open enrollment from June 2007 to February 2009. Eligible patients underwent five courses of induction chemotherapy followed by high-dose chemotherapy with hematopoietic stem cell rescue. Surgery for the primary tumor was scheduled after three or four courses of induction chemotherapy. Radiotherapy was administered to the primary tumor site and to any bone metastases present at the end of induction chemotherapy. RESULTS: The estimated 3-year progression-free and overall survival rates of the 50 patients enrolled were 36.5 +/- 7.0 and 69.5 +/- 6.6%, respectively. High-dose chemotherapy caused severe toxicity including three treatment-related deaths. In response to this, the high-dose chemotherapy regimen was modified during the trial by infusing melphalan before administering carboplatin and etoposide. The modified high-dose chemotherapy regimen was less toxic. Univariate analysis revealed that patients younger than 547 days and patients whose tumor showed a whole chromosomal gains / losses pattern had a significantly poor prognosis. Notably, the progression-free survival of cases with MYCN amplification were not inferior to those without MYCN amplification. CONCLUSIONS: The outcome of patients treated with the JN-H-07 protocol showed improvement over the results reported by previous studies conducted in Japan. Molecular and genetic profiling may enable a more precise stratification of the high-risk cohort. PMID- 29700638 TI - Prognostic impact of bleomycin pulmonary toxicity on the outcomes of patients with germ cell tumors. AB - Bleomycin pulmonary toxicity (BPT) has been well described in patients with germ cell tumors treated with bleomycin etoposide and cisplatin chemotherapy (BEP). To assess the prognostic impact of BPT, we retrospectively identified 52 patients who underwent bleomycin etoposide and cisplatin chemotherapy from 2008 to 2017 in our institution, and evaluated the risk factors of BPT and its effect on prognosis. Patients who had received chemotherapy at another institution were excluded. BPT was defined as bleomycin discontinuation in response to pulmonary function test decline, pulmonary symptoms, or interstitial pneumonia on computed tomography without infection. We divided the patients into two groups according to this definition: BPT and non-BPT. Their median age was 34.2 years, and their median body mass index was 22.8 kg/m2. Twenty patients had a smoking history, 37 were diagnosed with non-seminoma, and 20 had lung metastasis. The median cumulative bleomycin dose was 270 mg/body. Fifteen patients were classified into the BPT group and 37 into the non-BPT group. Only body mass index < 22 was identified as a predictor of BPT in multivariable logistic models. Age or use of granulocyte-colony stimulating factor did not have a significant impact. Kaplan Meier analysis revealed that the presence of BPT had no significant impact on either 5-year overall survival or progression-free survival. Lower body mass index can increase the risk of BPT in patients with germ cell tumors undergoing BEP. However, discontinuation of bleomycin with BPT does not adversely influence the survival outcomes. PMID- 29700639 TI - Rhipicephalus microplus infected by Metarhizium: unveiling hemocyte quantification, GFP-fungi virulence, and ovary infection. AB - Hemocytes, cells present in the hemocoel, are involved in the immune response of arthropods challenged with entomopathogens. The present study established the best methodology for harvesting hemocytes from Rhipicephalus microplus and evaluated the number of hemocytes in addition to histological analysis from ovaries of fungus-infected females and tested the virulence of GFP-fungi transformants. Different centrifugation protocols were tested, and the one in which presented fewer disrupted cells and higher cell recovery was applied for evaluating the effect of Metarhizium spp. on hemocytes against R. microplus. After processing, protocol number 1 (i.e., hemolymph samples were centrifuged at 500*g for 3 min at 4 degrees C) was considered more efficient, with two isolates used (Metarhizium robertsii ARSEF 2575 and Metarhizium anisopliae ARSEF 549), both wild types and GFP, to assess their virulence. In the biological assays, the GFP-fungi were as virulent as wild types, showing no significant differences. Subsequently, hemocyte quantifications were performed after inoculation, which exhibited notable changes in the number of hemocytes, reducing by approximately 80% in females previously treated with Metarhizium isolates in comparison to non treated females. Complementarily, 48 h after inoculation, in which hemolymph could not be obtained, histological analysis showed the high competence of these fungi to colonize ovary from ticks. Here, for the first time, the best protocol (i.e., very low cell disruption and high cell recovery) for R. microplus hemocyte obtaining was established aiming to guide directions to other studies that involves cellular responses from ticks to fungi infection. PMID- 29700637 TI - Lateral preoptic and ventral pallidal roles in locomotion and other movements. AB - The lateral preoptic area (LPO) and ventral pallidum (VP) are structurally and functionally distinct territories in the subcommissural basal forebrain. It was recently shown that unilateral infusion of the GABAA receptor antagonist, bicuculline, into the LPO strongly invigorates exploratory locomotion, whereas bicuculline infused unilaterally into the VP has a negligible locomotor effect, but when infused bilaterally, produces vigorous, abnormal pivoting and gnawing movements and compulsive ingestion. This study was done to further characterize these responses. We observed that bilateral LPO infusions of bicuculline activate exploratory locomotion only slightly more potently than unilateral infusions and that unilateral and bilateral LPO injections of the GABAA receptor agonist muscimol potently suppress basal locomotion, but only modestly inhibit locomotion invigorated by amphetamine. In contrast, unilateral infusions of muscimol into the VP affect basal and amphetamine-elicited locomotion negligibly, but bilateral VP muscimol infusions profoundly suppress both. Locomotor activation elicited from the LPO by bicuculline was inhibited modestly and profoundly by blockade of dopamine D2 and D1 receptors, respectively, but was not entirely abolished even under combined blockade of dopamine D1 and D2 receptors. That is, infusing the LPO with bic caused instances of near normal, even if sporadic, invigoration of locomotion in the presence of saturating dopamine receptor blockade, indicating that LPO can stimulate locomotion in the absence of dopamine signaling. Pivoting following bilateral VP bicuculline infusions was unaffected by dopamine D2 receptor blockade, but was completely suppressed by D1 receptor blockade. The present results are discussed in a context of neuroanatomical and functional organization underlying exploratory locomotion and adaptive movements. PMID- 29700640 TI - Molecular identification of Sarcocystis lutrae (Apicomplexa: Sarcocystidae) in muscles of five species of the family Mustelidae. AB - Carnivores usually act as definitive hosts of Sarcocystis species. However, the number of reports on sarcocyst formation in musculature of predators is on the increase. In the present study, muscle samples of 68 mustelids collected in Lithuania were examined for sarcocysts of Sarcocystis species. Sarcocysts were detected in diaphragm, tongue and limb muscles of ten animals (14.7%) but were not discovered in the heart. Based on 18S rDNA, 28S rDNA, cox1 and ITS1 sequence analysis, Sarcocystis lutrae was identified in three American minks (Neovison vison), two beech martens (Martes foina), three Eurasian badgers (Meles meles), one Eurasian otter (Lutra lutra) and one European polecat (Mustela putorius). The intraspecific variability of this Sarcocystis species was determined only in ITS1 region. Based on the phylogenetic analysis, no clear separation of S. lutrae by intermediate hosts or geographical locations was established. This paper represents the first identification of S. lutrae in the American mink, the beech marten and the European polecat. Current results indicate that S. lutrae is a common species in the muscles of various European mustelids. PMID- 29700641 TI - Bowel perforation in type IV vascular Ehlers-Danlos syndrome. A systematic review. AB - Spontaneous gastrointestinal (GI) perforation is a well-known complication occurring in patients suffering from Type IV vascular Ehlers-Danlos syndrome (EDS IV). The aim of the present study was to review the current literature on spontaneous GI perforation in EDS IV and illustrate the surgical management and outcome when possible. A systematic review of all the published data on EDS IV patients with spontaneous GI perforation between January 2000 and December 2015 was conducted using three major databases PUBMED, EMBASE, and Cochrane Central Register of Controlled Trails. References of the selected articles were screened to avoid missing main articles. Twenty-seven published case reports and four retrospective studies, including 31 and 527 cases, respectively, matched the search criteria. A case from our institution was added. Mean age was 26 years (range 6-64 years). The most frequent site of perforation was the colon, particularly the sigmoid, followed by small bowel, upper rectum, and finally stomach. The majority of cases were initially managed with Hartmann's procedure. In recurrent perforations, total colectomy was performed. The reperforation rate was considerably higher in the "partial colectomy with anastomosis" group than in the Hartmann group. Colonic perforation is the most common spontaneous GI perforation in EDS IV patients. An unexpected fragility of the tissues should raise the possibility of a connective tissue disorder and prompt further investigation with eventual management of these high-risk patients with a multidisciplinary team approach in dedicated centres. In the emergency setting, a Hartmann procedure should be performed. PMID- 29700642 TI - Evaluation of corneal biomechanics in patients with keratectasia following LASIK using dynamic Scheimpflug analyzer. AB - PURPOSE: To investigate the corneal biomechanics in eyes with keratectasia following LASIK using a dynamic Scheimpflug analyzer. DESIGN: Case-Control study. METHOD: The subjects in the study included 12 eyes with keratectasia after LASIK (KE), 24 eyes with keratoconus (KC), 17 eyes without keratectasia after LASIK (LASIK), and 34 eyes with normal corneas (Normal). Corneal biomechanics of the four groups were evaluated using a dynamic Scheimpflug analyzer. RESULTS: Compared with Normal (7.06 +/- 0.54), the radius at the highest concavity (radius, mm) of LASIK (5.96 +/- 0.76), KE (4.93 +/- 0.61) and KC (5.39 +/- 1.02) were significantly small. The Deflection Amplitude (HCDLA, mm) of Normal (0.94 +/ 0.07) was significantly lower than those of KE (1.11 +/- 0.10) and KC (1.06 +/- 0.16), and was not significantly different from that of LASIK (0.98 +/- 0.07). There were significant differences between LASIK and KE in radius and HCDLA (P < 0.05), whereas KE and KC had no differences in these parameters. CONCLUSIONS: Corneal biomechanical features evaluated using the dynamic Scheimpflug analyzer suggest that biomechanical properties in eyes with keratectasia, keratoconus, and LASIK are different from those of normal eyes. Although the biomechanics in eyes with keratectasia differs from that in eyes with LASIK, it is similar to that in eyes with keratoconus. PMID- 29700643 TI - Link between overweight/obese in children and youngsters and occurrence of multiple sclerosis. AB - BACKGROUND/AIMS: The prevalence of overweight/obesity is a major problem in the world, and the number of MS cases is increasing. This literature study examines the relationship between overweight/obesity in children and adolescents and later occurrence of MS. METHOD: This is a complete literature survey. The search database is primarily Pubmed using MeSH terms "multiple sclerosis", "obesity", and "overweight", and text words not to restrict searches. RESULTS: All included studies show a link between being overweight/obese and the presence of MS among people below 20 years of age. The relation is especially true for young girls. The same relation in boys is not significant. CONCLUSION: The literature survey convincingly revealed a link between young overweight/obese and occurrence of MS, in particular for girls. There is a need for more and larger studies to investigate the molecular mechanisms that link obesity and MS. PMID- 29700644 TI - Factors affecting the health-related quality of life of caregivers of patients with muscular dystrophy. AB - Muscular dystrophy (MD) is a group of progressive muscle weakness diseases. The caregiver burden, increasing as the disease progresses, can be associated with impaired health-related quality of life (HRQOL). The aims of this study were to investigate the HRQOL in caregivers of patients with MD and identify the factors associated with HRQOL. A cross-sectional assessment of caregiver HRQOL was performed with the Short Form-36 and compared with norms. The factors affecting HRQOL were investigated by patient and caregiver characteristics. The Muscular Dystrophy Functional Rating Scale was used to assess the functional status (mobility, basic activities of daily living, arm function, and impairment) of patients. The demographic data and social interaction activities of caregivers were assessed. Caregivers (n = 62) had poor HRQOL. Caregiver HRQOL was associated with the patient's functional status, especially in the domains of Vitality and Mental Health. Numerous visits by neighbors and close friends of the caregiver family indicated better HRQOL (in the body pain, general health, vitality, role emotion and mental health domains). Caregiver HRQOL was associated with caregiver education level, while patient age, caregiver age, length of caregiving, and family income were not. These findings demonstrate that caregivers have poor HRQOL, and the mental domain of quality of life is associated with the patient's functional status, social interaction, and caregiver education level. We suggest that rehabilitation programs focus on caregiver HRQOL, promote the patient's functional status with assistive technology, enhance professional caring techniques, and encourage participation in social groups to improve caregiver HRQOL. PMID- 29700645 TI - Dilemma of multiple system atrophy and spinocerebellar ataxias. AB - Multiple system atrophy (MSA) and spinocerebellar ataxias (SCAs) are both progressive neurodegenerative disorders, which can manifest cerebellar dysfunctions and parkinsonism-related symptoms, although the former is sporadic and the latter is autosomal dominant disease. Routinely, diagnosis is primarily based on clinical information-thorough history and physical examination should be included. Provided family history obtained, distinguishing SCAs from MSA is easy. However, how can we diagnose MSA or SCAs, in case of insufficient and unconvinced clinical symptoms or family history? Especially, familial MSA cases had been reported recently. We may drop into a dilemma resulting from analogous manifestations between MSA and SCAs. Herein, we aim to give a comprehensive introduction of MSA and SCAs, mainly in phenotype and genotype, and then address the connection and difference between them. Recently, some studies had been put forward to figure out the overlapped features between MSA and SCAs. Through this review, we want to discuss the possibility of misdiagnosis between MSA and SCAs. PMID- 29700646 TI - Modeling human orthostatic responses on the Moon and on Mars. AB - PURPOSE: Since manned missions to the Moon and Mars are planned, we conducted active standing tests with lunar, Martian, terrestrial, and 1.8 loads of inertial resistance (+Gz) modeled through defined parabolic flight maneuvers. We hypothesized that the cardiovascular response to active standing is proportional to the +Gz load. METHODS: During partial-+Gz parabolic flights, 14 healthy test subjects performed active stand-up maneuvers under 1 +Gz, lunar (0.16 +Gz), Martian (0.38 +Gz), and hyper inertial resistance (1.8 +Gz) while heart rate and finger blood pressure were continuously monitored. We quantified amplitudes and timing of orthostatic response immediately following standing up. RESULTS: The maximum early heart rate increase was 21 (SD +/- 10) bpm with lunar, 23 (+/- 11) bpm with Martian, 34 (+/- 17) bpm with terrestrial +Gz, and 40 (+/- 11) bpm hyper +Gz. The time to maximum heart rate increased gradually with increasing loads of inertial resistance. The transient blood pressure reduction was most pronounced with hyper +Gz but did not differ significantly between lunar and Martian +Gz. The mean arterial pressure nadir was reached significantly later with Martian and lunar compared to 1 +Gz. Paradoxically, the time for blood pressure to recover was shortest with terrestrial +Gz. CONCLUSION: While load of inertial resistance directly affects the magnitude of the transient blood pressure reduction and heart rate response to active standing, blood pressure stabilization is most rapidly attained during terrestrial +Gz. The observation might suggest that the human cardiovascular system is tuned to cope with orthostatic stress on earth. PMID- 29700647 TI - Blunt bowel and mesenteric trauma: role of clinical signs along with CT findings in patients' management. AB - BACKGROUND: Bowel and/or mesentery injuries represent the third most common injury among patients with blunt abdominal trauma. Delayed diagnosis increases morbidity and mortality. The aim of our study was to evaluate the role of clinical signs along with CT findings as predictors of early surgical repair. MATERIAL AND METHODS: Between March 2014 and February 2017, charts and CT scans of consecutive patients treated for blunt abdominal trauma in two different trauma centers were reread by two experienced radiologists. We included all adult patients who underwent contrast-enhanced CT of the abdomen and pelvis with CT findings of blunt bowel and/or mesenteric injury (BBMI). We divided CT findings into two groups: the first included three highly specific CT signs and the second included six less specific CT signs indicated as "minor CT findings." The presence of abdominal guarding and/or abdominal pain was considered as "clinical signs." Reference standards included surgically proven BBMI and clinical follow up. Association was evaluated by the chi-square test. A logistic regression model was used to estimate odds ratio (OR) and confidence intervals (CI). RESULTS: Thirty-four (4.1%) out of 831 patients who sustained blunt abdominal trauma had BBMI at CT. Twenty-one out of thirty-four patients (61.8%) underwent surgical repair; the remaining 13 were treated conservatively. Free fluid had a significant statistical association with surgery (p = 0.0044). The presence of three or more minor CT findings was statistically associated with surgery (OR = 8.1; 95% CI, 1.2-53.7). Abdominal guarding along with bowel wall discontinuity and extraluminal air had the highest positive predictive value (100 and 83.3%, respectively). CONCLUSION: In patients without solid organ injury (SOI), the presence of free fluid along with abdominal guarding and three or more "minor CT findings" is a significant predictor of early surgical repair. The association of bowel wall discontinuity with extraluminal air warrants exploratory laparotomy. PMID- 29700648 TI - An Unsupervised Approach for Extraction of Blood Vessels from Fundus Images. AB - Pathological disorders may happen due to small changes in retinal blood vessels which may later turn into blindness. Hence, the accurate segmentation of blood vessels is becoming a challenging task for pathological analysis. This paper offers an unsupervised recursive method for extraction of blood vessels from ophthalmoscope images. First, a vessel-enhanced image is generated with the help of gamma correction and contrast-limited adaptive histogram equalization (CLAHE). Next, the vessels are extracted iteratively by applying an adaptive thresholding technique. At last, a final vessel segmented image is produced by applying a morphological cleaning operation. Evaluations are accompanied on the publicly available digital retinal images for vessel extraction (DRIVE) and Child Heart And Health Study in England (CHASE_DB1) databases using nine different measurements. The proposed method achieves average accuracies of 0.957 and 0.952 on DRIVE and CHASE_DB1 databases respectively. PMID- 29700649 TI - The addition of albumin improves Schwann cells viability in nerve cryopreservation. AB - The purpose of the current study was to establish a valid protocol for nerve cryopreservation, and to evaluate if the addition of albumin supposed any advantage in the procedure. We compared a traditional cryopreservation method that uses dimethyl sulfoxide (DMSO) as cryoprotectant, to an alternative method that uses DMSO and albumin. Six Wistar Lewis rats were used to obtain twelve 20 mm fragments of sciatic nerve. In the first group, six fragments were cryopreserved in 199 media with 10% DMSO, with a temperature decreasing rate of 1 degrees C per minute. In the second group, six fragments were cryopreserved adding 4% human albumin. The unfreezing process consisted of sequential washings with saline in the first group, and saline and 20% albumin in the second group at 37 degrees C until the crioprotectant was removed. Structural evaluation was performed through histological analysis and electronic microscopy. The viability was assessed with the calcein-AM (CAM) and 4',6-diamino-2-fenilindol (DAPI) staining. Histological results showed a correct preservation of peripheral nerve architecture and no significant differences were found between the two groups. However, Schwann cells viability showed in the CAM-DAPI staining was significantly superior in the albumin group. The viability of Schwann cells was significantly increased when albumin was added to the nerve cryopreservation protocol. However, no significant structural differences were found between groups. Further studies need to be performed to assess the cryopreserved nerve functionality using this new method. PMID- 29700650 TI - Effect of metronidazole ophthalmic solution on corneal neovascularization in a rat model. AB - PURPOSE: To evaluate the effect of metronidazole ophthalmic solutions on corneal neovascularization (CNV) in a rat model. METHODS: A chemical burn was created in the right central cornea of 40 rats. Animals were randomized and distributed into four study groups (n = 10 rats per group) designated Met_0.1%, Met_0.5%, sham, and untreated groups. Chemical-burned corneas in the Met_0.1% and Met_0.5% groups received ophthalmic solutions of 0.1 and 0.5% metronidazole, respectively. Corneas in the sham group received phosphate-buffered saline (metronidazole diluent). All treated eyes received ophthalmic solution at intervals of 6 h, for up to 30 days. Untreated corneas received no treatment. CNV was evaluated postinjury using corneal photographs at different evaluation time points. The main CNV outcome measures were: burn intensity, index of CNV, and percentage of vascularized corneal area. Five rats from each group were euthanized, on days 15 and 30; the samples were collected for histological analyses. Differences with P < 0.05 were considered significant. RESULTS: CNV was observed in the eyes from day 7 postinjury. However, the indices of CNV for the Met_0.1% and Met_0.5% groups were smaller than those for the sham and untreated groups (P < 0.05). Furthermore, corneas treated with 0.1 or 0.5% metronidazole had smaller vascularized areas compared to control corneas. On histological study, the presence of blood vessels confirmed clinical outcomes. CONCLUSIONS: Regular instillation of 0.1 or 0.5% metronidazole had a significant inhibitory effect for CNV on chemical burns induced in a rat model. PMID- 29700651 TI - Comparison of anterior segment parameters and axial length measurements performed on a Scheimpflug device with biometry function and a reference optical biometer. AB - PURPOSE: To compare measurements of axial length (AL), corneal curvature (K), anterior chamber depth (ACD) and white-to-white (WTW) distance on a new device combining Scheimpflug camera and partial coherence interferometry (Pentacam AXL) with a reference optical biometer (IOL Master 500). To evaluate differences between IOL power calculations based on the two biometers. METHODS: Ninety-seven eyes of 97 consecutive cataract or refractive lens exchange patients were examined preoperatively on IOL Master 500 and Pentacam AXL units. Comparisons between two devices were performed for AL, K, ACD and WTW. Intraocular lens (IOL) power targeting emmetropia was calculated with SRK/T and Haigis formulas on both devices and compared. RESULTS: There were statistically significant differences between two devices for all measured parameters (P < 0.05), except ACD (P = 0.36). Corneal curvature measured with Pentacam AXL was significantly flatter then with IOL Master. The mean difference in AL was clinically insignificant (0.01 mm; 95% LoA 0.16 mm). Pentacam AXL yielded higher IOL power in 75% of eyes for Haigis formula and in 62% of eyes for SRK/T formula, with a mean difference within +/- 0.5 D for 72 and 86% of eyes, respectively. CONCLUSIONS: There were statistically significant differences between AL, K and WTW measurements obtained with the compared biometers. Flatter corneal curvature measurements on Pentacam AXL necessitate formulas optimisation for Pentacam AXL. PMID- 29700652 TI - Arginase inhibition prevents the development of hypertension and improves insulin resistance in obese rats. AB - This study investigated the temporal activation of arginase in obese Zucker rats (ZR) and determined if arginase inhibition prevents the development of hypertension and improves insulin resistance in these animals. Arginase activity, plasma arginine and nitric oxide (NO) concentration, blood pressure, and insulin resistance were measured in lean and obese animals. There was a chronological increase in vascular and plasma arginase activity in obese ZR beginning at 8 weeks of age. The increase in arginase activity in obese animals was associated with a decrease in insulin sensitivity and circulating levels of arginine and NO. The rise in arginase activity also preceded the increase in blood pressure in obese ZR detected at 12 weeks of age. Chronic treatment of 8-week-old obese animals with an arginase inhibitor or L-arginine for 4 weeks prevented the development of hypertension and improved plasma concentrations of arginine and NO. Arginase inhibition also improved insulin sensitivity in obese ZR while L arginine supplementation had no effect. In conclusion, arginase inhibition prevents the development of hypertension and improves insulin sensitivity while L arginine administration only mitigates hypertension in obese animals. Arginase represents a promising therapeutic target in ameliorating obesity-associated vascular and metabolic dysfunction. PMID- 29700653 TI - Proanthocyanidin-containing polyphenol extracts from fruits prevent the inhibitory effect of hydrogen sulfide on human colonocyte oxygen consumption. AB - Hydrogen sulfide (H2S), a metabolic end product synthesized by the microbiota from L-cysteine, has been shown to act at low micromolar concentration as a mineral oxidative substrate in colonocytes while acting as an inhibitor of oxygen consumption at higher luminal concentrations (65 uM and above). From the previous works showing that polyphenols can bind volatile sulfur compounds, we hypothesized that different dietary proanthocyanidin-containing polyphenol (PACs) plant extracts might modulate the inhibitory effect of H2S on colonocyte respiration. Using the model of human HT-29 Glc-/+ cell colonocytes, we show here that pre-incubation of 65 uM of the H2S donor NaHS with the different polyphenol extracts markedly reduced the inhibitory effect of NaHS on colonocyte oxygen consumption. Our studies on HT-29 Glc-/+ cell respiration performed in the absence or the presence of PACs reveal rapid binding of H2S with the sulfide oxidizing unit and slower binding of H2S to the cytochrome c oxidase (complex IV of the respiratory chain). Despite acute inhibition of colonocyte respiration, no measurable effect of NaHS on paracellular permeability was recorded after 24 h treatment using the Caco-2 colonocyte monolayer model. The results are discussed in the context of the binding of excessive bacterial metabolites by unabsorbed dietary compounds and of the capacity of colonocytes to adapt to changing luminal environment. PMID- 29700654 TI - The protein-protein interaction network and clinical significance of heat-shock proteins in esophageal squamous cell carcinoma. AB - Heat-shock proteins (HSPs), one of the evolutionarily conserved protein families, are widely found in various organisms, and play important physiological functions. Nevertheless, HSPs have not been systematically analyzed in esophageal squamous cell carcinoma (ESCC). In this study, we applied the protein-protein interaction (PPI) network methodology to explore the characteristics of HSPs, and integrate their expression in ESCC. First, differentially expressed HSPs in ESCC were identified from our previous RNA-seq data. By constructing a specific PPI network, we found differentially expressed HSPs interacted with hundreds of neighboring proteins. Subcellular localization analyses demonstrated that HSPs and their interacting proteins distributed in multiple layers, from membrane to nucleus. Functional enrichment annotation analyses revealed known and potential functions for HSPs. KEGG pathway analyses identified four significant enrichment pathways. Moreover, three HSPs (DNAJC5B, HSPA1B, and HSPH1) could serve as promising targets for prognostic prediction in ESCC, suggesting these HSPs might play a significant role in the development of ESCC. These multiple bioinformatics analyses have provided a comprehensive view of the roles of heat-shock proteins in esophageal squamous cell carcinoma. PMID- 29700655 TI - Quality of life in cancer patients-a comparison of inpatient, outpatient, and rehabilitation settings. AB - PURPOSE: The aim of this study was to compare quality of life (QoL) data from cancer patients in different clinical settings with data from the general population. METHODS: A sample of 4020 German cancer patients (1735 inpatients, 1324 outpatients, 961 participants in rehabilitation treatment) was tested with the EORTC QLQ-C30. RESULTS: Compared with the general population, cancer patients reported markedly worse QoL. There were clinically significant differences on all 15 scales of the EORTC QLQ-C30 (except one). For the sum score, averaging across 13 scales, the effect size of the difference between cancer patients and the general population was d = 1.16. Inpatients reported the greatest detriments to QoL, followed by the rehabilitation patients and the outpatients (mean sum scores 68.6, 71.0, and 72.3, respectively, compared with 89.2 in the general population). Mean scores for different groups of cancer sites are given separately for the three settings. CONCLUSION: The detriments to QoL were stronger than in comparable studies conducted on data from clinical trials. Since these detriments were found in all three settings to a similar degree, health care providers should offer their services not only to inpatients but to outpatients and patients treated in rehabilitation clinics as well. The data can be used for QoL comparisons of assessments from different settings. PMID- 29700656 TI - Enhancing enzyme-aided production of fermentable sugars from poplar pulp in the presence of non-ionic surfactants. AB - Addition of surfactants to enzymatic hydrolysis has been reported to enhance the hydrolytic potential of enzymes in the bioconversion of lignocellulosic biomass to fermentable sugars. The objective of this investigation was to evaluate the effects of four non-ionic surfactants (PEG4000, PEG8000, TitronX-100, and Tween80) on the efficiency of enzymatic hydrolysis of steam-pretreated poplar using a commercial cellulase preparation (Cellic(r) CTec2). Statistical discriminant analysis at four variable factors (surfactant type, surfactant concentration, hydrolysis time, and substrate consistency) revealed that enzymatic hydrolysis was significantly enhanced in the presence of PEG4000, with 19.2% increase in glucose yield over control without surfactant, whereas ANOVA test indicated substrate consistency and hydrolysis time as the most significant factors (P < 0.05). Hydrolysis of poplar pulp at 5% w/w pulp consistency with CTec2 in presence of 1% w/w PEG4000 produced the highest glucose yield of 58.5% after 96 h reaction time. PMID- 29700657 TI - New lipopeptide produced by Corynebacterium aquaticum from a low-cost substrate. AB - Conventional biosurfactants have high production costs. Therefore, the use of low cost carbon sources for their production is attractive for industry. The ability to remain stable under various environmental conditions further extends industrial application. Here we aimed to evaluate the stability of a new lipopeptide produced by Corynebacterium aquaticum using fish residue as an unconventional energy source. The biosurfactant was produced using 3% fish residue, 2% of the microorganism, and mineral medium. Biosurfactant characterization was performed by thin layer chromatography (TLC), as well as by testing its infrared, surface tension, emulsifying activity, and ionic character. The stability of the biosurfactant was evaluated by testing its surface tension at a range of temperatures, pH, and saline concentrations, as well as after 6 months of storage. The biosurfactant was characterized as a lipopeptide due to its retention time, which was coincident with the amino acid and lipid chains obtained in the TLC analysis, being confirmed by some regions of absorption verified in the infrared analysis. The surface tension and emulsifying activity of the biosurfactant were 27.8 mN/m and 87.6%, respectively, and showed anionic character. The biosurfactant was stable at temperatures of 20 to 121 degrees C, in saline concentrations of 1 to 7%, and at pH close to neutrality. Based on our findings, it is possible to use unconventional sources of energy to produce a lipopeptide biosurfactant that can act under various environments. PMID- 29700658 TI - Soluble lipase-catalyzed synthesis of methyl esters using a blend of edible and nonedible raw materials. AB - This work investigates the use of blends of edible and nonedible raw materials as an alternative feedstock to fatty acid methyl esters (FAME) production through enzymatic catalysis. As biocatalyst, liquid lipase from Thermomyces lanuginosus (CalleraTM Trans L), was used. Under reaction conditions of 35 degrees C, methanol to feedstock molar ratio of 4.5:1 and 1.45% of catalyst load, the best process performance was reached using 9% of water concentration in the medium yield of 79.9% after 480 min of reaction. In terms of use of tallow mixed with soybean oil, the best yield was obtained when 100% of tallow was used in the process-84.6% after 480 min of reaction-behavior that was associated with the degree of unsaturation of the feedstock, something by that time, not addressed in papers of the area. The results show that tallow can be used as an alternative to FAME production, catalyzed by soluble lipase. PMID- 29700659 TI - Mathematical Basis of Predicting Dominant Function in Protein Sequences by a Generic HMM-ANN Algorithm. AB - The accurate annotation of an unknown protein sequence depends on extant data of template sequences. This could be empirical or sets of reference sequences, and provides an exhaustive pool of probable functions. Individual methods of predicting dominant function possess shortcomings such as varying degrees of inter-sequence redundancy, arbitrary domain inclusion thresholds, heterogeneous parameterization protocols, and ill-conditioned input channels. Here, I present a rigorous theoretical derivation of various steps of a generic algorithm that integrates and utilizes several statistical methods to predict the dominant function in unknown protein sequences. The accompanying mathematical proofs, interval definitions, analysis, and numerical computations presented are meant to offer insights not only into the specificity and accuracy of predictions, but also provide details of the operatic mechanisms involved in the integration and its ensuing rigor. The algorithm uses numerically modified raw hidden markov model scores of well defined sets of training sequences and clusters them on the basis of known function. The results are then fed into an artificial neural network, the predictions of which can be refined using the available data. This pipeline is trained recursively and can be used to discern the dominant principal function, and thereby, annotate an unknown protein sequence. Whilst, the approach is complex, the specificity of the final predictions can benefit laboratory workers design their experiments with greater confidence. PMID- 29700660 TI - Drug Repositioning by Integrating Known Disease-Gene and Drug-Target Associations in a Semi-supervised Learning Model. AB - Computational drug repositioning has been proven as a promising and efficient strategy for discovering new uses from existing drugs. To achieve this goal, a number of computational methods have been proposed, which are based on different data sources of drugs and diseases. These methods approach the problem using either machine learning- or network-based models with an assumption that similar drugs can be used for similar diseases to identify new indications of drugs. Therefore, similarities between drugs and between diseases are usually used as inputs. In addition, known drug-disease associations are also needed for the methods as prior information. It should be noted that those associations are still not well established due to the fact that many of marketed drugs have been withdrawn and this could affect the outcome of the methods. In this study, we propose a novel method named RLSDR (Regularized Least Square for Drug Repositioning) to find new uses of drugs. More specifically, it relies on a semi supervised learning model, Regularized Least Square, thus it does not require definition of non-drug-disease associations as previously proposed machine learning-based methods. In addition, the similarity between drugs measured by chemical structures of drug compounds and the similarity between diseases which share phenotypes can be represented in a form of either similarity network or similarity matrix as inputs of the method. Moreover, instead of using a gold standard set of known drug-disease associations, we construct an artificial set of the associations based on known disease-gene and drug-target associations. Experiment results demonstrate that RLSDR achieves better prediction performance on the artificial set of drug-disease associations than that on the gold-standard ones in terms of area under the Receiver Operating Characteristic (ROC) curve (AUC). In addition, it outperforms two representative network-based methods irrespective of the prior information of drug-disease associations. Novel indications for a number of drugs are also identified and validated by evidences from a different data resource. PMID- 29700663 TI - Reaching and Supporting At-Risk Community Based Seniors: Results of a Multi church Partnership. AB - The purpose of this study was to determine the impact of a nurse-led, church based educational support group for "at-risk," older African Americans on hospitalization and emergency department use. Study nurses enrolled 81 "at-risk" older adult members of ten churches. Participants completed a trifold pamphlet identifying personal health information and support, and they attended eight monthly educational/support group sessions in their church during the 10-month intervention. Study nurses completed a risk assessment interview with each senior both pre- and post-participation. The study nurse completed post-program assessments with 64 seniors, a 79% retention rate. At the program's conclusion researchers conducted a focus group with the study RNs and used an anonymous written survey to gather participant appraisals of program elements. Neither hospitalization nor emergency department/urgent care usage was significantly different from pre- to post-program. Session attendance was moderate to high and over half of the seniors brought a family member or friend to one or more sessions. The majority of seniors initiated positive health changes (e.g., smoking cessation, weight loss, or diet changes). Participants expressed high satisfaction and expressed satisfaction to perceive that they were supporting other seniors in their community. We conclude that this intervention was successful in engaging and motivating seniors to initiate health behavior change and contributed to a health-supportive church-based community. To demonstrate a statistically significant difference in hospital and ED usage, however, a stronger intervention or a larger sample size is needed. PMID- 29700662 TI - Is the Fractional Laser Still Effective in Assisting Cutaneous Macromolecule Delivery in Barrier-Deficient Skin? Psoriasis and Atopic Dermatitis as the Disease Models. AB - PURPOSE: Most of the investigations into laser-assisted skin permeation have used the intact skin as the permeation barrier. Whether the laser is effective in improving cutaneous delivery via barrier-defective skin is still unclear. METHODS: In this study, ablative (Er:YAG) and non-ablative (Er:glass) lasers were examined for the penetration of peptide and siRNA upon topical application on in vitro skin with a healthy or disrupted barrier. RESULTS: An enhanced peptide flux (6.9 fold) was detected after tape stripping of the pig stratum corneum (SC). A further increase of flux to 11.7 fold was obtained after Er:YAG laser irradiation of the SC-stripped skin. However, the application of Er:glass modality did not further raise the flux via the SC-stripped skin. A similar trend was observed in the case of psoriasiform skin. Conversely, the flux was enhanced 3.7 and 2.6 fold after treatment with the Er:YAG and the Er:glass laser on the atopic dermatitis (AD)-like skin. The 3-D skin structure captured by confocal microscopy proved the distribution of peptide and siRNA through the microchannels and into the surrounding tissue. CONCLUSIONS: The fractional laser was valid for ameliorating macromolecule permeation into barrier-disrupted skin although the enhancement level was lower than that of normal skin. PMID- 29700665 TI - Psychological Distress Behavioral Patterns Among Latinos: We Don't See Ourselves as Worthless. AB - A cross-sectional study of 4921 Latinos from the National Health Interview Survey was conducted to examine behavioral patterns of psychological distress among Latinos. Latent class analysis was used to ascertain psychological distress behavioral profiles among Latinos. Analysis revealed four latent classes of distress, which included moderate psychological distress (13.6%); mild sadness, nervousness, and restlessness (13.0%); high psychological distress (2.8%); and no psychological distress (70.7%). Worthlessness, a widely-accepted dimension of distress, was not a significant behavioral trait. Results from the present study suggest that underlying cultural elements affect the subjective interpretations of symptoms reported by Latinos. These findings highlight distress profiles among Latinos and the possibility of overlooking behaviors that are uniquely indicative of distress, potentially leading to the underreporting of serious psychological distress in this population. Furthermore, these findings shed light on other paradoxical issues impacting the mental health of Latinos. PMID- 29700664 TI - Halving the volume of AnaConDa: initial clinical experience with a new small volume anaesthetic reflector in critically ill patients-a quality improvement project. AB - AnaConDa-100 ml (ACD-100, Sedana Medical, Uppsala, Sweden) is well established for inhalation sedation in the intensive care unit. But because of its large dead space, the system can retain carbon dioxide (CO2) and increase ventilatory demands. We therefore evaluated whether AnaConDa-50 ml (ACD-50), a device with half the internal volume, reduces CO2 retention and ventilatory demands during sedation of invasively ventilated, critically ill patients. Ten patients participated in this cross-over protocol. After sedation with isoflurane via ACD 100 for 24 h, the 5-h observation period started. During the first hour, ACD-100 was used; for the next 2 h, ACD-50; and for the last 2 h, ACD-100 was used again. Sedation was titrated to Richmond Agitation and Sedation Scale (RASS) score - 3 to - 4 and a processed electroencephalogram (Narcotrend Index, Narcotrend-Gruppe, Hannover, Germany) was recorded. Minute ventilation, CO2 elimination, and isoflurane consumption were compared. All patients were deeply sedated (Narcotrend Index, mean +/- SD: 38 +/- 10; RASS scores - 3 to - 5) and breathed spontaneously with pressure support throughout the observation period. Infusion rates of isoflurane and opioid, either remifentanil or sufentanil, as well as ventilator settings were unchanged. Minute ventilation and end-tidal CO2 were significantly reduced with the ACD-50, respiratory rate remained unchanged, and tidal volume decreased by 66 +/- 43 ml. End-tidal isoflurane concentrations were also slightly reduced while haemodynamic measures remained constant. The ACD-50 reduces the tidal volume needed to eliminate carbon dioxide without augmenting isoflurane consumption. PMID- 29700666 TI - Paranoia Symptoms Moderate the Impact of Emotional Context Processing on Community Functioning of Individuals with Schizophrenia. AB - This study examined whether better emotional context processing is associated with better community functioning among persons with schizophrenia, and whether the relationship between the two variables is moderated by level of paranoid symptoms. The Brief Psychiatric Rating Scale-Expanded Version, Emotional Context Processing Scale, and Multnomah Community Ability Scale were administered to 39 community-dwelling participants with schizophrenia or schizoaffective disorder. Emotional context processing had a small-to-moderate association with community functioning. However, the association between emotional context processing and community functioning was moderated by level of paranoid symptoms. Emotional context processing in participants with mild paranoid symptoms was strongly associated with better community functioning, whereas emotional context processing in those with severe paranoid symptoms was not. Emotional context processing and the degree of paranoia should be considered in treatment plans designed to enhance the community functioning of individuals with schizophrenia to help them improve their understanding of social situations. PMID- 29700661 TI - Parkinson Disease from Mendelian Forms to Genetic Susceptibility: New Molecular Insights into the Neurodegeneration Process. AB - Parkinson disease (PD) is known as a common progressive neurodegenerative disease which is clinically diagnosed by the manifestation of numerous motor and nonmotor symptoms. PD is a genetically heterogeneous disorder with both familial and sporadic forms. To date, researches in the field of Parkinsonism have identified 23 genes or loci linked to rare monogenic familial forms of PD with Mendelian inheritance. Biochemical studies revealed that the products of these genes usually play key roles in the proper protein and mitochondrial quality control processes, as well as synaptic transmission and vesicular recycling pathways within neurons. Despite this, large number of patients affected with PD typically tends to show sporadic forms of disease with lack of a clear family history. Recent genome-wide association studies (GWAS) meta-analyses on the large sporadic PD case-control samples from European populations have identified over 12 genetic risk factors. However, the genetic etiology that underlies pathogenesis of PD is also discussed, since it remains unidentified in 40% of all PD-affected cases. Nowadays, with the emergence of new genetic techniques, international PD genomics consortiums and public online resources such as PDGene, there are many hopes that future large-scale genetics projects provide further insights into the genetic etiology of PD and improve diagnostic accuracy and therapeutic clinical trial designs. PMID- 29700667 TI - Association of Therapeutic Alliance with Outcomes Over Two Years in Youth and Family Service. AB - This study examines therapeutic alliance (TA) over 2 years and the association with clinical outcomes for children and youth in a home and school-based behavioral health service characterized by innovative TA practices. Caregiver report of TA and functioning were collected monthly and discussed to inform service planning. Trajectory analysis was conducted to discern distinct patterns of TA ratings over time with linear mixed models to examine factors associated with the resulting TA patterns. We identified 1714 Medicaid-eligible youth and families. The majority of families (84%) reported high and steady ratings of TA, 5% reported lower but improving TA ratings, and 11% reported declining TA ratings over time. Average TA rating was associated with family and child functioning, yet all TA groups experienced improved functioning over time. Measurement of TA over time may help clinicians target and improve care for children and families. PMID- 29700668 TI - Work Engagement, Burnout and Personal Accomplishments Among Social Workers: A Comparison Between Those Working in Children and Adults' Services in England. AB - Social workers (SWs) provide emotional and practical support to vulnerable service users who are likely to suffer from emotional trauma and mental health conditions. Stress and burnout levels are reported to be high among SWs, however, little is known about their relationships with different characteristics. The current article utilises unique and large dataset (n = 3786) on SWs working in adults and children's services to examine factors associated with burnout. Employing job-demand/resources model and structural equations modelling, we highlight the varying significant impact of work-engagement, administrative support and work experience as moderating factors to burnout across adult and children service specialism in this sample. PMID- 29700669 TI - Is There a Role for Postmastectomy Radiation (PMRT) in Patients with T1-2 Tumors and One to Three Positive Lymph Nodes Treated in the Modern Era? PMID- 29700670 TI - Value of Omentoplasty in Abdominoperineal Resection with Primary Perineal Closure for Rectal Cancer. PMID- 29700671 TI - Flubendiamide affects visual and locomotory activities of Drosophila melanogaster for three successive generations (P, F1 and F2). AB - Flubendiamide is widely used in agricultural fields to exterminate a broad spectrum of pests (lepidopteran insects) by disrupting their muscle function. The main objective of this study was to find the effects of flubendiamide on a non target organism, Drosophila melanogaster (dipteran insect). In the present study, different sub-lethal concentrations of Flubendiamide caused a significant (P < 0.05) decrease in acetylcholinesterase activity and increase in cytochrome P450 activity in adult D. melanogaster. Phototaxis and climbing behaviours were found to significantly (P < 0.05) alter in exposed flies. The observed alteration in phototaxis and climbing behaviours were not restricted to P generation, but were found to be transmitted to subsequent generations (F1 and F2 generation) that had never been directly exposed to the test chemical during their life time. It is only their predecessors (P generation) who have been affronted with different concentrations of Flubendiamide. Humans and Drosophilids share almost 60% genomic similarity and 75% disease gene resemblance. Moreover, most of the circuits governing the behaviours studied involve the inhibition and excitation of neurotransmitters, which are conserved in humans and flies. Thus, the present findings suggest that chronic flubendiamide exposure might induce alteration in neurotransmission leading to discrepancy in the behavioural responses (vision and flight) in other beneficial insects and insect-dependent organisms. PMID- 29700672 TI - Simulated Gastrointestinal Digestion, Bioaccessibility and Antioxidant Capacity of Polyphenols from Red Chiltepin (Capsicum annuum L. Var. glabriusculum) Grown in Northwest Mexico. AB - Chiltepin, a wild chili mostly used in different traditional foods and traditional medicine in Northwest Mexico, represents a source of polyphenols. However, studies about the bioaccessibility of polyphenols as a parameter to measure the nutritional quality and bioefficacy of them in the fruit after consumption are scarce. Chiltepin showed phenolic acids and flavonoids contents between 387 and 65 MUg/g, respectively. Nevertheless, these values decreased after the digestion process. Before digestion, gallic acid, 4-hydroxibenzoinc acid, chlorogenic acid, caffeic acid, p-coumaric acid, quercetin and luteolin were the main polyphenols found in chiltepin by HPLC-DAD and confirmed by FIA-ESI IT-MS/MS. Gallic and chlorogenic acids were non-detected in the gastric phase, while only p-coumaric acid (5.35 +/- 3.89 MUg/g), quercetin (5.91 +/- 0.92 MUg/g) and luteolin (2.86 +/- 0.62 MUg/g) were found in the intestinal phase. The bioaccessibility of phenolic acids, flavonoids, and total polyphenols after the intestinal phase was around 24, 17 and 23%, respectively. Overall, results indicated that release of polyphenols from chiltepin fruit might be affected by the food matrix and gastrointestinal conditions due to the low bioaccessibility values observed. PMID- 29700673 TI - Pazopanib efficacy in recurrent central nervous system hemangiopericytomas. AB - INTRODUCTION: There is currently no treatment for solitary fibrous tumors/hemangiopericytomas (SFT/H) of the central nervous system recurring after multiple surgeries and radiotherapies. The NAB2-STAT6 gene fusion is the hallmark of these tumors, and upregulates Early Growth Factor, activating several growth pathways. METHODS: We treated two patients presenting pluri-recurrent meningeal SFT/H with Pazopanib, a broad-spectrum tyrosine kinase inhibitor. We analyzed the exome and RNA sequencing data of one of them and, in addition to another meningeal SFT/H, compared it to the transcriptomic profiling of 5 systemic SFT/H. RESULTS: A dramatic clinical and radiological response was observed in both cases, respectively 84 and 43% decrease after 3 months. As a comparison, Pazopanib has only a stabilizing effect in systemic SFT/H. Indeed, central nervous system SFT/H show overexpression of different tyrosine kinases targeted by Pazopanib. CONCLUSIONS: Two consecutive patients with untreatable central nervous system SFT/H showed a spectacular partial response to Pazopanib, an unprecedented result in SFT/H. This result could be explained by differences in expression profiles and calls for a confirmation in a larger cohort of patients. PMID- 29700674 TI - Protective Factors Among Transgender and Gender Variant Youth: A Systematic Review by Socioecological Level. AB - Transgender and gender variant (GV) youth experience elevated risk for poor health and academic outcomes due mainly to social experiences of stigma and discrimination. To supplement the growing evidence on health risks encountered by transgender/GV youth, we identified factors theorized to be protective for these youth across all four levels of Bronfenbrenner's socioecological model (individual, relationship, community, societal). We conducted a systematic search of peer-reviewed research. The articles included in this review were published in peer-reviewed journals in English or Spanish between 1999 and 2014, analyzed data from a sample or subsample of transgender or GV participants with a mean age between 10 and 24 years, and examined the relationship of at least one theorized protective factor to a health or behavioral outcome. Twenty-one articles met inclusion criteria. Transgender/GV youth in included articles ranged from 11 to 26 years of age, were racially/ethnically diverse, and represented varied gender identities. Within these articles, 27 unique protective factors across four levels of the ecological model were identified as related to positive health and well-being. Self-esteem at the individual level, healthy relationships with parents and peers at the relationship-level, and gay-straight alliances at the community level emerged as protective factors across multiple studies. Our findings underscore the relative lack of research on transgender/GV youth and protective factors. Novel recruitment strategies for transgender/GV youth and better measurement of transgender identities are needed to confirm these protective relationships and identify others. Growth in these areas will contribute to building a body of evidence to inform interventions. PMID- 29700675 TI - TALEN-mediated targeted mutagenesis of fatty acid desaturase 2 (FAD2) in peanut (Arachis hypogaea L.) promotes the accumulation of oleic acid. AB - KEY MESSAGE: A first creation of high oleic acid peanut varieties by using transcription activator-like effecter nucleases (TALENs) mediated targeted mutagenesis of Fatty Acid Desaturase 2 (FAD2). Transcription activator like effector nucleases (TALENs), which allow the precise editing of DNA, have already been developed and applied for genome engineering in diverse organisms. However, they are scarcely used in higher plant study and crop improvement, especially in allopolyploid plants. In the present study, we aimed to create targeted mutagenesis by TALENs in peanut. Targeted mutations in the conserved coding sequence of Arachis hypogaea fatty acid desaturase 2 (AhFAD2) were created by TALENs. Genetic stability of AhFAD2 mutations was identified by DNA sequencing in up to 9.52 and 4.11% of the regeneration plants at two different targeted sites, respectively. Mutation frequencies among AhFAD2 mutant lines were significantly correlated to oleic acid accumulation. Genetically, stable individuals of positive mutant lines displayed a 0.5-2 fold increase in the oleic acid content compared with non-transgenic controls. This finding suggested that TALEN-mediated targeted mutagenesis could increase the oleic acid content in edible peanut oil. Furthermore, this was the first report on peanut genome editing event, and the obtained high oleic mutants could serve for peanut breeding project. PMID- 29700676 TI - FFPE breast tumour blocks provide reliable sources of both germline and malignant DNA for investigation of genetic determinants of individual tumour responses to treatment. AB - BACKGROUND: Bio-banked formalin-fixed paraffin-embedded (FFPE) tissues provide an excellent opportunity for translational genomic research. Historically matched blood has not always been collected as a source of germline DNA. This project aimed to establish if normal FFPE breast tissue could be used as an alternative to blood. METHODS: Exome sequencing was carried out on matched tumour tissue, normal breast tissue and blood on five patients in the START trial. Retrieved samples had been archived at different centres for at least 13 years. Following tissue macro-dissection and DNA extraction, targeted exome capture was performed using SureSelect Human All Exome v5 reagents (Agilent). Illumina paired-end libraries were prepared from the captured target regions and sequenced on a HiSeq2500 (Illumina) acquiring 2 * 75 bp reads. Somatic variants were called using the MuTect software analysis tool and copy number abnormalities (CNA) were identified using CNVkit. Targeted sequencing and droplet digital PCR were used to validate somatic variants and CNA, respectively. RESULTS: Overlap of somatic variants and CNA called on tumour versus blood and tumour versus normal breast tissue was good. Agreement in somatic variant calling ranged from 76.9 to 93.6%. Variants with an allele frequency lower than 10% were more difficult to validate irrespective of the type of germline DNA used. Pearson's correlation coefficients for paired comparisons of CNA using blood or normal tissue as reference ranged from 0.70 to 0.94. CONCLUSIONS: There is good correlation between the somatic mutations and CNA called using archived blood or normal breast tissue as germline reference material. PMID- 29700677 TI - A DFT study of the structure-property relationships of bistetrazole-based high nitrogen energetic metal complexes. AB - In this work, six series of new energetic metal complexes were designed. Each complex contained a large, high-energy, high-nitrogen, anionic chelating ligand (either the 5,5'-bistetrazolate anion, the 5,5'-azobistetrazolate anion, or the 5,5'-(hydrazine-1,2-diyl)bis-[1H-tetrazol-1-ide] anion-each of which has a different bridging group), Cu or Ni as the metal atom, and two small complexing agent ligands (NH3 and/or NH2NO2). The molecular and electronic structures, heats of formation, densities, detonation properties, and impact sensitivities of the novel complexes were studied using density functional theory. Furthermore, the effects of varying the large chelating ligand (and thus the bridging group), the small complexing agents, and the metal atom on the structure and properties of the complex were investigated and analyzed in depth. The results show that the particular metal, bridging group, and complexing agents included in the energetic complex influence its structure and properties, but the effects of varying the constituents of the complex are complicated or unclear, and these effects are sometimes intertwined. In addition, the detonation pressures, detonation velocities, and impact sensitivities of the novel complexes ranged from 25.9 to 38.6 GPa, from 7.21 to 8.80 km s-1, and from 17 to 48 cm, respectively. Five of the complexes (B3, C3, D3, E3, and F3) appear to possess comparable performance to the famous and widely used high explosive 1,3,5-trinitro-1,3,5-triazinane, making these new complexes attractive to energetic materials experimentalists. PMID- 29700678 TI - Investigating species boundaries using DNA and morphology in the mite Tyrophagus curvipenis (Acari: Acaridae), an emerging invasive pest, with a molecular phylogeny of the genus Tyrophagus. AB - Mites of the genus Tyrophagus (Acari: Acaridae) are among the most widespread and common mites, inhabiting diverse natural and anthropogenic habitats. Some species are pests of agricultural products and stored food and/or live in house dust, causing allergies to humans. We sequenced 1.2 kb of the mitochondrial COI gene for 38 individuals belonging to seven species of Tyrophagus, including T. curvipenis, T. putrescentiae, T. fanetzhangorum, T. longior, T. perniciosus, and T. cf. similis. Molecular phylogenetic analyses (1) recovered two major clades corresponding to the presence or absence of eyespots, and (2) separated all included morphological species. Tyrophagus curvipenis and T. putrescentiae had the lowest between-species genetic distances (range, mean +/- SD): 14.20-16.30, 15.17 +/- 0.40 (K2P). The highest within-species variation was found in T. putrescentiae 0.00-4.33, 1.78 +/- 1.44 (K2P). In this species, we recovered two distinct groups; however, no geographical or ecological dissimilarities were observed between them. Based on our analyses, we document important morphological differences between T. curvipenis and T. putrescentiae. For the first time, we record the occurrence of T. curvipenis in the New World and suggest that it may be an emerging pest as it is currently spreading in agricultural produce. PMID- 29700679 TI - Adult Connection in Assault Injury Prevention among Male Youth in Low-Resource Urban Environments. AB - Strengths-based strategies to reduce youth violence in low-resource urban communities are urgently needed. Supportive adolescent-adult relationships may confer protection, but studies have been limited by self-reported composite outcomes. We conducted a population-based case-control study among 10- to 24-year old males in low-resource neighborhoods to examine associations between supportive adult connection and severe assault injury. Cases were victims of gunshot assault injury (n = 143) and non-gun assault injury (n = 206) from two level I trauma centers. Age- and race-matched controls (n = 283) were recruited using random digit dial from the same catchment. Adolescent-adult connections were defined by: (1) brief survey questions and (2) detailed family genograms. Analysis used conditional logistic regression. There were no significant associations between positive adult connection, as defined by brief survey questions, and either gunshot or non-gun assault injury among adolescents with high prior violence involvement (GSW OR = 2.46, 95% CI 0.81-7.49; non-gun OR = 1.59, 95% CI 0.54-4.67) or low prior violence involvement (GSW OR = 0.92, 95% CI 0.34-2.44; non-gun OR = 1.96, 95% CI 0.73-5.28). In contrast, among adolescents with high levels of prior violence involvement, reporting at least one supportive adult family member in the family genogram was associated with higher odds of gunshot assault injury (OR = 4.01, 95% CI 1.36-11.80) and non-gun assault injury (OR = 4.22, 95% CI 1.48-12.04). We were thus unable to demonstrate that positive adult connections protected adolescent males from severe assault injury in this highly under-resourced environment. However, at the time of injury, assault injured adolescents, particularly those with high prior violence involvement, reported high levels of family support. The post-injury period may provide opportunities to intervene to enhance and leverage family connections to explore how to better safeguard adolescents. PMID- 29700681 TI - Study of the Efficiency of the Hydroporation for Delivery of Plasmid DNA to the Cells on the Model of Toxic Neuropathy. AB - We compared the efficiency of delivery of plasmid DNA (active ingredient concentration 1 mg/kg) that provides production of nerve growth factor (NGF) after intravenous administration to rats and after administration by hydroporation. The method of hydroporation ensured plasmid penetration into the liver tissue and lengthened the time of its detection in the organ. DNA concentration in 1 h after its introduction by hydroporation or intravenous route was 0.7 and 0.05 ng/mg tissue, respectively. The use of this transfection method ensured preservation of NGF DNA in the liver tissue at a level of 0.24 ng/mg of tissue 1 day after administration of the plasmid construct, while after intravenous administration, expression of the analyzed DNA was not detected in blood and liver samples. After hydroporation, the maximum of relative normalized expression of cDNA (270 rel. units) was observed after 4 h, and after 1 day, this parameter decreased to 35 rel. units. Introduction of plasmid DNA of NGF by hydroporation prevented the development of disorders of neuromuscular conduction in a rats model of toxic neuropathy induced by subacute administration of malathion in a dose of 0.5 LD50. PMID- 29700680 TI - Can tissue biomarkers reliably predict the biological behavior of craniopharyngiomas? A comprehensive overview. AB - BACKGROUND: The growing interest in the molecular and genetic alterations of craniopharyngiomas (CPs) is embodied in recent studies revealing insights into the CP tumorigenesis and identifying novel molecular pathways amenable of targeted therapies. The actual impact of this new information, however, remains inconclusive. METHODS: We present a comprehensive review of the accumulated knowledge on molecular biology of CPs and a critical analysis on the strengths and weaknesses of the studies focused on CP molecular/genetic alterations published to date. RESULTS: A thorough analysis of the alterations of beta catenin/CTNNB1 and BRAF genes investigated in 1123 CP cases included in 27 studies, showed that, on average, CTNNB1 mutations were present in two-thirds of adamantinomatous CPs and BRAF mutations in 90% of papillary CPs. Their role as oncogenic drivers has not been well established. Although rare, coexistence of both mutations may occur. The involvement of pituitary stem cells in human CP tumorigenesis is still uncertain. Expression of stem markers in human CP samples predominantly occurred along the CP border in contact with brain tissue. Finally, none of the various molecular alterations which have been proposed as markers for CP recurrence can be used today as reliable predictors of the CP behavior. CONCLUSIONS: The isolated evaluation of CPs' molecular or genetic profiles that do not take into consideration fundamental pathological and therapeutic factors, specifically the tumor topography and the degree of tumor removal, may actually generate confusion regarding the reliability of some biomarkers to predict the CP biological behavior. PMID- 29700683 TI - In memoriam Jurgen Rost (1952-2017). PMID- 29700682 TI - EUS-Guided Hepaticojejunostomy Using Novel Plastic Stent Combined with Antegrade Metal Stent Placement. AB - BACKGROUND: Endoscopic ultrasound-guided hepaticojejunostomy (EUS-HJS) combined with antegrade stenting (AS) can proceed if patients are complicated with duodenal obstruction or surgical anatomy such as Roux-en-Y esophagojejunostomy. A novel plastic stent (Gadelius Medical Co. Ltd., Tokyo, Japan) that is designed to prevent stent migration into the abdominal cavity was made available in Japan. Here, we describe technical tips for EUS-HJS combined with EUS-AS using this plastic stent. TECHNICAL PRESENTATION: After the intrahepatic bile duct is punctured, the guidewire is inserted into the intestine across the bile duct obstruction site. Next, the fistula is dilated using a balloon catheter. And then, metal stent placement is antegradely performed. Finally, stent placement using this novel plastic stent is performed from the intrahepatic bile duct to the intestine. CONCLUSION: Compared with EUS-HJS using a metal stent, EUS-HJS using this novel plastic stent has several advantages such as cost benefit, easy re-intervention, and preventing vomiting due to reflux bile juice. Therefore, EUS HJS combined with AS using this novel plastic stent may be preferable compared with using a metal stent. PMID- 29700684 TI - Multiple Imputation for Bounded Variables. AB - Missing data are a common issue in statistical analyses. Multiple imputation is a technique that has been applied in countless research studies and has a strong theoretical basis. Most of the statistical literature on multiple imputation has focused on unbounded continuous variables, with mostly ad hoc remedies for variables with bounded support. These approaches can be unsatisfactory when applied to bounded variables as they can produce misleading inferences. In this paper, we propose a flexible quantile-based imputation model suitable for distributions defined over singly or doubly bounded intervals. Proper support of the imputed values is ensured by applying a family of transformations with singly or doubly bounded range. Simulation studies demonstrate that our method is able to deal with skewness, bimodality, and heteroscedasticity and has superior properties as compared to competing approaches, such as log-normal imputation and predictive mean matching. We demonstrate the application of the proposed imputation procedure by analysing data on mathematical development scores in children from the Millennium Cohort Study, UK. We also show a specific advantage of our methods using a small psychiatric dataset. Our methods are relevant in a number of fields, including education and psychology. PMID- 29700685 TI - High-luminance perovskite light-emitting diodes with high-polarity alcohol solvent treating PEDOT:PSS as hole transport layer. AB - BACKGROUND: Perovskite light-emitting diodes (PeLEDs) are fabricated with a structure of indium tin oxide (ITO)/poly(3,4-ethylenedioxythiophene):polystyrene sulfonate (PEDOT:PSS)/CH3NH3PbBr3 (MAPbBr3)/1,3,5-tris(2-N-phenylbenzimidazolyl) benzene (TPBi)/Ag. PEDOT: PSS films treated with alcohols including methanol, ethanol, and isopropanol are used to realize high-performance PeLEDs. Among them, by using PEDOT:PSS film treated by methanol as the hole transport layer, the PeLED with a maximum luminance of 2075 cd m-2 and a maximum current efficiency of 0.38 cd A-1 is achieved. Meanwhile, the result shows that the luminance of PeLEDs increases with the polarity of alcohol solvent. The conductivity of PEDOT:PSS films and crystallization of perovskite films are analyzed to gain a deep illumination into the influence of alcohol solvent treatment on device performance. It is also found that the treatment brings not only an improved hole injection capability but also a significantly enhanced crystallization of perovskite. This work indicates that our founding brings a simple and effective method to improve the device performance of PeLEDs. PMID- 29700686 TI - Follow-up of Temporary Implantable Nitinol Device (TIND) Implantation for the Treatment of BPH: a Systematic Review. AB - PURPOSE OF REVIEW: The purpose of the present systematic review is to offer a narrative synthesis of the available literature regarding the role of the temporary implantable nitinol device (TIND) (Medi-Tate(r); Medi-Tate Ltd., Or Akiva, Israel) for the treatment of benign prostatic hyperplasia (BPH)-related lower urinary tract symptoms (LUTS), specifically focusing on the follow-up data. RECENT FINDINGS: Current available evidences are limited in this topic. Sample size of patients available for analysis is small. Moreover, the duration of follow-up period is intermediate and longer follow-up is required. At the available 3 years follow-up, the TIND implantation is safe, effective, and well tolerated. The extended follow-up of the first and only available cohort of patients who underwent TIND for LUTS related to BPH corroborated previous literature findings. Further studies are required in order to assess the durability of TIND outcomes over a longer follow-up, to better define the indications of this approach, and to demonstrate the advantages of second generation device over the first. PMID- 29700687 TI - Medical Treatment Options for Patients with Epidermal Growth Factor Receptor Mutation-Positive Non-Small Cell Lung Cancer Suffering from Brain Metastases and/or Leptomeningeal Disease. AB - Brain metastases and/or leptomeningeal disease (LMD) with associated central nervous system (CNS) metastases are known complications of advanced epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). It is important, therefore, to assess the activity of EGFR tyrosine kinase inhibitors (TKIs) versus such CNS complications. This review explores the literature reporting the intracranial activity of EGFR TKIs, and finds that there is evidence for varying efficacy of the approved agents, erlotinib, gefitinib, afatinib, and osimertinib in patients with CNS metastases. Other EGFR TKIs in development, such as AZD3759, may have a future role as therapeutic options in this setting. Emerging evidence indicates that the second- and third-generation EGFR TKIs, afatinib and osimertinib, effectively penetrate the blood-brain barrier, and therefore represent viable treatment options for CNS lesions, and can reduce the risk of CNS progression. These agents should therefore be considered as first-line treatment options in patients with EGFR mutation positive NSCLC who have brain metastases and/or LMD. While there are currently no prospective data comparing the intracranial efficacy of second- and third generation EGFR TKIs in this setting, CNS activity and protection offered by different EGFR TKIs should be an additional consideration when making decisions about the optimal sequence of treatment with EGFR TKIs in order to maximize survival benefit in individual patients. PMID- 29700689 TI - Imaging inflammation in atherosclerotic plaques: Just make it easy! AB - The presence of inflammatory cells is a hallmark of unstable atherosclerotic plaques. Several imaging approaches have been developed for the noninvasive detection of inflammatory activities in atherosclerotic plaques. Positron emission tomography (PET) imaging with the injection of 18F-fluorodeoxyglucose (FDG) is currently the most widely used imaging technique to evaluate the density of activated macrophages in atherosclerotic plaques. Nevertheless, FDG-PET imaging has logistical and technical constraints that represent an important obstacle to the wider use of this approach for the evaluation of patients with atherosclerosis. In a similar way as in the oncological field, the balance between the benefits and costs of new drugs need to be improved in patients with cardiovascular diseases. PET imaging of plaque inflammation might represent a very useful tool to identify patients who could benefit the most from anti inflammatory treatments and to exclude patients with other causes of inflammation who are the most likely to develop severe side effects under these drugs. The availability of radiotracers targeting more specifically inflammation in atherosclerotic plaques would greatly facilitate the logistic organization of this imaging and help to expand the use of PET for the evaluation of atherosclerotic patients. PMID- 29700688 TI - Elucidating Solvation Structures for Rational Design of Multivalent Electrolytes A Review. AB - Fundamental molecular-level understanding of functional properties of liquid solutions provides an important basis for designing optimized electrolytes for numerous applications. In particular, exhaustive knowledge of solvation structure, stability, and transport properties is critical for developing stable electrolytes for fast-charging and high-energy-density next-generation energy storage systems. Accordingly, there is growing interest in the rational design of electrolytes for beyond lithium-ion systems by tuning the molecular-level interactions of solvate species present in the electrolytes. Here we present a review of the solvation structure of multivalent electrolytes and its impact on the electrochemical performance of these batteries. A direct correlation between solvate species present in the solution and macroscopic properties of electrolytes is sparse for multivalent electrolytes and contradictory results have been reported in the literature. This review aims to illustrate the current understanding, compare results, and highlight future needs and directions to enable the deep understanding needed for the rational design of improved multivalent electrolytes. PMID- 29700690 TI - Structural-dynamical transition in the Wahnstrom mixture. AB - In trajectory space, dynamical heterogeneities in glass-forming liquids correspond to the emergence of a dynamical phase transition between an active phase poor in local structure and an inactive phase which is rich in local structure. We support this scenario with the study of a model additive mixture of Lennard-Jones particles, quantifying how the choice of the relevant structural and dynamical observable affects the transition in trajectory space. We find that the low mobility, structure-rich phase is dominated by icosahedral order. Applying a non-equilibrium rheological protocol, we connect local order to the emergence of mechanical rigidity. PMID- 29700691 TI - 'Nano-immuno test' for the detection of live Mycobacterium avium subspecies paratuberculosis bacilli in the milk samples using magnetic nano-particles and chromogen. AB - Early rapid detection of Mycobacterium avium subspecies paratuberculosis (MAP) bacilli in milk samples is the major challenge since traditional culture method is time consuming and laboratory dependent. We report a simple, sensitive and specific nano-technology based 'Nano-immuno test' capable of detecting viable MAP bacilli in the milk samples within 10 h. Viable MAP bacilli were captured by MAP specific antibody-conjugated magnetic nano-particles using resazurin dye as chromogen. Test was optimized using true culture positive (10-bovine and 12 goats) and true culture negative (16-bovine and 25-goats) raw milk samples. Domestic livestock species in India are endemically infected with MAP. After successful optimization, sensitivity and specificity of the 'nano-immuno test' in goats with respect to milk culture was 91.7% and 96.0%, respectively. Whereas, it was 90.0% (sensitivity) and 92.6% (specificity) with respect to IS900 PCR. In bovine milk samples, sensitivity and specificity of 'nano-immuno test' with respect to milk culture was 90.0% and 93.7%, respectively. However, with respect to IS900 PCR, the sensitivity and specificity was 88.9% and 94.1%, respectively. Test was validated with field raw milk samples (goats-258 and bovine-138) collected from domestic livestock species to detect live/viable MAP bacilli. Of 138 bovine raw milk samples screened by six diagnostic tests, 81 (58.7%) milk samples were positive for MAP infection in one or more than one diagnostic tests. Of 81 (58.7%) positive bovine raw milk samples, only 24 (17.4%) samples were detected positive for the presence of viable MAP bacilli. Of 258 goats raw milk samples screened by six diagnostic tests, 141 (54.6%) were positive for MAP infection in one or more than one test. Of 141 (54.6%) positive raw milk samples from goats, only 48 (34.0%) were detected positive for live MAP bacilli. Simplicity and efficiency of this novel 'nano-immuno test' makes it suitable for wide-scale screening of milk samples in the field. Standardization, validation and re-usability of functionalized nano-particles and the test was successfully achieved in field samples. Test was highly specific, simple to perform and easy to read by naked eyes and does not require laboratory support in the performance of test. Test has potential to be used as screening test to estimate bio-load of MAP in milk samples at National level. PMID- 29700693 TI - Prolonged Post-Traumatic Vasospasm Resulting in Delayed Cerebral Ischemia After Mild Traumatic Brain Injury. PMID- 29700692 TI - Mannitol and Hypertonic Saline Reduce Swelling and Modulate Inflammatory Markers in a Rat Model of Intracerebral Hemorrhage. AB - BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) leaves most survivors dependent at follow-up. The importance of promoting M2-like microglial responses is increasingly recognized as a key element to ameliorate brain injury following ICH. The osmotherapeutic agents, mannitol and hypertonic saline (HTS), which are routinely used to reduce intracranial pressure, have been shown to reduce neuroinflammation in experimental ischemic and traumatic brain injury, but anti inflammatory effects of osmotherapies have not been investigated in ICH. METHODS: We studied the effects of iso-osmotic mannitol and HTS in rat models of ICH utilizing high-dose and moderate-dose collagenase injections into the basal ganglia, associated with high and low mortality, respectively. We studied the effects of osmotherapies, first given 5 h after ICH induction, and then administered every 12 h thereafter (4 doses total). Immunohistochemistry was used to quantify microglial activation and polarization. RESULTS: Compared to controls, mannitol and HTS increased plasma osmolarity 1 h after infusion (301 +/ 1.5, 315 +/- 4.2 and 310 +/- 2.0 mOsm/kg, respectively), reduced mortality at 48 h (82, 36 and 53%, respectively), and reduced hemispheric swelling at 48 h (32, 21, and 17%, respectively). In both perihematomal and contralateral tissues, mannitol and HTS reduced activation of microglia/macrophages (abundance and morphology of Iba1 + cells), and in perihematomal tissues, they reduced markers of the microglia/macrophage M1-like phenotype (nuclear p65, TNF, and NOS2), increased markers of the microglia/macrophage M2-like phenotype (arginase, YM1, and pSTAT3), and reduced infiltration of CD45 + cells. CONCLUSIONS: Repeated dosing of osmotherapeutics at regular intervals may be a useful adjunct to reduce neuroinflammation following ICH. PMID- 29700694 TI - A rare and threatening complication in a cirrhotic patient. PMID- 29700695 TI - Visceral adiposity index (VAI), a powerful predictor of incident hypertension in prehypertensives. PMID- 29700696 TI - The vexed question of whether or not to measure levels of direct oral anticoagulants before surgery or invasive procedures. AB - Direct oral anticoagulants (DOAC) possess high bioavailability, and their anticoagulant effect is more predictable than that of vitamin K antagonists, hence they do not require routine dose adjustment based on laboratory testing. However, there are circumstances when laboratory testing may be useful, including patients who need to undergo surgery or invasive procedures. Most guidelines state that patients on DOAC may safely undergo surgery/invasive procedures by stopping anticoagulation for a few days before intervention without testing if renal function is within normal limits. This review article discusses the pros and cons of measuring (or not measuring) DOAC levels before surgery/invasive procedures by a multidisciplinary team of experts with different background, including the thrombosis laboratory, clinical thrombosis, internal medicine, cardiology and nephrology. The conclusion is that measuring DOAC with dedicated tests before surgical or invasive procedures is important for patient safety. It provides the best and most direct evidence to rule in (or to rule out) clinically relevant concentrations of residual drugs. Regulatory agencies should urgently approve their use in clinical practice. Hospital administrators should make them available, and clinical laboratories should set up the relative methods and make them available to clinicians. PMID- 29700697 TI - Essential Elements of Early Post Discharge Care of Patients with Heart Failure. AB - PURPOSE OF REVIEW: Heart failure is associated with an enormous burden on both patients and health care systems in the USA. Several national policy initiatives have focused on improving the quality of heart failure care, including reducing readmissions following hospitalization, which are common, costly, and, at least in part, preventable. The transition from inpatient to ambulatory care setting and the immediate post-hospitalization period present an opportunity to further optimize guideline concordant medical therapy, identify reversible issues related to worsening heart failure, and evaluate prognosis. It can also provide opportunities for medication reconciliation and optimization, consideration of device-based therapies, appropriate management of comorbidities, identification of individual barriers to care, and a discussion of goals of care based on prognosis. RECENT FINDINGS: Recent studies suggest that attention to detail regarding patient comorbidities, barriers to care, optimization of both diuretic and neurohormonal therapies, and assessment of prognosis improve patient outcomes. Despite the fact that the transition period appears to be an optimal time to address these issues in a comprehensive manner, most patients are not referred to programs specializing in this approach post hospital discharge. The objective of this review is to provide an outline for early post discharge care that allows clinicians and other health care providers to care for these heart failure patients in a manner that is both firmly rooted in the guidelines and patient-centered. Data regarding which intervention is most likely to confer benefit to which subset of patients with this disease is lacking and warrants further study. PMID- 29700698 TI - A novel nonsense EIF1AX mutation identified in a thyroid nodule histologically diagnosed as oncocytic carcinoma. PMID- 29700699 TI - Concentration, Source, and Potential Human Health Risk of Heavy Metals in the Commonly Consumed Medicinal Plants. AB - A trend toward the use of traditional and herbal medicines has developed nowadays, and there is a growing concern regarding them being polluted with heavy metals. This study measured the heavy metal concentrations in eight different types of medicinal herbs and eight different types of herbal distillates sold in the markets in Sanandaj, Kurdistan, Iran. The concentration of some metals (Cd, Cu, Mn, Fe, Zn, Al, Co, Ni, Cr, Pb, and Mg) was quantified by inductively coupled plasma mass spectrometry, and the associated health risk for adults and children was estimated. The mean concentration of all the metals was within the permissible limits set by the WHO. The medicinal herbs contained significantly more Al, As, Cd, Cr, Fe, Mn, Ni, Pb, and Zn (p < 0.02) than the herbal distillates. However, the concentrations of Cu and Hg were higher in the herbal distillates. The non-carcinogenic risks of consumption of traditional medicines in adults and children were assessed based on the target hazard quotients (THQs). The THQs for individual metals (except Al and Cr) from individual herbs were less than 1, which is considered as safe for human consumption. PMID- 29700701 TI - Greetings from the chief editor. PMID- 29700700 TI - Mercury, Lead, Cadmium, and Barium Levels in Human Breast Milk and Factors Affecting Their Concentrations in Hamadan, Iran. AB - Breast milk is considered the best source of nutrition for all infants. However, exposure of newborns to toxic metals is of special interest due to their potential harmful effects. Thus, the primary aims of this study were to determine the concentration of toxic heavy metals including lead, mercury, cadmium, and barium in breast milk samples from Hamadan, Iran, in relation to some sociodemographic variables. A total of 100 breast milk samples were collected and their heavy metal contents were measured by inductively coupled plasma mass spectroscopy (ICP-MS). The median breast milk concentrations of Pb, Hg, and Ba were 41.9, 2.8, and 1.95 MUg/L, respectively. Cd levels were < 1 MUg/L in all samples. The Pb level in 94% of the samples was higher than the recommended Pb limit of < 5 MUg/L in breast milk suggested by World Health Organization (WHO). Hg levels in 54% of the breast milk samples were higher than the normal mean concentration (1.7 MUg/L) suggested by WHO. We found no correlation between Hg levels in breast milk and sociodemographic factors. Ba levels in all the breast milk samples were lower than the WHO's proposed health-based drinking water guideline (0.7 mg/L). Considering the results of the present study and the vulnerability of infants, along with the well-known toxicity of these metals, further studies are warranted to identify the main sources of exposure that contribute their concentration in breast milk, establish harmless intake values of toxic metals in breast milk, and develop preventive measures. PMID- 29700702 TI - The impact of serum uric acid reduction on renal function and blood pressure in chronic kidney disease patients with hyperuricemia. AB - BACKGROUND: Febuxostat is tolerable in chronic kidney disease (CKD) patients with hyperuricemia. However, the long-term effect of lowering uric acid with febuxostat on renal function and blood pressure has not been elucidated. METHODS: This was a 2 years retrospective observational study. 86 CKD patients with hyperuricemia who continued with allopurinol (allopurinol group, n = 30), switched from allopurinol to febuxostat (switched group, n = 25), or were newly prescribed febuxostat (febuxostat group, n = 31) were included in this study. Serum uric acid, estimated glomerular filtration rate (eGFR), blood pressure, and urinary protein were analyzed. Moreover, the impact of serum uric acid reduction on renal function and blood pressure was assessed. RESULTS: Serum uric acid in the switched and febuxostat groups was significantly reduced at 6 months (switched group; 8.49 +/- 1.32-7.19 +/- 1.14 mg/dL, p < 0.0001, febuxostat group; 9.43 +/- 1.63-6.31 +/- 0.90 mg/dL, p < 0.0001). In the allopurinol group, serum uric acid was increased (6.86 +/- 0.87-7.10 +/- 0.85 mg/dL, p = 0.0213). eGFR was significantly increased (35.2 +/- 12.8-37.3 +/- 13.9 mL/min/1.73 m2, p = 0.0232), while mean arterial pressure (93.1 +/- 10.8-88.2 +/- 9.5 mmHg, p = 0.0039) was significantly decreased at 6 months in the febuxostat group, resulting in the retention of eGFR for 2 years. CONCLUSIONS: The impact of serum uric acid reduction might have beneficial effects on CKD progression and blood pressure. However, a large prospective study is needed to determine the long-term efficacy of febuxostat therapy in CKD patients with hyperuricemia. PMID- 29700703 TI - Lack of correlation between aristolochic acid exposure and hepatocellular carcinoma. PMID- 29700704 TI - Synthesis of antibacterial poly(o-chloroaniline)/chromium hybrid composites with enhanced electrical conductivity. AB - Electrically conductive polyorthochloroaniline/chromium nanocomposites (POC/Cr NCs) were prepared by in situ chemical oxidative polymerization of orthochloroaniline in the presence of Cr nanoparticles (Cr NPs). The load percentage of Cr nanofiller was varied in POC matrix to investigate the effect of Cr nanoparticles on the properties of the nanocomposites. The composition, structure, and morphology of POC and its composites were examined by Scanning electron microscopy, Fourier transform infrared spectroscopy, and UV-visible spectroscopic analysis. The antibacterial potential of POC and its composites was evaluated by the disc diffusion method against Escherichia coli and Bacillus subtilis. The results showed the improved antibacterial potential with the increase in the load percentage of nanofiller. The electrical conductivity of polymer and its composites was measured and correlated with the load percentage. The results showed that electrical conductivity of the composites was enhanced with the increase in load percentage of Cr nanoparticles. PMID- 29700705 TI - Imaging scoring systems for preoperative molecular diagnoses of lower-grade gliomas. AB - Recent advance in molecular characterization of gliomas showed that patient prognosis and/or tumor chemosensitivity correlate with certain molecular signatures; however, this information is available only after tumor resection. If molecular information is available by routine radiological examinations, surgical strategy as well as overall treatment strategy could be designed preoperatively.With the aim to establish an imaging scoring system for preoperative diagnosis of molecular status in lower-grade gliomas (WHO grade 2 or 3, LrGGs), we investigated 8 imaging features available on routine CT and MRI in 45 LGGs (discovery cohort) and compared them with the status of 1p/19q codeletion, IDH mutations, and MGMT promoter methylation. The scoring systems were established based on the imaging features significantly associated with each molecular signature, and were tested in the another 52 LrGGs (validation cohort).For prediction of 1p/19q codeletion, the scoring system is composed of calcification, indistinct tumor border on T1, paramagnetic susceptibility effect on T1, and cystic component on FLAIR. For prediction of MGMT promoter methylation, the scoring system is composed of indistinct tumor border, surface localization (FLAIR), and cystic component. The scoring system for prediction of IDH status was not established. The 1p/19q score >= 3 showed PPV of 96.2% and specificity of 98.1%, and the MGMT methylation score >= 2 showed PPV of 77.4% and specificity of 67.6% in the entire cohort.These scoring systems based on widely available imaging information may help to preoperatively design personalized treatment in patients with LrGG. PMID- 29700706 TI - Single-Walled Carbon Nanotube Dominated Micron-Wide Stripe Patterned-Based Ferroelectric Field-Effect Transistors with HfO2 Defect Control Layer. AB - Ferroelectric field-effect transistors (FeFETs) with single-walled carbon nanotube (SWCNT) dominated micron-wide stripe patterned as channel, (Bi,Nd)4Ti3O12 films as insulator, and HfO2 films as defect control layer were developed and fabricated. The prepared SWCNT-FeFETs possess excellent properties such as large channel conductance, high on/off current ratio, high channel carrier mobility, great fatigue endurance performance, and data retention. Despite its thin capacitance equivalent thickness, the gate insulator with HfO2 defect control layer shows a low leakage current density of 3.1 * 10-9 A/cm2 at a gate voltage of - 3 V. PMID- 29700707 TI - Parent Perceptions of Community Autism Spectrum Disorder Stigma: Measure Validation and Associations in a Multi-site Sample. AB - In this study we developed a brief, English/Spanish bilingual parent-reported scale of perceived community autism spectrum disorder (ASD) stigma and tested it in a multi-site sample of Latino and non-Latino white parents of children with ASD. Confirmatory factor analysis of the scale supported a single factor solution with 8 items showing good internal consistency. Regression modeling suggested that stigma score was associated with unmet ASD care needs but not therapy hours or therapy types. Child public insurance, parent nativity, number of children with ASD in the household, parent-reported ASD severity, and family structure, were associated with higher stigma score. The scale and the scale's associations with service use may be useful to those attempting to measure or reduce ASD stigma. PMID- 29700708 TI - Brief Report: Sex Differences in Parental Concerns for Toddlers with Autism Risk. AB - Research on sex differences in autism spectrum disorder (ASD) suggests both higher prevalence and a more easily observable presentation of core ASD symptomology in males, which may lead to sex differences in parental concerns. The current study examined whether sex and diagnosis relate to the timing, number, and types of pre-diagnosis concerns for 669 (Nmale = 468) toddlers who screened at risk for ASD. No sex differences in parents' concerns emerged for toddlers diagnosed with ASD; however, in the overall at-risk sample, parents of boys endorsed ASD symptoms, including restricted and repetitive behaviors, more than parents of girls. Future research should examine why sex differences in pre diagnosis concerns emerge and how they might impact early diagnosis for at-risk boys versus girls. PMID- 29700709 TI - The Deer Mouse (Peromyscus maniculatus) as an Enzootic Reservoir of Plague in California. AB - It has long been theorized that deer mice (Peromyscus maniculatus) are a primary reservoir of Yersinia pestis in California. However, recent research from other parts of the western USA has implicated deer mice as spillover hosts during epizootic plague transmission. This retrospective study analyzed deer mouse data collected for plague surveillance by public health agencies in California from 1971 to 2016 to help elucidate the role of deer mice in plague transmission. The fleas most commonly found on deer mice were poor vectors of Y. pestis and occurred in insufficient numbers to maintain transmission of the pathogen, while fleas whose natural hosts are deer mice were rarely observed and even more rarely found infected with Y. pestis on other rodent hosts. Seroprevalence of Y. pestis antibodies in deer mice was significantly lower than that of several chipmunk and squirrel species. These analyses suggest that it is unlikely that deer mice play an important role in maintaining plague transmission in California. While they may not be primary reservoirs, results supported the premise that deer mice are occasionally exposed to and infected by Y. pestis and instead may be spillover hosts. PMID- 29700710 TI - HER2 genomic amplification in circulating tumor DNA and estrogen receptor positivity predict primary resistance to trastuzumab emtansine (T-DM1) in patients with HER2-positive metastatic breast cancer. AB - BACKGROUND: Trastuzumab emtansine (T-DM1) is approved for the treatment of patients with human epidermal growth factor receptor 2 (HER2)-positive advanced breast cancer (ABC), and has high efficacy. However, some patients exhibit primary resistance to T-DM1, and thus methods that can predict resistance in clinical practice are needed. Genomic analysis of circulating tumor DNA (ctDNA) in plasma is a non-invasive and reproducible method. This study aimed to predict primary resistance to T-DM1 by combining genomic analysis of ctDNA and other clinicopathological features of patients with HER2-positive ABC. METHODS: The study population comprised 34 patients with HER2-positive ABC who had been treated with T-DM1. Correlations between clinicopathological characteristics of patients and primary resistance to T-DM1 were examined, and HER2 gene copy number and PIK3CA gene mutations were analyzed using plasma ctDNA samples obtained from 16 patients before T-DM1 administration. RESULTS: Among the 34 patients, nine (26.5%) had progressive disease at the first efficacy analysis; these patients were considered to have primary resistance to T-DM1. No significant difference was found in the rate of primary resistance to T-DM1 between groups. Among 16 patients whose ctDNA was analyzed, four showed primary resistance to T-DM1. These four patients showed negative HER2 gene amplification in ctDNA and were ER positive and/or PR-positive by immunohistochemistry. CONCLUSIONS: HER2 gene amplification in ctDNA and ER and PR status may predict primary resistance to T DM1. A liquid biopsy before the initiation of T-DM1 treatment could be a non invasive way to predict whether a patient would exhibit primary resistance to T DM1. PMID- 29700711 TI - Cyclin-dependent kinase 4/6 inhibitors in hormone receptor-positive early breast cancer: preliminary results and ongoing studies. AB - The cyclin D-cyclin-dependent kinase (CDK) 4/6-inhibitors (CDK4/6i) induce cell cycle arrest in the G1 phase what eventually can prevent the proliferation of cancer cells. The CDK4/6i have changed the landscape of treatment options for ER positive, HER2-negative metastatic breast cancer. Currently, palbociclib, ribociclib, and abemaciclib are approved by the US Food and Drug Administration in this setting. This success encouraged the researchers to examine CDK4/6i activity in (neo)adjuvant setting. In this review, clinical data to date and ongoing clinical trials with palbociclib, ribociclib, and abemaciclib in the early breast cancer are discussed. A literature search of these topics was carried out using PubMed and data reported at international oncology meetings and clinicaltrials.gov were included. Currently, we have the early promising data from Phase II clinical trials of CDK4/6i efficacy in the neoadjuvant setting in women with HR-positive breast cancer. Moreover, there are numerous studies that are in progress today in (neo)adjuvant setting. PMID- 29700712 TI - Toxicity prediction and assessment of an environmentally realistic pesticide mixture to Daphnia magna and Raphidocelis subcapitata. AB - In a regulatory perspective addressing the cumulative effect of co-occurring chemicals is the first and most important step in providing a more realistic hazard assessment of chemical cocktails to both man and environment. This study was conducted to show if joint effects on the immobilisation of the crustacean Daphnia magna and on the growth inhibition of algae Raphidocelis subcapitata follow additivity (concentration addition (CA) or independent action (IA) predictions) or if there is an interaction between chemicals in the organisms upon exposure to an environmentally realistic mixture of chlorpyrifos and terbuthylazine, with expected different molecular sites of action. A pattern of antagonism at lower doses and synergism at higher doses was found for acute immobility data, while no deviation from the additive conceptual models was observed in the algae inhibition test. Results in relation to the relevant set of regulatory acceptable concentrations (RACs) and environmental quality standards (EQSs) derived for individual chlorpyrifos and terbuthylazine were evaluated. PMID- 29700713 TI - Acute and chronic effects of exposure to the juvenile hormone analog fenoxycarb during sexual reproduction in Daphnia magna. AB - Recent studies have demonstrated that insect growth regulating insecticides are able to affect reproductive endpoints in zooplankton species at very low levels. For the cyclic parthenogenetic water flea Daphnia, most of this research has focused on the asexual part of the life cycle and induction of male offspring. Even though Daphnia and many other aquatic invertebrates rely on sexual reproduction and subsequent production of dormant eggs to recover from environmentally harsh conditions, much less is known about the effects of toxicants on the sexual reproductive phase. Using fenoxycarb as a model pesticide, we exposed male and female neonate Daphnia magna, under conditions inducing a switch to sexual reproduction, and tested for effects on dormant egg (ephippia) production and sex ratio of parthenogenetic offspring. Subsequently, we assessed whether fenoxycarb exposure affected the quality of the produced dormant eggs and viability of the hatchlings. Our results showed that exposure to sub-lethal concentrations of fenoxycarb caused a sharp decrease in parthenogenetic reproduction, while inducing male offspring. Dormant egg production was marginally negatively affected, but survival and fitness of the hatched individuals were not significantly affected. This indicates that under pesticide stress, surviving adult females invested in sexual reproduction at the expense of parthenogenetic reproduction. Exposure to toxicants during the sexual reproductive phase, could affect the active aquatic phase as well as the dormant phase in natural zooplankton populations. This indicates the need for further ecotoxicological research and development of test protocols taking into account the full life cycle of zooplankton species. PMID- 29700714 TI - Advancing the Multi-Informant Assessment of Sluggish Cognitive Tempo: Child Self Report in Relation to Parent and Teacher Ratings of SCT and Impairment. AB - Despite increasing interest in sluggish cognitive tempo (SCT) in children and advancements in its measurement, little research has examined child self-reported SCT. Child self-report of SCT is important for the multi-informant assessment of SCT. The current study used a large, school-based sample of children and a multi informant design to examine child self-reported SCT using the Child Concentration Inventory - Version 2 (CCI-2) which was recently revised based on meta-analytic findings and parallels the item content of validated parent and teacher rating scales. The study involved 2142 unique children (ages 8-13 years, 50.51% males). Children (n = 1980) completed measures of SCT, loneliness, and preference for solitude. Mothers (n = 1648), fathers (n = 1358), and teachers (n = 1773) completed measures of SCT, attention-deficit/hyperactivity disorder-IN (ADHD-IN), academic impairment, social impairment, and conflicted shyness. Children's self reported SCT demonstrated good reliability with the 15 SCT symptoms showing moderate to strong loadings on the SCT factor. The child self-report SCT factor also showed moderate convergent validity with mother, father, and teacher ratings of children's SCT. In addition, higher child-reported SCT predicted greater mother, father, and teacher ratings of children's academic impairment even after controlling for mother, father, and teacher ratings of children's SCT and ADHD IN. Higher child-rated SCT also predicted greater mother ratings of children's social impairment after controlling for mother ratings of children's SCT and ADHD IN. The present study provides initial empirical support for the reliability and validity of child-reported SCT as part of the multi-informant assessment of SCT. A key direction for future research includes evaluating the unique contributions of different informants and their utility within specific contexts to guide evidence-based recommendations for assessing SCT. PMID- 29700715 TI - Factors influencing inguinal hernia symptoms and preoperative evaluation of symptoms by patients: results of a prospective study including 1647 patients. AB - BACKGROUND: Current recommendations for hernia treatment suggest applying techniques aimed at reducing postoperative pain in patients experiencing intense preoperative pain. However, there is still no reliable stratification method of preoperative pain, its circumstances, intensity and frequency, and the current assessments of hernia symptoms are performed by means of a subjective evaluation. The aim of this work is to discuss preoperative pain before hernia repair and determine its nature depending on the type and length of hernia persistence and the patient's age. MATERIALS AND METHODS: The data from 1647 patients before inguinal hernia repairs (2010-2017) were registered prospectively in the National Hernia Repair Register (demographic data, pain score and influence on everyday activities). RESULTS: The most common symptom upon admission was pain (949 patients at rest; 57.6% and 1561 at physical activity; 94.8%). A significant influence of hernia persistence on the pain occurrence and intensity was not observed between patients with hernia < 12-months (60.8%;VAS5.0) and > 5-years (58.3%;VAS5.4) (p = 0.068). The occurrence and intensity of pain was significantly higher patients < 40-years (63.7%;VAS5.4) than patients > 60-years (54.3%;VAS4.8) (p = 0.008). CONCLUSIONS: While pain at rest is not a significant problem, undertaking physical activities may intensify pain and increase the number of patients suffering from it. Preoperative assessment of pain may help determine the group of younger patients who could benefit the most from inguinal hernia repair. New indications for prompter admission for treatment should be planned in future studies of patients showing pain at rest for possible prevention of postoperative neuropathy. PMID- 29700716 TI - Open versus robotic-assisted transabdominal preperitoneal (R-TAPP) inguinal hernia repair: a multicenter matched analysis of clinical outcomes. AB - PURPOSE: To compare the perioperative outcomes of initial, consecutive robotic assisted transabdominal preperitoneal (R-TAPP) inguinal hernia repair (IHR) cases with consecutive open cases completed by the same surgeons. METHODS: Multicenter, retrospective, comparative study of perioperative results from open and robotic IHR using standard univariate and multivariate regression analyses for propensity score matched (1:1) cohorts. RESULTS: Seven general surgeons at six institutions contributed 602 consecutive open IHR and 652 consecutive R-TAPP IHR cases. Baseline patient characteristics in the unmatched groups were similar with the exception of previous abdominal surgery and all baseline characteristics were comparable in the matched cohorts. In matched analyses, postoperative complications prior to discharge were comparable. However, from post discharge through 30 days, fewer patients experienced complications in the R-TAPP group than in the open group [4.3% vs 7.7% (p = 0.047)]. The R-TAPP group had no reoperations post discharge through 30 days of follow-up compared with five patients (1.1%) in the open group (p = 0.062), respectively. Multivariate logistic regression analysis which demonstrated patient age > 65 years and the open approach were risk factors for complications within 30 days post discharge in the matched group [age > 65 years: odds ratio (OR) = 3.33 (95% CI 1.89, 5.87; p < 0.0001); open approach: OR = 1.89 (95% CI 1.05, 3.38; p = 0.031)]. CONCLUSIONS: In this matched analysis, R-TAPP provides similar postoperative complications prior to discharge and a lower rate of postoperative complications through 30 days compared to open repair. R-TAPP is a promising and reproducible approach, and may facilitate adoption of minimally invasive repairs of inguinal hernias. PMID- 29700717 TI - Enriched Environment Elicits Proangiogenic Mechanisms After Focal Cerebral Ischemia. AB - Brain has limited capacity for spontaneous recovery of lost function after stroke. Exposure to enriched environment (EE) can facilitate functional recovery, but mechanisms underlying this effect are poorly understood. Here, we used a middle cerebral artery occlusion (MCAO) model to investigate the impact of EE on angiogenesis in the post-ischemic brain in adult male Sprague Dawley rats, and examined whether blood-borne factors may contribute. Compared with standard cage (SC), exposure to EE was associated with greater improvement in neurological function, higher peri-infarct vascular density, and higher chronic post-ischemic cerebral blood flow assessed by laser speckle imaging. The effect persisted for at least 28 days. EE also enhanced the expression of hepatocyte growth factor in the peri-ischemic cortex when measured 15 days after MCAO. Interestingly, serum from rats exposed to EE after MCAO showed elevated levels of hepatocyte growth factor, and plasma or serum from rats exposed to EE after MCAO enhanced the survival and proliferation of cultured endothelial cells, in vitro, when compared with control plasma or serum from SC group after MCAO. Together, our data suggest that exposure to EE promotes angiogenesis in the ischemic brain that may in part be mediated by blood-borne factors. PMID- 29700720 TI - Conservative laparoscopic approach in a large splenic epidermoid cyst. PMID- 29700719 TI - Influence of Time-Series Normalization, Number of Nodes, Connectivity and Graph Measure Selection on Seizure-Onset Zone Localization from Intracranial EEG. AB - We investigated the influence of processing steps in the estimation of multivariate directed functional connectivity during seizures recorded with intracranial EEG (iEEG) on seizure-onset zone (SOZ) localization. We studied the effect of (i) the number of nodes, (ii) time-series normalization, (iii) the choice of multivariate time-varying connectivity measure: Adaptive Directed Transfer Function (ADTF) or Adaptive Partial Directed Coherence (APDC) and (iv) graph theory measure: outdegree or shortest path length. First, simulations were performed to quantify the influence of the various processing steps on the accuracy to localize the SOZ. Afterwards, the SOZ was estimated from a 113 electrodes iEEG seizure recording and compared with the resection that rendered the patient seizure-free. The simulations revealed that ADTF is preferred over APDC to localize the SOZ from ictal iEEG recordings. Normalizing the time series before analysis resulted in an increase of 25-35% of correctly localized SOZ, while adding more nodes to the connectivity analysis led to a moderate decrease of 10%, when comparing 128 with 32 input nodes. The real-seizure connectivity estimates localized the SOZ inside the resection area using the ADTF coupled to outdegree or shortest path length. Our study showed that normalizing the time series is an important pre-processing step, while adding nodes to the analysis did only marginally affect the SOZ localization. The study shows that directed multivariate Granger-based connectivity analysis is feasible with many input nodes (> 100) and that normalization of the time-series before connectivity analysis is preferred. PMID- 29700718 TI - Intermittent Fasting: Is the Wait Worth the Weight? AB - PURPOSE OF REVIEW: We review the underlying mechanisms and potential benefits of intermittent fasting (IF) from animal models and recent clinical trials. RECENT FINDINGS: Numerous variations of IF exist, and study protocols vary greatly in their interpretations of this weight loss trend. Most human IF studies result in minimal weight loss and marginal improvements in metabolic biomarkers, though outcomes vary. Some animal models have found that IF reduces oxidative stress, improves cognition, and delays aging. Additionally, IF has anti-inflammatory effects, promotes autophagy, and benefits the gut microbiome. The benefit-to-harm ratio varies by model, IF protocol, age at initiation, and duration. We provide an integrated perspective on potential benefits of IF as well as key areas for future investigation. In clinical trials, caloric restriction and IF result in similar degrees of weight loss and improvement in insulin sensitivity. Although these data suggest that IF may be a promising weight loss method, IF trials have been of moderate sample size and limited duration. More rigorous research is needed. PMID- 29700721 TI - Measuring Depth of Invasion in Early Squamous Cell Carcinoma of the Oral Tongue: Positive Deep Margin, Extratumoral Perineural Invasion, and Other Challenges. AB - The 8th edition of American Joint Committee on Cancer (AJCC 8th) staging manual incorporated depth of invasion (DOI) into pT stage of oral cavity cancer. The aim of this study was to characterize several histological findings that may complicate measurement of DOI in early conventional squamous cell carcinomas (SCC) of the oral tongue: (1) lack of or minimal residual carcinoma following biopsy; (2) positive deep margin; (3) extratumoral perineural invasion (PNI); and (4) lymphatic or vascular invasion. Conventional SCC of the oral tongue (n = 407) with the largest dimension of <= 4 cm and with a negative elective cervical lymph node dissection (pN0) were reviewed. A clear plastic ruler was used to measure DOI by dropping a "plumb line" to the deepest point of the invasive tumor from the level of the basement membrane of the normal mucosa closest to the invasive tumor. Examples of identifying reference point on the mucosal surface of oral tongue from which to measure the DOI are illustrated. In the experience of one contributing institution, the residual carcinoma was absent in 14.2% of glossectomies (34/239), while in 4.8% of cases (10/205) there was only minimal residual carcinoma. In 11.5% (21/183) of pT2 cases the deep margin was positive and thus DOI and pT may be underestimated. Of all cases with PNI, extratumoral PNI was identified in 23.1% (31/134) of cases, but represented the deepest point of invasion in only two cases. In one case, lymphatic invasion represented the deepest point of invasion and could have led to upstaging from pT1 to pT2. In conclusion, DOI measurement for SCC of the oral tongue may require re-examination of the diagnostic biopsy in up to 20% of cases due to the absence or only minimal residual carcinoma in glossectomy specimens. In 11.5% of apparently pT2 cases, DOI may be underestimated due to the positive deep margin. Rarely, extratumoral PNI or lymphatic invasion may be the deepest point of invasion. Overall, two issues (absent or minimal residual disease and positive deep margin) may confound DOI measurement in early SCCs of oral tongue. PMID- 29700722 TI - Oral Mycosis Fungoides: A Report of Three Cases and Review of the Literature. AB - Mycosis fungoides (MF) and Sezary syndrome are clonal T-cell proliferations that exhibit skin homing and represent the majority of cutaneous T-cell lymphomas. Early MF is a diagnostic challenge as both the clinical and microscopic features often mimic benign inflammatory conditions. Oral MF is very rare and has been associated in the past with advanced disease and a poor prognosis. Skin lesions are present for an average of > 6 years before oral involvement occurs. The clinical appearance is highly variable with tongue, palate and gingiva most often affected. We report 3 additional cases of oral MF, including one in which oral lesions are the initial disease presentation. Survival in patients presenting with oral MF is improving and can be attributed to advances in therapy. PMID- 29700725 TI - Towards the construction of high-quality mutagenesis libraries. AB - OBJECTIVES: To improve the quality of mutagenesis libraries in directed evolution strategy. RESULTS: In the process of library transformation, transformants which have been shown to take up more than one plasmid might constitute more than 20% of the constructed library, thereby extensively impairing the quality of the library. We propose a practical transformation method to prevent the occurrence of multiple-plasmid transformants while maintaining high transformation efficiency. A visual library model containing plasmids expressing different fluorescent proteins was used. Multiple-plasmid transformants can be reduced through optimizing plasmid DNA amount used for transformation based on the positive correlation between the occurrence frequency of multiple-plasmid transformants and the logarithmic ratio of plasmid molecules to competent cells. CONCLUSIONS: This method provides a simple solution for a seemingly common but often neglected problem, and should be valuable for improving the quality of mutagenesis libraries to enhance the efficiency of directed evolution strategies. PMID- 29700724 TI - Facing temptation: The neural correlates of gambling availability during sports picture exposure. AB - Nowadays, sports betting has become increasingly available and easy to engage in. Here we examined the neural responses to stimuli that represent sporting events available for betting as compared to sporting events without a gambling opportunity. We used a cue exposure task in which football (soccer) fans (N = 42) viewed cues depicting scheduled football games that would occur shortly after the scanning session. In the "betting" condition, participants were instructed to choose, at the end of each block, the game (and the team) they wanted to bet on. In the "watching" condition, participants chose the game they would prefer to watch. After the scanning session, participants completed posttask rating questionnaires assessing, for each cue, their level of confidence about the team they believed would win and how much they would enjoy watching the game. We found that stimuli representing sport events available for betting elicited higher fronto-striatal activation, as well as higher insular cortex activity and functional connectivity, than sport events without a gambling opportunity. Moreover, games rated with more confidence towards the winning team resulted in greater brain activations within regions involved in affective decision-making (ventromedial prefrontal cortex), cognitive inhibitory control (medial and superior frontal gyri) and reward processing (ventral and dorsal striatum). Altogether, these novel findings offer a sensible simulation of how the high availability of sports betting in today's environment impacts on the reward and cognitive control systems. Future studies are needed to extend the present findings to a sample of football fans that includes a samilar proportion of female and male participants. PMID- 29700726 TI - Recent developments in chromatographic purification of biopharmaceuticals. AB - Over the last several decades, researchers have time and again proposed use of non-chromatographic methods for processing of biotherapeutic products. However, chromatography continues to be the backbone of downstream processing, particularly at process scale. There are many reasons for this, critical ones being the unparalleled scalability, robustness, and selectivity that process chromatography offers over its peers. It is no surprise then that process chromatography has been a topic of major developments in resin matrix, ligand chemistry, modalities, high throughput process development, process modelling, and approaches for control. In this review, we attempt to summarize major developments in the above-mentioned areas. Greater significance has been given to advancements in the last 5 years (2013-2017). PMID- 29700727 TI - Analysis of Sulfate Patterns in Glycosaminoglycan Oligosaccharides by MSn Coupled to Infrared Ion Spectroscopy: the Case of GalNAc4S and GalNAc6S. AB - We report distinctive spectroscopic fingerprints of the monosaccharide standards GalNAc4S and GalNAc6S by coupling mass spectrometry and ion spectroscopy in the 3 MUm range. The disaccharide standards CSA and CSC are used to demonstrate the applicability of a novel approach for the analysis of sulfate position in GalNAc containing glycosaminoglycans. This approach was then used for the analysis of a sample containing CSA and CSC disaccharides. Finally, we discuss the generalization of the coupling of mass spectrometry with ion spectroscopy for the structural analysis of glycosaminoglycans on a tetrasaccharide from dermatan sulfate source. Graphical abstract ?. PMID- 29700728 TI - Improved Quantitative Dynamic Range of Time-of-Flight Mass Spectrometry by Simultaneously Waveform-Averaging and Ion-Counting Data Acquisition. AB - Two different types of data acquisition methods, "averaging mode" and "ion counting mode", have been used in a time-of-flight (TOF) mass spectrometry. The most common method is an averaging mode that sums waveform signals obtained from each flight cycle. While it is possible to process many ions arriving at the same TOF in one flight cycle, low-abundance ions are difficult to measure because ion signals are overwhelmed by noises from the detection system. An ion-counting mode is suitable for the detection of such low-concentration ions, but counting loss occurs when two or more ions arrive at the detector within the dead time of the acquisition system. In this study, we introduce a technique that combines two methods to measure target ions with a high concentration difference, i.e., averaging mode and ion-counting mode are used simultaneously for high abundant and trace ions, respectively. By processing waveforms concurrently during data acquisition, one can choose to analyze either or both types of data to achieve a highly quantitative mass spectrum over a wide range of sample concentrations. The result of the argon isotope analysis shows that this method provides a more accurate determination of the isotope ratio compared to averaging mode alone at one-twentieth of the analysis time required by ion-counting alone. Graphical Abstract ?. PMID- 29700729 TI - Possible use of miRNAs-146a and -499 expression and their polymorphisms as diagnostic markers for rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a systemic autoimmune disorder affecting the peripheral joints. Different microRNAs had been investigated in RA including miRNA-146a meanwhile, miRNA-499 there were no studies to prove its expression in RA serum samples. This study was performed to investigate expression of both miRNAs-146a and -499 and their polymorphisms in Egyptian patients with RA and to evaluate their relationship with clinico-pathological data. The present study includes 108 subjects classified into two main groups: 52 RA patients and 56 unrelated healthy controls. RA patients were subclassified according to DAS28 score into inactive (23 patients) and active (29 patients). Quantitative expression of serum miRNA-146a, miRNA-499 as well as their Genotyping rs2910164 (C/G) and rs3746444 (T/C), respectively, were done to all subjects using real time PCR. Serum miRNA-146a and -499 were significantly over expressed in RA patients, but they were not correlated to disease activity. Serum miRNA-146a was negatively correlated with anti-nuclear antibodies (ANA). miRNA-146a (rs2910164) genotyping revealed that the GG genotype and the frequency of the G allele were significantly higher in RA patients compared to the controls. miRNA-499 (rs3746444), genotyping revealed that the CC genotype and the frequency of the C allele were significantly higher. It can be concluded that both miRNAs-146a and 499 can be used as diagnostic markers for RA patients. Both miRNA-146a (rs2710164) and miRNA-499 (rs3746444) were significantly associated with RA susceptibility. The C allele of miRNA-146a (rs2710164) can be considered to be protective. On the other hand, the C allele of miRNA-499 (rs3746444) was significantly associated with RA susceptibility. PMID- 29700730 TI - Surgically acquired sperm use for assisted reproductive technology: trends and perinatal outcomes, USA, 2004-2015. AB - PURPOSE: To compare national trends and perinatal outcomes following the use of ejaculated versus surgically acquired sperm among IVF cycles with male factor infertility. METHODS: This retrospective cohort includes US fertility clinics reporting to the National ART Surveillance System between 2004 and 2015. Fresh, non-donor IVF male factor cycles (n = 369,426 cycles) were included. We report the following outcomes: (1) Trends in surgically acquired and ejaculated sperm. (2) Adjusted risk ratios comparing outcomes for intracytoplasmic sperm injection (ICSI) cycles using surgically acquired (epididymal or testicular) versus ejaculated sperm. (3) Outcomes per non-canceled cycle: biochemical pregnancy, intrauterine pregnancy, and live birth (>= 20 weeks). (4) Outcomes per pregnancy: miscarriage (< 20 weeks) and singleton pregnancy. (5) Outcomes per singleton pregnancy: normal birthweight (>= 2500 g) and full-term delivery (>= 37 weeks). RESULTS: Percentage of male factor infertility cycles that used surgically acquired sperm increased over the study period, 9.8 (2004) to 11.6% (2015), p < 0.05. The proportion of cycles using testicular sperm increased significantly over the study period, 4.9 (2004) to 6.5% (2015), p < 0.05. Among fresh, non donor male factor ART cycles which used ICSI (n = 347,078 cycles), cycle, pregnancy, and perinatal outcomes were statistically significant but clinically similar with confidence intervals approaching one between cycles involving epididymal versus ejaculated sperm and between testicular versus ejaculated sperm. Results were similar among cycles with a sole diagnosis of male factor (no female factors), and for the subset in which the female partner was < 35 years old. CONCLUSION: Among couples undergoing ART for treatment of male factor infertility, pregnancy and perinatal outcomes were similar between cycles utilizing ejaculated sperm or surgically acquired testicular and epididymal sperm. PMID- 29700732 TI - Correction to: A meta-analysis of consanguinity and breast cancer. AB - The original version of this article contained an author name error. Gabiella Jones has been corrected to Gabriela Jones. The original article has been corrected. PMID- 29700731 TI - Cross-sectional prevalence of Fasciola gigantica infections in beef cattle in Botswana. AB - A cross-sectional study was carried out to determine the prevalence and distribution of Fasciola gigantica infections in communally grazed and ranch grazed beef cattle through coprological examination. A total of 8646 cattle (4618 adults, 2843 weaners and 1185 calves) faecal samples were collected during the 24 months of study. Results from this study indicated that only 64 (0.74%; 95% CI 0.57, 0.94%) of the samples were positive for F. gigantica eggs. The positive samples were detected in one (Central) of the six study districts and was restricted to the Tuli Block (commercial) farms in Machaneng village in eastern Botswana. The prevalence of fluke eggs was significantly higher in adult cattle (12.85%; 95% CI 9.72, 16.54%) than weaners (6.49%; 95% CI 3.40, 11.06%) and calves (0.79%; 95% CI 0.02, 4.31%), (chi2(2) = 19.01, p < 0.001). Thus, adults (OR = 18.57; 95% CI 2.54, 135.81%) were approximately 20 times more likely to be infected than calves. By taking liver inspection as a gold standard for diagnosis of fasciolosis, the sensitivity of the sedimentation technique was found to be 72.41% and the specificity 100%, with moderate relationship (kappa = 0.53; 95% CI 0.31-0.75) between the two methods. This study has demonstrated that infection of cattle from Botswana, with F. gigantica, was low and distribution of the fluke appeared to be linked to suitable environmental conditions for the intermediate host snail. However, detailed surveillance studies, involving more cattle and areas, are required to verify the true prevalence. Such information would assist in the design of appropriate, strategic and effective fluke control programmes. PMID- 29700733 TI - The surgical management of severe dentofacial infections (DFI)-a prospective study. AB - Dentofacial infections (DFI) lead to morbidity and rarely, mortality. We hypothesised that certain clinical and laboratory parameter factors may be associated with a more severe course and an increased length of stay. We designed a prospective study that included all patients admitted with a DFI to the Oral and Maxillofacial Department between July 2014 and July 2015. A total of 125 were enrolled. We found that serum concentration of CRP on admission and increasing number of fascial spaces involved by the infection were significant predictors of hospital stay (p = 0.02 and p = 0.01, respectively). The average length of stay for a dentofacial infection requiring admission was 4.5 days. Most patients require surgical intervention in combination with intravenous antibiotics for successful resolution. Improved and timely access to primary dental care is likely to reduce the burden for patients their families and the acute hospital service as a consequence of advanced DFI. PMID- 29700734 TI - Animal Contributed Papers. PMID- 29700735 TI - Animal Posters. PMID- 29700736 TI - Education Symposia and Workshops. PMID- 29700737 TI - Education Silent Abstracts. PMID- 29700738 TI - Plant Posters. PMID- 29700739 TI - Keynote Symposium. PMID- 29700740 TI - Plant Contributed Papers. PMID- 29700742 TI - Plenary Symposia. PMID- 29700743 TI - Plant Symposia and Workshops. PMID- 29700744 TI - Animal Symposia and Workshops. PMID- 29700745 TI - Characterizing the correlation between dephosphorization and solution pH in a calcined water treatment plant sludge. AB - This study focused on characterizing the correlation between the dephosphorization process of calcined water treatment plant sludge (C-WTPS) and the solution initial pH in batch experiments. The specific aim was to illustrate the effect of different initial pH on the adsorption and desorption of phosphorous in C-WTPS. In addition, the effects of solution initial pH on the release of ammonia nitrogen and total organic carbon (TOC) from C-WTPS and the change of pH after adsorption were also investigated. The results demonstrated that the initial pH significantly influenced the adsorption of phosphorus on C WTPS. When initial pH was increased from 3 to 10, the phosphorous absorption capacity reduced by 76.5%. Especially, when the initial pH reached to 11, the phosphorus adsorption capacity became a negative value, indicating that C-WTPS released phosphorus into the solution. The addition of C-WTPS to the solution had little impact on the initial pH of the solution. The absorbed phosphorous on C WTPS was relatively stable in the pH range of 3 to 10. Nevertheless, when the solution pH was higher than 11, it can be easily released into the solution. Furthermore, by comparison with WTPS, C-WTPS released less ammonia nitrogen and TOC into the solution and adsorbed more phosphorus from the solution in the experimental pH range. Therefore, C-WTPS is more suitable to serve as a cost effective sorbent for phosphorus removal. PMID- 29700746 TI - Exploring an in situ LED-illuminated isothermal micro-calorimetric method to investigating the thermodynamic behavior of Chlorella vulgaris during CO2 bio fixation. AB - Much endeavor has been dispensed recently to evaluate the potential of CO2 mitigation by microalgae. We introduce an alternative, novel, LED-illumination isothermal microcalorimetric method to assess the thermodynamic behaviors of microalgae for better understanding of their carbon sequestration capacity. Microalgae thermodynamic behaviors were recorded as power-time curves, and their indices such as total heat evolution (QT), maximum power output (Pmax) and heat generated by per algae cell (JN/Q) were obtained. The values for highest (74.80 g L-1) and control sample (0.00 g L-1) of QT, Pmax and JN/Q were 20.85 and 2.32 J; 252.17 and 57.67 MUW; 7.91 * -06 and 8.80 * -07 J cell-1, respectively. According to the values of QT, a general order to promote the CO2 sequestration was found at 74.8 g L-1 > 29.92 g L-1 > 14.96 g L-1 > 7.48 g L-1 > 0 g L-1 of C sources, which directly corresponded to carbon availability in the growth medium. Chlorella vulgaris GIEC-179 showed the highest peak Pmax at 74.8 g L-1 concentration which was directly transformed to their biomass during bio-fixation of CO2 process. This study is applicable for better understanding of CO2 fixation performance of algae. PMID- 29700747 TI - Towards saving freshwater: halophytes as unconventional feedstuffs in livestock feed: a review. AB - Water represents 71% of all earth area and about 97% of this water is salty water. So, only 3% of the overall world water quantity is freshwater. Human can benefit only from 1% of this water and the remaining 2% freeze at both poles of earth. Therefore, it is important to preserve the freshwater through increasing the plants consuming salty water. The future prosperity of feed resources in arid and semi-arid countries depends on economic use of alternative resources that have been marginalized for long periods of time, such as halophytic plants, which are one such potential future resource. Halophyte plants can grow in high salinity water and soil and to some extent during drought. The growth of these plants depends on the contact of the salted water with plant roots as in semi desert saline water, mangrove swamps, marshes, and seashores. Halophyte plants need high levels of sodium chloride in the soil water for growth, and the soil water must also contain high levels of salts, as sodium hydroxide or magnesium sulfate. There are many uses for halophyte plants, including feed for animals, vegetables, drugs, sand dune stabilizers, wind shelter, soil cover, wetland cultivation, laundry detergents, and paper production. This paper will focus on the use of halophytes as a feed additive for animals. In spite of the good nutritional value of halophytes, some anti-nutritional factors as nitrates, nitrite complexes, tannins, glycosides, phenolic compounds, saponins, oxalates, and alkaloids may be present in some of them. The presence of such anti nutritional agents makes halophytes unpalatable to animals, which tends to reduce feed intake and nutrient use. Therefore, the negative effects of these plants on animal performance are the only objection against using halophytes in animal feed diets. This review article highlights the beneficial impact of considering halophytes in animal feeding on saving freshwater and illustrates its nutritive value for livestock from different aspects. PMID- 29700748 TI - Effective sorption of atrazine by biochar colloids and residues derived from different pyrolysis temperatures. AB - Biochar has attracted much attention, which owns many environmental and agronomic benefits, including carbon sequestration, improvement of soil quality, and immobilization of environmental contaminants. Biochar has been also investigated as an effective sorbent in recent publications. Generally, biochar particles can be divided into colloids and residues according to particle sizes, while understanding of adsorption capacities towards organic pollutants in each section is largely unknown, representing a critical knowledge gap in evaluations on the effectiveness of biochar for water treatment application. Scanning electron microscopy (SEM) images, X-ray diffraction (XRD), Raman spectra, Fourier transform infrared spectroscopy (FTIR), X-ray photoelectron spectroscopy (XPS), and Brunauer-Emmett-Teller (BET) method are used to examine the structures and surface properties of biochar colloids and residues derived from corn straws prepared at different pyrolysis temperatures. Also, their roles in atrazine (a typical organic pollutant) removal are investigated by batch adsorption experiments and fitted by different kinetic and thermodynamic models, respectively. The adsorption capacities of biochar colloids are much more than those of residues, resulting from the colloids containing abundant oxygen functional groups and mineral substances, and the adsorption capacities of biochar colloids and residues increase with the increase of pyrolysis temperatures. The highest adsorption performance of 139.33 mg g-1 can be obtained in biochar colloids prepared at 700 degrees C, suggesting the important functions of biochar colloids in the application of atrazine removal by biochar. PMID- 29700749 TI - Changes in the nutritional composition of maize flour due to Tribolium castaneum infestation and application of carbon dioxide to manage this pest. AB - Maize flour was infested with fresh emerged Tribolium castaneum adults, and its nutritional composition was evaluated after 0, 45, and 90 days of the infestation. Furthermore, 99% carbon dioxide was applied to different developmental stages of T. castaneum for its management. There were six treatments and five replicates; for each replicate, maize flour (150 g) was taken in a 250-ml plastic jar container, insects were released in the flour, and jars were placed into the incubator at a temperature of 28 +/- 1 degrees C, 60 +/- 5% RH. Similarly, the application of 99% CO2 was done with four exposure times of 12, 24, 48, and 72 h, at 35 degrees C 65 +/- 5% RH. Present results showed major fluctuations in the nutritive composition of maize flour. Increase in the moisture, fat, fiber, protein, and ash contents was directly proportional to the increase in infestation level and time, contrary to the depletion of carbohydrates and total weight loss. The results of CO2 treatment indicated that pupa was the most resilient stage as compared with larvae and adult stage. The observed susceptibility order was as follows: adult > larvae > pupae. The maximum mortality of adult, larval, and pupal stages was recorded after 24, 48, and 72 h of CO2 application, respectively. These findings might be helpful to develop an ecofriendly technique to manage this crucial pest. PMID- 29700751 TI - Modeling the oxygen transport process under preferential flow effect in landfill. AB - Evaluation of oxygen distribution during aeration in landfill is significantly important to determine the design parameters of an injection well. A coupling model describing gas preferential transport in a landfill was developed, which linked the effect of advection-diffusion and oxidation reaction and mass exchange between the fracture and the matrix system. The quantitative simulation of the variation in gas distribution during vertical well aeration in short term was presented, combined with the typical cases in field site. The parameter sensitivity in the coupling model to gas transport was addressed. Simulation result of the oxygen and methane concentrations by using the dual advective diffusive (DAD) model, which considered the immobile zone effect, was closer to the monitoring data than that by using single advective-diffusive model. The variation of the AR under aeration was presented with the key parameters to provide the theory evidence for gas well design in landfill. This study provided reference for the design of the gas injection well distribution in aerobic landfill. PMID- 29700752 TI - Antituberculosis drug isoniazid degraded by electro-Fenton and photoelectro Fenton processes using a boron-doped diamond anode and a carbon-PTFE air diffusion cathode. AB - Solutions with 0.65 mM of the antituberculosis drug isoniazid (INH) in 0.050 M Na2SO4 at pH 3.0 were treated by electro-Fenton (EF) and UVA photoelectro-Fenton (PEF) processes using a cell with a BDD anode and a carbon-PTFE air-diffusion cathode. The influence of current density on degradation, mineralization rate, and current efficiency has been thoroughly evaluated in EF. The effect of the metallic catalyst (Fe2+ or Fe3+) and the formation of products like short-chain linear aliphatic carboxylic acids were assessed in PEF. Two consecutive pseudo first-order kinetic regions were found using Fe2+ as catalyst. In the first region, at short time, the drug was rapidly oxidized by ?OH, whereas in the second region, at longer time, a resulting Fe(III)-INH complex was much more slowly removed by oxidants. INH disappeared completely at 300 min by EF, attaining 88 and 94% mineralization at 66.6 and 100 mA cm-2, respectively. Isonicotinamide and its hydroxylated derivative were identified as aromatic products of INH by GC-MS and oxalic, oxamic, and formic acids were quantified by ion-exclusion HPLC. The PEF treatment of a real wastewater polluted with the drug led to slower INH and TOC abatements because of the parallel destruction of its natural organic matter content. PMID- 29700750 TI - Selenium and silicon reduce cadmium uptake and mitigate cadmium toxicity in Pfaffia glomerata (Spreng.) Pedersen plants by activation antioxidant enzyme system. AB - Cadmium (Cd) is toxic to plants and animals, making it necessary to develop strategies that seek to reduce its introduction into food chains. Thus, the aim of this study was to investigate whether silicon (Si) and selenium (Se) reduce Cd concentrations in Pfaffia glomerata medicinal plant and attenuate the oxidative stress promoted by this metal. These plants were cultivated in hydroponics under the following treatments: control (nutrient solution), 2.5 MUM Se, 2.5 mM Si, 50 MUM Cd, 50 MUM Cd + 2.5 MUM Se, 50 MUM Cd + 2.5 mM Si. After 14 days of exposure to treatments, leaves and roots were collected for the determination of dry weight of shoot and roots, Cd concentrations, chlorophyll and carotenoids content, and biochemical parameters (lipid peroxidation and guaiacol peroxidase and superoxide dismutase activities). The data were submitted to analysis of variance and means were compared with Scott-Knott test at 5% error probability. Roots of P. glomerata plants showed a significant reduction on dry weight accumulation when exposed to Cd. However, both Se and Si promoted a significant reduction of deleterious effects of Cd. The Cd concentrations in the tissues were reduced in the presence of Se or Si. Plants treated with Cd together with Se or Si presented higher pigment content than those with only Cd, thus showing a reduction in the negative effects caused by this element. In the treatments in which Se and Si were added in the growth medium together with Cd, an activation of superoxide dismutase and guaiacol peroxidase enzymes was observed in the roots and shoot, which may have contributed to lower lipid peroxidation. Thus, Se and Si reduce Cd concentrations and have potential to ameliorate Cd toxicity in P. glomerata plants, which can be used to increase productivity and quality of medicinal plants. PMID- 29700753 TI - Cluster analysis of microclimate data to optimize the number of sensors for the assessment of indoor environment within museums. AB - For the first time, the cluster analysis (k-means) has been applied on long time series of temperature and relative humidity measurements to identify the thermo hygrometric features in a museum. Based on ASHRAE (2011) classification, 84% of time all rooms in the Napoleonic Museum in Rome (case study) were found in the class of control B. This result was obtained by analyzing all recorded data in 10 rooms of the museum as well as using the cluster aggregation. The use of objective-oriented methodology allows to achieve an acceptable knowledge of the microclimate in case of multi-room buildings, reducing computations with large amounts of collected data and time-consuming in redundant elaborations. The cluster analysis enables to reduce the number of the sensors in microclimate monitoring programs within museums, provided that the representativeness of the instrument location is known, and professional conservators have assessed that the artifacts are well preserved. PMID- 29700754 TI - Development of Fe/Nb-based solar photocatalysts for water treatment: impact of different synthesis routes on materials properties. AB - Semiconductors based on Fe/Nb oxides can present both solar sensitivity and high catalytic activity. However, there is still a lack regarding the comparison between different routes to produce Fe/Nb-based solar photocatalysts and the evaluation of the impact of the synthesis operating conditions on the material properties. In this work, Fe/Nb2O5 ratio, type of precipitating agent, presence/absence of washing stage, and temperature of calcination were verified to be the most relevant parameters in the synthesis by the co-precipitation method. These factors led to remarkable differences in the properties and performance of the photocatalysts produced by each distinct synthesis route. Composition, iron species present in the materials, crystallinity characteristics, and pH of the catalysts were affected, leading to different photocatalytic activities under UV-Vis light. Due to their characteristics, the synthesized materials are potential photocatalysts for application in solar processes. Graphical abstract ?. PMID- 29700755 TI - Does Non-Adherence Increase Treatment Costs in Schizophrenia? AB - INTRODUCTION: Medication non-adherence is a serious barrier to treatment of schizophrenia. Understanding the impact of non-adherence on costs is essential to the assessment of the cost effectiveness of interventions in which adherence to treatment is a concern. OBJECTIVES: We undertook a comprehensive review of the available literature on the impact on costs of non-adherence to antipsychotics in the treatment of schizophrenia. METHODS: We performed a search on multiple databases (MEDLINE, Embase, PsycINFO and Health Management Information Consortium) for any study reporting the impact of adherence to antipsychotics on costs in patients with schizophrenia up to February 2018. We included trials of behavioural interventions but excluded comparisons of different pharmacological therapies. Studies were included if at least one-third of the study population had schizophrenia and costs were reported. RESULTS: Thirty-four publications on 28 studies met the inclusion criteria. Twenty studies reported analyses of administrative databases, primarily Medicaid. Findings on healthcare costs were mixed but suggested that lower pharmacy costs in non-adherent patients may outweigh increased hospitalisation costs where drug costs are relatively high. A few studies published analysis of prospective cohort data, or trials of behavioural interventions intended to influence adherence, mainly in a European setting. Findings were again mixed but indicate that increasing adherence does not reduce overall costs. CONCLUSIONS: Inference from analysis of administrative data is limited by the risk of selection bias. Inference from trials is limited by small sample sizes. The literature does not consistently support an assumption that non-adherence increases healthcare costs. PMID- 29700757 TI - Echocardiographic and pathologic findings of wild-type transthyretin senile systemic amyloidosis developed in early 50s. PMID- 29700756 TI - Complete assignment of Ala, Ile, Leu, Met and Val methyl groups of human blood group A and B glycosyltransferases using lanthanide-induced pseudocontact shifts and methyl-methyl NOESY. AB - Human blood group A and B glycosyltransferases (GTA, GTB) are highly homologous glycosyltransferases. A number of high-resolution crystal structures is available showing that these enzymes convert from an open conformation into a catalytically active closed conformation upon substrate binding. However, the mechanism of glycosyltransfer is still under debate, and the precise nature as well as the time scales of conformational transitions are unknown. NMR offers a variety of experiments to shine more light on these unresolved questions. Therefore, in a first step we have assigned all methyl resonance signals in MILVA labeled samples of GTA and GTB, still a challenging task for 70 kDa homodimeric proteins. Assignments were obtained from methyl-methyl NOESY experiments, and from measurements of lanthanide-induced pseudocontact shifts (PCS) using high resolution crystal structures as templates. PCSs and chemical shift perturbations, induced by substrate analogue binding, suggest that the fully closed state is not adopted in the presence of lanthanide ions. PMID- 29700758 TI - Assessing sarcopenia with vastus lateralis muscle ultrasound: an operative protocol. AB - BACKGROUND: Muscle ultrasound (MUS) has so far not been implemented for sarcopenia assessment in clinical geriatric practice due to allegedly low reproducibility of results in the absence of standardization of procedures. However, rigorous and standardized application of this technique yields highly reproducible results. Its application, especially if integrated with clinical evaluation and comprehensive geriatric assessment, proofs very useful for rapidly obtaining information on muscle mass and architecture. OBJECTIVE: Here, we present a standardized protocol for performing right vastus lateralis (RVL) MUS and measuring parameters of muscle size and architecture. METHODS: RVL muscle thickness (MT), fascicle length (FL), pennation angle (PA), echo-intensity (EI) and cross-sectional area (CSA) can be assessed with this protocol. A portable instrument equipped with a 5-cm long 3-11 mHz linear probe should be used with both B-mode real-time and extended-field-of-view (EFOV) techniques. Longitudinal B-mode and transverse EFOV images should be acquired during each exam, and analyzed with NIH-ImageJ software. CONCLUSIONS: This operative protocol represents a good compromise between the feasibility of MUS in clinical settings and the need of obtaining precise measurements of muscle parameters. Future studies should verify the reproducibility of the proposed technique, and its correlation with appendicular lean mass and parameters of muscle function. PMID- 29700759 TI - Primary care providers' lived experiences of genetics in practice. AB - To effectively translate genetic advances into practice, engagement of primary care providers (PCPs) is essential. Using a qualitative, phenomenological methodology, we analyzed key informant interviews and focus groups designed to explore perspectives of urban and rural PCPs. PCPs endorsed a responsibility to integrate genetics into their practices and expected advances in genetic medicine to expand. However, PCPs reported limited knowledge and difficulties accessing resources, experts, and continuing education. Rural practitioners' additional concerns included cost, distance, and poor patient engagement. PCPs' perspectives are crucial to develop relevant educational and systems-based interventions to further expand genetic medicine in primary care. PMID- 29700760 TI - Factors Associated With Insulin Resistance in Adults With HIV Receiving Contemporary Antiretroviral Therapy: a Brief Update. AB - PURPOSE OF REVIEW: This narrative review summarizes recent data on factors associated with insulin resistance (IR) in adults with HIV, including contemporary antiretroviral therapy (ART). RECENT FINDINGS: IR remains common in persons with HIV, even those receiving contemporary ART. Generalized and abdominal obesity and ectopic fat are correlates of IR, and emerging data have identified associations with biomarkers of inflammation and immune activation. Small studies suggest associations between mitochondria and IR. In ART-naive individuals, IR increased within 4 weeks of starting ART in persons receiving contemporary boosted protease inhibitors or an integrase inhibitor. The importance of IR in non-diabetic persons with HIV will continue to grow as the population ages and obesity increases. Non-invasive estimates of IR appear to perform well in persons with HIV, but clinically relevant cutoffs are uncertain. Unexpected metabolic effects of newer HIV integrase inhibitors have been reported; thus, careful observation for and studies of IR are still warranted. PMID- 29700761 TI - Development and first evaluation of a novel multiplex real-time PCR on whole blood samples for rapid pathogen identification in critically ill patients with sepsis. AB - Molecular tests may enable early adjustment of antimicrobial therapy and be complementary to blood culture (BC) which has imperfect sensitivity in critically ill patients. We evaluated a novel multiplex real-time PCR assay to diagnose bloodstream pathogens directly in whole blood samples (BSI-PCR). BSI-PCR included 11 species- and four genus-specific PCRs, a molecular Gram-stain PCR, and two antibiotic resistance markers. We collected 5 mL blood from critically ill patients simultaneously with clinically indicated BC. Microbial DNA was isolated using the Polaris method followed by automated DNA extraction. Sensitivity and specificity were calculated using BC as reference. BSI-PCR was evaluated in 347 BC-positive samples (representing up to 50 instances of each pathogen covered by the test) and 200 BC-negative samples. Bacterial species-specific PCR sensitivities ranged from 65 to 100%. Sensitivity was 26% for the Gram-positive PCR, 32% for the Gram-negative PCR, and ranged 0 to 7% for yeast PCRs. Yeast detection was improved to 40% in a smaller set-up. There was no overall association between BSI-PCR sensitivity and time-to-positivity of BC (which was highly variable), yet Ct-values were lower for true-positive versus false positive PCR results. False-positive results were observed in 84 (4%) of the 2200 species-specific PCRs in 200 culture-negative samples, and ranged from 0 to 6% for generic PCRs. Sensitivity of BSI-PCR was promising for individual bacterial pathogens, but still insufficient for yeasts and generic PCRs. Further development of BSI-PCR will focus on improving sensitivity by increasing input volumes and on subsequent implementation as a bedside test. PMID- 29700763 TI - Reliability, Accuracy, and Use Frequency of Evaluation Methods for Amount of Tongue Coating. AB - OBJECTIVE: To classify the evaluation methods for amount of tongue coating (TC) and investigate their reliability, accuracy, and frequency of use. METHODS: Articles published from 1985 to 2015 were searched for evaluation methods for the amount of TC in PubMed and the Cochrane Library. Only clinical researches were included except protocol articles. The methods were classified according to their characteristics. RESULTS: Finally, 113 articles were selected. The evaluation method for the amount of TC from the articles was classified into 4 types: intuitive, specificative, computerized, and weighing TC. The reliability in the intuitive and specificative methods (kappa =0.33-0.92) showed varying levels among the studies. In general, the amount of TC calculated by the specificative method (Spearman's r=0.68-0.80) was more strongly related to the directly measured value than to the value estimated by the computerized method (Pearson's r=0.442). The number of articles published on this topic has increased consistently, and the specificative method was the most frequently used. Despite the higher reliability of the computerized method, it has not been widely used. CONCLUSIONS: The high prevalence of the specificative method would continue in clinical practice because of its convenience and accuracy. However, to establish higher reliability, the limitation of the subjectivity of the assessors should be overcome through calibration training. In the computerized method, novel algorithms are needed to obtain a higher accuracy so that it can help the practitioners confidently estimate the amount of TC. PMID- 29700762 TI - A host-protein signature is superior to other biomarkers for differentiating between bacterial and viral disease in patients with respiratory infection and fever without source: a prospective observational study. AB - Bacterial and viral infections often present with similar symptoms. Etiologic misdiagnosis can alter the trajectory of patient care, including antibiotic overuse. A host-protein signature comprising tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), interferon gamma-induced protein-10 (IP-10), and C-reactive protein (CRP) was validated recently for differentiating bacterial from viral disease. However, a focused head-to-head comparison of its diagnostic performance against other biomarker candidates for this indication was lacking in patients with respiratory infection and fever without source. We compared the signature to other biomarkers and prediction rules using specimens collected prospectively at two secondary medical centers from children and adults. Inclusion criteria included fever > 37.5 degrees C, symptom duration <= 12 days, and presentation with respiratory infection or fever without source. Comparator method was based on expert panel adjudication. Signature and biomarker cutoffs and prediction rules were predefined. Of 493 potentially eligible patients, 314 were assigned unanimous expert panel diagnosis and also had sufficient specimen volume. The resulting cohort comprised 175 (56%) viral and 139 (44%) bacterial infections. Signature sensitivity 93.5% (95% CI 89.1-97.9%), specificity 94.3% (95% CI 90.7-98.0%), or both were significantly higher (all p values < 0.01) than for CRP, procalcitonin, interleukin-6, human neutrophil lipocalin, white blood cell count, absolute neutrophil count, and prediction rules. Signature identified as viral 50/57 viral patients prescribed antibiotics, suggesting potential to reduce antibiotic overuse by 88%. The host-protein signature demonstrated superior diagnostic performance in differentiating viral from bacterial respiratory infections and fever without source. Future utility studies are warranted to validate potential to reduce antibiotic overuse. PMID- 29700764 TI - Thoughts and Approaches of Integrated Chinese and Western Medicine for the Treatment of Oligo-astheno-teratozoospermia. AB - Oligo-astheno-teratozoospermia (OAT) which perplexes doctors and patients due to its complicated etiology, atypical symptoms and poor clinical efficacy, is a general term for the three pathological states of abnormal semen. OAT is the main factor of male infertility. It is also a hot and difficult point in present studies. Empiric drug is the most popular treatment of this disease in the modern medicine. Chinese medicine (CM) is one of the main methods for the treatment of this disease, and it has certain clinical effect. The author believes that the use of modern medical technology to make the diagnosis as clear as possible is the key to treat OAT. The combination of syndrome and disease differentiation is the main mode in the treatment of OAT. Microscopic syndrome differentiation and macroscopic evidence embodies the basic principle of "Si Wai Chuai Nei" and broadens the perspective of CM syndrome differentiation. Classification and treatment are basic methods for the treatment of OAT. The treatment should not be limited to the Shen (Kidney), instead it should focus on the whole body condition. At different stages, the treatment should also pay attention to strengthening the Pi (Spleen), nourishing the Gan (Liver) and promoting blood circulation. Complementing Chinese and Western medicine, and highlighting the characteristics and advantages of CM treatment, have a great guiding value for the treatment of OAT. PMID- 29700765 TI - Platelets' increase is associated with improvement of liver fibrosis in entecavir treated chronic hepatitis B patients with significant liver fibrosis. AB - BACKGROUND AND AIM: Reduction of platelet count is often observed in chronic hepatitis B (CHB) patients with significant liver fibrosis. In this cohort study, we investigated whether platelets' increase after entecavir (ETV) therapy was associated with the improvement of liver fibrosis. METHODS: We collected the data of a cohort 82 CHB patients with paired liver biopsies before and after 78-week ETV therapy, and assessed the platelets' change following the treatment and further investigated the associated clinical factors with platelets' change. RESULTS: Platelet count increased after treatment, which occurred mainly in patients with low baseline level of platelet count (< 200 * 109/L) or with significant fibrosis (Ishak >= 3). Regression analysis showed that baseline platelet count was the main factor associated with post-treatment increase of platelets (beta = - 0.215, p = 0.015). In patients with significant fibrosis, correlation and linear regression analysis revealed that post-treatment platelets' increase was correlated with improvement of liver fibrosis assessed by reduction of quantitative collagen percentage area (r = 0.392, p = 0.006) (beta = 2.449, p = 0.035), but no correlation between changes in platelet counts and Ishak fibrosis score. Receiver operating curve analysis showed an increase of 12.5 * 109/L in platelet count could identify improvement of liver fibrosis (AUC = 0.70). CONCLUSION: Platelets' increase after ETV therapy was associated to the improvement of liver fibrosis with reduction of collagen percentage area in CHB patients with significant fibrosis. PMID- 29700766 TI - Fabrication of Nanosuspension Directly Loaded Fast-Dissolving Films for Enhanced Oral Bioavailability of Olmesartan Medoxomil: In Vitro Characterization and Pharmacokinetic Evaluation in Healthy Human Volunteers. AB - Olmesartan medoxomil (OM) is an antihypertensive drug with poor water solubility and low oral bioavailability (28.6%). Accordingly, this study aimed to formulate and evaluate OM nanosuspension incorporated into oral fast-dissolving films (FDFs) for bioavailability enhancement. OM nanosuspension was prepared by antisolvent-precipitation-ultrasonication method and characterized regarding particle size (122.67 +/- 5.03 nm), span value (1.40 +/- 0.51), and zeta potential (- 46.56 +/- 1.20 mV). Transmission electron microscopy (TEM) of the nanosuspension showed spherical non-aggregating nanoparticles. The nanosuspension was then directly loaded into FDFs by solvent casting technique. A full factorial design (22 * 31) was implemented for optimization of the FDFs using Design Expert(r) software. Physical and mechanical characteristics in addition to dissolution profiles of the FDFs were investigated. The optimum formula (FDF1) showed 0.43 +/- 0.02 kg/mm2 tensile strength, 20.50 +/- 2.12 s disintegration time, and 87.53 +/- 2.50 and 95.99 +/- 0.25% OM dissolved after 6 and 10 min, respectively. Accelerated and long-term shelf stability studies confirmed the stability of FDF1. More than 75% OM was dissolved within 10 min from FDF1 compared with 9.80 and 47.80% for films prepared using coarse drug powder and market tablet, respectively. Relative bioavailability of FDF1 compared to market tablet was assessed in healthy human volunteers. The Cmax value increased significantly from 66.62 +/- 14.95 to 179.28 +/- 23.96 ng/mL for market tablet and FDF1, respectively. Similarly, the AUC0-72 value significantly increased from 498.36 +/- 217.46 to 1083.67 +/- 246.32 ng h/mL for market tablet and FDF1, respectively. Relative bioavailability of FDF1 was 209.28%. The highlighted results verified the effectiveness of OM nanosuspension-loaded FDFs in improving OM bioavailability. PMID- 29700768 TI - Proteomic Analysis of Cerebral Cortex Extracts from Sus scrofa with Induced Hemorrhagic Stroke. AB - Cerebrovascular diseases, including stroke and micro stroke, are the main causes of death in contemporary society. Hemorrhagic stroke is the fast emerging defficiency in the brain function resulting from disturbance of blood supply to the brain caused by the rapture of blood vessels (Lopez et al. in Proteomics Clin Appl 6:190-200, 2012). The influence of a model hemorrhagic stroke on white pigs with the change in the protein profile of their cortical samples 24 h and 2 months after the stroke was examined using mass-spectrometric analysis. Different proteins (n = 30) were identified, and their content was elevated. These proteins are involved in the mechanisms of neuroprotection, including compensation of oxidative stress (TXN, SNCA, PRDX6, ENO1), prevention of unwanted protein aggregation and apoptosis (PTMA, SNCA, SNCB), release of neurotransmitters (GAPDH, PEBP1) and assembly of the cytoskeleton (ACTA2, PTMA, TUBA4A, TUBA1D), etc. Also, a group of seven Ras family proteins involved in the regulation of cell proliferation and differentiation was found in the samples taken 24 h following the stroke. The relative concentrations of most of the proteins in the samples taken 2 months after the stroke demonstrate intermediate values between the control sample and the sample taken in 24 h, indicating the extinction of change in the protein profile with time. During the first 24 h after the stroke, there is an increase in protein fractions participating in exocytosis, synaptic plasticity/signaling, and support of neurotransmitter transport. Such shift in the weight of protein functional clusters can be attributed to activation of compensatory mechanisms in the body focused on neuroprotection. PMID- 29700767 TI - Effects of Post-Weaning Chronic Stress on Nociception, Spinal Cord MU-Opioid, and alpha2-Adrenergic Receptors Expression in Rats and Their Offspring. AB - Stressful situations can change biological process in human and animal, and some of these changes may transfer to the next generations. We used a communication box to induce chronic electrical foot-shock stress in rats. Tail flick latency and formalin test were done to determine the level of pain sensation. Real-time RT-PCR was used to measure the level of spinal cord MU-opioid (MOR) and alpha2 adrenergic receptors (alpha2-AR) mRNA. We demonstrate that chronic stress can change nociception and leads to hyperalgesia. Moreover, spinal cord MOR mRNA level decreased following chronic stress. We did not observe any significant changes in the level of spinal cord alpha2-AR mRNA between stressed and non stressed rats. In addition, non-stressed sons of stressed mothers showed hyperalgesia compared to the control group. They showed lesser level of MOR mRNA level in comparison to the control rats. Furthermore, stressed sons of stressed mothers illustrated more hyperalgesia than the other stressed groups. We indicate that chronic stress can reduce spinal cord MOR mRNA level and lead to hyperalgesia. Additionally, these changes can transfer to offspring. PMID- 29700769 TI - Clinical characteristics of two cohorts of infantile spasms: response to pyridoxine or topiramate monotherapy. AB - BACKGROUND: Infantile spasms (IS) was an epileptic disease with varied treatment widely among clinicians. Here, we aimed to compare and analyze the clinical characteristics of IS response to pyridoxine or topiramate monotherapy (TPM control IS). METHODS: The clinical manifestations, treatment processes and outcomes were analyzed in 11 pyridoxine responsive IS and 17 TPM-control IS. RESULTS: Of the 11 patients with pyridoxine responsive IS, nine were cryptogenic/idiopathic. Age of seizure onset was 5.36 +/- 1.48 months. Spasms were controlled within a week in most of the patients. At the last follow-up, EEG returned to normal in 8. Psychomotor development was normal in 6, mild delay in 3, severe delay in 2. Of the 17 patients with TPM-control IS, 10 were cryptogenic/idiopathic. The age of seizure onset was 5.58 +/- 2.09 months. All patients were controlled within a month. At the last follow-up, EEG was normal in 10. Psychomotor development was normal in 8, mild delay in 5, severe delay in 4. Genetic analysis did not show any meaningful results. CONCLUSIONS: The clinical characteristics and disease courses of pyridoxine responsive IS and TPM-control IS were similar, which possibly clued for a same pathogenic mechanism. Pyridoxine should be tried first in all IS patients, even in symptomatic cases. If patients were not responsive to pyridoxine, TPM could be tried. PMID- 29700770 TI - Conventional repair of total anomalous venous drainage without primary sutureless technique: surgical tips to prevent pulmonary vein obstruction. AB - OBJECTIVES: Although primary sutureless technique for total anomalous pulmonary venous drainage has been introduced to reduce postoperative pulmonary vein obstruction (PVO), controversy still exists about superiority of the procedure between the conventional repair and primary sutureless technique at the initial repair. In our unit, the conventional repair has been consistently used based on four important surgical policies: (1) mark incision lines between 2 chambers to gain anatomically natural alignment, (2) place precise stitches by "intima-to intima" using monofilament suture, (3) adequate orifice size should be guaranteed in greater than expected mitral valve size, (4) do not hesitate to undertake a redo additional anastomosis by a different approach when an echocardiography shows the velocity more than 1.5 m/s. This study aims to evaluate mid-term outcome of the conventional repair for total anomalous pulmonary venous drainage. METHODS: Between 2004 and 2016, consecutive 15 patients who underwent the conventional repair without the primary sutureless technique were included in this study. Survival, Freedom from reoperation, and PVO were retrospectively reviewed. RESULTS: Mean follow-up period was 4.6 +/- 3.7 years. Except for one patient who died of uncontrollable pleural effusion, all other patients survived with 5-year survival rate of 93.3%. For the 14 survivors, there was no PVO, nor reoperation. CONCLUSIONS: Following these policies, the mid-term outcome of the conventional total anomalous pulmonary venous drainage repair was excellent without the primary sutureless technique showing no obstruction. The conventional repair can be safely applied at the initial operation when the morphological condition allows for it. PMID- 29700771 TI - Atraumatic tension hemothorax associated with ruptured aneurysm of intercostal artery-azygous fistula: a case report. AB - Atraumatic tension hemothorax is extremely rare. We report a case of 62-year-old woman presented with obstructive and hypovolemic shock status by tension hemothorax due to ruptured aneurysm of congenital intercostal artery-azygous fistula. Contrast-enhanced computed tomography and aortography revealed an aberrant 12th intercostal artery flowing into the aneurysm with a fistula draining into the azygous vein and the rupture of aneurysm. Our experience indicates that the rupture of congenital arteriovenous fistulas (AVFs) of systemic circulation in the thoracic cavity might cause not only hypovolemic shock but also atraumatic tension hemothorax. Surgery following preoperative endovascular embolization offers a feasible treatment strategy for ruptured aneurysms associated with AVFs. PMID- 29700772 TI - Cost-Effectiveness of Insulin Degludec Versus Insulin Glargine U100 in Patients with Type 1 and Type 2 Diabetes Mellitus in Serbia. AB - INTRODUCTION: This study investigates the cost-effectiveness of insulin degludec versus insulin glargine U100 in patients with type 1 and type 2 diabetes mellitus in Serbia. METHODS: A cost-utility analysis, implementing a simple short-term model, was used to compare treatment costs and outcomes with degludec versus glargine U100 in patients with type 1 (T1DM) and type 2 diabetes (T2DM). Cost effectiveness was analysed in a 1-year setting, based on data from clinical trials. Costs were estimated from the healthcare payer perspective, the Serbian Health Insurance Fund (RFZO). The outcome measure was the incremental cost effectiveness ratio (ICER) or cost per quality-adjusted life-year (QALY) gained. RESULTS: Degludec is highly cost-effective compared with glargine U100 for people with T1DM and T2DM in Serbia. The ICERs are estimated at 417,586 RSD/QALY gained in T1DM, 558,811 RSD/QALY gained in T2DM on basal oral therapy (T2DMBOT) and 1,200,141 RSD/QALY gained in T2DM on basal-bolus therapy (T2DMB/B). All ICERs fall below the commonly accepted thresholds for cost-effectiveness in Serbia (1,785,642 RSD/QALY gained). In all three patient groups, insulin costs are higher with degludec than with glargine U100, but these costs are partially offset by savings from a lower daily insulin dose in T1DM and T2DMBOT, a reduction in hypoglycaemic events in all three patient groups and reduced costs of SMBG testing in the T2DM groups with degludec versus glargine U100. CONCLUSION: Degludec is a cost-effective alternative to glargine U100 for patients with T1DM and T2DM in Serbia. Degludec may particularly benefit those suffering from hypoglycaemia or where the patient would benefit from the option of flexible dosing. FUNDING: Novo Nordisk. PMID- 29700774 TI - Correction to: Cotinine: A Therapy for Memory Extinction in Post-traumatic Stress Disorder. AB - The original version of this article unfortunately contained mistake in its Funding inforation. That is, the Grant Number has an error currently read as "This work was supported by the Fondo de Ciencia y Tecnologia (FONDECYT) de Chile, Grant #1150149". PMID- 29700773 TI - Correction to: Transplantation of Human Chorion-Derived Cholinergic Progenitor Cells: a Novel Treatment for Neurological Disorders. AB - The original version of this article unfortunately contained mistake in the affiliation. Affiliation 1 should be read as "Neuroscience Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran". The original article has been corrected. PMID- 29700775 TI - Somatostatin Maintains Permeability and Integrity of Blood-Brain Barrier in beta Amyloid Induced Toxicity. AB - In Alzheimer's disease (AD), the impaired clearance of beta-amyloid peptide (Abeta) due to disrupted tight junction and transporter proteins is the prominent cause of disease progression. Somatostatin (SST) blocks the aggregation of Abeta and inflammation whereas reduction of SST levels in the CSF and brain tissue is associated with impaired cognitive function and memory loss. However, the role of SST in preservation of blood-brain barrier (BBB) integrity and functionality in Abeta-induced toxicity is not known. In the present study using human CMEC/D3 cells, we demonstrate that SST prevents Abeta-induced BBB permeability by regulating LRP1 and RAGE expression and improving the disrupted tight junction proteins. Furthermore, SST abrogates Abeta-induced JNK phosphorylation and expression of MMP2. Taken together, results presented here suggest that SST might serve as a therapeutic intervention in AD via targeting multiple pathways responsible for neurotoxicity, impaired BBB function, and disease progression. PMID- 29700776 TI - A Novel Application of Indocyanine Green Immunofluorescence in Emergent Colorectal Surgery. AB - Here, we report on the feasibility of ICG fluorescence imaging to localize lesions in emergent minimally invasive surgery. A 49-year old female presented to the emergency department with a previously unknown malignant bowel obstruction. She was taken emergently to the operating room for a laparoscopic extended right hemicolectomy, based on tumor location from imaging. With intraoperative difficulty localizing the lesion, an on-table colonoscopy was performed. When the tumor was encountered, peritumoral ICG injections were performed, and the fluorescence lymphoscintigraphy was performed intraoperatively in an attempt to visualize the primary tumor laparoscopically. Intraoperative ICG Immunofluorescence allowed precise, real-time localization of the mass in the descending colon. This information changed the course of the operation, as a laparoscopic left hemicolectomy was then performed instead of the planned extended right hemicolectomy. The patient underwent an end-to-end anastomosis without the need for a defunctioning ileostomy. From this case, we demonstrate the use of ICG fluorescence imaging for tumor localization in the emergent setting is safe, feasible, and effective. This information gained from this technology enables real-time decision making, and can even change the operative plan in the emergent setting for the best patient outcomes. What does this paper add to the existing literature? This paper offers a novel application of an emerging technology- ICG fluorescence- that in this capacity allowed precise, real-time localization of a previously unknown mass in the emergent setting, and changed the course of the operation. PMID- 29700777 TI - Prediction of the partition coefficients using QSPR modeling and simulation of paclitaxel release from the diffusion-controlled drug delivery devices. AB - An in silico approach is proposed to first predict the partition coefficient of the model drug, paclitaxel, in different biocompatible and biodegradable polymer versus the blood plasma using artificial neural networks (ANNs) and semi empirical quantitative structure property relationships (QSPRs). A simplified molecular-input line-entry system (SMILES) notation is used to represent the structures of the different polymers and the drug. The SMILES notation is then used to calculate the various structure-based descriptors. These descriptors are then used in the ANNs and semi-empirical QSPRs to predict the properties for a given drug-polymer device. A fluid flow model is subsequently solved to simulate the controlled drug release in the blood plasma. The effects of various parameters are also studied on the drug release profiles from these devices. The proposed approach provides a systematic framework to simulate the controlled release of the drug from the diffusion-controlled drug-polymer release systems. The developed models can be used in a reverse engineer framework to design the controlled delivery devices for a target drug release profile in near future. PMID- 29700778 TI - Editorial of the "ionic liquids and biomolecules" special issue. PMID- 29700780 TI - Clinical and radiological findings of a rare case: reversible Parkinsonism in cerebral venous sinus thrombosis. PMID- 29700779 TI - Ionic liquids: a brief history. AB - There is no doubt that ionic liquids have become a major subject of study for modern chemistry. We have become used to ever more publications in the field each year, although there is some evidence that this is beginning to plateau at approximately 3500 papers each year. They have been the subject of several major reviews and books, dealing with different applications and aspects of their behaviours. In this article, I will show a little of how interest in ionic liquids grew and developed. PMID- 29700781 TI - Interleukin-18 promoter polymorphisms and idiopathic Parkinson disease: an Egyptian study. AB - Etiology of sporadic Parkinson's disease (PD) is largely unknown. The contribution of genetic factors to the pathogenesis of PD is supported by the demonstration of high concordance in twins, increased risk among relatives of PD patients and existence of familial cases. This study aimed to examine the relation between interleukin 18 (IL-18) gene promoter polymorphisms and idiopathic PD, and its impact on clinical presentation and disease severity. 30 idiopathic PD patients and 15 age- and sex-matched healthy subjects were included. Disease severity was assessed using Unified Parkinson's Disease Rating Scale (UPDRS). Genetic testing for IL-18 gene promoter -607C/A single nucleotide polymorphisms (SNP) was done using real-time polymerase chain reaction (PCR) technique. A raised risk of PD development was found in patients with A/C and C/C genotypes of the site -607C/A (odds ratios = 1.83 and 1.98, respectively). The distribution of the genotypes showed no significant relation to gender or predominant clinical presentation. The age at onset of disease was significantly lower in C/C and A/A genotypes compared to A/C genotype (p = 0.001 and 0.04, respectively). Patients with A/A genotype showed significantly higher mentation score of UPDRS compared to patients with A/C and C/C genotypes (p = 0.003 and p = 0.002, respectively). Polymorphisms of IL-18 gene promoter increase the risk of developing idiopathic PD. The polymorphisms may affect phenotypic expression rather than being a direct cause of idiopathic PD. PMID- 29700782 TI - Fabrication and Testing of Electrospun Polyurethane Blended with Chitosan Nanoparticles for Vascular Graft Applications. AB - In this study, a small vascular graft based on polyurethane (PU) blended with chitosan (Ch) nanoparticles was fabricated using electrospinning technique. Initially, the chitosan nanoparticles were synthesized using ionic gelation method. UV-Vis spectrophotometer confirmed the presence of synthesized Ch nanoparticles by exhibiting absorption peak at 288 nm and the Fourier-transform infrared spectroscopy (FTIR) analysis confirmed the existence of the chitosan. Further, the synthesized Ch nanoparticles showed size diameter in the range of 134 +/- 58 nm as measured using ImageJ. In the electrospun PU/chitosan graft, the fiber diameter and pore size diameter was found to be reduced compared to the pure PU owing to incorporation of chitosan into PU matrix. The FTIR spectrum revealed the presence of chitosan in the prepared nanocomposite membrane by the formation of the hydrogen bond and peak shift of CH and NH stretching. Moreover, the contact angle measurements revealed that the prepared graft showed decreased contact angle indicating hydrophilic nature compared to the pristine PU. The cytocompatibility studies revealed the non-toxic behavior of the fabricated graft. Hence, the prepared graft exhibiting significant physiochemical and non toxic properties may be a plausible candidate for cardiovascular graft applications. PMID- 29700783 TI - Modeling Right Ventricle Failure After Continuous Flow Left Ventricular Assist Device: A Biventricular Finite-Element and Lumped-Parameter Analysis. AB - The risk of right ventricle (RV) failure remains a major contraindication for continuous-flow left ventricular assist device (CF-LVAD) implantation in patients with heart failure. It is therefore critical to identify the patients who will benefit from early intervention to avoid adverse outcomes. We sought to advance the computational modeling description of the mechanisms underlying RV failure in LVAD-supported patients. RV failure was studied by computational modeling of hemodynamic and cardiac mechanics using lumped-parameter and biventricular finite element (FE) analysis. Findings were validated by comparison of bi-dimensional speckle-tracking echocardiographic strain assessment of the RV free wall vs. patient-specific computational strain estimations, and by non-invasive lumped based hemodynamic predictions vs. invasive right heart catheterization data. Correlation analysis revealed that lumped-derived RV cardiac output (R = 0.94) and RV stroke work index (R = 0.85) were in good agreement with catheterization data collected from 7 patients with CF-LVAD. Biventricular FE analysis showed abnormal motion of the interventricular septum towards the left ventricular free wall, suggesting impaired right heart mechanics. Good agreement between computationally predicted and echocardiographic measured longitudinal strains was found at basal (- 19.1 +/- 3.0% for ECHO, and - 16.4 +/- 3.2% for FEM), apical (- 20.0 +/- 3.7% for ECHO, and - 17.4 +/- 2.7% for FEM), and mid-level of the RV free wall (- 20.1 +/- 5.9% for echo, and - 18.0 +/- 5.4% for FEM). Simulation approach here presented could serve as a tool for less invasive and early diagnosis of the severity of RV failure in patients with LVAD, although future studies are needed to validate our findings against clinical outcomes. PMID- 29700784 TI - Author's Reply to Cheung et al. Comment on: "Endurance Performance is Influenced by Perceptions of Pain and Temperature: Theory, Applications and Safety Considerations". PMID- 29700785 TI - Comment on: "Endurance Performance is Influenced by Perceptions of Pain and Temperature: Theory, Applications and Safety Considerations". PMID- 29700786 TI - A Discussion of Commercially Available Intra-ocular Telescopic Implants for Patients with Age-Related Macular Degeneration. AB - Age-related macular degeneration (AMD) is the leading cause of visual impairment in the western world, causing significant reduction in quality of life. Despite treatment advances, the burden of visual impairment caused by AMD continues to rise. In addition to traditional low vision rehabilitation and support, optical and electronic aids, and strategies to enhance the use of peripheral vision, implantable telescopic devices have been indicated as a surgical means of enhancing vision. Here we examine the literature on commercially available telescopic devices discussing their design, mode of action, surgical procedure and published outcomes on visual acuity, quality of life, surgical complication rates and cost effectiveness data where available.Funding Article processing charges were funded by VisionCare Inc. PMID- 29700788 TI - Vascular Ehlers-Danlos Syndrome Presenting as a Pulsatile Neck Mass: a Case Report and Review of Literature. AB - Ehlers-Danlos syndrome refers to a spectrum of connective tissue disorders typically caused by mutations in genes responsible for the synthesis of collagen. Patients with Ehlers-Danlos syndrome often exhibit hyperflexibility of joints, increased skin elasticity, and tissue fragility. Vascular Ehlers-Danlos (vEDS) is a subtype of Ehlers-Danlos syndrome with a predilection to involve blood vessels. As such, it often manifests as vascular aneurysms and vessel rupture leading to hemorrhage. There are few reports describing primary prevention of aneurysms in the setting of undiagnosed, suspected vEDS. We present a case of a 30-year-old woman who presents with a pulsatile neck mass found to have multiple arterial aneurysms on imaging, hyperflexibility, and characteristic facial features consistent with vEDS. As described in this case, management of a suspected connective tissue disorder is a multidisciplinary approach including vascular surgery, medical therapy, and genetic testing to confirm the diagnosis. We review literature regarding the care of patients with vascular Ehlers-Danlos as it might pertain to hospitalized patients. PMID- 29700787 TI - Exploring the Use of Molecular Biomarkers for Precision Medicine in Age-Related Macular Degeneration. AB - Precision medicine aims to improve patient care by adjusting medication to each patient's individual needs. Age-related macular degeneration (AMD) is a heterogeneous eye disease in which several pathways are involved, and the risk factors driving the disease differ per patient. As a consequence, precision medicine holds promise for improved management of this disease, which is nowadays a main cause of vision loss in the elderly. In this review, we provide an overview of the studies that have evaluated the use of molecular biomarkers to predict response to treatment in AMD. We predominantly focus on genetic biomarkers, but also include studies that examined circulating or eye fluid biomarkers in treatment response. This involves studies on treatment response to dietary supplements, response to anti-vascular endothelial growth factor, and response to complement inhibitors. In addition, we highlight promising new therapies that have been or are currently being tested in clinical trials and discuss the molecular studies that can help identify the most suitable patients for these upcoming therapeutic approaches. PMID- 29700790 TI - Impact of Medical Scribes on Physician and Patient Satisfaction in Primary Care. AB - BACKGROUND: Use of electronic health records (EHRs) is associated with physician stress and burnout. While emergency departments and subspecialists have used scribes to address this issue, little is known about the impact of scribes in academic primary care. OBJECTIVE: Assess the impact of a scribe on physician and patient satisfaction at an academic general internal medicine (GIM) clinic. DESIGN: Prospective, pre-post-pilot study. During the 3-month pilot, physicians had clinic sessions with and without a scribe. We assessed changes in (1) physician workplace satisfaction and burnout, (2) time spent on EHR documentation, and (3) patient satisfaction. PARTICIPANTS: Six GIM faculty and a convenience sample of their patients (N = 325) at an academic GIM clinic. MAIN MEASURES: A 21-item pre- and 44-item post-pilot survey assessed physician workplace satisfaction and burnout. Physicians used logs to record time spent on EHR documentation outside of clinic hours. A 27-item post-visit survey assessed patient satisfaction during visits with and without the scribe. KEY RESULTS: Of six physicians, 100% were satisfied with clinic workflow post-pilot (vs. 33% pre pilot), and 83% were satisfied with EHR use post-pilot (vs. 17% pre-pilot). Physician burnout was low at baseline and did not change post-pilot. Mean time spent on post-clinic EHR documentation decreased from 1.65 to 0.76 h per clinic session (p = 0.02). Patient satisfaction was not different between patients who had clinic visits with vs. without scribe overall or by age, gender, and race. Compared to patients 65 years or older, younger patients were more likely to report that the physician was more attentive and provided more education during visits with the scribe present (p = 0.03 and 0.02, respectively). Male patients were more likely to report that they disliked having a scribe (p = 0.03). CONCLUSION: In an academic GIM setting, employment of a scribe was associated with improved physician satisfaction without compromising patient satisfaction. PMID- 29700789 TI - Pay-for-Performance and Veteran Care in the VHA and the Community: a Systematic Review. AB - BACKGROUND: Although pay-for-performance (P4P) strategies have been used by the Veterans Health Administration (VHA) for over a decade, the long-term benefits of P4P are unclear. The use of P4P is further complicated by the increased use of non-VHA healthcare providers as part of the Veterans Choice Program. We conducted a systematic review and key informant interviews to better understand the effectiveness and potential unintended consequences of P4P, as well as the implementation factors and design features important in both VHA and non VHA/community settings. METHODS: We searched PubMed, PsycINFO, and CINAHL through March 2017 and reviewed reference lists. We included trials and observational studies of P4P targeting Veteran health. Two investigators abstracted data and assessed study quality. We interviewed VHA stakeholders to gain further insight. RESULTS: The literature search yielded 1031 titles and abstracts, of which 30 studies met pre-specified inclusion criteria. Twenty-five examined P4P in VHA settings and 5 in community settings. There was no strong evidence supporting the effectiveness of P4P in VHA settings. Interviews with 17 key informants were consistent with studies that identified the potential for overtreatment associated with performance metrics in the VHA. Key informants' views on P4P in community settings included the need to develop relationships with providers and health systems with records of strong performance, to improve coordination by targeting documentation and data sharing processes, and to troubleshoot the limited impact of P4P among practices where Veterans make up a small fraction of the patient population. DISCUSSION: The evidence to support the effectiveness of P4P on Veteran health is limited. Key informants recognize the potential for unintended consequences, such as overtreatment in VHA settings, and suggest that implementation of P4P in the community focus on relationship building and target areas such as documentation and coordination of care. PMID- 29700791 TI - Patients' Perception of Newly Initiated Oral Anticoagulant Treatment for Atrial Fibrillation: an Observational Study. PMID- 29700792 TI - Preventive effect of Shenkang injection against high glucose-induced senescence of renal tubular cells. AB - Shenkang injection (SKI) is a classic prescription composed of Radix Astragali, rhubarb, Astragalus, Safflower, and Salvia. This treatment was approved by the State Food and Drug Administration of China in 1999 for treatment of chronic kidney diseases based on good efficacy and safety. This study aimed to investigate the protective effect of SKI against high glucose (HG)-induced renal tubular cell senescence and its underlying mechanism. Primary renal proximal tubule epithelial cells were cultured in (1) control medium (control group), medium containing 5 mmol/L glucose; (2) mannitol medium (mannitol group), medium containing 5 mmol/L glucose, and 25 mmol/L mannitol; (3) HG medium (HG group) containing 30 mmol/L glucose; (4) SKI treatment at high (200 mg/L), medium (100 mg/L), or low (50 mg/L) concentration in HG medium (HG + SKI group); or (5) 200 mg/L SKI treatment in control medium (control + SKI group) for 72 h. HG-induced senescent cells showed the emergence of senescence associated heterochromatin foci, up-regulation of P16INK4 and cyclin D1, increased senescence-associated beta-galactosidase activity, and elevated expression of membrane decoy receptor 2. SKI treatment potently prevented these changes in a dose-independent manner. SKI treatment prevented HG-induced up-regulation of pro-senescence molecule mammalian target of rapamycin and p66Shc and down-regulation of anti-senescence molecules klotho, sirt1, and peroxisome proliferator-activated receptor-g in renal tubular epithelial cells. SKI may be a novel strategy for protecting against HG-induced renal tubular cell senescence in treatment of diabetic nephropathy. PMID- 29700793 TI - Prophylactic use of thoracic endovascular aortic repair in a young patient with impending aortic rupture. PMID- 29700794 TI - Entrapment of dissection flap and intimal tissue cleavage during rotational atherectomy. PMID- 29700795 TI - Changes in the ADC of diffusion-weighted MRI with the oscillating gradient spin echo (OGSE) sequence due to differences in substrate viscosities. AB - PURPOSE: Compared with the conventional pulsed gradient spin-echo (PGSE) sequence, diffusion-weighted imaging (DWI) with the oscillating gradient spin echo (OGSE) sequence can shorten the diffusion time by changing the frequency. The purpose was to investigate whether n-alkanes are suitable as isotropic phantoms for estimating the diffusion coefficient with the OGSE sequence. MATERIALS AND METHODS: We investigated changes in the apparent diffusion coefficient (ADC) due to differences in the viscosities of nine n-alkane phantoms with different numbers of carbon atoms from C8H18 to C16H34 using OGSE and PGSE sequences at 21 degrees C. Effective diffusion times of 4.3, 5.1, 6.5, 9.3, 20, 40, and 60 ms were used. The T2 relaxation times of each n-alkane phantom were measured using quantitative synthetic magnetic resonance imaging (MRI). Circular regions of interest were placed manually within the alkane phantoms on ADC and T2 maps. RESULTS: In each alkane phantom, changes in mean ADC values were almost constant with changes in diffusion times. Viscosities and ADC values showed inverse proportionality, as expected theoretically. CONCLUSION: The ADC values of alkanes do not depend on diffusion times. The n-alkanes can be useful phantoms for assessing the accuracy of clinical protocols of DWI with the OGSE sequence. PMID- 29700796 TI - Susceptibility difference weighted imaging in vertical-field MRI. AB - To realize susceptibility-weighted imaging in vertical-field magnetic resonance imaging (MRI), we developed an image-processing method called "susceptibility difference weighted imaging" (SDWI). In SDWI, contrasts are enhanced using a susceptibility map calculated by using a weighted least-square algorithm with a small iteration number. Experiments were performed on human volunteers to compare image contrast obtained from the conventional method (SWI) and SDWI. In horizontal-field MRI, SDWI results show that veins and deep-gray-matter nuclei were visualized as well as those with SWI. In vertical-field MRI, SDWI visualized veins and deep-gray-matter nuclei without severe streaking artifacts, while SWI did not. In our experiments, the time taken to calculate the susceptibility map in SDWI was less than 10 s. The results indicate that susceptibility-weighted imaging is feasible in vertical-field MRI using SDWI. PMID- 29700797 TI - Quantitation of specific binding ratio in 123I-FP-CIT SPECT: accurate processing strategy for cerebral ventricular enlargement with use of 3D-striatal digital brain phantom. AB - This study aimed to evaluate the effect of ventricular enlargement on the specific binding ratio (SBR) and to validate the cerebrospinal fluid (CSF)-Mask algorithm for quantitative SBR assessment of 123I-FP-CIT single-photon emission computed tomography (SPECT) images with the use of a 3D-striatum digital brain (SDB) phantom. Ventricular enlargement was simulated by three-dimensional extensions in a 3D-SDB phantom comprising segments representing the striatum, ventricle, brain parenchyma, and skull bone. The Evans Index (EI) was measured in 3D-SDB phantom images of an enlarged ventricle. Projection data sets were generated from the 3D-SDB phantoms with blurring, scatter, and attenuation. Images were reconstructed using the ordered subset expectation maximization (OSEM) algorithm and corrected for attenuation, scatter, and resolution recovery. We bundled DaTView (Southampton method) with the CSF-Mask processing software for SBR. We assessed SBR with the use of various coefficients (f factor) of the CSF Mask. Specific binding ratios of 1, 2, 3, 4, and 5 corresponded to SDB phantom simulations with true values. Measured SBRs > 50% that were underestimated with EI increased compared with the true SBR and this trend was outstanding at low SBR. The CSF-Mask improved 20% underestimates and brought the measured SBR closer to the true values at an f factor of 1.0 despite an increase in EI. We connected the linear regression function (y = - 3.53x + 1.95; r = 0.95) with the EI and f factor using root-mean-square error. Processing with CSF-Mask generates accurate quantitative SBR from dopamine transporter SPECT images of patients with ventricular enlargement. PMID- 29700799 TI - Spinal anesthesia for Cesarean delivery in obese parturients: is this the best option? PMID- 29700798 TI - Harnessing Technology to Implement Measurement-Based Care. PMID- 29700800 TI - In reply: Spinal anesthesia for Cesarean delivery in obese parturients: is this the best option? PMID- 29700801 TI - Ketamine-based anesthesia improves electroconvulsive therapy outcomes: a randomized-controlled study. AB - BACKGROUND: Major depressive disorder (MDD) is a common and debilitating condition that can be challenging to treat. Electroconvulsive therapy (ECT) is currently the therapeutic gold standard for treatment-resistant MDD. We tested our hypothesis that ketamine-based anesthesia for ECT results in superior improvement in treatment-resistant MDD outcomes compared with propofol-based anesthesia. METHODS: Patients with treatment-resistant MDD were enrolled in a randomized clinical trial with assignment to ketamine- or propofol-based anesthesia arms. Using a modified intention-to-treat analysis, we compared the median number of ECT treatments required to achieve a 50% reduction (primary outcome) and a score <= 10 (secondary outcome) on the Montgomery-Asberg depression rating scale (MADRS) between anesthesia groups. RESULTS: The study was terminated as significant results were found after the first planned interim analysis with 12 patients in each of the ketamine (intervention) and propofol (control) groups. All ketamine patients achieved at least a 50% MADRS reduction after a median of two ECT treatments whereas ten propofol patients (83%) achieved the same outcome after a median of four ECT treatments. All ketamine patients and seven propofol patients (58%) achieved MDD remission (MADRS <= 10). Log rank tests showed that both time-to-50% reduction and remission differed significantly between groups. Adverse events and recovery time were similar between groups. CONCLUSIONS: In this early-terminated small-sized study, ketamine-based anesthesia compared with propofol-based anesthesia provided response and remission after fewer ECT sessions. TRIAL REGISTRATION: www.clinicaltrials.gov (NCT01935115). Registered 4 September 2013. PMID- 29700802 TI - Acute and chronic effects of metabolic acidosis on renal function and structure. AB - BACKGROUND: Emerging evidence suggests that chronic metabolic acidosis (CMA) may have significant implications in terms of worsening renal disease in CKD patients, but the effect of CMA on renal function and structure has not been fully elucidated. METHOD: We studied the acute and chronic consequences of an acid load (AL) on glomerular filtration rate (GFR) and renal histology in C57BL/6 mice. FITC-inulin clearance was performed at several time points; markers of renal fibrosis were studied at mRNA and protein levels; finally, kidney expression of candidate molecules triggering changes in renal function was studied. RESULTS: Glomerular hyperfiltration occurred within 1-3 days from AL; after 1 week, the GFR returned to baseline and then declined progressively within 15-21 days. The GFR decline was accompanied by the onset of renal fibrosis, as shown by Masson trichrome staining. Markers of renal fibrosis, namely alpha smooth muscle actin and collagen-1, increased after 1 day of acid loading in both mRNA and protein levels and remained higher than baseline for up to 21 days. Well known mediators of renal fibrosis, including transforming growth factor (TGF) beta and the intrarenal renin-angiotensin system (RAS) axis, were increased even before the decline of the GFR. CONCLUSION: Acid load caused hyperfiltration acutely and a progressive decline of the GFR chronically; the evidence of renal fibrosis indicates that structural and not only functional renal changes occurred. The concomitant upregulation of TGF-beta and intrarenal RAS axis indicates that those factors may be potentially involved in the progression of kidney disease in this setting. PMID- 29700803 TI - Lumbosacral loadbearing, sagittal shift in the line of gravity and joint surface areas. PMID- 29700804 TI - Roles of Xenopus chemokine ligand CXCLh (XCXCLh) in early embryogenesis. AB - Several chemokine molecules control cell movements during early morphogenesis. However, it is unclear whether chemokine molecules affect cell fate. Here, we identified and characterized the CXC-type chemokine ligand in Xenopus laevis, Xenopus CXCLh (XCXCLh), during early embryogenesis. XCXCLh is expressed in the dorsal vegetal region at the gastrula stage. Both overexpression and knockdown of XCXCLh in the dorsal region inhibited gastrulation. XCXCLh contributed to the attraction of mesendodermal cells and accelerated the reassembly of scratched culture cells. Also, XCXCLh contributed to early endodermal induction. Overexpression of VegTmRNA or high concentrations of calcium ions induced XCXCLh expression. XCXCLh may play roles in both cell movements and differentiation during early Xenopus embryogenesis. PMID- 29700805 TI - Pathogenetic implication of fusion genes in acute promyelocytic leukemia and their diagnostic utility. AB - Acute promyelocytic leukemia (APL) has been recognized as a discrete subset of hematopoietic malignancies constituting approximately 10% of acute myeloid leukemia cases. The hallmark reciprocal chromosomal translocation t(15;17) involving fusion between the retinoic acid receptor (RARalpha) gene and promyelocytic leukemia (PML) gene is a characteristic feature in APL which consequently results in the emergence of PML-RARalpha chimeric gene. This gene has been substantiated to be responsible for cellular transformation and is a prime target of all-trans-retinoic acid (ATRA) as well as arsenic-trioxide (ATO) therapy. Since this initial discovery, about 10 diverse translocation partner genes of RARalpha have been reported that result in variant APL forms strongly suggesting that disruption of RARalpha underlies its pathogenesis. The nature of the fusion partner has a significant bearing upon disease characteristics including sensitivity to retinoids and ATO and thereby underpins the need for rapid and accurate diagnosis and also demands a highly specific treatment approach. In this article we laid emphasis on the rearrangement of the RARalpha gene and its different fusion partners resulting in variant forms of APL, their implication in underlying molecular pathogenesis of APL and also the different diagnostic modalities that should be employed for their rapid and accurate diagnosis. PMID- 29700806 TI - Onychoscopic evaluation of onychomycosis in a tertiary care teaching hospital: a cross-sectional study from South India. AB - BACKGROUND: Onychoscopy is the dermoscopic evaluation of nail and associated structures. It is useful in identifying the various onychoscopic patterns which act as a link between naked eye examination and nail histopathology and may help in avoiding nail biopsy in unnecessary cases. OBJECTIVES: To evaluate the onychoscopic patterns in confirmed cases of onychomycosis. METHODS: An observational, prospective, cross-sectional study was performed in 500 patients with symptoms related to the nails and nail folds. Onychomycosis was confirmed in 234 patients by KOH mount/fungal culture/biopsy. These patients underwent dermoscopy with a handheld 20* polarized contact dermoscope (Heine's delta 20 T). The dermoscopic patterns were identified, and their correlation with the clinical subtype of onychomycosis was analyzed. RESULTS: The study included 234 confirmed cases of onychomycosis. The common dermoscopic patterns observed were spikes (43.16%), jagged (29.9%), longitudinal striae (49.1%), linear edge (3.4%), and distal irregular termination (34.6%). The statistically significant findings of distal and lateral subungual onychomycosis (DLSO) were longitudinal striae, spikes, and jagged patterns. The new patterns observed in our study are bluish streaks and globules (8.9%) and bluish gray globules (7.6%) in cases of DLSO which were not statistically significant. CONCLUSION: Onychoscopy, being handy, inexpensive, and noninvasive, has the potential to reduce the invasive procedures. Statistically significant patterns in DLSO and total dystrophic onychomycosis (TDO) are described in our study. Few new patterns have been described whose significance has to be tested by conducting larger sample size studies. PMID- 29700807 TI - Clinical and dermoscopic spectrum of discoid lupus erythematosus: novel observations from lips and oral mucosa. AB - BACKGROUND: Under dermoscopy, discoid lupus erythematosus (DLE) exhibits specific findings. Commonly DLE lesions affect sun-exposed sites, especially the face. However, most of the dermoscopic reports come from scalp DLE. To our knowledge, the dermoscopic pattern for mucosal and labial DLE has not been previously reported. METHODS: This study included 20 patients with histopathologically confirmed DLE lesions. Full history taking was obtained with photo documentation of lesions including the sites involved, the number of lesions per site, and the total number of lesions affecting every patient. Finally, a dermoscopic examination was performed. RESULTS: Almost 85% of patients had only cutaneous DLE lesions, while 15% showed both cutaneous and mucosal lesions. Follicular keratotic plugging (56.1%) and scales (52.6%) were the most frequently detected dermoscopic criteria. A significant correlation was found between lesion's age and the following dermoscopic criteria: (early lesions: follicular keratotic plugs and perifollicular white halos; while late lesions: telangiectasia and white structureless areas). Furthermore, telangiectasia, white structureless areas, and ulceration were found in dermoscopy of mucosal DLE. Also, telangiectasia, brown pigment spots, scales, white structureless areas, bleeding spots, and erosions were detected in dermoscopy of labial DLE. Moreover, labial storiform telangiectasia was seen under dermoscopy in patients with associated SLE. CONCLUSIONS: Dermoscopy is a valuable tool for diagnosing DLE at different sites and in differentiating between the early and end-stage lesions. Herein, we reported the first dermoscopic view for DLE affecting the lips and oral mucosa. Labial storiform telangiectasia could be a dermoscopic sign of coexisting SLE. PMID- 29700808 TI - A pruritic maculopapular eruption leaving a reticular hyperpigmentation. PMID- 29700810 TI - Refining the phenotype associated with biallelic DNAJC21 mutations. AB - Inherited bone marrow failure syndromes (IBMFS) are caused by mutations in genes involved in genomic stability. Although they may be recognized by the association of typical clinical features, variable penetrance and expressivity are common, and clinical diagnosis is often challenging. DNAJC21, which is involved in ribosome biogenesis, was recently linked to bone marrow failure. However, the specific phenotype and natural history remain to be defined. We correlate molecular data, phenotype, and clinical history of 5 unreported affected children and all individuals reported in the literature. All patients present features consistent with IBMFS: bone marrow failure, growth retardation, failure to thrive, developmental delay, recurrent infections, and skin, teeth or hair abnormalities. Additional features present in some individuals include retinal abnormalities, pancreatic insufficiency, liver cirrhosis, skeletal abnormalities, congenital hip dysplasia, joint hypermobility, and cryptorchidism. We suggest that DNAJC21-related diseases constitute a distinct IBMFS, with features overlapping Shwachman-Diamond syndrome and Dyskeratosis congenita, and additional characteristics that are specific to DNAJC21 mutations. The full phenotypic spectrum, natural history, and optimal management will require more reports. Considering the aplastic anemia, the possible increased risk for leukemia, and the multisystemic features, we provide a checklist for clinical evaluation at diagnosis and regular follow-up. PMID- 29700811 TI - Timing of elective pre-labour caesarean section: A decision analysis. AB - BACKGROUND: Since caesarean sections (CSs) before 39+0 weeks gestation are associated with higher rates of neonatal respiratory morbidity, it is recommended to delay elective CSs until 39+0 weeks. However, this bears the risk of earlier spontaneous labour resulting in unplanned CSs, which has workforce and resource implications, specifically in smaller obstetric units. AIM: To assess, in a policy of elective CSs from 39+0 weeks onward, the number of unplanned CSs to prevent one neonate with respiratory complications, as compared to early elective CS. MATERIALS AND METHODS: We performed a decision analysis comparing early term elective CS at 37+0-6 or 38+0-6 weeks to elective prelabour CS, without strict medical indication, at 39+0-6 weeks, with earlier unplanned CS, in women with uncomplicated singleton pregnancies. We used literature data to calculate the number of unplanned CSs necessary to prevent one neonate with respiratory morbidity. RESULTS: Planning all elective CSs at 39+0-6 weeks required 10.9 unplanned CSs to prevent one neonate with respiratory morbidity, compared to planning all elective CSs at 38+0-6 weeks. Compared to planning all elective CSs at 37+0-6 weeks we needed to perform 3.3 unplanned CSs to prevent one neonate with respiratory morbidity. CONCLUSION: In a policy of planning all elective pre labour CSs from 39+0 weeks of gestation onward, between three and 11 unplanned CSs have to be performed to prevent one neonate with respiratory morbidity. Therefore, in our opinion, fear of early term labour and workforce disutility is no argument for scheduling elective CSs <39+0 weeks. PMID- 29700809 TI - The opposing roles of CD4+ T cells in anti-tumour immunity. AB - Cancer immunotherapy focuses mainly on anti-tumour activity of CD8+ cytotoxic T lymphocytes (CTLs). CTLs can directly kill all tumour cell types, provided they carry recognizable antigens. However, CD4+ T cells also play important roles in anti-tumour immunity. CD4+ T cells can either suppress or promote the anti-tumour CTL response, either in secondary lymphoid organs or in the tumour. In this review, we highlight opposing mechanisms of conventional and regulatory T cells at both sites. We outline how current cancer immunotherapy strategies affect both subsets and how selective modulation of each subset is important to maximize the clinical response of cancer patients. PMID- 29700812 TI - Privileges and penalties in the legal profession: an intersectional analysis of career progression. AB - Intersectionality theory is concerned with integrating social characteristics to better understanding complex human relations and inequalities in organizations and societies (McCall ). Recently, intersectionality research has taken a categorical and quantitative turn as scholars critically adopt but retain existing social categories to explain differences in labour market outcomes. A key contention is that social categories carry penalties or privileges and their intersection promotes or hinders the life chances of particular groups and individuals. An emergent debate is whether the intersection of disadvantaged characteristics (such as female gender or minority ethnic status) produce penalties that are additive, multiplicative or ameliorative. Research is inconclusive and as yet pays little attention to moderating factors such as employer type, size, geographic location or work profile. Drawing on administrative records for individuals qualified as solicitors in England and Wales, collected by the Solicitors Regulation Authority (SRA), combined with aggregated workforce data and firm characteristics of their law firms, we undertake a statistical analysis of the intersection of gender and ethnicity in the profession with a degree of precision and nuance not previously possible. In response to calls to broaden studies of inequalities and intersectionality beyond their effect on pay or income (Castilla ) we focus on career progression to partnership as our key measure of success. The original contribution of our study is twofold. First, we establish statistically different profiles of law firms, showing how the solicitors' profession is stratified by gender, ethnicity and socio-economic background, as well as the type of legal work undertaken by developing a model of socio-economic stratification in the profession. Second, we demonstrate that while penalties tend to be additive (i.e. the sum of the individual ethnic and gender penalties) this varies significantly by law firm profile and in some situations the effect is ameliorative. PMID- 29700814 TI - Forecasting Clinical Dose-Response From Preclinical Studies in Tuberculosis Research: Translational Predictions With Rifampicin. AB - A crucial step for accelerating tuberculosis drug development is bridging the gap between preclinical and clinical trials. In this study, we developed a preclinical model-informed translational approach to predict drug effects across preclinical systems and early clinical trials using the in vitro-based Multistate Tuberculosis Pharmacometric (MTP) model using rifampicin as an example. The MTP model predicted rifampicin biomarker response observed in 1) a hollow-fiber infection model, 2) a murine study to determine pharmacokinetic/pharmacodynamic indices, and 3) several clinical phase IIa early bactericidal activity (EBA) studies. In addition, we predicted rifampicin biomarker response at high doses of up to 50 mg/kg, leading to an increased median EBA0-2 days (90% prediction interval) of 0.513 log CFU/mL/day (0.310; 0.701) compared to the standard dose of 10 mg/kg of 0.181 log/CFU/mL/day (0.076; 0.483). These results suggest that the translational approach could assist in the selection of drugs and doses in early phase clinical tuberculosis trials. PMID- 29700813 TI - The impact of a computerised test of attention and activity (QbTest) on diagnostic decision-making in children and young people with suspected attention deficit hyperactivity disorder: single-blind randomised controlled trial. AB - BACKGROUND: Diagnosis of attention deficit hyperactivity disorder (ADHD) relies on subjective methods which can lead to diagnostic uncertainty and delay. This trial evaluated the impact of providing a computerised test of attention and activity (QbTest) report on the speed and accuracy of diagnostic decision-making in children with suspected ADHD. METHODS: Randomised, parallel, single-blind controlled trial in mental health and community paediatric clinics in England. Participants were 6-17 years-old and referred for ADHD diagnostic assessment; all underwent assessment-as-usual, plus QbTest. Participants and their clinician were randomised to either receive the QbTest report immediately (QbOpen group) or the report was withheld (QbBlind group). The primary outcome was number of consultations until a diagnostic decision confirming/excluding ADHD within 6 months from baseline. Health economic cost-effectiveness and cost utility analysis was conducted. Assessing QbTest Utility in ADHD: A Randomised Controlled Trial was registered at ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT02209116). RESULTS: One hundred and thirty-two participants were randomised to QbOpen group (123 analysed) and 135 to QbBlind group (127 analysed). Clinicians with access to the QbTest report (QbOpen) were more likely to reach a diagnostic decision about ADHD (hazard ratio 1.44, 95% CI 1.04-2.01). At 6-months, 76% of those with a QbTest report had received a diagnostic decision, compared with 50% without. QbTest reduced appointment length by 15% (time ratio 0.85, 95% CI 0.77-0.93), increased clinicians' confidence in their diagnostic decisions (odds ratio 1.77, 95% CI 1.09-2.89) and doubled the likelihood of excluding ADHD. There was no difference in diagnostic accuracy. Health economic analysis showed a position of strict dominance; however, cost savings were small suggesting that the impact of providing the QbTest report within this trial can best be viewed as 'cost neutral'. CONCLUSIONS: QbTest may increase the efficiency of ADHD assessment pathway allowing greater patient throughput with clinicians reaching diagnostic decisions faster without compromising diagnostic accuracy. PMID- 29700815 TI - UVA-1 phototherapy for the management of atopic dermatitis: a large retrospective study conducted in a low-middle income country. AB - BACKGROUND: Medium-dose ultraviolet light A - 1 (UVA-1) phototherapy, given in short courses, has shown efficacy in atopic dermatitis flares; little is known about its use, efficacy, and side effects in prolonged exposure used in the chronic disease despite its extensive use. METHODS: A descriptive retrospective study was conducted; convenience sampling of patients with atopic dermatitis treated with UVA-1 phototherapy was made; evaluation of clinical response by SCORAD, adverse effects, and protocols used in each patient were evaluated. RESULTS: Patients exposed to UVA-1 phototherapy showed a decrease in the SCORAD (30.1 points) - total cumulative dose-dependent (P < 0.0001) - regardless of multiple variables studied. There were low rates of relapse and adverse effects. The most frequent doses were 30 and 60 J/cm2 , three times per week; patients had similar clinical responses and adverse effects in these groups independent of the other variables studied (P = 0.057). CONCLUSION: UVA-1 phototherapy can be an alternative for patients with severe atopic dermatitis even at lower doses than those described in other series (30 J/cm2 ) and not only for acute flares. Cumulative total dose is a variable that affects the clinical response directly. Large prospective studies are needed. PMID- 29700816 TI - Rigidity of the far-right? Motivated social cognition in a nationally representative sample of Hungarians on the eve of the far-right breakthrough in the 2010 elections. AB - We investigated the "rigidity of the right" hypothesis in the context of the far right breakthrough in the 2010 Hungarian parliamentary elections. This hypothesis suggests that psychological characteristics having to do with need for security and certainty attract people to a broad-based right-wing ideology. A nationally representative sample (N = 1000) in terms of age, gender and place of residence was collected by means of the random walking method and face-to-face interviews. Voters of JOBBIK (n = 124), the radically nationalist conservative far-right party, scored lower on System Justifying Belief, Belief in a Just World (Global) and higher on Need for Cognition than other voters. Our results contradict the "rigidity of the right" hypothesis: JOBBIK voters scored, on many measures, opposite to what the hypothesis would predict. PMID- 29700817 TI - Medicine based evidence and personalized care of patients. AB - BACKGROUND: For the past 70- years patient care has been dominated by Evidence Based Medicine (EBM) with its emphasis on Randomized Controlled Trials (RCTs) and clinical guidelines to standardize medical decision-making. METHODS: Critical assessment of the literature and analyses of the arguments that favor patient care based primarily on individual variability in disease risk or treatment response versus emphasis on group standardization. RESULTS: Medicine Based Evidence (MBE) is used to guide decision making for an individual patient at hand by profiling the clinical features (biology) and life experience (biography) of the patient and then finding approximate matches to the patient in a clinical library of patients assembled from diverse sources (RCTs, cohorts, registries, electronic health records and more). CONCLUSION: Medicine is transitioning from population based model of clinical care that relies on average results from RCTs to an individual-based model of "personalized" medicine. For individualized care of the patient at hand, MBE is the preferred scientific strategy to generate evidence for patient care. PMID- 29700818 TI - Angiosarcoma of the scalp responding to nivolumab: a case report. PMID- 29700820 TI - Elevated atmospheric carbon dioxide concentrations promote ant tending of aphids. AB - Animal mutualisms, which involve beneficial interactions between individuals of different species, are common in nature. Insect-insect mutualism, for example, is widely regarded as a keystone ecological interaction. Some mutualisms are anticipated to be modified by climate change, but the focus has largely been on plant-microbe and plant-animal mutualisms rather than those between animals. Ant aphid mutualisms, whereby ants tend aphids to harvest their honeydew excretions and, in return, provide protection for the aphids, are widespread. The mutualism is heavily influenced by the quality and quantity of honeydew produced by aphids, which is directly affected by host plant quality. As predicted increases in concentrations of atmospheric carbon dioxide (eCO2 ) are widely reported to affect plant nutritional chemistry, this may also alter honeydew quality and hence the nature of ant-aphid mutualisms. Using glasshouse chambers and field based open-top chambers, we determined the effect of eCO2 on the growth and nutritional quality (foliar amino acids) of lucerne (Medicago sativa). We determined how cowpea aphid (Aphis craccivora) populations and honeydew production were impacted when feeding on such plants and how this affected the tending behaviour of ants (Iridomyrmex sp.). eCO2 stimulated plant growth but decreased concentrations of foliar amino acids by 29% and 14% on aphid-infested plants and aphid-free plants, respectively. Despite the deterioration in host plant quality under eCO2 , aphids maintained performance and populations were unchanged by eCO2 . Aphids induced higher concentrations of amino acids (glutamine, asparagine, glutamic acid and aspartic acid) important for endosymbiont-mediated synthesis of essential amino acids. Aphids feeding under eCO2 also produced over three times more honeydew than aphids feeding under ambient CO2 , suggesting they were imbibing more phloem sap at eCO2 . The frequency of ant tending of aphids more than doubled in response to eCO2 . To our knowledge, this is the first study to demonstrate the effects of atmospheric change on an ant-aphid mutualism. In particular, these results highlight how impending changes to concentrations of atmospheric CO2 may alter mutualistic behaviour between animals. These could include positive impacts, as reported here, shifts from mutualism to antagonism, partner switches and mutualism abandonment. PMID- 29700819 TI - Circular RNA expression profile and potential function of hsa_circ_0045272 in systemic lupus erythematosus. AB - Circular RNAs (circRNAs) represent a class of non-coding RNAs that form covalently closed RNA circles with extensive expression and conservation in mammals. Circular RNAs regulate gene expression through acting as competitive endogenous RNAs (ceRNAs) and modulating gene transcription. Accumulating evidence supports the implication of circRNAs in a variety of human diseases, but studies of circRNA role in systemic lupus erythematosus (SLE) are lacking. The present study measured the circRNA expression profiles in T cells from patients with SLE and healthy controls with human circRNA microarray and identified 127 differentially expressed circRNAs in SLE patients. Down-regulation of hsa_circ_0045272 in SLE T cells was verified with quantitative PCR. Jurkat cells with stable hsa_circ_0045272 knockdown were generated using specific lentiviral short hairpin RNA for functional studies. Flow cytometric analysis indicated that hsa_circ_0045272 knockdown significantly up-regulated the early apoptosis of Jurkat cells. Meanwhile, ELISA showed that hsa_circ_0045272 knockdown significantly enhanced interleukin-2 production of activated Jurkat cells. Then, ceRNAs were predicted for hsa_circ_0045272 and the significant down-regulation of two mRNAs predicted as ceRNAs, NM_003466 (PAX8) and NM_015177 (DTX4), but not their corresponding proteins, was validated. Furthermore, dual luciferase reporter assay indicated binding of hsa_circ_0045272 with hsa-miR-6127. Circular RNA-mRNA co-expression networks showed the correlation of circRNAs with mRNAs and provided additional clues to circRNA functions. Our study demonstrated dysregulated circRNAs in SLE and revealed the function of hsa_circ_0045272 in negatively regulating apoptosis and interleukin-2 secretion and its potential mechanism. The implication of hsa_circ_0045272 and other abnormal circRNAs in SLE merits further investigation. PMID- 29700821 TI - Efficacy of low-molecular-weight heparin on the outcomes of in vitro fertilization/intracytoplasmic sperm injection pregnancy in non-thrombophilic women: a meta-analysis. AB - INTRODUCTION: The aim of our study was to evaluate the effect of low-molecular weight heparin on pregnancy outcomes in women without thrombophilia during in vitro fertilization/intracytoplasmic sperm injection treatment. MATERIAL AND METHODS: We searched Pubmed, Web of Science, Embase, Cochrane and CNKI (from inception to 2 February 2018). Our study identified randomized controlled trials or quasi-randomized controlled trials comparing low-molecular-weight heparin subcutaneous treatment with no treatment or only luteal support control. The outcomes included live birth rate, clinical pregnancy rate and miscarriage rate. RESULTS: Five trials, including 935 women receiving in vitro fertilization/intracytoplasmic sperm injection treatment, were included in meta analyses. There were 458 women receiving low-molecular-weight heparin and 477 in the control group. No significant differences for live birth rate, clinical pregnancy rate and miscarriage rate were found between the low-molecular-weight heparin and control groups. Of them, four trials reported live birth rate as an outcome and the risk ratio was 1.13 (95% confidence interval 0.88-1.43, p = 0.34). All five trials reported clinical pregnancy rate as an outcome, the risk ratio was 1.08 (95% confidence interval 0.87-1.32, p = 0.47). Three trials reported miscarriage rate and the risk ratio was 0.58 (95% confidence interval 0.30-1.10, p = 0.09). In women with two or more failed in vitro fertilization/intracytoplasmic sperm injection cycles, the risk ratio of live birth rate was 1.15 and the risk ratio of clinical pregnancy rate was 1.17. In women with three or more failed in vitro fertilization/intracytoplasmic sperm injection cycles, the risk ratios of live birth rate and clinical pregnancy rate were 1.36 and 1.35, respectively. CONCLUSIONS: Our results suggested that low molecular-weight heparin had no effect on pregnancy success rate in non thrombophilic women undergoing in vitro fertilization/intracytoplasmic sperm injection treatment. However, to justify the use of low-molecular-weight heparin in clinical practice, multicenter trials are still necessary. PMID- 29700823 TI - The cholinergic system in the basal forebrain of the Atlantic white-sided dolphin (Lagenorhynchus acutus). AB - The basal forebrain (BFB) cholinergic neurotransmitter system is important in a number of brain functions including attention, memory, and the sleep-wake cycle. The size of this region has been linked to the increase in encephalization of the brain in a number of species. Cetaceans, particularly those belonging to the family Delphinidae, have a relatively large brain compared to its body size and it is expected that the cholinergic BFB in the dolphin would be a prominent feature. However, this has not yet been explored in detail. This study examines and maps the neuroanatomy and cholinergic chemoarchitecture of the BFB in the Atlantic white-sided dolphin (Lagenorhynchus acutus). As in some other mammals, the BFB in this species is a prominent structure along the medioventral surface of the brain. The parcellation and distribution of cholinergic neural elements of the dolphin BFB was comparable to that observed in other mammals in that it has a medial septal nucleus, a nucleus of the vertical limb of the diagonal band of Broca, a nucleus of the horizontal limb of the diagonal band of Broca, and a nucleus basalis of Meynert. The observed BFB cholinergic system of this dolphin is consistent with evolutionarily conserved and important functions for survival. PMID- 29700822 TI - Genetic analysis of adult leukoencephalopathy patients using a custom-designed gene panel. AB - Leukoencephalopathies encompass all clinical syndromes that predominantly affect brain white matter. Genetic diagnosis informs clinical management of these patients, but a large part of the genetic contribution to adult leukoencephalopathy remains unresolved. To examine this genetic contribution, we analyzed genomic DNA from 60 Japanese patients with adult leukoencephalopathy of unknown cause by next generation sequencing using a custom-designed gene panel. We selected 55 leukoencephalopathy-related genes for the gene panel. We identified pathogenic mutations in 8 of the 60 adult leukoencephalopathy patients (13.3%): NOTCH3 mutations were detected in 5 patients, and EIF2B2, CSF1R, and POLR3A mutations were found independently in 1 patient each. These results indicate that cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) caused by NOTCH3 mutations is the most frequent adult leukoencephalopathy in our cohort. Moreover, brain imaging analysis indicates that CADASIL patients who do not present typical phenotypes may be underdiagnosed if not examined genetically. PMID- 29700824 TI - Clinical, molecular genetics and therapeutic aspects of syndromic obesity. AB - Obesity has become a major health problem worldwide. To date, more than 25 different syndromic forms of obesity are known in which one (monogenic) or multiple (polygenic) genes are involved. This review gives an overview of these forms and focuses more in detail on 6 syndromes: Prader Willi Syndrome and Prader Willi like phenotype, Bardet Biedl Syndrome, Alstrom Syndrome, Wilms tumor, Aniridia, Genitourinary malformations and mental Retardation syndrome and 16p11.2 (micro)deletions. Years of research provided plenty of information on the molecular genetics of these disorders and the obesity phenotype leading to a more individualized treatment of the symptoms, however, many questions still remain unanswered. As these obesity syndromes have different signs and symptoms in common, it makes it difficult to accurately diagnose patients which may result in inappropriate treatment of the disease. Therefore, the big challenge for clinicians and scientists is to more clearly differentiate all syndromic forms of obesity to provide conclusive genetic explanations and eventually deliver accurate genetic counseling and treatment. In addition, further delineation of the (functions of the) underlying genes with the use of array- or next-generation sequencing-based technology will be helpful to unravel the mechanisms of energy metabolism in the general population. PMID- 29700826 TI - How do parents' educational fields affect the choice of educational field? AB - This study examines the links between parental education and students' choice of field of study in Norwegian higher education. In our interpretation of the results, we suggest a status group perspective that integrates risk aversion models, micro-class theory, and cultural reproduction schemes. Complete Norwegian register data for all individuals born from 1955 to 1980 allow for a fine-grained examination of diverse fields of study not attempted in earlier studies. The findings reveal that intergenerational reproduction of educational fields is widespread, but its extent varies across fields of study. The tendency is most pronounced among children of professional, educated parents with masters and higher-level degrees. Moreover, the analysis shows that students who do not choose the same field as their parents nonetheless tend to choose educational fields close to those of their parents. PMID- 29700825 TI - Synthetic polymers as substrates for a DNA-sliding clamp protein. AB - The clamp protein (gp45) of the DNA polymerase III of the bacteriophage T4 is known to bind to DNA and stay attached to it in order to facilitate the process of DNA copying by the polymerase. As part of a project aimed at developing new biomimetic data-encoding systems we have investigated the binding of gp45 to synthetic polymers, that is, rigid, helical polyisocyanopeptides. Molecular modelling studies suggest that the clamp protein may interact with the latter polymers. Experiments aimed at verifying these interactions are presented and discussed. PMID- 29700827 TI - Why we miss fetal growth restriction: Identification of risk factors for severely growth-restricted fetuses remaining undelivered by 40 weeks gestation. AB - BACKGROUND: Severe fetal growth restriction (FGR) is a leading cause of adverse perinatal morbidity and mortality; however, in Victoria, 35% of severely growth restricted infants are undelivered by 40 weeks gestation. AIMS: We aimed to identify factors associated with failure to deliver severely growth-restricted fetuses by 40 weeks gestation. METHODS: We conducted a retrospective case-control study of term singletons born <3rd centile for gestation at a single tertiary centre (2010-2017). Infants with a planned delivery for FGR between 37.0-39.6 weeks gestation ('planned birth' group; n = 187) were compared with those undelivered by 40.0 weeks ('undelivered' group; n = 233). Variables assessed included the presence of risk factors for FGR, model of care, symphyseal-fundal height measurements and third trimester ultrasounds. RESULTS: An equivalent proportion of women were 'high-risk' for FGR on history (31.3% vs 38.0%, P = 0.187) in the planned and undelivered groups. Women booked under low-risk models (shared care and midwifery-led care) were significantly more likely to be in the undelivered group compared to those booked under traditional collaborative models (79.8% vs 37.4%, P < 0.001). Women in the undelivered group were less likely to have received a third trimester ultrasound (93.0% vs 40.3%, P < 0.001); however, they were more likely to have had a reassuring ultrasound with an estimation of fetal weight or abdominal circumference >10th centile (78.7% vs 16.1%, P < 0.001). CONCLUSIONS: Failure to deliver the severely growth-restricted fetus before 40.0 weeks is more likely to occur in the following situations: (i) failure to receive an indicated third trimester ultrasound; (ii) the presence of falsely reassuring third trimester ultrasound scan; and (iii) booking under a low risk rather than traditional collaborative models of care. PMID- 29700829 TI - Teacher beliefs about the aetiology of individual differences in cognitive ability, and the relevance of behavioural genetics to education. AB - BACKGROUND: Despite a large body of research that has explored the influence of genetic and environmental factors on educationally relevant traits, few studies have explored teachers' beliefs about, or knowledge of, developments in behavioural genetics related to education. AIMS: This study aimed to describe the beliefs and knowledge of UK teachers about behavioural genetics and its relevance to education, and to test for differences between groups of teachers based on factors including years of experience and age of children taught. SAMPLE: Data were gathered from n = 402 teachers from a representative sample of UK schools. Teachers from primary and secondary schools, and from across the state and independent sectors, were recruited. METHODS: An online questionnaire was used to gather demographic data (gender, age, years of experience, age of children taught, and state vs. independent) and also data on beliefs about the relative influence of nature and nurture on cognitive ability; knowledge of behavioural genetics; openness to genetic research in education; and mindset. Data were analysed using descriptive statistics, ANOVA, correlations, and multiple regression. RESULTS: Teachers perceived genetic and environmental factors as equally important influences on cognitive ability and tended towards a growth mindset. Knowledge about behavioural genetics was low, but openness to learning more about genetics was high. Statistically significant differences were observed between groups based on age of children taught (openness higher among primary teachers) and state versus independent (more growth-minded in state sector). CONCLUSIONS: Although teachers have a limited knowledge of behavioural genetics, they are keen to learn more. PMID- 29700830 TI - Long QT: A syndrome or acquired finding? PMID- 29700828 TI - Therapeutic potential to reduce brain injury in growth restricted newborns. AB - Brain injury in intrauterine growth restricted (IUGR) infants is a major contributing factor to morbidity and mortality worldwide. Adverse outcomes range from mild learning difficulties, to attention difficulties, neurobehavioral issues, cerebral palsy, epilepsy, and other cognitive and psychiatric disorders. While the use of medication to ameliorate neurological deficits in IUGR neonates has been identified as warranting urgent research for several years, few trials have been reported. This review summarises clinical trials focusing on brain protection in the IUGR newborn as well as therapeutic interventions trialled in animal models of IUGR. Therapeutically targeting mechanisms of brain injury in the IUGR neonate is fundamental to improving long-term neurodevelopmental outcomes. Inflammation is a key mechanism in neonatal brain injury; and therefore an appealing target. Ibuprofen, an anti-inflammatory drug currently used in the preterm neonate, may be a potential therapeutic candidate to treat brain injury in the IUGR neonate. To better understand the potential of ibuprofen and other therapeutic agents to be neuroprotective in the IUGR neonate, long-term follow-up information of neurodevelopmental outcomes must be studied. Where agents such as ibuprofen are shown to be effective, have a good safety profile and are relatively inexpensive, they can be widely adopted and lead to improved outcomes. PMID- 29700831 TI - Reliability of the Australian Therapy Outcome Measures for Occupational Therapy (AusTOMs-OT). AB - BACKGROUND/AIM: The delivery of evidence-based health care requires the routine adoption of outcome measures that are valid and reliable. The Australian Therapy Outcome Measures for Occupational Therapy (AusTOMs-OT) was developed in Australia to capture a global snapshot of status for any client, and has preliminary psychometric evidence to support use. Building on the psychometric evidence of the AusTOMs-OT will provide therapists and researchers with further information as to how best to apply the AusTOMs-OT in their field. This study reports on the reliability of the 12 AusTOMs-OT scales, which are each scored on the four domains of Impairment, Activity Limitation, Participation Restriction and Distress/Wellbeing. METHODS: A total of 31 occupational therapists rated 12 written case studies on two occasions, separated by two weeks. Test-retest reliability, inter-rater reliability, intra-rater reliability (using intra-class correlation coefficients (ICCs)) and measurement error were calculated, in line with the COnsensus-based guidelines for the Selection of health Measurement Instruments (COSMIN). RESULTS: The ICCs for inter-rater reliability for all domains for all scales ranged from 0.531 to 0.922 suggesting moderate to very high reliability. Therapist intra-rater reliability ranged from ICC 0.675 to 1.000, suggesting moderate to high consistency. The stability of the scales was demonstrated with test-retest ICCs coefficients ranging from 0.616 to 0.960. The measurement error was found to be below 0.5 point for all scales and domains except for Scale 1, Impairment (just over at 0.604) and similarly the error range for each scale was also all below 1 point except Scale 1, Impairment. CONCLUSION: The AusTOMs-OT scales possess moderate to very high reliability across the 12 scales. Occupational therapists can continue to use AusTOMs-OT with confidence with all clients to establish global outcomes and to build evidence to underpin practice. PMID- 29700832 TI - 'Ingredients' of a supportive web of caring relationships at the end of life: findings from a community research project in Austria. AB - In accordance with the pluralisation of life plans in late modernity, the societal organisation of care at the end of life is diverse. Although the public discourse in western societies is dominated by questions about optimising specialised palliative care services, public health approaches, which take into account the social determinants and inequalities in end-of-life care, have gained in importance over the last decade. Conceptual aspects, dimensions of impact and benefit for the dying and their communities are well discussed in the public health end-of-life care research literature. Our research focuses on the preconditions of a supportive caring web in order to understand how communities can build on their social capital to deal with existential uncertainty. As part of a large-scale community research project, we carried out focus groups and interviews with community members. Through dispositive analysis, we generated a set of care-web 'ingredients', which constitute and foster a caring community. These 'ingredients' need to be cultivated through an ongoing process of co creation. This requires: (i) a focus on relationships and social systems; (ii) the creation of reflective spaces; and (iii) the strengthening of social capital, and d) the addressing of inequalities in care. PMID- 29700833 TI - Influence of high-pressure processing on the generation of gamma-aminobutyric acid and microbiological safety in coffee beans. AB - BACKGROUND: The aim of this study was to investigate the influence of high pressure processing (HPP) on gamma-aminobutyric acid (GABA) content, glutamic acid (Glu) content, glutamate decarboxylase (GAD) activity, growth of Aspergillus fresenii, and accumulated ochratoxin A (OTA) content in coffee beans. RESULTS: The results indicated that coffee beans subjected to HPP at pressures >=50 MPa for 5 min increased GAD activity and promoted the conversion of Glu to GABA, and showed a significantly doubling of GABA content compared with unprocessed coffee beans. Additionally, investigation of the influence of HPP on A. fresenii growth on coffee beans showed that application >=400 MPa reduced A. fresenii concentrations to <1 log. Furthermore, during a 50-day storage period, we observed that a processing pressure of 600 MPa completely inhibited A. fresenii growth, and on day 50 the OTA content of coffee beans subjected to processing pressures of 600 MPa was 0.0066 MUg g-1 , which was significantly lower than the OTA content of 0.1143 MUg g-1 in the control group. CONCLUSION: This study shows that HPP treatment can simultaneously increase GABA content and inhibit the growth of A. fresenii, thereby effectively reducing the production and accumulation of OTA and maintaining the microbiological safety of coffee beans. (c) 2018 Society of Chemical Industry. PMID- 29700834 TI - Psychopathic traits are differentially associated with efficiency of neural communication. AB - Recent advances in the application of graph theory made it possible to quantify the efficiency of communication within a neural network, going beyond traditional connectivity methods that only identify the degree to which neural regions are connected. Psychopathic traits, namely, interpersonal-affective and impulsive antisocial traits, have been linked to widespread and distinct disruptions in neural connectivity. The efficiency of neural communication for individuals high on these psychopathic traits, though, is unknown. In the present study, resting state EEG was used to generate a connectivity matrix (i.e., weighted phase lag index) for multiple frequency bands. These connectivity matrices were examined using minimum spanning tree analysis, a graph theory approach that allows for the examination of neural efficiency, and regressed on Self-Report Psychopathy-Short Form scores (n = 158, unselected community sample). Results indicated that individuals with higher interpersonal-affective traits had significantly less efficient communication within alpha1 (i.e., long-range neural communication) and gamma (i.e., short-range neural communication) frequency bands. Conversely, individuals with higher impulsive-antisocial traits had more efficient communication within these same frequency bands. Overall, elevated psychopathic traits were related to alterations in the basic efficiency of neural communication. Moreover, this unique application of graph analysis provides a new avenue for inquiry into the mechanisms underlying the chronic and severe behavior of individuals with psychopathic traits. PMID- 29700835 TI - Light-emitting Diode Blue Light Alters the Ability of Penicillium digitatum to Infect Citrus Fruits. AB - Penicillium digitatum (Pers.:Fr.) Sacc. is the main fungus causing postharvest losses in citrus fruits. Previous work showed the potential of LED blue light (LBL) in controlling P. digitatum growth. Here, we have investigated whether LBL alters the ability of this fungus to infect citrus fruits. Before fruit infection, Petri plates inoculated with the same conidia concentration were held under darkness (control) or LBL (100 MUmol m-2 s-1 ) for 8 d (continuous light), or were treated with the same LBL for 3 d and then shifted to darkness for 5 d (non-continuous light). Spores from cultures exposed to continuous light showed very low capacity to germinate (1.8% respect to control) but a high viability and a similar morphology and ability to infect the fruits than spores from control cultures. The number of spores produced in plates exposed to non-continuous light was slightly lower than in control plates, but they showed much lower viability and lower capacity to infect the fruits. This effect was more likely related to aberrant morphology of spores, which formed aggregates, than to its metabolic activity or its ability to produce ethylene that might contribute to destroy natural defense barriers from the fruit. PMID- 29700836 TI - The effect of gadolinium-based contrast agents on rat testis. AB - Previous studies have reported that repeated administrations of linear gadolinium based contrast agents lead to their accumulation in the brain and other tissues in individuals with normal renal functions. The purpose of this prospective animal study was to investigate the effect of multiple administrations of macrocyclic ionic (gadoteric acid) and linear nonionic (gadodiamide) gadolinium based contrast agents (GBCAs) on rat testis tissue and to compare these molecules in terms of tissue damage. Thirty-two male Sprague-Dawley rats were kept without drugs for 5 weeks after administration of 0.1 mmol mg-1 kg-1 (0.2 ml/kg) gadodiamide and gadoteric acid for 4 days over 5 weeks. Biochemical, histopathological and immunohistochemical changes in testis tissue were evaluated at the end of 10 weeks. When used in repeated clinical doses, gadolinium was observed to increase apoptosis in the Leydig cells of the rat testis, and to increase serum Ca+2 levels and reduce testosterone levels (p < .05). Although the difference was not statistically significant, a greater loss of spermatozoa and immature germinal cell accumulation were observed in the seminiferous tubule lumen in the GBCA groups compared with the control and saline groups (p > .05). Both linear and macrocyclic contrast agents have toxic effects on testis tissue, irrespective of the type of drug. PMID- 29700837 TI - Gender differences in the quality of psychosocial stimulation in rural Bangladesh homes. AB - BACKGROUND: Little is known about whether and to what extent gender differences affect the stimulation children receive at home, which is crucial to child development. The aim of this study was to document the differences, if any, in the quality of psychosocial stimulation boys and girls receive at home in middle childhood in rural Bangladesh. METHODS: This study was done as a part of a long term follow-up study of a cluster randomized controlled trial in 2015. The Middle Childhood-Home Observation for Measurement of the Environment (MC-HOME) was adapted and used to measure the quality of home stimulation. Post hoc analysis of the long-term follow-up study was done. Data were analysed using t-test and chi squared test for continuous and dichotomous variables, respectively. Multiple regression analysis was conducted to control for confounders. RESULTS: A total of 372 child-mother dyads participated in the study. Socio-economic and anthropometric characteristics of the boys and girls did not differ except that more girls had electricity at home (p = .027). Girls were found significantly advantaged over boys in total MC-HOME scores (p = .014) at age around 8 years. CONCLUSIONS: These findings will play a role for child development policy formulation in Bangladesh. However, though the difference is statistically significant, the strength of relationship is very weak and may not be of functional importance. PMID- 29700838 TI - Antioxidant activity of Nigella sativa Seeds Aqueous Extract and its use for cryopreservation of buffalo spermatozoa. AB - The free radical scavenging activity (RSA) of Nigella sativa extract and its efficiency for cryopreservation of buffalo spermatozoa was investigated. In experiment 1, Nigella sativa extract was prepared and evaluated for RSA using 2,2 diphenyl-1-picrylhydrazyl assay. The results showed increased pattern of RSA at 1%-5% of Nigella sativa extract. In experiment 2, buffalo semen from three bulls (24 ejaculates) was incubated at 0%, 0.1%, 0.3%, 0.5%, 1%, 1.5%, 2%, 3%, 4%, 5% and 6% extract to assess in vitro tolerability to Nigella sativa in terms of progressive motility (PM). Buffalo spermatozoa showed tolerance to all levels; rather, sperm PM was increased at 1%-4% extract. In experiment 3, semen from three bulls (24 ejaculates) was cryopreserved with 0%, 1%, 2%, 3%, 4% and 5% of Nigella sativa extract. Sperm PM and plasma membrane integrity (PMI) were evaluated after dilution and cooling, while PM, PMI, viability and DNA integrity were evaluated after thawing. Nigella sativa extract at 4% in extender improved (p < .05) post-dilution, post-cooling and post-thaw sperm quality. In conclusion, Nigella sativa extract at all concentrations (1%-6%) showed antioxidant activity and its supplementation at 4% in extender improved buffalo sperm quality at all stages of cryopreservation. PMID- 29700839 TI - Multistep estimators of the between-study variance: The relationship with the Paule-Mandel estimator. AB - A wide variety of estimators of the between-study variance are available in random-effects meta-analysis. Many, but not all, of these estimators are based on the method of moments. The DerSimonian-Laird estimator is widely used in applications, but the Paule-Mandel estimator is an alternative that is now recommended. Recently, DerSimonian and Kacker have developed two-step moment based estimators of the between-study variance. We extend these two-step estimators so that multiple (more than two) steps are used. We establish the surprising result that the multistep estimator tends towards the Paule-Mandel estimator as the number of steps becomes large. Hence, the iterative scheme underlying our new multistep estimator provides a hitherto unknown relationship between two-step estimators and Paule-Mandel estimator. Our analysis suggests that two-step estimators are not necessarily distinct estimators in their own right; instead, they are quantities that are closely related to the usual iterative scheme that is used to calculate the Paule-Mandel estimate. The relationship that we establish between the multistep and Paule-Mandel estimator is another justification for the use of the latter estimator. Two-step and multistep estimators are perhaps best conceptualized as approximate Paule-Mandel estimators. PMID- 29700840 TI - Quality of life, anxiety, depression and burden among stroke caregivers: A longitudinal, observational multicentre study. AB - AIM: To longitudinally describe stroke caregivers' quality of life, anxiety, depression and burden and to identify predictors of stroke caregivers' quality of life, anxiety, depression and burden. BACKGROUND: Caregivers have a key role in stroke survivor care and the first year of caregiving is the most challenging. To give tailored interventions, it is important to capture changes and identify predictors of caregiver quality of life, anxiety, depression and burden during the first year. DESIGN: A 12-month longitudinal study. Data were collected between June 2013-May 2016. METHODS: Changes in stroke caregiver quality of life, anxiety and depression and burden and their predictors were identified using linear mixed-effects models. RESULTS: The caregivers (N = 244) were 53 years old and mostly female. Caregiver quality of life did not change significantly over the 12 months, anxiety and depression decreased up to 9 months and caregiver burden decreased from baseline to 3 months, then increased up to 9 months. Higher caregiver quality of life was predicted by caregiver younger age, higher education, living with a stroke survivor, survivor older age and higher physical functioning; higher anxiety and depression were predicted by older caregiver age and younger survivor age; higher burden was predicted by caregiver male gender, the caregiver not living with survivor and survivor lower physical functioning. CONCLUSION: The first 9 months of caregiving are particularly problematic for caregivers. The trajectories of the above variables and their predictors may be useful for policy makers, clinicians, investigators and educators to give better care to stroke caregivers and their survivors. PMID- 29700841 TI - When I say ... validity argument. PMID- 29700842 TI - Systematic review of Latin American national oral health surveys in adults. AB - BACKGROUND: Oral diseases represent a main public health problem worldwide. There is scarce information about oral health indicators in adults in middle-income countries in Latin America and Africa. OBJECTIVES: To identify and describe national health surveys with national representative samples that included oral health assessment for adults in Latin America. METHODS: A systematic review was conducted in scientific and regional bibliographic databases (PubMed, SciELO, Wos and Embase); this was complemented with searchings in grey literature (Google Scholar, Open Grey and government health organization websites), from August 2016 to May 2017 (from 2000 to date). Studies conducted, supervised or funded by Ministries of Health or National Health Institutes were included. Data extracted included country, year, methods, interview and dental examination. Two researchers independently performed search and data extraction. Results were discussed as a group. RESULTS: Only 5 countries in Latin America have developed national health surveys evaluating the dental status in adults, with overall national representative samples during 2000-2015: Brazil, Colombia, Panama, Chile and Uruguay. Main differences were observed in the type of dental indicators selected, measure of dental services access and the professional who performed the dental examination. While some dental surveys were specifically designed as oral health surveys (Brazil, Colombia, Panama and Uruguay) and the examination was performed by dentists, other surveys represent a module within a general health survey (Chile) and the examination was performed by nurses. CONCLUSIONS: There are a small number of Latin American countries that report research about dental status with national representation samples. Most of these studies have been conducted as national oral health surveys, and fieldwork was carried out by dentists. The development of oral health research in this part of the world should be promoted as these surveys provide relevant information to monitor oral health and evaluate the effectiveness of health programmes. PMID- 29700843 TI - Spermatogenesis-associated 48 is essential for spermatogenesis in mice. AB - Azoospermia, oligospermia and teratozoospermia all seriously impact male reproductive health. Spermatogenesis is a complex and precisely regulated process in which germ cells proliferate and differentiate and involves the regulation of multiple testis-specific genes. Here, we identified testis-specific gene spermatogenesis-associated 48 (SPATA48), the expression of which was age dependent, indicating that it is involved in spermatogenesis. In humans and mice with azoospermia, expression of SPATA48 disappeared in the testis. Spata48-/- knockout male mice had smaller testis and defective spermatogenesis compared to wild-type (WT) mice. This study can help in the exploration of the genetic basis of male infertility and identify new targets for the diagnosis and treatment of male infertility. PMID- 29700844 TI - Process evaluation of implementing Protected Mealtimes under clinical trial conditions. AB - AIM: To evaluate the implementation of Protected Mealtimes and contrast the findings with implementation fidelity. BACKGROUND: Protected Mealtimes is a systems approach developed to address the issue of malnutrition in hospitalized patients. Previous studies have used a pre--post study design, with no high quality trials previously undertaken to measure the effect of the intervention. DESIGN: A prospective, stepped-wedge cluster randomized controlled trial was undertaken October-November 2015. This process evaluation was conducted using qualitative and quantitative methods to explain discrepancies between expected and observed clinical trial outcomes. METHODS: Qualitative data were collected using focus groups with the healthcare team and contrasted with fidelity data. Quantitative data were collected using attendance lists, audits and observations and analysed descriptively. Concept-driven coding was undertaken using a framework derived from studies citing the Theoretical Domains Framework. FINDINGS: Staff training in the trial protocol was viewed positively, however, not all staff attended. Staff were generally enthusiastic about Protected Mealtimes with many programme aspects successfully implemented. Limited staffing resources, particularly of nursing staff, hindered implementation. The presence of trial observers affected staff morale by increasing feelings of stress and anxiety. CONCLUSION: Process data allowed challenges for the implementation of Protected Mealtimes under clinical trial conditions to be described. Given our inability to implement the trial protocol fully due to the complexity of the mealtime environment and the lack of efficacy on nutritional intake, alternative approaches should be considered to resolve the problem of hospital malnutrition. PMID- 29700845 TI - Re-racialization of Addiction and the Redistribution of Blame in the White Opioid Epidemic. AB - New York City has the largest number of opioid dependent people of U.S. cities, and within New York, Whites have the highest rate of prescription opioid and heroin overdose deaths. The rise of opioid abuse among Whites has resulted in popular narratives of victimization by prescribers, framing of addiction as a biological disease, and the promise of pharmaceutical treatments that differ from the criminalizing narratives that have historically described urban Latino and black narcotic use. Through an analysis of popular media press and interviews with opioid prescribers and community pharmacists in Staten Island-the epicenter of opioid overdose in New York City and the most suburban and white of its boroughs-we found that narratives of white opioid users disrupted notions of the addict as "other," producing alternative logics of blame that focus on prescribers and the encroachment of dealers from outside of white neighborhoods. PMID- 29700846 TI - Rethinking medical oaths using the Physician Charter and ethical virtues. AB - OBJECTIVE: Medical oaths express ethical values that are essential to the trust within the patient-physician relationship and medicine's commitment to society. However, the contents of oaths vary between medical schools and therefore raise questions about which ethical values should be included in a medical oath. More than a decade has passed since this variability was last analysed in North America, and since that time the Physician Charter on Medical Professionalism has gained considerable attention, raising the possibility that the Charter may be influencing medical oaths and making them more consistent. METHODS: The authors conducted a content analysis of 84 oaths available in 2015 from medical schools in the USA and Canada affiliated with the Association of American Medical Colleges, organising the content into three categories: (i) ethical values, (ii) principles and commitments in the Physician Charter, and (iii) ethical virtues. RESULTS: Only five ethical values were expressed in the majority of oaths (confidentiality, obligation to the profession, beneficence, avoiding discrimination, and honour and integrity), and respect for patient autonomy was uncommon. Only three of the Physician Charter's principles and commitments (primacy of patient welfare, social justice and confidentiality) and one virtue (honour and integrity) were reflected in the majority of oaths. CONCLUSIONS: Medical oaths in North America appear to be highly variable in content. Greater attention to resources like the Physician Charter can help improve the ethical content and consistency of oaths across different institutions, and throughout their education medical students should be encouraged to discuss and reflect on the principles and virtues they will profess when they graduate. PMID- 29700847 TI - Pressure-assisted capillary electrophoresis frontal analysis for faster binding constant determination. AB - Adding external pressure during the process of capillary electrophoresis usually add to the band broadening, especially if the pressure induced flow is significant. The resolution is normally negatively affected in pressure-assisted capillary electrophoresis (PACE). Frontal analysis (FA), however, can potentially benefit from using an external pressure while avoiding the drawbacks in other modes of CE. In this work, possible impact from the external pressure was simulated by COMSOL Multiphysics(r). Under a typical CE-FA set-up, it was found that the detected concentrations of analyte will not be significantly affected by an external pressure less than 5 psi. Besides, the measured ligand concentration in PACE-FA was also not affected by common variables (molecular diffusion coefficient (10-8 to 10-11 m2 /s), capillary length etc). To provide an experimental proof, PACE-FA is used to study the binding interactions between hydroxypropyl beta-cyclodextrin (HP-beta-CD) and small ligand molecules. Taking the HP-beta-CD /benzoate pair as an example, the binding constants determined by CE-FA (18.3 +/- 0.8 M-1 ) and PACE-FA (16.5 +/- 0.5 M-1 ) are found to be similar. Based on the experimental results, it is concluded that PACE-FA can reduce the time of binding analysis while maintaining the accuracy of the measurements. PMID- 29700848 TI - Non-pharmacological therapies for sleep disturbances in people with Parkinson's disease: A systematic review. AB - AIM: To determine the effectiveness of non-pharmacological therapies for sleep disturbances in people with Parkinson's disease (PD). BACKGROUND: Sleep disturbances, which are common in people with PD, may diminish their quality of life. Non-pharmacological therapies are preferred over pharmacological therapies for improving sleep quality, owing to fewer adverse effects. DESIGN: Systematic literature review. DATA SOURCES: A systematic search of eight databases and hand searching was conducted for papers published between 1 January 2000 - 1 January 2016. REVIEW METHODS: The Cochrane methods were followed. Risk of bias was assessed using the Cochrane Collaboration Risk of Bias Tool. RESULTS: Eight studies were identified for data extraction. Therapeutic domains included physical exercise, cognitive behavioural and complementary interventions. Therapies in four of the eight studies significantly improved sleep quality and the unified PD rating scale score. Other studies showed no clear effects on sleep (N = 1), limited effects on sleep (N = 1) or effects in both the intervention and control groups, indicating that the intervention had no distinctive effects (N = 2). CONCLUSIONS: The non-pharmacological intervention types and sleep-related measured outcomes were heterogeneous. Most therapies had inconsistent effects on sleep. The insufficient evidence for non-pharmacological treatments seems related to the unique motor-associated clinical features of PD, which restrict the use of physical exercise therapy, or to individual "wearing-off" periods, which limit group therapy. Further studies on non-pharmacological therapies are required to identify the best interventions for improving sleep quality in people with PD. PMID- 29700849 TI - Have out-of-pocket health care payments risen under free health care policy? The case of Sri Lanka. AB - Compared to its neighbors, Sri Lanka performs well in terms of health. Health care is provided for free in the public sector, yet households' out-of-pocket health expenditures are steadily increasing. We explore whether this increase can be explained by supply shortages and insufficient public health care financing or whether it is rather the result of an income-induced demand for supplementary and higher quality services from the private sector. We focus on total health care expenditures and health care expenditures for specific services such as expenses on private outpatient treatments and expenses on laboratory and other diagnostic services. Overall, we find little indication that limited supply of public health care per se pushes patients into the private sector. Yet income is identified as one key driver of rising health care expenditures, ie, as households get richer, they spend an increasing amount on private services suggesting a dissatisfaction with the quality offered by the public sector. Hence, quality improvements in the public sector seem to be necessary to ensure sustainability of the public health care sector. If the rich and the middle class increasingly opt out of public health care, the willingness to pay taxes to finance the free health care policy will certainly shrink. PMID- 29700850 TI - Using data from multiple studies to develop a child growth correlation matrix. AB - In many countries, the monitoring of child growth does not occur in a regular manner, and instead, we may have to rely on sporadic observations that are subject to substantial measurement error. In these countries, it can be difficult to identify patterns of poor growth, and faltering children may miss out on essential health interventions. The contribution of this paper is to provide a framework for pooling together multiple datasets, thus allowing us to overcome the issue of sparse data and provide improved estimates of growth. We use data from multiple longitudinal growth studies to construct a common correlation matrix that can be used in estimation and prediction of child growth. We propose a novel 2-stage approach: In stage 1, we construct a raw matrix via a set of univariate meta-analyses, and in stage 2, we smooth this raw matrix to obtain a more realistic correlation matrix. The methodology is illustrated using data from 16 child growth studies from the Bill and Melinda Gates Foundation's Healthy Birth Growth and Development knowledge integration project and identifies strong correlation for both height and weight between the ages of 4 and 12 years. We use a case study to provide an example of how this matrix can be used to help compute growth measures. PMID- 29700851 TI - "Accept and Utilize": Alternative Medicine, Minimality, and Ethics in an Indonesian Healing Collective. AB - Cosmopolitan forms of alternative medicine have become very popular in contemporary Indonesia. Many healers have trained in an eclectic range of techniques, predicated on ontological claims so diverse that they call each other's legitimacy into question. This article explores how a collective of alternative healers in central Java navigated the quandaries presented by such therapeutic eclecticism over a six-year period. Healers' engagement with, or indifference toward, the principles underpinning therapeutic efficacy fluctuated in ways that allowed them to surmount the dilemmas of Islamization, the changing demographic of their collective's membership, and the threat of commercialization, thereby maintaining a medical landscape in which alternative healing was widely available and accessible. Transformations in their understanding, experience, and practice of healing should thus be understood in terms of how enduring ethical commitments are refracted through ongoing engagements with a changing social world. PMID- 29700852 TI - LC-MS/MS method for the simultaneous determination of tenofovir, emtricitabine, elvitegravir and rilpivirine in dried blood spots. AB - A simple, short, and rugged LC-MS/MS method for the simultaneous determination of tenofovir, emtricitabine, elvitegravir and rilpivirine was developed and validated. Dried blood spots were prepared with 25 MUL of spiked whole blood. A 3 mm punch was extracted with methanol containing labeled internal standards. Ten microliters was injected into the LC-MS/MS using isocratic mobile phase composed of 0.1% formic acid in water and 0.1% formic acid in acetonitrile (45: 55 v/v) at a flow rate of 0.25 mL/min. The method was validated in the range of 10-2000 ng/mL for all four analytes. The intra-assay accuracy (RE) of the method was 4.73-4.78, 1.35-2.89, -8.89 to -0.49 and - 1.40-1.81 for tenofovir, emtricitabine, elvitegravir and rilpivirine, respectively. The inter-assay accuracy was within +/-15% of nominal and precision (CV) was <15%. The hematocrit effect on quantification was nonsignificant at the tested hematocrit levels (35 70%). The dried blood spot method showed good agreement with the plasma method, and hence can be used as an alternative to plasma method. PMID- 29700853 TI - Detection of selection signatures for agonistic behaviour in cattle. AB - The identification of genomic regions including signatures of selection produced by domestication and its subsequent artificial selection processes allows the understanding of the evolution of bovine breeds. Although several studies describe the genomic variability among meat or milk production cattle breeds, there are limited studies orientated towards bovine behavioural features. This study is focused on mapping genomic signatures of selection which may provide insights of differentiation between neutral and selected polymorphisms. Their effects are studied in the Lidia cattle traditionally selected for agonistic behaviour compared with Spanish breeds showing tamed behaviour. Two different approaches, BayeScan and SelEstim, were applied using genotypic 50K SNP BeadChip data. Both procedures detected two genomic regions bearing genes previously related to behavioural traits. The frequencies of the selected allele in these two regions in Lidia breed were opposite to those found in the tamed breeds. In these genomic regions, several putative genes associated with enriched metabolic pathways related to the behavioural development were identified, as neurochondrin gene (NCDN) or glutamate ionotropic receptor kainate type subunit 3 (GRIK3) both located at BTA3 or leucine-rich repeat and Ig domain containing 2 (LINGO2) and phospholipase A2-activating protein (PLAA) at BTA8. PMID- 29700854 TI - Development of 3D imaging technique of reconstructed human epidermis with immortalized human epidermal cell line. AB - The epidermis, the outermost layer of the skin, retains moisture and functions as a physical barrier against the external environment. Epidermal cells are continuously replaced by turnover, and thus to understand in detail the dynamic cellular events in the epidermis, techniques to observe live tissues in 3D are required. Here, we established a live 3D imaging technique for epidermis models. We first obtained immortalized human epidermal cell lines which have a normal differentiation capacity and fluorescence-labelled cytoplasm or nuclei. The reconstituted 3D epidermis was prepared with these lines. Using this culture system, we were able to observe the structure of the reconstituted epidermis live in 3D, which was similar to an in vivo epidermis, and evaluate the effect of a skin irritant. This technique may be useful for dermatological science and drug development. PMID- 29700855 TI - Long-term extrapulmonary comorbidities after lung transplantation in cystic fibrosis: Update of specificities. AB - Lung transplantation (LT) is the standard therapeutic option for cystic fibrosis (CF) patients with end-stage lung disease. Both conditions lead to extrarespiratory complications, such as diabetes, renal insufficiency, bone disease, and cancer. The purpose of this study was to provide an update of the nonrespiratory comorbidities following LT in adult patients with CF and their specificities regarding their multisystemic underlying condition despite their younger age compared to other patients undergoing LT. Diabetes, renal insufficiency, metabolic bone disease, hypertension, liver disease, and cancer are the comorbidities considered in this review. The increase in CF adults living with a lung transplant justifies an update of knowledge for this specific situation (the prevalence of these complications, underlying risk factors), to provide better medical care and establish early diagnosis strategies. PMID- 29700856 TI - Defining the width of the normal tibial plateau relative to the distal femur: Critical normative data for identifying pathologic widening in tibial plateau fractures. AB - Tibial plateau widening in the setting of fracture is an indication for surgical treatment, and restoring width is an important goal of surgery. In order to identify and correct pathological widening, the width of the normal tibial plateau must first be defined. The aim of this study was to establish normative data for the width of the tibial plateau relative to the distal femur to enable surgeons to identify and correct pathological widening in the setting of tibial plateau fracture. Fifty-one uninjured anteroposterior (AP) knee radiographs and 11 XR and CT scans of lateral tibial plateau fractures were retrospectively reviewed. The distances measured included maximal distal femoral width, femoral articular width, tibial articular width, and lateral plateau widening. On average, lateral plateau widening was +0.02 +/- 2.03 mm, indicating that the most lateral aspect of the tibial plateau is collinear with the most lateral aspect of the lateral epicondyle of the femur. In the fracture population, average widening was 7.13 +/- 3.59 mm on XR and 6.57 +/- 3.34 mm on CT, with an absolute difference between XR and CT of 1.19 +/- 0.66 mm. In conclusion, this study is the first to define the radiographic anatomy of the proximal tibia quantitatively. In the setting of tibial plateau fracture, residual widening of 2.1 mm could be within normal variation. However, the authors consider widening >2.1 mm pathological. These values can be used for assessing pathological widening of tibial plateau fractures. Clin. Anat. 31:688-692, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29700857 TI - Bioinspired Stimuli-Responsive Color-Changing Systems. AB - Stimuli-responsive colors are a unique characteristic of certain animals, evolved as either a method to hide from enemies and prey or to communicate their presence to rivals or mates. From a material science perspective, the solutions developed by Mother Nature to achieve these effects are a source of inspiration to scientists for decades. Here, an updated overview of the literature on bioinspired stimuli-responsive color-changing systems is provided. Starting from natural systems, which are the source of inspiration, a classification of the different solutions proposed is given, based on the stimuli used to trigger the color-changing effect. PMID- 29700858 TI - Gender differences in the fluorescence of human skin in young healthy adults. AB - BACKGROUND: Human skin naturally contains many endogenous fluorophores; therefore, fluorescence techniques can be used for monitoring of the human skin even in in vivo mode. The aim of this work was to study skin autofluorescence in vivo regarding the possible effect of gender. MATERIALS AND METHODS: Fluorescence emission spectra of young healthy Caucasian adults in 3 anatomical regions (forehead, hand, and inner upper arm) were taken with excitation at 280, 325, or 400 nm. RESULTS: Three emission bands were found in the spectra for both men and women: (1) an intensive band peaked at 340/280 nm (peak emission/excitation wavelength), corresponding to aromatic amino acids of proteins in epidermis; (2) a broad band with emission between 360 nm and 480 nm (excitation 325 nm) with a base peak around 390 nm and 2 side peaks at 420 and 450 nm, mainly due to collagen cross-links in dermis with a possible weak contribution of elastin and mitochondrial NADPH; (3) a weak but distinct peak at 600/400 nm corresponding presumably to skin unmetalled porphyrins. CONCLUSION: The intensity of skin autofluorescence showed differences between genders and among anatomical regions. The 340 nm intensity was 1.4 times higher in the male group in all 3 anatomical regions studied. The highest intensity of skin autofluorescence for the peaks at 340/280 nm and 600/400 nm was found on the forehead, whereas the 390/325 nm band was most intensive on the inner upper arm in both genders. PMID- 29700859 TI - Imprinting Chirality onto the Electronic States of Colloidal Perovskite Nanoplatelets. AB - The direct synthesis of chiroptical organic-inorganic methylammonium lead bromide perovskite nanoplatelets that are passivated by R- or S-phenylethylammonium ligands is reported. The circular dichroism spectra can be divided into two components: (1) a region associated with a charge transfer transition between the ligand and the nanoplatelet, 300-350 nm, and (2) a region corresponding to the excitonic absorption maximum of the perovskite, 400-450 nm. The temperature- and concentration-dependent circular dichroism spectra indicate that the chiro optical response arises from chiral imprinting by the ligand on the electronic states of the quantum-confined perovskite rather than chiral ligand-induced stereoselective aggregation. PMID- 29700860 TI - Summoning compassion to address the challenges of conservation. AB - Conservation practice is informed by science, but it also reflects ethical beliefs about how humanity ought to value and interact with Earth's biota. As human activities continue to drive extinctions and diminish critical life sustaining ecosystem processes, achieving conservation goals becomes increasingly urgent. However, the determination to react decisively can drive conservationists to handle complex challenges without due deliberation, particularly when wildlife individuals are sacrificed for the so-called greater good of wildlife collectives (populations, species, ecosystems). With growing recognition of the widespread sentience and sapience of many nonhuman animals, standard conservation practices that categorically prioritize collectives without due consideration for the well being of individuals are ethically untenable. Here we highlight 3 overarching ethical orientations characterizing current and historical practices in conservation that suppress compassion: instrumentalism, collectivism, and nativism. We examine how establishing a commitment to compassion could reorient conservation in more ethically expansive directions that incorporate recognition of the intrinsic value of wildlife, the sentience of nonhuman animals, and the values of novel ecosystems, introduced species, and their members. A compassionate conservation approach allays practices that intentionally and unnecessarily harm wildlife individuals, while aligning with critical conservation goals. Although the urgency of achieving effective outcomes for solving major conservation problems may enhance the appeal of quick and harsh measures, the costs are too high. Continuing to justify moral indifference when causing the suffering of wildlife individuals, particularly those who possess sophisticated capacities for emotion, consciousness, and sociality, risks estranging conservation practice from prevailing, and appropriate, social values. As conservationists and compassionate beings, we must demonstrate concern for both the long-term persistence of collectives and the well-being of individuals by prioritizing strategies that do both. PMID- 29700861 TI - Structural and Chemical Changes to CH3 NH3 PbI3 Induced by Electron and Gallium Ion Beams. AB - Organic-inorganic hybrid perovskites, such as CH3 NH3 PbI3, have shown highly promising photovoltaic performance. Electron microscopy (EM) is a powerful tool for studying the crystallography, morphology, interfaces, lattice defects, composition, and charge carrier collection and recombination properties at the nanoscale. Here, the sensitivity of CH3 NH3 PbI3 to electron beam irradiation is examined. CH3 NH3 PbI3 undergoes continuous structural and compositional changes with increasing electron dose, with the total dose, rather than dose rate, being the key operative parameter. Importantly, the first structural change is subtle and easily missed and occurs after an electron dose significantly smaller than that typically applied in conventional EM techniques. The electron dose conditions under which these structural changes occur are identified. With appropriate dose-minimization techniques, electron diffraction patterns can be obtained from pristine material consistent with the tetragonal CH3 NH3 PbI3 phases determined by X-ray diffraction. Radiation damage incurred at liquid nitrogen temperatures and using Ga+ irradiation in a focused ion beam instrument are also examined. Finally, some simple guidelines for how to minimize electron beam-induced artifacts when using EM to study hybrid perovskite materials are provided. PMID- 29700862 TI - The quantitative assessment of epicardial fat distribution on human hearts: Implications for epicardial electrophysiology. AB - Epicardial electrophysiological procedures rely on dependable interfacing with the myocardial tissue. For example, epicardial pacing systems must generate sustainable chronic pacing capture, while epicardial ablations must effectively deliver energy to the target hyper-excitable myocytes. The human heart has a significant adipose layer which may impede epicardial procedures. The objective of this study was to quantitatively assess the relative location of epicardial adipose on the human heart, to define locations where epicardial therapies might be performed successfully. We studied perfusion-fixed human hearts (n = 105) in multiple isolated planes including: left ventricular margin, diaphragmatic surface, and anterior right ventricle. Relative adipose distribution was quantitatively assessed via planar images, using a custom-generated image analysis algorithm. In these specimens, 76.7 +/- 13.8% of the left ventricular margin, 72.7 +/- 11.3% of the diaphragmatic surface, and 92.1 +/- 8.7% of the anterior right margin were covered with superficial epicardial adipose layers. Percent adipose coverage significantly increased with age (P < 0.001) and history of coronary artery disease (P < 0.05). No significant relationships were identified between relative percent adipose coverage and gender, body weight or height, BMI, history of hypertension, and/or history of congestive heart failure. Additionally, we describe two-dimensional probability distributions of epicardial adipose coverage for each of the three analysis planes. In this study, we detail the quantitative assessment and probabilistic mapping of the distribution of superficial epicardial adipose on the adult human heart. These findings have implications relative to performing epicardial procedures and/or designing procedures or tools to successfully perform such treatments. Clin. Anat. 31:661 666, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29700863 TI - Divergent Elementoboration: 1,3-Haloboration versus 1,1-Carboboration of Propargyl Esters. AB - This work showcases the 1,3-haloboration reaction of alkynes in which boron and chlorine add to propargyl systems in a proposed sequential oxazoliumborate formation with subsequent ring-opening and chloride migration. In addition, the functionalization of these propargyl esters with dimethyl groups in the propargylic position leads to stark differences in reactivity whereby a formal 1,1-carboboration prevails to give the 2,2-dichloro-3,4-dihydrodioxaborinine products as an intramolecular chelate. Density functional theory calculations are used to rationalize the distinct carboboration and haloboration pathways. Significantly, this method represents a metal-free route to highly functionalized compounds in a single step to give structurally complex products. PMID- 29700864 TI - Bicuspid and tricuspid aortic valve do not have the same ascending aorta morphology. AB - Bicuspid aortic valves are associated with histopathological abnormalities of the aorta. Their diameters have been measured in several studies, but the literature concerning changes in the overall anatomy of the ascending aorta is limited. We wanted to know whether the anatomy of the valve, bicuspid or tricuspid, is associated with anatomical differences. We prospectively included patients requiring aortic valve surgery. The protocol included a chest CT scan before the operation to determine the angulations and straight lengths of aortic segments 0 and 1. All of the patients underwent surgery to assess their aortic valve morphology. We included 107 patients, 25 (23%) with bicuspid diagnostic valves and 82 (77%) with tricuspid ones. Most angulations were similar between the groups. However, the angle between the ring and the plane of the top of the commissures of the semilunar cusps was lower in bicuspid than tricuspid aortic valves. The straight lengths in the aortic root did not differ significantly, but the lengths separating these planes from the BCAT plane were consistently greater in the bicuspid group. The angle between the ring plane and the patient's vertical axis was lower in the bicuspid, the plane of the ring being verticalized in this group. In conclusion, we were able to confirm significant morphological differences in addition to the diameters. However, this study does not establish causal relationships among valve morphology, ascending aortic morphology, histology, and possibly associated pathologies. An extremely large cohort will be required indicate such causal connections. Clin. Anat. 31:693-697, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29700865 TI - Targeted nerve biopsy: A technique in evolution. PMID- 29700866 TI - Identifying the cause and preventing childhood deaths. PMID- 29700867 TI - Characteristics and service needs of women and babies admitted to residential parenting units in New South Wales: A mixed-methods study. AB - AIMS AND OBJECTIVES: To examine the characteristics and service needs of women and babies admitted to residential parenting services (RPS) in the first year following birth in New South Wales, Australia. BACKGROUND: In Australia, there is a tiered system to support maternal, child and family health, which includes RPS. DESIGN: Sequential explanatory mixed-methods design. METHODS: Individual patient data were obtained from a random review of 10% of all medical records (n = 300 of 3,011 admissions) of women with an infant of <12 months of age who were admitted to RPS in 2013. Following review of the medical records, qualitative data were collected via interviews with eight women who accessed RPS. Chi-square analysis and Student's t test were used to analyse quantitative data. Qualitative data were analysed using a descriptive interpretive approach. An integrative approach was taken in reporting the findings. RESULTS: Women admitted to the RPS were on average 32 years of age, were Australian born (72%) and had a university qualification (40%), and most were employed. The majority of women were primiparous (60%) and had a vaginal birth (61%). Women with male infants were much more likely to be admitted to the RPS (58%) compared to the NSW male-to female ratio (51.3% vs. 48.7%). Over 50% of women reported mental health issues with 27% having an Edinburgh Postnatal Depression Scale score >=13 on admission. The primary reason women sought parenting support was for sleep and settling (83%). During their stay, services used by women included social workers (44%), psychologists (52%) and psychiatrists (4.5%). CONCLUSION: Women who access RPS report psychosocial and mental health issues. Services provided by RPS support women during this challenging early parenting period by providing multidisciplinary, holistic and peer support. RELEVANCE TO CLINICAL PRACTICE: A high prevalence of mental health issues identified in this study indicated a need for ongoing training and support for RPS staff. Ensuring clinicians have the appropriate skill sets to best support their clientele will maximise the outcomes for women and families who access RPS during the early parenting period. PMID- 29700868 TI - Surface enhanced Raman spectroscopy distinguishes amyloid Beta-protein isoforms and conformational states. AB - Amyloid beta-protein (Abeta) self-association is one process linked to the development of Alzheimer's disease (AD). Abeta peptides, including its most abundant forms, Abeta40 and Abeta42, are associated with the two predominant neuropathologic findings in AD, vascular and parenchymal amyloidosis, respectively. Efforts to develop therapies for AD often have focused on understanding and controlling the assembly of these two peptides. An obligate step in these efforts is the monitoring of assembly state. We show here that surface-enhanced Raman spectroscopy (SERS) coupled with principal component analysis (PCA) readily distinguishes Abeta40 and Abeta42. We show further, through comparison of assembly dependent changes in secondary structure and morphology, that the SERS/PCA approach unambiguously differentiates closely related assembly stages not readily differentiable by circular dichroism spectroscopy, electron microscopy, or other techniques. The high discriminating power of SERS/PCA is based on the rich structural information present in its spectra, which comprises not only on interatomic resonances between covalently associated atoms and hydrogen bond interactions important in controlling secondary structure, but effects of protein orientation relative to the substrate surface. Coupled with the label-free, single molecule sensitivity of SERS, the approach should prove useful for determining structure activity relationships, suggesting target sites for drug development, and for testing the effects of such drugs on the assembly process. The approach also could be of value in other systems in which assembly dependent changes in protein structure correlate with the formation of toxic peptide assemblies. PMID- 29700869 TI - Tree nut allergies: Allergen homology, cross-reactivity, and implications for therapy. AB - Tree nut allergy is a potentially life-threatening disease that is increasing in prevalence, now affecting 1% of the general population in the United States. While other food allergies often resolve spontaneously, tree nut allergies are outgrown in less than 10% of cases. Due to the likelihood of cross-sensitization to multiple tree nut allergens, the current treatment guideline is strict avoidance of all nuts once one tree nut allergy has been diagnosed. For example, walnut and pecan are highly cross-reactive, along with cashew and pistachio, but the extent of clinical, IgE-mediated cross-reactivity among other tree nuts remains unclear, therefore making avoidance of all tree nuts a safe approach. There have been recent advances in immunotherapy for food allergies. For instance, there are investigational immunotherapies for milk, egg and peanut allergies, specifically oral immunotherapy, sublingual immunotherapy and epicutaneous immunotherapy. However, there are no large randomized controlled clinical trials for tree nut allergies. Even though there has been less research into tree nut allergy immunotherapies, the evidence of T-cell cross-reactivity among tree nuts exists in animal models and in T cells from allergic patients indicates that immunotherapeutic interventions may be possible. Here, we review the literature regarding epidemiology, allergen homology and cross-reactivity among tree nuts, and explore how current findings can be employed for effective therapy. PMID- 29700870 TI - The cost-effectiveness of first trimester screening and early preventative use of aspirin in women at high risk of early onset pre-eclampsia. AB - OBJECTIVE: Pre-eclampsia (PE) remains a leading cause of maternal and fetal morbidity and mortality. A first trimester screening algorithm predicting the risk of early onset PE has been developed and validated. Early prediction coupled with initiation of aspirin at 11 to 13 weeks in women identified as high risk is effective at reducing the prevalence of early onset PE. The aim of this study is to evaluate the cost-effectiveness of this first trimester screening program coupled with early use of low-dose aspirin in women at high risk of developing early onset PE versus current practice. METHODS: A decision analysis was performed based on a theoretical population of live births in Canada in one year (n=387,516). The clinical and financial impact of early preventative screening using the Fetal Medicine Foundation (FMF) algorithm for prediction of early onset PE coupled with early (<16 weeks) use of low dose aspirin in those at high risk was simulated and compared with current practice using decision trees. The probabilities at each decision point and associated costs of utilized resources were calculated based on published literature and public databases. RESULTS: Of the theoretical 387,516 births per year, the estimated prevalence of early PE in the first trimester screening and ASA group was 705 versus 1801 women in the current practice group. This was associated with an estimated total cost of $9,523,485.26 compared to $23,910,467.06 with current practice for the diagnosis and management of women with early onset PE. This equals an annual maternal cost savings to the Canadian health care system of approximately $14,386,981.80 CAD. CONCLUSIONS: The implementation of a first trimester screening program for PE and intervention with aspirin in those identified as high risk of early PE has the potential to prevent a significant number of early onset PE cases with a substantial associated cost-savings to the health care system. PMID- 29700871 TI - One model to rule them all? Governing images in the shadow of the disease model of addiction. PMID- 29700872 TI - Oral immunotherapy with omalizumab reverses the Th2 cell-like programme of regulatory T cells and restores their function. AB - BACKGROUND: Oral immunotherapy (OIT) successfully desensitizes patients with food allergies, but the immune mechanisms mediating its efficacy remain obscure. OBJECTIVES: We tested the hypothesis that allergen-specific regulatory T (Treg) cell function is impaired in food allergy and is restored by anti-IgE antibody (omalizumab)-supplemented OIT. METHODS: Peanut-specific T effector (Teff) and Treg cell proliferative responses, activation markers and cytokine expression were analysed by flow cytometry in 13 peanut-allergic subjects before the start of omalizumab-supplemented OIT and periodically in some subjects thereafter for up to 2 years. Peripheral blood regulatory T cells (Treg cells) were analysed for their peanut-specific suppressor function before and at 1 year following OIT. This study was registered on ClinicalTrials.gov (NCT01290913). RESULTS: Proliferation of allergen-specific Teff and Treg cells precipitously declined following the initiation of omalizumab therapy prior to OIT, followed by partial recovery after the initiation of OIT. At baseline, peanut-specific Treg cells exhibited a Th2 cell-like phenotype, characterized by increased IL-4 expression, which progressively reversed upon OIT. Peanut-specific Treg cell suppressor activity was absent at the start of omalizumab/OIT therapy but became robust following OIT. Absent peanut-specific Treg cell function could also be recovered by the acute blockade of IL-4/IL-4R receptor signalling in Treg cells, which inhibited their IL-4 production. CONCLUSIONS AND CLINICAL RELEVANCE: OIT supplemented by omalizumab promotes allergen desensitization through an initial omalizumab-dependent step that acutely depletes allergen-reactive T cells, followed by an increase in allergen-specific Treg cell activity due to the reversal of their Th2 cell-like programme. Improved Treg cell function may be a key mechanism by which OIT ameliorates food allergy. PMID- 29700873 TI - An examination of perceptions of individuals with an intellectual disability, with and without co-morbid schizophrenia: effects of labels on stigma. AB - BACKGROUND: Research demonstrates negative perceptions of individuals with intellectual disabilities (ID) and individuals with schizophrenia, but no study has examined ID with a co-morbid psychiatric disorder. The present study examined the social distance desired from and perceptions of dangerousness of ID, schizophrenia and co-morbid schizophrenia and ID and examined the impact of providing a label for the behaviours presented in a vignette. METHODS: A total of 160 participants, all university students, were randomly assigned to one of six vignettes detailing a person with schizophrenia, ID, or a person with both presenting problems. Half of the participants were randomly assigned to read vignettes that had a label provided for the behaviours of the target. RESULTS: Participants desired more social distance from the unlabelled than labelled targets. Presence of schizophrenia resulted in increased social distance, but co morbid ID and schizophrenia elicited less desire for social distance than schizophrenia alone. Schizophrenia resulted in more perceived danger, but labelled co-morbid schizophrenia and ID resulted in little perceived danger. CONCLUSIONS: Labels resulted in positive outcomes, particularly, when ID was co morbid with schizophrenia. Schizophrenia stigma appears to be impacted by an ID label, indicating educating the public about the spectrum of co-morbidity may be useful. PMID- 29700874 TI - The concept of compassion within UK media-generated discourse: A corpus-informed analysis. AB - AIMS AND OBJECTIVES: To examine how the concept of compassion is socially constructed within UK discourse, in response to recommendations that aspiring nurses gain care experience prior to entering nurse education. BACKGROUND: Following a report of significant failings in care, the UK government proposed prior care experience for aspiring nurses as a strategy to enhance compassion amongst the profession. Media reporting of this generated substantial online discussion, which formed the data for this research. There is a need to define how compassion is constructed through language as a limited understanding exists, of what compassion means in health care. This is important, for any meaningful evaluation of quality, compassionate practices. DESIGN: A corpus-informed discourse analysis. METHODS: A 62,626-word corpus of data was analysed using Laurence Anthony software "AntCon", a free corpus analysis toolkit. Frequent words were retrieved and used as a focal point for further analysis. Concordance lines were computed and analysed in the context of which frequent word-types occurred. Patterns of language were revealed and interpreted through researcher immersion. RESULTS: Findings identified that compassion was frequently described in various ways as a natural characteristic attribute. A pattern of language also referred to compassion as something that was not able to be taught, but could be developed through the repetition of behaviours observed in practice learning. In the context of compassion, the word-type "nurse" was used positively. CONCLUSION: This study adds to important debates highlighting how compassion is constructed and defined in the context of nursing. Compassion is constructed as both an individual, personal trait and a professional behaviour to be learnt. Educational design could include effective interpersonal skills training, which may help enhance and develop compassion from within the nursing profession. Likewise, ways of thinking, behaving and communicating should also be addressed by established practitioners to maintain compassionate interactions between professionals as well as nurse-patient relationships. Future research should focus on how compassionate practice is defined by both health professionals and patients. RELEVANCE TO CLINICAL PRACTICE: To maintain nursing as an attractive profession to join, it is important that nurses are viewed as compassionate. This holds implications for professional morale, associated with the continued retention and recruitment of the future workforce. Existing ideologies within the practice placement, the prior care experience environment, as well as the educational and organisational design, are crucial factors to consider, in terms of their influences on the expression of compassion in practice. PMID- 29700876 TI - The daily dynamics of loss orientation and life engagement in advanced cancer: A pilot study to characterise patterns of adaptation at the end of life. AB - Individual adaptation at the end of life may be characterised by how patients fluctuate in their orientation towards losses and death or engagement in meaningful activities in daily life. To describe these intraindividual patterns of change, we conducted a daily diary study over 7 days with 17 advanced cancer patients from in- and outpatient oncology and psycho-oncology clinics. Patients reported on the daily frequency of behaviours associated with loss orientation and life engagement using a standardised questionnaire. We characterised each patient's pattern of change with three parameters: the mean level (5-point-scale from 0 = never to 4 = always), mean fluctuation between successive days (MSSD) and the association between changes in loss and life orientation over time. We further explored the relationship between these patterns and free-text diaries. The daily assessment protocol was acceptable and feasible (46% participation rate, 97% diary completion rate). Individuals differed in mean levels of loss orientation (range: M = 0.1 to 2.7) and life engagement (M = 0.9 to 3.9), the degree of fluctuation (MSSD = 0.1 to 1.5 and MSSD = 0.3 to 0.9), and the correlations between these changes over time (r = -.83 to +.46), revealing distinctive intraindividual patterns. Further study of individual profiles in loss and life orientation can promote personalised balancing between facing "reality" and sustaining "hope" in end-of-life conversations. PMID- 29700875 TI - Family functioning in the context of an adult family member with illness: A concept analysis. AB - AIM: To describe and explain how the concept of family functioning has been used in the targeted sample of health literature on adult family members with illness. BACKGROUND: Understanding the influence of illness on family functioning is central to the provision of patient- and family-centred care. There is lack of consistency in utilising family functioning which creates confusion about the concept and can interfere with theory development in nursing science. A clear conceptual definition of attributes of family functioning based on concept analysis could act as a guide in the development of instruments to assess family functioning, the design of family-based interventions and their application in clinical practice. DESIGN: Concept analysis. DATA SOURCES: Academic Search Premier, ProQuest Research Library, Family & Society Studies Worldwide, PsycINFO, SocINDEX, PubMed and CINAHL databases were searched within the last 20 years (1997-Dec. 2016) using the terms "family function*" and "patient." Studies of paediatric patients and non-English articles were excluded. METHOD: Rodgers' evolutionary perspective. RESULTS: The findings suggest that family functioning in the context of illness is defined as family members' ability to maintain cohesive relationships with one another, fulfil family roles, cope with family problems, adjust to new family routines and procedures and effectively communicate with each other. CONCLUSION: Further research is needed to inform nurses' practice when assessing families or providing patient- and family-centred interventions to support family functioning across different sociocultural and political contexts, and further identification and evaluation of antecedents and consequences regarding family functioning from a nursing perspective. RELEVANCE TO CLINICAL PRACTICE: Having a comprehensive understanding of the attributes, antecedents and consequences of ineffective family functioning can facilitate healthcare providers' ability to identify strengths and potential targets to improve family functioning among their clients. PMID- 29700877 TI - Use of new Intrauterine Shunt for fetal fluid accumulations. Single Center experience from first 17 cases. AB - Pleural effusion is the most common fluid-accumulation in the fetus with a prevalence of 1:15.000-24.000 pregnancies.1 The clinical picture is highly variable ranging from spontaneous resolution to lung hypoplasia, hydrops and death.1 Treatment options include thoracocentesis, thoraco-amniotic shunting and pleurodesis using OK-432.2 The conventional thoraco-amniotic shunts are applied using a 13-16G trochar.3,4 Somatex(r) Intrauterine Shunt (IUS) was launched in 2014 and consists of a self-expanding nitinol wire mesh with an inner silicone coating to be inserted through an 18G/1.2 mm needle. PMID- 29700878 TI - Adaptation of evidence-based guideline recommendations to address urinary incontinence in nursing home residents according to the ADAPTE-process. AB - AIMS AND OBJECTIVES: To adapt international guideline recommendations for the conservative management of urinary incontinence (UI), defined as any involuntary loss of urine, in Austrian nursing home residents following the ADAPTE-process. BACKGROUND: Many international guidelines for managing UI are available. Nevertheless, the international recommendations have not yet been adapted to address the Austrian nursing home context. This crucial adaptation process will enhance the acceptance and applicability of the recommendations as well as encourage adherence among Austrian nurses and nursing home residents. DESIGN: This study is a methodological study based on the ADAPTE-process, including a systematic search, quality appraisal of the guidelines using the Appraisal of Clinical Guidelines for REsearch & Evaluation II (AGREE II) instrument as well as an external review by means of a Delphi technique. The guidelines had to be topic relevant, published within the last 3 years and achieve a rigor of development score of 80% using the AGREE II instrument. METHODS: We searched international guideline databases to identify adequate guidelines. Two raters assessed the quality of each guideline, ascertaining that it fulfilled the inclusion criteria using the AGREE II instrument. We translated the identified recommendations into German and externally reviewed for their applicability in the Austrian context. RESULTS: We identified 1,612 hits in 10 databases. After applying inclusion and exclusion criteria, we assessed five international clinical guidelines for quality using the AGREE II instrument. One clinical guideline fulfilled the inclusion criteria. This clinical guideline contains 116 recommendations, of which 29 were applicable in the Austrian nursing home setting. CONCLUSION: We identified only one suitable guideline, possibly due to the stringent nature of the inclusion criteria. However, following low-quality guidelines may result in the use of recommendations that are not based on evidence and, therefore, may lead to suboptimal nursing care and outcomes. PMID- 29700879 TI - Morphometry of the nulliparous pelvic floor. AB - OBJECTIVES: To describe morphometry of the pelvic floor in a large population of nulliparous women, comparing those with and those without pelvic pain. We also aimed to assess its association with characteristics such as age and body mass index (BMI). METHODS: This was a prospective study performed between January 2013 and November 2015 in non-pregnant nulliparous women attending a general gynecology clinic. Following collection of demographic data, women were examined using translabial four-dimensional (4D) ultrasound. Dynamic volumes of pelvic floor muscle were obtained at rest, on maximal contraction and on Valsalva maneuver, and analyzed at a later date by an assessor blinded to demographic details. Standard measurements for each volume included levator hiatal area and anteroposterior and transverse diameters, and pubovisceral muscle length and width. Subanalysis was performed comparing women with and those without pelvic pain. Linear regression analysis was performed to assess the association between characteristics, including age and BMI, and levator hiatal area at rest. RESULTS: Three hundred and sixty eight nulliparous women were examined using translabial 4D ultrasound. Median levator hiatal area was 10.62 cm2 at rest, 11.95 cm2 on Valsalva maneuver and 8.18 cm2 on maximal contraction. There was no difference between women with and those without pelvic pain when comparing biometric measurements of the pelvic floor musculature, except for in pubovisceral muscle width during the contraction phase. Regression analysis demonstrated that higher age and BMI were associated with increased levator hiatal area measurement. CONCLUSIONS: Pelvic floor morphometry in nulliparous women is unchanged by pelvic pain, but levator hiatal area is increased in women with higher BMI and age. Copyright (c) 2018 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29700880 TI - Children's and young people's experiences of a parent's critical illness and admission to the intensive care unit: A qualitative meta-synthesis. AB - BACKGROUND: Little is known about how children and young people experience and manage the critical illness of a parent and a parent's admission to the intensive care unit (ICU). OBJECTIVE: The aim of this study was to search and interpret the existing literature describing children's and young people's experiences of a parent's illness trajectory in the ICU. METHOD: A qualitative meta-synthesis was conducted based on a systematic literature search of online databases. FINDINGS: Four main themes were identified and synthesised to describe the integrated experiences of children and young people: (a) the parent-child bond, (b) the unfamiliar environment, (c) the impact of the illness and (d) the experience of being overseen as close family members. CONCLUSION: Experiencing a parent's critical illness and admittance to the ICU is overwhelming. The bond between the parent and child is exposed by the separation from the ill parent. To comprehend and manage the experience, children and young people seek information depending on their individual capacities. They express a need to be close to their ill parent and to be seen and approached as close members of the family. However, children experience being overseen in their needs for support during their parent's ICU illness with the risk of being left in loneliness, sadness and lack of understanding of the parent's illness. RELEVANCE FOR CLINICAL PRACTICE: Children and young people as relatives need to be acknowledged as close members of the family, when facing the illness trajectory of a parent, who is admitted to the ICU. They need to be seen as close family members and to be approached in their needs for support in order to promote their well-being during a family illness crisis. Early supportive interventions tailored to include children of the intensive care patient are recommended. PMID- 29700881 TI - Elucidation of the developmental mechanism of ovarian mature cystic teratomas using B allele-frequency plots of single nucleotide polymorphism array data. AB - Ovarian mature cystic teratomas (MCTs) originate from post-meiotic germ cells. Conventional methods such as karyotyping or short tandem repeat-polymorphism analysis may be used to better classify MCTs, although such data would be insufficient. The aim of this study was to elucidate the origin of ovarian MCTs using B allele-frequency (BAF) plots of single nucleotide polymorphism array data. MCTs can be classified in terms of the zygosity of the centromeres and distal chromosome regions. We evaluated the zygosity of all chromosomes from 38 MCT specimens using BAF plot data. BAF plots were used to determine the homozygous and heterozygous regions over the whole genome. Theoretically, MCTs originated from the fusion of two ova (previously referred to as type V MCTs) should have a mixed pattern of centromeric zygosity, that is, a combination of heterozygous and homozygous regions in the centromeric regions. However, no MCTs in this study met this criterion. We identified 13 type I MCTs, 14 type II MCTs, and 11 type III MCTs. In addition, BAF plots facilitated the construction of recombination maps at the whole-genome level for type I and II MCTs. No crossover, especially in the short arms, contributed to the failure of meiosis I, resulting in type I MCTs. Crossover in all arms might assure the normal progress of meiosis in human oocytes. In conclusion, our findings indicate that BAF plots can elucidate the developmental mechanism of MCTs, and further serve as useful analytical tools for analyzing human oocyte meiosis, and related aberrations. PMID- 29700882 TI - A qualitative approach exploring the experiences of smoking and quitting attempts in type 1 diabetes. AB - AIMS AND OBJECTIVES: To explore the experiences of smoking and quitting attempts in people with type 1 diabetes, including their perceptions of existing services for smoking cessation. BACKGROUND: In the UK, approximately a fifth of the population with type 1 diabetes smoke and despite the adverse effects of smoking, these individuals continue with their smoking habits. There is limited information on the barriers and facilitators to quitting smoking in people with type 1 diabetes. METHODS: This study adopted a qualitative study design using semi-structured individual interviews guided by PRIME theory. Participants (n = 12) were purposively sampled and recruited from two diabetes outpatient clinics in London (UK). Audio-recorded interviews were transcribed verbatim and analysed using the Framework method. RESULTS: Most smokers with type 1 diabetes reported lack of motivation to stop smoking due to the addictive nature of cigarettes. Further barriers to quitting included self-image and habits associated with smoking, such as social activities. Generally, most reported limited awareness about the risks associated with smoking and diabetes. Moreover, the perceived negative attitude towards nicotine replacement therapy and pharmacotherapy impeded their willingness to alter their smoking habits. Nonetheless, these patients suggested that informative guidance from medical professionals and strategies to tackle cravings related to nicotine as helpful approaches to improve quitting attempts. CONCLUSION: Internal and external factors influence quitting attempts among smokers with type 1 diabetes, with particular emphasis on self-image and societal norms. It is evident that existing strategies for smoking cessation recommended by the National Institute for Health and Care Excellence have either not been implemented or not well received by people with type 1 diabetes. RELEVANCE TO CLINICAL PRACTICE: Strategies and resources, such as staff training, to increase delivery of smoking cessation support to patients with diabetes are needed. PMID- 29700883 TI - Using learning flexibly and remembering after a delay: understanding cognitive dysfunction in adults with Down syndrome. AB - BACKGROUND: Episodic memory deficits are a characteristic of cognitive dysfunction in people with Down syndrome (DS). However, less is known about the processes (i.e. encoding, retention or using learned information flexibly) that underlie these deficits. METHOD: We explored these abilities by administering a relational memory and inference task to participants with DS and mental age matched controls and testing both immediately and after a 24-h delay. RESULTS: Adults with DS learned paired associates more slowly than controls but showed good recognition at both the immediate and delayed tests. Despite memory for learned pairs, adults with DS were less able to use relational learning flexibly to make inferential judgements than controls. CONCLUSIONS: These results deepen our understanding of the cognitive profile of adults with DS, demonstrating deficits in both encoding new information, and flexibly using such information. These results have important implications for workplace training and intervention programs for people with DS. PMID- 29700884 TI - Co-Template Directed Synthesis of Gold Nanoparticles in Mesoporous Titanium Dioxide. AB - A bottom-up synthetic methodology to encapsulate pre-synthesized, well-defined gold nanoparticles (AuNPs) into mesoporous titanium dioxide framework (Au@mTiO2 ) is reported. This method employs two structurally and chemically similar templates of amphiphilic block copolymers as well as poly(ethylene oxide) tethered AuNPs, which showed excellent stability during sol-gel transition and thermal annealing at elevated temperatures. Such synthesis enabled precise control of sizes and loading of AuNPs within the mesoporous TiO2 framework. In light-driven methanol dehydrogenation, the presence of AuNPs significantly enhanced the photocatalytic activity of mTiO2 . This co-template-directed synthesis presents new opportunities to understand the effect of AuNP size in photocatalysis using Au@mTiO2 materials. PMID- 29700885 TI - Social networks, cooperative breeding, and the human milk microbiome. AB - OBJECTIVES: We present the first available data on the human milk microbiome (HMM) from small-scale societies (hunter-gatherers and horticulturalists in the Central African Republic [CAR]) and explore relationships among subsistence type and seasonality on HMM diversity and composition. Additionally, as humans are cooperative breeders and, throughout our evolutionary history and today, we rear offspring within social networks, we examine associations between the social environment and the HMM. Childrearing and breastfeeding exist in a biosocial nexus, which we hypothesize influences the HMM. METHODS: Milk samples from hunter gatherer and horticultural mothers (n = 41) collected over two seasons, were analyzed for their microbial composition. A subsample of these women's infants (n = 33) also participated in detailed naturalistic behavioral observations which identified the breadth of infants' social and caregiving networks and the frequency of contact they had with caregivers. RESULTS: Analyses of milk produced by CAR women indicated that HMM diversity and community composition were related to the size of the mother-infant dyad's social network and frequency of care that infants receive. The abundance of some microbial taxa also varied significantly across populations and seasons. Alpha diversity, however, was not related to subsistence type or seasonality. CONCLUSION: While the origins of the HMM are not fully understood, our results provide evidence regarding possible feedback loops among the infant, the mother, and the mother's social network that might influence HMM composition. PMID- 29700886 TI - Lysophosphatidylserine receptor P2Y10: A G protein-coupled receptor that mediates eosinophil degranulation. AB - BACKGROUND: P2Y10, along with GPR34 and GPR174, is a G protein-coupled receptor that is activated by an endogenous lipid mediator lysophosphatidylserine (LysoPS). Its expression pattern and its function are completely unknown. We have previously shown that P2Y10 is one of the highly up-regulated genes at the late differentiation stage during in vitro eosinophilopoiesis. OBJECTIVE: We explored the expression and functions of P2Y10 in human cord blood (CB)-derived and peripheral blood (PB) eosinophils. METHODS: Real-time PCR, FACS, Western blot, ELISA, and chemotaxis assays were performed to determine the expression and function of P2Y10. RESULTS: As CB cells differentiated towards eosinophils, P2Y10 mRNA and protein were abundantly expressed. P2Y10 was the most highly expressed in the granulocytes from PB, to a lesser extent in monocytes, and least in lymphocytes. Further fractionation of granulocytes revealed that eosinophils express P2Y10 much more strongly than do neutrophils. PB eosinophils solely expressed P2Y10 among the three LysoPS receptors, while PB neutrophils expressed the three at comparable levels. LysoPS activated both CB and PB eosinophils to induce a robust ERK phosphorylation. Importantly, LysoPS was capable of triggering degranulation of ECP in PB eosinophils. This response was significantly reduced by pharmacological inhibitors of TNF-alpha-converting enzyme (TACE), epidermal growth factor receptor (EGFR), and ERK1/2, which were known to be required in P2Y10-mediated signalling pathways. However, LysoPS had no effect on chemotaxis, differentiation, or eosinophil survival. CONCLUSIONS AND CLINICAL RELEVANCE: LysoPS provokes eosinophil degranulation through P2Y10. Therefore, P2Y10 is a potential therapeutic target to control eosinophil associated diseases. PMID- 29700888 TI - Labor supply effects of long-term care reform in Germany. AB - Many informal caregivers are of working age, facing the double burden of providing care and working. Negative labor supply effects can severely reduce the comparative cost advantage of informal over formal care arrangements. When designing long-term care (LTC) policies, it is crucial to understand the effects not only on health outcomes but also on labor supply behavior of informal caregivers. We evaluate labor supply reactions to the introduction of the German long-term care insurance in 1995 using a difference-in-differences approach. The long-term care insurance changes the caregivers' trade-off between labor supply and care provision. The aim of the reform was to strengthen informal care arrangements. We find a strong negative labor supply effect for men but not for women. We argue that the LTC benefits increased incentives for older men to leave the labor market. The results reveal a trade-off for policy makers that is important for future reforms-in particular for countries that mainly base their LTC system on informal care. PMID- 29700887 TI - CIC-NUTM1 fusion: A case which expands the spectrum of NUT-rearranged epithelioid malignancies. AB - NUT carcinoma (NC) shows very aggressive clinical behavior, occurs predominantly in the thorax and head and neck region of children and adults, and is defined by the presence of NUT (aka NUTM1) rearrangement, mostly BRD4-NUTM1 fusion resulting from t(15;19)(q13; p13.1). So-called "NUT variants" harbor alternate fusions between NUTM1 and BRD3, NSD3, ZNF532, or unknown partners. Rare cases of pediatric tumors with CIC-NUTM1 fusion were recently reported in somatic soft tissue, brain, and kidney. However, such cases have not been identified in adult patients and the presence of a fusion between CIC, characteristic of CIC rearranged sarcoma, and NUTM1-a defining feature of NC-poses a diagnostic challenge. We herein report a case of malignant epithelioid neoplasm with myoepithelial features harboring CIC-NUTM1 fusion arising in soft tissue of the head in a 60-year-old man. Immunohistochemistry revealed strong expression of NUT, but only weak ETV4 staining and negativity for keratins, EMA, p40, CD99, and WT1. SMARCB1 expression was retained. Fluorescence in situ hybridization and targeted next-generation sequencing identified a CIC-NUTM1 fusion resulting from t(15;19)(q14;q13.2). In light of morphologic features that overlap with those of NC from typical anatomical sites we have seen previously, the tumor was best classified as falling within the NC spectrum rather than CIC-associated sarcoma. This case highlights the emerging diagnostic challenges generated by newly detected gene fusions of unknown clinical and biologic significance. Careful integration of cytogenetic, molecular, and immunohistochemical findings with morphologic appearances in the diagnostic workup of undifferentiated neoplasms is essential. PMID- 29700889 TI - Fluorescent Molecular Rotors for Viscosity Sensors. AB - Fluorescent molecular rotors (FMRs) can act as viscosity sensors in various media including subcellular organelles and microfluidic channels. In FMRs, the rotation of rotators connected to a fluorescent pi-conjugated bridge is suppressed by increasing environmental viscosity, resulting in increasing fluorescence (FL) intensity. In this minireview, we describe recently developed FMRs including push pull type pi-conjugated chromophores, meso-phenyl (borondipyrromethene) (BODIPY) derivatives, dioxaborine derivatives, cyanine derivatives, and porphyrin derivatives whose FL mechanism is viscosity-responsive. In addition, FMR design strategies for addressing various issues (e.g., obtaining high FL contrast, internal FL references, and FL intensity-contrast trade-off) and their biological and microfluidic applications are also discussed. PMID- 29700890 TI - No association between cardiac ion channel variants and sudden infant death. PMID- 29700892 TI - Prevention of perioperative venous thromboembolism in pediatric patients: Guidelines from the Association of Paediatric Anaesthetists of Great Britain and Ireland (APAGBI). AB - The Association of Paediatric Anaesthetists of Great Britain and Ireland (APAGBI) Guidelines Working Group on Thromboprophylaxis in Children has reviewed the literature and where possible provided advice on the care of children in the perioperative period. Areas reviewed include the incidence of perioperative venous thromboembolism (VTE), risk factors, evidence for mechanical and chemical prophylaxis, and complications. Safe practice of regional anesthesia with anticoagulant prophylaxis is detailed. In summary, there are few areas of strong evidence. Routine prophylaxis cannot be recommended for young children. Postpubertal adolescents (approximately 13 years and over) are at a slightly increased risk of VTE and should be assessed for prophylaxis and may warrant intervention if other risk factors are present. However, the incidence of VTE is significantly lower than in the adult population. This special interest review presents a summary and discussion of the key recommendations, a decision-making algorithm and a risk assessment chart. For the full guideline, go to www.apagbi.org.uk/publications/apa-guidelines. PMID- 29700891 TI - Discovering cortical sulcal folding patterns in neonates using large-scale dataset. AB - The folding of the human cerebral cortex is highly complex and variable across individuals, but certain common major patterns of cortical folding do exist. Mining such common patterns of cortical folding is of great importance in understanding the inter-individual variability of cortical folding and their relationship with cognitive functions and brain disorders. As primary cortical folds are mainly genetically influenced and are well established at term birth, neonates with minimal exposure to the complicated postnatal environmental influences are ideal candidates for mining the major patterns of cortical folding. In this paper, we propose a sulcal-pit-based method to discover the major sulcal patterns of cortical folding. In our method, first, the sulcal pattern is characterized by the spatial distribution of sulcal pits, which are the locally deepest points in cortical sulci. Since deep sulcal pits are genetically related, relatively consistent across individuals, and also stable during brain development, they are well suited for representing and characterizing the sulcal patterns. Then, the similarity between the distributions of sulcal pits is measured from the spatial, geometrical, and topological points of view. Next, a comprehensive similarity matrix is constructed for the whole dataset by adaptively fusing these measurements together, thus capturing both their common and complementary information. Finally, leveraging the similarity matrix, a hierarchical affinity propagation algorithm is used to group similar sulcal folding patterns together. The proposed method has been applied to 677 neonatal brains, and revealed multiple distinct and meaningful sulcal patterns in the central sulcus, superior temporal sulcus, and cingulate sulcus. PMID- 29700893 TI - Action and semantic tool knowledge - Effective connectivity in the underlying neural networks. AB - Evidence from neuropsychological and imaging studies indicate that action and semantic knowledge about tools draw upon distinct neural substrates, but little is known about the underlying interregional effective connectivity. With fMRI and dynamic causal modeling (DCM) we investigated effective connectivity in the left hemisphere (LH) while subjects performed (i) a function knowledge and (ii) a value knowledge task, both addressing semantic tool knowledge, and (iii) a manipulation (action) knowledge task. Overall, the results indicate crosstalk between action nodes and semantic nodes. Interestingly, effective connectivity was weakened between semantic nodes and action nodes during the manipulation task. Furthermore, pronounced modulations of effective connectivity within the fronto-parietal action system of the LH (comprising lateral occipito-temporal cortex, intraparietal sulcus, supramarginal gyrus, inferior frontal gyrus) were observed in a bidirectional manner during the processing of action knowledge. In contrast, the function and value knowledge tasks resulted in a significant strengthening of the effective connectivity between visual cortex and fusiform gyrus. Importantly, this modulation was present in both semantic tasks, indicating that processing different aspects of semantic knowledge about tools evokes similar effective connectivity patterns. Data revealed that interregional effective connectivity during the processing of tool knowledge occurred in a bidirectional manner with a weakening of connectivity between areas engaged in action and semantic knowledge about tools during the processing of action knowledge. Moreover, different semantic tool knowledge tasks elicited similar effective connectivity patterns. PMID- 29700894 TI - Consensus statement on clear fluids fasting for elective pediatric general anesthesia. AB - Pediatric anesthetic guidelines for the management of preoperative fasting of clear fluids are currently 2 hours. The traditional 2 hours clear fluid fasting time was recommended to decrease the risk of pulmonary aspiration and is not in keeping with current literature. It appears that a liberalized clear fluid fasting regime does not affect the incidence of pulmonary aspiration and in those who do aspirate, the sequelae are not usually severe or long-lasting. With a 2 hour clear fasting policy, the literature suggests that this translates into 6-7 hours actual duration of fasting with several studies up to 15 hours. Fasting for prolonged periods increases thirst and irritability and results in detrimental physiological and metabolic effects. With a 1-hour clear fluid policy, there is no increased risk of pulmonary aspiration and studies demonstrate the stomach is empty. There is less nausea and vomiting, thirst, hunger, and anxiety, if allowed a drink closer to surgery. Children appear more comfortable, better behaved and possibly more compliant. In children less than 36 months this has positive physiological and metabolic effects. It is practical to allow children to drink until 1 hour prior to anesthesia on the day of surgery. In this joint consensus statement, the Association of Paediatric Anaesthetists of Great Britain and Ireland, the European Society for Paediatric Anaesthesiology, and L'Association Des Anesthesistes-Reanimateurs Pediatriques d'Expression Francaise agree that, based on the current convincing evidence base, unless there is a clear contraindication, it is safe and recommended for all children able to take clear fluids, to be allowed and encouraged to have them up to 1 hour before elective general anesthesia. PMID- 29700895 TI - Parental characteristics in association with disordered eating in 11- to 12-year olds: A study within the Danish National Birth Cohort. AB - We examined the association between parental characteristics and disordered eating among 11- to 12-year-olds within the Danish National Birth Cohort. Frequency of fasting, purging, and binge eating was obtained by self-report from 37,592 children and combined into a measure of disordered eating (no, monthly, and weekly). Information on parental characteristics was obtained during pregnancy, from the 7-year follow-up, and by linkage to population registers. Data were analysed using multinomial logistic regression models with robust standard errors. In total, 3.1% reported weekly and 4.1% reported monthly disordered eating. Parental young age, low educational level, and overweight/obesity were associated with disordered eating. The relative risk ratios for, respectively, weekly and monthly disordered eating according to maternal eating disorder were 1.01 [0.75, 1.37] and 1.09 [0.84, 1.42]. Disordered eating is common among children and is associated with several parental characteristics. We found social inequality in disordered eating, but our data did not support an association with maternal eating disorder. PMID- 29700896 TI - Task-related fMRI in hemiplegic cerebral palsy-A systematic review. AB - RATIONALE: Functional magnetic resonance imaging (fMRI) is used widely to study reorganization after early brain injuries. Unilateral cerebral palsy (UCP) is an appealing model for studying brain plasticity by fMRI. AIM: To summarize the results of task-related fMRI studies in UCP in order to get better understanding of the mechanism of neuroplasticity of the developing brain and its reorganization potential and better translation of this knowledge to clinical practice. METHODS: A systematic search was conducted on the PubMed database by keywords: "cerebral palsy", "congenital hemiparesis", "unilateral", "Magnetic resonance imaging" , "fMRI", "reorganization", and "plasticity" The exclusion criteria were as follows: case reports; reviews; studies exploring non-UCP patients; and studies with results of rehabilitation. RESULTS: We found 7 articles investigated sensory tasks; 9 studies-motor tasks; 12 studies-speech tasks. Ipsilesional reorganization is dominant in sensory tasks (in 74/77 patients), contralesional-in only 3/77. In motor tasks, bilateral activation is found in 64/83, only contralesional-in 11/83, and only ipsilesional-8/83. Speech perception is bilateral in 35/51, only or dominantly ipsilesional (left-sided) in 8/51, and dominantly contralesional (right-sided) in 8/51. Speech production is only or dominantly contralesional (right-sided) in 88/130, bilateral-26/130, and only or dominantly ipsilesional (left-sided)-in 16/130. DISCUSSION: The sensory system is the most "rigid" to reorganization probably due to absence of ipsilateral (contralesional) primary somatosensory representation. The motor system is more "flexible" due to ipsilateral (contralesional) motor pathways. The speech perception and production show greater flexibility resulting in more bilateral or contralateral activation. CONCLUSIONS: The models of reorganization are variable, depending on the development and function of each neural system and the extent and timing of the damage. The plasticity patterns may guide therapeutic intervention and prognostics, thus proving the fruitiness of the translational approach in neurosciences. PMID- 29700897 TI - Urbanization drives contemporary evolution in stream fish. AB - Human activities reduce biodiversity but may also drive diversification by modifying selection. Urbanization alters stream hydrology by increasing peak water velocities, which should in turn alter selection on the body morphology of aquatic species. Here, we show how urbanization can generate evolutionary divergence in the body morphology of two species of stream fish, western blacknose dace (Rhinichthys obtusus) and creek chub (Semotilus atromaculatus). We predicted that fish should evolve more streamlined body shapes within urbanized streams. We found that in urban streams, dace consistently exhibited more streamlined bodies while chub consistently showed deeper bodies. Comparing modern creek chub populations with historical museum collections spanning 50 years, we found that creek chub (1) rapidly became deeper bodied in streams that experienced increasing urbanization over time, (2) had already achieved deepened bodies 50 years ago in streams that were then already urban (and showed no additional deepening over time), and (3) remained relatively shallow bodied in streams that stayed rural over time. By raising creek chub from five populations under common conditions in the laboratory, we found that morphological differences largely reflected genetically based differences, not velocity-induced phenotypic plasticity. We suggest that urbanization can drive rapid, adaptive evolutionary responses to disturbance, and that these responses may vary unpredictably in different species. PMID- 29700898 TI - Development and stability of a heat-stable formulation of carbetocin for the prevention of postpartum haemorrhage for use in low and middle-income countries. AB - Postpartum haemorrhage is a leading cause of maternal death worldwide. Oxytocin, currently the drug of choice for prevention of PPH, requires constant refrigeration. In pursuit of an alternative medicine, Ferring Pharmaceuticals have developed a heat-stable formulation of carbetocin, an oxytocin analogue. This study aimed to define that formulation, and to investigate its stability under ICH climate zone IV conditions (30 degrees C/75% relative humidity) for at least 3 years and at extreme temperatures, such as 60 degrees C, for shorter periods of time. The development resulted in a heat-stable carbetocin formulation consisting of 0.1 mg/mL carbetocin in sodium succinate buffer, mannitol, and methionine. The optimum pH was determined to be pH 5.45 (5.25-5.65). The generated stability data of this formulation show that >=95% purity of the peptide was maintained for a minimum of 3 years at 30 degrees C, 6 months at 40 degrees C, 3 months at 50 degrees C and 1 month at 60 degrees C. In addition, the heat-stable carbetocin formulation was not sensitive to freezing or light. The reported highly stable peptide formulation facilitates the distribution in low and middle-income countries, where maintaining cold chain distribution is difficult. Ferring Pharmaceuticals, the World Health Organization, and MSD for Mothers have established a collaboration to develop this heat-stable formulation of carbetocin for the prevention of post-partum hemorrhage in women after vaginal childbirth, with the aim of making the medicine available in the public sector of developing countries that have a high burden of maternal mortality. PMID- 29700899 TI - Cyclic intravenous pamidronate in a very low-birthweight infant with osteogenesis imperfecta. PMID- 29700900 TI - Barriers and facilitators to health care professionals discussing child weight with parents: A meta-synthesis of qualitative studies. AB - INTRODUCTION: Childhood obesity is one of the most serious global public health challenges. However, obesity and its consequences are largely preventable. As parents play an important role in their children's weight-related behaviours, good communication between parents and health care professionals (HCPs) is essential. This systematic review provides a meta-synthesis of qualitative studies exploring the barriers and facilitators experienced by HCPs when discussing child weight with parents. METHODS: Searches were conducted using the following databases: MEDLINE (OVID), Psych INFO (OVID), EMBASE (OVID), Web of Knowledge and CINAHL. Thirteen full-text qualitative studies published in English language journals since 1985 were included. Included studies collected data from HCPs (e.g., nurses, doctors, dieticians, psychologists, and clinical managers) concerning their experiences of discussing child weight-related issues with parents. An inductive thematic analysis was employed to synthesize findings. FINDINGS: Emerging subthemes were categorized using a socio-ecological framework into intra/interpersonal factors, organizational factors, and societal factors. Perceived barriers and facilitators most commonly related to intra/interpersonal level factors, that is, relating to staff factors, parental factors, or professional-parent interactions. HCPs also attributed a number of barriers, but not facilitators, at the organizational and societal levels. CONCLUSION: The findings of this review may help to inform the development of future weight related communication interventions. Whilst intra/interpersonal interventions may go some way to improving health care practice, it is crucial that all stakeholders consider the wider organizational and societal context in which these interactions take place. Statement of contribution What is already known on the subject? Childhood obesity is one of the United Kingdom's most serious current public health challenges. Health care professionals are in a prime position to identify child weight issues during routine consultations. However, they often feel unable or unequipped to raise the topic and provide information on child weight management. What does this study add? To our knowledge, this is the first review to synthesize barriers and facilitators to discussing child weight. This review interprets key barriers and facilitators in the context of the socio-ecological model. Supports the development of interventions matched to the appropriate level of the socio-economic model. PMID- 29700901 TI - Individualized predictive signatures for 5-fluorouracil-based chemotherapy in right- and left-sided colon cancer. AB - 5-Fluorouracil (5-FU)-based adjuvant chemotherapy (ACT) is widely used for the treatment of colon cancer. Colon cancers with different primary tumor locations are clinically and molecularly distinct, implied through their response to 5-FU based ACT. In this work, using 69 and 133 samples of patients with stage II-III right-sided and left-sided colon cancer (RCC and LCC) treated with post-surgery 5 FU-based ACT, we preselected gene pairs whose relative expression orderings were significantly correlated with the disease-free survival of patients by univariate Cox proportional hazards model. Then, from the identified prognostic-related gene pairs, a forward-stepwise selection algorithm was formulated to search for an optimal subset of gene pairs that resulted in the highest concordance index, referred to as the gene pair signature (GPS). We identified prognostic signatures, 3-GPS and 5-GPS, for predicting response to 5-FU-based ACT of patients with RCC and LCC, respectively, which were validated in independent datasets of GSE14333 and GSE72970. With the aid of the signatures, the transcriptional and genomic characteristics between the predicted responders and non-responders were explored. Notably, both in RCC and LCC, the predicted responders to 5-FU-based ACT were characterized by hypermutation, whereas the predicted non-responders were characterized by frequent copy number alternations. Finally, in comparison with the established relative expression ordering-based signature, which was developed without considering the differences between RCC and LCC, the newly proposed signatures had a better predictive performance. In conclusion, 3-GPS or 5-GPS can robustly predict response to 5-FU-based ACT for patients with RCC or LCC, respectively, in an individual level. PMID- 29700903 TI - Integrating clinical and economic evidence in clinical guidelines: More needed than ever! AB - RATIONALE, AIMS, AND OBJECTIVES: In recent years, several expensive new health technologies have been introduced. The availability of those technologies intensifies the discussion regarding the affordability of these technologies at different decision-making levels. On the meso level, both hospitals and clinicians are facing budget constraints resulting in a tension to balance between different patients' interests. As such, it is crucial to make optimal use of the available resources. Different strategies are in place to deal with this problem, but decisions on a macro level on what to fund or not can limit the role and freedom of clinicians in their decisions on a micro level. At the same time, without central guidance regarding such decisions, micro level decisions may lead to inequities and undesirable treatment variation between clinicians and hospitals. The challenge is to find instruments that can balance both levels of decision making. DISCUSSION: Clinicians are becoming increasingly aware that their decisions to spend more resources (like time and budget) on 1 particular patient group reduce the resources available to other patients. Involving clinicians in thinking about the optimal use of limited resources, also in an attempt to bridge the world of economic reasoning and clinical practice, is crucial therefore. We argue that clinical guidelines may prove a clear vehicle for this by including both clinical and economic evidence to support the recommendations made. The development of such guidelines requires cooperation of clinicians, and health economists are cooperating with each other. CONCLUSION: The development of clinical guidelines which combine economic and clinical evidence should be stimulated, to balance central guidance and uniformity while maintaining necessary decentralized freedom. This is an opportunity to combine the reality of budgets and opportunity costs with clinical practice. Missing this opportunity risks either variation and inequity or central and necessarily crude measures. PMID- 29700904 TI - Trajectories of dispensed prescription opioids among beneficiaries enrolled in a Medicaid controlled substance "lock-in" program. AB - PURPOSE: "Lock-in" programs (LIPs) are used by health insurers to address potential substance (eg, opioid) misuse among beneficiaries. We sought to (1) examine heterogeneity in trajectories of dispensed opioids (in average daily morphine milligram equivalents (MMEs)) over time: prior to, during, and following release from a LIP, and (2) assess associations between trajectory patterns and beneficiary characteristics. METHODS: Medicaid claims were linked to Prescription Drug Monitoring Program records for a cohort of beneficiaries enrolled in the North Carolina Medicaid LIP (n = 2701). Using latent class growth analyses, we estimated trajectories of average daily MMEs of opioids dispensed to beneficiaries across specific time periods of interest. RESULTS: Five trajectory patterns appeared to sufficiently describe underlying heterogeneity. Starting values and slopes varied across the 5 trajectory groups, which followed these overall patterns: (1) start at a high level of MMEs, end at a high level of MMEs (13.1% of cohort); (2) start medium, end medium (13.2%); (3) start medium, end low (21.5%); (4) start low, end medium (22.6%); and (5) start low, end low (29.6%). We observed strong associations between patterns and beneficiaries' demographics, substance use-related characteristics, comorbid conditions, and healthcare utilization. CONCLUSIONS: In its current form, the Medicaid LIP appeared to have limited impact on beneficiaries' opioid trajectories. However, strong associations between trajectory patterns and beneficiary characteristics provide insight into potential LIP design modifications that might improve program impact (eg, LIP integration of substance use disorder assessment and referral to treatment, assessment and support for alternate pain therapies). PMID- 29700902 TI - The Leiden Family Lab study on Social Anxiety Disorder: A multiplex, multigenerational family study on neurocognitive endophenotypes. AB - OBJECTIVES: Social anxiety disorder (SAD) is a serious and prevalent psychiatric condition, with a heritable component. However, little is known about the characteristics that are associated with the genetic component of SAD, the so called "endophenotypes". These endophenotypes could advance our insight in the genetic susceptibility to SAD, as they are on the pathway from genotype to phenotype. The Leiden Family Lab study on Social Anxiety Disorder (LFLSAD) is the first multiplex, multigenerational study aimed to identify neurocognitive endophenotypes of social anxiety. METHODS: The LFLSAD is characterized by a multidisciplinary approach and encompasses a variety of measurements, including a clinical interview, functional and structural magnetic resonance imaging and an electroencephalography experiment. Participants are family members from 2 generations, from families genetically enriched for SAD. RESULTS: The sample (n = 132 participants, from 9 families) was characterized by a high prevalence of SAD, in both generations (prevalence (sub)clinical SAD: 38.3%). Furthermore, (sub)clinical SAD was positively related to self-reported social anxiety, fear of negative evaluation, trait anxiety, behavioral inhibition, negative affect, and the level of depressive symptoms. CONCLUSIONS: By the multidimensional character of the measurements and thorough characterization of the sample, the LFLSAD offers unique opportunities to investigate candidate neurocognitive endophenotypes of SAD. PMID- 29700905 TI - Waxing and waning of forests: Late Quaternary biogeography of southeast Africa. AB - African ecosystems are at great risk. Despite their ecological and economic importance, long-standing ideas about African forest ecology and biogeography, such as the timing of changes in forest extent and the importance of disturbance, have been unable to be tested due to a lack of sufficiently long records. Here, we present the longest continuous terrestrial record of late Quaternary vegetation from southern Africa collected to date from a drill core from Lake Malawi covering the last ~600,000 years. Pollen analysis permits us to investigate changes in vegetation structure and composition over multiple climatic transitions. We observe nine phases of forest expansion and collapse related to regional hydroclimate change. The development of desert, steppe and grassland vegetation during arid periods is likely dynamically linked to thresholds in regional hydrology associated with lake level and moisture recycling. Species composition of these dryland ecosystems varied greatly and is unlike the vegetation found at Malawi today, with assemblages suggesting strong Somali-Masai affinities. Furthermore, nearly all semiarid assemblages contain low forest taxa abundances, suggesting that moist lowland gallery forests formed refugia along waterways during arid times. When the region was wet, forests were species-rich and very high afromontane tree abundances suggest frequent widespread lowland colonization by modern high elevation trees. Furthermore, species composition varied little amongst forest phases until ~80 ka when disturbance tolerant tree taxa characteristic of the modern vegetation increased in abundance. The waxing and waning of forests has important implications for understanding the processes that control modern tropical vegetation biogeography as well as the environments of early humans across Africa. Finally, this work highlights the resilience of montane forests during previous warm intervals, which is relevant for future climate change; however, we point to a fundamental shift in disturbance regimes which are crucial for the structure and composition of modern East African landscapes. PMID- 29700906 TI - Endogenously generated gamma-band oscillations in early visual cortex: A neurofeedback study. AB - Human subjects were trained with neurofeedback (NFB) to enhance the power of narrow-band gamma oscillations in circumscribed regions of early visual cortex. To select the region and the oscillation frequency for NFB training, gamma oscillations were induced with locally presented drifting gratings. The source and frequency of these induced oscillations were determined using beamforming methods. During NFB training the power of narrow band gamma oscillations was continuously extracted from this source with online beamforming and converted into the pitch of a tone signal. We found that seven out of ten subjects were able to selectively increase the amplitude of gamma oscillations in the absence of visual stimulation. One subject however failed completely and two subjects succeeded to manipulate the feedback signal by contraction of muscles. In all subjects the attempts to enhance visual gamma oscillations were associated with an increase of beta oscillations over precentral/frontal regions. Only successful subjects exhibited an additional marked increase of theta oscillations over precentral/prefrontal and temporal regions whereas unsuccessful subjects showed an increase of alpha band oscillations over occipital regions. We argue that spatially confined networks in early visual cortex can be entrained to engage in narrow band gamma oscillations not only by visual stimuli but also by top down signals. We interpret the concomitant increase in beta oscillations as indication for an engagement of the fronto-parietal attention network and the increase of theta oscillations as a correlate of imagery. Our finding support the application of NFB in disease conditions associated with impaired gamma synchronization. PMID- 29700907 TI - Psychosexual development and satisfaction with timing of developmental milestones among adult survivors of childhood cancer. AB - OBJECTIVE: To extend the limited research on psychosexual development among childhood cancer survivors, by not only focusing on the prevalence and age of milestone attainment, but also survivors' attitudes toward the timing of reaching such milestones. METHODS: Adult survivors of childhood cancer (N = 90; Mage = 29.8, SD = 5.2), recruited from a US pediatric institution, completed online surveys indicating whether they had reached 5 milestones of psychosexual development (ie, first kiss, first boy-/girlfriend, first physical intimacy, sexual debut, first time in love), age at attainment, and perceptions about the timing (ie, right time, wished it had happened earlier, wished they had waited). RESULTS: Almost all survivors had reached each milestone (>=90%), except for sexual debut (83.3%). Survivors reported their first kiss as the earliest milestone at age 14.6 (N = 82, 92%) and falling in love as the latest milestone at age 18.8 (N = 80; 90%). This timing did not differ by sex/cancer-specific factors. Most survivors (~60%) felt they reached each milestone at the right time. Compared with US normative data, both male and female survivors were less likely to have experienced their sexual debut and were approximately 1.5 years older at sexual debut. Nevertheless, 59% of survivors felt that this timing was right and 31% wished they had waited longer. CONCLUSIONS: This is the first study to demonstrate that although childhood cancer survivors may delay some aspects of psychosexual development, most are satisfied with this timing. Research and clinical practice should emphasize survivors' perceptions/satisfaction toward psychosexual development rather than focusing only on normative milestone attainment. PMID- 29700908 TI - Turning a Blind Eye? Punishment of Friends and Unfamiliar Peers After Observed Exclusion in Adolescence. AB - In order to decrease the occurrence of social exclusion in adolescence, we need to better understand how adolescents perceive and behave toward peers involved in exclusion. We examined the role of friendships in treatment of perpetrators and victims of social exclusion. Eighty-nine participants (aged 9-16) observed exclusion of an unfamiliar peer (victim) by their best friend and another unfamiliar peer. Subsequently, participants could give up valuable coins to altruistically punish or help peers. Results showed that participants altruistically compensated victims and punished unfamiliar excluders, but refrained from punishing their friends. Our findings show that friendship with excluders modulates altruistic punishment of peers and provide mechanistic insight into how friendships may influence treatment of peers involved in social exclusion during adolescence. PMID- 29700909 TI - A Copper(I)-Catalyzed Enantioselective gamma-Boryl Substitution of Trifluoromethyl-Substituted Alkenes: Synthesis of Enantioenriched gamma,gamma-gem Difluoroallylboronates. AB - The first catalytic enantioselective gamma-boryl substitution of CF3 -substituted alkenes is reported. A series of CF3 -substituted alkenes was treated with a diboron reagent in the presence of a copper(I)/Josiphos catalyst to afford the corresponding optically active gamma,gamma-gem-difluoroallylboronates in high enantioselectivity. The thus obtained products could be readily converted into the corresponding difluoromethylene-containing homoallylic alcohols using highly stereospecific allylation reactions. PMID- 29700910 TI - Indanol-Based Chiral Organoiodine Catalysts for Enantioselective Hydrative Dearomatization. AB - Rapid development in the last decade has rendered chiral organoiodine(I/III) catalysis a reliable methodology in asymmetric catalysis. However, due to the severely limited numbers of effective organoiodine catalysts, many reactions still give low to modest enantioselectivity. We report herein a solution to this issue through the introduction of a pivotal indanol scaffold to the catalyst design. Our catalyst architecture exhibits the advantage of high modularity and thereby expedites catalyst optimization. The catalyst was optimized for the challenging and highly sought-after hydrative dearomatization of 2-substituted phenols at the 4-position. PMID- 29700911 TI - Alarmins as biomarkers of gastrointestinal surgical injury - a pilot study. AB - The dysregulation of inflammatory response to surgical injury affects outcomes. Alarmins, the earliest bioactive substances from damaged cells, play a crucial role in initiating the inflammation. We analyzed serum levels of alarmins (S100A8, S100A12, high mobility group box, and heat shock protein 70) after major abdominal surgery (MAS) in surgical (S) (n = 82) and nonsurgical (NS) groups (n = 35). The main objective was determining a role of selected alarmins in host response to MAS. The secondary objectives were (i) evaluation of the relationship among alarmins and selected biomarkers (C-reactive protein, interleukin-6), (ii) influence of the place of gastrointestinal resection, and (iii) role of alarmins in MAS for cancer. Except for HMGB1, the levels of all alarmins were higher in the S group compared with the NS group. In the S group, positive correlations were found between S100A8 and both IL-6 and CRP. Additionally, the S100A8 level was higher (p < 0.01) in patients who underwent upper gastrointestinal tract (GIT) surgery compared to middle and lower GIT resections. Alarmins levels did not differ between cancer and noncancer patients. MAS is able to elicit increase in alarmin levels. S100A8 can be considered a potential biomarker of surgical injury, especially in the upper part of the GIT. PMID- 29700912 TI - Coexistence of MACC1 and NM23-H1 dysregulation and tumor budding promise early prognostic evidence for recurrence risk of early-stage colon cancer. AB - The tumor-node-metastasis (TNM) classification, the presence of a mucinous component, and signet ring cells are well-known criteria for identifying patients at a high risk for recurrence and determining the therapeutic approach for early stage colon cancer (eCC). Nevertheless, recurrence can unexpectedly occur in some eCC cases after surgical resection. The aims of the present study were to evaluate the relation of dysregulated MACC1, c-MET, and NM23-H1 expression with the histopathological features of tumors in recurrence formation in eCC cases. A total of 100 sporadic eCC patients without poor prognosis factors were evaluated in this study. The relationship between the altered expression of MACC1, c-MET, and NM23-H1 and pathological microenvironmental features, including the presence of tumor budding and desmoplasia, were assessed. The primary outcomes, including 5-year overall survival (OS) and disease-free survival (DFS), were also measured. Compared with nonrecurrent patients, the expression level of MACC1 was 8.27-fold higher, and NM23-H1 was 11.36-fold lower in patients with recurrence during the 5 year follow-up (p = 0.0345 and p = 0.0301, respectively). In addition, the coexistence of high MACC1 and low NM23-H1 expression and tumor budding was associated with short OS (p < 0.001). We suggest that the combination of reduced NM23-H1, induced MACC1, and the presence of tumor budding are promising biomarkers for the prediction of recurrence and may aid the stratification of patients with stage II colon cancer for adjuvant chemotherapy. PMID- 29700913 TI - Native aortic endocarditis due to an unusual pathogen: Actinotignum schaalii. AB - We report a case of aortic native valve endocarditis due to Actinotignum schaalii in an 89-year-old man with prostatism history but no signs of urinary infection. Actinotignum schaalii was isolated not only from positive blood culture but also from cardiac valve culture using mass spectrometry and 16S rDNA sequencing. Actinotignum schaalii is recognized as commensal of genitourinary tract, but it was underdiagnosed. The advances in bacterial identification such as MALDI-TOF MS probably explain the increasing described cases of infections due to A. schaalii these last years. PMID- 29700914 TI - Controlled Nucleation and Controlled Growth for Size Predicable Synthesis of Nanoscale Metal-Organic Frameworks (MOFs): A General and Scalable Approach. AB - Nanoscale metal-organic frameworks (nanoMOFs) are promising porous nanomaterials for diverse applications, such as catalysis, imaging, functional membranes, and drug delivery. At the nanoscale, the size of materials is critical for their properties and utility. Herein, a straightforward and convenient strategy is developed for size precisely controlled synthesis of nanoMOFs. Unlike other approaches, this strategy can directly give nanoMOFs of predicable sizes within a wide range without the time consuming trial-and-error process and without the addition of additives. In this approach, the preciseness of size control is ensured by the separated and controlled nucleation and growth. The size controlled synthesis of 9 kinds of most widely studied nanoMOFs confirms the versatility of this strategy. More importantly, this approach can be utilized for scale-up synthesis of nanoMOFs with the same precise size control. PMID- 29700915 TI - Stable Copper(I)-Mediated Base Pairing in DNA. AB - A GNA (glycol nucleic acid) functionalized nucleoside analogue containing the artificial nucleobase 1H-imidazo[4,5-f][1,10]phenanthroline (P) was used to form a copper(I)-mediated base pair within a DNA duplex. The geometrical constraints imposed by the artificial nucleobase play a pivotal role in this unprecedented stabilization of copper(I) in aqueous medium via metal-mediated base pairing. The formation of the copper(I)-mediated base pair was investigated by temperature dependent UV spectroscopy and CD spectroscopy. The metal-mediated base pair stabilizes the DNA oligonucleotide duplex by 23 degrees C. A redox chemistry approach confirmed that this base pair formation was due to the incorporation of copper(I) into the duplex. This first report of a copper(I)-mediated base pair adds metal-based diversity to the field and consequently opens up the range of possible applications of metal-modified nucleic acids. PMID- 29700916 TI - UNC119A Decreases the Membrane Binding of Myristoylated c-Src. AB - Plasma membrane localization of myristoylated c-Src, a proto-oncogene protein tyrosine kinase, is required for its signaling activity. Recent studies proposed that UNC119 protein functions as a solubilizing factor for myristoylated proteins, thereby regulating their subcellular distribution and signaling. The underlying molecular mechanism by which UNC119 regulates the membrane binding of c-Src has remained elusive. By combining different biophysical techniques, we have found that binding of a myristoylated c-Src-derived N-terminal peptide (Myr Src) by UNC119A results in a reduced membrane binding affinity of the peptide, due to the competition of binding to membranes. The dissociation of Myr-Src from membranes is facilitated in the presence of UNC119A, as a consequence of which the clustering propensity of this peptide on the membrane is partially impaired. By these means, UNC119A is able to regulate c-Src spatially in the cytoplasm and on cellular membranes, and this has important implications for its cellular signaling. PMID- 29700917 TI - Diverse meta-C-H Functionalization of Arenes across Different Linker Lengths. AB - Arenes containing conformationally flexible long alkyl chains have been successfully functionalized at the meta-position. Good to excellent meta selectivity is achieved for systems with up to 20 atoms between the target C-H bond and the coordinating heteroatom of the directing group. The palladium catalyzed functionalization reactions include alkylation, cyanation, olefination, and acetoxylation. The meta selectivity is exclusively governed by the design of flexible pyrimidine-based scaffolds. PMID- 29700918 TI - High rates of ocular complications in a cohort of Haitian children and adolescents with diabetes. AB - BACKGROUND: Ophthalmic complications of pediatric diabetes are rare, and rates are unknown in Haitian youth. OBJECTIVES: To determine the prevalence and predictors of diabetic retinopathy (DR) and cataracts in a cohort of Haitian youth with insulin-treated diabetes. METHODS: We performed a cross-sectional retrospective review of pediatric patients with diabetes from a pediatric chronic disease center in Haiti, from December 1, 2012 to November 1, 2016. Data collection included demographic and anthropometric information, total daily insulin dose and result of eye examination by a local ophthalmologist. RESULTS: Of 67 patients (54% female, mean age at diagnosis 14.6 +/- 3.9 years, mean diabetes duration 3.3 +/- 3.0 years, mean HbA1c 84 +/- 22 mmol/mol (9.8% +/- 2.0%), mean current insulin requirement 0.49 +/- 0.28 IU/kg/day), DR was diagnosed in 10/57 (18%) and cataracts in 10/62 (16%), at a mean age of 19.0 +/- 4.3 and 19.1 +/- 3.3 years, respectively. Diabetes duration was 4.9 +/- 5.4 and 3.0 +/- 1.5 years at the time of diagnosis of DR and cataracts, respectively. Age at complication, insulin requirement, sex, body mass index, family history, mean HbA1c and diabetes duration were not significant predictors of an ocular complication. CONCLUSIONS: In this cohort of Haitian youth, DR and cataracts occur prematurely. Low-insulin requirements years after diagnosis, possibly allowing for prolonged undetected hyperglycemia prediagnosis, may explain complication risk. The phenotypes of diabetes in pediatric populations of African ancestry may be distinct. Ophthalmologic evaluation should possibly start at diagnosis, and screening guidelines may need to be adapted. PMID- 29700919 TI - Transient bilateral epiblepharon occurring during pregnancy. PMID- 29700920 TI - Prediabetes, diabetes mellitus, and anti-diabetic treatment: Is anyone still healthy? PMID- 29700921 TI - Sensitization to various minor house dust mite allergens is greater in patients with atopic dermatitis than in those with respiratory allergic disease. AB - BACKGROUND: Various allergenic proteins are produced by house dust mites (HDM). However, the allergenicity and clinical implications of these allergens are unknown. OBJECTIVE: The purpose of this study was to identify allergens in Dermatophagoides farinae and elucidate the sensitization profiles to these in Korean patients suffering from respiratory (allergic rhinitis and/or asthma) and atopic dermatitis symptoms. METHODS: IgE reactivities in sera from 160 HDM allergy patients were analysed by one- and two-dimensional gel electrophoresis and immunoblotting. IgE-reactive components were identified by liquid chromatography-coupled electrospray ionization-tandem mass spectrometry. Nine recombinant mite allergens (Der f 1, Der f 2, Der f 10, Der f 11, Der f 13, Der f 14, Der f 30, Der f 32 and Der f Alt a 10) were produced, and the IgE reactivity in sera to each was determined by ELISAs. RESULTS: Der f 1 and Der f 2 were recognized by IgE in serum samples from 88.1% and 78.1% of all patients, respectively. Patients with respiratory allergies were mainly sensitized to these major allergens, whereas patients with atopic dermatitis symptoms showed polysensitization to major and minor allergen components (including Der f 11, Der f 13, Der f 14, Der f 32 and Der f Alt a 10). CONCLUSIONS: Patients with respiratory allergic disease sensitize to major allergen components of HDM. Those with atopic dermatitis were sensitized to a broader range of minor allergen components of HDM (Der f 11, Der f 13, Der f 14, Der f 32 and Der f Alt a 10). PMID- 29700922 TI - The responses of the inflammatory marker, pentraxin 3, to dietary sodium and potassium interventions. AB - Pentraxin-3 is a sensitive marker of inflammation that plays dual roles, pathogenic and cardioprotective, in the progression of cardiovascular diseases. Inflammation is intimately involved in salt-induced hypertension. We investigated the responses of pentraxin-3 to sodium and potassium supplementation to elucidate the potential role of pentraxin-3 in salt-induced hypertension. A total of 48 participants from northwest China were enrolled. All participants were maintained on a 3-day normal diet, which was sequentially followed by a 7-day low-sodium diet, a 7-day high-sodium diet, and a 7-day high-sodium plus potassium diet. Plasma concentrations of pentraxin-3 were assessed using ELISA. Plasma pentraxin 3 decreased significantly during the low-salt period compared to baseline (0.57 +/- 0.19 ng/mL vs 0.72 +/- 0.33 ng/mL, P = .012) and increased during the high salt period (0.68 +/- 0.26 ng/mL vs 0.57 +/- 0.19 ng/mL, P = .037). Potassium supplementation inhibited salt-induced increase in pentraxin-3 (0.56 +/- 0.21 ng/mL vs 0.68 +/- 0.26 ng/mL, P = .015). Ln-transformed pentraxin-3 at baseline was inversely correlated with BMI (r = -.349, P = .02), DBP (r = -.414, P = .005), MAP (r = -.360, P = .017). We found a positive correlation between the ln transformed concentrations of pentraxin-3 and 24-hour urinary sodium during low and high Na+ periods (r = .269, P = .012) and a negative relationship with 24 hours urinary potassium excretion during high-salt and high-salt plus potassium periods (r = -.246, P = .02). These correlations remained significant after adjusting for confounders. Pentraxin-3 responses were more prominent in salt sensitive individuals than salt-resistant individuals. Dietary salt and potassium interventions significantly altered circulating pentraxin-3. PMID- 29700923 TI - The impact of fixed-dose combination versus free-equivalent combination therapies on adherence for hypertension: a meta-analysis. AB - Nonadherence to antihypertensive medication is considered as a reason of inadequate control of blood pressure. This meta-analysis aimed to systemically evaluate the impact of fixed-dose combination (FDC) therapy on hypertensive medication adherence compared with free-equivalent combination therapies. Articles were retrieved from MEDLINE and Embase databases using a combination of terms "fixed-dose combinations" and "adherence or compliance or persistence" and "hypertension or antihypertensive" from January 2000 to June 2017 without any language restriction. A meta-analysis was performed to parallel compare the impact of FDC vs free-equivalent combination on medicine adherence or persistence. Studies were independently reviewed by two investigators. Data from eligible studies were extracted and a meta-analysis was performed using R version 3.1.0 software. A total of nine studies scored as six of nine to eight of nine for Newcastle-Ottawa rating with 62 481 patients with hypertension were finally included for analysis. Results showed that the mean difference of medication adherence for FDC vs free-equivalent combination therapies was 14.92% (95% confidence interval, 7.38%-22.46%). Patients in FDC group were more likely to persist with their antihypertensive treatment, with a risk ratio of 1.84 (95% confidence interval, 1.00-3.39). This meta-analysis confirmed that FDC therapy, compared with free-equivalent combinations, was associated with better medication adherence or persistence for patients with hypertension. It can be reasonable for physicians, pharmacists, and policy makers to facilitate the use of FDCs for patients who need to take two or more antihypertensive drugs. PMID- 29700924 TI - Depolymerization of Trityl End-Capped Poly(Ethyl Glyoxylate): Potential Applications in Smart Packaging. AB - The temperature-dependent depolymerization of self-immolative poly(ethyl glyoxylate) (PEtG) capped with triphenylmethyl (trityl) groups is studied and its potential application for smart packaging is explored. PEtGs with four different trityl end-caps are prepared and found to undergo depolymerization to volatile products from the solid state at different rates depending on temperature and the electron-donating substituents on the trityl aromatic rings. Through the incorporation of hydrophobic dyes including Nile red and IR-780, the depolymerization is visualized as a color change of the dye as it changes from a dispersed to aggregated state. The ability of this platform to provide information on thermal history through an easily readable signal makes it promising in smart packaging applications for sensitive products such a food and other cargo that is susceptible to degradation. PMID- 29700925 TI - Effect of a punctal plug on ocular surface disease in patients using topical prostaglandin analogues: a randomized controlled trial. AB - IMPORTANCE: Ocular surface disease (OSD) is common and can reduce treatment compliance and quality of life. BACKGROUND: To determine whether a punctal plug improves OSD and reduces intraocular pressure (IOP) in patients using prostaglandin analogue monotherapy. DESIGN: Randomized controlled trial. PARTICIPANTS: Sixty eligible subjects aged >18 years with symptomatic OSD from glaucoma clinics were invited to participate. Lacrimal or glaucoma surgery, lid malposition and contact lens wear were exclusion criteria. METHODS: One eye received an inferior punctal plug, leaving the fellow eye as a control. MAIN OUTCOME MEASURES: Ocular surface disease index (OSDI), tear film breakup time (TF BUT), Oxford cornea score, tear osmolarity and IOP were compared at baseline and 6 weeks by masked investigators. RESULTS: From 60 eligible, 48 (80.0%) participated (mean age 69.6 years; 60.0% female). OSDI reduced following plug insertion (mean difference [MD] 14.5, 95% confidence interval [CI] 5.06-23.94, P < 0.001). Compared to control eyes, in eyes receiving plugs the TF-BUT increased (MD 2.3 s, 95% CI 1.4-3.2, P < 0.001), the Oxford cornea score decreased (MD 0.5, 95% CI 0.3-0.7, P < 0.001), and tear osmolarity decreased (MD 10 mOsm/L, 95% CI 3.5-16.5, P = 0.003). Punctal plugs resulted in a significantly lowered IOP (MD 1.5 mmHg, 95% CI 0.1-2.9, P = 0.032). Sub-group analyses showed similar efficacy regardless of prostaglandin preservative status or lubricant drop use. Plugs were well tolerated but extrusion occurred in 8.5%, and epiphora increased in 6.5% eyes. CONCLUSIONS AND RELEVANCE: Punctal plug insertion improves subjective and objective measures of OSD and results in a reduced IOP in patients with symptomatic ocular surface disease using prostaglandin analogue monotherapy. PMID- 29700926 TI - Robot-assisted aortic valve surgery: State of the art and challenges for the future. AB - Robotic cardiac surgery was FDA-approved in 2002 and since then several different procedures have been performed to facilitate a truly minimally invasive approach. The use of robotics in aortic valve surgery, however, is still in its infancy. In this article, we report our clinical experience and chronological development with robot-assisted aortic valve surgery. This includes a description of how robotic assistance was gradually integrated during right mini-thoracotomy aortic valve replacement, a series of cases in which the robot was docked for parts of the procedure, a single case of a totally endoscopic robot-assisted aortic valve replacement with a stentless valve, and three cases of aortic valve papillary fibroelastoma resections. All of these were performed safely with early postoperative recovery and excellent clinical results. Additionally, we review the latest literature describing robot-assisted aortic valve surgery. Finally, we describe current issues, and challenges for robot-assisted aortic valve surgery. PMID- 29700927 TI - Effects of an orexin receptor antagonist on blood pressure and metabolic parameters. PMID- 29700928 TI - Labeling membrane receptors with lectins and evaluation of the midgut histochemistry of Tuta absoluta (Meyrick) (Lepidoptera: Gelechiidae) populations with different levels of susceptibility to formulated Bt. AB - BACKGROUND: Studies show that insects can adapt to the toxins of Bacillus thuringiensis under field and laboratory conditions through the development of resistance to the bacterium and its formulations. This has been demonstrated in the failure to control Tuta absoluta populations in Brazil. This study evaluated membrane receptors using peroxidase-labeled lectins and the midgut histochemistry of T. absoluta populations to assess susceptibility to the insecticides Bt fomulations. The histochemistry analysis used Periodic Acid-Schiff for glycogen and Ponceau Xylidine for total proteins. The presence of glucose/mannose and N acetylgalactosamine (GalNAc) was analyzed using specific lectins. One susceptible and one tolerant population were used in the study; insects were exposed to the insecticide concentrations recommended by the manufacturers. The midgut was collected after an interval of 20 min and analyzed using optical microscopy. RESULTS: Bt fomulation interferes with the glycogen content, whereas XenTari(r) interferes with the protein content, irrespective of the level of susceptibility. High expression of GalNAc residues was observed using soybean lectin labeling, indicating a direct relationship between the glycosylation pattern and susceptibility to Bt fomulation in the Pelotas population. CONCLUSION: The use of Bt fomulation caused greater alterations in the larval intestinal histophysiology compared to the use of XenTari(r) . (c) 2018 Society of Chemical Industry. PMID- 29700929 TI - Ten years on from the World Health Organization Commission of Social Determinants of Health: Progress or procrastination? PMID- 29700930 TI - An evaluation of the 'Yaka ?arali'' Tackling Indigenous Smoking program in East Arnhem Land: Yolnu people and their connection to narali'. AB - ISSUE ADDRESSED: Smoking prevalence estimated between 65% and 84% has been reported among the Yolnu peoples of East Arnhem Land, Northern Territory. We report on findings of an evaluation of the Yaka ?arali' Tackling Indigenous Smoking program in East Arnhem Land. METHODS: Qualitative interviews with Yolnu (N = 23) and non-Yolnu (N = 7) informants were conducted in seven communities between June 2014 and September 2015, with the support of Cultural Mentors, in homeland communities throughout East Arnhem Land. The data was coded using NVivo software, analysed line-by-line and categorised by the researcher (MT) under three a priori categories established as evaluation parameters. In addition, the meanings of narali' and Yolnu cultural obligations to narali' were analysed using an inductive process. RESULTS: Data were coded under three a priori themes: Yolnu trying to quit smoking (interest in quitting, access to support); the Yaka ?arali program (efficacy and recognition); Yolnu workforce (roles and responsibilities). Yolnu informants, including Elders and leaders, both smokers and non-smokers uniformly acknowledged the deep cultural and traditional connection with narali' attributing this relationship with its introduction by the Macassans and its subsequent adoption into ceremony. CONCLUSIONS: Given the strong cultural and traditional connection to narali', care must be taken to ensure tobacco control measures maintain congruence with local values and expectations. SO WHAT?: Tailored, localised programs, developed in consultation with communities, Elders and leaders are needed to respect and accommodate the tight connection that the Yolnu have with narali', maintained over hundreds of years. PMID- 29700931 TI - Are older Australians with chronic diseases online? AB - ISSUE ADDRESSED: Health information can be easily and cheaply provided through the Internet. However, we do not know whether older adults, those people most likely to be living with a chronic disease, are online or whether they use the Internet to find health information. METHODS: In order to establish the proportion of older Australians online, the impact of their current health status and chronic disease diagnosis on Internet usage and whether they use the Internet to search for health information, a paper-based survey was developed and mailed to 9000 older adults, resident in New South Wales, Australia (response rate = 46.8% ). RESULTS: Results showed that many older Australians are online (52.3%) and that the majority who are use the Internet to find health information (68.5%). Respondents were more likely to use the Internet if they reported good health. The presence of most chronic diseases reduced use of the Internet; however, this was not the case for those reporting asthma, anxiety or sleep apnoea. Internet use decreased as the number of reported co-morbidities increased. However, once online, self-perceived overall health and number of chronic diseases did not affect use of the Internet to find health information. CONCLUSIONS: This study is important as there is currently little information available about Internet use for health information by older Australians. Findings show that the provision of health information online has the potential to reinforce existing barriers created by the social determinants of health. SO WHAT?: There is a role for the Internet in providing preventative, health promotion information, to older adults, who are already online and younger, computer literate audiences. However, practitioners need to consider the fact that this mode of delivery reinforces existing social divides; requires people to have Internet access and be both literate and e-literate. PMID- 29700932 TI - Yarning quiet ways: Aboriginal carers' views on talking to youth about sexuality and relationships. AB - ISSUE ADDRESSED: Research suggests that young Indigenous people want carers to take a more active role in discussions about sexual health. The aim of this study was to ascertain carers' perspectives of: the importance of providing young people with information about sex and sexual health; what they want young people to know about sex and sexual health; and facilitators and barriers to discussing sex and sexual health with youth. METHODS: Thirteen focus groups and three interviews were conducted with 81 carers in four rural and urban regions of Western Australia. Data were coded using a thematic approach, analysed using inductive Framework Analysis, and interpreted using the Aboriginal Family Wellbeing Model of Empowerment. RESULTS: Many participants recognised the need for talking with young people about sex, and said they drew upon resources such as books, pamphlets and television and used humour to impart lessons. However, a large proportion of participants reported difficulties in educating youth about sex. Participants noted that colonisation had disrupted traditional structures for educating young people, and that sex was a challenging topic. The forced removal of children had interfered with Indigenous family structures and deprived some participants of the opportunity to acquire knowledge and skills from their own parents. CONCLUSIONS: Our findings emphasise the potential role of culture and empowerment in further improving outcomes related to relationships and sexual health. There is a need for more research into models of culturally-empowering, family-centred strategies for improving the sexual literacy of Indigenous youth. PMID- 29700933 TI - Skills, systems and supports: An Aboriginal Community Controlled Health Service (Apunipima) approach to building health promotion evaluation capacity of staff. AB - ISSUE ADDRESSED: Building the health promotion evaluation capacity of a workforce requires more than a focus on individual skills and confidence. We must also consider the organisational systems and supports that enable staff to embed learnings into practice. This paper describes the processes used to build health promotion evaluation capacity of staff in an Aboriginal Community Controlled Health Service (ACCHS). METHODS: To build health promotion evaluation capacity three approaches were used: (i) workshops and mentoring; (ii) strengthening systems to support program reporting; and (iii) recruitment of staff with skills and experience. Pre- and post-questionnaires determined levels of individual skills and confidence, updated systems were assessed for adequacy to support new health promotion practices and surveys captured the usefulness of workshops and mentoring. RESULTS: There was increased participant skills and confidence. Participants completed program impact evaluation reports and results were successfully presented at national conferences. The health promotion team was then able to update in-house systems to support new health promotion practices. Ongoing collaboration with experienced in-house researchers provided basic research training and professional mentoring. CONCLUSIONS: Building health promotion evaluation capacity of staff in an ACCHS can be achieved by providing individual skill development, strengthening organisational systems and utilising professional support. SO WHAT?: Health promotion practitioners have an ongoing professional obligation to improve the quality of routine practice and embrace new initiatives. This report outlines a process of building evaluation capacity that promotes quality reporting of program impacts and outcomes, reflects on ways to enhance program strengths, and communicates these findings internally and to outside professional bodies. This is particularly significant for ACCHSs responsible for addressing the high burden of preventable disease in Aboriginal and Torres Strait Islander populations. PMID- 29700934 TI - The oral health behaviours and fluid consumption practices of young urban Aboriginal preschool children in south-western Sydney, New South Wales, Australia. AB - ISSUE ADDRESSED: Australian Aboriginal children have a higher risk of dental caries yet there is limited focus on oral health risk factors for urban Aboriginal preschool children. This study examined the oral health behaviours and fluid consumption practices of young children from an urban Aboriginal community in south-western Sydney, Australia. METHODS: In total, 157 Aboriginal children who were recruited to the "Gudaga" longitudinal birth cohort participated in this study. A survey design was employed and parents responded to the oral health questions when their child was between 18 and 60 months. RESULTS: Few parents (20%) were concerned about their child's oral health across the time period. By 60 months, only 20% of children had seen a dentist while 80% were brushing their teeth at least once daily. High levels of bottle use were seen up to 30 months. Consumption of sugary drinks was also very high in the early years, although this was replaced by water by 36 months. CONCLUSIONS: While there are some encouraging findings, such as the rates of tooth brushing and increasing rates of water consumption, the findings do highlight the poor uptake of dental services and high levels of bottle usage among urban aboriginal children during their early years. SO WHAT?: Targeted oral health promotional programs are needed in the urban Aboriginal community to better support parents understanding of good oral health practices in the early years and engagement with dental health services. PMID- 29700935 TI - A qualitative study of the role of playgroups in building community capacity. AB - ISSUE ADDRESSED: Given that approximately half of all Australian families with children aged 2-3 years participate in playgroups, these settings may provide an important venue for social support and community capacity building. The aim of this study is to assess the benefits that parents and the wider community derive from such participation. METHODS: We examined community capacity building opportunities through qualitative interviews conducted with a self-selected sample of 33 playgroup participants. All participants were the child's biological mother, and many had been involved in the playgroup committee of management, including 11 participants who were currently, or had previously been, a playgroup coordinator. RESULTS: We found that playgroups act as key sites for building community capacity through developing community connections, skill building and creating leadership pathways. We found that playgroup committee participation was often women's first foray into community volunteering, and often translated into future community leadership, such as kindergarten committees of management and primary school councils. CONCLUSIONS: Community playgroups play a key role in building the capacity of communities and provide a vehicle for the development of new volunteers. SO WHAT?: Local governments, schools and other community organisations that rely on volunteer committees would benefit from providing support to community playgroups to foster future community leaders. PMID- 29700936 TI - Online scan of FASD prevention and health promotion resources for Aboriginal and Torres Strait Islander communities. AB - ISSUE ADDRESSED: Foetal Alcohol Spectrum Disorder (FASD) includes a range of life long impairments caused by alcohol exposure in utero. Health professionals are vital to preventing FASD but many are hesitant to discuss FASD with clients due to their need for additional resources to aid the conversation. This scan sought to identify the scope and gaps in publicly available FASD prevention and health promotion resources, and assess their cultural appropriateness for use among five key groups of Indigenous Australian people including: (i) pregnant women, (ii) women of childbearing age, (iii) grandmothers and aunties, (iv) men, and (v) health professionals. METHODS: Relevant resources published 1995-2017 were identified through the Australian Indigenous HealthInfoNet, FASD organisation websites, grey literature, Google searches, and field experts. Results were screened by inclusion and cultural appropriateness criteria developed and piloted by the research team, and further screened by health professionals attending FASD training workshops. RESULTS: 115 of the 2146 identified resources were eligible. Relevant resources were found for all five key groups; however, no resources were specifically designed for men, grandmothers or aunties. CONCLUSIONS: A range of high-quality, culturally appropriate resources were identified, however, health professionals attending the training workshops were not aware of their availability. Further resource development is suggested for men, grandmothers and aunties. SO WHAT?: Prioritisation of active dissemination and implementation strategies is suggested to increase awareness and use of future resource developments. The inclusion of a resource trial among health professionals is a recommended strategy to increase awareness and use of newly developed resources. PMID- 29700937 TI - Is this health campaign really social marketing? A checklist to help you decide. AB - ISSUE ADDRESSED: Social marketing (SM) campaigns can be a powerful disease prevention and health promotion strategy but health-related campaigns may simply focus on the "promotions" communication activities and exclude other key characteristics of the SM approach. This paper describes the application of a checklist for identifying which lifestyle-related chronic disease prevention campaigns reported as SM actually represent key SM principles and practice. METHODS: A checklist of SM criteria was developed, reviewed and refined by SM and mass media campaign experts. Papers identified in searches for "social marketing" and "mass media" for obesity, diet and physical activity campaigns in the health literature were classified using the checklist. RESULTS: Using the checklist, 66.6% of papers identified in the "SM" search and 39% of papers identified from the "mass media" search were classified as SM campaigns. Inter-rater agreement for classification using the abstract only was 92.1%. CONCLUSIONS: Health-related campaigns that self-identify as "social marketing" or "mass media" may not include the key characteristics of a SM approach. Published literature can provide useful guidance for developing and evaluating health-related SM campaigns, but health promotion professionals need to be able to identify what actually comprises SM in practice. SO WHAT?: SM could be a valuable strategy in comprehensive health promotion interventions, but it is often difficult for non experts to identify published campaigns that represent a true SM approach. This paper describes the application of a checklist to assist policy makers and practitioners in appraising evidence from campaigns reflecting actual SM in practice. The checklist could also guide reporting on SM campaigns. PMID- 29700938 TI - Cooking for One or Two: Applying Participatory Action Research to improve community-dwelling older adults' health and well-being. AB - ISSUE ADDRESSED: This paper describes the process of the redevelopment and expansion of Cooking for One or Two, a community-based nutrition education program for older adults. METHODS: This project took place in a large regional city in NSW Australia from September 2011 to September 2013. Previous Cooking for One or Two participants and Hunter Medical Research Institute Research Register members were recruited for focus groups (n = 37), recipe testing (n = 19) and telephone interviews (n = 55) to aid in the development and expansion of the program. RESULTS: Participant's experiences and preferences informed the development of a supplementary cookbook and add-on education modules. Through a variety of methods, the research team sought ongoing feedback on the content and direction of the program. Content experts also reviewed the health promotion information for appropriateness. CONCLUSIONS: Utilising the Participatory Action Research process resulted in an expanded set of materials for Cooking for One or Two that can enable older people to engage in peer-to-peer education and to take care of their nutritional and social health. The process is a valuable example of the success of ongoing collaboration between researchers and program developers with the target population. SO WHAT?: While the research team developed evidence based content for the expanded program, the key to success was the continued engagement with the target population. This engagement fostered a sense of ownership over the program by participants and has led to continued support by the target population. PMID- 29700939 TI - Impact evaluation of "Have Fun - Be Healthy" program: A community based health promotion intervention to prevent childhood obesity. AB - ISSUE ADDRESSED: Childhood obesity is rising in prevalence in Australia. This study aimed to evaluate the impact of the "Have Fun-Be Healthy" (HFBH) intervention, delivered in the Playgroup setting, to generate short term changes in dietary, physical activity and sedentary behaviours of children under 5 years and self-efficacy of parents and primary carers. METHODS: This intervention consisted of eight structured cooking and physical play sessions delivered over a period of 8 weeks by trained facilitators. Pre- and post-intervention data collection was performed using survey questionnaires administered to parents and carers of children under 5 years from low socioeconomic backgrounds recruited through convenience sampling. RESULTS: A total of 640 pre-intervention surveys and 312 post-intervention surveys were returned. The matched response rate was 45.5%. There was an improvement in mean intake of healthy foods and mean physical activity with a decrease in mean intake of unhealthy food and mean screen time in children (P > .05). Following the intervention, parental/carer self-efficacy in promoting healthy eating and limiting screen time of children improved significantly (P < .05). Children's physical activity levels and consumption of healthy foods were positively correlated with parental/carer self-efficacy (P < .01) while screen time and consumption of unhealthy foods were negatively correlated (P < .01). CONCLUSIONS: HFBH intervention was successful in improving the dietary, physical activity and screen time in children and parental self efficacy. SO WHAT?: Being amongst the first of its' kind in Australia, the findings of this study can have implications for developing and implementing similar future health promotion interventions in comparable settings. PMID- 29700940 TI - Engaging a disadvantaged community with a fruit and vegetable box scheme. AB - ISSUE ADDRESSED: Interventions which target the determinants of unhealthy diets are required to promote healthy eating and reduce the burdens of diet-related diseases such as cardiovascular disease, diabetes and some cancers. METHODS: Qualitative interviews (n = 12) were conducted to explore the perspectives and experiences of local stakeholders regarding the implementation and uptake of a healthy eating initiative (a fruit and vegetable box scheme) in a disadvantaged, regional community. RESULTS: Factors affecting the community's engagement included marketing strategies, customer experiences, a community-centred approach, partnerships and logistics. CONCLUSIONS: Community engagement is often essential for an intervention to be effective. The factors which influence community engagement should be considered during planning, especially when targeting disadvantaged groups. SO WHAT?: Behavioural change interventions may continue to be met with limited success if community engagement and the overarching structural barriers to healthy eating are not addressed. PMID- 29700941 TI - Features of successful sexual health promotion programs for young people: findings from a review of systematic reviews. AB - ISSUE ADDRESSED: Young people have a high burden of sexual and reproductive health (SRH) problems, and it is important to reach this group through health promotion initiatives. We conducted a systematic review of reviews to identify successful elements of health promotion programs for improving SRH of young people. METHODS: We identified and collated systematic reviews published in 2005 2015 which focused on young people (10-24 years), reported on SRH outcomes (pregnancy, sexually transmissible infections, condoms/contraceptive use, risky sexual behaviour, sexual healthcare access or intimate partner violence), and included primary studies predominantly conducted in high-income countries. This report focuses on features of successful SRH programs identified in the interpretation and discussion of included systematic reviews. RESULTS: We identified 66 systematic reviews, of which 37 reported on program features which were anecdotally or statistically associated with improved program effectiveness and success. Common features of effective interventions were: longer term or repeated implementation; multi-setting and multi-component; parental involvement; culturally/gender/age appropriate; and inclusion of skills-building. SO WHAT?: There is marked consistency of features improving SRH program effectiveness for young people despite the wide variation in interventions reviewed. There is a need to better implement this knowledge in future programs, and our findings provide useful guidance for optimising the design of SRH interventions for young people. PMID- 29700942 TI - Not so different? Comparison of risk profile of gay men who acquired HIV while travelling with those who acquired HIV in Australia. AB - ISSUE ADDRESSED: Many countries now identify HIV and international mobility as a priority issue within a global and shared epidemic, including Australia. To support health promotion in this complex area, we investigated recent HIV infections that occurred among Australian gay men while travelling and compared to HIV infections that occurred in Australia. METHODS: 446 gay men recently diagnosed with HIV completed an on-line survey regarding the high risk event (HRE) where they believed that they acquired HIV. Those who acquired HIV while in their usual place of residence (308 men), those who were travelling within Australia (59 men), and those who were travelling overseas (79 men) were compared. RESULTS: Those who acquired HIV while overseas had very similar risk profiles, sexual behaviour, and made similar assumptions about their partners and their own HIV status, as those who acquired HIV in Australia. Only HIV status disclosure at the HRE differed across locations (P = .030). Three quarters (74.7%) of the men who acquired HIV while overseas were not diagnosed until they returned to Australia. CONCLUSIONS: Our findings challenge the idea that there are necessarily differences in behaviour and assumptions for HIV transmission in Australia and overseas. However, the men travelling may be in communities where HIV status is less commonly disclosed, and where HIV prevalence is higher. SO WHAT?: A deeper understanding of contextual factors may be required for HIV prevention and health promotion strategies targeting gay men travelling to locations with different cultural, HIV prevalence, and HIV testing considerations. This would also identify opportunities for new tools such as Pre Exposure Prophylaxis and self-testing. PMID- 29700943 TI - People's health and the social determinants of health. PMID- 29700944 TI - Exercise at an onsite facility with or without direct exercise supervision improves health-related physical fitness and exercise participation: An 8-week randomised controlled trial with 15-month follow-up. AB - ISSUE ADDRESSED: Physical activity and exercise participation is limited by a perceived lack of time, poor access to facilities and low motivation. The aim was to assess whether providing an exercise program to be completed at the workplace with or without direct supervision was effective for promoting health-related physical fitness and exercise participation. METHODS: Fifty university employees aged (Mean +/- SD) 42.5 +/- 11.1 years were prescribed a moderate- to vigorous intensity aerobic and resistance exercise program to be completed at an onsite facility for 8 weeks. Participants were randomly allocated to receive direct exercise supervision or not. Cardiorespiratory fitness (VO2max ) and maximal muscular strength were assessed at baseline and 8 weeks. Self-report physical activity was assessed at baseline, 8 weeks and 15 months post-intervention. RESULTS: Attendance or exercise session volume were not different between groups. Cardiorespiratory fitness (Mean +/- 95% CI); +1.9 +/- 0.7 mL.kg.min-1 ; P < .001), relative knee flexion (+7.4 +/- 3.5 Nm.kg-1 %; P < .001) and extension (+7.4 +/- 4.6 Nm.kg-1 %; P < .01) strength increased, irrespective of intervention group. Self-reported vigorous-intensity physical activity increased over the intervention (mean +/- 95% CI; +450 +/- 222 MET.minutes per week; P < .001), but did not remain elevated at 15 months (+192 +/- 276 MET.minutes per week). CONCLUSION: Providing a workplace exercise facility to complete an individually-prescribed 8-week exercise program is sufficient to improve health related physical fitness in the short-term independent to the level of supervision provided, but does not influence long-term participation. SO WHAT?: Lower cost onsite exercise facility supervision is as effective at improving physical health and fitness as directly supervised exercise, however ongoing support may be required for sustained physical activity behaviour change. PMID- 29700945 TI - Nutrition "fat facts" are not common knowledge. AB - ISSUE ADDRESSED: Individuals who are knowledgeable about nutrition are more likely to eat healthily. Yet, few studies have investigated levels of nutrition knowledge using a validated tool. The present study measured nutrition knowledge using the Re-examined General Nutrition Knowledge Questionnaire (R-GNKQ) to confirm influencing demographic characteristics. METHODS: Adults aged 18-60 years were recruited. Nutrition knowledge was assessed using the R-GNKQ, examining four domains (dietary guidelines, sources of nutrients, choosing everyday foods, and diet-disease relationships) with 96 questions. RESULTS: Of 606 respondents (mean age 38.8 +/- 11.8 years), 506 completed all questions. R-GNKQ score was positively associated with education (p<0.001) and age (p<0.001). Those with the highest education levels scored higher across 89% of the R-GNKQ and the oldest (>=50 years) respondents scored higher than younger respondents. Other characteristics that were associated with higher levels of knowledge were being female, and having a healthy BMI. Lowest knowledge pertained to questions about diet-disease relationships and fatty acids in foods. CONCLUSIONS: The majority of individuals had a good understanding about the Australian Dietary Guidelines, however the health benefits of adhering to the dietary guidelines was less well understood. Gaps in knowledge pertained to the specific details of how to adhere to the guidelines, particularly knowledge about the types of beneficial fats and their everyday food sources. SO WHAT?: Those with lower educational attainment, younger, males and those with higher BMI's would benefit from nutrition communications that identify foods with beneficial fatty acids to assist with adherence to the Australian Dietary Guidelines. PMID- 29700946 TI - The birthweight toll of mining pollution: evidence from the most contaminated mine site in the Andean region. AB - OBJECTIVE: To assess the effect of mining pollution on birthweight. DESIGN: A retrospective before-and-after study with an untreated comparison group. SETTING: La Oroya, a mining town in the Peruvian Andes, considered the most contaminated town in the Andean region. POPULATION: All pregnant women who delivered in the social security healthcare system in years 2005, 2006, 2008 and 2009. A total of 214 983 births records were used, 957 from La Oroya and 214 026 from the rest of the country. METHODS: A difference-in-difference estimation is used to assess the effect of mining pollution on birthweight before and after two business policy changes: a partial environmental improvement and a subsequent closure of smelter operations in La Oroya. Birthweight was compared with a group not affected by the environmental changes in La Oroya. MAIN OUTCOME MEASURES: Birthweight in grams. RESULTS: A steep reduction in mining pollution due to the closure of smelter operations in La Oroya showed an increased birthweight of 71.6 g after controlling for socio-economic and medical characteristics. None of the environmental improvements prior to the closure had a statistically significant effect on birthweight. CONCLUSIONS: Mining pollution in La Oroya had a negative impact on birthweight. Partial environmental improvements were not enough to improve birthweight. Only after the closure of all mining and smelter operations in La Oroya was a significant gain in birthweight shown. TWEETABLE ABSTRACT: The closure of the most contaminated mine site in the Andean region increased birthweight by 72 g. PMID- 29700947 TI - Fetal RHD genotyping is a cost-effective option for supporting targeted anti-D prophylaxis in D-negative pregnancies. PMID- 29700948 TI - Fixed-dose combinations: A valuable tool to improve adherence to antihypertensive treatment. PMID- 29700949 TI - Optimal planning of phase II/III programs for clinical trials with multiple endpoints. AB - Owing to increased costs and competition pressure, drug development becomes more and more challenging. Therefore, there is a strong need for improving efficiency of clinical research by developing and applying methods for quantitative decision making. In this context, the integrated planning for phase II/III programs plays an important role as numerous quantities can be varied that are crucial for cost, benefit, and program success. Recently, a utility-based framework has been proposed for an optimal planning of phase II/III programs that puts the choice of decision boundaries and phase II sample sizes on a quantitative basis. However, this method is restricted to studies with a single time-to-event endpoint. We generalize this procedure to the setting of clinical trials with multiple endpoints and (asymptotically) normally distributed test statistics. Optimal phase II sample sizes and go/no-go decision rules are provided for both the "all or-none" and "at-least-one" win criteria. Application of the proposed method is illustrated by drug development programs in the fields of Alzheimer disease and oncology. PMID- 29700950 TI - Predictors for unsuccessful pessary fitting in women with symptomatic pelvic organ prolapse: a prospective study. AB - OBJECTIVE: To evaluate the success rate of vaginal pessary fitting and identify the risk factors associated with unsuccessful pessary fitting in a large cohort of patients with symptomatic pelvic organ prolapse (POP). DESIGN: Prospective observational study. SETTING: The Department of Obstetrics and Gynaecology, Peking Union Medical College Hospital, Beijing, China. POPULATION: Women with symptomatic POP between May 2015 and December 2016 (n = 343). METHODS: A successful pessary fitting was defined as a patient fitted with a pessary at the initial fitting and continued use 2 weeks later. The independent samples t-test, non-parametric test, Chi-square test, Fisher's exact test, logistic regression and receiver operating characteristic curves were used for the data analysis. MAIN OUTCOME MEASURES: The success rate of vaginal pessary fitting and the risk factors associated with unsuccessful pessary fitting. RESULTS: 302 patients had successful pessary fitting (88.0% success rate). A higher body mass index [BMI; 24.7 +/- 3.1 kg/m2 in the successful group versus 25.7 +/- 3.8 kg/m2 in the unsuccessful group, odds ratio (OR) 1.174, 95% CI 1.055-1.307, P = 0.003] and a shorter TVL [8.0 (8-9) cm in the successful group versus 7.0 (6.8-8) cm in the unsuccessful group, OR 0.338, 95% CI 0.223-0.513, P < 0.001) were independent predictors of an unsuccessful pessary fitting. The receiver operating characteristic curve showed that patients with a total vaginal length (TVL) less than 7.3 cm had a higher unsuccessful pessary fitting rate (sensitivity = 0.82, specificity = 0.64). CONCLUSIONS: A higher BMI and shorter TVL were independent predictors of an unsuccessful pessary fitting. Patients with a TVL <7.3 cm are not appropriate candidates for a vaginal pessary. TWEETABLE ABSTRACT: A higher BMI and shorter TVL (<7.3 cm) were independent predictors of an unsuccessful pessary fitting. PMID- 29700951 TI - Recommended treatment protocols to improve management of hypertension globally: A statement by Resolve to Save Lives and the World Hypertension League (WHL). PMID- 29700952 TI - Recurrent subconjunctival haemorrhage in Achenbach's syndrome. PMID- 29700953 TI - New guidelines for hypertension in children and adolescents. PMID- 29700955 TI - Relationship between sodium, pentraxin-3 and aldosterone in inflammation and cardiovascular risk. PMID- 29700954 TI - Influence of respiratory motion management technique on radiation pneumonitis risk with robotic stereotactic body radiation therapy. AB - PURPOSE/OBJECTIVES: For lung stereotactic body radiation therapy (SBRT), real time tumor tracking (RTT) allows for less radiation to normal lung compared to the internal target volume (ITV) method of respiratory motion management. To quantify the advantage of RTT, we examined the difference in radiation pneumonitis risk between these two techniques using a normal tissue complication probability (NTCP) model. MATERIALS/METHOD: 20 lung SBRT treatment plans using RTT were replanned with the ITV method using respiratory motion information from a 4D-CT image acquired at the original simulation. Risk of symptomatic radiation pneumonitis was calculated for both plans using a previously derived NTCP model. Features available before treatment planning that identified significant increase in NTCP with ITV versus RTT plans were identified. RESULTS: Prescription dose to the planning target volume (PTV) ranged from 22 to 60 Gy in 1-5 fractions. The median tumor diameter was 3.5 cm (range 2.1-5.5 cm) with a median volume of 14.5 mL (range 3.6-59.9 mL). The median increase in PTV volume from RTT to ITV plans was 17.1 mL (range 3.5-72.4 mL), and the median increase in PTV/lung volume ratio was 0.46% (range 0.13-1.98%). Mean lung dose and percentage dose-volumes were significantly higher in ITV plans at all levels tested. The median NTCP was 5.1% for RTT plans and 8.9% for ITV plans, with a median difference of 1.9% (range 0.4 25.5%, pairwise P < 0.001). Increases in NTCP between plans were best predicted by increases in PTV volume and PTV/lung volume ratio. CONCLUSIONS: The use of RTT decreased the risk of radiation pneumonitis in all plans. However, for most patients the risk reduction was minimal. Differences in plan PTV volume and PTV/lung volume ratio may identify patients who would benefit from RTT technique before completing treatment planning. PMID- 29700956 TI - Mechanochemistry in [6]Cycloparaphenylene: A Combined Raman Spectroscopy and Density Functional Theory Study. AB - Raman spectroscopy under high pressures up to 10 GPa and density functional computations up to 30 GPa are combined to obtain insights into the behavior of a prototypical nanohoop conjugated molecule, [6]cycloparaphenylene ([6]CPP). Upon increasing pressure, the nanohoop undergoes deformations, first reversible ovalization and then at even higher pressures aggregates are formed. This irreversible aggregation is caused by the formation of new intermolecular sigma bonds. Frequencies and derivatives of the Raman frequency shifts as a function of pressure are well reproduced by the computations. The frequency behavior is tied to changes in aromatic/quinonoid character of the nanohoop. The modeling at moderate high pressures reveals the deformation of the [6]CPP molecules into oval like and peanut-like shapes. Surprisingly the pressure derivatives of the observed Raman mode shifts undergo a sudden change around a pressure value that is common to all Raman modes, indicating an underlying geometrical change extended over the whole molecule that is interpreted by the computational modeling. Simulations predict that under even larger deformations caused by higher pressures, oligomerization reactions would be triggered. Our simulations demonstrate that these transformations would occur regardless of the solvent, however pressures at which they happen are influenced by solvent molecules encapsulated in the interior of the [6]CPP. PMID- 29700957 TI - Pilocarpine test may predict success of argon laser peripheral iridoplasty. PMID- 29700958 TI - Endpoints, reliability, and meaningful changes in clinical trials for children with irritable bowel syndrome. The Rome foundation pediatric subcommittee on clinical trials. PMID- 29700959 TI - Statistical considerations about the design and endpoints of randomized clinical trials for children with irritable bowel syndrome. PMID- 29700960 TI - Efficacy of linaclotide in irritable bowel syndrome with constipation: Real-world data. PMID- 29700961 TI - When all seems lost: management of refractory constipation-Surgery, rectal irrigation, percutaneous endoscopic colostomy, and more. AB - While the pharmacological armamentarium for chronic constipation has expanded over the past few years, a substantial proportion of constipated patients do not respond to these medications. This review summarizes the pharmacological and behavioral options for managing constipation and details the management of refractory constipation. Refractory constipation is defined as an inadequate improvement in constipation symptoms evaluated with an objective scale despite adequate therapy (ie, pharmacological and/or behavioral) that is based on the underlying pathophysiology of constipation. Minimally invasive (ie, rectal irrigation and percutaneous endoscopic colostomy) and surgical therapies are used to manage refractory constipation. This review appraises these options, and in particular, percutaneous endoscopic colostomy, which as detailed by an article in this issue, is a less invasive option for managing refractory constipation than surgery. While these options benefit some patients, the evidence of the risk: benefit profile for these therapies is limited. PMID- 29700962 TI - Randomized, double-blind, placebo-controlled study vs data in the daily practice using linaclotide in patients with irritable bowel syndrome with constipation. PMID- 29700963 TI - Reduction in pain: Is it worth the gain? The effect of opioids on the GI tract. AB - The use of opioid medications for acute and chronic pain has increased significantly in the past 20 years in the United States. Given the high density of opioid receptors in the gastrointestinal tract, side effects are common in these patients including constipation, dysphagia, bloating, nausea, and vomiting. These side effects, which are experienced by most patients who take opioids, can lead to significant impairment in quality of life. Unlike other side effects from opioids, gastrointestinal side effects do not diminish with continued use, often leading patients to reduce or discontinue their opioid treatment to relieve these side effects. Therefore, physicians must be aware and anticipate potential side effects in patients receiving opioids to ensure appropriate pain management. PMID- 29700964 TI - Refractive regression after laser in situ keratomileusis. AB - Uncorrected refractive errors are a leading cause of visual impairment across the world. In today's society, laser in situ keratomileusis (LASIK) has become the most commonly performed surgical procedure to correct refractive errors. However, regression of the initially achieved refractive correction has been a widely observed phenomenon following LASIK since its inception more than two decades ago. Despite technological advances in laser refractive surgery and various proposed management strategies, post-LASIK regression is still frequently observed and has significant implications for the long-term visual performance and quality of life of patients. This review explores the mechanism of refractive regression after both myopic and hyperopic LASIK, predisposing risk factors and its clinical course. In addition, current preventative strategies and therapies are also reviewed. PMID- 29700965 TI - BOIN-ET: Bayesian optimal interval design for dose finding based on both efficacy and toxicity outcomes. AB - One of the main purposes of a phase I dose-finding trial in oncology is to identify an optimal dose (OD) that is both tolerable and has an indication of therapeutic benefit for subjects in subsequent phase II and III trials. Many phase I dose-finding methods based solely on toxicity considerations have been proposed under the assumption that both toxicity and efficacy monotonically increase with the dose level. Such an assumption may not be necessarily the case, however, when evaluating the OD for molecular targeted, cytostatic, and biological agents, as well as immune-oncology therapy. To address this issue, we extend the Bayesian optimal interval (BOIN) design, which is nonparametric and thus does not require the assumption used in model-based designs, in order to identify an OD based on both efficacy and toxicity outcomes. The new design is named "BOIN-ET." A simulation study is presented that includes a comparison of this proposed method to the model-based approaches in terms of both efficacy and toxicity responses. The simulation shows that BOIN-ET has advantages in both the percentages of correct ODs selected and the average number of patients allocated to the ODs across a variety of realistic settings. PMID- 29700966 TI - Application of the microbial community coalescence concept to riverine networks. AB - Flows of water, soil, litter, and anthropogenic materials in and around rivers lead to the mixing of their resident microbial communities and subsequently to a resultant community distinct from its precursors. Consideration of these events through a new conceptual lens, namely, community coalescence, could provide a means of integrating physical, environmental, and ecological mechanisms to predict microbial community assembly patterns better in these habitats. Here, we review field studies of microbial communities in riverine habitats where environmental mixing regularly occurs, interpret some of these studies within the community coalescence framework and posit novel hypotheses and insights that may be gained in riverine microbial ecology through the application of this concept. Particularly in the face of a changing climate and rivers under increasing anthropogenic pressures, knowledge about the factors governing microbial community assembly is essential to forecast and/or respond to changes in ecosystem function. Additionally, there is the potential for microbial ecology studies in rivers to become a driver of theory development: riverine systems are ideal for coalescence studies because regular and predictable environmental mixing occurs. Data appropriate for testing community coalescence theory could be collected with minimal alteration to existing study designs. PMID- 29700967 TI - Retrospective cohort study on Korean adolescents' sleep, depression, school adjustment, and life satisfaction. AB - Sleep patterns have an important role in the physical and psychological health of adolescents. In this study, we investigated the effects of sleep duration on depression, school adjustment, and life satisfaction of adolescents. A retrospective cohort study was conducted using secondary data on first and second grade students in middle schools from the Korean Children and Youth Panel Survey. Those who responded to all items about sleep were selected, and those who were within 30 min of sleep duration difference across 1 year were selected. Participants who had no change in variables of personal factors, parental factors, and family environment across 1 year were selected (n = 421). Longer total sleep duration and shorter weekend oversleeping had effects on lower depression, higher school adjustment, and greater life satisfaction after adjusting for personal factors, parental factors, and family environment. Therefore, we propose that school nurses assess adolescents' sleep patterns and counsel and educate adolescents and their parents about the influence of sleep patterns on adolescents. PMID- 29700968 TI - Carrier Transport and Photoresponse in GeSe/MoS2 Heterojunction p-n Diodes. AB - Simple stacking of thin van der Waals 2D materials with different physical properties enables one to create heterojunctions (HJs) with novel functionalities and new potential applications. Here, a 2D material p-n HJ of GeSe/MoS2 is fabricated and its vertical and horizontal carrier transport and photoresponse properties are studied. Substantial rectification with a very high contrast (>104 ) through the potential barrier in the vertical-direction tunneling of HJs is observed. The negative differential transconductance with high peak-to-valley ratio (>105 ) due to the series resistance change of GeSe, MoS2 , and HJs at different gate voltages is observed. Moreover, strong and broad-band photoresponse via the photoconductive effect are also demonstrated. The explored multifunctional properties of the GeSe/MoS2 HJs are expected to be important for understanding the carrier transport and photoresponse of 2D-material HJs for achieving their use in various new applications in the electronics and optoelectronics fields. PMID- 29700969 TI - Challenges in ileus research. PMID- 29700970 TI - Executive functioning and central coherence in anorexia nervosa: Pilot investigation of a neurocognitive endophenotype. AB - A neurocognitive profile characterized by problems in set shifting, executive functioning, and central coherence may pre-date and maintain anorexia nervosa (AN). To test this pattern as a possible endophenotype for AN, 10 youth with current AN, 14 healthy youth, and their biological parents, participated in a neuropsychological battery. Youth with AN demonstrated significantly weaker central coherence, related to enhanced detail-focused processing. Youth with AN and their parents demonstrated significantly greater psychopathology relative to controls, and youth-parent scores were significantly correlated. The study, limited by a small sample size, found little evidence supporting a neuropsychological endophenotype for AN. Identifying a neurocognitive profile for children and adolescents with AN has important implications for the treatment of young patients. PMID- 29700971 TI - Can a disaster affect rheumatoid arthritis status? A retrospective cohort study after the 2011 triple disaster in Fukushima, Japan. AB - OBJECTIVE: As status of rheumatoid arthritis (RA) is highly affected by environmental factors, a catastrophic disaster may also affect RA activity. Herein we conducted a retrospective cohort study in the disaster area of the 2011 triple disaster in Fukushima, Japan: an earthquake, tsunamis and a nuclear accident. METHODS: Clinical records of RA patients who attended a hospital near the Fukushima Daiichi Nuclear Power Plant were collected. For those who underwent whole-body counter testing, internal radiation exposure levels were also collected. As clinical parameters may fluctuate in the absence of a disaster, changes in values before and after the disaster were also compared. Logistic regression was conducted to identify factors affecting RA status. RESULTS: Fifty three patients (average age, 64.2 years; females, 83%; average disease duration, 15.7 years) were included in the study. Five patients lived within the no-entry zone, 37 evacuated immediately after the disaster, and four temporarily stopped RA treatment. The proportions of patients who showed worsened tender joint counts, swollen joint counts and rheumatoid factor values were significantly higher after the disaster compared to those before. Among the 16 patients who underwent whole-body counter testing, only one showed a detectable, but negligible, radioactive cesium level. Use of methotrexate was identified as a possible preventive factor for RA exacerbation in this setting. CONCLUSION: This is the first study to analyze detailed profiles of RA patients after a disaster. As methotrexate may prevent disease exacerbation, continuity of care for this common chronic disease should be considered in disaster settings. PMID- 29700973 TI - Photoelectrochemical Performance for Water Oxidation Improved by Molecular Nickel Porphyrin-Integrated WO3 /TiO2 Photoanode. AB - A WO3 /TiO2 heterojunction photoanode was prepared by in situ growth of WO3 on a mesoporous TiO2 electrode. The photoinduced charge-transfer properties and chargeseparation improvement in this kind of type-II heterojunction were characterized by transient surface photovoltage spectra. By using sulfite oxidation as a hole scavenger, we demonstrated that 72 % of the photo-generated holes are reaching the surface of the photoanode, but the efficiency of hole injection (etaox ) into the electrolyte was only 48 %. For the first time, a NiII meso-tetra(4-carboxyphenyl)porphyrin (NiTCPP) was incorporated as a water oxidation catalyst into the WO3 /TiO2 heterojunction photoanode, which promoted the value of etaox to 81 %. The maximum applied bias photon-to-current efficiency for the WO3 /TiO2 /NiTCPP photoanode was determined to be 0.2 % at 1.01 V vs. the reversible hydrogen electrode (RHE), under which condition a Faradic efficiency of 89 % for water oxidation was achieved (averaged over 1 h of photolysis). PMID- 29700972 TI - A panel consisting of three novel circulating lncRNAs, is it a predictive tool for gastric cancer? AB - Early detection is vital for prolonging 5-year survival for patients with gastric cancer (GC). Numerous studies indicate that circulating long non-coding RNAs (lncRNAs) can be used to diagnose malignant tumours. This study aimed to investigate the capacity of novel lncRNAs for diagnosing GC. A lncRNA microarray assay was used to screen differentially expressed lncRNAs between plasma of patients with GC and healthy controls. Plasma samples from 100 patients with healthy controls were used to construct a multiple-gene panel. An additional 50 pairs of GC patients with healthy controls were used to evaluate the diagnostic accuracy of the panel. Expression levels of lncRNAs were quantified through real time polymerase chain reaction. The receiver operating characteristic curve and area under curve (AUC) were used to estimate the diagnostic capacity. We identified three lncRNAs, CTC-501O10.1, AC100830.4 and RP11-210K20.5 that were up regulated in the plasma of GC patients with AUCs 0.724, 0.730 and 0.737, respectively (P < .01). Based on the logistic regression model, the combined AUC of the three lncRNAs was 0.764. The AUC of the panel was 0.700 in the validation cohort. These findings indicate that plasma lncRNAs can serve as potential biomarkers for detection of GC. PMID- 29700974 TI - Interpolation to define clinical tumor stage in prostate cancer using clinical description of digital rectal examination. AB - AIM: This study aims to assess characteristics of patients with prostate cancer for whom clinical T stage category (cT) was not documented in the medical record and assess whether specialists had concordant conclusions regarding cT based on digital rectal examination (DRE) notes. METHODS: Data from the Prostate Cancer Outcome Registry - Victoria (PCOR-Vic) were interrogated. Four specialists independently assigned cT to DRE notes. Words, or part thereof, associated with agreement between clinicians were identified. RESULTS: Of the 10 587 men, cT was documented in 8758 (82.7%) cases. Multivariate analysis indicated that poor cT documentation was associated with older patient age (odds ratio [OR] 0.80, 95% confidence interval [CI] 0.66-0.99 if 75.1-85 years; OR 0.50, 95%CI 0.36-0.72 if >85 years); diagnosis via transperineal compared to transrectal ultrasound-guided biopsy (TRUS) (OR 0.68, 95%CI 0.51-0.91); diagnosed in a private hospital (OR 0.85, 95%CI 0.75-0.96); and a diagnostic Gleason score of >8 compared to <=6 (OR 0.59, 95%CI = 0.48-0.73). cT was more likely documented in men diagnosed via transurethral resection of prostate (OR 2.06, 95%CI 1.64-2.58) compared to TRUS and/or if receiving treatment in a radiotherapy center (OR 3.44, 95%CI 2.80-4.23 for external beam radiotherapy; OR 3.57 95%CI 2.44-5.23 for brachytherapy and OR 1.34, 95%CI 1.06-1.69 for combination surgery and radiotherapy) compared to those undergoing radical prostatectomy. Agreement in cT assignment ranged from kappa of 0.158 to 0.582. Stem word components in DRE notes associated with poorest level of agreement were "abnorm," "hard," "nodul" and those with highest level of agreement were terms "benign" and "smooth." CONCLUSIONS: Mode of diagnosis/subsequent treatment, and cancer characteristics were associated with cT documentation. Third party interpretation of clinical notes is problematic. PMID- 29700975 TI - Use of homeobox gene expression patterns to determine anatomical regions of origin for body surface tissues derived from adult mice. AB - Anatomical regions of the skin have distinct functions and anatomical characteristics, including thicker or thinner epidermis, more or fewer hair follicles, and lighter or darker skin. For a better therapeutic outcome of skin transplantation, site-specific characteristics of grafted tissues need to be taken into account in terms of their functionality and beauty. However, there is no method for evaluating positional information of epidermal cells. Homeobox genes are expressed along the anterior-posterior axis and direct the body plan in the animal development process. Although the expression of several HOX genes is known to be retained as the positional information in adult tissue, their expression patterns in the body surface tissues in adult mammals are still incompletely understood. In this study, we investigated the expression patterns of 40 homeobox genes, including 39 Hox genes and the paired box 6 (Pax6) gene, in body surface tissues of adult mice. On the basis of the results obtained, we proposed, for the first time, a method for determining anatomical regions of origin for body surface tissues derived from adult mice using Hox genes and Pax6. Evaluation of expression levels of at least 7 Hox genes and Pax6 should be sufficient to distinguish 11 anatomical body surface tissues derived from the adult mouse body. The proposed method may be useful not only for determining the origin of surface tissues from specific anatomical regions of the mammalian body but also for predicting positional information of epithelial cells generated from pluripotent stem cells. PMID- 29700977 TI - Polymer Nanosheet Containing Star-Like Copolymers: A Novel Scalable Controlled Release System. AB - Poly(epsilon-caprolactone) (PCL)-based nanomaterials, such as nanoparticles and liposomes, have exhibited great potential as controlled release systems, but the difficulties in large-scale fabrication limit their practical applications. Among the various methods being developed to fabricate polymer nanosheets (PNSs) for different applications, such as Langmuir-Blodgett technique and layer-by-layer assembly, are very effort consuming, and only a few PNSs can be obtained. In this paper, poly(epsilon-caprolactone)-based PNSs with adjustable thickness are obtained in large quantity by simple water exposure of multilayer polymer films, which are fabricated via a layer multiplying coextrusion method. The PNS is also demonstrated as a novel controlled guest release system, in which release kinetics are adjustable by the nanosheet thickness, pH values of the media, and the presence of protecting layers. Theoretical simulations, including Korsmeyer Peppas model and Finite-element analysis, are also employed to discern the observed guest-release mechanisms. PMID- 29700976 TI - Relationship between Salmonella infection, shedding and serology in fattening pigs in low-moderate prevalence areas. AB - Salmonella is a major foodborne pathogen causing important zoonosis worldwide. Pigs asymptomatically infected in mesenteric lymph nodes (MLN) can be intermittent shedders of the pathogen through faeces, being considered a major source of human infections. European baseline studies of fattening pig salmonellosis are based on Salmonella detection in MLN. This work studies the relationship between Salmonella infection in MLN and intestinal content (IC) shedding at slaughter and the relationship between the presence of the pathogen and the serologic status at farm level. Mean Salmonella prevalence in the selected pigs (vertically integrated production system of Navarra, Spain) was 7.2% in MLN, 8.4% in IC and 9.6% in serum samples. In this low-moderate prevalence context, poor concordance was found between MLN infection and shedding at slaughter and between bacteriology and serology. In fact, most of shedders were found uninfected in MLN (83%) or carrying different Salmonella strains in MLN and in IC (90%). The most prevalent Salmonellae were Typhimurium resistant to ACSSuT +/- Nx or ASSuT antibiotic families, more frequently found invading the MLN (70%) than in IC (33.9%). Multivariable analysis revealed that risk factors associated with the presence of Salmonella in MLN or in IC were different, mainly related either to good hygiene practices or to water and feed control, respectively. Overall, in this prevalence context, detection of Salmonella in MLN is an unreliable predictor of faecal shedding at abattoir, indicating that subclinical infections in fattening pigs MLN could have limited relevance in the IC shedding. PMID- 29700978 TI - Enhanced hepatic differentiation of human amniotic epithelial cells on polyethylene glycol-linked multiwalled carbon nanotube-coated hydrogels. AB - Polyethylene glycol-linked multiwalled carbon nanotube-coated poly-acrylamide hydrogel (CNT-PA) was customized to mimic human liver stiffness and nanostructured surface in liver cells for modulating differentiation of human amniotic epithelial cells (hAECs) into functional hepatocyte-like cells (HLCs) in vitro. This composite of CNT-PA matrix enhanced the hepatic differentiation of hAECs into HLCs with suppression of pluripotent markers and up-regulation of hepatic markers at both transcript and protein levels. Furthermore, the HLCs on CNT-PA demonstrated hepatocytic functions in terms of albumin secretion, higher uptake of indocyanine green, and comparable CYP3A4 enzymatic function and inducibility when matched against HepG2 cells. Taken together, CNT-PA provides an efficient and scalable platform for the expansion of HLCs from hAECs and could be explored further for downstream development. PMID- 29700979 TI - Synthesis of Lead-free CsGeI3 Perovskite Colloidal Nanocrystals and Electron Beam induced Transformations. AB - Colloidal nanocrystals (NCs) of metal halide perovskite have recently aroused great research interest, due to their remarkable optical and electronic properties. We report a solution synthesis of a new member in this category, that is, all-inorganic lead-free cesium germanium iodine (CsGeI3 ) perovskite NCs. These CsGeI3 colloidal NCs are confirmed to adopt a rhombohedral structure. Moreover, the electron beam-induced transformations of these lead-free perovskite NCs have been investigated for the first time. The fracture of single-crystalline CsGeI3 nanocubes occurs first, followed by the emergence and growth of cesium iodine (CsI) single crystals and the final fragmentation into small debris with random orientations. Notably, the electron-reduced Ge species in CsGeI3 nanocubes exhibit a distinctive transformation path, compared to heavier Pb atoms in lead halide perovskite NCs. PMID- 29700980 TI - High Efficiency Light-Emitting Transistor with Vertical Metal-Oxide Heterostructure. AB - The monolithic integration of light-emission with a standard logic transistor is a much-desired multifunctionality. Here, a high-efficiency light-emitting transistor (LET) employing an inorganic quantum dots (QDs) emitter and a laser annealed vertical metal-oxide heterostructure is reported. The experimental results show that the peak efficiency and luminance of this QDs LET (QLET) are 11% and 8000 cdm-2 , respectively at a monochromatic emitting light wavelength of 585 nm. As far as it is known, these are among the highest values ever achieved for LETs. More importantly, the QLET exhibits an ultrahigh electron mobility of up to 25 cm2 V-1 S-1 , a lower efficiency roll-off (7% at high 3000 cdm-2 ), and excellent stability with long-duration gate stress switching cycles. Additionally, this approach is compatible with those used in conventional large area silicon electronic manufacturing and can enable a scalable and cost effective procedure for future integrated versatile displays and lighting applications. PMID- 29700982 TI - FaptaSyme: A Strategy for Converting a Monomer/Oligomer-Nonselective Aptameric Sensor into an Oligomer-Selective One. AB - Aptameric sensors can bind molecular targets and produce output signals, a phenomenon that is used in bioassays. In some cases, it is important to distinguish between monomeric and oligomeric forms of a target. Here, we propose a strategy to convert a monomer/oligomer-nonselective sensor into an oligomer selective sensor. We designed an aptazyme that produced a high fluorescent output in the presence of oligomeric alpha-synuclein (a molecular marker of Parkinson's disease) but not its monomeric form. The strategy is potentially useful in the design of point-of-care tests for the diagnosis of neurodegenerative diseases. PMID- 29700981 TI - Telocytes and interstitial cells of Cajal in the biliary system. AB - A novel type of interstitial tissue cells in the biliary tree termed telocytes (TCs), formerly known as interstitial Cajal-like cells (ICLCs), exhibits very particular features which unequivocally distinguish these cells from interstitial cells of Cajal (ICCs) and other interstitial cell types. Current research substantiates the existence of TCs and ICCs in the biliary system (gallbladder, extrahepatic bile duct, cystic duct, common bile duct and sphincter of Oddi). Here, we review the distribution, morphology and ultrastructure of TCs and ICCs in the biliary tree, with emphasis on their presumptive roles in physiological and pathophysiological processes. PMID- 29700983 TI - Perivascular scaffolds loaded with adipose tissue-derived stromal cells attenuate development and progression of abdominal aortic aneurysm in rats. AB - Abdominal aortic aneurysm (AAA) is the pathological dilation and weakening of the abdominal aorta wall. Inflammation, degradation of the extracellular matrix (ECM) and loss of smooth muscle cells and skewing of their function are pivotal in AAA pathology. We developed a recombinant collagen-based patch (RCP) to provide structural integrity and deliver Adipose tissue-Derived Stromal Cells (ASC) for repair. Patches supported adhesion and function as well as proliferation of ASC. ASC-loaded RCPs or bare patches, applied around the aorta after AAA induction in rats, both maintained structural integrity of the aortic wall at time of explant (2w). However, wall thinning, accompanied by loss of elastin fibers and loss of medial SMC, was only attenuated in ASC-loaded RCP-treated AAA rats. Interestingly, this coincided with migration of ASC into the media and a reduced influx of macrophages. We hypothesize that the medially-migrated ASC dampened or skewed the adverse innate immunity and thus suppressed SMC apoptosis, phenotypic skewing and elastin degradation. We conclude that the periadventitial delivery of ASC with RCP suppresses development and progression of AAA, which is has an expected future clinical benefit in combination with an appropriate early screening program of patients at risk for aneurysms. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2494-2506, 2018. PMID- 29700984 TI - Hemocompatible and Bioactive Heparin-Loaded PCL-alpha-TCP Fibrous Membranes for Bone Tissue Engineering. AB - The combination of bioactive components such as calcium phosphates and fibrous structures are encouraging niche-mimetic keys for restoring bone defects. However, the importance of hemocompatibility of the membranes is widely ignored. Heparin-loaded nanocomposite poly(epsilon-caprolactone) (PCL)-alpha-tricalcium phosphate (alpha-TCP) fibrous membranes are developed to provide bioactive and hemocompatible constructs for bone tissue engineering. Nanocomposite membranes are optimized based on bioactivity, mechanical properties, and cell interaction. Consequently, various concentrations of heparin molecules are loaded within nanocomposite fibrous membranes. In vitro heparin release profiles reveal a sustained release of heparin over the period of 14 days without an initial burst. Moreover, heparin encapsulation enhances mesenchymal stem cell (MSC) attachment and proliferation, depending on the heparin content. It is concluded that the incorporation of heparin within TCP-PCL fibrous membranes provides the most effective cellular interactions through synergistic physical and chemical cues. PMID- 29700985 TI - The earliest Timematids in Burmese amber reveal diverse tarsal pads of stick insects in the mid-Cretaceous. AB - Many extant insects have developed pad structures, euplantulae or arolia on their tarsi to increase friction or enhance adhesion for better mobility. Many polyneopteran insects with euplantulae, for example, Grylloblattodea, Mantophasmatodea and Orthoptera, have been described from the Mesozoic. However, the origin and evolution of stick insects' euplantulae are poorly understood due to rare fossil records. Here, we report the earliest fossil records of Timematodea hitherto, Tumefactipes prolongates gen. et sp. nov. and Granosicorpes lirates gen. et sp. nov., based on three specimens from mid-Cretaceous Burmese amber. Specimens of Tumefactipes prolongates gen. et sp. nov. have extremely specialized and expanded euplantulae on their tarsomere II. These new findings are the first known and the earliest fossil records about euplantula structure within Phasmatodea, demonstrating the diversity of euplantulae in Polyneoptera during the Mesozoic. Such tarsal pads might have increased friction and helped these mid-Cretaceous stick insects to climb more firmly on various surfaces, such as broad leaves, wetted tree branches or ground. These specimens provide more morphological data for us to understand the relationships of Timematodea, Euphasmatodea, Orthoptera and Embioptera, suggesting that Timematodea might be monophyletic with Euphasmatodea rather than Embioptera and Phasmatodea should have a closer relationship with Orthoptera rather than Embioptera. PMID- 29700986 TI - Hydrophobic Patterning-Based 3D Microfluidic Cell Culture Assay. AB - Engineering physiologically relevant in vitro models of human organs remains a fundamental challenge. Despite significant strides made within the field, many promising organ-on-a-chip models fall short in recapitulating cellular interactions with neighboring cell types, surrounding extracellular matrix (ECM), and exposure to soluble cues due, in part, to the formation of artificial structures that obstruct >50% of the surface area of the ECM. Here, a 3D cell culture platform based upon hydrophobic patterning of hydrogels that is capable of precisely generating a 3D ECM within a microfluidic channel with an interaction area >95% is reported. In this study, for demonstrative purposes, type I collagen (COL1), Matrigel (MAT), COL1/MAT mixture, hyaluronic acid, and cell-laden MAT are formed in the device. Three potential applications are demonstrated, including creating a 3D endothelium model, studying the interstitial migration of cancer cells, and analyzing stem cell differentiation in a 3D environment. The hydrophobic patterned-based 3D cell culture device provides the ease-of-fabrication and flexibility necessary for broad potential applications in organ-on-a-chip platforms. PMID- 29700987 TI - Protein molecular modeling techniques investigating novel TAB2 variant R347X causing cardiomyopathy and congenital heart defects in multigenerational family. AB - BACKGROUND: Haploinsufficiency of TAB2 is known to cause congenital heart defects and cardiomyopathy due to its important roles in cardiovascular tissue, both during development and through adult life. We report a sibling pair displaying adult-onset cardiomyopathy, hypermobility, and mild myopia. Our proband, a 39 year-old male, presents only with the above symptoms, while his 36-year-old sister was also notable for a ventricular septal defect in her infancy. METHODS: Whole-exome sequencing was utilized to identify the molecular basis of the phenotype found in two siblings. A molecular modeling technique that takes advantage of conformational sampling advances (Maxwell's demon molecular dynamics and Monte Carlo) were used to make a model of the mutant variant for comparative analytics to the wild-type. RESULTS: Exome sequencing revealed a novel, heterogeneous pathogenic variant in TAB2, c.1039 C>T (p.R347X), that was present in both individuals. This pathogenic variant removes just over half the residues from the TAB2 protein and severely impacts its functional ability, which we describe in detail. CONCLUSIONS: Analysis of the proband's family showed a history of cardiomyopathy, but no congenital heart defects or connective tissue disease. We highlight the heterogeneity in phenotype of TAB2 pathogenic variants and confirm the pathogenicity of this new variant through neoteric protein modeling techniques. PMID- 29700988 TI - Brief Report: Leg Length Inequality and Hip Osteoarthritis in the Multicenter Osteoarthritis Study and the Osteoarthritis Initiative. AB - OBJECTIVE: Studies suggest that persons with a leg length inequality (LLI) of >=2 cm have an increased risk of developing knee osteoarthritis (OA) in that limb. The present study was undertaken to examine whether LLI also confers an increased risk of hip OA. METHODS: Using long limb radiographs from subjects in the Multicenter Arthritis Study (MOST) and the Osteoarthritis Initiative (OAI), we measured LLI and scored hip radiographs that were obtained at baseline and 3-5 year follow-up. The associations of LLI of >=1 cm and LLI of >=2 cm with radiographic hip OA were examined cross-sectionally and longitudinally, assessing risk in shorter limbs and longer limbs compared to limbs from subjects with no LLI. We carried out logistic regression analyses with generalized estimating equations and adjusted for age, sex, body mass index, height, and cohort of origin. RESULTS: There were 1,966 subjects from the MOST and 2,627 subjects from the OAI. Twelve percent had LLI of >=1 cm and 1% had LLI of >=2 cm. For LLI >=1 cm, the adjusted odds ratio for prevalent hip OA in the shorter leg was 1.47 (95% confidence interval [95% CI] 1.07-2.02) and for LLI >=2 cm, it was 2.15 (95% CI 0.87-5.34). For LLI >=1 cm, the odds of incident hip OA in the shorter leg were 1.39 (95% CI 0.81-2.39) while for LLI >=2 cm, they were 4.20 (95% CI 1.26-14.03). We found no increased risk of hip OA in longer limbs. CONCLUSION: Our findings suggest that, as with knee OA, legs that are at least 2 cm shorter than the contralateral leg are at increased risk of hip OA. PMID- 29700989 TI - Alginate-Encapsulated Bacteria for the Treatment of Hypersaline Solutions in Microbial Fuel Cells. AB - A microbial fuel cell (MFC) based on a new wild-type strain of Salinivibrio sp. allowed the self-sustained treatment of hypersaline solutions (100 g L-1 , 1.71 m NaCl), reaching a removal of (87+/-11) % of the initial chemical oxygen demand after five days of operation, being the highest value achieved for hypersaline MFC. The degradation process and the evolution of the open circuit potential of the MFCs were correlated, opening the possibility for online monitoring of the treatment. The use of alginate capsules to trap bacterial cells, increasing cell density and stability, resulted in an eightfold higher power output, together with a more stable system, allowing operation up to five months with no maintenance required. The reported results are of critical importance to efforts to develop a sustainable and cost-effective system that treats hypersaline waste streams and reduces the quantity of polluting compounds released. PMID- 29700991 TI - A New Treatment Modality for Rheumatoid Arthritis: Combined Photothermal and Photodynamic Therapy Using Cu7.2 S4 Nanoparticles. AB - Rheumatoid arthritis (RA) is a worldwide inflammatory disease that seriously threatens human health and needs more effective treatment approaches. Near infrared (NIR) light can efficiently penetrate inflamed joints affected by RA, so phototherapy, including photothermal therapy (PTT) and photodynamic therapy (PDT), may provide new opportunities. In this work, the unique Cu7.2 S4 nanoparticles (NPs) are prepared for RA treatment enlightened by the fact that copper (Cu)-based nanomaterials can simultaneously serve as PTT agents and photosensitizers (for PDT). Meanwhile, Cu can promote ostogenesis and chondrogenesis. The Cu7.2 S4 NPs combined with NIR (808 nm, 1 W cm-2 ) irradiation not only achieve better bone preservation, including higher bone mineral density (BMD) and bone volume/total volume, but also inhibit inflamed synovial invasion, cartilage erosion, and expression of proinflammatory cytokines in vivo. Moreover, the Cu7.2 S4 NPs can effectively kill clinical pathogenic Staphylococcus aureus and Escherichia coli to prevent bacterial infection during intra-articular injection. Therefore, the combined PTT and PDT using the multifunctional Cu7.2 S4 NPs could be a novel RA treatment modality with full potential. PMID- 29700992 TI - Waist-to-height ratio as a risk marker for metabolic syndrome in childhood. A meta-analysis. AB - BACKGROUND: Individuals with abdominal obesity have a higher cardiovascular risk, regardless of the degree of global overweight. OBJECTIVE: To estimate the accuracy of the Waist/height ratio (WtHR) as a risk marker for metabolic syndrome (MS) in children or adolescents. METHODS: Published cohort or cross-sectional studies (Pubmed, Embase-SCOPUS and CINAHL) were searched, with no limits of time. Studies providing Waist/height ratio and clustered criteria of metabolic syndrome were included. RESULTS: Thirty-one studies (66,912 subjects) were selected. Overall, a high WtHR (>=0.5) was associated with a four-fold increased risk of clustered criteria of MS (odds ratio [OR] 4.15, 95% confidence interval [95% CI]: 2.69 to 6.42) and two-fold increased risk when adjusted by general obesity (adjusted OR 2.26, 95% CI: 1.29 to 3.98). The WtHR, as a quantitative measure, showed a pooled area under the curve of 0.76 (95% CI: 0.71 to 0.80) and, as a dichotomous measure, with a cut-off point close to 0.5, a sensitivity of 60% (95% CI: 50% to 68.8%) and a specificity of 79% (95% CI: 71.6% to 83.9%). CONCLUSIONS: Measuring WtHR may be considered in regular health checks of children and adolescents, as it can measure cardiovascular risk regardless of the degree of general obesity. PMID- 29700993 TI - Discovery of Antimicrobial Lipodepsipeptides Produced by a Serratia sp. within Mosquito Microbiomes. AB - The Anopheles mosquito that harbors the Plasmodium parasite contains a microbiota that can influence both the vector and the parasite. In recent years, insect associated microbes have highlighted the untapped potential of exploiting interspecies interactions to discover bioactive compounds. In this study, we report the discovery of nonribosomal lipodepsipeptides that are produced by a Serratia sp. within the midgut and salivary glands of Anopheles stephensi mosquitoes. The lipodepsipeptides, stephensiolides A-K, have antibiotic activity and facilitate bacterial surface motility. Bioinformatic analyses indicate that the stephensiolides are ubiquitous in nature and are likely important for Serratia spp. colonization within mosquitoes, humans, and other ecological niches. Our results demonstrate the usefulness of probing insect-microbiome interactions, enhance our understanding of the chemical ecology within Anopheles mosquitoes, and provide a secondary-metabolite scaffold for further investigate of this complex relationship. PMID- 29700994 TI - Improving Interpretation of New and Old Serum Biomarkers of Drug-Induced Liver Injury Through Mechanistic Modeling. AB - The study by Mason et al. in this issue used mechanistic modeling and simulation to address how both the dose of acetaminophen consumed and the time since ingestion can be estimated from biomarkers measured in a single serum sample in mice. Translation into the clinic would potentially be an advance in the treatment of acetaminophen poisoning. Importantly, this approach could transform the evaluation of liver safety in clinical trials of new drug candidates. PMID- 29700990 TI - Promise of chemokine network-targeted nanoparticles in combination nucleic acid therapies of metastatic cancer. AB - Chemokines and chemokine receptors play key roles in cancer progression and metastasis. Although multiple chemokines and chemokine receptors have been investigated, inhibition of CXCR4 emerged as one of the most promising approaches in combination cancer therapy, especially when focused on the metastatic disease. Small RNA molecules, such as small interfering RNA (siRNA) and microRNA (miRNA), represent new class of therapeutics for cancer treatment through RNA interference mediated gene silencing. However, the clinical applicability of siRNA and miRNA is severely limited by the lack of effective delivery systems. There is a significant therapeutic potential for CXCR4-targeted nanomedicines in combination with the delivery of siRNA and miRNA in cancer. Recently developed CXCR4-targeted polymeric drugs and nanomedicines, including cyclam- and chloroquine-based polymeric CXCR4 antagonists are introduced here and their ability to deliver functional siRNA and miRNA is discussed. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Nanotechnology Approaches to Biology > Nanoscale Systems in Biology. PMID- 29700995 TI - Overnight sleep duration and obesity in 2-5 year-old American Indian children. AB - BACKGROUND: Sleep has emerged as a potentially modifiable risk factor for obesity in children. OBJECTIVES: The purpose of this investigation was to evaluate the association between overnight sleep duration and obesity among American Indian (AI) children ages 2-5 years. METHODS: Data were examined from the baseline assessment of children enrolling in the Healthy Children, Strong Families study, which is a randomized lifestyle intervention trial in five diverse rural and urban AI communities nationally among children ages 2-5 years. Multivariable models were built to assess the relationship between sleep duration and BMI z score while controlling for potential sociodemographic and behavioural covariates. RESULTS: Three hundred and ninety-eight children had sufficient data to be included in analysis. In multivariable models controlling for potential covariates, overnight sleep duration was significantly and inversely associated with BMI z-score (B = -0.158, t = -1.774, P = 0.006). Similarly, when controlling for covariates, children who slept 12 or more hours had significantly lower BMI z scores compared with those who slept 8 to 10 h (P = 0.018) or less than 8 h (P = 0.035); the difference between 12+ hours and 10 to 12-h groups did not reach statistical significance (P = 0.073) but supported a linear relationship between overnight sleep duration and BMI. Weekday-to-weekend variability in overnight sleep duration was not associated with BMI z-score (B = 0.010, t = 0.206, P = 0.837). CONCLUSIONS: Overnight sleep duration is independently and inversely related to BMI z-score among AI children ages 2-5 years, even when controlling for important sociodemographic and obesogenic lifestyle factors. This represents the first report, to our knowledge, of sleep duration as a risk factor for obesity among AI children. PMID- 29700997 TI - Observations often trump experiments. PMID- 29700996 TI - Exposure to Bisphenol A and phthalates metabolites in the third trimester of pregnancy and BMI trajectories. AB - BACKGROUND: Bisphenol A (BPA) and phthalates metabolites are linked to a variety of adverse health consequences but studies have not explored their association with growth trajectories. OBJECTIVE: Explore body mass index (BMI) trajectories for tertile exposures to BPA and phthalates metabolites in the third trimester of pregnancy. METHODS: We constructed BMI (kg/m2 ) trajectories from birth to 14 years in a birth cohort of 249 children from Mexico City using tertiles of third trimester maternal urinary concentrations of BPA and phthalates metabolites. Fractional age polynomials and mixed effects models were fit separately by sex. Predicted models were plotted for each metabolite tertile with the covariates mother's education and BMI centered at average values. RESULTS: Highest predicted BMI trajectories for female children were observed for third tertile exposure to the phthalate metabolite mono(2-ethyl-5-carboxypentyl) phthalate. In male children, first tertile exposure to mono-isobutyl phthalate and monobenzyl phthalate and second tertile exposure to mono(2-ethylhexyl) phthalate and mono(2 ethyl-5-hydroxyhexyl) phthalate predicted the highest BMI trajectory by adolescence. There was no relationshsip between BPA and child growth trajectory. CONCLUSIONS: These results suggest sex-specific differences in BMI trajectories by levels of metabolite exposure. Additional studies are needed to consider growth through adolescence in assessing the association of pregnancy exposures on child's BMI. PMID- 29700998 TI - Caesarean section is the safest mode of delivery for extremely preterm breech singleton infants: FOR: Caesarean delivery of extremely preterm breech singletons. PMID- 29700999 TI - AGAINST: Caesarean section is not the safest for extremely preterm breech. PMID- 29701000 TI - Mode of delivery of the very preterm baby. PMID- 29701002 TI - Is caesarean section the best option for dystocia at full dilatation? PMID- 29701003 TI - Corrigendum. PMID- 29701004 TI - Ambulatory blood pressure threshold for black Africans: more questions than answers. PMID- 29701005 TI - Cytomegalovirus (CMV) in cervical cancer screening tests: A series of 8 cases and review of the literature. AB - OBJECTIVE: Cytomegalovirus (CMV) is a ubiquitous infection typically affecting over 50% of the US population by age 40. We report 8 cases of CMV infections detected in cervical cancer screening tests, the largest series of cases thus far reported in gynecologic cytology specimens. METHODS: A retrospective review of our pathology archival computer database was performed from January 1, 1994 through December 31, 2016 for CMV infections reported in cervical cytology specimens. The slides were retrieved for review if available. RESULTS: The eight patients ranged in age from 21-46 years, with a median age of 27 years and average age of 29.5 years. Two patients were significantly immunocompromised with one patient having AIDS and one patient diagnosed with autoimmune disease. The remaining six patients are considered immunocompetent. Cases were identified most often in the fall and winter months (6 of 8 cases). Seven cases were found using Surepath Pap (SP) liquid-based processing and one case was reported in a classic Papanicolaou smear (CPS). CONCLUSION: There was no correlation of cytologic presentation of CMV with a distinct cytohormonal pattern or inflammatory constituents. Rare diagnostic cells with changes of CMV infection were seen in 75% of the cases. The presence of CMV did not usually result in adverse patient outcome, except where CMV was one of the multiple opportunistic infections detected in the patient with AIDS. PMID- 29701007 TI - Is there a deprivation and maternal education gradient to child obesity and moderate-to-vigorous physical activity? Findings from the Millennium Cohort Study. AB - OBJECTIVE: The primary aim was to examine associations between individual-level and area-level measures of socioeconomic status (SES) and different measures of overweight/obesity in 7-year-old English children. A secondary aim was to examine associations between individual-level and area-level measures of SES and moderate to-vigorous intensity physical activity (MVPA). METHODS: Data were from wave four of the Millennium Cohort Study. Children were classified as normal weight, overweight/obese and centrally obese. MVPA was accelerometer derived. Individual level and area-level SES were defined using self-reported maternal education and the 2004 English Indices of Multiple Deprivation, respectively. Adjusted linear and multinomial logistic regressions were conducted. RESULTS: Three thousand seven hundred seventeen children (1890 girls) had complete data. Children in the lowest maternal education group and highest deprivation decile were at greatest risk of overweight and central obesity. MVPA was inversely associated with deprivation, and the most deprived children were most likely to achieve 60 min of daily MVPA. CONCLUSIONS: Individual-level and area-level SES were independently related to overweight and central obesity. Higher rates of overweight and central obesity among deprived children are not due to physical inactivity. Further research examining the concurrent effect of diet and MVPA on child weight status by deprivation is warranted. PMID- 29701006 TI - Nanotherapeutics for multiple myeloma. AB - Multiple myeloma (MM) is an age-related hematological malignancy with an estimated 30,000 new cases and 13,000 deaths per year. A disease of antibody secreting malignant plasma B-cells that grow primarily in the bone marrow (BM), MM causes debilitating fractures, anemia, renal failure, and hypercalcemia. In addition to the abnormal genetic profile of MM cells, the permissive BM microenvironment (BMM) supports MM pathogenesis. Although advances in treatment options have significantly enhanced survival in MM patients, transient perfusion of small-molecule drugs in the BM does not provide sufficient residence to enhance MM cell-drug interaction, thus allowing some myeloma cells to escape the first line of treatment. As such, there remains a crucial need to develop advanced drug delivery systems that can navigate the complex BMM and effectively reach the myeloma cells. The high vascular density and spongy nature of bone structure suggest that nanoparticles (NPs) can serve as smart drug-delivery systems capable of extravasation and retention in various BM compartments to exert a durable therapeutic effect. In this focus article, we first summarize the pathophysiology of MM, emphasizing how the BM niche presents serious challenges for effective treatment of MM with small-molecule drugs. We then pivot to current efforts to develop NP-based drug carriers and intrinsically therapeutic nanotherapeutics. The article concludes with a brief perspective on the opportunities and challenges in developing and translating nanotherapeutics to improve the treatment outcomes of MM patients. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease. PMID- 29701008 TI - Evaluating the contribution of differences in lean mass compartments for resting energy expenditure in African American and Caucasian American children. AB - BACKGROUND: Resting energy expenditure (REE), adjusted for total lean mass (LM), is lower in African American (AA) than Caucasian American (CA) children. Some adult studies suggest that AA-CA differences in lean mass compartments explain this REE difference. Similar data are limited in children. OBJECTIVE: To evaluate differences in compartment-specific lean mass between AA and CA children and examine the individual contributions of high-metabolic rate-at-rest trunk lean mass (TrLM) and low-metabolic-rate-at-rest appendicular lean mass (AppLM) for AA CA differences in REE. METHODS: We studied a convenience sample of 594 AA (n = 281) and CA (n = 313) children. REE was measured by using indirect calorimetry; dual-energy X-ray absorptiometry was used to assess body composition. ANCOVAs were performed to examine AA-CA differences in TrLM, AppLM and REE. After accounting for age, sex, height, pubertal development, bone mass and adiposity, REE was evaluated adjusting for total LM (model A) and separately adjusting for TrLM and AppLM (model B). RESULTS: African American children had greater adjusted AppLM (17.8 +/- 0.2 [SE] vs. 16.0 +/- 0.2 kg, p < 0.001) and lower TrLM (17.2 +/- 0.2 vs. 17.7 +/- 0.2 kg, p = 0.022) than CA children. REE adjusted for total LM was 77 +/- 16 kcal/d lower in AA than CA (p < 0.001). However, after accounting separately for AppLM and TrLM, the discrepancy in REE between the groups declined to 28 +/- 19 kcal/d (p = 0.14). In the adjusted model, both TrLM (p < 0.001) and AppLM (p < 0.027) were independently associated with REE. CONCLUSION: In children, AA-CA differences in REE appear mostly attributable to differences in body composition. Lower REE in AA children is likely due to lower TrLM and greater AppLM. PMID- 29701009 TI - The importance of pulse pressure on cardiovascular risk and total mortality in the general population: Is sex relevant? AB - The aim of the present study is to investigate the predictive value of pulse pressure (PP) on cardiovascular events in the general population and in both sexes, separately. The study involved 2045 participants from the PAMELA study who underwent 24-hour ambulatory blood pressure (BP) monitoring. The participants were followed from the initial medical visit for a time interval of 137 +/- 23 months. It was found that office, home, and 24-hour blood pressures were significantly higher in the individuals who experienced cardiovascular (CV) events. Office, 24-hour, and daytime PP were independent predictors of CV events after adjustment for main demographic and clinical parameters in the whole study population. Nighttime PP was an additional independent predictor in men. In conclusion, PP represents an important predictor of cardiovascular events in the general population, particularly among men. Daytime and 24-hour PP have greater predictive importance than nighttime PP in the general population. PMID- 29701010 TI - Alterations in the 5' untranslated region of the 5-enolpyruvylshikimate-3 phosphate synthase (EPSPS) gene influence EPSPS overexpression in glyphosate resistant Eleusine indica. AB - BACKGROUND: The herbicide glyphosate inhibits the enzyme 5-enolpyruvylshikimate-3 phosphate synthase (EPSPS). Overexpression of the EPSPS gene is one of the molecular mechanisms conferring glyphosate resistance in weeds, but the transcriptional regulation of this gene is poorly understood. The EPSPS gene was found to be significantly up-regulated following glyphosate treatment in a glyphosate-resistant Eleusine indica population from southern China. To further investigate the regulation of EPSPS overexpression, the promoter of the EPSPS gene from this E. indica population was cloned and analyzed. RESULTS: Two upstream regulatory sequences, Epro-S (862 bp) and Epro-R (877 bp), of EPSPS were obtained from glyphosate-susceptible (S) and -resistant (R) E. indica plants, respectively, by high-efficiency thermal asymmetric interlaced polymerase chain reaction (HiTAIL-PCR). The Epro-S and Epro-R sequences were 99% homologous, except for two insertions (3 and12 bp) in the R sequence. The 12-base insertion in the Epro-R sequence was located in the 5' untranslated region (UTR) pyrimidine nucleotide-rich (Py-rich) stretch element. Promoter activity tests showed that the 12-base insertion resulted in significant enhancement of Epro-R promoter activity, whereas the 3-base insertion had little effect on Epro-R promoter activity. CONCLUSION: Alterations in the 5' UTR Py-rich stretch element of EPSPS are responsible for glyphosate-induced EPSPS overexpression. Thus, EPSPS transcriptional regulation confers glyphosate resistance in this E. indica population. (c) 2018 Society of Chemical Industry. PMID- 29701011 TI - Professor Cees Veeger and the early years of bioinorganic chemistry. PMID- 29701012 TI - Noninvasive photoacoustic and fluorescent tracking of optical dye labeled T cellular activities of diseased sites at new depth. AB - The migration of immune cells is crucial to the immune response. Visualization of these processes has previously been limited because of the imaging depth. We developed a deep-penetrating, sensitive and high-resolution method to use fast photoacoustic tomography (PAT) to image the dynamic changes of T cells in lymph node and diseases at new depth (up to 9.5 mm). T cells labeled with NIR-797 isothiocyanate, an excellent near-infrared photoacoustic and fluorescent agent, were intravenously injected to the mice. We used fluorescence imaging to determine the location of T cells roughly and photoacoustic imaging is used to observe T-cell responses in diseased sites deeply and carefully. The dynamic changes of T cells in lymph node, acute disease (bacterial infection) and chronic disease (tumor) were observed noninvasively by photoacoustic and fluorescence imaging at different time points. T cells accumulated gradually and reached a maximum at 4 hours and declined afterwards in lymph node and bacterial infection site. At tumor model, T cells immigrated to the tumor with a maximum at 12 hours. Our study can not only provide a new observing method for immune activities tracking, but also enable continuous monitoring for therapeutic interventions. PMID- 29701013 TI - Visualization of the activation of the histamine H3 receptor (H3R) using novel fluorescence resonance energy transfer biosensors and their potential application to the study of H3R pharmacology. AB - Activation of the histamine-3 receptor (H3R) is involved in memory processes and cognitive action, while blocking H3R activation can slow the progression of neurological disorders, such as Alzheimer's disease, schizophrenia and narcolepsy. To date, however, no direct way to examine the activation of H3R has been utilized. Here, we describe a novel biosensor that can visualize the activation of H3R through an intramolecular fluorescence resonance energy transfer (FRET) signal. To achieve this, we constructed an intramolecular H3R FRET sensor with cyan fluorescent protein (CFP) attached at the C terminus and yellow fluorescent protein (YFP) inserted into the third intracellular loop. The sensor was found to internalize normally on agonist treatment. We measured FRET signals between the donor CFP and the acceptor YFP in living cells in real time, the results of which indicated that H3R agonist treatment (imetit or histamine) increases the FRET signal in a time- and concentration-dependent manner with Kon and Koff values consistent with published data and which maybe correlated with decreasing cAMP levels and the promotion of ERK1/2 phosphorylation. The FRET signal was inhibited by H3R antagonists, and the introduction of mutations at F419A, F423A, L426A and L427A, once again, the promotion of ERK1/2 phosphorylation, was diminished. Thus, we have built a H3R biosensor which can visualize the activation of receptor through real-time structure changes and which can obtain pharmacological kinetic data at the same time. The FRET signals may allow the sensor to become a useful tool for screening compounds and optimizing useful ligands. PMID- 29701014 TI - Mineralization of gellan gum hydrogels with calcium and magnesium carbonates by alternate soaking in solutions of calcium/magnesium and carbonate ion solutions. AB - Mineralization of hydrogels is desirable prior to applications in bone regeneration. CaCO3 is a widely used bone regeneration material, and Mg, when used as a component of calcium phosphate biomaterials, has promoted bone-forming cell adhesion and proliferation and bone regeneration. In this study, gellan gum hydrogels were mineralized with carbonates containing different amounts of calcium (Ca) and magnesium (Mg) by alternate soaking in, firstly, a calcium and/or magnesium ion solution and, secondly, a carbonate ion solution. This alternate soaking cycle was repeated five times. Five different calcium and/or magnesium ion solutions, containing different molar ratios of Ca to Mg ranging from Mg free to Ca free were compared. Carbonate mineral formed in all sample groups subjected to the alternate soaking cycle. Ca : Mg elemental ratio in the mineral formed was higher than in the respective mineralizing solution. Mineral formed in the absence of Mg was predominantly CaCO3 in the form of a mixture of calcite and vaterite. Increasing the Mg content in the mineral formed led to the formation of magnesian calcite and decreased the total amount of the mineral formed and its crystallinity. Hydrogel mineralization and increasing Mg content in mineral formed did not obviously improve proliferation of MC3T3-E1 osteoblast like cells or differentiation after 7 days. PMID- 29701015 TI - A case series: Association of anaphylaxis with a significant decrease in platelet levels and possible secondary risk of thrombosis. AB - INTRODUCTION: Anaphylaxis is a life threatening systemic inflammatory process that share mediators involved in the coagulation cascade. Platelet activating factor, known to increase platelet aggregation, has also been implicated as an important mediator of anaphylaxis. Although other inflammatory reactions are associated with an increased risk of thrombosis, anaphylaxis is currently not reported as one of them. Furthermore the role platelets may have in the perianaphylaxis period is not well understood. We here in present a retrospective case series of three patients that had platelet aberrations suggestive of PAF involvement and clinically significant thrombosis in close relationship with anaphylaxis. OBJECTIVE: To investigate platelet response before and after anaphylaxis and indirect observation evidence of platelet activating factors involvement with possible increased risk of thrombosis. METHODS: A retrospective investigation into medical records including medication administrations times, laboratory, and radiology results. Platelet levels pre- and post- anaphylaxis were statistically analyzed. RESULTS: Case 1, a 44 year old man had an anaphylactic reaction shortly after envenomation and subsequently suffered an acute infarction with thrombus in a cerebral artery. Case 2 is a 49 year old man with idiopathic anaphylaxis who developed a deep vein thrombosis after a protracted anaphylaxis event. Case 3 involved an 18 year old female with acute myeloid leukemia was found to have a thrombus in the celiac trunk following anaphylaxis. A paired two-tailed Wilcoxon test on the subjects pre and post anaphylactic platelet levels resulted in a overall P < 0.0001. CONCLUSIONS AND CLINICAL RELEVANCE: These three cases illustrate the potential role platelets may have in anaphylaxis and possible increased secondary risk for the development of thrombosis. Larger studies are required to determine incidence and risk factors for blood clots following anaphylaxis in order to provide management or screening recommendations. PMID- 29701016 TI - Functional Integrity and Gene Expression Profiles of Human Cord Blood-Derived Hematopoietic Stem and Progenitor Cells Generated In Vitro. AB - To date, different experimental strategies have been developed for the ex vivo expansion of human hematopoietic stem (HSCs) and progenitor (HPCs) cells. This has resulted in significant advances on the use of such expanded cells in transplantation settings. To this day, however, it is still unclear to what extent those stem and progenitor cells generated in vitro retain the functional and genomic integrity of their freshly isolated counterparts. In trying to contribute to the solving of this issue, in the present study we have selected and purified three different hematopoietic cell populations: HSCs (CD34+ CD38- CD45RA- CD71- Lin- cells), myeloid progenitor cells (CD34+ CD38+ CD45RA+ CD71- Lin- cells), and erythroid progenitor cells (CD34+ CD38+ CD45RA- CD71+ Lin- cells), obtained directly from fresh human umbilical cord blood (UCB) units or generated in vitro under particular culture conditions. We, then, compared their functional integrity in vitro and their gene expression profiles. Our results indicate that in spite of being immunophenotipically similar, fresh and in vitro generated cells showed significant differences, both in functional and genetic terms. As compared to their fresh counterparts, those HSCs generated in our culture system showed a deficient content of long-term culture-initiating cells, and a marked differentiation bias toward the myeloid lineage. In addition, in vitro generated HSCs and HPCs showed a limited expansion potential. Such functional alterations correlated with differences in their gene expression profiles. These observations are relevant in terms of HSC biology and may have implications in UCB expansion and transplantation. Stem Cells Translational Medicine 2018;7:602-614. PMID- 29701018 TI - Advances in optical coherence tomography in dermatology-a review. AB - Optical coherence tomography (OCT) was introduced as an imaging system, but like ultrasonography, other measures, such as blood perfusion and polarization of light, have enabled the technology to approach clinical utility. This review aims at providing an overview of the advances in clinical research based on the improving technical aspects. OCT provides cross-sectional and en face images down to skin depths of 0.4 to 2.00 mm with optical resolution of 3 to 15 MUm. Dynamic optical coherence tomography (D-OCT) enables the visualization of cutaneous microvasculature via detection of rapid changes in the interferometric signal of blood flow. Nonmelanoma skin cancer (NMSC) is the most comprehensively investigated topic, resulting in improved descriptions of morphological features and diagnostic criteria. A refined scoring system for diagnosing NMSC, taking findings from conventional and D-OCT into account, is warranted. OCT diagnosis of melanoma is hampered by the resolution and the optical properties of melanin. D OCT may be of value in diseases characterized with dynamic changes in the vasculature of the skin and the addition of functional measures is strongly encouraged. In conclusion, OCT in dermatology is still an emerging technology that has great potential for improving further in the future. PMID- 29701019 TI - Deep tissue imaging with acousto-optical tomography and spectral hole burning with slow light effect: a theoretical study. AB - Biological tissue is a highly scattering medium that prevents deep imaging of light. For medical applications, optical imaging offers a molecular sensitivity that would be beneficial for diagnosing and monitoring of diseases. Acousto optical tomography has the molecular sensitivity of optical imaging with the resolution of ultrasound and has the potential for deep tissue imaging. Here, we present a theoretical study of a system that combines acousto-optical tomography and slow light spectral filters created using spectral hole burning methods. Using Monte Carlo simulations, a model to obtain the contrast-to-noise ratio (CNR) deep in biological tissue was developed. The simulations show a CNR > 1 for imaging depths of ~5 cm in a reflection mode setup, as well as, imaging through ~12 cm in transmission mode setups. These results are promising and form the basis for future experimental studies. PMID- 29701017 TI - Outer membrane vesicles for vaccination and targeted drug delivery. AB - Extracellular vesicles (EVs) are cell membrane-derived compartments that spontaneously secrete from a wide range of cells and tissues. EVs have shown to be the carriers in delivering drugs and small interfering RNA. Among EVs, bacterial outer membrane vesicles (OMVs) recently have gained the interest in vaccine development and targeted drug delivery. In this review, we summarize the current discoveries of OMVs and their functions. In particular, we focus on the biogenesis of OMVs and their functions in bacterial virulence and pathogenesis. Furthermore, we discuss the applications of OMVs in vaccination and targeted drug delivery. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Infectious Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies Biology-Inspired Nanomaterials > Lipid-Based Structures. PMID- 29701020 TI - Intrauterine photoacoustic and ultrasound imaging probe. AB - Intrauterine photoacoustic and ultrasound imaging are probe-based imaging modalities with translational potential for use in detecting endometrial diseases. This deep-tissue imaging probe design allows for the retrofitting of commercially available endometrial sampling curettes. The imaging probe presented here has a 2.92-mm diameter and approximate length of 26 cm, which allows for entry into the human endometrial cavity, making it possible to use photoacoustic imaging and high-resolution ultrasound to characterize the uterus. We demonstrate the imaging probes' ability to provide structural information of an excised pig uterus using ultrasound imaging and detect photoacoustic signals at a radial depth of 1 cm. PMID- 29701021 TI - [Functional genetic screening using CRISPR-Cas9 system]. AB - Functional genetic screening as an important method for exploring biological processes, diseases development research and functional annotation of genetic elements, has been widely used in pharmaceutical research, new therapeutic targets identifying and screening, and tumor resistance. CRISPR-Cas9 (Clustered regularly interspaced short palindromic repeat sequences/CRISPR-associated protein 9) is the newest tool in the geneticist's toolbox, allowing researchers to edit genome with unprecedented ease, accuracy and high-throughput. CRISPR-Cas9 system provides a high-throughput, practical and efficient tool for the discovery of functionally important genes responsible for certain phenotypes. In this review, we summarize the characterization of CRISPR/Cas9 system and applications of this new genetic toolkit in functional genetic screening. PMID- 29701022 TI - [Advances in structure-function relation of plant type III polyketide synthases by site-directed mutagenesis]. AB - Plant type III polyketide synthases (PKSs), the pivotal enzymes in the biosynthesis of polyketides, produce backbones of many structurally diverse and functionally different polyketides. So far, a variety of functionally diverse plant type III PKSs have been cloned and identified from plant origin. Site directed mutagenesis is a useful technique to study the complex relationship between protein structure and function. This review summarized advances in the structure-function relation of plant type III polyketide synthases by site directed mutagenesis in recent years, including the modification of the amino acid residues influencing enzyme architectures (such as controlling the specificity of starter substrates, the number of condensation reactions, and the cyclization reactions of the intermediate product). This review provides information to study the structure-function relation of plant type III polyketide synthases. PMID- 29701023 TI - [Progress in bio-degradation of mycotoxin zearalenone]. AB - Zearalenone (ZEN) and its derivatives are non-steroidal estrogenic mycotoxins mainly produced by Fusarium species. They are widely distributed in grain feeds originated from maize, barley, wheat and sorghum, causing serious harm to animal and human health. Currently, there is a pressing need of an efficient technology for ZEN degradation and detoxification. Because traditional physical and chemical methods could not effectively detoxify ZEN in grains, and might also affect the grain nutrients and food taste, and even result in secondary pollution, the biological technologies are developed to detoxify ZEN and its derivatives. In this paper, we reviewed the structure of ZEN and its derivatives, the fungi and bacteria species with ability of degradation of ZEN. In addition, the characterization, protein sequences and conformation of currently identified ZEN degrading enzymes, the only solved ZHD structure from Clonostachys rose were analyzed and compared, and the enzymes heterologous expression and application were also reviewed. This review will provide reference for reducing the cost of ZEN degrading enzymes by biological technologies such as enzyme engineering and fermentation engineering. PMID- 29701024 TI - [A systematic review of biosynthesis of poly (3-hydroxypropionate)]. AB - Poly (3-hydroxypropionate) (P3HP), a new member of thermoplastic of family polyhydroxyalkanoates (PHAs), has excellent characteristics of biodegradability and biocompatibility. By now no reports can be found about wild-type bacteria that naturally synthesize P3HP, so the main way to produce P3HP is chemical and biological methods. Chemical method by adding high cost 3-HP monomers or their structural analogs as precursors, has the drawbacks of toxicity, low effectiveness and high cost. Biological method using engineered strain may utilize inexpensive and renewable carbon source to produce P3HP and has gradually become more and more popular. We systematically review here the biosynthesis of P3HP research progress. The advantages and disadvantages of biosynthesis pathways of glycerol pathway, malonyl-CoA pathway and beta-alanine pathway were analyzed. PMID- 29701025 TI - [Advances in biotic and abiotic mutual promoting mechanism for chlorinated aliphatic hydrocarbons degradation]. AB - Chlorinated aliphatic hydrocarbons (CAHs) with characteristics of high toxicity, biological accumulation and recalcitrance to degradation as well as carcinogenicity, teratogenesis and mutagenicity, are seriously harmful to human health and ecological environment. CAHs degradation depends on biotic and abiotic responses that exist diversified interactive effects, so it is important to clarify the mechanism of CAHs degradation via biotic and abiotic mutual promoting to significantly enhance the CAHs-contaminated site restoration. In this work, a series of pathways for CAHs degradation was first introduced and summarized as three means on reductive dechlorination, aerobic cometabolism and direct oxidation, and biotic and abiotic typical factors affecting CAHs degradation were concluded from these. Then, mechanisms of induced degradation and synergistic degradation were indicated from the perspective of mutual promoting degradation both with biotic and abiotic responses, and furthermore, the application and technical limitations of CAHs degradation enhanced via biotic and abiotic mutual promoting were reviewed and analyzed. Finally, the development of CAHs degradation technology in future was prospected. PMID- 29701026 TI - [Progress in the spectral library based protein identification strategy]. AB - Exponential growth of the mass spectrometry (MS) data is exhibited when the mass spectrometry-based proteomics has been developing rapidly. It is a great challenge to develop some quick, accurate and repeatable methods to identify peptides and proteins. Nowadays, the spectral library searching has become a mature strategy for tandem mass spectra based proteins identification in proteomics, which searches the experiment spectra against a collection of confidently identified MS/MS spectra that have been observed previously, and fully utilizes the abundance in the spectrum, peaks from non-canonical fragment ions, and other features. This review provides an overview of the implement of spectral library search strategy, and two key steps, spectral library construction and spectral library searching comprehensively, and discusses the progress and challenge of the library search strategy. PMID- 29701027 TI - [Genetic evolution of HA and NA genes of H9N2 influenza viruses isolated in regions of Hunan Province, China, in 2015]. AB - The high prevalence of influenza A virus is identified in Hunan Province because of the high density of poultry farms. To survey the variations of H9N2 subtype avian influenza virus in Hunan province, we analyzed HA and NA genes of 10 virus strains isolated from different areas of Hunan Province. All these strains belong to the Eurasian lineage, Y280-like sub-lineage. The cleavage sites in their HA genes were all RSSR?GLT, corresponding to the feature of low pathogenic AIV. All strains had an L (Leu) at the site 234 in the HA genes, indicating the ability of binding with the SAalpha-2,6 receptor. NA gene stalk deletions at aa 63-65 were also detected from all the isolates, indicating a possibility of increased virus replication in mammals. Our findings suggest that more attention should be paid to the surveillance of H9N2 influenza virus and its direction of reassortment. PMID- 29701028 TI - [Characterization and optimization of a heterotrophic bacterium for sulfide degradation]. AB - The emission of hydrogen sulfide in the waste gas from slaughter plant, fishmeal feed processing and some other food industrial processing could cause serious air pollution to the surrounding environment. The purpose of this study was to screen heterotrophic bacterium strains for the removal of hydrogen sulfide odor. One heterotrophic bacterial mutant ZJNB-B3 was derived from the sulfide degrader Bacillus cereus XJ-2 and its sulfide removal efficiency was 97%. Based on the morphology studies, biochemical tests and 16S rRNA gene analysis, the strain was identified as Bacillus cereus ZJNB-B3. The NCBI GenBank accession number is MF679650. Batch tests showed that the strain tolerated up to 300 mg/L of toxic S2 concentration. Response surface methodology was applied to optimize the conditions of degradation of sulfide. The optimal parameters were as follows: initial sulfide concentration 211.8 mg/L, initial pH 6.72, inoculum volume 5.04%, and incubation temperature 30 C. The accumulated sulfate concentration was 63.8 mg/L and the sulfide removal efficiency was 97.3% after 48 h incubation. No sulfuric acid was generated during sulfide oxidation by the strain. Sulfide could be removed effectively by this strain under mild pH conditions. The results suggested that the strain may have great industrial application potential. This study provides the fundamentals for the removal of hydrogen sulfide gas. PMID- 29701029 TI - [Expression, purification and characterization of diphtheria toxin mutant CRM197 in Eschrichia coli]. AB - CRM197 (cross-reacting material 197), a non-toxic mutant of diphtheria toxin, has wide application potential in biopharmaceuticals. However, it is difficult to express CRM197 in bacteria other than Corynebacterium diphtheriae. Here we proposed a new alternative method to produce soluble CRM197 without label in Escherichia coli. In particular, a synthetic gene coding for CRM197, optimized for E. coli codon usage, was cloned in the pET32a (+) vector. Accordingly, the over-expression of the protein was simply induced with IPTG in E. coli BL21 (DE3). The target protein was soluble and accounted for about 40% of the total protein in the supernatant. Following an ultrasonic cytolysis step, the recombinant protein was purified by anion exchange, affinity and desalting chromatography and the purity of the final preparation reached 95%. Cytotoxicity tests showed that the IC50 value of CRM197 was 2.1*107 times the IC50 value of diphtheria toxin, and 9.6 times the IC50 value of diphtheria toxoid, telling that the target protein is safe and non-toxic. Subsequently, we found that both the high dose (20 MUg) and the low dose (2 MUg) of CRM197 were equally efficient in inducing an immune response against diphtheria toxiod in mice, and the antibodies titer of mice after three immunizations with low dose could reach 1:409 600. In conclusion, our findings provide a highly efficient strategy for the rapid production and purification of unlabeled and soluble recombinant CRM197 in E. coli, with good immunogenicity and safety. PMID- 29701030 TI - [Preparation of anti-hCG single domain antibody by antibody grafting technique using an antigen-binding peptide]. AB - We used the antibody grafting technology to prepare anti-hCG single-domain antibodies on the basis of antigen-binding peptide to simplify the single-domain antibody preparation process and improving the biochemical stability of peptide. By using a universal single-domain antibody backbone (cAbBCII10), CDR1 or CDR3 was replaced by the hCG-binding peptide, and the grafted antibody gene sequences were synthesized and cloned into the prokaryotic expression vector pET30a(+) in fusion with a C-terminal sfGFP gene, i.e. pET30a-(His6)-cAbBCII10-CDR1/hCGBP1 sfGFP and pET30a-(His6)-cAbBCII10-CDR3/hCGBP3-sfGFP. The recombinant plasmids were transformed into E. coli BL21(DE3), and the fusion proteins were induced by IPTG. Highly soluble recombinant fusion proteins were obtained and purified by Ni NTA affinity column. SDS-PAGE confirmed the purified protein as the target protein. The antigen-antibody binding assay showed that both the CDR1 and CDR3 grafted antibodies have hCG-binding activities. While the titers of the two grafted antibodies were similar, the binding affinity of CDR3 grafted antibody was higher than that of CDR1 grafted protein (about 2-3 times). The grafted antibodies retained the relatively high biochemical stability of the single domain antibody backbone and were relatively thermostable and alkaline tolerant. The obtained antibodies also had a relatively high antigen-binding specificity to hCG. This study provided a reliable experimental basis for further optimization of anti-hCG single domain antibody by antibody grafting technology using antigen binding peptide. PMID- 29701031 TI - [Comparison of urinary proteomes among rats, guinea pigs and golden hamsters]. AB - Biomarkers are the detectable changes associated with physiological or pathological changes. Urine as excreta of the body, without the mechanisms to maintain a homeostatic internal environment, can reflect a variety of changes in the body. Using animal models can simulate human disease processes, monitor disease changes, and provide clues to early diagnosis. Rats as commonly used model animals are not the dominant models for all disease, thus comparing the urinary proteins of rats with other animals to provide clues to the selection of other animal dominant models. In this study, urinary proteins were digested and profiled by liquid chromatography and tandem mass spectrometry (LC-MS/MS). The urinary proteins of rats, guinea pigs and golden hamsters were compared. The results showed that the number of urine proteins in the three different animals was different, and also different in every system of the body. This provides a basis for selecting the best animal models for different diseases. PMID- 29701032 TI - [Expression and self-assembly of HIV-1 CAP2NC protein]. AB - We constructed the CAP2NC prokaryotic expression vector of HIV-1 NL4-3 strain and obtained relatively pure CAP2NC protein by optimizing its purification conditions to explore its in vitro self-assembly conditions. Primers were designed according to the CAP2NC DNA sequence of HIV-1 NL4-3 strain. The target gene was amplified by PCR and cloned into prokaryotic expression vector pTO-T7. Then the recombinant strain was transformed into Escherichia coli BL21 (DE3). IPTG induced protein expression, then the protein was purified by hydrophobic chromatography. SDS-PAGE and Western blotting were performed to analyze the target protein, and the biological activity of the antigen was identified through ELISA. The self assembly of CAP2NC protein was analyzed by transmission electron microscopy and gel filtration chromatography. The protein had good reaction with the specific antibodies of p24 and formed different structures in various conditions. When 10% yeast RNA was added to the protein complex, the recombinant protein only formed into a tubular structure, which was similar to the self-assembled structure of the HIV-1 virus capsid. The results showed that the HIV-1 CAP2NC protein had in vitro self-assembly activity, and the RNA affected the structure of CAP2NC protein assembly. The protein can be used as a simple and effective molecular model to study its structure, and then it can provide a reference for the study of HIV immature virus particles. PMID- 29701033 TI - [Identification of mouse brain neuropeptides by high throughput mass spectrometry]. AB - Neuropeptides play an important role in the physiological functions of the human body. The physiological activities such as pain, sleep, mood, learning and memory are affected by neuropeptides. Neuropeptides mainly exist in the nerve tissue of the body, and a small amount of them are distributed in body fluid and organs. At present, analysis of large-scale identification of neuropeptides in whole brain tissue is still challenging. Therefore, high-throughput detection of these neuropeptides is greatly significant to understand the composition and function of neuropeptides. In this study, 1 830 endogenous peptides and 99 novel putative neuropeptides were identified by extraction of endogenous peptides from whole brain tissue of mice by liquid phase tandem mass spectrometry (LC-MS / MS). The identification of these endogenous peptides provides not only a reference value in the treatment and mechanism studies of diseases and the development of drugs, but also the basis for the study of a new neuropeptides and their functions. PMID- 29701034 TI - [Two-plasmid scarless genetic modification in Escherichia coli hfq and rne-710]. AB - Gene modification is an important technique to understand gene function. We firstly constructed Deltahfq::Spe and Deltarne-710::Spe mutant strains of Escherichia coli MG1655. The fragment lacking of hfq and rne-710 was ligated to the auxiliary plasmid and separately replace the spectinomycin box by homologous recombinase system to obtain the Deltahfq and Deltarne-710 mutant strains. The combination of two-plasmid scarless genetic modification and fusion PCR led to a new way for the long DNA fragment gene deletions. PMID- 29701035 TI - [Expression, purification and characterization of N-glycosylation mutant human IFN-lambda1 in Pichia pastoris]. AB - IFN-lambda1 is a member of a new family of interferons called type III IFNs with similar functions to type IIFNs. Previously we obtained recombinant soluble human rhIFN-lambda1 from Pichia pastoris. However, the hyper-glycosylation from P. pastoris brings immunogenicity and low purification recovery rate. To overcome this disadvantage, in this study, we constructed an rhIFN-lambda1 mutant (rhIFN lambda1-Nm) devoid of the potential N-glycosylation sites by site-directed mutagenesis. rhIFN-lambda1-Nm was successfully expressed and secreted extracellularly in P. pastoris (GS115) using methanol inducible AOX1 promoter with alpha-mating factor signal sequence. rhIFN-lambda1-Nm was purified and characterized. There was no significant difference between rhIFN-lambda1-Nm and rhIFN-lambda1 in structure and bioactivity. The molecular weight was low after N glycosylation mutation whereas the glycosylation was much lower. The mutational rhIFN-lambda1 (rhIFN-lambda1-Nm) could legitimately be developed as substitutes for rhIFN-lambda1, and thus it may be developed into a more promising therapeutic reagent in the future. PMID- 29701036 TI - Emergency management of burns: part 1. AB - Caring for patients with burn injuries can be traumatic for staff. Non-specialist clinicians in emergency departments are often the first point of contact for patients with burn injuries and their families. Lack of burns education, exacerbated by infrequent presentations, can add to front-line clinicians' stress and anxiety. Assessment relies on accurate evaluation of burn aetiology, and the size and depth of the injuries, and initial management is directly responsible for patients' outcomes and quality of life. This is the first article in a two part series that highlights the criteria and process of referral to a specialist burn service and gives an overview of the challenges posed by the burn mechanism and subsequent unique treatment considerations. The aim of the two articles is to enhance emergency clinicians' knowledge and confidence in burn management, and to build awareness of the clinical guidance and support available via the specialist burn service providers. PMID- 29701037 TI - [Warming acupuncture combined with conventional acupuncture for diabetic peripheral neuropathy with syndrome of yang deficiency and cold coagulation, obstruction of collaterals and blood stasis]. AB - OBJECTIVE: To compare the clinical efficacy differences between warming acupuncture and conventional acupuncture for diabetic peripheral neuropathy (DPN) with syndrome of yang deficiency and cold coagulation, obstruction of collaterals and blood stasis. METHODS: A total of 64 patients were randomly divided into a warming acupuncture group and a conventional acupuncture group, 32 cases in each one. Based on basic treatment of blood glucose regulation, warming acupuncture was applied at Pishu (BL 20), Shenshu (BL 23), Guanyuanshu (BL 26), Zusanli (ST 36), Chongyang (ST 42), Quchi (LI 11) and Hegu (LI 4) in the warming acupuncture group, while acupuncture was applied at the identical acupoints in the conventional acupuncture group. Both the treatments were given once a day with an interval of one day every six days; totally the treatment was given for 4 weeks. The TCM symptom score, Toronto clinical scoring system (TCSS) and nerve conduction velocity (NCV) before and after treatment were compared in the two groups. RESULTS: After treatment, the TCM symptom scores in the two groups were significantly reduced (both P<0.01); the improvement of TCM symptom in the warming acupuncture group was superior to that in the conventional acupuncture group (P<0.05). After treatment, the TCSS scores in the two groups were significantly reduced (both P<0.01); the TCSS score in the warming acupuncture group was significantly lower than that in the conventional acupuncture group (P<0.05). After treatment, the NCV of motor nerve of tibial nerve and nervus peroneus communis, as well as sensory nerve of tibial nerve and sural nerve was improved in the warming acupuncture group (all P<0.05), while only the NCV of motor nerve and sensory nerve of tibial nerve was improved in the conventional acupuncture group (both P<0.05); there were no significant difference between the two groups (all P>0.05). CONCLUSION: Warming acupuncture and conventional acupuncture could both increase TCM symptom score, improve NCV in patients of DPN with syndrome of yang deficiency and cold coagulation, obstruction of collaterals and blood stasis; warming acupuncture has advantage in symptom improvement. PMID- 29701039 TI - [Clinical observation of acupuncture at Zhiyang (GV 9) Bazhen points combined with pantoprazole for gastroesophageal reflux cough with damp-heat type]. AB - OBJECTIVE: On the basic treatment, to observed the effect difference between acupuncture at Zhiyang (GV 9) Bazhen points combined with pantoprazole and simple pantoprazole for gastroesophageal reflux cough with damp-heat type. METHODS: A total of 102 patients were randomly assigned into an observation group and a control group, 51 cases in each group. The patients in the two groups were given domperidone tablets (10 mg each time, 3 times a day). The patients in the control group were treated with pantoprazole capsule (40 mg each time, once a day). On the basis of the control group, the patients in the observation group were treated with Zhiyang (GV 9) Bazhen points, once a day, 5 times a week. All the treatment was given for 8 weeks. The indexes were observed before and after treatment, including cough symptom at daytime and nighttime scores, TCM symptom (heartburn, acid regurgitation, chest pain, epigastric pain, throat discomfort) scores and quality of life scores of cough questionnaire in Leicester (physiological, psychological and social aspects). The clinical effects were compared. RESULTS: After treatment, the daytime and nighttime cough scores, TCM symptom (heartburn, acid regurgitation, chest pain, epigastric pain, throat discomfort) scores were lower, and the quality of life scores of cough questionnaire in Leicester (physiological, psychological and social aspects) were higher than those before treatment in the two groups (all P<0.05), with better results in the observation group (all P<0.05). The total effective rate of the observation group was 94.1% (48/51), which was better than 80.4% (41/51) of the control group (P<0.05). CONCLUSION: On the basic treatment, acupuncture at Zhiyang (GV 9) Bazhen points combined with pantoprazole can improve TCM symptoms, such as cough, of the patients with gastroesophageal reflux cough with damp-heat type, and improve their quality of life. PMID- 29701038 TI - [Dynamic scalp acupuncture combined with PNF therapy for upper limb motor impairment in ischemic stroke spastic hemiplegia]. AB - OBJECTIVE: On the basic therapy, to assess the clinical effects of dynamic scalp acupuncture, scalp acupuncture combined with proprioceptive neuromuscular facilitation (PNF) therapy and simple PNF therapy for upper limb motor impairment in ischemic post-stroke spastic hemiplegia. METHODS: A total of 90 cases were randomly assigned into a PNF group, a dynamic scalp acupuncture group and a scalp acupuncture group, 30 cases in each group. Basic therapy and PNF therapy were applied in the three groups. PNF therapy was used during scalp acupuncture in the dynamic scalp acupuncture group. PNF therapy was applied after scalp acupuncture in the scalp acupuncture group. The points were the upper 1/5 and middle 2/5 of Dingnieqianxiexian (MS 6) and Dingniehouxiexian (MS 7) at the lesion side, the hemiparalysis contralateral side. The treatment was given for 6 months, once a day and 1 month as a course. The modified Ashworth scale (MAS), the Fugl-Meyer motor assessment (FMA) and Barthel index (BI) were observed before treatment and 2 weeks, 1 month, 3 months, and 6 months after treatment. RESULTS: The MAS 1 month, 3 months and 6 months after treatment were improved compared with those before treatment in the three groups ( all P<0.05), and the MAS results in the dynamic scalp acupuncture group were better than those in the PNF and scalp acupuncture group (all P<0.05). The FMA and BI scores 1 month, 3 months and 6 months after treatment were higher than those before treatment (all P<0.05). The FMA Scores in the 3 time points and after treatment in the dynamic scalp acupuncture group were higher than those in the other two groups (all P<0.05). CONCLUSION: PNF therapy during scalp acupuncture can relieve the spasmodic condition of patients with upper limb motor impairment in ischemic post-stroke spasmodic hemiplegia, and improve the limb function and life activity, which is better than PNF therapy after scalp acupuncture and simple PNF therapy. PMID- 29701040 TI - [Clinical therapeutic effects on rheumatoid arthritis treated with the assisted therapy of acupuncture at the points detected with thermosensitive moxibustion in Zhuang medicine]. AB - OBJECTIVE: To evaluate the clinical therapeutic effects and safety on rheumatoid arthritis (RA) treated with acupuncture at the points detected with thermosensitive moxibustion in Zhuang medicine combined with western medication. METHODS: A total of 168 RA patients in compliance with the inclusive criteria were collected and randomized into an observation group and a control group, 84 cases in each one. In the control group, in reference to the updated guideline of new drugs by the European League Against Rheumatism (EULAR) in 2013, the medication scheme was formulated for oral administration, methotrexate tablet 7.5 mg, once a week; salazosulfapyridine enteric-coated tablets, 100 mg, twice a day; hydroxychloroquine sulfate tablets, 20 mg, twice a day; and meloxicam tablets, 15 mg, once a day. In the observation group, besides the treatment as the control group, the acupuncture therapy at the points detected with thermosensitive moxibustion in Zhuang medicine was given. The mild moxibustion was applied near to the affected joint with the moxa material of Zhuang herbal medicine to detect the sensitization points. Afterwards, the acupuncture technique of Zhuang medicine was given on those points, without any manipulation applied. The needles were retained for 30 min, once daily. The treatment for 2 weeks was as one course, continuously for 2 courses. The indexes were observed before and after treatment in the two groups including gripping power, the time of morning stiffness, the swollen joint count 28 (SJC 28), the tender joint count 28 (TJC 28), the disease activity score 28 (DAS 28), the score of patient global assessment of disease activity (PtGA) and the score of provider global assessment of disease activity (PhGA), as well as rheumatoid factors (RF), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and anti-cyclic peptide containing citrulline (A-CCP). The clinical therapeutic effects were evaluated in the two groups. RESULTS: After 4-week treatment, a total of 163 patients accomplished the clinical trial, 81 cases in the observation group and 82 cases in the control group. The results of gripping power, the time of morning stiffness, SJC 28, TJC 28, PtGA, PhGA, DAS 28, RF, CRP, ESR and A-CCP were all improved as compared with those before treatment (all P<0.05). In 4 weeks of treatment, the results of gripping power, the time of morning stiffness, SJC 28, TJC 28, PtGA, PhGA, DAS 28, as well as CRP and ESR in the observation group were better than those in the control group (all P<0.05). The results of RF and A-CCP were not different significantly between the two groups (both P>0.05). The total effective rate was 85.19% (69/81) in the observation group, higher than 70.73% (58/82) in the control group (P<0.05). CONCLUSION: The acupuncture therapy at the points detected with thermosensitive moxibustion in Zhuang medicine achieves the satisfactory clinical effects with few adverse effects. PMID- 29701041 TI - [Acupuncture combined with femoral nerve block for postoperative analgesia after total knee arthroplasty and functional rehabilitation: a randomized controlled trial]. AB - OBJECTIVE: To observe the therapeutic effects on the postoperative analgesia after total knee arthroplasty (TKA) and functional rehabilitation with acupuncture at the distal points along the affected meridians and femoral nerve block. METHODS: A total of 60 patients with knee prosthesis were collected and randomized into an observation group and a control group, 30 cases in each one. All of the patients received the femoral nerve block before operation. The analgesia pump was used for analgesia after operation and TKA postoperative rehabilitation was adopted. Additionally, in the observation group, acupuncture was applied to Taichong (LR 3), Kunlun (BL 60), Taixi (KI 3), Shenmai (BL 62), Sanyinjiao (SP 6) and Houxi (SI 3) unilaterally on the affected side, as well as Chize (LU 5), Quchi (LI 11) and Shousanli (LI 10) bilaterally. The needles were remained for 30 min, once a day, totally for 2 weeks. Separately, 4 h, 8 h, 12 h, 24 h and 48 h in resting after operation, as well as during the passive functional exercises 12 h, 24 h, 48 h, 7 d and 14 d after operation, the scores of visual analogue score (VAS) were recorded. HSS score, ROM before operation and 7 d and 14 d after operation, the analgesia satisfaction, the analgesic dose as well as the adverse reactions were recorded. RESULTS: Regarding the VAS scores, 8 h, 12 h, 24 h and 48 h in resting after operation, the results in the observation group were lower than those in the control group (all P<0.05). The VAS scores during the passive functional exercises 12 h, 24 h 48 h and 7 d after operation in the observation group were lower than those in the control group (all P<0.05). The analgesia satisfaction in the observation group was higher than that in the control group (P<0.05). 72 h, 7 d and 14 d after operation, HSS scores in the observation group were better than those in the control group (all P<0.05) and the effects of ROM in the observation group were better than those in the control group (both P<0.05). Regarding the safety, the adverse reaction rate in the observation group was lower than that in the control group (P<0.05). CONCLUSION: The combined treatment with acupuncture along the meridians and femoral nerve block achieves the remarkably analgesia effects after TKA and definite effects of the joint function recovery. This combined therapy is favorable in safety and adverse reactions. PMID- 29701042 TI - [Effects of transcutaneous electrical acupoint stimulation on quality of recovery during early period after laparoscopic cholecystectomy]. AB - OBJECTIVE: To evaluate the effect of transcutaneous electrical acupoint stimulation (TEAS) on the quality of recovery during the early period after laparoscopic cholecystectomy and the dosage of anesthetic and analgesic. METHODS: One hundred patients who received laparoscopic cholecystectomy with gradeIand II of American Society of Anesthesiologists (ASA) criteria were randomly assigned into an observation group and a control group according to random number table, 50 cases in each group. The patients in the two groups were treated with conventional endotracheal intubation anesthesia, anesthesia induction and maintenance. The patients in the observation group were treated with TEAS (2 Hz/100 Hz, 8 to 12 mA) at bilateral Hegu (LI 4) and Neiguan (PC 6), as well as Zusanli (ST 36) and the non-acupoint 2 cun outboard from Zusanli (ST 36) from 30 min before anesthesia induction to the end of operation. The patients in the control group were applied by stimulation electrode in the corresponding points without electrical stimulation. The dosage of intraoperative remifentanil and the analgesic dosage of dezocine for postoperation were recorded. The recovery time, extubation time, the changes of heart rate (HR) and mean arterial pressure (MAP) during extubation were recorded. The quality of recovery was assessed by the quality of recovery-40 questionnaire (QoR-40) 1 day before surgery (T0),and 4 h (T1), 8 h (T2), 24 h (T3), 48 h (T4) after surgery. The patient's cognitive function was assessed by mini-mental state examination (MMSE) scale at the 5 time points. The incidences of postoperative nausea and vomiting were recorded at T1 through T4. RESULTS: The dosages of intraoperative remifentanil and dezocine in the observation group were less than those in the control group; the recovery time and extubation time were shorter than those in the control group; the HR of extubation was lower than that in the control group (all P<0.05). There was no statistic difference about MAP between the two groups (P>0.05). Compared with T0, the total scores of QoR-40 decreased in the two groups at T1, T2, T3 (all P<0.05), and the total scores in the observation group were higher than those in the control group (all P<0.05). The emotional state, physical comfort, psychological support, self-care ability, pain scores at T1 in the observation group and at T1, T2, T3 in the control group were lower than those at T0 (all P<0.05). The emotional state, physical comfort, psychological support, self-care ability, pain scores in the observation group were higher than those in the control group at T1, T2, T3 (all P<0.05). Compared with T0, the MMSE scores in the two groups decreased at T1 and T2 (all P<0.05). At T1, T2, T3, the MMSE scores in the observation group were higher than those in the control group (all P<0.05). At T1 and T2, the incidence rates of nausea and vomiting were 22.0% (11/50), 12.0% (6/50) respectively in the observation group, which were lower than 32.0% (16/50) and 24.0% (12/50) in the control group (both P<0.05). At T3 and T4, the incidence rates of nausea and vomiting were 6.0% (3/50), 2.0% (1/50) respectively in the observation group, which were not significantly different from 8.0% (4/50) and 4.0% (2/50) in the control group (both P>0.05). CONCLUSION: TEAS can improve the quality of recovery during the early period after laparoscopic cholecystectomy and reduce the dosage of anesthetic and analgesic. PMID- 29701043 TI - [Therapeutic effects on ovulation and reproduction promotion with acupuncture and clomiphene in polycystic ovary syndrome]. AB - OBJECTIVE: To compare the difference in the therapeutic effects on ovulation disorder in polycystic ovary syndrome (PCOS) between the combined therapy of electroacupuncture and clomiphene and the single medication of clomiphene and to explore the effect mechanism. METHODS: A total of 80 patients of PCOS were randomized into an acupuncture plus medication group (40 cases) and a medication group (40 cases). In the medication group, since the 5th day of menstruation or medicine-withdrawal bleeding, clomiphene was prescribed for oral administration, continuously for 5 days. In the acupuncture plus medication group, the medication was the same as the medication group. Additionally, 30 min electroacupuncture (continuous wave, 2 Hz) was applied to Qihai (CV 6), Guanyuan (CV 4), Zigong (EX CA 1), Dahe (KI 12), Sanyinjiao (SP 6), Zhongji (CV 3), Diji (SP 8), Shenshu (BL 23), Sanjiaoshu (BL 22) and Ciliao (BL 32), etc. The treatment started on the 5th day of menstruation or medicine-withdrawal bleeding, once every two days, 3 times a week. One cycle of menstruation or 1 month was taken as one course. The treatment cycles were 3 months in the two groups. The level of estradiol (E2) and progesterone (P) in the serum, the endometrial thickness and morphology, ovulation rate and clinical pregnancy rate, as well as the clinical therapeutic effects were compared after treatment in the two groups. RESULTS: Two cases were dropped out because the herbal medicine was taken simultaneously in the acupuncture plus medication group. In the medication group, the medication was discontinued in 3 cases due to gastrointestinal adverse reactions. The total effective rate was 86.8% (33/38) in the acupuncture plus medication group, better than 64.9% (24/37) in the medication group (P<0.05). The ovulation rate in the acupuncture plus medication group was higher than that in the medication group [(86.8%, 33/38) vs (64.9% 24/37), P<0.05]. The pregnancy rate in the acupuncture plus medication group was higher than the medication group in tendency, without significant difference [21.1% (8/38) vs 16.2% (6/37), P>0.05]. After treatment, the results of endometrial thickness and morphology (A-type rate) in the acupuncture plus medication group were better than those in the medication group (P<0.01, P<0.05). After treatment, regarding the levels of E2 and P in the serum in the window period of implantation, the results in the acupuncture plus medication group were higher remarkably than those in the medication group (both P<0.01). CONCLUSION: The combined intervention of electroacupuncture and clomiphene achieves the definite effects of ovulation and pregnancy promotion in PCOS. It remarkably increases the levels of E2 and P in the serum, the endometrial thickness and A-type rate. The therapeutic effects of the combined intervention are remarkably better than those of the simple application of clomiphene. This combined intervention is safe and tolerable for the adverse reactions. The effect mechanisms may be related to the improvements of estrogen, progestin and endometrial receptivity. PMID- 29701044 TI - [Special penetration needling for refractory peripheral facial paralysis]. AB - OBJECTIVE: To observe the clinical effect difference between special penetration needling and conventional penetration needling for the refractory peripheral facial paralysis. METHODS: A total of 97 patients with intractable facial paralysis were randomized into an observation group (49 cases and 2 dropping) and a control group (48 cases and 4 dropping). In the observation group, special penetration needling at an angle about 45 degrees between the penetration needle and paralysis muscle bundle was used, Yangbai (GB 14) through Touwei (ST 8), Yangbai (GB 14) through Shangxing (GV 23), Sizhukong (TE 23) through Yuyao (EX-HN 4), Qianzhen (Extra) through Yingxiang (LI 20), mutual penetration between Yingxiang (LI 20) and Jiache (ST 6). Conventional penetration needling was applied in the control group, Yangbai (GB 14) through Yuyao (EX-HN 4), Cuanzhu (BL 2) through Yuyao (EX-HN 4), mutual penetration between Dicang (ST 4) and Jiache (ST 6), Qianzheng (Extra) through Dicang (ST 4), Sibai (ST 2) through Yingxiang (LI 20). Three groups of electroacupuncture (discontinuous wave, 1 Hz) with tolerance were connected respectively in the two groups, Yangbai (GB 14) and Sizhukong (TE 23), Yangbai (GB 14) and Qianzheng (Extra), Yingxiang (LI 20) and Jiache (ST 6) in the observation group, Yangbai (GB 14) and Cuanzhu (BL 2), Dicang (ST 4) and Jiache (ST 6), Qianzheng (Extra) and Sibai (ST 2) in the control group. TDP was applied in the two groups at the affected Yifeng (TE 17), Jiache (ST 6) and Qianzheng (Extra), which were around the ear. Perpendicular insertion was used at Yifeng (TE 17) at the affected side and Hegu (LI 4) at the healthy side and bilateral Zusanli (ST 36). The needles were retained for 30 min. The treatment was given for 3 courses, once a day and 10 days as a course, 5 days at the interval. House-Brackmann (H-B) facial nerve grading score was recorded before and after treatment. The clinical effects were compared. RESULTS: The H-B scores after treatment in the two groups were higher than those before treatment (both P<0.05), with better result in the observation group (P<0.05). The cured and markedly effective rate of the observation group was 74.5% (35/47), which was better than 47.7% (21/44) of the control group (P<0.01). CONCLUSION: Special penetration needling at an angle about 45 degrees between the penetration needle and paralysis muscle bundle is better than conventional penetration needling for refractory facial paralysis. PMID- 29701045 TI - [Effects of subcutaneous embedding of thumb-tack needle on tear film in patients with dry eye]. AB - OBJECTIVE: To observe the effects of subcutaneous embedding of thumb-tack needle combined with mytear and simple mytear on tear film in patients with dry eye. METHODS: Eighty patients of dry eye (160 eyes) were randomly divided into an observation group and a control group, 40 cases in each group. The 0.1% sodium hyaluronate eye drop (alice) was applied in the control group, four times per day for two weeks. On the basis of the control group, the subcutaneous embedding of thumb-tack needle was used at 1 Cuanzhu (BL 2), Sizhukong (SJ 23), Sibai (ST 2), 2 Yintang (EX-HN 3), Yuyao (EX-HN 4), Taiyang (EX-HN 5). The two groups of acupoints were used alternately. The thumb-tack needle was placed for 2 to 3 days, once a week for two weeks. The subjective symptom score, Schirmer I test (SIT), tear break-up time (BUT) and corneal fluorescein staining (CFS) were compared before treatment, after treatment and during 2-week follow-up visit in the two groups. The effects of the two groups were compared. RESULTS: Compared before treatment, the subjective symptom score and CFS were reduced but SIT and BUT were increased after treatment and during follow-up visit in the two groups (all P<0.05), which in the observation group were superior to those in the control group (all P<0.05). The total effective rate was 90.0% (36/40) in the observation group, which was superior to 85.0% (34/40) in the control group (P<0.05). CONCLUSION: The subcutaneous embedding of thumb-tack needle could increase the amount of SIT, prolong BUT and repair pathological damage of cornea, which could relieve the symptoms of dry eye and improve visual quality. PMID- 29701046 TI - [Discussion on the direction of moxibustion]. AB - The types of moxibustion are various and its therapeutic effect could be influenced by many factors. The clinical manipulation of moxibustion usually involves sequential order, indicating the significance of direction in moxibustion. From the relationship between moxibustion direction and propagated sensation along channel, moxibustion direction and directional supplementation and reducing and others, this article proposes moxibustion direction could be one of the key factors to influence the clinical efficacy of moxibustion. It is hoped to improve moxibustion and increase clinical efficacy. PMID- 29701047 TI - [The effects of electroacupuncture at shu and mu points of stomach on gastric motility, the NMDA of vagus nerve dorsal nucleus and serum NO expression in functional dyspepsia rats]. AB - OBJECTIVE: To research the central molecular mechanism of gastric motility in functional dyspepsia (FD) rats treated with electroacupuncture (EA) at shu and mu points of stomach. METHODS: A total of 30 SD rats were randomized into a blank group, a model group, a Zhongwan+Weishu group, a Weishu group and a Zhongwan group, 6 rats in each group. FD rats were established by moderate clipping tail infuriation and irregular feeding except in the blank group. EA was used at "Zhongwan"(CV 12),"Weishu"(BL 21), and"Zhongwan"(CV 12) +"Weishu"(BL 21) in the corresponding groups for 7 days, once a day, and 20 min a time. No intervention was used in the blank and model groups. Grabbing and fixation were applied in the model group. Gastric antrum motion range and frequency were recorded by gastrointestinal pressure transducer. The expression of subunit NR1 of N-methyl-D aspartate recepter (NMDAR) in dorsal motor nucleus of the vagus (DMV) was determined by Western blotting. The content of serum nitric oxide (NO) was measured by ELISA. RESULTS: Compared with the blank group, the gastric antrum motion range and NR1 in the DMV decreased and the serum NO content increased in the model group (all P<0.05). Compared with the model group, the gastric antrum motion range and NR1 in the DMV increased and the serum NO content decreased in the three EA groups (all P<0.05). Compared with the Zhongwan and Weishu groups, the gastric antrum motion range and NR1 in the DMV increased in the Zhongwan + Weishu group (all P<0.05). Compared with Zhongwan + Weishu and Zhongwan groups, the expression of NO in the Weishu group decreased (both P<0.05). The gastric antrum motion frequency among the 5 groups had no statistical significance (all P>0.05). CONCLUSION: EA at the shu and mu points can regulate the gastric motility in FD rats which may be by modulating the activity of NMDAR in the central DMV region, thus regulating the serum NO content. PMID- 29701048 TI - [Mechanism of thermosensitive moxibustion on knee osteoarthritis in rabbit models]. AB - OBJECTIVE: To observe the impacts of thermosensitive moxibustion (TSM) on the expressions of nitric oxide (NO), typeIdisintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4), typeIIcollagen and proteoglycan (PG) in the rabbit models of knee osteoarthritis (KOA) and explore the mechanism of TSM on KOA. METHODS: A total of 42 Japanese long-eared male rabbits were divided into a blank group (6 rabbits), a model group (6 rabbits), a moxibustion group (24 rabbits) and a sham-operation group (6 rabbits) according to the random number table. In the blank group, the rabbits were fed normally. In the model and moxibustion groups, the papain injection was given to establish KOA models. The rabbits in the sham-operation group were treated with the intracavity injection of 0.9% NaCl solution. The rabbits were forced to move for 30 min every day, continuously for 15 days during modeling. At the end of modeling, in the moxibustion group, moxibusiton was applied at "Dubi" (ST 35), once a day, 40 min each time, for 14 days totally. According to the temperature changes during moxibustion, the rabbits were divided into a TSM group and a non-TSM group. 6 rabbits were collected randomly from the two groups. The usual feeding was given in the blank group, the model group and the sham-operation group, without any intervention. The body mass and behavioristics changes were observed in each group. At the end of treatment, the nitrate reduction method was adopted to determine NO expression in the serum. The real-time PCR was adopted to determine the expressions of ADAMTS-4, typeIIcollagen and PG in the cartilage. RESULTS: 1 After modeling, compared with the blank group, the body mass was all reduced and the Lequesne MG score was increased in the model group, TSM group, non-TSM group and sham-operation group (P<0.05, P<0.01). After intervention, compared with the blank group, the body mass was decreased and the Lequesne MG score was increased in the model and sham-operation groups (P<0.05, P<0.01). Compared with the model group, the body mass was increased and the lequesne MG score was decreased in the TSM, non-TSM, and sham-operation groups (P<0.05, P<0.01). Compared with the non TSM group, the body mass in the TSM group was increased remarkably (P<0.05), but the difference in Lequesne MG score was not statistically significant (P>0.05). 2 After intervention, compared with the blank group, the expressions of NO and ADAMTS-4 were all increased and the expressions of typeIIcollagen and PG were decreased in the model group, TSM group, non-TSM group and sham-operation group (P<0.05, P<0.01). Compared with the model group, the expressions of NO and ADAMTS 4 were all remarkably lower and the expressions of typeIIcollagen and PG were increased in the TSM group, non-TSM group and sham-operation group (P<0.05, P<0.01). Compared with the non-TSM group, the expressions of NO and ADAMTS-4 were all remarkably lower and the expressions of typeIIcollagen and PG were increased in the TSM group after intervention (all P<0.05). CONCLUSION: The thermosensitive moxibustion alleviates the inflammatory reactions and protects the joint cartilage through inhibiting the expressions of NO and ADAMTS-4 to achieve the effects in the treatment of KOA. PMID- 29701049 TI - [Analysing the defect of control design of acupuncture: taking RCTs of treating simple obesity with acupuncture for example]. AB - OBJECTIVE: By analysing the defect of control design in randomized controlled trials (RCTs) of simple obesity treated with acupuncture and using acupuncture as the contrast, presenting the essential factors which should be taken into account as designing the control of clinical trial to further improve the clinical research. METHODS: Setting RCTs of acupuncture treating simple obesity as a example, we searched RCTs of acupuncture treating simple obesity with acupuncture control. According to the characteristics of acupuncture therapy, this research sorted and analysed the control approach of intervention from aspects of acupoint selection, the penetration of needle, the depth of insertion, etc, then calculated the amount of difference factor between the two groups and analyzed the rationality. RESULTS: In 15 RCTs meeting the inclusion criterias, 7 published in English, 8 in Chinese, the amount of difference factors between two groups greater than 1 was 6 (40%), 4 published in English abroad, 2 in Chinese, while only 1 was 9 (60%), 3 published in English, 6 in Chinese. CONCLUSION: Control design of acupuncture in some clinical RCTs is unreasonable for not considering the amount of difference factors between the two groups. PMID- 29701050 TI - [Clinical application of "categorization by analogy" in acupuncture for pain syndromes]. AB - The"categorization by analogy"is one of the most primitive thinking methods for ancient people to explore the world, which has exerted far-reaching impact on the origin and development of TCM. With examples of Sanjian (LI 3) for neck pain, Chize (LU 5) for low back pain and Chengshan (BL 57) for dysmenorrhea, the clinical application of"categorization by analogy"in acupuncture for pain syndromes was discussed, hoping more acupuncturists will pay attention to the guiding role of"categorization by analogy"in acupuncture clinical treatment. PMID- 29701051 TI - [Development of the connotation of deficiency and excess and acupuncture reinforcing and reducing theory]. AB - There are connotations on regulating deficiency and excess by acupuncture reinforcing and reducing in Neijing (the Internal Canon of Medicine), including regulating yin and yang, regulating blood and qi, regulating weakened body resistance and state of evil domination, regulating the deficiency and excess of syndrome. The deficiency and excess usually mean the objects received reinforcing and reducing, such as tangible blood stasis, pus, water, etc, and invisible qi. The deficiency and excess had always mean the symptoms of diseases since Nanjing (Classic of Questioning), and the reinforcing and reducing of acupuncture was regulating qi. Therefore the connotations of reinforcing and reducing of acupuncture changed and there were complex acupuncture reinforcing and reducing manipulations. The various deficiency and excess connotations and stressing on acupuncture regulating qi made important changes for the theories and methods of acupuncture reinforcing and reducing which showed the profound impacts of the philosophical thought of qi monism in ancient China on acupuncture and moxibustion science. PMID- 29701052 TI - [Discussion on relationship between "living alone with closed windows and doors" and depression]. AB - "Living alone with closed windows and doors"was mentioned in the pathological manifestations of stomach meridian of foot-yangming in Neijing (The Inner Canon of Huangdi), which is similar to the symptoms of depression. Currently the treatment of depression is mostly based on"spirit being stored in five organs"theory, and little attention is paid on stomach meridian of foot-yangming. From the pathological manifestations of"living alone with closed windows and doors"in stomach meridian of foot-yangming, the relationship between stomach meridian and depression is discussed from ying-yang and qi-blood. In addition, the close relationship between the stomach meridian and qi-blood, qi movement of five organs, heart and brain is discussed to explore the mechanism of treating depression. In conclusion, the literature and modern research regarding treating depression from stomach meridian are summarized, hoping to provide more clinical methods for the treatment of depression. PMID- 29701053 TI - [Discussion of mechanism on acupoint embedding for obesity]. AB - To explore the mechanism of acupoint embedding for obesity based on the western pathological mechanism of chronic low inflammatory response inducing the imbalance between"promoting inflammation"and"anti-inflammation"in immune reaction, and the pathological nature of deficient healthy qi and state of evil domination in the TCM theory induced by the"stagnation heat, phlegm heat, dampness heat, stasis heat"on the basis of qi deficiency. The mechanism may be improving the secretory disorder of adipose tissue and metabolic inflammatory response by the enhanced anti-inflammatory phagocytosis clearance ability in the immune system which is caused by the new inflammatory reaction under the stimulation of innate immune response pattern. The model of"inhibiting chronic low inflammation reaction through the innate immunity"may be an important mechanism of acupoint embedding for obesity. PMID- 29701054 TI - [Statistics and analysis on acupuncture and moxibustion projects of the National Natural Science Foundation of China of traditional Chinese medicine universities and colleges in recent 10 years: taking the General Program and National Science Fund for Young Scholars as examples]. AB - To analyze statistically the situation of the National Natural Science Foundation of China (NSFC) from 2007 to 2016 in the field of acupuncture and moxibustion for supporting the national Universities colleges of traditional Chinese medicine on the General Program (GP) and the National Science Fund for Young Scholars (NSFYS). In view of five aspects, named fund, supporting units, key words, method, disorder and signal path, the differences were compared between GP and NSFYS, the following characteristics were summarized. 1 The fund aid was increased from 2007 through 2013 and down-regulated from 2013 through 2016. In recent ten years, the funding condition was fluctuated, but increasing in tendency generally. 2 The relevant projects of the same research direction had been approved continuously for over 3 years in a part of TCM universities, in which, the research continuity was the hot topic. 3 Regarding the therapeutic methods, acupuncture was the chief therapy; electroacupuncture, moxibustion and acupoints were involved as well. 4 The disorders involved in the research were cerebral ischemia, myocardial ischemia and reperfusion injury. It is suggested that the ischemic disorder is predominated in the research. 5 The signal path occupied the main research index system, including cell proliferation, metabolism, immune, apoptosis and autophagy. The researches on the other aspects were less. PMID- 29701055 TI - [Prescription analysis of electroacupuncture for simple obesity based on complex network technique]. AB - OBJECTIVE: To analyze the core acupoints and compatibility of electroacupuncture (EA) for simple obesity based on complex network technique, and to explore the usage of EA waveform. METHODS: The clinical research literature regarding EA for simple obesity published from January of 1980 to June of 2016 were searched in PubMed, CNKI, WanFang, VIP, CBM and TCM online database to establish a prescription database of EA for simple obesity. The Matlab2014a software was used to perform the center analysis and cluster analysis, and the analysis of core points and compatibility were conducted. Gephi 9.1 software was used to demonstrate the complex network diagram to further analyze the usage of EA waveform. RESULTS: Totally 238 prescriptions were obtained. The selection of acupoints at yang-meridians were equally important with acupoints at yin meridians. The meridians with highest core degree were stomach meridian, conception vessel and spleen meridian. The acupoints with highest core degree were Sanyinjiao (SP 6), Tianshu (ST 25) and Zusanli (ST 36). The cluster analysis indicated three acupoint clusters, including the key-acupoint cluster, syndrome acupoint cluster, and ashi-point cluster; it was revealed Tianshu (ST 25) and Zhongwan (CV 12) had the highest intensity of compatibility. The sparse-dense wave was mostly used in EA for simple obesity, followed by continuous wave, indicating both sparse-dense wave and continuous wave had high clinical application value. CONCLUSION: The acupoints of EA for simple obesity are mainly in stomach meridian, conception vessel and spleen meridian; sparse-dense wave is mostly used, followed by continuous wave. PMID- 29701056 TI - [Current situation and existing problems of acupuncture for primary hypertension]. AB - OBJECTIVE: To analyze the present situation and existing problems of acupuncture for primary hypertension (PH) based on clinical research literature in recent 20 years. METHODS: The clinical research literature regarding acupuncture for PH were searched from China National Knowledge Infrastructure (CNKI), VIP data network (VIP) and Wanfang database from 1997 through 2016; a total of 218 papers met the inclusive criteria. Microsoft Excel and Apriori algorithm of SPSS Clementine software were applied to analyze the data. RESULTS: The main acupoints of acupuncture for PH were Taichong (LR 3), Quchi (LI 11), Zusanli (ST 36) and Hegu (LI 4), but its support degree was only 12.21%. 127 papers were randomized controlled trials, accounting for 58.26%. 158 papers had clear diagnostic criteria, accounting for 72.48%. 138 papers had clear efficacy evaluation criteria, accounting for 63.30%. Only 5.05% of the papers were classified as high quality literature by using Jadad scale. CONCLUSION: In recent 20 years, some rules existed in acupoint selection for PH, but the support degree was low so it could not accurately guide clinical treatment. Although the clinical literature quality of acupuncture for PH was gradually increasing, the proportion of high quality literature was low, therefore modern medical research model and foreign similar research should be followed to design a more rigorous trial protocol. As a result, the quality of clinical research is increased to provide reference for future clinical treatment. PMID- 29701057 TI - Transovarial persistence of Babesia ovata DNA in a hard tick, Haemaphysalis longicornis, in a semi-artificial mouse skin membrane feeding system. PMID- 29701058 TI - Perturbing Tandem Energy Transfer in Luminescent Heterobinuclear Lanthanide Coordination Polymer Nanoparticles Enables Real-Time Monitoring of Release of the Anthrax Biomarker from Bacterial Spores. AB - Lanthanide-based luminescent sensors have been widely used for the detection of the anthrax biomarker dipicolinic acid (DPA). However, mainly based on DPA sensitization to the lanthanide core, most of them failed to realize robust detection of DPA in bacterial spores. We proposed a new strategy for reliable detection of DPA by perturbing a tandem energy transfer in heterobinuclear lanthanide coordination polymer nanoparticles simply constructed by two kinds of lanthanide ions, Tb3+ and Eu3+, and guanosine 5'-monophosphate. This smart luminescent probe was demonstrated to exhibit highly sensitive and selective visual luminescence color change upon exposure to DPA, enabling accurate detection of DPA in complex biosystems such as bacterial spores. DPA release from bacterial spores on physiological germination was also successfully monitored in real time by confocal imaging. This probe is thus expected to be a powerful tool for efficient detection of bacterial spores in responding to anthrax threats. PMID- 29701059 TI - Probing Graphene Interfacial Reactivity via Simultaneous and Colocalized Raman Scanning Electrochemical Microscopy Imaging and Interrogation. AB - Addressing challenges in interfacial electrochemistry requires multimodal approaches that correlate the local structure and reactivity of materials with high spatial and temporal versatility. Here, we introduce spatiotemporally correlated Raman spectroscopy and scanning electrochemical microscopy (SECM) to study the impact that structural heterogeneities, interfacial decomposition products, and layer number have on the electron-transfer properties of graphene electrodes. By colocalizing the SECM probe and laser line, we successfully obtained congruent SECM and Raman images at a rate of 5 s per pixel with sub-10 MUm resolution, obtaining full spectra per pixel at a signal-to-noise ratio as high as ~20. SECM imaging of a micropatterned graphene electrode showed its reactivity to be highly dependent on the intensity of the G peak, an indicator of the number of graphene layers. We further monitored the impact of excursions to positive potentials using the [Fe(CN)6]3-/4- redox pair as mediator. Raman-SECM allowed us to decouple the contributions to the redox response of different structural effects including exfoliation, increase in defect density, and surface film formation, on the same site and in real time. The coupling of in situ Raman spectroscopy and SECM provides a powerful surface-sensitive analytical approach to elucidate interfacial properties relevant to energy, catalysis, and sensing. PMID- 29701060 TI - Modulation of the Reduction Potential of TiO2- x by Fluorination for Efficient and Selective CH4 Generation from CO2 Photoreduction. AB - Photocatalytic reduction of CO2 holds great promises for addressing both the environmental and energy issues that are facing the modern society. The major challenge of CO2 photoreduction into fuels such as methane or methanol is the low yield and poor selectivity. Here, we report an effective strategy to enhance the reduction potential of photoexcited electrons by fluorination of mesoporous single crystals of reduced TiO2- x. Density functional theory calculations and photoelectricity tests indicate that the Ti3+ impurity level is upswept by fluorination, owing to the built-in electric field constructed by the substitutional F that replaces surface oxygen vacancies, which leads to the enhanced reduction potential of photoexcited electrons. As a result, the fluorination of the reduced TiO2- x dramatically increases the CH4 production yield by 13 times from 0.125 to 1.63 MUmol/g.h under solar light illumination with the CH4 selectivity being improved from 25.7% to 85.8%. Our finding provides a metal-free strategy for the selective CH4 generation from CO2 photoreduction. PMID- 29701061 TI - Unusual Temperature Dependence of Nanoscale Structural Organization in Deep Eutectic Solvents. AB - In a recent work, we reported the existence of nanoscale spatial organization in (alkylamide + Li+/ClO4-)-based deep eutectic solvents (DESs). We also described that the nanoscale organization in these systems was primarily due to ion-pair self-segregation. This segregation also accompanied prominent interaction between the ionic species of the electrolyte and alkylamide polar groups. In the present study, we show that for the DESs studied, the intensity of the prepeak, the so called marker of the nanoscale heterogeneity, in the X-ray and neutron scattering structure functions increases upon increasing temperature. Herein, we show that the increase in the heterogeneity is because of the enhanced correlations between the ionic species at higher temperature. We also show that the rate of enhancement in the ionic correlations with temperature is more than the rate of diminution in the electrolyte-alkylamide cross-correlations. The alkylamide alkylamide correlations are largely unaffected by any change in the temperature. PMID- 29701062 TI - Ultrathin Bismuth Film on 1T-TaS2: Structural Transition and Charge-Density-Wave Proximity Effect. AB - We have fabricated bismuth (Bi) ultrathin films on a charge-density-wave (CDW) compound 1T-TaS2 and elucidated electronic states by angle-resolved photoemission spectroscopy and first-principles band-structure calculations. We found that the Bi film on 1T-TaS2 undergoes a structural transition from (111) to (110) upon reducing the film thickness, accompanied by a drastic change in the energy band structure. We also revealed that while two-bilayer-thick Bi(110) film on Si(111) is characterized by a dispersive band touching the Fermi level ( EF), the energy band of the same film on 1T-TaS2 exhibits holelike dispersion with a finite energy gap at EF. We discuss the origin of such intriguing differences in terms of the CDW proximity effect. PMID- 29701063 TI - Dual Role of Multiroom-Structured Sn-Doped NiO Microspheres for Ultrasensitive and Highly Selective Detection of Xylene. AB - Sn-doped NiO multiroom spheres with unique microreactor morphology were prepared by facile ultrasonic spray pyrolysis of a solution containing tin oxalate, nickel nitrate, and dextrin and subsequent heat treatment. The multiroom structure was formed by phase segregation between the molten metal source and liquidlike dextrin and sequent decomposition of dextrin during spray pyrolysis, which played the dual roles of enhancing gas response and selectivity. The response (resistance ratio) of the Sn-doped NiO multiroom spheres to 1 ppm p-xylene was as high as 65.4 at 300 degrees C, which was 50.3 and 9.0 times higher than those of pure NiO multiroom spheres and Sn-doped NiO dense spheres, respectively. In addition, the Sn-doped NiO multiroom sensors showed a high selectivity to xylene. The unprecedented high response that enables the sensing of sub-ppm xylene was explained by the high gas accessibility of the multiroom structures and the Sn doping-induced change in oxygen adsorption as well as the charge carrier concentration, whereas the high xylene selectivity was attributed to the decomposition/re-forming of xylene into smaller or more active species within the unique multiroom structure of Sn-doped NiO microreactors characterized by high catalytic activities. The multiroom oxide spheres can be used as a new and generalized platform to design high-performance gas sensors. PMID- 29701064 TI - Electrocatalytic Oxidation of Tris(2-carboxyethyl)phosphine at Pyrroloquinoline Quinone Modified Carbon Nanotube through Single Nanoparticle Collision. AB - Inspired by the addition-elimination catalytic mechanism of natural pyrroloquinoline quinone (PQQ) containing proteins, PQQ-modified hybrid nanomaterials have been increasingly developed recently as biomimetic heterogeneous electrocatalysts. However, up until now, no existing electrochemical approach was able to assess the intrinsic catalytic activity of PQQ sites, impeding the design of efficient PQQ-based electrocatalysts. Herein, in this work, we introduced a new method to calculate the turnover frequency (TOF) of any individual PQQ functional group for electrocatalytic oxidation of tris(2-carboxyethyl)phosphine (TCEP), through the study of single PQQ-decorated carbon nanotube (CNT) collisions at a carbon fiber ultramicroelectrode by chronoamperometry. The core advantage of this approach is being able to resolve the number of PQQ catalytic sites grafted on each individual CNT, so that the charge of any CNT collision event can be accurately translated into the intrinsic activity of the respective PQQ functional groups. The resulting collision-induced current responses clearly showed that the functionalization of CNTs with PQQ could indeed enhance its catalytic performance by 3 times, reaching a TOF value of 133 s-1 at 1.0 V vs Ag/AgCl. Such a single CNT collision technique, which is proposed for the first time in this work, can open up a new avenue for studying the intrinsic (electro)catalytic performance at a molecular level. PMID- 29701065 TI - Total Synthesis of Natural Hyacinthacine C5 and Six Related Hyacinthacine C5 Epimers. AB - The total synthesis of natural (+)-hyacinthacine C5 was achieved, which allowed correction of its initially proposed structure, as well as six additional hyacinthacine C-type compounds. These compounds were readily accessible from two epimeric anti-1,2-amino alcohols. Keeping a common A-ring configuration, chemical manipulation occurred selectively on the B-ring of the hyacinthacine C-type products through methods of syn-dihydroxylation, SN2 ring-opening of a cyclic sulfate, and also employing either ( R)- or ( R, S)-alpha-methylallyl amine for the Petasis borono Mannich reaction. Our small analogue library was then assessed for its glycosidase inhibitory potency against a panel of glycosidases. (-)-6- Epi-hyacinthacine C5 and (+)-7- epi-hyacinthacine C5 (compound names are based on the corrected structure of hyacinthacine C5) proved most active, with inhibitory activities ranging between weak (IC50 = 130 MUM) and moderate (IC50 = 9.9 MUM) against the alpha-glucosidases of rat intestinal maltase, isomaltase, and sucrase, thus identifying potential new leads for future antidiabetic drug development. PMID- 29701067 TI - A cluster and inferential analysis of myocardial infarction symptom presentation by age. AB - BACKGROUND: Pre-hospital delay time in myocardial infarction is usually longer in older than in younger patients, with symptom presentation known to be a contributing factor. AIM: The aim of this article is to examine symptom presentation differences, by age, in patients with myocardial infarction. METHODS: This is a cross-sectional study using secondary analysis of a multi-site randomised controlled trial on pre-hospital delay time. Data were analysed using logistic regression and factor analysis. RESULTS: Post-myocardial infarction patients were recruited prior to discharge ( n=1211), 54% were >=65 years and 80% male. The average number of symptoms was three, with the >=65 years age group reporting significantly less symptoms. Logistic regression controlling for gender, diabetes and diagnosis with 11 symptoms (chi2=52.09, p<0.001) was significant. Those >=65 years had less chest symptoms, sweating, stomach upset and left arm pain, in addition to longer pre-hospital delay time. This group also had less symptom clustering and fewer symptoms within atypical clusters. Non chest clusters occurred in 22% and 18% of the older and younger group respectively. Of note, two clusters 'atypical' (upset stomach/sweating) and 'typical arm' (right and left arm pain symptoms), accounted for 14% and 5% of myocardial infarction presentations in the >=65 years group, within which 25% and 24% had no chest symptoms. CONCLUSIONS: The results of this study indicate that myocardial infarction symptom presentation in older patients is likely to be less recognisable and more complex. Increased awareness of the presentation profile of older patients could expedite their triage, diagnosis and, consequently, their prognosis. PMID- 29701068 TI - Corrigendum: Molecular identification of species of Physalis (Solanaceae) using a candidate DNA barcode: the chloroplast psbA-trnH intergenic region. PMID- 29701069 TI - Immunohistochemical examination of osteopontin and sirtuin-1 expression in cattle tuberculosis. AB - We evaluated osteopontin (OPN) and sirtuin-1 (SIRT-1) expression in bovine tuberculosis lesions. The organs of cattle with tuberculosis (TB) were examined for morphology, histopathology and immunohistochemistry of OPN and SIRT-1 expression. Macroscopic lesions commonly were localized in the lungs and mediastinal lymph nodes as well as in livers and hearts. Mycobacterial agents were detected in lesions using the Ziehl-Neelsen method. No OPN or SIRT-1 expression was detected by immunohistochemistry in normal tissues, whereas a marked increase in their expressions was observed in tuberculous lesions. The most intense immunopositive cells were Langerhans giant cells and inflammatory cells. Our findings indicate that OPN and SIRT-1 participate in the pathogenesis of bovine TB. PMID- 29701070 TI - The Role of 3D Reconstruction True-Volume Analysis in Osteochondral Lesions of the Talus: A Case Series. AB - BACKGROUND: Evaluation and management of osteochondral lesions of the talus (OLTs) often warrant advanced imaging studies, especially in revision or cases with cystic defects. It is possible that orthopedic surgeons may overestimate the size and misinterpret the morphology of OLT from conventional computed tomography (CT), thereby influencing treatment strategies. The purpose of this study was to determine the utility of a novel means to estimate the true-volume of OLTs using 3D reconstructed images and volume analysis. METHODS: With Institutional Review Board approval, an institutional radiology database was queried for patients with cystic OLTs that failed previous microfracture, having compatible CT scans and magnetic resonance imaging (MRI) between 2011 and 2016. Fourteen patients met inclusion criteria. Of these, 5 cases were randomly selected for 3D CT reconstruction modeling. Ten orthopedic surgeons independently estimated the volume of these 5 OLTs via standard CT. Then 3D reconstructions were made and morphometric true-volume (MTV) analysis measurements of each OLT were generated. The percent change in volumes from CT were compared to MTVs determined from 3D reconstructive analysis. RESULTS: On average, the volume calculated by conventional CT scanner grossly overestimated the actual size of the OLTs. The volume calculated on conventional CT scanner overestimated the size of OLTs compared to the 3D MTV reconstructed analysis by 285% to 864%. CONCLUSIONS: Our results showed that conventional measurements of OLTS with CT grossly overestimated the size of the lesion. The 3D MTV analysis of cystic osteochondral lesions may help clinicians with preoperative planning for graft selection and appropriate volume while avoiding unnecessary costs incurred with overestimation. LEVEL OF EVIDENCE: Level IV, case series. PMID- 29701066 TI - 11th GCC Closed Forum: cumulative stability; matrix stability; immunogenicity assays; laboratory manuals; biosimilars; chiral methods; hybrid LBA/LCMS assays; fit-for-purpose validation; China Food and Drug Administration bioanalytical method validation. AB - The 11th Global CRO Council Closed Forum was held in Universal City, CA, USA on 3 April 2017. Representatives from international CRO members offering bioanalytical services were in attendance in order to discuss scientific and regulatory issues specific to bioanalysis. The second CRO-Pharma Scientific Interchange Meeting was held on 7 April 2017, which included Pharma representatives' sharing perspectives on the topics discussed earlier in the week with the CRO members. The issues discussed at the meetings included cumulative stability evaluations, matrix stability evaluations, the 2016 US FDA Immunogenicity Guidance and recent and unexpected FDA Form 483s on immunogenicity assays, the bioanalytical laboratory's role in writing PK sample collection instructions, biosimilars, CRO perspectives on the use of chiral versus achiral methods, hybrid LBA/LCMS assays, applications of fit-for-purpose validation and, at the Global CRO Council Closed Forum only, the status and trend of current regulated bioanalytical practice in China under CFDA's new BMV policy. Conclusions from discussions of these topics at both meetings are included in this report. PMID- 29701071 TI - Surface plasmon resonance as a tool for ligand-binding assay reagent characterization in bioanalysis of biotherapeutics. AB - Ligand-binding assay (LBA) performance depends on quality reagents. Strategic reagent screening and characterization is critical to LBA development, optimization and validation. Application of advanced technologies expedites the reagent screening and assay development process. By evaluating surface plasmon resonance technology that offers high-throughput kinetic information, this article aims to provide perspectives on applying the surface plasmon resonance technology to strategic LBA critical reagent screening and characterization supported by a number of case studies from multiple biotherapeutic programs. PMID- 29701072 TI - Outcome of trabeculectomy with Ologen versus Mitomycin C: A comparative prospective study in Bangladesh. AB - AIMS: To compare the efficacy and safety of trabeculectomy with Ologen versus Mitomycin C in primary glaucoma Materials and methods: This is a prospective study of patients aged 18 years and above, diagnosed with primary glaucoma randomised to having trabeculectomy with Ologen or Mitomycin C. The primary outcome measure was success of trabeculectomy defined as intraocular pressure >5 mmHg but <=21 mmHg. Complete success was defined as intraocular pressure achieved without anti-glaucoma medication and qualified success was defined as intraocular pressure achieved with additional anti-glaucoma medication. RESULTS: At the end of 12 months follow-up, the postoperative mean intraocular pressure in the Ologen group was 12.8 +/- 1.6 mmHg and 13.4 +/- 2.2 mmHg in the Mitomycin C group. The Ologen group achieved complete success in 86.5% and qualified success in 13.5% of the patients, while the Mitomycin C group achieved complete and qualified success in 85.5% and 14.5%, respectively. There was no statistically significant difference in the success rate of both the groups ( p = 0.57). Furthermore, no significant intraocular pressure difference was noted between the two groups at the end of 12 months follow-up ( p = 0.14). CONCLUSION: Trabeculectomy augmented with Ologen appeared to be as successful and safe as trabeculectomy augmented with Mitomycin C, with no reported adverse reaction to Ologen. PMID- 29701074 TI - Thymidine phosphorylase: the unforeseen driver in colorectal cancer treatment? AB - 5-Fluorouracil- and leucovorin-based chemotherapy regimens are the backbone of colorectal cancer treatment. The addition of oxaliplatin, irinotecan and monoclonal antibodies to this backbone has largely improved clinical outcomes, but has also led to new questions, with conflicting data frequently reported in studies. Thymidine phosphorylase (TP) is a nucleoside-metabolizing enzyme involved in 5-fluorouracil pharmacokinetics, as well as inflammatory responses, neoangiogenesis and apoptosis. TP expression is regulated by hypoxia, inflammatory cytokines and antitumoral agents. We hypothesize that TP could be the unforeseen driver in the conflicting data observed with different regimens commonly used in colorectal cancer treatment. Greater comprehension of the role of this enzyme in tumor progression and pyrimidine metabolism may lead to more accurate, patient-tailored therapy. PMID- 29701073 TI - Sexual behavior and HIV risk across the life course in rural South Africa: trends and comparisons. AB - There is limited information about sexual behavior among older Africans, which is problematic given high HIV rates among older adults. We use a population-based survey among people aged 15-80+ to examine the prevalence of sexual risk and protective behaviors in the context of a severe HIV epidemic. We focus on variation across the life course, gender and HIV serostatus to compare the similarities and differences of young, middle aged, and older adults. Younger adults continue to be at risk of HIV, with potential partners being more likely to have been diagnosed with an STI and more likely to have HIV, partner change is high, and condom use is low. Middle aged and older adults engage in sexual behavior that makes them vulnerable at older ages, including extramarital sex, low condom use, and cross-generational sex with people in age groups with the highest rates of HIV. We find insignificant differences between HIV positive and negative adults' reports of recent sexual activity. This study provides new information on sexual behavior and HIV risk across the life course in rural South Africa to inform HIV prevention and treatment programing. PMID- 29701075 TI - Knowledge about HIV, HBV and HCV modes of transmission among pregnant women in Nampula - Mozambique. AB - The assessment of pregnant women's knowledge about modes of infections transmission is essential to tailor programs to their needs. This study aimed to assess knowledge about human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) among pregnant women in Nampula - Mozambique, a high-risk area for sexually transmitted infections. At their first antenatal visit, women were invited to participate and data were collected by trained nurses at six public health facilities. Knowledge about HIV transmission modes was high but relevant misconceptions remained. However, knowledge regarding HBV and HCV transmission modes was very limited. There was a significant association between knowledge level and socioeconomic position, making education and women's empowerment key factors in a comprehensive strategy to prevent infections. PMID- 29701076 TI - Trifluridine/tipiracil: an emerging strategy for the management of gastrointestinal cancers. AB - Fluoropyrimidines are currently the backbone of treatment for gastrointestinal (GI) cancers but development of resistance to these agents remains a major problem. Trifluridine/tipiracil is an oral chemotherapeutic agent recently approved for third-line treatment of chemorefractory metastatic colorectal cancer. This article reviews the clinical value of trifluridine/tipiracil as a monotherapy, including recent trials in GI cancers, and the potential benefit of combining it with other agents in patients with GI cancers, including the preclinical rationale for combination therapy and recently completed and ongoing clinical trials. Data gathered so far suggest that trifluridine/tipiracil has the potential to form the chemotherapeutic backbone in the continuum of care for GI cancers in the future. PMID- 29701078 TI - Genotype-guided warfarin therapy: current status. AB - Warfarin pharmacogenomics has been an extensively studied field in the last decades as it is focused on personalized therapy to overcome the wide interpatient warfarin response variability and decrease the risk of side effects. In this expert review, besides briefly summarizing the current knowledge about warfarin pharmacogenetics, we also present an overview of recent studies that aimed to assess the efficacy, safety and economic issues related to genotype based dosing algorithms used to guide warfarin therapy, including randomized and controlled clinical trials, meta-analyses and cost-effectiveness studies. To date, the findings still present disparities, mostly because of standard limitations. Thus, further studies should be encouraged to try to demonstrate the benefits of the application of warfarin pharmacogenomic dosing algorithms in clinical practice. PMID- 29701077 TI - A Combination of NT-4/5 and GDNF Is Favorable for Cultured Human Nigral Neural Progenitor Cells. AB - Idiopathic Parkinson's disease (PD) is a progressive neurodegenerative disorder, clinically manifested by cardinal motor symptoms including tremor at rest, bradykinesia, and muscle rigidity. Transplantation of dopaminergic (DAergic) neurons is an experimental therapy for PD, however, it is limited by suboptimal integration and low survival of grafts. Pretreatment of donor tissue may offer a strategy to improve properties of transplanted DAergic neurons and thereby clinical outcome. We have previously shown that a combination of neurotrophin-4/5 (NT-4/5) and glial cell line-derived neurotrophic factor (GDNF) demonstrated additive effects on rat ventral mesencephalic (VM) tissue. The present study investigated the effects of NT-4/5 and GDNF as single factors, or in combination on DAergic neurons, in organotypic explant cultures of fetal human ventral mesencephalon. For that purpose, free-floating roller-tube cultures were prepared from VM and the equally sized pieces grown for 1 week in the presence or absence of neurotrophic factors. Both neurotrophic factors increased dopamine content in the culture medium and in the number of tyrosine hydroxylase immunoreactive neurons, most prominently after combined GDNF + NT-4/5 treatment. Culture volumes did not differ between groups while content of lactate dehydrogenase in the culture medium was moderately reduced in all treated groups. In conclusion, we identified that a combination of GDNF and NT-4/5 robustly promoted differentiation and survival of human fetal VM DAergic neurons, an observation with potential promising impact for cell replacement approaches in PD. PMID- 29701079 TI - Utility of mitochondrial CO1 sequences for species discrimination of Spirotrichea ciliates (Protozoa, Ciliophora). AB - Ciliates are a diverse species group of the Protozoa, and nuclear and mitochondrial genes have been utilized to discover new species and discriminate closely related species. The mitochondrial cytochrome c oxidase subunit 1 (CO1) gene has been used to discriminate metazoan species and has also been applied for some groups in the phylum Ciliophora. However, it is difficult to produce a universal primer as a standard barcode, because unlike metazoans, mitochondrial DNA sequences of ciliates are long and highly variable. Therefore, to design the new primer set, we sequenced the mitochondrial genomes of two pseudokeronopsids in the class Spirotrichea using next-generation sequencing technology (HiSeqTM 2000). Based on putative CO1 gene fragments of the pseudokeronopsids, we designed the new primer set and successfully sequenced the CO1 of 69 populations representing 47 species (five orders, 14 families, and 27 genera). We found that CO1 showed higher resolution for separating congeneric species than did nuclear SSU rRNA gene sequences, and we identified some putative cryptic species. PMID- 29701080 TI - Adherence to iron chelation therapy in patients who switched from deferasirox dispersible tablets to deferasirox film-coated tablets. AB - OBJECTIVE: To compare real-world adherence to and persistence with deferasirox film-coated tablets (DFX-FCT) and deferasirox dispersible tablets (DFX-DT) among patients who switched from DFX-DT to DFX-FCT, overall and by disease type (sickle cell disease [SCD], thalassemia, and myelodysplastic syndrome [MDS]). METHODS: Patients were >=2 years old and had >=2 DFX-FCT claims over the study period and >=2 DFX-DT claims before the index date (first DFX-FCT claim). The DFX-DT period was defined from the first DFX-DT claim to the index date; the DFX-FCT period was defined from the index date to the end of the study period. Adherence was measured as medication possession ratio (MPR) and proportion of days covered (PDC). Persistence was defined as continuous medication use without a gap >=30 or 60 days between refills. Comparisons were conducted using paired-sample Wilcoxon sign-rank and McNemar's tests. RESULTS: In total, 606 patients were selected (SCD: 348; thalassemia: 107; MDS: 106; other: 45). Adherence and persistence in the DFX-FCT vs DFX-DT period was significantly higher across all measures: mean MPR was 0.80 vs 0.76 (p < .001); 60.9% vs 54.3% of patients had MPR >= 0.8 (p = .009); mean 3-month PDC was 0.83 vs 0.71 (p < .001); 64.2% vs 45.4% of patients had 3-month PDC >= 0.8 (p < .001); 87.2% vs 63.4% of patients had 3-month persistence with no gap >=30 days and 96.1% vs 79.9% with no gap >=60 days (p < .001). Adherence and persistence improved after switching across all diseases, particularly MDS. CONCLUSIONS: Adherence and persistence improved significantly after switching from DFX-DT to DFX-FCT for all diseases, but especially MDS. PMID- 29701081 TI - Human charcoal-stripped serum supplementation enhances both the stearoyl-coenzyme a desaturase 1 activity of cumulus cells and the in vitro maturation of oocytes. AB - Obtaining a better outcome in assisted reproductive technology remains to be attained. In the case of in vitro fertilization (IVF), oocyte maturity is paramount for achieving a successful pregnancy. Maternal serum supplementation of in vitro maturation (IVM) medium can increase the rate of oocyte IVM. The aim of the present study was to compare the effect of whole and charcoal-stripped serum supplementation on IVM and the activity index of stearoyl-coenzyme A desaturase 1 (SCD1) in cumulus cells enclosing the oocyte as a molecular indicator of oocyte quality. Cumulus cells and germinal vesicle immature oocytes were collected from 76 women with polycystic ovarian syndrome during an IVF cycle. Serum samples were pooled from healthy women and were applied as whole or charcoal-stripped serum supplements. SCD1 expression and activity were measured by quantitative polymerase chain reaction (PCR) and gas-liquid chromatography, respectively. Charcoal-stripped serum at an amount of 10% showed a higher potency in increasing the SCD1 expression and activity index than whole serum (>1.5 fold, p < 0.001). An increase in the IVM rate was also observed in oocytes cultured in the presence of 10% charcoal-stripped serum compared to the control group (1.9 fold, p = 0.031). Therefore, charcoal-based lipid depletion as a simple and preparative strategy may increase the beneficial effect of serum supplementation in oocyte IVM culture. PMID- 29701082 TI - The protective effect of melatonin in lungs of newborn rats exposed to maternal nicotine. AB - We investigated possible healing effects of melatonin (MEL) on biochemical and histological changes in the lungs of rat offspring caused by exposure to nicotine (NT) in utero. Pregnant rats were divided randomly into five groups. The SP group was treated with physiological saline. The EA group was treated with ethyl alcohol. The MEL group was treated with MEL. The NT group was treated with NT. The NT + MEL group was treated with NT and MEL. At the end of the study, the biochemistry and histopathology of lung tissue of the offspring were examined. Reduced alveolar development and increased numbers of alveolar macrophages and mast cells were observed in the NT group compared to the SP, EA and MEL groups. We also found increased malondialdehyde (MDA) levels and decreased total glutathione (GSH) levels in the NT group. Application of MEL ameliorated the histological and biochemical damage caused by NT. The number of alveoli was greater in the NT + MEL group than in the NT group. Also, the increased numbers of alveolar macrophages and mast cells resulting from exposure to NT were decreased following MEL treatment. We found that MEL caused a significant decrease in the level of MDA. Maternal exposure to NT caused significant structural and biochemical changes in the lungs of the offspring and administration of MEL ameliorated the changes. PMID- 29701083 TI - Elevated Glucose Levels Preserve Glucose Uptake, Hyaluronan Production, and Low Glutamate Release Following Interleukin-1beta Stimulation of Differentiated Chondrocytes. AB - Objective Chondrocytes are responsible for remodeling and maintaining the structural and functional integrity of the cartilage extracellular matrix. Because of the absence of a vascular supply, chondrocytes survive in a relatively hypoxic environment and thus have limited regenerative capacity during conditions of cellular stress associated with inflammation and matrix degradation, such as osteoarthritis (OA). Glucose is essential to sustain chondrocyte metabolism and is a precursor for key matrix components. In this study, we investigated the importance of glucose as a fuel source for matrix repair during inflammation as well as the effect of glucose on inflammatory mediators associated with osteoarthritis. Design To create an OA model, we used equine chondrocytes from 4 individual horses that were differentiated into cartilage pellets in vitro followed by interleukin-1beta (IL-1beta) stimulation for 72 hours. The cells were kept at either normoglycemic conditions (5 mM glucose) or supraphysiological glucose concentrations (25 mM glucose) during the stimulation with IL-1beta. Results We found that elevated glucose levels preserve glucose uptake, hyaluronan synthesis, and matrix integrity, as well as induce anti-inflammatory actions by maintaining low expression of Toll-like receptor-4 and low secretion of glutamate. Conclusions Adequate supply of glucose to chondrocytes during conditions of inflammation and matrix degradation interrupts the detrimental inflammatory cycle and induces synthesis of hyaluronan, thereby promoting cartilage repair. PMID- 29701084 TI - PROMS are great value, but sometimes we need more information. PMID- 29701085 TI - Mid-term results of anatomical total shoulder arthroplasty for primary osteoarthritis using a short-stemmed cementless humeral component. AB - Aims: The aim of this study was to evaluate the clinical and radiological outcome of using an anatomical short-stem shoulder prosthesis to treat primary osteoarthritis of the glenohumeral joint. Patients and Methods: A total of 66 patients (67 shoulders) with a mean age of 76 years (63 to 92) were available for clinical and radiological follow-up at two different timepoints (T1, mean 2.6 years, sd 0.5; T2, mean 5.3 years, sd 0.7). Postoperative radiographs were analyzed for stem angle, cortical contact, and filling ratio of the stem. Follow up radiographs were analyzed for timing and location of bone adaptation (cortical bone narrowing, osteopenia, spot welds, and condensation lines). The bone adaptation was classified as low (between zero and three features of bone remodelling around the humeral stem) or high (four or more features). Results: The mean Constant score improved significantly from 28.5 (sd 11.6) preoperatively to 75.5 (sd 8.5) at T1 (p < 0.001) and remained stable over time (T2: 76.6, sd 10.2). No stem loosening was seen. High bone adaptation was present in 42% of shoulders at T1, with a slight decrease to 37% at T2. Cortical bone narrowing and osteopenia in the region of the calcar decreased from 76% to 66% between T1 and T2. Patients with high bone adaptation had a significantly higher mean filling ratio of the stem at the metaphysis (0.60, sd 0.05 vs 0.55, sd 0.06; p = 0.003) and at the diaphysis (0.65 sd 0.05 vs 0.60 sd 0.05; p = 0.007). Cortical contact of the stem was also associated with high bone adaptation (14/25 shoulders, p = 0.001). The clinical outcome was not influenced by the radiological changes. Conclusion: Total shoulder arthroplasty using a short-stem humeral component resulted in good clinical outcomes with no evidence of loosening. However, approximately 40% of the shoulders developed substantial bone loss in the proximal humerus at between four and seven years of follow-up. Cite this article: Bone Joint J 2018;100-B:603-9. PMID- 29701086 TI - Longer duration of symptoms at the time of presentation is not associated with worse survival in primary bone sarcoma. AB - Aims: The primary aim of this study was to determine the effect of the duration of symptoms (DOS) prior to diagnosis on the overall survival in patients with a primary bone sarcoma. Patients and Methods: In a retrospective analysis of a sarcoma database at a single institution between 1990 and 2014, we identified 1446 patients with non-metastatic and 346 with metastatic bone sarcoma. Low-grade types of tumour were excluded. Our data included the demographics of the patients, the characteristics of the tumour, and the survival outcome of patients. Cox proportional hazards analysis and Kaplan-Meier survival analysis were performed, and the survivorship of the non-metastatic and metastatic cohorts were compared. Results: In the non-metastatic cohort, a longer DOS was associated with a slightly more favourable survival (hazard ratio (HR) 0.996, 95% confidence interval (CI) 0.994 to 0.998, p < 0.001). In all types of tumour, there was no difference in survival between patients with a DOS of greater than four months and those with a DOS of less than four months (p = 0.566). There was no correlation between the year of diagnosis and survival (p = 0.741). A diagnosis of chondrosarcoma (HR 0.636, 95% CI 0.474 to 0.854, p = 0.003) had the strongest positive effect on survival, while location in the axial skeleton (HR 1.76, 95% CI 1.36 to 2.29, p < 0.001) had the strongest negative effect on survival. Larger size of tumour (HR 1.05, 95% CI 1.03 to 1.06, p < 0.001) and increased age of the patient (HR 1.02, 95% CI 1.01 to 1.03, p < 0.001) had a slightly negative effect on survival. Metastatic and non-metastatic cohorts had similar median DOS (16 weeks, p = 0.277), although the median survival (15.5 months vs 41 months) and rates of survival at one year (69% vs 89%) and five years (20% vs 59%) were significantly shorter in the metastatic cohort. Conclusion: A longer DOS prior to diagnosis is not associated with a poorer overall survival in patients with a primary bone sarcoma. Location in the axial skeleton remains the strongest predictor of a worse prognosis. This may be helpful in counselling patients referred for evaluation on a delayed basis. Cite this article: Bone Joint J 2018;100-B:652-61. PMID- 29701087 TI - The positive predictive value of asymmetrical skin creases in the diagnosis of pathological developmental dysplasia of the hip. AB - Aims: The aim of this study was to identify the association between asymmetrical skin creases of the thigh, buttock or inguinal region and pathological developmental dysplasia of the hip (DDH). Patients and Methods: Between 1 January 1996 and 31 December 2016, all patients referred to our unit from primary or secondary care with risk factors for DDH were assessed in a "one stop" clinic. All had clinical and sonographic assessment by the senior author (RWP) with the results being recorded prospectively. The inclusion criteria for this study were babies and children referred with asymmetrical skin creases. Those with a neurological cause of DDH were excluded. The positive predictive value (PPV) for pathological DDH was calculated. Results: A total of 105 patients met the inclusion criteria. There were 71 girls and 34 boys. Only two were found to have pathological DDH. Both also had unilateral limited abduction of the hip in flexion and a positive Galeazzi sign with apparent leg-length discrepancy. Thus, if the specialist examination of a patient with asymmetrical skin creases was normal, the PPV for DDH was 0%. Conclusion: Isolated asymmetrical skin creases are an unreliable clinical sign in the diagnosis of pathological DDH. Greater emphasis should be placed on the presence of additional clinical signs to guide radiological screening in babies and children. Cite this article: Bone Joint J 2018;100-B:675-9. PMID- 29701088 TI - Outcome of autologous bone grafting with preservation of articular cartilage to treat osteochondral lesions of the talus with large associated subchondral cysts. AB - Aims: The aim of this study was to evaluate antegrade autologous bone grafting with the preservation of articular cartilage in the treatment of symptomatic osteochondral lesions of the talus with subchondral cysts. Patients and Methods: The study involved seven men and five women; their mean age was 35.9 years (14 to 70). All lesions included full-thickness articular cartilage extending through subchondral bone and were associated with subchondral cysts. Medial lesions were exposed through an oblique medial malleolar osteotomy, and one lateral lesion was exposed by expanding an anterolateral arthroscopic portal. After refreshing the subchondral cyst, it was grafted with autologous cancellous bone from the distal tibial metaphysis. The fragments of cartilage were fixed with 5-0 nylon sutures to the surrounding cartilage. Function was assessed at a mean follow-up of 25.3 months (15 to 50), using the American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot outcome score. The radiological outcome was assessed using MRI and CT scans. Results: The mean AOFAS score improved from 65.7 (47 to 81) preoperatively to 92 (90 to 100) at final follow-up, with 100% patient satisfaction. The radiolucent area of the cysts almost disappeared on plain radiographs in all patients immediately after surgery, and there were no recurrences at the most recent follow-up. The medial malleolar screws were removed in seven patients, although none had symptoms. At this time, further arthroscopy was undertaken, when it was found that the mean International Cartilage Repair Society (ICRS) arthroscopic score represented near-normal cartilage. Conclusion: Autologous bone grafting with fixation of chondral fragments preserves the original cartilage in the short term, and could be considered in the treatment for adult patients with symptomatic osteochondral defect and subchondral cysts. Cite this article: Bone Joint J 2018;100-B:590-5. PMID- 29701089 TI - Does virtual reality simulation have a role in training trauma and orthopaedic surgeons? AB - Aims: The aim of this study was to assess the current evidence relating to the benefits of virtual reality (VR) simulation in orthopaedic surgical training, and to identify areas of future research. Materials and Methods: A literature search using the MEDLINE, Embase, and Google Scholar databases was performed. The results' titles, abstracts, and references were examined for relevance. Results: A total of 31 articles published between 2004 and 2016 and relating to the objective validity and efficacy of specific virtual reality orthopaedic surgical simulators were identified. We found 18 studies demonstrating the construct validity of 16 different orthopaedic virtual reality simulators by comparing expert and novice performance. Eight studies have demonstrated skill acquisition on a simulator by showing improvements in performance with repeated use. A further five studies have demonstrated measurable improvements in operating theatre performance following a period of virtual reality simulator training. Conclusion: The demonstration of 'real-world' benefits from the use of VR simulation in knee and shoulder arthroscopy is promising. However, evidence supporting its utility in other forms of orthopaedic surgery is lacking. Further studies of validity and utility should be combined with robust analyses of the cost efficiency of validated simulators to justify the financial investment required for their use in orthopaedic training. Cite this article: Bone Joint J 2018;100-B:559-65. PMID- 29701090 TI - A consensus exercise identifying priorities for research into clinical effectiveness among children's orthopaedic surgeons in the United Kingdom. AB - Aims: High-quality clinical research in children's orthopaedic surgery has lagged behind other surgical subspecialties. This study used a consensus-based approach to identify research priorities for clinical trials in children's orthopaedics. Methods: A modified Delphi technique was used, which involved an initial scoping survey, a two-round Delphi process and an expert panel formed of members of the British Society of Children's Orthopaedic Surgery. The survey was conducted amongst orthopaedic surgeons treating children in the United Kingdom and Ireland. Results: A total of 86 clinicians contributed to both rounds of the Delphi process, scoring priorities from one (low priority) to five (high priority). Elective topics were ranked higher than those relating to trauma, with the top ten elective research questions scoring higher than the top question for trauma. Ten elective, and five trauma research priorities were identified, with the three highest ranked questions relating to the treatment of slipped capital femoral epiphysis (mean score 4.6/ 5), Perthes' disease (4.5) and bone infection (4.5). Conclusion: This consensus-based research agenda will guide surgeons, academics and funders to improve the evidence in children's orthopaedic surgery and encourage the development of multicentre clinical trials. Cite this article: Bone Joint J 2018;100-B:680-4. PMID- 29701091 TI - A comparison of the cost-effectiveness of intramedullary nail fixation and locking plate fixation in the treatment of adult patients with an extra-articular fracture of the distal tibia. AB - Aims: The aim of this study was to compare the cost-effectiveness of intramedullary nail fixation and 'locking' plate fixation in the treatment of extra-articular fractures of the distal tibia. Patients and Methods: An economic evaluation was conducted from the perspective of the United Kingdom National Health Service (NHS) and personal social services (PSS), based on evidence from the Fixation of Distal Tibia Fractures (UK FixDT) multicentre parallel trial. Data from 321 patients were available for analysis. Costs were collected prospectively over the 12-month follow-up period using trial case report forms and participant-completed questionnaires. Cost-effectiveness was reported in terms of incremental cost per quality adjusted life year (QALY) gained, and net monetary benefit. Sensitivity analyses were conducted to test the robustness of cost-effectiveness estimates. Results: Mean NHS and PSS costs were significantly lower for patients treated with an intramedullary nail than for those treated with a locking plate (-L970, 95% confidence interval (CI) -1685 to -256; p = 0.05). There was a small increase in QALYs gained in the nail fixation group (0.01, 95% CI -0.03 to 0.06; p = 0.52). The probability of cost-effectiveness for nail fixation exceeded 90% at cost-effectiveness thresholds as low as L15 000 per additional QALY. The cost-effectiveness results remained robust to several sensitivity analyses. Conclusion: This trial-based economic evaluation suggests that nail fixation is a cost-effective alternative to locking plate fixation. Cite this article: Bone Joint J 2018;100-B:624-33. PMID- 29701092 TI - The functional and dynamometer-tested results of transtendinous flexor hallucis longus transfer for neglected ruptures of the Achilles tendon at six years' follow-up. AB - Aims: Flexor hallucis longus (FHL) tendon transfer is a well-recognized technique in the treatment of the neglected tendo Achillis (TA) rupture. Patients and Methods: We report a retrospective review of 20/32 patients who had undergone transtendinous FHL transfer between 2003 and 2011 for chronic TA rupture. Their mean age at the time of surgery was 53 years (22 to 83). The mean time from rupture to surgery was seven months (1 to 36). The mean postoperative follow-up was 73 months (29 to 120). Six patients experienced postoperative wound complications. Results: The mean postoperative Achilles tendon Total Rupture Score (ATRS) was 83 (40 to 100) and the mean American Orthopaedic Foot & Ankle Society (AOFAS) score was 94.3 (82 to 100). Tegner scoring showed a mean reduction of one level from the pre-injury level of activity. There was a mean reduction of 24% (4 to 54) in dynamometer-measured strength of ankle plantarflexion, in comparison with the non-operated side. The hallux had a mean of only 40% (2 to 90) strength of plantarflexion in comparison with the contralateral side. Conclusion: We conclude that transtendinous FHL transfer for neglected TA ruptures, with a long harvest to allow reattachment of the triceps surae, provides reliable long-term function and good ankle plantarflexion strength. Despite the loss of strength in hallux plantar flexion, there is little comorbidity from the FHL harvest. Cite this article: Bone Joint J 2018;100-B:584 9. PMID- 29701093 TI - The natural alpha angle of the femoral head-neck junction. AB - Aims: Asphericity of the femoral head-neck junction is common in cam-type femoroacetabular impingement (FAI) and usually quantified using the alpha angle on radiographs or MRI. The aim of this study was to determine the natural alpha angle in a large cohort of patients by continuous circumferential analysis with CT. Methods: CT scans of 1312 femurs of 656 patients were analyzed in this cross sectional study. There were 362 men and 294 women. Their mean age was 61.2 years (18 to 93). All scans had been performed for reasons other than hip disease. Digital circumferential analysis allowed continuous determination of the alpha angle around the entire head-neck junction. All statistical tests were conducted two-sided; a p-value < 0.05 was considered statistically significant. Results: The mean maximum alpha angle for the cohort was 59.0 degrees (sd 9.4). The maximum was located anterosuperiorly at 01:36 on the clock face, with two additional maxima of asphericity at the posterior and inferior head-neck junction. The mean alpha angle was significantly larger in men (59.4 degrees , sd 8.0) compared with women (53.5 degrees , sd 7.4 degrees ; p = 0.0005), and in Caucasians (60.7 degrees , sd 9.0 degrees ) compared with Africans (56.3 degrees , sd 8.0; p = 0.007) and Asians (50.8 degrees , sd 7.2; p = 0.0005). The alpha angle showed a weak positive correlation with age (p < 0.05). If measured at commonly used planes of the radially reconstructed CT or MRI, the alpha angle was largely underestimated; measurement at the 01:30 and 02:00 positions showed a mean underestimation of 4 degrees and 6 degrees , respectively. Conclusion: This study provides important data on the normal alpha angle dependent on age, gender, and ethnic origin. The normal alpha angle in men is > 55 degrees , and this should be borne in mind when making a diagnosis of cam-type morphology. Cite this article: Bone Joint J 2018;100-B:570-8. PMID- 29701094 TI - Patient-reported outcome measures after surgery for an acetabular fracture. AB - Aims: The aim of this study was to record the incidence of post-traumatic osteoarthritis (OA), the need for total hip arthroplasty (THA), and patient reported outcome measures (PROMS) after surgery for a fracture of the acetabulum, in our centre. Patients and Methods: All patients who underwent surgery for an acetabular fracture between 2004 and 2014 were included. Patients completed the 36-Item Short Form Health Survey (SF-36) and the modified Harris Hip Score (mHHS) questionnaires. A retrospective chart and radiographic review was performed on all patients. CT scans were used to assess the classification of the fracture and the quality of reduction. Results: A total of 220 patients were included, of which 55 (25%) developed post-traumatic OA and 33 (15%) underwent THA. A total of 164 patients completed both questionnaires. At a mean follow-up of six years (2 to 10), the mean SF-36 score for patients with a preserved hip joint was higher on role limitations due to physical health problems than for those with OA or those who underwent THA. In the dimension of bodily pain, patients with OA had a significantly better score than those who underwent THA. Patients with a preserved hip joint had a significantly better score on the function scale of the mHHS and a better total score than those with OA or who underwent THA. Conclusion: Of the patients who were treated surgically for an acetabular fracture (with a mean follow-up of six years), 15% underwent THA at a mean of 2.75 years postoperatively. Patients with a THA had a worse functional outcome than those who retain their native hip joint. We recommend using PROMS and CT scans when reviewing these patients. Cite this article: Bone Joint J 2018;100 B:640-5. PMID- 29701095 TI - Infographic: Economic justification for intramedullary nail fixation over locking plate fixation for extra-articular distal tibial fractures. PMID- 29701096 TI - The role of grade in local recurrence and the disease-specific survival in chondrosarcomas. AB - Aims: The purpose of this study was to describe the effect of histological grade on disease-specific survival in patients with chondrosarcoma. Patients and Methods: A total of 343 patients with a chondrosarcoma were included. The histological grade was assessed on the initial biopsy and on the resection specimen. Where the histology showed a mixed grade, the highest grade was taken as the definitive grade. When only small focal areas showed higher grade, the final grade was considered as both. Results: The concordance between the highest preoperative biopsy grading and the highest final grading of the resection specimen in total was only 43% (146/343). In 102 specimens (30%), a small number of cells or focal areas of higher grade were observed in contrast to the main histology. The disease-specific survival, stratified according to the predominant histological grade, showed greater variation than when stratified according to the highest grade seen in the resection specimen. Conclusion: The diagnostic biopsy in chondrosarcoma is unreliable in assessing the definitive grade and the malignant potential of the tumour. When categorizing the grade of the resection specimen, the prognosis for local recurrence and disease-specific survival should be based on the highest grade seen, even when seen in only a few cells. Cite this article: Bone Joint J 2018;100-B:662-6. PMID- 29701097 TI - 'Rail and Nail' bifocal management of atrophic femoral nonunion. AB - Aims: The management of a significant bony defect following excision of a diaphyseal atrophic femoral nonunion remains a challenge. We present the outcomes using a combined technique of acute femoral shortening, stabilized with a long retrograde intramedullary nail, accompanied by bifocal osteotomy compression and distraction osteogenesis with a temporary monolateral fixator. Patients and Methods: Eight men and two women underwent the 'rail and nail' technique between 2008 and 2016. Proximal locking of the nail and removal of the external fixator was undertaken once the length of the femur had been restored and prior to full consolidation of the regenerate. Results: The mean lengthening was 7 cm (3 to 11). The external fixator was removed at a mean of 127 days (57 to 220). The mean bone healing index was 28 days/cm and the mean external fixation index was 20 days/cm (11 to 18). There were no superficial or deep infections. Conclusion: This small retrospective study shows encouraging results for a combined technique, enabling compression of the femoral osteotomy, alignment, and controlled lengthening. Removal of the fixator and proximal locking of the nail reduces the risk of complications and stabilizes the femur with the maximum working length of the nail. Cite this article: Bone Joint J 2018;100-B:634-9. PMID- 29701098 TI - The influence of obesity on functional outcome and quality of life after total knee arthroplasty. AB - Aims: This study investigated the influence of body mass index (BMI) on patients' function and quality of life ten years after total knee arthroplasty (TKA). Patients and Methods: A total of 126 patients who underwent unilateral TKA in 2006 were prospectively included in this retrospective study. They were categorized into two groups based on BMI: < 30 kg/m2 (control) and >= 30 kg/m2 (obese). Functional outcome was assessed using the Knee Society Function Score (KSFS), Knee Society Knee Score (KSKS), and Oxford Knee Score (OKS). Quality of life was assessed using the Physical (PCS) and Mental Component Scores (MCS) of the 36-Item Short-Form Health Survey. Results: Results Patients in the obese group underwent TKA at a younger age (mean, 63.0 years, sd 8.0) compared with the control group (mean, 65.6 years, sd 7.6; p = 0.03). Preoperatively, both groups had comparable functional and quality-of-life scores. Ten years postoperatively, the control group had significantly higher OKS and MCS compared with the obese group (OKS, mean 18 (sd 5) vs mean 22 (sd 10), p = 0.03; MCS, mean 56 (sd 10) vs mean 50 (sd 11), p = 0.01). After applying multiple linear regression with the various outcomes scores as dependent variables and age, gender, and Charlson Comorbidity Index as independent variables, there was a clear association between obesity and poorer outcome in KSFS, OKS, and MCS at ten years postoperatively (p < 0.01 in both KSFS and OKS, and p = 0.03 in MCS). Both groups had a high satisfaction rate (97.8% in the control group vs 87.9% in the obese group, p = 0.11) and fulfillment of expectations at ten years (98.9% in the control group vs 100% in the obese group, p = 0.32). Conclusion: Although both obese and non-obese patients have significant improvements in function and quality of life postoperatively, obese patients tend to have smaller improvements in the OKS and MCS ten years postoperatively. It is important to counsel patients on the importance of weight management to achieve a more sustained outcome after TKA. Cite this article: Bone Joint J 2018;100-B:579-83. PMID- 29701099 TI - Management of extra-articular segmental defects in long bone using a titanium mesh cage as an adjunct to other methods of fixation. AB - Aims: This study reviews the use of a titanium mesh cage (TMC) as an adjunct to intramedullary nail or plate reconstruction of an extra-articular segmental long bone defect. Patients and Methods: A total of 17 patients (aged 17 to 61 years) treated for a segmental long bone defect by nail or plate fixation and an adjunctive TMC were included. The bone defects treated were in the tibia (nine), femur (six), radius (one), and humerus (one). The mean length of the segmental bone defect was 8.4 cm (2.2 to 13); the mean length of the titanium mesh cage was 8.3 cm (2.6 to 13). The clinical and radiological records of the patients were analyzed retrospectively. Results: The mean time to follow-up was 55 months (12 to 126). Overall, 16 (94%) of the patients achieved radiological filling of their bony defect and united to the native bone ends proximally and distally, resulting in a functioning limb. Complications included device failure in two patients (12%), infection in two (12%), and wound dehiscence in one (6%). Four patients (24%) required secondary surgery, four (24%) had a residual limb-length discrepancy, and one (6%) had a residual angular limb deformity. Conclusion: A titanium mesh cage is a useful adjunct in the treatment of an extra-articular segmental defect in a long bone. Cite this article: Bone Joint J 2018;100-B:646 51. PMID- 29701100 TI - In defence of the posterior malleolus. AB - The posterior malleolus of the ankle is the object of increasing attention, with considerable enthusiasm for CT scanning and surgical fixation, as expressed in a recent annotation in The Bone & Joint Journal. Undoubtedly, fractures with a large posterior malleolar fragment that allow posterior talar subluxation from the mortise are served better by fixation. However, in all other situations, the existing literature does not support this widespread change in practice. The available biomechanical evidence shows that the posterior malleolus has little part to play in the stability or contact stresses of the ankle joint. Radiographic studies have not shown that CT scanning offers helpful information on pathoanatomical classification, case selection, or prognosis, or that scanning improves the likelihood of an adequate surgical reduction. Clinical studies have not shown any improvement in patient outcome after surgical fixation, and have confirmed that the inevitable consequence of increased intervention is an increased rate of complications. A careful and thoughtful evaluation of indications, risks, and benefits of this fashionable concept is required to ensure that we are deploying valuable resources with efficacy, and that we do no harm. Cite this article: Bone Joint J 2018;100-B:566-9. PMID- 29701101 TI - Thoracic aortic aneurysm is an independent factor associated with diffuse idiopathic skeletal hyperostosis. AB - Aims: Although we often encounter patients with an aortic aneurysm who also have diffuse idiopathic skeletal hyperostosis (DISH), there are no reports to date of an association between these two conditions and the pathogenesis of DISH remains unknown. This study therefore evaluated the prevalence of DISH in patients with a thoracic aortic aneurysm (AA). Patients and Methods: The medical records of 298 patients who underwent CT scans for a diagnosis of an AA or following high-energy trauma were retrospectively examined. A total of 204 patients underwent surgery for an AA and 94 had a high-energy injury and formed the non-AA group. The prevalence of DISH was assessed on CT scans of the chest and abdomen and the relationship between DISH and AA by comparison between the AA and non-AA groups. Results: The prevalence of DISH in the AA group (114/204; 55.9%) was higher than that in the non-AA group (31/94; 33.0%). On multivariate analysis, the factors of AA, male gender, and ageing were independent predictors of the existence of DISH, with odds ratios of 2.9, 1.9, and 1.03, respectively. Conclusion: This study revealed that the prevalence of DISH is higher in patients with an AA than in those without an AA, and that the presence of an AA significantly influenced the prevalence of DISH. Cite this article: Bone Joint J 2018;100-B:617-21. PMID- 29701102 TI - The indications and donor-site morbidity of tibial cortical strut autografts in the management of defects in long bones. AB - Aims: The primary aim of this study was to determine the morbidity of a tibial strut autograft and characterize the rate of bony union following its use. Patients and Methods: We retrospectively assessed a series of 104 patients from a single centre who were treated with a tibial strut autograft of > 5 cm in length. A total of 30 had a segmental reconstruction with continuity of bone, 27 had a segmental reconstruction without continuity of bone, 29 had an arthrodesis and 18 had a nonunion. Donor-site morbidity was defined as any event that required a modification of the postoperative management. Union was assessed clinically and radiologically at a median of 36 months (IQR, 14 to 74). Results: Donor-site morbidity occurred in four patients (4%; 95% confidence interval (CI) 1 to 10). One patient had a stress fracture of the tibia, which healed with a varus deformity, requiring an osteotomy. Two patients required evacuation of a haematoma and one developed anterior compartment syndrome which required fasciotomies. The cumulative probability of union was 90% (95% CI 80 to 96) at five years. The type of reconstruction (p = 0.018), continuity of bone (p = 0.006) and length of tibial graft (p = 0.037) were associated with the time to union. Conclusion: The tibial strut autograft has a low risk of morbidity and provides adequate bone stock for treating various defects of long bones. Cite this article: Bone Joint J 2018;100-B:667-74. PMID- 29701103 TI - Results of primary repair of distal triceps tendon ruptures in a general population. AB - Aims: The aim of the study was to analyze the results of primary tendon reinsertion in acute and chronic distal triceps tendon ruptures (DTTRs) in the general population. Patients and Methods: A total of 28 patients were operated on for primary DTTR reinsertions, including 21 male patients and seven female patients with a mean age of 45 years (14 to 76). Of these patients, 23 sustained an acute DTTR and five had a chronic injury. One patient had a non-simultaneous bilateral DTTR. Seven patients had DTTR-associated ipsilateral fracture or dislocation. Comorbidities were present in four patients. Surgical treatment included transosseous and suture-anchors reinsertion in 22 and seven DTTRs, respectively. The clinical evaluation was performed using Mayo Elbow Performance Score (MEPS), the modified American Shoulder and Elbow Surgeons Score (m-ASES), the Quick Disabilities of the Arm, Shoulder and Hand score (QuickDASH), and the Medical Research Council (MRC) Scale. Results: A total of 27 patients (28 DTTRs) were available for review at a mean of 47.5 months (12 to 204). The mean MEPS, QuickDASH, and m-ASES scores were 94 (60 to 100), 10 (0 to 52), and 94 (58 to 100), respectively. Satisfactory results were observed in 26 cases (93%). Muscle strength was 5/5 and 4/5 in 18 and ten DTTRs, respectively. One patient with chronic renal failure experienced a traumatic rerupture of distal triceps. One patient (1 DTTR) experienced mild elbow stiffness. Conclusion: Primary repair of acute and chronic DTTRs in a general population yields satisfactory results in the majority of patients with a low rerupture rate. Cite this article: Bone Joint J 2018;100-B:610-16. PMID- 29701104 TI - The inter- and intraobserver reliability for the radiological parameters of flatfoot, before and after surgery. AB - Aims: Various radiological parameters are used to evaluate a flatfoot deformity and their measurements may differ. The aims of this study were to answer the following questions: 1) Which of the 11 parameters have the best inter- and intraobserver reliability in a standardized radiological setting? 2) Are pre- and postoperative assessments equally reliable? 3) What are the identifiable sources of variation? Patients and Methods: Measurements of the 11 parameters were recorded on anteroposterior and lateral weight-bearing radiographs of 38 feet before and after surgery for flatfoot, by three observers with different experience in foot surgery (A, ten years; B, three years; C, third-year orthopaedic resident). The inter- and intraobserver reliability was calculated. Results: Preoperative interobserver reliability was high for four, moderate for five, and low for two parameters. Postoperative interobserver reliability was high for four, moderate for five, and low for two parameters. Intraobserver reliability was excellent for all parameters preoperatively as recorded by observer A (PB) and B (MP), and for eight parameters as recorded by observer C (SR). Intraobserver reliability was excellent for ten parameters postoperatively as recorded by observer A and B, and for eight parameters as recorded by observer C. Conclusion: The following parameters can be recommended. For preoperative and postoperative evaluation of flatfoot: anteroposterior, talonavicular coverage angle; lateral, talometatarsal I angle, calcaneal pitch angle, and cuneiform medial height (high interobserver reliability); and anteroposterior, talometatarsal II angle; lateral, talocalcaneal angle,tibiocalcaneal angle (moderate interobserver reliability). For more experienced observers, we also recommend the anteroposterior talometatarsal I angle (moderate reliability). The inter- and intraobserver reliability for most parameters were similar pre- and postoperatively. The experience of the observer and the definition and ability to measure the parameters themselves were sources of variation. Cite this article: Bone Joint J 2018;100-B:596-602. PMID- 29701105 TI - A prospective study of the impact of AGTR1 A1166C on the effects of candesartan in patients with heart failure. AB - AIM: To evaluate the impact of AGTR1 A1166C (rs5186) on the response to candesartan in patients with heart failure. MATERIALS & METHODS: Prospective, multicentre, open-label study. We studied 299 symptomatic patients with heart failure presenting a left ventricular ejection fraction <=40%. RESULTS: Reductions in the primary end points of natriuretic peptides were not significantly associated with AGTR1 A1166C. Nevertheless, carrying the 1166C allele was associated with a greater compensatory increase in renin activity (p = 0.037) after 16 weeks of treatment with candesartan and a more modest effect on aldosterone concentrations (p = 0.022). CONCLUSION: AGTR1 1166C carriers may experience a greater long-term compensatory renin-angiotensin-aldosterone system activation following treatment with candesartan. Whether these associations ultimately influence clinical outcomes requires investigation. Clinicaltrials.gov : NCT00400582. PMID- 29701106 TI - Thymoquinone is protective against 2,3,7,8-tetrachlorodibenzo-p-dioxin induced hepatotoxicity. AB - We investigated changes in rat liver tissues following administration of thymoquinone (TQ) against 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced hepatotoxicity. Fifty rats were assigned randomly to five groups of 10 as follows: control, corn oil, TCDD, TQ and TCDD + TQ. Biochemical and histopathological analyses were conducted on liver tissue. We found that 30 day TCDD administration caused histopathological changes in liver including thickening of Glisson's capsule, intracytoplasmic vacuolization in hepatocytes, sinusoidal dilation, vascular and sinusoidal congestion and inflammatory cell infiltration. TCDD administration increased malondialdehyde (MDA), total oxidant status (TOS), alanine aminotransferase (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) levels in rat liver tissue and reduced glutathione (GSH), superoxide dismutase (SOD), catalase (CAT) and total antioxidant status (TAS) levels compared to all other groups. In the TQ treated group, GSH, SOD, CAT and TAS levels increased compared to all other groups. MDA, TOS, ALT, AST, ALP levels decreased compared to all other groups. Our histological findings were consistent with the biochemical findings. The oxidative and histologic effects of TCDD were eliminated by TQ treatment. TCDD administration caused oxidative stress in rat liver and TQ administered with TCDD prevented TCDD induced hepatotoxicity. TQ could be considered an alternative anti-TCDD toxicity agent. PMID- 29701107 TI - Do Women With Breast Cancer Who Choose Adjunctive Integrative Oncology Care Receive Different Standard Oncologic Treatment? AB - PURPOSE: To determine if women with breast cancer who choose adjunctive naturopathic oncology (NO) specialty care receive different standard oncologic treatment when compared with breast cancer patients who receive only standard care. PARTICIPANTS: Women with breast cancer stages 0 to 4, aged 18+ who spoke English and sought care from outpatient naturopathic doctor clinics were enrolled in an observational study of clinical and quality of life outcomes. Women who sought NO care 2 or more times within the first 2 years postdiagnosis were identified as NO cases. A matched comparison group of breast cancer patients were identified using the Western Washington Cancer Surveillance System(CSS). METHODS: A longitudinal cohort design. In addition to self-report data, the CSS provided data on demographics, stage at the time of diagnosis, and initial treatment. Oncology medical records were abstracted in order to provide additional information on standard oncologic treatment for all participants. RESULTS: Cohorts were well matched with regard to demographic, histologic, and prognostic indicators at the time of diagnosis. Approximately 70% of women in both cohorts received standard oncologic care that met the National Comprehensive Cancer Network guidelines. There were no statistically significant differences between the cohorts in treatment received. Fewer women in the NO cohort with estrogen receptor-positive breast cancer appear to have received antiestrogen therapy. CONCLUSIONS: Women in both cohorts appear to receive guideline-concordant care. However, women who receive adjunctive NO care may be less likely to receive antiestrogen therapy. PMID- 29701109 TI - Attitudes Toward Return of Genetic Research Results to Relatives, Including After Death: Comparison of Cancer Probands, Blood Relatives, and Spouse/Partners. AB - Genetic research generates results with implications for relatives. Recommendations addressing relatives' access to a participant's genetic research findings include eliciting participant preferences about access and choosing a representative to make decisions about access upon participant incapacity/death. Representatives are likely to be blood relatives or spouse/partners (who may share genetically related children). This raises the question of whether relatives hold similar attitudes about access or divergent attitudes that may yield conflict. We surveyed pancreatic cancer biobank participants (probands) and relatives in a family registry (blood relatives and spouse/partners of probands); 1,903 (>55%) surveys were returned. Results revealed few attitudinal differences between the groups. A slightly higher proportion of blood relatives agreed with statements reflecting proband privacy. In conclusion, probands' decisions on access are likely to be accepted by relatives; in choosing a representative, probands may not face major differences in attitudes about privacy/sharing between a blood relative and a spouse/partner. PMID- 29701110 TI - A Framework for Community and Stakeholder Engagement: Experiences From a Multicenter Study in Southern Africa. AB - Community and stakeholder engagement (CSE) are central to conducting multicenter health research. Multicenter studies are, however, considerably more complex because they involve a geographically diverse pool of participants and researchers, making uniform application of CSE strategies difficult. This article describes a framework to achieve CSE based on the experiences of a conducting a multicenter study in Southern Africa. The CSE framework is divided into three phases: before research commences, during, and after the study. This CSE framework offers a practical step-by-step guide on the operational aspects of CSE in a multicenter study. The framework shows the importance of consistent monitoring and evaluation during implantation of CSE. PMID- 29701108 TI - Acute Kidney Injury as a Condition of Renal Senescence. AB - Acute kidney injury (AKI), characterized by a sharp drop in glomerular filtration, continues to be a significant health burden because it is associated with high initial mortality, morbidity, and substantial health-care costs. There is a strong connection between AKI and mechanisms of senescence activation. After ischemic or nephrotoxic insults, a wide range of pathophysiological events occur. Renal tubular cell injury is characterized by cell membrane damage, cytoskeleton disruption, and DNA degradation, leading to tubular cell death by necrosis and apoptosis. The senescence mechanism involves interstitial fibrosis, tubular atrophy, and capillary rarefaction, all of which impede the morphological and functional recovery of the kidneys, suggesting a strong link between AKI and the progression of chronic kidney disease. During abnormal kidney repair, tubular epithelial cells can assume a senescence-like phenotype. Cellular senescence can occur as a result of cell cycle arrest due to increased expression of cyclin kinase inhibitors (mainly p21), downregulation of Klotho expression, and telomere shortening. In AKI, cellular senescence is aggravated by other factors including oxidative stress and autophagy. Given this scenario, the main question is whether AKI can be repaired and how to avoid the senescence process. Stem cells might constitute a new therapeutic approach. Mesenchymal stem cells (MSCs) can ameliorate kidney injury through angiogenesis, immunomodulation, and fibrosis pathway blockade, as well as through antiapoptotic and promitotic processes. Young umbilical cord-derived MSCs are better at increasing Klotho levels, and thus protecting tissues from senescence, than are adipose-derived MSCs. Umbilical cord-derived MSCs improve glomerular filtration and tubular function to a greater degree than do those obtained from adult tissue. Although senescence-related proteins and microRNA are upregulated in AKI, they can be downregulated by treatment with umbilical cord-derived MSCs. In summary, stem cells derived from young tissues, such as umbilical cord-derived MSCs, could slow the post-AKI senescence process. PMID- 29701111 TI - Detection of cytokinins and auxin in plant tissues using histochemistry and immunocytochemistry. AB - We report a new method for histochemical localization of cytokinins (CKs) in plant tissues based on bromophenol blue/silver nitrate staining. The method was validated by immunohistochemistry using anti-trans-zeatin riboside antibody. Indole-3-acetic acid (auxin, IAA) was localized by anti-IAA antibody in plant tissues as a proof for IAA histolocalization. We used root sections, because they are major sites of CKs synthesis, and insect galls of Piptadenia gonoacantha that accumulate IAA. Immunostaining confirmed the presence of zeatin and sites of accumulation of IAA indicated by histochemistry. The colors developed by histochemical reactions in free-hand sections of plant tissues were similar to those obtained by thin layer chromatography (TLC), which reinforced the reactive sites of zeatin. The histochemical method for detecting CKs is useful for galls and roots, whereas IAA detection is more efficient for gall tissues. Therefore, galls constitute a useful model for validating histochemical techniques due to their rapid cell cycles and relatively high accumulation of plant hormones. PMID- 29701112 TI - Multitasking discoidin domain receptors are involved in several and specific hallmarks of cancer. AB - Discoidin domain receptors, DDR1 and DDR2, are two members of collagen receptor family that belong to tyrosine kinase receptor subgroup. Unlike other matrix receptor-like integrins, these collagen receptors have not been extensively studied. However, more and more studies are focusing on their involvement in cancer. These two receptors are present in several subcellular localizations such as intercellular junction or along type I collagen fibers. Consequently, they are involved in multiple cellular functions, for instance, cell cohesion, proliferation, adhesion, migration and invasion. Furthermore, various signaling pathways are associated with these multiple functions. In this review, we highlight and characterize hallmarks of cancer in which DDRs play crucial roles. We discuss recent data from studies that demonstrate the involvement of DDRs in tumor proliferation, cancer mutations, drug resistance, inflammation, neo angiogenesis and metastasis. DDRs could be potential targets in cancer and we conclude this review by discussing the different ways to inhibits them. PMID- 29701113 TI - The Use of Magnetic Resonance Imaging in Planning a Pedicled Perforator Flap for Pressure Sores in the Gluteal Region. AB - Pedicled perforator flaps (PPFs) have been widely used to treat pressure sores in the gluteal region. Selection of a reliable perforator is crucial for successful surgical treatment of pressure sores using PPFs. In this study, we evaluate the role of magnetic resonance imaging (MRI) in planning PPF reconstruction of pressure sores in the gluteal region. A retrospective chart review was performed in patients who had undergone these PPF reconstructions and who had received preoperative MRI. Preoperatively, the extent of infection and necrotic tissue was evaluated using MRI, and a reliable perforator was identified, considering the perforator location in relation to the defect, perforator size, and perforator courses. Intraoperatively, the targeted perforator was marked on the skin at the locations measured on the MRI images, and the marked location was confirmed using intraoperative handheld Doppler. Superior gluteal artery, inferior gluteal artery, or parasacral perforators were used for the PPFs. Surgical outcomes were evaluated. A total of 12 PPFs were performed in 12 patients. Superior gluteal artery perforator flaps were performed in 7 patients, inferior gluteal artery perforator flaps were performed in 3 patients, and parasacral perforator flaps were performed in 2 patients. We could identify a reliable perforator on MRI, and it was found at the predicted locations in all cases. There was only one case of partial flap necrosis. There was no recurrence of the pressure sores during the mean follow-up period of 6.7 months (range = 3-15 months). In selected patients with gluteal pressure sores, MRI is a suitable means for not only providing information about disease extent and comorbidities but also for evaluating perforators for PPF reconstructions. PMID- 29701114 TI - Blood biomarkers and treatment response in major depression. AB - INTRODUCTION: Millions of people worldwide suffer from depression, but despite advances in pharmacological therapies, many patients do not experience symptomatic remission or treatment response, even after treatments with several medications. As such, there is an urgent need to identify biomarkers that can not only predict the treatment response but also allow a rational selection of optimal therapy for each patient. Areas covered: This review examines the recent findings, coming from different 'omic sciences,' in human blood-based biomarkers associated with antidepressant treatment response with particular attention on genetic/epigenetic and biochemical biomarkers. Specific emphasis will be placed on key molecules related to neuroplasticity and inflammation because of their involvement in the pathophysiology of depression and antidepressant response. Expert commentary: Biomarker identification is still an ongoing work. Indeed, to date, no biomarkers have sufficiently proven specificity, sensitivity, and reproducibility to be used in the clinical setting. However, 'omic' approaches hold great promise in identifying multiple features for predicting antidepressant response, making a personalized treatment strategy possible for each patient, and thereby assist with quick and efficacious responsiveness. It is thus necessary that future studies take an integrative approach that includes clinical assessment, environment influences, and molecular and biological biomarkers. PMID- 29701115 TI - Medium-Term Health of Seniors Following Exposure to a Natural Disaster. AB - The article aims to describe the medium-term impacts of a major earthquake event (Chile, February 27, 2010) on 26 seniors. The authors adopted a qualitative study approach. Data obtained using the Impact of Event Scale-Revised (IES-R) show the presence of manifestations of posttraumatic stress in the majority of respondents. In addition, data collected in interviews demonstrated a progressive deterioration of the health of respondents over a period of 4 years following the disaster. Seniors are particularly vulnerable to the effects of material loss, emotional stress, and postdisaster health complications. These impacts are exacerbated by low economic status. Furthermore, broader research is necessary involving elderly living in poverty who have survived natural disasters and others without such experiences, in order to better identify and differentiate between health complications associated with exposure to disaster events and those linked more strictly with natural aging processes. PMID- 29701116 TI - Distinct trajectories of athlete development: A retrospective analysis of professional rugby league players. AB - : Contemporary models of athlete development (e.g., Development Model of Sport Participation) suggest attainment benefits from early age multi-sport "sampling" behaviour before progressive transition into "invested" single-sport involvement in teenage years compared to intensive early-age specialisation. However, specific examinations of these development patterns across a number of team sports and cultural contexts remains limited. This study involved a large sample of professional Australian Rugby League (RL) players (N = 224) who progressed along the RL system pathways. It defined two contrasting athlete development trajectories based upon initial entry into formal age group representative teams ("Early": U16, U18; "Later": U20+) to compare their developmental participation patterns using the National Rugby League Athlete Development Questionnaire (NRLADQ). Between-Within Analyses of Variance (BW-ANOVA)'s identified interaction effects as the 'Later' group reported lower volumes of deliberate practice from 10-20 years, RL-game involvement from 10-20 years, deliberate play from 5-12 years, and a later reduction in other sporting involvement. Group differences in RL-related deliberate practice and play were supported by qualitative descriptions of training at age-categories. CONCLUSION: RL professional senior elite success level can be attained via early intensified specialised investment and accelerated youth success as well as by a rather decelerated, much less cost intensive participation pattern. PMID- 29701117 TI - The histological structure and histochemistry of the mucosa of the nasal conchae in geese, Anser anser. AB - We investigated the histological structure and histochemistry of the nasal conchae of geese and compared these structures with those of other avian species. The rostral, middle and caudal conchae were dissected from the nasal cavity of eight geese, fixed in Carnoy's solution and embedded in paraffin. The entrance of the rostral concha was lined by keratinized stratified squamous epithelium, which toward the middle concha was replaced by modified keratinized squamous epithelium, the deep layer of which opened into tubular glandular structures containing secretory epithelium on crypt-like invaginations. The lamina propria of the rostral concha contained numerous Grandry's and Herbst corpuscles, which are pressure-sensitive receptors peculiar to waterfowl. The lamina propria of the middle concha contained solitary lymphoid follicles and lymphocyte infiltrations. The cartilaginous component of the middle concha was highly convoluted and resembled a spiral of two and a half scrolls, which were lined by pseudostratified columnar epithelium. We observed that unlike mammals, this epithelium contained mostly intraepithelial alveolar glands rather than goblet cells. The caudal concha was similar to the middle concha, but less convoluted. It was lined by olfactory epithelium and its lamina propria contained serous Bowman's glands as well as olfactory nerve fibers. Histochemical examination demonstrated that while none of the conchae contained sulfated mucins, except for the cartilage, the intraepithelial glands of the rostral and middle conchae contained mostly carboxylated acidic mucin and some neutral mucin, and were thus of the mixed type. The outermost scroll of the spiral of the middle concha contained some periodate-Schiff stained mucins. Of the glands of the mucosa of the middle concha, the deep tubuloalveolar glands in the convex parts of the scrolls contained primarily acidic mucins, while the shallow intraepithelial alveolar glands in the concave parts of the scrolls contained primarily neutral mucins. Our findings indicate that the rostral and caudal conchae primarily have a sensory function and the middle concha participates in mucosal defense. PMID- 29701118 TI - Health Promotion at the Construction Work Site: The Lunch Truck Pilot Study. AB - The transient nature of construction work makes it difficult to conduct longitudinal worksite-based health promotion activities. As part of a workplace health assessment pilot study, we worked with a commercial lunch truck company to disseminate four types of health education materials including cancer screening, workplace injury prevention, fruit and vegetable consumption, and smoking cessation to construction workers purchasing food items from the truck during their job breaks. Two weeks following the worksite assessment, we followed up with these workers to ascertain their use of the health promotion materials. Of the 54 workers surveyed, 83% reported reviewing and sharing the cancer screening materials with their families, whereas 44% discussed the cancer screening materials with coworkers. Similar proportions of workers reviewed, shared, and discussed the other health promotion materials with their family. Lunch trucks may be an effective strategy and delivery method for educating construction workers on healthy behaviors and injury prevention practices. PMID- 29701119 TI - Does blood flow restriction training increase the diameter of forearm vessels in chronic kidney disease patients? A randomized clinical trial. AB - INTRODUCTION:: Blood flow restriction training can be used as an alternative to conventional exercise in chronic kidney disease patients with indication of arteriovenous fistula. OBJECTIVE:: Evaluating the efficacy of blood flow restriction training in the diameter and distensibility change of the cephalic vein and the diameter and flow of the radial artery, muscle strength and forearm circumference in chronic kidney disease patients with arteriovenous fistula pre creation. METHODS:: A blind randomized clinical trial consisting of 26 chronic kidney disease patients allocated into a blood flow restriction training group (blood flow restriction; n = 12) and a group without blood flow restriction training (control group; n = 14). Blood flow restriction was performed at 50% of systolic blood pressure and using 40% of handgrip strength as load for the isometric exercises in both groups. RESULTS:: An increase in the diameter of the cephalic vein in the 2 cm (p = 0.008) and 10 cm segments (p = 0.001) was observed in the control group. The diameter of the radial artery increased in all segments in the blood flow restriction group (2, 10 and 20 cm; p = 0.005, p = 0.021 and p = 0.018, respectively) and in the 10 and 20 cm segments (p = 0.017 and p = 0.026) in the control group. Handgrip strength only increased in the control group (p = 0.003). CONCLUSION:: Physical training associated with blood flow restriction increased cephalic vein diameters in both groups and was effective in increasing the diameter of the radial artery; however, it did not demonstrate superiority over the exercise group protocol without blood flow restriction. PMID- 29701120 TI - Comparison of two types of catheters through femoral vein catheterization in patients with lung cancer undergoing chemotherapy: A retrospective study. AB - PURPOSE:: This study aimed to investigate the effects and complications of different types of peripherally inserted central catheters through femoral vein catheterization in patients with lung cancer undergoing chemotherapy. METHODS:: A retrospective analysis of 158 patients with lung cancer undergoing implantation of a venous access through femoral vein catheterization was performed. The patients were divided into two groups by convenience sampling: the single-lumen silicone Groshong peripherally inserted central catheters with valved tip were used in patients in group A, the single-lumen power-injectable polyurethane peripherally inserted central catheters with no valve were used in patients in group B. The gravity flow rate and indwelling time of the catheter and incidences of total obstruction, transient obstruction, irreversible obstruction, catheter related thrombosis, catheter breakage, and accidental dislodgment were compared between the two groups. RESULTS:: The catheter indwelling time and incidences of irreversible obstruction, catheter-related thrombosis, and accidental dislodgment in the two groups were not statistically significantly different ( p > 0.05). The catheter gravity flow rate and incidences of total obstruction, transient obstruction, and catheter breakage were statistically significantly different between the two groups ( p < 0.01). CONCLUSION:: Single-lumen power-injectable peripherally inserted central catheters with no valve had a high gravity flow rate, were strong and not prone to rupture, tolerant to high-pressure injection, and were more suitable for femorally inserted central venous catheterization in patients with lung cancer undergoing chemotherapy. PMID- 29701121 TI - What do we need to transfer pharmacogenetics findings into the clinic? PMID- 29701122 TI - Thermal drying of industrial sludge using forced aeration. AB - This study investigated an industrial biosludge drying system using hot gases from a coal furnace, seeking to increase the solids content of the biosludge above 50% (w.b.), considered suitable for combustion in biomass boilers. Biosludge was collected from a paper mill activated sludge plant. Biosludge mixtures with eucalyptus chips and eucalyptus bark in two different proportions (15% and 25%) were placed into a drying chamber. Hot gases generated by the furnace, with a flowrate of 0.64 +/- 0.02 m3 s-1 at 100 +/- 20 degrees C, were applied to the piles through a blowing system. The results demonstrated that the 75% biosludge/25% eucalyptus bark mixture achieved the best drying ratio, increasing the total solids content from 31% to 72%, over a 5-h drying period. Nevertheless, all other treatments involving the addition of a bulking agent achieved solids content above 50%, confirming the positive effect of adding dried material to the sludge. These results indicate a potential use of hot gases that are currently available and released into the atmosphere by paper mills. PMID- 29701123 TI - Cardiodynamicsgram: a novel tool for monitoring cardiac function in exercise training. AB - This study evaluated the feasibility of cardiodynamicsgram (CDG) for monitoring the cardiac functions of athletes and exercisers. CDG could provide an effective, simple, and economical tool for exercise training. Seventeen middle-distance race athletes aged 14-28 years old were recruited. CDG tests and blood test including creatine kinase (CK), CK-MB isoenzyme, and high-sensitivity troponin I (hsTnI) were performed before a high-intensity prolonged training, as well as 2 and 14 h after training, respectively. The CDG test result was unsatisfactory when the CK test result was used as standard. However, the accuracy of CDG test was about 80% when CK-MB and hsTnI were used as standards. Thus, CDG offers a noninvasive, simple, and economical approach for monitoring the cardiac function of athletes and exercisers during exercise training. Nonetheless, the applicability of CDG needs further investigation. PMID- 29701124 TI - The use of tofacitinib in the treatment of inflammatory bowel disease. AB - Janus kinases (JAK) play a major role in the immunologic pathways and specifically in signal transduction in inflammatory bowel disease. Thus, they can serve as a target for new therapeutic options. Tofacitinib is a novel, first-in class, pan-Janus kinase inhibitor. It has been found to be effective and safe in the treatment of moderate-to-severe ulcerative colitis. In this review, we will describe the drug's mechanism of action as well as the clinical evidence for its effectiveness in treating patients with inflammatory bowel disease. PMID- 29701125 TI - Technical and clinical performance of a new assay to detect squamous cell carcinoma antigen levels for the differential diagnosis of cervical, lung, and head and neck cancer. AB - In squamous cell carcinoma, squamous cell carcinoma antigen levels are often elevated. This multi-center study evaluated the technical performance of a new Elecsys(r) squamous cell carcinoma assay, which measures serum squamous cell carcinoma antigen 1 and 2 levels in an equimolar manner, and investigated the potential of squamous cell carcinoma antigen for differential diagnosis of cervical, lung, and head and neck squamous cell carcinoma.Assay precision and method comparison experiments were performed across three European sites. Reference ranges for reportedly healthy individuals were determined using samples from banked European and Chinese populations. Differential diagnosis experiments determined whether cervical, lung, or head and neck cancer could be differentiated from apparently healthy, benign, or other malignant cohorts using squamous cell carcinoma antigen levels alone. Squamous cell carcinoma antigen cut off levels were calculated based on squamous cell carcinoma antigen levels at 95% specificity. Repeatability coefficients of variation across nine analyte concentrations were <=5.3%, and intermediate precision coefficients of variation were <=10.3%. Method comparisons showed good correlations with Architect and Kryptor systems (slopes of 1.1 and 1.5, respectively). Reference ranges for 95th percentiles for apparently healthy individuals were 2.3 ng/mL (95% confidence interval: 1.9-3.8; European cohort, n = 153) and 2.7 ng/mL (95% confidence interval: 2.2-3.3; Chinese cohort, n = 146). Strongest differential diagnosis results were observed for cervical squamous cell carcinoma: receiver operating characteristic analysis showed that squamous cell carcinoma antigen levels (2.9 ng/mL cut-off) differentiate cervical squamous cell carcinoma (n = 127) from apparently healthy females (n = 286; area under the curve: 86.2%; 95% confidence interval: 81.8-90.6; sensitivity: 61.4%; specificity: 95.6%), benign diseases (n = 187; area under the curve: 86.3%; 95% confidence interval: 81.2-91.3; sensitivity: 61.4%; specificity: 95.0%), and other cervical cancers (n = 157; area under the curve: 78.9%; 95% confidence interval: 70.8-87.1; sensitivity: 61.4%; specificity: 86.7%). Squamous cell carcinoma may also aid in the differential diagnosis of lung cancer. The Elecsys squamous cell carcinoma assay exhibited good technical performance and is suitable for differential diagnosis of cervical squamous cell carcinoma in clinical practice. PMID- 29701126 TI - "What do we know about tacrolimus pharmacogenetics in transplant recipients?" PMID- 29701127 TI - SLC04A1, SLC22A2 and SLC28A2 variants not related to methotrexate efficacy or toxicity in rheumatoid arthritis patients. AB - AIM: A third of rheumatoid arthritis patients discontinue methotrexate treatment due to inefficacy or toxic side effects. Recently, an association between SLC04A1 rs2236553, SLC22A2 rs624249 and rs316019, and SLC28A2 rs10519020 and rs1060896 with the efficacy and toxicity of methotrexate was reported. This study aims to replicate these findings in an independent cohort (n = 324). METHODS: Regression analyses tested the associations between genotype and methotrexate response or toxicity. RESULTS: In the discovery study, there was a significant association between toxicity and rs624249, and rs1060896. These associations were not replicated in the independent cohort. Neither study observed an association between methotrexate efficacy and SLC04A1, SLC22A2 or SLC28A2 variants. CONCLUSION: Current evidence does not support associations between variants in SLC04A1, SLC22A2 and SLC28A2 with methotrexate efficacy or toxicity. PMID- 29701130 TI - Modelling Allee effects in a transgenic mosquito population during range expansion. AB - Mosquitoes are vectors for many diseases that cause significant mortality and morbidity. As mosquito populations expand their range, they may undergo mate finding Allee effects such that their ability to successfully reproduce becomes difficult at low population density. With new technology, creating target specific gene modification may be a viable method for mosquito population control. We develop a mathematical model to investigate the effects of releasing transgenic mosquitoes into newly established, low-density mosquito populations. Our model consists of two life stages (aquatic and adults), which are divided into three genetically distinct groups: heterogeneous and homogeneous transgenic that cause female infertility and a homogeneous wild type. We perform analytical and numerical analyses on the equilibria to determine the level of saturation needed to eliminate mosquitoes in a given area. This model demonstrates the potential for a gene drive system to reduce the spread of invading mosquito populations. PMID- 29701129 TI - Feasibility and implementation of CYP2C19 genotyping in patients using antiplatelet therapy. AB - AIM: A tailored antiplatelet strategy based on CYP2C19 genotype may reduce atherothrombotic and bleeding events. We describe our experience with CYP2C19 genotyping, using on-site TaqMan or Spartan genotyping or shipment to a central laboratory. METHODOLOGY: Data from two ongoing projects were used: Popular Risk Score project (non-urgent percutaneous coronary intervention patients) and the Popular Genetics study (ST-segment elevation myocardial infarction patients). For both projects, the time to genotyping result was calculated. RESULTS: In the Popular Risk Score project (n = 2556), median time from blood collection to genotyping result was 4:04 h. In the Popular Genetics study (n = 1038), median time from randomization to genotyping result was 2:24 h. CONCLUSION: CYP2C19 genotyping is feasible in everyday clinical practice, both in the acute and non acute settings. PMID- 29701132 TI - Aryl Hydrocarbon Receptor Activation: From Coal to Dioxin. PMID- 29701133 TI - A New Perspective on Vacuum-Assisted Closure for the Treatment of Anastomotic Leak Following Low Anterior Resection for Rectal Cancer, Is It Worthy? AB - BACKGROUND: Anastomotic dehiscence is a common complication of anterior resection. In this work, we evaluate the management of the pelvic cavity after low rectal resection using vacuum closure (VAC) with a gastroscope, and we establish factors that determine the success of closure and analyzed the rate of ileostomy closure after leakage was resolved. PATIENTS AND METHODS: This is a descriptive case series analysis conducted at a tertiary hospital. Twenty-two patients with low colorectal anastomosis leakage or opening of the rectal stump after anterior resection for rectal cancer were included. They were treated with VAC therapy. RESULTS: The total number of endoscopic sessions was 3.1 +/- 1.9 in the anterior resection with anastomosis group and 3.2 +/- 1.8 in the Hartmann group. In 11 patients the therapy was administered in an ambulatory setting. The mean time to healing was 22.3 +/- 14.7 days. Full resolution was achieved in 19 patients (followed-up 1 year). Ileostomy closure was carried out in 5 patients (38.46%) during follow-up. None of these patients showed leakage signs. Statistically significant differences were obtained depending on the onset of therapy, with better results in patients who underwent earlier vacuum-assisted therapy (before the sixth week after initial surgery), P = .041. CONCLUSIONS: VAC therapy is an alternative to surgery that can be safely administered in an ambulatory setting. Early administration in the 6 weeks following surgery is an independent predictive factor for successful closure; however, colonic transit was only recovered in a small percentage of patients. PMID- 29701134 TI - Mixed Reality Technology-Assisted Orthopedics Surgery Navigation. PMID- 29701135 TI - From Illusion to Reality: A Brief History of Robotic Surgery. AB - PURPOSE: Robotic surgery is currently employed for many surgical procedures, yielding interesting results. METHODS: We performed an historical review of robots and robotic surgery evaluating some critical phases of its evolution, analyzing its impact on our life and the steps completed that gave the robotics its current popularity. RESULTS: The origins of robotics can be traced back to Greek mythology. Different aspects of robotics have been explored by some of the greatest inventors like Leonardo da Vinci, Pierre Jaquet-Droz, and Wolfgang Von Kempelen. Advances in many fields of science made possible the development of advanced surgical robots. Over 3000 da Vinci robotic platforms are installed worldwide, and more than 200 000 robotic procedures are performed every year. CONCLUSION: Despite some potential adverse events, robotic technology seems safe and feasible. It is strictly linked to our life, leading surgeons to a new concept of surgery and training. PMID- 29701136 TI - The Hippocratic Method of Surgical Cauterization for the Tumescence Spleen in the Rare "Spetses Syndrome". AB - Spleen in antiquity was considered by the Hippocratic medicine as a viscerous organ of spongy character, which could clear human body of the black bile. According to the Hippocratic doctrine of the 4 humors, black bile could cause a series of diseases. Both the anatomical position and shape of the spleen were also recognized. In the case of a splenic hardening, with simultaneous augmentation of its dimensions and dermal ulceration and/or splenic abscess, some interventions were proposed. Thus, herbal medicine, phlebotomy, and minimal surgery with local cauterization were applied for treatment, to confront a disease that was considered serious but not fatal. The Hippocratic physicians encountered various spleen diseases and among them they most probably confronted a rare splenic pathological entity, named centuries later as "Spetses syndrome," a rare type of thalassemia of the Spetses island of Saronikos Gulf. Although the approach seems in modern terms rather primitive, the ancient Greek medico philosophers most likely understood the significance of the spleen. PMID- 29701137 TI - Impact of food pantry donations on diet of a low-income population. AB - OBJECTIVE: This cross-sectional study assessed the effect of food donations on total nutrient intake of clients of a food pantry in Central Texas. METHODS: Nutrient intakes of total, base and food donation diets were estimated for 112 food pantry recipients using specific questionnaires; and then compared to the dietary reference intakes (DRI) and 2015-2020 US Dietary Guidelines. RESULTS: Food donations accounted for more than half of the client's daily intake of energy, carbohydrates, vitamin B6, phosphorus, copper and selenium. Yet, daily total intake remained less than their DRIs for carbohydrates, poly-unsaturated fats, dietary fiber, fat soluble vitamins and vitamin C, and was even lower for calcium, magnesium and potassium. Total food intake of clients almost met the US Dietary Guidelines for refined grains, fruits, vegetables, and meat; however, the amount of whole grains and dairy was inadequate. CONCLUSIONS: Supplemental foods offered at food pantries are an important resource for improving nutrient intake of low-income populations. PMID- 29701139 TI - Corrigendum. PMID- 29701138 TI - Process identification of the SCR system of coal-fired power plant for de-NOx based on historical operation data. AB - The selective catalytic reduction (SCR) system, as one principal flue gas treatment method employed for the NOx emission control of the coal-fired power plant, is nonlinear and time-varying with great inertia and large time delay. It is difficult for the present SCR control system to achieve satisfactory performance with the traditional feedback and feedforward control strategies. Although some improved control strategies, such as the Smith predictor control and the model predictive control, have been proposed for this issue, a well matched identification model is essentially required to realize a superior control of the SCR system. Industrial field experiment is an alternative way to identify the SCR system model in the coal-fired power plant. But it undesirably disturbs the operation system and is costly in time and manpower. In this paper, a process identification model of the SCR system is proposed and developed by applying the asymptotic method to the sufficiently excited data, selected from the original historical operation database of a 350 MW coal-fired power plant according to the condition number of the Fisher information matrix. Numerical simulations are carried out based on the practical historical operation data to evaluate the performance of the proposed model. Results show that the proposed model can efficiently achieve the process identification of the SCR system. PMID- 29701140 TI - Expression of Plasma hsa-miR122 in HBV-Related Hepatocellular Carcinoma (HCC) in Vietnamese Patients. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death in the world and considered as one of the most susceptible cancers in humans. The microRNA molecule, hsa-miR122, considered as a potential biological marker linked with the injury of hepatocellular tissue, is the most common microRNA in human liver cancer. Understanding the expression profile of hsa miR122 plays an important role in the diagnosis of HCC. OBJECTIVE: Identification and comparison of cut-off values of plasma hsa-miR122 expression were conducted in blood samples of healthy control, HBV infected and HBV-related HCC Vietnamese patients. METHODS AND RESULT: Fifty-two blood samples of healthy control and HBV related HCC cases, collected between 2015 and 2017 were obtained from Ho Chi Minh City Oncology Hospital, Vietnam. Written informed consent was attained from all patients and the Human Research Ethics Committee, Oncology Hospital (#08/BVUB HDDD) approved the research protocol. Total RNA was isolated from blood samples with TrizolTM Reagent (Thermo Fisher Scientific, USA). To analyze the expression level of hsa-miR122, miRNA specific reverse transcription was performed using Sensi- FASTTM cDNA Synthesis Kit (Bioline, UK) as described by the manufacturer, followed by running RT-qPCR with SensiFASTTMSYBR No-ROX Kit (Bioline, UK). The housekeeping gene, GAPDH (glyceraldehyde-3-phosphate dehydrogenase) was used for normalization. The presence of hsamiR122 and HBV-DNA was identified in human blood using RT-PCR and LAMP techniques. Downregulation of plasma hsa-miR122 was observed in HBV-related HCC patients with a .Ct value of 7.9 +/- 2.1 which was significantly lower than found in healthy control (p<0.01). The loss of hsa miR122 expression was observed in HBV infected patients. We also identified the difference of diagnostic values of this microRNA in different populations and provided a high diagnostic accuracy of HCC (AUC = 0.984 with sensitivity and specificity of 96% and 94%, respectively). CONCLUSION: hsa-miR122 was downregulated in HBV-related HCC patients and found to be lower by approximately 10 fold than in healthy control, resulting in a potential biomarker for microRNA based diagnosis of HCC in human blood. PMID- 29701141 TI - Structure-Based Virtual Screening and Biochemical Evaluation for the Identification of Novel Trypanosoma brucei Aldolase Inhibitors. AB - INTRODUCTION: The glycolytic enzyme fructose-1,6-bisphosphate aldolase is a validated molecular target in human African trypanosomiasis (HAT) drug discovery, a neglected tropical disease (NTD) caused by the protozoan Trypanosoma brucei. Herein, a structure-based virtual screening (SBVS) approach to the identification of novel T. brucei aldolase inhibitors is described. Distinct molecular docking algorithms were used to screen more than 500,000 compounds against the X-ray structure of the enzyme. This SBVS strategy led to the selection of a series of molecules which were evaluated for their activity on recombinant T. brucei aldolase. The effort led to the discovery of structurally new ligands able to inhibit the catalytic activity of the enzyme. RESULTS: The predicted binding conformations were additionally investigated in molecular dynamics simulations, which provided useful insights into the enzyme-inhibitor intermolecular interactions. CONCLUSION: The molecular modeling results along with the enzyme inhibition data generated practical knowledge to be explored in further structure based drug design efforts in HAT drug discovery. PMID- 29701142 TI - Polyamines and Related Nitrogen Compounds in the Chemotherapy of Neglected Diseases Caused by Kinetoplastids. AB - Neglected diseases due to the parasitic protozoa Leishmania and Trypanosoma (kinetoplastids) affect millions of people worldwide, and the lack of suitable treatments has promoted an ongoing drug discovery effort to identify novel nontoxic and cost-effective chemotherapies. Polyamines are ubiquitous small organic molecules that play key roles in kinetoplastid parasites metabolism, redox homeostasis and in the normal progression of cell cycles, which differ from those found in the mammalian host. These features make polyamines attractive in terms of antiparasitic drug development. The present work provides a comprehensive insight on the use of polyamine derivatives and related nitrogen compounds in the chemotherapy of kinetoplastid diseases. The amount of literature on this subject is considerable, and a classification considering drug targets and chemical structures were made. Polyamines, aminoalcohols and basic heterocycles designed to target the relevant parasitic enzyme trypanothione reductase are discussed in the first section, followed by compounds directed to less common targets, like parasite SOD and the aminopurine P2 transporter. Finally, the third section comprises nitrogen compounds structurally derived from antimalaric agents. References on the chemical synthesis of the selected compounds are reported together with their in vivo and/or in vitro IC50 values, and structureactivity relationships within each group are analyzed. Some favourable structural features were identified from the SAR analyses comprising protonable sites, hydrophobic groups and optimum distances between them. The importance of certain pharmacophoric groups or amino acid residues in the bioactivity of polyamine derived compounds is also discussed. PMID- 29701143 TI - Ubiquitin Proteasome System as a Potential Drug Target for Malaria. AB - Parasites of Plasmodium genus are responsible for causing malaria in humans. Resistant strains to all available antimalarials can be found in several locations around the globe, including parasites resistant to the latest generation of combination drugs, such as piperaquine + artemisinin. Plasmodium develops between two completely different hosts such as a vertebrate one and the mosquito vector, thus it has the ability to adapt to very extreme and different environments. Through the complex life cycle in the hosts, Plasmodium invades and replicates in totally different cells thus making the study of the biology of the parasite and the identification of targets for drug development affecting all stages very difficult. It was shown that host molecules, such as melatonin and derivatives, have a role in the progression and regulation of the parasite cell cycle; In fact, when the parasite is exposed to melatonin there is an increase in transcription levels of genes encoding for proteins related to the Ubiquitin Proteasome (UPS) System. This system is essential for the survival of the parasite, and drugs such as bortezomib, MLN-273, ZL3B, epoxomicins and salinosporamides are capable of eliminating the parasite by inhibiting the degradation of proteins via the proteasome system. In addition, the Plasmodium UPS shows low similarity to the ubiquitin proteasome system in Humans; the identification of unique targets to be used for therapeutic molecules development increases the importance of UPS studies in malaria challenging. Drugs that cause oxidative stress, such as artemisinin, show a strong synergistic effect with proteasome inhibitors, increasing the possibilities of combined therapies, which are more effective with lower concentration of drugs. Thus, the study of the mechanism of action of the UPS and the identification of potential targets for new drugs development are promising alternative strategies to fight the drug resistance problem in malaria parasites. PMID- 29701144 TI - Current and Future Prospects of Nitro-compounds as Drugs for Trypanosomiasis and Leishmaniasis. AB - Interest in nitroheterocyclic drugs for the treatment of infectious diseases has undergone a resurgence in recent years. Here we review the current status of monocyclic and bicyclic nitroheterocyclic compounds as existing or potential new treatments for visceral leishmaniasis, Chagas' disease and human African trypanosomiasis. Both monocyclic (nifurtimox, benznidazole and fexinidazole) and bicyclic (pretomanid (PA-824) and delamanid (OPC-67683)) nitro-compounds are prodrugs, requiring enzymatic activation to exert their parasite toxicity. Current understanding of the nitroreductases involved in activation and possible mechanisms by which parasites develop resistance is discussed along with a description of the pharmacokinetic / pharmacodynamic behaviour and chemical structure-activity relationships of drugs and experimental compounds. PMID- 29701145 TI - A Potential Therapeutic Target RNA-binding Protein, Arid5a for the Treatment of Inflammatory Disease Associated with Aberrant Cytokine Expression. AB - BACKGROUND: Infection, tissue damage and aging can cause inflammation with high levels of inflammatory cytokines. Overproduction of inflammatory cytokines often leads to systemic inflammatory response syndrome (SIRS), severe sepsis, and septic shock. However, prominent therapeutic targets have not been found, although the incidence of sepsis is likely to increase annually. Our recent studies indicate that some RNA-binding proteins, which control gene expression of inflammatory cytokines at the post-transcriptional level, may play a critical role in inflammatory diseases such as sepsis. RESULTS: 1) One of the RNA-binding proteins, AT-rich interactive domain-containing 5a (Arid5a) promotes cytokine production through control of mRNA half-lives of pro-inflammatory molecules such as IL-6, STAT3, T-bet, and OX40 in activated macrophages and T cells. Arid5a KO mice are refractory to endotoxin shock, bleomycininduced lung injury, and inflammatory autoimmune disease. 2) Chlorpromazine (CPZ), which is recognized as a psychotic drug, impairs post-transcriptional gene expression of Il6 in LPS stimulated macrophages: CPZ inhibits the binding activity of Arid5a to the 3'UTR of Il6 mRNA, thereby destabilizing Il6 mRNA possibly through suppression of Arid5a expression. 3) CPZ has strong suppressive effects on cytokine production such as TNF-alpha in vivo. Mice with treatment of CPZ are resistant to lipopolysaccharide (LPS)-induced shock. CONCLUSION: Thus, Arid5a contributes to the activation of macrophages and T cells through positive control of mRNA half lives of inflammatory cytokines and its related molecules, which might lead to cytokine storm. Interestingly, Arid5a was identified from an inhibitory effect of CPZ on IL-6 production in macrophages activated by LPS. Therefore, CPZ derivatives or Arid5a inhibitors may have a potential to suppress severe sepsis through control of post-transcriptional gene expression. PMID- 29701146 TI - Role of Melatonin in the Inflammatory Process and its Therapeutic Potential. AB - Melatonin is an indolamine synthesized and secreted by the pineal gland along with other extrapineal sources including immune system cells, the brain, skin and the gastrointestinal tract. Growing interest in this compound as a potential therapeutic agent in several diseases stems from its pleiotropic effects. Thus, melatonin plays a key role in various physiological activities that include regulation of circadian rhythms, immune responses, the oxidative process, apoptosis or mitochondrial homeostasis. Most of these processes are altered during inflammatory pathologies, among which neurodegenerative and bowel diseases stand out. Therapeutic assays with melatonin indicate that it has a beneficial therapeutic value in the treatment of several inflammatory diseases, such as Alzheimer, Amiotrophic Lateral, Multiple Sclerosis and Huntigton's disease as well as ulcerative colitis. However, contradictory effects have been demonstrated in Parkinson's and Chron's diseases, which, in some cases, the reported effects were beneficial while in others the pathology was exacerbated. These various results may be related to several factors. In the first place, it should be taken into account that at the beginning of the inflammation phase there is a production of reactive oxygen species (ROS) that should not be blocked by exclusively antioxidant molecules, since, on the one hand, it would be interfering with the action of neutrophils and macrophages and, on the other, with the apoptotic signals activated by ROS. It is also important to keep in mind that the end result of an anti-inflammatory molecule will depend on the degree of inflammation or whether or not it has been resolved and has therefore become chronic. In this review we present the use of melatonin in the control of inflammation underlying the above mentioned diseases. These actions are mediated through their receptors but also with their direct antioxidant action and melatonin's ability to break the vicious cycle of ROSinflammation. This review is aimed at evaluating the effect of melatonin on activity of the inflammatory process and at its immunomodulator effects. PMID- 29701147 TI - Molecular Targets of Phytochemicals for Skin Inflammation. AB - Skin is a protective organ and the largest of the human body. Due to its pivotal role in aesthetic appearance, skin health has a significant impact on quality of life. Chronic inflammation of the skin often marks the beginning of various skin diseases. Immune-mediated responses serve to protect the body from external insults and require succinct control, and can lead to ongoing cellular damage and various skin conditions if left unchecked. Studies have shown that phytochemicals can alter processes involved in skin inflammation and alleviate the effects of aging, cancer, atopic dermatitis, psoriasis, and vitiligo. Direct molecular targets of some phytochemicals have been identified and their precise mechanisms of action investigated. In this review, we summarize recent findings on the effects of phytochemicals on skin inflammation and the mechanisms of action involved. PMID- 29701148 TI - Quantification of Methamphetamine "Shabu" in Biological Matrices to Detect Prenatal Exposure: A Case Report and a Literature Review. AB - BACKGROUND: Methamphetamine misuse represents an increasing global public health problem. Its consumption during pregnancy becomes a relevant issue, since it has clinical consequences for the child's health and the pregnant woman. Despite this, there are only few data in the literature that include analytical results in the matrices used to detect prenatal exposure. OBJECTIVES: 1) Present a case report of prenatal methamphetamine exposure with toxicological analytical confirmation in biological matrices; and 2) Perform a compilation of prenatal methamphetamine exposure studies and case reports which include toxicological analytical results. METHODS: Prenatal methamphetamine exposure was confirmed using a traditional "screen with reflex" approach. Methamphetamine and amphetamine were quantified in urine, meconium and hair samples of the neonate and mother by gas chromatography-mass spectrometry. Also, a detailed revision of the existent literature that provides information on the analytical toxicology results has been included. RESULTS: In the neonatal biological matrices test results of methamphetamine/amphetamine were: urine 2,966.43/1,638.71 ng/mL, meconium 1,450/<0.1 ng/g and hair 36.54/9.66 ng/mg. In the maternal biological matrices, test results were: urine 13,393.89/3,074.95 ng/mL and hair 11.29/3.37 ng/mg (0-3 cm), 4.68/2.58 (3-6 cm), 6.43/3.13 ng/mg (6-9 cm) and 4.72/2.49 ng/mg (9-12 cm). These results confirm a recent and continued regular substance use throughout pregnancy including delivery. CONCLUSION: The data provided will be useful for clinical purposes to improve the diagnostic and follow- up of acute and chronic intoxications. Additionally, results will be used to support interpretations in the field of forensic and legal medicine. PMID- 29701150 TI - The critical role of abnormal trophoblast development in the etiology of preeclampsia. AB - BACKGROUND: The pregnancy pathology preeclampsia is still among the leading causes of maternal and perinatal morbidity and mortality. At the same time, its etiology is far from being identified and remains obscure in a number of facets. A number of hypotheses have been developed to explain the altered interplay between placenta and mother leading to the clinical symptoms of preeclampsia. However, none of them offers the opportunity to explain the variability of cases with late-onset versus early-onset, mild versus disease and with or without additional fetal growth restriction. CONCLUSION: This paper identifies the weaknesses of the most important current hypothesis and at the same time offers a set of new elucidations including maternal susceptibility, and villous/extravillous trophoblast differentiation to explain the development of preeclampsia. Such elucidations allow following new scientific routes and pathways to untangle the etiology of preeclampsia. PMID- 29701149 TI - Nigella sativa L. and Its Bioactive Constituents as Hepatoprotectant: A Review. AB - BACKGROUND: The pharmacological properties of Nigella sativa L. are well attributed to the presence of bioactive compounds, mainly, thymoquinone (TQ), thymol (THY) and alpha hederin and their antioxidant effects. TQ, THY and alpha hederin (alpha-hederin) provide protection to liver from injury via different mechanisms including inhibition of iron-dependent lipid peroxidation, elevation in total thiol content and (GSH) level, radical scavenging, increasing the activity of quinone reductase, catalase, superoxide dismutase (SOD) and glutathione transferase (GST), inhibition of NF-kappaB activity and inhibition of both (COX) and (LOX) protects liver from injuries. Review and Conclusion: The main aim of this literature review is to reflect the relevant role of ROS in inducing hepatic diseases and also the preventive role of N. sativa L. in hepatic diseases. The present article is directed towards highlighting the beneficial contribution of researchers to explore the pharmacological actions with therapeutic potential of this precious natural herb and its bioactive compounds pertaining to the hepatoprotective effects. We systematically searched for research literature through well-framed review question and presented the data in the tabular forms for the convenience of the readers. Two hundred and forty-one papers were embodied in this review, oxidative effect and the reactive oxygen species (ROS) are known to be the major causes of many diseases such as hepatic cancer. Many drugs and chemicals have shown to incite oxidative damage by generation of ROS in the body. Therefore, this review intends to focus the role of ROS in liver diseases and the mechanisms through which N. sativa prevents hepatic diseases. The mechanisms by which N. sativa impede progression in chronic liver diseases should be used as a preventive medicine in patients with hepatic disorders. PMID- 29701152 TI - Memorization Test and Resting State EEG Components in Mild and Subjective Cognitive Impairment. AB - BACKGROUND: Mild (MCI) and Subjective Cognitive Impairment (SCI) are conditions at risk of developing Alzheimer's disease (AD). Differential between normal aging at early stages can be really challenging; available biomarkers need to be combined and can be quite invasive and expensive. OBJECTIVE: The aim of this pilot study is to examine possible EEG alterations in MCI and SCI compared to controls, analyzing if a cognitive task could highlight early AD hallmarks. METHOD: We recruited 11 MCI, 8 SCI and 7 healthy subjects as controls (CS), all matched for age and education. Neuropsychological assessment and EEG recording, at resting state and during a mental memory task, were performed. Classical spectral measures and nonlinear parameters were used to characterize EEGs. RESULTS: During cognitive task, alpha-band power reduction was found predominantly in frontal regions in SCI and CS, diffused to all regions in MCI; moreover, decreased EEG complexity was found in SCI compared to controls. The alpha -band power attenuation restricted to frontal regions in SCI during a free recall task (involving frontal areas), suggests that MCI patients compensate for encoding deficit by activating different brain networks to perform the same task. Furthermore, EEG complexity reduction - that has been found already in SCI - could be a possible early hallmark of AD. CONCLUSION: This study draws attention on the importance of nonlinear approach in EEG analysis and the potential role of cognitive task in highlighting EEG alterations at very early stages of cognitive impairment; EEG could therefore have a practical impact on dementia diagnosis. PMID- 29701153 TI - Semantic Intrusions and Failure to Recover From Semantic Interference in Mild Cognitive Impairment: Relationship to Amyloid and Cortical Thickness. AB - BACKGROUND: Accumulating evidence indicates that the failure to recover from the effects of proactive semantic interference [frPSI] represents an early cognitive manifestation of preclinical Alzheimer's disease. A limitation of this novel paradigm has been a singular focus on the number of targets correctly recalled, without examining co-occurring semantic intrusions [SI] that may highlight specific breakdowns in memory. OBJECTIVES: We focused on SI and their relationship to amyloid load and regional cortical thickness among persons with amnestic mild cognitive impairment (aMCI). METHODS: Thirty-three elders diagnosed with aMCI underwent F-18 florbetaben amyloid PET scanning with MRI scans of the brain. We measured the correlation of SI elicited on cued recall trials of the Loewenstein-Acevedo Scales for Semantic Interference and Learning [LASSI-L] with mean cortical amyloid load and regional cortical thickness in AD prone regions. RESULTS: SI on measures sensitive to frPSI was related to greater total amyloid load and lower overall cortical thickness [CTh]. In particular, SI were highly associated with reduced CTh in the left entorhinal cortex [r=-.71; p<.001] and left medial orbital frontal lobe [r=-.64; p<.001]; together accounting for 66% of the explained variability in regression models. CONCLUSION: Semantic intrusions on measures susceptible to frPSI related to greater brain amyloid load and lower cortical thickness. These findings further support the hypothesis that frPSI, as expressed by the percentage of intrusions, may be a cognitive marker of initial neurodegeneration and may serve as an early and distinguishing test for preclinical AD that may be used in primary care or clinical trial settings. PMID- 29701155 TI - Dietary Fat Intake and Risk of Alzheimer's Disease and Dementia: A Meta-Analysis of Cohort Studies. AB - BACKGROUND: Epidemiological studies showed that dietary fat intake is associated with Alzheimer's disease (AD) and dementia risk, however, the association remain inconsistent. This metaanalysis aimed to systematically examine the association of dietary fat intake with AD and dementia risk. METHODS: We have systematically searched PubMed, Embase and the Cochrane Library up to May 1st 2017. Prospective cohort studies were included if they reported on the association of dietary fat intake with AD and dementia risk. Multivariate-adjusted relative risks (RRs) for the highest versus lowest category were pooled by using a random-effects model. RESULTS: A total of 8630 participants and 633 cases from four independent prospective cohort studies were included in the present meta-analysis. A higher dietary saturated fat intake was significantly associated with an increased risk of 39% and 105% for AD (RR: 1.39; 95% CI: 1.00, 1.94) and dementia (RR: 2.05; 95% CI: 1.06, 3.98), respectively. Dose-response analysis indicated a 4 g/day increment of saturated fat intake was related to 15% higher risk of AD (RR: 1.15; 95% CI: 1.01, 1.31). However, there was no significant association found between dietary intake of total, monounsaturated, polyunsaturated fat and AD or dementia risk. CONCLUSIONS: This meta-analysis provides significant evidence of positive association between higher saturated fat intake and AD and dementia risk. PMID- 29701154 TI - Technological Solutions for Older People with Alzheimer's Disease: Review. AB - In the nineties, numerous studies began to highlight the problem of the increasing number of people with Alzheimer's disease in developed countries, especially in the context of demographic progress. At the same time, the 21st century is typical of the development of advanced technologies that penetrate all areas of human life. Digital devices, sensors, and intelligent applications are tools that can help seniors and allow better communication and control of their caregivers. The aim of the paper is to provide an up-to-date summary of the use of technological solutions for improving health and safety for people with Alzheimer's disease. Firstly, the problems and needs of senior citizens with Alzheimer's disease (AD) and their caregivers are specified. Secondly, a scoping review is performed regarding the technological solutions suggested to assist this specific group of patients. Works obtained from the following libraries are used in this scoping review: Web of Science, PubMed, Springer, ACM and IEEE Xplore. Four independent reviewers screened the identified records and selected relevant articles which were published in the period from 2007 to 2018. A total of 6,705 publications were selected. In all, 128 full papers were screened. Results obtained from the relevant studies were furthermore divided into the following categories according to the type and use of technologies: devices, processing, and activity recognition. The leading technological solution in the category of devices are wearables and ambient noninvasive sensors. The introduction and utilization of these technologies, however, bring about challenges in acceptability, durability, ease of use, communication, and power requirements. Furthermore, it needs to be pointed out that these technological solutions should be based on open standards. PMID- 29701156 TI - Diagnostic Issues in Early-onset Obsessive-Compulsive Disorder and Their Treatment Implications. AB - BACKGROUND: The lifespan approach and recent shift in the conceptualization of Obsessive-Compulsive Disorder (OCD) promoted by the Diagnostic and Statistical Manual of Mental Disorders Fifth Edition (DSM5) along with novel insights into the pathogenesis of this heterogeneous disorder are driving the development of new outcome measures and new treatments for a disease that, on the other hand, is characterized by high rates of refractoriness. OBJECTIVE AND METHODS: The aim of this review is to provide a discussion of the translational evidence about Early Onset OCD (EO) in compliance with a neurodevelopmental and RdoC perspective. RESULTS AND CONCLUSION: There is evidence that EO might be considered the neurodevelopmental subtype of OCD. Indeed there is evidence that different clusters of symptoms and dimensions at an early stage predict different trajectories in phenotype and that distinct neurocircuit patwhays underpin the progression of the disorder. Despite the development of high refractoriness in the course of the disorder, evidence suggests that EO may be particularly treatment responsive in the early stages, thus showing the need for early recognition and additional recovery oriented studies in this subgroup. Consistent with the neurodevelopmental perspective, immunity and glutamate neurotransmission are emerging as novel pathways for parsing out the neurobiology of OCD, the EO form in particular, supporting the implementation of new multisystemic models of the OCD phenotype. Brain connectivity patterns, immune and microbiome profiles are standing out as promising areas for biomarkers with the potential for targeted personalized therapies in EO. PMID- 29701157 TI - Pharmacological Treatment Of Body Dysmorphic Disorder. AB - Body dysmorphic disorder is a challenging disorder that manifests as erroneously perceived flaws in one's physical appearance and repetitive behaviors in response to appearance concerns. This disorder is also frequently comorbid with other psychiatric disorders, including major depressive disorder and autism spectrum disorder. It is currently understood to arise from a combination of biological, psychological, and environmental factors. Treatment of body dysmorphic disorder typically consists of a combination of pharmacotherapy and cognitive behavioral therapy. However, not all patients respond to treatment, and BDD symptoms remain even in those who do respond. This review outlines current pharmacological and neuromodulation treatments for body dysmorphic disorder, and suggests directions for future studies of novel treatments such as augmentation with atypical antipsychotics and the use of intranasal oxytocin in cases of body dysmorphic disorder that show residual symptomatology even with tailored monotherapy. There is emerging evidence suggesting that non-invasive neurostimulatory techniques, such as repetitive transcranial magnetic stimulation, may be of value in treatment-resistant cases. PMID- 29701158 TI - Molecular Docking, In-Silico ADMET Study and Development of 1,6- Dihydropyrimidine Derivative as Protein Tyrosine Phosphatase Inhibitor: An Approach to Design and Develop Antidiabetic Agents. AB - BACKGROUND: 1,6-Dihydropyrimidine exerts notable pharmacological efficiency and emerged as integral backbones for treatment of type-II diabetes mellitus. To optimize the in vitro and In-silico study we carried out on substituted 1,6 Dihydropyrimidine. The objective of the present study is to evaluate the binding interaction of 1,6-Dihydropyrimidine compounds with Protein Tyrosine Phosphatase (PTP1B) enzyme and also check ADME/T properties of best scored compounds. METHODS: The In-silico study (docking) was carried out through target Protein Tyrosine Phosphatase (PTP1B) retrieved from protein data bank having PDB ID: 2QBS and the anti diabetic activity of the test compounds was tested against protein tyrosine phosphatase (PTP1B) enzyme by using Calbiochem (r) PTP1B colorimetric assay kit. RESULTS AND CONCLUSION: The results of molecular Docking revealed that, with respect to their free binding energy 6A, 3K, 1B and 2K compounds have the lowest binding energy compared to positive control. In-silico ADME/T predictions revealed that all best scored compounds had good absorption as well as solubility characteristics through substrate binding sites. After conducting the in vitro studies it was observed that compounds having -3NO2, 3,4-OCH3, 4-NO2 and 4-Cl substitution on phenyl ring in the basic moiety shows good anti diabetic activity The present computational approach provided valuable information on the binding process of 1,6-Dihydropyrimidine compounds to the binding site of PTP-1B. These compounds may serve as potential lead compound for developing new 1,6- Dihyropyrimidine as a promising anti diabetic agent. PMID- 29701159 TI - Beware of External Validation! - A Comparative Study of Several Validation Techniques used in QSAR Modelling. AB - BACKGROUND: Proper validation is an important aspect of QSAR modelling. External validation is one of the widely used validation methods in QSAR where the model is built on a subset of the data and validated on the rest of the samples. However, its effectiveness for datasets with a small number of samples but a large number of predictors remains suspect. OBJECTIVE: Calculating hundreds or thousands of molecular descriptors using currently available software has become the norm in QSAR research, owing to computational advances in the past few decades. Thus, for n chemical compounds and p descriptors calculated for each molecule, the typical chemometric dataset today has a high value of p but small n (i.e. n << p). Motivated by the evidence of inadequacies of external validation in estimating the true predictive capability of a statistical model in recent literature, this paper performs an extensive and comparative study of this method with several other validation techniques. METHODOLOGY: We compared four validation methods: Leave-one-out, K-fold, external and multi-split validation, using statistical models built using the LASSO regression, which simultaneously performs variable selection and modelling. We used 300 simulated datasets and one real dataset of 95 congeneric amine mutagens for this evaluation. RESULTS: External validation metrics have high variation among different random splits of the data, hence are not recommended for predictive QSAR models. LOO has the overall best performance among all validation methods applied in our scenario. CONCLUSION: Results from external validation are too unstable for the datasets we analyzed. Based on our findings, we recommend using the LOO procedure for validating QSAR predictive models built on high-dimensional small-sample data. PMID- 29701160 TI - Non Pregnant Human Uterus as Source of Mesenchymal Stem Cells. AB - Stem/progenitor cells for cell therapy and regenerative medicine should ideally be available in large numbers, after having been isolated using minimally invasive or non-invasive methodologies. Also, they should exhibit wide differentiation potential into multiple lineages, as well as capability to be used successfully in autologous or allogeneic transplantation, and all this in accordance with the applicable guidelines of good manufacturing practice. Thus, the identification and characterization of alternative sources of mesenchymal stem cells (MSCs) is of great importance. The human uterus emerges as an interesting source of MSCs. Both endometrial MSCs (eMSCs) and human uterine cervical stem cells (hUCESCs) were easily obtained with minimal morbidity. Both eMSCs and hUCESCs show a high proliferation rate, which allows for the harvesting of high amounts of these cells, both for research studies and potential therapeutic uses. It has been demonstrated that eMSCs have wide capability of differentiation into many cellular lineages, as well as potential therapeutic effects in several pathological processes. Similarly, hUCESCs'secretome (conditioned medium) shows potent antiinflammatory, anti-tumor, anti-bacterial and regenerative properties. PMID- 29701161 TI - Multi-Drug Resistant Clinical Pseudomonas aeruginosas Inhibited by Ferula gummosa Boiss. AB - BACKGROUND: Multi-drug resistance among Pseudomonas aeruginosa (P. aeruginosa) clinical isolates is increasing and becoming a serious problem for public health authorities worldwide. OBJECTIVE: The aim of the current study is to introduce a potent antibacterial compound against the resistant P. aeruginosa. METHODS: In this study, we evaluated the antibacterial effects of extracts and essential oils of Ferula gummosa Boiss (F. gummosa) on 33 P. aeruginosa clinical isolates by microdilution method and assessed the association of antimicrobial activity with the extended spectrum beta-lactamase (ESBL) producing, biofilm forming and aliginate production of the strains. In addition, the presence of some genes involved in these properties, including blaGES- 1, blaRER-1, blaCTX-M, blaVEB-1, blaOXA-1, blaOXA-4, blaOXA-10, ppyR, pslA, pelA, algU, algL, algD, fliC and oxaA was determined using PCR. RESULTS: We revealed that all of our extracts and essential oils had significant antibacterial effects (p<0.001), but the aqueous extracts showed a relatively lower antibacterial activity compared with the methanolic ones. Furthermore, the minimum inhibitory concentration required for the ESBL producing strains was significantly higher than the non-ESBL producing ones (p<0.001). Loss of some genes such as blaPER-1, blaGES-1, blaOXA-1 and blaOXA-4 caused sensitivity to F. gummosa derivatives (p<0.05). CONCLUSION: The findings of this study indicate that the antibacterial effects of the extract and essential oils of F. gummosa may be a potential novel treatment against drug resistant P. aeruginosa clinical isolates. PMID- 29701162 TI - Hydrogen Sulfide in Diabetic Complications: Focus on Molecular Mechanisms. AB - BACKGROUND: A growing number of studies have indicated that hydrogen sulfide (H2S) affects the development of diabetes and its complications, but the specific mechanism is not completely clear. OBJECTIVE: To summarize the effects and recent molecular mechanisms of H2S in various diabetic complications. METHODS: Articles regarding the role of H2S channels in diabetic complications and relevant mechanisms were selected. Relevant articles published from 2006 to present were selected from PubMed. The search terms were "hydrogen sulfide" and "diabetes". Important references from selected articles were also retrieved. RESULTS: The reduction of endogenous H2S contribute to diabetic injury and the supply of exogenous H2S protect tissues from diabetic injury through anti-apoptosis, anti fibrosis, inhibited oxidative stress and inflammation in different complications, including cardiomyopathy, vascular injury, retinopathy, nephropathy, and encephalopathy. CONCLUSION: H2S may play an important role in diabetic complications and may be a potential target for therapeutic intervention of diabetic related diseases. PMID- 29701163 TI - Vitamin D status in coronary artery disease: association with IL-35 and TGF-beta1 and disease severity. AB - BACKGROUND: The exact mechanisms underlying the protective effect of vitamin D in the pathogenesis of atherosclerosis and coronary heart disease are obscure. OBJECTIVE: Here, we have addressed the relation between vitamin D status and regulatory T cells (Tregs) inhibitory cytokines in patients suffering from coronary artery disease (CAD). MATERIALS AND METHODS: 81 patients were divided into single (n= 20), double (n=20) and triple (n=20) vessel disease groups and compared to no vessel disease (No VD) group (n=21). Interleukin (IL) -35 and TGF- beta1 were measured using ELISA. Vitamin D was measured using Electrochemiluminescence assay. RESULTS: Vitamin D, TGF-beta1 and IL-35 concentrations in No VD (32.4+/-15.2, 667.7+/-427.6, 12.1+/-11.9 respectively) group were significantly higher than patients with 1 or more vessel disease (18.1+/-9.8, 360.4+/-354.1 and 6.8+/-8.1 respectively, p<0.05). Subgroup analysis revealed that TGF-beta1 and IL-35 (but not vitamin D) were significantly higher in double vessel disease patients (591.9+/-465.7 and 9.2+/-8.0 respectively) compared to those with triple vessel disease (173.1+/-163.3 and 3.6+/-1.4 respectively, p<0.05). Both TGF-beta1 and IL-35 were positively correlated to the serum level of vitamin D (r= 0.38, p= 0.001 and r=0.26, p= 0.028 respectively). Vitamin D, TGF-beta1 and IL-35 revealed a negative correlation (r= -0.36, r=-0.46 and r-0.024 respectively) with severity of CAD (p< 0.05). Compared to normal serum vitamin D patients (326.6+/-351.7 pg/mL vs. 754.5+/-560 pg/mL, p=0.036 respectively) TGF-beta1 (but not IL-35), was significantly lower in vitamin D deficient patients. CONCLUSION: The results suggested that, although decreased TGF-beta1 and IL-35 plasma levels correlate positively with decreased vitamin D levels and negatively with severity of CAD, but only TGF-beta1 has a significant association with vitamin D deficiency in CAD patients. It seems that the antiatherosclerotic effect of vitamin D is at least partly attributed to the up regulation of anti-inflammatory cytokines especially TGF- beta1. PMID- 29701164 TI - Biometric Characterization and Morphophysiological Quality of Peach Rootstock Seeds Using Images of their Seedling Vigor. AB - BACKGROUND: This study aimed to evaluate the efficiency of using the computerized imaging Seed Analysis System (SAS) in the biometric and morphophysiological characterization of seeds and the initial growth of seedlings from peach rootstocks. METHODS: The experimental design was completely randomized with five replicates of 20 seeds. The variables analyzed were the seed humidity content, length and width of seeds measured by SAS technology and manual measurements, mean germination time, germination percentage, radicle length and width, taproot length, length of the aerial part and taproot/aerial part ratio. RESULTS: The highest seed length, germination percentage (100%) and lower germination time (11.3), were obtained with the cv. Capdeboscq while, 'Tsukuba 1', 2' and 3' had intermediate seedlings length, varying from 1.55 to 1.65 cm with mean germination times between 14.5 and 18.0 days and average germination percentage of 96%. The computerized analysis of images is fast and efficient for biometric evaluations such as seed width and length, as well as initial growth of peach tree seedlings. The cvs Capdeboscq, Flordaguard and Tsukuba 2 presented greater radicle width, length and a mean taproot/aerial part ratio equal to 2, as well as higher number of adventitious roots, which indicated a strong positive correlation between radicle length, taproot length and initial seedling growth. CONCLUSION: The continuity of the research will certainly allow the development of reliable procedures for other species, besides allowing the identification of wider alternatives for the use of this system for the expansion of knowledge in the areas of physiology and evaluation of the physiological potential of seeds. PMID- 29701165 TI - Flow Cytometric Analysis of Pro-inflammatory Cytokine Production in Hyperglycemic Mouse Model. AB - OBJECTIVE: The sharp increase of pro-inflammatory cytokine becomes a severe problem in some degenerative diseases. This study aimed to investigate the effect of Cherry Leaf Extract (CLE) on pro-inflammatory cytokine production in hyperglycaemic mouse model. A recent patent mentioned that Muntinga calabura is a flavonoid-containing plant which is capable of reinforcing the stomach, appetizing, helping digestion (CN 201611138374), and improving stomach distention (CN106071017A). The efficacy of this miracle plant has inspired this experiment. METHODS: In this study, we induced hyperglycemia with high-fat diet and 20% fructose drink. Hyperglycemic mice were orally administered with CLE with the doses 420, 700, and 28000 mg/kg BW for two weeks. After treatment, the pro inflammatory molecule was analyzed by flow cytometry from splenic cells. RESULTS: This study showed that CLE decreased the production of pro-inflammatory molecules such as IL-6, NF-kappaB, TNF-alpha, and IFN gamma. In hyperglycemic mice, we found CD68+IL-6+, NK1.1+IL- 6+, B220+NFkappaB+, CD4+TNF-alpha+, and CD4+IFN gamma + increased significantly (p < 0.05) compared to control mice without manipulation. After treatment with 420, 700, or 2800 mg/kg BW of CLE, the pro inflammatory molecules decreased significantly (p < 0.05), and reached a normal physiology level. CONCLUSION: CLE can suppress pro-inflammatory cytokines in hyperglycemic mouse model, suggesting this medicinal herb may be beneficial as a potential strategy for future therapeutic interventions in degenerative diseases or a disease involving cell activation. PMID- 29701166 TI - Nuts and Grains: Microbiology and Preharvest Contamination Risks. AB - Low-water-activity foods have been involved in recalls and foodborne disease outbreaks. Increased consumption; better detection methods and reporting systems; improved surveillance, trace-back, and ability to connect sporadic foodborne illnesses; and inadequate implementation of food safety programs are some of the likely reasons for the increase in frequency of recalls and outbreaks linked to dry foods. Nuts and grains can be contaminated with foodborne pathogens at any stage during production, processing, storage, and distribution. Focusing on preharvest contamination, the various potential sources of contamination include soil, animal intrusion, contaminated harvesting equipment, harvest and preharvest handling, storage conditions, and others. The low water activity of nuts and grains prevents the growth of most foodborne pathogens on their surfaces. The long-term survival of bacterial foodborne pathogens (Salmonella, Escherichia coli O157:H7, and Listeria monocytogenes) on dry foods has been documented in the literature for different nut types. Preventing contamination is the key to avoiding foodborne disease risks linked to dry foods. The implementation of good agricultural practices and other food safety systems provides a proactive approach to address concerns thoroughly. A plethora of research is available on preventing the growth of mycotoxin-producing fungi on the surface of nuts and grains. Milling is an effective mechanism to reduce the microbial load on grains. This review focuses on providing information about associated foodborne microorganisms, preharvest contamination sources, and good agricultural practice recommendations for nuts and grains. PMID- 29701167 TI - Amaze: a double-blind, multicentre randomised controlled trial to investigate the clinical effectiveness and cost-effectiveness of adding an ablation device-based maze procedure as an adjunct to routine cardiac surgery for patients with pre existing atrial fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) can be treated using a maze procedure during planned cardiac surgery, but the effect on clinical patient outcomes, and the cost-effectiveness compared with surgery alone, are uncertain. OBJECTIVES: To determine whether or not the maze procedure is safe, improves clinical and patient outcomes and is cost-effective for the NHS in patients with AF. DESIGN: Multicentre, Phase III, pragmatic, double-blind, parallel-arm randomised controlled trial. Patients were randomised on a 1 : 1 basis using random permuted blocks, stratified for surgeon and planned procedure. SETTING: Eleven acute NHS specialist cardiac surgical centres. PARTICIPANTS: Patients aged >= 18 years, scheduled for elective or in-house urgent cardiac surgery, with a documented history (> 3 months) of AF. INTERVENTIONS: Routine cardiac surgery with or without an adjunct maze procedure administered by an AF ablation device. MAIN OUTCOME MEASURES: The primary outcomes were return to sinus rhythm (SR) at 12 months and quality-adjusted life-years (QALYs) over 2 years after randomisation. Secondary outcomes included return to SR at 2 years, overall and stroke-free survival, drug use, quality of life (QoL), cost-effectiveness and safety. RESULTS: Between 25 February 2009 and 6 March 2014, 352 patients were randomised to the control (n = 176) or experimental (n = 176) arms. The odds ratio (OR) for return to SR at 12 months was 2.06 [95% confidence interval (CI) 1.20 to 3.54; p = 0.0091]. The mean difference (95% CI) in QALYs at 2 years between the two trial arms (maze/control) was -0.025 (95% CI 0.129 to 0.078; p = 0.6319). The OR for SR at 2 years was 3.24 (95% CI 1.76 to 5.96). The number of patients requiring anticoagulant drug use was significantly lower in the maze arm from 6 months after the procedure. There were no significant differences between the two arms in operative or overall survival, stroke-free survival, need for cardioversion or permanent pacemaker implants, New York Heart Association Functional Classification (for heart failure), EuroQol-5 Dimensions, three-level version score and Short Form questionnaire-36 items score at any time point. Sixty per cent of patients in each trial arm had a serious adverse event (p = 1.000); most events were mild, but 71 patients (42.5%) in the maze arm and 84 patients (45.5%) in the control arm had moderately severe events; 31 patients (18.6%) in the maze arm and 38 patients (20.5%) in the control arm had severe events. The mean additional cost of the maze procedure was L3533 (95% CI L1321 to L5746); the mean difference in QALYs was -0.022 (95% CI -0.1231 to 0.0791). The maze procedure was not cost-effective at L30,000 per QALY over 2 years in any analysis. In a small substudy, the active left atrial ejection fraction was smaller than that of the control patients (mean difference of -8.03, 95% CI -12.43 to -3.62), but within the predefined clinically equivalent range. LIMITATIONS: Low recruitment, early release of trial summaries and intermittent resource-use collection may have introduced bias and imprecise estimates. CONCLUSIONS: Ablation can be practised safely in routine NHS cardiac surgical settings and increases return to SR rates, but not survival or QoL up to 2 years after surgery. Lower anticoagulant drug use and recovery of left atrial function support anticoagulant drug withdrawal provided that good atrial function is confirmed. FURTHER WORK: Continued follow up and long-term clinical effectiveness and cost-effectiveness analysis. Comparison of ablation methods. TRIAL REGISTRATION: Current Controlled Trials ISRCTN82731440. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 19. See the NIHR Journals Library website for further project information. PMID- 29701169 TI - A newly diagnosed case of polymorphous low-grade neuroepithelial tumor of the young. AB - Polymorphous low-grade neuroepithelial tumor of the young (PLNTY) is a recently described variant of low-grade neuroepithelial tumors that exhibits infiltrative growth, histopathological variability with frequently prominent oligodendroglioma like components, intense labeling for CD34, absence of 1P/19Q codeletion, a distinct DNA methylation signature and genetic alterations involving MAP kinase pathway constituents of either the B-Raf proto-oncogene BRAF or fibroblast growth factor receptors 2 or 3 (FGFR2 and FGFR3). We here report a newly diagnosed case of PLNTY involving the temporal lobe in a 31-year-old man with chronic focal epilepsy. This tumor had histologic and immunophenotypic features similar to the recently described PLNTY and proved BRAF V600E mutant. Biomolecular profiling is becoming increasingly important in characterizing neuroepithelial tumors. Furthermore, biomolecular features such as CD34 expression and BRAF mutation have been reported to be significantly associated with the clinical behavior of these tumors. Like other low-grade neuroepithelial tumors, PLNTYs appear to be generally indolent with excellent seizure relief after total surgical resection. It is important to recognize cases of PLNTY in order to guide clinical management including the indication for surgery.?. PMID- 29701171 TI - Risk factors for rhabdomyolysis with HMG-CoA reductase inhibitors identified using a postmarketing surveillance database in Japan?. AB - OBJECTIVE: To investigate quantitatively the risk factors for rhabdomyolysis or related symptoms associated with HMG-CoA reductase inhibitors (statins), we used the lipid-lowering drug database (32,157 patients) developed by the RAD-AR Council, Japan, based on the postmarketing surveillance (PMS) data of pharmaceutical companies to perform a nested case-control study. MATERIALS AND METHODS: Of 26,849 patients taking statins, the case group was composed of 51 patients who experienced rhabdomyolysis or related symptoms while taking statins, and the control group was 1,020 patients randomly selected from patients who did not experience rhabdomyolysis or related symptoms while taking statins. Relevant factors that can be extracted from the database were: sex, age, body mass index (BMI), statin use duration, complications, concomitant medication, and clinical laboratory test values. RESULTS: Among those taking statins, 51 experienced rhabdomyolysis or related symptoms. Factors differing significantly between the two groups by univariate analysis were age, duration of statin intake, combination drugs (Ca antagonists, angiotensin II receptor blocker (ARB), cardiac drugs, benzodiazepines, mucoprotective drugs, insulin, alpha-glucosidase inhibitors), clinical laboratory results (high-density lipoprotein cholesterol (HDL-C), aspartate aminotransferase, alkaline phosphatase, total bilirubin), and complications (alcoholic hepatitis). Conditional multivariate logistic analysis of these factors yielded adjusted/odds ratios of 8.82 for the concomitant administration of an ARB and 3.45 for increased AST and 3.20 for increased total bilirubin levels. CONCLUSION: Risk factors for rhabdomyolysis or related symptoms associated with taking statins were combination with ARB and increases in AST or total bilirubin levels.?. PMID- 29701170 TI - Diagnosing and treating dementia in German primary and specialized care between 2011 and 2015?. AB - BACKGROUND: Whilst there was no upturn in detection rate of persons with dementia (PwD) in German general practitioner (GP) practices before 2012, dementia diagnoses markedly increased in 2013 and 2014. OBJECTIVE: (1) Verify the increase of dementia diagnoses in GP practices and neurologist/psychiatrist (NP) practices; (2) examine the subsequent prescription of antidementia drugs. MATERIALS AND METHODS: We performed a retrospective, longitudinal analysis of 874 GP and 141 NP practices collecting clinical data about 220,213 patients who received a dementia diagnosis (ICD-10: G30, F01, F03) between 2011 and 2015. RESULTS: In GP practices, documented dementia diagnoses increased by 73% between 2012 and 2014 (mean 6.4 - 11.1 PwD/practice) and decreased by 26% in 2015 (8.3 PwD/practice). This trend was mostly due to the subgroup of nonspecific (+63%) and vascular dementia (+170%). The upturn has been accompanied by a downturn of the proportion of PwD receiving antidementia drugs (2012: 13.9% vs. 2014: 7.8%). Neither of these trends was found in NP practices. CONCLUSION: The upturn parallels the introduction of monetary incentives for both patients and GPs. It should be examined if these monetary incentives will also lead to an improvement in treatment and care of PwD in the long run.?. PMID- 29701172 TI - Tocilizumab histologically improved AA renal amyloidosis in a patient with multicentric Castleman disease: A case report?. AB - Multicentric Castleman disease (MCD) is a rare systemic lymphoproliferative disorder and is infrequently associated with renal complications that include amyloid A (AA) amyloidosis. Although it has been reported that patients with MCD and amyloidosis usually have a poor prognosis, recently, tocilizumab, a humanized anti-interleukin-6 receptor antibody, has emerged as an effective and specific treatment for AA amyloidosis secondary to chronic inflammatory disorders. Here we report a case of an MCD patient with secondary AA renal amyloidosis who was successfully treated with tocilizumab. The patient was initially referred to nephrology specialists because of a decline in renal function and proteinuria. Percutaneous renal biopsy revealed the presence of Congo red-positive amorphous depositions and AA protein-positive areas in glomeruli, vessel walls, and interstitium, confirming a diagnosis of renal AA amyloidosis secondary to MCD. At 1 year after starting tocilizumab treatment, a second renal biopsy showed the clearance of amyloid deposits in the interstitium. These observations suggest that tocilizumab may be an effective therapy for AA amyloidosis secondary to MCD.?. PMID- 29701173 TI - Cyclical cardiorenal syndrome in late-stage kidney disease?. AB - INTRODUCTION: In patients with late-stage chronic kidney disease (LS-CKD, estimated glomerular filtration rate (eGFR) < 30 mL/min) there is a high prevalence of congestive heart failure (CHF). We have observed a cyclical nature in the "cardiorenal syndrome" in LS-CKD, not previously described. The purpose of this article is to describe the syndrome and review its characteristics. MATERIALS AND METHODS: Patients enrolled in the Northwell Health Healthy Transitions in Late Stage Kidney Disease Program (HT) were followed, all with eGFR 0 - 30 mL/min. Patients were observed for a 1-year period for signs of destabilized cardiorenal syndrome. The primary outcome of interest was an episode of cyclical cardiorenal syndrome (CCRS), defined as CHF symptoms leading to increased diuretic dose or increased renin-angiotensin-aldosterone system inhibitors (RAASi) followed within 60 days by acute kidney failure (AKI), or, conversely, an episode of AKI with reduction in diuretic or RAASi, followed within 60 days by worsening of CHF. RESULTS: Of 302 HT patients, 63 (20.9%) patients had at least one episode of CCRS. Of the 63 patients, there were 89 CCRS episodes (ranging 1 - 3 per patient) and 32 (35.0%) associated hospitalizations for CHF. Of 89 CCRS episodes, 67 (75.3%) started with an episode of CHF, 22 (24.7%) started with AKI. Of 67 cases of CHF with subsequent AKI, the associated medication change was a diuretic dose increase in 61 cases (91.0%), increase in RAASi dose in 3 cases (4.5%), and increases in both in 3 cases (4.5%). Of 22 cases of AKI leading to subsequent CHF, the associated medication change was a diuretic dose decrease in 19 (86.4%) and a decrease in both diuretic and RAASi dose in 3 (13.6%). CONCLUSION: CCRS occurs in ~ 1/5 of late-stage CKD patients with CHF. Further study would help to elucidate the extent to which fragmented care between cardiologists and nephrologists contributes to the problem.?. PMID- 29701174 TI - Mean platelet volume/platelet count ratio and mortality in patients on peritoneal dialysis?. AB - OBJECTIVES: The association between mean platelet volume/platelet count ratio (MPV/PC) and mortality has been demonstrated in various populations but not in peritoneal dialysis (PD) patients. This study investigated the association between MPV/PC and all-cause and cardiovascular mortality in PD patients. MATERIALS AND METHODS: In this single-center retrospective cohort study, 338 patients who underwent incident PD from January 2006 to June 2014 and had baseline MPV/PC were enrolled and followed until June 30, 2015. RESULTS: The mean patient age was 50.5 +/- 14.9 years (58.2% men, 22.8% diabetic). During a median follow-up of 25 (IQR 17 - 39) months, 58 patients died; 30 deaths were due to cardiovascular disease. The patients were stratified into two groups according to the PC, MPV, and MPV/PC quartiles. The all-cause and cardiovascular mortality were compared between both groups. MPV and MPV/PC and all-cause and cardiovascular mortality were significantly associated, even after adjusting for age, gender, Davies score, hemoglobin, albumin, and usage of platelet inhibitors. Only the association between baseline MPV/PC and all-cause and cardiovascular mortality was similar when we examined PC, MPV, and MPV/PC without stratification. In the multivariable adjusted model, each 0.01 increase in MPV/PC was associated with an adjusted hazard ratio (AHR) of 0.67 (95% CI, 0.51 - 0.89) for all-cause mortality and an AHR of 0.63 (95% CI, 0.42 - 0.96) for cardiovascular mortality. CONCLUSION: MPV/PC may be a more reliable and accurate risk factor compared to MPV or PC alone.?. PMID- 29701175 TI - Sclerostin is not associated with cardiovascular event or fracture in kidney transplantation candidates?. AB - BACKGROUND: Sclerostin, a bone-derived protein, has been linked to cardiovascular calcifications in chronic kidney disease (CKD). The aim of this study was to investigate the associations between sclerostin and mineral and bone disorder in CKD, specifically whether sclerostin levels could predict cardiovascular event, fracture, or all-cause mortality. MATERIALS AND METHODS: Kidney transplantation candidates (n = 157) underwent computed tomography scans of the chest, abdomen, and pelvis. Calcification scores were calculated for coronary arteries, thoracic aorta, and the aortic and mitral valves. Volumetric bone mineral density (BMD) was measured at the spine and hip. Sclerostin and markers of bone turnover were determined from fasting blood samples. RESULTS: Compared to patients with a calcification score of 0, sclerostin levels were higher in patients with calcifications at the coronary arteries (+23%, p < 0.001) and the thoracic aorta (+27%, p = 0.001), but not in patients with calcifications at the aortic (+1%, p = 0.85) or mitral (+8%, p = 0.20) valves. During a median follow-up of 3.7 years, 28 patients had a major cardiovascular event, 19 patients sustained a fragility fracture, and 32 patients died. Sclerostin levels above the median did not predict major cardiovascular event (p = 0.15), fracture (p = 0.58), or mortality (p = 0.65). CONCLUSION: Sclerostin was positively associated with the presence of vascular calcifications, but was not predictive of events associated with mineral and bone disorder in a cohort of kidney transplantation candidates.?. PMID- 29701176 TI - Consequences of delay in screening, monitoring, and treatment of angiomyolipoma and tuberous sclerosis: A case report?. AB - BACKGROUND: Tuberous sclerosis complex (TSC) is a multisystem disorder that results in tumor growth in various organs. TSC can affect the kidneys in the form of renal angiomyolipomas and cysts that can lead to chronic kidney disease. CASE PRESENTATION: A 38-year-old woman was referred to Kennedy Krieger Institute for comprehensive TSC management. Before referral, the patient had gone most of her life without a definite diagnosis of TSC despite visually-prominent signs such as forehead plaques, facial angiofibromas, and ungual fibromas. Eventually, complications of the disease led to the patient requiring hemodialysis at age 34 and a complete bilateral nephrectomy at age 36. However, the patient was not diagnosed with TSC until an evaluation at the National Institutes of Health at age 37. After becoming a patient at our clinic, a multidisciplinary approach was taken to provide comprehensive care by including various disciplines such as nephrology, neurology, pulmonology, ophthalmology, dentistry, dermatology, and cardiology. DISCUSSION AND CONCLUSION: TSC consensus recommendations aid in diagnosis, monitoring, and treatment of TSC and its associated manifestations, including those involving the kidneys. Our case underscores the importance of early identification of TSC to prevent future complications and promotes use of a multidisciplinary team to provide comprehensive care.?. PMID- 29701177 TI - A case of infection-related glomerulonephritis with massive eosinophilic infiltration?. AB - Infection-related glomerulonephritis (IRGN) is rarely complicated with eosinophil infiltration into the glomerulus. Here we report a case of eosinophilic proliferative glomerulonephritis related with infection. A 70-year-old man with respiratory symptoms displayed hypereosinophilia, hypocomplementemia, impaired renal function, and nephrotic syndrome. Renal biopsy revealed endocapillary proliferative glomerulonephritis with immunostaining for immunoglobulin G and complement 3, and subepithelial hump-like electron-dense deposits, thus fulfilling the criteria for IRGN. Immunostaining for the nephritis-associated plasmin receptor (NAPlr) in the glomerulus confirmed the diagnosis of IRGN. Of note, eosinophils infiltrated into the glomerular subendothelial spaces, renal tubules, peritubular capillaries, and the interstitium in the kidney as well as in the alveolar walls and pulmonary arteries in the lung. Corticosteroid therapy rapidly improved hypereosinophilia as well as respiratory symptoms and renal function. Urinary protein exertion was decreased, and serum level of complement and albumin was increased. These findings suggest that eosinophil infiltration might play a prominent role in respiratory and renal disorders. Severe endothelial damage of glomeruli and tubulointerstitial nephritis, caused by eosinophil-rich inflammation, might significantly contribute to exacerbation of renal insufficiency.?. PMID- 29701178 TI - FOURIER to ODYSSEY: the end of the journey for lipid-lowering therapy trials? Lessons from recent clinical trials with anti-PCSK9 antibodies. PMID- 29701180 TI - The biomechanics of simple steatosis and steatohepatitis. AB - Magnetic resonance and ultrasound elastography techniques are now important tools for staging high-grade fibrosis in patients with chronic liver disease. However, uncertainty remains about the effects of simple accumulation of fat (steatosis) and inflammation (steatohepatitis) on the parameters that can be measured using different elastographic techniques. To address this, we examine the rheological models that are capable of capturing the dominant viscoelastic behaviors associated with fat and inflammation in the liver, and quantify the resulting changes in shear wave speed and viscoelastic parameters. Theoretical results are shown to match measurements in phantoms and animal studies reported in the literature. These results are useful for better design of elastographic studies of fatty liver disease and steatohepatitis, potentially leading to improved diagnosis of these conditions. PMID- 29701179 TI - Guidelines for certification of International Normalized Ratio (INR) for vitamin K antagonists monitoring according to the EN ISO 22870 standards. AB - Point of care testing (POCT) must comply with regulatory requirements according to standard EN ISO 22870, which identify biologists as responsible for POCT. INR for vitamin K antagonists (VKAs) monitoring is a test frequently performed in haemostasis laboratories. Bedside INR is useful in emergency room, in particular in case of VKAs overdosage but also for specific populations of patients like paediatrics or geriatrics. INR POCT devices are widely used at home by the patients for self-testing, but their use in the hospital by the clinical staff for bedside measurement is growing, with devices which now comply with standard for POCT accreditation for hospital use. The majority of point of care devices for INR monitoring has shown a good precision and accuracy with results similar to those obtained in laboratory. With the aim to help the multidisciplinary groups for POCT supervision, the medical departments and the biologists to be in accordance with the standard, we present the guidelines of the GFHT (Groupe francais d'etude sur l'hemostase et la thrombose, subcommittee "CEC et biologie delocalisee") for the certification of POCT INR. These guidelines are based on the SFBC guidelines for the certification of POCT and on the analysis of the literature to ascertain the justification of clinical need and assess the analytical performance of main analysers used in France, as well as on a survey conducted with biologists. PMID- 29701181 TI - Multi-frequency difference method for intracranial hemorrhage detection by magnetic induction tomography. AB - OBJECTIVE: Frequency-difference magnetic induction tomography (fdMIT) is a promising technique for the continuous monitoring of intracranial hemorrhage. The dual-frequency difference MIT (dfdMIT) will sometimes produce artefacts in the reconstructed images. To overcome this problem, a multi-frequency difference MIT (mfdMIT) method is proposed. APPROACH: To test the performance of this algorithm, 2D head models comprising six tissue types with different hemorrhage sizes were simulated, and images of the hemorrhage were reconstructed by mfdMIT and dfdMIT. Imaging errors and correlation coefficients were calculated with different levels of added phase noise and conductivity noise. MAIN RESULTS: A hemorrhage with a diameter of 20 mm can be reconstructed with 20 dB noise by the mfdMIT method, and the imaging error is reduced by about 60%. The results show that the conductivity of brain tissues changing with frequency will cause artefacts on the reconstructed images of the hemorrhage by dfdMIT, but the artefacts can be effectively suppressed with mfdMIT by separating the hemorrhage from other brain tissues. SIGNIFICANCE: The mfdMIT method increases the reconstructed image precision, which promotes the development of medical imaging by MIT. PMID- 29701182 TI - Wearable technology reveals gait compensations, unstable walking patterns and fatigue in people with multiple sclerosis. AB - OBJECTIVE: People with multiple sclerosis (PwMS) often experience a decline in gait performance, which can compromise their independence and increase falls. Ankle joint contractures in PwMS are common and often result in compensatory gait patterns to accommodate reduced ankle range of motion (ROM). APPROACH: Using advances in wearable technology, the aim of this study was to quantify head and pelvis movement patterns that occur in PwMS with disability and determine how these secondary gait compensations impact on gait stability. Twelve healthy participants and 12 PwMS participated in the study. Head and pelvis movements were measured using two tri-axial accelerometers. Measures of gait compensation, mobility, variability, asymmetry, stability and fatigue were assessed during a 6 min walking test. MAIN RESULTS: Compared to healthy controls, PwMS had greater vertical asymmetry in their head and pelvic movements (Cohen's d = 1.85 and 1.60). Lower harmonic ratios indicated that PwMS were more unstable than controls (Cohen's d = -1.61 to -3.06), even after adjusting for their slower walking speeds. In the PwMS, increased compensatory movements were correlated with reduced ankle active ROM (r = -0.71), higher disability (EDSS) scores (r = 0.58), unstable gait (r = -0.76), reduced mobility (r = -0.76) and increased variability (r = 0.83). SIGNIFICANCE: Wearable device technology provides an efficient and reliable way to screen for excessive compensatory movements often present in PwMS and provides clinically important information that impacts on mobility, stride time variability and gait stability. This information may help clinicians identify PwMS at high risk of falling and develop better rehabilitation interventions that, in addition to improving mobility, may help target the underlying causes of unstable gait. PMID- 29701183 TI - [In vitro study of joint intervention of E-cad and Bmi-1 mediated by transcription activator-like effector nuclease in nasopharyngeal carcinoma]. AB - OBJECTIVE: To explore the effect of intervention of E-cadherin (E-cad) and B lymphoma Moloney murine leukemia virus insertion region-1 (Bmi-1) mediated by transcription activator-like effector nuclease (TALEN) on the biological behaviors of nasopharyngeal carcinoma cells.? Methods: Multi-locus gene targeting vectors pUC-DS1-CMV-E-cad-2A-Neo-DS2 and pUC-DS1-Bmi-1 shRNA-Zeo-DS2 were constructed, and the E-cad and Bmi-1 targeting vectors were transferred with TALEN plasmids to CNE-2 cells individually or simultaneously. The integration of target genes were detected by PCR, the expressions of E-cad and Bmi-1 were detected by Western blot. The changes of cell proliferation were detected by cell counting kit-8 (CCK-8) assay. The cell cycle and apoptosis were detected by flow cytometry. The cell migration and invasion were detected by Transwell assay.? Results: The E-cad and Bmi-1 shRNA expression elements were successfully integrated into the genome of CNE-2 cells, the protein expression level of E-cad was up-regulated, and the protein expression level of Bmi-1 was down-regulated. The intervention of E-cad and Bmi-1 didn't affect the proliferation, cell cycle and apoptosis of CNE-2 cells, but it significantly inhibited the migration and invasion ability of CNE-2 cells. Furthermore, the intervention of E-cad and Bmi-1 together significantly inhibited the migration ability of nasopharyngeal carcinoma cells compared with the intervention of E-cad or Bmi-1 alone (all P<0.01).? Conclusion: The joint intervention of E-cad and Bmi-1 mediated by TALEN can effectively inhibit the migration and invasion of nasopharyngeal carcinoma cells in vitro, which may lay the preliminary experimental basis for gene therapy of human cancer. PMID- 29701184 TI - [Expression profiles of CaMKIIgamma during ?osteoclast differentiation]. AB - OBJECTIVE: To study the expression profiles and the role of Ca2+/calmodulin dependent protein kinase IIgamma (CaMKIIgamma) during osteoclast differentiation.? Methods: Mouse RAW264.7 cells were induced for osteoclastogenesis with 50 ng/mL receptor activator of nuclear factor-kappaB ligand (RANKL) and the cells were harvested at 0, 1, 3 and 5 days after induction. Tartrate-resistant acid phosphotase staining was performed to verify osteoclasts formation. RT-PCR, Western blot and immunofluorescent cytochemistry were used to detect the CaMKIIgamma gene expression during osteoclastogenesis.? Results: The osteoclasts were formed at day 3 under RANKL induction and more osteoclasts were observed at day 5. At day 0, 1, 3 and 5, the relative level of CaMKIIgamma mRNA were (1.067+/-0.179), (1.840+/-0.070), (9.493+/-0.453) and (30.767+/-0.573), respectively, and the relative protein level were (0.454+/ 0.065), (0.613+/-0.021), (0.858+/-0.019) and (0.980+/-0.023), respectively. CaMKIIgamma expression was increased in a time-dependent manner except relative protein level at day 1 (P<0.01), which showed no significant difference at day 0 (P>0.05). Immunofluorescence assay showed that CaMKIIgamma protein was also increased with differentiation of osteoclasts.? Conclusion: The CaMKIIgamma expression was increased in a time-depended manner during osteoclast differentiation and it might play a vital role during osteoclastogenesis. PMID- 29701185 TI - [Expression of vascular relevant factors in rabbits with deep II degree burn based on the Notch signaling pathway]. AB - OBJECTIVE: To investigate the relationship between the Notch signaling pathway and expression of vascular relevant factors in rabbit deep II degree burn model.? Methods: A total of 120 New Zealand white rabbits were randomly divided into a block group, a model group, and a control group. The block group was injected 2 mg/kg gamma-secretase inhibitor (GSI) once a day at 1 d before the model establishment, and 1-14 d after the deep II degree burns model establishment. The model group were injected physiological saline at the same time. The control group was only injected with the same amount of saline. The expressions of vascular endothelial growth factor (VEGF), vascular endothelial growth factor receptor 2 (VEGFR-2), matrix metalloprotein 2 (MMP-2) and matrix metalloprotein 9 (MMP-9) were detected by immunohistochemistry.? Results: The expressions of VEGF and VEGFR-2 in the model group and the block group were significantly increased within 21 days after modeling, while decreased after 21 days; the expressions of MMP-2 and MMP-9 were decreased within 21 days after modeling, while increased after 21 days, with significant differences compared with the control group (P<0.05). The expressions of VEGF and VEGFR-2 in the model group were higher than that in the block group, and the expressions of MMP-2 and MMP-9 were lower than those in the block group (P<0.05). The expression of VEGFR-2 was positively correlated with VEGF, while MMP-2 and MMP-9 were negatively correlated with VEGF within 21 days after modeling.? Conclusion: In the rabbit deep II degree burn model, the Notch signaling pathway was blocked to attenuate the expressions of VEGF and VEGFR-2, and to up-regulate the expressions of MMP-2 and MMP-9. PMID- 29701186 TI - [Expression of thioredoxin-2 in human lens epithelial cells with oxidative damage and its significance]. AB - OBJECTIVE: To explore whether thioredoin-2 (Trx-2) is involved in the development of cataract and to study the effect of Trx-2 on hydrogen peroxide (H2O2)-induced injury in human lens epithelial cells.? Methods: A total of 10 volunteers (removing the lens due totraumatism) and 30 patients received phacoemulsification (age more than 60 years) were selected. The expression of Trx-2 protein in lens epithelial cells from cataract patients and volunteers were detected by the immunohistochemical streptavidin-peroxidase (SP) method. SRA01/04 cells were cultured and were divided into six groups according to different treatment: a control group, H2O2-treated groups at 20, 50 or ?100 MUmol/L, a negative control group (transfected with pCMV6 plasmid plus 100 MUmol/L H2O2), and a Trx-2 overexpression group (transfected with pCMV6-Trx-2 plasmid plus 100 MUmol/L H2O2). Methyl thiazolyltetrazolium (MTT) assay and flow cytometry was performed to measure the cell viability and apoptosis for SRA01/04 cells, respectively. The activities of superoxide dismutase (SOD) and catalase (CAT), the content of glutathione (GSH) and malondialdehyde (MDA) in human lens epithelial cells were measured via chemical chromatometry. Western blot was used to measure the protein levels of Trx-2, B-cell lymphoma 2 protein (Bcl-2), Bcl-2 associated X protein (Bax) and caspase-3.? Results: Compared with the volunteers, the expression of Trx-2 was significantly decreased in lens epithelial cells in patients with cataract (P<0.05). Compared with the control group, the expression of Trx-2 protein in the 20, 50 or 100 MUmol/L H2O2 groups was decreased (all P<0.05). Compared with the control group, the cell survival rates were decreased in the 100 MUmol/L H2O2 group and the negative control group (both P<0.05), along with enhanced apoptotic rates, inhibited cellular SOD activities and CAT activities, reduced GSH contents, augmented MDA contents, down-regulated Trx-2 and Bcl-2 expression and up-regulated Bax and caspase-3 expression (all P<0.05). Compared with the negative control group, the cell survival rate was increased in the Trx 2 overexpression group (P<0.05), along with suppressed apoptosis, increased SOD activities and CAT activities, elevated GSH contents, decreased MDA content, up regulated Trx-2 and Bcl-2 expression and down-regulated Bax and caspase-3 expression (P<0.05).? Conclusion: Trx-2 might be involved in the apoptosis of lens epithelial cells in patients with cataract. The overexpression of Trx-2 obviously attenuated H2O2-induced injury of human lens epithelial cells, which might be associated with the inhibition of H2O2-mediated oxidative stress. PMID- 29701187 TI - [Effects of 7-difluoromethy-5, 4'-dimethoxygenistein on ?stress urinary incontinence model in rats and its mechanisms]. AB - OBJECTIVE: To investigate the effects of 7-difluoromethy-5, 4'-dimethoxygenistein (DFMG) on stress urinary incontinence (SUI) model in Sprague Dawley (SD) rats and its possible mechanisms.? Methods: SD rat model of SUI was established through simulating pregnancy, birth trauma and ovarian castration. The rats were divided into a normal control group, a SUI group, and a DFMG group at 10 or 20 mg/kg. They were treated with 10 mg/kg normal saline (NS), 10 mg/kg NS, 10 mg/kg DFMG and 20 mg/kg DFMG, respectively, via gastric gavage every other day. Maximal bladder capacity (MBC), leak point pressure (LPP), abdominal leak point pressure (ALPP), hematoxylin-eosin (HE) staining, and Masson staining were performed to detect the index for the model. MiR-26b and its down-stream gene phosphatase and tensin homolog deleted on chromosome 10 (PENT) mRNA in urethral sphincter muscles cells (USMCs) were analyzed by RT-PCR. The protein levels of PENT, phosphatidylinositol 3-kinase (PI3K), protein kinaseB (AKT), B-cell lymphoma 2 (Bcl-2), Bcl-2 associated X protein (Bax), cytochrome C(Cyt-c) and caspase-3 were examined by Western blot. The apoptotic rate of USMCs was determined by flow cytometry (FCM), and the proliferative rate of USMCs was examined by MTT assay.? Results: The SD rat model of SUI was successfully established. HE staining and Masson staining showed that the pathological features of urethral sphincter were improved in the DFMG-treated groups compared with the SUI group. The urine dynamics indexes of model rats, such as MBC, LPP and ALPP, were improved (all P<0.05). The results of RT-PCR showed that the miR-26b mRNA was up-regulated (P<0.05) and PENT mRNA was down-regulated (P<0.05) in the DFMG-treated groups compared with the SUI group. Simultaneously, compared with the SUI group, the protein levels of PENT, Bax, Cyt-c and caspase-3 were down-regulated (all P<0.05) and the protein levels of PI3K, AKT and Bcl-2 protein were up-regulated (all P<0.05), accompanied by the decreased apoptotic rate of USMCs (P<0.05) and the increased proliferative rate of USMCs (P<0.05) in the DFMG-treated groups.? Conclusion: The DFMG can significantly improve the symptoms of urinary dynamics, which might be related to the up-regulation of miR-26b expression and the regulation of PI3/AKT-Bcl-2/ Bax signaling pathways. PMID- 29701188 TI - [Clinical value of surfactant protein-A in ?exudate pleural effusion]. AB - OBJECTIVE: To evaluate the clinical value of surfactant protein-A (SP-A) in exudate pleural effusion (EPE).? Methods: This clinical study was prospective, observational and cross-sectional. Two hundred and fifteen patients with pleural effusion were divided into the transudate pleural effusions (TPE) group and the EPE group. TPE patients served as the control group. The concentrations of pleural effusions SP-A (SP-Apl) and serum SP-A (SP-Ase) were measured by ELISA, and receiver operator characteristic (ROC) curve and multivarate Cox analysis of SP-A was analysed for its clinical value.? Results: SP-Apl concentrations in the EPE group were significantly higher than that in the TPE group [(189.8+/-43.4) ng/mL vs (22.3+/-5.1) ng/mL, P<0.01]; SP-Ase concentrations in the EPE group were higher than that in the TPE group [(78.9+/-11.3) ng/mL vs (25.8+/-12.4) ng/mL, P<0.05]; SP-Apl concentrations were significantly higher than the concentrations of SP-Ase in the EPE group (P<0.01). In EPE group, SP-Apl and SP-Ase concentration in the patients with primary lung adenocarcinomas were the highest. The cut off value of SP-Apl concentrations was more than 484.5 ng/mL, yielding a 85.4% sensitivity and 95.2% specificity for diagnosing primary lung adenocarcinomas, with an area under the curve (AUC) of 0.943 (95% CI 0.852 to 0.934, P<0.01); when SP-Ase concentration was more than 84.2 ng/mL, it yielded a 76.4% sensitivity and 94.3% specificity for diagnosing primary lung adenocarcinomas, with an AUC of 0.910 (95% CI 0.921 to 0.953, P<0.01).? Conclusion: While SP-Apl concentration is more than 484.5 ng/mL and/or SP-Ase concentration is more than 84.2 ng/mL, it may be helpful for the diagnosis of primary lung adenocarcinomas with the usage of pleural effusion. PMID- 29701189 TI - Plasma concentrations of neurotransmitters and postpartum depression. AB - OBJECTIVE: To determine associations between postpartum depression (PPD) and plasma neurotransmitters.? Methods: We conducted a case-control study nested to a prospective cohort established in 3 comprehensive tertiary hospitals in Changsha, Hunan, China from February to September 2007. The Chinese version of the Edinburgh Postnatal Depression Scale (EPDS) was used at 2 weeks postpartum to screen PPD, with a score of 13 or higher as the cut-off for PPD. The women with matched age but without PPD and delivery within 5 years were selected as controls. The levels of plasma monoamine neurotransmitters including serotonin (5 hydroxytryptamine, 5-HT), dopamine (DA), and norepinephrine (NE), and peptide neurotransmitters including neuropeptide Y (NPY) and substance P (SP) in maternal blood samples taken at 2 weeks postpartum were measured and compared between PPD women (n=42) and controls (n=42).? Results: Plasma levels of 5-HT and NPY were significantly lower while plasma levels of NE and SP were significantly higher in PPD women than those in the controls. For women with PPD, a negative correlation between NPY and NE (r=-0.36, P<0.05) was observed.? Conclusion: There are changes in plasma levels of neurotransmitters in women with PPD, and there are potential interactions between different neurotransmitters. PMID- 29701190 TI - [Relationship between unexplained palpitation in ?children and head-up tilt test]. AB - OBJECTIVE: To explore the relationship between unexplained palpitation in children and head-up tilt test (HUTT).? Methods: A total of 142 children with the main symptom of unexplained palpitation were admitted to the Specialist Out Patient Clinic of Children's Cardiovascular Disease from Sept. 2008 to Feb. 2017 in the Second Xiangya Hospital, Central South University. Among them, 63 cases were male, 79 cases were female, with the mean age of (10.12+/-2.88) years old. The detailed history, physical examinations, conventional 12 electrocardiogram, chest X-ray, echocardiography, myocardial enzymes and thyroid function were all examined. The disorders of heart disease, systemic disease and drug effect were ruled out. The HUTT inspection was then given to them.? Results: Among the 142 palpitation cases, 79 cases were HUTT positive (55.6%) and 63 cases were HUTT negative (44.4%). The age in HUTT positive patients was older than that in HUTT negative patients (P<0.05), with no significant difference in gender (P>0.05). There were three types of hemodynamic changes in HUTT positive patients. Among them, 38 cases were postural orthostatic tachycardia syndrome (48.1%), 36 cases were the vasovagal syncope vasodepressive type (45.6%) and 5 cases were the vasovagal syncope mixed type (6.3%). There were no hemodynamic types for vasovagal syncope cardioinhibitory type, orthostatic hypotension and orthostatic hypertension.? Conclusion: Among the clinically unexplained palpitations children, more than half are caused by unbalanced autonomic nervous function. HUTT can help clear the cause of unexplained palpitations. PMID- 29701191 TI - [Influential factors of cerebral oxygen saturation in ?pediatric cardiovascular surgery]. AB - OBJECTIVE: To determine the intervention measures for the decrease of cerebral tissue oxygen saturation during anesthesia for the congenital heart disease in children.? Methods: Twenty-eight children with cardiac surgery were enrolled. Anesthesia was deepened with propofol (3 mg/kg) intravenous injection. The data of cerebral tissue oxygen saturation(SctO2), mean arterial pressure (MAP), HR, bispectral index (BIS), arterial partial pressure of oxygen (PaO2), arterial partial pressure of carbon dioxide (PaCO2), hemoglobin (Hb) and middle cerebral artery (MCA) mean flow velocity (Vm) at different points were collected after intravenous injection of propofol at 3 mg/kg. The changes of SctO2 and the influential factors were analyzed.? Results: SctO2 decreased by 4.99% after deepen anesthesia, with 95% CI 4.33% to 5.65% (P>0.05). There was no significant differince in MAP, PaO2, PaCO2, and Hb between the time points after deepen anesthesia and the baseline (P>0.05). MCA Vm decreased obviously after deepen anesthesia for 1, 5, 10 min (P<0.05). The decrease in MAP, HR, PaCO2 and MCA Vm is positively correlated with the decrease in SctO2.? Conclusion: The decrease of MAP, HR, PaCO2, and MCA Vm is the risk factor for SctO2. To avoid the decrease, it needs to maintain the stability of SctO2 and prevent neurological complications. PMID- 29701192 TI - [Therapeutic effect of mucopolysaccharide polysulfate cream in prevention of postoperative scars]. AB - OBJECTIVE: To assess the therapeutic effect of mucopolysaccharide polysulfate cream in prevention of postoperative scars.? Methods: One hundred postoperative patients were divided into an experimental group and a control group (each n=50). After stitch removal, the experimental group wiped mucopolysaccharide polysulfate cream, and the control group wiped urea cream. The scars of the two groups were evaluated by Vancouver Scar Scale (VSS) on the day of stitch removal and in the 4th, 8th, 12th, 16th, 20th, 24th, 28th, and 32th weeks during the treat process.? Results: At the beginning of treatment, the total VSS scores in the experimental group were always lower than that in the control group (P<0.05). There was no difference between the two groups in the color scores at each time point of follow-up (P>0.05). Form the 20th week, the vascular distribution scores in the experimental group were lower than that in the control group (P<0.05). And the thickness and flexibility scores in the experimental group were lower at each time point of follow-up (P<0.05). There were no differences between the two groups in wounds in head, face, or neck in the total VSS scores and all index scores (P>0.05), and the total VSS scores in the experimental group, who had wounds in chest, shoulder, or back, or had wounds in waist, abdomen, or hip, or had wounds in extremity, were lower than that in the control group (P<0.05). The vascular distribution and thickness scores in the experimental group, who had wounds in chest, shoulder, or back, were better than that in the control group (P<0.05). ? Conclusion: Wiping mucopolysaccharide polysulfate cream after operation as soon as possible can effectively prevent scar hyperplasia, and it is worth to be widely applied in clinic. PMID- 29701193 TI - [Esthetic evaluation of frontal smile on different crown heights of lateral incisor and canine]. AB - OBJECTIVE: To investigate the effect of different crown heights of lateral incisor and canine on smile esthetics perception between orthodontists and patients.? Methods: A total of 31 orthodontists and 56 patients on smile aesthetics perception were investigated. We adjusted the height of lateral incisor and canine to get 20 kinds of anterior tooth area morphology by Photoshop and asked interviewees to grade. Scores of satisfaction were recorded by Likert method.? Results: Subjects in the 2 groups preferred smiles with upper anterior teeth edge parallel to lower lip. There was better acceptance for longer canines and less satisfaction at shorter lateral incisors in patients. Patients also got higher discrete degree of evaluation results and more rigorous about smile esthetics than orthodontists.? Conclusion: Orthodontists and patients have different satisfaction at esthetics of anterior teeth. Esthetics preference should be considered in orthodontic treatment schedule. PMID- 29701194 TI - [Risk factors for delayed breastfeeding initiation based on decision tree model and logistic regression model]. AB - OBJECTIVE: To determine influential factors for delayed breastfeeding initiation.? Methods: Using questionnaires to collect the data of 950 pregnant women and infants' feeding practices in Changsha, Hunan, logistic regression and decision tree model were used to determine influential factors for delayed breastfeeding initiation.? Results: Mothers with timely breastfeeding initiation were 594 (62.5%), and those with delayed breastfeeding initiation accounted for 356 (37.5%). Mothers with timely breastfeeding initiation were more likely to use exclusive breastfeeding than those with delayed breastfeeding initiation (P<0.05). Four risk factors were found by logistic regression model and decision tree model, including cesarean delivery, using feeding-bottle before breastfeeding initiation, falling ill, and vomiting during pregnancy. Receiver operating characteristic curve showed no significant difference in the predictive effect of the 2 models (Z=0.142, P=0.889).? Conclusion: Cesarean delivery, using feeding-bottle before initiation of breastfeeding, and poor physical condition during pregnancy exert negatively effects on breastfeeding initiation. Health workers should help mother to timely initiate breastfeeding and enhance their confidence in exclusive breastfeeding. PMID- 29701195 TI - [YAP/TAZ regulates multiple signal pathways in the genesis and development of hepatic fibrosis]. AB - Hepatic fibrosis is a repair response to liver injury, and hepatic stellate cell activation is the center of hepatic fibrosis, which involves Hippo, Notch, Wnt/beta-catenin, and TGF-beta/Smad signaling pathways. YAP/TAZ is an important nucleus factor for Hippo tumor suppressor pathway and its activity is the key to the growth of whole organs, cell proliferation, and specific amplification of progenitor cells in the process of tissue renewal and regeneration. As the hub of signaling pathways, such as Hippo, Notch, Wnt/beta-catenin, TGF-beta/Smad signaling, YAP/TAZ regulates the genesis and development of liver fibrosis. PMID- 29701196 TI - [Research progress in renal injury relevant to primary Sjogren's syndrome]. AB - Primary Sjogren's syndrome (pSS) is a chronic autoimmune disease characterized by lymphoplasmacytic infiltration of the exocrine glands that results in multiple organs and systems damage. Renal injury affects 0.3%-27.0% patients. The most frequent form of nephropathy in pSS is tubulointerstitial nephritis. The main clinical manifestation is renal tubular acidosis. The renal prognosis in patients with pSS is usually favorable, but renal failure may occur. At present, it still lacks of strict consensus or guideline for the treatment. PMID- 29701197 TI - [Role of drug transporters in rational use of drugs ?at high altitude area]. AB - Pharmacokinetics plays a key role in rational use of medicines. Many factors can affect the drug's pharmacokinetics. Previous studies mainly focused on the impact of hypoxia on hepatic drug metabolizing enzyme, but uncommon on drug transporters. Actually, drug transporter is a key factor for activation of the drugs transport across the cell membrane into the inside of cells, such as multidrug resistance protein (MDR), breast cancer resistance protein (BCRP), multidrug resistance associated protein (MRP), organic cation transporter (OCT), organic anion-transporting polypeptide (OATP), organic anion transporter (OAT), qligopeptide transporter (PEPT), etc. They are widely present in the small intestine villus epithelial cells, renal tubular epithelial cells, hepatocytes and biliary epithelial cells. They play a very important role in drug absorption, distribution, metabolism and excretion. The changes in drug transporters under hypoxia in intestinal could affect the bioavailability of drugs; the changes in drug transporters in organs could affect drug's distribution, subsequent drug's indications and adverse reactions; the changes in drug transporters in liver and kidney could affect the metabolism and excretion rate of drugs, thereby the drug's residence time and half-life. PMID- 29701198 TI - [A case of severe obstructive sleep apnea hypopnea syndrome with urinary and anal incontinence]. AB - A case of a young male patient, who came to the Second Xiangya Hospital, Central South University because of snoring for 10 years and nocturnal gatism for half month, was analyzed retrospectively. He was diagnosed as obstructive sleep apnea hypopnea syndrome (OSAHS) finally. The patient had been diagnosed and treated as stroke in the local hospital, while urinary and anal incontinence were not relieved. It was a dilemma for him to be properly diagnosed and treated. Polysomnography in our hospital revealed apnea hypopnea index (AHI) at 44.7 events/h, oxygen desaturation index (ODI) at 70.8 events/h and the longest apnea time at 185 seconds while the lowest blood oxygen saturation reduced to 31%. In addition, 413 events of apnea accounted for 61.2% of the sleep time and the minimal heart rate was 23 times/min. The patient was diagnosed as severe OSAHS with hypoxia metabolic brain disease, moderate pulmonary arterial hypertension, secondary polycythemia and obesity hypoventilation syndrome finally. He received the treatment of positive airway pressure non-invasive ventilator with an average pressure at 11.7 cmH2O with reduced AHI and increased blood oxygen saturation. The urinary and anal incontinence disappeared during the first night of treatment and it has been totally resolved so far. We considered that gatism was secondary to OSAHS with severe hypoxia resulted from attenuated regulation of primary defecation in the night. Physicians should pay attention to OSAHS when accepting obese patients with nocturnal incontinence, obvious daytime sleepiness and night snoring. Urinary and anal incontinence could be completely disappeared under therapy of positive airway pressure. PMID- 29701199 TI - [Concurrent nodal and extranodal lymphoma misdiagnosed as metastatic gingival carcinoma: A case report]. AB - Early diagnosis of malignant lymphoma is often difficult since the clinical manifestation of the lymphoma occurred in the maxillofacial region is very similar to that of the squamous cell carcinoma. When the pathological diagnosis is not clear, the surgeon is easy to misdiagnose and lead to mistreatment. A patient visited the Affiliated Haikou Hospital of Xiangya School of Medicine, Central South Universily for gingival mass with an ipsilateral submaxillary enlargement. The clinical manifestation and preoperative MRI are very prone to squamous cell carcinoma with metastasis, so we did not take a preoperative pathological examination. The gingival mass was surgical removed firstly, but frozen pathological result showed that it was malignant small round cell tumor. Since the patient was diagnosed as high degree malignant of small round cell tumor and the submandibular region have been significantly metastasized, so we carried out the combined radical dissection of gingival, mandible and neck surgery. The postoperative pathological report was malignant lymphoma, suggesting that the patient was a case of misdiagnosis and mistreatment. This article draws lessons from misdiagnosis and provided experience for seeking improvement measures. PMID- 29701201 TI - Workers' Memorial Day - April 28, 2018. PMID- 29701200 TI - Quercetin Inhibits the Migration and Invasion of HCCLM3 Cells by Suppressing the Expression of p-Akt1, Matrix Metalloproteinase (MMP) MMP-2, and MMP-9. AB - BACKGROUND Quercetin is a natural bioactive flavonoid that is present in a wide variety of vegetables and fruits and exhibits a promising anti-metastasis property in various human cancer cells. However, the effect of quercetin on human HCCLM3 cells is unclear. MATERIAL AND METHODS In the current study, a wound healing assay was performed using quercetin-treated HCCLM3 cells to further explore whether quercetin affects the motility of human HCCLM3 cells. Transwell assay was used to explore the potential effect of quercetin in HCCLM3 cells on cell migration and cell invasion. Western blotting analysis was used to explore the expression of p-Akt1, MMP-2, and MMP-9 in quercetin-treated HCCLM3 cells. RESULTS The wound-healing time was delayed in quercetin-treated HCCLM3 cells, and the ability to migrate and invade was inhibited in quercetin-treated human HCCLM3 cells. Moreover, the protein levels of p-Akt1, MMP-2, and MMP-9 were down regulated in quercetin-treated HCCLM3 cells, as detected by Western blotting. CONCLUSIONS Our data show that quercetin attenuated cell migration and invasion by suppressing the protein levels of p-Akt1, MMP-2, and MMP-9 in HCCLM3 cells. PMID- 29701202 TI - Rapid and selective DNA-based detection of melamine using alpha-hemolysin nanopores. AB - We have developed a rapid and selective approach for the detection of melamine based on simple DNA probes and alpha-hemolysin nanopores. The limit of detection can be as low as 10 pM. PMID- 29701203 TI - A four-component coupling reaction of carbon dioxide, amines, cyclic ethers and 3 triflyloxybenzynes for the synthesis of functionalized carbamates. AB - A novel four-component coupling reaction of carbon dioxide, amines, cyclic ethers and 3-triflyloxybenzynes has been developed for the first time, providing an efficient method for the synthesis of a series of functionalized carbamate derivatives in moderate to high yields. The process proceeds under mild, transition metal-free and fluoride-free conditions, leading to the formation of two new C-O bonds, one new C-N bond and one C-H bond in a single step. PMID- 29701204 TI - Textured surfaces as a new platform for nanoparticle synthesis. AB - We present a new, surface-based microfluidic platform for the synthesis of nanoparticles. In this platform chemical reagents are carried in separate droplets, then mixed and later transported to a desired location on the surface using surface textured ratchet tracks. This brings the advantages of both synthesizing and transporting nanoparticles in situ without having cross contamination between samples and addressing each sample independently. This platform is also capable of carrying multiple synthesis reactions concurrently. PMID- 29701205 TI - Multi-color electrochromism containing green color based on electrochemically polymerized star-shaped phenyl bithiophene. AB - A star-shaped thiophene derivative, namely PHBT, consisting of one central core of phenyl and three arms of bithiophene, was newly synthesized and characterized, in order to further investigate the relationship between the star-shaped monomer structure (central core and peripheral arm) and the polymeric electrochromic properties. Then it was further successfully prepared into the corresponding cross-linked polymer pPHBT via electrochemical polymerization. After applying positive voltage, pPHBT exhibited excellent electrochromic properties with surprising multi-color changes between three colors, orange-yellow, green and blue, and a fast color switching speed. Furthermore, electronic structure, cyclic voltammetry and electrochromic results of pPHBT can contribute much to explain the electrochromic behavior of pTPABT with the triphenylamine core and the quadruple thiophene arm. The electrochromism of pTPABT might consist of two parts derived from the oxidative states of triphenylamine and quadruple thiophene groups, respectively. This offers a new insight into the electrochromism mechanics of conjugated polymers. PMID- 29701206 TI - Halimane diterpenoids: sources, structures, nomenclature and biological activities. AB - Covering: 1970 to 2017 Diterpenes with a halimane skeleton constitute a small group of natural products that can be biogenetically considered as being between labdane and clerodane diterpenoids. Some of these compounds show biological activities, such as antitumour, mosquito repellency, germination inhibition and antimicrobial, as well as being biomarkers for tuberculosis. To the best of our knowledge, there are no reviews on these compounds. In this review, halimane skeleton diterpenoids are classified according to their biogenetic origin, characterization and/or the enzymes involved in their biosynthesis. Herein, a review of their synthesis or synthetic approaches is communicated. PMID- 29701207 TI - New highlights on the health-improving effects of sulforaphane. AB - In this paper, we review recent evidence about the beneficial effects of sulforaphane (SFN), which is the most studied member of isothiocyanates, on both in vivo and in vitro models of different diseases, mainly diabetes and cancer. The role of SFN on oxidative stress, inflammation, and metabolism is discussed, with emphasis on those nuclear factor E2-related factor 2 (Nrf2) pathway-mediated mechanisms. In the case of the anti-inflammatory effects of SFN, the point of convergence seems to be the downregulation of the nuclear factor kappa-light chain-enhancer of activated B cells (NF-kappaB), with the consequent amelioration of other pathogenic processes such as hypertrophy and fibrosis. We emphasized that SFN shows opposite effects in normal and cancer cells at many levels; for instance, while in normal cells it has protective actions, in cancer cells it blocks the induction of factors related to the malignity of tumors, diminishes their development, and induces cell death. SFN is able to promote apoptosis in cancer cells by many mechanisms, the production of reactive oxygen species being one of the most relevant ones. Given its properties, SFN could be considered as a phytochemical at the forefront of natural medicine. PMID- 29701208 TI - Modulation of electronic and magnetic properties of edge hydrogenated armchair phosphorene nanoribbons by transition metal adsorption. AB - Based on first-principles calculations, we present a systematic investigation of the electronic and magnetic properties of armchair phosphorene nanoribbons (APNRs) functionalized by 3d transition metal (TM) atoms. We found that the central hollow site is the most favorable adsorption site for Mn, Co and Ni, while Fe preferentially occupies the edge hollow site. All of the TM atoms bind to the adjacent P and their adsorption energies are in the range of -4.29 eV to 1.59 eV. Meanwhile, the large ratio of the adsorption energy to the cohesive energy of the metal bulk phase indicates that TM atoms have a preferred 2D growth mode on the edge hydrogenated armchair phosphorene nanoribbons (H-APNRs). The magnetic moments reduce by about 2-4 MUB, relative to their free atom states, depending on whether the TM atom is in the high-spin or low-spin state. This reduction is mainly attributed to the electrons transferring from the high-level TM 4s shell to the low-lying 3d shell. Our results demonstrate that TM atom adsorption is a feasible approach to functionalizing the H-APNRs chemically, which results in peculiar electronic and magnetic properties for potential applications in nano-electronics and spintronics. PMID- 29701209 TI - Time-dependent changes in the growth of ultrathin ionic liquid films on Ag(111). AB - Various amounts of the ionic liquids (ILs) [C1C1Im][Tf2N] and [C8C1Im][Tf2N] were deposited in vacuo by physical vapour deposition (PVD) on single crystalline Ag(111) at room temperature and subsequently monitored by angle-resolved X-ray photoelectron spectroscopy (ARXPS) as a function of time. For very low coverages of up to one closed molecular layer, an initial wetting layer was rapidly formed for both ILs. Deposition of higher amounts of [C1C1Im][Tf2N] revealed an initial three-dimensional film morphology. On the time scale of hours, characteristic changes of the XPS signals were observed. These are interpreted as island spreading and a transformation towards a nearly two dimensional [C1C1Im][Tf2N] film as the final state. In contrast, a film morphology close to 2D was found from the very beginning for [C8C1Im][Tf2N] deposited on Ag(111) demonstrating the influence of the alkyl chain length on the growth kinetics. These studies also highlight the suitability of time-resolved ARXPS for the investigation of IL/solid interfaces, which play a crucial role in IL thin film applications such as in catalysis, sensor, lubrication, and coating technologies. PMID- 29701210 TI - High-temperature superconductivity at the lanthanum cuprate/lanthanum-strontium nickelate interface. AB - The utilization of interface effects in epitaxial systems at the nanoscale has emerged as a very powerful approach for engineering functional properties of oxides. Here we present a novel structure fabricated by a state-of-the-art oxide molecular beam epitaxy method and consisting of lanthanum cuprate and strontium (Sr)-doped lanthanum nickelate, in which interfacial high-temperature superconductivity (Tc up to 40 K) occurs at the contact between the two phases. In such a system, we are able to tune the superconducting properties simply by changing the structural parameters. By employing electron spectroscopy and microscopy combined with dedicated conductivity measurements, we show that decoupling occurs between the electronic charge carrier and the cation (Sr) concentration profiles at the interface and that a hole accumulation layer forms, which dictates the resulting superconducting properties. Such effects are rationalized in the light of a generalized space-charge theory for oxide systems that takes account of both ionic and electronic redistribution effects. PMID- 29701211 TI - Planar pentacoordinate carbon in CGa5+ derivatives. AB - We report a family of systems having a planar pentacoordinate carbon (ppC) based on the next heavier analogue of CAl5+, the ppC system par excellence. Although because of the larger size of Ga, the ppC isomer is not even a local minimum in CGa5+, a single isoelectronic substitution of Ga by smaller sized Be maximizes the bonding in the ppC form. Retaining the 18 valence electron rule, the global minimum structures of CGa4Be, CGa3Be2-, CGa2Be32-, and CGaBe43- clusters and their corresponding lithium salts have a ppC. PMID- 29701212 TI - The phonon confinement effect in two-dimensional nanocrystals of black phosphorus with anisotropic phonon dispersions. AB - The RWL model for the phonon confinement effect in nanocrystals (NCs) had been found to result in deviations and limitations for crystals exhibiting obvious anisotropic phonon dispersions and modified models have been proposed to overcome these deficiencies. Here, we examine this issue in black phosphorus (BP), a typical anisotropic two-dimensional crystal exhibiting pronounced anisotropy in phonon dispersions. A detailed study is performed on the Raman spectra of BP NCs prepared by the ion implantation technique. With decreasing NC size, the peak positions of the three characteristic Raman modes, Ag1, B2g and Ag2 modes, remain almost unchanged, while the Ag1 and Ag2 modes show significant asymmetrical broadening tails towards higher- and lower-frequency sides, respectively. It is found that the RWL model based on one-dimensional phonon dispersion along Gamma-Y and Gamma-X axes in the Brillouin zone (BZ) cannot interpret the unusual frequency invariance and inhomogeneous line shape broadening of these three modes. However, after considering the contribution of two-dimensional anisotropic phonon dispersions from the whole BZ, the frequency and asymmetrical broadening of the Ag1 and Ag2 modes can be well reproduced. This study demonstrates that the RWL model can be applicable for crystals with anisotropic phonon dispersions once the phonons in the whole two-dimensional or three-dimensional BZ are properly taken into account, and provides a physically sound route into understanding the phonon confinement effect for anisotropic systems. PMID- 29701213 TI - Influence of the nanofiber chemistry and orientation of biodegradable poly(butylene succinate)-based scaffolds on osteoblast differentiation for bone tissue regeneration. AB - Innovative nanofibrous scaffolds have attracted considerable attention in bone tissue engineering, due to their ability to mimic the hierarchical architecture of an extracellular matrix. Aiming at investigating how the polymer chemistry and fiber orientation of electrospun scaffolds (ES) based on poly(butylene succinate) (PBS) and poly(butylene succinate/diglycolate) (P(BS80BDG20)) affect human osteoblast differentiation, uniaxially aligned (a-) and randomly (r-) distributed nanofibers were produced. Although human osteoblastic SAOS-2 cells were shown to be viable and adherent onto all ES materials, a-P(BS80BDG20) exhibited the best performance both in terms of cellular phosphorylated focal adhesion kinase expression and in terms of alkaline phosphatase activity, calcified bone matrix deposition and quantitative gene expression of bone specific markers during differentiation. It has been hypothesized that the presence of ether linkages may lead to an increased density of hydrogen bond acceptors along the P(BS80BDG20) backbone, which, by interacting with cell membrane components, can in turn promote a better cell attachment on the copolymer mats with respect to the PBS homopolymer. Furthermore, although displaying the same chemical structure, r P(BS80BDG20) scaffolds showed a reduced cell attachment and osteogenic differentiation in comparison with a-P(BS80BDG20), evidencing the importance of nanofiber alignment. Thus, the coupled action of polymer chemical structure and nanofiber alignment played a significant role in promoting the biological interaction. PMID- 29701214 TI - Atomically flat and thermally stable graphene on Si(111) with preserved intrinsic electronic properties. AB - Silicon and graphene are two wonder materials, and their hybrid heterostructures are expected to be very interesting fundamentally and practically. In the present study, by adopting fast dry transfer and ultra-high vacuum annealing, atomically flat monolayer graphene is successfully prepared on the chemically active Si(111) substrate. More importantly, the graphene overlayer largely maintains its intrinsic electronic properties, as validated by the results of the energy dependent electronic transparency, Dirac point observation and quantum coherence characteristics, and further confirmed by first-principles calculations. The intrinsic properties of graphene are retained up to 1030 K. The system of atomically flat and thermally stable graphene on a chemically active silicon surface with preserved inherent characteristics renders the graphene/silicon hybrid a promising system in the design of high-performance devices and the exploitation of interfacial topological quantum effects. PMID- 29701215 TI - Correction: New carbon allotropes in sp + sp3 bonding networks consisting of C8 cubes. AB - Correction for 'New carbon allotropes in sp + sp3 bonding networks consisting of C8 cubes' by Jian-Tao Wang et al., Phys. Chem. Chem. Phys., 2018, 20, 7962-7967. PMID- 29701216 TI - Effects of graphene/BN encapsulation, surface functionalization and molecular adsorption on the electronic properties of layered InSe: a first-principles study. AB - By using first-principles calculations, we investigated the effects of graphene/boron nitride (BN) encapsulation, and surface functionalization by metallic elements (K, Al, Mg and typical transition metals) and molecules (tetracyanoquinodimethane (TCNQ) and tetracyanoethylene (TCNE)) on the electronic properties of layered indium selenide (InSe). It was found that an opposite trend of charge transfer is possible for graphene (donor) and BN (acceptor), which is dramatically different from phosphorene where both graphene and BN play the same role (donor). For an InSe/BN heterostructure, a change of the interlayer distance due to out-of-plane compression can effectively modulate the band gap. Strong acceptor abilities to InSe were found for the TCNE and TCNQ molecules. For K, Al and Mg-doped monolayer InSe, charge transfer from the K and Al atoms to the InSe surface was observed, causing an n-type conduction of InSe, while p-type conduction of InSe was observed in the case of Mg-doping. The atomically thin structure of InSe enables the possible observation and utilization of the dopant induced vertical electric field across the interface. A proper adoption of the n- or p-type dopants allows for the modulation of the work function, the Fermi level pinning, the band bending, and the photo-adsorbing efficiency near the InSe surface/interface. Investigation of the adsorption of transition metal atoms on InSe showed that Ti-, V-, Cr-, Mn-, and Co-adsorbed InSe are spin-polarized, while Ni-, Cu-, Pd-, Ag- and Au-adsorbed InSe are non-spin-polarized. Our results shed light on the possible ways to protect InSe structures and modulate their electronic properties for nanoelectronics and electrochemical device applications. PMID- 29701217 TI - A reaction-based ratiometric fluorescent sensor for the detection of Hg(ii) ions in both cells and bacteria. AB - A novel reaction-based fluorescent probe (ATC-Hg) was designed and synthesized via the "covalent assembly" principle, which exhibited excellent selectivity and high sensitivity for Hg2+ and CH3Hg+. Moreover, it is the first Hg(ii) sensitive fluorescent probe that has been successfully applied in imaging in both cells and Escherichia coli. PMID- 29701218 TI - Synthesis of C-functionalized TE1PA and comparison with its analogues. An example of bioconjugation on 9E7.4 mAb for multiple myeloma 64Cu-PET imaging. AB - In view of the excellent copper(ii) and 64-copper(ii) complexation of a TE1PA ligand, a monopicolinate cyclam, in both aqueous medium and in vivo, we looked for a way to make it bifunctional, while maintaining its chelating properties. Overcoming the already known drawback of grafting via its carboxyl group, which is essential to the overall properties of the ligand, a TE1PA bifunctional derivative bearing an additional isothiocyanate coupling function on a carbon atom of the macrocyclic ring was synthesized. This led to an architecture that is comparable to that of other commercially available bifunctional copper(ii) chelators such as p-SCN-Bn-DOTA already used in clinical trials for 64Cu-immuno PET imaging. The C-functionalization of TE1PA on one carbon atom in the beta-N position of the cyclam backbone was successfully achieved by adapting our patented methodology to the huge challenge, allowing the regiospecific mono-N functionalization of the unsymmetrical ligand. The obtained ligand p-SCN-Bn-TE1PA was coupled to a 9E7.4 murine antibody (mAb), an IgG2a anti CD-138 for multiple myeloma (MM) targeting. The conjugation efficiency was assessed by looking at the 64Cu radiolabeling and the radiopharmaceutical 64Cu-9E7.4-p-SCN-Bn-TE1PA immunoreactivity, and in particular by comparing with 9E7.4-p-SCN-Bn-NOTA and 9E7.4-p-SCN-Bn-DOTA obtained from commercial and presumably highly efficient chelators NOTA and DOTA, respectively. The results are quite clear, showing that p-SCN-Bn-TE1PA has a coupling rate 5 times higher and an immunoreactivity 1.5 to 2 times greater than those of its two competitors. p-SCN-Bn-TE1PA also outperforms TE1PA conjugated via its carboxylic function on the same antibody. The first 64Cu-immuno-PET preclinical study in a syngeneic model of MM was performed, confirming the good in vivo properties of 64Cu-9E7.4-p-SCN-Bn-TE1PA for PET imaging, considering the high clearance even after 24 h and the particularly important tumor-to-liver ratio that was increasing at 48 h. PMID- 29701219 TI - Asymmetric transfer hydrogenation reactions of N-sulfonylimines by using alcohols as hydrogen sources. AB - A palladium/zinc co-catalytic system was established and successfully utilized in the asymmetric transfer hydrogenation reactions of N-sulfonylimines with alcohols as hydrogen sources. Simple alcohols such as methanol, ethanol and benzyl alcohols are all variable hydrogen sources that can reduce various N sulfonylimines to the corresponding chiral amines with high optical purities in presence of this co-catalytic system. Primary mechanistic study revealed that the reaction may initiate with a Pd-hydride intermediate. PMID- 29701220 TI - Efficient synthesis of 3-sulfolenes from allylic alcohols and 1,3-dienes enabled by sodium metabisulfite as a sulfur dioxide equivalent. AB - We present herein an efficient and practical method for a gram scale synthesis of 3-sulfolenes using sodium metabisulfite as a safe, inexpensive, and easy to handle sulfur dioxide equivalent. Diversely-substituted 3-sulfolenes can be prepared by reacting a variety of 1,3-dienes or allylic alcohols with sodium metabisulfite in aqueous hexafluoroisopropanol (HFIP) or in aqueous methanol in the presence of potassium hydrogen sulfate. Advantageously, the method enables conversion of allylic alcohols directly to 3-sulfolenes, bypassing intermediate 1,3-dienes. PMID- 29701221 TI - Cysteine-activated hydrogen sulfide (H2S) delivery through caged carbonyl sulfide (COS) donor motifs. AB - Hydrogen sulfide (H2S) is an important biomolecule, and controllable H2S donors are needed to investigate H2S biological functions. Here we utilize cysteine mediated addition/cyclization chemistry to unmask an acrylate-functionalized thiocarbamate and release carbonyl sulfide (COS), which is quickly converted to H2S by carbonic anhydrase (CA). PMID- 29701223 TI - Advances in heterocycle synthesis via [3+m]-cycloaddition reactions involving an azaoxyallyl cation as the key intermediate. AB - Heterocyclic compounds are widely found in many natural isolates and medicinally relevant compounds, as well as some fine chemicals. The development of general and efficient methods for the construction of heterocyclic compounds is one of the most important tasks in synthetic organic chemistry. Along these lines, [3+m] cycloaddition reactions involving in situ generated azaoxyallyl cations as the 3 atom units have emerged as a powerful method for the synthesis of nitrogen containing heterocycles. In this feature article, we highlight recent advances in this rapidly growing area, mainly focusing on the reaction design as well as the reaction mechanism. PMID- 29701222 TI - Progressive cationic functionalization of chlorin derivatives for antimicrobial photodynamic inactivation and related vancomycin conjugates. AB - It is known that multiple cationic charges are required to produce broad-spectrum antimicrobial photosensitizers (PS) for photodynamic inactivation (aPDI) or photodynamic therapy of bacteria and fungi. In the present study we describe the synthesis and aPDI testing of a set of derivatives prepared from the parent pheophytin molecule with different numbers of attached side arms (1-3) each consisting of five quaternized cationic groups (pentacationic), producing the corresponding [Zn2+]pheophorbide-a-N(C2N+C1C3)5 (Zn-Phe-N5+, 5 charges), [Zn2+]chlorin e6-[N(C2N+C1C3)5]2 (Zn-Chl-N10+, 10 charges) and [Zn2+]mesochlorin e6-[N(C2N+C1C3)5]3 (Zn-mChl-N15+, 15 charges). Moreover, a conjugate between Zn Phe-N5+ and the antibiotic vancomycin called Van-[Zn2+]-m-pheophorbide N(C2N+C1C3)5 (Van-Zn-mPhe-N5+) was also prepared. The aPDI activities of all compounds were based on Type-II photochemistry (1O2 generation). We tested these compounds against Gram-positive methicillin-resistant Staphylococcus aureus (MRSA), Gram-negative Escherichia coli, and the fungal yeast Candida albicans. All three compounds were highly active against MRSA, giving eradication (>=6 logs of killing) with <1.0 MUM and 10 J cm-2 of 415 nm light. The order of activity was Zn-Phe-N5+ > Zn-Chl-N10+ > Zn-mChl-N15+. In the case of E coli the activity was much lower (eradication was only possible with 50 MUM Zn-mChl-N15+ and 20 J cm-2). The order of activity was the reverse of that found with MRSA (Zn-mChl N15+ > Zn-Chl-N10+ > Zn-Phe-N5+). Activity against C. albicans was similar to E. coli with Zn-mChl-N15+ giving eradication. The activity of Van-Zn-mPhe-N5+ was generally lower than that of Zn-Phe-N5+ (except for E. coli). Red (660 nm) light was also effective as might be expected from the absorption spectra. An initial finding that Van-Zn-mPhe-N5+ might have higher activity against vancomycin resistant Enterococcus fecium (VRE) strains (compared to vancomycin sensitive strains) was disproved when it was found that VRE strains were also more sensitive to aPDI with Zn-Phe-N5+. The minimum inhibitory concentrations of Van Zn-mPhe-N5+ were higher than those of Van alone, showing that the antibiotic properties of the Van moiety were lessened in the conjugate. In conclusion, Zn Phe-N5+ is a highly active PS against Gram-positive species and deserves further testing. Increasing the number of cationic charges increased aPDI efficacy on C. albicans and Gram-negative E. coli. PMID- 29701224 TI - Layer-dependent transport and optoelectronic property in two-dimensional perovskite: (PEA)2PbI4. AB - Recently, two-dimensional (2D) layered organic-inorganic hybrid perovskites have attracted a huge amount of interest due to their unique layered structure, and potential optical properties. However, amongst researchers it has long been disputed as to whether it is suitable for use as a photovoltaic material or light emitting device. Here, we present a detailed theoretical investigation to discuss the photovoltaic and optoelectronic properties of a novel synthetic 2D layered perovskite (PEA)2PbI4. Based on the calculated geometric and electronic structure, charge carrier mobilities of the 2D layered (PEA)2PbI4 are predicted theoretically. In addition, the linear dichroism and exciton binding energies are also calculated. We found that the carrier mobilities of the 2D layered (PEA)2PbI4 reach the same order of magnitude as those of the optoelectronic material MoS2, but smaller than those of the photovoltaic material MAPbI3 and Si crystal, whereas exciton binding energies (Eb) enlarge with the thinning layers, being obviously higher than MAPbI3 and Si crystal. Moreover, the system exhibits a strong linear dichroism, suggesting weak absorption along the c axis in the visible spectrum, which is detrimental to photovoltaics. Our work provides a theoretical basis to prove that ultrathin two-dimensional (2D) materials may be potential candidates for optoelectronic detection devices, rather than solar absorbers. PMID- 29701228 TI - Cultivating crystal lattice distortion in IrO2via coupling with MnO2 to boost the oxygen evolution reaction with high intrinsic activity. AB - Here, we report an effective strategy to lower Ir consumption and boost the OER performance in acid by loading IrO2 onto MnO2, in which the IrO2 crystals are well dispersed and undergo a so-called z-extension Jahn-Teller distortion in the octahedral structure. Compared with IrO2, the mass activity and intrinsic activity for IrO2/MnO2 were largely increased. PMID- 29701229 TI - Stable ruthenium olefin metathesis catalysts bearing symmetrical NHC ligands with primary and secondary N-alkyl groups. AB - Four novel stable Hoveyda-Grubbs-type catalysts containing N,N'-dineopentyl- and N,N'-dicyclohexyl-substituted N-heterocyclic carbene (NHC) ligands with syn and anti phenyl groups on the ring backbone were synthesized and fully characterized. The catalytic potential of these complexes was investigated in metathesis reactions of both standard and renewable substrates. Compared to the Hoveyda Grubbs second generation catalyst (HGII), all of the new catalysts showed high performances in most of the examined metathesis transformations. In particular, N,N'-dicyclohexyl catalysts gave improved results in the challenging ring-closing metathesis (RCM) reaction to form tetrasubstituted olefins, while catalysts with neopentyl N-groups were found to be more active and Z-selective in cross metathesis (CM) reactions. Modest enantioselectivities in the asymmetric ring closing metathesis (ARCM) of achiral trienes with different steric hindrance were observed in the presence of catalysts bearing chiral C2-symmetric NHC ligands. PMID- 29701230 TI - Multi-affinity sites of magnetic guanidyl-functionalized metal-organic framework nanospheres for efficient enrichment of global phosphopeptides. AB - Magnetic guanidyl-functionalized metal-organic framework (MOF) nanospheres with multi-affinity sites composed of an inherent Zn-O cluster based on MOAC and specific recognized groups (amino group and guanidyl group) were for the first time synthesized by a combination strategy of epitaxial growth and post-synthetic modification of magnetic amino-derived MOFs, and they exhibit great potential for efficient enrichment of global phosphopeptides. PMID- 29701231 TI - Total synthesis of complex alkaloids by nucleophilic addition to amides. AB - Nucleophilic addition to amides has been recognized as a promising transformation for total synthesis of complex alkaloids. Amides can accept two different organometallic reagents through the nucleophilic addition, which enables it to serve as a stable surrogate of multi-substituted amines. However, the nucleophilic addition has been overlooked for a long time due to three main reasons: low electrophilicity of amide carbonyls, potential hydrolysis of the reaction intermediate and excess addition of an organometallic reagent. This mini review focuses on the recent progress of total synthesis of complex alkaloids based on the nucleophilic additions to N-alkoxyamides, tertiary amides and secondary amides. PMID- 29701232 TI - Influence of dielectric inhomogeneities on the structure of charged nanoparticles in neutral polymer solutions. AB - We study the structural characteristics of a system of charged nanoparticles in a neutral polymer solution while accounting for the differences in the dielectric constant between the particles, polymer and the solvent. We use a hybrid computational methodology involving a combination of single chain in mean-field simulations and the solution of the Poisson's equation for the electrostatic field. We quantify the resulting particle structural features in terms of radial distribution function among particles as a function of the dielectric contrast, particle charge, particle volume fraction and polymer concentration. In the absence of polymers, charged macroions experience increased repulsion with a lowering of the ratio of particle to solvent dielectric constant. The influence of the dielectric contrast between the particle and the solvent however diminishes with an increase in the particle volume fraction and/or its charge. In the presence of neutral polymers, similar effects manifest, but with the additional physics arising from the fact that the polymer-induced interactions are influenced by the dielectric contrast of the particle and solvent. PMID- 29701233 TI - Ichthyosis Prematurity Syndrome due to a Novel SLC27A4 Homozygous Mutation in an Italian Patient. PMID- 29701235 TI - Slowly Progressing Asymptomatic Disseminated Telangiectasias: A Quiz. PMID- 29701234 TI - Skin Manifestations in Patients with Adult-onset Immunodeficiency due to Anti interferon-gamma Autoantibody: A Relationship with Systemic Infections. AB - Adult-onset immunodeficiency due to anti-interferon-gamma autoantibody is an emerging acquired immunodeficiency with frequent skin manifestations. A retrospective chart review was conducted and identified 41 patients with the syndrome. Skin involvement was detected in 33 (80%) patients, 15 (45%) with infective skin diseases and 27 (82%) with reactive skin disorders. Reactive lesions were mostly neutrophilic dermatoses, e.g. Sweet syndrome. Of note, the presence of neutrophilic dermatoses was highly associated with infections of other sites. An adjusted odds ratio for the existence of infections in patients with neutrophilic dermatoses was 14.79 (95% CI: 5.13, 42.70; p < 0.001). Moreover, neutrophilic dermatoses were significantly correlated with opportunistic infections observed in those with defects in cell-mediated immunity including non-tuberculous mycobacterium and disseminated fungal infection. The odds ratio for opportunistic infections in the presence of neutrophilic dermatoses was 12.35 (95% CI: 5.00, 30.55; p <0.001). Thus, the presence of neutrophilic dermatoses in patients with the syndrome can signal opportunistic infections that warrant physician attention. PMID- 29701236 TI - Failure of a Print Media Sun Safety Campaign to Reach High-risk Occupational Groups. PMID- 29701237 TI - Coccygeal Nodule in an Infant: A Quiz. PMID- 29701238 TI - Painful Erythematous-violaceous Toe: A Quiz. PMID- 29701239 TI - Psoriasis-like Dermatitis in Adulthood: A Skin Manifestation of Holocarboxylase Synthetase Deficiency. PMID- 29701240 TI - A 10-year longitudinal follow-up study of a U.K. paediatric transplant population to assess for skin cancer. AB - BACKGROUND: Our earlier study, published in 2004,found no skin cancer in a cohort of paediatric organ transplant recipients (POTRs) 5-16 years post transplantation. We re-evaluated the same cohort 10 years later. OBJECTIVES: To determine the prevalence of premalignant and malignant skin lesions and identify known risk factors associated with melanocytic naevi in a U.K. paediatric transplant population. METHODS: Ninety-eight POTRs from the original 2004 study were invited to participate in this longitudinal follow-up study. History of sun exposure, demographics and transplantation details were collected using face-to face interviews, questionnaires and case note reviews. Skin examination was performed for regional count of malignant lesions, benign and atypical naevi. RESULTS: Of the 98 patients involved in the initial study, 45 POTRs (eight kidney, 37 liver), with a median follow-up of 19 years (range 15-26 years), agreed to participate. Neither skin cancer nor premalignant lesions were detected in these patients. When compared with the 2004 cohort, 41 patients in our current cohort had increased numbers of benign naevi (P < 0.001) with 11 patients having >= 50 benign naevi. Seventy-one per cent of benign naevi in our 2014 cohort occurred on sun-exposed sites (13% head/neck, 35% arms and 23% legs). Patients who regularly used sunscreen had more benign naevi on their arms (P = 0.008). CONCLUSIONS: Although skin cancer was not observed in our cohort, we identified a significant increase in the number of benign naevi, particularly in those reporting frequent sunburn and sunscreen use. PMID- 29701241 TI - 'Essentially it's just a lot of bedrooms': architectural design, prescribed personalisation and the construction of care homes for later life. AB - This article draws on ethnographic data from a UK Economic and Social Research Council (ESRC) funded study called 'Buildings in the Making'. The project aims to open up the black box of architectural work to explore what happens between the commissioning of architectural projects through to the construction of buildings, and seeks to understand how ideas about care for later life are operationalised into designs. Drawing on recent scholarship on 'materialities of care' and 'practising architectures', which emphasise the salience of material objects for understanding the politics and practices of care, we focus here on 'beds'. References to 'beds' were ubiquitous throughout our data, and we analyse their varied uses and imaginaries as a 'way in' to understanding the embedded nature of architectural work. Four themes emerged: 'commissioning architectures and the commodification of beds'; 'adjusting architectures and socio-spatial inequalities of beds'; 'prescribing architectures and person-centred care beds'; and 'phenomenological architectures and inhabiting beds'. We offer the concept prescribed personalisation to capture how practising architectures come to reconcile the multiple tensions of commodification and the codification of person centred care, in ways that might mitigate phenomenological and serendipitous qualities of life and living in care settings during later life. PMID- 29701242 TI - Kinematic motion abnormalities and bimanual performance in children with unilateral cerebral palsy. AB - AIM: To evaluate the relationship between the movement abnormalities of the impaired upper limb in children with unilateral cerebral palsy (CP) and bimanual performance. METHOD: Twenty-three children with unilateral CP (mean age 11y 10mo [SD 2y 8mo]) underwent evaluation of bimanual performance (Assisting Hand Assessment [AHA]) and a three-dimensional movement analysis to measure deviations in the movement of their affected upper limb, and compared with 23 typically developing children (TDC) (mean age 11y 11mo [SD 2y 5mo]). Kinematic indices, such as the Global Arm Profile Score (APS), which summarizes the global movement deviation of the upper limb from the norm, and the Global Arm Variable Score (AVS), which represent movement deviations for a given joint, were calculated and correlated to AHA. RESULTS: Values of kinematic indices were significantly higher in children with unilateral CP than in TDC. A strong correlation between Global APS and AHA score (r=-0.75) was found. Other significant correlations were found with Global-AVS, especially in distal joints. INTERPRETATION: Children with unilateral CP had more movement deviations than TDC. The global movement deviation of the impaired upper limb was strongly correlated with bimanual performance. The influence of distal abnormalities confirms the importance of considering these limitations in therapeutics. WHAT THIS PAPER ADDS: Children with unilateral cerebral palsy had more movement deviations than typically developing children in unimanual tasks. A strong relationship was found between movement deviations of the impaired upper limb and bimanual performance. PMID- 29701243 TI - CERRADO SMALL MAMMALS: abundance and distribution of marsupials, lagomorphs, and rodents in a Neotropical savanna. AB - Patterns in distribution and local abundance of species within a biome are central concerns in ecology and allow the understanding of the effects of habitat loss on rates of species extinction; provide support for the creation and management of reserves; and contribute to the identification and quantification of the processes that allow niche partitioning by species. However, despite the importance in the conservation and management of the ecosystems, most systematized information on the abundance and distribution of small mammals is restricted to the northern hemisphere or forest ecosystems. For tropical biomes, an important part of this information remains dispersed and difficult to access in the form of theses, technical reports, or unpublished data sets. Here we present a comprehensive data set of abundance and richness of small mammals in the Cerrado, the largest Neotropical savanna. This data set includes 2,599 records of 446 sites from 96 studies. More than 50% of references in this data set are peer-reviewed journal articles, but 45.78% of communities were compiled from theses. The data set comprises 24,283 individuals of 55 genera and at least 118 species of small mammals including 29 marsupials, two lagomorphs (one exotic), and 87 rodents (three exotic). Local species richness ranged from 1 to 26 species (5.82 +/- 3.55, average species richness +/- SD). We observed hyperdominance of a few species; the 10 most abundant species in this data set represented 60.19% of all recorded individuals. The hairy-tailed bolo mouse (Necromys lasiurus) represented over than 20% of all individuals and occurred at more than 50% of sites. Furthermore, we identified 18 environments, 16 native vegetation types, and 2 anthropic environments. Typical savanna and gallery forest were the most frequently sampled vegetation types (comprising 46.94% of all sampled sites) and the most speciose ones (57 species for typical savanna and 53 species for gallery forest). The information contained in this data set can be used to analyze ecological questions such as the relationship between local abundance and regional distribution, the relevance of local and regional factors to community structuring, and the role of phylogenetic mechanisms in community assemblage. It can also be useful in conservation efforts in this biodiversity hotspot. No copyright, proprietary, or cost restrictions apply. Please cite this paper when the data are used in publications. We also request that researchers and teachers inform us of how they are using the data. PMID- 29701244 TI - Calcification Moderates the Increased Susceptibility to UV Radiation of the Coccolithophorid Gephryocapsa oceanica Grown under Elevated CO2 Concentration: Evidence Based on Calcified and Non-calcified Cells. AB - The physiological performance of calcified and non-calcified cells of Gephyrocapsa oceanica (NIES-1318) and their short-term responses to UV radiation were compared for cultures grown under present-day (LC, 400 MUatm) and high pCO2 (HC, 1000 MUatm) conditions. Similar growth rates and Fv /Fm values were observed in both types of cell under LC conditions, indicating that the loss of calcification in the non-calcified cells did not lead to a competitive disadvantage under such conditions. Detrimental effects of elevated pCO2 were observed in both cell types, with the growth rate of non-calcified cells decreasing more markedly, which might reflect a negative impact of higher cytoplasmic H+ . When exposed to short-term UV radiation, similar trends in effective quantum yield were observed in both cell types acclimated to LC conditions. Elevated pCO2 and associated seawater chemical changes strongly reduced effective quantum yield in non-calcified cells but no significant influence was observed in calcified cells. Based on these findings and comparisons with previous studies, we suggest that the negative impact of elevated cytoplasmic H+ would exacerbate the detrimental effects of UV radiation while the possession of calcification attenuated this influence. PMID- 29701245 TI - A morphological database for 606 Colombian bird species. AB - Colombia is the country with the highest bird diversity in the world. Despite active research in ornithology, compelling morphological information of most bird species is still sparse. However, morphological information is the baseline to understand how species respond to environmental variation and how ecosystems respond to species loss. As part of a national initiative, the Instituto Alexander von Humboldt in collaboration with 12 Colombian institutions and seven biological collections, measured up to 15 morphological traits of 9,892 individuals corresponding to 606 species: 3,492 from individuals captured in field and 6,400 from museum specimens. Species measured are mainly distributed in high Andean forest, paramo, and wetland ecosystems. Seven ornithological collections in Colombia and 18 paramo complexes throughout Colombia were visited from 2013 to 2015. The morphological traits involved measurements from bill (total and exposed culmen, bill width and depth), wing (length, area, wingspan, and the distance between longest primary and longest secondary), tail (length and shape), tarsus (length), hallux (length and claw hallux), and mass. The number of measured specimens per species was variable, ranging from 1 to 321 individuals with a median of four individuals per species. Overall, this database gathered morphological information for >30% of Colombian bird diversity. No copyright, proprietary, or cost restrictions apply; the data should be cited appropriately when used. PMID- 29701247 TI - Does perinatal exposure to exogenous oxytocin influence child behavioural problems and autistic-like behaviours to 20 years of age? AB - BACKGROUND: The neuropeptide and hormone oxytocin is known to have a significant impact on social cognition and behaviour in humans. There is growing concern regarding the influence of exogenous oxytocin (OT) administration in early life on later social and emotional development, including autism spectrum disorder (ASD). No study has examined offspring development in relation to the dose of exogenous oxytocin administered during labour. METHODS: Between 1989 and 1992, 2,900 mothers were recruited prior to the 18th week of pregnancy, delivering 2,868 live offspring. The Child Behaviour Checklist was used to measure offspring behavioural difficulties at ages 5, 8, 10, 14 and 17 years. Autism spectrum disorder was formally diagnosed by consensus of a team of specialists. At 20 years, offspring completed a measure of autistic-like traits, the Autism Spectrum Quotient (AQ). Oxytocin exposure prior to birth was analysed using categorical and continuous approaches (maternal oxytocin dose) with univariate and multivariate statistical techniques. RESULTS: Categorical analyses of oxytocin exposure prior to birth demonstrated no group differences in any measures of child behaviour. A small in magnitude dose-response association was observed for clinically significant total behaviour symptoms (adjusted odds ratio 1.03; 95% CI: 1.01-1.06, p < .01). Exogenous oxytocin administration prior to birth was not associated with ASD (OR: 0.64; 95% CI: 0.15-2.12, p = .46) or high levels of autistic-like traits (p = .93), as assessed by the AQ. CONCLUSIONS: This study is the first to investigate longitudinal mental health outcomes associated with the use of oxytocin-based medications during labour. The results do not provide evidence to support the theory that exogenous OT has a clinically significant negative impact on the long-term mental health of children. PMID- 29701246 TI - Early programming and late-acting checkpoints governing the development of CD4 T cell memory. AB - CD4 T cells contribute to protection against pathogens through numerous mechanisms. Incorporating the goal of memory CD4 T-cell generation into vaccine strategies therefore offers a powerful approach to improve their efficacy, especially in situations where humoral responses alone cannot confer long-term immunity. These threats include viruses such as influenza that mutate coat proteins to avoid neutralizing antibodies, but that are targeted by T cells that recognize more conserved protein epitopes shared by different strains. A major barrier in the design of such vaccines is that the mechanisms controlling the efficiency with which memory cells form remain incompletely understood. Here, we discuss recent insights into fate decisions controlling memory generation. We focus on the importance of three general cues: interleukin-2, antigen and co stimulatory interactions. It is increasingly clear that these signals have a powerful influence on the capacity of CD4 T cells to form memory during two distinct phases of the immune response. First, through 'programming' that occurs during initial priming, and second, through 'checkpoints' that operate later during the effector stage. These findings indicate that novel vaccine strategies must seek to optimize cognate interactions, during which interleukin-2-, antigen- and co-stimulation-dependent signals are tightly linked, well beyond initial antigen encounter to induce robust memory CD4 T cells. PMID- 29701250 TI - Stifle stabilisation in dogs without meniscal exam: A counterpoint argument. PMID- 29701248 TI - Carotid body activity - are we eating our way into the ventilatory pathway? PMID- 29701251 TI - Determination of antibiotic resistance and high-performance liquid chromatography profiles for Mycobacterium species. AB - BACKGROUND: Incidence of mycobacterial infections has been increasing. However, diagnosis and treatment of mycobacterial infections can be difficult. The aim of this study was to investigate high-performance liquid chromatography (HPLC) analysis of the mycolic acids for rapid identification and dendrogram cluster analysis of mycobacterium species. METHODS: Clinical specimens received for mycobacterial culture and antimicrobial susceptibility test were processed by standard laboratory protocols. Positive cultures were analyzed with HPLC method. Mycolic acid analysis with HPLC was used for diagnosis of tuberculosis and other mycobacterial infections. These reports were compared with Sherlock Library mycobacterial species, and the similarity index was analyzed. This value was formed by a software in multidimensional space that was the calculation of the average distance between the nearest library profile and unknown profile. RESULTS: The ninety-two samples were identified as M. tuberculosis. (similarity index between 0.593 and 0.994). One of the other strains was identified as M. avium intracellulare (strain No. 82) (SI = 0.906); one of them was identified as M. interjectum (strain no. 89) (SI = 0.644). Total 94 samples were identified, and dendrogram was applied to these samples. Profile A (10.6%), profile B (59.6%), profile C (11.7%), profile D (3.2%), and other profiles as single different profiles were identified. Rates for each as 1% (89, 94, 1, 82, 26, 42, 32, 41, 100, 43, 47, 44, 40, 35). CONCLUSION: High-performance liquid chromatography is a useful, rapid, reliable, and practical method for diagnosis of mycobacterium species. PMID- 29701252 TI - Cannabis, from plant to pill. AB - The therapeutic application of cannabis is attracting substantial public and clinical interest. The cannabis plant has been described as a veritable 'treasure trove', producing more than 100 different cannabinoids, although the focus to date has been on the psychoactive molecule delta-9-tetraydrocannabinol (THC) and cannabidiol (CBD). Other numerous secondary metabolites of cannabis, the terpenes, some of which share the common intermediary geranyl diphosphate (GPP) with the cannabinoids, are hypothesized to contribute synergistically to their therapeutic benefits, an attribute that has been described as the 'entourage effect'. The effective delivery of such a complex multicomponent pharmaceutical relies upon the stable genetic background and standardized growth of the plant material, particularly if the raw botanical product in the form of the dried pistillate inflorescence (flos) is the source. Following supercritical CO2 extraction of the inflorescence (and possibly bracts), the secondary metabolites can be blended to provide a specific ratio of major cannabinoids (THC : CBD) or individual cannabinoids can be isolated, purified and supplied as the pharmaceutical. Intensive breeding strategies will provide novel cultivars of cannabis possessing elevated levels of specific cannabinoids or other secondary metabolites. PMID- 29701253 TI - Identification of a novel missense KRT86 mutation in a Chinese family with monilethrix. PMID- 29701254 TI - Photoreceptor cells as a source of fundus autofluorescence in recessive Stargardt disease. AB - Bisretinoid fluorophores form in photoreceptor outer segments from nonenzymatic reactions of vitamin A aldehyde. The short-wavelength autofluorescence (SW-AF) of fundus flecks in recessive Stargardt disease (STGD1) suggests a connection to these fluorophores. Through multimodal imaging, we sought to elucidate this link. Flecks observed in SW-AF images often colocalized with foci exhibiting reduced or absent near-infrared autofluorescence signal, the source of which is melanin in retinal pigment epithelial (RPE) cells. With serial imaging, changes in near infrared autofluorescence (NIR-AF) preceded the onset of fleck hyperautofluorescence in SW-AF images and fleck profiles in NIR-AF images tended to be larger. Flecks in SW-AF and NIR-AF images also corresponded to hyperreflective lesions traversing photoreceptor-attributable bands in horizontal SD-OCT scans. The hyperreflective lesions interrupted adjacent OCT reflectivity bands and were associated with thinning of the outer nuclear layer. These SD-OCT findings are attributable to photoreceptor cell degeneration. Progressive increases and decreases in the SW-AF intensity of flecks were evident in color coded quantitative fundus autofluorescence maps. In some cases, flecks appeared to spread radially from the fovea to approximately 8 degrees of eccentricity, beyond which a circumferential spread characterized the distribution. Since the NIR-AF signal is derived from melanin and loss of this autofluorescence is indicative of RPE atrophy, the SW-AF of flecks cannot be accounted for by bisretinoid lipofuscin in RPE. Instead, we suggest that the bisretinoid serving as the source of the SW-AF signal, resides in photoreceptors, the cell that is also the site of bisretinoid synthesis. PMID- 29701256 TI - Homonymous hemiretinal macular ganglion cell complex thinning following occipital lobe trauma. PMID- 29701255 TI - Collaborate across silos: Perceived barriers to integration of care for the elderly from the perspectives of service providers. AB - PURPOSE: To examine the barriers that hinder collaboration between health care and social care services and to report recommendations for effective collaboration to meet the growing support and care needs of our ageing population. METHODS: Data for this qualitative study were obtained from interviews with 7 key informants (n = 42) and 22 focus groups (n = 117) consisting of service providers who were from the health care or social care sectors and supporting elderly patients with multiple chronic diseases or long term care needs. Data collection was conducted from 2015 to 2016. The data were analysed using an inductive approach on the basis of thematic analysis. FINDINGS: Qualitative analysis reviewed a number of factors that play a significant role in setting up barriers at the operational level, including fragmentation and lack of sustainability of discharge programmes provided by non-governmental organisations, lack of capacity of homes for the elderly, limitation of time and resources, and variation of roles in supporting end-of-life care decisions between the medical and social sectors. Other barriers are those of communication to be found at the structural level and perceptual ones that exist between professionals. Of these, perceptual barriers affect attitudes and create mistrust and interprofessional stereotypes and a hierarchy between the health care and social care sectors. CONCLUSION: Health care and social care service providers recognise the need for collaborative work to enhance continuity of care and ageing in place; however, their efforts are hindered by the identified barriers that need to be dealt with in practical terms and by a change of policy. PMID- 29701257 TI - Repeated hyperhidrosis and chilblain-like swelling with ulceration of the fingers and toes in hereditary sensory and autonomic neuropathy type II. PMID- 29701259 TI - Peristomal pyoderma gangrenosum with high serum levels of interleukin-8. PMID- 29701258 TI - Evaluation of smartphone-based testing to generate exploratory outcome measures in a phase 1 Parkinson's disease clinical trial. AB - BACKGROUND: Ubiquitous digital technologies such as smartphone sensors promise to fundamentally change biomedical research and treatment monitoring in neurological diseases such as PD, creating a new domain of digital biomarkers. OBJECTIVES: The present study assessed the feasibility, reliability, and validity of smartphone based digital biomarkers of PD in a clinical trial setting. METHODS: During a 6 month, phase 1b clinical trial with 44 Parkinson participants, and an independent, 45-day study in 35 age-matched healthy controls, participants completed six daily motor active tests (sustained phonation, rest tremor, postural tremor, finger-tapping, balance, and gait), then carried the smartphone during the day (passive monitoring), enabling assessment of, for example, time spent walking and sit-to-stand transitions by gyroscopic and accelerometer data. RESULTS: Adherence was acceptable: Patients completed active testing on average 3.5 of 7 times/week. Sensor-based features showed moderate-to-excellent test retest reliability (average intraclass correlation coefficient = 0.84). All active and passive features significantly differentiated PD from controls with P < 0.005. All active test features except sustained phonation were significantly related to corresponding International Parkinson and Movement Disorder Society Sponsored UPRDS clinical severity ratings. On passive monitoring, time spent walking had a significant (P = 0.005) relationship with average postural instability and gait disturbance scores. Of note, for all smartphone active and passive features except postural tremor, the monitoring procedure detected abnormalities even in those Parkinson participants scored as having no signs in the corresponding International Parkinson and Movement Disorder Society-Sponsored UPRDS items at the site visit. CONCLUSIONS: These findings demonstrate the feasibility of smartphone-based digital biomarkers and indicate that smartphone sensor technologies provide reliable, valid, clinically meaningful, and highly sensitive phenotypic data in Parkinson's disease. (c) 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 29701260 TI - C-reactive protein: An independent predictor for dedifferentiated chondrosarcoma. AB - Dedifferentiated chondrosarcoma is a rare primary bone malignancy with a very poor prognosis. The aim of the study was to identify pretreatment serum markers as prognostic factors for the overall survival (OS) of patients with dedifferentiated chondrosarcoma. We retrospectively reviewed 33 patients with histologically confirmed dedifferentiated chondrosarcoma treated at our department from 1977 to 2015. Kaplan-Meier estimation, uni- and multivariable Cox proportional hazard model were performed to evaluate the association between serum markers such as the C-reactive protein and OS. In univariable analysis, CRP was strongly associated with OS (HR 1.35; 95%CI 1.13-1.61; p = 0.001). This association prevailed after adjustment for AJCC tumor stage (HR 1.31; 95%CI 1.02 1.57; p = 0.031) in multivariable analysis. In conclusion, our data gave evidence that baseline CRP is an independent predictor for OS in patients with dedifferentiated chondrosarcoma. CRP could be exploited for the clinical prediction of this disease in the future. (c) 2018 The Authors. Journal of Orthopaedic Research(r) Published by Wiley Periodicals, Inc. on behalf of Orthopaedic Research Society. J Orthop Res 36:2797-2801, 2018. PMID- 29701262 TI - Lifestyle of the biotroph Agrobacterium tumefaciens in the ecological niche constructed on its host plant. AB - Agrobacterium tumefaciens constructs an ecological niche in its host plant by transferring the T-DNA from its Ti plasmid into the host genome and by diverting the host metabolism. We combined transcriptomics and genetics for understanding the A. tumefaciens lifestyle when it colonizes Arabidopsis thaliana tumors. Transcriptomics highlighted: a transition from a motile to sessile behavior that mobilizes some master regulators (Hfq, CtrA, DivK and PleD); a remodeling of some cell surface components (O-antigen, succinoglucan, curdlan, att genes, putative fasciclin) and functions associated with plant defense (Ef-Tu and flagellin pathogen-associated molecular pattern-response and glycerol-3-phosphate and nitric oxide signaling); and an exploitation of a wide variety of host resources, including opines, amino acids, sugars, organic acids, phosphate, phosphorylated compounds, and iron. In addition, construction of transgenic A. thaliana lines expressing a lactonase enzyme showed that Ti plasmid transfer could escape host mediated quorum-quenching. Finally, construction of knock-out mutants in A. tumefaciens showed that expression of some At plasmid genes seemed more costly than the selective advantage they would have conferred in tumor colonization. We provide the first overview of A. tumefaciens lifestyle in a plant tumor and reveal novel signaling and trophic interplays for investigating host-pathogen interactions. PMID- 29701261 TI - A critical review of the environmental occurrence and potential effects in aquatic vertebrates of the potent androgen receptor agonist 17beta-trenbolone. AB - Trenbolone acetate is widely used in some parts of the world for its desirable anabolic effects on livestock. Several metabolites of the acetate, including 17beta-trenbolone, have been detected at low nanograms per liter concentrations in surface waters associated with animal feedlots. The 17beta-trenbolone isomer can affect androgen receptor signaling pathways in various vertebrate species at comparatively low concentrations/doses. The present article provides a comprehensive review and synthesis of the existing literature concerning exposure to and biological effects of 17beta-trenbolone, with an emphasis on potential risks to aquatic animals. In vitro studies indicate that, although 17beta trenbolone can activate several nuclear hormone receptors, its highest affinity is for the androgen receptor in all vertebrate taxa examined, including fish. Exposure of fish to nanograms per liter water concentrations of 17beta-trenbolone can cause changes in endocrine function in the short term, and adverse apical effects in longer exposures during development and reproduction. Impacts on endocrine function typically are indicative of inappropriate androgen receptor signaling, such as changes in sex steroid metabolism, impacts on gonadal stage, and masculinization of females. Exposure of fish to 17beta-trenbolone during sexual differentiation in early development can greatly skew sex ratios, whereas adult exposures can adversely impact fertility and fecundity. To fully assess ecosystem-level risks, additional research is warranted to address uncertainties as to the degree/breadth of environmental exposures and potential population level effects of 17beta-trenbolone in sensitive species. Environ Toxicol Chem 2018;37:2064-2078. Published 2018 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. PMID- 29701263 TI - Neurological adverse event profile of magnetic resonance imaging-guided focused ultrasound thalamotomy for essential tremor. AB - BACKGROUND: Magnetic resonance imaging-guided focused ultrasound thalamotomy is approved by the U.S. Food and Drug Administration for treatment of essential tremor. Although this incisionless technology creates an ablative lesion, it potentially avoids serious complications of open stereotactic surgery. OBJECTIVE: To determine the safety profile of magnetic resonance imaging-guided focused ultrasound unilateral thalamotomy for essential tremor, including frequency, and severity of adverse events, including serious adverse events. METHODS: Analysis of safety data for magnetic resonance imaging-guided focused ultrasound thalamotomy (186 patients, five studies). RESULTS: Procedure-related serious adverse events were very infrequent (1.6%), without intracerebral hemorrhages or infections. Adverse events were usually transient and were commonly rated as mild (79%) and rarely severe (1%). As previously reported, abnormalities in sensation and balance were the commonest thalamotomy-related adverse events. CONCLUSION: The overall safety profile of magnetic resonance imaging-guided focused ultrasound thalamotomy supports its role as a new option for patients with medically refractory essential tremor. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29701264 TI - Rat Small Intestinal Mucosal Epithelial Cells Absorb Dietary 1,3-Diacylglycerol Via Phosphatidic Acid Pathways. AB - Compared with triacylglycerol (TAG), dietary 1,3-diacylglycerol (1,3-DAG) is associated with reduced serum lipid and glucose levels. We investigated the metabolism of 1,3-DAG by assaying its intermediate metabolites during digestion and absorption in the rat small intestine. After gavage with TAG emulsion, TAG was digested mainly to 2-monoacylglycerol (2-MAG) and unesterified fatty acid (FFA) in the rat small intestinal lumen. 2-MAG was directly absorbed into the small intestinal epithelial cells and esterified to 1,2(2,3)-DAG, and further esterified to TAG. After gavage with 1,3-DAG emulsion, 1,3-DAG was digested mainly to 1(3)-MAG and FFA in the rat small intestinal lumen with subsequent significant increase of 1-MAG and 1,3-DAG concentrations in small intestinal mucosal epithelial cells, and the 2-MAG, 1,2(2,3)-DAG, and TAG concentrations in mucosal epithelial cells were not significantly different after 1,3-DAG than after TAG gavage, suggesting that the metabolic pathway of 1,3-DAG is different from that of TAG. In intestinal mucosal epithelial cells, we further assayed enzyme levels and gene expression of proteins in the phosphatidic acid (PtdOH) pathway. The glycerol kinase, phosphatidate phosphatase, and diacylglycerol acyltransferase-2 expression and the relative expression of mRNA of enzymes were significantly increased in the 1,3-DAG group compared with the TAG group, suggesting that TAG synthesis from dietary 1,3-DAG was mainly via PtdOH pathways, which may partially account for the effect of dietary DAG on postprandial serum TAG. PMID- 29701265 TI - Cyclopropaneoctanoic Acid 2-Hexyl Upregulates the Expression of Genes Responsible for Lipid Synthesis and Release in Human Hepatic HepG2 Cells. AB - Recently we have found cyclopropaneoctanoic acid 2-hexyl (CPOA2H) in humans and demonstrated its elevated levels in patients with metabolic diseases associated with hypertriglyceridemia. However, it is still unclear whether CPOA2H may influence lipid metabolism in lipogenic tissues. To verify this, HepG2 hepatocytes and 3T3-L1 adipocytes were cultured with various concentrations of CPOA2H, and then the expressions of genes associated with lipid metabolism were determined. Incubation with CPOA2H at concentrations found in patients with metabolic diseases enhanced the expression of hepatocyte genes associated with lipid synthesis and release, in particular, the fatty acid synthase gene (nearly 20-fold increase in the mRNA level). In contrast, incubation with CPOA2H caused the downregulation of most adipocyte genes associated with lipid synthesis, whereas the level of leptin mRNA was increased. These findings suggest that CPOA2H may contribute to hypertriglyceridemia in patients with metabolic diseases, upregulating the expression of hepatocyte genes responsible for lipid synthesis and release. PMID- 29701266 TI - Sex-specific Alterations in Serology and the Expression of Liver FATP4 Protein in Offspring Exposed to High-Fat Diet during Pregnancy and/or Lactation. AB - Changes in dietary composition will have a significant impact on the nutritional status of the mother and the offspring. To examine the relevant hormone level changes during lactation and the expression of fatty acid transporters in the placenta and liver under the condition of a high-fat (HF) diet, we established HF animal models and conducted a cross-fostering program to mimic the shift in diet. On gestation day (GD)18, the weight of placenta in the HF group was significantly higher than that in the control group (p < 0.05). HF-fed male pups had a significantly lower serum insulin level, but the same phenomenon was not found in females. On the contrary, serum triacylglycerol (TAG) level presented a tendency to decrease only in female offspring. Oil red O staining showed lipid accumulation in the HF diet offspring livers. The mRNA levels of FATP4 in the placenta in the HF diet group were significantly upregulated compared to the control diet group (p < 0.05). High-fat diet (HFD) consumption also altered the liver mRNA levels of FATP4, SREBP-1, and SCD-1 in the male offspring, while the changes in protein levels of FATP4 were not observed in either sex. In conclusion, maternal HF diet has a profound impact on offspring growth, metabolism, and the risk of metabolic disorders, which would depend on the exposure period of pregnancy and lactation. PMID- 29701267 TI - Costunolide promotes imatinib-induced apoptosis in chronic myeloid leukemia cells via the Bcr/Abl-Stat5 pathway. AB - Costunolide, a sesquiterpene lactone, is a small molecular monomer extracted from Inula helenium (Compositae). In the present study, we assessed the antileukemia effects of costunolide on the human chronic myeloid leukemia cell line K562 and its combined activity with imatinib. A Cell Counting Kit-8 assay demonstrated that costunolide significantly inhibited K562 cell proliferation and enhanced imatinib-induced anti-proliferative activity. We found that costunolide significantly induced mitochondrial apoptosis in K562 cells by modulating the protein levels of Bcl-2 family members and by inducing caspase activation. Costunolide promoted imatinib-induced apoptosis via the Bcr/Abl-signal transducer and activator of transcription 5 pathway. Costunolide inhibited proliferation by inducing cell cycle arrest in the G2 /M phase by decreasing cyclin B1 and cyclin dependent kinase 2 expression and increasing p21 expression. Together, these results demonstrate that costunolide may be a potent therapeutic agent against chronic myeloid leukemia. PMID- 29701268 TI - Direct Synthesis of Polycyclic Tropinones by a Condensation-[4+3]-Cycloaddition Cascade Reaction. AB - A concise method of constructing polycyclic tropinone frameworks was developed. The single-step synthesis of polycyclic tropinone consists of an intramolecular [4+3] cycloaddition reaction of N-nosyl-pyrrole with oxyallyl cation that was generated in situ by an intermolecular condensation reaction of the nucleophilic functional groups on a tethered pyrrole with the aldehyde of 2-(silyloxy) acrolein. This cascade reaction afforded various polycyclic tropinones including tri-, tetra-, and pentacyclic systems in high yields as single diastereomers. PMID- 29701269 TI - Mechanical and migratory properties of normal, scar, and Dupuytren's fibroblasts. AB - Mechanical properties of myofibroblasts play a key role in Dupuytren's disease. Here, we used atomic force microscopy to measure the viscoelastic properties of 3 different types of human primary fibroblasts derived from a same patient: normal and scar dermal fibroblasts and palmar fascial fibroblasts from Dupuytren's nodules. Different stiffness hydrogels (soft ~1 kPa and stiff ~ 50 kPa) were used as cell culture matrix to mimic the mechanical properties of the natural tissues, and atomic force microscopy step response force curves were used to discriminate between elastic and viscous properties of cells. Since transforming growth factor beta1 (TGF-beta1) is known to induce expression of alpha-smooth muscle actin positive stress fibers in myofibroblasts, we investigated the behavior of these fibroblasts before and after applying TGF-beta1. Finally, we performed an in vitro cell motility test, the wound healing or scratch assay, to evaluate the migratory properties of these fibroblasts. We found that (1) Dupuytren's fibroblasts are stiffer than normal and scar fibroblasts, the elastic modulus E ranging from 4.4, 2.1, to 1.8 kPa, for Dupuytren's, normal and scar fibroblasts, respectively; (2) TGF-beta1 enhances the level of alpha-smooth muscle actin expression and thus cell stiffness in Dupuytren's fibroblasts (E, ~6.2 kPa); (3) matrix stiffness influences cell mechanical properties most prominently in Dupuytren's fibroblasts; and (4) Dupuytren's fibroblasts migrate slower than the other fibroblasts by a factor of 3. Taking together, our results showed that mechanical and migratory properties of fibroblasts might help to discriminate between different pathological conditions, helping to identify and recognize specific cell phenotypes. PMID- 29701270 TI - Topographical cues of direct metal laser sintering titanium surfaces facilitate osteogenic differentiation of bone marrow mesenchymal stem cells through epigenetic regulation. AB - OBJECTIVES: To investigate the role of hierarchical micro/nanoscale topography of direct metal laser sintering (DMLS) titanium surfaces in osteogenic differentiation of bone marrow mesenchymal stem cells (BMSCs), as well as the possible underlying epigenetic mechanism. MATERIALS AND METHODS: Three groups of titanium specimens were prepared, including DMLS group, sandblasted, large-grit, acid-etched (SLA) group and smooth titanium (Ti) group. BMSCs were cultured on discs followed by surface characterization. Cell adhesion and proliferation were examined by SEM and CCK-8 assay, while osteogenic-related gene expression was detected by real-time RT-PCR. Immunofluorescence, western blotting and in vivo study were also performed to evaluate the potential for osteogenic induction of materials. In addition, to investigate the underlying epigenetic mechanisms, immunofluorescence and western blotting were performed to evaluate the global level of H3K4me3 during osteogenesis. The H3K4me3 and H3K27me3 levels at the promoter area of the osteogenic gene Runx2 were detected by ChIP assay. RESULTS: The DMLS surface exhibits greater protein adsorption ability and shows better cell adhesion performance than SLA and Ti surfaces. Moreover, both in vitro and in vivo studies demonstrated that the DMLS surface is more favourable for the osteogenic differentiation of BMSCs than SLA and Ti surfaces. Accordingly, osteogenesis-associated gene expression in BMSCs is efficiently induced by a rapid H3K27 demethylation and increase in H3K4me3 levels at gene promoters upon osteogenic differentiation on DMLS titanium surface. CONCLUSIONS: Topographical cues of DMLS surfaces have greater potential for the induction of osteogenic differentiation of BMSCs than SLA and Ti surfaces both in vitro and in vivo. A potential epigenetic mechanism is that the appropriate topography allows rapid H3K27 demethylation and an increased H3K4me3 level at the promoter region of osteogenesis-associated genes during the osteogenic differentiation of BMSCs. PMID- 29701271 TI - Quantifying Rome symptoms for diagnosis of the irritable bowel syndrome. AB - BACKGROUND: Irritable bowel syndrome (IBS) is a common functional gastrointestinal disorder, diagnosed on symptom-based criteria. Many have reported discrepancies between formal Rome criteria and diagnoses made in clinical practice. The aim of the study was to explore whether a quantitative version of the Rome criteria would better represent a clinical diagnosis of IBS than the current dichotomous criteria for symptom measure. METHODS: As part of a large, case-control study, participants completed a validated bowel disease questionnaire. Rome criteria were analyzed based on 15 individual symptoms. Penalized logistic regression model with stepwise selection was used to identify significant symptoms of IBS which were independently associated with case-control status. KEY RESULTS: In cases with a clinical diagnosis of IBS, 347 (70%) met Rome criteria for IBS. Increasing number of Rome symptoms were found related to the odds of being diagnosed with IBS. Nearly half of the Rome-negative case group experienced infrequent symptoms suggesting milder disease. Five of 15 Rome symptoms were associated with predicting case-control status in the final model, with 96% correctly classified among Rome-positive cases, 76% for Rome-negative cases, and 91% for controls. CONCLUSIONS AND INFERENCES: Irritable bowel syndrome appears to be a spectrum disorder. Quantifying individual symptoms of Rome criteria has greater utility than the current application in representing the degree of IBS affectedness and appears to better reflect a clinical diagnosis of IBS applied by physicians. The use of a quantitative diagnostic Rome "score" may be helpful in clinical practice and research studies to better reflect the degree an individual is affected with IBS. PMID- 29701273 TI - SATB2 targeted by methylated miR-34c-5p suppresses proliferation and metastasis attenuating the epithelial-mesenchymal transition in colorectal cancer. AB - OBJECTIVES: SATB2 has been shown to be markedly reduced in colorectal cancer (CRC) tissues relative to paired normal controls; however, the mechanism behind remains not well understood. To investigate why SATB2 was down-regulated in CRC, we attempted to analyse it from the angle of miRNA-mRNA modulation. MATERIALS AND METHODS: SATB2 expression was detected in CRC tissues using immunohistochemistry and verified using real-time PCR on mRNA level, followed by analysis of clinicopathological significance of its expression. Metastatic variation of CRC cells was evaluated both in vivo and in vitro. To find out the potential miRNA that directly regulate the SATB2, luciferase reporter assay was performed following the bioinformatic prediction. RESULTS: SATB2 was confirmed to be closely linked with the metastasis and shorter overall survival of CRC in our own cases. Silencing of SATB2 was shown to be able to promote the metastatic ability of CRC cells in vivo, enhancing the epithelial-mesenchymal transition (EMT). Mechanistically, miR-34c-5p was identified to be a novel miRNA that can directly modulate the SATB2. It turned out that the promoter of miR-34c-5p was methylated, which leads to the repression of miR-34c-5p in CRC. Treatment with 5-Aza-dC can reasonably and significantly restore the level of miR-34c-5p in CRC cells relative to control, thereby down-regulating the SATB2. CONCLUSIONS: Together, our study revealed that SATB2 targeted by methylated miR-34c-5p can suppress the metastasis, weakening the EMT in CRC. PMID- 29701274 TI - Nature of nursing errors and their contributing factors in intensive care units. AB - BACKGROUND: Errors tend to be multifactorial and so learning from nurses' experiences with them would be a powerful tool toward promoting patient safety. AIM: To identify the nature of nursing errors and their contributing factors in intensive care units (ICUs). METHODS: A semi-structured interview with 112 critical care nurses to elicit the reports about their encountered errors followed by a content analysis. RESULTS: A total of 300 errors were reported. Most of them (94.3%) were classified in more than one error category, e.g. 'lack of intervention', 'lack of attentiveness' and 'documentation errors': these were the most frequently involved error categories. Approximately 40% of reported errors contributed to significant harm or death of the involved patients, with system-related factors being involved in 84.3% of them. More errors occur during the evening shift than the night and morning shifts (42.7% versus 28.7% and 16.7%, respectively). There is a statistically significant relation (p <= 0.001) between error disclosure to a nursing supervisor and its impact on the patient. CONCLUSIONS: Nurses are more likely to report their errors when they feel safe and when the reporting system is not burdensome, although an internationally standardized language to define and analyse nursing errors is needed. Improving the health care system, particularly the managerial and environmental aspects, might reduce nursing errors in ICUs in terms of their incidence and seriousness. RELEVANCE TO CLINICAL PRACTICE: Targeting error-liable times in the ICU, such as mid-evening and mid-night shifts, along with improved supervision and adequate staff reallocation, might tackle the incidence and seriousness of nursing errors. Development of individualized nursing interventions for patients with low health literacy and patients in isolation might create more meaningful dialogue for ICU health care safety. PMID- 29701272 TI - dCK negatively regulates the NRF2/ARE axis and ROS production in pancreatic cancer. AB - OBJECTIVES: Decreased deoxycytidine kinase (dCK) expression is a reported indicator of gemcitabine efficacy in pancreatic cancer, due to the impact of this kinase on gemcitabine metabolism. The transcription factor NF-E2 p45-related factor 2 (NRF2, also called Nfe2l2), a master regulator of redox homoeostasis, has been reported to tightly control the expression of numerous ROS detoxification genes and participates in drug resistance. However, the contribution of dCK to the NRF2 signalling axis has seldom been discussed and needs investigation. MATERIALS AND METHODS: By overexpressing dCK in pancreatic cancer cells, we assessed the impact of dCK on NRF2 transcriptional activity. Furthermore, we measured the impact of dCK expression on the intracellular redox balance and reactive oxygen species (ROS) production. By utilizing immunohistochemical staining and tissues from pancreatic cancer patients, we assessed the correlation between dCK and NRF2 expression. Through proliferation and metastasis assays, we examined the impact of dCK expression on cell proliferation and metastasis. RESULTS: dCK negatively regulates NRF2 transcriptional activity, leading to the decreased expression of ARE-driven antioxidant genes. In addition, dCK negatively regulates intracellular redox homoeostasis and ROS production. Negative correlations between dCK and NRF2 levels in pancreatic cancer cell lines and patient samples were observed. In vitro cell line studies suggested that dCK negatively regulated proliferation and metastasis. CONCLUSION: Decreased dCK expression promotes NRF2-driven antioxidant transcription, which further enhances gemcitabine treatment resistance, forming a feedback loop. PMID- 29701275 TI - Involving Synergy of Green Light and Acidic Responses in Control of Unimolecular Multicolor Luminescence. AB - Conversion of multicolor luminescence is one of desirable goals in study and development of next-generation molecular emitters, whereas involving visible light into the control of the above-mentioned ability has been poorly addressed due to the need of a relatively complicate molecular design. In this work, we present a novel dyad with a linkage of 4-piperazinyl-1,8-naphthalimide and cyanostyryl-modified azulene moiety, upon which the luminescence signal can be orthogonally controlled by protonation and green light irradiation. The superior features of the protonation induced excited state energy alteration, followed by green light driven photoisomerization led to a progressive luminescent color conversion among blue, yellow and green at the single molecular level. This strategy may bring in novel insights for preparing advanced function-integrated optoelectronic materials. PMID- 29701276 TI - Supramolecular Recognition and Selective Protein Uptake by Peptide Hybrids. AB - The intracellular transport of exogenous proteins has emerged as one of the most promising methodologies for biotechnology and chemical biology. Currently, protein delivery is mainly achieved by liposome encapsulation, translational fusion, and ionic/hydrophobic non-covalent aggregation with transporting molecular vehicles. This work introduces the concept of supramolecular recognition and selective transport of proteins by peptide hybrid materials. A helical amphiphilic cationic peptide that bears two orthogonal alkoxyamines for the precise anchoring of protein ligands has been designed. After the attachment of these protein ligands, the peptide showed a high binding affinity for its target protein (i.e., mannose/Concanavalin A, Biotin/Streptavidin). The resulting peptide/protein hybrids were taken up by human cells such as HeLa and HepG2. The concept described in this manuscript could potentially be adapted, through the appropriate choice of ligands, to the transport of other proteins with suitable supramolecular binding motifs. PMID- 29701277 TI - Review article: therapeutic bile acids and the risks for hepatotoxicity. AB - BACKGROUND: Bile acids play important roles in cholesterol metabolism and signal through farnesoid X receptor and G protein-coupled receptors. Given their importance in liver biology, bile acid therapy enables therapeutic applications beyond the treatment of cholestatic liver disease. However, predicting hepatotoxicity of bile acids in humans is obscured due to inconsistent extrapolations of animal data to humans. AIM: To review the evidence that could explain discordant bile acids hepatotoxicity observed in humans and animals. METHOD: Literature search was conducted in PubMed using keywords "bile acid," "transporter," "hepatotoxicity," "clinical study," "animal study," "species difference," "mechanism," "genetic disorder." Relevant articles were selected for review. RESULTS: Clinically significant hepatotoxicity was reported in response to certain bile acids, namely chenodeoxycholic acid, which was given a boxed warning for potential hepatotoxicity. The chemical structure, specifically the number and orientation of hydroxyl groups, significantly affects their hydrophobicity, an important factor in bile acid toxicity. Experimental studies show that hydrophobic bile acids can lead to liver injury through various mechanisms, such as death receptor signalling, mitochondrial dysfunction and inflammation. Although animal studies play a central role in investigating bile acid safety, there are considerable differences in bile acid composition, metabolism and hepatobiliary disposition across species. This does not allow appropriate safety inference, especially for predicting hepatotoxicity in humans. Exploring evidences stemming from inborn errors, genetic models of disease and toxicology studies further improves an understanding of bile acid hepatotoxicity. CONCLUSION: Species differences should be considered in the development of bile acid related therapeutics. Although the mechanism of bile acid hepatotoxicity is still not fully understood, continued mechanistic studies will deepen our understanding. PMID- 29701278 TI - The impact of general anesthesia on child development and school performance: a population-based study. AB - BACKGROUND: There has been considerable interest in the possible adverse neurocognitive effects of exposure to general anesthesia and surgery in early childhood. AIMS: The aim of this data linkage study was to investigate developmental and school performance outcomes of children undergoing procedures requiring general anesthesia in early childhood. METHODS: We included children born in New South Wales, Australia of 37+ weeks' gestation without major congenital anomalies or neurodevelopmental disability with either a school entry developmental assessment in 2009, 2012, or Grade-3 school test results in 2008 2014. We compared children exposed to general anesthesia aged <48 months to those without any hospitalization. Children with only 1 hospitalization with general anesthesia and no other hospitalization were assessed separately. Outcomes included being classified developmentally high risk at school entry and scoring below national minimum standard in school numeracy and reading tests. RESULTS: Of 211 978 children included, 82 156 had developmental assessment and 153 025 had school test results, with 12 848 (15.7%) and 25 032 (16.4%) exposed to general anesthesia, respectively. Children exposed to general anesthesia had 17%, 34%, and 23% increased odds of being developmentally high risk (adjusted odds ratio [aOR]: 1.17; 95% CI: 1.07-1.29); or scoring below the national minimum standard in numeracy (aOR: 1.34; 95% CI: 1.21-1.48) and reading (aOR: 1.23; 95% CI: 1.12 1.36), respectively. Although the risk for being developmentally high risk and poor reading attenuated for children with only 1 hospitalization and exposure to general anesthesia, the association with poor numeracy results remained. CONCLUSION: Children exposed to general anesthesia before 4 years have poorer development at school entry and school performance. While the association among children with 1 hospitalization with 1 general anesthesia and no other hospitalization was attenuated, poor numeracy outcome remained. Further investigation of the specific effects of general anesthesia and the impact of the underlying health conditions that prompt the need for surgery or diagnostic procedures is required, particularly among children exposed to long duration of general anesthesia or with repeated hospitalizations. PMID- 29701279 TI - Reuse of data sources to evaluate drug safety signals: When is it appropriate? PMID- 29701280 TI - Enhancing Nanos expression via the bacterial TomO protein is a conserved strategy used by the symbiont Wolbachia to fuel germ stem cell maintenance in infected Drosophila females. AB - The toxic manipulator of oogenesis (TomO) protein has been identified in the wMel strain of Wolbachia that symbioses with the vinegar fly Drosophila melanogaster, as a protein that affects host reproduction. TomO protects germ stem cells (GSCs) from degeneration, which otherwise occurs in ovaries of host females that are mutant for the gene Sex-lethal (Sxl). We isolated the TomO homologs from wPip, a Wolbachia strain from the mosquito Culex quinquefasciatus. One of the homologs, TomOwPip 1, exerted the GSC rescue activity in fly Sxl mutants when lacking its hydrophobic stretches. The GSC-rescuing action of the TomOwPip 1 variant was ascribable to its abilities to associate with Nanos (nos) mRNA and to enhance Nos protein expression. The analysis of structure-activity relationships with TomO homologs and TomO deletion variants revealed distinct modules in the protein that are each dedicated to different functions, i.e., subcellular localization, nos mRNA binding or Nos expression enhancement. We propose that modular reshuffling is the basis for structural and functional diversification of TomO protein members. PMID- 29701281 TI - Systematic review of the prevalence of nodal metastases and the prognostic utility of sentinel lymph node biopsy in cutaneous squamous cell carcinoma. AB - Cutaneous squamous cell carcinoma (cSCC) is the second most common skin cancer and its incidence is rising. The prognosis is mostly good but patients with high risk cSCC have a greater risk of recurrence and death. The aim of the present study was to conduct a systematic review analyzing the prevalence, predictors and prognostic utility of sentinel lymph node (SLN) involvement in cSCC. We performed a published work search in Ovid MEDLINE and reviewed the reference lists of selected studies. Based on the 23 studies included in the systematic review, the proportion of patients with cSCC and positive SLN biopsy findings was 8% (95% confidence interval, 5.1-10.8%; I2 = 44.51%). We found no studies reporting on predictors of SLN involvement in cSCC or on the prognostic utility of this finding following adjustment for confounders. The rate of positive SLN in cSCC is less than previously reported. Criteria for recommending SLN biopsy as a staging tool for cSCC vary considerably from study to study, and none of the studies were large enough to reliably identify predictors of SLN positivity. No randomized controlled trials have yet analyzed whether SLN biopsy may improve the prognosis of cSCC. More studies are required on the prognostic value of SLN positivity and the associated risk factors in cSCC. PMID- 29701282 TI - Dissecting "Peer Presence" and "Decisions" to Deepen Understanding of Peer Influence on Adolescent Risky Choice. AB - This study evaluated the aspects of complex decisions influenced by peers, and components of peer involvement influential to adolescents' risky decisions. Participants (N = 140) aged 13-25 completed the Columbia Card Task (CCT), a risky choice task, isolating deliberation-reliant and affect-reliant decisions while alone, while a friend monitors choices, and while a friend is merely present. There is no condition in which a nonfriend peer is present. Results demonstrated the risk-increasing peer effect occurred in the youngest participants in the cold CCT and middle-late adolescents in the hot CCT, whereas other ages and contexts showed a risk-decreasing peer effect. Mere presence was not sufficient to influence risky behavior. These boundaries in age, decision, and peer involvement constrain prevailing models of adolescent peer influence. PMID- 29701283 TI - Therapeutic effect of Northern Labrador tea extracts for acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is an aggressive hematological malignancy that is one of the more common pediatric malignancies in addition to occurring with high incidence in the aging population. Unfortunately, these patient groups are quite sensitive to toxicity from chemotherapy. Northern Labrador tea, or Rhododendron tomentosum Harmaja (a.k.a. Ledum palustre subsp. decumbens) or "tundra tea," is a noteworthy medicinal plant used by indigenous peoples in Alaska, Canada, and Greenland to treat a diversity of ailments. However, laboratory investigations of Northern Labrador tea, and other Labrador tea family members, as botanical sources for anticancer compounds have been limited. Utilizing an AML cell line in both in vitro and in vivo studies, as well as in vitro studies using primary human AML patient samples, this study demonstrated for the first time that Northern Labrador tea extracts can exert anti-AML activity and that this may be attributed to ursolic acid as a constituent component. Therefore, this medicinal herb holds the potential to serve as a source for further drug discovery efforts to isolate novel anti-AML compounds. PMID- 29701284 TI - Microscopic positive margins in papillary thyroid cancer do not impact disease recurrence. AB - BACKGROUND: The prognostic significance of microscopic positive margins in papillary thyroid carcinoma (PTC) remains unclear. The aim of this study was to determine if microscopic positive margins are associated with increased risk of disease recurrence. METHODS: This is a retrospective analysis of 610 patients with PTC using multivariate Cox regression to evaluate the association between microscopic positive margins and disease-free survival. RESULTS: Microscopic positive margins were found in 67 (11%) patients and associated with extrathyroidal extension (P < 0.001), multifocality (P < 0.001), nodal metastases (P < 0.001), lymphovascular invasion (P < 0.001), age >=55 years (P = 0.048), administration of radioactive iodine (RAI) therapy (P = 0.001) and a trend towards larger tumour size (18 versus 15 mm; P = 0.074). After a median follow-up of 3.4 years, there were 83 recurrences. Although involved margins were associated with increased risk of recurrence on univariate analysis (hazard ratio 2.6, 95% confidence interval 1.5-4.6; P = 0.001), there was no association after adjusting for age, nodal metastases, tumour size and extrathyroidal extension on multivariate analysis (hazard ratio 1.5, 95% confidence interval 0.8-2.9; P = 0.242). Similar results were obtained after adjusting for RAI and if margins were analysed as focal versus widely positive. In our study cohort, patients with involved margins generally had other indications for RAI. However, in the nine patients who did not receive RAI, there was no recurrence in the thyroid bed. CONCLUSION: Despite a strong association between microscopic positive margins and other adverse prognostic factors in PTC, there is no independent association with disease recurrence on multivariate analysis. Microscopic positive margins are rare (1.1%) in the absence of other indications for RAI. PMID- 29701285 TI - Reduction in baseline corticosterone secretion correlates with climate warming and drying across wild lizard populations. AB - Climate change should lead to massive loss of biodiversity in most taxa, but the detailed physiological mechanisms underlying population extinction remain largely elusive so far. In vertebrates, baseline levels of hormones such as glucocorticoids (GCs) may be indicators of population state as their secretion to chronic stress can impair survival and reproduction. However, the relationship between GC secretion, climate change and population extinction risk remains unclear. In this study, we investigated whether levels of baseline corticosterone (the main GCs in reptiles) correlate with environmental conditions and associated extinction risk across wild populations of the common lizard Zootoca vivipara. First, we performed a cross-sectional comparison of baseline corticosterone levels along an altitudinal gradient among 14 populations. Then, we used a longitudinal study in eight populations to examine the changes in corticosterone levels following the exposure to a heatwave period. Unexpectedly, baseline corticosterone decreased with increasing thermal conditions at rest in females and was not correlated with extinction risk. In addition, baseline corticosterone levels decreased after exposure to an extreme heatwave period. This seasonal corticosterone decrease was more pronounced in populations without access to standing water. We suggest that low basal secretion of corticosterone may entail downregulating activity levels and limit exposure to adverse climatic conditions, especially to reduce water loss. These new insights suggest that rapid population decline might be preceded by a downregulation of the corticosterone secretion. PMID- 29701286 TI - Physiological characterization of ocular melanosis-affected canine melanocytes. AB - OBJECTIVE: Cairn terriers with ocular melanosis (OM) accumulate large, heavily pigmented melanocytes in the anterior uvea. Darkly pigmented plaques develop within the sclera, leading us to hypothesize that OM uveal melanocytes may have an abnormal migratory capacity. ANIMALS STUDIED: Globes from OM-affected Cairn terriers and unaffected control eyes enucleated for reasons unrelated to this study were used for immunohistochemistry and to culture melanocytes for in vitro cell behavior assays. PROCEDURES: The scleral plaques of six dogs were immunolabeled for HMB-45, MelanA, PNL2, CD18, CD204, and Iba-1 and compared with the pigment cells accumulated within the irides. Cultured uveal melanocytes from OM-affected and control dogs were compared using conventional assays measuring cell proliferation, invasion capability, and melanin production. RESULTS: Melanocytes isolated from OM eyes had significantly elevated levels of per-cell melanin content and production compared to controls. The majority of pigmented cells in the scleral plaques were HMB45 positive indicating a melanocytic origin. Many were also CD18 positive. No differences were observed between cultured melanocytes from OM-affected and control uvea for standard in vitro proliferation or invasion assays. CONCLUSION: Pigmented cells which accumulate in the sclera of OM-affected Cairn terriers are predominantly melanocytes; however, in vitro assays of uveal melanocytes did not reveal differences in migratory behavior between OM and control cells. Migratory behavior of OM-melanocytes may be environment-dependent. We suggest that RNA sequencing and differential expression analysis would be a useful next step in understanding this disease. PMID- 29701287 TI - Being respected by nurses: Measuring older patients' perceptions. AB - AIM AND OBJECTIVE: To investigate older patients' perceptions of respect in hospital nursing care and to test a newly developed instrument measuring the phenomenon. BACKGROUND: Respect manifests itself in the older patient-nurse relationship in terms of nurses being with and doing for the patient. Empirical studies investigating respect from the older patients' perspective are rare. There is a need to maintain respectful behaviours and attitudes within hospital based nursing practice. Furthermore, there is a lack of instruments measuring respect in the care provided by nurses. DESIGN AND METHODS: A descriptive, cross sectional explorative survey design was used. Data were collected between February and May 2016 by interviewing face-to-face 196 older patients in two hospitals in Finland. Respect was measured using the ReSpect scale (Parts A and B) developed for this study. Respect is based on the two dimensions of respect, nurses' Being with and Doing for patients. Data were analysed using descriptive and inferential statistical methods including the psychometric testing of the new instrument. RESULTS: Older patients perceived respect in their care frequently and to a great extent, although there were also shortcomings. The findings highlight the need to improve respect to patients in care delivery by showing an interest in their views, acknowledging them positively and supporting their individual capacities. A two-factor structure of the ReSpect scale Part A and a four-factor structure of the Part B were confirmed. CONCLUSIONS: Findings from this study suggest that older hospital patients perceived respect by nurses overall, but the area where there is the most room for improvement is that of listening and encouraging. The psychometric analysis demonstrated that the ReSpect scale shows promise in measuring respect. IMPLICATIONS FOR PRACTICE: The ReSpect scale could be a useful tool to measure respect, an important element of value-based health care. PMID- 29701288 TI - Cytokine expression profile in the bone-anchored hearing system: 12-week results from a prospective randomized, controlled study. AB - OBJECTIVE: To study the effect of implanting the percutaneous bone-anchored hearing system (BAHS) itself and inflammation of the peri-abutment skin warrant clarification. In this study, we aimed to acquire further insight into the immune responses related to BAHS surgery and peri-implant skin inflammation. MATERIALS AND METHODS: During surgery and 12 weeks post-implantation, skin biopsies were obtained. If applicable, additional biopsies were taken during cases of inflammation. The mRNA expression of IL-1beta, IL-6, IL-8, TNFalpha, IL-17, IL 10, TGF-beta, MIP-1alpha, MMP-9, TIMP-1, COL1alpha1, VEGF-A, FGF-2 TLR-2, and TLR 4 was quantified using qRT-PCR. RESULTS: Thirty-five patients agreed to the surgery and 12-week biopsy. Twenty-two patients had mRNA of sufficient quality for analysis. Ten were fitted with a BAHS using the minimally invasive Ponto surgery technique. Twelve were fitted with a BAHS using the linear incision technique with soft-tissue preservation. Five biopsies were obtained during episodes of inflammation. The post-implantation mRNA expression of IL-1beta (P = .002), IL-8 (P = .003), MMP9 (P = .005), TIMP-1 (P = .002), and COL1alpha1 (P < .001) was significantly up-regulated. IL-6 (P = .009) and FGF-2 (P = .004) mRNA expression was significantly down-regulated after implantation. Within patients, no difference between post-implantation mRNA expression (at 12 weeks) and when inflammation was observed. Between patients, the expression of IL-1beta (P = .015) and IL-17 (P = .02) was higher during cases of inflammation compared with patients who had no inflammation at 12-week follow-up. CONCLUSIONS: As part of a randomized, prospective, clinical trial, the present study reports the molecular profile of selected cytokines in the soft tissue around BAHS. Within the limit of this study, the results showed that 12 weeks after BAHS implantation the gene expression of some inflammatory cytokines (IL-8 and IL-1beta) is still relatively high compared with the baseline, steady-state, expression. The up-regulation of anabolic (COL1alpha1) and tissue-remodeling (MMP-9 and TIMP1) genes indicates an ongoing remodeling process after 12 weeks of implantation. The results suggest that IL-1beta, IL-17, and TNF-alpha may be interesting markers associated with inflammation. PMID- 29701289 TI - Traversing Steric Limitations by Cooperative Lewis Base/Palladium Catalysis: An Enantioselective Synthesis of alpha-Branched Esters Using 2-Substituted Allyl Electrophiles. AB - Cooperative catalysis enables the direct enantioselective alpha-allylation of linear prochiral esters with 2-substituted allyl electrophiles. Critical to the successful development of the method was the recognition that metal-centered reactivity and the source of enantiocontrol are independent. This feature is unique to simultaneous catalysis events and permits logical tuning of the supporting ligands without compromising enantioselectivity. PMID- 29701290 TI - Method of pedicle division during laparoscopic right hemicolectomy affects lymph node yield and short-term outcomes. AB - BACKGROUND: Several ways of performing laparoscopic right hemicolectomy (RHC) have evolved. The vascular pedicle can be divided into extracorporeal (RHC-EC) or intracorporeal (RHC-IC). It is not known whether vessel ligation during RHC-EC is as central as during RHC-IC. We compare these approaches in terms of pathological and short-term clinical outcomes. METHODS: Patients undergoing elective laparoscopic RHC in a single centre (July 2013-September 2016) were identified. Data collection included operative details, length of stay, complications, specimen parameters including number and involvement of lymph nodes and recurrence. RESULTS: One hundred and sixty-nine patients were included (94 RHC IC, 75 RHC-EC). For caecal and ascending colon cancers, mesocolic width was greater after RHC-IC than RHC-EC (7.9 cm versus 6.6 cm, P < 0.05), as was lymph node yield (19.5 versus 17.3, P < 0.05). There was no significant difference in length of colon resected, distal resection margin, number of positive nodes, proportion of node-positive tumours and R1 rate. Operative duration was higher for RHC-IC (163 min versus 91 min, P < 0.001), as was incidence of ileus (35% versus 15%, P < 0.05). Length of stay also tended to be higher (7.4 days versus 6.0 days, P = 0.19). There was no difference in disease recurrence (follow-up 12 months). Body mass index was positively correlated with lymph node yield for RHC EC, but not for RHC-IC. CONCLUSION: Lymph node yield after laparoscopic RHC is adequate, whether the vascular pedicle is taken intracorporeal or extracorporeal, supporting the use of both approaches. RHC-IC yields more lymph nodes and greater mesocolic width, but involves a longer operation and higher incidence of ileus. PMID- 29701291 TI - Non-steroidal anti-inflammatory-induced small bowel diaphragm disease requiring bowel resection for recurrent small bowel obstruction. PMID- 29701292 TI - Therapeutic experience with hepatoblastoma associated with trisomy 18. AB - Trisomy 18 is often fatal, but patients with this disease can now have longer survival due to proactive treatment intervention. However, hepatoblastomas may develop in these patients. In this study, we report four cases of hepatoblastoma associated with trisomy 18. All of the patients had congenital heart disease and three had undergone intracardiac surgical repair. Tumor growth was relatively slow in all cases, and there were no problems with chemotherapy tolerability and surgical resection. Three of the patients are currently disease-free and the fourth is alive with remaining of the tumor. These cases suggest that combined chemotherapy and surgical resection may be an option to treat hepatoblastoma associated with trisomy 18 when cardiac pulmonary function is relatively stable. PMID- 29701294 TI - Pigment and Binder Concentrations in Modern Paint Samples Determined by IR and Raman Spectroscopy. AB - Knowledge of the techniques employed by artists, such as the composition of the paints, colour palette, and painting style, is of crucial importance not only to attribute works of art to the workshop or artist but also to develop strategies and measures for the conservation and restoration of the art. While much research has been devoted to investigating the composition of an artist's materials from a qualitative point of view, little effort has been made in terms of quantitative analyses. This study aims to quantify the relative concentrations of binders (acrylic and alkyd) and inorganic pigments in different paint samples by IR and Raman spectroscopies. To perform this quantitative evaluation, reference samples of known concentrations were prepared to obtain calibration plots. In a further step, the quantification method was verified by additional test samples and commercially available paint tubes. The results obtained confirm that the quantitative method developed for IR and Raman spectroscopy is able to efficiently determine different pigment and binder concentrations of paint samples with high accuracy. PMID- 29701295 TI - Idiopathic congenital right atrial dilation: Fetal presentation. PMID- 29701293 TI - Oxidation of Naphthalene with a Manganese(IV) Bis(hydroxo) Complex in the Presence of Acid. AB - Naphthalene oxidation with metal-oxygen intermediates is a difficult reaction in environmental and biological chemistry. Herein, we report that a MnIV bis(hydroxo) complex, which was fully characterized by various physicochemical methods, such as ESI-MS, UV/Vis, and EPR analysis, X-ray diffraction, and XAS, can be employed for the oxidation of naphthalene in the presence of acid to afford 1,4-naphthoquinone. Redox titration of the MnIV bis(hydroxo) complex gave a one-electron reduction potential of 1.09 V, which is the most positive potential for all reported nonheme MnIV bis(hydroxo) species as well as MnIV oxo analogues. Kinetic studies, including kinetic isotope effect analysis, suggest that the naphthalene oxidation occurs through a rate-determining electron transfer process. PMID- 29701297 TI - Inter-individual differences in weight change following exercise interventions: a systematic review and meta-analysis of randomized controlled trials. AB - Previous reports of substantial inter-individual differences in weight change following an exercise intervention are often based solely on the observed responses in the intervention group. Therefore, we aimed to quantify the magnitude of inter-individual differences in exercise-mediated weight change. We synthesized randomized controlled trials (RCTs) of structured, supervised exercise interventions. Fourteen electronic databases were searched for relevant studies published up to March 2017. Search terms focused on structured training, RCTs and body weight. We then sifted these results for those RCTs (n = 12, 1500 participants) that included relevant comparator group data. Standard deviations (SDs) of weight change were extracted, thereby allowing the SD for true inter individual differences in weight loss to be calculated for each study. Using a random effects meta-analysis, the pooled SD (95% CI) for true individual responses was 0.8 (-0.9 to 1.4) kg. The 95% prediction interval (based on 2SDs) for true inter-individual responses was -2.8 to 3.6 kg. The probability (% chance) that the true individual response variability would be clinically meaningful (>2.5 kg) in a future study in similar settings was 23% ('unlikely'). Therefore, we conclude that evidence is limited for the notion that there are clinically important individual differences in exercise-mediated weight change. PMID- 29701296 TI - Repression of microRNA-382 inhibits glomerular mesangial cell proliferation and extracellular matrix accumulation via FoxO1 in mice with diabetic nephropathy. AB - OBJECTIVES: Diabetic nephropathy (DN) is a nerve damaging disorder, characterized by glomerular mesangial cell expansion and accumulation of extracellular matrix (ECM) proteins. In this study, we aimed to investigate mesangial cell proliferation and ECM accumulation when promoting or suppressing endogenous miR 382 in glomerular mesangial cells of DN. MATERIALS AND METHODS: Model establishment consisted of DN induction by streptozotocin (STZ) in mice. The underlying regulatory mechanisms of miR-382 were analysed in concert with the treatment of miR-382 mimics, miR-382 inhibitors or siRNA against FoxO1 in cultured glomerular mesangial cells isolated from DN mice. RESULTS: FoxO1 was identified as the downregulated gene in DN based on the microarray data of GSE1009. We found that miR-382 was significantly upregulated in renal tissues of DN mice and its downregulation dephosphorylated FoxO1, reduced glomerular mesangial cell proliferation and ECM accumulation in vitro. The determination of luciferase activity suggested that miR-382 negatively targeted FoxO1. Expectedly, distinct levels of phosphorylated FoxO1 were observed in the renal cortices of DN mice, while the silencing of FoxO1 was found to increase glomerular mesangial cell proliferation and ECM accumulation in vitro. Reduced glomerular mesangial cell proliferation and ECM accumulation elicited by miR-382 inhibitors were reversed by silencing FoxO1. CONCLUSIONS: This study demonstrates miR-382 suppression exerts a potent anti-proliferative effect that may be applied to inhibit glomerular mesangial cell proliferation and ECM accumulation in DN. PMID- 29701298 TI - Effects of multidisciplinary interventions on weight loss and health outcomes in children and adolescents with morbid obesity. AB - OBJECTIVE: Morbid obesity is the fastest growing subcategory of childhood obesity, associated with an increased health risk that persists into adulthood. There is an urgent need to develop multifaceted interventions that target initial and long-term lifestyle changes. This review investigates the effects of multidisciplinary interventions on weight loss and health outcomes in children and adolescents with morbid obesity. The influence of age, gender and family participation on health outcomes and intensive treatment alternatives are explored. METHODS: The review includes 16 studies conducted between 1995 and 2017. Studies examined youth with morbid obesity, 4-18 years old, undergoing multidisciplinary treatment. RESULTS: All studies found a reduction in body mass index (BMI or z-score) and if measured, cardiovascular risk factors. Physical activity, nutrition education, behavioural modification and family involvement are commonly included treatment components and have improved weight loss and health-related outcomes. However, initial weight loss was often not sustainable, despite the favourable interventional effect on cardiometabolic risk markers. Weight loss was prolonged in younger children and among the male sex. CONCLUSIONS: There is not a 'one-size-fits-all' treatment approach, and matched care to personal needs is preferable. The integration of a chronic care approach is critical for the successful adaption of sustainable health behaviours. PMID- 29701299 TI - A cumulative meta-analysis of the effects of individual physical activity interventions targeting healthy adults. AB - Despite a large and increasing evidence base on physical activity interventions, the high rates of physical inactivity and associated chronic diseases are continuing to increase globally. The purpose of this cumulative meta-analysis was to investigate the evolution of randomized controlled trial evidence of individual-level physical activity interventions to asses if new trials are contributing novel evidence to the field. Through a two-staged search process, primary studies examining the effects of interventions targeted at increasing physical activity within healthy adult populations were pooled and selected from eligible systematic reviews. Cumulative meta-analyses were performed on effect sizes immediately post-intervention (n = 62), and for long-term behaviour change (>=12-month post-baseline; n = 27). Sufficiency and stability of the evidence was assessed through application of pre-published indicators. Meta-analyses suggest overall positive intervention effects on physical activity. The evidence base for effectiveness immediately post-intervention reached levels of sufficiency and stability in 2007; and for long-term follow-up in 2011. In the time since, intervention effectiveness has not substantially changed, and further trials are unlikely to change the direction and magnitude of effect. Substantial evidence exists demonstrating that physical activity interventions can modify individual behaviour in controlled settings. Researchers are urged to shift focus towards investigating the optimization, implementation, sustainability and cost effectiveness of interventions. PMID- 29701300 TI - M/XDR-TB treatment perspective: How to avoid mountains of pills via digital technologies. PMID- 29701301 TI - M/XDR-TB treatment perspective: How to avoid mountains of pills via digital technologies - Reply. PMID- 29701302 TI - High-resolution capillary zone electrophoresis for transferrin glycoform analysis associated with congenital disorders of glycosylation. AB - High-resolution capillary zone electrophoresis is used to assess the transferrin profile in serum of patients with eight different congenital disorders of glycosylation that represent type I, type II, and mixed type I/II disorders. Capillary zone electrophoresis data are compared to patterns obtained by gel isoelectric focusing. The high-resolution capillary zone electrophoresis method is shown to represent an effective tool to assess the diversity of transferrin patterns. Hypoglycosylated disialo-, monosialo-, and asialo-transferrin in type I cases can be distinguished from the corresponding underdesialylated transferrin glycoforms present in type II disorders. The latter can be separated from and detected ahead of their corresponding hypoglycosylated forms of type I patients. Both types of glycoforms are detected in sera of mixed type I/II patients. The assay has the potential to be used as screening method for congenital disorders of glycosylation. It can be run with a few microliters of serum when microvials are used. PMID- 29701303 TI - Estimations of energy of noncovalent bonding from integrals over interatomic zero flux surfaces: Correlation trends and beyond. AB - Bonding energies of 50 associates composed by neutral molecules (atoms) and bounded by various weak noncovalent interactions are calculated within the DFT framework using the PBE0/aug-cc-pVTZ combination. The electronic virial and electron density values at bond critical points together with their integrals over interatomic surfaces are tested to check their ability to estimate bonding energies. Two correlations schemes dealing with integrals over interatomic surface are suggested to estimate bonding energy of any noncovalent interaction. The physical meaning of explored and several known correlations is discussed. Methods to estimate interatomic surface integrals of electronic virial and electron density are proposed. (c) 2018 Wiley Periodicals, Inc. PMID- 29701304 TI - Linear keratinocytic epidermal nevi on trunk skin caused by a somatic FGFR2 p.C382R mutation. PMID- 29701305 TI - Machine Learning for Organic Synthesis: Are Robots Replacing Chemists? AB - Machines learn chemistry: An artificial intelligence algorithm has learned to predict the outcomes of C-N coupling reactions from a few thousand nanomole-scale experiments. This Highlight discusses this work in the context of other state-of the-art approaches for predicting the yields of organic reactions and explains the significance of the results. PMID- 29701306 TI - The bigger picture: young children's perception of fatness in the context of other physical differences. AB - BACKGROUND: Negative obesity stereotypes and anti-fat attitudes have been observed in children from age three. It is uncertain whether this is specific to fatness or generalizable to other visible differences. OBJECTIVES: To determine whether young children base decisions about qualities in others and friendship choices more on fatness than other visible differences between people. METHODS: Using a personal construct theory approach, 85 children (mean age 5.7, 42 girls) completed a simple repertory grid. The children were asked about differences (constructs) between four illustrations (elements) that showed children as healthy weight, fat, the opposite gender and in a wheelchair. Children were also asked about friendship with the illustrated children and self-image preferences. Their answers were grouped using thematic analysis. RESULTS: The fat, opposite gender and wheelchair-bound characters were equally chosen by children as different to the standard character. When identifying differences, fatness or body shape was referred to significantly less than gender or being in a wheelchair. Children were more likely to reject an opposite gender character as a friend, or as someone they would like to be, than to reject the fat character. Only one child, themselves overweight, voiced strong anti-fat attitudes. CONCLUSIONS: Apparent negativity towards fatness is fostered by failure to consider other visible differences and by children's 'like me' peer preferences. It was less desirable in the eyes of most 5-year old girls to be a boy than to be fat. This offers some reassurance to those working to improve children's health literacy in obesity. PMID- 29701307 TI - Exogenous fatty acids alter phospholipid composition, membrane permeability, capacity for biofilm formation, and antimicrobial peptide susceptibility in Klebsiella pneumoniae. AB - Klebsiella pneumoniae represents a major threat to human health due to a combination of its nosocomial emergence and a propensity for acquiring antibiotic resistance. Dissemination of the bacteria from its native intestinal location creates severe, complicated infections that are particularly problematic in healthcare settings. Thus, there is an urgency for identifying novel treatment regimens as the incidence of highly antibiotic-resistant bacteria rises. Recent findings have highlighted the ability of some Gram-negative bacteria to utilize exogenous fatty acids in ways that modify membrane phospholipids and influence virulence phenotypes, such as biofilm formation and antibiotic resistance. This study explores the ability of K. pneumoniae to assimilate and respond to exogenous fatty acids. The combination of thin-layer chromatography liquid chromatography-mass spectrometry confirmed adoption of numerous exogenous polyunsaturated fatty acids (PUFAs) into the phospholipid species of K. pneumoniae. Membrane permeability was variably affected as determined by two dye uptake assays. Furthermore, the availability of many PUFAs lowered the MICs to the antimicrobial peptides polymyxin B and colistin. Biofilm formation was significantly affected depending upon the supplemented fatty acid. PMID- 29701308 TI - Multicolour imaging in a patient with optic disc pit maculopathy. PMID- 29701309 TI - Magnetic resonance-guided stereotactic laser pallidotomy for dystonia. PMID- 29701310 TI - Longitudinal left ventricular function is globally depressed within a week of STEMI. AB - Sixty percent of stroke volume (SV) is generated by atrioventricular plane displacement (AVPD) in a healthy left ventricle (LV). The aims were to determine the effect of ST-elevation myocardial infarction (STEMI) on AVPD and contribution of AVPD to SV and to study the relationship between AVPD and infarct size (IS) and location. Patients from CHILL-MI and MITOCARE studies with cardiovascular magnetic resonance within a week of STEMI (n = 177, 59 +/- 11 years) and healthy controls (n = 20, 62 +/- 11 years) were included. Left ventricular volumes were quantified in short-axis images. AVPD was measured in six locations in long-axis images. Longitudinal contribution to SV was calculated as AVPD multiplied by the short-axis epicardial area. Patients (IS 17 +/- 10% of LV) had decreased ejection fraction (48 +/- 8%) compared to controls (60 +/- 5%, P<0.001). Global AVPD was decreased in patients (11 +/- 2 mm versus 15 +/- 2 mm in controls, P<0.001) and this held true for both infarcted and remote segments. AVPD contribution to SV was lower in patients (58 +/- 9%) than in controls (64 +/- 8%) (P<0.001). There was a weak negative correlation between IS and AVPD (r2 =0.06) but no differences in global AVPD linked to infarct location. Decrease in global and regional AVPD occur even in remote myocardium within 1 week of STEMI. Global AVPD decrease is independent of MI location, and MI size has only minor effect. Longitudinal pumping is slightly lower compared to controls but remains to be the main component to SV even after STEMI. These results highlight the difficulty in determining infarct location and size from longitudinal measures of LV function. PMID- 29701311 TI - Crystallization of a Novel Germanosilicate ECNU-16 Provides Insights into the Space-Filling Effect on Zeolite Crystal Symmetry. AB - Synthesis of new zeolites involving organic molecules relies heavily on the trial and-error approach, because it is difficult to interpret the determining effects of organics on zeolite crystal symmetry. Here, the intrinsic relationships among the space-filling of organics, included volume of channels, and zeolite crystal symmetry, are systematically demonstrated by experimental and computational means. Under controlled conditions, the "dimer" and "monomer" organics of 1-ethyl 3-methylimidazolium selectively direct different, but related, germanosilicates, the ECNU-16 with a new topology and the existing IM-16 with the UOS topology, respectively. The comprehensive computational study reveals that the zeolite phase selectivity is determined by the unique space-filling behavior of the "dimer" and "monomer" organics, which is closely correlated to their rotation freedom, as well as the included volume of host zeolite channels. The elucidation of this crucial space-filling effect from the fundamental viewpoint will provide new guidelines for the rational design and synthesis of new zeolites in future. PMID- 29701312 TI - Tidal breath eNO measurements in a cohort of unsedated hospitalized neonates-A method validation. AB - AIM: Exhaled Nitric oxide (eNO) is an inflammatory marker. In 2002 Hall et al. [J Appl Physiol. 92:59-66] established an infant eNO measurement method, fulfilling four criteria of feasibility: simple, non-invasive, without impact on the natural breathing pattern, and accounting for flow by NO output (V'NO). Although tidal breathing is accepted as an eNO measurement method in uncooperative patients, it is seldom used outside research labs. The variability and lack of validated methods have restrained from exploring the area in preterm and term neonates the last years. This study aimed to validate clinically feasible longitudinal online tidal eNO and V'NO in a real-life birth cohort of un-sedated, hospitalized preterm, and term neonates. METHOD: We included 149 newborns, GA 28-42 weeks. Each scheduled for six repeated, non-invasive, on-line eNO measurements with Ecomedics CLD 88sp and NO-free air. We used three 60-second-eNO measurements. The method was adapted to fit preterm and term neonates with unstable respiration, without excluding sighs and surrounding breaths. RESULT: Protocol measurements with a maximum mutual difference of 1 ppb succeeded in 85-99%, increasing with postnatal age. We performed mixed model analyses in three hierarchical measurement levels. Despite the irregular breathing of newborns, the predictions of individual eNO levels in the average infant was a 0.05 SD. Exhaled NO was flow dependent (P = 0.028); V'NO but not eNO was associated with preterm birth (P < 0.001) and >24 h CPAP treatment (P = 0.0316). CONCLUSION: We validated clinically, non-invasive, online eNO measurements in neonates. The method was well tolerated and exhibited low subject-specific-prediction-variance and high success rates. PMID- 29701313 TI - Low inorganic arsenic in hydrolysed rice formula used for cow's milk protein allergy. PMID- 29701314 TI - Reconstruction of structure and function in tissue engineering of solid organs: Toward simulation of natural development based on decellularization. AB - Failure of solid organs, such as the heart, liver, and kidney, remains a major cause of the world's mortality due to critical shortage of donor organs. Tissue engineering, which uses elements including cells, scaffolds, and growth factors to fabricate functional organs in vitro, is a promising strategy to mitigate the scarcity of transplantable organs. Within recent years, different construction strategies that guide the combination of tissue engineering elements have been applied in solid organ tissue engineering and have achieved much progress. Most attractively, construction strategy based on whole-organ decellularization has become a popular and promising approach, because the overall structure of extracellular matrix can be well preserved. However, despite the preservation of whole structure, the current constructs derived from decellularization-based strategy still perform partial functions of solid organs, due to several challenges, including preservation of functional extracellular matrix structure, implementation of functional recellularization, formation of functional vascular network, and realization of long-term functional integration. This review overviews the status quo of solid organ tissue engineering, including both advances and challenges. We have also put forward a few techniques with potential to solve the challenges, mainly focusing on decellularization-based construction strategy. We propose that the primary concept for constructing tissue-engineered solid organs is fabricating functional organs based on intact structure via simulating the natural development and regeneration processes. PMID- 29701315 TI - Incongruence in molecular species delimitation schemes: What to do when adding more data is difficult. AB - Using multiple, independent approaches to molecular species delimitation is advocated to accommodate limitations and assumptions of a single approach. Incongruence in delimitation schemes is a potential by-product of employing multiple methods on the same data, and little attention has been paid to its reconciliation. Instead, a particular scheme is prioritized, and/or molecular delimitations are coupled with additional, independent lines of evidence that mitigate incongruence. We advocate that incongruence within a line of evidence should be accounted for before comparing across lines of evidence that can themselves be incongruent. Additionally, it is not uncommon for empiricists working in nonmodel systems to be data-limited, generating some concern for the adequacy of available data to address the question of interest. With conservation and management decisions often hinging on the status of species, it seems prudent to understand the capabilities of approaches we use given the data we have. Here, we apply two molecular species delimitation approaches, spedeSTEM and BPP, to the Castilleja ambigua (Orobanchaceae) species complex, a relatively young plant lineage in western North America. Upon finding incongruence in our delimitation, we employed a post hoc simulation study to examine the power of these approaches to delimit species. Given the data we collected, we find that spedeSTEM lacks the power to delimit while BPP is capable, thus allowing us to address incongruence before proceeding in delimitation. We suggest post hoc simulation studies like this compliment empirical delimitation and serve as a means of exploring conflict within a line of evidence and dealing with it appropriately. PMID- 29701316 TI - Calculation of the excited states properties of LH1 complex of Thermochromatium tepidum. AB - Calculation of the excited states properties of pigment complexes is one of the key problems in the photosynthesis research. The excited states of LH1 complex of Thermochromatium tepidum were studied by means of the high-precision quantum chemistry methods. The influence of different parameters of the calculation procedure was examined. The optimal scheme of calculation was chosen by comparison of calculated results with the experimental data on absorption, electronic and magnetic circular dichroism spectra. The high importance of the account of the second excited states of bacteriochlorophylls and of site heterogeneity was shown. (c) 2018 Wiley Periodicals, Inc. PMID- 29701317 TI - Omics research project on prospective cohort studies from the Tohoku Medical Megabank Project. AB - Population-based prospective cohort studies are indispensable for modern medical research as they provide important knowledge on the influences of many kinds of genetic and environmental factors on the cause of disease. Although traditional cohort studies are mainly conducted using questionnaires and physical examinations, modern cohort studies incorporate omics and genomic approaches to obtain comprehensive physical information, including genetic information. Here, we report the design and midterm results of multi-omics analysis on population based prospective cohort studies from the Tohoku Medical Megabank (TMM) Project. We have incorporated genomic and metabolomic studies in the TMM cohort study as both metabolome and genome analyses are suitable for high-throughput analysis of large-scale cohort samples. Moreover, an association study between the metabolome and genome show that metabolites are an important intermediate phenotype connecting genetic and lifestyle factors to physical and pathologic phenotypes. We apply our metabolome and genome analyses to large-scale cohort samples in the following studies. PMID- 29701318 TI - Construction of Bifunctional Co/H-ZSM-5 Catalysts for the Hydrodeoxygenation of Stearic Acid to Diesel-Range Alkanes. AB - Bifunctional Co/H-ZSM-5 zeolites were prepared by a surface organometallic chemistry grafting route, namely, by the stoichiometric reaction between cobaltocene and the Bronsted acid sites in zeolites. The catalyst was applied to a model reaction of the catalytic hydrodeoxygenation of stearic acid (SA). The cobalt species existed in the form of isolated Co2+ ions at the exchange positions after grafting, transformed to CoO species on the surface of the zeolite, stabilized inside the zeolite channels upon calcination in air, and finally reduced by hydrogen to homogeneous clusters of metallic cobalt species approximately 1.5 nm in size. During this process, the Bronsted acid sites of the H-ZSM-5 zeolites were preserved with a slightly reduced acid strength. The as prepared bifunctional catalyst exhibited an approximately 16 times higher activity for the hydrodeoxygenation of SA (2.11 gSA gcat-1 h-1 ) than the reference catalyst (0.13 gSA gcat-1 h-1 ) prepared by solid-state ion exchange and a high C18 /C17 ratio of approximately 24. The remarkable hydrodeoxygenation performance of the bifunctional Co/H-ZSM-5 was owed to the effective synergy between the uniformed metallic cobalt clusters and the Bronsted acid sites in H ZSM-5. The simplified reaction network and kinetics of the SA hydrodeoxygenation catalyzed by the as-prepared bifunctional Co/H-ZSM-5 zeolites were also investigated. PMID- 29701320 TI - Corrigendum: Vicinal Disulfide Constrained Cyclic Peptidomimetics: a Turn Mimetic Scaffold Targeting the Norepinephrine Transporter. PMID- 29701319 TI - Serum carbohydrate antigen 153 and renal function in patients with type 2 diabetes mellitus. AB - OBJECTIVE: The aim of our study was to investigate the correlation between serum carbohydrate antigen 153 (CA153) and renal function in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 184 patients with T2DM were included, and renal function was assessed by the modification of diet in renal disease (MDRD) formula adjusted coefficient of the Chinese people. RESULTS: Serum CA153 concentrations were positively correlated with blood glucose (BG) and glycated hemoglobin (HbA1c) (r = .204, P = .005; r = .165, P = .025) in patients with T2DM. There was a negative correlation between serum CA153 and estimated glomerular filtration rate (GFR) (r = -.229, P = .002) in whole patients with T2DM; similarly, the correlations were observed in both women and men (r = -.228, P = .028 for women, r = -.231, P = .028 for men). Multiple linear regression analysis suggested that serum CA153 was still significantly correlated with estimated GFR (beta = -0.286, P < .001). CONCLUSIONS: Serum CA153 is negatively correlated with estimated GFR in patients with T2DM, and serum CA153 may be a potentially useful clinical biomarker to assess renal function in the study population. PMID- 29701321 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 19/2018. PMID- 29701322 TI - Corrigendum: Iterative C-H Functionalization Leading to Multiple Amidations of Anilides. PMID- 29701323 TI - A Bio-inspired Cu4 O4 Cubane: Effective Molecular Catalysts for Electrocatalytic Water Oxidation in Aqueous Solution. AB - Inspired by the cubic Mn4 CaO5 cluster of natural oxygen-evolving complex in Photosystem II, tetrametallic molecular water oxidation catalysts, especially M4 O4 cubane-like clusters (M=transition metals), have aroused great interest in developing highly active and robust catalysts for water oxidation. Among these M4 O4 clusters, however, copper-based molecular catalysts are poorly understood. Now, bio-inspired Cu4 O4 cubanes are presented as effective molecular catalysts for electrocatalytic water oxidation in aqueous solution (pH 12). The exceptional catalytic activity is manifested with a turnover frequency (TOF) of 267 s-1 for [(LGly -Cu)4 ] at 1.70 V and 105 s-1 for [(LGlu -Cu)4 ] at 1.56 V. Electrochemical and spectroscopic study revealed a successive two-electron transfer process in the Cu4 O4 cubanes to form high-valent CuIII and CuIII O. intermediates during the catalysis. PMID- 29701324 TI - The Hydrolysis of AlN Powder - A Powerful Tool in Advanced Materials Engineering. AB - The tendency for aluminium nitride (AlN) powder to undergo hydrolysis, which can lead to a complete degradation of the material, is unique in metal nitrides. Although this form of hydrolysis has been known for a long time, it is generally considered as a nuisance, because it prevents the aqueous powder processing of AlN-based ceramics. However, careful investigations of the course of hydrolysis, the reaction kinetics and the evolution of aluminium hydroxides have uncovered exceptional possibilities for the exploitation of this naturally driven process in the area of advanced materials engineering. It can be employed as superior synthesis path for hierarchically-assembled, mesoporous alumina powders or coatings consisting of 2D nanocrystalline lamellas. The beneficial surface characteristics of the powder serve as an ideal template for further modifications useful in catalysis, while the powder's flowability enables facile preparation of high-performance hierarchically porous structures. The coatings, on the other hand, are suitable as templates for superhydrophobic surfaces or as adhesive coatings for cementing zirconia dental ceramics. Finally, the hydrolysis assisted solidification (HAS) process has proved to be an important asset in the processing science and technology for fabrication of porous and dense ceramics and nanocomposites. PMID- 29701325 TI - Pediatric maxillofacial trauma: Epidemiologic study between the years 2012 and 2015 in an Israeli medical center. AB - BACKGROUND/AIM: Trauma is the leading cause of morbidity and mortality in the pediatric population worldwide, and Israel is no different in this aspect. Of these injuries, craniofacial trauma is a significant cause of morbidity in the pediatric population. The high occurrence of pediatric trauma is possibly related to a lower perception for the hazards that surround them, combined with the restless and adventurous nature that is typical of children. The aim was to perform a retrospective, epidemiological study on facial trauma in children examined in the emergency room in order to analyze the different patterns in pediatric maxillofacial trauma, to emphasize this data and educate those involved in preventing and treating children's injuries. MATERIALS AND METHODS: The database of pediatric maxillofacial trauma patients younger than 18 years registered at the Department of Oral and Maxillofacial Surgery at the Baruch Padeh Medical Center, Poriya during a period of 4 years (2012-2015) was reviewed and examined. The data collected were analyzed for each year separately and then comparisons and cross sections were made. RESULTS: This study examined 3034 files of pediatric maxillofacial and head trauma patients aged under 18. The comparison of frequency of the injuries between seasons reveals more injuries occur in the summer and 69.3% of the injuries occurred in boys. Average age was 6.5 years, with the most prevalent group being 0-5 years. The most common type of injury was blunt head trauma followed by facial lacerations and dental injuries. Most (84.5%) of the injuries occurred outside the education system. The number of injuries at the Arab villages was higher than in the Jewish villages. CONCLUSION: There is a marked difference in the injured children population with an increase incidence in the Arab child population and children under the age of 6. PMID- 29701326 TI - Cre-Mediated Transgene Integration in Chinese Hamster Ovary Cells Using Minicircle DNA Vectors. AB - Bacterial backbone sequences of conventional plasmid vectors have been reported to exhibit negative effects on transgene expression in mammalian cells, such as cytotoxicity and gene silencing. Minicircle DNA vectors can be employed to overcome these issues and to improve the transfection efficiency because of their smaller size. In this study, transgenes are integrated into the hypoxanthine phosphoribosyltransferase (hprt) locus of Chinese hamster ovary (CHO) cells by the Cre-loxP system using minicircle DNA vectors as transgene donors. The targeted transgene integration efficiency is improved 2-3-fold (~1.4%) using minicircle DNA vectors compared with conventional plasmid vectors. Moreover, clones with expected structures after transgene integration are obtained with a high frequency. When a transgene together with bacterial sequences derived from a plasmid vector is integrated into the hprt locus, the cell growth rate and antibody titer decrease. These results indicate that minicircle DNA vectors are more suitable than conventional plasmid vectors for transgene delivery in recombinant protein production using CHO cells. PMID- 29701327 TI - Vitamin D during pregnancy and offspring body composition: a prospective cohort study. AB - BACKGROUND: Evidence regarding the association between gestational vitamin D status and offspring body composition during childhood is inconsistent. Therefore, we aimed to determine the association between maternal vitamin D and offspring lean and fat mass in the Vitamin D in Pregnancy birth cohort. METHODS: Subjects were mother-child pairs recruited from the Australian-based Vitamin D in Pregnancy cohort study. Mothers were recruited before 16 weeks' gestation and provided a blood sample at both recruitment and at 28-32 weeks' gestation. Serum vitamin D [25(OH)D] was measured by radioimmunoassay (Tyne and Wear, UK). Offspring lean and fat mass were quantified by using dual-energy X-ray absorptiometry (GE Lunar Prodigy, Madison, WI, USA) at 11 years of age. RESULTS: Median maternal 25(OH)D levels were 55.9 (42.2-73.3) and 56.1 (43.6-73.9) at recruitment and 28-32 weeks' gestation, respectively. Maternal smoking was identified as an effect modifier in the association between maternal vitamin D status at recruitment and offspring body composition. In smokers, but not non smokers, serum 25(OH)D status at recruitment was negatively associated with offspring fat mass percentage and positively associated with lean mass (both p < 0.05). There was no association with 25(OH)D status at 28-32 weeks' gestation. CONCLUSIONS: Maternal vitamin D status in early pregnancy, in smokers, is associated with offspring body composition. These important findings warrant confirmation in larger studies and trials. PMID- 29701328 TI - Repeat retropubic suburethral sling procedure is effective for recurrent female stress urinary incontinence. AB - OBJECTIVE: The aim of the present study was to investigate the effectiveness of repeat retropubic suburethral sling for recurrent stress urinary incontinence (SUI) in women. METHODS: A retrospective review was performed of 35 women with SUI who underwent repeat retropubic suburethral sling procedures between May 1994 and November 2014. Treatment outcome was assessed directly or by telephone interview. Sling position and urethral incompetence during straining and coughing after the procedure were evaluated. RESULTS: The overall continence rate after repeat suburethral sling procedures was 60% (21/35). Among the 35 women, 19 underwent a simple retropubic suburethra sling procedure and 16 underwent combined suburethral sling and other pelvic floor surgery; the success rate for these 2 groups was 84.2% (16/19) and 31.3% (5/16; P = .001), respectively. The success rate was 60% in patients with normal detrusor function (n = 18/30) and in those with detrusor underactivity (n = 3/5; P = 1.0). For patients with intrinsic sphincter deficiency and bladder base hypermobility, the success rate was 63.6% (n = 14/22) and 53.8% (n = 7/13), respectively (P = .36). Among the 25 patients with transrectal ultrasound follow-up data, the success rate following placement of the second sling at the bladder neck, proximal urethra, middle urethra, and distal urethra was 50% (2/4), 87.5% (7/8), 36.4% (4/11), and 0% (0/2), respectively (P = .122). CONCLUSION: Repeat suburethral sling procedures for recurrent SUI are safe and effective. The position of the second sling at the proximal urethra resulted in a relatively higher continence rate relative to other sites. PMID- 29701329 TI - Bioprocessing of Recombinant CHO-K1, CHO-DG44, and CHO-S: CHO Expression Hosts Favor Either mAb Production or Biomass Synthesis. AB - Chinese hamster ovary (CHO) cells comprise a variety of lineages including CHO DXB11, CHO-K1, CHO-DG44, and CHO-S. Despite all CHO cell lines sharing a common ancestor, extensive mutagenesis, and clonal selection has resulted in substantial genetic heterogeneity among them. Data from sequencing show that different genes are missing in individual CHO cell lines and each cell line harbors a unique set of mutations with relevance to the bioprocess. However, not much literature is available about the influence of genetic differences of CHO on the performance of bioprocess operations. In this study, the host cell-specific differences among three widely used CHO cell lines (CHO-K1, CHO-S, and CHO-DG44) and recombinantly expressed the same monoclonal antibody (mAb) in an isogenic format by using bacterial artificial chromosomes (BACs) as transfer vector in all cell lines is examined. Cell-specific growth and product formation are studied in batch, fed batch, and semi-continuous perfusion cultures. Further, two different cell culture media are used to investigate their effects. The authors find CHO cell line-specific preferences for mAb production or biomass synthesis that are determined by the host cell line. Additionally, quality attributes of the expressed mAb are influenced by the host cell line and media. PMID- 29701330 TI - Marriage and Family Therapy Students' Experience with Common Factors Training. AB - With the increased empirical and theoretical support for common factors in the psychotherapy literature, marriage and family therapy (MFT) scholars have begun discussing the inclusion of common factors in MFT training. However, there is very little empirical research on common factors training or how to include common factors in MFT curricula. The purpose of this phenomenological study was to investigate MFT students' experience with common factors training. Seventeen master's degree students who received training in common factors participated in the study. Data was comprised of participants' journal reflections and focus group interviews on their experience learning about common factors and how this influenced their work with clients. Participants' responses to the training were overwhelmingly positive and highlighted the ways in which studying common factors enhanced their confidence, understanding of MFT models, conceptual abilities, and clinical practice. Additional results and discussion about incorporating common factors in MFT training are presented. PMID- 29701331 TI - The Correlation Between DsRed mRNA Levels and Transient DsRed Protein Expression in Plants Depends on Leaf Age and the 5' Untranslated Region. AB - The yield of recombinant proteins in plants determines their economic competitiveness as a production platform compared to microbes and mammalian cells. The promoter, untranslated regions (UTRs) and codon usage can all contribute to the yield, but potential interactions among these components have not been examined in detail. Here the effect of two promoters (35SS and nos) and four 5'UTRs on the spatiotemporal expression of DsRed mRNA and the accumulation of DsRed protein during transient expression in tobacco (Nicotiana tabacum) mediated by Agrobacterium tumefaciens is investigated. The authors found that the mRNA levels peaked 2-3 days post-infiltration (dpi), and rapidly declined thereafter, whereas DsRed protein was first detected after ~3 days and concentrations continued to increase until at least 5 dpi. This temporal decoupling of mRNA and protein expression was strongest in the older leaves, which also produced the lowest DsRed yields. The accumulation of DsRed linearly correlated with mRNA levels in all but the youngest leaves, where more DsRed was synthesized per mRNA molecule. This was the case for both promoters, although the nos promoter had a higher protein/mRNA ratio than the 35SS promoter. Furthermore, the type of 5'UTR affected DsRed protein accumulation by 50% starting from similar levels of mRNA. The authors concluded that DsRed mRNA levels are not the limiting factor for DsRed protein expression in plants, but that translation associated processes such as initiation, elongation, and release are bottlenecks that should be addressed in future studies. PMID- 29701332 TI - [4DVisions17 Congress: A milestone for a new age in SPCCTV]. PMID- 29701333 TI - [The Meeting!] PMID- 29701334 TI - [Four perspectives on the same surgical practice]. PMID- 29701335 TI - Survival After Bilateral Internal Mammary Artery In Coronary Artery Bypass Grafting: Are Women at Risk? AB - INTRODUCTION: To compare survival and safety of BIMA versus SIMA CABG between males and females at our tertiary care center. METHODS: Single-center retrospective cohort including consecutive patients with at least 2 left coronary system (LCS) vessel disease who underwent isolated CABG with at least 1 IMA conduit and a minimum of 2 conduits targeting the LCS between 2004 and 2013. All cause mortality was the primary outcome, secondary outcomes were in-hospital mortality and reoperation due to sternal wound complications (SWC). Kaplan-Meier analysis after inverse probability weighting using propensity score (IPW) was used to compare BIMA and SIMA CABG amongst genders. Results were confirmed by subgroup analysis. RESULTS: BIMA CABG was performed in 39% out of 2424 eligible procedures and in 27% of 460 females. No differences were found in survival after BIMA and SIMA CABG (median and maximum follow-up of 5.5 and 12 years, respectively) but a statistical interaction was observed with gender (P<0.001). Females who underwent BIMA CABG showed higher mortality (weighted HR in females subset: 3.16; 95%CI: 1.56-6.29, P=0.001). BIMA CABG showed a higher incidence of reoperations due to SWC (IPW adjusted model OR: 1.74; 95% CI: 1.16-2.60) that were mostly ascribable to males (weighted OR in males: 3.10; 95%CI: 1.74-5.51, P<0.001). CONCLUSION: Females may experience higher mortality after BIMA CABG which should be further explored. PMID- 29701336 TI - CABG: To CBP or Not To CBP - A Propensity Score Matched Survival. AB - INTRODUCTION: Over the past 3 decades two main strategies have been employed for surgical coronary revascularization (CABG): on- pump CABG with cardioplegia (ONCAB) and off-pump CABG (OPCAB). The objective of this study is to evaluate the short-term and long-term survival of the two strategies. METHODS: This study consists of 8-year cohort, retrospective single-center analysis with an intention to-treat design. 2954 patients underwent CABG (OPCAB n=2123; ONCAB= 831) for CAD. As these two groups were statistically different regarding several parameters, a propensity score model was applied and a more homogeneous cohort (n= 1441; OPCAB= 885; ONCAB=556) was analyzed. Univariate analysis, Kaplan-Meier curves and when appropriate a multivariate analysis was applied to the overall group and 6 subgroups: 2 vessel disease, 3 vessel disease, left stem disease, diabetic patients; patients with creatinin clearance bellow 50ml/min; and patients with body mass index above 30 kg/m2. RESULTS: Our study show: No difference in 30-days mortality, long-term survival (mean 71 months follow-up), AKY and stroke rates; Higher rates of bypass per patient (2.3% vs 2.8%, p<0,001) and complete revascularization (76% vs 83%) in the ONCAB group; Fewer re-operation for bleeding (0.8 vs 3.8%, p<0.001), fewer peak troponin>19mg/ dl (4.7% vs 9.9%, p<0,001), and fewer IABP use (1.5% vs 3.3%, p=0,027) in the OPCAB group. Sub group analysis showed no difference between the two groups with exception of a higher rate of troponin peak >19mg/dl adjusted for CAD extension in the left-main stem disease group undergoing ONCAB (OR=2,3 +-0.8 p=0,018). CONCLUSION: The major randomized controlled trials comparing the two strategies show: No difference in 30-days mortality, 1-year survival, AKY and stroke rates; Less re revascularization rates and higher bypass per patient and bypass patency with ONCAB. Despite the large volume of evidence generated around both on-pump and off pump CABG strategies, studies fail to demonstrate clear benefit of either strategy regarding mortality and most common complications. Our results are similar of those found in the literature as neither strategy has unequivocal superior results. ONCAB shows consistently higher rates of complete revascularization and higher number of grafts. OPCAB shows lesser troponin levels suggestive of less myocardial damage. Major limitations include: analysis not matched for surgeon performance; cardiac related events, re-revascularization need and graft patency not evaluated; isolated use of troponin levels for evaluation myocardial damage. PMID- 29701337 TI - The First 24 Robotic Surgeries of Hospital da Luz. AB - INTRODUCTION: Robotic assisted thoracic surgery (RATS) has been growing all over the world, presenting itself as an improvement over video-assisted thoracic surgery (VATS). The main advantages are the precision of the movements, as well as the three-dimensional vision with the consequent perception of the depth of the surgical field. Thus, technically more difficult procedures, such as anatomic segmentectomies and bronchoplastic resections, are facilitated. This surgical approach also improves the quality of mediastinal lymph node dissection, extremely important in lung cancer patients. OBJECTIVE: Analysis of the first 24 robotic thoracic surgeries performed at Hospital da Luz. METHODS: All robotic thoracic surgeries performed at Hospital da Luz from 2/6/2016 to this date were evaluated, concerning diagnosis, type of surgery, chest drainage time, hospitalization time, morbidity and mortality. RESULTS: Twenty-four RATS were performed, with patients having a mean age of 60.5 (39-76) years, eleven of them being male. All surgeries were performed with 3 ports of 8mm and a 12mm port for the assistant. Eighteen surgeries of pulmonary resection (75%), five surgeries for mediastinal lesions (20.8%), and one for intercostal nerve harvest for reinnervation of the brachial plexus, were performed. In the pulmonary surgeries, eleven were lobectomies (61.1%), five were anatomic segmentectomies (27.8%) and two wedge resections (11.1%). Neoplastic disease was the reason for the sixteen lung anatomic resections, two for metastatic disease and fourteen for primary lung cancer. In each case, a systemic lymph node dissection was performed. All procedures were performed without intra- or postoperative complications. Mean drainage time was 3.4 days [2-6], and mean hospitalization time was 4.8 days [3 8]. There were no mortality or major morbidity. There were two patients with prolonged air-leak up to 6 days. The morbidity after discharge was 12.5%, consisting of an apical pneumothorax that resolved spontaneously, a basal pleural effusion that resolved with outpatient thoracentesis, and a respiratory infection treated with antibiotic. CONCLUSION: The overall evaluation of this technique is still precocious, but allows to affirm that an experienced surgeon in vats surgery has a faster learning curve with this new approach. The innovation and development of new techniques in thoracic surgery are fundamental in order to allow more effective treatments, with less pain and, when possible, lung parenchyma sparing surgeries in patients with early neoplastic lung disease. PMID- 29701339 TI - Surgical Treatment Options of Subclavian Artery Pseudoaneurysms: A Case Report and Litterature Review. AB - INTRODUCTION: Subclavian artery pseudoaneurysms are rare and occur mostly as a consequence of an inadvertent arterial puncture during central venous catheterization, endovascular therapeutic procedures or after penetrating or blunt trauma. They usually have a late clinical presentation, with pain, swelling or other compressive symptoms. The optimal treatment in this situation is still a matter of debate. The authors describe a case of late presentation of subclavian artery pseudoaneurysm after transjugular hepatic biopsy and discuss the several options for treatment. METHODS: A 41-year-old woman was admitted in our hospital due to symptomatic subclavian artery pseudoaneurysm. She underwent a biopsy 20 years earlier for an undetermined febrile syndrome. The pseudoaneurysm was diagnosed during investigation of a right non-pulsatile cervical mass that was associated to cervical edema and Horner's syndrome. CTA revealed a pseudoaneurysm of right subclavian artery with 35 mm of diameter and an arteriovenous fistula to jugular vein which presented with significant enlargement. Additionally, the vertebral venous plexus was also ingurgitated. The pseudoaneurysm caused a left shift of the thyroid, common carotid artery and trachea. The vertebral artery arised 4 mm distal to pseudoaneurysm. RESULTS: After a multidisciplinary evaluation including vascular surgery, neuroradiology and cardiac surgery, she underwent surgical exclusion of false aneurysm and arteriovenous fistula via partial upper sternotomy with cervicotomy. Care was taken to preserve the vertebral artery. There was a complete resolution of compressive symptoms and there were no complications during the first year of follow up. CONCLUSION: Subclavian artery pseudoaneurysms impose a major surgical challenge, especially when originating from the proximal third. Large pseudoaneurysms may rupture or produce signs and symptoms of compression. If intervention is considered necessary, several options are available: open surgical resection and vascular reconstruction, endovascular exclusion, stentgraft implantation or ultrasound guided thrombin injection have all been described. The choice of procedure should be tailored to the patient, based on comorbidities, clinical presentation and anatomic characteristics. When compressive symptoms exist, an open approach is advised. However, because of their location, surgical exposure of the pseudoaneurysm may be technically difficult, requiring a sternotomy or a clavicular resection for adequate exposure. An endovascular approach demands an adequate landing zone and absence of severe tortuosity. When arteriovenous fistulae and enlargement of vertebral veins are verified, with subsequent increase in venous pressure, there is a risk of cervical radiculopathy (2-4%). This case report describes an uncommon presentation of subclavian pseudoaneurysm and exemplifies the complexity of their treatment. PMID- 29701338 TI - Arterial Vascular Complications in Peripheral Venoarterial Extracorporeal Membrane Oxygenation Support. AB - INTRODUCTION: Extracorporeal membrane oxygenation (ECMO) has been evolved as a life-saving measure for patients requiring emergent support of respiratory and cardiac function.The femoral artery is the standard site for vascular access when initiating adult venoarterial (VA) ECMO.Cannulation-related complications are a known source of morbidity and it has been speculated that patients undergoing ECMO via femoral arterial cannulation are more likely to develop peripheral vascular complications (up to 70%). In patients with severe peripheral arterial disease (PAD) these risks are even higher and its presence may be considered a relative contraindication for femoral artery cannulation. METHODS: Retrospective institutional review of patients requiring ECMO (January 2011-August 2017).The primary outcome of this study was to investigate the prevalence of cannulation- related complications on VA ECMO and to determine its effect on patient morbimortality.We evaluated demographics and co-morbidities data.Patients were divided into two groups (complications present VS not present) and statistic analysis was performed to determine the impact of different variables such as co morbidities,cannulation strategy and time on ECMO in each group.Operative reports were reviewed to analyze the surgical procedures implied for treating vascular complications. RESULTS: Eighty-two patients underwent ECMO therapy during the period of study, 56,1% were male with a mean age of 55,8 years.The median time on the ECMO device was 5,5 days.The VA mode was used in 61 patients, 56 with peripheral cannulation.Femoral arterial access was established in 52 patients (73% percutaneously).Vascular complications were observed in 28,6% of the VA femoral ECMOs:12 acute limb ischemias and 3 major hemorrhages. At the time of femoral cannulation, distal peripheral catheter (DPC) was placed in 5 patients and none developed subsequent limb ischemia.For those who developed limb ischemia, several interventions were performed: DPC placement in 9 cases, fasciotomy in 4 and 2 major amputations. Thirty patients underwent arterial cannulas open surgical removal:8 underwent balloon catheter trombectomy and 5 needed femoral reconstruction.There was an association between PAD (p=0,03) and ischemic cardiopathy (p=0,02;OR 4,5) with the present of vascular complications after ECMO implantation.VA femoral ECMO mortality was 69,2% (n=36).Vascular complications after ECMO support are not associated with higher mortality rates (p>0,05). CONCLUSION: Cannulation of femoral vessels remains associated with considerable rates of vascular events (28.6%).PAD and ischemic cardiopathy are associated with vascular complications in this form of cannulation.Physical examination and the assessment of ankle-brachial index before ECMO implantation is therefore recommended.Improved efforts at preventing these complications need to be developed to avoid additional morbidity in an already critical patient population. PMID- 29701340 TI - Comparaison Between Endovascular Approach and Aorto-Bifemoral Bypass for Tasc D Aorto-iliac Disease Patients Treated between 2011-2017. AB - INTRODUCTION: In the last few years, endovascular approaches have been demonstrating remarkable results on the treatment of aortoiliac TASC D lesions. However, the results remain conflictuous and proper evidence regarding the best treatment option for this group of patients is still lacking. Through this work, we aim to compare patency, cost-effectiveness and quality of life in patients successfully treated by these two approaches. METHODS: Patients with TASC D aorto iliac disease, from two independent Vascular Surgery Centers, treated either by open surgery and endovascular intervention between 2011- 2017, were retrospectively analyzed and consecutively included (n=59). Patients were then divided in 2 groups: Open Group (OG), in which aorto-bifemoral bypass was performed (n=27); and Endo Group (EG), in which an endovascular approach was preferred (n=32). Surgical decision between these two procedures was made individually by the surgeon, according to clinical criteria. Baseline characteristics (age, diabetes, smoking history, chronic kidney disease and rutherford grade of ischemia) were also evaluated. Quality of life (QoL) was later assessed by means of three physical and telephonic validated questionnaires (EQ-5D-5L; peripheral artery questionnaire; walking impairment questionnaire). RESULTS: There were significant statistical differences between the OG and EG, regarding mean age (62 vs 65 years, p=0,044) and tobacco use (100 vs 75%, p=0,05), but both groups were comparable for the remaining baseline characteristics. Technical success was achieved in 100% of the cases of OG, while only in 65% was it obtained in the EG (p=0,001). Consequently, re-intervention rate was higher in the later. Regarding infection rate, it was significantly higher in the OG (11.1% vs 0%, p=0,05). No differences between groups were found regarding limb salvage (96,3% vs 100%, p> 0,05). Cost-analysis revealed that endovascular procedures were significantly more expensive than open interventions (1053? vs 2080?, p=0,001), with similar inpatient lengths. Nonetheless, ICU occupation was significantly lower in the EG (3,8 vs 0,05 days, p=0,05). No differences between groups were found in the questionaries of QoL (p>0,05). CONCLUSION: Despite higher rates of technical success in the OG, patency and limb salvage seems quite similar between the two techniques. Also, endovascular approach of the aortoiliac sector remains significantly less invasive than the conventional alternative. Based on this, and despite the higher success rate of open surgery, shouldn't we give an opportunity to the "endovascular first" approach? PMID- 29701341 TI - Outcomes After Catheter Direct Thrombolysis for Acute Limb Ischaemia - Single Center Experience. AB - INTRODUCTION: The aim of this study is to evaluate the outcome of catheter directed thrombolysis (CDT) in acute lower limb ischaemia depending on the underlying etiology. METHODS: Retrospective single center analysis of electronic clinical data on patients with acute lower limb ischaemia treated with CDT. Between January 2011 and September 2017, 128 procedures in 106 patients were included. The etiology of ischaemia was native artery thrombosis in 39 procedures (30,5%), PTFE graft thrombosis in 56 (43,8%), intra-stent thrombosis in 11 (8,6%), emboly in 9 (7%), popliteal aneurysm thrombosis in 9 (7%), vein graft thrombosis in 2 (1,6%) and popliteal artery entrapment in 2 (1,6%). RESULTS: Median follow-up time was 14 months [range: 6-31], during which 22% needed further intervention. The need for reintervention was 27,6% in native artery thrombosis group, 65,2% in PTFE graft thrombosis group, 18,2% in intra- stent thrombosis group. No reinterventions occurred neither in popliteal aneurysm group or emboly group. Amputation free survival was 83,3% (SE 4,6%) at 27 months and cumulative incidence of death was 10,1% (SE 5,2%) at 32 months, with no differences between the groups. CONCLUSION: Intra-arterial thrombolytic therapy achieves good mid-term clinical outcomes, reducing obviating the need to open surgical treatment in many patients. These results support the choice for CDT as a valid option in acute limb ischaemia of several etiologies. PMID- 29701342 TI - Endovascular Removal of Foreign Bodies. AB - INTRODUCTION: Intravascular or catheter embolization of a foreign body, either by fracture or migration, is a rare condition, occurring in approximately 1%. This study is focused on the migration of catheters since they represent the majority of cases of embolization. We present one of the largest published series of removal of foreign bodies with endovascular techniques. The objective of the present study is to demonstrate the different locations where foreign bodies, in most cases catheters, can reach, the technique used to remove them and the affected population. METHODS: This is a 9 years retrospective study in which we report the cases of foreign bodies removal performed by an endovascular approach between 2009 and 2017 in our institution. It includes 53 patients: 28 women and 25 men. The average age was 58 years (ranging from 15 to 87 years). The catheters were implanted by a heterogeneous group of professionals. RESULTS: Thirty three totally implantable catheters (Implantofix (r)), sixteen peripheral inserted central catheter, three Guide Wires, one angioplasty balloon and one Amplazer vascular plug were extracted. The most common sites for the lodging of one of the ends of the intravascular foreign bodies were the right atrium (35,8%) the superior vena cava (11,3%) and the right ventricle (11,3%). In 98,1% of the cases, only one venous access was used for extraction of foreign bodies, and in 96,2% of the cases the right femoral access was used. The loop-snare technique was used in 45 cases (84,9%) and in 8 cases a basket was the option. The most common cause of catheter embolization was the disconnection between the catheter and the port during the surgery for its removal, which occurred in 55,1% of the cases. Fracture of totally implantable catheters occurred in 12,2%. The fracture of a peripheral inserted central catheter represents 32,7% of cases of embolization. Atrial fibrillation, occurred in 8 cases. The mortality rate during the procedure was zero. Technical performance was 100% successful. CONCLUSION: Percutaneous intervention for removal of intravascular foreign bodies is currently the best treatment option for patients. It is a minimally invasive, procedure, with low complication rates. Embolised material can be quite safely retrieved, and presents an attractive alternative to surgical removal of these devices. However, this work should serve as a consideration about the safety of the removal of catheters as well as their quality in order to reduce this type of complications. PMID- 29701343 TI - Influence of Interhospital Transfer on Outcomes of Symptomatic and Ruptured Abdominal Aortic Aneurysms. AB - INTRODUCTION: Symptomatic or ruptured abdominal aortic aneurysms (rAAA) maintains a high mortality index despite technical advances in its treatment. The influence of patients' geographic location on rAAA outcomes, when the rupture occurs or when the AAA becomes symptomatic, has not been a commonly studied issue. Due to the lack of research on this matter, the impact of interhospital transfer on mortality is ambiguous. OBJECTIVE: Evaluate the influence of the geographic location of patients with symptomatic AAA or rAAA on AAA mortality. METHODS: Retrospective review of all cases of symptomatic AAA and rAAA submitted to surgery in a tertiary institution, between January 2011 and August 2017. The main outcome was in-hospital mortality. Secondary outcomes were admission to intensive care unit (ICU), length of ICU and hospital stay, type of repair and anesthesia and weekend presentation. Data was submitted to univariable analysis and logistic regression. Statistical significance was considered if the p value was <0.05. RESULTS: During the defined period of 80 months, a total of 135 patients were admitted with the diagnosis of symptomatic or rAAA and submitted to surgery. Most patients had a ruptured AAA (90.4%, n=122), while symptomatic AAA represented a minority (9.6%, n=13). All patients (91.1% male gender, mean age 74+/-10 years) were submitted to surgery, 83 (61.5%) by endovascular repair and 52 (38.5%) by open repair, 30.4% with local anesthesia and sedation (n=41), all in the endovascular group. 92 patients (68.1%) were transferred from other hospitals, with a mean distance of 113+/-88 km. In this cohort, in-hospital mortality was 31.5% in transferred patients and 34.9% in not transferred patients. Subgroup analysis revealed that there were no significant differences between transferred and not transferred patients' groups concerning main outcome (p=0.35), baseline characteristics (age and gender), type of surgery and anesthesia, weekend presentation, ICU admission, length of ICU and hospital stay. Logistic regression analysis revealed that the variables associated with mortality were female gender (odds ratio [OR] 2.28; 95% confidence interval [CI] 1.40-3.70; p<0.01), open repair (OR 2.79; 95% CI 1.68-4.63; p<0.01) and general anesthesia (OR 9.16; 95% CI 2.33-36.06; p<0.01). CONCLUSION: Our study revealed that transfer of patients for urgent repair of AAA was not associated with an increased mortality. The hypothetical increased mortality due to transfer might have been compensated by endovascular treatment and local anesthesia in some cases. Further studies must be carried out, particularly comparing endovascular and open repair in emergency setting. PMID- 29701344 TI - Median Arcuate Ligament Syndrome - Literature Review and Case Report. AB - INTRODUCTION: Median arcuate ligament syndrome (MALS) or Dunbar syndrome is a rare clinical entity characterized by celiac trunk compression by median arcuate ligament and variable gastrointestinal symptoms (postprandial epigastric pain, nausea, weight loss, anorexia and diarrhea). However, some degree of radiographic compression is observed in 10%-24% of asymptomatic patients. Besides the extrinsic vascular compression, MALS has a multifactorial etiology and it has been suggested as a neurogenic disease resulting in altered sensation and pain from the somatic nerves in the splanchnic plexus. MALS is a diagnosis of exclusion, so other causes must be excluded. Treatment options include release of median arcuate ligament (open, laparoscopic or robot-assisted) and open vascular reconstruction. Endovascular treatment is currently used only as adjuvant procedure after surgical approach, in refractory cases with residual stenosis of celiac trunk. OBJECTIVE: To report a case of MALS and to review current literature. METHODS: The authors report a clinical case and present a literature review using PubMed with the terms "median arcuate ligament", "Dunbar syndrome" and "MALS treatment" as major topics. The bibliography of relevant articles has been checked to identify other significant papers. RESULTS: A 34-year-old woman, previously healthy, recurred to a General Practitioner with a recurrent epigastric pain, exacerbated by ingestion, without relieving factors, in the previous 6 months. Patient also reported anorexia and unprovoked weight loss of 8Kg over 3 months. Physical examination was normal. Other gastrointestinal pathologies were ruled out. Computed Tomography Angiography (CTA) abdomen revealed a focal 80% stenosis of the celiac trunk, located 8mm from its origin in aorta and a post- -stenotic enlargement of 9mm. An open decompression of the celiac trunk was performed. Through an 8cm median supraumbilical laparotomy, supraceliac abdominal aorta was approached. The compressive band across the celiac trunk was identified and cut. Further dissection was performed until the celiac artery became completely exposed and its branches identified. The postoperative period was uneventful and the patient was discharged 5 days later, with normal gastrointestinal transit and without recurrence of the abdominal pain. 1 month later, the patient remained asymptomatic. A long-term follow-up with annual duplex scan and clinical evaluation must be done, in order to evaluate the need of a revascularization due to persistent stenosis or aneurysmal degeneration. CONCLUSION: MALS diagnostic and therapeutic approach must be patient focused, bearing in mind the multiple clinical presentation and treatment options. Open surgical decompression of median arcuate ligament is the base of therapy. PMID- 29701345 TI - Emergency Nightmares - Rupture of Type III Thoracoabdominal Aneurysm. AB - : Introduction The rupture of thoracoabdominal aneurysms (rTAA) represents one of the major challenges to the vascular surgeon. Recent developments in the endovascular armamentarium and the high mortality from open surgery make endovascular treatment an attractive option. Devices to be used in an emergency environment should be "off-the-shelf" and include, among others, EVAR snorkel/chimney and branched endoprosthesis (T-branch, Cook(r)). METHODS: We describe the case of a 70-year-old patient who was admitted to the emergency room due continuous low back pain with 3 days of evolution. RESULTS: The tomographic computer angiography showed a type III thoracoabdominal aneurysm, with a transverse maximum diameter of 75x81mm in the infrarenal aorta and an exuberant hematoma in the left retroperitoneum, but no active extravasation of the contrast was observed (Figure 1). There was still marked tortuosity and moderate iliac calcification. It was decided to place a branched endoprosthesis (34 mm diameter at the top and 18 mm at the bottom). The branched endoprosthesis was extra corporeally oriented, and introduced through a right femoral approach. The final position was verified with the digital subtraction angiography in anteroposterior incidence, ensuring that the distal border of each branch was 1.5 to 2 cm above the target vessel and that the stent marks presented the desired position. After the endoprosthesis was opened, the branches are catheterized by the left axillary access, however, it was verified that the endoprosthesis had an antero posteriorly inverted implantation. It was possible to catheterize the superior mesenteric artery and the left renal artery (celiac trunk occlusion was documented intraoperatively); occlusion of the remaining endoprosthesis branches was performed with an Amplatzer. The patient evolved with multiorgan dysfunction and died at 24 hours post-operatively. CONCLUSION: Implantation of an off-the shelf branched endoprosthesis requires specific anatomical criteria such as aortic diameter> 25mm to allow catheterization of the vessels, the possibility of incorporating each target vessel at a 90o angle in relation to each branch and visceral arteries with a diameter between 4 and 8 mm. Anatomy review is important to understand the lengths and positions of the branches. It should be borne in mind that it is possible that the device might have to be rotated during implantation to better align the marks and that both incidences (anteroposterior and profile) may be useful in confirming the position, something that should be thoroughly pursued to safeguard a correct implantation regardless of the initial stent position in your delivery system. PMID- 29701346 TI - Endovascular Solutions for Thoracic Aortic Aneurysms with Challenging Anatomies. AB - INTRODUCTION: The suitability of the proximal and distal landing zones remains one of the main limitations to thoracic endovascular aortic repair. The advent of custom-made scalloped stent grafts widened the endovascular options in some challenging anatomies. METHODS: The authors present three cases of thoracic aortic aneurysm (TAA), with three different hostile anatomies, successfully treated with custom-made scalloped stent grafts. RESULTS: Case1: Male patient, 47 years old, no relevant medical history. Angio-CT revealed a 54mm post- traumatic TAA, extending distally from the origin of the left subclavian artery. Inadequate sealing in Ishimaru zone 2 was evident. The patient was sequentially treated by means of a carotid-subclavian bypass followed by TEVAR with proximal scallop to the left common carotid artery. Proper proximal sealing was obtained. Case2: Male patient, 76 years old, diagnosed with a 65mm diameter TAA, involving the origin of the left subclavian artery. Presence of a bovine trunk, and inadequate landing zone distally to it, were noted. The patient was sequentially treated by means of a carotid-subclavian bypass followed by TEVAR with proximal scallop to the bovine trunk. Proper sealing in Ishimaru zone 2 was granted. Case3: Male patient, 77 years old, multiple comorbidities. Angio-CT revealed a 59,3mm saccular aneurysm of the distal thoracic descending aorta, extending proximally from the origin of the celiac trunk. Good collateralization was observed after celiac trunk occlusion test. Proper distal seal was obtained by means of selective embolization of the celiac trunk followed by TEVAR with distal scallop to the superior mesenteric artery. All procedures were uneventful, with no reported endoleaks, birdbeaks, migrations or re- interventions. There are no reported complications at 1-year follow-up. CONCLUSION: Custom-made scalloped thoracic stentgrafts are an accessible, reproducible and safe therapeutic option when dealing with hostile descending thoracic anatomies, and should be considered as a minimally-invasive effective solution in selected cases. PMID- 29701347 TI - Giant Ruptured Common Iliac Artery Infected Aneurysm. AB - INTRODUCTION: Saccular mycotic aorto-iliac aneurysms are extremely rare and when presented with ruptured, they are an important life- threatening condition. METHODS: We present a 52 years old male transferred from another Hospital and admitted to the emergency room with a ruptured iliac artery aneurysm. RESULTS: He complained of persistent fever and abdominal discomfort that swiftly established as hemorrhagic shock. Imagiological study with angioCT revealed a ruptured left common iliac artery saccular aneurysm with 90mm. The patient was instantaneously and successfully submitted to endoaneurismorraphy, common and external iliac artery ligation and construction of an extra anatomic bypass, right to left femoro-femoral bypass. Blood culture revealed a Streptococcus anginosus and the patient received appropriate targeted antibiotics. Post-operative period was uneventful and the patient discharged ten days after admission. He has now eleven months of follow up with no intercurrences. CONCLUSION: Long term antibiotics along with aggressive surgical debridement of the infected tissue and vascular revascularization with an extra anatomic bypass remain the most definitive solution while endovascular aneurysm repair may generally constitute a bridge life-saving procedure in mycotic infected aneurysms. Even though surgical approach carries a relative risk of perioperative morbidity it is a feasible and durable solution for extreme situations like the one here described. PMID- 29701348 TI - In the Current Era of Endovascular Surgery, What is the Role of Axillofemoral Bypass? AB - INTRODUCTION: Nowadays, axillofemoral bypass is viewed as an end-of-line solution for lower limb revascularization, owing to its classically described poor long term patency, and recent advances in endovascular options for patients with complex aortoiliac anatomy not suitable for open reconstruction. There is a marked difference in patient profiles in published series of axillofemoral bypass, reflecting changing procedures indications due to technical innovations. The objective of this study is to determine the contemporary profile of patients treated with axillofemoral bypass and their outcome. METHODS: Patients who underwent axillofemoral bypass surgery in a tertiary hospital from April 2011 to September 2017 were identified. Surgical indication, patency, amputation and death rates were recorded. Patients were grouped in axillouni vs axillobifemoral, 1st revascularization procedure vs reintervention, and primary aortoiliac occlusive disease vs primary aneurysmal disease, and were compared using Kaplan Meier survival analysis. RESULTS: 54 patients were included. 80% underwent an axillobifemoral bypass. Median age was 67 years; 96% were male. The most prevalent cardiovascular risk factors were HTA (81%) and history of smoking (76%). Primary vascular disease was aneurysmal in 24% of patients. The remaining group had peripheral occlusive arterial disease. In 53%, axillofemoral bypass was the first revascularization performed (naif group). On these, indications for this procedure were aorto-iliac occlusive disease (89%) and AA thrombosis (19%). In patients previously submitted to revascularization (47%), the most common first procedures were aortobifemoral bypass (56%), femoro-femoral bypass (44%) and EVAR (36%). Indications for axillofemoral bypass on this group were: prosthesis thrombosis (64%), secondary aorto-enteric fistulae (28%) and prosthesis infection (8%). Primary patency of axillofemoral bypass was 93% at 1 month and 80% at 5 years (Graphic 1). Differences were not significant regardless the vascular surgery status (naif vs reintervention), but axillobifemoral bypass and aneurysmal disease groups had a higher patency than axillounifemoral bypass and occlusive disease groups, respectively. No patient with aneurysmal disease required amputation over a 5-year follow-up. In primary occlusive disease group, 88% of patients were free-of-amputation at 1 month and 83% at 5 years. Patients who underwent this procedure had a survival rate of 78% at 1 month and 59% at 5 years (Graphic 2). No major difference was recorded between study groups. CONCLUSION: Axillofemoral bypass, although being an increasingly uncommon procedure, still allows acceptable rates of patency and limb salvage. As patients with aortoiliac disease usually have multiple comorbidities and a short life- expectancy, axillofemoral bypass is attractive owing to its less invasive character. PMID- 29701349 TI - Pulmonary Hypertension in Valvular Heart Disease Surgery: Risk and Prognosis. AB - INTRODUCTION: Left heart disease is the most common cause of pulmonary hypertension (PH), and when present is associated with higher surgical risk. OBJECTIVES: Analyze the effect of PH severity on morbidity, early and late mortality in patients with pulmonary artery systolic pressure (PASP) over 30mmHg that underwent valvular heart surgery. METHODS: Retrospective observational study including all patients with PH, defined as PASP>30 mmHg that underwent isolated valvular heart surgery, between 2007 and 2016. Exclusion criteria were: active endocarditis, congenital heart disease, transcatheter aortic valve implantation, reoperations and emergent surgery. The study population included 607 patients with a mean age of 69.6 years and a mean PASP of 52.5 mmHg. Mean follow-up for all-cause mortality was 4.4(0-11) years in 99.7% of patients. MACCE (Major Adverse Cardiac and Cerebrovascular event) was defined as at least one of the following: in-hospital mortality, stroke, post-operative myocardial infarction, severe arrhythmia or multiple organ failure. PASP was evaluated as a continuous variable. Simple and multivariable logistic regression was performed to evaluate the in-hospital mortality and MACCE. Cox regression was used for long term follow up and one-sample log-rank test for comparison with age adjusted general population. RESULTS: The in-hospital mortality was 3.2% and PASP was an independent predictor on univariable analysis (OR:1.06; 95%CI:1.03- 1.09; p<0.001). On multivariable logistic regression PH remains an independent predictor of in- -hospital mortality (OR:1.08; 95%CI:1.04-1.12; p<0.001) in addition to age (OR:1.08; 95%CI:1.01-1.17; p=0.044). MACCE was observed in 11.4% and PASP was an independent predictor on univariable analysis (OR:1.03; 95%CI:1.01- 1.04; p<0.001). On multivariable logistic regression PASP remains an independent predictor of MACCE (OR:1.02; 95%CI:1.01-1.04; p=0.011) as well as hemodialysis (OR:7.16; 95%CI:1.73-29.63; p=0.007). The independent predictors of long term mortality were male gender (p=0.011), older age (p<0.001), higher body mass index (p=0.013), urgent surgery (p=0.027), pulmonary disease (p=0.042) and more than one valve procedure (p=0.004 for 2 valves and p=0.006 for 3 valves). PASP was not an independent predictor of long term mortality (p=0.142). Compared with an age adjusted general population, patients with PH had a significantly lower survival rate(p<0.001), more evident 4 years after the procedure. CONCLUSIONS: Higher PASP is a risk factor for in-hospital mortality and MACCE, but there was no significant impact on long term mortality. PMID- 29701350 TI - Rapid Deployment Aortic Valves in Elderly Patients: Age is not just a Number. AB - INTRODUCTION: Aortic valve stenosis (AS) is the most common valvular pathology in the elderly. Surgical aortic valve replacement (AVR) remains the gold-standard of treatment for AS. However, emerging transcatheter aortic valve replacement (TAVR) has become an increasing alternative to surgery. In a recent survey from the European Society of Cardiology, 9,4% of the physicians stated that age was the main reason to propose for a TAVR instead of surgery. METHODS: We performed a single-center retrospective study including 353 patients (149 patients over 80 years-old, compared to 204 patients between 60-69 years-old) consecutively submitted to AVR between January 1, 2013, and December 31, 2016, to compare the results of both groups in AVR surgery and how we can improve surgery outcome in older patients. RESULTS: The demographic and clinical characteristics between the two groups were similar. There were no significant differences in survival between the two groups at 30 days (96,57% 60-69yo vs. 96,64% >80yo), 12 months (89,57% 60-69yo vs. 93,51% >80yo) and 24 months (85,92% 60-69yo vs. 87,62% >80yo). The postoperative complication rates were similar in the two groups, excluding the rate of post-operative atrial fibrillation, higher in the >80 years old group (29,06% vs. 17,28%, p=0,0147). ICU and average hospital length of stay was similar between the two groups (p>0,05). In all patients, Euroscore II was directly correlated to intensive care unit length of stay (p=0,0044). In all patients, extracorporeal circulation and aortic cross-clamp times were directly correlated to invasive ventilation time (p=0,0254 and p=0,0101) and to post- operative bleeding (p=0,0002 and p=0,0015). However, in the subgroup analysis, aortic cross-clamp time was directly correlated to ventilation time (p=0,0397) and to intensive care unit length of stay (p=0,0493) in the >80yo patients, but that was not verified in the 60-69yo patients (p=0,0942, p=0,3801, respectively). CONCLUSION: Survival rates are similar between the two groups, with similar post operative complications. Post-operative atrial fibrillation and the use of blood and blood products are more common in patients over 80 years-old. In older patients, lower periods of extracorporeal circulation and aortic cross- -clamp much be achieved to reduce invasive ventilation time, post-operative bleeding and ICU and hospital length of stay, improving post-operative recovery. It has been shown that rapid deployment aortic valves reduce extracorcoporeal circulation and aortic cross-clamp times, so their use in elderly patients must improve surgery recovery and outcome. PMID- 29701351 TI - Heart transplantation: Early Results of Two Different Regimes of Immnunosuppression. AB - INTRODUCTION: The management of induction and maintenance immunosuppression therapy after heart transplantation (HT) remains a controversial issue. The dosage and the timing has been a changing target. We aimed at evaluate the incidence of acute cellular rejection (ACR) [>=1R grade], major infection and survival in first year after HT in patients receiving two different induction immunosuppression regimes and with a reduction in intensity of triple maintenance immunosuppression dose. METHODS: From November-2003 to June-2016, 317 patients were submitted to HT. After excluding those with pediatric age (n=8), those with previous renal or hepatic transplantation (n=2), those submitted to retransplantation (n=2), patients with early death without endomiocardial biopsy (n=10) and those in a transition maintenance regime (n=26), the study population resulted in 269 patients. These patients were divided in two groups: patients receiving the previous regime of two doses of basiliximab (group A, n=211) and those receiving a single dose of basiliximab (group B, n=58). All the patients were treated with a maintenance standard triple immunosuppressive regimen of corticosteroids, an inhibitor of calcineurin and mycophenolate mofetil but more immunosuppressive load in group A. RESULTS: Mean age of the recipients (group A vs. group B) was 54.6+/-10.6vs.55.0+/-9.8 years (p=0.808); 77.3%vs.75.9% were male (p=0.861); 28.4%vs.28.1% were diabetic (p=0.957); and ischemic etiology was present in 39.8%vs 41.0% of the patients (p=0.798), respectively. No differences were found, at first year, between the two groups concerning global ACR incidence (55.0%vs.56.9%, p=0.882, respectively) but major ACR (>=2R grade) was slightly superior in group B (16.6%vs.27.6%, p=0.080, respectively). Time-free from major ACR at 3rd, 6th and 12th months was, respectively 91.0+/-2.0%vs.84.5%+/-4.8%; 86.7+/-2.3%vs.74.1+/-5.7%; and 83.4+/-2.6%vs.72.4+/-5.9% (p=0.048). Time-free from major infection at 3rd, 6th and 12th months was, respectively 89.6+/ 2.1%vs.82.8+/-5.0%; 87.7+/-2.3%vs.79.3+/-5.3%; and 84.4+/-2.5%vs.79.3+/-5.3% (p=0.253). No differences were found concerning survival at 3rd, 6th and 12th months (94.3+/-1.6%vs.94.8+/-2.9%; 92.4+/-1.8%vs.93.1+/-3.3%; and 90.0+/ 2.1%vs.91.4+/-3.7%, (p=0.771) respectively). CONCLUSION: With this study, we verified that lowering doses of induction and maintenance therapy was responsible for increase cases of major ACR at first year of heart transplant. However, no differences were found concerning the incidence of major infection and early survival. Hence, effective immunosuppression induction regimen can apparently be done safely with a single dose regime without compromising survival at first year after HT. PMID- 29701352 TI - Two Years of Experience in the Implantation of Heartmate III. AB - INTRODUCTION: Left ventricular assist devices as long-term mechanical circulatory support are increasingly used as an option for medically refractory advanced heart failure. Heartmate III is one of the alternative devices for circulatory support in those patients. OBJECTIVES: Analyze a two years Heartmate III implantation Program. METHODS: From November 2015 to August 2017, Heartmate III was implanted in 16 patients with chronic end-stage heart failure, in 81% (n = 13) as a bridge to transplant and 19% (n = 3) as destination therapy. We did a review off demographic, clinical and surgical data, and we analyzed the overall survival using the Kaplan-Meier method, excluding patients who were transplanted. RESULTS: Heartmate III was implanted in 16 male patients (100%) with age 55.8 +/- 11.1 years (limits 38-74 years) and body surface area 2.0 +/- 0.19 m2. The baseline hemodynamic data revealed a cardiac index 2.1 +/- 0.4 l / min / m2 and a left ventricular ejection fraction of 20.7 +/- 7.3%. Ischemic cardiomyopathy was the most common etiology in this chronic heart failure population (n = 9; 56%). Seven patients (44%) were classified INTERMACS 4; five (31%) in profile 2; three (19%) in profile 3 and one (6%) in profile 1. The implantation of the devices was performed under Cardiopulmonary Bypass (78.6 +/- 25.7 min), and 25% of the patients (n = 4) had right ventricular dysfunction, requiring postoperative temporary right ventricle support. As complications, 6 patients (38%) manifested bleeding requiring surgery and 2 (12%) reported gastrointestinal bleeding, 4 (25%) developed driveline infection, 3 of them were treated (18%) with conservative therapy and in 1 patient (6%) with driveline transposition. During the total follow-up time (19 months), three patients (18%) were transplanted; two deaths occured due to pulmonary embolism and ischemic stroke respectively; verified by the Kaplan Meier method, an overall survival rate of 92.9 +/- 6.9%, stable from 6 months after implantation. CONCLUSION: The 6 months survival rate of 92.9% proves the efficacy of this therapy for our patients and all of them were INTERMACS profils lower than 4. Despite the small number of patients enrolled and the follow-up duration limiting our study, we demonstrated the first experience of our center in the treatment of high-risk population. In conclusion, we show that the Heartmate III was consistent in low INTERMACS profile patients. PMID- 29701353 TI - Freedom Solo Versus Trifecta Bioprotheses: Clinical and Hemodynamic Evaluation after Propensity Score Matching. AB - INTRODUCTION: To compare stentless Freedom Solo and stented Trifecta aortic bioprostheses regarding hemodynamic profile, left ventricular mass regression, early and late postoperative outcomes and survival. METHODS: Longitudinal cohort study of consecutive patients undergoing aortic valve replacement (from 2009 to 2016) with either Freedom Solo or Trifecta at one centre. Local databases and national records were queried. Postoperative echocardiography (3-6 months) was obtained for hemodynamic profile (mean transprosthetic gradient and effective orifice area) and left ventricle mass determination. After propensity score matching (21 covariates), Kaplan-Meier analysis and cumulative incidence analysis were performed for survival and combined outcome of structural valve deterioration and endocarditis, respectively. Hemodynamics and left ventricle mass regression were assessed by a mixed- -effects model including propensity score as a covariate. RESULTS: From a total sample of 397 Freedom Solo and 525 Trifecta patients with a median follow-up time of 4.0 (2.2- 6.0) and 2.4 (1.4 3.7) years, respectively, a matched sample of 329 pairs was obtained. Well balanced matched groups showed no difference in survival (hazard ratio=1.04, 95% confidence interval=0.69-1.56) or cumulative hazards of combined outcome (subhazard ratio=0.54, 95% confidence interval=0.21-1.39). Although Trifecta showed improved hemodynamic profile compared to Freedom Solo, no differences were found in left ventricle mass regression. CONCLUSION: Trifecta has a slightly improved hemodynamic profile compared to Freedom Solo but this does not translate into differences in the extent of mass regression, postoperative outcomes or survival, which were good and comparable for both bioprostheses. Long-term follow up is needed for comparisons with older models of bioprostheses. PMID- 29701354 TI - Isolated Tricuspid Valve Surgery: Repair Versus Replacement. AB - INTRODUCTION: Isolated tricuspid valve surgery (ITVS) is an uncommon procedure with few studies published. We report our series of ITVS and compare surgical outcomes and mortality in patients undergoing valve repair (TVR) versus replacement (TVRep). METHODS: Retrospective study including all patients who underwent ITVS (n = 34) between July 2008 and June 2017, divided in two groups according to type of procedure: TVR 20 patients and TVRep 14 patients. We reviewed preoperative characteristics and analysed operative data, outcomes and mortality in both groups. RESULTS: Thirty-four patients underwent ITVS, mean age 58,1+/-15,9 years, 50% female and mean BMI 26,1kg/ m2. TVR was performed in 58,8% and TVRep in 41,2% of patients. Patients had similar demographic and baseline characteristics, except for previous cardiac surgery (TVRep 78,6% vs.TVR 35,%, p<0,05). Mean logistic EuroSCORE was 10,1% for TVRep and 6,6% for TVR (p<0,05). Etiologies were functional insufficiency (68%), endocarditis (18%), degenerative (9%), rheumatic (3%) and congenital (3%). TVR was the preferred surgical approach. Ring annuloplasty was performed for all TVR and bioprosthesis was used for all TVRep. Postoperative complications were: need for transfusional support (76,5%), inotropic support longer than 48 hours (38,2%), prolonged invasive ventilation over 24 hours (35,3%), new onset of atrial fibrillation (11,8%), duplication or postoperative creatinine over 2 mg/dl (8,8%), dialysis (8,8%), stroke (5,9%), intra-aortic balloon pump (5,9%), permanent pacemaker implantation (2,9%) and sepsis (2,9%). TVRep was associated with superior length of surgery (TVRep 291 vs. TVR 186 minutes), longer ICU stay (TVRep 17,1 vs.TVR 2,8 days), longer hospital stay (TVRep 37,1 vs.TVR 11,7 days), prolonged invasive ventilation (TVRep 71,4% vs.TVR 10%) and longer inotropic support (TVRep 78,6% vs.TVR 10%) (p<0,05). Overall 30-day and 1-year mortality were 8,8% and 17,6%, respectively. Type of procedure was not associated to 30-day mortality (TVRep 14,3% vs. TVR 5%, p<0,05), but TVRep was associated with higher 1-year mortality (TVRep 35,7% vs. TVR 5%, p<0,05). CONCLUSIONS: TVR showed better outcomes, with less postoperative complications and mortality than TVRep. This difference cannot be linked to type of pathology, although patients in the latter group may be associated to greater complexity, with higher risk and were often reoperations. PMID- 29701355 TI - Aortic Valve Replacement With Perceval(r) Bioprosthesis: Initial Single-Center Experience. AB - INTRODUCTION: Aortic valve replacement (AVR) is the gold standard for the treatment of severe or symptomatic aortic valve stenosis. Less invasive procedures have been developed as an alternative to the conventional technique of full sternotomy approach with stented prosthesis. The Perceval(r) aortic valve (LivaNova, Milan, Italy) is a sutureless bioprosthesis, of which several reports have shown promising results in terms of mortality, morbidity and hemodynamic performance, especially with a less invasive approach. METHODS: Between March 2016 and September 2017, 43 patients underwent AVR with Perceval(r) bioprosthesis. The mean age was 74.3+/-6.8 years, 24 (55.8%) patients were female, and the mean EuroSCORE II was 4.1+/-0.6. Concomitant procedures were CABG (n=11; 25.6%), mitral valve surgery (n=2; 4.7%) and tricuspid valve surgery (n=1; 2.4%). RESULTS: Isolated AVR were performed in 31 patients (72%), with a less invasive approach in 29 cases (67%), of which 20 patients with upper ministernotomy and 9 patients with right anterior mini-thoracotomy. Cardiopulmonary bypass and cross- clamp times were 69.8+/-26.6 and 49.2+/-18.1 minutes for isolated AVR and 106.1+/-32.6 and 82.9+/-24.9 minutes for combined procedures, respectively. Preoperative peak and mean gradients were 81.6+/-24.8 and 49.7+/-16.1 mmHg, decreasing to 22.4+/-10.2 and 11.9+/-5.8 mmHg, respectively, during follow up (mean 9.1+/-6.0 months). The mean effective orifice area improved from 0.77+/-0.18 to 1.83+/-0.45 cm2, and mean left ventricular ejection fraction from 55.0+/-10.0 to 55.2+/-8.4%; mean left ventricular mass decreased from 221.6+/-55.7 to 180.2+/-42.4 g/m2. Trivial paravalvular leakage occurred in 2 patients, without clinical relevance. Five patients (11.6%) needed pacemaker implantation because complete heart-block before discharge (in 4 patients postdilation modelling wasn't performed). In hospital mortality was 9.3% (n=4), all non-valve related (mean EuroSCORE II of 9.15+/-4.0). CONCLUSION: AVR with the Perceval bioprosthesis is associated with low mortality rates and excellent hemodynamic performance. Sutureless technology may reduce operative times, especially in combined procedures, making minimally invasive AVR more easily reproducible. PMID- 29701356 TI - Arterial Switch: How to Predict Reoperation. AB - INTRODUCTION: Jatene surgery or arterial switch is performed at our institution since 1989. It is mandatory to submit our results to an evaluation that allow us to identify the main causes of reoperation and, more importantly, to determine what variables predict the need of reoperation. METHODS: In this retrospective analysis were included all the 91 patients with d-TGA who underwent an arterial switch operation at Santa Marta Hospital between 1999 and 2016. RESULTS: Mean follow-up was 6 years (range 1-21 years). 71% of the patients had simple TGA and 29% had complex TGA. The need of reoperation was 21%(n=19). Pulmonary artery stenosis was the main (47%) indication for reoperation. The overall cumulative mortality was 9.9%. The gender (P= 0.8), diagnosis (simple or complex TGA) (P= 0,5) or the existence of previous surgeries(P=0.9) were unable to predict the need of reoperation. The presence of coronary patterns anomalies was the only variable reaching statistical significance (P< 0.05), both in univariate and multivariate analysis. CONCLUSION: In our series, the main indication for reoperation after arterial switch operation was pulmonary artery stenosis and the only predictive variable was the presence of coronary anomalies. PMID- 29701357 TI - Frozen Elephant Trunk with E-Vita Open Hybrid Prosthesis for Surgical Correction of Multisegmental Thoracic Aortic Pathology: Review of Results. AB - INTRODUCTION: The Frozen Elephant Trunk (FET) surgery allows correction of ascending, arch and proximal descending aortic pathology, using a hybrid prosthesis at the same time. It is a complex intervention and requires a multidisciplinary team that, besides scheduling and performing the surgery, accompanies the patient (pt) throughout the postoperative period. OBJECTIVES: To review short and medium term clinical results with this technique. METHODS: Between January 2010 and September 2017, we operated 34 patients (pts) using FET. The surgery was performed under cardiopulmonary bypass (CPB) with cardio circulatory arrest in deep hypothermia, always with bilateral antegrade selective cerebral protection and under noninvasive neuromonitorization. Antegrade and retrograde, hematic, cold, intermittent cardioplegia was used. All patients were followed in our outpatient clinic with imaging techniques. RESULTS: The mean age of the pts was 62.8 +/- 11.5 years, 16 males. The mean follow-up period was 18.7 +/- 16.1 months. Diagnoses were: chronic type A dissection 9 pts, ascending aortic aneurysm and distal arch 9 pts, pseudoaneurysm 1 pt, mega-aorta syndrome 11 pts. No pt was operated in acute situation. Seven pts (20.6%) were reoperations and in 4 pts (11.8%) associated cardiac procedures were required. The left subclavian was conserved in 24 pts (70.6%). CPB, aortic clamping and distal ischemia mean times were, respectively; 260, 149 and 54 minutes. Hospital mortality occurred in five pts (14.7%), 3 of which at the beginning of the series, due to mesenteric ischemia. The hospital morbidity consisted of: ventilator-associated pneumonia 3 pts (8.8%), stroke 2 pts (5.9%), perioperative infarction 1 pt (2.9%) and paraplegia 1 pt (2.9%). Seven pts (20.6%) required 9 endovascular re-interventions (TEVAR) in the distal descending aorta and in two of these an abdominal fenestrated endoprosthesis was implanted by the vascular team. Three pts presented early type IIB endoleaks, which resolved spontaneously in follow-up CT. Among the others there were no endoleaks and the expected involution of the aneurysmal sac and positive remodeling of the aorta was observed. All survivors are clinically stable, asymptomatic, in class NYHA I. CONCLUSION: The overall results are in line with the literature. Mesenteric ischaemia is the leading cause of in-hospital death. FET is a safe and effective intervention. The expandable segment of the hybrid prosthesis is an excellent landing zone to complete the procedure, when necessary, with the second stage TEVAR. Survivors acquire an excellent quality of life in the medium term. Clinical follow-up and lifelong imaging techniques are mandatory. PMID- 29701358 TI - Carotid Stenosis in Cardiac Surgery Patients. AB - INTRODUCTION: Ischemic stroke is a potential perioperative complication after an open heart surgery (OHS). Whether a carotid stenosis or occlusion is associated with an increased risk of perioperative stroke in patients or just a risk factor has been a concern of intense debate in the literature. METHODS: We retrospectively analyzed patients submitted to OHS between January and December2016 with known asymptomatic carotid disease. The data from 85 consecutive patients undergoing coronary artery bypass grafting, valve replacement, or both was collected. The final events registered were stroke, acute myocardial infarct or death. Our aim was to assess whether the presence of carotid stenosis precluded a higher rate of stroke after cardiac surgery. RESULTS: 70 male and 15 female patients, with a medium age of 74(min 45,max84) years were analyzed. 45(53%) patients were submitted to bypass grafting, 21(25%) to valve replacement and 19(22%) to both. Of these patients,42(49%) had unilateral significant carotid stenosis equal or greater than 50%, 12(14%) had bilateral significant stenosis and 20(24%) had a stenosis equal or greater than70%. 2(2%) patients had a previous history of neurologic event. In the peri operative period, 3 patients (3,5%) developed transient ischemic attack (TIA) or stroke, 3(3,5%) a cardiac event and 6(7%) patients died (3 due to a cardiac event and 2 due to a neurologic event). Two (67%) of the neurologic events occurred in the corresponding side of an hemodynamic carotid stenosis although both this patients had also significant aortic arch calcification and atrial fibrillation. None of the patients that developed post-operative TIA or stroke had previously a neurologic event. CONCLUSION: Some studies reported an average stroke incidence around 1.9%following OHS. Despite carotid stenosis, other risk factors should be taken into consideration before considering OHS such as advanced age, prior stroke/TIA, unstable angina, predicted prolonged time for cardiopulmonary bypass, severe aortic arch disease and atrial fibrillation. In our studied population two of the post-operative neurologic events occurred in patients with significant bilateral stenosis, one side between50-69% and the other side 70-99%. According to the new guidelines "Management of Atherosclerotic Carotid and Vertebral Artery Disease:2017 Clinical Practice Guidelines of the European Society for Vascular Surgery" staged or synchronous carotid intervention may be considered for OHS patients with bilateral asymptomatic 70-99% carotid stenosis, or a 70-99% stenosis with contralateral occlusion. Our results may suggest that a sub-group of patients with bilateral significant (>50%) carotid stenosis may benefit from staged or synchronous carotid intervention. PMID- 29701359 TI - Cardiac Catheterization After CABG With BIMA Grafting: Independent Predictors and Mid-term Bypass Viability. AB - INTRODUCTION: Coronary artery bypass graft (CABG) patency is an important variable, but rarely studied as the main outcome. The best use of bilateral internal mammary artery (BIMA) grafting regarding configuration type or combination with saphenous vein graft (SVG) is still debated. PURPOSE: To find independent predictors for need of cardiac catheterization and for significant lesions in CABG follow-up. METHODS: Retrospective cohort including all patients who underwent isolated CABG with BIMA grafts between 2004 and 2013 in a tertiary center. Preoperative, surgical and postoperative data were collected through clinical files and informatics databases. Kaplan-Meier curves, Cox regression and logistic regression were used to find predictors for the need of catheterization and for significant angiographic lesions after CABG. Secondary end-points studied were mid- term survival and need of re-revascularization either surgically or percutaneously. RESULTS: We included 1030 patients in this analysis. Median follow-up time was 5.5 years and 150 (15%) patients were re-catheterized in that period. Most of these procedures was due to ischemia suspicion (74%) and 61 (41%) were positive for significant angiographic lesions of conduits (IMA: 3.2% and SVG: 3.8%, p=0.488). In multivariate analysis, SVG use was found as an independent predictor of cardiac catheterization on follow-up (HR: 1.610, CI 95%: 1.038-2.499, p=0.034). On the other side, independent predictors of graft lesions were younger age (OR: 0.951, CI 95%: 0.921-0.982, p=0.002), female gender (OR: 2.231, CI 95%: 1.038-4.794, p=0.040), arterial hypertension (OR: 1.968, CI 95%: 1.022-3.791, p=0.043) and 3-vessel disease (OR: 2.820, CI 95%: 1.155-6.885, p=0.023). Among the patients with significant angiographic lesions, 48 underwent repeat revascularization (44 PCI e 4 CABG). Arterial hypertension and younger age were independent predictors of re-revascularization. CONCLUSION: In BIMA patients the addition of SVG predicts the need of catheterization; however prevalence of significant angiographic lesions was similar in IMA and SVG. Our results suggest that arterial hypertension is an independent predictor of graft patency and re revascularization rate. PMID- 29701360 TI - TEVAR - A Primary or Adjunct Procedure Helpful in the Surgical Correction of Complex Pathology of the Thoracic Aorta? AB - INTRODUCTION: Thoracic Endovascular Aortic Repair (TEVAR) made possible the treatment of aortic disease that previously could only be approached openly, associated with a considerable morbidity and mortality. However, it also brings new challenges influencing patient selection - favourable landing zone, good peripheral access, propensity for endoleak (EL) - that requires rigorous clinical and imaging follow- -up. OBJECTIVE: Review all patients that underwent TEVAR in our Department and assess morbidity and mortality. METHODS: From November 2007 to September 2017, 57 TEVAR were performed in our Department to 52 patients. All patients performed postoperative CT angiography within 30 days after surgery. Follow-up was carried in our Outpatient Clinic with annual imaging. Statistical analysis was performed with SPSSTM 22 ((c) IBM). RESULTS: Patients' mean age was 65.6 +/- 10.3 years and 69.2% were male (n = 36). Mean follow-up was 48.1 +/- 34.1 months. The most frequent surgical indication was thoracic aortic aneurysm (42.1%), followed by chronic type B aortic dissection (35.1%), pseudoaneurysm (10.5%), reintervention by EL (7.0%), penetrating aortic ulcer (3.5%) and traumatic dissection of the aorta (1.8%). Surgery was elective in 87.7% of cases and part of a dual stage strategy in 17.3%. In-hospital mortality was 3.9%. Survival at 1, 2 and 5 years was 87.9%, 85.6% and 71.5%, respectively. Reported complications were: need for endovascular reintervention 7.7%; complication of femoral access 7.7%; and cerebellar infarction 1.9%. Throughout follow-up, no EL was detected in 56.1% of patients. There was an incidence of early EL in 38.4%, of which 45.0% had spontaneous resolution, documented in subsequent CT scans. The most frequent was type IA (42.9%) that was also the one with the highest spontaneous resolution rate (62.5%). Mean time to diagnosis of late EL was 36.9 +/- 21.4 months and occurred in 11.5% of patients, the most frequent being type IA (50.0%); there was no spontaneous resolution observed. In all cases of reintervention due to EL a good surgical result was obtained. CONCLUSION: TEVAR is a procedure with low morbidity and mortality, good long-term outcome and a relatively low incidence of EL. Most patients do not have EL during their follow up and have an excellent survival. The most frequent early EL is type IA and about half resolve in the following months. Although rare, late EL did not present spontaneous resolution. The treatment of EL can easily be achieved with new intervention and excellent result. PMID- 29701361 TI - Postoperative Atrial Fibrillation After Coronary Artery Bypass Grafting Surgery. AB - INTRODUCTION: Postoperative atrial fibrillation (PoAF) is the most common arrhythmia following cardiac surgery, which increase the patient's morbidity and mortality. PURPOSE: The aim of this study was to evaluate new onset of atrial fibrillation (AF) after isolated coronary artery bypass grafting (CABG) surgery, its clinical and surgical predictors, and its impact in immediate and long-term outcomes. METHODS: Retrospective study including all CABG surgeries performed in a tertiary centre, between 2004 and 2011. Patients with documented episodes of AF or pacing rhythm before cardiac surgery were excluded. Preoperative, surgical and postoperative data were collected through clinical files and informatics databases. Qui-square tests and independent t-tests were used to compare categorical and continuous data, respectively, between patients with and without PoAF. A multivariate logistic regression model was used to identify independent risk factors of PoAF. To determine the effect of PoAF in long-term survival, we used Kaplan-Meier curves, Log Rank test and multivariate Cox regression (maximum follow-up time: 13 years). RESULTS: We included 2511 patients, mean age of 63+/ 10 years, 78.7% being male. PoAF occurred in 450 patients (18.0%), 3+/-3 days after surgery, the majority pharmacologically cardioverted with amiodarone (96.2%). These patients were older (67+/-9 vs. 62+/-10 years, p<0.001), more frequently obese (27.8% vs. 22.9%, p=0.026), hypertensive (76.7% vs. 69.7%, p=0.003) and had lower preoperative creatinine clearance (CC) values (73.2+/-27.4 vs. 81.4+/-28.3 ml/min, p<0.001), longer cardiopulmonary bypass time (60.0% vs. 54.8%, p=0.043) compared with patients without PoAF. In multivariate analysis, older age (OR: 1.035, 95% CI: 1.015-1.056, p=0.001), lower preoperative CC values (OR: 0.992, 95% CI: 0.985-0.999, p=0.032) and larger left atrial diameter (OR: 1.058, 95% CI: 1.024-1.093, p=0.001) were determined as independent predictors of PoAF. These patients also revealed longer hospitalization time (8 [4 to 193] vs. 6 [4 to 114] days, p<0.001) and higher hospital mortality (2.9% vs. 0.8%, p<0.001). Regarding long-term survival, patients with PoAF showed lower cumulative survival than patients without AF events (52% vs. 66%, p<0.001). PoAF was also found as an independent predictor of mortality in multivariate Cox regression (HR: 1.394, 95% CI: 1.147- 1.695, p=0.001). CONCLUSION: PoAF incidence after CABG surgery was 18%. Older age, lower CC values and larger left atrial diameter were settled as PoAF independent predictors. Additionally, the occurrence of this arrhythmia was independently associated with lower long-term survival, after CABG surgery. PMID- 29701362 TI - Bilateral Internal Thoracic Artery Grafting in Patients with Diabetes Mellitus. AB - INTRODUCTION: Bilateral internal thoracic artery (BITA) grafting in patients with diabetes mellitus is controversial due to a higher risk for sternal infection. The purpose of this study is to compare the rates of mediastinitis as well as mortality rates of BITA grafting to that of single internal thoracic artery (SITA) grafting and saphenous vein grafts in patients with diabetes. METHODS: Between 2007 and 2015 all consecutive diabetic patients with multivessel disease who underwent primary coronary artery bypass graft surgery with BITA were compared with patients who underwent coronary artery bypass graft surgery with SITA and saphenous vein grafts (the control group). Patients submitted to single grafts were excluded from the analysis. Propensity score matching was used to account for differences between groups in preoperative characteristics. The frequency of peri-operative mediastinitis was compared between BITA and control group. Mortality rates between were compared between groups at 1-month post surgery and 2-year post-surgery. RESULTS: A total of 1005 patients were included in our sample in which 188 (19%) patients performed BITA grafting. BITA patients were younger (BITA group mean age 60.0 years vs control group 69.9 years; p<0.001), less often female (BITA group 11.7% vs control group 28.2%; p<0.001), and less often insulin treated (BITA group 9.6% vs control group 18.8%; p=0.002) compared to the control group. All other characteristics were not statistically different between groups, namely CCS, NYHA score, three vessel coronary artery disease, left main disease, previous myocardial infarction, hypertension, COPD and body mass index. After propensity score matching, 344 patients were included in the analysis, 138 in the BITA group and 206 in the control group. In this analysis both groups were not statistically different in every characteristic evaluated including age, sex and insulin-treated diabetic patients. The rate of peri-operative mediastinitis in matched groups was comparable (BITA group 2.3% vs control group 1.5; p=0.605). Mortality rates were comparable between groups at 1 month post-surgery (BITA group 1.4% vs control group 0.5%; p=0.346) and 2-year post- -surgery (BITA group 3% vs control group 2%; p=0.557). CONCLUSION: The findings of this sample suggest that the short and mid-term outcomes of patients with diabetes and multivessel disease who undergo BITA grafting is similar to other grafting procedures. BITA grafting in diabetic patients seems to be safe in terms of sternal wound problems. Longer term follow-up is required to determine BITA grafting survival improvement. PMID- 29701363 TI - David Operation in the Bicuspid Aortic Valve Population. AB - INTRODUCTION: Bicuspid aortic valve (BAV) is the single most common cardiac congenital mal-formation with a prevalence of 1-2%. It is frequently associated with aortic disease including annular ectasia. Increasing evidence suggests that valve-sparing root re-implantation surgery combined with primary aortic valve repair can be performed with good midterm results in patients with BAV. METHODS: Our objective is to compare the short and long term results of David procedure in BAV patients with aortic root ectasia. Retrospective analysis of our institution's database retrieved 42 patients with aortic annular ectasia who underwent valve-sparing root re-implantation surgery with David technic from 2007 to 2015. This cohort included 11 patients with BAV and 31 with tricuspid aortic valve (TAV). Pre, intra and post-operative variables of these two groups were statistically analyzed using univariate analysis. Continuous variables are expressed as means+-standard deviation. Categorical variables are expressed as percentages. Univariate analysis was performed using students t-test for continuous variables and x2 for categorical variables. Long-term survival and freedom from re-intervention was analyzed using Kaplan-Meier curves. RESULTS: Follow-up was achieved in 100% of cases with an average follow-up of 60 months. Mean age of the studied population was 50 years. Comorbidities and demographics were similar in the BAV and TAV groups with the exception of a younger operative age in the BAV group (p=0,028). Mean cardiopulmonary bypass time and mean ischemic time was 162' and 133' respectively. Combined procedures were performed in 3 (7,1%) of patients. The BAV group showed longer cardio- pulmonary bypass e aortic cross-clamp times (p=0,024; p=0,022) and a universal need for aortic plasty. Short-term results and complications were similar in the two groups with the exception of a higher need for pacemaker implantation in the BAV group (p<0,001). Post-operative results including in-hospital mortality, stroke, AMI, pre-discharge echocardiographic evaluation and long-term survival and freedom from re-intervention were similar between the two groups. CONCLUSION: Our experience reinforces the idea that, however challenging, the aortic valve sparing re-implantation procedure in the setting of BAV, has acceptable short and long-term results, similar to those observed in TAV patients. The pitfalls of this setting are the universal need for aortic valve plasty and higher risk for AV block. A more significant cohort of patients; echocardiographic long-term evaluation and long-term comparison with the gold-standard technic (Bentall procedure) may further clarify the benefits of this approach in BAV patients. PMID- 29701364 TI - Clinical Utility of Frailty Scales for the Prediction of Postoperative Complications: Systematic Review and Meta-Analysis. AB - INTRODUCTION: Frailty can be defined as a biological syndrome of reduced reserve and resistance to stressful events. Evidence suggests that this syndrome is linked to adverse outcomes in various surgical populations. Several instruments have been developed to measure frailty, however there is no consensus about which one is the most useful in the surgical population. Therefore, this study aims to evaluate the utility of different frailty scales in the prediction of postoperative complications in older surgical population. METHODS: This review and meta-analysis assembles prospective cohort studies reporting frailty and postoperative outcomes. Searches were performed in PubMed/Medline, Scielo, Cochrane Library and ScienceDirect databases. Statistical analyses was performed using Review Manager software and the pooled Odds Rattios was calculated. RESULTS: A total of 15 articles were included in the present review. Frailty was significantly associated with postoperative complications (OR=2.53, 95% CI: 2.07 3.10; p<0.00001), mortality until 30 days (OR=3.49, 95% CI: 2.40-5.09, p<0.00001) and higher 1-year mortality (OR= 2.90, 95% CI: 1.99-4.24, p<0.00001), and with hospital length of stay >5days or >14days (OR=2.78, 95% CI: 1.45-5.30, p=0.002 and OR=2.40 (95% CI: 1.08-5.36, p= 0.03, respectively). In addition, our meta analysis showed that frailty is a significant predictor of renal failure (OR=5.03, 95% CI: 1.74-14.54, p=0.003), neurological complications (OR= 3.41, 95% CI: 1.08-10.73, p=0.04), respiratory complications (OR=9.21 (95% CI: 2.35- 36.02, p=0.001), wound infection (OR=2.85 (95% CI: 1.65-4.94, p=0.0002) and sepsis (OR=3.84 (95% CI: 1.37-10.71, p=0.01). CONCLUSION: Overall, frailty significantly increases the risk for developing adverse outcomes after surgery, so early detection of frailty may be a window of opportunity for intervention and a key factor for improving clinical outcomes. Moreover, future studies are required for the standardization of the frailty scales used. PMID- 29701365 TI - Long-term Outcomes in Octogenarians Following Isolated Aortic Valve Replacement. AB - INTRODUCTION: Isolated aortic valve replacement (AVR) in elderly patients is associated with increased operative risk, due to higher prevalence of associated risk factors and other comorbidities, making outcome prediction essential. In patients with symptomatic severe aortic disease, advanced age is often a reason for a transcatheter rather than surgical aortic valve replacement. In the era of TAVI, there has been renewed interest in the outcomes of conventional AVR for high and intermediate risk patients. This study evaluates the short and long-term outcomes of elective AVR in elderly patients. METHODS: Between July 2011 and May 2015, 100 patients, aged 80 years or older, underwent elective AVR in our unit. The notes of these patients were retrospectively reviewed and follow-up information was obtained from their cardiologists and general practitioners. The average age was 82.8+/-2.3 years, 53.0% were female, 96.0% had severe aortic valve stenosis and their mean EuroSCORE II was 4.1+/-3.2 (intermediate risk). Preoperatively, 35.0% of patients were in NYHA class III or IV. Statistical analyses were done using IBM SPSS version 24. RESULTS: Median UCI and hospital stay was 2.0+/-3.7 and 7.0+/-9.5 days, respectively. Post-operatively, 2 patients required insertion of a permanent pacemaker, 3 patients suffered an ischemic stroke without sequelae, 3 required temporary renal replacement therapy, 7 required resternotomy for bleeding, 3 had sternal wound infections. No myocardial infarction was observed. In-hospital mortality was 4.0%, which was in accordance with the mean EuroSCORE II (4.1+/-3.2, p>0.05). One- year survival was 85.0%, three-year survival was 81.4% and five-year survival was 59.4%. At follow-up, 96.0% of patients were New York Heart Association (NYHA) Class I or II and 2 late endocarditis occurred and were medically treated. Structural valve deterioration was observed in 2 patients at 3 years follow-up. CONCLUSION: The outcome after AVR in octogenarians is satisfactory; the operative risk is acceptable and might even be reduced with an individual approach to perioperative management in high risk patients. Patient age should not be the primary exclusion for conventional cardiac surgery for aortic valve disease. PMID- 29701366 TI - Cardiac Surgery, with Synchronous Carotid Angioplasty, our Experience. AB - INTRODUCTION: The identification of carotid stenosis in patients proposed for coronary artery bypass grafting, proves that atherosclerosis is a systemic disease. In patients with carotid disease and in need of cardiac surgery, there are still questions about the best method of treatment - medical, surgical or percutaneous, the degree of stenosis considered for intervention and the best time for treatment (pre, peri or postoperative heart surgery). The surgical treatment of the carotid stenosis is currently the gold standard. However, percutaneous treatment has expanded its indications. It is our goal to present the initial results of our experience in the implementation of a synchronous strategy for the treatment of percutaneous carotid disease treatment, followed by cardiac surgery. METHODS: Between July/2013 and August/2017, 37 patients were eligible for this procedure. Demographic, perioperative and postoperative data were collected to evaluate the incidence of cerebrovascular complications (severe stroke, death due to stroke, transient ischemic stroke), cardiac complications (acute myocardial infarction (AMI)), or renal impairment. RESULTS: The majority of patients (83.7%) were male, with a mean age of 74 years (51-90). Coronary artery disease was the most prevalent surgical indication (59%). Hypertension, dyslipidemia, and smoking, in this order of magnitude, were the most prevalent risk factors. One patient had documented previous stroke. The efficacy of carotid angioplasty was 97.3%, as in one patient it was impossible due to technical reasons. In six patients, the carotid procedure was associated with percutaneous treatment of coronary disease. The interval between both procedures was 1 hour, in average. In- hospital mortality was 5,4% (2 patients) and 1 AMI was documented. Renal injury and atrial fibrillation were the most common complications, found in 27% and 19%, respectively. The mean follow-up time was 523 days (50-1525 days). Two deaths were documented during follow-up. No re stenosis was found. CONCLUSION: The approach presented here (percutaneous treatment of carotid stenosis, concomitant treatment of coronary disease and proximity between procedures) is feasible and effective in reducing the risk of cerebrovascular complications in patients in need of cardiac surgery. Long-term follow-up results, associated with permeability studies, may boost this technique for clinical acceptance, with changes in guidelines, in this set of patients. PMID- 29701367 TI - Severe Intraoperative Complications During VATS Anatomical Ressections and their Surgical Resolution in a Portuguese Thoracic Surgery Centre - A 9-Year Review. AB - INTRODUCTION: Many studies have demonstrated that video-assisted thoracoscopic surgery (VATS) is not only feasible and safe but is actually the approach chosen for an increasing number of pulmonary anatomic resections. There are however few studies reporting on severe intraoperative complications during VATS anatomical ressections and their resolution. OBJECTIVE: Our aim is to analyse the incidence of severe intraoperative complications during VATS anatomical ressections, at our department, in the past nine years, and describe their technical resolution during the surgery. METHODS: We performed the retrospective analysis of the patients submitted to lobectomy, bilobectomy or segmentectomy by VATS or VATS converted to thoracotomy at Hospital de Santa Marta, between May 2008 and September 2017. Severe intraoperative complications were defined as an event that results in a life threatening situation or an injury to a proximal airway, blood vessel or organ that would lead to an unplanned additional anatomical resection. RESULTS: A total of 151 patients were submitted to anatomical ressections, 90,7% (n=137) of them for a primary lung cancer, other indications were metastatic disease 6%(n=9) and benign disease in 3,3% (n=5). The surgery was a lobectomy in 94% of the cases (n=142), a segmentectomy in 5% (n=8), and one bilobectomy. The conversion rate to thoracotomy was 12% (n=18), most of which were for technical/ oncological reasons (n=11), and 7 others were to control bleeding. Four (2,6%) severe intraoperative complications were identified. Three of them (2%) were erroneous transections of bronchovascular structures (left main bronchus, left main pulmonary artery and both left pulmonary veins); and one was a membranous airway injury proximal to the staple line. There were no intraoperative deaths. The three patients with erroneous bronchovascular transection were converted to thoracotomy and the bronchial or vascular re-anastomosis was performed, therefore avoiding a left pneumonectomy. In the patient with the membranous airway injury, the bronchoplastic suture was performed by VATS. All four patients were primary lung cancer patients. In all these cases the patients were discharged alive and well and are undergoing their follow-up program with no signs of disease recurrence. CONCLUSION: Albeit rare, severe complications during VATS Lobectomy can occur but when they happen the thoracic surgeon has to be ready to solve them with the minimal repercussion for the patient. PMID- 29701368 TI - Three-year Experience on 477 Patients Undergoing Uniportal Video-Assisted Thoracoscopic Surgery. AB - INTRODUCTION: Uniportal video-assisted thoracic surgery (VATS) technique has been described both for diagnostic and therapeutic indications. Outcomes after uniportal VATS have never been reported in Portuguese large series. We review the safety and efficiency of our initial experience with uniportal VATS. METHODS: In a retrospective study of prospectively collected data, 477 uniportal VATS procedures were analyzed between June 2014 and June 2017. All procedures were performed without rib spreading. Patients' demographic data, preoperative and postoperative management as well as results were analyzed. RESULTS: The mean age of patients was 47,9 years (range, 10 to 86), and 155 (32,5%) patients were female. The uniportal VATS procedures included 156 (32,7%) anatomical major lung resections, 80 (16,8%) one or multiple wedge resections, 172 (36,1%) blebectomies and/ or pleurectomies, 24 (5%) mediastinal lesions, 16 (3,3%) empyema drainage and decortications and other indications in 29 (6,1%) cases. Median operative ime and surgical drainage for uniportal VATS for anatomical major lung resections was 95 minutes (range, 40 to 245) and 100 ml (range, 0 to 650), respectively. Conversion to either 2 or 3 port VATS or mini-thoracotomy was necessary in 7.1% of the surgeries, often due to adhesions, incomplete lung collapse or bleeding. The chest drain was removed after a median of 3 days (range, 0 to 34). Median hospital stay was 3 days (range, 1 to 41). Postoperative complication rate was 12,4% mainly due to prolonged air leak 8,4% (n=40). There was no perioperative mortality. CONCLUSION: Uniportal VATS is a feasible and safe technique for various indications in thoracic surgery. The perioperative results are promising. Excellent results with minimal morbidity and short hospital stay are amongst its strong points. It can be performed by thoracic surgeons experienced in the postero-lateral thoracotomy approach. PMID- 29701369 TI - Uniportal Video-Assisted Thorascoscopic Surgery - The New Paradigm in the Surgical Treatment of Lung Cancer. AB - INTRODUCTION: The progressive development and improvement of minimally invasive approaches in the field of thoracic surgery allowed to establish video-assisted thoracoscopic (VATS) anatomic lung resections as the present technique of choice in the treatment of early stage lung cancer. METHODS: The purpose of this study was to evaluate the surgical outcomes of patients who performed uniportal VATS anatomic lung resections for the treatment of primary lung cancer. The patients' demographics, approach and type of surgery, postoperative morbidity and mortality and overall survival were analyzed. RESULTS: From December 2013 through September 2017, 173 patients underwent uniportal VATS anatomic lung resections for the treatment of lung cancer. Surgery was performed in 92 male and 81 female with a mean age of 63.5 years (range 19- 83 years). All surgeries began by a single- port VATS approach, being necessary to add an extra port in 9 surgeries and conversion to mini-thoracotomy in 10 procedures (conversion rate of 5.8%) due to bleeding and/ or technical difficulties. All kinds of anatomic lung resection were performed: 154 lobectomies, which represents 89.0% of the procedures (93 upper lobectomies, 12 middle lobectomies and 49 lower lobectomies), 10 bilobectomies (5.8%) and 9 anatomic segmentectomies (5.2%). Mean lymph node stations dissected was 2.48 stations (range 1-8 stations). The mean surgical time was 112.2 minutes (range 40-245 minutes) and mean intra-operative drainage was 155.6ml (range 0-1400ml). Median hospitalization time was 5 days (range 2-28 days). There was no operative or 30-days mortality and the main complication observed was persistent air leakage in 38 patients (22.0%). Non-small-cell lung cancer (NSCLC) was the main histologic type of cancer (n=149; 86.1%), followed by carcinoid tumours (n=20; 11.6%) and other histologic type (n=4; 2.3%). The mean follow-up time was 15 months (range 0-45 months) and the overall survival was 94.5%. CONCLUSION: We believe that uniportal VATS anatomic lung resection with systematic lymphadenectomy is technically safe and feasible and it is an alternative approach to thoracotomy or conventional thoracoscopic in the treatment of lung cancer. This approach has demonstrated to be reproducible, comprising all the advantages of a minimal invasive surgery, without jeopardizing the efficiency of the oncologic treatment. Therefore, we suggest that this technique could have a broader implementation and development in all national surgical centers. The issues of patient acceptability, cosmetic and oncologic results, and cost-effectiveness remain to be determined in the future throughout multi-institution randomized controlled trials and long-term follow-up. PMID- 29701370 TI - Major Complications of Videomediastinoscopy and their Resolution - a 5 year experience. AB - INTRODUCTION: Videomediastinoscopy is an invasive procedure for mediastinal assessment, with low rates of morbidity and mortality. Despite the low risk of complications, they can be potentially lethal if not immediately controlled. OBJECTIVE: The goal of this study is to analyse the overall incidence of complications of videomediastinoscopies, performed in the last 5 years at our department, as well as their resolution and outcomes. METHODS: A retrospective review of all videomediastinoscopies performed at a single institution during a 5 year period was performed. Major complications were defined as life-threatening events. RESULTS: During the study period, from July 2012 to July 2017, were performed 160 mediastinoscopies, 67 were diagnostic and 93 for staging. There were 3 major complications (1.87%), of which a severe haemorrhage from a bronchial artery, a tracheal rupture, and a massive haemorrhage from an innominate artery laceration. In this 3 cases, the diagnosis were lung cancer in 2 patients and lymphoma in the other one. There were no intraoperative deaths. One patient died in the postoperative period due to mediastinitis and disease progression. The patient who suffered innominate artery laceration, had a stroke due to dissection of the right carotid artery. During follow-up, one patient died from progression of oncologic disease, and the other one is alive 4 years later. CONCLUSION: Although mediastinoscopy has a low rate of complications, these can be potentially lethal and the thoracic surgeon should be able to resolve them rapidly. Due to the scarcity of publications on this subject, it is important to describe potential complications of this surgical procedure and their clinical resolution. PMID- 29701371 TI - Surgical Treatment of Complications 55 Years After Extraperiosteal Lucite Ball Plombage for Pulmonary Tuberculosis. AB - INTRODUCTION: In the 1930-50s, before the introduction of antimicrobial drugs and development of techniques of pulmonary resssection, collapse therapy was the mainstream of treatment for cavitary pulmonary tuberculosis. The methods to achieve the collapse included artificial pneumothorax with air refills, phrenic nerve crush, thoracoplasty and extrapleural plombage. The plombage involves creating a cavity surgically under the ribs in the upper chest wall and filling the space with inert material, such fat, paraffin wax, rubber ballons, oil and methyl-methacrylate (Lucite) balls. The theory behind Plombage treatment is that collapse of the lung promote de healing process and limit the spread of tuberculous infection to other areas of the lung. However, with time, the presence of these materials for a prolonged period of time resulted in complications, such as erosion of major vessels, respiratory insufficiency, infection and migration. METHODS: We present a clinical case of one patient presented with a late complication of lucite ball plombage after 55 years. RESULTS: An 78-year-old man with a history of pulmonary tuberculosis treated with plombage in 1962, ischemic heart disease, hypertension and diabetes mellitus, was admitted to hospital for axillary swelling and pleurocutaneous fistula. The x-ray of the chest and computed tomography showed the apex of the left hemithorax filled with multiple lucite balls, each approximately 2,5cm in diameter, and extrusion of a ball into the axillary fistuluous tract. In this context, the patient complied with multiple antibiotic regimens without success. So, the patient was submitted to surgical extraction of 21 lucite balls, pleurocutaneous drainage and thoracoplasty (7 ribs and the tip of the scapula was remove). The cultures turned out to be negative and the patient made an uneventful recovery with discharge on the 19th postoperative day. Pathologic examination revealed active chronic inflammatory process and negative microorganism screening. CONCLUSION: Despite the rapid decline in collapse therapy since the appearance of antitubercular chemotherapy, there are still such elderly patients who remain asymptomatic while carrying residual plombage material. There is no need for routine ablation of any this material, however if any foreign material becames a source of complication should be extracted without delay. As the number of living patients treated by plombage is attenuating rapidly, fewer and fewer will be seen in the future, and no one is likely to accumulate considerable experience with this problem. PMID- 29701372 TI - Unusual Behavior of a Lung Inflammatory Myofibroblastic Tumor: Case Report. AB - INTRODUCTION: 55 years old, male patient. History of heavy smoking (65 UMA) and COPD. Admitted to hospital due to a left pneumonia. Thoracic CT and PET-Scan, showed left lower lobe mass measuring 92x89 mm (SUVmax 49). Several mediastinal node groups presented increased uptake of FDG. A fiberoptic bronchoscopy was performed. Citology of the bronchoalveolar lavage suggested a squamous carcinoma. EBUS of node stations 4R, 4L e 7 without evidence of malignancy. METHODS: The case was taken to a multidisciplinary meeting staged as IIIA (T3N2M0). Neoadjuvant therapy (four cycles cysplatine and gemcitabine) was decided based on station 5, suspected disease. A left lower lobectomy was performed after a cervical mediastinoscopy excluded metastasis of node stations 4R and 4L. Histology of the specimen was compatible with inflammatory myofibroblastic tumor (IMT). No lymph node involvement was reported. It was restaged as IIB (ypT3N0M0). RESULTS: Three months after surgery one de novo nodule in the lingula with 12,7 of SUVmax was reported. The nodule was removed confirming a IMT metastasis. Four months after the nodule ressection a CT showed new lung and liver nodules. A total oclusion of the left main bronchus was documented and bronchoscopic debulking of the endobronchial mass again revealed IMT. Paliative radiotherapy was decided in the multidisciplinar group targeting the left main bronchus (five sessions of radiotherapy on a dose of 20Gy in 4Gy daily fractions). Ten months after surgery due to the onset of back pain, a CT revealed a sacrum lesion whose needle biopsy was suspicious for multiple myeloma. The patient was referred to another oncological center where previous non-surgical cases had been sent in the past. The patient is now proposed for histology reassessment and discussion by the hematology and pneumology medical teams. CONCLUSION: Inflammatory myofibrobastic tumors are considered benign or low-grade malignant tumors. The size of the tumour (cut-off of 3 cm) and secure surgical resection with free margins are the major determinants for recurrence and survival. There are some cases reported in the literature of distant metastasis and sarcomatous transformation after multiple recurrences. In our patient, the lesion was bigger than 3 cm and he underwent a complete resection. Nothing could foresee this aggressive metastatic behavior, especially when the recurrence did not show a sarcomatous transformation. PMID- 29701373 TI - Uniportal VATS Lobectomy: Subxiphoid Approach. AB - INTRODUCTION: Interest in uniportal video-assisted thoracic surgery (VATS) is rapidly growing worldwide because it represents the surgical approach to the lung with the least possible trauma and in recent years the subxiphoid approach has been used in the field of thoracic surgery as it is associated with lesser pain because there is no intercostal nerve damage and it provides excellent cosmetic outcomes. This technique was recently introduced for major pulmonary resections and even bilateral approaches in selected patients. METHODS: We present a case of a 66 years old male, former smoker (45 unit pack year) who had a thorax CT (computorized tomography) scan for worsening complaints of cough with sputum production. The CT scan revealed a right upper lobe nodule (16x14mm) with ground glass density and fissure retraction. The pulmonary function tests showed mild bronchial and bronchiolar obstruction. It was decided to undergo surgical treatment. The surgical approach was a subxiphoid uniportal lung resection. RESULTS: The patient was positioned in a left lateral position with 60 degrees of inclination. The surgeon and scrub nurse were located in front of the patient and the assistant in the opposite side. A 3cm midline vertical incision was made below the sterno-costal triangle. The rectus abdominis was divided and the xiphoid process was partially resected. The right pleura was opened by finger dissection. The pericardial fatty tissue was removed and a soft tissue retractor was placed. A 10- mm, 30-degrees video camera and double articulated instruments combined with several specific longer VATS instruments were used through the same subxiphoid incision.It was performed a wedge resection and after the diagnosis of adenocarcinoma in the intraoperative histological examination, the patient underwent a right upper lobectomy and complete mediastinal lymphadenectomy by the same approach.The post-operative period was uneventful, the chest tube was removed in the third postoperative day. The pain control was excellent, with a maximum of pain grade 1 in the Visual Analogue Scale.The patient was discharged in the fourth postoperative day. CONCLUSION: The subxiphoid approach is a variant of uniportal VATS approach without opening the intercostal space with its striking advantages in terms of pain control and cosmetics in selected patients. However, this technique has yet some limitations such as the control of major bleeding and the performance of a complete oncologic lymph node dissection related to its surgical complexity expected in emerging techniques. Further studies are necessary to certify the feasibility, safety and benefits of this approach. PMID- 29701374 TI - Bilateral Recurrent Spontaneous Pneumothorax as a Late Consequence of Oesophageal Surgery: Case Report. AB - INTRODUCTION: We report a case of a patient with recurrent bilateral spontaneous pneumothorax presumably originating in a left bulla. METHODS: A 68 year old male, was admitted to the emergency department with shortness of breath and bilateral chest pain. He had had oesophageal cancer resection 2 years before, with a posterior mediastinal reconstruction using a gastric tube. Afterwards he had to be operated twice for hiatal hernia. RESULTS: Bilateral chest tubes were inserted, with complete resolution in 72 hours. He was readmitted 20 days later, with a bilateral recurrence. A pneumologist was called upon. The thoracic CT scan revealed large bulla in the left upper lobe. There was no evidence of pneumomediastinum or mediastinal fluid collections. Communication between the two pleura was suspected. After discussion with the surgeon responsible for the previous interventions only the left chest was drained with bilateral lung expansion after suction. A left VATS approach revealed a partially adherent left lung, in its mediastinal face. Inflated bulla could be partially observed firmly glued to the upper mediastinum. A leak could not be demonstrated within the left thorax. Due to the firm adhesions of a presumably nonruptured bula to the phrenic nerve, a decision was made not to dissect it. A pleurectomy was performed. In the 3 days that followed, the fistula persisted and increased, in spite of lung expansion. A left thoracotomy was then performed. The full extent of the anterior mediastinal face of then left lung was dissected by opening the bulla that were partially left on the mediastinal pleura. Resection was made using tristaple endoGIA staplers (r). The posterior mediastinum was manually dissected free up to the presumed gastric tube location. At the end of surgery, no major air leaks were documented. Communication with the right pleura could not be located, not even with the aid of a 30o camera, but a large amount of fluid (1000cc) missing, was recovered after turning the patient. The postoperative period was prolonged ut to the 16th day, by a small but persistent air leak. CONCLUSION: Although no visual proof of communication between the two pleural cavities could be found, the control of the right pneumotorax by contralateral drainage, the resolution of the case by left pleurectomy and bulla resection backup this theory. This is an unique case, not previously reported, resolved by a multidisciplinary discussion of all the specialists involved in the treatment. PMID- 29701375 TI - Surgical Treatment for Elderly Patients with Lung Cancer. AB - INTRODUCTION: Non-small cell lung cancer is a very common disease in the elderly population and its incidence in this particular population is expected to increase further, because of the ageing of the Western population. Pulmonary resection is often not recommended in the elderly, even though they have no medical contraindications to surgery. Such patients are postulated to have a limited life expectancy, the rate of complications and perioperative death is considered to be higher than younger population. However, decision making is extremely difficult, since this group in under- represented in clinical trials. METHODS: This study aim to do a retrospective analysis of comorbidity, surgical procedures and pos- operative complications for surgery in patients older than 70 years of age who underwent a pulmonary resection for lung cancer. We analysed the clinical records of all patients with Non-small cell lung cancer submitted to surgery during the period 2012 to 2016 in our department and divide them in 2 groups: elderly group (more than 70 years old) and group control. RESULTS: In the five years study period, our department performed pulmonary resection in 601 patients with NSCLC, of whom 209 (34,8%) were 70 years and older. The mean age was 74,6 years old in the elderly group and 58,6 in the control group. Preoperative comorbidities such as cardiac and previous neoplasic diseases were more frequent in the elderly group, and the percentage of smokers was higher in the control group (80,1% vs 61,7%). A segmentar or wedge resection was performed more frequent for the elderly group (16,7%) than in the control group (6,6%), whereas pneumonectomies and lobectomies were performed more frequently. The ratio of pos-operative complications, especially cardiac complications, was higher in the elderly patients (12,9% vs 8,2%), however, there was no significant difference in prevalence of pulmonary/ respiratory complications, such pulmonary leakage, pneumonia or empyema between the 2 groups. There was no operative or hospital death in any of the groups. CONCLUSION: Advanced age alone is not a contraindication to surgical resection on NSCLC. Elderly patients should be offered the best treatment possible, considering surgical risk on an individualized basis, and keeping in mind that surgery offers the best results when the disease is resectable. PMID- 29701376 TI - What About Having a Hydropneumothorax Every Month? AB - INTRODUCTION: Endometriosis is a pathological, benign, inflammatory condition characterized by the presence of endometrial glands and stroma outside the uterine cavity, typically in the pelvis. In rare conditions, this estrogen dependent disease may be extrapelvic, presenting with a variety of symptoms, including Thoracic Endometriosis. METHODS: A 37 year-old woman presented with her third right hydropneumothorax in three months. Her medical history included infertility, an ovarian mass (in study), biliary diskinesia and protein C deficiency. The CT showed a bleb in the right inferior lobe and a pleural effusion. A detailed clinical history revealed a temporal relationship of the hydropneumothoraxes and her menses. RESULTS: She underwent a videothoracoscopy: there were macroscopic tissue alterations all over the parietal and visceral pleura. We performed a biopsy of one of those spots (of the parietal pleura) and an atypical resection of the apex of the apical segment of the right inferior lobe, where the bleb was. A talc pleurodesis was also performed. The patient was discharged at day 1 and is currently under regular follow-up in ambulatory, with no recurrent pneumothoraxes for two months. The histopathology was compatible with a pleural Endometriosis. CONCLUSION: Thoracic endometriosis is a clinical diagnosis, although the histopathologic confirmation is preferred (but not necessary): it should be suspected in reproductive age women who present with hemothorax, pneumothorax, hemoptysis, chest or scapular pain, lung nodules or diaphragmatic rupture perimenstrually, especially right-sided. Most commonly it presents as catamenial pneumothorax and/or hemothorax. Those with high clinical suspicion and/ or imaging supportive of the diagnosis, should undergo an interventional procedure (thoracoscopy), both for diagnose and management. Primary treatment is chest tube drainage. Prevention of recurrence can be medical (hormonal suppression) or surgical (lung resection, pleurectomy, pleurodesis). PMID- 29701377 TI - Smajor Hemorrahage During Mediastinoscopy: Do You Panic or Do you Have a Protocol? AB - INTRODUCTION: Although uncommon, major vessel hemorrhage is the most feared complication of mediastinoscopy. Our goal was to determine the optimal management strategy and to develop a simple and accessible protocol for optimizing care in these situations. METHODS: Data collection after reviewing the relevant literature. A literature review was conducted using the following databases: PubMed, Medline, Embase and ScienceDirect. RESULTS: The protocol consists of three distinct parts - initial checklist, considerations in minor bleeding and performance in major bleeding. In this last section we propose an initial approach based mainly on fluid resuscitation and immediate surgical correction if the former has not been successful. CONCLUSION: Mediastinoscopy continues to be an important and effective diagnostic tool. However, it can cause important iatrogenic lesions which the anesthesiologist and surgical team must be prepared to diagnose early and treat properly. PMID- 29701379 TI - Which Aneurysm Characteristics Predict EVAR Nonsuccess. AB - INTRODUCTION: Hostile anatomic characteristics in patients undergoing endovascular abdominal aortic aneurysm repair (EVAR) may lead to technical nonsuccess of the procedure, late complications, reintervention or death. The authors analyzed anatomical abdominal aortic aneurysm specific considerations so as technical endoprosthesis implantation and correlate them with endoleak development and postoperative survival. METHODS: Authors retrospectively reviewed all consecutive, elective, EVAR's that occurred between 2010 and 2016, with available data, at one institution for abdominal, infra renal, aortic aneurysms. The patients comorbidities were registered and preoperative CT scan was analyzed considering the proximal zone (diameter, length, presence of thrombus or calcification), the distal zone (length and diameter), aortic aneurysm (maximum diameter, angulation, axis deviation, mural thrombus and patency of the inferior mesenteric artery and the lumbar arteries) and concomitant iliac aneurysm or peripheral occlusive disease. Outcomes were endoleak development and death. RESULTS: We analyzed 56 patients, 54 (96%) male with a medium age of 78 (min 61, max 89) years. During a medium 3,4 years of follow up, 12 (21%) patients developed endoleak (10 type II and 2 type I) and 18 (32%) died. The adjusted analysis showed a statistically significant association between aneurysm angulation (p=0,046), patency of the inferior mesenteric artery and the lumbar arteries (p=0,044) and aneurysm diameter (p=0,009) with endoleak development. Notice that 40% of the aneurysms that impaired a significant axis deviation developed endoleak. All except one endoleak were diagnosed within the first year after EVAR. None of the deaths that occurred during the follow up period were correlated to post intervention aneurysm enlargement or rupture. However we found a statistically significant association between patency of the inferior mesenteric artery and the lumbar arteries (p=0,042) and early death during the first year after EVAR. CONCLUSION: Even though many aneurysm are suitable for EVAR, unfavorable aneurysm morphologic characteristics and predictable complicated endograft placement should be taken into consideration. For such clinical cases, a surgical approach should be considered. We believe that current recommendations for follow up with angioCT only at 1 and 12 months during the first year following EVAR is a good practice conduction since most of endoleaks developed during these period. If neither endoleak nor aneurysm enlargement is documented during first year after EVAR, colour duplex ultrasonography is a good alternative for annual postoperative surveillance. PMID- 29701378 TI - Amniotic Membrane in the Treatment of Varicose Ulcers: a Center Experience. AB - INTRODUCTION: Amniotic membrane (AM) is an option as a cover in varicose leg ulcers, promoting epithelization. Anti-inflammatory and analgesic proprieties are described, as well as high levels of growth factors and angiogenesis. The costs are inferior to surgical plasty. The aim of this work is to describe the results of AM in the treatment of varicous leg ulcers in a group of patients refractory to the best medical treatment. METHODS: A pilot prospective trial was conducted. Thirteen patients were selected for the treatment with AM from an outpatient clinic. The inclusion criteria included: ulcer area inferior to 100 cm2, ulcer size variation inferior to 30% in the last month, duration superior to 2 years and refractory to best medical treatment including compressive therapy. The exclusion criteria were ABI>0,8m active infection, bone exposure, severe myopathy of the low limb and acute decompensation of systemic chronic disease. The first five cases were applied on the enfermary (mean stay 3 days), the last 8 patients were applied in the outpatient clinic. After the treatment behavioral reinforcement was made. RESULTS: The mean sample age was 56 YO (50-71), 70% were female, 30% were diabetic, and post-thrombotic syndrome was present in 54% (7), only one patient was an active smoker. After 2 years a recurrence was observed in 23% (3) cases. CONCLUSION: AM is effective in the treatment of varicose ulcers unresponsive to best medical treatment. PMID- 29701380 TI - Renal Autotransplantation - The Solution for Different Pathologies. AB - INTRODUCTION: Renal autotransplantation (RA) is a safe and effective procedure to reconstruct the urinary tract which first successful surgery was performed by Hardy in 1963. The main indications reported for performing RA generally includes renovascular disease, ureteral pathologies and neoplastic disease. RA may be also useful as the last recourse in preventing kidney loss in highly selected patients, especially when conventional methods have failed. METHODS: The authors pretend to describe four total different situations where the RA was the key solution for the pathology initially presented. RESULTS: 1- 52 years old male with a previous history of right nephrectomy that occurred during an exacerbation of his basal Chron disease so as left ureter cutaneostomie, presented with repetitive urinary tract infections that led to renal function impairment; 2- 57 years old female with the diagnosis of renal artery aneurysm while being studied as a potential renal donor; 3- 49 years old male admitted in the emergency room after a penetrating trauma which conditioned bowel and ureteral lesions with postoperative consecutive and recurrent peritoneal infections that compounded a necessity for a left ureter cutaneostomie, that the patient accurately refused; 4 24 years old female with the diagnosis of Nutcracker syndrome identified after being studied regarding repetitive urgency admissions with frank hematuria. Every patient was submitted to RA. The intervention and postoperative course were uneventful. We performed an ultrasound evaluation on the day after each procedure to attest normal renal perfusion. CONCLUSION: The RA were realized in the two patients with ureteral lesions because there was no viable alternative but kidney loss. The other two clinical cases were treated with RA because they concerned a complex renovascular disease (one arterial and the other venous). Despite the existence of an endovascular option for these patients, long term follow up studies are still lacking. The RA is a viable option in specific situations for kidney salvage. The recent development of laparoscopic nephrectomy significantly decreased the surgical hostility to the patient and promoted the RA value on the treatment of complex vascular pathologies, traumatic disease and specific medical situations. It represents a credible alternative with attested results already described in the literature thus requiring a vast Institutional experience with conventional renal transplantation. PMID- 29701381 TI - Abdominal Aortic Aneurysm in Women: Retrospective Analysis of the Cases that Undergo Surgical Repair. AB - INTRODUCTION: The prevalence of infra-renal aortic abdominal aneurysms (AAA) is about 3 to 4 times higher in men, with a recommendation I 1a for screening men > 65y. Althoug women only represente 20% of the total AAAs they have a significant higher rupture rate - threefold higher - and a worse outcome after ruptured AAA repair. Screening is not consensual but can be recommended for women > 65y who have smoked or have a family history of AAA. Against screening is the fact that the AAA in women have not only a lower incidence but also a late presentation (>80y) but references have been made to the fact that smoking became popular more than 30 years after than men and so the effects just now can start to be seen. METHODS: A retrospective review was made to all women with an infra- renal AAA who undergo a surgical treatment, elective or urgent, in the past 7 years (January 2010 - August 2017) in our hospital. Information was obtained through the clinical process. It was made an evaluation of the demographic information and anatomic features. RESULTS: 15 cases were reviewed, 4 elective and 11 ruptured surgical repairs. The mean age was 74 and only 4 women were more than 80 years old, with a minium age of 57. More than half the patients were previously diagnosis with hypertension but only 30% had high cholesterol. Only one was a known smoker. None had a diagnosis of cardiac disease. One had a sintomatic cerebrovascular disease. Within the elective cases, all open repair, the intra hospitalar mortality was zero with a mean stay of 7,5 days. The ruptured cases, 1 endovascular, had a perioperative mortality of 50% The mean aortic diametre at rupture was less than 6 cm. CONCLUSION: Data supports the evidence of the morbidity of a ruptured AAA and the high intra-hospitalar mortality in women. Early detection and elective repair should be considered. Sex-specific research is needed to provide the best medical treatment. PMID- 29701382 TI - Institutional Protocol for Prevention of TEVAR-related Spinal Cord Ischemia - The First 9 Cases. AB - INTRODUCTION: Spinal cord ischemia (SCI) is a feared complication after endovascular correction of thoracic aortic diseases (TEVAR). The guidelines of the European Society for Vascular Surgery recommend prophylactic lumbar drainage (LD) of cerebrospinal fluid in high-risk patients undergoing TEVAR. Our institutional protocol considers as high-risk patients as: coverage of the origin of the Adamkiewicz artery (T9-T12), aortic coverage >15 cm, involvement of collaterals (treated or untreated abdominal aortic aneurysm, left subclavian artery revascularization or bilateral occlusion of the internal iliac arteries) and symptomatic SCI. The objective of the study was to demonstrate the efficacy and safety of LD in preventing or treating SCI after TEVAR. METHODS: Patients submitted to LD in the perioperative period of TEVAR under the institutional protocol, between May 2015 and April 2017, were prospectively included. PRIMARY OUTCOME: prevention and/or reversal of neurological symptoms (efficacy). Secondary Outcome: complications related to the technique (safety). RESULTS: We included 8 patients with thoracoabdominal aneurysms and 1 patient with type B aortic dissection, aged 63- 75 years. Eight interventions were elective and one was urgent. The LD catheter was placed before surgery in 8 cases and in the postoperative period in 1 case due to symptomatology of SCI that reverted after liquor drainage. Of those placed pre-operatively, 2 had symptoms of SCI in the postoperative period, which alleviated with increased drainage and hemodynamic and hemoglobin optimization. The patient undergoing urgent TEVAR for ruptured thoracoabdominal aneurysm evolved with multiorgan dysfunction and death 24 hours after surgery. There were no other complications. CONCLUSION: In this initial experience, the institutional protocol with LD placement proved to be safe and effective in preventing and treating SCI after TEVAR. PMID- 29701383 TI - Aneurysms of the Upper Limb: Review of an Experience. AB - INTRODUCTION: True arterial aneurysms of the upper limb are rare and their treatment is intended to avoid complications as distal embolization or compression of surrounding neurovascular structures. The purpose of this study is to review the experience in the surgical treatment of true arterial aneurysms of the upper limb. METHODS: Retrospective study of patients with true arterial aneurysms of the upper limb surgically treated between January 2007 and August 2017. Nine patients were identified and data was collected regarding sex, age, past medical history, aneurysm's aetiology, surgical procedure, complications and the need for re-intervention. RESULTS: From a total of nine patients, seven were male and two were female, with ages between 29 and 68 years old (medium age of 55,5). One of the patients had surgery twice because of two aneurysms of the upper limb. From a total of 10 cases, two were subclavian, one was axillary and seven were brachial aneurysms. Three of them had degenerative/idiopathic aetiology, one was associated to a cervical rib and six occurred in the setting of arteriovenous fistula or kidney graft. Three patients had emergent surgery and the others had elective surgery. All of them were submitted to aneurysmectomy. As 30-day complications, there were two haematomas, one compartment syndrome and two early graft occlusions. Four patients needed re-intervention. During the follow up period, all the grafts initially preserved were patent. There were no further known complications or amputation procedures. One of the patients who had emergent surgery and presented with finger paresis remained with hypomotility after the surgery. CONCLUSION: True arterial aneurysms of the upper limb are uncommon. In this review most of the aneurysms were found in patients with haemodialysis vascular access or kidney grafts. Despite the need for early re intervention in some cases, the surgical treatment of true arterial aneurysms of the upper limb is a low morbidity procedure. PMID- 29701384 TI - Endothelial Function and Vascular Properties in Severe Aortic Stenosis Before and After Aortic Valve Replacement Surgery. AB - INTRODUCTION: The degenerative process that results in aortic valve stenosis (AS) has pathophysiological features similar to the atherosclerotic process. We therefore hypothesized that, as in atherosclerosis, endothelial and vascular dysfunction could be a pathophysiologic feature of AS. AIM: To evaluate endothelial function before and after aortic valve replacement (AVR) surgery in patients with severe AS. To correlate endothelial function with severity of AS and clinical profile. METHODS: Two noninvasive methods were used to evaluate endothelial function (Reactive Hyperemia Index (RHI) measure with EndoPATTM2000 system) and vascular properties (carotid-femoral Pulse Wave Velocity (PWV) measured by Complior(r) Analyse) in 13 patients with severe AS undergoing AVR. Sample was collected by convenience in a single-center between February and July of 2017. Pre- -operative, surgical and post-operative data were collected through clinical files and informatics databases. PWV, RHI, Augmentation Index (AI) were assessed at the day of surgery and 2.4+/-1.2 months post-operatively. Mean transvalvular gradients (MTG), aortic valve area (AVA) and left ventricular function were evaluated by transthoracic echocardiography at 3.4+/-1.6 months of follow-up. Wilcoxon or paired t-tests were used to compare pre- and post operative values of continuous variables. Spearman correlations (rho) were done to find associations between endothelial/ vascular function parameters and clinical data. RESULTS: In our sample, mean age was 70+/-8 years and 69% were females. Arterial hypertension was present in 11 (85%) patients, diabetes in 3 (23%) and pre-operative NYHA functional class >=III in 4 (31%). No patient was currently smoker and only 2 had previous history of smoking. No significant changes were observed between pre- and post-operative endothelial/vascular function values. PWV (m/s), AI (%) and RHI before and after AVR surgery were: 10.5 (6.1 to 16) vs. 9.4 (4.7 to 21.6), p=0.701; 33% [-24 to 54] vs. 23% [0 to 47], p=0.116 and 1.83 (1.08 to 3.13) vs. 1.71 (1.06 to 3.12), p=0.638, respectively. We found a significant inverse correlation between pre- operative AVA and AI (rho= -0.652, p=0.016) and a positive correlation between age and post operative PWV (rho= 0.639, p=0.019). Pre- and post-operative MTG and AVA were 54+/-5 mmHg and 0.7+/- 0.1 cm2 vs.12+/-4 mmHg and 2.0+/-0.5 cm2, respectively (p<0.001). CONCLUSION: Considering small sample size, no differences were found in indices of endothelial/vascular function before and after AVR surgery due to AS. However, it seems that endothelial dysfunction is associated with severity of AS assessed by AVA. PMID- 29701385 TI - Predictors of Acute Kidney Injury in the Postoperative Period of Cardiac Surgery Associated with Cardiopulmonary Bypass. AB - INTRODUCTION: Acute kidney injury (AKI) in the postoperative period of cardiac surgery occurs in 1 to 30% of the patients, mainly caused by ischemia secondary to renal hypoperfusion. Cardiopulmonary bypass (CPB) has a deleterious effect on renal function, constituting an aggression to the patient's homeostasis. AIM: To evaluate the incidence of AKI in the postoperative period of cardiac surgery in patients without preoperative renal insufficiency who underwent cardiac surgery with CPB, and explore the association between incidence of AKI and predictors related to CPB. METHODS: Observational, retrospective, cross-sectional study. Participants were divided in two groups, those who developed AKI in the postoperative period and those who did not develop AKI. KDIGO Clinical Practice Guideline for Acute Kidney Injury classification was used to characterize AKI. The preoperative variables analysed were anthropometric data, cardiovascular risk factors and blood parameters. The type of surgery, intraoperative variables related to CPB and postoperative creatinine variation were also analysed. The association between variables was studied using binary logistic regression. RESULTS: Of the 329 patients included, 62 (18.8%), developed AKI. There were statistically significant differences between the groups in age (p<0.001), CPB time (p=0.011), diuresis during CPB (p=0.038) and mannitol and furosemide administration during CPB (respectively, p=0.032 and p=0.013). Odds ratio showed a significant positive association between AKI and age (OR (95%)- 1.08 (1.04 1.11)), CPB time (OR (95%)-1.01 (1.00-1.01)), mannitol and furosemide administration during CPB (respectively, OR (95%)-2.29 (1.08-4.89) and OR (95%) 2.54 (1.21-5.30)). CONCLUSIONS: This study shows that a significant number of patients developed AKI in the postoperative period of cardiac surgery and this incidence was influenced by factors related to CPB. PMID- 29701386 TI - Simplified Technique for Aortic Arch Replacement in Patients at High Risk for Frozen Elephant Trunk. AB - INTRODUCTION: Surgical approach of multisegmental pathology of the thoracic aorta, namely aortic arch / descending aorta is challenging. The Frozen Elephant Trunk (FET) has good results, with acceptable risk. However, in the subgroup of patients (pts) older than 75 years and with important comorbidities, the surgical risk is very high. OBJECTIVES: Review short-term results of this original, simplified and potentially hybrid technique developed in our Department for this subgroup of patients. METHODS: From January 2016 to September 2017, 10 pts were operated with this technique - mean age 70.2 +/- 15.3 years, 7 males. The diagnoses were: 6 pts with aneurysmal disease and 4 pts with aortic dissection. Four pts had previous cardiac surgery. The surgical concept consists of 3 key points: 1) Use of a patient-tailored graft, built in a back-table, to replace the ascending aorta and arch, with side-branches proximally anastomosed to reroute the supra-aortic vessels, allowing a proximal, long Landing Zone for eventual TEVAR. 2) Debranching of the supra-aortic vessels. 3) Maintain bilateral anterograde selective cerebral perfusion. All pts were operated on cardiopulmonary bypass (CPB) with a period of hypothermic (24oC) cardiocirculatory arrest for the open distal anastomosis. Preservation of the left subclavian artery depended on paraplegia risk and was individually assessed preoperatively. In a second stage, a TEVAR was electively deployed in 2 patients. All patients were followed in our clinic and imaging clinic at 6 months and annually after surgery. RESULTS: Mean CPB, aortic cross clamping and visceral ischemia were, respectively, 196, 120 and 44 minutes. One pt died in- hospital due to bowel ischemia. Four pts had respiratory complications requiring prolonged ventilation. The mean ICU and hospital stay was, respectively, 7,8 and 23,6 days. The mean follow-up was 15.2 months and three pts died during this follow-up. One pt was re-hospitalized with deep sternal wound infection. Of the survivors, one had a stroke at 6 months postoperatively and the remainder are asymptomatic. The postoperative period of the 2 pts submitted to TEVAR was uneventful; to date, they remain surgically stable, without needing re-intervention. CONCLUSION: The technique is effective and avoids the burden of FET. The short-term results are encouraging but, in the long-term, they should be evaluated to determine their role among arch interventions, specially their value in relation to recent pure endovascular techniques with fenestrated or branched endoprosthesis. Long ICU and hospital stay points towards the implementation of measures and protocols to improve them. PMID- 29701387 TI - Ross Surgery: Our Experience. AB - INTRODUCTION: At Santa Marta Hospital, Ross Surgery was performed for the first time in 1999. Seventeen years later, it is mandatory to evaluate the mid and long term results of our experience, as well as prospect the future of this procedure. METHODS: Between March 1999 and June 2016, 23 Ross procedures were performed at our institution. We did a retrospective analysis of the patient's data, results of the surgery, complications, freedom from reoperation and mortality. RESULTS: The majority (36,4%) of the patients had aortic stenosis, 22,7% had aortic regurgitation and 27,3% had aortic stenosis and regurgitation. Sub-valvular stenosis was present in 13,6% of patients. The mean follow-up is 12 years. Eighty percent (n=16) of the survivors are in class I of NYHA, with the remaining 20% (n=4) in class II. In our series, 81% of the patients are free from reoperation. The overall cumulative mortality was 9%. There was no operative mortality. CONCLUSION: Ross surgery has specific indications and in this group of patients the advantages are undeniable and the results, according to our series are positive and encouraging. PMID- 29701388 TI - Trifecta Bioprothesis for Aortic Valve Replacement: Our Experience. AB - INTRODUCTION: Bioprosthesis are increasingly used for aortic valve replacement (AVR), as a result of increasing elderly patients, as well as, continuous improvements in durability and hemodynamic performance of pericardial prosthesis. The Trifecta aortic prosthesis is a latest-generation trileaflet stented pericardial valve designed for supra-annular placement in the aortic position. This study establishes the safety and early clinical and hemodynamic performance of the Trifecta valve. METHODS: We retrospectively analyzed the data of 373 consecutive patients that underwent surgical implantation of the pericardial stented aortic prosthesis (Trifecta valve; St Jude Medical, St Paul, Minn) at our institution from March 2014 (first implant) to March 2017 (3 years). Pre operative, operative and post-operative parameters and clinical outcomes, as well as, echocardiography data were evaluated. RESULTS: The mean age was 73,96 years +/- 51, 176 (47,18%) patients were male, mean body mass index of 28,14 +/- 12 and 75 (20,11%) were 380-years old. Concomitant procedures were performed in 123 (32,98%) patients. Isolated AVR was undertaken through conventional sternotomy (62,5%), partial sternotomy (35%) or anterior right minithoracotomy (2,5%). Prosthesis sizes implanted were: 19 mm (n=37), 21 mm (n=138), 23 mm (n=196) and 25 mm (n=2). The overall follow-up included 669 late patient-years. Early (<= 30 day) mortality occurred in 20 patients (5.36%), and there were 4 (1.07%) late (>= 31 days) deaths yielding a linearized mortality rate of 2.98% per late patient year. For isolated AVR, mortality occurred in 12 (3.22%) patients. The incidence of new onset atrial fibrillation/flutter was of 28.95% (n=108). Five patients had necessity for implantation of postoperative permanent pacemaker (1,34%), and four mediastinitis/ sternal dehiscence (1.07%) and thirty nine cases of major bleeding required surgery (10.46%). There were 2 early thromboembolic events, including 1 (0,27%) stroke and 1 (0,27%) systemic embolic event. There were no instances of early valve thrombosis, endocarditis, or clinically significant haemolysis. There were no late thromboembolic events or valve structural deterioration. In total, there was 1 late valve explant due to an endocarditis. Overall, freedom from valve explant was 99,77% per late patient- -year. At postoperative echocardiography, average mean gradients across all valve sizes was 10.63mmHg. Mean follow-up was 4+/- 2 months. No severe aortic regurgitation was observed. CONCLUSION: The present systematic review demonstrated that AVR with this prosthesis provided excellent early safety and hemodynamic outcomes with acceptable mean gradients; nevertheless, their timing, pathological characteristics, and clinical presentation mandate continued follow-up. PMID- 29701390 TI - Ascending Aorta Aneurysms in Octogenarians. AB - INTRODUCTION: Older age is often regarded as a relative contraindication for open surgery for aortic aneurysms. These individuals often have a greater comorbidity burden that predispose them for development of postoperative complications. The aim of our study is to evaluate the surgical outcomes of selected octogenarians after open aortic surgery. METHODS: We performed a retrospective observational study. We collected data from patients operated on by our team between January of 2012 to September of 2017. We performed univariate logistic regression and survival analysis to construct Kaplan Meier survival curves. RESULTS: We analysed data from 430 patients, and 31 patients fulfilled the inclusion criteria. 67.7% of the patients were male. The mean age was 81.5 +/- 1.8 years. The preoperative comorbidities were hypertension (83.9%), aortic valve disease (54.8%), dyslipidaemia (48.4%), renal impairment (9.7%), type 2 diabetes mellitus (9.7%) and COPD (3.2%). As for the procedures performed the majority was aortic valve replacement and graft interposition (48.4%) followed by graft interposition (35.5%), ascending aorta and arch replacement (9.7%) and graft interposition and combined CABG (6.5%). 16.1% of the procedures were reoperations and 6.5% were performed as urgent. In-hospital mortality was 9.4% and 1-year survival was 77.4%. The mean survival time after surgery was 736.4 +/- 530.3 days. As for complications, 22.6% developed respiratory complications, 6.5% had infectious complications and 3.2 developed renal and central nervous system complications. Older age was not related to early (p = 0.266) or late mortality (p = 0.779). There was no association between older age and longer ICU stay (p = 0.781) or total hospital stay (p = 0.985). CONCLUSIONS: Highly selected octogenarians benefit from surgery, having a similar rate of postoperative complications and survival, as described in the literature. PMID- 29701389 TI - Coronary Allograft Vasculopathy after Cardiac Transplantation: Prevalence, Prognostic and Risk Factors. AB - INTRODUCTION: Coronary allograft vasculopathy (CAV) is still a serious long-term complication after cardiac transplantation. PURPOSE: To evaluate the prevalence of CAV in a single institution, its impact on survival and to explore associated risk factors. METHODS: From November-2003 through June-2016, 316 patients were submitted to cardiac transplantation. After excluding those with paediatric age (n=8), those with previous renal or hepatic transplantation (n=2) and those who didn't survive the first year after cardiac transplantation (n=40), the study population resulted in 266 patients. Forty two patients (15.8%) with CAV, diagnosed by a new >50% coronary artery stenosis in any vessel during follow-up, were compared with a non-CAV group. RESULTS: Both groups share de same median age (54+10years). Recipient male sex predominated in the CAV group (93% vs. 74%), as did ischemic etiology (52% vs. 37%). Although not reaching statistical significance, CAV patients also had more dyslipidemia (60% vs. 50%), history of smoking (52% vs. 44%) and peripheral vascular disease (45% vs. 29%). The incidence of celular acute rejection 1R is more frequent in CAV group (69% vs. 60%) such as 2R or 3R (29% vs. 27%). Prolonged use of inotropic support and mechanical assistance after cardiac transplantation were comparable between both groups. The survival of this patients, who were submitted to cardiac transplantation and had lived at least 1 year, between CAV and non-CAV group was comparable at 5-year (91% vs. 85%), but tended to be lower for CAV patients in 10 year interval (52% vs. 73%). CONCLUSION: This data confirms CAV as a common long term complication following cardiac transplantation. Although short to mid-term survival seems not to be affected by CAV, long-term survival appears lower, hence a longer follow-up is needed. PMID- 29701391 TI - Diagnostic Challenges in Chronic Constrictive Pericarditis. AB - INTRODUCTION: Chronic constrictive pericarditis (CCP) is a disease that has multiple possible causes and is associated with variable clinical findings, depending on its severity. It develops insidiously, and in many cases, particularly in developed countries, no antecedent diagnosis can be found. These cases are termed idiopathic. Tuberculosis is the leading cause of constrictive pericarditis in developing nations but represents only a small minority in developed countries. METHODS: Here the authors describe two different case reports where tuberculosis was the probable cause of CCP. RESULTS: A 21-year-old man born in Cape Verde living in Europe for 4 years and a 24-year-old man born in Guine Bissau were both admitted due to intense precordial pain and syncope after exertion. Interestingly both had fatigability, dyspnea, chest discomfort and palpitations on exertion, as well as progressive involuntary weight loss and decubitus cough. On physical examination they had tachycardia, jaundice, cachexia, elevated jugular venous pressure, hepatomegaly and ascites. Both electrocardiograms showed prominent P waves and chest X-ray showed bilateral pulmonary interstitial infiltrates and enlargement of the right cavities. Analytically, elevated bilirubin, leukopenia and thrombocytopenia was also found in both. Echocardiography revealed findings, in both cases, compatible with CCP including less common signs as annulus reversus and annulus paradoxus. Thoraco abdomino-pelvic CT from both patients revealed chronic liver disease with congestion, pleural effusion, pericardial calcifications, ascites and massive mediastinal and abdominal adenopathies. Blood cultures and IGRA test were negative. However, given the presumptive diagnosis of tuberculosis (TB), anti-TB therapy was started. Despite the diagnosis of "end-stage" CCP with very high operative risk multidisciplinary team decided after informed consent, to perform total anterior pericardiectomy, that occurred without complications. Pericardial and mediastinal biopsies, pericardial/pleural fluid cultures/ immune-phenotyping were inconclusive. Anti- tuberculosis therapy was maintained. After surgery, the patients had a remarkable clinical improvement (NYHA I) that persisted in 6- month follow-up. CONCLUSION: These two case reports illustrate that despite the markedly elevated operative risk of pericardiectomy in "end-stage" forms of disease after patients informed consent must be a considered option. The other point to consider is that, despite rare, tuberculosis still is a possible diagnosis to consider in CCP in Portugal. PMID- 29701392 TI - Cardiac Fibroelastoma: 10-Year Experience. AB - INTRODUCTION: Papillary fibroelastoma is one of the most common types of primary cardiac tumour. Though a rare pathology, its importance relates to its form of presentation, with stroke and sudden death, and the questions regarding its management. OBJECTIVES: To review the casuistic of cardiac tumours in our service, in special the papillary fibroelastomas. METHODS: clinical case series overviewing the period from 1st January 2008 to 30th September 2017. We analysed all patients submitted to cardiac surgery due to cardiac masses or tumours and verified all the pathology results to confirm the diagnosis. RESULTS: In the period selected, around 6500 surgeries were performed. Of those, 59 patients were operated on due to cardiac tumours. 81.4% were myxomas, 13.6% were papillary fibroelastomas, 3.4% were cardiac sarcomas and 1.7% were metastasis. Of the patients that had papillary fibroelastomas (n=8), 5 were male, and the mean age was 51.5 +/- 16.2 years. 62.5% (n=5) had origin in the aortic valve and 37.5% (n=3) in the mitral valve. Regarding presentation, 3 patients presented with stroke, 2 patients had episodes of syncope and 3 patients were asymptomatic. After surgery, all patients remained asymptomatic and there was no evidence of recurrence. At the end of follow-up all patients were alive. CONCLUSION: Although a rare pathology, papillary fibroelastomas remain important due to their potential for embolization and cardiac chamber obstruction, therefore should be primarily treated with surgery. PMID- 29701393 TI - IGG4 Disease And Slerosing Aortitis. AB - INTRODUCTION: IgG4-related disease (IgG4-RD) is an immune- -mediated fibro inflammatory condition with unknown etiology that can affect various organs. Although its prevalence is still unknown, it appears to be more frequent in adult males. Cardiovascular manifestations are rare and can include idiopathic retroperitoneal periaortic fibrosis, inflammatory aortic aneurism, inflammatory periarteritis and inflammatory pericarditis. Vascular involvement is a well recognized feature and large vessel commitment, especially the aorta, can be the only manifestation of the disease. The gold standard diagnosis is histological. METHODS: A 47-year-old man presented rupture of two aortic aneurysms: one thoracic and one abdominal, and underwent surgical correction. A segment of the aorta artery wall measuring 3x2x0.5cm, exhibited smooth intimate and white vinous adventitia, medium tunic was white, through firm tissue with loss of elasticity. RESULTS: In addition to heterogenous collagenation with destruction of the elastic network of the aortic mediae tunica, there was fibrin deposition and neutrophil overlap. Lymphoid follicles with reactive germinate centers were along the tunica media and adventitia, without phenotype of endothelitis and absence of either macrophages and Langerhans cells (CD1a). Plasmocytes showed immunopositivity to IgG4, with heterogeneous and well defined localization, supporting the diagnosis of igG4 Disease. Serological studies showed negativity for vasculitis, hereditary connective tissue diseases were not component of the clinical set and normal serum IgG4 concentration was determined. CONCLUSION: Few cases of involvement of large vessels by IgG4- -RD have been reported in literature. Serum IgG4 concentration may be normal in one third of patients. In this case, IgG4 immunostaining was crucial for the diagnosis of IgG4-RD aortitis, together with the hyaline destruction of the tunica media (ESP 2015 / Aagaimy 2013). There is still no clinical knowledge for the treatment and monitoring of the involvement of large vessels by IgG4-RD. PMID- 29701394 TI - Ascending Aorta Aneyrysms Over 70mm. AB - INTRODUCTION: Current guidelines suggest that patients with aortic diameter over 55-60 mm should undergo ascending aorta replacement, depending on associated valve pathology and other comorbidities. Studies show that the risk of aortic rupture over 60 mm is over 30%. Even though, we still receive in our practice patients that present with aneurysms of greater dimensions. The aim of our study is to evaluate the surgical outcomes of patients presenting with ascending aorta with diameter larger than 70 mm. METHODS: We performed a retrospective observational study. We collected data from patients operated on by our team between January of 2012 to September of 2017. We performed univariate logistic regression and survival analysis to construct Kaplan Meier survival curves. RESULTS: We analysed data from 430 patients, and 31 patients fulfilled the inclusion criteria. 64.5% of the patients were male. The mean age was 67.9 +/- 12.9 years. The preoperative comorbidities were hypertension (64.5%), dyslipidaemia (45.2%), aortic valve disease (35.4%), renal impairment (9.7%) and COPD (3.2%). The average diameter was 82.3 +/- 18.6 mm, with values ranging from 70 to 160 millimeters. As for the procedures performed the majority was interposition of prosthetic graft (45.2%), followed by aortic valve replacement and graft interposition (35.5%), Frozen Elephant Trunk (12.9%), tube interposition and combined CABG (3.2%) and aortic root replacement with graft interposition (3.2%). 9.7% of the procedures were reoperations and 9.7% were performed as urgent. In-hospital mortality was 3.2% and 1-year survival was 83.9%. The mean survival time after surgery was 1135.9 +/- 777.1 days. As for complications, 29% developed respiratory complications, 9.7% had cardiac complications, 6.5% had central nervous system complications and 3.2% developed renal and vascular complications. Greater diameter was not associated with early (p = 0.929) or late mortality (p = 0.987). CONCLUSIONS: These results show that patients with aneurysms greater than 70 mm can be safely operated on, with no increase in complications in the postoperative period or greater mortality. PMID- 29701395 TI - Elective 2nd Stage TEVAR to Complete Frozen Elephant Trunk in the Surgical Correction of Complex Multisegmental Pathology of the Thoracic Aorta. AB - INTRODUCTION: Classical conventional surgery to treat multi-segmental thoracic aortic disease in two operative stages, sternotomy and left thoracotomy, is associated with significant mortality and complications. The Frozen Elephant Trunk (FET) associated with an endovascular procedure (TEVAR) allows an extensible and simplified surgical approach of the descending and thoracoabdominal aorta without increasing the risk. METHODS: Retrospective study of 8 patients (pts), 5 males, mean age 67.5 +/- 4.2 years, with ascending and arch disease associated with descending aortic disease (chronic dissection 2 pts, aneurysmal disease 6 pts), treated between January 2014 and September 2017. All survivors are periodically followed up in our outpatient clinic with CT or MRI angiography. RESULTS: The average follow-up period is 18,7 +/- 12,2 months. In the first stage (FET) - the left subclavian was conserved in all cases. In six of these pts, after an average period of 37 days, a TEVAR was performed, to complete the exclusion of the aneurysmal sac or the false lumen in the descending aorta. In 2 pts, the interval was longer and in the same intervention, a fenestrated endoprosthesis was implanted in the abdominal aorta by the vascular team. After TEVAR, mean ICU time was 16 hours and hospitalization was 5,2 days. One pt died in the 1st month post-intervention TEVAR + EVAR fenestrated. The remaining pts are stable and asymptomatic, in Class I NYHA, without endoleaks and with the expected involution of the aneurysmal sac and positive remodeling of the aorta. There were no cases of paraplegia or other neurological complications documented. CONCLUSION: This strategy is safe and effective. Clinical follow- -up associated with close postoperative imaging surveillance is required not only to determine the optimal interval between the two stages, which is dependent on the anatomy and underlying pathology of each patient, but also to identify possible complications. The quality of life of these pts in the medium-term is excellent. PMID- 29701396 TI - Takayasus's Aortitis Induced Ascending Aorta Dissection. AB - INTRODUCTION: Takayasu aortitis is a well known yet rare form of large vessel vasculitis. Also known as pulseless disease, occlusive thromboaortopathy, and Martorell syndrome, is a chronic inflammatory aortitis. Vessel inflammation leads to wall thickening, fibrosis, stenosis, and thrombus formation. METHODS: A 64 year-old woman was referred to emergency for lack of pulse in the upper and lower limbs and changes in heart rate. AngioRMN revealed dissection of the ascending aorta while in PET, intense uptake of FDG-F18 involving ascending, crossa, descending thoracic and abdominal segments of the aorta, was evident urgent surgical correction occurred. An aorta ring segment with 2.5cm length, showed whitish and smooth intimate, with linear transversal laceration, with regular borders. Dissection 1cm long of the medial tunica was occupied by a clot in continuity with a thrombus occupying the neoformed lumen. RESULTS: Microscopy examination confirmed hyalinization of the tunica media with impregnation of fibrin / thrombus with blood cell elements. Endothelial inflammatory characteristics together with vasa vasorum and vascular trajectory of the periphery of the tunica media with inflammatory cells involvement allowed the diagnosis of Takayasu aortitis. CONCLUSION: Takayasu aortitis is rare in the presented age group, with early non-specific symptoms. The diagnosis of aortic dissection was crucial, constituting a medical emergency. Heather L-Gomik (2008) supports the hyaline structural alteration of the tunica media. The disease has been recognized for more than 100 years, and patients with Takayasu aortitis remain relatively poor and treatment is suboptimal. Key areas for improvement include the need for increase disease awareness and earlier diagnosis, and improved means for monitoring disease activity. The demonstration of diferential expression of Toll-like receptors in arteries, is particularly intriguing and worthy of further investigation. PMID- 29701397 TI - Syphilitic Aortitis Diagnosis in Clinical Setting. AB - INTRODUCTION: Cardiovascular syphilis can manifest as aortic aneurysms, aortic regurgitation and coronary ostial stenosis. Tertiary syphilis was the most commom reported cause of thoracic aortic aneurysm in the pre-antibiotic era, contributing to 5- 10% of cardiovascular deaths. However, in the 21st century, it has virtually disappered from the devoloping nations. Tertiay syphilis may develop in about one third of cases of untreated syphilis. In the pre-penicilin era, it was calculated that cardiovascular syphilis was responsible for 10-15% of clinical syphilis. METHODS: We present a rare case of syphilitic aortitis in a era of highly effective antibiotics. RESULTS: A 48-year-old man with no known clinical cardiac pathology went to emergency with an episode of chest pain of short duration and great intensity, being hospitalized with a differential diagnosis of coronary disease, ascending aortic aneurysm and aortic valve regurgitation. Two segments of the aorta, 5cm and 9.5cm length were observed, both had thickened wall (1cm), and firm plaques with diferent shapes and sizes. The intima of the aorta appeared rough and pitted, with the appearance of tree bark. There were heterogeneous lesions of the tunica media: hyalinization and calcification, macrophages aggregates, areas of hemorrhage and lymphoplasmacytic infiltrate forming vascular sheaths. Adventitia exhibited hyperplasia of nerve pathways with surrounding lymphoplasmocytic infiltrate. The diagnosis of syphilitic aortitis was purposed and serological analysis revealed positivity for Treponema pallidum. Patient underwent surgical correction of an aortic aneurysm. CONCLUSION: The serological positivity for Treponema pallidum and the histopathological study allowed the currently rare diagnosis of Ascending Aortic Aneurysm by Tertiary Syphilis. In the present scenario with early and widespread use of antibiotics, it is considered a very rare disease. PMID- 29701398 TI - Trauma: An Unusual Cause of Endocarditis. AB - INTRODUCTION: Infective endocarditis (IE) remains a dangerous condition with considerable associated mortality. Usual risk factors for IE include the presence of a prosthetic heart valve, structural or congenital heart disease, intravenous drug use, and a recent history of invasive procedures. METHODS: The authors describe the case report of a patient with IE having trauma as an unusual risk factor. RESULTS: A 33-year old male patient was referred to our department due to infective endocarditis. The patient had a fever of unknown origin for 15 days before going to the emergency department. After admission it was identified by transthoracic echocardiography a 14mm posterior abscess of the aortic valve provoking major aortic regurgitation with moderate LV dysfunction. After careful evaluation of the clinical history it was found that the patient had a known bicuspid aortic valve with follow-up since the age of 14. All other usual risk factors for IE were excluded, including intravenous drug use and recent history of invasive procedures. The only relevant previous event was a traumatic haemathoma in his left jaw caused by a working accident with an iron beam in a construction site as the patient is a civil engineer. Vancomycin plus gentamicin were empirically started after blood cultures taken. The isolated infective agent was Staphylococcus lugdunensis methicillin sensitive and the antibiotherapy was de-escalated to flucloxacilin plus gentamicin. Due to cardiac dysfunction the patient was submitted to cardiac surgery on the fourth day of directed antibiotic therapy and a replacement of the aortic valve by a mechanical prosthetic valve and closure of the abscess with bovine pericardial patch was performed. The valve sent to microbiology evaluation showed the same infective provocative agent. The patient had a good clinical and laboratorial recovery completing the 42-day antibiotic scheme. After antibiotherapy period completion, echocardiography was repeated and the abscess found was larger then the previous one, presenting itself like an aortic pseudo aneurysm. The patient was resubmitted to surgery with re-closure of the initial abscess with autologous pericardial patch and replacement of the prosthetic mechanical valve for an undersized one. The patient was discharger clinically well, having a complete normal life at the moment. CONCLUSION: This clinical case illustrates trauma as an unusual cause of endocarditis and emphasizes the importance of a detailed clinical history. PMID- 29701399 TI - Predictors of Prognosis in Patients with Type B Aortic Dissection. AB - INTRODUCTION: Type B aortic dissection (TBAD) affects mostly men with an estimated annual incidence between 2.9 and 4.0 per 100,000, and it appears to be increasing. DISSECT classification was published in 2013 aiming to reunite clinical and anatomical characteristics of interest to clinicians involved in TBAD management. In Portugal, the incidence of the condition, as well as its characteristics and outcomes, are not well documented. The aim of this paper is to describe the reality of a tertiary institution with a referral area of about 0,6 million habitants. METHODS: It is a retrospective study that included all patients with TBAD admitted from March of 2006 to 2016. The patients were categorized according to their demographic and clinical characteristics. For each patient, the computerized tomography scan that enable the TBAD diagnosis was classified using DISSECT classification. Overall mortality rates and aorta related mortality rates were estimated using Kaplan-Meier method. Cox regression was used to study determinants of mortality. RESULTS: We included 35 patients, estimating a TBAD incidence of approximately 0.6 per 100,000 person-year. The majority were men (83%) with a mean age of 60+/-12 years-old; 71% were hypertensive, 56% were ex-smokers or active smokers and 13% had diabetes. As to DISSECT classification, 76% were acute (Duration), 66% had a primary Intimal tear location in aortic arch, the maximum trans-aortic diameter was 44+/-13mm (Size), 60% extended from aortic arch to abdomen or iliac arteries (Segmental extent), 26% presented with Complications, being rupture and branch vessel malperfusion the most frequent, and 28% had partial Thrombosis of false lumen (versus 66% with permeability of false lumen). Eight patients underwent surgery (24%), 6 of them in acute phase and 2 of them in subacute phase. At 12 months, overall survival of whole series was 73,1%+/-8,3% and survival free from aortic-related mortality was 83+/-6,7% (Figure 1 A and B). The presence of complications was identified as an independent risk factor of overall mortality but not to aortic-related mortality. CONCLUSION: The incidence of TBAD verified was lower than what has been described in literature. DISSECT classification can be easily applied to TBAD cases. The presence of complications predicts higher mortality. Further studies are needed to characterize TBAD in Portugal. PMID- 29701400 TI - Endovascular Treatment of Carotid Blowout Syndrome. AB - INTRODUCTION: Carotid blowout syndrome (CBS) is a life threatening complication associated with head and neck cancers (HNC) and its treatment. The mortality rate was reported to range from 3% to over 50% in the literature. Direct surgical repair of the ruptured internal carotid artery is often not technically possible due to the difficult anatomy and underlying poor co-morbid status. Endovascular techniques such as coil embolization and stent grafting offer an alternative to surgical ligation with better patient outcomes. METHODS: We describe the successful use of an endovascular approach in a case of emergent rupture of the common carotid artery (CCA) with massive bleeding in a patient submitted to radiotheraphy for the treatment of a neck malignancy. RESULTS: A 75-year-old man with a squamous cell carcinoma of the esophagus having undergone chemotherapy and radiotherapy, was admitted to the emergency room with haematemesis with approximately 1 hour of evolution. An angiogram revealed, in the right common carotid artery, contrast extravasation with a possible fistula communicating to the esophagus. A self-expandable covered stent was deployed in the right common carotid artery. Successful repair of the vessel was confirmed in the control angiogram. The patient was discharged 10 days later without neurological deficit or recurrent bleeding. Carotid blowout syndrome is one of the most complex bleeding complications that may occur in HNC patients. It is usually a life threatening event and is accompanied with unexpectedly massive bleeding and high mortality/morbidity rates. Short and long term effects of radiation over arteries have been reported. Radiation can induce damage to the vasa vasorum of large arteries and it might lead to the rupture of arteries. In the HNC population with previous surgery or radiotherapy, a high index of suspicion must be maintained for CBS in patients presenting with any recent history of oral bleeding or haemorrhaging from an exposed neck wound. CONCLUSION: Current evidence shows that there was no significant difference in technical and hemostatic outcomes between the reconstructive and deconstructive endovascular methods. Permanent vessel occlusion resulted in higher immediately cerebral ischemia and stent grafting induced the more potentially delayed complications, such as infection, rebleeding, and stent thrombosis. In the present case, the endovascular management of CBS of the common carotid artery had high technical success and allowed immediate haemostasis. It has been suggested that self-expanding stent grafts are useful for the initial control of carotid bleeding but are associated with more delayed complications. PMID- 29701401 TI - Endovascular Treatment of Proper Hepatic Artery Aneurysm - Case Report. AB - INTRODUCTION: Hepatic artery aneurysms (HAAs) are rare, representing about 0.1-2% of all arterial aneurysms. They are the second most common splanchnic aneurysms, after splenic artery aneurysms. They have the highest rate of rupture among all splanchnic artery aneurysms and frequently become symptomatic. METHODS: To present a case of a hepatic artery aneurysm treated by endovascular technique. RESULTS: A 65-year old man who had a medical history of hypertension, dyslipidemia and smoking, with an incidental finding on a CT imaging of a hepatic artery aneurysm (maximum diameter 75mm) was admitted for selective arteriography and treatment. He was asymptomatic. We proceeded to aneurysm exclusion with a self-expandable covered stent (Viabahn(r)) 6x100mm. Final angiography revealed permeability of right hepatic artery, splenic artery and gastroduodenal artery, and no visible endoleaks. He was discharged on the 4th postoperative day, asymptomatic and without analytic changes. On a 6 months follow-up, CT-angio confirmed a fully patent stent with no visible endoleaks and complete aneurysm exclusion. CONCLUSION: HAAs should be diagnosed before rupture. Abdominal pain, bleeding or compression may be the first symptoms. Exclusion by endovascular techniques, namely through covered- stent use, may be a good option. PMID- 29701402 TI - Endovascular Treatment of a Complicated Type B Acute Aortic Dissection with 3-D ultrasound Control. AB - INTRODUCTION: Acute type B aortic dissection (ATBAD), identified within 2 weeks of symptom onset, accounts for 25%-40% of all aortic dissections. Approximately 25% of patients presenting with ATBAD are complicated at admission by malperfusion syndrome or hemodynamic instability, resulting in a high risk of early death when untreated. METHODS: We present a case of a patient with a complicated type B dissection treated by an endovascular technique with control of the sealing zone with transesophageal Echocardiogram (TEE) and 3-D images. RESULTS: A 56-year-old patient was admitted to the intensive care unit for having a type B aortic dissection complicated by persistent chest pain and uncontrolled hypertension. We perform a TEVAR (thoracic endovascular aortic repair) with a GORE(r) TAG(r) conformable thoracic stent graft with active control system to seal the primary entry tear, which covered the left subclavian artery. The origin of the left subclavian artery was covered by the stent graft and a vascular plug was put in place, to avoid endoleak. The procedure was performed with transesophageal echocardiogram with 3-D images to determine if the stent graft was in the true lumen. CONCLUSION: The treatment of acute, complicated type B aortic dissection has evolved in the past several years. Thoracic endovascular aortic repair when anatomy is suitable, has been regarded as the preferable treatment to seal the primary entry tear, redirect and re-establish adequate true lumen flow, and thereby promote aortic remodeling. The availability of TEVAR, albeit applied until recently as an off- -label treatment, has clearly produced better results than procedures such as open surgical or endovascular fenestration. However, the results of this treatment may improve when associated with other imaging tests. The TEE has a high performance in the diagnosis of this pathology, especially in regard to the detection of the flap and the two lumens, as well as for the calculation of the size of the entrance tear. It presents an added value in the endovascular treatment, since it helps in the implantation of the devices both for the location of the true lumen, its definitive position and the result of the procedure. TEVAR is the preferred treatment for acute, complicated type B aortic dissection with improved late survival and positive aortic remodelling. The efficacy of this treatment is significantly increased in association with other imaging techniques such as transesophageal echography. PMID- 29701403 TI - Hostile Thoracic Aortic Aneurysm Treated by Fenestrated Thoracic Stentgraft with Proximal Sealing in Ishimaru Zone 0. AB - INTRODUCTION: Thoracic endovascular aortic aneurysm repair (TEVAR) is an established treatment for thoracic aortic disease in both the acute and elective setting, with such a widespread use that almost 50% of all thoracic aortic surgery in Europe is performed by these means. Nonetheless, the feasibility of TEVAR is determined by several anatomic factors, and the suitability of the proximal and distal landing zones remain one of the main limitations to its use. The advent of custom-made thoracic stent grafts widened the endovascular options in some challenging anatomies. METHODS: The authors present a case report of a descending thoracic aortic pseudo-aneurysm, with no suitable proximal landing zone, successfully treated by means of a custom- -made fenestrated thoracic stent graft. RESULTS: Male patient, 57 years old, with multiple cardiovascular risk factors and past medical history of coronary hearth disease, pulmonary emphysema and high speed trauma 20 years before. The patient was referred after being diagnosed with an asymptomatic saccular pseudo-aneurysm of the descending thoracic aorta, with 50mm of largest diameter and located at the level of the aortic isthmus. Inadequate proximal sealing was evident, even if deliberate left subclavian and carotid coverage were performed. Due to the prohibitive open surgical risk, and taking into account the post-traumatic etiology of the lesion, an endovascular solution was planned. The patient was therefore sequentially treated by means of a left carotid- subclavian bypass followed by custom-made fenestrated TEVAR, with a single fenestration for both the left common carotid artery and brachiocephalic trunk, granting proper sealing in the distal ascending aorta (Ishimaru zone 0). Rapid pacing was used during the implantation, with heart frequency of 180 bpm and systolic pressures of 40mmHg, allowing for a more precise deployment with no windsock effect. The procedure was successful and uneventful, with no intra-operative endoleaks, birdbeaks or retrograde dissections. There are no reported complications at 6 months follow-up. CONCLUSION: Custom-made fenestrated thoracic stentgrafts are an accessible, reproducible and safe therapeutic option when dealing with hostile thoracic arch anatomies, and should be considered as a minimally-invasive effective solution in selected cases. PMID- 29701404 TI - Digital Subtraction Angiography or Computed Tomography Angiography in the Preoperative Evaluation of Lower Limb Peripheral Artery Disease - A Comparative Analysis. AB - INTRODUCTION: For several years, digital subtraction angiography (DSA) was considered the gold standard method for the evaluation of PAD patients. This is an invasive technique and allows a good evaluation of collaterals and the vessel lumen, even in cases with associated calcification. Nevertheless, recent technical development of computed tomography angiography (CTA) has improved its specificity and sensibility, besides the fact that CTA is a fast and non-invasive procedure. OBJECTIVE: To characterize a cohort of lower limb PAD patients and clarify if there are differences among the patients preoperatively evaluated by DSA or CTA. METHODS: This retrospective study focused on PAD patients with a Rutherford classification >= 3 and submitted to intervention (endovascular revascularization or open surgery). The CTA group included all patients submitted to this method as their preoperative exam, between March 2009 and April 2017. In the same period of time, patients submitted to DSA as their preoperative exam, were randomly selected. The exclusion criteria were: realization of the exam for a different diagnosis than PAD, amputation not preceded by revascularization, absence of intervention during a period of 1 year after the realization of the exam. The groups were compared upon the type of surgery (open vs endovascular), number of revascularization sectors, reintervention, amputation, mortality and length of hospital stay. RESULTS: 34 CTA patients and 71 DSA patients were included. The groups were demographically and clinically homogeneous. In what regards to arterial lesions, the DSA group showed more often lesions of the distal sector with TASC C or D classification (25% in DSA group and 0% in CTA group; p=0,001), as well as scarcity of runoff vessels (0 or 1 in 72% of DSA patients group and 26% in CTA group; p=0.001). There were no differences about the endovascular and open surgery ratio (1.8 to CTA and 1.4 to DSA; p=0.305), reintervention rates (21% CTA and 16% DSA; p=0.517), major amputation (9% CTA and 11% DSA; p=1), minor amputation (9% CTA and 16% DSA; p=0.541), mortality (18% CTA and 23% DSA; p=0,602), or length of hospital stay (median and (interquartile range) of 14 (27) for CTA and 14 (17) for DSA; p=0.933). CONCLUSION: CTA seems to be a method for morphological and therapeutic planning of PAD that is non inferior to DSA. PMID- 29701405 TI - Deep Vein Thrombosis as First Manifestation of Hibernoma - A Case Report. AB - INTRODUCTION: Hibernoma is a very rare benign tumor that arises from vestigial remnants of fetal brown adipose cells and usually manifests as a slowly growing, painless soft-tissue mass. It mainly occurs in adults, in the third and fourth decade of life, slightly more in women and is commonly seen in the subcutaneous regions of the back, neck, thighs and retroperitoneum. It was originally described in 1906 by Merkel, who named it "pseudolipoma". In 1914, Gery derived the name hibernoma from the tumor's histological similarity to brown fat in hibernating animals. A hibernoma may be confused with a lipoma clinically and cannot be completely distinguished from hypervascular lesions such as lipossarcoma. METHODS: A 36-year-old woman presented with pain and edema of the left leg. It was diagnosed with non-recent femoro- -popliteal venous thrombosis, was medicated with rivaroxaban and prescribed compression stocking. RESULTS: The edema subsided after 2 weeks but she still complained of pain in the thigh several weeks after first visit along with subtle localized soft enlargement in the upper thigh. It was requested a CT scan that showed a nodular image with 60X 47 mm medially to vastus intermedius and beneath the sartorius and rectus femoris muscles, which was suspected to be a lipossarcoma. In this context, a magnetic ressonance imaging was requested and showed contact with femoral vessels with no cleavage plan, suspected to be a mixoid lipossarcoma. The biopsy didn't show malignancy. She was operated with local excision of the mass and preservation of adjacent structures. Pathologic evaluation revealed a hibernoma with 11.5 cm, PS100 positive and MDM2 negative. The patient was evaluated at outpatient clinic 6 months after surgery and had no evidence of relapse. CONCLUSION: The first clinical manifestation of this patient was a deep vein thrombosis and the diagnosis of the lipomatous tumor was delayed. Clinical awareness of less frequent causes of DVT is a key point to timely detection of this lesions that are rare and curable. The increased vascularity of this lesion raised suspicion of malignancy. Malignancy potential is perhaps the most difficult aspect to ascertain in this patient, being only completely disclosed after surgical excision. Optimal treatment is complete surgical resection. Local recurrence does not occur with complete excision. No reports of metastases of malignant transformation have been identified in the reviewed literature. PMID- 29701406 TI - Infrarenal Abdominal Penetrating Aortic Ulcer, an Atypical Location of a Rare Disease. AB - INTRODUCTION: Penetrating aortic ulcer (PAU) is classically included in acute aortic syndromes, together with aortic dissection and intramural hematoma. These three disorders are considered different stages of the same disease. PAU is the result of medial degeneration with disruption of the intima, mainly due to atherosclerotic risk factors. Most of them are located on descending thoracic aorta and only a few small series and case reports demonstrate location on infrarenal abdominal aorta. Clinical presentation varies in spectrum, from asymptomatic to fatal aortic rupture. Treatment options include medical therapy, particularly strict blood pressure control, and surgical approach. Nowadays endovascular exclusion is commonly performed, although open surgical reconstruction remains the gold standard. METHODS: Report a case of endovascular repair of an infrarenal abdominal PAU. RESULTS: A 72-year-old man, with hypertension, type 2 diabetes, hypercholesterolemia, lumbar osteoarthrosis, was referred to Vascular Surgery outpatient clinic with the diagnosis of infrarenal abdominal PAU on a Computed Tomography Angiography (CTA). This exam was performed due to chronic lumbar complaints from lumbar osteoarthrosis. The patient denied any other complaint. Physical examination was normal. A thoraco-abdomino-pelvic CTA revealed two sites of PAU in the infrarenal aorta with 10mm and 21mm of depth and associated aortic enlargement of 39mm maximum diameter. This exam revealed an enlargement of the depth of the PAU and the aorta diameter in 2 and 3mm, respectively, in the course of 2 months. An EVAR was performed, in a standard aorto-biiliac fashion. The post-operative period was uneventful and the patient discharged 3 days later. 1 month after the surgery, patient remained asymptomatic and the follow-up CTA demonstrated exclusion of both PAU, no endoleaks and stability of aortic diameter. A long term follow-up should be maintained, as for regular EVAR. CONCLUSION: PAU is a rare clinical entity, with infrarenal abdominal aorta location even scarcer. Asymptomatic patient must be regularly followed and threshold to treatment low, bearing in mind the possible catastrophic evolution of the disease. Endovascular approach should be considered as a first approach, considering the technical feasibility and the comorbidities associated with this elderly population. PMID- 29701407 TI - Creative Vascular Access Construction in Same Patient. AB - INTRODUCTION: Creating and maintaining a functional vascular access(VA) is a critical factor in the survival of a dialysis patient. However, it will not function forever, implying a creative attitude from the vascular surgeon either to maintain its functionality or built a new one wherever possible, being it autologous or synthetic. METHODS: Describe the VA history of a 59years-old male with morbid obesity and end-stage chronic kidney disease. RESULTS: His VA construction started in2012 with failed attempts in both forearms until a functional brachiocephalic artery-venous fistula(AVF) in the right upper limb was achieved, but was deemed to ligation as severe venous hypertension secondary to central venous disease related to CVC use. As he had no good superficial conduit in the left arm we decided to harvest the deemed right cephalic vein and implant it in the left arm, creating an autologous arteriovenous shunt between the brachial artery and axillary vein(AV). Despite initial patency, it failed irreversibly weeks after creation. As no more superficial veins were available in the upper limbs, a prosthetic access was the next step. We decided for a hybrid graft(HG) between the left brachial artery and the AV because the patient biotope and a scarred axilla impeded a safe reintervention on the AV. This graft was being used since 2015 with multiple interventions for maintaining patency (PTA, segmental graft replacement and thrombectomies). Recently we noticed a significant diffuse prosthesis deterioration and reduced AVF flow with no possible segmental reconstruction. We were then forced to proceed with total graft substitution preserving the outflow stented segment of the HG, using an early cannulation graft(ECG) and prevent CVC use. After this successful reconstruction, the patient started hemodialysis on the following day with no intercurrences registered. DISCUSSION: Generally, CVC's are related with poorer dialysis quality and patient survival.Hence, fighting for any other functional access is very important. The range of solutions will depend on the vascular surgeon capacities, imagination and device access. Once faced with no more feasible direct autologous access, there is a range of complex autologous fistulas, including veins translocations. When no more native vessel can be used for puncture, we still have a wide armamentarium (normal grafts, ECG or HG) that should be considered according to patient specifications. HG besides some hemodynamic advantages, can be very useful when the landing vessels are difficult to access. ECG offer the advantage of almost immediate cannulation, preventing CVC placement and its associated comorbidities. PMID- 29701408 TI - Percutaneous Treatment Pseudo-Aneurism of the Hand in Hemophilic Patient. AB - INTRODUCTION: Pseudo aneurysms of the hand are infrequent lesions, usually associated with perforating trauma. The diagnosis is based on clinical suspicion and image confirmation of a pulsatile swelling. Various treatment modalities are currently described in the literature. METHODS: Presentation of a clinical case and discussion of the treatment strategy instituted. RESULTS: Clinical case: Man, 35 years old, with hemophilia A. History of perforating trauma of the palmar face of the right hand 3 weeks ago, having been sutured in the local hospital. Since then he notices a pulsatile swelling in the palm of the hand associated with paresthesias and decreased sensitivity in the index finger. A pseudo-aneurysm with 2x3cm was observed, partially thrombosed, and with probable origin in the palmar arch or in the common digital artery. He underwent angiography demonstrating the patency of the palmar arch but without perfusion of the pseudo aneurysm, and the control dupplex scan showed complete thrombosis of the false aneurysm. After 2 months of follow-up, the dupplex scan was repeated and repermeabilization of the pseudo-aneurysm was verified. The patient was then treated with percutaneous Doppler-guided thrombin injection. Immediate thrombosis of the lesion was found, with no evidence of ischemic complications. He remained asymptomatic under clinical surveillance. CONCLUSION: For small pseudo-aneurysm conservative non- -interventional treatment with external compression may be effective. Conventional surgical treatment with simple ligation or arterial reconstruction may be indicated in larger pseudo-aneurysm. Recently, endovascular techniques such as coil embolization have also been described. Hemophilia A is a genetic disease of recessive hereditary transmission linked to the X chromosome, with deficiency of factor VIII of the coagulation cascade, which manifests with increased risk of hemorrhage. In this particular case, given the risk of hemorrhage, we chose minimally invasive percutaneous treatment, with clinical and imagological success and no complications. Percutaneous treatment by ecodoppler- guided injection of thrombin is an effective and safe treatment, particularly in pseudo-aneurysm associated with surgical risk factors. PMID- 29701409 TI - Acute Iatrogenic Limb Ischaemia, a Report of 2 Late Presentation Cases. AB - INTRODUCTION: With increasing use of percutaneous vascular procedures, access complications that present to a vascular surgeon increase. The most limb threatening condition is acute limb ischaemia. Acute limb ischaemia is the most common vascular surgical emergency. In spite of recent advances in vascular surgery, it continues to carry a poor prognosis, if not early diagnosed and managed. METHODS: This is a case-report of 2 patients referenced to a vascular surgery emergency department of a tertiary hospital with late acute limb ischaemia. RESULTS: Patient 1: Male, 42 years, alcoholic, autonomous, presented with pain with elbow active movements in a secondary hospital. Excluded acute orthopaedic injury, doctor recorded signs of acute limb ischaemia and referenced patient to a tertiary hospital, where vascular surgeon diagnosed an acute advanced upper limb ischaemia. Bed-side Eco-Doppler showed an echogenic linear material on a thrombosed umeral artery, surgically confirmed to be a guidewire (Fig.1. Surgical extraction of intra-umeral guidewire). Reviewing patient history, this guidewire should have been missed over 6 months, by the time the patient was hospitalized on an ICU for alcoholic coma. Patient underwent umeral, radial and ulnar thromboembolectomy and had a no-reflow status. However, poor persistent global status, with limited mobilization, pressure forces and prolonged vasotropic support, promoted progression of a cyanotic leg plaque to a necrotic evolving leg ulcer with septic response, despite persistent good perfusion of the foot (Fig.2. Necrotic evolving leg ulcer). Unfortunately, the two reported patients underwent urgent major limb amputation, patient 1 above the elbow, and patient 2 above the knee. CONCLUSION: Acute limb ischaemia continues to carry a poor limb and life prognosis if not early diagnosed. We should be alert for the increasingly prevalence of iatrogenic acute limb ischaemia, and regularly evaluate perfusion status of limbs after any percutaneous procedure. PMID- 29701410 TI - Digital Artery Aneurysm - Case Report. AB - INTRODUCTION AND METHODS: A 71-year-old patient, housewife, with a history of hypertension, elevated cholesterol and hypotyroidism was referred to the outpatient clinic for tumefaction of the right hand 5th finger noticed 3-4 months earlier. She denied past or recent history of trauma, cardiac or infectious disease and had no familial history of aneurysmatic disease. She was asymptomatic except for local slight discomfort when she had to press or push something with her hand. She had no sensitivity or mobility impairment. On examination a round, soft, pulsatile mass in the lateral aspect of the 5th finger was evident. All peripheral pulses were palpable with no evidence of abnormal or augmented pulsatility or thrill. Her peripheral pulses were palpable and symmetrical and didn't have augmented abdominal pulsatility. An ultrasound scan revealed a round mass measuring 14x7mm, having high intensity and pulsatile flow inside with turbulence suggesting aneurysm of or related with the proper digital artery. RESULTS: She was submited to ressection of the aneurysm under digital nerve block and use of a ring tourniquet at the finger base. An oblique incision was made and under carefull dissection the aneurysm was disclosed and extirped after control and ligation of the inflow and outflow vessels. Eight months after surgery the patient remained asymptomatic with no signs of local recurrence. Hystologic examination revealed a sacular aneurysmatic formation surrounded by papillary endothelial hyperplastic lesions. CONCLUSION: Digital artery aneurysms are very rare and most related with occupational or sports trauma. They are recognized sometimes by causing local discomfort or neurological symptoms due to nerve compression. Most cases can be treated by straight ressection after ligation of proximal and distal contiguous vessels taking care not to compromise flow to the distal finger. PMID- 29701411 TI - True Brachial Artery Aneurysm after Arteriovenous Fistula for Hemodialysis - Case Report. AB - INTRODUCTION: Brachial artery aneurysms are relatively uncommon and generally due to infectious, post-traumatic or iatrogenic etiology. They seem to affect 4.5% of arteriovenous fistula. The usual manifestation is an accidental finding of a pulsatile, painless, and asymptomatic mass. Complications include sac thrombosis, thromboembolic ischaemic events, and disruption with profuse bleeding. METHODS: The aim of this study is to present a case of true brachial artery aneurysm in end-stage renal disease patient after arteriovenous fistula creation. RESULTS: Sixty-six-year-old men with a past medical history of hypertension, dyslipidemia, smoking and poliquistic renal disease. He started a hemodialysis program in March 2006, using a brachiocephalic fistula on the left upper limb, built in February 2005. Submitted to kidney transplant in June 2010 and subsequent fistula ligation in December 2012. He goes to the emergency service in June 2016 with a pulsatile mass on the medial aspect of the left arm. Pain, redness and heat were present. Radial pulse was palpable. Inflammatory parameters were high and ultrasound revealed a fusiform aneurysm of the brachial artery with partial thrombosis and triphasic flow. An MRI was performed, documenting a brachial artery aneurysm, with 44mm greatest diameter and an extension of 17.5cm. Patient was hospitalized under antibiotic therapy and submitted to a reversed great saphenous vein interposition graft. Discharge from hospital occurred on the 7th postoperative day, with no sensitive or motor deficits and a present radial pulse. CONCLUSION: Arterial aneurysm is a rare, but significant complication long after the creation of a hemodialysis access. High flow, immunosuppression and increased resistance following ligation of the AV fistula may accelerate this process. PMID- 29701412 TI - Functional Popliteal Artery Entrapment Syndrome. AB - INTRODUCTION: Popliteal artery entrapment is an uncommon syndrome, caused by extrinsic compression of the popliteal artery by muscular or tendinous structures. It occurs mainly in young individuals, with no atherosclerostic risk factors, and a mean age of presentation of 20 to 40 years, and has higher prevalence in males (83% of patients). Clinical presentation depends on the degree of arterial lesion, the most common being intermittent claudication, with critical ischemia being frequent. Occasionally, it may present as acute ischaemia. METHODS: A 40-year-old female patient, physical education teacher, presented with a history of left foot paresthesia and left calf muscle pain during jogging for one year. The patient used to previously run 10 kilometers, currently mentioning claudication at 500 meters. No other medical conditions were mentioned. Lower extremity arterial duplex ultrasound revealed left popliteal artery compression and occlusion during active plantar flexion and passive dorsal flexion. The patient was referred to a vascular surgery center. Physical examination revealed palpable bilateral lower extremity pulses, with left asymmetry. Lower limb angiography and magnetic resonance imaging (MRI) were performed which demonstrated left popliteal artery compression and occlusion during a resisted plantar flexion. MRI revealed no anatomic anomalies, pointing to a probable functional entrapment caused by calf muscle hypertrophy (typo VI). RESULTS: Entrapment correction surgery was performed through a posterior approach and exposure. During the procedure, the artery showed no signs of significant fibrosis. Since compression by the medial head of the gastrocnemius muscle was observed, myotomy of its lateral fibers was performed. The patient was discharged on the second day post-surgery. After three months, the patient remained free of symptoms, having taken up sports practice with no limitations. CONCLUSION: Continuous popliteal artery compression leads to its progressive fibrosis, which may cause thrombosis or post-stenotic aneurysmal dilation. Treatment should be performed as soon as possible as to avoid this course and the eventual necessity of interposition or bypass grafting. Futhermore, late intervention worsens the interposition/ bypass grafting prognosis5. In this sense, the possibility of this diagnosis should be considered in a young patient presenting with intermittent claudication. Diagnostic tests are often decisive for differential diagnosis and to establish the disease subtype and intervention strategy. In most patients, a culprit muscular or tendinous anomaly is detected before surgery, however, in some individuals, especially physically active ones, compression results from muscular hypertrophy. PMID- 29701413 TI - True Brachial Artery Aneurysm in a Patient with Vascular Access for Haemodialysis and Kidney Graft. AB - INTRODUCTION: True brachial artery aneurysms are rare and some of them have been described as a late complication in patients with vascular access for haemodialysis and kidney graft. The purpose of this paper is to present a clinical case of a patient with a true brachial artery aneurysm and its following treatment. METHODS: This case concerns a caucasian male patient with 43 years old who had vesicoureteral reflux at 7 years old, and subsequent end-stage renal disease, and started on haemodialysis at the age of twelve. The patient had homolateral radial and brachiocephalic arteriovenous fistulas (AVF), two sequential kidney grafts and was under immunosuppressant therapy for several years. As part of the medical history he also had bilateral amaurosis, Hepatitis B and C and was submitted to total parathyroidectomy and a following auto transplant. In the latest years the patient presented with several aneurysms related to the vascular access. After the finding of an anastomotic false aneurysm and venous aneurysms complicating the AVF, the patient had removal of the aneurysms and ligation of the AVF. Later, he was diagnosed, in different times, with two true brachial artery aneurysms. At the time of the diagnosis of the first true aneurysm, the patient presented with local pain and occasional paraesthesias relative to compression symptoms. At physical examination the patient had a brachial pulsatile mass and a palpable radial pulse. The Doppler ultrasound exam revealed a true brachial artery aneurysm with 4,5 cm diameter. After two years, the patient was once again diagnosed with a true brachial artery aneurysm with 3,1 cm diameter. At this time the patient was asymptomatic and had palpable brachial mass and radial pulse. RESULTS: At the time of the diagnosis of the first true brachial aneurysm the patient was submitted to partial aneurysmectomy and brachiobrachial graft with PTFE 8. The patency of the graft persisted until the diagnosis of the second aneurysm. After two years, the patient was submitted to partial aneurysmectomy and axilobrachial graft with PTFE 8. During the follow-up period, the patient remained asymptomatic, had palpable radial pulse and the Doppler ultrasound exam confirmed the patency of the graft. CONCLUSION: The surveillance of patients with long duration AVF and kidney grafts might be advantageous in the early detection of arterial aneurysms. The surgical treatment in this group of patients is a first treatment option that is associated to a low morbidity. PMID- 29701414 TI - Hilar Renal Artery Aneurysm - Ex-vivo Reconstruction and Autotransplantation. AB - INTRODUCTION: Renal artery aneurysm (RAA) is a rare clinical entity with an estimated prevalence of 0.15% to 0.1%in the general population. The majority of patients present asymptomatically and the diagnosis is made incidentally during a hypertension study test, and more rarely, fortuitously after backache. Indications to treat have been subject of intense debate, nevertheless there seems to be some consensus that RAAs greater than 2 cm in diameter, expanding RAA, with thrombus or in pregnant women should be treated. Treatment options vary between surgical or endovascular approach. The complex (hilar) RAA constitute a subset of RAA that present a therapeutic dilemma because of their anatomic location and may require extracorporeal arterial reconstruction and auto transplantation. METHODS: We describe a 71-year-old woman with a personal history of hypertension for more than twenty years but normal renal function. Following the study for an abdominal discomfort a complex RAA was incidentally diagnosed. Computed tomographic angiography with three-dimensional reconstruction revealed a 13mm, saccular aneurysm located at the right renal hilum. RESULTS: We performed hand-assisted laparoscopic nephrectomy with ex vivo repair of the RAA. The aneurysm was resected and a polar renal artery was implanted over the resected area with a latero-terminal anastomosis. Complementarily, the renal vein was augmented with a spiral great saphenous vein graft and finally the kidney was implanted into the right iliac fossa. The intervention and postoperative course were uneventful and the patient submitted to ultrasound evaluation on the day after procedure. It revealed normal renal perfusion with normal flow indices. In the last follow-up realized, two months after surgery the patient was alive with a well-functioning auto-transplant. CONCLUSION: RAA may be nowadays more frequently diagnosed due to the increasing use of imaging techniques. While renal artery trunk aneurysms are most often treated using an endovascular procedure it is not suitable for renal artery branch aneurysms. Hand-assisted laparoscopic nephrectomy with ex vivo repair and auto-transplantation is a challenging but feasible option for treating hilum RAA. PMID- 29701415 TI - Antiphospholipid Syndrome and Acute Postpartum Limb Ischemia. AB - INTRODUCTION: The diagnosis of Antiphospholipid syndrome (APS) implies the identification of antiphospoholipid antibodies and arterial/venous thrombosis or pregnancy loss. During pregnancy, there is an increased risk of thrombotic complications. METHODS: Present a case of acute lower limb ischemia in a patient with APS during postpartum period Materials/ Methods: review of a clinical case and available literature Results: Patient diagnosed with APS (triple antibody positive and antecedent of 3 previous abortions) underwent cesarean at 29 weeks of gestation. She was medicated with aspirin 00mg/day and enoxaparin 60mg/day and had discharge on the second postoperative day. After 3 days she came to the emergency department with acute limb ischemia. AngioCT revealed thrombosis of the right iliac axis and pulmonary thromboembolism. Endovenous hypocoagulation with unfractionated heparin was immediately started. Due to the high thrombotic risk associated with any type of surgical intervention and improvement of ischemia with hypocoagulation, it was decided to postpone surgical revascularization. At the 10th day of hospitalization angioCT was repeated with maintenance of the iliac thrombosis and clinically the patient had severe claudication and ankle-arm index of 0.26. On the 16th day of hospitalization (after 5 plasmapheresis sessions), she was submitted to trans-femoral thrombectomy, with a good femoral pulse at the end of the procedure. On the 3rd postoperative day we detected pulse loss and angioCT confirmed re-thrombosis of the iliac axis and an oclusion of the popliteal artery. A new attempt at revascularization was made and a new transfemoral thrombectomy was performed, with immediate pulse recovery. We performed intraoperative angiography that confirmed occlusion of the popliteal artery and we proceeded trans-popliteal thrombectomy. Intraoperative control angiography revealed permeability of ilio- -femoro-popliteal axes with some defects of filling of the crural arteries (anterior tibial and peroneal arteries). After the procedure the patient become assymptomatic, with an ankle arm index of 0.55 (with normal flow in femoral and popliteal artery but monophasyc flow in distal arteries) and had discharged medicated with aspirin, antivitaminik K and corticoid. CONCLUSION: The beneficial/risk of revascularization surgery should be well considered as well as the timing in which it should be performed. Plasmapheresis is important to minimize the thrombotic risk associated with the surgical procedure. Intra-operative angiography is essencial since arterial thrombosis can occur in several sectors, which can conditionate the success of revascularization procedure. PMID- 29701416 TI - Co-existence of Abdominal Aortic Aneurysm with Urologic Neoplasm: Which Should Be Treated First in the Endovascular Era? AB - INTRODUCTION: Prevalence of Abdominal Aortic Aneurysm (AAA) with concomitant malignancy rounds 3-13%. Considering only urological neoplasms the prevalence is around 3.6%. Survival at 5 years of bladder carcinoma without extravesical invasion (stage II) rounds 63%. Endovascular Aneurysm Repair (EVAR), due to its minimally invasive profile, is an option for treatment of AAA prior to urological surgery as it does not require laparotomy not conditioning the delay of oncologic surgery. METHODS: Male, 62 years old. History of smoking and coronary artery disease and urothelial carcinoma of the bladder (T2N0M0). In the abdominal CT scan used for neoplasm staging a para-renal AAA with 50 mm of maximum diameter was firstly detected. This aneurysm presented only 5 mm of proximal neck length, insufficient for a safe proximal sealing with standard endografts. In consequence the treatment of choice was a tetra-fenestrated endograft (F-EVAR). RESULTS: F EVAR occurred without complications: no endoleaks, access complications or branch thrombosis. Three months after F-EVAR, the patient underwent radical cystectomy with jejunocystoplasty, which also occurred without intercurrences. Two days after FEVAR patient was discharged home. After one year of follow-up, abdominal CT scan did not reveal any complications related to the endovascular procedure. The patient died 18 months after the intervention as a consequence of metastatic evolution of bladder primary neoplasm. CONCLUSION: The coexistence of AAA with neoplastic urologic pathology although rare is not negligible. In the above case, the patient presented AAA with about 5 cm (1-11% risk of rupture per year), associated with T2N0M0 bladder urothelial carcinoma (survival at around 63% at 5 years). Given the need for treatment of both pathologies, the doubt persisted about which procedure should be performed first: aneurysm repair or cystectomy. Prior to the advent of EVAR, AAA repair would require laparotomy with a potentially greater risk of complications in the subsequent urologic procedure, prosthesis infection and significant delay of the cystectomy. With the emergence of endovascular techniques, AAA repair occurs without conditioning postponement or significant complications during a subsequent urological procedure and then "EVAR first" was the decision. Two days after FEVAR patient was discharged home and three months latter cystectomy was performed also without complications. IN CONCLUSION: in case of concomitant AAA and abdominal malignancy balance between risk of rupture and progression of the neoplastic disease need to be weighted. With the advent of endovascular disease EVAR prior to the oncologic surgery represents an efficient, prompt and safe solution. PMID- 29701417 TI - Surgical Thrombectomy, Fibrinolysis, Angioplasty and Stenting: A Combined Approach for Treatment of a May-Thurner Syndrome Presenting as Phlegmasia Cerulea Dolens. AB - INTRODUCTION: Phlegmasia cerulea dolens (PCD) is a rare complication of deep venous thrombosis (DVT). Massive ileo-femoral DVT is usually the cause and prompt treatment is mandatory as it represents a medical emergency. Reported amputation rates range from 12% to 25% and mortality ranges from 25% to 40%. Limb ischemia results from obstruction to arterial inflow secondary to extreme levels of venous hypertension. Primary treatment goal is restoration of venous outflow and can be achieved by endovascular or surgical techniques. After thrombus removal an underlying iliac vein stenosis may be present. May-Thurner syndrome, a condition where the left common iliac vein is compressed by the right iliac artery, is the most prevelant iliac stenotic lesion. METHODS: We report a case of a 57 years-old male, smoker, with no significant medical history, who presented to the emergency department with excruciating sudden left limb pain and swelling, with no trauma history, with a 2-hour onset. On physical examination he showed significant edema, purplish discoloration of the entire leg and absent dorsalis pedis artery pulse. RESULTS: Hipocoagulation with intravenous heparin was immediately initiated and emergent surgical venous thrombectomy was performed associated with direct intravenous fibrinolytic agent injection. Postprocedure phlebography showed a left common iliac vein lesion which was treated with angioplasty and venous stent placement. Pain, edema and coloration improved markedly after procedure without any complications. The patient was discharged home with anticoagulation treatment and compression stocking. CONCLUSION: Endovascular approaches such as catheter-directed thrombolysis (CDT) or pharmacomecanical thrombolysis (PMT) are becoming the treatment of choice to achieve venous outflow in DVT. In cases of PCD, when rapid restauration of venous outflow is mandatory, CDT has the disadvantage of having a long mean treatment time. This way, surgical thrombectomy still plays an important role in cases of PCD, especially if PMT is not available. In our case, the combined used of surgical thrombectomy with direct intravenous thrombolytic infusion provided effective treatment of PCD and uncovered an underlying left common iliac vein stenosis, which was successfully managed by angioplasty and stenting. PMID- 29701418 TI - Traumatic Carotid-Jugular Av Fistula in a Child. AB - INTRODUCTION: Traumatic Arteriovenous fistulae of the neck vessels are a rare condition, comprising less than 4% of traumatic fistulae found anywhere else in the body. METHODS: The authors propose to report a clinical case of such a condition in a 10-year-old boy who sustained a gunshot wound in the left side of the neck. RESULTS: Shortly after the event, the patient was admitted to paediatric ICU and intubated for airway protection. A palpable thrill in the left side of the neck was noticed, giving rise to the need of imaging study. A communication between the left common carotid artery and the internal jugular vein was confimed by AngioCT. No signs of cerebral hypoperfusion or cardiac overload were present. The surgical correction was performed by direct suture repair of both vessels involved. No complications on the postoperative period. During follow up, antiagregation with acetilsalicilic acid for 1 month was prescribed and no complications occured. CONCLUSION: The patient lives a normal life with no limitations. PMID- 29701419 TI - Carotid Paraganglioma - Classical Surgical Technique. AB - INTRODUCTION: A carotid body tumor is a rare neoplasm, generally benign, that predominantly affects people between their fourth and fith decades of life. It manifests as a pulsatile and generally painless cervical mass with firm consistency, located below the angle of the jaw. Clinically it can cause localized pain, dysphagia, hiccups, hoarseness and hypersensitive carotid body syndrome. Surgery is the treatment of choice, bearing in mind the possibility of malignant transformation, peritumoral invasion and metastasis. The most widely used technique is surgical resection, with or without concomitant preoperative endovascular embolisation. Overall complication rates, stroke rates between 0 and 8% and cranial nerve palsy less than 1% to 49%. Mortality rates vary from 0 to 3%. METHODS: Clinical case of a 69 years old male patient diagnosed with a carotid body tumor in a routine ultrasound exam. The patient was asyntomatic. Complementary exams were then conducted - CT scan and MRI supported the diagnosis. Neck CT scan: Well defined, nodular formation, enhanced after intravenous contrast, localized on the jugular-carotid region, with an aproximate diameter of 36 mm. Neck MRI: Expansive heterogenous solid lesion, localized on carotid bulb, well defined, enhanced after intravenous contrast, compatible with carotid paraganglioma - Shamblin's II. RESULTS: Patient was submited to a complete surgical classic ressection of the tumor, without any previously procedure. Proximal dissection was made with a help of a nose and ear surgeon. No post-surgery complications, except wound infection at week 3. No nerve damage. CONCLUSION: Follow up to 1 year without any complain and no lesions. In an era of multiple techniques there should always be a place for classic, well planned surgeries. PMID- 29701420 TI - Lumbar Cerebrospinal Fluid Drainage in Endovascular Aortic Repair - Reference Centre Experience. AB - INTRODUCTION: Spinal cord ischemia (SCI) and the resulting paraplegia are one of the most feared postoperative complications after thoraco-abdominal aortic surgery, with an incidence 4,3-8,0% after thoracic endovascular aortic repair (TEVAR), increasing patients morbi-mortality. Lumbar cerebrospinal fluid (CSF) drainage catheter is recommended as preventive measure in high risk patients. OBJECTIVE: To evaluate the efficiency and safety of CSF drainage catheter as preventive or therapeutic measure in endovascular aortic repair (EAR). METHODS: Retrospective study in 19 patients submitted to TEVAR or fEVAR (fenestrated endovascular aneurism repair), in whom CSF drainage catheter was used, between January 2010 and March 2017. Collected data regarding demographic, perioperative patients characteristics, neurologic symptoms (NS) and other complications. All patients were submitted to general anesthesia (GA) as result of complexity and length of surgery. Known risk factors (RF) for SCI were taken into account. RESULTS: 19 patients, 89,5% (n=17) male, mean age of 66+/-9 years. 63,2% were classified as ASA III and 36,8% as ASA IV. 9 patients submitted to TEVAR (47,4%); the remaining were submitted to fEVAR. 73,7 % were programed procedures. There were intraoperative complications in 3 patients: iliac artery (IA) rupture in 2 patients, laceration of the axillary artery in 1 patient, all required surgical repair. All catheters were placed in awake patients, before GA induction, and were left in place 2,5 days. 7 patients needed drainage because of CSF pressure>10mmHg intra- or postoperatively. 3 patients developed early symptoms of SCI (decreased mobility and strength of legs). Complete recovery occurred in all patients, except one who recovered just partially. 1 patient developed late NS: paraparesia on 40th postoperative day (POD) as result of spinal stroke. 30 days mortality was 10,5% (n=2), due to cardiorespiratory arrest- 1 by hypovolemic shock (on 3rd POD), 1 by unknown cause (14th POD). CONCLUSION: This study was limited by the small sample size. CSF drainage catheter was an efficient measure in prevention and treatment of SCI in this sample, since there was no case of complications due to SCI. CSF drainage seems to be an effective technique in preventing SCI. Further studies are required to determine the effectiveness and compare the different methods available for the prevention of SCI complications. PMID- 29701421 TI - Rapid Pacing for Thoracic Endovascular Aortic Repair: a Case Report. AB - INTRODUCTION: Endovascular aortic interventions are suitable alternatives to open surgery, being less invasive and having lower mortality and complications. Accurate positioning of the stent graft is a critical point because of systolic thrush. Techniques used to prevent it include pharmacological (antihypertensive drugs, nitroglycerin, adenosine) and mechanical methods (temporary caval occlusion by balloon). Rapid Right Ventricular Pacing (RRVP) is an emerging alternative with good patient tolerance and low level of complications. METHODS: A 79 years-old male, American Society of Anaesthesiology (ASA) status 3 (hypertension, chronic obstructive pulmonary disease and hyperuricemia), with an aortic arch aneurysm previously submitted to an ascendant aortic debranching, was proposed for Thoracic Endovascular Aortic Repair (TEVAR). ASA standard, invasive blood pressure, depth of anaesthesia and cerebral oximetry monitoring were used. RESULTS: Patient was sedo-analgesiated with Midazolam 2mg and Fentanyl 100mcg. A flow directed Pacing catheter was passed through an 8.5FR introducer inserted in right internal jugular vein. RRVP was tested to a cardiac frequency of 180 without patient complaint. Two vascular Valiant Thoracic endoprosthesis were placed through a femoral access. At the time of testing position and prothesis deployment, RRVP was started and systolic blood pressure dropped to 50mmHg. After stopping the RRVP in both placements, normal rhythm and blood pressure were observed. No relevant changes in cerebral monitoring were found. Final angiography showed no endoleak of prosthesis. The patient was admitted at Post- Anaesthetic Care Unit and discharged after 24hours. CONCLUSION: RRVP results in accelerated heart rate, with consequent decrease of intra-aortic blood flow, allowing more precise graft deployment without displacement, which is associated with lower incidence of endoleak. The faster onset of RRVP and rapid return to normal values can shorten the duration of the procedure. The procedure is done with minimal sedation, important in individuals with poor clinical status. This also allows to continually monitor the patient's neurologic status, possibly detecting any prosthetic displacement or acute event. Most complications are puncture- related. Rhythm-associated complications can occur in patients with heart diseases. In this case, no cardiac events were found. RRVP has been used in TEVAR with reliable results and is a good option for difficult cases. It's associated with a lower incidence of complications and less secondary effects than traditional measures, allowing to maintain patients with mild sedation, shortening hospital's length of stay. RRVP seems to be advantageous over traditional methods of controlling blood pressure in patients submitted to TEVAR. PMID- 29701423 TI - Reversal of Acute Spinal Cord Injury in the Immediate Post-Operative Period After Thoracoabdominal Aneurysm Repair with CSF Drainage. AB - INTRODUCTION: Spinal cord injury after thoracoabdominal aortic aneurysm surgery is a devastating and unpredictable complication (1). With surgical manipulation, particularly with aortic clamping, cerebrospinal fluid (CSF) pressure may rise, and its pressure exceeds the spinal arterial pressure, spinal perfusion may be reduced, leading to neurological dysfunction. METHODS AND RESULTS: This clinical case reports to a 70-year-old male patient with an early onset of post-operative paraesthesia of the lower limbs in the immediate post-operative period of thoracoabdominal aortic aneurysm repair. Reversal of the neurological deficit was achieved after emergency CSF drainage. CONCLUSION: CSF drainage has a therapeutic potential value of reducing its pressure, allowing an improvement of spinal perfusion pressure, therefore diminishing the risk of an ischemic and permanent lesion(2), thus it may have a role in preventing and/or treating acute paraplegia. PMID- 29701422 TI - Risk Factors for Postoperative Transfusion in Cardiac Surgery with CPB. AB - INTRODUCTION: The use of blood products is routine in cardiac surgery. Use of blood derivates may vary among institutions and entail high costs and possible complications. This study aims to identify predictors of the need for postoperative blood products transfusion after cardiac surgery with cardiopulmonary bypass (CPB), in order to focus on preventive measures for high risk populations. METHODS: Observational retrospective study carried out in 104 consecutive adults who underwent cardiac surgery using CPB in our hospital. Blood products used were categorized according to the Universal Definition of Perioperative Bleeding (UDPB) in adult cardiac surgery1 (table 1). Clinical, demographic and surgical variables were analyzed. Statistical analysis was performed using SPSSv23. Quantitative variables are expressed as mean +/- standard deviation and qualitative variables as proportions (%). Values of p<0.05 were considered statistically significant. RESULTS: 104 patients, 74 males (71,2%), with an average age of 67,2+/-13,4 years were included. Mean body mass index (BMI) was 26,1+/-4,2Kg/m2, and 5,8% were ASA II, 92,3 % ASA III and 1,9% ASA IV. Operative procedures included coronary artery bypass in 32 (30,8%) patients, valvar operations in 59 (56,7%), and combined procedures in 7 (6,7%), with 6 omissions. Forty patients (38,5%) received at least one blood product in final postoperative 24h. The distribution of blood products used according to UDPB in adult cardiac surgery is expressed in table 2. There were no significant statistical differences in blood products transfusion between gender, age, BMI, diabetes, Left Ventricular Ejection Fraction (EFLV) and CBP duration. Although there was no significant correlation between hypertension and postoperative use of blood products, there was a strong positive association between the absence of hypertension and UDPB class 0. In our population, there was a significant association between the type of surgery and UDPB score. There seems to be a strong positive association between valvular surgery and UDPB class 0 and between combined procedures and UDPB class1. Reoperation for bleeding within 24h was required in 3,8%. CONCLUSIONS: In our population, the independent predictor of postoperative bleeding was the type of surgery, with a strong positive association between valvular surgery and combined procedures and UDPB class 0 and 1, respectively. The percentage of reoperations due to bleeding after cardiac surgery is in accordance with the literature. PMID- 29701424 TI - Perioperative Family Centered Care: Nursing Interventions that Support Child and Family's Emotional Management. AB - INTRODUCTION: Hospitalization is a negative tonality experience for both child and family, being fear and anxiety their emotional mirror. Concerning the surgical experience, the environment, invasiveness, fear of pain, of not waking up from anaesthesia and parental separation are both causes and enhancers of child and family perioperative distress. A study concerning parent's emotional experience of child's submitted to cardiac surgery, refer guilt for their son's cardiopathy, a roller coaster of emotions, impotence and being seated on pins and needles while waiting during the surgery. OBJECTIVE: Identify and map the scientific production concerning nursing interventions that promote child and family's perioperative emotional management. METHODS: Literature was searched in CINAHL and MEDLINE, and also on Joanna Briggs Institute (JBI) Database of Systematic Reviews and Implementation Reports and Cochrane Library. Search was done using all identified keywords and index terms. The study will consider quantitative and qualitative studies, as well as systematic reviews. The quantitative studies will include, although not being limited to experimental and epidemiological study designs. The qualitative studies will include, although not being limited to phenomenology, grounded theory and ethnography. The systematic reviews will include meta analysis and meta synthesis. Unpublished literature will also be considered. RESULTS: Specifically in paediatric perioperative care, the use of preoperative programs based on psycho-emotional resources adapted to the child's age range, results in fear and anxiety's reduction and consequently increasing well- -being. Regarding parental presence during anaesthetic induction, it has a very important effect in decreasing both child and parent's anxiety. However, it should be supported and programed so that it is safe and effective. Communication with family during surgery, attending to multidisciplinary organization, periodicity and supported by a nursing liaison program, is particularly important in decreasing family's anxiety during intraoperative period. CONCLUSION: Family centred care are the paediatrics' care philosophy. Concerning the perioperative period, it expresses through several interventions like preoperative preparation, parental presence and nursing liaison. These nursing interventions are particularly important in decreasing stress and anxiety, promoting safety, respect and well-being, and also because it promotes the child's development and facilitates future experiences. PMID- 29701425 TI - Analgesia Management for Mitral Valve Repair Via Minithoracotomy - A Case Report. AB - INTRODUCTION: Minimally invasive cardiac surgery (MICS), via minithoracotomy, is thought to be a fast track to extubation and recovery after surgery. Chronic pain, due to intercostal nerve injury, develops in up to 50% of postthoracotomy patients.A number of regional anaesthesia and analgesia techniques may be employed, and the anaesthesiologists play a key role in facilitating optimal outcomes after surgery. METHODS: We report a case of postoperative pain management with a local anesthetic infiltration for MICS. RESULTS: A 63-year-old woman, 80kg, American Society Anaesthesiology (ASA) physical status 3 [arterial hypertension, atrial fibrillation (AF), rheumatic mitral stenosis and class II NYHA heart failure] was presented for an elective minimally invasive mitral valve repair through a minithoracotomy and cryoablation of AF. No relevant facts were found on pre-operative evaluation. Calculated EuroScore II was 1.55%. After premedication with intravenous (IV) midazolam 1.5mg, radial arterial and jugular central venous catether were placed. General anaesthesia was induced with IV remifentanil 1mcg/kg/h, propofol 50mg, rocuronium 1mg/ kg. A transesophageal echocardiography probe was inserted atraumatically, which revealed thickened mitral valve leaflets. ASA standard, invasive blood pressure, central venous pressure, depth of anaesthesia and cerebral oximetry monitoring were used. Urine output and arterial blood gas were measured periodically. A right lateral minithoracotomy was performed. After cardiopulmonary bypass (CPB) by femoral cannulation, cryoablation was performed followed by placement of the mechanical prosthesis. Total bypass time was 186min including 139min aortic cross-clamping time. At the ending of CPB, there was no need for inotropic support. Analgesia with paracetamol 1g, tramadol 100mg and morphine 10mg was performed after protamine reversion. Immediately before closure of skin, catheter was placed nearly to intercostal space (figures 1, 2) and ropivacaine 0,75% 75mg was administered. Anaesthesia and surgery were uneventful. Patient was shifted to intensive care unit (ICU), being extubated 3 hours after surgery. There was no need for additional bolus of ropivacaine during 2 days of ICU stay. She was discharged home on the 4th postoperative day, without complications. In a telephone interview 3 weeks after surgery, the patient referred no pain and good satisfaction with analgesia management. CONCLUSION: Thoracotomy incisions are associated with severe pain, leading to a decrease in pulmonary function, an increase in metabolic and hormonal activity and increased cardiac morbidity. Regional analgesia techniques have an opioid-sparing effect, reducing stress response and pain chronification. The local infiltration through catheter with local anaesthetics allows excellent analgesia for 8-12 hours, providing a route of additional analgesia according to pain control. PMID- 29701426 TI - Is Invasive Pressure Monitoring More Reliable Than Non-Invasive in Patients with Cardiovascular Pathology? - A Case Report. AB - INTRODUCTION: Patients undergoing carotid endarterectomy (CEA) require strict arterial blood pressure (BP) control to maintain adequate cerebral perfusion. Invasive blood pressure (IBP) is the gold standard, however artifacts may lead to erroneous readings. METHODS: We report a case of CEA using IBP monitoring. RESULTS: A 64-year-old man, American Society Anaesthesiology (ASA) physical status 3 (diffuse atheromathosis, dyslipidemia and non-medicated hypertension), was presented for an elective right CEA. ASA standard, neuromuscular block monitoring, anesthesia depth and cerebral oximetry were used as monitorization. On preanaesthetic assessment noninvasive BP (NIBP) had no significant difference between right and left arms (180/90 mmHg). IBP monitoring was placed in left radial artery after several attempts in both arms. Surgery was performed under balanced general anesthesia (GA). Intra-operatively the patient remained stable (140/86 mmHg) however the systolic carotid artery stump pressure (SP) was 210 220mmHg. This finding was confirmed by measuring NIBP in both legs. At this point NIBP was used to monitor and guide the BP target until the end of the procedure and during postoperative period (PO) in postanesthetic care unit (PACU). Surgery proceeded uneventfully. After discharge to the ward (48h stay at PACU), a hypertensive crisis lead to cervical neck haematoma which required emergent surgery under GA. Intraoperatively the BP was assessed with NIBP. After a new period of 48h at PACU the patient was discharged to the ward and subsequently from the hospital on the 8th postoperative day, without further complications. CONCLUSION: IBP allow beat-by-beat measures with optimization of BP in order to improve cerebral perfusion during CEA. IBP can be inaccurate in patients with diffuse atheromatosis. NIBP may be an alternative, however is not continuous and is expected to be less accurate than the IBP.1 The high IBP-NIBP difference (>40 mmHg) was clinically relevant and in this patient might be explained by diffuse atheromatosis. NIBP was compatible with carotid SP, indicating that, in this case was a reliable and accurate method of monitoring. PMID- 29701427 TI - Heparin Resistance During Surgical Resection of Inferior Vena Cava and Right Atrial Tumor Thrombus: A Case Report. AB - INTRODUCTION: Heparin resistance is the failure of unusually high doses of heparin to achieve a target activated clotting time (ACT). We present the case of a 47-year-old female patient, ASA 2, who was diagnosed with a neuroendocrine retroperitoneal tumor with thrombus in the left renal vein, inferior vena cava and right atrium. General and cardiothoracic surgeons collaborated to remove the tumor under cardiopulmonary bypass. Heparin resistance was considered and treated with 1000 UI of antithrombin III concentrate. The authors review the mechanisms and management of this entity. PMID- 29701428 TI - Anaesthetic Management in a Duchennne Muscle Dystrophy Patient for Treatment of Recurrent Pneumothorax. AB - INTRODUCTION: Duchenne muscular dystrophy (DMD) is an x linked recessive disorder. Long term prognosis is ominous, with development of respiratory distress and cardiomyopathy in advanced stage of the disease and expected death in the teens-to-mid 20s due to respiratory or cardiac failure. Peri-operative management of this patients is challenging due to difficult airway anatomy (macroglossia, limited neck and mandibular mobility). Additionally, they are at risk of developing malignant hyperthermia, rhabdomyolysis and hyperkalemic cardiac arrest when exposed to halogenated inhalational anaesthetics and depolarizing muscle relaxants. METHODS: We describe a case of DMD proposed to a thoracotomy for treatment of recurrent pneumothorax and its anaesthetic approach. RESULTS: A 22-year-old male patient with DMD presented at emergency department due dyspnoea starting at 3 days associated with right scapular pain, enhanced by breathing. The patient already presents with mild cardiomyopathy (ejection fraction of 55%, mild mitral and tricuspid regurgitation), severe restrictive respiratory defect, requiring continuous BiPAP. The patient was markedly denourished (BMI of 12 kg/m2) and presented with nearly absent breathing sounds on the right side. Chest radiography showed large pneumothorax on the right side with no signs of tension. Drainage was performed. Despite initial success, recurrence of pneumothorax occurred on the several attempts of clamping. A bronchopleural fistula was suspected and operative treatment was considered. Considering the comorbidities, he was graded ASA IV with a difficult airway due to macroglossia, limited neck and mandibular mobility. Oro-tracheal intubation was performed with slight sedation (propofol, without neuromuscular blocks). Difficult airway anatomy (direct laryngoscopy - Cormack 4) successfully approached with a bougie and Mccoy blade. Fibreoptic intubation approach was immediately available in the operating room, if required. Total intravenous anaesthesia was decided (remifentanil and propofol, administered by continuous infusion, without neuromuscular blockers). Volume controlled protective ventilation as used (tidal volume 6-8ml/kg, respiratory frequency of 14-16/ min; FiO2: 0,5). No bronchopleural fistula was detected and pleurodesis was performed with biologic glue. Patient remained intubated and was transferred to the ICU for monitoring, having been discharged on the 2nd day to the ward. Despite this, pneumothorax recurrence occurred, and surgery was performed again, using the same anaesthetic approach, this time with successful closure of the bronchopleural fistula. CONCLUSION: Total intravenous anaesthesia, without neuromuscular blockers, is a safe and effective option for DMD patients. Anaesthesiologists must consider the possibility of cardio-pulmonary disabilities, difficult airway management, as well as the high risk of malignant hyperthermia in these patients. PMID- 29701429 TI - Pharmacotherapy and ROP: Going Back to the Basics. AB - Retinopathy of prematurity (ROP) is a leading cause of blindness in preterm infants around the world. Through the development of animal models and clinical trials our understanding of the pathophysiology of this disease and approach to therapy has evolved significantly since ROP was first described in the 1940s in the United States. The mainstay of treatment in ROP remains ablative laser therapy to the avascular retina but pharmacologic agents are being more and more commonly used with new targets for pharmacotherapy emerging. This paper summarizes our current understanding of the pathophysiology of ROP based on the data gleaned from animal models and discusses current approaches to pharmacotherapy. PMID- 29701430 TI - ? PMID- 29701431 TI - [Current developments in Parkinson's disease]. AB - Our understanding of Parkinson's disease has considerably evolved in the last few years. While the cardinal motor features bradykinesia, rigidity, and tremor define the disease and respond to dopamine replacement therapy, there is a wider spread neurodegeneration causing non motor symptoms and their impact on the quality of life of patients is being increasingly recognized. The follow-up requires a good collaboration between primary care physicians and neurologists. The purpose of this article is to offer a practical treatment guide of uncomplicated Parkinson's disease for general practitioners and internal medicine specialists. The management of late complications of Parkinson's disease will be addressed in another article. PMID- 29701432 TI - [Advanced Parkinson's disease : indication for complex treatments]. AB - Advanced Parkinson's disease (PD) is characterized by severe motor and non-motor complications that negatively impact on patients' autonomy and health-related quality of life. In early disease, the therapeutic strategy consists of gradual increase in dopaminergic treatment and levodopa dose fragmentation. In more advanced stages, this approach becomes insufficient and three therapeutic options can be considered: deep brain stimulation (DBS), continuous subcutaneous apomorphine infusion, and continuous levodopa/carbidopa intestinal gel infusion. PMID- 29701433 TI - [Genetic aspects of movement disorders of adulthood]. AB - Movement disorders of monogenic origin are rare. In case of a specific phenotype, classical targeted sequencing of the gene can be used. When the clinical picture is not well defined, or when there is genetic heterogeneity or a large differential diagnosis, high-throughput sequencing is a useful tool for the analysis of numerous genes simultaneously. To discuss which approach is optimal, a multidisciplinary consultation by a movement disorders specialist and a geneticist is recommended. For some genetic movement disorders there is specific treatment available. The most common movement disorders, such as Parkinson's disease and essential tremor, have probably a complex etiology, including polygenic and environmental factors. Less than 5 % of Parkinsonian patients have a monogenic, hereditary form of the disease. PMID- 29701434 TI - [Sleep-related movement disorders]. AB - Sleep is characterized, from a behavioral point of view, by a physical quiescence. However, sleep can be disrupted by movements which can occur before falling asleep, during the sleep-wake transition, or during sleep. Some of these movements may be considered quasi-physiological because they are very common in the general population and have little or no clinical impact. However, others may have an impact on sleep quality, or be associated with other neurological conditions. Patients' symptoms and complaints, the movements' description by witnesses, home video and video-polysomnographic recordings in the sleep laboratory allow to establish the diagnosis. The instauration of a treatment should be guided by clinical repercussions. PMID- 29701435 TI - [Movement disorders emergencies]. AB - Unlike most basal ganglia disorders, which usually progress slowly and relentlessly, a number of movement disorders may develop as acute or subacute conditions. Their occurrence commonly prompts patients to rush into the emergency room. A proper diagnosis is not always straightforward and requires a detailed analysis of the movement disorder phenomenology and a thorough medication screening, as many of these acute situations may be iatrogenic and drug-related. An accurate identification of the problem may enable an effective management and an appropriate therapy. This article is an overview of three distinct movement disorder emergencies, namely acute dystonia, acute chorea, and acute complications that can be observed in Parkinson's disease. Each topic is illustrated with a case report. PMID- 29701436 TI - [Abnormal movements and internal medicine pathologies]. AB - Hyperkinesias can be revelaed by an internal medicine pathology. An acute chorea can be found in association with non ketotic hypergycemia, lupus, antiphospholipid syndrome, endocrinopathies, pregnancy or oral contraceptive initiation, or psychostimulant medication. Acute dystonic syndromes are found in association with the initiation of an old generation neuroleptic, metoclopramide, oral contraceptive and pregnancy. It should be differentiated from hyper- or hypo calcemie tetany. Tremors are found in association with many drugs and hormones. Akathisisc syndromes, classically found in association with chronic neuroleptic use, include restless legs, found in association with iron deficiency anemia, pregnancy, many drugs and polyneuropathies, as well as in the withdrawal syndrome of benzodiazepines and opiates. PMID- 29701437 TI - [Novelties in ENT - 2017]. AB - Rhinology : balloon sinuplasty and its potential commercial links ; factors of recurrence of sinunasal polyposis ; olfactory dysfunction and biofilms. Otology : effect of music and headphones on children ; vaccination and otitis media. Pharyngo-laryngology : interest of DISE (Drug Induce Sleep Endoscopy) in case of Sleep Apnea Syndrome; adenotonsillectomy and interest of robotic surgery.Salivary glands : presence of Helicobacter pylori in buccal cavity ; pepsin testing in saliva in case of reflux ; antibacterial effect of xylitol ; interest of propolis in treating candidosis. Thyroid : incidence and screening. PMID- 29701438 TI - ? PMID- 29701439 TI - ? PMID- 29701440 TI - ? PMID- 29701441 TI - ? PMID- 29701442 TI - ? PMID- 29701443 TI - ? PMID- 29701444 TI - HIIT produces increases in muscle power and free testosterone in male masters athletes AB - High-intensity interval training (HIIT) improves peak power output (PPO) in sedentary aging men but has not been examined in masters endurance athletes. Therefore, we investigated whether a six-week program of low-volume HIIT would (i) improve PPO in masters athletes and (ii) whether any change in PPO would be associated with steroid hormone perturbations. Seventeen male masters athletes (60 +/- 5 years) completed the intervention, which comprised nine HIIT sessions over six weeks. HIIT sessions involved six 30-s sprints at 40% PPO, interspersed with 3 min active recovery. Absolute PPO (799 +/- 205 W and 865 +/- 211 W) and relative PPO (10.2 +/- 2.0 W/kg and 11.0 +/- 2.2 W/kg) increased from pre- to post-HIIT respectively (P < 0.001, Cohen's d = 0.32-0.38). No significant change was observed for total testosterone (15.2 +/- 4.2 nmol/L to 16.4 +/- 3.3 nmol/L (P = 0.061, Cohen's d = 0.32)), while a small increase in free testosterone occurred following HIIT (7.0 +/- 1.2 ng/dL to 7.5 +/- 1.1 ng/dL pre- to post-HIIT (P = 0.050, Cohen's d = 0.40)). Six weeks' HIIT improves PPO in masters athletes and increases free testosterone. Taken together, these data indicate there is a place for carefully timed HIIT epochs in regimes of masters athletes. PMID- 29701445 TI - Ending Open Defecation: A Review of Community-Led Sanitation Programs. PMID- 29701447 TI - Direct Measurement of the Intrinsic Sharpness of Magnetic Interfaces Formed by Chemical Disorder Using a He+ Beam. AB - Using ion beams to locally modify material properties and subsequently drive magnetic phase transitions is rapidly gaining momentum as the technique of choice for the fabrication of magnetic nanoelements. This is because the method provides the capability to engineer in three dimensions on the nanometer length scale. This will be an important consideration for several emerging magnetic technologies (e.g., spintronic devices and racetrack and random-access memories) where device functionality will hinge on the spatial definition of the incorporated magnetic nanoelements. In this work, the fundamental sharpness of a magnetic interface formed by nanomachining FePt3 films using He+ irradiation is investigated. Through careful selection of the irradiating ion energy and fluence, room-temperature ferromagnetism is locally induced into a fractional volume of a paramagnetic (PM) FePt3 film by modifying the chemical order parameter. A combination of transmission electron microscopy, magnetometry, and polarized neutron reflectometry measurements demonstrates that the interface over which the PM-to-ferromagnetic modulation occurs in this model system is confined to a few atomic monolayers only, while the structural boundary transition is less well-defined. Using complementary density functional theory, the mechanism for the ion-beam-induced magnetic transition is elucidated and shown to be caused by an intermixing of Fe and Pt atoms in antisite defects above a threshold density. PMID- 29701446 TI - Prenatal Organophosphate Pesticide Exposure and Traits Related to Autism Spectrum Disorders in a Population Living in Proximity to Agriculture. AB - BACKGROUND: Prenatal exposure to organophosphate (OP) pesticides has been linked with poorer neurodevelopment and behaviors related to autism spectrum disorders (ASD) in previous studies, including in the Center for Health Assessment of Mothers and Children of Salinas (CHAMACOS) study, a birth cohort living in the agricultural Salinas Valley in California. OBJECTIVES: To investigate the association of prenatal exposure to OP pesticides with traits related to ASD, in childhood and adolescents in CHAMACOS. METHODS: We assessed OP exposure during pregnancy with measurements of dialkyl phosphates (DAP) metabolites in urine, and residential proximity to OP use during pregnancy using California's Pesticide Use Reporting (PUR) data and estimated associations with ASD-related traits using linear regression models. We measured traits reported by parents and teachers as well as the child's performance on tests that evaluate the ability to use facial expressions to recognize the mental state of others at 7, 101/2, and 14 years of age. RESULTS: Prenatal DAPs were associated with poorer parent and teacher reported social behavior [e.g., a 10-fold DAP increase was associated with a 2.7 point increase (95% confidence interval (CI): 0.9, 4.5) in parent-reported Social Responsiveness Scale, Version 2, T-scores at age 14]. We did not find clear evidence of associations between residential proximity to OP use during pregnancy and ASD-related traits. CONCLUSIONS: These findings contribute mixed evidence linking OP pesticide exposures with traits related to developmental disorders like ASD. Subtle pesticide-related effects on ASD-related traits among a population with ubiquitous exposure could result in a rise in cases of clinically diagnosed disorders like ASD. https://doi.org/10.1289/EHP2580. PMID- 29701448 TI - Review of the Electronic, Optical, and Magnetic Properties of Graphdiyne: From Theories to Experiments. AB - Graphdiyne (GDY), a two-dimensional artificial-synthesis carbon material, has aroused tremendous interest because of its unique physical properties. The very high activity affords the possibility to chemically dope GDY with metal atoms or lightweight elements such as hydrogen and halogen and so on. Chemical doping has been confirmed to be an effective method to lead to various GDY derivatives with useful physical properties. Thus, this review is intended to provide an overview of the electronic, optical, and magnetic properties of pristine GDY and its derivatives reported from theories to experiments. Because of the importance of pristine GDY and its derivatives in real applications, we also summarize the main physical applications of GDY and its derivatives reported in recent years in this review. We believe that the review will be valuable to all those interested in GDY. PMID- 29701449 TI - Green Synthesis of Three-Dimensional MnO2/Graphene Hydrogel Composites as a High Performance Electrode Material for Supercapacitors. AB - Graphene hydrogels (GHs) and their composites have attracted wide attention because of the special structure of graphene assembly and exceptional electrochemical performance as electrodes for energy storage devices. Here, we report a GH with three-dimensional architecture prepared by a hydrothermal method via a self-assembled process in glucose and ammonia system as well as subsequent freeze-drying. The delta-MnO2/GH composite was then obtained by immersing GH in KMnO4 solution with a certain concentration under heat treatment. The asymmetric supercapacitor MnO2/GH//GH consisting of pseudocapacitive nanosheet-like delta MnO2/GH as the cathode and electric double-layer capacitive GH as the anode provides high energy density of 34.7 W h/kg at a power density of 1.0 kW/kg. Importantly, it is found that the pseudocapacitive behavior of MnO2 has great effects on the rate performance of the supercapacitor, which is identified by kinetic analysis. PMID- 29701450 TI - Improving the Performance of Hard Carbon//Na3V2O2(PO4)2F Sodium-Ion Full Cells by Utilizing the Adsorption Process of Hard Carbon. AB - Hard carbon has been regarded as a promising anode material for Na-ion batteries. Here, we show, for the first time, the effects of two Na+ uptake/release routes, i.e., adsorption and intercalation processes, on the electrochemical performance of half and full sodium batteries. Various Na+-storage processes are isolated in full cells by controlling the capacity ratio of anode/cathode and the sodiation state of hard carbon anode. Full cells utilizing adsorption region of hard carbon anode show better cycling stability and high rate capability compared to those utilizing intercalation region of hard carbon anode. On the other hand, the intercalation region promises a high working voltage full cell because of the low Na+ intercalation potential. We believe this work is enlightening for the further practical application of hard carbon anode. PMID- 29701451 TI - Hierarchically Mesostructured Aluminum Current Collector for Enhancing the Performance of Supercapacitors. AB - Aluminum (Al) current collector is one of the most important components of supercapacitors, and its performance has vital effects on the electrochemical performance and cyclic stability of supercapacitors. In the present work, a scalable and low-cost, yet highly efficient, picosecond laser processing method of Al current collectors was developed to improve the overall performance of supercapacitors. The laser treatment resulted in hierarchical micro nanostructures on the surface of the commercial Al foil and reduced the surface oxygen content of the foil. The electrochemical performance of the Al foil with the micro-nanosurface structures was examined in the symmetrical activated carbon based coin supercapacitors with an organic electrolyte. The results suggest that the laser-treated Al foil (laser-Al) increased the capacitance density of supercapacitors up to 110.1 F g-1 and promoted the rate capability due to its low contact resistance with the carbonaceous electrode and high electrical conductivity derived from its larger specific surface areas and deoxidized surface. In addition, the capacitor with the laser-Al current collector exhibited high cyclic stability with 91.5% capacitance retention after 10 000 cycles, 21.3% higher than that with pristine-Al current collector due to its stronger bonding with the carbonaceous electrode that prevented any delamination during aging. Our work has provided a new strategy for improving the electrochemical performance of supercapacitors. PMID- 29701452 TI - Enhancing Catalyzed Decomposition of Na2CO3 with Co2MnO x Nanowire-Decorated Carbon Fibers for Advanced Na-CO2 Batteries. AB - The metal-CO2 batteries, especially Na-CO2, batteries come into sight owing to their high energy density, ability for CO2 capture, and the abundance of sodium resource. Besides the sluggish electrochemical reactions at the gas cathodes and the instability of the electrolyte at a high voltage, the final discharge product Na2CO3 is a solid and poor conductor of electricity, which may cause the high overpotential and poor cycle performance for the Na-CO2 batteries. The promotion of decomposition of Na2CO3 should be an efficient strategy to enhance the electrochemical performance. Here, we design a facile Na2CO3 activation experiment to screen the efficient cathode catalyst for the Na-CO2 batteries. It is found that the Co2MnO x nanowire-decorated carbon fibers (CMO@CF) can promote the Na2CO3 decomposition at the lowest voltage among all these metal oxide decorated carbon fiber structures. After assembling the Na-CO2 batteries, the electrodes based on CMO@CF show lower overpotential and better cycling performance compared with the electrodes based on pristine carbon fibers and other metal oxide-modified carbon fibers. We believe this catalyst screening method and the freestanding structure of the CMO@CF electrode may provide an important reference for the development of advanced Na-CO2 batteries. PMID- 29701453 TI - Orbital Redistribution Enhanced Perpendicular Magnetic Anisotropy of CoFe3N Nitrides by Adsorbing Organic Molecules. AB - Organic/ferromagnetic spinterface plays a significant role in organic spintronics and the manipulation of spinterface will help to optimize the performance of molecular devices. Here, we systematically investigate how the magnetic anisotropy can be tailed by adsorbing different organic molecules on CoFe3N surface. It is found that the adsorption of C6H6, C6F6, and SC4H4 molecules on the FeCo-hollow site enhances the perpendicular magnetic anisotropy (PMA) of CoFe3N. The redistribution of Fe/Co d-orbitals near the Fermi level has an important effect on the modulation of PMA. Asymmetric SC4H4 adsorbed system has a larger PMA than symmetric C6H6 and its halide due to the hybridization between S p z and Fe d z2 orbitals instead of C atom. Our results indicate that appropriate organic molecule adsorption can improve the magnetic properties of ferromagnets, which benefits organic spintronic devices. PMID- 29701454 TI - Comparative Analysis of Aqueous Binders for High-Energy Li-Rich NMC as a Lithium Ion Cathode and the Impact of Adding Phosphoric Acid. AB - Even though electrochemically inactive, the binding agent in lithium-ion electrodes substantially contributes to the performance metrics such as the achievable capacity, rate capability, and cycling stability. Herein, we present an in-depth comparative analysis of three different aqueous binding agents, allowing for the replacement of the toxic N-methyl-2-pyrrolidone as the processing solvent, for high-energy Li1.2Ni0.16Mn0.56Co0.08O2 (Li-rich NMC or LR NMC) as a potential next-generation cathode material. The impact of the binding agents, sodium carboxymethyl cellulose, sodium alginate, and commercial TRD202A (TRD), and the related chemical reactions occurring during the electrode coating process on the electrode morphology and cycling performance is investigated. In particular, the role of phosphoric acid in avoiding the aluminum current collector corrosion and stabilizing the LR-NMC/electrolyte interface as well as its chemical interaction with the binder is investigated, providing an explanation for the observed differences in the electrochemical performance. PMID- 29701455 TI - Defect-Mediated In-Plane Electrical Conduction in Few-Layer sp2-Hybridized Boron Nitrides. AB - In-plane electrical conduction in sp2-hybridized boron nitride (sp2-BN) is presented to explore a huge potential of sp2-BN as an active material for electronics and ultraviolet optoelectronics. Systematic investigation on temperature-dependent current-voltage ( I- V) characteristics of a few-layer sp2 BN grown by metal-organic vapor-phase epitaxy reveals two types of predominant conduction mechanisms that are Ohmic conduction at the low bias region and space charge-limited conduction at the high bias region. From the temperature-dependent I- V characteristics, two shallow traps with activation energies of approximately 25 and 185 meV are observed. On the basis of the near-edge X-ray absorption fine structure spectroscopy, boron-boron (B-B) homoelemental bonding which can be related to grain boundary and nitrogen vacancy (VN) are proposed as the origin of the shallow traps mediating the in-plane conduction in the sp2-BN layer. In addition, a drastic enhancement in the electrical conductivity is observed with the increasing amount of VN that acts as a donor, implying that controlled generation of VN can be an alternative and better approach for the n-type doping of the sp2-BN film rather than ineffective conventional substitutional doping methods. PMID- 29701456 TI - Clickable-Zwitterionic Copolymer Capped-Quantum Dots for in Vivo Fluorescence Tumor Imaging. AB - In the last decades, fluorescent quantum dots (QDs) have appeared as high performance biological fluorescent nanoprobes and have been explored for a variety of biomedical optical imaging applications. However, many central challenges still exist concerning the control of the surface chemistry to ensure high biocompatibility, low toxicity, antifouling, and specific active targeting properties. Regarding in vivo applications, circulation time and clearance of the nanoprobe are also key parameters to control the design and characterization of new optical imaging agents. Herein, the complete design and characterization of a peptide-near-infrared-QD-based nanoprobe for biomedical optical imaging is presented from the synthesis of the QDs and the zwitterionic-azide copolymer ligand, enabling a bio-orthogonal coupling, till the final in vivo test through all the characterization steps. The developed nanoprobes show high fluorescence emission, controlled grafting rate, low toxicity, in vitro active specific targeting, and in vivo long circulating blood time. This is, to our knowledge, the first report characterizing the in vivo circulation kinetics and tumor accumulation of targeted zwitterionic QDs. PMID- 29701457 TI - Type I Collagen-Derived Injectable Conductive Hydrogel Scaffolds as Glucose Sensors. AB - The advent of home blood glucose monitoring revolutionized diabetes management, and the recent introduction of both wearable devices and closed-loop continuous systems has enormously impacted the lives of people with diabetes. We describe the first fully injectable soft electrochemical glucose sensor for in situ monitoring. Collagen, the main component of a native extracellular matrix in humans and animals, was used to fabricate an in situ gellable self-supporting electroconductive hydrogel that can be injected onto an electrode surface or into porcine meat to detect glucose amperometrically. The study provides a proof-of principle of an injectable electrochemical sensor suitable for monitoring tissue glucose levels that may, with further development, prove clinically useful in the future. PMID- 29701458 TI - Stabilization of Lithium-Metal Batteries Based on the in Situ Formation of a Stable Solid Electrolyte Interphase Layer. AB - Lithium (Li) metals have been considered most promising candidates as an anode to increase the energy density of Li-ion batteries because of their ultrahigh specific capacity (3860 mA h g-1) and lowest redox potential (-3.040 V vs standard hydrogen electrode). However, unstable dendritic electrodeposition, low Coulombic efficiency, and infinite volume changes severely hinder their practical uses. Herein, we report that ethyl methyl carbonate (EMC)- and fluoroethylene carbonate (FEC)-based electrolytes significantly enhance the energy density and cycling stability of Li-metal batteries (LMBs). In LMBs, using commercialized Ni rich Li[Ni0.6Co0.2Mn0.2]O2 (NCM622) and 1 M LiPF6 in EMC/FEC = 3:1 electrolyte exhibits a high initial capacity of 1.8 mA h cm-2 with superior cycling stability and high Coulombic efficiency above 99.8% for 500 cycles while delivering a unprecedented energy density. The present work also highlights a significant improvement in scaled-up pouch-type Li/NCM622 cells. Moreover, the postmortem characterization of the cycled cathodes, separators, and Li-metal anodes collected from the pouch-type Li/NCM622 cells helped identifying the improvement or degradation mechanisms behind the observed electrochemical cycling. PMID- 29701459 TI - Giant Gold Nanowire Vesicle-Based Colorimetric and SERS Dual-Mode Immunosensor for Ultrasensitive Detection of Vibrio parahemolyticus. AB - Conventional methods for the detection of Vibrio parahemolyticus (VP) usually need tedious, labor-intensive processes, and have low sensitivity, which further limits their practical applications. Herein, we developed a simple and efficient colorimetry and surface-enhanced Raman scattering (SERS) dual-mode immunosensor for sensitive detection of VP, by employing giant Au vesicles with anchored tiny gold nanowires (AuNW) as a smart probe. Due to the larger specific surface and special hollow structure of giant Au vesicles, silver staining would easily lead to vivid color change for colorimetric analysis and further amplify SERS signals. The t-test was further used to determine if two sets of data from colorimetry and SERS were significantly different from each other. The result shows that there was no significant difference between data from the two methods. Two sets of data can mutually validate each other and avoid false positive and negative detection. The designed colorimetry-SERS dual-mode sensor would be very promising in various applications such as food safety inspection, personal healthcare, and on-site environmental monitoring. PMID- 29701460 TI - Highly Tunable and Scalable Fabrication of 3D Flexible Graphene Micropatterns for Directing Cell Alignment. AB - Patterning graphene allows to precisely tune its properties to manufacture flexible functional materials or miniaturized devices for electronic and biomedical applications. However, conventional lithographic techniques are cumbersome for scalable production of time- and cost-effective graphene patterns, thus greatly impeding their practical applications. Here, we present a simple scalable fabrication of wafer-scale three-dimensional (3D) graphene micropatterns by direct laser tuning graphene oxide reduction and expansion using a LightScribe DVD writer. This one-step laser-scribing process can produce custom-made 3D graphene patterns on the surface of a disk with dimensions ranging from microscale up to decimeter scale in about 20 min. Through control over laser scribing parameters, the resulting various 3D graphene patterns are exploited as scaffolds for controlling cell alignment. The 3D graphene patterns demonstrate their potential to biomedical applications, beyond the fields of electronics and photonics, which will allow to incorporate flexible graphene patterns for 3D cell or tissue culture to promote tissue engineering and drug testing applications. PMID- 29701461 TI - Using Chemical Synthesis to Probe Structure-Activity Relationships of the Glycoactive Bacteriocin Glycocin F. AB - Glycocin F, a bacteriocin produced by Lactobacillus plantarum KW30, is glycosylated with two N-acetyl-d-glucosamine sugars, and has been shown to exhibit a rapid and reversible bacteriostasis on susceptible cells. The roles of certain structural features of glycocin F have not been studied to date. We report here the synthesis of various glycocin F analogues through solid-phase peptide synthesis (SPPS) and native chemical ligation (NCL), allowing us to probe the roles of different structural features of this peptide. Our results indicate that the bacteriostatic activity of glycocin F is controlled by the glycosylated interhelical loop, while the glycosylated flexible tail appears to be involved in localizing the peptide to its cellular target. PMID- 29701462 TI - Functionalized Peptides: Ideal Targets for Collaborative Chemistry. PMID- 29701463 TI - Method Using Water-Based Solvent to Prepare Li7La3Zr2O12 Solid Electrolytes. AB - Li-garnet Li7La3Zr2O12 (LLZO) is a promising candidate of solid electrolytes for high-safety solid-state Li+ ion batteries. However, because of its high reactivity to water, the preparation of LLZO powders and ceramics is not easy for large-scale amounts. Herein, a method applying water-based solvent is proposed to demonstrate a possible solution. Ta-doped LLZO, that is, Li6.4La3Zr1.4Ta0.6O12 (LLZTO), and its LLZTO/MgO composite ceramics are made by attrition milling, followed by a spray-drying process using water-based slurries. The impacts of parameters of the method on the structure and properties of green and sintered pellets are studied. A relative density of ~95%, a Li-ion conductivity of ~3.5 * 10-4 S/cm, and uniform grain size LLZTO/MgO garnet composite ceramics are obtained with an attrition-milled LLZTO/MgO slurry that contains 40 wt % solids and 2 wt % polyvinyl alcohol binder. Li-sulfur batteries based on these ceramics are fabricated and work under 25 degrees C for 20 cycles with a Coulombic efficiency of 100%. This research demonstrates a promising mass production method for the preparation of Li-garnet ceramics. PMID- 29701464 TI - Computer-Assisted Design of a Superior Be2BO3F Deep-Ultraviolet Nonlinear-Optical Material. AB - Deep-ultraviolet (DUV) nonlinear-optical (NLO) materials generating coherent DUV light by a direct second-harmonic-generation (SHG) process have long been pursued as industrially useful lasers. For several decades, KBe2BO3F2 (KBBF) has been regarded as the best DUV-NLO material; it is characterized by a short DUV phase matching edge of 161 nm and a large SHG coefficient of 0.47 pm/V. However, it suffers a strong layering tendency, hindering the growth of large crystals for commercial use. Here, we use a computer-aided swarm structure searching technique to design an alternative DUV-NLO material with a new atmospheric-pressure phase Be2BO3F2 with a P62 c space group (gamma-BBF) that outperforms the DUV-NLO properties of KBBF. The predicted DUV phase-matching edge and SHG coefficient of gamma-BBF are 152 nm and 0.70 pm/V, respectively. The structure of gamma-BBF reduces the layering tendency compared with KBBF because of the absence of K atoms in the gamma-BBF crystal. Our work paves the way for superior DUV-NLO materials that can be grown as large crystals for commercial applications. PMID- 29701465 TI - Photoswitching Behavior of 5-Phenylazopyrimidines: In Situ Irradiation NMR and Optical Spectroscopy Combined with Theoretical Methods. AB - The photoswitching behavior of 5-phenylazopyrimidines was investigated by optical methods and NMR spectroscopy with in situ irradiation sustained by mathematical modeling and DFT calculations. Irradiation of various compounds with electron donating groups on the pyrimidine ring and substituents with electron-withdrawing as well as electron-donating substituent in the para-position of the phenyl ring were examined. All compounds could be successfully converted to the cis isomer; this isomerization and the subsequent thermal fading were studied. Switching cycles can be repeated without signs of photodegradation for most of the compounds, which makes them adept to molecular photoswitches. Interestingly, the chloro and cyano derivatives can be switched without UV light, which makes them vis(pi -> pi*)-vis(n -> pi*) photoswitches. Surprisingly equal trans-to- cis photoisomerization quantum yields for pi -> pi* and n -> pi* excitation indicate the blocking of the inversion pathway following pi -> pi* excitation. In contrast to that, DFT computations suggest the inversion mechanism for the reverse thermal cis-to- trans isomerization of 5-phenylazopyrimidines. PMID- 29701466 TI - Correction to Optimized Inhibitors of Soluble Epoxide Hydrolase Improve in Vitro Target Residence Time and in Vivo Efficacy. PMID- 29701467 TI - Bicyclic Piperazine Mimetics of the Peptide beta-Turn Assembled via the Castagnoli-Cushman Reaction. AB - 5-Oxopiperazine-2-carboxamides and respective carboxylic acids (obtained by the Castagnoli-Cushman reaction of protected iminodiacetic anhydride) were converted into cis- and trans-configured bicyclic piperazines containing two stereogenic centers. The latter are not only well-established mimetics of peptide beta-turn but also attractive, high-Fsp3 cores for drug design in general. The methodology was applied to the preparation of ring-expanded version of bicyclic piperazines not described in the literature. PMID- 29701468 TI - Highly Luminescent Cyclometalated Iridium Complexes Generated by Nucleophilic Addition to Coordinated Isocyanides. AB - In this work, we report a new class of blue-emitting cyclometalated iridium complexes supported by acyclic diaminocarbene (ADC) ancillary ligands. These neutral, tris-chelated complexes are not obtainable via traditional synthesis routes and instead are generated through metal-mediated nucleophilic addition to a metal-bound isocyanide, which is followed by orthometalation of the ADC under mild conditions. Importantly, four of the variants exhibit efficient phosphorescence when immobilized in PMMA matrix, achieving quantum yields of 79% for blue emitters with a 2-(2,4-difluorophenyl)pyridine (F2ppy) C^N ligand and 30 37% for orange emitters with a 2-phenylbenzothiazole (bt) C^N ligand. Electrochemical studies demonstrate significantly higher-lying HOMO levels in the ADC complexes relative to the NHC analogues, a phenomenon that results in enhanced charge-transfer character in the excited states of the ADC complexes. This study demonstrates that ADC ancillary ligands not only give rise to new structures for Ir(III)-based phosphorescent emitters but also are promising targets for use in light-emitting devices and other thin-film optical applications. PMID- 29701469 TI - Ligand Desolvation Steers On-Rate and Impacts Drug Residence Time of Heat Shock Protein 90 (Hsp90) Inhibitors. AB - Residence time and more recently the association rate constant kon are increasingly acknowledged as important parameters for in vivo efficacy and safety of drugs. However, their broader consideration in drug development is limited by a lack of knowledge of how to optimize these parameters. In this study on a set of 176 heat shock protein 90 inhibitors, structure-kinetic relationships, X-ray crystallography, and molecular dynamics simulations were combined to retrieve a concrete scheme of how to rationally slow down on-rates. We discovered that an increased ligand desolvation barrier by introducing polar substituents resulted in a significant kon decrease. The slowdown was accomplished by introducing polar moieties to those parts of the ligand that point toward a hydrophobic cavity. We validated this scheme by increasing polarity of three Hsp90 inhibitors and observed a 9-, 13-, and 45-fold slowdown of on-rates and a 9-fold prolongation in residence time. This prolongation was driven by transition state destabilization rather than ground state stabilization. PMID- 29701470 TI - Molecular Mechanism of Loading Sulfur Hexafluoride in gamma-Cyclodextrin Metal Organic Framework. AB - gamma-Cyclodextrin metal-organic framework (gamma-CD-MOF) is a new type of highly porous carrier for potential loading of therapeutic or diagnostic gas like sulfur hexafluoride (SF6). Here, loading of SF6 into gamma-CD-MOF was investigated for its mechanism by molecular simulation and quantitative determination of SF6 using quantitative nuclear magnetic resonance (qNMR). For the SF6 loading, gamma-CD-MOF was first degassed to remove the air without thermal decomposition or loss of framework crystallinity, then placed in the copper tube, and sealed to adsorb SF6 under 1.2 MPa and 25 degrees C for 12 h. The qNMR was employed for the determination of SF6 loaded in gamma-CD-MOF using Span 80 as suspending agent and trifluoroacetic acid as internal standard. Then, the thermodynamic parameters had been estimated. Finally, molecular modeling combining with 19F NMR spectra was conducted to reveal the status of SF6 molecules in gamma-CD-MOF. The results demonstrated that the content of SF6 loaded in gamma-CD-MOF was 2.67 +/- 0.46 wt %. After exposing to the environment of free SF6 at 0.1 MPa for 10 days, the relative content was 74.7%. It was confirmed that SF6 preferred to stay in the cavity of gamma-CD-MOF cubes rather than in the gamma-CD molecular pairs, which was a nonchemical adsorptive process. In conclusion, this research has established qNMR method and molecular simulation to demonstrate SF6 molecules in gamma-CD-MOF and its loading mechanism. PMID- 29701471 TI - Copper-Catalyzed Radical Reductive Arylation of Styrenes with Aryl Iodides Mediated by Zinc in Water. AB - A copper/aniline catalyst system enables the radical arylation of styrenes using aryl iodides mediated by zinc in water. This transformation provides an efficient synthetic methodology for the convenient synthesis of diarylethane. PMID- 29701472 TI - Short and Protecting-Group-Free Approach to the (-)-Delta8-THC-Motif: Synthesis of THC-Analogues, (-)-Machaeriol B and (-)-Machaeriol D. AB - Friedel-Crafts alkylation of resorcinols with ( S)- cis-verbenol and subsequent cyclization allows the construction of the tetrahydrodibenzopyran core of (-) Delta8-THC which is also found in other natural products in one step. Using a benzofuryl substituted resorcinol, followed by diastereoselective hydroboration and oxidative or reductive workup, directly provides (-)-machaeriol B and D in 42% and 43% overall yields. Bromoresorcinol as a coupling partner delivers Br-THC that can be applied for late-stage diversification by Suzuki-Miyaura cross coupling to readily access (-)-Delta8-THC analogues. PMID- 29701473 TI - Highly Efficient 17.6% Tin-Lead Mixed Perovskite Solar Cells Realized through Spike Structure. AB - Frequently observed high Voc loss in tin-lead mixed perovskite solar cells is considered to be one of the serious bottle-necks in spite of the high attainable Jsc due to wide wavelength photon harvesting. An amicable solution to minimize the Voc loss up to 0.50 V has been demonstrated by introducing an n-type interface with spike structure between the absorber and electron transport layer inspired by highly efficient Cu(In,Ga)Se2 solar cells. Introduction of a conduction band offset of ~0.15 eV with a thin phenyl-C61-butyric acid methyl ester layer (~25 nm) on the top of perovskite absorber resulted into improved Voc of 0.75 V leading to best power conversion efficiency of 17.6%. This enhancement is attributed to the facile charge flow at the interface owing to the reduction of interfacial traps and carrier recombination with spike structure as evidenced by time-resolved photoluminescence, nanosecond transient absorption, and electrochemical impedance spectroscopy measurements. PMID- 29701474 TI - Cu-Catalyzed Oxyalkynylation and Aminoalkynylation of Unactivated Alkenes: Synthesis of Alkynyl-Featured Isoxazolines and Cyclic Nitrones. AB - A convenient and efficient vicinal oxyalkynylation/aminoalkynylation of internal unactivated alkenes is achieved by means of a Cu-catalyzed radical cascade reaction of unsaturated ketoximes with ethynylbenziodoxolone (EBX) reagents. This protocol enables the synthesis of structurally valuable isoxazolines or cyclic nitrones and the introduction of an important alkyne group in a single operation. The reaction is characterized by a broad substrate scope for both unsaturated ketoximes and alkynylation reagents and a low catalyst loading. PMID- 29701476 TI - Synthesis, Structural Characterization, and Luminescence Switching of Diarylethene-Conjugated Ru(II)-Terpyridine Complexes by trans-cis Photoisomerization: Experimental and DFT/TD-DFT Investigation. AB - We synthesized and thoroughly characterized a new family of diarylethene conjugated mononuclear Ru(II)-terpyridine complexes and investigated in detail their photophysical, electrochemical, and spectroelectrochemical behaviors. Interestingly, the compounds show moderately strong room-temperature luminescence predominantly from their 3MLCT state with luminescence lifetime varying between 8.43 and 22.82 ns. Because of the presence of diarylethene unit, all the monometallic complexes underwent trans-to-cis photoisomerization upon interaction with UV light with substantial changes in their absorption and luminescence spectra. Reverting back from the cis to the trans form is also made possible upon treatment with visible light or by heat. Trans-to-cis isomerization leads to almost complete quenching of luminescence, while backward cis-to-trans isomerization gives rise to restoration of the original luminescence for all the complexes. Thus, "on-off" and "off-on" emission switching was made possible upon successive interaction of the complexes with UV and visible light. Computational investigation involving density functional theory (DFT) and time-dependent DFT methods was done for proper assignment of the experimental absorption and emission spectral bands in the complexes. Finally, experimentally observed trend on the absorption and emission spectral behaviors of the complexes upon photoisomerization was also compared with the calculated results. PMID- 29701477 TI - Ring Expansion, Ring Contraction, and Annulation Reactions of Allylic Phosphonates under Oxidative Cleavage Conditions. AB - Oxidative cleavage of cycloalkenylalkylphosphonates 1 followed by treatment with base gives rise to homologated cycloalkenones 2 in good to excellent yields. Subjecting cycloalk-2-enylphosphonates 3 to identical conditions provides the one carbon ring-contracted compounds 4 in excellent yields. Oxidative cleavage of gamma,delta-unsaturated ketophosphonates 6 followed by treatment with base affords 2-cyclopenten-1-ones 7 in good overall yields. This method may offer a practical alternative to existing methods for effecting one-carbon ring expansion, ring contraction, and annulation reactions. PMID- 29701475 TI - Fluorine-Substituted Pyrrolo[2,3- d]Pyrimidine Analogues with Tumor Targeting via Cellular Uptake by Folate Receptor alpha and the Proton-Coupled Folate Transporter and Inhibition of de Novo Purine Nucleotide Biosynthesis. AB - Novel fluorinated 2-amino-4-oxo-6-substituted pyrrolo[2,3- d]pyrimidine analogues 7-12 were synthesized and tested for selective cellular uptake by folate receptors (FRs) alpha and beta or the proton-coupled folate transporter (PCFT) and for antitumor efficacy. Compounds 8, 9, 11, and 12 showed increased in vitro antiproliferative activities (~11-fold) over the nonfluorinated analogues 2, 3, 5, and 6 toward engineered Chinese hamster ovary and HeLa cells expressing FRs or PCFT. Compounds 8, 9, 11, and 12 also inhibited proliferation of IGROV1 and A2780 epithelial ovarian cancer cells; in IGROV1 cells with knockdown of FRalpha, 9, 11, and 12 showed sustained inhibition associated with uptake by PCFT. All compounds inhibited glycinamide ribonucleotide formyltransferase, a key enzyme in the de novo purine biosynthesis pathway. Molecular modeling studies validated in vitro cell-based results. NMR evidence supports the presence of an intramolecular fluorine-hydrogen bond. Potent in vivo efficacy of 11 was established with IGROV1 xenografts in severe compromised immunodeficient mice. PMID- 29701479 TI - Recovery at low altitude regions of patients from high altitude neighbourhood. PMID- 29701480 TI - A Critical Review of Properties and Analytical Methods for the Determination of Docetaxel in Biological and Pharmaceutical Matrices. AB - Docetaxel (DTX) is an antineoplastic agent of the second generation of the taxoid family. It is a semi-synthetic drug prepared from a precursor extracted of the plant Taxus baccata. The commercial formulation of DTX, Taxotere(r), employs the surfactant polysorbate 80, due to the low water solubility of the drug, causing several side effects. Therefore, there is a need to develop delivery systems to reduce the side effects of DTX. In addition, this drug has been qualitative and quantitatively analyzed in pharmaceutical formulations and biological samples. Thus, several techniques and analytical methods have been reported with the aim of optimizing the analytical signal, increasing sensitivity, selectivity and reducing the effects of interference. Herein, we highlight immunoassay, capillary electrophoresis and chromatographic methods. This review presents a summary of physicochemical and pharmacokinetics properties, mechanisms of action, drug delivery systems and analytical methods used in quantification of DTX in diverse matrices such as blood, plasma, oral fluid, urine, carcinoma cells, pharmaceutical formulations and delivery systems. PMID- 29701481 TI - Characterization of highly pathogenic avian influenza H5N8 virus from Egyptian domestic waterfowl in 2017. AB - In 2016, the highly pathogenic avian influenza (HPAI) H5N8 virus was detected in wild birds for the first time in Egypt. In the present study, we identified the HPAI virus H5N8 of clade 2.3.4.4 from domestic waterfowl in Egypt, suggesting its transmission to the domestic poultry from the migratory birds. Based on partial haemagglutinin gene sequence, this virus has a close genetic relationship with subtype H5N8 viruses circulating in Asia and Europe. Pathologically, H5N8 virus in hybrid duck induced nervous signs accompanied by encephalomalacia, haemorrhages, nonsuppurative encephalitis and nonsuppurative vasculitis. The granular layer of cerebellum showed multifocal areas of hydropic degeneration and the Purkinje cell neurons were necrotized or lost. Additionally, the lung, kidney and spleen were congested, and necrotizing pancreatitis was also observed. The co circulation of both HPAI H5N1 and H5N8 subtypes with the low pathogenic avian influenza H9N2 subtype complicate the control of avian influenza in Egypt with the possibility of emergence of new reassortant viruses. Therefore, continuous monitoring with implementation of strict control measures is required. Research highlights HPAI H5N8 virus clade 2.3.4.4 was detected in domestic ducks and geese in Egypt in 2017. Phylogenetically, the virus was closely related to HPAI H5N8 viruses identified in Asia and Europe Nonsuppurative encephalitis was widely observed in HPAI H5N8 virus-infected ducks. Degeneration of the cerebellar granular layer was found in most of the brain tissues examined. PMID- 29701482 TI - Neuromuscular fatigue during repeated sprint exercise: underlying physiology and methodological considerations. AB - Neuromuscular fatigue occurs when an individual's capacity to produce force or power is impaired. Repeated sprint exercise requires an individual to physically exert themselves at near-maximal to maximal capacity for multiple short-duration bouts, is extremely taxing on the neuromuscular system, and consequently leads to the rapid development of neuromuscular fatigue. During repeated sprint exercise the development of neuromuscular fatigue is underlined by a combination of central and peripheral fatigue. However, there are a number of methodological considerations that complicate the quantification of the development of neuromuscular fatigue. The main goal of this review is to synthesize the results from recent investigations on the development of neuromuscular fatigue during repeated sprint exercise. Hence, we summarize the overall development of neuromuscular fatigue, explain how recovery time may alter the development of neuromuscular fatigue, outline the contributions of peripheral and central fatigue to neuromuscular fatigue, and provide some methodological considerations for quantifying neuromuscular fatigue during repeated sprint exercise. PMID- 29701483 TI - On task: Considerations and future directions for studies of corticospinal excitability in exercise neuroscience and related disciplines. AB - Over the last few decades, transcranial magnetic stimulation (TMS) has emerged as a conventional laboratory technique in human neurophysiological research. Exercise neuroscientists have used TMS to study central nervous system contributions to fatigue, training, and performance in health, injury, and disease. In such studies, corticospinal excitability is often assessed at rest or during simple isometric tasks with the implication that the results may be extrapolated to more functional and complex movement outside of the laboratory. However, the neural mechanisms that influence corticospinal excitability are both state- and task-dependent. Furthermore, there are many sites of modulation along the pathway from the motor cortex to the muscle; a fact that is somewhat obscured by the all-encompassing and poorly defined term "corticospinal excitability". Therefore, the tasks we use to assess corticospinal excitability and the conclusions that we draw from such a global measure of the motor pathway must be taken into consideration. The overall objective of this review is to highlight the task-dependent nature of corticospinal excitability and the tools used to assess modulation at cortical and spinal sites of modulation. By weighing the advantages and constraints of conventional approaches to studying corticospinal excitability, and considering some new and novel approaches, we will continue to advance our understanding of the neural control of movement during exercise. PMID- 29701484 TI - Diversity of Bacillus-like bacterial community in the rhizospheric and non rhizospheric soil of halophytes (Salsola stocksii and Atriplex amnicola), and characterization of osmoregulatory genes in halophilic Bacilli. AB - Salinity is one of the major abiotic stresses; a total of 3% of the world's land mass is affected by salinity. Approximately 6.3 million hectares of land in Pakistan is affected by salinity to varying degrees, and most of the areas are arid to semiarid with low annual precipitation. The aim of the present study is to identify and characterize Bacillus and Bacillus-derived bacterial genera from the rhizospheric and non-rhizospheric soil samples from the Khewra Salt Mine, Pakistan, by using culture-independent and -dependent methods. Seven Bacillus like bacterial genera, Bacillus, Halobacillus, Virgibacillus, Brevibacillus, Paenibacillus, Tumebacillus, and Lysinibacillus, were detected by using pyrosequencing analysis, whereas only four genera, Bacillus, Halobacillus, Oceanobacillus, and Virgibacillus, were identified by culture-dependent methods. Most of the Bacillus-like isolates identified in this study were moderately halophilic, alkaliphilic, and mesophilic bacteria and were considered a good source of hydrolytic enzymes because of their ability to degrade proteins, carbohydrates, and lipids. Eight Bacillus-like strains from the genera Bacillus, Halobacillus, Oceanobacillus, and Virgibacillus showed positive results for the presence of ectABC gene cluster (ectoine), six strains could synthesize betaine from choline, and six strains tested positive for the synthesis of proline from either glutamate or ornithine by using proline dehydrogenase enzyme. PMID- 29701485 TI - Internet gaming disorder should qualify as a mental disorder. PMID- 29701486 TI - Can an automated sleep detection algorithm for waist-worn accelerometry replace sleep logs? AB - The purpose of this study was to test whether estimates of bedtime, wake time, and sleep period time (SPT) were comparable between an automated algorithm (ALG) applied to waist-worn accelerometry data and a sleep log (LOG) in an adult sample. A total of 104 participants were asked to log evening bedtime and morning wake time and wear an ActiGraph wGT3X-BT accelerometer at their waist for 24 h/day for 7 consecutive days. Mean difference and mean absolute difference (MAD) were computed. Pearson correlations and dependent-sample t tests were used to compare LOG-based and ALG-based sleep variables. Effect sizes were calculated for variables with significant mean differences. A total of 84 participants provided 2+ days of valid accelerometer and LOG data for a total of 368 days. There was no mean difference (p = 0.47) between LOG 472 +/- 59 min and ALG SPT 475 +/- 66 min (MAD = 31 +/- 23 min, r = 0.81). There was no significant mean difference between bedtime (2348 h and 2353 h for LOG and ALG, respectively; p = 0.14, MAD = 25 +/- 21 min, r = 0.92). However, there was a significant mean difference between LOG (0741 h) and ALG (0749 h) wake times (p = 0.01, d = 0.11, MAD = 24 +/- 21 min, r = 0.92). The LOG and ALG data were highly correlated and relatively small differences were present. The significant mean difference in wake time might not be practically meaningful (Cohen's d = 0.11), making the ALG useful for sample estimates. MAD, which gives a better estimate of the expected differences at the individual level, also demonstrated good evidence supporting ALG individual estimates. PMID- 29701487 TI - Patient preferences for diabetes-related complications in Taiwan. AB - BACKGROUND: As the prevalence of diabetes mellitus (DM) continues to increase rapidly, there has been a rising need not only to assess the clinical outcomes but also the impact of DM on the health-related quality of life (HRQoL) of affected individuals. Most previous studies have found that having complications is strongly associated with decreased HRQoL in DM patients. As such, it is crucial to measure individuals' preferences for DM-related complications in order to assess the magnitude of complications' effect on overall HRQoL. In addition, preference scores are an essential component of cost-utility analyses (CUAs), which studies can incorporate healthcare costs, HRQoL and clinical outcomes of DM into one analysis. OBJECTIVE: The aims of this study were to assess the preference scores of DM-related complications using both the standard gamble (SG), a choice-based method, and visual analogue scale (VAS), a scaling method. We also aimed to assess several possible factors that might be associated with the preference scores of the complications. METHODS: This is a cross-sectional interview-administered survey, and 213 patients with type 2 DM were interviewed. The respondents' preference scores of eleven DM-related complications were obtained using VAS and SG techniques. Demographic information, clinical characteristics and risk attitudes were also collected to explore factors that may affect patients' preference scores. RESULTS: Nearly one quarter of participants in Taiwan ranked at least one of the complications worse than death. The mean VAS scores ranged from 0.004 (amputation) to 0.47 (nocturnal hypoglycemia) while the mean adjusted SG scores ranged from 0.30 (blindness) to 0.66 (nocturnal hypoglycemia). There were significant differences in all of the complications' preference scores depending on risk attitudes. CONCLUSION: Both the VAS and SG methods were used to elicit the preference scores of DM-related complications, and the preference scores derived could be useful for future cost utility analyses. PMID- 29701488 TI - Effectiveness of a Dietary Supplement Containing Hydrolyzed Collagen, Chondroitin Sulfate, and Glucosamine in Pain Reduction and Functional Capacity in Osteoarthritis Patients. AB - This observational, open, multicenter clinical trial with a single treatment group aimed to evaluate the effectiveness of a dietary supplement whose main ingredients are hydrolyzed gelatin, chondroitin sulfate, glucosamine sulfate, and devil's claw and bamboo extracts for pain reduction and improvement of functional capacities in patients with osteoarthritis (OA) of the knee and/or hip (REDART study). In all, 130 patients with OA recruited from Spanish hospitals received the dietary supplement for 6 months. The primary outcome was the patients' global assessment of pain in the affected joint as measured with a visual analogue scale (VAS). Other outcome measurements included the Lequesne Functional Index (subindexes for pain/discomfort, distance walked, and daily living) and the Western Ontario and McMaster Universities Arthritis Index (WOMAC; subindexes for pain, stiffness, and physical function). Scores were taken at months 3 and 6 of the treatment. Patients (N = 78) showed a reduction of pain of 3.77 +/- 1.77 points after 6 months (p < .0001) in the VAS. The total reduction in the Lequesne Functional Index was 6.30 +/- 4.08 points after 6 months (p < .0001), with significant reductions in all subindexes of the scale. A similar pattern was found for the WOMAC index, with an overall reduction of 22.49 +/- 14.03 points after 6 months (p < .0001) and significant reductions in all subindexes. No major adverse events were noted during the treatment. This exploratory study shows that treatment with the dietary supplement significantly reduces pain and improves locomotor function in patients with OA of the knee and/or hip. PMID- 29701489 TI - Impact of inpatient mental health rehabilitation on psychiatric readmissions: a propensity score matched case control study. AB - BACKGROUND: Examination of readmission data is a standard method for evaluating health service outcomes. Limited work has evaluated the efficacy of mental health rehabilitation, despite the need for evidence-based approaches. AIMS: To evaluate the impact of inpatient mental health rehabilitation using metrics of psychiatric readmissions routinely collected at occasions of service. METHODS: Consumers (n = 252) of a nonacute inpatient mental health rehabilitation unit were case matched with normative clients from community mental health services. The impact of inpatient care was measured on: (1) the occurrence of a psychiatric readmission within 12 months of discharge; (2) the total number of psychiatric readmissions within 12 months of discharge; and (3) the number of days to a psychiatric readmission after discharge. RESULTS: The proportion of consumers experiencing a readmission significantly decreased following inpatient care, comparable to the normative group. The number of readmissions also significantly decreased, approaching normative group levels, except in consumers with comorbid bipolar, substance use, or personality disorder. Time to a readmission significantly increased following inpatient care, approximating normative group values, and was related to the number of previous admissions. CONCLUSION: Routinely collected service data demonstrated nonacute inpatient mental health rehabilitation reduces re-hospitalization, which will have benefits for both consumers and health services. PMID- 29701490 TI - Influence of gut microbiota and intestinal barrier on enterogenic infection after liver transplantation. AB - Liver transplantation is currently a standard therapy for patients with end-stage liver diseases and hepatocellular carcinoma. Given that liver transplantation has undergone a thriving development in these decades, the survival rates after liver transplantation have markedly improved as a result of the critical advancement in surgical techniques, immunosuppressive therapies, and post-operative care. However, infection remains a fatal complication after liver transplantation surgery. In particular, enterogenic infection represents a major complication in liver transplant recipients. This article gives an overview of infection cases after liver transplantation and focuses on the discussion of enterogenic infection in terms of its pathophysiology, risk factor, outcome, and treatment. PMID- 29701491 TI - Effects of Shiitake Intake on Serum Lipids in Rats Fed Different High-Oil or High Fat Diets. AB - Shiitake (Lentinula edodes) extract, eritadenine, has been shown to reduce cholesterol levels, and its hypocholesterolemic actions are involved in the metabolism of methionine. However, the mechanisms by which eritadenine affects cholesterol metabolism in animals fed a high-fat diet containing different sources of lipids have not yet been elucidated in detail. This study was conducted to investigate the effects of shiitake supplementation on serum lipid concentrations in rats fed a diet including a high amount of a plant oil (HO [high oil] and HOS [high oil with shiitake] groups), animal fat (HF [high fat] and HFS [high fat with shiitake] groups), or MCT- (medium-chain triglyceride-) rich plant oil (HM [high MCT] and HMS [high MCT with shiitake] groups). Rats in the HOS, HFS, and HMS groups were fed shiitake. When rats were fed a diet containing shiitake, serum triglyceride, cholesterol levels, and LCAT (lecithin cholesterol acyltransferase) activities were lower in rats given MCT-rich plant oil than in those that consumed lard. The lipid type in the diet with shiitake also affected serum cholesterol levels and LCAT activities. The diet containing MCT-rich plant oil showed the greatest rates of decrease in all serum lipid profiles and LCAT activities. These results suggest that shiitake and MCT-rich plant oil work together to reduce lipid profiles and LCAT activity in serum. PMID- 29701492 TI - Mental health and debt collection: a story of progress? Exploring changes in debt collectors' attitudes and practices when working with customers with mental health problems, 2010-2016. AB - BACKGROUND: In recent years, the UK debt collection industry has taken steps to improve its policies and practices in relation to customers with mental health problems. Little data, however, have been collected to evidence change. AIMS: This paper examines whether the reported attitudes and practices of debt collection staff when working with customers with mental health problems have changed between 2010 and 2016. METHOD: This paper draws on descriptive and regression analyses of two cross-sectional surveys of debt collection staff: one conducted in 2010 and one conducted in 2016. RESULTS: All variables analysed show statistically significant changes between 2010 and 2016 indicative of improved reported attitudes and practices. CONCLUSIONS: While results suggest an improvement in attitudes and practice may have occurred between 2010 and 2016, research is required to understand this potential shift, its likely causes, and concrete impact on customers. PMID- 29701493 TI - Effect of cellobiose supplementation and dietary soluble fibre content on in vitro caecal fermentation of carbohydrate-rich substrates in rabbits. AB - The in vitro caecal fermentation of five substrates low in starch and protein content [d-(+)-glucose (GLU), d-cellobiose (CEL), sugar beet pectin (PEC), sugar beet pulp (SBP) and wheat straw (WS)] was investigated using soft faeces from rabbits receiving different levels of cellobiose and soluble fibre as inoculum. A total of 24 rabbits were supplemented 3 levels of cellobiose in the drinking water (0.0, 7.5, 15.0 g/l) and fed two experimental diets containing either low soluble fibre (LSF) or high soluble fibre (HSF) levels (84.0 and 130 g/kg dry matter). All substrates were subjected to a two-step pepsin/pancreatin in vitro pre-digestion, and the whole residue was used as substrate for the in vitro incubations. Gas production was measured until 144 h, and volatile fatty acid (VFA) production was determined at 24 h incubation. Experimental treatments did not affect SBP fermentation and had only a subtle influence on fermentation of WS and GLU. In contrast, cellobiose supplementation * donors' diet interactions were detected for most gas production parameters for CEL. Both the fractional gas production (k) and maximal gas production rates were linearly increased (p <= 0.042) and the initial delay in the onset of gas production (Lag) linearly decreased (p < 0.001) by cellobiose supplementation with the HSF inoculum, with no differences between the 7.5 and 15.0 doses. In contrast, with the LSF inoculum cellobiose supplementation only affected k values, which were quadratically increased (p = 0.043) and had maximal values for the 7.5 dose. A quadratic effect (p <= 0.018) of cellobiose supplementation was observed for total VFA production at 24 h when CEL and PEC were fermented, obtaining the maximal VFA production for the 7.5 dose of cellobiose. Total VFA production for CEL was greater with LSF than with HSF inoculum (20.7 vs. 12.9 mmol/l; p = 0.014), but the opposite was found for WS (3.97 vs. 6.21 mmol/l; p = 0.005). The use of LSF inoculum for CEL fermentation sharply reduced acetate (p = 0.001) and increased butyrate proportions (p <= 0.001) compared with the HSF inoculum. A positive relationship between total VFA caecal concentrations in rabbits receiving the same experimental treatments and in vitro values was only observed when WS was used as substrate (r = 0.90; p = 0.015; n = 6). The results suggest that experimental factors influenced the fermentative activity of caecal digesta, but the observed response differed with the incubated substrate, being the CEL the most affected. PMID- 29701494 TI - Change in body mass index within the first-year post-injury: a VA Traumatic Brain Injury (TBI) model systems study. AB - OBJECTIVE: To describe change in body mass index (BMI) and weight classification 1-year post- traumatic brain injury (TBI) among Veterans and service members. DESIGN: Prospective observational cohort study. SETTING: VA Polytrauma Rehabilitation Centers. PARTICIPANTS: Veterans and service members (N = 84) enrolled in VA Traumatic Brain Injury Model Systems (VA TBIMS) study with BMI scores at enrollment and 1-year post-injury. INTERVENTIONS: N/A. MAIN OUTCOME MEASURES: BMI scores from height and weight and weight classifications (underweight, normal weight, overweight, obese classes 1-3) defined by WHO. RESULTS: Twenty per cent were obese at time of injury and 24% were obese at 1 year post-injury. Cross-tab analyses revealed 7% of normal weight and 24% overweight participants at time of injury as obese Class 1 one-year post-injury. Univariate models found BMI and tobacco smoking at time of injury were significant predictors of higher BMI scores 1-year post-TBI. Multivariable models found BMI at time of injury and motor functioning, were significant predictors. Preinjury BMI, tobacco smoking and PTSD symptom severity predicted change in weight category. CONCLUSION: While obesity among service members and Veterans post-TBI is below national averages, trends in weight gain between time of injury and 1-year follow-up were observed. Implications for health promotion and chronic disease management efforts with regards to rehabilitation for injured military are discussed. List of Abbreviations: BMI, Body mass index; BRFSS, Behavioural Risk Factor Surveillance; GCS, Glasgow Coma Scale; FIM, Functional Independence Measure; NIDILRR, National Institute on Independent Living and Rehabilitation Research; PCL-C, PTSD checklist-civilian; PSTD, Post-traumatic stress disorder; VA, Veterans Affairs; VA PRC, Veterans Affairs Polytrauma Rehabilitation; VA TBIMS, Veterans Affairs TBI Model Systems. PMID- 29701495 TI - Mental health status and healthcare utilization among community dwelling older adults. AB - BACKGROUND: Shifts in mental health utilization patterns are necessary to allow for meaningful access to care for vulnerable populations. There have been long standing issues in how mental health is provided, which has caused problems in that care being efficacious for those seeking it. AIMS: To assess the relationship between mental health status and healthcare utilization among adults >=65 years. METHODS: A negative binomial regression model was used to assess the relationship between mental health status and healthcare utilization related to office-based physician visits, while a two-part model, consisting of logistic regression and negative binomial regression, was used to separately model emergency visits and inpatient services. RESULTS: The receipt of care in office based settings were marginally higher for subjects with mental health difficulties. Both probabilities and counts of inpatient hospitalizations were similar across mental health categories. The count of ER visits was similar across mental health categories; however, the probability of having an emergency department visit was marginally higher for older adults who reported mental health difficulties in 2012. CONCLUSION: These findings are encouraging and lend promise to the recent initiatives on addressing gaps in mental healthcare services. PMID- 29701496 TI - Evaluation of hospital length of stay and revenues as a function of admission mode, clinical pathways including observation unit stay and hospitalization characteristics. AB - : Objectives Hospital length of stay (days) and revenues per day (euros) could be different depending on admission mode. To determine the impact of admission mode as a function of clinical pathway, we conducted the present study. DATA SOURCES: We included 159,206 admissions to three academic hospitals during a four-year period. Data were obtained from the electronic system of the hospital trust. Study design A case (through-emergency department)-control (elective (EA)) study was conducted (77,052), matched by age, stay severity and type, disease-related group, and discharge mode. PRINCIPAL FINDINGS: Through-emergency department were significantly elderly, more severe, had more intensive care stays, a higher mortality rate, longer length of stay (days) (9.5 +/- 12 vs. 6.8 +/- 9.5; p < 0.0001), and lower revenues per day (647 +/- 451 vs. 721 +/- 422; p = 0.01). In case-control study, mean differences between cases and controls were: longer length of stay -0.64 and revenues per day -75.6; for >=75 years -1.2 and -102.1; medical -0.9 and -90.4; and discharge to facilities care centers -1.5 and -81.8. Among cases, 40% had a stay in observation unit before being admitted in hospital ward. Differences were strongly reduced for patients who did not go to observation unit before being admitted. Differences were reduced from 0.64 to 0.2 days for length of stay and from 79 to 41 euros for revenues per day when patients did not stay in observation unit before being admitted. Conclusions We conclude that admission mode is associated with length of stay and revenues. However, as differences are weak, elective admissions should not be prioritized on economic arguments. Otherwise, our study indicates that among through emergency department admissions, observation unit stay is associated with longer length of stay and lower revenues. PMID- 29701497 TI - Opposite roles of group IV BBX proteins: Exploring missing links between structural and functional diversity. AB - BBX proteins are a family of zinc finger transcription factors that are versatile regulators of plant development. The 32 BBX proteins in Arabidopsis are subdivided into five structural groups based on their domain structure. Members of group IV play important and diverse roles in light-regulated development. The N-terminal B-box domains mediate DNA binding and transcriptional regulation. The C-terminal region determines the functional diversity of the structurally similar group IV members as reported in our recent study investigating the basis of functional diversification between BBX21 and BBX24. We also found that multi layered regulation of HY5 by the BBX proteins leads to a diverse repertoire of developmental effects. Here we provide a comprehensive structure-function analysis of the group IV BBX proteins. PMID- 29701499 TI - Comparing physical and mental health literacy. AB - BACKGROUND: This study attempted to ascertain whether people had better mental vs physical health literacy by comparing their knowledge of six conditions. AIMS: The aim was to link two different literatures which have remained apart. METHODS: In all, 186 young British participants (52% male) with an average age of 25 years completed an online questionnaire describing six vignettes characters. Three described mental health conditions (anorexia, bipolar disorder and schizophrenia) and three physical health conditions (asthma, diabetes and osteoarthritis). Participants were required to name the illness and rate how treatable and manageable they believed the condition is. They were also asked to rate how much the problem would affect an individual's daily life and suggest whether the individual should seek professional help. RESULTS: The recognition of specific mental health conditions (anorexia, borderline personality disorder, schizophrenia) was marginally higher than the recognition of physical health conditions (arthritis, asthma, diabetes). Ratings about treatment and the effect of each illness showed considerable variation. CONCLUSION: The results suggest that people are equally and relatively poorly informed about relatively common mental compared to physical illnesses. PMID- 29701498 TI - Not only priming: Soil microbiota may protect tomato from root pathogens. AB - An increasing number of studies have investigated soil microbial biodiversity. However, the mechanisms regulating plant responses to soil microbiota are largely unknown. A previous work tested the hypothesis that tomato plants grown on native soils with their complex microbiotas respond differently from tomato growing in a sterile substrate. Two soils, suppressive or conducive to Fusarium oxysporum f. sp. lycopersici (FOL), and two genotypes susceptible and resistant to the same pathogen were considered. The work highlighted that the two tested soil microbiotas, irrespectively of their taxonomic composition, elicit the PAMP triggered Immunity Pathway, the first level of plant defence, as well as an increased lignin synthesis, leading to an active protection when FOL is present in the soil. Here, we tested the expression of a panel of genes involved in Effector-Triggered Immunity (ETI), demonstrating that soil microbiota, beside genotype, affects plant resistance to FOL also modulating this pathway. PMID- 29701501 TI - Stroke care and malpractice. PMID- 29701500 TI - Does surgical technique influence the postoperative hemodynamic disturbances and neurological outcomes in carotid endarterectomy? AB - INTRODUCTION: The carotid endarterectomy is already well established in patients with symptomatic or asymptomatic internal carotid artery (ICA) stenosis. The aim of this study was to determine whether there is a difference in postoperative blood pressure changes, stroke rate and postoperative complications following eversion carotid endarterectomy (E-CEA) and conventional carotid endarterectomy (C-CEA). METHODS: From 1 January 2010 to 31 March 2017 consecutive patients admitted to our department with symptomatic or asymptomatic ICA stenosis were included in this retrospective study. During the 7-year period, 175 CEAs were performed in 166 consecutive patients (25 females, 141 males; mean age 70.6 +/- 14.4 years; range 47 to 92 years). RESULTS: The mean operative and cross-clamping time were shorter for E-CEA (72 +/- 14.3 minutes vs. 115 +/- 17.4 minutes, p < .001), (22 +/- 7.7 vs 34 +/- 6.3, p < .001) respectively. No significant difference was noted between the groups for the occurrence of perioperative stroke (p = .501). No significant difference was noted for postoperative blood pressure difference on the 6th hour and the 24th hour after surgery between E-CEA and C-CEA (p = .130). CONCLUSIONS: E-CEA was associated with significant reduction in operative time and cross-clamping time however, increases postoperative bleeding. No difference was noted for postoperative stroke and blood pressure distortion between E-CEA and C-CEA. PMID- 29701502 TI - Effects and biotransformation of the mycotoxin deoxynivalenol in growing pigs fed with naturally contaminated pelleted grains with and without the addition of Coriobacteriaceum DSM 11798. AB - Deoxynivalenol (DON) is one of the most prevalent Fusarium mycotoxins in grain and can cause economic losses in pig farming due to reduced feed consumption and lower weight gains. Biodetoxification of mycotoxins using bacterial strains has been a focus of research for many years. However, only a few in vivo studies have been conducted on the effectiveness of microbial detoxification of fusariotoxins. This study was therefore aimed at investigating the effect of a feed additive containing the bacterial strain Coriobacteriaceum DSM 11798 (the active ingredient in Biomin(r) BBSH 797) on growth performance and blood parameters, as well as uptake and metabolism of DON, in growing pigs. Forty-eight crossbred (Landrace-Yorkshire/Duroc-Duroc) weaning pigs were fed with pelleted feed made from naturally contaminated oats, with DON at four concentration levels: (1) control diet (DON < 0.2 mg kg-1), (2) low-contaminated diet (DON = 0.92 mg kg-1), (3) medium-contaminated diet (DON = 2.2 mg kg-1) and (4) high-contaminated diet (DON = 5.0 mg kg-1) and equivalent diets containing DSM 11798 as feed additive. During the first 7 days of exposure, pigs in the highest-dose group showed a 20 28% reduction in feed intake and a 24-34% reduction in weight gain compared with pigs in the control and low-dose groups. These differences were levelled out by study completion. Towards the end of the experiment, dose-dependent reductions in serum albumin, globulin and total serum protein were noted in the groups fed with DON-contaminated feed compared with the controls. The addition of DSM 11798 had no effect on the DON-related clinical effects or on the plasma concentrations of DON. The ineffectiveness of the feed additive in the present study could be a consequence of its use in pelleted feed, which might have hindered its rapid release, accessibility or detoxification efficiency in the pig's gastrointestinal tract. PMID- 29701503 TI - Impact evaluation of assistive technology support for the people with dementia. AB - This study explores important factors of assistive technology (AT) and evaluates their relative impact on AT effectiveness and retention. Questionnaire based survey is used for data collection from 327 people with dementia (PWD). This empirical study uses statistical techniques including exploratory factor analysis for factor identification, linear regression for impact study, Kruskal Wallis H and Mann Whitney U tests for the statistical significant study in terms of demographic and characteristics. The exploratory factor analysis results into 11 factors: operational support, physical support, psychological support, social support, cultural match, reduced external help, affordability, travel help, compatibility, effectiveness and retention. The results reveal that social support, psychological support and travel help and reduced external help strongly impact on AT effectiveness and retention. The users are motivated by socialization support through using AT without any external help. The use of AT during travelling improves confidence of the PWD and helps them psychologically. PMID- 29701504 TI - The neutrophil to lymphocyte ratio in patients supported with extracorporeal membrane oxygenation. AB - INTRODUCTION: The neutrophil to lymphocyte ratio (NLR) has proven to be a robust predictor of mortality in a wide range of cardiovascular diseases. This study investigated the predictive value of the NLR in patients supported by extracorporeal membrane oxygenation (ECMO) systems. METHODS: This study included 107 patients who underwent ECMO implantation for cardiogenic shock. Median preoperative NLR was used to divide the cohort, with Group 1 NLR <14.2 and Group 2 with NLR >=14.2. Survival, the primary outcome, was compared between groups. RESULTS: The study cohort was composed of 64 (60%) males with an average age 53.1 +/- 14.9 years. Patients in Group 1 had an average NLR of 7.5 +/- 3.5 compared to 27.1 +/- 19.9 in Group 2. Additionally, those in Group 2 had significantly higher preoperative blood urea nitrogen (BUN) and age. Survival analysis indicated a thirty-day survival of 56.2%, with significantly worsened mortality in patients with NLR greater than 14.2, p=0.047. DISCUSSION: Our study shows the NLR has prognostic value in patients undergoing ECMO implantation. Leukocytes are known contributors to myocardial damage and neutrophil infiltration is associated with damage caused by myocardial ischemia. PMID- 29701505 TI - Variation and Likeness in Ambient Artistic Portraiture. AB - An artist-led exploration of portrait accuracy and likeness involved 12 Artists producing 12 portraits referencing a life-size 3D print of the same Sitter. The works were assessed during a public exhibition, and the resulting likeness assessments were compared to portrait accuracy as measured using geometric morphometrics (statistical shape analysis). Our results are that, independently of the assessors' prior familiarity with the Sitter's face, the likeness judgements tended to be higher for less morphologically accurate portraits. The two highest rated were the portrait that most exaggerated the Sitter's distinctive features, and a portrait that was a more accurate (but not the most accurate) depiction. In keeping with research showing photograph likeness assessments involve recognition, we found familiar assessors rated the two highest ranked portraits even higher than those with some or no familiarity. In contrast, those lacking prior familiarity with the Sitter's face showed greater favour for the portrait with the highest morphological accuracy, and therefore most likely engaged in face-matching with the exhibited 3D print. Furthermore, our research indicates that abstraction in portraiture may not enhance likeness, and we found that when our 12 highly diverse portraits were statistically averaged, this resulted in a portrait that is more morphologically accurate than any of the individual artworks comprising the average. PMID- 29701506 TI - Outcomes of laparoscopic subtotal colectomy with cecorectal anastomosis for slow transit constipation: a single center retrospective study. AB - PURPOSE: To study the safety and efficacy of laparoscopic subtotal colectomy (LASC) with cecorectal anastomosis for slow-transit constipation (STC). METHODS: This study was a retrospective review of all patients undergoing LASC with cecorectal anastomosis for STC between March 2010 and May 2017. The main variables included the operative time, blood loss, length of postoperative hospital stay, complications, and long-term outcomes. RESULTS: In this analysis, 56 patients were included. There were 17 males and 39 females aged between 34 and 80 years old. The mean operative time was 208 +/- 21 min, and the mean perioperative blood loss was 116 +/- 48 mL. The mean postoperative hospital stay was 7.7 +/- 3.5 days, and the incidence of perioperative complications was 19.6%, with no mortality. One patient required reoperation because of intra-abdominal bleeding. During the follow-up period, 26.8% of patients suffered from chronic pain and bloating, with no recurrence of STC. The causes of these symptoms included small bowel obstruction (7.1%), slow transit (10.7%), anastomotic stenosis (5.4%) and gastroptosis (3.6%). Postoperatively, after 12 months, the frequency of defecation was 2-4 times per day. Patients with follow-up of at least 60 months, the mean frequency of defecation was 0.9 +/- 0.5 times per day. The percentage of satisfaction was 82.1%. CONCLUSION: LASC with cecorectal anastomosis is a safe and effective surgical approach for STC, with the majority of patients being satisfied with the outcome of surgery. PMID- 29701507 TI - Metallic characteristics of PM2.5 and PM2.5-10 for clustered Aeolian Dust Episodes occurred in an extensive fluvial basin during rainy season. AB - : Aeolian dust episodes (ADEs) have been an emergency disaster in the Kaoping River Valley during the rainy season (May-September), which can severely deteriorate ambient particulate air quality in the region surrounding the Kaoping River. Thus, this study aims to characterize the metallic fingerprint of Aeolian dust (AD) and investigate the effects of ADEs on ambient particulate air quality along the Kaoping River Valley. Four manual sampling sites adjacent to the riverside were selected to collect fine (PM2.5) and coarse (PM2.5-10) aerosol samples during and after the ADEs in the periods of six events. A total of 13 metallic elements were analyzed using an inductively coupled plasma-atomic emission spectrometer. With metallic elements analysis and nonparametric statistical methods of Wilcoxon rank-sum test and Kruskal-Wallis test, this study successfully derived the metallic indicators of ADEs. The mass ratios of crustal elements (Fe, Ca, or Al) to reference element (Cd) obtained during the ADEs were much higher than those obtained after the ADEs. High mass ratios of Fe/Cd, Ca/Cd, and Al/Cd in PM2.5-10 were observed on the influenced areas of ADEs. Among them, (Fe/Cd)2.5-10 was proven as the best indicator which can be applied to effectively validate the existence of ADEs and evaluate their influences on ambient air quality. Moreover, PM2.5 concentrations during the ADEs were 3-3.6 fold higher than those after the ADEs. PM2.5 should be a contributor to AD, even though the mass ratios of PM2.5/PM10 ranged from 0.05 to 0.20 during the ADEs. Our findings provide valuable information regarding the characteristics of the AD during the ADEs in the Kaoping River. IMPLICATIONS: Indicators of (Fe/Cd)2.5-10 are approximately applied to observe the effects of ADEs. Local governments could realize the mechanisms of S- and NW-type aeolian dust episodes (ADEs). They can cause deterioration in different ways for the regional air quality surrounding Kaoping River Valley. Residents who have been living in the influenced areas can take precautions to prevent damage from aeolian dust. Strategies for curbing ADEs must reduce the area of bare lands by artificial measures in the long period of the sunny days during the rainy season. Future research should examine physical conditions of topsoils and other chemical composition in aeolian dust. PMID- 29701508 TI - Heart rate variability testing: could it change spending for rheumatoid arthritis patients in the United States? An exploratory economic analysis. AB - BACKGROUND: Autonomic nervous system (ANS) testing with heart rate variability (HRV) has been shown in early research to predict 52-week outcomes in rheumatoid arthritis (RA). HRV testing could be combined with putative ANS biologic pathways to improve treatment response for RA patients. This study explored potential costs and health outcomes of introducing HRV testing into RA treatment, without and with ANS optimization. METHODS: A decision tree exploratory economic model compared HRV testing to standard care in moderate-to-severe biologic-eligible patients over a 10-year time horizon. HRV data was derived from an observational study of RA patients (n = 33). Patients were stratified into treatment groups based on HRV test scores indicating "low probability of response" and "moderate to high probability of response". This study explored adding ANS optimization based on HRV score followed by clinically-appropriate treatment. Costs and quality-adjusted life-years (QALYs) for the US population were estimated. RESULTS: HRV testing in biologic-eligible patients decreased non-effective biologic use, reducing US healthcare costs by $34.6 billion over 10 years with QALYs unchanged. When combined with ANS optimization in biologic-eligible patients, HRV testing could increase costs by $3.6 billion over 10 years but save over 350,000 QALYs. Among all RA patients, HRV testing with ANS optimization could save over $8 billion and over 100,000 QALYs over 10 years, depending on the positive predictive value (PPV) of the HRV test. CONCLUSIONS: The potential economic impact of introducing HRV testing and ANS optimization into RA treatment appears substantial and cost-effective based on the exploratory analysis. Additional rigorous studies are warranted in larger patient samples to better inform decision-making. PMID- 29701509 TI - The effect of an occupational therapy mental health day treatment centre on the use of inpatient services in the Western Cape, South Africa. AB - PURPOSE: The aim of this study was to determine whether attendance at an occupational therapy-led day treatment centre for mental health care users affects the use of inpatient services in South Africa. METHODS: A retrospective pre-test/post-test quasi-experimental study design was used to compare admissions and days spent in hospital during the 24 months before and after attendance at the centre, using the hospital's electronic records. Total population sampling yielded data for 44 mental health care users who made first contact with the service between July 2009 and June 2010. Data were compared using the Kruskal Wallis test, Wilcoxon Signed Ranks test and Mann-Whitney U test. RESULTS: There was a significant decrease in the number of admissions (z = -4.093, p = 0.00) and the number of days spent in hospital (z = -4.730, p = 0.00). Participants were admitted to psychiatric care 33 times less in the 24 months' post-intervention, indicating a medium effect (r = 0.436). They also spend 2569 days less in hospital, indicating a large effect (r = 0.504). CONCLUSION: The findings suggest that an occupational therapy-led day treatment centre could be effective in reducing the use of inpatient mental health services in South Africa. Implications for Rehabilitation Attendance at an occupational therapy-led community day treatment centre decreases the number of admissions and number of days spent in hospital and is therefore beneficial to mental health care users and service providers. The study indicates that the successful implementation of a community day treatment centre for mental health care users on the grounds of a tertiary hospital by utilising existing resources is possible. PMID- 29701510 TI - High, low, or familiar? Nest site preferences of experienced laying hens. AB - 1. The aim of this study was to investigate which nest heights are preferred by laying hens in the absence of familiar nest locations and whether preferred nest heights are more attractive than a familiar location. In two experiments, a total of 108 hens of four different layer breeds, which were at least 50 weeks of age, were studied. 2. In the first experiment, hens were given individual free choice between nests for 1-week at four different heights (0 cm, 39 cm, 78 cm, and 117 cm above ground). Hens of the four breeds differed in their nest height preferences (P = 0.0013). However, hens of three breeds preferred ground level nests (P < 0.007) and the fourth line showed an equal preference for the ground level and level three, the latter level corresponding to the height of the nests in their home compartments. 4. In the second experiment, hens from the four breeds were given a choice between ground level nests and nests at a familiar location, i.e. at the same location as in their home compartment. Hens of all strains preferred the familiar nest location (P = 0.002) and preferences did not differ between strains (P = 0.77). 5. Laying hens seem to prefer nests at ground level in the absence of a familiar nest. However, if possible, experienced 50 week old hens continue to use a familiar nest location instead of a ground nest location. The results are discussed with respect to a potential primary preference that may be modifiable by experience and with respect to possible relevance in commercial housing. PMID- 29701511 TI - School Shootings - 'It wouldn't happen here'? PMID- 29701512 TI - ANZJP this month. PMID- 29701513 TI - Rehabilitees perspective on goal setting in rehabilitation - a phenomenological approach. AB - PURPOSE: Setting meaningful goals for the rehabilitation process after acute illness is essential for rehabilitees recovery. The aim of this study was to understand the meanings of the goal setting situation with professionals from rehabilitees point of view. METHOD: We included 20 acute stroke and back pain rehabilitees (mean age 66 y) who set goals with a multidisciplinary rehabilitation team. Data was collected by interviewing the rehabilitees after the goal setting situations. A qualitative analysis from a phenomenological perspective using Spiegelberg's seven-phase meaning analysis was performed to reveal meanings. RESULTS: The five meanings were identified as: (i) "trust in the rehabilitation situation, professionals, oneself, and relatives;" (ii) "respectful presence;" (iii) "confusing awareness;" (iv) "disturbing pain;" and (v) "fear of unpredictability." When professionals committed to working in a patient-centred manner, the rehabilitees felt respected and they trusted professionals and thus their self-efficacy was empowered. Moreover, relatives were an important support in the situation. However, disturbing pain and fear of the future limited patients level of participation in the situation. CONCLUSION: Rehabilitee commitment to rehabilitation can be supported with equality in communication and presence of relatives, while pain and uncertainty because of changed health limit participation in a goal setting situation. Implications for Rehabilitation Multidisciplinary rehabilitation professionals should be recommended to support the active role of a patient in the goal setting situation. Relatives are recommended to participate in goal setting situation as they are an important support for rehabilitees. Professionals should be recommended to remove obstacles that restrain patient's participation in the goal setting situation. Professionals should be recommended to recognize patients with changed health and offer psychosocial support for those in need to improve their participation in rehabilitation process. PMID- 29701514 TI - Productivity loss of caregivers of schizophrenia patients: a cross-sectional survey in Japan. AB - BACKGROUND: When a family member is diagnosed with schizophrenia, it causes stress to the caregiver that can eventually result in missed work days and lower work performance. AIM: This study aims at revealing productivity costs for caregivers of schizophrenia patients in Japan. METHOD: A cross-sectional survey of caregivers was conducted and resulted in 171 respondents. The assessment of work productivity included calculating the costs of absenteeism, presenteeism and total productivity costs. This was accomplished using the "Work Productivity and Activity Impairment Questionnaire" (WPAI). RESULTS: A relative majority of caregivers in the sample provided care for their spouse (47%), 18% cared for their brother or sister and 16% provided care for their child. Per capita productivity costs totaled JPY 2.42 million, with JPY 2.36 million (97%) of that amount being due to presenteeism. CONCLUSIONS: The burden on caregivers is substantial enough to warrant structured support programs aimed at maintaining careers' physical and mental health, helping them provide more effective care to schizophrenia patients and eventually increase productivity at work. PMID- 29701516 TI - Clinical findings and outcomes for dogs with uveodermatologic syndrome. AB - OBJECTIVE To evaluate signalment, clinical signs, treatment, and factors affecting visual prognosis in dogs with uveodermatologic syndrome (UDS). DESIGN Retrospective case series and nested cohort study. ANIMALS 50 dogs (37 Akitas and 13 non-Akitas) with UDS evaluated at 4 ophthalmology practices. PROCEDURES Data were collected from the medical records regarding signalment, clinical signs, biopsy results, medications, adverse effects, vision and glaucoma status at initial and subsequent examinations, and duration of follow-up. Various factors were examined for associations with development of blindness or glaucoma following initial examination. RESULTS The most common ophthalmic signs included aqueous flare (n = 35 [70%]), iris abnormalities (29 [58%]), retinal detachment (23 [46%]), and choroidal depigmentation or chorioretinal infiltrates (10 [20%]). At initial examination, 36% (18/50) of dogs had glaucoma and 57% (26/46) were blind in both eyes. Twenty-five (50%) dogs had vision at their final visit, representing 78% of the 32 dogs that had vision at initial examination or regained vision during the follow-up period. In dogs that lost vision, median time to permanent blindness in both eyes was 13.5 months (range, 0.4 to 59 months) after initial examination. No significant associations with time to glaucoma or vision loss were identified for signalment variables, specific medications, or duration of clinical signs prior to initial examination. CONCLUSIONS AND CLINICAL RELEVANCE UDS commonly resulted in glaucoma, vision loss, or both in affected dogs. No evaluated factor was associated with visual prognosis; however, a subset of patients maintained vision through to the final recheck examination. PMID- 29701518 TI - In This Issue * May 15, 2018. PMID- 29701515 TI - Intracranial pressure changes after mild traumatic brain injury: a systematic review. AB - OBJECTIVE: Intracranial pressure (ICP) after mild traumatic brain injury (mTBI) is poorly studied due to lack of sensitive non-invasive methods. The purpose of this review was to summarize the existing knowledge of changes in ICP after mTBI. Literature selection: PubMed, Embase, CINAHL, and Scopus were searched by three reviewers independently up to December 2016. INCLUSION CRITERIA: animal and human studies measuring ICP and brain oedema after an mTBI. EXCLUSION CRITERIA: moderate and severe forms of traumatic brain injury, repeat samples, and studies that measured ICP at the time of impact but not after. Study quality was assessed using Downs and Black criteria. RESULTS: Of 1067 papers, 9 studies were included. In human studies, one provided direct evidence on increased, one provided indirect evidence of increased, and two provided indirect evidence of decreased ICP. In animal studies, three studies provided direct evidence of increased, one provided indirect evidence of increased, and one provided indirect evidence of no change in ICP. CONCLUSION: The existing research suggests that there may be increased ICP after mTBI and animal studies suggest an elevation for days which returns to baseline, which corresponds with functional and symptomatic recovery. Future human studies using sensitive indirect methods to measure ICP longitudinally after mTBI are needed. PMID- 29701519 TI - Chylous ascites associated with abdominal trauma and intestinal resection anastomosis in a pet ferret (Mustela putorius furo). AB - CASE DESCRIPTION A 10-week-old 0.73-kg (1.6-lb) castrated male domestic ferret (Mustela putorius furo) was referred for exploratory laparotomy because of pneumoperitoneum and possible septic peritonitis after being bitten by the owner's dog. CLINICAL FINDINGS Abdominal exploration revealed a large laceration of the duodenum, tears of the jejunal mesentery, and 2 small tears in the abdominal wall. Chylous abdominal effusion developed 48 hours after surgery. TREATMENT AND OUTCOME Postoperative care included supportive treatment, analgesia, and antimicrobials. An abdominal drain was placed during the laparotomy and enabled monitoring of abdominal fluid production. Enteral feeding was provided through an esophagostomy tube. The chylous fluid production rapidly decreased after treatment with octreotide was initiated, and the ferret improved. Chyloabdomen resolved after 8 days of hospitalization and medical treatment. CLINICAL RELEVANCE Findings suggested that chylous ascites can potentially develop secondary to blunt abdominal trauma in ferrets. In this ferret, chyloabdomen was successfully treated with octreotide administration and abdominal drainage. PMID- 29701520 TI - What Is Your Diagnosis? PMID- 29701522 TI - Theriogenology Question of the Month. PMID- 29701521 TI - Evaluation of various gastrojejunostomy tube constructs for enteral support of small animal patients. AB - OBJECTIVE To evaluate the feasibility of manufacturing gastrojejunostomy tubes from jejunostomy and gastrostomy tubes that would allow for gastric and enteral feeding of and aspiration of gastric contents from small animal patients. DESIGN In vitro study. SAMPLE 9 gastrojejunostomy constructs. PROCEDURES Commercially available gastrostomy and jejunostomy tubes were combined to create 9 constructs. Three investigators tested each construct with 4 solutions (tap water, a commercial enteral diet, and 2 canned food-water mixtures) and 3 syringe sizes for ease of injection through the gastrostomy and jejunostomy tubes and aspiration through the gastrostomy tube. Flow rates were calculated and analyzed to evaluate effects of tube diameter and syringe size for each solution. RESULTS The 20F/8F, 24F/8F, 28F/8F, and 28F/10F (gastrostomy tube/jejunostomy tube) constructs allowed for injection and aspiration of all solutions. The 5F jejunostomy tubes allowed only water to be injected, whereas the 8F jejunostomy tubes did not allow injection of the canned food-water mixtures. The 20F/10F construct did not allow injection or aspiration through the gastrostomy tube, whereas the 18F/8F construct allowed injection but not aspiration through the gastrostomy tube. Faster flow rates through the gastrostomy tube were associated with larger gastrostomy tube diameter, smaller jejunostomy tube diameter, and smaller syringe size. Faster flow rates through the jejunostomy tube were associated with smaller jejunostomy tube diameter. CONCLUSIONS AND CLINICAL RELEVANCE Results suggested that homemade gastrojejunostomy constructs would allow for administration of a variety of enteral diets. Limitations to the administration and aspiration of various enteral diets as well as patient needs should be considered before a gastrojejunostomy tube combination is chosen. PMID- 29701523 TI - Pathology in Practice. PMID- 29701524 TI - The importance of veterinary career awareness. PMID- 29701525 TI - What Is Your Neurologic Diagnosis? PMID- 29701526 TI - Letters to the Editor. PMID- 29701527 TI - Executive summary of the Merck Animal Health Veterinary Wellbeing Study. PMID- 29701528 TI - Pathology in Practice. PMID- 29701529 TI - Evaluation of the diagnostic utility of cytologic examination of renal fine needle aspirates from dogs and the use of ultrasonographic features to inform cytologic diagnosis. AB - OBJECTIVE To describe cytologic characteristics of renal fine-needle aspirate (FNA) samples from dogs, evaluate proportions of cytologic specimens deemed adequate for interpretation (diagnostic yield), assess diagnostic utility of cytologic examination for neoplastic and nonneoplastic diseases, and characterize ultrasonographic features of evaluated kidneys to determine whether the imaging characteristics could be used to inform cytologic interpretations. DESIGN Retrospective, observational study. SAMPLE 102 cytologic specimens and 97 ultrasonographic studies from 100 dogs. PROCEDURES Medical records were reviewed to identify dogs that underwent ultrasound-guided renal FNA. Slides were categorized as adequate or inadequate for interpretation; adequate slides were used for retrospective cytologic diagnosis. Sensitivity, specificity, and predictive values of cytologic examination for detection of neoplastic and nonneoplastic conditions were calculated by comparison with histologic or lymphoid cell clonality assay results. Ultrasonographic characteristics of neoplastic and nonneoplastic renal lesions were described. RESULTS 74 of 102 (72%) specimens had slides adequate for interpretation; 26 were included in the diagnostic accuracy analysis. Sensitivity of cytologic examination was 78% and 50% for detection of neoplastic and nonneoplastic conditions, respectively, with specificities of 50% and 77%, respectively; sensitivity for detection of lymphoma was 100%. Ultrasonographic appearance of kidneys with confirmed neoplasia varied; masses were most commonly found in kidneys with carcinoma (5/5), lymphoma (5/7), or other neoplasia (3/4) and absent in kidneys with nonneoplastic conditions (n = 5). CONCLUSIONS AND CLINICAL RELEVANCE Renal FNA specimens were adequate for interpretation at rates comparable with those reported for other organs and were considered clinically useful for diagnosis of neoplasia. Imaging characteristics may potentially aid differentiation between neoplastic and nonneoplastic lesions; however, further investigation is needed. PMID- 29701530 TI - ECG of the Month. PMID- 29701531 TI - Characterization of subclinical bacteriuria, bacterial cystitis, and pyelonephritis in dogs with chronic kidney disease. AB - OBJECTIVE To determine the prevalence of bacteriuria (ie, a positive microbial culture result for >= 1 urine sample) in dogs with chronic kidney disease (CKD) and characterize findings of subclinical bacteriuria (SBU), bacterial cystitis, or pyelonephritis in these patients. DESIGN Retrospective, observational study. ANIMALS 182 dogs. PROCEDURES Medical records from January 2010 through July 2015 were reviewed to identify dogs with CKD that underwent urinalysis and urine microbial culture. Signalment, clinicopathologic data, stage of CKD according to previously published guidelines, results of urinalysis and urine culture, and abdominal ultrasonographic findings were recorded. Dogs with positive urine culture results were categorized as having SBU, bacterial cystitis, or pyelonephritis on the basis of these data. Prevalence of bacteriuria was calculated. Associations between CKD stage, presence of bacteriuria, and diagnosis category were analyzed statistically. RESULTS 33 of 182 (18.1%) dogs (40/235 [17.0%] urine samples) had positive culture results. All dogs received antimicrobials on the basis of culture and susceptibility test findings. Most positive culture results (18/40 [45%] samples) were found for dogs with SBU, followed by dogs with pyelonephritis (16/40 [40%]) and cystitis (6/40 [15%]). Escherichia coli was the most frequently observed isolate (29/40 [73%] cultures from 25/33 dogs). The CKD stage was not associated with presence of bacteriuria or diagnosis category. CONCLUSIONS AND CLINICAL RELEVANCE The prevalence of positive urine culture results in dogs with CKD was lower than that reported for dogs with some systemic diseases that may predispose to infection. Prospective research is needed to assess the clinical importance of SBU in dogs with CKD. PMID- 29701532 TI - Clinical and intestinal histologic features of horses treated for recurrent colic: 66 cases (2006-2015). AB - OBJECTIVE To describe gastrointestinal histologic findings for horses with recurrent colic and evaluate possible associations between initial clinical signs, biopsy method, histologic diagnosis, and outcome 1 year after hospital discharge. DESIGN Retrospective case series. ANIMALS 66 horses with a history of recurrent colic for which gastrointestinal specimens had been submitted for histologic examination. PROCEDURES Histologic diagnosis was categorized as inflammatory, neoplastic, ischemic, other, and undiagnosed. Relationships among initial clinical features, biopsy method, histologic diagnosis, and outcome 1 year after hospital discharge (ie, alive vs dead and persistent recurrent colic [yes vs no]) and between corticosteroid treatment and outcome were investigated. Odds ratios and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. RESULTS Inflammatory disease (36/66 [55%]) was the most common histologic diagnosis. Horses undergoing rectal biopsy alone were significantly (OR, 14.4; 95% Cl, 2.7 to 76.1) more likely to not have a histologic diagnosis than were horses in which other biopsy methods were used. In multivariable modelling, persistence of recurrent colic (HR, 15.2; 95% Cl, 1.9 to 121.2) and a history of weight loss (HR, 4.9; 95% Cl, 1.4 to 16.5) were significantly associated with outcome (alive vs dead) 1 year after surgery. Corticosteroid treatment was not significantly associated with either outcome. CONCLUSIONS AND CLINICAL RELEVANCE Results indicated that a high proportion (36/66 [55%]) of horses with recurrent colic had inflammatory gastrointestinal disease. Use of rectal biopsy alone to obtain biopsy specimens was more likely to result in no histologic diagnosis. Use of corticosteroids in horses with inflammatory gastrointestinal disease was not associated with outcome but warrants further investigation. PMID- 29701533 TI - Preventive strategies for patients with both heart disease and depression. PMID- 29701534 TI - Development and validation of an HPLC method with fluorescence detection for the determination of fluorescent whitening agents migrating from plastic beverage cups. AB - An HPLC method with fluorescence detection has been developed and validated for the quantification of six fluorescent whitening agents (FWA) in plastic beverage cups after extraction and in food simulants after migration at 70 degrees C for 2 h. The sensitivity of the method was high with LODs ranging from 0.053 to 0.251 MUg kg-1 and LOQs from 0.107 to 0.504 MUg kg-1. Accuracy and precision were highly acceptable, with recoveries greater than 82% and RSDs (%) below 16%. The expanded combined uncertainty was found to be less than 23% for the measurements of all studied FWAs. In extracting the analytes from food contact materials (FCM), accelerated solvent extraction (ASE) and Soxhlet extraction were applied using ethanol as the extraction solvent. The results obtained for FWA in 10 different food plastic cups, made from different polymers, were compared. The ASE technique proved to be faster, more effective and efficient than Soxhlet extraction. Migration tests with official food simulants from Regulation (EU) No 10/2011 showed that the substances studied could potentially migrate using the selected migration conditions. The most pronounced effect was observed in case of simulant D1 (50% w/v ethanol in water). The analytical method proved to be a simple, fast, sensitive and reliable tool for the simultaneous quantification of six of the most used FWAs in both FCM extracts and food simulants after migration experiments. PMID- 29701535 TI - Editor's Presentation. PMID- 29701536 TI - Concentrations of infliximab and anti-drug antibodies in relation to clinical response in patients with rheumatoid arthritis. AB - OBJECTIVE: The efficacy of anti-tumour necrosis factor-alpha (anti-TNF-alpha) treatment with infliximab (IFX) may be reduced by the development of anti-drug antibodies (ADAs). This study evaluated drug concentration and the presence of ADAs, relative to response, in rheumatoid arthritis (RA) patients treated with IFX. METHOD: Ninety-four RA patients were consecutively included and assessed for disease activity at baseline, and after 14, and 30 or 52 weeks. Serum IFX concentration and ADAs were analysed using in-house enzyme-linked immunosorbent assays. ADA analysis was based on binding to TNF-alpha-coated plates, with the lower detection limit set at mean + 2 sd of controls. RESULTS: At 14 and 52 weeks, 74.5% of the patients had moderate to good response. Good responders had significantly higher IFX concentrations than moderate and poor responders at 52 weeks (6.6 +/- 1.4 ug/mL vs 3.6 +/- 1.3 ug/mL and 2.6 +/- 1.6 ug/mL, respectively). An IFX concentration >=4.66 ug/mL at 14 weeks yielded a moderate to good response at 30/52 weeks, with 91.3% specificity and 39.3% sensitivity. Eleven patients dropped out owing to lack of efficacy and eight owing to side effects; three with IFX concentration <= 0.5 ug/mL were ADA positive. At an IFX concentration <= 0.5 ug/mL, 43.8% and 30.1% at 14 and 52 weeks, respectively, were ADA positive. None of the good responders had ADAs. CONCLUSION: One-quarter of patients had an IFX concentration <= 0.5 ug/mL but only 11.7% had ADAs. High IFX concentration was related to a good response, suggesting that the lack of response could be due to a lack of IFX, rather than to the presence of ADAs. PMID- 29701537 TI - How best management practices affect emissions in gas turbine power plants-An important factor to consider when strengthening emission standards. AB - : The Beijing Municipal Environmental Protection Bureau (EPB) is considering strengthening the Emission Standard of Air Pollutants for Stationary Gas Turbines, originally published in 2011 (DB11/847-2011), with a focus on reducing nitrogen oxides (NOx) emissions. A feasibility study was conducted to evaluate the current operation of 12 existing combined-cycle gas turbine power plants and the design of two new plants in Beijing and their emission reduction potential, in comparison with a state-of-the-art power plant in California. The study found that best management practices (BMPs) could potentially improve the emission level of the power plants, and should be implemented to minimize emissions under current design characteristics. These BMPs include (1) more frequent tuning of turbine combustors; (2) onsite testing of natural gas characteristics in comparison to turbine manufacturer's specifics and tuning of turbine to natural gas quality; (3) onsite testing of aqueous ammonia to ensure adequate ammonia concentration in the mixed solution, and the purity of the solution; (4) more careful inspection of the heat recovery steam generator (HRSG), and the selective catalytic reduction (SCR) during operation and maintenance; (5) annual testing of the catalyst coupon on the SCR to ensure catalyst effectiveness; and (6) annual ammonia injection grid (AIG) tuning. The study found that without major modification to the plants, improving the management of the Beijing gas turbine power plants may potentially reduce the current hourly average NOx emission level of 5-10 parts per million (ppm; ranges reflects plant variation) by up to 20%. The exact improvement associated with each BMP for each facility requires more detailed analysis, and requires engagement of turbine, HRSG, and SCR manufacturers. This potential improvement is an important factor to consider when strengthening the emission standard. However, note that with the continuous needs of improving air quality within the area, more expensive control measures, such as retrofitting the turbines or the HRSGs, may be considered. IMPLICATIONS: This study analyzed the potential emission reductions associated with implementing the best management practices (BMPs) on the combined cycle and cogeneration power plants in Beijing. It determined that implementing the BMPs could potentially achieve up to 580 metric tonnes, or 0.6%, reductions of all NOx emissions in Beijing. Many other cities in China and Asia battling air quality issues may find the information useful in order to evaluate the emission reduction potential of their own gas turbine power plants. PMID- 29701538 TI - Some is better than none! Association of physical activity pattern and mortality. PMID- 29701539 TI - An Update in Abdominal Organ Transplantation Anesthesia in 2018: Society for the Advancement of Transplant Anesthesia (SATA). PMID- 29701540 TI - Vacuolar trafficking in pollen tube growth and guidance. AB - Vacuoles are versatile organelles in plant cells, critical for growth and responses to environmental cues. Vacuoles are dynamic tubular structures in pollen tubes, the male gametophytes. Mutations at vacuolar fusion machinery caused male gametophytic lethality by affecting pollen tube growth and guidance, which are critical steps leading to angiosperm reproduction. In comparison, the role of vacuolar trafficking and its cargoes in this process is less understood. In this mini-review, we summarize old and recent findings that indicate the involvement of vacuolar trafficking in pollen tube growth and guidance. We also point at future studies that would provide insights into a key role of vacuolar trafficking and its cargos in pollen tube growth and guidance. PMID- 29701541 TI - Response of high leaf-oil Arabidopsis thaliana plant lines to biotic or abiotic stress. AB - Recent studies have shown that it is possible to engineer substantial increases in triacylglycerol (TAG) content in plant vegetative biomass, which offers a novel approach for increasing the energy density of food, feed, and bioenergy crops or for creating a sink for the accumulation of unusual, high-value fatty acids. However, whether or not these changes in lipid metabolism affect plant responses to biotic and/or abiotic stresses is an open question. Here we show that transgenic Arabidopsis thaliana plant lines engineered for elevated leaf oil content, as well as lines engineered for accumulation of unusual conjugated fatty acids in leaf oil, had similar short-term responses to heat stress (e.g., 3 days at 37 degrees C) as wild-type plants, including a reduction in polyunsaturated fatty acid (PUFA)-containing polar lipids and an increase in PUFA-containing neutral lipids. At extended time periods (e.g., 14 days at 37 degrees C), however, plant lines containing accumulated conjugated fatty acids displayed earlier senescence and plant death. Further, no-choice feeding studies demonstrated that plants with the highest leaf oil content generated cabbage looper (Trichoplusia ni) insects with significantly heavier body weights. Taken together, these results suggest that biotic and abiotic responses will be important considerations when developing and deploying high-oil-biomass crops in the field. PMID- 29701542 TI - For the further training of individuals in neurosurgery: a history of the William P. Van Wagenen Fellowship. AB - The William P. Van Wagenen Fellowship, celebrating its 50th anniversary, is an annual award given by the AANS and administered by the Neurosurgery Research and Education Foundation (NREF). Named after its benefactor, Dr. William Van Wagenen, the fellowship continues his legacy of mentorship and innovation. As the premier research award for young neurosurgeons, it has provided a foundation for career development for many thought leaders in the field. The award was created in the spirit of Van Wagenen's belief in collaboration with other institutions as a means of refining neurosurgical technique, creating new research initiatives, and improving patient outcomes. Van Wagenen's commitment was informed by his early experiences in neurosurgery with his mentor Dr. Harvey Cushing, who helped to fund Van Wagenen's scientific endeavors in Europe. This journey catalyzed Van Wagenen's lifelong commitment to mentorship, which is exemplified by his instrumental role in the creation of the Harvey Cushing Society, now the AANS. Over the last 50 years, the recipients of this award have used the endowment to lay the groundwork for many scientific and technical innovations in neurosurgery. The fellowship remains an unmatched opportunity to explore new lines of investigation, foster academic and research goals, incorporate new technology and skills into American neurosurgical practice, and motivate young neurosurgeons to transform the field. The legacy of mentorship, scientific inquiry, and clinical excellence personified by Cushing and Van Wagenen is memorialized in the William P. Van Wagenen Fellowship. PMID- 29701543 TI - Global hydrocephalus epidemiology and incidence: systematic review and meta analysis. AB - OBJECTIVE Hydrocephalus is one of the most common brain disorders, yet a reliable assessment of the global burden of disease is lacking. The authors sought a reliable estimate of the prevalence and annual incidence of hydrocephalus worldwide. METHODS The authors performed a systematic literature review and meta analysis to estimate the incidence of congenital hydrocephalus by WHO region and World Bank income level using the MEDLINE/PubMed and Cochrane Database of Systematic Reviews databases. A global estimate of pediatric hydrocephalus was obtained by adding acquired forms of childhood hydrocephalus to the baseline congenital figures using neural tube defect (NTD) registry data and known proportions of posthemorrhagic and postinfectious cases. Adult forms of hydrocephalus were also examined qualitatively. RESULTS Seventy-eight articles were included from the systematic review, representative of all WHO regions and each income level. The pooled incidence of congenital hydrocephalus was highest in Africa and Latin America (145 and 316 per 100,000 births, respectively) and lowest in the United States/Canada (68 per 100,000 births) (p for interaction < 0.1). The incidence was higher in low- and middle-income countries (123 per 100,000 births; 95% CI 98-152 births) than in high-income countries (79 per 100,000 births; 95% CI 68-90 births) (p for interaction < 0.01). While likely representing an underestimate, this model predicts that each year, nearly 400,000 new cases of pediatric hydrocephalus will develop worldwide. The greatest burden of disease falls on the African, Latin American, and Southeast Asian regions, accounting for three-quarters of the total volume of new cases. The high crude birth rate, greater proportion of patients with postinfectious etiology, and higher incidence of NTDs all contribute to a case volume in low- and middle income countries that outweighs that in high-income countries by more than 20 fold. Global estimates of adult and other forms of acquired hydrocephalus are lacking. CONCLUSIONS For the first time in a global model, the annual incidence of pediatric hydrocephalus is estimated. Low- and middle-income countries incur the greatest burden of disease, particularly those within the African and Latin American regions. Reliable incidence and burden figures for adult forms of hydrocephalus are absent in the literature and warrant specific investigation. A global effort to address hydrocephalus in regions with the greatest demand is imperative to reduce disease incidence, morbidity, mortality, and disparities of access to treatment. PMID- 29701544 TI - Safe and stable noninvasive focal gene delivery to the mammalian brain following focused ultrasound. AB - OBJECTIVE Surgical infusion of gene therapy vectors has provided opportunities for biological manipulation of specific brain circuits in both animal models and human patients. Transient focal opening of the blood-brain barrier (BBB) by MR guided focused ultrasound (MRgFUS) raises the possibility of noninvasive CNS gene therapy to target precise brain regions. However, variable efficiency and short follow-up of studies to date, along with recent suggestions of the potential for immune reactions following MRgFUS BBB disruption, all raise questions regarding the viability of this approach for clinical translation. The objective of the current study was to evaluate the efficiency, safety, and long-term stability of MRgFUS-mediated noninvasive gene therapy in the mammalian brain. METHODS Focused ultrasound under the control of MRI, in combination with microbubbles consisting of albumin-coated gas microspheres, was applied to rat striatum, followed by intravenous infusion of an adeno-associated virus serotype 1/2 (AAV1/2) vector expressing green fluorescent protein (GFP) as a marker. Following recovery, animals were followed from several hours up to 15 months. Immunostaining for GFP quantified transduction efficiency and stability of expression. Quantification of neuronal markers was used to determine histological safety over time, while inflammatory markers were examined for evidence of immune responses. RESULTS Transitory disruption of the BBB by MRgFUS resulted in efficient delivery of the AAV1/2 vector to the targeted rodent striatum, with 50%-75% of striatal neurons transduced on average. GFP transgene expression appeared to be stable over extended periods of time, from 2 weeks to 6 months, with evidence of ongoing stable expression as long as 16 months in a smaller cohort of animals. No evidence of substantial toxicity, tissue injury, or neuronal loss was observed. While transient inflammation from BBB disruption alone was noted for the first few days, consistent with prior observations, no evidence of brain inflammation was observed from 2 weeks to 6 months following MRgFUS BBB opening, despite delivery of a virus and expression of a foreign protein in target neurons. CONCLUSIONS This study demonstrates that transitory BBB disruption using MRgFUS can be a safe and efficient method for site-specific delivery of viral vectors to the brain, raising the potential for noninvasive focal human gene therapy for neurological disorders. PMID- 29701545 TI - Letter to the Editor. Brachyury as prognostic biomarker in chordoma. PMID- 29701546 TI - Effectiveness of perioperative antiepileptic drug prophylaxis for early and late seizures following oncologic neurosurgery: a meta-analysis. AB - OBJECTIVE The purpose of this meta-analysis was to evaluate the impact of perioperative antiepileptic drug (AED) prophylaxis on short- and long-term seizure incidence among patients undergoing brain tumor surgery. It is the first meta-analysis to focus exclusively on perioperative AED prophylaxis among patients undergoing brain tumor surgery. METHODS The authors searched PubMed/MEDLINE, Embase, Cochrane Central Register of Controlled Trials, clinicaltrials.gov, and the System for Information on Gray Literature in Europe for records related to perioperative AED prophylaxis for patients with brain tumors. Risk of bias in the included studies was assessed using the Cochrane risk of bias tool. Incidence rates for early seizures (within the first postoperative week) and total seizures were estimated based on data from randomized controlled trials. A Mantel-Haenszel random-effects model was used to analyze pooled relative risk (RR) of early seizures (within the first postoperative week) and total seizures associated with perioperative AED prophylaxis versus control. RESULTS Four RCTs involving 352 patients met the criteria of inclusion. The results demonstrated that perioperative AED prophylaxis for patients undergoing brain tumor surgery provides a statistically significant reduction in risk of early postoperative seizures compared with control (RR = 0.352, 95% confidence interval 0.130-0.949, p = 0.039). AED prophylaxis had no statistically significant effect on the total (combined short- and long-term) incidence of seizures. CONCLUSIONS This meta-analysis demonstrates for the first time that perioperative AED prophylaxis for brain tumor surgery provides a statistically significant reduction in early postoperative seizure risk. PMID- 29701547 TI - The influence of cerebrospinal fluid on blood coagulation and the implications for ventriculovenous shunting. AB - OBJECTIVE The effect of CSF on blood coagulation is not known. Enhanced coagulation by CSF may be an issue in thrombotic complications of ventriculoatrial and ventriculosinus shunts. This study aimed to assess the effect of CSF on coagulation and its potential effect on thrombotic events affecting ventriculovenous shunts. METHODS Two complementary experiments were performed. In a static experiment, the effect on coagulation of different CSF mixtures was evaluated using a viscoelastic coagulation monitor. A dynamic experiment confirmed the amount of clot formation on the shunt surface in a roller pump model. RESULTS CSF concentrations of 9% and higher significantly decreased the activated clotting time (ACT; 164.9 seconds at 0% CSF, 155.6 seconds at 9% CSF, and 145.1 seconds at 32% CSF). Increased clot rates (CRs) were observed starting at a concentration of 5% (29.3 U/min at 0% CSF, 31.6 U/min at 5% CSF, and 35.3 U/min at 32% CSF). The roller pump model showed a significantly greater percentage of shunt surface covered with deposits when the shunts were infused with CSF rather than Ringer's lactate solution (90% vs 63%). The amount of clot formation at the side facing the blood flow (impact side) tended to be lower than that at the side facing away from the blood flow (wake side; 71% vs 86%). CONCLUSIONS Addition of CSF to blood accelerates coagulation. The CSF-blood foreign material interaction promotes clot formation, which might result in thrombotic shunt complications. Further development of the ventriculovenous shunt technique should focus on preventing CSF-blood-foreign material interaction and stagnation of CSF in wake zones. PMID- 29701548 TI - Global neurosurgery: the current capacity and deficit in the provision of essential neurosurgical care. Executive Summary of the Global Neurosurgery Initiative at the Program in Global Surgery and Social Change. AB - OBJECTIVE Worldwide disparities in the provision of surgical care result in otherwise preventable disability and death. There is a growing need to quantify the global burden of neurosurgical disease specifically, and the workforce necessary to meet this demand. METHODS Results from a multinational collaborative effort to describe the global neurosurgical burden were aggregated and summarized. First, country registries, third-party modeled data, and meta analyzed published data were combined to generate incidence and volume figures for 10 common neurosurgical conditions. Next, a global mapping survey was performed to identify the number and location of neurosurgeons in each country. Finally, a practitioner survey was conducted to quantify the proportion of disease requiring surgery, as well as the median number of neurosurgical cases per annum. The neurosurgical case deficit was calculated as the difference between the volume of essential neurosurgical cases and the existing neurosurgical workforce capacity. RESULTS Every year, an estimated 22.6 million patients suffer from neurological disorders or injuries that warrant the expertise of a neurosurgeon, of whom 13.8 million require surgery. Traumatic brain injury, stroke-related conditions, tumors, hydrocephalus, and epilepsy constitute the majority of essential neurosurgical care worldwide. Approximately 23,300 additional neurosurgeons are needed to address more than 5 million essential neurosurgical cases-all in low- and middle-income countries-that go unmet each year. There exists a gross disparity in the allocation of the surgical workforce, leaving large geographic treatment gaps, particularly in Africa and Southeast Asia. CONCLUSIONS Each year, more than 5 million individuals suffering from treatable neurosurgical conditions will never undergo therapeutic surgical intervention. Populations in Africa and Southeast Asia, where the proportion of neurosurgeons to neurosurgical disease is critically low, are especially at risk. Increasing access to essential neurosurgical care in low- and middle-income countries via neurosurgical workforce expansion as part of surgical system strengthening is necessary to prevent severe disability and death for millions with neurological disease. PMID- 29701549 TI - Letter to the Editor. The causative role of sinus stenosis in idiopathic intracranial hypertension. PMID- 29701550 TI - Brain invasion and the risk of seizures in patients with meningioma. AB - OBJECTIVE Identification of risk factors for perioperative epilepsy remains crucial in the care of patients with meningioma. Moreover, associations of brain invasion with clinical and radiological variables have been largely unexplored. The authors hypothesized that invasion of the cortex and subsequent increased edema facilitate seizures, and they compared radiological data and perioperative seizures in patients with brain-invasive or noninvasive meningioma. METHODS Correlations of brain invasion with tumor and edema volumes and preoperative and postoperative seizures were analyzed in univariate and multivariate analyses. RESULTS Totals of 108 (61%) females and 68 (39%) males with a median age of 60 years and harboring totals of 92 (52%) grade I, 79 (45%) grade II, and 5 (3%) grade III tumors were included. Brain invasion was found in 38 (22%) patients and was absent in 138 (78%) patients. The tumors were located at the convexity in 72 (41%) patients, at the falx cerebri in 26 (15%), at the skull base in 69 (39%), in the posterior fossa in 7 (4%), and in the ventricle in 2 (1%); the median tumor and edema volumes were 13.73 cm3 (range 0.81-162.22 cm3) and 1.38 cm3 (range 0.00-355.80 cm3), respectively. As expected, edema volume increased with rising tumor volume (p < 0.001). Brain invasion was independent of tumor volume (p = 0.176) but strongly correlated with edema volume (p < 0.001). The mean edema volume in noninvasive tumors was 33.0 cm3, but in invasive tumors, it was 130.7 cm3 (p = 0.008). The frequency of preoperative seizures was independent of the patients' age, sex, and tumor location; however, the frequency was 32% (n = 12) in patients with invasive meningioma and 15% (n = 21) in those with noninvasive meningioma (p = 0.033). In contrast, the probability of detecting brain invasion microscopically was increased more than 2-fold in patients with a history of preoperative seizures (OR 2.57, 95% CI 1.13-5.88; p = 0.025). In univariate analyses, the rate of preoperative seizures correlated slightly with tumor volume (p = 0.049) but strongly with edema volume (p = 0.014), whereas seizure semiology was found to be independent of brain invasion (p = 0.211). In multivariate analyses adjusted for age, sex, tumor location, tumor and edema volumes, and WHO grade, rising tumor volume (OR 1.02, 95% CI 1.00-1.03; p = 0.042) and especially brain invasion (OR 5.26, 95% CI 1.52-18.15; p = 0.009) were identified as independent predictors of preoperative seizures. Nine (5%) patients developed new seizures within a median follow-up time of 15 months after surgery. Development of postoperative epilepsy was independent of all clinical variables, including Simpson grade (p = 0.133), tumor location (p = 0.936), brain invasion (p = 0.408), and preoperative edema volume (p = 0.081), but was correlated with increasing preoperative tumor volume (p = 0.004). Postoperative seizure-free rates were similar among patients with invasive and those with noninvasive meningioma (p = 0.372). CONCLUSIONS Brain invasion was identified as a new and strong predictor for preoperative, but not postoperative, seizures. Although also associated with increased peritumoral edema, seizures in patients with invasive meningioma might be facilitated substantially by cortical invasion itself. Consideration of seizures in consultations between the neurosurgeon and neuropathologist can improve the microscopic detection of brain invasion. PMID- 29701551 TI - Letter to the Editor. Resection for WHO Grade III gliomas. PMID- 29701552 TI - Recurrent papillary craniopharyngioma with BRAF V600E mutation treated with dabrafenib: case report. AB - The authors present the case of a man with a papillary craniopharyngioma, first diagnosed at 47 years of age, who experienced multiple recurrences. Review of the pathologic specimen from his first resection demonstrated the BRAF V600E mutation. With his most recent recurrence following previous surgery and radiotherapy, at 52 years of age, the decision was made to initiate treatment with the BRAF V600E inhibitor dabrafenib. Imaging following initiation of dabrafenib demonstrated reduction in tumor size. He remained on dabrafenib therapy for approximately 1 year and continued to demonstrate a good clinical result. At that time the decision was made to discontinue dabrafenib therapy and follow up with serial imaging. After more than 1 year of follow-up since stopping dabrafenib, the patient has continued to do well with no radiographic evidence of tumor progression and continues to be monitored with frequent interval imaging. PMID- 29701553 TI - Letter to the Editor. Collecting data about the transorbital endoscopic eyelid approach. PMID- 29701554 TI - Long-term results of middle cerebral artery aneurysm clipping in the Barrow Ruptured Aneurysm Trial. AB - OBJECTIVE A direct comparison of endovascular versus microsurgical treatment of ruptured middle cerebral artery (MCA) aneurysms in randomized trials is lacking. As endovascular treatment strategies continue to evolve, the number of reports of endovascular treatment of these lesions is increasing. Herein, the authors report a detailed post hoc analysis of ruptured MCA aneurysms treated by microsurgical clipping from the Barrow Ruptured Aneurysm Trial (BRAT). METHODS The cases of patients enrolled in the BRAT who underwent microsurgical clipping for a ruptured MCA aneurysm were reviewed. Characteristics of patients and their clinical outcomes and long-term angiographic results were analyzed. RESULTS Fifty patients underwent microsurgical clipping of a ruptured MCA aneurysm in the BRAT, including 21 who crossed over from the endovascular treatment arm. Four patients with nonsaccular (e.g., dissecting, fusiform, or blister) aneurysms were excluded, leaving 46 patients for analysis. Most (n = 32; 70%) patients presented with a Hunt and Hess grade II or III subarachnoid hemorrhage, with a high prevalence of intraparenchymal blood (n = 23; 50%), intraventricular blood (n = 21; 46%), or both. At the last follow-up (up to 6 years after treatment), clinical outcomes were good (modified Rankin Scale score 0-2) in 70% (n = 19) of 27 Hunt and Hess grades I-III patients and in 36% (n = 4) of 11 Hunt and Hess grade IV or V patients. There were no instances of rebleeding after the surgical clipping of aneurysms in this series at the time of last clinical follow-up. CONCLUSIONS Microsurgical clipping of ruptured MCA aneurysms has several advantages over endovascular treatment, including durability over time. The authors report detailed outcome data of patients with ruptured MCA aneurysms who underwent microsurgical clipping as part of a prospective, randomized trial. These results should be used for comparison with future endovascular and surgical series to ensure that the best results are being achieved for patients with ruptured MCA aneurysms. PMID- 29701555 TI - Stereotactic radiosurgery for trigeminal neuralgia: a systematic review. AB - OBJECTIVES The aims of this systematic review are to provide an objective summary of the published literature specific to the treatment of classical trigeminal neuralgia with stereotactic radiosurgery (RS) and to develop consensus guideline recommendations for the use of RS, as endorsed by the International Society of Stereotactic Radiosurgery (ISRS). METHODS The authors performed a systematic review of the English-language literature from 1951 up to December 2015 using the Embase, PubMed, and MEDLINE databases. The following MeSH terms were used in a title and abstract screening: "radiosurgery" AND "trigeminal." Of the 585 initial results obtained, the authors performed a full text screening of 185 studies and ultimately found 65 eligible studies. Guideline recommendations were based on level of evidence and level of consensus, the latter predefined as at least 85% agreement among the ISRS guideline committee members. RESULTS The results for 65 studies (6461 patients) are reported: 45 Gamma Knife RS (GKS) studies (5687 patients [88%]), 11 linear accelerator (LINAC) RS studies (511 patients [8%]), and 9 CyberKnife RS (CKR) studies (263 patients [4%]). With the exception of one prospective study, all studies were retrospective. The mean maximal doses were 71.1-90.1 Gy (prescribed at the 100% isodose line) for GKS, 83.3 Gy for LINAC, and 64.3-80.5 Gy for CKR (the latter two prescribed at the 80% or 90% isodose lines, respectively). The ranges of maximal doses were as follows: 60-97 Gy for GKS, 50-90 Gy for LINAC, and 66-90 Gy for CKR. Actuarial initial freedom from pain (FFP) without medication ranged from 28.6% to 100% (mean 53.1%, median 52.1%) for GKS, from 17.3% to 76% (mean 49.3%, median 43.2%) for LINAC, and from 40% to 72% (mean 56.3%, median 58%) for CKR. Specific to hypesthesia, the crude rates (all Barrow Neurological Institute Pain Intensity Scale scores included) ranged from 0% to 68.8% (mean 21.7%, median 19%) for GKS, from 11.4% to 49.7% (mean 27.6%, median 28.5%) for LINAC, and from 11.8% to 51.2% (mean 29.1%, median 18.7%) for CKR. Other complications included dysesthesias, paresthesias, dry eye, deafferentation pain, and keratitis. Hypesthesia and paresthesia occurred as complications only when the anterior retrogasserian portion of the trigeminal nerve was targeted, whereas the other listed complications occurred when the root entry zone was targeted. Recurrence rates ranged from 0% to 52.2% (mean 24.6%, median 23%) for GKS, from 19% to 63% (mean 32.2%, median 29%) for LINAC, and from 15.8% to 33% (mean 25.8%, median 27.2%) for CKR. Two GKS series reported 30% and 45.3% of patients who were pain free without medication at 10 years. CONCLUSIONS The literature is limited in its level of evidence, with only one comparative randomized trial (1 vs 2 isocenters) reported to date. At present, one can conclude that RS is a safe and effective therapy for drug-resistant trigeminal neuralgia. A number of consensus statements have been made and endorsed by the ISRS. PMID- 29701557 TI - Stereotactic radiosurgery for trigeminal pain secondary to recurrent malignant skull base tumors. AB - OBJECTIVE The objective of this study was to assess outcomes after Gamma Knife radiosurgery (GKRS) re-irradiation for palliation of patients with trigeminal pain secondary to recurrent malignant skull base tumors. METHODS From 2009 to 2016, 26 patients who had previously undergone radiation treatment to the head and neck received GKRS for palliation of trigeminal neuropathic pain secondary to recurrence of malignant skull base tumors. Twenty-two patients received single fraction GKRS to a median dose of 17 Gy (range 15-20 Gy) prescribed to the 50% isodose line (range 43%-55%). Four patients received fractionated Gamma Knife Extend therapy to a median dose of 24 Gy in 3 fractions (range 21-27 Gy) prescribed to the 50% isodose line (range 45%-50%). Those with at least a 3-month follow-up were assessed for symptom palliation. Self-reported pain was evaluated by the numeric rating scale (NRS) and MD Anderson Symptom Inventory-Head and Neck (MDASI-HN) pain score. Frequency of as-needed (PRN) analgesic use and opioid requirement were also assessed. Baseline opioid dose was reported as a fentanyl equivalent dose (FED) and PRN for breakthrough pain use as oral morphine equivalent dose (OMED). The chi-square and Student t-tests were used to determine differences before and after GKRS. RESULTS Seven patients (29%) were excluded due to local disease progression. Two experienced progression at the first follow-up, and 5 had local recurrence from disease outside the GKRS volume. Nineteen patients were assessed for symptom palliation with a median follow-up duration of 10.4 months (range 3.0-34.4 months). At 3 months after GKRS, the NRS scores (n = 19) decreased from 4.65 +/- 3.45 to 1.47 +/- 2.11 (p < 0.001); MDASI-HN pain scores (n = 13) decreased from 5.02 +/- 1.68 to 2.02 +/- 1.54 (p < 0.01); scheduled FED (n = 19) decreased from 62.4 +/- 102.1 to 27.9 +/- 45.5 mcg/hr (p < 0.01); PRN OMED (n = 19) decreased from 43.9 +/- 77.5 to 10.9 +/- 20.8 mg/day (p = 0.02); and frequency of any PRN analgesic use (n = 19) decreased from 0.49 +/- 0.55 to 1.33 +/- 0.90 per day (p = 0.08). At 6 months after GKRS, 9 (56%) of 16 patients reported being pain free (NRS score 0), with 6 (67%) of the 9 being both pain free and not requiring analgesic medications. One patient treated early in our experience developed a temporary increase in trigeminal pain 3-4 days after GKRS requiring hospitalization. All subsequently treated patients were given a single dose of intravenous steroids immediately after GKRS followed by a 2-3-week oral steroid taper. No further cases of increased or new pain after treatment were observed after this intervention. CONCLUSIONS GKRS for palliation of trigeminal pain secondary to recurrent malignant skull base tumors demonstrated a significant decrease in patient-reported pain and opioid requirement. Additional patients and a longer follow-up duration are needed to assess durability of symptom relief and local control. PMID- 29701556 TI - Estimating the global incidence of traumatic brain injury. AB - OBJECTIVE Traumatic brain injury (TBI)-the "silent epidemic"-contributes to worldwide death and disability more than any other traumatic insult. Yet, TBI incidence and distribution across regions and socioeconomic divides remain unknown. In an effort to promote advocacy, understanding, and targeted intervention, the authors sought to quantify the case burden of TBI across World Health Organization (WHO) regions and World Bank (WB) income groups. METHODS Open source epidemiological data on road traffic injuries (RTIs) were used to model the incidence of TBI using literature-derived ratios. First, a systematic review on the proportion of RTIs resulting in TBI was conducted, and a meta-analysis of study-derived proportions was performed. Next, a separate systematic review identified primary source studies describing mechanisms of injury contributing to TBI, and an additional meta-analysis yielded a proportion of TBI that is secondary to the mechanism of RTI. Then, the incidence of RTI as published by the Global Burden of Disease Study 2015 was applied to these two ratios to generate the incidence and estimated case volume of TBI for each WHO region and WB income group. RESULTS Relevant articles and registries were identified via systematic review; study quality was higher in the high-income countries (HICs) than in the low- and middle-income countries (LMICs). Sixty-nine million (95% CI 64-74 million) individuals worldwide are estimated to sustain a TBI each year. The proportion of TBIs resulting from road traffic collisions was greatest in Africa and Southeast Asia (both 56%) and lowest in North America (25%). The incidence of RTI was similar in Southeast Asia (1.5% of the population per year) and Europe (1.2%). The overall incidence of TBI per 100,000 people was greatest in North America (1299 cases, 95% CI 650-1947) and Europe (1012 cases, 95% CI 911-1113) and least in Africa (801 cases, 95% CI 732-871) and the Eastern Mediterranean (897 cases, 95% CI 771-1023). The LMICs experience nearly 3 times more cases of TBI proportionally than HICs. CONCLUSIONS Sixty-nine million (95% CI 64-74 million) individuals are estimated to suffer TBI from all causes each year, with the Southeast Asian and Western Pacific regions experiencing the greatest overall burden of disease. Head injury following road traffic collision is more common in LMICs, and the proportion of TBIs secondary to road traffic collision is likewise greatest in these countries. Meanwhile, the estimated incidence of TBI is highest in regions with higher-quality data, specifically in North America and Europe. PMID- 29701558 TI - Syringobulbia in pediatric patients with Chiari malformation type I. AB - OBJECTIVE Syringobulbia (SB) is a rare entity, with few cases associated with Chiari malformation type I (CM-I) in the pediatric population. The authors reviewed all pediatric cases of CM-I-associated SB managed at their institution in order to better understand the presentation, treatment, and surgical outcomes of this condition. METHODS A prospectively maintained institutional database of craniovertebral junction abnormalities was analyzed to identify all cases of CM-I and SB from the MRI era (i.e., after 1984). The authors recorded presenting symptoms, physical examination findings, radiological findings, surgical treatment strategy, intraoperative findings, and outcomes. SB cases associated with tumors, infections, or type II Chiari malformations were excluded. RESULTS The authors identified 326 pediatric patients with CM-I who were surgically treated. SB was identified in 13 (4%) of these 326 patients. Headache and neck pain were noted in all 13 cases. Cranial nerve abnormalities were common: vagus and glossopharyngeal nerve dysfunction was the most frequent observation. Other cranial nerves affected included the trigeminal, abducens, and hypoglossal nerves. Several patients exhibited multiple cranial nerve palsies at presentation. Central sleep apnea was present in 6 patients. Syringomyelia (SM) was present in all 13 patients. SB involved the medulla in all cases, and extended rostrally into the pons and midbrain in 2 patients; in 1 of these 2 cases the cavity extended further rostrally to the cerebrum (syringocephaly). SB communicated with the fourth ventricle in 7 of the 13 cases. All 13 patients were treated with posterior fossa decompression with intradural exploration to ensure CSF egress out of the fourth ventricle and through the foramen magnum. The foramen of Magendie was found to be occluded by an arachnoid veil in 9 cases. Follow-up evaluation revealed that SB improved before SM. Cranial nerve palsies regressed in 11 of the 13 patients, and SB improved in all 13. CONCLUSIONS The incidence of SB in our surgical series of pediatric patients with CM-I was 4%, and all of these patients had accompanying SM. The SB cavity involved the medulla in all cases and was found to communicate with the fourth ventricle in 54% of cases. Posterior fossa decompression with intradural exploration and duraplasty is an effective treatment for these patients. PMID- 29701559 TI - Complications following lengthening of spinal growing implants: is postoperative admission necessary? AB - OBJECTIVE The aim of this study was to evaluate the effect of postoperative admission status on 30-day perioperative complications in patients with growing spinal instrumentation undergoing surgical lengthening. METHODS This retrospective case-control study of records from the 2014-2015 National Surgical Quality Improvement Program-Pediatric database was performed to identify surgical lengthening procedures of spinal implants in patients with growing instrumentation by Current Procedural Terminology code. The 30-day postoperative complications were classified according to the Clavien-Dindo system. Patients were subdivided according to their postsurgical admission status. Admission status, American Society of Anesthesiologists (ASA) Physical Status classification, tracheostomy, neuromuscular diagnosis, ventilator dependence, and nutritional support were considered as possible risk factors in univariate and multivariate logistic regression analyses. RESULTS A total of 796 patients were identified (mean age 9.09 +/- 3.44 years; 54% of patients were female), of whom 73% underwent lengthening on an inpatient basis. Patients with a tracheostomy or ventilator dependence were more likely to be admitted postoperatively. The overall rate of major complications was 3.5% and did not differ based on admission status (2.8% inpatient vs 3.8% outpatient, p = 0.517). On univariate analysis, ventilator dependence (9.5% vs 2.7%, p = 0.002), need for nutritional support (7.1% vs 2.5%, p = 0.006), and ASA class > II (4.8% vs 1.3%, p = 0.04) placed patients at a higher risk for any postoperative complications. Multivariate analysis identified only ventilator dependence as an independent risk factor for any perioperative complication. CONCLUSIONS Postoperative admission status did not affect the rate of 30-day perioperative complications, readmission, or rate of unplanned operations following lengthening of growing spinal instrumentation. Outpatient lengthening appears to be safe; however, consideration for postoperative admission should be given for those who are ventilator dependent. PMID- 29701560 TI - High prevalence of prior contact sports play and concussion among orthopedic and neurosurgical department chairs. AB - OBJECTIVE Increased understanding of the consequences of traumatic brain injury has heightened concerns about youth participation in contact sports. This study investigated the prevalence of high school and collegiate contact sports play and concussion history among surgical department chairs. METHODS A cross-sectional survey was administered to 107 orthopedic and 74 neurosurgery chairs. Responses were compared to published historical population norms for contact sports (high school 27.74%, collegiate 1.44%), football (high school 10.91%, collegiate 0.76%), and concussion prevalence (12%). One-proportion Z-tests, chi-square tests, and binary logistic regression were used to analyze differences. RESULTS High school contact sports participation was 2.35-fold higher (65.3%, p < 0.001) for orthopedic chairs and 1.73-fold higher (47.9%, p = 0.0018) for neurosurgery chairs than for their high school peers. Collegiate contact sports play was 31.0 fold higher (44.7%, p < 0.001) for orthopedic chairs and 15.1-fold higher (21.7%, p < 0.001) for neurosurgery chairs than for their college peers. Orthopedic chairs had a 4.30-fold higher rate of high school football participation (46.9%, p < 0.001) while neurosurgery chairs reported a 3.05-fold higher rate (33.3%, p < 0.001) than their high school peers. Orthopedic chairs reported a 28.1-fold higher rate of collegiate football participation (21.3%, p < 0.001) and neurosurgery chairs reported an 8.58-fold higher rate (6.5%, p < 0.001) compared to their college peers. The rate at which orthopedic (42.6%, p < 0.001) and neurosurgical (42.4%, p < 0.001) chairs reported having at least 1 concussion in their lifetime was significantly higher than the reported prevalence in the general population. After correction for worst possible ascertainment bias, all results except high school contact sports participation remained significant. CONCLUSIONS The high prevalence of youth contact sports play and concussion among surgical specialty chairs affirms that individuals in careers requiring high motor and cognitive function frequently played contact sports. The association highlights the need to further examine the relationships between contact sports and potential long-term benefits as well as risks of sport-related injury. PMID- 29701561 TI - Granulocyte-colony stimulating factor administration for neurological improvement in patients with postrehabilitation chronic incomplete traumatic spinal cord injuries: a double-blind randomized controlled clinical trial. AB - OBJECTIVE Granulocyte-colony stimulating factor (G-CSF) is a major growth factor for activation and differentiation of granulocyte colonies in the bone marrow. This cytokine has been widely and safely employed in different conditions over many years. The purpose of this study was to investigate the efficacy of G-CSF administration for traumatic spinal cord injury (TSCI). METHODS This double-blind parallel randomized, placebo-controlled, clinical trial, a phase III study, was performed from June 2013 to June 2016 in the Brain and Spinal Cord Injury Research (BASIR) center at Tehran University of Medical Sciences (TUMS). It included 120 patients with incomplete chronic TSCI, American Spinal Injury Association (ASIA) Impairment Scale (AIS) B, C, or D, of at least 6 months' duration. Sixty patients were allocated into the treatment group and 60 patients into the control group. All the patients had completed an outpatient rehabilitation program in the postacute period and were in a neurological and functional plateau. Patients were assessed with the ASIA grading system, the Spinal Cord Independence Measure (SCIM-III), and the International Association of Neurorestoratology-Spinal Cord Injury Functional Rating Scale (IANR-SCIFRS) just before intervention and at 1, 3, and 6 months after 7 subcutaneous administrations of 300 MUg/day of G-CSF in the treatment group and placebo in the control group (administered once per day over the course of 1 week). Randomization was performed with randomized block design, and the patients and evaluators were blinded regarding the treatment groups. One patient did not receive the entire allocated intervention and 5 patients were lost to follow-up. Thus data from 114 patients were included in the analysis. RESULTS One hundred twenty patients were randomized and allocated into the study groups. Among them, 56 patients (93.3%) in the G-CSF group and 58 patients (96.6%) in the placebo group completed the study protocol. After 6 months of follow-up, AIS in the placebo group remained unchanged, whereas in the G-CSF group, 1 patient improved from AIS B to C, and 4 patients improved from AIS C to D. The mean (+/- SE) improvement in ASIA motor score in the G-CSF group was 5.5 +/- 0.62, which was significantly more than in the placebo group (0.77 +/- 0.20) (p < 0.001). The mean light touch and pinprick sensory scores, respectively, increased by 6.1 +/- 1.1 and 8.7 +/- 1.5 in the G-CSF group and by 1.3 +/- 0.52 and 0.89 +/- 0.44 scores in the placebo group (p < 0.001). Evaluation of functional improvement by the IANR-SCIFRS instrument revealed significantly more improvement in the G-CSF group (3.5 +/- 0.37) than in the placebo group (0.41 +/- 0.12) (p < 0.001). Also, a significant difference was observed in functional improvement between the 2 groups as measured by SCIM-III instrument (7.5 +/- 0.95 vs 2.1 +/- 0.51, p < 0.001). CONCLUSIONS Administration of G-CSF for incomplete chronic spinal cord injuries is associated with significant motor, sensory, and functional improvement. Clinical trial registration no.: IRCT201108297441N1 ( www.irct.ir ). PMID- 29701562 TI - Letter to the Editor. Rotational thromboelastometry-guided transfusion protocol. PMID- 29701563 TI - Implementation of an infection prevention bundle and increased physician awareness improves surgical outcomes and reduces costs associated with spine surgery. AB - OBJECTIVE Previous studies have demonstrated the efficacy of infection prevention protocols in reducing infection rates. This study investigated the effects of the development and implementation of an infection prevention protocol that was augmented by increased physician awareness of spinal fusion surgical site infection (SSI) rates and resultant cost savings. METHODS A cohort clinical investigation over a 10-year period was performed at a single tertiary spine care academic institution. Preoperative infection control measures (chlorohexidine gluconate bathing, Staphylococcus aureus nasal screening and decolonization) followed by postoperative infection control measures (surgical dressing care) were implemented. After the implementation of these infection control measures, an awareness intervention was instituted in which all attending and resident neurosurgeons were informed of their individual, independently adjudicated spinal fusion surgery infection rates and rankings among their peers. During the course of these interventions, the overall infection rate was tracked as well as the rates for those neurosurgeons who complied with the preoperative and postoperative infection control measures (protocol group) and those who did not (control group). RESULTS With the implementation of postoperative surgical dressing infection control measures and physician awareness, the postoperative spine surgery infection rate decreased by 45% from 3.8% to 2.1% (risk ratio 0.55; 95% CI 0.32-0.93; p = 0.03) for those in the protocol cohort, resulting in an estimated annual cost savings of $291,000. This reduction in infection rate was not observed for neurosurgeons in the control group, although the overall infection rate among all neurosurgeons decreased by 54% from 3.3% to 1.5% (risk ratio 0.46; 95% CI 0.28-0.73; p = 0.0013). CONCLUSIONS A novel paradigm for spine surgery infection control combined with physician awareness methods resulted in significantly decreased SSI rates and an associated cost reduction. Thus, information sharing and physician engagement as a supplement to formal infection control measures result in improvements in surgical outcomes and costs. PMID- 29701564 TI - Influence of racial disparities on patient-reported satisfaction and short- and long-term perception of health status after elective lumbar spine surgery. AB - OBJECTIVE In spine surgery, racial disparities have been shown to impact various aspects of surgical care. Previous studies have associated racial disparities with inferior surgical outcomes, including increased complication and 30-day readmission rates after spine surgery. Recently, patient-reported outcomes (PROs) and satisfaction measures have been proxies for overall quality of care and hospital reimbursements. However, the influence that racial disparities have on short- and long-term PROs and patient satisfaction after spine surgery is relatively unknown. The aim of this study was to investigate the impact of racial disparities on 3- and 12-month PROs and patient satisfaction after elective lumbar spine surgery. METHODS This study was designed as a retrospective analysis of a prospectively maintained database. The medical records of adult (age >= 18 years) patients who had undergone elective lumbar spine surgery for spondylolisthesis (grade 1), disc herniation, or stenosis at a major academic institution were included in this study. Patient demographics, comorbidities, postoperative complications, and 30-day readmission rates were collected. Patients had prospectively collected outcome and satisfaction measures. Patient reported outcome instruments-Oswestry Disability Index (ODI), visual analog scale for back pain (VAS-BP), and VAS for leg pain (VAS-LP)-were completed before surgery and at 3 and 12 months after surgery, as were patient satisfaction measures. RESULTS The authors identified 345 medical records for 53 (15.4%) African American (AA) patients and 292 (84.6%) white patients. Baseline patient demographics and comorbidities were similar between the two cohorts, with AA patients having a greater body mass index (33.1 +/- 6.6 vs 30.2 +/- 6.4 kg/m2, p = 0.005) and a higher prevalence of diabetes (35.9% vs 16.1%, p = 0.0008). Surgical indications, operative variables, and postoperative variables were similar between the cohorts. Baseline and follow-up PRO measures were worse in the AA cohort, with patients having a greater baseline ODI (p < 0.0001), VAS-BP score (p = 0.0002), and VAS-LP score (p = 0.0007). However, mean changes from baseline to 3- and 12-month PROs were similar between the cohorts for all measures except the 3-month VAS-BP score (p = 0.046). Patient-reported satisfaction measures at 3 and 12 months demonstrated a significantly lower proportion of AA patients stating that surgery met their expectations (3 months: 47.2% vs 65.5%, p = 0.01; 12 months: 35.7% vs 62.7%, p = 0.007). CONCLUSIONS The study data suggest that there is a significant difference in the perception of health, pain, and disability between AA and white patients at baseline and short- and long-term follow-ups, which may influence overall patient satisfaction. Further research is necessary to identify patient-specific factors associated with racial disparities that may be influencing outcomes to adequately measure and assess overall PROs and satisfaction after elective lumbar spine surgery. PMID- 29701565 TI - Letter to the Editor. Thinking laterally: beyond transoral decompression for irreducible ADD with os odontodieum. PMID- 29701566 TI - The subatlantic triangle: gateway to early localization of the atlantoaxial vertebral artery. AB - OBJECTIVE Exposure of the vertebral artery (VA) between C-1 and C-2 vertebrae (atlantoaxial VA) may be necessary in a variety of pathologies of the craniovertebral junction. Current methods to expose this segment of the VA entail sharp dissection of muscles close to the internal jugular vein and the spinal accessory nerve. The present study assesses the technique of exposing the atlantoaxial VA through a newly defined muscular triangle at the craniovertebral junction. METHODS Five cadaveric heads were prepared for surgical simulation in prone position, turned 30 degrees -45 degrees toward the side of exposure. The atlantoaxial VA was exposed through the subatlantic triangle after reflecting the sternocleidomastoid and splenius capitis muscles inferiorly. The subatlantic triangle was formed by 3 groups of muscles: 1) the levator scapulae and splenius cervicis muscles inferiorly and laterally, 2) the longissimus capitis muscle inferiorly and medially, and 3) the inferior oblique capitis superiorly. The lengths of the VA exposed through the triangle before and after unroofing the C-2 transverse foramen were measured. RESULTS The subatlantic triangle consistently provided access to the whole length of atlantoaxial VA. The average length of the VA exposed via the subatlantic triangle was 19.5 mm. This average increased to 31.5 mm after the VA was released at the C-2 transverse foramen. CONCLUSIONS The subatlantic triangle provides a simple and straightforward pathway to expose the atlantoaxial VA. The proposed method may be useful during posterior approaches to the craniovertebral junction should early exposure and control of the atlantoaxial VA become necessary. PMID- 29701567 TI - Letter to the Editor. Tranexamic acid for reducing intra- and postoperative blood loss in posterior lumbar interbody fusion: Is it safe enough? PMID- 29701568 TI - Results of a quality improvement initiative reassessing an institutional lumbar drain infection prevention protocol. AB - OBJECTIVE The objective of this study was to determine the effects of a quality improvement initiative in which daily antibiotics and daily sampling of cerebrospinal fluid (CSF) were discontinued for patients with lumbar drains. METHODS The frequency of surgical site infections (SSIs), antibiotic-related complications (development of Clostridium difficile infection [CDI] and growth of resistant bacteria), and cost for patients with lumbar drains were compared during 3 periods: 1) prolonged prophylactic systemic antibiotics (PPSA) until the time of drain removal and daily CSF sampling (September 2013-2014), 2) PPSA and CSF sampling once after placement then as needed (January 2015-2016), and 3) antibiotics only during placement of the lumbar drain and CSF sampling once after placement then as needed (April 2016-2017). RESULTS Thirty-nine patients were identified in period 1, 53 patients in period 2, and 39 patients in period 3. There was no change in the frequency of SSI after discontinuation of routine CSF testing or PPSA (0% in period 1, 2% in period 2, and 0% in period 3). In periods 1 and 2, 3 patients developed infections due to resistant organisms and 2 patients had CDI. In period 3, 1 patient had an infection due to a resistant organism. The median cost of CSF tests per patient was $100.68 (interquartile range [IQR] $100.68-$134.24) for patients in period 1 and $33.56 (IQR $33.56 $33.56) in periods 2 and 3 (p < 0.001). The median cost of antibiotics per patient was $26.32 (IQR $26.32-$30.65) in periods 1 and 2 and $3.29 ($3.29-$3.29) in period 3 (p < 0.001). The cost associated with growth of resistant bacteria and CDI was $91,291 in periods 1 and 2 and $25,573 in period 3. CONCLUSIONS After discontinuing daily antibiotics and daily CSF sampling for patients with lumbar drains, the frequency of SSI was unchanged and the frequency of antibiotic related complications decreased. PMID- 29701569 TI - Letter to the Editor. Cortical bone trajectory screw technique. PMID- 29701570 TI - Letter to the Editor. Radiographic differentiation of idiopathic spinal cord herniation versus dorsal arachnoid webs. PMID- 29701571 TI - Multiple extraspinal recurrences of ependymoma 13 years after spinal cordectomy: case report. AB - Ependymomas of the spinal cord remain confined to the CNS and vary in presentation, depending on WHO grade. Higher-grade lesions usually cannot be surgically removed due to their infiltrative growth pattern. Spinal cordectomy has been proposed as a rescue treatment to improve survival in patients with high grade as well as recurrent lesions. This report details an instructive and unique case of long-term follow-up of a patient who underwent cordectomy from T-4 through S-5 for what was initially diagnosed as a high-grade glial neoplasm of the spinal cord in 1993. The patient lived symptom free for 13 years after spinal cord resection and then presented with numerous bilateral extraspinal (intraabdominal and intrathoracic) tumors, which eventually led to her death 15 years after the cordectomy. In this case, spinal cordectomy was effective in preventing the ascending spread of the neoplasm, but ultimately not effective in preventing recurrence in the plicated distal dural sac. PMID- 29701573 TI - Editorial: The Advances in Treatment for Coronary Artery Disease, Voices from Interventional Cardiologists at the Fortieth Year of Percutaneous Coronary Intervention. PMID- 29701572 TI - Detection and phylogenetic characterization of porcine circovirus 2 from pigs in Mozambique. AB - Porcine circovirus-associated diseases (PCVADs), caused by porcine circovirus 2 (PCV-2), have a significant economic impact on the swine industry worldwide. In Africa, there is little information, to date, regarding the occurrence of PCV-2, and it has not been reported in Mozambique's swine population. We randomly collected mesenteric lymph nodes ( n = 111) from slaughtered pigs from 9 districts in southern Mozambique. PCV-2 DNA was detected in 54% (62 of 111) of the samples and 78% (23 of 31) of the farms. PCV-2 antigen was detected by immunohistochemistry in lymph nodes (6 of 62; 10%) that were positive for PCV-2 by PCR. Histopathologic changes observed in these lymph nodes were lymphoid depletion, multifocal nodal necrosis, and infiltrates of histiocytes and multinucleate giant cells. One positive sample from each district was selected in order to obtain sequences covering the ORF2 region. Five sequences clustered with PCV-2d, of which 3 sequences from Maputo, Namaacha, and Moamba were grouped with PCV-2d-2; 2 sequences from Manhica and Matola were grouped as PCV-2d-1; and 4 sequences from Boane, Matutuine, Chibuto, and Xai-Xai were closely related to PCV 2b-1A/B genotypes. Our study indicates that a diversity of PCV-2 viruses is circulating in the Mozambican swine population. PMID- 29701575 TI - Paenibacillus esterisolvens sp. nov., isolated from soil. AB - A Gram-stain-positive, aerobic, motile with peritrichous flagella, rod-shaped bacterium, designated CFH S0170T, was isolated from a soil sample collected from Catba island in Ha Long Bay, Hai Phong City, Vietnam. Comparison of the 16S rRNA gene sequences showed that strain CFH S0170T belonged to the genus Paenibacillus and showed closest relationship with Paenibacillus vulneris CCUG 53270T (98.1 % similarity). Phylogenetic analysis demonstrated that the novel candidate formed a coherent branch with P. vulneris CCUG 53270T and Paenibacillus yunnanensis YN2T. Furthermore, the novel strain shared 87.2 % rpoB gene sequence similarity with P. vulneris CCUG 53270T. Growth of strain CFH S0170T occurred at 10-40 degrees C, pH 6.0-8.0 and with 0-2.0 % (w/v) NaCl. Strain CFH S0170T contained mannose, glucose and rhamnose as the major whole-cell sugars. The cell-wall peptidoglycan contained meso-diaminopimelic acid, glutamic acid, lysine and aspartic acid. The polar lipid profile contained diphosphatidylglycerol, phosphatidylethanolamine, glycolipids and phospholipids. The dominant cellular fatty acids included anteiso C15 : 0 and C15 : 0. The genomic DNA G+C content was 50.9 mol%. On the basis of phenotypic, chemotaxonomic and phylogenetic analysis, strain CFH S0170T is affiliated to the genus Paenibacillus, but could be distinguished from other valid species of this genus. It is concluded that strain CFH S0170T should be considered to represent a novel species of the genus Paenibacillus, for which the name Paenibacillus esterisolvens sp. nov. is proposed. The type strain is CFH S0170T (=KCTC 33624T=BCRC 80802T). PMID- 29701574 TI - Camelliibacillus cellulosilyticus gen. nov., sp. nov., a cellulose-degrading bacterium isolated from tea. AB - A Gram-stain-positive, oxidase- and catalase-positive, endospore-forming, aerobic, non-motile and rod-shaped bacterium (THG-YT1T) was isolated from green tea. Growth occurred at 10-40 degrees C (optimum, 25-30 degrees C), at pH 6-8 (optimum, 7) and at 0-2 % NaCl (optimum, 0 %). Based on 16S rRNA gene sequences, phylogenetic analyses showed that strain THG-YT1T formed a distinct lineage with respect to closely related genera in the family Bacillaceae. Strain THG-YT1T was most closely related to the genera within the families Pullulanibacillus, Scopulibacillus, Tuberibacillus and Caenibacillu, with levels of 16S rRNA gene sequence similarity to the type species of members of these genera of less than 95.0 %. The menaquinone was MK-7. The polar lipids were phosphatidylethanolamine, two unidentified aminophospholipids, two unidentified aminolipids and two unidentified glycolipids. The major fatty acids of strain THG-YT1T were C18 : 3omega7c and anteiso-C17 : 0. The cell-wall peptidoglycan type was A1gamma with meso-diaminopimelic acid as the diagnostic diamino acid plus alanine and glutamic acid. The cell-wall sugar was glucose. The DNA G+C content of strain THG-YT1T was determined to be 53.5 mol%. Based on the data presented here, strain THG-YT1T represents a novel species of a new genus of the family Bacillaceae, for which the name Camelliibacillus cellulosilyticus gen. nov., sp. nov. is proposed. The type strain is Camelliibacillus cellulosilyticus THG-YT1T(=KACC 19471T=CGMCC 1.16306T). PMID- 29701576 TI - Marinicaulis flavus gen. nov., sp. nov., a novel stalked bacterium of the family Parvularculaceae. AB - A Gram-stain-negative, aerobic, ovoid or short rod-shaped bacterium with prosthecates and flagella, designated SY-3-19T, was isolated from the surface seawater of the South China Sea, and subjected to a polyphasic taxonomic study. The isolate grew at 4-40 degrees C and pH 5.0-9.0 (optimum 28 degrees C and pH 6.5-7.5), and with 0.5-16.0 % (w/v) NaCl (optimum 4 %). It was positive for oxidase and catalase activity. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain SY-3-19T constituted a separate branch in the family Parvularculaceae, sharing the highest sequence similarities to the genera Aquisalinus (91.9 %), Amphiplicatus (91.1 %) and Parvularcula(91.0-89.4 %). The sole respiratory quinone was ubiquinone-10 and the principal fatty acids (>10 %) were summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c), summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), 11 methyl C18 : 1omega7c and C16 : 0. The polar lipids of strain SY-3-19T consisted of phosphatidylglycerol, nine unidentified glycolipids and four unidentified lipids. The DNA G+C content was 60.9 mol%. On the basis of morphological, physiological and chemotaxonomic characteristics, together with the results of phylogenetic analysis, strain SY-3 19T is described as a novel species in a novel genus, for which the name Marinicaulis flavus gen. nov., sp. nov. (type strain SY-3-19T=MCCC 1K03432T=KCTC 62156T) is proposed. PMID- 29701577 TI - Terasakiella salincola sp. nov., a marine alphaproteobacterium isolated from seawater, and emended description of the genus Terasakiella. AB - A Gram-reaction-negative, S-shaped, motile, poly-beta-hydroxybutyrate accumulating, facultatively anaerobic, beige-pigmented bacterium, designated strain KMU-80T, was isolated from seawater collected from the Republic of Korea. Phylogenetic analysis based on the 16S rRNA gene sequence revealed that the novel isolate was affiliated with the family Methylocystaceae, of the class Alphaproteobacteria, and that it possessed the greatest sequence similarity (96.7 %) to Terasakiella pusilla NBRC 13613T. The DNA G+C content of KMU-80T was 48.3 mol%, and ubiquinone 10 was the sole respiratory quinone. The predominant cellular fatty acids consisted of C18 : 1omega7c (60.2 %), C16 : 0 (13.4 %) and C16 : 1omega7c and/or C16 : 1omega6c (11.1 %). Strain KMU-80T had phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, an unidentified aminolipid, an unidentified phospholipid and four unidentified lipids as polar lipids. Based on its distinct phylogenetic position and the combination of genotypic and phenotypic characteristics, this strain is considered to represent a novel species of the genus Terasakiella, for which the name Terasakiella salincola sp. nov. is proposed. The type strain of T. salincola sp. nov. is KMU-80T (= KCCM 90274T = NBRC 112846T). An amended description of the genus Terasakiella is also provided. PMID- 29701578 TI - Why Medicaid Managed Care Is Looking Outside the Traditional Coverage Box. AB - Social determinants of health come into focus to keep beneficiaries out of the hospital. PMID- 29701579 TI - Take a Bow, Pharma, for the Hepatitis C Drugs. AB - The direct-acting virals revolutionized the treatment of hepatitis C. They also ushered turbocharged pricing. At least patients-and society-got a major health benefit in return. PMID- 29701580 TI - Aetna's California Case Puts New Focus on Prior Authorization. AB - The CNN story once again puts controversy about prior authorization into the spotlight. But is it necessary to review a patient's entire medical record? PMID- 29701582 TI - Social Determinants of Health: Stretching Health Care's Job Description. AB - Providers and payers are being asked to tackle the 'upstream' causes of poor health. Medicaid managed care organizations are being asked to screen enrollees for social needs. Some targeted efforts have translated into cost savings and make sense in value-based arrangements. But are we asking the health sector to take on too much? PMID- 29701581 TI - Opioid Deaths Among Women Not Getting the Attention They Warrant. AB - Deaths of women from opioid addiction spiked 400%, according to CDC data. Alison Colbert of Duquesne University argues for a gender-specific approach. PMID- 29701583 TI - 3 Social Determinants Strategies. AB - A look at three different approaches that seek to address social needs in a strategic and somewhat comprehensive way. At this point, all of them are experiments, and no one knows which will prove to be sustainable, replicable, or even beneficial to the patients and communities they seek to serve. PMID- 29701585 TI - Karl Brown's Hardscrabble Roots Prepared Him for His Medicaid Mission. AB - The CMO of Molina Healthcare of Utah grew up, let's say, not rich. He says that and a varied background-including a stint in the Air Force-helps him deal with changing policies involving a challenging population. PMID- 29701584 TI - Ending Medicaid as We've Known It. AB - CMS is granting waivers that impose work and other new requirements on some Medicaid beneficiaries. Medicaid managed care plans are wary of the added administrative complexity-and possibly a change in the Medicaid population's risk profile. PMID- 29701586 TI - How RWE Is Becoming the Real Deal. AB - The randomized controlled trial reigns supreme, but the FDA is working on ways to incorporate real-world evidence into its approval processes. PMID- 29701587 TI - Finding Our Way To Serving the Underserved. AB - It's a must because there is a cost to keeping the underserved that way whether that means funding integrated primary care to help people live healthier lives or footing the bill when people get care in the emergency department. PMID- 29701588 TI - Questions Health Plans Must Ask Before Considering a Laboratory Benefit Management or Prior Authorization Program. AB - These eight questions show that the use of an LBM or a PAP should be just one of the potential results of your laboratory benefit management program, not the program itself. You shouldn't have to pay for services you already provide yourselves or add a middleman that's not necessary. PMID- 29701589 TI - New Test for Diagnosing Insulin Resistance Could Turn the Tide Against Diabetes. AB - Diabetes is the scourge of our times, but we have been chasing the wrong culprits. A simple, $40 test of insulin resistance could put us on the right track. PMID- 29701590 TI - Medical Tourism: Once Ready for Takeoff, Now Stuck at the Gate. AB - Consultants predicted it would be a major business. Large employers and insurers were experimenting with it. But medical tourism has not lived up to the heady expectations. The ACA and moderation of increases in health care costs cooled off interest. Besides, who really wants to go to an unfamiliar place for health care? PMID- 29701591 TI - Dissecting the schistosome cloak. AB - Two proteins required for the growth of a skin-like structure called the tegument in parasitic flatworms could be new targets for drugs to kill these parasites. PMID- 29701592 TI - Marking the differences in motoneurons. AB - A subgroup of the neurons that control muscles becomes less excitable shortly before the symptoms of ALS develop. PMID- 29701593 TI - Emergency involuntary treatment law for people with mental disorders: A comparative analysis of legislation in LMICs. PMID- 29701594 TI - The impact of maternal incarceration on their daughter's empathy. PMID- 29701595 TI - Factors influencing advance directives among psychiatric inpatients in India. AB - OBJECTIVES: Advance directives are documents stating treatment preferences in case of future lack of decision making capacity. In India, as in many other countries, legislators advocate Psychiatric Advance Directives (PADs), while evidence on its use is limited. This study examined factors influencing PADs by gathering inpatients perspectives on PADs at discharge and investigating patient characteristics associated with the expression of treatment wishes in PADs. METHODS: We conducted a hospital based descriptive study in Bangalore. 200 patients were included. The Mini International Neuropsychiatric Interview, CGI-S and CGI-I (Clinical Global Impression scales), the Insight Scale-2, and an Illness insight assessment were completed within 3days of admission. We used the Bangalore Advance Directive Interview (BADI) to assess attitudes towards PADs. 182 subjects were reassessed within 3days of discharge, along with an interview on their perspectives on PADs. RESULTS: 67% welcomed the need for PADs in India. 95.6% made their own PADs. 80% followed their doctors' advice in their PAD. Subjects lacking insight or remaining symptomatic at discharge opted significantly more often against ECT, antipsychotics, and inpatient care. Linear regression showed that low socio-economic status, unwillingness to stay in hospital, and having received ECT before were inversely associated with the expression of treatment wishes in PADs. CONCLUSIONS: This study's findings are relevant for India and Western countries alike while generating legislation including patients' perspectives. A majority of patients favoured PADs. Absent insight, severe psychopathology and incomplete recovery may negatively influence the way PADs are completed. Therefore, clinicians must assess patient's capacity to formulate PADs carefully, as capacity may significantly influence patients' views. The timing of when to formulate one's PAD within the illness process may be essential. PMID- 29701596 TI - Voluntary or involuntary acute psychiatric hospitalization in Norway: A 24h follow up study. AB - : The Norwegian Mental Health Care Act states that patients who are involuntarily admitted to a hospital must be reevaluated by a psychiatrist or a specialist in clinical psychology within 24h to assess whether the patient fulfills the legal criteria for the psychiatric status and symptoms. International research on the use of coercive hospitalization in psychiatry is scarce, and an investigation of Norway's routine re-evaluation of involuntarily referred patients may expand knowledge about this aspect of psychiatric treatment. The aim of this study was to investigate the extent to which Involuntarily Hospitalized (IH) patients were converted to a Voluntary Hospitalization (VH), and to identify predictive factors leading to conversion. The Multi-center Acute Psychiatry study (MAP) included all cases of acute consecutive psychiatric admissions across twenty Norwegian acute psychiatric units in health trusts in Norway across 3months in 2005-06, representing about 75% of the psychiatric acute emergency units in Norway. The incident of conversion from involuntarily hospitalization (IH) to voluntary hospitalization (VH) was analyzed using generalized linear mixed modeling. Out of 3338 patients referred for admission, 1468 were IH (44%) and 1870 were VH. After re-evaluation, 1148 (78.2%) remained on involuntary hospitalization, while 320 patients (21.8%) were converted to voluntary hospitalization. The predictors of conversion from involuntary to voluntary hospitalization after re-evaluation of a specialist included patients wanting admission, better scores on Global Assessment of Symptom scale, fewer hallucinations and delusions and higher alcohol intake. CONCLUSION: The 24h re-evaluation period for patients referred for involuntary hospitalization, as stipulated by the Norwegian Mental Health Care Act, appeared to give adequate opportunity to reduce unnecessary involuntary hospitalization, while safeguarding the patient's right to VH. PMID- 29701597 TI - The problem of false positives and false negatives in violent video game experiments. AB - The problem of false positives and negatives has received considerable attention in behavioral research in recent years. The current paper uses video game violence research as an example of how such issues may develop in a field. Despite decades of research, evidence on whether violent video games (VVGs) contribute to aggression in players has remained mixed. Concerns have been raised in recent years that experiments regarding VVGs may suffer from both "false positives" and "false negatives." The current paper examines this issue in three sets of video game experiments, two sets of video game experiments on aggression and prosocial behaviors identified in meta-analysis, and a third group of recent null studies. Results indicated that studies of VVGs and aggression appear to be particularly prone to false positive results. Studies of VVGs and prosocial behavior, by contrast are heterogeneous and did not demonstrate any indication of false positive results. However, their heterogeneous nature made it difficult to base solid conclusions on them. By contrast, evidence for false negatives in null studies was limited, and little evidence emerged that null studies lacked power in comparison those highlighted in past meta-analyses as evidence for effects. These results are considered in light of issues related to false positives and negatives in behavioral science more broadly. PMID- 29701598 TI - Severe mental illness and firearm access: Is violence really the danger? AB - In response to a spate of mass shootings, national debate over the root of America's gun violence epidemic has centered on mental illness. Consequently, calls have been made to legislatively restrict firearm access among individuals with mental illness to reduce gun violence. While there is a link between mental illness and suicide, a dearth of empirical evidence exists to inform public policy on the link between firearm access and mental illness. The current study addresses this gap by exploring the nature of firearm-related risk among disordered individuals as compared to others from the same communities. We examined a subsample of the MacArthur Violence Risk Assessment Study, including 255 recently discharged psychiatric patients and 490 census-matched community residents. We conducted binomial logistic regressions to explore the impact of firearm access and patient status on violence and suicidality. In total, 15.3% reported firearm access, 23.5% violence, and 21.5% suicidality. Multivariate analyses revealed that, in the context of firearm access, patients were no more likely to perpetrate violence (OR=0.588; 95% CI=0.196-1.764) but were significantly more likely to report suicidality (OR=4.690; 95% CI=1.147-19.172). These results indicate that firearms constitute a serious risk factor for suicide, not violence, for disordered individuals. Thus, legislative efforts to reduce firearm-related risk among disordered individuals should focus on self harm, not violence. Moreover, claims that mental illness is a principal cause of gun violence may reduce help-seeking among individuals at high risk for suicide. Researchers should devote further attention to addressing these claims empirically. PMID- 29701599 TI - Will-making in Irish nursing homes: Staff perspectives on testamentary capacity and undue influence. AB - Allegations of lack of testamentary capacity or of undue influence are grounds for many disputed wills. Some people who make (or change an existing) will are resident in a nursing home. A substantial proportion of this population have cognitive or communication difficulties or are physically frail, and concerns regarding testamentary capacity or undue influence may be more likely to arise as a result. A questionnaire examining the experiences and views of staff regarding will-making by nursing home residents was posted to the Directors of Nursing of a random sample of 148 of the approximately 600 nursing homes in the Republic of Ireland and 81 responded. Over 10% of respondents reported seeing cases where they felt a resident who lacked capacity was visited by a solicitor or where a resident was placed under undue pressure to make or change a will or both. In most such cases, staff felt they could do little to intervene. In general, responses to the questionnaire suggested staff misunderstanding of the confidential nature of the relationship between a solicitor and a client and that respondents had an exaggerated view of the power and responsibility of doctors and of family members to influence residents' decisions and interactions with solicitors regarding will-making. This study suggests the need for improved Guidelines for staff regarding will-making in residential care including advice on how to proceed where concerns including undue pressure arise. PMID- 29701600 TI - The credibility of testimony from minors allegedly victims of abuse within the Italian legislative framework. AB - The authors aim to analyze the key aspects related to the testimony of children who might have been victims of sexual harassment and abuse. The issue of medico legal psychiatric assessment of minors who claim to have been sexually abused is extremely contentious and widely-debated, not only due to the growing spread of such claims, but also on account of the technical challenges it raises. For these reasons, national as well as European lawmakers have intervened by enacting new legislation, and scientific communities have established new sets of guidelines aimed at improving the overall conditions under which a child is called to testify as well as the process through which depositions are collected and evaluated, so as to ensure that any assessment of the reliability of the testimony is scientifically grounded. The authors also highlight the importance of regulatory measures meant to minimize the risk that the questioning of a child might negatively affect his or her emotional balance by limiting and lessening stressful conditions and anxiety, which may traumatize and irretrievably scar the child. Moreover, they stress the importance of dealing with the social issue of child abuse by strengthening a preventive set of measures. PMID- 29701601 TI - Do state physician health programs encourage referrals that violate the Americans with Disabilities Act? AB - The websites of many physician health programs provide lists describing signs of impairment or indications to refer physician-employees for evaluation and possible treatment. This study aimed (1) to determine how many of these descriptions likely provide physicians' employers with sufficient evidence to legally request mental health examinations under the general regulations of the Americans with Disabilities Act (ADA); and (2) to find out who they described. The authors applied US Equal Employment Opportunity Commission guidance documents and sought expert legal advice to evaluate the descriptions for their consistency with the ADA. They used directed content analysis to review and code these descriptions into categories. Very few, if any, of the 571 descriptions appeared to provide sufficient evidence for employers to request an examination under the ADA. About 14%, however, could refer to physicians attempting to defend themselves, assert their ADA rights, or otherwise complain about the hospital; and 27% either described physicians who complain or else had discriminatory effects in one of several different ways. Leaders within the medical field should ensure that their policies and state laws pertaining to physician impairment comply with and incorporate the language of the ADA. They should also reevaluate the functions of these policies, laws, and physician health programs, and the implications for patient safety, physician wellness, suicide, and other important issues. PMID- 29701602 TI - Bulk and interface quantum states of electrons in multi-layer heterostructures with topological materials. AB - In this article we describe the bulk and interface quantum states of electrons in multi-layer heterostructures in one dimension, consisting of topological insulators (TIs) and topologically trivial materials. We use and extend an effective four-band continuum Hamiltonian by introducing position dependence to the eight material parameters of the Hamiltonian. We are able to demonstrate complete conduction-valence band mixing in the interface states. We find evidence for topological features of bulk states of multi-layer TI heterostructures, as well as demonstrating both complete and incomplete conduction-valence band inversion at different bulk state energies. We show that the linear k z terms in the low-energy Hamiltonian, arising from overlap of p z orbitals between different atomic layers in the case of chalcogenides, control the amount of tunneling from TIs to trivial insulators. Finally, we show that the same linear k z terms in the low-energy Hamiltonian affect the material's ability to form the localised interface state, and we demonstrate that due to this effect the spin and probability density localisation in a thin film of Sb2Te3 is incomplete. We show that changing the parameter that controls the magnitude of the overlap of p z orbitals affects the transport characteristics of the topologically conducting states, with incomplete topological state localisation resulting in increased backscattering. PMID- 29701603 TI - Gray: a ray tracing-based Monte Carlo simulator for PET. AB - Monte Carlo simulation software plays a critical role in PET system design. Performing complex, repeated Monte Carlo simulations can be computationally prohibitive, as even a single simulation can require a large amount of time and a computing cluster to complete. Here we introduce Gray, a Monte Carlo simulation software for PET systems. Gray exploits ray tracing methods used in the computer graphics community to greatly accelerate simulations of PET systems with complex geometries. We demonstrate the implementation of models for positron range, annihilation acolinearity, photoelectric absorption, Compton scatter, and Rayleigh scatter. For validation, we simulate the GATE PET benchmark, and compare energy, distribution of hits, coincidences, and run time. We show a [Formula: see text] speedup using Gray, compared to GATE for the same simulation, while demonstrating nearly identical results. We additionally simulate the Siemens Biograph mCT system with both the NEMA NU-2 scatter phantom and sensitivity phantom. We estimate the total sensitivity within [Formula: see text]% when accounting for differences in peak NECR. We also estimate the peak NECR to be [Formula: see text] kcps, or within [Formula: see text]% of published experimental data. The activity concentration of the peak is also estimated within 1.3%. PMID- 29701604 TI - Functional thiols as repair and doping agents of defective MoS2 monolayers. AB - Recent experimental and theoretical studies indicate that thiols (R-SH) can be used to repair sulfur vacancy defects in MoS2 monolayers (MLs). This density functional theory study investigates how the thiol repair mechanism process can be used to dope MoS2 MLs. Fluorinated thiols as well as amine-containing ones are used to p- and n-dope the MoS2 ML, respectively. It is shown that functional groups are only physisorbed on the repaired MoS2 surface. This explains the reversible doping with fluorinated thiols. PMID- 29701605 TI - Determination of the hydrogen-bond network and the ferrimagnetic structure of a rockbridgeite-type compound, [Formula: see text]. AB - Applying neutron powder diffraction, four unique hydrogen positions were determined in a rockbridgeite-type compound, [Formula: see text] [Formula: see text]. Its honeycomb-like H-bond network running without interruption along the crystallographic [Formula: see text] axis resembles those in alkali sulphatic and arsenatic oxyhydroxides. They provide the so-called dynamically disordered H-bond network over which protons are superconducting in a vehicle mechanism. This is indicated by dramatic increases of dielectric constant and loss factor at room temperature. The relevance of static and dynamic disorder of OH and HOH groups are explained in terms of a high number of structural defects at octahedral chains alternatingly half-occupied by [Formula: see text] cations. The structure is built up by unusual octahedral doublet, triplet, and quartet clusters of aliovalent 3d transition metal cations, predicting complicate magnetic ordering and interaction. The ferrimagnetic structure below the Curie temperature [Formula: see text]-83 K could be determined from the structure analysis with neutron diffraction data at 25 K. PMID- 29701606 TI - Stability of the antiferromagnetic state in the electron doped iridates. AB - Iridates such as Sr2IrO4 are of considerable interest owing to the formation of the Mott insulating state driven by a large spin-orbit coupling. However, in contrast to the expectation from the Nagaoka theorem that a single doped hole or electron destroys the anti-ferromagnetic (AFM) state of the half-filled Hubbard model in the large U limit, the anti-ferromagnetism persists in the doped Iridates for a large dopant concentration beyond half-filling. With a tight binding description of the relevant [Formula: see text] states by the third neighbor (t 1, t 2, t 3, U) Hubbard model on the square lattice, we examine the stability of the AFM state to the formation of a spin spiral state in the strong coupling limit. The third-neighbor interaction t 3 is important for the description of the Fermi surface of the electron doped system. A phase diagram in the parameter space is obtained for the regions of stability of the AFM state. Our results qualitatively explain the robustness of the AFM state in the electron doped iridate (such as Sr2-x La x IrO4), observed in many experiments, where the AFM state continues to be stable until a critical dopant concentration. PMID- 29701607 TI - The flaky porous Fe3O4 with tunable dimensions for enhanced microwave absorption performance in X and C bands. AB - Special electric and magnetic characteristics make Fe3O4 widely applied in the electromagnetic (EM) wave absorption region. However, for pure Fe3O4, it is still a challenge to simultaneously obtain high absorption intensity and broadband absorption at a low thickness, owing to its low dielectric property. As we realized, flake configuration and the porous structure have obviously promote the EM wave absorption property. Because the former can lead to multi-reflection between flakes and the latter is conductive to interface polarization, flaky Fe3O4 with a porous and coarse surface was designed to overcome the deficiency of traditional Fe3O4 particles. The experimental results demonstrate that the flaky configuration is conductive to enhancing the dielectric coefficient and optimizing impedance matching. Moreover, the complex permittivity rises with the aspect ratio of the sheet. Under a suitable dimension, the flaky Fe3O4 could acquire targeted EM wave absorption capacity in the X band (8-12 GHz). In detail, the maximum reflection loss (RL) could reach a strong intensity of -49 dB at 2.05 mm. The effective absorption bandwidth (EAB) with RL below -10 dB is 4.32 (7.52 11.84) GHz, which is almost equivalent to the whole X band (8-12 GHz). Even more exciting, when regulating the thickness between 2.05 and 3.05 mm, the EAB could cover the entire C and X bands (4-12 GHz). This study provides a good reference for the future development of other ferromagnetic materials toward specific microwave bands. PMID- 29701609 TI - Transport of nano-objects in narrow channels: influence of Brownian diffusion, confinement and particle nature. AB - This paper presents experimental results about transport of dilute suspensions of nano-objects in silicon-glass micrometric and sub-micrometric channels. Two kinds of objects are used: solid, rigid latex beads and spherical capsule-shaped, soft polymersomes. They are tracked using fluorescence microscopy. Three aspects are studied: confinement (ratio between particle diameter and channel depth), Brownian diffusion and particle nature. The aim of this work is to understand how these different aspects affect the transport of suspensions in narrow channels and to understand the different mechanisms at play. Concerning the solid beads we observe the appearance of two regimes, one where the experimental mean velocity is close to the expected one and another where this velocity is lower. This is directly related to a competition between confinement, Brownian diffusion and advection. These two regimes are shown to be linked to the inhomogeneity of particles distribution in the channel depth, which we experimentally deduce from velocity distributions. This inhomogeneity appears during the entrance process into the sub-micrometric channels, as for hydrodynamic separation or deterministic lateral displacement. Concerning the nature of the particles we observed a shift of transition towards the second regime likely due to the relationships between shear stress and polymersomes mechanical properties which could reduce the inhomogeneity imposed by the geometry of our device. PMID- 29701608 TI - Quantitative myocardial perfusion from static cardiac and dynamic arterial CT. AB - Quantitative myocardial blood flow (MBF) estimation by dynamic contrast enhanced cardiac computed tomography (CT) requires multi-frame acquisition of contrast transit through the blood pool and myocardium to inform the arterial input and tissue response functions. Both the input and the tissue response functions for the entire myocardium are sampled with each acquisition. However, the long breath holds and frequent sampling can result in significant motion artifacts and relatively high radiation dose. To address these limitations, we propose and evaluate a new static cardiac and dynamic arterial (SCDA) quantitative MBF approach where (1) the input function is well sampled using either prediction from pre-scan timing bolus data or measured from dynamic thin slice 'bolus tracking' acquisitions, and (2) the whole-heart tissue response data is limited to one contrast enhanced CT acquisition. A perfusion model uses the dynamic arterial input function to generate a family of possible myocardial contrast enhancement curves corresponding to a range of MBF values. Combined with the timing of the single whole-heart acquisition, these curves generate a lookup table relating myocardial contrast enhancement to quantitative MBF. We tested the SCDA approach in 28 patients that underwent a full dynamic CT protocol both at rest and vasodilator stress conditions. Using measured input function plus single (enhanced CT only) or plus double (enhanced and contrast free baseline CT's) myocardial acquisitions yielded MBF estimates with root mean square (RMS) error of 1.2 ml/min/g and 0.35 ml/min/g, and radiation dose reductions of 90% and 83%, respectively. The prediction of the input function based on timing bolus data and the static acquisition had an RMS error compared to the measured input function of 26.0% which led to MBF estimation errors greater than threefold higher than using the measured input function. SCDA presents a new, simplified approach for quantitative perfusion imaging with an acquisition strategy offering substantial radiation dose and computational complexity savings over dynamic CT. PMID- 29701610 TI - Two-dimensional dispersion of magnetostatic volume spin waves. AB - Owing to the dipolar (magnetostatic) interaction, long-wavelength spin waves in in-plane magnetized films show an unusual dispersion behavior, which can be mathematically described by the model of [Formula: see text] and [Formula: see text] and refinements thereof. However, solving the two-dimensional dispersion [Formula: see text] requires the evaluation of a set of coupled transcendental equations and one has to rely on numerics. In this work, we present a systematic perturbative analysis of the spin wave model. An expansion in the in-plane wavevector [Formula: see text] allows us to obtain explicit closed-form expressions for the dispersion relation and mode profiles in various asymptotic regimes. Moreover, we derive a very accurate semi-analytical expression for the dispersion relation of the lowest-frequency mode that is straightforward to evaluate. PMID- 29701611 TI - Entropy production and rectification efficiency in colloid transport along a pulsating channel. AB - We study the current rectification of particles moving in a pulsating channel under the influence of an applied force. We have shown the existence of different rectification scenarios in which entropic and energetic effects compete. The effect can be quantified by means of a rectification coefficient that is analyzed in terms of the force, the frequency and the diffusion coefficient. The energetic cost of the motion of the particles expressed in terms of the entropy production depends on the importance of the entropic contribution to the total force. Rectification is more important at low values of the applied force when entropic effects become dominant. In this regime, the entropy production is not invariant under reversal of the applied force. The phenomenon observed could be used to optimize transport in microfluidic devices or in biological channels. PMID- 29701612 TI - Coexisting exchange bias effect and ferroelectricity in geometrically frustrated ZnCr2O4. AB - Concomitant occurrence of exchange bias effect and ferroelectric order is revealed in antiferromagnetic spinel ZnCr2O4. The exchange bias effect is observed below antiferromagnetic Neel temperature (T N) with a reasonable value of exchange bias field ([Formula: see text] Oe at 2 K). Intriguingly, the [Formula: see text] ratio is found unusually high as ~2.2, where H C is the coercivity. This indicates that large H C is not always primary for obtaining large exchange bias effect. Ferroelectric order is observed at T N, where non centrosymmetric magnetic structure with [Formula: see text] space group associated with the magnetoelectric coupling correlates the ferroelectric order, proposing that, ZnCr2O4 is an improper multiferroic material. Rare occurrence of exchange bias effect and ferroelectric order in ZnCr2O4 attracts the community for fundamental interest and draws special attention in designing new materials for possible electric field control of exchange bias effect. PMID- 29701613 TI - Hydrazone linked doxorubicin-PLA prodrug nanoparticles with high drug loading. AB - An optimal drug delivery system should be characterized by biocompatibility, biodegradability, high drug loading and favorable drug release profile. To achieve this goal a hydrazone linked doxorubicin-poly(lactic acid) prodrug (PLA DOX) was synthesized by the functionalization of a short polymer chain produced by ring opening polymerization. The hydrophobic prodrug generated in this way was nanoprecipitated using a block copolymer to form polymeric nanoparticles (NPs) with a quantitative loading efficiency and a high and tunable drug loading. The effects of the concentration of the PLA-DOX prodrug and surfactant were studied by dynamic light scattering showing a range of NP size between 50 and 90 nm and monodispersed size distributions with polydispersity indexes lower then 0.27 up to a maximum DOX concentration of 27% w/w. The release profile of DOX from these NPs, tested at different pH conditions, showed a higher release rate in acidic conditions, consistent with the nature of the hydrazone bond which was used to conjugate the drug to the polymer. In vitro cytotoxicity studies performed on BV2 microglia-like cell line highlighted a specific cytotoxic effect of these NPs suggesting the maintenance of the drug efficacy and a modified release profile upon encapsulation of DOX in the NPs. PMID- 29701614 TI - DNA nanostructure-based fluorescence thermometer with silver nanoclusters. AB - DNA nanostructure-based fluorescence thermometers were fabricated by linking fluorescent silver nanoclusters (AgNCs) and guanine-rich(G-rich)DNA chains via a thermally sensitive DNA stem-loop at terminals 5' and 3'. Variations of temperature alter the distance between the AgNCs and G-rich DNA chain, affecting the interaction between them. As a result, the intensity of fluorescence emission from the AgNCs at 636 nm can be sensitively modulated. It was found that the intensity of such red emission is more temperature sensitive than the equivalent green emission at 543 nm; sensitivity of -3.6%/ degrees C was achieved. Through variation of the melting temperature of the DNA stem-loop, the response temperature range of the thermometers could be readily adjusted. Novel DNA nanostructure-based fluorescence thermometers as described in this work are anticipated to be able to measure the temperature of biological systems at small scales-even a single cell. PMID- 29701615 TI - Simulated Driving Performance, Self-Reported Driving Behaviors, and Mental Health Symptoms in Adolescent Novice Drivers. AB - BACKGROUND: Risky driving behaviors contribute to adolescent injury, disability, and death, yet little is known about how mental health factors are associated with adolescent driving behaviors. OBJECTIVES: The purpose of the research was to determine the association of risky driving behaviors and mental health symptoms in novice adolescent drivers. METHODS: We recruited a convenience sample (n = 60) of adolescents to complete an assessment of driving performance errors in a high fidelity simulator (Simulated Driving Assessment [SDA] Error Score) and a self report measure of risky driving (Behavior of Young Novice Drivers Survey [BYNDS]). Participants also completed a mental health assessment of self-reported symptoms of depression (Center for Epidemiologic Studies-Depression Scale) and attention-deficit/hyperactivity disorder (ADHD; inattention and hyperactivity impulsivity), conduct disorder, and oppositional defiant disorder (Conners-3 self report and parent report). We evaluated the cross-sectional relationships between SDA Error Score, BYNDS, and mental health survey data with descriptive statistics, bivariate correlations, and linear regression. RESULTS: In linear regression models, higher self-reported inattentive ADHD T-scores were associated with higher SDA Error Score (model adjusted R = .20). Higher self-reported T scores of hyperactive-impulsive ADHD and conduct disorder were associated with higher BYNDS total scores (model adjusted R = .32). Parent report measures were not associated with adolescent BYNDS total score or SDA Error Score. DISCUSSION: These data highlight the association of risky driving with adolescent symptoms of inattention, hyperactivity, and conduct disorder. The early stage of independent driving is an important time for addressing the relationship between driving performance and mental health conditions. PMID- 29701616 TI - Identifying and managing depression in patients with coronary artery disease. AB - Coronary artery disease (CAD) is the leading cause of death among adults in the United States. Despite advances in cardiac care, patients who have CAD and a diagnosis of depression have higher rates of morbidity and mortality. This article examines the epidemiology, clinical presentation, screening tools, and treatment recommendations for these patients. PMID- 29701617 TI - Commentary on Bupivacaine as an Adjunct to Lidocaine in Mohs Micrographic Surgery. PMID- 29701618 TI - Evaluating the Therapeutic Success of Keloids Treated With Cryotherapy and Intralesional Corticosteroids Using Noninvasive Objective Measures. AB - BACKGROUND: Intralesional corticosteroid injections combined with cryotherapy are considered a first-line therapy for keloids. However, objective evaluation on its efficacy is widely missing. OBJECTIVE: In this study, the authors evaluated the therapeutic benefits of cryotherapy directly followed by intralesional crystalline triamcinolone acetonide injections using ultrasound and a 3D topographic imaging device. MATERIALS AND METHODS: Fifteen patients with keloids were treated with cryotherapy and intralesional injections of triamcinolone acetonide for a total of 4 times at intervals of 4 weeks. Objective assessment was performed at each visit. RESULTS: After the last treatment, a significant average reduction of scar volume of 34.3% and an average decrease in scar height of 41.3% as determined by 3D imaging was observed compared with baseline. Ultrasound revealed an average reduction of scar height of 31.7% and an average decrease in tissue penetration depth of 37.8% when compared with baseline measurements. CONCLUSION: Objective measurements of relevant keloid characteristics as height, volume, and penetration depth help in quantifying the therapeutic effect. The observed results confirm that intralesional injections of crystalline triamcinolone acetonide combined with cryotherapy represent a powerful approach to reduce scar height and volume significantly. PMID- 29701619 TI - Treatment of Ingrowing Toenails With Phenol 88% or Trichloroacetic Acid 100%: A Comparative, Prospective, Randomized, Double-Blind Study. AB - BACKGROUND: Phenol is the gold standard for chemical matricectomy in ingrowing toenail. Recently, trichloroacetic acid (TCA) was used as cauterant. Both agents have high success rates but a postoperative healing time claimed to be faster for TCA rather than phenol. OBJECTIVE: Comparing the efficacy, the postoperative oozing time, the inflammatory reaction, and the postoperative pain. MATERIALS AND METHODS: Comparative, prospective, randomized, double-blind study. Eighty-four patients with 96 ingrowing toenails were randomized in 2 groups. Forty-six ingrowing toenails were treated with phenol 88% and 50 with TCA 100% within a 4 month period. Patients were observed 4 times for the presence of oozing and for the degree of inflammation. Patients assessed also oozing and pain on a scale basis during 34 days. RESULTS: Oozing was observed to be less with phenol treatment, as from the second week. Inflammation was also significantly inferior in the phenol group at Week 4. Patients evaluated the incidence of pain below 2/10 for both cauterants, while oozing was higher with TCA during 34 days. The overall success rates of both groups were similar with 100%. CONCLUSION: Phenol and TCA are both effective but TCA does not offer any advantage in terms of postoperative morbidity compared with phenol. PMID- 29701620 TI - Use of Nitrous Oxide in Dermatology: A Systematic Review. AB - BACKGROUND: Many dermatologic procedures are painful and can be distressing to patients. OBJECTIVE: To determine whether nitrous oxide has been used in dermatology and whether literature supports its use in terms of providing analgesia and anxiety associated with dermatologic procedures. METHODS: A search of PubMed and Cochrane databases was conducted through July 15, 2016, to identify studies involving nitrous oxide use in dermatology. RESULTS: Eight studies were identified and reviewed. The use of nitrous oxide/oxygen mixture resulted in a significant reduction in pain when used for photodynamic therapy, botulinum toxin therapy for hyperhidrosis of both the palms and axilla, aesthetic procedures involving various laser procedures, and in the treatment of bed sores and leg ulcers. However, pain scores were higher when nitrous oxide/oxygen was used in the debridement of chronic ulcers when compared with the use of topical anesthesia. In addition, nitrous oxide has been reported effective at reducing pain in hair transplants, dermabrasion, excision and repairs, and pediatric procedures. CONCLUSION: Current literature provides some evidence that nitrous oxide, used alone or as adjunct anesthesia, is effective at providing analgesia for many dermatologic procedures. Nitrous oxide has many potential applications in dermatology; however, further evidence from randomized controlled trials is needed. PMID- 29701621 TI - Safety and Effectiveness of the Hyaluronic Acid Dermal Filler VYC-17.5L for Nasolabial Folds: Results of a Randomized, Controlled Study. AB - BACKGROUND: Juvederm Vollure XC (VYC-17.5L) belongs to a family of nonanimal hyaluronic acid (HA) gels based on the Vycross technology platform. OBJECTIVE: To evaluate the safety and effectiveness of VYC-17.5L for correction of moderate to severe nasolabial folds (NLFs) compared with a control HA dermal filler. METHODS: In this double-blind study, 123 adults with 2 moderate or severe NLFs as measured on the 5-point photonumeric NLF severity scale (NLFSS) were randomized to VYC 17.5L in 1 NLF and control in the contralateral NLF. The coprimary effectiveness end points at Month 6 were difference in improvement in mean NLFSS score for VYC 17.5L versus control and NLFSS responder rate (>=1-point improvement) for VYC 17.5L. RESULTS: The coprimary effectiveness end points were met. NLFSS scores improved by 1.4 with VYC-17.5L and by 1.3 with control; NLFSS responder rate with VYC-17.5L was 93.2%. More than three-quarters of subjects (82%) treated with VYC 17.5L were very satisfied at Month 6. Investigators reported that VYC-17.5L was smoother and more natural looking and easier to inject and mold than control. VYC 17.5L resulted in significantly fewer severe injection site responses than control. CONCLUSION: VYC-17.5L was safe and effective for correcting moderate to severe NLFs, with results lasting through 6 months in 93% of subjects. PMID- 29701622 TI - Platelet-Rich Plasma Versus Tretinoin in Treatment of Striae Distensae: A Comparative Study. AB - BACKGROUND: Striae distensae (SD) are dermal scars associated with atrophy of the epidermis. OBJECTIVE: To evaluate the effect and safety of intralesional injection of platelet-rich plasma (PRP) versus topical tretinoin 0.05% in treatment of SD. METHODS: Thirty patients (27 females and 3 males) had bilateral striae distensae were enrolled in this study. In every patient, half of the selected striae were treated with PRP intralesional injection. The other half was treated by topical tretinoin. Skin biopsies were taken from both sides before and after the treatment. Digital photographs were taken at the baseline and at the end of follow-up period. Clinical improvement was evaluated by 2 blind dermatologists in addition to the patient's satisfaction rating. RESULTS: There was statistically significant improvement in the SD treated with PRP and topical tretinoin cream. The improvement was more in the SD treated with PRP injections (p = .015). Patient's satisfaction showed that the improvement was more in the PRP-treated side (p = .003). Collagen and elastic fibers in the dermis were increased in all biopsies after treatment. CONCLUSION: PRP injection and topical tretinoin are safe for the treatment of SD, but PRP is more effective and it gives better therapeutic response than tretinoin. PMID- 29701623 TI - Histologic and Clinical Changes in Vulvovaginal Tissue After Treatment With a Transcutaneous Temperature-Controlled Radiofrequency Device. AB - BACKGROUND: Although transcutaneous temperature-controlled radiofrequency (TTCRF) may effectively treat vulvovaginal laxity (VVL), atrophic vaginitis (AV), orgasmic dysfunction (OD), and stress urinary incontinence (SUI), there is a lack of histopathologic evidence to validate its use. OBJECTIVE: Evaluate clinical and histological changes induced by vulvovaginal TTCRF. MATERIALS AND METHODS: This was a prospective, nonrandomized trial. Ten female subjects with mild-to-moderate VVL, with or without AV, OD, and/or SUI underwent 3 TTCRFs at 4-week intervals. Five subjects underwent pre- and post-treatment biopsies of the labia majora and vaginal canal for histology. Assessments were performed at baseline and Days 10, 30, 60, and 120. RESULTS: Investigator-rated VVL improved significantly from baseline to Day 10, with improvement maintained through Day 120 (p = .001 and .001, respectively). Sexual satisfaction improved significantly by Day 60 (p = .001). Improvement in AV reached significance at Day 120 (p = .048). Although OD and SUI improved steadily, the difference in improvement did not reach statistical significance. Histology revealed that post-treatment increases in collagen, elastin, vascularity, and small nerve fibers. CONCLUSION: Transcutaneous temperature-controlled RF resulted in significant improvements in AV, VVL, and sexual satisfaction with milder improvements in OD and SUI. Post treatment histology demonstrated neocollagenesis, neoelastogenesis, neoangiogenesis, and the first reported finding of TTCRF-related neurogenesis. PMID- 29701624 TI - Efficacy and Safety of a Novel Method of Insulated Intralesional Radiofrequency Ablation for Deep Dermal and Subcutaneous Lesions: A 3-Year Institutional Experience. AB - BACKGROUND: Although insulated intralesional radiofrequency ablation (IL-RFA) is being increasingly used in other specialties, not much information on its safety and efficacy in dermatology is available. OBJECTIVE: To describe our experience with insulated IL-RFA for various dermatological conditions. METHODS: This is a retrospective review of the patients who underwent IL-RFA in the past 3 years. Our technique involved creating a small window in the proximal end of plastic sheath of an intravenous cannula using a surgical blade, and then touching the RF probe to the cannula through the window to deliver the electric current. Information regarding diagnosis, number of sessions, adverse effects, and follow up was recorded. Clinical improvement was assessed on a visual analog scale by the patient and 2 independent observers. RESULTS: Data on 19 patients with lymphangioma circumscriptum (n = 9), venous or capillary-venous malformation (n = 4), angiolymphoid hyperplasia with eosinophilia (n = 3), arteriovenous malformation, hidradenitis suppurativa, and hypertrophic scar (n = 1 each) was available. The mean number of IL-RFA sessions was 2.26 +/- 1.61. The mean patient and physician global assessment scores were 7.6 +/- 2.22 and 7.3 +/- 2.42, respectively. Adverse effects were seen in 9 (47.4%) patients. All patients, except 1, had sustained improvement in the mean follow-up period of 11.4 +/- 11.6 months. CONCLUSION: Insulated IL-RFA seems to be safe and effective in selectively targeting deep-seated cutaneous lesions. PMID- 29701625 TI - Mortality in a cohort of asbestos-exposed workers undergoing health surveillance. AB - BACKGROUND: The coastal area of Friuli Venezia Giulia (FVG) region, north-eastern Italy, was characterized by work activities in which asbestos was used until the early 1990s, particularly in shipbuilding. A public health surveillance program (PHSP) for asbestos-exposed workers was established, although limited evidence exists about the efficacy of such programs in reducing disease occurrence and mortality. OBJECTIVES: To compare mortality in a cohort of 2,488 men occupationally exposed to asbestos, enrolled in a PHSP in FVG between the early 1990s and 2008, with that of the general population of FVG and Italy. METHODS: Standardized Mortality Ratios (SMR), with 95% Confidence Interval (95% CI), for all causes, all cancers, lung (LC) and pleural cancer (PC) were estimated in the cohort and in subgroups of workers with the first hire in shipbuilding that caused asbestos exposure (<1974, 1974-1984, 1985-1994). RESULTS: A strong excess in mortality for PC with reference to FVG (SMR=6.87, 95% CI 4.45-10.17) and Italian population (SMR=13.95, 95% CI 9.02-20.64) was observed. For LC, the FVG based SMR was 1.49 (95% CI 1.17-1.89) and the Italy-based 1.43 (95% CI 1.12 1.81). Mortality among workers with the first hire in shipbuilding before 1974 was high for PC (FVG-based SMR=8.98, 95% CI 5.56-13.75; Italy-based SMR=18.41, 95% CI 11.40-28.17) and for LC (FVG-based SMR =1.60, 95% CI 1.18-2.11; Italy based SMR=1.54, 95% CI 1.14-2.03). Further, for LC between 1974 and 1984, the FVG based SMR was 2.45 (95% CI 1.06-4.82), and the Italy-based SMR was 2.33 (95% CI 1.01-4.60). CONCLUSIONS: This cohort experienced an excess mortality for pleural and lung cancer, compared with regional and national populations. For lung cancer, the excess was stronger in workers with the first hire in shipbuilding before 1985, suggesting a key role of asbestos exposure. PMID- 29701626 TI - Moral Distress (MD) and burnout in mental health nurses: a multicenter survey. AB - INTRODUCTION: Moral Distress (MD) is a common experience among nurses and if it is not recognised and treated, it may lead to serious consequences on nurses' health and quality of care. MD has been studied in several healthcare contexts. However, there are only few studies on MD in psychiatry and in Italy there are no data in this field. Objective: To assess the presence of MD among mental health nurses in Italy and verify whether there is a relationship between MD and burnout. METHODS: We conducted a multicentre survey among nurses of Mental Health services of four hospitals in Milan. The MD Scale for Psychiatric NursesItalianrevised (MDS-PItarev) and the Maslach Burnout Inventory (MBI) were used for data collection. Factor analysis and calculation of content validity index (CVI) and Cronbach's alpha were performed on the Italian version of the MDS PIta. Three items of the old version of the scale were removed, because judged not relevant in the Italian context. The revised scale maintained excellent CVI (0.89) and Cronbach's alpha (0.93). RESULTS: Of 285 questionnaires distributed, 228 (80%) were returned. The median of MD was 2 (scale range 0-6); MD is correlated with two burnout dimensions: emotional exhaustion (rho(rho)=0.28, p<0,001) and depersonalization (rho=0.20, p<0,001). CONCLUSIONS: This is the first study about MD among psychiatric nurses in Italy. We found a medium-low level of MD among nurses who participated in the survey. We also found a modest but significant correlation between MD and two dimensions of MBI. Further studies are needed to confirm these results. PMID- 29701627 TI - [Effectiveness of Health and Safety at Work Services (PSAL) in reducing occupational injuries in Lombardy Region]. AB - INTRODUCTION: In recent years, Italy has seen a reduction in workplace accidents due to several factors, including the controls carried out by the Health and Safety at Work Services (PSAL) of the Local Health Units (ATS). OBJECTIVE: To verify the contribution of PSAL Services to injury reduction. In particular, to identify the existence of a difference between incidence rates of accidents in companies before and after inspections and possible variations in rates between inspected and non-inspected companies. METHODS: We analyzed data of the activities carried out by the PSAL Services of the Lombardy Region in the system I.M.Pre.S@ (Computerization and Health Prevention Monitoring) in the period 2010 2015, together with data from the Regional Accident Database of the National Institute for Insurance against Accidents at Work (INAIL). The "difference in difference" (DID) method was used to evaluate the different effect on inspected and non-inspected industries. RESULTS: Between the pre- and post-vigilance periods, inspected companies showed a greater reduction either of total injury rates (DID=-2.7 per 1000 worker-years; 90% confidence interval (CI): -4.1; -1.3) or of severe injury rates (DID=-1.1; 90% CI: -1.7; -0.5). These effects were visible in the majority of ATS and occupational sectors. CONCLUSIONS: This study, made possible by a valid and efficient regional data tracking system, has shown the positive effect of the PSAL prevention actions on the frequency of both total and severe injuries. PMID- 29701628 TI - Seroprevalence survey of arboviruses in workers from Tuscany, Italy. AB - BACKGROUND: Arthropod-borne viruses (Arbovirus) play an important role among emerging and re-emerging infectious diseases and in the spreading of infections in new geographic areas. Although some arboviral infections may be asymptomatic or mild flu-like illnesses, many occur as severe forms of meningitis and meningoencephalitis. OBJECTIVES: To assess whether arboviral infections may be associated with occupational risk, in a population of agricultural and forestry workers potentially at high risk for arthropods bite and sting. METHODS: A seroprevalence survey for arboviruses belonging to the genera Flaviviruses (West Nile, Tick-borne encephalitis and Usutu viruses) and Phlebovirus (Toscana virus) was carried out in Grosseto province (Tuscany, Italy). One hundred and one serum samples of occupationally exposed workers and 100 serum samples of not exposed workers were analyzed using commercial and home-made serological assays. Serological data were obtained in 2012 and analyzed according to demographic characteristics, recollection of insect-bites, and time spent in outdoor activities. RESULTS: A total seropositivity of 10% (21/201) was observed for Toscana virus. No difference in seroprevalence for Toscana virus was observed among the exposed (10/101) versus the not exposed (11/100) workers. No seropositivity for West Nile, Usutu and Tick-borne encephalitis viruses was detected. CONCLUSIONS: Although circulation of Toscana virus is recognized in the study area, our results did not reveal a higher risk for workers exposed to arthropods bite and sting. Health surveillance programs remain useful to monitor the potential emergence of arboviruses. PMID- 29701629 TI - [The evaluation of organizational well-being in the public sector: an integration of the ANAC questionnaire]. AB - BACKGROUND: In Italy, the work-related stress and organizational well-being evaluation is subject to specific norms and regulations. The Italian National Anti-Corruption Authority (Autorita Nazionale Anticorruzione - ANAC) has developed a questionnaire to assess the organizational well-being of the employees in Public Administration Institutions. OBJECTIVES: The study aims to analyse, according to the Job Demands-Resources Theory, the relationship between some job demands (workload, discrimination) and job resources (supervisors and colleagues support, job autonomy, fairness, career opportunities, membership), and some outcomes (work-related stress, emotional exhaustion, job satisfaction). METHODS: The research involved a public administration and was conducted through a self-report questionnaire (N=414, 60% of the employees). The ANAC questionnaire was integrated with measures from national and international literature on the topic of well-being and stress at work. RESULTS: Multiple regression analyses highlighted the relationship between outcomes, job demands and resources. Work related stress showed a positive relation with demands (work load beta coefficient=0.22; perceived discrimination beta=0.14) and a negative one with some resources (supervisors' support beta=-0.21 and membership beta=-0.11). Emotional exhaustion had a negative relationship with some job resources, specifically career opportunities (beta=-0.14), autonomy (beta=-0.21) and membership (beta=-0.25). Job satisfaction showed a positive relationship with all job resources considered. CONCLUSIONS: The study seeks to integrate the assessment of well-being and work-related stress thus highlighting the importance of linking the different outcomes with job demands and resources. The results identify possible practices to promote well-being in the organization. PMID- 29701630 TI - Assessing and managing the shift work disorder in healthcare workers. AB - BACKGROUND: Shift work disorder (SWD) is a major concern for both healthcare workers (HCWs) employed in hospital wards and healthcare organizations. The consequences of SWD may lead to increased service costs and lower standards of care. OBJECTIVES: To identify and evaluate the latest developments in assessing and managing the occupational risk of SWD in shift-HCWs through a search of the literature published in the last five years. METHODS: We performed a search of the literature starting from June 2012, using MEDLINE/Pubmed. The articles were reviewed and categorized into one or more of the following categories based on their subject matter: Risk assessment, Risk management, Occurrence rates. RESULTS: A total of 25 publications matched the inclusion criteria. The topics discussed, in order of frequency (from the highest to the lowest), were: "Risk Assessment" (84%), "Occurrence Rates" (64%) and "Risk Management" (48%). Number of nights worked per year, long night-time working hours, frequent missing of nap opportunities during night-shift, quick returns and unhealthy workplace were found as organizational determinants of SWD that should be prioritized in the risk assessment of shift work in the healthcare sector. CONCLUSIONS: Organizational interventions targeted on both healthy shift-work scheduling and improvement of the workplace safety are proposed to moderate the occurrence of SWD and, consequently, to ensure HCWs' wellness and suitable standards of patient care. Further studies aimed to investigate the effectiveness of such interventions in minimizing SWD occurrence are needed. PMID- 29701631 TI - Special Issue "H. pylori Virulence Factors in the Induction of Gastric Cancer". AB - Twenty-five years ago, Helicobacter pylori was identified as the causative agent of gastric disorders,ranging from acute inflammation [...]. PMID- 29701632 TI - Household Food Insecurity as a Predictor of Stunted Children and Overweight/Obese Mothers (SCOWT) in Urban Indonesia. AB - (1) Background: The double burden of malnutrition has been increasing in countries experiencing the nutrition transition. This study aimed to determine the relationship between household food insecurity and the double burden of malnutrition, defined as within-household stunted child and an overweight/obese mother (SCOWT). (2) Methods: A cross-sectional survey was conducted in the urban city of Surabaya, Indonesia in April and May 2015. (3) Results: The prevalence of child stunting in urban Surabaya was 36.4%, maternal overweight/obesity was 70.2%, and SCOWT was 24.7%. Although many households were food secure (42%), there were high proportions of mild (22.9%), moderate (15.3%) and severe (19.7%) food insecurity. In a multivariate logistic regression, the household food insecurity access scale (HFIAS) category significantly correlated with child stunting and SCOWT. Compared to food secure households, mildly food insecure households had the greatest odds of SCOWT (adjusted odds ratio (aOR) = 2.789; 95% confidence interval (CI) = 1.540-5.083), followed by moderately food insecure (aOR = 2.530; 95% CI = 1.286-4.980) and severely food insecure households (aOR = 2.045; 95% CI = 1.087-3.848). (4) Conclusions: These results support the hypothesis that the double burden of malnutrition is related to food insecurity, and the HFIAS category is a predictor of SCOWT. PMID- 29701633 TI - Effector-Immunity Pairs Provide the T6SS Nanomachine its Offensive and Defensive Capabilities. AB - Type VI protein secretion systems (T6SSs) are specialized transport apparatus which can target both eukaryotic and prokaryotic cells and play key roles in host pathogen-microbiota interactions. Therefore, T6SSs have attracted much attention as a research topic during the past ten years. In this review, we particularly summarized the T6SS antibacterial function, which involves an interesting offensive and defensive mechanism of the effector-immunity (E-I) pairs. The three main categories of effectors that target the cell wall, membranes, and nucleic acids during bacterial interaction, along with their corresponding immunity proteins are presented. We also discuss structural analyses of several effectors and E-I pairs, which explain the offensive and defensive mechanisms underpinning T6SS function during bacterial competition for niche-space, as well as the bioinformatics, proteomics, and protein-protein interaction (PPI) methods used to identify and characterize T6SS mediated E-I pairs. Additionally, we described PPI methods for verifying E-I pairs. PMID- 29701634 TI - Hemiptera Mitochondrial Control Region: New Sights into the Structural Organization, Phylogenetic Utility, and Roles of Tandem Repetitions of the Noncoding Segment. AB - As a major noncoding fragment, the control region (CR) of mtDNA is responsible for the initiation of mitogenome transcription and replication. Several structural features of CR sequences have been reported in many insects. However, comprehensive analyses on the structural organization and phylogenetic utility, as well as the role of tandem replications (TRs) on length variation, high A+T content, and shift of base skew of CR sequences are poorly investigated in hemipteran insects. In this study, we conducted a series of comparative analyses, using 116 samples covering all 11 infraorders of the five currently recognized monophyletic groups in the Hemiptera. Several structural elements (mononucleotide stretches containing conserved sequence blocks (CSBs), TRs, and GA-rich region) were identified in the mitochondrial control region in hemipteran insects, without showing a consistent location. The presence and absence of certain specific structural elements in CR sequences show the various structural organizations of that segment among the five monophyletic groups, which indicates the diversification of the control region’s structural organization in Hemiptera. Among the many groups within Hemiptera, eight monophyletic groups and three consistent phylogenetic trees were recovered, using CSBs datasets by maximum likelihood and Bayesian methods, which suggests the possible utility of CR sequences for phylogenetic reconstruction in certain groups of Hemiptera. Statistical analyses showed that TRs may contribute to the length variation, high AT content, and the shift of base skewing of CR sequences toward high AT content in the Hemiptera. Our findings enrich the knowledge of structural organization, phylogenetic utility, and roles of tandem replication of hemipteran CR, and provide a possible framework for mitochondrial control region analyses in hemimetabolous insects. PMID- 29701635 TI - The Design and Optimization of Plasmonic Crystals for Surface Enhanced Raman Spectroscopy Using the Finite Difference Time Domain Method. AB - We present computational studies of quasi three-dimensional nanowell (NW) and nanopost (NP) plasmonic crystals for applications in surface enhanced Raman spectroscopy (SERS). The NW and NP plasmonic crystals are metal coated arrays of cylindrical voids or posts, respectively, in a dielectric substrate characterized by a well/post diameter (D), relief depth (R D), periodicity (P), and metal thickness (M T). Each plasmonic crystal is modeled using the three-dimensional finite-difference time-domain (FDTD) method with periodic boundary conditions in the x- and y-directions applied to a computational unit cell to simulate the effect of a periodic array. Relative SERS responses are calculated from time averaged electric field intensity enhancements at λ exc and λ scat or at λ mid via G SERS 4 = g 2 ( λ exc ) × g 2 ( λ scat ) or G mid 4 = g 4 ( λ mid ) , respectively, where g 2 = | E | 2 / | E 0 | 2 . Comparisons of G SERS 4 and G mid 4 are made to previously reported experimental SERS measurements for NW and NP geometries. Optimized NW and NP configurations based on variations of D, P, R D, and M T using G SERS 4 are presented, with 6× and 2× predicted increases in SERS, respectively. A novel plasmonic crystal based on square NP geometries are considered with an additional 3× increase over the optimized cylindrical NP geometry. NW geometries with imbedded spherical gold nanoparticles are considered, with 10× to 10 3 × increases in SERS responses over the NW geometry alone. The results promote the use of FDTD as a viable in silico route to the design and optimization of SERS active devices. PMID- 29701636 TI - Dynamic Geochemistry of Tetraethyl Lead Dust during the 20th Century: Getting the Lead In, Out, and Translational Beyond. AB - This commentary provides a brief overview of policy decisions that permitted getting tetraethyl lead (TEL) into petrol; global geochemical lead-dust deposition evidence; 1975 catalytic converter requirements; concern about habitability of cities; a personal perspective on legacy lead research that accelerated getting TEL out of petrol; and translational beyond, including New Orleans pre- vs. post-Hurricane Katrina observations about legacy lead interventions that effectively improve urban children’s health outcomes. PMID- 29701637 TI - Ethics of End of Life Decisions in Pediatrics: A Narrative Review of the Roles of Caregivers, Shared Decision-Making, and Patient Centered Values. AB - Background: This manuscript reviews unique aspects of end of life decision-making in pediatrics. Methods: A narrative literature review of pediatric end of life issues was performed in the English language. Results: While a paternalistic approach is typically applied to children with life-limiting medical prognoses, the cognitive, language, and physical variability in this patient population is wide and worthy of review. In end of life discussions in pediatrics, the consideration of a child’s input is often not reviewed in depth, although a shared decision-making model is ideal for use, even for children with presumed limitations due to age. This narrative review of end of life decision-making in pediatric care explores nomenclature, the introduction of the concept of death, relevant historical studies, limitations to the shared decision-making model, the current state of end of life autonomy in pediatrics, and future directions and needs. Although progress is being made toward a more uniform and standardized approach to care, few non-institutional protocols exist. Complicating factors in the lack of guidelines include the unique facets of pediatric end of life care, including physical age, paternalism, the cognitive and language capacity of patients, subconscious influencers of parents, and normative values of death in pediatrics. Conclusions: Although there have been strides in end of life decision making in pediatrics, further investigation and research is needed in this field. PMID- 29701638 TI - Rapid Determination of Chlorophyll and Pheophytin in Green Tea Using Fourier Transform Infrared Spectroscopy. AB - The chlorophyll, pheophytin, and their proportions are critical factors to evaluate the sensory quality of green tea. This research aims to establish an effective method to determine the quantification of chlorophyll and pheophytin in green tea, based on Fourier transform infrared (FT-IR) spectroscopy. First, five brands of tea were collected for spectral acquisition, and the chlorophyll and pheophytin were measured using the reference method. Then, a relation between these two pigments and FT-IR spectroscopy were developed based on chemometrics. Additionally, the characteristic IR wavenumbers of these pigments were extracted and proved to be effective for a quantitative determination. Successively, non linear models were also built based on these characteristic wavenumbers, obtaining coefficients of determination of 0.87, 0.80, 0.85 and 0.89; and relative predictive deviations of 2.77, 2.62, 2.26 and 3.07 for the four pigments, respectively. These results demonstrate the feasibility of FT-IR spectroscopy for the determination of chlorophyll and pheophytin. PMID- 29701641 TI - A Distance Bounding Protocol for Location-Cloaked Applications. AB - Location-based services (LBSs) assume that users are willing to release trustworthy and useful details about their whereabouts. However, many location privacy concerns have arisen. For location privacy protection, several algorithms build a cloaking region to hide a user’s location. However, many applications may not operate adequately on cloaked locations. For example, a traditional distance bounding protocol (DBP)—which is run by two nodes called the prover and the verifier—may conclude an untight and useless distance between these two entities. An LBS (verifier) may use this distance as a metric of usefulness and trustworthiness of the location claimed by the user (prover). However, we show that if a tight distance is desired, traditional DBP can refine a user’s cloaked location and compromise its location privacy. To find a proper balance, we propose a location-privacy-aware DBP protocol. Our solution consists of adding some small delays before submitting any user’s response. We show that several issues arise when a certain delay is chosen, and we propose some solutions. The effectiveness of our techniques in balancing location refinement and utility is demonstrated through simulation. PMID- 29701640 TI - Wearable Sensors and the Assessment of Frailty among Vulnerable Older Adults: An Observational Cohort Study. AB - Background: The geriatric syndrome of frailty is one of the greatest challenges facing the U.S. aging population. Frailty in older adults is associated with higher adverse outcomes, such as mortality and hospitalization. Identifying precise early indicators of pre-frailty and measures of specific frailty components are of key importance to enable targeted interventions and remediation. We hypothesize that sensor-derived parameters, measured by a pendant accelerometer device in the home setting, are sensitive to identifying pre frailty. Methods: Using the Fried frailty phenotype criteria, 153 community dwelling, ambulatory older adults were classified as pre-frail (51%), frail (22%), or non-frail (27%). A pendant sensor was used to monitor the at home physical activity, using a chest acceleration over 48 h. An algorithm was developed to quantify physical activity pattern (PAP), physical activity behavior (PAB), and sleep quality parameters. Statistically significant parameters were selected to discriminate the pre-frail from frail and non-frail adults. Results: The stepping parameters, walking parameters, PAB parameters (sedentary and moderate-to-vigorous activity), and the combined parameters reached and area under the curve of 0.87, 0.85, 0.85, and 0.88, respectively, for identifying pre frail adults. No sleep parameters discriminated the pre-frail from the rest of the adults. Conclusions: This study demonstrates that a pendant sensor can identify pre-frailty via daily home monitoring. These findings may open new opportunities in order to remotely measure and track frailty via telehealth technologies. PMID- 29701639 TI - Energy Deficit Required for Rapid Weight Loss in Elite Collegiate Wrestlers. AB - To determine energy density for rapid weight loss (RWL) of weight-classified sports, eight male elite wrestlers were instructed to lose 6% of body mass (BM) within 53 h. Energy deficit during the RWL was calculated by subtracting total energy expenditure (TEE) determined using the doubly labeled water method (DLW) from energy intake (EI) assessed with diet records. It was also estimated from body composition change estimated with the four-component model (4C) and other conventional methods. BM decreased significantly by 4.7 ± 0.5 kg (6.4 ± 0.5%). Total body water loss was the major component of the BM loss (71.0 ± 7.6%). TEE was 9446 ± 1422 kcal, and EI was 2366 ± 1184 kcal during the RWL of 53-h; therefore, the energy deficit was 7080 ± 1525 kcal. Thus, energy density was 1507 ± 279 kcal/kg ?BM during the RWL, comparable with values obtained using the 4C, three-component model, dual energy X-ray absorptiometry, and stable isotope dilution. Energy density for RWL of wrestlers is lower than that commonly used (7400 or 7700 kcal/kg ΔBM). Although RWL is not recommended, we propose that commonly practiced extreme energy restriction such as 7400 or 7700 kcal/kg ΔBM during RWL appears to be meaningless. PMID- 29701642 TI - Characterization of NS5A and NS5B Resistance-Associated Substitutions from Genotype 1 Hepatitis C Virus Infected Patients in a Portuguese Cohort. AB - This study is focused on the prevalent NS5 coding region resistance-associated substitutions (RASs) in DAA-naive genotype (GT)1 HCV-infected patients and their potential impact on success rates. Plasma RNA from 81 GT1 HCV-infected patients was extracted prior to an in-house nested RT-PCR of the NS5 coding region, which is followed by Sanger population sequencing. NS5A RASs were present in 28.4% (23/81) of all GT1-infected patients with 9.9% (8/81) having the Y93C/H mutation. NS5B RASs showed a prevalence of 14.8% (12/81) and were only detected in GT1b. Overall 38.3% (31/81) of all GT1 HCV-infected patients presented baseline RASs. The obtained data supports the usefulness of resistance testing prior to treatment since a statistically significant association was found between treatment failure and the baseline presence of specific NS5 RASs known as Y93C/H (p = 0.04). PMID- 29701643 TI - Highly Stable and Flexible Pressure Sensors with Modified Multi-Walled Carbon Nanotube/Polymer Composites for Human Monitoring. AB - A facile method for preparing an easy processing, repeatable and flexible pressure sensor was presented via the synthesis of modified multi-walled carbon nanotubes (m-MWNTs) and polyurethane (PU) films. The surface modification of multi-walled carbon nanotubes (MWNTs) simultaneously used a silane coupling agent (KH550) and sodium dodecyl benzene sulfonate (SDBS) to improve the dispersibility and compatibility of the MWNTs in a polymer matrix. The electrical property and piezoresistive behavior of the m-MWNT/PU composites were compared with raw multi walled carbon nanotube (raw MWNT)/PU composites. Under linear uniaxial pressure, the m-MWNT/PU composite exhibited 4.282%kPa−1 sensitivity within the pressure of 1 kPa. The nonlinear error, hysteresis error and repeatability error of the piezoresistivity of m-MWNT/PU decreased 9%, 16.72% and 54.95% relative to raw MWNT/PU respectively. Therefore, the piezoresistive response of m-MWNT/PU had better stability than that of raw MWNT/PU composites. The m-MWNT/PU sensors could be utilized in wearable devices for body movement detection, monitoring of respiration and pressure detection in garments. PMID- 29701644 TI - Associations between Urban Sprawl and Life Expectancy in the United States. AB - In recent years, the United States has had a relatively poor performance with respect to life expectancy compared to the other developed nations. Urban sprawl is one of the potential causes of the high rate of mortality in the United States. This study investigated cross-sectional associations between sprawl and life expectancy for metropolitan counties in the United States in 2010. In this study, the measure of life expectancy in 2010 came from a recently released dataset of life expectancies by county. This study modeled average life expectancy with a structural equation model that included five mediators: annual vehicle miles traveled (VMT) per household, average body mass index, crime rate, and air quality index as mediators of sprawl, as well as percentage of smokers as a mediator of socioeconomic status. After controlling for sociodemographic characteristics, this study found that life expectancy was significantly higher in compact counties than in sprawling counties. Compactness affects mortality directly, but the causal mechanism is unclear. For example, it may be that sprawling areas have higher traffic speeds and longer emergency response times, lower quality and less accessible health care facilities, or less availability of healthy foods. Compactness affects mortality indirectly through vehicle miles traveled, which is a contributor to traffic fatalities, and through body mass index, which is a contributor to many chronic diseases. This study identified significant direct and indirect associations between urban sprawl and life expectancy. These findings support further research and practice aimed at identifying and implementing changes to urban planning designed to support health and healthy behaviors. PMID- 29701646 TI - The Sheltering of Unwanted Cattle, Experiences in India and Implications for Cattle Industries Elsewhere. AB - Reverence for the cow has been a centerpiece of Hindu culture, the roots of which can be traced back to the Indus Valley Civilization around 3000 BCE. Historical and anthropological literature demonstrates how over the millennia the animal’s status as a religious symbol steadily increased and the concept of its sanctity grew in complexity, becoming deeply entrenched and assuming a core identity of the religion. The cow has also been used as a symbol of political opposition to external influences and invading powers. Nowhere else in the world has an animal maintained such divine significance into modern day. This literature review explores the interplay of complex cultural, religious, social and political factors that led to the phenomenon of the sacred cow, a ban on its slaughter and the advent of the modern gaushala. The review also discusses the moral implications of preservation of animal life past their commercial use, the impact on their welfare and need for objectively assessing whether there is a place for such strategies in other animal industries worldwide. PMID- 29701645 TI - Effects of 200 Gy 60Co-gamma Radiation on the Regulation of Antioxidant Enzymes, Hsp70 Genes, and Serum Molecules of Plutella xylostella (Linnaeus). AB - The diamondback moth, Plutella xylostella (Linnaeus), is one of the notorious pests causing substantial loses to many cruciferous vegetables across the nations. The effects of 60Co-γ radiation on physiology of P. xylostella were investigated and the results displayed that 200 Gy irradiation significantly alters the antioxidant enzyme regulation in six-day-old male pupae of P. xylostella. First, in our research, we detected Oxidase system and stress response mechanism of irradiated pupae, the results displayed that 200 Gy irradiation significantly alters the antioxidant enzyme regulation in six-day-old male pupae of P. xylostella. The levels of superoxide dismutase (SOD) and catalase (CAT) were increased significantly in contrast the level of peroxidase (POD) and glutathione S-transferase (GST) were decreased in 12-24 h post treatment. The heat shock proteins (Hsps) gene expression level was significant increasing, maximum > 2-folds upregulation of genes were observed in peak. However, they also had a trend of gradual recovery with development. Second, we detected the testis lactate dehydrogenase (LDH) and acid phosphatase (ACP) activity found that in male adults testis they increased significantly than control during its development. Thus the present research investigation highlights that the 60Co-γ radiation treatments alters the physiological development of diamondback moth. The results showed that 200 Gy dosage resulted in stress damage to the body and reproductive system of the diamondback moth. PMID- 29701647 TI - Dog and Cat Interactions in a Remote Aboriginal Community. AB - This study examined dog and cat demographics, roaming behaviours, and interspecific interactions in a remote Aboriginal island community using multiple methods. Our results revealed temporal differences between the roaming behaviours of dogs, cats, and wildlife. Dogs showed crepuscular behaviour, being active around dawn (5:30 a.m. to 9:30 a.m.) and dusk (6:00 p.m. and 11:35 p.m.). The majority of cats were active between dawn (6:30 a.m.) and dusk (7:30 p.m.) and travelled shorter distances than dogs. However, some cats were also observed roaming between dusk and dawn, and were likely to be hunting since flightless wildlife were also recorded on our remote-sensing cameras during this time. These baseline data provide evidence to suggest that new management programs are needed to reduce the number of roaming cats and therefore their potential impacts on native wildlife. Collaborations between Aboriginal owners and other stakeholders is necessary to design innovative and effective animal management and policy on the island. PMID- 29701648 TI - Smart Metamaterial Based on the Simplex Tensegrity Pattern. AB - In the present paper, a novel cellular metamaterial that was based on a tensegrity pattern is presented. The material is constructed from supercells, each of which consists of eight 4-strut simplex modules. The proposed metamaterial exhibits some unusual properties, which are typical for smart structures. It is possible to control its mechanical characteristics by adjusting the level of self-stress or by changing the properties of structural members. A continuum model is used to identify the qualitative properties of the considered metamaterial, and to estimate how the applied self-stress and the characteristics of cables and struts affect the whole structure. The performed analyses proved that the proposed structure can be regarded as a smart metamaterial with orthotropic properties. One of its most important features are unique values of Poisson’s ratio, which can be either positive or negative, depending on the applied control parameters. Moreover, all of the mechanical characteristics of the proposed metamaterial are prone to structural control. PMID- 29701649 TI - Fabrication of Metal-Substituted Polyoxometalates for Colorimetric Detection of Dopamine and Ractopamine. AB - A novel colorimetric detection method based on the peroxidase-like activity of metal-substituted polyoxometalates (POMs) of SiW9M3 (M = Co2+, Fe3+, Cu2+, Mn2+) has been established. POMs can catalyze oxidation of dopamine (DA) and ractopamine (RAC) by H2O2 in aqueous solutions. SiW9Co3-based POMs detect DA at concentrations as low as 5.38 × 10−6 mol·L−1 simply by observation of the color change from colorless to orange using the naked eye. RAC is detected by observing the change from colorless to slight red by SiW9Cu3 with a detection limit of 7.94 × 10−5 mol·L−1. This study shows that colorimetric DA and RAC detection using SiW9Co3 and SiW9Cu3 is highly selective and sensitive as well as visually observable. PMID- 29701650 TI - A Sensitive Gold Nanoplasmonic SERS Quantitative Analysis Method for Sulfate in Serum Using Fullerene as Catalyst. AB - Fullerene exhibited strong catalysis of the redox reaction between HAuCl4 and trisodium citrate to form gold nanoplasmon with a strong surface-enhanced Raman scattering (SERS) effect at 1615 cm−1 in the presence of Vitoria blue B molecule probes. When fullerene increased, the SERS peak enhanced linearly due to formation of more AuNPs as substrate. Upon addition of Ba2+, Ba2+ ions adsorb on the fullerene surface to inhibit the catalysis of fullerene that caused the SERS peak decreasing. Analyte SO42− combined with Ba2+ to form stable BaSO4 precipitate to release free fullerene that the catalysis recovered, and the SERS intensity increased linearly. Thus, a new SERS quantitative analysis method was established for the detection of sulfate in serum samples, with a linear range of 0.03-3.4 μM. PMID- 29701651 TI - Effects of Pre-Treatments on Bioactivity of High-Purity Titanium. AB - Titanium and its alloys are frequently employed in medical and dental clinics due to their good tissue compatibility, including commercially available pure Ti, Ti6A4V, or Ti-15Zr-4Ta-4Nb. Yet, they may behave very differently when in contact with our plasma because of their own chemical composition. The present study was designed to compare the in vitro behavior of highly pure Ti (>99.99%; hpTi) with those of the above titanium specimens when they were subjected to heating in air (HT), H2O2 and heating (CHT), and heating in air after forming grooves on the surface (GT). Since one of the measures of material-tissue compatibility has been in vitro apatite formation in artificial plasma, like simulated body fluid (SBF) of the Kokubo recipe, the apatite deposition in SBF on their surface and in their grooves were examined in terms of the X-ray diffraction, scanning electron microscopy, and energy dispersion X-ray analysis. The results showed that hpTi was as active in in vitro apatite deposition as the other reference titanium samples mentioned above. Moreover, GT specimens of hpTi induced apatite deposition on the platform of the grooves as well as in the grooves. Therefore, hpTi was concluded to have better activity, and to be clinically applicable. PMID- 29701652 TI - Research on the Single Grit Scratching Process of Oxygen-Free Copper (OFC). AB - Single grit scratching is a basic form of material removal for many processes, such as grinding single point diamond turning and coating bonding performance tests. It has been widely used in the study of micro-scale and nano-scale material removal mechanisms. In this study, single grit linearly loading scratching tests were carried out on a scratching tester. A Rockwell indenter made of natural diamond was selected as the tool used, and the material of the workpiece was oxygen-free copper. Scratch topography was measured using a super depth microscope to analyze the material deformation of the scratching process. A single grit scratching simulation has been developed by AdvantEdge™ to comprehensively study the material deformation of scratching processes. A material constitutive model and friction model were acquired using a quasi-static uniaxial compression experiment and a reciprocating friction test, respectively. These two models were used as the input models in the finite simulations. The simulated scratching forces aligned well with the experimental scratching forces, which verified the precision of the simulation model. Since only the scratching force could be obtained in the scratching experiment, the plastic strain, material flow, and residual stress of the scratching were further analyzed using simulations. The results showed that the plastic strain of the workpiece increased with the increase in scratching depth, and further analysis showed that the workpiece surface was distributed with residual compressive stress and the sub-surface was distributed with residual tensile stress in single grit scratching. PMID- 29701653 TI - Synthesis and Luminescent Properties of Europium Complexes Covalently Bonded to Hybrid Materials Based on MCM-41 and Poly(Ionic Liquids). AB - Due to the wide potential application in the fields of sensing, lighting materials, and optical-electrical multifunctional devices, rare earth complex hybrid materials have been studied extensively over the past decades. A poly(ionic liquid)/mesoporous-based hybrid system which has been functionalized by the covalently linked europium complexes was reported here. Through surface modification with a coupling agent bearing an vinyl group, MCM-41 was chosen as the carrier matrix for poly(ionic liquids) (PILs) and europium compounds, and based on that, novel luminescent hybrid materials were prepared by confining the ionic liquid and europium complexes into the inorganic Si-O frameworks. The resulting organic/inorganic materials are chemically bonded hybrids which show good photoluminescent properties such as broad excitation spectra, line-like emission spectra, and long luminescence lifetimes. The PILs/MCM-41/Eu3+ hybrid reported here is a rare earth multifunctional material which is believed to have potential applications in the field of optical-electrical materials. PMID- 29701654 TI - Current Conjugation Methods for Immunosensors. AB - Recent advances in the development of immunosensors using polymeric nanomaterials and nanoparticles have enabled a wide range of new functions and applications in diagnostic and prognostic research. One fundamental challenge that all immunosensors must overcome is to provide the specificity of target molecular recognition by immobilizing antibodies, antibody fragments, and/or other peptides or oligonucleotide molecules that are capable of antigen recognition on a compact device surface. This review presents progress in the application of immobilization strategies including the classical adsorption process, affinity attachment, random cross-linking and specific covalent linking. The choice of immobilization methods and its impact on biosensor performance in terms of capture molecule loading, orientation, stability and capture efficiency are also discussed in this review. PMID- 29701655 TI - The Comprehensive Snack Parenting Questionnaire (CSPQ): Development and Test Retest Reliability. AB - The narrow focus of existing food parenting instruments led us to develop a food parenting practices instrument measuring the full range of food practices constructs with a focus on snacking behavior. We present the development of the questionnaire and our research on the test-retest reliability. The developed Comprehensive Snack Parenting Questionnaire (CSPQ) covers 21 constructs. Test retest reliability was assessed by calculating intra class correlation coefficients and percentage agreement after two administrations of the CSPQ among a sample of 66 Dutch parents. Test-retest reliability analysis revealed acceptable intra class correlation coefficients (≥0.41) or agreement scores (≥0.60) for all items. These results, together with earlier work, suggest sufficient psychometric characteristics. The comprehensive, but brief CSPQ opens up chances for highly essential but unstudied research questions to understand and predict children’s snack intake. Example applications include studying the interactional nature of food parenting practices or interactions of food parenting with general parenting or child characteristics. PMID- 29701656 TI - Enteral Nutrition in the Management of Pediatric and Adult Crohn's Disease. AB - Genetic and environmental factors are thought to profoundly influence the pathophysiology of Crohn’s disease (CD). Changes in dietary and hygiene patterns affect the interactions between the immune system and environment. The gut microbiome is responsible for mediating host immune response with significant dysbiosis observed in individuals with CD. Diet therapy using exclusive enteral nutrition (EEN) has been studied as primary therapy for the management of CD. EEN may cultivate the presence of beneficial microbiota, improve bile acid metabolism, and decrease the number of dietary microparticles possibly influencing disease and immune activity. In this review, we will address the current evidence on EEN in the management of adult and pediatric CD. In adults, EEN appears to be moderately beneficial for the induction of remission of CD; however, its use is understudied and underutilized. Stronger evidence is in place to support the use of EEN in pediatric CD with the added benefit of nutrition support and steroid-sparing therapy during the growth phase. Overall, EEN is an established therapy in inducing CD remission in the pediatric population while its role as primary therapy of adult Crohn’s disease remains to be defined. PMID- 29701657 TI - Characterization of Silver Nanomaterials Derived from Marine Streptomyces sp. Al Dhabi-87 and Its In Vitro Application against Multidrug Resistant and Extended Spectrum Beta-Lactamase Clinical Pathogens. AB - A novel antagonistic marine Streptomyces sp. Al-Dhabi-87 that was recovered from the Gulf region of Saudi Arabia was used to synthesize silver nanoparticles (NP) from the culture free extract. The produced NP were confirmed by UV-visible spectroscopy (UV-Vis), high-resolution scanning electron microscope (HRSEM), transmission electron microscope (TEM), Fourier-transform infrared spectroscopy (FTIR), Energy Dispersive Spectroscopy (EDAX), and X-ray Powder Diffraction (XRD), and broth micro dilution techniques were employed for the determination of minimum inhibitory concentrations (MIC) values. The synthesized NP was authenticated by alterations in color and wavelength scanning. HRSEM and TEM analysis confirmed that the size of the NP ranged from 10 to 17 nm and that it was spherical in shape. In addition, the FTIR spectrum revealed a variation in the band values from 500 to 3300 cm−1 respectively. Rietveld refinement analysis of the XRD data confirmed the size of the NP, which coincided with the results of the TEM analysis. In addition, the Riveted refinement analysis supported the TEM data. The NP documented significant activity against the wound infection microbial strains, such as Enterococcus faecalis, Staphylococcus epidermidis, and Staphylococcus aureus. Gram negative bacteria, such as Pseudomonas aeruginosa, Klebsiella pneumonia, and Escherichia coli revealed MIC values of 0.039, 0.078, and 0.152 mg/mL, respectively. The promising activity of NP towards extended-spectrum beta-lactamases E.coli, drug resistant Acinetobacter baumannii, and multidrug resistant S. aureus (at 0.018, 0.039, and 0.039 mg/mL, respectively) was advantageous. Overall, NP that were obtained from the novel Streptomyces sp. Al-Dhabi-87, with its promising antimicrobial activity towards the drug resistant pathogens, would be useful for healing infectious diseases. PMID- 29701658 TI - Determination of Arsenic Species in Ophiocordyceps sinensis from Major Habitats in China by HPLC-ICP-MS and the Edible Hazard Assessment. AB - This study sought to determine the concentration and distribution of arsenic (As) species in Ophiocordyceps sinensis (O. sinensis), and to assess its edible hazard for long term consumption. The total arsenic concentrations, measured through inductively coupled plasma mass spectrometry (ICP-MS), ranged from 4.00 mg/kg to 5.25 mg/kg. As determined by HPLC-ICP-MS, the most concerning arsenic species—AsB, MMAV, DMAV, AsV, and AsSH—were either not detected (MMAV and DMAV) or were detected as minor As species (AsB: 1.4-2.9%; AsV: 1.3-3.2%, and AsSH: 4.1-6.0%). The major components were a cluster of unknown organic As (uAs) compounds with AsSH, which accounted for 91.7-94.0% of the As content. Based on the H2O2 test and the chromatography behavior, it can be inferred that, the uAs might not be toxic organic As. Estimated daily intake (EDI), hazard quotient (HQ), and cancer risk (CR) caused by the total As content; the sum of inorganic As (iAs) and uAs, namely i+uAs; and iAs exposure from long term O. sinensis consumption were calculated and evaluated through equations from the US Environmental Protection Agency and the uncertainties were analyzed by Monte Carlo Simulation (MCS). EDItotal As and EDIi+uAs are approximately ten times more than EDIiAs; HQtotalAs and HQi+uAs > 1 while HQiAs < 1; and CRtotal As and CRi+uAs > 1 × 10−4 while CRiAs < 1 × 10−4. Thus, if the uAs is non-toxic, there is no particular risk to local consumers and the carcinogenic risk is acceptable for consumption of O. sinensis because the concentration of toxic iAs is very low. PMID- 29701659 TI - The Effect of Depressive Symptoms on the Association between Gluten-Free Diet Adherence and Symptoms in Celiac Disease: Analysis of a Patient Powered Research Network. AB - BACKGROUND: The prevalence of depression in celiac disease (CD) is high, and patients are often burdened socially and financially by a gluten-free diet. However, the relationship between depression, somatic symptoms and dietary adherence in CD is complex and poorly understood. We used a patient powered research network (iCureCeliac(r)) to explore the effect that depression has on patients' symptomatic response to a gluten-free diet (GFD). METHODS: We identified patients with biopsy-diagnosed celiac disease who answered questions pertaining to symptoms (Celiac Symptom Index (CSI)), GFD adherence (Celiac Dietary Adherence Test (CDAT)), and a 5-point, scaled question regarding depressive symptoms relating to patients' celiac disease. We then measured the correlation between symptoms and adherence (CSI vs. CDAT) in patients with depression versus those without depression. We also tested for interaction of depression with regard to the association with symptoms using a multiple linear regression model. RESULTS: Among 519 patients, 86% were female and the mean age was 40.9 years. 46% of patients indicated that they felt "somewhat," "quite a bit," or "very much" depressed because of their disorder. There was a moderate correlation between worsened celiac symptoms and poorer GFD adherence (r = 0.6, p < 0.0001). In those with a positive depression screen, there was a moderate correlation between worsening symptoms and worsening dietary adherence (r = 0.5, p < 0.0001) whereas in those without depression, the correlation was stronger (r = 0.64, p < 0.0001). We performed a linear regression analysis, which suggests that the relationship between CSI and CDAT is modified by depression. CONCLUSIONS: In patients with depressive symptoms related to their disorder, correlation between adherence and symptoms was weaker than those without depressive symptoms. This finding was confirmed with a linear regression analysis, showing that depressive symptoms may modify the effect of a GFD on celiac symptoms. Depressive symptoms may therefore mask the relationship between inadvertent gluten exposure and symptoms. Additional longitudinal and prospective studies are needed to further explore this potentially important finding. PMID- 29701660 TI - In Situ Formation of AgCo Stabilized on Graphitic Carbon Nitride and Concomitant Hydrolysis of Ammonia Borane to Hydrogen. AB - The development of highly-efficient heterogeneous supported catalysts for catalytic hydrolysis of ammonia borane to yield hydrogen is of significant importance considering the versatile usages of hydrogen. Herein, we reported the in situ synthesis of AgCo bimetallic nanoparticles supported on g-C3N4 and concomitant hydrolysis of ammonia borane for hydrogen evolution at room temperature. The as-synthesized Ag0.1Co0.9/g-C3N4 catalysts displayed the highest turnover frequency (TOF) value of 249.02 mol H2·(molAg·min)−1 for hydrogen evolution from the hydrolysis of ammonia borane, which was higher than many other reported values. Furthermore, the Ag0.1Co0.9/g-C3N4 catalyst could be recycled during five consecutive runs. The study proves that Ag0.1Co0.9/g-C3N4 is a potential catalytic material toward the hydrolysis of ammonia borane for hydrogen production. PMID- 29701661 TI - From Inpatient to Clinic to Home to Hospice and Back: Using the "Pop Up" Pediatric Palliative Model of Care. AB - Children and young people with life-limiting illnesses who need palliative care often have complex diverse medical conditions that may involve multiple hospital presentations, medical admissions, care, or transfer to other medical care facilities. In order to provide patients with holistic care in any location, palliative care clinicians need to carefully consider the ways to maintain continuity of care which enhances the child's quality of life. An emerging model of care known as "Pop Up" describes the approaches to supporting children and young people in any facility. A Pop Up is a specific intervention over and above the care that is provided to a child, young person and their family aimed at improving the confidence of local care providers to deliver ongoing care. This paper looks at some of the factors related to care transfer for pediatric palliative patients from one care facility to another, home and the impact of this on the family and medical care. PMID- 29701662 TI - Feasibility of a Lactobacillus casei Drink in the Intensive Care Unit for Prevention of Antibiotic Associated Diarrhea and Clostridium difficile. AB - Background: Over 70% of patients are prescribed antibiotics during their intensive care (ICU) admission. The gut microbiome is dramatically altered early in an ICU stay, increasing the risk for antibiotic associated diarrhea (AAD) and Clostridium difficile infections (CDI). Evidence suggests that some probiotics are effective in the primary prevention of AAD and CDI. Aim: To demonstrate safety and feasibility of a probiotic drink in ICU patients. Methods: ICU patients initiated on antibiotics were recruited, and matched with contemporary controls. Study patients received two bottles daily of a drink containing 10 billion Lactobacillus casei which was bolused via feeding tube. Tolerance to probiotics and enteral nutrition, development of adverse events, and incidence of AAD was recorded. CDI rates were followed for 30 days post antibiotic treatment. Results: Thirty-two patients participated in the trial. There were no serious adverse events in the probiotic group, compared to three in the control group. AAD was documented in 12.5% of the probiotic group and 31.3% in the control group. One patient in the probiotic group developed CDI compared to three in the control group. Discussion: A probiotic containing drink can safely be delivered via feeding tube and should be considered as a preventative measure for AAD and CDI in ICU. PMID- 29701664 TI - Disability-Adjusted Life Years for Cancer in 2010-2014: A Regional Approach in Mexico. AB - The disability-adjusted life years (DALYs) were used to estimate the regional (state of Colima, Mexico) cancer burden in 2010-2014. The years of life lost (YLL) were estimated with mortality data and years lived with disability (YLD) using incidence data. The DALYs were calculated as the arithmetic addition of YLL and YLD. Sex and cancer site-specific estimations were made and DALY rates were used to identify the leading causes of disease burden. Data from 2532 deaths were analyzed and, for all malignant tumors combined, 18,712.9 DALYs and 20,243.3 DALYs were estimated in males and females respectively. The overall contribution of YLL in DALY estimates was higher among females (93.7% vs. 87.4%). Age standardized DALY rates (and 95% confidence intervals, CI) per 100,000 inhabitants were used to rank the leading causes of disease burden and, among males, malignant tumors from the prostate, lower respiratory tract, and colon and rectum accounted the highest rates (45.7, 95% CI 32.7-59.3; 37.6, 95% CI 25.7 49.9; and 25.9, 95% CI 16.0-36.1 DALYs). Breast, cervix uteri, and lower respiratory tract cancer showed the highest burden in females (66.0, 95% CI 50.3 82.4; 44.4, 95% CI 31.5-57.7; and 20.9, 95% CI 12.0-30.0 DALYs). The present study provides an indication of the burden of cancer at the regional level, underscoring the need to expand cancer prevention, screening, and awareness programs, as well as to improve early diagnosis and medical treatment. PMID- 29701663 TI - Campylobacteriosis, Salmonellosis, Yersiniosis, and Listeriosis as Zoonotic Foodborne Diseases: A Review. AB - Zoonoses are diseases transmitted from animals to humans, posing a great threat to the health and life of people all over the world. According to WHO estimations, 600 million cases of diseases caused by contaminated food were noted in 2010, including almost 350 million caused by pathogenic bacteria. Campylobacter, Salmonella, as well as Yersinia enterocolitica and Listeria monocytogenes may dwell in livestock (poultry, cattle, and swine) but are also found in wild animals, pets, fish, and rodents. Animals, often being asymptomatic carriers of pathogens, excrete them with faeces, thus delivering them to the environment. Therefore, pathogens may invade new individuals, as well as reside on vegetables and fruits. Pathogenic bacteria also penetrate food production areas and may remain there in the form of a biofilm covering the surfaces of machines and equipment. A common occurrence of microbes in food products, as well as their improper or careless processing, leads to common poisonings. Symptoms of foodborne infections may be mild, sometimes flu-like, but they also may be accompanied by severe complications, some even fatal. The aim of the paper is to summarize and provide information on campylobacteriosis, salmonellosis, yersiniosis, and listeriosis and the aetiological factors of those diseases, along with the general characteristics of pathogens, virulence factors, and reservoirs. PMID- 29701665 TI - Adropin Contributes to Anti-Atherosclerosis by Suppressing Monocyte-Endothelial Cell Adhesion and Smooth Muscle Cell Proliferation. AB - Adropin, a peptide hormone expressed in liver and brain, is known to improve insulin resistance and endothelial dysfunction. Serum levels of adropin are negatively associated with the severity of coronary artery disease. However, it remains unknown whether adropin could modulate atherogenesis. We assessed the effects of adropin on inflammatory molecule expression and human THP1 monocyte adhesion in human umbilical vein endothelial cells (HUVECs), foam cell formation in THP1 monocyte-derived macrophages, and the migration and proliferation of human aortic smooth muscle cells (HASMCs) in vitro and atherogenesis in Apoe-/- mice in vivo. Adropin was expressed in THP1 monocytes, their derived macrophages, HASMCs, and HUVECs. Adropin suppressed tumor necrosis factor alpha-induced THP1 monocyte adhesion to HUVECs, which was associated with vascular cell adhesion molecule 1 and intercellular adhesion molecule 1 downregulation in HUVECs. Adropin shifted the phenotype to anti-inflammatory M2 rather than pro inflammatory M1 via peroxisome proliferator-activated receptor gamma upregulation during monocyte differentiation into macrophages. Adropin had no significant effects on oxidized low-density lipoprotein-induced foam cell formation in macrophages. In HASMCs, adropin suppressed the migration and proliferation without inducing apoptosis via ERK1/2 and Bax downregulation and phosphoinositide 3-kinase/Akt/Bcl2 upregulation. Chronic administration of adropin to Apoe-/- mice attenuated the development of atherosclerotic lesions in the aorta, with reduced the intra-plaque monocyte/macrophage infiltration and smooth muscle cell content. Thus, adropin could serve as a novel therapeutic target in atherosclerosis and related diseases. PMID- 29701668 TI - Cross-Participant EEG-Based Assessment of Cognitive Workload Using Multi-Path Convolutional Recurrent Neural Networks. AB - Applying deep learning methods to electroencephalograph (EEG) data for cognitive state assessment has yielded improvements over previous modeling methods. However, research focused on cross-participant cognitive workload modeling using these techniques is underrepresented. We study the problem of cross-participant state estimation in a non-stimulus-locked task environment, where a trained model is used to make workload estimates on a new participant who is not represented in the training set. Using experimental data from the Multi-Attribute Task Battery (MATB) environment, a variety of deep neural network models are evaluated in the trade-space of computational efficiency, model accuracy, variance and temporal specificity yielding three important contributions: (1) The performance of ensembles of individually-trained models is statistically indistinguishable from group-trained methods at most sequence lengths. These ensembles can be trained for a fraction of the computational cost compared to group-trained methods and enable simpler model updates. (2) While increasing temporal sequence length improves mean accuracy, it is not sufficient to overcome distributional dissimilarities between individuals’ EEG data, as it results in statistically significant increases in cross-participant variance. (3) Compared to all other networks evaluated, a novel convolutional-recurrent model using multi-path subnetworks and bi-directional, residual recurrent layers resulted in statistically significant increases in predictive accuracy and decreases in cross participant variance. PMID- 29701667 TI - Identification of Ophiocordyceps sinensis and Its Artificially Cultured Ophiocordyceps Mycelia by Ultra-Performance Liquid Chromatography/Orbitrap Fusion Mass Spectrometry and Chemometrics. AB - Since the cost of Ophiocordyceps sinensis, an important fungal drug used in Chinese medicine, has increased dramatically, and the counterfeits may have adverse health effects, a rapid and precise marker using the peptide mass spectrometry identification system could significantly enhance the regulatory capacity. In this study, we determined the marker peptides in the digested mixtures of fungal proteins in wild O. sinensis fruiting bodies and various commercially available mycelium fermented powders using ultra-performance liquid chromatography/Orbitrap Fusion mass spectrometry coupled with chemometrics. The results indicated the following marker peptides: TLLEAIDSIEPPK (m/z 713.39) was identified in the wild O. sinensis fruiting body, AVLSDAITLVR (m/z 579.34) was detected in the fermented O. sinensis mycelium powder, FAELLEK (m/z 849.47) was found in the fermented Ophiocordyceps mycelium powder, LESVVTSFTK (m/z 555.80) was discovered in the artificial Ophiocordyceps mycelium powder, and VPSSAVLR (m/z 414.75) was observed in O. mortierella mycelium powder. In order to verify the specificity and applicability of the method, the five marker peptides were synthesized and tested on all samples. All in all, to the best of our knowledge, this is the first time that mass spectrometry has been employed to detect the marker peptides of O.sinensis and its related products. PMID- 29701666 TI - TGF-beta and the Tissue Microenvironment: Relevance in Fibrosis and Cancer. AB - Transforming growth factor-β (TGF-β) is a cytokine essential for the induction of the fibrotic response and for the activation of the cancer stroma. Strong evidence suggests that a strong cross-talk exists among TGF-β and the tissue extracellular matrix components. TGF-β is stored in the matrix as part of a large latent complex bound to the latent TGF-β binding protein (LTBP) and matrix binding of latent TGF-β complexes, which is required for an adequate TGF-β function. Once TGF-β is activated, it regulates extracellular matrix remodelling and promotes a fibroblast to myofibroblast transition, which is essential in fibrotic processes. This cytokine also acts on other cell types present in the fibrotic and tumour microenvironment, such as epithelial, endothelial cells or macrophages and it contributes to the cancer associated fibroblast (CAF) phenotype. Furthermore, TGF-β exerts anti-tumour activity by inhibiting the host tumour immunosurveillance. Aim of this review is to update how TGF-β and the tissue microenvironment cooperate to promote the pleiotropic actions that regulate cell responses of different cell types, essential for the development of fibrosis and tumour progression. We discuss recent evidences suggesting the use of TGF-β chemical inhibitors as a new line of defence against fibrotic disorders or cancer. PMID- 29701669 TI - Differentiating Medicated Patients Suffering from Major Depressive Disorder from Healthy Controls by Spot Urine Measurement of Monoamines and Steroid Hormones. AB - Introduction: Major Depressive Disorder (MDD) is a common psychiatric disorder. Currently, there is no objective, cost-effective and non-invasive method to measure biological markers related to the pathogenesis of MDD. Previous studies primarily focused on urinary metabolite markers which are not proximal to the pathogenesis of MDD. Herein, we compare urinary monoamines, steroid hormones and the derived ratios amongst MDD when compared to healthy controls. Methods: Morning urine samples of medicated patients suffering from MDD (n = 47) and healthy controls (n = 41) were collected. Enzyme-linked immunosorbent assay (ELISA) was performed to measure five biomarkers: cortisol, dopamine, noradrenaline, serotonin and sulphate derivative of dehydroepiandrosterone (DHEAS). The mean urinary levels and derived ratios of monoamines and steroid hormones were compared between patients and controls to identify potential biomarkers. The receiver operative characteristic curve (ROC) analysis was conducted to evaluate the diagnostic performance of potential biomarkers. Results: Medicated patients with MDD showed significantly higher spot urine ratio of DHEAS/serotonin (1.56 vs. 1.19, p = 0.004) and lower ratio of serotonin/dopamine (599.71 vs. 888.60, p = 0.008) than healthy controls. A spot urine serotonin/dopamine ratio cut-off of >667.38 had a sensitivity of 73.2% and specificity of 51.1%. Conclusions: Our results suggest that spot urine serotonin/dopamine ratio can be used as an objective diagnostic method for adults with MDD. PMID- 29701670 TI - Biomethanation of Harmful Macroalgal Biomass in Leach-Bed Reactor Coupled to Anaerobic Filter: Effect of Water Regime and Filter Media. AB - Ulva is a marine macroalgal genus which causes serious green tides in coastal areas worldwide. This study investigated anaerobic digestion as a way to manage Ulva waste in a leach-bed reactor coupled to an anaerobic filter (LBR-AF). Two LBR-AF systems with different filter media, blast furnace slag grains for R1, and polyvinyl chloride rings for R2, were run at increasing water replacement rates (WRRs). Both achieved efficient volatile solids reduction (68.4-87.1%) and methane yield (148-309 mL/g VS fed) at all WRRs, with the optimal WRR for maximum methane production being 100 mL/d. R1 maintained more stable methanation performance than R2, possibly due to the different surface properties (i.e., biomass retention capacity) of the filter media. Such an effect was also noted in the different behaviors of the LBR and AF between R1 and R2. The molecular analysis results revealed that the development of the microbial community structure in the reactors was primarily determined by the fermentation type, i.e., dry (LBR) or wet (AF). PMID- 29701671 TI - Proteopeptidomic, Functional and Immunoreactivity Characterization of Bothrops moojeni Snake Venom: Influence of Snake Gender on Venom Composition. AB - Venom composition varies across snakes from all taxonomic levels and is influenced by the snakes’ age, habitat, diet, and sexual dimorphism. The present study reports the first in-depth investigation of venom composition in male and female Bothrops moojeni (B. moojeni) snakes (BmooM and BmooF, respectively) through three proteomics approaches associated with functional, cytotoxic, and immunoreactivity characterization. Compared with BmooM venom, BmooF venom exhibited weaker hyaluronidase, metalloproteinase, and phospholipase activity; stronger recognition by anti-bothropic serum; 1.4-fold stronger cytotoxicity; and greater number of peptides. The increased L-amino acid oxidase expression probably accounted for the stronger immunoreactivity and cytotoxicity of BmooF venom. BmooF and BmooM venom shared only 19% peptides. Some venom components were gender-specific, such as phospholipases B, phospholipase inhibitor, and hyaluronidases in BmooM, and cysteine-rich secretory proteins in BmooF. In conclusion, we describe herein the first proteomics study of B. moojeni snake venom and an in-depth characterization of gender-specific differences in venom composition. Altogether, our findings not only stress the importance of considering the snake’s gender during antivenom production, but also help to identify new potential drugs and biotechnological tools. PMID- 29701672 TI - Comparison of Serum Metabolite Changes of Radiated Mice Administered with Panax quinquefolium from Different Cultivation Regions Using UPLC-Q/TOF-MS Based Metabolomic Approach. AB - Chemometric analysis of bioactive compounds revealed that American ginsengs (AGs) from different cultivation regions of China had a difference in quality, which indicates their possible pharmacological difference. A UPLC-Q/TOF-MS-based untargeted metabolomic approach was used to uncover serum metabolite changes in radiated mice pre-administered with AG root decoctions from seven cultivation regions and to further assess their quality difference. OPLS-DA revealed that 51 metabolites (ESI−) and 110 (ESI+) were differentially expressed in sera between the control and the radiated model mice. Heatmap analysis further revealed that AG could not reverse most of these radiation-altered metabolites, which indicates dietary supplement of AG before cobalt radiation had the weak potential to mediate serum metabolites that were altered by the sub-lethal high dose radiation. In addition, 83 (ESI−) and 244 (ESI+) AG altered metabolites were detected in radiated mice under radiation exposure. Both OPLS-DA on serum metabolomes and heatmap analysis on discriminant metabolites showed that AGs from different cultivation regions differentially influenced metabolic alterations in radiated mice, which indicates AGs from different cultivation regions showed the pharmacological difference in modulation of metabolite changes. AGs from Shandong, Shanxi, and Beijing provinces had more similar pharmacological effects than AGs from USA, Canada, Jilin, and Heilongjiang. Finally, 28 important potential biomarkers were annotated and assigned onto three metabolic pathways including lipid, amino acid, and energy metabolisms. PMID- 29701674 TI - Development of an Analytical Method for Simultaneous Determination of the Modified Forms of 4,15-Diacetoxyscirpenol and their Occurrence in Japanese Retail Food. AB - 4,15-Diacetoxyscirpenol (4,15-DAS) is a type A trichothecene mycotoxin produced by Fusarium species. Four modified forms of 4,15-DAS including 7 hydroxydiacetoxyscirpenol, 7,8-dihydroxydiacetoxyscirpenol, 4β,8α,15 triacetoxy-3α,7α-dihydroxy-12,13-epoxytrichothec-9-ene and 4,15 diacetylnivalenol were purified from cultures of F. equiseti. An analytical method using a multifunctional column has been developed for the simultaneous determination of 4,15-DAS, its four modified forms, T-2 toxin, HT-2 toxin and neosolaniol in cereals. The performance of the current method was evaluated, and a total of 248 samples of five different commodities were analyzed for over two years by this method. 4,15-DAS was detected in Job’s tears products, corn flour and azuki bean, but it was not found in wheat flour or rye flour. The four modified forms of 4,15-DAS were detected in samples of Job’s tears products, contaminated by 4,15-DAS. This is the first report on quantification of the modified forms of 4,15-DAS in cereals. PMID- 29701675 TI - Comparative Analysis of the Complete Chloroplast Genomes of Four Aconitum Medicinal Species. AB - Aconitum (Ranunculaceae) consists of approximately 400 species distributed in the temperate regions of the northern hemisphere. Many species are well-known herbs, mainly used for analgesia and anti-inflammatory purposes. This genus is well represented in China and has gained widespread attention for its toxicity and detoxification properties. In southwestern China, several Aconitum species, called ‘Dula’ in the Yi Nationality, were often used to control the poisonous effects of other Aconitum plants. In this study, the complete chloroplast (cp) genomes of these species were determined for the first time through Illumina paired-end sequencing. Our results indicate that their cp genomes ranged from 151,214 bp (A. episcopale) to 155,769 bp (A. delavayi) in length. A total of 111-112 unique genes were identified, including 85 protein coding genes, 36-37 tRNA genes and eight ribosomal RNA genes (rRNA). We also analyzed codon usage, IR expansion or contraction and simple sequence repeats in the cp genomes. Eight variable regions were identified and these may potentially be useful as specific DNA barcodes for species identification of Aconitum. Phylogenetic analysis revealed that all five studied species formed a new clade and were resolved with 100% bootstrap support. This study will provide genomic resources and potential plastid markers for DNA barcoding, further taxonomy and germplasm exploration of Aconitum. PMID- 29701676 TI - Anti-Inflammatory Effect of Baicalein on Polyinosinic-Polycytidylic Acid-Induced RAW 264.7 Mouse Macrophages. AB - Baicalein (3,3′,4′,5,6-pentahydroxyflavone) is a well-known antioxidant found in many plants, such as in the roots of Scutellaria baicalensis. In this study, we evaluate the inhibitory effect of baicalein on the inflammatory cascade in RAW 264.7 mouse macrophages induced by viral-like material. Experimental assays used in this study included Griess reagent assay for nitric oxide (NO) production, Fluo-4 assay for intracellular calcium release, multiplex cytokine assay, and quantitative real time RT-PCR assay. To induce inflammation, RAW 264.7 cells were treated with polyinosinic-polycytidylic acid (poly I:C), a synthetic analog of double-stranded RNA (dsRNA). Baicalein at concentrations up to 100 μM significantly inhibited the production of NO, IL 1α, IL-6, G-CSF, GM-CSF, VEGF, MCP-1, IP-10, LIX, and RANTES as well as calcium release in RAW 264.7 cells induced by poly I:C (50 µg/mL) (all p < 0.05). Baicalein at concentrations up to 50 μM also significantly inhibited mRNA expression of STAT1, STAT3, CHOP, and Fas in poly I:C-induced RAW 264.7 cells (p < 0.05). In conclusion, baicalein has anti-inflammatory effect in double stranded RNA (dsRNA)-induced macrophages by inhibiting NO, cytokines, chemokines, and growth factors via the endoplasmic reticulum stress-CHOP/STAT pathway. PMID- 29701677 TI - Adaptive Monostatic System for Measuring Microwave Reflections from the Breast. AB - A second-generation monostatic radar system to measure microwave reflections from the human breast is presented and analyzed. The present system can measure the outline of the breast with an accuracy of ±1 mm and precisely place the microwave sensor in an adaptive matter such that microwaves are normally incident on the skin. Microwave reflections are measured between 10 MHz to 12 GHz with sensitivity of 65 to 75 dB below the input power and a total scan time of 30 min for 140 locations. The time domain reflections measured from a volunteer show fidelity above 0.98 for signals in a single scan. Finally, multiple scans of a breast phantoms demonstrate the consistency of the system in terms of recorded reflection, outline measurement, and image reconstruction. PMID- 29701673 TI - T Cell Calcium Signaling Regulation by the Co-Receptor CD5. AB - Calcium influx is critical for T cell effector function and fate. T cells are activated when T cell receptors (TCRs) engage peptides presented by antigen presenting cells (APC), causing an increase of intracellular calcium (Ca2+) concentration. Co-receptors stabilize interactions between the TCR and its ligand, the peptide-major histocompatibility complex (pMHC), and enhance Ca2+ signaling and T cell activation. Conversely, some co-receptors can dampen Ca2+ signaling and inhibit T cell activation. Immune checkpoint therapies block inhibitory co-receptors, such as cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) and programmed death 1 (PD-1), to increase T cell Ca2+ signaling and promote T cell survival. Similar to CTLA-4 and PD-1, the co-receptor CD5 has been known to act as a negative regulator of T cell activation and to alter Ca2+ signaling and T cell function. Though much is known about the role of CD5 in B cells, recent research has expanded our understanding of CD5 function in T cells. Here we review these recent findings and discuss how our improved understanding of CD5 Ca2+ signaling regulation could be useful for basic and clinical research. PMID- 29701679 TI - Artificial Intelligence-Based Semantic Internet of Things in a User-Centric Smart City. AB - Smart city (SC) technologies can provide appropriate services according to citizens’ demands. One of the key enablers in a SC is the Internet of Things (IoT) technology, which enables a massive number of devices to connect with each other. However, these devices usually come from different manufacturers with different product standards, which confront interactive control problems. Moreover, these devices will produce large amounts of data, and efficiently analyzing these data for intelligent services. In this paper, we propose a novel artificial intelligence-based semantic IoT (AI-SIoT) hybrid service architecture to integrate heterogeneous IoT devices to support intelligent services. In particular, the proposed architecture is empowered by semantic and AI technologies, which enable flexible connections among heterogeneous devices. The AI technology can support very implement efficient data analysis and make accurate decisions on service provisions in various kinds. Furthermore, we also present several practical use cases of the proposed AI-SIoT architecture and the opportunities and challenges to implement the proposed AI-SIoT for future SCs are also discussed. PMID- 29701680 TI - Haliotis discus discus Sialic Acid-Binding Lectin Reduces the Oncolytic Vaccinia Virus Induced Toxicity in a Glioblastoma Mouse Model. AB - Although oncolytic viruses provide attractive vehicles for cancer treatment, their adverse effects are largely ignored. In this work, rat C6 glioblastoma cells were subcutaneously xenografted into mice, and a thymidine kinase-deficient oncolytic vaccinia virus (oncoVV) induced severe toxicity in this model. However, oncoVV-HddSBL, in which a gene encoding Haliotis discus discus sialic acid binding lectin (HddSBL) was inserted into oncoVV, significantly prolonged the survival of mice as compared to the control virus. HddSBL reduced the tumor secreted serum rat IL-2 level upregulated by oncoVV, promoted viral replication, as well as inhibited the expression of antiviral factors in C6 glioblastoma cell line. Furthermore, HddSBL downregulated the expression levels of histone H3 and H4, and upregulated histone H3R8 and H4R3 asymmetric dimethylation, confirming the effect of HddSBL on chromatin structure suggested by the transcriptome data. Our results might provide insights into the utilization of HddSBL in counteracting the adverse effects of oncolytic vaccinia virus. PMID- 29701681 TI - Regularized Multi-View Subspace Clustering for Common Modules Across Cancer Stages. AB - Discovering the common modules that are co-expressed across various stages can lead to an improved understanding of the underlying molecular mechanisms of cancers. There is a shortage of efficient tools for integrative analysis of gene expression and protein interaction networks for discovering common modules associated with cancer progression. To address this issue, we propose a novel regularized multi-view subspace clustering (rMV-spc) algorithm to obtain a representation matrix for each stage and a joint representation matrix that balances the agreement across various stages. To avoid the heterogeneity of data, the protein interaction network is incorporated into the objective of rMV-spc via regularization. Based on the interior point algorithm, we solve the optimization problem to obtain the common modules. By using artificial networks, we demonstrate that the proposed algorithm outperforms state-of-the-art methods in terms of accuracy. Furthermore, the rMV-spc discovers common modules in breast cancer networks based on the breast data, and these modules serve as biomarkers to predict stages of breast cancer. The proposed model and algorithm effectively integrate heterogeneous data for dynamic modules. PMID- 29701683 TI - The Incorporation of Strontium to Improve Bone-Regeneration Ability of Mesoporous Bioactive Glasses. AB - Over the recent years, mesoporous bioactive glasses (MBGs) gained interest as bone regeneration systems, due to their excellent bioactivity and ability to release therapeutic molecules. In order to improve the bone regeneration ability of MBGs, the incorporation of Sr2+ ions, due to its recognized pro-osteogenenic potential, represents a very promising strategy. In this study, MBGs based on the SiO2-CaO system and containing different percentages (2 and 4 mol %) of strontium were prepared by two synthesis methods, in the form of microspheres and nanoparticles. Sr-containing MBGs were characterized by FE-SEM, XRD and N2 adsorption/desorption analysis. The in vitro bioactivity in SBF resulted excellent. The assessment of fibroblast cell (line L929) viability showed that Sr containing MBGs were biocompatible both in form of micro- and nanoparticles. The osteogenic response of osteoblast-like SAOS-2 cells was investigated by analysing the expression of GAPDH, COL1a1, RANKL, SPARC, OPG and ALPL genes, as cell differentiation markers. The results indicate that the incorporation of Sr into MBG is beneficial for bone regeneration as promotes a pro-osteogenic effect, paving the way to the design of advanced devices enabled by these nanocarriers also in combination with drug release, for the treatment of bone pathologies, particularly in patients with osteoporosis. PMID- 29701682 TI - Circulating MicroRNA Biomarkers in Melanoma: Tools and Challenges in Personalised Medicine. AB - Effective management of melanoma depends heavily on early diagnosis. When detected in early non-metastatic stages, melanoma is almost 100% curable by surgical resection, however when detected in late metastatic stages III and IV, 5 year survival rates drop to ~50% and 10-25%, respectively, due to limited efficacy of current treatment options. This presents a pressing need to identify biomarkers that can detect patients at high risk of recurrence and progression to metastatic disease, which will allow for early intervention and survival benefit. Accumulating evidence over the past few decades has highlighted the potential use of circulating molecular biomarkers for melanoma diagnosis and prognosis, including lactate dehydrogenase (LDH), S100 calcium-binding protein B (S100B) and circulating tumor DNA (ctDNA) fragments. Since 2010, circulating microRNAs (miRNAs) have been increasingly recognised as more robust non-invasive biomarkers for melanoma due to their structural stability under the harsh conditions of the blood and different conditions of sample processing and isolation. Several pre analytical and analytical variables challenge the accurate quantification of relative miRNA levels between serum samples or plasma samples, leading to conflicting findings between studies on circulating miRNA biomarkers for melanoma. In this review, we provide a critical summary of the circulating miRNA biomarkers for melanoma published to date. PMID- 29701684 TI - Three-Dimensional Terahertz Coded-Aperture Imaging Based on Matched Filtering and Convolutional Neural Network. AB - As a promising radar imaging technique, terahertz coded-aperture imaging (TCAI) can achieve high-resolution, forward-looking, and staring imaging by producing spatiotemporal independent signals with coded apertures. However, there are still two problems in three-dimensional (3D) TCAI. Firstly, the large-scale reference signal matrix based on meshing the 3D imaging area creates a heavy computational burden, thus leading to unsatisfactory efficiency. Secondly, it is difficult to resolve the target under low signal-to-noise ratio (SNR). In this paper, we propose a 3D imaging method based on matched filtering (MF) and convolutional neural network (CNN), which can reduce the computational burden and achieve high resolution imaging for low SNR targets. In terms of the frequency-hopping (FH) signal, the original echo is processed with MF. By extracting the processed echo in different spike pulses separately, targets in different imaging planes are reconstructed simultaneously to decompose the global computational complexity, and then are synthesized together to reconstruct the 3D target. Based on the conventional TCAI model, we deduce and build a new TCAI model based on MF. Furthermore, the convolutional neural network (CNN) is designed to teach the MF TCAI how to reconstruct the low SNR target better. The experimental results demonstrate that the MF-TCAI achieves impressive performance on imaging ability and efficiency under low SNR. Moreover, the MF-TCAI has learned to better resolve the low-SNR 3D target with the help of CNN. In summary, the proposed 3D TCAI can achieve: (1) low-SNR high-resolution imaging by using MF; (2) efficient 3D imaging by downsizing the large-scale reference-signal matrix; and (3) intelligent imaging with CNN. Therefore, the TCAI based on MF and CNN has great potential in applications such as security screening, nondestructive detection, medical diagnosis, etc. PMID- 29701686 TI - Modeling Habitat Suitability of Migratory Birds from Remote Sensing Images Using Convolutional Neural Networks. AB - With the application of various data acquisition devices, a large number of animal movement data can be used to label presence data in remote sensing images and predict species distribution. In this paper, a two-stage classification approach for combining movement data and moderate-resolution remote sensing images was proposed. First, we introduced a new density-based clustering method to identify stopovers from migratory birds’ movement data and generated classification samples based on the clustering result. We split the remote sensing images into 16 × 16 patches and labeled them as positive samples if they have overlap with stopovers. Second, a multi-convolution neural network model is proposed for extracting the features from temperature data and remote sensing images, respectively. Then a Support Vector Machines (SVM) model was used to combine the features together and predict classification results eventually. The experimental analysis was carried out on public Landsat 5 TM images and a GPS dataset was collected on 29 birds over three years. The results indicated that our proposed method outperforms the existing baseline methods and was able to achieve good performance in habitat suitability prediction. PMID- 29701685 TI - Effect of Hydrophobic Polypeptide Length on Performances of Thermo-Sensitive Hydrogels. AB - Thermosensitive gels are commonly used as drug carriers in medical fields, mainly due to their convenient processing and easy functionalization. However, their overall performance has been severely affected by their unsatisfying biocompatibility and biodegradability. To this end, we synthesized poly(l alanine) (PLAla)-based thermosensitive hydrogels with different degrees of polymerization by ring-opening polymerization. The obtained mPEG45−PLAla copolymers showed distinct transition temperatures and degradation abilities. It was found that slight changes in the length of hydrophobic side groups had a decisive effect on the gelation behavior of the polypeptide hydrogel. Longer hydrophobic ends led to a lower gelation temperature of gel at the same concentration, which implied better gelation capability. The hydrogels showed rapid gelling, enhanced biocompatibility, and better degradability. Therefore, this thermosensitive hydrogel is a promising material for biomedical application. PMID- 29701678 TI - Connexins: Synthesis, Post-Translational Modifications, and Trafficking in Health and Disease. AB - Connexins are tetraspan transmembrane proteins that form gap junctions and facilitate direct intercellular communication, a critical feature for the development, function, and homeostasis of tissues and organs. In addition, a growing number of gap junction-independent functions are being ascribed to these proteins. The connexin gene family is under extensive regulation at the transcriptional and post-transcriptional level, and undergoes numerous modifications at the protein level, including phosphorylation, which ultimately affects their trafficking, stability, and function. Here, we summarize these key regulatory events, with emphasis on how these affect connexin multifunctionality in health and disease. PMID- 29701687 TI - Electronic and Magnetic Properties of Ni-Doped Zinc-Blende ZnO: A First Principles Study. AB - The electronic structure, band structure, density of state, and magnetic properties of Ni-doped zinc-blende (ZB) ZnO are studied by using the first principles method based on the spin-polarized density-functional theory. The calculated results show that Ni atoms can induce a stable ferromagnetic (FM) ground state in Ni-doped ZB ZnO. The magnetic moments mainly originate from the unpaired Ni 3d orbitals, and the O 2p orbitals contribute a little to the magnetic moments. The magnetic moment of a supercell including a single Ni atom is 0.79 μB. The electronic structure shows that Ni-doped ZB ZnO is a half metallic FM material. The strong spin-orbit coupling appears near the Fermi level and shows obvious asymmetry for spin-up and spin-down density of state, which indicates a significant hybrid effects from the Ni 3d and O 2p states. However, the coupling of the anti-ferromagnetic (AFM) state show metallic characteristic, the spin-up and spin-down energy levels pass through the Fermi surface. The magnetic moment of a single Ni atom is 0.74 μB. Moreover, the results show that the Ni 3d and O 2p states have a strong p-d hybridization effect near the Fermi level and obtain a high stability. The above theoretical results demonstrate that Ni-doped zinc blende ZnO can be considered as a potential half metal FM material and dilute magnetic semiconductors. PMID- 29701688 TI - Electrochemical Biosensor for Nitrite Based on Polyacrylic-Graphene Composite Film with Covalently Immobilized Hemoglobin. AB - A new biosensor for the analysis of nitrite in food was developed based on hemoglobin (Hb) covalently immobilized on the succinimide functionalized poly(n butyl acrylate)-graphene [poly(nBA)-rGO] composite film deposited on a carbon paste screen-printed electrode (SPE). The immobilized Hb on the poly(nBA)-rGO conducting matrix exhibited electrocatalytic ability for the reduction of nitrite with significant enhancement in the reduction peak at −0.6 V versus Ag/AgCl reference electrode. Thus, direct determination of nitrite can be achieved by monitoring the cathodic peak current signal of the proposed polyacrylic-graphene hybrid film-based voltammetric nitrite biosensor. The nitrite biosensor exhibited a reproducible dynamic linear response range from 0.05-5 mg L−1 nitrite and a detection limit of 0.03 mg L−1. No significant interference was observed by potential interfering ions such as Ca2+, Na+, K+, NH4+, Mg2+, and NO3− ions. Analysis of nitrite in both raw and processed edible bird’s nest (EBN) samples demonstrated recovery of close to 100%. The covalent immobilization of Hb on poly(nBA)-rGO composite film has improved the performance of the electrochemical nitrite biosensor in terms of broader detection range, lower detection limit, and prolonged biosensor stability. PMID- 29701690 TI - Smart Web-Based Platform to Support Physical Rehabilitation. AB - The enhancement of ubiquitous and pervasive computing brings new perspectives in medical rehabilitation. In that sense, the present study proposes a smart, web based platform to promote the reeducation of patients after hip replacement surgery. This project focuses on two fundamental aspects in the development of a suitable tele-rehabilitation application, which are: (i) being based on an affordable technology, and (ii) providing the patients with a real-time assessment of the correctness of their movements. A probabilistic approach based on the development and training of ten Hidden Markov Models (HMMs) is used to discriminate in real time the main faults in the execution of the therapeutic exercises. Two experiments are designed to evaluate the precision of the algorithm for classifying movements performed in the laboratory and clinical settings, respectively. A comparative analysis of the data shows that the models are as reliable as the physiotherapists to discriminate and identify the motion errors. The results are discussed in terms of the required setup for a successful application in the field and further implementations to improve the accuracy and usability of the system. PMID- 29701689 TI - In Silico and In Vitro Analyses of LncRNAs as Potential Regulators in the Transition from the Epithelioid to Sarcomatoid Histotype of Malignant Pleural Mesothelioma (MPM). AB - Malignant pleural mesothelioma (MPM) is a rare malignancy, with extremely poor survival rates. At present, treatment options are limited, with no second line chemotherapy for those who fail first line therapy. Extensive efforts are ongoing in a bid to characterise the underlying molecular mechanisms of mesothelioma. Recent research has determined that between 70-90% of our genome is transcribed. As only 2% of our genome is protein coding, the roles of the remaining proportion of non-coding RNA in biological processes has many applications, including roles in carcinogenesis and epithelial-mesenchymal transition (EMT), a process thought to play important roles in MPM pathogenesis. Non-coding RNAs can be separated loosely into two subtypes, short non-coding RNAs (<200 nucleotides) or long (>200 nucleotides). A significant body of evidence has emerged for the roles of short non-coding RNAs in MPM. Less is known about the roles of long non-coding RNAs (lncRNAs) in this disease setting. LncRNAs have been shown to play diverse roles in EMT, and it has been suggested that EMT may play a role in the aggressiveness of MPM histological subsets. In this report, using both in vitro analyses on mesothelioma patient material and in silico analyses of existing RNA datasets, we posit that various lncRNAs may play important roles in EMT within MPM, and we review the current literature regarding these lncRNAs with respect to both EMT and MPM. PMID- 29701693 TI - Erratum: l-Carnitine Supplementation in Recovery after Exercise; Nutrients 2018, 10, 349. AB - The Nutrients Editorial Office would like to report errors in the published paper [1]. The details are as follows: [...]. PMID- 29701692 TI - Correction: DeClercq, V.; et al. Association between Diet Quality and Adiposity in the Atlantic PATH Cohort. Nutrients 2017, 9, 1155. AB - The authors request the following corrections to their paper [1]. [...]. PMID- 29701694 TI - Preparation and Characterization of PVA Alkaline Solid Polymer Electrolyte with Addition of Bamboo Charcoal. AB - Natural bamboo charcoal (BC) powder has been developed as a novel filler in order to further improve performances of the polyvinyl alcohol (PVA)-based alkaline solid polymer electrolyte (ASPE) by solution casting method. X-ray diffraction patterns of composite polymer electrolyte with BC revealed the decrease in the degree of crystallinity with increasing content of BC. Scanning electron microscopy images showed pores on a micrometer scale (average diameter about 2 μm) distributed inside and on the surface of the membranes, indicating a three dimension network formed in the polymer framework. The ionic conductivity was measured by the alternating-current (AC) impedance method, and the highest conductivity value of 6.63 × 10−2 S·cm−1 was obtained with 16 wt % of BC content and mKOH:mPVA = 2:1.5 at 30 °C. The contents of BC and KOH could significantly influence the conductivity. The temperature dependence of the bulk electrical conductivity displayed a combination of Arrhenius nature, and the activation energy for the ion in polymer electrolyte has been calculated. The electrochemical stability window of the electrolyte membrane was over 1.6 V. The thermogravimetric analysis curves showed that the degradation temperatures of PVA-BC-KOH ASPE membranes shifted toward higher with adding BC. A simple nickel-hydrogen battery containing PVA-BC-KOH electrolyte membrane was assembled with a maximum discharge capacity of 193 mAh·g−1. PMID- 29701691 TI - Paneth Cells during Viral Infection and Pathogenesis. AB - Paneth cells are major secretory cells located in the crypts of Lieberkühn in the small intestine. Our understanding of the diverse roles that Paneth cells play in homeostasis and disease has grown substantially since their discovery over a hundred years ago. Classically, Paneth cells have been characterized as a significant source of antimicrobial peptides and proteins important in host defense and shaping the composition of the commensal microbiota. More recently, Paneth cells have been shown to supply key developmental and homeostatic signals to intestinal stem cells in the crypt base. Paneth cell dysfunction leading to dysbiosis and a compromised epithelial barrier have been implicated in the etiology of Crohn’s disease and susceptibility to enteric bacterial infection. Our understanding of the impact of Paneth cells on viral infection is incomplete. Enteric α-defensins, produced by Paneth cells, can directly alter viral infection. In addition, α-defensins and other antimicrobial Paneth cell products may modulate viral infection indirectly by impacting the microbiome. Here, we discuss recent insights into Paneth cell biology, models to study their function, and the impact, both direct and indirect, of Paneth cells on enteric viral infection. PMID- 29701695 TI - A Chemical Investigation of the Leaves of Morus alba L. AB - The leaves of Morus alba L. are an important herbal medicine in Asia. The systematic isolation of the metabolites of the leaves of Morus alba L. was achieved using a combination of liquid chromatography techniques. The structures were elucidated by spectroscopic data analysis and the absolute configuration was determined based on electronic circular dichroism (ECD) spectroscopic data and hydrolysis experiments. Their biological activity was evaluated using different biological assays, such as the assessment of their capacity to inhibit the aldose reductase enzyme; the determination of their cytotoxic activity and the evaluation of their neuroprotective effects against the deprivation of serum or against the presence of nicouline. Chemical investigation of the leaves of Morus alba L. resulted in four new structures 1-4 and a known molecule 5. Compounds 2 and 5 inhibited aldose reductase with IC50 values of 4.33 μM and 6.0 μM compared with the potent AR inhibitor epalrestat (IC50 1.88 × 10−3 μM). Pretreatment with compound 3 decreased PC12 cell apoptosis subsequent serum deprivation condition and pretreatment with compound 5 decreased nicouline induced PC12 cell apoptosis as compared with control cells (p < 0.001). PMID- 29701698 TI - Appdaptivity: An Internet of Things Device-Decoupled System for Portable Applications in Changing Contexts. AB - Currently, applications in the Internet of Things (IoT) are tightly coupled to the underlying physical devices. As a consequence, upon adding a device, device replacement or user’s relocation to a different physical space, application developers have to re-perform installation and configuration processes to reconfigure applications, which bears costs in time and knowledge of low-level details. In the emerging IoT field, this issue is even more challenging due to its current unpredictable growth in term of applications and connected devices. In addition, IoT applications can be personalised to each end user and can be present in different environments. As a result, IoT scenarios are very changeable, presenting a challenge for IoT applications. In this paper we present Appdaptivity, a system that enables the development of portable device-decoupled applications that can be adapted to changing contexts. Through Appdaptivity, application developers can intuitively create portable and personalised applications, disengaging from the underlying physical infrastructure. Results confirms a good scalability of the system in terms of connected users and components involved. PMID- 29701697 TI - Marine and Freshwater Feedstocks as a Precursor for Nitrogen-Containing Carbons: A Review. AB - Marine-derived as well as freshwater feedstock offers important benefits, such as abundance, morphological and structural variety, and the presence of multiple elements, including nitrogen and carbon. Therefore, these renewal resources may be useful for obtaining N- and C-containing materials that can be manufactured by various methods, such as pyrolysis and hydrothermal processes supported by means of chemical and physical activators. However, every synthesis concept relies on an efficient transfer of nitrogen and carbon from marine/freshwater feedstock to the final product. This paper reviews the advantages of marine feedstock over synthetic and natural but non-marine resources as precursors for the manufacturing of N-doped activated carbons. The manufacturing procedure influences some crucial properties of nitrogen-doped carbon materials, such as pore structure and the chemical composition of the surface. An extensive review is given on the relationship between carbon materials manufacturing from marine feedstock and the elemental content of nitrogen, together with a description of the chemical bonding of nitrogen atoms at the surface. N-doped carbons may serve as effective adsorbents for the removal of pollutants from the gas or liquid phase. Non-recognized areas of adsorption-based applications for nitrogen-doped carbons are presented, too. The paper proves that nitrogen-doped carbon materials belong to most of the prospective electrode materials for electrochemical energy conversion and storage technologies such as fuel cells, air-metal batteries, and supercapacitors, as well as for bioimaging. The reviewed material belongs to the widely understood field of marine biotechnology in relation to marine natural products. PMID- 29701696 TI - Estrogen and/or Estrogen Receptor alpha Inhibits BNIP3-Induced Apoptosis and Autophagy in H9c2 Cardiomyoblast Cells. AB - The process of autophagy in heart cells maintains homeostasis during cellular stress such as hypoxia by removing aggregated proteins and damaged organelles and thereby protects the heart during the times of starvation and ischemia. However, autophagy can lead to substantial cell death under certain circumstances. BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3), a hypoxia induced marker, has been shown to induce both autophagy and apoptosis. A BNIP3 docked organelle, e.g., mitochondria, also determines whether autophagy or apoptosis will take place. Estrogen (E2) and estrogen receptor (ER) alpha (ERα) have been shown to protect the heart against mitochondria-dependent apoptosis. The aim of the present study is to investigate the mechanisms by which ERα regulates BNIP3-induced apoptosis and autophagy, which is associated with hypoxic injury, in cardiomyoblast cells. An in vitro model to mimic hypoxic injury in the heart by engineering H9c2 cardiomyoblast cells to overexpress BNIP3 was established. Further, the effects of E2 and ERα in BNIP3-induced apoptosis and autophagy were determined in BNIP3 expressing H9c2 cells. Results from TUNEL assay and Immunoflourecense assay for LC3 puncta formation, respectively, revealed that ERα/E2 suppresses BNIP3-induced apoptosis and autophagy. The Western blot analysis showed ERα/E2 decreases the protein levels of caspase 3 (apoptotic marker), Atg5, and LC3-II (autophagic markers). Co immunoprecipitation of BNIP3 and immunoblotting of Bcl-2 and Rheb showed that ERα reduced the interaction between BNIP3 and Bcl-2 or Rheb. The results confirm that ERα binds to BNIP3 causing a reduction in the levels of functional BNIP3 and thereby inhibits cellular apoptosis and autophagy. In addition, ERα attenuated the activity of the BNIP3 promoter by binding to SP-1 or NFκB sites. PMID- 29701699 TI - Simultaneous Determination of Decursin, Decursinol Angelate, Nodakenin, and Decursinol of Angelica gigas Nakai in Human Plasma by UHPLC-MS/MS: Application to Pharmacokinetic Study. AB - Coumarins in Cham-dang-gwi, the dried root of Angelica gigas Nakai (AGN), possess pharmacological effects on anemia, pain, infection, and articular rheumatism. The AGN root containes decursin (D), decursinol angelate (DA), nodakenin, and decursinol (DOH), a major metabolite of D and DA. The aim of this study was to develop a simultaneous determination method for these four coumarins in human plasma using ultra high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). Chromatographic separation was performed on dual columns (Kinetex® C18 column and Capcell core C18 column) with mobile phase consisting of water and acetonitrile at a flow rate of 0.3 mL/min using gradient elution. Multiple reaction monitoring was operated in positive ion mode with precursors to product ion transition values of m/z 328.9→228.8, 328.9→228.9, 409.4→248.8, and 246.8→212.9 to measure D, DA, nodakenin, and DOH, respectively. Linear calibration curves were fitted over concentration range of 0.05-50 ng/mL for these four components, with correlation coefficient greater than 0.995. Inter- and intra-day accuracies were between 90.60% and 108.24%. These precisions were within 11.19% for all components. The established method was then applied to a pharmacokinetic study for the four coumarins after usual dosing in Korean subjects. PMID- 29701700 TI - Using the Transient Response of WO3 Nanoneedles under Pulsed UV Light in the Detection of NH3 and NO2. AB - Here we report on the use of pulsed UV light for activating the gas sensing response of metal oxides. Under pulsed UV light, the resistance of metal oxides presents a ripple due to light-induced transient adsorption and desorption phenomena. This methodology has been applied to tungsten oxide nanoneedle gas sensors operated either at room temperature or under mild heating (50 °C or 100 °C). It has been found that by analyzing the rate of resistance change caused by pulsed UV light, a fast determination of gas concentration is achieved (ten-fold improvement in response time). The technique is useful for detecting both oxidizing (NO2) and reducing (NH3) gases, even in the presence of different levels of ambient humidity. Room temperature operated sensors under pulsed UV light show good response towards ammonia and nitrogen dioxide at low power consumption levels. Increasing their operating temperature to 50 °C or 100 °C has the effect of further increasing sensitivity. PMID- 29701701 TI - A Systematic Review of the Time Series Studies Addressing the Endemic Risk of Acute Gastroenteritis According to Drinking Water Operation Conditions in Urban Areas of Developed Countries. AB - Time series studies (TSS) can be viewed as an inexpensive way to tackle the non epidemic health risk from fecal pathogens in tap water in urban areas. Following the PRISMA recommendations, I reviewed TSS addressing the endemic risk of acute gastroenteritis risk according to drinking water operation conditions in urban areas of developed countries. Eighteen studies were included, covering 17 urban sites (seven in North-America and 10 in Europe) with study populations ranging from 50,000 to 9 million people. Most studies used general practitioner consultations or visits to hospitals for acute gastroenteritis (AGE) as health outcomes. In 11 of the 17 sites, a significant and plausible association was found between turbidity (or particle count) in finished water and the AGE indicator. When provided and significant, the interquartile excess of relative risk estimates ranged from 3-13%. When examined, water temperature, river flow, and produced flow were strongly associated with the AGE indicator. The potential of TSS for the study of the health risk from fecal pathogens in tap water is limited by the lack of specificity of turbidity and its site-sensitive value as an exposure proxy. Nevertheless, at the DWS level, TSS could help water operators to identify operational conditions most at risk, almost if considering other water operation indicators, in addition to turbidity, as possible relevant proxies for exposure. PMID- 29701702 TI - Metabolomic Profiles of Dinophysis acuminata and Dinophysis acuta Using Non Targeted High-Resolution Mass Spectrometry: Effect of Nutritional Status and Prey. AB - Photosynthetic species of the genus Dinophysis are obligate mixotrophs with temporary plastids (kleptoplastids) that are acquired from the ciliate Mesodinium rubrum, which feeds on cryptophytes of the Teleaulax-Plagioselmis-Geminigera clade. A metabolomic study of the three-species food chain Dinophysis-Mesodinium Teleaulax was carried out using mass spectrometric analysis of extracts of batch cultured cells of each level of that food chain. The main goal was to compare the metabolomic expression of Galician strains of Dinophysis acuminata and D. acuta that were subjected to different feeding regimes (well-fed and prey-limited) and feeding on two Mesodinium (Spanish and Danish) strains. Both Dinophysis species were able to grow while feeding on both Mesodinium strains, although differences in growth rates were observed. Toxin and metabolomic profiles of the two Dinophysis species were significantly different, and also varied between different feeding regimes and different prey organisms. Furthermore, significantly different metabolomes were expressed by a strain of D. acuminata that was feeding on different strains of the ciliate Mesodinium rubrum. Both species-specific metabolites and those common to D. acuminata and D. acuta were tentatively identified by screening of METLIN and Marine Natural Products Dictionary databases. This first metabolomic study applied to Dinophysis acuminata and D.acuta in culture establishes a basis for the chemical inventory of these species. PMID- 29701704 TI - Real-Time Vision-Based Stiffness Mapping ?. AB - This paper presents new findings concerning a hand-held stiffness probe for the medical diagnosis of abnormalities during palpation of soft-tissue. Palpation is recognized by the medical community as an essential and low-cost method to detect and diagnose disease in soft-tissue. However, differences are often subtle and clinicians need to train for many years before they can conduct a reliable diagnosis. The probe presented here fills this gap providing a means to easily obtain stiffness values of soft tissue during a palpation procedure. Our stiffness sensor is equipped with a multi degree of freedom (DoF) Aurora magnetic tracker, allowing us to track and record the 3D position of the probe whilst examining a tissue area, and generate a 3D stiffness map in real-time. The stiffness probe was integrated in a robotic arm and tested in an artificial environment representing a good model of soft tissue organs; the results show that the sensor can accurately measure and map the stiffness of a silicon phantom embedded with areas of varying stiffness. PMID- 29701703 TI - Molecular and Clinical Issues about the Risk of Venous Thromboembolism in Older Patients: A Focus on Parkinson's Disease and Parkinsonism. AB - Venous thromboembolism (VTE) is a common and potentially life-threatening condition which includes both deep-vein thrombosis (DVT) and pulmonary embolism (PE). VTE has a significant clinical and epidemiological impact in the elderly, and its incidence increases to more than 1% per year in older patients, suggesting the presence of specific age-related risk factors in this population. Immobilization seems to predominate as the main cause in patients admitted for medical acute illness in medicine wards, and there is evidence of a high risk in older patients with immobilization resulting from advanced forms of Parkinson’s disease (PD), regardless of the presence of an acute medical condition. In this review, we would to discuss the recent evidence on clinical, molecular and epidemiological features of VTE in older frail subjects focusing on patients with PD and parkinsonism. We also discuss some therapeutic issues about the risk prevention and we suggest a thorough comprehensive geriatric assessment that can represent an optimal strategy to identify and prevent the VTE risk in these patients. PMID- 29701705 TI - Characterization of RUNX1T1, an Adipogenesis Regulator in Ovine Preadipocyte Differentiation. AB - Runt-related transcription factor 1 translocation partner 1 (RUNX1T1), a potential novel regulator of adipogenesis, exists in two splice variants: a long (RUNX1T1-L) and a short (RUNX1T1-S) isoform. However, there is no data showing the existence of RUNX1T1 in ovine subcutaneous fat at different stages of developmental and its role on ovine adipogenesis. Therefore, the objectives of this study were to evaluate the presence of RUNX1T1 in subcutaneous fat of five day-old to 24-month-old sheep and to investigate the role of RUNX1T1 in ovine adipogenesis. In this study, we detected a 1829 bp cDNA fragment of RUNX1T1 which contains a 1815 bp coding sequence that encodes 602-amino acid and 14 bp of 5' untranslated region, respectively. The amino acid sequence of RUNX1T1 has 31.18 94.21% homology with other species' protein sequences. During fat development, the RUNX1T1 protein expression was higher in subcutaneous fat of 24-month-old Hu sheep. In addition, the expression of RUNX1T1-L mRNA decreased first, then subsequently increased during ovine preadipocyte differentiation. Knockdown of RUNX1T1-L in ovine preadipocytes promoted preadipocyte differentiation and lipid accumulation. Taken together, our data suggests that RUNX1T1 is an important functional molecule in adipogenesis. Moreover, it showed for the first time that RUNX1T1-L was negatively correlated with the ovine preadipocyte differentiation. PMID- 29701707 TI - Study on the Mechanical Properties of Bionic Coupling Layered B4C/5083Al Composite Materials. AB - Based on microstructure characteristics of Meretrix lusoria shell and Rapana venosa shell, bionic coupling layered B4C/5083Al composites with different layered structures and hard/soft combination models were fabricated via hot pressed sintering. The simplified bionic coupling models with hard and soft layers were similar to layered structure and hardness tendency of shells, guiding the bionic design and fabrication. B4C/5083Al composites with various B4C contents and pure 5083Al were treated as hard and soft layers, respectively. Hot pressed sintering maintained the designed bionic structure and enhanced high bonding strength between ceramics and matrix. Compared with B4C/5083Al composites, bionic layered composites exhibited high mechanical properties including flexural strength, fracture toughness, compressive strength and impact toughness. The hard layers absorbed applied loads in the form of intergranular fracture. Besides connection role, soft layers restrained slabbing phenomenon and reset extension direction of cracks among layers. The coupling functions of bionic composites proved the feasibility and practicability of bionic fabrication, providing a new method for improvement of ceramic/Al composite with properties of being lightweight and high mechanical strength. PMID- 29701706 TI - Anticancer Profiling for Coumarins and Related O-Naphthoquinones from Mansonia gagei against Solid Tumor Cells In Vitro. AB - Napthoquinones and coumarins are naturally occurring compounds with potential anticancer activity. In the current study, two O-naphthoquinons (mansonone-G and mansonone-N) and six coumarins (mansorin-A, mansorin-B, mansorin-C, mansorins-I, mansorin-II, and mansorin-III) were isolated from the heartwood of Mansonia gagei family Sterculariaceae. Isolated compounds were examined for their potential anticancer activity against breast (MCF-7), cervix (HeLa), colorectal (HCT-116) and liver (HepG2) cancer cells using Sulfarhodamine-B (SRB) assay. Mansorin-II and mansorin-III showed relatively promising cytotoxic profile in all cell lines under investigation with inhibitory concentrations (IC50s) in the range of 0.74 µM to 36 µM and 3.95 µM to 35.3 µM, respectively. In addition, mansorin-B, mansorin-C, mansorin-II and mansorin-III significantly increased cellular entrapment of the P-glycoprotein (P-gp) substrate, doxorubicin, in colorectal cancer cells expressing the P-gp pump. The inhibitory effect of the isolated compounds on P-gp pump was examined using human recombinant P-gp molecules attached to ATPase subunit. Mansorin-B and mansonone-G were found to inhibit the P-gp attached ATPase subunit. On the other hand, mansorin-C, mansorin-III and mansorin-II inhibited P-gp pump via dual action (P gp related ATPase subunit inhibition and P-gp substrate binding site occupation). However, mansorin II was examined for its potential chemomodulatory effect to paclitaxel (PTX) against colorectal cancer cells (HCT-116 and CaCo-2). Mansorin II significantly reduced the IC50 of PTX in HCT-116 cells from 27.9 ± 10.2 nM to 5.1 ± 1.9 nM (synergism with combination index of 0.44). Additionally, Mansorin-II significantly reduced the IC50 of PTX in CaCo-2 cells from 2.1 ± 0.8 µM to 0.13 ± 0.03 µM (synergism with combination index of 0.18). Furthermore, cell cycle analysis was studied after combination of mansorin-II with paclitaxel using DNA flow cytometry analysis. Synergism of mansorin-II and PTX was reflected in increasing apoptotic cell population in both HCT-116 and CaCo-2 cells compared to PTX treatment alone. Combination of mansorin-II with PTX in CaCo-2 cells significantly increased the cell population in G2/M phase (from 2.9 ± 0.3% to 7.7 ± 0.8%) with reciprocal decrease in G0/G1 cell fraction from 52.1 ± 1.1% to 45.5 ± 1.0%. Similarly in HCT-116 cells, mansorin-II with PTX significantly increased the cell population in G2/M phase (from 33.4 ± 2.8% to 37.6 ± 1.3%) with reciprocal decrease in the S-phase cell population from 22.8 ± 1.7% to 20.2 ± 0.8%. In conclusion, mansorin-II synergizes the anticancer effect of paclitaxel in colorectal cancer cells, which might be partially attributed to enhancing its cellular entrapment via inhibiting P-gp efflux pump. PMID- 29701708 TI - Novel Gold Dendritic Nanoforests Combined with Titanium Nitride for Visible-Light Enhanced Chemical Degradation. AB - In this study, gold dendritic nanoforests (Au DNFs)-titanium nitride (TiN) composite was firstly proposed for visible-light photodegradation of pollutants. A high-power impulse magnetron sputtering system was used to coat TiN films on silicon wafers, and a fluoride-assisted galvanic replacement reaction was applied to deposit Au DNFs on TiN/Si substrates. Scanning electron microscope images and X-ray diffraction patterns of TiN/Si, Au DNFs/Si, and Au DNFs/TiN/Si samples verified that this synthesis process was accurately controlled. The average reflectance of Au DNFs/Si and Au DNFs/TiN/Si considerably declined to approximately 10%, because the broadband localized surface plasmon resonances of Au DNFs cause broadband absorbance and low reflectance. In photocatalytic performance, 90.66 ± 1.41% 4-nitrophenol was successfully degraded in 180 min by Au DNFs/TiN/Si under visible-light irradiation. Therefore, Au DNFs/TiN/Si has the chance to be a visible-light photocatalyst for photodegradation of pollutants. PMID- 29701709 TI - Effects of Essential Oils from Zingiberaceae Plants on Root-Rot Disease of Panax notoginseng. AB - Replanting obstacles of Panax notoginseng caused by complex factors, including pathogens, have received great attention. In this study, essential oils (EOs) from either Alpinia officinarum Hance or Amomum tsao-ko (Zingiberaceae) were found to inhibit the growth of P. notoginseng-associated pathogenic fungi in vitro. Subsequent GC-MS analysis revealed the chemical profiles of two plant derived EOs. Linalool and eucalyptol were found to be abundant in the EOs and tested for their antifungal activities. In addition, the synergistic effects of A. tsao-ko EOs and hymexazol were also examined. These findings suggested that Zingiberaceae EOs might be a good source for developing new green natural pesticides fighting against root-rot of P. notoginseng. PMID- 29701710 TI - An Integrated Approach of Proteomics and Computational Genetic Modification Effectiveness Analysis to Uncover the Mechanisms of Flood Tolerance in Soybeans. AB - Flooding negatively affects the growth of soybeans. Recently, omic approaches have been used to study abiotic stress responses in plants. To explore flood tolerant genes in soybeans, an integrated approach of proteomics and computational genetic modification effectiveness analysis was applied to the soybean (Glycine max L. (Merrill)). Flood-tolerant mutant and abscisic acid (ABA) treated soybean plants were used as the flood-tolerant materials. Among the primary metabolism, glycolysis, fermentation, and tricarboxylic acid cycle were markedly affected under flooding. Fifteen proteins, which were related to the affected processes, displayed similar protein profiles in the mutant and ABA treated soybean plants. Protein levels of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), aconitase 1, and 2-oxoglutarate dehydrogenase were higher in flood-tolerant materials than in wild-type soybean plants under flood conditions. These three proteins were positioned in each of the three enzyme groups revealed by our computational genetic modification effectiveness analysis, and the three proteins configured a candidate set of genes to promote flood tolerance. Additionally, transcript levels of GAPDH were similar in flood tolerant materials and in unstressed plants. These results suggest that proteins related to energy metabolism might play an essential role to confer flood tolerance in soybeans. PMID- 29701711 TI - Anti-EGFR Indocyanine Green-Mitomycin C-Loaded Perfluorocarbon Double Nanoemulsion: A Novel Nanostructure for Targeted Photochemotherapy of Bladder Cancer Cells. AB - The use of phototherapy as an adjuvant bladder cancer treatment has long been considered, but its application has been severely hampered due to a lack of tumor specificity, unpredicted cytotoxicity, and insufficient anticancer efficacy. In this study, we aim to manufacture anti-EGFR indocyanine green (ICG) mitomycin C (MMC) encapsulated perfluorocarbon double nanoemulsions (EIMPDNEs), and explore their photochemotherapeutic efficacy on EGFR-expressing bladder cancer cells in vitro. The EIMPDNEs were manufactured using a double emulsification technique followed by antibody conjugation on the particles’ surfaces. The EIMPDNE were 257 ± 19.4 nm in size, with a surface charge of −12.3 ± 2.33 mV. The EGFR targetability of the EIMPNDE was confirmed by its enhanced binding efficiency to T24 cells when compared with the performance of nanodroplets without EGFR conjugation (p < 0.05). In comparison with freely dissolved ICG, the EIMPDNEs with equal ICG content conferred an improved thermal stability to the encapsulated ICG, and were able to provide a comparable hyperthermia effect and significantly enhanced the production of singlet oxygen under 808 nm near infrared (NIR) exposure with an intensity of 6 W cm−2 for 5 min (p < 0.05). Based on viability analyses, our data showed that the EIMPDNEs were effective in bladder cancer cell eradication upon NIR exposure (808 nm; 6 W cm−2), and the resulting cell death rate was even higher than that caused by a five-fold higher amount of entrapped MMC alone. With the merits of improved ICG stability, EGFR binding specificity, and effective cancer cell eradication, the EIMPDNEs exhibit potential for use in EGFR-expressing bladder cancer therapy with lower chemotoxicity. PMID- 29701712 TI - LiGe(SiMe3)3: A New Substituent for the Synthesis of Metalloid Tin Clusters from Metastable Sn(I) Halide Solutions. AB - The most fruitful synthetic route to metalloid tin clusters applies the disproportionation reaction of metastable Sn(I) halide solutions, whereby Si(SiMe3)3 is mostly used as the stabilizing substituent. Here, we describe the synthesis and application of the slightly modified substituent Ge(SiMe3)3, which can be used for the synthesis of metalloid tin clusters to give the neutral cluster Sn10[Ge(SiMe3)3]6 as well as the charged clusters {Sn10[Ge(SiMe3)3]5}− and {Sn10[Ge(SiMe3)3]4}2−. The obtained metalloid clusters are structurally similar to their Si(SiMe3)3 derivatives. However, differences with respect to the stability in solution are observed. Additionally, a different electronic situation for the tin atoms is realized as shown by 119mSn Mössbauer spectroscopy, giving further insight into the different kinds of tin atoms within the metalloid cluster {Sn10[Ge(SiMe3)3]4}2−. The synthesis of diverse derivatives gives the opportunity to check the influence of the substituent for further investigations of metalloid tin cluster compounds. PMID- 29701713 TI - Plasmonic Multichannel Refractive Index Sensor Based on Subwavelength Tangent Ring Metal-Insulator-Metal Waveguide. AB - In this paper, a multichannel refractive index sensor based on a subwavelength metal-insulator-metal (MIM) waveguide coupled with tangent-ring resonators is proposed. When two tangent-ring resonators were placed above the MIM waveguide, Fano resonance with asymmetrical line shape appeared in the transmission spectrum due to the interference between the light-dark resonant modes. The sensitivity and figure of merit were as high as 880 nm/RIU and 964, respectively. Through adding more tangent-ring resonators, multiple Fano resonances with ultrasharp peaks/dips were achieved in the wavelength range of 800-2000 nm. Besides, negative group delays were also observed in the Fano resonant dips. Two dimensional finite-difference time-domain (FDTD) method was used to simulate and analyze the performances of the proposed structures. These kinds of multiring structures can find important applications in the on-chip optical sensing and optical communication areas. PMID- 29701714 TI - Doxorubicin Release Controlled by Induced Phase Separation and Use of a Co Solvent. AB - Electrospun-based drug delivery is emerging as a versatile means of localized therapy; however, controlling the release rates of active agents still remains as a key question. We propose a facile strategy to control the drug release behavior from electrospun fibers by a simple modification of polymer matrices. Polylactic acid (PLA) was used as a major component of the drug-carrier, and doxorubicin hydrochloride (Dox) was used as a model drug. The influences of a polar co solvent, dimethyl sulfoxide (DMSO), and a hydrophilic polymer additive, polyvinylpyrrolidone (PVP), on the drug miscibility, loading efficiency and release behavior were investigated. The use of DMSO enabled the homogeneous internalization of the drug as well as higher drug loading efficiency within the electrospun fibers. The PVP additive induced phase separation in the PLA matrix and acted as a porogen. Preferable partitioning of Dox into the PVP domain resulted in increased drug loading efficiency in the PLA/PVP fiber. Fast dissolution of PVP domains created pores in the fibers, facilitating the release of internalized Dox. The novelty of this study lies in the detailed experimental investigation of the effect of additives in pre-spinning formulations, such as co solvents and polymeric porogens, on the drug release behavior of nanofibers. PMID- 29701715 TI - Research on Occupational Safety, Health Management and Risk Control Technology in Coal Mines. AB - This paper studies the occupational safety and health management methods as well as risk control technology associated with the coal mining industry, including daily management of occupational safety and health, identification and assessment of risks, early warning and dynamic monitoring of risks, etc.; also, a B/S mode software (Geting Coal Mine, Jining, Shandong, China), i.e., Coal Mine Occupational Safety and Health Management and Risk Control System, is developed to attain the aforementioned objectives, namely promoting the coal mine occupational safety and health management based on early warning and dynamic monitoring of risks. Furthermore, the practical effectiveness and the associated pattern for applying this software package to coal mining is analyzed. The study indicates that the presently developed coal mine occupational safety and health management and risk control technology and the associated software can support the occupational safety and health management efforts in coal mines in a standardized and effective manner. It can also control the accident risks scientifically and effectively; its effective implementation can further improve the coal mine occupational safety and health management mechanism, and further enhance the risk management approaches. Besides, its implementation indicates that the occupational safety and health management and risk control technology has been established based on a benign cycle involving dynamic feedback and scientific development, which can provide a reliable assurance to the safe operation of coal mines. PMID- 29701716 TI - Comparing Building and Neighborhood-Scale Variability of CO2 and O3 to Inform Deployment Considerations for Low-Cost Sensor System Use. AB - The increased use of low-cost air quality sensor systems, particularly by communities, calls for the further development of best-practices to ensure these systems collect usable data. One area identified as requiring more attention is that of deployment logistics, that is, how to select deployment sites and how to strategically place sensors at these sites. Given that sensors are often placed at homes and businesses, ideal placement is not always possible. Considerations such as convenience, access, aesthetics, and safety are also important. To explore this issue, we placed multiple sensor systems at an existing field site allowing us to examine both neighborhood-level and building-level variability during a concurrent period for CO2 (a primary pollutant) and O3 (a secondary pollutant). In line with previous studies, we found that local and transported emissions as well as thermal differences in sensor systems drive variability, particularly for high-time resolution data. While this level of variability is unlikely to affect data on larger averaging scales, this variability could impact analysis if the user is interested in high-time resolution or examining local sources. However, with thoughtful placement and thorough documentation, high-time resolution data at the neighborhood level has the potential to provide us with entirely new information on local air quality trends and emissions. PMID- 29701717 TI - Correction: Renzaho, A.M.N., et al. The Synergetic Effect of Targeted Resource Transfers for Families, Child Sensitive Social Protection Programs, and Capacity Building for Effective Social Protection on Children's Nutritional Status in Nepal. Int. J. Environ. Res. Public Health 2017, 14, 1502. PMID- 29701718 TI - Structure-Function Mutational Analysis and Prediction of the Potential Impact of High Risk Non-Synonymous Single-Nucleotide Polymorphism on Poliovirus 2A Protease Stability Using Comprehensive Informatics Approaches. AB - Polio viral proteinase 2A performs several essential functions in genome replication. Its inhibition prevents viral replication, thus making it an excellent substrate for drug development. In this study, the three-dimensional structure of 2A protease was determined and optimized by homology modelling. To predict the molecular basis of the interaction of small molecular agonists, docking simulations were performed on a structurally diverse dataset of poliovirus 2A protease (PV2Apr°) inhibitors. Docking results were employed to identify high risk missense mutations that are highly damaging to the structure, as well as the function, of the protease. Intrinsic disorder regions (IDRs), drug binding sites (DBS), and protein stability changes upon mutations were also identified among them. Our results demonstrated dominant roles for Lys 15, His 20, Cys 55, Cys 57, Cys 64, Asp 108, Cys 109 and Gly 110, indicating the presence of various important drug binding sites of the protein. Upon subjecting these sites to single-nucleotide polymorphism (SNP) analysis, we observed that out of 155 high risk SNPs, 139 residues decrease the protein stability. We conclude that these missense mutations can affect the functionality of the 2A protease, and that identified protein binding sites can be directed for the attachment and inhibition of the target proteins. PMID- 29701719 TI - Novel Targets for Treating Ischemia-Reperfusion Injury in the Liver. AB - Liver ischemia-reperfusion injury (IRI) is a major complication of hemorrhagic shock, liver transplantation, and other liver surgeries. It is one of the leading causes for post-surgery hepatic dysfunction, always leading to morbidity and mortality. Several strategies, such as low-temperature reperfusion and ischemic preconditioning, are useful for ameliorating liver IRI in animal models. However, these methods are difficult to perform in clinical surgeries. It has been reported that the activation of peroxisome proliferator activated receptor gamma (PPARγ) protects the liver against IRI, but with unidentified direct target gene(s) and unclear mechanism(s). Recently, FAM3A, a direct target gene of PPARγ, had been shown to mediate PPARγ’s protective effects in liver IRI. Moreover, noncoding RNAs, including LncRNAs and miRNAs, had also been reported to play important roles in the process of hepatic IRI. This review briefly discussed the roles and mechanisms of several classes of important molecules, including PPARγ, FAM3A, miRNAs, and LncRNAs, in liver IRI. In particular, oral administration of PPARγ agonists before liver surgery or liver transplantation to activate hepatic FAM3A pathways holds great promise for attenuating human liver IRI. PMID- 29701720 TI - Sufficient Social Support as a Possible Preventive Factor against Fighting and Bullying in School Children. AB - Background: This study aims to explore how sufficient social support can act as a possible preventive factor against fighting and bullying in school-aged children in 9 European countries. Methods: Data for this study were collected during the 2013/2014 Health Behaviour in School-aged Children (HBSC) survey. The sample consisted of 9 European countries, involving 43,667 school children in total, aged 11, 13 and 15 years. The analysed data focus on social context (relations with family, peers, and school) as well as risk behaviours such as smoking, drunkenness, fighting and bullying in adolescents. The relationships between social support and violent behaviour variables were estimated using multiple regression models and multivariate analyses. Results: Bullying, across 9 countries, was more prevalent than fighting, except for Armenia, Israel, and Poland. The prevalence among countries differed considerably, with fighting being most expressed in Armenia and bullying—in Latvia and Lithuania. The strongest risk factors for bullying and fighting were male gender (less expressed for bullying), smoking and alcohol consumption. In addition, for bullying the social support was similarly strong factor like above-mentioned factors, while for fighting—less significant, but still independent. All forms of social support were significantly relate with lower violent behaviour of school children, and family support was associated most strongly. Regardless the socioeconomic, historical, and cultural differences among selected countries, the enhancement and reinforcement of the social support from possible many different resources should be taken into consideration in prevention programs against school violence behaviours. PMID- 29701721 TI - Improving Fall Detection Using an On-Wrist Wearable Accelerometer. AB - Fall detection is a very important challenge that affects both elderly people and the carers. Improvements in fall detection would reduce the aid response time. This research focuses on a method for fall detection with a sensor placed on the wrist. Falls are detected using a published threshold-based solution, although a study on threshold tuning has been carried out. The feature extraction is extended in order to balance the dataset for the minority class. Alternative models have been analyzed to reduce the computational constraints so the solution can be embedded in smart-phones or smart wristbands. Several published datasets have been used in the Materials and Methods section. Although these datasets do not include data from real falls of elderly people, a complete comparison study of fall-related datasets shows statistical differences between the simulated falls and real falls from participants suffering from impairment diseases. Given the obtained results, the rule-based systems represent a promising research line as they perform similarly to neural networks, but with a reduced computational cost. Furthermore, support vector machines performed with a high specificity. However, further research to validate the proposal in real on-line scenarios is needed. Furthermore, a slight improvement should be made to reduce the number of false alarms. PMID- 29701722 TI - Cooperative Monocular-Based SLAM for Multi-UAV Systems in GPS-Denied Environments. AB - This work presents a cooperative monocular-based SLAM approach for multi-UAV systems that can operate in GPS-denied environments. The main contribution of the work is to show that, using visual information obtained from monocular cameras mounted onboard aerial vehicles flying in formation, the observability properties of the whole system are improved. This fact is especially notorious when compared with other related visual SLAM configurations. In order to improve the observability properties, some measurements of the relative distance between the UAVs are included in the system. These relative distances are also obtained from visual information. The proposed approach is theoretically validated by means of a nonlinear observability analysis. Furthermore, an extensive set of computer simulations is presented in order to validate the proposed approach. The numerical simulation results show that the proposed system is able to provide a good position and orientation estimation of the aerial vehicles flying in formation. PMID- 29701724 TI - Fused Microknot Optical Resonators in Folded Photonic Tapers for in-Liquid Durable Sensing. AB - Optical microknot fibers (OMFs) serve as localized devices, where photonic resonances (PRs) enable self-interfering elements sensitive to their environment. However, typical fragility and drifting of the knot severely limit the performance and durability of microknots as sensors in aqueous settings. Herein we present the fabrication, electrical fusing, preparation, and persistent detection of volatile liquids in multiple wetting-dewetting cycles of volatile compounds and quantify the persistent phase shifts with a simple model relating to the ambient liquid, enabling durable in-liquid sensing employing OMF PRs. PMID- 29701723 TI - Integrated Chemometrics and Statistics to Drive Successful Proteomics Biomarker Discovery. AB - Protein biomarkers are of great benefit for clinical research and applications, as they are powerful means for diagnosing, monitoring and treatment prediction of different diseases. Even though numerous biomarkers have been reported, the translation to clinical practice is still limited. This mainly due to: (i) incorrect biomarker selection, (ii) insufficient validation of potential biomarkers, and (iii) insufficient clinical use. In this review, we focus on the biomarker selection process and critically discuss the chemometrical and statistical decisions made in proteomics biomarker discovery to increase to selection of high value biomarkers. The characteristics of the data, the computational resources, the type of biomarker that is searched for and the validation strategy influence the decision making of the chemometrical and statistical methods and a decision made for one component directly influences the choice for another. Incorrect decisions could increase the false positive and negative rate of biomarkers which requires independent confirmation of outcome by other techniques and for comparison between different related studies. There are few guidelines for authors regarding data analysis documentation in peer reviewed journals, making it hard to reproduce successful data analysis strategies. Here we review multiple chemometrical and statistical methods for their value in proteomics-based biomarker discovery and propose to include key components in scientific documentation. PMID- 29701725 TI - Effect of Fish Collagen Hydrolysates on Type I Collagen mRNA Levels of Human Dermal Fibroblast Culture. AB - Fish discards and subproducts may represent an important source of raw material, not only for the food industry, but for other different kind of industries, such as the nutraceutical and cosmetic industries. Collagen, which is mainly obtained from animal skins, is an important structural protein in the animal kingdom having many different applications. It is well known that fish skins constitute a significant subproduct in the fishery industry, especially in the case of some species, where fish skins may represent up to 20% of the total body weight of fish. Peptides from collagen hydrolysates have been described to be useful for preventing skin aging and osteoarthritis, however, the mechanism for these biological activities is not well known. Fibroblasts are the main cell types involved in the collagen synthesis, and in the present work, human dermal fibroblasts have been exposed to the treatment of collagen peptides of two different molecular weight ranges. Results show that higher molecular weight collagen peptides produce higher synthesis of collagen type I mRNA and, therefore, it may suggest that prior molecular weight selection may be an important step to maximize the effect of collagen hydrolysates on collagen type I synthesis by dermal fibroblasts. PMID- 29701726 TI - Sensor Access to the Cellular Microenvironment Using the Sensing Cell Culture Flask. AB - The Sensing Cell Culture Flask (SCCF) is a cell culture monitoring system accessing the cellular microenvironment in 2D cell culture using electrochemical microsensors. The system is based on microfabricated sensor chips embedded in standard cell culture flasks. Ideally, the sensor chips could be equipped with any electrochemical sensor. Its transparency allows optical inspection of the cells during measurement. The surface of the sensor chip is in-plane with the flask surface allowing undisturbed cell growth on the sensor chip. A custom developed rack system allows easy usage of multiple flasks in parallel within an incubator. The presented data demonstrates the application of the SCCF with brain tumor (T98G) and breast cancer (T-47D) cells. Amperometric oxygen sensors were used to monitor cellular respiration with different incubation conditions. Cellular acidification was accessed with potentiometric pH sensors using electrodeposited iridium oxide films. The system itself provides the foundation for electrochemical monitoring systems in 3D cell culture. PMID- 29701727 TI - The Design, Development and Evaluation of the Vegetarian Lifestyle Index on Dietary Patterns among Vegetarians and Non-Vegetarians. AB - Traditionally, healthful diets and lifestyles have been examined only in relation to single nutrients, foods, or food groups in terms of dietary exposure. An alternative approach is to conceptualize an index based on vegetarian food pyramid guidelines as a measure of overall diet and lifestyle quality. Our objectives were to: (1) develop the Vegetarian Lifestyle Index (VLI); and (2) evaluate adherence to the Vegetarian Food Guide Pyramid (VFGP) among a low-risk population of Adventists. The index was based on the operationalization of 14 dietary and lifestyle components. All components were equally weighted. Higher score reflected greater adherence to the VFGP. The analytic sample (n = 90,057) comprised 47.7% non-vegetarians, 5.6% semi-, 10.1% pesco-, and 29.0% lacto-ovo vegetarians, and 7.7% vegans, of which 1.1% were current smokers and 9.9% were alcohol consumers. Population mean VLI score was 7.43 (SD = 1.75) ranging from 1 to 12.5. Non-vegetarians (6.14; 95% confidence interval (CI), 6.06-6.21) had a significantly lower mean compared to semi- (7.31; 95% CI, 7.22-7.40), pesco- (7.41; 95% CI, 7.32-7.49), and lacto-ovo-vegetarians (8.16; 95% CI, 8.08-8.24), as well as vegans (8.88; 95% CI, 8.78-8.96). Vegetarians scored on average 1.18 to 2.73 more points than their non-vegetarian counterparts. Results demonstrate that the index has strong discriminant ability across distinct dietary patterns. Additionally, the VLI provides a useful measure of diet and lifestyle adherence to further refine vegetarian food pyramid guidelines. PMID- 29701728 TI - Synthesis and Antibacterial Activity of New Thiazolidine-2,4-dione-Based Chlorophenylthiosemicarbazone Hybrids. AB - Series of new thiazolidine-2,4-dione-based chlorophenylthiosemicarbazone hybrids (17-40) were synthesized by the reaction of condensation chlorophenylthiosemicarbazides with formylphenyl 2-(2,4-dioxothiazolidin-5 yl/ylidene)acetates. New compounds were tested on reference strains of Gram positive and Gram-negative bacteria. The antibacterial activity of target compounds was determined by broth dilution method. Most active compounds possess minimum inhibitory concentration (MIC) = 3.91 mg/L. These compounds were non toxic at concentrations close to their antibacterial effect. The antibacterial activity of some compounds was similar to or higher than the activity of used reference drugs such as oxacillin and cefuroxime. The structure-activity relationships (SARs) analysis collectively suggests that at least two different molecular mechanisms of their antibacterial activity should be expected. PMID- 29701729 TI - Council for International Organizations of Medical Sciences (CIOMS) Ethical Guidelines: advancements and unsolved topics in 2016 upgrade. AB - In 2016, the new edition of the Council for International Organizations of Medical Sciences (CIOMS) Ethical Guidelines was released, which are universally acknowledged as ethical standards in biomedical research. In this article, we critically analyze the improvements and shortcomings of the CIOMS Ethical Guidelines 2016. Among the improvements are the relevance assigned to the social value of research and its effects on decision-making and the creation of public policies; the research development in low-resources scenarios; the communities? involvement in the research process; the determination of participants? vulnerability and changes on informed consent related proceedings. Despite the improved harmonization with scientific, technologic and social changes, and that the guidelines provide a tool for researchers and members of research ethics committees alike, some topics remain unsolved, namely the management of participants? minimal risk and conflicts of interest involved in research, and the development of research in low-incomes scenarios. Nonetheless, we recognize that these new guidelines constitute a progress regarding the context and needs of populations in which research will be conducted, with greater community involvement in the different phases of the investigation project, thus allowing them to access the potential benefits. The impact of the CIOMS Ethical Guidelines 2016, should be appraised over time, particularly in socio-sanitary inequities scenarios and in the context of commercial interests of industry on biomedical research. PMID- 29701731 TI - Purcell effect in active diamond nanoantennas. AB - We suggest a novel class of active nanoantennas based on diamond nanoparticles with embedded nitrogen-vacancy centres coupled to Mie resonances of nanoparticles. We theoretically study the optical properties of such nanoantennas including the field enhancement and Purcell effect, and experimentally demonstrate the enhancement of the fluorescence rate of the emitters due to particle resonances, as compared to a nonresonant regime. Our results pave the way towards active dielectric nanophotonics for quantum light sources, bioimaging, and quantum information processing. PMID- 29701732 TI - Metal complexes of folic acid for lithium ion storage. AB - As a natural abundant biomolecule, folic acid (FA) was explored for the first time as a material for lithium ion storage. Most impressively, after the cooperation of metal ions (Co2+, Ni2+ and Fe3+), the fabricated complexes presented an enhancement in capacity retention as well as a long cycling life. This work suggests an effective strategy to enhance the performance of organic electrode materials. PMID- 29701733 TI - Strategies toward realization of unsupported transition metal-boron donor acceptor complexes: an insight from theory. AB - Pre-pyramidalization of the boron centre in the Lewis acidic groups is a prerequisite for the formation of unsupported donor-acceptor complexes with Lewis basic metal fragments such as [Pt(NHC)2]. PMID- 29701730 TI - Prevalence of Autism Spectrum Disorder Among Children Aged 8 Years - Autism and Developmental Disabilities Monitoring Network, 11 Sites, United States, 2014. AB - PROBLEM/CONDITION: Autism spectrum disorder (ASD). PERIOD COVERED: 2014. DESCRIPTION OF SYSTEM: The Autism and Developmental Disabilities Monitoring (ADDM) Network is an active surveillance system that provides estimates of the prevalence of autism spectrum disorder (ASD) among children aged 8 years whose parents or guardians reside within 11 ADDM sites in the United States (Arizona, Arkansas, Colorado, Georgia, Maryland, Minnesota, Missouri, New Jersey, North Carolina, Tennessee, and Wisconsin). ADDM surveillance is conducted in two phases. The first phase involves review and abstraction of comprehensive evaluations that were completed by professional service providers in the community. Staff completing record review and abstraction receive extensive training and supervision and are evaluated according to strict reliability standards to certify effective initial training, identify ongoing training needs, and ensure adherence to the prescribed methodology. Record review and abstraction occurs in a variety of data sources ranging from general pediatric health clinics to specialized programs serving children with developmental disabilities. In addition, most of the ADDM sites also review records for children who have received special education services in public schools. In the second phase of the study, all abstracted information is reviewed systematically by experienced clinicians to determine ASD case status. A child is considered to meet the surveillance case definition for ASD if he or she displays behaviors, as described on one or more comprehensive evaluations completed by community-based professional providers, consistent with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnostic criteria for autistic disorder; pervasive developmental disorder-not otherwise specified (PDD-NOS, including atypical autism); or Asperger disorder. This report provides updated ASD prevalence estimates for children aged 8 years during the 2014 surveillance year, on the basis of DSM-IV-TR criteria, and describes characteristics of the population of children with ASD. In 2013, the American Psychiatric Association published the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5), which made considerable changes to ASD diagnostic criteria. The change in ASD diagnostic criteria might influence ADDM ASD prevalence estimates; therefore, most (85%) of the records used to determine prevalence estimates based on DSM-IV-TR criteria underwent additional review under a newly operationalized surveillance case definition for ASD consistent with the DSM-5 diagnostic criteria. Children meeting this new surveillance case definition could qualify on the basis of one or both of the following criteria, as documented in abstracted comprehensive evaluations: 1) behaviors consistent with the DSM-5 diagnostic features; and/or 2) an ASD diagnosis, whether based on DSM-IV-TR or DSM-5 diagnostic criteria. Stratified comparisons of the number of children meeting either of these two case definitions also are reported. RESULTS: For 2014, the overall prevalence of ASD among the 11 ADDM sites was 16.8 per 1,000 (one in 59) children aged 8 years. Overall ASD prevalence estimates varied among sites, from 13.1-29.3 per 1,000 children aged 8 years. ASD prevalence estimates also varied by sex and race/ethnicity. Males were four times more likely than females to be identified with ASD. Prevalence estimates were higher for non-Hispanic white (henceforth, white) children compared with non-Hispanic black (henceforth, black) children, and both groups were more likely to be identified with ASD compared with Hispanic children. Among the nine sites with sufficient data on intellectual ability, 31% of children with ASD were classified in the range of intellectual disability (intelligence quotient [IQ] <70), 25% were in the borderline range (IQ 71-85), and 44% had IQ scores in the average to above average range (i.e., IQ >85). The distribution of intellectual ability varied by sex and race/ethnicity. Although mention of developmental concerns by age 36 months was documented for 85% of children with ASD, only 42% had a comprehensive evaluation on record by age 36 months. The median age of earliest known ASD diagnosis was 52 months and did not differ significantly by sex or race/ethnicity. For the targeted comparison of DSM-IV-TR and DSM-5 results, the number and characteristics of children meeting the newly operationalized DSM-5 case definition for ASD were similar to those meeting the DSM-IV-TR case definition, with DSM-IV-TR case counts exceeding DSM-5 counts by less than 5% and approximately 86% overlap between the two case definitions (kappa = 0.85). INTERPRETATION: Findings from the ADDM Network, on the basis of 2014 data reported from 11 sites, provide updated population-based estimates of the prevalence of ASD among children aged 8 years in multiple communities in the United States. The overall ASD prevalence estimate of 16.8 per 1,000 children aged 8 years in 2014 is higher than previously reported estimates from the ADDM Network. Because the ADDM sites do not provide a representative sample of the entire United States, the combined prevalence estimates presented in this report cannot be generalized to all children aged 8 years in the United States. Consistent with reports from previous ADDM surveillance years, findings from 2014 were marked by variation in ASD prevalence when stratified by geographic area, sex, and level of intellectual ability. Differences in prevalence estimates between black and white children have diminished in most sites, but remained notable for Hispanic children. For 2014, results from application of the DSM-IV TR and DSM-5 case definitions were similar, overall and when stratified by sex, race/ethnicity, DSM-IV-TR diagnostic subtype, or level of intellectual ability. PUBLIC HEALTH ACTION: Beginning with surveillance year 2016, the DSM-5 case definition will serve as the basis for ADDM estimates of ASD prevalence in future surveillance reports. Although the DSM-IV-TR case definition will eventually be phased out, it will be applied in a limited geographic area to offer additional data for comparison. Future analyses will examine trends in the continued use of DSM-IV-TR diagnoses, such as autistic disorder, PDD-NOS, and Asperger disorder in health and education records, documentation of symptoms consistent with DSM-5 terminology, and how these trends might influence estimates of ASD prevalence over time. The latest findings from the ADDM Network provide evidence that the prevalence of ASD is higher than previously reported estimates and continues to vary among certain racial/ethnic groups and communities. With prevalence of ASD ranging from 13.1 to 29.3 per 1,000 children aged 8 years in different communities throughout the United States, the need for behavioral, educational, residential, and occupational services remains high, as does the need for increased research on both genetic and nongenetic risk factors for ASD. PMID- 29701734 TI - Hierarchical TiN nanoparticles-assembled nanopillars for flexible supercapacitors with high volumetric capacitance. AB - Titanium nitride (TiN) is an attractive electrode material in fast charging/discharging supercapacitors because of its excellent conductivity. However, the low capacitance and mechanical brittleness of TiN restricts its further application in flexible supercapacitors with high energy density. Thus, it is still a challenge to rationally design TiN electrodes with both high electrochemical and mechanical properties. Herein, the hierarchical TiN nanoparticles-assembled nanopillars (H-TiN NPs) array as binder free electrodes were obtained by nitriding of hierarchical titanium dioxide (TiO2) nanopillars, which was produced by a simple hydrothermal treatment of anodic TiO2 nanotubes (NTs) array in water. The porous TiN nanoparticles connected to each other to form ordered nanopillar arrays, effectively providing larger specific surface area and more active sites for charge storage. The H-TiN NPs delivered a high volumetric capacitance of 120 F cm-3 at 0.83 A cm-3, which is better than that of TiN NTs arrays (69 F cm-3 at 0.83 A cm-3). After assembling into all-solid-state devices, the H-TiN NPs based supercapacitors exhibited outstanding volumetric capacitance of 5.9 F cm-3 at 0.02 A cm-3 and a high energy density of 0.53 mW h cm-3. Our results reveal a new strategy to optimize the supercapacitive performance of metal nitrides. PMID- 29701735 TI - (Ar-CO-C[triple bond, length as m-dash]C)(PEt3)Au and (Ar-C[triple bond, length as m-dash]C)(PEt3)Au complexes bearing pyrenyl and ferrocenyl groups: synthesis, structure, and luminescence properties. AB - Two types of (acetylide)(triethylphosphine)gold(i) complexes ArCOC[triple bond, length as m-dash]CAuPEt3 (1a and 1b) and ArC[triple bond, length as m dash]CAuPEt3 (2a and 2b) bearing Ar = pyren-1-yl or ferrocenyl group were synthesized and the effect of a carbonyl moiety on the structure, propensity to ligand scrambling in solution and luminescence properties were investigated. We found that the complexes bearing acetylenic ketone-derived ligands underwent ligand scrambling in solution to afford mixtures of ArCOC[triple bond, length as m-dash]CAuPEt3 and [(ArCOC[triple bond, length as m-dash]C)2Au]-[Au(PEt3)2]+. The latter complexes were isolated and their structures were confirmed by single crystal X-ray diffraction studies. The aurophilic interaction of AuAu in these complexes resulted in the formation of wire-like structures. PMID- 29701736 TI - Ion mobility and gas phase H/D exchange: revealing the importance of a single hydrogen bond for the chiral recognition of crown ether ammonium complexes. AB - Two new BINOL-based chiral crown ether/ammonium complexes are studied by travelling-wave ion-mobility spectrometry. Homo- and heterochiral crown ether/ammonium complexes differ in their collision cross sections, and these differences go along with changes in hydrogen bonding as revealed by gas phase H/D-exchange experiments. Applications for the determination of enantiomeric excess are discussed. PMID- 29701737 TI - Correction: Nanocrystals self-assembled in superlattices directed by the solvent organic capping interaction. AB - Correction for 'Nanocrystals self-assembled in superlattices directed by the solvent-organic capping interaction' by Cleocir Jose Dalmaschio et al., Nanoscale, 2013, 5, 5602-5610. PMID- 29701738 TI - Creation of oxygen reduction reaction active sites on titanium oxynitride without increasing the nitrogen doping level. AB - The oxygen reduction reaction (ORR) active sites on titanium oxynitride (TiOxNy) have been investigated using catalysts with various nitrogen doping levels, leaving some margins to determine their origin. Herein, low-temperature annealing enhanced the ORR activity of carbon-support-free TiOxNy with a constant nitrogen doping level, indicating that oxygen vacancies produced the sites. PMID- 29701744 TI - Anisotropic drop spreading on superhydrophobic grates during drop impact. AB - We study the influence of geometric anisotropy of micro-grate structures on the spreading dynamics of water drops after impact. It is found that the maximal spreading diameter along the parallel direction to grates becomes larger than that along the transverse direction beyond a certain Weber number, while the extent of such an asymmetric spreading increases with the structural pitch of grates and Weber number. By employing grates covered with nanostructures, we exclude the possible influences coming from the Cassie-to-Wenzel transition and the circumferential contact angle variation on the spreading diameter. Then, based on a simplified energy balance model incorporating slip length, we propose that slip length selectively enhances the spreading diameter along the parallel direction, being responsible for the asymmetric drop spreading. We believe that our work will help better understand the role of microstructures in controlling the drop dynamics during impact, which has relevance to various engineering applications. PMID- 29701745 TI - A tethered bilayer lipid membrane that mimics microbial membranes. AB - A model membrane system has been developed, which mimics the outer membrane of Gram negative bacteria. The structure is based on a tethered monolayer which has been fused with vesicles containing lipopolysaccharide molecules. The effect of the composition of the monolayer and the lipids in the outer layer on the structural and electrical properties of the membrane has been investigated. By using electrochemical impedance spectroscopy as well as neutron scattering techniques, it could be shown that a relatively high tethering density and a small amount of diluting lipids in the outer membrane leaflet leads to the formation of a stable solid supported membrane. The influence of divalent ions on the membrane stability has been probed as well as the interaction of the bilayer with the antibiotic colistin. A number of different architectures were developed, suited to both the study of bacterial membrane proteins and the screening of antimicrobial activity of potential drug candidates. PMID- 29701746 TI - An Sn-induced resonant level in beta-As2Te3. AB - Distortion of the density of states by an impurity-induced resonant level has been shown to provide an effective strategy to improve the thermoelectric performance of semiconductors such as Bi2Te3, PbTe or SnTe. Here, combining first principles calculations and transport property measurements, we demonstrate that Sn is a resonant impurity that distorts the valence band edge in p-type beta As2Te3. This remarkable effect is characterized as a prominent, sharp peak in the electronic density of states near the Fermi level. To illustrate the particular influence of Sn on the thermopower of beta-As2Te3, the theoretical Ioffe Pisarenko curve, computed within the Boltzmann transport theory, is compared with the experimental results obtained on three series of polycrystalline samples with substitution of Ga and Bi for As and I for Te. While Ga and I behave as conventional, rigid-band-like dopants and follow theoretical predictions, Sn results in significant deviations from the theoretical curve with a clear enhancement of the thermopower. Both electronic band structure calculations and transport property measurements provide conclusive evidence that this enhancement and hence, the good thermoelectric performances achieved at mid temperatures in beta-As2-xSnxTe3 can be attributed to a resonant level induced by Sn atoms. The possibility to induce resonant states in the electronic band structure of beta As2Te3 opens new avenues to further optimize its thermoelectric performance. PMID- 29701747 TI - Cluster Locator, online analysis and visualization of gene clustering. AB - Summary: Genes sharing functions, expression patterns or quantitative traits are not randomly distributed along eukaryotic genomes. In order to study the distribution of genes that share a given feature, we present Cluster Locator, an online analysis and visualization tool. Cluster Locator determines the number, size and position of all the clusters formed by the protein-coding genes on a list according to a given maximum gap, the percentage of gene clustering of the list and its statistical significance. The output includes a visual representation of the distribution of genes and gene clusters along the reference genome. Availability and implementation: Cluster Locator is freely available at http://clusterlocator.bnd.edu.uy/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29701748 TI - Mlh1 deficiency in normal mouse colon mucosa associates with chromosomally unstable colon cancer. AB - Colorectal cancer (CRC) genome is unstable and different types of instabilities, such as chromosomal instability (CIN) and microsatellite instability (MSI) are thought to reflect distinct cancer initiating mechanisms. Although 85% of sporadic CRC reveal CIN, 15% reveal mismatch repair (MMR) malfunction and MSI, the hallmarks of Lynch syndrome with inherited heterozygous germline mutations in MMR genes. Our study was designed to comprehensively follow genome-wide expression changes and their implications during colon tumorigenesis. We conducted a long-term feeding experiment in the mouse to address expression changes arising in histologically normal colonic mucosa as putative cancer preceding events, and the effect of inherited predisposition (Mlh1+/-) and Western-style diet (WD) on those. During the 21-month experiment, carcinomas developed mainly in WD-fed mice and were evenly distributed between genotypes. Unexpectedly, the heterozygote (B6.129-Mlh1tm1Rak) mice did not show MSI in their CRCs. Instead, both wildtype and heterozygote CRC mice showed a distinct mRNA expression profile and shortage of several chromosomal segregation gene-specific transcripts (Mlh1, Bub1, Mis18a, Tpx2, Rad9a, Pms2, Cenpe, Ncapd3, Odf2 and Dclre1b) in their colon mucosa, as well as an increased mitotic activity and abundant numbers of unbalanced/atypical mitoses in tumours. Our genome-wide expression profiling experiment demonstrates that cancer preceding changes are already seen in histologically normal colon mucosa and that decreased expressions of Mlh1 and other chromosomal segregation genes may form a field-defect in mucosa, which trigger MMR-proficient, chromosomally unstable CRC. PMID- 29701749 TI - Simultaneous determination of rosuvastatin, naringin and naringenin in rat plasma by RRLC-MS/MS and its application to a pharmacokinetic drug interaction study. AB - A rapid resolution liquid chromatography tandem mass spectrometry method was developed and validated for simultaneous determination of rosuvastatin, naringin and naringenin in rat plasma. Chromatographic separation of analytes and internal standard (fluvastatin for rosuvastatin, while isoquercitrin for naringin and naringenin) was performed on Agilent Poroshell 120 EC-C18 column (3.0 * 50 mm, 2.7 MUm) using gradient elution with a mobile phase of methanol and water, both with 0.1% formic acid (v/v). The detection was operated in multiple reaction monitoring mode to monitor the precursor-to-product ion transitions of m/z 579.1 >270.8 for naringin, m/z 270.9->150.7 for naringenin, m/z 463.1->299.8 for isoquercitrin in negative ionization mode, and m/z 482.2->258.1 for rosuvastatin, m/z 412.1->224.1 for fluvastatin in positive ionization mode. Polarity switch (negative-positive-negative ionization mode) was performed in a total runtime of 5.0 min. The method was validated over a concentration range of 10-2,000 ng/mL for the above three analytes. The intra-day and inter-day precisions and accuracies of the quality control samples at low, medium and high concentration levels exhibited relative standard deviations <10% and the accuracy values ranged from -7.2% to 8.4%. The proposed method was successfully applied to the pharmacokinetic drug interaction study of rosuvastatin combined with naringin in rats. PMID- 29701750 TI - Rapid Screening for 15 Sulfonamide Residues in Foods of Animal Origin by High Performance Liquid Chromatography-UV Method. AB - A rapid and simple high-performance liquid chromatography-ultraviolet method was developed for the separation and quantification of 15 sulfonamides (SAs) in foods of animal origin without the need of clean-up procedure. A mixture of acetonitrile-formic acid-ammonium acetate-water was used as the mobile phase to separate 15 SAs on a C18 column with gradient. The selected SAs were separated completely from the matrix mixture based on different retention behaviors at different concentration of acetonitrile. The effects of the additive of formic acid and ammonium acetate in mobile phases on the separation of SAs were also investigated. The additive can greatly improve the resolution between SAs and impurities, so that the SAs can be quantified directly under the optimized chromatographic condition the sample preparation which does not need extra sample clean-up procedure. Complete baseline separation of 15 SAs was achieved in <40 min, the linear range is 0.01-130 MUg/mL with a correlation coefficient R2-value > 0.999. Excellent method reproducibility was found by intra- and inter-day precisions with the relative standard deviation <9.5%. The detection limit was <11.0 ng/mL and it can be used for routine screening of the SA residues in foods of animal origin. PMID- 29701751 TI - Lifespan Trajectories of White Matter Changes in Rhesus Monkeys. AB - Progress in neurodevelopmental brain research has been achieved through the use of animal models. Such models not only help understanding biological changes that govern brain development, maturation and aging, but are also essential for identifying possible mechanisms of neurodevelopmental and age-related chronic disorders, and to evaluate possible interventions with potential relevance to human disease. Genetic relationship of rhesus monkeys to humans makes those animals a great candidate for such models. With the typical lifespan of 25 years, they undergo cognitive maturation and aging that is similar to this observed in humans. Quantitative structural neuroimaging has been proposed as one of the candidate in vivo biomarkers for tracking white matter brain maturation and aging. While lifespan trajectories of white matter changes have been mapped in humans, such knowledge is not available for nonhuman primates. Here, we analyze and model lifespan trajectories of white matter microstructure using in vivo diffusion imaging in a sample of 44 rhesus monkeys. We report quantitative parameters (including slopes and peaks) of lifespan trajectories for 8 individual white matter tracts. We show different trajectories for cellular and extracellular microstructural imaging components that are associated with white matter maturation and aging, and discuss similarities and differences between those in humans and rhesus monkeys, the importance of our findings, and future directions for the field.Significance Statement: Quantitative structural neuroimaging has been proposed as one of the candidate in vivo biomarkers for tracking brain maturation and aging. While lifespan trajectories of structural white matter changes have been mapped in humans, such knowledge is not available for rhesus monkeys. We present here results of the analysis and modeling of the lifespan trajectories of white matter microstructure using in vivo diffusion imaging in a sample of 44 rhesus monkeys (age 4-27). We report and anatomically map lifespan changes related to cellular and extracellular microstructural components that are associated with white matter maturation and aging. PMID- 29701752 TI - MiR-223 promotes the doxorubicin resistance of colorectal cancer cells via regulating epithelial-mesenchymal transition by targeting FBXW7. AB - Although doxorubicin has become a key drug in cancer treatment, the resistance of colorectal carcinoma to doxorubicin is a major problem in clinical practice. F box and WD repeat domain-containing 7 (FBXW7) plays important roles in human cancers and is one of the major causes of drug resistance. The miR-223/FBXW7 pathway has been reported to be a crucial clue to the mechanism of chemoresistance in many human cancers, such as gastric cancer, breast cancer, and non-small cell lung cancer. However, it is unclear whether similar mechanisms of doxorubicin resistance are involved in colorectal cancer (CRC). The aim of the current study was to evaluate the role of miR-223/FBXW7 pathway in chemosensitivity in different CRC cell lines and to investigate the relevant underlying mechanisms. We found that high levels of FBXW7 expression were associated with increased doxorubicin sensitivity in different CRC cell lines, and FBXW7 was regulated by miR-223. Overexpression of miR-223 decreased FBXW7 expression and the sensitivity of CRC cells to doxorubicin, while suppression of miR-223 had the opposite effect. Moreover, epithelial-mesenchymal transition (EMT) was proved to be regulated by miR-223/FBXW7 pathway and involved in the drug resistance. In conclusion, miR-223/FBXW7 axis regulates doxorubicin sensitivity through EMT in CRC, which may lead to the development of individualized treatment in clinical practice. PMID- 29701754 TI - Evaluating the Effect of Implantable Mesh in Mammaplasty. PMID- 29701753 TI - Medical History, Medication Use, and Risk of Nasopharyngeal Carcinoma. AB - Because persistent inflammation may render the nasopharyngeal mucosa susceptible to carcinogenesis, chronic ear-nose-throat (ENT) disease and its treatment might influence the risk of nasopharyngeal carcinoma (NPC). Existing evidence is, however, inconclusive and often based on methodologically suboptimal epidemiologic studies. In a population-based case-control study in southern China, we enrolled 2,532 persons with NPC and 2,597 controls, aged 20-74 years, from 2010 to 2014. Odds ratios were estimated for associations between NPC risk and history of ENT and related medications. Any history of chronic ENT disease was associated with a 34% increased risk of NPC. Similarly, use of nasal drops or aspirin was associated with approximately doubled risk of NPC. However, in secondary analyses restricted to chronic ENT diseases and related medication use at least 5 years prior to diagnosis/interview, most results were statistically nonsignificant, except a history of uncured ENT diseases, untreated nasal polyps, and earlier age at first diagnosis of ENT disease and first or most recent aspirin use. Overall, these findings suggest that ENT disease and related medication use are most likely early indications rather than causes of NPC, although the possibility of a modestly increased NPC risk associated with these diseases and related medications cannot be excluded. PMID- 29701755 TI - Domain-functional analyses of PIWIL1 and PABPC1 indicate their synergistic roles in protein translation via 3'-UTRs of meiotic mRNAs. AB - Translational regulation plays a central role during post-meiotic development of male germ cells. Previous studies suggested that P-element induced wimpy testis like 1 (PIWIL1), a PIWI-interacting RNA (piRNA) binding protein that is critical for sperm development, participates in the maintenance and translational regulation of post-meiotic mRNAs in haploid spermatids. However, how PIWIL1 regulates protein translation remains largely unclear. Using biochemical assays, we show here that PIWIL1 utilizes different domains to interact with post-meiotic mRNAs and Poly-A binding protein cytoplasmic 1 (PABPC1), a general protein translation regulator. PIWIL1 binds 3'-untranslated regions (3'-UTRs) of several spermiogenic mRNAs via its N-terminal domain, whereas its interactions with PABPC1 are mediated through its N- and C-terminal domains in an RNA-dependent manner. Using a heterologous cell system, we analyzed its effects on protein translation via luciferase reporter assay and sucrose gradient sedimentation. It was found that PIWIL1 augments protein translation with PABPC1 in the presence of 3'-UTRs of post-meiotic mRNAs. While both the N-terminal RNA recognition motif (RRM) domain and the central linker region of PABPC1 stimulate translation, only the PIWI Argonaute and Zwille (PAZ) domain of PIWIL1 positively affects translation of reporter mRNAs. Interestingly, the PAZ domain was found absent from polysomal fractions, in contrast to the N- and C-terminal domains of PIWIL1. Taken together, the results suggest that PIWIL1 interacts with various partners using different domains and participates in translational regulation partly through 3'-UTRs. It will be of interest to further explore how PIWIL1 elicit its versatile functions, including translational regulation of post-meiotic mRNAs through intrinsic structural changes and extrinsic signals during mouse spermiogenesis under more physiological settings. PMID- 29701756 TI - Multi-Drug Resistance in Burns Units-More Than Just a Burning Issue. PMID- 29701757 TI - Rapid and Sensitive Quantification of Ursolic Acid and Oleanolic Acid in Human Plasma Using Ultra-performance Liquid Chromatography-Mass Spectrometry. AB - Ultra-performance liquid chromatography (UPLC) interfaced with atmospheric pressure chemical ionization mass-spectrometry was used to separate and quantify ursolic acid (UA) and oleanolic acid (OA) in human plasma. UA and OA were extracted from 0.5 mL human plasma using supported liquid extraction and separated utilizing an Acquity UPLC HSS column. The method has been validated for both UA and OA quantitation with a limit of detection of 0.5 ng/mL. The UPLC separations are carried out with isocratic elution with methanol and 5 mM ammonium acetate in water (85:15) as a mobile phase at a flow rate of 0.4 mL/min. The assay was linear from 1 ng/mL to 100 ng/mL for both analytes. The total analysis time was 7 min with the retention times of 3.25 (internal standard), 3.65 (UA) and 3.85 min (OA). Recovery of drug from plasma ranged from 70% to 115%. Analysis of quality control samples at 3, 30 and 80 ng/mL (n = 14) had an intra-day coefficient of variation of 9.9%, 4.3% and 5.5%, respectively. A proof of-concept study in human patients who consumed apple peels indicates that this analytical method could be applied to clinical studies of UA and/or OA in human subjects. PMID- 29701758 TI - BNPMDA: Bipartite Network Projection for MiRNA-Disease Association prediction. AB - Motivation: A large number of resources have been devoted to exploring the associations between microRNAs (miRNAs) and diseases in the recent years. However, the experimental methods are expensive and time-consuming. Therefore, the computational methods to predict potential miRNA-disease associations have been paid increasing attention. Results: In this paper, we proposed a novel computational model of Bipartite Network Projection for MiRNA-Disease Association prediction (BNPMDA) based on the known miRNA-disease associations, integrated miRNA similarity and integrated disease similarity. We firstly described the preference degree of a miRNA for its related disease and the preference degree of a disease for its related miRNA with the bias ratings. We constructed bias ratings for miRNAs and diseases by using agglomerative hierarchical clustering according to the three types of networks. Then, we implemented the bipartite network recommendation algorithm to predict the potential miRNA-disease associations by assigning transfer weights to resource allocation links between miRNAs and diseases based on the bias ratings. BNPMDA had been shown to improve the prediction accuracy in comparison with previous models according to the area under the receiver operating characteristics (ROC) curve (AUC) results of three typical cross validations. As a result, the AUCs of Global LOOCV, Local LOOCV and 5-fold cross validation obtained by implementing BNPMDA were 0.9028, 0.8380 and 0.8980 +/- 0.0013, respectively. We further implemented two types of case studies on several important human complex diseases to confirm the effectiveness of BNPMDA. In conclusion, BNPMDA could effectively predict the potential miRNA disease associations at a high accuracy level. Availability and implementation: BNPMDA is available via http://www.escience.cn/system/file?fileId=99559. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29701759 TI - Polyspermy produces viable haploid/diploid mosaics in sturgeon. AB - Most of sturgeon species (Acipenseridae) are currently critically endangered. Attempts to revive these populations include artificial breeding in hatcheries. However, under artificial reproduction, sturgeon embryos occasionally develop atypically, showing 3, 5, 6, 7, 9, or 10 cells at the 2- to 4-cell stage. This study was undertaken with the objective of understanding the mechanism of the atypical division (AD) in embryos during artificial breeding. Using several sturgeon species, we tested two hypotheses: (1) polyspermy and (2) retention of the second polar body. We found that (1) AD embryos survive similar to controls, (2) the ratio of AD embryos is positively correlated with the amount of sperm used for fertilization, (3) the number of micropyles and the area covered by them in AD embryos is significantly greater when compared to controls, (4) numerous spermatozoa nuclei are in the cytoplasm after fertilization, (5) all AD embryos are mosaics, and (6) AD fishes with n/2n ploidy contain diploid cells from maternal and paternal genetic markers, while the haploid cells contained only paternal ones. These results clearly indicate that AD embryos arise from plasmogamy where the accessory spermatozoon/spermatozoa entry the egg and develop jointly with zygotic cells. This suggests that a well-controlled fertilization procedure is needed to prevent the production of sturgeon with irregular ploidy, which can have detrimental genetic effects on sturgeon populations. On the other hand, if AD fish can produce haploid-derived clonal gametes, induction of multiple-sperm mosaicism might be a useful tool for the rapid production of isogenic strains of sturgeons. PMID- 29701760 TI - Optical techniques for perfusion monitoring of the gastric tube after esophagectomy: a review of technologies and thresholds. AB - Anastomotic leakage is one of the most severe complications after esophageal resection with gastric tube reconstruction. Impaired perfusion of the gastric fundus is seen as the main contributing factor for this complication. Optical modalities show potential in recognizing compromised perfusion in real time, when ischemia is still reversible. This review provides an overview of optical techniques with the aim to evaluate the (1) quantitative measurement of change in perfusion in gastric tube reconstruction and (2) to test which parameters are the most predictive for anastomotic leakage.A Pubmed, MEDLINE, and Embase search was performed and articles on laser Doppler flowmetry (LDF), near-infrared spectroscopy (NIRS), laser speckle contrast imaging (LSCI), fluorescence imaging (FI), sidestream darkfield microscopy (SDF), and optical coherence tomography (OCT) regarding blood flow in gastric tube surgery were reviewed. Two independent reviewers critically appraised articles and extracted the data: Primary outcome was quantitative measure of perfusion change; secondary outcome was successful prediction of necrosis or anastomotic leakage by measured perfusion parameters.Thirty-three articles (including 973 patients and 73 animals) were selected for data extraction, quality assessment, and risk of bias (QUADAS-2). LDF, NIRS, LSCI, and FI were investigated in gastric tube surgery; all had a medium level of evidence. IDEAL stage ranges from 1 to 3. Most articles were found on LDF (n = 12), which is able to measure perfusion in arbitrary perfusion units with a significant lower amount in tissue with necrosis development and on FI (n = 12). With FI blood flow routes could be observed and flow was qualitative evaluated in rapid, slow, or low flow. NIRS uses mucosal oxygen saturation and hemoglobin concentration as perfusion parameters. With LSCI, a decrease of perfusion units is observed toward the gastric fundus intraoperatively. The perfusion units (LDF, LSCI), although arbitrary and not absolute values, and low flow or length of demarcation to the anastomosis (FI) both seem predictive values for necrosis intraoperatively. SDF and OCT are able to measure microvascular flow, intraoperative prediction of necrosis is not yet described.Optical techniques aim to improve perfusion monitoring by real-time, high-resolution, and high-contrast measurements and could therefore be valuable in intraoperative perfusion mapping. LDF and LSCI use perfusion units, and are therefore subjective in interpretation. FI visualizes influx directly, but needs a quantitative parameter for interpretation during surgery. PMID- 29701761 TI - Size of recurrent laryngeal nerve as a new risk factor for postoperative vocal cord paralysis. AB - Recurrent laryngeal nerve paralysis (RLNP) is a frequent and serious complication following esophageal cancer surgery. Therefore, this study aims to evaluate the correlation between recurrent laryngeal nerve (RLN) size and RLNP. This was a retrospective study of esophageal cancer patients who underwent thoracoscopic esophagectomy from January 2012 to December 2014. Eighty-four patients were included in the primary analysis. Diameter of the RLN was measured using the digital video recording of surgical procedures by the ratio between scissor and RLN. For evaluation of vocal cord paralysis or paresis, indirect laryngoscopy was performed. Because RLNP more frequently occurs on the left side than the right, we evaluated the correlation between size of the left RLN and left RLNP. The median size of the left RLN was 1.51 mm. We found that the incidence of postoperative left RLNP (Clavien-Dindo classification >=1) was significantly higher (71% vs. 24%; P < 0.001) in thin RLNs (<=1.5 mm) than in thick RLNs (>1.5 mm). Thin RLN (P < 0.001), female sex (P = 0.025), and being overweight (P = 0.034) were identified as significant independent risk factors for postoperative RLNP. RLNP more easily occurred when the RLN was thin. It is difficult to confirm occurrence of postoperative RLNP before and at extubation. Therefore, it is helpful to know its risk factors including size of RLN. PMID- 29701762 TI - Post genome-wide association analysis: dissecting computational pathway/network based approaches. AB - Over thousands of genetic associations to diseases have been identified by genome wide association studies (GWASs), which conceptually is a single-marker-based approach. There are potentially many uses of these identified variants, including a better understanding of the pathogenesis of diseases, new leads for studying underlying risk prediction and clinical prediction of treatment. However, because of inadequate power, GWAS might miss disease genes and/or pathways with weak genetic or strong epistatic effects. Driven by the need to extract useful information from GWAS summary statistics, post-GWAS approaches (PGAs) were introduced. Here, we dissect and discuss advances made in pathway/network-based PGAs, with a particular focus on protein-protein interaction networks that leverage GWAS summary statistics by combining effects of multiple loci, subnetworks or pathways to detect genetic signals associated with complex diseases. We conclude with a discussion of research areas where further work on summary statistic-based methods is needed. PMID- 29701763 TI - PIK3CA mutations are associated with reduced pathological complete response rates in primary HER2-positive breast cancer: pooled analysis of 967 patients from five prospective trials investigating lapatinib and trastuzumab. PMID- 29701765 TI - Moving on After Discontinuation of Anti-TNF Therapy-What Comes Next? PMID- 29701764 TI - Pathway level alterations rather than mutations in single genes predict response to HER2-targeted therapies in the neo-ALTTO trial. PMID- 29701766 TI - Colonization With Levofloxacin-resistant Extended-spectrum beta-Lactamase producing Enterobacteriaceae and Risk of Bacteremia in Hematopoietic Stem Cell Transplant Recipients. AB - Background: Bacteremia caused by extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae (ESBL-E) is associated with inadequate empirical therapy and substantial mortality in neutropenic patients. Strategies are needed to identify neutropenic patients at high risk of these infections. Methods: From April 2014 to September 2016, we collected perianal swabs, both at admission and weekly thereafter, from patients undergoing hematopoietic stem cell transplantation (HSCT). Patients received prophylactic levofloxacin while neutropenic. Swabs were plated onto selective agar, colonies were identified and underwent antimicrobial susceptibility testing, and phenotypic ESBL testing and polymerase chain reaction for beta-lactamase genes were performed on ceftriaxone resistant Enterobacteriaceae. We then determined the prevalence of pre-transplant ESBL-E colonization and risk of ESBL-E bacteremia. Colonizing and bloodstream isolates from patients with ESBL-E bacteremia underwent multilocus sequence typing and pulsed-field gel electrophoresis. Results: We analyzed 312 patients, including 212 allogeneic and 100 autologous HSCT recipients. Ten percent (31/312) of patients had pre-transplant ESBL-E colonization. Susceptibility rates of colonizing ESBL-E were: levofloxacin, 25%; cefepime, 9%; piperacillin-tazobactam, 84%; and meropenem, 97%. Of 31 patients colonized with ESBL-E pre-transplant, 10 (32%) developed ESBL-E bacteremia during their transplant admission, compared to 1 (0.4%) of 281 patients not colonized with ESBL-E (P < .001). All bloodstream ESBL-E were levofloxacin-resistant and colonizing and bloodstream isolates from individual patients had identical genotypic profiles. Conclusions: HSCT recipients who are colonized with levofloxacin-resistant ESBL-E pre-transplant and receive levofloxacin prophylaxis have high rates of bacteremia from their colonizing strain during neutropenia. Assessing for ESBL-E colonization in neutropenic patients could lead to optimization of empirical antibacterial therapy. PMID- 29701767 TI - Development of Full Sweet, Umami, and Bitter Taste Responsiveness Requires Regulator of G protein Signaling-21 (RGS21). AB - The mammalian tastes of sweet, umami, and bitter are initiated by activation of G protein-coupled receptors (GPCRs) of the T1R and T2R families on taste receptor cells. GPCRs signal via nucleotide exchange and hydrolysis, the latter hastened by GTPase-accelerating proteins (GAPs) that include the Regulators of G protein Signaling (RGS) protein family. We previously reported that RGS21, uniquely expressed in Type II taste receptor cells, decreases the potency of bitter stimulated T2R signaling in cultured cells, consistent with its in vitro GAP activity. However, the role of RGS21 in organismal responses to GPCR-mediated tastants was not established. Here, we characterized mice lacking the Rgs21 fifth exon. Eliminating Rgs21 expression had no effect on body mass accumulation (a measure of alimentation), fungiform papillae number and morphology, circumvallate papillae morphology, and taste bud number. Two-bottle preference tests, however, revealed that Rgs21-null mice have blunted aversion to quinine and denatonium, and blunted preference for monosodium glutamate, the sweeteners sucrose and SC45647, and (surprisingly) NaCl. Observed reductions in GPCR-mediated tastant responses upon Rgs21 loss are opposite to original expectations, given that loss of RGS21-a GPCR signaling negative regulator-should lead to increased responsiveness to tastant-mediated GPCR signaling (all else being equal). Yet, reduced organismal tastant responses are consistent with observations of reduced chorda tympani nerve recordings in Rgs21-null mice. Reduced tastant-mediated responses and behaviors exhibited by adult mice lacking Rgs21 expression since birth have thus revealed an underappreciated requirement for a GPCR GAP to establish the full character of tastant signaling. PMID- 29701768 TI - Exon-specific U1 snRNAs improve ELP1 exon 20 definition and rescue ELP1 protein expression in a familial dysautonomia mouse model. AB - Familial dysautonomia (FD) is a rare genetic disease with no treatment, caused by an intronic point mutation (c.2204+6T>C) that negatively affects the definition of exon 20 in the elongator complex protein 1 gene (ELP1 also known as IKBKAP). This substitution modifies the 5' splice site and, in combination with regulatory splicing factors, induces different levels of exon 20 skipping, in various tissues. Here, we evaluated the therapeutic potential of a novel class of U1 snRNA molecules, exon-specific U1s (ExSpeU1s), in correcting ELP1 exon 20 recognition. Lentivirus-mediated expression of ELP1-ExSpeU1 in FD fibroblasts improved ELP1 splicing and protein levels. We next focused on a transgenic mouse model that recapitulates the same tissue-specific mis-splicing seen in FD patients. Intraperitoneal delivery of ELP1-ExSpeU1s-adeno-associated virus particles successfully increased the production of full-length human ELP1 transcript and protein. This splice-switching class of molecules is the first to specifically correct the ELP1 exon 20 splicing defect. Our data provide proof of principle of ExSpeU1s-adeno-associated virus particles as a novel therapeutic strategy for FD. PMID- 29701770 TI - Speaking up behaviors and safety climate in an Austrian university hospital. AB - Objective: To analyze speaking up behavior and safety climate with a validated questionnaire for the first time in an Austrian university hospital. Design: Survey amongst healthcare workers (HCW). Data were analyzed using descriptive statistics, Cronbach's alpha was calculated as a measure of internal consistencies of scales. Analysis of variance and t-tests were used. Setting: The survey was conducted in 2017. Participants: About 2.149 HCW from three departments were asked to participate. Intervention: To measure speaking up behavior and safety climate. Main Outcome Measure: To explore psychological safety, encouraging environment and resignation towards speaking up. Results: About 859 evaluable questionnaires were returned (response rate: 40%). More than 50% of responders perceived specific concerns about patient safety within the last 4 weeks and observed a potential error or noticed rule violations. For the different items, between 16% and 42% of HCW reported that they remained silent though concerns for safety. In contrast, between 96% and 98% answered that they did speak up in certain situations. The psychological safety for speaking up was lower for HCW with a managerial function (P < 0.001). HCW with managerial functions perceived the environment as less encouraging to speak up (P < 0.05) than HCW without managerial function. Conclusions: We identified speaking up behaviors for the first time in an Austrian university hospital. Only moderately frequent concerns were in conflict with frequent speaking up behaviors. These results clearly show that a paradigm shift is needed to increase speaking up culture. PMID- 29701771 TI - Leveraging Organismal Biology to Forecast the Effects of Climate Change. AB - Despite the pressing need for accurate forecasts of ecological and evolutionary responses to environmental change, commonly used modeling approaches exhibit mixed performance because they omit many important aspects of how organisms respond to spatially and temporally variable environments. Integrating models based on organismal phenotypes at the physiological, performance, and fitness levels can improve model performance. We summarize current limitations of environmental data and models and discuss potential remedies. The paper reviews emerging techniques for sensing environments at fine spatial and temporal scales, accounting for environmental extremes, and capturing how organisms experience the environment. Intertidal mussel data illustrate biologically important aspects of environmental variability. We then discuss key challenges in translating environmental conditions into organismal performance including accounting for the varied timescales of physiological processes, for responses to environmental fluctuations including the onset of stress and other thresholds, and for how environmental sensitivities vary across lifecycles. We call for the creation of phenotypic databases to parameterize forecasting models and advocate for improved sharing of model code and data for model testing. We conclude with challenges in organismal biology that must be solved to improve forecasts over the next decade. PMID- 29701772 TI - Inositol trisphosphate receptor-mediated Ca2+ signalling stimulates mitochondrial function and gene expression in core myopathy patients. AB - Core myopathies are a group of childhood muscle disorders caused by mutations of the ryanodine receptor (RyR1), the Ca2+ release channel of the sarcoplasmic reticulum. These mutations have previously been associated with elevated inositol trisphosphate receptor (IP3R) levels in skeletal muscle myotubes derived from patients. However, the functional relevance and the relationship of IP3R mediated Ca2+ signalling with the pathophysiology of the disease is unclear. It has also been suggested that mitochondrial dysfunction underlies the development of central and diffuse multi-mini-cores, devoid of mitochondrial activity, which is a key pathological consequence of RyR1 mutations. Here we used muscle biopsies of central core and multi-minicore disease patients with RyR1 mutations, as well as cellular and in vivo mouse models of the disease to characterize global cellular and mitochondrial Ca2+ signalling, mitochondrial function and gene expression associated with the disease. We show that RyR1 mutations that lead to the depletion of the channel are associated with increased IP3-mediated nuclear and mitochondrial Ca2+ signals and increased mitochondrial activity. Moreover, western blot and microarray analysis indicated enhanced mitochondrial biogenesis at the transcriptional and protein levels and was reflected in increased mitochondrial DNA content. The phenotype was recapitulated by RYR1 silencing in mouse cellular myotube models. Altogether, these data indicate that remodelling of skeletal muscle Ca2+ signalling following loss of functional RyR1 mediates bioenergetic adaptation. PMID- 29701769 TI - ASAS-SSR Triennnial Reproduction Symposium: Looking Back and Moving Forward-How Reproductive Physiology has Evolved: Fetal origins of impaired muscle growth and metabolic dysfunction: Lessons from the heat-stressed pregnant ewe. AB - Intrauterine growth restriction (IUGR) is the second leading cause of perinatal mortality and predisposes offspring to metabolic disorders at all stages of life. Muscle-centric fetal adaptations reduce growth and yield metabolic parsimony, beneficial for IUGR fetal survival but detrimental to metabolic health after birth. Epidemiological studies have reported that IUGR-born children experience greater prevalence of insulin resistance and obesity, which progresses to diabetes, hypertension, and other metabolic disorders in adulthood that reduce quality of life. Similar adaptive programming in livestock results in decreased birth weights, reduced and inefficient growth, decreased carcass merit, and substantially greater mortality rates prior to maturation. High rates of glucose consumption and metabolic plasticity make skeletal muscle a primary target for nutrient-sparing adaptations in the IUGR fetus, but at the cost of its contribution to proper glucose homeostasis after birth. Identifying the mechanisms underlying IUGR pathophysiology is a fundamental step in developing treatments and interventions to improve outcomes in IUGR-born humans and livestock. In this review, we outline the current knowledge regarding the adaptive restriction of muscle growth and alteration of glucose metabolism that develops in response to progressively exacerbating intrauterine conditions. In addition, we discuss the evidence implicating developmental changes in beta adrenergic and inflammatory systems as key mechanisms for dysregulation of these processes. Lastly, we highlight the utility and importance of sheep models in developing this knowledge. PMID- 29701773 TI - Effects of active dry yeast on ruminal pH characteristics and energy partitioning of finishing steers under thermoneutral or heat-stressed environment. AB - The objective of this trial was to determine the effects of supplementing active dried yeast (ADY) in the diets of finishing steers on energy and nitrogen metabolism and ruminal pH characteristics under thermoneutral (TN) or heat stressed (HS) conditions. Eight British cross steers received 1 of 2 treatments (TRT) [either a control finishing diet (CON) or supplemented with 3 g/d of ADY] under 1 of 2 temperatures [TEMP: TN = 18 +/- 0.55 degrees C and 20 +/- 1.2% relative humidity (RH) or HS = 35 +/- 0.55 degrees C and 42 +/- 6.1% RH]. Steers were orally administered an indwelling rumen pH and temperature recording bolus. Data collection occurred for 48 consecutive hours inside 2 calorimetry chambers. Data were analyzed as a 4 * 8 Latin rectangle design with fixed effects of TRT and TEMP and random effects of steer and period. There were no TRT * TEMP interactions for metabolism or calorimetric measurements (P >= 0.1510). In vivo DM digestibility (DMD) was greater for ADY-fed steers than for CON-fed steers (77.1% vs. 75.3%, respectively; P = 0.0311). No TRT (P = 0.3032) or TEMP (P = 0.1833) effect was observed for nitrogen retention. Energy partitioning suggested DE and ME (Mcal/kg) were greater for ADY-fed steers than for CON-fed steers (P = 0.0097 and P = 0.0377, respectively). Steers under HS had reduced DMI but greater DMD than TN steers (77.1% vs. 75.3%, respectively; P = 0.0316) and greater CH4 per unit of DM (8.53 vs. 6.47 g/kg, respectively; P = 0.0145). Although DE was greater for HS than TN (3.16 vs. 3.06 Mcal/kg, respectively; P = 0.0123), heat production energy (HE) tended to be greater for HS than TN (18.1 vs. 17.0 Mcal/d, respectively; P = 0.0743), resulting in a less retained energy (0.412 vs. 0.100 Mcal/kg; P = 0.0147). There was a tendency for an interaction of mean ruminal pH (P = 0.1279) where pH of ADY-fed steers was greater than pH of CON-fed steers under TN conditions (5.81 vs. 5.57, respectively), but not under HS conditions (5.37 vs. 5.41, respectively). Duration (DUR) and area under the curve (AUC) for pH > 5.6 had similar tendencies; under TN conditions, the DUR and AUC for pH > 5.6 in ADY-fed steers were greater than in CON-fed steers (P = 0.0726 and P = 0.0954, respectively), but under HS conditions, there was no difference between ADY and CON. We conclude that supplementing ADY in the diets of finishing steers improved DMD, DE, ME, and mean ruminal pH under TN conditions, but not in extreme HS conditions likely due to reduced DMI and greater HE requirements. PMID- 29701774 TI - Associations Between Plasma Chemerin Concentrations and Bone Quality in Adults From the General Population. AB - Chemerin is an adipokine associated with parameters of inflammation and the metabolic syndrome. Small observational studies suggested that high circulating chemerin levels are also related to bone erosion. We aimed to determine whether plasma chemerin levels are related to bone quality in the general population and to investigate the influence of body mass index (BMI) on that relation. For our analyses, we obtained data from 3583 adults who participated in the population based Study of Health in Pomerania-Trend. The participants were divided into three groups according to their BMI: lean (<25 kg/m2), overweight (25 to 30 kg/m2), and obese (>=30 kg/m2). Chemerin concentrations were determined in EDTA plasma. Bone quality was assessed using quantitative ultrasound at the heel. Broadband ultrasound attenuation (BUA), speed of sound (SOS), stiffness index, and osteoporotic fracture risk were derived from this measurement. Sex- and BMI specific linear regression models revealed inverse associations between chemerin levels and BUA in obese men. In obese women, inverse relations between chemerin levels and SOS or stiffness index were found. Logistic regression models revealed positive associations between chemerin levels and osteoporotic fracture risk. In lean or overweight subjects, no statistically significant associations were found. Our sex- and BMI-specific analyses showed that inverse associations between chemerin levels and bone quality are restricted to obese men and women. The observed association may be due to a chemerin-induced negative affect on bone metabolism, possibly due to abrogation of osteoblastogenesis or stimulation of adipogenesis. PMID- 29701776 TI - Metagenomic binning reveals versatile nutrient cycling and distinct adaptive features in alphaproteobacterial symbionts of marine sponges. AB - Marine sponges are early-branched metazoans known to harbor dense and diverse microbial communities. Yet the role of the so far uncultivable alphaproteobacterial lineages that populate these sessile invertebrates remains unclear. We applied a sequence composition-dependent binning approach to assemble one Rhodospirillaceae genome from the Spongia officinalis microbial metagenome and contrast its functional features with those of closely related sponge associated and free-living genomes. Both symbiotic and free-living Rhodospirillaceae shared a suite of common features, possessing versatile carbon, nitrogen, sulfur and phosphorus metabolisms. Symbiotic genomes could be distinguished from their free-living counterparts by the lack of chemotaxis and motility traits, enrichment of genes required for the uptake and utilization of organic sulfur compounds-particularly taurine-, higher diversity and abundance of ABC transporters, and a distinct repertoire of genes involved in natural product biosynthesis, plasmid stability, cell detoxification and oxidative stress remediation. These sessile symbionts may more effectively contribute to host fitness via nutrient exchange, and also host detoxification and chemical defense. Considering the worldwide occurrence and high diversity of sponge-associated Rhodospirillaceae verified here using a tailored in silico approach, we suggest that these organisms are not only relevant to holobiont homeostasis but also to nutrient cycling in benthic ecosystems. PMID- 29701775 TI - Pharmacokinetics of rifampicin in adult TB patients and healthy volunteers: a systematic review and meta-analysis. AB - Objectives: The objectives of this study were to explore inter-study heterogeneity in the pharmacokinetics (PK) of orally administered rifampicin, to derive summary estimates of rifampicin PK parameters at standard dosages and to compare these with summary estimates for higher dosages. Methods: A systematic search was performed for studies of rifampicin PK published in the English language up to May 2017. Data describing the Cmax and AUC were extracted. Meta analysis provided summary estimates for PK parameter estimates at standard rifampicin dosages. Heterogeneity was assessed by estimation of the I2 statistic and visual inspection of forest plots. Summary AUC estimates at standard and higher dosages were compared graphically and contextualized using preclinical pharmacodynamic (PD) data. Results: Substantial heterogeneity in PK parameters was evident and upheld in meta-regression. Treatment duration had a significant impact on the summary estimates for rifampicin PK parameters, with Cmax 8.98 mg/L (SEM 2.19) after a single dose and 5.79 mg/L (SEM 2.14) at steady-state dosing, and AUC 72.56 mg.h/L (SEM 2.60) and 38.73 mg.h/L (SEM 4.33) after single and steady-state dosing, respectively. Rifampicin dosages of at least 25 mg/kg are required to achieve plasma PK/PD targets defined in preclinical studies. Conclusions: Vast inter-study heterogeneity exists in rifampicin PK parameter estimates. This is not explained by the available modifying variables. The recommended dosage of rifampicin should be increased to improve efficacy. This study provides an important point of reference for understanding rifampicin PK at standard dosages as efforts to explore higher dosing strategies continue in this field. PMID- 29701777 TI - Berbamine suppresses cell proliferation and promotes apoptosis in ovarian cancer partially via the inhibition of Wnt/beta-catenin signaling. AB - Ovarian cancer is a common and lethal cancer affecting women globally. Berbamine is a natural compound from the plant Berberis amurensis, which is used in Chinese traditional medicine. Recent studies have shown the anti-tumor effects of berbamine in several types of cancers but not in ovarian cancer. In the present study, we investigated the potential anti-tumor effects of berbamine in ovarian cancer and explored the underlying molecular mechanisms. Berbamine suppressed the cell viability of ovarian cancer cells in a concentration-dependent manner as revealed by methyl thiazolyl tetrazolium assay. Berbamine also suppressed the cell growth and invasion of ovarian cancer cells as measured by colony formation and cell invasion assays, respectively. Flow cytometry experiments showed that berbamine increased cell apoptotic rate and induced cell cycle arrest at G0/G1 phase in ovarian cancer cells. Western blot analysis showed that berbamine increased the protein levels of cleaved caspase-3, cleaved caspase-9, Bax, and decreased the protein level of Bcl-2 in ovarian cancer cells. Quantitative real time PCR and western blot analysis demonstrated that berbamine treatment inhibited the Wnt/beta-catenin signaling in ovarian cancer cells. The inhibitory effects of berbamine on cell viability and invasion of ovarian cancer cells can be partially reversed by lithium chloride (LiCl) treatment. Growth of tumors developed from SKOV3 cells was significantly suppressed in berbamine-treated group, and berbamine treatment enhanced caspase-3 and -9 cleavage and reduced beta-catenin protein level in tumor tissues. In summary, berbamine exerts its anti-cancer effects in vitro and in vivo via induction of apoptosis, partially associated with the inhibition of Wnt/beta-catenin signaling. PMID- 29701778 TI - Voltage and pace-capture mapping of linear ablation lesions overestimates chronic ablation gap size. AB - Aims: Conducting gaps in lesion sets are a major reason for failure of ablation procedures. Voltage mapping and pace-capture have been proposed for intra procedural identification of gaps. We aimed to compare gap size measured acutely and chronically post-ablation to macroscopic gap size in a porcine model. Methods and results: Intercaval linear ablation was performed in eight Gottingen minipigs with a deliberate gap of ~5 mm left in the ablation line. Gap size was measured by interpolating ablation contact force values between ablation tags and thresholding at a low force cut-off of 5 g. Bipolar voltage mapping and pace capture mapping along the length of the line were performed immediately, and at 2 months, post-ablation. Animals were euthanized and gap sizes were measured macroscopically. Voltage thresholds to define scar were determined by receiver operating characteristic analysis as <0.56 mV (acutely) and <0.62 mV (chronically). Taking the macroscopic gap size as gold standard, error in gap measurements were determined for voltage, pace-capture, and ablation contact force maps. All modalities overestimated chronic gap size, by 1.4 +/- 2.0 mm (ablation contact force map), 5.1 +/- 3.4 mm (pace-capture), and 9.5 +/- 3.8 mm (voltage mapping). Error on ablation contact force map gap measurements were significantly less than for voltage mapping (P = 0.003, Tukey's multiple comparisons test). Chronically, voltage mapping and pace-capture mapping overestimated macroscopic gap size by 11.9 +/- 3.7 and 9.8 +/- 3.5 mm, respectively. Conclusion: Bipolar voltage and pace-capture mapping overestimate the size of chronic gap formation in linear ablation lesions. The most accurate estimation of chronic gap size was achieved by analysis of catheter-myocardium contact force during ablation. PMID- 29701780 TI - Change in frequency of patient requests for diagnostic screening and interventions during primary care encounters from 1985 to 2014. AB - Background: The reason why patients contact a care provider, the reason for encounter (RFE), reflects patients' personal needs and expectations regarding medical care. RFEs can be symptoms or complaints, but can also be requests for diagnostic or therapeutic interventions. Objectives: Over the past 30 years, we aim to analyse the frequency with which patients consult a GP to request an intervention, and to analyse the impact of these requests on the subsequent diagnostic process. Methods: We included all patients with a request for diagnostics, medication prescription or referral from 1985 to 2014. We analysed the number of requests, granted requests and interventions originating from a request. We compared the final diagnosis (symptom or disease diagnosis) between patients with and without a request. Design and Setting: This is a retrospective cohort study with data from Family Medicine Network, a Dutch primary healthcare registration network. Results: Over time, patients more often present to their GP with a request for intervention. GPs are increasingly compliant with these requests. Patients presenting with a request for intervention are more likely to be diagnosed with a symptom rather than a disease. Conclusion: This study provides insight into the changes in patients' and GPs' behaviour and patients' influence on the medical process, and confirms the clinical relevance of the RFE. This study could support GPs in daily practice when deciding whether or not to grant a request. PMID- 29701779 TI - The eXceptional nature of the X chromosome. AB - The X chromosome is unique in the genome. In this review we discuss recent advances in our understanding of the genetics and epigenetics of the X chromosome. The X chromosome shares limited conservation with its ancestral homologue the Y chromosome and the resulting difference in X-chromosome dosage between males and females is largely compensated for by X-chromosome inactivation. The process of inactivation is initiated by the long non-coding RNA X-inactive specific transcript (XIST) and achieved through interaction with multiple synergistic silencing pathways. Identification of Xist-interacting proteins has given insight into these processes yet the cascade of events from initiation to maintenance have still to be resolved. In particular, the initiation of inactivation in humans has been challenging to study as: it occurs very early in development; most human embryonic stem cell lines already have an inactive X; and the process seems to differ from mouse. Another difference between human and mouse X inactivation is the larger number of human genes that escape silencing. In humans over 20% of X-linked genes continue to be expressed from the otherwise inactive X chromosome. We are only beginning to understand how such escape occurs but there is growing recognition that escapees contribute to sexually dimorphic traits. The unique biology and epigenetics of the X chromosome have often led to its exclusion from disease studies, yet the X constitutes 5% of the genome and is an important contributor to disease, often in a sex-specific manner. PMID- 29701781 TI - Mutant APP and amyloid beta-induced defective autophagy, mitophagy, mitochondrial structural and functional changes and synaptic damage in hippocampal neurons from Alzheimer's disease. AB - The purpose of our study was to determine the toxic effects of hippocampal mutant APP (mAPP) and amyloid beta (Abeta) in human mAPP complementary DNA (cDNA) transfected with primary mouse hippocampal neurons (HT22). Hippocampal tissues are the best source of studying learning and memory functions in patients with Alzheimer's disease (AD) and healthy controls. However, investigating immortalized hippocampal neurons that express AD proteins provide an excellent opportunity for drug testing. Using quantitative reverse transcriptase-polymerase chain reaction, immunoblotting & immunofluorescence and transmission electron microscopy, we assessed messenger RNA (mRNA) and protein levels of synaptic, autophagy, mitophagy, mitochondrial dynamics, biogenesis, dendritic protein MAP2 and assessed mitochondrial number and length in mAPP-HT22 cells that express Swedish/Indiana mutations. Mitochondrial function was assessed by measuring the levels of hydrogen peroxide, lipid peroxidation, cytochrome c oxidase activity and mitochondrial adenosine triphosphate. Increased levels of mRNA and protein levels of mitochondrial fission genes, Drp1 and Fis1 and decreased levels fusion (Mfn1, Mfn2 and Opa1) biogenesis (PGC1alpha, NRF1, NRF2 & TFAM), autophagy (ATG5 & LC3BI, LC3BII), mitophagy (PINK1 & TERT, BCL2 & BNIPBL), synaptic (synaptophysin & PSD95) and dendritic (MAP2) genes were found in mAPP-HT22 cells relative to WT-HT22 cells. Cell survival was significantly reduced mAPP-HT22 cells. GTPase-Drp1 enzymatic activity was increased in mAPP-HT22 cells. Transmission electron microscopy revealed significantly increased mitochondrial numbers and reduced mitochondrial length in mAPP-HT22 cells. These findings suggest that hippocampal accumulation of mAPP and Abeta is responsible for abnormal mitochondrial dynamics and defective biogenesis, reduced MAP2, autophagy, mitophagy and synaptic proteins & reduced dendritic spines and mitochondrial structural and functional changes in mAPP hippocampal cells. These observations strongly suggest that accumulation of mAPP and Abeta causes mitochondrial, synaptic and autophagy/mitophagy abnormalities in hippocampal neurons, leading to neuronal dysfunction. PMID- 29701783 TI - Infected Teflon felt strip-paracardiac abscess after Dor's procedure. AB - Foreign material used for reconstructing or suturing the cardiac chambers carries the risk of infection. When such a scenario is encountered, it is better to be aggressive in removing the infected source surgically, as conservative management will most often result in recurrence. Herein, we present an unusual case of infected prosthetic material after cardiac surgery that was managed surgically. This case reminds us of the surgical principle of eradicating the source of infection, which should be given priority. PMID- 29701782 TI - Grape seed procyanidin extract inhibits adipogenesis and stimulates lipolysis of porcine adipocytes in vitro. AB - The objective of this article was to evaluate in vitro effect of grape seed procyanidin extract (GSPE) on differentiation, proliferation, and lipolysis of porcine adipocytes, providing a molecular basis for the use of GSPE in pig fat regulation. Primary preadipocytes isolated from subcutaneous adipose tissue of pigs were used as the in vitro cell model. Treatment of GSPE repressed preadipocyte differentiation, as evidenced by reduced lipid accumulation, decreased mRNA expressions of peroxisome proliferator-activated receptor gamma (PPARgamma) and fatty acid-binding protein 4 (FABP4), as well as enhanced expressions of preadipocyte factor-1. Activity of glycerol-3-phosphate dehydrogenase (GPDH), one of the most important enzymes in the pathway for triacylglycerol biosynthesis, was also decreased. Furthermore, GSPE could suppress preadipocyte proliferation by inducing G0/G1 cell cycle arrest and cell apoptosis. In porcine mature adipocytes, treatment with GSPE attenuated lipid content and GPDH activity, and the release of both free fatty acid and glycerol were enhanced; mRNA expressions of key lipolytic transcription factors, including hormone-sensitive lipase (HSL) and adipose triglyceride lipase (ATGL), were elevated in GSPE-treated adipocytes. In summary, our results suggest GSPE inhibits porcine preadipocyte differentiation and proliferation and stimulates lipolysis of mature adipocytes, thus providing novel insights for further exploring the use of GSPE as a fat accumulation inhibitor. PMID- 29701784 TI - Renin-angiotensin system blockers in early pregnancy among women with chronic hypertension: getting to the heart of the risk-benefit equation. PMID- 29701785 TI - Mitochondrial Adaptations to Variable Environments and Their Role in Animals' Stress Tolerance. AB - Mitochondria are the key organelles involved in energy and redox homeostasis, cellular signaling, and survival. Animal mitochondria are exquisitely sensitive to environmental stress, and stress-induced changes in the mitochondrial integrity and function have major consequences for the organismal performance and fitness. Studies in the model organisms such as terrestrial mammals and insects showed that mitochondrial dysfunction is a major cause of injury during pathological conditions and environmental insults such as hypoxia, ischemia reperfusion, and exposure to toxins. However, animals from highly stressful environments (such as the intertidal zone of the ocean) can maintain mitochondrial integrity and function despite intense and rapid fluctuations in abiotic conditions and associated changes in the intracellular milieu. Recent studies demonstrate that mitochondria of intertidal organisms (including mollusks, crustaceans, and fish) are capable of maintaining activity of mitochondrial electron transport system (ETS), ATP synthesis, and mitochondrial coupling in a broad range of temperature, osmolarity, and ion content. Mitochondria of intertidal organisms such as mollusks are also resistant to hypoxia-reoxygenation injury and show stability or even upregulation of the mitochondrial ETS activity and ATP synthesis capacity during intermittent hypoxia. In contrast, pH optima for mitochondrial ATP synthesis and respiration are relatively narrow in intertidal mollusks and may reflect adaptation to suppress metabolic rate during pH shifts caused by extreme stress. Sensitivity to anthropogenic pollutants (such as trace metals) in intertidal mollusks appears similar to that of other organisms (including mammals) and may reflect the lack of adaptation to these evolutionarily novel stressors. The mechanisms of the exceptional mitochondrial resilience to temperature, salinity, and hypoxic stress are not yet fully understood in intertidal organisms, yet recent studies demonstrate that they may involve rapid modulation of the ETS capacity (possibly due to post-translation modification of mitochondrial proteins), upregulation of antioxidant defenses in anticipation of oxidative stress, and high activity of mitochondrial proteases involved in degradation of damaged mitochondrial proteins. With rapidly developing molecular tools for non-model organisms, future studies of mitochondrial adaptations should pinpoint the molecular sites associated with the passive tolerance and/or active regulation of mitochondrial activity during stress exposures in intertidal organisms, investigate the roles of mitochondria in transduction of stress signals, and explore the interplay between bioenergetics and mitochondrial signaling in facilitating survival in these highly stressful environments. PMID- 29701786 TI - Intracranial mycotic aneurysm is associated with cerebral bleeding post-valve surgery for infective endocarditis. AB - OBJECTIVES: The presence of cerebral haemorrhage (CH) preoperatively is a risk factor of in-hospital cerebrovascular complications post-valve surgery for acute infective endocarditis. However, factors related to cerebrovascular complications in the long term are poorly understood. We reviewed a series of these patients to investigate risk factors of in-hospital and long-term outcomes. METHODS: An institutional series of 148 patients who underwent valve surgery for active infective endocarditis between 2000 and 2016 were enrolled. Patients were divided into 2 groups based on the presence of preoperative CH:CH group (n = 25) and non CH group (n = 123). Of them, 14 (10%) patients were preoperatively diagnosed with mycotic aneurysm (MA). RESULTS: The 30-day mortality was 5% with no difference between the 2 groups. The 5-year survival rate was 92% in the CH group and 77% in the non-CH group. Freedom from CH at 5 years was 92% in the CH group and 97% in the non-CH group. There was no difference in the postoperative haemorrhage rate between patients who had surgery within 14 days from the onset of CH and those who had surgery after 14 days. Freedom from CH at 5 years was 99% in patients without MA and 71% in those with MA. The presence of MA preoperatively was the only independent risk factor of postoperative CH (P = 0.002). CONCLUSIONS: Valve surgery for acute infective endocarditis is safe, even in patients with CH preoperatively, regardless of the timing of surgery. Patients with intracranial MA are associated with postoperative CH in the hospital and long term. PMID- 29701788 TI - Is longitudinal tau PET ready for use in Alzheimer's disease clinical trials? PMID- 29701787 TI - Nucleus basalis of Meynert degeneration precedes and predicts cognitive impairment in Parkinson's disease. AB - Currently, no reliable predictors of cognitive impairment in Parkinson's disease exist. We hypothesized that microstructural changes at grey matter T1-weighted MRI and diffusion tensor imaging in the cholinergic system nuclei and associated limbic pathways underlie cognitive impairment in Parkinson's disease. We performed a cross-sectional comparison between patients with Parkinson's disease with and without cognitive impairment. We also performed a longitudinal 36-month follow-up study of cognitively intact Parkinson's disease patients, comparing patients who remained cognitively intact to those who developed cognitive impairment. Patients with Parkinson's disease with cognitive impairment showed lower grey matter volume and increased mean diffusivity in the nucleus basalis of Meynert, compared to patients with Parkinson's disease without cognitive impairment. These results were confirmed both with region of interest and voxel based analyses, and after partial volume correction. Lower grey matter volume and increased mean diffusivity in the nucleus basalis of Meynert was predictive for developing cognitive impairment in cognitively intact patients with Parkinson's disease, independent of other clinical and non-clinical markers of the disease. Structural and microstructural alterations in entorhinal cortex, amygdala, hippocampus, insula, and thalamus were not predictive for developing cognitive impairment in Parkinson's disease. Our findings provide evidence that degeneration of the nucleus basalis of Meynert precedes and predicts the onset of cognitive impairment, and might be used in a clinical setting as a reliable biomarker to stratify patients at higher risk of cognitive decline. PMID- 29701789 TI - Functional 'unlocking': bedside detection of covert awareness after severe brain damage. PMID- 29701790 TI - Disease progression models for dominantly-inherited Alzheimer's disease. PMID- 29701791 TI - The snowball effect of RNA binding protein dysfunction in amyotrophic lateral sclerosis. PMID- 29701792 TI - Editorial. PMID- 29701793 TI - Conservation tillage and organic farming induce minor variations in Pseudomonas abundance, their antimicrobial function and soil disease resistance. AB - Conservation tillage and organic farming are strategies used worldwide to preserve the stability and fertility of soils. While positive effects on soil structure have been extensively reported, the effects on specific root- and soil associated microorganisms are less known. The aim of this study was to investigate how conservation tillage and organic farming influence the frequency and activity of plant-beneficial pseudomonads. Amplicon sequencing using the 16S rRNA gene revealed that Pseudomonas is among the most abundant bacterial taxa in the root microbiome of field-grown wheat, independent of agronomical practices. However, pseudomonads carrying genes required for the biosynthesis of specific antimicrobial compounds were enriched in samples from conventionally farmed plots without tillage. In contrast, disease resistance tests indicated that soil from conventional no tillage plots is less resistant to the soilborne pathogen Pythium ultimum compared to soil from organic reduced tillage plots, which exhibited the highest resistance of all compared cropping systems. Reporter strain-based gene expression assays did not reveal any differences in Pseudomonas antimicrobial gene expression between soils from different cropping systems. Our results suggest that plant-beneficial pseudomonads can be favoured by certain soil cropping systems, but soil resistance against plant diseases is likely determined by a multitude of biotic factors in addition to Pseudomonas. PMID- 29701794 TI - Effects of grazing different ergovaline concentrations on vasoactivity of bovine lateral saphenous vein. AB - Previous research has demonstrated that exposure to ergot alkaloids reduces vasoactivity of serotonin (5HT) receptors. Chemical suppression of tall fescue seedhead production is a tool to reduce the level of exposure to ergot alkaloids by a grazing animal. Therefore, the objective was to evaluate contractility of lateral saphenous veins biopsied from mixed breed steers following a 87- to 101-d grazing period on 3-ha pastures of bermudagrass (Cynodon dactylon; n = 5 steers; BW = 340 +/- 9 kg), or toxic endophyte-infected tall fescue (Lolium arundinaceum) that was not treated (n = 5 steers; BW = 300 +/- 6; 0.56 ppm ergovaline) or was treated (n = 5 steers; BW = 294 +/- 9 kg; 0.24 ppm ergovaline) with herbicide containing aminopyralid and metsulfuron-methyl. To evaluate contractility, biopsied veins were mounted in a multimyograph and exposed to increasing concentrations of a tall fescue seed extract (EXT; ergovaline source) and 5HT1B (CP 93129), 5HT1D (L-694,247), and 5HT2A (TCB2) agonists. All contractility data were normalized to a maximal response of 1 * 10-4 M norepinephrine and were analyzed as a split plot treatment design using SAS for effects of pasture treatment, agonist concentration, and the interaction. There was no contractile response to any concentration of 5HT1B agonist in any of the pasture treatments. There were pasture * concentration interactions for contractile responses to 5HT2A agonist (P < 0.01) and EXT (P < 0.01). For both EXT and TCB2, veins from bermudagrass steers were more vasoactive to the higher concentrations of these compounds (P < 0.05), and there were no differences between veins collected from the unsuppressed or seedhead-suppressed treatments (P = 0.66). There was also a pasture * concentration interaction for the contractile responses to 5HT1D agonist (P < 0.01). However, these responses were not sigmoidal and reached a zenith at 5 * 10-7 and 1 * 10-6 M. At these concentrations, the response was greatest for veins from the unsuppressed treatment (P < 0.05) and did not differ between veins from suppressed and bermudagrass treatments (P = 0.41). Although reduced levels of ergovaline in seedhead-suppressed pastures did not alter vasoactivity of 5HT2A or 5HT1B receptors in the lateral saphenous vein, elevated vasoactivity of 5HT1D in veins from unsuppressed tall fescue pasture treatment suggests that lower ergovaline levels in seedhead-suppressed pastures can influence the vascular effects of ergot alkaloids. PMID- 29701796 TI - Effect of supplementation with methyl-donor nutrients on neurodevelopment and cognition: considerations for future research. AB - Pregnancy represents a critical period in fetal development, such that the prenatal environment can, in part, establish a lifelong trajectory of health or disease for the offspring. Poor nutrition (macro- or micronutrient deficiencies) can adversely affect brain development and significantly increase offspring risk for metabolic and neurological disease development. The concentration of dietary methyl-donor nutrients is known to alter DNA methylation in the brain, and alterations in DNA methylation can have long-lasting effects on gene expression and neuronal function. The decreased availability of methyl-donor nutrients to the developing fetus in models of poor maternal nutrition is one mechanism hypothesized to link maternal malnutrition and disease risk in offspring. Animal studies indicate that supplementation of both maternal and postnatal (early- and later-life) diets with methyl-donor nutrients can attenuate disease risk in offspring; however, clinical research is more equivocal. The objective of this review is to summarize how specific methyl-donor nutrient deficiencies and excesses during pre- and postnatal life alter neurodevelopment and cognition. Emphasis is placed on reviewing the current literature, highlighting challenges within nutrient supplementation research, and considering potential strategies to ensure robust findings in future studies. PMID- 29701797 TI - Commentary on Appropriate Use Criteria for SIJ Pain. PMID- 29701795 TI - Seed dormancy release accelerated by elevated partial pressure of oxygen is associated with DOG loci. AB - Seed dormancy determines the timing of seed germination and may be released by dry storage, also referred to as after-ripening. Studies on dormancy-release mechanisms are often hampered by the long after-ripening requirements of seeds. After-ripening is thought to be mainly caused by oxidative processes during seed dry storage. These processes are also the main cause of seed ageing. Increasing partial oxygen pressure through the elevated partial pressure of oxygen (EPPO) system has been shown to mimic and accelerate dry seed ageing. In this study, we investigated whether the EPPO system may also release primary seed dormancy in Arabidopsis thaliana. EPPO mimics dry after-ripening at the genetic level, as quantitative trait locus (QTL) analysis after EPPO treatment identified the DELAY OF GERMINATION loci DOG1, DOG2, and DOG6 that were first described in a study using dry after-ripening to release seed dormancy. QTL analysis also showed that dormancy release by cold stratification (another common method to break seed dormancy) partly overlaps with release by after-ripening and EPPO treatment. We conclude that EPPO is an appropriate method to mimic and accelerate dormancy release and, as such, may have applications in both research and industry. PMID- 29701798 TI - In Reply to Letter by Dr. Laslett. PMID- 29701799 TI - Sex Ratios and Mating Status of the Horn Fly on Pastured Cattle as a Function of Repellent-Oil Treatments. AB - Haematobia irritans (L.) (Diptera: Muscidae) were netted from pastured cattle in California over two summers, with the goal of documenting on-host sex ratios and mating success as they might vary with repellent applications. Sex ratios were calculated from 100 adults per herd per date, and mating status of females (n = 30 per herd per date) was assessed by dissection of spermathecae. Flies were collected before, during, and after 2-wk treatment periods with each of two repellent-oil mixtures: a 15% mixture of fatty acids (C8, C9, C10) in mineral oil or a 2% solution of geraniol in mineral oil. During the treatment period, flies were collected 3-4 d after the prior treatment and immediately before the next treatment. A separate herd used in the second year was untreated. Overall, the proportion female was 0.65 +/- 0.01 (mean +/- SE) (range 0.28-0.81). Sex ratios were not altered over time by treatments with either repellent. Overall, proportion of females mated was 0.744 +/- 0.018 (range 0.40-1.00). Mating status was significantly affected by the two repellent treatments, which did not differ from each other. For treatment herds, proportion mated before treatment was 0.789 +/- 0.039, dropping significantly to 0.659 +/- 0.038 during the treatment period, and rebounding to 0.750 +/- 0.035 after treatments ceased. Treatments probably killed or repelled the existing heterogeneous fly population, and during treatment relatively more flies were unmated recent arrivals. PMID- 29701800 TI - Ancestral Function and Diversification of a Horizontally Acquired Oomycete Carboxylic Acid Transporter. AB - Horizontal gene transfer (HGT) can equip organisms with novel genes, expanding the repertoire of genetic material available for evolutionary innovation and allowing recipient lineages to colonize new environments. However, few studies have characterized the functions of HGT genes experimentally or examined postacquisition functional divergence. Here, we report the use of ancestral sequence reconstruction and heterologous expression in Saccharomyces cerevisiae to examine the evolutionary history of an oomycete transporter gene family that was horizontally acquired from fungi. We demonstrate that the inferred ancestral oomycete HGT transporter proteins and their extant descendants transport dicarboxylic acids which are intermediates of the tricarboxylic acid cycle. The substrate specificity profile of the most ancestral protein has largely been retained throughout the radiation of oomycetes, including in both plant and animal pathogens and in a free-living saprotroph, indicating that the ancestral HGT transporter function has been maintained by selection across a range of different lifestyles. No evidence of neofunctionalization in terms of substrate specificity was detected for different HGT transporter paralogues which have different patterns of temporal expression. However, a striking expansion of substrate range was observed for one plant pathogenic oomycete, with a HGT derived paralogue from Pythium aphanidermatum encoding a protein that enables tricarboxylic acid uptake in addition to dicarboxylic acid uptake. This demonstrates that HGT acquisitions can provide functional additions to the recipient proteome as well as the foundation material for the evolution of expanded protein functions. PMID- 29701801 TI - Determinants of Uncontrolled Hypertension in Rural Communities in South Asia Bangladesh, Pakistan, and Sri Lanka. AB - BACKGROUND: Uncontrolled blood pressure (BP) is a leading risk factor for death and disability in South Asia. We aimed to determine the cross-country variation, and the factors associated with uncontrolled BP among adults treated for hypertension in rural South Asia. METHODS: We enrolled 1,718 individuals aged >=40 years treated for hypertension in a cross-sectional study from rural communities in Bangladesh, Pakistan, and Sri Lanka. Multivariable logistic regression model was used to determine the factors associated with uncontrolled BP (systolic BP >=140 mmHg or diastolic BP >=90 mmHg). RESULTS: Among hypertensive individuals, 58.0% (95% confidence interval (CI) 55.7, 60.4) had uncontrolled BP: 52.8% (49.0, 56.6) in Bangladesh, 70.6% (65.7, 75.1) in Pakistan, and 56.5% (52.7, 60.1) in Sri Lanka. The odds (odds ratio (95% CI)) of uncontrolled BP were significantly higher in individuals with lower wealth index (1.17 (1.02, 1.35)); single vs. married (1.46 (1.10, 1.93)); higher log urine albumin-to-creatinine ratio (1.41 (1.24, 1.60)); lower estimated glomerular filtration rate (1.23 (1.01, 1.49)); low vs. high adherence to antihypertensive medication (1.50 (1.16, 1.94)); and Pakistan (2.91 (1.60, 5.28)) vs. Sri Lanka. However, the odds were lower in those with vs. without self-reported kidney disease (0.51 (0.28, 0.91)); and receiving vs. not receiving statins (0.62 (0.44, 0.87)). CONCLUSIONS: The majority of individuals with treated hypertension have uncontrolled BP in rural Bangladesh, Pakistan, and Sri Lanka with significant disparities among and within countries. Urgent public health efforts are needed to improve access and adherence to antihypertensive medications in disadvantaged populations in rural South Asia. PMID- 29701802 TI - A2-type cyclin is required for the asymmetric entry division in rice stomatal development. AB - In rice, and other major cereal grass crops, stomata are arranged in linear files parallel to the long growth axis of leaves. Each stomatal unit comprises two dumbbell-shaped guard cells flanked by two subsidiary cells. These morphological and developmental characteristics enable grass stomata to respond to environmental changes more efficiently. Cyclin-dependent kinases (CDKs) and their cyclin partners co-ordinate cell proliferation and differentiation during the development of multicellular organisms. In contrast to animals, plants have many more types and members of cyclins. In Arabidopsis, four A2-type cyclins (CYCA2s) function redundantly in regulating CDKB1 activity to promote the asymmetric division for stomatal initiation and the symmetric division of guard mother cells (GMCs). In this study, we examine the function of the single A2-type cyclin in rice, OsCYCA2;1, as well the single B1-type CDK, OsCDKB1;1. Cross-species complementation tests demonstrated that OsCYCA2;1 and OsCDKB1;1 could complement the defective stomatal phenotypes of Arabidopsis cyca2 and cdkb1 mutants, but also could suppress DNA endoduplication and cell enlargement. The early asymmetric divisions that establish the stomatal lineages are often missing within the stomatal cell files of OsCYCA2;1-RNAi rice transgenic lines, leading to a significantly reduced stomatal production. However, GMC divisions are not disrupted either in OsCYCA2;1-RNAi or in OsCDKB1;1-RNAi rice transgenic lines as expected. Our results demonstrate a conserved but diverged function and behavior of rice A2-type cyclins, which might be associated with the distinct stomatal development pathways between rice and Arabidopsis. PMID- 29701803 TI - Rapid increase of 'brain-type' transferrin in cerebrospinal fluid after shunt surgery for idiopathic normal pressure hydrocephalus: a prognosis marker for cognitive recovery. AB - Idiopathic normal pressure hydrocephalus (iNPH) is a dementia-inducing disorder. Primary cause of iNPH is speculated to be a reduction of cerebrospinal fluid (CSF) absorption, which secondarily induces hydrocephalus, compression of brain, and reduction of CSF production. Patients are treated by surgically inserting a shunt to deliver excess CSF to the abdominal cavity. The prognosis for cognitive improvement after shunt surgery has been difficult to predict. We therefore investigated various CSF proteins, hoping to find a biomarker predictive of cognitive performance one to two years after shunt surgery. CSF proteins of 34 iNPH and 15 non-iNPH patients were analysed by Western blotting, revealing two glycan isoforms of transferrin (Tf); 'brain-type' Tf with N acetylglucosaminylated glycans and 'serum-type' Tf with alpha2, 6-sialylated glycans. Brain-type Tf levels decreased in iNPH but rapidly returned to normal levels within 1-3 months after shunt surgery. This change was positively correlated with recovery from dementia, per Mini-Mental State Examination and Frontal Assessment Battery scores at 11.8 +/- 7.7 months post-operation, suggesting that brain-type Tf is a prognostic marker for recovery from dementia after shunt surgery for iNPH. Histochemical staining with anti-Tf antibody and an N-acetylglucosamine-binding lectin suggests that brain-type Tf is secreted from choroid plexus, CSF-producing tissue. PMID- 29701804 TI - Redefining nitric oxide production in legume nodules through complementary insights from electron paramagnetic resonance spectroscopy and specific fluorescent probes. AB - Nitric oxide (NO) is a signaling molecule with multiple functions in plants. Given its critical importance and reactivity as a gaseous free radical, we have examined NO production in legume nodules using electron paramagnetic resonance (EPR) spectroscopy and the specific fluorescent dye 4,5-diaminofluorescein diacetate. Also, in this context, we critically assess previous and current views of NO production and detection in nodules. EPR of intact nodules revealed that nitrosyl-leghemoglobin (Lb2+NO) was absent from bean or soybean nodules regardless of nitrate supply, but accumulated in soybean nodules treated with nitrate that were defective in nitrite or nitric oxide reductases or that were exposed to ambient temperature. Consequently, bacteroids are a major source of NO, denitrification enzymes are required for NO homeostasis, and Lb2+NO is not responsible for the inhibition of nitrogen fixation by nitrate. Further, we noted that Lb2+NO is artifactually generated in nodule extracts or in intact nodules not analyzed immediately after detachment. The fluorescent probe detected NO formation in bean and soybean nodule infected cells and in soybean nodule parenchyma. The NO signal was slightly decreased by inhibitors of nitrate reductase but not by those of nitric oxide synthase, which could indicate a minor contribution of plant nitrate reductase and supports the existence of nitrate- and arginine-independent pathways for NO production. Together, our data indicate that EPR and fluorometric methods are complementary to draw reliable conclusions about NO production in plants. PMID- 29701805 TI - Cardiac rehabilitation fitness changes and subsequent survival. AB - Aims: Assessments of cardiac rehabilitation (CR) in coronary heart disease (CHD) cohorts usually examine mortality in aggregate. This study examines the prognosis and characteristics of patients who enrolled and completed CR, stratified by their level of improvement in cardiorespiratory fitness (CRF) by examining the characteristics, outcomes and predictors of non-response in CRF (NonRes) compared with low-responders (LowRes) and high-responders (HighRes) after CR. Methods and results: A total of 1171 CHD patients were referred for a phase II CR programme after therapy for an acute coronary syndrome, coronary artery bypass graft procedure or a percutaneous coronary intervention between 1 January 2000 and 30 June 2013 underwent cardiopulmonary exercise testing before and after CR. This cohort was divided according to absolute improvements in CRF (i.e. change in peak oxygen consumption expressed in mL?kg-1?min-1). Mortality was analysed after 0.5 13.4 years of follow-up (mean 6.4 years). A total of 266 (23%) subjects were NonRes. After adjustment for body mass index, age, gender, left ventricular ejection fraction and baseline CRF, NonRes, and LowRes had a statistically significant three-fold and two-fold higher mortality, respectively, when compared with HighRes (HighRes 8% vs. LowRes 17% vs. NonRes 22%; P < 0.001). Age, female gender, baseline CRF, hostility, and presence of diabetes were significant predictors of NonRes and LowRes. In addition, higher waist circumference was a predictor of NonRes. Conclusion: Significant proportions of subjects referred to CR have no/low improvement in CRF and higher associated mortality risks. Greater attention is required to increase improvements in CRF following CR and avoid NonRes. PMID- 29701806 TI - High fibroblast growth factor 23 is associated with coronary calcification in patients with high adiponectin: analysis from the Korean Cohort Study for Outcome in Patients with Chronic Kidney Disease study. AB - Background: The association between fibroblast growth factor 23 (FGF23) and coronary artery calcification (CAC) was inconclusive. Recently it was shown that adiponectin modulates renal handling of calcium and phosphorus. We hypothesized that adiponectin plays a role in the effect of FGF23 on CAC and explored whether the association between FGF23 and CAC is modified by serum adiponectin level in chronic kidney disease (CKD) patients. Methods: This cross-sectional study analyzed 1435 predialysis CKD patients from the Korean Cohort Study for Outcome in Patients with CKD cohort. Participants were divided into two groups according to their serum adiponectin (upper half and lower half). Each group was further divided into three groups according to their FGF23 levels as follows: low (<5.0 RU/mL), middle (5.0-29.9 RU/mL) and high (>=30.0 RU/mL). The coronary artery calcium score (CACS) was assessed using cardiac computed tomography and CAC was defined as a CACS >100. Results: The median CACS did not differ between the low and high adiponectin groups {3.2 [interquartile range (IQR) 0.0-98.1] versus 0.5 [0.0-99.5], P = 0.988}. The CACS ratio comparing high FGF23 to low FGF23 was significantly increased in the high adiponectin group, but not in the low adiponectin group [2.35 (IQR 1.14-4.85) versus 1.10 (0.60-2.03)]. The odds ratio for CAC in the high FGF23 group compared with the low group was 1.97 (IQR 1.10 3.53). The association between FGF23 and CAC was modified significantly by adiponectin level (P for interaction = 0.023). Conclusions: High serum FGF23 was associated with CAC in CKD patients with high adiponectin, but not in those with low adiponectin. Further studies are warranted to verify the role of adiponectin in FGF23-related CAC. PMID- 29701808 TI - The lectin pathway in renal disease: old concept and new insights. AB - The complement system is composed of a network of at least 40 proteins, which significantly contributes to health and disease. The lectin pathway (LP) is one of three pathways that can activate the complement system. Next to protection of the host against pathogens, the LP has been shown to play a crucial role in multiple renal diseases as well as during renal replacement therapy. Therefore, several complement-targeted drugs are currently being explored in clinical trials. Among these complement inhibitors, specific LP inhibitors are also being tested in renal abnormalities such as in immunoglobulin A nephropathy and lupus nephritis. Using various in vitro models, Yaseen et al. (Lectin pathway effector enzyme mannan-binding lectin-associated serine protease-2 can activate native complement component 3 (C3) in absence of C4 and/or C2. FASEB J 2017; 31: 2210 2219) showed that Mannan-associated serine protease2 can directly activate C3 thereby bypassing C2 and C4 in the activation of the LP. These new findings broaden our understanding of the mechanisms of complement activation and could potentially impact our strategies to inhibit the LP in renal diseases. In support of these findings, we present data of human renal biopsies, demonstrating the occurrence of the LP bypass mechanism in vivo. In conclusion, this review provides a detailed overview of the LP and clarifies the recently described bypass mechanism and its relevance. Finally, we speculate on the role of the C4 bypass mechanism in other renal diseases. PMID- 29701807 TI - Evidence That Environmental and Familial Risks for Psychosis Additively Impact a Multidimensional Subthreshold Psychosis Syndrome. AB - Background: The observed link between positive psychotic experiences (PE) and psychosis spectrum disorder (PSD) may be stronger depending on concomitant presence of PE with other dimensions of psychopathology. We examined whether the effect of common risk factors for PSD on PE is additive and whether the impact of risk factors on the occurrence of PE depends on the co-occurrence of other symptom dimensions (affective dysregulation, negative symptoms, and cognitive alteration). Method: Data from the Netherlands Mental Health Survey and Incidence Study 2 were used. Risk factors included childhood adversity, cannabis use, urbanicity, foreign born, hearing impairment, and family history of affective disorders. Logistic regression models were applied to test (1) the additive effect of risk factors (4 levels) on PE and (2) the moderating effects of symptom dimensions on the association between risk factors (present/absent) and PE, using additive interaction, expressed as the interaction contrast ratio. Results: Risk factors were additive: the greater the number of risk factors, the greater the odds of PE. Furthermore, concomitant presence of the other symptom dimensions all increased the impact of risk factors on PE. After controlling for age, sex, and education, only affective dysregulation and negative symptoms remained significant moderators; only affective dysregulation remained a significant moderator if all dimensions were adjusted for each other. Conclusions: Risk factors may not be directly associated with PE but additively give rise to a multidimensional subthreshold state anticipating the multidimensional clinical syndrome. Early motivational and cognitive impairments in the context of PE may be reducible to affective dysregulation. PMID- 29701809 TI - Receptor Blockade: A Novel Approach to Protect the Brain From Pneumococcal Invasion. AB - Background: Pneumococci are the major cause of bacterial meningitis globally. To cause meningitis pneumococci interact with the 2 endothelial receptors, polymeric immunoglobulin receptor (pIgR) and platelet endothelial cell adhesion molecule (PECAM-1), to penetrate the blood-brain barrier (BBB) and invade the brain. Methods: C57BL/6 mice were infected intravenously with bioluminescent pneumococci, and treated with ceftriaxone (1 hour postinfection) and anti-pIgR and PECAM-1 antibodies (1 or 5 hours postinfection), then monitored for 5 and 10 days. Bacterial brain invasion was analyzed using IVIS imaging and bacterial counts. Results: Ceftriaxone, given early after pneumococcal challenge, cleared pneumococci from the blood but not from the brain. After combining ceftriaxone with receptor blockade, using anti-pIgR and PECAM-1 antibodies, we found 100% survival after 5 and 10 days of infection, in contrast to 60% for ceftriaxone alone. Combined antibiotic and antibody treatment resulted in no or few viable bacteria in the brain and no microglia activation. Antibodies remained bound to the receptors during the study period. Receptor blockade did not interfere with antibiotic permeability through the BBB. Conclusions: We suggest that adjunct treatment with pIgR and PECAM-1 antibodies to antibiotics may prevent pneumococcal meningitis development and associated brain damages. However, further evaluations are required. PMID- 29701810 TI - Relationship between the gut microbiome and brain function. AB - It has become increasingly evident in recent years that the gut microbiome and the brain communicate in a bidirectional manner, with each possibly affecting the other's functions. Substantial research has aimed to understand the mechanisms of this interaction and to outline strategies for preventing or treating nervous system-related disturbances. This review explores the evidence demonstrating how the gut microbiome may affect brain function in adults, thereby having an impact on stress, anxiety, depression, and cognition. In vitro, in vivo, and human studies reporting an association between a change in the gut microbiome and functional changes in the brain are highlighted, as are studies outlining the mechanisms by which the brain affects the microbiome and the gastrointestinal tract. Possible modes of action to explain how the gut microbiome and the brain functionally affect each other are proposed. Supplemental probiotics to combat brain-related dysfunction offer a promising approach, provided future research elucidates their mode of action and possible side effects. Further studies are warranted to establish how pre- and probiotic interventions may help to balance brain function in healthy and diseased individuals. PMID- 29701811 TI - Spatio-temporal Aspects of Ca2+ Signalling: Lessons from Guard Cells and Pollen Tubes. AB - Changes in cytosolic Ca2+ concentration ([Ca2+]cyt) serve to transmit information in eukaryotic cells. The involvement of this second messenger in plant cell growth as well as osmotic- and water relations is well established. After almost 40 years of intense research on the coding and decoding of plant Ca2+ signals, numerous proteins involved in Ca2+ action have been identified. However, we are still far from understanding the complexity of Ca2+ networks. New in vivo Ca2+ imaging techniques combined with molecular genetics allow visualisation of spatio temporal aspects of Ca2+ signalling. In parallel, cell biology together with protein biochemistry and electrophysiology are able to dissect information processing by this second messenger in space and time. Here we focus on the time resolved changes in cellular events upon Ca2+ signals, concentrating on the two best-studied cell types, pollen tubes and guard cells. We put their signalling networks side by side, compare them with those of other cell types and discuss rapid signalling in the context of Ca2+ transients and oscillations to regulate ion homeostasis. PMID- 29701812 TI - Pain Intensity, Disability, and Quality of Life in Patients with Chronic Low Back Pain: Does Age Matter? AB - Objective: Nonspecific chronic low back pain (CLBP) is a frequent medical condition among middle-aged and older adults. Its detrimental consequences for functional ability and quality of life are well known. However, less is known about associations of chronological age with disability and well-being among CLBP patients. Coping with pain may be harder with advancing age due to additional age associated losses of physical, sensory, and other resources, resulting in higher disability and lower quality of life. Alternatively, older patients may feel less impaired and report higher quality of life than younger patients because the experience of chronic pain may be better anticipated and more "normative" in old age. Methods: We investigated an age-heterogeneous sample of 228 CLBP patients (mean age = 59.1 years, SD = 10.2 years, range 41-82 years). Our outcomes were pain intensity, pain disability (as assessed by self-reported activity restrictions and performance-based tests), and measures of quality of life (health-related quality of life: SF-12 physical and mental health; well-being: anxiety, depression, perceived control over life, affective distress). Results: Although older patients had higher performance-based disability, they scored higher on mental health and on most measures of well-being than younger patients. Conclusions: Our findings provide evidence for a "paradoxical" pattern of age effects in CLBP patients and are thus in line with other studies based on nonclinical samples: Although disability in CLBP patients increases with advancing age, indicators of quality of life are equal or even higher in older patients. PMID- 29701814 TI - Oxytocin Reduces Cigarette Consumption in Daily Smokers. AB - Introduction: Despite widespread knowledge of the dangers of cigarette consumption, smoking continues to be a public health concern. One compound that has shown potential for treatment in preclinical models is the neuropeptide oxytocin (OT). The purpose of the present study was to examine the effects of intranasal oxytocin on cigarette craving, behavioral economic demand for cigarettes, and cigarette consumption, in regular smokers after 18 hours of abstinence. Method: Otherwise healthy daily smokers (n= 35) completed two sessions where they received OT (40 IU intranasal) or placebo (PBO) and completed measures of craving and cigarette demand, and were given 6 opportunities to smoke partial cigarettes in exchange for money. Results: On average participants smoked few cigarettes after receiving OT than after receiving PBO, and they reported less desire for additional cigarettes during the smoking period. OT did not affect cigarette demand or standardized measures of cigarette craving. Conclusions: This study suggests that OT decreases some indices of smoking desire and consumption, providing modest support for the idea that OT might be effective for reducing cigarette smoking. Implications: This study provides new evidence that oxytocin might have clinical value in the treatment of addictive disorders, in this case tobacco addiction. The study adds to a growing literature suggesting that this neuropeptide, which is mainly known for its role in social bonding and attachment, may also affect mood and motivational states relevant to addiction. PMID- 29701813 TI - A Microneedle Patch for Measles and Rubella Vaccination Is Immunogenic and Protective in Infant Rhesus Macaques. AB - Background: New methods to increase measles and rubella (MR) vaccination coverage are needed to achieve global and regional MR elimination goals. Methods: Here, we developed microneedle (MN) patches designed to administer MR vaccine by minimally trained personnel, leave no biohazardous sharps waste, remove the need for vaccine reconstitution, and provide thermostability outside the cold chain. This study evaluated the immunogenicity of MN patches delivering MR vaccine to infant rhesus macaques. Results: Protective titers of measles neutralizing antibodies (>120 mIU/mL) were detected in 100% of macaques in the MN group and 75% of macaques in the subcutaneous (SC) injection group. Rubella neutralizing antibody titers were >10 IU/mL for all groups. All macaques in the MN group were protected from challenge with wild-type measles virus, whereas 75% were protected in the SC group. However, vaccination by the MN or SC route was unable to generate protective immune responses to measles in infant macaques pretreated with measles immunoglobulin to simulate maternal antibody. Conclusions: These results show, for the first time, that MR vaccine delivered by MN patch generated protective titers of neutralizing antibodies to both measles and rubella in infant rhesus macaques and afforded complete protection from measles virus challenge. PMID- 29701815 TI - Legionella pneumophila effector WipA, a bacterial PPP protein phosphatase with PTP activity. AB - The gram-negative bacterium Legionella pneumophila invades human's lung and causes Legionnaires' disease. To benefit its survival and replication in cellular milieu, L. pneumophila secrets at least 330 effector proteins into host cells. We found that the effector WipA has the protein tyrosine phosphatase (PTP) activity but does not depend on the classical CX5R motif for activity, suggesting that WipA is an unconventional PTP. Meanwhile, the presence of three other highly conserved motifs typically seen in protein serine/threonine phosphatases and the poor inhibition of WipA activity by okadaic acid led us to propose that WipA is a bacterial protein phosphatase. In addition, the determination of the 2.55-A crystal structure of WipA revealed that WipA resembles cold-active protein tyrosine phosphatase (CAPTPase), and therefore very likely shares the same catalytic mechanism. PMID- 29701816 TI - Electron diffraction covering a wide angular range from Bragg diffraction to small-angle diffraction. AB - We construct an electron optical system to investigate Bragg diffraction (the crystal lattice plane, 10-2 to 10-3 rad) with the objective lens turned off by adjusting the current in the intermediate lenses. A crossover was located on the selected-area aperture plane. Thus, the dark-field imaging can be performed by using a selected-area aperture to select Bragg diffraction spots. The camera length can be controlled in the range of 0.8-4 m without exciting the objective lens. Furthermore, we can observe the magnetic-field dependence of electron diffraction using the objective lens under weak excitation conditions. The diffraction mode for Bragg diffraction can be easily switched to a small-angle electron diffraction mode having a camera length of more than 100 m. We propose this experimental method to acquire electron diffraction patterns that depict an extensive angular range from 10-2 to 10-7 rad. This method is applied to analyze the magnetic microstructures in three distinct magnetic materials, i.e. a uniaxial magnetic structure of BaFe10.35Sc1.6Mg0.05O19, a martensite of a Ni-Mn Ga alloy, and a helical magnetic structure of Ba0.5Sr1.5Zn2Fe12O22. PMID- 29701817 TI - Effects of Elevated CO2 on Plant Chemistry, Growth, Yield of Resistant Soybean, and Feeding of a Target Lepidoptera Pest, Spodoptera litura (Lepidoptera: Noctuidae). AB - Atmospheric CO2 level arising is an indisputable fact in the future climate change, as predicted, it could influence crops and their herbivorous insect pests. The growth and development, reproduction, and consumption of Spodoptera litura (F.) (Lepidoptera: Noctuidae) fed on resistant (cv. Lamar) and susceptible (cv. JLNMH) soybean grown under elevated (732.1 +/- 9.99 MUl/liter) and ambient (373.6 +/- 9.21 MUl/liter) CO2 were examined in open-top chambers from 2013 to 2015. Elevated CO2 promoted the above- and belowground-biomass accumulation and increased the root/shoot ratio of two soybean cultivars, and increased the seeds' yield for Lamar. Moreover, elevated CO2 significantly reduced the larval and pupal weight, prolonged the larval and pupal life span, and increased the feeding amount and excretion amount of two soybean cultivars. Significantly lower foliar nitrogen content and higher foliar sugar content and C/N ratio were observed in the sampled foliage of resistant and susceptible soybean cultivars grown under elevated CO2, which brought negative effects on the growth of S. litura, with the increment of foliar sugar content and C/N ratio were greater in the resistant soybean in contrast to the susceptible soybean. Furthermore, the increment of larval consumption was less than 50%, and the larval life span was prolonged more obvious of the larvae fed on resistant soybean compared with susceptible soybean under elevated CO2. It speculated that the future climatic change of atmospheric CO2 level arising would likely cause the increase of the soybean yield and the intake of S. litura, but the resistant soybean would improve the resistance of the target Lepidoptera pest, S. litura. PMID- 29701818 TI - Determinants of IBD Heritability: Genes, Bugs, and More. AB - Defining the etiology of inflammatory bowel disease (IBD) continues to elude researchers, in part due to the possibility that there may be different triggers for a spectrum of disease phenotypes that are currently classified as either Crohn's disease (CD) or ulcerative colitis (UC). What is clear is that genetic susceptibility plays an important role in the development of IBD, and large genome-wide association studies using case-control approaches have identified more than 230 risk alleles. Many of these identified risk alleles are located in a variety of genes important in host-microbiome interactions. In spite of these major advances, the mechanisms behind the genetic influence on disease development remain unknown. In addition, the identified genetic risks have thus far failed to fully define the hereditability of IBD. Host genetics influence host interactions with the gut microbiota in maintaining health through a balance of regulated immune responses and coordinated microbial composition and function. What remains to be defined is how alterations in these interactions can lead to disease. The nature and cause of changes in the microbiota in patients with IBD are poorly understood. In spite of the large catalog of alterations in the microbiota of IBD patients, inflammation itself can alter the microbiota, leaving open the question of which is cause or effect. The composition and function of the gut microbiota are influenced by many factors, including environmental factors, dietary factors, and, as recent studies have shown, host genetic makeup. More than 200 loci have shown potential to influence the microbiota, but replication and larger studies are still required to validate these findings. It would seem reasonable to consider the combination of both host genetic makeup and the inheritance of the microbiota as interdependent heritable forces that could explain the nature of an individual's susceptibility to IBD or indeed the actual cause of IBD. In this review, we will consider the contribution of the host genetics, the microbiome, and the influence of host genetics on the microbiota to the heritability of IBD. PMID- 29701819 TI - Genome-wide association study for bone strength in laying hens. AB - Bone fracture in egg laying hens is a growing welfare and economic concern in the industry. Although environmental conditions and management (especially nutrition) can exacerbate it, the primary cause of bone weakness and the resulting fractures is believed to have a genetic basis. To test this hypothesis, we performed a genome-wide association study to identify the loci associated with bone strength in laying hens. Genotype and phenotype data were obtained from 752 laying hens belonging to the same pure line population. These hens were genotyped for 580,961 SNPs, with 232,021 SNPs remaining after quality control. Each of the SNPs were tested for association with tibial breaking strength using the family-based score test for association. A total of 52 SNPs across chromosomes 1, 3, 8, and 16 were significantly associated with tibial breaking strength with the genome-wide significance threshold set as a corrected P value of 10e-5. Based on the local linkage disequilibrium around the significant SNPs, 5 distinct and novel QTLs were identified on chromosomes 1 (2 QTLs), 3 (1 QTL), 8 (1 QTL) and 16 (1 QTL). The strongest association was detected within the QTL region on chromosome 8, with the most significant SNP having a corrected P value of 4e-7. A number of candidate genes were identified within the QTL regions, including the BRD2 gene that is required for normal bone physiology. Bone-related pathways involving some of the genes were also identified including chloride channel activity, which regulates bone reabsorption, and intermediate filament organization, which plays a role in the regulation of bone mass. Our result supports previous studies that suggest that bone strength is highly regulated by genetics. It is therefore possible to reduce bone fractures in laying hens through genetic selection and ultimately improve hen welfare. PMID- 29701820 TI - Cerebello-cortical network fingerprints differ between essential, Parkinson's and mimicked tremors. AB - Cerebello-thalamo-cortical loops play a major role in the emergence of pathological tremors and voluntary rhythmic movements. It is unclear whether these loops differ anatomically or functionally in different types of tremor. We compared age- and sex-matched groups of patients with Parkinson's disease or essential tremor and healthy controls (n = 34 per group). High-density 256 channel EEG and multi-channel EMG from extensor and flexor muscles of both wrists were recorded simultaneously while extending the hands against gravity with the forearms supported. Tremor was thereby recorded from patients, and voluntarily mimicked tremor was recorded from healthy controls. Tomographic maps of EEG-EMG coherence were constructed using a beamformer algorithm coherent source analysis. The direction and strength of information flow between different coherent sources were estimated using time-resolved partial-directed coherence analyses. Tremor severity and motor performance measures were correlated with connection strengths between coherent sources. The topography of oscillatory coherent sources in the cerebellum differed significantly among the three groups, but the cortical sources in the primary sensorimotor region and premotor cortex were not significantly different. The cerebellar and cortical source combinations matched well with known cerebello-thalamo-cortical connections derived from functional MRI resting state analyses according to the Buckner-atlas. The cerebellar sources for Parkinson's tremor and essential tremor mapped primarily to primary sensorimotor cortex, but the cerebellar source for mimicked tremor mapped primarily to premotor cortex. Time-resolved partial-directed coherence analyses revealed activity flow mainly from cerebellum to sensorimotor cortex in Parkinson's tremor and essential tremor and mainly from cerebral cortex to cerebellum in mimicked tremor. EMG oscillation flowed mainly to the cerebellum in mimicked tremor, but oscillation flowed mainly from the cerebellum to EMG in Parkinson's and essential tremor. The topography of cerebellar involvement differed among Parkinson's, essential and mimicked tremors, suggesting different cerebellar mechanisms in tremorogenesis. Indistinguishable areas of sensorimotor cortex and premotor cerebral cortex were involved in all three tremors. Information flow analyses suggest that sensory feedback and cortical efferent copy input to cerebellum are needed to produce mimicked tremor, but tremor in Parkinson's disease and essential tremor do not depend on these mechanisms. Despite the subtle differences in cerebellar source topography, we found no evidence that the cerebellum is the source of oscillation in essential tremor or that the cortico-bulbo-cerebello-thalamocortical loop plays different tremorogenic roles in Parkinson's and essential tremor. Additional studies are needed to decipher the seemingly subtle differences in cerebellocortical function in Parkinson's and essential tremors. PMID- 29701821 TI - Phylogenetic Comparative Methods on Phylogenetic Networks with Reticulations. AB - The goal of phylogenetic comparative methods (PCMs) is to study the distribution of quantitative traits among related species. The observed traits are often seen as the result of a Brownian Motion (BM) along the branches of a phylogenetic tree. Reticulation events such as hybridization, gene flow or horizontal gene transfer, can substantially affect a species' traits, but are not modeled by a tree. Phylogenetic networks have been designed to represent reticulate evolution. As they become available for downstream analyses, new models of trait evolution are needed, applicable to networks. We develop here an efficient recursive algorithm to compute the phylogenetic variance matrix of a trait on a network, in only one preorder traversal of the network. We then extend the standard PCM tools to this new framework, including phylogenetic regression with covariates (or phylogenetic ANOVA), ancestral trait reconstruction, and Pagel's $?lambda$ test of phylogenetic signal. The trait of a hybrid is sometimes outside of the range of its two parents, for instance because of hybrid vigor or hybrid depression. These two phenomena are rather commonly observed in present-day hybrids. Transgressive evolution can be modeled as a shift in the trait value following a reticulation point. We develop a general framework to handle such shifts and take advantage of the phylogenetic regression view of the problem to design statistical tests for ancestral transgressive evolution in the evolutionary history of a group of species. We study the power of these tests in several scenarios and show that recent events have indeed the strongest impact on the trait distribution of present-day taxa. We apply those methods to a data set of Xiphophorus fishes, to confirm and complete previous analysis in this group. All the methods developed here are available in the Julia package PhyloNetworks. PMID- 29701822 TI - Permanent His-bundle pacing: a systematic literature review and meta-analysis. AB - Aims: Permanent cardiac pacing of the His-bundle restores and retains normal electrical activation of the ventricles. Data on His-bundle pacing (HBP) are largely limited to small single-centre reports, and clinical benefits and risks have not been systematically examined. We sought to systematically examine published studies of patients undergoing permanent HBP and quantify the benefits and risks of the therapy. Methods and results: PubMed, Embase, and Cochrane Library were searched for full-text articles on permanent HBP. Clinical outcomes of interest included implant success rate, procedural and lead complications, pacing thresholds, QRS duration, and ejection fraction at follow-up, and mortality. Data were extracted and summarized. Where possible, meta-analysis of aggregate data was performed. Out of 2876 articles, 26 met the inclusion criteria representing 1438 patients with an implant attempt. Average age of patients was 73 years and 62.1% were implanted due to atrioventricular block. Overall average implant success rate was 84.8% and was higher with use of catheter-delivered systems (92.1%; P < 0.001). Average pacing thresholds were 1.71 V at implant and 1.79 V at >3 months follow-up; although, pulse widths varied at testing. Average left ventricular ejection fractions (LVEFs) were 42.8% at baseline and 49.5% at follow-up. There were 43 complications observed in 907 patients across the 17 studies that reported safety information. Conclusion: Among 26 articles of permanent HBP, the implant success rate averaged 84.8% and LVEF improved by an average of 5.9% during follow-up. Specific reporting of our clinical outcomes of interest varied widely, highlighting the need for uniform reporting in future HBP trials. PMID- 29701823 TI - Latino Immigrant Family Socialization Scale: Development and Validation of a Multidimensional Ethnic-Racial Socialization Measurement. AB - The study describes multiple steps taken to develop and test the Latino Immigrant Family Socialization (LIFS) scale. Scale items were developed based on qualitative interviews, and feedback on the items was solicited from content experts including an academic, practitioner, and a group of promotoras (or lay health workers). The scale was completed by 300 Latino immigrant parents in the state of Arizona. Exploratory and confirmatory factor analysis confirmed a six factor model. The six factors were cultural socialization, adapt, advocate, value diversity, promote mistrust, and educate about nativity and documentation. Follow up studies are needed to continue the measurement validation process and assess how strategies are used in conjunction with each other, the application of the six strategies across different policy contexts, and how the ethnic-racial socialization process supports children's health and well-being. PMID- 29701824 TI - Genotoxicity Assessment of Nanomaterials: Recommendations on Best Practices, Assays, and Methods. AB - Nanomaterials (NMs) present unique challenges in safety evaluation. An international working group, the Genetic Toxicology Technical Committee of the International Life Sciences Institute's Health and Environmental Sciences Institute, has addressed issues related to the genotoxicity assessment of NMs. A critical review of published data has been followed by recommendations on methods alterations and best practices for the standard genotoxicity assays: bacterial reverse mutation (Ames); in vitro mammalian assays for mutations, chromosomal aberrations, micronucleus induction, or DNA strand breaks (comet); and in vivo assays for genetic damage (micronucleus, comet and transgenic mutation assays). The analysis found a great diversity of tests and systems used for in vitro assays; many did not meet criteria for a valid test, and/or did not use validated cells and methods in the Organization for Economic Co-operation and Development Test Guidelines, and so these results could not be interpreted. In vivo assays were less common but better performed. It was not possible to develop conclusions on test system agreement, NM activity, or mechanism of action. However, the limited responses observed for most NMs were consistent with indirect genotoxic effects, rather than direct interaction of NMs with DNA. We propose a revised genotoxicity test battery for NMs that includes in vitro mammalian cell mutagenicity and clastogenicity assessments; in vivo assessments would be added only if warranted by information on specific organ exposure or sequestration of NMs. The bacterial assays are generally uninformative for NMs due to limited particle uptake and possible lack of mechanistic relevance, and are thus omitted in our recommended test battery for NM assessment. Recommendations include NM characterization in the test medium, verification of uptake into target cells, and limited assay-specific methods alterations to avoid interference with uptake or endpoint analysis. These recommendations are summarized in a Roadmap guideline for testing. PMID- 29701826 TI - The epidemiology of Brucellosis in Greece, 2007-2012: a 'One Health' approach. AB - Background: Brucellosis remains a disease that is very difficult to control and eradicate in Greece. Information exchange between the responsible authorities is crucial in order to support public health infrastructure in the sense of the 'One Health' strategy model. Methods: The data for 2007-2012 were retrieved from the notifiable diseases system and analysed statistically for correlations between human brucellosis cases and the disease in small ruminants. Disease-related risk factors were also estimated with parallel exploitation mapping software. Results: In Greece the dominant strain for brucellosis is Brucella melitensis. The average incidence in Greece was estimated to be 1.43/100,000. The majority of human cases were males (67.60%). The age distribution of brucellosis patients differs significantly between men and women. Brucellosis in male patients was related to high risk jobs and animal contact, while brucellosis in females was related to recent consumption of dairy products. Seasonality of the disease was different in relation to the European countries an observation attributed to the traditional customs. There was a statistically significant difference in human brucellosis incidence between the eradication and vaccination zones. Conclusion: The updated information on brucellosis in Greece revealed differences in seasonality and transmission patterns. A more active cooperation between the involved public health-related sectors should be followed in order to effectively fight brucellosis as there are still foci of brucellosis in Greece. PMID- 29701825 TI - Predicting gene structure changes resulting from genetic variants via exon definition features. AB - Motivation: Genetic variation that disrupts gene function by altering gene splicing between individuals can substantially influence traits and disease. In those cases, accurately predicting the effects of genetic variation on splicing can be highly valuable for investigating the mechanisms underlying those traits and diseases. While methods have been developed to generate high quality computational predictions of gene structures in reference genomes, the same methods perform poorly when used to predict the potentially deleterious effects of genetic changes that alter gene splicing between individuals. Underlying that discrepancy in predictive ability are the common assumptions by reference gene finding algorithms that genes are conserved, well-formed and produce functional proteins. Results: We describe a probabilistic approach for predicting recent changes to gene structure that may or may not conserve function. The model is applicable to both coding and non-coding genes, and can be trained on existing gene annotations without requiring curated examples of aberrant splicing. We apply this model to the problem of predicting altered splicing patterns in the genomes of individual humans, and we demonstrate that performing gene-structure prediction without relying on conserved coding features is feasible. The model predicts an unexpected abundance of variants that create de novo splice sites, an observation supported by both simulations and empirical data from RNA-seq experiments. While these de novo splice variants are commonly misinterpreted by other tools as coding or non-coding variants of little or no effect, we find that in some cases they can have large effects on splicing activity and protein products and we propose that they may commonly act as cryptic factors in disease. Availability and implementation: The software is available from geneprediction.org/SGRF. Supplementary information: Supplementary information is available at Bioinformatics online. PMID- 29701827 TI - Differential Responses of the HPA Axis to Mild Blast Traumatic Brain Injury in Male and Female Mice. AB - Traumatic brain injury (TBI) affects 10 million people worldwide, annually. TBI is linked to increased risk of psychiatric disorders. TBI, induced by explosive devices, has a unique phenotype. Over one-third of people exposed to blast induced TBI (bTBI) have prolonged neuroendocrine deficits, shown by anterior pituitary dysfunction. Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis is linked to increased risk for psychiatric disorders. Not only is there limited information on how the HPA axis responds to mild bTBI (mbTBI), sex differences are understudied. We examined central and peripheral HPA axis reactivity, 7 to 10 days after mbTBI in male and female mice. Males exposed to mbTBI had increased restraint-induced serum corticosterone (CORT), but attenuated restraint-induced corticotropin-releasing factor (CRF)/c-Fos-immunoreactivity (ir) in the paraventricular nucleus of the hypothalamus (PVN). Females displayed an opposite response, with attenuated restraint-induced CORT and enhanced restraint-induced PVN CRF/c-Fos-ir. We examined potential mechanisms underlying this dysregulation and found that mbTBI did not affect pituitary (pro opiomelanocortin and CRF receptor subtype 1) or adrenal (11beta-hydroxylase, 11beta-dehydrogenase 1, and melanocortin 2 receptor) gene expression. mbTBI did not alter mineralocorticoid or glucocorticoid gene expression in the PVN or relevant limbic structures. In females, but not males, mbTBI decreased c-Fos-ir in non-neuroendocrine (presumably preautonomic) CRF neurons in the PVN. Whereas we demonstrated a sex-dependent link to stress dysregulation of preautonomic neurons in females, we hypothesize that mbTBI may disrupt limbic pathways involved in HPA axis coordination in males. Overall, mbTBI altered the HPA axis in a sex-dependent manner, highlighting the importance of developing therapies to target individual strategies that males and females use to cope with mbTBI. PMID- 29701829 TI - Erratum. PMID- 29701828 TI - Sex bias of the birth litter affects surge but not tonic LH secretion in gilts. AB - The physiology and behavior of gilts that develop in a male-biased litter can differ from gilts that develop in a female-biased litter. We hypothesized that gilts from male-biased litters will have a delayed and attenuated luteinizing hormone (LH) surge, and reduced LH pulse frequency and amplitude compared to gilts from female-biased litters. Gilts were selected at birth from male-biased (>60% males n = 10) or female-biased (>60% females n = 9) litters. From 18 wk of age, detection of puberty using daily boar contact began and their subsequent estrous periods were synchronized with oral progestogen (altrenogest). On day 3 after altrenogest withdrawal, blood samples were obtained from 6 gilts per sex bias group at 10 min intervals from 0900 to 2100 h to determine LH pulse amplitude and frequency. From 0900 on day 4, all 19 gilts were sampled every 4 h until the end of estrus to characterize LH surge dynamics. There were no differences between groups in LH pulse characteristics. Compared to gilts from female-biased litters, the LH surge in gilts from male-biased litters was delayed [56.00 +/- 3.32 h vs. 43.11 +/- 3.76 h (mean +/- standard error of the mean (SEM)), P < 0.05], the duration was decreased [29.78 +/- 2.12 h vs. 37.71 +/- 1.19 h (mean +/- SEM), P < 0.05] and the total secretion as measured by area under the curve was decreased (91.42 +/- 9.52 ng/mL vs. 120.28 +/- 9.48 ng/mL, P < 0.05). Our results indicate that a male-biased uterine environment has different effects on the tonic secretion of LH than the LH surge, with only some elements of the LH surge being affected. PMID- 29701830 TI - Identification of Novel Neisseria gonorrhoeae Lineages Harboring Resistance Plasmids in Coastal Kenya. AB - Background: Africa has the highest incidence of gonorrhea in the world. However, little is known about gonococcal populations in this continent or mechanisms of antimicrobial resistance (AMR). Methods: Whole-genome sequence data were analyzed from 103 Neisseria gonorrhoeae isolates from 73 patients, mainly men who have sex with men, from coastal Kenya. We annotated loci, defined the core genome, defined mechanisms of AMR, and performed phylogenetic analysis. For patients with multiple episodes of gonorrhea, we determined whether infections occurred with related strains. Results: We identified 3 clusters of isolates that are phylogenetically distinct from isolates found elsewhere. Plasmids were virtually ubiquitous: pTetM and pblaTEM were found in 97%, and 55% of isolates, respectively. This was associated with high doxycycline use for undiagnosed sexually transmitted infections. Twenty-three percent of multiple episodes of gonorrhea in the same individual were caused by a related strain, suggesting inadequate treatment or reinfection. Conclusions: The prevalence of plasmid mediated AMR in Kenyan gonococci contrasts with that in wealthy countries, where AMR is largely chromosomally mediated. Antimicrobials have a profound effect on the maintenance of lineages harboring plasmids. Doxycycline can select for tetracycline and penicillin resistance, through plasmid cooperation. Understanding the mechanisms of AMR in high-risk groups is required to inform treatment strategies. PMID- 29701831 TI - Agreement between self-reported and objectively measured sleep duration among white, black, Hispanic, and Chinese adults in the United States: Multi-Ethnic Study of Atherosclerosis. AB - Study Objectives: To identify systematic biases across groups in objectively and subjectively measured sleep duration. Methods: We investigated concordance of self-reported habitual sleep duration compared with actigraphy- and single-night in-home polysomnography (PSG) across white, black, Hispanic, and Chinese participants in the Multi-Ethnic Study of Atherosclerosis. Results: Among 1910 adults, self-reported sleep duration, determined by differences between bed and wake times, was overestimated in all racial groups compared with PSG and actigraphy. Compared with whites (rho = 0.45), correlations were significantly lower only in blacks (rho = 0.28). Self-reporting bias for total sleep time compared with wrist actigraphy was 66 min (95% confidence interval [CI]: 61-71) for whites, 58 min (95% CI: 48-69) for blacks, 66 min (95% CI: 57-74) for Hispanics, and 60 min (95% CI: 49-70) for Chinese adults. Compared with PSG, self reporting bias in whites at 73 min (95% CI: 67-79) was higher than in blacks (54 min [95% CI: 42-65]) and Chinese (49 min [95% CI: 37-61]) but not different from Hispanics (67 min [95% CI: 56-78]). Slight agreement/concordance was observed between self-reported and actigraphy-based total sleep time (kw = 0.14 for whites, 0.10 for blacks, 0.17 for Hispanics, and 0.11 for Chinese) and PSG (kw = 0.08 for whites, 0.04 for blacks, 0.05 for Hispanics, and 0.01 for Chinese) across race/ethnicity. Conclusions: Self-reported sleep duration overestimated objectively measured sleep across all races, and compared with PSG, overestimation is significantly greater in whites compared with blacks. Larger reporting bias reduces the ability to identify significant associations between sleep duration and health among blacks compared with whites. Sleep measurement property differences should be considered when comparing sleep indices across racial/ethnic groups. PMID- 29701832 TI - Measurement of Current Substance Use in a Cohort of HIV-Infected Persons in Continuity HIV Care, 2007-2015. AB - Accurate, routine measurement of recent illicit substance use is challenging. The Johns Hopkins Human Immunodeficiency Virus Clinical Cohort (Baltimore, Maryland) collects 2 imperfect but routine measurements of recent substance use: medical record review and self-interview. We used Bayesian latent class modeling to estimate sensitivity and specificity of each measurement as well as prevalence of substance use among 2,064 patients engaged in care during 2007-2015. Sensitivity of medical record review was higher than sensitivity of self-interview for cocaine and heroin use; posterior estimates ranged from 44% to 76% for cocaine use and from 39% to 67% for heroin use, depending on model assumptions and priors. In contrast, sensitivity of self-interview was higher than sensitivity of medical record review for any alcohol use, hazardous alcohol use, and cigarette smoking. Posterior estimates of sensitivity of self-interview were generally above 80%, 85%, and 87% for each substance, respectively. Specificity was high for all measurements. From one model, we estimated prevalence of substance use in the cohort to be 12.5% for cocaine, 9.3% for heroin, 48.5% for alcohol, 21.4% for hazardous alcohol, and 55.4% for cigarettes. Prevalence estimates from other models were generally comparable. Measurement error of substance use is nontrivial and should be accounted for in subsequent analyses. PMID- 29701834 TI - Adjustment of the GRACE score by 2-hour post-load glucose improves prediction of long-term major adverse cardiac events in acute coronary syndrome in patients without known diabetes. AB - Aims: Global Registry of Acute Coronary Events (GRACE) risk score (GRS), a powerful predictor of prognosis after acute coronary event (ACE), does not include a glucometabolic measure. We investigate whether 2 h post-load plasma glucose (2h-PG) could improve GRS based prognostic models in ACE patients without known diabetes mellitus (DM). Methods and results: A retrospective cohort study of 1056 ACE survivors without known DM who had fasting plasma glucose (FPG) and 2h-PG measured pre-discharge. Death and non-fatal myocardial infarction were recorded as major adverse cardiac events (MACE) during follow-up. GRS for discharge to 6 months was calculated. Cox proportional-hazards regression was used to identify predictors of event free survival. The predictive value of 2h-PG alone and combined with GRS was estimated using likelihood ratio test, Akaike's information criteria, continuous net reclassification improvement (NRI>0), and integrated discrimination improvement (IDI). During 40.8 months follow-up 235 MACEs (22.3%) occurred, more frequently in the upper 2h-PG quartiles. Two-hour PG, but not FPG, adjusted for GRS independently predicted MACE (hazard ratio 1.091, 95% confidence interval 1.043-1.142; P = 0.0002). likelihood ratio test showed that 2h-PG significantly improved the prognostic models including GRS (chi2 = 20.56, 1 df; P = 0.000). Models containing GRS and 2h-PG yielded lowest corrected Akaike's information criteria, compared to that with only GRS. 2h-PG, when added to GRS, improved net reclassification significantly (NRIe>0 6.4%, NRIne>0 24%, NRI>0 0.176; P = 0.017 at final follow-up). Two-hour PG, improved integrated discrimination of models containing GRS (IDI of 0.87%, P = 0.008 at final follow-up). Conclusion: Two-hour PG, but not FPG, is an independent predictor of adverse outcome after ACE even after adjusting for the GRS. Two-hour PG, but not FPG, improves the predictability of prognostic models containing GRS. PMID- 29701833 TI - The perspectives of adolescents conceived using surrogacy, egg or sperm donation. AB - STUDY QUESTION: What are the perspectives of adolescents conceived using surrogacy, egg or sperm donation regarding their conception and the third party involved? SUMMARY ANSWER: The majority of adolescents described feeling indifferent about their conception, and yet simultaneously reported an interest in the third party involved, or were in contact with them. WHAT IS KNOWN ALREADY: There is an assumption that children conceived through reproductive donation will feel negatively about their origins in adolescence. However, little is known about the views of adolescents who have been conceived through different types of reproductive donation. STUDY DESIGN, SIZE, DURATION: Forty-four adolescents, all of whom had been told about their conception in childhood, participated in a semi structured interview as part of the sixth phase of a longitudinal, multi-method, multi-informant study of assisted reproduction families in the UK. PARTICIPANTS/MATERIALS, SETTING, METHODS: All adolescents were aged 14 years, had been conceived using surrogacy (n = 22), egg donation (n = 13) or sperm donation (n = 9) to heterosexual couples, and varied in terms of their information about, and contact with, the third party involved in their conception. Semi-structured interviews were conducted in participants' homes. Interviews were analysed qualitatively to determine adolescents' perceptions of their conception, and their thoughts and feelings about the surrogate or donor involved. MAIN RESULTS AND THE ROLE OF CHANCE: Adolescents were found to feel positive (n = 7), indifferent (n = 32) or ambivalent (n = 5) about their conception. Amongst adolescents not in contact with the surrogate or donor, most were interested (n = 16) in the surrogate or donor, and others were ambivalent (n = 4), or not interested (n = 6) in them. Adolescents in contact with the surrogate or donor expressed positive (n = 14), ambivalent (n = 1) or negative (n = 1) feelings about them. LIMITATIONS, REASONS FOR CAUTION: Of 56 adolescents invited to take part in the study, 47 consented to take part, giving a response rate of 84%. It was not possible to obtain information from adolescents who do not know about their conception. WIDER IMPLICATIONS OF THE FINDINGS: The findings contradict the assumption that children conceived through reproductive donation will feel negatively about their origins in adolescence and suggest that it may be helpful to draw a distinction between adolescents' feelings about their conception in general, and their feelings about the surrogate or donor in particular. STUDY FUNDING/COMPETING INTEREST(S): This study was funded by the Wellcome Trust [097857/Z/11/Z]. The authors have no conflicts of interest to declare. PMID- 29701836 TI - Diagnostic Value of Serum Concentration and Integrity of Circulating Cell-Free DNA in Breast Cancer: A Comparative Study With CEA and CA15-3. AB - Breast cancer (BC) is one of the most common types of malignant neoplasm in women; the incidence of BC increases yearly. In a previous study, a novel and sensitive method for quantitying cell-free DNA (CFD) in human blood was established and tested for its ability to predict which patients harbored tumors. Our objective in this study was to investigate the clinical value of serum concentration and the integrity of circulating free DNA (CFD) as a biomarker for auxiliary diagnosis of BC. The concentration of CFD was quantitated by branched DNA (bDNA)-based Alu assay. Carcinoembryonic antigen (CEA) and cancer antigen 15 3 (CA 15-3) concentrations were determined via Abbott ARCHITECT I2000 SR testing. We report that the median (quartile interval) values of serum ALU115 and ALU247/115 in patients with BC were significantly higher than those in patients with benign mammary hyperplasia and in healthy control individuals (1083.66 ng/mL [1.81] vs 145.87 ng/mL [0.33] and 228.19 ng/mL [0.48]; P <.001); there was no significant difference between the latter 2 groups (P> .05). The cutoff values of ALU115, ALU247/115, CEA, and CA15-3 were set as 300.96 ng per mL, 0.78, 5 ng per mL, and 31.3 ng per mL, respectively. The area under the receiver operating characteristic (ROC) curve was 0.70 (95% confidence interval [CI], 0.58-0.81), 0.97 (<.001->.99), 0.75 (0.65-0.86), and 0.89 (0.82-0.96), respectively. Combined detection of the 4 indices significantly improved the diagnostic accuracy of BC, with sensitivity of 97.5% and negative predictive value of 96.4%. Also, serum ALU115 was significantly correlated with lymph-node metastasis (P = .048), and the ALU247/115 index was significantly correlated with tumor stage (P = .001) and lymph-node metastasis (P = .008) in patients with BC. Serum cell-free DNA (CFD) and its integrity may prove to be useful biomarkers for auxiliary diagnosis, grading of malignant neoplasms, and prognostic prediction of BC. PMID- 29701835 TI - Malaria and the Microbiome: A Systematic Review. AB - Background: The microbiome influences malaria parasite fitness and transmission efficiency in mosquitoes and appears to affect malaria dynamics in mammalian hosts as well. Nascent research examining the interrelationship of malaria and the mammalian microbiome has yielded interesting insights inviting further study. Methods: We conducted a systematic review of the literature examining associations between the microbiome and malaria in mammalian hosts. An electronic search algorithm was adapted to PubMed, MEDLINE, Scopus, Embase, and Web of Science, and reference lists of relevant sources were manually searched. Identified studies were screened and assessed independently by 2 authors, and results were compiled in a qualitative synthesis of the evidence. Results: Ten relevant studies were identified. They demonstrate associations between certain intestinal communities and protection against Plasmodium infection and modulation of disease severity. Plasmodium infection acutely and reversibly reshapes gut microbial composition in mice. The makeup of human skin microbial communities may influence mosquito attraction and thus disease transmission. Conclusions: Early research supports a relationship between malaria and the microbiome. The evidence is incomplete, but the observed associations are evocative and signal a promising avenue of inquiry. Microbiome-based studies of malaria can be readily integrated into field-based research. PMID- 29701838 TI - Rethinking phylogenetic comparative methods. AB - As a result of the process of descent with modification, closely related species tend to be similar to one another in a myriad different ways. In statistical terms, this means that traits measured on one species will not be independent of traits measured on others. Since their introduction in the 1980s, phylogenetic comparative methods (PCMs) have been framed as a solution to this problem. In this article, we argue that this way of thinking about PCMs is deeply misleading. Not only has this sowed widespread confusion in the literature about what PCMs are doing but has led us to develop methods that are susceptible to the very thing we sought to build defenses against-unreplicated evolutionary events. Through three Case Studies, we demonstrate that the susceptibility to singular events is indeed a recurring problem in comparative biology that links several seemingly unrelated controversies. In each Case Study, we propose a potential solution to the problem. While the details of our proposed solutions differ, they share a common theme: unifying hypothesis testing with data-driven approaches (which we term "phylogenetic natural history") to disentangle the impact of singular evolutionary events from that of the factors we are investigating. More broadly, we argue that our field has, at times, been sloppy when weighing evidence in support of causal hypotheses. We suggest that one way to refine our inferences is to re-imagine phylogenies as probabilistic graphical models; adopting this way of thinking will help clarify precisely what we are testing and what evidence supports our claims. PMID- 29701837 TI - Identification of novel circulatory microRNA signatures linked to patients with ischemic stroke. AB - MicroRNAs (miRNAs) are involved in growth, development, and occurrence and progression of many diseases. MiRNA-mediated post-transcriptional regulation is poorly understood in vascular biology and pathology. The purpose of this is to determine circulatory miRNAs as early detectable peripheral biomarkers in patients with ischemic stroke (IS). MiRNAs expression levels were measured in IS serum samples and healthy controls using Illumina deep sequencing analysis and identified differentially expressed miRNAs. Differentially expressed miRNAs were further validated using SYBR-green-based quantitative real-time PCR (qRT-PCR) assay in postmortem IS brains, lymphoblastoid IS cell lines, oxygen and glucose deprivation/reoxygenation -treated human and mouse neuroblastoma cells, and mouse models of hypoxia and ischemia (HI)-induced stroke. A total of 4656 miRNAs were differentially expressed in IS serum samples relative to healthy controls. Out of 4656 miRNAs, 272 were found to be significantly deregulated in IS patients. Interestingly, we found several novel and previously unreported miRNAs in IS patients relative to healthy controls. Further analyses revealed that some candidate miRNAs and its target genes were involved in the regulation of the stroke. To the best of our knowledge, this is the first study identified potential novel candidate miRNAs in IS serum samples from the residents of rural West Texas. MiRNAs identified in this study could potentially be used as a biomarker and the development of novel therapeutic approaches for stroke. Further studies are necessary to better understand miRNAs-regulated stroke cellular changes. PMID- 29701839 TI - Arabidopsis research requires a critical re-evaluation of genetic tools. AB - HIGHLIGHT: An increasing number of reports question conclusions based on loss-of function lines that have unexpected genetic backgrounds. In this opinion paper, we urge researchers to meticulously (re)investigate phenotypes retrieved from various genetic backgrounds and be critical regarding some previously drawn conclusions. As an example, we provide new evidence that acr4-2 mutant phenotypes with respect to columella stem cells are due to the lack of ACR4 and not - at least not as a major contributor - to a mutation in QRT1. In addition, we take the opportunity to alert the scientific community about the qrt1-2 background of a large number of Syngenta Arabidopsis Insertion Library (SAIL) T-DNA lines, a feature that is not commonly recognized by Arabidopsis researchers. This qrt1-2 background might have an important impact on the interpretation of the results obtained using these research tools, now and in the past. In conclusion, as a community, we should continuously assess and - if necessary - correct our conclusions based on the large number of (genetic) tools our work is built on. In addition, the positive or negative results of this self-criticism should be made available to the scientific community. PMID- 29701840 TI - A Lipid/DNA Adjuvant-Inactivated Influenza Virus Vaccine Protects Rhesus Macaques From Uncontrolled Virus Replication After Heterosubtypic Influenza A Virus Challenge. AB - Background: Influenza A virus (IAV) vaccines offer little protection from mismatched viruses with antigenically distant hemagglutinin (HA) glycoproteins. We sought to determine if a cationic lipid/DNA complex (CLDC) adjuvant could induce heterosubtypic protection if added to a whole inactivated IAV vaccine (WIV). Methods: Adult rhesus macaques (RMs) were vaccinated and at 2 weeks boosted with either an H1N1-WIV or an H3N2-WIV, with and without CLDC adjuvant. Four weeks postboost, animals were challenged with an H1N1 IAV matched to the H1N1-WIV vaccine. Results: After challenge, viral RNA (vRNA) levels in the trachea of control RMs and RMs vaccinated with the unadjuvanted H1 or H3 WIV vaccines were similar. However, vRNA levels in the trachea of both the H1 WIV/CLDC- and the H3-WIV/CLDC-vaccinated RMs (P < 0.01 and P < 0.05, respectively) were significantly lower than in unvaccinated control RMs. Heterosubtypic protection in H3-WIV/CLDC RMs was associated with significantly higher levels of nucleoprotein (NP) and matrix-1-specific immunoglobulin G antibodies (P < 0.05) and NP-specific nonneutralizing antibody-dependent natural killer cell activation (P < 0.01) compared with unprotected H3-WIV RMs. Conclusions: Addition of the CLDC adjuvant to a simple WIV elicited immunity to conserved virus structural proteins in RMs that correlate with protection from uncontrolled virus replication after heterosubtypic influenza virus challenge. PMID- 29701841 TI - On the role of genetic polymorphisms in the sulfation of cholesterol by human cytosolic sulphotransferase SULT2B1b. AB - Sulphated cholesterol, like its unsulphated counterpart, is known to be biologically active and serves a myriad of biochemical/physiological functions. Of the 13 human cytosolic sulphotransferases (SULTs), SULT2B1b has been reported as the main enzyme responsible for the sulphation of cholesterol. As such, SULT2B1b may play the role as a key regulator of cholesterol metabolism. Variations in the sulphating activity of SULT2B1b may affect the sulphation of cholesterol and, consequently, the related physiological events. This study was designed to evaluate the impact of the genetic polymorphisms on the sulphation of cholesterol by SULT2B1b. Ten recombinant SULT2B1b allozymes were generated, expressed, and purified. Purified SULT2B1b allozymes were shown to display differential cholesterol-sulphating activities, compared with the wild-type enzyme. Kinetic studies revealed further their distinct substrate affinity and catalytic efficiency toward cholesterol. These findings showed clearly the impact of genetic polymorphisms on the cholesterol-sulphating activity of SULT2B1b allozymes, which may underscore the differential metabolism of cholesterol in individuals with different SULT2B1b genotypes. PMID- 29701842 TI - The Emerging Immunogenetic Architecture of Schizophrenia. AB - Schizophrenia is a severe psychiatric disorder of complex etiology. Immune processes have long been proposed to contribute to the development of schizophrenia, and accumulating evidence supports immune involvement in at least a subset of cases. In recent years, large-scale genetic studies have provided new insights into the role of the immune system in this disease. Here, we provide an overview of the immunogenetic architecture of schizophrenia based on findings from genome-wide association studies (GWAS). First, we review individual immune loci identified in secondary analyses of GWAS, which implicate over 30 genes expressed in both immune and brain cells. The function of the proteins encoded by these immune candidates highlight the role of the complement system, along with regulation of apoptosis in both immune and neuronal cells. Next, we review hypothesis-free pathway analyses which have so far been inconclusive with respect to identifying immune pathways involved in schizophrenia. Finally, we explore the genetic overlap between schizophrenia and immune-mediated diseases. Although there have been some inconsistencies across studies, genome-wide pleiotropy has been reported between schizophrenia and Crohn's disease, multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes, and ulcerative colitis. Overall, there are multiple lines of evidence supporting the role of immune genes in schizophrenia. Current evidence suggests that specific immune pathways are involved-likely those with dual functions in the central nervous system. Future studies focused on further elucidating the relevant pathways hold the potential to identify novel biomarkers and therapeutic targets for schizophrenia. PMID- 29701843 TI - CO2 and temperature effects on morphological and physiological traits affecting risk of drought-induced mortality. AB - Despite a wealth of eco-physiological assessments of plant response to extreme drought, few studies have addressed the interactive effects of global change factors on traits driving mortality. To understand the interaction between hydraulic and carbon metabolic traits influencing tree mortality, which may be independently influenced by atmospheric [CO2] and temperature, we grew Eucalyptus sideroxylon A. Cunn. ex Woolls from seed in a full-factorial [CO2] (280, 400 and 640 MUmol mol-1, Cp, Ca and Ce, respectively) and temperature (ambient and ambient +4 degrees C, Ta and Te, respectively) experiment. Prior to drought, growth across treatment combinations resulted in significant variation in physiological and morphological traits, including photosynthesis (Asat), respiration (Rd), stomatal conductance, carbohydrate storage, biomass and leaf area (LA). Ce increased Asat, LA and leaf carbohydrate concentration compared with Ca, while Cp generated the opposite response; Te reduced Rd. However, upon imposition of drought, Te hastened mortality (9 days sooner compared with Ta), while Ce significantly exacerbated drought stress when combined with Te. Across treatments, earlier time-to-mortality was mainly associated with lower (more negative) leaf water potential (Psil) during the initial drought phase, along with higher water loss across the first 3 weeks of water limitation. Among many variables, Psil was more important than carbon status in predicting time-to mortality across treatments, yet leaf starch was associated with residual variation within treatments. These results highlight the need to carefully consider the integration, interaction and hierarchy of traits contributing to mortality, along with their responses to environmental drivers. Both morphological traits, which influence soil resource extraction, and physiological traits, which affect water-for-carbon exchange to the atmosphere, must be considered to adequately predict plant response to drought. Researchers have struggled with assessing the relative importance of hydraulic and carbon metabolic traits in determining mortality, yet an integrated trait, time dependent framework provides considerable insight into the risk of death from drought for trees. PMID- 29701845 TI - Expansion of transcatheter aortic valve implantation: new indications and socio economic considerations. PMID- 29701844 TI - Substituting ground woody plants for cottonseed hulls in kid goat feedlot diets: growth performance and blood serum chemistry. AB - Boer * Spanish kid goats (n = 48) were used to evaluate effects of using ground woody products in feedlot diets on growth performance and blood serum chemistry. A completely randomized study design was used with 2 feeding periods (Period 1 = 70% concentrate, days 0 to 26; Period 2 = 86% concentrate, days 27 to 64). Goats were individually fed 1 of 6 diets that differed only by roughage source (n = 4 wether males and 4 females/treatment; initial BW = 22 +/- 2 kg): cottonseed hulls (CSH; control) or ground wood consisting of redberry (RED), blueberry (BLUE), one seed (ONE), or eastern red cedar (ERC) Juniperus spp., or Prosopis glandulosa (MESQ). Ground woody diets were individually compared with CSH. During Period 1, goats fed CSH had greater (P < 0.05) average daily DMI (DMI), ADG, and G:F than goats fed MESQ and tended to have greater (P < 0.10) ADG and G:F than goats fed BLUE. A Treatment * d interaction (P = 0.008) was observed for goat BW during Period 1 and goats fed CSH tended (P < 0.09) to have greater BW on day 27 than goats fed BLUE or MESQ. During Period 2, Treatment * d interactions were not observed (P > 0.29) for DMI, ADG, G:F, or BW and no differences were observed between goats fed CSH and goats fed any of the treatment diets. Various blood serum variables were different between CSH and goats fed diets containing woody plants (mainly during Period 1); however, blood serum profiles did not indicate hepatotoxicity or any other health issue. Collectively, results suggested that ground Juniperus pinchotii, Juniperus ashei, or Juniperus monosperma can completely replace CSH in goat feedlot diets without negatively affecting growth performance or animal health. During Period 1, feeding diets to goats that contain 30% Juniperus virginiana (ERC) or P. glandulosa (MESQ) may not be economically justifiable in most scenarios, even though goat health, assessed by blood serum profiles, was not negatively affected. However, using 14% J. virginiana (ERC) or P. glandulosa (MESQ) in finishing diets is warranted. PMID- 29701846 TI - Brexit poses serious threats to the availability and affordability of food in the United Kingdom. AB - Brexit will have profound implications for health and health policy yet, while much attention has focused on health professionals, medicines and health protection, the risk of food insecurity, and thus health, has received less attention. We identify five major threats to the availability and affordability of food supplies. These are a lack of regulatory alignment restricting ability to import foods from the EU and beyond, a shortage of agricultural labour in the UK, increased prices of imported foods due to tariffs, damage to supply chains, for example, due to customs delays and loss of interoperability of transportation, and damage to agricultural production and food flows in Ireland. PMID- 29701847 TI - Protecting Mental Health of Hospital Workers after Mass Casualty Events: A Social Work Imperative. PMID- 29701848 TI - Lessons Learned: Providing Peer Support to Culturally Diverse Families of Children with Disabilities or Special Health Care Needs. PMID- 29701849 TI - Origin of Nontreponemal Antibodies During Treponema pallidum Infection: Evidence From a Rabbit Model. AB - The origin of nontreponemal antibodies during syphilis infection is hotly debated. Here, we analyzed the immune response in rabbits immunized with various antigens. Inactivated treponemes elicited the production of low-titer nontreponemal antibodies in some rabbits. Cardiolipin combined with bovine serum albumin also induced anticardiolipin antibody production. These findings indicate that Treponema pallidum contained a cardiolipin antigen with weak immunogenicity. However, active T. pallidum induced higher nontreponemal antibody production with strong immunogenicity at an earlier time point, and the antibody titer was consecutive, suggesting the high nontreponemal antibody titer resulted from the combined effects of both the T. pallidum cardiolipin antigen and the damaged host cell cardiolipin antigen during syphilis infection, the latter of which plays a major role in the induction of nontreponemal antibody production. Our study provides direct animal evidence of the origin of nontreponemal antibodies during T. pallidum infection. PMID- 29701850 TI - Safeguarding the Anomalous Vertebral Artery While Dissecting, Drilling, and Instrumentation of C1-2 Joint for Congenital Atlantoaxial Dislocation: 2 Dimensional Operative Video. AB - The pathology in congenital atlantoaxial instability is usually in C1-2 joints. Addressing the joints appears to be the most rationale approach. The joints are usually approached posteriorly, manipulated, and fused. Understanding the normal and abnormal anatomy is important. Normally, the third segment of the vertebral artery courses lateral to the C1-2 joint. However, in about 20% of the cases with complex congenital craniovertberal junction anomalies the artery crosses the joint posteriorly. The artery in such cases may be injured while joint manipulation and instrumentation with disastrous consequences. Alternatively, occipital squama can be fused to the cervical spine. However, this requires fusion of multiple segments affecting the neck movements significantly. An anomalous vertebral artery can be dissected, mobilized, and safeguarded while dissecting, manipulating, and fusing the C1-2 joint. In this operative video, authors have highlighted the technique to safeguard the anomalous vertebral artery during joint manipulation. Proper informed consent was obtained from the patient. PMID- 29701851 TI - Child Care: A Grave Concern for Social Workers and What We Can Do. PMID- 29701852 TI - Epidemiology and Risk Factors for Cryptosporidiosis in Children From 8 Low-income Sites: Results From the MAL-ED Study. AB - Background: Cryptosporidium species are enteric protozoa that cause significant morbidity and mortality in children worldwide. We characterized the epidemiology of Cryptosporidium in children from 8 resource-limited sites in Africa, Asia, and South America. Methods: Children were enrolled within 17 days of birth and followed twice weekly for 24 months. Diarrheal and monthly surveillance stool samples were tested for Cryptosporidium by enzyme-linked immunosorbent assay. Socioeconomic data were collected by survey, and anthropometry was measured monthly. Results: Sixty-five percent (962/1486) of children had a Cryptosporidium infection and 54% (802/1486) had at least 1 Cryptosporidium-associated diarrheal episode. Cryptosporidium diarrhea was more likely to be associated with dehydration (16.5% vs 8.3%, P < .01). Rates of Cryptosporidium diarrhea were highest in the Peru (10.9%) and Pakistan (9.2%) sites. In multivariable regression analysis, overcrowding at home was a significant risk factor for infection in the Bangladesh site (odds ratio, 2.3 [95% confidence interval {CI}, 1.2-4.6]). Multiple linear regression demonstrated a decreased length-for-age z score at 24 months in Cryptosporidium-positive children in the India (beta = -.26 [95% CI, -.51 to -.01]) and Bangladesh (beta = -.20 [95% CI, -.44 to .05]) sites. Conclusions: This multicountry cohort study confirmed the association of Cryptosporidium infection with stunting in 2 South Asian sites, highlighting the significance of cryptosporidiosis as a risk factor for poor growth. We observed that the rate, age of onset, and number of repeat infections varied per site; future interventions should be targeted per region to maximize success. PMID- 29701853 TI - Deep reinforcement learning of cell movement in the early stage of C.elegans embryogenesis. AB - Motivation: Cell movement in the early phase of Caenorhabditis elegans development is regulated by a highly complex process in which a set of rules and connections are formulated at distinct scales. Previous efforts have demonstrated that agent-based, multi-scale modeling systems can integrate physical and biological rules and provide new avenues to study developmental systems. However, the application of these systems to model cell movement is still challenging and requires a comprehensive understanding of regulatory networks at the right scales. Recent developments in deep learning and reinforcement learning provide an unprecedented opportunity to explore cell movement using 3D time-lapse microscopy images. Results: We present a deep reinforcement learning approach within an agent-based modeling system to characterize cell movement in the embryonic development of C.elegans. Our modeling system captures the complexity of cell movement patterns in the embryo and overcomes the local optimization problem encountered by traditional rule-based, agent-based modeling that uses greedy algorithms. We tested our model with two real developmental processes: the anterior movement of the Cpaaa cell via intercalation and the rearrangement of the superficial left-right asymmetry. In the first case, the model results suggested that Cpaaa's intercalation is an active directional cell movement caused by the continuous effects from a longer distance (farther than the length of two adjacent cells), as opposed to a passive movement caused by neighbor cell movements. In the second case, a leader-follower mechanism well explained the collective cell movement pattern in the asymmetry rearrangement. These results showed that our approach to introduce deep reinforcement learning into agent based modeling can test regulatory mechanisms by exploring cell migration paths in a reverse engineering perspective. This model opens new doors to explore the large datasets generated by live imaging. Availability and implementation: Source code is available at https://github.com/zwang84/drl4cellmovement. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29701854 TI - Adherence to recommended electronic health record safety practices across eight health care organizations. AB - Objective: The Safety Assurance Factors for EHR Resilience (SAFER) guides were released in 2014 to help health systems conduct proactive risk assessment of electronic health record (EHR)- safety related policies, processes, procedures, and configurations. The extent to which SAFER recommendations are followed is unknown. Methods: We conducted risk assessments of 8 organizations of varying size, complexity, EHR, and EHR adoption maturity. Each organization self-assessed adherence to all 140 unique SAFER recommendations contained within 9 guides (range 10-29 recommendations per guide). In each guide, recommendations were organized into 3 broad domains: "safe health IT" (total 45 recommendations); "using health IT safely" (total 80 recommendations); and "monitoring health IT" (total 15 recommendations). Results: The 8 sites fully implemented 25 of 140 (18%) SAFER recommendations. Mean number of "fully implemented" recommendations per guide ranged from 94% (System Interfaces-18 recommendations) to 63% (Clinical Communication-12 recommendations). Adherence was higher for "safe health IT" domain (82.1%) vs "using health IT safely" (72.5%) and "monitoring health IT" (67.3%). Conclusions: Despite availability of recommendations on how to improve use of EHRs, most recommendations were not fully implemented. New national policy initiatives are needed to stimulate implementation of these best practices. PMID- 29701855 TI - Family or career? I want both-the control of meiosis. AB - In this paper I describe my professional and personal journey in science. In the 20th century there were fewer women scientists than man scientists. My personal experience and opinion is that women avoided academic careers. How one can combine family and career is discussed. The interest in science and the interactions I had with prominent leading Yeast Scientists changed my point of view, I matured and developed an academic career. My research focused on how budding yeast cells chose to exit the cell cycle and enter meiosis. My journey started using classical Genetic techniques. The development of Genetic engineering techniques enabled us to verify models and elucidate how entry into meiosis is controlled. PMID- 29701856 TI - Comparative Analysis Between Lateral Orbital Rim Preservation and Osteotomy for Transorbital Endoscopic Approaches to the Cavernous Sinus: An Anatomic Study. AB - BACKGROUND: Transorbital endoscopic approach (TOEA) to the cavernous sinus (CS) is a novel surgical technique. However, the necessity of lateral orbital rim (LOR) osteotomy is questionable. OBJECTIVE: To illustrate the surgical dissection of TOEAs to CS and to investigate the additional benefit of LOR osteotomy. METHODS: Anatomic dissections were carried out in 7 cadaveric heads (14 sides). The TOEAs were performed before and after LOR osteotomy; herein referred as the lateral transorbital approach (LTOA) and the lateral orbital wall approach (LOWA), respectively. The stereotactic measurements of the area of exposure, surgical freedom, and angles of attack around CS were quantified. RESULTS: LOWA increased larger area of exposure than LTOA at entry site (5.3 +/- 0.6 cm2 and 2.6 +/- 0.6 cm2, respectively; P < .001) but both of these techniques provided similar area of exposure at the surgical target site. With regard to the surgical freedoms, those afforded by LOWA were all significantly superior at all of the surgical targets with the difference ranged from 106.6% to 172.5%. No significant differences were found between the vertical angles produced by either approach. On the other hand, the horizontal angles achieved by LOWA were significantly more favorable. CONCLUSION: The TOEAs, either with or without LOR osteotomy are feasible for CS exposure. Although the incremental effect of maneuverability is attained following the LOR osteotomy, it should be performed selectively. Additional research is needed to further validate the safety and efficacy, as well as for precisely defining the clinical application of these techniques. PMID- 29701858 TI - The Importance of Culture. PMID- 29701857 TI - Early Adaptive Functioning Trajectories in Preschoolers With Autism Spectrum Disorders. AB - Background: In preschoolers with autism spectrum disorder (ASD) symptom, severity has a negative impact on the development of adaptive functioning, with critical consequences on the quality of life of those children. Developmental features such as reduced social interest or the presence of behavioral problems can further impede daily life learning experiences. Objectives: The first aim of this study is to confirm the negative impact of high symptom severity on adaptive functioning trajectories in preschoolers with ASD. The second objective intends to explore whether reduced social interest and severe behavioral problems negatively affect developmental trajectories of adaptive functioning in young children with ASD. Methods: In total, 68 children with ASD and 48 age and gender matched children with typical development (TD) between 1.6 and 6 years were included in our study, and longitudinal data on adaptive functioning were collected (mean length of the longitudinal data collection was 1.4 years +/- 0.6). Baseline measures of symptom severity, social interest, and behavioral problems were also obtained. Results: We confirmed that children with ASD show parallel developmental trajectories but a significantly lower performance of adaptive functioning compared with children with TD. Furthermore, analyses within ASD children demonstrated that those with higher symptom severity, reduced social interest, and higher scores of behavioral problems exhibited especially lower or faster declining trajectories of adaptive functioning. Conclusions: These findings bolster the idea that social interest and behavioral problems are crucial for the early adaptive functioning development of children with autism. The current study has clinical implications in pointing out early intervention targets in children with ASD. PMID- 29701859 TI - Strategies to Promote Learning and Engage Participants. AB - This article, the fifth part of the educational design series, addresses how nurse planners and nursing professional development practitioners can meet educational design process 5 in the American Nurses Credentialing Center primary accreditation criteria. This criterion corresponds with the Association for Nursing Professional Development's Nursing Professional Development: Scope and Standards of Practice. J Contin Educ Nurs. 2018;49(5):197-199. PMID- 29701860 TI - Quality and Safety as a Core Leadership Competency. AB - A leader's toolbox of competencies comprises knowledge, skills, and abilities in clinical care, finance, human resource management, and more. As essential as these are, a strong command of quality and safety competencies is sovereign in leading and managing, ensuring an optimal patient experience. Four core areas of quality and safety competencies are presented: systems science, knowledge workers, implementation science and big data, and quality safety tools and techniques. J Contin Educ Nurs. 2018;49(5):200-202. PMID- 29701861 TI - Strategies for Integrating Global Awareness and Engagement Into Clinical Practice. AB - Nurse educators are faced with the challenge of educating learners about global health for clinical practice, particularly as cultural diversity increases in their own communities. This third article in the four-part Teaching Tips series focuses on active teaching-learning strategies for global health awareness and engagement in clinical practice using interprofessional education global health competencies and evidence-based interactive teaching strategies. Tips and topic ideas are offered for integrating global awareness and engagement in both the academic and practice settings to prepare today's nurses for systems-based culturally competent care in clinical practice. J Contin Nurs Educ. 2018;49(5):203-205. PMID- 29701862 TI - Nurses' Perceptions and Practices Related to Alarm Management: A Quality Improvement Initiative. AB - BACKGROUND: The purpose of this quality improvement project was to develop, implement, and assess the effects of an alarm management policy and educational program on nurses' perceptions and practices of alarm management in an acute care hospital. METHOD: Nurses from an acute care hospital in the southeastern United States attended a mandatory alarm management education program. The hospital implemented the evidence-based alarm management education to achieve the NPSG.06.01.01: Alarm Management. Pre- and posttests were administered to evaluate the education and the changes in nurses' perceptions and practices of clinical alarms. RESULTS: A total of 417 nurses received the educational intervention. All participants completed the pretest, and 215 (51%) completed the voluntary posttest. Significant improvements were made in alarm perceptions and practices. Nurses suggested unit-specific alarm education, improved staffing, and updated equipment. CONCLUSION: Findings support the benefits of continued education in alarm management for nurses. Bedside nurses are a critical member of a multidisciplinary alarm management team because they are at the forefront of patient safety and most at risk for experiencing alarm fatigue. J Contin Educ Nurs. 2018;49(5):207-215. PMID- 29701863 TI - The Effects of Preceptor Training on New Graduate Registered Nurse Transition Experiences and Organizational Outcomes. AB - BACKGROUND: New graduate RNs (NGRNs) may experience difficulties in their transition to independent practice. The main role of preceptors is to guide, validate, and supervise the care that NGRNs provide. However, preceptors may not receive training to serve in the role. METHOD: A literature review of the past 5 years was conducted, with 10 articles meeting the inclusion criteria to analyze the effects of preceptor training on NGRN outcomes. RESULTS: Ten studies indicated a range of positive effects of preceptor training on NGRN transition experiences and organizational outcomes, including critical thinking and retention. Findings on NGRNs' stress levels are contradictory and ambiguous. CONCLUSION: A variety of positive outcomes can be realized for NGRNs who partner with formally trained preceptors. J Contin Educ Nurs. 2018;49(5):216-220. PMID- 29701864 TI - The Role of the Nurse Educator in Sustaining Compassion in the Workplace: A Case Study From an Intensive Care Unit. AB - Intensive care unit (ICU) nurses are frequently exposed to emotional and stressful situations in the workplace, which has changed little over the decades. Compassion fatigue is caused by sustained exposure to situations that conflict with one's values and beliefs in the ICU, eroding clinical team relationships and ultimately the quality and safety of patient care. Continuing education in the intensive care setting is a priority, as ICU nurses need to remain abreast of the rapid developments in high-acuity care delivery; however, attention also needs to be directed to nurses' emotional well-being. Nurse educators are well positioned to create and sustain open dialogue that contributes to group cohesion and assists nurses' well-being. J Contin Educ Nurs. 2018;49(5):221-224. PMID- 29701865 TI - Factors Influencing Registered Nurses' Perceptions of Their Professional Identity: An Integrative Literature Review. AB - BACKGROUND: This review synthesizes contemporary research investigating the factors influencing RNs' perceptions of their professional identity. METHOD: The method used was an integrative literature review. RESULTS: Factors influencing RNs' perceptions of their professional identity were synthesized into three categories: the self, the role, and the context. The self is the nurse who enacts the role in practice, and the context is the practice setting. Poor alignment of these categories leads to stress, tension, and uncertainty affecting work-force retention. Strong alignment leads to satisfaction with the nursing role, increased staff retention, and improved quality of care and patient outcomes. These three categories should be considered when planning nursing professional development activities. CONCLUSION: This integrative review identified a lack of research addressing how nurses' perceptions of their professional identity change over time. A deeper understanding of their perspective is needed to establish whether career longevity and continued professional development are influences. J Contin Educ Nurs. 2018;49(5):225-232. PMID- 29701866 TI - Preceptors' Perception of Role Competency. AB - BACKGROUND: Many variables contribute to the success of nursing students and new nurses in their transition to practice. Clinical orientation and training usually falls to staff nurse preceptors. Inherent in this dynamic is the assumption that staff nurses are prepared and able to assume this responsibility. Ideal characteristics and attributes of preceptor competency have not been conclusively defined. METHOD: This qualitative study explored the defining attributes of preceptor role competency as described by preceptors who attended one of 44 continuing education preceptor academies over 9 years in Missouri. RESULTS: Analysis revealed that communication, expertise, flexibility, evaluation skills, and patience are among the most important competencies of nurse preceptors. CONCLUSION: Understanding role expectations would benefit both preceptors and nurse educators who select, train, and support nurse preceptors. Identification of essential preceptor competencies can inform preceptor preparation courses and identify needs for continuing education of preceptors. J Contin Educ Nurs. 2018;49(5):233-240. PMID- 29701867 TI - Pregnancy Complications Associated With Maternal Hypothyroidism: A Systematic Review. AB - Importance: Hypothyroidism is one of the most prevalent diseases in pregnancy, but there is no consensus about its management in pregnant women. Objective: In this systematic review, we evaluated the association between pregnancy complications and treated or untreated maternal hypothyroidism. Evidence Acquisition: PubMed and reference lists were searched for the Medical Subject Headings terms "pregnancy complications" and "hypothyroidism." The eligibility criteria for inclusion in the study were an original study published between 2002 and 2013. Six reviewers independently selected the studies, and 3 extracted the data. Two reviewers assessed the risk of bias and quality of the studies. Results: Eighteen studies were included in the systematic review. The most prevalent complications associated with maternal hypothyroidism were abortion, intrauterine fetal death, preterm delivery, and preeclampsia. The pregnancy outcome depended on the treatment that was received by the patient. Conclusions: Strong evidence indicates that maternal hypothyroidism is associated with maternal-fetal complications, but no consensus was found among the studies reviewed herein. The dose of levothyroxine that is required to maintain euthyroidism is still questioned, but studies have suggested that levothyroxine should be adjusted according to the gestational period and laboratory profile. PMID- 29701868 TI - Devices for Measuring Cervical Dilation During Labor: Systematic Review and Meta analysis. AB - Importance: Measurement of cervical dilation is one of the major indicators of labor progression. At present, the criterion standard for this evaluation is digital examination, which results are sometimes inaccurate and extremely dependent on the subject (ie, obstetrician or midwife) experience. Objective: In this systematic and meta-analysis review, the authors have gathered the vast majority of the instruments used for measuring cervical dilation and their clinical application; main features, potentialities, and the most significant constraints are underlined for each device. Evidence Acquisition: Three of the most popular databases (ie, Web of Science, PubMed, and ClinicalTrials.gov) were used to identify all available cervimeters, by using single or combinations of the following keywords: "cervical," "dilation or dilatation," "cervimetry," "cervix," "uterine," "measurement," "labour or labor," "birth," and "monitoring." Only articles describing the design or a specific clinical application of an instrument for cervical dilation measurement during labor were selected. Results: Twenty-five articles were deeply investigated by classifying them in 4 different homogenous groups on the basis of the method proposed for measuring cervical dilation. Suitable devices have not been realized yet, and this is the reason why nowadays the gynecologist/obstetrician still evaluates labor progression by digital examination. Conclusions and Relevance: Based on a critical analysis of the selected devices, ultrasound seems to be the most promising technology for future cervimetry realization; ultrasound is accurate in distance measurement, and the behind technology can be miniaturized. However, additional studies are necessary for optimizing the technology and developing an optimal solution. PMID- 29701869 TI - Obstructive Sleep Apnea and the Impact on Surgical Outcomes in Gynecology. AB - Importance: Obstructive sleep apnea syndrome (OSAS) is a common medical condition in the United States and affects gynecologic surgical outcomes. Objective: The aim of this review was to improve perioperative diagnosis and management of OSAS in patients presenting for gynecologic surgery and ultimately improve perioperative outcomes. The role of preoperative evaluation and screening is also addressed. Evidence Acquisition: Medical databases were queried for publications pertaining to OSAS complications, risk factors, screening, and perioperative management. Pertinent articles were reviewed by the study authors. Results: Obstructive sleep apnea syndrome is underdiagnosed in the preoperative surgical population. Obesity and other risk factors for OSAS are prevalent in patients with gynecologic issues but are not fully assessed with screening prior to surgery. Effective treatment modalities, such as continuous positive airway pressure, and perioperative management strategies are available to improve patient outcomes. Conclusions and Relevance: Increased diagnosis and treatment for OSAS in the perioperative period can improve perioperative outcomes, surgical outcomes, and long-term patient outcomes. Strategies to increase effective management in patients presenting for gynecologic surgery are needed. PMID- 29701870 TI - An overview of plant division-plane orientation. AB - Contents Summary 505 I. Introduction 505 II. Models of plant cell division 505 III. Establishing the division plane 506 IV. Maintaining the division plane during mitosis and cytokinesis 509 Acknowledgements 510 References 510 SUMMARY: Plants, a significant source of planet-wide biomass, have an unique type of cell division in which a new cell wall is constructed de novo inside the cell and guided towards the cell edge to complete division. The elegant control over positioning this new cell wall is essential for proper patterning and development. Plant cells, lacking migration, tightly coordinate division orientation and directed expansion to generate organized shapes. Several emerging lines of evidence suggest that the proteins required for division-plane establishment are distinct from those required for division-plane maintenance. We discuss recent shape-based computational models and mutant analyses that raise questions about, and identify unexpected connections between, the roles of well known proteins and structures during division-plane orientation. PMID- 29701871 TI - Pediatric Intestinal Failure: The Key Outcomes for the First 100 Patients Treated in a National Tertiary Referral Center During 1984-2017. AB - BACKGROUND: Pediatric-onset intestinal failure (IF) remains a severe illness with life-threatening consequences. In this study, we analyzed a single center's outcomes of IF over 3 decades. METHODS: All children with IF who required parenteral nutrition (PN) >2 months or small-intestinal resection >=50% managed since 1984 were included for retrospective outcome analyses. RESULTS: In total, 100 patients with median PN duration of 1.2 (interquartile range, 0.4-3.5) years were identified. Causes of IF were short bowel syndrome (SBS; n = 78), primary intestinal motility disorders (n = 14), and congenital intestinopathies (n = 8). Patients with SBS had median 40 (25-60) cm of small bowel remaining. Overall, Kaplan-Meier 5- and 10-year weaning-off estimates were 67% (95% CI, 57-77) and 73% (95% CI, 63-84), respectively. Weaning off PN was predicted by remaining bowel anatomy, multidisciplinary treatment era, and absence of immune deficiency. Catheter-related bloodstream infections decreased from 1.4 to 0.6/1000 PN days (P = .0003) with systematic use of taurolidine locks. None had progressive liver disease. Thirty-one percent of patients with SBS underwent autologous intestinal reconstructive surgery. Five patients received and 2 were listed for isolated intestinal transplantation. Eight patients died, and overall 15-year survival rate estimate was 91% (95% CI, 85-98). CONCLUSIONS: Despite reassuring rates of survival and weaning off PN, long-term PN failed in 14% of patients solely because of catheter complications in the recent era. Achievement of enteral autonomy in those with the shortest remaining small bowel and functional cause of IF remains challenging. PMID- 29701872 TI - Management of Ready-to-Use Parenteral Nutrition in Newborns: Systematic Review. AB - Parenteral support has increased the possibility of neonatal recovery. However, complications associated with its use have been documented. One commercial method developed to decrease the complications of this type of support is the ready-to use parenteral nutrition (PN), a 3-chamber bag that provides a complete nutrient mix. This systematic review seeks, through the Preferred Reporting Items for Systematic Reviews and Meta-Analyses methodology, to establish the benefits in newborns. Seven databases and gray literature were used. The search was limited to publications from 2007-2017 and to articles written in English, Spanish, and Portuguese. Articles that did not meet the inclusion criteria and studies with low quality evaluated with the Scottish Intercollegiate Guidelines Network guidelines, which were without information about the study or analytical methods, were excluded. A total of 24,193 articles were obtained, which were initially evaluated by title and abstract according to the inclusion criteria. A total of 24,167 articles were discarded, obtaining 27 eligible for follow-up evaluation. After a detailed evaluation of the full text, 13 articles were selected. It was found that ready-to-use PN has the potential benefit to reduce the risks for infections, provide an adequate supply of nutrients, generate growth within the expected range, provide ease of use, decrease prescription errors, and potentially reduce costs. It is necessary to evaluate the short- and long-term impact of its use. PMID- 29701873 TI - Children With Intestinal Failure Undergoing Intestinal Rehabilitation Are at Risk for Essential Fatty Acid Deficiency. AB - BACKGROUND: Essential fatty acid (EFA) status may be compromised during the intestinal failure (IF) rehabilitation. Parenteral lipid restriction is used to treat intestinal failure associated liver disease (IFALD), while the enteral fatty acid (FA) absorption remains limited. We analyzed the FA status among pediatric IF and intestinal insufficiency patients. METHODS: We evaluated 49 patients aged 0-18 years attending our nationwide IF referral center. Their serum FA fractions were determined and examined against previous nutrition, parenteral lipid emulsion, and intestinal anatomy data. The patients were divided into 3 subgroups according to their dependence on parenteral nutrition (PN): full enteral (EN) (n = 33), supplemental PN (n = 14) or predominantly PN (n = 20). Trien:tetraen ratio (TTR) >=0.2 was considered diagnostic for essential fatty acid deficiency (EFAD) and increased risk was suspected if TTR exceeded 0.1. RESULTS: We identified 8 (16%) patients with elevated TTR >=0.1; in 3 of them the ratio exceeded 0.2. Five of these children belonged to supplemental PN group. This group carried the highest incidence of elevated TTR (P = 0.0016), with median TTR at 0.06 (interquartile range 0.03-0.09) and two-thirds of the analyzed TTR >=0.5. Increased EFAD risk was associated with young age (P = 0.0291), current PN with low parenteral lipid content (P = 0.0003), and short remaining small bowel (P = 0.0013). CONCLUSIONS: IF children with supplemental PN carry the highest overall risk for EFAD. Young age, current PN, and short remaining small bowel also increase the risk for EFAD. PMID- 29701874 TI - How do arbuscular mycorrhizal fungi handle phosphate? New insight into fine tuning of phosphate metabolism. AB - Contents Summary 1116 I. Introduction 1116 II. Foraging for phosphate 1117 III. Fine-tuning of phosphate homeostasis 1117 IV. The frontiers: phosphate translocation and export 1119 V. Conclusions and outlook 1120 Acknowledgements 1120 References 1120 SUMMARY: Arbuscular mycorrhizal fungi form symbiotic associations with most land plants and deliver mineral nutrients, in particular phosphate, to the host. Therefore, understanding the mechanisms of phosphate acquisition and delivery in the fungi is critical for full appreciation of the mutualism in this association. Here, we provide updates on physical, chemical, and biological strategies of the fungi for phosphate acquisition, including interactions with phosphate-solubilizing bacteria, and those on the regulatory mechanisms of phosphate homeostasis based on resurveys of published genome sequences and a transcriptome with reference to the latest findings in a model fungus. For the mechanisms underlying phosphate translocation and export to the host, which are major research frontiers in this field, not only recent advances but also testable hypotheses are proposed. Lastly, we briefly discuss applicability of the latest tools to gene silencing in the fungi, which will be breakthrough techniques for comprehensive understanding of the molecular basis of fungal phosphate metabolism. PMID- 29701875 TI - Estimation of the optimal surrogate based on a randomized trial. AB - A common scientific problem is to determine a surrogate outcome for a long-term outcome so that future randomized studies can restrict themselves to only collecting the surrogate outcome. We consider the setting that we observe n independent and identically distributed observations of a random variable consisting of baseline covariates, a treatment, a vector of candidate surrogate outcomes at an intermediate time point, and the final outcome of interest at a final time point. We assume the treatment is randomized, conditional on the baseline covariates. The goal is to use these data to learn a most-promising surrogate for use in future trials for inference about a mean contrast treatment effect on the final outcome. We define an optimal surrogate for the current study as the function of the data generating distribution collected by the intermediate time point that satisfies the Prentice definition of a valid surrogate endpoint and that optimally predicts the final outcome: this optimal surrogate is an unknown parameter. We show that this optimal surrogate is a conditional mean and present super-learner and targeted super-learner based estimators, whose predicted outcomes are used as the surrogate in applications. We demonstrate a number of desirable properties of this optimal surrogate and its estimators, and study the methodology in simulations and an application to dengue vaccine efficacy trials. PMID- 29701876 TI - Arabidopsis pollen tube germination and growth depend on the mitochondrial calcium uniporter complex. AB - The mitochondrial calcium uniporter complex (MCUc) was recently characterized in details in metazoans and consists of pore-forming units (MCUs) and regulatory factors that channel calcium (Ca2+ ) ion into the mitochondria. MCUs participate in many stress and developmentally related processes involving Ca2+ . Although multiple homologues of MCUs and one regulatory subunit are usually present in plants, the first functional characterization and contribution to Ca2+ related processes of these proteins have been reported recently. Here, we focused on two predicted Arabidopsis MCUs and studied their role in the germination and the growth of pollen tube, a tip-growing cell type highly dependent on Ca2+ homeostasis. Heterologous expression of MCU1 or MCU2 in yeast is sufficient to generate a mitochondrial Ca2+ influx. MCU1 and MCU2 fluorescent reporters are co expressed in the vegetative cell mitochondria of the pollen grain but are undetectable in the embryo sac. We demonstrate that MCU1 and MCU2 can form a heterotypic complex. Phenotypic analyses revealed an impaired pollen tube germination and growth in vitro only for the mcu2 mutants suggesting a predominant role of MCU2. Our results show that mitochondrial Ca2+ controlled by MCUs is an additional player in Arabidopsis pollen tube germination and growth. PMID- 29701877 TI - Nutrition Therapy in Australia and New Zealand Intensive Care Units: An International Comparison Study. AB - BACKGROUND: The Augmented Versus Routine Approach to Giving Energy Trial (TARGET) is the largest blinded enteral nutrition (EN) intervention trial evaluating energy delivery to be conducted in the critically ill. To determine the external validity of TARGET results, nutrition practices in intensive care units (ICUs) in Australia and New Zealand (ANZ) are described and compared with international practices. METHODS: This was a retrospective analysis of prospectively collected data for the International Nutrition Surveys, 2007-2013. Data are presented as mean (SD). RESULTS: A total of 17,154 patients (ANZ: n = 2776 vs international n = 14,378) from 923 ICUs (146 and 777, respectively) were included. EN was the most common route of feeding (ANZ: 85%, n = 2365 patients vs international: 84%, n = 12,034; P = .258), and EN concentration was also similar (<1.25 kcal/mL ANZ: 70%, n = 12,396 vs international: 65%, n = 56,891 administrations; P < .001). Protein delivery was substantially below the estimated prescriptions but similar between the regions (0.6 [0.4] g/kg/day vs 0.6 [0.4] g/kg/day; P = .849). Patients in ANZ received slightly more energy (1133 [572] vs 948[536] kcal/day; P < .001), possibly because more energy was prescribed (1947 [348] vs 1747 [376] kcal/day; P < .001), nutrition protocols were more commonly used (98% vs 75%; P < .001) and included recommendations for therapies such as prokinetic agents (87% vs 51%, n = 399; P < .001) and small bowel feeding (62% vs 40%; P < .001) when compared with international ICUs. CONCLUSIONS: Key elements of nutrition practice are similar in ANZ and international ICUs. These data can be used to determine the external validity and relevance of TARGET results. PMID- 29701878 TI - Targeted Full Energy and Protein Delivery in Critically Ill Patients: A Pilot Randomized Controlled Trial (FEED Trial). AB - BACKGROUND: International guidelines recommend greater protein delivery to critically ill patients than they currently receive. This pilot randomized clinical trial aimed to determine whether a volume-target enteral protocol with supplemental protein delivered greater amounts of protein and energy to critically ill patients compared with standard care. METHODS: Sixty participants received either the intervention (volume-based protocol, with protein supplementation) or standard nutrition care (hourly-rate-based protocol, without protein supplementation) in the intensive care unit (ICU). Coprimary outcomes were average daily protein and energy delivery. Secondary outcomes included change in quadriceps muscle layer thickness (QMLT, ultrasound) and malnutrition (subjective global assessment) at ICU discharge. RESULTS: Mean (SD) protein and energy delivery per day from nutrition therapy for the intervention were 1.2 (0.30) g/kg and 21 (5.2) kcal/kg compared with 0.75 (0.11) g/kg and 18 (2.7) kcal/kg for standard care. The mean difference between groups in protein and energy delivery per day was 0.45 g/kg (95% CI, 0.33-0.56; P < .001) and 2.8 kcal/kg (95% CI, 0.67-4.9, P = .01). Muscle loss (QMLT) at discharge was attenuated by 0.22 cm (95% CI, 0.06-0.38, P = .01) in patients receiving the intervention compared with standard care. The number of malnourished patients was fewer in the intervention [2 (7%) vs 8 (28%); P = .04]. Mortality and duration of admission were similar between groups. CONCLUSIONS: A high-protein volume-based protocol with protein supplementation delivered greater amounts of protein and energy. This intervention was associated with attenuation of QMLT loss and reduced prevalence of malnutrition at ICU discharge. PMID- 29701879 TI - Lifting the veil: richness measurements fail to detect systematic biodiversity change over three decades. AB - While there is widespread recognition of human involvement in biodiversity loss globally, at smaller spatial extents, the effects are less clear. One reason is that local effects are obscured by the use of summary biodiversity variables, such as species richness, that provide only limited insight into complex biodiversity change. Here, we use 30 yr of invertebrate data from a metacommunity of 10 streams in Wales, UK, combined with regional surveys, to examine temporal changes in multiple biodiversity measures at local, metacommunity, and regional scales. There was no change in taxonomic or functional alpha-diversity and spatial beta-diversity metrics at any scale over the 30-yr time series, suggesting a relative stasis in the system and no evidence for on-going homogenization. However, temporal changes in mean species composition were evident. Two independent approaches to estimate species niche breadth showed that compositional changes were associated with a systematic decline in mean community specialization. Estimates of species-specific local extinction and immigration probabilities suggested that this decline was linked to lower recolonization rates of specialists, rather than greater local extinction rates. Our results reveal the need for caution in implying stasis from patterns in alpha-diversity and spatial beta-diversity measures that might mask non-random biodiversity changes over time. We also show how different but complementary approaches to estimate niche breadth and functional distinctness of species can reveal long term trends in community homogenization likely to be important to conservation and ecosystem function. PMID- 29701880 TI - Student courage: An essential for today's health education. AB - AIM: The aim of this concept analysis is to propose the new concept of student courage as it operates within the context of healthcare professionals' education. BACKGROUND: Nurses have a moral obligation that often requires courage. However, nursing students do not have the capacity to act with moral courage until they are close to licensure. Student courage is propositioned as a precursor to moral courage. DESIGN: The Walker and Avant approach is used to examine the attributes, antecedents, consequences, and empiric referents of student courage. Cases are provided to represent how student courage can be operationalized and to distinguish student courage from moral courage. RESULTS: The analysis demonstrates that the concept of student courage has four critical attributes: (a) persistence, (b) bravery, (c) overcoming fear, and (d) self-advocacy. Positive and negative consequences are associated with student courage and include: (a) moral distress, (b) criticism, (c) empowerment, and (d) self knowledge. CONCLUSIONS: This concept analysis helps fill the gap for nursing students transitioning into a professional role as well as clarifying a nursing student's role in patient care. PMID- 29701881 TI - Pentameric last-digit preference and stage border avoidance in pathology measurement. AB - AIMS: Cancer treatment relies on accurate staging, an essential aspect of which is determination of the size of a tumour. Measuring the size of a tumour in daily practice often proves problematic and results in rounding of values to approximate values. It has been shown that size values are most frequently reported with end digits of 0 or 5. METHODS AND RESULTS: We sought to determine whether this observation holds true in our national cancer registry of breast and lung tumours. Data from patients with breast and lung cancer were retrieved from the Netherlands National Cancer Registry and analysed for tumour size. Whereas a preference for terminal digits of 0 or 5 (pentameric preference) was clearly present for lung cancer, critical pentameric values at stage boundaries were avoided in breast cancer. CONCLUSIONS: In conclusion, pathologists adopt a practical approach to tumour size measurement by rounding values and avoiding stage border boundary values, thus circumventing potential difficulties in treatment decisions. PMID- 29701882 TI - An empirical test for a zone of canalization in thermal reaction norms. AB - Theoretical models on the evolution of phenotypic plasticity predict a zone of canalization where reaction norms cross, and genetic variation is minimized in the environment a population most frequently encounter. Empirical tests of this prediction are largely missing, in particular for life-history traits. We addressed this prediction by quantifying thermal reaction norms of three life history traits (somatic growth rate, age and size at maturation) of a Norwegian population of Daphnia magna and testing for the occurrence of an intermediate temperature (Tm ) at which genetic variance in the traits is minimized. Size at maturation changed relatively little with temperature compared to the other traits, and there was no genetic variance in the shape of the reaction norm. Consequently, age at maturation and somatic growth rate were strongly negatively correlated. Both traits showed a strong genotype-environment interaction, and the estimated Tm was 14 degrees C for both age at maturation and growth rate. This value of Tm corresponds well with mean summer temperatures experienced by the population and suggests that the population has evolved under stabilizing selection in temperatures that fluctuate around this mean temperature. These results suggest local adaptation to temperature in the studied population and allow predicting evolutionary trajectories of thermal reaction norms under changing thermal regimes. PMID- 29701883 TI - Dual immune effect of iNKT cells considering human cutaneous and visceral leishmaniasis: An example of cell plasticity according to different disease scenarios. AB - Although the semi-invariant natural killer T cells (iNKT) are a small subpopulation of cells in the peripheral blood, they are presumed to play a role in early stages of infection against various pathogens, including protozoa. This work investigates the activation status and cytokine profile of iNKT cells during human Leishmania infantum and Leishmania braziliensis infection. We studied iNKT cells in patients with symptomatic active visceral leishmaniasis (AVL) (n = 8), patients with symptomatic active cutaneous leishmaniasis (ACL) (n = 13), negative endemic controls (NEC) (n = 6) and non-endemic controls (NonEC) (n = 6), with and without total Leishmania antigen stimulus (TLA). The number of iNKT cells in the peripheral blood of patients with ACL and AVL unaltered in relation to control groups. Moreover, the iNKT cells from ACL showed a hyperactivation profile compared to patients with AVL. Additionally, TLA induced IFN-gamma production in iNKT cells from patients with ACL, while in iNKT of patients with AVL, TLA induced a decrease in this cytokine. Higher IL-17 and IL-10 production by iNKT cells from patients with ACL were also observed compared to all other groups. There were no changes in iNKT IL-10-producing cells in AVL after TLA stimulation. However, TLA induced increase in IL-10 in iNKT cells in patients with ACL. These findings suggest that, although iNKT cells showed distinct profiles in patients with ACL and AVL, they play a dual role in immune modulation in both Leishmania infections. PMID- 29701884 TI - Retinal vascular diameters in relation to physical activity in Danish children - The CHAMPS Eye Study. AB - Our objective was to determine associations between retinal vascular caliber and physical activity (PA) in a school-based child cohort. In a prospective study, we created a childhood cumulative average PA-index using objectively measured PA (accelerometry) assessed at four periods between 2009 and 2015. Cumulative exposure to PA intensities was estimated. Cross-sectional examinations on biomarkers, anthropometry, and ophthalmological data including retinal fundus photographs were performed in 2015. Semi-automated measurements of retinal vascular diameters were performed and summarized into central retinal arteriolar and venular equivalents (CRAE, CRVE). We included 307 participants. Mean age in 2015 was 15.4 years (0.7). The mean CRAE and CRVE were 156.5 MUm (2.8) and 217.6 MUm (7.7), respectively. After adjusting for age, gender, and axial length, more time in PA was independently related to thinner retinal venules (beta-coefficient = -1.25 MUm/%, 95% confidence interval = -2.20, -0.30, P < .01). Sedentary time was associated with wider venules (P < .01). Furthermore, birthweight (beta coefficient = 0.56 MUm/%, 95% confidence interval = 0.18, 0.95, P < .01) was associated with CRVE. Blood pressure was associated with thinner retinal arterioles (beta-coefficient = -0.19 MUm/mmHg, 95% confidence interval = -0.36, 0.01, P = .04). We concluded that children with higher PA in childhood had thinner retinal venular caliber. Our results suggest that PA during childhood positively impacts the retinal microcirculation and that retinal vascular analysis may be a possible assessment to detect microvascular impairments in children with an increased risk of future cardiovascular disease. PMID- 29701885 TI - Physical deterioration in an acute mental health unit: A quantitative retrospective analysis of medical emergencies. AB - Nursing management of physical deterioration of patients within acute mental health settings is observed, recorded, and actively managed with the use of standardized Adult Deterioration Detection System (ADDS) charts. Patient deterioration may require the urgent assistance of a hospital rapid response or Medical Emergency Team. A five-and-a-half-year (2011-2016) audit of hospital-wide Medical Emergency Team attendances was conducted in an acute mental health unit of a single large 250 bed regional hospital in Victoria, Australia. Data were extracted from the hospitals' quality and patient safety program, RISKMan, and entered into a statistical data program for analysis. A total of 140 patient records were analysed, and the 'Worried' category (34%, n = 47) was the principle reason for a Medical Emergency Team call in a mental health ward, followed by hypotension (23%, n = 31) and a low Glasgow Coma Score (16%, n = 22). Upon further investigation of the 'Worried' category, the most common conditions recorded were an altered conscious state (22%, n = 9), low oxygen saturation (20%, n = 8), or chest pain (17%, n = 7). Activation of Medical Emergency Team calls predominantly occurred in the daylight morning hours (6am-12md). When data were compared to the general hospital patients, the context of the physiological deterioration of the mental health patients was strikingly similar. Further research is recommended to ascertain the extent and frequency with which staff working in mental health units are performing vital signs monitoring as an essential component of detection of early signs of physiological deterioration. PMID- 29701886 TI - DBS Electrodes With Single Disconnected Contacts: Long-Term Observation and Implications for the Management. AB - OBJECTIVES: To evaluate the long-term course of quadripolar DBS electrodes with disconnected single contacts that cannot be used for DBS. MATERIALS AND METHODS: Quadripolar electrodes with open circuits of single contacts or monopolar impedances >6500 Omega were identified from a cohort of 2082 electrodes from 1044 patients with variable movement disorders. The long-term course was analyzed from follow-up data. RESULTS: Disconnected contacts were found in 58 electrodes (2.8%) from 49 patients (4.7%). The dysfunction was restricted to one contact in 51 electrodes (87.9%), two contacts in 5 electrodes (8.6%), three contacts in 2 electrodes (3.4%). Onset was related to surgery (implantation, impulse generator replacement, or other surgical revision) in 34 electrodes (58.6%), trauma in 2 electrodes, undetermined in 11 electrodes, and occurred spontaneously after previous normal measurements in 11 electrodes (19.0%). Repeated measurements at follow-ups of >=3 months were available in 39 electrodes. In 16 electrodes (41.0%) abnormal impedances persisted constantly during observations up to 111/2 years (47 +/- 35 months, median 41 months). In 21 electrodes (53.8%) abnormal impedances remained restricted to the initial contact(s) but varied considerably between measurements during up to six years (39 +/- 18 months, median 38 months). Only two electrodes (5.1%) with initially one disconnected contact developed a disconnection of a second contact. CONCLUSIONS: Disconnections of single contacts occur with increasing cumulative incidence during long-term DBS. Surgery is the main causative risk factor. In the majority of electrodes, the dysfunction remains restricted to the initial contact(s). PMID- 29701887 TI - Comparison of single- and dual-monitor approaches to differentiate sitting from lying in free-living conditions. AB - High levels of sedentary time have been detrimentally linked to health outcomes. Differentiating sitting from lying may help to further understand the mechanisms associated with these health impacts. This study compares the inter-method agreement between the "single-monitor" method (thigh-worn activPAL3TM ) and a more robustly validated "dual-monitor" method (trunk and thigh-worn activPAL3TM ) in their classifications of sitting and lying under free-living conditions. Thirty-five participants (20-50 years) wore two activity monitors (thigh and trunk) for 24 hours. Total time spent lying and sitting was calculated for both methods, and agreement was determined using ICC and Bland-Altman methods. As there was no gold standard, further data were collected from five participants during structured activities that were designed to challenge classification, to better understand any disagreement between the methods. ICCs were 0.81 for sitting time and 0.64 for lying time. The single-monitor method detected less lying time than the dual-monitor method, with a mean difference of -25 minutes (95% agreement limits: -172 to 221 minutes), including three cases with extreme disagreement (mostly in daytime lying classification). The additional data collection suggested a major source of disagreement was failure of the single monitor method to identify lying that involved no rotation around the longitudinal axis. In conclusion, there was some agreement between the single- and dual-monitor estimates of lying time under free-living conditions, but measures were not interchangeable. The main disagreement was in how the methods classified daytime lying and lying tasks involving no lateral movement. Both methods yield promise for measuring time in bed. PMID- 29701888 TI - Evaluating Gaps in Care of Malnourished Patients on General Medicine Floors in an Acute Care Setting. AB - BACKGROUND: As described in detail in the literature, patients identified with malnutrition are at increased risk for poor clinical outcomes. Despite this knowledge, malnourished patients do not always receive optimal nutrition management while admitted into a hospital because of what we describe as gaps in care throughout their admission. We hypothesized that the 3 main gaps in care were poor dietitian-doctor communication, excessive time spent nil per os (NPO) for procedures and testing, and/or inaccurate or incomplete dietary discharge instructions. The objectives of this study were to determine and to characterize gaps in nutrition care after a malnutrition diagnosis. METHODS: This retrospective study involved postdischarge chart reviews of malnourished adult medicine patients admitted to an acute care facility from September 1, 2014, to November 30, 2014 (n = 242). RESULTS: Of the malnourished patients, 76% had at least 1 gap in care. The most prevalent gap (68%) involved discharge diet instructions, most often because of the omission of the dietitian recommendation for oral supplementation. Thirty-five percent of malnourished patients had a gap in care because of procedures or testing extending the period held NPO, and 13% had a gap in care because of poor communication, thus delaying orders and/or interventions. CONCLUSIONS: This is the first study to evaluate gaps in care of patients diagnosed with malnutrition. Identification of these gaps allows us the opportunity to develop strategies for this vulnerable population to improve areas such as discharge documentation and time spent NPO to provide the best and safest nutrition care. PMID- 29701889 TI - Emergency Department Adult Fiberoptic Intubations: Incidence, Indications, and Implications for Training. AB - OBJECTIVE: The objective was to describe the frequency, indications, and outcomes of flexible fiberoptic intubations (FFI) performed in the emergency department (ED). METHODS: From the National Emergency Airway Registry (NEAR), we identified all encounters from July 1, 2002, through December 31, 2012, with the use of FFI. We determined patient, provider, and intubation characteristics; success and failure rates; and modes of intubation rescue. RESULTS: Among 17,910 intubations of patients > 15 years old at 13 EDs, FFI was used in 204 cases (1.1%, 95% confidence interval [CI] = 0.26%-2.0%). FFI was the first method chosen (primary FFI) in 180 encounters (1%, 95% CI = 0.2%-1.8%). The most common indication for FFI was airway obstruction (36.1%, 95% CI = 24.6%-47.7%). For primary FFI, first attempt intubation success was 51.1% (95% CI = 43.6%-58.6%), and overall intubation success with FFI was 74.3% (95% CI = 65.7%-82.9%). FFI was used as a rescue airway strategy in 24 cases (0.1% of all encounters) and was successful in 17 of those (70.8%, 95% CI = 65.4%-85.2%). CONCLUSIONS: Emergency department FFI is uncommon and typically used as a nonsurgical alternative for airway obstruction. First-attempt ED FFI is successful in half of cases and in two thirds of rescue attempts. These data provide an important baseline to help better characterize the nature of FFI as a rare critical procedure in the ED and offer an empiric basis for ongoing discussions on the optimal role of FFI in ED training and practice. PMID- 29701890 TI - The reward-like nature of social cues that indicate successful altruistic punishment. AB - Altruistic punishment is the attempt to penalize deviant behavior of another person even though it is accompanied by personal costs. Here, we investigated the influence of the reaction on the socioemotional level of the other person following altruistic punishment behavior on future decision making and neural responses. We used a modified ultimatum game, which included an emotional facial feedback of the proposer following the decision of the participant. We found higher acceptance rates for proposers showing a smile upon acceptance or a sad face upon rejection of an offer, compared to proposers showing a neutral facial expression. On the neural level, we found a reversed N2 effect for negative emotional faces in the context of altruistic punishment, compared to a control condition. Specifically, when following the rejection of an unfair offer, negative emotional faces showed a reward-like positivity that might signal successful altruistic punishment. In addition, differential effects for P3 amplitudes might signal the subjective importance of a desired outcome. Our results are in line with the interpretation that rejection of unfair offers in the ultimatum game is due to intended altruistic punishment. Social cues may exhibit reward-like properties when indicating successful altruistic punishment and can influence subsequent decision making. PMID- 29701892 TI - BN-Patterning of Metallic Substrates through Metal Coordination of Decoupled Borazines. AB - We report on the synthesis of pyridine-terminated borazine derivatives, their molecular self-assembly as well as the electronic properties investigated on silver and copper surfaces by means of scanning tunneling microscopy and X-ray photoelectron spectroscopy. The introduction of pyridine functionalities allows us to achieve distinct supramolecular architectures with control of the interdigitation of the molecules by surface templating. On silver surfaces, the borazine derivatives arrange in a dense-packed hexagonal structure through van der Waals and H-bonding interactions, whereas on Cu(111), the molecules undergo metal coordination. The porosity and coordination symmetry of the reticulated structure depends on the stoichiometric ratio between copper adatoms and the borazine ligands, permitting an unusual three-fold coordinated Cu-pyridyl network. Finally, spectroscopy measurements indicate that the borazine core is electronically decoupled from the metallic substrate. We thus demonstrate that BNC-containing molecular units can be integrated into stable metal-coordination architectures on surfaces, opening pathways to patterned, BN-doped sheets with specific functionalities, for example, regarding the adsorption of polar guest gases. PMID- 29701891 TI - Cell-Lineage Tracing in Zebrafish Embryos with an Expanded Genetic Code. AB - Cell-lineage tracing is used to study embryo development and stem-cell differentiation as well as to document tumor cell heterogeneity. Cre recombinase mediated cell labeling is the preferred approach; however, its utility is restricted by when and where DNA recombination takes place. We generated a photoactivatable Cre recombinase by replacing a critical residue in its active site with a photocaged lysine derivative through genetic code expansion in zebrafish embryos. This allows high spatiotemporal control of DNA recombination by using 405 nm irradiation. Importantly, no background activity is seen before irradiation, and, after light-triggered removal of the caging group, Cre recombinase activity is restored. We demonstrate the utility of this tool as a cell-lineage tracer through its activation in different regions and at different time points in the early embryo. Direct control of Cre recombinase by light will allow more precise DNA recombination, thereby enabling more nuanced studies of metazoan development and disease. PMID- 29701893 TI - Complex Febrile Seizures, Lumbar Puncture, and Central Nervous System Infections: A National Perspective. AB - OBJECTIVES: The objective was to determine the national lumbar puncture (LP) practice patterns relative to the incidence of central nervous system (CNS) infections among children presenting to the emergency department (ED) with complex febrile seizures (CFS). METHODS: This was a retrospective study of ED visits for CFS from 2007 to 2014 in patients aged 0 to 5 years using a national sample. Primary outcomes include the frequency of LP, incidence of CNS infections, and ED disposition. RESULTS: Of 28,810 ED visits for CFS (44.4% female; mean age = 1.39 years), LP was performed in 7,445 (25.8%, 95% confidence interval [CI] 23.5%-28.2%). There was no significant difference in the proportion due to hospital teaching status or geographical region. The proportion decreased from 31.4% to 17.8% over the study period (Rao-Scott statistic = 5.85, p < 0.001). CNS infection was diagnosed in 80 (0.3%) encounters (95% CI = 41-112). The most commonly associated infections were otitis media (16.8%), upper respiratory infections (15.8%), and other viral infections (14.6%). A total of 14,696 encounters (51.0%, 95% CI = 47.9%-54.1%) resulted in a hospital admission. CONCLUSIONS: Although rates have been declining, LP was performed in one-fourth of ED encounters for CFS over the 8-year study period. The incidence of CNS infections was very low, however, suggesting that this procedure could be avoided in many patients. PMID- 29701894 TI - Fluorescent labeling of endogenous platelets for intravital microscopy: Effects on platelet function. AB - OBJECTIVE: Monitoring endogenous platelets during intravital microscopy often involves two approaches: fluorescently labeled antibodies or genetic models of platelet-specific fluorescent protein expression. Due to limited data available on platelet functional changes induced by these methods, we compared functional effects of these methods on platelets. METHODS: Platelet aggregation to collagen and thrombin, and collagen matrix-mediated platelet adhesion/aggregation under flow were tested. We assessed platelets from mice expressing EYFP on platelets (Cre(+)), littermate controls (Cre(-)), C57BL/6 mice, and platelets from vehicle control and x-488 treatment. We utilized intravital microscopy to monitor platelets in vivo using Cre(+) mice and x-488 treatment. RESULTS: Both genetic and antibody-based approaches yielded substantial platelet-specific fluorescence. Platelets from Cre(+) and Cre(-) mice behaved similarly in aggregation and adhesion/aggregation under flow. However, they exhibited significantly enhanced aggregation and higher adhesion/aggregation as compared to platelets from C57BL/6 mice. Compared to vehicle control, x-488 platelet labeling did not induce significant functional changes in vitro. Both methods of platelet labeling provided satisfactory platelet detectability in vivo. CONCLUSIONS: x-488 antibody labeling of platelets induced less alteration of platelet function than genetic approaches under our experimental conditions and seems more suitable for monitoring of endogenous platelets. PMID- 29701895 TI - Interactions Between Flavonoid-Rich Extracts and Sodium Caseinate Modulate Protein Functionality and Flavonoid Bioaccessibility in Model Food Systems. AB - : With growing interest in formulating new food products with added protein and flavonoid-rich ingredients for health benefits, direct interactions between these ingredient classes becomes critical in so much as they may impact protein functionality, product quality, and flavonoids bioavailability. In this study, sodium caseinate (SCN)-based model products (foams and emulsions) were formulated with grape seed extract (GSE, rich in galloylated flavonoids) and green tea extract (GTE, rich in nongalloylated flavonoids), respectively, to assess changes in functional properties of SCN and impacts on flavonoid bioaccessibility. Experiments with pure flavonoids suggested that galloylated flavonoids reduced air-water interfacial tension of 0.01% SCN dispersions more significantly than nongalloylated flavonoids at high concentrations (>50 MUg/mL). This observation was supported by changes in stability of 5% SCN foam, which showed that foam stability was increased at high levels of GSE (>=50 MUg/mL, P < 0.05) but was not affected by GTE. However, flavonoid extracts had modest effects on SCN emulsion. In addition, galloylated flavonoids had higher bioaccessibility in both SCN foam and emulsion. These results suggest that SCN-flavonoid binding interactions can modulate protein functionality leading to difference in performance and flavonoid bioaccessibility of protein-based products. PRACTICAL APPLICATION: As information on the beneficial health effects of flavonoids expands, it is likely that usage of these ingredients in consumer foods will increase. However, the necessary levels to provide such benefits may exceed those that begin to impact functionality of the macronutrients such as proteins. Flavonoid inclusion within protein matrices may modulate protein functionality in a food system and modify critical consumer traits or delivery of these beneficial plant-derived components. The product matrices utilized in this study offer relevant model systems to evaluate how fortification with flavonoid-rich extracts allows for differing effects on formability and stability of the protein-based systems, and on bioaccessibility of fortified flavonoid extracts. PMID- 29701896 TI - Fetal bovine serum-free culture of endothelial progenitor cells-progress and challenges. AB - Two decades after the first report on endothelial progenitor cells (EPC), their key role in postnatal vasculogenesis and vascular repair is well established. The therapeutic potential of EPC and their growing use in clinical trials calls for the development of more robust, reproducible, and safer methods for the in vitro expansion and maintenance of these cells. Despite many limitations associated with its usage, fetal bovine serum (FBS) is still widely applied as a cell culture supplement. Although different approaches aiming at establishing FBS-free culture have been developed for many cell types, adequate solutions for endothelial cells, and for EPC in particular, are still scarce, possibly due to the multiple challenges that have to be faced when culturing these cells. In this review, we provide a brief overview on the therapeutic relevance of EPC and critically analyse the available literature on FBS-free endothelial cell culture methods, including xeno-free, serum-free, and chemically defined systems. PMID- 29701897 TI - SIRT1 attenuates murine allergic rhinitis by downregulated HMGB 1/TLR4 pathway. AB - Conventional allergic rhinitis (AR) treatments have limitations due to the lack of safety and complete cure strategy. We evaluated the effects of silent information regulator 1 (SIRT1), a multifunctional molecule involved in a variety of inflammatory pathways, on murine AR model. Ovalbumin (OVA)-induced murine model was constructed, and recombinant SIRT1 was administered into the nostril continuously. The expression of SIRT1 was measured at mRNA and protein levels, and the allergic symptoms were evaluated. Protein levels of OVA-specific IgE, leukotriene C4 (LTC4), eosinophil cation protein (ECP), prostaglandin D2 (PGD2), as well as different inflammatory cytokine mediators in the serum and nasal lavage fluid (NLF), were assessed by ELISA. The effects of SIRT1 on human primary nasal epithelial cells challenged with tumour necrosis factor (TNF)-alpha were also evaluated by investigating the HMGB1/TLR4 signalling pathway. Administration of SIRT1 significantly alleviated OVA-induced AR symptoms with lower numbers of sneezing and nasal rubbing events, decreased levels of OVA-specific IgE, LTC4, ECP, PGD2, less inflammatory cells and downregulated levels of Th2 type cytokines. SIRT1 also reduced the genes of HMGB1/TLR4 signalling pathway in the murine model and cultured human nasal epithelial cells. Expression of SIRT1 is impaired in OVA-induced AR model. The administration of SIRT1 alleviates the allergic symptoms of mice, regulates the production of pro-inflammatory mediators predominantly produced by Th2 cells in AR and attenuates expressions of proteins relevant to HMGB1/TLR4 signalling pathway. All the results showed that SIRT1 is promising as a therapeutic agent of AR. PMID- 29701898 TI - Syntheses, Crystal Structures and Properties of a Series of 3D Metal-Inorganic Frameworks Containing Pentazolate Anion. AB - Pentazolate anion (cyclo-N5- ), and/or N3- , NO3- were used as the ligands to obtain a series of nitrogen-rich energetic three-dimensional (3D) frameworks [Cu(N5 )(N3 )]n , [Ag(N5 )]n , [Ba(N5 )(NO3 )(H2 O)3 ]n , and [NaBa3 (N5 )6 (NO3 )(H2 O)3 ]n by self-assembly. These frameworks were characterized by single crystal X-ray diffraction, SEM, IR and Raman spectroscopy, elemental analysis, and thermal analysis. All the frameworks exhibited regular supramolecular structures and excellent stabilities at room temperature which can be attributed to the strong coordination bonds between cyclo-N5- anions and metal ions. The successful stabilization of the cyclo-N5- in more 3D multi-ligand metal-N5- frameworks after Na-N5- frameworks has been demonstrated. This breakthrough offers new opportunities for the future of metal-pentazolate frameworks and polynitrogen chemistry. PMID- 29701899 TI - The tomato Ethylene Response Factor Sl-ERF.B3 integrates ethylene and auxin signaling via direct regulation of Sl-Aux/IAA27. AB - Plant growth and development is coordinated by complex networks of interacting hormones, and cross-talk between ethylene and auxin signaling is essential for a wide range of plant developmental processes. Nevertheless, the molecular links underlying the interaction between the two hormones remain poorly understood. In order to decipher the cross-talk between the Ethylene Response Factor Sl-ERF.B3 and Sl-IAA27, mediating ethylene and auxin signaling, respectively, we combined reverse genetic approaches, physiological methods, transactivation experiments and electrophoretic mobility shift assays. Sl-ERF.B3 is responsive to both ethylene and auxin and ectopic expression of its dominant repressor version (ERF.B3-SRDX) results in impaired sensitivity to auxin with phenotypes recalling those previously reported for Sl-IAA27 downregulated tomato lines. The expression of Sl-IAA27 is dramatically reduced in the ERF.B3-SRDX lines and Sl-ERF.B3 is shown to regulate the expression of Sl-IAA27 via direct binding to its promoter. The data support a model in which the ethylene-responsive Sl-ERF.B3 integrates ethylene and auxin signaling via regulation of the expression of the auxin signaling component Sl-IAA27. The study uncovers a molecular mechanism that links ethylene and auxin signaling in tomato. PMID- 29701900 TI - Single S1 Dorsal Root Ganglia Stimulation for Intractable Complex Regional Pain Syndrome Foot Pain After Lumbar Spine Surgery: A Case Series. AB - INTRODUCTION: Intractable complex regional pain syndrome (CRPS)-related chronic foot pain, is a common therapeutic challenge for interventional pain management physicians and patients alike. Dorsal root ganglia (DRG) stimulation is a very target specific dorsal column stimulation technique with very promising clinical outcomes. Patients with CRPS foot pain and previous back surgery can benefit from DRG stimulation but also run a significant risk of epidural trauma from the DRG sheath advancement. Most sensory innervation to the foot is from L5 and S1 dermatomes. Although there is dual modulation from L5 and S1 DRG, significant "cross talk" exists between these structures such that a DRG lead solely at S1 could provide pain relief for the entire foot. In this case series, we examined the outcomes obtained from placement of solely S1 DRG stimulating electrodes in patients with CRPS-related chronic foot pain, and examine whether this may provide a reduced risk of dural injury. Furthermore, we describe the technical aspects of a S1 DRG placement and discuss relevant anatomical issues pertaining to this approach. MATERIALS AND METHODS: Five patients (four female, one male) with chronic foot pain participated. The oldest was 71 and the youngest 49. Three patients were diagnosed with foot CRPS-1, and two patients with foot CRPS-2. All patients had back surgery in the past and all underwent a trial and subsequent S1 DRG implantation. The patients were evaluated with a numeric rating score (NRS) for pain and function before the procedure and one, two, three, and six months after the procedure. The first patient underwent an L5 and S1 trial and developed CSF leak and postdural puncture headache. Two months later, the patient was re trialed and implanted with a single S1 electrode. The other four patients were trialed and implanted with single S1 DRG electrodes. RESULTS: All five patients had severe pain (8-10 NRS) and significant loss of function and quality of life (2-4 NRS) before the procedure. All five patients had excellent (0-3 NRS) pain relief and functional restoration (8-10 NRS) with a single S1 electrode trial, and all five proceeded with permanent implantation. The pain relief from the S1 DRG stimulation extended to the entire foot without any sparing. All patients were able to discontinue or significantly reduce their oral pain medications. The one-, two-, three-, and six-month follow-up showed preservation of therapeutic efficacy. CONCLUSIONS: A single S1 DRG electrode placement in patients diagnosed with CRPS of the foot and who had previous back surgery is therapeutically effective and can minimize the risk of dural trauma and CSF leak. PMID- 29701902 TI - Low doses of Paclitaxel repress breast cancer invasion through DJ-1/KLF17 signalling pathway. AB - Paclitaxel (taxol) is an important agent against many tumours, including breast cancer. Ample data documents that paclitaxel inhibits breast cancer metastasis while others prove that paclitaxel enhances breast cancer metastasis. The mechanisms by which paclitaxel exerts its action are not well established. This study focuses on the effect of paclitaxel, particularly the low doses on breast cancer metastasis and the mechanisms that regulate it. Current results show that, paclitaxel exerts significant cytotoxicity even at low doses in both MCF-7 and MDA-MB-231 cells. Interestingly, paclitaxel significantly inhibits cell invasion and migration, decreases Snail and increases E-cadherin mRNA expression levels at the indicated low doses. Furthermore, paclitaxel-inhibiting breast cancer metastasis is associated with down-regulation of DJ-1 and ID-1 mRNA expression level with a concurrent increase in KLF17 expression. Under the same experimental conditions, paclitaxel induces KLF17 and concurrently represses ID-1 protein levels. Our results show for the first time that paclitaxel inhibits breast cancer metastasis through regulating DJ-1/KLF17/ID-1 signalling pathway; repressed DJ-1 and ID-1 and enhanced KLF17 expression. PMID- 29701901 TI - No Gut No Gain! Enteral Bile Acid Treatment Preserves Gut Growth but Not Parenteral Nutrition-Associated Liver Injury in a Novel Extensive Short Bowel Animal Model. AB - BACKGROUND: Parenteral nutrition (PN) provides nutrition intravenously; however, this life-saving therapy is associated with significant liver disease. Recent evidence indicates improvement in PN-associated injury in animals with intact gut treated with enteral bile acid (BA), chenodeoxycholic acid (CDCA), and a gut farnesoid X receptor (FXR) agonist, which drives the gut-liver cross talk (GLCT). We hypothesized that similar improvement could be translated in animals with short bowel syndrome (SBS). METHODS: Using piglets, we developed a novel 90% gut resected SBS model. Fifteen SBS piglets receiving PN were given CDCA or control (vehicle control) for 2 weeks. Tissue and serum were analyzed posteuthanasia. RESULTS: CDCA increased gut FXR (quantitative polymerase chain reaction; P = .008), but not downstream FXR targets. No difference in gut fibroblast growth factor 19 (FGF19; P = .28) or hepatic FXR (P = .75), FGF19 (P = .86), FGFR4 (P = .53), or Cholesterol 7 alpha-hydroxylase (P = .61) was noted. PN resulted in cholestasis; however, no improvement was noted with CDCA. Hepatic fibrosis or immunostaining for Ki67, CD3, or Cytokeratin 7 was not different with CDCA. PN resulted in gut atrophy. CDCA preserved (P = .04 vs control) gut mass and villous/crypt ratio. The median (interquartile range) for gut mass for control was 0.28 (0.17-0.34) and for CDCA was 0.33 (0.26-0.46). CONCLUSIONS: We note that, unlike in animals with intact gut, in an SBS animal model there is inadequate CDCA-induced activation of gut-derived signaling to cause liver improvement. Thus, it appears that activation of GLCT is critically dependent on the presence of adequate gut. This is clinically relevant because it suggests that BA therapy may not be as effective for patients with SBS. PMID- 29701904 TI - TRPV4 activates cytosolic phospholipase A2 via Ca2+ -dependent PKC/ERK1/2 signalling in controlling hypertensive contraction. AB - Activation of TRPV4 (transient receptor potential vanilloid 4) has been reported to result in endothelium-dependent contraction in the aortae of hypertensive mice. This contraction involved increased cPLA2 (cytosolic phospholipase A2 ) activity. The mechanism by which TRPV4 regulates cPLA2 activity to induce contraction in hypertension, however, is unknown. Through measurements of arterial tension and protein level, we showed that high-salt diet induced hypertension increases activity of PKC (protein kinase C) and ERK1/2 (extracellular signal-regulated kinase 1/2). GSK1016790A, a TRPV4 agonist and ACh (acetylcholine) induced contractions were suppressed by Go6983, a PKC inhibitor and PD98059, an ERK1/2 inhibitor. TRPV4 activation increased activity of PKC and ERK1/2 in endothelial cells from hypertensive mice and this response was suppressed by HC067047, a TRPV4 inhibitor and BAPTA/AM, a Ca2+ chelator. PLA2 assay and western blotting showed that blocking of PKC or ERK1/2 inhibited TRPV4 or ACh-induced cPLA2 activity. Enzyme immunoassay showed that GSK1016790A or ACh triggered the release of PGF2alpha (prostaglandin F2alpha ) was reduced by inhibition of PKC or ERK1/2. These data further suggest Ca2+ /PKC/ERK1/2 axis as a novel mechanism for TRPV4 in the activation of cPLA2 in hypertension. PMID- 29701905 TI - EDITORIAL. PMID- 29701903 TI - Impact of miR-140 Deficiency on Non-Alcoholic Fatty Liver Disease. AB - SCOPE: We have previously shown that loss of miR-140 has a pro-fibrotic effect in the mammary gland. This study aims to investigate whether miR-140 loss and obesity act synergistically to promote non-alcoholic fatty liver disease (NAFLD), and to identify the underlying mechanisms. METHODS AND RESULTS: Liver tissues were isolated from lean-fat-diet and high-fat-diet fed wild-type and miR-140 knockout mice. Using molecular staining and immunohistochemistry techniques, increased development of NAFLD and fibrotic indicators in miR-140 knockout mice were identified. Utilizing an in vitro model system, miR-140 was demonstrated to target TLR-4, and miR-140 overexpression was shown to be sufficient to inhibit palmitic acid signaling through the TLR-4/NFkappaB pathway. CONCLUSION: These findings demonstrate that loss of miR-140 results in increased expression of TLR 4, sensitizing cells to palmitic acid signaling and in increased inflammatory activity through the TLR4/NFkappaB pathway. This signaling axis promotes NAFLD development in a high-fat diet context and indicates the potential utility of miR 140 rescue as a therapeutic strategy in NAFLD. PMID- 29701906 TI - Whether to ask or not: How Valid Are Memory Complaints in Alzheimer's Disease? PMID- 29701907 TI - Correlation between the median particle size of chewed frankfurter sausage and almonds during masticatory performance test. AB - The correlation between chewing and gastric function is best reflected when the same food type is used during both tests. We proposed frankfurter sausage as test food for masticatory performance as it can also be used in gastric emptying test. The suitability of frankfurter sausage to determine masticatory performance, however, has never been examined. To examine the correlations between the median particle size of frankfurter sausage and almonds (as standard test food) after different numbers of chewing cycles. Twenty-seven subjects performed masticatory performance tests by chewing 2 types of test foods, that is, a piece of almond or 5-g frankfurter sausage cubes placed in a sealed latex bag, for 5 and 15 chewing cycles. For each individual, right and left sides were tested separately. Chewed samples obtained from both sides were pooled. Median particle sizes were determined using a multiple sieving method. Spearman's rank correlation was used to examine any correlation between median particle sizes of the 2 test foods after 5 and 15 cycles. Median particle sizes after 5 and 15 cycles were 2.04 +/- 0.87 and 0.95 +/- 0.58 mm for almonds and 4.16 +/- 0.19 and 3.73 +/- 0.25 mm for frankfurter sausage, respectively. Significant correlations were observed between the median particle size of chewed frankfurter sausage after 15 cycles and that of chewed almonds after 5 and 15 cycles (r = .76, P < .01 and r = .52, P = .01, respectively). Frankfurter sausage chewed for 15 cycles may be suitable for the determination of masticatory performance in conjunction with gastric emptying test. PMID- 29701908 TI - Advances in osteobiologic materials for bone substitutes. AB - A significant challenge in the current orthopedics is the development of suitable osteobiologic materials that can replace the conventional allografts, autografts, and xenografts and thereby serve as implant materials as bone substitutes for bone repair or remodelling. The complex biology behind the nanostructure and microstructure of bones and their repair mechanisms, which involve various types of chemical and biomechanical signalling amongst different cells, has set strong requirements for biomaterials to be used in bone tissue engineering. This review presents an overview of various types of osteobiologic materials to facilitate the formation of the functional bone tissue and healing of the bone, covering metallic, ceramic, polymeric, and cell-based graft substitutes, as well as some biomolecular strategies including stem cells, extracellular matrices, growth factors, and gene therapies. Advantages and disadvantages of each type, particularly from the perspective of osteoinductive and osteoconductive capabilities, are discussed. Although the numerous challenges of bone regeneration in tissue engineering and regenerative medicine are yet to be entirely addressed, further advancements in osteobiologic materials will pave the way towards engineering fully functional bone replacement grafts. PMID- 29701909 TI - The impact of direct-acting antiviral agents on liver and kidney transplant costs and outcomes. AB - Direct-acting antiviral medications (DAAs) have revolutionized care for hepatitis C positive (HCV+) liver (LT) and kidney (KT) transplant recipients. Scientific Registry of Transplant Recipients registry data were integrated with national pharmaceutical claims (2007-2016) to identify HCV treatments before January 2014 (pre-DAA) and after (post-DAA), stratified by donor (D) and recipient (R) serostatus and payer. Pre-DAA, 18% of HCV+ LT recipients were treated within 3 years and without differences by donor serostatus or payer. Post-DAA, only 6% of D-/R+ recipients, 19.8% of D+/R+ recipients with public insurance, and 11.3% with private insurance were treated within 3 years (P < .0001). LT recipients treated for HCV pre-DAA experienced higher rates of graft loss (adjusted hazard ratio [aHR] 1.34 1.852.10 , P < .0001) and death (aHR 1.47 1.681.91 , P < .0001). Post DAA, HCV treatment was not associated with death (aHR 0.34 0.671.32 , P = .25) or graft failure (aHR 0.32 0.641.26 , P = .20) in D+R+ LT recipients. Treatment increased in D+R+ KT recipients (5.5% pre-DAA vs 12.9% post-DAA), but did not differ by payer status. DAAs reduced the risk of death after D+/R+ KT by 57% (0.19 0.430.95 , P = .04) and graft loss by 46% (0.27 0.541.07 , P = .08). HCV treatment with DAAs appears to improve HCV+ LT and KT outcomes; however, access to these medications appears limited in both LT and KT recipients. PMID- 29701910 TI - Can you spot a liar? Deception, mindreading, and the case of autism spectrum disorder. AB - Detection of deception is of fundamental importance for everyday social life and might require "mindreading" (the ability to represent others' mental states). People with diminished mindreading, such as those with autism spectrum disorder (ASD), might be at risk of manipulation because of lie detection difficulties. In Experiment 1, performance among 216 neurotypical adults on a realistic lie detection paradigm was significantly negatively associated with number of ASD traits, but not with mindreading ability. Bayesian analyses complemented null hypothesis significance testing and suggested the data supported the alternative hypothesis in this key respect. Cross validation of results was achieved by randomly splitting the full sample into two subsamples of 108 and rerunning analyses. The association between lie detection and ASD traits held in both subsamples, showing the reliability of findings. In Experiment 2, lie detection was significantly impaired in 27 adults with a diagnosis of ASD relative to 27 matched comparison participants. Results suggest that people with ASD (or ASD traits) may be particularly vulnerable to manipulation and may benefit from lie detection training. Autism Res 2018, 11: 1129-1137. (c) 2018 The Authors Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc. LAY SUMMARY: Detection of deception is of fundamental importance for everyday social life. People with diminished understanding of other minds, such as those with autism spectrum disorder (ASD), might be at risk of manipulation because of lie detection difficulties. We found that lie detection ability was related to how many ASD traits neurotypical people manifested and also was significantly diminished among adults with a full diagnosis of ASD. PMID- 29701911 TI - Dysmobility Syndrome Independently Increases Fracture Risk in the Osteoporotic Fractures in Men (MrOS) Prospective Cohort Study. AB - We proposed the term "dysmobility syndrome" (DS) to identify individuals with impaired musculoskeletal health, a risk factor for falls and fractures. Whether DS is associated with increased risk of incident fracture is unknown. The Osteoporotic Fractures in Men (MrOS) study enrolled 5994 men ages >=65 years, between March 2000 and April 2002. We used baseline data to determine whether DS increased fracture risk, independent of the Fracture Risk Assessment Tool (FRAX). Men met DS criteria at baseline if they had three or more of the following: appendicular lean mass/height2 <7.26 kg/m2 , total body fat >30%, spine or hip T score <= -2.5, grip strength <30 kg, gait speed <1.0 m/s, and one or more fall within 12 months. We examined whether baseline DS increased the risk of hip and major osteoporotic fractures (MOFs) over a median of 14 years (IQR, 9 to 15 years). Among 5834 men mean age 74 +/- 6 years, 471 (8%) had DS and 635 (11%) experienced an MOF, including 274 (5%) hip fractures. Age (per SD increase) conferred an HR of 1.72 (95% CI, 1.59 to 1.86), DS conferred an HR of 3.45 (95% CI, 2.78 to 4.29) and FRAX calculated with BMD (per %) conferred an HR of 1.10 (95% CI, 1.08 to 1.11) for MOF. Prediction of MOF using the FRAX score provided a concordance value of 0.67 +/- 0.012 (concordance values are mean +/- SE). Concordance increased to 0.69 +/- 0.012 by adding DS and to 0.70 +/- 0.012 by adding DS and age to the multivariate model. Kaplan-Meier curves indicated that men with both DS and a FRAX risk above the National Osteoporosis Foundation (NOF) treatment thresholds had higher MOF (HR 6.23; 95% CI, 3.10 to 12.54) and hip (HR 7.73; 95% CI, 5.95 to 10.04) fracture risk than men with neither condition. We suggest further studies to determine the optimal criteria for DS, and to test DS as a predictor of falls and fractures, especially in women. (c) 2018 American Society for Bone and Mineral Research. PMID- 29701912 TI - Gut Microbiota as a Modulator of Paneth Cells During Parenteral Nutrition in Mice. AB - BACKGROUND: Parenteral nutrition (PN) leads to decreased production of Paneth cell-derived antimicrobial peptides and is accompanied by dysbiosis of the gut. The role of gut microbiota in regulating Paneth cell function during PN is unknown. METHODS: Male C57BL/6 mice received either an antibiotic cocktail (Abx) or nothing (Normal) in their drinking water for 2 weeks before being fed either standard laboratory chow (Abx-Chow and Normal-Chow) or a continuous infusion of PN solution (Abx-PN and Normal-PN) for 7 days. In a separate experiment, the intestinal contents of mice having received 7 days of Chow or PN were transferred by gavage to germ-free (GF) mice. RESULTS: Antibiotic treatment decreased the protein levels of lysozyme and RegIIIgamma and the mRNA level of alpha-defensin 5, with no further effect by PN compared with chow. However, these measurements were higher in Abx-PN mice than in Normal-PN mice. When compared with Chow->GF, PN->GF mice demonstrated lower body weight, shorter intestinal length, severe atrophy of the ileum villus, and lower levels of lysozyme and RegIIIgamma protein and alpha-defensin 5 mRNA. Interleukin (IL)-22 and IL-17 mRNA levels declined in the ileum. Principal component analysis revealed major differences between the metabolite compositions of the Chow and PN, as well as the Chow->GF and PN->GF groups that appears to indicate aberrant tryptophan metabolism. CONCLUSIONS: Gut microbiota plays a vital role in PN-related Paneth cell dysfunction. Dysbiosis during PN might alter the production of microbial metabolites, thereby influencing the production of Paneth cell-derived antimicrobial peptides. PMID- 29701913 TI - The influence of ABCB1 and P2Y12 genetic variants on clinical outcomes in Chinese intracranial artery stenosis patients. AB - For intracranial artery stenosis patients, high inter-individual variability in response to antiplatelet drug therapy results in recurrent ischemic events. We aimed to evaluate the association of drug-related genetic polymorphisms with adverse clinical outcomes. We consecutively enrolled 157 patients receiving dual antiplatelet therapy (aspirin plus clopidogrel), and adverse clinical events occurred in 10 patients during the one year follow-up. The P2Y12 polymorphisms (rs9859538 and rs10935842) were associated with increased likelihood of relapse events (OR=2.934, 95%CI=1.022-8.425, P-value=0.045), and the two variants are in complete linkage disequilibrium. The mutation of ABCB1 rs1128503 may decrease the recurrence of clinical events (OR=0.211, 95%CI=0.046-0.957, P-value=0.044). Genetic testing (ABCB1 and P2Y12) may provide useful information to prevent ischemic events prior to the initiation of antiplatelet therapy. This article is protected by copyright. All rights reserved. PMID- 29701914 TI - Temporal changes in peritoneal cell phenotype and neoelastic matrix induction with hyaluronan oligomers and TGF-beta1 after implantation of engineered conduits. AB - The neoassembly and maturation of elastic matrix is an important challenge for engineering small-diameter grafts for patients with peripheral artery disease. We have previously shown that hyaluronan oligomers and transforming growth factor beta (elastogenic factors or EFs) promote elastogenesis in smooth muscle cell (SMC) culture. However, their combined effects on macrophages and inflammatory cells in vivo are unknown. This information is needed to use the body (e.g., peritoneal cavity) as an "in vivo bioreactor" to recruit autologous cells to implanted EF-functionalized scaffolds. In this study, we determined if peritoneal fluid cells respond to EFs like smooth muscle cells and if these responses differ between cells sourced during different stages of inflammation triggered by scaffold implantation. Electrospun poly(epsilon-caprolactone)/collagen conduits were implanted in the peritoneal cavity prior to peritoneal fluid collection at 3 42 days postimplantation. Cells from the fluid were cultured in vitro with and without EFs to determine their response. Their phenotype/behaviour was assessed with a DNA assay, quantitative real-time PCR, and immunofluorescence. The EFs reduced peritoneal cell proliferation, maintained cell contractility, and unexpectedly did not exhibit proelastic effects, which we attributed to differences in cell density. We found the greatest elastin deposition in regions containing a high cell density. Further, we found that cells isolated from the peritoneal cavity at longer times after conduit implantation responded better to the EFs and exhibited more CD31 expression than cells at an earlier time point. Overall, this study provides information about the potential use of EFs in vivo and can guide the design of future tissue-engineered vascular grafts. PMID- 29701915 TI - Complete adult neurogenesis within a Wallerian degenerating nerve expressed as an ectopic ganglion. AB - Neurogenesis in the adult peripheral nervous system remains to be demonstrated. We transplanted embryonic neural stem cells into a Wallerian degenerating nerve graft and observed development of a nodular structure consisting of neurons, glia, and Schwann cells. Histological analysis revealed a structure loosely resembling the spinal cord, including a synaptic network that formed along the neuron. Furthermore, the new axons reinnervated the paralysed muscle, forming both de novo and revived neuromuscular junctions. Reinnervation of the paralysed muscle resulted in significantly greater mean wet muscle weight and muscle fibre cross-sectional area on the cell transplantation side than on the surgical control side (body weight 0.071 +/- 0.011% vs. 0.051 +/- 0.007%, p = .006; area 355.6 +/- 345.2 vs. 114.0 +/- 132.0 MUm2 , p < .001). Electrophysiological experiments demonstrated a functional connection between the neurons and muscle; hence, we identified this nodule as an ectopic ganglion. Surprisingly, in green rat experiments, most of these glial cells, but none of the neurons, expressed enhanced green fluorescent protein, suggesting that the cells constituting the ectopic ganglion were derived from both transplanted stem cells and endogenous stem cells. Such adult neurogenesis in a peripheral nerve related to neural stem cell transplantation has not been reported previously, and these results form the basis for a novel regenerative medicine approach in paralysed muscle. PMID- 29701916 TI - High-Protein Hypocaloric Nutrition for Non-Obese Critically Ill Patients. AB - High-protein hypocaloric nutrition, tailored to each patient's muscle mass, protein-catabolic severity, and exogenous energy tolerance, is the most plausible nutrition therapy in protein-catabolic critical illness. Sufficient protein provision could mitigate the rapid muscle atrophy characteristic of this disease while providing urgently needed amino acids to the central protein compartment and sites of tissue injury. The protein dose may range from 1.5 to 2.5 g protein (1.8-3.0 g free amino acids)/kg dry body weight per day. Nutrition should be low in energy (~70% of energy expenditure or ~15 kcal/kg dry body weight per day) because efforts to match energy provision to energy expenditure are physiologically irrational, risk toxic energy overfeeding, and have repeatedly failed in large clinical trials to demonstrate clinical benefit. The American Society for Parenteral and Enteral Nutrition currently suggests high-protein hypocaloric nutrition for obese critically ill patients. Short-term high-protein hypocaloric nutrition is physiologically and clinically sensible for most protein catabolic critically ill patients, whether obese or not. PMID- 29701917 TI - Enabling Generalized Coordination Numbers to Describe Strain Effects. AB - The world's growing energetic demand calls for efficient generation and interconversion of different types of energy. Heterogeneous catalysis can help cope with such demand, provided that rational, accurate and affordable design methods lead to the discovery of cost-effective and efficient catalysts. Here we derive a simple descriptor to simultaneously capture two parameters commonly used in catalytic materials design: strain and coordination. We test the descriptor with four different adsorbates on four active sites of two metals, and applying strain in the range of +/-3 %, usually observed experimentally at catalytic metal surfaces. Furthermore, we use the descriptor to illustrate catalyst design availing strain and nearest-neighbor effects simultaneously for the oxygen reduction reaction, a reaction of high importance in fuel cells. The connection between coordination and strain helps in the search for robust yet rapid catalyst design methodologies. PMID- 29701918 TI - Emulsion and Foam Templating-Promising Routes to Tailor-Made Porous Polymers. AB - Emulsions, foams, and foamed emulsions have been used successfully as templates for the synthesis of macroporous polymers. Based on this knowledge this Minireview presents strategies to use, optimise, and upscale these templating methods to synthesise tailor-made porous polymers. The uniqueness of such polymers lies in the ability to tailor their structures and, therefore, their properties. However, systematic studies on structure-property relations are lacking mainly because the templating scientific community is "split into two": the polydisperse and monodisperse camps. Thus, it is time to build a bridge between the camps, that is, to synthesise porous polymers with very different structures from the same precursors to determine the relationship between the structure and the properties. PMID- 29701919 TI - Electrophysiological assessment of a peptide amphiphile nanofiber nerve graft for facial nerve repair. AB - Facial nerve injury can cause severe long-term physical and psychological morbidity. There are limited repair options for an acutely transected facial nerve not amenable to primary neurorrhaphy. We hypothesize that a peptide amphiphile nanofiber neurograft may provide the nanostructure necessary to guide organized neural regeneration. Five experimental groups were compared, animals with (1) an intact nerve, (2) following resection of a nerve segment, and following resection and immediate repair with either a (3) autograft (using the resected nerve segment), (4) neurograft, or (5) empty conduit. The buccal branch of the rat facial nerve was directly stimulated with charge balanced biphasic electrical current pulses at different current amplitudes whereas nerve compound action potentials (nCAPs) and electromygraphic responses were recorded. After 8 weeks, the proximal buccal branch was surgically reexposed and electrically evoked nCAPs were recorded for groups 1-5. As expected, the intact nerves required significantly lower current amplitudes to evoke an nCAP than those repaired with the neurograft and autograft nerves. For other electrophysiologic parameters such as latency and maximum nCAP, there was no significant difference between the intact, autograft, and neurograft groups. The resected group had variable responses to electrical stimulation, and the empty tube group was electrically silent. Immunohistochemical analysis and transmission electron microscopy confirmed myelinated neural regeneration. This study demonstrates that the neuroregenerative capability of peptide amphiphile nanofiber neurografts is similar to the current clinical gold standard method of repair and holds potential as an off-the-shelf solution for facial reanimation and potentially peripheral nerve repair. PMID- 29701920 TI - A complicated relationship between peanut environmental exposure and the development of allergic sensitization to peanuts. PMID- 29701921 TI - Best of the other journals. PMID- 29701922 TI - Eosinophils on trial. PMID- 29701924 TI - In Vitro Performance Testing of Legacy and ENFit Gastrostomy Tube Devices Under Gravity Flow Conditions. AB - BACKGROUND: Changes in connector design for the gastrostomy tube were implemented to reduce the risk of misconnections. This study aimed to determine whether there are differences in gravity flow rates between legacy devices and the ENFit devices intended to replace them. MATERIALS AND METHODS: We compared 5 legacy gastrostomy tube brands with 3 corresponding ENFit brands, sized between 14 French (Fr) and 24 Fr. Seven commercial diets were used. One comparison involved low-profile devices. RESULTS: Whether an ENFit device manifested a lower flow rate than a legacy device was not a strong function of diet. One 14-Fr ENFit device, because of its reduced distal inner tube diameter, produced an average feeding time of 56 (+/-13) minutes from a 20-minute baseline. For other 14-Fr ENFit devices, the increase was much less pronounced (25 +/- 4 minutes). At larger sizes, both decreases and increases in feeding time were observed, depending on device type; on average, the 20-minute feeding time increased to 25 (+/-7) minutes. For low-profile devices, across all sizes, an increase in 20 minute feeding time occurred, but the difference was small (23 +/- 2). CONCLUSION: Statistically lower flow rates were observed for 70% of ENFit devices relative to their legacy counterparts. We estimate that 30% of the differences may be noticeable. In the scenarios studied, lower flow rates (relative to other devices at the same Fr number) arise from energy losses in straight tubing. This difference can be reduced by increasing the tube inner diameters in distal end of ENFit tubes. PMID- 29701927 TI - Relationship. PMID- 29701925 TI - Collagen type I induces EGFR-TKI resistance in EGFR-mutated cancer cells by mTOR activation through Akt-independent pathway. AB - Primary resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is a serious problem in lung adenocarcinoma patients harboring EGFR mutations. The aim of this study was to examine whether and how collagen type I (Col I), the most abundantly deposited matrix in tumor stroma, affects EGFR-TKI sensitivity in EGFR-mutant cells. We evaluated the EGFR-TKI sensitivity of EGFR mutated cancer cells cultured with Col I. Changes in the activation of downstream signaling molecules of EGFR were analyzed. We also examined the association between the Col I expression in tumor stroma in surgical specimens and EGFR-TKI response of postoperative recurrence patients with EGFR mutations. Compared to cancer cells without Col I, the survival rate of cancer cells cultured with Col I was significantly higher after EGFR-TKI treatment. In cancer cells cultured with and without Col I, EGFR-TKI suppressed the levels of phosphorylated (p-)EGFR, p ERK1/2, and p-Akt. When compared to cancer cells without Col I, expression of p P70S6K, a hallmark of mTOR activation, was dramatically upregulated in cancer cells with Col I. This activation was maintained even after EGFR-TKI treatment. Simultaneous treatment with EGFR-TKI and mTOR inhibitor abrogated Col I-induced resistance to EGFR-TKI. Patients with Col I-rich stroma had a significantly shorter progression-free survival time after EGFR-TKI therapy (238 days vs 404 days; P < .05). Collagen type I induces mTOR activation through an Akt independent pathway, which results in EGFR-TKI resistance. Combination therapy using EGFR-TKI and mTOR inhibitor could be a possible strategy to combat this resistance. PMID- 29701928 TI - Prevention of Dopamine Dysregulation Syndrome in Parkinson's Disease: A Case Report. PMID- 29701929 TI - Psychiatric and Psychological Impact of Chronic Skin Disease. AB - Chronic skin disease has a devastating effect on a person's physical and psychological well-being. Skin disease significantly impacts all aspects of a patient's life including school, relationships, career choices, social and leisure activities, and sexual life. The physical, psychological, and social consequences affect not only the patients, but also caregivers and family members as well. Common psychological problems associated with skin disease include, but are not limited to, feelings of stress, anxiety, anger, depression, shame, social isolation, low self-esteem, and embarrassment. Besides psychopharmacology, multiple psychotherapeutic techniques have proved to be helpful in addressing the psychological sequelae of skin disease. PMID- 29701926 TI - Associations Between Lean Mass, Muscle Strength and Power, and Skeletal Size, Density and Strength in Older Men. AB - Studies examining the relationship between muscle parameters and bone strength have not included multiple muscle measurements and/or both central and peripheral skeletal parameters. The purpose of this study was to explore the relationship between lean mass, muscle strength and power, and skeletal size, bone density, and bone strength. We studied the association between appendicular lean mass (ALM), grip strength, and leg power, and central quantitative computed tomography (QCT) parameters in 2857 men aged 65 years or older; peripheral QCT was available on a subset (n = 786). ALM, grip strength, and leg power were measured by dual energy X-ray absorptiometry (DXA), Jamar dynamometer, and the Nottingham Power Rig, respectively. Multivariable models adjusting for potential confounders including age, race, study site, BMI, and muscle measurements were developed and least squares means were generated from linear regression models. For the multivariable model, percent differences of bone parameters between lowest (Q1) and highest quartiles (Q4) of ALM, grip strength, and leg power were reported. ALM was significantly associated with central and peripheral QCT parameters: percent higher values (Q4 versus Q1) ranging from 3.3% (cortical volumetric bone mineral density [vBMD] of the femoral neck) to 31% (vertebral strength index of the spine). Grip strength was only significantly associated with radial parameters: percent higher values (Q4 versus Q1) ranging from 2.5% (periosteal circumference) to 7.5% (33% axial strength index [SSIx]). Leg power was associated with vertebral strength and lower cross-sectional area with percent lower values (Q4 versus Q1) of -11.9% and -2.7%, respectively. In older men, stronger associations were observed for ALM compared to muscle strength and power. Longitudinal studies are needed to examine the relationship between independent changes in muscle measurements and skeletal size, density and strength. (c) 2018 American Society for Bone and Mineral Research. PMID- 29701930 TI - Mediagenic Psychosis in Dementia: A Case Report. PMID- 29701932 TI - Tardive Dyskinesia: Is Vitamin E Singing the Prostate Blues? PMID- 29701931 TI - Cyclosporine-Olanzapine Drug-Drug Interaction. PMID- 29701933 TI - Injectable Risperidone During Hemodialysis. PMID- 29701934 TI - A Commentary on Existential Psychopharmacologic Clinical Practice: Advocating a Humanistic Approach to the "Med Check". PMID- 29701935 TI - Risk Factors for Overdose in Treatment-Seeking Youth With Substance Use Disorders. AB - OBJECTIVE: Overdoses (ODs) are among the leading causes of death in youth with substance use disorders (SUDs). Our aim was to identify the prevalence of OD and characteristics associated with a history of OD in youth presenting for SUD outpatient care. METHODS: A systematic retrospective medical record review was conducted of consecutive psychiatric and SUD evaluations for patients aged 16 to 26 years with DSM-IV-TR criteria SUD at entry into an outpatient SUD treatment program for youth between January 2012 and June 2013. Unintentional OD was defined as substance use without intention of self-harm that was associated with a significant impairment in level of consciousness. Intentional OD was defined as ingestion of a substance that was reported as a suicide attempt. T tests, Pearson chi2 tests, and Fisher exact tests were performed to evaluate characteristics associated with a history of OD. RESULTS: We examined the medical records of 200 patients (157 males and 43 females) with a mean +/- SD age of 20.2 +/- 2.8 years. At intake, 58 patients (29%) had a history of OD, and 62% of those patients had a history of unintentional OD only (n = 36). Youth with >= 2 SUDs were 3 times more likely to have a history of OD compared to youth with 1 SUD (all P < .05). Compared to those without a history of OD, those with an OD were more likely to be female and have lifetime histories of alcohol, cocaine, amphetamine, anxiety, depressive, and/or eating disorders (all P < .05). CONCLUSIONS: High rates of OD exist in treatment-seeking youth with SUD. OD was associated with more SUDs and psychiatric comorbidity. PMID- 29701936 TI - The Impact of Captivity and Posttraumatic Stress Disorder on Cognitive Performance Among Former Prisoners of War: A Longitudinal Study. AB - OBJECTIVE: War captivity is a potent pathogen for various aspects of mental health, including cognitive impairments. However, little is known about the long term impact of war captivity and posttraumatic stress disorder (PTSD) on cognitive functioning among former prisoners of war (ex-POWs). This study assesses the effect of captivity, PTSD trajectories, and the accumulating differential effect in the prediction of cognitive performance. METHODS: This longitudinal research includes 4 assessments (1991 [T1], 2003 [T2], 2008 [T3], 2015 [T4]) of Israeli ex-POWs and comparable combatants from the 1973 Yom Kippur War. Accordingly, 95 ex-POWs and 26 comparable combatants were included in this study. PTSD was assessed according to the DSM-IV, and cognitive performance was assessed using the Montreal Cognitive Assessment (MoCA). RESULTS: Ex-POWs reported higher levels of PTSD symptoms compared to controls (P = 0.007). No difference was found between the groups regarding MoCA total score. Ex-POWs with chronic PTSD were found to have more difficulty in overall cognitive functioning, compared to ex-POWs with delayed, recovery, and resilient trajectories (P = 0.03). Finally, physical and psychological suffering in captivity and intrusion symptoms predicted cognitive performance (P < .001, R2 = 37.9%). These findings support the potent pathogenic effects of war captivity on cognitive abilities, more than 4 decades after the end of the traumatic event. CONCLUSIONS: Our results showed captivity to be a unique and powerful traumatic experience, leading to PTSD and long-lasting and enduring neuropsychological implications. These findings highlight the importance of viewing ex-POWs, in particular those suffering from chronic PTSD, especially as they age, as a high-risk population for cognitive disorders. This requires the appropriate diagnosis and cognitive therapy as a way to preserve cognitive abilities among this population. PMID- 29701937 TI - Mediation Analyses of Insight, Quality of Life, Depression, and Suicidality: Results From the FACE-SZ Cohort. AB - OBJECTIVE: The relationship between greater insight and increased risk of suicide in patients with schizophrenia is debated. The purpose of this study was to assess whether quality of life (QoL) and depression mediated the association between insight and suicidality. METHODS: Between March 2010 and December 2015, 527 community-dwelling adults with stable schizophrenia according to DSM-IV criteria were included in a multicenter cross-sectional study, the FondaMental Academic Centers of Expertise for Schizophrenia (FACE-SZ) Study. Structural equation modeling was used for mediation analyses among insight, QoL, depression, and suicidality, controlling for the global level of schizophrenic symptoms. RESULTS: The model provided a good fit for the data (chi23 = 1.4, P = .708, Tucker-Lewis index = 1, comparative fit index = 1, root mean square error of approximation = 0, standardized root mean square residual = 0.008) and explained 27% of the variance in suicidality. Poorer QoL and greater severity of depression mediated 68.4% of the positive association between insight and suicidality (full mediation). Poorer QoL mediated 48% of the positive effect of insight on depression (partial mediation). The severity of depression mediated 91.2% of the negative relationship between QoL and suicidality (full mediation). CONCLUSIONS: Insight appears to be an indirect risk factor for suicide in patients with schizophrenia, with the link being mediated by poorer QoL and worse underlying depression, mainly by a sequential pathway but also by a less important parallel pathway. PMID- 29701938 TI - Childhood Adversity and Schizophrenia: The Protective Role of Resilience in Mental and Physical Health and Metabolic Markers. AB - OBJECTIVE: To determine the impact of childhood adversity and current (adulthood) resilience on mental and physical health and markers of metabolic function among adults with schizophrenia and nonpsychiatric comparison participants (NCs). METHODS: We conducted a cross-sectional study of 114 participants with schizophrenia (DSM-IV-TR criteria) and 101 NCs aged 26-65 years during 2012-2017. Sociodemographic, clinical, and laboratory measures were examined. Childhood Trauma Questionnaire was used to retrospectively assess emotional abuse/neglect, physical abuse/neglect, and sexual abuse experienced during childhood. Connor Davidson Resilience Scale was employed to measure resilience. RESULTS: Persons with schizophrenia reported more severe childhood trauma, lower resilience, and worse mental and physical health and had worse metabolic biomarker levels than NCs. Trauma severity correlated with worse depression in the NCs (r = 0.34), but not in the schizophrenia group (r = 0.02). In both groups, trauma severity was associated with worse physical well-being, higher fasting insulin levels, and greater insulin resistance (P <= .02). Notably, resilience appeared to counteract effects of trauma and diagnosis on mental and physical health. The schizophrenia subgroup with high resilience and severe trauma reported mental and physical well being and had glycosylated hemoglobin levels and insulin resistance scores that were comparable to those of NCs with low resilience and severe trauma. CONCLUSIONS: To our knowledge, this is the first study to quantitatively assess effects of both childhood trauma and resilience in schizophrenia on health, notably metabolic function. Interventions to bolster resilience in the general population and in people with schizophrenia may improve outcomes for those with a history of childhood adversity. PMID- 29701939 TI - Bilateral Repetitive Transcranial Magnetic Stimulation Decreases Suicidal Ideation in Depression. AB - OBJECTIVE: The purpose of this study was to evaluate the effects of repetitive transcranial magnetic stimulation (rTMS) on suicidal ideation in patients with treatment-resistant major depression (TRD) (patients who failed to clinically respond to at least 2 medication trials). METHODS: We pooled data from 2 published prospective randomized controlled trials of rTMS applied to the dorsolateral prefrontal cortex in patients with TRD. We compared the effect of bilateral, left unilateral, and sham rTMS on suicidal ideation as measured by the suicide item of the 17-item Hamilton Depression Rating Scale (HDRS) (N = 156). RESULTS: Suicidal ideation resolved in 40.4%, 26.8%, and 18.8% of participants randomized to bilateral, left unilateral, and sham rTMS, respectively. The difference between bilateral and sham was significant (OR = 3.03; 95% CI, 1.19 7.71; P = .02), unlike the difference between left unilateral and sham (OR = 1.59; 95% CI, 0.61-4.12; P = .33). There was a modest correlation between change in suicidal ideation and change in depression severity (Pearson r = 0.38; P < .001) and no difference in change of HDRS-16 score between suicide remitters and nonremitters (P = .32). CONCLUSIONS: Bilateral rTMS was superior to sham rTMS in reducing suicidal ideation in patients with TRD. Only a small portion of the reduction in suicidal ideation was attributable to the reduction in depressive symptoms. These data suggest that suicidal ideation could be a specific target symptom construct for rTMS. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT01515215 and NCT00305045. PMID- 29701940 TI - Urinary Phthalate Metabolite Concentrations and Breast Cancer Incidence and Survival following Breast Cancer: The Long Island Breast Cancer Study Project. AB - BACKGROUND: Phthalates, known endocrine disruptors, may play a role in breast carcinogenesis. Few studies have examined phthalates in relation to breast cancer (BC), and, to our knowledge, none have considered survival following BC. OBJECTIVES: We examined 11 urinary phthalate metabolites, individually and as molar sum groupings, in association with BC incidence and subsequent survival. METHODS: Our study includes 710 women diagnosed with first primary BC in 1996 1997 and 598 women without BC from Long Island, New York. Within 3 mo of diagnosis, participants provided spot urine samples. Nine phthalate metabolites were measured in all women; two [monocarboxyoctyl phthalate (MCOP) and monocarboxy-isononyl phthalate (MCNP)] were measured in 320 women with and 205 without BC. Women with BC were followed since diagnosis using the National Death Index; during follow-up (median=17.6 y), we identified 271 deaths (98 BC related). We examined creatinine-corrected metabolite concentrations in association with: BC, using logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) and all-cause/BC-specific mortality, using Cox regression to estimate hazard ratios (HRs) and 95% CIs. We also examined effect modification by body mass index (BMI) and estrogen receptor (ER) status. RESULTS: The highest (vs. lowest) quintiles of mono(3-carboxypropyl) phthalate (MCPP), monobenzyl phthalate (MBzP), MCNP, and MCOP were associated with BC ORs ranging from 0.71-0.73. The highest (vs. lowest) quintiles of mono(2-ethylhexyl) phthalate (MEHP) and MCOP were associated with BC-specific mortality HRs of 0.54 (95% CI: 0.28, 1.04) and 0.55 (95% CI: 0.23, 1.35), respectively. For BC-specific mortality, interactions were significant between BMI and mono(2-ethyl-5-oxyhexyl) phthalate (MEOHP), mono(2-ethyl-5-hydroxyhexyl) phthalate (MEHHP), and mono(2 ethyl-5-carboxypentyl) phthalate (MECPP), with positive associations among women with BMI<25 and inverse associations among women with BMI>=25.0 kg/m2. CONCLUSIONS: Consistent with laboratory evidence, we observed inverse associations between urinary concentrations of several phthalate metabolites and BC and subsequent survival; however, these results should be interpreted with caution given that biospecimen collection among women with BC occurred after diagnosis, which may be of particular concern for our case-control findings. https://doi.org/10.1289/EHP2083. PMID- 29701942 TI - Blastomere nucleation: Predictive factors and influence of blastomere with no apparent nuclei on blastocyst development and implantation. AB - OBJECTIVE: To investigate whether embryos presenting blastomere(s) with no apparent nucleus (BNAN) on days 2 and 3 are more likely to fail to develop into blastocysts, hatch and implant. METHODS: A total of 5705 zygotes obtained from 743 intracytoplasmic sperm injection (ICSI) cycles were analyzed. The presence and incidence of BNAN on days 2 and 3 of embryo development were recorded and then associated with ICSI outcomes. RESULTS: The occurrence of BNAN on day 2 of embryo development was determinant to the decreased odds of blastocyst formation (OR: 0.57, CI: 0.50-0.65), quality (OR: 0.56, CI: 0.43-0.73) and hatching status (OR: 0.66, CI: 0.50-0.87). The presence of BNAN on day 3 of embryo development was determinant to the decreased odds of blastocyst formation (OR: 0.67, CI: 0.58 0.78) and hatching status (OR: 0.61, CI: 0.45-0.83). The occurrence of BNAN on day 2 of embryo development was determinant to the decreased odds of blastocyst implantation (OR: 0.50, CI: 0.27-0.94). CONCLUSION: The presence of BNAN on day 2 or day 3 reduces development to blastocyst stage, hatching and implantation. Careful nuclear observation, taking into account the absence of blastomere nucleus, should be part of the strategies used for embryo selection. PMID- 29701943 TI - Egg Component-Composited Inverse Opal Particles for Synergistic Drug Delivery. AB - Microparticles have a demonstrated value in drug delivery systems. The attempts to develop this technology focus on the generation of functional microparticles by using innovative but accessible materials. Here, we present egg component composited microparticles with a hybrid inverse opal structure for synergistic drug delivery. The egg component inverse opal particles were produced by using egg yolk to negatively replicate colloid crystal bead templates. Because of their huge specific surface areas, abundant nanopores, and complex nanochannels of the inverse opal structure, the resultant egg yolk particles could be loaded with different kinds of drugs, such as hydrophobic camptothecin (CPT), by simply immersing them into the corresponding drug solutions. Attractively, additional drugs, such as the hydrophilic doxorubicin (DOX), could also be encapsulated into the particles through the secondary filling of the drug-doped egg white hydrogel into the egg yolk inverse opal scaffolds, which realized the synergistic drug delivery for the particles. It was demonstrated that the egg-derived inverse opal particles were with large quantity and lasting releasing for the CPT and DOX codelivery, and thus could significantly reduce cell viability, and enhance therapeutic efficacy in treating cancer cells. These features of the egg component-composited inverse opal microparticles indicated that they are ideal microcarriers for drug delivery. PMID- 29701941 TI - Effects of Neonicotinoid Pesticides on Promoter-Specific Aromatase (CYP19) Expression in Hs578t Breast Cancer Cells and the Role of the VEGF Pathway. AB - BACKGROUND: Aromatase (CYP19) is a key enzyme in estrogens biosynthesis. In the mammary gland, CYP19 gene is expressed at low levels under the regulation of its I.4 promoter. In hormone-dependent breast cancer, fibroblast cells surrounding the tumor express increased levels of CYP19 mRNA due to a decrease of I.4 promoter activity and an increase of PII, I.3, and I.7 promoter activity. Little is known about the effects of environmental chemicals on the promoter-specific CYP19 expression. OBJECTIVE: We aimed to determine the effects of two neonicotinoids (thiacloprid and imidacloprid) on promoter-specific CYP19 expression in Hs578t breast cancer cells and understand the signaling pathways involved. METHODS: Hs578t cells were exposed to various signaling pathway stimulants or neonicotinoids for 24 h. Promoter-specific expression of CYP19 was determined by real-time quantitative polymerase chain reaction and catalytic activity of aromatase by tritiated water release assay. RESULTS: To our knowledge, we are the first to demonstrate that the normal I.4 promoter and the breast cancer-relevant PII, I.3, and I.7 promoters of CYP19 are active in these cells. We found that the expression of CYP19 via promoters PII, I.3, and I.7 in Hs578t cells was, in part, dependent on the activation of two VEGF signaling pathways: mitogen-activated protein kinase (MAPK) 1/3 and phospholipase C (PLC). Exposure of Hs578t cells to environmental concentrations of imidacloprid and thiacloprid resulted in a switch in CYP19 promoter usage, involving inhibition of I.4 promoter activity and an increase of PII, I.3, and I.7 promoter-mediated CYP19 expression and aromatase catalytic activity. Greater effects were seen at lower concentrations. Our results suggest that thiacloprid and imidacloprid exert their effects at least partially by inducing the MAPK 1/3 and/or PLC pathways. CONCLUSIONS: We demonstrated in vitro that neonicotinoids may stimulate a change in CYP19 promoter usage similar to that observed in patients with hormone dependent breast cancer. https://doi.org/10.1289/EHP2698. PMID- 29701944 TI - Biosynthesis of t-Butyl in Apratoxin A: Functional Analysis and Architecture of a PKS Loading Module. AB - The unusual feature of a t-butyl group is found in several marine-derived natural products including apratoxin A, a Sec61 inhibitor produced by the cyanobacterium Moorea bouillonii PNG 5-198. Here, we determine that the apratoxin A t-butyl group is formed as a pivaloyl acyl carrier protein (ACP) by AprA, the polyketide synthase (PKS) loading module of the apratoxin A biosynthetic pathway. AprA contains an inactive "pseudo" GCN5-related N-acetyltransferase domain (PsiGNAT) flanked by two methyltransferase domains (MT1 and MT2) that differ distinctly in sequence. Structural, biochemical, and precursor incorporation studies reveal that MT2 catalyzes unusually coupled decarboxylation and methylation reactions to transform dimethylmalonyl-ACP, the product of MT1, to pivaloyl-ACP. Further, pivaloyl-ACP synthesis is primed by the fatty acid synthase malonyl acyltransferase (FabD), which compensates for the PsiGNAT and provides the initial acyl-transfer step to form AprA malonyl-ACP. Additionally, images of AprA from negative stain electron microscopy reveal multiple conformations that may facilitate the individual catalytic steps of the multienzyme module. PMID- 29701945 TI - Versatile Platform for Nanoparticle Surface Bioengineering Based on SiO2-Binding Peptide and Proteinaceous Barnase*Barstar Interface. AB - Nanoparticle surface engineering can change its chemical identity to enable surface coupling with functional biomolecules. However, common surface coupling methods such as physical adsorption or chemical conjugation often suffer from the low coupling yield, poorly controllable orientation of biomolecules, and steric hindrance during target binding. These issues limit the application scope of nanostructures for theranostics and personalized medicine. To address these shortfalls, we developed a rapid and versatile method of nanoparticle biomodification. The method is based on a SiO2-binding peptide that binds to the nanoparticle surface and a protein adaptor system, Barnase*Barstar protein pair, serving as a "molecular glue" between the peptide and the attached biomolecule. The biomodification procedure shortens to several minutes, preserves the orientation and functions of biomolecules, and enables control over the number and ratio of attached molecules. The capabilities of the proposed biomodification platform were demonstrated by coupling different types of nanoparticles with DARPin9.29 and 4D5scFv-molecules that recognize the human epidermal growth factor receptor 2 (HER2/neu) oncomarker-and by subsequent highly selective immunotargeting of the modified nanoparticles to different HER2/neu overexpressing cancer cells in one-step or two-step (by pretargeting with HER2/neu-recognizing molecule) modes. The method preserved the biological activity of the DARPin9.29 molecules attached to a nanoparticle, whereas the state-of-the-art carbodiimide 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/ N hydroxysulfosuccinimide method of conjugation led to a complete loss of the functional activity of the DARPin9.29 nanoparticle-protein complex. Moreover, the method allowed surface design of nanoparticles that selectively interacted with antigens in complex biological fluids, such as whole blood. The demonstrated capabilities show this method to be a promising alternative to commonly used chemical conjugation techniques in nanobiotechnology, theranostics, and clinical applications. PMID- 29701946 TI - Electronic Cortisol Detection Using an Antibody-Embedded Polymer Coupled to a Field-Effect Transistor. AB - A field-effect transistor-based cortisol sensor was demonstrated in physiological conditions. An antibody-embedded polymer on the remote gate was proposed to overcome the Debye length issue (lambdaD). The sensing membrane was made by linking poly(styrene- co-methacrylic acid) (PSMA) with anticortisol before coating the modified polymer on the remote gate. The embedded receptor in the polymer showed sensitivity from 10 fg/mL to 10 ng/mL for cortisol and a limit of detection (LOD) of 1 pg/mL in 1* PBS where lambdaD is 0.2 nm. A LOD of 1 ng/mL was shown in lightly buffered artificial sweat. Finally, a sandwich ELISA confirmed the antibody binding activity of antibody-embedded PSMA. PMID- 29701947 TI - Photochemical Control of Exciton Superradiance in Light-Harvesting Nanotubes. AB - Photosynthetic antennae and organic electronic materials use topological, structural, and molecular control of delocalized excitons to enhance and direct energy transfer. Interactions between the transition dipoles of individual chromophore units allow for coherent delocalization across multiple molecular sites. This delocalization, for specific geometries, greatly enhances the transition dipole moment of the lowest energy excitonic state relative to the chromophore and increases its radiative rate, a phenomenon known as superradiance. In this study, we show that ordered, self-assembled light harvesting nanotubes (LHNs) display excitation-induced photobrightening and photodarkening. These changes in quantum yield arise due to changes in energetic disorder, which in turn increases/decreases excitonic superradiance. Through a combination of experiment and modeling, we show that intense illumination induces different types of chemical change in LHNs that reproducibly alter absorption and fluorescence properties, indicating control over excitonic delocalization. We also show that changes in spectral width and shift can be sensitive measures of system dimensionality, illustrating the mixed 1-2D nature of LHN excitons. Our results demonstrate a path forward for mastery of energetic disorder in an excitonic antenna, with implications for fundamental studies of coherent energy transport. PMID- 29701948 TI - Enhanced Photocatalytic Activity of TiO2 Nanoparticles Supported on Electrically Polarized Hydroxyapatite. AB - Fast recombination of photogenerated charge carriers in titanium dioxide (TiO2) remains a challenging issue, limiting the photocatalytic activity. This study demonstrates increased photocatalytic performance of TiO2 nanoparticles supported on electrically polarized hydroxyapatite (HA) films. Dense and thermally stable yttrium and fluorine co-doped HA films with giant internal polarization were synthesized as photocatalyst supports. TiO2 nanoparticles deposited on the support were then used to catalyze the photochemical reduction of aqueous silver ions to produce silver nanoparticles. It was found that significantly more silver nanoparticles were produced on polarized HA supports than on depolarized HA supports. In addition, the photodegradation of methyl orange with TiO2 nanoparticles on polarized HA supports was found to be much faster than with TiO2 nanoparticles on depolarized HA supports. It is proposed that separation of photogenerated electrons and holes in TiO nanoparticles is promoted by the internal polarization of the HA support, and consequently, the recombination of charge carriers is mitigated. The results imply that materials with large internal polarization can be used in strategies for enhancing quantum efficiency of photocatalysts. PMID- 29701949 TI - A Sensitive Near-Infrared Fluorescent Sensor for Mitochondrial Hydrogen Sulfide. AB - Hydrogen sulfide (H2S) is an important gasotransmitter. Although a large number of fluorescent probes for cellular H2S have been reported, only a few can detect H2S in mitochondria, a cellular organelle connecting H2S with mitochondrial function and metabolic pathways. We hereby describe a novel near-infrared fluorescent probe, nimazide, by introducing sulfonyl azide to the core structure of a QSY-21 dark quencher. Nimazide responded quickly to H2S, resulting in robust fluorescence turn-off changes. This conversion displayed high specificity and fast kinetics. More impressively, we observed a robust fluorescence decrease in live cells loaded with mitochondrial nimazide in response to extracellular addition of nanomolar H2S, and successfully imaged biologically generated mitochondrial H2S in live mammalian cells. Nimazide is one of the most sensitive fluorescent probes for mitochondrial H2S. PMID- 29701950 TI - Rational Design and Development of Lanthanide-Doped NaYF4@CdS-Au-RGO as Quaternary Plasmonic Photocatalysts for Harnessing Visible-Near-Infrared Broadband Spectrum. AB - Utilization of the total solar spectrum efficiently for photocatalysis has remained a huge challenge for a long time. However, designing a system by rationally combining nanocomponents with complementary properties, such as upconversion nanoparticles, semiconductors, plasmonic metals, and carbonaceous support, offers a promising route for efficient utilization of solar energy by harnessing the broadband spectrum. In this work, a series of novel quaternary plasmonic photocatalysts comprising of lanthanide-doped NaYF4@CdS (UC) core-shell nanostructures decorated with Au nanoparticles (Au NPs) supported on reduced graphene oxide (RGO) nanosheets were prepared using the multistep hydrothermal method. The different components of the prepared nanocomposites could be efficiently employed to utilize both the visible and near-infrared (NIR) regions. Specifically in this work, the utility of these quaternary nanocomposites for photocatalytic degradation of a colorless pharmaceutical pollutant, ciprofloxacin, under visible and NIR light irradiations has been demonstrated. In comparison to bare counterparts, our quaternary nanocomposites exhibit an enhanced photocatalytic activity attributable to the synergistic effect of different components arranged in such a way that favors harnessing energy from the broad spectral region and efficient charge separation. The combination of upconversion and plasmonic properties along with the advantages of a carbonaceous support can provide new physical insights for further development of photocatalysts, which could utilize the broadband spectrum. PMID- 29701952 TI - Photoresponsive Drug/Gene Delivery Systems. AB - Light as an external stimulus can be precisely manipulated in terms of irradiation time, site, wavelength, and density. As such, photoresponsive drug/gene delivery systems have been increasingly pursued and utilized for the spatiotemporal control of drug/gene delivery to enhance their therapeutic efficacy and safety. In this review, we summarized the recent research progress on photoresponsive drug/gene delivery, and two major categories of delivery systems were discussed. The first category is the direct responsive systems that experience photoreactions on the vehicle or drug themselves, and different materials as well as chemical structures responsive to UV, visible, and NIR light are summarized. The second category is the indirect responsive systems that require a light-generated mediator signal, such as heat, ROS, hypoxia, and gas molecules, to cascadingly trigger the structural transformation. The future outlook and challenges are also discussed at the end. PMID- 29701951 TI - Mechanism of Integrated beta-Lactam Formation by a Nonribosomal Peptide Synthetase during Antibiotic Synthesis. AB - Modular nonribosomal peptide synthetases (NRPSs) are large, multidomain engines of bioactive natural product biosynthesis that function as molecular "assembly lines" in which monomer units are selectively bound, modified, and linked in a specific order and number dictated by their mega-enzyme templates. Recently, a condensation domain in an NRPS was discovered to carry out the synthesis of an integrated beta-lactam ring from a substrate seryl residue during antibiotic biosynthesis. We report here a series of experiments supporting a mechanism that involves C-N bond formation by stepwise elimination/addition reactions followed by canonical NRPS-catalyzed amide bond synthesis to achieve beta-lactam formation. Partitioning of reactive intermediates formed during the multistep catalytic cycle provided insight into the ability of the NRPS to overcome the reversibility of corresponding reactions in solution and enforce directionality during synthesis. PMID- 29701953 TI - Fully Rollable Lead-Free Poly(vinylidene fluoride)-Niobate-Based Nanogenerator with Ultra-Flexible Nano-Network Electrodes. AB - A fully rollable nanocomposite-based nanogenerator (NCG) is developed by integrating a lead-free piezoelectric hybrid layer with a type of nanofiber supported silver nanowire (AgNW) network as electrodes. The thin-film nanocomposite is composed of electroactive polyvinylidene fluoride (PVDF) polymer matrix and compositionally modified potassium sodium niobate-based nanoparticles (NPs) with a high piezoelectric coefficient ( d33) of 53 pm/V, which is revealed by the piezoresponse force microscopy measurements. Under periodical agitation at a compressive force of 50 N and 1 Hz, the NCG can steadily render high electric output up to an open-circuit voltage of 18 V and a short-circuit current of 2.6 MUA. Of particular importance is the decent rollability of the NCG, as indicated by the negligible decay in the electric output after it being repeatedly rolled around a gel pen for 200 cycles. Besides, the biocompatible NCG can potentially be used to scavenge biomechanical energy from low-frequency human motions, as demonstrated by the scenarios of walking and elbow joint movement. These results rationally expand the feasibility of the developed NCG toward applications in lightweight, diminutive, and multifunctional rollable or wearable electronic devices. PMID- 29701954 TI - Neuronal Calcium Recording with an Engineered TEV Protease. AB - Technologies for measuring the transient Ca2+ spikes that accompany neural signaling have revolutionized our understanding of the brain. Nevertheless, microscopic visualization of Ca2+ spikes on the time scale of neural activity across large brain regions or in thick specimens remains a significant challenge. The recent development of stable integrators of Ca2+, instead of transient reporters, provides an avenue to investigate neural signaling in otherwise challenging systems. Here, we describe an engineered Ca2+-sensing enzyme consisting of a split Tobacco Etch Virus (TEV) protease with each half tethered to a calmodulin or M13 Ca2+ binding domain. This Split TEV, Ca2+ Activated Neuron Recorder (SCANR) remains separate and catalytically incompetent until a spike in cellular Ca2+ triggers its reconstitution and the subsequent turnover of a caged, genetically encoded reporter substrate. We report the identification of a successful Ca2+-sensing split TEV from a library of chimeras and deployment of the enzyme in primary rat hippocampal neurons. PMID- 29701955 TI - Influence of Smoking Puff Parameters and Tobacco Varieties on Free Radicals Yields in Cigarette Mainstream Smoke. AB - Cigarette smoke is a major exogenous source of free radicals, and the resulting oxidative stress is one of the major causes of smoking-caused diseases. Yet, many of the factors that impact free radical delivery from cigarettes remain unclear. In this study, we machine-smoked cigarettes and measured the levels of gas- and particulate-phase radicals by electron paramagnetic resonance (EPR) spectroscopy using standardized smoking regimens (International Organization of Standardization (ISO) and Canadian Intense (CI)), puffing parameters, and tobacco blends. Radical delivery per cigarette was significantly greater in both gas (4 fold) and particulate (6-fold) phases when cigarettes were smoked under the CI protocol compared to the ISO protocol. Total puff volume per cigarette was the major factor with radical production being proportional to total volume, regardless of whether volume differences were achieved by changes in individual puff volume or puff frequency. Changing puff shape (bell vs sharp vs square) or puff duration (1-5 s), without changing volume, had no effect on radical yields. Tobacco variety did have a significant impact on free radical production, with gas-phase radicals highest in reconstituted > burley > oriental > bright tobacco and particulate-phase radicals highest in burley > bright > oriental > reconstituted tobacco. Our findings show that modifiable cigarette design features and measurable user smoking behaviors are key factors determining free radical exposure in smokers. PMID- 29701956 TI - Ultrathin Piezotronic Transistors with 2 nm Channel Lengths. AB - Because silicon transistors are rapidly approaching their scaling limit due to short-channel effects, alternative technologies are urgently needed for next generation electronics. Here, we demonstrate ultrathin ZnO piezotronic transistors with a ~2 nm channel length using inner-crystal self-generated out-of plane piezopotential as the gate voltage to control the carrier transport. This design removes the need for external gate electrodes that are challenging at nanometer scale. These ultrathin devices exhibit a strong piezotronic effect and excellent pressure-switching characteristics. By directly converting mechanical drives into electrical control signals, ultrathin piezotronic devices could be used as active nanodevices to construct the next generation of electromechanical devices for human-machine interfacing, energy harvesting, and self-powered nanosystems. PMID- 29701958 TI - High Voltage Magnesium-ion Battery Enabled by Nanocluster Mg3Bi2 Alloy Anode in Noncorrosive Electrolyte. AB - Currently, developing high voltage (beyond 2 V) rechargeable Mg-ion batteries still remains a great challenge owing to the limit of corrosive electrolyte and low compatibility of anode material. Here we report a facile one step solid state alloying route to synthesize nanoclustered Mg3Bi2 alloy as a high-performance anode to build up a 2 V Mg-ion battery using noncorrosive electrolyte. The fabricated nanoclustered Mg3Bi2 anode delivers a high reversible specific capacity (360 mAh g-1) with excellent stability (90.7% capacity retention over 200 cycles) and high Coulombic efficiency (average 98%) at 0.1 A g-1. The good performance is attributed to the stable nanostructures, which effectively accommodate the reversible Mg2+ ion insertion/deinsertion without losing electric contact among clusters. Significantly, the nanoclustered Mg3Bi2 anode can be coupled with high voltage cathode Prussian Blue to assemble a full cell using noncorrosive electrolyte, showing a stable cycling (88% capacity retention over 200 cycles at 0.2 A g-1) and good rate capability (103 mAh g-1 at 0.1 A g-1 and 58 mAh g-1 at 2 A g-1). The energy and power density of the as-fabricated full cell can reach up to 81 Wh kg-1 and 2850 W kg-1, respectively, which are both the highest values among the reported Mg-ion batteries using noncorrosive electrolytes. This study demonstrates a cost-effective route to fabricate stable and high voltage rechargeable Mg-ion battery potentially for grid-scale energy storage. PMID- 29701957 TI - A Novel M1 PAM VU0486846 Exerts Efficacy in Cognition Models without Displaying Agonist Activity or Cholinergic Toxicity. AB - Selective activation of the M1 subtype of muscarinic acetylcholine receptor, via positive allosteric modulation (PAM), is an exciting strategy to improve cognition in schizophrenia and Alzheimer's disease patients. However, highly potent M1 ago-PAMs, such as MK-7622, PF-06764427, and PF-06827443, can engender excessive activation of M1, leading to agonist actions in the prefrontal cortex (PFC) that impair cognitive function, induce behavioral convulsions, and result in other classic cholinergic adverse events (AEs). Here, we report a fundamentally new and highly selective M1 PAM, VU0486846. VU0486846 possesses only weak agonist activity in M1-expressing cell lines with high receptor reserve and is devoid of agonist actions in the PFC, unlike previously reported ago-PAMs MK-7622, PF-06764427, and PF-06827443. Moreover, VU0486846 shows no interaction with antagonist binding at the orthosteric acetylcholine (ACh) site (e.g., neither bitopic nor displaying negative cooperativity with [3H]-NMS binding at the orthosteric site), no seizure liability at high brain exposures, and no cholinergic AEs. However, as opposed to ago-PAMs, VU0486846 produces robust efficacy in the novel object recognition model of cognitive function. Importantly, we show for the first time that an M1 PAM can reverse the cognitive deficits induced by atypical antipsychotics, such as risperidone. These findings further strengthen the argument that compounds with modest in vitro M1 PAM activity (EC50 > 100 nM) and pure-PAM activity in native tissues display robust procognitive efficacy without AEs mediated by excessive activation of M1. Overall, the combination of compound assessment with recombinant in vitro assays (mindful of receptor reserve), native tissue systems (PFC), and phenotypic screens (behavioral convulsions) is essential to fully understand and evaluate lead compounds and enhance success in clinical development. PMID- 29701959 TI - Prebiotic Mannan-Oligosaccharides Augment the Hypoglycemic Effects of Metformin in Correlation with Modulating Gut Microbiota. AB - Type 2 diabetes (T2D) induced by obesity and high-fat diet is significantly associated with gut microbiota dysbacteriosis. Because the first line clinical medicine of metformin has several intestinal drawbacks, combination usage of metformin with a prebiotic of konjac mannan-oligosaccharides (MOS) was conceived and implemented aiming to investigate whether there were some intestinal synergetic effects and how MOS would function. Composite treatment of metformin and MOS demonstrated synergistic effects on ameliorating insulin resistance and glucose tolerance, also on repairing islet and hepatic histology. In addition, MF+MOS altered the gut community composition and structure by decreasing the relative abundances of family Rikenellaceae and order Clostridiales while increasing an unnamed OTU05945 of family S24-7, Akkermansia muciniphila, and Bifidobacterium pseudolongum. The present study suggested that usage of MOS could augment the hypoglycemic effects of metformin in association with gut microbiota modulation, which could provide references for further medication. PMID- 29701960 TI - DFT Study on the Mechanism of Hydrogen Storage Based on the Formate-Bicarbonate Equilibrium Catalyzed by an Ir-NHC Complex: An Elusive Intramolecular C-H Activation. AB - A novel iridium based, water-soluble phosphine-NHC (N-heterocyclic carbene) complex, Na2[Ir( emim)(eta4-COD)( mtppts)] was previously developed in our research group. It was shown that it is a very effective catalyst for the reversible storage of hydrogen based on the formate-bicarbonate equilibrium. In this paper, we present a DFT investigation on the noninnocent behavior of the NHC ligand toward C-H activation of the N-ethyl side chain and its possible role in the hydrogen storage mechanism. After preliminary investigations, using both computations and NMR measurements, we conclude that the COD ligand leaves the precatalyst irreversibly and the C-H activation takes place on a monophosphine complex. Two main pathways are considered in which the active Ir(III) complexes are generated differently: One is the cyclometalation path involving the ethyl side chain, the other is the oxidative addition step of a water molecule which has a higher barrier but provide a more stable starting state. We find that though the latter, a catalytic cycle where a hydride is abstracted from formate and gets protonated by solvent molecules gives the lowest calculated energy barrier, +25.8 kcal mol-1. That is, avoiding further redox processes is preferred. There are other pathways involving thermodynamically accessible C-H activated iridacycles but those involve slightly higher overall activation barriers due to the required Ir(I)/Ir(III) transitions. The cycle which involves only iridacycle intermediates offer the lowest energy span (energy difference calculated between only the highest and lowest energy points inside the cycle), however. Together with the experimental results, this implies that C-H activation of the N-ethyl side chain happens off-cycle or the starting solvent addition step of the dominant pathway is blocked kinetically. We also discuss the hydrogen uptake reaction catalyzed by cyclometalated species where the reduction of CO2 is preferred over reversing the first main cycle. PMID- 29701962 TI - Design, Synthesis, and Testing of Potent, Selective Hepsin Inhibitors via Application of an Automated Closed-Loop Optimization Platform. AB - Hepsin is a membrane-anchored serine protease whose role in hepatocyte growth factor (HGF) signaling and epithelial integrity makes it a target of therapeutic interest in carcinogenesis and metastasis. Using an integrated design, synthesis, and screening platform, we were able to rapidly develop potent and selective inhibitors of hepsin. In progressing from the initial hit 7 to compound 53, the IC50 value against hepsin was improved from ~1 MUM to 22 nM, and the selectivity over urokinase-type plasminogen activator (uPA) was increased from 30-fold to >6000-fold. Subsequent in vitro ADMET profiling and cellular studies confirmed that the leading compounds are useful tools for interrogating the role of hepsin in breast tumorigenesis. PMID- 29701961 TI - Post-Translational Tyrosine Geranylation in Cyanobactin Biosynthesis. AB - Prenylation is a widespread modification that improves the biological activities of secondary metabolites. This reaction also represents a key modification step in biosyntheses of cyanobactins, a family of ribosomally synthesized and post translationally modified peptides (RiPPs) produced by cyanobacteria. In cyanobactins, amino acids are commonly isoprenylated by ABBA prenyltransferases that use C5 donors. Notably, mass spectral analysis of piricyclamides from a fresh-water cyanobacterium suggested that they may instead have a C10 geranyl group. Here we characterize a novel geranyltransferase involved in piricyclamide biosynthesis. Using the purified enzyme, we show that the enzyme PirF catalyzes Tyr O-geranylation, which is an unprecedented post-translational modification. In addition, the combination of enzymology and analytical chemistry revealed the structure of the final natural product, piricyclamide 7005E1, and the regioselectivity of PirF, which has potential as a synthetic biological tool providing drug-like properties to diverse small molecules. PMID- 29701963 TI - Poecillastrin H, a Chondropsin-Type Macrolide with a Conjugated Pentaene Moiety, from a Characella sp. Marine Sponge. AB - Poecillastrin H (1), a chondropsin-type macrolide with a conjugated pentaene moiety, was isolated from the Characella sp. marine sponge. The planar structure of 1 was elucidated by analysis of spectroscopic data. The absolute configuration of the beta-hydroxyaspartic acid residue (beta-OHAsp) was determined to be d- threo by Marfey's analysis, and the mode of lactone ring formation through the OHAsp residue was determined by chemical degradation. Poecillastrin H was extremely sensitive toward light and showed potent cytotoxic activity against 3Y1 cells with an IC50 value of 4.1 nM. PMID- 29701964 TI - Phytoremediation Reduces Dust Emissions from Metal(loid)-Contaminated Mine Tailings. AB - Environmental and health risk concerns relating to airborne particles from mining operations have focused primarily on smelting activities. However, there are only three active copper smelters and less than a dozen smelters for other metals compared to an estimated 500000 abandoned and unreclaimed hard rock mine tailings in the US that have the potential to generate dust. The problem can also extend to modern tailings impoundments, which may take decades to build and remain barren for the duration before subsequent reclamation. We examined the impact of vegetation cover and irrigation on dust emissions and metal(loid) transport from mine tailings during a phytoremediation field trial at the Iron King Mine and Humboldt Smelter Superfund (IKMHSS) site. Measurements of horizontal dust flux following phytoremediation reveals that vegetated plots with 16% and 32% canopy cover enabled an average dust deposition of 371.7 and 606.1 g m-2 y-1, respectively, in comparison to the control treatment which emitted dust at an average rate of 2323 g m-2 y-1. Horizontal dust flux and dust emissions from the vegetated field plots are comparable to emission rates in undisturbed grasslands. Further, phytoremediation was effective at reducing the concentration of fine particulates, including PM1, PM2.5, and PM4, which represent the airborne particulates with the greatest health risks and the greatest potential for long distance transport. This study demonstrates that phytoremediation can substantially decrease dust emissions as well as the transport of windblown contaminants from mine tailings. PMID- 29701965 TI - Reaction Mechanism and Kinetics for Ammonia Synthesis on the Fe(111) Surface. AB - The Haber-Bosch industrial process for synthesis of ammonia (NH3) from hydrogen and nitrogen produces the millions of tons of ammonia gas annually needed to produce nitrates for fertilizers required to feed the earth's growing populations. This process has been optimized extensively, but it still uses enormous amounts of energy (2% of the world's supply), making it essential to dramatically improve its efficiency. To provide guidelines to accelerate this improvement, we used quantum mechanics to predict reaction mechanisms and kinetics for NH3 synthesis on Fe(111)-the best Fe single crystal surface for NH3 synthesis. We predicted the free energies of all reaction barriers for all steps in the mechanism and built these results into a kinetic Monte Carlo model for predicting steady state catalytic rates to compare with single-crystal experiments at 673 K and 20 atm. We find excellent agreement with a predicted turnover frequency (TOF) of 17.7 s-1 per 2 * 2 site (5.3 * 10-9 mol/cm2/sec) compared to TOF = 10 s-1 per site from experiment. PMID- 29701966 TI - Phage Display of Dynamic Covalent Binding Motifs Enables Facile Development of Targeted Antibiotics. AB - Antibiotic resistance of bacterial pathogens poses an increasing threat to the wellbeing of our society and urgently calls for new strategies for infection diagnosis and antibiotic discovery. The antibiotic resistance problem at least partially arises from extensive use of broad-spectrum antibiotics. Ideally, for the treatment of infection, one would like to use a narrow-spectrum antibiotic that specifically targets and kills the disease-causing strain. This is particularly important considering the commensal bacterial species that are beneficial and sometimes even critical to the health of a human being. In this contribution, we describe a phage display platform that enables rapid identification of peptide probes for specific bacterial strains. The phage library described herein incorporates 2-acetylphenylboronic acid moieties to elicit dynamic covalent binding to the bacterial cell surface. Screening of the library against live bacterial cells yields submicromolar and highly specific binders for clinical strains of Staphylococcus aureus and Acinetobacter baumannii that display antibiotic resistance. We further show that the identified peptide probes can be readily converted to bactericidal agents that deliver generic toxins to kill the targeted bacterial strain with high specificity. The phage display platform described here is applicable to a wide array of bacterial strains, paving the way to facile diagnosis and development of strain-specific antibiotics. PMID- 29701967 TI - Development of Functional or Medical Foods for Oral Administration of Insulin for Diabetes Treatment: Gastroprotective Edible Microgels. AB - Insulin and an antacid [Mg(OH)2] were co-encapsulated inside calcium alginate microgels (diameter = 280 MUm) using a vibrating nozzle injector. Confocal microscopy indicated that insulin was successfully encapsulated inside the microgels and remained inside them after they were exposed to simulated gastric conditions. Localized fluorescence intensity measurements indicated that the internal pH of the antacid-loaded microgels was around pH 7.4 after incubation in acidic gastric fluids but below the limit of detection (pH < 4) in the antacid free microgels. After incubation in small intestine conditions, around 30% of the insulin was released from the antacid-loaded microgels over a 2 h period. Encapsulation of insulin within the antacid-loaded microgels increased its biological activity after exposure to simulated gastric conditions. In particular, the encapsulated insulin significantly increased Akt phosphorylation at both Thr308 and Ser473 in L6 myotubes when compared to free insulin. PMID- 29701968 TI - Controlling Vertical and Lateral Electron Migration Using a Bifunctional Chromophore Assembly in Dye-Sensitized Photoelectrosynthesis Cells. AB - Integration of photoresponsive chromophores that initiate multistep catalysis is essential in dye-sensitized photoelectrosynthesis cells and related devices. We describe here an approach that incorporates a chromophore assembly surface-bound to metal oxide electrodes for light absorption with an overlayer of catalysts for driving the half-reactions of water splitting. The assembly is a combination of a core-twisted perylene diimide and a ruthenium polypyridyl complex. By altering the connection sequence of the two subunits in the assembly, in their surface binding to either TiO2 or NiO, the assembly can be tuned to convert visible light into strongly oxidizing equivalents for activation of an electrodeposited water oxidation catalyst (NiCo2O x) at the photoanode, or reducing equivalents for activation of an electrodeposited water reduction catalyst (NiMo0.05S x) at the photocathode. A key element in the design of the photoelectrodes comes from the synergistic roles of the vertical (interlayer) charge transfer and lateral (intralayer) charge hopping in determining overall cell efficiencies for photoelectrocatalysis. PMID- 29701969 TI - pH-Dependent Bioavailability, Speciation, and Phytotoxicity of Tungsten (W) in Soil Affect Growth and Molybdoenzyme Activity of Nodulated Soybeans. AB - Increasing use of tungsten (W)-based products opened new pathways for W into environmental systems. Due to its chemical alikeness with molybdenum (Mo), W is expected to behave similarly to its "twin element", Mo; however, our knowledge of the behavior of W in the plant-soil environment remains inadequate. The aim of this study was to investigate plant growth as well as W and nutrient uptake depending on soil chemical properties such as soil pH and texture. Soybean ( Glycine max cv. Primus) was grown on two acidic soils differing in soil texture that were either kept at their natural soil pH (pH of 4.5-5) or limed (pH of >=7) and amended with increasing concentrations of metallic W (control and 500 and 5000 mg kg-1). In addition, the activity of molybdoenzymes involved in N assimilation (nitrate reductase) and symbiotic N2 fixation (nitrogenase) was also investigated. Our results showed that the risk of W entering the food web was significantly greater in high-pH soils due to increased solubility of mainly monomeric W. The effect of soil texture on W solubility and phytoavailability was less pronounced compared to soil pH. Particularly at intermediate W additions (W 500 mg kg-1), symbiotic nitrogen fixation was able to compensate for reduced leaf nitrate reductase activity. When W soil solution concentrations became too toxic (W 5000 mg kg-1), nodulation was more strongly inhibited than nitrogenase activity in the few nodules formed, suggesting a more-efficient detoxification and compartmentalization mechanism in nodules than in soybean leaves. The increasing presence of polymeric W species observed in low-pH soils spiked with high W concentrations resulted in decreased W uptake. Simultaneously, polymeric W species had an overall negative effect on nutrient assimilation and plant growth, suggesting a greater phytotoxicity of W polymers. Our study demonstrates the importance of accounting for soil pH in risk assessment studies of W in the plant soil environment, something that has been completely neglected in the past. PMID- 29701970 TI - [2]Catenanes Displaying Switchable Gin-Trap-Like Motion. AB - Sodium ion-controlled switching from "folded" to "linear" states results in significant changes in the molecular shape of a [2]catenane, such that it mimics the operation of a gin trap, with a fluorescent alarm signal appearing when pyrene side arms were present on its two macrocyclic components. PMID- 29701971 TI - Chiral Bifunctional Thioureas and Squaramides and Their Copolymers as Recoverable Organocatalysts. Stereoselective Synthesis of 2-Substituted 4-Amino-3 nitrobenzopyrans and 3-Functionalized 3,4-Diamino-4 H-Chromenes. AB - Novel styryl-substituted thioureas and squaramides were obtained in three steps from commercially available 4-hydroxy-3,5-dichloroaniline. These organocatalysts promote cascade reactions in high yields and excellent stereoselection. By using only a 5 mol % loading of catalyst, it is possible to obtain 2,3,4-trisubstituted benzopyrans by reaction of alpha-amido sulfones derived from salicyladehydes and nitrostyrenes or 2,3,4-trisubstituted 4 H-chromenes by reaction of the same alpha amido sulfones with (phenylsulfonyl)acetonitrile in excellent diastereo- and enantioselectivities. Two polymeric thioureas and squaramides were prepared by copolymerization of the best monomeric catalysts with styrene and divinylbenzene and used for the same transformations. These polymers behave also as excellent stereoselective catalysts that can be recovered and reused for five cycles. PMID- 29701972 TI - Characterization of Brominated Disinfection Byproducts Formed During the Chlorination of Aquaculture Seawater. AB - Although brominated disinfection byproducts (Br-DBPs) have been reported to form from reactions between bromide, dissolved organic matter (DOM), and disinfectants, their formation during the disinfection of aquaculture seawater via chlorination has been rarely studied. Herein, after 5 days of disinfection of raw aquaculture seawater samples with sodium dichloroisocyanurate (NaDDC), trichloroisocyanuric acid (TCCA) and chlorine dioxide (ClO2), 181, 179, and 37 Br DBPs were characterized by ultrahigh-resolution Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR MS). Sunlight irradiation of the chlorinated aquaculture seawater with TCCA and NaDDC was found to reduce the formation of Br DBPs, possibly due to the photodegradation of the important HBrO/HClO intermediate and the degradation of formed Br-DBPs. The formation of Br-DBPs chlorinated by ClO2 increased under sunlight irradiation. The number of Br-DBPs formed during chlorination processes agreed well with the total organic bromine (TOBr) content measured by inductively coupled plasma mass spectrometry (ICP-MS). Most of the Br-DBPs were highly unsaturated and phenolic compounds, which were primarily generated through electrophilic substitution by bromine coupled with other reactions. In addition, some emerging aromatic Br-DBPs with high relative intensities were also assigned, and these compounds might be highly lipophilic and could potentially accumulate in marine organisms. Our findings call for further focus on and investigation of the Br-DBPs produced in chlorinated aquaculture seawater. PMID- 29701973 TI - Conformal Regression for Quantitative Structure-Activity Relationship Modeling Quantifying Prediction Uncertainty. AB - Making predictions with an associated confidence is highly desirable as it facilitates decision making and resource prioritization. Conformal regression is a machine learning framework that allows the user to define the required confidence and delivers predictions that are guaranteed to be correct to the selected extent. In this study, we apply conformal regression to model molecular properties and bioactivity values and investigate different ways to scale the resultant prediction intervals to create as efficient (i.e., narrow) regressors as possible. Different algorithms to estimate the prediction uncertainty were used to normalize the prediction ranges, and the different approaches were evaluated on 29 publicly available data sets. Our results show that the most efficient conformal regressors are obtained when using the natural exponential of the ensemble standard deviation from the underlying random forest to scale the prediction intervals, but other approaches were almost as efficient. This approach afforded an average prediction range of 1.65 pIC50 units at the 80% confidence level when applied to bioactivity modeling. The choice of nonconformity function has a pronounced impact on the average prediction range with a difference of close to one log unit in bioactivity between the tightest and widest prediction range. Overall, conformal regression is a robust approach to generate bioactivity predictions with associated confidence. PMID- 29701975 TI - Characterizing the Biochemical Response to Schistosoma mansoni Infection and Treatment with Praziquantel in Preschool and School Aged Children. AB - Schistosomiasis is a widespread chronic neglected tropical disease prevalent mostly in children in under-resourced rural areas. Its pathological effects have been clinically characterized, yet the molecular-level effects are understudied. In this study, the biochemical effects of Schistosoma mansoni infection and praziquantel treatment were studied in 130 preschool aged and 159 school aged infected children and 11 noninfected children in Azaguie, Cote d'Ivoire. Urine samples were collected prior to receiving 20, 40, or 60 mg/kg of praziquantel or a placebo, as well as 24 h post-treatment, and at the 3-week follow up. Urinary metabolic phenotypes were measured using 1H NMR spectroscopy, and metabolic variation associated with S. mansoni infection and praziquantel administration was identified using multivariate statistical techniques. Discriminatory metabolic signatures were detected between heavily infected and noninfected children at baseline as well as according to the dose of praziquantel administered 24 h post treatment. These signatures were primarily associated with the metabolic activity of the gut microbiota, gut health and growth biomarkers and energy and liver metabolism. These analyses provide insights into the metabolic phenotype of schistosomiasis and treatment with praziquantel in two important demographics. PMID- 29701974 TI - Understanding InP Nanowire Array Solar Cell Performance by Nanoprobe-Enabled Single Nanowire Measurements. AB - III-V solar cells in the nanowire geometry might hold significant synthesis-cost and device-design advantages as compared to thin films and have shown impressive performance improvements in recent years. To continue this development there is a need for characterization techniques giving quick and reliable feedback for growth development. Further, characterization techniques which can improve understanding of the link between nanowire growth conditions, subsequent processing, and solar cell performance are desired. Here, we present the use of a nanoprobe system inside a scanning electron microscope to efficiently contact single nanowires and characterize them in terms of key parameters for solar cell performance. Specifically, we study single as-grown InP nanowires and use electron beam induced current characterization to understand the charge carrier collection properties, and dark current-voltage characteristics to understand the diode recombination characteristics. By correlating the single nanowire measurements to performance of fully processed nanowire array solar cells, we identify how the performance limiting parameters are related to growth and/or processing conditions. We use this understanding to achieve a more than 7-fold improvement in efficiency of our InP nanowire solar cells, grown from a different seed particle pattern than previously reported from our group. The best cell shows a certified efficiency of 15.0%; the highest reported value for a bottom-up synthesized InP nanowire solar cell. We believe the presented approach have significant potential to speed-up the development of nanowire solar cells, as well as other nanowire-based electronic/optoelectronic devices. PMID- 29701976 TI - Efficient Green Emission from Wurtzite Al xIn1- xP Nanowires. AB - Direct band gap III-V semiconductors, emitting efficiently in the amber-green region of the visible spectrum, are still missing, causing loss in efficiency in light emitting diodes operating in this region, a phenomenon known as the "green gap". Novel geometries and crystal symmetries however show strong promise in overcoming this limit. Here we develop a novel material system, consisting of wurtzite Al xIn1- xP nanowires, which is predicted to have a direct band gap in the green region. The nanowires are grown with selective area metalorganic vapor phase epitaxy and show wurtzite crystal purity from transmission electron microscopy. We show strong light emission at room temperature between the near infrared 875 nm (1.42 eV) and the "pure green" 555 nm (2.23 eV). We investigate the band structure of wurtzite Al xIn1- xP using time-resolved and temperature dependent photoluminescence measurements and compare the experimental results with density functional theory simulations, obtaining excellent agreement. Our work paves the way for high-efficiency green light emitting diodes based on wurtzite III-phosphide nanowires. PMID- 29701977 TI - Expanded Kinetic Control for Persistent Micelle Templates with Solvent Selection. AB - The precision control of nanoscale materials remains a challenge for the study of nanostructure-performance relationships. Persistent micelle templates (PMT) are a kinetic-controlled self-assembly approach that decouples pore and wall control. Here, block copolymer surfactants form persistent micelles that maintain constant template size as material precursors are added, despite the shifting equilibrium dimensions. Earlier PMT demonstrations were based upon solvent mixtures where kinetic rates were adjusted with the amount of water cosolvent. This approach is however limited because ever-higher water contents can lead to secondary porosity within the material walls. Herein, we report an improved method to regulate the PMT kinetics via the majority solvent. This enables a new avenue for the expansion of the PMT window to realize templated materials with a greater extent of tunability. In addition, we report a new small-angle X-ray scattering (SAXS) based log-log analysis method to independently test the micelle-templated series for consistency with the expected lattice expansion with an increasing material:template ratio. The PMT window identified by the log-log analysis of the SAXS data agreed well with independent scanning electron microscopy measurements. The combination of improved micelle control with solvent selection along with SAXS validation will accelerate the development of a myriad of nanomaterial applications. PMID- 29701978 TI - Scalable Synthesis of Mycocyclosin. AB - We report herein the scalable total synthesis of the secondary metabolite, mycocyclosin, initially isolated from Mycobacterium tuberculosis. Mycocylosin bears a highly strained 3,3'-dityrosine biaryl system which arises biosynthetically from an intramolecular oxidative dehydrogenative cross-coupling of cyclo(l-Tyr-l-Tyr) (cYY) catalyzed by the P450 enzyme CYP121. CYP121 is found exclusively in M. tuberculosis. Scalable access to mycocyclosin and related derivatives via a Pd(II)-catalyzed macrocyclization is anticipated to facilitate the biological evaluation of these compounds as novel tuberculosis antimicrobials. PMID- 29701979 TI - Fluorouracil-Loaded Gold Nanoparticles for the Treatment of Skin Cancer: Development, in Vitro Characterization, and in Vivo Evaluation in a Mouse Skin Cancer Xenograft Model. AB - Fluorouracil (5-FU) is an antimetabolite drug used in the treatment of various malignancies, such as colon and skin cancers. However, its systemic administration results in severe side effects. Topical 5-FU delivery for the treatment of skin cancer could circumvent these shortcomings, but it is limited by the drug poor permeability through the skin. To enhance 5-FU efficacy against skin cancer and reduce its systemic side effects, it was loaded into a gold nanoparticle (GNP)-based topical delivery system. 5-FU was loaded onto GNPs capped with CTAB through ionic interactions between 5-FU and CTAB. GNPs were prepared at different 5-FU/CTAB molar ratios and evaluated using different techniques. GNP stability and drug release were studied as a function of salt concentration and solution pH. Optimum 5-FU/CTAB-GNPs were incorporated into gel and cream bases, and their ex vivo permeability was evaluated in mice dorsal skin. The in vivo anticancer efficacy of the same preparations was evaluated in A431 tumor-bearing mice. The GNPs had spherical shape and a size of ~16-150 nm. Maximum 5-FU entrapment was achieved at 5-FU/CTAB molar ratio of 1:1 and pH 11.5. Drug release from GNPs was sustained and pH-dependent. 5-FU GNP gel and cream had around 2-fold higher permeability through mice skin compared with free 5-FU gel and cream formulations. Further, in vivo studies in a mouse model having A431 skin cancer cells implanted in the subcutaneous space showed that the GNP gel and cream achieved 6.8- and 18.4-fold lower tumor volume compared with the untreated control, respectively. These results confirm the potential of topical 5-FU/CTAB GNPs to enhance drug efficacy against skin cancer. PMID- 29701980 TI - Disentangling Strong-Field Multielectron Dynamics with Angular Streaking. AB - The study into the interaction between a strong laser field and atoms/molecules has led to significant advances in developing spectroscopic tools in the attosecond time-domain and methods for controlling chemical reactions. There has been great interest in understanding the complex electronic and nuclear dynamics of molecules in strong laser fields. However, it is still a formidable challenge to fully model such dynamics. Conventional experimental tools such as photoelectron spectroscopy encounter difficulties in revealing the involved states because the electron spectra are largely dictated by the property of the laser field. Here, with strong field angular streaking technique, we measure the angle-dependent ionization yields that directly reflect the symmetry of the ionizing orbitals of methyl iodide and thus reveal the ionization/dissociation dynamics. Moreover, kinematically complete measurements of momentum vectors of all fragments in dissociative double ionization processes allow access to electron-momentum correlations that reveal correlated multielectron dynamics. PMID- 29701981 TI - Correction to "DFT Modeling of Cross-Linked Polyethylene: Role of Gold Atoms and Dispersion Interactions". PMID- 29701982 TI - DNA Photo-cross-linking Using Pyranocarbazole and Visible Light. AB - This report presents a novel photo-cross-linker that can cross-link to pyrimidines in nucleic acids under visible light irradiation (lambda > 400 nm). This method offers ultrafast photo-cross-linking without any cytotoxicity due to UV irradiation. PMID- 29701983 TI - Enantioselective [3 + 2] Formal Cycloaddition of 1-Styrylnaphthols with Quinones Catalyzed by a Chiral Phosphoric Acid. AB - The first highly enantioselective [3 + 2] formal cycloaddition of 1 styrylnaphthols (or phenol) with quinones catalyzed by a chiral phosphoric acid has been reported. A class of trans-2,3-diarylbenzofurans were prepared efficiently (up to 99% yield, >20:1 dr, 99% ee). This organocatalytic procedure allows lowering of the catalyst loading to 0.5 mol % without considerable loss in reactivity and enantioselectivity. PMID- 29701984 TI - Chiral Polyfunctional Thiols and Their Conjugated Precursors upon Winemaking with Five Vitis vinifera Sauvignon blanc Clones. AB - Five co-located clones of Sauvignon blanc grapes were fermented under controlled conditions at laboratory-scale to investigate the impact of yeast strain, commercial enzyme, or nutrient addition on the concentrations of enantiomers of 3 sulfanylhexan-1-ol (3-SH) and 3-sulfanylhexyl acetate (3-SHA) in resulting wines. The relationship of these enantiomers with the odorless 3-SH precursors present in diastereomeric forms in grape juice was also examined. Possible variations may have existed due to clone type, not only for the diastereomers of 3-SH precursors in juices but also for the enantiomers of 3-SH and 3-SHA in the resulting wines, although there was no obvious stereochemical relationship between precursors and free thiols. From a flavor enhancement perspective, the use of a commercial enzyme in the juice significantly enhanced 3-SH production for some clones. In contrast, less impact on the production of 3-SH and 3-SHA was seen as a result of yeast strain and nutrient regardless of clone type. PMID- 29701985 TI - Phenothiazinimides: Atom-Efficient Electrophilic Amination Reagents. AB - Phenothiazinimides, a fairly unknown class of imines, were prepared and found to be very reactive as ultrasimple atom-efficient electrophilic amination reagents for phenols and indoles under metal-free conditions. PMID- 29701986 TI - Improved Extraction Repeatability and Spectral Reproducibility for Liquid Extraction Surface Analysis-Mass Spectrometry Using Superhydrophobic Superhydrophilic Patterning. AB - A major problem limiting reproducible use of liquid extraction surface analysis (LESA) array sampling of dried surface-deposited liquid samples is the unwanted spread of extraction solvent beyond the dried sample limits, resulting in unreliable data. Here, we explore the use of the Droplet Microarray (DMA), which consists of an array of superhydrophilic spots bordered by a superhydrophobic material giving the potential to confine both the sample spot and the LESA extraction solvent in a defined area. We investigated the DMA method in comparison with a standard glass substrate using LESA analysis of a mixture of biologically relevant compounds with a wide mass range and different physicochemical properties. The optimized DMA method was subsequently applied to urine samples from a human intervention study. Relative standard deviations for the signal intensities were all reduced at least 3-fold when performing LESA-MS on the DMA surface compared with a standard glass surface. Principal component analysis revealed more tight clusters indicating improved spectral reproducibility for a human urine sample extracted from the DMA compared to glass. Lastly, in urine samples from an intervention study, more significant ions (145) were identified when using LESA-MS spectra of control and test urine extracted from the DMA. We demonstrate that DMA provides a surface-assisted LESA MS method delivering significant improvement of the surface extraction repeatability leading to the acquisition of more robust and higher quality data. The DMA shows potential to be used for LESA-MS for controlled and reproducible surface extraction and for acquisition of high quality, qualitative data in a high-throughput manner. PMID- 29701987 TI - Detection of Nonvolatile Inorganic Oxidizer-Based Explosives from Wipe Collections by Infrared Thermal Desorption-Direct Analysis in Real Time Mass Spectrometry. AB - Infrared thermal desorption (IRTD) was coupled with direct analysis in real time mass spectrometry (DART-MS) for the detection of both inorganic and organic explosives from wipe collected samples. This platform generated discrete and rapid heating rates that allowed volatile and semivolatile organic explosives to thermally desorb at relatively lower temperatures, while still achieving elevated temperatures required to desorb nonvolatile inorganic oxidizer-based explosives. IRTD-DART-MS demonstrated the thermal desorption and detection of refractory potassium chlorate and potassium perchlorate oxidizers, compounds difficult to desorb with traditional moderate-temperature resistance-based thermal desorbers. Nanogram to sub-nanogram sensitivities were established for analysis of a range of organic and inorganic oxidizer-based explosive compounds, with further enhancement limited by the thermal properties of the most common commercial wipe materials. Detailed investigations and high-speed visualization revealed conduction from the heated glass-mica base plate as the dominant process for heating of the wipe and analyte materials, resulting in thermal desorption through boiling, aerosolization, and vaporization of samples. The thermal desorption and ionization characteristics of the IRTD-DART technique resulted in optimal sensitivity for the formation of nitrate adducts with both organic and inorganic species. The IRTD-DART-MS coupling and IRTD in general offer promising explosive detection capabilities to the defense, security, and law enforcement arenas. PMID- 29701988 TI - Giant Enhancement in Radiative Heat Transfer in Sub-30 nm Gaps of Plane Parallel Surfaces. AB - Radiative heat transfer rates that exceed the blackbody limit by several orders of magnitude are expected when the gap size between plane parallel surfaces is reduced to the nanoscale. To date, experiments have only realized enhancements of ~100 fold as the smallest gap sizes in radiative heat transfer studies have been limited to ~50 nm by device curvature and particle contamination. Here, we report a 1,200-fold enhancement with respect to the far-field value in the radiative heat flux between parallel planar silica surfaces separated by gaps as small as ~25 nm. Achieving such small gap sizes and the resultant dramatic enhancement in near-field energy flux is critical to achieve a number of novel near-field based nanoscale energy conversion systems that have been theoretically predicted but remain experimentally unverified. PMID- 29701989 TI - Application of Fungicides and Microalgal Phenolic Extracts for the Direct Control of Fumonisin Contamination in Maize. AB - Fungicides and, for the first time, microalgal phenolic extracts (MPE) from Spirulina sp. and Nannochloropsis sp. were applied on maize culture media under field conditions to evaluate their ability to minimize Fusarium species development and fumonisin production. An in vitro assay against F. verticillioides was carried out using maize grains as the culture medium. An open field experiment was carried out in Northwest Italy under natural infection conditions. The compared treatments were factorial combinations of two insecticide treatments (an untreated control and pyrethroid, used against European Corn Borer), four antifungal treatments (an untreated control, MPE from Spirulina sp., MPE from Nannochloropsis sp., and a synthetic fungicide), and two timings of the application of the antifungal compounds (at maize flowering and at the milk stage). The MPE compounds were capable of inhibiting fumonisin production in vitro more efficiently than tebuconazole. Insecticide application reduced the infection by Fusarium species and subsequent fumonisin contamination. However, fumonisins in maize fields were not significantly controlled by either fungicide or MPE application. PMID- 29701990 TI - Transcriptomic and Neuropeptidomic Analysis of the Stick Insect, Carausius morosus. AB - One of the most thoroughly studied insect species, with respect to locomotion behavior, is the stick insect Carausius morosus. Although detailed information exists on premotor networks controlling walking, surprisingly little is known about neuropeptides, which are certainly involved in motor activity generation and modulation. So far, only few neuropeptides were identified from C. morosus or related stick insects. We performed a transcriptome analysis of the central nervous system to assemble and identify 65 neuropeptide and protein hormone precursors of C. morosus, including five novel putative neuropeptide precursors without clear homology to known neuropeptide precursors of other insects ( Carausius neuropeptide-like precursor 1, HanSolin, PK-like1, PK-like2, RFLamide). Using Q Exactive Orbitrap and MALDI-TOF mass spectrometry, 277 peptides including 153 likely bioactive mature neuropeptides were confirmed. Peptidomics yielded a complete coverage for many of the neuropeptide propeptides and confirmed a surprisingly high number of heterozygous sequences. Few neuropeptide precursors commonly occurring in insects, including those of insect kinins and sulfakinins, could neither be found in the transcriptome data nor did peptidomics support their presence. The results of our study represent one of the most comprehensive peptidomic analyses on insects and provide the necessary input for subsequent experiments revealing neuropeptide function in greater detail. PMID- 29701992 TI - Amyloid Fibrils: Versatile Biomaterials for Cell Adhesion and Tissue Engineering Applications. AB - Extracellular matrices (ECM) play an enormous role in any living system, controlling various factors and eventually fates of cells. ECM regulates cell fate by providing constant exogenous signals altering intracellular signal transduction for diverse pathways including proliferation, migration, differentiation, and apoptosis. Biomaterial scaffolds are designed to mimic the natural extracellular matrix such that the cells could recapitulate natural events alike their natural niche. Therefore, the success of tissue engineering is largely dependent on how one can engineer the natural matrix properties at nanoscale precision. In this aspect, several recent studies have suggested that, as long as amyloid fibrils are not toxic, they can be utilized for cell adhesion and tissue engineering applications due to its ECM mimetic surface topography and ability to mediate active cell adhesion via focal adhesions. Although historically associated with human diseases, amyloids have presently emerged as one of the excellent biomaterials evolved in nature. In this review, we focus on the recent advances of amyloid-based biomaterials for cell adhesion and tissue engineering applications. PMID- 29701991 TI - Enhancing Magnetic Light Emission with All-Dielectric Optical Nanoantennas. AB - Electric and magnetic optical fields carry the same amount of energy. Nevertheless, the efficiency with which matter interacts with electric optical fields is commonly accepted to be at least 4 orders of magnitude higher than with magnetic optical fields. Here, we experimentally demonstrate that properly designed photonic nanoantennas can selectively manipulate the magnetic versus electric emission of luminescent nanocrystals. In particular, we show selective enhancement of magnetic emission from trivalent europium-doped nanoparticles in the vicinity of a nanoantenna tailored to exhibit a magnetic resonance. Specifically, by controlling the spatial coupling between emitters and an individual nanoresonator located at the edge of a near-field optical scanning tip, we record with nanoscale precision local distributions of both magnetic and electric radiative local densities of states (LDOS). The map of the radiative LDOS reveals the modification of both the magnetic and electric quantum environments induced by the presence of the nanoantenna. This manipulation and enhancement of magnetic light-matter interaction by means of nanoantennas opens up new possibilities for the research fields of optoelectronics, chiral optics, nonlinear and nano-optics, spintronics, and metamaterials, among others. PMID- 29701993 TI - Evaluating the Mechanisms of Light-Triggered siRNA Release from Nanoshells for Temporal Control Over Gene Regulation. AB - The ability to regulate intracellular gene expression with exogenous nucleic acids such as small interfering RNAs (siRNAs) has substantial potential to improve the study and treatment of disease. However, most transfection agents and nanoparticle-based carriers that are used for the intracellular delivery of nucleic acids cannot distinguish between diseased and healthy cells, which may cause them to yield unintended widespread gene regulation. An ideal delivery system would only silence targeted proteins in diseased tissue in response to an external stimulus. To enable spatiotemporal control over gene silencing, researchers have begun to develop nucleic acid-nanoparticle conjugates that keep their nucleic acid cargo inactive until it is released from the nanoparticle on demand by externally applied near-infrared laser light. This strategy can overcome several limitations of other nucleic acid delivery systems, but the mechanisms by which these platforms operate remain ill understood. Here, we perform a detailed investigation of the mechanisms by which silica core/gold shell nanoshells (NSs) release conjugated siRNA upon excitation with either pulsed or continuous wave (CW) near-infrared (NIR) light, with the goal of providing insight into how these nanoconjugates can enable on-demand gene regulation. We demonstrate that siRNA release from NSs upon pulsed laser irradiation is a temperature-independent process that is substantially more efficient than siRNA release triggered by CW irradiation. Contrary to literature, which suggests that only pulsed irradiation releases siRNA duplexes, we found that both modes of irradiation release a mixture of siRNA duplexes and single stranded oligonucleotides, but that pulsed irradiation results in a higher percentage of released duplexes. To demonstrate that the siRNA released from NSs upon pulsed irradiation remains functional, we evaluated the use of NSs coated with green fluorescent protein (GFP)-targeted siRNA (siGFP-NS) for on-demand knockdown of GFP in cells. We found that GFP-expressing cells treated with siGFP NS and irradiated with a pulsed laser experienced a 33% decrease in GFP expression compared to cells treated with no laser. Further, we observed that light-triggered gene silencing mediated by siGFP-NS is more potent than using commercial transfection agents to deliver siRNA into cells. This work provides unprecedented insight into the mechanisms by which plasmonic NSs release siRNA upon light irradiation and demonstrates the importance of thoroughly characterizing photoresponsive nanosystems for applications in triggered gene regulation. PMID- 29701994 TI - Modified Floating Electrode-Based Sensors for the Quantitative Monitoring of Drug Effects on Cytokine Levels Related with Inflammatory Bowel Diseases. AB - Modified floating electrode-based sensors were developed to quantitatively monitor the levels of tumor necrosis factor alpha (TNF-alpha), a pro-inflammatory cytokine related with inflammatory bowel disease (IBD), and to evaluate the effect of drugs on the cytokine levels. Here, antibodies (anti-TNF-alpha) were immobilized on the floating electrodes of carbon nanotube devices, enabling selective and real-time detection of TNF-alpha among various cytokines linked to IBD. This sensor was able to measure the concentrations of TNF-alpha with a detection limit of 1 pg/L, allowing the quantitative estimation of TNF-alpha secretion from mouse macrophage Raw 264.7 cells stimulated by lipopolysaccharides (LPS). Notably, this method also allowed us to monitor the anti-inflammatory effect of a drug, lupeol, on the activation of the LPS-induced nuclear factor kappaB signaling in Raw 264.7 cells. These results indicate that our novel TNF sensor can be a versatile tool for biomedical research and clinical applications such as screening drug effects and monitoring inflammation levels. PMID- 29701995 TI - Optimization of Surface Display of DENV2 E Protein on a Nanoparticle to Induce Virus Specific Neutralizing Antibody Responses. AB - The dengue virus (DENV) causes over 350 million infections, resulting in ~25,000 deaths per year globally. An effective dengue vaccine requires generation of strong and balanced neutralizing antibodies against all four antigenically distinct serotypes of DENV. The leading live-attenuated tetravalent dengue virus vaccine platform has shown partial efficacy, with an unbalanced response across the four serotypes in clinical trials. DENV subunit vaccine platforms are being developed because they provide a strong safety profile and are expected to avoid the unbalanced immunization issues associated with live multivalent vaccines. Subunit vaccines often lack immunogenicity, requiring either a particulate or adjuvanted formulation. Particulate formulations adsorbing monomeric DENV-E antigen to the particle surface incite a strong immune response, but have no control of antigen presentation. Highly neutralizing epitopes are displayed by DENV-E quaternary structures. To control the display of DENV-E and produce quaternary structures, particulate formulations that covalently attach DENV-E to the particle surface are needed. Here we develop a surface attached DENV2-E particulate formulation, as well as analysis tools, using PEG hydrogel nanoparticles created with particle replication in nonwetting templates (PRINT) technology. We found that adding Tween-20 to the conjugation buffer controls DENV E adsorption to the particle surface during conjugation, improving both protein stability and epitope display. Immunizations with the anionic but not the cationic DENV2-E conjugated particles were able to produce DENV-specific and virus neutralizing antibody in mice. This work optimized the display of DENV-E conjugated to the surface of a nanoparticle through EDC/NHS chemistry, establishing a platform that can be expanded upon in future work to fully control the display of DENV-E. PMID- 29701996 TI - An Alternative Approach for the Analysis of Time-to-Event and Survival Outcomes in Pulmonary Medicine. PMID- 29701997 TI - The Changing Landscape of Chronic Obstructive Pulmonary Disease. PMID- 29701998 TI - Importance of dosimetry protocol for cell irradiation on a low X-rays facility and consequences for the biological response. AB - PURPOSE: The main objective of radiobiology is to establish links between doses and radiation-induced biological effects. In this context, well-defined dosimetry protocols are crucial to the determination of experimental protocols. This work proposes a new dosimetry protocol for cell irradiation in a SARRP and shows the importance of the modification of some parameters defined in dosimetry protocol for physical dose and biological outcomes. MATERIALS AND METHODS: Once all parameters of the configuration were defined, dosimetry measurements with ionization chambers and EBT3 films were performed to evaluate the dose rate and the attenuation due to the cell culture medium. To evaluate the influence of changes in cell culture volume and/or additional filtration, 6-well plates containing EBT3 films with water were used to determine the impact on the physical dose at 80 kV. Then, experiments with the same irradiation conditions were performed by replacing EBT3 films by HUVECs. The biological response was assessed using clonogenic assay. RESULTS: Using a 0.15 mm copper filter lead to a variation of +1% using medium thickness of 0.104 cm to -8% using a medium thickness of 0.936 cm on the physical dose compare to the reference condition (0.313 cm). For the 1 mm aluminum filter, a variation of +8 to -40% for the same medium thickness conditions has been observed. Cells irradiated in the same conditions showed significant differences in survival fraction, corroborating the effects of dosimetric changes on physical dose. CONCLUSIONS: This work shows the importance of dosimetry in radiobiology studies and the need of an accurate description of the dosimetry protocol used for irradiation. PMID- 29701999 TI - Mechanisms underlying the increased cardiac norepinephrine spillover in heart failure. AB - Patients with heart failure (HF) have increased levels of cardiac norepinephrine (NE) spillover, which is an independent predictor of mortality. We hypothesized that this increase in NE spillover in HF depends not only on increases in sympathetic nerve activity (SNA) but also on changes in the mechanisms controlling NE release and reuptake. Such changes would lead to differences between the increases in directly recorded SNA and NE spillover to the heart in HF. Experiments were conducted in conscious sheep implanted with electrodes to record cardiac SNA (CSNA). In addition, arterial pressure and cardiac NE spillover were determined. In HF, the levels of both CSNA (102 +/- 8 vs. 45 +/- 8 bursts/min, P < 0.05) and cardiac NE spillover (21.6 +/- 3.8 vs. 3.9 +/- 0.8 pmol/min, P < 0.05) were significantly higher than in normal control animals. In HF, baroreflex control of cardiac NE spillover was impaired, and when CSNA was abolished by increasing arterial pressure, there was no reduction in cardiac NE spillover. A decrease in cardiac filling pressures in the HF group led to a significant increase in CSNA, but it significantly decreased cardiac NE spillover. In HF, the levels of cardiac NE spillover were enhanced above those expected from the high level of SNA, suggesting that changes in mechanisms controlling NE release and reuptake further increase the high level of NE at the heart, which will act to enhance the deleterious effects of increased CSNA in HF. NEW & NOTEWORTHY This is the first study, to our knowledge, to compare direct recordings of cardiac sympathetic nerve activity with simultaneously measured cardiac norepinephrine (NE) spillover. Our results indicate that in heart failure, increased cardiac sympathetic nerve activity is a major contributor to the increased NE spillover. In addition, there is enhanced NE spillover for the levels of synaptic nerve activity. PMID- 29702000 TI - The effect of intravenous insulin, apheresis and oral lipid-lowering agents on non-fasting hypertriglyceridemia and associated pancreatitis. AB - OBJECTIVES: There is evidence that increasing severity of hypertriglyceridemia increases the risk of acute pancreatitis. There is a debate about superiority of treatment methods and previous works have specifically called for direct comparison between IV insulin and apheresis techniques. Identify patient characteristics predictive of lipid-lowering therapy selection in a large community hospital for treatment of hypertriglyceridemia; evaluate for a concentration-dependent relationship between hypertriglyceridemia severity and risk of acute pancreatitis; assess for differences in clinical outcomes between patients treated with IV insulin versus apheresis. METHODS: Single center, retrospective cohort study including patients with hypertriglyceridemia between January 2007 and December 2016. Main measures included frequency of pancreatitis, choice of lipid-lowering therapy, and clinical comparisons of diet, oral lipid lowering agents, IV insulin, and apheresis. RESULTS: Initial serum triglyceride level and disease acuity was higher among patients in insulin and apheresis groups. Neither triglyceride level, Charlson comorbidity index, age, BISAP score, nor initial CRP predicted use of IV insulin versus apheresis. Prevalence of pancreatitis increased with higher triglyceride level, reaching 48% with triglycerides >2000 md/dL (p < 0.001). There was a significant decrease in serum triglycerides at each time interval (p < 0.05) in patients treated with IV insulin and apheresis, but no difference in clearance rate between the two. Length of stay did not differ between IV insulin and apheresis. CONCLUSION: The presence of pancreatitis, hyperglycemia, and hypertriglyceridemia severity influenced selection of therapies like IV insulin and apheresis. We found no superiority of either IV insulin or apheresis in the treatment of severe hypertriglyceridemia among patients hospitalized for pancreatitis. PMID- 29702002 TI - #13ReasonsWhy Health Professionals and Educators are Tweeting: A Systematic Analysis of Uses and Perceptions of Show Content and Learning Outcomes. AB - This study is a content analysis of health professionals' and educators' tweets about a popular Netflix show that depicts teen suicide: 13 Reasons Why. A content analysis of 740 tweets was conducted to determine the main themes associated with professionals' and educators' tweets about the show, as well as the valence of the tweets. Additionally, a thematic analysis of linked content in tweets (n = 178) was conducted to explore additional content shared about the show and modeling outcomes. Results indicated the largest percentage of tweets was related to social learning, particularly about outcomes that could occur from viewing the show. The valence of the tweets about outcomes was more positive than negative. However, linked materials commonly circulated in tweets signified greater concern with unintended learning outcomes. Some of the linked content included media guidelines for reporting on suicide with recommendations that entertainment producers follow the guidelines. This study emphasizes the importance of including social learning objectives in future typologies of Twitter uses and demonstrates the importance of examining linked content in Twitter studies. PMID- 29702001 TI - Clearance of Somatic Mutations at Remission and the Risk of Relapse in Acute Myeloid Leukemia. AB - Purpose The aim of the current study was to determine whether the degree of mutation clearance at remission predicts the risk of relapse in patients with acute myeloid leukemia (AML). Patients and Methods One hundred thirty-one previously untreated patients with AML who received intensive induction chemotherapy and attained morphologic complete remission (CR) at day 30 were studied. Pretreatment and CR bone marrow were analyzed using targeted capture DNA sequencing. We analyzed the association between mutation clearance (MC) on the basis of variant allele frequency (VAF) at CR (MC2.5: if the VAF of residual mutations was < 2.5%; MC1.0: if the VAF was < 1%; and complete MC [CMC]: if no detectable residual mutations) and event-free survival, overall survival (OS), and cumulative incidence of relapse (CIR). Results MC1.0 and CMC were associated with significantly better OS (2-year OS: 75% v 61% in MC1.0 v non-MC1.0; P = .0465; 2-year OS: 77% v 60% in CMC v non-CMC; P = .0303) and lower CIR (2-year CIR: 26% v 46% in MC1.0 v non-MC 1.0; P = .0349; 2 year-CIR: 24% v 46% in CMC v non-CMC; P = .03), whereas there was no significant difference in any of the above outcomes by MC2.5. Multivariable analysis adjusting for age, cytogenetic risk, allogeneic stem-cell transplantation, and flow cytometry-based minimal residual disease revealed that patients with CMC had significantly better event free survival (hazard ratio [HR], 0.43; P = .0083), OS (HR, 0.47; P = .04), and CIR (HR, 0.27; P < .001) than did patients without CMC. These prognostic associations were stronger when preleukemic mutations, such as DNMT3A, TET2, and ASXL1, were removed from the analysis. Conclusion Clearance of somatic mutation at CR, particularly in nonpreleukemic genes, was associated with significantly better survival and less risk of relapse. Somatic mutations in nonpreleukemic genes may function as a molecular minimal residual disease marker in AML. PMID- 29702003 TI - High Positive End-Expiratory Pressure Allows Extubation of an Obese Patient. PMID- 29702005 TI - Best of JNSPG 2017. PMID- 29702004 TI - Human tRNA-Derived Small RNAs Modulate Host-Oral Microbial Interactions. AB - Coevolution of the human host and its associated microbiota has led to sophisticated interactions to maintain a delicate homeostasis. Emerging evidence suggests that in addition to small molecules, peptides, and proteins, small regulatory noncoding RNAs (sRNAs) might play an important role in cross-domain interactions. In this study, we revealed the presence of diverse host transfer RNA-derived small RNAs (tsRNAs) among human salivary sRNAs. We selected 2 tsRNAs (tsRNA-000794 and tsRNA-020498) for further study based on their high sequence similarity to specific tRNAs from a group of Gram-negative oral bacteria, including Fusobacterium nucleatum, a key oral commensal and opportunistic pathogen. We showed that the presence of F. nucleatum triggers exosome-mediated release of tsRNA-000794 and tsRNA-020498 by human normal oral keratinocyte cells. Furthermore, both tsRNA candidates exerted a growth inhibition effect on F. nucleatum, likely through interference with bacterial protein biosynthesis, but did not affect the growth of Streptococcus mitis, a health-associated oral Gram positive bacterium whose genome does not carry sequences bearing high similarity to either tsRNA. Our data provide the first line of evidence for the modulatory role of host-derived tsRNAs in the microbial-host interaction. PMID- 29702006 TI - Short- and Long-Term Effects of Late Maxillary Advancement With the Liou-Alt RAMEC Protocol in Unilateral Cleft Lip and Palate. AB - OBJECTIVE: The objective of this retrospective longitudinal study was to evaluate short- and long-term results of the application of the Liou Alt-RAMEC (alternate rapid maxillary expansion and constriction) technique, a late orthopedic maxillary protraction technique, with intraoral anchorage, in patients with cleft. MATERIALS AND METHODS: Twenty-six patients with unilateral cleft lip and palate (UCLP) were consecutively treated with the Alt-RAMEC technique. The average age of the patients was 11.7 years (10.3-13.2 years) before protraction and 18.3 years (17.4-21.1 years) at long-term follow-up. A sample of nontreated patients with UCLP was used as a control group. It was matched for sex, skeletal class III, and age (11.3 years). The control sample had records at the end of growth (18.7 years). RESULTS: The sagittal advancement of A-point, after the application of the technique, was 5.7 (2.17) mm. Some mandibular dentoalveolar and positional adaptation was noted. The position of the maxilla was stable in the long term. On the other hand, the UCLP control group showed hardly any growth at the maxillary level during the long-term follow-up period. CONCLUSION: Our results showed that the Alt-RAMEC technique, performed at the correct time, with a double-hinged expander, followed by class III spring or elastic traction, 24 hours per day, allows for satisfactory maxillary protraction, with, at this stage, apparently stable long-term results. Nevertheless, as only 50% of the patients had long-term follow-up data, we are still unable to predict the percentage of patients which will not eventually need orthognathic surgery. PMID- 29702007 TI - Dual inhibition of STAT1 and STAT3 activation downregulates expression of PD-L1 in human breast cancer cells. AB - OBJECTIVES: Breast cancer is the most commonly diagnosed cancer, and it is a leading cause of cancer-related deaths in females worldwide. Triple-negative breast cancer (TNBC) constitutes 15% of breast cancer and shows distinct metastasis profiles with poor prognosis. Strong PD-L1 expression has been observed in some tumors, supporting their escape from immune surveillance. Targeting PD-L1 could be a promising therapeutic approach in breast cancer patients. We investigated potential molecular mechanisms for constitutive expression of PD-L1 by inhibiting upstream STAT1 and STAT3 signals. METHODS: PD L1 expression in three breast cancer cell lines was measured using quantitative PCR and western blotting. Activation of STAT1 and STAT3 was blocked using pharmacological inhibitors and siRNA. The mechanism underlying the constitutive expression of PD-L1 was investigated using ChIP and co-immunoprecipitation assays. RESULTS: We found that individual inhibition of STAT1 and STAT3 activation partially downregulated PD-L1, while combined inhibition completely downregulated PD-L1 expression. Moreover, our results suggest that pSTAT1-pSTAT3 dimerize in cytosol and translocate to the nucleus, where they bind to PD-L1 promoter and induce PD-L1 expression. CONCLUSION: These findings provide a rationale for combined targeting of STAT1 and STAT3 for the development of immune based cancer therapies for down regulation of PD-L1 expression. PMID- 29702008 TI - Natural History over 8 Years of Pulmonary Vascular Disease in a Patient Carrying Biallelic EIF2AK4 Mutations. PMID- 29702009 TI - Hypoxic conditioning in blood vessels and smooth muscle tissues: effects on function, mechanisms, and unknowns. AB - Hypoxic preconditioning, the protective effect of brief, intermittent hypoxic or ischemic episodes on subsequent more severe hypoxic episodes, has been known for 30 yr from studies on cardiac muscle. The concept of hypoxic preconditioning has expanded; excitingly, organs beyond the heart, including the brain, liver, and kidney, also benefit. Preconditioning of vascular and visceral smooth muscles has received less attention despite their obvious importance to health. In addition, there has been no attempt to synthesize the literature in this field. Therefore, in addition to overviewing the current understanding of hypoxic conditioning, in the present review, we consider the role of blood vessels in conditioning and explore evidence for conditioning in other smooth muscles. Where possible, we have distinguished effects on myocytes from other cell types in the visceral organs. We found evidence of a pivotal role for blood vessels in conditioning and for conditioning in other smooth muscle, including the bladder, vascular myocytes, and gastrointestinal tract, and a novel response in the uterus of a hypoxic-induced force increase, which helps maintain contractions during labor. To date, however, there are insufficient data to provide a comprehensive or unifying mechanism for smooth muscles or visceral organs and the effects of conditioning on their function. This also means that no firm conclusions can be drawn as to how differences between smooth muscles in metabolic and contractile activity may contribute to conditioning. Therefore, we have suggested what may be general mechanisms of conditioning occurring in all smooth muscles and tabulated tissue-specific mechanistic findings and suggested ideas for further progress. PMID- 29702010 TI - Pulp Regeneration by 3-dimensional Dental Pulp Stem Cell Constructs. AB - Dental pulp regeneration therapy for the pulpless tooth has attracted recent attention, and clinical trial studies are underway with the tissue engineering approach. However, there remain many concerns, including the extended period for regenerating the dental pulp. In addition, the use of scaffolds increases the risk of inflammation and infection. To establish a basic technology for novel dental pulp regenerative therapy that allows transplant of pulp-like tissue, we attempted to fabricate scaffold-free 3-dimensional (3D) cell constructs composed of dental pulp stem cells (DPSCs). Furthermore, we assessed viability of these 3D DPSC constructs for dental pulp regeneration through in vitro and in vivo studies. For the in vitro study, we obtained 3D DPSC constructs by shaping sheet like aggregates of DPSCs with a thermoresponsive hydrogel. DPSCs within constructs remained viable even after prolonged culture; furthermore, 3D DPSC constructs possessed a self-organization ability necessary to serve as a transplant tissue. For the in vivo study, we filled the human tooth root canal with DPSC constructs and implanted it subcutaneously into immunodeficient mice. We found that pulp-like tissues with rich blood vessels were formed within the human root canal 6 wk after implantation. Histologic analyses revealed that transplanted DPSCs differentiated into odontoblast-like mineralizing cells at sites in contact with dentin; furthermore, human CD31-positive endothelial cells were found at the center of regenerated tissue. Thus, the self-organizing ability of 3D DPSC constructs was active within the pulpless root canal in vivo. In addition, blood vessel-rich pulp-like tissues can be formed with DPSCs without requiring scaffolds or growth factors. The technology established in this study allows us to prepare DPSC constructs with variable sizes and shapes; therefore, transplantation of DPSC constructs shows promise for regeneration of pulpal tissue in the pulpless tooth. PMID- 29702011 TI - Spirometric Volumes and Breathlessness Across Levels of Airflow Limitation: The COPDGene Study. PMID- 29702012 TI - Physical Therapists' Use of Evaluation Measures to Inform the Prescription of Ankle-Foot Orthoses for Children with Cerebral Palsy. AB - AIMS: To examine how physical therapists (PTs) use evaluation measures to guide prescription and re-assessment of ankle-foot orthoses (AFOs) for children with CP. METHODS: PTs in Canada who work with children with CP were invited to complete an online survey. Survey questions examined PT evaluation and interpretation of findings at initial AFO prescription and re-assessment. Closed ended responses were analyzed using descriptive statistics, and a conventional content analysis examined responses to open-ended questions. RESULTS: Sixty responses from ten provinces were analyzed. Three themes emerged from the open ended responses, which were supported by closed-ended responses. (1) Focus on impairment-level measures. Although evaluation primarily involved observational, non-standardized measures of impairments and gait pattern, most respondents also considered participation-level constructs. (2) Lack of confidence/knowledge. Respondents reported a moderate level of confidence concerning decision-making about AFO type and characteristics. 3) Inconsistent practices between therapists, possibly reflecting the paucity of available evidence or individualization of the prescription. CONCLUSIONS: Non-standardized, observational assessment methods, and impairment-level constructs appear to guide AFO prescription decisions. Integrating current knowledge into practice, developing best practice guidelines, and developing standardized tools to assess the effects of AFOs on participation may promote confidence, consistency, and improved outcomes. PMID- 29702013 TI - God, I Can't Stop Thinking About Sex! The Rebound Effect in Unsuccessful Suppression of Sexual Thoughts Among Religious Adolescents. AB - The rebound effect of thought suppression refers to attempts to suppress thoughts that result in an increase of those thoughts. The aim of this three-study research was to investigate the suppression of thoughts and its possible importance in the cognitive model of predicted compulsive sexual behavior (CSB) among Israeli Jewish religious and secular adolescents. Study 1 (N = 661): Do religious and secular adolescents differ in CSB and related psychopathology? Study 2 (N = 522): Does CSB mediate the link between religiosity and well-being? Study 3 (N = 317): Does religiosity relate to suppression of sexual thoughts, which relates to higher CSB and lower well-being? The analyses indicated that religious adolescents are higher in CSB than secular ones, and that sexual suppression and CSB mediate the link between religiosity and well-being. Results are discussed and address the need for a broader understanding of CSB and the function of thought suppression. PMID- 29702014 TI - Mucocelelike Lesions in the Breast: Radiologic and Clinicopathologic Correlations With Upgrade Rate. AB - OBJECTIVE: The purpose of this article is to investigate the radiologic and clinicopathologic findings of mucocelelike lesions (MLLs) and the rate of pathologic upgrade with factors predicting it. MATERIALS AND METHODS: We reviewed our institution's database from January 2006 to December 2012 and enrolled 89 women with 89 MLLs. The pathologic findings from the initial biopsies identified 71 lesions without and 18 lesions with associated high-risk lesions. Images were reviewed according to the BI-RADS lexicon. Clinical and pathologic results were analyzed statistically, and upgrade rates were calculated. RESULTS: Of the 89 lesions, 67 (75.3%) underwent surgical excision and 22 (24.7%) did not. After surgical excision (n = 67), one lesion was upgraded to mucinous carcinoma, three were upgraded to ductal carcinoma in situ, and 16 were upgraded to MLLs with associated high-risk lesions (29.9% total upgrade rate; 20/67). A statistically significant higher percentage of MLLs with associated high-risk lesions was observed in the surgical excision group (94.4% vs 70.4%; p = 0.036). The final pathologic diagnosis revealed larger lesions (16.4 +/- 9.1 vs 12.6 +/- 6.8 mm; p = 0.024) and younger patients in the high-risk group (46.9 +/- 7.7 vs 50.6 +/- 9.1 years; p = 0.049). Although no significant differences were observed in the imaging findings, including the BI-RADS category, upgraded lesions were seen as a mass with calcification as a predominant feature. CONCLUSION: This study revealed no significant differences in imaging findings or BI-RADS category between high risk and non-high-risk breast MLLs. However, we confirmed that high-risk lesions typically are seen as larger masses with calcifications. PMID- 29702015 TI - Interobserver Variability of Sonographic Features Used in the American College of Radiology Thyroid Imaging Reporting and Data System. AB - OBJECTIVE: The purpose of this study was to assess interobserver variability in assigning features in the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS) lexicon and in making recommendations for thyroid nodule biopsy. MATERIALS AND METHODS: The study cohort comprised 100 nodules in 92 patients who underwent fine-needle aspiration with definitive cytologic results (Bethesda category II or VI) or diagnostic lobectomy between April 2009 and May 2010. Eight board-certified radiologists evaluated the nodules according to the five feature categories that constitute ACR TI-RADS and gave a biopsy recommendation based on their own practice. Variability in feature assignment and biopsy recommendation was assessed with the Fleiss kappa statistic. RESULTS: Agreement in interpretation was fair to moderate for all features except shape (kappa = 0.61) and macrocalcifications (kappa = 0.73), which had substantial agreement. The features with the poorest agreement were margin and other types of echogenic foci, which had kappa values ranging from 0.25 to 0.39, indicating fair agreement. Interobserver agreement regarding biopsy recommendation was fair (kappa = 0.22) based on radiologists' current practice. Applying ACR TI-RADS resulted in moderate agreement (kappa = 0.51). CONCLUSION: Variability in interpreting thyroid nodule sonographic features was highest for margin and all types of echogenic foci, except for macrocalcifications. Because radiologists' interpretations of these features change the level of suspicion of thyroid malignancy, the results of this study suggest a need for further education. Despite the variability in assigning features, adoption of ACR TI-RADS improves agreement for recommending biopsy. PMID- 29702016 TI - Static and Functional MR Urography to Assess Congenital Anomalies of the Kidney and Urinary Tract in Infants and Children: Comparison With MAG3 Renal Scintigraphy and Sonography. AB - OBJECTIVE: The purpose of this study is to compare functional MR urography (MRU) with the results of ultrasound and radionuclide 99mTc-mercaptoacetyltriglycine (MAG3) scintigraphy in evaluating morphologic findings, split renal function, and urinary tract obstruction in pediatric patients. MATERIALS AND METHODS: Pediatric patients with proven congenital anomalies of the kidney and urinary tract were included (n = 112). The morphologic findings of MRU were compared with previous diagnostic ultrasound findings. For evaluation of split renal function and urinary tract obstruction, MAG3 scintigraphy was used as a reference standard. RESULTS: MRU provided detailed morphologic information of the whole urinary tract for all 112 patients. In 94.6% of cases (n = 106), diagnostic findings could be verified, and in 5.4% of cases (n = 6), more detailed information could be gained. Equivalent split renal function showed good concordance between functional MRU and MAG3 scintigraphy. However, in kidneys with restricted function (< 35%), functional MRU underestimated the remaining renal function, with a mean difference of 6.6% and an SD of 24.4%. For evaluation of relevant urinary tract obstruction, the sensitivity of functional MRU was 100%, specificity was 81.6%, positive predictive value was 70.8%, and negative predictive value was 100%. CONCLUSION: Regarding split renal function, functional MRU shows a lack of accuracy in comparison with the clinical standard MAG3 scintigraphy, especially in patients with severely diminished function of one kidney. However, functional MRU allows an adequate assessment of urinary tract obstruction and a high-resolution morphologic evaluation of the whole urinary tract. Thus, functional MRU is suitable to add diagnostic value, especially as a complementary examination for complex individual cases in the presurgical state. PMID- 29702017 TI - Is Prostate Imaging Reporting and Data System Version 2 Sufficiently Discovering Clinically Significant Prostate Cancer? Per-Lesion Radiology-Pathology Correlation Study. AB - OBJECTIVE: The objective of our study was to evaluate the performance of multiparametric MRI with Prostate Imaging Reporting and Data System version 2 (PI RADSv2) for detecting prostate cancer (PCA) and clinically significant PCA through this per-lesion one-to-one correlation study between pathologically proven lesions and MRI-visible lesions. MATERIALS AND METHODS: A total of 93 PCA lesions from 44 patients who underwent radical prostatectomy were included in this retrospective study. Two radiologists scored every visible lesion with a PI RADSv2 score of 3, 4, or 5 in each patient's multiparametric MRI examination using PI-RADSv2. A per-lesion one-to-one correlation between MRI-visible lesions and pathologically confirmed PCA lesions was conducted during regular radiology pathology meetings at our center. The detection rates of clinically significant PCA and the proportions of clinically significant PCAs from MRI-visible and MRI invisible PCAs were calculated. The performance of PI-RADSv2 for detecting clinically significant PCA was evaluated using the positive predictive value (PPV), negative predictive value (NPV), and area under the ROC curve (AUC) value. RESULTS: Using a PI-RADSv2 score of 3, 4, or 5 as an MRI-visible lesion, 46.88% of clinically significant PCA lesions were detected. The PPV, NPV, and AUC were 96.77%, 45.16%, and 0.72, respectively. Tumor volume and secondary Gleason grade showed a statistically significant difference between MRI-visible and MRI invisible clinically significant PCAs. CONCLUSION: Multiparametric MRI with PI RADSv2 missed a considerable number of clinically significant PCA lesions in this per-lesion analysis, causing a relatively low NPV and diagnostic performance compared with previous per-patient studies. However, the high PPV indicates that multiparametric MRI with PI-RADSv2 may be useful for follow-up of active surveillance and planning focal therapy. PMID- 29702018 TI - Percutaneous Ablation for Hepatocellular Carcinoma. AB - OBJECTIVE: The purpose of this article is to discuss the use, comparative efficacy, and general technical considerations of percutaneous ablation, alone or in combination with other therapies, for the treatment of hepatocellular carcinoma (HCC). CONCLUSION: Percutaneous ablation is a mainstay treatment for early-stage HCC, offering survival comparable to that of surgical resection for small lesions. It can act as a primary curative therapy or bridge therapy for patients waiting to undergo liver transplant. New ablation modalities and combining tumor ablation with other therapies, such as transarterial chemoembolization, can improve clinical outcomes and allow treatment of larger lesions. Combining thermal ablation with systemic chemotherapy, including immunotherapy, is an area of future development. PMID- 29702019 TI - A Third-Generation Adaptive Statistical Iterative Reconstruction Technique: Phantom Study of Image Noise, Spatial Resolution, Lesion Detectability, and Dose Reduction Potential. AB - OBJECTIVE: The purpose of this study was to assess image noise, spatial resolution, lesion detectability, and the dose reduction potential of a proprietary third-generation adaptive statistical iterative reconstruction (ASIR V) technique. MATERIALS AND METHODS: A phantom representing five different body sizes (12-37 cm) and a contrast-detail phantom containing lesions of five low contrast levels (5-20 HU) and three sizes (2-6 mm) were deployed. Both phantoms were scanned on a 256-MDCT scanner at six different radiation doses (1.25-10 mGy). Images were reconstructed with filtered back projection (FBP), ASIR-V with 50% blending with FBP (ASIR-V 50%), and ASIR-V without blending (ASIR-V 100%). In the first phantom, noise properties were assessed by noise power spectrum analysis. Spatial resolution properties were measured by use of task transfer functions for objects of different contrasts. Noise magnitude, noise texture, and resolution were compared between the three groups. In the second phantom, low contrast detectability was assessed by nine human readers independently for each condition. The dose reduction potential of ASIR-V was estimated on the basis of a generalized linear statistical regression model. RESULTS: On average, image noise was reduced 37.3% with ASIR-V 50% and 71.5% with ASIR-V 100% compared with FBP. ASIR-V shifted the noise power spectrum toward lower frequencies compared with FBP. The spatial resolution of ASIR-V was equivalent or slightly superior to that of FBP, except for the low-contrast object, which had lower resolution. Lesion detection significantly increased with both ASIR-V levels (p = 0.001), with an estimated radiation dose reduction potential of 15% +/- 5% (SD) for ASIR-V 50% and 31% +/- 9% for ASIR-V 100%. CONCLUSION: ASIR-V reduced image noise and improved lesion detection compared with FBP and had potential for radiation dose reduction while preserving low-contrast detectability. PMID- 29702020 TI - Comparing the Diagnostic Accuracy of Ultrasound and CT in Evaluating Acute Cholecystitis. AB - OBJECTIVE: In 2013, a multidisciplinary group at our Veterans Administration hospital collaborated to improve the diagnosis and treatment of patients with acute cholecystitis (AC) at our facility. Our role in this project was to evaluate the diagnostic accuracies of ultrasound (US) and CT. MATERIALS AND METHODS: AC was diagnosed in 60 patients (62 patient encounters) between July 1, 2013, and July 1, 2015. Of these patients, 56 underwent US, 48 underwent CT, and 42 underwent both. For the same time period, 60 patients without AC underwent US and 60 patients without AC underwent CT, and these imaging studies served as comparison studies. The groups were combined for a total of 182 unique patient encounters. A single radiologist reviewed the studies and tabulated the data. RESULTS: The sensitivity of CT for detecting AC was significantly greater than that of US: 85% versus 68% (p = 0.043), respectively; however, the negative predictive values of CT and US did not differ significantly: 90% versus 77% (p = 0.24-0.26). Because there were no false-positives, the specificity and positive predictive values for both modalities were 100%. Among the 42 patients who underwent CT and US, both modalities were positive for AC in 25 patients, CT was positive and US was negative in 10 patients, and US was positive and CT was negative in two patients; in five patients, both US and CT were negative. CONCLUSION: CT was significantly more sensitive for diagnosing AC than US. CT and US are complementary, and the other modality should be considered if there is high clinical suspicion for AC and the results of the first examination are negative. PMID- 29702021 TI - A Women in Radiology Group Fosters Career Development for Faculty and Trainees. AB - OBJECTIVE: The objective of our study was to evaluate the outcomes of a women in radiology (WIR) group during the first 6 years of its existence, including members' satisfaction, activities, and differences based on seniority. MATERIALS AND METHODS: An anonymous questionnaire was distributed to group members. Survey questions were related to the usefulness of sessions, mentoring, professional opportunities, and camaraderie. Comparisons were made on the basis of training status and seniority. Continuous variables were compared using means, t tests, and correlations, and categoric variables were compared using counts, percentages, and chi-square tests or Mantel-Haenszel tests. RESULTS: Surveys were sent to 61 women, including trainees and faculty; the response rate was 49% (38% of trainees and 53% of faculty). Overall satisfaction score for WIR sessions was high (mean summary score, 1.42 +/- 0.37 [SD], with 1 meaning very satisfied and 4 meaning very unsatisfied). Trainees and junior faculty were more likely than senior faculty to report expanded internal networking opportunities (94% vs 69%; p = 0.07), to have gained a mentor (67% vs 8%; p = 0.001), and to have increased research involvement (33% vs 0%; p = 0.02). Both groups were equally likely to have become mentors. Almost all respondents (93%) reported increased camaraderie among women in the department. CONCLUSION: A WIR group can provide career development tools for its members. In this study, trainees and junior faculty reported increased networking and research involvement and gaining a mentor but were equally likely as senior faculty to have become mentors. Most members reported increased camaraderie among women in the department. A WIR group may help to accelerate professional development among trainees and junior faculty, thereby contributing to a more diverse and enabled workforce. PMID- 29702022 TI - Acute Gouty Knee Arthritis: Ultrasound Findings Compared With Dual-Energy CT Findings. AB - OBJECTIVE: The purpose of this study was to compare findings of ultrasound (US) with dual-energy CT (DECT) findings in patients presenting with suspected gouty knee arthritis. SUBJECTS AND METHODS: This prospective study included 65 patients (52 men and 13 women; median age, 61.7 years [range, 38-87 years]) with an initial clinical diagnosis of acute gouty knee arthritis who underwent DECT performed using a 128-MDCT scanner and US performed using a 5-18-MHz transducer. Both intra- and extraarticular findings obtained using each modality were tabulated. RESULTS: DECT identified gout as the final diagnosis for 52 of 65 patients (80.0%). An alternative diagnosis was confirmed for the remaining 13 patients. US detected gout in 31 of 52 patients (sensitivity, 59.6%) and produced findings negative for gout in seven of 13 patients (specificity, 53.8%). The double contour sign on US was positive for gout in 23 of 52 patients (44.2%) and negative in 12 of 13 patients (92.3%). Extraarticular urate deposition was identified by DECT in 44 of 52 patients, compared with identification by US in 11 of 52 patients (p < 0.001). CONCLUSION: The sensitivity of US for the diagnosis of gouty knee arthritis is limited, particularly with respect to extraarticular urate deposition. The double contour sign is the single most valuable sign for the assessment of gouty knee arthritis by US. PMID- 29702023 TI - Skeletal Metastases and Benign Mimics on NaF PET/CT: A Pictorial Review. AB - OBJECTIVE: The aim of this article is to present examples in which sodium fluoride labelled with 18F (NaF) bone PET/CT would be a useful adjunct to guide complex clinical decisions about the staging, restaging, and treatment approach for patients with skeletal metastases and benign causes of NaF activity that can be mistaken for bone metastases. We present a pictorial review of selected cases of this cohort of patients. CONCLUSION: NaF PET/CT hybrid fusion imaging is extremely useful in identifying potential causes of pain in patients with malignancies that have an affinity for skeletal metastases. This technique can help detect bone metastases, in problem solving, and to direct appropriate management. PMID- 29702024 TI - VIDEO: Preoperative CT Angiography for Fibular Free Flap Reconstructions. AB - OBJECTIVE: The objective of this video article is to provide an introduction to the use of fibular free flaps. Normal and variant vascular anatomy of the fibular free flap is discussed, as are imaging acquisition and CT angiography interpretation, computer-assisted design and manufacturing, and the limitations of the fibular free flap. CONCLUSION: The fibular free flap is commonly used for head and neck reconstructive surgery. Variation exists between individuals regarding the origin of the peroneal artery and the perforating arteries. Our method of performing CT angiography and reporting its findings for patients undergoing a fibular free flap procedure provides a reproducible means of identifying important elements of the vasculature and effectively communicating their locations to surgeons. Accurate communication can maximize the success of the flap harvesting and the preoperative manufacture of custom fibular cutting guides. PMID- 29702025 TI - DEPP/DEPP1/C10ORF10 regulates hepatic glucose and fat metabolism partly via ROS induced FGF21. AB - Decidual protein induced by progesterone (DEPP/DEPP1/C10ORF10) is induced by denying access to food and reduced by refeeding in insulin-sensitive organs in vivo. The negative regulation of DEPP by insulin is also proven in several cell lines. However, the functions of DEPP in insulin-sensitive organs remain unknown. In the present study, we investigated the impact of DEPP on hepatic energy metabolism and addressed the underlying mechanisms. The metabolic effects of DEPP were investigated in mice with adenovirus-mediated hepatic overexpression. Liver triglyceride (TG), glycogen, and serum metabolites were detected by biochemical assays. Energy homeostasis was measured by indirect calorimetry. Quantitative PCR was used to examine expression of genes involved in fatty acid oxidation, ketogenesis, lipogenesis, and gluconeogenesis. To evaluate the role of fibroblast growth factor 21 (FGF21) mediating the metabolic effects of DEPP, FGF21 antibody was administrated intraperitoneally to mice at 24 h after the delivery of adenovirus, and the metabolic alterations were examined. Reactive oxygen species (ROS) levels were measured by catalase activity assay, live cell fluorescence, or quantitative PCR. Effects of DEPP on the phenotype of db/db mice were also assessed. Acute hepatic overexpression of DEPP significantly reduced serum glucose and TG levels, dramatically elevated beta-hydroxybutyrate levels, and improved glucose clearance. Compared with controls, DEPP overexpression reduced food intake, the energy expenditure rate, and the respiratory quotient. DEPP overexpression significantly increased fatty acid oxidation and ketogenesis but suppressed lipid synthesis and gluconeogenesis. Investigations of the underlying mechanisms revealed that DEPP regulates energy metabolism by inducing oxidative stress. With the impairment of the ROS scavenging system and promotion of ROS formation, DEPP overexpression leads to ROS accumulation. FGF21 is upregulated in response to oxidative stress and mediates the effects of DEPP on fatty acid oxidation, ketogenesis, and lipid synthesis but not gluconeogenesis, as evidenced by the fact that the FGF21 antibody dramatically suppressed a DEPP-induced increase of fatty acid oxidation and ketogenesis, reversed the reduction of lipid synthesis, but did not change the suppression of gluconeogenesis. Moreover, overexpression of DEPP in db/ db mice led to a marked reduction in body weight and serum glucose levels and significantly improved insulin sensitivity. Hepatic overexpression of DEPP in mice promotes fatty acid oxidation and ketogenesis and suppresses lipogenesis and gluconeogenesis, which is partly mediated by FGF21 induced by elevated cellular ROS levels.-Li, W., Ji, M., Lin, Y., Miao, Y., Chen, S., Li, H. DEPP/DEPP1/C10ORF10 regulates hepatic glucose and fat metabolism partly via ROS-induced FGF21. PMID- 29702027 TI - Green Juice in Human Metabolism: A Randomized Trial. AB - OBJECTIVE: Fruits and vegetables contain many compounds presenting potential antioxidant activity. The objective of this study was to evaluate the effect of a green juice recipe in adult metabolism in order to identify new preventive dietary sources. METHOD: This was a single-blind randomized controlled clinical trial. Recruitment and data were, respectively, made and collected at the Universidade Federal de Ciencias da Saude de Porto Alegre. Individuals who met all the inclusion criteria during the period of recruitment were included. Green juice (experimental group) or placebo (control group) were consumed from Monday to Friday between 8 and 9 am, in the amount of 300 mL for 60 days (except Saturdays and Sundays). To verify the effect of green juice on metabolism, the following were evaluated: (a) glycemia, plasma lipid profile, renal and liver functions, redox profile, and antioxidant enzymes; (b) anthropometry; and (c) well-being and anxiety. RESULTS: This study included 14 participants in the test group (juice group) and 13 controls (placebo group), with mean ages of 31.07 and 30.15 years, respectively. We did not observe a significant difference between the treatments. Dietary properties of vegetable and fruit juices are an area of significant interest. CONCLUSIONS: Together with an analysis of previous works, we suggest that green juice did not cause an improvement in metabolic function and there is a need for further research on this issue, mainly through different interventions and other samples. PMID- 29702026 TI - Dietary polyphenols promote resilience against sleep deprivation-induced cognitive impairment by activating protein translation. AB - Previous evidence has suggested that dietary supplementation with a bioactive dietary polyphenol preparation (BDPP) rescues impairment of hippocampus-dependent memory in a mouse model of sleep deprivation (SD). In the current study, we extend our previous evidence and demonstrate that a mechanism by which dietary BDPP protects against SD-mediated cognitive impairment is via mechanisms that involve phosphorylation of the mammalian target of rapamycin complex 1 and its direct downstream targets, including the eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) and the ribosomal protein S6 kinase beta-1 (p70S6K). In additional mechanistic studies in vitro, we identified the brain bioavailable phenolic metabolites derived from the metabolism of dietary BDPP that are responsible for the attenuation of SD-mediated memory impairments. On the basis of high-throughput bioavailability studies of brain bioavailable metabolites after dietary BDPP treatment, we found that select polyphenol metabolites [ e.g., cyanidin-3'- O-glucoside and 3-(3'-hydroxyphenyl) propionic acid] were able to rescue mTOR and p70S6K phosphorylation in primary cortico hippocampal neuronal cultures, as well as rescue 4E-BP1 phosphorylation in response to treatment with 4EGI-1, a specific inhibitor of eIF4E-eIF4G interaction. Our findings reveal a previously unknown role for dietary polyphenols in the rescue of SD-mediated memory impairments via mechanisms involving the promotion of protein translation.-Frolinger, T., Smith, C., Cobo, C. F., Sims, S., Brathwaite, J., de Boer, S., Huang, J., Pasinetti, G. M. Dietary polyphenols promote resilience against sleep deprivation-induced cognitive impairment by activating protein translation. PMID- 29702028 TI - Association of Binge Eating Behavior with Total and Abdominal Adipose Tissue in a Large Sample of Participants Starting a Weight Loss or Maintenance Program. AB - OBJECTIVE: It is not clear whether binge eating (BE) behavior is associated with body composition independently of body mass index (BMI). Our aim has been to evaluate the BMI-independent contribution of BE severity and BE status on the total amount of fat mass and abdominal fat distribution in a large sample of participants. METHOD: We performed a cross-sectional study among 8524 participants followed at a nutritional center. BMI and waist circumference (WC) were measured, body fat (BF) was estimated by skinfold measurement, and abdominal visceral (VAT) and subcutaneous (SAT) adipose tissues were measured by ultrasonography. BE was assessed using the Binge Eating Scale (BES). The association between the continuous BES score (BE severity) and adiposity was assessed in the whole sample after adjustment for BMI and other confounders. The effect of BE status on adiposity was also assessed by matching binge eaters (BES >= 18), for sex, age, and BMI, with non-binge eaters (BES < 18). RESULTS: We found that 17.7% of the participants were binge eaters. Continuous BES score was associated with increasing WC (0.03 cm, 95% confidence interval [CI], 0.02 to 0.05 every 1 BES unit, p < 0.001) and decreasing BF (0.01%, 95% CI, -0.02 to 0.00 every 1 BES unit, p = 0.003). No association was found between BE severity and VAT and SAT. After matching, the BF of binge eaters was 0.29% (95% CI, -0.50 to -0.07, p = 0.01) lower than that of non-binge eaters. CONCLUSIONS: Given the very small effect size, BE severity and status are not associated in a biologically meaningful manner with BF content and distribution. PMID- 29702031 TI - Corepresentation During Joint Action in Marmoset Monkeys ( Callithrix jacchus). AB - Behavioral coordination is a fundamental element of human cooperation. It is facilitated when individuals represent not only their own actions but also those of their partner. Identifying whether action corepresentation is unique to humans or also present in other species is therefore necessary to fully understand the evolution of human cooperation. We used the auditory joint Simon task to assess whether action corepresentation occurs in common marmosets, a monkey species that engages extensively in coordinated action during cooperative infant care. We found that marmosets indeed show a joint Simon effect. Furthermore, when coordinating their behavior in the joint task, they were more likely to look at their partner than in a joint control condition. Corepresentation is thus not unique to humans but also present in the cooperatively breeding marmosets. Since marmosets are small-brained monkeys, our results suggest that routine coordination in space and time, rather than complex cognitive abilities, plays a role in the evolution of corepresentation. PMID- 29702030 TI - Effects of co-exposure to lead and zinc on redox status, kidney variables, and histopathology in adult albino rats. AB - Lead (Pb) is a toxic metal that induces a wide range of biochemical and physiological effects in humans. Oxidative damage has been proposed as a possible mechanism involved in Pb toxicity. The current study was carried out to evaluate the antioxidant activities of zinc (Zn) supplement against lead acetate-induced kidney injury in rats. In this study, adults male rats were treated for 15 days with Pb (0.344 g/kg body weight (bw)) associated or not with Zn (10 mg/kg bw). Our study showed that supplementation with Zn prevented renal dysfunction as indicated by plasma biomarkers (urea, uric acid, creatinine, lactate dehydrogenase, and alkaline phosphatase levels) and oxidative stress-related parameters (thiobarbituric acid reactive substances, protein carbonyl, advanced oxidation protein product, superoxide dismutase, catalase, glutathione peroxidase, and vitamins (A, E)) in kidney tissue. The corrective effect of Zn on Pb-induced kidney nephrotoxicity recovered normal kidney histology. Overall, this study indicates that Zn alleviated the toxic effects of this heavy metal on renal tissue, suggesting its role as a potential antioxidant and nephroprotective agent. PMID- 29702029 TI - The Influence of Habitual Protein Intake on Body Composition and Muscular Strength in Career Firefighters. AB - OBJECTIVE: The aim of this research was to determine the relationship among protein (PRO) intake, body composition, and muscle strength in overweight and obese firefighters. A secondary objective was to evaluate differences in body composition and muscle strength among overweight and obese firefighters with low (L; < 0.8 g.kg-1), moderate (M; 0.8-1.0 g.kg-1), and high (H; > 1.0 g.kg-1) PRO intake. METHODS: Relative PRO intake [r_PRO] was evaluated from 3-day dietary logs, self-reported by 43 overweight and obese male career firefighters (mean +/- standard deviation; age = 37.3 +/- 7.2 years; body mass index = 33.2 +/- 5.0 kg.m 2; percent body fat [%BF] = 28.9 +/- 4.0%). Body composition (fat mass [FM], %BF, lean mass [LM], percent LM [%LM]) and muscle strength (peak torque [PT], relative peak torque [r_PT] of the leg extensors) were measured using dual-energy x-ray absorptiometry and isokinetic dynamometry, respectively. RESULTS: Greater r_PRO was associated with less FM, %BF, LM (r = -0.498 to -0.363) and greater %LM (r = 0.363), but not muscle strength (p > 0.05). Fat mass (r = -0.373) and %BF (r = 0.369) were associated with lower r_PT; %LM was associated with greater r_PT (r = 0.373). Individuals with L r_PRO had greater FM (mean difference +/- standard error: L-H = 10.08 +/- 3.18 kg), %BF (L-H = 3.8% +/- 1.4%) and lower %LM (L-H = 3.7% +/- 1.3%) than those with H r_PRO (p < 0.05) but no significant differences in muscle strength (p > 0.05). CONCLUSIONS: Protein intake > 0.8 g.kg-1 was associated with more favorable body composition in male career firefighters. PMID- 29702032 TI - Effect of Midmorning Puree Snacks on Subjective Appetite, Food Intake, and Glycemic and Insulin Responses in Healthy Adults. AB - OBJECTIVE: Dietary pattern changes, as a part of a healthy lifestyle, may improve weight management. The objective of this study was to examine the effect of midmorning puree snacks varying in macronutrient composition and energy content on subjective appetite, food intake, and glycemic and insulin responses in healthy adults. METHOD: In a randomized, repeated measures crossover design, 6 treatments (snack skipping and purees: control [186 kcal], maltodextrin [272 kcal], whey protein [201 kcal], oat [276 kcal], and coconut oil [276 kcal]) were administered to 23 normal weight adults (n = 14 males, n = 9 females). Subjective appetite, blood glucose, and insulin responses were measured at regular intervals for 2 hours immediately followed by an ad libitum pizza lunch. In vitro digestion experiments were conducted to corroborate results of the human trial. RESULTS: Compared to snack skipping, all snack treatments similarly reduced subjective average appetite (net area under the curve), but only oat (p < 0.032) and coconut oil (p < 0.031) purees significantly decreased test meal food intake. However, caloric compensation did not differ among snack treatments (p < 0.73). Both blood glucose (incremental area under the curve [iAUC]; p < 0.0001) and serum insulin (iAUC; p < 0.0001) were affected by treatment. A positive correlation was found between blood glucose iAUC and in vitro glucose release (r = 0.993, p < 0.0001). The release of free fatty acids (FFAs) was sustained, and oats were difficult to disintegrate during in vitro digestion. CONCLUSIONS: Compared with snack skipping, coconut oil and oat puree snacks suppressed short-term food intake, which was likely due to the sustained release of FFA and slowly digestible oats, respectively. Our in vitro digestion model predicted the relative differences in the glycemic response in vivo. PMID- 29702033 TI - Adding Multimedia Cues to Medical Providers' Online Biographies: Do Pictures, Video, and B-Roll Matter? AB - Developing engaging online healthcare provider biographies for prospective patients to consult is becoming a big business. Health-care systems are beginning to add more multichannel components-like videos-to these provider search tools at increasingly higher costs. Prior research finds that prospective patients desire videos offering additional footage (i.e., b-roll) displaying how a provider might interact with a patient during a consultation. Shooting and editing b-roll footage to add to providers' videos takes additional time and resources. Using predictions and questions generated from uncertainty reduction and cue summation theories, this study sought to determine whether the addition of multichannel media (e.g., a video with added b-roll) offers any greater effects in the form of reduced uncertainty, provider likability, patient satisfaction, or trust than biographies providing fewer multichannel cues. A between-subjects online experiment randomly exposed participants (n = 523) to one of four biographies with increasing levels of multichannel components (i.e., text only biography, text with picture, video, video with b-roll). Results revealed that the two video biographies generated more significant effects than text-only biographies. However, the biography with just the video of the provider (i.e., a-roll only) and the video including added b-roll were not significantly different from one another on any of the dependent variables measured. These findings indicate that there may be a limit to the number of multichannel components needed to be an effective biography to help patients select their next healthcare provider. Both theoretical and practical implications of these results are discussed, in addition to future directions for research. PMID- 29702034 TI - The Political Self: How Identity Aligns Preferences With Epistemic Needs. AB - Numerous studies have indicated that the need for closure predicts political preferences. We examined a potential moderator of this relationship: political identity centrality, or the extent to which individuals' political preferences are central to their self-concept. We tested three hypotheses. First, we predicted that need for closure would be more strongly related to political identity (symbolic ideology and party identification; Hypothesis 1) and issue positions (operational ideology; Hypothesis 2) among individuals who see their political preferences as more self-central. Then we predicted that the stronger relationship between need for closure and issue positions among individuals high in centrality would be accounted for by stronger relationships between need for closure and political identity and between political identity and issue positions (Hypothesis 3). Data from a nationally representative survey provide evidence for these hypotheses, suggesting that the relationship between epistemic needs and political preferences differs as a function of how self-relevant politics is. PMID- 29702035 TI - Occupational tuberculosis in healthcare workers in sub-Saharan Africa: A systematic review. AB - This article investigates the incidence, prevalence and factors associated with occupational tuberculosis (TB) in healthcare workers (HCWs) in sub-Saharan Africa (SSA). Studies were extracted from MEDLINE, PsycINFO, CINAHL, Cochrane Library, and SCOPUS databases following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement from inception to the 2nd of June 2017. Twenty-one studies met the inclusion criteria. The median prevalence of latent TB infection in HCWS was 62% (IQR 22%) and the median incidence of TB disease was 3871/100,000 (IQR 9314/100,000). The risk factors associated with LTBI or active TB disease were workplace, history of contact with TB patients, and longer duration of employment. The findings of this review demonstrate that the risk of acquiring TB among HCWs in SSA is high. This may impact on the recruitment, longevity and retention of HCWs. PMID- 29702037 TI - Profiling analysis of 17beta-estradiol-regulated lncRNAs in mouse thymic epithelial cells. AB - Thymus is the primary organ for T cell differentiation and maturation. Many studies have demonstrated that estrogen plays a crucial role in thymic epithelial cell (TEC) proliferation during thymic involution. LncRNAs are involved in various biological processes; however, estrogen-mediated lncRNA expression in TECs has not been yet reported. To address this question, the mouse medullary thymic epithelial cell line 1 (MTEC1) was treated with 17beta-estradiol (E2). By using CCK8 assay and flow cytometry, we found that E2 was able to inhibit viability and proliferation of MTEC1 cells. The expression profiles of lncRNAs in MTEC1 cells with or without E2 treatment were then measured by RNA-Seq, and a total of 962 lncRNAs and 2,469 mRNAs were shown to be differentially expressed. The reliability of RNA-Seq was confirmed by quantitative RT-PCR. Correlation analysis was conducted to investigate the potential function of lncRNAs. According to gene ontology (GO) analysis, differentially expressed lncRNAs were mainly related to cell proliferation, cell cycle and cell apoptosis. KEGG pathway analysis indicated that these lncRNAs were associated with several pathways, namely immunological activity, metabolism and cytokine-cytokine receptor interaction. In conclusion, our study provided a novel direction for studying the relationship between lncRNAs and E2 in the thymus. PMID- 29702038 TI - Fear, Sadness and Hope: Which Emotions Maximize Impact of Anti-Tobacco Mass Media Advertisements among Lower and Higher SES Groups? AB - Emotive anti-tobacco advertisements can increase quitting. Discrete emotion theories suggest evoking fear may be more effective than sadness; less research has focused on hope. A weekly cross-sectional survey of smokers and recent quitters (N = 7683) measured past-month quit attempts. The main predictor was level of exposure to four different types of anti-tobacco advertisements broadcast in the two months prior to quit attempts: advertisements predominantly evoking fear, sadness, hope, or evoking multiple negative emotions (i.e., fear, guilt, and/or sadness). Greater exposure to fear-evoking advertisements (OR = 2.16, p < .01) increased odds of making a quit attempt and showed similar effectiveness among those in lower and higher SES areas. Greater exposure to advertisements evoking multiple negative emotions increased quit attempts (OR = 1.70, p < .01), but interactions indicated this was driven by those in lower SES, but not higher SES areas. Greater exposure to hope-evoking advertisements enhanced effects of fear-evoking advertisements among those in higher SES, but not lower SES areas. Findings suggest to be maximally effective across the whole population avoid messages evoking sadness and use messages eliciting fear. If the aim is to specifically motivate those living in lower SES areas where smoking rates are higher, multiple negative emotion messages, but not hope-evoking messages, may also be effective. PMID- 29702039 TI - Communication and Healthcare: Self-Reports of People with Hearing Loss in Primary Care Settings. AB - OBJECTIVES: To assess the experiences of people with hearing loss in healthcare environments to characterize miscommunication and unmet needs, and guide recommendations for improving outcomes and access. METHODS: Anonymous survey developed by subject-matter experts was posted on a large national hearing-loss consumer and advocacy organization website and email listserv. Data were collected and managed via RedCAP. RESULTS: Responses were received from 1581 individuals. Respondents reported moderate or significant difficulty communicating with all listed providers. Three communication situations emerged as often presenting communication difficulties: hearing one's name when called in the waiting room, hearing when the speaker's back was turned, and hearing when communicating by telephone. Despite 93% of respondents indicating they sometimes or often let providers know about their hearing loss, 29.3% of all respondents still reported that no arrangements were made to improve communication. CONCLUSIONS: This study clearly demonstrates the ongoing difficulties faced by individuals with hearing loss, particularly older adults, as they attempt to navigate both providers and situations associated with a typical primary care office visit. CLINICAL IMPLICATIONS: Inexpensive and efficient changes to improve communication include (1) Improving one-on-one provider communication by facing the individual with good lighting, clear speaking, and not obstructing one's mouth; (2) Environmental changes such as using visual or tactile alerting devices in waiting rooms and adding noise-dampening carpeting and curtains; and (3) Avoiding telephones and conveying health information in writing. PMID- 29702036 TI - Regulators of G protein signaling in cardiovascular function during pregnancy. AB - G protein-coupled receptor signaling mechanisms are implicated in many aspects of cardiovascular control, and dysfunction of such signaling mechanisms is commonly associated with disease states. Investigators have identified a large number of regulator of G protein signaling (RGS) proteins that variously contribute to the modulation of intracellular second-messenger signaling kinetics. These many RGS proteins each interact with a specific set of second-messenger cascades and receptor types and exhibit tissue-specific expression patterns. Increasing evidence supports the contribution of RGS proteins, or their loss, in the pathogenesis of cardiovascular dysfunctions. This review summarizes the current understanding of the functional contributions of RGS proteins, particularly within the B/R4 family, in cardiovascular disorders of pregnancy including gestational hypertension, uterine artery dysfunction, and preeclampsia. PMID- 29702040 TI - Impact of Diets Rich in Whole Grains and Fruits and Vegetables on Cardiovascular Risk Factors in Overweight and Obese Women: A Randomized Clinical Feeding Trial. AB - OBJECTIVE: Previous interventions have reported desirable effects of diets rich in whole grains or rich in fruits and vegetables on cardiovascular disease (CVD) risk factors and weight management. However, data are lacking regarding the effect of these fiber sources separately. The aim of this randomized clinical feeding trial was to investigate the effects of fiber-rich diets with different sources of fiber (fruits, vegetables, and whole grains) on weight loss and CVD risk factors in overweight and obese women. METHODS: Overweight and obese women (N = 75) were randomized to one of three weight loss diets that were rich in whole grains, fruits and vegetables, or both for 10 weeks. Body weight, waist circumference, and risk factors of CVD were examined at baseline and 10 weeks. RESULTS: During the 10-week dietary intervention phase, the reductions in weight (p = 0.03), waist circumference (p = 0.001), systolic blood pressure (p = 0.04), fasting blood sugar (p = 0.03), and triglycerides (p = 0.001) were higher in the whole grains group compared with the fruits and vegetables group or the combination diet group. Also, the whole grain group had a greater increase (p = 0.01) in high-density lipoprotein cholesterol compared to the other groups. The change in other risk factors, including diastolic blood pressure and low-density lipoprotein cholesterol, was not different among the three diet groups. Within group comparisons revealed significant reductions in weight, waist circumference, and fasting blood sugar in all groups. Only the fruits and vegetables group and the whole grains group had significant decreases in low-density lipoprotein cholesterol over 10 weeks (p <= 0.03). CONCLUSIONS: This trial suggests that in overweight and obese women, a weight loss diet rich in whole grains may have a more beneficial effect on CVD risk factors than diets rich in fruits and vegetables or a combination of whole grains and fruits and vegetables. PMID- 29702041 TI - Influence of the C677T Polymorphism of the MTHFR Gene on Oxidative Stress in Women With Overweight or Obesity: Response to a Dietary Folate Intervention. AB - : The C677T polymorphism of the methylenetetrahydrofolate reductase gene (MTHFR) is related to folate metabolism and can alter the levels of biochemical markers. OBJECTIVE: Investigate the influence of the MTHFR C677T polymorphism on the effects of a dietary folate intervention on oxidative stress in women with overweight or obesity. METHODS: Forty-eight adult women with overweight or obesity were subjected to a 24-hour dietary recall, anthropometric measurements, biochemical analysis, and genotyping of the MTHFR C677T polymorphism. They were allocated by convenience sampling to 2 groups, which received 300 g of folate rich vegetables containing 191 ug/d (Group 1) (n = 24) or 95 ug/d (Group 2) (n = 24) of folate for 8 weeks. RESULTS: The dietary intervention increased the serum folic acid levels in the 2 analyzed groups. The intervention with 191 ug/d of folate led to relevant results in terms of homocysteine levels (p = 0.0005) and total antioxidant capacity (p = 0.0261); the effect was larger among carriers of the TT genotype. CONCLUSIONS: The study demonstrated the beneficial effect of folate intake in terms of a TAC elevation for the CC and TT genotypes of the MTHFR C677T polymorphism, an increase in folic acid levels for all genotypes, and a reduction in the Hcy levels for the TT genotype in response to an intervention consisting of an intake of 191 ug/d of folate supplied by vegetables. PMID- 29702042 TI - Corrigendum. PMID- 29702043 TI - A range of kindness activities boost happiness. AB - This experiment investigates the effects of a seven-day kindness activities intervention on changes in subjective happiness. The study was designed to test whether performing different types of kindness activities had differential effects on happiness. Our recent systematic review and meta-analysis of the psychological effects of kindness (Curry, et al. 2018) revealed that performing acts of kindness boosts happiness and well-being. However, we noted in that review that rarely had researchers specifically compared the effects of kindness to different recipients, such as to friends or to strangers. Thus in a single factorial design (n=683) we compare acts of kindness to strong social ties, weak social ties, novel acts of self kindness, and observing acts of kindness, against a no acts control group. The results indicate that performing kindness activities for seven days increases happiness. In addition, we report a positive correlation between the number of kind acts and increases in happiness. Neither effect differed across the experimental the groups, suggesting that kindness to strong ties, to weak ties, and to self, as well as observing acts of kindness, have equally positive effects on happiness. PMID- 29702044 TI - New partnerships in widowhood in Spain: Realities and desires. AB - Widowhood has traditionally been associated with the end of the family cycle; however, social and generational transformations in Spain are providing a new context for the development of new partnerships in widowhood. This study analyzes widowed persons who have found new partners and those who would be willing to do so, focusing on their characteristics and motives and related sociodemographic factors. Research is based on a sample of 306 widows and widowers in Spain taken from the survey Social Networks and Well-Being. The results reveal the importance of sociodemographic factors for both those who wish to have a partner as well as for those who have one. For the former, elements associated with quality of life are very important, while among those with a new partner, the key is not having an extensive family support network. The principal motives for looking for a new relationship are related to enjoying life more and not feeling alone; while those who reject a new relationship do so because of the belief that their lost partner is irreplaceable. PMID- 29702045 TI - Positron Emission Tomography (PET) and Pharmacokinetics: Classical Blood Sampling Versus Image-Derived Analysis of [18F]FAZA and [18F]FDG in a Murine Tumor Bearing Model. AB - PURPOSE: Pharmacokinetic (PK) data are generally derived from blood samples withdrawn serially over a defined period after dosing. In small animals, blood sampling after dosing presents technical difficulties, particularly when short time intervals and frequent sampling are required. Positron emission tomography (PET) is a non-invasive functional imaging technique that can provide semi quantitative temporal data for defined volume regions of interest (vROI), to support kinetic analyses in blood and other tissues. The application of preclinical small-animal PET to determine and compare PK parameters for [18F]FDG and [18F]FAZA, radiopharmaceuticals used clinically for assessing glucose metabolism and hypoxic fractions, respectively, in the same mammary EMT6 tumor bearing mouse model, is reported here. METHODS: Two study groups were used: normal BALB/c mice under isoflurane anesthesia were intravenously injected with either [18F]FDG or [18F]FAZA. For the first group, blood-sampling by tail artery puncture was used to collect blood samples which were then analyzed with Radio microTLC. Dynamic PET experiments were performed with the second group of mice and analyzed for blood input function and tumor uptake utilizing a modified two compartment kinetic model. Heart and inferior vena cava vROIs were sampled to obtain image-derived data. PK parameters were calculated from blood samples and image-derived data. Time-activity curves (TACs) were also generated over regions of liver, kidney and urinary bladder to depict clearance profiles for each radiotracer. RESULTS: PK values generated by classical blood sampling and PET image-derived analysis were comparable to each other for both radiotracers. Heart vROI data were suitable for analysis of [18F]FAZA kinetics, but metabolic uptake of radioactivity mandated the use of inferior vena cava vROIs for [18F]FDG analysis. While clearance (CL) and blood half-life (t1/2) were similar for both [18F]FDG and [18F]FAZA for both sampling methods, volume of distribution yielded larger differences, indicative of limitations such as partial volume effects within quantitative image-derived data. [18F]FDG underwent faster blood clearance and had a shorter blood half-life than [18F]FAZA. Kinetic analysis of tumor uptake from PET image data showed higher uptake and longer tumor tissue retention of [18F]FDG, indicative of the tumor's glucose metabolism rate, versus lower tumor uptake and retention of [18F]FAZA. While [18F]FAZA possesses a somewhat greater hepatobiliary clearance , [18F]FDG clears faster through the renal system which results in faster radioactivity accumulation in the urinary bladder. CONCLUSIONS: The present study provides a working example of the applicability of functional PET imaging as a suitable tool to determine PK parameters in small animals. The comparative analysis in the current study demonstrates that it is feasible to use [18F]FDG PET and [18F]FAZA PET in the same model to analyze their blood PK parameters, and to estimate kinetic parameters for these tracers in tumor. This non-invasive imaging-based determination of tissue kinetic parameters facilitates translation from pre-clinical to clinical phases of drug development. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 29702046 TI - Are Excipients Inert? Phenytoin Pharmaceutical Investigations with New Incompatibility Insights. AB - PURPOSE: The U.S. Pharmacopeia defines excipients as substances other than the active pharmaceutic ingredient (API) that are added in a drug delivery system in order to aid in the manufacturing process and enhance stability, bioavailability, safety, effectiveness and delivery of the drug. The 1968 phenytoin intoxication outbreak in Brisbane, Australia, is a classic example of an API-excipient interaction. When administered with CaSO4 the absorption of phenytoin was reduced due to an interaction between the API and the excipient. When CaSO4 was replaced by lactose, the amount of drug absorbed was much higher, resulting in the observed intoxication. It was hypothesized that phenytoin was converted to a calcium salt prior to ingestion. The purpose of this study was to mechanistically investigate the interactions between excipients and phenytoin to confirm the hypothesis of the previous reports. METHODS: Titration experiments with phenytoin and calcium salt were performed. Isothermal micro calorimetry was used to determine incompatibilities between excipients, phenytoin and milk. NMR was used to characterize the compounds. Dissolution tests containing CaSO4, lactose or sorbitol as excipients were also performed. Both Canadian and United States of America commercially available capsules were tested with milk and water. RESULTS: The calorimeter results indicate that phenytoin sodium interacts with CaSO4 in aqueous media and the dissolution profile of CaSO4 containing capsules showed a reduced dissolution rate. In addition, phenytoin sodium also interacts with lactose through a Maillard reaction that can occur at body temperature. Likewise, commercial Phenytoin sodium products interacted with milk and the products containing lactose showed browning in water. CONCLUSION: In Canada and the USA, the reference product contains lactose as an excipient in the formulation, whereas the Canadian generic formulations do not contain lactose. Any clinical relevance of these difference has not been determined. A new incompatibility between phenytoin and lactose has been discovered and an incompatibility with calcium was confirmed, which may have implications in regard to excipients and food effects. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 29702047 TI - Pharmaceutical Characterization of MyoNovin, a Novel Skeletal Muscle Regenerator: in silico, in vitro and in vivo Studies. AB - PURPOSE: MyoNovin is a novel skeletal muscle-regenerating compound developed through synthesis of two nitro groups onto a guaifenesin backbone to deliver nitric oxide to skeletal muscle with a potential to treat muscle atrophy. The purpose of this study was to utilize in silico, in vitro, and in vivo approaches to characterize MyoNovin and examine its safety, biodistribution, and feasibility for drug delivery. METHODS: In silico software packages were used to predict the physicochemical and biopharmaceutical properties of MyoNovin. In vitro cardiotoxicity was assessed using human cardiomyocytes (RL-14) while effects on CYP3A4 metabolic enzyme and antioxidant activity were examined using commercial kits. A novel HPLC assay was developed to measure MyoNovin concentration in serum, and delineate initial pharmacokinetic and acute toxicity after intravenous administration (20 mg/kg) to male Sprague-Dawley rats. RESULTS: MyoNovin showed relatively high lipophilicity with a LogP value of 3.49, a 20-fold higher skin permeability (19.89 cm/s*107) compared to guaifenesin (0.66 cm/s*107), and ~10 fold higher effective jejunal permeability (2.24 cm/s*104) compared to guaifenesin (0.26 cm/s*104). In vitro, MyoNovinwas not cytotoxic to cardiomyocytes at concentrations below 8 MUM and did not inhibit CYP3A4 or show antioxidant activity. In vivo, MyoNovin had a short half-life (t1/2) of 0.16 h, and a volume of distribution Vss of 0.62 L/kg. Biomarkers of MyoNovincardiac and renal toxicity did not differ significantly from baseline control levels. CONCLUSIONS: The predicted high lipophilicity and skin permeability of MyoNovin render it a potential candidate for transdermal administration while its favourable intestinal permeation suggests it may be suitable for oral administration. Pharmacokinetics following IV administration of MyoNovin were delineated for the first time in a rat model. Preliminary single 20 mg/kg dose assessment of MyoNovin suggest no influenceon cardiac troponin or beta-N Acetylglucosaminidase. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 29702048 TI - Nerve Transfer Surgery for Penetrating Upper Extremity Injuries. AB - CONTEXT: Nerve transfer surgery is an option for repair of penetrating injuries of the upper extremity. In the right setting, it has advantages over tendon transfers and nerve grafting. OBJECTIVE: To review our experience since 2006 of nerve transfer surgery in the upper extremities. DESIGN: We included cases performed to repair penetrating trauma within three months of injury with at least three years' follow-up. MAIN OUTCOME MEASURES: Preoperative and postoperative muscle strength of the affected extremity. RESULTS: All 16 patients were males aged 16 to 43 years. Six patients underwent nerve transfer surgery because of elbow flexion; 5, finger extension; 3, finger flexion; and 2, wrist pronation. Nine patients (56%) had associated vascular injury, and 4 (25%) had fractures. Average follow-up was 6 years. No perioperative complications occurred. Patients had a mean of 3.7 operations after the initial trauma. All patients received physical therapy. All patients improved from 0 of 5 muscle strength preoperatively to a mean of 3.8 (range = 2/5 to 5/5) within 1 year after surgery. In all cases, strength was maintained, and 8 (50%) had continued improvement after Year 1. Ten (63%) returned to their previous employment level. Mean Disabilities of the Arm, Shoulder and Hand score improved from 68 to 83 postoperatively. CONCLUSION: Nerve transfer is a safe, effective technique for correcting penetrating trauma-related nerve injury. In appropriate patients it offers advantages over other techniques. Outcomes can be maintained long term, and many patients can return to their previous level of function. PMID- 29702050 TI - A Patient-Centered Approach to a Rural General Practice in Distress and the Search for a Solution. AB - CONTEXT: A general practice in rural UK (Cumbria) was overwhelmed by staff burnout. OBJECTIVE: To present a case study for how the staff of a practice came together, used data, agreed on a plan for improvement, implemented the plan, improved subjective distress, and objectively evaluated the intervention. DESIGN: We conducted an audit using the electronic health record for patients coming to the practice 5 or more times annually from 2008 to 2012 (frequent attenders). We planned an intervention to reduce utilization (frequency of visits) while still serving patients. The intervention used a genogram, psychoeducation, and up to six 30-minute sessions of solutions-focused psychotherapy, in which difficult interpersonal relationships were identified and efforts were made to resolve 1 major problem related to those relationships. MAIN OUTCOME MEASURES: Quantitative data (number of visits per year) and qualitative data about the changes that resulted in the practice from the audit and the intervention. RESULTS: The frequency of visits for patients with mental health conditions (41.0% of all frequent attenders in the practice) dropped significantly from 2007 to 2012 (p = 0.019; initial visits per year, 10.0, standard deviation = 2.51; final visits per year = 5.6, standard deviation = 3.8). The frequency of visits for patients without mental health diagnoses did not change. CONCLUSION: Intervening with frequent attenders of primary care who have mental health conditions improved their symptoms and reduced their health care utilization, with beneficial impact on practitioners and improvement in the morale of the staff. PMID- 29702049 TI - Adverse Childhood Experiences among a Community of Resilient Centenarians and Seniors: Implications for a Chronic Disease Prevention Framework. AB - CONTEXT: Research has linked adverse childhood experiences (ACEs) with chronic disease in adults and diminished life span. Adverse biological embedding of ACEs potentially occurs through inflammatory mechanisms; inflammatory marker alterations are identified as candidate biomarkers for mediating health consequences. Lifestyle practices of residents of California's Loma Linda Blue Zone, one of five worldwide longevity hotspots, may provide insight into inflammation remediation and chronic disease prevention. Little research has been done on centenarians' early-life experiences or on ACEs in a longevity community. OBJECTIVE: To interview centenarians and seniors in this region regarding their childhood experiences to inform chronic disease prevention frameworks. DESIGN: Qualitative study of Loma Linda Blue Zone community members. Childhood exposures and practices were assessed using focus groups and semistructured key informant interviews, with open-ended questions on general hardships and ACEs and supplemented with lifestyle and resiliency factor questions. Data were audiorecorded and transcribed. Integrative grounded theory methods guided coding and theming. MAIN OUTCOME MEASURES: Exposure to ACEs and practice of resiliency factors. RESULTS: Participants (7 centenarians and 29 seniors) reported exposure to multiple ACEs (domains: Economic deprivation, family dysfunction, and community violence). Community members reported practicing resiliency factors, each with anti-inflammatory properties suggesting mitigation of ACE-related toxic stress. CONCLUSION: This is one of the first studies of its kind to identify a community of resilient members despite their tremendous burden of ACEs. Embedding the identified resiliency factors into chronic disease prevention frameworks has potential for mitigating systemic inflammation, alleviating chronic disease burden, and promoting a culture of health. PMID- 29702051 TI - Blue Eyes. PMID- 29702052 TI - Nebraska Farm Scenes. PMID- 29702053 TI - Thoughts on Sexual Health. AB - As a practicing obstetrician/gynecologist for more than 18 years, I have realized the importance of sexual health as well as the embarrassing lack of training in this very important part of our patients' overall mental and physical health. If anyone should be expected to be not only comfortable but knowledgeable about sex, it should be us. Unfortunately, many of us had little or no education in sexual health during medical school or residency. I have been on a journey to educate myself so I might better help my patients. PMID- 29702054 TI - Prevalence and Safety of Intravenous Immunoglobulin Administration During Maintenance Chemotherapy in Children with Acute Lymphoblastic Leukemia in First Complete Remission: A Health Maintenance Organization Perspective. AB - CONTEXT: Children with acute lymphoblastic leukemia (ALL) in first complete remission (CR1) experience hypogammaglobulinemia and are at risk of sepsis during maintenance chemotherapy. Intravenous immunoglobulin (IVIG) has been used to try to circumvent this risk, but no data exist regarding its safety and prevalence in a health maintenance organization. OBJECTIVE: To evaluate the prevalence and safety of IVIG in children with ALL in CR1 during maintenance chemotherapy. DESIGN: A multicenter, retrospective cohort study of consecutive children with ALL in CR1 during maintenance chemotherapy from 2008 to 2014. Groups treated with or without IVIG were compared using nonparametric statistics. Multivariate logistic regression involved all variables available before maintenance therapy began. RESULTS: One hundred eighteen patients were included (53% males), aged 9 months to 19 years. Thirty of 31 patients (97%) who had immunoglobulins analyzed before IVIG were hypogammaglobulinemic. Thirty-six patients (30%) received IVIG during maintenance chemotherapy. Patients received an average of 10.5 IVIG doses (range = 1-31). Ninety-seven percent of doses were administered without a transfusion reaction. Other factors associated with IVIG use were prior double delayed intensification (odds ratio = 5.36, 95% confidence interval = 1.3-27.49, p = 0.026) and episodes of bacteremia or fungemia before maintenance chemotherapy (odds ratio = 3.04, 95% confidence interval = 1.25-7.51, p = 0.015). CONCLUSION: Use of IVIG in children with ALL in CR1 with hypogammaglobulinemia occurred in approximately 30% of patients and was well tolerated. Administration of IVIG significantly correlated with a history of double-delayed intensification and prior bacteremia or fungemia. PMID- 29702055 TI - Barriers and Facilitators to the Deprescribing of Nonbenzodiazepine Sedative Medications Among Older Adults. AB - INTRODUCTION: Nonbenzodiazepine sedative-hypnotic medications, or "Z-drugs," are commonly used to treat insomnia among older adults (>= 65 years), despite a lack of evidence of long-term effectiveness and evidence linking long-term use with poor outcomes. OBJECTIVE: To understand patient and clinician barriers and facilitators to deprescribing, or discontinuation, of Z-drugs. METHODS: We conducted a qualitative interview study among older adults who received a deprescribing intervention and among their clinicians at Kaiser Permanente Northwest. Semistructured interviews explored perceived barriers and facilitators to successful deprescribing of Z-drugs. Interviews were audiorecorded with participant permission. Content was analyzed using QSR NVivo 10 software. RESULTS: From the perspectives of patients, the greatest challenges to deprescribing are factors related to their insomnia, including the need for effective treatment of their insomnia; health care system factors, including a desire for personalized approaches to care; and their own positive personal experiences with sedative medication use. From the clinician perspective, a lack of institutional structures and resources to support deprescribing, the attitudes and practices of previous clinicians, and patient-related factors such as dependence and a lack of alternatives to treat insomnia were the most important barriers to deprescribing. CONCLUSIONS: Health care systems must provide individualized care that supports patient goals for restful sleep and quality of life while also providing evidence-based care that takes patient safety into account. To accomplish this, systems must support patients and clinicians and provide a multidisciplinary approach that addresses insomnia treatment, provides patient education about sedative medication use, and supports the discontinuation process. PMID- 29702056 TI - Association of Psychiatric Diagnostic Conditions with Hospital Care Outcomes of Patients with Orthopedic Injuries. AB - CONTEXT: Psychiatric comorbidity is common in orthopedic injury, but the effects on hospital care outcomes have been identified only generally. OBJECTIVE: To quantify psychiatric comorbidity and its outcome effects in a large, multicenter population of inpatients with orthopedic injuries. DESIGN: Retrospective analysis of patient discharge data from 507 California hospitals from 2001 to 2010. Study sample included orthopedic diagnoses using International Classification of Diseases codes for major pelvic and lower extremity injuries in patients older than age 17 years. From the injury data, we extracted psychiatric diagnoses, alcoholism, substance abuse, and sociodemographic characteristics. MAIN OUTCOME MEASURES: Length of stay, surgical complications, and inpatient deaths. RESULTS: The entire injury admissions represented about 1.9% of all hospital admissions and were predominantly older than age 64 years, white, and women with conventional health care insurance. The most common comorbidity in the patients with injury was psychiatric illness (24.7%). The most common psychiatric diagnoses in orthopedic injury admissions were dementia (14.3%) and depression (6.9%) without association. Compared with the injury admissions with no psychiatric diagnosis, admissions with psychiatric diagnosis had higher odds of a hospital stay of 7 or more days, surgical treatment complications, and inhospital death. CONCLUSION: Psychiatric comorbidity adversely affects several hospital outcomes in patients with orthopedic injuries: Length of stay, surgical complications, and inpatient mortality. In low-income populations, the adverse psychiatric effects are incrementally worse. The adverse effects of psychiatric comorbidity, particularly dementia and depression, on hospital outcomes should stimulate improved psychiatric care of many patients at risk of poor clinical outcomes. PMID- 29702057 TI - Undifferentiated Pleomorphic Sarcoma after Pirfenidone Use: A Case Report. AB - INTRODUCTION: Pirfenidone was approved in 2014 for the treatment of idiopathic pulmonary fibrosis. Pirfenidone inhibits several factors such as tissue growth factor-beta and platelet-derived growth factor, leading to decreased epithelial and fibroblast proliferation and collagen synthesis. The drug improves progression-free survival and is well tolerated, with minimal side effects. However, data on its long-term effects are lacking. CASE PRESENTATION: We present a rare case in which an undifferentiated pleomorphic sarcoma developed in a 59 year-old man with idiopathic pulmonary fibrosis who was treated with pirfenidone for more than a year. DISCUSSION: Undifferentiated pleomorphic sarcoma, also known as malignant fibrous histiocytoma, is a soft-tissue sarcoma arising from fibroblasts. The disease presents in the extremities and the trunk of elderly patients, and rarely in the retroperitoneum. Surgical excision is the mainstay of treatment; however, recurrence is common in the form of lung and lymph node metastases. In this report we review this rare malignancy and highlight the need for postmarketing longitudinal studies to determine additional adverse effects in patients with idiopathic pulmonary fibrosis who are on pirfenidone therapy. PMID- 29702058 TI - Three Sides to Every Story: Preparing Patient and Family Storytellers, Facilitators, and Audiences. AB - BACKGROUND: There is a growing recognition that patient engagement is necessary for the cultivation of patient- and family-centered care (PFCC) in the hospital setting. Acting on the emerging understanding that hearing stories from our patients gives valuable insight about our ability to provide compassionate PFCC, we developed an educational patient experience curriculum at our acute care teaching hospital. OBJECTIVES: To understand the benefits and consequences of patient storytelling and to explore the impact of our curriculum on participants. METHODS: The curriculum was codesigned with patients to illustrate the value and meaning of PFCC to health professional audiences. We surveyed audience members at nursing orientation events and interviewed the patient storytellers who shared their stories. RESULTS: Participants indicated that patient stories could serve as lessons or reminders about the dimensions of PFCC and could inspire changes to practice. Storytellers reported an immensely rewarding experience and highlighted the value of educating and connecting with participants. However, they reported that the experience could also pose emotional challenges. CONCLUSION: Careful and considerate facilitation of storytelling sessions is crucial to the delivery of a curriculum that is beneficial to both patients and participants. Our storytelling framework offers a novel approach to engaging patients in education, and it contributes to our existing understanding of how patient engagement efforts resonate within organizations. PMID- 29702059 TI - Implementing a Narrative Medicine Curriculum During the Internship Year: An Internal Medicine Residency Program Experience. AB - INTRODUCTION: Narrative medicine develops professional and communication skills that align with Accreditation Council for Graduate Medical Education competencies. However, little is known about a narrative medicine curriculum's impact on physicians in training during residency. Implementing a narrative medicine curriculum during residency can be challenging because of time constraints and limited opportunity for nonclinical education. METHODS: Six sessions were implemented throughout one academic year to expose first-year internal medicine residents (interns) to narrative medicine. Attendance and participation were documented. At the end of the year, interns completed an open ended survey to gauge their perception of their experience with the sessions. RESULTS: In total, 17 interns attended at least 1 narrative medicine session, and each session averaged 5.4 attendees. Thirteen eligible interns completed the survey. Thematic analysis identified 3 predominant themes: Mindfulness, physician well-being, and professionalism. DISCUSSION: Overall, the narrative medicine sessions were well attended and the curriculum was well received. This intervention demonstrates the value of a narrative medicine curriculum during medical resident training. Large prospective studies are necessary to identify the long-term benefits of such a curriculum. PMID- 29702060 TI - Editorial Comment. PMID- 29702061 TI - Aggrecanase degradation of type III collagen is associated with clinical knee pain. AB - There is a lack of biochemical markers for non-invasive and objective assessment of symptomatic osteoarthritis (OA). Aggrecanase activity has been shown to be associated with joint deterioration and symptomatic disease through the degradation of extracellular matrix proteins, such as type III collagen. Our study aimed to identify and develop a novel biomarker by measuring an aggrecanase mediated type III collagen neoepitope, and correlate levels of this biomarker with OA joint pain. Mass spectrometric analysis of purified type III collagen, degraded by the aggrecanase A Disintigrin and Metalloproteinase with Thrombospondin motif (ADAMTS), revealed a fragment generated by ADAMTS-1, -4 and 8. A monoclonal antibody was raised against the neoepitope of this fragment (COL3 ADAMTS) and a competitive ELISA was developed and tested; using serum samples from a cross-sectional cohort of patients with different degrees of knee OA (n = 261). The COL3/ADAMTS ELISA was technically robust and specific for the ADAMTS-1, -4 and -8 generated neoepitope. COL3/ADAMTS was released form cytokine stimulated synovial cultures, indicating a biologic link between the marker and synovium. In OA patients, serum COL3/ADAMTS was independently associated with pain scores (rho = -0.13-0.17, p < 0.05). This association was associated significantly with the presence of radiographic OA. Together, these data indicate that COL3/ADAMTS could be a marker of early osteoarthritis and the underlining pathology. PMID- 29702062 TI - In response to a letter to Editor by Vivek Kumar Garg., et al. on our paper: "Dysregulation of serum NADPH oxidase1 and ferritin levels provides insights into diagnosis of Parkinson's disease". Hemmati-Dinarvand, M., et al. 2017; 50 (18):1087-1092. PMID- 29702063 TI - Alpha-synuclein mitochondrial interaction leads to irreversible translocation and complex I impairment. AB - alpha-synuclein is involved in both familial and sporadic Parkinson's disease. Although its interaction with mitochondria has been well documented, several aspects remains unknown or under debate such as the specific sub-mitochondrial localization or the dynamics of the interaction. It has been suggested that alpha synuclein could only interact with ER-associated mitochondria. The vast use of model systems and experimental conditions makes difficult to compare results and extract definitive conclusions. Here we tackle this by analyzing, in a simplified system, the interaction between purified alpha-synuclein and isolated rat brain mitochondria. This work shows that wild type alpha-synuclein interacts with isolated mitochondria and translocates into the mitochondrial matrix. This interaction and the irreversibility of alpha-synuclein translocation depend on incubation time and alpha-synuclein concentration. FRET experiments show that alpha-synuclein localizes close to components of the TOM complex suggesting a passive transport of alpha-synuclein through the outer membrane. In addition, alpha-synuclein binding alters mitochondrial function at the level of Complex I leading to a decrease in ATP synthesis and an increase of ROS production. PMID- 29702064 TI - Circular RNA circMYO9B facilitates breast cancer cell proliferation and invasiveness via upregulating FOXP4 expression by sponging miR-4316. AB - Recently, circular RNAs (circRNAs) have been demonstrated as essential regulators in human cancers. However, the function and mechanism of circRNAs in breast cancer (BC) remain largely unknown and require to be investigated. In the present study, we found that circMYO9B was highly expressed in BC tissues by bioinformatics analysis. And we showed that circMYO9B expression was positively correlated with patients' prognosis. Moreover, we found that circMYO9B knockdown significantly suppressed the proliferation, migration and invasion of BC cells in vitro. In vivo assays also indicated that circMYO9B silence delayed tumor growth. In mechanism, we found that circMYO9B promoted the expression of FOXP4 by sponging miR-4316 in BC cells. We showed that the expression of miR-4316 was inversely associated with that of circMYO9B or FOXP4 in BC tissues. Finally, we found that restoration of FOXP4 expression significantly reversed the effects of circMYO9B knockdown on BC cell proliferation, migration and invasion. In conclusion, our findings demonstrated a key role of circMYO9B/miR-4316/FOXP4 axis in regulating BC progression. PMID- 29702065 TI - Reply. PMID- 29702066 TI - Reply. PMID- 29702067 TI - A randomized clinical trial of knotless barbed suture vs conventional suture for closure of the uterine incision at cesarean delivery. PMID- 29702068 TI - Serum CA125 levels predict outcome of interval debulking surgery after neoadjuvant chemotherapy in patients with advanced ovarian cancer. AB - OBJECTIVE: To evaluate the correlation between the changes of serum CA125 level and the outcome of interval debulking surgery (IDS) after neoadjuvant chemotherapy (NACT) in patients with advanced epithelial ovarian cancer (EOC). METHODS: A retrospective review for 62 patients with FIGO stage III or IV EOC treated with NACT-IDS was conducted. Demographic data, clinical characters, pathological features and prognosis were collected. Continuous variables were evaluated by Student's t-test or Mann-Whitney U test. Categorical variables were evaluated by chi square test or Fisher's exact test as appropriate for category size. Standard univariate analyses and multivariable analysis with logistic regression were performed to identify independent predictor of optimal IDS. Kaplan-Meier method was used to analyze the prognosis. RESULTS: No statistical difference was found on serum CA125 levels between suboptimal (n = 34)IDS and optimal (n = 28) IDS either before NACT (median levels: 1552.2 U/mL and 1715.5 U/mL, p = 0.453) or before IDS (median levels: 27.25 U/mL and 26.4 U/mL, p = 0.713). Those with optimal IDS achieved longer progression free survival (PFS) and overall survival (OS) than those with suboptimal IDS (median PFS: 22 and 13.5 months, p < 0.001; median OS: 33.5 and 21 months, p = 0.005). Eighteen of 31 patients (58.1%) with serum CA125 declines >=0.95828 achieved optimal IDS compared to 10 of the 31 patients (32.3%) with serum CA125 declines <0.95828 (p = 0.041). Standard univariate analyses and multivariable analysis showed that serum CA125 declines >=0.95828 could be an independent predictor of optimal IDS. CONCLUSION: Patients who underwent optimal IDS have better prognosis compare to suboptimal IDS. The changes of serum CA125 after neoadjuvant chemotherapy might predict optimal interval debulking surgery in patients with advanced epithelial ovarian cancer. PMID- 29702069 TI - Gait and Balance Measures Can Identify Change From a Cerebrospinal Fluid Tap Test in Idiopathic Normal Pressure Hydrocephalus. AB - OBJECTIVES: To identify in patients with idiopathic normal pressure hydrocephalus (iNPH) undergoing a cerebrospinal fluid (CSF) tap test (TT) for consideration of a ventricular peritoneal (VP) shunt: (1) gait and balance measures, which identify symptom change; (2) differences present between pre- and post-CSF TT scores between patients classified as responders and nonresponder; (3) ability of patients with iNPH to accurately quantify change in their gait and balance symptoms from a CSF TT. DESIGN: Prospective observational study. Post-CSF TT assessment was completed 2-4 hours post. SETTING: Tertiary referral neurological and neurosurgical hospital. PARTICIPANTS: Patients (N=74) with iNPH receiving a 30 mL CSF TT for consideration of a VP shunt. INTERVENTIONS: Patients underwent a battery of gait and balance measures pre- and post-CSF TT and indicated their perceived change on a global rating of change (GRC). Patients deemed to improve and offered VP shunt insertion by a neurologist or neurosurgeon were labeled responders. MAIN OUTCOME MEASURES: Performance oriented mobility assessment (Tinetti), Berg Balance Scale (BBS), timed Up and Go (TUG), 10-meter walk test (10MWT), GRC. RESULTS: Forty patients were classified responders, 34 nonresponders. Significant differences were identified for responders: Tinetti (3.88 points), TUG (3.98 seconds), 10MWT (0.08 m/sec), and BBS (5.29 points). Significant differences were found for nonresponders for the Tinetti (0.91 points) and BBS (2.06 points). Change scores for responders and nonresponders were significantly different for all tests between responders and nonresponders. GRC scores for gait (+2 for responders, 0 for nonresponders) and balance (+2.5 for responders, 0 for nonresponders) were both significantly different. CONCLUSIONS: The Tinetti, BBS, and TUG can identify change in patients undergoing a CSF TT for iNPH. Patients appear to be able to accurately identify if change has occurred. PMID- 29702070 TI - Effects of Home-Based Versus Clinic-Based Rehabilitation Combining Mirror Therapy and Task-Specific Training for Patients With Stroke: A Randomized Crossover Trial. AB - OBJECTIVE: We investigated the treatment effects of a home-based rehabilitation program compared with clinic-based rehabilitation in patients with stroke. DESIGN: A single-blinded, 2-sequence, 2-period, crossover-designed study. SETTING: Rehabilitation clinics and participant's home environment. PARTICIPANTS: Individuals with disabilities poststroke. INTERVENTIONS: During each intervention period, each participant received 12 training sessions, with a 4-week washout phase between the 2 periods. Participants were randomly allocated to home-based rehabilitation first or clinic-based rehabilitation first. Intervention protocols included mirror therapy and task-specific training. MAIN OUTCOME MEASURES: Outcome measures were selected based on the International Classification of Functioning, Disability and Health. Outcomes of impairment level were the Fugl Meyer Assessment, Box and Block Test, and Revised Nottingham Sensory Assessment. Outcomes of activity and participation levels included the Motor Activity Log, 10 meter walk test, sit-to-stand test, Canadian Occupational Performance Measure, and EuroQoL-5D Questionnaire. RESULTS: Pretest analyses showed no significant evidence of carryover effect. Home-based rehabilitation resulted in significantly greater improvements on the Motor Activity Log amount of use subscale (P=.01) and the sit-to-stand test (P=.03) than clinic-based rehabilitation. The clinic-based rehabilitation group had better benefits on the health index measured by the EuroQoL-5D Questionnaire (P=.02) than the home-based rehabilitation group. Differences between the 2 groups on the other outcomes were not statistically significant. CONCLUSIONS: The home-based and clinic-based rehabilitation groups had comparable benefits in the outcomes of impairment level but showed differential effects in the outcomes of activity and participation levels. PMID- 29702071 TI - Incentive Spirometry After Lung Resection: A Randomized Controlled Trial. AB - BACKGROUND: Incentive spirometry (IS) is thought to reduce the incidence of postoperative pulmonary complications (PPC) after lung resection. We sought to determine whether the addition of IS to routine physiotherapy following lung resection results in a lower rate of PPC, as compared with physiotherapy alone. METHODS: A single-blind prospective randomized controlled trial was conducted in adults undergoing lung resection. Individuals with previous lung surgery or home oxygen were excluded. Participants randomized to the control arm (PHY) received routine physiotherapy alone (deep breathing, ambulation and shoulder exercises). Those randomized to the intervention arm (PHY/IS) received IS in addition to routine physiotherapy. The trial was powered to detect a 10% difference in the rate of PPC (beta = 80%). Student's t test and chi-square were utilized for continuous and categorical variables, respectively, with a significance level of p = 0.05. RESULTS: A total of 387 participants (n = 195 PHY/IS; n = 192 PHY) were randomized between 2014 and 2017. Baseline characteristics were comparable for both arms. The majority of patients underwent a pulmonary lobectomy (PHY/IS = 59.5%, PHY = 61.0%; p = 0.84), with no difference in the rates of minimally invasive and open procedures. There were no differences in the incidence of PPC at 30 days postoperatively (PHY/IS = 12.3%, PHY = 13.0%; p = 0.88). There were no differences in rates of pneumonia (PHY/IS = 4.6%, PHY = 7.8%; p = 0.21), mechanical ventilation (PHY/IS = 2.1%, PHY = 1.0%; p = 0.41), home oxygen (PHY/IS = 13.8%, PHY = 14.6%; p = 0.89), hospital length of stay (PHY/IS = 4 days, PHY = 4 days; p = 0.34), or rate of readmission to hospital (PHY/IS = 10.3%, PHY = 9.9%; p = 1.00). CONCLUSIONS: The addition of IS to routine postoperative physiotherapy does not reduce the incidence of PPC after lung resection. PMID- 29702072 TI - Structure of APP-C991-99 and implications for role of extra-membrane domains in function and oligomerization. AB - The 99 amino acid C-terminal fragment of Amyloid Precursor Protein APP-C99 (C99) is cleaved by gamma-secretase to form Abeta peptide, which plays a critical role in the etiology of Alzheimer's Disease (AD). The structure of C99 consists of a single transmembrane domain flanked by intra and intercellular domains. While the structure of the transmembrane domain has been well characterized, little is known about the structure of the flanking domains and their role in C99 processing by gamma-secretase. To gain insight into the structure of full-length C99, REMD simulations were performed for monomeric C99 in model membranes of varying thickness. We find equilibrium ensembles of C99 from simulation agree with experimentally-inferred residue insertion depths and protein backbone chemical shifts. In thin membranes, the transmembrane domain structure is correlated with extra-membrane structural states and the extra-membrane domain structural states become less correlated to each other. Mean and variance of the transmembrane and G37G38 hinge angles are found to increase with thinning membrane. The N-terminus of C99 forms beta-strands that may seed aggregation of Abeta on the membrane surface, promoting amyloid formation. In thicker membranes the N-terminus forms alpha-helices that interact with the nicastrin domain of gamma-secretase. The C-terminus of C99 becomes more alpha-helical as the membrane thickens, forming structures that may be suitable for binding by cytoplasmic proteins, while C-terminal residues essential to cytotoxic function become alpha helical as the membrane thins. The heterogeneous but discrete extra-membrane domain states analyzed here open the path to new investigations of the role of C99 structure and membrane in amyloidogenesis. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy. PMID- 29702074 TI - Retinal Neuroprotection: Overcoming the Translational Roadblocks. AB - PURPOSE: To elucidate the issues that have prevented successful translation of neuroprotective therapeutic modalities for retinal disease from the preclinical to the clinical realm and to suggest strategies to circumvent these barriers in order to develop novel treatments to prevent vision loss. DESIGN: Interpretive essay. METHODS: Review and synthesis of selected reports of neuroprotective approaches for retinal disease, with interpretation and perspective. RESULTS: Retinal neuroprotection is defined as any measure that reduces the death of retinal cells or axonal extensions into the optic nerve, and there is a great unmet need for such therapeutic modalities. Despite encouraging preclinical data, the translation of neuroprotective therapies to the clinic has been fraught with failure. Fundamental issues that have plagued this transition include the animal models used in preclinical studies, the reproducibility of the preclinical data, and the choice of meaningful clinical trial endpoints. Developing animal models that more aptly mimic human disease, defining a set of guidelines for preclinical evaluation of neuroprotective therapies in retinal disease, and identifying and validating biomarkers as surrogate clinical endpoints that shorten and optimize drug development timelines may circumvent some of these barriers to translation. CONCLUSIONS: Neuroprotective therapeutic approaches have the potential to prevent vision loss in millions of people affected with eye diseases worldwide. However, a stigma currently accompanies the concept of neuroprotection because of the many past failures to bridge the gap between the preclinical and clinical realms. Understanding and addressing the fundamental reasons for the failure of translatable research provides hope for the future development of neuroprotective therapies. PMID- 29702075 TI - Longitudinal Study of Visual Function in Vogt-Koyanagi-Harada Disease Using Full Field Electroretinography. AB - PURPOSE: To investigate the dynamic changes of full-field electroretinography (ffERG) and its relationship with structural changes in Vogt-Koyanagi-Harada (VKH) disease. DESIGN: Interventional case series. METHODS: A total of 42 VKH patients (84 eyes) and 45 normal controls (90 eyes) were included in this study. All of the patients showed active uveitis and were referred to us within 2 months after disease onset. Dynamic changes of retinal function were evaluated by ffERG before treatment and 2, 6, and 12 months after treatment with systemic corticosteroids and cyclosporine. The relationship between ffERG data with structural changes as disclosed by B-scan ultrasonography, fundus fluorescein angiography (FFA), indocyanine green angiography, and optical coherence tomography were also evaluated. RESULTS: All investigated VKH patients showed a significantly decreased visual acuity and retinal structural changes before treatment. These changes significantly improved at 2 months and no abnormalities were apparent at 6 months following treatment. Full-field ERG showed significantly decreased amplitudes and prolonged implicit times for all dark adapted (DA) and light-adapted ffERG responses before treatment. All these parameters, except the a-wave amplitude in the DA response, were improved at 2 months and returned to the normal level at 12 months. CONCLUSION: Our findings show that ffERG is a more sensitive method to detect improvement of visual function in VKH following treatment when compared to corrected distance visual acuity and the various imaging techniques to detect structural abnormalities in VKH. PMID- 29702076 TI - Prevention of progression of diabetic nephropathy by the SGLT2 inhibitor ipragliflozin in uninephrectomized type 2 diabetic mice. AB - Diabetic nephropathy is the leading cause of end-stage renal disease in the world. Although recent development of sodium-glucose cotransporter (SGLT) 2 inhibitors offers a new antidiabetic therapeutic strategy, it remains unclear whether such treatments are beneficial for limiting the progression of type 2 diabetic overt nephropathy. This study examined the effect of the SGLT2 inhibitor ipragliflozin on the progression of nephropathy in uninephrectomized KK/Ay type 2 diabetic mice, which exhibit not only typical diabetic symptoms such as hyperglycemia, hyperinsuemia, glucose intolerance, insulin resistance, hyperlipidemia, inflammation, and obesity, but also moderate hypertension and overt nephropathy with decline in renal function. Four-week repeated administration of ipragliflozin improved various diabetic symptoms, including hyperglycemia, insulin resistance, and inflammation by increasing urinary glucose excretion. In addition, ipragliflozin ameliorated albuminuria/proteinuria; decline in renal function, as measured by creatinine clearance; hypertension; and renal injury, including glomerulosclerosis and interstitial fibrosis. These effects were significant at doses of 1 mg/kg or higher and were similar to those observed following administration of losartan (30 mg/kg). These results suggest that the SGLT2 inhibitor ipragliflozin prevents progression to diabetic overt nephropathy in uninephrectomized type 2 diabetic mice. SGLT2 inhibitors may therefore represent a promising therapeutic option for the management of type 2 diabetes to slow the progression of diabetic nephropathy. PMID- 29702077 TI - Phosphosulindac is efficacious in an improved concanavalin A-based rabbit model of chronic dry eye disease. AB - Dry eye disease (DED) currently has no satisfactory treatment partly because of the lack of informative animal models. We evaluated the anti-inflammatory phosphosulindac (PS) for the treatment of DED using a new rabbit model of DED based on the concanavalin A (Con A) acute DED model: we injected all lacrimal glands with Con A weekly under ultrasound guidance, which prolonged DED to >3 weeks, and thoroughly assessed efficacy with tear break-up time (TBUT), tear osmolarity, Schirmer test, and tear lactoferrin levels. Rabbits with DED (n = 8 10 eyes per group) were treated topically with PS or vehicle 3*/day for 21days. PS restored TBUT, tear osmolarity, and lactoferrin levels (P < 0.0001-0.04) to normal but did not significantly improve the results of the Schirmer test. PS showed no side effects and was much more efficacious than cyclosporine or lifitegrast. In the cornea, PS suppressed the activation of nuclear factor kappa B, the levels of transforming growth factor beta, interleukin-1 beta, interleukin 6, and interleukin-8, and the levels of matrix metalloproteinase (MMP)-1 and MMP 9, and MMP activity. Levels of prostaglandin E2 (PGE2) in tears and cornea were preserved in PS-treated rabbits. Ketorolac and diclofenac, two ophthalmic NSAIDs causing corneal melt, nearly completely suppressed PGE2 levels but had no effect on MMPs. The effects of PS on PGE2 and MMPs likely account for its apparent ocular safety. Our results establish an animal model for acute and chronic DED suitable for drug efficacy studies and indicate that PS merits evaluation for DED. PMID- 29702078 TI - Therapeutic efficacy of the live-attenuated Mycobacterium tuberculosis vaccine, MTBVAC, in a preclinical model of bladder cancer. AB - Intravesical instillation of bacillus Calmette-Guerin (BCG) has been a first-line therapy for non-muscle-invasive bladder cancer for the last 4 decades. However, this treatment causes serious adverse events in a significant number of patients and a substantial percentage of recurrence episodes. MTBVAC is a live-attenuated vaccine derived from a Mycobacterium tuberculosis clinical isolate and is currently under evaluation in clinical trials to replace BCG as a tuberculosis vaccine. Here, we describe for the first time the potential of MTBVAC as a bladder cancer therapy in vitro and in vivo in a preclinical model. MTBVAC colonized human bladder tumor cells to a much greater extent than BCG via a mechanism mediated by macropinocytosis and induced cell growth inhibition after internalization. In vivo testing in an orthotopic murine model of bladder cancer demonstrated a higher antitumor effect of MTBVAC in experimental conditions in which BCG did not work. Our data encourage further studies to support the possible application of MTBVAC as a new immunotherapeutic agent for bladder cancer. PMID- 29702073 TI - Membranes as modulators of amyloid protein misfolding and target of toxicity. AB - Abnormal protein aggregation is a hallmark of various human diseases. alpha Synuclein, a protein implicated in Parkinson's disease, is found in aggregated form within Lewy bodies that are characteristically observed in the brains of PD patients. Similarly, deposits of aggregated human islet amyloid polypeptide (IAPP) are found in the pancreatic islets in individuals with type 2 diabetes mellitus. Significant number of studies have focused on how monomeric, disaggregated proteins transition into various amyloid structures leading to identification of a vast number of aggregation promoting molecules and processes over the years. Inasmuch as these factors likely enhance the formation of toxic, misfolded species, they might act as risk factors in disease. Cellular membranes, and particularly certain lipids, are considered to be among the major players for aggregation of alpha-synuclein and IAPP, and membranes might also be the target of toxicity. Past studies have utilized an array of biophysical tools, both in vitro and in vivo, to expound the membrane-mediated aggregation. Here, we focus on membrane interaction of alpha-synuclein and IAPP, and how various kinds of membranes catalyze or modulate the aggregation of these proteins and how, in turn, these proteins disrupt membrane integrity, both in vitro and in vivo. The membrane interaction and subsequent aggregation has been briefly contrasted to aggregation of alpha-synuclein and IAPP in solution. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy. PMID- 29702080 TI - Continuation of long-acting reversible contraceptives among Medicaid patients. AB - OBJECTIVE: Our objective was to compare continuation and complication rates of subdermal etonogestrel implants and intrauterine devices (IUDs) using Medicaid insurance claims. STUDY DESIGN: We performed a retrospective cohort study using insurance claims data for 15- to 44-year-old subjects receiving implants or IUDs from 2012 to 2015 in a Medicaid managed care organization in Washington, DC, and Maryland. We performed a planned Kaplan-Meier survival analysis for long-acting reversible contraceptive (LARC) continuation, defined as the absence of a claim for LARC removal, during periods of continuous insurance plan enrollment. RESULTS: Three thousand one hundred three subjects received 1335 implants and 1970 IUDs, with implants more common than IUDs among subjects 15-19 years old (rate ratio=2.42), and implants less common than IUDs for subjects 20-44 years old (rate ratio=0.54). Implants had higher continuation rates at 1 year than IUDs (81.0% vs. 76.7%, p=.01). The difference was larger among subjects 25 to 44 years old (84.1% vs. 79.3%, p=.03) compared with subjects 15 to 19 years old (89.5% vs. 86.8%, p=.09) and subjects 20 to 24 years old (75.7% vs. 73.2%, p=.44). Claims for potential complications were similarly uncommon for both implants and IUDs (8.09% vs. 6.95%, p=.65), as were claims for pregnancies prior to LARC removal (0.82% vs. 0.86%, p=.86). CONCLUSION: Among a sample of 15- to 44-year-old Medicaid recipients, both implants and IUDs had high continuation rates and low complication rates; however, implants were slightly more likely than IUDs to remain in use 1 year after insertion. IMPLICATIONS: Among 15- to 44-year-old Medicaid recipients, both etonogestrel implants and IUDs have high continuation rates and low complication rates at 1-year postinsertion; however, implants are slightly more likely than IUDs to remain in use at 1 year. PMID- 29702079 TI - The ubiquitin proteasome system as a potential therapeutic target for systemic sclerosis. AB - The present review aims to summarize available knowledge on the role of the ubiquitin-proteasome system (UPS) in the pathogenesis of scleroderma and scleroderma-related disease mechanisms. This will provide the reader with a more mechanistic understanding of disease pathogenesis and help to identify putative novel targets within the UPS for potential therapeutic intervention. Because of the heterogenous manifestations of scleroderma, we will primarily focus on conserved mechanisms that are involved in the development of lung scleroderma phenotypes. PMID- 29702081 TI - Contraceptive information on pregnancy resource center websites: a statewide content analysis. AB - OBJECTIVE: Most pregnancy resource centers (PRCs) in the US are affiliated with national organizations that have policies against promoting or providing contraceptives, yet many provide information about contraception on their websites. In 2016, the state of Georgia passed a new law to publicly fund PRCs. This study sought to describe the contraceptive information on Georgia PRC websites. STUDY DESIGN: We systematically identified all accessible Georgia PRC websites April-June 2016. We downloaded entire websites and used defined protocols to code and thematically analyze content about contraceptives. RESULTS: Of the 64 websites reviewed, 20 (31%) presented information about contraceptives. Most of the content was dedicated to emergency contraception. Emphasis on risks and side effects was the most prominent theme. However, no site presented information about the frequency or prevalence of risks and side effects. Sites also emphasized contraceptive failure and minimized effectiveness. We found a high degree of inaccurate and misleading information about contraceptives. CONCLUSIONS: Georgia PRC websites presented skewed information that may undermine confidence in the safety and efficacy of contraceptive methods and discourage use. Public funding for PRCs, an increasing national trend, should be rigorously examined. Increased regulation is urgently needed to ensure that online information about contraceptives presented by publicly funded centers is unbiased, complete and accurate. IMPLICATIONS: We examined contraceptive information on Georgia PRC websites and found sites minimize benefits and emphasize barriers to use. They contain high levels of medically inaccurate and misleading information that may undermine public health goals. Public funding for PRCs should be rigorously examined; increased regulation is urgently needed. PMID- 29702082 TI - Multiple contraceptive method use and prevalence of fertility awareness based method use in the United States, 2013-2015. AB - OBJECTIVES: Contraceptive prevalence in the United States is typically calculated according to the most effective method of contraception reported. This could theoretically underestimate the number of women using fertility-awareness based methods (FABMs), including those who use other methods (e.g., condoms) during the fertile window, but the extent of any such underestimation has not been assessed. STUDY DESIGN: We used data from the 2013-2015 National Survey of Family Growth to examine the extent to which women report use of an FABM alone or with other methods. We investigated FABM use patterns and compared demographic profiles of FABM users versus other contraceptive users. We considered how to most appropriately define FABM prevalence. RESULTS: One in six (16.5%) female contraceptors 15-44 reported use of multiple contraceptive methods in their month of interview. Among women reporting current FABM use, 67% used it alone or with withdrawal, 24% also used condoms or emergency contraception, and 9% also used hormonal contraception or sterilization. An FABM was the most effective method reported for 2.2% of current contraceptive users; while 3.2% of contraceptors reported any current FABM use. We posit an FABM prevalence of 3% (1,113,000 users) among US female contraceptors (2013-2015). FABM users had similar sociodemographic characteristics as other method users, but were more likely married. CONCLUSIONS: Currently, consideration of multiple method use has modest implications for estimation of FABM prevalence among contraceptors (i.e., an increase from 2.2% to 3%). However, multiple method use patterns with FABMs may merit special consideration if FABM use continues to increase. IMPLICATIONS: Researchers and providers need to be familiar with the unique patterns of use among FABM users in order to more effectively measure and counsel about these methods. PMID- 29702083 TI - alphavbeta5 integrin mediates the effect of vitronectin on the initial stage of differentiation in mouse cerebellar granule cell precursors. AB - Vitronectin (VN), one of the extracellular matrix proteins, controls the maturation of cerebellar granule cells (CGCs) through the promotion of the initial differentiation stage progress. However, the receptors of VN in the initial differentiation stage of CGC precursors (CGCPs) have not been clarified. In this study, we characterized the receptor candidates for VN in CGCPs. First, we confirmed that alphavbeta3 and alphavbeta5 integrins, which are receptor candidates for VN, were co-localized with VN in the developing cerebellum and primary cultured CGCPs. Next, the knockdown (KD) of alphav, beta3, and beta5 integrins with small interference RNA (siRNA) for each integrin reduced the ratio of Tuj1, a final differentiation marker, -positive CGCPs. We further studied whether alphavbeta3 and alphavbeta5 integrins control the initial differentiation stage. The KD of alphav and beta5, but not beta3, integrins significantly increased the ratio of transient axonal glycoprotein 1 (TAG1), an initial differentiation marker, -positive CGCPs, whereas the KD of alphav and beta3 integrins, not beta5 integrin, stimulated the proliferation of CGCPs. Overexpression of beta5 integrin stimulated the progress of the initial differentiation stage as well. To confirm the interaction between alphavbeta5 integrin and VN, VN was added to beta5 integrin-KD CGCPs. The promotion of the progress of initial differentiation by VN was abrogated by beta5 integrin KD using small hairpin RNA (shRNA). Taken together, our results indicated that alphavbeta5 integrin, as the very receptor of VN, is responsible for the progress of the initial differentiation stage in mouse CGCPs. PMID- 29702084 TI - Medial frontal theta dissociates unsuccessful from successful avoidance and is modulated by lack of perseverance. AB - Medial frontal activity in the EEG is enhanced following negative feedback and varies in relation to dimensions of impulsivity. In 22 undergraduate students (Mage = 18.92 years, range 18-22 years), we employed a probabilistic negative reinforcement learning paradigm in which choices to avoid were followed by cues indicating successful or unsuccessful avoidance of an impending aversive noise. Our results showed that medial frontal theta power was enhanced following a cue that signaled avoidance was unsuccessful. In addition, self-reported lack of perseverance, a dimension of impulsivity characterized by an inability to maintain focus and determination during a challenging task, was negatively correlated with medial frontal theta elicited to an unsuccessful avoidance cue. We also observed robust differences in alpha attenuation and beta modulation following unsuccessful avoidance cue presentation. To our knowledge, this is the first study in humans to show a functional relation between medial frontal theta modulation and avoidance success. We discuss our findings in the context of frontal theta and self-regulation, negative reinforcement, and anxiety. PMID- 29702085 TI - TNF-alpha-sensitive brain pericytes activate microglia by releasing IL-6 through cooperation between IkappaB-NFkappaB and JAK-STAT3 pathways. AB - Interleukin (IL)-6 is an important mediator of neurovascular dysfunction, neurodegeneration and/or neuroinflammation. We previously reported that brain pericytes released higher levels of IL-6 than did glial cells (astrocytes and microglia) in response to tumor necrosis factor (TNF)-alpha. Moreover, pericytes stimulated with TNF-alpha enhanced activation of BV-2 microglia. In this study, we investigated the mechanisms of TNF-alpha mediated induction of IL-6 release from brain pericytes and astrocytes and whether pericyte-derived IL-6 would facilitate activation of BV-2 microglia. Using rat brain pericyte and astrocyte primary cultures and pharmacological inhibitors, we found that, TNF-alpha induced the highest levels of IL-6 release from pericytes by activating the inhibitor kappa B (IkappaB)-nuclear factor kappa-light-chain-enhancer of activated B cells (NFkappaB) and Janus family of tyrosine kinase (JAK)-signal transducer and activator of transcription (STAT)3 pathways. STAT3 contributed to TNF-alpha induced nuclear translocation of phospho-NFkappaB in pericytes. TNF-alpha-induced IL-6 release in astrocytes was mediated by NFkappaB but not by STAT3. The presence of pericytes amplified TNF-alpha-induced iNOS mRNA expression in BV-2 microglia. This effect was blocked by a neutralizing antibody for IL-6. These findings indicated that crosstalk between the IkappaB-NFkappaB and JAK-STAT3 pathways is a pericyte specific mechanism, not occurring in astrocytes, for TNF alpha-induced IL-6 release. IL-6 derived from pericytes enhanced microglial activation. Our findings increase understanding of the role of pericyte-microglia crosstalk in the brain under neuroinflammatory conditions and suggest a potentially attractive therapeutic target for brain inflammation. PMID- 29702086 TI - Melatonin decreases neuronal excitability in a sub-population of dorsal root ganglion neurons. AB - Melatonin, a powerful antioxidant, participates in the regulation of important physiological and pathological processes. We investigated the actions of melatonin on neuronal excitability of intact dorsal root ganglions (DRG) from rats using intracellular recording techniques in current clamps. Melatonin blocked the generation of action potentials in a concentration-dependent manner. Bath applied melatonin (1.0-1000.0 nM) hyperpolarized the resting membrane potential, and increased the input resistance and rheobase. Melatonin also altered the active electrophysiological properties of the action potential, amplitude and maximum descendant inclination, in a statistically significant way. In order to provide evidence on the mechanism of action of melatonin in the DRG, quantitative PCR (qPCR) was performed. Analyses were performed for melatonin membrane receptors, MT1 and MT2, and it was observed that the DRG expresses MT1 receptors. In addition, we noted that the melatonin-induced effects were blocked in the presence of luzindole, a melatonin receptor antagonist. The minimal effective concentrations of melatonin (10.0 nM) and the blockade of effects caused by luzindole suggest that the effects of melatonin are hormonal, and are induced when it binds to MT1 receptors. PMID- 29702087 TI - Out of focus - Brain attention control deficits in adult ADHD. AB - Modern environments are full of information, and place high demands on the attention control mechanisms that allow the selection of information from one (focused attention) or multiple (divided attention) sources, react to changes in a given situation (stimulus-driven attention), and allocate effort according to demands (task-positive and task-negative activity). We aimed to reveal how attention deficit hyperactivity disorder (ADHD) affects the brain functions associated with these attention control processes in constantly demanding tasks. Sixteen adults with ADHD and 17 controls performed adaptive visual and auditory discrimination tasks during functional magnetic resonance imaging (fMRI). Overlapping brain activity in frontoparietal saliency and default-mode networks, as well as in the somato-motor, cerebellar, and striatal areas were observed in all participants. In the ADHD participants, we observed exclusive activity enhancement in the brain areas typically considered to be primarily involved in other attention control functions: During auditory-focused attention, we observed higher activation in the sensory cortical areas of irrelevant modality and the default-mode network (DMN). DMN activity also increased during divided attention in the ADHD group, in turn decreasing during a simple button-press task. Adding irrelevant stimulation resulted in enhanced activity in the salience network. Finally, the irrelevant distractors that capture attention in a stimulus-driven manner activated dorsal attention networks and the cerebellum. Our findings suggest that attention control deficits involve the activation of irrelevant sensory modality, problems in regulating the level of attention on demand, and may encumber top-down processing in cases of irrelevant information. PMID- 29702088 TI - Combined effects of cadmium and tetrabromobisphenol a (TBBPA) on development, antioxidant enzymes activity and thyroid hormones in female rats. AB - Tetrabromobisphenol A (TBBPA) is one of the world's most widely used brominated flame retardants (BFRs) and considered as persistent halogenated contaminant. E wastes contain a range of toxic chemicals, including BFRs and heavy metals, exerting adverse impacts to human health and environment. Nevertheless, comprehensive evaluation on combined toxicity of these co-existing pollutants is limited. This study conducted a subchronic effects of cadmium and TBBPA on the development and antioxidative defense system as well as thyroid functions in female rats through single and combined exposure at environmentally relevant doses for a 20-day consecutive administration. Body indexes, histopathology, redox status, and thyroid hormones levels were assessed. Slower body weight gains and reduced ovary weight (20.8% and 32.4% for combined and single-Cd exposures, respectively) were observed with significant variation from controls in high dose treatments. Co-exposure resulted in a slight enhancement in TSH levels compared to control (by 7.6% for high dose) without significance. TBBPA-Cd interactions are involved in the changes of kidney weight as well as the induction of SOD activities and MDA levels. The disturbances in the redox status may be a result of an independent effect of Cd and/or TBBPA and also of their interaction. The results implied under these treatment, kidney was more sensitive with significant increased organ coefficient and alteration for antioxidative indices (increasing by 46% for SOD activity). This study represents the toxic effects of Cd and TBBPA co-exposure through oral administration in pubertal rats, which may provide useful information for health risk assessment for young exposed individuals. PMID- 29702089 TI - Oxyresveratrol ameliorates nonalcoholic fatty liver disease by regulating hepatic lipogenesis and fatty acid oxidation through liver kinase B1 and AMP-activated protein kinase. AB - Oxyresveratrol (OXY) is a naturally occurring polyhydroxylated stilbene that is abundant in mulberry wood (Morus alba L.), which has frequently been supplied as a herbal medicine. It has been shown that OXY has regulatory effects on inflammation and oxidative stress, and may have potential in preventing or curing nonalcoholic fatty liver disease (NAFLD). This study examined the effects of OXY on in vitro model of NAFLD in hepatocyte by the liver X receptor alpha (LXRalpha) mediated induction of lipogenic genes and in vivo model in mice along with its molecular mechanism. OXY inhibited the LXRalpha agonists-mediated sterol regulatory element binding protein-1c (SREBP-1c) induction and expression of the lipogenic genes and upregulated the mRNA of fatty acid beta-oxidation-related genes in hepatocytes, which is more potent than genistein and daidzein. OXY also induced AMP-activated protein kinase (AMPK) activation in a time-dependent manner. Moreover, AMPK activation by the OXY treatment helped inhibit SREBP-1c using compound C as an AMPK antagonist. Oral administration of OXY decreased the Oil Red O stained-positive areas significantly, indicating lipid droplets and hepatic steatosis regions, as well as the serum parameters, such as fasting glucose, total cholesterol, and low density lipoprotein-cholesterol in high fat diet fed-mice, as similar with orally treatment of atorvastatin. Overall, this result suggests that OXY has the potency to inhibit hepatic lipogenesis through the AMPK/SREBP-1c pathway and can be used in the development of pharmaceuticals to prevent a fatty liver. PMID- 29702090 TI - The endogenous agonist, beta-alanine, activates glycine receptors in rat spinal dorsal neurons. AB - beta-alanine is a structural analog of glycine and gamma-aminobutyric acid (GABA) and is thought to be involved in the modulation of nociceptive information at the spinal cord. However, it is not known whether beta-alanine exerts its effect in substantia gelatinosa (SG) neurons of the spinal dorsal horn, where glycine and GABA play an important role in regulating nociceptive transmission from the periphery. Here, we investigated the effects of beta-alanine on inhibitory synaptic transmission in adult rat SG neurons using whole-cell patch-clamp. beta alanine dose-dependently induced outward currents in SG neurons. Current-voltage plots revealed a reversal potential at approximately -70 mV, which was close to the equilibrium potential of Cl-. Pharmacological analysis revealed that beta alanine activates glycine receptors, but not GABAA receptors. These results suggest that beta-alanine hyperpolarizes the membrane potential of SG neurons by activating Cl- channels through glycine receptors. Our findings raise the possibility that beta-alanine may modulate pain sensation through glycine receptors. PMID- 29702091 TI - Inhibition of MALAT1 sensitizes liver cancer cells to 5-flurouracil by regulating apoptosis through IKKalpha/NF-kappaB pathway. AB - Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) is involved in tumor cell growth process. However, its role and molecular mechanism in liver cancer is still not fully understood. In this study, we found that MALAT1 was significantly expressed in liver cancer cell lines. And knockdown of MALAT1 suppressed proliferation, migration and invasion of HepG2 cells, accompanied with decrease of Rho-associated coiled-coil-forming protein kinase 1 (ROCK1), alpha smooth muscle actin (alpha-SMA), N-cadherin, Vimentin and TWIST. Significantly, MALAT1 deletion sensitized HepG2 cells to 5-FU-induced cell cycle arrest in G1 phase, as evidenced by the significant reduction in Cyclin D1 and CDK4 and increase in p53, p21 and p27 protein levels. In addition, MALAT1 knockdown triggered 5-FU induced apoptosis in HepG2 cells by inducing intrinsic apoptosis related signals, including Cyto-c, Apaf-1, cleaved Caspase-9/-7/-3 and poly (ADP ribose) polymerase (PARP). Furthermore, phosphorylated nuclear factor-kappaB (p NF-kappaB) was also down-regulated by MALAT1 silence. Importantly, suppression of IKKalpha/NF-kappaB significantly elevated apoptosis and reduced liver cancer cell viability in MALAT1-knockdown cells with 5-FU incubation. The nude mice transplantation model also confirmed the promoted sensitivity of MALAT1-silenced HepG2 cells to 5-FU by blocking tumor cell proliferation and inducing apoptosis. Therefore, our data supplied a potential mechanism by which knockdown of MALAT1 might play an important role in augmenting sensitivity of HepG2 cells to 5-FU in therapeutic approaches, demonstrating suppressing of MALAT1 may serve as a combination with chemotherapeutic agents in liver cancer treatment. PMID- 29702092 TI - IL-21 alleviates allergic asthma in DOCK8-knockout mice. AB - Patients with DOCK8 deficiency are at increased susceptibility to develop allergic diseases such as food allergy and asthma. Here, we aimed to analyze the pathogenesis of asthma in DOCK8-deficient patients. In our mouse model, DOCK8 knockout (KO) mice sensitized with low-dose OVA were challenged with 1.5% OVA to induce allergic asthma. As compared to that in WT mice, remarkable airway hyperresponsiveness was observed in KO mice. Increased inflammatory cells and eosinophils infiltrated in airway lumen in KO mice especially around bronchi. KO mice showed higher levels of serum IgE and OVA-specific IgE and significantly elevated IgE-producing B cells in blood and in spleen. Surprisingly, nasal administration with rmIL-21 significantly reduced the airway hyperresponsiveness, inflammatory infiltration, as well as the serum IgE and IgE-producing B cells. DOCK8-knockout mice are susceptible to low-dose OVA induced allergic airway inflammation and airway hyperresponsiveness. Supplementary nasal administration of rmIL-21 alleviates allergic asthma in this mouse model. PMID- 29702093 TI - Detection of the receptor for advanced glycation endproducts in neuronally derived exosomes in plasma. AB - Exosomes are nanovesicles that participate in cell-to-cell communication and are secreted by a variety of cells including neurons. Recent studies suggest that neuronally-derived exosomes are detectable in plasma and that their contents likely reflect expression of various biomarkers in brain tissues. The receptor for advanced glycation endproducts (RAGE) has been implicated in the pathophysiology of Alzheimer's disease (AD) and is increased in brain regions affected by AD. The goal of our project was to determine whether RAGE is present in plasma exosomes, and specifically exosomes derived from neurons. Exosomes were isolated from plasma samples (n = 8) by precipitation (ExoQuick) and ultracentrifugation methods. Neuronally-derived exosomes were isolated using a biotin-tagged L1 Cell Adhesion Molecule (L1CAM) specific antibody and streptavidin-tagged agarose resin. RAGE expression was measured by Western blots and ELISA. Western Blotting showed that RAGE is present in L1CAM-positive exosomes isolated using both methods. Mean (SD) exosomal RAGE levels were 164 (60) pg/ml by ExoQuick and were highly correlated with plasma sRAGE levels (r = 0.87, p = 0.005), which were approximately 7.5-fold higher than exosomal levels. Weak to moderate correlations were found between exosomal RAGE and age, BMI, and cognitive function. These results show for the first time that RAGE is present in neuronally-derived plasma exosomes, and suggest that exosomal RAGE may be a novel biomarker that reflects pathophysiological processes in the brain. PMID- 29702094 TI - ROS mediated EGFR/MEK/ERK/HIF-1alpha Loop Regulates Glucose metabolism in pancreatic cancer. AB - To investigate the glycometabolism associated mechanism in invasion and metastasis of pancreatic cancer, We screened out genes involved in anaerobic glycolysis headed by HIF-1alpha,using pre-established a pair of pancreatic cancer cell lines. In this study, we further detected the glucose metabolism state not only in the cells but all also in two groups of patients with different SUVmax on 18F-FDG PET/CT. The data suggests that ROS mediated EGFR/MEK/ERK/HIF-1alpha loop is activated in high glucose metabolic samples both in vitro and in vivo: The increasing of HIF-1alpha expression is controlled by activation of EGFR/MEK/ERK pathway in hypoxia condition, HIF-1alpha inhibits excessive release of ROS, the reduction of ROS further activates EGFR to form a positive feedback loop. This difference is closely related to invasion and metastasis capacity of pancreatic cancer, and can be rescued by separate or combined inhibition of EGFR or HIF 1alpha in various degree. These results indicate a new clue to develop therapy of pancreatic cancer by regulating the glucose metabolism. PMID- 29702095 TI - Evidence that interferon-tau secreted from Day-7 embryo in vivo generates anti inflammatory immune response in the bovine uterus. AB - Recent studies suggest that Day-7 bovine embryo starts to communicate with the uterine epithelium through interferon-tau (IFNT) signaling. However, immune modulatory role of IFNT in the uterus just after the embryo moves from the oviduct is unclear. We aimed to examine the hypothesis that Day-7 bovine embryo secretes IFNT in the uterus, which induces anti-inflammatory response in immune cells. The uterine flush (UF) with multiple embryos was collected from Day-7 donor pregnant cows and peripheral blood mononuclear cells (PBMCs) were then cultured in UF. Transcripts detected in PBMCs revealed that UF from pregnant cows down-regulated pro-inflammatory cytokines (TNFA, IL1B) and up-regulated anti inflammatory cytokine (IL10) expression, with activation of interferon-stimulated genes (ISGs; ISG15, OAS1) as compared with UF from non-pregnant cows. An addition of specific anti-IFNT antibody to the UF inhibited the effect on PBMCs, indicating that IFNT is a major factor for such immune modulation. The observation that conditioned media from bovine uterine epithelial cells both stimulated with IFNT in vitro and supplemented with fresh IFNT induced similar PBMCs gene expression, confirming that IFNT directly acts on this immune crosstalk. This study shows that IFNT secreted from Day-7 embryo in vivo generates anti-inflammatory response in immune cells, which may provide immunological tolerance to accept the embryo. PMID- 29702096 TI - Noninvasive Detection of High Grade Prostate Cancer by DNA Methylation Analysis of Urine Cells Captured by Microfiltration. AB - PURPOSE: With the aim of developing a noninvasive test to detect clinically significant prostate cancer we investigated the potential of capturing cells from urine by microfiltration coupled with analysis of DNA methylation biomarkers. MATERIALS AND METHODS: In this prospective study urine from men suspected of having prostate cancer who were scheduled for transrectal ultrasound guided biopsy of the prostate was collected before digital rectal examination in 99, after digital rectal examination in 58 and from a urethral catheter in 7. Cells were isolated from whole volume voided urine using a filtration device containing a membrane filter with a pore size of 8 MUm. Ten additional men provided 4 or 5 urine cell samples by self-collection prior to biopsy. Cellular DNA was analyzed for 5 methylation biomarkers using ddPCRTM (droplet digital polymerase chain reaction). RESULTS: Prostate cancer was diagnosed in 117 patients (71%). Across all tumor grades the sensitivity of urine DNA testing was 81% and 60% in samples obtained before and after digital rectal examination, respectively. In a prediction model including prostate specific antigen, patient age and the result of urine DNA analysis to detect high grade disease (Gleason score 7 or greater) an AUC of 0.95 (95% CI 0.90-1.00) was obtained for post-digital rectal examination samples. Analysis of repeat samples demonstrated substantial intraindividual variation in the shedding of cancerous cells in urine. CONCLUSIONS: Capturing cells from urine by microfiltration provides a novel tool to detect prostate cancer noninvasively with high sensitivity for high grade disease. Repeat sampling may increase sensitivity, particularly when urine is obtained without prior physical manipulation of the prostate. PMID- 29702098 TI - Does Post-Void Residual Volume Predict Worsening Urological Symptoms in Patients with Multiple Sclerosis? AB - PURPOSE: Our goal was to examine how post-void residual urine volume relates to urinary symptoms in patients with multiple sclerosis. MATERIALS AND METHODS: We retrospectively reviewed the records of patients with multiple sclerosis who had lower urinary tract symptoms and presented to a tertiary neurourology clinic. Patients for whom post-void residual volume was recorded at the initial urological assessment were included in our analysis. Results of the AUA (American Urological Association) SI (Symptom Index) and the M-ISI (Michigan Incontinence Symptom Index) completed at this visit were analyzed to assess the severity of lower urinary tract symptoms and incontinence. A chart review was performed to obtain information on demographics and documented urinary tract infections. RESULTS: Between 2014 and 2017, 110 patients diagnosed with multiple sclerosis underwent post-void residual volume measurement at our clinic. Average post-void residual volume was 123.4 cc (range 0 to 650 cc). The mean AUA symptom score was 19.1 with an average bother score of 4.1. Analysis of post-void residual volume as a continuous variable did not show an association between increasing post-void residual volume and an increasing AUA SI or bother score (p = 0.53 and 0.44, respectively). When evaluated by post-void residual volume tertile, no relationship was found between post-void residual volume, and the AUA SI and the M-ISI (p = 0.54 and 0.57, respectively). No correlation was also found between increasing post-void residual volume and a recent history of recurrent urinary tract infections (p = 0.27). CONCLUSIONS: Post-void residual volume was not associated with worsening obstructive lower urinary tract symptoms as assessed by the AUA SI, worsening incontinence as measured by the M-ISI score or an increased risk of recurrent urinary tract infections in select patients with multiple sclerosis and lower urinary tract symptoms. PMID- 29702097 TI - Can Renal and Bladder Ultrasound Replace Computerized Tomography Urogram in Patients Investigated for Microscopic Hematuria? AB - PURPOSE: Computerized tomography urogram is recommended when investigating patients with hematuria. We determined the incidence of urinary tract cancer and compared the diagnostic accuracy of computerized tomography urogram to that of renal and bladder ultrasound for identifying urinary tract cancer. MATERIALS AND METHODS: The DETECT (Detecting Bladder Cancer Using the UroMark Test) I study is a prospective observational study recruiting patients 18 years old or older following presentation with macroscopic or microscopic hematuria at a total of 40 hospitals. All patients underwent cystoscopy and upper tract imaging comprising computerized tomography urogram and/or renal and bladder ultrasound. RESULTS: A total of 3,556 patients with a median age of 68 years were recruited in this study, of whom 2,166 underwent renal and bladder ultrasound, and 1,692 underwent computerized tomography urogram in addition to cystoscopy. The incidence of bladder, renal and upper tract urothelial cancer was 11.0%, 1.4% and 0.8%, respectively, in macroscopic hematuria cases. Patients with microscopic hematuria had a 2.7%, 0.4% and 0% incidence of bladder, renal and upper tract urothelial cancer, respectively. The sensitivity and negative predictive value of renal and bladder ultrasound to detect renal cancer were 85.7% and 99.9% but they were 14.3% and 99.7%, respectively, to detect upper tract urothelial cancer. Renal and bladder ultrasound was poor at identifying renal calculi. Renal and bladder ultrasound sensitivity was lower than that of computerized tomography urogram to detect bladder cancer (each less than 85%). Cystoscopy had 98.3% specificity and 83.9% positive predictive value. CONCLUSIONS: Computerized tomography urogram can be safely replaced by renal and bladder ultrasound in patients who have microscopic hematuria. The incidence of upper tract urothelial cancer is 0.8% in patients with macroscopic hematuria and computerized tomography urogram is recommended. Patients with suspected renal calculi require noncontrast renal tract computerized tomography. Imaging cannot replace cystoscopy to diagnose bladder cancer. PMID- 29702099 TI - Prostate Ablation Using High Intensity Focused Ultrasound: A Literature Review of the Potential Role for Patient Preference Information. AB - PURPOSE: The FDA (Food and Drug Administration) recently allowed the marketing of 2 high intensity focused ultrasound devices for prostate tissue ablation indications after previous rejections for a prostate cancer indication due to insufficient data on clinical effectiveness or direct patient benefit. We reviewed the safety and effectiveness of high intensity focused ultrasound and knowledge regarding patient preferences, such as tolerance for adverse events associated with high intensity focused ultrasound ablation of tissue, in men with prostate cancer. This may inform decision making for device developers and the FDA. MATERIALS AND METHODS: We searched PubMed(r) and gray literature, including FDA reports for relevant data on 1) the safety and effectiveness of primary and salvage high intensity focused ultrasound of localized prostate cancer in studies performed in or outside the United States and 2) patient preference information on high intensity focused ultrasound related safety and effectiveness outcomes. RESULTS: We found no high intensity focused ultrasound effectiveness data relevant to clinical decision making, such as overall or prostate cancer specific survival, in the United States. Long-term effectiveness data from outside the United States were sparse and outcomes varied. We also found no patient preference data on high intensity focused ultrasound treatment in men with prostate cancer. CONCLUSIONS: The lack of long-term high intensity focused ultrasound oncological data in an American population has brought new challenges to prostate cancer stakeholders, including clinicians, patients and the FDA. Patient preference information from future patient studies on high intensity focused ultrasound could provide additional information to patients, clinicians, and current and prospective device developers. In addition, it can be used by regulators in benefit-risk evaluations of this class of treatment devices. PMID- 29702100 TI - Signaling pathways activated by resolvin E1 to stimulate mucin secretion and increase intracellular Ca2+ in cultured rat conjunctival goblet cells. AB - Glycoconjugate mucin secretion from conjunctival goblet cells is tightly regulated by nerves and specialized pro-resolving mediators (SPMs) to maintain ocular surface health. Here we investigated the actions of the SPM resolvin E1 (RvE1) on cultured rat conjunctival goblet cell glycoconjugate secretion and intracellular [Ca2+] ([Ca2+]i) and the signaling pathways used by RvE1. Goblet cells were cultured from rat conjunctiva in RPMI medium. The amount of RvE1 stimulated glycoconjugate mucin secretion was determined using an enzyme-linked lectin assay with Ulex Europaeus Agglutinin 1 lectin. Cultured goblet cells were also incubated with the Ca2+ indicator dye fura 2/AM and [Ca2+]i was measured. Cultured goblet cells were incubated with inhibitors to phospholipase (PL-) C, D, and A2 signaling pathways. RvE1 stimulated glycoconjugate secretion in a concentration dependent manner and was inhibited with the Ca2+ chelator BAPTA. The Ca2+i response was also increased in a concentration manner when stimulated by RvE1. Inhibition of PLC, PLD, and PLA2, but not Ca2+/calmodulin-dependent kinase blocked RvE1-stimulated increase in [Ca2+]i and glycoconjugate secretion. We conclude that under normal, physiological conditions RvE1 stimulates multiple pathways to increase glycoconjugate secretion and [Ca2+]i. RvE1 could be an important regulator of goblet cell glycoconjugate mucin secretion to maintain ocular surface health. PMID- 29702101 TI - The impact of chromoendoscopy for surveillance of the duodenum in patients with MUTYH-associated polyposis and familial adenomatous polyposis. AB - BACKGROUND AND AIMS: Duodenal polyposis and cancer have become a key issue for patients with familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). Almost all patients with FAP will develop duodenal adenomas, and 5% will develop cancer. The incidence of duodenal adenomas in MAP appears to be lower than in FAP, but the limited available data suggest a comparable increase in the relative risk and lifetime risk of duodenal cancer. Current surveillance recommendations, however, are the same for FAP and MAP, using the Spigelman score (incorporating polyp number, size, dysplasia, and histology) for risk stratification and determination of surveillance intervals. Previous studies have demonstrated a benefit of enhanced detection rates of adenomas by use of chromoendoscopy both in sporadic colorectal disease and in groups at high risk of colorectal cancer. We aimed to assess the effect of chromoendoscopy on duodenal adenoma detection, to determine the impact on Spigelman stage and to compare this in individuals with known pathogenic mutations in order to determine the difference in duodenal involvement between MAP and FAP. METHODS: A prospective study examined the impact of chromoendoscopy on the assessment of the duodenum in 51 consecutive patients with MAP and FAP in 2 academic centers in the United Kingdom (University Hospital Llandough, Cardiff, and St Mark's Hospital, London) from 2011 to 2014. RESULTS: Enhanced adenoma detection of 3 times the number of adenomas after chromoendoscopy was demonstrated in both MAP (P = .013) and FAP (P = .002), but did not affect adenoma size. In both conditions, there was a significant increase in Spigelman stage after chromoendoscopy compared with endoscopy without dye spray. Spigelman scores and overall adenoma detection was significantly lower in MAP compared with FAP. CONCLUSIONS: Chromoendoscopy improved the diagnostic yield of anomas in MAP and FAP 3-fold, and in both MAP and FAP this resulted in a clinically significant upstaging in Spigelman score. Further studies are required to determine the impact of improved adenoma detection on the management and outcome of duodenal polyposis. PMID- 29702102 TI - ER-localized protein-Herpud1 is a new mediator of IL-4-induced macrophage polarization and migration. AB - ER-localized proteins have been reported function in endoplasmic reticulum, unfolded protein degradation and destruction of misfolded proteins by the ER associated protein degradation (ERAD) system, but their function in the chemotaxis of macrophage cells remained un-addressed. Here, we showed that ER protein with ubiquitin like domain 1(Herpud1) was upregulated in IL-4-treated M2 macrophage cells and its expression pattern was similar with macrophage polarization markers, such as Arg1, Mrc1 and Fizz1. Inhibition of Herpud1 by using specific target shRNA decreased these marker's expression at mRNA and protein level in IL-4-treated or -untreated M2 macrophage cells. IL-4 treatment promoted M2 macrophage cell migration and polarization, but this promotion was weakened by Herpud1 depletion and we got similar results by inhibition of ER stress response with chemical molecule 4-phenylbutyric acid (4-PBA) in IL-4 treated or untreated-M2 macrophage cells with Herpud1 overexpression. These results indicated that depending on ER-associated protein degradation (ERAD) to help unfolded protein degradation or destruction is not the only function of Herpud1 and acting as a mediator of IL-4 induced macrophage activation and polarization maybe another unrevealed function, elucidating the role of Herpud1 associated M2 macrophage cell polarization and activation are helpful for exploration the function of macrophage cells in immune response. PMID- 29702103 TI - The miR-200b/200a/429 cluster prevents metastasis and induces dormancy in a murine claudin-low mammary tumor cell line. AB - The miR-200 family of microRNAs consisting of miR-141, miR-200a, miR-200b, miR 200c and miR-429 are emerging as important regulators of breast cancer progression. This family of microRNAs maintain mammary epithelial identity and downregulation of miR-200 expression has been associated with epithelial-to mesenchymal transition in mammary tumors. Therefore, re-expression of one or more miR-200 family members in mammary tumor cells with mesenchymal characteristics may restore an epithelial phenotype including growth and metastasis suppression. To test this hypothesis, the miR-200b/200a/429 cluster was re-expressed in a murine claudin-low cell line, RJ423. Re-expression of the miR-200b/200a/429 cluster in RJ423 cells significantly suppressed the expression of Vim, Snai1, Twist1, Twist2 and Zeb1, reverted RJ423 cells to a more epithelial morphology and significantly inhibited proliferation in vitro. Moreover, the miR-200b/200a/429 cluster prevented lung metastasis in an experimental metastasis model and although tumor initiation was not prevented, re-expression of the miR 200b/200a/429 cluster induced a dormancy-like state where mammary tumors failed to grow beyond ~150 mm3 or grew extremely slowly following intra-mammary injection. These dormant tumors contained elevated levels of collagen and were highly vascularized. Therefore, re-expression of the miR-200b/200a/429 cluster in the claudin-low mammary tumor cell line, RJ423, is sufficient to alter cell morphology, impair metastasis and induce tumor dormancy. PMID- 29702104 TI - Vasotocinergic control of agonistic behavior told by Neotropical fishes. AB - The hypothalamic neuropeptides of the vasopressin-oxytocin family (and their homologs for non-mammalian species) are key modulators of the Social Brain Network, acting via specific receptors reported in all the nuclei of this network. Different conclusive examples have proven the context-dependency actions of hypothalamic nonapeptides on social behavior in several vertebrate taxa. Teleost fishes provide endless possibilities of experimental model systems to explore the underlying mechanisms of nonapeptide actions on social behavior given that they are the most diverse group of vertebrates. Although it has been difficult to identify commonalities of nonapeptide actions across species, indisputable evidence in many teleost species have demonstrated a clear role of vasotocin in the modulation of aggressive and sexual behaviors. Though Neotropical South American fish contribute an important percentage of teleost diversity, most native species remain unexplored as model systems for the study of the neuroendocrine bases of social behavior. In this review, we will revise recent data on the two model systems of Neotropical fish, South American cichlids and weakly electric fish that have contributed to this issue. PMID- 29702105 TI - The volcano mouse Neotomodon alstoni of central Mexico, a biological model in the study of breeding, obesity and circadian rhythms. AB - The "Mexican volcano mouse" Neotomodon alstoni, is endemic of the Transverse Neovolcanic Ridge in central Mexico. It is considered as least concern species and has been studied as a potential laboratory model from different perspectives. Two lines of research in neuroendocrinology have been addressed: reproduction and parental care, particularly focused on paternal attention and the influence of testosterone, and studies on physiology and behavior of circadian rhythms, focused on the circadian biology of the species, its circadian locomotor activity and daily neuroendocrine regulation of metabolic parameters related to energy balance. Some mice, when captive, spontaneously develop obesity, which allows for comparisons between lean and obese mice of daily changes in neuronal and metabolic parameters associated with changes in food intake and locomotor activity. This review includes studies that consider this species an attractive animal model where the alteration of circadian rhythms influences the pathogenesis of obesity, specifically with the basic regulation of food intake and metabolism and differences related to sex. This study can be considered as a reference to the comparative animal physiology among rodents. PMID- 29702107 TI - Entry and Disassembly of Large DNA Viruses: Electron Microscopy Leads the Way. AB - Nucleocytoplasmic large DNA viruses are a steadily growing group of viruses that infect a wide range of hosts and are characterized by large particle dimensions and genome sizes. Understanding how they enter into the host cell and deliver their genome in the cytoplasm is therefore particularly intriguing. Here, we review the current knowledge on the entry of two of the best-characterized nucleocytoplasmic large DNA viruses: the poxvirus Vaccinia virus (VACV) and the giant virus Mimivirus. While previous studies on VACV had proposed both direct fusion at the plasma membrane and endocytosis as entry routes, more recent biochemical and morphological data argue for macropinocytosis as well. Notably, direct imaging by electron microscopy (EM) also supported the existence of parallel ways of entry for VACV. Instead, all the giant viruses studied so far only enter cells by phagocytosis as observed by EM, and we discuss the mechanisms for opening of the particle, fusion of the viral and phagosomal membranes and genome delivery via a unique portal, specific for each giant virus. VACV core uncoating, in contrast, remains a morphologically ill-defined process. We argue that correlated light and electron microscopy methods are required to study VACV entry and uncoating in a direct and systematic manner. Such EM studies should also address whether entry of single particles and viral aggregates is different and thus provide an explanation for the different modes of entry described in the literature. PMID- 29702106 TI - Pathology and reproductive health of queen conch (Lobatus gigas) in St. Kitts. AB - Queen conch, Lobatus gigas, are one of the largest commercial fisheries in the Caribbean and are severely depleted due to overharvesting. Dwindling and fragmented populations are at high risk to stochastic events such as disease epidemics; however, there is a paucity of literature regarding queen conch disease. A histopathological survey was conducted to assess the disease status of St. Kitts' queen conch populations, and contribute to the little information known about L. gigas pathology. Using a standard dissection and sampling protocol, pathology status was assessed in 61 L. gigas sampled opportunistically from fishermen in St. Kitts from October 2015 to November 2016. Pathology was observed in 13.1% (8/61) of the study population, mostly comprising internal parasitism (n = 5), especially encysted metazoan parasites (likely digenean metacercaria), observed in the gill, mantle, digestive gland and large intestine. Parasitism appeared incidental, having little impact on the host's health and minimal host response to the infection. Additionally, aspects of L. gigas reproductive health were analyzed: reproductive season in St. Kitts was confirmed from May to September; lip thickness is suggested as a better regulation measure for protecting juvenile populations compared to shell length; and variation in gonad color is found to be an unreliable predictor of reproductive activity. We conclude that disease appears to be uncommon in fisherman-caught L. gigas from St. Kitts. Pathologies observed elsewhere, including imposex and apicomplexan infection of the digestive gland, could not be substantiated in the study population. The cryptic nature of sick gastropods, as well as high predation rate and selection pressure for diseased queen conch may yield underrepresentation of pathology in such surveys. Future disease surveys could benefit from targeting stunted individuals, those showing unusual behavior, or those grown in an aquaculture environment. PMID- 29702108 TI - Emerging Paradigms for Synthetic Design of Functional Amyloids. AB - Many living organisms make use of diverse amyloid proteins as functional building blocks to fulfill a variety of physiological applications. This fact, along with the intrinsic self-assembly and outstanding material properties of amyloids, has prompted a significant amount of research in the synthetic design of functional amyloids to form diverse nanoarchitectures, molecular materials, and hybrid or composite materials. In particular, a new research paradigm has recently been advanced that uses synthetic biology to harness functional amyloids with cells as living materials or functional devices. Here we outline important progress in the synthetic design of functional amyloids, in the context of both non-living and living systems. We propose several important tools and underline emerging techniques and principles that might be useful in advancing the future synthetic design of functional amyloids. PMID- 29702109 TI - Epidemics of random walkers in metapopulation model for complete, cycle, and star graphs. AB - We present the metapopulation dynamic model for epidemic spreading of random walkers between subpopulations. A subpopulation is represented by a node on a graph. Each agent or individual is either susceptible (S) or infected (I). All agents move by random walk on the graph; namely, each agent randomly determines the destination of migration. The reaction-diffusion equations are presented as ordinary differential equations, not partial differential equations. To evaluate the risk of each subpopulation (node), we obtain the solutions of reaction diffusion equations analytically and numerically for small, complete, cycle and star graphs. If a graph is homogeneous, or if every node has the same degree, then the solution never changes for any nodes. However, when a graph is heterogeneous, the infection density in equilibrium differs entirely among nodes. For example, on star graphs, the hub seems to be a supply source of disease because the infection density at the hub is much higher than that at the other nodes. On every graph, the epidemic thresholds are identical for all nodes. PMID- 29702110 TI - A guideline to study the feasibility domain of multi-trophic and changing ecological communities. AB - The feasibility domain of an ecological community can be described by the set of environmental abiotic and biotic conditions under which all co-occurring and interacting species in a given site and time can have positive abundances. Mathematically, the feasibility domain corresponds to the parameter space compatible with positive (feasible) solutions at equilibrium for all the state variables in a system under a given model of population dynamics. Under specific dynamics, the existence of a feasible equilibrium is a necessary condition for species persistence regardless of whether the feasible equilibrium is dynamically stable or not. Thus, the size of the feasibility domain can also be used as an indicator of the tolerance of a community to random environmental variations. This has motivated a rich research agenda to estimate the feasibility domain of ecological communities. However, these methodologies typically assume that species interactions are static, or that input and output energy flows on each trophic level are unconstrained. Yet, this is different to how communities behave in nature. Here, we present a step-by-step quantitative guideline providing illustrative examples, computational code, and mathematical proofs to study systematically the feasibility domain of ecological communities under changes of interspecific interactions and subject to different constraints on the trophic energy flows. This guideline covers multi-trophic communities that can be formed by any type of interspecific interactions. Importantly, we show that the relative size of the feasibility domain can significantly change as a function of the biological information taken into consideration. We believe that the availability of these methods can allow us to increase our understanding about the limits at which ecological communities may no longer tolerate further environmental perturbations, and can facilitate a stronger integration of theoretical and empirical research. PMID- 29702111 TI - New advances in scanning microscopy and its application to study parasitic protozoa. AB - Scanning electron microscopy has been used to observe and study parasitic protozoa for at least 40 years. However, field emission electron sources, as well as improvements in lenses and detectors, brought the resolution power of scanning electron microscopes (SEM) to a new level. Parallel to the refinement of instruments, protocols for preservation of the ultrastructure, immunolabeling, exposure of cytoskeleton and inner structures of parasites and host cells were developed. This review is focused on protozoan parasites of medical and veterinary relevance, e.g., Toxoplasma gondii, Tritrichomonas foetus, Giardia intestinalis, and Trypanosoma cruzi, compilating the main achievements in describing the fine ultrastructure of their surface, cytoskeleton and interaction with host cells. Two new resources, namely, Helium Ion Microscopy (HIM) and Slice and View, using either Focused Ion Beam (FIB) abrasion or Microtome Serial Sectioning (MSS) within the microscope chamber, combined to backscattered electron imaging of fixed (chemically or by quick freezing followed by freeze substitution and resin embedded samples is bringing an exponential amount of valuable information. In HIM there is no need of conductive coating and the depth of field is much higher than in any field emission SEM. As for FIB- and MSS-SEM, high resolution 3-D models of areas and volumes larger than any other technique allows can be obtained. The main results achieved with all these technological tools and some protocols for sample preparation are included in this review. In addition, we included some results obtained with environmental/low vacuum scanning microscopy and cryo-scanning electron microscopy, both promising, but not yet largely employed SEM modalities. PMID- 29702112 TI - Alpha-syntrophin deficient mice are protected from adipocyte hypertrophy and ectopic triglyceride deposition in obesity. AB - Alpha-syntrophin (SNTA) is a molecular adapter protein which is expressed in adipocytes. Knock-down of SNTA in 3T3-L1 preadipocytes increases cell proliferation, and differentiated adipocytes display small lipid droplets. These effects are both characteristics of healthy adipose tissue growth which is associated with metabolic improvements in obesity. To evaluate a role of SNTA in adipose tissue morphology and obesity associated metabolic dysfunction, SNTA deficient mice were fed a standard chow or a high fat diet. Mice deficient of SNTA had less fat mass and smaller adipocytes in obesity when compared to control animals. Accordingly, these animals did not develop liver steatosis and did not store excess triglycerides in skeletal muscle upon high fat diet feeding. SNTA-/- animals were protected from hyperinsulinemia and hepatic insulin resistance. Of note, body-weight, food uptake, and serum lipids were normal in the SNTA null mice. SNTA was induced in adipose tissues but not in the liver of diet induced obese and ob/ob mice. In human subcutaneous and visceral fat of seven patients SNTA was similarly expressed and was not associated with body mass index. Current data demonstrate beneficial effects of SNTA deficiency in obesity which is partly attributed to smaller adipocytes and reduced white adipose tissue mass. Higher SNTA protein in fat depots of obese mice may contribute to adipose tissue hypertrophy and ectopic lipid deposition which has to be confirmed in humans. PMID- 29702113 TI - Hoarseness of Voice After Endoscopic Dilation of an Esophageal Stricture. PMID- 29702114 TI - "Dwarfing" White Strands on Screening Colonoscopy! PMID- 29702116 TI - A Rare But Recognizable Cholestatic Liver Disease. PMID- 29702115 TI - Germline Duplication of SNORA18L5 Increases Risk for HBV-related Hepatocellular Carcinoma by Altering Localization of Ribosomal Proteins and Decreasing Levels of p53. AB - BACKGROUND & AIMS: Single nucleotide polymorphisms could affect risk for hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). We performed a germline copy number variation (CNV)-based genome-wide association study (GWAS) in populations of Chinese ancestry to search for germline CNVs that increase risk of HCC. METHODS: We conducted a CNV-based GWAS of 1583 HCC cases (persons with chronic HBV infection and HCC) and 1540 controls (persons with chronic HBV infection without HCC) in Chinese populations. Identified candidates were expressed in L-02, HepG2, or TP53-/- or wild-type HCT116 cells, and knocked down with short hairpin RNAs in HepG2, Bel-7402, and SMMC-7721 cells; proliferation, colony formation, and apoptosis were measured. Formation of xenograft tumors from cell lines was monitored in nude mice. Subcellular localization of ribosome proteins and levels or activity of p53 were investigated by co immunoprecipitation, immunofluorescence, and immunoblot analyses. Levels of small nucleolar RNA H/ACA box 18-like 5 (SNORA18L5) were quantified by quantitative reverse transcription polymerase chain reaction. RESULTS: We identified a low frequency duplication at chromosome 15q13.3 strongly associated with risk of HBV related HCC (overall P = 3.17 * 10-8; odds ratio, 12.02). Copy numbers of the 15q13.3 duplication correlated with the expression of SNORA18L5 in liver tissues. Overexpression of SNORA18L5 increased HCC cell proliferation and growth of xenograft tumors in mice; knockdown reduced HCC proliferation and tumor growth. SNORA18L5 overexpression in HepG2 and SMMC-7721 cells inhibited p53-dependent cell cycle arrest and apoptosis. Overexpression of SNORA18L5 led to hyperactive ribosome biogenesis, increasing levels of mature 18S and 28S ribosomal RNAs and causing the ribosomal proteins RPL5 and RPL11 to stay in the nucleolus, which kept them from binding to MDM2. This resulted in increased MDM2-mediated ubiquitination and degradation of p53. Levels of SNORA18L5 were increased in HCC tissues compared with nontumor liver tissues and associated with shorter survival times of patients. CONCLUSIONS: In a CNV-based GWAS, we associated duplication at 15q13.3 with increased risk of HBV-related HCC. We found SNORA18L5 at this location to promote HCC cell proliferation and tumor growth in mice. SNORA18L5 increases ribosome biogenesis, facilitates ribosomal RNA maturation, and alters localization of RPL5 and RPL11, allowing for increased MDM2-mediated proteolysis of p53 and cell cycle arrest. PMID- 29702119 TI - Glomeruloid hemangioma associated with TAFRO syndrome. AB - Glomeruloid hemangioma is a rare cutaneous lesion which has been considered as a specific cutaneous marker of POEMS syndrome. Herein, we present the first case of glomeruloid hemangioma associated with TAFRO syndrome, a unique variant of idiopathic multicentric Castleman's disease (iMCD). The patient is a 74-year-old female presented with fever, cervical lymphadenopathy, thrombocytopenia, bilateral pleural effusions and ascites. Biopsy of the lymph node revealed MCD like histology and bone marrow biopsy showed mild reticulin fibrosis, consistent with TAFRO syndrome. The patient simultaneously developed multiple skin lesions which were histologically confirmed as glomeruloid hemangioma. Multiple immunoglobulin-positive granules were detected in the proliferating endothelial cells. Glomeruloid hemangioma is not specific to POEMS syndrome and can be a manifestation of TAFRO syndrome. PMID- 29702118 TI - Improvement in Gastrointestinal Symptoms After Cognitive Behavior Therapy for Refractory Irritable Bowel Syndrome. AB - BACKGROUND & AIMS: There is an urgent need for safe treatments for irritable bowel syndrome (IBS) that relieve treatment-refractory symptoms and their societal and economic burden. Cognitive behavior therapy (CBT) is an effective treatment that has not been broadly adopted into routine clinical practice. We performed a randomized controlled trial to assess clinical responses to home based CBT compared with clinic-based CBT and patient education. METHODS: We performed a prospective study of 436 patients with IBS, based on Rome III criteria, at 2 tertiary centers from August 23, 2010, through October 21, 2016. Subjects (41.4 +/- 14.8 years old; 80% women) were randomly assigned to groups that received the following: standard-CBT (S-CBT, n = 146, comprising 10 weekly, 60-minute sessions that emphasized the provision of information about brain-gut interactions; self-monitoring of symptoms, their triggers, and consequences; muscle relaxation; worry control; flexible problem solving; and relapse prevention training), or 4 sessions of primarily home-based CBT requiring minimal therapist contact (MC-CBT, n = 145), in which patients received home-study materials covering the same procedures as S-CBT), or 4 sessions of IBS education (EDU, n = 145) that provided support and information about IBS and the role of lifestyle factors such as stress, diet, and exercise. The primary outcome was global improvement of IBS symptoms, based on the IBS-version of the Clinical Global Impressions-Improvement Scale. Ratings were performed by patients and board-certified gastroenterologists blinded to treatment allocation. Efficacy data were collected 2 weeks, 3 months, and 6 months after treatment completion. RESULTS: A higher proportion of patients receiving MC-CBT reported moderate to substantial improvement in gastrointestinal symptoms 2 weeks after treatment (61.0% based on ratings by patients and 55.7% based on ratings by gastroenterologists) than those receiving EDU (43.5% based on ratings patients and 40.4% based on ratings by gastroenterologists) (P < .05). Gastrointestinal symptom improvement, rated by gastroenterologists, 6 months after the end of treatment also differed significantly between the MC-CBT (58.4%) and EDU groups (44.8%) (P = .05). Formal equivalence testing applied across multiple contrasts indicated that MC-CBT is at least as effective as S-CBT in improving IBS symptoms. Patients tended to be more satisfied with CBT vs EDU (P < .05) based on immediate posttreatment responses to the Client Satisfaction Questionnaire. Symptom improvement was not significantly related to concomitant use of medications. CONCLUSIONS: In a randomized controlled trial, we found that a primarily home-based version of CBT produced significant and sustained gastrointestinal symptom improvement for patients with IBS compared with education. Clinicaltrials.gov no.: NCT00738920. PMID- 29702121 TI - Do isolated packaging variables influence consumers' attention and preferences? AB - Developments in neuroscience have provided the opportunity to know unconscious consumer reactions and acknowledge direct measures of cognitive constructs like attention. Given the ever-increasing concern over packaging's contribution to creating a positive first impression, the current research seeks to examine consumers' attention and declarative preferences regarding the three main different packaging attributes as isolated variables: images, texts and colours. The experiment exposed participants (N = 40) to 63 stimuli, which were based on modifications of the three main packaging attributes of three products of three different food categories. This study used electroencephalogram (EEG) and eye tracking (ET) to measure attention, and a declarative test was employed to examine preference. First, the results presented herein show that the presence of visual elements, either images or texts on packages, increased the participants' level of attention. Second, the results reveal that colour modifications do not have a significant effect on participants' neurophysiological attention levels. Third, the results demonstrated that the neurophysiological effects among the participants do not necessarily coincide with their subjective evaluations of preference. Hence, this study increases awareness of the relevance of combining traditional market research tools that rely on explicit consumer responses with neuroscientific techniques. These findings indicate, first of all, that more research is needed to ascertain the extent to which consumers' neurophysiological outcomes correspond to their declarative preferences and second, that neurophysiological methods should be given more attention in research. PMID- 29702120 TI - Chinese herbal extract Su-duxing had potent inhibitory effects on both wild-type and entecavir-resistant hepatitis B virus (HBV) in vitro and effectively suppressed HBV replication in mouse model. AB - This study aimed to investigate anti-HBV effect and major active compounds of Su duxing, a medicine extracted from Chinese herbs. HBV-replicating cell lines HepG2.2.15 (wild-type) and HepG2.A64 (entecavir-resistant) were used for in vitro test. C57BL/6 mice infected by adeno-associated virus carrying 1.3 mer wild-type HBV genome were used for in vivo test. Inhibitory rates of Su-duxing (10 MUg/mL) on HBV replicative intermediate and HBsAg levels were 75.1%, 51.0% in HepG2.2.15 cells and 65.2%, 42.9% in HepG2.A64 cells. The 50% inhibitory concentration of Su duxing and entecavir on HBV replicative intermediates had 0.2-fold and 712.5-fold increase respectively for entecavir-resistant HBV compared to wild-type HBV. Su duxing and entecavir combination showed a better anti-HBV effect than each single of agents. Mice treated with Su-duxing (45.0 mg kg-1 d-1 for 2 weeks) had 1.39 log10 IU/mL decrease of serum HBV DNA, and 48.9% and 51.7% decrease of serum HBsAg and HBeAg levels. GeneChip and KEGG analysis proposed that anti-HBV mechanisms included relief of HBx stability and viral replication, deregulation of early cell cycle checkpoints, and induction of type I interferon. Quantitative RT-PCR verified that CCNA2, ATF4, FAS and CDKN1A expression levels had significant difference between Su-duxing-treated and control groups. Six active compounds (Matrine, Oxymatrine, Chlorogenic acid, Sophocarpine, Baicalein, and Wogonin) against HBV were identified in Su-duxing. Greater anti-HBV effects were observed in some compound pairs compared to each single compound. In conclusion, Su-duxing had potent inhibitory effects on both wild-type and entecavir-resistant HBV. Its effects were associated with coordinated roles of active compounds in its composition. PMID- 29702117 TI - Association Between Risk Factors for Colorectal Cancer and Risk of Serrated Polyps and Conventional Adenomas. AB - BACKGROUND & AIMS: Serrated polyps (SPs) and conventional adenomas are precursor lesions for colorectal cancer (CRC), but they are believed to arise via distinct pathways. We characterized risk factor profiles for SPs and conventional adenomas in a post hoc analysis of data from 3 large prospective studies. METHODS: We collected data from the Nurses' Health Study, the Nurses' Health Study 2, and the Health Professionals Follow-up Study on subjects who developed SPs or conventional adenomas. Our analysis comprised 141,143 participants who had undergone lower gastrointestinal endoscopy, provided updated diet and lifestyle data every 2-4 years, and were followed until diagnosis of a first polyp. We assessed 13 risk factors for CRC in patients with SPs or conventional adenomas and examined the associations according to histopathology features. RESULTS: We documented 7945 SPs, 9212 conventional adenomas, and 2382 synchronous SPs and conventional adenomas during 18-20 years of follow-up. Smoking, body mass index, alcohol intake, family history of CRC, and height were associated with higher risk of SPs and conventional adenomas, whereas higher intake of vitamin D and marine omega-3 fatty acid were associated with lower risk. The associations tended to be stronger for synchronous SPs and conventional adenomas. Smoking, body mass index, and alcohol intake were more strongly associated with SPs than conventional adenomas (P for heterogeneity <.05), whereas physical activity and intake of total folate and calcium were inversely associated with conventional adenomas but not SPs. For SPs and conventional adenomas, the associations tended to be stronger for polyps in the distal colon and rectum, of 10 mm or larger or with advanced histology. CONCLUSIONS: In an analysis of data from 3 large prospective studies, we found that although SPs and conventional adenomas share many risk factors, some factors are more strongly associated with one type of lesion than the other. These findings provide support for the etiologic heterogeneity of colorectal neoplasia. PMID- 29702122 TI - Temporally dissociable effects of ketamine on neuronal discharge and gamma oscillations in rat thalamo-cortical networks. AB - BACKGROUND: Sub-anesthetic doses of the non-competitive N-methyl-d-aspartate receptor (NMDA-R) antagonist ketamine evoke transient psychotomimetic effects, followed by persistent antidepressant effects in treatment-resistant depressed patients and rodents through still poorly understood mechanisms. Since phencyclidine (PCP) disinhibits thalamo-cortical networks by blocking NMDA-Rs on GABAergic neurons of the reticular thalamic nucleus (RtN), we examined ketamine's actions in the same areas. METHODS: Single units and local field potentials were recorded in chloral hydrate anesthetized male Wistar rats. The effects of cumulative ketamine doses (0.25-5 mg/kg, i.v.) on neuronal discharge and oscillatory activity were examined in RtN, mediodorsal and centromedial (MD/CM) thalamic nuclei, and layer VI of the medial prefrontal cortex (mPFC). RESULTS: Ketamine (1, 2 and 5 mg/kg, i.v.) significantly decreased the discharge of MD/CM, RtN and layer VI mPFC pyramidal neurons. Simultaneously, ketamine decreased the power of low frequency oscillations in all areas examined and increased gamma oscillations in mPFC and MD/CM. Lower ketamine doses (0.25 and 0.5 mg/kg, i.v.) were ineffective. CONCLUSIONS: As observed for PCP, ketamine markedly inhibited the activity of RtN neurons. However, unlike PCP, this effect did not translate into a disinhibition of MD/CM and mPFC excitatory neurons, possibly due to a more potent and simultaneous blockade of NMDA-Rs by ketamine in MD/CM and mPFC neurons. Hence, the present in vivo results show that ketamine evokes an early transient inhibition of neuronal discharge in thalamo-cortical networks, following its rapid pharmacokinetics, which is likely associated to its psychotomimetic effects. The prolonged increase in gamma oscillations may underlie its antidepressant action. PMID- 29702123 TI - First characterization of two C-type lectins of the tubeworm Alaysia sp. from a deep-sea hydrothermal vent. AB - C-type lectins (CTLs) play an important role in innate immune defense. In this study, we identified and characterized two CTLs (Lec1 and Lec2) from the tubeworm Alaysia sp. collected from a hydrothermal vent in Pacmanus. Lec1 and Lec2 possess the typical CTL domain but share low sequence identities (10.8%-20.4%) with known CTLs. Recombinant (r) of Lec1 and Lec2 bound to various PAMPs and a wide arrange of bacteria from neritic and deep-sea environments in a Ca2+-independent manner, but only rLec1 caused agglutination of the bound bacteria. The activities of rLec1 and rLec2 were most stable and highest at 4 degrees C, the ambient temperature of the hydrothermal vent, and decreased at higher temperatures. Both lectins inhibited bacterial growth in a highly selective manner and agglutinated the erythrocytes of fish, rabbit, and chicken in a Ca2+-dependent manner. These results provided the first insights into the functional properties of CTLs in deep-sea Alaysia sp. PMID- 29702125 TI - Travelling waves in somitogenesis: Collective cellular properties emerge from time-delayed juxtacrine oscillation coupling. AB - The sculpturing of the vertebrate body plan into segments begins with the sequential formation of somites in the presomitic mesoderm (PSM). The rhythmicity of this process is controlled by travelling waves of gene expression. These kinetic waves emerge from coupled cellular oscillators and sweep across the PSM. In zebrafish, the oscillations are driven by autorepression of her genes and are synchronized via Notch signalling. Mathematical modelling has played an important role in explaining how collective properties emerge from the molecular interactions. Increasingly more quantitative experimental data permits the validation of those mathematical models, yet leads to increasingly more complex model formulations that hamper an intuitive understanding of the underlying mechanisms. Here, we review previous efforts, and design a mechanistic model of the her1 oscillator, which represents the experimentally viable her7;hes6 double mutant. This genetically simplified system is ideally suited to conceptually recapitulate oscillatory entrainment and travelling wave formation, and to highlight open questions. It shows that three key parameters, the autorepression delay, the juxtacrine coupling delay, and the coupling strength, are sufficient to understand the emergence of the collective period, the collective amplitude, and the synchronization of neighbouring Her1 oscillators. Moreover, two spatiotemporal time delay gradients, in the autorepression and in the juxtacrine signalling, are required to explain the collective oscillatory dynamics and synchrony of PSM cells. The highlighted developmental principles likely apply more generally to other developmental processes, including neurogenesis and angiogenesis. PMID- 29702124 TI - Identification of large cryptic plasmids in Clostridioides (Clostridium) difficile. AB - Clostridioides (Clostridium) difficile is a major bacterial pathogen of both humans and animals. Several species of pathogenic clostridia are known to harbour large plasmids with combinations of virulence, antibiotic resistance and metabolism determinants. Small cryptic plasmids have been previously identified in C. difficile, but there is a lack of recent work examining the prevalence and heterogeneity of plasmids in this diverse bacterial species. A survey of clinical and historical isolates of C. difficile showed that several strains carry large plasmids. Following whole-genome sequencing of these diverse strains, 42-47 kb plasmids with high nucleotide identity were found to be carried in 4.9% (n = 451) of isolates, with no firm connection to the strain backgrounds. These plasmids appear to have arisen as a result of recombination with a bacteriophage, but contain key plasmid features, such as a putative plasmid replication and partitioning locus. As no virulence factors or antibiotic resistance determinants were identified, further work is required to identify the selective advantage that must exist for the host isolates to maintain these large plasmids. PMID- 29702126 TI - Irbesartan attenuates advanced glycation end products-mediated damage in diabetes associated osteoporosis through the AGEs/RAGE pathway. AB - AIMS: Diabetes-associated osteoporosis is mainly caused by the formation and accumulation of advanced glycation end products (AGEs). Angiotensin II type 1 receptor blocker (ARB) has anabolic bone effects on the physicochemical properties of the bone in diabetes. We hypothesized that ARB could inhibit AGEs induced deleterious effects. MAIN METHODS: In this study, we chose seven-week-old Leprdb/Lepr+ (db/+) and Leprdb/Leprdb (db/db) mice. After 12 week intervention by irbesartan, the microarchitecture and mechanical strength of the bone of seven week-old db/db mice were investigated systematically. Meanwhile, the molecular mechanisms of the osteoblasts were analyzed, after AGEs or irbesartan were added to the culture. Also, intracellular formation of reactive oxygen species (ROS) was measured with DCF fluorescence. KEY FOUNDINGS: Results showed that 12-week irbesartan treatment could dramatically improve trabecular bone microarchitecture through increasing BV/TV (p = 0.003, +46.7%), Tb.N (p = 0.020, +52.0%), and decreasing that of Tb.Sp (p = 0.005, -21.2%) and SMI (p = 0.007, -26.4%), comparing with the db/db group. Irbesartan could also substantially raise biomechanical parameters including max load (p = 0.013, +20.7%), fracture load (p = 0.014, +70.5%), energy absorption (p = 0.019, +99.4%). Besides, it could inhibit AGEs-induced damage of cell proliferation and osteogenic differentiation of osteoblasts, as well as suppressing the activation of apoptosis caused by AGEs. Moreover, co-incubation with irbesartan could prevent the AGEs-induced increase of intracellular oxidative stress and RAGE expression in osteoblasts. SIGNIFICANCE: In conclusion, this study suggested that irbesartan might play a protective role in diabetes-related bone damages by blocking the deleterious effects of AGEs/RAGE-mediated oxidative stress. This may provide a revolutionary benefits to therapy with irbesartan on diabetic osteoporosis. PMID- 29702127 TI - Vascular endothelial growth factor improves the cognitive decline of Alzheimer's disease via concurrently inducing the expression of ADAM10 and reducing the expression of beta-site APP cleaving enzyme 1 in Tg2576 mice. AB - Alzheimer's disease (AD) is primarily characterized by the production and deposit of beta-amyloid protein (Abeta) in beta-amyloid plaques (APs). On this basis, we investigated whether vascular endothelial growth factor (VEGF), a growth factor with important neuroprotective activity, may provide a therapeutic opportunity for treating AD. We initially found that the expression and production of VEGF was downregulated in the brains of Tg2576 mice during the course of AD development and progression. Restoring VEGF in the brains of Tg2576 mice antagonized the production and deposit of Abeta in Tg2576 mice. The addition of VEGF concurrently increased the expression of disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) and decreased the expression of beta-site APP cleaving enzyme 1 (BACE1), which contributes to the enhanced clearance of Abeta in vivo. By decreasing the production and deposit of Abeta, VEGF improved the cognitive decline of Tg2576 mice. These observations provide a novel implication for VEGF as a therapeutic approach for the treatment of AD. PMID- 29702128 TI - Systematic review and meta-analysis of strategies to increase vegetable consumption in preschool children aged 2-5 years. AB - BACKGROUND: Most children do not meet daily recommendations for fruit and vegetable intake, and consumption of vegetables remains especially low. Eating habits track from childhood to adulthood hence establishing liking and intake of vegetables is important. OBJECTIVE: To identify the most successful strategies to enhance vegetable intake in preschool children aged 2-5 years. DESIGN: The research was a systematic review and a meta-analysis of published studies. A comprehensive search strategy was performed using key databases such as Medline, Embase, PsychINFO, EBSCO and CENTRAL. Articles published between 2005-January 2016, specifically with measured vegetable consumption were included. RESULTS: 30 articles and 44 intervention arms were identified for inclusion (n = 4017). Nine dominant intervention strategies emerged to promote vegetable intake in preschool children. These included; choice, pairing (stealth), education, food service, modelling, reward, taste exposure, variety and visual presentation. The meta analysis revealed that interventions implementing repeated taste exposure had better pooled effects than those which did not. Intake increased with number of taste exposures and intake was greater when vegetables offered were in their plain form rather than paired with a flavor, dip or added energy (e.g. oil). Moreover, intake of vegetables which were unfamiliar/disliked increased more than those which were familiar/liked. CONCLUSIONS: Repeated taste exposure is a simple technique that could be implemented in childcare settings and at home by parents. Health policy could specifically target the use of novel and disliked vegetables in childcare settings with emphasis on a minimum 8-10 exposures. The systematic review protocol was registered on the PROSPERO (number: CRD42016033984). PMID- 29702129 TI - An endogenous adeno-associated virus element in elephants. AB - An endogenous viral element derived from adeno-associated virus containing a nearly intact open reading frame (ORF) of the rep gene (enAAV-rep) has been identified in the genomes of various mammals including degu and African elephant. Particularly, in degu, mRNA expression of enAAV-rep has been observed specifically in the liver. Here we newly identified enAAV-rep in Asian elephant and rock hyrax, both of which are afrotherians. The enAAV-rep of African and Asian elephants appeared to be orthologous and originated from an integration event of the entire genome of AAV into the ancestral genome of elephants more than 6 million years ago, whereas that of rock hyrax appeared to have originated independently. Negative selection operating at the amino acid sequence level was detected for the ORF of enAAV-rep in elephants. As in degu, mRNA expression of enAAV-rep was specifically observed in the liver in Asian elephant. Integrations of enAAV-rep appeared to have occurred independently on the evolutionary lineages of elephants and degu, suggesting that the AAV Rep protein has been co-opted repeatedly in the mammalian liver. PMID- 29702130 TI - Drosophila pericardial nephrocyte ultrastructure changes during ageing. AB - Here we show that a labyrinth channel compartment and slit diaphragms, which are the histological structures enabling insect nephrocytes ultrafiltration, are established during embryogenesis first by the garland nephrocytes (GCNs). The later pericardial nephrocytes, which represent the majority of functional nephrocytes in larvae and adults, lack these characteristic features at the embryonic stage. During larval development, a subpopulation of the pericardial cells survives and matures into functional nephrocytes (PCNs) displaying a fully differentiated slit diaphragm and a labyrinth channel compartment. Likely the embryonic pericardial cells have primary functions other than ultrafiltration (e.g. in production and secretion of ECM constituents). We also show, for the first time, that PCNs in the adult fly undergo dramatic histological degeneration upon ageing. The slit diaphragms disappear, the labyrinth channel system degenerates and the lysosomal compartment becomes highly enriched with electron dense material. When using nephrocytes as a model for genetic screening purposes or to investigate the specific role of genes involved in endocytosis, histological changes occurring upon ageing need to be taken into account when interpreting structural data. PMID- 29702131 TI - Electronic cigarette substitution in the experimental tobacco marketplace: A review. AB - The evolution of science derives, in part, from the development and use of new methods and techniques. Here, we discuss one development that may have impact on the understanding of tobacco regulatory science: namely, the application of behavioral economics to the complex tobacco marketplace. The purpose of this paper is to review studies that examine conditions impacting the degree to which electronic nicotine delivery system (ENDS) products substitute for conventional cigarettes in the Experimental Tobacco Marketplace (ETM). Collectively, the following factors constitute the current experimental understanding of conditions that will affect ENDS use and substitution for conventional cigarettes: increasing the base price of conventional cigarettes, increasing taxation of conventional cigarettes, subsidizing the price of ENDS products, increasing ENDS nicotine strength, and providing narratives that illustrate the potential health benefits of ENDS consumption in lieu of conventional cigarettes. Each of these factors are likely moderated by consumer characteristics, which include prior ENDS use, ENDS use risk perception, and gender. Overall, the ETM provides a unique method to explore and identify the conditions by which various nicotine products may interact with one another that mimics the real world. In addition, the ETM permits the efficacy of a broad range of potential nicotine policies and regulations to be measured prior to governmental implementation. PMID- 29702132 TI - Complete genome sequence of Bacillus velezensis QST713: A biocontrol agent that protects Agaricus bisporus crops against the green mould disease. AB - Bacillus subtilis QST713 is extensively used as a biological control agent in agricultural fields including in the button mushroom culture, Agaricus bisporus. This last use exploits its inhibitory activity against microbial pathogens such as Trichoderma aggressivum f. europaeum, the main button mushroom green mould competitor. Here, we report the complete genome sequence of this bacterium with a genome size of 4 233 757 bp, 4263 predicted genes and an average GC content of 45.9%. Based on phylogenomic analyses, strain QST713 is finally designated as Bacillus velezensis. Genomic analyses revealed two clusters encoding potential new antimicrobials with NRPS and TransATPKS synthetase. B. velezensis QST713 genome also harbours several genes previously described as being involved in surface colonization and biofilm formation. This strain shows a strong ability to form in vitro spatially organized biofilm and to antagonize T. aggressivum. The availability of this genome sequence could bring new elements to understand the interactions with micro or/and macroorganisms in crops. PMID- 29702133 TI - Primary prevention of Clostridium difficile infections with a specific probiotic combining Lactobacillus acidophilus, L. casei, and L. rhamnosus strains: assessing the evidence. AB - Clostridium difficile infection (CDI) has become the leading healthcare associated infection and cause of outbreaks around the world. Although various innovative treatments have been developed, preventive strategies using multi faceted infection control programmes have not been successful in reducing CDI rates. The major risk factor for CDI is the disruption of the normally protective gastrointestinal microbiota, typically by antibiotic use. Supplementation with specific probiotics has been effective in preventing various negative outcomes, including antibiotic-associated diarrhoea and CDI. However, a consensus of which probiotic strains might prevent CDI has not been reached and meta-analyses report high degrees of heterogeneity when studies of different probiotic products are pooled together. We searched the literature for probiotics with sufficient evidence to assess clinical efficacy for the prevention of CDI and focused on one specific probiotic formulation comprised of three lactobacilli strains (Lactobacillus acidophilus CL1285, Lactobacillus casei LBC80R, Lactobacillus rhamnosus CLR2, Bio-K+) for its ability to prevent CDI in healthcare settings. A literature search on this probiotic formulation was conducted using electronic databases (PubMed, Google Scholar), abstracts from infectious disease and infection control meetings, and communications from the probiotic company. Supporting evidence was found for its mechanisms of action against CDI and that it has an excellent safety and tolerability profile. Evidence from randomized controlled trials and facility-level interventions that administer Bio-K+ show reduced incidence rates of CDI. This probiotic formulation may have a role in primary prevention of healthcare-associated CDI when administered to patients who receive antibiotics. PMID- 29702134 TI - Threonine 454 phosphorylation in Grainyhead-like 3 is important for its function and regulation by the p38 MAPK pathway. AB - The mammalian Grainyhead-like 3 (GRHL3) transcription factor is essential for epithelial development and plays a protective role against squamous cell carcinoma of the skin and of the oral cavity. A single nucleotide polymorphism (SNP) in GRHL3, rs141193530 (p.P455A), is associated with non-melanoma skin cancer in human patients. Moreover, it is known that this SNP, as well as another variant, rs41268753 (p.T454M), are associated with nonsyndromic cleft palate and that rs41268753 negatively affects GRHL3 transcriptional activity. These SNPs are located in adjacent codons of the GRHL3 gene, and the occurrence of either SNP abolishes a putative threonine-proline phosphorylation motif at T454 in the encoded protein. The role of phosphorylation in regulating mammalian GRHL function is currently unknown. In this work we show that GRHL3 is phosphorylated at several residues in a human keratinocyte cell line, among them at T454. This site is essential for the full transcriptional activity of GRHL3. The T454 residue is phosphorylated by p38 MAPK in vitro and activation of p38 signaling in cells causes an increase in GRHL3 activity. The regulation of GRHL3 function by this pathway is dependent on T454, as the substitution of T454 with methionine inhibits the activation of GRHL3. Taken together, our results show that T454 is one of the phosphorylated residues in GRHL3 in keratinocytes and this residue is important for the upregulation of GRHL3 transcriptional activity by the p38 pathway. PMID- 29702135 TI - Zhiheshouwu ethanol extract induces intrinsic apoptosis and reduces unsaturated fatty acids via SREBP1 pathway in hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is the major incidence and one of the most life threatening cancer. How to conquer HCC is a worldwide issue for patients. Zhiheshouwu (Polygoni multiflori Radix Praeparata) is a Chinese medicinal herb exhibiting both lowering lipid and inhibiting cancer cells. However, it remains a matter if its inhibiting cancer cells is related to its lowering lipid. In this study, we investigate the effects of Zhiheshouwu ethanolic extract (HSWE) on apoptosis and the underlying mechanisms in Bel-7402 cells. The results showed that HSWE inhibited the proliferation with an increased level of ALT and AST in Bel-7402 cells. The decreased mitochondrial membrane potential (DeltaPsim) was observed in HSWE-treated Bel-7402 cells. The flow cytometry results showed that HSWE triggered apoptosis. Since mitochondrial injury is characterized as intrinsic apoptotic cell death, these data indicated that HSWE may induce intrinsic apoptosis in Bel-7402 cells. In addition, HSWE decreased the production of unsaturated fatty acids, and inhibited the mRNA and protein of SCD1 and its up stream factor, sterol-regulatory element binding proteins 1 (SREBP1), a master transcriptional regulator of lipogenic gene. Taken together, these data suggest that HSWE induces an intrinsic apoptosis, and reduced unsaturated fatty acids by blocking SREBP1 in hepatocellular carcinoma cells. PMID- 29702136 TI - Brain changes after spinal cord injury, a quantitative meta-analysis and review. AB - Spinal Cord Injuries (SCI) lead to alterations in brain structure and brain function by direct effects of nerve damage, by secondary mechanisms, and also by longer term injury consequences such as paralysis and neuropathic pain. Here, we review neuroimaging studies of patients with traumatic spinal cord injuries, perform a quantitative meta-analysis of motor and motor imagery studies, summarize structural studies, evidence of cortical reorganization, and provide an overview of diffusion and spectroscopy studies. The meta-analysis showed significantly altered motor cortex, as well as cerebellar and parietal lobe changes, and qualitatively consistent reports of alterations in somatosensory brain structure, cortical reorganization, white matter diffusion and thalamic metabolites. Larger samples in combination with standardized imaging protocols and data sharing will further our understanding of brain changes after SCI and help in defining short and long-term changes in brain systems in SCI patients. Such data would provide a basis for clinical trials, treatment outcomes, and guide novel interventions. PMID- 29702137 TI - Reduced clearance of venlafaxine in a combined treatment with quetiapine. AB - Venlafaxine and the atypical antipsychotic quetiapine are often administered concomitantly. Both drugs share several metabolic hepatic pathways. However, pharmacokinetic interactions between venlafaxine and quetiapine have not been studied yet. A therapeutic drug monitoring database containing serum concentrations of venlafaxine (VEN) and its active metabolite O desmethylvenlafaxine (ODVEN) was analyzed. Two groups of patients were compared: venlafaxine monotherapy V0 (n = 153) and co-medication with quetiapine, VQUE (n = 71). Serum concentrations of VEN, ODVEN, and active moiety, AM (VEN + ODVEN), metabolite to parent compound ratio (ODVEN/VEN) and dose adjusted serum concentrations were compared using non-parametrical tests without information on CYP2D6 genotype. The two groups did not differ in terms of the daily dosage of venlafaxine, age, or sex. Median serum concentrations in the quetiapine group showed significantly, 15.8% and 29.3% higher values for AM and ODVEN (p = 0.002, Cohen's d = 0,41; p = 0.003, d = 0,44), respectively. Dose adjusted serum concentrations of active moiety and ODVEN revealed comparable differences (p = 0.038, d = 0,32; p = 0.015, d = 0,28) with significantly higher values in the co medicated group. Significantly higher values for ODVEN and AM suggest a reduced clearance of ODVEN and active moiety when quetiapine is co-administered. This may be a consequence of a reduced metabolism of venlafaxine to the inactive metabolite N-desmethylvenlafaxine via CYP3A4, the main metabolizing enzyme for quetiapine, and a shift towards a higher proportion of the active metabolite ODVEN. Therapeutic drug monitoring is recommended in the case of co-medication to ensure clinical efficacy and patient safety. Although the increase of AM is moderate, we consider it relevant for clinicians given the prevalence of concomitant medication of quetiapine and venlafaxine. PMID- 29702138 TI - Antimicrobial cholic acid derivatives from the Pitch Lake bacterium Bacillus amyloliquefaciens UWI-W23. AB - Six cholic acid derivatives (1-6) were isolated from broth cultures of Bacillus amyloliquefaciens UWI-W23, an isolate from the Trinidad Pitch Lake. The compounds were extracted via solvent extraction and/or XAD resin adsorption and purified using silica gel column chromatography. Their structures were elucidated using 1D, 2D NMR and ESI-MS spectrometry and FT-IR spectrophotometry. One of the compounds, taurodeoxycholate (2) is for the first time being reported from a bacterial source while deoxycholate (4) is for the first time being reported from a Gram-positive bacterium. The other compounds have not been previously isolated from Bacillus spp. viz. cholate (1), taurocholic acid (3); glycodeoxycholic acid (5) and glycocholic acid (6). All six compounds exhibited antimicrobial activity against P. aeruginosa and B. cereus with MICs ranging from 7 to 250 ug/mL. Cholate (1) also showed activity against MRSA (MICs = 125 ug/mL) and glycocholic acid (6) against S. cerevisiae (MICs = 15.6 ug/mL). PMID- 29702139 TI - Renal health after long-term exposure to tenofovir disoproxil fumarate (TDF) in HIV/HBV positive adults in Ghana. AB - OBJECTIVES: The study assessed markers of renal health in HIV/HBV co-infected patients receiving TDF-containing antiretroviral therapy in Ghana. METHODS: Urinary protein-to-creatinine ratio (uPCR) and albumin-to-protein ratio (uAPR) were measured cross-sectionally after a median of four years of TDF. At this time, alongside extensive laboratory testing, patients underwent evaluation of liver stiffness and blood pressure. The estimated glomerular filtration rate (eGFR) was measured longitudinally before and during TDF therapy. RESULTS: Among 101 participants (66% women, median age 44 years, median CD4 count 572 cells/mm3) 21% and 17% had detectable HIV-1 RNA and HBV DNA, respectively. Overall 35% showed hypertension, 6% diabetes, 7% liver stiffness indicative of cirrhosis, and 18% urinary excretion of Schistosoma antigen. Tubular proteinuria occurred in 16% of patients and was independently predicted by female gender and hypertension. The eGFR declined by median 1.8 ml/min/year during TDF exposure (IQR -4.4, -0.0); more pronounced declines (>= 5 ml/min/year) occurred in 22% of patients and were associated with receiving ritonavir-boosted lopinavir rather than efavirenz. HBV DNA, HBeAg, transaminases, and liver stiffness were not predictive of renal function abnormalities. CONCLUSIONS: The findings mandate improved diagnosis and management of hypertension and suggest targeted laboratory monitoring of patients receiving TDF alongside a booster in sub-Saharan Africa. PMID- 29702140 TI - Addressing hyperglycemia in pregnancy: The impact on maternal health and beyond. PMID- 29702141 TI - DRm217 attenuates myocardial ischemia-reperfusion injury via stabilizing plasma membrane Na+-K+-ATPase, inhibiting Na+-K+-ATPase/ROS pathway and activating PI3K/Akt and ERK1/2. AB - Na+-K+-ATPase has close relationship with myocardial ischemia/reperfusion (IR) injury. Activation of Na+-K+-ATPase with its DR region specific antibody produces cardioprotective effect. In this study, we aimed to explore whether DRm217, a proved DR region specific antibody, could protect myocardial cells against IR injury and uncover the mechanisms under it. By employing H9c2 myocardial cell and SD rat, we found that DRm217 protected cardiac cells against IR-induced cell injury and apoptosis. DRm217 produced protective effect via stabilizing Na+-K+ ATPase membrane expression and inhibiting Na+-K+-ATPase/Src/NADPH oxidase dependent ROS accumulation. PI3K/Akt and ERK1/2 participated in DRm217-induced cardiomyocyte survival, but not in DRm217-related ROS reduction. Therefore, DRm217 can be used as a potential cardioprotective adjuvant in myocardial IR therapy and interference of Na+-K+-ATPase/ROS pathway will be a promising modality for clinical myocardial IR therapy. PMID- 29702142 TI - Dual TLR agonist nanodiscs as a strong adjuvant system for vaccines and immunotherapy. AB - Recent studies have shown that certain combinations of Toll-like receptor (TLR) agonists can induce synergistic immune activation. However, it remains challenging to achieve such robust responses in vivo in a manner that is effective, facile, and amenable for clinical translation. Here, we show that MPLA, a TLR4 agonist, and CpG, a TLR9 agonist, can be efficiently co-loaded into synthetic high-density lipoprotein nanodiscs, forming a potent adjuvant system (ND-MPLA/CpG) that can be readily combined with a variety of subunit antigens, including proteins and peptides. ND-MPLA/CpG significantly enhanced activation of dendritic cells, compared with free dual adjuvants or nanodiscs delivering a single TLR agonist. Importantly, mice immunized with physical mixtures of protein antigens ND-MPLA/CpG generated strong humoral responses, including induction of IgG responses against protein convertase subtilisin/kexin 9 (PCSK9), leading to 17-30% reduction of the total plasma cholesterol levels. Moreover, ND-MPLA/CpG exerted strong anti-tumor efficacy in multiple murine tumor models. Compared with free adjuvants, ND-MPLA/CpG admixed with ovalbumin markedly improved antigen specific CD8+ T cell responses by 8-fold and promoted regression of B16F10-OVA melanoma (P < 0.0001). Furthermore, ND-MPLA/CpG admixed with E7 peptide antigen elicited ~20% E7-specific CD8+ T cell responses and achieved complete regression of established TC-1 tumors in all treated animals. Taken together, our work highlights the simplicity, versatility, and potency of dual TLR agonist nanodiscs for applications in vaccines and cancer immunotherapy. PMID- 29702143 TI - Prolonging pulse duration in ultrasound-mediated gene delivery lowers acoustic pressure threshold for efficient gene transfer to cells and small animals. AB - While ultrasound-mediated gene delivery (UMGD) has been accomplished using high peak negative pressures (PNPs) of 2 MPa or above, emerging research showed that this may not be a requirement for microbubble (MB) cavitation. Thus, we investigated lower-pressure conditions close to the MB inertial cavitation threshold and focused towards further increasing gene transfer efficiency and reducing associated cell damage. We created a matrix of 21 conditions (n = 3/cond.) to test in HEK293T cells using pulse durations spanning 18 MUs-36 ms and PNPs spanning 0.5-2.5 MPa. Longer pulse duration conditions yielded significant increase in transgene expression relative to sham with local maxima between 20 J and 100 J energy curves. A similar set of 17 conditions (n = 4/cond.) was tested in mice using pulse durations spanning 18 MUs-22 ms and PNPs spanning 0.5-2.5 MPa. We observed local maxima located between 1 J and 10 J energy curves in treated mice. Of these, several low pressure conditions showed a decrease in ALT and AST levels while maintaining better or comparable expression to our positive control, indicating a clear benefit to allow for effective transfection with minimized tissue damage versus the high-intensity control. Our data indicates that it is possible to eliminate the requirement of high PNPs by prolonging pulse durations for effective UMGD in vitro and in vivo, circumventing the peak power density limitations imposed by piezo-materials used in US transducers. Overall, these results demonstrate the advancement of UMGD technology for achieving efficient gene transfer and potential scalability to larger animal models and human application. PMID- 29702144 TI - Streptoxamine, an unprecedented benzoisoindole-deferoxamine hybrid from the locust-derived Streptomyces sp. HKHCa2. AB - An unusual benzoisoindole-deferoxamine hybrid, streptoxamine (1), has been isolated from the ethyl acetate crude extract of the fermentation broth of a locust-associated actinomycete, Streptomyces sp. HKHCa2, which was isolated from an insect, Oxya chinensis. The structure of this secondary metabolite was elucidated on the basis of its one-dimension, two-dimension NMR, and mass spectroscopic data. This natural product features a hybrid pattern of a benzoisoindole with an "iron carrier" deferoxamine B through C-N linkage. Compound 1 showed weak antibacterial activity against the gram-positive bacteria, Staphylococcus aureus and Mycobacterium smegmatis. PMID- 29702145 TI - Activation of M2 muscarinic acetylcholine receptors by a hybrid agonist enhances cytotoxic effects in GB7 glioblastoma cancer stem cells. AB - In previous studies, we found that the orthosteric muscarinic agonist arecaidine propargyl ester (APE) (100 MUM) induced a decreased cell proliferation and severe apoptosis in glioblastoma cancer stem cells (GSCs). In this report, we have investigated the effects mediated by hybrid (orthosteric/allosteric) muscarinic agonists P-6-Iper and N-8-Iper on GSCs survival. At variance with APE, the agonist N-8-Iper inhibited cell growth in a dose dependent manner and also impaired cell survival at low doses. The inhibitory effects of the N-8-Iper action appear to be mediated by M2 receptor activation, since they were strongly reduced by co-administration of the selective M2 receptor antagonist methoctramine as well as upon M2 receptor silencing. Moreover, analysis of the expression of phosphorylated histone H2AX (gamma-H2AX) indicated that the treatment with N-8-Iper produced a decreased cell survival by induction of DNA damage. The ability of N-8-Iper to produce a cytotoxic effect and apoptosis at low doses indicates that this muscarinic agonist is a suitable probe in a putative therapeutic intervention on glioblastoma through M2 receptor activation. PMID- 29702146 TI - Regulation of the ARE-binding proteins, TTP (tristetraprolin) and HuR (human antigen R), in inflammatory response in astrocytes. AB - Control of decay of mRNA containing the adenine-uridine rich elements (AREs) is an important post-transcriptional mechanism involved in the regulation of inflammatory gene expression. Two widely recognized proteins in this machinery are HuR (human antigen R) - a protein that stabilizes ARE-containing mRNA and TTP (tristetraprolin) - a protein that shortens half-lives of ARE-containing mRNA. Although HuR and TTP regulation mechanisms have been well studied in cells of hematopoietic origin, there are no respective data in astrocytes, cells of ectodermal origin which play an important role in neuroinflammation. Therefore we evaluated the existence of TTP and HuR in primary astrocytes and characterized the features of their regulation after stimulation by the proinflammatory stimuli thrombin, ATP, and agonists of TLR4, TLR2. All proinflammatory stimuli increased levels of TTP mRNA, but not HuR mRNA. Transcripts of both HuR and TTP underwent stabilization upon lipopolysaccharide (LPS) treatment, measured with the actinomycin D protocol. This effect was abolished by treatment with SB203580, an inhibitor of r38 MARK. Both TTP and HuR transcripts were sensitive to modulation by anisomycin and cycloheximide. LPS induced translocation of HuR protein from nucleus to cytoplasm. TTP is localized in the cytosolic fraction and localization is not sensitive to LPS treatment. Our data for the first time reveal specificity of regulation of ARE-binding proteins in astrocytes. We propose possibilities to manipulate brain inflammatory processes via post-transcription regulatory steps in astrocytes. PMID- 29702147 TI - Adenosine signaling and the immune system: When a lot could be too much. AB - Adenosine is increasingly recognized as a key mediator of the immune response. Signals delivered by extracellular adenosine are detected and transduced by G protein-coupled cell-surface receptors, classified into four subtypes: A1, A2A, A2B and A3. These receptors, expressed virtually on all immune cells, modulate all aspects of immune/inflammatory responses. These immunoregulatory effects, which are mostly anti-inflammatory, contribute to the general tissue protective effects of adenosine and its receptors. In some instances, however, the effect of adenosine on the immune system is deleterious, as prolonged adenosine signaling can hinder anti-tumor and antibacterial immunity, thereby promoting cancer development and progression and sepsis, respectively. PMID- 29702148 TI - Immunomodulatory effects of CD38-targeting antibodies. AB - The fist in class CD38-targeting antibody, daratumumab, is currently approved as single agent and in combination with standards of care for the treatment of relapsed and refractory multiple myeloma. Based on the high activity and favorable toxicity profile of daratumumab, other CD38 antibodies, such as isatuximab, MOR202, and TAK-079, are being evaluated in MM and other malignancies. The CD38-targeting antibodies have classic Fc-dependent immune effector mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and complement-dependent cytotoxicity (CDC). These mechanisms of action are dependent on CD38 expression on the tumor cells. There is increasing evidence that CD38 antibodies also improve host-anti-tumor immune response by eliminating CD38-positive immune suppressor cells, including regulatory T cells, regulatory B cells, and myeloid derived suppressor cells. Indeed, daratumumab treatment results in a marked increase in T cell numbers and activity. CD38-targeting antibodies probably also reduce adenosine production in the bone marrow microenvironment, which may contribute to improved T cell activity. Preclinical and clinical studies have demonstrated that CD38-targeting antibodies have synergistic activity with several other anti-cancer drugs, including various agents with immune stimulating activity, such as lenalidomide and pomalidomide, as well as PD1/PD-L1 inhibitors. PMID- 29702149 TI - The link between bone microenvironment and immune cells in multiple myeloma: Emerging role of CD38. AB - The relationship between bone and immune cells is well established both in physiological and pathological conditions. Multiple myeloma (MM) is a plasma cell malignancy characterized by an increase of number and activity of osteoclasts (OCLs) and a decrease of osteoblasts (OBs). These events are responsible for bone lesions of MM patients. OCLs support MM cells survival in vitro and in vivo. Recently, the possible role of OCLs as immunosuppressive cells in the MM BM microenvironment has been underlined. OCLs protect MM cells against T cell mediated cytotoxicity through the expression of several molecules including programmed death-ligand (PD-L) 1, galectin (Gal) 9, CD200, and indoleamine-2,3 dioxygenase (IDO). Among the molecules that could be involved in the link between immune-microenvironment and osteoclastogenesis the role of CD38 has been hypothesized. CD38 is a well-known adhesion molecule and an ectoenzyme highly expressed by MM cells. Moreover, CD38 is expressed by OCLs and at the surface level on OCL precursors. Targeting CD38 with monoclonal antibodies showed inhibition of both osteoclastogenesis and OCL-mediated suppression of T cell function. This review elucidates this evidence indicating that osteoclastogenesis affect MM immune-microenvironment being a potential target to improve anti-MM immunity and to ameliorate bone disease. PMID- 29702150 TI - Mapping three guanine oxidation products along DNA following exposure to three types of reactive oxygen species. AB - Reactive oxygen and nitrogen species generated during respiration, inflammation, and immune response can damage cellular DNA, contributing to aging, cancer, and neurodegeneration. The ability of oxidized DNA bases to interfere with DNA replication and transcription is strongly influenced by their chemical structures and locations within the genome. In the present work, we examined the influence of local DNA sequence context, DNA secondary structure, and oxidant identity on the efficiency and the chemistry of guanine oxidation in the context of the Kras protooncogene. A novel isotope labeling strategy developed in our laboratory was used to accurately map the formation of 2,2-diamino-4-[(2-deoxy-beta-D erythropentofuranosyl)amino]- 5(2 H)-oxazolone (Z), 8-oxo-7,8-dihydro-2' deoxyguanosine (OG), and 8-nitroguanine (8-NO2-G) lesions along DNA duplexes following photooxidation in the presence of riboflavin, treatment with nitrosoperoxycarbonate, and oxidation in the presence of hydroxyl radicals. Riboflavin-mediated photooxidation preferentially induced OG lesions at 5' guanines within GG repeats, while treatment with nitrosoperoxycarbonate targeted 3'-guanines within GG and AG dinucleotides. Little sequence selectivity was observed following hydroxyl radical-mediated oxidation. However, Z and 8-NO2-G adducts were overproduced at duplex ends, irrespective of oxidant identity. Overall, our results indicate that the patterns of Z, OG, and 8-NO2-G adduct formation in the genome are distinct and are influenced by oxidant identity and the secondary structure of DNA. PMID- 29702151 TI - Adolescent perceptions of orthodontic treatment risks and risk information: A qualitative study. AB - INTRODUCTION: For effective risk communication, clinicians must understand patients' values and beliefs in relation to the risks of treatment. This qualitative study aimed to explore adolescent perceptions of orthodontic treatment risks and risk information. METHODS: Five focus groups were carried out with 32 school/college pupils aged 12-18 in Wales, UK. Participants were purposively selected and had all experienced orthodontic treatment. A thematic approach was used for analysis and data collection was completed at the point of data saturation. RESULTS: Four themes emerged from the data; (a) day-to-day risks of orthodontic treatment, (b) important orthodontic risk information, (c) engaging with orthodontic risk information and (d) managing the risks of orthodontic treatment. Day-to-day risks of orthodontic treatment that were affecting participants "here and now" were of most concern. Information about preventing the risks of treatment was deemed to be important. Participants did not actively seek risk information but engaged passively with information from convenient sources. Perceptions of risk susceptibility influenced participants' management of the risks of orthodontic treatment. CONCLUSIONS: This study demonstrates that adolescent patients can understand information about the nature and severity of orthodontic treatment risks. However, adolescent patients can have false perceptions if the risks are unfamiliar, perceived only to have a future impact or if seen as easy to control. Adolescent patients must be provided with timely and easily accessible risk information and with practical solutions to prevent the risks of treatment. CLINICAL SIGNIFICANCE: The views and experiences gathered in this study can assist clinicians to better understand their young patients' beliefs about treatment risks, facilitate effective risk communication and contribute to improved patient-centred care. PMID- 29702152 TI - Water-associated attributes in the contemporary dentin bonding milieu. AB - OBJECTIVES: The water-associated attributes of resin-dentin interfaces created by contemporary adhesives are important determinants of bond integrity and stability. In the present work, these attributes were estimated from the perspectives of causality, to examine the behavior of the first and most-recently launched versions of universal adhesives when applied in either the etch-and rinse mode or the self-etch mode. METHODS: The immediate cause of interfacial permeability and the time-dependent cause of water sorption were investigated in conjunction with the intermediate effect of interface degradation and the more long-term effect of loss of mechanical strength, before and after thermomechanical cycling. The results were compared with control etch-and-rinse and self-etch adhesives. RESULTS: Although the introduction of this new class of universal adhesives has brought forth significant changes to the dental adhesion arena, including more application options, reduced bonding armamentarium and increased user friendliness, the water-associated attributes that are critical for making resin-dentin bonds more durable to environmental challenges and less susceptible to degradation have remained unchanged at large, when compared with benchmarks established by former classes of adhesives. CONCLUSION: It appears that the current trend of adhesive development has brought forth significant changes but lacks the vigor that demarcates progress and technological sublimity. CLINICAL SIGNIFICANCE: The advent of the user friendly universal adhesives has brought forth significant changes to the dental adhesion arena. However, the elements that are critical for making resin-dentin bonds more durable to environmental challenges and less susceptible to degradation have remained unchanged at large. PMID- 29702153 TI - Reply by the Authors. PMID- 29702154 TI - Efficacy and Safety of Ureteroscopy for Stone Disease in a Solitary Kidney: Findings From a Systematic Review. AB - Management of stone disease in solitary kidney remains a difficult treatment entity for the urologist. The challenge exists to deliver high clearance while maintaining strong safety profile. Twelve eligible studies were included, comprising a total of 693 patients with a male:female ratio of 2:1. Overall, 114 (16.4%) complications were reported. No fatalities were reported in any of the studies. Clavien III complications were recorded in less than 0.5% of the patients. This review confirms the effectiveness, safety, and reliability of this technique for this unique cohort of patients. PMID- 29702155 TI - Re: Huang et al.: The Application of Suctioning Flexible Ureteroscopy With Intelligent Pressure Control in Treating Upper Urinary Tract Calculi on Patients With a Solitary Kidney (Urology 2018;111:44-47). PMID- 29702156 TI - Renal Cell Carcinoma Associated With Xp11.2 Translocation/TFE3 Gene-fusion: A Long Response to mammalian target of rapamycin (mTOR) Inhibitors. AB - OBJECTIVE: To demonstrate that patients with Xp11.2/TFE3 gene-fusion translocation renal cell carcinoma (RCC), despite having an aggressive course in young adults, could have valid treatment options such as mammalian target of rapamycin (mTOR) inhibitors with good outcomes. Furthermore, to explain possible mechanisms of action of mTOR inhibitors in this type of RCC. MATERIALS AND METHODS: We report a case of a 44-year-old man who has been treated with everolimus for a Xp11.2 translocation/TFE3 gene-fusion RCC after 2 previous failed treatments with tyrosine kinase inhibitor. During the follow-up, we evaluated type and duration of response with everolimus. RESULTS: The patient obtained a long-lasting response of disease of 25 months with everolimus without any symptom. CONCLUSION: We believe that mTOR inhibitors could be a good line option treatment to consider for this type of patients. PMID- 29702158 TI - Re: Morris and Krieger: Does Circumcision Increase Meatal Stenosis Risk?-A Systematic Review and Meta-analysis (Urology 2017;110:16-26). PMID- 29702157 TI - Pediatric Robotic Prostatectomy and Pelvic Lymphadenectomy for Embryonal Rhabdomyosarcoma. AB - We present the first published case of a pediatric robot-assisted prostatectomy and pelvic lymphadenectomy for refractory prostatic embryonal rhabdomyosarcoma. The patient is a 7-year-old male who had been treated with 3 cycles of chemotherapy and radiation, who underwent prostatectomy and lymphadenectomy for a recurrent mass. Surgery was uncomplicated and yielded negative surgical margins. We highlight the surgical technique and feasibility of utilizing robotic surgery for pediatric prostatectomy. PMID- 29702160 TI - Evidence of impaired proactive control under positive affect. AB - If it can be assumed that positive affect modulates cognitive control, the underlying mechanisms remain unclear. The main aim of this study was to investigate how positive affect influences proactive and reactive modes of control and to explore the temporal dynamic of this influence, in terms of its transient and/or sustained effects. We used the AX-continuous performance task, combined with event-related potentials (ERP) recording. The results showed that positive affect impaired proactive control. More specifically, response preparation was weaker, as highlighted by a decreased contingent negative variation (CNV), prior to the target. As a consequence, conflict detection, as reflected by the N2 component, was decreased under positive affect. The P3a, associated with conflict resolution, remained unaffected by positive emotion, suggesting a lack of reactive control modulation. These effects were diffuse and did not appear on a transient timescale, highlighting the importance of positive emotion's time course for how it influences cognitive control processes. PMID- 29702159 TI - Quinolinic acid and glutamatergic neurodegeneration in Caenorhabditis elegans. AB - Quinolinic acid (QUIN) is an endogenous neurotoxin that acts as an N-methyl-D aspartate receptor (NMDAR) agonist generating a toxic cascade, which can lead to neurodegeneration. The action of QUIN in Caenorhabditis elegans and the neurotoxins that allow the study of glutamatergic system disorders have not been carefully addressed. The effects of QUIN on toxicological and behavioral parameters in VM487 and VC2623 transgenic, as well as wild-type (WT) animals were performed to evaluate whether QUIN could be used as a neurotoxin in C. elegans. QUIN reduced survival of WT worms in a dose-dependent manner. A sublethal dose of QUIN (20 mM) increased reactive oxygen species (ROS) levels in an nmr-1/NMDAR dependent manner, activated the DAF-16/FOXO transcription factor, and increased expression of the antioxidant enzymes, superoxide dismutase-3, glutathione S transferase-4, and heat shock protein-16.2. QUIN did not change motor behavioral parameters, but altered the sensory behavior in N2 and VM487 worms. Notably, the effect of QUIN on the sensory behavioral parameters might occur, at least in part, secondary to increased ROS. However, the touch response behavior indicates a mechanism of action that is independent of ROS generation. In addition, non lethal doses of QUIN triggered neurodegeneration in glutamatergic neurons. Our findings indicate that C. elegans might be useful as a model for studies of QUIN as a glutamatergic neurotoxin in rodent models. PMID- 29702161 TI - Racial bias in empathy: Do we process dark- and fair-colored hands in pain differently? An EEG study. AB - The aim of this study was to identify racial bias influences on empathic processing from early stimulus encoding, over categorization until late motor processing stages by comparing brain responses (electroencephalogram) to pictures of fair- and dark-colored hands in painful or neutral daily-life situations. Participants performed a pain judgment task and a skin color judgment task. Event related brain potentials (ERPs) substantiated former findings of automatic empathic influences on stimulus encoding, reflected by the early posterior negativity (EPN), and late controlled influences on the stimulus categorization, as reflected by the late posterior positivity (P3b). Concerning the racial bias in empathy (RBE) effect, more positive amplitudes in the 280-340 ms time window over frontocentral electrodes in the painful than the neutral condition for fair- but not dark-colored hands speak for an early influence of racial bias. This was further supported by correlations with empathic concern scores for fair- but not dark-colored stimuli. Additionally, P3b amplitude differences between fair- and dark-colored hands to painful stimuli increased with the implicit racial attitude of participants, suggesting that the categorization stage is not completely immune to racial bias. Regarding the motor processing stages, power change values in the upper beta-band (19-30 Hz) revealed for painful compared to neutral stimuli larger facilitation of sensorimotor activity before the response and larger inhibition after the response, independent of skin color. In conclusion, present findings speak for an influence of the RBE on early perceptual encoding but also on the late categorization stage that depends on the participant's implicit attitude towards racial outgroups. PMID- 29702162 TI - EEG alpha activity during imagining creative moves in soccer decision-making situations. AB - This study investigated task-related changes of EEG alpha power while participants were imagining creative moves in soccer decision-making situations. After presenting brief video clips of a soccer scene, participants had to imagine themselves as the acting player and to think either of a creative/original or an obvious/conventional move (control condition) that might lead to a goal. Performance of the soccer task generally elicited comparatively strong alpha power decreases at parietal and occipital sites, indicating high visuospatial processing demands. This power decrease was less pronounced in the creative vs. control condition, reflecting a more internally oriented state of information processing characterized by more imaginative mental simulation rather than stimulus-driven bottom-up processing. In addition, more creative task performance in the soccer task was associated with stronger alpha desynchronization at left cortical sites, most prominently over motor related areas. This finding suggests that individuals who generated more creative moves were more intensively engaged in processes related to movement imagery. Unlike the domain-specific creativity measure, individual's trait creative potential, as assessed by a psychometric creativity test, was globally positively associated with alpha power at all cortical sites. In investigating creative processes implicated in complex creative behavior involving more ecologically valid demands, this study showed that thinking creatively in soccer decision-making situations recruits specific brain networks supporting processes related to visuospatial attention and movement imagery, while the relative increase in alpha power in more creative conditions and in individuals with higher creative potential might reflect a pattern relevant across different creativity domains. PMID- 29702163 TI - Transient global cerebral ischemia differentially affects cortex, striatum and hippocampus in Bilateral Common Carotid Arterial occlusion (BCCAo) mouse model. AB - Despite the advancements in medical sciences in last few decades, we are yet to develop promising therapeutics for stroke, which is one of the current global non communicative disease concerns. The occurrence of stroke is likely to increase further due to the transition in our lifestyles. Inadequate knowledge of the sequential region-specific pathological events induced by cerebral ischemia is one of the underlying reasons. Hence to address this, we have used Bilateral Common Carotid Arterial occlusion (BCCAo) model that mimics human cardiac arrest condition. After ischemic insult, motor coordination and cognitive functions were analysed through series of behavioral tasks. Animals were sacrificed and brain regions viz. cortex, striatum and hippocampus, were isolated further for histopathology and molecular investigations. All the molecular studies were performed at 1d and 7d post-ischemia and reperfusion by immunohistochemistry, RT qPCR and western blot analysis, for hypoxic, inflammatory and apoptotic markers. Our study indicates that unlike cortex and striatum, hippocampus was found to be consistently late ischemic susceptible at a behavioral and molecular level which might be regulated by c-Jun N-terminal kinases (JNK) and AKT signaling mechanism with associative changes in NMDA receptors. This study shows a region-specific temporal molecular response to global ischemia in the brain, which is important to get better insight into the pathophysiology since each region consists of different subsets of neurons that are having different susceptibility and tolerance pattern/level. This insight into a temporally different ischemic response and the underlying molecular basis might help in strategizing the effective therapeutics against stroke. PMID- 29702164 TI - Antibacterial macro molecules from marine organisms. AB - Marine ecosystem comprises of microorganisms, plants, invertebrates and vertebrates which were rich source of diverse antimicrobial products, which were structurally unique belonging to a known class of macromolecules like peptides, terpenes, alkaloids and proteins, etc. Natural macromolecules from marine ecological niches are a promising source of antibacterial agents against several drug resistant strains of pathogenic microorganisms; whereas rest of the metabolites were derived from marine flora and fauna while some arise from microbes associated with living organisms. >30,000 natural macromolecules have been identified and reported from marine organisms, however only few macromolecules are being explored and validated. The discovery of marine antibacterial macromolecules plays a significant part in the field of drug discovery and biomedical research. Despite the fact that literatures were documented on the antifungal, antiviral, antimalarial and anticancer properties, this review exclusively highlights the different antibacterial natural macromolecules from marine sources like bacteria, fungi, sponge, algae, bryozoans, tunicates, corals, cnidarians, arthropods and echinoderm along with their mode of action. PMID- 29702165 TI - Magnetically triggered release of amoxicillin from xanthan/Fe3O4/albumin patches. AB - This work was motivated by the need of stimuli responsive drug carriers, which can be activated by low cost non-invasive stimuli such as external magnetic field (EMF). Thus, novel antimicrobial materials based on xanthan gum (XG), magnetic nanoparticles (MNP), bovine serum albumin (BSA) and amoxicillin (Amox) were designed in order to promote the release of Amox under magnetic stimuli. Firstly, surfaces with different functionalities were prepared by sequential deposition of thin layers on Si wafers and characterized by means of ellipsometry and atomic force microscopy. Amox adsorbed preferentially onto XG or BSA films. In solution, favorable interactions between Amox and BSA were evidenced by substantial changes in the BSA secondary structure, as revealed by circular dichroism. Patches of XG and XG/MNP/BSA were immersed in 2 g L-1 Amox, yielding 10 +/- 3 and 17 +/- 4 MUg/cm3 Amox loading, respectively. The inclusion of 0.2 wt% Fe3O4 in the patches and their exposure to EMF enabled in vitro release of Amox, at pH 5.5 and 0.02 mol L-1 NaCl, following the quasi-Fickian behavior. Amox diffused from XG/MNP/BSA patches in agar medium containing Staphylococcus aureus and Escherichia coli, inhibiting their growth. The inhibition of E. coli growth was particularly efficient under EMF. PMID- 29702166 TI - Development of high-performance biodegradable rigid polyurethane foams using all bioresource-based polyols: Lignin and soy oil-derived polyols. AB - Development of biodegradable polyurethane materials is the most promising in the wider context of the "greening" of industrial chemistry. To tackle this challenge, a novel biodegradable polyurethane foam from all bioresource-based polyols (lignin and soy oil-derived polyols) and polymeric methyldiphenyl diisocyanate (pMDI) have been synthesized via a one-pot and self-rising process. All these foam samples have the internal cellular morphology and microstructure. FTIR result exhibits characteristic peaks of polyurethane, and indicates covalent bonds between soy-based polyurethane and lignin, and the lignin powders can react with pMDI via active -H and -CNO. In addition, hydrogen bonding also plays an important role in forming the 3D structures. These interactions and chemical bonds made the prepared foam samples form the 3D macromolecular structure with improved mechanical, thermal, and biodegradable properties. The reaction process is time-saving and cost-effective as it requires no blowing agent and minimum processing steps, while exploring the potential of using the higher content of nature bioresource constituents. PMID- 29702167 TI - Pumpkin polysaccharide modifies the gut microbiota during alleviation of type 2 diabetes in rats. AB - Pumpkin polysaccharide is able to alleviate diabetes, but understanding of the underlining mechanism is still limited. In this study, we hypothesized that the alleviating effects of pumpkin polysaccharide is modulated via changes in the gut microbiota and short-chain fatty acid (SCFA) production in type 2 diabetic rats. After the type 2 diabetic model successfully was established, three groups of high-fat diet induced diabetic rats were intragastrically administered pumpkin polysaccharide, metformin, or saline solution respectively. We utilized 16S rRNA gene sequencing and multivariate statistics to analyze the structural and key species of gut microbiota in the type 2 diabetic rats. The results revealed that pumpkin polysaccharide alleviated the type 2 diabetes by improving the insulin tolerance and decreasing the levels of serum glucose (GLU), total cholesterol (TC), and low-density lipoprotein (LDL-C), while increasing the levels of high density lipoprotein (HDL-C). Simultaneously, pumpkin polysaccharide changed the structure of gut microbiota and had selective enrichment in key species of Bacteroidetes, Prevotella, Deltaproteobacteria, Oscillospira, Veillonellaceae, Phascolarctobacterium, Sutterella, and Bilophila. The correlations between the key species and SCFA production indicated the underlining mechanisms of pumpkin polysaccharide on type 2 diabetes. PMID- 29702168 TI - Use of chitosan heterofunctionality for enzyme immobilization: beta-galactosidase immobilization for galacto-oligosaccharide synthesis. AB - Chitosan partially functionalized with aldehyde groups was used for enzyme immobilization, favoring first the enzyme adsorption through its amino groups and then the covalent bonding of the adsorbed catalyst through the aldehyde groups of the support. Using this strategy, immobilized A. oryzae beta-galactosidase had a better performance than when only the aldehyde groups were used. The performance was further improved by modifying the support aldehyde group density to 200 MUmoles?g-1. The biocatalyst under optimized immobilization conditions had 2951 IU?g-1 and half-life of 46.3 min at 60 degrees C, while its agarose counterpart had 2294 IU?g-1 and half-life of 59.5 min. Both biocatalysts were applied in galacto-oligosaccharide synthesis. After 10 sequential batches, the cumulative productivity (gGOS?h-1?gprotein-1) obtained with the chitosan and the agarose biocatalysts were 4.7 and 4.0 times the value when soluble enzyme was used respectively. This methodology had not been reported previously with chitosan, showing the high versatility of this low cost carrier and its high potential for enzyme immobilization. PMID- 29702169 TI - Purification, characterization of Chondroitinase ABC from Sphingomonas paucimobilis and in vitro cardiocytoprotection of the enzymatically degraded CS A. AB - An extracellular chondroitinase ABC (ChSase ABC) produced by Sphingomonas paucimobilis was purified to homogeneity through ammonium sulfate precipitation, DEAE-Sepharose Fast Flow and Sephadex G-100 chromatography. The molecular weight was 82.3 kDa. It showed specific lyase activity toward chondroitin sulfate A (CS A), CS-B, CS-C and hyaluronan (HA). Using CS-A as substrate, the specific activity was 98.04 U/mg, the maximal reaction rate (Vmax) and Michaelis-Menten constant (Km) were 0.49 MUmol/min/ml and 0.79 mg/ml, respectively. Highest activity was obtained at pH 6.5 and 40 degrees C, and Hg2+ could strongly inhibit the enzyme activity. Mass spectrometry analysis indicated CS-A was degraded to unsaturated disaccharides by ChSase ABC. In vitro cytotoxic tests showed that CS-A oligosaccharide at the concentration of 50 and 100 MUg/ml could promote the proliferation of normal H9c2 myocardial cells, decrease the damage induced by isoproterenol (ISO) and accelerate the recovery of cells injured by ISO. These findings suggested that ChSase ABC from Sphingomonas paucimobilis could be a promising tool for the structural analysis and bioactive oligosaccharide preparation of glucosaminoglycans. PMID- 29702170 TI - Phosphorylated serine clusters of phosvitin plays a crucial role in the regulatory mineralization. AB - Phosphorylation of phosvitin has been proved to play an important role in the mineralization, but the active region of phosvitin is still not known yet. Four phosvitin phosphopeptides (PPPs) were obtained after separating from ion exchange column and desalting from gel filtration, and named as PPP0, PPP1, PPP3 and PPP4, respectively. The effect of PPP on the mineralization was investigated by pH-stat system, Fourier transform infrared spectroscopy, X-ray diffraction and scanning electron microscope. SDS-PAGE and circular dichroism were applied to study the composition and the structure of PPP. Results showed that the order of promoting mineralization was as follows: PPP3 > phosvitin > PPP4 > PPP1 > control > PPP0. PPP0 and PPP1 was not involved in the mineralization, while the structure of PPP4 was too compact to promote mineralization because of its high beta-sheet conformation. PPP3, which contained a 10 kDa peptide, is the most effective promoter for mineralization. LTQ-MS/MS results indicated that the phosphorylated serine clusters of phosvitin was the active region for promoting mineralization. PMID- 29702171 TI - An ultrasensitive amperometric determination of lactate by lactate dehydrogenase nanoparticles immobilized onto Au electrode. AB - The nanoparticles (NPs) of commercial lactate dehydrogenase (LDH) from rabbit muscle were prepared, characterized and immobilized covalently onto Au electrode to construct an improved amperometric lactate biosensor. The biosensor showed optimum response within 2.5 s at an applied potential of 0.10 V, pH 7.0 and 35 degrees C. The biosensor had a wider working range linear (0.01 MUM to 55 mM) with a higher sensitivity (3.45 +/- 0.02 MUA cm-2 mM-1) and a lower detection limit (0.01 MUM) compared to earlier biosensors. The analytical recovery of added lactate in sera was 98.61% and within and between batches coefficients of variations (CVs) were 1.38% and 1.03%, respectively. A good correlation coefficient (R2 = 0.99) was observed between sera lactate values as measured by the standard enzymatic colorimetric method and the present biosensor. The biosensor measured lactic acid in the sera of apparently healthy subjects and persons suffering from cardiogenic shocks. There was a 10% loss in the initial activity of LDHNPs/Au electrode after its regular use over a period of 210 days, while being stored dry at 4 degrees C. PMID- 29702172 TI - Electrospun plant mucilage nanofibers as biocompatible scaffolds for cell proliferation. AB - Electrospun nanofibers (ESNFs) were prepared from mucilage isolated from chan and linaza beans and mozote stem commercially available in Costa Rica. Poly(vinyl alcohol) (PVA) was used as an aiding agent. Mucilage/PVA mixed solutions of different volume ratios (100:0, 80:20, 60:40, 40:60, 20:80 and 0:100) were prepared and adjusted to be similar in viscosity and electrical conductivity suitable for electrospinning. Morphology of the ESNFs was examined using scanning electron microscopy (SEM). Fourier transform infrared spectrometer (FTIR) and differential scanning calorimetry (DSC) studies were used to characterize chemical composition and thermal characteristics of the nanofibers (NFs). The ability of the NFs to support fibroblast cell proliferation was investigated in vitro using the optimized mucilage/PVA solutions. Results show plant mucilage based ESNFs are well-suited for fibroblast cell growth, significantly better than ESNFs of PVA; and the mucilage of chan beans is better than those of mozote and linaza for supporting cell proliferation. PMID- 29702173 TI - Lignin and holocellulose from pecan nutshell as reinforcing fillers in poly (lactic acid) biocomposites. AB - Lignocellulose from agro-food biowaste represents a valuable source of cost effective structural fillers for wholly renewable polymer composites. In this work, pecan (Carya illinoinensis) nutshell (NS) fiber and its structural components, holocellulose (HC) and acid insoluble lignin (AIL), were isolated, characterized and used as reinforcing fillers to manufacture poly(lactic acid) (PLA) based biocomposites. Thermal, morphological and mechanical properties of the prepared materials were analyzed. NS and HC acted as heterogeneous nucleating agents, potentially able to control PLA physical aging. Moreover, they significantly enhanced the viscoelastic response of PLA, mainly restricting the melt molecular mobility due to hydrodynamic effects and the formation of a three dimensional particulate network. Flexural tests demonstrated that HC induced a 25% increase in modulus compared to the plain polymer. AIL, conversely, conferred higher ductility to the PLA matrix producing an increase in stress and strain at break of 55% and 65%, respectively. Finally, all the biocomposites showed lower resilience with respect to plain PLA due to the lack of chemical adhesion between filler and matrix. These results emphasize the potential of NS as a source of reinforcing filler in polymer-based biocomposites. PMID- 29702175 TI - Pro-inflammatory roles of chondroitin sulfate proteoglycans in disorders of the central nervous system. AB - The extracellular matrix of the central nervous system is an interconnected network of proteins and sugars. It is crucial for homeostasis, but its remodeling in neurological diseases impacts both injury and repair. Here we introduce an extracellular matrix family member that participates in immune-matrix interactions, the chondroitin sulfate proteoglycans. Chondroitin sulfate proteoglycans integrate signals from the microenvironment to activate immune cells, and they boost inflammatory responses by binding immunological receptors including toll-like receptors, selectins, CD44, and beta1 integrin. Chondroitin sulfate proteoglycans also bind signaling molecules for immune cells such as cytokines and chemokines, and they activate matrix-degrading enzymes. Chondroitin sulfate proteoglycans accumulate in the damaged CNS, including during traumatic brain/spinal cord injury and multiple sclerosis, and they help drive pathogenesis. This Review aims to give new insights into the remodeling of chondroitin sulfate proteoglycans during inflammation, and how these matrix glycoproteins are able to drive neuroinflammation. PMID- 29702174 TI - Beneficial effects of extracellular polysaccharide from Rhizopus nigricans on the intestinal immunity of colorectal cancer mice. AB - An extracellular polysaccharide (EPS1-1) extracted from the fermentation broth of Rhizopus nigricans has been proved to enhance the immunity of immunosuppressed mice. The purpose of this study was to investigate the beneficial effects of EPS1 1 on the intestinal immunity of mice with colorectal cancer induced by azoxymethane (AOM) and dextran sodium sulfate (DSS). The results showed that EPS1 1 could resist hydrolysis in an artificial stomach. Oral EPS1-1 modulated gut microbiota and increased the concentration of total short-chain fatty acids (SCFAs) in the feces of colorectal cancer mice compared with the AOM/DSS only treated mice. Furthermore, EPS1-1 increased the villus length, ratio of villus length and crypt depth in colonic tissues, and improved the number of acid mucus secreting goblet cells in mice with colorectal cancer. These findings suggest that EPS1-1 might play an important role in the improvement of intestinal function in mice with colorectal cancer, which indicate its strong potential as efficient bio-secure immunotherapy for clinical applications or adjuvant drug. PMID- 29702176 TI - Bipolar affective disorder and borderline personality disorder: Differentiation based on the history of early life stress and psychoneuroendocrine measures. AB - INTRODUCTION: Borderline Personality Disorder (BPD) and Bipolar Affective Disorder (BD) have clinical characteristics in common which often make their differential diagnosis difficult. The history of early life stress (ELS) may be a differentiating factor between BPD and BD, as well as its association with clinical manifestations and specific neuroendocrine responses in each of these diagnoses. OBJECTIVE: Assessing and comparing patients with BD and BPD for factors related to symptomatology, etiopathogenesis and neuroendocrine markers. METHODOLOGY: The study sample consisted of 51 women, divided into 3 groups: patients with a clinical diagnosis of BPD (n = 20) and BD (n = 16) and healthy controls (HC, n = 15). Standardized instruments were used for the clinical evaluation, while the history of ELS was quantified with the Childhood Trauma Questionnaire (CTQ), and classified according to the subtypes: emotional abuse, physical abuse, sexual abuse, emotional neglect and physical neglect. The functioning of the hypothalamic-pituitary-adrenal (HPA) axis was evaluated by measuring a single plasma cortisol sample. RESULTS: Patients with BPD presented with more severe psychiatric symptoms of: anxiety, impulsivity, depression, hopelessness and suicidal ideation than those with BD. The history of ELS was identified as significantly more prevalent and more severe in patients (BPD and BP) than in HC. Emotional abuse, emotional neglect and physical neglect also showed differences and were higher in BPD than BD patients. BPD patients had greater severity of ELS overall and in the subtypes of emotional abuse, emotional neglect and physical neglect than BD patients. The presence of ELS in patients with BPD and BP showed significant difference with lower cortisol levels when compared to HC. The endocrine evaluation showed no significant differences between the diagnoses of BPD and BD. Cortisol measured in patients with BPD was significantly lower compared to HC in the presence of emotional neglect and physical neglect. A significant negative correlation between the severity of hopelessness vs cortisol; and physical neglect vs cortisol were found in BPD with ELS. The single cortisol sample showed a significant and opposite correlations in the sexual abuse diagnosis-related groups, being a negative correlation in BD and positive in BPD. DISCUSSION: Considering the need for a multi-factorial analysis, the differential diagnosis between BPD and BD can be facilitated by the study of psychiatric symptoms, which are more severe in the BPD patients with a history of early life stress. The function of the HPA axis assessed by this cortisol measure suggests differences between BPD and BP with ELS history. CONCLUSION: The integrated analysis of psychopathology, ELS and neuroendocrine function may provide useful indicators to differentiate BPD and BD diagnoses. These preliminary data need to be replicated in a more significant sample with improved and multiple assessments of HPA axis activity. PMID- 29702177 TI - Whole-body pulsed EMF stimulation improves cognitive and psychomotor activity in senescent rats. AB - During advanced aging passive exercise (PE) is becoming a valuable therapeutic intervention to improve physical and mental performances. In the present study chronic low frequency pulsed electromagnetic field (EMF) exposure was presented to senescent rats in order to clarify the behavioural effects related to cognitive and motility functions. Male Wistar rats of 30-32 months old were treated with EMF for six weeks, 3 times per week, 24 min per sessions prior to the age of 32 months. Stimulation intensities varied from 45 to 1250 MUT. Psychomotility was estimated in an open field (OF), attention ability in novel object recognition (NOR), and spatial learning in the Morris water maze (MWM) tests. The results showed that EMF stimulation enhanced novelty-induced motility of vertical type, i.e. frequency of rearing activity was increased. In the cognitive tests EMF exposure increased attention-based discrimination in NOR and facilitated working memory type of spatial learning in the MWM tests. No undesirable type of side effects could be obtained even after the highest dose used. It is concluded that EMF stimulation in senescent age supports cognitive and psychomotor function in rats. The notion that PE may have complementary beneficial action on brain and motor functions in senescent age is strengthened by the present experimental results. PMID- 29702178 TI - Female hatchling American kestrels have a larger hippocampus than males: A link with sexual size dimorphism? AB - The brain and underlying cognition may vary adaptively according to an organism's ecology. As with all raptor species, adult American kestrels (Falco sparverius) are sexually dimorphic with females being larger than males. Related to this sexual dimorphism, kestrels display sex differences in hunting and migration, with females ranging more widely than males, suggesting possible sex differences in spatial cognition. However, hippocampus volume, the brain region responsible for spatial cognition, has not been investigated in raptors. Here, we measured hippocampus and telencephalon volumes in American kestrel hatchlings. Female hatchlings had a significantly larger hippocampus relative to the telencephalon and brain weight than males (~12% larger), although telencephalon volume relative to brain weight and body size was similar between the sexes. The magnitude of this hippocampal sex difference is similar to that reported between male and female polygynous Microtus voles and migratory and non-migratory subspecies of Zonotrichia sparrows. Future research should determine if this sex difference in relative hippocampus volume of hatchling kestrels persists into adulthood and if similar patterns exist in other raptor species, thus potentially linking sex differences in the brain to sex differences of space use of adults in the wild. PMID- 29702179 TI - State of the Art in Pediatric Lung Transplantation. AB - Pediatric lung transplantation is a highly specialized therapy for end-stage pulmonary disease in children, and is performed in only a handful of transplant centers around the world. Advancement in the field has been made on many fronts in recent years, including in public policy and organ allocation strategies, donor selection and management, emerging technologies for donor lung rehabilitation and bridge-to-transplant support of listed candidates, and ongoing refinement of surgical techniques. Despite this progress, children continue to suffer discrepant waitlist mortality and longer waiting times than their adult counterparts, and face special challenges of donor availability and size matching. Here, we assess the current state of the art in pediatric lung transplantation, reviewing progress made to date and further opportunities to improve care for this unique group of patients. PMID- 29702180 TI - Hypoplastic Left Heart Syndrome With a Hypoplastic Lung in Congenital Diaphragmatic Hernia: What Should Be Done First? PMID- 29702181 TI - MiR-98 suppresses the effects of tumor-associated macrophages on promoting migration and invasion of hepatocellular carcinoma cells by regulating IL-10. AB - We aim to investigate the role of miR-98-mediated macrophage polarization in hepatocellular carcinoma (HCC) progression and to explore the underlying mechanism. A total of 25 paired HCC and matched adjacent normal tissues (ANTs) were collected. We incubated human blood monocytes isolated from healthy male donors with culture medium collected from HepG2 cells for 7 days. The mRNA and protein expression was detected by qRT-PCR and Western blot, respectively. Levels of cytokines secreted in culture medium were measured using the specific ELISA kits. The miR-98 mimic/inhibitor was transfected to explore the role of miR-98 in HCC-conditioned tumor-associated macrophages (TAMs). HepG2 cells were then cultured with condition medium from HCC-conditioned TAMs pretreated with miR-98 mimic/inhibitor, and cell migration and invasion assays were performed. Luciferase reporter assay was performed to analyze the interaction between miR-98 and interleukin (IL)-10. Our results showed that miR-98 was downregulated and IL 10 was upregulated in HCC tissues and HCC-conditioned TAMs. Further studies identified that IL-10 was a direct target gene of miR-98 in HCC-conditioned TAMs. Moreover, miR-98 regulated the levels of inflammatory cytokines in HCC conditioned TAMs. HCC-conditioned TAMs pretreated with miR-98 regulated migration and invasion of HepG2 cells in vitro, and the effects were significantly reversed by IL-10. In conclusion, miR-98 not only regulated expression of inflammatory cytokines in HCC-conditioned TAMs, but also modulated the capacity of HCC conditioned TAMs to regulate HepG2 cell migration and invasion, at least in part, by targeting IL-10. As a result, miR-98 may suppress the progress of HCC. PMID- 29702182 TI - Cellular mechanism of resistance of human colorectal adenocarcinoma cells against apoptosis-induction by Russell's Viper venom l-amino acid oxidase (Rusvinoxidase). AB - The present study highlights the cellular mechanism of resistance in human adenocarcinoma (Colo-205) cells against apoptosis induction by Rusvinoxidase, an l-amino acid oxidase purified from Russell's Viper venom (RVV). The significantly lower cytotoxicity as well as apoptotic activity of Rusvinoxidase towards Colo 205 cells (compared to MCF-7 breast cancer cells) is correlated with lower depletion of cellular glutathione content and increased down-regulation of catalase activity of Colo-205 cells following Rusvinoxidase treatment. Exposure to Rusvinoxidase subsequently diminished reactive oxygen species (ROS) production and failed to impair mitochondrial membrane potential, resulting in apoptosis induction resistance in Colo-205 cells. Further, higher expression levels of caspase 8, compared to caspase 9, indicate that Rusvinoxidase preferentially triggers the extrinsic pathway of apoptosis in Colo-205 cells. A time-dependent lower ratio of the relative expression of Bax and Bcl-xL (pro- and anti-apoptotic proteins) in Colo-205 cells, compared to our previous study on MCF-7 cells, unambiguously supports a higher cellular resistance mechanism in Colo-205 cells against Rusvinoxidase-induced apoptosis. PMID- 29702183 TI - Quantifying iron content in magnetic resonance imaging. AB - Measuring iron content has practical clinical indications in the study of diseases such as Parkinson's disease, Huntington's disease, ferritinopathies and multiple sclerosis as well as in the quantification of iron content in microbleeds and oxygen saturation in veins. In this work, we review the basic concepts behind imaging iron using T2, T2*, T2', phase and quantitative susceptibility mapping in the human brain, liver and heart, followed by the applications of in vivo iron quantification in neurodegenerative diseases, iron tagged cells and ultra-small superparamagnetic iron oxide (USPIO) nanoparticles. PMID- 29702184 TI - Multisensory vestibular, vestibular-auditory, and auditory network effects revealed by parametric sound pressure stimulation. AB - Multisensory convergence and sensorimotor integration are important aspects for the mediation of higher vestibular cognitive functions at the cortical level. In contrast to the integration of vestibulo-visual or vestibulo-tactile perception, much less is known about the neural mechanism that mediates the integration of vestibular-otolith (linear acceleration/translation/gravity detection) and auditory processing. Vestibular-otolith and auditory afferents can be simultaneously activated using loud sound pressure stimulation, which is routinely used for testing cervical and ocular vestibular evoked myogenic potentials (VEMPs) in clinical neurotological testing. Due to the simultaneous activation of afferents there is always an auditory confound problem in fMRI studies of the neural topology of these systems. Here, we demonstrate that the auditory confounding problem can be overcome in a novel way that does not require the assumption of simple subtraction and additionally allows detection of non linear changes in the response due to vestibular-otolith interference. We used a parametric sound pressure stimulation design that took each subject's vestibular stimulation threshold into account and analyzed for changes in BOLD-response below and above vestibular-otolith threshold. This approach helped to investigate the functional neuroanatomy of sound-induced auditory and vestibular integration using functional magnetic resonance imaging (fMRI). Results revealed that auditory and vestibular convergence are contained in overlapping regions of the caudal part of the superior temporal gyrus (STG) and the posterior insula. In addition, there are regions that were responsive only to suprathreshold stimulations, suggesting vestibular (otolith) signal processing in these areas. Based on these parametric analyses, we suggest that the caudal part of the STG and posterior insula could contain areas of vestibular contribution to auditory processing, i.e., higher vestibular cortices that provide multisensory integration that is important for tasks such as spatial localization of sound. PMID- 29702185 TI - COL5A1 may contribute the metastasis of lung adenocarcinoma. AB - BACKGROUND: Lung cancer leads to the largest number of cancer-related deaths worldwide and is usually accompanied with metastasis which is the primary cause of those death and correlated with poor prognosis. However, the mechanism of lung cancer metastasis is still lack of definition. METHODS: We compared the primary lung adenocarcinoma (AD) and its metastasis tissues induced by overexpression of KrasG12D and inactivation of P53 in mouse lungs by analyzing GSE40222 about the differentially expressed genes (DEGs), pathways and hub genes. And human lung AD databases are used to verify the conversed changes of identified key gene and then followed functional studies are performed to explore the functions of key gene. RESULTS: We identified 165 genes differentially expressed in lung AD metastasis compared to primary AD. Pathway analysis identified 649 GO biological processes and 8 KEGG pathways, such as ECM-receptor interaction. Biological network interaction identified the hub genes during lung adenocarcinoma metastasis, such as the up-regulated COL5A1, a novel gene in AD metastasis. We found it's also increased in human AD and advanced stage. Knockdown of COL5A1 in human AD metastatic cells inhibited cell growth and invasion, and induced cell apoptosis. Notably, higher expression of COL5A1 was observed in the lung AD patients with recurrence and short survive. CONCLUSION: By analyzing mouse lung AD and its metastases, we identified the potential key genes and pathways regulating lung AD metastasis, such as COL5A1. The following analysis of COL5A1 in human AD database and cells explores its functions, holding the implications of target therapy in AD metastasis and also providing more clues for future studies. PMID- 29702186 TI - Molecular and functional characterization of the magnesium transporter gene ZmMGT12 in maize. AB - Magnesium (Mg) is an essential mineral element for normal plant growth and development, and the CorA/MRS2/MGT-type Mg transporters play a significant role in maintaining Mg homeostasis in plants. In total, 12 maize CorA-like Mg2+ transporters have been identified, but none of them had been functionally characterized. Accordingly, we cloned and functionally characterized ZmMGT12 from the maize CorA-like gene family. ZmMGT12 exhibited the structure typical of Mg2+ transporters, i.e., two conserved TM domains and a GMN tripeptide motif. ZmMGT12, Arabidopsis AtMGT6, and rice OsMRS2-6 shared high protein sequence identity and thus clustered in the same phylogenetic branch, suggesting that they could be homologs. A functional complementation assay in the Salmonella typhimurium MM281 mutant indicated that ZmMGT12 possessed Mg2+ transport ability. ZmMGT12 was expressed in roots, stems, and leaves, with the highest expression in leaves. Moreover, ZmMGT12 expression was induced by light and exhibited a circadian expression pattern. In addition, the expression level of ZmMGT12 in leaf tissue was related to chlorophyll synthesis. Overexpression of ZmMGT12 in Arabidopsis caused no phenotypic change in transgenic plants, including in fresh shoot weight, chlorophyll content, shoot Mg2+ content, and chloroplast Mg2+ content. Together, these results suggest that ZmMGT12 is a Mg2+ transporter and may play a role in Mg transport into chloroplasts. PMID- 29702187 TI - Solubilization conditions for bovine heart mitochondrial membranes allow selective purification of large quantities of respiratory complexes I, III, and V. AB - Ascertaining the structure and functions of mitochondrial respiratory chain complexes is essential to understanding the biological mechanisms of energy conversion; therefore, numerous studies have examined these complexes. A fundamental part of that research involves devising a method for purifying samples with good reproducibility; the samples obtained need to be stable and their constituents need to retain the same structure and functions they possess when in mitochondrial membranes. Submitochondrial bovine heart particles were isolated using differential centrifugation to adjust to a membrane concentration of 46.0% (w/v) or 31.5% (w/v) based on weight. After 0.7% (w/v) deoxycholic acid, 0.4% (w/v) decyl maltoside, and 7.2% (w/v) potassium chloride were added to the mitochondrial membranes, those membranes were solubilized. At a membrane concentration of 46%, complex V was selectively solubilized, whereas at a concentration of 31.5% (w/v), complexes I and III were solubilized. Two steps sucrose density gradient centrifugation and anion-exchange chromatography on a POROS HQ 20 MUm column-enabled selective purification of samples that retained their structure and functions. These two steps enabled complexes I, III, and V to be purified in two days with a high yield. Complexes I, III, and V were stabilized with n-decyl-beta-D-maltoside. A total of 200 mg-300 mg of those complexes from one bovine heart (1.1 kg muscle) was purified with good reproducibility, and the complexes retained the same functions they possessed while in mitochondrial membranes. PMID- 29702188 TI - Consistent head up cardiopulmonary resuscitation haemodynamics are observed across porcine and human cadaver translational models. AB - AIM: The objectives were: 1) replicate key elements of Head Up (HUP) cardiopulmonary resuscitation (CPR) physiology in a traditional swine model of ventricular fibrillation (VF), 2) compare HUP CPR physiology in pig cadavers (PC) to the VF model 3) develop a new human cadaver (HC) CPR model, and 4) assess HUP CPR in HC. METHODS: Nine female pigs were intubated, and anesthetized. Venous, arterial, and intracranial access were obtained. After 6 min of VF, CPR was performed for 2 min epochs as follows: Standard (S)-CPR supine (SUP), Active compression decompression (ACD) CPR + impedance threshold device (ITD-16) CPR SUP, then ACD + ITD HUP CPR. The same sequence was performed in PC 3 h later. In 9 HC, similar vascular and intracranial access were obtained and CPR performed for 1 min epochs using the same sequence as above. RESULTS: The mean cerebral perfusion pressure (CerPP, mmHg) was 14.5 +/- 6 for ACD + ITD SUP and 28.7 +/- 10 for ACD + ITD HUP (p = .007) in VF, -3.6 +/- 5 for ACD + ITD SUP and 7.8 +/- 9 for ACD + ITD HUP (p = .007) in PC, and 1.3 +/- 4 for ACD + ITD SUP and 11.3 +/- 5 for ACD + ITD HUP (p = .007) in HC. Mean systolic and diastolic intracranial pressures (ICP) (mmHg) were significantly lower in the ACD + ITD HUP group versus the ACD + ITD SUP group in all three CPR models. CONCLUSION: HUP CPR decreased ICP while increasing CerPP in pigs in VF as well as in PC and HC CPR models. This first-time demonstration of HUP CPR physiology in humans provides important implications for future resuscitation research and treatment. PMID- 29702189 TI - Prognostic value of serum phosphate level in adult patients resuscitated from cardiac arrest. AB - BACKGROUND: Several studies have reported increased levels of phosphate after cardiac arrest. Given the relationship between phosphate level and the severity of ischaemic injury reported in previous studies, higher phosphate levels may be associated with worse outcomes. We investigated the prognostic value of phosphate level after the restoration of spontaneous circulation (ROSC) in adult cardiac arrest patients. METHODS: This study was a retrospective observational study including adult cardiac arrest survivors treated at the Chonnam National University Hospital between January 2014 and June 2017. From medical records, data regarding clinical characteristics, outcome at hospital discharge, and laboratory parameters including phosphate levels after ROSC were collected. The primary outcome was poor outcome at hospital discharge, defined as Cerebral Performance Categories 3-5. RESULTS: Of the 674 included patients, 465 had poor outcome at hospital discharge. Serum phosphate level was significantly higher in patients with poor outcome than in those with good outcome (p < 0.001). Phosphate level was correlated with time to ROSC (r = 0.350, p < 0.001). Receiver operating characteristic curve analysis revealed an area under the curve of 0.805 (95% confidence interval [CI], 0.777-0.838) for phosphate level. In multivariate analysis, a higher phosphate level was independently associated with poor outcome at hospital discharge (odds ratio, 1.432; 95% CI, 1.245-1.626; p < 0.001). CONCLUSIONS: A higher phosphate level after ROSC was independently associated with poor outcome at hospital discharge in adult cardiac arrest patients. However, given its modest prognostic performance, phosphate level should be used in combination with other prognostic indicators. PMID- 29702190 TI - miRNA 146a promotes chemotherapy resistance in lung cancer cells by targeting DNA damage inducible transcript 3 (CHOP). AB - The underlying molecular mechanism of lung cancer drug resistance is poorly understood. The mediator of endoplasmic reticulum stress CHOP (DNA damage inducible transcript 3) promotes stress-induced apoptosis and appears to function as a transcription factor in multiple diseases. However, its potential contributions to multidrug resistance in solid tumors is unknown. Here, we investigated CHOP expression in tumor tissues form 69 lung cancer patients, finding that deficient CHOP expression is associated with poor prognosis. Cisplatin-resistant lung cancer cells exhibited lower expression of CHOP compared to that in sensitive lung cancer cells, and silencing or augmenting CHOP expression enhanced or impaired cisplatin resistance, respectively. Mechanistic investigations revealed that CHOP is directly associated with the regulation of autophagy or apoptosis-regulatory genes including LC3-II, death receptor 5 (DR5), and telomere repeat-binding factor 3. Notably, CHOP was identified as a target of miR-146a, and increased miR-146a expression in lung cancer cells was suggested to be responsible for CHOP mRNA down-regulation. Further, animal models confirmed that abnormally expressed miR-146a in lung cancer cells does not affect growth, but rather alters chemotherapy sensitivity. Together, CHOP is a useful prognostic marker and miR-146a is a potential therapeutic target for multidrug-resistant lung cancer. PMID- 29702191 TI - Knockdown of TGF-beta1 expression in human umbilical cord mesenchymal stem cells reverts their exosome-mediated EMT promoting effect on lung cancer cells. AB - The effect of mesenchymal stem cells (MSCs) on lung cancer cells is controversial, and the underlying mechanisms remain unclear, which harms the utilization of MSCs in tumor therapy. In this study, we found that human umbilical cord MSC-conditioned medium (MSC-CM) promotes EMT, invasion, and migration, yet inhibits proliferation and promotes apoptosis of lung cancer cells. The EMT-promoting effect of MSCs was mediated by exosomes derived from MSCs (MSC-exo) and eliminated by inhibiting exosome release. Moreover, silencing TGF-beta1 expression in MSCs can revert the EMT-promoting effect and enhance the anti-proliferative and pro-apoptotic effect of MSCs on lung cancer cells via MSC exo. Further investigation found that Smad2/3, Akt/GSK-3beta/beta-catenin, NF kappaB, ERK, JNK, and p38 MAPK in TGF-beta1 signaling pathways could be activated by MSC-exo in lung cancer cells, while silencing TGF-beta1 expression in MSCs may deactivate these pathways. These findings suggest a method by which MSCs may be safely employed in lung cancer therapy. PMID- 29702192 TI - Pseudolaric acid B triggers ferroptosis in glioma cells via activation of Nox4 and inhibition of xCT. AB - Ferroptosis is a form of programmed cell death decided by iron-dependent lipid peroxidation, but its role in glioma cell death remains unclear. In this study, we found Pseudolaric acid B (PAB) inhibited the viabilities of glioma cells in vitro and in vivo, which was accompanied by abnormal increases of intracellular ferrous iron, H2O2 and lipid peroxidation, as well as depletion of GSH and cysteine. In vitro studies revealed that the lipid peroxidation and the cell death caused by PAB were both inhibited by iron chelator deferoxamine, but exacerbated by supplement of ferric ammonium citrate. Inhibition of lipid peroxidation with ferrostatin-1 or GSH rescued PAB-induced cell death. Morphologically, the cells treated with PAB presented intact membrane, shrunken mitochondria with increased membrane density, and normal-sized nucleus without chromatin condensation. Mechanistically, PAB improved intracellular iron by upregulation of transferrin receptor. The increased iron activated Nox4, which resulted in overproduction of H2O2 and lipid peroxides. Moreover, PAB depleted intracellular GSH via p53-mediated xCT pathway, which further exacerbated accumulation of H2O2 and lipid peroxides. Thus, PAB triggers ferroptosis in glioma cells and is a potential medicine for glioma treatment. PMID- 29702193 TI - miR-19a-mediated downregulation of RhoB inhibits the dephosphorylation of AKT1 and induces osteosarcoma cell metastasis. AB - Osteosarcoma is a primary malignancy that develops in bone, along with serious recurrence and metastasis. As an isoform of Rho family GTPases, RhoB could suppress cell proliferation, invasion, and anti-angiogenesis. But it is not clear how RhoB involves in tumor metastasis. Here we found that expression of RhoB was decreased in osteosarcoma primary samples and cell lines. Ectopic expression of RhoB restrains the migration of osteosarcoma cells in vitro and in vivo, and induces osteosarcoma cell apopotsis. Further study showed that overexpression of RhoB could increase the proportion of B55 in PP2A complex and enhance the dephosphorylation of AKT1 by interacting with B55. Moreover, we demonstrated that miR-19a, which exhibits abnormal expression in highly metastatic osteosarcoma cell lines, could inhibit the expression of RhoB and promote the lung metastasis of osteosarcoma cells in vivo. Our results indicate that miR-19a-mediated RhoB is a critical regulator for the dephosphorylation of AKT1 in osteosarcoma cells. It may have a possible strategy on suppressing osteosarcoma metastasis by miR-19a inhibitory oligonucleotides. The miR-19a/RhoB/AKT1 network may help us to better understand the mechanism of osteosarcoma metastasis. PMID- 29702194 TI - Tumor suppressive microRNA-124a inhibits stemness and enhances gefitinib sensitivity of non-small cell lung cancer cells by targeting ubiquitin-specific protease 14. AB - Increasing evidence has shown that microRNAs (miRNAs) play a significant functional role by directly regulating respective targets in cancer stem cell (CSC)-induced non-small cell lung cancer (NSCLC) progression and resistance to therapy. In this study, we found that hsa-miR-124a was downregulated during spheroid formation of the NSCLC cell lines SPC-A1 and NCI-H1650 and NSCLC tissues compared with normal lung cells and tissues. Patients with lower hsa-miR-124a expression had shorter overall survival (OS) and progression free survival (PFS). Moreover, ubiquitin-specific protease 14 (USP14) was confirmed to be a direct target of hsa-miR-124a. Furthermore, concomitant low hsa-miR-124a expression and high USP14 expression were correlated with a shorter median OS and PFS in NSCLC patients. Cellular functional analysis verified that the tumor suppressor hsa-miR 124a negatively regulated cell growth and self-renewal, and promoted apoptosis and gefitinib sensitivity of lung cancer stem cells by suppressing its target gene USP14. Our results provide the first evidence that USP14 is a direct target of hsa-miR-124a, and that hsa-miR-124a inhibits stemness and enhances the gefitinib sensitivity of NSCLC cells by targeting USP14. Thus, hsa-miR-124a and USP14 may be useful as tumor biomarkers for the diagnosis and treatment of NSCLC. PMID- 29702195 TI - Hedgehog signaling negatively co-regulates BH3-only protein Noxa and TAp73 in TP53-mutated cells. AB - In the present study, we show that pharmacological repression by the Hedgehog (Hh) pathway inhibitor (HPI) GANT61 induces expression of the proapoptotic protein Noxa in TP53-mutated embryonal pediatric tumor cells driven by Hh signaling (i.e. rhabdomyosarcoma (RMS) and medulloblastoma (MB)). Similarly, genetic silencing of Gli1 by siRNA causes increased Noxa mRNA and protein levels, while overexpression of Gli1 results in decreased Noxa expression. Furthermore, TAp73 mRNA and protein levels are increased upon Gli1 knockdown, while Gli1 overexpression reduces TAp73 mRNA and protein levels. However, knockdown of TAp73 fails to block Noxa induction in GANT61-treated cells, suggesting that Noxa is not primarily regulated by TAp73. Interestingly, mRNA levels of the transcription factor EGR1 correlate with those of Noxa and TAp73. Silencing of EGR1 results in decreased Noxa and TAp73 mRNA levels, indicating that EGR1 is involved in regulating transcriptional activity of Noxa and TAp73. These findings suggest that Gli1 represses Noxa and TAp73, possibly via EGR1. These findings could be exploited for the treatment of Hh-driven tumors, e.g. for their sensitization to chemotherapeutic agents. PMID- 29702196 TI - PA28gamma acts as a dual regulator of IL-6 and CCL2 and contributes to tumor angiogenesis in oral squamous cell carcinoma. AB - PA28gamma promotes tumor development and progression and is suggested to play a role in tumor angiogenesis, but the molecular mechanisms have not been investigated. Here, we found that PA28gamma enhanced the ability of OSCC cells to promote the migration, invasion, and tube formation of HUVECs and promoted tumor induced angiogenesis in xenograft mice models in vivo. Then, a mechanism study revealed that the expression and secretion of IL-6 and CCL2 were dependent on PA28gamma expression. Furthermore, blocking IL-6 or CCL2 or the transcription factor NF-kappaB induced the inhibition of tube formation in HUVECs co-cultured with PA28gamma-overexpression OSCC cell supernatants. Moreover, we revealed that p-STAT3 and p-AKT, which are downstream of the IL-6 and CCL2 signaling axis, were downregulated in HUVECs co-cultured with the PA28gamma-silenced supernatant and were upregulated with the PA28gamma-overexpressing supernatant. In addition, IL 6, CCL2 and PA28gamma expressions were correlated in a clinical OSCC cohort. Collectively, our study indicates that PA28gamma contributes to tumor angiogenesis by regulating IL-6 and CCL2. PA28gamma may be a novel therapeutic target as a dual regulator of IL-6 and CCL2 for treating PA28gamma-positive OSCC. PMID- 29702197 TI - Mutations in the estrogen receptor alpha hormone binding domain promote stem cell phenotype through notch activation in breast cancer cell lines. AB - The detection of recurrent mutations affecting the hormone binding domain (HBD) of estrogen receptor alpha (ERalpha/ESR1) in endocrine therapy-resistant and metastatic breast cancers has prompted interest in functional characterization of these genetic alterations. Here, we explored the role of HBD-ESR1 mutations in influencing the behavior of breast cancer stem cells (BCSCs), using various BC cell lines stably expressing wild-type or mutant (Y537 N, Y537S, D538G) ERalpha. Compared to WT-ERalpha clones, mutant cells showed increased CD44+/CD24- ratio, mRNA levels of stemness genes, Mammosphere Forming Efficiency (MFE), Self-Renewal and migratory capabilities. Mutant clones exhibited high expression of NOTCH receptors/ligands/target genes and blockade of NOTCH signaling reduced MFE and migratory potential. Mutant BCSC activity was dependent on ERalpha phosphorylation at serine 118, since its inhibition decreased MFE and NOTCH4 activation only in mutant cells. Collectively, we demonstrate that the expression of HBD-ESR1 mutations may drive BC cells to acquire stem cell traits through ER/NOTCH4 interplay. We propose the early detection of HBD-ESR1 mutations as a challenge in precision medicine strategy, suggesting the development of tailored approaches (i.e. NOTCH inhibitors) to prevent disease development and metastatic spread in BC mutant-positive patients. PMID- 29702198 TI - A toolbox for microbore liquid chromatography tandem-high-resolution mass spectrometry analysis of albumin-adducts as novel biomarkers of organophosphorus pesticide poisoning. AB - Exposure to toxic organophosphorus pesticides (OPP) represents a serious problem in the public healthcare sector and might be forced in terroristic attacks. Therefore, reliable verification procedures for OPP-intoxications are required for forensic, toxicological and clinical reasons. We developed and optimized a toolbox of methods to detect adducts of human serum albumin (HSA) with OPP considered as long-term biomarkers. Human serum was incubated with diethyl-oxono and diethyl-thiono pesticides for adduct formation used as reference. Afterwards serum was subjected to proteolysis using three proteases separately thus yielding phosphorylated tyrosine residues (Y*) detected as single amino acid (pronase), as hexadecapeptide LVRY*411TKKVPQVSTPTL (pepsin) and as the tripeptide Y*411TK (trypsin), respectively. Adducts were analyzed via microbore liquid chromatography coupled to electrospray ionization (MULC-ESI) and tandem-high resolution mass spectrometry (MS/HR MS). Using paraoxon-ethyl as model OPP for adduct formation, methods were optimized with respect to MS/HR MS-parameters, protease concentrations and incubation time for proteolysis. HSA-adducts were found to be stable in serum in vitro at +37 degrees C and -30 degrees C for at least 27 days and resulting biomarkers were stable in the autosampler at 15 degrees C for at least 24 h. Limits of identification of adducts varied between 0.25 MUM and 4.0 MUM with respect to the corresponding pesticide concentrations in serum. Applicability of the methods was proven by successful detection of the adducts in samples of OPP-poisoned patients thus demonstrating the methods as a reliable toolbox for forensic and toxicological analysis. PMID- 29702199 TI - Androgen- and estrogen-receptor mediated activities of 4-hydroxytestosterone, 4 hydroxyandrostenedione and their human metabolites in yeast based assays. AB - 4-Hydroxyandrost-4-ene-3,17-dione, also named formestane, is an irreversible aromatase inhibitor and therapeutically used as anti-breast cancer medication in post-menopausal women. Currently, no therapeutical indication led to approval of its 17-hydroxylated analog 4-hydroxytestosterone, an anabolic steroid. However, it is currently investigated in a clinical trial for breast cancer. In context with sports doping, aromatase inhibitors are administered to reduce estrogenic side effects of misused anabolic substances or their metabolites. Therefore, both substances are prohibited in sports by the World Anti-Doping Agency (WADA). Analysis of urinary phase I and phase II metabolites showed similar results for both compounds. In the current investigation, 4-hydroxyandrost-4-ene-3,17-dione, 4-hydroxytestosterone and seven of their described urinary metabolites as well as 2alpha-hydroxyandrostenedione were tested in the yeast androgen screen and the yeast estrogen screen. Androgenic effects were observed for all tested substances, except for one, which showed anti-androgenic properties. With regard to the yeast estrogen screen, estrogenic effects were observed for only two metabolites at rather high concentrations, while six out of the ten substances tested showed anti-estrogenic properties. In terms of the strong androgenic effect observed for 4-hydroxytestosterone (10-8 M), 4-hydroxyandrost-4-ene-3,17 dione (10-8 M) and two more urinary metabolites, the yeast androgen assay may also be used to trace abuse in urine samples. PMID- 29702200 TI - Long-term neurological and neuropsychological complications of sulfur mustard and Lewisite mixture poisoning in Chinese victims exposed to chemical warfare agents abandoned at the end of WWII. AB - In August 2003, 44 victims were poisoned by chemical warfare agents (CWAs) leaked from five drums that were excavated at a construction site in Qiqihar, Northeast China. The drums were abandoned by the former Japanese imperial army during World War II and contained a mixture of Sulfur mustard (SM) and Lewisite. We carried out a total of six regular check-ups between 2006 and 2014, and from 2008 we added neurological evaluations including neuropsychological test and autonomic nervous function test in parallel with medical follow-up as much as was possible. Severe autonomic failure, such as hyperhidrosis, pollakiuria, diarrhoea, diminished libido, and asthenia appeared in almost all victims. Polyneuropathy occurred in 35% of the victims and constricted vision occurred in 20% of them. The rates of abnormal response on cold pressor test (CPT), active standing test (AST), Heart rate variability (CVR-R), performed in 2014, were 63.1%, 31.6%, and 15.9%, respectively. On neuropsychological testing evaluated in 2010, a generalized cognitive decline was observed in 42% of the victims. Memories and visuospatial abilities were affected in the remaining victims. Finally, a 17-item PTSD questionnaire and the Beck Depression Inventory evaluated in 2014 revealed long-lasting severe PTSD symptoms and depression of the victims. Our findings suggest that an SM/Lewisite compound have significant adverse consequences directly in cognitive and emotional network and autonomic nervous systems in the brain. PMID- 29702202 TI - Eczema complicated by allergic contact dermatitis to topical medications and excipients. PMID- 29702201 TI - Changes of NK cell subsets with time post-transplant in peripheral blood of renal transplant recipients. AB - BACKGROUND: There is evidence that NK cells with low cytotoxicity but strong immunoregulatory characteristics contribute to good graft outcome. We attempted to investigate which NK cell subsets increase post-transplant and might affect graft function. METHOD: Lymphocyte and NK cell subsets were determined in whole blood using eight-colour-fluorescence flow cytometry in patients pre-transplant and post-transplant. In total, 31 transplant recipients were studied. RESULTS: When cell numbers were compared in 9 patients pre- and 6 months post-transplant, post-transplant CD56dimCD16+ (p = 0.011) NK cells with the phenotype CD158a+ (p = 0.008), CD158e+ (p = 0.038), NKG2A+ (p = 0.008), NKG2D+ (p = 0.011), IFNyR+ (p = 0.008), perforin+ (p = 0.008), granzymeB+ (p = 0.008), perforin+granzymeB+ (p = 0.008) and perforin-granzymeB- (p = 0.021) were lower than those pre-transplant, indicating a post-transplant reduction of cytotoxic NK cells. In 28 patients NK cell subsets were analyzed with respect to time post-transplant (median 888 days post-transplant). CD56dimCD16+ NK cells co-expressing CD158a (p = 0.014), NKG2D (p = 0.047), IL4R (p = 0.038), IL10R (p = 0.008) and IFNy (p = 0.036) as well as CD56bright NK cells with the phenotype TGFbeta+ (p = 0.017), TGFR+ (p = 0.035), CD158a+ (p = 0.042) and perforin-granzymeB- (p = 0.048) increased with time post transplant. CONCLUSION: Post-transplant, cytotoxic NK cells were lower than pre transplant and remained low, whereas NK cell subsets with potentially immunoregulatory properties increased. PMID- 29702203 TI - RASAL2 inhibits tumor angiogenesis via p-AKT/ETS1 signaling in bladder cancer. AB - Muscle-invasive or metastatic bladder cancer (BCa) is a life-threatening disease for patients, and tumor angiogenesis is believed to play a critical role in the progression of BCa. However, its underlying mechanism of tumor angiogenesis is still poorly understood. In this study, we discovered that RASAL2, a RAS GTPase activating protein, could inhibit BCa angiogenesis based on our shRNA/siRNA knockdown or ectopic cDNA expression experiments. Mechanistically, RASAL2 downregulation could enhance the phosphorylation of AKT and then subsequently upregulate the expression of ETS1 and VEGFA. Furthermore, there was a negative correlation between RASAL2 and VEGFA or CD31 expression in subcutaneous xenograft and human BCa specimens. Taken together, we provide a new insight into the molecular mechanism of BCa progression, in which RASAL2 can be a new therapeutic target. PMID- 29702204 TI - Chronic intermittent hypoxia induces changes on the expression and activity of neprilysin (EC 3.4.24.11) in the brain of rats. AB - Obstructive sleep apnea (OSA) is a frequent sleeping breathing disorder associated with cognitive impairments. Neprilysin (NEP) is responsible for degrading several substrates related to cognition; however, the effect of chronic intermittent hypoxia (CIH) on NEP is still unknown. This study aimed to evaluate the expression and activity of NEP in cognitive-related brain structures of rats submitted to CIH. Western blot, qRT-PCR and enzyme activity assay, demonstrated that a six-week intermittent hypoxia increased NEP expression and activity, selectively in temporal cortex, but not in the hippocampus and frontal cortex. The increase in NEP activity and expression was reverted followed by two weeks recovery in normoxia. These data show that CIH protocol increases the expression and activity of NEP selectively in the temporal cortex. Additional mechanisms must be investigated to elucidate the effects of CIH in cognition. PMID- 29702205 TI - Sex differences in a rabbit eyeblink conditioning model of PTSD. AB - We have developed a rabbit model of posttraumatic stress disorder (PTSD) which recapitulates several core features of PTSD, particularly hyperarousal and conditioned responding to trauma-associated cues. The work conducted with this model has all been done in male rabbits and, given sex differences in PTSD prevalence, it is important to expand our animal model of PTSD to include female rabbits to determine if they develop core features of PTSD, and if those core features can be treated. This is particularly important because, contrary to human studies, nearly all animal studies have found that males are consistently more vulnerable to various forms of acute and chronic stress than females. Using eyeblink conditioning in which we paired tone with a brief periorbital shock, we found that although both male and female rabbits acquired identical levels of conditioning, females showed more hyperarousal after conditioning but seemed to respond somewhat better to treatment. PMID- 29702208 TI - The plasticity of pancreatic cancer metabolism in tumor progression and therapeutic resistance. AB - Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer that is highly refractory to the current standards of care. The difficulty in treating this disease is due to a number of different factors, including altered metabolism. In PDA, the metabolic rewiring favors anabolic reactions which supply the cancer cell with necessary cellular building blocks for unconstrained growth. Furthermore, PDA cells display high levels of basal autophagy and macropinocytosis. KRAS is the driving oncogene in PDA and many of the metabolic changes are downstream of its activation. Together, these unique pathways for nutrient utilization and acquisition result in metabolic plasticity enabling cells to rapidly adapt to nutrient and oxygen fluctuations. This remarkable adaptability has been implicated as a cause of the intense therapeutic resistance. In this review, we discuss metabolic pathways in PDA tumors and highlight how they contribute to the pathogenesis and treatment of the disease. PMID- 29702206 TI - Applications of metabolomics to study cancer metabolism. AB - Reprogrammed metabolism supports tumor growth and provides a potential source of therapeutic targets and disease biomarkers. Mass spectrometry-based metabolomics has emerged as a broadly informative technique for profiling metabolic features associated with specific oncogenotypes, disease progression, therapeutic liabilities and other clinically relevant aspects of tumor biology. In this review, we introduce the applications of metabolomics to study deregulated metabolism and metabolic vulnerabilities in cancer. We provide examples of studies that used metabolomics to discover novel metabolic regulatory mechanisms, including processes that link metabolic alterations with gene expression, protein function, and other aspects of systems biology. Finally, we discuss emerging applications of metabolomics for in vivo isotope tracing and metabolite imaging, both of which hold promise to advance our understanding of the role of metabolic reprogramming in cancer. PMID- 29702207 TI - Metabolic reprogramming of the tumor microenvironment by p62 and its partners. AB - The concerted metabolic reprogramming across cancer and normal cellular compartments of the tumor microenvironment can favor tumorigenesis by increasing the survival and proliferating capacities of transformed cells. p62 has emerged as a critical signaling adaptor, beyond its role in autophagy, by playing an intricate context-dependent role in metabolic reprogramming of the cell types of the tumor and stroma, which shapes the tumor microenvironment to control tumor progression. Focusing on metabolic adaptations, we review the cellular processes upstream and downstream of p62 that regulate how distinct cell types adapt to the challenging and evolving environmental conditions during tumor initiation and progression. In addition, we describe partners of p62 that, in a collaborative or independent manner, can also rewire cell metabolism. Finally, we discuss the potential therapeutic implications of targeting p62 in cancer, considering its multifaceted roles in diverse cell types of the tumor microenvironment. PMID- 29702209 TI - Contribution of yersiniabactin to the virulence of an Escherichia coli sequence type 69 ("clonal group A") cystitis isolate in murine models of urinary tract infection and sepsis. AB - Escherichia coli sequence type 69 (ST69; "clonal group A") is an important extraintestinal pathogen. To clarify the yersiniabactin siderophore system's role in ST69's extraintestinal virulence we compared a wild-type ST69 cystitis isolate, isogenic irp2 (yersiniabactin) mutants, and irp2-complemented mutants in murine models of sepsis and urinary tract infection (UTI). irp2 mutants were attenuated mildly in the UTI model and profoundly in the sepsis model. In both models, complementation with a functional copy of irp2 restored full parental virulence. These findings suggest that in ST69 the yersiniabactin system has a minor role in urovirulence and a major role in sepsis causation. PMID- 29702210 TI - Antibacterial mechanisms of cinnamon and its constituents: A review. AB - BACKGROUND: In the current healthcare environment, an alarming rise in multi-drug resistant bacterial infections has led to a global health threat. The lack of new antibiotics has created a need for developing alternative strategies. OBJECTIVE: Understanding the antibacterial mechanisms of cinnamon and its constituents is crucial to enhance it as a potential new source of antibiotic. The objective of this review is to provide a compilation of all described mechanisms of antibacterial action of cinnamon and its constituents and synergism with commercial antibiotics in order to better understand how cinnamon and its constituents can collaborate as alternative treatment to multi-drug resistant bacterial infections. METHODS: The relevant references on antibacterial activities of cinnamon and its constituents were searched. Meanwhile, the references were classified according to the type of mechanism of action against bacteria. Relationships of cinnamon or its constituents and antibiotics were also analyzed and summarized. RESULTS: Cinnamon extracts, essential oils, and their compounds have been reported to inhibit bacteria by damaging cell membrane; altering the lipid profile; inhibiting ATPases, cell division, membrane porins, motility, and biofilm formation; and via anti-quorum sensing effects. CONCLUSION: This review describes the antibacterial effects of cinnamon and its constituents, such as cinnamaldehyde and cinnamic acid, against pathogenic Gram-positive and Gram-negative bacteria. The review also provides an overview of the current knowledge of the primary modes of action of these compounds as well as the synergistic interactions between cinnamon or its constituents with known antibacterial agents. This information will be useful in improving the effectiveness of therapeutics based on these compounds. PMID- 29702212 TI - Human skin barrier structure and function analyzed by cryo-EM and molecular dynamics simulation. AB - In the present study we have analyzed the molecular structure and function of the human skin's permeability barrier using molecular dynamics simulation validated against cryo-electron microscopy data from near native skin. The skin's barrier capacity is located to an intercellular lipid structure embedding the cells of the superficial most layer of skin - the stratum corneum. According to the splayed bilayer model (Iwai et al., 2012) the lipid structure is organized as stacked bilayers of ceramides in a splayed chain conformation with cholesterol associated with the ceramide sphingoid moiety and free fatty acids associated with the ceramide fatty acid moiety. However, knowledge about the lipid structure's detailed molecular organization, and the roles of its different lipid constituents, remains circumstantial. Starting from a molecular dynamics model based on the splayed bilayer model, we have, by stepwise structural and compositional modifications, arrived at a thermodynamically stable molecular dynamics model expressing simulated electron microscopy patterns matching original cryo-electron microscopy patterns from skin extremely closely. Strikingly, the closer the individual molecular dynamics models' lipid composition was to that reported in human stratum corneum, the better was the match between the models' simulated electron microscopy patterns and the original cryo-electron microscopy patterns. Moreover, the closest-matching model's calculated water permeability and thermotropic behaviour were found compatible with that of human skin. The new model may facilitate more advanced physics-based skin permeability predictions of drugs and toxicants. The proposed procedure for molecular dynamics based analysis of cellular cryo-electron microscopy data might be applied to other biomolecular systems. PMID- 29702211 TI - miR-146a-5p promotes replication of infectious bronchitis virus by targeting IRAK2 and TNFRSF18. AB - Avian infectious bronchitis virus (IBV) is a coronavirus which infects chickens (Gallus gallus) of all ages and causes significant economic losses to the poultry industry worldwide. The present study aims to analyze the miRNAs related to pathogenicity of nephropathogenic IBVs. It was found that four miRNAs (miR-1454, miR-3538, miR-146a-5p and miR-215-5p) were related to the infection of virulent nephropathogenic IBV with transcript per million (TPM) > 500 and more than a 2 fold alteration. In vitro study results showed that the alterations of these four miRNAs were consistent with in vivo data. In vitro, we found that high levels of miR-146a-5p could enhance the replication of IBV at the early stage of infection, and its down regulated level could slow down the replication of IBV. Finally, high levels of exogenous miR-146a-5p in HD11 cells led to down regulation of IL-1 receptor associated kinase-2 (IRAK2) and Tumor necrosis factor receptor superfamily member 18 (TNFRSF18) genes. Luciferase reporter assays revealed that miR-146a-5p could bind to the 3'-UTRs of IRAK2 and TNFRSF18. This is the first study demonstrating that IBV induced miR-146a-5p is related to virus pathogenesis by down regulating IRAK2 and TNFRSF18, which may serve as a therapeutic strategy for the prevention of IBV infections. PMID- 29702213 TI - Is Amazonia a 'museum' for Neotropical trees? The evolution of the Brownea clade (Detarioideae, Leguminosae). AB - The flora of the Neotropics is unmatched in its diversity, however the mechanisms by which diversity has accumulated are debated and largely unclear. The Brownea clade (Leguminosae) is a characteristic component of the Neotropical flora, and the species within it are diverse in their floral morphology, attracting a wide variety of pollinators. This investigation aimed to estimate species divergence times and infer relationships within the group, in order to test whether the Brownea clade followed the 'cradle' or 'museum' model of diversification, i.e. whether species evolved rapidly over a short time period, or gradually over many millions of years. We also aimed to trace the spatio-temporal evolution of the clade by estimating ancestral biogeographical patterns in the group. We used BEAST to build a dated phylogeny of 73 Brownea clade species using three molecular markers (ITS, trnK and psbA-trnH), resulting in well-resolved phylogenetic relationships within the clade, as well as robust divergence time estimates from which we inferred diversification rates and ancestral biogeography. Our analyses revealed an Eocene origin for the group, after which the majority of diversification happened in Amazonia during the Miocene, most likely concurrent with climatic and geological changes caused by the rise of the Andes. We found no shifts in diversification rate over time, suggesting a gradual accumulation of lineages with low extinction rates. These results may help to understand why Amazonia is host to the highest diversity of tree species on Earth. PMID- 29702214 TI - Comparative transcriptomics and genomic patterns of discordance in Capsiceae (Solanaceae). AB - The integration of genomics and phylogenetics allows new insight into the structure of gene tree discordance, the relationships among gene position, gene history, and rate of evolution, as well as the correspondence of gene function, positive selection, and gene ontology enrichment across lineages. We explore these issues using the tribe Capsiceae (Solanaceae), which is comprised of the genera Lycianthes and Capsicum (peppers). In combining the annotated genomes of Capsicum with newly sequenced transcriptomes of four species of Lycianthes and Capsicum, we develop phylogenies for 6747 genes, and construct a backbone species tree using both concordance and explicit phylogenetic network approaches. We quantify phylogenetic discordance among individual gene trees, measure their rates of synonymous and nonsynonymous substitution, and test whether they were positively selected along any branch of the phylogeny. We then map these genes onto the annotated Capsicum genome and test whether rates of evolution, gene history, and gene ontology vary significantly with gene position. We observed substantial discordance among gene trees. A bifurcating species tree placing Capsicum within a paraphyletic Lycianthes was supported over all phylogenetic networks. Rates of synonymous and nonsynonymous substitution varied 41-fold and 130-fold among genes, respectively, and were significantly lower in pericentromeric regions. We found that results of concordance tree analyses vary depending on the subset of genes used, and that genes within the pericentromeric regions only capture a portion of the observed discordance. We identified 787 genes that have been positively selected throughout the diversification history of Capsiceae, and discuss the importance of these genes as targets for investigation of economically important traits in the domesticated peppers. PMID- 29702215 TI - New insights into the phylogeny of the TMBIM superfamily across the tree of life: Comparative genomics and synteny networks reveal independent evolution of the BI and LFG families in plants. AB - The Transmembrane BAX Inhibitor Motif containing (TMBIM) superfamily, divided into BAX Inhibitor (BI) and Lifeguard (LFG) families, comprises a group of cytoprotective cell death regulators conserved in prokaryotes and eukaryotes. However, no research has focused on the evolution of this superfamily in plants. We identified 685 TMBIM proteins in 171 organisms from Archaea, Bacteria, and Eukarya, and provided a phylogenetic overview of the whole TMBIM superfamily. Then, we used orthology and synteny network analyses to further investigate the evolution and expansion of the BI and LFG families in 48 plants from diverse taxa. Plant BI family forms a single monophyletic group; however, monocot BI sequences transposed to another genomic context during evolution. Plant LFG family, which expanded trough whole genome and tandem duplications, is subdivided in LFG I, LFG IIA, and LFG IIB major phylogenetic groups, and retains synteny in angiosperms. Moreover, two orthologous groups (OGs) are shared between bryophytes and seed plants. Other several lineage-specific OGs are present in plants. This work clarifies the phylogenetic classification of the TMBIM superfamily across the three domains of life. Furthermore, it sheds new light on the evolution of the BI and LFG families in plants providing a benchmark for future research. PMID- 29702216 TI - Hidden and cryptic species reflect parallel and correlated evolution in the phylogeny of the genus Callyntra (Coleoptera: Tenebrionidae) of Central Chile. AB - The origin of cryptic species has traditionally been associated with events of recent speciation, genetic constraints, selection of an adaptive character, sexual selection and/or convergent evolution. Species of the genus Callyntra inhabit coastal terraces, mountain slopes, and peaks; their elytral designs are associated with each of these habitats. However, cryptic species have been described within each of these habitats; the taxonomy of this group has been problematic, thus establishing the phylogenetic relationships in this group is fundamental to clarify the systematics and evolutionary patterns of Callyntra. We reconstructed the phylogeny of this group using two mitochondrial genes (COI, 16S) and one nuclear gene (Mp20). We also performed species delimitation using PTP based methods (PTP, mlPTP, bPTP) and GMYC, and evaluated the evolution of the elytral design related to habitat preference. The results showed a tree with five clades, that together with the different methods of species delimitation recovered the described species and suggested at least five new species. The elytral design and habitat preference showed phylogenetic signals. We propose a new classification based on monophyletic groups recovered by phylogenetic analyses. We also suggest that parallel evolution in different habitats and later stasis in the elytral design would be the cause of the origin of cryptic species in this group from central Chile. PMID- 29702218 TI - Mitogenomics reveals phylogenetic relationships of caudofoveate aplacophoran molluscs. AB - The worm-shaped, shell-less aplacophoran molluscs Caudofoveata and Solenogastres have recently received attention as part of the clade Aculifera, but relationships within these two lineages are still largely unknown. Here, we use complete mitochondrial genomes to shed light on higher-level relationships within Caudofoveata. Mitochondrial genomes have been sequenced for many diverse molluscs, but only two mitochondrial genomes from aplacophoran molluscs (the caudofoveates Scutopus ventrolineatus and Chaetoderma nitidulum) are available to date. We sequenced and assembled complete or near complete mitochondrial genomes of five additional species of Caudofoveata (Falcidens acutargatus, Falcidens halanychi, Scutopus robustus, Psilodens balduri and Spathoderma clenchi) and one species of Solenogastres (Neomenia carinata) for comparison to available mitochondrial genomes of aculiferans. Comparison of mitochondrial gene order among different lineages revealed a highly conserved order of protein coding genes corresponding to the hypothesized ancestral gene order for Mollusca. Unique arrangements of tRNAs were found among lineages of aculiferan molluscs as well as among caudofoveate taxa. Phylogenetic analyses of amino acid sequences for the 13 protein-coding genes recovered a monophyletic Aplacophora. Within Caudofoveata, Chaetodermatidae, but not Limifossoridae, was recovered monophyletic. Taken together, our results suggest that mitochondrial genomes can serve as useful molecular markers for aculiferan phylogenetics, especially for more recent phylogenetic events. PMID- 29702217 TI - Resolving the systematic positions of enigmatic taxa: Manipulating the chloroplast genome data of Saxifragales. AB - Accurately resolving the phylogeny of enigmatic taxa is always a challenge in phylogenetic inference. Such uncertainties could be due to systematic errors or model violations. Here, we provide an example demonstrating how these factors affect the positioning of Paeoniaceae within Saxifragales based on chloroplast genome data. We newly assembled 14 chloroplast genomes from Saxifragales, and by combining these genomes with those of 63 other angiosperms, three datasets were assembled to test different hypotheses proposed by recent studies. These datasets were subjected to maximum parsimony, maximum likelihood and Bayesian analyses with site-homogeneous/heterogeneous models, different data partitioning strategies, and the inclusion/exclusion of weak phylogenetic signals. Three datasets exhibited remarkable heterogeneity among sites and among taxa of Saxifragales. Phylogenetic analyses under homogeneous models or maximum parsimony showed a closer relationship of Paeoniaceae with herbaceous families in the order. Data partitioning strategies did not change the general tree topology. However, PhyloBayes analysis under the CAT+GTR model resulted in a relationship closer to woody families. We conclude that although genomic data significantly increase the phylogenetic resolution of enigmatic taxa with high support, the phylogenetic results inferred from such data might be analysis or signal dependent. The analytical pipeline outlined here combines phylogenomic inference methods with evaluation of lineage-specific rates of substitution, model selection, and assessment of systematic error. These methods would be applicable to resolve similar difficult questions in the tree of life. PMID- 29702219 TI - Dispersal and speciation: The cross Atlantic relationship of two parasitic cnidarians. PMID- 29702220 TI - Dicam promotes proliferation and maturation of chondrocyte through Indian hedgehog signaling in primary cilia. AB - OBJECTIVES: Primary cilium is required for mechano-biological signal transduction in chondrocytes, and its interaction with extracellular matrix is critical for cartilage homeostasis. However, the role of cilia-associated proteins that affect the function of cilia remains to be elucidated. Here, we show that Dicam has a novel function as a modulator of primary cilia-mediated Indian hedgehog (Ihh) signaling in chondrocytes. METHODS: Cartilage-specific Dicam transgenic mouse was constructed and the phenotype of growth plates at embryonic day 15.5 and 18.5 was analyzed. Primary chondrocytes and tibiae isolated from embryonic day 15.5 mice were used in vitro study. RESULTS: Dicam was mainly expressed in resting and proliferating chondrocytes of the growth plate and was increased by PTHrP and BMP2 in primary chondrocytes. Cartilage-specific Dicam gain-of-function demonstrated increased length of growth plate in long bones. Dicam enhanced both proliferation and maturation of growth plate chondrocytes in vivo and in vitro, and it was accompanied by enhanced Ihh and PTHrP signaling. Dicam was localized to primary cilia of chondrocytes, and increased the number of primary cilia and their assembly molecule, IFT88/Polaris as well. Dicam successfully rescued the knock-down phenotype of IFT88/Polaris and it was accompanied by increased number of cilia in tibia organ culture. CONCLUSION: These findings suggest that Dicam positively regulates primary cilia and Ihh signaling resulting in elongation of long bone. PMID- 29702221 TI - Challenges in the local delivery of peptides and proteins for oral mucositis management. AB - Oral mucositis, a common inflammatory side effect of oncological treatments, is a disorder of the oral mucosa that can cause painful ulcerations, local motor disabilities, and an increased risk of infections. Due to the discomfort it produces and the associated health risks, it can lead to cancer treatment restrains, such as the need for dose reduction, cycle delays or abandonment. Current mucositis management has low efficiency in prevention and treatment. A topical drug application for a local action can be a more effective approach than systemic routes when addressing oral cavity pathologies. Local delivery of growth factors, antibodies, and anti-inflammatory cytokines have shown promising results. However, due to the peptide and protein nature of these novel agents, and the several anatomic, physiological and environmental challenges of the oral cavity, their local action might be limited when using traditional delivering systems. This review is an awareness of the issues and strategies in the local delivery of macromolecules for the management of oral mucositis. PMID- 29702222 TI - Pressure support ventilation vs Continuous positive airway pressure for treating of acute cardiogenic pulmonary edema: A pilot study. AB - Non-invasive ventilation is usually adopted as a support to medical therapy in patients with acute pulmonary edema, but which modality between Pressure Support Ventilation (PSV) and Continuous Positive Airway Pressure (CPAP) has better favourable effects is not been yet well known. Aim of this observational study was to provide data on these different non-invasive ventilation modalities in the management of acute cardiogenic pulmonary edema. One-hundred-fifty-three patients consecutively admitted to the Emergency Room of two different Center were enrolled and randomly assigned to CPAP or PSV. Data relative to mortality, need of endotracheal intubation, sequential blood gas analysis were compared. Furthermore, there were no significant differences regarding mortality in the two groups, but patients treated with PSV had a significant lower rate of endotracheal intubation and a higher improvement of blood gas analyses parameters. In conclusion, our data support only a slight advantage in favour to PSV versus CPAP. PMID- 29702224 TI - SigEMD: A powerful method for differential gene expression analysis in single cell RNA sequencing data. AB - Differential gene expression analysis is one of the significant efforts in single cell RNA sequencing (scRNAseq) analysis to discover the specific changes in expression levels of individual cell types. Since scRNAseq exhibits multimodality, large amounts of zero counts, and sparsity, it is different from the traditional bulk RNA sequencing (RNAseq) data. The new challenges of scRNAseq data promote the development of new methods for identifying differentially expressed (DE) genes. In this study, we proposed a new method, SigEMD, that combines a data imputation approach, a logistic regression model and a nonparametric method based on the Earth Mover's Distance, to precisely and efficiently identify DE genes in scRNAseq data. The regression model and data imputation are used to reduce the impact of large amounts of zero counts, and the nonparametric method is used to improve the sensitivity of detecting DE genes from multimodal scRNAseq data. By additionally employing gene interaction network information to adjust the final states of DE genes, we further reduce the false positives of calling DE genes. We used simulated datasets and real datasets to evaluate the detection accuracy of the proposed method and to compare its performance with those of other differential expression analysis methods. Results indicate that the proposed method has an overall powerful performance in terms of precision in detection, sensitivity, and specificity. PMID- 29702223 TI - An integrative approach to investigate the association among high-sensitive C reactive protein, body fat mass distribution, and other cardiometabolic risk factors in young healthy women. AB - Prior research has indicated that as an important biomarker of chronic low-grade inflammation, high-sensitivity C-reactive protein (hs-CRP) can play important roles on the onset of metabolic syndrome and cardiovascular diseases (CVD). We conducted an integrative approach, which combines biological wet-lab experiments, statistical analysis, and semantics-oriented bioinformatics & computational analysis, to investigate the association among hs-CRP, body fat mass (FM) distribution, and other cardiometabolic risk factors in young healthy women. Research outcomes in this study resulted in two novel discoveries. Discovery 1: There are four primary determinants for hs-CRP, i.e., central/abdominal FM (a.k.a. trunk FM) accumulation, leptin, high density lipoprotein cholesterol (HDL C), and plasminogen activator inhibitior-1 (PAI-1). Discovery 2: Chronic inflammation may involve in adipocyte-cytokine interaction underlying the metabolic derangement in healthy young women. PMID- 29702225 TI - LC/MS at the whole protein level: Studies of biomolecular structure and interactions using native LC/MS and cross-path reactive chromatography (XP-RC) MS. AB - Interfacing liquid chromatography (LC) with electrospray ionization (ESI) to enable on-line MS detection had been initially implemented using reversed phase LC, which in the past three decades remained the default type of chromatography used for LC/MS and LC/MS/MS studies of protein structure. In contrast, the advantages of other types of LC as front-ends for ESI MS, particularly those that allow biopolymer higher order structure to be preserved throughout the separation process, enjoyed relatively little appreciation until recently. However, the past few years witnessed a dramatic surge of interest in the so-called "native" (with "non-denaturing" being perhaps a more appropriate adjective) LC/MS and LC/MS/MS analyses within the bioanalytical and biophysical communities. This review focuses on recent advances in this field, with an emphasis on size exclusion and ion exchange chromatography as front-end platforms for protein characterization by LC/MS. Also discussed are the benefits provided by the integration of chemical reactions in the native LC/MS analyses, including both ion chemistry in the gas phase (e.g., limited charge reduction for characterization of highly heterogeneous biopolymers) and solution-phase reactions (using the recently introduced technique cross-path reactive chromatography). PMID- 29702227 TI - Engineering expression and function of membrane proteins. AB - Membrane proteins are involved in a diverse array of cellular functions and part of many important metabolic pathways. As such, they are attractive targets in the pharmaceutical and bio-based chemical industries. Despite their great potential, many challenges remain before membrane proteins gain widespread success in biotechnology. The two biggest issues are that expression of membrane proteins leads to inhibition of cellular growth and metabolism, and native membrane proteins often lack a desired function or specificity for use in engineered processes. To address these issues, protein engineering and synthetic biology approaches are leading the charge to develop membrane proteins for biotechnological applications. Here, we describe current methods for engineering membrane proteins and optimizing their expression levels in bacteria. We highlight success stories and describe challenges that still face this growing field. PMID- 29702226 TI - Hidden motions and motion-induced invisibility: Dynamics-based spectral editing in solid-state NMR. AB - Solid-state nuclear magnetic resonance (ssNMR) spectroscopy enables the structural characterization of a diverse array of biological assemblies that include amyloid fibrils, non-amyloid aggregates, membrane-associated proteins and viral capsids. Such biological samples feature functionally relevant molecular dynamics, which often affect different parts of the sample in different ways. Solid-state NMR experiments' sensitivity to dynamics represents a double-edged sword. On the one hand, it offers a chance to measure dynamics in great detail. On the other hand, certain types of motion lead to signal loss and experimental inefficiencies that at first glance interfere with the application of ssNMR to overly dynamic proteins. Dynamics-based spectral editing (DYSE) ssNMR methods leverage motion-dependent signal losses to simplify spectra and enable the study of sub-structures with particular motional properties. PMID- 29702228 TI - Cryo-electron microscopy of membrane proteins. AB - Membrane proteins represent a large proportion of the proteome, but have characteristics that are problematic for many methods in modern molecular biology (that have often been developed with soluble proteins in mind). For structural studies, low levels of expression and the presence of detergent have been thorns in the flesh of the membrane protein experimentalist. Here we discuss the use of cryo-electron microscopy in breakthrough studies of the structures of membrane proteins. This method can cope with relatively small quantities of sample and with the presence of detergent. Until recently, cryo-electron microscopy could not deliver high-resolution structures of membrane proteins, but recent developments in transmission electron microscope technology and in the image processing of single particles imaged in the microscope have revolutionized the field, allowing high resolution structures to be obtained. Here we focus on the specific issues surrounding the application of cryo-electron microscopy to the study of membrane proteins, especially in the choice of a system to keep the protein soluble. PMID- 29702230 TI - Adverse events of fluoroquinolones vs. other antimicrobials prescribed in primary care: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Fluoroquinolones (FQs) are second-line antimicrobial agents. Once the decision to prescribe an antimicrobial is made, the choice of antimicrobial should be based on both the benefits and adverse effects. This systematic review quantifies the occurrence of common adverse events (AEs) related to FQs in relation to any other antimicrobial for any indication in primary care. METHODS: We searched randomized controlled trials from Embase, PubMed, Cochrane Central Register of Controlled Trials and CINHAL. FQs had to be administered orally, for any indication, to adults and in primary care. Data were extracted independently in standard forms in "Covidence". Pooled estimates of the intervention effects for AEs were determined by the Peto odds ratios (ORs) and 95% confidence intervals (CIs) in Revman. RESULTS: In the 39 studies selected, the most commonly reported AEs were nausea, vomiting, diarrhoea, headache, dizziness, and rash. A meta-analysis of 28 studies reporting AEs showed central nervous system (CNS) related AEs (OR 1.40 (1.12-1.75) P = 0.003, heterogeneity (I2) = 0%) and gastrointestinal (GI)-related AEs (OR 1.20 (1.06-1.36) P = 0.005, I2 = 80%) were significantly associated with FQs compared with other antimicrobials. Compared with FQs, co-amoxiclav showed significantly more total AEs (OR 0.70 (0.54-0.90) P = 0.006, I2 = 78%) and GI-related AEs (OR 0.69 (0.52-0.91) P = 0.008, I2 = 94%). Withdrawal or discontinuation due to drug-related AEs was higher for FQs (OR 1.19 (1.00-1.42) P = 0.05, I2 = 5%). Sensitivity analyses did not change these results. CONCLUSION: FQs are associated with more CNS- and GI-related AEs compared with other types of antimicrobial. This information is relevant to support decision making in relation to antimicrobial prescribing. PMID- 29702229 TI - MAP kinase Slt2 orthologs play similar roles in conidiation, trap formation, and pathogenicity in two nematode-trapping fungi. AB - Mitogen-activated protein (MAP) kinase Slt2 is a key player in the cell-wall integrity pathway of budding yeast. In this study, we functionally characterized Slt2 orthologs AoSlt2 and MhSlt2 from the nematode-trapping fungi Arthrobotrys oligospora and Monacrosporium haptotylum, respectively. We found that disruption of AoSlt2 and MhSlt2 led to reduced mycelial growth, increased sensitivity to environmental stresses such as sodium dodecyl sulfate, Congo red, and H2O2, and an inability to produce conidia and nematode-trapping structures. Real-time polymerase chain reaction-based analyses showed that the transcription of sporulation-related (AbaA, Sep2, and MedA) and cell wall synthesis-related (Chs, Glu, and Gfpa) genes was down-regulated in the mutants compared with the wild type strains. Moreover, the mutant strains showed reduced extracellular proteolytic activity and decreased transcription of three homologous serine protease-encoding genes. These results show for the first time that MAP kinase Slt2 orthologs play similar roles in regulating mycelial growth, conidiation, trap formation, stress resistance, and pathogenicity in the divergent nematode trapping fungal species A. oligospora and M. haptotylum. PMID- 29702231 TI - Molecular simulations for amorphous drug formulation: Polymeric matrix properties relevant to hot-melt extrusion. AB - In the present study molecular modelling was used to evaluate polymeric drug carrier matrix properties suitable for hot-melt extrusion (HME). Specifically, the effect of three commonly used plasticizers, namely, citric acid (CA), triethyl citrate (TEC) and polyethylene glycol (PEG), on Soluplus(r) (polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, SOL) properties were evaluated with the aid of classical molecular dynamics (MD) and docking simulations. Differential scanning calorimetry (DSC) and ATR-FTIR spectroscopy of polymer-plasticizer mixtures were used to experimentally verify the in silico predictions. Computed Tg value by MD simulations for SOL was in reasonable agreement with the experimentally determined Tg value (72.0 vs. 69.4 degrees C, for MD and DSC measurement, respectively). Solubility parameter calculations with the aid of MD simulations along with calculated molecular lipophilicity potential interaction (MLPI) scores based on molecular docking, suggested component miscibility only in the case of SOL and PEG. This was verified by a positive deviation of the Tg values determined by DSC, compared to the Gordon-Taylor theoretical predictions. Additionally, the calculated MLPI scores suggested strong interactions between SOL and PEG, verified also by ATR FTIR. Finally, MD simulations of the hydration process suggested strong hydrogen bonding between SOL - CA, and CA - water molecules. PMID- 29702232 TI - Biopharmaceutical evaluation of surface active ophthalmic excipients using in vitro and ex vivo corneal models. AB - The objective of this study was to systematically investigate the effects of surface active ophthalmic excipients on the corneal permeation of ophthalmic drugs using in vitro (HCE-T cell-based model) and ex vivo (freshly excised porcine cornea) models. The permeation of four ophthalmic drugs (i.e., timolol maleate, chloramphenicol, diclofenac sodium and dexamethasone) across in vitro and ex vivo corneal models was evaluated in the absence and presence of four commonly used surface active ophthalmic excipients (i.e., Polysorbate 80, Tyloxapol, Cremophor(r) EL and Pluronic(r) F68). The concentration and self aggregation-dependent effects of surface active ophthalmic excipients on ophthalmic drug permeability were studied from the concentration region where only dissolved monomer molecules of surface active ophthalmic excipients exist, as well as the concentration region in which aggregates of variable size and dispersion are spontaneously formed. Neither the surface active ophthalmic excipients nor the ophthalmic drugs at all concentrations that were tested significantly affected the barrier properties of both corneal models, as assessed by transepithelial electrical resistance (TEER) monitoring during the permeability experiments. The lowest concentration of all investigated surface active ophthalmic excipients did not significantly affect the ophthalmic drug permeability across both of the corneal models that were used. For three ophthalmic drugs (i.e., chloramphenicol, diclofenac sodium and dexamethasone), depressed in vitro and ex vivo permeability were observed in the concentration range of either Polysorbate 80, Tyloxapol, Cremophor(r) EL or Pluronic(r) F68, at which self-aggregation is detected. The effect was the most pronounced for Cremophor(r) EL (1 and 2%, w/V) and was the least pronounced for Pluronic(r) F68 (1%, w/V). However, all surface active ophthalmic excipients over the entire concentration range that was tested did not significantly affect the in vitro and ex vivo permeability of timolol maleate, which is the most hydrophilic ophthalmic drug that was investigated. The results of the dynamic light scattering measurements point to the association of ophthalmic drugs with self-aggregates of surface active ophthalmic excipients as the potential mechanism of the observed permeability-depressing effect of surface active ophthalmic excipients. A strong and statistically significant correlation was observed between in vitro and ex vivo permeability of ophthalmic drugs in the presence of surface active ophthalmic excipients, which indicates that the observed permeability-altering effects of surface active ophthalmic excipients were comparable and were mediated by the same mechanism in both corneal models. PMID- 29702233 TI - Molecular dynamics, physical and thermal stability of neat amorphous amlodipine besylate and in binary mixture. AB - In this paper, a stable amorphous solid dispersion of an antihypertensive drug, amlodipine besylate (AMB) was prepared by entrapping it in a polymer matrix, polyvinyl pyrrollidone, in different weight ratios (AMB/PVP 05:95, 10:90, 20:80, 30:70). The glass forming ability of all binary dispersions were studied by means of differential scanning calorimetry and found good correlation between experimental Tg and Fox Flory's prediction. By considering the daily dosage limit of 5 mg, a weight ratio of 05:95 was further considered for the study. The structures of neat and binary of AMB were characterized by density functional theory, Fourier transform infrared spectroscopy, Fourier transform Raman spectroscopy and UV-visible spectroscopy. Further, detailed molecular dynamics of both pure and binary were investigated using broadband dielectric spectroscopy to judge the physical stability of the amorphous dispersions. Translation-rotation coupling of AMB possibly explains the dual conductivity and dipolar nature of the secondary relaxation in neat AMB. Thus, the binary dispersion of AMB with commercially acceptable weight ratio with strong glass forming behaviour and better shelf life was prepared and characterized for practical applications. PMID- 29702234 TI - Immuno-protective role of biologically synthesized dietary selenium nanoparticles against multiple stressors in Pangasinodon hypophthalmus. AB - An environment friendly and sustainable approach is being emerged in the area of nanotechnology for accelerated growth and development of culturable aquatic animals hence green chemistry is gaining momentum in recent years. The present study has been carried out to delineate the effects of selenium nanoparticles (Se NPs) on growth performance, antioxidative status and immunity of fish reared under lead (Pb) and high temperature (34 degrees C). Three hundred and fifteen fish were equally distributed in seven treatments in triplicates. Three isocaloric and isonitrogenous experimental diets viz. control (Se-NPs-0 mg/kg), Se-NPs at 1 mg/kg and Se-NPs at 2 mg/kg were formulated. The fish were reared under lead (Pb, 1/21st of LC50 (4 ppm)) and high temperature (34 degrees C) stress and fed with or without dietary Se-NPs. The effects of dietary Se-NPs were studied in terms of growth performance (Weight gain %, feed conversion ratio, protein efficiency ratio and specific growth rate), antioxidative status (catalase, superoxide dismutase, glutathione-S-transferase and glutathione peroxidase), neurotransmitter enzymes (AChE), stress biomarkers (heat shock protein 70, serum cortisol, blood glucose, vitamin C), immunological status (total protein, A/G ratio and respiratory burst activity) in Pangasinodon hypophthalmus post challenge with Aeromonas veronii biovar sobria. Results of the investigation demonstrated significant improvement of growth performance, antioxidative status, neurotransmitter enzyme activity, stress markers and more importantly enhanced immunity of the fish with dietary incorporation of Se-NPs at 1 mg/kg. In addition, post bacterial infection, the relative % survival increased and cumulative mortality % decreased in the group fed with Se-NPs at 1 mg/kg diet. Pb and high temperature treated and fed with control diet group showed devastating impact on the growth performance, antioxidative status, stress markers and immunity of the fish. Similarly, application of Se-NPs at 2 mg/kg showed poor growth performance and elevated level of oxidative stress and other stress biomarkers including other biochemical attributes. Inclusive results indicated that, Se-NPs at 1 mg/kg has capability to enhance overall performance and alleviate multiple stresses in P. hypophthalmus. Hence, Se-NPs at optimum level have ability to develop green chemistry in feed industry for better growth performance of the fish. PMID- 29702235 TI - Inositol-requiring enzyme 1 involved in regulating hemocyte apoptosis upon heat stress in Patinopecten yessoensis. AB - The inositol-requiring enzyme 1 (IRE1), one of the primary endoplasmic reticulum (ER) transmembrane receptor proteins, is involved in regulating unfolded protein response (UPR) signaling pathway and plays an import role in maintaining cell homeostasis. In the present study, an IRE1 homologue was identified from Patinopecten yessoensis (designated as PyIRE1). The cDNA of PyIRE1 was of 3314 bp with a 2646 bp open reading frame (ORF) of IRE1 encoding a polypeptide of 881 amino acids. There was a signal peptide, four pyrrolo-quinoline quinine (PPQ) domains, a transmembrane helix region, a Serine/Threonine protein kinases domain (S_TKc) and a protein kinases or N-glycanases containing protein domain (PUG) in the deduced amino acid sequence of PyIRE1. The PyIRE1 mRNA was constitutively expressed in all the tested tissues, with the highest expression level in gills. PyIRE1 protein was mainly located in the ER of P. yessoensis hemocytes. The expression profiles of PyIRE1, glucose-regulated protein 94 (designated as PyGRP94) and glucose-regulated protein 78 (designated as PyGRP78) were determined by SYBR Green qRT-PCR after heat shock treatment. The mRNA expression levels of all these three genes were significantly up-regulated and reached their peak values at 2 h (3.97-fold, p < 0.05), 8 h (19.67-fold, p < 0.05) and 4 h (27.37 fold, p < 0.05) in hemocytes, 2 h (3.55-fold, p < 0.05), 12 h (8.58-fold, p < 0.05) and 8 h (35.31-fold, p < 0.05) in gills after heat shock treatment, respectively. After the injection with PyIRE1 dsRNA, the mRNA expression of pro apoptotic B-cell lymphoma-2 (Bcl-2) family member PyBax and the activity of caspase-3 significantly decreased in comparison with the control group (p < 0.05) after heat shock treatment. These results collectively suggested that PyIRE1, as an ER stress sensor, was potentially involved in the response upon heat stress by regulating the expression of PyBax and apoptosis of hemocytes in P. yessoensis. PMID- 29702236 TI - Probiotic potential of Bacillus velezensis JW: Antimicrobial activity against fish pathogenic bacteria and immune enhancement effects on Carassius auratus. AB - This study evaluated the probiotic potential of B. velezensis JW through experimental and genomic analysis approaches. Strain JW showed antimicrobial activity against a broad range of fish pathogenic bacteria including Aeromonas hydrophila, Aeromonas salmonicida, Lactococcus garvieae, Streptococcus agalactiae, and Vibrio Parahemolyticus. Fish (Carassius auratus) were fed with the diets containing 0 (control), 107, and 109 cfu/g of B. velezensis JW for 4 weeks. Various immune parameters were examined at 1, 2, 3, and 4 weeks of post feeding. Results showed that JW supplemented diets significantly increased acid phosphatase (ACP), alkaline phosphatase (AKP), and glutathione peroxidase (GSH PX) activity. The mRNA expression of immune-related genes in the head kidney of C. auratus was measured. Among them, the interferon gamma gene (IFN- gamma) and tumor necrosis factor-alpha (TNF-alpha) showed higher expression after 3 and 4 weeks of feeding (P < 0.05). The expression of interleukin-1 (IL-1) only being significantly upregulated by 109 cfu/g of JW after 1 week of feeding (P < 0.05). The upregulation of interleukin-4 (IL-4) increased over time from 1st to 4th week. The expression of interleukin-10 (IL-10) and interleukin-12 (IL-12) showed an opposite expression pattern with IL-10 significantly upregulated and IL-12 significantly downregulated by JW containing diets at 2, 3, and 4 weeks of post feeding (P < 0.05). Moreover, fish fed with JW supplemented diets showed significantly improved survival rate after A. hydrophila infection. The analysis of the genome of JW revealed several features aiding host health and being relevant to the GIT adaptation. Four bacteriocins, three Polyketide Synthetase (PKS), and five Nonribosomal Peptide-Synthetase (NRPS) gene clusters were identified in the genome. In summary, the above results clearly proved that B. velezensis JW has the potential to be developed as a probiotic agent in aquaculture. PMID- 29702237 TI - Molecular characterization and functional analysis of two phospholipid hydroperoxide isoforms from Larimichthys crocea under Vibrio parahaemolyticus challenge. AB - Glutathione peroxidases family is a key role in the antioxidant system in oxybiotic organisms for cell redox homeostasis. One of their members, phospholipid hydroperoxide glutathione peroxidase (GPx4) have unique monomeric structure and can directly react with complex lipid and membrane-bound peroxides under the presence of glutathione(GSH). In this paper, two complete GPx4 cDNAs (designated as LcGPx4a and LcGPx4b) from Larimichthys crocea are identified by rapid amplification of cDNA ends. The cDNA of LcGPx4a was consisted of a 5' untranslated region (UTR) of 258 bp, a 3'-UTR of 330 bp, and an open reading frame (ORF) of 561 bp encoding 186 amino acid (aa) polypeptides. And the full length sequence of LcGPx4b was 1164 bp with a 5'-UTR of 34 bp, a 3'-UTR of 551 bp and an ORF of 576 bp encoding a polypeptide of 191 aa residues with a predicted signal peptide of 15 aa. The characteristic selenocysteine insertion (SECIS) sequence was detected in the 3'UTR of the two sequences with 78 bp in length. The conserved active site of selenocysteine (Sec) encoded by TGA was also identified and formed a tetrad functional structure with glutamine, tryptophan, and asparagine in LcGPx4a and LcGPx4b. Two signature site motifs ("LRILAFPSNQFGNQEPG" and "LRILGFPCNQFGGQEPG") were both conserved in the deduced amino acid of LcGPx4a and LcGPx4b. The genomic structure analysis revealed that the two sequences both had 7 exons and 6 introns, and the Sec opal codon and SECIS element were located at the third and seventh exons, respectively. LcGPx4a and LcGPx4b both have a wide distribution in 9 tissues with various relative expression levels and a highest expression pattern in the liver. Under Vibrio parahaemolyticus challenge, their relative expression levels were altered in the liver, spleen, kidney, and head kidney but with different magnitudes and response time. LcGPx4a and LcGPx4b showed a significantly up-regulated trend in the spleen during experimental period. Above results suggested that LcGPx4a and LcGPx4b were two conserved immune molecules and might play a role in the immune response of fish with a tissue-depemdent manners. PMID- 29702238 TI - Adaptive response of pearl oyster Pinctada fucata martensii to low water temperature stress. AB - The pearl oyster Pinctada fucata martensii is a warm-water shellfish that is sensitive to cold environments. To investigate its potential adaptation to low temperature stress, the selected line (SL) and based population (BP) were sampled to undergo transcriptome sequence. Results of transcriptome analysis showed 572 significant differentially expressed genes. The typical HSP70 and HSP40 exhibited the polar expression model in the two groups. Meanwhile, the related genes that involved in energy release mediated by oxidative phosphorylation and the biosynthesis of unsaturated fatty acid were increased in the SL. The apparent enrichment of different expressed genes in amino acid metabolism indicated that the small molecule system with amino acids was one of the main regulator for low temperature stress. The different expressions of immune-related and lysosome protein encoding genes also reflected the variation of immunity in the two groups and indicated that it could affect the adaptation ability in different temperature. In addition, the similar trends of different expression of typical genes between two groups were obtained by using RNA-seq and qRT-PCR. These results suggested that multi-system adjustments are involved in the processes of low water temperature stress in pearl oyster, providing insights into the response systems of shellfish to acclimatise with ambient environment change. PMID- 29702239 TI - Immuno-related gene transcription and antibody response in nodavirus (RGNNV and SJNNV)-infected European sea bass (Dicentrarchus labrax L.). AB - The immune response of European sea bass to RGNNV and SJNNV infections has been evaluated by quantifying the transcription of some genes involved in the IFN I system, as well as in the inflammatory and adaptive immune mechanisms. The transcription of IFN-I, ISG-12, ISG-15 and MxA genes has been analyzed in brain and head kidney, showing that RGNNV genotype induces a more intense response of the IFN I system than SJNNV in both organs. In addition, the results obtained indicate the importance of the inflammatory response in nodavirus pathogenesis, with the transcription of IL-8 and TNF-alpha significantly higher in brain than in head kidney, being RGNNV the strongest inductor. An important difference between the immune response induced by both genotypes refers to the IgM titre in sera, which was higher in SJNNV-inoculated fish. The acquired response is also important locally, since TR-gamma transcription is higher in brain than in head kidney (especially in the RGNNV-inoculated group). To our knowledge, this is the first study addressing the sea bass anti-SJNNV immune response. PMID- 29702240 TI - Redox-responsive microbeads containing thiolated pectin-doxorubicin conjugate inhibit tumor growth and metastasis: An in vitro and in vivo study. AB - The objective of this study was to investigate the in vitro cytotoxicity and in vivo anticancer efficacy of redox-responsive microbeads containing thiolated pectin-doxorubicin (DOX) conjugate. Oral microbeads were coated with an enteric polymer to protect the drug from release in the upper gastrointestinal (GI) tract and allow redox-triggered drug release in the colon. Morphology, particle size, drug content, and in vitro drug release behavior of the microbeads were characterized; in vitro cytotoxicity was tested on mouse colon carcinoma, human colorectal adenocarcinoma, and human bone osteosarcoma cell lines. In vivo anticancer efficacy of coated microbeads was examined in BALB/c mice with murine colon carcinoma. These coated microbeads significantly inhibited the growth of all cell lines. The in vivo study confirmed delivery of DOX to the colorectal tumor site, redox-responsiveness, and anticancer efficacy of coated microbeads. Coated microbeads also effectively inhibited primary tumor growth and suppressed tumor metastases without gross toxicity to the non-target tissue. No noticeable damage was found in mouse GI tissues, indicating lack of DOX toxicity. These novel coated microbeads containing thiolated pectin-DOX conjugate may be a promising vehicle for targeted clinical delivery of DOX to the colorectal cancer site by oral administration. PMID- 29702241 TI - Enhanced biopharmaceutical effects of tranilast on experimental colitis model with use of self-micellizing solid dispersion technology. AB - The present study aimed to clarify the applicability of a self-micellizing solid dispersion of tranilast (SMSD/TL) to the treatment of inflammatory bowel diseases (IBD) using an experimental colitis model. SMSD/TL with several loading amounts ranging from 10 to 50% was prepared using a wet-milling system. The physicochemical properties of SMSD/TL were evaluated in terms of the dissolution behavior, morphology, and particle size distribution. Animal studies were conducted to evaluate oral bioavailability in rats and anti-inflammatory effects in a rat model of chemically induced colitis. SMSD/TL with drug loading of 15% (SMSD/TL15) showed enhanced dissolution behavior at pH 1.2, compared with other tested other formulations. After the dispersion of SMSD/TL15 in deionized water, fine micelles formed with an average diameter of 137 nm. SMSD/TL15 (10 mg-TL/kg) exhibited about 147- and 34-fold greater value for Cmax and the area under the curve of plasma concentration vs. time than crystalline TL, respectively. Although the anti-inflammatory effect on the colitis model was very limited in the crystalline TL (2 mg/kg) group, inflammatory events, such as myeloperoxidase activity and thickening of the submucosa in colon tissues, were significantly suppressed in the SMSD/TL15 (2 mg-TL/kg) group. Based on these findings, SMSD/TL might be a more efficacious dosage option for improved IBD treatment. PMID- 29702242 TI - Long-term maintenance of luteinizing hormone-responsive testosterone formation by primary rat Leydig cells in vitro. AB - The inability of cultured primary Leydig cells to maintain luteinizing hormone (LH)-responsive testosterone formation in vitro for more than 3-5 days has presented a major challenge in testing trophic effects of regulatory factors or environmental toxicants. Our primary objective was to establish culture conditions sufficient to maintain LH-responsive testosterone formation by Leydig cells for at least a month. When isolated rat adult Leydig cells were cultured in DMEM/F12 and M199 culture medium containing insulin (10MUg/ml), PDGFAA (10 ng/ml), lipoprotein (0.25 mg/ml), horse serum (1%) and a submaximal concentration of LH (0.2 ng/ml), the cells retained the ability to produce testosterone in vitro for at least 4 weeks. By using the longer-term culture conditions of this system, we were able to detect suppressive effects on testosterone production by low levels of the toxicant MEHP (mono-(2-ethylhexyl) phthalate), an active metabolite of the plasticizer DEHP, that were not detected by short-term culture. PMID- 29702243 TI - Differential susceptibility of whitefly-associated bacteria to antibiotic as revealed by metagenomics analysis. AB - BACKGROUND: Recent reports have suggested that different symbionts of Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) have differential susceptibility to antibiotic treatment. Changes in the community structure of B. tabaci-associated bacterial microbiota (BABM) following antibiotic treatment, however, remain poorly understood, although increasing numbers of B. tabaci-associated bacteria have been reported in recent years. METHODOLOGY AND RESULTS: The BABM of male or female B. tabaci Q (also known as B. tabaci MED species) were analyzed after being fed on artificial diet containing the antibiotic rifampicin and compared with untreated controls. The bacterial 16S rDNA gene amplicon metagenomic sequencing method was used in the analyses. The results showed that the BABM in male and female adults have different characteristics, and that the community structure of the BABM changes drastically following antibiotic treatment. Further analysis of the endosymbionts in B. tabaci showed that the relative abundance of the primary endosymbiont, Portiera, increased in females but was unchanged in male whiteflies, while that of the secondary endosymbiont, Hamiltonella, significantly decreased in both male and female whiteflies. The secondary endosymbionts, Cardinium and Rickettsia, were apparently not affected in either male or female whiteflies. CONCLUSIONS: The community structure of BABM can be drastically altered following treatment with the antibiotic, rifampicin. This may be due to different antibiotic susceptibilities among the bacterial species. These results provide valuable insights into the innate differences in the BABM of male and female whiteflies, as well as structural changes that occur in the BABM in response to exposure to an antibiotic. PMID- 29702244 TI - Hydroxysteroid dehydrogenase family proteins on lipid droplets through bacteria, C. elegans, and mammals. AB - Lipid droplets (LDs) are the main fat storing sites in almost all species from bacteria to humans. The perilipin family has been found as LD proteins in mammals, Drosophila, and a couple of slime molds, but no bacterial LD proteins containing sequence conservation were identified. In this study, we reported that the hydroxysteroid dehydrogenase (HSD) family was found on LDs across all organisms by LD proteomic analysis. Imaging experiments confirmed LD targeting of three representative HSD proteins including ro01416 in RHA1, DHS-3 in C. elegans, and 17beta-HSD11 in human cells. In C. elegans, 17beta-HSD11 family proteins (DHS 3, DHS-4 and DHS-19) were localized on LDs in distinct tissues. In intestinal cells of C. elegans, DHS-3 targeted to cytoplasmic LDs, while DHS-9 labeled nuclear LDs. Furthermore, the N-terminal hydrophobic domains of 17beta-HSD11 family were necessary for their targeting to LDs. Last, 17beta-HSD11 family proteins induced LD aggregation, and deletion of DHS-3 in C. elegans caused lipid decrease. Independent of their presumptive catalytic sites, 17beta-HSD11 family proteins regulated LD dynamics and lipid metabolism through affecting the LD associated ATGL, which was conserved between C. elegans and humans. Together, these findings for HSDs provide a new insight not only into the mechanistic studies of the dynamics and functions of LDs in multiple organisms, but also into understanding the evolutionary history of the organelle. PMID- 29702245 TI - Female mice carrying a defective Alox15 gene are protected from experimental colitis via sustained maintenance of the intestinal epithelial barrier function. AB - Lipoxygenases (ALOXs) are involved in the regulation of cellular redox homeostasis. They also have been implicated in the biosynthesis of pro- and anti inflammatory lipid mediators and play a role in the pathogenesis of inflammatory diseases, which constitute a major health challenge owing to increasing incidence and prevalence in all industrialized countries around the world. To explore the pathophysiological role of Alox15 (leukocyte-type 12-LOX) in mouse experimental colitis we tested the impact of systemic inactivation of the Alox15 gene on the extent of dextrane sulfate sodium (DSS) colitis. We found that in wildtype mice expression of the Alox15 gene was augmented during DSS-colitis while expression of other Alox genes (Alox5, Alox15b) was hardly altered. Systemic Alox15 (leukocyte-type 12-LOX) deficiency induced less severe colitis symptoms and suppressed in vivo formation of 12-hydroxyeicosatetraenoic acid (12-HETE), the major Alox15 (leukocyte-type 12-LOX) product in mice. These alterations were paralleled by reduced expression of pro-inflammatory gene products, by sustained expression of the zonula occludens protein 1 (ZO-1) and by a less impaired intestinal epithelial barrier function. These results are consistent with in vitro incubations of colon epithelial cells, in which addition of 12S-HETE compromised enantioselectively transepithelial electric resistance. Consistent with these data transgenic overexpression of human ALOX15 intensified the inflammatory symptoms. In summary, our results indicate that systemic Alox15 (leukocyte-type 12-LOX) deficiency protects mice from DSS-colitis. Since exogenous 12-HETE compromises the expression of the tight junction protein ZO-1 the protective effect has been related to a less pronounced impairment of the intestinal epithelial barrier function. PMID- 29702247 TI - Young mothers and higher incidence of maternal meiosis-I non- disjunction: Interplay of environmental exposure and genetic alterations during halt phase in trisomy 21. AB - Trisomy 21 is a genetic condition caused when chromosomes fail to separate during meiosis. We have studied conventional karyotype and QF-PCR using STR markers with high polymorphism and heterogeneity and the results were analyzed, to determine the paternal and meiotic origin of trisomy 21. This study was conducted using a detailed questionnaire to include: paternal, maternal, clinical and family history for various confounding factors such as age and regional environmental exposures where the parents resided. Out of 120 samples 95% (N = 114) were of maternal origin, including 92% (N = 105) of meiosis 1 errors and 8% (N = 9) meiosis 2 errors. Paternal origin accounted for 5% (N = 6) and were all due to meiosis-I errors. The higher incidence of maternal meiosis-I observed in the present study suggests that human trisomy 21 non-disjunction is a result of multiple factors contributing to the origin of the genetic condition. PMID- 29702246 TI - Placental lipid droplet composition: Effect of a lifestyle intervention (UPBEAT) in obese pregnant women. AB - Maternal obesity is associated with adverse outcomes. Placental lipid droplets (LD) have been implicated in maternal-fetal lipid transfer but it is not known whether placental LD fat composition is modifiable. We evaluated the effects of a diet and physical activity intervention in obese pregnant women compared to routine antenatal care (UPBEAT study) on placental LD composition. LD were isolated by ultracentrifugation. Total FAs and phospholipids (phosphatidylcholines, PCs; sphingomyelins, SMs and lyso-phosphatidylcholines, Lyso-PCs) were analyzed by LC-MS/MS. Placenta MFSD2a expression was assessed by western blot. Placental LDs from obese women were comprised of predominantly saturated and monounsaturated FAs. TG and Chol composition was similar between intervention (n = 20) and control (n = 23) groups. PCs containing dihomo-gamma linolenic acid in LD were positively associated with gestational weight gain (P < 0.007), and lowered by the intervention. In the whole sample, PCs carrying DHA and arachidonic acid were inversely associated with placental weight. Placenta MFSD2a expression was associated with DHA cord blood metabolites and relationships were observed between LD lipids, especially DHA carrying species, and cord blood metabolites. We describe placenta LD composition for the first time and demonstrate modest, potentially beneficial effects of a lifestyle intervention on LD FAs in obese pregnant women. PMID- 29702249 TI - Nanoreactors: Strategies to encapsulate enzyme biocatalysts in virus-like particles. AB - Enzyme-mediated biocatalysis is generally more selective and environmentally friendly and requires less energy than chemocatalysis. However, factors such as temperature, acidity and the presence of proteases can negate enzyme activity. Encapsulation in virus-like particles is one promising method to mitigate these difficulties. Encapsulation also can be used to create multi-reaction nanoreactors that increase process efficiency by isolating reaction intermediates. To successfully encapsulate enzymes, a variety of methods involving both non-covalent and covalent interactions have been developed. Here we review promising virus-like particle encapsulation strategies, their advantages and remaining challenges. PMID- 29702248 TI - Fertility in male rats: Disentangling adverse effects of arsenic compounds. AB - Arsenic impairs male reproductive functions. However, it is not clear whether different arsenic compounds similarly affect fertility. In this study, we compared the impact of sodium arsenite and arsenate on sperm quality and fertility. After 56 d exposure, male Wistar rats were mated and pregnant females were evaluated by fertility indexes. Clearly, exposure to 10 mg/L arsenite reduced daily sperm production via H2O2 overproduction and germ cells loss. Animals from this group also showed a decrease in epididymal sperm counts and percentage of sperm with intact membranes. Moreover, they presented low fertility potential and high preimplantation loss. In contrast, 10 mg/L arsenate caused oxidative stress in testis, mineral imbalance in epididymis, and sperm membranes damage, with no effects on fertility. Both arsenic compounds at 0.01 mg/L altered reproductive parameters. We concluded that arsenite is more harmful than arsenate to sperm quality and male fertility, with negative influences in early pregnancy. PMID- 29702250 TI - Type 2 diabetes impairs angiogenesis and osteogenesis in calvarial defects: MicroCT study in ZDF rats. AB - OBJECTIVES: The present study was motivated by the fact that bone regeneration in the compromised vascular microenvironment of T2DM is challenging and the factors that determine the adverse bone regeneration outcomes are poorly understood. For this purpose the effect of T2DM on osteogenic and angiogenic healing potential of calvarial bone, was evaluated in Zucker diabetic fatty (ZDF) rats, an established rat model for obese T2DM. MATERIALS AND METHODS: The study used 16-week-old ZDF rats and their age-matched controls, Zucker Lean (ZL). Circular defects of different sizes were created on the animal calvaria, either a single 8-mm diameter (n = 6) defect, or 6-4-2-mm-diameter multidefects (n = 6). Bone regeneration was evaluated at 0, 4, 6 and 8 weeks post surgery using in vivo micro-CT and after animal sacrifice using ex vivo micro-CT. Vascular network parameters within the defects, were quantified by perfusing the animal vasculature with microfil(r) and scanning it after decalcification. RESULTS: Compared to results obtained from the ZL rats, defects of 8-mm-diameter in ZDF rats displayed impaired healing kinetics and significantly reduced newly formed bone volume (p < 0.01) and surface area (p < 0.01), 8 weeks post surgery. Defects of 6-4-2-mm-diameter exhibited bone formation, which was independent of either the size or the diabetic condition. Compared to results from the ZL, in the ZDF rats, vasculature volume and surface area were significantly (p < 0.05) reduced in all size-defects. CONCLUSION: The present study provided evidence that T2DM impairs bone formation in critical-size calvarial defects and markedly reduces angiogenesis in all defects regardless of the defect size tested. PMID- 29702252 TI - Direct and specific inhibition of constitutive nitric oxide synthase uniquely regulates brush border membrane Na-absorptive pathways in intestinal epithelial cells. AB - Pharmacological manipulations of constitutive nitric oxide (cNO) levels have been shown to have variable effects on Na absorption in vivo and in vitro in different tissues. Species differences, untoward in vivo effects (e.g. ENS, blood flow) and pharmacological non-specificity may account for these confounding observations. Thus, to directly and specifically determine the effect of cNO on brush border membrane Na/H exchange (NHE3) and Na-dependent glucose co-transport (SGLT-1), we inhibited cNO synthase (NOS3) with its siRNA in rat small intestinal epithelial cells (IEC-18) in vitro. As expected, intracellular cNO levels were reduced in siRNA NOS3 transfected cells. In these cells, SGLT-1 was significantly reduced compared to control. In contrast, NHE3 was significantly increased in siRNA NOS3 transfected cells. To determine if SGLT-1 changes were secondary to altered Na/K ATPase, its activity was measured and found to be increased in NOS3 silenced cells. The mechanism of inhibition of SGLT-1 was secondary to diminished affinity of the co-transporter for glucose in NOS3 silenced cells. In contrast, the mechanism of stimulation of NHE3 is by increasing BBM exchanger numbers in siRNA NOS3 cells while the affinity was unaffected. Western blot studies of immunoreactive BBM proteins also confirmed the kinetic studies. All these data indicates that direct and specific inhibition of NOS3 with its siRNA inhibits SGLT-1 while stimulating NHE3 in the BBM. Thus, cNO uniquely and compensatorily regulates BBM NHE3 and SGLT-1 to maintain cellular Na homeostasis and these unique alterations by cNO are mediated by its intracellular 2nd messenger cGMP. PMID- 29702253 TI - Infectious disease profiles of Syrian and Eritrean migrants presenting in Europe: A systematic review. AB - BACKGROUND: In the past decade, a large influx of migrants presented in Europe. Their country of origin was mainly either Syria or Eritrea. Public health institutions in host countries in Europe are challenged to screen and care for migrant populations with regard to infectious diseases. METHODS: We performed a systematic literature review (according to PRISMA guidelines) to define the infectious disease profile of migrants originating in Syria and Eritrea. RESULTS: The search resulted in 825 papers of possible relevance for infectious diseases in migrants from Syria, of which, after screening, we included 35 in the systematic review. A further 265 papers of possible relevance for infectious diseases in Eritrean migrants were screened, of which we included 27 in the systematic review. In migrants from Syria, leishmaniasis was the most frequently reported infectious disease. In addition, colonisation with drug resistant, Gram negativ bacteria was reported. In the Eritrean migrants the infectious disease most described in the selected papers was louse-borne relapsing fever. Other frequently reported infectious diseases were scabies and Plasmodium vivax malaria. CONCLUSION: Our systematic analysis defines the profiles of infectious diseases for migrants from Syria and Eritrea and serves as an evidence base for public health screening and care of presenting migrants. PMID- 29702251 TI - Structure/function of the soluble guanylyl cyclase catalytic domain. AB - Soluble guanylyl cyclase (GC-1) is the primary receptor of nitric oxide (NO) in smooth muscle cells and maintains vascular function by inducing vasorelaxation in nearby blood vessels. GC-1 converts guanosine 5'-triphosphate (GTP) into cyclic guanosine 3',5'-monophosphate (cGMP), which acts as a second messenger to improve blood flow. While much work has been done to characterize this pathway, we lack a mechanistic understanding of how NO binding to the heme domain leads to a large increase in activity at the C-terminal catalytic domain. Recent structural evidence and activity measurements from multiple groups have revealed a low activity cyclase domain that requires additional GC-1 domains to promote a catalytically-competent conformation. How the catalytic domain structurally transitions into the active conformation requires further characterization. This review focuses on structure/function studies of the GC-1 catalytic domain and recent advances various groups have made in understanding how catalytic activity is regulated including small molecules interactions, Cys-S-NO modifications and potential interactions with the NO-sensor domain and other proteins. PMID- 29702254 TI - Despite antibiotic treatment of travellers' diarrhoea, pathogens are found in stools from half of travellers at return. AB - BACKGROUND: Among visitors to the (sub)tropics, 20-50% contract travellers' diarrhoea (TD) and 5-30% take antibiotics. While shortening the duration of illness, antimicrobials predispose to acquisition of multi-drug resistant bacteria. Therefore, liberal use is no longer advocated. Although antibiotics kill pathogens, no data support the view that they could prevent post-infectious sequelae. We investigated how antibiotic use for TD abroad impacts the pathogen findings at return. MATERIALS AND METHODS: We revisited 456 travellers' clinical data and stool pathogens examined by qPCR for Salmonella, Yersinia, Campylobacter, Shigella, Vibrio cholerae and enteroaggregative (EAEC), enteropathogenic (EPEC), enterotoxigenic (ETEC), enterohaemorrhagic (EHEC) and enteroinvasive (EIEC) Escherichia coli. RESULTS: Among travellers with TD, antibiotic users had pathogen-positive samples less frequently than non-users (50% versus 83%). The difference was significant for EPEC (23% versus 47%) and EAEC (27% versus 54%), but not ETEC (17% versus 26%) or the other pathogens. Shigella/EIEC was found more often among antibiotic users than non-users (4% versus 1%). CONCLUSION: Despite antibiotic treatment of TD, half of the users still had stool pathogens at return, reflecting either antibiotic resistance of pathogens or recolonisation/reinfection while abroad. Treatment of TD with antibiotics during travel should not be interpreted to indicate eradication of pathogens. PMID- 29702255 TI - The role of sphingolipid metabolism disruption on lipopolysaccharide-induced lung injury in mice. AB - AIM: This study assessed pulmonary outcomes generated by inhibiting key enzymes of sphingolipid metabolism pathways related to ceramide synthesis in a murine model of lung injury induced by lipopolysaccharide (LPS). METHODS: C57BL/6 male adult mice received LPS intratracheally and the expressions of acid sphingomyelinase (ASM), neutral sphingomyelinase (NSM), serine palmitoyl transferase (SPT) and dihydroceramide synthase (DS) were assessed at 2, 4, 6, 12 and 24 h after LPS instillation in lung homogenate (n = 30). The pharmacological inhibition of ASM, NSM, SPT and DS were assayed in other mice groups by three different doses of desipramine, GW4869, myriocin and fumonisin, respectively (n = 90). Their most effective doses were administered intraperitoneally 1 or 2 h before LPS to different animal groups (n = 120). Mice underwent determination of pulmonary mechanics, lung histopathological aspects and apoptosis. RESULTS: The expression levels of the enzymes reached their peak at 2-4 h after LPS administration. ASM inhibition attenuated alveolar collapse and GW4869 decreased lung elastance, proinflammatory cytokines' levels and was more effective to improve alveolar collapse than desipramine. On the other hand, SPT blockage aggravated lung lesion and no effects it was observed with fumonisin. Moreover, simultaneous administration of inhibitors (desipramine + GW4869, myriocin + fumonisin and all inhibitors together) resulted in no changes. CONCLUSION: Blockage of sphingomyelinases and the de novo pathways improved and aggravated lung injury, respectively, putatively suggesting specific targets to therapeutic strategies in LPS-induced lung injury. PMID- 29702256 TI - Association between activities of SOD, MDA and Na+-K+-ATPase in peripheral blood of patients with acute myocardial infarction and the complication of varying degrees of arrhythmia. AB - OBJECTIVE: To investigate the changes of ambulatory electrocardiography and peripheral blood SOD, MDA and Na+-K+-ATP enzymes in patients of acute myocardial infarction (AMI) complicated with arrhythmia. METHODS: From January 2012 to March 2015, 135 cases AMI complicated with arrhythmia in our hospital were divided into 2 groups: 70 cases in the AMI uncomplicated with arrhythmia and 65 cases in the AMI complicated with arrhythmia. 62 cases volunteers accepted physical examination in our hospital in the same period were collected as the control group. 24 hour-electrocardiogram detected by ambulatory electrocardiogram (AECG), SOD and MDA in peripheral blood detected by diagnostic reagent kit and Na+-K+-ATP enzymes in peripheral blood detected by malachite green Kit Method phosphate determination method were collected. ROC curve was used to evaluate the prognostic value of SOD, MDA and Na+-K+-ATP enzymes in AMI patients. RESULTS: Compared with the control group, the patients had unusual ambulatory electrocardiography had increased (P <0.05), peripheral blood SOD and Na+-K+-ATP enzymes had decreased, peripheral blood MDA had increased in 2 AMI groups (P <0.05). Compared with AMI uncomplicated with arrhythmia group, the patients had unusual ambulatory electrocardiography had increased (P <0.05), peripheral blood SOD and Na+-K+-ATP enzymes had decreased, peripheral blood MDA had increased in AMI complicated with arrhythmia group (P <0.05). Among 135 cases AMI patients, 120 (88.9%) survived and 15 (11.1%) died, of whom 11 cases were AMI complicated with arrhythmia group, 4 cases were AMI uncomplicated with arrhythmia group. Compared with the AMI uncomplicated with arrhythmia group, the dead patients were more in the AMI complicated with arrhythmia group (c2 = 4.287, P = 0.038). Compared with the survival group, the SOD and Na+-K+-ATP enzymes were significantly lower (P <0.05) and MDA significantly higher (P <0.05) in the death group. The area under the ROC curve of SOD, MDA and Na+-K+-ATP enzymes were 0.958, 0.954 and 0.993 respectively, and the cut-off values were 30.66 ng/ml, 576.70 nmol/ml and 57.42 nmol/mgh, respectively. CONCLUSION: Ambulatory electrocardiography has a close relationship with the peripheral blood SOD, MDA and Na+-K+-ATP enzymes in AMI patients complicated with arrhythmia, which might predict AMI condition. PMID- 29702257 TI - Verbal Instruction Can Induce Extinction of Fear of Movement-Related Pain. AB - : The fear avoidance model of chronic musculoskeletal pain highlights the importance of pain-related fear in chronification of pain. Although several interventions have been developed on the basis of this model, the following issues remain unresolved: first, whether movement conditioned to pain can evoke fear responses particularly sympathetic activation, and second, whether verbal instructions can attenuate conditioned fear of movement-related pain as with direct experience. To investigate these issues, we induced proprioceptive conditioning (learning the relationship between proprioceptive sensations and an aversive event) and extinction learning in healthy volunteers, and we compared psychophysiological and subjective indices of fear between an instructed and a normal extinction group. Using paired presentation of painful heat stimuli as an unconditioned stimulus and flexion of the wrist as a conditioned stimulus, all participants acquired the conditioned fear response (skin potential response) to the conditioned stimulus. The instructed extinction group was then told that the movement was no longer followed by painful stimulus at the beginning of the extinction phase, and only this group showed significant decreases on both indices of fear. This finding indicates that verbal instruction can attenuate conditioned fear of movement-related pain, supporting the clinical importance of providing information regarding the relationship between movement and pain. PERSPECTIVE: This article presents evidence that, in a laboratory setting, verbal instructions rapidly decrease conditioned fear of movement-related pain on psychophysiological as well as subjective indices. This result indicates that it is important for chronic musculoskeletal pain patients to precisely understand the relationship between movement and pain in clinical situations. PMID- 29702258 TI - Photodynamic therapy does not induce cyclobutane pyrimidine dimers in the presence of melanin. AB - Photodynamic therapy (PDT) is an office-based treatment for precancerous and early cancerous skin changes. PDT induces cell death through the production of reactive oxygen species (ROS). Cyclobutane pyrimidine dimers (CPDs) are the most important DNA changes responsible for ultraviolet (UV) carcinogenesis. Recently ROS induced by UVA were shown to generate CPDs via activating melanin. This raised the possibility that PDT induced ROS may also induce CPDs and mutagenesis in melanin containing cells. Previously the effect of PDT on CPDs in melanin containing cells has not been assessed. Our current work aimed to compare the generation of CPDs in melanin containing cells subjected to UVA treatment and porfimer sodium red light PDT. We used ELISA to detect CPDs. After UVA we found a dose dependent increase in CPDs in melanoma cells (B16-F10, MNT-1) with CPD levels peaking hours after discontinuation of UVA treatment. This indicated the generation of UVA induced dark-CPDs in the model. Nevertheless, PDT in biologically relevant doses was unable to induce CPDs. Our work provides evidence for the lack of CPD generation by PDT in melanin containing cells. PMID- 29702259 TI - Allopatric speciation of Meteterakis (Heterakoidea: Heterakidae), a highly dispersible parasitic nematode, in the East Asian islands. AB - To clarify how the species diversity of highly dispersible parasites has developed, molecular phylogenetic analyses of Meteterakis spp., multi-host endoparasitic nematodes of reptiles and amphibians from the East Asian islands, were conducted. The results demonstrated the existence of two major clades, the J and A-groups, with exclusive geographic ranges that are discordant with the host faunal province. However, diversification within the J-group was concordant with the host biogeography and suggested co-divergence of this group with vicariance of the host fauna. In contrast, the phylogenetic pattern within the A-group was discordant with host biogeography and implied diversification by repeated colonization. In addition, the mosaic distribution pattern of a J-group and an A group species in the Japanese Archipelago, along with comparison of population genetic parameters and the genetic distance from their closest relatives, suggested the initial occurrence of a J-group lineage followed by exclusion in the western part of this region caused by invasion of an A-group lineage. Thus, the present study suggested that the species diversity of highly dispersible parasites including Meteterakis is formed not only by co-divergence with host faunal vicariance but also by peripatric speciation and exclusive interactions between species. PMID- 29702260 TI - The efficacy and safety of medical leech therapy for osteoarthritis of the knee: A meta-analysis of randomized controlled trials. AB - BACKGROUND: It is controversial on whether medical leech therapy is effective in improving pain and functional outcome in patients with knee osteoarthritis (OA). Therefore, we perform a meta-analysis from randomized controlled trials (RCTs) to evaluate the efficacy and safety of medical leech therapy in patients with knee OA. MATERIALS AND METHODS: The PubMed, EMBASE, ScienceDirect, and Cochrane Library databases were systematically searched for literature up to January 2018. RCTs involving medical leech therapy in patients with knee OA were included. Two independent reviewers performed independent data abstraction. The I2 statistic was used to assess heterogeneity. A fixed or random effects model was adopted for meta-analysis. All meta-analyses were performed by using STATA 12.0. RESULTS: Four RCTs with 264 patients were included in this meta-analysis. The current meta analysis showed that there were significant differences in terms of visual analogue scale (VAS) scores and WOMAC scores at 1 week, 4weeks and 7 weeks compared with control groups. However, leech therapy was associated with a significantly higher incidence of adverse events. The overall evidence quality is moderate, which means that further research is likely to significantly change confidence in the effect estimate but may change the estimate. CONCLUSION: Medical leech therapy was associated with a significantly improved outcome in pain relief and functional recovery in patients with symptomatic knee OA. However, given the inherent limitations in the included studies, this conclusion should be interpreted cautiously. PMID- 29702261 TI - Control of Grain Size and Weight by the OsMKKK10-OsMKK4-OsMAPK6 Signaling Pathway in Rice. AB - Grain size is one of the key agronomic traits that determine grain yield in crops. However, the mechanisms underlying grain size control in crops remain elusive. Here we demonstrate that the OsMKKK10-OsMKK4-OsMAPK6 signaling pathway positively regulates grain size and weight in rice. In rice, loss of OsMKKK10 function results in small and light grains, short panicles, and semi-dwarf plants, while overexpression of constitutively active OsMKKK10 (CA-OsMKKK10) results in large and heavy grains, long panicles, and tall plants. OsMKKK10 interacts with and phosphorylates OsMKK4. We identified an OsMKK4 gain-of function mutant (large11-1D) that produces large and heavy grains. OsMKK4A227T encoded by the large11-1D allele has stronger kinase activity than OsMKK4. Plants overexpressing a constitutively active form of OsMKK4 (OsMKK4-DD) also produce large grains. Further biochemical and genetic analyses revealed that OsMKKK10, OsMKK4, and OsMAPK6 function in a common pathway to control grain size. Taken together, our study establishes an important genetic and molecular framework for OsMKKK10-OsMKK4-OsMAPK6 cascade-mediated control of grain size and weight in rice. PMID- 29702262 TI - Signaling pathways involved in the rapid biphasic effect of aldosterone on Na+/H+ exchanger in rat proximal tubule cells. AB - The receptors and signaling pathways for nongenomic effects of aldosterone (Aldo) on the proximal Na+/H+ exchanger are still unknown; therefore, the aim of this study was to investigate the mineralocorticoid receptor (MR) and/or glucocorticoid receptor (GR) participation in rapid Aldo effects on NHE1 (basolateral Na+/H+ exchanger isoform) and cytosolic calcium concentration ([Ca2+]i). In addition, phospholipase C (PLC), protein kinase C (PKC), and mitogen-activated protein kinase kinase (MEK) involvement in signaling pathways of such effects was evaluated, using immortalized proximal tubule cells of rat (IRPTC) as an experimental model. MR and GR expression was investigated using reverse transcription polymerase chain reaction and immunoblotting. The intracellular pH recovery rate (after acid loading) and [Ca2+]i were determined by the probes BCECF-AM and FURA 2-AM, respectively. Aldo (10-12 M) promoted a moderate increase in [Ca2+]i and stimulation of NHE1, whereas Aldo (10-6 M) greatly increased the [Ca2+]i, but inhibited the NHE1. BAPTA-AM (a calcium chelator), GR antagonism and inhibition of PLC, PKC and MEK pathway abolished the biphasic and dose-dependent effect of Aldo on NHE1 and decreased the [Ca2+]i; whereas MR do not appear to participate in this rapid signaling in IRPTC cells. The reduction of GR content, by gene silencing, abolished the Aldo effect on NHE1, in low concentration, confirming the importance of this receptor in the rapid modulation of proximal sodium and hydrogen transports. PMID- 29702263 TI - A sorafenib-sparing effect in the treatment of thyroid carcinoma cells attained by co-treatment with a novel isoflavone derivative and 1,25 dihydroxyvitamin D3. AB - BACKGROUND: Sorafenib improves progression-free survival in patients with progressive radioactive iodine-refractory differentiated thyroid carcinoma, but causes severe side effects. Estrogens may accelerate thyroid carcinoma cell growth. Our group recently reported that isoflavone derivative 7-(O) carboxymethyl daidzein conjugated to N-t-boc-hexylenediamine (cD-tboc), a novel anti-estrogenic compound, retards the growth of both thyroid carcinoma cell lines and cultured human carcinoma cells. Vitamin D receptor (VDR) is expressed in malignant cells and responds to 1,25 dihydroxyvitamin D3 (1.25D) by decreased proliferative activity in vitro. The purpose of this study was to examine the effects of vitamin D metabolites (VDM) on the expression of estrogen receptors (ERs), VDR, and 1OHase mRNA, and to evaluate the inhibitory effect of low doses of sorafenib in combination with cDtboc and VDM on cell proliferation in cultured human papillary thyroid carcinoma (PTC). METHODS: In 19 cultured PTC specimens and 19 normal thyroid specimens, harvested during thyroidectomies from the same patients, expression levels of ERalpha, ERbeta, VDR, and 1 alpha-hydroxylase (1OHase) mRNA (by quantitative real-time PCR) were determined at baseline and after treatment with VMD. Cell proliferation was determined by measurement of 3[H] thymidine incorporation after treatment with sorafenib alone, sorafenib with added 1.25D or cD-tboc, and sorafenib with both 1.25D and cD-tboc added. RESULTS: 1,25D increased mRNA expression of all tested genes in the malignant and normal thyroid cells, while the ERalpha mRNA of the normal cells was unaffected. 1.25D dose-dependently inhibited cell proliferation in the malignant cells. The inhibitory effect of sorafenib on cell proliferation in the malignant cells was amplified after the addition of cDtboc and 1.25D, such that the maximal inhibition was not only greater, but also had been attained at a 10-fold lower concentration of sorafenib (20 MUg/ml). This inhibition was similar to that of the generally used concentration of sorafenib (200 MUg/ml) alone. CONCLUSIONS: The demonstration that low concentrations of cDtboc and 1.25D markedly amplify the inhibitory effect of sorafenib on the growth of human PTC supports the use of a 10-fold lower concentration of sorafenib. The findings may promote a new combination treatment for progressive radioactive iodine-refractory PTC. PMID- 29702264 TI - Severe laryngeal and pulmonary tuberculosis under anti-TNF-alpha therapy. PMID- 29702265 TI - Cost of managing meningitis and encephalitis among adult patients in the United States of America. AB - OBJECTIVE: To determine the associated costs related to the diagnosis and treatment of meningitis and encephalitis (ME) in adult patients in the USA. METHODS: A retrospective observational study design was used to assess the use and costs of diagnostic tests and antimicrobial treatment and the total hospitalization costs for adult patients with suspected ME, who received a lumbar puncture procedure during an emergency department visit or during the first two service days of an inpatient stay. Related costs were calculated by timing of lumbar puncture performed and infectious etiology. RESULTS: A total 26429 adult patients with suspected ME diagnosed between 2011 and 2014 were included in the study. The mean hospitalization cost was $15 572+/-27168, with antimicrobial medication cost of $1144+/-4052 and laboratory test cost of $210+/-244. The total visit cost increased with delayed lumbar puncture procedure, intensive care unit stay, and if the etiology was fungi, arbovirus, or bacteria. CONCLUSIONS: Higher diagnostic and treatment costs are associated with a delayed lumbar puncture procedure, the etiological agent, and the requirement for an intensive care unit stay. PMID- 29702266 TI - Genome sequence of Mycobacterium yongonense RT 955-2015 isolate from a patient misdiagnosed with multidrug-resistant tuberculosis: First clinical detection in Tanzania. AB - BACKGROUND: Mycobacterium yongonense is a recently described novel species belonging to Mycobacterium avium complex, which is the most prevalent aetiology of non-tuberculous mycobacteria associated with pulmonary infections, and poses tuberculosis diagnostic challenges in high-burden, resource-constrained settings. METHODS: Whole genome shotgun sequencing and comparative microbial genomic analyses were used to characterize the isolate from a patient diagnosed with multidrug-resistant tuberculosis (MDR-TB) after relapse. RESULTS: The genome sequence of the first case of M. yongonense (M. yongonense RT 955-2015) in Tanzania is presented. Sequence analysis revealed that the RT 955-2015 strain had a high similarity to M. yongonense 05-1390(T) (98.74%) and Mycobacterium chimaera DSM 44623(T) (98%). Its 16S rRNA showed similarity to Mycobacterium paraintracellulare KCTC 290849(T) (100%), Mycobacterium intracellulare ATCC 13950(T) (100%), M. chimaera DSM 44623(T) (99.9%), and M. yongonense 05-1390(T) (98%). The strain exhibited a substantially different rpoB sequence to that of M. yongonense 05-1390 (95.16%), but closely related to that of M. chimaera DSM 44623(T) (99.86%), M. intracellulare ATCC 13950(T), (99.53%), and M. paraintracellulare KCTC 290849(T) (99.53%). CONCLUSIONS: In light of the OrthoANI algorithm and phylogenetic analysis, it was concluded that the isolate was M. yongonense Type II genotype, which is an indication that the patient was misdiagnosed with TB/MDR-TB and received inappropriate treatment. PMID- 29702267 TI - Design of far-infrared acousto-optic tunable filter based on backward collinear interaction. AB - The paper proposes a design of acousto-optic cell applying backward collinear interaction and acoustic mode transformation in a KRS-5 crystal. This cell may serve as an acousto-optic tunable filter for far-infrared spectral range and is able to operate both with collimated optical beams and with divergent beams forming images. The problem of acoustic mode transformation by wave reflection from the crystal facet away from symmetry planes has been solved. Polarization properties of the backward collinear interaction in optically isotropic media are discussed. PMID- 29702268 TI - Vascular Entrapment of Both the Sciatic and Pudendal Nerves Causing Persistent Sciatica and Pudendal Neuralgia. AB - STUDY OBJECTIVE: To demonstrate the laparoscopic approach to malformed branches of the vessels entrapping the nerves of the sacral plexus. DESIGN: A step-by-step explanation of the surgery using video (educative video) (Canadian Task force classification II). The university's Ethics Committee ruled that approval was not required for this video. SETTING: Kocaeli Derince Education and Research Hospital, Kocaeli, Turkey. PATIENT: A 26-year-old patient who had failed medical therapy and presented with complaints of numbness and burning pain on the right side of her vagina and pain radiating to her lower limbs for a period of approximately 36 months. INTERVENTION: The peritoneum was incised along the external iliac vessels, and these vessels were separated from the iliopsoas muscle on the right side of the pelvis. The laparoscopic decompression of intrapelvic vascular entrapment was performed at 3 sites: the lumbosacral trunk, sciatic nerve, and pudendal nerve. The aberrant dilated veins were gently dissected from nerves, and then coagulated and cut with the LigaSure sealing device (Medtronic, Minneapolis, Minn). MEASUREMENTS AND MAIN RESULTS: The operation was completed successfully with no complications, and the patient was discharged from the hospital 24 hours after the operation. At a 6-month follow up, she reported complete resolution of dyspareunia and sciatica (visual analog scale score 1 of 10). CONCLUSION: A less well-known cause of chronic pelvic pain is compression of the sacral plexus by dilated or malformed branches of the internal iliac vessels. Laparoscopic management of vascular entrapment of the sacral plexus has been described by Possover et al [1,2] and Lemos et al [3]. This procedure appears to be feasible and effective, but requires significant experience and familiarity with laparoscopy techniques and pelvic nerve anatomy. PMID- 29702269 TI - Uterine Tumors Resembling Ovarian Sex Cord Tumors Identified at Resectoscopic Endometrial Ablation: Report of 2 Cases. AB - STUDY OBJECTIVES: To report 2 cases of uterine tumors resembling ovarian sex cord tumors (UTROSCTs) and examine the clinical significance of these tumors found during hysteroscopic endometrial ablation despite benign preoperative endometrial biopsy analysis and imaging suggestive of leiomyoma. DESIGN: Case report (Canadian Task Force classification III). SETTING: Tertiary care hospital. PATIENTS: Two patients with abnormal uterine bleeding. INTERVENTIONS: Hysteroscopic endometrial ablation/resection. MEASUREMENTS AND MAIN RESULTS: Pathological analysis of intrauterine tissue/lesions obtained by curettage or resection identified 2 unexpected UTROSCTs masquerading as leiomyomas. Following hysterectomy, no residual UTROSCT was identified in the specimens, and both women are well, one at 1 year postsurgery and the other at 3 years postsurgery. CONCLUSION: Obtaining additional tissue by routine curettage before endometrial ablation and/or endomyometrial resection, in conjunction with removal of any intrauterine lesions, can identify rare unexpected endometrial lesions not sampled by endometrial biopsy, not detected with ultrasound, and masquerading as leiomyomas during endometrial ablation. PMID- 29702270 TI - Adnexal Torsion during Pregnancy: Pregnancy Outcomes after Surgical Intervention A Retrospective Case-Control Study. AB - STUDY OBJECTIVE: To investigate the pregnancy and neonatal outcomes of surgical treatment for adnexal torsion (AT) during pregnancy. DESIGN: A retrospective case control study (Canadian Task Force classification II-2). SETTING: A tertiary care academic medical center. MEASUREMENTS AND MAIN RESULTS: The study group included all parturients who underwent surgery for suspected AT during pregnancy from January 2005 to January 2017. The control group included parturients with an uneventful pregnancy matched by maternal age, parity, multiple gestation, and pregnancy complications. The primary outcome was gestational age at delivery. Secondary outcomes were perinatal outcomes and intraoperative and immediate postoperative complications. Among 85 study group patients with suspected AT, 78 (91.7%) underwent laparoscopy and 7 (8.3%) laparotomy. Torsion was diagnosed in 84 patients (98.8%). The gestational age at delivery was similar between the study and control groups (38.7 +/- 1.5 vs 38.6 +/- 1.6 weeks, respectively; p = .908) as was preterm labor (5.8% in both groups, p = 1.00). There was no significant difference between the study and control groups in pregnancy and neonatal outcomes, including Apgar scores, mean cord blood pH (7.25 +/- 0.1 and 7.26 +/- 0.08, respectively), and birth weight (3040 +/- 473 g and 3115 +/- 584 g, respectively). In the study group, the mean gestational age at surgery was 11.2 +/- 6 weeks (range, 4-34 weeks). The average operative time was 40.2 +/- 22 minutes. In the postoperative follow-up, 3 (3.5%) patients had a first trimester miscarriage. A previous cesarean delivery was a risk factor for ovarian torsion during pregnancy (p = .012). CONCLUSION: Adnexal detorsion with or without additional surgical procedures during pregnancy did not affect the gestational age at delivery and did not appear to increase fetal or maternal complication rates. PMID- 29702271 TI - Effect of Premedication Hyoscine-N-Butylbromide before Hysterosalpingography for Diagnosis of Proximal Tubal Obstruction in Infertile Women: a Randomized Double Blind Controlled Trial. AB - STUDY OBJECTIVE: To assess the effect of hyoscine-N-butylbromide (HBB) as premedication on the rate of proximal tubal obstruction during hysterosalpingography (HSG). DESIGN: A randomized, double-blind controlled trial (Canadian Task Force classification I). SETTING: The Infertility Clinic of Songklanagarind Hospital. PATIENTS: One hundred and forty-six infertile women indicated for HSG investigation. INTERVENTIONS: Patients were randomly assigned to receive either oral HBB 20 mg or placebo 30 minutes before the procedure between May 1, 2016 and March 31, 2017. If proximal tubal obstruction was found, participants would be assigned to undergo a second confirming HSG or laparoscopy with chromopertubation within 6 months. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the rate of proximal tubal obstruction. The secondary outcome was the false positive result of proximal tubal occlusion from HSG. Proximal tubal obstruction was found in 6 of 70 and 16 of 71 in the HBB and placebo groups, respectively. The rate of proximal tubal obstruction in the HBB group was significantly lower than in the placebo group (8.6% vs. 22.5%, p = .04; absolute difference, 13.9%; 95% confidence interval [CI]: 0.02-0.26; relative risk [RR]: 0.38; 95% CI: 0.16-0.92). After the second HSG or laparoscopy was performed (n = 22), the HBB group revealed a false occlusion in 20% (1/6 patients), and the placebo group had a higher false occlusion in 69.2% (9/16 patients). CONCLUSION: Premedication with HBB before HSG can reduce the rate of diagnosis of proximal tubal obstruction and false occlusion. PMID- 29702272 TI - Rehabilitation-specific challenges and advantages in the integration of migrant physicians in Germany: a multiperspective qualitative interview study in rehabilitative settings. AB - OBJECTIVES: In Germany, rehabilitative healthcare institutions increasingly rely on migrant physicians to meet their staffing needs. Yet until now, research on the integration of migrant physicians has focussed entirely on the acute care setting. This study is the first to address the specific advantages and challenges to integration in the field of rehabilitative medicine where a high number of migrant physicians work. From the experiences of migrant physicians and their colleagues, we provide actionable suggestions to counteract potential sources of conflict and thereby improve the integration of migrant physicians in the German workforce. STUDY DESIGN: We conducted a qualitative interview study. METHODS: We conducted 23 interviews with a total of 26 participants occupying a variety of roles in two different rehabilitation centres (maximum variation sampling). Interviews were recorded, transcribed verbatim and parsed through thematic analysis. RESULTS: Our research revealed advantages and challenges to integration in three distinct areas: rehabilitative care institutions, competencies of migrant professionals and interpersonal relations. The first set of issues hinges on the work processes within rehabilitative hospitals, professional prospects there and the location of the institutions themselves. Second, migrant physicians may encounter difficulties because of limited linguistic skills and country-specific knowledge. And finally, aspects of their interactions with care teams and patients may constitute barriers to integration. CONCLUSIONS: Some of the factors influencing the integration of migrant physicians are the same in both rehabilitative and acute medicine, but the rehabilitative setting presents distinct advantages and challenges that are worthy of study in their own right. We outline several measures which could help overcome challenges to the integration of migrant physicians, including those associated with professional relationships. Further research is needed to develop concrete support programmes. PMID- 29702273 TI - Effectiveness of occupational safety and health training for migrant farmworkers: a scoping review. AB - OBJECTIVES: Migrant farmworkers report higher rates of work-related illnesses, injuries and fatalities compared with local workers. Language and cultural barriers represent a relevant source of risk, which can be reduced by means of targeted training interventions. However, very little evidence is available about the effectiveness of Occupational Safety and Health (OSH) training programmes addressing migrant farmworkers. STUDY DESIGN: We carried out a scoping review. METHODS: Currently available literature about the effectiveness of OSH training for migrant farmworkers-in terms of improvements in at least one of the following: safety knowledge, behaviours, attitudes and beliefs and health outcomes-was searched from four databases: PubMed, PsycINFO, Scopus and Web of Science. The screening was performed independently by two authors, and any disagreement was resolved through discussion until consensus was achieved. Once the articles eligible for inclusion were selected, the objectives, design, sample and setting, interventions and findings of each study were recorded. No quality assessment tool for publications considered by this study has been used because a scoping review does not aim for critical appraisal. RESULTS: Twenty-nine publications met the inclusion criteria. Of these, nine cross-sectional studies discussed the effectiveness of training activities in terms of whether participating in any programme had or did not have a significant effect on the dependent variables, when training was considered along with other sociodemographic factors. In the majority of these studies, training appeared to have low or no effect on the dependent variables considered. Twenty mainly within subject experimental studies addressed the effectiveness of specific training methods, reporting significant improvements especially for interventions based on a participatory approach. CONCLUSIONS: Training could greatly contribute to an effective attainment of OSH information, but the present review shows that more evidence is needed to guide the future development of effective training activities. PMID- 29702274 TI - A flow cytometric approach to engineering Escherichia coli for improved eukaryotic protein glycosylation. AB - A synthetic pathway for production of the eukaryotic trimannosyl chitobiose glycan (mannose3-N-acetylglucosamine2, Man3GlcNAc2) and its transfer to specific asparagine residues in target proteins was previously engineered in Escherichia coli, providing this simple microbe with the ability to perform a complex post translational protein modification. Here, we leveraged a flow cytometric fluorescence-based assay to improve Man3GlcNAc2 glycan biosynthesis in E. coli cells. Specifically, pathway improvements were identified, including reducing pathway enzyme expression levels and overexpressing nucleotide sugar biosynthesis genes, which enhanced production of lipid-linked Man3GlcNAc2 by nearly 50-fold to 13.9 MUg/L. In turn, cells producing higher levels of the Man3GlcNAc2 substrate yielded up to 10 times more glycosylated acceptor protein (to ~ 14 mg/L) than their non-optimized counterparts. These results demonstrate the use of flow cytometry screening as a powerful tool for interrogating the surfaces of glyco engineered bacteria and identifying meaningful improvements in glycan biosynthesis. We anticipate this approach will enable further optimization of bacterial glycan biosynthesis pathways using new strain engineering tools from metabolic engineering and synthetic biology. PMID- 29702275 TI - Recent advances in metabolic engineering of Saccharomyces cerevisiae: New tools and their applications. AB - Metabolic engineering aims to develop efficient cell factories by rewiring cellular metabolism. As one of the most commonly used cell factories, Saccharomyces cerevisiae has been extensively engineered to produce a wide variety of products at high levels from various feedstocks. In this review, we summarize the recent development of metabolic engineering approaches to modulate yeast metabolism with representative examples. Particularly, we highlight new tools for biosynthetic pathway optimization (i.e. combinatorial transcriptional engineering and dynamic metabolic flux control) and genome engineering (i.e. clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR associated (Cas) system based genome engineering and RNA interference assisted genome evolution) to advance metabolic engineering in yeast. We also discuss the challenges and perspectives for high throughput metabolic engineering. PMID- 29702276 TI - RapidRIP quantifies the intracellular metabolome of 7 industrial strains of E. coli. AB - Fast metabolite quantification methods are required for high throughput screening of microbial strains obtained by combinatorial or evolutionary engineering approaches. In this study, a rapid RIP-LC-MS/MS (RapidRIP) method for high throughput quantitative metabolomics was developed and validated that was capable of quantifying 102 metabolites from central, amino acid, energy, nucleotide, and cofactor metabolism in less than 5 minutes. The method was shown to have comparable sensitivity and resolving capability as compared to a full length RIP LC-MS/MS method (FullRIP). The RapidRIP method was used to quantify the metabolome of seven industrial strains of E. coli revealing significant differences in glycolytic, pentose phosphate, TCA cycle, amino acid, and energy and cofactor metabolites were found. These differences translated to statistically and biologically significant differences in thermodynamics of biochemical reactions between strains that could have implications when choosing a host for bioprocessing. PMID- 29702277 TI - Development of an Escherichia coli-based biocatalytic system for the efficient synthesis of N-acetyl-D-neuraminic acid. AB - N-acetyl-d-neuraminic acid (Neu5Ac) is a valuable resource that has seen increasing demand in both medicine and biotechnology. Although enzymatic systems and whole-cell biocatalysts have been developed for the synthesis of Neu5Ac, low yield and productivity still hamper the use of these methods on larger scales. We report the creation of an Escherichia coli biocatalyst for the efficient synthesis of Neu5Ac using a metabolic and protein engineering strategy. Expression of the two enzymes, N-acetyl-D-glucosamine 2-epimerase (AGE) and Neu5Ac lyase (NAL), was balanced using promoter engineering. Genes encoding competing pathways and GlcNAc catabolism were deleted, and then a structure guided process was used to identify a more efficient NAL and an AGE mutant with a higher rate of Neu5Ac synthesis. The resulting biocatalyst produced 351.8 mM Neu5Ac with a yield of 58.6% from GlcNAc. This work exemplifies the use of rational design and protein engineering to construct a complex bacterial biocatalyst that can serve as a platform for the large-scale synthesis of a useful biological material. PMID- 29702278 TI - Asiatic acid attenuates CCl4-induced liver fibrosis in rats by regulating the PI3K/AKT/mTOR and Bcl-2/Bax signaling pathways. AB - Liver fibrosis is a major pathological feature of chronic liver diseases, and effective therapies are limited at present. Asiatic acid (AA) is a triterpenoid isolated from Centella asiatica, which exhibits efficient anti-inflammatory and anti-oxidative activities. In this study, we attempted to evaluate the potential therapeutic effect of AA on CCl4-induced liver fibrosis in rats and to investigate the underlying molecular mechanisms. Liver fibrosis-related indexes including body weight, biochemical parameters, histological changes, the mRNA expression levels of inflammatory cytokines and biomarkers, and changes in the expression of related proteins in liver tissue were assessed. The results showed that AA treatment effectively ameliorated CCl4-induced liver injury and fibrosis. Mechanistically, AA treatment attenuated CCl4-induced oxidative stress, inflammation, and hepatocyte apoptosis and regulated the Bcl-2/Bax signaling pathway in the liver. Additionally, we demonstrated that AA also inhibited hepatic stellate cell activation and extra cellular matrix (ECM) synthesis by regulating the PI3K/AKT/mTOR signaling pathway. In conclusion, these findings suggest that AA prevents the progression of liver fibrosis through multiple mechanisms and indicate that AA might be used for the treatment of liver fibrosis in the future. PMID- 29702279 TI - Cordycepin alleviates lipopolysaccharide-induced acute lung injury via Nrf2/HO-1 pathway. AB - AIMS: The present study is to investigate the protective effect of cordycepin on inflammatory reactions in rats with acute lung injury (ALI) induced by lipopolysaccharide (LPS), as well as the underlying mechanism. METHODS: Wistar rat model of ALI was induced by intravenous injection of LPS (30 mg/kg body weight). One hour later, intravenous injection of cordycepin (1, 10 or 30 mg/kg body weight) was administered. The wet-to-dry weight ratio of lung tissues and myeloperoxidase activity in the lung tissues were measured. The contents of nitrite and nitrate were measured by reduction method, while chemiluminescence was used to determine the content of superoxide. Quantitative real-time polymerase chain reaction and Western blotting were used to determine the expression of mRNA and protein, respectively. Colorimetry was performed to determine the enzymatic activity of heme oxygenase-1 (HO-1). Nuclear translocation of Nrf2 was identified by Western blotting. The plasma contents of cytokines were measured by enzyme-linked immunosorbent assay. RESULTS: Cordycepin enhanced the expression and enzymatic activity of HO-1 in ALI rats, and activated Nrf2 by inducing the translocation of Nrf2 from cytoplasm to nucleus. In addition, cordycepin regulated the secretion of TNF-alpha, IL-6 and IL-10 via HO 1, and suppressed inflammation in lung tissues of ALI rats by inducing the expression of HO-1. HO-1 played important roles in the down-regulation of superoxide levels in lung tissues by cordycepin, and HO-1 expression induced by cordycepin affected nitrite and nitrate concentrations in plasma and iNOS protein expression in lung tissues. Cordycepin showed protective effect on injuries in lung tissues. CONCLUSION: The present study demonstrates that cordycepin alleviates inflammation induced by LPS via the activation of Nrf2 and up regulation of HO-1 expression. PMID- 29702280 TI - Crosstalk between Toll-like receptor 3 and Notch signaling contributes to CD14+ monocytes activity in enterovirus 71 infected hand, foot, and mouth disease. AB - Interaction between Toll-like receptor (TLR) and Notch signaling contributes to inflammatory response in nephropathy and fungicidal infection, however, the role of this crosstalk remains not fully elucidated in enterovirus 71 (EV71)-induced hand, foot, and mouth disease (HFMD). The aim of this study was to investigate the crosstalk between TLR and Notch in inflammatory regulation in EV71 infection. Thirty-seven EV-71-indcued HFMD (16 mild and 21 severe cases) and eleven normal control (NC) were enrolled. CD14+ monocytes were purified, and were stimulated with either TLR3/4 agonists [poly(I: C) or LPS] or Notch signaling inhibitor. TLRs and Notch receptors expression, proinflammatory cytokines production, and important molecules in signaling pathways were measured by real-time PCR, ELISA, and Western blot. TLR3 and TLR4 was significantly elevated in CD14+ monocytes from HFMD patients than NC. Notch1 and Notch2 mRNA was also remarkably increased in CD14+ monocytes from severe HFMD. Poly(I: C) stimulation resulted in robust increase of IL-8, IL-6, and TNF-alpha by CD14+ monocytes in severe HFMD compared to NC. Activation of Notch1, Notch2, and target genes, Hes1 and Hes5 was also enhanced upon ploy(I: C) treatment. Although inhibition of Notch signaling did not affect TLR3 expression, poly(I: C)-induced inflammatory response was robustly attenuated, which was accompanied by silencing Src phosphorylation in CD14+ monocytes from severe HFMD patients. The current data indicated that crosstalk between TLR3 and Notch signaling modulated CD14+ monocytes function and inflammatory responses in the progression of EV71-induced HFMD. PMID- 29702281 TI - Intestinal dysbacteriosis potentiates ovalbumin-induced allergic airway inflammation by inhibiting microRNA-130a to upregulate tumor necrosis factor alpha. AB - Allergic airway diseases (AAD), including chronic disorders such as allergic rhinitis, are resulted from complicated immunological interactions. Intestinal dysbacteriosis (ID) has been implicated in immune response to respiratory infections. We aimed to investigate the effect of ID on a mouse model of AAD, and the potential molecular factors involved. Ovalbumin (OVA) was employed to sensitize and challenge mice to elicit allergic inflammation in the upper as well as the lower airways. OVA-induced AAD model mice and control mice were raised with or without antibiotics treatment to establish the combinational AAD + ID mouse model. Characteristic symptoms of AAD were evaluated in regard to allergic symptoms, serum OVA specific IgE level, as well as inflammation cells, cytokines and microRNA expression profile in nasal lavage fluid (NALF) and bronchoalveolar lavage fluid (BALF). In AAD mice, ID caused increased nasal rubbing, sneezing, serum OVA specific IgE level and pro-inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) in NALF and BALF. ID also inhibited microRNA-130a of AAD mice. Further molecular experiments indicated that microRNA-130a could specifically target and repress TNF-alpha. ID increases the susceptibility to AAD and allergic inflammatory response, possibly by inhibiting microRNA-130a to upregulate TNF alpha. PMID- 29702282 TI - Wedelolactone inhibits osteoclastogenesis but enhances osteoblastogenesis through altering different semaphorins production. AB - Our previous study showed that wedelolactone, isolated from Ecliptae herba, enhanced osteoblastogenesis but inhibited osteoclastogenesis through Sema3A signaling pathway. This study aims to investigate the role of other semaphorins in wedelolactone-enhanced osteoblastogenesis and -inhibited osteoclastogenesis. Wedelolactone inhibited RANKL-induced Sema4D and Sema7A production, but had no effect on RANKL-reduced Sema6D expression in osteoclastic RAW264.7 cells. In mouse bone marrow mesenchymal stem cells (BMSC), wedelolactone reversed osteogenic medium(OS)-reduced Sema7A expression and OS-enhanced Sema3E mRNA expression, but no effect on OS-reduced Sema3B mRNA expression. Addition of Sema4D antibody promoted wedelolactone-reduced TRAP activity and bone resorption pit formation. Wedelolactone combined with Sema4D antibody inhibited the formation of Sema4D-Plexin B1 complex. In co-culture of BMSC with RAW264.7 cells, Sema7A antibody, similar with Sema 3A antibody, reversed wedelolactone-enhanced ALP activity and mineralization level, but promoted wedelolactone-inhibited TRAP activity. However, Sema3E and Sema3B antibodies had no effect. Further, wedelolactone enhanced the binding of Sema7A with PlexinC1 and Beta1, but addition of Sema7A antibody partially blocked this binding. Our data demonstrated that wedelolactone inhibited Sema4D production and Sema4D-PlexinB1 complex formation in RAW264.7 cells, thereafter inhibiting osteoclastogenesis. At the same time, wedelolactone enhanced osteoblastogenesis through promoting Sema7A production and Sema7A-PlexinC1-Beta1 complex formation in BMSC. PMID- 29702283 TI - Basophil biomarkers as useful predictors for sublingual immunotherapy in allergic rhinitis. AB - Prevalence of allergic diseases is increasing worldwide. Allergen-specific immunotherapy (ASIT) is potentially the only curative treatment for allergy, but there is a lack of reliable methods to monitor the immune responses to ASIT and to predict clinical efficacy. Recently, the definition of allergen sensitivity threshold (CD-Sens) by Basophil Activation Tests has been suggested as potential method in this context. The aim of this study was to compare trends of CD-Sens, measured by the markers CD63 and CD203c, and clinical symptoms in subjects with allergic rhinitis receiving Sublingual Immunotherapy (SLIT). 26 rhinitis patients allergic to Parietaria were selected and matched into two groups; a SLIT treated group (SG) and a reference group (RG) treated by traditional anti-allergic medications. Visual Analogue Scale (VAS) score for the four cardinal symptoms of rhinitis and peripheral blood was collected before the first dose of SLIT (T0) and after 12 months (T12) to define the severity of the symptoms and the sensitivity of basophils to Parietaria. The comparison between T0 and T12 in SG patients showed a significant decrease of symptom severity (VAS score) and an increased tolerability of basophils to Parietaria (CD-Sens) both by CD63 and CD203c. But, only CD203c seems to be correlated with the clinical symptoms. These data corroborate the hypothesis that SLIT could change the immunological course of allergic sensitization already in the first year, and that an immunological parameter as CD-Sens measured by CD63 and CD203c expression on stimulated basophils could be useful to monitor the changes in the immune system. PMID- 29702284 TI - Glycyrrhizin ameliorates atopic dermatitis-like symptoms through inhibition of HMGB1. AB - Atopic dermatitis (AD) is a chronic relapsing inflammatory skin disease prevalent worldwide. This study investigated the effects of glycyrrhizin, an extract of licorice root, on the well-established model of 2,4-dinitrochlorobenzene-induced AD-like symptoms in mice. The severity of dermatitis, histopathological changes, serum IgE levels, changes in expression of high-mobility group box 1 (HMGB1), the receptor for advanced glycation end products (RAGE), nuclear factor (NF)-kappaB and inflammatory cytokines were evaluated. Treatment with glycyrrhizin inhibited the HMGB1 signaling cascade and ameliorated the symptoms of AD. Furthermore, in an in vitro study, the expression of RAGE was detected in a mouse mast cell line, P815 cells, and rmHMGB1 was found to be a potent inducer of mast cell activation by increasing Ca2+ influx, upregulating the CD117 and activating NF-kappaB signaling; these effects were also inhibited by glycyrrhizin. These findings implicate HMGB1 in the pathogenesis of AD and suggest that GL could be an effective therapeutic approach for cutaneous inflammation. PMID- 29702285 TI - Afatinib and Cetuximab in Four Patients With EGFR Exon 20 Insertion-Positive Advanced NSCLC. AB - INTRODUCTION: EGFR exon 20 insertions comprise 4% to 9% of EGFR mutated NSCLC. Despite being an oncogenic driver, they are associated with primary resistance to EGFR tyrosine kinase inhibitors (TKIs). We hypothesized that dual EGFR blockade with afatinib, an irreversible EGFR TKI, and cetuximab, a monoclonal antibody against EGFR, could induce tumor responses. METHODS: Four patients with EGFR exon 20 insertion-positive NSCLC were treated with afatinib 40 mg once daily and cetuximab 250 mg/m2 to 500 mg/m2 every 2 weeks. RESULTS: All patients had stage IV adenocarcinoma of the lung harboring an EGFR exon 20 insertion mutation. Previous lines of treatment consisted of platinum doublet chemotherapy (n = 4) and EGFR TKI (n = 2). Three of four patients showed a partial response according to Response Evaluation Criteria in Solid Tumors (RECIST 1.1). Median progression free survival was 5.4 months (95% confidence interval: 0.0 - 14.2 months; range 2.7 months - 17.6 months). Toxicity was manageable with appropriate skin management and dose reduction being required in two patients. CONCLUSIONS: Dual EGFR blockade with afatinib and cetuximab may induce tumor responses in patients with EGFR exon 20 insertion-positive NSCLC. PMID- 29702286 TI - Expression Patterns, Prognostic Value, and Intratumoral Heterogeneity of PD-L1 and PD-1 in Thymoma and Thymic Carcinoma. AB - INTRODUCTION: Thymic epithelial tumors (TETs) including thymoma and thymic carcinoma are rare tumors with little data available to guide treatment. Immunotherapy with checkpoint blockade has shown promising activity, but data regarding the expression patterns and prognostic implications of programmed death 1 (PD-1) and its ligand (PD-L1) in TETs have yielded conflicting results. Intratumoral heterogeneity of PD-1/L1 expression has been shown in other cancers, but has not been described in the TET literature. METHODS: We performed a retrospective single-center review of 35 patients with resected TET. PD-1/L1 expression was assessed by immunohistochemistry using PD-1 clone: NAT105 and PD L1 clone: 22C3. Tumor samples from 35 patients were evaluated including 32 patients with thymoma and 3 patients with thymic carcinoma. RESULTS: PD-L1 expression was detected in 83% (29 of 35) tumor samples, including 100% (3 of 3) of thymic carcinoma patients and 81% (26 of 32) of thymoma patients. PD-1 expression was detected in 77% (27 of 35), including 33% (1 of 3) of thymic carcinoma patients and 81% (26 of 32) thymoma patients. High PD-1 expression was associated with lower grade tumors. Unlike prior studies, PD-L1 expression was not associated with higher grade tumors or higher stage. Neither PD-L1 nor PD-1 expression was significantly associated with survival. Three patients with thymoma had multiple tumor sections evaluated for expression of PD-1/L1, with differing expression patterns of both PD-L1 and PD-1 observed in two patients. CONCLUSIONS: This study confirms high expression of PD-L1 and PD-1 in TET and shows for the first time intratumoral heterogeneity of PD-L1 and PD-1 in thymoma patients. PMID- 29702287 TI - Identification of Mutation Accumulation as Resistance Mechanism Emerging in First Line Osimertinib Treatment. AB - INTRODUCTION: The survival of patients with EGFR mutation-positive lung cancer has dramatically improved since the introduction of EGFR tyrosine kinase inhibitors (EGFR-TKIs). Recently, osimertinib showed significantly prolonged progression-free survival than first-generation EGFR-TKI in first-line treatment, suggesting that a paradigm change that would move osimetinib to first-line treatment is indicated. We performed N-ethyl-N-nitrosourea (ENU) mutagenesis screening to uncover the resistant mechanism in first- and second-line osimertinib treatment. METHODS: Ba/F3 cells harboring EGFR activating-mutation with or without secondary resistant mutation were exposed to ENU for 24 hours to introduce random mutations and selected with gefitinib, afatinib, or osimertinib. Mutations of emerging resistant cells were assessed. RESULTS: The resistance of T790M and C797S to gefitinib and osimertinib, respectively, was prevalent in the mutagenesis screening with the Ba/F3 cells harboring activating-mutation alone. From C797S/activating-mutation expressing Ba/F3, the additional T790M was a major resistant mechanism in gefitinib and afatinib selection and the additional T854A and L792H were minor resistance mechanisms only in afatinib selection. However, the additional T854A or L792H mediated resistance to all classes of EGFR-TKI. Surprisingly, no resistant clone due to secondary mutation emerged from activating-mutation alone in the gefitinib + osimertinib selection. CONCLUSIONS: We showed the resistance mechanism to EGFR-TKI focusing on first- and second-line osimertinib using ENU mutagenesis screening. Additional T854A and L792H on C797S/activating-mutation were found as afatinib resistance and not as gefitinib resistance. Thus, compared to afatinib, the first-generation EGFR-TKI might be preferable as second-line treatment to C797S/activating-mutation emerging after first-line osimertinib treatment. PMID- 29702288 TI - Functionality of decellularized matrix in cartilage regeneration: A comparison of tissue versus cell sources. AB - : Increasing evidence indicates that decellularized extracellular matrices (dECMs) derived from cartilage tissues (T-dECMs) or chondrocytes/stem cells (C dECMs) can support proliferation and chondrogenic differentiation of cartilage forming cells. However, few review papers compare the differences between these dECMs when they serve as substrates for cartilage regeneration. In this review, after an introduction of cartilage immunogenicity and decellularization methods to prepare T-dECMs and C-dECMs, a comprehensive comparison focuses on the effects of T-dECMs and C-dECMs on proliferation and chondrogenic differentiation of chondrocytes/stem cells in vitro and in vivo. Key factors within dECMs, consisting of microarchitecture characteristics and micromechanical properties as well as retained insoluble and soluble matrix components, are discussed in-depth for potential mechanisms underlying the functionality of these dECMs in regulating chondrogenesis. With this information, we hope to benefit dECM based cartilage engineering and tissue regeneration for future clinical application. STATEMENT OF SIGNIFICANCE: The use of decellularized extracellular matrix (dECM) is becoming a promising approach for tissue engineering and regeneration. Compared to dECM derived from cartilage tissue, recently reported dECM from cell sources exhibits a distinct role in cell based cartilage regeneration. In this review paper, for the first time, tissue and cell based dECMs are comprehensively compared for their functionality in cartilage regeneration. This information is expected to provide an update for dECM based cartilage regeneration. PMID- 29702289 TI - Decellularized matrices in regenerative medicine. AB - : Of all biologic matrices, decellularized extracellular matrix (dECM) has emerged as a promising tool used either alone or when combined with other biologics in the fields of tissue engineering or regenerative medicine - both preclinically and clinically. dECM provides a native cellular environment that combines its unique composition and architecture. It can be widely obtained from native organs of different species after being decellularized and is entitled to provide necessary cues to cells homing. In this review, the superiority of the macro- and micro-architecture of dECM is described as are methods by which these unique characteristics are being harnessed to aid in the repair and regeneration of organs and tissues. Finally, an overview of the state of research regarding the clinical use of different matrices and the common challenges faced in using dECM are provided, with possible solutions to help translate naturally derived dECM matrices into more robust clinical use. STATEMENT OF SIGNIFICANCE: Ideal scaffolds mimic nature and provide an environment recognized by cells as proper. Biologically derived matrices can provide biological cues, such as sites for cell adhesion, in addition to the mechanical support provided by synthetic matrices. Decellularized extracellular matrix is the closest scaffold to nature, combining unique micro- and macro-architectural characteristics with an equally unique complex composition. The decellularization process preserves structural integrity, ensuring an intact vasculature. As this multifunctional structure can also induce cell differentiation and maturation, it could become the gold standard for scaffolds. PMID- 29702290 TI - Construction of tendon replacement tissue based on collagen sponge and mesenchymal stem cells by coupled mechano-chemical induction and evaluation of its tendon repair abilities. AB - : Tissue engineering is an ideal therapeutic strategy for the development of functional tendon replacement tissue for tendon repair in the clinic. Currently, the synergistic roles of mechano-chemical factors and the mechanisms involved in tendon repair and regeneration are not fully understood. In this study, we developed a three-dimensional (3D) culture system based on a silicone chamber and collagen sponge scaffold that can deliver cyclic mechanical stretch and biochemical stimulation to bone marrow-derived mesenchymal stem cells (BMSCs) seeded on the scaffold. We found that the combined stimulation of cyclic stretch and transforming growth factor beta 1 (TGF-beta1) treatment not only increased cell viability but also synergistically promoted the differentiation of BMSCs into tenocytes in a 3D culture environment. Meanwhile, the combined stimulation increased the Young's modulus of the BMSC-collagen sponge constructs by reducing the porosity of the scaffold compared to the non-treated constructs. Furthermore, a rat Achilles tendon in situ repair experiment showed that enhanced tendon regeneration was achieved using the BMSC-collagen sponge construct combined with cyclic stretch and TGF-beta1, as confirmed by Achilles functional index (AFI) measurement, morphological observation, histological analysis, and mechanical testing. These results suggest that this approach could offer a practical benefit in tendon healing and future tendon tissue engineering. STATEMENT OF SIGNIFICANCE: This study aims to disclose the crucial roles of the coupled induction by mechano-chemical stimulation in tendon tissue engineering and clarifies their collaborative control mechanisms. We developed a three dimensional (3D) culture system based on a silicone chamber and collagen sponge scaffold that could deliver cyclic mechanical stretch and biochemical stimulation to bone marrow-derived mesenchymal stem cells (BMSCs). We found that the combined stimulation of cyclic stretch and transforming growth factor beta 1 (TGF-beta1) could result in an improvement of tissue-engineered construct for enhancing tendon healing. These results suggest that this approach could offer a practical benefit in tendon healing and future tendon tissue engineering. PMID- 29702291 TI - Multilayered coating of titanium implants promotes coupled osteogenesis and angiogenesis in vitro and in vivo. AB - : We used surface-modified titanium (Ti) substrates with a multilayered structure composed of chitosan-catechol (Chi-C), gelatin (Gel) and hydroxyapatite (HA) nanofibers, which were previously shown to improve osteogenesis, as a platform to investigate the interaction of osteogenesis and angiogenesis during bone healing. Combined techniques of Transwell co-culture, wound healing assay, enzyme linked immunosorbent assay (ELISA), quantitative real-time polymerase chain reaction (qRT-PCR), western blotting and immunohistochemical staining were used to evaluate adhesion, morphology and migration of adipose-derived mesenchymal stem cells (Ad-MSCs) and human umbilical vein endothelial cells (HUVECs) grown on different Ti substrates. We investigated the effect of substrates on the osteogenic differentiation of Ad-MSCs and reciprocal paracrine effects of Ad-MSCs on HUVECs or vice versa. The multilayered Ti substrates directly regulated the cellular functions of Ad-MSCs and angiogenic HUVECs and mediated communication between them by enhancing paracrine effects via cell-matrix interactions in vitro. The in vivo results showed that the change of microenvironment induced by surface-modified Ti implants promoted the adhesion, recruitment and proliferation of MSCs and facilitated coupled osteogenesis and angiogenesis in bone healing. The study proved that multilayer-film-coated Ti substrates positively mediated cellular biological function in vitro and improved bone healing in vivo. STATEMENT OF SIGNIFICANCE: Recent studies have revealed that osteogenesis and angiogenesis are coupled, and that communication between osteoblasts and endothelial cells is essential for bone healing and remodeling processes; however, these conclusions only result from in vitro studies or in vivo studies using transgenic murine models. Relatively little is known about the communication between osteoblasts and endothelial cells in peri-implants during bone healing processes. Our results revealed the cellular/molecular mechanism of how multilayered Ti substrates mediate reciprocal paracrine effects between adipose-derived mesenchymal stem cells and human umbilical vein endothelial cells; moreover, the interactions between the cell-matrix and peri-implant was proven in vivo with enhanced bone healing. This study contributes to our understanding of the fundamental mechanisms of angiogenesis and osteogenesis that affect peri-implantation, and thus, provides new insights into the design of future high-quality orthopedic implants. PMID- 29702292 TI - Tissue-engineered spiral nerve guidance conduit for peripheral nerve regeneration. AB - : Recently in peripheral nerve regeneration, preclinical studies have shown that the use of nerve guidance conduits (NGCs) with multiple longitudinally channels and intra-luminal topography enhance the functional outcomes when bridging a nerve gap caused by traumatic injury. These features not only provide guidance cues for regenerating nerve, but also become the essential approaches for developing a novel NGC. In this study, a novel spiral NGC with aligned nanofibers and wrapped with an outer nanofibrous tube was first developed and investigated. Using the common rat sciatic 10-mm nerve defect model, the in vivo study showed that a novel spiral NGC (with and without inner nanofibers) increased the successful rate of nerve regeneration after 6 weeks recovery. Substantial improvements in nerve regeneration were achieved by combining the spiral NGC with inner nanofibers and outer nanofibrous tube, based on the results of walking track analysis, electrophysiology, nerve histological assessment, and gastrocnemius muscle measurement. This demonstrated that the novel spiral NGC with inner aligned nanofibers and wrapped with an outer nanofibrous tube provided a better environment for peripheral nerve regeneration than standard tubular NGCs. Results from this study will benefit for future NGC design to optimize tissue-engineering strategies for peripheral nerve regeneration. STATEMENT OF SIGNIFICANCE: We developed a novel spiral nerve guidance conduit (NGC) with coated aligned nanofibers. The spiral structure increases surface area by 4.5 fold relative to a tubular NGC. Furthermore, the aligned nanofibers was coated on the spiral walls, providing cues for guiding neurite extension. Finally, the outside of spiral NGC was wrapped with randomly nanofibers to enhance mechanical strength that can stabilize the spiral NGC. Our nerve histological data have shown that the spiral NGC had 50% more myelinated axons than a tubular structure for nerve regeneration across a 10 mm gap in a rat sciatic nerve. Results from this study can help further optimize tissue engineering strategies for peripheral nerve repair. PMID- 29702293 TI - Incidence of Hepatitis B Virus Reactivation and Hepatotoxicity in Patients Receiving Long-term Treatment With Tumor Necrosis Factor Antagonists. AB - BACKGROUND & AIMS: Tumor necrosis factor (TNF) antagonists are the first-line treatment for many autoimmune diseases. However, they have been associated with reactivation of hepatitis B virus (HBV). We determined the rate of HBV reactivation and hepatotoxicity grade 3 or 4 (HT >=3) in patients treated with an anti-TNF agent for an autoimmune disease. METHODS: We collected data from 8887 adult patients in the Kaiser Permanente Northern California database who began treatment with TNF antagonists for autoimmune diseases (dermatologic, rheumatologic, or gastrointestinal) from 2001 through 2010, followed through December 2012. We obtained data on HBV infection (52% of patients were screened for HBV before treatment), demographic features, comorbidities, and use of immunosuppressive agents. HBV reactivation was defined as 1 of the following: >1 log increase in HBV DNA, HBV DNA-positive when previously negative, HBV DNA >2000 IU/mL if no baseline level was available, or reverse seroconversion. HT >=3 was defined according to the National Cancer Institute Common Toxicity Criteria. We performed multivariable logistic regression to identify factors associated with HT >=3. RESULTS: Twenty-three patients tested positive for HB surface antigen (HBsAg) at baseline and 9 of these had HBV reactivation; of the 4267 patients with unknown HBV status at baseline, 2 had HBV reactivation. None of the 178 patients who were HBsAg negative and positive for the hepatitis B core antibody (anti-HBc+) had HBV reactivation. HBV reactivation occurred in 1/5 HBsAg+ patients who received prophylactic antiviral therapy and 8/18 who did not (P = .61). No one with HBV reactivation had liver failure. HT >=3 occurred in 273 patients (2.7%), but only 3 cases were attributed to HBV. Cirrhosis was significantly associated with HT >=3 (P < .001). CONCLUSION: In a retrospective analysis of patients treated with TNF antagonists for autoimmune diseases, we found HBV reactivation in 39% of patients who were HBsAg+ before therapy, but not in any patients who were HBsAg-negative and anti-HBc+ before therapy. Patients should be screened for HBV infection before anti-TNF therapy; HBsAg+ patients should receive prophylactic antiviral therapy, but not HBsAg-negative, anti-HBc+ patients. PMID- 29702294 TI - Worldwide Practice Patterns in Lynch Syndrome Diagnosis and Management, Based on Data From the International Mismatch Repair Consortium. AB - BACKGROUND & AIMS: Families with a history of Lynch syndrome often do not adhere to guidelines for genetic testing and screening. We investigated practice patterns related to Lynch syndrome worldwide, to ascertain potential targets for research and public policy efforts. METHODS: We collected data from the International Mismatch Repair Consortium (IMRC), which comprises major research and clinical groups engaged in the care of families with Lynch syndrome worldwide. IMRC institutions were invited to complete a questionnaire to characterize diagnoses of Lynch syndrome and management practice patterns. RESULTS: Fifty-five providers, representing 63 of 128 member institutions (49%) in 21 countries, completed the questionnaire. For case finding, 55% of respondents reported participating in routine widespread population tumor testing among persons with newly diagnosed Lynch syndrome-associated cancers, whereas 27% reported relying on clinical criteria with selective tumor and/or germline analyses. Most respondents (64%) reported using multigene panels for germline analysis, and only 28% reported testing tumors for biallelic mutations for cases in which suspected pathogenic mutations were not confirmed by germline analysis. Respondents reported relying on passive dissemination of information to at-risk family members, and there was variation in follow through of genetic testing recommendations. Reported risk management practices varied-nearly all programs (98%) recommended colonoscopy every 1 to 2 years, but only 35% recommended chemoprevention with aspirin. CONCLUSIONS: There is widespread heterogeneity in management practices for Lynch syndrome worldwide among IMRC member institutions. This may reflect the rapid pace of emerging technology, regional differences in resources, and the lack of definitive data for many clinical questions. Future efforts should focus on the large numbers of high-risk patients without access to state-of-the-art Lynch syndrome management. PMID- 29702295 TI - Functional Dyspepsia and Severity of Psychologic Symptoms Associate With Postprandial Symptoms in Patients With Irritable Bowel Syndrome. AB - BACKGROUND & AIMS: Patients with irritable bowel syndrome (IBS) have an increased response of postprandial symptoms to a combined lactulose nutrient challenge test, compared with healthy volunteers. We investigated the associations among comorbid functional dyspepsia (FD), severity of psychologic symptoms, and breath test results in response to this test. METHODS: We performed a prospective study of 205 patients with IBS (Rome III criteria), 94 of whom also had FD (IBS-FD), and 83 healthy volunteers in Sweden from 2008 through 2015. All participants completed a breath hydrogen test after a 400-mL liquid meal with 25 g lactulose. Gastrointestinal (GI) symptom severity was assessed using a graded scale and digestive comfort was recorded before the meal and every 15 minutes until 240 minutes after the meal. GI symptom scores over time were compared between groups using linear mixed models with anxiety, depression, and somatization as covariates. RESULTS: Average levels of all GI symptoms varied over time among all groups (P < .0001). Patients with IBS-FD had higher levels of bloating (P = .004), abdominal pain (P = .005), and lower levels of digestive comfort (P < .01) than patients with only IBS. We observed a difference in increase in abdominal pain from baseline between IBS-FD and IBS groups (P = .013). Anxiety levels were associated with levels of all symptoms (all P < .025) except abdominal pain, which was associated with somatization severity (P < .0001). Furthermore, anxiety levels associated with level of exhaled hydrogen (P = .0042). CONCLUSIONS: In a prospective study of patients with IBS, we found those with FD to have increased GI symptoms before and after a liquid meal with lactulose. Anxiety and somatization have an independent additional effect. The presence of comorbid FD and levels of psychologic symptoms affect reports of food-related symptoms in patients with IBS. ClinicalTrial.gov no: NCT01252550. PMID- 29702296 TI - Advances in Management of Esophageal Motility Disorders. AB - The widespread adoption of high-resolution manometry (HRM) has led to a restructuring in the classification of esophageal motility disorder classification summarized in the Chicago Classification, currently in version 3.0. It has become apparent that the cardinal feature of achalasia, impaired lower esophageal sphincter relaxation, can occur in several disease phenotypes: without peristalsis, with premature (spastic) distal esophageal contractions, with panesophageal pressurization, or even with preserved peristalsis. Furthermore, despite these advances in diagnostics, no single manometric pattern is perfectly sensitive or specific for idiopathic achalasia and complimentary assessments with provocative maneuvers during HRM or interrogating the esophagogastric junction with the functional luminal imaging probe during endoscopy can be useful in clarifying equivocal or inexplicable HRM findings. Using these tools, we have come to conceptualize esophageal motility disorders as characterized by obstructive physiology at the esophagogastric junction, smooth muscle esophagus, or both. Recognizing obstructive physiology as a primary target of therapy has become particularly relevant with the development of a minimally invasive technique for performing a calibrated myotomy of the esophageal circular muscle, the POEM procedure. Now and going forward, optimal management is to render treatment in a phenotype-specific manner: e.g. POEM calibrated to patient specific physiology for spastic achalasia and spastic disorders of the smooth muscle esophagus, more conservative strategies (pneumatic dilation) for the disorders limited to the sphincter. PMID- 29702297 TI - Course of Esophageal Candidiasis and Outcomes of Patients at a Single Center. PMID- 29702298 TI - Increased Risk of Acute Myocardial Infarction and Heart Failure in Patients With Inflammatory Bowel Diseases. AB - BACKGROUND & AIMS: There are conflicting data as to whether inflammatory bowel diseases (IBDs) increase risk for cardiovascular disease. We sought to examine the risk of acute myocardial infarction (AMI) and heart failure in patients with IBD. METHODS: We identified patients diagnosed with IBD in Olmsted County, Minnesota, from 1980 through 2010 (n = 736). For each patient, 2 individuals without IBD (controls, n = 1472) were randomly selected, matched for age, sex, and index date of disease diagnosis. Primary outcomes were AMI and heart failure. Cox proportional hazards analysis was used to estimate the risk of AMI and heart failure. RESULTS: After adjustments for traditional cardiovascular disease risk factors, IBD associated independently with increased risk of AMI (adjusted hazard ratio [aHR], 2.82; 95% CI, 1.98-4.04) and heart failure (aHR, 2.03; 95% CI, 1.36 3.03). The relative risk of AMI was significantly increased in patients with Crohn's disease (aHR vs controls, 2.89; 95% CI, 1.65-5.13) or ulcerative colitis (aHR vs controls, 2.70; 1.69-4.35). The relative risk of AMI was increased among users of systemic corticosteroids (aHR vs controls, 5.08; 95% CI, 3.00-8.81) and nonusers (aHR vs controls, 1.79; 95% CI, 1.08-2.98). The relative risk of heart failure was significantly increased among patients with ulcerative colitis (aHR, 2.06; 95% CI, 1.18-3.65), but not Crohn's disease. The relative risk of heart failure was increased among users of systemic corticosteroids (aHR, 2.51; 95% CI, 1.93-4.57), but not nonusers. CONCLUSIONS: In a population-based cohort study, we found that despite a lower prevalence of traditional risk factors for AMI and heart failure, patients with IBD are at increased risk for these cardiovascular disorders. PMID- 29702300 TI - Budesonide Suppositories Are Effective and Safe for Treating Acute Ulcerative Proctitis. AB - BACKGROUND & AIMS: Although proctitis is the most limited form of ulcerative colitis, it causes unpleasant symptoms. Topical mesalamine, the standard treatment, is not always effective. We conducted a randomized phase 2 trial to determine the efficacy and safety of 2 doses of a budesonide suppository vs mesalamine suppositories vs combined budesonide and mesalamine suppositories for proctitis. METHODS: We performed a prospective, double-blind, double-dummy, multicenter trial in 337 patients with active proctitis to compare the efficacies of 4 different suppository treatments. Patients were randomly assigned to groups given 2 mg budesonide suppositories (2 mg BUS; n = 89 patients), 4 mg BUS (n = 79), 1 g mesalamine suppositories (1 g MES; n = 81), or the combination of 2 mg BUS and 1 g MES (n = 88). The study was performed from November 2013 through July 2015 at 36 study sites in Europe and Russia. The primary end point was the time to resolution of clinical symptoms, defined as the first of 3 consecutive days with a score of 0 for rectal bleeding and stool frequency. RESULTS: The mean time to resolution of symptoms in the 4 mg BUS (29.8 days) and combination of 2 mg BUS and 1 g MES (29.3 days) groups resembled that of the standard 1 g MES treatment (29.2 days), but was significantly longer in the 2 mg BUS group (35.5 days). Furthermore, proportions of patients with deep, clinical, and endoscopic remission, as well as mucosal healing, were similar among the 1 g MES, 4 mg BUS, and combination therapy groups, but significantly lower in the group that received 2 mg BUS. No safety signals were observed, and the patients' treatment acceptance was high (67%-85% of patients). CONCLUSIONS: In a multicenter randomized trial, we found that the efficacy and safety of 4 mg BUS in treatment of active proctitis did not differ significantly from those of 1 g MES. Budesonide suppositories offer an alternative therapy to mesalamine for topical treatment of proctitis. Clinicaltrialsregister.eu no: 2012-003362-41. PMID- 29702299 TI - Diets That Promote Colon Inflammation Associate With Risk of Colorectal Carcinomas That Contain Fusobacterium nucleatum. AB - BACKGROUND & AIMS: Specific nutritional components are likely to induce intestinal inflammation, which is characterized by increased levels of interleukin 6 (IL6), C-reactive protein (CRP), and tumor necrosis factor-receptor superfamily member 1B (TNFRSF1B) in the circulation and promotes colorectal carcinogenesis. The inflammatory effects of a diet can be estimated based on an empiric dietary inflammatory pattern (EDIP) score, calculated based on intake of 18 foods associated with plasma levels of IL6, CRP, and TNFRSF1B. An inflammatory environment in the colon (based on increased levels of IL6, CRP, and TNFRSF1B in peripheral blood) contributes to impairment of the mucosal barrier and altered immune cell responses, affecting the composition of the intestinal microbiota. Colonization by Fusobacterium nucleatum has been associated with the presence and features of colorectal adenocarcinoma. We investigated the association between diets that promote inflammation (based on EDIP score) and colorectal cancer subtypes classified by level of F nucleatum in the tumor microenvironment. METHODS: We calculated EDIP scores based on answers to food frequency questionnaires collected from participants in the Nurses' Health Study (through June 1, 2012) and the Health Professionals Follow-up Study (through January 31, 2012). Participants in both cohorts reported diagnoses of rectal or colon cancer in biennial questionnaires; deaths from unreported colorectal cancer cases were identified through the National Death Index and next of kin. Colorectal tumor tissues were collected from hospitals where the patients underwent tumor resection and F nucleatum DNA was quantified by a polymerase chain reaction assay. We used multivariable duplication-method Cox proportional hazard regression to assess the associations of EDIP scores with risks of colorectal cancer subclassified by F nucleatum status. RESULTS: During 28 years of follow-up evaluation of 124,433 participants, we documented 951 incident cases of colorectal carcinoma with tissue F nucleatum data. Higher EDIP scores were associated with increased risk of F nucleatum-positive colorectal tumors (Ptrend = .03); for subjects in the highest vs lowest EDIP score tertiles, the hazard ratio for F nucleatum-positive colorectal tumors was 1.63 (95% CI, 1.03-2.58). EDIP scores did not associate with F nucleatum-negative tumors (Ptrend = .44). High EDIP scores associated with proximal F nucleatum-positive colorectal tumors but not with proximal F nucleatum-negative colorectal tumors (Pheterogeneity = .003). CONCLUSIONS: Diets that may promote intestinal inflammation, based on EDIP score, are associated with increased risk of F nucleatum-positive colorectal carcinomas, but not carcinomas that do not contain these bacteria. These findings indicate that diet-induced intestinal inflammation alters the gut microbiome to contribute to colorectal carcinogenesis; nutritional interventions might be used in precision medicine and cancer prevention. PMID- 29702301 TI - A quantitative review on outcome-to-antidepressants in melancholic unipolar depression. AB - The aim of this study was to explore outcome to antidepressants profile in melancholic unipolar depression. We conducted a systematic review of electronic databases and meta-analysis of randomized and nonrandomized trials comparing: 1) outcome to antidepressants and placebo between melancholic and non-melancholic depression; 2) outcome to different antidepressant classes in melancholic depression. Two outcomes were considered: clinical remission and response. Significant lower odds of remission to antidepressants in melancholic than in non melancholic depressions were found. Although no significant differences were observed in the response to antidepressants between both subtypes of depression, those with melancholic features had lower odds of response to placebo. Finally, treatment of melancholic depression with serotonin reuptake inhibitors was associated with lower odds of remission compared with tricyclic antidepressants, and similar outcome compared with venlafaxine. Melancholia seems to show a differential pattern of outcome to antidepressants, which could be clinically valuable for a better implementation of personalized medicine of depression. Due to several limitations, further research is needed to support these preliminary findings. PMID- 29702302 TI - Cluster analysis reveals subclinical subgroups with shared autistic and schizotypal traits. AB - Autism and schizophrenia spectrum research is typically based on coarse diagnostic classification, which overlooks individual variation within clinical groups. This method limits the identification of underlying cognitive, genetic and neural correlates of specific symptom dimensions. This study, therefore, aimed to identify homogenous subclinical subgroups of specific autistic and schizotypal traits dimensions, that may be utilised to establish more effective diagnostic and treatment practices. Latent profile analysis of subscale scores derived from an autism-schizotypy questionnaire, completed by 1678 subclinical adults aged 18-40 years (1250 females), identified a local optimum of eight population clusters: High, Moderate and Low Psychosocial Difficulties; High, Moderate and Low Autism-Schizotypy; High Psychosis-Proneness; and Moderate Schizotypy. These subgroups represent the convergent and discriminant dimensions of autism and schizotypy in the subclinical population, and highlight the importance of examining subgroups of specific symptom characteristics across these spectra in order to identify the underlying genetic and neural correlates that can be utilised to advance diagnostic and treatment practices. PMID- 29702303 TI - The moderating role of cognitive biases on the relationship between negative affective states and psychotic-like experiences in non-clinical adults. AB - Negative emotions and cognitive biases are important factors underlying psychotic symptoms and psychotic-like experiences (PLEs); however, it is not clear whether these factors interact when they influence psychotic phenomena. The aim of our study was to investigate whether psychosis-related cognitive biases moderate the relationship between negative affective states, i.e. anxiety and depression, and psychotic-like experiences. The study sample contains 251 participants who have never been diagnosed with psychiatric disorders. Anxiety, depression, cognitive biases, and psychotic-like experiences were assessed with self-report questionnaires. A moderation analysis was performed to examine the relationship between the study variables. The analyses revealed that the link between anxiety and positive PLEs is moderated by External Attribution bias, whereas the relationship between depression and positive PLEs is moderated by Attention to Threat bias. Attributional bias was also found to moderate the association between depression and negative subclinical symptoms; Jumping to Conclusions bias served as a moderator in the link between anxiety and depression and negative PLEs. Further studies in clinical samples are required to verify the moderating role of individual cognitive biases on the relationship between negative emotional states and full-blown psychotic symptoms. PMID- 29702304 TI - The factor structure of the short form of the Wisconsin schizotypy scales. AB - The Chapman psychosis-proneness scales-also known as Wisconsin schizotypy scales (WSS)-are among the most used tools to measure schizotypy. The factor structure of the short-form WSS was investigated in a mixed sample of patients with chronic mental disorders and of healthy subjects from the general population. One hundred patients with a chronic mental disorder were enrolled over a 6-month period. For each patient, two controls of same sex and similar age (+/-5 years) were enrolled; 131 accepted to take part in the study. The unidimensional, the correlated four-factor, the second-order two-factor models, and the bifactor model with two or four orthogonally independent factors of the short-form WSS were tested with confirmatory factor analysis. Good reliability of the short-form WSS was confirmed, as its capacity of differentiating people with and without schizotypy. The bifactor models were superior to other models. However, in both bifactor models the explained common variance (ECV) attributable to the general factor and the percentage of uncontaminated correlations (PUC) were too low to use a general summary score as a measure of a single latent schizotypy variable. Symptoms scores derived from the short-form WSS can be better appreciated within a multidimensional model of schizotypy. PMID- 29702305 TI - All-cause mortality in older adults with affective disorders and dementia under treatment with antipsychotic drugs: A matched-cohort study. AB - We aimed to compare the mortality risk between patients with affective disorders and dementia under treatment with antipsychotics. To do this, a matched-cohort study based on an electronic database of a tertiary teaching hospital in Argentina was performed. Antipsychotic exposure was defined as any antipsychotic drug initiated by the patient. Primary outcome was defined as all-cause mortality during the 5-year follow-up period. To estimate the association between baseline diagnosis (affective disorders vs. dementia) and all-cause mortality, we used a multivariate generalized linear model with robust standard errors. Of 1008 eligible patients, 114 age-matched pairs were included in the present study. The primary event occurred in 23 patients (20%) and 17 patients (15%) in the dementia and affective disorder group respectively. In the adjusted model, the risk of all cause mortality for the affective disorders group was 0.92 times the risk for the dementia group (95%CI, 0.54-1.59, p = 0.77). In conclusion, older patients with affective disorders starting antipsychotic treatment presented with a similar risk of all-cause mortality during the 5-year follow-up when compared to older patients with dementia who were also initiating either typical or atypical antipsychotic medications. Closer medical attention to older patients with mental conditions under antipsychotic treatment remains warranted. PMID- 29702306 TI - Network analysis of empathy items from the interpersonal reactivity index in 1973 young adults. AB - The aim of this work is to perform a network analysis on the French adaptation of the interpersonal reactivity index (IRI) scale from a large Belgian database and provide additional information for the construct of empathy. We analyze a database of 1973 healthy young adults who were queried on the IRI scale. A regularized partial correlation network is estimated. In the visualization of the model, items are displayed as nodes, edges represent regularized partial correlations between the nodes. Centrality denotes a node's connectedness with other nodes in the network. The spinglass algorithm and the walktrap algorithm are used to identify communities of items, and state-of-the-art stability analyses are carried out. The spinglass algorithm identifies four communities, the walktrap algorithm five communities. Positive edges are found among nodes belonging to the same community as well as among nodes belonging to different communities. Item 14 ("Other people's misfortunes do not usually disturb me a great deal") shows the highest strength centrality score. The network edges and node centrality order are accurately estimated. Network analysis highlights interesting connections between indicators of empathy; how these results impact empathy models must be assessed in further studies. PMID- 29702307 TI - Social-cognitive risk factors for violence in psychosis: A discriminant function analysis. AB - It has been proposed that mixed findings in studies investigating social cognition as a risk factor for violence in psychosis may be explained by utilizing a framework distinguishing between social-cognitive tests which measure relatively more basic operations (e.g. facial affect recognition) and measures of more complex operations (mentalizing, metacognition). The current study investigated which social cognitive and metacognitive processes are related to a violent history over and above illness-related deficits. Data from control participants (n = 33), patients with a psychotic disorder and no violent history (n = 27), and patients with a psychotic disorder in a forensic clinic (n = 23) were analyzed utilizing discriminant analysis. Metacognition and associative learning emerged as significant factors in predicting group membership between the three groups. In a follow-up analysis between only the patient groups, metacognitive Self-Reflectivity and Empathic Accuracy emerged as statistically significant predictors of group membership. The control group presented with higher levels of social cognitive and metacognitive capacity than patient groups, and the forensic patient group had lower levels than the non-forensic patient group. Our findings support previous research findings implying impaired metacognitive Self-Reflectivity in particular as a risk factor for violence. PMID- 29702309 TI - Clinical Significance of the Circle of Willis in Patients with Symptomatic Internal Carotid Artery Occlusion. AB - BACKGROUND: Despite improvements in medical treatment, many patients experience ischemic stroke owing to internal carotid artery occlusion. We retrospectively evaluated a novel method based on the arterial structure of the circle of Willis (CoW) to identify patients at a high risk of recurrent stroke. METHODS: The study enrolled 104 patients with symptomatic occlusion of the internal carotid artery. CoW integrity was evaluated by a quantitative scoring system based on conventional angiography. Patients were categorized into a good integrity (n = 45) or poor integrity (n = 59) group. Primary endpoint was early neurologic deterioration, recurrent ischemic stroke, or transient ischemic attack. RESULTS: History of ischemic stroke before initial presentation was more prevalent in the poor integrity group (22.2% vs. 47.5%, P = 0.01), and there were no differences between the 2 groups in terms of stroke risk factors. Overall estimated rate of the primary endpoint was 25.6% 2 years after angiography. It was 5.7% in the good integrity group and 39.8% in the poor integrity group (P < 0.001). In a Cox regression analysis, male sex (P = 0.01, hazard ratio = 6.60), use of a tissue plasminogen activator (P = 0.00, hazard ratio = 6.10), and poor integrity of CoW (P = 0.00, hazard ratio = 5.42) were risk factors for the primary endpoint. Patients in the poor integrity group with decreased vascular reserve experienced frequent primary endpoint events compared with patients in the good integrity group (P = 0.00). CONCLUSIONS: Patients with poor integrity of CoW are vulnerable to recurrent ischemic stroke and appear to require more aggressive treatment. PMID- 29702308 TI - Unilateral versus Bilateral Pedicle Screw Fixation Combined with Transforaminal Lumbar Interbody Fusion for the Treatment of Low Lumbar Degenerative Disc Diseases: Analysis of Clinical and Radiographic Results. AB - OBJECTIVE: To compare the clinical and radiographic results of unilateral pedicle screw fixation (UPSF) and bilateral pedicle screw fixation (BPSF) after unilateral transforaminal lumbar interbody fusion (TLIF) for the treatment of lumbar degenerative disc diseases (DDDs). METHODS: A total of 63 patients who underwent UPSF or BPSF combined with unilateral TLIF at L4-L5 or L5-S1 in our hospital between 2014 and 2016 were included in this analysis. The perioperative outcomes and radiographic results were recorded at preoperative and postoperative follow-up. Fusion rates were determined according to the Bridwell-Lenke grading system. Clinical outcomes were evaluated using the visual analog scale, Oswestry Disability Index, and lumbar Japanese Orthopedic Association score. RESULTS: According to the perioperative assessment, the duration of operation, intraoperative and postoperative blood loss, duration of pain medication use, and hospital costs were significantly (P < 0.0001) lower in the UPSF group compared with the BPSF group. After a mean follow-up of 24 months, both the UPSF and BPSF groups showed significantly (P < 0.05) maintained disc height and segmental lordosis of the surgical segment and achieved similar clinical outcomes at the final postoperative follow-up. The impact on the cranial adjacent vertebral level was significantly (P < 0.05) less in the UPSF group than the BPSF group in the short term. CONCLUSIONS: UPSF techniques with TLIF can attain similar clinical efficiency as BPSF techniques in treating single-level low lumbar DDD, but with fewer surgical injuries and at lower cost. BPSF with TLIF likely causes more degeneration at the cranial adjacent segment compared with UPSF techniques. The long-term results require more study. PMID- 29702310 TI - Endoscopic Anterior Approach for Cervical Disc Disease (Disc Preserving Surgery). AB - OBJECTIVE: To report our experience of endoscopic disc removal by anterior approach for management of cervical myelopathy in 210 patients. METHODS: A retrospective study of 187 cases of single- and 23 cases of double-level disc disease was performed. Cases of myelopathy with or without unilateral or bilateral radiculopathy and unilateral radiculopathy with either soft or hard disc prolapse were included. Patients with >=3 disc levels, unstable spine, infections, trauma, significant posterior compression, congenital canal stenosis, disc extending more than half the vertebral body height, and prior surgery at the same level were excluded. RESULTS: C5-6 (n = 119 patients), C6-7 (n = 58 patients), C4-5 (n = 49 patients), C3-4 (n = 6 patients), and C2-3 (n = 1 patient) levels were represented. Visual analog scale and Nurick grading system were used to assess severity of neck and arm pain and functional outcomes, respectively. Preoperative mean visual analog scale scores for arm and neck pain were 6.7 and 3.2, respectively, which improved to 1.7 and 1.1 at 3 months after surgery. The average preoperative Nurick grade improved from 2.64 to 0.81 at 6 months postoperatively. Follow-up was 6-54 months. CONCLUSIONS: Endoscopic anterior discectomy (disc preserving surgery) is an effective and safe alternative in cervical disc disease. Although there was reduction in disc height, clinical outcome was good at an average 29 months of follow-up. Long-term follow-up is required to assess any progressive disc degeneration and clinical results. PMID- 29702311 TI - Initial Experience with Intraoperative Phosphorous-32 Brachytherapy During Resection of Malignant Spinal Tumors. AB - INTRODUCTION: Brachytherapy is a major adjuvant modality for neoplasms, but few have trialed its use for spinal tumors. This study examines perioperative and oncologic outcomes of patients with malignant spinal tumors who underwent resection with intraoperative phosphorous-32 (P32) brachytherapy. METHODS: Consecutive adult patients who underwent P32 brachytherapy during malignant spinal tumor resection were retrospectively identified from 2014 to 2015. Complications, tumor recurrence, and survival were reviewed. A comprehensive review of the literature was performed. RESULTS: A total of 8 patients were included. Average age was 54.3 years, and 25.0% were males. Tumor types included metastatic leiomyosarcoma, chordoma, multifocal recurrent ependymomas, breast metastasis, malignant meningioma, and myxofibrosarcoma. One-half of patients underwent en bloc tumor resection. P32 plaques were applied to 2 sites per patient for mean 13.1 minutes per site with a goal penetration of 10 Gy to 1-mm depth. Perioperative complications occurred in 3 patients (37.5%), including a persistent cerebral spinal fluid leak, deep infection requiring reoperation, and sacral insufficiency fracture. At a mean 25.6 months follow-up, local recurrence rate was 25.0%, and overall survival was 75.0%. Mean time to recurrence was 14.4 months. Survival at 6, 12, 18, and 24 months was 100.0%, 100.0%, 85.7%, and 71.4%, respectively. CONCLUSIONS: The use of P32 is safe and feasible. P32 intraoperative brachytherapy does not seem to increase the rate of complications. The sample size of this series is small with heterogeneity in tumor type, but recurrence and survival outcomes seem promising compared with previous reports. Further clinical trials are needed. PMID- 29702313 TI - Comparison of Complications and Surgical Outcomes of Adolescent Idiopathic Scoliosis Between Junior Attending Surgeons and Senior Attending Surgeons. AB - BACKGROUND: To our knowledge, few studies have compared complications and surgical outcomes of adolescent idiopathic scoliosis (AIS) between junior attending surgeons and senior attending surgeons. OBJECTIVES: To compare surgical strategies, complications, and outcomes of posterior corrective surgery for AIS between junior attending surgeons and senior attending surgeons. METHODS: According to experience level of operation surgeons, the patients were assigned to 2 groups. Group A was the "junior surgeon" group. Group B was the "senior surgeon" group. The following parameters were compared between the 2 groups: age, sex, diagnosis, hospital of record, surgeon experience level, type of instrumentation, type of screws, estimated blood loss, duration of surgery, length of fusion, correction techniques, main curve correction, and thoracic kyphosis correction. RESULTS: A total of 132 patients with AIS were included in group A, whereas 207 were in group B. The translational technique was used more often in group A (P < 0.05). whereas the derotation technique was used more often in group B (P < 0.05). Senior surgeons used more monoaxial screws than junior surgeons (P < 0.05). The junior group had significantly greater estimated blood loss than the senior group (P < 0.05). The senior group had significant better correction rates of severe main curve (>70 degrees ) and thoracic kyphosis than the junior group (P < 0.05). CONCLUSIONS: Senior attending surgeons outperformed junior surgeons in blood loss control, thoracic kyphosis correction, and correction of severe curves. PMID- 29702312 TI - Intracranial Arterial Fenestration and Risk of Aneurysm: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Previous studies have been inconsistent regarding risk for intracranial aneurysm related to intracranial arterial fenestration. We conducted a meta-analysis to examine the association between intracranial arterial fenestration and risk of aneurysm. METHODS: We performed a systematic review of PubMed and Embase through August 2017 for potentially relevant articles. Summary odds ratios with 95% confidence intervals were pooled using a random-effects model. RESULTS: Of 446 articles found, 7 were selected for meta-analysis. Pooled odds ratios revealed an increased risk of aneurysm owing to fenestration of 1.50 (95% confidence interval, 0.61-3.71; P = 0.38). Subgroup analyses based on the population presenting with various indications suggested that pooled odds ratios indicated a significant increase in risk for aneurysm of 2.43 (95% confidence interval, 1.04-5.69; P = 0.04). CONCLUSIONS: Our findings indicate that intracranial arterial fenestration may be associated with increased risk for aneurysm formation. PMID- 29702314 TI - Ethyl p-coumarate exerts antifungal activity in vitro and in vivo against fruit Alternaria alternata via membrane-targeted mechanism. AB - The fungus Alternaria alternata can cause food contamination by black spot rot and food safety issues due to the production of mycotoxins. In particular, A. alternata can infect many fresh fruits and vegetables and lead to considerable postharvest decay during storage and processing. The use of plant-derived products in postharvest disease management may be an acceptable alternative to traditional chemical fungicides. The aim of this study was to assess the antifungal activity of ethyl p-coumarate (EpCA) against Alternaria alternata in vitro and in vivo, and to determine the underlying mechanism. Results indicated that EpCA exhibited pronounced antifungal activity against in vitro mycelial growth of A. alternata, with half-inhibition concentration of 176.8 MUg/mL. Spore germination of the pathogen was inhibited by EpCA in a dose-dependent manner. Moreover, in vivo test confirmed that both 100 and 800 MUg/mL EpCA significantly reduced disease development of black spot rot in jujube fruit caused by A. alternata. The EpCA treatments increased plasma membrane permeability as great leakage of intercellular electrolytes, soluble proteins and sugars of A. alternata occurred during incubation. The EpCA treatments also caused increase of the influx of propidium iodide, a fluorescence dye binding nucleus DNA, into the affected spores, indicating the disrupted plasma membrane integrity. Observations of ultrastructure further evidenced the damage to plasma membrane and morphology of A. alternata caused by EpCA, which resulted in distortion, sunken and shrivelled of spores and mycelia of the pathogen. In addition, fluorometric assay by confocal laser scanning microscopy confirmed that the EpCA treatments induced endogenous reactive oxygen species (ROS) formation in the spores of A. alternata, with stronger and more stable accumulation of ROS at higher concentration of EpCA. Therefore, heavy oxidative damage to cellular membranes and organelles might happen as demonstrated by the severe occurrence of lipid peroxidation of the pathogen treated with EpCA. Taken together, these results indicated that EpCA exerts antifungal activity via membrane-targeted mechanism and it would be a promising candidate to control postharvest diseases of fruits. PMID- 29702315 TI - Enteroaggregative Escherichia coli is the predominant diarrheagenic E. coli pathotype among irrigation water and food sources in South Africa. AB - Diarrheagenic E. coli (DEC) has been implicated in foodborne outbreaks worldwide and have been associated with childhood stunting in the absence of diarrhoea. Infection is extraordinarily common, but the routes of transmission have not been determined. Therefore, determining the most prevalent pathotypes in food and environmental sources may help provide better guidance to various stakeholders in ensuring food safety and public health and advancing understanding of the epidemiology of enteric disease. We characterized 205 E. coli strains previously isolated from producer distributor bulk milk (PDBM)(118), irrigation water (48), irrigated lettuce (29) and street vendor coleslaw (10) in South Africa. Enteropathogenic E. coli (EPEC), enterotoxigenic E. coli (ETEC), enteroaggregative E. coli (EAEC) and diffusely adherent E. coli (DAEC) were sought. We used PCR and partial gene sequencing for all 205 strains while 46 out of 205 that showed poor resolution were subsequently characterized using cell adherence (HeLa cells). PCR and partial gene sequencing of aatA and/or aaiC genes confirmed EAEC (2%, 5 out of 205) as the only pathotype. Phylogenetic analysis of sequenced EAEC strains with E. coli strains in GenBank showing >=80% nucleotide sequence similarity based on possession of aaiC and aatA generated distinct clusters of strains separated predominantly based on their source of isolation (food source or human stool) suggesting a potential role of virulence genes in source tracking. EAEC 24%, 11 out of 46 strains (PDBM = 15%, irrigation water = 7%, irrigated lettuce = 2%) was similarly the predominant pathotype followed by strains showing invasiveness to HeLa cells, 4%, 2 out of 46 (PDBM = 2%, irrigated lettuce = 2%), among stains characterized using cell adherence. Therefore, EAEC may be the leading cause of DEC associated food and water-borne enteric infection in South Africa. Additionally, solely using molecular based methods targeting virulence gene determinants may underestimate prevalence, especially among heterogeneous pathogens such as EAEC. PMID- 29702316 TI - Modelling the sporulation of some fungi associated with cheese, at different temperature and water activity regimes. AB - The objectives of this study were to determine, in-vitro, the influence of temperature (T; 10-30 degrees C, step 5 degrees ), water activity (aw, 0.83 0.99; step 0.04) and time on sporulation (SPO) of some cheese-related fungi belonging to Penicillium spp. and A. versicolor. Overall, sporulation started rapidly (8 h in optimal conditions); it was significantly influenced by T and aw and the fungi studied were clearly distinguished based on their thermo-hydro adaptation. Boundary conditions for sporulation were defined for all the fungi considered and the sporulation rate was successfully modelled, especially based on T and time regimes. Penicillium crustosum, P. nordicum and P. verrucosum showed optimum for SPO at T between 20 and 25 degrees C and their sporulation continued up to aw = 0.87 (aw = 0.83 for P. nordicum). They resulted the fungi best adapted to the environmental conditions of ripening grana cheese storehouses; therefore, it is expected they dominate on the grana cheese surface. Studies on cheese are necessary to validate these results obtained on artificial media and without fungi co-occurrence. PMID- 29702318 TI - Control of Salmonella enterica and Listeria monocytogenes in hummus using allyl isothiocyanate. AB - Hummus (chickpea dip) is a ready-to-eat product which has been implicated in several foodborne outbreaks and food recalls. This study aimed to screen the antimicrobial activity of allyl isothiocyanate (AITC) against 5 strains of each of Salmonella enterica and Listeria monocytogenes using a disc diffusion method. Additionally, the antimicrobial activity of 0.1-1.5% (v/w) AITC against both pathogens and aerobic bacteria in hummus was also investigated. The inhibition zones of AITC were 8.5-15 and 7.0-8.5 mm against the S. enterica and L. monocytogenes strains, respectively, at 37 degrees C. S. enterica numbers were reduced by >6 log10 CFU/g in hummus containing >=0.5% AITC by 3 days at both 4 and 10 degrees C. While 0.1-0.25% AITC reduced S. enterica by 2.5-5.1 log10 CFU/g at 4 degrees C or by 4.7-6.0 log10 CFU/g at 10 degrees C by 10 days. Similarly, L. monocytogenes numbers decreased by >6 log10 CFU/g in hummus with >=0.5% or >=1.0% AITC at 4 or 10 degrees C, respectively, by 3 days. Further, 0.25% AITC significantly reduced L. monocytogenes in hummus by 2.7 and 4.3 log10 CFU/g at 4 and 10 degrees C, respectively. Moreover, 0.1% AITC reduced L. monocytogenes by 1.8 log10 CFU/g in hummus at 10 degrees C and inhibited the growth at 4 degrees C for up to 10 days. The aerobic bacterial count also significantly decreased in un-inoculated hummus treated with 1.0-1.5% AITC at both 4 and 10 degrees C, while a concentration of 0.25-0.5% AITC inhibited their growth at 4 degrees C. AITC can be used to reduce the risk of salmonellosis or listeriosis in hummus and extend its shelf-life. PMID- 29702317 TI - Microbial dynamics of model Fabriano-like fermented sausages as affected by starter cultures, nitrates and nitrites. AB - The present study promotes the valorization of Fabriano-like fermented sausages, which are central-Italy salami with an origin that dates to the early 17th century, for the possible future selection of autochthonous starter cultures to be used with respect to local traditions. To the best of the authors' knowledge, this study represents the first attempt to define the microbial dynamics in Fabriano-like fermented sausage and the effect of nitrates/nitrites and starter cultures on its natural bacterial biota. Culture and RNA-based techniques (RT-PCR DGGE and Illumina sequencing) were used to assess the microbial ecology of model Fabriano-like fermented sausages together with the impact of starter cultures and different nitrate and nitrite concentrations. The meat batter was used to produce two batches of fermented sausages that were prepared as follows: i) without commercial starters or ii) with the use of starter cultures composed of Pediococcus pentosaceus and Staphylococcus xylosus. Each batch was further divided into three different batches with the addition of 0/0 mg kg-1 nitrate/nitrite, 75/60 mg kg-1 nitrate/nitrite and 150/125 mg kg-1 nitrate/nitrite to the first, second and third batch, respectively. The samples, which were produced in triplicate, were analyzed on the day of production and after 7, 21, and 42 days of ripening. Enterobacteriaceae counts were always higher in model Fabriano-like sausages produced without the use of starter cultures at all of the sampling times irrespective of the tested nitrate/nitrite concentrations. Lactobacilli counts were positively influenced by the starters, although this influence was not evident over time; moreover, the effect of nitrates and nitrites on the counts of lactobacilli differed over time. As a general trend, coagulase-negative cocci counts were apparently not influenced by the tested nitrate/nitrite concentrations. Regarding the effect of nitrates/nitrites on the microbial diversity revealed by RT-PCR-DGGE, the higher the concentration, the lower the presence of some genera/species such as Pseudomonas spp., Serratia liquefaciens and Staphylococcus spp. However, Illumina sequencing detected Pseudomonas spp. as a minority species after 7, 21 and 42 days of ripening irrespective of the nitrate/nitrite concentration. The presence of Staphylococcus species was highlighted by both RT-PCR-DGGE and Illumina sequencing at all of the stages of ripening, although its presence was massively detected in fermented sausages produced without the use of nitrates/nitrites at the end of ripening. Overall, the data collected clearly highlighted the dominance of Lactobacillus sakei in all of the fermented sausages during ripening (from day 7 to day 42) and irrespective of the nitrate/nitrite concentration and added starter cultures. Moreover, Pediococcus spp. was principally detected in model Fabriano-like fermented sausage with added starter cultures irrespective of the nitrate/nitrite concentration. PMID- 29702319 TI - Synthesis of mesoporous silica-calcium phosphate hybrid nanoparticles and their potential as efficient adsorbent for cadmium ions removal from aqueous solution. AB - Since adsorption and nanomaterials had been respectively found to be the most promising technique and the preferred adsorbents for heavy metal ions removal, in this study, novel mesoporous silica-calcium phosphate (MS-CP) hybrid nanoparticles were synthesized by a facile one-pot method, and subsequently assessed as adsorbent for Cd2+ removal from aqueous solution. MS-CP were characterized by scanning and transmission electron microscopies, etc. The influences of initial Cd2+ concentration, contact time, solution temperature and solution pH on removal efficiency of Cd2+ were investigated in detail. The results revealed that MS-CP were nanospheres of ~20 nm and presented a bimodal pore distribution (3.82 nm and 12.40 nm), a high surface area (314.56 m2/g) and a large pore volume (1.21 cm3/g). The Cd2+ removal experiments demonstrated that MS CP had a high adsorption capacity due to electrostatic interaction between Cd2+ and silanol groups on MS-CP surface, as well as ion-exchange between Cd2+ and calcium in MS-CP. Additionally, removal efficiency of Cd2+ increased with increasing contact time and solution temperature, while decreased as initial Cd2+ concentration increased. The maximum adsorption capacity of Cd2+ by MS-CP was above 153 mg/L. These results suggested that the as-synthesized MS-CP could be promising adsorbent for Cd2+ removal from aqueous solution. PMID- 29702320 TI - Self-assembled supramolecular system PDINH on TiO2 surface enhances hydrogen production. AB - Constructing organic-inorganic hybrids is one of the hopeful strategies to improve photocatalyst performance. In this study, perylene-3,4,9,10 tetracarboxylic diimide (PDINH) and commercial TiO2 P25 are chosen as raw materials to construct a PDINH/TiO2 organic-inorganic hybrid, which has higher photocatalytic H2 production activity and photocurrent intensity than pure PDINH and TiO2, respectively. The apparent quantum efficiency for H2 production over 0.5%PDINH/TiO2 reaches as high as 70.69% using irradiation at 365 nm. Moreover, XRD, DRS, HRTEM, FT-IR, and XPS are used to characterize the crystal structure, optical absorption, morphology, molecular structure, and chemical bonds, as well as the elemental and chemical states of PDINH/TiO2 organic-inorganic hybrid. The interfaces between PDINH and TiO2, which largely determine photocatalytic performance, is also analyzed systematically. Furthermore, charge density difference (Deltarho) is used to analyze the electron-ion interactions of PDINH and TiO2, and reveals that substantial charge transfer occurs from PDINH to TiO2. PMID- 29702321 TI - Bifunctional nanoscale magnetic chains with high saturation magnetization and catalytic activity. AB - The conventional stirring method cannot be employed for chip-on-lab reactions such as microfluidic and microdroplet reactions as well as nanoscale reactions. Therefore, it is necessary to design a nanoscale magnetic stirrer with a high magnetic response towards the external magnetic field. In this work, one dimentional core@shell structured Fe-Fe2O3@poly(cyclotriphosphazene-co-4,4' sulfonyldiphenol) magnetic nanochains modified by nickel hydroxide (denoted as Fe Fe2O3@PZS@Ni(OH)2 NCs) as nanoscale magnetic stirrer and recyclable self-mixing nanocatalysts are successfully prepared through three steps: synthesis of Fe Fe2O3 nanochains (NCs) with high saturation magnetization, coating with poly (cyclotriphosphazene-co-4,4'-sulfonyldiphenol) (PZS), and nickel hydroxide's anchoring on the surface of Fe-Fe2O3@PZS NCs. The cross-linked polymer PZS is used to protect Fe-Fe2O3 NCs from chemical corrosion and as a platform for subsequent immobilization of nickel hydroxide. Characterization results show that the Fe-Fe2O3@PZS@Ni(OH)2 NCs own chainlike structure and high saturation magnetization of 103 emu g-1 at room temperature, exhibiting high magnetic response to the external rotating magnetic field. In the macro-reaction system for 4-nitrophenol (4-NP) reduction, the as-prepared Fe-Fe2O3@PZS@Ni(OH)2 NCs show an apparent rate constant of about 0.60 min-1. Furthermore, the Fe Fe2O3@PZS@Ni(OH)2 catalyst is reused ten times while no obvious loss of catalytic activity was observed. In the micro-reaction system, the Fe-Fe2O3@PZS@Ni(OH)2 NCs also display good magnetic response and favorable catalytic activity for the hydrogenation of methylene blue. These results indicate that the bifunctional Fe Fe2O3@PZS@Ni(OH)2 NCs with high saturation magnetization have great potential as excellent nanocatalysts and as promising nanoscale magnetic stirrers. PMID- 29702322 TI - Capillary condensation and gelling of microemulsions with clay additives. AB - The capillary condensation in bicontinuous microemulsions takes place when two parallel surfaces are narrowed that result in a completely lamellar microemulsion. We expected that this phase transition is also observable when the amount of hydrophilic surfaces from clay particles is raised, because hydrophilic surfaces induce lamellar ordering locally. Using small angle neutron scattering, the structure of microemulsions was observed as a function of clay content. The critical concentration is indicated by discontinuous structural changes and depends on the platelet diameter and is explained by the free energy of the platelets competing with the fluctuating medium. The gel phase transition is observed in the spectroscopic measurements where the diffusion motion is widely suppressed in the gel phase, but otherwise superimposes with the membrane undulations. PMID- 29702323 TI - Two-component gelator isomers with different combination of amine and acid: Helical/non-helical morphology and selective adsorption of dyes. AB - Hydrogels induced by two-component gelator isomers based on the different amine/acid interactions were investigated. Scanning electron microscopy and atomic force microscopy images of the xerogel obtained from the two hydrogels revealed different assembly morphologies. While left-handed helical fibers were observed for the amine-acid based xerogel, acid-amine underwent self-assembly to afford smooth fibers. Fourier transform infrared spectroscopy, fluorescence, and X-ray diffraction measurements combined with density functional theory calculations suggested that the different self-assembly patterns of gelators resulted in opposite electric charges on the xerogel surfaces, in line with Zeta potential measurements. Based on these opposite charges resulting from their different self-assemblies, both xerogels demonstrated efficient dye adsorption abilities with different selectivities. Interestingly, the adsorption performance was not influenced by the salt in the dye solution. Furthermore, the xerogels still showed high dye adsorption efficiency after four cycles. These results provide a two-component hydrogel method for the purification of dye-polluted water systems, while also paving the way for future design of functionalized supramolecular self-assembly systems. PMID- 29702324 TI - Bismuth oxychloride (BiOCl)/copper phthalocyanine (CuTNPc) heterostructures immobilized on electrospun polyacrylonitrile nanofibers with enhanced activity for floating photocatalysis. AB - The 2,9,16,23-tetranitro phthalocyanine copper (II) nanostructures and bismuth oxychloride nanosheets were grown on electrospun polyacrylonitrile (PAN) nanofibers in sequence by solvothermal method. As a result, the BiOCl/CuTNPc heterostructures were uniformly immobilized on the PAN nanofibers. The obtained BiOCl/CuTNPc/PAN nanofibers had excellent photocatalytic activity for the degradation of rhodamine B (RhB) under UV-vis light irradiation. The first-order rate constant of the BiOCl/CuTNPc/PAN nanofibers was 5.86 and 6.31 times as much as CuTNPc/PAN and BiOCl/PAN nanofibers, respectively. The high photocatalytic activity could be attributed to the formation of BiOCl/CuTNPc heterostructures, which helped the separation of the photogenerated electron-hole pairs. Concurrently, the marcoporous structure of the BiOCl/CuTNPc/PAN nanofibers improved the photocatalytic activity due to the increased interface contacts between the photocatalyst and the RhB solution. The BiOCl/CuTNPc/PAN nanofibers did not need to be separated for reuse due to their flexible self-supporting properties originating from the PAN nanofibers. Moreover, the film-like BiOCl/CuTNPc/PAN nanofibers could float easily on the liquid and maximize the absorption of sunlight during photocatalysis. It was expected that the BiOCl/CuTNPc/PAN nanofibers with high photocatalytic activity and easily separable property will possess great potential in the field of industrial applications and environmental remediation. PMID- 29702325 TI - Amorphous tantalum oxyhydroxide homojunction: In situ construction for enhanced hydrogen production. AB - An amorphous tantalum oxyhydroxide TaOx(OH)y homojunction is constructed by anchoring TaOx(OH)y (2x + y = 5) nanoparticles (NPs, size: 4-10 nm) in situ on the surface of TaOx(OH)y sphere (SP). The formation of amorphous homojunction (TaOx(OH)y NPs/SP) is demonstrated by detailed characterizations of transmission electron microscopy, thermogravimetric analysis/mass spectrometer, Fourier transfer infrared spectra and X-ray photoelectron spectroscopy. In the absence of cocatalyst, the constructed amorphous homojunction exhibits a photocatalytic H2 evolution rate of 311.1 MUmol/g/h, about 5, 40 and 1000 times higher than that of 66.8 MUmol/g/h for bare TaOx(OH)y SP, 7.6 MUmol/g/h for commercial Ta2O5, and 0.3 MUmol/g/h for the most widely used photocatalyst P25 (mixed-phase titania). The splendid performance is attributed to the special amorphous homojunction that produces a type-II band alignment and robust separation of photo-excited charge carriers, as uncovered by ultraviolet photoelectron, photoluminescence spectroscopy, and surface/transient photovoltage data. Our findings for amorphous homojunction may provide a new strategy of developing effective noncrystalline photocatalysts. PMID- 29702326 TI - Geochemistry and carbon isotopic ratio for assessment of PM10 composition, source and seasonal trends in urban environment. AB - Investigating the nature of PM10 is crucial to differentiate sources and their relative contributions. In this study we compared the levels, and the chemical and mineralogical properties of PM10 particles sampled in different seasons at monitoring stations representative of urban background, urban traffic and suburban traffic areas of Naples city. The aims were to relate the PM10 load and characteristics to the location of the monitoring stations, to investigate the different sources contributing to PM10 and to highlight PM10 seasonal variability. Bulk analyses of chemical species in the PM10 fraction included total carbon and nitrogen, delta13C and other 20 elements. Both natural and anthropogenic sources were found to contribute to the exceedances of the EU PM10 limit values. The natural contribution was mainly related to marine aerosols and soil dust, as highlighted by X-ray diffractometry and SEM-EDS microscopy. The percentage of total carbon suggested a higher contribution of biogenic components to PM10 in spring. However, this result was not supported by the delta13C values which were seasonally homogeneous and not sufficient to extract single emission sources. No significant differences, in terms of PM10 load and chemistry, were observed between monitoring stations with different locations, suggesting a homogeneous distribution of PM10 on the studied area in all seasons. The anthropogenic contribution to PM10 seemed to dominate in all sites and seasons with vehicular traffic acting as a main source mostly by generation of non exhaust emissions Our findings reinforce the need to focus more on the analysis of PM10 in terms of quality than of load, to reconsider the criteria for the classification and the spatial distribution of the monitoring stations within urban and suburban areas, with a special attention to the background location, and to emphasize all the policies promoting sustainable mobility and reduction of both exhaust and not-exhaust traffic-related emissions. PMID- 29702327 TI - Clinical and research uses of genetic risk scores in type 1 diabetes. AB - Type 1 diabetes (T1D) is a chronic disease of high blood glucose caused by autoimmune destruction of pancreatic beta cells eventually resulting in severe insulin deficiency. T1D has a significant heritable risk. Genetic associations found are particularly strong in the HLA class II region but T1D is a polygenic disease associated with over 60 loci across the genome. Polygenic risk scores are one method of summing these genetic risk elements as a single continuous variable. This review discusses the clinical and research utility of genetic risk scores in T1D particularly in disease prediction and progression. We also explore creative uses of genetic risk scores in big data and the limitations of using a genetic risk score. The increase in publically available genetic data and rapid fall in costs of genotyping mean that a T1D genetic risk score (T1D GRS) is likely to prove useful for disease prediction, discrimination, investigation of unusual cohorts, and investigation of biology in large datasets where genetic data are available. PMID- 29702328 TI - In vivo and ex vivo elastic properties of brain tissues measured with ultrasound elastography. AB - Determining the mechanical properties of brain tissues is essential in the field of brain biomechanics. In this paper, we use ultrasound-based shear wave elastography to measure both in vivo and ex vivo elastic properties of brain tissues. Our results demonstrate that the shear modulus from in vivo measurements is about 47% higher than that given by the ex vivo measurements (p value = 0.0063). The change in ex vivo elastic properties within 60-min post-mortem is negligible. The results also show that within 60-min post-mortem and in a temperature range of 37-23 degrees C, the elastic properties of brain tissues approximately linearly depend on the temperature in both cooling and re-heating processes. PMID- 29702329 TI - Secular trends and etiologies of venous thromboembolism in Chinese from 2004 to 2016. AB - INTRODUCTION: Current epidemiological data for venous thromboembolism (VTE) are derived primarily from Caucasian populations from North America. Little is known for other ethnic groups. This study aimed to describe the incidence, etiologies, and the secular trends of VTE in a Chinese population. MATERIALS AND METHODS: This was an observational study using a hospital VTE registry. RESULTS AND CONCLUSIONS: Between 2004 and 2016, 2214 patients (mean age 66.2 +/- 17.4 years, 57.2% female) were hospitalized for a novel occurrence of venous thromboembolism. Of these, 1444 patients (65.2%) had deep venous thrombosis and 770 patients (34.8%) had pulmonary embolism. Over the 13-year period, there was an increasing trend in the incidence of VTE from 28.1 per 100,000 population per year in 2004 to 48.3 per 100,000 population per year in 2016. There has been a disproportional increase in the incidence of VTE among those aged 75 years or above. Etiologically, the most common cause of VTE was active malignancy with an incidence that increased from 34.8% in 2005 to 60.9% in 2014. In conclusion, the incidence of venous thromboembolism in Hong Kong appears to be lower than that in previous Caucasian series. Nonetheless there has been an increasing incidence of VTE over the past decade, primarily related to aging and malignancy. PMID- 29702330 TI - Stutter analysis of complex STR MPS data. AB - Stutters are common and well documented artefacts of amplification of short tandem repeat (STR) regions when using polymerase chain reaction (PCR) occurring as strands one or more motifs shorter or longer than the parental allele. Understanding the mechanism and rate by which stutters are created is especially important when the samples contain small amounts of DNA or DNA from multiple contributors. It has been shown that there is a linear relationship between the longest uninterrupted stretch (LUS) and the stutter ratio. This holds if there is only a single type of stutter variant. However, with massively parallel sequencing (MPS), we see that alleles may create different stutters corresponding to stuttering of different parts of the parental allele. This calls for a refinement of the LUS concept. We analysed all uninterrupted stretches, here called blocks, and identified the block from which the stutter originated. We defined the block length of the missing motif (BLMM) as the length of the identified block. We found that the relationship between the stutter ratio and BLMM was linear using a simple system of recurrence relations. We found that the mean square error decreased by a factor up to 17.5 for compound and complex autosomal markers when using BLMM instead of LUS. PMID- 29702331 TI - Frontal crashworthiness characterisation of a vehicle segment using curve comparison metrics. AB - The objective of this work is to propose a methodology for the characterization of the collision behaviour and crashworthiness of a segment of vehicles, by selecting the vehicle that best represents that group. It would be useful in the development of deformable barriers, to be used in crash tests intended to study vehicle compatibility, as well as for the definition of the representative standard pulses used in numerical simulations or component testing. The characterisation and selection of representative vehicles is based on the objective comparison of the occupant compartment acceleration and barrier force pulses, obtained during crash tests, by using appropriate comparison metrics. This method is complemented with another one, based exclusively on the comparison of a few characteristic parameters of crash behaviour obtained from the previous curves. The method has been applied to different vehicle groups, using test data from a sample of vehicles. During this application, the performance of several metrics usually employed in the validation of simulation models have been analysed, and the most efficient ones have been selected for the task. The methodology finally defined is useful for vehicle segment characterization, taken into account aspects of crash behaviour related to the shape of the curves, difficult to represent by simple numerical parameters, and it may be tuned in future works when applied to larger and different samples. PMID- 29702332 TI - The influence of bus and taxi drivers' public self-consciousness and social anxiety on aberrant driving behaviors. AB - The study examined how bus and taxi drivers' public self-consciousness interacted with social anxiety to influence their aberrant driving behaviors. Questionnaires were distributed to 331 male and female Taiwanese bus and taxi drivers whose working environment involves frequent and direct interaction with passengers. Questionnaire statements measured drivers' dispositional public self consciousness and social anxiety, and their intentions and driving behaviors related to speeding, errors and violations. The study utilized a mediating model and path analysis explored causal relationships between the constructs. The study found that both public self-consciousness and social anxiety explained bus drivers' aberrant driving behaviors. Female drivers reported less aberrant driving behaviors than their male counterparts did. Bus drivers reported less aberrant driving behaviors than taxi drivers. Drivers with crash involvement within three years reported higher public self-consciousness than did those without that involvement. The suitable research frameworks, which describe the influence of public self-consciousness and social anxiety on aberrant driving behaviors, fit to bus and taxi drivers are different, so as different to male and female drivers. The study findings suggest bus and taxi driver should receive special training in general attitude as a condition of their employment in order to avoid aggressive behaviors and provide a better and safer service to the public. PMID- 29702333 TI - An exploratory study of long-haul truck drivers' secondary tasks and reasons for performing them. AB - Research on drivers has shown how certain visual-manual secondary tasks, unrelated to driving, increase the risk of being involved in crashes. The purpose of the study was to investigate (1) if long-haul truck drivers in Sweden engage in secondary tasks while driving, what tasks are performed and how frequently, (2) the drivers' self-perceived reason/s for performing them, and (3) if psychological factors might reveal reasons for their engaging in secondary tasks. The study comprised 13 long-haul truck drivers and was conducted through observations, interviews, and questionnaires. The drivers performed secondary tasks, such as work environment related "necessities" (e.g., getting food and/or beverages from the refrigerator/bag, eating, drinking, removing a jacket, face rubbing, and adjusting the seat), interacting with a mobile phone/in-truck technology, and doing administrative tasks. The long-haul truck drivers feel bored and use secondary tasks as a coping strategy to alleviate boredom/drowsiness, and for social interaction. The higher number of performed secondary tasks could be explained by lower age, shorter driver experience, less openness to experience, lower honesty-humility, lower perceived stress, lower workload, and by higher health-related quality of life. These explanatory results may serve as a starting point for further studies on large samples to develop a safer and healthier environment for long-haul truck drivers. PMID- 29702334 TI - microRNAs in Sudden Unexpected Death in Epilepsy (SUDEP): Location matters. PMID- 29702335 TI - DRD2/ANKK1 gene polymorphisms in forensic autopsies of methamphetamine intoxication fatalities. AB - Dopamine D2 receptor/ankyrin repeat and kinase domain containing 1 (DRD2/ANKK1) gene polymorphisms have been associated with responses to psychotropic drugs and addiction. We analyzed two DRD2/ANKK1 polymorphisms, Taq1A and -141C Ins/Del, in 37 fatal methamphetamine (MA) intoxication cases and 235 control cases in which MA and psychotropic drugs were not detected. The association among polymorphism, cause of death, and cerebrospinal fluid (CSF) dopamine concentration was evaluated. The Taq1A polymorphism distribution in the fatal MA intoxication cases differed from in the controls (P = 0.030) with a significantly high A1/A1 + A1/A2 genotype frequency. No significant associations were observed between -141C Ins/Del polymorphisms and MA intoxication cases or between DRD2/ANKK1 polymorphisms and CSF dopamine concentrations. Our findings suggest that the DRD2/ANKK1 Taq1A polymorphism is associated with susceptibility to fatal MA intoxication. PMID- 29702336 TI - A cluster-analytic profiling of heroin-dependent patients based on level, clinical adequacy, and patient-desired adjustment of buprenorphine dosage during buprenorphine-naloxone maintenance treatment in sixteen Spanish centers. AB - BACKGROUND: Buprenorphine dosage is a crucial factor influencing outcomes of buprenorphine treatment for heroin use disorders. Therefore, the aim of the present study is to identify naturally occurring profiles of heroin-dependent patients regarding individualized management of buprenorphine dosage in clinical practice of buprenorphine-naloxone maintenance treatment. METHODS: 316 patients receiving buprenorphine-naloxone maintenance treatment were surveyed at 16 Spanish centers during the stabilization phase of this treatment. Patients were grouped using cluster analysis based on three key indicators of buprenorphine dosage management: dose, adequacy according to physician, and adjustment according to patient. The clusters obtained were compared regarding different facets of patient clinical condition. RESULTS: Four clusters were identified and labeled as follows (buprenorphine average dose and percentage of participants in each cluster are given in brackets): "Clinically Adequate and Adjusted to Patient Desired Low Dosage" (2.60 mg/d, 37.05%); "Clinically Adequate and Adjusted to Patient Desired High Dosage" (10.71 mg/d, 29.18%); "Clinically Adequate and Patient Desired Reduction of Low Dosage" (3.38 mg/d, 20.0%); and "Clinically Inadequate and Adjusted to Patient Desired Moderate Dosage" (7.55 mg/d, 13.77%). Compared to patients from the other three clusters, participants in the latter cluster reported more frequent use of heroin and cocaine during last week, lower satisfaction with buprenorphine-naloxone as a medication, higher prevalence of buprenorphine-naloxone adverse effects and poorer psychological adjustment. CONCLUSIONS: Our results show notable differences between clusters of heroin dependent patients regarding buprenorphine dosage management. We also identified a group of patients receiving clinically inadequate buprenorphine dosage, which was related to poorer clinical condition. PMID- 29702337 TI - Correlates and subgroups of injecting drug use in UK gay and bisexual men: Findings from the 2014 Gay Men's Sex Survey. AB - BACKGROUND: Evidence to understand which gay and bisexual men (GBM) inject drugs remains scant, especially in the UK. We describe correlates of last-year injecting in UK GBM, and characterise subgroups of GBM who inject drugs by types of drugs used. METHODS: Using data from the 2014 Gay Men's Sex Survey, an opportunistic internet-based survey conducted of GBM living in the UK, we examined via logistic regression correlates with any injecting of six drugs (amphetamine/speed, crystal methamphetamine, heroin, mephedrone, GHB/GBL, and ketamine) in the last year. We estimated latent class models to understand underlying subgroups of injecting drug use among GBM reporting injecting drug use in the last year. RESULTS: Injecting was most common in GBM who were of middle age, who were HIV seropositive, and who lived in London, and was significantly associated with sexual risk with multiple partners in the last year, whether steady or non-steady. Most GBM who engaged in injecting either injected crystal methamphetamine, mephedrone or both (class 1, chemsex, 88.6% of injectors), whereas a smaller group had a focus on opiates (class 2, opiate, 7.9%). A small but identifiable subgroup (class 3, eclectic, 3.5%) engaged in injecting across the range of drugs examined. CONCLUSIONS: This is the first epidemiological analysis to describe subgroups of injecting, and to describe correlates of injecting drug use, in UK GBM. Implications for design of harm reduction services include a need to focus on injecting drug use beyond opiates, currently the focus of most harm reduction services. PMID- 29702338 TI - Genetic correlation of antisocial behaviour with alcohol, nicotine, and cannabis use. AB - BACKGROUND: There is high comorbidity between antisocial behaviour (ASB) and substance use, and twin studies have shown that part of the covariation is due to overlapping genetic influences. Here we used measured genetic effects to estimate the genetic correlations of ASB with nicotine, alcohol, and cannabis use. METHODS: We meta-analysed data from two genome-wide association studies for ASB and used existing summary statistics from the largest genome-wide association studies into substance use (ever smoking, cigarettes smoked per day, weekly alcohol consumption, and lifetime cannabis use). We performed cross-trait LD score regression to estimate genetic correlations between ASB and substance use phenotypes explained by all single nucleotide polymorphisms (SNPs). When significant, we tested whether the signs of the regression coefficients of SNPs from the ASB and substance use phenotypes were in the same direction across multiple p-value thresholds and examined enrichment in overlap of the strongest associated SNPs. RESULTS: We found nominally significant genetic correlations of ASB with lifetime cannabis use (rg = 0.69, p=.016) and cigarettes per day (rg = 0.59, p = 0.036) but not with weekly alcohol consumption or ever smoking. Sign tests revealed consistent directions of effect of SNPs for ASB and cannabis use for all p-value thresholds except the most stringent one, whereas for ASB with cigarettes per day no consistent evidence was found. We found no evidence of enrichment in overlap of the most associated SNPs across these traits. CONCLUSION: Using measured genetic variants, we found preliminary support for a genetic correlation of ASB with lifetime cannabis use and cigarettes per day. PMID- 29702339 TI - Investigation on the interaction of Rutin with serum albumins: Insights from spectroscopic and molecular docking techniques. AB - The binding interaction of Rutin, a flavonoid, with model transport proteins, bovine serum albumin (BSA) and human serum albumin (HSA), were investigated using different spectroscopic techniques, such as fluorescence, time-resolved single photon counting (TCSPC) and circular dichroism (CD) spectroscopy as well as molecular docking method. The emission studies revealed that the fluorescence quenching of BSA/HSA by Rutin occurred through a simultaneous static and dynamic quenching process, and we have evaluated both the quenching constants individually. The binding constants of Rutin-BSA and Rutin-HSA system were found to be 2.14 * 106 M-1 and 2.36 * 106 M-1 at 298 K respectively, which were quite high. Further, influence of some biologically significant metal ions (Ca2+, Zn2+ and Mg2+) on binding of Rutin to BSA and HSA were also investigated. Thermodynamic parameters justified the involvement of hydrogen bonding and weak van der Waals forces in the interaction of Rutin with both BSA and HSA. Further a site-marker competitive experiment was performed to evaluate Rutin binding site in the albumins. Additionally, the CD spectra of BSA and HSA revealed that the secondary structure of the proteins was perturbed in the presence of Rutin. Finally protein-ligand docking studies have also been performed to determine the probable location of the ligand molecule. PMID- 29702341 TI - A network-based frequency analysis of Inclusive Wealth to track sustainable development in world countries. AB - Using human (HC), natural (NC), and produced (PC) capital from Inclusive Wealth as representatives of the triple bottom line of sustainability and utilizing elements of network science, we introduce a Network-based Frequency Analysis (NFA) method to track sustainable development in world countries from 1990 to 2014. The method compares every country with every other and links them when values are close. The country with the most links becomes the main trend, and the performance of every other country is assessed based on its 'orbital' distance from the main trend. Orbital speeds are then calculated to evaluate country specific dynamic trends. Overall, we find an optimistic trend for HC only, indicating positive impacts of global initiatives aiming towards socio-economic development in developing countries like the Millennium Development Goals and 'Agenda 21'. However, we also find that the relative performance of most countries has not changed significantly in this period, regardless of their gradual development. Specifically, we measure a decrease in produced and natural capital for most countries, despite an increase in GDP, suggesting unsustainable development. Furthermore, we develop a technique to cluster countries and project the results to 2050, and we find a significant decrease in NC for nearly all countries, suggesting an alarming depletion of natural resources worldwide. PMID- 29702340 TI - In vitro photodynamic activity of lipid vesicles with zinc phthalocyanine derivative against Enterococcus faecalis. AB - Zinc(II) phthalocyanine bearing eight non-peripheral 2-propoxy substituents was subjected to physicochemical study and, after incorporation in lipid vesicles, assessed as a potential photosensitizer for antibacterial photodynamic therapy. The phthalocyanine derivative obtained in the macrocyclization reaction was characterized by MS and NMR techniques. Moreover, its chemical purity was confirmed by HPLC analysis. X-ray structural analysis revealed that overcrowding of the phthalocyanine derivative leads to a strong out-of-plane distortion of the pi-system of the macrocycle core. In the UV-Vis absorption spectra of zinc(II) phthalocyanine two characteristic bands were found: the Soret (300-450 nm) and the Q band (600-800 nm). Photophysical properties of mono- and diprotonated forms of phthalocyanine derivative were studied with time-resolved fluorescence spectroscopy. Its tri- and tetraprotonated forms could not be obtained, because compound decomposes in higher acid concentrations. The presented zinc(II) phthalocyanine showed values of singlet oxygen generation PhiDelta = 0.18 and 0.16, the quantum yield of the photodecomposition PhiP = 3.06?10-4 and 1.23?10-5 and the quantum yield of fluorescence PhiFL = 0.005 and 0.004, designated in DMF and DMSO, respectively. For biological studies, phthalocyanine has been incorporated into modified liposome vesicles containing ethanol. In vitro bacteria photoinactivation study revealed no activity against Escherichia coli and 5.7 log reduction of the Enterococcus faecalis growth. PMID- 29702342 TI - Discrepant effects of alpha-endosulfan, beta-endosulfan, and endosulfan sulfate on oxidative stress and energy metabolism in the livers and kidneys of mice. AB - Endosulfan, an organochloride pesticide, has been used for many commercial purposes. Endosulfan is composed of two isomers, alpha-endosulfan and beta endosulfan. In biological and soil systems, endosulfan is metabolized into endosulfan sulfate. In this study, the different toxicological effects of alpha endosulfan, beta-endosulfan, and endosulfan sulfate on the livers and kidneys of mice were comprehensively investigated. The results demonstrated that both endosulfan isomers and endosulfan sulfate disturbed the hepatic and renal antioxidant systems. Furthermore, 1H NMR metabolomics analysis revealed that endogenous metabolites involved in oxidative stress and energy metabolism were altered after exposure to these compounds. In the liver, the changes in hepatic endogenous metabolites and the induction of hepatic CYP450 mRNA isoforms were similar among mice treated with the three compounds, and the sulfate metabolite was the exclusive exogenous compound detected. Therefore, the metabolism of alpha and beta-endosulfan to endosulfan sulfate is likely the main cause of toxicological effects in the livers of mice. However, in kidneys, the changes in the metabolome and in CYP450 mRNA expression induced by alpha-endosulfan and beta endosulfan were stereoselective. Additionally, endosulfan sulfate, which induced a significant increase of renal Cyp3a11, showed a more robust disturbance of renal metabolites than either of the two isomers. These findings revealed that more attention should be given to the toxicological evaluation of endosulfan sulfate in the future. PMID- 29702343 TI - Ethylenediamine disuccinic acid enhanced phytoextraction of nickel from contaminated soils using Coronopus didymus (L.) Sm. AB - In a screenhouse, the applicability of biodegradable chelant ethylenediamine disuccinic acid (EDDS) to enhance Ni-phytoextraction by Coronopus didymus was tested for the first time. This study assayed the hypothesis based upon the role of EDDS on physiological and biochemical alterations and ameliorating phytoextraction capacity of C. didymus under nickel (Ni) stress. Pot experiments were conducted for 6 weeks and C. didymus plants were cultivated in soil artificially contaminated with 30, 50, and 70 mg kg-1 Ni treatments. Soil was amended with EDDS (2 mmol kg-1). Plants were harvested, 1 week after EDDS application. At 70 mg kg-1 Ni level, EDDS application dramatically enhanced the root and shoot Ni concentration from 665 and 644 to 1339 and 1338 mg kg-1, respectively. Combination of Ni + EDDS induced alterations in biochemical parameters of plants. EDDS addition posed pessimistic effects on growth, biomass, photosynthetic activity and protein content of the plants. Besides, application of EDDS stimulated the generation of superoxide anion, H2O2 content and MDA level. However, EDDS assisted mount in antioxidant activities (superoxide dismutase, catalase and glutathione peroxidase) considerably neutralised the toxicity induced by reactive oxygen species in plant tissues. The results revealed EDDS efficacy to ameliorate the performance of antioxidant enzymes and improved Ni translocation in plant tissues, thus strongly marked its affinity to be used together with C. didymus for Ni-phytoextraction. PMID- 29702344 TI - TBT is still a matter of concern in Peru. AB - Tributyltin (TBT) environmental concentrations as well as imposex levels have been declining in several coastal areas worldwide. However, recent studies have shown that TBT contamination is still an important issue along some Latin American coastal areas. Thus, the incidence of imposex and butyltin compounds (BTs) in sediments and gastropod tissues was spatially and temporally (2009 and 2012) appraised in Lima (Peru) along potential TBT sources (harbors and marinas). Despite the general pattern of reduction close to Callao harbor, a clear increment in the levels of imposex (RPLI = 0.0 to 8.4 and 0.0 to 28.4/VDSI = 0.0 to 3.3 and 0.0 to 3.5) and TBT in tissues (25 to 112 and 62 to 146 ng Sn g-1) of Thaisella chocolata were seen from 2009 to 2012 in two sampling sites, respectively, located nearby a newly established marina. Thus, despite the international restrictions on the use of TBT-based antifouling paints are apparently reducing the inputs at international harbors, the present study clearly shows that marinas are still acting as important sources of TBT to the study area due possibly to the lack of legal restrictions on production, trading and/or use of TBT. The present findings reinforce what has been seen along many other Latin American coastal areas. PMID- 29702345 TI - Coupled heating/acidification pretreatment of chemical sludge for dewatering by using waste sulfuric acid at low temperature. AB - A cost-effective approach for pretreatment of chemical sludge for further dewatering, based on the idea of "using waste to treat waste", is provided. It is a coupled heating/acidification pretreatment method, where waste sulfuric acid is employed and relatively low temperatures (<100 degrees C) are applied. Effects of reaction time, temperature, and dosage of waste acid on dewatering performance (both dewatering speed and degree) are studied. Under the optimal conditions (reaction time: 30 min; temperature: 90 degrees C; waste acid dosage: 0.175 g/(g dried sludge)), the method of this work demonstrates three advantages compared to the conventional method using lime+polyacrylamide: lower moisture content of treated sludge; higher calorific value for incineration process; and lower cost. Detailed mechanism of the pretreatment for dewatering is investigated via characterizations and statistical analyses of various parameters, among which zeta potential, particle size, protein and polysaccharide contents, soluble chemical oxygen demand (SCOD), reduction of combined water and volatile suspended solid (VSS), are associated with dewatering performance. Both heating and acidification generate disintegration of cells in sludge, giving rise to two phenomena: more organic matters are released into solution and more bound water turns into free water. Meantime, the released organic polymers flocculate sludge particles, further accelerating the solid-liquid separation process. PMID- 29702346 TI - Occurrence and characteristics of PCDD/Fs formed from Chlorobenzenes production in China. AB - China had a large production capacity of chlorobenzenes. An extensive investigation was conducted to understand the occurrence and characteristics of PCDD/Fs from four chlorobenzene production plants. The concentrations of PCDD/Fs in mono-CB production and in a new di-CB production routine were revealed. Concentrations of PCDD/Fs in residues, byproducts, products and wastewater varied between 8.4*103-4.0*106 ng TEQ/kg, 1.5-5.0*104 ng TEQ/kg, ND~0.12 ng TEQ/kg and 6.0*104-9.1*104 pg TEQ/L, respectively. OCDF, 2,3,4,7,8-PeCDF, 1,2,3,4,7,8-HxCDF, and 2,3,7,8-TeCDF were the most abundant congeners of the 17 2,3,7,8-substituted PCDD/Fs. In most samples, PCDFs contributed more than 99% of the total TEQs of PCDD/Fs, in which 2,3,4,7,8-PeCDF was the dominating contributor. It is inferred PCDFs were mainly formed in the chlorination reactions. The emission factors were suggested and the amount of PCDD/Fs formed in CB production was estimated to be 450 g TEQ in 2012. Residue, byproduct and wastewater were potentially the main pathways of PCDD/Fs to the environmental releases. PMID- 29702347 TI - Towards understanding the role of amines in the SO2 hydration and the contribution of the hydrated product to new particle formation in the Earth's atmosphere. AB - By theoretical calculations, the gas-phase SO2 hydration reaction assisted by methylamine (MA) and dimethylamine (DMA) was investigated, and the potential contribution of the hydrated product to new particle formation (NPF) also was evaluated. The results show that the energy barrier for aliphatic amines (MA and DMA) assisted SO2 hydration reaction is lower than the corresponding that of water and ammonia assisted SO2 hydration. In these hydration reactions, nearly barrierless reaction (only a barrier of 0.1 kcal mol-1) can be found in the case of SO2 + 2H2O + DMA. These lead us to conclude that the SO2 hydration reaction assisted by MA and DMA is energetically facile. The temporal evolution for hydrated products (CH3NH3+-HSO3--H2O or (CH3)2NH2+-HSO3--H2O) in molecular dynamics simulations indicates that these complexes can self-aggregate into bigger clusters and can absorb water and amine molecules, which means that these hydrated products formed by the hydration reaction may serve as a condensation nucleus to initiate the NPF. PMID- 29702348 TI - Exploring diagnosis and imaging biomarkers of Parkinson's disease via iterative canonical correlation analysis based feature selection. AB - Parkinson's disease (PD) is a neurodegenerative disorder that progressively hampers the brain functions and leads to various movement and non-motor symptoms. However, it is difficult to attain early-stage PD diagnosis based on the subjective judgment of physicians in clinical routines. Therefore, automatic and accurate diagnosis of PD is highly demanded, so that the corresponding treatment can be implemented more appropriately. In this paper, we focus on finding the most discriminative features from different brain regions in PD through T1 weighted MR images, which can help the subsequent PD diagnosis. Specifically, we proposed a novel iterative canonical correlation analysis (ICCA) feature selection method, aiming at exploiting MR images in a more comprehensive manner and fusing features of different types into a common space. To state succinctly, we first extract the feature vectors from the gray matter and the white matter tissues separately, represented as insights of two different anatomical feature spaces for the subject's brain. The ICCA feature selection method aims at iteratively finding the optimal feature subset from two sets of features that have inherent high correlation with each other. In experiments we have conducted thorough investigations on the optimal feature set extracted by our ICCA method. We also demonstrate that using the proposed feature selection method, the PD diagnosis performance is further improved, and also outperforms many state-of-the art methods. PMID- 29702349 TI - Editorial overview: The new microscopy. PMID- 29702350 TI - Evaluation of RIDA(r)GENE norovirus GI/GII real time RT-PCR using stool specimens collected from children and adults with acute gastroenteritis. AB - BACKGROUND: Norovirus is the leading cause of epidemic and sporadic acute gastroenteritis (AGE) in the United States. Widespread prevalence necessitates implementation of accurate norovirus detection assays in clinical diagnostic laboratories. OBJECTIVE: To evaluate RIDA(r)GENE norovirus GI/GII real-time RT PCR assay (RGN RT-PCR) using stool samples from patients with sporadic AGE. STUDY DESIGN: Patients between 14 days to 101 years of age with symptoms of AGE were enrolled prospectively at four sites across the United States during 2014-2015. Stool specimens were screened for the presence of norovirus RNA by the RGN RT-PCR assay. Results were compared with a reference method that included conventional RT-PCR and sequencing of a partial region of the 5'end of the norovirus ORF2 gene. RESULTS: A total of 259 (36.0%) of 719 specimens tested positive for norovirus by the reference method. The RGN RT-PCR assay detected norovirus in 244 (94%) of these 259 norovirus positive specimens. The sensitivity and specificity (95% confidence interval) of the RGN RT-PCR assay for detecting norovirus genogroup (G) I was 82.8% (63.5-93.5) and 99.1% (98.0-99.6) and for GII was 94.8% (90.8-97.2) and 98.6% (96.9-99.4), respectively. Seven specimens tested positive by the RGN-RT PCR that were negative by the reference method. The fifteen false negative samples were typed as GII.4 Sydney, GII.13, GI.3, GI.5, GI.2, GII.1, and GII.3 in the reference method. CONCLUSIONS: The RGN RT-PCR assay had a high sensitivity and specificity for the detection of norovirus in stool specimens from patients with sporadic AGE. PMID- 29702351 TI - Hepatitis E virus infection in different groups of Estonian patients and people who inject drugs. AB - BACKGROUND: Previously we demonstrated a high prevalence of hepatitis E virus (HEV) in domestic pigs and wild boars, the main reservoir and possible source of HEV infections in humans. But so far there are no reports about spread of HEV in Estonian human population. OBJECTIVES: The present study aimed to determine the prevalence and genotyping of HEV in different groups of the Estonian adult population. STUDY DESIGN: Totally 1426 human serum samples were tested (763 patients with clinically diagnosed nonA/B/C hepatitis, 176 hemodialysis patients, 282 patients with suspected HEV infection and 205 people who injected drugs (PWID)). Presence of anti-HEVantibodies was assessed by ELISA and confirmed by immunoblotting. All anti-HEV positive sera were analyzed for RNA by qPCR. Amplified ORF2 region was sequenced and used for phylogenetic analysis. RESULTS: Antibody assay revealed 49 samples from 1426 (3.4%) with acute (17) or past (32) HEV infection. HEV RNA was detected in 10 anti-HEV IgM positive samples, including 9 samples from patients with suspected HEV infection and 1 hemodialysis patient. Anti-HEV IgG were found in 7.8% patients with suspected HEV infection, in 4% hemodialysis patients, in 2.4% PWID and in 1.96% patients with nonA/B/C hepatitis. All groups demonstrated a trend to share of anti-HEV seroprevalence increasing with age. Phylogenetic analysis of 9 HEV RNA sequences revealed that 3 sequences belonged to HEV genotype 1; 6 ones to genotype 3 (1 sequence belonged to sub-genotype 3a, two ones - sub-genotype 3e, and three ones - to sub-genotype 3f). CONCLUSIONS: Despite the high seroprevalence among domestic pigs, no evidence of HEV transmission from Estonian pigs to humans was found. The results of our study suggest that HEV infections in Estonia are most likely associated with travel or with consumption of imported food products. PMID- 29702353 TI - Reductive amination assistance for quantification of oseltamivir phosphate and oseltamivir carboxylate by HPLC-MS/MS. AB - Oseltamivir phosphate (OP) is the first line therapy for influenza, and its primary metabolite oseltamivir carboxylate (OC) is the active agent via inhibition of neuraminidase of influenza virus. Dosages of OP and OC might affect human causing nausea and vomiting and it is therefore necessary to evaluate their toxicity and safety. The separation system: liquid chromatography-tandem mass spectrometry (LC-MS/MS) is a powerful technique to monitor OP and OC. However, quantification of OP and OC needs isotopic analogs as internal standards to monitor the stability of the sample pretreatment procedures and instruments. In this study, we demonstrated a modified method (i.e., reductive amination) to synthesize OP and OC deuterated and hydrogenated analogs as internal standards (ISs) and for illustration of calibration curves, respectively. This modification allowed to overcome ISs selection and to enhance the signal intensities via high yield reductive amination in MS detection. We utilized the multiple reaction monitoring (MRM) mode to target m/z values of precursor and product ions. N dimethylated OP and N-dimethylated OC showed linearity ranging from 1 to 1000 ng/mL with coefficient of determination (R2) values of 0.9995 and 0.9999, respectively. Additionally, the relative standard deviations (RSD) of intra-day ranged from 0.3% to 5.2%, and the RSD of inter-day ranged from 2.0% to 18.8%, respectively. This quantitative method utilized spiked OP and OC at low (20 ng/mL), intermediate (100 ng/mL), and high (500 ng/mL) concentrations in human serum samples. The average recoveries for OP and OC were 84.6%-107.7% and 94.9% 98.5%, respectively. PMID- 29702352 TI - Fabrication of size controlled nanocomposite based on zirconium alkoxide for enrichment of Gallic acid in biological and herbal tea samples. AB - In this work, novel water-dispersible size controlled nanocomposite based on zirconium alkoxide as metal organic precursor was fabricated and subsequently applied for rapid, efficient and selective preconcentration of gallic acid in human plasma and herbal tea samples. The resultant nanocomposite (Fe3O4@Zr(OtBu)4@Laurate) was characterized by Fourier transform infrared, scanning electron microscope and X-ray spectrometer, while laurate forms aggregates on the surface of the nanocomposite and thereby improves sorption of gallic acid. The effects of some variables on efficiency of gallic acid from real samples were optimized by central composite design; while optimum points were achieved as follows: pH 3.5, 35.0 mg of nanocomposite, 150.0 MUL of eluent and 3.0 min sonication time. Chromatographic separation was carried out on analytical Nucleosil C18 column (250 * 4.6 mm I.D., 5 MUm particle size) at ambient temperature with methanol: water (40:60, v/v) pH adjusted at 3.5 follow by UV detection at 270 nm. Acceptable limit of detection (0.2 MUg kg-1) and wide linear range (1.0-700.0 MUg kg-1) in coincidence with reasonable enrichment factor (EF = 125) are the unique advantages, which promise this method for quantification of this compound in real samples with complicated matrices. PMID- 29702354 TI - The enrichment of chlorogenic acid from Eucommia ulmoides leaves extract by mesoporous carbons. AB - Herein, we report an efficient separation and enrichment method for chlorogenic acid from crude extracts of Eucommia ulmoides leaves using carbon adsorbents. The effects of the pore structure of the carbon adsorbents on the adsorption capacity were studied. Of the four adsorbents investigated, mesoporous carbon (MC3) showed the highest adsorption capacity (294 mg/g of carbon) for chlorogenic acid due to its high mesopore volume. The static adsorption of CGA on carbon can be accurately described using the Freundlich equation. The kinetics of adsorption follow a pseudo-second-order process. External mass transfer was the controlling step of the adsorption process. Dynamic adsorption on MC3 demonstrated that chlorogenic acid began to break through after 28 bed volumes of extract was loaded. This mesoporous carbon-treatment procedure is safe, economic and has the potential to be scaled up for commercial application. PMID- 29702356 TI - Identification of CPE and GAIT elements in 3'UTR of macrophage migration inhibitory factor (MIF) involved in inflammatory response induced by LPS in Ciona robusta. AB - Innate immune responses face infectious microorganisms by inducing inflammatory responses. Multiple genes within distinct functional categories are coordinately and temporally regulated by transcriptional 'on' and 'off' switches that account for the specificity of gene expression in response to external stimuli. Mechanisms that control transcriptional and post-transcriptional regulation are important in coordinating the initiation and resolution of inflammation. Macrophage migration inhibitory factor (MIF) is an important cytokine that, in Ciona robusta, is related to inflammatory response. It is well known that in C. robusta, formerly known as Ciona intestinalis, the pharynx is involved in the inflammatory reaction induced by lipopolysaccharide (LPS) injection in the body wall. Using this biological system, we describe the identification of two C. robusta MIFs (CrMIF1 and CrMIF2). The phylogenetic tree and modeling support a close relationship with vertebrate MIF family members. CrMIF1 and CrMIF2 possess two evolutionally conserved catalytic sites: a tautomerase and an oxidoreductase site with a conserved CXXC motif. Real-time PCR analysis shows a prompt expression induced by LPS inoculation in CrMIF1 and a late upregulation of CrMIF2 and in silico analyses of 3'UTR show a cis-acting GAIT element and a CPE element in 3'-UTR, which are not present in the 3'-UTR of CrMIF1, suggesting that different transcriptional and post-transcriptional control mechanisms are involved in the regulation of gene expression of MIF during inflammatory response in C. robusta. PMID- 29702355 TI - Synthesis and activity of benzopiperidine, benzopyridine and phenyl piperazine based compounds against Leishmania infantum. AB - In the present study, anti-leishmanial evaluation of twenty four structurally diverse compounds based on benzopiperidine, benzopyridine and phenylpiperazine nucleuses against Leishmania infantum has been reported. Cytotoxicity studies of all the compounds were performed on murine non-infected splenocytes. Tested compounds exhibited weak to potent activity against promastigote (IC50 3.21 +/- 1.40 to >100 MUM) as well as amastigote (IC50 6.84 +/- 2.5 to 92.47 +/- 17.61 MUM) forms of tested strains. Moreover, two compounds F13 and F15 exhibited potent activity (IC50 < 10 MUM) against both forms of the parasite with selectivity index ranges from 11.40 to 22.10. Overall, the current study afforded few hits with novel anti-leishmanial activity in low micromolar concentration, further hit optimization studies can be performed to get more potent candidates against the selected species of parasite. PMID- 29702357 TI - Serial multiple mediation of organizational commitment and job burnout in the relationship between psychological capital and anxiety in Chinese female nurses: A cross-sectional questionnaire survey. AB - BACKGROUND: Nurses play an important role in medical and health services but anxiety among those in this profession is widespread. Anxiety not only damages the physical and mental health of the individual, but also reduces the efficiency of their work and the quality of care, ultimately impacting on patient care. Therefore, it is necessary to elucidate the factors that lead to anxiety and explore measures to reduce the impact these factors have on nurses. OBJECTIVE: The purpose of this study was to investigate the serial-multiple mediation of psychological capital (PsyCap), organizational commitment, job burnout, and anxiety among Chinese female nurses. DESIGN: A cross-sectional stratified cluster sampling study. PARTICIPANTS: The study consisted of 1354 Chinese female nurses from two tertiary grade A hospitals in Heilongjiang Province, China. METHODS: The Zung Self-Rating Anxiety Scale, the Chinese psychological capital questionnaire, the Chinese Maslach Burnout Inventory, and the Chinese Employee Organizational Commitment Questionnaire were used to gather data. Descriptive analysis, independent-samples T-test, one-way analysis of variance, Spearman correlation analyses, ordinary least-squares regression and the bootstrap method were used to analyze data. RESULTS: The prevalence rate of anxiety among nurses was found to be 41.1%, and there were significant differences in anxiety symptoms in age (F = 15.54, p < 0.001) and marital status (F = 5.41, p < 0.001), but not education (F = 1.50, p = 0.224) among nurses. Overall, the serial-multiple mediation of organizational commitment and job burnout in the relationship between PsyCap and anxiety was found to be statistically significant. CONCLUSIONS: The results of the present study showed that positive PsyCap was sequentially associated with increased organizational commitment first, and then decreased job burnout, which was in turn related to reduced symptoms of anxiety among female nurses. PMID- 29702358 TI - A medicolegal analysis of malpractice claims involving anesthesiologists in the gastrointestinal endoscopy suite (2007-2016). AB - STUDY OBJECTIVE: Gastrointestinal endoscopy cases make up the largest portion of out of operating room malpractice claims involving anesthesiologists. To date, there has been no closed claims analysis specifically focusing on the claims from the endoscopy suite. We aim to identify associated case characteristics and contributing factors. DESIGN: Retrospective review of closed claims. SETTING: Multi-institutional setting of hospitals that submit data to the Controlled Risk Insurance Company (CRICO) Comparative Benchmarking System, a database representing approximately 30% of annual malpractice cases in the United States. PATIENTS: A total of 58 claims in the gastrointestinal endoscopy suite between January 1, 2007 and December 31, 2016. INTERVENTIONS: Gastrointestinal endoscopy procedures. MEASUREMENTS: We analyzed associated factors for each case as well as payments, and severity scores. MAIN RESULTS: There was a difference in the percent of cases that resulted in payment by procedure type, with 91% of endoscopic retrograde cholangiopancreatography (ERCP) cases resulting in payment compared with 37.5% of colonoscopy cases, 25% of combined esophagogastroduodenoscopy (EGD)/colonoscopy cases, 21.4% of EGD cases and 0.0% of endoscopic ultrasound cases (P = 0.0008). Oversedation was a possible contributing factor in 62.5% of cases. The mean payment for all claims involving anesthesiologists in the endoscopy suite was $99,754. CONCLUSIONS: There are differences in the rates of payment of malpractice claims between procedures. ERCPs made up a disproportionate percentage of the total amount paid to patients. While a significant percent of cases involved possible oversedation, these errors were compounded by other factors, such as failure to resuscitate or recognize the acute clinical change. With medically complex patients undergoing endoscopic procedures, it is critical to have well prepared anesthesia providers. PMID- 29702359 TI - Combined simultaneous arginine clonidine stimulation test: Timing of peak growth hormone (GH) concentration and correlation with clinical indices of GH status. AB - BACKGROUND: The aims of this study were to determine if it is possible to truncate a combined simultaneous arginine clonidine stimulation test, and to correlate the outcome of the test with clinical indices of GH status. METHODS: Charts of subjects who underwent a combined simultaneous arginine clonidine stimulation test between January 1, 2007 and August 31, 2016 were reviewed. RESULTS: 131/203 (64.5%) tests performed in children with growth failure demonstrated a peak GH >= 10 ng/ml. 6/7 (85.7%) tests performed in adolescents at the end of GH treatment had a peak GH >= 5 ng/ml. Among these negative tests, 97.8% had a passing GH by 120 min. 58/98 (59.1%) tests that had a sample at 150 min were negative. 3/58 (5.2%) had a passing GH level only at 150 min. Therefore, if the test were shortened to 120 min, 5.2% of normal responders would be missed. There was a weak correlation of peak GH with baseline growth velocity and serum IGF-1 z-score. A trend towards an inverse correlation between peak GH level and change in growth velocity pre- and post-GH was seen. CONCLUSIONS: If the combined simultaneous arginine clonidine test were shortened to 120 min, 5.2% of normal responders would be missed. Although this test has not been compared to any "gold standard" GH stimulation test, the outcome of this test does correlate weakly with clinical indices of GH status and spares patients the inconvenience of sequential testing. PMID- 29702360 TI - Differential metabolism of diastereoisomeric diterpenes by Preussia minima, found as endophytic fungus in Cupressus lusitanica. AB - The plant diastereoisomeric diterpenes ent-pimara-8(14)-15-dien-19-oic acid, obtained from Viguiera arenaria, and isopimara-8(14)-15-dien-18-oic acid, isolated from Cupressus lusitanica, were distinctly functionalized by the enzymes produced in whole cell cultures of the fungus Preussia minima, isolated from surface sterilized stems of C. lusitanica. The ent-pimaradienoic acid was transformed into the known 7beta-hydroxy-ent-pimara-8(14)-15-dien-19-oic acid, and into the novel diterpenes 7-oxo-8 beta-hydroxy-ent-pimara-8(14)-15-dien-19 oic and 7-oxo-9beta-hydroxy-ent-pimara-8(14)-15-dien-19-oic acids. Isopimara 8(14)-15-dien-18-oic acid was converted into novel diterpenes 11alpha hydroxyisopimara-8(14)-15-dien-18-oic acid, 7beta,11alpha-dihydroxyisopimara 8(14)-15-dien-18-oic acid, and 1beta,11alpha-dihydroxyisopimara-8(14)-15-dien-18 oic acid, along with the known 7beta-hydroxyisopimara-8(14)-15-dien-18-oic acid. All compounds were isolated and fully characterized by 1D and 2D NMR, especially 13C NMR. The diterpene bioproduct 7-oxo-9beta-hydroxy-ent-pimara-8(14)-15-dien-19 oic acid is an isomer of sphaeropsidin C, a phytotoxin that affects cypress trees produced by Shaeropsis sapinea, one of the main phytopathogen of Cupressus. The differential metabolism of the diterpene isomers used as substrates for biotransformation was interpreted with the help of computational molecular docking calculations, considering as target enzymes those of cytochrome P450 group. PMID- 29702361 TI - A new quadrature annular resonator for 3 T MRI based on artificial-dielectrics. AB - Dielectric resonators have previously been constructed for ultra-high frequency magnetic resonance imaging and microscopy. However, it is challenging to design these dielectric resonators at clinical field strengths due to their intrinsically large dimensions, especially when using materials with moderate permittivity. Here we propose and characterize a novel approach using artificial dielectrics which reduces substantially the required outer diameter of the resonator. For a resonator designed to operate in a 3 Tesla scanner using water as the dielectric, a reduction in outer diameter of 37% was achieved. When used in an inductively-coupled wireless mode, the sensitivity of the artificial dielectric resonator was measured to be slightly higher than that of a standard dielectric resonator operating in its degenerate circularly-polarized hybrid electromagnetic modes (HEM11). This study demonstrates the first application of an artificial-dielectric approach to MR volume coil design. PMID- 29702362 TI - Effects of superparamagnetic iron oxide nanoparticles on the longitudinal and transverse relaxation of hyperpolarized xenon gas. AB - SuperParamagnetic Iron Oxide Nanoparticles (SPIONs) are often used in magnetic resonance imaging experiments to enhance Magnetic Resonance (MR) sensitivity and specificity. While the effect of SPIONs on the longitudinal and transverse relaxation time of 1H spins has been well characterized, their effect on highly diffusive spins, like those of hyperpolarized gases, has not. For spins diffusing in linear magnetic field gradients, the behavior of the magnetization is characterized by the relative size of three length scales: the diffusion length, the structural length, and the dephasing length. However, for spins diffusing in non-linear gradients, such as those generated by iron oxide nanoparticles, that is no longer the case, particularly if the diffusing spins experience the non linearity of the gradient. To this end, 3D Monte Carlo simulations are used to simulate the signal decay and the resulting image contrast of hyperpolarized xenon gas near SPIONs. These simulations reveal that signal loss near SPIONs is dominated by transverse relaxation, with little contribution from T1 relaxation, while simulated image contrast and experiments show that diffusion provides no appreciable sensitivity enhancement to SPIONs. PMID- 29702363 TI - Preparation and cathodoluminescence characteristics of rare earth activated BaAl2O4 phosphors. AB - Undoped and Pr, Sm and Tb activated BaAl2O4 phosphors have been synthesized by solid state reaction method and combustion method. The structure and morphological observation of the phosphor samples were monitored by X-ray powder diffraction (XRD) and environmental scanning electron microscope (ESEM) coupled to an energy dispersive X-ray spectrometer (EDS). The all diffraction peaks are well assigned to standard data card (PDF?17-306). Emission properties of the samples were explored using light emission induced by an electron beam (i.e cathodoluminescence, CL) at room temperature (RT). Undoped BaAl2O4 sample exhibits a broad defect emission from 300 to 500 nm from the aluminate defect centres. CL spectra recorded at room temperature display that the as-prepared BaAl2O4:Ln (Ln=Pr, Sm and Tb) phosphors exhibit different luminescence colors coming from different rare earth activator ions. The transition 4G5/2 -> 6H7/2 located at 606 and 610 nm for Sm3+ can occur as hypersensitive transition having the selection rule DeltaJ = +/- 1. For the Tb3+ doped samples, they exhibit D45 green line emissions. The proposed luminescent mechanisms of all doped rare earth ions are also discussed. PMID- 29702364 TI - Mechanisms and therapeutic targets for bone damage in rheumatoid arthritis, in particular the RANK-RANKL system. AB - Rheumatoid arthritis (RA), a chronic inflammatory disorder, causes swelling, bone erosion, and joint deformity. Bone erosion in RA-affected joints arises from activation of osteoclasts by inflammatory processes. RA patients may also have primary, disease-related, or glucocorticoid-induced osteoporosis, caused by a disrupted balance between osteoclasts and osteoblasts. Disease-modifying antirheumatic drugs (DMARDs) interfere with the processes causing inflammation in the joint but do not sufficiently treat bone erosion and osteoporosis. Denosumab, an inhibitor of receptor activator of nuclear factor kappa-B ligand (RANKL), protects bones in osteoporosis patients. Clinical studies have demonstrated that denosumab can also prevent bone erosion in RA patients. Because joint destruction progresses in some patients treated with DMARDs alone, denosumab will likely become standard treatment for some RA patients. PMID- 29702365 TI - AAC services for multilingual populations: South African service provider perspectives. AB - BACKGROUND: In South Africa, many persons in need of augmentative and alternative communication (AAC) come from multilingual backgrounds. There is as yet a limited evidence base (locally and internationally) for the provision of AAC services to multilingual populations. The perspectives of service providers can assist in gaining an understanding of current practices and the factors that influence these. AIMS: The study aimed to obtain the perspectives of AAC service providers about practices in providing AAC systems and AAC intervention to clients from multilingual backgrounds. METHODS & PROCEDURES: Fifteen AAC service providers were purposefully chosen to participate in one of three focus groups - two face to-face and one online focus group. Data from the face-to-face focus groups was transcribed verbatim. Thematic analysis was used to identify themes and subthemes in the data. OUTCOMES & RESULTS: Four overarching themes were identified, namely (a) current practices, (b) factors influencing current practices, (c) service provides' orientation towards different language options in AAC intervention, and (d) needs and desired developments regarding AAC technology. This paper reports on the first three themes. Service providers reported their practices to range from a focus on L1 exclusively, L2 exclusively, to a multilingual (sequential or simultaneous) approach. The South African language context, family language preferences and choices, service provider skill and knowledge, as well as AAC technology were identified as factors influencing their practices. Although many viewed access to multiple languages through AAC as positive, they also expressed concerns and reservations about providing multilingual AAC services. CONCLUSIONS & IMPLICATIONS: Although service providers in general saw the need to give clients from multilingual backgrounds access to multiple languages using AAC, this did not always translate into multilingual AAC practices. Both extrinsic factors (e.g. the lack of appropriate AAC devices, software and apps giving access to non-English languages) and intrinsic factors (service providers' language competency and their beliefs about the cognitive demands of multilingual AAC systems) influenced their practices and choices. Appropriate AAC service delivery to multilingual populations in South Africa would require not only appropriate AAC technology developments, but also research evidence to establish the efficacy of multilingual AAC interventions for clients with a variety of characteristics. PMID- 29702366 TI - Effects of melatonin administration on seminal plasma metabolites and sperm fertilization competence during the non-reproductive season in ram. AB - The purpose of this study was to investigate the effects of ram melatonin treatment on the sperm quality and metabolite composition of the seminal plasma in the non-breeding season. Four mature rams were treated with 54 mg melatonin in March subcutaneous implants and four untreated rams served as control. At 0, 30, 90 and 120 days semen samples were collected and sperm, separated from seminal plasma, was evaluated for its capacity to fertilize and produce embryos in vitro. Seminal plasma metabolites were extracted and analyzed by capillary electrophoresis/mass spectroscopy. In the resulting electropherograms, the area corresponding to selected metabolites was extracted and quantified. Ram melatonin treatment affected the in vitro fertilization competence of sperm. Blastocyst output increased until 90 days after treatment (27.20 +/- 7.35 vs 54.7 +/- 4.4% at 0 and 90 days respectively; p < 0.05) while the untreated group did not show statistical differences. In treated rams, the concentration of melatonin in seminal plasma increased from 3.34 +/- 1.70 at day 0-9.65 +/- 2.89 AU (Arbitrary Units) after 90 days, then decreased to reach the level of the untreated ram after 120 days (p < 0.05). During 90 days after melatonin treatment, an increase (p < 0.05) in seminal plasma concentrations of glutamic acid (6.28 +/- 1.53 vs 14.93 +/- 1.53 AU at 0 and 90 days respectively), glutamine (16.89 +/- 4.65 vs 54.51 +/- 4.65 AU), carnitine (22.97 +/- 9.81 vs 104.30 +/- 9.81 AU), acetyl carnitine (48.15 +/- 17.32 vs 217.69 +/- 17.32 AU), choline (1.82 +/- 1.55 vs 14.16 +/- 1.55 AU) and arginine (1.31 +/- 1.08 vs 14.25 +/- 1.08 AU) was detected. Tyrosine concentration increased during 30 days from melatonin treatment (12.79 +/- 3.93 vs 27.08 +/- 3.04 AU) but at 90 days its levels were similar to the untreated group. In conclusion, melatonin treatment during the non breeding season improves the concentration of several metabolites in seminal plasma and sperm fertilization competence in Sarda breed ram. PMID- 29702367 TI - Targeting natural compounds against HER2 kinase domain as potential anticancer drugs applying pharmacophore based molecular modelling approaches. AB - Human epidermal growth factor receptors are implicated in several types of cancers characterized by aberrant signal transduction. This family comprises of EGFR (ErbB1), HER2 (ErbB2, HER2/neu), HER3 (ErbB3), and HER4 (ErbB4). Amongst them, HER2 is associated with breast cancer and is one of the most valuable targets in addressing the breast cancer incidences. For the current investigation, we have performed 3D-QSAR based pharmacophore search for the identification of potential inhibitors against the kinase domain of HER2 protein. Correspondingly, a pharmacophore model, Hypo1, with four features was generated and was validated employing Fischer's randomization, test set method and the decoy test method. The validated pharmacophore was allowed to screen the colossal natural compounds database (UNPD). Subsequently, the identified 33 compounds were docked into the proteins active site along with the reference after subjecting them to ADMET and Lipinski's Rule of Five (RoF) employing the CDOCKER implemented on the Discovery Studio. The compounds that have displayed higher dock scores than the reference compound were scrutinized for interactions with the key residues and were escalated to MD simulations. Additionally, molecular dynamics simulations performed by GROMACS have rendered stable root mean square deviation values, radius of gyration and potential energy values. Eventually, based upon the molecular dock score, interactions between the ligands and the active site residues and the stable MD results, the number of Hits was culled to two identifying Hit1 and Hit2 has potential leads against HER2 breast cancers. PMID- 29702368 TI - De novo transcriptome analysis and differentially expressed genes in the ovary and testis of the Japanese mantis shrimp Oratosquilla oratoria by RNA-Seq. AB - The mantis shrimp Oratosquilla oratoria is a widely distributed, commercially important crustacean species. Although its conservation and the development of successful artificial breeding technologies have recently received considerable attention, there are currently no available data regarding the molecular mechanisms in controlling reproduction. In this study, we performed transcriptome sequencing of the testis, ovary, female and male eyestalks and the androgenic gland of O. oratoria, and compared the expression pattern of transcripts from the testis and ovary libraries to identify genes involved in gonadal development. A total of 147,130,937 clean reads were retrieved after removing the adapters in reads and filtering out low-quality data. All the reads were assembled into 94,990 unigenes (23,133 in testis and ovary) with an average length of 783 base pairs (bp) and N50 of 1502 bp. A search of all-unigenes against COG, GO, KEGG, KOG, Pfam, Swiss-Prot and Nr databases resulted in a total of 19,404 annotated unigenes. Comparison of the sequences in the ovary and testis libraries revealed that 1188 unigenes were up-regulated in the ovary and 2732 were up-regulated in the testis. Twenty ovary-up-regulated and 21 testis-up-regulated unigenes were confirmed by quantitative real-time PCR. Additionally, 13,437 simple sequence repeats (SSRs) and 275,799 putative single nucleotide polymorphisms (SNPs) were identified. The important functional genes and pathways identified here provide a valuable dataset for understanding the molecular mechanisms controlling gonad development in O. oratoria, and the numerous (13,437 SSRs and 275,799 SNPs) molecular markers obtained here will provide fundamental basis for functional genomic and population genetic studies of O. oratoria. PMID- 29702369 TI - Barefoot plantar pressure measurement in Chronic Exertional Compartment Syndrome. AB - BACKGROUND: Patients with Chronic Exertional Compartment Syndrome (CECS) have exercise-limiting pain that subsides at rest. Diagnosis is confirmed by intramuscular compartment pressure (IMCP) measurement. Accompanying CECS, subjective changes to gait (foot slap) are frequently reported by patients. This has not previously been investigated. The aim of this study was to investigate differences in barefoot plantar pressure (BFPP) between CECS cases and asymptomatic controls prior to the onset of painful symptoms. METHODS: 40 male military volunteers, 20 with symptoms of CECS and 20 asymptomatic controls were studied. Alternative diagnoses were excluded with rigorous inclusion criteria, magnetic resonance imaging and dynamic IMCP measurement. BFPP was measured during walking and marching. Data were analysed for: Stance Time (ST); foot progression angle (FPA); centre of force; plantarflexion rate after heel strike (IFFC-time); the distribution of pressure under the heel; and, the ratio between inner and outer metatarsal loading. Correlation coefficients of each variable with speed and leg length were calculated followed by ANCOVA or t-test. Receiver operating characteristic (ROC) curves were constructed for IFFC-time. RESULTS: Caseshad shorter ST and IFFC-times than controls. FPA was inversely related to walking speed (WS) in controls only. The area under the ROC curve for IFFC-time ranged from 0.746 (95%CI: 0.636-0.87) to 0.773 (95%CI: 0.671-0.875) representing 'fair predictive validity'. CONCLUSION: Patients with CECS have an increased speed of ankle plantarflexion after heel strike that precedes the onset of painful symptoms likely resulting from a mechanical disadvantage of Tibialis Anterior. These findings provide further insight into the pathophysiology of CECS and support further investigation of this non-invasive diagnostic. The predictive value of IFFC-time in the diagnosis of CECS is comparable to post-exercise IMCP but falls short of dynamic IMCP measured during painful symptoms. PMID- 29702370 TI - Dual-task interference during gait on irregular terrain in people with Parkinson's disease. AB - BACKGROUND: Gait impairments in people with Parkinson's disease (PD) are accentuated in dual-task conditions. Most PD studies on dual-task gait have measured only straight line walking and treadmill gait. Gait alterations on irregular terrain are poorly understood. RESEARCH QUESTION: To what extent does walking on irregular terrain exacerbate dual-task interference in people with PD, compared to age-matched control participants? METHODS: Gait data were collected for nine participants with mild to moderate PD and nine healthy age-matched participants on regular and irregular terrains. Gait was tested as a single task and in dual-task conditions with serial 7 subtractions. The spatiotemporal variables (speed, cadence, single limb support, step length and width), kinematic variables (range of motion for hip, knee and ankle joints) and stability variables (trunk range of motion and center of mass acceleration RMS) were compared across conditions. RESULTS: People with PD showed reduced gait speed and cadence and increased mediolateral center of mass acceleration when walking on irregular terrain with dual-tasks. Surface irregularity was associated with increased ankle transverse motion in both groups. Increased hip and knee sagittal motion was observed in the control participants when terrain changed from regular to irregular under dual-task conditions. This was not statistically significant for the PD group. SIGNIFICANCE: Dual-task walking on irregular terrain exacerbated the gait deficits, particularly for people with PD. Gait speed, cadence and mediolateral body stability were compromised when people with PD walked on irregular terrain whilst performing dual-tasks. There was an increase in ankle transverse motion in both groups when traversing irregular terrain. This might have been an adaptive strategy, to prevent tripping. PMID- 29702371 TI - Kinematic error magnitude in the single-mass inverted pendulum model of human standing posture. AB - BACKGROUND: Many postural control studies employ a single-mass inverted pendulum model (IPM) to represent the body during standing. However, it is not known to what degree and for what conditions the model's kinematic assumptions are valid. RESEARCH QUESTION: Our first objective was to quantify the IPM error, corresponding to a distance change between the ankle joint and center of mass (COM) during unrestricted, natural, unperturbed standing. A second objective was to quantify the error of having the ankle joint angle represent the COM angle. METHODS: Eleven young participants completed five standing conditions: quiet standing with eyes open (EO) and closed (EC), voluntarily swaying forward (VSf) and backward (VSb), and freely moving (FR). The modified Helen-Hayes marker model was used to capture the body kinematics. RESULTS: The COM distance changed <0.1% during EO and EC, <0.25% during VSf and VSb, and <1.5% during FR. The ankle angle moderately and positively correlated with the COM angle for EO, EC, and VSf, indicating that temporal features of the ankle angle moderately represent those of the COM angle. However, a considerable offset between the two existed, which needs to be considered when estimating the COM angle using the ankle angle. For VSb and FR, the correlation coefficients were low and/or negative, suggesting that a large error would result from using the ankle angle as an estimate of the COM angle. SIGNIFICANCE: Insights from this study will be critical for deciding when to use the IPM in postural control research and for interpreting associated results. PMID- 29702372 TI - Cerebrospinal fluid beta-amyloid42 and neurofilament light relate to white matter hyperintensities. AB - White matter hyperintensities (WMHs) are associated with poorer brain health, but their pathophysiological substrates remain elusive. To better understand the mechanistic underpinnings of WMHs among older adults, this study examined in vivo cerebrospinal fluid biomarkers of beta-amyloid42 deposition (Abeta42), hyperphosphorylated tau pathology, neurodegeneration (total tau), and axonal injury (neurofilament light [NFL]) in relation to log-transformed WMHs volume. Participants free of clinical stroke and dementia were drawn from the Vanderbilt Memory & Aging Project (n = 148, 72 +/- 6 years). Linear regression models adjusted for age, sex, race/ethnicity, education, intracranial volume, modified Framingham Stroke Risk Profile (excluding points assigned for age), cognitive diagnosis, and APOE-epsilon4 carrier status. Abeta42 (beta = -0.001, p = 0.007) and NFL (beta = 0.0003, p = 0.01) concentrations related to WMHs but neither hyperphosphorylated tau nor total tau associations with WMHs reached statistical significance (p-values > 0.21). In a combined model, NFL accounted for 3.2% of unique variance in WMHs and Abeta42 accounted for an additional 4.3% beyond NFL, providing novel evidence of the co-occurrence of at least 2 distinct pathways for WMHs among older adults, including amyloid deposition and axonal injury. PMID- 29702373 TI - The association of mid-to late-life systemic inflammation with white matter structure in older adults: The Atherosclerosis Risk in Communities Study. AB - We examined whether the pattern of middle- to late-life systemic inflammation was associated with white matter (WM) structural abnormalities in older adults. A total of 1532 participants (age = 76.5; standard deviations = 5.4) underwent 3T brain magnetic resonance imaging to quantify white matter hyperintensity volume and whole-brain WM microstructural integrity (fractional anisotropy, mean diffusivity). High-sensitivity C-reactive protein (CRP), a marker of systemic inflammation, was measured at 3 visits (21 and 14 years before, and concurrent with, neuroimaging). Participants were categorized into 1 of 6 groups based on their 21-year pattern of low (<3 mg/L) versus elevated (>=3 mg/L) CRP. Compared to the group with low CRP at all 3 visits, the group that transitioned from low to elevated CRP during midlife demonstrated greatest white matter hyperintensity volume and poorest WM microstructural integrity, after adjusting for demographic variables and cardiovascular risk factors. Participants with high CRP at all visits also demonstrated greater WM structural abnormalities, but only after accounting for differential attrition. These results suggest that increasing and persistent inflammation in the decades spanning middle-to late-life may promote WM disease in older adults. PMID- 29702374 TI - An exploration of the frequency, location, and content of parents' health- and weight-focused conversations with their children and associations with child weight status. AB - INTRODUCTION: Although parental weight-focused conversations with children have been associated with more unhealthy weight and weight-related outcomes in children and adolescents, little is known about the content and context of these conversations or conversations about healthy eating in the home environment. This study examines the frequency, location, and content of health- and weight-focused conversations in the home environment and examines the association between specific types of health- and weight-focused conversations with child overweight status. METHODS: Mixed-methods data were collected from parents of children from primarily low-income, minority homes (n = 110). Quantitative data included the frequency and location (i.e., "the context") of different types of health- and weight-focused conversations, while open-ended, write-in survey questions investigated "the content" of these conversations. RESULTS: Parents reported having more health-focused conversations with their child compared to weight focused conversations; parents of children who were overweight had more frequent health- and weight-focused conversations than parents of children who were not overweight. The most frequent location for these conversations was during a family meal. In addition, parental health- and weight-focused conversations were more common with overweight children (p < 0.05). Open-ended, write-in responses from parents for both health- and weight-focused conversations included conversations about moderation/portion control, unhealthy foods, and healthy foods. DISCUSSION: Open-ended, write-in results suggested that parental conversations about healthy eating were similar to conversations about weight. Results of this mixed-methods study provide an incremental next step in better understanding the nature of parental health- and weight-focused conversations with children. PMID- 29702375 TI - The role of chloramine species in NDMA formation. AB - N-nitrosodimethylamine (NDMA), a probable human carcinogen disinfection by product, has been detected in chloraminated drinking water systems. Understanding its formation over time is important to control NDMA levels in distribution systems. The main objectives of this study were to investigate the role of chloramine species (i.e., monochloramine and dichloramine); and the factors such as pH, sulfate, and natural organic matter (NOM) influencing the formation of NDMA. Five NDMA precursors (i.e., dimethylamine (DMA), trimethylamine (TMA), N,N dimethylisopropylamine (DMiPA), N,N-dimethylbenzylamine (DMBzA), and ranitidine (RNTD)) were carefully selected based on their chemical structures and exposed to varying ratios of monochloramine and dichloramine. All amine precursors reacted relatively fast to form NDMA and reached their maximum NDMA yields within 24 h in the presence of excess levels of chloramines (both mono- and dichloramine) or excess levels of dichloramine conditions (with limited monochloramine). When the formation of dichloramine was suppressed (i.e., only monochloramine existed in the system) over the 5 day contact time, NDMA formation from DMA, TMA, and DMiPA was drastically reduced (~0%). Under monochloramine abundant conditions, however, DMBzA and RNTD showed 40% and 90% NDMA conversions at the end of 5 day contact time, respectively, with slow formation rates, indicating that while these amine precursors react preferentially with dichloramine to form NDMA, they can also react with monochloramine in the absence of dichloramine. NOM and pH influenced dichloramine levels that affected NDMA yields. NOM had an adverse effect on NDMA formation as it created a competition with NDMA precursors for dichloramine. Sulfate did not increase the NDMA formation from the two selected NDMA precursors. pH played a key role as it influenced both chloramine speciation and protonation state of amine precursors and the highest NDMA formation was observed at the pH range where dichloramine and deprotonated amines coexisted. In selected natural water and wastewater samples, dichloramine led to the formation of more NDMA than monochloramine. PMID- 29702376 TI - Phosphorus speciation in sewage sludge and the sludge-derived biochar by a combination of experimental methods and theoretical simulation. AB - Sewage sludge is an inevitable byproduct from municipal wastewater treatment processes and conversion of sewage sludge into high value-added biochar is an effective strategy for resource utilization of sewage sludge. The characterization on P speciation is important to control the practical applications and environmental behavior of the sewage sludge and its derived biochar. The mobility and bioavailability of P is closely related to its speciation, but knowledge gap in P speciation is still existed which needs to be narrowed by a systematic study including existing experimental methods and techniques as well as theoretical prediction. To achieve a comprehensive understanding of P speciation, this study conducted a series of research combining conventional fractionation of P with consideration of major concomitant elements (Al, Ca, Fe), advanced analytical techniques (solution and solid-state 31P nuclear magnetic resonance (NMR), X-ray diffraction (XRD)), and theoretical simulation with respect to solubility of major elements in different acid-base extractants. Results showed that Ca and Fe were dominantly extracted by HCl whereas P and Al were both NaOH- and HCl-soluble. Inorganic orthophosphates were detected as predominant molecular configurations of P from solution 31P NMR spectra, while the existence of calcium and aluminum orthophosphates was revealed by solid-state 31P NMR. Moreover, the poor-crystalline AlPO4 mineral was further evidenced by XRD patterns of the sewage sludge and biochar. Finally, a theoretical simulation of P-containing minerals was performed on the basis of results above, which suggested the existence of variscite/berlinite and amorphous Ca3(PO4)2 in the sludge and biochar. This study does not only explore the P speciation in the sewage sludge and its derived biochar, but also provides a methodology for further research on P speciation. Through the intensive study on the environmental behavior of P, this work might further contribute to the fundamental knowledge basis for the recycle of P during integrate waste management. PMID- 29702377 TI - Severity of mental health concerns in pediatric primary care and the role of child psychiatry access programs. AB - OBJECTIVE: To describe the clinical severity of patients for whom Primary Care Providers (PCPs) requested consultation from Maryland's Child Psychiatry Access Program (CPAP), and examine the proportion and associated characteristics of severe cases being managed alone by PCPs versus co-managed with mental health specialists. METHODS: Data were collected for 872 cases based on calls received between October 2012 and December 2016. Severity was measured by consultant assigned Clinical Global Impression-Severity (CGI-S) score. The unadjusted odds of a PCP managing a case alone for select patient and provider characteristics was calculated in a sub-sample of 229 severe cases. RESULTS: 73.8% of cases were categorized as mild-moderate (CGI-S 1-4) and 26.3% as severe (CGI-S 5-7). 67.3% of severe cases were managed by a PCP alone; 32.8% were co-managed. The unadjusted odds of a severe case managed alone was lower for cases with greater numbers of psychotropic medications (OR 0.76, 95% CI 0.6, 0.96), prescription of antidepressants (OR 0.51, 95% CI 0.28, 0.95), or antipsychotics (OR 0.45, 95% CI 0.22, 0.94) compared to co-managed cases. CONCLUSIONS: PCPs manage patients with severe mental health concerns, often without assistance from specialists. CPAPs should systematically consider how to support the PCPs' role managing clinically severe cases. PMID- 29702378 TI - Emergent literacy in print and electronic contexts: The influence of book type, narration source, and attention. AB - Young children learn from traditional print books, but there has been no direct comparison of their learning from print books and tablet e-books while controlling for narration source. The current project used a between-subjects design and examined how 4-year-olds (N = 100) learned words and story content from a print book read aloud by a live adult, a print book narrated by an audio device, an e-book read aloud by a live adult, and an e-book narrated by an audio device. Attention to the book and prior experience with tablet e-books were also measured and included in analyses. When controlling for vocabulary, the overall pattern of results revealed that children learned more words from the e-book and from the audio narrator, but story comprehension did not differ as a function of condition. Attention predicted learning, but only in some print book contexts, and significant effects of prior experience did not emerge. PMID- 29702379 TI - The specificity of parenting effects: Differential relations of parent praise and criticism to children's theories of intelligence and learning goals. AB - Individuals who believe that intelligence can be improved with effort (an incremental theory of intelligence) and who approach challenges with the goal of improving their understanding (a learning goal) tend to have higher academic achievement. Furthermore, parent praise is associated with children's incremental theories and learning goals. However, the influences of parental criticism, as well as different forms of praise and criticism (e.g., process vs. person), have received less attention. We examine these associations by analyzing two existing datasets (Study 1: N = 317 first to eighth graders; Study 2: N = 282 fifth and eighth graders). In both studies, older children held more incremental theories of intelligence, but lower learning goals, than younger children. Unexpectedly, the relation between theories of intelligence and learning goals was nonsignificant and did not vary with children's grade level. In both studies, overall perceived parent praise positively related to children's learning goals, whereas perceived parent criticism negatively related to incremental theories of intelligence. In Study 2, perceived parent process praise was the only significant (positive) predictor of children's learning goals, whereas perceived parent person criticism was the only significant (negative) predictor of incremental theories of intelligence. Finally, Study 2 provided some support for our hypothesis that age-related differences in perceived parent praise and criticism can explain age-related differences in children's learning goals. Results suggest that incremental theories of intelligence and learning goals might not be strongly related during childhood and that perceived parent praise and criticism have important, but distinct, relations with each motivational construct. PMID- 29702380 TI - Direct growth of metal-organic frameworks thin film arrays on glassy carbon electrode based on rapid conversion step mediated by copper clusters and hydroxide nanotubes for fabrication of a high performance non-enzymatic glucose sensing platform. AB - The direct growth of self-supported metal-organic frameworks (MOFs) thin film can be considered as an effective strategy for fabrication of the advanced modified electrodes in sensors and biosensor applications. However, most of the fabricated MOFs-based sensors suffer from some drawbacks such as time consuming for synthesis of MOF and electrode making, need of a binder or an additive layer, need of expensive equipment and use of hazardous solvents. Here, a novel free standing MOFs-based modified electrode was fabricated by the rapid direct growth of MOFs on the surface of the glassy carbon electrode (GCE). In this method, direct growth of MOFs was occurred by the formation of vertically aligned arrays of Cu clusters and Cu(OH)2 nanotubes, which can act as both mediator and positioning fixing factor for the rapid formation of self-supported MOFs on GCE surface. The effect of both chemically and electrochemically formed Cu(OH)2 nanotubes on the morphological and electrochemical performance of the prepared MOFs were investigated. Due to the unique properties of the prepared MOFs thin film electrode such as uniform and vertically aligned structure, excellent stability, high electroactive surface area, and good availability to analyte and electrolyte diffusion, it was directly used as the electrode material for non enzymatic electrocatalytic oxidation of glucose. Moreover, the potential utility of this sensing platform for the analytical determination of glucose concentration was evaluated by the amperometry technique. The results proved that the self-supported MOFs thin film on GCE is a promising electrode material for fabricating and designing non-enzymatic glucose sensors. PMID- 29702381 TI - Nonenzymatic electrochemical sensor based on imidazole-functionalized graphene oxide for progesterone detection. AB - The modification of electrode surfaces has been the target of study for many researchers in order to improve the analytical performance of electrochemical sensors. Herein, the use of an imidazole-functionalized graphene oxide (GO-IMZ) as an artificial enzymatic active site for voltammetric determination of progesterone (P4) is described for the first time. The morphology and electrochemical performance of electrode modified with GO-IMZ were characterized by scanning electron microscopy and cyclic voltammetry, respectively. Under optimized conditions, the proposed sensor showed a synergistic effect of the GO sheets and the imidazole groups anchored on its backbone, which promoted a significant enhancement on electrochemical reduction of P4. Figures of merits such as linear dynamic response for P4 concentration ranging from 0.22 to 14.0 MUmol L-1, limit of detection of 68 nmol L-1 and limit of quantification and 210 nmol L-1 were found. In addition, presented a higher sensitivity, 426 nA L umol 1, when compared to the unmodified electrode. Overall, the proposed device showed to be a promising platform for a simple, rapid, and direct analysis of progesterone. PMID- 29702382 TI - Flexible multichannel vagus nerve electrode for stimulation and recording for heart failure treatment. AB - Vagus nerve stimulation is an emerging bioelectronic medicine to modulate cardiac function, as the nerve provides parasympathetic innervation to the heart. In this study, we developed a polyimide based 2D cuff electrode to wrap around on the vagus nerve. Thanks to the tiny size and bendable protruding structure of the contact tips of the device, the electrode sites are able to flexibly bend to touch the nerve, selectively record and stimulate the vagus nerve. Gold, platinum and platinum black materials were chosen to compose the electrodes for nerve stimulation and recording, respectively. Since the platinum black has ~30 times larger charge delivery capacity (CDC) than gold, Pt black electrode is used for nerve stimulation. The electrochemical impedance spectroscopy and cyclic voltammetry measurement of the three materials were conducted in vitro, revealing the results of 405 kOmega, 41 kOmega, 10.5 kOmega, @1 kHz and 0.81 mC/cm2, 4.26 mC/cm2, 25.5 mC/cm2, respectively (n = 3). The cuff electrodes were implanted into the right-sided vagus nerve of rats for in vivo experiment. Biphasic current configuration was implemented for nerve stimulation with frequency of 10 Hz, pulse during of 300 MUs and various currents stimulus. The result shows the heart beat frequency drops up to 36% during the stimulation and was able to return the regular frequency as stimulation was removed. Subsequently, the vagus nerve signals were recorded with the four channel cuff electrodes. The magnitude of the compound nerve action potentials (CNAPs) is ~10 MUV and the signal to noise ratio (SNR) is ~20. PMID- 29702383 TI - An enzyme-free and label-free surface plasmon resonance biosensor for ultrasensitive detection of fusion gene based on DNA self-assembly hydrogel with streptavidin encapsulation. AB - In this research, an enzyme-free and label-free surface plasmon resonance (SPR) biosensing strategy has been developed for ultrasensitive detection of fusion gene based on the heterogeneous target-triggered DNA self-assembly aptamer-based hydrogel with streptavidin (SA) encapsulation. In the presence of target, the capture probes (Cp) immobilized on the chip surface can capture the PML/RARalpha, forming a Cp-PML/RARalpha duplex. After that, the aptamer-based network hydrogel nanostructure is formed on the gold surface via target-triggered self-assembly of X shaped polymers. Subsequently, the SA can be encapsulated into hydrogel by the specific binding of SA aptamer, forming the complex with super molecular weight. Thus, the developed strategy achieves dramatic enhancement of the SPR signal. Using PML/RARalpha "S" subtype as model analyte, the developed biosensing method can detect target down to 45.22 fM with a wide linear range from 100 fM to 10 nM. Moreover, the high efficiency biosensing method shows excellent practical ability to identify the clinical PCR products of PML/RARalpha. Thus, this proposed strategy presents a powerful platform for ultrasensitive detection of fusion gene and early diagnosis and monitoring of disease. PMID- 29702384 TI - Signal processing approach to probe chemical space for discriminating redox signatures. AB - The discovery of discriminating molecular biomarkers often couples omics for data acquisition with advanced information processing methods for data analysis. Here, we move information processing upstream for data acquisition and report that a sample's "chemical space" can be actively probed using a tailored sequence of redox-based input signals. Specifically, we use a redox-active iridium salt (K3IrCl6) and an oxidative pulse-redox-relaxation input sequence to probe serum samples for chemical information. Optical and electrical output responses are collected simultaneously and analyzed using signal metrics that are sensitive to component and concentration dependent chemical information. We use the example of schizophrenia to illustrate the potential of this signal processing approach to rapidly discover discriminating signatures using simple and inexpensive instrumentation. These studies indicate that redox-probing provides an orthogonal measurement approach to accelerate biomarker discovery and further suggest a simple means to supply chemical information for the internet-of-things in medical and consumer applications. PMID- 29702385 TI - Dual functional rhodium oxide nanocorals enabled sensor for both non-enzymatic glucose and solid-state pH sensing. AB - Both pH-sensitive and glucose-responsive rhodium oxide nanocorals (Rh2O3 NCs) were synthesized through electrospinning followed by high-temperature calcination. The as-prepared Rh2O3 NCs were systematically characterized using various advanced techniques including scanning electron microscopy, X-ray powder diffraction and Raman spectroscopy, and then employed as a dual functional nanomaterial to fabricate a dual sensor for both non-enzymatic glucose sensing and solid-state pH monitoring. The sensing performance of the Rh2O3 NCs based dual sensor toward pH and glucose was evaluated using open circuit potential, cyclic voltammetry and amperometric techniques, respectively. The results show that the as-prepared Rh2O3 NCs not only maintain accurate and reversible pH sensitivity of Rh2O3, but also demonstrate a good electrocatalytic activity toward glucose oxidation in alkaline medium with a sensitivity of 11.46 MUA mM-1 cm-2, a limit of detection of 3.1 MUM (S/N = 3), and a reasonable selectivity against various interferents in non-enzymatic glucose detection. Its accuracy in determining glucose in human serum samples was further demonstrated. These features indicate that the as-prepared Rh2O3 NCs hold great promise as a dual functional sensing material in the development of a high-performance sensor forManjakkal both solid-state pH and non-enzymatic glucose sensing. PMID- 29702386 TI - Morphology-dependent electrochemical behavior of 18-facet Cu7S4 nanocrystals based electrochemical sensing platform for hydrogen peroxide and prostate specific antigen. AB - 18-facet polyhedron Cu7S4 nanocrystal and CuS sphere were prepared from Cu2O precursor, and CuS flower was synthesized through a simple solvothermal approach. Their electrochemical performances were investigated towards H2O2 and it was interesting to discover that Cu7S4 nanocrystal had the best electrochemical catalysis compared with CuS sphere and CuS flower. It can deduce that the special structure of Cu7S4 nanocrystal endowed it more exposed active points, higher surface area and higher Cu/S ratio. Therefore, Cu7S4 nanocrystal was firstly employed to prepare a nonenzymatic biosensor for H2O2. Satisfactory results were obtained. In addition, a label-free sensing platform for prostate specific antigen (PSA) was constructed based on electrochemical catalysis towards H2O2 of Cu7S4 nanocrystal. The label-free immunosenosr offered accurate PSA in the range of 0.001-15 ng/mL with the detection limit of 0.001 ng/mL. Besides, the immunosensor possessed good sensitivity, selectivity and stability and could detect PSA in real sample. More importantly, this work demonstrated that Cu7S4 nanocrystal hold great promising application in electrochemical sensors. PMID- 29702387 TI - Multifunctional 3D electrode platform for real-time in situ monitoring and stimulation of cardiac tissues. AB - Cardiovascular diseases are a major cause of death around the world underlining the importance of efficient treatments including novel medication. In vitro models of cardiac tissues are highly desired for monitoring electrophysiological response to screen pharmaceutical compounds at an early stage. Here, we report a platinum based 3D pillar electrode platform with cell growth guiding channel, which allows integrated, continuous electrical stimulation and recording of the cardiac tissues. This platform was successfully used to culture beating cardiomyocytes over weeks. The Pt-PDMS pillar electrode showed an impedance of 2.5 +/- 0.3 kOmega at 10 Hz that is stable for using in cell cultures at 37 degrees C. Electrically pacing the cells improved maturation of the cardiac tissues. Contraction activities of 3D cardiac tissues were monitored in real-time through the pillar electrodes to evaluate physiological parameters. Adding 100 nM Isoproterenol clearly increased the spontaneous beating rate and decreased the extracellular field potential duration of the microtissues observed with electrical recording through the pillar electrodes. Overall, this platform has a potential to be applied in drug screening for in situ monitoring the biophysical parameters of the heart tissue in real-time. PMID- 29702388 TI - Photoelectrochemical platform for cancer cell glutathione detection based on polyaniline and nanoMoS2 composites modified gold electrode. AB - Herein, a visible light photoelectrochemical (PEC) platform based on polyaniline (PANI) and nanoMoS2 composites as optoelectronic material for glutathione detection without any auxiliary of biomolecules or labeled materials was developed. Firstly, the nanoMoS2 was prepared via a simple ultrasound exfoliation method. The PANI was synthesized by chemical oxidative polymerization method. Then composite of PANI and nanoMoS2 was used to modify gold electrode. It was found that the composite membrane showed excellent PEC properties. And glutathione enhanced the PEC signal greatly. Based on this finding a method for glutathione detection was fabricated. Under the optimum conditions, the linear response of glutathione concentrations ranged from 1.0 * 10-10 to 1.0 * 10-4 mol L-1 was obtained with a detection limit of 3.1 * 10-11 mol L-1. The relative standard deviation was 2.9% at 2.0 * 10-9 M (n = 10). This method showed high sensitivity and simpleness which opened up a new promising signal-on PEC platform for future bioassay. PMID- 29702389 TI - A Novel Triple Stage Ion Trap MS method validated for curcumin pharmacokinetics application: A comparison summary of the latest validated curcumin LC/MS methods. AB - Even through more sensitive methods for quantifying trace levels of curcumin in plasma were urgently needed, beyond tandem mass spectrometry, the Paul trap MS/MS/MS has never been tested for curcumin quantification. Because of its unique trap function to accumulate target compounds selectively by optimizing multiple stage MS experiments, it showed great potential to remove background issues reported at low concentration ranges. A novel Triple stage Ion Trap Mass Spectrometry coupled with High Performance Liquid Chromatography (HPLC ITMS/MS/MS) method has been developed and validated as a curcumin quantification method, for the first time. The use of isotope labeled curcumin-d6 as a novel internal standard (IS) is suggested and tested according to FDA validation procedure. A simplified sample preparation is introduced and validated by coupling a novel acetonitrile precipitation with molecular weight cut-off size exclusion method. This method demonstrated excellent recovery rate of 96.69% 109.26% and minimum matrix effect of 95.40%-110.98%. The lower limit of detection (LLOD) and lower limit of quantification (LLOQ) for curcumin in rat plasma were 0.1 ng/ml and 1 ng/ml respectively. The linear calibration curve for quantifying curcumin in rat plasma was 1-3000 ng/ml (r2 > 0.99) with intra-day and inter-day RSD and accuracy within +/-5.11%. Its application in a Pharmacokinetics (PK) study demonstrated detection of curcumin at a very low plasma level (1.0 ng/ml) and it would be applied to larger sample size animal and clinical pharmacokinetic studies. The presented ITMS/MS/MS quantification method has shown its advantages, including better sensitivity, accuracy, precision, wider calibration range and simplicity in sample preparation, when comparing with other curcumin LC/MS analysis methods in the latest 4 years. PMID- 29702390 TI - Development and application of bio-sample quantification to evaluate stability and pharmacokinetics of inulin-type fructo-oligosaccharides from Morinda Officinalis. AB - Inulin-type fructooligosaccharides (FOS) purified from Morinda Officinalis, with degrees of polymerization (DP) from 3 to 9, have been approved in China as an oral prescribed drug for mild and moderate depression episode, while the stability and oral absorption of this FOS mixtures are largely unknown. As the main active component and quality control marker for above FOS, DP5 was selected as the representative FOS in this study. Desalting method by ion exchange resin was developed to treat bio-sample, followed by separation and quantification by high performance liquid chromatography-charged aerosol detector. Results showed that the DP5 was stepwisely hydrolyzed in simulated gastric fluid and gut microbiota, while maintained stable in intestinal fluid. DP5 has poor permeability across Caco-2 monolayer with Papp of 5.22 * 10-7 cm/s, and very poor oral absorption with bioavailability of (0.50 +/- 0.12)% in rat. In conclusion, FOS in Morinda Officinalis demonstrated poor chemical stability in simulated gastric fluid and human gut microbiota, and low oral absorption in rats. PMID- 29702391 TI - Novel biosensing system for the simultaneous multiplex fluorescent determination of catecholamines and their metabolites in biological liquids. AB - A novel original biosensing system for the simultaneous multiplex determination of general markers of catecholamine-producing diseases - catecholamines (dopamine, epinephrine, norepinephrine) and their metabolites (homovanillic and vanillylmandelic acids) in biological liquids without preliminary separation of analytes, in the absence of specific antibodies and receptors and with minimum pretreatment of a samples has been developed. This outstanding approach includes the unique combination of obtaining highly fluorescent derivatives of the analytes as a result of their interaction with two different amines benzylamine and 1,2-diphenylethylenediamine in the presence of peroxidase as a catalyst, with the application of first-order derivative fluorescence spectroscopy for the resolution of their spectra. Fluorescence is measured in 96-well microplates, which wells contain a bio-recognizing film consisted of horseradish peroxidase immobilized in the polymer chitosan. Spectra of the solutions are recorded in the range 400-500 nm (lambdaex ~ 305-356 nm). The proposed procedures provide sensitive (in the range of 3-200 nM), selective, and reproducible (RSDs <= 1%, n = 6) multiplex determination of the catecholamines and their metabolites in biological liquids were successfully applied for the rapid simultaneous (20 samples per 15-30 min) screening of human urine and mice blood plasma. The validated results showed good linearity, precision, accuracy and selectivity of this method. PMID- 29702392 TI - Fully validated SRM-MS-based method for absolute quantification of PIVKA-II in human serum: Clinical applications for patients with HCC. AB - Protein induced by vitamin K absence or antagonist-II (PIVKA-II), an abnormal form of prothrombin, is used as a serological biomarker that aids in the diagnosis of hepatocellular carcinoma (HCC). PIVKA-II is typically measured by liquid binding assay (LiBA). However, without an internal standard, it is difficult to obtain accurate results. Thus, we aimed to develop a selected reaction monitoring-mass spectrometry (SRM-MS)-based assay to quantify PIVKA-II in serum. Our SRM-MS assay entailed the addition of a protein analog as an internal standard, the enrichment of PIVKA-II using a monoclonal antibody, chymotrypsin digestion, online desalting, and SRM-MS analysis. The performance of the SRM-MS assay was compared with that of LiBA in 400 human serum samples (100 chronic hepatitis, 100 liver cirrhosis, and 200 HCC). Integrated multinational guidelines were followed to validate the assay for clinical implementation. The linearity ranged from 1.28 to 100,000 ng/mL, and the use of a labeled protein analog as an internal standard allowed the error from the sample preparation to be corrected, improving the precision and accuracy. The SRM-MS assay was validated to meet all of the criteria of the compliance with guidelines per the US Food and Drug Administration (FDA), European medicines agency (EMA), Korea FDA (KFDA), and Clinical & Laboratory Standards Institute (CLSI). We have developed and validated a robust and reproducible SRM-MS assay that is superior to the conventional method of distinguishing HCC from noncancer patients, based on PIVKA II levels, and satisfies clinical standards. This method has potential applications in quantifying other protein biomarkers. PMID- 29702393 TI - Drug policy constellations: A Habermasian approach for understanding English drug policy. AB - BACKGROUND: It is increasingly accepted that a view of policy as a rational process of fitting evidence-based means to rationally justified ends is inadequate for understanding the actual processes of drug policy making. We aim to provide a better description and explanation of recent English drug policy decisions. METHOD: We develop the policy constellation concept from the work of Habermas, in dialogue with data from two contemporary debates in English policy; on decriminalisation of drug possession and on recovery in drug treatment. We collect data on these debates through long-term participant observation, stakeholder interviews (n = 15) and documentary analysis. RESULTS: We show the importance of social asymmetries in power in enabling structurally advantaged groups to achieve the institutionalisation of their moral preferences as well as the reproduction of their social and economic power through the deployment of policies that reflect their material interests and normative beliefs. The most influential actors in English drug policy come together in a 'medico-penal constellation', in which the aims and practices of public health and social control overlap. Formal decriminalisation of possession has not occurred, despite the efforts of members of a challenging constellation which supports it. Recovery was put forward as the aim of drug treatment by members of a more powerfully connected constellation. It has been absorbed into the practice of 'recovery oriented' drug treatment in a way that maintains the power of public health professionals to determine the form of treatment. CONCLUSION: Actors who share interests and norms come together in policy constellations. Strategic action within and between constellations creates policies that may not take the form that was intended by any individual actor. These policies do not result from purely rational deliberation, but are produced through 'systematically distorted communication'. They enable the most structurally favoured actors to institutionalise their own normative preferences and structural positions. PMID- 29702394 TI - Exploring what shapes injection and non-injection among a sample of marginalized people who use drugs. AB - BACKGROUND: Few studies have specifically explored what influences people who use drugs to consume them in certain ways (i.e., smoking, injecting). While a great deal of research has examined the transition from non-injection to injection routes of drug administration, less is known about people who use drugs (PWUD) but have never injected or have stopped injecting. This paper draws on actor network theory to explore what moves people to inject or not, among both people who currently smoke/sniff drugs (PWSD) and people who currently inject drugs (PWID), to better understand factors that shape/influence methods of drug consumption. METHODS: Two-stage interviews (a quantitative survey followed by a qualitative interview) were conducted with 26 PWSD and 24 PWID. Interviews covered a range of topics related to drug use, including reasons for injecting drugs, never injecting, and stopping injecting. Data were analysed by drawing on actor-network theory to identify forces involved in shaping drug consumption practices. RESULTS: We present three transformative drug use events to illustrate how specific methods of drug consumption are shaped by an assemblage of objects, actors, affects, spaces and processes. Rather than emphasising the role of broad socio-structural factors (i.e., poverty, drug policy) participant narratives reveal how a variety of actors, both human and non-human, assembled in unique ways produce drug consumption events that have the capacity to influence or transform drug consumption practices. CONCLUSION: Actor-network theory and event analysis provide a more nuanced understanding of drug consumption practices by drawing together complex material, spatial, social and temporal aspects of drug use, which helps identify the variety of forces involved in contexts that are thought to shape substance use. By attending to events of drug consumption we can better understand how contexts shape drug use and related harms. With greater insight into the transformative capacity of drug use events, strategies may be better tailored to prevent drug use-related harms. PMID- 29702395 TI - Socioemotional dysfunctions at age 10 years in extremely preterm newborns with late-onset bacteremia. PMID- 29702396 TI - Perinatal stress moderates the link between early and later emotional skills in very preterm-born children: An 11-year-long longitudinal study. AB - BACKGROUND: Very preterm (VPT) birth refers to an early stressful event putting children at heightened risk for emotional difficulties. However, there is an important individual variability, leaving unexplained why some VPT children do not develop emotional difficulties, while others develop such difficulties in the early years or later in life. AIM: In this study, we examined whether perinatal stress is a risk factor explaining heterogeneities in emotional problems in VPT children. METHODS: Thirty-six VPT children and 22 full-term born (FT) children participated in an 11 year-long study. Risk for perinatal stress was assessed at birth with the Perinatal Risk Inventory. Mothers reported children's emotional difficulties at 18 months of child age on the Symptom Checklist and at 11 years on the Child Behavior Checklist. RESULTS: Results indicated significant differences in emotional scores at 11 years not only between VPT and FT children but also between the low and high perinatal stress groups. More importantly, emotional scores at 18 months influenced variability in internalizing scores at 11 years only in VPT children with high perinatal stress. CONCLUSION: Although prematurity affects the emotional abilities of preadolescents, the link between emotional skills in early and later childhood is moderated by the severity of perinatal stress. In particular, VPT children who are born with more complications, and as such experience a more stressful perinatal environment, are more likely to show emotional difficulties at preadolescence. PMID- 29702397 TI - Evaluation of thermokarst lake water balance in the Qinghai-Tibet Plateau via isotope tracers. AB - Thermokarst lakes are a ubiquitous landscape feature, which widely distributed in the pan-arctic and some low latitude regions, and are associated with regional hydrological processes. The studies were taken to obtain a better understanding of the water balance of thermokarst lakes in the Qinghai-Tibet Plateau (QTP) in order to gain insight of the regional hydrological cycle. The characteristics of the stable isotopes delta 18O and delta D were investigated in precipitation, permafrost meltwater, and thermokarst lake water in the continuous permafrost region of the QTP and analyzed the lake water balance using the isotope mass model. The results showed that the delta D-delta 18O relationship in the thermokarst lakes (delta D = 5.45 delta 18O - 18.95) differed from that of the local precipitation (delta D = 8.30 delta 18O + 18.49) and permafrost meltwater (delta D = 5.78 delta 18O - 23.41), and the mean isotope compositions in the thermokarst lakes were -7.20/00 in delta 18O and -58.00/00 in delta D. The more positive isotope signals in thermokarst lakes than in the precipitation and permafrost meltwater revealed that the lakes had experienced stronger isotope enrichment. Additionally, the evaporation-to-inflow ratio (E/I) values were < 1 in most of the thermokarst lakes (84%), which might be explained by the recent expansion of the lake surfaces. However, 16% of the thermokarst lakes had shrunk, owing to thermokarst erosion, lateral expansion as the temperature increases, and lower recharge volume. Moreover, precipitation on the lake surface was only 14 18% of the inflow volume in the thermokarst lakes, and the surface-subsurface inflow and permafrost meltwater are very important for recharging the lakes and maintaining the water balance. The results of this study provide a comprehensive understanding of the influence of climate warming on hydrological processes in the permafrost regions in the QTP. PMID- 29702398 TI - Profiling physicochemical and planktonic features from discretely/continuously sampled surface water. AB - There is an increasing need for assessing aquatic ecosystems that are globally endangered. Since aquatic ecosystems are complex, integrated consideration of multiple factors utilizing omics technologies can help us better understand aquatic ecosystems. An integrated strategy linking three analytical (machine learning, factor mapping, and forecast-error-variance decomposition) approaches for extracting the features of surface water from datasets comprising ions, metabolites, and microorganisms is proposed herein. The three developed approaches can be employed for diverse datasets of sample sizes and experimentally analyzed factors. The three approaches are applied to explore the features of bay water surrounding Odaiba, Tokyo, Japan, as a case study. Firstly, the machine learning approach separated 681 surface water samples within Japan into three clusters, categorizing Odaiba water into seawater with relatively low inorganic ions, including Mg, Ba, and B. Secondly, the factor mapping approach illustrated Odaiba water samples from the summer as rich in multiple amino acids and some other metabolites and poor in inorganic ions relative to other seasons based on their seasonal dynamics. Finally, forecast-error-variance decomposition using vector autoregressive models indicated that a type of microalgae (Raphidophyceae) grows in close correlation with alanine, succinic acid, and valine on filters and with isobutyric acid and 4-hydroxybenzoic acid in filtrate, Ba, and average wind speed. Our integrated strategy can be used to examine many biological, chemical, and environmental physical factors to analyze surface water. PMID- 29702399 TI - Microplastic pollution in North Yellow Sea, China: Observations on occurrence, distribution and identification. AB - Microplastics are emerging contaminants and have attracted widespread environmental concerns about their negative effects on the marine ecosystems. In this study, we investigated the abundances, distributions and characteristics of microplastics in surface seawater and sediments from the North Yellow Sea. The results showed that the abundance of microplastics was 545 +/- 282 items/m3 in surface seawater and 37.1 +/- 42.7 items/kg dry weight in sediments, representing a medium microplastic pollution level compared with other sea areas. Small microplastics (<1 mm) made up >70% of the total microplastic numbers. Films and fibers were the dominant shapes of microplastics in both the surface seawater and sediments. Transparent microplastics were generally more common than microplastics of other colors. Based on the identification by a Fourier transform infrared microscope, polyethylene (PE) was the dominant composition of microplastics in surface seawater, while polypropylene (PP) was the most common polymer type in sediments. These results will improve our understanding of the environmental risks posed by microplastics to marine ecosystems. PMID- 29702400 TI - Shifts in distribution of herbivorous geese relative to hydrological variation in East Dongting Lake wetland, China. AB - Studies on distribution dynamics of waterbirds and the relation with hydrological changes are essential components of ecological researches. East Dongting Lake is a Ramsar site and especially important wintering ground for herbivorous geese along the East Asian-Australasian Flyway. In this paper, based on annual (2008/09 2016/17) waterbird census data, we investigated the spatial-temporal distributions of three herbivorous goose species (Lesser White-fronted Goose Anser erythropus, Bean Goose Anser fabalis, and Greater White-fronted Goose Anser albifrons) within East Dongting Lake, and analyzed their distribution dynamics (denoted by percentage similarity index, PSI) relative to variations in hydrological regime. The results demonstrated that the distribution of the globally vulnerable Lesser White-fronted Geese changed obviously between years, whereas that of Bean Geese was more stable. Greater White-fronted Geese suffered drastic distribution variation during the study period. The PSI of Lesser White fronted Geese was negatively correlated with between-year difference in water recession time and mean water level in October, whereas no obvious trend was found in Bean Geese. The Normalized Difference Vegetation Index (NDVI) was applied to detect changes in food resources of the geese, and significant correlations were also found between NDVI and hydrological factors. It was inferred that the variations in hydrological regime affected the annual distribution dynamics of Lesser White-fronted Geese by changing food conditions; whereas the effect on Bean Geese were not reflected in this study. Species traits may explain the differences in distribution dynamics among the three goose species. It was speculated that Lesser White-fronted Geese might be more sensitive to habitat change, whereas Bean Geese were more resilient. We suggested that regulating hydrological regime was crucial in management works. Our study could offer scientific information for species conservation in the context of habitat changes in East Dongting Lake wetland and provide potential insights into habitat management in this area. PMID- 29702401 TI - Phosphorus retention and internal loading in the Bay of Quinte, Lake Ontario, using diagenetic modelling. AB - Internal phosphorus (P) loading significantly contributes to hysteresis in ecosystem response to nutrient remediation, but the dynamics of sediment P transformations are often poorly characterized. Here, we applied a reaction transport diagenetic model to investigate sediment P dynamics in the Bay of Quinte, a polymictic, spatially complex embayment of Lake Ontario, (Canada). We quantified spatial and temporal variability of sediment P binding forms and estimated P diffusive fluxes and sediment P retention in different parts of the bay. Our model supports the notion that diagenetic recycling of redox sensitive and organic bound P forms drive sediment P release. In the recent years, summer sediment P diffusive fluxes varied in the range of 3.2-3.6 mg P m-2 d-1 in the upper bay compared to 1.5 mg P m-2 d-1 in the middle-lower bay. Meanwhile sediment P retention ranged between 71% and 75% in the upper and middle-lower bay, respectively. The reconstruction of temporal trends of internal P loading in the past century, suggests that against the backdrop of reduced external P inputs, sediment P exerts growing control over the lake nutrient budget. Higher sediment P diffusive fluxes since mid-20th century with particular increase in the past 20 years in the shallower upper basins, emphasize limited sediment P retention potential and suggest prolonged ecosystem recovery, highlighting the importance of ongoing P control measures. PMID- 29702402 TI - A machine learning method to estimate PM2.5 concentrations across China with remote sensing, meteorological and land use information. AB - BACKGROUND: Machine learning algorithms have very high predictive ability. However, no study has used machine learning to estimate historical concentrations of PM2.5 (particulate matter with aerodynamic diameter <= 2.5 MUm) at daily time scale in China at a national level. OBJECTIVES: To estimate daily concentrations of PM2.5 across China during 2005-2016. METHODS: Daily ground-level PM2.5 data were obtained from 1479 stations across China during 2014-2016. Data on aerosol optical depth (AOD), meteorological conditions and other predictors were downloaded. A random forests model (non-parametric machine learning algorithms) and two traditional regression models were developed to estimate ground-level PM2.5 concentrations. The best-fit model was then utilized to estimate the daily concentrations of PM2.5 across China with a resolution of 0.1 degrees (~10 km) during 2005-2016. RESULTS: The daily random forests model showed much higher predictive accuracy than the other two traditional regression models, explaining the majority of spatial variability in daily PM2.5 [10-fold cross-validation (CV) R2 = 83%, root mean squared prediction error (RMSE) = 28.1 MUg/m3]. At the monthly and annual time-scale, the explained variability of average PM2.5 increased up to 86% (RMSE = 10.7 MUg/m3 and 6.9 MUg/m3, respectively). CONCLUSIONS: Taking advantage of a novel application of modeling framework and the most recent ground-level PM2.5 observations, the machine learning method showed higher predictive ability than previous studies. CAPSULE: Random forests approach can be used to estimate historical exposure to PM2.5 in China with high accuracy. PMID- 29702403 TI - Transfer of polycyclic aromatic hydrocarbons from mother to fetus in relation to pregnancy complications. AB - The accumulation and transfer of carcinogens, including polycyclic aromatic hydrocarbons (PAHs), in the human body, especially from mother to fetus, has been the subject of many research studies, but the related data are limited and the mechanisms are unknown. This is the first study to investigate the distribution of PAHs in paired samples of maternal blood, placenta tissue, and umbilical cord blood in relation to pregnancy complications. Sixty-four pairs of samples were collected in Kunming, China; 18 were from healthy pregnant women and 46 were from patients with pregnancy complications. The predominant PAHs in these pregnant women were high-molecular-weight (HMW) compounds, mainly from the incomplete combustion or pyrolysis of biomass. In the control group, the total amount of HMW compounds (SigmaHMWPAHs) was significantly higher in maternal blood than in umbilical cord blood, which suggested that placenta may decrease PAH transfer in healthy pregnant women. However, this phenomenon was not observed for low molecular-weight PAHs or in the case group. In the control group, Sigma16PAH and SigmaHMWPAH in the placenta were higher than those in maternal blood and umbilical cord blood; for the case group, a contrasting result was observed. SigmaHMWPAHs in the placenta was significantly higher in the control group than in the case group. The same results were observed after the exclusion of the impact of the genotypes of the PAH metabolic enzymes (both phase I and phase II enzymes). Thus, the decreased PAH transfer from mother to fetus may partially result from the accumulation of PAHs inside the placenta. PMID- 29702404 TI - MGST1, a GSH transferase/peroxidase essential for development and hematopoietic stem cell differentiation. AB - We show for the first time that, in contrast to other glutathione transferases and peroxidases, deletion of microsomal glutathione transferase 1 (MGST1) in mice is embryonic lethal. To elucidate why, we used zebrafish development as a model system and found that knockdown of MGST1 produced impaired hematopoiesis. We show that MGST1 is expressed early during zebrafish development and plays an important role in hematopoiesis. High expression of MGST1 was detected in regions of active hematopoiesis and co-expressed with markers for hematopoietic stem cells. Further, morpholino-mediated knock-down of MGST1 led to a significant reduction of differentiated hematopoietic cells both from the myeloid and the lymphoid lineages. In fact, hemoglobin was virtually absent in the knock-down fish as revealed by diaminofluorene staining. The impact of MGST1 on hematopoiesis was also shown in hematopoietic stem/progenitor cells (HSPC) isolated from mice, where it was expressed at high levels. Upon promoting HSPC differentiation, lentiviral shRNA MGST1 knockdown significantly reduced differentiated, dedicated cells of the hematopoietic system. Further, MGST1 knockdown resulted in a significant lowering of mitochondrial metabolism and an induction of glycolytic enzymes, energetic states closely coupled to HSPC dynamics. Thus, the non selenium, glutathione dependent redox regulatory enzyme MGST1 is crucial for embryonic development and for hematopoiesis in vertebrates. PMID- 29702405 TI - Regulation of AMPK-related glycolipid metabolism imbalances redox homeostasis and inhibits anchorage independent growth in human breast cancer cells. AB - Breast cancer is one of the most lethal tumors in the world, among which 15% are triple-negative breast cancers (TNBCs) with higher metastasis and lower survival rate. Anoikis resistance is a key process during tumor metastasis, which is usually accompanied with metabolism reprogram. In this study, we established an anchorage independent growth model for MDA-MB-231 cells and investigated the changes in metabolism and redox homeostasis. Results showed that during detached growth, MDA-MB-231 cells tend to generate ATP through fatty acid oxidation (FAO), instead of glycolysis. Amount of glucose was used for pentose phosphate pathway (PPP) to keep redox balance. Moreover, we discovered that a synthesized flavonoid derivative GL-V9, exhibited a potent inhibitory effect on the anchorage independent growth of TNBCs in vitro and anti-metastasis effect in vivo. In terms of the mechanism, GL-V9 could promote the expression and activity of AMPK, leading to the decrease of G6PD and the increase of p-ACC. Thus, the level of PPP was suppressed, whereas FAO was highly enhanced. The reprogram of glycolipid metabolism destroyed the redox balance ultimately and induced cell death. This paper indicated a novel regulating mechanism of redox homeostasis involving with glycolipid metabolism, and provided a potential candidate for the anti-metastatic therapy of TNBCs. PMID- 29702406 TI - Oxygen-dependence of mitochondrial ROS production as detected by Amplex Red assay. AB - The initial rates of superoxide plus hydrogen peroxide (ROS) generation by intact or permeabilized rat heart mitochondria and coupled inside-out bovine heart submitochondrial particles (SMP) oxidizing NAD-dependent substrates, NADH, and succinate were measured by detecting resorufin formation in the Amplex Red assay at various oxygen concentrations. Linear dependences of the initial rates on oxygen concentration within the range of ~125-750 MUM were found for all significant mitochondrial generators, i.e. the respiratory complexes and ammonium stimulated dihydrolipoamide dehydrogenase. At lower oxygen concentrations upon its decrease from air saturation level to zero, the time-course of resorufin formation by SMP catalyzing coupled oxidation of succinate (the total ROS production by respiratory complexes II and III and by the reverse electron transfer (RET)-mediated by complex I) also corresponds to the linear dependence on oxygen with the same first-order rate constant determined in the initial rate studies. Prolonged incubation of SMP generating succinate-supported complex I mediated ROS affected neither their NADH oxidase nor ROS generating activity. In contrast to SMP significant deviation from the first-order oxygen dependence in the time-course kinetics during coupled oxidation of succinate by intact mitochondria was evident. Complex I catalyzes the NADH:resorufin oxidoreductase reaction resulting in formation of colorless reduced resorufin. Hydrogen peroxide oxidizes reduced resorufin in the presence of peroxidase, thus showing its dihydroresorufin peroxidase activity. Combined NADH:resorufin reductase and dihydroresorufin peroxidase activities result in underestimation of the amount of hydrogen peroxide generated by mitochondria. We conclude that only initial rates of the mitochondrial ROS production, not the amount of resorufin accumulated, should be taken as the reliable measure of the mitochondrial ROS-generating activity, because of the cycling of the oxidized and reduced resorufin during Amplex Red assays fed by NADH and other possible reductant(s) present in mitochondria. PMID- 29702407 TI - Generalized seizures presurgically in a cohort of children with hemispherectomy: Predictors and a potential link to surgical outcome? AB - PURPOSE: Generalized seizures were often thought to be contraindications for hemispherectomy. However, few studies had investigated this issue comprehensively, as well as the predictors for generalized seizures in hemispheric lesion. We studied the predictors of generalized seizures and their potential link to seizure outcomes in a cohort of children who underwent hemispherectomy. METHODS: A cohort of 76 children with hemispherectomy were reviewed and dichotomized into two groups with and without generalized seizures confirmed by vEEG presurgically. All preoperative evaluation data correlated to generalized seizures and postoperative prognosis were collected and analysed. RESULTS: Of 76 patients, 11 (14.5%) cases were documented with various generalized seizures, including atypical absence (54.5%, 6/11), myoclonic (45.5%, 5/11), atonic (36.4%, 4/11), myoclonic-atonic (18.2%, 2/11), myoclonic-absence (9.1%, 1/11) and spasms (9.1%). Electrical status epilepticus during sleep (ESES) was recorded in 3 patients (27.3%, 3/11). At last follow-up, 72.7% (8/11) patients remained seizure-free. ESES was a predictor of generalized seizures (chi2 = 4.69, P = 0.043). No correlation was found between generalized seizures and unfavourable postoperative seizure outcome (P = 0.153). For different seizure types, focal to bilateral tonic-clonic seizures (P = 0.020) and myoclonic-atonic seizures (P = 0.002) might correlate with unfavourable outcomes. CONCLUSION: Generalized seizures were not an absolute contraindication for hemispherectomy. Those patients with ESES might experience generalized seizures presurgically. Focal to bilateral tonic-clonic seizures and myoclonic-atonic seizures pre surgery may indicate unfavourable post-operative seizure outcomes. PMID- 29702408 TI - Dysregulated long non-coding RNAs in the temporal lobe epilepsy mouse model. AB - PURPOSE: To perform comprehensive profiling of long non-coding RNAs (LncRNAs) in temporal lobe epilepsy. METHODS: We performed extensive profiling of LncRNAs and mRNAs in the mouse pilocarpine model in specific brain regions, the hippocampus and cortex, and compared the results to those of the control mouse. Differentially expressed LncRNAs and mRNAs were identified with a microarray analysis (Arraystar Mouse LncRNA Expression Microarray V3.0). Then, gene ontology (GO) and pathway analysis were performed to investigate the potential roles of the differentially expressed mRNAs in the pilocarpine model. Protein-protein interactions transcribed by dysregulated mRNAs with/without co-dysregulated LncRNAs were analyzed using STRING v10 (http://string-db.org/). RESULTS: A total of 22 and 83 LncRNAs were up- and down-regulated (>=2.0-fold, all P < .05), respectively, in the hippocampus of the epilepsy model, while 46 and 659 LncRNAs were up- and down-regulated, respectively, in the cortex of the epilepsy model. GO and pathway analysis revealed that the dysregulated mRNAs were closely associated with a process already known to be involved in epileptogenesis: acute inflammation, calcium ion regulation, extracellular matrix remodeling, and neuronal differentiation. Among the LncRNAs, we identified 10 LncRNAs commonly dysregulated with corresponding mRNAs in the cortex. The STRING analysis showed that the dysregulated mRNAs were interconnected around two centers: the mTOR pathway-related genes and REST pathway-related genes. CONCLUSION: LncRNAs were dysregulated in the pilocarpine mouse model according to the brain regions of the hippocampus and cortex. The dysregulated LncRNAs with co-dysregulated mRNAs might be possible therapeutic targets for the epigenetic regulation of chronic epilepsy. PMID- 29702409 TI - Clinical outcomes of VNS therapy with AspireSR(r) (including cardiac-based seizure detection) at a large complex epilepsy and surgery centre. AB - PURPOSE: To compare the efficacy of AspireSR(r) to preceding VNS battery models for battery replacements, and to determine the efficacy of the AspireSR(r) for new implants. METHODS: Data were collected retrospectively from patients with epilepsy who had VNS AspireSR(r) implanted over a three-year period between June 2014 and June 2017 by a single surgeon. Cases were divided into two cohorts, those in whom the VNS was a new insertion, and those in whom the VNS battery was changed from a previous model to AspireSR(r). Within each group, the seizure burden was compared between the periods before and after insertion of AspireSR(r). RESULTS: Fifty-one patients with a newly inserted AspireSR(r) VNS model had a significant reduction in seizure frequency (p < 0.001), with 59% (n = 30) reporting >=50% reduction. Of the 62 patients who had an existing VNS, 53% (n = 33) reported >=50% reduction in seizure burden when the original VNS was inserted. After the battery was changed to the AspireSR(r), 71% (n = 44) reported a further reduction of >=50% in their seizure burden. The size of this reduction was at least as large as that resulting from the insertion of their existing VNS in 98% (61/62) of patients. CONCLUSION: The results suggest that approximately 70% of patients with existing VNS insertions could have significant additional benefit from cardiac based seizure detection and closed loop stimulation from the AspireSR(r) device. For new insertions, the AspireSR(r) device has efficacy in 59% of patients. The 'rule of thirds' used in counseling patients may need to be modified accordingly. PMID- 29702410 TI - Scared or scarred: Could 'dissociogenic' lesions predispose to nonepileptic seizures after head trauma? AB - A history of head injury is common in patients with psychogenic nonepileptic seizures (PNES). This association has so far been interpreted as either spurious or psychologically mediated. Biased recall and misattribution could foster illness beliefs about brain damage that promote symptom production. Furthermore, the emotional impact of head injury could induce long-term changes in stress responsivity. Lastly, maladaptive cognitive-behavioural processes involving symptom modelling and aversive conditioning, known to play a role in functional neurological disorders, could contribute to the development of PNES after head trauma. Lesional effects of head injury, on the other hand, remain unexplored in the context of PNES. However, even mild traumatic brain injury without structural MRI abnormalities on routine imaging can lead to disruptions of network connectivity that correlate with short-term cognitive impairments and psychiatric symptoms. Since alterations in global functional connectivity have been demonstrated in PNES patients using imaging and electroencephalography, we hypothesize that, in some patients, TBI and the associated disruption of long range association fibres could contribute to the individual propensity for dissociative experiences in general and PNES in particular. This possibility is explored in the context of new cognitive-behavioural models of PNES pathogenesis, and the concept of a "dissociogenic" brain lesion is introduced. PMID- 29702411 TI - Towards acute pediatric status epilepticus intervention teams: Do we need "Seizure Codes"? AB - PURPOSE: To identify areas of treatment delay and barriers to care in pediatric status epilepticus, review ongoing quality improvement initiatives, and provide suggestions for further innovations to improve and standardize these patient care processes. METHODS: Narrative review of current status epilepticus management algorithms, anti-seizure medication administration and outcomes associated with delays, and initiatives to improve time to treatment. Articles reviewing or reporting quality improvement initiatives were identified through a PubMed search with keywords "status epilepticus," "quality improvement," "guideline adherence," and/or "protocol;" references of included articles were also reviewed. RESULTS: Rapid initiation and escalation of status epilepticus treatment has been associated with shortened seizure duration and more favorable outcomes. Current evidence-based guidelines for management of status epilepticus propose medication algorithms with suggested times for each management step. However, time to antiseizure medication administration for pediatric status epilepticus remains delayed in both the pre- and in-hospital settings. Barriers to timely treatment include suboptimal preventive care, inaccurate seizure detection, infrequent or restricted use of home rescue medications by caregivers and pre-hospital emergency personnel, delayed summoning and arrival of emergency personnel, and use of inappropriately dosed medications. Ongoing quality improvement initiatives in the pre- and in-hospital settings targeting these barriers are reviewed. CONCLUSION: Improved preventive care, seizure detection, and rescue medication education may advance pre-hospital management, and we propose the use of acute status epilepticus intervention teams to initiate and incorporate in-hospital interventions as time-sensitive "Seizure Code" emergencies. PMID- 29702412 TI - Vagus nerve stimulation for 6- to 12-year-old children with refractory epilepsy: Impact on seizure frequency and parenting stress index. AB - OBJECTIVES: Refractory epilepsy (RE) is frequently associated with neuropsychological impairment in children and may disrupt their social development. Vagus nerve stimulation (VNS) had been reported to have beneficial effects on behavioral outcomes. The aim of this study was to compare Parenting Stress Index (PSI) scores before and after VNS device implantation in children with RE, especially those who experienced seizure frequency reduction. METHODS: We conducted a one-group pretest-posttest study in school age children with RE. Seizure frequency and PSI were recorded at 12months after VNS device implantation. RESULTS: Treatment with VNS was significantly associated with reduced seizure frequency and parental stress as measured by PSI. Factors contributing to seizure frequency included idiopathic/cryptogenic etiology and neurobehavioral comorbidities. In children with reduced seizure frequency, statistically significant improvements in the child domain of the PSI on the subscales of mood and reinforces parent were found. In the parent domain, the scores for social isolation were reduced. CONCLUSIONS: Treatment with VNS was significantly associated with reduced seizure frequency and improved PSI scores, especially within the child domain on the mood and reinforces parent subscales. These findings suggest that VNS reduced not only seizure frequency but also the psychological burden on children with RE. PMID- 29702413 TI - Risk of readmission for suicide attempt after epilepsy hospitalization. AB - OBJECTIVE: The objective of this study was to examine if epilepsy admissions are associated with a higher readmission risk for suicide attempt, independent of psychiatric comorbidity, compared with index admissions for other medical causes. METHODS: The Nationwide Readmissions Database is a nationally representative dataset containing data from roughly 15 million hospital discharges. Analysis of International Classification of Disease Clinical Modification 9 (ICD-9-CM) codes in the year 2013 revealed 58,278 index admissions for epilepsy; this group was compared with admissions for stroke (N=215,821) and common medical causes (N=973,078). Ninety-day readmission rates for suicide attempts were calculated. Cox regression tested for associations between admission type and suicide attempt readmissions up to 1year following index admission. RESULTS: There were 402/100,000 readmissions for suicide attempt within 90days from index admission in the group with epilepsy; 43/100,000 in the stroke group; and between 37 and 89/100,000 in the medical group. Unadjusted hazard ratios (HR) for suicide readmissions within 1year in the group with epilepsy compared with the stroke group were 9.61 (95% confidence interval (CI): 7.69-11.90, p<2.0*10-16) and 5.02 compared with the medical group (95% CI: 4.40-5.73, p<2.0*10-16). The HR for readmission in the group with epilepsy, after adjustment for sociodemographic and psychiatric variables, were elevated at 4.91 compared with the stroke group (95% CI: 3.83-6.27, p<2.0*10-16), and 2.66 compared with the medical group (95% CI: 2.32-3.05, p<2.0*10-16). CONCLUSION: Independent of psychiatric comorbidities, epilepsy admissions may be independently associated with more than a threefold increased risk of hospital readmission for suicide in the year following index admission in comparison with patients recently hospitalized because of stroke or other common medical disorders. PMID- 29702414 TI - Integration of temporal and spatial properties of dynamic connectivity networks for automatic diagnosis of brain disease. AB - Functional connectivity networks (FCNs) using resting-state functional magnetic resonance imaging (rs-fMRI) have been applied to the analysis and diagnosis of brain disease, such as Alzheimer's disease (AD) and its prodrome, i.e., mild cognitive impairment (MCI). Different from conventional studies focusing on static descriptions on functional connectivity (FC) between brain regions in rs fMRI, recent studies have resorted to dynamic connectivity networks (DCNs) to characterize the dynamic changes of FC, since dynamic changes of FC may indicate changes in macroscopic neural activity patterns in cognitive and behavioral aspects. However, most of the existing studies only investigate the temporal properties of DCNs (e.g., temporal variability of FC between specific brain regions), ignoring the important spatial properties of the network (e.g., spatial variability of FC associated with a specific brain region). Also, emerging evidence on FCNs has suggested that, besides temporal variability, there is significant spatial variability of activity foci over time. Hence, integrating both temporal and spatial properties of DCNs can intuitively promote the performance of connectivity-network-based learning methods. In this paper, we first define a new measure to characterize the spatial variability of DCNs, and then propose a novel learning framework to integrate both temporal and spatial variabilities of DCNs for automatic brain disease diagnosis. Specifically, we first construct DCNs from the rs-fMRI time series at successive non-overlapping time windows. Then, we characterize the spatial variability of a specific brain region by computing the correlation of functional sequences (i.e., the changing profile of FC between a pair of brain regions within all time windows) associated with this region. Furthermore, we extract both temporal variabilities and spatial variabilities from DCNs as features, and integrate them for classification by using manifold regularized multi-task feature learning and multi-kernel learning techniques. Results on 149 subjects with baseline rs-fMRI data from the Alzheimer's Disease Neuroimaging Initiative (ADNI) suggest that our method can not only improve the classification performance in comparison with state-of-the art methods, but also provide insights into the spatio-temporal interaction patterns of brain activity and their changes in brain disorders. PMID- 29702415 TI - Robust variational segmentation of 3D bone CT data with thin cartilage interfaces. AB - We present a two-stage variational approach for segmenting 3D bone CT data that performs robustly with respect to thin cartilage interfaces. In the first stage, we minimize a flux-augmented Chan-Vese model that accurately segments well separated regions. In the second stage, we apply a new phase-field fracture inspired model that reliably eliminates spurious bridges across thin cartilage interfaces, resulting in an accurate segmentation topology, from which each bone object can be identified. Its mathematical formulation is based on the phase field approach to variational fracture, which naturally blends with the variational approach to segmentation. We successfully test and validate our methodology for the segmentation of 3D femur and vertebra bones, which feature thin cartilage regions in the hip joint, the intervertebral disks, and synovial joints of the spinous processes. The major strength of the new methodology is its potential for full automation and seamless integration with downstream predictive bone simulation in a common finite element framework. PMID- 29702416 TI - Reliability verification of vehicle speed estimate method in forensic videos. AB - In various types of traffic accidents, including car-to-car crash, vehicle pedestrian collision, and hit-and-run accident, driver overspeed is one of the critical issues of traffic accident analysis. Hence, analysis of vehicle speed at the moment of accident is necessary. The present article proposes a vehicle speed estimate method (VSEM) applying a virtual plane and a virtual reference line to a forensic video. The reliability of the VSEM was verified by comparing the results obtained by applying the VSEM to videos from a test vehicle driving with a global positioning system (GPS)-based Vbox speed. The VSEM verified by these procedures was applied to real traffic accident examples to evaluate the usability of the VSEM. PMID- 29702417 TI - Sensitive naked eye detection and quantification assay for nitrite by a fluorescence probe in various water resources. AB - An uncontrolled increase of nitrite concentration in groundwater, rivers and lakes is a growing threat to public health and environment. It is important to monitor the nitrite levels in water and clinical diagnosis. Herein, we developed a switch-off fluorescence probe (PyI) for the sensitive detection of nitrite ions in the aqueous media. This probe selectively recognizes nitrite ions through a distinct visual color change from colorless to pink with a detection limit of 0.1 MUM. This method has been successfully applied to the determination of nitrites in tap water, lake water and Yellow River water with recoveries in the range of 94.8%-105.4%. PMID- 29702418 TI - Low temperature investigations of dynamic properties in l-leucine - chloranilic acid complex. AB - Inelastic neutron scattering (INS) and infra-red (IR) spectroscopy methods were used for determination of dynamic structure of l-leucine - chloranilic acid complex. A theoretical dynamic pattern calculated by the density functional theory (DFT) method for periodic boundary conditions accompanied the experimental ones. Normal modes in the vibrational spectra were defined and described. The characteristic presence of the Hadzi's trio enriched by numerous submaxima is observed in the wavenumber range 3200-800 cm-1. Bands assigned to CH3 torsion vibrations in the leucine cation were observed at 231 cm-1 and 258 cm-1 in the INS spectrum. Temperature-dependent far-infrared spectra in the temperature range 9 K-290 K were obtained. Vibrational bands were analyzed as a function of temperature. Activation energies for reorientational motion of CH3 and CH2 groups were determined by means of the band shape analysis performed for torsional and twisting vibrations of these groups. The estimated energy is equal to Ea = 2.7 +/ 0.2 kJ/mol and Ea = 2.17 +/- 0.12 kJ/mol for CH3 and CH2 groups, respectively. A phase transition at about 130 K in the l-leucine - chloranilic acid complex was observed. PMID- 29702419 TI - Enzyme adsorption properties on dilute acid pretreated biomass by low vacuum scanning electron microscopy and structural analysis of lignin. AB - In this study, enzyme adsorption properties were investigated as a function of the structural change of lignin in dilute acid pretreated biomass using oxalic and sulfuric acid catalysts under the same reaction conditions. Although the contents of glucan and lignin in the dilute acid pretreated biomass were similar regardless of the catalysts used, the enzymatic hydrolysis efficiency and degree of enzyme adsorption differed considerably. The highest efficiencies were 87.79% and 96.49% for the oxalic acid and sulfuric acid catalysts, respectively. The reasons for this observation were investigated by low vacuum-scanning electron microscopy and the structural analysis of lignin. In the oxalic acid pretreated biomass, the enzyme was irreversibly adsorbed onto the lignin. The oxalic acid pretreated biomass possessed a higher content of G-type lignin than did the sulfuric acid pretreated biomass. This type of lignin has a high affinity for the enzyme, inducing irreversible enzyme adsorption onto the biomass. PMID- 29702420 TI - Enhanced short-chain fatty acids production from waste activated sludge by combining calcium peroxide with free ammonia pretreatment. AB - This study reported a new low-cost and high-efficient combined method of CaO2 + free ammonia (FA) pretreatment for sludge anaerobic fermentation. Experimental results showed that the optimal short-chain fatty acids (SCFA) yield of 338.6 mg COD/g VSS was achieved when waste activated sludge (WAS) was pretreated with 0.05 g/g VSS of CaO2 + 180 mg/L of FA for 3 d, which was 2.5-fold of that from CaO2 pretreatment and 1.5-fold of that from FA pretreatment. The mechanism investigations exhibited that the CaO2 + FA could provided more biodegradable substrates, this combination accelerated the disintegration of sludge cells, which thereby providing more organics for subsequent SCFA production. It was also found that the combination of CaO2 and FA inhibited the specific activities of hydrolytic microbes, SCFA producers, and methanogens to some extents, but its inhibition to methanogens was much severer than that to the other two types of microbes. PMID- 29702421 TI - Cellulose degradation potential of Paenibacillus lautus strain BHU3 and its whole genome sequence. AB - The aim of this work was to study cellulose degradation and whole genome sequence of Paenibacillus lautus BHU3 isolate. The 16S rRNA gene sequence analysis revealed genetic relatedness (99%) of Iso 7 with Paenibacillus lautus, Iso 8 with Paenibacillus lactis, and Iso 9 with Bacillus amyloliquefaciens. Clear zone formation followed by CMCase and FPase assays exhibited cellulolytic potential in the order: P. lautus > P. lactis > B. amyloliquefaciens. The most potent isolate, Paenibacillus lautus strain BHU3 was subjected to whole genome analysis with reference to the genomic basis of cellulose degradation. Results showed that P. lautus strain BHU3 contains 6234 protein coding genes of which, 316 were associated with the carbohydrate metabolism. Further, genomic CAZymes analysis indicated that the P. lautus strain BHU3 comprising a range of glycoside hydrolase (GH) family genes (143), may play the vital role(s) in enhancing the cellulolytic attributes, and could be the useful tool for lignocellulosic biomass degradation and waste management. PMID- 29702422 TI - Assessing the removal of organic micropollutants by a novel baffled osmotic membrane bioreactor-microfiltration hybrid system. AB - A novel approach was employed to study removal of organic micropollutants (OMPs) in a baffled osmotic membrane bioreactor-microfiltration (OMBR-MF) hybrid system under oxicanoxic conditions. The performance of OMBR-MF system was examined employing three different draw solutes (DS), and three model OMPs. The highest forward osmosis (FO) membrane rejection was attained with atenolol (100%) due to its higher molar mass and positive charge. With inorganic DS caffeine (94-100%) revealed highest removal followed by atenolol (89-96%) and atrazine (16-40%) respectively. All three OMPs exhibited higher removal with organic DS as compared to inorganic DS. Significant anoxic removal was observed for atrazine under very different redox conditions with extended anoxic cycle time. This can be linked with possible development of different microbial consortia responsible for diverse enzymes secretion. Overall, the OMBR-MF process showed effective removal of total organic carbon (98%) and nutrients (phosphate 97% and total nitrogen 85%), respectively. PMID- 29702423 TI - Microbial interactions trigger the production of antibiotics. AB - Since the discovery of penicillin, antibiotics have been instrumental in treating infectious diseases. However, emerging antibiotic multi-resistance coinciding with a nearly exhausted drug pipeline is a major concern for the future of the therapy of infections. A novel approach for the discovery of antibiotics relies on the analysis of microbial consortia in their ecological context, taking into account the potential natural role of antibiotics. Co-cultivations of microorganisms have been successfully applied for the isolation of unknown secondary metabolites including antibiotics, and, thus, open new avenues to the production of bioactive compounds while at the same time providing insight into the natural function of the produced molecules and the regulation of their formation. PMID- 29702424 TI - Bio-inspired spiking neural network for nonlinear systems control. AB - Spiking neural networks (SNN) are the third generation of artificial neural networks. SNN are the closest approximation to biological neural networks. SNNs make use of temporal spike trains to command inputs and outputs, allowing a faster and more complex computation. As demonstrated by biological organisms, they are a potentially good approach to designing controllers for highly nonlinear dynamic systems in which the performance of controllers developed by conventional techniques is not satisfactory or difficult to implement. SNN-based controllers exploit their ability for online learning and self-adaptation to evolve when transferred from simulations to the real world. SNN's inherent binary and temporary way of information codification facilitates their hardware implementation compared to analog neurons. Biological neural networks often require a lower number of neurons compared to other controllers based on artificial neural networks. In this work, these neuronal systems are imitated to perform the control of non-linear dynamic systems. For this purpose, a control structure based on spiking neural networks has been designed. Particular attention has been paid to optimizing the structure and size of the neural network. The proposed structure is able to control dynamic systems with a reduced number of neurons and connections. A supervised learning process using evolutionary algorithms has been carried out to perform controller training. The efficiency of the proposed network has been verified in two examples of dynamic systems control. Simulations show that the proposed control based on SNN exhibits superior performance compared to other approaches based on Neural Networks and SNNs. PMID- 29702425 TI - Impact of frailty on complications in patients with thoracic and thoracolumbar spinal fracture. AB - OBJECTIVES: It is well-documented that geriatric patients are at risk for serious injuries after fracture due to pre-existing medical conditions, physical changes of aging, and medication effects. Frailty has been demonstrated to be a predictor of morbidity and mortality in inpatient head and neck surgery, and for surgical intervention for adult spinal deformity and degenerative spine disease. However, the impact of frailty on complications following thoracolumbar/thoracic fractures are unknown and has not been previously assessed in the literature, particularly in a nationwide setting. PATIENTS AND METHODS: This was a retrospective study of the prospectively-collected American College of Surgeons National Surgical Quality Improvement database for the years 2007 through 2012. Patients who underwent spinal decompression (+/- fusion) or an alternative intervention, defined as vertebroplasty or kyphoplasty (VP/KP) for thoracic or thoracolumbar fracture were identified. Frailty status was determined using a modified frailty index from the Canadian Study of Health and Aging Frailty Index, with frailty defined as a score = 0.27. 30-day morbidity and mortality were compared between frail and non-frail patients in each treatment group. RESULTS: A total of 303 patients were included in this study. Of these, 38% of patients had VP/KP and 62% underwent surgery. Within the VP/KP cohort, 26% were frail. The proportion of these patients who developed at least one complication was 3.3% versus 3.6% for non-frail patients (p = 1.0). The 30-day mortality for frail versus not frail patients in this cohort was 0% versus 2.4% (p = 1.0). Among the surgical group, 13% were frail. In contrast, the likelihood of complications was 33.3% among frail patients and 4.2% for non-frail patients (p < 0.001). Frail patients also had a 16.7% 30-day mortality rate as compared to 0.6% in the non-frail group (p = 0.001). When comparing the frail versus non-frail patients overall, frail patients had a complication rate of 16.7%, as opposed to 4.0% in non-frail patients. CONCLUSION: Frailty and surgical intervention are correlated with a higher 30-day complication rate in patients with thoracic and thoracolumbar fracture. This finding is an important consideration for surgical decision-making and patient counseling on treatment options. PMID- 29702426 TI - Diagnosing cancer in patients with 'non-alarm' symptoms: Learning from diagnostic care innovations in Denmark. PMID- 29702427 TI - The role of nighttime water balance on Olea europaea plants subjected to contrasting water regimes. AB - The climate change scenarios besides foreseeing a severe drought imposition also emphasize the temperature rising in the Mediterranean region, with special prominence at nighttime. Despite the high olive tree tolerance to severe environmental conditions, stomatal nighttime water loss can change plant water relations, and the related consequences and opportunities, especially under water scarcity, must be clarified. A set of 3-year-old potted olive trees were subjected to three cycles of drought, imposed by withholding irrigation, while another group were continuously irrigated. At the end of the latter and more severe drought cycle, daytime gas exchange parameters, water status and membrane integrity was negatively affected by drought imposition. Moreover, the nighttime transpiration rate was far above cuticular water loss, suggesting sustained stomatal aperture during nighttime, leading to substantial water losses, which was higher under drought in the first hours of darkness. The higher nighttime stomatal conductance of droughted plants were related with higher starch concentration in their leaves, a thicker trichome layer and a lower intercellular CO2 concentration, in a closely association with an inferior nighttime respiration. Still, whole-plant transpiration on droughted plants were much lower than leaf transpiration-based estimates, which is interpreted as compensation by water inputs due to dew deposition on leaves. Although unexpected, the increased of stomatal conductance in the first hours of the night, until a certain level of water deficit intensity, could be linked with potential benefits to the plants. PMID- 29702428 TI - Myeloperoxidase modification of high-density lipoprotein suppresses human endothelial cell proliferation and migration via inhibition of ERK1/2 and Akt activation. AB - BACKGROUND AND AIMS: Preclinical studies show high-density lipoproteins (HDL) have a protective and reparative effect on the endothelium. HDL is, however, susceptible to oxidation, which affects function. Myeloperoxidase (MPO)-induced modification of HDL results in loss of anti-apoptotic and anti-inflammatory functions, however, its effect on endothelial proliferation and migration has not been characterized. METHODS: HUVECs were co-incubated with MPO-oxidised- or native-HDL (nHDL) in proliferation and migration assays. Signalling proteins were assessed in Western blots. RESULTS: nHDL caused dose-dependent increases of endothelial proliferation and migration. Consistent with an increase in cellular proliferation, HDL also stimulated proliferative cellular nuclear antigen (PCNA) expression and ERK phosphorylation in a concentration-dependent manner, which did not occur with MPO-oxidised HDL. HDL increased Akt phosphorylation, a driver of cellular migration. Contrastingly, MPO-oxidised HDL was unable to increase Akt phosphorylation and extensively-oxidised HDL inhibited Akt phosphorylation. CONCLUSIONS: HDL promotes endothelial proliferation and migration, mediated in part via activation of ERK and Akt signalling. MPO-induced oxidative modification of HDL attenuates the endothelial-protective effects of HDL. These findings suggest that in an oxidative milieu, present in ageing and disease, HDL is likely to become ineffective. This has implications for HDL-raising therapies and emphasizes the need for strategies that prevent oxidation-related HDL dysfunction. PMID- 29702429 TI - Secular trends in the incidence, risk factors, and prognosis of transient ischemic attack in Japan: The Hisayama Study. AB - BACKGROUND AND AIMS: We aimed to investigate secular trends in the incidence, risk factors, and prognosis of transient ischemic attack (TIA) in a general Japanese population. METHODS: Two cohorts consisting of stroke-free Japanese individuals aged >=40 years in 1961 (n = 1621) and 1988 (n = 2646) were followed up for 24 years. The associations of potential risk factors with the development of TIA were estimated by a Cox proportional hazards model. The influence of TIA on the risk of total stroke over the subsequent 10 years was compared between the sub-cohorts of subjects with TIA and age- and sex-matched control subjects from each cohort. RESULTS: During follow-up, 28 subjects in the 1961 cohort and 34 in the 1988 cohort experienced TIA. The age-standardized incidence of TIA was significantly lower in the 1988 cohort than the 1961 cohort (0.66 vs. 1.01 per 1000 person-years, p = 0.02). While elevated systolic blood pressure was significantly associated with the risk of TIA in both cohorts, glucose intolerance and higher serum cholesterol levels were associated with TIA risk only in the 1988 cohort. The subjects experiencing TIA had approximately 7-8-fold higher risks for the 10-year incidence of total and ischemic strokes compared with the corresponding control subjects without TIA both in the 1961 and 1988 sub cohorts, and the relative risks were not significantly different between sub cohorts. CONCLUSIONS: Our results suggest that the incidence of TIA decreased during the past half century, probably due to the spread of antihypertensive treatments in the general Japanese population. PMID- 29702431 TI - Short-chain fatty acids suppress food intake by activating vagal afferent neurons. AB - Fermentable carbohydrates including dietary fibers and resistant starch produce short-chain fatty acids (SCFAs), including acetate, propionate and butyrate, through microbial fermentation in the intestine of rodents and humans. Consumption of fermentable carbohydrate and SCFAs suppress food intake, an effect involving the brain. However, their signaling pathway to the brain remains unclear. Vagal afferents serve to link intestinal information to the brain. In the present study, we explored possible role of vagal afferents in the anorexigenic effect of SCFAs. Intraperitoneal (ip) injection of three SCFA molecules (6 mmol/kg) suppressed food intake in fasted mice with the rank order of butyrate > propionate > acetate. The suppressions of feeding by butyrate, propionate and acetate were attenuated by vagotomy of hepatic branch and blunted by systemic treatment with capsaicin that denervates capsaicin-sensitive sensory nerves including vagal afferents. Ip injection of butyrate induced significant phosphorylation of extracellular-signal-regulated kinase 1/2, cellular activation markers, in nodose ganglia and their projection site, medial nucleus tractus solitaries. Moreover, butyrate directly interacted with single neurons isolated from nodose ganglia and induced intracellular Ca2+ signaling. The present results identify the vagal afferent as the novel pathway through which exogenous SCFAs execute the remote control of feeding behavior and possibly other brain functions. Vagal afferents might participate in suppression of feeding by intestine-born SCFAs. PMID- 29702430 TI - Metabolic products of the intestinal microbiome and extremes of atherosclerosis. AB - BACKGROUND AND AIMS: There is increasing awareness that the intestinal microbiome plays an important role in human health. We investigated its role in the burden of carotid atherosclerosis, measured by ultrasound as total plaque area. METHODS: Multiple regression with traditional risk factors was used to identify three phenotypes among 316/3056 patients attending vascular prevention clinics. Residual score (RES; i.e. the distance off the regression line, similar to standard deviation) was used to identify the 5% of patients with much less plaque than predicted by their risk factors (Protected, RES <-2), the 90% with about as much plaque as predicted (Explained, RES -2 to 2), and the 5% with much more plaque than predicted (Unexplained RES >2). Metabolic products of the intestinal microbiome that accumulate in renal failure - gut-derived uremic toxins (GDUT) - were assayed in plasma by ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry. RESULTS: Plasma levels of trimethylamine n-oxide (TMAO), p-cresyl sulfate, p-cresyl glucuronide, and phenylacetylglutamine were significantly lower among patients with the Protected phenotype, and higher in those with the Unexplained phenotype, despite no significant differences in renal function or in dietary intake of nutrient precursors of GDUT. In linear multiple regression with a broad panel of risk factors, TMAO (p = 0.011) and p-cresyl sulfate (p = 0.011) were significant independent predictors of carotid plaque burden. CONCLUSIONS: The intestinal microbiome appears to play an important role in atherosclerosis. These findings raise the possibility of novel approaches to treatment of atherosclerosis such as fecal transplantation and probiotics. PMID- 29702432 TI - Altered resting-state connectivity within default mode network associated with late chronotype. AB - Current evidence suggests late chronotype individuals have an increased risk of developing depression. However, the underlying neural mechanisms of this association are not fully understood. Forty-six healthy, right-handed individuals free of current or previous diagnosis of depression, family history of depression or sleep disorder underwent resting-state functional Magnetic Resonance Imaging (rsFMRI). Using an Independent Component Analysis (ICA) approach, the Default Mode Network (DMN) was identified based on a well validated template. Linear effects of chronotype on DMN connectivity were tested for significance using non parametric permutation tests (applying 5000 permutations). Sleep quality, age, gender, measures of mood and anxiety, time of scan and cortical grey matter volume were included as covariates in the regression model. A significant positive correlation between chronotype and functional connectivity within nodes of the DMN was observed, including; bilateral PCC and precuneus, such that later chronotype (participants with lower rMEQ scores) was associated with decreased connectivity within these regions. The current results appear consistent with altered DMN connectivity in depressed patients and weighted evidence towards reduced DMN connectivity in other at-risk populations which may, in part, explain the increased vulnerability for depression in late chronotype individuals. The effect may be driven by self-critical thoughts associated with late chronotype although future studies are needed to directly investigate this. PMID- 29702434 TI - Ethnic variations in mental health among 10-15-year-olds living in England and Wales: The impact of neighbourhood characteristics and parental behaviour. AB - Several studies indicate that young people from certain ethnic minority groups in Britain have significant mental health advantages over their White majority counterparts, but the reasons for these differences have not been adequately explored. This work analyses the impact of neighbourhood characteristics, measured by socioeconomic deprivation; crime; living conditions; ethnic density and parenting behaviour on the mental health of young people. To determine the impact of these factors on mental health among young people, geocoded data from waves 1, 3 and 5 of the UK Household Longitudinal Study (UKHLS) are merged with small area statistics from the 2011 census, and multilevel linear regression models are fitted to the sample of 5513 (7302 observations) 10-15-year-olds of varying ethnicity residing in England and Wales. We find that mental health is generally poorer for White British youths, even after accounting for individual/family-level predictors, neighbourhood characteristics and parental behaviour than it is for minority youths. In keeping with results from studies of adult populations, neighbourhoods with high levels of deprivation are associated with poorer mental health. However, some aspects of parenting behaviour appear to have a more significant impact on the mental health of young people from ethnic minority backgrounds than on White British youths. Further research into factors that influence inter-ethnic disparities in mental health among young people is warranted, given that clear differences remain after the models in this study are fully adjusted. PMID- 29702433 TI - Individual differences in corticolimbic structural profiles linked to insecure attachment and coping styles in motor functional neurological disorders. AB - BACKGROUND: Insecure attachment and maladaptive coping are important predisposing vulnerabilities for Functional Neurological Disorders (FND)/Conversion Disorder, yet no prior structural neuroimaging studies have investigated biomarkers associated with these risk factors in FND populations. This magnetic resonance imaging study examined cortical thickness and subcortical volumes associated with self-reported attachment and coping styles in patients with FND. We hypothesized that insecure attachment and maladaptive coping would relate to limbic-paralimbic structural alterations. METHODS: FreeSurfer cortical thickness and subcortical volumetric analyses were performed in 26 patients with motor FND (21 women; 5 men) and 27 healthy controls (22 women; 5 men). For between-group comparisons, patients with FND were stratified by Relationship Scales Questionnaire, Ways of Coping Scale-Revised, and Connor-Davidson Resilience Scale scores. Within-group analyses were also performed in patients with FND. All analyses were performed in the complete cohort and separately in women only to evaluate for gender-specific effects. Cortical thickness analyses were whole-brain corrected at the cluster wise level; subcortical analyses were Bonferroni corrected. RESULTS: In women with FND, dismissing attachment correlated with reduced left parahippocampal cortical thickness. Confrontive coping was associated with reduced right hippocampal volume, while accepting responsibility positively correlated with right precentral gyrus cortical thickness. These findings held adjusting for anti depressant use. All FND-related findings were within the normal range when compared to healthy women. CONCLUSION: These observations connect individual differences in limbic-paralimbic and premotor structures to attachment and coping styles in FND. The relationship between parahippocampal thickness and dismissing attachment may indicate aberrant social-emotional and contextual appraisal in women with FND. PMID- 29702436 TI - Intra-individual variability across cognitive task in drug-naive pediatric patients with obsessive compulsive disorder. AB - Attention deficit is commonly observed in several psychiatric conditions. In particular, patients with attention deficit hyperactivity disorder exhibit not only attention deficit, but also intra-individual variability in response times (IIV-RT) during the performance of cognitive tasks related to attention span and sustained attention. Although obsessive compulsive disorder (OCD) is commonly observed across childhood, little is known about abnormalities in IIV-RT during the auditory odd-ball task, and how these changes relate to event-related potentials (ERPs) components. In the present study, we compared the ERPs of 15 adolescent and pediatric patients with OCD with 15 healthy age, sex, and IQ matched controls. We found that tau of IIV-TR was not significantly different between the OCD group and controls, whereas the OCD group exhibited lower mu and sigma compared to controls. Furthermore, we revealed that P300 amplitude was significantly attenuated in the OCD group at Fz, C3, and C4, compared with controls. The present study thereby provided the first evidence that individuals with pediatric or adolescent OCD exhibit lower variability in reaction time in IIV-RT during an auditory odd-ball task than controls. These results suggest that there are no impairments in attention span and sustained attention in pediatric and adolescent patients with OCD. PMID- 29702437 TI - Synthesis methods influence characteristics, behaviour and toxicity of bare CuO NPs compared to bulk CuO and ionic Cu after in vitro exposure of Ruditapes philippinarum hemocytes. AB - Copper oxide (CuO) nanoparticles (NPs) are increasingly investigated, developed and produced for a wide range of industrial and consumer products. Notwithstanding their promising novel applications, concern has been raised that their increased use and disposal could consequently increase their release into marine systems and potentially affect species within. To date the understanding of factors and mechanisms of CuO (nano-) toxicity to marine invertebrates is still limited. Hence, we studied the characteristics and behaviour of two commercially available CuO NPs of similar size, but produced employing distinct synthesis methods, under various environmentally and experimentally relevant conditions. In addition, cell viability and DNA damage, as well as gene expression of detoxification, oxidative stress, inflammatory response, DNA damage repair and cell death mediator markers were studied in primary cultures of hemocytes from the marine clam Ruditapes philippinarum and, where applicable, compared to bulk CuO and ionic Cu (as CuSO4) behaviour and effects. We found that the synthesis method can influence particle characteristics and behaviour, as well as the toxicity of CuO NPs to Ruditapes philippinarum hemocytes. Our results further indicate that under the tested conditions aggregating behaviour influences the toxicity of CuO NPs by influencing their rate of extra- and intracellular dissolution. In addition, gene expression analysis identified similar transcriptional de-regulation for all tested copper treatments for the here measured suite of genes. Finally, our work highlights various differences in the aggregation and dissolution kinetics of CuO particles under environmental (marine) and cell culture exposure conditions that need consideration when extrapolating in vitro findings. PMID- 29702435 TI - An AOP-based alternative testing strategy to predict the impact of thyroid hormone disruption on swim bladder inflation in zebrafish. AB - The adverse outcome pathway (AOP) framework can be used to help support the development of alternative testing strategies aimed at predicting adverse outcomes caused by triggering specific toxicity pathways. In this paper, we present a case-study demonstrating the selection of alternative in chemico assays targeting the molecular initiating events of established AOPs, and evaluate use of the resulting data to predict higher level biological endpoints. Based on two AOPs linking inhibition of the deiodinase (DIO) enzymes to impaired posterior swim bladder inflation in fish, we used in chemico enzyme inhibition assays to measure the molecular initiating events for an array of 51 chemicals. Zebrafish embryos were then exposed to 14 compounds with different measured inhibition potentials. Effects on posterior swim bladder inflation, predicted based on the information captured by the AOPs, were evaluated. By linking the two datasets and setting thresholds, we were able to demonstrate that the in chemico dataset can be used to predict biological effects on posterior chamber inflation, with only two outliers out of the 14 tested compounds. Our results show how information organized using the AOP framework can be employed to develop or select alternative assays, and successfully forecast downstream key events along the AOP. In general, such in chemico assays could serve as a first-tier high throughput system to screen and prioritize chemicals for subsequent acute and chronic fish testing, potentially reducing the need for long-term and costly toxicity tests requiring large numbers of animals. PMID- 29702438 TI - Effect of grinding and long-term storage on the toxicity of white snakeroot (Ageratina altissima) in goats. AB - White snakeroot (Ageratina altissima) contains the putative toxin tremetone and can produce a disease called "trembles" or "milk sickness". However the toxicity of tremetone has not been demonstrated in vivo. It has been reported that the plant is less toxic after drying and grinding. The objectives of these studies were to determine: 1) the toxic effect of grinding white snakeroot 4 months prior to dosing and, 2) the toxic effect of storing white snakeroot at ambient temperature for 5 years. Dried white snakeroot, ground 1 day, 1 month, and 4 months prior to dosing, was orally gavaged to goats at 2% of their body weight for up to 28 days or until they were minimally poisoned (minimal muscular weakness and increased serum creatine kinase (CK) activities). All four goats dosed with white snakeroot that had been ground 4 months previously and stored at room temperature were poisoned, became exercise intolerant, and had increased serum CK activities (>5600 U/ L). White snakeroot stored for 5 years was toxic as 3 of 5 dosed goats developed clinical disease within only 6 days of dosing even though approximately 80% of the tremetone in the plant had disappeared during the 5-year storage period. The results from this study demonstrate that previous grinding and extended storage did not significantly alter white snakeroot toxicity. The results also indicate that tremetone concentration is not the singular indicator of toxicity and that other white snakeroot toxins or toxic tremetone degradation products remain in dried, stored white snakeroot. PMID- 29702439 TI - Establishing the competences of clinical reasoning for nursing students in Taiwan: From the nurse educators' perspectives. AB - BACKGROUND: Clinical reasoning is an essential core competence for nurses. Maintaining quality of care and safety of patients results from cultivation of student's clinical reasoning competency. However, the concept of clinical reasoning in nursing students is complex and its meaning and process needs further clarification. OBJECTIVES: The objectives were to explore the meaning of clinical reasoning competency in Taiwanese nursing students and to operationalize the concept in order to structure a framework illustrating the process of clinical reasoning. SETTING AND PARTICIPANTS: Thirteen seasoned nursing experts who had more than ten years of experience in nursing education or clinical practice participated in the interviews. The interviews were conducted in settings that the participants perceived as convenient, quiet and free of disturbance. METHODS: Semi-structured interviews were conducted. The interviews were audio-recorded and field notes were taken. The data were analyzed using Waltz et al.'s (2010) method of content analysis. RESULTS: The data revealed four domains and 11 competency indicators. The four domains include: awareness of clinical cues, confirmation of clinical problems, determination and implementation of actions, and evaluation and self-reflection. Each domain comprises of 2-4 indicators of clinical reasoning competency. In addition, this study established a framework for cultivation of clinical reasoning competency in nursing students. CONCLUSION: The indicators of clinical reasoning competency in nursing students are interwoven, interactive and interdependent to form a dynamic process. The findings of this study may facilitate evaluation of nursing students' clinical reasoning competency and development of instruments to assess clinical reasoning in nursing students. PMID- 29702440 TI - Nurse educators' critical thinking: A mixed methods exploration. AB - : Nurse educator's critical thinking remains unexamined as a key factor in the development of students' critical thinking. OBJECTIVES: The objective of this study is to understand how nurse educators reveal their critical thinking in the clinical setting while supervising students. DESIGN: This study uses a single phase triangulation mixed methods design with multiple data gathering techniques. PARTICIPANTS/SETTINGS: Participants for this study are clinical nurse educators from a large Western Canadian baccalaureate nursing program who teach 2nd or 3rd year students in medical-surgical settings. METHODS: Participants for this study completed a demographic survey, the California Critical Thinking Skills Test (CCTST), the California Critical Thinking Disposition Inventory (CCTDI), participant observation in a clinical practice setting, and semi-structured interviews. RESULTS: The results from the California Critical Thinking assessments (CCTST and CCTDI) show that participants are positively inclined and have a moderate to strong ability to think critically, similar to other studies. Participants find it difficult to describe how they reveal their critical thinking in the clinical setting, yet all participants use role modeling and questioning to share their critical thinking with students. When the quantitative and qualitative results are compared, it is apparent that the confidence in reasoning subscale of the California Critical Thinking Skills Test is higher in those educators who more frequently demonstrate and voice engagement in reflective activities. Dispositions associated with critical thinking, as measured by the California Critical Thinking Disposition Inventory, are more easily observed compared to critical thinking skills. CONCLUSIONS: This study is a beginning exploration of nurse educators' critical thinking-in-action. Our mixed methods approach uncovers a valuable approach to understanding the complexity of nurse educators' critical thinking. Further study is needed to uncover how nurse educators' can specifically enact their thinking abilities to support student learning in the clinical setting. PMID- 29702441 TI - Experience of nursing students with standardized patients in simulation-based learning: Q-methodology study. AB - BACKGROUND: Standardized patients (SPs) boost self-confidence, improve problem solving, enhance critical thinking, and advance clinical judgment of nursing students. OBJECTIVE: The aim of this study was to examine nursing students' experience with SPs in simulation-based learning. DESIGN: Q-methodology was used. SETTING: Department of nursing in Seoul, South Korea. PARTICIPANTS: Fourth-year undergraduate nursing students (n = 47). METHODS: A total of 47 fourth-year undergraduate nursing students ranked 42 Q statements about experiences with SPs into a normal distribution grid. RESULTS: The following three viewpoints were obtained: 1) SPs are helpful for patient care (patient-centered view), 2) SPs roles are important for nursing student learning (SPs roles-centered view), and 3) SPs can promote competency of nursing students (student-centered view). CONCLUSION: These results indicate that SPs may improve nursing students' confidence and nursing competency. Professors should reflect these three viewpoints in simulation-based learning to effectively engage SPs. PMID- 29702442 TI - Examining the impact of modality and learning style preferences on recall of psychiatric nursing and pharmacology terms. AB - The purpose of this experimental research study was to explore how modality and learning style preferences impact non-prescribing, first-year Licensed Vocational Nurse (LVN) students' recall of vocabulary. Independent t-test results indicated a statistically significant mean difference in short-term recall of pharmacological and psychiatric terms, with learners receiving visual text instruction recalling significantly more vocabulary than learners receiving audio text instruction. A correlation was not found between learning preferences and vocabulary recall. PMID- 29702443 TI - Immediate and delayed neuroendocrine responses to social exclusion in males and females. AB - Social exclusion is a complex phenomenon, with wide-ranging immediate and delayed effects on well-being, hormone levels, brain activation and motivational behavior. Building upon previous work, the current fMRI study investigated affective, endocrine and neural responses to social exclusion in a more naturalistic Cyberball task in 40 males and 40 females. As expected, social exclusion elicited well-documented affective and neural responses, i.e., increased anger and distress, as well as increased exclusion-related activation of the anterior insula, the posterior-medial frontal cortex and the orbitofrontal cortex. Cortisol and testosterone decreased over the course of the experiment, whereas progesterone showed no changes. Hormone levels were not correlated with subjective affect, but they were related to exclusion-induced neural responses. Exclusion-related activation in frontal areas was associated with decreases in cortisol and increases in testosterone until recovery. Given that results were largely independent of sex, the current findings have important implications regarding between-sex vs. within-sex variations and the conceptualization of state vs. trait neuroendocrine functions in social neuroscience. PMID- 29702444 TI - Spousal bereavement is associated with more pronounced ex vivo cytokine production and lower heart rate variability: Mechanisms underlying cardiovascular risk? AB - The loss of a spouse is a highly stressful event that puts people at excess risk of mortality. Excess mortality among those who are widowed is highest in the first six months after the death of a spouse and decreases over time. Heart disease accounts for the largest proportion of these deaths. The psychological stress associated with stressful life events can enhance inflammation and lower heart rate variability (HRV). Both lower HRV and higher inflammation are risk factors for cardiovascular morbidity and mortality. Thirty-two recently bereaved individuals (Mean = 89.68 days since death, SD = 17.09) and 33 age-matched comparisons completed a blood draw, EKG, and self-report questionnaires. In both adjusted and unadjusted models, spousal bereavement was associated with enhanced pro-inflammatory cytokine production by in vitro lipolysaccharide-stimulated peripheral blood leukocytes. Moreover, spousal bereavement was associated with lower HRV in comparison to the comparison group. This study is the first to demonstrate that bereavement is associated with a more pronounced ex vivo cytokine production and lower HRV in a population that exclusively consisted of widows and widowers. These findings add to the growing literature revealing the mechanisms that underlie bereavement-related cardiovascular problems. Future longitudinal studies are needed to determine the temporal relation between these risks. Understanding the biological mechanisms that underlie this stressful life event could allow researchers to create therapeutic targets for interventions to reduce or prevent the toll of a "broken heart." PMID- 29702445 TI - Insulin treatment partially prevents cognitive and hippocampal alterations as well as glucocorticoid dysregulation in early-onset insulin-deficient diabetic rats. AB - The diagnosis of Type 1 Diabetes (T1D) in ever younger children led us to question the impact of insulin deficiency or chronic hyperglycemia on cerebral development and memory performances. Here, we sought abnormalities in these traits in a model of streptozotocin-induced diabetes in juvenile rats treated or not by insulin. We made the assumption that such alterations would be related, at least in part, to excessive glucocorticoid exposition in hippocampal neurons. We have compared 3 groups of juvenile rats: controls, untreated diabetics and insulin-treated diabetics. Diabetes was induced by streptozotocin (65 mg/kg IP/day, 2 consecutive days), at postnatal days 21 and 22 and a subcutaneous pellet delivering 2 U of insulin/day was implanted in treated diabetic rats 3 days later. Three weeks after diabetes induction, cognitive performances (Y maze, object location and recognition tests), in vivo brain structure (brain volume and water diffusion by structural magnetic resonance imaging), and hippocampal neurogenesis (immunohistochemical labeling) measurements were undertaken. Corticosterone levels were evaluated in plasma under basal and stress conditions, and within hippocampus together with 11beta-dehydrocorticosterone to assess 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) activity. The comparison of the three experimental groups revealed that, compared to controls, untreated diabetic rats showed decreased cognitive performances in Y-maze and object location test (p < 0.05), decreased brain and hippocampal microstructure (p < 0.05), and decreased maturation and survival of hippocampal newborn neurons (p < 0.05). These alterations were associated with increased plasma corticosterone at the baseline nadir of its secretion (p < 0.001) and during the recovery phase following a restraint stress (p < 0.001), as well as increased hippocampal corticosterone levels (p < 0.01) and 11beta-HSD1 activity (p < 0.05). As untreated diabetic rats, insulin-treated diabetic rats displayed decreased brain volume and water diffusion (p < 0.05 compared to controls) and intermediate memory performances and hippocampal neurogenesis (p value not significant compared to either controls or untreated diabetics). Moreover, they were similar to controls for basal plasma and hippocampal corticosterone and 11beta-HSD1 activity but show increased plasma corticosterone during the recovery phase following a restraint stress similar to untreated diabetics (p < 0.001 compared to controls). Thus, insulin did not completely prevent several hippocampal dependent behavioral and structural alterations induced by diabetes in juvenile rats which may relate to the higher cognitive difficulties encountered in T1D children compared to non-diabetic controls. Although insulin restored basal corticosterone and 11beta-HSD1 activity (in hippocampus and plasma), the negative feedback regulation of corticosterone secretion after stress was still impaired in insulin-treated diabetic rats. Further characterization of insulin control on glucocorticoid regulation and availability within hippocampus is awaited. PMID- 29702446 TI - Aminobenzothiazole derivatives stabilize the thermolabile p53 cancer mutant Y220C and show anticancer activity in p53-Y220C cell lines. AB - Many cancers have the tumor suppressor p53 inactivated by mutation, making reactivation of mutant p53 with small molecules a promising strategy for the development of novel anticancer therapeutics. The oncogenic p53 mutation Y220C, which accounts for approximately 100,000 cancer cases per year, creates an extended surface crevice in the DNA-binding domain, which destabilizes p53 and causes denaturation and aggregation. Here, we describe the structure-guided design of a novel class of small-molecule Y220C stabilizers and the challenging synthetic routes developed in the process. The synthesized chemical probe MB710, an aminobenzothiazole derivative, binds tightly to the Y220C pocket and stabilizes p53-Y220C in vitro. MB725, an ethylamide analogue of MB710, induced selective viability reduction in several p53-Y220C cancer cell lines while being well tolerated in control cell lines. Reduction of viability correlated with increased and selective transcription of p53 target genes such as BTG2, p21, PUMA, FAS, TNF, and TNFRSF10B, which promote apoptosis and cell cycle arrest, suggesting compound-mediated transcriptional activation of the Y220C mutant. Our data provide a framework for the development of a class of potent, non-toxic compounds for reactivating the Y220C mutant in anticancer therapy. PMID- 29702447 TI - Synthesis, anionophoric activity and apoptosis-inducing bioactivity of benzimidazolyl-based transmembrane anion transporters. AB - In this paper we show that a series of 1,3-bis(benzimidazol-2-yl)benzene (m Bimbe) derivatives exhibit excellent performance as transmembrane anion transporters with anticancer activity. The transport efficiency of m-Bimbe and its derivatives has been firstly optimized by adding a strong electron withdrawing nitro group at the 5-position of the central phenyl subunits to enhance the CH...anion interactions. Evidences for the interactions were obtained from ESI MS, spectrophotometric and 1H NMR titrations. These compounds exhibit potent anionophoric activity in both liposomal models and live cells. In particular, the 5-nitrated derivatives having nitro or trifluoromethyl groups at the benzimidazoloyl subunits exhibit 2370- and 1721-fold enhanced anionophoric activity with the EC50 values as low as 36 and 50 nM, respectively. These compounds can disturb the cellular homeostasis of chloride anions, modify the intracellular pH and induce the basification of acidic organelles. Most of this series of m-Bimbe derivatives exhibit potent cytotoxicity toward the tested human solid tumor cell lines, and the 5-nitrated derivative bearing trifluoromethyl groups at the benzimidazoloyl subunits is the most active with the IC50 value in the low micromolar range. Mechanistic studies suggest that the transport of chloride anions across the cellular membranes plays a critical role in the cytotoxic effect and these compounds induce cell death probably via an apoptotic process. PMID- 29702448 TI - New pyrazolopyridine analogs: Synthesis, antimicrobial, antiquorum-sensing and antitumor screening. AB - New pyrazolopyridine analogs were prepared and tested for antimicrobial efficacy toward Staphylococcus aureus, Bacillus cereus, Escherichia coli, Pseudomonas aeruginosa, Candida albicans, Aspergillus fumigatus and Aspergillus flavus. Results revealed that compound 6 has prominent and broad spectrum antimicrobial activity. Compound 8 showed good antibacterial efficacy over the four tested bacterial strains. In addition, compounds 2-4 displayed interesting efficacy over S. aureus, B. cereus and P. aeruginosa as well as moderate efficacy toward E. coli, C. albicans, A. fumigatus and A. flavus. Furthermore, compounds 9 and 10 exhibited interesting efficacy over P. aeruginosa. Antiquorum-sensing efficacy of the same analogs toward Chromobacterium violaceum was also examined, whereas compounds 3, 4 and 6 displayed acceptable activity. In vitro antitumor assay of the new pyrazolopyridines toward liver (HepG2), breast (MCF-7) and cervix (Hela) cancer cells illustrated that compounds 2 and 5 have the highest antitumor activity over the three cell lines. Moreover, compound 4 exhibited interesting efficacy on all tested cell lines, whereas compound 7 showed good activity on MCF 7 cells. The most active in vitro antitumor analogs, 2, 4, 5 and 7 were assessed for in vivo antitumor efficacy on Ehrlich ascites carcinoma (EAC) cells, whereas compound 5 displayed the highest efficacy. In addition, cytotoxicity testing toward W138 and WISH normal cells revealed that all tested analogs are less cytotoxic than doxorubicin. The new analogs were evaluated for DNA-binding affinity, whereas compounds 2, 4 and 5 displayed the highest affinity. In silico studies concluded that all the new pyrazolopyridines are foreseen to have excellent oral absorption. PMID- 29702449 TI - The limited oncogenic potential of unilocular adnexal cysts: A systematic review and meta-analysis. AB - The reported frequency of malignant diseases in unilocular cysts varies in different studies, giving conflicting results. To quantify the risk of malignancies among echoic and anechoic unilocular adnexal cysts, in premenopausal and postmenopausal women, we performed a PubMed/MEDLINE search of papers published in English evaluating the histopathological diagnoses of removed ovarian cysts diagnosed as simple unilocular cysts at pre-operative ultrasound examination. From 34 selected publications, we extracted data on ovarian malignancy in the total series, and separately for premenopausal and postmenopausal women, and women with cysts < 5 cm and >=5 cm in diameter. Of the 2177 surgically removed lesions classified as unilocular cysts on pre-operative ultrasound, 24 (1.1%; 95% CI: 0.74-1.66) were malignant (among these 12 had borderline malignancy: 0.6%). The rates were lower for premenopausal women (6/987, 0.6%) than postmenopausal ones (12/372, 3.2%). Of the 2290 surgically removed lesions classified as anechoic unilocular cysts on ultrasound, 20 (0.9%; 95% CI: 0.57-1.35) were malignant (among these 8 had borderline malignancy: 0.3%). The rates were lower for premenopausal women (3/907, 0.3%) than postmenopausal ones (13/681, 1.9%) (Pearson chi-square P = 0.002). When we performed meta-analysis selecting studies including only anechoic unilocular cysts published after 2000 and with 100 or more patients, the estimate was 0.5 (95% CI 0.1-1.2) with no heterogeneity (heterogeneity chi-square P = 0.175). The oncogenic risk of unilocular adnexal cysts is low, suggesting that the final choice about surgical treatment of these cysts should be based on the combination of each patient's overall risk profile as well as personal priorities. PMID- 29702450 TI - Medium-term follow-up after supervised pelvic floor muscle training for patients with anterior vaginal wall prolapse. AB - OBJECTIVE: The objective of this study was to determine changes in quality of life, urogenital symptoms, and adherence to pelvic floor muscle training (PFMT) for pelvic organ prolapse (POP) in the medium term. STUDY DESIGN: The present study conducted a pretest-posttest quasi-experimental study design. Of 29 participants in 4-month supervised PFMT, 27 completed all assessments in a follow up study. Twenty subjects were included in final analysis except 7 participants who underwent surgery during follow-up. To evaluate urogenital symptoms, they completed a prolapse-quality of life (P-QOL) questionnaire and POP-specific QOL. A urologist evaluated the prolapse status of all participants with POP-Q. In addition, the participants were asked about their adherence to PFMT, PFMT obstacles, and where PFMT was performed. All outcome measures were assessed at the following three time points: before PFMT, immediately after PFMT with one-on one session, and at follow-up via a phone call. Values of p < 0.05 were considered significant. RESULTS: Of the 29 participants in the 4-month supervised PFMT, 27 completed all assessments in a follow-up study (response rate: 93.1%). The percentages of patients who continued PFMT at least 4 times declined substantially in non-operated at follow-up compared with supervised PFMT period. POP-specific QOL such as general health, prolapse impact, and role limitation were significantly worse at follow-up compared with immediately after PFMT despite initial improvement in the short term (p < 0.05). CONCLUSION: POP specific QOL gradually worsened compared with patients immediately after supervised PFMT in mild to moderate POP women who were followed up without surgery at a 2-year follow-up. Adherence to home-based PFMT might decline without further supervision. It might indicate that to PFMT would be required to maintain symptoms and QOL in medium term. Further study will be needed to clarify if PFMT is effective to improve urogenital symptoms and QOL in long term among the patients with POP. PMID- 29702452 TI - Decision-making performance of depressed patients within 72 h following a suicide attempt. AB - BACKGROUND: The significance of decision-making in suicidal behaviour is often highlighted; however, the performance of persons in suicide crisis is unknown. This study aimed to explore the comprehensive decision-making profile of depressed patients following a suicide attempt. METHODS: Decision-making was measured by reward- ("ABCD") and punishment- ("EFGH") sensitive versions of the Iowa Gambling Task (IGT) in 59 medication-free depressed patients within 72 h after a suicide attempt and in 46 healthy control subjects. Severity of depressive symptoms was assessed in the patient group by the Hamilton Depression Rating Scale. RESULTS: Performance of the two groups differed significantly on the IGT ABCD, while a trend towards significant differences was seen on the IGT EFGH. Severity of depressive symptoms did not affect the depressed participants' decision-making performance. LIMITATIONS: Subjects were not matched for years of education. Administration of the IGT ABCD and IGT EFGH was not counterbalanced. Methods of suicide attempts and history of previous attempts were not collected. CONCLUSIONS: Individuals with a recent suicide attempt showed decision-making dysfunction on both IGT versions. However, on the EFGH, the overall difference between groups was not significant, depressed participants' performance remained poor during all blocks. Their behaviour reflected a focus on best immediate possible outcomes, not regarding future adverse consequences. This could be a result of psychological and cognitive alterations which modulate suicidal behaviour independent from mood. Further longitudinal studies should verify this possibility. Investigation of state-dependent neuropsychological characteristics of suicidal behaviour might be essential for detecting acute suicidal crisis. PMID- 29702451 TI - Developmental evaluation of family functioning deficits in youths and young adults with childhood-onset bipolar disorder. AB - BACKGROUND: Childhood-onset bipolar disorder (BD) is a serious condition that affects the patient and family. While research has documented familial dysfunction in individuals with BD, no studies have compared developmental differences in family functioning in youths with BD vs. adults with prospectively verified childhood-onset BD. METHODS: The Family Assessment Device (FAD) was used to examine family functioning in participants with childhood-onset BD (n = 116) vs. healthy controls (HCs) (n = 108), ages 7-30 years, using multivariate analysis of covariance and multiple linear regression. RESULTS: Participants with BD had significantly worse family functioning in all domains (problem solving, communication, roles, affective responsiveness, affective involvement, behavior control, general functioning) compared to HCs, regardless of age, IQ, and socioeconomic status. Post-hoc analyses suggested no influence for mood state, global functioning, comorbidity, and most medications, despite youths with BD presenting with greater severity in these areas than adults. Post-hoc tests eliminating participants taking lithium (n = 17) showed a significant diagnosis by-age interaction: youths with BD had worse family problem solving and communication relative to HCs. LIMITATIONS: Limitations include the cross sectional design, clinical differences in youths vs. adults with BD, ambiguity in FAD instructions, participant-only report of family functioning, and lack of data on psychosocial treatments. CONCLUSIONS: Familial dysfunction is common in childhood-onset BD and endures into adulthood. Early identification and treatment of both individual and family impairments is crucial. Further investigation into multi-level, family-based mechanisms underlying childhood-onset BD may clarify the role family factors play in the disorder, and offer avenues for the development of novel, family-focused therapeutic strategies. PMID- 29702453 TI - Characterizing regional-scale temporal evolution of air dose rates after the Fukushima Daiichi Nuclear Power Plant accident. AB - In this study, we quantify the temporal changes of air dose rates in the regional scale around the Fukushima Dai-ichi Nuclear Power Plant in Japan, and predict the spatial distribution of air dose rates in the future. We first apply the Bayesian geostatistical method developed by Wainwright et al. (2017) to integrate multiscale datasets including ground-based walk and car surveys, and airborne surveys, all of which have different scales, resolutions, spatial coverage, and accuracy. This method is based on geostatistics to represent spatial heterogeneous structures, and also on Bayesian hierarchical models to integrate multiscale, multi-type datasets in a consistent manner. We apply this method to the datasets from three years: 2014 to 2016. The temporal changes among the three integrated maps enables us to characterize the spatiotemporal dynamics of radiation air dose rates. The data-driven ecological decay model is then coupled with the integrated map to predict future dose rates. Results show that the air dose rates are decreasing consistently across the region. While slower in the forested region, the decrease is particularly significant in the town area. The decontamination has contributed to significant reduction of air dose rates. By 2026, the air dose rates will continue to decrease, and the area above 3.8 MUSv/h will be almost fully contained within the non-residential forested zone. PMID- 29702454 TI - Method for source localization proposed and applied to the October 2017 case of atmospheric dispersion of Ru-106. AB - An efficient numerical method for the temporal and spatial localization of an unknown point source of an atmospheric tracer is proposed. The method, which is based on inverse modelling techniques, employs available data from a network of ground-level stations on the condition that the measurements represent the plume geographically and temporally. The method, which employs a level-of-agreement approach, is applied to the October 2017 air concentration measurements of Ru-106 in Europe. PMID- 29702455 TI - Heterogeneous activation of peroxymonosulfate by LaCo1-xCuxO3 perovskites for degradation of organic pollutants. AB - Recently cobalt-based heterogeneous catalysts have been widely investigated for peroxymonosulfate (PMS) activation in sulfate radical-based advanced oxidation processes. However, the improvement of the catalytic performance for PMS activation remains to be a challenge. As the limiting step, the rapid transformation of CoII/CoIII redox pairs is crucial for PMS activation. Perovskites attract increasing attention due to their controllable oxidation state of B-site metal and formation of oxygen vacancies, which accelerates the cycle of redox pairs. LaCo1-xMxO3 (M = Cu, Fe and Mn) perovskites as heterogeneous catalysts of PMS were synthesized for the degradation of phenol. The results showed that LaCo0.4Cu0.6O3 exhibited the highest catalytic activity. The pseudo first-order kinetic constant of phenol degradation on LaCo0.4Cu0.6O3 is 0.302 min-1, being about 5 times as high as Co2+ with same molar concentration of cobalt in LaCo0.4Cu0.6O3. XPS analysis confirmed that substitution of copper could promote the cycle of CoII/CoIII, thus enhance the catalytic efficiency for PMS activation. The facilitated cycle of CoII/CoIII played a crucial role in the generation of sulfate radicals, hydroxyl radicals and singlet oxygen. And sulfate radical was the primary radical responsible for pollutants degradation. The results provide insights into constructing novel perovskite catalysts for the removal of organic pollutants in water. PMID- 29702456 TI - Efficient oxidation and sorption of arsenite using a novel titanium(IV) manganese(IV) binary oxide sorbent. AB - Owing to the high toxicity and mobility, the removal of arsenite (As(III)) is significantly more difficult than arsenate (As(V)), thus representing a major challenge in arsenite-contaminated water treatment. For efficient elimination of As(III), we successfully fabricated a novel Ti-Mn binary oxide via a simultaneous oxidation and coprecipitation process. The amorphous oxide was aggregated from nanosized particles with a high specific surface area of 349.5 m2/g. It could effectively oxidize As(III) to As(V) and had a high As(III) sorption capacity of 107.0 mg/g. As(III) sorption occurred rapidly and equilibrium was achieved within 24 h. The kinetic data was well fitted by the pseudo-second-order equation, indicating a chemical sorption process. The material was almost independent upon the presence of competitive ions. The As(III) removal by the sorbent is a combined process coupled oxidation with sorption, where the MnO2 content is mainly responsible for oxidizing As(III) to As(V) and the formed As(V) is then adsorbed onto the surface of amorphous TiO2 content, through replacing the surface hydroxyl group or the adsorbed As(III) and forming inner-sphere surface complexes. Furthermore, the arsenic-containing oxide could be effectively regenerated and reused. The bi-functional sorbent could be used as a potentially attractive sorbent for As(III) removal in drinking water treatment and environmental remediation. PMID- 29702457 TI - Experimental investigation of photocatalytic effects of concrete in air purification adopting entire concrete waste reuse model. AB - This research investigated the capacities of recycled aggregate concrete adopting entire concrete waste reuse model in degrading NO2. Two major issues within environmental sustainability were addressed: concrete waste reuse rate and mitigation of hazards substances in the polluted air. The study consisted of two stages: identification of proper replacement rates of recycled concrete wastes in new concrete mixture design, and the evaluation of photocatalytic performance of recycled aggregate concrete in degrading NO2. It was found that replacement rates up to 3%, 30%, and 50% for recycled power, recycled fine aggregate, and recycled coarse aggregate respectively could be applied in concrete mixture design without deteriorating concrete strength. Recycled aggregates contained both positive attributes ("internal curing") and negative effects (e.g., lower hardness) to concrete properties. It was found that 30%-50% of natural coarse aggregate replaced by recycled coarse aggregates coated with TiO2 would significantly improve the photocatalytic performance of concrete measured by degradation rate of NO2. Micro-structures of recycled aggregates observed under microscope indicated that soaking recycled aggregates in TiO2 solution resulted in whiskers that filled the porosity within recycled aggregates which enhanced concrete strength. PMID- 29702458 TI - Retention of cesium and strontium by uranophane, Ca(UO2)2(SiO3OH)2.5H2O. AB - This work determines the capacity of uranophane, one of the long-term uranyl secondary solid phases formed on the spent nuclear fuel (SNF), to retain radionuclides (cesium and strontium) released during the dissolution of the SNF. Sorption was fast in both cases, and uranophane had a high sorption capacity for both radionuclides (maximum sorption capacities of 1.53.10-5 mol m-2 for cesium and 3.45.10-3 mol m-2 for strontium). The high sorption capacity of uranophane highlights the importance of the formation of uranyl silicates as secondary phases during the SNF dissolution, especially in retaining the release of radionuclides not retarded by other mechanisms such as precipitation. PMID- 29702459 TI - Inhibition of NADPH oxidase increases defense enzyme activities and improves maize seed germination under Pb stress. AB - Contaminated soil accumulated high levels of Pb, which shows great risk to human health and crop growth. To alleviate Pb impaired seed germination and seedling growth, effects of three methods were compared. Here, effects of the heavy metal chelator EDTA, reactive oxygen species (ROS) scavenger (e.g. dimethylthiourea/DMTU, glutathione and melatonin), and specific inhibitors of NADPH oxidase or NOX (e.g. imidazole/IMZ and diphenylene iodonium/DPI), on maize seed germination and seedling growth were examined under Pb stress. IMZ and DPI increased seed germination by 1-2-fold under Pb stress, compared with less than 50% for ROS scavengers, while EDTA decreased germination. Pb-induced H2O2 accumulation was reduced more dramatically by IMZ than DMTU. Compared with DMTU, Pb-impaired SOD and CAT enzyme can be reversed more significantly by IMZ. Thus, inhibiting the NOX was more efficient than using ROS scavengers for improving seed germination under Pb stress. Compared with EDTA and ROS scavenger, IMZ and DPI treatment cannot protect seedling growth under Pb stress. In addition, IMZ is cheap and highly efficient, making it suitable for improving seed germination in Pb-polluted soil. PMID- 29702460 TI - Assessing lead toxicity in the clam Ruditapes philippinarum: Bioaccumulation and biochemical responses. AB - Lead (Pb) is a non-essential metal. Its occurrence in the environment is related principally to anthropogenic contamination. Pb is toxic to aquatic organisms and can provoke damage to membranes and inhibit the activity of essential enzymes. The filter-feeding, Manila clam Ruditapes philippinarum is widely used as a biomonitor organism to assess metal toxicity. Among biomarkers related to the Pb toxicity, the enzymatic activity of delta-aminolevulinic acid dehydratase (delta ALAD) has been adopted as a specific tool. Metallothionein (MT), lipid peroxidation (LPO) and antioxidant enzymes activities, such as catalase (CAT), glutathione peroxidase (GPx), glutathione reductase (GR) and glutathione S transferase (GST) and superoxidase dismutase (SOD) have also been employed to assess the toxic effect of metals. Two target tissues, the gills and the digestive gland, were selected to examine biomarker responses. In order to assess the effects of Pb accumulation and the mechanisms involved in the recovery from it, clams were exposed at two Pb levels (10 and 100 ug/L) for 7 days and were later maintained in clean water for 7 days as a depuration period. Pb accumulation was dependent on the exposure concentration and higher Pb levels were observed in the gills compared to the digestive gland. Inhibition of delta ALAD, GST and SOD and the induction of MT and LPO over the exposure period were observed in the gills and the digestive gland of R. philippinarum. The depuration period showed a continuous inhibition of the delta-ALAD activity and induction of MT and LPO in both tissues. These results demonstrate that lead induced an exposure effect and the 7 days of depuration were not sufficient to recover the basal health status of the clams. PMID- 29702462 TI - Manual dexterity and brain structure in patients with schizophrenia: A whole brain magnetic resonance imaging study. AB - The Purdue Pegboard Test (PPT) is a motor coordination task used to assess manual dexterity. Although several brain regions are thought to be involved in PPT performance, the relationship of the task with decreased insular volume has not been investigated. The PPT was administered to 83 subjects diagnosed with schizophrenia (mean +/- standard deviation age: 38.6 +/- 11.2 years; 47 males, 36 females) and 130 healthy controls (42.1 +/- 15.2 years; 67 males, 63 females). All subjects were Japanese and right-handed. Gray matter volume was analyzed using voxel-based morphometry in statistical parametric mapping, while white matter measures were analyzed using diffusion tensor imaging in tract-based spatial statistics. For the patients with schizophrenia, the left-hand scores positively correlated with the right insular and bilateral operculum volumes, while the summation score (sum of left-, right-, and both-hands scores) positively correlated with the right insular volume, and the summation and assembly (number of assemblies completed) scores correlated with the diffuse white matter fractional anisotropy, axial diffusivity, and radial diffusivity values. In contrast, no significant correlations were found for the controls. These results suggested that decreased insular volume and white matter measures contributed to the impairments in manual dexterity observed in subjects with schizophrenia. PMID- 29702461 TI - Higher 5-HT1A autoreceptor binding as an endophenotype for major depressive disorder identified in high risk offspring - A pilot study. AB - Higher serotonin-1A (5-HT1A) receptor binding potential (BPF) has been found in major depressive disorder (MDD) during and between major depressive episodes. We investigated whether higher 5-HT1A binding is a biologic trait transmitted to healthy high risk (HR) offspring of MDD probands. Data were collected contemporaneously from: nine HR, 30 depressed not-recently medicated (NRM) MDD, 18 remitted NRM MDD, 51 healthy volunteer (HV) subjects. Subjects underwent positron emission tomography (PET) using [11C]WAY100635 to quantify 5-HT1A BPF, estimated using metabolite, free fraction-corrected arterial input function and cerebellar white matter as reference region. Multivoxel pattern analyses (MVPA) of PET data evaluated group status classification of individuals. When tested across 13 regions of interest, an effect of diagnosis is found on BPF which remains significant after correction for sex, age, injected mass and dose: HR have higher BPF than HV (84.3% higher in midbrain raphe, 40.8% higher in hippocampus, mean BPF across all 13 brain regions is 49.9% +/- 11.8% higher). Voxel-level BPF maps distinguish HR vs. HV. Elevated 5-HT1A BPF appears to be a familially transmitted trait abnormality. Future studies are needed to replicate this finding in a larger cohort and demonstrate the link to the familial transmission of mood disorders. PMID- 29702464 TI - Transforming growth factor-beta1 impairs lymph node homing of dendritic cells by downregulating C-type lectin receptor-2 expression. AB - Trafficking of dendritic cells (DCs) from peripheral tissues to draining lymph nodes is a prerequisite for induction of adaptive immunity. An immunosuppressive cytokine transforming growth factor (TGF)-beta1, however, inhibits migration of DCs by downregulating the expression of chemokine receptor CCR-7. Whether TGF beta1 engages any other receptor to mediate this inhibitory effect is currently unknown. In this article, we report that TGF-beta1 attenuated the lymph node homing ability of mouse DCs by reducing C-type lectin receptor-2 (CLEC-2) expression. Notably, TGF-beta1 inhibited CLEC-2 expression in DCs via c-Src. DCs silenced for c-Src were resistant to TGF-beta1-induced inhibition of CLEC-2 expression. Furthermore, silencing of c-Src substantially improved the lymph node homing capacity of TGF-beta1-treated DCs by restoring CLEC-2 expression. These results document a critical role for c-Src and CLEC-2 in TGF-beta1-mediated impairment of DC migration and define a previously unknown mechanism by which TGF beta1 attenuates the lymph node homing ability of DCs. PMID- 29702463 TI - Amyand's hernia complicated with appendix perforation treated by two-stage surgery consisting of laparoscopic appendectomy followed by elective inguinal hernioplasty: A case report. AB - INTRODUCTION: An inguinal hernia with an incarcerated appendix is defined as Amyand's hernia, and it is relatively rare. Amyand's hernia complicated with appendicitis, especially perforated appendicitis, is even rarer. Postoperative surgical site infection (SSI) is a dangerous complication, especially in Amyand's hernia with appendix perforation. The selection of an appropriate surgical approach is necessary to prevent postoperative SSI. Here, we report a case of Amyand's hernia complicated with appendix perforation that was successfully managed using a two-stage surgical approach consisting of laparoscopic appendectomy followed by elective inguinal hernioplasty. PRESENTATION OF CASE: A 70-year-old male presented with fever and right lower quadrant pain from the day before. After the patient was diagnosed with acute appendicitis within a right inguinal hernia, emergency laparoscopy was performed. The appendix was incarcerated in the right internal inguinal ring and perforated at the base. We decided to take a two-stage surgical approach to avoid postoperative SSI and performed only laparoscopic appendectomy. No postoperative complications occurred. Inguinal hernioplasty was performed 1 month after the first operation. There were no adhesions in the preperitoneal space, and no adverse events occurred postoperatively. CONCLUSIONS: A two-stage surgical approach consisting of laparoscopic appendectomy followed by elective inguinal hernioplasty was used successfully to treat Amyand's hernia complicated with appendix perforation without causing postoperative SSI. PMID- 29702465 TI - GALNT14 Involves the Regulation of Multidrug Resistance in Breast Cancer Cells. AB - GALNT14 is a member of N-acetylgalactosaminyltransferase enzyme family and mediates breast cancer cell development. Here, we find that GALNT14 regulates multidrug resistance (MDR) in breast cancer. The expression of GALNT14 is associated with MDR in breast cancer. Higher level of GALNT14 facilitates MCF-7 cells to resist Adriamycin, whereas knockdown of GALNT14 sensitizes cells to Adriamycin. Moreover, the expression of GALNT14 associates with the expression of P-gp, the efflux pump localized on the cell membrane, which could be the underlying mechanism of how GALNT14 induces MDR. In-depth analysis shows that GALNT14 regulates the stability of P-gp. Finally, GALNT14 associates with higher level of P-gp in chemotherapy-resistant human breast cancer tissues. Taken together, our studies reveal a molecular mechanism in breast cancer MDR. PMID- 29702466 TI - ADP-ribosylating enterotoxins as vaccine adjuvants. AB - Most infections are caused by pathogens that access the body at mucosal sites. Hence, development of mucosal vaccines to prevent local infection or invasion of pathogens appears highly warranted, especially since only mucosal immunization will stimulate strong local IgA responses and tissue resident memory CD4 and CD8 T cells. The most significant obstacle to developing such vaccines is the lack of approved adjuvants that can effectively and safely enhance relevant mucosal and systemic immune responses. The most potent mucosal adjuvants known today are the adenosine diphosphate (ADP)-ribosylating bacterial enterotoxins cholera toxin (CT) and Escherichia coli heat-labile toxins (LTs). Unfortunately, these molecules are also very toxic, which precludes their clinical use. However, much effort has been devoted to developing derivatives of these enterotoxins with low or no toxicity and retained adjuvant activity. Although it is fair to say that we know more about how these toxins affect the immune system than ever before, we still lack a detailed understanding of how and why these toxins are effective adjuvants. In the present review, we provide a state-of-the-art overview of the mechanism of action of the holotoxins and the strategies used for improving the toxin-based adjuvants. PMID- 29702467 TI - Trained immunity as a novel therapeutic strategy. AB - Recent studies have shown that upon certain vaccinations or infections human innate immune cells can undergo extensive metabolic and epigenetic reprogramming, which results in enhanced immune responses upon heterologous re-infection, a process termed trained immunity. Trained immunity has also been shown to be inappropriately activated in inflammatory diseases. This provides the potential for identifying novel therapeutic targets: potentiation of trained immunity could protect from secondary infections and reverse immunotolerant states, while inhibition of trained immunity might reduce excessive immune activation in chronic inflammatory conditions. By targeting specific mechanisms of trained immunity on either immunologic, metabolic or epigenetic level, novel therapeutic approaches could be developed. PMID- 29702468 TI - Physical activity among indigenous Australian children and youth in remote and non-remote areas. AB - Sport and physical activity (PA) hold particular significance in Australian Indigenous communities, and have the potential to address many of the health and education challenges faced by Indigenous communities. Optimal levels of PA are an important foundation in efforts to build healthy communities and reduce social disadvantage experienced to date. Yet little evidence relating to the current levels of PA within these communities, or the relationship between PA and outcomes, has been available. Drawing on national survey data from the Australian Bureau of Statistics, we examine levels of PA in the Australian Aboriginal and Torres Strait Islander Health Survey 2012-13. These data describe PA levels among Indigenous Australians, aged 5-17 years, in remote and non-remote communities. We also examine the relationship between PA and participation in education and self reported health among 15-17 year olds. Overall, participation rates appear to be high, with 64-84% of youth reporting at least 60 min of PA on the previous day. A gender gap was also evident, with lower levels of activity among girls. PA decreased with age, particularly at or around the age of puberty. There were no significant associations between PA and either self-reported health or engagement in study. There was a relationship between high PA and low area-level socio economic status in remote areas, but no association in non-remote areas. The differences between remote and non-remote areas highlight the importance of disaggregated analysis of Indigenous populations and are consistent with qualitative studies identifying locally contextualised factors influential in promoting PA. PMID- 29702469 TI - Neutral and acid-adapted fatty acid vesicles of conjugated linoleic acid. AB - FAVs (fatty acid vesicles), originated from natural biomass and created available biointerface, have advantages of biocompatibility, low-cost, and easy self assembly in aqueous solution due to their dynamic feature. However, there is no example of applying FAVs in contact with human body since they are inherently alkaline-adapted and pH windows for the FAV formation and application are very narrow and far away from the physiological pH range. In this work an attempt to turn the alkaline-adapted FAVs into neutral and acid-adapted ones was made by fabricating the amphiphile-hybrid vesicles of CLA (conjugated linoleic acid) with a typical cosmetic emulsifier SDS (sodium dodecylsulfate) and/or a co-emulsifier DA (dodecyl alcohol). pH windows for the SDS- and/or DA-hybrid FAV formation of CLA were judged by using dynamic light scattering criterion, and confirmed by small-angle X-ray scattering and room temperature transmission electron microscopy. The experimental results show that with the aid of H-bonding and ion dipole forces among molecules of CLA, SDS and DA within the hybrid vesicle walls that were identified by Fourier transform infrared analysis, much wider pH windows of 2.5-11.7 for the hybrid FAVs were obtained by expansion from 8.0-9.0 for FAV of CLA alone, which was composition-dependent and made the hybrid FAVs become neutral and acid-adapted. PMID- 29702470 TI - Fabrication of a promising immobilization platform based on electrochemical synthesis of a conjugated polymer. AB - Since conjugated polymers are an important class of materials with remarkable properties in biosensor applications, in this study, a novel glucose biosensor based on a conjugated polymer was fabricated via the electropolymerization of the monomer 10,13-bis(4-hexylthiophen-2-yl)dipyridol[3,2-a:2',3'-c]phenazine onto a graphite electrode surface. Glucose oxidase (GOx) was used as the model biological recognition element. As a result of the enzymatic reaction between GOx and glucose, the glucose amount was determined by monitoring the change in the oxygen level associated with substrate concentration via the amperometric detection technique. The proposed system possessed superior properties with KMapp value of 0.262 mM, 2.88 * 10-3 mM limit of detection and 105.12 MUA mM-1 cm-2 sensitivity. These results show that conjugated polymer film provides an effective and stable immobilization matrix for the enzyme. Finally, the biosensor was applied successfully to several commercially available beverage samples for glucose determination proving an inexpensive and highly sensitive system applicable for real time analyses. PMID- 29702471 TI - Characterization of hybrid microparticles/Montmorillonite composite with raspberry-like morphology for Atorvastatin controlled release. AB - In this work, we prepared a novel composite based on hybrid gelatin carriers and montmorillonite clay (MMT) to analyze its viability as controlled drug delivery system. The objective of this research involves the characterization of composites formed by structured lipid-gelatin micro-particles (MP) and MMT clay. This analysis included the evaluation of the composite according to its rheological properties, morphology (SEM), particle size, XRD, FT-IR, and in vitro drug release. The effect of pH in the properties of the composite is evaluated. A novel raspberry-like or armor MP/MMT clay composite is reported, in which the pH has an important effect on the final structure of the composite for ad-hoc drug delivery systems. For pH values below the isoelectric point, we obtained defined morphologies with entrapment efficiencies up to 67%. The pH level controls the MP/MMT composite release mechanism, restringing drug release in the stomach-like environment. Intended for oral administration, these results evidence that the MP/MMT composite represents an attractive alternative for intestinal-colonic controlled drug delivery systems. PMID- 29702472 TI - Fundamental motor skills, nutritional status, perceived competence, and school performance of Brazilian children in social vulnerability: Gender comparison. AB - Being at risk or in social vulnerability situations can affect important aspects of child development. The aim of this study was to investigate fundamental motor skills (locomotor and object control) and school (writing, arithmetic, reading) performances, the perceived competence and the nutritional status of girls and boys living in social vulnerability in the poorest regions of Brazil. Two hundred eleven (211) children (87 girls, 41%), 7-10-year-old (M = 8.3, SD = 0.9), from public schools in Ceara (Brazil), living in social vulnerability, participated in the study. Children were assessed using the Test of Gross Motor Development - 2, the Body Mass Index (BMI), the Self-Perception Profile for Children, and the School Performance Test. Multivariate analysis of covariance (MANCOVA), adjusted for age, did not show any significant effect for locomotion. There was an effect of gender on the object control. Boys showed higher scores in striking, kicking, throwing, and rolling a ball. Quade's nonparametric analysis showed no difference in BMI between the genders. Most children presented healthy weight. The MANCOVA showed no effect of gender on children's scores on perceived competence on the subscales; moderate scores were found for most children. There were no gender effects on school performance; both boys and girls demonstrated inferior performance. Boys and girls in social vulnerability showed inferior performance in most motor skills, moderate perceived competence and inferior school performance. These results reveal that the appropriate development of these children is at risk and that intervention strategies should be implemented to compensate the difficulties presented. PMID- 29702474 TI - Hydroxyapatite-ciprofloxacin delivery system: Synthesis, characterisation and antibacterial activity. AB - The main objective of this study was to synthesize hydroxyapatite-ciprofloxacin composites using a chemical precipitation method and to evaluate the properties and in vitro release profile of the drug from the hydroxyapatite-ciprofloxacin composites. Composite characterization was achieved by FT-IR, XRD and DLS. Ciprofloxacin determination was accomplished by HPLC, resulting in good incorporation efficiency of the drug (18.13 %). The in vitro release study (Higuchi model C = K t1/2 and Ritger-Peppas model, C = K t0.6) showed a diffusion controlled mechanism. The antibacterial activity showed that the bacterial growth inhibition zones were approximately equal for the synthesis composites and for the mechanical mixture on the Staphylococcus aureus germ. The use of hydroxyapatite, which is a biocompatible, bioactive and osteoconductive material, with ciprofloxacin, which has good antibacterial activity in this composite, makes it suitable for the development of bone grafts. Furthermore, the synthesis process allows a slow local release of the drug. PMID- 29702475 TI - TLC determination of some flavanones in the buds of different genus Populus species and hybrids. AB - Flavonoids in the buds of eight Populus species and hybrids were detected and compared with the aid of an optimized TLC method. Separation of 17 flavonoid aglycones belonging to different groups, namely, flavones, flavonols, flavanones and flavanonols, previously described as constituents of poplar buds, was performed on silica gel plates using a hexane/ethyl acetate/formic acid (60:40:1.3, V/V/V) mixture as the mobile phase. Pinocembrin and pinostrobin were found in the majority of analyzed poplar buds. For quantitative analysis of both compounds, two TLC evaluation modes, densitometric and videodensitometric, were compared and the established methods were validated. Concentrations of flavanones in some extracts differed slightly or significantly due to the analyzed plant matrix complexity and the TLC evaluation mode applied. Poplar buds rich in flavanones originated from P. * canadensis 'Robusta' (1.82 and 2.23 g per 100 g, resp.) and P. balsamifera (1.17 and 2.24 g per 100 g, resp.). PMID- 29702473 TI - Long-Term Effectiveness of a Smartphone App for Improving Healthy Lifestyles in General Population in Primary Care: Randomized Controlled Trial (Evident II Study). AB - BACKGROUND: Information and communication technologies are currently among the supporting elements that may contribute to improving health and changing lifestyles. OBJECTIVE: The aim of this study was to evaluate the long-term effectiveness of adding an app to standardized counseling in order to increase physical activity (PA) and adherence to the Mediterranean diet and to analyze the effects of app adherence in lifestyle changes. METHODS: A randomized, multicenter clinical trial with a 12 month-follow up was conducted, involving 833 participants recruited by random sampling in 6 primary Spanish care centers (415 vs 418). Counseling on PA and the Mediterranean diet was given to both groups by a research nurse; however, the counseling + app group (intervention group) received additional training in the use of an app that was designed to promote the Mediterranean diet and PA over a 3-month period. Main outcomes and measures included PA by accelerometer and the 7-day Physical Activity Recall (PAR) questionnaire and adherence to the Mediterranean diet by an adherence screener questionnaire. We considered adherence to the app to be high when it was used for more than 60 days. RESULTS: The mean age was 51 years (SD 12) in the intervention group and 52.3 years (SD 12.0) in the counseling-only group; females predominated in both groups (60.0%, 249/415 and 64.1%, 268/418, respectively). PA by accelerometer declined in both groups at 12 months (P value for tendency in moderate to vigorous PA, [MVPA]=.15). The intervention subgroup with high app adherence had better behavior than the low adherence subgroup (P value for tendency in MVPA=.001). PA analyzed by 7-day PAR did not show changes at 12 months in any of the groups (P value for tendency=.25). In the Mediterranean diet, an increase in adherence was observed in both groups at 12 months with no differences between them (P value for tendency=.46). In these two cases, the group with high app adherence also had better behavior, although without reaching significance for the tendency (P>.05). CONCLUSIONS: The participants with strongest app adherence showed better outcomes in terms of maintenance of healthy lifestyles at 12 months than those with weaker adherence. Overall, however, we found no differences between intervention group and counseling-only group in PA increase and adherence to the Mediterranean diet in the long term. PMID- 29702476 TI - Effect of lemongrass water extract supplementation on atherogenic index and antioxidant status in rats. AB - Cymbopogon citratus (DC) Stapf., commonly known as lemongrass, possesses strong antioxidant and cardiotonic properties. Lemongrass water extract contains several polyphenolic compounds including gallic acid, isoquercetin, quercetin, rutin, catechin and tannic acid. Rutin, isoquercetin catechin and quercetin are the flavonoids most abundantly found in the extract. The extract significantly decreased total cholesterol, low-density lipoprotein and atherogenic index in rats after treatment (p < 0.05). Expression of genes and protein of sterol regulatory element binding protein-1c (SREBP1c) and HMG-CoA reductase (HMGR) was also lowered significantly in treated groups (p < 0.05). Moreover, serum antioxidant capacity increased in treated rats in comparison with untreated ones (p < 0.05) and was associated with decreased serum lipid peroxidation. PMID- 29702477 TI - In vitro oxidative stress regulatory potential of Citrullus colocynthis and Tephrosia apollinea. AB - The present study investigates the potential role of medicinal plants Citrullus colocynthis and Tephrosia apollinea in ameliorating the oxidative stress developed during the generation of reactive oxygen species. Organic extracts of different organs (leaf, stem and root) of these medicinal plants obtained in n hexane, chloroform, n-butanol and water were assayed for radical scavenging, total antioxidant capacity, anti-lipid peroxidation and reduced glutathione. The total phenolic content (TPC) of both selected medicinal plants was also evaluated. The results indicated that extracts of T. apollinea leaf, stem and root have higher TPC compared to those of C. colocynthis. Similarly, the results of the present study revealed higher bioactivity of C. colocynthis than that of T. apollinea in various antioxidant assays. Various plant parts of each plant were also compared. PMID- 29702478 TI - Reversed phase HPLC for strontium ranelate: Method development and validation applying experimental design. AB - A reverse-phase HPLC (RP-HPLC) method was developed for strontium ranelate using a full factorial, screening experimental design. The analytical procedure was validated according to international guidelines for linearity, selectivity, sensitivity, accuracy and precision. A separate experimental design was used to demonstrate the robustness of the method. Strontium ranelate was eluted at 4.4 minutes and showed no interference with the excipients used in the formulation, at 321 nm. The method is linear in the range of 20-320 MUg mL-1 (R2 = 0.99998). Recovery, tested in the range of 40-120 MUg mL-1, was found to be 96.1-102.1 %. Intra-day and intermediate precision RSDs ranged from 1.0-1.4 and 1.2-1.4 %, resp. The limit of detection and limit of quantitation were 0.06 and 0.20 MUg mL 1, resp. The proposed technique is fast, cost-effective, reliable and reproducible, and is proposed for the routine analysis of strontium ranelate. PMID- 29702479 TI - Preparation and characterization of simvastatin/DMbetaCD complex and its pharmacokinetics in rats. AB - Simvastatin is poorly bioavailable because it is practically insoluble in water and shows dissolution rate-limited absorption. Solubilizing effects of several beta-cyclodextrin (betaCD) derivatives such as HPbetaCD, SBEbetaCD and DMbetaCD on simvastatin in aqueous solution were investigated using the phase solubility technique. The solubility diagram of simvastatin with each betaCD derivative could be classified as AL-type, indicating soluble complex formation of 1:1 stoichiometry. Among the above betaCD derivatives DMbetaCD was found to be the ideal complexing agent for improving drug solubility. The simvastatin complex with DMbetaCD was prepared using the co-evaporation method and was then characterized by differential scanning calorimetry (DSC), Fourier-transform infrared spectroscopy (FT-IR) and in vitro dissolution. Dissolution and pharmacokinetic studies indicated that the simvastatin/DMbetaCD complex exhibited an increased dissolution rate, rapid absorption, and improved bioavailability in rats compared to free drug. Maximum plasma concentration (cmax) and the time to reach it (tmax) were 21.86 MUg mL-1 and 1.4 h for the drug complex, 8.25 MUg mL-1 and 3.0 h for free drug, respectively. Main pharmacokinetic parameters such as tmax, cmax were significantly different (p < 0.01) between the simvastatin complex and free drug. Bioavailability of the simvastatin complex relative to free drug was up to 167.0 %. PMID- 29702480 TI - Spectrofluorimetric method for atenolol determination based on gold nanoparticles. AB - A simple and sensitive spectrofluorimetric method for determination of atenolol (ATE) using gold nanoparticles (AuNPs) was developed. The method is based on the quenching effect of atenolol on photoluminescence of AuNPs at lambdaem = 705 nm. Variables affecting luminescence of gold nanoparticles such as the solvent, pH value and surfactant were studied and optimized. The method was preliminarily validated according to ICH guidelines. A linear correlation was recorded within the range of 1.0-10 mg mL-1 ATE with the coefficient of determination R2 of 0.999. The limit of detection and limit of quantitation for atenolol were found to be 0.87 and 2.64 mg mL-1, resp. Good recoveries in the range of 98.7-100.0 % were obtained for spiked samples. The proposed method was applied successfully to assaying atenolol in pharmaceuticals formulations. PMID- 29702481 TI - Paeoniflorin inhibits the growth of bladder carcinoma via deactivation of STAT3. AB - Bladder cancer (BCa) is one of the most common urinary cancers. The present study aims to investigate whether Paeoniflorin (Pae) can exert inhibitory effects on BCa. The results showed that Pae inhibited proliferation of human BCa cell lines in a concentration- and time-dependent manner. Pae and cisplatin (Cis) synergistically inhibited the growth of tumours in RT4-bearing mice. Pae treatment neutralized the body loss induced by Cis. Moreover, Pae induced apoptosis in RT4 cells and increased the activities of caspase3, caspase8 and caspase9. Western blotting and immunohistochemical analysis revealed that the phosphorylated signal transducer and activator of transcription-3 (p-STAT3) level were decreased in Pae-treated RT4 cells and Pae-treated tumour-bearing mice. Furthermore, STAT3 transcriptional target B-cell lymphoma-2 was decreased in Pae treated RT4 cells. Interestingly, Pae prevented translocation of STAT3 to the nucleus in RT4 cells. Collectively, Pae inhibits the growth of BCa, at least in part, via a STAT3 pathway. PMID- 29702482 TI - Development and evaluation of orally disintegrating tablets containing the mosapride resin complex. AB - The purpose of this study was to prepare a mosapride citrate-resin (Amberlite(r) IRP 88) complex and orally fast-disintegrating tablets of the resin complex. The resinate complex of mosapride-Amberlite(r) IRP 88, mass ratio 2:1, was prepared in an ethanol-water solution. The effects of alcohol concentration, temperature, and pH of the solution on complex formation were evaluated. The complex physicochemical properties were characterized by differential scanning calorimetry, X-ray diffraction and scanning electron microscopy. Orally disintegrating tablets were prepared by direct compression and were optimized using the response surface method. Optimized orally fast-disintegrating tablets disintegrated within 18 s. The pH dependence of mosapride release from the tablet decreased drug dissolution in simulated saliva, whereas it promptly released in the pH 1.0 solution. The data reported herein clearly demonstrate that tablets containing the mosapride-Amberlite(r) IRP 88 complex for oral disintegration could be particularly useful for patients with swallowing difficulties. PMID- 29702483 TI - Topical antifungal bigels: Formulation, characterization and evaluation. AB - Bigels with antifungal substances, ciclopirox olamine and terbinafine hydrochloride, were made of hydrogel (poloxamer 407 gel) and oleogel (polyethylene and liquid paraffin mixture). Prepared bigels were found physically stable at room temperature for six months and at least four months at 40 degrees C. Released amount of drug decreased when oleogel concentration in the formulation increased. Release test results depended on the insertion place of active substances. The amount of released substance was highest when ciclopirox olamine was incorporated in both phases in an equal quantity, and terbinafine hydrochloride in oleogel or in hydrogel. All formulations showed great inhibition of Microsporum canis. Thus, bigels with ciclopirox olamine and terbinafine hydrochloride are a promising dosage form for topical use. PMID- 29702484 TI - HCV core antigen comes of age: a new opportunity for the diagnosis of hepatitis C virus infection. AB - The diagnosis of hepatitis C virus (HCV) infection has been traditionally based on the detection of the host antibody response. Although antibody assays are available in different formats and are fairly accurate, they cannot distinguish between an ongoing infection with HCV replicative activity and a past infection where HCV has been cleared, spontaneously or after a successful therapy. As a chronic infection is mostly asymptomatic until the late clinical stages, there is a compelling need to detect active HCV infection by simple and reproducible methods. On this purpose, the clinical guidelines have suggested to search for the HCV ribonucleic acid (HCV-RNA) after anti-HCV has been detected, but this second step carries several limitations especially for population screening. The availability of fast and automated serological assays for the hepatitis C core antigen (HCVAg) has prompted an update of the guidelines that now encompass the use of HCVAg as a practical alternative to HCV-RNA, both for screening and monitoring purposes. In this paper, we summarize the features, benefits and limitations of HCVAg testing and provide an updated compendium of the evidences on its clinical utility and on the indications for use. PMID- 29702485 TI - Procalcitonin for diagnosing and monitoring bacterial infections: for or against? PMID- 29702486 TI - Effects of artemisinin, with or without lumefantrine and amodiaquine on gastric ulcer healing in rat. PMID- 29702487 TI - Percutaneous Radiofrequency Ablation of Pulmonary Metastasis and Thoracic Paravertebral Block Under Computed Tomographic Scan Guidance: A Case Report. AB - Pain during and after pulmonary percutaneous radiofrequency ablation (RFA) may be severe enough to require opioids. Thoracic paravertebral block (TPVB) is a regional anesthetic technique that can relieve pain during and after abdominal or thoracic painful procedures. We report the use of TPVB to relieve postprocedural pain in a 50-year-old woman after RFA of lung metastasis. The TPVB was performed under computed tomographic guidance by the anesthesiologist. The patient was pain free (rest and mobilization) during the first postoperative 36 hours. TPVB may represent an easy, safe, and effective strategy to prevent or treat postoperative pain after pulmonary RFA. PMID- 29702488 TI - Self-awareness of Driving Ability in the Healthy Elderly and Patients With Mild Cognitive Impairment (MCI). AB - INTRODUCTION: According to latest research, a percentage of cognitively impaired drivers fail to recognize their areas of weakness and overestimate their driving abilities. METHODS: Twenty-seven individuals with amnestic mild cognitive impairment (MCI) and 26 healthy elderly drivers participated in a driving simulator study. After the driving assessment, participants were asked to self evaluate their performance in comparison with what they considered as average for people of similar age and educational level. RESULTS: According to the applied mixed analysis of variance model, the MCI patients presented increased difficulties in estimating their driving performance to a greater extent in the rural environment in comparison with the urban condition. DISCUSSION: Our findings suggest that the ability of MCI patients to evaluate their driving performance accurately seems to be enhanced or compromised, depending on the number of cues available in their environment, suggesting that providing feedback may improve their metacognitive abilities. PMID- 29702489 TI - What's new in short bowel syndrome? AB - PURPOSE OF REVIEW: Short bowel syndrome (SBS) is a rare disease but with many complications due to intestinal failure, parenteral nutrition and underlying disease. A better prevention, comprehension and treatment could improve the outcome of these patients. RECENT FINDINGS: Recent studies have been published on acute intestinal failure, first cause of SBS, and gives us strategy to avoid extended intestinal resection and thus SBS. There has been progress in the comprehension of intestinal adaptation, characterized by improvements in intestinal absorption, changes on hormonal secretion, development of a hyperphagia and dysbiosis of the gut microbiota. Hormonal treatment focusing on intestinal rehabilitation by promoting intestinal hyperadaptation has been proposed in patients with SBS, who require parenteral nutrition and intravenous fluids, such as glucagon-like peptide-2 (GLP-2) analog which is now recommended by the latest European Society for Clinical Nutrition and Metabolism Guidelines. SUMMARY: Multimodal treatment of acute meseteric ischemia may avoid intestinal resection and is an effective prevention strategy for SBS. New understandings in intestinal adaptation can help us to optimize this adaptation, including with hormonal therapy. GLP-2 analog is now the treatment of reference in SBS patients with chronic intestinal failure. PMID- 29702490 TI - Rationale to reduce calcium intake in adult patients with chronic kidney disease. AB - PURPOSE OF REVIEW: Calcium is an essential ion for the maintenance of normal bone health and physiologic functions. The extracellular and intracellular levels of calcium are maintained through hormonal regulation called homeostasis. Balance, the net intake minus excretion of calcium, is maintained by hormonal regulation of intestinal absorption and fecal/urinary excretion. Homeostasis and balance are disconnected in patients with chronic kidney disease (CKD). The purpose of this review is to understand how calcium homeostasis and balance are impaired in CKD. RECENT FINDINGS: Two formal calcium balance studies have found that an oral intake of 800-1000 mg of calcium in adults with CKD leads to neutral calcium balance, whereas amounts greater than that lead to positive calcium balance. In patients with CKD, the main determinant of positive calcium balance is the intake and the lack of urinary calcium excretion. SUMMARY: Calcium balance is different in patients with advanced CKD compared with patients without CKD. Thus, the oral intake of calcium in the form of diet and binders should not exceed 800-1000 mg/day to achieve neutral calcium balance in adult patients with CKD stages 3b/4. PMID- 29702491 TI - Acute kidney injury to chronic kidney disease transition: insufficient cellular stress response. AB - PURPOSE OF REVIEW: Recent epidemiological and preclinical mechanistic studies provide strong evidence that acute kidney injury (AKI) and chronic kidney disease (CKD) form an interconnected syndrome. Injured kidneys undergo a coordinated reparative process with an engagement of multiple cell types after injury; however, maladaptation to the injury subjects kidneys to a vicious cycle of fibrogenesis and nephron loss. In this review, we will outline and discuss the pathogenesis of AKI-to-CKD transition with an emphasis on dysregulated 'cellular stress adaptation' as a potential therapeutic target. RECENT FINDINGS: Recent studies identify the crucial role of injured tubular epithelial cells in the transition from AKI to CKD. Damaged tubular cells undergo reactivation of developmental and epithelial-mesenchymal transition signaling, metabolic alteration, and cell-cycle arrest, thereby driving inflammation and fibrogenesis. Recent work highlights that cellular stress-adaptive pathways against hypoxic and oxidative stress provide insufficient protection after severe AKI episode. SUMMARY: Insufficient cellular stress adaptation may underpin the persistent activation of inflammatory and fibrogenic signaling in damaged kidneys. We propose that harnessing cellular stress-adaptive responses will be a promising therapeutic strategy to halt or even reverse the deleterious process of AKI-to CKD transition. PMID- 29702492 TI - Management of stones and bones: reduction of uncertainty through research. PMID- 29702493 TI - New HIV drugs: 2018 and beyond. PMID- 29702495 TI - Cryopreservation by vitrification: a promising approach for transplant organ banking. AB - PURPOSE OF REVIEW: The objective of this review is to describe the physical and biological barriers to organ cryopreservation, historic approaches for conventional cryopreservation and evolving techniques for ice-free cryopreservation by vitrification. RECENT FINDINGS: Vitrification is a process whereby a biologic substance is cooled to cryogenic temperatures without the destructive phase transition of liquid to solid ice. Recent advances in cryoprotective solutions, organ perfusion techniques and novel heating technologies have demonstrated the potential for vitrification and rewarming organs on a scale applicable for human transplantation. SUMMARY: Successful strategies for organ cryopreservation could enable organ banking, which would recast the entire process in which organs are recovered, allocated, stored and prepared for transplant. PMID- 29702494 TI - Current vaccines for the prevention of herpes zoster. AB - PURPOSE OF REVIEW: To summarize the recent advances in the prevention of herpes zoster. The recent Food and Drug Administration (FDA) approval of an adjuvanted subunit vaccine may have a significant impact on the prevention of herpes zoster ophthalmicus. RECENT FINDINGS: There are currently two commercially available vaccines for the prevention of herpes zoster: a live-attenuated vaccine and a new recombinant subunit vaccine. The latter has been shown to be more effective, have fewer contraindications, but requires two separate inoculations, has higher reactogenicity, and has only short-term postmarketing surveillance. SUMMARY: The adjuvanted zoster subunit vaccine offers several advantages over the previously available vaccine. Following the current treatment recommendations, physicians should recommend vaccination to all patients older than 50 years of age with no contraindications, this should also prevent ophthalmic complications of the disease. PMID- 29702496 TI - Quantifying the genetic risk for the development of axial spondyloarthropathy: could this become a diagnostic tool? AB - PURPOSE OF REVIEW: To assess the utility of recent genetic findings in ankylosing spondylitis (AS) and axial spondyloarthropathy (SpA) in relation to diagnostic testing, prognosis and responses to biologic treatment and the development of new therapies. RECENT FINDINGS: AS and other forms of SpA are polygenic with more than 100 genes contributing to disease susceptibility. The role of genes in determining the outcome of the disease and response to treatment is less clear. Here, we review some of the progress that has been made over the past decade in understanding the genetic contribution to these diseases and how this may be used to inform the development of new treatments. In those with a high pretest probability of SpA human leukocyte antigen (HLA)-B27 testing can increase the posttest predictive value to almost 100% in some cases. There are currently no reliable genetic predictors of disease severity or response to treatment. SUMMARY: The utility of HLA-B27 as a diagnostic tool when coupled with careful clinical assessment is well established but other genetic markers probably have relatively little to add. In contrast, novel drug targets are likely to be identified from genetic association studies. PMID- 29702497 TI - A narrative review and update on management following negative prostate biopsy. AB - PURPOSE OF REVIEW: Prostate cancer has traditionally been diagnosed using systematic transrectal ultrasound-guided biopsy. However, given the inherent nature of sampling, a negative biopsy does not exclude clinically significant prostate cancer (csPCa), and continued controversy exists in the optimal management following initial biopsy. Numerous avenues for evaluation include multiparametric MRI (mpMRI), use of molecular biomarkers, repeat biopsy, and observation. RECENT FINDINGS: mpMRI has shown promise in guiding further biopsy management: for individuals with identified target lesions, increased accuracy and detection using combination targeted and systematic sampling has been repeatedly demonstrated in the literature as an effective strategy. For those with negative MRIs and/or negative biomarker (blood, urinary, tissue) studies, increasing evidence has suggested that these individuals may be able to avoid biopsy altogether, albeit at a small risk of missing csPCa. Observation should be based on an individual's risk of csPCa versus their competing health risks, and saturation biopsy reserved for rare cases with high clinical suspicion. SUMMARY: Management following an initial negative prostate biopsy requires careful discussion with the patient, their risk tolerance, and threshold for intervention. Although subject to availability, mpMRI and molecular biomarkers may better risk stratify patients, identify target lesions, and in certain cases, spare biopsy altogether. PMID- 29702498 TI - The sirtuin1 gene associates with left ventricular myocardial hypertrophy and remodeling in two chronic kidney disease cohorts: a longitudinal study. AB - BACKGROUND: Oxidative stress and inflammation are major drivers of myocardial hypertrophy in chronic kidney disease (CKD). The silent information regulator gene 1 (Sirt1) is a fundamental mediator of the response to oxidative stress and inflammation and promotes myocardial growth under stress conditions; therefore, it may contribute to myocardial hypertrophy and concentric remodeling of the left ventricle (LV) in CKD. METHODS: We investigated the cross-sectional and longitudinal relationship between three candidate polymorphisms in the Sirt1 gene and LV parameters in two cohorts of CKD patients including 235 stage G5D patients and 179 stages G1-5 patients, respectively. RESULTS: In both cohorts, the C allele of the Sirt1 rs7069102 polymorphism associated with the posterior wall thickness in separate and combined analyses (beta = 0.15, P = 2 * 10) but was unrelated with the LV volume and the LV mass index indicating a peculiar association of this allele with LV concentric remodeling. Accordingly, the same allele was linked with the LV mass-to-volume ratio in separate and combined (beta = 0.14, P = 2 * 10) analyses in the same cohorts. Furthermore, in longitudinal analyses patients harboring the C allele showed a more pronounced increase in LV mass-to-volume ratio over time than patients without such an allele (regression coefficient = 0.14, 95% confidence interval: 0.05-0.23; P = 3 * 10 in the combined analysis). CONCLUSION: The rs7069102 polymorphism in the Sirt1 gene is associated with LV concentric remodeling in two independent cohorts of stages G5D and G1-5 CKD patients. These results offer a genetic basis to the hypothesis that the Sirt1 gene plays a causal role in myocardial hypertrophy and LV concentric remodeling in these patients. PMID- 29702499 TI - New antihyperglycaemic agents and cardiovascular disease: let's be optimistic. AB - PURPOSE OF REVIEW: Cardiovascular disease (CVD) substantially increases mortality in diabetes mellitus. This narrative review highlights recent research on the putative associations between dipeptyl peptidase 4 inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium glucose co-transporter 2 inhibitors (SGLT-2is) and several cardiovascular risk factors. RECENT FINDINGS: New antihyperglycaemic agents favourably modulate several CVD risk factors, including fasting and postprandial plasma glucose levels, body weight, blood pressure, lipids, microalbuminuria, nonalcoholic fatty liver disease, serum uric acid, and arterial stiffness. Liraglutide (in LEADER), semaglutide (in SUSTAIN 6), empagliflozin (in EMPA-REG OUTCOME), and canagliflozin (in CANVAS) were all associated with reduction of the primary composite outcome (i.e. cardiovascular death, nonfatal myocardial infarction or stroke). Of note, patients at higher CVD risk, with optimally controlled CVD risk factors seem to benefit more. SUMMARY: Recent trials with SGLT-2is and GLP-1RAs show superiority in CVD event reduction as opposed to only noninferiority. It is still unclear if the results can be generalised to the lower risk population with diabetes but without CVD. Head-to head comparison and CVD outcome trials involving combination of these two drug classes are also expected to facilitate decision making in clinical practice. PMID- 29702500 TI - Future pharmacological therapy in hypertension. AB - PURPOSE OF REVIEW: Hypertension (HTN) is a widespread and growing disease, with medication intolerance and side-effect present among many. To address these obstacles novel pharmacotherapy is an active area of drug development. This review seeks to explore future drug therapy for HTN in the preclinical and clinical arenas. RECENT FINDINGS: The future of pharmacological therapy in HTN consists of revisiting old pathways to find new targets and exploring wholly new approaches to provide additional avenues of treatment. In this review, we discuss the current status of the most recent drug therapy in HTN. New developments in well trod areas include novel mineralocorticoid antagonists, aldosterone synthase inhibitors, aminopeptidase-A inhibitors, natriuretic peptide receptor agonists, or the counter-regulatory angiotensin converting enzyme 2/angiotensin (Ang) (1 7)/Mas receptor axis. Neprilysin inhibitors popularized for heart failure may also still hold HTN potential. Finally, we examine unique systems in development never before used in HTN such as Na/H exchange inhibitors, vasoactive intestinal peptide agonists, and dopamine beta hydroxylase inhibitors. SUMMARY: A concise review of future directions of HTN pharmacotherapy. PMID- 29702501 TI - The latest consensus on antiemetics. AB - PURPOSE OF REVIEW: The present review summarizes and discuss the most recent updated antiemetic consensus. RECENT FINDINGS: Two new neurokinin (NK)1-receptor antagonists, netupitant and rolapitant, have been approved by the Food and Drug Administration and the European Medicines Agency and incorporated in the latest versions of the MASCC/ESMO, ASCO, and NCCN guidelines. Guidelines all recommend a combination of a serotonin (5-HT)3-receptor antagonist, dexamethasone, and a NK1 receptor antagonist in patients receiving highly emetogenic chemotherapy (HEC) with the addition of the multireceptor targeting agent, olanzapine, as an option in cisplatin or anthracycline-cyclophosphamide chemotherapy. A combination of a 5 HT3-receptor antagonist, dexamethasone, and a NK1-receptor antagonist is also recommended in patients receiving carboplatin-based chemotherapy, although based on a lower level of evidence. In spite of the development of new antiemetics, nausea has remained a significant adverse effect. Olanzapine is an effective antinausea agent, but sedation can be a problem. Therefore, the effect and tolerability of multitargeting, nonsedative agents like amisulpride, should be explored. SUMMARY: Guidelines recommend a combination of a 5-HT3-receptor antagonist, dexamethasone, and an NK1-receptor antagonist in HEC and carboplatin based chemotherapy. The addition of olanzapine can be useful in cisplatin-based and anthracycline-cyclophosphamide-based chemotherapy in particular if the main problem is nausea. PMID- 29702502 TI - Peri-operative oral caffeine does not prevent postoperative atrial fibrillation after heart valve surgery with cardiopulmonary bypass: A randomised controlled clinical trial. AB - BACKGROUND: Raised plasma levels of endogenous adenosine after cardiac surgery using cardiopulmonary bypass (CPB) have been related to the incidence of postoperative atrial fibrillation (POAF). OBJECTIVE: We wished to assess if caffeine, an adenosine receptor antagonist could have a beneficial effect on the incidence of POAF. DESIGN: A randomised controlled study. SETTING: Single University Hospital. PATIENTS: One hundred and ten patients scheduled for heart valve surgery with CPB. INTERVENTIONS: We randomly assigned patients to receive peri-operative oral caffeine (400 mg every 8 h for 2 days) or placebo. Adenosine plasma concentrations and caffeine pharmacokinetic profile were evaluated in a subgroup of 50 patients. MAIN OUTCOME MEASURES: The primary endpoint was the rate of atrial fibrillation during postoperative hospital stay. RESULTS: The current study was stopped for futility by the data monitoring board after an interim analysis. The incidence of atrial fibrillation was similar in the caffeine and in the placebo group during hospital stay (33 vs. 29%, P = 0.67) and the first 3 postoperative days (18 vs. 15%; P = 0.60). Basal and postoperative adenosine plasma levels were significantly associated with the primary outcome. Adenosine plasma levels were similar in the two treatment groups. Caffeine administration was associated with a higher incidence of postoperative nausea and vomiting (27 vs. 7%, P = 0.005). CONCLUSION: Oral caffeine does not prevent POAF after heart valve surgery with CPB but increased the incidence of postoperative nausea and vomiting. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, no.: NCT01999829. PMID- 29702503 TI - Postpartum Depression Screening for New Mothers at Well Child Visits. AB - BACKGROUND: Postpartum depression (PPD) is a debilitating emotional experience that can affect mothers and their infants. Screening for PPD is encouraged during pediatric well-child visits (WCVs); however, the frequency, referral process, and documentation relative to screening in clinical practice require further study. OBJECTIVES: There were three purposes to this study: 1) determine prevalence of mothers who scored in the at-risk range using the Edinburgh Postnatal Depression Scale (EPDS) at each of the 2-, 4-, and 6-month WCVs in a pediatric outpatient practice; 2) examine feasibility factors relative to extending the current standard of care for PPD screening; and 3) examine visit documentation for at risk mothers. DESIGN: A prospective cohort study design was used to screen mothers during their infants' 6-month WCV for PPD using the EPDS. Feasibility in adding the 6-month time frame was assessed using an investigator-designed clinical team survey. Visit documentation content was obtained through medical record review. RESULTS: Forty-three postpartum women were included in the study. Prevalence rates among participants were 10%, 12.5%, and 14% for 2-month, 4 month, and 6-month WCVs, respectively. The clinical team found the additional screening at the 6-month visit to be feasible. Documentation for mothers identified to be at-risk varied greatly. CONCLUSIONS: Prevalence of PPD among participants is consistent with previously reported rates. Areas identified for improved clinical practice include the content of the visit that is documented in the medical record and reviewed with mothers identified to be at-risk, time allotted for the clinical team to screen new mothers, and appropriate referral to outside sources. PMID- 29702504 TI - Health and Social Needs of Young Mothers. AB - PURPOSE: Teen parenting rates are disproportionately high among minority youth in the Southern United States. We explored barriers and unmet needs relating to medical and social support as perceived by these teen mothers, and elicited suggestions for improving their healthcare through the medical home. STUDY DESIGN AND METHODS: We conducted four focus groups of 18- to 24-year-old mothers in New Orleans with questions designed to prompt discussions on young motherhood and healthcare. All 18 participants identified as African American, became mothers when <20, and their children were <5 at the time of the study. Two researchers independently analyzed focus group transcripts and coded them thematically, revealing various unmet social and health needs. RESULTS: Seven main themes emerged, which revealed a concerning lack of mental healthcare, few with consistent medical homes, inadequate contraceptive knowledge and access, and a desire for parenting education and support groups. Suggestions for improving care largely centered around logistical and material support, such as extended clinic hours, transportation, and baby supplies. CLINICAL IMPLICATIONS: Findings suggest a need for improved medical knowledge, healthcare access, and social support for teen mothers. This may be provided through a multidisciplinary medical home model, such as a Teen-Tot clinic, where the unique challenges of adolescent parenting are continuously considered. PMID- 29702505 TI - Skin to Skin Contact: Newborn Temperature Stability in the Operating Room. AB - PURPOSE: The purpose of this project was to assess temperature stability in newborns undergoing early intraoperative skin-to-skin contact (SSC) after elective cesarean birth. METHOD: This feasibility study examined electronic medical record data of 91 mother-baby dyads who participated in early intraoperative SSC after an elective cesarean birth. Infant axillary temperatures were obtained just before initiation and upon completion of intraoperative SSC. RESULTS: The mean age of women in this sample was 35 (SD, 4.2) years. They were an average of 39 4/7 weeks gestation, and largely Caucasian 55% (n = 50) and Asian 30 (33%). Fifty-eight percent (n = 53) of infants were male, weighing an average of 3,566 g (SD, 401.83). Nineteen (21%) of infants demonstrated no temperature change pre to post SSC, with an increase noted in 32 (35%) infants, and a decrease in 40 (44%). CLINICAL IMPLICATIONS: Findings provide support for continued intraoperative SSC. Areas for improvement were also identified, for example, missing medical record data. PMID- 29702507 TI - Safety Bundle for Severe Hypertension During Pregnancy and Postpartum. PMID- 29702506 TI - Underserved Pregnant and Postpartum Women's Access and Use of Their Health Records. AB - PURPOSE: The purpose of this study was to examine knowledge of and experiences with use of their electronic health record (EHR) among mostly Hispanic women during pregnancy and postpartum. METHODS: Women who were in the MOMS Orange County prenatal or postpartum home visitation program completed surveys and participated in focus groups. Descriptive and content analyses were used. RESULTS: Twenty-six women participated. Nearly all women (24, 92.3%) knew what health records were and most (80.8%) felt that keeping their records would increase or greatly increase their confidence in caring for themselves and their families. Approximately one third reported already keeping a copy of their health records. Common barriers to accessing and understanding health records included healthcare providers' noncompliance with the Health Information Technology for Economic and Clinical Health Act, limited EHR adoption, unfriendly patient portals, complicated medical terminology, rushed appointments with healthcare providers, lack of Spanish interpreters, and lack of Spanish-speaking healthcare providers. CLINICAL IMPLICATIONS: Programs are needed to educate and support women and providers in using health records to promote health literacy, pregnancy management, and patient-provider relationships in underserved populations. PMID- 29702508 TI - Rethinking Blood Pressure Monitoring in Children and Adolescents. PMID- 29702509 TI - Iron Adequacy During Pregnancy. PMID- 29702510 TI - Remember the Mothers: The Safe Motherhood Quilt Project. PMID- 29702512 TI - Uterine Activity: What You Don't Know Can Hurt You. PMID- 29702513 TI - Perceptions of Adult Women on Losing Their Mothers at an Early Age: Implications for Nursing Care During Childbirth. PMID- 29702514 TI - Skin to Skin Contact: Newborn Temperature Stability in the Operating Room. PMID- 29702516 TI - Incidence and Risk Factors for Proximal Junctional Kyphosis: Results of a Multicentric Study of Adult Scoliosis: Erratum. PMID- 29702515 TI - Integrated Care for the Use of Direct-acting Antivirals in Patients With Chronic Hepatitis C and Substance Use Disorder. AB - OBJECTIVES: Since little is currently known about predictors of response to direct-acting antiviral agents (DAAs) in people who inject drugs, we undertook an analysis of patients attending a hepatitis clinic with addiction services (outpatient clinics and inpatient services) to examine the outcomes associated with the treatment of difficult-to-manage patients with substance use. Our experience was based on integrated care. METHOD: A retrospective analysis was undertaken of 50 patients with hepatitis C virus (HCV) and a history of addiction who received treatment with DAAs, according to European guidelines. These regimens were sofosbuvir/ledipasvir for 8 weeks (n = 3), sofosbuvir/ledipasvir +/ ribavirin for 12 weeks (n = 19), sofosbuvir/daclatasvir for 12 weeks (n = 20), sofosbuvir/simeprevir (n = 1), or sofosbuvir/daclatasvir for 24 weeks (n = 7). Characteristics of patients who did versus did not achieve a sustained virologic response (SVR) 12 weeks after treatment were compared by univariate analysis. RESULTS: Forty-two patients (84%) were male; mean age was 46.2 +/- 7.3 years. Genotypes were 1 (n = 21), 2 (n = 4), 3 (n = 18), 4 (n = 6), or 6 (n = 1). Most patients were treatment-naive (n = 38). Five patients had coinfection with human immunodeficiency virus (n = 4) or hepatitis B (n = 1), 28 (56%) had evidence of cirrhosis on FibroScan (>12.5 kPa), and 34 (68%) were receiving opioid substitution therapy. Psychiatric disease, illicit drug use, unemployment, and homelessness/precarious housing were common. Forty-five patients (90%) achieved SVR, 2 were lost to follow-up, and 3 had treatment relapse. CONCLUSIONS: SVR was not significantly associated with sociodemographic or virological characteristics, treatment, social environment, alcohol/drug use, and adherence. Although adherence was slightly worse than in "usual" patients, it did not affect the SVR rate. In these difficult-to-manage patients with HCV and substance use disorder, the real-world SVR rate (90%) was similar to that in nonaddicted populations. PMID- 29702517 TI - Assessing Repeated-Sprint Ability in Division I Collegiate Women Soccer Players. AB - Lockie, RG, Liu, TM, Stage, AA, Lazar, A, Giuliano, DV, Hurley, JM, Torne, IA, Beiley, MD, Birmingham-Babauta, SA, Stokes, JJ, Risso, FG, Davis, DL, Moreno, MR, and Orjalo, AJ. Assessing repeated-sprint ability in Division I collegiate women soccer players. J Strength Cond Res XX(X): 000-000, 2018-Repeated-sprint ability (RSA) is a key component of soccer, and is the capacity to repeatedly produce near-maximal to maximal sprints with short recovery periods. Repeated-sprint ability has received little analysis in collegiate women soccer players. The purpose of this study was to investigate relationships between RSA and tests of soccer-specific performance. Nineteen players from the same Division I collegiate women's soccer team were recruited. The RSA test consisted of six 20-m sprints completed on 15-second cycles. The measurements taken were total time (TT) and percent decrement (PD; percent change from first to last sprint). Subjects also completed tests of: lower-body strength (1 repetition maximum [1RM] back squat); jump performance (vertical and standing long jumps); linear (0-5, 0-10, and 0-30 m sprint intervals) and change-of-direction (505 from each leg) speed; and soccer specific fitness (Yo-Yo intermittent recovery test level 1 [YYIRT1]). Pearson's correlations (p <= 0.05) were used to calculate relationships between RSA TT and PD with the performance tests. Total time exhibited significant relationships with the 0-10 (r = 0.50) and 0-30 m (r = 0.71) sprint intervals, and the left-leg 505 (r = 0.57). However, lower-body strength measured by the 1RM back squat and jump performance did not relate to TT. Percent decrement correlated only with the left-leg 505 (r = 0.53) and no other performance test. This included the YYIRT1, although both PD and YYIRT1 performance are limited by fatigue. The results from this study indicated that faster linear sprinting speed could positively influence RSA in Division I collegiate women soccer players. PMID- 29702518 TI - Team Dynamics, Running, and Skill-Related Performances of Brazilian U11 to Professional Soccer Players During Official Matches. AB - Palucci Vieira, LH, Aquino, R, Moura, FA, Barros, RMLd, Arpini, VM, Oliveira, LdP, Bedo, BLdS, and Pereira Santiago, PR. Team dynamics, running, and skill related performances of Brazilian U11 to professional soccer players during official matches. J Strength Cond Res XX(X): 000-000, 2018-Analyses of movements during soccer competition have been used previously to help develop conditioning programs. However, this has not been extensively studied in youth populations. Therefore, the purposes of this study were to examine (1) dynamics of collective tactical movements, (2) running, and (3) skill-related performances during soccer matches disputed by children to senior players. A total of 120 Brazilian players in the age groups U11, U13, U15, U17, U20, and professional (PRO) were monitored during official competition matches (N = 12). Using semiautomatic video-based tracking (30 Hz), match running variables including total distance traveled, average speed, maximum sprint speed, and high-intensity activities were evaluated. Tactical metrics were computed as team surface area, spread, and median frequency. Through notational analysis, technical skills such as involvements with the ball, passes, ball touches, duels, and goal attempts were also recorded. One-way analysis of variance and magnitude-based inferences were used to detect differences between ages. Although the average speed, team surface area, and spread tended to present stabilized increases from the U15 (e.g., U15 > U13 > U11), maximal sprinting speed (PRO > U17 > U15, U13, U11) and percentage at very high-intensity activities (U20 > PRO, U17 > U15 > U13 > U11) demonstrated continuous gains. Median frequencies were higher in the younger groups (U13, U15, U17 > U20, PRO), although the percentage of successful passes was higher in the older groups (PRO > U17, U15 > U13, U11). We concluded that Brazilian U11 to PRO players present different performance profiles for running, collective movement dynamics, and technical skills, and that the rate of development regarding these components varies. Coaches should be aware of these differences to select and adapt training content for each age group. PMID- 29702519 TI - New Tool to Control and Monitor Weighted Vest Training Load for Sprinting and Jumping in Soccer. AB - Carlos-Vivas, J, Freitas, TT, Cuesta, M, Perez-Gomez, J, De Hoyo, M, and Alcaraz, PE. New tool to control and monitor weighted vest training load for sprinting and jumping in soccer. J Strength Cond Res XX(X): 000-000, 2018-The purpose of this study was to develop 2 regression equations that accurately describe the relationship between weighted vest loads and performance indicators in sprinting (i.e., maximum velocity, Vmax) and jumping (i.e., maximum height, Hmax). Also, this study aimed to investigate the effects of increasing the load on spatio temporal variables and power development in soccer players and to determine the "optimal load" for sprinting and jumping. Twenty-five semiprofessional soccer players performed the sprint test, whereas a total of 46 completed the vertical jump test. Two different regression equations were developed for calculating the load for each exercise. The following equations were obtained: % body mass (BM) = -2.0762.%Vmax + 207.99 for the sprint and % BM = -0.7156.%Hmax + 71.588 for the vertical jump. For both sprinting and jumping, when the load increased, Vmax and Hmax decreased. The "optimal load" for resisted training using weighted vest was unclear for sprinting and close to BM for vertical jump. This study presents a new tool to individualize the training load for resisted sprinting and jumping using weighted vest in soccer players and to develop the whole force-velocity spectrum according to the objectives of the different periods of the season. PMID- 29702520 TI - Relationship Between Selected Physical Qualities, Bowling Kinematics, and Pace Bowling Skill in Club-Standard Cricketers. AB - Feros, SA, Young, WB, and O'Brien, BJ. Relationship between selected physical qualities, bowling kinematics, and pace bowling skill in club-standard cricketers. J Strength Cond Res XX(X): 000-000, 2018-Although strength and conditioning of cricket pace bowlers has become more specialized in recent times, little is understood about the interplay between physical capacities, pace bowling kinematics, and pace bowling skill measures. This study sought to determine these interrelationships. Thirty-one male club-standard pace bowlers completed 3 test sessions on separate occasions 4-7 days apart. The first testing session comprised an 8-over pace bowling assessment, where bowling skill and selected bowling kinematics were measured. A physical test battery was completed over the remaining 2 sessions. Peak and mean ball release (BR) speed were related with 1 repetition maximum pull-up strength (rs = 0.56, p = 0.005) and correlated with 20-m sprint time (rs = -0.42, p = 0.022; rs = -0.37, p = 0.044, respectively). Mean radial error was associated with 10-m and 20-m sprint times (rs = 0.41, p = 0.030; rs = 0.38, p = 0.037, respectively), and correlated with height and peak power from 3 countermovement jumps (CMJs) (rs = -0.39, p = 0.036; rs = -0.41, p = 0.031, respectively), and mean peak power from 20 CMJs (rs = 0.45, p = 0.020). Bivariate variable error was correlated with front-leg extension angle at BR (rs = 0.41, p = 0.036), and also with approach speed (rs = 0.36, p = 0.050). These relationships may assist strength and conditioning coaches in designing more effective training programs to enhance bowling speed and accuracy. Training interventions are warranted, however, to validate these associations. PMID- 29702521 TI - DNA damage pathways and B-cell lymphomagenesis. AB - PURPOSE OF REVIEW: Recent lymphoma genome sequencing projects have shed light on the genomic landscape of indolent and aggressive lymphomas, as well as some of the molecular mechanisms underlying recurrent mutations and translocations in these entities. Here, we review these recent genomic discoveries, focusing on acquired DNA repair defects in lymphoma. In addition, we highlight recently identified actionable molecular vulnerabilities associated with recurrent mutations in chronic lymphocytic leukemia (CLL), which serves as a model entity. RECENT FINDINGS: The results of several large lymphoma genome sequencing projects have recently been reported, including CLL, T-PLL and DLBCL. We align these discoveries with proposed mechanisms of mutation acquisition in B-cell lymphomas. Moreover, novel autochthonous mouse models of CLL have recently been generated and we discuss how these models serve as preclinical tools to drive the development of novel targeted therapeutic interventions. Lastly, we highlight the results of early clinical data on novel compounds targeting defects in the DNA damage response of CLL with a particular focus on deleterious ATM mutations. SUMMARY: Defects in DNA repair pathways are selected events in cancer, including lymphomas. Specifically, ATM deficiency is associated with PARP1- and DNA-PKcs inhibitor sensitivity in vitro and in vivo. PMID- 29702522 TI - Three-dimensional genome organization in normal and malignant haematopoiesis. AB - PURPOSE OF REVIEW: The three-dimensional organization of the genome inside the nucleus impacts on key aspects of genome function, including transcription, DNA replication and repair. The chromosome maintenance complex cohesin and the DNA binding protein CTCF cooperate to drive the formation of self-interacting topological domains. This facilitates transcriptional regulation via enhancer promoter interactions, controls the distribution and release of torsional strain, and affects the frequency with which particular translocations arise, based on the spatial proximity of translocation partners. Here we discuss recent insights into the mechanisms of three-dimensional genome organization, their relationship to haematopoietic differentiation and malignant transformation. RECENT FINDINGS: Cohesin mutations are frequently found in myeloid malignancies. Significantly, cohesin mutations can drive increased self-renewal of haematopoietic stem and progenitor cells, which may facilitate the accumulation of genetic lesions and leukaemic transformation. It is therefore important to elucidate the mechanisms that link cohesin to pathways that regulate the balance between self-renewal and differentiation. Chromosomal translocations are key to lymphoid malignancies, and recent findings link three-dimensional genome organization to the frequency and the genomic position of DNA double strand breaks. SUMMARY: Three-dimensional genome organization can help explain genome function in normal and malignant haematopoiesis. PMID- 29702523 TI - The crosstalk between hematopoietic stem cells and their niches. AB - PURPOSE OF REVIEW: Hematopoietic stem cells (HSCs) reside in specific microenvironments also called niches that regulate HSC functions. Understanding the molecular and cellular mechanisms involved in the crosstalk between HSCs and niche cells is a major issue in stem cell biology and regenerative medicine. The purpose of this review is to discuss recent advances in this field with particular emphasis on the transcriptional landscape of HSC niche cells and the roles of extracellular vesicles (EVs) in the dialog between HSCs and their microenvironments. RECENT FINDINGS: The development of high-throughput technologies combined with computational methods has considerably improved our knowledge on the molecular identity of HSC niche cells. Accumulating evidence strongly suggest that the dialog between HSCs and their niches is bidirectional and that EVs play an important role in this process. SUMMARY: These advances bring a unique conceptual and methodological framework for understanding the molecular complexity of the HSC niche and identifying novel HSC regulators. They are also promising for exploring the reciprocal influence of HSCs on niche cells and delivering specific molecules to HSCs in regenerative medicine. PMID- 29702524 TI - Genetic convergence of rare lymphomas. AB - PURPOSE OF REVIEW: We review the genetic foundations of different rare lymphomas to examine their shared origins. These data indicate the potential application of genomics to improve the diagnosis and treatment of these rare diseases. RECENT FINDINGS: Next generation sequencing technologies have provided an important window into the genetic underpinnings of lymphomas. A growing body of evidence indicates that although some genetic alterations are specific to certain diseases, others are shared across different lymphomas. Many such genetic events have already demonstrated clinical utility, such as BRAF V600E that confers sensitivity to vemurafenib in patients with hairy cell leukemia. SUMMARY: The rareness of many lymphoma subtypes makes the conduct of clinical trials and recruitment of significant numbers of patients impractical. However, a knowledge of the shared genetic origins of these rare lymphomas has the potential to inform 'basket' clinical trials in which multiple lymphoma subtypes are included. These trials would include patients based on the presence of alterations in targetable driver genes. Such approaches would be greatly strengthened by a systematic assessment of significant patient numbers from each subtype using next generation sequencing. PMID- 29702525 TI - Feasibility of Dynamic Contrast-Enhanced Magnetic Resonance Imaging Using Low Dose Gadolinium: Comparative Performance With Standard Dose in Prostate Cancer Diagnosis. AB - OBJECTIVES: This study investigates whether administration of low doses of gadolinium-based contrast agent (GBCA) for dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) can be as effective as a standard dose in distinguishing prostate cancer (PCa) from benign tissue. In addition, we evaluated the combination of kinetic parameters from the low- and high-dose injection as a new diagnostic marker. MATERIALS AND METHODS: Patients (n = 17) with histologically confirmed PCa underwent preoperative 3 T MRI. Dynamic contrast-enhanced MRI images were acquired at 8.3-second temporal resolution with a low dose (0.015 mmol/kg) and close to the standard dose (0.085 mmol/kg) of gadobentate dimeglumine bolus injections. Low-dose images were acquired for 3.5 minutes, followed by a 5-minute gap before acquiring standard dose images for 8.3 minutes. The data were analyzed qualitatively to investigate whether lesions could be detected based on early focal enhancement and quantitatively by fitting signal intensity as a function of time with an empirical mathematical model to obtain a maximum enhancement projection (MEP) and signal enhancement rate (alpha). RESULTS: Both low- and standard-dose DCE-MRI showed similar sensitivity (13/26 = 50%) and lesion conspicuity score (4.0 +/- 1.0 vs 4.2 +/- 0.9; P = 0.317) for PCa diagnosis on qualitative analysis. Prostate cancer showed significantly increased alpha compared with benign tissue for low (9.98 +/- 5.84 vs 5.12 +/- 2.95 s) but not for standard (4.27 +/- 2.20 vs 3.35 +/- 1.48 s) dose. The ratio of low-dose alpha to standard-dose alpha was significantly greater (P = 0.02) for PCa (2.8 +/- 2.3) than for normal prostate (1.6 +/- 0.9), suggesting changes in water exchange and T2* effects associated with cancer. In addition, decreases in the percentage change in T1 relaxation rate as a function of increasing contrast media concentration (ie, the "saturation effect") can also contribute to the observed differences in high-dose and low-dose alpha. Area under the receiver operating characteristic curve for differentiating PCa from benign tissue using alpha was higher for low dose (0.769) compared with standard dose (0.625). There were no significant differences between MEP calculated for PCa and normal tissue at the low and standard doses. Moderate significant Pearson correlation for DCE parameters, MEP (r = 0.53) and alpha (r = 0.58), was found between low and standard doses of GBCA. CONCLUSIONS: These preliminary results suggest that DCE-MRI with a low GBCA dose distinguishes PCa from benign prostate tissue more effectively than does the standard GBCA dose, based on signal enhancement rate. Diagnostic accuracy is similar on qualitative assessment. Prostate cancer diagnosis may be feasible with DCE-MRI with low-dose GBCA. In addition, comparison of enhancement kinetics after low and high doses of contrast media may provide diagnostically useful information. PMID- 29702526 TI - Predictive Value of Soluble Programmed Death-1 for Severe Sepsis and Septic Shock During the First Week in an Intensive Care Unit. AB - OBJECTIVE: Programmed death-1 (PD-1)/programmed death ligand-1 (PD-L1) exists in both membrane-bound and soluble forms. In this study, we evaluated the predictive value of soluble PD-1 (sPD-1) for severity and 28-day mortality in patients with severe sepsis and septic shock during the first week in an intensive care unit (ICU). METHODS: In this prospective cohort study, patients were classified into the severe sepsis group or the septic shock group according to the severity of their condition on ICU admission. All patients were also separated into the survivor or nonsurvivor groups according to their 28-day outcomes. Peripheral blood sPD-1 and soluble PD-L1 (sPD-L1) levels, PD-1 expression on CD4 and CD8 T cells, and PD-L1 expression on monocytes were measured and compared between the groups on days 1 and 7 after ICU admission. RESULTS: In all, 45 healthy volunteers and 112 patients were recruited. Serum sPD-1 levels were positively correlated with the severity of sepsis, sPD-L1 levels, PD-1 expression on CD4 or CD8 T cells, and PD-L1 expression on monocytes. The sPD-1 was an independent predictive factor for 28-day mortality both on day 1 and day 7. The area under the curve (AUC) of the sPD-1 on day 7 (0.871) was higher than that on day 1 (0.785) (P < 0.05), and better than the AUC of the percentages of PD-L1 on monocytes (0.770) on day 7 (P < 0.05). CONCLUSION: Serum sPD-1 shows valuable predictive ability for the severity and 28-day mortality of severe sepsis and septic shock during the first week of ICU treatment. PMID- 29702527 TI - Comparative Impacts of Scala Vestibuli Versus Scala Tympani Cochlear Implantation on Auditory Performances and Programming Parameters in Partially Ossified Cochleae. AB - OBJECTIVE: To compare scala vestibuli versus scala tympani cochlear implantation in terms of postoperative auditory performances and programming parameters in patients with severe scala tympani ossification. STUDY DESIGN: Retrospective case control study. SETTING: Tertiary referral center. PATIENTS: One hundred three pediatric and adult patients who underwent cochlear implant surgery between 2000 and 2016. Three groups were formed: a scala vestibuli group, a scala tympani with ossification group, and a scala tympani without ossification group. Patients were matched based on their age, sex, duration of deafness, and side of implantation (ratio of 1:2:2). INTERVENTIONS: Postoperative evaluation of auditory performances and programming parameters following intensive functional rehabilitation program completion. MAIN OUTCOME MEASURES: Multimedia adaptive test (MAT), hearing in noise test (HINT SNR +10 dB, HINT SNR +5 dB, and HINT SNR +0 dB), impedances, neural response telemetry thresholds (NRT), neural response imaging thresholds (NRI), comfortable levels (C-levels), and threshold levels (T levels) were compared between groups. RESULTS: Twenty-one patients underwent scala vestibuli cochlear implantation: 19 adults and two children. Auditory performances were similar between groups, although sentence recognition in a noisy environment was slightly higher in the scala vestibuli group. Impedance values were also higher in the scala vestibuli group, but all other programming parameters were similar between groups. CONCLUSIONS: We present the largest series of patients with scala vestibuli cochlear implantation. This approach provides at least comparable auditory performances without having any deleterious effects on programming parameters. This viable and useful insertion route might be the primary surgical alternative when facing partial cochlear ossification. PMID- 29702528 TI - Mahvash Disease: 10 Years After Discovery. PMID- 29702530 TI - Proceedings of the 2nd International Conference for Cancer Metabolism and Therapy, October 13-15, 2017, Wenzhou, China. PMID- 29702531 TI - Intraductal Papillary Mucinous Neoplasm of the Pancreas as the Main Focus for Early Detection of Pancreatic Adenocarcinoma. AB - For early detection of pancreatic cancer, interests are now focused on the detection of high-risk individuals to undergo screening examinations. Intraductal papillary mucinous neoplasm (IPMN) is a unique dual precursor of pancreatic cancer, characterized by progression to invasive cancer and the development of pancreatic adenocarcinoma either concomitantly (synchronous occurrence) or even after resection of IPMN (metachronous occurrence). Careful examination and surveillance of patients with IPMN may therefore lead to early detection of pancreatic cancer. By reviewing only reports describing detailed breakdown of the morphological types of IPMN and numbers of patients with noninvasive and invasive carcinoma in each type, the rough frequencies of noninvasive carcinoma in main duct IPMNs and branch duct IPMNs (BD-IPMNs) are 20% and 10%, respectively, and those of invasive carcinoma are 40% and 13%, respectively. Roughly 5% of all patients with IPMN had concomitant adenocarcinoma. The real frequency of carcinoma in BD-IPMNs would be far lower because most patients with small asymptomatic BD-IPMNs do not undergo resection. Intraductal papillary mucinous neoplasm can be the main focus for early detection of pancreatic cancer to achieve favorable prognosis after surgical resection. The optimal protocol for surveillance and method for early detection of pancreatic cancer are to be determined. PMID- 29702529 TI - The Interface of Pancreatic Cancer With Diabetes, Obesity, and Inflammation: Research Gaps and Opportunities: Summary of a National Institute of Diabetes and Digestive and Kidney Diseases Workshop. AB - A workshop on "The Interface of Pancreatic Cancer with Diabetes, Obesity, and Inflammation: Research Gaps and Opportunities" was held by the National Institute of Diabetes and Digestive and Kidney Diseases on October 12, 2017. The purpose of the workshop was to explore the relationship and possible mechanisms of the increased risk of pancreatic ductal adenocarcinoma (PDAC) related to diabetes, the role of altered intracellular energy metabolism in PDAC, the mechanisms and biomarkers of diabetes caused by PDAC, the mechanisms of the increased risk of PDAC associated with obesity, and the role of inflammatory events and mediators as contributing causes of the development of PDAC. Workshop faculty reviewed the state of the current knowledge in these areas and made recommendations for future research efforts. Further knowledge is needed to elucidate the basic mechanisms contributing to the role of hyperinsulinemia, hyperglycemia, adipokines, and acute and chronic inflammatory events on the development of PDAC. PMID- 29702532 TI - Right Atrial Tumor Thrombus: A New Mechanism for Neuroendocrine Tumor-Induced Heart Complications. PMID- 29702533 TI - Mouse Pancreatic Tumor Model Independent of Tumor Suppressor Gene Inactivation. PMID- 29702534 TI - Dakin Solution for Irrigation of Pancreatic Fluid Collections. PMID- 29702535 TI - Renal Replacement Therapy in Eritrea. AB - Historically, communicable diseases in addition to maternal, perinatal, and malnutrition have accounted for the greatest burden of morbidity and mortality in many developing countries. This spectrum however has recently begun to shift toward chronic noncommunicable diseases, including diabetes and hypertension. Although great strides have been made in the diagnosis and care of chronic kidney disease in the industrialized world, the availability of renal replacement therapy and kidney transplantation is unequivocally lower in Africa than in any other region of the world. Here, we provide a critical assessment of the growing prevalence of kidney disease and current treatments in Eritrea, a young, developing country located in Northeast Africa. PMID- 29702537 TI - Ronald W. Busuttil, MD, PhD: William P. Longmire, Jr, Chair of Surgery, Chief of Liver and Pancreas Transplantation, Director, UCLA-Dumont Transplant & Liver Cancer Center. PMID- 29702538 TI - Utilization of Declined Liver Grafts Yields Comparable Transplant Outcomes and Previous Decline Should Not Be a Deterrent to Graft Use. AB - BACKGROUND: In the United Kingdom, up to 20% of liver graft offers are not used for transplantation, and the reasons for graft refusal are multifactorial and not consistent among transplant units. METHODS: Liver grafts previously declined by other transplant centers in the United Kingdom but transplanted in our unit in Birmingham between 2011 and 2015 were analyzed. According to the indicated reason for previous declines, liver grafts were categorized into 3 refusal groups: "quality," "logistics," and "other reasons." Results were compared with a matched, low-risk cohort of livers primarily accepted and transplanted at our center. RESULTS: During the study period, 206 livers (donation after brain death: n = 141 (68.4%); donation after circulatory arrest: n = 65 (31.6%) were transplanted, which were previously discarded by a median of 4 other UK centers. The majority of declines were donor quality (n = 102; 49.5%), refusals followed by logistics (n = 45; 21.8%), and other reasons (n = 59; 28.6%). Transplantation from both graft types (donation after brain death and donation after circulatory arrest) and all 3 refusal groups achieved equally good outcomes with an overall low complication rate. The incidence of primary nonfunction (2.4% vs 1.7%; P = 0.5483), in-hospital mortality (6.3% vs 4.1%; P = 0.2293) and 3-year graft (82.5% vs 84.1%; P = 0.6872) and patient (85.4% vs 87.6%; P = 0.8623) survival was comparable between livers previously declined and livers primarily accepted and transplanted at our center. CONCLUSIONS: Transplantation of declined livers can achieve comparable outcomes to primary liver low-risk graft offers. Previous refusal should not be taken as a barrier to use the graft, and with appropriate recipient selection, more lives could be saved. PMID- 29702539 TI - Effect of Ex Vivo-Expanded Recipient Regulatory T Cells on Hematopoietic Chimerism and Kidney Allograft Tolerance Across MHC Barriers in Cynomolgus Macaques: Erratum. PMID- 29702540 TI - Safety of Dexamethasone for Nausea and Vomiting Prophylaxis in Children Receiving Hematopoietic Stem Cell Transplantation. AB - BACKGROUND: Many children undergoing hematopoietic stem cell transplantation (HSCT) experience chemotherapy-induced nausea and vomiting (CINV) despite receiving prophylaxis. Guideline-consistent CINV prophylaxis includes dexamethasone, but uncertainty with regard to safety potentially limits the use of dexamethasone in children. We describe immediate adverse events (AEs) attributable to dexamethasone given for CINV prophylaxis to children during HSCT conditioning. MATERIALS AND METHODS: Children enrolled in a previous prospective study were retrospectively analyzed. Objective parameters related to specific AEs occurring within 5 days of dexamethasone administration were abstracted from health records and graded according to the Common Terminology Criteria for Adverse Events version 4.03 (CTCAE v4.03). Their association to dexamethasone was assessed using the Liverpool Causality Assessment Tool. RESULTS: Forty-six children (median age, 10.2 y) were eligible for analysis. The most frequent AEs attributable to dexamethasone (Liverpool Causality Assessment Tool category of probable or definite) were hyperglycemia (63%; CTCAE v4.03 grade 3: 2%), hypertension (52%; CTCAE v4.03 grade 3: 15%), and bradycardia (46%; CTCAE v4.03 grade 3: 0%). Other AEs included dyspepsia or gastroesophageal reflux disease (24%) and alterations in mood and behavior (9%). No AE exceeded CTCAE v4.03 grade 3 in severity. CONCLUSIONS: In children undergoing HSCT who received dexamethasone for CINV prophylaxis, immediate AEs attributable to dexamethasone were most often of minor clinical importance and transient. PMID- 29702541 TI - Novel Variations of FANCA Gene Provokes Fanconi Anemia: Molecular Diagnosis in a Special Chinese Family. AB - Fanconi anemia (FA) is a rare autosomal recessive or X-linked disorder with highly variable clinical manifestations and an incidence of ~1 to 5 in 1 million births. To date, 15 bona fide FA genes have been reported to be responsible for the known FA complementation groups and the FANCA gene accounts for almost 60%. In the present study, we report a special Chinese family, which has 2 children with classic FA characteristics. Via 2-step analysis of the whole-exome sequencing data and verification using multiplex ligation-dependent probe amplification test, one child was found to have a novel compound heterozygous mutation of a splicing variant (c.1471-1G>A) and a large intragenic deletion (exons 23-30 del) of the FANCA gene. The other child had the same splicing variant and another novel large deletion (exons 1-18 del) in the FANCA gene. Clone sequencing showed the c.1471-1G>A variant generate an altered transcript with 1 cryptic splice site in intron 15, resulting in a premature termination codon (p.Val490HisfsX6). This study not only shows the complexity of FA molecular diagnosis via comprehensively studying the FA pathogenic genes and the mutational spectrum, but also has significant reference value for the future molecular diagnosis of FA. PMID- 29702542 TI - Undifferentiated Embryonal Sarcoma of the Liver (UESL) in Adolescents: An Unexpected Diagnosis. AB - Definitive diagnosis of pediatric liver masses can be challenging, because clinical manifestations are nonspecific, and ultimate diagnosis may be delayed. We describe 2 patients with liver masses that initially were misdiagnosed and treated as infectious hepatic lesions. Only after histologic examination the correct diagnosis of undifferentiated embryonal sarcoma of the liver was defined. Both patients underwent a complete tumor resection followed by chemotherapy with a favorable outcome. PMID- 29702543 TI - A Novel Mutation c.153 C>A in a Tunisian Girl With Wolman Disease and Unusual Presentation: Hemophagocytic Lymphohistiocytosis. AB - Wolman disease is an ultrarare lysosomal storage disease caused by a mutation in the LIPA gene. The clinical features of Wolman disease include early onset of vomiting, diarrhea, failure to thrive, hepatosplenomegaly, and bilateral adrenal calcification. We report the case of a 3-month-old infant who presented clinical features of hemophagocytic lymphohistiocytosis. Genetic sequence analysis of the LIPA gene revealed homozygous mutation c.153 C>A (p.Tyr51*). The parents were heterozygous for this mutation. Prenatal diagnosis has been carried out in the next pregnancy. To our knowledge, this mutation has never been reported before, and this is an unusual case of secondary hemophagocytic lymphohistiocytosis complicating Wolman disease. PMID- 29702544 TI - Characterization of 4 New Mutations in the CYBB Gene in 10 Iranian Families With X-linked Chronic Granulomatous Disease. AB - Chronic granulomatous disease (CGD) is an inherited disease of the innate immune system that results from defects in 1 of the 5 subunits of nicotinamide adenine dinucleotide phosphate oxidase complex and leads to life-threatening infections with granuloma formation. During 3 years of study, we recognized 10 male patients with X-linked CGD from a tertiary referral center for immune deficiencies in Iran. The CGD patients were diagnosed according to clinical features and biochemical tests, including nitroblue tetrazolium and dihydrorhodamine-1, 2, 3 tests, performed on patients and their mothers. In all patients, Western blot analysis showed a gp91 phenotype. Mutation screening by single strand conformation polymorphism and multiplex ligation-dependent probe amplification analysis of the CYBB gene encoding gp91, followed by sequencing, showed 9 different mutations, 4 of them novel as far as we know. PMID- 29702545 TI - Steroid Responsive Atypical Hemolytic Uremic Syndrome Triggered by Influenza B Infection. AB - Atypical hemolytic uremic syndrome (aHUS) is characterized by uncontrolled complement activation leading to thrombotic microangiopathy and severe end-organ damage. The most common trigger for an episode of aHUS in the background of genetic deregulation of the alternative complement pathway is systemic infection. There are only 4 reported cases of aHUS triggered by influenza B thus far. Current accepted therapies for aHUS include plasma exchange and eculizumab. We describe a unique patient with aHUS with a rare membrane cofactor protein mutation triggered by influenza B infection, who achieved complete remission with treatment with high-dose corticosteroids after failure of plasmapheresis. PMID- 29702547 TI - Development and Regulation of Novel Influenza Virus Vaccines: A United States Young Scientist Perspective. AB - Vaccination against influenza is the most effective approach for reducing influenza morbidity and mortality. However, influenza vaccines are unique among all licensed vaccines as they are updated and administered annually to antigenically match the vaccine strains and currently circulating influenza strains. Vaccine efficacy of each selected influenza virus vaccine varies depending on the antigenic match between circulating strains and vaccine strains, as well as the age and health status of the vaccine recipient. Low vaccine effectiveness of seasonal influenza vaccines in recent years provides an impetus to improve current seasonal influenza vaccines, and for development of next generation influenza vaccines that can provide broader, long-lasting protection against both matching and antigenically diverse influenza strains. This review discusses a perspective on some of the issues and formidable challenges facing the development and regulation of the next-generation influenza vaccines. PMID- 29702546 TI - Mutation of CD2AP and SH3KBP1 Binding Motif in Alphavirus nsP3 Hypervariable Domain Results in Attenuated Virus. AB - Infection by Chikungunya virus (CHIKV) of the Old World alphaviruses (family Togaviridae) in humans can cause arthritis and arthralgia. The virus encodes four non-structural proteins (nsP) (nsP1, nsp2, nsP3 and nsP4) that act as subunits of the virus replicase. These proteins also interact with numerous host proteins and some crucial interactions are mediated by the unstructured C-terminal hypervariable domain (HVD) of nsP3. In this study, a human cell line expressing EGFP tagged with CHIKV nsP3 HVD was established. Using quantitative proteomics, it was found that CHIKV nsP3 HVD can bind cytoskeletal proteins, including CD2AP, SH3KBP1, CAPZA1, CAPZA2 and CAPZB. The interaction with CD2AP was found to be most evident; its binding site was mapped to the second SH3 ligand-like element in nsP3 HVD. Further assessment indicated that CD2AP can bind to nsP3 HVDs of many different New and Old World alphaviruses. Mutation of the short binding element hampered the ability of the virus to establish infection. The mutation also abolished ability of CD2AP to co-localise with nsP3 and replication complexes of CHIKV; the same was observed for Semliki Forest virus (SFV) harbouring a similar mutation. Similar to CD2AP, its homolog SH3KBP1 also bound the identified motif in CHIKV and SFV nsP3. PMID- 29702548 TI - The Effect of Pet Therapy and Artist Interactions on Quality of Life in Brain Tumor Patients: A Cross-Section of Art and Medicine in Dialog. AB - With the evolution of modern medical treatment strategies, there also comes the realization that many times we reach a point where traditional goals of medical care, such as overall survival or disease-free survival, are not realistic goals for many patients facing devastating illnesses. One such disease is malignant primary brain tumors, known as malignant glioma (MG). With median survival of only 20.9 months following best available standard of care treatment strategies, including surgery, chemotherapy, radiation, and tumor treating fields, MG is one of the deadliest malignancies of the modern era. Along the course of treating patients with MG, clinicians often realize that traditional treatment therapies can at best provide incremental benefit of symptom management without any survival benefit. However, even in these difficult situations, it is possible to make significant positive changes in patients’ health-related quality of life (HRQoL) using creative, non-traditional interventions. In this paper, we describe the initial findings from our project that takes a unique approach to studying the intersections of clinical care and art by using pet therapy and art making as interventions for patients diagnosed with brain tumors. Our preliminary findings suggest that pet therapy and the ability to reflect as well as speak about their journey through a life-altering disease significantly increases patients’ overall feeling of wellbeing and reduces anxiety about future uncertainty. PMID- 29702549 TI - Synthesis and Pharmacological Studies of Unprecedented Fused Pyridazino[3',4':5,6][1,2,4]triazino[3,4-b][1,3,4]thiadiazine Derivatives. AB - A novel fused system with three or four fused rings—pyridazino[3′,4′:5,6][1,2,4]triazino[4,3 b][1,2,4,5]tetrazine and pyridazino[3′,4′:5,6][1,2,4]triazino[3,4 b]pyrimido[4,5-e][1,3,4]thiadiazine was obtained from the starting materials 4(6H)-amino-3-hydrazino-7-(2-thienyl)pyridazino[3,4-e][1,2,4]-triazine 2 and 9 amino-3-(2-thienyl)-2H,8H-pyridazino[3′,4′:5,6][1,2,4]triazino[3,4 b][1,3,4]thiadiazine-8-carbonitrile 12. Each of the starting compounds was subjected to a number of cyclization reactions to obtain a series of new heterocyclic fused systems, 3-10 and 13-23, via bifunctional reagents. Some of the synthesized compounds were screened against three cell lines including HepG2, HCT-116 and MCF-7 to discover their anticancer activity. The synthesized compounds were characterized depending on their elemental analyses and spectral data. PMID- 29702550 TI - Chiropractic Manipulation Increases Maximal Bite Force in Healthy Individuals. AB - Recent research has shown that chiropractic spinal manipulation can alter central sensorimotor integration and motor cortical drive to human voluntary muscles of the upper and lower limb. The aim of this paper was to explore whether spinal manipulation could also influence maximal bite force. Twenty-eight people were divided into two groups of 14, one that received chiropractic care and one that received sham chiropractic care. All subjects were naive to chiropractic. Maximum bite force was assessed pre- and post-intervention and at 1-week follow up. Bite force in the chiropractic group increased compared to the control group (p = 0.02) post-intervention and this between-group difference was also present at the 1-week follow-up (p < 0.01). Bite force in the chiropractic group increased significantly by 11.0% (±18.6%) post-intervention (p = 0.04) and remained increased by 13.0% (±12.9%, p = 0.04) at the 1 week follow up. Bite force did not change significantly in the control group immediately after the intervention (−2.3 ± 9.0%, p = 0.20), and decreased by 6.3% (±3.4%, p = 0.01) at the 1-week follow-up. These results indicate that chiropractic spinal manipulation can increase maximal bite force. PMID- 29702551 TI - Kruppel-Like Factor 15 Is Critical for the Development of Left Ventricular Hypertrophy. AB - Left ventricular hypertrophy (LVH) is an independent risk factor for adverse cardiovascular events and is often present in patients with hypertension. Treatment to reduce blood pressure and regress LVH is key to improving health outcomes, but currently available drugs have only modest cardioprotective effects. Improved understanding of the molecular mechanisms involved in the development of LVH may lead to new therapeutic targets in the future. There is now compelling evidence that the transcription factor Kruppel-like factor 15 (KLF15) is an important negative regulator of cardiac hypertrophy in both experimental models and in man. Studies have reported that loss or suppression of KLF15 contributes to LVH, through lack of inhibition of pro-hypertrophic transcription factors and stimulation of trophic and fibrotic signaling pathways. This review provides a summary of the experimental and human studies that have investigated the role of KLF15 in the development of cardiac hypertrophy. It also discusses our recent paper that described the contribution of genetic variants in KLF15 to the development of LVH and heart failure in high-risk patients. PMID- 29702552 TI - Self-Reported Environmental Tobacco Smoke Exposure and Avoidance Compared with Cotinine Confirmed Tobacco Smoke Exposure among Pregnant Women and Their Infants. AB - BACKGROUND: Exposure to environmental tobacco smoke (ETS) presents substantial health risks for pregnant women and newborn infants. Measurements of ETS include invasive and expensive biochemical tests, as well as less invasive and lower cost, self-reported exposure and avoidance measures. Better understanding of self report measures will help to select ETS assessments for evaluation. METHODS: This analysis was conducted within the context of a tailored video intervention to reduce tobacco smoking and ETS exposure during pregnancy and after delivery in the control group sample of 147 nonsmoking women. Measurements of salivary cotinine concentration, self-reported ETS exposure, and avoidance behaviors were captured at 32 weeks’ gestation and 6 months postpartum. RESULTS: Salivary cotinine concentration was significantly related to ETS avoidance among pregnant nonsmokers at 32 weeks’ gestation, but not ETS exposure. At 6 months postpartum, both the reported ETS exposure of the infant and maternal avoidance behaviors to reduce her infant’s exposure were associated with the infant’s salivary cotinine concentration. At 32 weeks’ gestation and 6 months postpartum, avoidance behaviors decreased as exposure increased. DISCUSSION: This study suggests that for nonsmoking women during pregnancy, reports of tobacco smoke avoidance are more valid than reports of exposure. After delivery, self-reported ETS exposure or avoidance are associated with each other and the biochemical measurement of salivary cotinine. These results provide researchers and clinicians with evidence to support the inclusion of avoidance behaviors in the selection of ETS measures. PMID- 29702554 TI - All-Optical Photoacoustic Sensors for Steel Rebar Corrosion Monitoring. AB - This article presents an application of an active all-optical photoacoustic sensing system with four elements for steel rebar corrosion monitoring. The sensor utilized a photoacoustic mechanism of gold nanocomposites to generate 8 MHz broadband ultrasound pulses in 0.4 mm compact space. A nanosecond 532 nm pulsed laser and 400 μm multimode fiber were employed to incite an ultrasound reaction. The fiber Bragg gratings were used as distributed ultrasound detectors. Accelerated corrosion testing was applied to four sections of a single steel rebar with four different corrosion degrees. Our results demonstrated that the mass loss of steel rebar displayed an exponential growth with ultrasound frequency shifts. The sensitivity of the sensing system was such that 0.175 MHz central frequency reduction corresponded to 0.02 g mass loss of steel rebar corrosion. It was proved that the all-optical photoacoustic sensing system can actively evaluate the corrosion of steel rebar via ultrasound spectrum. This multipoint all-optical photoacoustic method is promising for embedment into a concrete structure for distributed corrosion monitoring. PMID- 29702553 TI - Cytokine and Chemokine Recovery Is Increased by Colloid Perfusates during Dermal Microdialysis. AB - : Cytokines and chemokines play important roles in cell signalling, and microdialysis is a promising tool for monitoring these inflammation markers ex vivo. Therefore, the collecting of these mediators at the highest concentrations possible is crucial. Depending on the size of the mediator of interest, the collection of these high molecular mass molecules has thus far been difficult due to their low recovery, even when using high cut-off (100 kDa) microdialysis membranes. This study aimed to optimize the recovery of various cytokines and chemokines by validating the use of different perfusates in cutaneous microdialysis, and comparing intravenous (i.v.) colloids, crystalloids, and a lipid emulsion formulations that are approved for i.v. APPLICATIONS: METHODS: In vitro and in vivo recovery experiments using six recombinant cytokines varying in molecular size (interleukin-2 (15 kDa), interleukin-6 (20.5 kDa), interleukin-8 (8 kDa), interleukin-12p70 (70 kDa), TNF-α (17.5 kDa), and vascular endothelial growth factor (VEGF) (38 kDa)) were performed in the presence of different perfusates for i.v. APPLICATIONS: Ringer’s lactate, dextran 60 kDa, hydroxyethyl starch 70 kDa, and hydroxyethyl starch 200 kDa solutions as well as a lipid emulsion formulation. Recovery was determined through (i) microdialysis of cytokines and chemokines in Ringer’s lactate solution or human serum in vitro, and (ii) retrodialysis of excised porcine and human skin cadavers in vitro and porcine skin in vivo. Furthermore, we used skin trauma (catheter insertion) and Ultraviolet B irradiation of 3 × 3 cm2 skin areas to sample cytokines and chemokines in vivo and compared the amounts that were obtained using crystalloid and colloid perfusates. All the cytokines and chemokines within the dialysates were quantified through a flow cytometry-based bead array assay. RESULTS: Overall, recovery was strongly increased by the colloids, particularly hydroxyethyl starch 70 kDa, in vitro, ex vivo, and in vivo. When compared with the recovery achieved using Ringer’s lactate, this increase was most effective for proteins ranging from 8 to 20.5 kDa. Hydroxyethyl starch 70 kDa significantly increased the recovery of interleukin (IL)-8 in human serum in vitro when compared with Ringer’s lactate. More cytokines and chemokines were recovered using colloids compared with crystalloids. However, the increase in recovery values was lower for IL-12p70 and VEGF. CONCLUSIONS: Regarding the dialysate volumes and final dialysate concentrations, colloid perfusates are overall superior to crystalloid perfusates, such as Ringer’s lactate, when sampling cytokines and chemokines, resulting in higher recoveries. However, the sampling of high-molecular-mass cytokines during microdialysis remains challenging, and experimental in vitro data are not completely comparable with data obtained ex vivo or in vivo. PMID- 29702555 TI - Deciphering the Molecular Mechanism Underlying the Inhibitory Efficacy of Taiwanese Local Pomegranate Peels against Urinary Bladder Urothelial Carcinoma. AB - Pomegranate (Punica granatum L.) fruit has been demonstrated to have the inhibitory activities to various tumors. In this study, we try to uncover the molecular mechanism underlying the inhibitory capability of Taiwanese local pomegranate fruit to urinary bladder urothelial carcinoma. The results collected from the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay indicated that the ethanol extract of pomegranate peel exhibited better inhibitory activity to human urinary bladder urothelial carcinoma T24 and J82 cells than that of pulp. Furthermore, the ethylacetate layer of peel ethanol extract was observed to have the best inhibitory activity against urinary bladder urothelial carcinoma cells. One of the eight fractions (PEPE2 fraction) collected from the ethylacetate layer with Diaion HP-20 column chromatography demonstrated the highest inhibitory activity in urinary bladder urothelial carcinoma cells. The results of the flow cytometry and apoptotic pathway studies suggested that the inhibitory activity of PEPE2 fraction were attributed to the UBUC cell apoptosis. To confirm the above results, our results of xenograft-induced bladder tumor in nude mice showed that the oral consumption of the ethylacetate layer (2, 5, 10 and 100 mg/kg) could decrease the volume and weight of T24 tumors and caused the apoptosis in the xenografted tumors, which was observed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end-labeling assay. This study provided the likelihood that the traditionally non-edible pomegranate peel waste is re-utilized to make an affordable and promising chemopreventive product to prevent UBUC incidence or recurrence. PMID- 29702556 TI - Multiple Isoforms of Anti-Lipopolysaccharide Factors and Their Antimicrobial Functions in the Ridgetail Prawn Exopalaemon carinicauda. AB - As a kind of antimicrobial peptides (AMP) in crustacean, anti-lipopolysaccharide factors (ALFs) have broad spectrum antimicrobial activities. In the present study, we identified four ALF genes, EcALF2-5, from the ridgetail prawn Exopalaemon carinicauda. Tissue distribution analysis showed that EcALF2 and EcALF4 transcripts were mainly located in gill, epidermis, and stomach, while EcALF3 and EcALF5 were mainly in hemocytes. Peptides corresponding to the LPS binding domain (LBD) of EcALFs were synthesized for analyzing their antimicrobial activities. Minimal inhibitory concentration (MIC) analysis showed that the synthetic LBD peptides of EcALF3 and EcALF4 could inhibit the growth of Gram positive and Gram-negative bacteria, while the synthetic LBD peptides of EcALF2 and EcALF5 showed antibacterial activity against Vibrio. Incubation of white spot syndrome virus (WSSV) with the synthetic LBD peptides of EcALF3, EcALF4, and EcALF5 could reduce the in vivo viral copy number in WSSV-infected prawns. After silencing of EcALFs, Vibrio exhibited a rapid proliferation in the hepatopancreas of the prawn. The present data showed the important function of different EcALFs in modulating the in vivo bacterial and viral propagation in E. carinicauda. This study will provide new clues into the disease control in aquaculture. PMID- 29702559 TI - An Improved BeiDou-2 Satellite-Induced Code Bias Estimation Method. AB - Different from GPS, GLONASS, GALILEO and BeiDou-3, it is confirmed that the code multipath bias (CMB), which originate from the satellite end and can be over 1 m, are commonly found in the code observations of BeiDou-2 (BDS) IGSO and MEO satellites. In order to mitigate their adverse effects on absolute precise applications which use the code measurements, we propose in this paper an improved correction model to estimate the CMB. Different from the traditional model which considering the correction values are orbit-type dependent (estimating two sets of values for IGSO and MEO, respectively) and modeling the CMB as a piecewise linear function with a elevation node separation of 10°, we estimate the corrections for each BDS IGSO + MEO satellite on one hand, and a denser elevation node separation of 5° is used to model the CMB variations on the other hand. Currently, the institutions such as IGS-MGEX operate over 120 stations which providing the daily BDS observations. These large amounts of data provide adequate support to refine the CMB estimation satellite by satellite in our improved model. One month BDS observations from MGEX are used for assessing the performance of the improved CMB model by means of precise point positioning (PPP). Experimental results show that for the satellites on the same orbit type, obvious differences can be found in the CMB at the same node and frequency. Results show that the new correction model can improve the wide-lane (WL) ambiguity usage rate for WL fractional cycle bias estimation, shorten the WL and narrow-lane (NL) time to first fix (TTFF) in PPP ambiguity resolution (AR) as well as improve the PPP positioning accuracy. With our improved correction model, the usage of WL ambiguity is increased from 94.1% to 96.0%, the WL and NL TTFF of PPP AR is shorten from 10.6 to 9.3 min, 67.9 to 63.3 min, respectively, compared with the traditional correction model. In addition, both the traditional and improved CMB model have a better performance in these aspects compared with the model which does not account for the CMB correction. PMID- 29702560 TI - Atomic Scale Simulation on the Anti-Pressure and Friction Reduction Mechanisms of MoS2 Monolayer. AB - MoS2 nanosheets can be used as solid lubricants or additives of lubricating oils to reduce friction and resist wear. However, the atomic scale mechanism still needs to be illustrated. Herein, molecular simulations on the indentation and scratching process of MoS2 monolayer supported by Pt(111) surface were conducted to study the anti-pressure and friction reduction mechanisms of the MoS2 monolayer. Three deformation stages of Pt-supported MoS2 monolayer were found during the indentation process: elastic deformation, plastic deformation and finally, complete rupture. The MoS2 monolayer showed an excellent friction reduction effect at the first two stages, as a result of enhanced load bearing capacity and reduced deformation degree of the substrate. Unlike graphene, rupture of the Pt-supported MoS2 monolayer was related primarily to out-of-plane compression of the monolayer. These results provide a new insight into the relationship between the mechanical properties and lubrication properties of 2D materials. PMID- 29702558 TI - A Low-Protein Diet for Diabetic Kidney Disease: Its Effect and Molecular Mechanism, an Approach from Animal Studies. AB - A low-protein diet (LPD) can be expected to retard renal function decline in advanced stages of chronic kidney disease (CKD), including diabetic kidney disease (DKD), and is recommended in a clinical setting. Regarding the molecular mechanisms of an LPD against DKD, previous animal studies have shown that an LPD exerts reno-protection through mainly the improvement of glomerular hyperfiltration/hypertension due to the reduction of intraglomerular pressure. On the other hand, we have demonstrated that an LPD, particularly a very-LPD (VLPD), improved tubulo-interstitial damage, inflammation and fibrosis, through the restoration of autophagy via the reduction of a mammalian target of rapamycin complex 1 (mTORC1) activity in type 2 diabetes and obesity animal models. Thus, based on animal studies, a VLPD may show a more beneficial effect against advanced DKD. Previous clinical reports have also shown that a VLPD, not a moderate LPD, slows the progression of renal dysfunction in patients with chronic glomerular nephritis. However, there is insufficient clinical data regarding the beneficial effects of a VLPD against DKD. Additionally, the patients with CKD, including DKD, are a high-risk group for malnutrition, such as protein-energy wasting (PEW), sarcopenia, and frailty. Therefore, an LPD, including a VLPD, should be prescribed to patients when the benefits of an LPD outweigh the risks, upon consideration of adherence, age, and nutritional status. As the future predicts, the development of a VLPD replacement therapy without malnutrition may be expected for reno-protection against the advanced stages of DKD, through the regulation of mTORC1 activity and adequate autophagy induction. However, further studies to elucidate detailed mechanisms by which a VLPD exerts reno-protection are necessary. PMID- 29702557 TI - CDG Therapies: From Bench to Bedside. AB - Congenital disorders of glycosylation (CDG) are a group of genetic disorders that affect protein and lipid glycosylation and glycosylphosphatidylinositol synthesis. More than 100 different disorders have been reported and the number is rapidly increasing. Since glycosylation is an essential post-translational process, patients present a large range of symptoms and variable phenotypes, from very mild to extremely severe. Only for few CDG, potentially curative therapies are being used, including dietary supplementation (e.g., galactose for PGM1-CDG, fucose for SLC35C1-CDG, Mn2+ for TMEM165-CDG or mannose for MPI-CDG) and organ transplantation (e.g., liver for MPI-CDG and heart for DOLK-CDG). However, for the majority of patients, only symptomatic and preventive treatments are in use. This constitutes a burden for patients, care-givers and ultimately the healthcare system. Innovative diagnostic approaches, in vitro and in vivo models and novel biomarkers have been developed that can lead to novel therapeutic avenues aiming to ameliorate the patients’ symptoms and lives. This review summarizes the advances in therapeutic approaches for CDG. PMID- 29702561 TI - Intracellular Transport of Silver and Gold Nanoparticles and Biological Responses: An Update. AB - Medicine, food, and cosmetics represent the new promising applications for silver (Ag) and gold (Au) nanoparticles (NPs). AgNPs are most commonly used in food and cosmetics; conversely, the main applications of gold NPs (AuNPs) are in the medical field. Thus, in view of the risk of accidentally or non-intended uptake of NPs deriving from the use of cosmetics, drugs, and food, the study of NPs-cell interactions represents a key question that puzzles researchers in both the nanomedicine and nanotoxicology fields. The response of cells starts when the NPs bind to the cell surface or when they are internalized. The amount and modality of their uptake depend on many and diverse parameters, such as NPs and cell types. Here, we discuss the state of the art of the knowledge and the uncertainties regarding the biological consequences of AgNPs and AuNPs, focusing on NPs cell uptake, location, and translocation. Finally, a section will be dedicated to the most currently available methods for qualitative and quantitative analysis of intracellular transport of metal NPs. PMID- 29702563 TI - Hepatitis C in Pregnancy. AB - The prevalence of hepatitis C in pregnancy is as high as 3.6% in large cohorts. The prevalence of hepatitis C acquired by vertical transmission is 0.2% to 0.4% in the United States and Europe. Although screening is not recommended in the absence of certain risk factors, the importance of understanding hepatitis C in pregnancy lies in its association with adverse maternal and neonatal outcomes. There is potential for those infants infected by vertical transmission to develop chronic hepatitis C, cirrhosis or hepatocellular carcinoma. The risk of vertical transmission is increased when mothers are co-infected with Human Immunodeficiency Virus (HIV) or possess a high viral load. There is no clear data supporting that mode of delivery increases or reduces risk. Breastfeeding is not associated with increased risk of transmission. Premature rupture of membranes, invasive procedures (such as amniocentesis), intrapartum events, or fetal scalp monitoring may increase risk of transmission. In pregnant patients, hepatitis C is diagnosed with a positive ELISA-3 and detectable Hepatitis C Virus (HCV) RNA viral load. Infants born to HCV-infected mothers should be tested for either HCV RNA on at least two separate occasions. Although prevention is not possible, there may be a role for newer direct acting anti-viral medications in the future. PMID- 29702562 TI - Positive and Negative Regulation of Angiogenesis by Soluble Vascular Endothelial Growth Factor Receptor-1. AB - Vascular endothelial growth factor receptor (VEGFR)-1 exists in different forms, derived from alternative splicing of the same gene. In addition to the transmembrane form, endothelial cells produce a soluble VEGFR-1 (sVEGFR-1) isoform, whereas non-endothelial cells produce both sVEGFR-1 and a different soluble molecule, known as soluble fms-like tyrosine kinase (sFlt)1-14. By binding members of the vascular endothelial growth factor (VEGF) family, the soluble forms reduce the amounts of VEGFs available for the interaction with their transmembrane receptors, thereby negatively regulating VEGFR-mediated signaling. In agreement with this activity, high levels of circulating sVEGFR-1 or sFlt1-14 are associated with different pathological conditions involving vascular dysfunction. Moreover, sVEGFR-1 and sFlt1-14 have an additional role in angiogenesis: they are deposited in the endothelial cell and pericyte extracellular matrix, and interact with cell membrane components. Interaction of sVEGFR-1 with α5β1 integrin on endothelial cell membranes regulates vessel growth, triggering a dynamic, pro-angiogenic phenotype. Interaction of sVEGFR-1/sFlt1-14 with cell membrane glycosphingolipids in lipid rafts controls kidney cell morphology and glomerular barrier functions. These cell-matrix contacts represent attractive novel targets for pharmacological intervention in addition to those addressing interactions between VEGFs and their receptors. PMID- 29702564 TI - Feasibility Study on S-Band Microwave Radiation and 3D-Thermal Infrared Imaging Sensor-Aided Recognition of Polymer Materials from End-of-Life Vehicles. AB - With the increase the worldwide consumption of vehicles, end-of-life vehicles (ELVs) have kept rapidly increasing in the last two decades. Metallic parts and materials of ELVs can be easily reused and recycled, but the automobile shredder residues (ASRs), of which elastomer and plastic materials make up the vast majority, are difficult to recycle. ASRs are classified as hazardous materials in the main industrial countries, and are required to be materially recycled up to 85-95% by mass until 2020. However, there is neither sufficient theoretical nor practical experience for sorting ASR polymers. In this research, we provide a novel method by using S-Band microwave irradiation together with 3D scanning as well as infrared thermal imaging sensors for the recognition and sorting of typical plastics and elastomers from the ASR mixture. In this study, an industrial magnetron array with 2.45 GHz irradiation was utilized as the microwave source. Seven kinds of ELV polymer (PVC, ABS, PP, EPDM, NBR, CR, and SBR) crushed scrap residues were tested. After specific power microwave irradiation for a certain time, the tested polymer materials were heated up to different extents corresponding to their respective sensitivities to microwave irradiation. Due to the variations in polymer chemical structure and additive agents, polymers have different sensitivities to microwave radiation, which leads to differences in temperature rises. The differences of temperature increase were obtained by a thermal infrared sensor, and the position and geometrical features of the tested scraps were acquired by a 3D imaging sensor. With this information, the scrap material could be recognized and then sorted. The results showed that this method was effective when the tested polymer materials were heated up to more than 30 °C. For full recognition of the tested polymer scraps, the minimum temperature variations of 5 °C and 10.5 °C for plastics and elastomers were needed, respectively. The sorting efficiency was independent of particle sizes but depended on the power and time of the microwave irradiation. Generally, more than 75% (mass) of the tested polymer materials could be successfully recognized and sorted under an irradiation power of 3 kW. Plastics were much more insensitive to microwave irradiation than elastomers. With this method, the tested mixture of the plastic group (PVC, ABS, PP) and the mixture of elastomer group (EPDM, NBR, CR, and SBR) could be fully separated with an efficiency of 100%. PMID- 29702565 TI - Self-Medication with Antibiotics, Attitude and Knowledge of Antibiotic Resistance among Community Residents and Undergraduate Students in Northwest Nigeria. AB - This study set out to evaluate self-medicated antibiotics and knowledge of antibiotic resistance among undergraduate students and community members in northern Nigeria. Antibiotic consumption pattern, source of prescription, illnesses commonly treated, attitude towards antibiotics, and knowledge of antibiotic resistance were explored using a structured questionnaire. Responses were analyzed and summarized using descriptive statistics. Of the 1230 respondents from undergraduate students and community members, prescription of antibiotics by a physician was 33% and 57%, respectively, amongst undergraduate students and community members. We tested the respondents’ knowledge of antibiotic resistance (ABR) and found that undergraduate students displayed less knowledge that self-medication could lead to ABR (32.6% and 42.2% respectively). Self-medication with antibiotics is highly prevalent in Northwest Nigeria, with most medicines being purchased from un-licensed stores without prescription from a physician. We also observed a significant gap in respondents’ knowledge of ABR. There is an urgent need for public health authorities in Nigeria to enforce existing laws on antibiotics sales and enlighten the people on the dangers of ABR. PMID- 29702566 TI - Preferential and Increased Uptake of Hydroxyl-Terminated PAMAM Dendrimers by Activated Microglia in Rabbit Brain Mixed Glial Culture. AB - Polyamidoamine (PAMAM) dendrimers are multifunctional nanoparticles with tunable physicochemical features, making them promising candidates for targeted drug delivery in the central nervous system (CNS). Systemically administered dendrimers have been shown to localize in activated glial cells, which mediate neuroinflammation in the CNS. These dendrimers delivered drugs specifically to activated microglia, producing significant neurological improvements in multiple brain injury models, including in a neonatal rabbit model of cerebral palsy. To gain further insight into the mechanism of dendrimer cell uptake, we utilized an in vitro model of primary glial cells isolated from newborn rabbits to assess the differences in hydroxyl-terminated generation 4 PAMAM dendrimer (D4-OH) uptake by activated and non-activated glial cells. We used fluorescently-labelled D4-OH (D Cy5) as a tool for investigating the mechanism of dendrimer uptake. D4-OH PAMAM dendrimer uptake was determined by fluorescence quantification using confocal microscopy and flow cytometry. Our results indicate that although microglial cells in the mixed cell population demonstrate early uptake of dendrimers in this in vitro system, activated microglia take up more dendrimer compared to resting microglia. Astrocytes showed delayed and limited uptake. We also illustrated the differences in mechanism of uptake between resting and activated microglia using different pathway inhibitors. Both resting and activated microglia primarily employed endocytotic pathways, which are enhanced in activated microglial cells. Additionally, we demonstrated that hydroxyl terminated dendrimers are taken up by primary microglia using other mechanisms including pinocytosis, caveolae, and aquaporin channels for dendrimer uptake. PMID- 29702568 TI - Tunable Polarity Carbon Fibers, a Holistic Approach to Environmental Protection. AB - The pollution of environmental resources is an issue of social concern worldwide. Chemistry is essential for the design of decontamination strategies and analytical approaches to detect and monitor the contamination. Sorptive materials are usually required in both approaches and green synthesis should be used to minimize their own environmental impact. Carbon fibers (CFs) obtained by the pyrolysis of natural cellulose-rich materials fulfill these requirements. In this article, thirty CFs obtained under different conditions are chemically characterized and their sorption ability towards selected pollutants, covering a wide range of polarity, is evaluated. This study provides more profound knowledge related to the polarity of these materials, their interactions with chemical substances and allows the prediction of more appropriate materials (pyrolysis temperature and time) in order to remove the given pollutant. Furthermore, the use of CFs as sorptive materials for the extraction of contaminants from water samples to assist with their instrumental detection is outlined. In this sense, the use of CFs and gas chromatography with mass spectrometric detection allows the detection of selected pollutants in the low ng/mL range. Thus, this article provides an integrated approach to the potential of CFs for environmental protection. PMID- 29702567 TI - A Perspective on the Application of Spatially Resolved ARPES for 2D Materials. AB - In this paper, a perspective on the application of Spatially- and Angle-Resolved PhotoEmission Spectroscopy (ARPES) for the study of two-dimensional (2D) materials is presented. ARPES allows the direct measurement of the electronic band structure of materials generating extremely useful insights into their electronic properties. The possibility to apply this technique to 2D materials is of paramount importance because these ultrathin layers are considered fundamental for future electronic, photonic and spintronic devices. In this review an overview of the technical aspects of spatially localized ARPES is given along with a description of the most advanced setups for laboratory and synchrotron based equipment. This technique is sensitive to the lateral dimensions of the sample. Therefore, a discussion on the preparation methods of 2D material is presented. Some of the most interesting results obtained by ARPES are reported in three sections including: graphene, transition metal dichalcogenides (TMDCs) and 2D heterostructures. Graphene has played a key role in ARPES studies because it inspired the use of this technique with other 2D materials. TMDCs are presented for their peculiar transport, optical and spin properties. Finally, the section featuring heterostructures highlights a future direction for research into 2D material structures. PMID- 29702569 TI - Diagnostic Accuracy of a 64-Slice Multi-Detector CT Scan in the Preoperative Evaluation of Periampullary Neoplasms. AB - Periampullary tumors are highly malignant masses with poor prognosis. Surgical resection is the only treatment for patients with this disease. The preoperative evaluation of masses is essential to determine the tumor resectability and vascular invasion. The aim of this study was to determine the diagnostic accuracy of 64-slice multi-detector computed tomography (MDCT) in detecting the resectability of periampullary masses. A cross-sectional study was conducted on patients with a definite diagnosis of periampullary cancer. All the participants underwent an MDCT scan before the surgical pancreaticoduodenectomy. The preoperative results were compared to the intraoperative findings and the diagnostic accuracy was determined based on the sensitivity and specificity of the MDCT. From June 2015 until June 2016, 32 patients with periampullary carcinoma were enrolled in the study. Of 32 masses, one of them considered nonresectable because of the gross vascular invasion in th CT images. After the operation, the overall resectability rate was 81.3%. The sensitivity and specificity of MDCT for tumor resectability was 100% and 16.7%, respectively, with an overall accuracy of 84.4%. To sum up, MDCT had high sensitivity but low specificity in the preoperative evaluation of preampullary carcinomas. The low specificity resulted from the low accuracy of the CT scan in detecting vascular involvement. PMID- 29702570 TI - Dechlorination of Hexachlorobenzene in Contaminated Soils Using a Nanometallic Al/CaO Dispersion Mixture: Optimization through Response Surface Methodology. AB - Hexachlorobenzene (HCB) contamination of soils remains a significant environmental challenge all over the world. Reductive stabilization is a developing technology that can decompose the HCB with a dechlorination process. A nanometallic Al/CaO (n-Al/CaO) dispersion mixture was developed utilizing ball milling technology in this study. The dechlorination efficiency of HCB in contaminated soils by the n-Al/CaO grinding treatment was evaluated. Response surface methodology (RSM) was employed to investigate the effects of three variables (soil moisture content, n-Al/CaO dosage and grinding time) and the interactions between these variables under the Box-Behnken Design (BBD). A high regression coefficient value (R2 = 0.9807) and low p value (<0.0001) of the quadratic model indicated that the model was accurate in predicting the experimental results. The optimal soil moisture content, n-Al/CaO dosage, and grinding time were found to be 7% (m/m), 17.7% (m/m), and 24 h, respectively, in the experimental ranges and levels. Under optimal conditions, the dechlorination efficiency was 80%. The intermediate product analysis indicated that dechlorination was the process by stepwise loss of chloride atoms. The main pathway observed within 24 h was HCB → pentachlorobenzene (PeCB) → 1,2,3,4-tetrachlorobenzene (TeCB) and 1,2,4,5-TeCB. The results indicated that the moderate soil moisture content was crucial for the hydrodechlorination of HCB. A probable mechanism was proposed wherein water acted like a hydrogen donor and promoted the hydrodechlorination process. The potential application of n Al/CaO is an environmentally-friendly and cost-effective option for decontamination of HCB-contaminated soils. PMID- 29702571 TI - Conservation of Monuments by a Three-Layered Compatible Treatment of TEOS-Nano Calcium Oxalate Consolidant and TEOS-PDMS-TiO2 Hydrophobic/Photoactive Hybrid Nanomaterials. AB - In the conservation of monuments, research on innovative nanocomposites with strengthening, hydrophobic and self-cleaning properties have attracted the interest of the scientific community and promising results have been obtained as a result. In this study, stemming from the need for the compatibility of treatments in terms of nanocomposite/substrate, a three-layered compatible treatment providing strengthening, hydrophobic, and self-cleaning properties is proposed. This conservation approach was implemented treating lithotypes and mortars of different porosity and petrographic characteristics with a three layered treatment comprising: (a) a consolidant, tetraethoxysilane (TEOS)-nano Calcium Oxalate; (b) a hydrophobic layer of TEOS-polydimethylsiloxane (PDMS); and (c) a self-cleaning layer of TiO2 nanoparticles from titanium tetra-isopropoxide with oxalic acid as hole-scavenger. After the three-layered treatment, the surface hydrophobicity was improved due to PDMS and nano-TiO2 in the interface substrate/atmosphere, as proven by the homogeneity and the Si-O-Ti hetero linkages of the blend protective/self-cleaning layers observed by Scanning Electron Microscope (SEM), Transmission Electron Microscope (TEM) and Fourier Transform Infrared Spectroscopy (FTIR). The aesthetic, microstructural, mechanical and permeabile compatibility of the majority of treated substrates ranged within acceptability limits. The improved photocatalytic activity, as proven by the total discoloration of methylene blue in the majority of cases, was attributed to the anchorage of TiO2, through the Si-O-Ti bonds to SiO2, in the interface with the atmosphere, thus enhancing photoactivation. PMID- 29702572 TI - Musical Experience, Sensorineural Auditory Processing, and Reading Subskills in Adults. AB - Developmental research suggests that sensorineural auditory processing, reading subskills (e.g., phonological awareness and rapid naming), and musical experience are related during early periods of reading development. Interestingly, recent work suggests that these relations may extend into adulthood, with indices of sensorineural auditory processing relating to global reading ability. However, it is largely unknown whether sensorineural auditory processing relates to specific reading subskills, such as phonological awareness and rapid naming, as well as musical experience in mature readers. To address this question, we recorded electrophysiological responses to a repeating click (auditory stimulus) in a sample of adult readers. We then investigated relations between electrophysiological responses to sound, reading subskills, and musical experience in this same set of adult readers. Analyses suggest that sensorineural auditory processing, reading subskills, and musical experience are related in adulthood, with faster neural conduction times and greater musical experience associated with stronger rapid-naming skills. These results are similar to the developmental findings that suggest reading subskills are related to sensorineural auditory processing and musical experience in children. PMID- 29702573 TI - Profiling of Heterobranchia Sea Slugs from Portuguese Coastal Waters as Producers of Anti-Cancer and Anti-Inflammatory Agents. AB - Bioprospection of marine invertebrates has been predominantly biased by the biological richness of tropical regions, thus neglecting macro-organisms from temperate ecosystems. Species that were not the object of studies on their biochemical composition include the Heterobranchia gastropods Armina maculata, Armina tigrina and Aglaja tricolorata, inhabitants of the Portuguese Atlantic coastal waters. Here, we present for the first time the fatty acid profile of neutral lipids and homarine content of these three species. Qualitative and quantitative differences in the fatty acid content among species points to the existence of a fatty acid profile of neutral lipids, particularly of each genus. The results from cytotoxicity assays, using the acetonic extracts of the gastropods on human gastric adenocarcinoma (AGS) and human lung adenocarcinoma (A549) cell lines, revealed a pronounced cytotoxic effect of the A. tigrina extract on both cell lines (IC50 values of 68.75 and 69.77 μg mL−1 for AGS and A549, respectively). It is worth noting the significant reduction of NO levels in LPS-challenged RAW 264.7 macrophages exposed to A. tricolorata extract, at concentrations as low as 125 μg mL−1. PMID- 29702574 TI - ParaBTM: A Parallel Processing Framework for Biomedical Text Mining on Supercomputers. AB - A prevailing way of extracting valuable information from biomedical literature is to apply text mining methods on unstructured texts. However, the massive amount of literature that needs to be analyzed poses a big data challenge to the processing efficiency of text mining. In this paper, we address this challenge by introducing parallel processing on a supercomputer. We developed paraBTM, a runnable framework that enables parallel text mining on the Tianhe-2 supercomputer. It employs a low-cost yet effective load balancing strategy to maximize the efficiency of parallel processing. We evaluated the performance of paraBTM on several datasets, utilizing three types of named entity recognition tasks as demonstration. Results show that, in most cases, the processing efficiency can be greatly improved with parallel processing, and the proposed load balancing strategy is simple and effective. In addition, our framework can be readily applied to other tasks of biomedical text mining besides NER. PMID- 29702575 TI - A One-Component, Fast-Cure, and Economical Epoxy Resin System Suitable for Liquid Molding of Automotive Composite Parts. AB - Imidazole cured epoxy resin systems were evaluated for one-component, fast-curing resins for liquid molding of automotive composite parts according to industry requirements. It was demonstrated that an epoxy resin-1-(cyanoethyl)-2-ethyl-4 methylimidazol(EP-1C2E4MIM) system would cure in a few minutes at 120 °C, while exhibiting acceptable pot life, viscosity profiles, and low water absorption. Moreover, this system yielded high Tg parts with mechanical properties similar to the amine-epoxy systems, which are the mainstream two component epoxy resin systems for automobiles. PMID- 29702576 TI - Multi-Response Optimization of Ultrasonic Assisted Enzymatic Extraction Followed by Macroporous Resin Purification for Maximal Recovery of Flavonoids and Ginkgolides from Waste Ginkgo biloba Fallen Leaves. AB - In the present study, the process of ultrasonic assisted enzymatic extraction (UAEE), followed by macroporous resin purification, was successfully developed to achieve maximal recovery of flavonoids and ginkgolides from Ginkgo biloba fallen leaves (GBFL). Three effective extracted factors, including UAE power, EtOH%, and the amount of cellulase were screened by Plackett-Burman design (PBD). The important variables were further optimized by rotatable central composite design (RCCD). After the combination of PBD and RCCD, the resulting optimal UAEE conditions were as follows: UAE power of 218 W; EtOH% of 68%; the amount of cellulase of 8.4 mg; UAE temperature of 40 °C; UAE time of 20 min; pH of 5.0; and, sample particle size of 40 mesh. Under the optimum conditions; the yields of flavonoids were 0.74 ± 0.05% (n = 3) and ginkgolides was 0.42 ± 0.06% (n = 3), which were close to the predicted values. Moreover, the further enriching flavonoids and ginkgolides from the obtained GBFL extracts using the above optimum UAEE condition was successfully achieved by macroporous resin DA 201. After column adsorption and desorption on DA-201; the percentage of total flavonoids was (25.36 ± 1.03)%; ginkgolides was (12.43 ± 0.85)% and alkylphenols was (0.003 ± 0.0005)% from the obtained dry extracts of GBFL which were complied with Chinese pharmacopoeias. Therefore, the present study provided a convenient and efficient method for extraction and purification of flavonoids and ginkgolides from waste GBFL. PMID- 29702577 TI - Genotypic Features of Clinical and Bovine Escherichia coli O157 Strains Isolated in Countries with Different Associated-Disease Incidences. AB - There is great geographical variation in the frequency of Escherichia coli O157 infections that correlates with important differences in the bovine reservoir of each country. Our group carried out a broad molecular characterization of human and bovine E. coli O157 strains circulating in Argentina using different methodologies. Our data allows us to conclude that in Argentina, a high homogeneity is observed in both cattle and human strains, with almost exclusive circulation of strains belonging to the hypervirulent clade 8 described by Manning. The aim of this review was to compare the genetic background of E. coli O157 strains isolated in countries that have conducted similar studies, to try to correlate specific O157 genotypes with the incidence and severity of E. coli O157 associated diseases. The characteristics of the strains that cause disease in humans reflect the predominant genotypes in cattle in each of the countries analyzed. The main features clearly linked to high incidence or severity of E. coli O157 infections are lineage-specific polymorphism assay-6 lineage I/II, clade 8 strains and probably, clade 6 strains, the stx2a/stx2c genotype, the presence of q933 and q21 simultaneously, and putative virulence factor EC_3286. In countries with an absence of these features in O157 strains, the overall incidence of O157 disease is low. Argentina, where these characteristics are detected in most strains, shows the highest incidence of hemolytic uremic syndrome (HUS) worldwide. PMID- 29702578 TI - Parental Translation into Practice of Healthy Eating and Active Play Messages and the Impact on Childhood Obesity: A Mixed Methods Study. AB - Childhood obesity is a significant health issue worldwide. Modifiable risk factors in early childhood relate to child healthy eating and active play, and are influenced by parents. The aim of the study was two-fold. Firstly, to determine the weight status of children aged between birth and 3.5 years in a rural and remote area of Australia. Secondly, to explore the relationship between child weight status and translation of advice on healthy eating and active play provided to parents by local, nurse-led, Maternal Child Health (MCH) services. Measured anthropometric data (n = 438) were provided by MCH services. Semi structured interviews were conducted with two MCH nurses and 15 parents. Prevalence of overweight/obesity was calculated. Local childhood overweight/obesity prevalence was lower than the national average at age 3.5 years (11.38%; 20%). Parents identified the MCH service as a key source of healthy eating and active play advice and reported mostly following recommendations but struggling with screen time and fussy eating recommendations. We observed a relaxation in parent attitudes towards healthy child behaviours which coincided with a trend towards obesity from 12 months (p < 0.001). MCH services provide useful and effective advice to parents but ongoing support is required to prevent obesity later in childhood. PMID- 29702579 TI - Performance Evaluation and Improving Mechanisms of Diatomite-Modified Asphalt Mixture. AB - Diatomite is an inorganic natural resource in large reserve. This study consists of two phases to evaluate the effects of diatomite on asphalt mixtures. In the first phase, we characterized the diatomite in terms of mineralogical properties, chemical compositions, particle size distribution, mesoporous distribution, morphology, and IR spectra. In the second phase, road performances, referring to the permanent deformation, crack, fatigue, and moisture resistance, of asphalt mixtures with diatomite were investigated. The characterization of diatomite exhibits that it is a porous material with high SiO2 content and large specific surface area. It contributes to asphalt absorption and therefore leads to bonding enhancement between asphalt and aggregate. However, physical absorption instead of chemical reaction occurs according to the results of FTIR. The resistance of asphalt mixtures with diatomite to permanent deformation and moisture are superior to those of the control mixtures. But, the addition of diatomite does not help to improve the crack and fatigue resistance of asphalt mixture. PMID- 29702581 TI - On the Nature of Energy-Feasible Wireless Nanosensor Networks. AB - Electromagnetic nanocommunications, understood as the communication between electronic nanoscale devices through electromagnetic waves in the terahertz band, has attracted increasing attention in recent years. In this regard, several solutions have already been proposed. However, many of them do not sufficiently capture the significance of the limitations in nanodevice energy-gathering and storing capacity. In this paper, we address key factors affecting the energy consumption of nanodevices, highlighting the effect of the communication scheme employed. Then, we also examine how nanodevices are powered, focusing on the main parameters governing the powering nanosystem. Different mathematical expressions are derived to analyze the impact of these parameters on its performance. Based on these expressions, the functionality of a nanogenerator is evaluated to gain insight into the conditions under which a wireless nanosensor network (WNSN) is viable from the energetic point of view. The results reveal that a micrometer sized piezoelectric system in high-lossy environments (exceeding 100 dB/mm) becomes inoperative for transmission distances over 1.5 mm by its inability to harvest and store the amount of energy required to overcome the path loss. PMID- 29702580 TI - Baicalin Inhibits Haemophilus Parasuis-Induced High-Mobility Group Box 1 Release during Inflammation. AB - Haemophilus parasuis (H. parasuis) can cause Glässer’s disease in pigs. However, the molecular mechanism of the inflammation response induced by H. parasuis remains unclear. The high-mobility group box 1 (HMGB1) protein is related to the pathogenesis of various infectious pathogens, but little is known about whether H. parasuis can induce the release of HMGB1 in piglet peripheral blood monocytes. Baicalin displays important anti-inflammatory and anti-microbial activities. In the present study, we investigated whether H. parasuis can trigger the secretion of HMGB1 in piglet peripheral blood monocytes and the anti inflammatory effect of baicalin on the production of HMGB1 in peripheral blood monocytes induced by H. parasuis during the inflammation response. In addition, host cell responses stimulated by H. parasuis were determined with RNA-Seq. The RNA-Seq results showed that H. parasuis infection provokes the expression of cytokines and the activation of numerous pathways. In addition, baicalin significantly reduced the release of HMGB1 in peripheral blood monocytes induced by H. parasuis. Taken together, our study showed that H. parasuis can induce the release of HMGB1 and baicalin can inhibit HMGB1 secretion in an H. parasuis induced peripheral blood monocytes model, which may provide a new strategy for preventing the inflammatory disorders induced by H. parasuis. PMID- 29702583 TI - Metal/Carbon Hybrid Nanostructures Produced from Plasma-Enhanced Chemical Vapor Deposition over Nafion-Supported Electrochemically Deposited Cobalt Nanoparticles. AB - In this work, we report development of hybrid nanostructures of metal nanoparticles (NP) and carbon nanostructures with strong potential for catalysis, sensing, and energy applications. First, the etched silicon wafer substrates were passivated for subsequent electrochemical (EC) processing through grafting of nitro phenyl groups using para-nitrobenzene diazonium (PNBT). The X-ray photoelectron spectroscope (XPS) and atomic force microscope (AFM) studies confirmed presence of few layers. Cobalt-based nanoparticles were produced over dip or spin coated Nafion films under different EC reduction conditions, namely CoSO4 salt concentration (0.1 M, 1 mM), reduction time (5, 20 s), and indirect or direct EC reduction route. Extensive AFM examination revealed NP formation with different attributes (size, distribution) depending on electrochemistry conditions. While relatively large NP with >100 nm size and bimodal distribution were obtained after 20 s EC reduction in H3BO3 following Co2+ ion uptake, ultrafine NP (<10 nm) could be produced from EC reduction in CoSO4 and H3BO3 mixed solution with some tendency to form oxides. Different carbon nanostructures including few-walled or multiwalled carbon nanotubes (CNT) and carbon nanosheets were grown in a C2H2/NH3 plasma using the plasma-enhanced chemical vapor deposition technique. The devised processing routes enable size controlled synthesis of cobalt nanoparticles and metal/carbon hybrid nanostructures with unique microstructural features. PMID- 29702582 TI - Transient Sulfenic Acids in the Synthesis of Biologically Relevant Products. AB - Sulfenic acids as small molecules are too unstable to be isolated and their transient nature offers the possibility to involve them in concerted processes that lead to the obtainment of functional groups such as sulfoxides, sulfones, and disulfides. All these functions are present in a number of natural and synthetic drugs and can represent structural motives inducing biologically relevant properties. In this small review the generation and reactions of sulfenic acid bearing naturally occurring residues are described. Carbohydrate and aminoacid-derived sulfenic acids have been used in concerted addition with triple bonds to obtain alliin derivatives and thiosugars in enantiomerically pure form. Glycoconjugates with sulfinyl, sulfonyl, and disulfane functional groups and pyridine-derived disulfides have been obtained from bis- and tris-sulfinyl precursors of sulfenic acids. Small families of such compounds have been subjected to preliminary biological tests. Starting from the evidence that the control of molecular architecture and the presence of suitable functional groups can play a significant role on the exhibition of biological properties, apoptotic effects on malignant cells by glycoconjugates and inhibitory activity against the important human pathogen S. aureus by pyrimidine-derived disulfides have been found. PMID- 29702584 TI - Colorimetric Humidity Sensor Using Inverse Opal Photonic Gel in Hydrophilic Ionic Liquid. AB - We demonstrate a fast response colorimetric humidity sensor using a crosslinked poly(2-hydroxyethyl methacrylate) (PHEMA) in the form of inverse opal photonic gel (IOPG) soaked in 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIM+][BF4−]), a non-volatile hydrophilic room temperature ionic liquid (IL). An evaporative colloidal assembly enabled the fabrication of highly crystalline opal template, and a subsequent photopolymerization of PHEMA followed by solvent-etching and final soaking in IL produced a humidity-responsive IOPG showing highly reflective structural color by Bragg diffraction. Three IOPG sensors with different crosslinking density were fabricated on a single chip, where a lightly crosslinked IOPG exhibited the color change response over entire visible spectrum with respect to the humidity changes from 0 to 80% RH. As the water content increased in IL, thermodynamic interactions between PHEMA and [BMIM+][BF4−] became more favorable, to show a red-shifted structural color owing to a longitudinal swelling of IOPG. Highly porous IO structure enabled fast humidity-sensing kinetics with the response times of ~1 min for both swelling and deswelling. Temperature-dependent swelling of PHEMA in [BMIM+][BF4−] revealed that the current system follows an upper critical solution temperature (UCST) behavior with the diffraction wavelength change as small as 1% at the temperature changes from 10 °C to 30 °C. PMID- 29702585 TI - Anthropogenic Food Subsidy to a Commensal Carnivore: The Value and Supply of Human Faeces in the Diet of Free-Ranging Dogs. AB - As the global population of free-ranging domestic dogs grows, there is increasing concern about impacts on human health and wildlife conservation. Effective management of dog populations requires reliable information on their diet, feeding behavior, and social ecology. Free-ranging dogs are reliant on humans, but anthropogenic food subsidies, particularly human faeces (i.e., coprophagy) have not previously been fully quantified. In this study we assess the contributions of different food types to the diet, and their influences on the social behaviour of free-ranging dogs in communal lands of rural Zimbabwe, with a focus on coprophagy. Free-ranging dog diets, body condition, and sociology were studied amongst 72 dogs over 18 months using scat analysis and direct observations. Human faeces constituted the fourth most common item in scats (56% occurrence) and contributed 21% by mass to the observed diet. Human faeces represented a valuable resource because relative to other food items it was consistently available, and of higher nutritional value than ‘sadza’ (maize porridge, the human staple and primary human-derived food), yielding 18.7% crude protein and 18.7 KJ/kg gross energy, compared to 8.3% and 18.5 KJ/kg for sadza, respectively. Human faeces had protein and energy values equivalent to mammal remains, another important food item. Dog condition was generally good, with 64% of adult females and 74% of adult males in the highest two body condition scores (on a five point scale), suggesting a plentiful and high quality food supply. Dogs largely fed alone, perhaps as a consequence of the small, inert, and spatially dispersed items that comprise their diet, and its abundance. We discuss the relationships between sanitation, human development, the supply of human faeces, female dog fertility, and population control. PMID- 29702586 TI - Empirical Determination of Efficient Sensing Frequencies for Magnetometer-Based Continuous Human Contact Monitoring. AB - The high linear correlation between the smartphone magnetometer readings in close proximity can be exploited for physical human contact detection, which could be useful for such applications as infectious disease contact tracing or social behavior monitoring. Alternative approaches using other capabilities in smartphones have aspects that do not fit well with the human contact detection. Using Wi-Fi or cellular fingerprints have larger localization errors than close human contact distances. Bluetooth beacons could reveal the identity of the transmitter, threatening the privacy of the user. Also, using sensors such as GPS does not work for indoor contacts. However, the magnetometer correlation check works best in human contact distances that matter in infectious disease transmissions or social interactions. The omni-present geomagnetism makes it work both indoors and outdoors, and the measured magnetometer values do not easily reveal the identity and the location of the smartphone. One issue with the magnetometer-based contact detection, however, is the energy consumption. Since the contacts can take place anytime, the magnetometer sensing and recording should be running continuously. Therefore, how we address the energy requirement for the extended and continuous operation can decide the viability of the whole idea. However, then, we note that almost all existing magnetometer-based applications such as indoor location and navigation have used high sensing frequencies, ranging from 10 Hz to 200 Hz. At these frequencies, we measure that the time to complete battery drain in a typical smartphone is shortened by three to twelve hours. The heavy toll raises the question as to whether the magnetometer-based contact detection can avoid such high sensing rates while not losing the contact detection accuracy. In order to answer the question, we conduct a measurement-based study using independently produced magnetometer traces from three different countries. Specifically, we gradually remove high frequency components in the traces, while observing the correlation changes. As a result, we find that the human coexistence detection indeed tends to be no less, if not more, effective at the sampling frequency of 1 Hz or even less. This is because unlike the other applications that require centimeter-level precision, the human contacts detected anywhere within a couple of meters are valid for our purpose. With the typical smartphone battery capacity and at the 1 Hz sensing, the battery consumption is well below an hour, which is smaller by more than two hours compared with 10 Hz sampling and by almost eleven hours compared with 200 Hz sampling. With other tasks running simultaneously on smartphones, the energy saving aspect will only become more critical. Therefore, we conclude that sensing the ambient magnetic field at 1 Hz is sufficient for the human contact monitoring purpose. We expect that this finding will have a significant practicability implication in the smartphone magnetometer-based contact monitoring applications in general. PMID- 29702587 TI - Perceived Discrimination among Black Youth: An 18-Year Longitudinal Study. AB - Background: Recent research has suggested vulnerability to perceived racial discrimination (PRD) as a mechanism behind high levels of depression seen in high socioeconomic status (SES) Black males. To better understand the effects of gender and SES on shaping experiences of PRD among Black youth in the United States, we used data from the Family and Community Health Study (FACHS) to explore the trajectory of PRD in Black youth by gender, SES, and place. Methods: Data came from FACHS, 1997-2017, which followed 889 children aged 10-12 years old at Wave 1 (n = 478; 53.8% females and n = 411; 46.2% males) for up to 18 years. Data were collected in seven waves. The main predictors of interest were gender, SES (parent education and annual family income), age, and place of residence. Main outcomes of interest were baseline and slope of PRD. Latent growth curve modeling (LGCM) was used for data analysis. Results: Gender, SES, place, and age were correlated with baseline and change in PRD over time. Male, high family income, and younger Black youth reported lower PRD at baseline but a larger increase in PRD over time. Youth who lived in Iowa (in a predominantly White area) reported higher PRD at baseline and also an increase in PRD over time. High parental education was not associated with baseline or change in PRD. Conclusion: In the United States, Black youth who are male, high income, and live in predominantly White areas experience an increase in PRD over time. Future research is needed on the interactions between gender, SES, and place on exposure and vulnerability of Black youth to PRD. Such research may explain the increased risk of depression in high SES Black males. PMID- 29702588 TI - Performance Analysis of Satellite Missions for Multi-Temporal SAR Interferometry. AB - Multi-temporal InSAR (MTI) applications pose challenges related to the availability of coherent scattering from the ground surface, the complexity of the ground deformations, atmospheric artifacts, and visibility problems related to ground elevation. Nowadays, several satellite missions are available providing interferometric SAR data at different wavelengths, spatial resolutions, and revisit time. A new and interesting opportunity is provided by Sentinel-1, which has a spatial resolution comparable to that of previous ESA C-band sensors, and revisit times improved by up to 6 days. According to these different SAR space borne missions, the present work discusses current and future opportunities of MTI applications in terms of ground instability monitoring. Issues related to coherent target detection, mean velocity precision, and product geo-location are addressed through a simple theoretical model assuming backscattering mechanisms related to point scatterers. The paper also presents an example of a multi-sensor ground instability investigation over Lesina Marina, a village in Southern Italy lying over a gypsum diapir, where a hydration process, involving the underlying anhydride, causes a smooth uplift and the formation of scattered sinkholes. More than 20 years of MTI SAR data have been processed, coming from both legacy ERS and ENVISAT missions, and latest-generation RADARSAT-2, COSMO-SkyMed, and Sentinel-1A sensors. Results confirm the presence of a rather steady uplift process, with limited to null variations throughout the whole monitored time period. PMID- 29702589 TI - A Coarse-to-Fine Geometric Scale-Invariant Feature Transform for Large Size High Resolution Satellite Image Registration. AB - Large size high resolution (HR) satellite image matching is a challenging task due to local distortion, repetitive structures, intensity changes and low efficiency. In this paper, a novel matching approach is proposed for the large size HR satellite image registration, which is based on coarse-to-fine strategy and geometric scale-invariant feature transform (SIFT). In the coarse matching step, a robust matching method scale restrict (SR) SIFT is implemented at low resolution level. The matching results provide geometric constraints which are then used to guide block division and geometric SIFT in the fine matching step. The block matching method can overcome the memory problem. In geometric SIFT, with area constraints, it is beneficial for validating the candidate matches and decreasing searching complexity. To further improve the matching efficiency, the proposed matching method is parallelized using OpenMP. Finally, the sensing image is rectified to the coordinate of reference image via Triangulated Irregular Network (TIN) transformation. Experiments are designed to test the performance of the proposed matching method. The experimental results show that the proposed method can decrease the matching time and increase the number of matching points while maintaining high registration accuracy. PMID- 29702591 TI - One-Dimensional Porous Silicon Nanowires with Large Surface Area for Fast Charge Discharge Lithium-Ion Batteries. AB - In this study, one-dimensional porous silicon nanowire (1D-PSiNW) arrays were fabricated by one-step metal-assisted chemical etching (MACE) to etch phosphorus doped silicon wafers. The as-prepared mesoporous 1D-PSiNW arrays here had especially high specific surface areas of 323.47 m2.g-1 and were applied as anodes to achieve fast charge-discharge performance for lithium ion batteries (LIBs). The 1D-PSiNWs anodes with feature size of ~7 nm exhibited reversible specific capacity of 2061.1 mAh.g-1 after 1000 cycles at a high current density of 1.5 A.g-1. Moreover, under the ultrafast charge-discharge current rate of 16.0 A.g-1, the 1D-PSiNWs anodes still maintained 586.7 mAh.g-1 capacity even after 5000 cycles. This nanoporous 1D-PSiNW with high surface area is a potential anode candidate for the ultrafast charge-discharge in LIBs with high specific capacity and superior cycling performance. PMID- 29702590 TI - Insulin-Like Growth Factor (IGF) System in Liver Diseases. AB - Hepatocyte differentiation, proliferation, and apoptosis are affected by growth factors produced in liver. Insulin-like growth factor 1 and 2 (IGF1 and IGF2) act in response to growth hormone (GH). Other IGF family components include at least six binding proteins (IGFBP1 to 6), manifested by both IGFs develop due to interaction through the type 1 receptor (IGF1R). The data based on animal models and/or in vitro studies suggest the role of IGF system components in cellular aspects of hepatocarcinogenesis (cell cycle progression, uncontrolled proliferation, cell survival, migration, inhibition of apoptosis, protein synthesis and cell growth), and show that systemic IGF1 administration can reduce fibrosis and ameliorate general liver function. In epidemiologic and clinicopathological studies on chronic liver disease (CLD), lowered serum levels, decreased tissue expression of IGF1, elevated production of IGF1R and variable IGF2 expression has been noted, from the start of preneoplastic alterations up to the developed hepatocellular carcinoma (HCC) stage. These changes result in well known clinical symptoms of IGF1 deficiency. This review summarized the current data of the complex role of IGF system components in the most common CLD (nonalcoholic fatty liver disease, cirrhosis, and hepatocellular carcinoma). Better recognition and understanding of this system can contribute to discovery of new and improved versions of current preventive and therapeutic actions in CLD. PMID- 29702592 TI - Clinicopathological Diversity of Canine Mammary Gland Tumors in Sri Lanka: A One Year Survey on Cases Presented to Two Veterinary Practices. AB - Mammary gland tumors (MGTs) are one of the most common neoplasms among dogs in Sri Lanka. However, the clinicopathological diversity of MGTs in Sri Lanka is largely unknown, impeding accurate diagnosis and effective treatment of the disease. The present study investigated the clinicopathological features of MGTs in 74 dogs presented to two veterinary practices in Sri Lanka treated surgically, over a one-year period. Information regarding the patient signalment, clinical presentation, and reproductive history were collected, and each neoplasm was examined histologically. Forty-one (54.4%) dogs were primarily presented for mammary neoplasia, while a MGT was an incidental finding in 33 (44.6%) dogs. The majority of tumors were histologically malignant (n = 65, 87.8%), and 18 malignant tumor sub-types were identified. A significantly higher proportion of malignant tumors were large (>3 cm diameter) and observed in inguinal mammary glands. Nulliparous (n = 42, 55.3%) dogs predominated in the group, and the mean age of MGT diagnosis was 8.0 ± 2.41 years. The present study identified tumor location and size to be predictive of malignancy. A high histological diversity of MGTs was observed. Overall, the present findings emphasize the necessity of improving awareness of MGTs among Sri Lankan clinicians as well as dog owners. PMID- 29702594 TI - Health Risk Behavior Patterns in a National Adult Population Survey. AB - Background: The aim of this paper is to analyze the co-occurrence of health risk behaviors (HRBs), namely, tobacco smoking, alcohol risk drinking, overeating, and physical inactivity, as well as their 16 combinations (patterns), which are stratified by age and gender. Methods: The data of 19,294 study participants, from a telephone survey among the adult general population of Germany that was conducted in 2012, were analyzed. Results: In adults, two or more of the four HBRs were found among 51.5% of females and 61.9% of males. The single most prevalent HRB pattern among all of the female (20.7, 19.6-21.8%) and male participants (18.2, 17.1-19.3%) was being overweight combined with a lack of physical activity, and its prevalence increased by 4% with each year of life. A multinomial regression analysis revealed that education was inversely associated with 11 of the 15 HRB patterns. The risk of having four, compared to zero, HRBs was 3.3 (2.5-4.4) for males relative to females. Conclusion: Similar to the findings from other western countries, the majority of the participants in this adult national sample from Germany had two or more HRBs. The most common of all possible HRB patterns was overweight and inactivity. The data confirm inverse relations between education and most HRB patterns. PMID- 29702593 TI - Polymeric Micelles of Biodegradable Diblock Copolymers: Enhanced Encapsulation of Hydrophobic Drugs. AB - Polymeric micelles are potentially efficient in encapsulating and performing the controlled release of various hydrophobic drug molecules. Understanding the fundamental physicochemical properties behind drug-polymer systems in terms of interaction strength and compatibility, drug partition coefficient (preferential solubilization), micelle size, morphology, etc., encourages the formulation of polymeric nanocarriers with enhanced drug encapsulating capacity, prolonged circulation time, and stability in the human body. In this review, we systematically address some open issues which are considered to be obstacles inhibiting the commercial availability of polymer-based therapeutics, such as the enhancement of encapsulation capacity by finding better drug-polymer compatibility, the drug-release kinetics and mechanisms under chemical and mechanical conditions simulating to physiological conditions, and the role of preparation methods and solvents on the overall performance of micelles. PMID- 29702595 TI - Optical Detection of Ketoprofen by Its Electropolymerization on an Indium Tin Oxide-Coated Optical Fiber Probe. AB - In this work an application of optical fiber sensors for real-time optical monitoring of electrochemical deposition of ketoprofen during its anodic oxidation is discussed. The sensors were fabricated by reactive magnetron sputtering of indium tin oxide (ITO) on a 2.5 cm-long core of polymer-clad silica fibers. ITO tuned in optical properties and thickness allows for achieving a lossy-mode resonance (LMR) phenomenon and it can be simultaneously applied as an electrode in an electrochemical setup. The ITO-LMR electrode allows for optical monitoring of changes occurring at the electrode during electrochemical processing. The studies have shown that the ITO-LMR sensor’s spectral response strongly depends on electrochemical modification of its surface by ketoprofen. The effect can be applied for real-time detection of ketoprofen. The obtained sensitivities reached over 1400 nm/M (nm·mg−1·L) and 16,400 a.u./M (a.u.·mg−1·L) for resonance wavelength and transmission shifts, respectively. The proposed method is a valuable alternative for the analysis of ketoprofen within the concentration range of 0.25-250 μg mL−1, and allows for its determination at therapeutic and toxic levels. The proposed novel sensing approach provides a promising strategy for both optical and electrochemical detection of electrochemical modifications of ITO or its surface by various compounds. PMID- 29702596 TI - Solution-Plasma-Mediated Synthesis of Si Nanoparticles for Anode Material of Lithium-Ion Batteries. AB - Silicon anodes have attracted considerable attention for their use in lithium-ion batteries because of their extremely high theoretical capacity; however, they are prone to extensive volume expansion during lithiation, which causes disintegration and poor cycling stability. In this article, we use two approaches to address this issue, by reducing the size of the Si particles to nanoscale and incorporating them into a carbon composite to help modulate the volume expansion problems. We improve our previous work on the solution-plasma-mediated synthesis of Si nanoparticles (NPs) by adjusting the electrolyte medium to mild buffer solutions rather than strong acids, successfully generating Si-NPs with <10 nm diameters. We then combined these Si-NPs with carbon using MgO-template-assisted sol-gel combustion synthesis, which afforded porous carbon composite materials. Among the preparations, the composite material obtained from the LiCl 0.2 M + H3BO3 0.15 M solution-based Si-NPs exhibited a high reversible capacity of 537 mAh/g after 30 discharge/charge cycles at a current rate of 0.5 A/g. We attribute this increased reversible capacity to the decreased particle size of the Si-NPs. These results clearly show the applicability of this facile and environmentally friendly solution-plasma technique for producing Si-NPs as an anode material for lithium-ion batteries. PMID- 29702597 TI - Corosolic Acid Induces Non-Apoptotic Cell Death through Generation of Lipid Reactive Oxygen Species Production in Human Renal Carcinoma Caki Cells. AB - Corosolic acid is one of the pentacyclic triterpenoids isolated from Lagerstroemia speciose and has been reported to exhibit anti-cancer and anti proliferative activities in various cancer cells. In the present study, we investigated the molecular mechanisms of corosolic acid in cancer cell death. Corosolic acid induces a decrease of cell viability and an increase of cell cytotoxicity in human renal carcinoma Caki cells. Corosolic acid-induced cell death is not inhibited by apoptosis inhibitor (z-VAD-fmk, a pan-caspase inhibitor), necroptosis inhibitor (necrostatin-1), or ferroptosis inhibitors (ferrostatin-1 and deferoxamine (DFO)). Furthermore, corosolic acid significantly induces reactive oxygen species (ROS) levels, but antioxidants (N-acetyl-l cysteine (NAC) and trolox) do not inhibit corosolic acid-induced cell death. Interestingly, corosolic acid induces lipid oxidation, and α-tocopherol markedly prevents corosolic acid-induced lipid peroxidation and cell death. Anti chemotherapeutic effects of α-tocopherol are dependent on inhibition of lipid oxidation rather than inhibition of ROS production. In addition, corosolic acid induces non-apoptotic cell death in other renal cancer (ACHN and A498), breast cancer (MDA-MB231), and hepatocellular carcinoma (SK-Hep1 and Huh7) cells, and α-tocopherol markedly inhibits corosolic acid-induced cell death. Therefore, our results suggest that corosolic acid induces non-apoptotic cell death in cancer cells through the increase of lipid peroxidation. PMID- 29702598 TI - Thermochromic Polymer Film Sensors for Detection of Incipient Thermal Damage in Carbon Fiber-Epoxy Composites. AB - Carbon fiber-epoxy composites have become prevalent in the aerospace industry where mechanical properties and light weight are at a premium. The significant non-destructive evaluation challenges of composites require new solutions, especially in detecting early-stage, or incipient, thermal damage. The initial stages of thermal damage are chemical rather than physical, and can cause significant reduction in mechanical properties well before physical damage becomes detectable in ultrasonic testing. Thermochromic fluorescent probe molecules have the potential to sense incipient thermal damage more accurately than traditional inspection methods. We have designed a molecule which transitions from a colorless, non-fluorescent state to a colorful, highly fluorescent state when exposed to temperature-time combinations that can cause damage in composites. Moreover, this molecule can be dispersed in a polymer film and attached to composite parts as a removable sensor. This work presents an evaluation of the sensor performance of this thermochromic film in comparison to ultrasonic C-scan as a method to detect incipient thermal damage in one of the most widely used carbon fiber-epoxy composite systems. Composite samples exposed to varying thermal exposures were used to evaluate the fluorescent thermal sensor films, and the results are compared to the results of ultrasonic imaging and short-beam shear tests for interlaminar shear strength. PMID- 29702600 TI - Long-Period Gratings in Highly Germanium-Doped, Single-Mode Optical Fibers for Sensing Applications. AB - Long-period fiber gratings (LPGs) are well known for their sensitivity to external influences, which make them interesting for a large number of sensing applications. For these applications, fibers with a high numerical aperture (i.e., fibers with highly germanium (Ge)-doped fused silica fiber cores) are more attractive since they are intrinsically photosensitive, as well as less sensitive to bend- and microbend-induced light attenuations. In this work, we introduce a novel method to inscribe LPGs into highly Ge-doped, single-mode fibers. By tapering the optical fiber, and thus, tailoring the effective indices of the core and cladding modes, for the first time, an LPG was inscribed into such fibers using the amplitude mask technique and a KrF excimer laser. Based on this novel method, sensitive LPG-based fiber optic sensors only a few millimeters in length can be incorporated in bend-insensitive fibers for use in various monitoring applications. Moreover, by applying the described inscription method, the LPG spectrum can be influenced and tailored according to the specific demands of a particular application. PMID- 29702601 TI - Trusted Operations on Sensor Data ?. AB - The widespread use of mobile devices has allowed the development of participatory sensing systems that capture various types of data using the existing or external sensors attached to mobile devices. Gathering data from such anonymous sources requires a mechanism to establish the integrity of sensor readings. In many cases, sensor data need to be preprocessed on the device itself before being uploaded to the target server while ensuring the chain of trust from capture to the delivery of the data. This can be achieved by a framework that provides a means to implement arbitrary operations to be performed on trusted sensor data, while guaranteeing the security and integrity of the data. This paper presents the design and implementation of a framework that allows the capture of trusted sensor data from both external and internal sensors on a mobile phone along with the development of trusted operations on sensor data while providing a mechanism for performing predefined operations on the data such that the chain of trust is maintained. The evaluation shows that the proposed system ensures the security and integrity of sensor data with minimal performance overhead. PMID- 29702599 TI - Noncoding RNA:RNA Regulatory Networks in Cancer. AB - Noncoding RNAs (ncRNAs) constitute the majority of the human transcribed genome. This largest class of RNA transcripts plays diverse roles in a multitude of cellular processes, and has been implicated in many pathological conditions, especially cancer. The different subclasses of ncRNAs include microRNAs, a class of short ncRNAs; and a variety of long ncRNAs (lncRNAs), such as lincRNAs, antisense RNAs, pseudogenes, and circular RNAs. Many studies have demonstrated the involvement of these ncRNAs in competitive regulatory interactions, known as competing endogenous RNA (ceRNA) networks, whereby lncRNAs can act as microRNA decoys to modulate gene expression. These interactions are often interconnected, thus aberrant expression of any network component could derail the complex regulatory circuitry, culminating in cancer development and progression. Recent integrative analyses have provided evidence that new computational platforms and experimental approaches can be harnessed together to distinguish key ceRNA interactions in specific cancers, which could facilitate the identification of robust biomarkers and therapeutic targets, and hence, more effective cancer therapies and better patient outcome and survival. PMID- 29702602 TI - Bioactive Bromotyrosine-Derived Alkaloids from the Polynesian Sponge Suberea ianthelliformis. AB - Herein, we describe the isolation and spectroscopic identification of eight new tetrabrominated tyrosine alkaloids 2-9 from the Polynesian sponge Suberea ianthelliformis, along with known major compound psammaplysene D (1), N,N dimethyldibromotyramine, 5-hydroxy xanthenuric acid, and xanthenuric acid. Cytotoxicity and acetylcholinesterase inhibition activities were evaluated for some of the isolated metabolites. They exhibited moderate antiproliferative activity against KB cancer cell lines, but psammaplysene D (1) displayed substantial cytotoxicity as well as acetylcholinesterase inhibition with IC50 values of 0.7 μM and 1.3 μM, respectively. PMID- 29702604 TI - Spectroscopic-Chemical Fingerprint and Biostimulant Activity of a Protein-Based Product in Solid Form. AB - A solid biostimulant (AA309) obtained through thermobaric hydrolysis applied on trimmings and shavings of bovine hides tanned with wet-blue technology was chemically characterized, and its effects in maize (Zea mays L.) were evaluated. AA309 contained 13.60% total nitrogen (N), mainly in organic forms (13.40%), and several amino acids, especially lysine, phenylalanine, glycine, aspartate, and isoleucine. AA309 was further analyzed using Fourier Transform Infrared (FT-IR) spectroscopy, which revealed the presence of amide I and amide II bands, indicative of peptide structures. When supplied to maize plants for 15 days at two N dosages (2.1 or 4.2 mg/kg), AA309 induced positive physiological responses, likely because of its content in amino acids functioning as signaling molecules. The low dosage was the most effective in improving leaf (+24%) and root (+98%) dry weight, photosynthetic activity (+70%), and accumulation of N (+80%), proteins (+65-75%) and antioxidants (+60%). Spectroscopic analyses (Solid-state Cross-Polarization Magic Angle Spinning Carbon-13 Nuclear Magnetic Resonance, CP/MAS 13C-NMR, and High resolution-magic angle spinning nuclear magnetic resonance, HR-MAS NMR) on plant tissues revealed the increase in proteins, lignin structures and cutin in AA309-treated plants compared to untreated plants. Our results indicate that AA309 could be used as a valuable biostimulant in agriculture. PMID- 29702605 TI - Advanced Glycation Endproducts Are Increased in the Animal Model of Multiple Sclerosis but Cannot Be Reduced by Pyridoxamine Treatment or Glyoxalase 1 Overexpression. AB - Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS). The immune response in MS patients leads to the infiltration of immune cells in the CNS and their subsequent activation. Immune cell activation induces a switch towards glycolysis. During glycolysis, the dicarbonyl product methylglyoxal (MGO) is produced. MGO is a glycating agent that can rapidly form advanced glycation endproducts (AGEs). In turn, AGEs are able to induce inflammatory responses. The glyoxalase system is the endogenous defense system of the body to reduce the burden of MGO thereby reducing AGE formation. This system consists of glyoxalase-1 and glyoxalase-2 which are able to detoxify MGO to D-lactate. We investigated whether AGE levels are induced in experimental autoimmune encephalitis (EAE), an inflammatory animal model of MS. Twenty seven days post EAE induction, MGO and AGE (Nε-(carboxymethyl)lysine (CML), Nε-(carboxyethyl)lysine (CEL), 5-hydro-5-methylimidazolone (MG-H1)) levels were significantly increased in the spinal cord of mice subjected to EAE. Yet, pyridoxamine treatment and glyoxalase-1 overexpression were unable to counteract AGE production during EAE and did not influence the clinical course of EAE. In conclusion, AGEs levels increase during EAE in the spinal cord, but AGE modifying treatments do not inhibit EAE-induced AGE production and do not affect disease progression. PMID- 29702603 TI - Italian Association of Clinical Endocrinologists (AME) and Italian Chapter of the American Association of Clinical Endocrinologists (AACE) Position Statement: Clinical Management of Vitamin D Deficiency in Adults. AB - Vitamin D deficiency is very common and prescriptions of both assay and supplementation are increasing more and more. Health expenditure is exponentially increasing, thus it is timely and appropriate to establish rules. The Italian Association of Clinical Endocrinologists appointed a task force to review literature about vitamin D deficiency in adults. Four topics were identified as worthy for the practicing clinicians. For each topic recommendations based on scientific evidence and clinical practice were issued according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) System. (1) What cut-off defines vitamin D deficiency: even though 20 ng/mL (50 nmol/L) can be considered appropriate in the general population, we recommend to maintain levels above 30 ng/mL (75 nmol/L) in categories at risk. (2) Whom, when, and how to perform screening for vitamin D deficiency: categories at risk (patients with bone, liver, kidney diseases, obesity, malabsorption, during pregnancy and lactation, some elderly) but not healthy people should be screened by the 25 hydroxy-vitamin D assay. (3) Whom and how to treat vitamin D deficiency: beyond healthy lifestyle (mostly sun exposure), we recommend oral vitamin D (vitamin D2 or vitamin D3) supplementation in patients treated with bone active drugs and in those with demonstrated deficiency. Dosages, molecules and modalities of administration can be profitably individually tailored. (4) How to monitor the efficacy of treatment with vitamin D: no routine monitoring is suggested during vitamin D treatment due to its large therapeutic index. In particular conditions, 25-hydroxy-vitamin D can be assayed after at least a 6-month treatment. We are confident that this document will help practicing clinicians in their daily clinical practice. PMID- 29702607 TI - Residential Consumer-Centric Demand-Side Management Based on Energy Disaggregation-Piloting Constrained Swarm Intelligence: Towards Edge Computing. AB - The emergence of smart Internet of Things (IoT) devices has highly favored the realization of smart homes in a down-stream sector of a smart grid. The underlying objective of Demand Response (DR) schemes is to actively engage customers to modify their energy consumption on domestic appliances in response to pricing signals. Domestic appliance scheduling is widely accepted as an effective mechanism to manage domestic energy consumption intelligently. Besides, to residential customers for DR implementation, maintaining a balance between energy consumption cost and users’ comfort satisfaction is a challenge. Hence, in this paper, a constrained Particle Swarm Optimization (PSO)-based residential consumer-centric load-scheduling method is proposed. The method can be further featured with edge computing. In contrast with cloud computing, edge computing—a method of optimizing cloud computing technologies by driving computing capabilities at the IoT edge of the Internet as one of the emerging trends in engineering technology—addresses bandwidth-intensive contents and latency-sensitive applications required among sensors and central data centers through data analytics at or near the source of data. A non-intrusive load monitoring technique proposed previously is utilized to automatic determination of physical characteristics of power-intensive home appliances from users’ life patterns. The swarm intelligence, constrained PSO, is used to minimize the energy consumption cost while considering users’ comfort satisfaction for DR implementation. The residential consumer-centric load-scheduling method proposed in this paper is evaluated under real-time pricing with inclining block rates and is demonstrated in a case study. The experimentation reported in this paper shows the proposed residential consumer-centric load-scheduling method can re-shape loads by home appliances in response to DR signals. Moreover, a phenomenal reduction in peak power consumption is achieved by 13.97%. PMID- 29702606 TI - Safety and Feasibility of Lin- Cells Administration to ALS Patients: A Novel View on Humoral Factors and miRNA Profiles. AB - Therapeutic options for amyotrophic lateral sclerosis (ALS) are still limited. Great hopes, however, are placed in growth factors that show neuroprotective abilities (e.g., nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF)) and in the immune modulating features, in particular, the anti-inflammatory effects. In our study we aimed to investigate whether a bone marrow-derived lineage-negative (Lin-) cells population, after autologous application into cerebrospinal fluid (CSF), is able to produce noticeable concentrations of trophic factors and inflammatory related proteins and thus influence the clinical course of ALS. To our knowledge, the evaluation of Lin- cells transplantation for ALS treatment has not been previously reported. Early hematopoietic Lin- cells were isolated from twelve ALS patients’ bone marrow, and later, the suspension of cells was administered into the subarachnoid space by lumbar puncture. Concentrations of selected proteins in the CSF and plasma were quantified by multiplex fluorescent bead based immunoassays at different timepoints post-transplantation. We also chose microRNAs (miRNAs) related to muscle biology (miRNA-1, miRNA-133a, and miRNA-206) and angiogenesis and inflammation (miRNA-155 and miRNA-378) and tested, for the first time, their expression profiles in the CSF and plasma of ALS patients after Lin- cells transplantation. The injection of bone marrow cells resulted in decreased concentration of selected inflammatory proteins (C3) after Lin- cells injection, particularly in patients who had a better clinical outcome. Moreover, several analyzed miRNAs have changed expression levels in the CSF and plasma of ALS patients subsequent to Lin- cells administration. Interestingly, the expression of miR-206 increased in ALS patients, while miR-378 decreased both in the CSF and plasma one month after the cells’ injection. We propose that autologous lineage-negative early hematopoietic cells injected intrathecally may be a safe and feasible source of material for transplantations to the central nervous system (CNS) environment aimed at anti-inflammatory support provision for ALS adjuvant treatment strategies. Further research is needed to evaluate whether the observed effects could significantly influence the ALS progression. PMID- 29702608 TI - Liver Injury by Carbon Tetrachloride Intoxication in 16 Patients Treated with Forced Ventilation to Accelerate Toxin Removal via the Lungs: A Clinical Report. AB - Carbon tetrachloride (CCl4) is an efficient but highly toxic solvent, used in households and commercially in the industry under regulatory surveillance to ensure safety at the working place and to protect the workers’ health. However, acute unintentional or intentional intoxications by CCl4 may rarely occur and are potentially life-threatening. In this review article, therapy options are discussed that are based on a literature review of traditional poisoning cases and the clinical experience with 16 patients with acute poisoning by CCl4. Among various therapy options, the CO2-induced hyperventilation therapy will be considered in detail as the most promising approach. This special therapy was developed because only around 1% of the intoxicating CCl4 is responsible for the liver injury after conversion to toxic radicals via microsomal cytochrome P450 2E1 whereas 99% of the solvent will leave the body unchanged by exhalation. Therefore, to enhance CCl4 elimination through the lungs, CO2 is added to the inspiration air at a flow rate of 2-3 L min−1 in order to achieve hyperventilation with a respiratory volume of 25-30 L min−1. Under this therapy, the clinical course was favorable in 15/16 patients, corresponding to 93.8%. In essence, patients with acute CCl4 intoxication should be treated by forced ventilation. PMID- 29702609 TI - Reactive Sintering Mechanism and Phase Formation in Ni-Ti-Al Powder Mixture During Heating. AB - This work aims to describe the formation of intermetallics in the Ni-Ti-Al system in dependence on the heating rate, which has been determined previously as the crucial factor of thermal explosion self-propagating synthesis (TE-SHS). The tested alloys contained 1-7 wt % aluminum. Thermal analysis has been realized by the optical pyrometer under the conditions of high heating rates up to 110 °C·min−1. TE-SHS process in Ni-Ti-Al system is initiated by exothermic reaction of nickel aluminides Ni2Al3 and NiAl3 at the temperature of 535-610 °C. The next reactions occur in dependence on the heating rate. Samples containing 1-3 wt % of aluminum exhibit the similar initiation temperature as Ni-Ti binary mixture. The samples containing 5 wt % and more of aluminum were fully reacted after sintering at 800 °C with the heating rate of 300 °C·min−1 and the initiation temperature of the TE-SHS was observed close to Al-Al3Ni eutectic temperature (between 630-640 °C). PMID- 29702610 TI - Study on Flake Formation Behavior and Its Influence Factors in Cr5 Steel. AB - A flake is a crack that is induced by trapped hydrogen within steel. To study its formation mechanism, previous studies mostly focused on the formation process and magnitude of hydrogen pressure in hydrogen traps such as cavities and cracks. However, according to recent studies, the hydrogen leads to the decline of the mechanical properties of steel, which is known as hydrogen embrittlement, is another reason for flake formation. In addition, the phenomenon of stress induced hydrogen uphill diffusion should not be neglected. All of the three behaviors are at work simultaneously. In order to further explore the formation mechanism of flakes in steel, the process of flake initiation and growth were studied with the following three coupling factors: trap hydrogen pressure, hydrogen embrittlement, and stress induced hydrogen re-distribution. The analysis model was established using the finite element method, and a crack whose radius is 0.5 mm was set in its center. The cohesive method and Bilinear Traction Separate Law (BTSL) were used to address the coupling effect. The results show that trap hydrogen pressure is the main driving force for flake formation. After the high hydrogen pressure was generated around the trap, a stress field formed. In addition, the trap is the center of stress concentration. Then, hydrogen is concentrated in a distribution around this trap, and most of the steel mechanical properties are reduced. The trap size is a key factor for defining the critical hydrogen content for flake formation and propagation. However, when the trap size exceeds the specified value, the critical hydrogen content does not change any more. As for the crack whose radius is 0.5 mm, the critical hydrogen content of Cr5VMo steel is 2.2 ppm, which is much closer to the maximum safe hydrogen concentration of 2.0 ppm used in China. The work presented in this article increases our understanding of flake formation and propagation mechanisms in steel. PMID- 29702611 TI - A Prospective Study on the Influence of Scholastic Factors on the Prevalence and Initiation of Illicit Drug Misuse in Adolescence. AB - BACKGROUND: This study aimed to prospectively investigate the scholastic factors related to illicit drug misuse (IDM) and the initiation of IDM among older adolescents from Bosnia and Herzegovina. METHODS: This 2-year prospective study included 436 participants (202 females), who were an average of 16 years old at the beginning of the study (baseline). The participants were tested at baseline and follow-up (20 months later). The predictors included variables of scholastic achievement (grade point average, school absences, unexcused absences and behavioral grade). The criteria were: (i) IDM at baseline; (ii) IDM at follow-up; and (iii) initiation of IDM over the study course. Results: Logistic regression indicated increased odds of IDM in adolescents who were more frequent absent from school (baseline: Odds Ratio (OR): 3.73, 95% Confidence Interval (CI): 2.12-6.57; follow-up: OR: 2.91, 95% CI: 1.90-4.65). The lower grade point average and more unexcused absences were evidenced for adolescents who consumed drugs on follow-up (OR: 1.67, 95% CI: 1.11-2.51; OR: 1.74, 95% CI: 1.30-2.32 for grade point average and unexcused absences, respectively). Initiation of IDM was predicted by frequent absences from school (OR: 2.2, 95% CI: 1.3-3.8), and lower behavioral grades (OR: 1.9, 95% CI: 1.2-3.3). CONCLUSIONS: The findings confirmed strong correlations between scholastic failure and IDM. Absences from school and lower behavioral grades at baseline were predictive of the initiation of IDM in older adolescents. PMID- 29702612 TI - How Well Do COP22 Attendees Understand Graphs on Climate Change Health Impacts from the Fifth IPCC Assessment Report? AB - Graphs are prevalent in the reports of the Intergovernmental Panel on Climate Change (IPCC), often depicting key points and major results. However, the popularity of graphs in the IPCC reports contrasts with a neglect of empirical tests of their understandability. Here we put the understandability of three graphs taken from the Health chapter of the Fifth Assessment Report to an empirical test. We present a pilot study where we evaluate objective understanding (mean accuracy in multiple-choice questions) and subjective understanding (self-assessed confidence in accuracy) in a sample of attendees of the United Nations Climate Change Conference in Marrakesh, 2016 (COP22), and a student sample. Results show a mean objective understanding of M = 0.33 for the COP sample, and M = 0.38 for the student sample. Subjective and objective understanding were unrelated for the COP22 sample, but associated for the student sample. These results suggest that (i) understandability of the IPCC health chapter graphs is insufficient, and that (ii) particularly COP22 attendees lacked insight into which graphs they did, and which they did not understand. Implications for the construction of graphs to communicate health impacts of climate change to decision-makers are discussed. PMID- 29702613 TI - Reactive Chemicals and Electrophilic Stress in Cancer: A Minireview. AB - Exogenous reactive chemicals can impair cellular homeostasis and are often associated with the development of cancer. Significant progress has been achieved by studying the macromolecular interactions of chemicals that possess various electron-withdrawing groups and the elucidation of the protective responses of cells to chemical interventions. However, the formation of electrophilic species inside the cell and the relationship between oxydative and electrophilic stress remain largely unclear. Derivatives of nitro-benzoxadiazole (also referred as nitro-benzofurazan) are potent producers of hydrogen peroxide and have been used as a model to study the generation of reactive species in cancer cells. This survey highlights the pivotal role of Cu/Zn superoxide dismutase 1 (SOD1) in the production of reactive oxygen and electrophilic species in cells exposed to cell permeable chemicals. Lipophilic electrophiles rapidly bind to SOD1 and induce stable and functionally active dimers, which produce excess hydrogen peroxide leading to aberrant cell signalling. Moreover, reactive oxygen species and reactive electrophilic species, simultaneously generated by redox reactions, behave as independent entities that attack a variety of proteins. It is postulated that the binding of the electrophilic moiety to multiple proteins leading to impairing different cellular functions may explain unpredictable side effects in patients undergoing chemotherapy with reactive oxygen species (ROS) inducing drugs. The identification of proteins susceptible to electrophiles at early steps of oxidative and electrophilic stress is a promising way to offer rational strategies for dealing with stress-related malignant tumors. PMID- 29702614 TI - Method for Compensating Signal Attenuation Using Stepped-Frequency Ground Penetrating Radar. AB - Ground penetrating radar (GPR) is a subsurface remote sensor that allows the user to detect, classify, and identify the buried target and structures. The radar signals are rapidly attenuated as they propagate into the ground; therefore, attenuation compensation is necessary for the visualization of the buried targets from GPR data. In this work, we developed a novel attenuation compensation approach based on the recently developed stepped-frequency continuous wave (SFCW) GPR system, which is a frequency domain sampling system with improved performance in dynamic range, sensitivity, and anti-interference ability. Because the regularly used time-varying gain function for compensating the attenuation of impulse GPR data does not make full use of the advancement of the SFCW modulation, an alternative procedure is proposed herein. The new approach is based the SFCW mechanism, and aims at improving the visualization of deeper targets by compensating the SFCW GPR signal attenuation. We first present the attenuation mode of the SFCW GPR echo, from which an inverse attenuation function is derived to compensate the amplitude loss. For the field measurement where the theoretical inverse attenuation function is difficult to achieve, we introduced a pseudo time-frequency distribution for estimating the inverse attenuation function. A procedure for amplitude attenuation has also been developed. Testing with both synthetic and experimental data return a good reconstruction of the signal amplitude, subsequently improving the ability for visualizing and detecting deeper targets. PMID- 29702615 TI - Incorporation of Synthetic mRNA in Injectable Chitosan-Alginate Hybrid Hydrogels for Local and Sustained Expression of Exogenous Proteins in Cells. AB - The application of synthetic messenger RNA (mRNA) exhibits various advantages, such as expression of desired proteins in cells without genomic integration. In the field of tissue engineering, synthetic mRNAs could be also used to modulate the protein expression in implanted cells. Therefore, in this study, we incorporated synthetic humanized Gaussia luciferase (hGLuc) mRNA into alginate, chitosan, or chitosan-alginate hybrid hydrogels and analyzed the release of hGLuc mRNA from these hydrogels. After 3 weeks, 79% of the incorporated mRNA was released from alginate hydrogels, approximately 42% was released from chitosan hydrogels, and about 70% was released from chitosan-alginate hydrogels. Due to the injectability, chitosan-alginate hybrid hydrogels were selected for further investigation of the bioactivity of embedded hGLuc mRNA and the stability of these hydrogels was examined after the incorporation of synthetic mRNA by rheometric analysis. Therefore, HEK293 cells were incorporated into chitosan alginate hydrogels containing mRNA transfection complexes and the luciferase activity in the supernatants was detected for up to 3 weeks. These results showed that the biodegradable chitosan-alginate hybrid hydrogels are promising delivery systems for sustained delivery of synthetic mRNAs into cells. Since chitosan alginate hybrid hydrogels are injectable, the hydrogels can be simultaneously loaded with cells and the desired synthetic mRNA for exogenous protein synthesis and can be administered by minimally invasive local injection for tissue engineering applications. PMID- 29702616 TI - Development and Validation of a Questionnaire on Breastfeeding Intentions, Attitudes and Knowledge of a Sample of Croatian Secondary-School Students. AB - BACKGROUND: Validating a questionnaire/instrument before proceeding to the field for data collection is important. METHODS: An 18-item breastfeeding intention, 39 item attitude and 44-item knowledge questionnaire was validated in a Croatian sample of secondary-school students (N = 277). RESULTS: For the intentions, principal component analysis (PCA) yielded a four-factor solution with 8 items explaining 68.3% of the total variance. Cronbach’s alpha (0.71) indicated satisfactory internal consistency. For the attitudes, PCA showed a seven-factor structure with 33 items explaining 58.41% of total variance. Cronbach’s alpha (0.87) indicated good internal consistency. There were 13 knowledge questions that were retained after item analysis, showing good internal consistency (KR20 = 0.83). In terms of criterion validity, the questionnaire differentiated between students who received breastfeeding education compared to students who were not educated in breastfeeding. Correlations between intentions and attitudes (r = 0.49), intentions and knowledge (r = 0.29), and attitudes and knowledge (r = 0.38) confirmed concurrent validity. CONCLUSIONS: The final instrument is reliable and valid for data collection on breastfeeding. Therefore, the instrument is recommended for evaluation of breastfeeding education programs aimed at upper-grade elementary and secondary school students. PMID- 29702617 TI - Economic Analysis of the Reduction of Blood Transfusions during Surgical Procedures While Continuous Hemoglobin Monitoring Is Used. AB - BACKGROUND: Two million transfusions are performed in Spain every year. These come at a high economic price for the health system, increasing the morbidity and mortality rates. The way of obtaining the hemoglobin concentration value is via invasive and intermittent methods, the results of which take time to obtain. The drawbacks of this method mean that some transfusions are unnecessary. New continuous noninvasive hemoglobin measurement technology can save unnecessary transfusions. METHODS: A prospective study was carried out with a historical control of two homogeneous groups. The control group used the traditional hemoglobin measurement methodology. The experimental group used the new continuous hemoglobin measurement technology. The difference was analyzed by comparing the transfused units of the groups. The economic savings was calculated by multiplying the cost of a transfusion by the difference in units, taking into account measurement costs. RESULTS: The percentage of patients needing a transfusion decreased by 7.4%, and the number of transfused units per patient by 12.56%. Economic savings per patient were ?20.59. At the national level, savings were estimated to be 13,500 transfusions (?1.736 million). CONCLUSIONS: Constant monitoring of the hemoglobin level significantly reduces the need for blood transfusions. By using this new measurement technology, health care facilities can significantly reduce costs and improve care quality. PMID- 29702618 TI - Glucose Gel as a Potential Alternative Treatment to Infant Formula for Neonatal Hypoglycaemia in Australia. AB - Infant formula is often used as a treatment for neonatal hypoglycaemia in Australia; however, there are concerns that this may jeopardise mother-baby bonding and breastfeeding. Successful use of glucose gel as an alternative treatment for hypoglycaemia has been reported. We wanted to investigate in a pilot study whether the use of glucose gel has the potential to quickly and safely restore normoglycaemia in the infants of diabetic mothers in an Australian setting. Infants with asymptomatic hypoglycaemia were treated with glucose gel (n = 36) and compared to a historical group of infants which had been treated with infant formula (n = 24). Within 15 min of the first treatment, the gel group had a mean blood glucose level (BGL) of 2.6 mmol/L, and 2.7 mmol/L 30 min after the second treatment. This was lower than the BGL after the first treatment for the formula group, which rose to a mean of 2.8 then to 3.2 mmol/L after the second treatment (p = 0.003). In successfully treated infants, administration of the gel resulted in normoglycaemia within 30 min. The likelihood of special care nursery admission was not significantly different between the groups, although we had a small sample size, and our findings should be interpreted with caution. These pilot results provide support for further investigations into the use of glucose gel as an alternative treatment to infant formula. PMID- 29702619 TI - Dust at Various Workplaces-Microbiological and Toxicological Threats. AB - The aim of the present study was to evaluate the relation between the chemical (analysis of elements and pH) and microbiological composition (culture and metagenomics analysis) of the dust at various workplaces (cement plant, composting plant, poultry farm, and cultivated area) and the cytotoxicity effect on the human adenocarcinoma lung epithelial adherent cell line A-549 (MTT assay test). Analysis of the Particulate Matter (PM) fraction showed that the dust concentration in cultivated areas exceeded the OELs. For the remaining workplaces examined, the dust concentration was lower than OELs limits. The number of microorganisms in the dust samples was 3.8 * 102-1.6 * 108 CFU/g bacteria and 1.5 * 102-6.5 * 106 CFU/g fungi. The highest number of microorganisms was noted for dust from cultivated areas (total number of bacteria, actinomycetes, P. fluorescens) and composting plants (xerophilic fungi and staphylococci), while the least number of microorganisms was observed for dust from cement plants. Many types of potentially pathogenic microorganisms have been identified, including bacteria, such as Bacillus, Actinomyces, Corynebacterium, Prevotella, Clostridium, and Rickettsia, and fungi, such as Alternaria, Cladosporium, Penicillium, and Aspergillus. The most cytotoxic to the human lung cell line A 549 was dust from cultivated areas (IC50 = 3.8 mg/mL after 72 h). The cytotoxicity of the tested dust samples depends on the PM concentration, the number of microorganisms, including potentially pathogenic genera, and the exposure time. PMID- 29702620 TI - C60 Bioconjugation with Proteins: Towards a Palette of Carriers for All pH Ranges. AB - The high hydrophobicity of fullerenes and the resulting formation of aggregates in aqueous solutions hamper the possibility of their exploitation in many technological applications. Noncovalent bioconjugation of fullerenes with proteins is an emerging approach for their dispersion in aqueous media. Contrary to covalent functionalization, bioconjugation preserves the physicochemical properties of the carbon nanostructure. The unique photophysical and photochemical properties of fullerenes are then fully accessible for applications in nanomedicine, sensoristic, biocatalysis and materials science fields. However, proteins are not universal carriers. Their stability depends on the biological conditions for which they have evolved. Here we present two model systems based on pepsin and trypsin. These proteins have opposite net charge at physiological pH. They recognize and disperse C60 in water. UV-Vis spectroscopy, zeta-potential and atomic force microscopy analysis demonstrates that the hybrids are well dispersed and stable in a wide range of pH’s and ionic strengths. A previously validated modelling approach identifies the protein-binding pocket involved in the interaction with C60. Computational predictions, combined with experimental investigations, provide powerful tools to design tailor-made C60@proteins bioconjugates for specific applications. PMID- 29702621 TI - A Review on Bacteriorhodopsin-Based Bioelectronic Devices. AB - Bacteriorhodopsin protein extracted from Halobacterium salinarum is widely used in many biohybrid electronic devices and forms a research subject known as bioelectronics, which merges biology with electronic technique. The specific molecule structure and components of bR lead to its unique photocycle characteristic, which consists of several intermediates (bR, K, L, M, N, and O) and results in proton pump function. In this review, working principles and properties of bacteriorhodopsin are briefly introduced, as well as bR layer preparation method. After that, different bR-based devices divided into photochemical and photoelectric applications are shown. Finally, outlook and conclusions are drawn to inspire new design of high-performance bR-based biohybrid electronic devices. PMID- 29702622 TI - Anthocidins A-D, New 5-Hydroxyanthranilic Acid Related Metabolites from the Sea Urchin-Associated Actinobacterium, Streptomyces sp. HDa1. AB - Four new 5-hydroxyanthranilic acid related compounds, named anthocidins A-D (1 4), two known analogues n-lauryl 5-hydroxyanthranilate (5) and isolauryl 5 hydroxyanthranilate (6), together with benzamide (7), 3-hydroxy-4 methoxycinnamamide (8), and (3S-cis)-hexahydro-3-[(3,4 dihydroxyphenyl)methyl]pyrrolo[1,2-a]pyrazine-1,4-dione (9), were isolated from the fermentation broth of the marine-derived actinomycete, Streptomyces sp. HDa1, which was isolated from the gut of a sea urchin, Anthocidaris crassispina, collected from Hainan Island, China. The structures of these secondary metabolites were elucidated on the basis of their 1D and 2D-NMR and mass spectroscopic data, and anthocidin A was confirmed by single-crystal X-ray diffraction with Cu Kalpha radiation. Anthocidins A-D (1-4) feature an acetyl group substitution at the amino group and varying alkyl side chains at the carboxyl group of 5-hydroxyanthranilic acid, and compound 5 was isolated as a natural product for the first time. The cytotoxic and antibacterial activity of compounds 1-9 were evaluated. PMID- 29702623 TI - Identification of Peptides in Flowers of Sambucus nigra with Antimicrobial Activity against Aquaculture Pathogens. AB - The elder (Sambucus spp.) tree has a number of uses in traditional medicine. Previous studies have demonstrated the antimicrobial properties of elderberry liquid extract against human pathogenic bacteria and also influenza viruses. These properties have been mainly attributed to phenolic compounds. However, other plant defense molecules, such as antimicrobial peptides (AMPs), may be present. Here, we studied peptide extracts from flowers of Sambucus nigra L. The mass spectrometry analyses determined peptides of 3 to 3.6 kDa, among them, cysteine-rich peptides were identified with antimicrobial activity against various Gram-negative bacteria, including recurrent pathogens of Chilean aquaculture. In addition, membrane blebbing on the bacterial surface after exposure to the cyclotide was visualized by SEM microscopy and SYTOX Green permeabilization assay showed the ability to disrupt the bacterial membrane. We postulate that these peptides exert their action by destroying the bacterial membrane. PMID- 29702625 TI - Overexpression of a Novel Apple NAC Transcription Factor Gene, MdNAC1, Confers the Dwarf Phenotype in Transgenic Apple (Malus domestica). AB - Plant height is an important trait for fruit trees. The dwarf characteristic is commonly associated with highly efficient fruit production, a major objective when breeding for apple (Malus domestica). We studied the function of MdNAC1, a novel NAC transcription factor (TF) gene in apple related to plant dwarfing. Localized primarily to the nucleus, MdNAC1 has transcriptional activity in yeast cells. Overexpression of the gene results in a dwarf phenotype in transgenic apple plants. Their reduction in size is manifested by shorter, thinner stems and roots, and a smaller leaf area. The transgenics also have shorter internodes and fewer cells in the stems. Levels of endogenous abscisic acid (ABA) and brassinosteroid (BR) are lower in the transgenic plants, and expression is decreased for genes involved in the biosynthesis of those phytohormones. All of these findings demonstrate that MdNAC1 has a role in plants dwarfism, probably by regulating ABA and BR production. PMID- 29702626 TI - Adaptive ISAR Imaging of Maneuvering Targets Based on a Modified Fourier Transform. AB - Focusing on the inverse synthetic aperture radar (ISAR) imaging of maneuvering targets, this paper presents a new imaging method which works well when the target's maneuvering is not too severe. After translational motion compensation, we describe the equivalent rotation of maneuvering targets by two variables-the relative chirp rate of the linear frequency modulated (LFM) signal and the Doppler focus shift. The first variable indicates the target's motion status, and the second one represents the possible residual error of the translational motion compensation. With them, a modified Fourier transform matrix is constructed and then used for cross-range compression. Consequently, the imaging of maneuvering is converted into a two-dimensional parameter optimization problem in which a stable and clear ISAR image is guaranteed. A gradient descent optimization scheme is employed to obtain the accurate relative chirp rate and Doppler focus shift. Moreover, we designed an efficient and robust initialization process for the gradient descent method, thus, the well-focused ISAR images of maneuvering targets can be achieved adaptively. Human intervention is not needed, and it is quite convenient for practical ISAR imaging systems. Compared to precedent imaging methods, the new method achieves better imaging quality under reasonable computational cost. Simulation results are provided to validate the effectiveness and advantages of the proposed method. PMID- 29702624 TI - Glutathione: Antioxidant Properties Dedicated to Nanotechnologies. AB - Which scientist has never heard of glutathione (GSH)? This well-known low molecular-weight tripeptide is perhaps the most famous natural antioxidant. However, the interest in GSH should not be restricted to its redox properties. This multidisciplinary review aims to bring out some lesser-known aspects of GSH, for example, as an emerging tool in nanotechnologies to achieve targeted drug delivery. After recalling the biochemistry of GSH, including its metabolism pathways and redox properties, its involvement in cellular redox homeostasis and signaling is described. Analytical methods for the dosage and localization of GSH or glutathiolated proteins are also covered. Finally, the various therapeutic strategies to replenish GSH stocks are discussed, in parallel with its use as an addressing molecule in drug delivery. PMID- 29702627 TI - Displacements Study of an Earth Fill Dam Based on High Precision Geodetic Monitoring and Numerical Modeling. AB - The aim of this paper is to study the behavior of an earth fill dam, analyzing the deformations determined by high precision geodetic techniques and those obtained by the Finite Element Method (FEM). A large number of control points were established around the area of the dam, and the measurements of their displacements took place during several periods. In this study, high-precision leveling and GNSS (Global Navigation Satellite System) techniques were used to monitor vertical and horizontal displacements respectively. Seven surveys were carried out: February and July 2008, March and July 2013, August 2014, September 2015 and September 2016. Deformations were predicted, taking into account the general characteristics of an earth fill dam. A comparative evaluation of the results derived from predicted (FEM) and observed deformations shows the differences on average being 20 cm for vertical displacements, and 6 cm for horizontal displacements at the crest. These differences are probably due to the simplifications assumed during the FEM modeling process: critical sections are considered homogeneous along their longitude, and the properties of the materials were established according to the general characteristics of an earth fill dam. These characteristics were taken from the normative and similar studies in the country. This could also be due to the geodetic control points being anchored in the superficial layer of the slope when the construction of the dam was finished. PMID- 29702629 TI - Unsupervised Learning for Monaural Source Separation Using Maximization Minimization Algorithm with Time-Frequency Deconvolution. AB - This paper presents an unsupervised learning algorithm for sparse nonnegative matrix factor time-frequency deconvolution with optimized fractional beta divergence. The beta-divergence is a group of cost functions parametrized by a single parameter beta. The Itakura-Saito divergence, Kullback-Leibler divergence and Least Square distance are special cases that correspond to beta=0, 1, 2, respectively. This paper presents a generalized algorithm that uses a flexible range of beta that includes fractional values. It describes a maximization minimization (MM) algorithm leading to the development of a fast convergence multiplicative update algorithm with guaranteed convergence. The proposed model operates in the time-frequency domain and decomposes an information-bearing matrix into two-dimensional deconvolution of factor matrices that represent the spectral dictionary and temporal codes. The deconvolution process has been optimized to yield sparse temporal codes through maximizing the likelihood of the observations. The paper also presents a method to estimate the fractional beta value. The method is demonstrated on separating audio mixtures recorded from a single channel. The paper shows that the extraction of the spectral dictionary and temporal codes is significantly more efficient by using the proposed algorithm and subsequently leads to better source separation performance. Experimental tests and comparisons with other factorization methods have been conducted to verify its efficacy. PMID- 29702628 TI - Synthesis, Stability and Relaxivity of TEEPO-Met: An Organic Radical as a Potential Tumour Targeting Contrast Agent for Magnetic Resonance Imaging. AB - Cancer is a widespread and life-threatening disease and its early-stage diagnosis is vital. One of the most effective, non-invasive tools in medical diagnostics is magnetic resonance imaging (MRI) with the aid of contrast agents. Contrast agents that are currently in clinical use contain metals, causing some restrictions in their use. Also, these contrast agents are mainly non-specific without any tissue targeting capabilities. Subsequently, the interest has notably increased in the research of organic, metal-free contrast agents. This study presents a new, stable organic radical, TEEPO-Met, where a radical moiety 2,2,6,6 tetraethylpiperidinoxide (TEEPO) is attached to an amino acid, methionine (Met), as a potentially tumour-targeting moiety. We describe the synthesis, stability assessment with electron paramagnetic resonance (EPR) spectroscopy and relaxation enhancement abilities by an in vitro nuclear magnetic resonance (NMR) and phantom MRI studies of TEEPO-Met. The new compound proved to be stable notably longer than the average imaging time in conditions mimicking a biological matrix. Also, it significantly reduced the relaxation times of water, making it a promising candidate as a novel tumour targeting contrast agent for MRI. PMID- 29702630 TI - Game-Based Virtual Reality Canoe Paddling Training to Improve Postural Balance and Upper Extremity Function: A Preliminary Randomized Controlled Study of 30 Patients with Subacute Stroke. AB - BACKGROUND Virtual reality (VR) training with motion-controlled console games can be incorporated into stroke rehabilitation programs. The use of a variety of gaming software can provide the patient with an opportunity to perform activities that are exciting, entertaining, and that may not be feasible in clinical environments. The aim of this preliminary randomized controlled study was to investigate the effects of game-based VR canoe paddling training, when combined with conventional physical rehabilitation programs, on postural balance and upper extremity function in 30 patients with subacute stroke. MATERIAL AND METHODS Thirty patients, who were within six months following the diagnosis of stroke, were randomly allocated to either the experimental group (n=15) or the control group (n=15). All participants participated in a conventional rehabilitation program. Also, the experimental group (n=15) performed the VR canoe paddling training for 30 minutes each day, three times per week, for five weeks. After five weeks, outcomes of changes in postural balance and upper extremity function were evaluated and compared between the two groups. RESULTS At five weeks, postural balance and upper extremity function showed significant improvements in both patients groups when compared with the baseline measurements (p<0.05). However, postural balance and upper extremity function were significantly improved in the experimental group when compared with the control group (p<0.05). CONCLUSIONS Game-based VR canoe paddling training is an effective rehabilitation therapy that enhances postural balance and upper extremity function in patients with subacute stroke when combined with conventional physical rehabilitation programs. PMID- 29702632 TI - What's in a sample? Increasing transparency in biospecimen procurement methods. PMID- 29702633 TI - ATAC Primer Tool for targeted analysis of accessible chromatin. PMID- 29702634 TI - Microbiology: making the best of PCR bias. PMID- 29702635 TI - Sorting apples from oranges in single-cell expression comparisons. PMID- 29702636 TI - Computational correction of index switching in multiplexed sequencing libraries. PMID- 29702631 TI - Prevention of Pertussis, Tetanus, and Diphtheria with Vaccines in the United States: Recommendations of the Advisory Committee on Immunization Practices (ACIP). AB - This report compiles and summarizes all recommendations from CDC's Advisory Committee on Immunization Practices (ACIP) regarding prevention and control of tetanus, diphtheria, and pertussis in the United States. As a comprehensive summary of previously published recommendations, this report does not contain any new recommendations and replaces all previously published reports and policy notes; it is intended for use by clinicians and public health providers as a resource. ACIP recommends routine vaccination for tetanus, diphtheria, and pertussis. Infants and young children are recommended to receive a 5-dose series of diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccines, with one adolescent booster dose of tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine. Adults who have never received Tdap also are recommended to receive a booster dose of Tdap. Women are recommended to receive a dose of Tdap during each pregnancy, which should be administered from 27 through 36 weeks' gestation, regardless of previous receipt of Tdap. After receipt of Tdap, adolescents and adults are recommended to receive a booster tetanus and diphtheria toxoids (Td) vaccine every 10 years to assure ongoing protection against tetanus and diphtheria. PMID- 29702637 TI - Adenine base editing in mouse embryos and an adult mouse model of Duchenne muscular dystrophy. AB - Adenine base editors (ABEs) composed of an engineered adenine deaminase and the Streptococcus pyogenes Cas9 nickase enable adenine-to-guanine (A-to-G) single nucleotide substitutions in a guide RNA (gRNA)-dependent manner. Here we demonstrate application of this technology in mouse embryos and adult mice. We also show that long gRNAs enable adenine editing at positions one or two bases upstream of the window that is accessible with standard single guide RNAs (sgRNAs). We introduced the Himalayan point mutation in the Tyr gene by microinjecting ABE mRNA and an extended gRNA into mouse embryos, obtaining Tyr mutant mice with an albino phenotype. Furthermore, we delivered the split ABE gene, using trans-splicing adeno-associated viral vectors, to muscle cells in a mouse model of Duchenne muscular dystrophy to correct a nonsense mutation in the Dmd gene, demonstrating the therapeutic potential of base editing in adult animals. PMID- 29702638 TI - Assessing the stability of polio eradication after the withdrawal of oral polio vaccine. AB - The oral polio vaccine (OPV) contains live-attenuated polioviruses that induce immunity by causing low virulence infections in vaccine recipients and their close contacts. Widespread immunization with OPV has reduced the annual global burden of paralytic poliomyelitis by a factor of 10,000 or more and has driven wild poliovirus (WPV) to the brink of eradication. However, in instances that have so far been rare, OPV can paralyze vaccine recipients and generate vaccine derived polio outbreaks. To complete polio eradication, OPV use should eventually cease, but doing so will leave a growing population fully susceptible to infection. If poliovirus is reintroduced after OPV cessation, under what conditions will OPV vaccination be required to interrupt transmission? Can conditions exist in which OPV and WPV reintroduction present similar risks of transmission? To answer these questions, we built a multi-scale mathematical model of infection and transmission calibrated to data from clinical trials and field epidemiology studies. At the within-host level, the model describes the effects of vaccination and waning immunity on shedding and oral susceptibility to infection. At the between-host level, the model emulates the interaction of shedding and oral susceptibility with sanitation and person-to-person contact patterns to determine the transmission rate in communities. Our results show that inactivated polio vaccine (IPV) is sufficient to prevent outbreaks in low transmission rate settings and that OPV can be reintroduced and withdrawn as needed in moderate transmission rate settings. However, in high transmission rate settings, the conditions that support vaccine-derived outbreaks have only been rare because population immunity has been high. Absent population immunity, the Sabin strains from OPV will be nearly as capable of causing outbreaks as WPV. If post-cessation outbreak responses are followed by new vaccine-derived outbreaks, strategies to restore population immunity will be required to ensure the stability of polio eradication. PMID- 29702639 TI - A Caenorhabditis elegans protein with a PRDM9-like SET domain localizes to chromatin-associated foci and promotes spermatocyte gene expression, sperm production and fertility. AB - To better understand the tissue-specific regulation of chromatin state in cell fate determination and animal development, we defined the tissue-specific expression of all 36 C. elegans presumptive lysine methyltransferase (KMT) genes using single-molecule fluorescence in situ hybridization (smFISH). Most KMTs were expressed in only one or two tissues. The germline was the tissue with the broadest KMT expression. We found that the germline-expressed C. elegans protein SET-17, which has a SET domain similar to that of the PRDM9 and PRDM7 SET-domain proteins, promotes fertility by regulating gene expression in primary spermatocytes. SET-17 drives the transcription of spermatocyte-specific genes from four genomic clusters to promote spermatid development. SET-17 is concentrated in stable chromatin-associated nuclear foci at actively transcribed msp (major sperm protein) gene clusters, which we term msp locus bodies. Our results reveal the function of a PRDM9/7-family SET-domain protein in spermatocyte transcription. We propose that the spatial intranuclear organization of chromatin factors might be a conserved mechanism in tissue-specific control of transcription. PMID- 29702640 TI - Transcription and translation of the sigG gene is tuned for proper execution of the switch from early to late gene expression in the developing Bacillus subtilis spore. AB - A cascade of alternative sigma factors directs developmental gene expression during spore formation by the bacterium Bacillus subtilis. As the spore develops, a tightly regulated switch occurs in which the early-acting sigma factor sigmaF is replaced by the late-acting sigma factor sigmaG. The gene encoding sigmaG (sigG) is transcribed by sigmaF and by sigmaG itself in an autoregulatory loop; yet sigmaG activity is not detected until sigmaF-dependent gene expression is complete. This separation in sigmaF and sigmaG activities has been suggested to be due at least in part to a poorly understood intercellular checkpoint pathway that delays sigG expression by sigmaF. Here we report the results of a careful examination of sigG expression during sporulation. Unexpectedly, our findings argue against the existence of a regulatory mechanism to delay sigG transcription by sigmaF and instead support a model in which sigG is transcribed by sigmaF with normal timing, but at levels that are very low. This low-level expression of sigG is the consequence of several intrinsic features of the sigG regulatory and coding sequence-promoter spacing, secondary structure potential of the mRNA, and start codon identity-that dampen its transcription and translation. Especially notable is the presence of a conserved hairpin in the 5' leader sequence of the sigG mRNA that occludes the ribosome-binding site, reducing translation by up to 4-fold. Finally, we demonstrate that misexpression of sigG from regulatory and coding sequences lacking these features triggers premature sigmaG activity in the forespore during sporulation, as well as inappropriate sigmaG activity during vegetative growth. Altogether, these data indicate that transcription and translation of the sigG gene is tuned to prevent vegetative expression of sigmaG and to ensure the precise timing of the switch from sigmaF to sigmaG in the developing spore. PMID- 29702642 TI - Polarization-resolved microscopy reveals a muscle myosin motor-independent mechanism of molecular actin ordering during sarcomere maturation. AB - Sarcomeres are stereotyped force-producing mini-machines of striated muscles. Each sarcomere contains a pseudocrystalline order of bipolar actin and myosin filaments, which are linked by titin filaments. During muscle development, these three filament types need to assemble into long periodic chains of sarcomeres called myofibrils. Initially, myofibrils contain immature sarcomeres, which gradually mature into their pseudocrystalline order. Despite the general importance, our understanding of myofibril assembly and sarcomere maturation in vivo is limited, in large part because determining the molecular order of protein components during muscle development remains challenging. Here, we applied polarization-resolved microscopy to determine the molecular order of actin during myofibrillogenesis in vivo. This method revealed that, concomitantly with mechanical tension buildup in the myotube, molecular actin order increases, preceding the formation of immature sarcomeres. Mechanistically, both muscle and nonmuscle myosin contribute to this actin order gain during early stages of myofibril assembly. Actin order continues to increase while myofibrils and sarcomeres mature. Muscle myosin motor activity is required for the regular and coordinated assembly of long myofibrils but not for the high actin order buildup during sarcomere maturation. This suggests that, in muscle, other actin-binding proteins are sufficient to locally bundle or cross-link actin into highly regular arrays. PMID- 29702641 TI - RosettaAntibodyDesign (RAbD): A general framework for computational antibody design. AB - A structural-bioinformatics-based computational methodology and framework have been developed for the design of antibodies to targets of interest. RosettaAntibodyDesign (RAbD) samples the diverse sequence, structure, and binding space of an antibody to an antigen in highly customizable protocols for the design of antibodies in a broad range of applications. The program samples antibody sequences and structures by grafting structures from a widely accepted set of the canonical clusters of CDRs (North et al., J. Mol. Biol., 406:228-256, 2011). It then performs sequence design according to amino acid sequence profiles of each cluster, and samples CDR backbones using a flexible-backbone design protocol incorporating cluster-based CDR constraints. Starting from an existing experimental or computationally modeled antigen-antibody structure, RAbD can be used to redesign a single CDR or multiple CDRs with loops of different length, conformation, and sequence. We rigorously benchmarked RAbD on a set of 60 diverse antibody-antigen complexes, using two design strategies-optimizing total Rosetta energy and optimizing interface energy alone. We utilized two novel metrics for measuring success in computational protein design. The design risk ratio (DRR) is equal to the frequency of recovery of native CDR lengths and clusters divided by the frequency of sampling of those features during the Monte Carlo design procedure. Ratios greater than 1.0 indicate that the design process is picking out the native more frequently than expected from their sampled rate. We achieved DRRs for the non-H3 CDRs of between 2.4 and 4.0. The antigen risk ratio (ARR) is the ratio of frequencies of the native amino acid types, CDR lengths, and clusters in the output decoys for simulations performed in the presence and absence of the antigen. For CDRs, we achieved cluster ARRs as high as 2.5 for L1 and 1.5 for H2. For sequence design simulations without CDR grafting, the overall recovery for the native amino acid types for residues that contact the antigen in the native structures was 72% in simulations performed in the presence of the antigen and 48% in simulations performed without the antigen, for an ARR of 1.5. For the non-contacting residues, the ARR was 1.08. This shows that the sequence profiles are able to maintain the amino acid types of these conserved, buried sites, while recovery of the exposed, contacting residues requires the presence of the antigen-antibody interface. We tested RAbD experimentally on both a lambda and kappa antibody-antigen complex, successfully improving their affinities 10 to 50 fold by replacing individual CDRs of the native antibody with new CDR lengths and clusters. PMID- 29702643 TI - Dependence of innate lymphoid cell 1 development on NKp46. AB - NKp46, a natural killer (NK) cell-activating receptor, is involved in NK cell cytotoxicity against virus-infected cells or tumor cells. However, the role of NKp46 in other NKp46+ non-NK innate lymphoid cell (ILC) populations has not yet been characterized. Here, an NKp46 deficiency model of natural cytotoxicity receptor 1 (Ncr1)gfp/gfp and Ncr1gfp/+ mice, i.e., homozygous and heterozygous knockout (KO), was used to explore the role of NKp46 in regulating the development of the NKp46+ ILCs. Surprisingly, our studies demonstrated that homozygous NKp46 deficiency resulted in a nearly complete depletion of the ILC1 subset (ILC1) of group 1 ILCs, and heterozygote KO decreased the number of cells in the ILC1 subset. Moreover, transplantation studies confirmed that ILC1 development depends on NKp46 and that the dependency is cell intrinsic. Interestingly, however, the cell depletion specifically occurred in the ILC1 subset but not in the other ILCs, including ILC2s, ILC3s, and NK cells. Thus, our studies reveal that NKp46 selectively participates in the regulation of ILC1 development. PMID- 29702644 TI - Material and shape perception based on two types of intensity gradient information. AB - Visual estimation of the material and shape of an object from a single image includes a hard ill-posed computational problem. However, in our daily life we feel we can estimate both reasonably well. The neural computation underlying this ability remains poorly understood. Here we propose that the human visual system uses different aspects of object images to separately estimate the contributions of the material and shape. Specifically, material perception relies mainly on the intensity gradient magnitude information, while shape perception relies mainly on the intensity gradient order information. A clue to this hypothesis was provided by the observation that luminance-histogram manipulation, which changes luminance gradient magnitudes but not the luminance-order map, effectively alters the material appearance but not the shape of an object. In agreement with this observation, we found that the simulated physical material changes do not significantly affect the intensity order information. A series of psychophysical experiments further indicate that human surface shape perception is robust against intensity manipulations provided they do not disturb the intensity order information. In addition, we show that the two types of gradient information can be utilized for the discrimination of albedo changes from highlights. These findings suggest that the visual system relies on these diagnostic image features to estimate physical properties in a distal world. PMID- 29702645 TI - Application of the hybrid ANFIS models for long term wind power density prediction with extrapolation capability. AB - In this paper, the suitability and performance of ANFIS (adaptive neuro-fuzzy inference system), ANFIS-PSO (particle swarm optimization), ANFIS-GA (genetic algorithm) and ANFIS-DE (differential evolution) has been investigated for the prediction of monthly and weekly wind power density (WPD) of four different locations named Mersing, Kuala Terengganu, Pulau Langkawi and Bayan Lepas all in Malaysia. For this aim, standalone ANFIS, ANFIS-PSO, ANFIS-GA and ANFIS-DE prediction algorithm are developed in MATLAB platform. The performance of the proposed hybrid ANFIS models is determined by computing different statistical parameters such as mean absolute bias error (MABE), mean absolute percentage error (MAPE), root mean square error (RMSE) and coefficient of determination (R2). The results obtained from ANFIS-PSO and ANFIS-GA enjoy higher performance and accuracy than other models, and they can be suggested for practical application to predict monthly and weekly mean wind power density. Besides, the capability of the proposed hybrid ANFIS models is examined to predict the wind data for the locations where measured wind data are not available, and the results are compared with the measured wind data from nearby stations. PMID- 29702646 TI - Characterization of a novel organic solute transporter homologue from Clonorchis sinensis. AB - Clonorchis sinensis is a liver fluke that can dwell in the bile ducts of mammals. Bile acid transporters function to maintain the homeostasis of bile acids in C. sinensis, as they induce physiological changes or have harmful effects on C. sinensis survival. The organic solute transporter (OST) transports mainly bile acid and belongs to the SLC51 subfamily of solute carrier transporters. OST plays a critical role in the recirculation of bile acids in higher animals. In this study, we cloned full-length cDNA of the 480-amino acid OST from C. sinensis (CsOST). Genomic analysis revealed 11 exons and nine introns. The CsOST protein had a 'Solute_trans_a' domain with 67% homology to Schistosoma japonicum OST. For further analysis, the CsOST protein sequence was split into the ordered domain (CsOST-N) at the N-terminus and disordered domain (CsOST-C) at the C-terminus. The tertiary structure of each domain was built using a threading-based method and determined by manual comparison. In a phylogenetic tree, the CsOST-N domain belonged to the OSTalpha and CsOST-C to the OSTbeta clade. These two domains were more highly conserved with the OST alpha- and beta-subunits at the structure level than at sequence level. These findings suggested that CsOST comprised the OST alpha- and beta-subunits. CsOST was localized in the oral and ventral suckers and in the mesenchymal tissues abundant around the intestine, vitelline glands, uterus, and testes. This study provides fundamental data for the further understanding of homologues in other flukes. PMID- 29702648 TI - Development of a cardiac loading device to monitor cardiac function during ex vivo graft perfusion. AB - BACKGROUND: Ex vivo heart perfusion systems, allowing continuous perfusion of the coronary vasculature, have recently been introduced to limit ischemic time of donor hearts prior to transplantation. Hearts are, however, perfused in an unloaded manner (via the aorta) and therefore, cardiac contractile function cannot be reliably evaluated. OBJECTIVES: We aim to develop a ventricular loading device that enables monitoring of myocardial function in an ex vivo perfusion system. In this initial study, was to develop a prototype for rat experimentation. METHODS: We designed a device consisting of a ventricular balloon and a reservoir balloon, connected through an electronic check valve, which opens and closes in coordination with changes in ventricular pressure. All balloons were produced in our laboratory and their properties, particularly pressure-volume relationships, were characterized. We developed a mock ventricle in vitro test system to evaluate the device, which was ultimately tested in ex vivo perfused rat hearts. RESULTS: Balloon production was consistent and balloon properties were maintained over time and with use on the device. Results from in vitro and ex vivo experiments show that the device functions appropriately; hemodynamic function can be measured and compares well to measurements made in an isolated, working (loaded) rat heart preparation. CONCLUSIONS: Our cardiac loading device appears to reliably allow measurement of several left ventricular hemodynamic parameters and provides the opportunity to control ventricular load. PMID- 29702647 TI - Global analysis of genetic circuitry and adaptive mechanisms enabling resistance to the azole antifungal drugs. AB - Invasive fungal infections caused by the pathogen Candida albicans have transitioned from a rare curiosity to a major cause of human mortality. This is in part due to the emergence of resistance to the limited number of antifungals available to treat fungal infections. Azoles function by targeting the biosynthesis of ergosterol, a key component of the fungal cell membrane. Loss-of function mutations in the ergosterol biosynthetic gene ERG3 mitigate azole toxicity and enable resistance that depends upon fungal stress responses. Here, we performed a genome-wide synthetic genetic array screen in Saccharomyces cerevisiae to map ERG3 genetic interactors and uncover novel circuitry important for azole resistance. We identified nine genes that enabled erg3-mediated azole resistance in the model yeast and found that only two of these genes had a conserved impact on resistance in C. albicans. Further, we screened a C. albicans homozygous deletion mutant library and identified 13 genes for which deletion enhances azole susceptibility. Two of the genes, RGD1 and PEP8, were also important for azole resistance acquired by diverse mechanisms. We discovered that loss of function of retrograde transport protein Pep8 overwhelms the functional capacity of the stress response regulator calcineurin, thereby abrogating azole resistance. To identify the mechanism through which the GTPase activator protein Rgd1 enables azole resistance, we selected for mutations that restore resistance in strains lacking Rgd1. Whole genome sequencing uncovered parallel adaptive mechanisms involving amplification of both chromosome 7 and a large segment of chromosome 3. Overexpression of a transporter gene on the right portion of chromosome 3, NPR2, was sufficient to enable azole resistance in the absence of Rgd1. Thus, we establish a novel mechanism of adaptation to drug-induced stress, define genetic circuitry underpinning azole resistance, and illustrate divergence in resistance circuitry over evolutionary time. PMID- 29702651 TI - Can only poorer European countries afford large carnivores? AB - BACKGROUND: One of the classic approaches in environmental economics is the environmental Kuznets curve, which predicts that when a national economy grows from low to medium levels, threats to biodiversity conservation increase, but they decrease when the economy moves from medium to high. We evaluated this approach by examining how population densities of the brown bear (Ursus arctos), gray wolf (Canis lupus), and Eurasian lynx (Lynx lynx) were related to the national economy in 24 European countries. METHODOLOGY/PRINCIPAL FINDINGS: We used forest proportions, the existence of a compensation system, and country group (former socialist countries, Nordic countries, other countries) as covariates in a linear model with the first- and the second-order polynomial terms of per capita gross domestic product (GDP). Country group was treated as a random factor, but remained insignificant and was ignored. All models concerning brown bear and wolf provided evidence that population densities decreased with increasing GDP, but densities of lynx were virtually independent of GDP. Models for the wolf explained >80% of the variation in densities, without a difference between the models with all independent variables and the model with only GDP. For the bear, the model with GDP alone accounted for 10%, and all three variables 33%, of the variation in densities. CONCLUSIONS: Wolves exhibit a higher capacity for dispersal and reproduction than bear or lynx, but still exists at the lowest densities in wealthy European countries. We are aware that several other factors, not available for our models, influenced large carnivore densities. Based on the pronounced differences among large carnivore species in their countrywide relationships between densities and GDP, and a strikingly high relationship for the gray wolf, we suggest that our results reflected differences in political history and public acceptance of these species among countries. The compensation paid for the damages caused by the carnivores is not a key to higher carnivore densities, but might be necessity for the presence of large carnivores to be accepted in countries with high GDP. PMID- 29702650 TI - Effects of growth rate, cell size, motion, and elemental stoichiometry on nutrient transport kinetics. AB - Nutrient acquisition is a critical determinant for the competitive advantage for auto- and osmohetero- trophs alike. Nutrient limited growth is commonly described on a whole cell basis through reference to a maximum growth rate (Gmax) and a half-saturation constant (KG). This empirical application of a Michaelis-Menten like description ignores the multiple underlying feedbacks between physiology contributing to growth, cell size, elemental stoichiometry and cell motion. Here we explore these relationships with reference to the kinetics of the nutrient transporter protein, the transporter rate density at the cell surface (TRD; potential transport rate per unit plasma-membrane area), and diffusion gradients. While the half saturation value for the limiting nutrient increases rapidly with cell size, significant mitigation is afforded by cell motion (swimming or sedimentation), and by decreasing the cellular carbon density. There is thus potential for high vacuolation and high sedimentation rates in diatoms to significantly decrease KG and increase species competitive advantage. Our results also suggest that Gmax for larger non-diatom protists may be constrained by rates of nutrient transport. For a given carbon density, cell size and TRD, the value of Gmax/KG remains constant. This implies that species or strains with a lower Gmax might coincidentally have a competitive advantage under nutrient limited conditions as they also express lower values of KG. The ability of cells to modulate the TRD according to their nutritional status, and hence change the instantaneous maximum transport rate, has a very marked effect upon transport and growth kinetics. Analyses and dynamic models that do not consider such modulation will inevitably fail to properly reflect competitive advantage in nutrient acquisition. This has important implications for the accurate representation and predictive capabilities of model applications, in particular in a changing environment. PMID- 29702649 TI - High mutation rates limit evolutionary adaptation in Escherichia coli. AB - Mutation is fundamental to evolution, because it generates the genetic variation on which selection can act. In nature, genetic changes often increase the mutation rate in systems that range from viruses and bacteria to human tumors. Such an increase promotes the accumulation of frequent deleterious or neutral alleles, but it can also increase the chances that a population acquires rare beneficial alleles. Here, we study how up to 100-fold increases in Escherichia coli's genomic mutation rate affect adaptive evolution. To do so, we evolved multiple replicate populations of asexual E. coli strains engineered to have four different mutation rates for 3000 generations in the laboratory. We measured the ability of evolved populations to grow in their original environment and in more than 90 novel chemical environments. In addition, we subjected the populations to whole genome population sequencing. Although populations with higher mutation rates accumulated greater genetic diversity, this diversity conveyed benefits only for modestly increased mutation rates, where populations adapted faster and also thrived better than their ancestors in some novel environments. In contrast, some populations at the highest mutation rates showed reduced adaptation during evolution, and failed to thrive in all of the 90 alternative environments. In addition, they experienced a dramatic decrease in mutation rate. Our work demonstrates that the mutation rate changes the global balance between deleterious and beneficial mutational effects on fitness. In contrast to most theoretical models, our experiments suggest that this tipping point already occurs at the modest mutation rates that are found in the wild. PMID- 29702652 TI - Impact of lower challenge doses of enterotoxigenic Escherichia coli on clinical outcome, intestinal colonization and immune responses in adult volunteers. AB - : A reliable and effective human challenge model is needed to help down-select the most promising ETEC vaccines currently under development. Such a model would need to reliably induce diarrhea in a high proportion of volunteers using the lowest possible inoculum to maximize safety and sensitivity. Previously we validated a challenge model that utilized a dose of 2x107 CFU of ETEC strain H10407 (LT+, ST+, CFA/I+ and O78+) to induce attack rates for moderate to severe diarrhea (MSD) of ~60-70%. Here we detail efforts to further refine the model in an attempt to determine if a lower challenge dose of H10407 can be used. Thirty subjects were randomized 1:1 to receive an oral administration of H10407 at doses of 106 or 105 CFU in bicarbonate buffer. After challenge, subjects were monitored for signs and symptoms of enteric illness and stool samples were collected to detect shedding of the challenge strain. Systemic and mucosal immune responses were measured using serum, antibody in lymphocyte supernatant and fecal samples. The attack rate was 13.3% (2/15) and 26.7% (4/15) for MSD in the 105 and 106 groups, respectively. Four MSD cases met criteria for early antibiotic treatment. All subjects but one shed the challenge strain in fecal samples. The frequency and magnitude of anti-LT toxin, CFA/I and LPS O78 immune responses were antigen, dose, severity of diarrhea and shedding levels dependent. Notably, although of lower magnitude, there were considerable immune responses in the subjects with no diarrhea. This may indicate that immune responses to asymptomatic infections of ETEC in children in the endemic countries may contribute to protection. Based on this and our prior studies, we conclude that a dose of 2x107 H10407 remains the lowest practical dose for use in future volunteer studies evaluating candidate vaccines and other preventive or therapeutic ETEC interventions. TRIAL REGISTRATION: ClinicalTrials.gov NCT00844493. PMID- 29702653 TI - Efficacy and safety of co-administered ivermectin plus albendazole for treating soil-transmitted helminths: A systematic review, meta-analysis and individual patient data analysis. AB - BACKGROUND: The soil-transmitted helminths (STH), Ascaris lumbricoides, Trichuris trichiura and hookworms, infect 1.5 billion people worldwide and cause an estimated burden of 3.3 million disability-adjusted life years (DALYs). Current control strategies focus on morbidity reduction through preventive chemotherapy (PC) but the most commonly used recommended drugs (albendazole and mebendazole) are particularly inefficacious against T. trichiura. This, together with the threat of emerging drug resistance, calls for new control strategies, including co-administration with other anthelminthics. Ivermectin plus albendazole is widely used against lymphatic filariasis, but its efficacy and safety against STH infections has not yet been fully understood. METHODS AND FINDINGS: We conducted a systematic literature review and meta-analysis on the efficacy and safety of ivermectin-albendazole co-administration in five different databases (i.e. PubMed, ISI Web of Science, ScienceDirect, CENTRAL and clinicaltrials.gov) from 1960 to January 2018. Four studies reporting efficacy of ivermectin-albendazole against STH infections and five studies on its safety met the selection criteria and were included for quantitative analysis. Ivermectin-albendazole was significantly associated with lower risk (risk ratio (RR) = 0.44, 95% confidence interval (CI) = 0.31-0.62) for T. trichiura infection after treatment compared to albendazole alone. The co-administration revealed no or only a marginal benefit on cure and egg reduction rates over albendazole alone for A. lumbricoides and hookworm infections. Adverse events (AEs) occurring after ivermectin-albendazole co-administration were mostly mild and transient. Overall, the number of individuals reporting any AE was not different (RR = 1.09, 95% CI = 0.87-1.36) in co-treated and albendazole-treated patients. However, although not statistically significant, sub-group analysis showed a tendency for slightly more AEs in patients with filariasis treated with ivermectin-albendazole compared to those treated with albendazole alone (RR = 1.29, 95% CI = 0.81-2.05). CONCLUSIONS: Our findings suggest a good tolerability and higher efficacy of ivermectin albendazole against T. trichiura compared to the current standard single-dose albendazole treatment, which supports the use of this co-administration in PC programs. Large-scale definitive randomized controlled trials are required to confirm our results. PMID- 29702654 TI - Identification and characterization of the Fasciola hepatica sodium- and chloride dependent taurine transporter. AB - The parasitic liver fluke Fasciola hepatica infests mainly ruminants, but it can also cause fasciolosis in people, who ingest the metacercariae encysted on plants. The drug of choice to treat fasciolosis is triclabendazole (TBZ), which has been on the market for several decades. This is also true for the other available drugs. Accordingly, drug-resistant flukes have been emerging at an increasing rate making it desirable to identify alternative drug targets. Here, we focused on the fact that adult F. hepatica persists in the hostile environment of the bile ducts of infected organisms. A common way to render bile acids less toxic is to conjugate them to taurine (2-aminoethanesulfonic acid). We cloned a transporter from the solute carrier-6 (SLC6) family, which was most closely related to the GABA-transporter-2 of other organisms. When heterologously expressed, this F. hepatica transporter supported the high-affinity cellular uptake of taurine (KM = 12.0 +/- 0.5 MUM) but not of GABA. Substrate uptake was dependent on Na+- and Cl- (calculated stoichiometry 2:1). Consistent with the low chloride concentration in mammalian bile, the F. hepatica transporter had a higher apparent affinity for Cl- (EC50 = 14+/-3 mM) than the human taurine transporter (EC50 = 55+/-7 mM). We incubated flukes with unconjugated bile acids in the presence and absence of taurine: taurine promoted survival of flukes; the taurine transporter inhibitor guanidinoethansulfonic acid abolished this protective effect of taurine. Based on these observations, we conclude that the taurine transporter is critical for the survival of liver flukes in the bile. Thus, the taurine transporter represents a candidate drug target. PMID- 29702655 TI - Risk of suicide following an alcohol-related emergency hospital admission: An electronic cohort study of 2.8 million people. AB - OBJECTIVE: Alcohol misuse is a well-known risk factor for suicide however, the relationship between alcohol-related hospital admission and subsequent risk of death from suicide is unknown. We aimed to determine the risk of death from suicide following emergency admission to hospital with an alcohol-related cause. METHODS: We established an electronic cohort study of all 2,803,457 residents of Wales, UK, aged from 10 to under 100 years on 1 January 2006 with six years' follow-up. The outcome event was death from suicide defined as intentional self harm (ICD-10 X60-84) or undetermined intent (Y10-34). The main exposure was an alcohol-related admission defined as a 'wholly attributable' ICD-10 alcohol code in the admission record. Admissions were coded for the presence or absence of co existing psychiatric morbidity. The analysis was by Cox regression with adjustments for confounding variables within the dataset. RESULTS: During the study follow-up period, there were 15,546,355 person years at risk with 28,425 alcohol-related emergency admissions and 1562 suicides. 125 suicides followed an admission (144.6 per 100,000 person years), of which 11 (9%) occurred within 4 weeks of discharge. The overall adjusted hazard ratio (HR) for suicide following admission was 26.8 (95% confidence interval (CI) 18.8 to 38.3), in men HR 9.83 (95% CI 7.91 to 12.2) and women HR 28.5 (95% CI 19.9 to 41.0). The risk of suicide remained substantial in subjects without known co-existing psychiatric morbidity: HR men 8.11 (95% CI 6.30 to 10.4) and women HR 24.0 (95% CI 15.5 to 37.3). The analysis was limited by the absence in datasets of potentially important confounding variables and the lack of information on alcohol-related harm and psychiatric morbidity in subjects not admitted to hospital. CONCLUSION: Emergency alcohol-related hospital admission is associated with an increased risk of suicide. Identifying individuals in hospital provides an opportunity for psychosocial assessment and suicide prevention of a targeted at-risk group before their discharge to the community. PMID- 29702656 TI - Measuring a new facet of post traumatic growth: Development of a scale of physical post traumatic growth in men with prostate cancer. AB - PURPOSE: This study developed a measure of physical post traumatic growth (physical post traumatic growth inventory; P-PTGI) in men with prostate cancer. METHODS: A pool of items was created from themes identified in a qualitative study. A quantitative study was then conducted to assess the psychometric properties of the P-PTGI in a sample of 693 prostate cancer survivors. RESULTS: Tests of dimensionality revealed that the 20-item P-PTGI contained two factors: Health Autonomy and Health Awareness. Results demonstrated that scale score reliability for the P-PTGI and its subscales was excellent. In support of the scale's convergent validity, scores on the P-PTGI correlated positively with mindfulness and quality of life, and correlated negatively with depression and anxiety. A statistically significant correlation between the P-PTGI and another robust indicator of post traumatic growth attests to its concurrent validity. CONCLUSIONS: While further investigation of the P-PTGI's psychometric properties is required, preliminary findings are promising. PMID- 29702657 TI - Anatomy of an online misinformation network. AB - Massive amounts of fake news and conspiratorial content have spread over social media before and after the 2016 US Presidential Elections despite intense fact checking efforts. How do the spread of misinformation and fact-checking compete? What are the structural and dynamic characteristics of the core of the misinformation diffusion network, and who are its main purveyors? How to reduce the overall amount of misinformation? To explore these questions we built Hoaxy, an open platform that enables large-scale, systematic studies of how misinformation and fact-checking spread and compete on Twitter. Hoaxy captures public tweets that include links to articles from low-credibility and fact checking sources. We perform k-core decomposition on a diffusion network obtained from two million retweets produced by several hundred thousand accounts over the six months before the election. As we move from the periphery to the core of the network, fact-checking nearly disappears, while social bots proliferate. The number of users in the main core reaches equilibrium around the time of the election, with limited churn and increasingly dense connections. We conclude by quantifying how effectively the network can be disrupted by penalizing the most central nodes. These findings provide a first look at the anatomy of a massive online misinformation diffusion network. PMID- 29702658 TI - Use of weighted multivariate estimates in trials of multi-serotype vaccines to simplify interpretation of treatment differences. AB - BACKGROUND: Many vaccines contain multiple components. Licensed pneumococcal conjugate vaccines (PCV) contain polysaccharides from 7, 10, or 13 different serotypes of Streptococcus pneumoniae. The main outcomes in randomised trials of pneumococcal vaccines are serotype-specific antibody measures. Comparisons are made between groups for each serotype, resulting in multiple separate comparisons of treatment effects which can be complicated to interpret. We investigated methods for computing the overall difference between vaccine groups across all serotypes. METHODS: Pneumococcal antibody concentrations were obtained from a randomised controlled trial of ten-valent pneumococcal vaccine, conducted in Kathmandu, Nepal. Infants received either 2 priming doses of vaccine at 6 and 14 weeks of age followed by a booster (2+1), or 3 priming doses at 6, 10, and 14 weeks of age with no booster (3+0). The overall difference between vaccine schedules across all serotypes was computed at each visit using a multivariate linear model with equal weights for each serotype. Alternative weights were derived from invasive pneumococcal disease cases in Nepal, Bangladesh and Pakistan, and from estimates of the relative invasiveness of each serotype and used in sensitivity analyses. RESULTS: When 10 separate estimates of treatment differences were computed the ratio of antibody responses for each serotype in the 2+1 group compared with the 3+0 group at 10 months of age varied greatly, with serotype-specific GMRs ranging from 2.80 for serotype 14, to 9.14 for serotype 18C. Using equal weights for each serotype, the overall geometric mean ratio (GMR) was 5.02 (95% CI 4.06-6.22) at 10 months of age, and 1.46 (95% CI 1.14-1.88) at 3 years of age. Using weights based on disease incidence gave GMRs ranging from 5.15 to 6.63 at 10 months of age, and 1.47 to 1.78 at 3 years of age. Using weights based on relative invasiveness gave estimates of 6.81 and 1.59, at 10 months and 3 years respectively. CONCLUSION: PCV clinical trial data have a multivariate structure with correlated outcomes for different serotypes. When analysing each serotype separately, the multiple estimates of the treatment effect can complicate the interpretation of trial results. Reporting a single overall estimate which accounts for the correlation between outcomes can simplify such interpretation. Treatment effects can be weighted equally or alternative weights derived from independent data can be used. Many modern vaccines have multiple components, such as quadrivalent meningococcal group ACWY vaccine or four-component group B meningococcal vaccine, thus these methods are widely applicable. PMID- 29702659 TI - Provider perspectives on PrEP for adolescent girls and young women in Tanzania: The role of provider biases and quality of care. AB - BACKGROUND: Oral pre-exposure prophylaxis (PrEP) has the potential to reduce HIV acquisition among adolescent girls and young women (AGYW) in sub-Saharan Africa. However, health care providers' (HCPs) perspectives and interactions with potential clients can substantially influence effective provision of quality health services. We examine if HCPs' knowledge, attitude, and skills, as well as their perceptions of facility readiness to provide PrEP are associated with their willingness to provide PrEP to AGYW at high risk of HIV in Tanzania. METHODS: A self-administered questionnaire was given to 316 HCPs from 74 clinics in two districts and 24 HCPs participated in follow-up in-depth interviews (IDIs). We conducted bivariate and multivariable Poisson regression to assess factors associated with willingness to provide PrEP to AGYW. Thematic content analysis was used to analyze the IDIs, which expanded upon the quantitative results. RESULTS: Few HCPs (3.5%) had prior PrEP knowledge, but once informed, 61.1% were willing to prescribe PrEP to AGYW. Higher negative attitudes toward adolescent sexuality and greater concerns about behavioral disinhibition due to PrEP use were associated with lower willingness to prescribe PrEP. Qualitatively, HCPs acknowledged that biases, rooted in cultural norms, often result in stigmatizing and discriminatory care toward AGYW, a potential barrier for PrEP provision. However, better training to provide HIV services was associated with greater willingness to prescribe PrEP. Conversely, HCPs feared the potential negative impact of PrEP on the provision of existing HIV services (e.g., overburdened staff), and suggested the integration of PrEP into non-HIV services and the use of paramedical professionals to facilitate PrEP provision. CONCLUSIONS: Preparing for PrEP introduction requires more than solely training HCPs on the clinical aspects of providing PrEP. It requires a two-pronged strategy: addressing HCPs' biases regarding sexual health services to AGYW; and preparing the health system infrastructure for the introduction of PrEP. PMID- 29702660 TI - Social network analysis of stakeholder networks from two community-based obesity prevention interventions. AB - INTRODUCTION: Studies of community-based obesity prevention interventions have hypothesized that stakeholder networks are a critical element of effective implementation. This paper presents a quantitative analysis of the interpersonal network structures within a sub-sample of stakeholders from two past successful childhood obesity prevention interventions. METHODS: Participants were recruited from the stakeholder groups (steering committees) of two completed community based intervention studies, Romp & Chomp (R&C), Australia (2004-2008) and Shape Up Somerville (SUS), USA (2003-2005). Both studies demonstrated significant reductions of overweight and obesity among children. Members of the steering committees were asked to complete a retrospective social network questionnaire using a roster of other committee members and free recall. Each participant was asked to recall the people with whom they discussed issues related to childhood obesity throughout the intervention period, along with providing the closeness and level of influence of each relationship. RESULTS: Networks were reported by 13 participants from the SUS steering committee and 8 participants from the R&C steering committee. On average, participants nominated 16 contacts with whom they discussed issues related to childhood obesity through the intervention, with approximately half of the relationships described as 'close' and 30% as 'influential'. The 'discussion' and 'close' networks had high clustering and reciprocity, with ties directed to other steering committee members, and to individuals external to the committee. In contrast, influential ties were more prominently directed internal to the steering committee, with higher network centralization, lower reciprocity and lower clustering. DISCUSSION AND CONCLUSION: Social network analysis provides a method to evaluate the ties within steering committees of community-based obesity prevention interventions. In this study, the network characteristics between a sub-set of stakeholders appeared to be supportive of diffused communication. Future work should prospectively examine stakeholder network structures in a heterogeneous sample of community-based interventions to identify elements most strongly associated with intervention effectiveness. PMID- 29702661 TI - Adaptive scales of integration and response latencies in a critically-balanced model of the primary visual cortex. AB - The primary visual cortex (V1) integrates information over scales in visual space, which have been shown to vary, in an input-dependent manner, as a function of contrast and other visual parameters. Which algorithms the brain uses to achieve this feat are largely unknown and an open problem in visual neuroscience. We demonstrate that a simple dynamical mechanism can account for this contrast dependent scale of integration in visuotopic space as well as connect this property to two other stimulus-dependent features of V1: extents of lateral integration on the cortical surface and response latencies. PMID- 29702662 TI - Fenoxycarb exposure disrupted the reproductive success of the amphipod Gammarus fossarum with limited effects on the lipid profile. AB - Insect growth regulator insecticides mimic the action of hormones on the growth and development of insect pests. However, they can affect the development of non target arthropods. In the present study, we tested the effects of the growth regulator insecticide fenoxycarb on several endpoints in the freshwater crustacean Gammarus fossarum (Amphipoda). Females carrying embryos in their open brood pouch were exposed to 50 MUg L-1 fenoxycarb throughout the entire oogenesis (i.e. 21 days). After exposure, newborn individuals from exposed embryos were removed from the maternal open brood pouch for lipidomic analysis, while males were added to assess the reproductive success. After fertilization, the lipid profile, energy reserve content (lipids, proteins and glycogen), and activity of phenoloxidase - an enzyme involved in the immune response - were measured in females. No significant effect of fenoxycarb exposure was observed on the lipid profile of both newborn individuals and females, while reproductive success was severely impaired in exposed females. Particularly, precopulatory behavior was significantly reduced and fertilized eggs were unviable. This study highlighted the deleterious effects of the insect growth regulator fenoxycarb on gammarid reproduction, which could have severe repercussions on population dynamics. PMID- 29702663 TI - Meta-analysis of sonication prosthetic fluid PCR for diagnosing periprosthetic joint infection. AB - Periprosthetic joint infection (PJI) is a catastrophic complication following total joint arthroplasty. Until now, the diagnosis of PJI is still confronted with difficulties, which is characterized by technical limitations. The question of whether sonication fluid PCR can provide high value in the diagnosis of PJI remains unanswered. This meta-analysis included 9 studies that evaluated PCR assays of sonication fluid for the diagnosis of PJI. The pooled sensitivity, specificity, Positive likelihood ratio (PLR), Negative likelihood ratio (NLR) and Diagnostic odds ratio (DOR) were 0.75 (95% confidence interval [CI], 0.71 to 0.81), 0.96 (CI, 0.94 to 0.97), 18.24 (CI, 6.07 to 54.78), 0.27 (CI, 0.20 to 0.36) and 86.97 (CI, 37.08 to 203.97), respectively. The AUC value of the SROC was 0.9244 (standard error, 0.0212). Subgroup analyses showed that use of multiplex PCR and may improve sensitivity and specificity. The results of this meta-analysis showed that PCR of fluid after sonication is reliable and of great value in PJI diagnosis. PMID- 29702664 TI - How digital design shapes political participation: A natural experiment with social information. AB - Political behaviour increasingly takes place on digital platforms, where people are presented with a range of social information-real-time feedback about the behaviour of peers and reference groups-which can stimulate (or depress) participation. This social information is hypothesized to impact the distribution of political activity, stimulating participation in mobilizations that are increasing in popularity, and depressing participation in those that appear to be less popular, leading to a non-normal distribution. Changes to these platforms can generate natural experiments allowing for an estimate of the impact of different kinds of social information on participation. This paper tests the hypothesis that social information shapes the distribution of political mobilizations by examining the introduction of trending information to the homepage of the UK government petition platform. The introduction of the trending feature did not increase the overall number of signatures per day, but the distribution of signatures across petitions changed significantly-the most popular petitions gained more signatures at the expense of those with fewer signatories. We further find significant differences between petitions trending at different ranks on the homepage. This evidence suggests that the ubiquity of trending information on digital platforms is introducing instability into political markets, as has been shown for cultural markets. As well as highlighting the importance of digital design in shaping political behaviour, the findings suggest that a non-negligible group of individuals visit the homepage of the site looking for petitions to sign, without having decided the issues they wish to support in advance. These 'aimless petitioners' are particularly susceptible to changes in social information. PMID- 29702665 TI - Network approach for decision making under risk-How do we choose among probabilistic options with the same expected value? AB - Conventional decision theory suggests that under risk, people choose option(s) by maximizing the expected utility. However, theories deal ambiguously with different options that have the same expected utility. A network approach is proposed by introducing 'goal' and 'time' factors to reduce the ambiguity in strategies for calculating the time-dependent probability of reaching a goal. As such, a mathematical foundation that explains the irrational behavior of choosing an option with a lower expected utility is revealed, which could imply that humans possess rationality in foresight. PMID- 29702666 TI - One step generation of customizable gRNA vectors for multiplex CRISPR approaches through string assembly gRNA cloning (STAgR). AB - Novel applications based on the bacterial CRISPR system make genetic, genomic, transcriptional and epigenomic engineering widely accessible for the first time. A significant advantage of CRISPR over previous methods is its tremendous adaptability due to its bipartite nature. Cas9 or its engineered variants define the molecular effect, while short gRNAs determine the targeting sites. A majority of CRISPR approaches depend on the simultaneous delivery of multiple gRNAs into single cells, either as an essential precondition, to increase responsive cell populations or to enhance phenotypic outcomes. Despite these requirements, methods allowing the efficient generation and delivery of multiple gRNA expression units into single cells are still sparse. Here we present STAgR (String assembly gRNA cloning), a single step gRNA multiplexing system, that obtains its advantages by employing the N20 targeting sequences as necessary homologies for Gibson assembly. We show that STAgR allows reliable and cost effective generation of vectors with high numbers of gRNAs enabling multiplexed CRISPR approaches. Moreover, STAgR is easily customizable, as vector backbones as well as gRNA structures, numbers and promoters can be freely chosen and combined. Finally, we demonstrate STAgR's widespread functionality, its efficiency in multi targeting approaches, using it for both, genome and transcriptome editing, as well as applying it in vitro and in vivo. PMID- 29702667 TI - Impact of white matter hyperintensities on the prognosis of cryptogenic stroke patients. AB - BACKGROUND: To our knowledge, little is known regarding whether white matter hyperintensities (WMH) affect the prognosis of cryptogenic stroke (CS) patients. Understanding this association may be helpful with expecting the prognosis of CS patients. METHODS: This retrospective observational study enrolled consecutive CS patients who underwent brain MRI and comprehensive cardiac evaluation. Severe WMH was defined as Fazekas' score >=3. We defined poor functional outcome as modified Rankin Scale score >=3 at 3 months. Long-term mortality and causes of death were identified using national death certificates and assessed by Kaplan-Meier method and regression analysis model. RESULTS: Among 2732 patients with first-ever ischemic stroke, 599 (21.9%) patients were classified as having CS. After exclusions, 235 patients were enrolled and followed up for a median of 7.7 years (IQR, 6.7-9.0). Severe WMH were found in 81 (34.5%) patients. After adjustments, severe WMH were an independent predictor for poor functional outcomes at 3 months (OR 5.25, 95% CI, 2.07-13.31). Subgroup analysis showed that severe WMH were an independent predictor for long-term mortality only in younger patients (age < 65) (HR 3.11, 95% CI, 1.29-7.50), but not in older patients (HR 1.19, 95% CI, 0.63 2.23). CONCLUSIONS: Severe WMH were independently associated with short-term functional outcomes in CS patients and independently associated with long-term mortality in younger CS patients. Grading WMH is of value in predicting prognosis of CS patients with young age. PMID- 29702668 TI - Aridity drives plant biogeographical sub regions in the Caatinga, the largest tropical dry forest and woodland block in South America. AB - Our aims were to quantify and map the plant sub regions of the the Caatinga, that covers 844,453 km2 and is the largest block of seasonally dry forest in South America. We performed spatial analyses of the largest dataset of woody plant distributions in this region assembled to date (of 2,666 shrub and tree species; 260 localities), compared these distributions with the current phytogeographic regionalizations, and investigated the potential environmental drivers of the floristic patterns in these sub regions. Phytogeographical regions were identified using quantitative analyses of species turnover calculated as Simpson dissimilarity index. We applied an interpolation method to map NMDS axes of compositional variation over the entire extent of the Caatinga, and then classified the compositional dissimilarity according to the number of biogeographical sub regions identified a priori using k-means analysis. We used multinomial logistic regression models to investigate the influence of contemporary climatic productivity, topographic complexity, soil characteristics, climate stability since the last glacial maximum, and the human footprint in explaining the identified sub regions. We identified nine spatially cohesive biogeographical sub regions. Current productivity, as indicated by an aridity index, was the only explanatory variable retained in the best model, explaining nearly half of the floristic variability between sub regions. The highest rates of endemism within the Caatinga were in the Core and Periphery Chapada Diamantina sub regions. Our findings suggest that the topographic complexity, soil variation, and human footprint in the Caatinga act on woody plant distributions at local scales and not as determinants of broad floristic patterns. The lack of effect of climatic stability since the last glacial maximum probably results from the fact that a single measure of climatic stability does not adequately capture the highly dynamic climatic shifts the region suffered during the Pleistocene. There was limited overlap between our results and previous Caatinga classifications. PMID- 29702670 TI - An efficient approach for feature construction of high-dimensional microarray data by random projections. AB - Dimensionality reduction of microarray data is a very challenging task due to high computational time and the large amount of memory required to train and test a model. Genetic programming (GP) is a stochastic approach to solving a problem. For high dimensional datasets, GP does not perform as well as other machine learning algorithms. To explore the inherent property of GP to generalize models from low dimensional data, we need to consider dimensionality reduction approaches. Random projections (RPs) have gained attention for reducing the dimensionality of data with reduced computational cost, compared to other dimensionality reduction approaches. We report that the features constructed from RPs perform extremely well when combined with a GP approach. We used eight datasets out of which seven have not been reported as being used in any machine learning research before. We have also compared our results by using the same full and constructed features for decision trees, random forest, naive Bayes, support vector machines and k-nearest neighbor methods. PMID- 29702671 TI - A remark on copy number variation detection methods. AB - Copy number variations (CNVs) are gain and loss of DNA sequence of a genome. High throughput platforms such as microarrays and next generation sequencing technologies (NGS) have been applied for genome wide copy number losses. Although progress has been made in both approaches, the accuracy and consistency of CNV calling from the two platforms remain in dispute. In this study, we perform a deep analysis on copy number losses on 254 human DNA samples, which have both SNP microarray data and NGS data publicly available from Hapmap Project and 1000 Genomes Project respectively. We show that the copy number losses reported from Hapmap Project and 1000 Genome Project only have < 30% overlap, while these reports are required to have cross-platform (e.g. PCR, microarray and high throughput sequencing) experimental supporting by their corresponding projects, even though state-of-art calling methods were employed. On the other hand, copy number losses are found directly from HapMap microarray data by an accurate algorithm, i.e. CNVhac, almost all of which have lower read mapping depth in NGS data; furthermore, 88% of which can be supported by the sequences with breakpoint in NGS data. Our results suggest the ability of microarray calling CNVs and the possible introduction of false negatives from the unessential requirement of the additional cross-platform supporting. The inconsistency of CNV reports from Hapmap Project and 1000 Genomes Project might result from the inadequate information containing in microarray data, the inconsistent detection criteria, or the filtration effect of cross-platform supporting. The statistical test on CNVs called from CNVhac show that the microarray data can offer reliable CNV reports, and majority of CNV candidates can be confirmed by raw sequences. Therefore, the CNV candidates given by a good caller could be highly reliable without cross-platform supporting, so additional experimental information should be applied in need instead of necessarily. PMID- 29702669 TI - Heat shock proteins expressed in the marsupial Tasmanian devil are potential antigenic candidates in a vaccine against devil facial tumour disease. AB - The Tasmanian devil (Sarcophilus harrisii), the largest extant carnivorous marsupial and endemic to Tasmania, is at the verge of extinction due to the emergence of a transmissible cancer known as devil facial tumour disease (DFTD). DFTD has spread over the distribution range of the species and has been responsible for a severe decline in the global devil population. To protect the Tasmanian devil from extinction in the wild, our group has focused on the development of a prophylactic vaccine. Although this work has shown that vaccine preparations using whole DFTD tumour cells supplemented with adjuvants can induce anti-DFTD immune responses, alternative strategies that induce stronger and more specific immune responses are required. In humans, heat shock proteins (HSPs) derived from tumour cells have been used instead of whole-tumour cell preparations as a source of antigens for cancer immunotherapy. As HSPs have not been studied in the Tasmanian devil, this study presents the first characterisation of HSPs in this marsupial and evaluates the suitability of these proteins as antigenic components for the enhancement of a DFTD vaccine. We show that tissues and cancer cells from the Tasmanian devil express constitutive and inducible HSP. Additionally, this study suggests that HSP derived from DFTD cancer cells are immunogenic supporting the future development of a HSP-based vaccine against DFTD. PMID- 29702672 TI - Characterization of HIV-1 gp120 antibody specificities induced in anogenital secretions of RV144 vaccine recipients after late boost immunizations. AB - Sexual transmission is the principal driver of the human immunodeficiency virus (HIV) pandemic. Understanding HIV vaccine-induced immune responses at mucosal surfaces can generate hypotheses regarding mechanisms of protection, and may influence vaccine development. The RV144 (ClinicalTrials.gov NCT00223080) efficacy trial showed protection against HIV infections but mucosal samples were not collected, therefore, the contribution of mucosal antibodies to preventing HIV-1 acquisition is unknown. Here, we report the generation, magnitude and persistence of antibody responses to recombinant gp120 envelope and antigens including variable one and two loop scaffold antigens (gp70V1V2) previously shown to correlate with risk in RV144. We evaluated antibody responses to gp120 A244gD and gp70V1V2 92TH023 (both CRF01_AE) and Case A2 (subtype B) in cervico-vaginal mucus (CVM), seminal plasma (SP) and rectal secretions (RS) from HIV-uninfected RV144 vaccine recipients, who were randomized to receive two late boosts of ALVAC HIV/AIDSVAX(r)B/E, AIDSVAX(r)B/E, or ALVAC-HIV alone at 0 and 6 months. Late vaccine boosting increased IgG geometric mean titers (GMT) to gp120 A244gD in AIDSVAX(r)B/E and ALVAC-HIV/AIDSVAX(r)B/E CVM (28 and 17 fold, respectively), followed by SP and RS. IgG to gp70V1V2 92TH023 increased in AIDSVAX(r)B/E and ALVAC-HIV/AIDSVAX(r)B/E CVM (11-17 fold) and SP (2 fold) two weeks post first boost. IgG to Case A2 was only detected in AIDSVAX(r)B/E and ALVAC HIV/AIDSVAX(r)B/E CVM. Mucosal IgG to gp120 A244gD (CVM, SP, RS), gp70V1V2 92TH023 (CVM, SP), and Case A2 (CVM) correlated with plasma IgG levels (p<0.001). Although the magnitude of IgG responses declined after boosting, anti-gp120 A244gD IgG responses in CVM persisted for 12 months post final vaccination. Further studies in localization, persistence and magnitude of envelope specific antibodies (IgG and dimeric IgA) in anogenital secretions will help determine their role in preventing mucosal HIV acquisition. PMID- 29702673 TI - Physical activity measured with wrist and ankle accelerometers: Age, gender, and BMI effects. AB - Physical activity (PA) is associated with various aspects of physical and mental health and varies by age and BMI. We aimed to compare PA measures obtained with wrist and ankle accelerometers and characterize their associations with age and BMI. We assessed PA mean and PA variability (indexed by coefficient of variation (CV)) at daytime and nighttime periods for seven consecutive days (M = 152.90 h) in 47 healthy participants (18-73 years old, 21 females). Diurnally, mean PA for both ankle and wrist and CV of PA for ankle decreased from the first to the second half of daytime (p < 0.05). There were no differences in mean PA between wrist and ankle at any time-period (p > 0.2). CV of ankle PA at daytime was significantly higher than wrist PA (p < .0001). The opposite pattern was observed at nighttime (p < .0001). Pearson correlation analyses were performed to assess the associations between wrist (or ankle) PA and age and BMI. Mean daytime (but not nighttime) activity for wrist and ankle decreased significantly with age (p < .05). PA variability also decreased with age for wrist and ankle during daytime and for ankle during nighttime (p < .05). BMI was negatively associated with wrist daytime PA variability (p < .05). There were no gender effects on activity measures. These findings indicate that wrist and ankle mean PA measures were not significantly different but were significantly different (p < 0.5) for PA variability in both daytime and nighttime. Age-related decreases of PA-mean and variability were observed during daytime in wrist and ankle, whereas higher wrist daytime variability was inversely associated with BMI. These findings provide new insights into PA features in free-living environment, which are relevant for public health and may have implications for clinical assessment of neurodegenerative disorders impacting PA and their interaction with demographics. PMID- 29702675 TI - A lightweight and secure two factor anonymous authentication protocol for Global Mobility Networks. AB - Global Mobility Networks(GLOMONETs) in wireless communication permits the global roaming services that enable a user to leverage the mobile services in any foreign country. Technological growth in wireless communication is also accompanied by new security threats and challenges. A threat-proof authentication protocol in wireless communication may overcome the security flaws by allowing only legitimate users to access a particular service. Recently, Lee et al. found Mun et al. scheme vulnerable to different attacks and proposed an advanced secure scheme to overcome the security flaws. However, this article points out that Lee et al. scheme lacks user anonymity, inefficient user authentication, vulnerable to replay and DoS attacks and Lack of local password verification. Furthermore, this article presents a more robust anonymous authentication scheme to handle the threats and challenges found in Lee et al.'s protocol. The proposed protocol is formally verified with an automated tool(ProVerif). The proposed protocol has superior efficiency in comparison to the existing protocols. PMID- 29702674 TI - Characterization of a morphogenetic furrow specific Gal4 driver in the developing Drosophila eye. AB - The ability to express a gene of interest in a spatio-temporal manner using Gal4 UAS system has allowed the use of Drosophila model to study various biological phenomenon. During Drosophila eye development, a synchronous wave of differentiation called Morphogenetic furrow (MF) initiates at the posterior margin resulting in differentiation of retinal neurons. This synchronous differentiation is also observed in the differentiating retina of vertebrates. Since MF is highly dynamic, it can serve as an excellent model to study patterning and differentiation. However, there are not any Gal4 drivers available to observe the gain- of- function or loss- of- function of a gene specifically along the dynamic MF. The decapentaplegic (dpp) gene encodes a secreted protein of the transforming growth factor-beta (TGF-beta) superfamily that expresses at the posterior margin and then moves with the MF. However, unlike the MF associated pattern of dpp gene expression, the targeted dpp-Gal4 driver expression is restricted to the posterior margin of the developing eye disc. We screened GMR lines harboring regulatory regions of dpp fused with Gal4 coding region to identify MF specific enhancer of dpp using a GFP reporter gene. We employed immuno-histochemical approaches to detect gene expression. The rationale was that GFP reporter expression will correspond to the dpp expression domain in the developing eye. We identified two new dpp-Gal4 lines, viz., GMR17E04-Gal4 and GMR18D08-Gal4 that carry sequences from first intron region of dpp gene. GMR17E04 Gal4 drives expression along the MF during development and later in the entire pupal retina whereas GMR18D08-Gal4 drives expression of GFP transgene in the entire developing eye disc, which later drives expression only in the ventral half of the pupal retina. Thus, GMR18D08-Gal4 will serve as a new reagent for targeting gene expression in the ventral half of the pupal retina. We compared misexpression phenotypes of Wg, a negative regulator of eye development, using GMR17E04-Gal4, GMR18D08-Gal4 with existing dpp-Gal4 driver. The eye phenotypes generated by using our newly identified MF specific driver are not similar to the ones generated by existing dpp-Gal4 driver. It suggests that misexpression studies along MF needs revisiting using the new Gal4 drivers generated in our studies. PMID- 29702676 TI - Predictors for patients understanding reason for hospitalization. AB - OBJECTIVE: To examine predictors for understanding reason for hospitalization. METHODS: This was a retrospective analysis of a prospective, observational cohort study of patients 65 years or older admitted for acute coronary syndrome, heart failure, or pneumonia and discharged home. Primary outcome was complete understanding of diagnosis, based on post-discharge patient interview. Predictors assessed were the following: jargon on discharge instructions, type of medical team, whether outpatient provider knew if the patient was admitted, and whether the patient reported more than one day notice before discharge. RESULTS: Among 377 patients, 59.8% of patients completely understood their diagnosis. Bivariate analyses demonstrated that outpatient provider being aware of admission and having more than a day notice prior to discharge were not associated with patient understanding diagnosis. Presence of jargon was not associated with increased likelihood of understanding in a multivariable analysis. Patients on housestaff and cardiology teams were more likely to understand diagnosis compared to non teaching teams (OR 2.45, 95% CI 1.30-4.61, p<0.01 and OR 3.83, 95% CI 1.92-7.63, p<0.01, respectively). CONCLUSIONS: Non-teaching team patients were less likely to understand their diagnosis. Further investigation of how provider-patient interaction differs among teams may aid in development of tools to improve hospital to community transitions. PMID- 29702677 TI - Acceptability of oral rapid HIV testing at dental clinics in communities with high HIV prevalence in South Florida. AB - BACKGROUND: Expanding HIV screening for populations at risk necessitates testing in nontraditional settings. We assessed HIV testing in dental clinics in South Florida, an urban area with the highest rates of HIV diagnoses in the United States in 2015. AIMS: We explored patients' acceptance of oral HIV rapid tests administered by dental providers and identified reasons for accepting or declining HIV testing. METHODS: During 2014 and 2015, dentists and hygienists at two federally qualified health center (FQHC) dental clinics who serve racial/ethnic minority patient populations in South Florida were trained to administer oral HIV rapid tests as a part of a routine dental visit. Patients presenting for dental services were offered a rapid HIV test and brief survey regarding their demographics, HIV testing history and behaviors. RESULTS: We enrolled 600 patients (median age = 43 years; IQR: 29-56 years), 45% non-Hispanic black and 35% Hispanic/Latino, 83% graduated high school, and 50% unemployed. Most (85%) accepted oral HIV rapid testing (none tested HIV-positive); 14% had never been tested for HIV. The most common reasons for testing were a desire to know HIV status (56%) and free testing (54%). Among 93 (15%) patients who declined testing, 58% were tested recently and 31% felt confident that they were HIV-negative; however, 74 (80%) who declined testing said they would feel comfortable discussing HIV prevention with their dentist. Additionally, 290 of 600 patients (48%) reported condomless vaginal or anal sex in the past 6 months. Further, among 119 patients who had condomless sex with an HIV-positive partner and/or one whose HIV status was unknown, 98 (82%) accepted the oral HIV test. CONCLUSION: Dental clinics may provide expanded opportunities for oral HIV rapid testing and conversations about HIV prevention in high HIV prevalence communities. PMID- 29702678 TI - Expression of the eight GABAA receptor alpha subunits in the developing zebrafish central nervous system. AB - GABA is a robust regulator of both developing and mature neural networks. It exerts many of its effects through GABAA receptors, which are heteropentamers assembled from a large array of subunits encoded by distinct genes. In mammals, there are 19 different GABAA subunit types, which are divided into the alpha, beta, gamma, delta, epsilon, pi, theta and rho subfamilies. The immense diversity of GABAA receptors is not fully understood. However, it is known that specific isoforms, with their distinct biophysical properties and expression profiles, tune responses to GABA. Although larval zebrafish are well-established as a model system for neural circuit analysis, little is known about GABAA receptors diversity and expression in this system. Here, using database analysis, we show that the zebrafish genome contains at least 23 subunits. All but the mammalian theta and epsilon subunits have at least one zebrafish ortholog, while five mammalian GABAA receptor subunits have two zebrafish orthologs. Zebrafish contain one subunit, beta4, which does not have a clear mammalian ortholog. Similar to mammalian GABAA receptors, the zebrafish alpha subfamily is the largest and most diverse of the subfamilies. In zebrafish there are eight alpha subunits, and RNA in situ hybridization across early zebrafish development revealed that they demonstrate distinct patterns of expression in the brain, spinal cord, and retina. Some subunits were very broadly distributed, whereas others were restricted to small populations of cells. Subunit-specific expression patterns in zebrafish resembled were those found in frogs and rodents, which suggests that the roles of different GABAA receptor isoforms are largely conserved among vertebrates. This study provides a platform to examine isoform specific roles of GABAA receptors within zebrafish neural circuits and it highlights the potential of this system to better understand the remarkable heterogeneity of GABAA receptors. PMID- 29702679 TI - Secretagogin is increased in plasma from type 2 diabetes patients and potentially reflects stress and islet dysfunction. AB - Beta cell dysfunction accompanies and drives the progression of type 2 diabetes mellitus (T2D), but there are few clinical biomarkers available to assess islet cell stress in humans. Secretagogin, a protein enriched in pancreatic islets, demonstrates protective effects on beta cell function in animals. However, its potential as a circulating biomarker released from human beta cells and islets has not been studied. In this study primary human islets, beta cells and plasma samples were used to explore secretion and expression of secretagogin in relation to the T2D pathology. Secretagogin was abundantly and specifically expressed and secreted from human islets. Furthermore, T2D patients had an elevated plasma level of secretagogin compared with matched healthy controls, which was confirmed in plasma of diabetic mice transplanted with human islets. Additionally, the plasma secretagogin level of the human cohort had an inverse correlation to clinical assessments of beta cell function. To explore the mechanism of secretagogin release in vitro, human beta cells (EndoC-betaH1) were exposed to elevated glucose or cellular stress-inducing agents. Secretagogin was not released in parallel with glucose stimulated insulin release, but was markedly elevated in response to endoplasmic reticulum stressors and cytokines. These findings indicate that secretagogin is a potential novel biomarker, reflecting stress and islet cell dysfunction in T2D patients. PMID- 29702680 TI - The economic burden of not meeting food recommendations in Canada: The cost of doing nothing. AB - Few studies have estimated the economic burden of chronic diseases (e.g., type 2 diabetes, cardiovascular diseases, cancers) attributable to unhealthy eating. In this study, we estimated the economic burden of chronic disease attributable to not meeting Canadian food recommendations. We first obtained chronic disease risk estimates for intakes of both protective (1. vegetables; 2. fruit; 3. whole grains; 4. milk; 5. nuts and seeds) and harmful (6. processed meat; 7. red meat; 8. sugar-sweetened beverages) foods from the Global Burden of Disease Study, and food intakes from the 2004 Canadian Community Health Survey 24-hour dietary recalls (n = 33,932 respondents). We then calculated population attributable fractions (PAFs) for all relevant food-chronic disease combinations by age and sex groups. These PAFs were then mathematically combined for each disease for each age and sex group. We then estimated attributable costs by multiplying these combined PAFs with estimated 2014 annual direct health care (hospital, drug, physician) and indirect (human capital approach) costs for each disease. We found that not meeting recommendations for the eight foods was responsible for CAD$13.8 billion/year (direct health care: CAD$5.1 billion, indirect: CAD$8.7 billion). Nuts and seeds and whole grains were the top cost contributors rather than vegetables and fruit. Our findings suggest that unhealthy eating constitutes a tremendous economic burden to Canada that is similar in magnitude to the burden of smoking and larger than that of physical inactivity which were estimated using similar approaches. A status quo in promotion of healthy eating will allow this burden to continue. Interventions to reduce the health and economic burden of unhealthy eating in Canada may be more effective if they are broad in focus and include promotion of nuts and seeds and whole grains along with vegetables and fruit rather than have a narrow focus such as primarily on vegetables and fruit. PMID- 29702681 TI - Knowledge of hepatitis C status moderates the relationship between history of drug treatment and sterile syringe use. AB - High-risk injection related behavior including use of non-sterile syringes is associated with negative health outcomes among people who inject drugs (PWID). Drug treatment programs have been reported to curb hepatitis C (HCV) transmission. This study aims to assess the role of drug treatment programs and knowledge of HCV status, and how they influence current injection-related risk. Data were collected in 2012 by the New Orleans arm of the CDC funded National HIV Behavioral Surveillance. Respondent driven sampling was used to recruit a sample of PWID. The analytic sample consisted of 473 participants. Univariate, bivariate, and linear regression analyses were performed. Findings indicated that history of drug treatment is associated with sterile syringe use among PWID. Further, knowledge of HCV status modifies the relationship between history of drug treatment and sterile syringe use in this sample. These findings highlight the importance of scaling up prevention efforts by expanding testing, counselling, and treatment for HCV among PWID who enter drug treatment facilities. PMID- 29702682 TI - Restrictive lung disorder is common in patients with kidney failure and associates with protein-energy wasting, inflammation and cardiovascular disease. AB - BACKGROUND: Cardiovascular disease (CVD), protein-energy wasting (PEW), and inflammation are common interrelated features of chronic kidney disease (CKD). Less is known about lung dysfunction in CKD and its possible role in this context. We evaluated lung function and its association with estimated glomerular filtration rate (GFR), CVD, PEW, and inflammation in individuals with normal to severely reduced GFR. METHODS: In 404 individuals with GFR category G1 (n = 31; GFR >90mL/min/1.73 m2), G2 (n = 46), G3 (n = 33), G4 (n = 49) and G5 (n = 245; GFR<15mL/min/1.73 m2), pulmonary function was assessed by spirometry. Obstructive (OLD) and restrictive (RLD) lung dysfunction was defined based on forced vital capacity (FVC), forced expiratory volume in the first second (FEV1) and peak expiratory flow (PEF), expressed as percentages of predicted values (%FEV1, %FVC and %PEF, respectively). PEW was evaluated by subjective global assessment, handgrip strength (HGS) and lean body mass index (LBMI), and inflammation by interleukin-6 and high sensitivity C-reactive protein. RESULTS: RLD (defined as FEV1/FVC >= 0.70 and %FVC<80) associated with GFR and was present in 36% of G5 and 14% of G1-4 individuals. OLD (FEV1/FVC<0.70) was less common with similar prevalence among G1-4 (9%) and G5 (11%) individuals. Notably, 64% of those with concomitant presence of PEW, inflammation and clinical signs of CVD had RLD while 79% of those lacking these complications had normal lung function. In multivariate logistic regression analysis, RLD associated with CVD, PEW and inflammation, after adjusting for Framingham's CVD risk score, serum albumin, and GFR category. CONCLUSIONS: RLD is a common complication in patients with advanced CKD, especially in those with concomitant presence of CVD, inflammation and PEW. RLD appears to be an integral albeit scarcely explored consequence of pulmonary renal interactions in CKD patients. PMID- 29702685 TI - Correction: Fitting power-laws in empirical data with estimators that work for all exponents. AB - [This corrects the article DOI: 10.1371/journal.pone.0170920.]. PMID- 29702684 TI - A 50-50% mixture of nitrous oxide-oxygen in transrectal ultrasound-guided prostate biopsy: A randomized and prospective clinical trial. AB - INTRODUCTION: Transrectal ultrasound-guided biopsy (TUSPB) is the standard method of diagnosis for prostate cancer, and although it is well tolerated by some patients, it presents a discomfort rate of 65 to 90%, which may be associated with pain. For convenience, it is agreed that a method of analgesia and sedation is necessary. For this purpose, this study aimed to evaluate the impact of inhalation of a 50-50% N2O-O2 gas mixture on pain intensity in these patients. MATERIAL AND METHODS: Randomized, double-blinded clinical trial, conducted at Antonio Pedro University Hospital (Hospital Universitario Antonio Pedro), Niteroi, RJ, Brazil, containing two groups of 42 patients: a control (C) group, which received 100% oxygen inhalation, and a nitrous oxide (NO) group, which received inhalation of the 50-50% N2O-O2 mixture, self-administered during TUSPB. The pain intensity and degree of satisfaction were evaluated through a visual analogue scale (VAS), as was the frequency of adverse events. RESULTS: Eighty four patients were included in the study, with 42 in each group. The mean pain intensity was lower in the NO group than in the C group [2.52 (0-10) vs 5.95 (0 10), p < 0.001], and the degree of satisfaction was higher in the NO group than in the C group (8.14 vs. 4.69, p < 0.001). The adverse effects were somnolence, dizziness, nausea, vomiting, discomfort and euphoria without differences between the groups. CONCLUSION: The 50-50% N2O-O2 mixture was effective in reducing pain intensity and increasing the degree of satisfaction in TUSPB, with tolerable side effects. PMID- 29702683 TI - Mental health problems in relation to eating behavior patterns, nutrient intakes and health related quality of life among Iranian female adolescents. AB - AIMS: To identify the association between mental health problems, eating behavior patterns, nutrient intakes and health related quality of life (HRQoL) among Iranian female adolescents. MATERIALS AND METHODS: The current cross-sectional study conducted among three high-schools randomly selected from 10-day-public high schools in the selected sub-county from Tabriz city-Iran between December 2015 through March 2016. Participants were a sample of 107 adolescent girls aged 15-17 years old. Anthropometric parameters were measured and assessments of HRQoL, mental health problems and eating behavioral patterns were performed by Short Form 36 (SF-36), Strengths and Difficulties Questionnaires (SDQ) and Eating Behavioral Pattern Questionnaire (EBPQ) respectively. Dietary intake was assessed using a semi-quantitative Food-Frequency Questionnaire (FFQ) adapted for the Iranian society. Quality of life was measured with HRQoL questionnaire. Quantitative analysis using independent sample t test was performed for comparison of continuous variables between two subgroups (unlikely, possible/probable) of each category of mental health problem. Multiple logistic regression was used to measure the potential predictors (e.g. eating patterns and HRQoL) of mental health problems in two models of crude and adjusted for age and body mass index (BMI). P values less than 0.05 were considered as statistically significant. RESULTS: Indicators of conduct problems and hyperactivity disorders were the most prevalent mental health problems among female adolescents (25.2% and 18.6% respectively). The prevalence of hyperactivity disorders among female adolescents was 35.5%. Female adolescents in high scores of 'snacking and convenience', 'planning ahead' and 'meal skipping' eating patterns were more likely to have indicators of emotional disorders (P < 0.05). Also, being in the high tertile of 'low fat eating' pattern made adolescents less likely to have hyperactivity disorders (P < 0.05). Moreover, according to our finding, high scores of vitality and mental health components of HRQoL were associated with reduced likelihood of emotional disorders, conduct disorders and hyperactivity disorders. No significant difference in terms of BMI and nutrient intakes in different categories of mental health problems according to SDQ scoring was identified. CONCLUSIONS: In the current study unhealthy eating patterns including 'snacking and convenience', 'planning ahead' and 'meal skipping' eating patterns were positive predictors of "emotional disorders" while "low fat" eating pattern was negative predictor of hyperactivity disorders. PMID- 29702686 TI - Multiple poliovirus-induced organelles suggested by comparison of spatiotemporal dynamics of membranous structures and phosphoinositides. AB - At the culmination of poliovirus (PV) multiplication, membranes are observed that contain phosphatidylinositol-4-phosphate (PI4P) and appear as vesicular clusters in cross section. Induction and remodeling of PI4P and membranes prior to or concurrent with genome replication has not been well studied. Here, we exploit two PV mutants, termed EG and GG, which exhibit aberrant proteolytic processing of the P3 precursor that substantially delays the onset of genome replication and/or impairs virus assembly, to illuminate the pathway of formation of PV induced membranous structures. For WT PV, changes to the PI4P pool were observed as early as 30 min post-infection. PI4P remodeling occurred even in the presence of guanidine hydrochloride, a replication inhibitor, and was accompanied by formation of membrane tubules throughout the cytoplasm. Vesicular clusters appeared in the perinuclear region of the cell at 3 h post-infection, a time too slow for these structures to be responsible for genome replication. Delays in the onset of genome replication observed for EG and GG PVs were similar to the delays in virus-induced remodeling of PI4P pools, consistent with PI4P serving as a marker of the genome-replication organelle. GG PV was unable to convert virus induced tubules into vesicular clusters, perhaps explaining the nearly 5-log reduction in infectious virus produced by this mutant. Our results are consistent with PV inducing temporally distinct membranous structures (organelles) for genome replication (tubules) and virus assembly (vesicular clusters). We suggest that the pace of formation, spatiotemporal dynamics, and the efficiency of the replication-to-assembly-organelle conversion may be set by both the rate of P3 polyprotein processing and the capacity for P3 processing to yield 3AB and/or 3CD proteins. PMID- 29702687 TI - Macrophage migration inhibitory factor is critical for dengue NS1-induced endothelial glycocalyx degradation and hyperpermeability. AB - Vascular leakage is one of the salient characteristics of severe dengue. Nonstructural protein 1 (NS1) of dengue virus (DENV) can stimulate endothelial cells to secrete endothelial hyperpermeability factor, macrophage migration inhibitory factor (MIF), and the glycocalyx degradation factor heparanase 1 (HPA 1). However, it is unclear whether MIF is directly involved in NS1-induced glycocalyx degradation. In this study, we observed that among NS1, MIF and glycocalyx degradation-related molecules, the HPA-1, metalloproteinase 9 (MMP-9) and syndecan 1 (CD138) serum levels were all increased in dengue patients, and only NS1 and MIF showed a positive correlation with the CD138 level in severe patients. To further characterize and clarify the relationship between MIF and CD138, we used recombinant NS1 to stimulate human cells in vitro and challenge mice in vivo. Our tabulated results suggested that NS1 stimulation could induce human endothelial cells to secrete HPA-1 and immune cells to secrete MMP-9, resulting in endothelial glycocalyx degradation and hyperpermeability. Moreover, HPA-1, MMP-9, and CD138 secretion after NS1 stimulation was blocked by MIF inhibitors or antibodies both in vitro and in mice. Taken together, these results suggest that MIF directly engages in dengue NS1-induced glycocalyx degradation and that targeting MIF may represent a possible therapeutic approach for preventing dengue-induced vascular leakage. PMID- 29702688 TI - Upregulation of the aging related LMNA splice variant progerin in dilated cardiomyopathy. AB - BACKGROUND: Mutations in the LMNA gene are a common cause (6-8%) of dilated cardiomyopathy (DCM) leading to heart failure, a growing health care problem worldwide. The premature aging disease Hutchinson-Gilford syndrome (HGPS) is also caused by defined mutations in the LMNA gene resulting in activation of a cryptic splice donor site leading to a defective truncated prelamin A protein called progerin. Low levels of progerin are expressed in healthy individuals associated with ageing. Here, we aimed to address the role of progerin in dilated cardiomyopathy. METHODS AND RESULTS: mRNA expression of progerin was analyzed in heart tissue of DCM (n = 15) and non-failing hearts (n = 10) as control and in blood samples from patients with DCM (n = 56) and healthy controls (n = 10). Sequencing confirmed the expression of progerin mRNA in the human heart. Progerin mRNA levels derived from DCM hearts were significantly upregulated compared to controls (1.27 +/- 0.42 vs. 0.81 +/- 0.24; p = 0.005). In contrast, progerin mRNA levels in whole blood cells were not significantly different in DCM patients compared to controls. Linear regression analyses revealed that progerin mRNA in the heart is significantly negatively correlated to ejection fraction (r = 0.567, p = 0.003) and positively correlated to left ventricular enddiastolic diameter (r = 0.551, p = 0.004) but not with age of the heart per se. Progerin mRNA levels were not influenced by inflammation in DCM hearts. Immunohistochemistry and Immunofluorescence analysis confirmed increased expression of progerin protein in cell nuclei of DCM hearts associated with increased TUNEL+ apoptotic cells. CONCLUSION: Our data suggest that progerin is upregulated in human DCM hearts and strongly correlates with left ventricular remodeling. Progerin might be involved in progression of heart failure and myocardial aging. PMID- 29702690 TI - An automated, high-throughput plant phenotyping system using machine learning based plant segmentation and image analysis. AB - A high-throughput plant phenotyping system automatically observes and grows many plant samples. Many plant sample images are acquired by the system to determine the characteristics of the plants (populations). Stable image acquisition and processing is very important to accurately determine the characteristics. However, hardware for acquiring plant images rapidly and stably, while minimizing plant stress, is lacking. Moreover, most software cannot adequately handle large scale plant imaging. To address these problems, we developed a new, automated, high-throughput plant phenotyping system using simple and robust hardware, and an automated plant-imaging-analysis pipeline consisting of machine-learning-based plant segmentation. Our hardware acquires images reliably and quickly and minimizes plant stress. Furthermore, the images are processed automatically. In particular, large-scale plant-image datasets can be segmented precisely using a classifier developed using a superpixel-based machine-learning algorithm (Random Forest), and variations in plant parameters (such as area) over time can be assessed using the segmented images. We performed comparative evaluations to identify an appropriate learning algorithm for our proposed system, and tested three robust learning algorithms. We developed not only an automatic analysis pipeline but also a convenient means of plant-growth analysis that provides a learning data interface and visualization of plant growth trends. Thus, our system allows end-users such as plant biologists to analyze plant growth via large-scale plant image data easily. PMID- 29702689 TI - Wheezing phenotypes and risk factors in early life: The ELFE cohort. AB - OBJECTIVE: Different phenotypes of wheezing have been described to date but not in early life. We aim to describe wheezing phenotypes between the ages of two months and one year, and assess risk factors associated with these wheezing phenotypes in a large birth cohort. METHODS: We studied 18,041 infants from the ELFE (French Longitudinal Study of Children) birth cohort. Parents reported wheezing and respiratory symptoms at two and 12 months, and answered a complete questionnaire (exposure during pregnancy, parental allergy). RESULTS: Children with no symptoms (controls) accounted for 77.2%, 2.1% had had wheezing at two months but no wheezing at one year (intermittent), 2.4% had persistent wheezing, while 18.3% had incident wheezing at one year. Comparing persistent wheezing to controls showed that having one sibling (ORa = 2.19) or 2 siblings (ORa = 2.23) compared to none, nocturnal cough (OR = 5.2), respiratory distress (OR = 4.1) and excess bronchial secretions (OR = 3.47) at two months, reflux in the child at 2 months (OR = 1.55), maternal history of asthma (OR = 1.46) and maternal smoking during pregnancy (OR = 1.57) were significantly associated with persistent wheezing. These same factors, along with cutaneous rash in the child at 2 months (OR = 1.13) and paternal history of asthma (OR = 1.32) were significantly associated with increased odds of incident wheezing. Having one sibling (ORa = 1.9) compared to none, nocturnal cough at 2 months (OR = 1.76) and excess bronchial secretions at 2 months (OR = 1.65) were significantly associated with persistent compared to intermittent wheezing. CONCLUSION: Respiratory symptoms (cough, respiratory distress, and excessive bronchial secretion) were significantly associated with a high risk of persistent wheezing at one year. Smoking exposure during pregnancy was also a risk factor for persistent and incident wheezing. PMID- 29702691 TI - Extracellular adenosine modulates host-pathogen interactions through regulation of systemic metabolism during immune response in Drosophila. AB - Phagocytosis by hemocytes, Drosophila macrophages, is essential for resistance to Streptococcus pneumoniae in adult flies. Activated macrophages require an increased supply of energy and we show here that a systemic metabolic switch, involving the release of glucose from glycogen, is required for effective resistance to S. pneumoniae. This metabolic switch is mediated by extracellular adenosine, as evidenced by the fact that blocking adenosine signaling in the adoR mutant suppresses the systemic metabolic switch and decreases resistance to infection, while enhancing adenosine effects by lowering adenosine deaminase ADGF A increases resistance to S. pneumoniae. Further, that ADGF-A is later expressed by immune cells during infection to regulate these effects of adenosine on the systemic metabolism and immune response. Such regulation proved to be important during chronic infection caused by Listeria monocytogenes. Lowering ADGF-A specifically in immune cells prolonged the systemic metabolic effects, leading to lower glycogen stores, and increased the intracellular load of L. monocytogenes, possibly by feeding the bacteria. An adenosine-mediated systemic metabolic switch is thus essential for effective resistance but must be regulated by ADGF-A expression from immune cells to prevent the loss of energy reserves and possibly to avoid the exploitation of energy by the pathogen. PMID- 29702692 TI - Relationships between infant mortality, birth spacing and fertility in Matlab, Bangladesh. AB - Although research on the fertility response to childhood mortality is widespread in demographic literature, very few studies focused on the two-way causal relationships between infant mortality and fertility. Understanding the nature of such relationships is important in order to design effective policies to reduce child mortality and improve family planning. In this study, we use dynamic panel data techniques to analyse the causal effects of infant mortality on birth intervals and fertility, as well as the causal effects of birth intervals on mortality in rural Bangladesh, accounting for unobserved heterogeneity and reverse causality. Simulations based upon the estimated model show whether (and to what extent) mortality and fertility can be reduced by breaking the causal links between short birth intervals and infant mortality. We find a replacement effect of infant mortality on total fertility of about 0.54 children for each infant death in the comparison area with standard health services. Eliminating the replacement effect would lengthen birth intervals and reduce the total number of births, resulting in a fall in mortality by 2.45 children per 1000 live births. These effects are much smaller in the treatment area with extensive health services and information on family planning, where infant mortality is smaller, birth intervals are longer, and total fertility is lower. In both areas, we find evidence of boy preference in family planning. PMID- 29702693 TI - Work characteristics, motivational orientations, psychological work ability and job mobility intentions of older workers. AB - Drawing on job design theories and a conceptual framework of work-related goals and motivation in later adulthood, the aim of this paper is to explore how work related and individual factors are separately and jointly related to psychological work ability and bridge employment intentions via late job mobility. The cross-sectional study is based on a sample of 171 older Spanish workers aged 45-65 and beyond. We differentiated between groups of older workers in mid career (45-55 years of age) and in their later careers (56 years and beyond). Our results confirm that task characteristics and, secondarily, knowledge characteristics are the most relevant factors in perceptions of psychological work ability among aged workers. Both age groups display a very marked personal mastery trait, which mediates the relationships between job characteristics and both psychological work ability and late job mobility intentions. The paper concludes with a discussion of theoretical and practical implications and suggestions for future research on the issues implied in the psychological adjustment of older workers in their mid and late careers. PMID- 29702694 TI - Test selection for antibody detection according to the seroprevalence level of Schmallenberg virus in sheep. AB - Schmallenberg virus (SBV), initially identified in Germany in 2011, spread rapidly throughout Europe causing significant economic losses in ruminant livestock. The ability to correctly detect emerging and re-emerging diseases such as SBV with reliable tests is of high importance. Firstly, we tested diagnostic performance, specificity, and sensitivity of three different assays used in SBV antibody detection using control sheep samples of determined status. After obtaining the results from the control samples, we assessed the potential of the assays to detect previously infected animals in field situations. The samples were investigated using IDEXX Schmallenberg virus Antibody Test Kit, ID Screen Schmallenberg virus Competition Multi-species ELISA and Serum Neutralisation Test (SNT). Analysis of control samples revealed that SNT was the most suitable test, which was therefore used to calculate concordance and test performance for the two other ELISA tests. To evaluate whether different assay performances had an impact under field conditions, sheep samples from two different contexts were tested: the emergence of SBV in Ireland and the re-emergence of SBV in Belgium. Comparing the results obtained from different assays to the non-reference standard assay SNT, we showed considerable differences in estimates of their sensitivity to detect SBV antibodies and to measure seroprevalence of the sheep flocks. Finally, a calculation of the number of randomly selected animals that needs to be screened from a finite flock, showed that SNT and ID.Vet are the most suitable to detect an introduction of the disease in low seroprevalence situations. The IDEXX ELISA test was only able to detect SBV antibodies in a higher seroprevalence context, which is not optimal for monitoring freedom of disease and surveillance studies. PMID- 29702695 TI - Performance of next-generation sequencing on small tumor specimens and/or low tumor content samples using a commercially available platform. AB - BACKGROUND: Next generation sequencing tests (NGS) are usually performed on relatively small core biopsy or fine needle aspiration (FNA) samples. Data is limited on what amount of tumor by volume or minimum number of FNA passes are needed to yield sufficient material for running NGS. We sought to identify the amount of tumor for running the PCDx NGS platform. METHODS: 2,723 consecutive tumor tissues of all cancer types were queried and reviewed for inclusion. Information on tumor volume, success of performing NGS, and results of NGS were compiled. Assessment of sequence analysis, mutation calling and sensitivity, quality control, drug associations, and data aggregation and analysis were performed. RESULTS: 6.4% of samples were rejected from all testing due to insufficient tumor quantity. The number of genes with insufficient sensitivity make definitive mutation calls increased as the percentage of tumor decreased, reaching statistical significance below 5% tumor content. The number of drug associations also decreased with a lower percentage of tumor, but this difference only became significant between 1-3%. The number of drug associations did decrease with smaller tissue size as expected. Neither specimen size or percentage of tumor affected the ability to pass mRNA quality control. A tumor area of 10 mm2 provides a good margin of error for specimens to yield adequate drug association results. CONCLUSIONS: Specimen suitability remains a major obstacle to clinical NGS testing. We determined that PCR-based library creation methods allow the use of smaller specimens, and those with a lower percentage of tumor cells to be run on the PCDx NGS platform. PMID- 29702696 TI - Adaptive fractional order sliding mode control for Boost converter in the Battery/Supercapacitor HESS. AB - In this paper, an adaptive fractional order sliding mode control (AFSMC) scheme is designed for the current tracking control of the Boost-type converter in a Battery/Supercapacitor hybrid energy storage system (HESS). In order to stabilize the current, the adaptation rules based on state-observer and Lyapunov function are being designed. A fractional order sliding surface function is defined based on the tracking current error and adaptive rules. Furthermore, through fractional order analysis, the stability of the fractional order control system is proven, and the value of the fractional order (lambda) is being investigated. In addition, the effectiveness of the proposed AFSMC strategy is being verified by numerical simulations. The advantages of good transient response and robustness to uncertainty are being indicated by this design, when compared with a conventional integer order sliding mode control system. PMID- 29702697 TI - SLAMM: Visual monocular SLAM with continuous mapping using multiple maps. AB - This paper presents the concept of Simultaneous Localization and Multi-Mapping (SLAMM). It is a system that ensures continuous mapping and information preservation despite failures in tracking due to corrupted frames or sensor's malfunction; making it suitable for real-world applications. It works with single or multiple robots. In a single robot scenario the algorithm generates a new map at the time of tracking failure, and later it merges maps at the event of loop closure. Similarly, maps generated from multiple robots are merged without prior knowledge of their relative poses; which makes this algorithm flexible. The system works in real time at frame-rate speed. The proposed approach was tested on the KITTI and TUM RGB-D public datasets and it showed superior results compared to the state-of-the-arts in calibrated visual monocular keyframe-based SLAM. The mean tracking time is around 22 milliseconds. The initialization is twice as fast as it is in ORB-SLAM, and the retrieved map can reach up to 90 percent more in terms of information preservation depending on tracking loss and loop closure events. For the benefit of the community, the source code along with a framework to be run with Bebop drone are made available at https://github.com/hdaoud/ORBSLAMM. PMID- 29702699 TI - Predicting language diversity with complex networks. AB - We analyze the model of social interactions with coevolution of the topology and states of the nodes. This model can be interpreted as a model of language change. We propose different rewiring mechanisms and perform numerical simulations for each. Obtained results are compared with the empirical data gathered from two online databases and anthropological study of Solomon Islands. We study the behavior of the number of languages for different system sizes and we find that only local rewiring, i.e. triadic closure, is capable of reproducing results for the empirical data in a qualitative manner. Furthermore, we cancel the contradiction between previous models and the Solomon Islands case. Our results demonstrate the importance of the topology of the network, and the rewiring mechanism in the process of language change. PMID- 29702698 TI - Comprehensive behavioral analysis of the Cdkl5 knockout mice revealed significant enhancement in anxiety- and fear-related behaviors and impairment in both acquisition and long-term retention of spatial reference memory. AB - Mutations in the Cyclin-dependent kinase-like 5 (CDKL5) gene cause severe neurodevelopmental disorders. Recently we have generated Cdkl5 KO mice by targeting exon 2 on the C57BL/6N background, and demonstrated postsynaptic overaccumulation of GluN2B-containing N-methyl-D-aspartate (NMDA) receptors in the hippocampus. In the current study, we subjected the Cdkl5 KO mice to a battery of comprehensive behavioral tests, aiming to reveal the effects of loss of CDKL5 in a whole perspective of motor, emotional, social, and cognition/memory functions, and to identify its undetermined roles. The neurological screen, rotarod, hot plate, prepulse inhibition, light/dark transition, open field, elevated plus maze, Porsolt forced swim, tail suspension, one-chamber and three chamber social interaction, 24-h home cage monitoring, contextual and cued fear conditioning, Barnes maze, and T-maze tests were applied on adult Cdkl5 -/Y and +/Y mice. Cdkl5 -/Y mice showed a mild alteration in the gait. Analyses of emotional behaviors revealed significantly enhanced anxiety-like behaviors of Cdkl5 -/Y mice. Depressive-like behaviors and social interaction of Cdkl5 -/Y mice were uniquely altered. The contextual and cued fear conditioning of Cdkl5 /Y mice were comparable to control mice; however, Cdkl5 -/Y mice showed a significantly increased freezing time and a significantly decreased distance traveled during the pretone period in the altered context. Both acquisition and long-term retention of spatial reference memory were significantly impaired. The morphometric analysis of hippocampal CA1 pyramidal neurons revealed impaired dendritic arborization and immature spine development in Cdkl5 -/Y mice. These results indicate that CDKL5 plays significant roles in regulating emotional behaviors especially on anxiety- and fear-related responses, and in both acquisition and long-term retention of spatial reference memory, which suggests that focus and special attention should be paid to the specific mechanisms of these deficits in the CDKL5 deficiency disorder. PMID- 29702700 TI - What capacity exists to provide essential inpatient care to small and sick newborns in a high mortality urban setting? - A cross-sectional study in Nairobi City County, Kenya. AB - INTRODUCTION: Appropriate demand for, and supply of, high quality essential neonatal care is key to improving newborn survival but evaluating such provision has received limited attention in low- and middle-income countries. Moreover, specific local data are needed to support healthcare planning for this vulnerable population. METHODS: We conducted health facility assessments between July 2015 April 2016, with retrospective review of admission events between 1st July 2014 and 30th June 2015, and used estimates of population-based incidence of neonatal conditions in Nairobi to explore access and evaluate readiness of public, private not-for-profit (mission), and private-for-profit (private) sector facilities providing 24/7 inpatient neonatal care in Nairobi City County. RESULTS: In total, 33 (4 public, 6 mission, and 23 private) facilities providing 24/7 inpatient neonatal care in Nairobi City County were identified, 31 were studied in detail. Four public sector facilities, including the only three facilities in which services were free, accounted for 71% (8,630/12,202) of all neonatal admissions. Large facilities (>900 annual admissions) with adequate infrastructure tended to have high bed occupancy (over 100% in two facilities), high mortality (15%), and high patient to nurse ratios (7-15 patients per nurse). Twenty-one smaller, predominantly private, facilities were judged insufficiently resourced to provide adequate care. In many of these, nurses provided newborn and maternity care simultaneously using resources shared across settings, newborn care experience was likely to be limited (<50 cases per year), there was often no resident clinician, and sick babies were often referred onwards. Results suggest 44% (9,764/21,966) of Nairobi's small and sick newborns may not access any of the identified facilities and a further 9% (2,026/21,966) access facilities judged to be inadequately equipped. CONCLUSION: Over 50% of Nairobi's sick newborns may not access a facility with adequate resources to provide essential care. A very high proportion of care accessed is provided by four public and one low cost mission facility; these face major challenges of high patient acuity (high mortality), high patient to nurse ratios, and often overcrowding. Reducing high neonatal mortality in this urban, predominantly poor, population will require effective long-term, multi-sectoral planning and investment. PMID- 29702701 TI - Glycolysis regulates pollen tube polarity via Rho GTPase signaling. AB - As a universal energy generation pathway utilizing carbon metabolism, glycolysis plays an important housekeeping role in all organisms. Pollen tubes expand rapidly via a mechanism of polarized growth, known as tip growth, to deliver sperm for fertilization. Here, we report a novel and surprising role of glycolysis in the regulation of growth polarity in Arabidopsis pollen tubes via impingement of Rho GTPase-dependent signaling. We identified a cytosolic phosphoglycerate kinase (pgkc-1) mutant with accelerated pollen germination and compromised pollen tube growth polarity. pgkc-1 mutation greatly diminished apical exocytic vesicular distribution of REN1 RopGAP (Rop GTPase activating protein), leading to ROP1 hyper-activation at the apical plasma membrane. Consequently, pgkc-1 pollen tubes contained higher amounts of exocytic vesicles and actin microfilaments in the apical region, and showed reduced sensitivity to Brefeldin A and Latrunculin B, respectively. While inhibition of mitochondrial respiration could not explain the pgkc-1 phenotype, the glycolytic activity is indeed required for PGKc function in pollen tubes. Moreover, the pgkc-1 pollen tube phenotype was mimicked by the inhibition of another glycolytic enzyme. These findings highlight an unconventional regulatory function for a housekeeping metabolic pathway in the spatial control of a fundamental cellular process. PMID- 29702708 TI - PROLONG Clinical Study Protocol: Hydroxyprogesterone Caproate to Reduce Recurrent Preterm Birth. AB - The objective of this commentary is to describe the background, rationale, and methods of the PROLONG (Progestin's Role in Optimizing Neonatal Gestation) trial, which is a multicenter, multinational, placebo-controlled, randomized clinical trial (RCT) designed to assess the safety and efficacy of Makena (hydroxyprogesterone caproate injection, 250 mg/mL) in reducing the risk of preterm birth (PTB) and neonatal morbidity/mortality in women pregnant with a singleton gestation who had a previous singleton spontaneous PTB. The total sample size of the RCT will include 1,707 women. The trial has two coprimary outcomes: PTB less than 35 weeks and a composite neonatal morbidity and mortality index. This study sample size will provide 90% power to assess for a 35% reduction in neonatal morbidity and mortality. Secondary outcomes will include 2 year follow-up of infants. The trial is ongoing and targeted to complete recruitment in 2018. PMID- 29702709 TI - Neonatal Outcomes Based on Duration of Exposure to Antenatal Corticosteroids in Indicated Preterm Deliveries. AB - OBJECTIVE: To evaluate how duration of exposure to antenatal corticosteroids (ACSs) prior to delivery affects neonatal outcomes in indicated preterm deliveries. STUDY DESIGN: This is a retrospective cohort of all indicated singleton preterm deliveries (23-34 weeks) in a single tertiary center from 2011 to 2014 comparing those who received ACS 2 to 7 days versus >7 days prior to delivery. The primary neonatal outcome was a composite of arterial cord pH < 7 or base excess <= 12, 5-minute Apgar <= 3, cardiopulmonary resuscitation, culture proven neonatal sepsis, intraventricular hemorrhage grade III/IV, necrotizing enterocolitis, and neonatal death. Analyses were stratified by delivering gestational age (230/7-276/7, 280/7-316/7, and 320/7-336/7 weeks). Multivariate logistic regression refined point estimates and adjusted for confounders. RESULTS: In total, 301 women delivered >48 hours after initial ACS dose, 230 delivered within 2 to 7 days, and 71 delivered >7 days. Infants with an interval of >7 days had no significant increase in the unadjusted composite neonatal outcome (p = 0.42), but when adjusted, the composite neonatal outcome (adjusted odds ratio [AOR]: 2.7; 95% confidence interval [CI]: 1.18-6.31) and neonatal death (AOR: 4.20; 95% CI: 1.39-12.69) were significantly increased with an ACS interval of >7 day. CONCLUSION: In this cohort, the benefit of ACS diminished >7 days after administration, particularly when delivery occurred at <32 weeks. PMID- 29702702 TI - Interaction of healthcare staff's attitude with barriers to physical activity in hemodialysis patients: A quantitative assessment. AB - BACKGROUND AND AIM OF THE STUDY: In hemodialysis patients, sedentarism is a potentially modifiable mortality risk factor. We explored whether healthcare staff's attitude towards exercise interacts with patient-perceived barriers in modifying the level of physical activity in this population. METHODS: In this prospective, cross-sectional, multicenter study we recruited 608 adult patients and 330 members of the healthcare staff in 16 hemodialysis units in Italy. We assessed patient-perceived barriers to, and healthcare staff's attitude towards, exercise by specific questionnaires. We fitted multilevel linear models to analyze the relationships of either barriers or staff's attitude, and their interaction, with a measure of patient self-reported physical activity (the Human Activity Profile-Adjusted Activity Score [HAP-AAS]), adjusting for multiple confounders. We also employed latent class analysis to dichotomize patients into those endorsing or not endorsing barriers. RESULTS: Most barriers were negatively associated with the HAP-AAS (adjusted change attributable to a given barrier ranging between -5.1 ["Feeling too old", 95% Confidence Interval: -9.4 to -0.8] and -15.6 ["Ulcers on legs and feet", 95%CI: -24.8 to -6.5]. We found a significant interaction between staff's attitude and barriers (adjusted P values ranging between 0.03 ["I do not believe that it is physician's or nurse's role providing advice on exercise to patients on dialysis"] and 0.001 ["I do not often ask patients about exercise"]). A beneficial effect of a proactive staff's attitude was evident only in patients not endorsing barriers. CONCLUSIONS: Barriers and non-proactive staff's attitude reduce physical activity in hemodialysis patients. Patients not endorsing barriers benefit the most from a proactive staff's attitude. PMID- 29702711 TI - Acute Post-Tracheostomy Clinical Decompensations in Infants-Are There Predictive Markers? AB - OBJECTIVE: To report on the population of infants receiving a tracheostomy, identify acute post-tracheostomy clinical decompensations, and seek predictive markers associated with acute complications following the placement of a tracheostomy. STUDY DESIGN: Retrospective deidentified clinical data was provided by the Infant Pulmonary Data Repository at Children's Mercy Hospital, Kansas City. Data from infants undergoing tracheostomy from January 1, 2008 through September 30, 2016 were divided into one of two study groups based on clinical correlations: (1) no acute decompensations within 72 hours post tracheostomy or (2) acute clinical decompensation defined as sustained escalation of respiratory care within the 72 hours following tracheostomy. RESULTS: Thirty four percent of infants undergoing tracheostomy during this period developed acute post-tracheostomy clinical decompensations. Elevated pre-tracheostomy positive end expiratory pressure, mean airway pressure, and echocardiogram findings suggestive of pulmonary hypertension (PH) or ventricular dysfunction were associated with acute post-tracheostomy clinical decompensations. Additionally acute post-tracheostomy clinical decompensation was associated with higher rate of death prior to discharge. CONCLUSION: Infants requiring higher respiratory support and infants with PH or ventricular dysfunction are at risk of acute post-tracheostomy clinical decompensation, thus identifying these patients may lead to better pre-tracheostomy counseling and potentially targeted treatments to decrease this risk. PMID- 29702710 TI - Neonatal Morbidities among Moderately Preterm Infants with and without Exposure to Antenatal Corticosteroids. AB - OBJECTIVE: We aimed to compare the rates of "surfactant treated respiratory disease" and other neonatal morbidities among moderately preterm (MPT) infants exposed to no, partial, or a complete course of antenatal corticosteroids (ANS). STUDY DESIGN: This observational cohort study evaluated MPT infants (290/7-336/7 weeks' gestational age), born between January 2012 and November 2013 and enrolled in the "MPT Registry" of the National Institute of Child Health and Human Development Neonatal Research Network. RESULTS: Data were available for 5,886 infants, including 676 with no exposure, 1225 with partial, and 3,985 with a complete course of ANS. Among no, partial, and complete ANS groups, respectively, there were significant differences in rates of delivery room resuscitation (4.1, 1.4, and 1.2%), surfactant-treated respiratory disease (26.5, 26.3, and 20%), and severe intracranial hemorrhage (3, 2, and 0.8%). Complete ANS course was associated with lower surfactant-treated respiratory disease, compared with partial ANS (odds ratio [OR] 0.62; 95% confidence interval [CI] 0.52-0.74), and no ANS groups (OR 0.52; 95% CI 0.41-0.66) on adjusted analysis. CONCLUSION: In MPT infants, ANS exposure is associated with lower delivery room resuscitation, surfactant-treated respiratory disease, and severe intracranial hemorrhage; with the lowest frequency of morbidities associated with a complete course. PMID- 29702712 TI - Development of a NeuroNICU with a Broader Focus on All Newborns at Risk of Brain Injury: The First 2 Years. AB - OBJECTIVE: Many critically ill neonates have an existing brain injury or are at risk of neurologic injury. We developed a "NeuroNICU" (neurologic neonatal intensive care unit) to better provide neurologically focused intensive care. STUDY DESIGN: Demographic and clinical variables, services delivered, and patient outcomes were recorded in a prospective database for all neonates admitted to the NeuroNICU between April 23, 2013, and June 25, 2015. RESULTS: In total, 546 neonates were admitted to the NeuroNICU representing 32% of all NICU admissions. The most common admission diagnoses were congenital heart disease (30%), extreme prematurity (18%), seizures (10%), and hypoxic-ischemic encephalopathy (9%). Neuromonitoring was common, with near-infrared spectroscopy used in 69%, amplitude-integrated electroencephalography (EEG) in 45%, and continuous video EEG in 35%. Overall, 43% received neurology or neurosurgery consultation. Death prior to hospital discharge occurred in 11%. Among survivors, 87% were referred for developmental follow-up, and among those with a primary neurologic diagnosis 57% were referred for neurology or neurosurgical follow-up. CONCLUSION: The NeuroNICU-admitted newborns with or at risk of brain injury comprise a high percentage of NICU volume; 38% had primary neurologic diagnoses, whereas 62% had medical diagnoses. We found many opportunities to provide brain focused intensive care, impacting a substantial proportion of newborns in our NICU. PMID- 29702713 TI - Predictors of Bleeding in Patients with Symptomatic Peripheral Artery Disease: A Cohort Study Using The Health Improvement Network in the United Kingdom. AB - The purpose of this analysis was to assess potential predictors of intra-cranial bleeding (ICB) and gastrointestinal bleeding (GIB) in patients with symptomatic peripheral artery disease (PAD) in UK primary care. Patients with symptomatic PAD diagnosed from 2000 to 2010 were identified from The Health Improvement Network (THIN; N = 28,484). A nested case-control analysis, adjusted for potential confounders, was performed to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for potential predictors of ICB or GIB. For GIB, follow-up was restricted to Hospital Episode Statistics-linked THIN practices. Median follow-up was 6 years. For ICB (153 cases), the OR (95% CI) was 3.85 (1.33-11.13) for previous ICB, 0.90 (0.61-1.34) for treated hypertension, 1.59 (0.65-3.87) for untreated hypertension and 1.38 (0.80-2.36) for current smoking. ORs for ICB were 0.78 (0.50-1.21), 0.40 (0.09-1.82) and 1.27 (0.47-3.47) with use of acetylsalicylic acid (ASA), clopidogrel and warfarin monotherapy, respectively, compared with non-use of such therapy. For GIB (506 cases), the OR was 1.40 (1.05 1.86) for peptic ulcer disease, 3.20 (1.81-5.64) for dual anti-platelet therapy use, 1.96 (1.46-2.64) for non-steroidal anti-inflammatory drug (NSAID) use and 1.01 (0.80-1.28) for proton pump inhibitor use. ORs for GIB were 1.78 (1.39 2.30), 2.03 (1.05-3.93) and 1.25 (0.72-2.16) with ASA, clopidogrel and warfarin monotherapy, respectively, compared with non-use. Previous ICB was a risk factor for ICB. Use of anti-platelet therapy or NSAIDs increased GIB risk. Identifying bleeding predictors could help optimize treatment strategies for patients with PAD. PMID- 29702714 TI - Abstracts of the 46th Annual Meeting of the SENP (Societe Europeenne De Neurologie Pediatrique)-Barcelona April 27th to 28th, 2018. PMID- 29702715 TI - Hemoptysis and Endometriosis: An Unusual Association - Case Report and Review of the Literature. AB - Thoracic endometriosis syndrome is a rare condition that includes four entities: catamenial pneumothorax, catamenial hemothorax, catamenial hemoptysis and lung nodules. We describe the case of a 23-year-old woman with complaints of hemoptysis during menstrual period in the two years prior to the appointment. Initially, a treatment for tuberculosis was established with no success. Further investigation showed a 4 mm nodule in the right lung, and the transvaginal ultrasonography indicated the presence of deep endometriosis. Considering the occurrence of symptoms only during menses, an empirical therapy was instituted with remission of the complaints. PMID- 29702716 TI - Effectiveness of Metformin in the Prevention of Gestational Diabetes Mellitus in Obese Pregnant Women. AB - OBJECTIVE: To assess the effectiveness of metformin in the incidence of gestational diabetes mellitus (GDM) in obese pregnant women attending a public maternity hospital in Joinville, Santa Catarina, Brazil. METHODS: Randomized clinical trial including obese pregnant women with a body mass index (BMI) >= 30 kg/m2, divided into two groups (control and metformin). Both groups received guidance regarding diet and physical exercise. The participants were assessed at two moments, the first at enrollment (gestational age <= 20) and the second at gestational weeks 24-28. The outcomes assessed were BMI and gestational diabetes mellitus (GDM) diagnosis. The data distribution was assessed with the Friedman test. For all the analytical models, the p-values were considered significant when lower than 0.05. The absolute risk reduction was also estimated. RESULTS: Overall, 164 pregnant women were assessed and further divided into 82 participants per group. No significant difference was observed in BMI variation between the control and metformin groups (0.9 +/- 1.2 versus 1.0 +/- 0.9, respectively, p = 0.63). Gestational diabetes mellitus was diagnosed in 15.9% (n = 13) of the patients allocated to the metformin group and 19.5% (n = 16) of those in the control group (p = 0.683). The absolute risk reduction was 3.6 (95% confidence interval 8.0-15.32) in the group treated with metformin, which was not significant. CONCLUSION: Metformin was not effective in reducing BMI and preventing GDM in obese pregnant women. PMID- 29702717 TI - Association between Hormonal Contraception and Injuries Induced by Human Papillomavirus in the Uterine Cervix. AB - OBJECTIVE: To evaluate the association between hormonal contraception and the appearance of human papillomavirus HPV-induced lesions in the uterine cervix of patients assisted at a school outpatient clinic - ObGyn outpatient service of the Universidade do Sul de Santa Catarina. METHODS: A case-control study, with women in fertile age, performed between 2012 and 2015. A total of 101 patients with cervical lesions secondary to HPV were included in the case group, and 101 patients with normal oncotic colpocytology, in the control group. The data were analyzed through the Statistical Package for the Social Sciences (SPSS, IBM Corp. Armonk, NY, US) software, version 24.0, using the 95% confidence interval. To test the homogeneity of the proportions, the chi-square (chi2) test was used for the qualitative variables, and the Student t-test, for the quantitative variables. RESULTS: When comparing the occurrence of HPV lesions in users and non-users of combined oral contraceptives (COCs), the association with doses of 0.03 mg or higher of ethinylestradiol (EE) was observed. Thus, a higher probability of developing cervical lesions induced by HPV was identified (odds ratio [OR]: 1.9 p = 0.039); and when these cases were separated by the degree of the lesion, the probability of these patients presenting with low-grade squamous intraepithelial lesion was 2.1 times higher (p = 0.036), but with no impact on high-grade squamous intraepithelial lesions and the occurrence of invasive cancer. No significant differences were found in the other variables analyzed. CONCLUSION: Although the results found in the present study suggest a higher probability of the users of combined hormonal contraceptives with a concentration higher than 0.03 mg of EE to develop low-grade intraepithelial lesions, more studies are needed to conclude causality. PMID- 29702718 TI - A Critical Review on Obstetric Follow-up of Women Affected by Systemic Lupus Erythematosus. AB - OBJECTIVE: To review the existing recommendations on the prenatal care of women with systemic lupus erythematosus (SLE), based on currently available scientific evidence. METHODS: An integrative review was performed by two independent researchers, based on the literature available in the MEDLINE (via PubMed), EMBASE and The Cochrane Library databases, using the medical subject headings (MeSH) terms "systemic lupus erythematosus" AND "high-risk pregnancy" OR "prenatal care." Studies published in English between 2007 and 2017 were included; experimental studies and case reports were excluded. In cases of disagreement regarding the inclusion of studies, a third senior researcher was consulted. Forty titles were initially identified; four duplicates were excluded. After reading the abstracts, 7 were further excluded and 29 were selected for a full-text evaluation. RESULTS: Systemic lupus erythematosus flares, preeclampsia, gestation loss, preterm birth, fetal growth restriction and neonatal lupus syndromes (mainly congenital heart-block) were the major complications described. The multidisciplinary team should adopt a specific monitoring, with particular therapeutic protocols. There are safe and effective drug options that should be prescribed for a good control of SLE activity. CONCLUSION: Pregnant women with SLE present an increased risk for maternal complications, pregnancy loss and other adverse outcomes. The disease activity may worsen and, thereby, increase the risk of other maternal-fetal complications. Thus, maintaining an adequate control of disease activity and treating flares quickly should be a central goal during prenatal care. PMID- 29702719 TI - Evaluation of a Novel Degradable Synthetic Biomaterial Patch for Augmentation of Tendon Healing in a Large Animal Model. AB - Tendon injury is common in sports. The standard of care (SOC) for tendon repair is surgical treatment. However, restored tendons often lack complete strength and functionality, and surgical repair is often unsuccessful. This controlled laboratory study investigates the healing of an Artelon patch (AP)-augmented tendon versus tendon repair alone in a preclinical canine patellar tendon defect model. Full-thickness proximal and distal flap defects were created in the patella tendons of eight purpose-bred research mongrel dogs. Dogs were randomly allocated into either the AP-augmented repair group or the SOC group (N = 8; four knees per group). Outcomes measures included limb function and pain; range of motion (ROM) and ultrasound assessment at 2, 4, and 8 weeks; and measurements of elongation, biomechanical testing, and histology at 8 weeks. Data were compared for statistically significant differences to preoperative measures and between groups (p < 0.05). The AP group had higher limb function scores compared with the SOC group at 2, 4, and 8 weeks, with statistically significant differences observed at 2 weeks (AP: 7.1 +/- 1.4, SOC: 5.5 +/- 0.4, p < 0.05) and 8 weeks (AP: 9.5 +/- 0.7, SOC: 7.0 +/- 0.9, p < 0.05). The ROM was significantly higher for the AP group at 4 weeks (AP: 105 degrees +/- 4, SOC: 89 degrees +/- 5, p < 0.05). Pain scores were statistically significantly lower in the AP group at 4 (AP: 0.6 +/- 0.5, SOC: 2.2 +/- 0.5) and 8 weeks (p < 0.05 for both comparisons). All animals in the AP group displayed full bridging tissue at week 4, while most animals of the SOC group displayed full bridging by week 8. Minimal tendon elongation was observed in both groups. Significantly more force was required to elongate tendons in the AP group compared with the SOC group (p < 0.05). Animals with AP-augmented tendon repair show an earlier regain of function, earlier regain of range of movement, less postoperative pain, and improved tendon strength when compared with animals treated with tendon repair alone. PMID- 29702720 TI - Patients Screening Positive for Body Dysmorphic Disorder Show No Significant Health-Related Quality of Life Gain after Functional Septorhinoplasty at a Tertiary Referral Center. AB - Body dysmorphic disorder (BDD) is a psychiatric disorder defined by an excessive concern about one's physical appearance, especially regarding slight or imagined abnormities of the body. This study was conducted to compare postoperative quality of life (QOL) changes after primary septorhinoplasty among patients screening positive and those screening negative for BDD. Two common instruments for the screening of BDD were used namely the Dysmorphic Concern Questionnaire (DCQ) and the BDD Concern Questionnaire (BDDQ). For the determination of QOL changes, three validated screening instruments were used. The Functional Rhinoplasty Outcome Inventory (FROI-17) and the Rhinoplasty Outcomes Evaluation (ROE) were used as disease-specific instruments and the Short Form 36 Health Survey (SF-36) was used as a general instrument. All patients completed the FROI 17, the ROE, and the SF-36 preoperatively and 60 months postoperatively. The BDD questionnaires were singularly obtained 60 months after surgery. The authors identified 9.8% of our patients with a possible BDD diagnosis. The patients screening positive for BDD showed significantly lower ROE scores postoperatively, compared with those screening negative for BDD. QOL gains detected by the disease specific instruments (ROE and FROI-17) were only significant in the non-BDD group. No significant QOL gains were detectable with the FROI-17, the ROE, and the SF-36 in the BDD group. In patients screening negative for BDD, QOL, as measured with the SF-36, improved significantly in five categories: physical functioning, role-functioning physical, bodily pain, general health, and social functioning. Patients screening positive for BDD did not improve in any categories of the general SF-36 questionnaire. Instead, their score in the "mental health" category was significantly lower 5 years after their surgery compared with preoperatively. Patients retrospectively screening positive for BDD in our cohort did not improve in QOL postoperatively. Alternative nonsurgical treatments such as cognitive behavioral treatment and/or selective serotonin reuptake inhibitors have been reported to be effective and should be considered as the treatment of choice. Some studies suggest that a smaller subgroup of BDD patients may benefit from functional rhinoplasty. Further research and larger long-term prospective outcome studies are needed to understand the influence of BDD symptoms on postoperative satisfaction and QOL changes after septorhinoplasty. PMID- 29702721 TI - Complications of Polydioxanone Foil Use in Nasal Surgery: A Case Series. AB - Polydioxanone (PDS) foil is widely recognized as a septal cartilage replacement during rhinoplasties and is thought to be completely resorbable and biodegradable. Since its United States Food and Drug Administration approval in 2010, PDS foil has drawn significant enthusiasm and many surgeons consider it an ideal implantable biomaterial as reflected in numerous studies highlighting its benefits. However, scant literature exists highlighting relevant complications of PDS plates that may potentially lead to cavalier overuse. This descriptive case series assesses the outcomes of PDS foil usage in three patients seen for septoplasty at two independent institutions over the past 5 years. Our results demonstrate that PDS plate usage can lead to septal cartilage loss and resultant saddle nose deformity associated with prolonged postoperative edema and inflammation. To our knowledge, this is the largest case series of this reported phenomenon. PMID- 29702723 TI - Professor Zofia Bielanska-Osuchowska (1919-2017). PMID- 29702722 TI - Phosphodiesterase 5 Inhibitors from Derris scandens. AB - Phosphodiesterase 5 inhibitors have been used as a first-line medicine for the treatment of erectile dysfunction. In the search for new phosphodiesterase 5 inhibitors from natural sources, we found that the 95% ethanol extract of Derris scandens stem showed phosphodiesterase 5 inhibitory activity with an IC50 value of about 7 ug/mL. Seven isoflavones and a coumarin constituent isolated from this plant were investigated for phosphodiesterase 5 inhibitory activity. The results showed that osajin (8: ), 4',5,7-trihydroxybiprenylisoflavone (4: ), and derrisisoflavone A (2: ) had the ability to inhibit phosphodiesterase 5 with IC50 values of 4, 8, and 9 uM, respectively. These compounds exhibited selectivity on phosphodiesterase 5 over phosphodiesterase 1, however, the selectivity on phosphodiesterase 5 over phosphodiesterase 6 was low. In order to quantitatively determine these bioactive constituents in D. scandens extract, LC-QTOF-MS method has been developed and validated. The limit of quantitation values in the range of 0.1 - 5 ug/mL were obtained. The assay showed satisfactory precision and accuracy. The results from our method showed that the 95% ethanol extract of D. scandens stem was comprised of all eight compounds, with derrisisoflavone A (2: ) and lupalbigenin (3: ) presenting as the major constituents. PMID- 29702724 TI - Using and navigating the plant tree of life. PMID- 29702725 TI - Effects of the Kv7 voltage-activated potassium channel inhibitor linopirdine in rat models of haemorrhagic shock. AB - Recently, we demonstrated that Kv7 voltage-activated potassium channel inhibitors reduce fluid resuscitation requirements in short-term rat models of haemorrhagic shock. The aim of the present study was to further delineate the therapeutic potential and side effect profile of the Kv7 channel blocker linopirdine in various rat models of severe haemorrhagic shock over clinically relevant time periods. Intravenous administration of linopirdine, either before (1 or 3 mg/kg) or after (3 mg/kg) a 40% blood volume haemorrhage, did not affect blood pressure and survival in lethal haemorrhage models without fluid resuscitation. A single bolus of linopirdine (3 mg/kg) at the beginning of fluid resuscitation after haemorrhagic shock transiently reduced early fluid requirements in spontaneously breathing animals that were resuscitated for 3.5 hours. When mechanically ventilated rats were resuscitated after haemorrhagic shock with normal saline (NS) or with linopirdine-supplemented (10, 25 or 50 MUg/mL) NS for 4.5 hours, linopirdine significantly and dose-dependently reduced fluid requirements by 14%, 45% and 55%, respectively. Lung and colon wet/dry weight ratios were reduced with linopirdine (25/50 MUg/mL). There was no evidence for toxicity or adverse effects based on measurements of routine laboratory parameters and inflammation markers in plasma and tissue homogenates. Our findings support the concept that linopirdine-supplementation of resuscitation fluids is a safe and effective approach to reduce fluid requirements and tissue oedema formation during resuscitation from haemorrhagic shock. PMID- 29702726 TI - Moss protonemata are dispersed by water, wind, and snails. AB - PREMISE OF THE STUDY: Mosses produce asexual propagules, which are dispersed, thus allowing population establishment and maintenance. However, it is unknown if or how protonemata-one of their asexually produced propagules-are dispersed. Moss protonemata were exposed to three dispersal vectors (water, wind, and snails) to describe the dispersal capability and survival after dispersal. METHODS: The protonemata of mosses Callicostella belangeriana and Taxiphyllum taxirameum were splashed with water drops from a 1 or 2 m height, exposed to two wind velocities (V1 = 2.74 mps and V2 = 3.76 mps), and fed to terrestrial snails. Dispersal of protonemata was described for wind and water by studying the dispersal distance and the relationships between protonemata sizes and dispersal distances. Survival after dispersal was recorded for the three vectors. KEY RESULTS: Water and wind dispersed protonemata up to 80 and 265.5 cm, respectively. The protonemata dispersed the farthest distance when splashed by 2 m drops and hit by V2 wind velocities. No, or little, relationship between protonemata size and dispersal distance was found for the water and wind vectors. Protonemata survived and became established after dispersal: survival was high when dispersed by water and snails, but was low for wind. CONCLUSIONS: For the first time, it was shown that protonemata are dispersed mostly close to the source, which is suggested to aid in moss population maintenance. PMID- 29702727 TI - On the robustness of N-mixture models. AB - N-mixture models provide an appealing alternative to mark-recapture models, in that they allow for estimation of detection probability and population size from count data, without requiring that individual animals be identified. There is, however, a cost to using the N-mixture models: inference is very sensitive to the model's assumptions. We consider the effects of three violations of assumptions that might reasonably be expected in practice: double counting, unmodeled variation in population size over time, and unmodeled variation in detection probability over time. These three examples show that small violations of assumptions can lead to large biases in estimation. The violations of assumptions we consider are not only small qualitatively, but are also small in the sense that they are unlikely to be detected using goodness-of-fit tests. In cases where reliable estimates of population size are needed, we encourage investigators to allocate resources to acquiring additional data, such as recaptures of marked individuals, for estimation of detection probabilities. PMID- 29702728 TI - Collagen IV and laminin-1 expression in embryonic mouse lens using principal components analysis technique. AB - Immunohistochemistry section staining is not always easy to interpret. Manual quantification of immunohistochemical staining is limited by the observer visual ability to detect changes in level staining. Hence, the quantification of immunostaining by means of digital image analysis allows us to measure accurately protein expression percentages in immunobiological stained tissues and ensures to overcome the visual limitations. We perform an experimental study to analyse the impact of folic acid (FA) deficiency into collagen IV and laminin-1 expression in the embryonic mouse lens. The study starts with microscope images of embryos mouse lens whose mothers fed a diet deficient in FA during 2 and 8 weeks. A principal component analysis (PCA) image processing is used to analyse these images coming from control and FA deficit groups. The method permits to define an index of over- or infraexpression of collagen IV and laminin-1 associated to different spatial organisation structures (PC processes). Additionally, it permits to determine in precise percentage the exact quantity of the overexpression or infraexpression and finally to comprehend molecular regionalisation and expression in both control and deficient groups. The results suggest that even with 2 weeks of deficit of FA the expression and distribution of both molecules is affected. PMID- 29702729 TI - Phylogenomic analyses reveal extensive gene flow within the magic flowers (Achimenes). AB - PREMISE OF THE STUDY: The Neotropical Gesneriaceae is a lineage known for its colorful and diverse flowers, as well as an extensive history of intra- and intergeneric hybridization, particularly among Achimenes (the magic flowers) and other members of subtribe Gloxiniinae. Despite numerous studies seeking to elucidate the evolutionary relationships of these lineages, relatively few have sought to infer specific patterns of gene flow despite evidence of widespread hybridization. METHODS: To explore the utility of phylogenomic data for reassessing phylogenetic relationships and inferring patterns of gene flow among species of Achimenes, we sequenced 12 transcriptomes. We used a variety of methods to infer the species tree, examine gene tree discordance, and infer patterns of gene flow. KEY RESULTS: Phylogenomic analyses resolve clade relationships at the crown of the lineage with strong support. In contrast to previous analyses, we recovered strong support for several new relationships despite a significant amount of gene tree discordance. We present evidence for at least two introgression events between two species pairs that share pollinators, and suggest that the species status of Achimenes admirabilis be reexamined. CONCLUSIONS: Our study demonstrates the utility of transcriptome data for phylogenomic analyses, and inferring patterns of gene flow despite gene tree discordance. Moreover, these data provide another example of prevalent interspecific gene flow among Neotropical plants that share pollinators. PMID- 29702730 TI - Foliar anatomy and microscopy of six Brazilian species of Baccharis (Asteraceae). AB - We report for the first time the presence of cluster crystals of calcium oxalate within the glandular trichomes and oil bodies in the mesophyll for Baccharis species. Moreover, the comparative leaf anatomy and micro-morphology of six species of Baccharis, namely B. illinita, B. microdonta, B. pauciflosculosa, B. punctulata, B. reticularioides, and B. sphenophylla is investigated by light and scanning electron microscopy. The studied species exhibited differences in their leaf anatomical features such as the morphology of the cuticle, type and occurrence of the stomata, presence or absence of glandular trichomes, shape of the flagelliform trichomes, and the arrangement of the mesophyll tissues. These differences can be helpful in the species identification and classification and could represent informative characters for the reconstruction of the evolution of the genus. PMID- 29702731 TI - Therapeutic Drug Monitoring of Teicoplanin in Haematological Malignancy Patients with Febrile Neutropenia and Optimizing Dosage Regimens. AB - This study used high-performance liquid chromatography to measure 202 teicoplanin plasma trough concentrations (Cmin ) in 114 haematological malignancy patients with febrile neutropenia. Patients were divided into two groups according to the mean initial dose (MID) over the first 3 days of treatment: (i) MID = 533.33 mg/day (loading dose group, 400 mg q12h for three doses followed by 400 mg qd, n = 62) and (ii) MID < 533.33 mg/day (unloaded or underloaded group, n = 52). During the first 3 days after treatment, the overall Cmin was higher in group 1 than in group 2 (10.96 +/- 5.44 mg/L versus 6.31 +/- 3.73 mg/L, mean +/- S.D.; p = 0.002), as was the qualifying rate of Cmin > 10 mg/L (54.5% versus 11.1%, p = 0.001), and the probability of Cmin < 5 mg/L was lower in group 1 than in group 2 (13.6% versus 40.7%, p = 0.037). After 3 days, the average Cmin and qualifying rates did not differ significantly between the two groups, and the average Cmin was <10 mg/L in both groups. Binary logistic regression analysis revealed that creatinine clearance (p = 0.004) and MID (p = 0.010) could affect Cmin during the first 3 days of treatment and that age (p = 0.022) only could affect Cmin after 3 days. In conclusion, it is necessary to apply loading dose to achieve teicoplanin Cmin > 10 mg/L rapidly and, from a pharmacokinetic/pharmacodynamic perspective, 600 mg is recommended as loading and maintenance dose for these patients when AUC24 /minimum inhibitory concentration > 345. PMID- 29702732 TI - New Insights Toward Quantitative Relationships between Lignin Reactivity to Monomers and Their Structural Characteristics. AB - The heterogeneous and complex structural characteristics of lignin present a significant challenge to predict its processability (e.g., depolymerization, modifications etc.) to valuable products. This study provides a detailed characterization and comparison of structural properties of seven representative biorefinery lignin samples derived from forest and agricultural residues, which were subjected to representative pretreatment methods. A range of wet chemistry and spectroscopy methods were applied to determine specific lignin structural characteristics such as functional groups, inter-unit linkages, and peak molecular weight. In parallel, oxidative depolymerization of these lignin samples to either monomeric phenolic compounds or dicarboxylic acids were conducted, and the product yields were quantified. Based on these results (lignin structural characteristics and monomer yields), we applied for the first time the multivariable linear estimation (MVLE) approach using R Statistics (an open source programming language and software environment for statistical computing and graphics) to gain insight toward a quantitative correlation between lignin structural properties and their conversion reactivity toward oxidative depolymerization to monomers. PMID- 29702733 TI - How Often Do Safety Signals Occur by Chance in First-in-Human Trials? AB - Clinicians working on first-in-human clinical studies need to be able to judge whether safety signals observed on an investigational drug were more likely to have occurred by chance or to have been caused by the drug. We retrospectively reviewed 84 Novartis studies including 1,234 healthy volunteers receiving placebo to determine the expected incidence of changes in commonly measured laboratory parameters and vital signs, in the absence of any active agent. We calculated the frequency of random incidence of safety signals, focusing on the liver, cardiovascular system, kidney, and pancreas. Using the liver enzyme alanine aminotransferase (ALT) as an example, we illustrate how a predictive model can be used to determine the probability of a given subject to experience an elevation of ALT above the upper limit of the normal range under placebo, conditional on the characteristics of this subject and the study. PMID- 29702734 TI - Heparin-dopamine functionalized graphene foam for sustained release of bone morphogenetic protein-2. AB - The recently developed three-dimensional (3D) graphene foam (GrF) is intriguing for potential bone tissue engineering applications because it provides stem cells with a 3D porous substrate for osteogenic differentiation. However, the nature of graphene's structure lacks functional groups, thus making it difficult for further modification such as immobilization or conjugation of growth factors, which are normally required to promote tissue regeneration. To explore the potential of GrF functionalization and sustained release of therapeutic proteins, we fabricated a modified 3D GrF scaffold with bio-inspired heparin-dopamine (Hepa Dopa) molecules using a highly scalable chemical vapour deposition method. Our data indicated that Hepa-Dopa modification resulted in significantly higher bone morphogenetic protein-2 (BMP2) binding ability and longer release capacity compared with the untreated scaffolds. Importantly, the heparin-functionalized 3D GrF significantly improved the exogenous BMP2-induced osteogenic differentiation. Therefore, our study, for the first time, indicated that the 3D GrF can be biomimetically functionalized with Hepa-Dopa and be used for sustained release of BMP2, thereby inducing osteogenic differentiation and suggesting promising potential as a new multifunctional carrier for therapeutic proteins and stem cells in bone tissue engineering. PMID- 29702735 TI - Effects of UGT1A1, CYP3A5 and ABCB1 Genetic Variants on Pharmacokinetics of Antihistamine Drug Mizolastine in Chinese Healthy Volunteers. AB - Mizolastine is a selective histamine H1 receptor antagonist for chronic urticaria or allergic rhinitis. We investigated whether the variant genotypes of metabolic enzymes UGT1A1, CYP3A5 and transporter ABCB1 influence pharmacokinetic phenotype of substrate mizolastine in Chinese volunteers. Genotyping of single nucleotide polymorphisms in UGT1A1*6 (G211A), CYP3A5*3 (A6986G) and ABCB1 (C3435T) was determined by the pyrosequencing method. After a single oral dose of 10 mg mizolastine, the plasma concentrations were measured using validated high performance liquid chromatography in 24 Chinese healthy volunteers. The results showed that the distributions of wild-type homozygotes and variant allele carriers (the sum of variant heterozygotes and variant homozygotes) were as follows: 17 cases (70.8%) versus seven cases (29.2%) in UGT1A1*6 genotypes, five cases (20.8%) versus 19 cases (79.2%) in CYP3A5*3 genotypes and seven cases (29.2%) versus 17 cases (70.8%) in ABCB1 3435T genotypes, respectively. There were no significant differences in pharmacokinetic parameters of mizolastine between the variant allele UGT1A1*6, CYP3A5*3 and ABCB1 3435T carriers and the wild-type homozygotes, and the ratios were as follows: Cmax was 101.03%, 86.02% and 105.78%; Tmax was 162.35%, 98.98% and 144.90%; AUC0-28 was 113.04%, 77.35% and 112.71%; and t1/2 was 95.77%, 72.40% and 100.97%, respectively. In conclusion, these results suggested that the UGT1A1, CYP3A5 and ABCB1 genetic polymorphisms might be not contributed to the interindividual variation of mizolastine pharmacokinetic phenotype in the Chinese population. PMID- 29702737 TI - New Styryl Phenanthroline Derivatives as Model D-pi-A-pi-D Materials for Non Linear Optics. AB - Four novel push-pull systems combining a central phenanthroline acceptor moiety and two substituted benzene rings, as a part of the conjugated pi-system between the donor and the acceptor moieties, have been synthetized through a straightforward and efficient one-step procedure. The chromophores display high fluorescence and a peculiar fluorosolvatochromic behaviour. Ultrafast investigation by means of state-of-the-art femtosecond-resolved transient absorption and fluorescence up-conversion spectroscopies allowed the role of intramolecular charge transfer (ICT) states to be evidenced, also revealing the crucial role played by both, the polarity and proticity of the medium on the excited state dynamics of the chromophores. The ICT processes, responsible for the solvatochromism, also lead to interesting non-linear optical (NLO) properties: namely great two photon absorption cross-sections (hundreds of GM), investigated by the Two Photon Excited Fluorescence (TPEF) technique, and large second order hyperpolarizability coefficients, estimated through a convenient solvatochromic method. PMID- 29702736 TI - Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure-FLT3 Relationship. AB - Sorafenib administered at the approved dose continuously is not tolerated long term in patients with acute myeloid leukemia (AML). The purpose of this study was to optimize the dosing regimen by characterizing the sorafenib exposure-response relationship in patients with AML. A one-compartment model with a transit absorption compartment and enterohepatic recirculation described the exposure. The relationship between sorafenib exposure and target modulation of kinase targets (FMS-like tyrosine kinase 3 (FLT3)-ITD and extracellular signal-regulated kinase (ERK)) were described by an inhibitory maximum effect (Emax ) model. Sorafenib could inhibit FLT3-ITD activity by 100% with an IC50 of 69.3 ng/mL and ERK activity by 84% with an IC50 of 85.7 ng/mL (both adjusted for metabolite potency). Different dosing regimens utilizing 200 or 400 mg at varying frequencies were simulated based on the exposure-response relationship. Simulations demonstrate that a 200 mg twice daily (b.i.d.) dosing regimen showed similar FLT3-ITD and ERK inhibitory activity compared with 400 mg b.i.d. and is recommended in further clinical trials in patients with AML. PMID- 29702738 TI - Total Syntheses of Trichorabdal A and Maoecrystal Z. AB - This work reports the total syntheses of Isodon diterpenes trichorabdal A and maoecrystal Z via a common bicyclo[3.2.1]octane intermediate, which chemically bridges the two distinct structures through a retro-aldol/aldol reaction cascade. Other synthetic features include an efficient cross-ring radical cyclization for rapid construction of an all carbon quaternary center commonly seen in Isodon diterpenoids, a challenging Ueno-Stork cyclization on to a sensitive 1,6-enone system, as well as a serial of chemoselective functional group manipulations in complex chemical environments. PMID- 29702739 TI - Midfacial growth patterns in males from newborn to 5 years old based on computed tomography. AB - OBJECTIVES: Growth patterns of the human facial skeleton have been of great interest and importance for biological anthropologists, forensic scientists, craniofacial surgeons, and orthopedists. Nevertheless, growth trends of the facial skeleton in infancy and early childhood are still poorly known and clinical CT data have been insufficiently used for studying craniofacial ontogeny. The purpose of this study was to provide a comprehensive quantitative description of human midfacial ontogeny in infancy and early childhood, and to contribute to debates regarding the role of modularity vs. integration in shaping the human face. METHODS: Our dataset includes 146 high resolution clinical CT datasets of males from the 2nd to 6th years of life and 101 dataset of infants (males) in the 1st year of life. Forty landmarks were collected from each 3D reconstructed skull, then 25 linear measurements describing the morphological features of the facial skeleton were calculated. The integration/modularity issue was addressed via comparison of intragroup correlation matrices at different ages. RESULTS: Growth trends for all the measurements are presented in charts and tables of statistical parameters that can be used as normative data. The midfacial variables display a great diversity of growth patterns. The correlation structure of the measurements is different at different ages. CONCLUSIONS: Variables commonly assigned to the same unit of the facial skeleton can exhibit rather different growth trends, but some measurements display seemingly coordinated patterns of growth change. The level of interindividual variation of most measurements is stable after the second half of the first year of life. PMID- 29702740 TI - Localization of ventricular activation origin using patient-specific geometry: Preliminary results. AB - BACKGROUND AND OBJECTIVES: Catheter ablation of ventricular tachycardia (VT) may include induction of VT and localization of VT-exit site. Our aim was to assess localization performance of a novel statistical pace-mapping method and compare it with performance of an electrocardiographic inverse solution. METHODS: Seven patients undergoing ablation of VT (4 with epicardial, 3 with endocardial exit) aided by electroanatomic mapping underwent intraprocedural 120-lead body-surface potential mapping (BSPM). Two approaches to localization of activation origin were tested: (1) A statistical method, based on multiple linear regression (MLR), which required only the conventional 12-lead ECG for a sufficient number of pacing sites with known origin together with patient-specific geometry of the endocardial/epicardial surface obtained by electroanatomic mapping; and (2) a classical deterministic inverse solution for recovering heart-surface potentials, which required BSPM and patient-specific geometry of the heart and torso obtained via computed tomography (CT). RESULTS: For the MLR method, at least 10-15 pacing sites with known coordinates, together with their corresponding 12-lead ECGs, were required to derive reliable patient-specific regression equations, which then enabled accurate localization of ventricular activation with unknown origin. For 4 patients who underwent epicardial mapping, the median of localization error for the MLR was significantly lower than that for the inverse solution (10.6 vs. 27.3 mm, P = 0.034); a similar result held for 3 patients who underwent endocardial mapping (7.7 vs. 17.1 mm, P = 0.017). The pooled localization error for all epicardial and endocardial sites was also significantly smaller for the MLR compared with the inverse solution (P = 0.005). CONCLUSIONS: The novel pace mapping approach to localizing the origin of ventricular activation offers an easily implementable supplement and/or alternative to the preprocedure inverse solution; its simplicity makes it suitable for real-time applications during clinical catheter-ablation procedures. PMID- 29702742 TI - Insights on clinical relevance of sarcopenia in patients with cirrhosis and sepsis. PMID- 29702741 TI - Living shorelines enhanced the resilience of saltmarshes to Hurricane Matthew (2016). AB - Nature-based solutions, such as living shorelines, have the potential to restore critical ecosystems, enhance coastal sustainability, and increase resilience to natural disasters; however, their efficacy during storm events compared to traditional hardened shorelines is largely untested. This is a major impediment to their implementation and promotion to policy-makers and homeowners. To address this knowledge gap, we evaluated rock sill living shorelines as compared to natural marshes and hardened shorelines (i.e., bulkheads) in North Carolina, USA for changes in surface elevation, Spartina alterniflora stem density, and structural damage from 2015 to 2017, including before and after Hurricane Matthew (2016). Our results show that living shorelines exhibited better resistance to landward erosion during Hurricane Matthew than bulkheads and natural marshes. Additionally, living shorelines were more resilient than hardened shorelines, as they maintained landward elevation over the two-year study period without requiring any repair. Finally, rock sill living shorelines were able to enhance S. alterniflora stem densities over time when compared to natural marshes. Our results suggest that living shorelines have the potential to improve coastal resilience while supporting important coastal ecosystems. PMID- 29702743 TI - Early hepatocellular carcinoma in South America: What is to blame? PMID- 29702744 TI - New perspectives on the complexity of genetic predisposition to autoimmune liver disease in indigenous Canadians. PMID- 29702745 TI - Aortic valve cell seeding into decellularized animal pericardium by perfusion assisted bioreactor. AB - Animal-derived pericardium is the elective tissue employed in manufacturing heart valve prostheses. The preparation of this tissue for biological valve production consists of fixation with aldehydes, which reduces, but not eliminates, the xenoantigens and the donor cellular material. As a consequence, especially in patients below 65-70 years of age, the employment of valve substitutes contaning pericardium is not indicated due to progressive calcification that causes tissue degeneration and recurrence of valve insufficiency. Decellularization with ionic or nonionic detergents has been proposed as an alternative procedure to prepare aldehyde- or xenoantigen-free pericardium for biological valve manufacturing. In the present contribution, we optimized a decellularization procedure that is permissive for seeding and culturing valve competent cells able to colonize and reconstitute a valve-like tissue. A high-efficiency cellularization was achieved by forcing cell penetration inside the pericardium matrix using a perfusion bioreactor. Because the decellularization procedure was found not to alter the collagen composition of the pericardial matrix and cells seeded in the tissue constructs consistently grew and acquired the phenotype of "quiescent" valve interstitial cells, our investigation sets a novel standard in pericardium application for tissue engineering of "living" valve implants. PMID- 29702746 TI - Four Food and Drug Administration draft guidance documents and the REGROW Act: A litmus test for future changes in human cell- and tissue-based products regulatory policy in the United States? AB - Modern regenerative medicine research has expanded well past the development of traditional drugs and medical devices with many promising new therapies encompassing an increasingly diverse range of substances, notably cell-based therapies. These substantial recent developments and the progress in the health care and therapeutics fields necessitate a new regulatory framework agile enough to accommodate these unique therapies and acknowledge their differences with traditional pharmaceuticals. In the United States, recent proposed changes in the regulatory framework for autologous human cells, tissues, and cellular and tissue based products (HCT/Ps) and their perceived risk-benefit analysis for patients remain controversial in the scientific field. To provide perspective on of the current status of the most recent attempts to redefine and conceptualize these changes in the United States, we will examine 4 draft guidance documents implemented by the Food and Drug Administration in interpreting relevant concepts and terminology pertaining to HCT/Ps: the Bipartisan Policy Center think tank report, "Advancing Regenerative Cellular Therapy: Medical Innovation for Healthier Americans," the proposed REGROW Act for HCT/Ps, and the current 24 Food and Drug Administration-approved HCT/Ps and related products in the United States. PMID- 29702748 TI - Chronic mucocutaneous candidiasis due to gain-of-function mutation in STAT1. AB - Chronic mucocutaneous candidiasis (CMC) is a heterogenous group of primary immunodeficiency diseases characterised by susceptibility to chronic or recurrent superficial Candida infection of skin, nails and mucous membranes. Gain-of function mutations in the STAT1 gene (STAT1-GOF) are the most common genetic aetiology for CMC, and mutation analysis should be considered. These mutations lead to defective responses in Type 1 and Type 17 helper T cells (Th1 and Th17), which, depending on the mutation, also predispose to infection with Staphylococci, Mycobacteria and Herpesviridae. We describe the clinical and genetic findings for three patients with CMC due to gain-of-function mutations in the STAT1 gene. PMID- 29702747 TI - Allogeneic chondrogenically differentiated human bone marrow stromal cells do not induce dendritic cell maturation. AB - Bone marrow stromal cell (BMSC)-mediated endochondral bone formation may be a promising alternative to the current gold standards of autologous bone transplantation, in the development of novel methods for bone repair. Implantation of chondrogenically differentiated BMSCs leads to bone formation in vivo via endochondral ossification. The success of this bone formation in an allogeneic system depends upon the interaction between the implanted constructs and the host immune system. The current study investigated the effect of chondrogenically differentiated human bone marrow stromal cell (hBMSC) pellets on the maturation and function of dendritic cells (DCs) by directly coculturing bone forming chondrogenic hBMSC pellets and immature or lipopolysaccharide (LPS) matured DCs in vitro. Allogeneic chondrogenic hBMSC pellets did not affect the expression of CD80, CD86, or HLADR on immature or LPS-matured DCs following 24, 48, or 72 hr of coculture. Furthermore, they did not induce or inhibit antigen uptake or migration of the DCs over time. IL-6 was secreted by allogeneic chondrogenic hBMSC pellets in response to LPS-matured DCs. Overall, this study has demonstrated that maturation of immature DCs was not influenced by allogeneic chondrogenic hBMSC pellets. This suggests that allogeneic chondrogenic hBMSC pellets do not stimulate immunogenic responses from DCs in vitro and are not expected to indirectly activate T cells via DCs. For this reason, allogeneic chondrogenic bone marrow stromal cell pellets are promising candidates for future tissue engineering strategies utilising allogeneic cells for bone repair. PMID- 29702750 TI - In systemic pseudohypoaldosteronism type 1 skin manifestations are not rare and the disease is not transient. PMID- 29702749 TI - Melatonin and its derivatives counteract the ultraviolet B radiation-induced damage in human and porcine skin ex vivo. AB - Melatonin and its derivatives (N1 -acetyl-N2 -formyl-5-methoxykynurenine [AFMK] and N-acetyl serotonin [NAS]) have broad-spectrum protective effects against photocarcinogenesis, including both direct and indirect antioxidative actions, regulation of apoptosis and DNA damage repair; these data were primarily derived from in vitro models. This study evaluates possible beneficial effects of melatonin and its active derivatives against ultraviolet B (UVB)-induced harm to human and porcine skin ex vivo and to cultured HaCaT cells. The topical application of melatonin, AFMK, or NAS protected epidermal cells against UVB induced 8-OHdG formation and apoptosis with a further increase in p53ser15 expression, especially after application of melatonin or AFMK but not after NAS use. The photoprotective action was observed in pre- and post-UVB treatment in both human and porcine models. Melatonin along with its derivatives upregulated also the expression of antioxidative enzymes after UVB radiation of HaCaT cells. The exogenous application of melatonin or its derivatives represents a potent and promising tool for preventing UVB-induced oxidative stress and DNA damage. This protection results in improved genomic, cellular, and tissue integrity against UVB-induced carcinogenesis, especially when applied prior to UV exposure. In addition, our ex vivo experiments provide fundamental justification for further testing the clinical utility of melatonin and metabolites as protectors again UVB in human subjects. Our ex vivo data constitute the bridge between vitro to vivo translation and thus justifies the pursue for further clinical utility of melatonin in maintaining skin homeostasis. PMID- 29702751 TI - Airway persistence by the emerging multi-azole-resistant Rasamsonia argillacea complex in cystic fibrosis. AB - Infections caused by Rasamsonia argillacea complex have been reported in various clinical settings. Cystic fibrosis (CF) is one of the main underlying conditions. An observational cohort study of CF patients with Rasamsonia in respiratory samples was conducted. Eight isolates from 6 patients were identified as R. argillacea complex and tested for antifungal susceptibility. All isolates had high MICs to voriconazole and posaconazole and low MECs to echinocandins. Four patients experienced lung function decline in the year preceding first Rasamsonia isolation. This continued in the year following first isolation in 3 out of 4 cases. Antifungal therapy was initiated in 2 patients, to which only one exhibited a clinical response. Three out of 6 patients died within 3 years of isolating Rasamsonia. Genotyping suggests that similar genotypes of Rasamsonia can persist in CF airways. Consistent with other fungi in CF, the clinical impact of airway colonisation by Rasamsonia is variable. In certain patients, Rasamsonia may be able to drive clinical decline. In others, though a clear impact on lung function may be difficult to determine, the appearance of Rasamsonia acts as a marker of disease severity. In others it does not appear to have an obvious clinical impact on disease progression. PMID- 29702752 TI - Phytomelatonin receptor PMTR1-mediated signaling regulates stomatal closure in Arabidopsis thaliana. AB - Melatonin has been detected in plants in 1995; however, the function and signaling pathway of this putative phytohormone are largely undetermined due to a lack of knowledge about its receptor. Here, we discovered the first phytomelatonin receptor (CAND2/PMTR1) in Arabidopsis thaliana and found that melatonin governs the receptor-dependent stomatal closure. The application of melatonin induced stomatal closure through the heterotrimeric G protein alpha subunit-regulated H2 O2 and Ca2+ signals. The Arabidopsis mutant lines lacking AtCand2 that encodes a candidate G protein-coupled receptor were insensitive to melatonin-induced stomatal closure. Accordingly, the melatonin-induced H2 O2 production and Ca2+ influx were completely abolished in cand2. CAND2 is a membrane protein that interacts with GPA1 and the expression of AtCand2 was tightly regulated by melatonin in various organs and guard cells. CAND2 showed saturable and specific 125 I-melatonin binding, with apparent Kd (dissociation constant) of 0.73 +/- 0.10 nmol/L (r2 = .99), demonstrating this protein is a phytomelatonin receptor (PMTR1). Our results suggest that the phytomelatonin regulation of stomatal closure is dependent on its receptor CAND2/PMTR1-mediated H2 O2 and Ca2+ signaling transduction cascade. PMID- 29702753 TI - Curcumin reverses diabetes-induced endothelial progenitor cell dysfunction by enhancing MnSOD expression and activity in vitro and in vivo. AB - Diabetes mellitus (DM) causes dysfunction of endothelial progenitor cells (EPCs), resulting in impaired wound healing. EPC therapy is a potential substitute to the current treatments of chronic wounds. Because EPCs isolated from diabetic patients are dysfunctional and therefore pose an obstacle in their efficacious employment in autologous cell therapy, a strategy to rescue them prior to transplantation would be expected to improve the efficacy of autologous cell therapy multifold. Compromised reactive oxygen species scavenging ability being the main cause of EPC dysfunction (EPCD), reactive oxygen species scavengers are likely to reverse or rescue EPCD. Therefore, in this study, we evaluated the potential of curcumin in reversing DM-induced EPCD. We found that in vitro treatment of bone marrow EPCs from diabetic mice (D-EPC) with curcumin restored their functionality, as judged by colony formation, tubule formation, and migration assays. Most importantly, autologous transplantation of curcumin treated D-EPCs onto diabetic wounds also resulted in accelerated wound healing. Furthermore, curcumin-treated diabetic mice exhibited improved wound healing, as compared with their vehicle-treated diabetic counterparts, underscoring the efficacy of curcumin in vivo as well. The levels and activity of manganese superoxide dismutase (MnSOD) in D-EPCs treated in vitro with curcumin or those isolated from curcumin-treated diabetic mice were comparable with those in non diabetic EPCs. Addition of methyl mercury chloride to inhibit MnSOD activity during curcumin treatment abolished the salutary effects of curcumin. Our data demonstrate that curcumin reverses DM-induced EPCD by boosting MnSOD expression and activity and emphasizes its potential for use in autologous cell therapy for diabetic wound management. PMID- 29702755 TI - Association of Up-Regulated Plasma Adiponectin With Risk of Incident Depression in a Community-Dwelling Elderly Population. AB - OBJECTIVE: Despite robust interest in the association between inflammation and depression, anti-inflammatory markers have been scarcely investigated as predictors of the future risk of depression. The aim of this study is to determine whether up-regulation of plasma adiponectin, an anti-inflammatory adipokine, precedes and predicts the development of depression in the elderly. METHODS: This prospective cohort study was launched in 2005. Among 1,000 participants who were randomly sampled from community-dwelling individuals 65 years or older, 633 euthymic individuals without prior history of depressive disorders were enrolled for a baseline evaluation and follow-up after 5 years. Incident clinically significant depression, including major and minor depressive disorders (by DSM-IV criteria), subsyndromal depression (by operational criteria), and euthymia after antidepressant treatment, was assessed by clinical interviews. RESULTS: Baseline plasma adiponectin values were divided into tertiles (low tertile: <= 5.685 MUg/mL, middle tertile: 5.686-10.367 MUg/mL, high tertile: >= 10.368 MUg/mL). Among the 261 euthymic individuals who responded to the 5-year follow-up evaluation, 17 developed incident depression (7 from the high tertile, 8 from the middle tertile, and 2 from the low tertile). The risk of incident depression was much higher in the high tertile group than in the low tertile group after adjusting for age, sex, body mass index, burden of chronic medical illnesses, and Mini-Mental State Examination score (odds ratio = 10.64; 95% CI, 1.21-93.84; P = .033). CONCLUSIONS: Up-regulation of plasma adiponectin may precede the onset of clinically significant depression in the elderly, and thus plasma adiponectin level is a potential candidate marker for the risk of depression. PMID- 29702754 TI - Prevalence of Impulsive-Compulsive Symptoms in Elderly Parkinson's Disease Patients: A Case-Control Study. AB - BACKGROUND: Impulse-control disorders (ICDs) are frequently described in patients with Parkinson's disease (PD), particularly among those treated with dopaminergic medications, but data on the prevalence of ICDs in elderly populations are lacking. OBJECTIVE: The aim of this study was to estimate the prevalence of ICDs by using an Italian validation of the Questionnaire for Impulsive-Compulsive Disorders in Parkinson's Disease (QUIP) and to identify associated sociodemographic and clinical factors in a sample of elderly PD patients and in a control group of similarly aged healthy volunteers. METHODS: Using the United Kingdom Parkinson's Disease Society Brain Bank diagnostic criteria, we included 115 consecutive PD and 105 healthy controls. They were recruited from June 2014 to December 2015. All participants completed the self-administered QUIP-Anytime for assessment of ICDs occurring any time during the course of PD. RESULTS: Mean +/- SD age was 75.7 +/- 7.0 years in the PD patients and 76.1 +/- 7.0 years in the control group. The mean disease duration was 6.8 years (range, 1-26 years). Among the PD patients, 44.7% (n = 51) had at least 1 ICD or related disorder compared to 25.2% (n = 26) in the control group (between-group difference: P = .003). Hypersexuality and compulsive shopping were significantly more common in the PD group than in the control group (P < .05). The prevalence of other compulsive behaviors was 42.5% in the PD group and 38.9% in the control group (P = NS). The Italian version of the QUIP-Anytime showed high test-retest reliability (kappa > 0.70 for all items). CONCLUSIONS: Our data confirm a high prevalence of ICD symptoms in elderly PD patients, approximately twice that seen in the general population. PMID- 29702757 TI - ? PMID- 29702756 TI - Antipsychotic-Free Status in Community-Dwelling Patients With Schizophrenia in China: Comparisons Within and Between Rural and Urban Areas. AB - OBJECTIVE: To date, no study has specifically compared antipsychotic-free patients with schizophrenia living in the community between rural and urban areas. This study examined the rural-urban differences among antipsychotic-free community-dwelling individuals with schizophrenia in China. METHODS: Data on 1,365 community-dwelling patients with schizophrenia (n = 742 in a rural area and n = 623 in an urban area) with diagnoses according to DSM-IV or ICD-10 were collected by interviews during 2013-2014 and 2015-2016. Data on patients' sociodemographic and clinical characteristics, prescriptions of psychotropic drugs, and antipsychotic treatment status were recorded using a standardized protocol and data collection procedure. RESULTS: The prevalence of antipsychotic free status in the total sample (N = 1,365) was 27.3%; the proportion of antipsychotic-free patients was significantly lower (17.5%) in the urban area (17.5%) than in the rural area (35.4%; chi2 = 55.03, P < .001). Binary logistic regression analysis revealed that antipsychotic-free patients, whether from the urban area or the rural area, were older (P = .001, odds ratio [OR] = 0.95 in urban; P = .006, OR = 0.97 in rural) and had poorer attitude toward medication treatment (P < .001, OR = 1.21 in urban; P < .001, OR = 1.31 in rural). Antipsychotic-free patients from the urban area also had fewer admissions, lower education level, and greater likelihood of living by themselves. Antipsychotic free patients from the rural area also had worse insight into the disease, fewer anxiety symptoms, more prominent positive symptoms, and lower body mass index and were more likely to be women. CONCLUSIONS: Antipsychotic-free status was more common in community-dwelling patients with schizophrenia in the rural area than in the urban area. Older age and poorer attitude toward medication treatment were common features of antipsychotic-free patients. There were correspondingly different risk factors for antipsychotic-free status between rural and urban areas. Building a positive medication treatment attitude is an important strategy for establishing medication adherence in older, community-dwelling patients with schizophrenia. PMID- 29702758 TI - ? PMID- 29702759 TI - ? PMID- 29702760 TI - ? PMID- 29702761 TI - ? PMID- 29702762 TI - ? PMID- 29702763 TI - ? PMID- 29702765 TI - ? PMID- 29702764 TI - ? PMID- 29702766 TI - Lista de Comprobacion CHEERS en Espanol: Estandares Consolidados de Reporte de Evaluaciones Economicas Sanitarias. PMID- 29702767 TI - Estandares Consolidados de Reporte de Evaluaciones Economicas Sanitarias: Version en Espanol de la Lista de Comprobacion CHEERS. AB - OBJECTIVE: It is important to have adequate and updated guides for reporting health economic evaluations (HEE). Due to their nature and methodological complexity, HEE have particular challenges for adequate reporting, which can be greater than more traditional study designs such as randomized controlled trials. CHEERS (Consolidated Health Economic Evaluation Reporting Standards) have recently been published in English. Our objectives were to adapt the CHEERS list to Spanish. METHODS AND RESULTS: We followed the recommended methods of the Equator (Enhancing the Quality and Transparency Of health Research) network. We made an initial translation to Spanish, a back translation to English, and an initial Spanish version that was circulated through ISPOR and REDETSA. Finally, a final Spanish version was consolidated. The list contains 24 items grouped in Title and Abstract; Introduction; Methods; Results; Discussion; and Other (which included conflict of interest reporting). The scope of use is independent of methodological vehicle (either single-study or evidence synthesis-based HEE); type of strategies to evaluate (clinical or public health; preventive, diagnostic, curative, palliative). Most of the items are generic and apply to any study design; while some of them are particularly oriented to single-study or evidence-synthesis/modeling studies. CONCLUSIONS: Diffusion and use of the CHEERS checklist in Spanish will contribute to a more consistent and transparent reporting of health economic evaluations in Spanish speaking contexts. PMID- 29702768 TI - ? PMID- 29702769 TI - Dengue Epidemiology and Burden of Disease in Latin America and the Caribbean: A Systematic Review of the Literature and Meta-Analysis. AB - INTRODUCTION: Dengue virus infection is the most common arthropod-borne disease worldwide with approximately 50 to 100 million cases of dengue infection occurring annually. Globally, dengue incidence has increased in the last 40 years, especially in Latin American and Caribbean (LAC) countries where the highest incidence is found. This systematic review aimed to present information on dengue disease burden and use of health resources in the LAC region in the last 15 years. METHODS: We searched the main international and regional databases and generic and academic Internet search engines. Gray literature was retrieved mainly from regional health ministries and Pan American Health Organization. A set of inclusion criteria was defined. RESULTS: We identified 2,041 articles of which 25 met these criteria, 13 for incidence and 12 for the use of resources and related costs. The pooled incidence of classic dengue fever was 72.1 cases per 100,000 persons-years in the 44 LAC countries analyzed (95% confidence interval 71.5-72.7), with an upward trend from 1995 up to 2010. Case-fatality ratio was highest in 1997 (0.12 [0.05-0.22]) and lowest in 2009, and the overall mortality was 0.02 per 100,000 people. More than 60% of the cases in the LAC region came from Brazil. The length of hospital stay ranged from 5 to 13 days. CONCLUSIONS: Activities to control dengue transmission in the region have been important but insufficient. The surveillance of dengue burden of disease and circulating strains help shape and evaluate the present and future health policies. PMID- 29702770 TI - Uso del Registro de Solicitudes de Medicamentos no Incluidos en el Listado de Medicamentos Esenciales como Nueva Fuente de Informacion en los Sistemas Nacionales de Farmacovigilancia. AB - OBJECTIVE: To describe the frequency of adverse drugs events (ADEs) as possible causes of request of drugs not included in national essential Medicines list in Colombia. METHODS: This was a descriptive study developed in a private medical insurance company in Bogota, Colombia. Data were obtained from drug request form of drugs not included in a national essential Medicines list. We analyzed the content of the notes to identify the records related to the occurrence of ADEs in the period 2008 to 2009. Information concerning the adverse event and the drug involved was recorded in a data collection instrument developed by the researchers. The pharmacological classification of drugs was performed according to the Anatomical Therapeutic Chemical Classification System (ATC). RESULTS: We study 3,336 request forms of drugs not included in a national essential Medicines list. The level 1 groups of the ATC of drugs with greater frequency of ADEs were the cardiovascular agents (47%), nervous system agents (24%) and antineoplastic and immunomodulating agents (15%). The great majority was cases of light severity (62.7%) and classified as possible (48.4%). CONCLUSION: The results of this study support the innovative approach of using request form of drug not included in national essential Medicines list to obtain information regarding ADEs in developing countries; recognizing the importance of looking for new sources of report of adverse reactions to diminish the under-notification of ADEs. PMID- 29702771 TI - The Impact of Psychotropic Drug Costs on the Brazilian Family Budget: An Analysis of the Family Budget Surveys of 2003 and 2009. AB - OBJECTIVE: To estimate the cost of psychotropic drugs and its impact on the Brazilian family budget in 2003 and 2009 comparatively. METHODS: This study had a cross-sectional design. Data were obtained from the Family Budget Surveys conducted in 2003 and 2009, including interviews in 48,470 and 55,970 homes of all Brazilian regions, respectively. The main measures are prevalence of psychotropic drug acquisition, monetary and nonmonetary expenses with psychotropic drugs, total spending on drugs, spending on health, total household spending, and estimated mean monthly household income. All incomes and expenses from the 2003 survey were adjusted by inflation. RESULTS: There was a reduction in the prevalence of psychotropic drug acquisition by Brazilian households from 13.0% in 2003 to 11.2% in 2009. The mean monthly household spending on psychotropic drugs, however, rose from R $54.38 in 2003 to R $78.73 in 2009. The percentage of spending on psychotropic drugs from the expenses with health increased 27%. CONCLUSIONS: The increase in spending on psychotropic drugs can be due to a rise in their prices, the acquisition of more modern or more expensive drugs, or the increase in the number of drugs used. Proportionally, spending on psychotropic drugs grew more than did spending on health by Brazilian families. PMID- 29702772 TI - Analisis de Minimizacion de Costo e Impacto Presupuestario del Tratamiento ARV con Abacavir/Lamivudina para el VIH/SIDA en Mexico. AB - OBJECTIVE: In Mexico, health authorities have raised reach the total of people living with HIV/ AIDS who need treatment have access to it, with the proper use of the best ARV therapies. Evaluate health spending would mean the management of patients with HIV/AIDS with the first-line therapy of abacavir/lamivudine with respect to tenofovir/emtricitabine and lamivudine-zidovudine. METHODS: A literature review was conducted to seek evidence from clinical studies that demonstrated similar efficacy of ARV treatment between abacavir-lamivudine medications compared with other options. To calculate the incremental cost between these treatments, there was a Budget Impact Analysis and a pharmacoeconomic model was constructed to estimate the economic benefits by increasing its market share. RESULTS: Increased market penetration of abacavir/lamivudine represent a save of $ 44.8 million for the National Health System in Mexico during the years 2012-2017, without compromising the quality and effectiveness of treatment. Furthermore, this increase in market share with abacavir-lamivudine, the National Health System could get an additional benefit to deal on average 5.197 with HIV patients by 5 years with ARV therapies in Mexico. CONCLUSIONS: The use of abacavir/lamivudine in ARV treatment of patients with HIV/AIDS is a cost saving for the Mexican health System, which leads to a potential reduction in resources of US$44.8 million in treatment costs in the five projected years. PMID- 29702773 TI - Costo-Efectividad de la Proteina C Reactiva, Procalcitonina y Escala de Rochester: Tres Estrategias Diagnosticas para la Identificacion de Infeccion Bacteriana Severa en Lactantes Febriles sin Foco. AB - OBJECTIVE: The optimal practice management of highly febrile 1- to 3-month-old children without a focal source has been controversial. The release of a conjugate pneumococcal vaccine may reduce the rate of occult bacteremia and alter the utility of empiric testing. The objective of this study was to determine the cost-effectiveness of 3 different screening strategies of Serious Bacterial Infections (SBI) in Children Presenting with Fever without Source in Argentina. METHODS: Cost-effectiveness (CE) analysis was performed to compare the strategies of procalcitonin, C reactive protein and Rochester criteria. A hypothetical cohort of 10 000 children who were 1 to 3 months of age and had a fever of >39 degrees C and no source of infection was modeled for each strategy. Our main outcome measure was incremental CE ratios. RESULTS: C reactive protein result in US$ 937 per correctly diagnosed cases of SBI. The additional cost per additional correct diagnosis using procalcitonin versus C reactive protein was U$6127 while Rochester criteria resulted dominated. CONCLUSIONS: C reactive protein is the strategy more cost-effective to detect SBI in children with Fever without Source in Argentina. Due to low proportion of correctly diagnosed cases (< 80%) of three tests in the literature and our study, however; an individualized approach for children with fever is still necessary to optimize diagnostic investigations and treatment in the different emergency care settings. PMID- 29702774 TI - ? PMID- 29702775 TI - ? AB - OBJECTIVES: The high costs generated by the current epidemiological profile and the introduction of new technologies, impact on public health systems, this situation is complicated when the health budget is low and causes the drug to be paid by the patient's pocket. In this situation it is necessary to design strategies that strengthen the approval of drugs that will be used in public health institutions in Mexico. To describe the results of the drug approval process for use in public health institutions to ensure the efficacy, safety, and efficiency of health technologies used in public health institutions in Mexico. METHODS: We conducted a cross-sectional drug approval process, from September 2011 to December 2012, with a descriptive analysis for each stage in the process considered. RESULTS: Of the 394 applications received for approval of health technology, 244 (62%) were for drugs; of these, 151 (62%) met the requirements for evaluation (32% and 68% were modifications inclusions), finally was approved of 42% (61% of the changes and 33% of inclusions). The 73% of the applications were for consensus approval, 12% were conditioned at low price and 6% were approved by majority vote. The main reasons for refusal were lack of clinical evidence (31%) and methodological problems in the economic evaluation (27%). CONCLUSIONS: The strengthening of the process was conducted with methodological rigor based on critical analysis of scientific evidence, with transparency and legitimacy under a legal framework to promote resource optimization. The highest percentage of requests was for drugs which are the most commonly used therapeutic technology; for this reason it requires a proper selection process to ensure greater health benefit that ensures efficient use of economic resources. The economic evaluation was a support tool to consider in addition to price, the value of health determined by the quality of evidence, establishing a GDP per capita as a threshold to define a drug as an efficient alternative. PMID- 29702776 TI - Evaluation of the Stroke-Specific Quality-of-Life (SSQOL) Scale in Mexico: A Preliminary Approach. AB - OBJECTIVES: The prevalence of stroke survivors with incomplete recovery in society has been estimated at 460/100,000 people, and one third of them require help in at least one daily activity. Two thirds of all deaths related to stroke in the world occur in low- and middle-income countries. The objective of the present work was to assess the reliability and validity of the previously translated Spanish Stroke-Specific Quality-of-Life (SSQOL) version 2.0 scales in Mexican stroke survivors. METHODS: An observational and cross-sectional pilot study was conducted. Thirty-one patients who suffered stroke up to 1 year prior to the present study were included. Patients were interviewed twice in a 7-day period; other indexes and scales were applied. The reliability was assessed by using Cronbach's alpha (internal consistency) and test-retest by using Spearman's rho scores; the acceptability was evaluated by the floor and ceiling effects. RESULTS: Ceiling and floor effects were observed for fewer than 20% of the patients. The overall internal consistency of the questionnaire was greater than 0.7 (Cronbach's alpha), with only two domains (family roles and personality) having lower internal consistency values. The results displayed high test-retest reliability: all domains had Spearman's rho scores of over 0.8. The questionnaire has adequate construct validity. CONCLUSIONS: Our preliminary results showed that the psychometric properties (acceptability and reliability) of the Spanish SSQOL questionnaire are good, encouraging, and comparable to those of other similar studies. This study is the first approach to validate the Spanish version of the SSQOL questionnaire in Mexican stroke survivors. PMID- 29702777 TI - ? AB - OBJECTIVE: To describe general population health related quality of life (HRQOL) in Argentina and perform an Atlas showing the country's results using data from the first "National Risk Factors Survey" and local social values. METHODS: Secondary cross-sectional study analyzing EQ-5D-3L responses. The variables of interest were self-reported visual analog scale in a 0-1 scale (SR-VAS), as well as time-trade off (TTO) and VAS preference values (PV). PV were assigned using weights derived from a previous local study. RESULTS: The survey included 41.392 subjects; the expanded population represented 96% of the adult population of Argentina. 8.82% of the population reported excellent health, 24.6% very good, 43.9% good and 22.3% regular or bad. 42.8% reported limitations in at least one of the EQ-5D domain. SR-VAS had a mean of 0.75 (IC95% 0.75-0.76), while general population mean social TTO and VAS based weights were 0.90 (0.898-0.905) and 0.87 (IC95% 0.867-0.874) respectively. The Atlas showed small differences among the provinces. CONCLUSIONS: This is a population based study aimed to describe in depth the HRQOL based in EQ-5D using local PV. It summarizes country level and geographic levels within the country, and constitutes a valuable resource and a starting point for future studies. PMID- 29702778 TI - Societal Preferences for EQ-5D Health States from a Brazilian Population Survey. AB - OBJECTIVE: To elicit preference weights for a subset of EuroQol five-dimensional (EQ-5D) questionnaire health states from a representative sample for the state of Minas Gerais, Brazil, using a time trade-off (TTO) method and to analyze these data so as to estimate social preference weights for the complete set of 243 states. METHODS: Data came from a valuation study with 3362 literate individuals aged between 18 and 64 years living in urban areas. The present study was based on quota sampling by age and sex. Face-to-face interviews were conducted in participants' own homes. A total of 99 EQ-5D questionnaire health states were selected, presorted into 26 blocks of six unique health states. Each participant valued one block together with the full health, worst health, and dead states. Each health state was evaluated by more than 100 individuals. TTO data were modeled at both individual and aggregate levels by using ordinary least squares and random effects methods. RESULTS: Values estimated by different models yielded very similar results with satisfactory goodness-of-fit statistics: the mean absolute error was around 0.03 and fewer than 25% of the states had a mean absolute error greater than 0.05. Dummies coefficients for each level within the EQ-5D questionnaire dimensions of health displayed an internally consistent ordering, with the mobility dimension demonstrating the largest value decrement. The values of mean observed transformed TTO values range from 0.869 to-0.235. CONCLUSIONS: The study demonstrates the feasibility of conducting face-to-face interviews using TTO in a Brazilian population setting. The estimated values for EQ-5D questionnaire health states based on this Minas Gerais survey represent an important first step in establishing national Brazilian social preference weights for the EQ-5D questionnaire. PMID- 29702780 TI - ? AB - INTRODUCTION: The relationship between socioeconomic position (SEP), migration and health is dynamic, difficult to predict, multifactorial and poorly studied in the Latin American region. Moreover, there are high levels of uncertainty about reasons, types, and consequences of migration to an individual, family, community, country of origin and the receiving country. OBJECTIVE: To discuss the evidence about the complex relationship between SEP, migration and health outcomes. RESULTS: According to international evidence available, migration has a direct impact on health outcomes in a population and, in turn, on public health policy decisions in each locality. The available evidence on this issue affects multiple parts of the social sciences. The "healthy migrant" effect is not consistently observed among immigrant populations, particularly after adjusting for PSE. Moreover, the immigrant population tends to assimilate in terms of risk factors and morbidity to the local population after about 10 years of stay in the foreign country. Migration has consequences for international relations, economic productive capacity of a country, inequality, demographic changes and health outcomes, to mention a few. CONCLUSION: There is now the opportunity to generate better and more evidence longitudinal population-based around the relationship between SEP, migration status and health. This will contribute to reduce uncertainty about the health status of immigrants that is required for decision- making in public health in Chile and the region. PMID- 29702781 TI - A Comparison of 1-Year Treatment Costs in Patients with Type 2 Diabetes Following Initiation of Insulin Glargine or Insulin Detemir in Argentina. AB - OBJECTIVE: To estimate and compare type 2 diabetes mellitus treatment costs in insulin-naive patients following initiation of therapy with either insulin glargine (IG) or insulin detemir (ID) over 1-year time horizon from a payers' perspective in Argentina. METHODS: We used a pharmacoeconomic model based on a randomized trial comparing IG and ID (Rosenstock J, Davies M, Home PD, et al. A randomised, 52-week, treat-to-target trial comparing insulin detemir with insulin glargine when administered as add-on to glucose-lowering drugs in insulin-naive people with type 2 diabetes. Diabetologia 2008;51:408-16) and Argentinean sources. Clinical, resource use, and cost data were combined to estimate direct medical costs (insulin, test strips, and needles) during the first year. Price per international unit of insulin is similar for IG and ID in the local market. Deterministic analysis was performed on insulin unit cost and probabilistic sensitivity analyses on clinical, resource use, and unit costs to evaluate contribution to variance on the difference in total annual treatment cost. RESULTS: Annual mean treatment cost (Argentinean pesos 2013) was AR $6229 for IG and AR $9257 for ID, showing 33% total cost reduction with IG (AR $3028; exchange rate US $1.00 = AR $5.30). Probabilistic sensitivity analysis showed that IG was cost saving in 88% of the simulations. The most influential parameter was the difference in insulin dose requirements. Threshold analysis showed that if the unit price of ID is reduced by 43%, ceteris paribus, the total annual costs per person for both insulin regimens would be the same. CONCLUSIONS: From a payer's perspective in Argentina, cost savings related to the use of IG represented one third of total treatment costs. Sensitivity analyses confirmed the robustness of these results. PMID- 29702782 TI - Economic Evaluation of Four Drug Administration Systems in Intensive Care Units in Colombia. AB - INTRODUCTION: Intensive care units (ICUs) are the most frequent setting for serious medical errors, which not only have serious health consequences but also an economic impact. In this article, using a theoretical model, we evaluate four medication administration systems: conventional preparation by nursing staff, MINIBAG Plus delivery system, compounding center preparation, and premix drugs. METHODS: We designed a decision tree model from a third-party payer perspective, and the time horizon of the acute event. Local costs, in Colombian pesos (US $1 = 1784 COP$), were obtained from tariff manuals, medication costs from Sismed information system, and clinical variables from the published literature, and uncertainty was dealt with by an expert panel. The drug used for the model was dopamine. RESULTS: Average costs for each dopamine dose delivered were $46,995 for premix, $47,625 for compounding center, $101,934 for MINIBAG Plus, and $108,870 for drug prepared in the ICU. The variability of these results is higher for compounding center than for premix, and even higher for MINIBAG Plus and nurse delivery. CONCLUSIONS: The use of premix drugs can be a cost-saving strategy, which decreases medical errors in drug administration in the ICU, particularly if it is part of an integral error reduction program. PMID- 29702783 TI - Asthma Control and Cost in Latin America. AB - OBJECTIVE: Few patients with asthma have disease that is well-controlled, particularly in Latin American countries. The purpose of this study was to investigate whether partly controlled and uncontrolled asthma are associated with increased costs for asthma-related medications and health care utilization compared with well-controlled asthma in five Latin American countries. METHODS: Using the Global Initiative for Asthma guidelines, we classified respondents from the Latin American Asthma Insights and Management survey into those with well controlled, partly controlled, and uncontrolled asthma and compared the utilization of health care services and costs among these groups. RESULTS: Most respondents to our survey (93%) had asthma that was classified as partly controlled or uncontrolled. Across all countries, patients whose asthma was partly controlled or uncontrolled had greater use of asthma-related medications and medical services than did patients whose asthma was well-controlled. After adjusting for age, sex, and country of residence, total costs for asthma-related medications and health care were greater in patients whose asthma was classified as partly controlled and uncontrolled. CONCLUSIONS: Our findings indicate that patients with asthma that are not well-controlled used more health care resources and had greater medical costs in Latin America. PMID- 29702784 TI - The Update of the Mexican Health Care Formulary and Supply Catalog in the Context of the Health Technology Assessment. AB - One of the instruments Mexico has available for the optimization of resources specifically allocated to health technologies is the Health Care Formulary and Supply Catalog (Cuadro Basico y Catalogo de Insumos del Sector Salud [CBCISS]). The aim of the CBCISS is to collaborate in the optimization of public resources through the use of technologies (supplies) that have proven their safety, therapeutic efficacy, and efficiency. The importance of the CBCISS lies in the fact that all public institutions within the National Health System must use only the established technologies it contains. The implementation of strategies that strengthen the CBCISS update process allows it to be thought of as an essential regulatory tool for the introduction of health technologies, with relevant contributions to the proper selection of cost-effective interventions. It ensures that each supply included on the list meets the criteria sufficient and necessary to ensure efficacy, safety, effectiveness, and, of course, efficiency, as evidence supporting the selection of suitable technologies. The General Health Council (Consejo de Salubridad General [CSG]) is a collegial body of constitutional origin that-in accordance with its authority-prepares, updates, publishes, and distributes the CBCISS. To perform these activities, the CSG has the CBCISS Inter-institutional Commission. The CBCISS update is performed through the processes of inclusion, modification, and exclusion of supplies approved by the Interior Commission. The CBCISS update process consists of three stages: the first stage involves a test that leads to the acceptance or inadmissibility of the requests, and the other two focus on an in-depth evaluation for the ruling. This article describes the experience of health technology assessment in Mexico, presents the achievements and outlines the improvements in the process of submission of new health technologies, and presents a preliminary analysis of the submissions evaluated until December 2012. During the analysis period, 394 submissions were received. After confirming compliance with the requirements, 59.9% of the submissions passed to the next stage of the process, technology assessment. In the third stage, the committee approved 44.9% of the submissions evaluated. The improvements established in the country in terms of health technology assessment allowed choosing the technologies that give more value for money in a context of public health institutions. PMID- 29702785 TI - Assessment of Health Care and Economic Costs Due to Episodes of Acute Pesticide Intoxication in Workers of Rural Areas of the Coquimbo Region, Chile. AB - BACKGROUND: The increase in agricultural activity that Chile experienced in the past 20 years resulted in a boost in the use of pesticides. Despite pesticides' productivity benefits, they caused health problems such as the increased frequency of episodes of acute poisoning, which constitutes a relevant problem in terms of occupational health. The Chilean authorities require several preventive measures at workplaces, which are not always implemented, increasing the risk of intoxications in farmers. So far in Chile, there are no studies concerning the public health care expenses associated with acute work-related pesticide intoxications. From the societal perspective, there are costs involved if the worker needs to take sick leave and families incur costs to take care of their sick members. OBJECTIVES: This study aimed to determine the costs associated with health care services used by people who suffered from work-related acute pesticide poisoning, as well as the economic costs for the families of the workers involved, and finally the costs of these episodes for the employer/industrial sector. METHODS: This study considered a 3-year period (January 2009 to December 2011). Three sources of data were reviewed: reported cases at the Regional Health Authority, for the profile of the intoxications; registers of patients attended in public hospitals, for data on costs of health care services; and public information of living conditions nationwide. RESULTS: The overall costs of a single case depend on the severity of intoxication, days of sick leave, and type of health care needed. Most cases (77%) would be ambulatory and would be assisted at an emergency room, with an average cost of US $330 per case. Those cases that might need hospitalization (23%) and, therefore, more days off work have an average cost of US $1158 per case. Taking into account the number of patients reported each year in the country, the cost per annum would be about US $185,000, but considering the underreporting of intoxications and underestimation of costs at the public insurance system fees, this amount could be six to eight times higher (US $1.1 million to US $1.4 million a year). CONCLUSIONS: This study is the first attempt to estimate costs related to this occupational and public health problem. There is an opportunity to further improve the cost-benefit balance of preventive measures that relate not only to acute poisonings but also to health problems originating from chronic and low dose exposure to pesticides (e.g., neuropsychological impairment). PMID- 29702786 TI - Costo Utilidad de Colagena Polivinil-Pirrolidona en el Tratamiento de Osteartrosis de Rodilla en Mexico. AB - OBJECTIVE: To assess the cost-utility of collagen-polyvinyl pyrrolidone (collagen PVP), a new drug developed and manufactured in Mexico, compared to non-steroidal anti-inflammatory drugs in the treatment of patients with knee osteoarthritis (OA) in Mexico. METHODS: A probabilistic Markov model with a lifetime horizon was designed to evaluate the costs and outcomes (QALYs) of collagen-PVP compared to NSAIDs in patients with OA. Data from randomized clinical trials conducted in Mexico were obtained as input for probabilities. Utility values were elicited from international publications and costs information and service utilization was obtained from official publications of the Instituto Mexicano de Seguro Social - IMSS. Cost per quality-adjusted life-years was calculated by using the Mexican Healthcare payer perspective. A discount rate of 5% for both cost and outcomes was used. Sensitivity analyzes were performed with variations in the parameters of gender, age, and price of collagen-PVP. RESULTS: Patients treated with collagen-PVP showed a gain of 6.62 QALYs compared with 5.36 in patients with NSAIDs. The cost-utility ratio was higher in the NSAID group (MEX$ 170,010.76/QALY) compared to collagen-PVP (MEX $ 130,953.63/QALY). The incremental cost-utility ratio was MEX $ 35,194.16. CONCLUSIONS: This is the first economic evaluation of a new medication developed in Mexico and conducted partially with local data. The results of this study allow concluding that collagen-PVP is deemed as the dominant alternative compared with NSAIDs in the treatment of knee osteoarthritis. PMID- 29702787 TI - Cost-Effectiveness Analysis of Atorvastatin versus Rosuvastatin in Primary and Secondary Cardiovascular Prevention Populations in Brazil and Columbia. AB - BACKGROUND: Latin America has witnessed a marked increase in cardiovascular (CV) disease, the leading cause of death in many countries. The benefits of lipid lowering therapy to reduce CV-related events are widely accepted. Clinical evidence suggests that rosuvastatin is associated with slightly greater reductions in low-density lipoprotein cholesterol levels than is atorvastatin at comparable doses. Rosuvastatin, however, is often priced at a premium. OBJECTIVE: Our objective was to examine the cost-effectiveness of using atorvastatin versus rosuvastatin in reducing CV events in Brazil and Colombia using real-world prices. METHODS: A global Markov cohort model of primary and secondary CV prevention was developed and adapted to Brazilian and Colombian settings. The risks and costs of major CV events and efficacy, adherence, and costs of statins were considered. Total gains in life-years, quality-adjusted life-years, major CV events avoided, and costs over the lifetime horizon were estimated. Several dose comparisons were considered. RESULTS: In the Colombian analyses, differences in drug costs between therapies were considerable while outcomes were similar. The incremental cost per quality-adjusted life-year gained for rosuvastatin versus atorvastatin was more than $700,000 and $200,000 in primary and secondary prevention, respectively. Brazilian analyses found lower incremental cost effectiveness ratios for rosuvastatin at some dose comparisons due to similar pricing between statins. Sensitivity analyses revealed that changes in treatment efficacy and adherence had the largest impact on results. CONCLUSIONS: In primary and secondary CV prevention, the efficacy advantage of rosuvastatin was minimal, while its acquisition cost was higher, particularly in Colombia. The incremental cost-effectiveness ratios were, therefore, generally in favor of atorvastatin being the cost-effective option. PMID- 29702789 TI - Cost-Effectiveness of Biologic Agents in the Treatment of Moderate-to-Severe Psoriasis: A Brazilian Public Health Service Perspective. AB - BACKGROUND: Psoriasis is a chronic disease that affects public health and budget payers. In Brazil, biologic therapy for psoriasis is mostly provided by means of lawsuit with no strategy for efficient allocation of resources. OBJECTIVE: This study aimed to identify which of the available biologic alternatives for psoriasis is the most efficient from the perspective of the Brazilian Public Health Service (SUS). METHODS: Direct costs and efficacy were expressed in Brazilian currency (real [R$]; US $1 = R$1.97) and Psoriasis Area Severity Index 75 (PASI75), respectively. The Markov model process included 12 cycles of 3 months each, comprising 3 years of horizon. Adalimumab (80 mg at week 0 followed by a maintenance dose of 40 mg at week 1 and then every other week), etanercept (50 mg twice weekly for 12 weeks followed by a maintenance dose of 25 mg weekly), infliximab (5 mg/kg at weeks 0, 2, and 6 and then every 8 weeks), and ustekinumab (45 mg at weeks 0 and 4 and then every 12 weeks) were assessed. One-way and horizon sensitivity analyses were performed. Moreover, probabilistic sensitivity analysis was applied to evaluate model robustness. The final result was interpreted as the cost for each patient who achieved and maintained PASI75 for at least 3 years. RESULTS: Adalimumab was the most cost-effective biologic therapy (R$120,981.45/PASI75) for moderate-to-severe psoriasis, followed by ustekinumab (R$126,336.67/PASI75), etanercept (R$225,074.71/PASI75), and infliximab (R$377,656.28/PASI75). One-way sensitivity analysis determined that the acquisition cost of biologics was the most sensitive parameter of the model. Horizon analysis suggests that the result was the same when the horizon was varied from 1 year to a lifetime. Probabilistic sensitivity analysis showed that adalimumab has 80% to 10% probability of being the most cost-effective biologic considering a willingness-to-pay value ranging from R$50,000 to R$500,000, whereas ustekinumab presented a probability of 20% to 90% for the same range. CONCLUSIONS: From the pharmacoeconomics point of view, adalimumab 80 mg at week 0 followed by a maintenance dose of 40 mg at week 1 and then every other week should be the first-line therapy for patients with plaque psoriasis concomitant or not to psoriatic arthritis or nail psoriasis. This study does not have the potential to evaluate the impact of incorporating a specific biologic agent on the final budget. Its goal is to point out which of the technologies is the most efficient, that is, the one that adds more value to the financial resource invested. PMID- 29702788 TI - ? AB - OBJECTIVE: To support an evidence-based decision regarding the inclusion of the anti TNF's adalimumab, etanercept or infliximab to the National Formulary of Uruguay for the treatment of psoriatic arthritis, in patients who did not respond to first-line treatment. METHODS: We perform a cost-utility evaluation using a Markov model, to estimate the incremental costs and quality-adjusted life years (QALY) gained with each of these biologic drugs compared with palliative care only. The model considered the perspective of the National Health System, with a time horizon of 40 years. RESULTS: Under base-case assumptions, infliximab results in an incremental cost-effectiveness ratio (ICER) of United States Dollars (USD) 47,294 compared to palliative care only. Adalimumab was extendedly dominated and etanercept was dominated. However, infliximab requires intravenous administration which could significantly reduce access to treatment, thus producing inequities for patients from different regions. The probabilistic sensitivity analysis shows that all biologics had null probabilities of being cost-effective considering a willingness-to-pay (WTP) threshold of one time the gross domestic product per capita of Uruguay per QALY. CONCLUSIONS: In our analysis from the perspective of the National Health System, the use of biologic drug treatments for psoriatic arthritis results in an ICER above the WTP ceiling proposed by the World Health Organization. Reduction of drug prices could bring more favorable cost-effectiveness results. PMID- 29702790 TI - Guidance Document: Global Pharmacoeconomic Model Adaption Strategies. AB - OBJECTIVE: The purpose of this guidance was to assist in the adaptation of pharmacoeconomic models originally developed in one country and intended for use in another. The intent was to produce user-friendly recommendations and a checklist for adapting a global model to treat a specific disease state. This guidance will allow model developers to tailor existing models so that they are "locally applicable," while maintaining the scientific integrity of the original pharmacoeconomic model and will benefit formulary decision makers and other stakeholders involved in evaluating pharmacoeconomic studies. METHODS: A working group of experts from various countries participated in the Global Pharmacoeconomic Model Guidance development to discuss the adaptation of pharmacoeconomic models. A systematic review of studies adapting pharmacoeconomic models and translation across countries was conducted and recommendations were made for adaptation. The working group interviewed internal and external stakeholders to solicit best practices for model adaptation and developed a draft set of key principles and general recommendations for global adaptation. RESULTS: The working group provided a set of 16 recommendations for adapting pharmacoeconomic models for local decision makers. The recommendations span various aspects of estimating or modeling both the costs and effectiveness of pharmacoeconomic models as well as guidance for ensuring local acceptability. CONCLUSIONS: These recommendations and the related principles not only will provide pharmacoeconomic models that are meaningful to local decision makers but also will improve the consistency and credibility of pharmacoeconomic model adaptations. The guidance may also help those who will build the original models to design them with the flexibility to allow pharmacoeconomic model adaptations as described in this document. PMID- 29702791 TI - One Small Step for Latin America, One More Leap for Value in Health Regional Issues. PMID- 29702792 TI - More Doctors: Thoughts about a Controversial Health Care Policy. PMID- 29702793 TI - Introducing the New Value in Health Regional Issues Journal: The Latin America Region Edition. PMID- 29702794 TI - Reviewer Acknowledgement. PMID- 29702795 TI - Social Cost of Substance Abuse in Russia. AB - OBJECTIVE: To summarize results of studies that estimate the social costs of alcohol, tobacco, and illicit drug abuse in Russia. The purpose of these studies was to inform policymakers about the real economic burden of risky behaviors and to provide conditions for evidence-based and well-informed decision making in this area. METHODS: The cost-of-illness method was applied to estimate the social cost of substance abuse. The intangible cost was not included in estimation. A prevalence-based approach was applied to estimate the tangible cost. For the estimation of direct costs, a top-down method was used. Indirect costs were estimated using two methods: the human capital and the friction cost. RESULTS: In 2008, the social cost of substance abuse in Russia comprised 677.2 billion rubles if the friction cost method is applied and 1965.9 billion rubles if the human capital method is used. The social cost of substance abuse is defined to the greatest extent by alcohol consumption, comprising about 45% of the economic burden. Illicit drug use comprises about 30% of the economic burden and tobacco consumption 25%. CONCLUSIONS: The results of economic studies demonstrated that psychoactive substances impose a considerable economic burden on society. Analysis of the substance abuse social cost pattern shows that the main losses that society bears because of these behavioral risk factors fall outside the health care system and lay in other sectors of the economy such as social care, law enforcement, and productivity losses. PMID- 29702796 TI - Work Productivity and Costs Related to Patients with Ankylosing Spondylitis, Rheumatoid Arthritis, and Psoriasis. AB - OBJECTIVES: To determine and compare the impact of rheumatoid arthritis (RA), ankylosing spondylitis (AS), and psoriasis on work productivity, to calculate the productivity costs (PC), and to map out factors that influence (functional status and disease activity) work productivity. METHODS: The Work Productivity and Activity Impairment questionnaire was used to evaluate productivity losses of patients with RA (n = 77), AS (n = 230), and psoriasis (n = 93). Demographic data, patient-reported outcomes (PROs) (Health Assessment Questionnaire [HAQ] and Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]), and clinical parameters (Disease Activity Score in 28 joints [DAS28], body surface area [BSA], and Psoriasis Area and Severity Index [PASI]) were collected. The correlations among PROs, clinical parameters, and overall productivity loss were examined, and multiple regression models were used to examine relationships among parameters and productivity loss. PC were calculated using the friction cost approach. RESULTS: Mean patient age and disease duration were 47.1 and 15.7 years, respectively. The mean HAQ and DAS28 in patients with RA were 1.22 and 5.6, respectively. The mean BASDAI score in patients with AS was 4.43. The mean BSA and PASI score in patients with psoriasis were 21.1% and 12.9, respectively. The percentage of patients with psoriatic arthritis (in those with psoriasis) was 24.7%. We did not find significant differences in Work Productivity and Activity Impairment domains among various diagnoses. Patients with AS, RA, and psoriasis reported overall work productivity losses of 40.9%, 42.9%, and 42.8%, respectively. Daily activity impairments were approximately 50.0%. Overall work productivity loss strongly correlated with PROs, whereas correlations with clinical parameters were weak. The HAQ and BASDAI were identified as major predictors of productivity impairment. CONCLUSIONS: The greatest loss in productivity was in those with psoriatic arthritis; however, it was not significant. In contrast to clinical parameters (DAS28, BSA, and PASI score), PROs (HAQ and BASDAI score) significantly influence loss of productivity. The average annual lost PC per patient was estimated to be ?2000. PMID- 29702797 TI - Investigating the Economic Impacts of New Public Pharmaceutical Policies in Greece: Focusing on Price Reductions and Cost-Sharing Rates. AB - OBJECTIVE: Since 2010, cost-containment efforts in Greece focused on the reduction of public pharmaceutical expenditure. Changes in cost-sharing levels, reductions in prices, and generic substitution are some of the measures implemented after the second quarter of 2012. The objective of this study was to investigate the economic impact of the measures on public funds and households. METHODS: Data on volume and value for prescribed drugs for each therapeutic category and cost-sharing levels were obtained from the National Organization for Health Care Services Provision (EOPYY), the main reimbursement agency covering 95% of the population. Four different periods were compared, taking into consideration the implementation of different regulation, data availability, and disease seasonality. The periods compared were January-March 2012 versus January March 2013 and April-August 2012 versus April-August 2013. RESULTS: In 2013, only 8% of prescribed drug boxes were provided with 0% cosharing arrangement versus 13% in 2012. Alpha 25% cost-sharing level was imposed on 77% of the prescribed medicines in 2013 compared with 53% in 2012. Consequently, the mean cost-sharing burden for pharmaceuticals in 2013 was estimated at 18% versus 13.3% in 2012. The average price per package declined in 2013 by 28%, from ?17.8 in 2012 to ?12.8 in 2013. Major (>50%) savings were achieved in cardiovascular and nervous system drugs, accounting in volume for almost 60% of total pharmaceutical consumption. CONCLUSIONS: The economic results of the measures for third-party payers were positive. The measures, however, should be reconsidered and examined more closely considering social effects, such as accessibility, especially for vulnerable groups in need of essential pharmaceutical care. PMID- 29702798 TI - What Are the Challenges in Conducting Cost-of-Illness Studies? PMID- 29702799 TI - Reviewer Acknowledgement. PMID- 29702800 TI - Health Facility Cost of Buruli Ulcer Wound Treatment in Ghana: A Case Study. AB - OBJECTIVE: To estimate the wound treatment cost borne by the Buruli Ulcer Treatment Centre of the Amasaman Government Hospital, Ghana. METHODS: Three different types of data collection approaches were used, namely, 1) observation checklist, 2) in-depth interviews, and 3) expenditure data review. Wound dressing processes were observed. Retrospective health facility cost data of Buruli ulcer (BU) wound treatment for the year 2011 were used. Cost data gathered covered medical and nonmedical items. Cost analyses were carried out to determine the health facility's financial and economic costs. RESULTS: The total annual financial cost was US $121,189.16, of which 99% was recurrent cost. This constitutes about 13% of the expenditure by the Amasaman Government Hospital for the year 2011. The total annual economic cost was US $143,609.22, of which 93% was recurrent cost. The main cost driver for both financial and economic costs was personnel. The annual BU wound treatment costs per capita were US $1615.86 for financial cost and US $1914.79 for economic cost, respectively. The study did not cover household patient costs. CONCLUSIONS: The cost of BU wound treatment takes a considerable amount of the hospital's expenditure. This shows the importance of health facility cost as one of the decision-making tools for both resource allocation and mobilization. Hospital management must therefore constantly examine its staffing norms and the associated cost to improve the hospital's resource allocation. PMID- 29702801 TI - Interim EQ-5D-5L Value Set for Poland: First Crosswalk Value Set in Central and Eastern Europe. AB - OBJECTIVE: To estimate an interim five-level EuroQol five-dimensional (EQ-5D-5L) value set for Poland on the basis of the crosswalk methodology developed by the EuroQol Group. METHODS: On the basis of data from 3691 respondents from six European countries, the EuroQol Group has developed a method of obtaining interim value sets for the EQ-5D-5L by means of mapping to the available three-level EuroQol five-dimensional (EQ-5D-3L) value sets ("crosswalk" methodology). A significant part of the data in this study came from Polish respondents (n = 972; 26.3%). Poland is the first Central European country with EQ-5D-3L time trade-off based social value set published. To obtain an interim EQ-5D-5L value set, we applied the crosswalk methodology to the Polish EQ-5D-3L value set. RESULTS: Estimated Polish values for 3125 EQ-5D-5L health states are presented. Both EQ-5D 5L and EQ-5D-3L value sets have the same range (from -0.523 to 1.000), but different means (0.448 vs. 0.380) and medians (0.483 vs. 0.403), respectively. Proportionately fewer states worse than dead were observed in the EQ-5D-5L (5.4%) value set than in the EQ-5D-3L (13.2%) value set. CONCLUSIONS: The crosswalk based value set is available for use in EQ-5D-5L studies in Poland to calculate health state utilities. It should be considered an interim value set until values based on preferences elicited directly from a sample representative of the Polish general population become available. This study helps users of the crosswalk algorithm understand the properties of the EQ-5D-5L values generated using this method, in comparison to EQ-5D-3L values obtained with the Polish time trade-off value set. It is likely that similar results would be observed for values sets in other countries because the same crosswalk methodology applies across all countries. PMID- 29702802 TI - Cost-Effectiveness of the Combined Use of Warfarin and Low-Dose Aspirin versus Warfarin Alone in Egyptian Patients with Aortic Valve Replacements: A Markov Model. AB - BACKGROUND: The combination of antiplatelet and anticoagulant therapy significantly reduces the rate of thromboembolic events in patients with heart valves compared with anticoagulant therapy alone. Cost-effectiveness of this therapy in Egypt, however, has not yet been established. OBJECTIVE: The aim of the present study was to evaluate the cost-effectiveness of the combined use of warfarin and low-dose aspirin (100 mg) versus warfarin alone in patients with mechanical aortic heart valve prostheses who began therapy at the age of 50 to 60 years over a 5-year period from the perspective of the medical providers. METHODS: A cohort Markov process model with five health states (recovery, reoperation, bleeding, thromboembolism, and death) based on Egyptian clinical practice was derived from published sources. The clinical parameters were derived from meta-analyses of randomized controlled trials of patients with mechanical valve prostheses. The quality of life of the health states was derived using the available published data. Direct medical costs were obtained from four top-rated governmental cardiology hospitals in Egypt. All costs and effects were discounted at 3.5% annually. All costs were converted using the purchasing power parity rate and are reported in US $ for the financial year of 2013. RESULTS: The total quality-adjusted life-years (QALYs) were estimated to be 1.1616 and 1.1199 for the warfarin plus aspirin group and the warfarin group, respectively, which resulted in a difference of 0.0416 QALYs. The total costs for the warfarin plus aspirin group and the warfarin group were US $307.33 and US $315.25, respectively (the difference was US $7.92), which yielded an incremental cost-effectiveness ratio of -190.38 for the warfarin plus aspirin group. Thus, the combined therapy was dominant. Various one-way sensitivity analyses indicated that probabilities of reoperation and bleeding in the recovery state had the greatest effects on incremental costs. The model parameters that had the greatest effects on incremental QALYs were the relative risk reduction of death and the utility value in the recovery state. CONCLUSIONS: The present study is the first cost-utility analysis to conclude that, from the perspective of Egyptian medical providers, combined therapy is more effective and less costly than warfarin alone for patients with mechanical aortic valve prostheses. For clinicians and patients who choose to focus on minimizing thromboembolic risk, these results suggest that combined therapy offers the best protection. This study helps to inform decisions about the allocation of health care system resources and to achieve better health in the Egyptian population. PMID- 29702803 TI - Mapping the Nottingham Health Profile onto the Preference-Based EuroQol-5D Instrument for Patients with Diabetes. AB - OBJECTIVE: The aim of this study was to derive a function that can map the Nottingham Health Profile (NHP) questionnaire onto a utility measure, the EuroQol five-dimensional (EQ-5D) questionnaire index, for diabetic patients. METHODS: A cross-sectional study was performed on diabetic patients in Hungary with different complications in which quality of life was measured by using both the NHP questionnaire and the EQ-5D questionnaire. Ordinary stepwise-backward least squares regression was used to develop a mapping function. Adjusted R2, Akaike's information criterion, and root mean square error were used to assess the performance of the model. The robustness of the models was tested using 10-fold cross-validation and bootstrapping. RESULTS: The best-fitting models were those that contained all the NHP statements as predictors and a stepwise reduced version that contained only 19 statements. The latter model, however, showed considerable variability in the selection of predictors. The adjusted R2 of the former model was 0.68, the root mean square error was 174, and the Akaike's information criterion was -559.9. CONCLUSIONS: The expected value of the EQ-5D questionnaire can be reasonably predicted on the basis of results of the NHP in patients with diabetes mellitus. The mapping function of the NHP onto the EQ-5D questionnaire is capable of estimating the expected EQ-5D questionnaire utility values in a group of patients with diabetes. The function's applicability for individual-level predictions, however, is limited. Further research is needed to find out whether mapping functions developed in Central-Eastern European countries are transferable to Western European countries. PMID- 29702804 TI - Health Care Financing in Ethiopia: Implications on Access to Essential Medicines. AB - BACKGROUND: The Ethiopian health care system is under tremendous reform. One of the issues high on the agenda is health care financing. In an effort to protect citizens from catastrophic effects of the clearly high share of out-of-pocket expenditure, the government is currently working to introduce health insurance. OBJECTIVE: This article aims to highlight the components of the Ethiopian health care financing reform and discuss its implications on access to essential medicines. METHODS: A desk review of government policy documents and proclamations was done. Moreover, a review of the scientific literature was done via PubMed and search of other local journals not indexed in PubMed. RESULTS: Revenue retention by health facilities, systematizing the fee waiver system, standardizing exemption services, outsourcing of nonclinical services, user fee setting and revision, initiation of compulsory health insurance (community-based health insurance and social health insurance), establishment of a private wing in public hospitals, and health facility autonomy were the main components of the health care financing reform in Ethiopia. Although limited, the evidence shows that there is increased health care utilization, access to medicines, and quality of services as a result of the reforms. CONCLUSIONS: Encouraging progress has been made in the implementation of health care financing reforms in Ethiopia. However, there is shortage of evidence on the effect of the health care financing reforms on access to essential medicines in the country. Thus, a clear need exists for well-organized research on the issue. PMID- 29702805 TI - Determinants of Cost-Related Nonadherence to Medications among Chronically Ill Patients in Maccabi Healthcare Services, Israel. AB - BACKGROUND: The effectiveness of value-based insurance design is based on nonadherence, which derives solely from patients' economic constraints. OBJECTIVE: Our objective was to examine the extent of cost-related nonadherence to chronic medications and to analyze its potential determinants. METHODS: We conducted a telephone survey among a representative sample of Maccabi Healthcare Services chronically ill patients aged 55 years or older (n = 522). We developed a 12-month recall questionnaire that included demographic and socioeconomic characteristics, out-of-pocket expenditure on prescribed medication, physician's provision of explanation regarding prescribed therapy, adherence, and reasons for nonadherence. Respondents were defined as nonadherent if they reported that they did not purchase prescribed medications in the previous year because of their cost. We applied the multivariable logistic regression model to examine predictors of nonadherence. RESULTS: Median (interquartile range) age of the study sample was 69 (13) years (53% males). One hundred sixty-five patients (31.6%) reported not purchasing prescribed medications mainly because of medications' adverse effects and/or cost. Fifty respondents (9.6%) reported cost related nonadherence. The multivariable logistic regression model revealed that cost-related nonadherence was associated with respondent's income lower than 4600 New Israeli shekel (odds ratio [OR] = 10.86; 95% confidence interval [CI] 1.45 81.12), unemployment (OR = 4.32; 95% CI 1.47-12.66), lack of physician explanation about the prescribed medication (OR = 2.38; 95% CI 1.18-4.78), and age (OR = 0.95; 95% CI 0.91-0.99). CONCLUSIONS: Cost-related nonadherence to chronic pharmaceuticals is self-reported among nearly 10% of the chronically ill patients and is strongly affected by low socioeconomic status, even under universal health insurance coverage and with relatively low co-payments as applied in Israel. Lack of information provided by physicians regarding the therapy is associated with a higher likelihood of cost-related nonadherence. PMID- 29702806 TI - An Overview of the Orphan Medicines Market in Turkey. AB - BACKGROUND: The health policies of many countries and regions have already defined orphan drugs for rare diseases. Although there is no official definition of orphan drugs in Turkey, all orphan drugs are covered by reimbursement, regardless of their market authorization status. Thus, a pharmacoeconomic analysis does not have to be presented to the Social Security Institution (Sosyal Guvenlik Kurumu) for reimbursement decisions on orphan drugs. OBJECTIVE: The aim of this study was to shed light on the use of orphan drugs to aid classifications of rare diseases and assessments of orphan drugs in Turkey. METHODS: Data for sales of authorized orphan drugs and all other drugs were extracted from the IMS Turkey for 2008, 2009, and 2010. Nonauthorized orphan drug sales data were extracted from records of the Turkish Pharmacists' Association for the same years. Government prices were obtained from the Sosyal Guvenlik Kurumu. RESULTS: The European Medicines Agency has classified more than 60 orphan drugs for rare diseases. Of these, 50 entered the Turkish market in recent years, half of which were authorized. The remaining drugs were imported through the early access procedure. Antineoplastic agents accounted for the largest percentage of orphan drugs, with 58% of the total market share. In 2010, there were 18 such agents in use, at a cost of ?120 million. CONCLUSIONS: Although legislation is not yet in place for orphan drugs in Turkey, recognized pricing and reimbursement policies are in operation. This situation facilitates an analysis of orphan drug prices and reimbursement policies in Turkey. PMID- 29702807 TI - Health Economic Data Requirements and Availability in the European Union: Results of a Survey Among 10 European Countries. AB - OBJECTIVES: To compare data requirements and their availability for health economic (HE) evaluations in five countries in Central/Eastern Europe (CEE) (Poland, the Czech Republic, Slovakia, Hungary, and Romania) and five countries in Western Europe (WE) (the United Kingdom, France, Germany, The Netherlands, and Sweden). METHODS: A questionnaire was developed and distributed to market access personnel from Pfizer who were asked to complete the questionnaire either from their own knowledge or with support of external experts. The questionnaire focused on the obligation to conduct HE assessment for reimbursement submissions, local HE guidelines, applied discount rates for future costs and effects, willingness-to-pay thresholds, and available data sources. RESULTS: HE is mandatory in all CEE and three WE participating countries for reimbursement applications of innovative drugs. Usually, cost-effectiveness analysis and budget impact analyses are required. The preferred outcome of cost-effectiveness analysis is quality-adjusted-life years. In Romania, France, and the Czech Republic, guidelines could not be identified at the time of the survey. The applicant usually prepares HE evaluations; in Sweden, the United Kingdom, The Netherlands, and Poland, unlocked models have to be presented for scrutiny. Discount rates vary from 1.5% to 5%, and, usually, is the same for costs and outcomes (except in The Netherlands and Poland). Only the United Kingdom, Poland, and Slovakia have an explicit willingness-to-pay threshold. In Poland, it is based on the gross domestic product per capita, and in Slovakia, it is based on multiples of average monthly salary. Differences were found on data availability. In WE, data can be acquired easier than in CEE. Health insurance funds do not provide their data unless they were published. Patient registries are either not available in CEE or difficult to access, so applicants mostly rely on retrospective medical chart data, hospital information systems, or expert panels. CONCLUSIONS: We found similar requirements for HE analyses in CEE and WE but differences in data availability. This results in less accurate inputs across the CEE, influencing analyses' outcomes. PMID- 29702808 TI - The Cost of Melanoma and Kidney, Prostate, and Ovarian Cancers in Russia. AB - OBJECTIVE: The objective of this study was to assess the total annual economic burden of melanoma and kidney, prostate, and ovarian cancers in Russia using the unified methods. METHODS: The general prevalence-based cost-of-illness model was developed to evaluate the annual health and social care costs and value of lost productivity attributable to the following cancers: melanoma and kidney, prostate, and ovarian cancers from the perspective of the overall governmental budget. All costs were calculated using the "bottom-up" costing technique for the total population of patients with studied cancer, including both newly diagnosed patients stratified by cancer stage and patients diagnosed in previous years who were still alive in the study year. RESULTS: The lowest aggregate annual cost was found for melanoma-?17.48 million (52.4% health care costs, 34.9% social care costs, 12.7% attributed to productivity loss) and the highest-?84.52 million-for prostate cancer (72.0%, 19.0%, and 9.0%, respectively). Estimations for kidney and ovarian cancers were ?45.33 and ?45.56 million, respectively, with a similar distribution (42.5%-45.2% health care costs, 39.0%-40.3% social care costs, 14.5% 18.5% lost productivity). Cost for a newly diagnosed patient was several times higher than for a patient diagnosed in previous years (?1144- ?1947 vs. ?145 ?417, respectively). For patients in the first year after diagnosis, the major part of economic burden was attributed to health care costs, whereas for those diagnosed before the study year, costs not related to health were more prominent, except for prostate cancer. CONCLUSIONS: The economic impact of cancers is more prominent during the first year after diagnosis. A considerable part of the economic burden of cancer lies outside the health sector. PMID- 29702809 TI - The Role of the National Health Insurance Fund Administration in the Development of Health Economics and Health Technology Assessment in Hungary. PMID- 29702810 TI - Cost-effectiveness versus Cost-Utility Analyses: What Are the Motives Behind Using Each and How Do Their Results Differ?-A Polish Example. AB - OBJECTIVES: We aimed to compare the use of cost-effectiveness analysis and cost utility analysis in health technology assessment in Poland. METHODS: We analyzed all the submissions (155) made to the Polish Agency for Health Technology Assessment in the period 2007 to 2011, with 316 intervention-comparator comparisons reporting incremental cost-effectiveness ratios (ICERs) or incremental cost-utility ratios (ICURs). We compared ICERs and ICURs when both were reported (31%), determined factors associated with reporting one or the other, and tested the precision of their assessment. RESULTS: In 13% of the cases, ICER and ICUR led to different decisions (were on opposite sides of the willingness-to-pay threshold). Cost-effectiveness analyses were more frequently performed in oncology, offering at the same time more favorable results. It was also more frequent for longer time-horizon models, although then ICER values were on average higher. CONCLUSIONS: In Poland, cost-utility analysis is a usual approach of increasing popularity. Interestingly, although assessing ICUR requires additional assumptions, it is estimated more precisely (reported ranges of values in sensitivity analyses are narrower), especially in oncology. ICER and ICUR disagree more often than previously shown in literature. There seem to be no clear signs of biases in submissions (selecting whether to present ICER or ICUR on the basis of their values), but the current study is limited because only the values presented by manufacturers in the submission are available. PMID- 29702811 TI - Medical and Productivity Costs of Rheumatoid Arthritis in The Czech Republic: Cost-of-Illness Study Based on Disease Severity. AB - OBJECTIVE: International pharmacoeconomic studies suggest that functional impairment can be a significant predictor for the evaluation of direct and productivity costs for rheumatoid arthritis (RA). We calculated the direct and productivity costs for five Health Assessment Questionnaire (HAQ) groups of patients (HAQ scores <0.6, 0.6 >= 1.1, 1.1 >= 1.6, 1.6 >= 2.1, and >=2.1) in the Czech Republic. METHODS: This was a retrospective cross-sectional study. We included 261 patients with RA, aged 18 to 84 years. We applied a bottom-up method by retrospectively reviewing individual patient medical records. Patients' demographic characteristics, patient-reported outcome, and clinical parameters were gathered at the time of data collection. For the calculation of productivity costs, we used the friction cost approach, based on patient absenteeism with a friction period of 130 workdays, with average monthly income used as the denominator. Costs were expressed as a mean value per patient with RA in each HAQ group. RESULTS: Mean patient age was 56.4 years. average time from diagnosis was 14.5 years, the mean HAQ score was 1.15, and the Disease Activity Score in 28 joints was 3.45. A total of 47.5% patients were treated with biologics. Mean annual direct medical costs for each HAQ group were ?5315, ?7357, ?7697, ?7716, and ?8968, respectively. The mean annual indirect costs associated with productivity loss were ?1414, ?1459, ?1610, ?1876, and ?2307, respectively. CONCLUSIONS: Direct costs and productivity costs for patients with RA are closely related to the value of the HAQ score. The annual mean total (direct plus productivity) costs per patient 1) treated with biologics, 2) without biologic treatment, and 3) from the overall cohort were ?14,763, ?3,559, and ?8,882, respectively. PMID- 29702812 TI - Estimation of the Direct Cost of HIV-Infected Patients in Greece on an Annual Basis. AB - OBJECTIVE: HIV infection is currently regarded as a global chronic disease. The purpose of this study was to assess the direct cost of illness per patient per year in Greece. METHODS: A retrospective study for the estimation of the direct cost of HIV infection was performed from the third-party payer perspective. Data from 447 patients monitored in a general hospital of Athens were collected from their medical records. The survey involved all services and treatments that patients (stratified into three health states according to the number of CD4 cells/ml as defined by the Centers for Disease Control and Prevention classification system for HIV infection) received in 1 year, as well as demographic data. RESULTS: The annual direct cost per patient was calculated at ?6859 +/- ?4699. Antiretroviral therapy cost was estimated at ?5741, while the annual cost of providing health care services regardless of health state was computed at ?1118, with laboratory investigation and imaging studies representing ?924 (13.5%), outpatient visits ?34 (0.5%), and hospitalization ?160 (2.3%) of total cost, respectively. Overall, direct cost per patient was found to increase as the CD4 T lymphocytes decreased, leading to prolonged hospitalization and an increase in the number of laboratory tests. Direct cost for patients with more than 500 CD4 cells/MUl was estimated at ?6067, whereas for those with 200 to 499 cells/MUl and less than 200 cells/MUl, it was assessed at ?6857 and ?7654, respectively. CONCLUSIONS: The direct cost of HIV infection per patient increased as CD4 T lymphocytes decreased. The largest part of expenses was attributed to antiretroviral therapy, followed by laboratory tests/imaging studies, hospitalization, and finally outpatient visits. PMID- 29702813 TI - Cost-Effectiveness Comparison of Fidaxomicin and Vancomycin for Treatment of Clostridium difficile Infection: A Markov Model Based on Data from a South West Balkan Country in Socioeconomic Transition. AB - BACKGROUND: Recent studies have shown that fidaxomicin, a novel antibiotic, can reduce the rate of complications and mortality in patients with colitis induced by Clostridium difficile. Introduction of fidaxomicin in clinical practice is limited by its high costs. OBJECTIVES: The purpose of this study was to estimate the cost effectiveness of using fidaxomicin versus vancomycin in patients with colitis induced by C. difficile who did not respond to oral metronidazole. METHODS: We constructed a Markov model that was than simulated by Monte-Carlo simulation using 1000 virtual patients with colitis induced by C. difficile. The perspective in our model was institutional. The time horizon was 3 months. Values of transition probabilities and therapy outcomes were estimated from the available literature, the prices of health services were obtained from the Republic Institute for Health Insurance Tariff Book, and the price of fidaxomicin was derived from data gained from the drug manufacturer. RESULTS: The total costs of treating one statistical patient for 3 months with fidaxomicin were higher (48,106.19 +/- 118.07 Republic of Serbia dinars [RSD]; 95% confidence interval 47,988.12-48,224.27) than the total costs of treating with vancomycin (25,872.85 +/- 41.44 RSD; 95% confidence interval 25,831.41-25,914.29). Our results showed that the treatment of infections induced by C. difficile with fidaxomicin correlated with a lower rate of mortality and with a smaller number of colectomies. The incremental cost-effectiveness ratio of fidaxomicin versus vancomycin for colitis induced by C. difficile per saved life was estimated at 2.97 million RSD and for one avoided colectomy at 10.07 million RSD. CONCLUSIONS: Results of our model indicate that fidaxomicin is a cost-effective therapy compared with vancomycin in patients with colitis induced by C. difficile if the outcome is life-year saved. However, if the outcome is the number of avoided colectomies, then fidaxomycin is not a cost-effective option compared with vancomycin. PMID- 29702814 TI - Use of the EQ-5D Instrument and Value Scale in Comparing Health States of Patients in Four Health Care Programs among Health Care Providers. AB - OBJECTIVES: The main objective of this article was to explore the use of the patient evaluation of health states in determining the quality of health care program provision among health care providers. The other objectives were to explore the effect of size and status of health care providers on patient reported outcomes. METHODS: The EuroQol five-dimensional questionnaire was used in four health care programs (hip replacement, hernia surgery, carpal tunnel release, and veins surgery) to evaluate patients' health states before and after the procedure, following carefully prepared instructions. Data were collected for a single year, 2011. The number of questionnaires filled by patients was 165 for hip replacement, 551 for hernia surgery, 437 for vein surgery, and 158 for carpal tunnel release. The data were analyzed using linear regression model and the EuroQol five-dimensional questionnaire value set for Slovenia. Differences between providers were determined using the Tukey test. Potential quality adjusted life-years (QALYs) gained for all four programs were calculated for the optimal allocation of patients among providers. RESULTS: There are significant differences among health care providers in the share of patients who reported positive changes in health care status as well as in average improvement in patient-reported outcomes in all four programs. In the case of optimal allocation, each patient undergoing hip replacement would gain 2.25 QALYs, each patient undergoing hernia surgery would gain 0.83 QALY, each patient undergoing veins surgery would gain 0.36 QALY, and each patient undergoing carpal tunnel release would gain 0.78 QALY. CONCLUSIONS: The analysis exposed differences in average health state valuations across four health care programs among providers. Further data on patient-reported outcomes for more than a single year should be collected. On the basis of trend data, further analysis to determine the possible causes for differences should be conducted and the possibility to use this approach for measuring health care providers' performance and its use in contracting should be explored. PMID- 29702815 TI - Widening Horizon of Pharmacoeconomics and Outcomes Research in the Asia-Pacific Region. PMID- 29702816 TI - How Does Out-of-Pocket Payment Affect Choices When Accessing Health Care?-A Qualitative Study on Hypertensive Outpatients in Southern Taiwan. AB - OBJECTIVES: The National Health Insurance in Taiwan provides the entire population with universal coverage and full freedom to access health care, and thus results in accelerating medical utilization and costs. A differential outpatient co-payment was introduced on July 15, 2005, to deter nonessential visits and encourage initial contact in primary care and a stepwise access to health care (referral system). A previous study, however, showed a limited impact of this co-payment policy on reducing medical utilization and improving the referral system. This qualitative study aimed to explore Taiwanese patients' decision-making process to access health care and how the cost issue impacts patients' access to health care and explore patients' cost-saving strategies. METHODS: Hypertensive patients from different tiers of medical facilities (community, regional hospitals, and medical centers) in the Kao-Ping area of southern Taiwan were invited to participate in focus groups from October 2008 to January 2009. RESULTS: Of all, 40 participants were recruited for nine focus groups. The physicians' reputation, tiers of hospitals, and the convenience of transport and registration are the three major reasons why participants accessed different medical facilities. Participants expressed that the current out-of pocket payment is affordable and not as important as other reasons for their choices. Continuous prescription was considered a cost-saving strategy for patients visiting higher tiers of medical facilities. Most participants were not fully aware of current National Health Insurance regulations such as co-payment, continuous prescriptions, and the referral policy. CONCLUSIONS: The current out of-pocket payment is affordable for hypertensive patients receiving regular treatments, but it fails to reduce the demand of health care. To establish a proper evaluation of the co-payment policy, future study is suggested to consider the views from health care providers and financially vulnerable patients. PMID- 29702817 TI - Reconciling Cancer Care Costs Reported by Different Government Agencies in Taiwan: Why Costing Approach Matters? AB - OBJECTIVES: Few studies have explored how differences in costing methods may contribute to a discrepancy in the cost of cancer reported by different government agencies. METHODS: By using claims data of cancer patients and controls identified from 2005 to 2007 claims data in Taiwan, we sought to understand the discrepancy in public reporting of cancer care costs by comparing four costing methods on the basis of the definition of cancer and cancer-related services employed by three agencies: Department of Health, Bureau of National Health Insurance (BNHI), and National Health Research Institute (NHRI). We also compared two costing approaches, the attributable cost approach versus the net cost approach, in terms of total cost, number of cancer cases, and average cost per patient. RESULTS: The estimated total cost of cancer was highest (1.65 billion relative value units [RVUs] in 2005) from the NHRI method and lowest from the Department of Health method (1.20 billion RVUs). The Department of Health and NHRI methods tended to report higher number of cancer cases than did the BNHI and net cost methods. The estimated cost per patient was lowest from the NHRI costing method (34,139 RVUs) and highest from the BNHI method (94,115 RVUs). Projection to national cost showed that the percentages of national health expenditure for cancer ranged from 3.9% to 5.3% in 2005. CONCLUSIONS: The estimated costs of cancer care can vary widely (more than 10 billion New Taiwan dollars) by costing methods. The BNHI costing method appeared to produce estimates similar to those produced by the net cost approach. PMID- 29702818 TI - Health Care System Information Sharing: A Step Toward Better Health Globally. PMID- 29702820 TI - Generalized Cost-Effectiveness Analysis of Pharmaceutical Interventions for Primary Prevention of Cardiovascular Disease in Thailand. AB - OBJECTIVES: To assess the cost-effectiveness of blood pressure (BP)-lowering and cholesterol-lowering drugs for cardiovascular disease (CVD) prevention. METHODS: We constructed a Markov model in which the Thai population was classified by 10 year absolute CVD risk and modeled the use of BP- and cholesterol-lowering drugs, including a "polypill" (three BP-lowering drugs and a statin). We applied "do nothing" as the comparator, a health sector perspective on lifetime cost effectiveness, 3% discounting of costs and effects, and used probabilistic sensitivity analysis. Outcomes are expressed as average and incremental cost effectiveness in Thai baht per disability-adjusted life-year averted. RESULTS: The polypill would be a very cost-effective option for CVD prevention even in people at modest risk (10-year risk of 5%-9.9%). Use of the three most cost effective BP drugs is also associated with a net cost saving and large health gain at risk levels greater than 5%. Adding a generic statin gives a price per disability-adjusted life-year of 0.5 (10-year risk at 20%+) to 1.5 (10-year risk at 5%-9.9%) times Thai per-capita gross domestic product using lowest available annual costs. However, at current average drug prices, adding a statin would be considered cost-effective only for those with a 10-year absolute CVD risk of 20% and more. CONCLUSIONS: Primary CVD prevention with the polypill or a combination of three generic BP-lowering drugs is very cost-effective in the Thai population. PMID- 29702821 TI - Cost of Illness of Chronic Hepatitis B Infection in Vietnam. AB - OBJECTIVES: To estimate the total financial burden of chronic hepatitis B virus (HBV) infection for Vietnam by quantifying the direct medical, the direct nonmedical, and indirect costs among patients with various stages of chronic HBV infection. METHODS: Direct medical cost data were retrieved retrospectively from medical histories of inpatients and outpatients in 2008 from a large referral hospital in Hanoi, Vietnam. Direct nonmedical and indirect costs data were obtained from face-to-face interviews of outpatients from the same hospital. The treatment cost per patient per chronic HBV infection stage was multiplied by the total estimated patients in Vietnam to get the total cost of illness for the nation. RESULTS: Nationally, the total cost attributable to chronic HBV infection and its complications in 2008 was estimated to be approximately US $4.4 billion, with the direct medical cost accounting for about 70% of that estimate. The cost of antivirals was the major cost driver in treating chronic HBV infection. The per-patient total annual direct medical cost increased with the severity of the disease, with the estimated costs for chronic HBV infection and hepatocellular carcinoma as US $450.35 and US $1883.05, respectively. When compared with the 2008 per-capita gross domestic product of ~US $1024, the financial burden of treating chronic HBV infection is very high in Vietnam. CONCLUSIONS: This study confirmed that chronic HBV infection poses a significant financial burden for the average patient and that lacking treatment would become a social issue in Vietnam. Although HBV vaccination has been universally implemented, more health care investment and the greater availability of affordable medications are still needed to attain equity in proper treatment for patients with HBV infection. PMID- 29702822 TI - Economic Evaluation of Rehabilitation Services for Inpatients with Stroke in Thailand: A Prospective Cohort Study. AB - OBJECTIVE: Rehabilitation can restore function and prevent permanent disability in patients with stroke. There is, however, only one study on cost-effectiveness of rehabilitation in Thailand. Our objective was to evaluate the cost-utility of rehabilitation for inpatients with stroke under Thai settings. METHODS: This was a prospective observational cohort study with a 4-month follow-up in two regional hospitals. The sample consisted of 207 first-episode stroke inpatients divided into rehabilitation and unexposed groups. Rehabilitation services during the subacute and nonacute phase were the intervention of concern. Main outcomes were patient's Barthel index for functional status and the EuroQol five-dimensional questionnaire as utility scores. A microcosting approach was employed considering a societal perspective. Effectiveness was defined as the improvement in functional status and quality-adjusted life-year (QALY). We used a longitudinal logistic model and multiple regressions. Cost-effectiveness ratios per QALY gained were presented. A probabilistic sensitivity analysis was conducted to estimate the uncertainty range. RESULTS: Compared with the unexposed group, the Barthel index and QALY of patients with rehabilitation were significantly improved (P < 0.010). The incremental cost-effectiveness ratio of rehabilitation services for patients with stroke was 24,571 baht per QALY. Cost-effectiveness acceptability curves suggested that the rehabilitation services were likely to represent good value for money at the ceiling ratio of 70,000 baht per QALY (compared with the threshold of 1 time per-capita gross domestic product per QALY gain or 100,000 baht per QALY). CONCLUSION: The rehabilitation services for stroke survivors were cost-effective under the Thai health care setting. PMID- 29702823 TI - Factors Influencing Oral Coxibs Utilization and Expenditure at a Thai Teaching Hospital, Fiscal Year 2007 to 2009. AB - OBJECTIVE: This study aimed to examine factors that influenced the rising Coxibs expenditure. METHODS: Retrospective utilization data were retrieved from hospital's database. Changes in Coxibs expenditure in 2007 and 2009, calculated by using the Laspeyres index, were attributed to two factors: cost per patient (P) and number of patients (Q) per year. By measuring quantity as defined daily dose, changes in P comprised two subfactors: cost per day (p) and days of therapy per patient (q); p was weighted average cost of Coxibs per day, and q was weighted average days of therapy of new and current patients. Furthermore, the pattern of concomitant drugs, proton pump inhibitors, was analyzed. RESULTS: Expenditure on Coxibs rose from 57.7 to 69.4 million baht from 2007 to 2009. With Laspeyres index, total index of 1.20 was a result of three main factors. The highest impact was from change in cost per day (p index at 1.17), which was a result of a slight increase in drug cost, mainly weighted by product mix, which tended to switch drug from low to high cost. Another positive impact was the number of Coxibs patients (Q index at 1.04). Finally, the negative impact was from days of therapy per patient (q index = 0.98). Although days of therapy per patient for both new and current patients were decreased, patient mix of more current patients slowed the decrease down. In addition, the percentage of proton pump inhibitors coprescription also rose from 30.8% in 2007 to 32.3% in 2009. CONCLUSION: Switching drug from low to high cost is a major factor that impacted the rising of expenditure on Coxibs. PMID- 29702824 TI - The Cost of Providing HIV/AIDS Counseling and Testing Services in Vietnam. AB - OBJECTIVE: This article aimed to provide estimates and analyses of the cost of providing voluntary counseling and testing (VCT) services for HIV/AIDS in a province in northern Vietnam. METHODS: This facility-based costing study was conducted in the Thai Nguyen province, located 85 km north of Hanoi. Cost data were collected in six facility-based VCT units and two freestanding ones by using an ingredient approach. Both financial and economic costs of VCT services for HIV/AIDS were estimated from the perspective of the service providers. RESULTS: The mean total annual financial costs of a facility-based and a freestanding VCT unit in the study site were US $15,673 and US $42,237, respectively. The mean total annual economic costs of these services were US $16,695 and US $44,682, respectively. The cost per visit to the facility-based VCT unit was lower than in the freestanding facility (financial cost of US $28.4 vs. US $36.8; economic cost of US $30.3 vs. US $38.9). The same was true for the cost per complete VCT procedure (financial cost of US $34.7 vs. US $38.0; economic cost of US $36.9 vs. US $40.2). The cost per HIV positive case detected in facility-based VCT unit was higher than that of the freestanding VCT unit (financial cost of US $149.3 vs. US $111.2; economic cost of US $159.0 vs. US $117.6). CONCLUSIONS: The results of the present study offer preliminary evidence on economic aspects of providing VCT services in Vietnam. The findings from this study can serve as a basis for further studies as well as for program and policy development. PMID- 29702825 TI - Attributable Cost and Length of Stay for Patients with Enoxaparin-Associated Bleeding. AB - OBJECTIVES: Patients receiving enoxaparin are at risk of bleeding. The study of the economic impact of enoxaparin-associated bleeding in Asian population, however, is limited. This study aimed to estimate the attributable costs and length of stay (LOS) of patients experiencing enoxaparin-associated bleeding compared with nonbleeding patients in the setting of acute coronary syndrome. METHODS: We conducted a retrospective cohort study of hospitalized patients with acute coronary syndrome who received enoxaparin in a large university-affiliated hospital. Cost and LOS were compared among three groups of patients according to the status of bleeding event. The attributable cost and LOS were estimated by using multiple linear regressions with log-transformed model and adjusted by confounders. The adjusted means of cost and LOS estimates were retransformed to their natural values by using Duan's smearing estimator. The differences of costs and LOS were presented as mean with 95% confidence intervals (CIs). RESULTS: Out of 346 patients, 134 experienced enoxaparin-associated bleeding (28 and 106 patients experienced major and minor bleeding, respectively). The average age and gender in both groups were similar. Compared to the nonbleeding group, the attributable cost and LOS were 108,226 Thai baht (95% CI: 87,068-129,386) and 8 days (95% CI: 7.1-9.0) for major bleeding and 72,997 Thai baht (95% CI: 57,822 88,172) and 3.1 days (95% CI: 2.5-3.7) for minor bleeding, respectively. CONCLUSIONS: Bleeding is significantly associated with increased cost and LOS among enoxaparin users. These findings suggest that strategies aiming to reduce bleeding events may potentially help reduce the cost of care among patients with acute coronary syndrome receiving enoxaparin therapy. PMID- 29702826 TI - Economic Evaluation of Anastrozole Versus Tamoxifen for Early Stage Breast Cancer in Singapore. AB - OBJECTIVES: In Singapore, breast cancer is the leading female malignancy and its incidence has increased threefold over the past decades. For treatment of postmenopausal, hormone receptor positive early stage breast cancer, tamoxifen or aromatase inhibitors such as anastrozole are prescribed either as first-line therapy or sequentially. Currently, anastrozole is patented with a higher drug cost compared with tamoxifen. Hence, the aim of this study was to conduct an economic evaluation of anastrozole versus tamoxifen in early stage breast cancer. METHODS: A Markov model with a lifetime horizon was developed by using results from the Arimidex, Tamoxifen, Alone or in Combination trial. Direct medical costs were estimated by billing data obtained via financial electronic databases. Utility scores were elicited from 20 experienced oncology nurses using the visual analogue scale. Cost per quality-adjusted life-years was calculated by using the societal perspective. A discount rate of 3% for both charges (expressed in 2010 Singapore dollars) and benefits was used. RESULTS: At an additional cost of S $17,597, anastrozole treatment resulted in a gain of 0.085 life-year survival and 0.154 quality-adjusted life-year. The incremental cost-effectiveness ratio of anastrozole was S $207,402 per life-year gained and S $114,061 per quality adjusted life-year gained compared with tamoxifen. CONCLUSION: This is the first economic evaluation that used 10-year results from the Arimidex, Tamoxifen, Alone or in Combination trial and utility elicited from the local population. If the World Health Organization's recommendation of 1 to 3 gross domestic product range is an acceptable threshold, anastrozole is deemed cost-effective compared with tamoxifen in the treatment of early stage breast cancer. PMID- 29702827 TI - Cost Assessment of Implementation of Immune Tolerance Induction in Iran. AB - OBJECTIVE: A number of hemophilia A patients who receive clotting factors may develop antibodies (inhibitors) against clotting factors. The immune tolerance induction (ITI) method has proved to be a very cost-effective alternative to bypassing agents. Iran's national health authority is interested in implementing the ITI method for the management of hemophilia patients with inhibitors. The objective of this study was to calculate the breakeven point between costs attributed to the ITI method and the use of bypassing agents for the management of high-responder hemophilia patients with inhibitors. METHODS: This study assessed costs attributed to the implementation of ITI for the management of Iranian hemophilia patients with costs of high-titer and high-responding inhibitors from the perspective of the national health system. The main objective was to find the breakeven point for the ITI method in comparison with the use of bypassing medicine, recombinant factor VIIa (Novoseven). RESULTS: Based on the sensitivity analysis performed, the breakeven point mainly depends on costs of factor VIII, Novoseven, and the success rate of the ITI intervention. According to this analysis, the breakeven point of ITI and Novoseven methods varies between 16 and 34 months posttreatment. The optimized point is about 17 months posttreatment. CONCLUSIONS: Iran's national health system spends more than 24 million euros for providing bypassing agents to about 124 hemophilia patients with inhibitors. Because of limited resources available in Iran's health sector, this is a huge burden. Results of this study show that the implementation of the ITI method for the management of Iranian hemophilia patients with inhibitors is a cost-saving method and Iran's health system will recover all the expenditure related to the implementation of ITI in less than 2 years and will make a considerable saving along with providing standard care for these patients. PMID- 29702828 TI - Cost-Effectiveness of Sertindole among Atypical Antipsychotics in the Treatment of Schizophrenia in South Korea. AB - OBJECTIVES: This study assessed the cost-effectiveness of sertindole compared with existing atypical antipsychotics in the treatment of patients with schizophrenia in the South Korean setting. METHODS: A Markov model was developed to estimate the cost-effectiveness of sertindole compared with risperidone, olanzapine, and quetiapine with a cycle of 6 months on a 5-year time horizon. Effectiveness was defined as the length of time without relapse and quality adjusted life-years. Parameter estimates including drug-induced adverse events, compliance rate, and relapse rate were based on published literature and clinical trial data. Resource utilization data were obtained from the 2010 National Health Insurance reimbursement data, and costs were estimated from the health care system's perspective. A discount rate of 5% was applied to both cost and effectiveness. One-way sensitivity analyses and probabilistic sensitivity analysis were carried out to check the robustness of the base-case analysis. RESULTS: The length of time without relapse was 1.90 years for all study drugs. The estimated quality-adjusted life-years were 1.27 for sertindole, followed by quetiapine, risperidone, and olanzapine. Total costs were 10.51 million Korean won (KRW) for sertindole, 12.86 million KRW for olanzapine, 8.38 million KRW for risperidone, and 8.91 million KRW for quetiapine. The incremental cost effectiveness ratios showed that sertindole was dominant only over olanzapine and was not cost-effective compared with risperidone and quetiapine. Various sensitivity analyses confirmed the results from the base-case analysis. CONCLUSIONS: Sertindole may be considered a valuable treatment option for South Korean patients who have failed the therapy with other atypical antipsychotic agents. PMID- 29702829 TI - Aprepitant for Patients Receiving Highly Emetogenic Chemotherapy: An Economic Analysis for Singapore. AB - BACKGROUND: Aprepitant (a neurokinin 1 receptor antagonist), in combination with a serotonin receptor antagonist (5-HT3 RA) and dexamethasone, has demonstrated superior efficacy on end points related to chemotherapy-induced nausea and vomiting (CINV) compared with standard care (combination 5-HT3 RA and dexamethasone). OBJECTIVE: To determine the cost-effectiveness of an aprepitant containing regimen compared with current clinical practice for the prevention of CINV in patients receiving highly emetogenic chemotherapy (HEC) in Singapore. METHODS: A decision-analytic model was constructed to assess the costs and outcomes associated with an aprepitant-containing regimen compared with standard care in the prevention of CINV following HEC. Three scenarios were modeled on the basis of results of four double-blind randomized clinical trials of aprepitant. CINV event probabilities were calculated on the basis of the occurrence of nausea and vomiting and the need for rescue medication in the 5 days following a single cycle of HEC. The analysis was conducted from the Singapore health care system perspective. RESULTS: Aprepitant reduced emesis and nausea, resulting in small but clinically important improvements when measured in quality-adjusted life years. The aprepitant-containing regimen was associated with higher acquisition costs but lower costs relating to patient management, hospitalization, and use of rescue medication. Across the scenarios, the incremental cost per emetic event avoided ranged from cost saving to Singapore $63 (US $51). The incremental cost effectiveness ratio ranged from cost saving to Singapore $49,800 per quality adjusted life-year gained (US $40,600). The analysis was relatively insensitive to changes in the inputs. CONCLUSIONS: Aprepitant is a clinically important and cost-effective therapy for the prevention of CINV in patients treated with HEC in Singapore. PMID- 29702830 TI - Cost-Effectiveness Analysis of Hepatitis B Immunization in Vietnam: Application of Cost-Effectiveness Affordability Curves in Health Care Decision Making. AB - OBJECTIVES: To perform a cost-effectiveness analysis and to identify the cost effectiveness affordability levels for a newborn universal vaccination program against hepatitis B virus (HBV) in Vietnam. METHODS: By using a Markov model, we simulated a Vietnamese birth cohort using 1,639,000 newborns in 2002 and estimated the incremental cost-effectiveness ratios for quality-adjusted life year gained following universal newborn HBV vaccination. Two types of analyses were performed, including and excluding expenditures on the treatment of chronic hepatitis B and its complications. We used Monte Carlo simulations to examine cost-effectiveness acceptability and affordability from the payer's perspective and constructed a cost-effectiveness affordability curve to assess the costs and health effects of the program. RESULTS: In the base-case analysis, newborn universal HBV vaccination reduced the carrier rate by 58% at a cost of US $42 per carrier averted. From the payer's perspective, incremental cost-effectiveness ratio per quality-adjusted life-year gained was US $3.77, much lower than the 2002 per-capita gross domestic product of US $440. Vaccination could potentially be affordable starting at a US $2.1 million budget. At the cost-effectiveness threshold of US $3.77 per quality-adjusted life-year and an annual budget of US $5.9 million, the probability that vaccination will be both cost-effective and affordable was 21%. CONCLUSIONS: Universal newborn HBV vaccination is highly cost effective in Vietnam. In low-income, high-endemic countries, where funds are limited and the economic results are uncertain, our findings on the cost effectiveness affordability options may assist decision makers in proper health investments. PMID- 29702831 TI - Are English and Chinese Versions of the Audit of Diabetes-Dependent Quality of Life Equivalent? An Exploratory Study Based on the Universalist Approach. AB - OBJECTIVE: To translate and culturally adapt the UK English Audit of Diabetes Dependent Quality of Life (ADDQOL) into Chinese for Singapore. METHODS: Translation was integrated into investigation of conceptual, item, semantic, and operation equivalence. Conceptual equivalence, item equivalence, and operation equivalence were assessed by literature review, expert judgment, and cognitive debriefing. Semantic equivalence was studied by using an optimized procedure including forward and backward translation, clinician review, and cognitive debriefings. Cognitive debriefings were done with five Chinese-speaking diabetic patients at polyclinics. Reliability, responsiveness, and construct validity tests were used to evaluate measurement equivalence. English- and Chinese speaking diabetic patients by convenient sampling at a Diabetes Society of Singapore's public event were recruited for the measurement equivalence study. Mann-Whitney U tests, chi-square tests, and descriptive analyses were used for group comparisons and Spearman's correlation coefficients for construct validity tests. RESULTS: Forty-two English-speaking and 26 Chinese-speaking diabetic patients (45.5% females) with a mean age of 54.2 +/- 10.07 years were recruited. Chinese-speaking respondents were more likely than the English-speaking group to be unemployed, less educated, and with poorer family functioning (P < 0.05). Conceptual equivalence, item equivalence, operation equivalence, and semantic equivalence were all demonstrated. Cronbach's alpha for internal consistency and intraclass correlation coefficient for test-retest reliability were 0.94 and 0.65, respectively. Distributions of responses were found to be similar except for some difference that can be justified by different demographic background. Convergent validity was suggested by weak to moderate correlations between "Present QOL" on the ADDQOL and EuroQol five-dimensional questionnaire (r = 0.268; P = 0.185) and six-dimensional health state short form (derived from short form 36 health survey) scores (r = 0.351; P = 0.078); divergent validity was shown by a weak correlation between ADDQOL average weighted impact (AWI) and ADDQOL "Present QOL" scores (r = 0.027, P = 0.896), a moderate correlation between ADDQOL AWI and six-dimensional health state short form (derived from short form 36 health survey) mental scores (r = 0.247; P = 0.224), and a positive correlation between ADDQOL AWI and family functioning scores (r = 0.288; P = 0.182). CONCLUSIONS: The ADDQOL has been translated and culturally adapted successfully into a Chinese version for Singapore. Our study provides justification for further research with large sample sizes among the Chinese speaking population in Singapore. PMID- 29702832 TI - Validation of the Schizophrenia Quality of Life Scale Revision 4 among Chronic Schizophrenia Patients in Malaysia. AB - OBJECTIVES: To explore the validity and reliability of a disease-specific health related quality-of-life questionnaire-the Schizophrenia Quality of Life Scale Revision 4 (SQLS-R4)-in patients with schizophrenia in Malaysia. METHODS: A total of 222 outpatients with schizophrenia receiving treatment at the Universiti Kebangsaan Malaysia Medical Centre completed the SQLS-R4 in either the Malay or the English language. A generic self-report health-related quality-of-life measure-the EuroQoL group EuroQol five-dimensional questionnaire-and a measure of symptom severity-the Clinical Global Impression-Schizophrenia scale-were also administered to assess validity. RESULTS: Good internal consistency reliability was found for both the psychosocial and vitality domains (Cronbach's alpha = 0.95 and 0.85, respectively). Most items were also significantly correlated with their own scale score (rs ranging from 0.29 to 0.74). There was a moderate correlation between the SQLS-R4 "vitality" domain and the EuroQol five-dimensional questionnaire "usual activities" domain (rs = 0.44) and a large correlation between the SQLS-R4 "psychosocial" domain and the EuroQol five-dimensional questionnaire "anxiety/depression" domain (rs = 0.44-0.57). Most of the symptom dimensions of the Clinical Global Impression-Schizophrenia scale were also moderately correlated with the SQLS-R4 subscale scores. CONCLUSIONS: The SQLS-R4 is a valid and reliable health-related quality-of-life instrument for use in minimally ill patients with schizophrenia in Malaysia, but some of the items may be redundant and irrelevant. Validation of SQLS-R4 in different types of patients and various levels of illness severity is required to further verify its application. PMID- 29702833 TI - Patient Utility Measurement for Managing Ureteral Stones: A Modified Standard Gamble Approach. AB - OBJECTIVES: To measure the utility of patients with ureteral stones under various medical regimes and to identify significant factors affecting utility for various health states. METHODS: A cross-sectional survey was conducted to measure the utility of 89 patients on each health state related to the clinical management of ureteral stones. Health states with respect to intervention and treatment modalities were classified into the acute phase (including medication, extracorporeal shock wave lithotripsy, ureterorenoscopic lithotripsy, and surgery) and the chronic phase (no specific intervention, lifestyle modification, maintenance with surveillance, and continued medication). Utility was measured by using the modified standard gamble. Demographic data and relevant history of treatment modalities and interventions for ureteral stones were collected by using a questionnaire. RESULTS: Utility scores of health states in the acute phase (ranging from 0.914 [surgery] to 0.967 [extracorporeal shock wave lithotripsy]) were lower than those in the chronic phase (ranging from 0.955 [maintenance with surveillance] to 0.974 [lifestyle modification]). Utility for surgery was lower than for nonsurgical methods. Utilities for the two lithotripsy modalities were close to that for medication. The utility figures for health states in the chronic phase were the highest for lifestyle modification, but the differences across health states were trivial. Sex, history of ureterorenoscopic lithotripsy, education level, and employment were significant covariates in the final multiple linear regression model. CONCLUSIONS: A modified standard gamble chained method was applied to measure the utility for health states in relation to the clinical management of ureteral stones. Patients preferred nonsurgical treatment over surgical treatment and hemodialysis regardless of health states. We also found that sex, a history of ureterorenoscopic lithotripsy, education level, and employment affected utility for health states related to clinical management. Our findings provide an insight into patient preference for the choice of treatment of ureteral stones. PMID- 29702834 TI - Health State Utility Assessment for Breast Cancer. AB - OBJECTIVES: 1) To develop both English and Chinese versions of the descriptions of health states describing different stages of breast cancer and different adverse effects related to tamoxifen and aromatase inhibitors for breast cancer and 2) to elicit individuals' preferences for these health states from a group of oncology nurses. METHODS: Twenty hypothetical health states and their descriptions were developed on the basis of literature review and oncology expert panel reviews. Health state utilities were obtained from 20 oncology nurses by using the visual analogue scale and standard gamble methods. After recalibration, the adjusted utility scores were on a scale of 0 (dead) and 1 (perfect health). RESULTS: The health states developed represented different disease stages and the presence and type of treatment side effects in breast cancer. For each health state, various general health-related quality-of-life domains, such as pain/discomfort and ability to work, were included in the descriptions, along with a state-specific description. The mean utility score of respondents' "current health" was greater than 0.9, while mean adjusted visual analogue scale derived utility scores ranged from 0.256 to 0.860 and median adjusted standard gamble-derived utility scores ranged from 0.284 to 0.673. Among the side effects evaluated in the "no recurrence" health state, ischemic cerebrovascular events, pulmonary embolism, and spine fracture had the greatest utility detriment. CONCLUSIONS: The study results indicate the value that individuals place on the avoidance of disease progression and the side effects of hormonal therapies in breast cancer. The health state descriptions developed can be used in future research to obtain society's utilities for use in a cost-utility analysis. PMID- 29702835 TI - Drug Utilization Reviews by Community Pharmacists in Japan: Identification of Potential Safety Concerns through the Brown Bag Program. AB - OBJECTIVES: Pharmacy-based drug utilization reviews were conducted through the Brown Bag program to understand drug-use patterns, identify potential safety concerns, and provide appropriate consultation for elderly individuals. METHODS: Community pharmacists in Hiroshima, Japan, participated in this review program from October to December 2009. Elderly individuals, 65 years or older, were recruited from community events or at pharmacies and were asked to bring all their prescription and nonprescription drugs including over-the-counter drugs and dietary supplements to the program. Pharmacists reviewed the medications and their usages and gave appropriate feedback if medications were used incorrectly, had potential interactions, or had safety concerns. The relationships among medication usage, participant responses, and potential safety concerns were analyzed by using logistic regression models. In addition, contraindications, duplicate medications, and potentially inappropriate medications were descriptively analyzed. RESULTS: Drug utilization reviews were conducted on 508 elderly participants at 177 community pharmacies. Of the 508 participants, 53% were 75 years old or older and 34% were men. Twenty-four percent of the elderly participants used prescription drugs only, and 73% used both prescription and nonprescription drugs. Pharmacists offered feedback to 250 participants (49%) concerning the risk of duplication/interaction, possible adverse drug reaction that can be averted, inappropriate/unnecessary medication, nonadherence, and overdose. Two cases of contraindicated drugs, 3 cases of duplicate medications, and 327 cases of potentially inappropriate medications were identified. CONCLUSIONS: The drug-use patterns among elderly individuals were identified. This medication review program conducted at community pharmacies was a useful approach to reduce concerns among users and prevent safety problems. PMID- 29702836 TI - Emerging Hub for Pharmacoeconomics and Outcomes Research: Asia-Pacific Region. PMID- 29702837 TI - Assessment of Adverse Events and Quality of Life of Cancer Patients in a Secondary Level Care, Rural Hospital in South India. AB - OBJECTIVE: To grade adverse events (AEs) occurring after chemotherapy in the cancer patients and to explore the quality-of-life (QOL) findings among posttherapy cancer patients in a rural, secondary level care Indian hospital. METHODS: A cross-sectional study was carried out during a 6-month period in a rural secondary level care hospital situated at Anantapur district in South India. Patient and cancer demographics were collected from the cases treated in the study site. The European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 v 3.0 Telugu (regional language of the study site) module and Common Terminology Criteria for Adverse Events v 4.0 of Cancer Therapy Evaluation Program, USA, were used to assess the QOL and severity grades of AEs, respectively. RESULTS: Most AEs were mild or moderate, with only a few being severe. Insomnia (27.98%), nausea (13.50%), vomiting (12.81%), fatigue (10.90%), and pain (11.68%) were common, with insomnia being the most frequent. The different scores of the QOL scale (functional, symptomatic, financial, and global health status scores) were assessed independently. Among the functional scale parameters, the cognitive and physical functioning scores were good (85.14 and 82.79, respectively) and the social, emotional, and role functioning scores were moderate (77.94, 72.30, and 71.65, respectively). The overall effect of symptoms on QOL showed that the pain score was higher and interfered to a higher extent in patients (36.02) and the dyspnea score was the least and occurred to a lesser extent (7.20). But certain variables such as anorexia, for example, showed a greater interquartile range and SD, which implied that it gave a lesser chance for the prediction of results for that particular condition. Financial burden existed to a moderate level on an average in all the patients. CONCLUSIONS: The occurrence and severity of AEs was low, indicating that the patients tolerated and responded well to therapy. The survivorship is yet to be estimated and the life expectancy to be studied by further investigation of the subjects. PMID- 29702838 TI - Health-Related Quality of Life among Nonprescription Medicine Customers in Malaysia. AB - OBJECTIVE: To describe the health-related quality of life (HRQOL) among nonprescription medicine customers in Malaysia and the factors that affect it. METHODS: A nationwide cross-sectional survey was conducted among pharmacy customers in 59 randomly selected community pharmacies in Malaysia. The self administered questionnaire included the EuroQoL five-dimensional (EQ-5D) questionnaire, the EuroQol visual analogue scale (EQ-VAS), nonprescription medicines purchase, and demographic questions. Data were analyzed by using the multivariate analysis of variance and multiple logistic regressions. RESULTS: A total of 2729 customers enrolled in this study, with a mean EQ-5D questionnaire score of 0.92+/-0.15 and a mean EQ-VAS score of 69.92+/-24.80. Compared with the Malaysian adult population, nonprescription medicine customers have a lower mean EQ-5D questionnaire score (t =-4.49, P<0.01) and EQ-VAS score (t =-25.87, P<0.01). We found that pain/discomfort (25.6%) and anxiety/depression (13.7%) were the major HRQOL problems. Locality, age, ethnicity, household income per month, type of occupation, and type of nonprescription medicine purchased were associated with health status of nonprescription medicine customers (F22,5286 = 2.555; Wilks' lambda = 0.979; P< 0.01). CONCLUSIONS: The HRQOL of nonprescription medicine customers is lower than that of the general Malaysian population. Lower health status was independently associated with older age, living in rural areas, having low income and education level, and purchasing blood and blood-forming medicines from community pharmacy. PMID- 29702839 TI - Clinical Characterization and the Caregiver Burden of Dementia in China. AB - OBJECTIVES: The prevalence of dementia in China is among the highest in the world, but systematic estimates of the rate of dementia subtypes and characterization of associated deficits are lacking. The primary aim of this study was to determine the clinical presentation of dementia and describe the caregiver burden in mainland China. METHODS: A 3-month, open-enrollment, multicenter, cross-sectional study was conducted at 48 tier-3 hospitals. Caregivers who qualified for study entry (provided amount and duration of care information), had intimate knowledge of patient status, and accompanied enrolled patients to study sites were asked to participate in an interview about patient care and caregiver burden. Caregiver burden was assessed via the Chinese version of the validated Zarit Burden Interview. RESULTS: A total of 1425 caregivers completed the survey. Patients had mild to moderate dementia (mean Clinical Dementia Rating score of 1.67+/-0.79), and the most common dementia subtypes were Alzheimer disease (46.7%) and vascular dementia (28.7%). Among caregivers, 57% were females, 52% were patients' spouses, and 67.3% had been caring for patients for 1 year or more. Most patients required family help and lived at home or with a family member. Caregiver awareness of dementia was limited. The mean total caregiver Zarit Burden Interview score was 26.6. Observations were similar across age, gender, education, dementia type, Clinical Dementia Rating score, and duration of care. CONCLUSIONS: China faces multiple obstacles in preparing to care for its fast-growing dementia population. Better understanding of patients and caregivers may mitigate these challenges by improving awareness and education. PMID- 29702840 TI - Epidemiology and Disease Burden of Ulcerative Colitis in Taiwan: A Nationwide Population-Based Study. AB - OBJECTIVES: A rising trend of incidence and prevalence of ulcerative colitis (UC) had been noticed in Asian countries. We conducted this study to investigate the epidemiology and medical burden of UC in Taiwan. METHODS: In this 10-year retrospective database study, we identified cases of patients with UC during 1998 to 2008 from the Taiwan National Health Insurance Research Database. Patients who had a catastrophic illness certificate were included in epidemiology and medical burden calculation. RESULTS: There were 1522 cases identified in our study period. The incidence increased twofold from 0.37 per 100,000 in 1998 to 0.78 per 100,000 in 2008. The incidence and prevalence had an increasing trend in our population. The cases onset age was 45.0 years on average. In our survey, most of the top 20 coexisting diseases were gastrointestinally relevant diseases, anemia (9.99%), and hypertension (7.69%). There were more than 70% patients using mesalamine, and the medical expenditure on mesalamine occupied the highest position in patients with UC. The average medical expenditure of patients with UC had a decreasing trend after 2001. CONCLUSIONS: This study had the largest sample and the longest study period for the epidemiology and medical burden estimation of UC in Taiwan. The incidence rates and medicine use of patients with UC had a definite rising trend across the years in Taiwan. Patients with anemia or choric diseases were observed in our population. More surveillance of UC-related diseases and health care costs need to be conducted in the future. PMID- 29702841 TI - Economic Evaluation of Lipid-Lowering Therapy in the Secondary Prevention Setting in the Philippines. AB - OBJECTIVE: To determine the cost-effectiveness of lipid-lowering therapy in the secondary prevention of cardiovascular events in the Philippines. METHODS: A cost utility analysis was performed by using Markov modeling in the secondary prevention setting. The models incorporated efficacy of lipid-lowering therapy demonstrated in randomized controlled trials and mortality rates obtained from local life tables. Average and incremental cost-effectiveness ratios were obtained for simvastatin, atorvastatin, pravastatin, and gemfibrozil. The costs of the following were included: medications, laboratory examinations, consultation and related expenses, and production losses. The costs were expressed in current or nominal prices as of the first quarter of 2010 (Philippine peso). Utility was expressed in quality-adjusted life-years gained. Sensitivity analyses were performed by using variations in the cost centers, discount rates, starting age, and differences in utility weights for stroke. RESULTS: In the analysis using the lower-priced generic counterparts, therapy using 40 mg simvastatin daily was the most cost-effective option compared with the other therapies, while pravastatin 40 mg daily was the most cost-effective alternative if the higher-priced innovator drugs were used. In all sensitivity analyses, gemfibrozil was strongly dominated by the statins. CONCLUSIONS: In secondary prevention, simvastatin or pravastatin were the most cost-effective options compared with atorvastatin and gemfibrozil in the Philippines. Gemfibrozil was strongly dominated by the statins. PMID- 29702842 TI - Economic Burden of Individual Suffering from Atrial Fibrillation-Related Stroke in China. AB - OBJECTIVE: Atrial fibrillation (AF) is an important risk factor for stroke. The primary purpose of this study was to estimate the 1-year direct and indirect costs of ischemic stroke in Chinese patients with AF. METHOD: A total of 300 charts were selected and reviewed in 18 hospitals from neurology departments in six major cities of China nationwide. Patients with primary diagnosis of ischemic stroke and secondary diagnosis of AF were selected for review. A total of 63 patients were selected from the chart review pool and followed up for 1 year to record their resource utilization and absenteeism from work following discharge. RESULTS: The mean+/-SD age of the cohort was 70.2+/-11.8 years, with an average hospitalization duration of stay of 17.9 days. The mean total direct cost for AF related stroke was estimated at 30,438.3 China Yuan (CNY) per patient-year. The major cost driver for direct cost was stroke's acute hospitalization expense, which accounted for 61.5% (CNY 18,706.1). Among the seven patients not reaching the legal retirement age, the indirect cost per person-year totaled 16,838.9 CNY, most of which (63.0%) was a result of early retirement. The analysis also suggested that higher hospital ranking (based on the tier system), longer hospital stay, higher modified Rankin Scale score, taking surgery during hospitalization, receiving thrombolysis therapy, and incidence of complications such as pneumonia or cerebral edema predicted higher inpatient costs. CONCLUSIONS: Hospital costs due to strokes among patients with AF are the predominant contributor to the total direct cost, which is consistent with current hospital-centered treatment pattern in China. However, literature suggested that AF-induced strokes are highly preventable with drugs and clinical procedures, which highlights the importance of optimal clinical management of stroke prevention in patients with AF. PMID- 29702843 TI - What Is Important During the Selection of Traditional Chinese Medicine (TCM) in a Health Care Reimbursement or Insurance System?" Critical Issues of Assessment from the Perspective of TCM Practitioners. AB - OBJECTIVE: Complementary and alternative medicine (CAM) has gained increasing popularity over the last several decades internationally, leading to an increasing interest from decision makers and researchers as to how to assess the effectiveness of CAM. The attempts, however, have been unsatisfactory. The most important reason is a lack of attention to the theoretical characteristics of CAM, which are completely different from those of allopathic medicine or biomedicine. This study attempted to survey expert Traditional Chinese Medicine (TCM) practitioners in China to elucidate critical issues when assessing the effectiveness of TCM. METHODS: A questionnaire (with 20 close-ended and 2 open ended questions) about the influencing factors of measuring the cost and effectiveness of TCM was distributed to TCM practitioners who had been working in the field of research for at least 5 years and had published at least one related scientific article in the last 5 years. Internal consistency test was performed for all questions to verify the reliability of the questionnaire. Principal component analysis was performed for remaining items after Kaiser-Meyer-Olkin (KMO) index and Bartlett's test of sphericity. A linear combination model was then built to evaluate the contribution of various factors involved for the selection of TCM into the health care reimbursement or insurance system. RESULTS: Of 429 questionnaires issued, 137 were returned from respondents from 31 medical and research institutions, giving a recovery rate of 31.93%. Internal consistency coefficient obtained was 0.745, indicating good reliability of this measurement scale, and the data passed the KMO test and Bartlett's test of sphericity (KMO index = 0.691). In addition, eight common factors were extracted after the rotation of principal-component analysis with a cumulative variance of 70.92%. CONCLUSIONS: Our findings suggested that factors to be considered during the selection of TCM in health care reimbursement or insurance system include patient preference, long-term outcomes, comparative study of alternative options between TCM and allopathic medicine or biomedicine, pharmacoeconomic evaluation results and the overall economic burden of patients, and side effects of TCM. In addition, the TCM experts stressed the need of cost-effectiveness assessment of the expensive TCM of similar therapeutic functions during the selection process. Moreover, during the evaluation of health-related quality of life of TCM, they warned to avoid overexaggeration of their roles and that the generic scale should be modified according to the clinical circumstances. PMID- 29702845 TI - Burden of Disease Studies in the Asia-Pacific Region: Are There Enough being Performed to Provide Information for Evidence-Based Health Policy? AB - OBJECTIVE: To review published studies of Burden of Disease (BOD) performed in the Asia-Pacific (AP) region. METHOD: Overlapping strategy of searching four electronic databases was used to identify studies of BOD published during 1993 2009. The quality of identified studies was assessed according to the categories of burden reflected and scope of BOD information included. Chronological and regional distributions of research output were analyzed. RESULTS: Among 524 articles identified for review, 27.7% (n=145) were classified as complete summary measures as being most informative BOD studies from health policy maker's perspective and 72.3% (n=379) as using only partial measures. Although an increasing trend of publication of BOD articles was observed, the quantity of publication was not commensurate with the number of diseases, especially for researches using summary measures. Unbalance of research output of BOD among different diseases areas and selected countries/regions was observed. CONCLUSION: The paucity of specific studies in AP region needs to be addressed. Furthermore, in order to improve the quality of research, a clear definition of BOD study and a uniform template for the research method from health policy-makers' perspective would be necessary. PMID- 29702844 TI - The Factors Contributing to Expenditures on Over-the-Counter Drugs in South Korea. AB - OBJECTIVES: To determine the factors contributing to the use of over-the-counter (OTC) drugs and to examine the relationship between the purchase of OTC drugs and the utilization of health care services in South Korea. METHODS: This study used data from the 2008 Korea Health Panel Survey. The respondents were classified according to the purpose of the OTC drug use. The first group (n = 364) included respondents who had purchased OTC drugs for self-medication, and the second group (n = 955) included respondents who had taken OTC drugs for nutrition for more than 3 months. Logistic regression analyses were conducted to identify the factors contributing to the purchase of OTC drugs. RESULTS: The self-medication group was more likely to be older and to have a chronic disease. In addition, the purchase of OTC drugs was related to the utilization of other health care services. The more outpatient services at clinics were used, the more the respondents tended to purchase OTC drugs for self-medication and nutrition. As hospital outpatient visits increased, however, the purchase of OTC drugs for self medication decreased and the purchase of OTC drugs for nutrition increased. CONCLUSIONS: This study shows that age and chronic disease are the major factors related to using OTC drugs for self-medication for long-term periods. Furthermore, this study suggests that the use of outpatient services is one of the factors associated with purchasing OTC drugs. Considering the potential adverse effects of OTC drugs, communication between physicians and patients should be encouraged at outpatient visits. PMID- 29702846 TI - Equity in Pharmaceutical Pricing and Reimbursement: Crossing the Income Divide in Asia Pacific. AB - OBJECTIVES: The article takes a three-dimensional approach (triangulation) in defining international pricing policy for pharmaceuticals using cost effectiveness analysis (CEA), willingness-to-pay (WTP) analysis, and ability-to pay (ATP) analysis. It attempts to find a balance between the various economic methods of which some focus on effectiveness while others are geared toward incorporating equity in the equation. METHODS: A critical review of the first two established economic methods and their ability to evaluate not only "efficacy" but also "fairness" in pricing decisions identifies a gap in the latter. Therefore, a third analytic method is presented that measures the ATP based on a country's score in the human development index of the United Nations Development Program for 120 countries. This approach allows practicing differential pricing among and within countries. To refine this equity-driven pricing concept, two additional parameters can be added to the model: the Oxford "Multidimensional Poverty Index" and the "Out-of-Pocket" or "Self Pay" health expenditure as reported by the World Bank. RESULTS: There is no hierarchy between the above three pricing methods. Because one method provides further insight into the other, however, it is recommended to start with CEA followed by WTP analysis. These types of analysis are closely linked in that the first provides the CE ratio for the compound investigated and the other sets the anticipated ceiling threshold of the payer's WTP (in a particular country). The ATP method provides a supplementary "equity" check and facilitates the process of equity-based differential pricing. CONCLUSIONS: A third method should be used in conjunction with the standard CEA and WTP analysis that measures the ATP with the human development index as yardstick to provide sustainable and equitable access to medicines. We recommend that ATP analysis becomes an additional practice in policy decision making and in defining international pricing strategies for pharmaceuticals. PMID- 29702847 TI - Cost-Effectiveness Analysis of a Screening Program for Breast Cancer in Vietnam. AB - OBJECTIVE: This study aimed to evaluate the cost-effectiveness of a screening program for breast cancer from the health care payers' perspective. METHODS: A Markov model was used to compare costs and effects of an annual screening program using clinical breast examination (CBE) with the absence of screening on a cohort of 4,103,285 asymptomatic women aged 40 years. The model was analyzed over the cohort's lifetime under the assumption that women participated in the screening program annually for 15 years. The model integrated both epidemiological and cost data for breast cancer from prior Vietnamese studies. Costs were measured in 2008 US dollars. Costs and effects were discounted annually at 3%. The incremental cost-effectiveness ratio (ICER) was defined as the difference in cost per life years saved (LYS). One-way and probabilistic sensitivity analyses were implemented to assess the uncertainty of inputs. RESULTS: The ICER for the breast cancer screening program with CBE was US $994.96 per LYS compared with the absence of screening. Earlier initiation of the program at age 35 years increased the ICER to US $1196.68 per LYS, while extending the duration of time screened to age 60 years decreased the ICER. Changing the participation rate to 70%, reducing the specificity of CBE testing, and increasing the cost of the screening program by 30% raised ICER estimates to US $1419.32, US $1124.15, and US $1292.03 per LYS, respectively. CONCLUSION: Breast cancer screening with CBE for women aged 40 to 55 years is considered very cost-effective in Vietnam according to the World Health Organization criteria. PMID- 29702848 TI - Cost-Effectiveness Analysis of Omalizumab for the Treatment of Severe Asthma in Japan and the Value of Responder Prediction Methods Based on a Multinational Trial. AB - OBJECTIVES: Omalizumab improves health outcomes for patients with severe asthma. The purpose of this study was to conduct a cost-utility analysis of omalizumab from a societal perspective by using the results from a randomized controlled trial in Japan, and explore the efficient use of omalizumab. METHODS: We developed a Markov model to compare omalizumab add-on therapy with standard therapy. Patients transitioned between symptom-free, day-to-day, and exacerbation states. Our model had a lifetime horizon in which 5-year omalizumab add-on therapy was followed by standard therapy. Preference-based utilities were extracted from another study. We estimated the expected value of perfect information for patients' response to omalizumab. RESULTS: In the base case, incremental cost-effectiveness ratio (ICER) for omalizumab add-on therapy was US $755,200 (95% credible interval [CI] $614,200-$1,298,500) per quality-adjusted life-year gained, compared with standard therapy alone. One-way sensitivity analyses indicated that the results were sensitive to asthma-related mortality, exacerbation risk, and omalizumab cost. The ICER for a responder subgroup was 22% lower than that in the base case. Individual and population expected value of perfect informations for the response were $4100 (95% CI $2500-$6000) and $28 million (95% CI $17 million-$42 million) per year, respectively. CONCLUSIONS: With a willingness-to-pay of $45,000 per quality-adjusted life-year, omalizumab was not cost-effective in Japan. Confining omalizumab therapy to previously predicted responders, however, may be a reasonable strategy to reduce the ICER, as the cost-effectiveness was observed to improve for these patients. Further studies should be conducted to explore responder prediction methods. Decreasing the price of omalizumab would improve cost-effectiveness. PMID- 29702849 TI - Future Prospects for Pharmacoeconomics and Outcomes Research in the Emerging Regions. PMID- 29702850 TI - Increasing Anti-Infective Drug Expenditure in Tianjin, China: A Decomposition Analysis. AB - OBJECTIVE: This study aimed to explore the driving factors of the increasing anti infective drug expenditures in Tianjin, China, and to provide evidence-based suggestions for policymakers. METHODS: Data were extracted from inpatient records in Urban Employee Basic Medical Insurance data of Tianjin, China, from 2003 January to December 2007. Expenditure increase for a basket of 63 constantly used anti-infective drugs was decomposed into three broad categories: price effects, quantity effects, and therapeutic choices. Furthermore, the injection anti infective drug expenditures from 2006 to 2007 were decomposed into six determinants. RESULTS: From 2003 January to December 2007, the expenditure for a fixed basket of drugs increased by 9%. The driving factors were therapeutic choices and quantity effects; each increased 48% and 10%, respectively. The relative price decreased by 33% during the study period. After adding new drugs to the formulary in 2005, the rate of increase in drug expenditure was 28% from 2006 to 2007; the driving factors were still therapeutic choice (16.8%) and quantity effects (14.9%). CONCLUSIONS: Therapeutic choice transferring from cheap drugs to expensive ones, rather than the price, was the main driving factor for increasing expenditures. Policymakers need to pay more attention to rationalize physicians' prescribing behavior to control the expenditure. PMID- 29702851 TI - Cost-Effectiveness of Clinical Pharmacy Education on Infection Management among Patients with Chronic Kidney Disease in an Indonesian Hospital. AB - OBJECTIVES: This study evaluated the clinical and economic impacts of clinical pharmacy education (CPE) on infection management among patients with chronic kidney disease (CKD) stages 4 and 5 in Haji Adam Malik Hospital, Indonesia. METHODS: A quasi-experimental economic evaluation comparing CPE impact on 6-month CKD mortality was conducted on the basis of payer perspective. The experimental group (n = 63) received care by health care providers who were given CPE on drug related problems and dose adjustment. The control group (n = 80) was based on the historical cohort of patients who received care before the CPE. Measure of clinical outcome applied in this study was number of lives saved/100 patients treated. Cost-effectiveness ratios for CKD stages 4 and 5 patients without CPE and with CPE and incremental cost-effectiveness ratios (ICERs) for CKD stages 4 and 5 patients were analyzed. RESULTS: Lives saved (%) in the treatment of CKD without CPE: CKD stage 4, 78.57; CKD stage 5, 57.58. Lives saved (%) in the treatment of CKD with CPE: CKD stage 4, 88.89; CKD stage 5, 65.45. Cost effectiveness ratios for stage 4 with and without CPEs were Rp3,348,733.27 and Rp3,519,931.009, respectively. Cost-effectiveness ratios for stage 5 with and without CPEs were Rp7,137,874.93 and Rp7,871,822.27, respectively. ICERs were Rp2,045,341.22 for CKD stage 4 and Rp1,767,585.60 for CKD stage 5. CONCLUSIONS: Treatment of CKD stages 4 and 5 with CPE was more effective and cost-effective compared with treatment of CKD stages 4 and 5 without CPE. The ICERs indicated that extra costs were required to increase life saved in both stages. PMID- 29702853 TI - Economic Evaluation of Pravastatin for Primary Prevention of Coronary Artery Disease Based on Risk Prediction from JALS-ECC in Japan. AB - OBJECTIVES: The clinical efficacy of 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitor (statin) therapy in cardiovascular disease has been established in clinical trials. Nonetheless, it is unclear to whom and when statin treatment should be initiated for patients without cardiovascular disease with regard to overall absolute risk reduction of cardiovascular disease and the cost-effectiveness of long-term statin therapy. The objective of this study was to examine the cost-effectiveness of pravastatin 10 mg/d compared with no-drug therapy for primary prevention of coronary artery disease (CAD), using cardiac risk factors from risk predictions for CAD from Japanese cohort studies. METHODS: A Markov transition model was used to evaluate the cost-effectiveness of pravastatin compared with no-drug therapy. The incidence of acute myocardial infarction was estimated by using risk predictions for CAD in Japan. A hypothetical population from 45 to 75 years old was examined by using the cardiac risk factors. Quality-adjusted life-years (QALYs) and incremental cost effectiveness ratio over a lifetime horizon were estimated from a perspective of payers. RESULTS: Incremental cost-effectiveness ratios of pravastatin therapy compared with no-drug therapy were 9,677,000 yen per QALY in 55-year-old men and 8,648,000 yen per QALY in 65-year-old men with diabetes mellitus, hypertension (grade II), and smoking as cardiac risk factors. Pravastatin therapy was not cost effective compared with no-drug therapy in all subgroups evaluated. CONCLUSIONS: Using risk prediction for CAD based on a Japanese cohort with no history of cardiovascular events, the cost-effectiveness of pravastatin for primary prevention of CAD may not be cost-effective in populations at both low and high cardiac risk. PMID- 29702852 TI - A Novel Estimation of the Impact of Treatment with Entecavir on Long-Term Mortality, Morbidity, and Health Care Costs of Chronic Hepatitis B in China. AB - OBJECTIVES: Health care decision makers are increasingly concerned about the value of chronic hepatitis B (CHB) treatments in China. This analysis aims at estimating the relative value of entecavir as a first-line option at treatment initiation and for different treatment durations from a holistic perspective. METHODS: CHB was simulated by using a Markov disease transition model with disease states based on available natural history data. The model assumed 5-year treatment duration with entecavir, lamivudine, telbivudine, and adefovir based on published clinical data. The speed of disease progression varies by viral load and hepatitis B "e" antigen status. Direct medical costs included medication and management of liver complications. The primary output was the estimated cost savings of entecavir per patient per day versus the comparator. RESULTS: For treatment duration of 5 years and a follow-up period of 30 years, entecavir treatment was translated into specific patient benefit of an estimated cost saving of $2.69 per day compared with no treatment. In addition, long-term usage of entecavir resulted in daily $2.33 and $1.73 cost saving compared with short term usage (1-year and 2-year, respectively). Among available treatment options in China, entecavir treatment exhibited about $0.90 to $1.81 daily cost saving versus the comparators. The detailed daily cost saving of entecavir is summarized as follows-entecavir versus lamivudine: $1.81, entecavir versus telbivudine: $0.90, entecavir versus adefovir: $2.02, and entecavir versus generic adefovir: $1.37. CONCLUSIONS: Long-term usage of entecavir exhibits the characteristics of a favorable CHB treatment, which translates into economic value as opposed to either no treatment or alternative strategies. PMID- 29702854 TI - Analysis of Excess Direct Medical Costs of Vision Impairment in Taiwan. AB - OBJECTIVES: To quantify the annual excess direct medical costs of vision impairment from the perspective of the Bureau of National Health Insurance in Taiwan and to examine whether the costs vary by severity and duration of vision impairment. METHODS: A retrospective matched cohort analysis was conducted by using data from the Longitudinal Health Insurance Databases between January 1, 2000, and December 31, 2008. All patients newly diagnosed with vision impairment were categorized as having moderate vision loss, severe vision loss, or blindness. Each patient with vision impairment was matched to one randomly selected patient with normal vision by age (+/-1 year) and sex. At each level of vision impairment, generalized linear models were used to quantify the total annual excess costs and component costs incurred in the first and second years. RESULTS: Vision impairment was associated with significantly higher crude excess medical costs. At each level of vision impairment, the total crude medical costs were attributable to different resource utilization and dominated by non-eye related medical care. After adjusting for covariates, the first-year annual excess costs increased with escalating severity of vision impairment: New Taiwan (NT) $9894 for moderate vision loss, NT $22,760 for severe vision loss, and NT $52,687 for blindness. Similarly, the second-year adjusted costs were estimated as NT $3477, NT $19,532, and NT $28,272 for moderate vision loss, severe vision loss, and blindness, respectively. CONCLUSIONS: Consistent with Western countries, vision impairment is associated with significantly increased health care costs in Taiwan. The excess costs seem to increase with severity of vision impairment and decrease in the second year. PMID- 29702855 TI - The Health Economic Impact of Universal Infant Vaccination with the 10-Valent Pneumococcal Nontypeable Haemophilus influenzae Protein D Conjugate Vaccine as Compared with 13-Valent Pneumococcal Conjugate Vaccine in Hong Kong. AB - BACKGROUND: Pneumococcal universal vaccination in Hong Kong was introduced in 2009. OBJECTIVES: We assessed the health and economic impact of the 10-valent pneumococcal nontypeable Haemophilus influenzae protein D conjugate vaccine (PCV 10) compared with the current 13-valent pneumococcal conjugate vaccine (PCV-13) recommended for Hong Kong in 2011, providing new elements to be considered by public health authorities in the future decision-making process for pneumococcal vaccines in this country. METHODS: An analytical model was used to estimate the annual economic and health outcomes of invasive pneumococcal disease (IPD), community-acquired pneumonia, and acute otitis media (AOM), including nontypeable H. influenzae-related AOM, for a birth cohort in Hong Kong from the payer perspective with a 10-year horizon. Clinical impact including morbidity mortality, quality-adjusted life-years (QALYs), incremental costs, and cost effectiveness comparing PCV-10 and PCV-13 were estimated. Probabilistic sensitivity analyses by using alternate scenarios were performed. RESULTS: Model projections indicate that PCV-13 and PCV-10 have approximately equivalent impact on the prevention of deaths caused by IPD and pneumonia. PCV-13 is projected to prevent 6 additional cases of IPD, whereas PCV-10 is projected to prevent 13,229 additional AOM cases and 101 additional QALYs. For the base case, PCV-10 vaccination is estimated to save 44.6 million Hong Kong dollars (34.1 million Hong Kong dollars discounted). Sensitivity analysis indicated that PCV-10 would generate more QALYs and save costs as compared with PCV-13. CONCLUSIONS: Universal infant vaccination with new available pneumococcal vaccines is expected to generate a significant additional impact on reducing the burden of pneumococcal diseases in Hong Kong. PCV-10 vaccination would be potentially a cost-saving strategy compared with PCV-13 vaccination, generating better cost offsets and higher QALY gains. PMID- 29702856 TI - A Cost-Effectiveness Analysis between Amlodipine and Angiotensin II Receptor Blockers in Stroke and Myocardial Infarction Prevention among Hypertension Patients in China. AB - OBJECTIVE: Uncontrolled hypertension (HTN) results in strokes, myocardial infarction (MI), and other complications, which are the leading cause of disability, death, and severe economic consequence. We conducted an economic evaluation to determine the costs and quality-adjusted life-years (QALYs) associated with amlodipine (Norvasc) and the angiotensin II receptor blockers (ARBs) in preventing stroke and MI among Chinese HTN patients. METHODS: A cost utility analysis was conducted from the third-party payer perspective. A Markov model was constructed to estimate 5-year costs and health consequences of amlodipine and valsartan. Effectiveness data were based on a published meta analysis. Utility data were retrieved from the published literature. Costs of MI were retrieved from China Health Statistics Yearbook. Costs of stroke were obtained from retrospective chart review and follow-up interviews in Chinese tertiary hospitals. Costs included costs of drugs, direct medical costs of HTN management, stroke/MI treatment, and follow-up management. Discounting rate used for costs and QALYs was 3%. RESULTS: Total direct medical and drug costs of amlodipine and valsartan (ARB) users were Y111,731,716 and Y132,058,611, respectively; total QALYs of amlodipine and valsartan users were 30,648.5 and 30,520.8, respectively. Amlodipine is dominant with lower costs and higher QALYs. This demonstrated that compared with valsartan, amlodipine is a cost-saving therapy with better QALY outcome. When irbesartan data were used in the comparison, the magnitude of cost saving changed but the overall conclusion remained the same. CONCLUSION: Amlodipine is a cost-saving therapy compared with ARBs in preventing stroke and MI for Chinese HTN patients. PMID- 29702857 TI - Economic Impact of Venous Thromboembolism Following Major Orthopaedic Surgery in Japan. AB - OBJECTIVES: Venous thromboembolism (VTE) is the most frequent complication following major orthopaedic surgery (MOS). Although studies in Western populations have demonstrated significantly higher costs for patients with VTE versus those without VTE after MOS, there is a paucity of such data in Japan. This study was conducted to understand the costs and VTE rates in Japanese patients. METHODS: Data were extracted from a hospital claims database. MOS was defined as total hip replacement, total knee replacement, or hip fracture repair. Subjects who underwent more than one MOS during the same admission were excluded. Identified VTE cases were matched on a 1:2 matching scheme on the basis of surgery type, hospital, and date of surgery (+/-6 months). The primary outcome was the difference in 90-day costs. Secondary outcomes included differences in total 6-month costs postsurgery and average length and cost of initial hospital stay. RESULTS: The 90-day cumulative VTE incidence was 0.774%, with 94% of the cases occurring within 30 days postsurgery. Total 90-day costs were significantly higher in patients with VTE (difference of 864,153 Japanese yen [US $10,538]). Average length of stay was longer for patients with VTE (66 days vs. 42 days). Costs incurred by patients with VTE were on average much higher than those incurred by patients without VTE throughout 5 months postsurgery. CONCLUSIONS: The development of a VTE in patients undergoing MOS results in a 1.5-fold increase in the length of stay and a 1.7-fold increase in 90-day costs. Findings indicate that the avoidance of VTEs through more effective prophylaxis will help to reduce the economic burden associated with MOS. PMID- 29702858 TI - Assessment of Costs Associated with Hospital-Acquired Infections in a Private Tertiary Care Hospital in India. AB - OBJECTIVE: This study aims to assess the costs associated with hospital-acquired infections (HAIs) in a private tertiary care hospital in northern India. METHODS: This retrospective case-control study covered four types of HAIs: urinary tract infections, ventilator-associated pneumonia, bloodstream infections, and surgical site infections. The "case" group comprised patients who had developed HAIs, whereas the "control" group had patients who had not acquired HAIs. The control group was matched with the case group on the criteria of age, diagnosis, and severity of illness. Drugs' acquisition costs, hospital rental, consultation fees, investigation costs, and antimicrobial costs were computed for patients over a period of 1 year, and comparisons were made between both the arms of the study. The costs were also compared within the different HAIs. RESULTS: Of the four types of HAIs studied, the most commonly encountered infection was bloodstream infection (38%). The pathogen most frequently responsible for causing HAIs was Acinetobacter baumanii. Patients aged between 60 and 69 years were found to be more susceptible to HAIs than the patients in other age groups. Furthermore, the most common diagnosis of patients who developed HAI was head injury followed by renal failure. Drugs' acquisition costs, rent, consultation fees, investigation costs, and antimicrobial costs were significantly higher for cases than for controls (P<0.001). Drugs' acquisition cost was the major contributor of the extra cost, and antimicrobial drugs constituted almost half of it. CONCLUSIONS: This study has provided evidence that the cost of drugs is a major contributor to costs of HAIs in an Indian setting. Continuous surveillance and prophylaxis is recommended for reducing HAIs. PMID- 29702859 TI - The Cost-Effectiveness Analysis of a Quadrivalent Human Papillomavirus Vaccine (6/11/16/18) for Females in Japan. AB - OBJECTIVE: We assessed the epidemiological and economic impact of a quadrivalent human papillomavirus (HPV) (6/11/16/18) vaccine for females in preventing cervical cancer, cervical intraepithelial neoplasia grades 2 and 3 (CIN 2/3), cervical intraepithelial neoplasia grade 1 (CIN 1), and genital warts in Japan by using a transmission dynamic model. METHODS: A published mathematical model of the transmission dynamics of HPV infection and disease was adapted for Japan. Model inputs were used from Japan or the Asia/Pacific region when available; otherwise, the default values in the original model were used. The transmission dynamic model was used to assess the epidemiological and economic impact of a quadrivalent HPV (6/11/16/18) vaccine for females in preventing cervical cancer, CIN 2/3, CIN 1, and genital warts in Japan.Maintaining current cervical cancer screening practices, we evaluated two strategies: routine vaccination of females by age 12 years (S1), and S1 combined with a temporary (5 years) female catch-up program for age 12 to 24 years (S2). The vaccine coverage rate was 80% for the routine and 50% for the catch-up vaccination programs. RESULTS: Compared with no vaccination, both vaccination strategies significantly reduced the incidence of HPV 6/11/16/18-related disease. The most effective strategy was S2. By using this strategy over 100 years in the Japanese population, the estimated cumulative percentage reduction in incident HPV 6/11/16/18-related genital warts-female, genital warts-male, cervical CIN 1, CIN 2/3, and cervical cancer cases was 90% (2,113,723 cases), 86% (2,082,637 cases), 72% (263,406 cases), 71% (1,328,366 cases), and 58% (323,145 cases), respectively. The cost-effectiveness ratios were JPY 1,244,000, and JPY 1,205,800 per quality-adjusted life-year gained for S1 and S2 compared with no vaccination, respectively, over a time horizon of 100 years. CONCLUSION: We conclude that a quadrivalent HPV vaccination program for females can reduce the incidence of cervical cancer, CIN, and genital warts in Japan at a cost-per-quality-adjusted life-year ratio within the range defined as cost effective. PMID- 29702860 TI - Validity and Reliability of KDQOL-36 in Thai Kidney Disease Patient. AB - OBJECTIVE: To evaluate the reliability and validity of the Thai version of the Kidney Disease Quality of Life 36 (KDQOL-36) questionnaire. The KDQOL-36 questionnaire consists of the short-form 12 health survey, and three dimensions of kidney disease questionnaires (the Symptom/ Problem List, Effects of Kidney Disease on Daily Life, and Burden of Kidney Disease). METHODS: Subjects were 167 hemodialysis patients and 62 peritoneal dialysis patients. Reliability was evaluated by intraclass correlation coefficients for test-retest reliability assessment with face-to-face interview and Cronbach's alpha for internal consistency. Construct validity was supported with convergent and discriminant validity by using correlation between six-dimensional health state short form (derived from short-form 36 health survey), the EuroQol five-dimensional questionnaire, the visual analogue scale parameter, and three dimensions of kidney disease questionnaires. Statistical analysis included descriptive statistics, Mann-Whitney U test, and Cronbach's alpha. RESULTS: Construct validity was satisfactory, with the significant difference being less than 0.001 between two groups (lowest through 25 percentile and higher than 75 percentile). The reliability coefficient for the Cronbach's alpha of the total scale of the KDQOL-36 questionnaire was greater than 0.700 for all domains, ranging from 0.706 to 0.827. Intraclass correlation coefficients ranged from 0.713 to 0.999. CONCLUSION: The Thai version of the KDQOL-36 questionnaire is reliable and valid for evaluating the quality of life in Thai dialysis patients. PMID- 29702861 TI - Further Steps in the Development of Pharmacoeconomics, Outcomes Research, and Health Technology Assessment in Central and Eastern Europe, Western Asia, and Africa. PMID- 29702862 TI - Cost-Effectiveness Analysis of Aripiprazole Augmentation Treatment of Patients with Major Depressive Disorder Compared to Olanzapine and Quetiapine Augmentation in Turkey: A Microsimulation Approach. AB - OBJECTIVES: Major depressive disorder (MDD) is a chronic illness associated with a major burden on quality of life (QOL) and health care resources. Aripiprazole augmentation to antidepressant treatment was recently approved for patients with MDD responding insufficiently to antidepressant treatment in Turkey. The objective was to estimate the cost-effectiveness of aripiprazole augmentation in this indication compared with olanzapine and quetiapine augmentation from a payer perspective. METHODS: A lifetime economic model was built simulating transitions of patients with MDD between major depressive episodes (MDEs) and remission. During MDEs, patients were treated with adjunctive aripiprazole, quetiapine, or olanzapine. Patients who did not respond switched to subsequent treatment lines. Comparative effectiveness between adjunctive aripiprazole, quetiapine, and olanzapine was estimated by using an indirect comparison. Resource utilization and costs were obtained from Turkish studies. RESULTS: Over a lifetime horizon, patients treated with aripiprazole spent less time in MDEs than did patients treated with quetiapine (-11 weeks) and olanzapine (-7 weeks). On average, patients treated with aripiprazole showed improvement in QOL compared with patients treated with quetiapine (+0.054 quality-adjusted life-years [QALYs]) and olanzapine (+0.039 QALYs) combined with cost saving of 593 Turkish lira (TL) versus quetiapine and 485 TL versus olanzapine. The probability that adjunctive aripiprazole would be cost-effective among the three strategies ranged between 74% and 75% for willingness-to-pay values between 0 TL and 100,000 TL per QALY gained. CONCLUSIONS: This is the first lifetime health-economic model in Turkey that takes patient heterogeneity into account when assessing QOL and costs of different adjunctive strategies in MDD. The results indicate that adjunctive treatment with aripiprazole provides health benefits at lower costs in patients with MDD when compared with quetiapine and olanzapine augmentation. PMID- 29702863 TI - Cost-Utility Analysis of Depot Atypical Antipsychotics for Chronic Schizophrenia in Croatia. AB - OBJECTIVES: As a nation with a developing economy, Croatia is faced with making choices between pharmaceutical products, including depot injectable antipsychotics. We conducted a pharmacoeconomic analysis to determine the cost effectiveness of atypical depots in Croatia. METHODS: A 1-year decision-analytic framework modeled drug use. We determined the average direct cost to the Croatian Institute for Health Insurance of using depot formulations of paliperidone palmitate long-acting injectable (PP-LAI), risperidone LAI (RIS-LAI), or olanzapine LAI (OLZ-LAI). An expert panel plus literature-derived clinical rates populated the core model, along with costs adjusted to 2012 by using the Croatian consumer price index. Clinical outcomes included quality-adjusted life-years, hospitalization rates, emergency room treatment rates, and relapse days. Robustness of results was examined with one-way sensitivity analyses on important inputs; overall, all inputs were varied over 10,000 simulations in a Monte Carlo analysis. RESULTS: Costs (quality-adjusted life-years) per patient were ?5061 (0.817) for PP-LAI, ?5168 (0.807) for RIS-LAI, and ?6410 (0.812) for OLZ-LAI. PP LAI had the fewest relapse days, emergency room visits, and hospitalizations. Results were sensitive against RIS-LAI with respect to drug costs and adherence rates, but were generally robust overall, dominating OLZ-LAI in 77.3% and RIS-LAI in 56.8% of the simulations. CONCLUSIONS: PP-LAI dominated the other drugs because it had the lowest cost and best clinical outcomes. Compared with depots of olanzapine and risperidone and oral olanzapine, PP-LAI was the cost-effective atypical LAI for treating chronic schizophrenia in Croatia. Using depot paliperidone in place of either olanzapine or risperidone would reduce the overall costs of caring for these patients. PMID- 29702864 TI - Cost-Utility Analysis of Pharmaceutical Care Intervention Versus Usual Care in Management of Nigerian Patients with Type 2 Diabetes. AB - OBJECTIVE: To assess the cost-effectiveness of pharmaceutical care (PC) intervention versus usual care (UC) in the management of type 2 diabetes. METHODS: This study was a randomized, controlled study with a 12-month patient follow-up in two Nigerian tertiary hospitals. One hundred and ten patients were randomly assigned to each of the "intervention" (PC) and the "control" (UC) groups. Patients in the UC group received the usual/conventional care offered by the hospitals. Patients in the PC group received UC and PC in the form of structural self-care education and training for 12 months. The economic evaluation was based on patients' perspective. Costs of management of individual complications were calculated from activities involved in their management by using activity-based costing. The impact of the interventions on quality of life was estimated by using the HUI23S4EN.40Q (Mark index 3) questionnaire. The primary outcomes were incremental cost-utility ratio and net monetary benefit. An intention-to-treat approach was used. Two-sample comparisons were made by using Student's t tests for normally distributed variables data at baseline, 6 months, and 12 months. Comparisons of proportions were done by using the chi-square test. RESULTS: The PC intervention led to incremental cost and effect of Nigerian naira (NGN) 10,623 ($69) and 0.12 quality-adjusted life-year (QALY) gained, respectively, with an associated incremental cost-utility ratio of NGN 88,525 ($571) per QALY gained. In the cost-effectiveness acceptability curve, the probability that PC was more cost-effective than UC was 95% at the NGN 250,000 ($1613) per QALY gained threshold and 52% at the NGN 88,600 ($572) per QALY gained threshold. CONCLUSIONS: The PC intervention was very cost-effective among patients with type 2 diabetes at the NGN 88,525 ($571.13) per QALY gained threshold, although considerable uncertainty surrounds these estimates. PMID- 29702865 TI - Economic Burden of Cardiovascular Diseases in the Russian Federation. AB - OBJECTIVES: In the Russian Federation, cardiovascular disease (CVD) is the primary cause of death and premature death; however, to date, there have been no systematic cost-of-illness studies to assess the economic impact of CVD. METHODS: The economic burden of CVD was estimated from statistic data on morbidity, mortality, and health care resource use. Health care costs were estimated on the basis of expenditure on primary, outpatient, emergency, and inpatient care, as well as medications. Non-health care costs included economic losses due to morbidity and premature death in the working age. RESULTS: CVD was estimated to cost Russia RUR 836.1 billion (?24,517.8 million) in 2006 and RUR 1076 billion (?24,400.4 million) in 2009. Of the total costs of CVD, 14.5% in 2006 and 21.3% in 2009 were due to health care, with 85.5% and 78.7%, respectively, due to non health care costs. CONCLUSIONS: CVD is a leading public health problem. We first assessed the economic burden of CVD in Russia. Our results can be used for planning investments in prevention programs and measures for improving care for patients with CVD. Regular monitoring of the economic burden of CVD in the future at the federal, regional, and municipal levels will allow assessment of the dynamics of economic burden, as well as the effectiveness of investments in the economy in primary and secondary prevention. Because data are relatively unavailable, there are important limitations to this study, which highlight the need for more accurate CVD-specific information. PMID- 29702866 TI - Cost for Treatment of Chronic Lymphocytic Leukemia in Specialized Institutions of Ukraine. AB - OBJECTIVE: The aim of this study was to identify, from a health care perspective, the cost of treatment for chronic lymphocytic leukemia in specialized hospitals in Ukraine. METHODS: Cost analysis was performed by using retrospective data between 2006 and 2010 from patient-file databases of two specialized hospitals (145 patients). Uncertainty was assessed by using bootstrapping and multivariate sensitivity analyses. Linear regression analysis was used to analyze whether patients' characteristics are related to health care costs. In addition, one-way analysis of variance (Welch test) and paired-sample t test were conducted to compare mean costs of treatment between the two hospitals and mean expenses for drugs and in-hospital stay. RESULTS: The average annual cost for a patient's drug treatment is 2047 EUR. The cost of hospitalization was significantly lower (t = 5.026; significance two-tailed = 0.000) and equal to 541 EUR per person, resulting in total expenditures of 2589 EUR. Mean total costs in the bootstrap analysis were equal to 2584 EUR (median 2576 EUR, 97.5th percentile 3223 EUR; 2.5th percentile 1987 EUR). The regression analysis did not reveal a relation between patients' characteristics and health care costs, although hospital choice was an influential parameter (beta = -0.260; significance = 0.002). Significant difference in mean costs of two analyzed hospitals was also confirmed by one-way analysis of variance (Welch statistics 19.222, P = 0.000). CONCLUSIONS: Drug treatment comprises the largest portion of total costs, but differences between hospitals exist. Because many patients in Ukraine pay out of pocket for in hospital drugs, these costs are a high economic burden for patients with chronic lymphocytic leukemia. PMID- 29702867 TI - Costs of Medically Attended Acute Gastrointestinal Infections: The Polish Prospective Healthcare Utilization Survey. AB - OBJECTIVES: The burden of acute gastrointestinal infections (AGIs) on the society has not been well studied in Central European countries, which prevents the implementation of effective, targeted public health interventions. METHODS: We investigated patients of 11 randomly selected general practices and 8 hospital units. Each patient meeting the international AGI case definition criteria was interviewed on costs incurred related to the use of health care resources. Follow up interview with consenting patients was conducted 2 to 4 weeks after the general practitioner (GP) visit or discharge from hospital, collecting information on self-medication costs and indirect costs. Costs were recalculated to US dollars by using the purchasing power parity exchange rate for Poland. RESULTS: Weighting the inpatient costs by age-specific probability of hospital referral by GPs, the societal cost of a medically attended AGI case was estimated to be US $168. The main cost drivers of direct medical costs were cost of hospital bed days (US $28), cost of outpatient pharmacotherapy (US $20), and cost of GP consultation (US $10). Patients covered only the cost of outpatient pharmacotherapy. Considering the AGI population GP consultation rate, the age adjusted societal cost of medically attended AGI episodes was estimated at US $2222 million, of which 53% was attributable to indirect costs. CONCLUSIONS: Even though AGIs generate a low cost for individuals, they place a high burden on the society, attributed mostly to indirect costs. Higher resources could be allocated to the prevention and control of AGIs. PMID- 29702868 TI - Radiology Services Costs and Utilization Patterns Estimates in Southeastern Europe-A Retrospective Analysis from Serbia. AB - OBJECTIVE: Assessment of costs matrix and patterns of prescribing of radiology diagnostic, radiation therapy, nuclear medicine, and interventional radiology services. Another aim of the study was insight into drivers of inappropriate resource allocation. METHODS: An in-depth, retrospective bottom-up trend analysis of services consumption patterns and expenses was conducted from the perspective of third-party payer, for 205,576 inpatients of a large tertiary care university hospital in Serbia (1,293 beds) from 2007 to 2010. RESULTS: A total of 20,117 patients in 2007, 17,436 in 2008, 19,996 in 2009, and 17,579 in 2010 were radiologically examined, who consumed services valued at ?2,713,573.99 in 2007, ?4,529,387.36 in 2008, ?5,388,585.15 in -2009, and ?5,556,341.35 in 2010. CONCLUSIONS: The macroeconomic crisis worldwide and consecutive health policy measures caused a drop in health care services diversity offered in some areas in the period 2008 to 2009. In spite of this, in total it increased during the time span observed. The total cost of services increased because of a rise in overall consumption and population morbidity. An average radiologically examined patient got one frontal chest graph, each 7th patient got an abdomen ultrasound examination, each 19th patient got a computed tomography endocranium check, and each 25th patient got a head nuclear magnetic resonance. Findings confirm irrational prescribing of diagnostic procedures and necessities of cutting costs. The consumption patterns noticed should provide an important momentum for policymakers to intervene and ensure higher adherence to guidelines by clinicians. PMID- 29702869 TI - Children Hospitalized for Varicella: Complications and Cost Burden. AB - OBJECTIVE: To evaluate the direct medical cost of hospital admissions for patients with varicella (i.e., chickenpox) to assess the cost burden of varicella from a health care perspective for ultimate use in health economics studies in Turkey. METHODS: Records of children hospitalized with varicella at the Bakirkoy Maternity and Children's Hospital between November of 2006 and June of 2011 were reviewed. Reasons for hospitalization, types of varicella-associated complications, and direct medical cost of hospitalization were noted. Patients with underlying risk factors were excluded. Data obtained from one hospital were used to estimate the national cost of the disease. RESULTS: During the 4.5-year study period, 234 patients were hospitalized with varicella. Of these cases, 48 (20%) children previously ill with underlying cancers or chronic diseases were excluded from the study. Ultimately, 186 previously healthy children (age range: 14 days to 159 months, median age: 14 months) were included. The main reasons for hospitalization were complications related to varicella (79%), the most frequent of which was skin and soft tissue infections, followed by neurological complications and pneumonia. The median cost of hospitalization per patient was US $283, 50% of which was attributed to medication costs. The annual cost for varicella hospitalizations in Turkey was estimated at US $396,200. CONCLUSIONS: A significant number of healthy children are hospitalized for varicella and associated complications. Descriptions of these complications and their related costs provide important data for cost-effectiveness studies for decisions about the inclusion of the varicella vaccine in a childhood vaccination program. PMID- 29702870 TI - The Methodological Challenges for the Estimation of Quality of Life in Children for Use in Economic Evaluation in Low-Income Countries. AB - OBJECTIVES: The assessment of quality of life (QOL) in children has been underresearched in high- and low-income countries alike. This is partly due to practical and methodological challenges in characterizing and assessing children's QOL. This article explores these challenges and highlights considerations in developing age-specific instruments for children affected by HIV and other health conditions in Africa and other low-income settings. METHODS: A literature search identified works that have 1) developed, 2) derived utilities for, or 3) applied QOL tools for use in economic evaluations of HIV interventions for children. We analyzed the existing tools specifically in terms of domains considered, variations in age bands, the recommended respondents, and the relevance of the tools to African and also other low-income country contexts. RESULTS: Only limited QOL research has been conducted in low-income settings on either adults or children with HIV. A few studies have developed and applied tools for children (e.g., in Thailand, Brazil, and India), but none have been in Africa. The existing methodological literature is inconclusive on the appropriate width or depth by which to define pediatric QOL. The existing instruments include QOL domains such as "physical functioning," "emotional and cognitive functioning," "general behavior (social, school, home)," "health perception," "coping and adaptation," "pain and discomfort," "extended effects," "life perspective," and "autonomy." CONCLUSIONS: QOL assessment in children presents a series of practical and methodological challenges. Its application in low-income settings requires careful consideration of a number of context-specific factors. PMID- 29702871 TI - The Impact of Pharmaceutical Care Intervention on the Quality of Life of Nigerian Patients Receiving Treatment for Type 2 Diabetes. AB - OBJECTIVES: To evaluate the impact of pharmaceutical care (PC) intervention on health-related quality of life (HRQOL) of patients with type 2 diabetes. METHODS: This study was a randomized, controlled study with a 12-month patient follow-up. The study protocol was approved by the Research Ethical Committees of the institutions in which this study was conducted. A total of 110 patients were randomly assigned to each of the "intervention" (PC) and "control" (usual care [UC]) groups. Patients in the UC group received the usual/conventional care offered by the hospitals. Patients in the PC group received UC and additional PC for 12 months. The HUI23S4EN.40Q (developed by HUInc - Mark index 2&3) questionnaire was used to assess the HRQOL of the patients at baseline, 6 months, and 12 months. Two-sample comparisons were made by using Student's t tests for normally distributed variables or Mann-Whitney U tests for nonnormally distributed data at baseline, 6 months, and 12 months. Comparisons of proportions were done by using the chi-square test. RESULTS: The overall HRQOL (0.86 +/- 0.12 vs. 0.64 +/- 0.10; P < 0.0001) and single attributes except "hearing" functioning of the patients were significantly improved at 12 months in the PC intervention arm when compared with the UC arm. The HRQOL utility score was highly negatively (deficit >=10%) associated with increasing age (>=52 years), diabetes duration (>4 years), emergency room visits, comorbidity of hypertension, and stroke in both PC and UC groups. CONCLUSION: Addition of PC to UC improved the quality of life in patients with type 2 diabetes. PMID- 29702872 TI - An Audit of Diabetes-Dependent Quality of Life (ADDQOL) in Older Patients with Diabetes Mellitus Type 2 in Slovenia. AB - OBJECTIVE: This article reports a study to measure diabetes-dependent quality of life (QOL) in older Slovenian patients with diabetes mellitus type 2 (DMT2). METHODS: A cross-sectional study of older (age >= 65 years) patients with DMT2 at outpatient diabetic centers was conducted in all regions in Slovenia. The Audit of Diabetes-Dependent Quality of Life questionnaire was carried out between January and May 2012. Statistical analysis was performed by using IBM SPSS Statistics software, version 18.0. RESULTS: After exclusion of noneligible respondents, a total of 285 respondents were included in the analysis, which represented a 57% response rate. Lower QOL was significantly connected to a heart attack episode (odds ratio 2.42; 95% confidence interval 1.06-5.20) and to the perception of not having diabetes under control (odds ratio 0.36; 95% confidence interval 0.18-0.69). Eleven (3.9%) patients reported no impact of DMT2 on their QOL at all, while in the remaining respondents, particular reference was put to the effects on freedom to eat, dependency on others, and family life. There was no significant difference between the older people living in urban and rural areas. CONCLUSIONS: The findings of the present study highlight the impact of DMT2 on QOL. DMT2 imposes a personal burden on individuals. Information on the QOL of older patients with diabetes is important to Slovenian policymakers and family physicians to identify and implement appropriate interventions for achieving better management of diabetes and ultimately improving the QOL of patients with diabetes. PMID- 29702873 TI - Patient-Reported Quality of Life During Antiretroviral Therapy in a Nigerian Hospital. AB - OBJECTIVES: We assessed the reported quality of life of patients with HIV/AIDS and explored the impact of patients' sociodemographic profile on the quality-of life domains. METHODS: Consenting outpatients who met criteria were consecutively selected in a secondary health care facility in Benin City, Nigeria. Quality of life was determined in the nine domains of HIV/AIDS Targeted Quality of Life (HAT QOL) instrument. Quality-of-life scores were computed on the scale of 0 to 100 and triangulated with a rated interval scale of 1 to 5 suited for quantitative analysis. Association between rated scores and each domain was explored by using Students' t test and analysis of variance at 95% confidence interval. RESULTS: Out of the 403 patients, 82.1% were females; 147 (36.1%) belonged to the modal age group of 20 to 30 years; the mean age for grouped data was 39.2 years. About 239 (58.7%) were not married. Also, 338 (83.0%) earned below $1500 per annum and 303 (74.40%) had basic education (grade 1 to grade 9). HAT-QOL scores indicated the following: overall function (89.96 +/- 5.62); life satisfaction (91.94 +/- 3.62); health worries (87.06 +/- 4.28); financial worries (81.00 +/- 3.95); medication worries (91.65 +/- 4.47); HIV mastery (71.00 +/- 3.11); disclosure worries (27.50 +/- 7.57); provider trust (91.63 +/- 1.96); and sexual function (70.25 +/- 3.51). Likert-type rated scores were in agreement with HAT-QOL scores. Provider trust was associated with gender, employment status, and educational level. Sexual function was associated with gender and age (P < 0.05). CONCLUSIONS: Patients reported satisfactory quality of life in the domains of overall function, life satisfaction, health worries, financial worries, medication worries, HIV mastery, provider trust, and sexual function. Quality of life was low in the domain of disclosure worries, indicating concerns for discrimination and stigmatization. Age, level of education, and employment status had a strong impact on the quality of life of patients with HIV/AIDs. PMID- 29702874 TI - Clinical Burden of Invasive Pneumococcal Disease in Selected Developing Countries. AB - OBJECTIVE: To measure the clinical burden of invasive pneumococcal disease (IPD) in selected developing countries. METHODS: This is an extensive literature review of published articles on IPD in selected developing countries from East Asia, South Asia, Middle East, sub-Saharan Africa, and Latin America. We reviewed all the articles retrieved from the knowledge bases that were published between the years 2000 and 2010. RESULTS: After applying the inclusion, exclusion, and quality criteria, the comprehensive review of the literature yielded 10 articles with data for pneumococcal meningitis, septicemia/bacteremia, and pneumonia. These selected articles were from 10 developing countries from five different regions. Out of the 10 selected articles, 8 have a detailed discussion on IPD, one of them has s detailed discussion on bacteremia and meningitis, and another one has discussed pneumococcal bacteremia. Out of these 10 articles, only 5 articles discussed the case-fatality ratio (CFR). In our article review, the incidence of IPD ranged from less than 5/100,000 to 416/100,000 population and the CFR ranged from 12.2% to 80% in the developing countries. CONCLUSIONS: The review demonstrated that the clinical burden of IPD was high in the developing countries. The incidence of IPD and CFR varies from region to region and from country to country. The IPD burden was highest in sub-Saharan African countries followed by South Asian countries. The CFR was low in high-income countries than in low-income countries. PMID- 29702875 TI - Capacity Building for HTA Implementation in Middle-Income Countries: The Case of Hungary. AB - OBJECTIVES: Middle-income countries often have no clear roadmap for implementation of health technology assessment (HTA) in policy decisions. Examples from high-income countries may not be relevant, as lower income countries cannot allocate so much financial and human resources for substantiating policy decisions with evidence. Therefore, HTA implementation roadmaps from other smaller-size, lower-income countries can be more relevant examples for countries with similar cultural environment and economic status. METHODS: We reviewed the capacity building process for HTA implementation in Hungary with special focus on the role of ISPOR Hungary Chapter. RESULTS: HTA implementation in Hungary started with capacity building at universities with the support of the World Bank in the mid 90's, followed by the publication of methodological guidelines for conducting health economic evaluations in 2002. The Hungarian Health Economics Association (META) - established in 2003 - has been recognized as a driving force of HTA implementation. META became the official regional ISPOR Chapter of Hungary in 2007. In 2004 the National Health Insurance Fund Administration made the cost-effectiveness and budget impact criteria compulsory prior to granting reimbursement to new pharmaceuticals. An Office of Health Technology Assessment was established for the critical appraisal of economic evaluations submitted by pharmaceutical manufacturers. In 2010 multicriteria decision analysis was introduced for new hospital technologies. CONCLUSION: The economic crisis may create an opportunity to further strengthen the evidence base of health care decision-making in Hungary. In the forthcoming period ISPOR Hungary Chapter may play an even more crucial role in improving the standards of HTA implementation and facilitating international collaboration with other CEE countries. PMID- 29702877 TI - A Framework for Applying Health Technology Assessment in Cyprus: Thoughts, Success Stories, and Recommendations. AB - OBJECTIVES: Health care decision making, assessment, and procurement of medicines is a complex, human resource-demanding, and time-consuming process. A thorough evaluation of all factors involved is necessary to optimize the process. The objective of this study was to describe and analyze the current stage of health technology assessment (HTA) in Cyprus. METHODS: Literature research and private communication with all involved parties and competent authority. Moreover, data, decisions, and recommendations of the Drug's Committee were used. RESULTS: Cyprus is a latecomer in this field. HTA has entered a growing phase after the 2007 reform. It has not reached its full potential, and the current state is applicable only to the public sector, because of the nonexistence of a national health system. Therefore, this poses both a great challenge and a great barrier considering maximization of the value of money spent and health access equity. CONCLUSIONS: There is definitely enough space and clear necessity for further dissemination, and early successes indicate that steps should be taken toward the introduction of an HTA procedure that will cover both private and public sectors. The introduction of a national health system will further enhance the uptake of HTA, optimize the process, and use the common knowledge strategy for evidence based decision making. PMID- 29702876 TI - What Influences Recommendations Issued by the Agency for Health Technology Assessment in Poland? A Glimpse Into Decision Makers' Preferences. AB - OBJECTIVE: This study aimed to evaluate the factors that are associated with positive (supporting public funding) and negative recommendations of the Agency for Health Technology Assessment in Poland. METHODS: Two independent analysts reviewed all the recommendations publicly available online before October 7, 2011. For each recommendation, predefined decision rationales, that is, clinical efficacy, safety, cost-effectiveness, and formal aspects, were sought, either advocating or discouraging the public financing. In the analysis, we used descriptive statistics and a logistic regression model so as to identify the association between predefined criteria and the recommendation being positive. RESULTS: We identified 344 recommendations-218 positive (62.8%) and 126 negative (37.2%). Negative recommendations were better justified and also the comments were less ambiguous in accordance with the recommendation (except for clinical efficacy). In general, the specified criteria supported the decision (either positive or negative) in 209 (60.8%), 107 (31.1%), 124 (36.0%), 96 (27.9%), and 61 (17.7%) recommendations, respectively, and ran contrary to the actual decision in the remaining ones. Threshold values for either cost-effectiveness or budget impact distinguishing positive from negative recommendations could not be specified. The following parameters reached statistical significance in logistic regression: clinical efficacy (both explicitly positive and explicitly negative evaluations impacted in opposite directions), lack of impact on hard end points, unfavorable safety profile, cost-effectiveness results, and formal shortcomings (all reduced the probability of a positive recommendation). CONCLUSIONS: Decision making of the Agency for Health Technology Assessment in Poland is multicriterial, and its results cannot be easily decomposed into simple associations or easily predicted. Still, efficacy and safety seem to contribute most to final recommendations. PMID- 29702878 TI - Systematic Review of Economic Evaluation Literature in Ghana: Is Health Technology Assessment the Future? AB - OBJECTIVES: In many countries, such as Ghana, there is an increasing impetus to use economic evaluation to allow more explicit and transparent health care priority setting. An important question for policymakers in low-income countries, however, is whether it is possible to introduce economic evaluation data into health care priority-setting decisions. METHODS: This article systematically reviewed the literature on economic evaluation on medical devices and pharmaceuticals in Ghana published between 1997 and 2012. Its aim was to analyze the quantity, quality, and targeting of economic evaluation studies that relate to medical devices and pharmaceuticals and provide a framework for those conducting similar health technology assessment reviews in similar contexts. RESULTS: The review revealed that the number of publications reporting economic evaluations was minimal with regard to medical devices and pharmaceuticals. CONCLUSIONS: With the introduction of the National Health Insurance Scheme since 2004 policymakers are confronted with the challenge of allocating scarce resources rationally. Priority setting therefore has to be guided by a sound knowledge of the costs of providing health services. The need for economic evaluation is thus important. More costing studies were found; there were very few cost-effectiveness analysis studies. If economic evaluation is useful for policymakers only when performed correctly and reported accurately, these findings depict barriers to using economic evaluation to assist decision-making processes in Ghana; hence, there is a need for an independent health technology assessment unit. PMID- 29702879 TI - Dossier System as a Practical Tool for Compiling Reimbursement Lists. AB - The article describes the procedure for preparing reimbursement lists with the "Dossier" automated system at the regional level. Basic advantages and characteristics of the system, procedures for filling out the application form (dossier) for the inclusion of the drug into reimbursement lists, and the algorithm of expert evaluation are presented. PMID- 29702880 TI - Impact of the Pharma Economic Act on Diffusion of Innovation and Reduction of Costs in the Hungarian Prescription Drug Market (2007-2010). AB - OBJECTIVE: In this study, we examined the impact of the Pharma Economic Act, which was introduced in Hungary in 2007. METHODS: We used detailed data on the Hungarian prescription drug market, which had been made publicly available by the authorities. We evaluated the effect of the Pharma Economic Act on both dynamic and static efficiencies and also on equity, which has been historically a controversial issue in Hungary. We analyzed the overall prescription drug market and statin and atorvastatin markets; as a proxy for determining dynamic efficiency, we examined the oncology drug market for some specific products (e.g., bortezomib) and the long-acting atypical antipsychotic drugs market. RESULTS: There is no denying that the authorities managed to control the overall prescription drug costs; however, they were still paying excessive rents for off patent drugs. Examples of oncology and long-acting atypical antipsychotic drugs showed that the diffusion of innovation was on per-capita basis at least comparable to G-5 countries. While the share of out-of-pocket co-payments markedly increased and the reimbursement was lowered, the concurrent price decreases often meant that the co-payment per milligram of a given dispensed drug was actually lower than that before the Act, thereby benefiting the patient. CONCLUSIONS: It appears that strong mechanisms to control volume rather than price on the supply side (marketing authorization holders) contained the drug expenditure, while offering enough room to strive for innovation. Making data on prescription drug expenditures and associated co-payments publicly available is an item that should be definitely followed by the surrounding jurisdictions. PMID- 29702881 TI - Performance Assessment of Ga District Mutual Health Insurance Scheme, Greater Accra Region, Ghana. AB - OBJECTIVE: This study assessed performance of the Ga District Mutual Health Insurance Scheme over the period 2007-2009. METHODS: The desk review method was used to collect secondary data on membership coverage, revenue, expenditure, and claims settlement patterns of the scheme. A household survey was also conducted in the Madina Township by using a self-administered semi-structured questionnaire to determine community coverage of the scheme. RESULTS: The study showed membership coverage of 21.8% and community coverage of 22.2%. The main reasons why respondents had not registered with the scheme are that contributions are high and it does not offer the services needed. Financially, the scheme depended largely on subsidies and reinsurance from the National Health Insurance Authority for 89.8% of its revenue. Approximately 92% of the total revenue was spent on medical claims, and 99% of provider claims were settled beyond the stipulated 4 week period. CONCLUSIONS: There is an increasing trend in medical claims expenditure and lengthy delay in claims settlements, with most of them being paid beyond the mandatory 4-week period. Introduction of cost-containment measures including co-payment and capitation payment mechanism would be necessary to reduce the escalating cost of medical claims. Adherence to the 4-week stipulated period for payment of medical claims would be important to ensure that health care providers are financially resourced to deliver continuous health services to insured members. Furthermore, resourcing the scheme would be useful for speedy vetting of claims and also, community education on the National Health Insurance Scheme to improve membership coverage and revenue from the informal sector. PMID- 29702882 TI - The Process of Privatization of Health Care Provision in Poland. AB - OBJECTIVES: In January 1999, a new institutional structure for Poland's health care system was laid out, instigated by the dramatic change in both the political and economic system. Following the dissolution of state socialism, private financing of health care services was encouraged to fill an important role in meeting rising consumer demand and to encourage a more efficient use of resources through competition and private initiative. However, from the outset of the intended transformations, systemic limitations to the privatization process hindered progression, resulting in varying rates of privatization amongst the distinct health care sectors. The aim of this paper is to describe the privatization process and to analyze its pace and differences in strategic approach in all major health care sectors. METHODS: Policy analysis of legislation, government directives, and published national and international scientific literature on Polish health reforms between 1999 and 2012 was conducted. RESULTS: The analysis demonstrates a clear disparity in privatization rates in different sectors. The pharmaceutical industry is fully privatized in 2012, and the ambulatory and dental sectors both systematically increased their private market shares to around 70% of all services provided. However, despite a steady increase in the number of private hospitals in Poland since 1999, their overall role in the health care system is comparatively limited. CONCLUSIONS: Unclear legal regulations have resulted in a gray area between public and private health care, where informal payments impede the intended function of the system. If left unchanged, official health care in Poland is likely to become an increasingly residual service for the worst-off population segments that are unable to afford the legal private sector or the informal payments which guarantee a higher quality service in the public sector. PMID- 29702883 TI - Transforming Public Servants' Health Care Organization in Greece through the Implementation of an Electronic Referral Project. AB - OBJECTIVE: The Greek Public Servants' Health Care Organization aiming to organize, monitor, and enhance the health care services provided to 1,500,000 public servants decided to respond to the national alert of the economic crisis through the reduction of costs caused by diagnostic tests (?300,000,000 claims for 2008), to improve working conditions of contracted physicians and laboratories, and to enhance services provided to insured members. In September 2010, the Greek Public Servants' Health Care Organization initiated a pilot project that electronically records the prescription process of the diagnostic tests, which is Web-based, is open source, and was provided for free to the contracted physicians and diagnostic centers. METHODS: In this article, we present some interesting findings resulting from the implementation of the pilot electronic referral project by examining a 9-month period. RESULTS: Fifty-eight percent of the physicians had the necessary equipment for the operation of the system, more than 3600 physicians used it, 17,495 public servants had been served through the system, and 178,456 paraclinical examinations had been prescribed with a cost of ?1,394,980. In addition, the analysis revealed that the implementation of an electronic referral system could provide significant benefits, such as a faster referral process, valid and coherent information, minimization of the risk of misinterpreting the electronic referral due to illegibility of handwriting, and improvement in quality of services. CONCLUSIONS: The Greek electronic referral system was one of the first attempts toward creating the basis of a society of transparency and cost control. The lessons learnt from this article should not be ignored in the process of redesigning and improving the electronic referral system for Greece. PMID- 29702885 TI - Note from the Editors. PMID- 29702884 TI - Recommendations for Reporting Pharmacoeconomic Evaluations in Egypt. AB - OBJECTIVE: Introduction of economic evaluations for pharmaceuticals or other health technologies can help the optimization of outcomes from resource allocations. This article aims to provide recommendations for researchers in presenting pharmacoeconomic evaluations in Egypt with special focus on pricing and/or reimbursement applications of pharmaceuticals. METHODS: The Minister of Health approved the initiative of establishing a focus group of decision makers that included academic and industry experts with experience in health economics, pharmacovigilance, and clinical pharmacy. The focus group has reviewed 17 economic evaluation guidelines available on the Web site of the International Society for Pharmacoeconomics and Outcomes Research for reporting health economic evaluations. To develop core assumptions before preparing a draft report, focus group meetings were held on a regular basis starting June 2012. The recommendations were developed by using the Quasi-Delphi method, taking into account current practices and capacities for conducting pharmacoeconomic evaluations in Egypt. CONCLUSIONS: Worldwide, health care decision makers are challenged to set priorities in an environment in which the demand for health care services outweighs the allocated resources. Effective pharmaceutical pricing and reimbursement systems, based on health technology assessment (HTA) that encompasses economic evaluations, are essential to an efficient sustainable health care system. The Egyptian Ministry of Health and Population was encouraged to establish a pharmacoeconomic unit, as an initial step, for the support of pricing and reimbursement decisions. We anticipate that standardization of reporting would lead to a progressive improvement in the quality of submissions over time and provide the Egyptian health care system with health economic evidence often unavailable in the past. Therefore, recommendations for pharmacoeconomic evaluations provide an essential tool for the support of a transparent and uniform process in the evaluation of the clinical benefit and costs of drugs that do not rely on the use of low acquisition cost as the primary basis for selection. These recommendations will help inform health care decisions in improving health care systems and achieving better health for the Egyptian population. PMID- 29702886 TI - Response to "Potential Regulatory and Commercial Environment for Biosimilars in Latin America" by Azevedo et al. PMID- 29702888 TI - Guide for Authors. PMID- 29702887 TI - Response to Letter from Dr. Jorge Revilla Beltri dated 22nd March, 2013. PMID- 29702889 TI - Reviewer Acknowledgement. PMID- 29702890 TI - Burden of Disease and Economic Impact of Dengue and Severe Dengue in Colombia, 2011. AB - OBJECTIVE: To assess the burden of dengue disease in Colombia and its associated costs. METHODS: We estimated the burden of dengue and severe dengue in Colombia for the period 2011 to 2014 on the basis of a dynamic model calibrated against Colombian surveillance data. The model estimated the annual number of dengue and severe dengue cases for those receiving medical care and those who do not. We calculated the average cost of care per patient on the basis of a bottom-up costing of cases, and additional costs were estimated for activities of vector control and other community interventions. Economic information from a sample of local and departmental vector control programs was reviewed. RESULTS: The dynamic model estimated that for 2011 and 2012 there would be 56,998 dengue cases requiring medical attention (22,799 ambulatory and 34,199 hospitalized), 1851 cases of severe dengue, and 205 deaths. The economic analysis, with 2011 data, showed that Colombia would spend between US $52.2 and US $61.0 million for dengue control activities and case management in an average year. Medical management costs would amount to US $16.9 million (CI 95% 15.2-18.5 million), while vector control activities and other community interventions would cost between US $37.08 and US $42.41 million. CONCLUSIONS: Dengue infection has an important impact on the health care system budget in Colombia. Most of the economic impact corresponds to community activities directed to prevent vector infestation (68.7% 71.0%), which are expensive and whose effectiveness is controversial. PMID- 29702891 TI - An Estimate of the Cost of Hepatitis C Treatment for the Brazilian Health System. AB - OBJECTIVES: Hepatitis C therapy in Brazil is expensive due to the cost of antiviral drugs and demands on medical resources. The objective of this study was to estimate the direct costs per patient of chronic hepatitis C therapy in a Brazilian setting. METHOD: A microcosting study from a public health system perspective. The costs included were those of antiviral drugs, secondary medicines, diagnostic tests, visits to physicians and other professionals, hospitalization, nurse, and pharmaceutical care. All costs were priced in 2010. The values were converted to US $ (2010). RESULTS: The total direct cost of hepatitis C treatment per patient with interferon alpha (IFN) plus ribavirin (RBV) was US $982.25, with peginterferon alpha (PEG) 2a 180 MUg plus RBV was US $10,658.08, and with PEG 2b 120 MUg plus RBV was US $12,597.63, taking into account entire treatment according to Brazilian guidelines and assuming that all patients completed full treatment. The antiviral drugs are the most expensive element of the cost of treatment, totaling more than 40% of the medical costs of IFN plus RBV therapy and more than 88% of PEG plus RBV therapy. Calculating an average of 10,000 treatments per year, the total direct cost is US $90,346,772.39. According to the Ministry of Health, 90% of the annual total cost of hepatitis C treatment is accounted for by antiviral drugs. CONCLUSIONS: In Brazil, antiviral drugs are the most expensive component of hepatitis C treatment. The cost of follow-up and support to patients is minimal compared with the cost of antiviral drugs. PMID- 29702892 TI - Bloodstream Infection in the Intensive Care Unit: Preventable Adverse Events and Cost Savings. AB - OBJECTIVES: Central line associated bloodstream infections (CLABSIs) impose a significant economic burden for patients admitted to the intensive care unit for adults (AICU). The objectives of the study were to evaluate the excess length of stay and extra costs attributable to CLABSIs diagnosed in the AICU. METHODS: Cases were selected as patients admitted to AICU from 2006 through 2009, who developed a CLABSI episode. These were matched (1:1) with appropriate controls. Matching criteria were selected to exclude other factors that could influence cost and care practices. The length of stay and resources used between AICU admission and discharge and until hospital discharge or death were measured. Incremental costs and lengths of stay were calculated for each pair of patients. RESULTS: Thirty cases and 30 controls were included in the study. A CLABSI episode resulted in an additional 10.5 days in the AICU and 9.1 days after AICU discharge, totaling an additional 19.6 days. The incremental cost associated with a CLABSI episode was US $65,993 in the AICU and US $23,893 after AICU discharge, totaling an incremental cost of US $89,886. CONCLUSIONS: By avoiding CLABSI events, cost offsets would be expected for payers with revenue losses to providers. An approach of sharing the gains resulting from preventive measures could be used to incentivize providers to maintain those investments, benefiting patients who will have a reduced risk of CLABSI development. PMID- 29702893 TI - Impacto de Dos Metodos Alternativos de Asignacion de Costos Indirectos Estructurales de Hospitales Publicos Chilenos en el Costo Final de Produccion de Servicios Sanitarios. AB - OBJECTIVE: The main goal of this study is to measure the impact of two alternative methods of overhead cost allocation of chilean public hospitals into the final production cost of 256 health care services which are recurrent in health problems whose burden of disease is high in Chile. METHODS: A purposively sample of six important hospitals of metropolitan region in Chile was considered. A survey was applied to them in order to collect analytic cost data of resource use (labor, medical supplies and use of capital) in the production of health care services. The data of overhead cost (electricity, central heating, laundry, administrative support, transport, maintenance, etc.) were obtained from the Information System of each hospital. The final cost of each health care service was calculated from the perspective of health public system, in two ways: (1) using a proxy rate of common use, and (2) using overhead cost rates as a result of a step-down methodology. The final costs calculated with each method were compared and analized. RESULTS: Considering that the gold standard method for allocation of overhead cost is the step-down methodology, the results using proxy rate revealed that 185 services (72,3%) are under costing, and 71 health care services (27,7%) are over costing. CONCLUSION: The use of proxy rates to allocate overhead costs into the final cost lead to important under costing and over costing of health services. This finding is important at least by two reasons: (1) for the management of hospitals, (2) in economic evaluations, the variations in cost can modify the ratio of cost-effectiveness, cost-utility or cost-benefit, influencing the health public decision. PMID- 29702894 TI - Costo Efectividad del Tratamiento de Tumores Neuroendocrinos Pancreaticos Avanzados no Operables con Sunitinib en Mexico. AB - OBJECTIVES: Sunitinib had showed a substantial clinical benefit in patients with non-resectable pancreatic Neuroendocrine Tumors (NET). The objective of this study was to estimate the cost-effectiveness of sunitinib in the treatment of non resectable pancreatic NET, from the perspective of the Social Security Mexican Institute (IMSS). METHODS: A Markov model (2-week cycles) was used to estimate the health and economic consequences of sunitinib 37.5mg/day+best supportive care (BSC) regarding placebo+BSC (ten-years horizon, discount rate: 5%). Effectiveness measures were: overall survival (OS), progression-free survival (PFS) and quality adjusted life years (QALY). Resource utilization (BSC, adverse events management, medical follow-up) was estimated through a survey with Mexican oncologists (n=10). Unit costs of medication and medical resources were obtained from institutional sources. Sensitivity analyses were performed and acceptability curves were constructed. RESULTS: Sunitinib+BSC gained 0.49 years (PFS), 1.18 years (OS) and 0.70 QALY against placebo+BSC. Sunitinib+BSC increased medical direct costs (2011 US$) per patient in $20,854, which was driven by acquisition costs of sunitinib and medical follow up before progression. ICER's were $42,157, $17,662 and $29,808 per progression-free year, life-year and QALY gained, respectively, which remained robust through+/-25% changes in main parameters. At willingness to pay higher than $40,000, $22,400 and $37,600 sunitinib+BSC becomes the most cost-effective alternative in regards to PFS, OS and QALYs, respectively. CONCLUSION: At IMSS, sunitinib+BSC would provide substantial clinical benefits to patients suffering unresectable pancreatic NET, although the latter would increase medical costs of treatment and clinical follow up. PMID- 29702895 TI - Analisis Costo Efectividad del Stent Farmacologico V/S Stent no Farmacologico en Cardiopatia Isquemica en Chile. AB - OBJECTIVE: To evaluate and compare the costs and effectiveness of two alternative stent, drug eluting stent (SF) and bare metal stent (SNF). MATERIAL AND METHODS: Cost-utility analysis based on a Markov model using data from a cohort study of Hospital Las Higueras of Talcahuano, Chile. The effectiveness measure was the rate of restenosis and the time of restenosis. The effectiveness outcomes are expressed in quality-adjusted life years (QALY) gained. Costs are expressed in national currency 2011. The evaluation perspective was from the public heath budget. We model a cohort from age 63 to 80 years, life expectancy in Chile. Apply discount rate of 0, 3% and 6% for results and costs. Sensitivity analysis is performed according to the ranges of variability in costs, the utility values of the variables and transition between states. RESULTS: No differences in restenosis rates between the two stents, although there were differences in the time of restenosis. The incremental cost effectiveness ratio (ICER) no discount rate was CH$ 235.749 per QALY gained when using drug-eluting stent, the value below the equivalent of 1 Gross Domestic Product (PIB) per capita for 2011 in Chile. CONCLUSIONS: The drug-eluting stent (SF) is cost effective compared to bare metal stent (SNF). The ICER is not affected by the sensitivity analysis (variability of cost, utility ranges used, probability of restenosis). PMID- 29702896 TI - The Cost-Effectiveness and Budget Impact of Introducing Indacaterol into the Colombian Health System. AB - OBJECTIVES: The main objectives were to estimate the cost-effectiveness and budget impact of indacaterol (a once-daily, long-acting-beta2-agonist) compared with 1) salmeterol/fluticasone, 2) formoterol/budesonide, and 3) tiotropium for the treatment of chronic obstructive pulmonary disease in Colombia. METHODS: A Markov model was utilized to simulate the progressive course of chronic obstructive pulmonary disease, distinguished by forced expiratory volume in 1 second predicted according to the four Global Initiative for Chronic Obstructive Lung Disease severity stages by using prebronchodilation values. Efficacy was based on the initial improvement in forced expiratory volume in 1 second, taken from either a network meta-analysis (salmeterol/fluticasone and formoterol/budesonide) or a randomized controlled trial (tiotropium). Colombian direct costs and life tables were incorporated in the adaptation, and analysis was performed from a health care payer perspective, discounting future costs (presented as US dollars) and benefits at 5%. A budget impact model was built to estimate the cost impact of indacaterol in Colombia over 3 and 5 years. RESULTS: Indacaterol was found to be dominant (i.e., less costly and more effective) against both salmeterol/fluticasone and formoterol/budesonide per life year and quality-adjusted life-year gained after a 5-year time horizon. The average cost saving against salmeterol/fluticasone and formoterol/budesonide was US $411 and US $909 per patient, respectively. All probabilistic sensitivity analysis simulations indicated indacaterol to be less costly than salmeterol/fluticasone and formoterol/budesonide. Indacaterol was more effective and more costly than tiotropium, corresponding to an incremental cost-utility ratio of US $2584 per quality-adjusted life-year. CONCLUSIONS: The results indicate that by replacing salmeterol/fluticasone or formoterol/budesonide with indacaterol, there are possible cost savings for the Colombian health care system. This was demonstrated by both cost-effectiveness and budget impact models. PMID- 29702897 TI - Economic Evaluation of Bariatric Surgery in Mexico Using Discrete Event Simulation. AB - OBJECTIVES: Morbid obesity represents high costs to health institutions in controlling associated comorbidities. It has been shown that bariatric surgery resolves or improves comorbidities, thus reducing resource utilization. This analysis estimated the total costs of treating morbid obesity and related comorbidities through conventional treatment compared to bariatric surgery under the Mexican public health system perspective. METHODS: An economic evaluation model was developed by using discrete event simulation. One hundred fifty patients were created in each arm, with considered comorbidities allocated randomly. Preoperative comorbidity prevalences and bariatric surgery's efficacy for resolving them were obtained from published literature. Comorbidity treatment costs were obtained from the 2007 Mexican Institute of Social Security diagnosis related group list and publications from the National Institute of Public Health. Only 12 patients were operated each month on the surgical arm. Complications associated with comorbidities were not considered. The considered time frame for simulation was 10 years, with a 4.5% annual discount rate. RESULTS: Return on investment, or cost breakeven point, for bariatric surgery was obtained after 6.8 years. Total costs for the surgical group were 52% less than conventional treatment group costs after 10 years. Bariatric surgery reduced the cost of treating type 2 diabetes, hypertension, and hypercholesterolemia by 59%, 53%, and 65%, respectively. Return on investment for bariatric surgery in patients with type 2 diabetes as the only comorbidity was 4.4 years. CONCLUSIONS: Despite conservative assumptions, investment in bariatric surgery is recouped in 6.8 years, generating relevant potential savings in the treatment of morbidly obese patients. In high-risk subpopulations, return on investment time is shorter. PMID- 29702898 TI - Cost-Effectiveness of Routine Screening for Cardiac Toxicity in Patients Treated with Imatinib in Brazil. AB - We performed a cost-effectiveness study of different strategies of screening for cardiotoxicity in patients receiving imatinib, the first strategy based on yearly echocardiograms in all patients and the second strategy based on yearly B-type natriuretic peptide level measurement, reserving echocardiograms for patients with an abnormal test result. Results are presented in terms of additional cost per diagnosis as compared with not performing any screening. From the Brazilian private sector's perspective, strategies 1 and 2 resulted in additional costs of US $30,951.53 and US $19,925.64 per diagnosis of cardiotoxicity, respectively. From the perspective of the Brazilian public health system, the same strategies generated additional costs of US $7,668.00 and US $20,232.87 per diagnosis, respectively. In our study, systematic screening for cardiotoxicity in patients using imatinib has a high cost per diagnosis. If screening is to be adopted, a strategy based on B-type natriuretic peptide level measurement, reserving echocardiography for patients with abnormal results, results in lower costs per diagnosis in the private sector. From the public health system's perspective, costs per diagnosis will greatly depend on the reimbursement values adopted for B type natriuretic peptide level measurement. PMID- 29702899 TI - Economic Burden of Incident Unplanned Starts on Peritoneal Dialysis in a High Specialty Health Care Facility in Mexico City. AB - OBJECTIVES: Few studies have examined hospitalization costs for unplanned initiation of peritoneal dialysis (PD). We used data from a health care facility in Mexico to examine first hospitalization costs associated with the unplanned initiation of PD. METHODS: Descriptive analyses focusing on initial hospitalization costs during the unplanned initiation of PD were conducted. In addition, multivariate regression models examined the association of costs with requiring urgent hemodialysis (HD) at the time of starting PD, and the association of driving distance with requiring urgent HD. RESULTS: Of 195 patients hospitalized in 2010 for PD catheter placement, 51 patients met criteria for unplanned PD initiation and 25 of them required urgent HD prior to PD initiation. Ninety-two percent of the patients received 90% or greater government subsidy of hospital costs. Average inpatient costs for the first hospitalization related to the unplanned initiation of PD were 64,174 Mexican Pesos (MXN) (US $4,657). Costs were 78,683 MXN ($5,710) per patient for those requiring urgent HD and 50,225 MXN ($3,645) for those who did not, a difference (P<0.05) of roughly 28,000 MXN ($2,032), and regression results were similar. In addition, long driving distance to the institution was significantly associated with requiring urgent HD. CONCLUSIONS: Our findings highlight potential cost savings to payers for developing better strategies to manage PD starts in Mexico and should help inform policy regarding oversight and coverage of low-income patients at risk of dialysis. PMID- 29702900 TI - Analisis de Costo-Efectividad de las Estrategias de Tamizacion de Cancer Colorrectal en Colombia. AB - OBJECTIVE: To evaluate the cost-effectiveness of different screening strategies for colorectal cancer in Colombia. METHODS: We designed a Markov model to compare the clinical and economic impact in terms of reducing the incidence and mortality from colorectal cancer (CRC). Six screening strategies for adults were compared: fecal occult blood (FOBT) immunochemical and guaiac type, conventional colonoscopy, flexible sigmoidoscopy, and FOBT guaiac and immunochemical type more sigmoidoscopy. We used the third-party payer perspective, including only direct costs, the time horizon was the life expectancy of the Colombian population. We estimated cost-effectiveness ratios (CERs) and incremental cost-effectiveness (ICER). Were performed deterministic sensitivity analysis and probabilistic. We applied a discount rate of 3% in the costs and health outcomes. RESULTS: The screening strategy more cost-effective was the FOBT biennial guaiac type. The cost per life year gained was US$10,347.37, US$18,380.64, and US$45,158.05. For FOBT guaiac biennial, FOBT guaiac annual and FOBT inmunoquimica biennial respectively. The ICER is sensitive to the percentage of false positive test for FOBT guaiac type values greater than 10%, and the cost of the test. CONCLUSIONS: The screening strategy more cost-effective for Colombia is the FOBT biennial guaiac type, using as a threshold the gross domestic product (GDP) per capita in Colombia. PMID- 29702901 TI - Analisis de Costo Efectividad de Estrategias de Tratamiento Antimicotico en Pacientes con Neutropenia Febril Persistente y Tratamiento Antibiotico de Amplio Espectro. AB - OBJECTIVE: To assess cost-effectiveness of antifungal treatment on patients with persistent fever neutropenia: empiric antifungal therapy (EAT) vs. anticipated antifungal therapy (AAT). METHODS: A decision model was performed to evaluate the cost-effectiveness of antifungal treatment strategies in patients with febrile neutropenia not responding to a broad spectrum antibiotic treatment. The strategies included were: 1) EAT with amphotericin B deoxycholate; 2) EAT with liposomal amphotericin B; 3) EAT with caspofungin; and 4) AAT with voriconazole and amphotericin B deoxycholate or liposomal amphotericin B or caspofungin in patients who initiate treatment despite having negative CT scan and galactomannan or fail to voriconazole. Effectiveness was measured as the number of deaths averted. Cost-effectiveness and incremental cost-effectiveness ratios were calculated. Deterministic and probabilistic sensitivity analyzes were performed. RESULTS: EAT with Amphotericin B deoxycholate was the least expensive and least effective strategy. The EAT with caspofungin was the most effective. The cost per death averted for caspofungin when compared with amphotericin B deoxycholate was $17,011,073.83, which would indicate that this strategy would be cost-effective for the country if the willingness to pay per death averted is equal to or greater than this value. EAT with liposomal amphotericin B and AAT with voriconazole were dominated by AET with caspofungin, which is less costly and more effective. CONCLUSIONS: EAT with caspofungin would be cost-effective for Colombia if the threshold per death averted is greater to $18.000.000. If the threshold is lesser the EAT with amphotericin B deoxycholate would be the election. PMID- 29702902 TI - Cost Utility of Sirolimus versus Tacrolimus for the Primary Prevention of Graft Rejection in Renal Transplant Recipients in Mexico. AB - OBJECTIVE: Therapies for end-stage renal disease improve quality of life, and survival. In Mexico, clinicians often must choose between different therapies without the availability of comparative outcomes evaluation. The present study evaluates the comparative cost-utility of sirolimus (SIR) versus tacrolimus (TAC) for the primary prevention of graft rejection in renal transplant recipients in Mexico. METHODS: We used modeling techniques to estimate the cost-effectiveness of SIR versus TAC to prevent graft rejection in patients with end-stage renal disease in the Mexican setting. The model estimates the cost of quality-adjusted life-year (QALY) per patient. We applied a 20-year horizon (1-year Markov cycles). Cost-effectiveness was expressed in terms of cost per QALY. All costs are presented in 2011 US dollars. Probabilistic sensitivity analyses were conducted. RESULTS: The total cost for the SIR treatment arm over the 20-year duration of the model is estimated to be $136,778. This compares with $142,624 for the TAC treatment arm, resulting in an incremental cost of SIR compared with that of TAC of-$5,846. Over 20 years, SIR was estimated to have 8.18 QALYs compared with 7.33 QALYs for TAC. The resulting incremental utility of SIR compared with that of TAC is 0.84 QALY gained. SIR is estimated to be both less costly and more effective than TAC, indicating that it is the dominant strategy. Notably, results suggest that SIR has a 78% probability of being dominant over the TAC strategy and a 100% probability of having an incremental cost effectiveness ratio at or below $10,064 (1 GDP) per QALY. CONCLUSIONS: These analyses suggest that in the Mexican setting, the use of SIR in place of TAC for the prevention of graft rejection in this population is likely to be cost saving. PMID- 29702903 TI - Colombian Health System on its Way to Improve Allocation Efficiency-Transition from a Health Sector Reform to the Settlement of an HTA Agency. AB - Over the past 20 years, Colombia has invested major efforts in ensuring universal health care access to its citizens while facing epidemiological transition and demographic changes. The country, as any other region in the world, is challenged by financial constraints and market pressures for entry of new and frequently costly technologies. After the 1993 health sector reform, Colombian citizens are entitled to health care access via mandatory health insurance through a benefits plan. Inclusions to this plan were the first attempt to establish a formal methodology of health technology assessment. Later on, the dynamics of insurers, market pressure, reimbursement decisions, and judicial actions drove the government toward the formulation of an infrastructure to improve efficiency in the use of resources. This article accounts for the steps undertaken by the Colombian health system until the establishment of a health technology assessment body and outlines the most important issues that can be learned from this process. PMID- 29702904 TI - Status Update of the Reimbursement Review Environment in the Public Sector across Four Latin American Countries. AB - In Latin America, social security and public sectors represent the largest financiers and providers of health care. Many countries in the region have compulsory packages of basic health care benefits. As part of an effort to improve quality of care and access, several health technology assessment agencies, both governmental and academia, among a number of Latin American countries have been formally established in the past few years. Several Latin American countries have recently developed and published methodological guidelines in economic evaluation, indicating that there is a growing interest in evaluating health-related products, drugs, and technologies used by the population. Presentations on the health care system and the role of health technology assessment, pharmacoeconomics, and risk sharing policies, from the public sector perspective, in the Latin American countries Argentina, Brazil, Colombia, and Mexico were made at the 3rd Latin American ISPOR Conference held in Mexico City in 2011 and are discussed in this article. In conclusion, there is a clear need for Latin American countries to evaluate the value of new technologies that are being incorporated into their health care system. In addition, health technology assessment guidelines are important for their local needs in terms of regulation along with common country unions. In the future, the Latin American region needs to increase drug access along with implementing cost-containment measures to improve quality and health outcomes. PMID- 29702905 TI - Potential Regulatory and Commercial Environment for Biosimilars in Latin America. AB - OBJECTIVES: Biosimilars are increasingly attractive to payers around the globe because of mounting financial pressure. Many Latin American governments are developing abbreviated regulatory pathways for biosimilars. There are limited data regarding how certain regulatory agencies in the region plan to address biosimilar access. This study explores potential opportunities and challenges for biosimilar drugs in Brazil, Mexico, Argentina, Chile, and Venezuela. METHODS: We conducted targeted literature reviews, followed by key informant interviews, to understand the expected regulatory environment for biosimilars. We also asked questions about the economic, political, and historical factors that could play a role in the extent to which biosimilar-specific pathways have been developed across countries to date, and will continue to evolve in the future. RESULTS: Brazil has led the development of biosimilar regulation in Latin America, with two distinct pathways, one for more complex molecules such as monoclonal antibodies and a less rigorous path for simpler molecules such as pegylated interferon and low molecular weight heparin. Other countries have been slower to respond, in part because of the degree of emphasis within each country for the advancement of biosimilar regulatory standards. Signs of relaxed standards akin to those seen in Brazil's "individual development" pathway were found in other countries. CONCLUSIONS: The example of the two-pathway system coupled with governmental prioritization of local manufacturing capabilities in Brazil should promote increased biosimilar utilization within the country. Assuming that the two-pathway system demonstrates success in Brazil, we hypothesize that other Latin American countries may adapt aspects of this "local" model for developing a regulatory pathway for biosimilars. PMID- 29702906 TI - Prevalence, Awareness, Treatment, and Burden of Major Depressive Disorder: Estimates from the National Health and Wellness Survey in Brazil. AB - OBJECTIVE: Major depressive disorder (MDD) is often underdiagnosed, undertreated, and associated with negative health outcomes. The current study examined the prevalence of MDD signs and symptoms in Brazil, including awareness, diagnosis, treatment, and the association of MDD with health outcomes. METHODS: Data were collected from the 2011 National Health and Wellness Survey in Brazil (N = 12,000). Excluding those with bipolar disorder, respondents who met Patient Health Questionnaire-9 criteria for MDD (n = 1105) were compared with those not qualifying as having MDD or any depressive symptoms (n = 8684), analyzing separately those currently taking (n = 184) or not taking (n = 155) prescription medication for depression. Sociodemographics and health status, symptoms, experience of depression, diagnosis, MDD severity, pharmacotherapy, productivity impairment (Work Productivity and Activity Impairment questionnaire), health status (Short-Form 12, version 2), and health care resource use were measured. Results were weighted and projected to the Brazil adult population. Differences were measured with column proportion and mean tests for categorical and continuous outcomes, respectively. RESULTS: MDD prevalence was 10.2%, with only 28.1% of the individuals with MDD diagnosed and 15.6% currently using prescription medication for depression. Males were especially likely to be unaware of MDD. Compared with non-MDD controls, patients with MDD (treated or untreated) reported significantly greater overall work impairment, worse mental and physical health status, and greater health care resource utilization (all P<0.05). There was a trend for worsening health outcomes with increasing MDD severity. CONCLUSIONS: These findings suggest that Brazilians may be underdiagnosed and undertreated for MDD. Individuals with MDD reported substantially poorer health outcomes, suggesting the need to increase MDD awareness, especially among males, and provide better access to treatment. PMID- 29702907 TI - Concurrent Validity and Reliability of the Brazilian Version of the Functioning Assessment Short Test in Patients with Schizophrenia. AB - OBJECTIVE: Many studies have documented the high rates of functional impairment among patients with schizophrenia. The majority of the available instruments used to assess functioning, however, focus on global measures of functional recovery rather than specific domains of psychosocial functioning. Most of these instruments have important limitations regarding use in psychiatry. The aim of the present study was to evaluate the psychometric properties of the Brazilian version of the Functioning Assessment Short Test (FAST) in patients with schizophrenia. METHODS: A convenience sample of 107 chronic outpatients with schizophrenia and 108 controls was assessed in a university hospital (Hospital de Clinicas de Porto Alegre, Brazil). Psychometric properties of FAST (internal consistency, concurrent validity, and test-retest reliability) were analyzed. RESULTS: The internal consistency obtained was high; the Cronbach's alpha was 0.89. FAST total score was higher in patients than in the control group (Z = 11.95; P<0.001). FAST test-retest agreement was excellent (intraclass correlation coefficient = 0.93; 95% confidence interval 0.81-0.97). In addition, FAST displayed a positive correlation with the Brief Psychiatric Rating Scale (rho = 0.41; P<0.001) and a negative correlation with the Global Assessment of Functioning scale (rho =-0.71; P = 0.001). CONCLUSIONS: Psychotic symptoms, comorbidity, and functional and cognitive impairment contribute to the decreased quality of life of patients with schizophrenia. It is important to obtain a valid and reliable instrument that is capable of evaluating the functional domains in this pathology. In this context, FAST showed accurate psychometrics properties and was able to detect functional differences between patients with the diagnosis of schizophrenia and healthy subjects. PMID- 29702908 TI - Performing Country-led Economic Evaluations to Inform Immunization Policy: ProVac Experiences in Latin America and the Caribbean. AB - New vaccines have been demonstrated to be effective in reducing morbidity and mortality, particularly in children, but come at increased costs to societies, governments, and their national immunization programs compared with other traditional childhood vaccines. Rational allocation of available resources requires systematic collection of the evidence base to decide whether to introduce a new vaccine, an important component of which is cost-effectiveness analysis. In this article, we develop in-depth case studies to examine the country experience of conducting cost-effectiveness analysis with the support of Pan American Health Organization ProVac Initiative and the implications of its process for decision making on new vaccine introduction in Latin America and the Caribbean. Key lessons regarding how cost-effectiveness analysis may be effectively used to inform evidence-based immunization policy are highlighted, drawing from the experience of Nicaragua and Paraguay. Based on the lessons identified, the vision going forward will focus on promoting the sustainability of multidisciplinary country teams while continuing to prioritize capacity development as an overarching guiding principle for preparing countries to face future new vaccine policy decisions. PMID- 29702909 TI - Consideraciones Regulatorias sobre Productos Biologicos en Brasil. AB - Biosimilars are biologics developed to compete with originator biologics that have been on the market for a long time and lost their patent and market protection. The WHO guidelines on evaluation of Biosimilars provide clear guidance for regulators on how to develop and gain approval for these products. The aim of this paper is to inform of the current status of development in regulation of Biosimilars in Brazil according WHO Guidelines. The result of the comparison shows the Brazilian regulation conflicts with the principles of the WHO guidelines. PMID- 29702910 TI - Institutionalizing Health Technology Assessment in Brazil: Challenges Ahead. AB - The evolving process of institutionalizing health technology assessment (HTA) in low- and middle-income countries is not yet fully understood. The present article aims to provide an analysis of some of the most recent changes in the development of HTA in Brazil, as well as the main challenges and potential barriers that may determine the process of institutionalizing HTA in the country vis-a-vis the recent approval of its federal HTA law at the end of 2011. Based on the authors' experience in HTA from an academic research perspective as well as from national and regional/local policymaking implementations, this article also proposes some measures to foster the institutionalization of HTA, for which Brazil would have to overcome three fundamental challenges for decision making: 1) Brazil has to complete an unfinished agenda regarding the implementation of its national Unified Health System (SUS), 2) the complex governance of the SUS has to be thoroughly reassessed, and 3) HTA institutionalization is to be promoted to strengthen decision making. The recent creation of a Brazilian national HTA body represents an important step not only in terms of the development of HTA in the country but also regarding the consolidation of the universal access to health care that is guaranteed by the Brazilian Federal Constitution since the creation of SUS in 1988. There is an urgent need to promote broader approaches to assess the complexity of the governance of the SUS, thus strengthening the process of HTA within the decision-making process. PMID- 29702911 TI - Diferenciacion en la Evaluacion Economica Tradicional para Medicamentos que se Utilizan en Fases Terminales, Recomendaciones Recientes del Reino Unido y su Consideracion para Mexico y otros Paises. PMID- 29702912 TI - Criterios Farmacoeconomicos Usados en Mexico para la Evaluacion de Tratamientos en Personas en Fases Terminales. AB - In Mexico, the primary aim of "Healthcare Supplies Catalog" (CBCISS) is guide the optimization of public resources to the attention of the health problems of the country, through the use of medicines, treatments, procedures and devices which have proven safety, efficacy and efficiency. Since May 2003, the Commission of CBCISS established as a requirement for updating submits a Health Economic Evaluation (EE) of the product. Therefore, in 2008, was a prepared and published methodological guideline for the conduct of studies of economic value (GCEEE). In 2011 was developed some strategies as updated the Internal Regulations and developed the Evaluation Guide Health Products (GEIS); both complement the GCEEE and oriented between other things, to increased the availability of technologies in different public institutions, decreased likelihood to commit injustices and inequities in access to supplies and standardize a transparent process. With the epidemiological transition, the cares of patients with chronic or terminal phase are contributing to the escalating costs of health care. The escalating costs are driven by the use of therapies that unfortunately have only marginal benefits, increasing the health and social costs, and upholding financial sustainability of healthcare systems. Therefore the stakeholders must decide the order of preference and establish an allocation methodology. PMID- 29702913 TI - Revisit What Is Next for Pharmacoeconomics and Outcomes Research in Asia. AB - As part of the global trend to address the constrained resources for population health care coverage, the concepts of pharmacoeconomics (PE) and health technology assessment (HTA) have been introduced to Asia in the last decade. Medicines are just one of numerous types of innovative technologies developed to address unmet medical need. Many of these medicines receive a great deal of attention because of their potential impact on limited health care budgets. There are a few key challenges for using PE and HTA in making informed decisions regarding the value of a given new health care technology in an Asian country. These challenges include 1) recognizing the multidimensional aspects of PE and HTA, which can include both health care and political considerations; 2) involving stakeholders (with a focus on patients) in decision making; 3) balancing short- and long-term overall benefits of innovative medicines; and 4) giving consideration to specific local cultural and health care characteristics. PMID- 29702914 TI - Usefulness of Patient-Generated Index for HIV to Measure Individual Quality of Life: A Study from Thailand. AB - OBJECTIVES: To measure health-related quality of life (HRQOL) in Thai HIV patients using the patient-generated index for HIV (PGI-HIV) and to compare the psychometric properties of the PGI-HIV with those of the EuroQol five-dimensional (EQ-5D) questionnaire and the Medical Outcome Study HIV Health Survey in terms of practicality, reliability, validity, and responsiveness. METHODS: In this study, two rounds of interviews were carried out in HIV outpatients who met the eligibility criteria and attended the HIV Clinic of Warinchamrap Hospital between January and March 2010. The patients were interviewed using a data collection form and three HRQOL measures (the PGI-HIV, the EQ-5D questionnaire, and the Medical Outcome Study HIV Health Survey) to assess the practicality and validity. The second interview was performed to check the test-retest reliability and responsiveness. RESULTS: A total of 210 patients completed the study. They were mostly women (69.5%), with a mean age of 39.2 +/- 11.1 years. The majority with the US Centers for Disease Control and Prevention clinical stage C took the current antiretroviral drugs within 1 year. The average PGI score was about 0.60, implying HIV/AIDS and antiretroviral drug therapy decreased the patients' quality of life by 40% from their healthy life. Three mostly cited impact domains were hyperlipidemia, lipid maldistribution and lipodystrophy, and hepatitis. The PGI HIV was considered as practical, with a mean difficulty score of 3.7 +/- 0.8, highly reliable (intraclass correlation coefficient = 0.75; P < 0.001), and responsive to HRQOL changes (effect size = 0.81; standardized response mean = 0.99), but not valid when compared with CD4 levels and viral loads (all Pearson' r < 0.2; P > 0.05). CONCLUSIONS: The PGI-HIV was used to measure the individual HRQOL in a Thai sample of HIV-positive patients. It proves to be practical, highly reliable, and very responsive to changes in patients' HRQOL. PMID- 29702915 TI - The Health Technology Assessment Environment in Mainland China, Japan, South Korea, and Taiwan-Implications for the Evaluation of Diabetes Mellitus Therapies. AB - BACKGROUND: Diabetes mellitus (DM) is associated with a significant global economic and humanistic burden. The condition presents a real challenge in Asia, which accounts for more than 60% of individuals with DM globally. Health technology assessment (HTA) is a field of scientific research used to inform policy and clinical decision making relating to the introduction and diffusion of health technologies. OBJECTIVES: This article, examines the present use and predicted evolution of HTA with respect to pricing and reimbursement of drugs in mainland China, Japan, South Korea, and Taiwan. It makes specific reference to important assessment considerations for DM therapies, which should assist key stakeholders in choosing which data to capture, and what approaches to use, to help quantify the value of treatment. METHODS: The findings are informed by two Advisory Board discussions, a literature review, and the authors' personal experience. RESULTS: HTA already has a key role in South Korea and Taiwan, with current systems undergoing important changes. In contrast, in mainland China and Japan, HTA is not yet formally utilized, although this appears likely to change. Several elements are important for HTA to be meaningful and impactful for DM therapies, including a clear, transparent analytical framework for HTA that includes all relevant costs and outcomes; availability of local DM epidemiologic, economic, and quality-of-life data; acceptance of modeling as a core methodology; availability of real-life patient data; and recognition of specific evidence requirements associated with biosimilars. HTA has the potential to assist payors in making informed decisions about the coverage of DM medications. PMID- 29702916 TI - Cost-Effectiveness of Periodontitis Management in Public Sector Specialist Periodontal Clinics: A Societal Perspective Research in Malaysia. AB - OBJECTIVES: The aim of this study was to evaluate the cost-effectiveness of the national public sector specialist periodontal program in the management of periodontal disease. METHODS: This was a multicenter, time motion, prospective, economic evaluation study involving a total of 165 patients with periodontitis recruited from five selected specialist periodontal clinics. Treatment costs were measured in 2012 Malaysian ringgit (MYR) and estimated from the societal perspective using step-down and activity-based costing methods, and substantiated by clinical pathways. A cost-effectiveness analysis was done to compare the specialist periodontal program with a hypothetical scenario in which patients attend biannual dental visits only for regular dental check-up and scaling. The incremental cost-effectiveness ratio was defined as the difference in cost per gain in quality-adjusted life-years (QALYs) and clinical attachment levels (CALs). One-way scenario-based sensitivity analyses were carried out to assess the uncertainty of inputs. RESULTS: The average cost for managing patients with periodontitis was MYR 376 per outpatient visit and MYR 2820 per annum. Clinically, a gain of an average of 0.3 mm of CAL was attained at post-treatment (paired t test, P < .001). Patients gained an average of 3.8 QALY post-treatment (paired t test, P < .001). For cost-effectiveness analysis, the specialist periodontal program was more cost-effective than the hypothesized biannual dental visits, with incremental cost-effectiveness ratios of MYR 451 and MYR 5713 per additional QALY and millimeter CAL gained, respectively. CONCLUSIONS: It is very cost-effective for the public sector to provide specialist periodontal treatment for patients with periodontitis according to the World Health Organization criteria and when compared with conventional biannual dental treatment. PMID- 29702917 TI - Resource Utilization and Direct Medical Costs of Chronic Hepatitis C in Thailand: A Heavy but Manageable Economic Burden. AB - OBJECTIVE: To estimate the cost for the management of chronic hepatitis C (CHC) and related morbidities by using a payer perspective in Thailand. METHODS: Data elements were extracted from medical records of 542 patients newly diagnosed with CHC in five tertiary care hospitals across Thailand. All patients were divided into five health states: noncirrhotic CHC, hepatitis C virus (HCV)-related compensated cirrhosis, HCV-related decompensated cirrhosis, HCV-related hepatocellular carcinoma, and HCV-related liver transplantation. Resource utilization data for each patient during a 12-month follow-up study period were compiled, and reference prices published by the Thai government were used to estimate the cost for each health state. The average cost was calculated and categorized into various groups, for example, laboratory and diagnostic tests, procedures, medication, and hospitalization. RESULTS: The average number of outpatient visits per patient was approximately six visits in all cohorts. The HCV-related hepatocellular carcinoma and liver transplantation cohorts had a higher average number of inpatient admissions per patient. The average number of days per admission varied from fewer than 3 days to 1 week or more across all the health states. The average annual total cost per patient varied across all health states from approximately 170,000 to 600,000 baht, and medication cost was the largest portion in every cohort, except the HCV-related liver transplantation cohort in year 1. Among all medications, the average annual antiviral medication cost per patient was the largest portion in the noncirrhotic CHC and HCV-related compensated cirrhosis cohorts. CONCLUSIONS: CHC was a costly disease in Thailand. The average annual medication cost was the largest portion in every health state, except HCV-related liver transplantation. PMID- 29702918 TI - Cost-Effectiveness of Partially Hydrolyzed Whey Protein Formula in the Primary Prevention of Atopic Dermatitis in At-Risk Urban Filipino Infants. AB - OBJECTIVE: To estimate, from a Filipino societal perspective, the cost effectiveness of preventing atopic dermatitis (AD) via early nutritional intervention with 100% whey-based partially hydrolyzed formula (PHF-W) versus standard cow's milk formula (SF) in healthy, urban infants with atopic heredity who are not exclusively breast-fed. METHODS: A Markov model was used to simulate over 6 years the incidence of AD, days with AD symptoms, quality-adjusted life years (QALYs), and AD-related direct and indirect (i.e., parents'/caregivers' productivity loss) costs incurred by hypothetical cohorts of healthy, at-risk infants fed with either PHF-W or SF as AD prevention for <= 17 weeks. Efficacy estimates of PHF-W versus SF in preventing AD were literature-based. The resources used to manage AD (by severity, age, and treatment modality) were estimated using clinical pathways derived from clinical expert opinion. Local costs were applied to resource use. Results were presented as point estimates and as 95 percent credible intervals (CIs, i.e., range of values around the point estimate that include 95% of model simulations) generated via multivariate probabilistic sensitivity analysis using Monte-Carlo simulation techniques. All costs are reported in Philippines pesos (?, where ?1000 = US $22.24). All reported outcomes were discounted at a rate of 3.5% per year. RESULTS: Based on the 6-year simulation, compared with SF, PHF-W was predicted to result in a 14 percentage point reduction (i.e., 39% vs. 25%) (95% CI 0.09-0.19) in the incidence of AD and a gain of 0.03 (i.e., 5.46 vs. 5.43) (95% CI 0.01-0.07) QALYs/patient. PHF-W's higher feeding formula cost (+?1,304/patient) (95% CI ?3,090 to ?5,779) were offset by reductions in AD-related costs ( ?11,959/patient; i.e., ?27,228 vs. ?15,269) (95% CI -?14,685 to -?7,284), including, in particular, the costs of pharmacotherapy, formula used as treatment, and visits to physicians. As a result, PHF-W became a net cost-saving strategy within 38 weeks. Overall, PHF-W resulted in net savings of -?10,654 (-US $237) (CI -?4,240 [-US $94] to -?14,544 [-US $323]) (i.e., ?27,228 [US $606] vs. ?16,574 [US $369]). Sensitivity analysis confirmed the robustness of results; the most influential variable was the first-year risk reduction in AD. CONCLUSIONS: Based on the present modeling exercise, compared with SF, PHF-W appears to substantially reduce the risk of AD and its associated direct and indirect medical costs in healthy, at-risk urban Filipino infants over a 6-year period. PMID- 29702919 TI - Estimating the Long-Term Clinical and Economic Outcomes of Daclatasvir Plus Asunaprevir in Difficult-to-Treat Japanese Patients Chronically Infected with Hepatitis C Genotype 1b. AB - OBJECTIVES: Japan has one of the highest endemic rates of hepatitis C virus (HCV) infection. Treatments in Japan are currently limited to interferon-alfa-based regimens, which are associated with tolerability and efficacy issues. A novel regimen combining two oral HCV therapies, daclatasvir and asunaprevir (DCV + ASV), has shown favorable results in Japanese patients with chronic genotype 1b HCV infection. Comparisons of clinical and economic outcomes associated with DCV + ASV treatment and current standards of care were investigated. METHODS: The MOdelling the NAtural histoRy and Cost-effectiveness of Hepatitis cost effectiveness model projected outcomes in 1000 patients aged 70 years with either chronic hepatitis C or compensated cirrhosis over a lifetime simulation. Japanese specific disease transition rates were used, and discounting was applied annually at a rate of 2%. Efficacy data for DCV + ASV and telaprevir triple therapy (telaprevir + pegylated interferon-alfa + ribavirin [TVR + pegIFN-alpha/RBV]) were obtained from a Japanese subgroup analysis found within a global meta analysis: sustained virological response rates of 74%, 85%, and 87% were reported for null responders (NRs), partial responders (PRs), and interferon-alfa ineligible/intolerant patients, respectively, treated with DCV + ASV, and rates of 42% and 59% were reported for NRs and PRs, respectively, treated with TVR + pegIFN-alpha/RBV. RESULTS: Initiating DCV + ASV treatment in patients in the chronic hepatitis C disease stage resulted in quality-adjusted life-year gains of 0.96 and 0.77 over TVR + pegIFN-alpha/RBV for NRs and PRs, respectively, and a gain of 2.61 in interferon-alfa-ineligible/intolerant patients over no treatment. Similarly, quality-adjusted life-year gains of 1.11, 0.90, and 3.05 were observed when initiating treatment in patients in the compensated cirrhosis stage. Cumulative lifetime events of decompensated cirrhosis, hepatocellular carcinoma, and liver-related mortality were reduced by up to 66, 115, and 128, respectively, with DCV + ASV treatment. CONCLUSIONS: There is a lack of successful therapies for patients with HCV who have previously failed to achieve sustained virological response or are ineligible for interferon-alfa-based therapies. Results demonstrate that the provision of an alternative, interferon-alfa-free regimen, such as DCV + ASV, offers significant value in terms of avoiding life-threatening liver complications and increasing patients' quality of life. PMID- 29702920 TI - Economic Impact of Pneumococcal Protein-D Conjugate Vaccine (PHiD-CV) on the Malaysian National Immunization Programme. AB - OBJECTIVE: To assess the cost-effectiveness of introducing pneumococcal polysaccharide and nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) in the National Immunization Programme of Malaysia. This study compared introducing PHiD-CV (10 valent vaccine) with current no vaccination, as well as against the alternative 13-valent pneumococcal conjugate vaccine (PCV13). METHODS: A lifetime Markov cohort model was adapted using national estimates of disease burden, outcomes of pneumococcal disease, and treatment costs of disease manifestations including pneumonia, acute otitis media, septicemia, and meningitis for a hypothetical birth cohort of 550,000 infants. Clinical information was obtained by review of medical records from four public hospitals in Malaysia from the year 2008 to 2009. Inpatient cost from the four study hospitals was obtained from a diagnostic-related group-based costing system. Outpatient cost was estimated using clinical pathways developed by an expert panel. The perspective assessed was that of the Ministry of Health, Malaysia. RESULTS: The estimated disease incidence was 1.2, 3.7, 70, and 6.9 per 100,000 population for meningitis, bacteremia, pneumonia, and acute otitis media, respectively. The Markov model predicted medical costs of Malaysian ringgit (RM) 4.86 billion (US $1.51 billion) in the absence of vaccination. Vaccination with PHiD-CV would be highly cost-effective against no vaccination at RM30,290 (US $7,407) per quality-adjusted life-year gained. On comparing PHiD-CV with PCV13, it was found that PHiD-CV dominates PCV13, with 179 quality-adjusted life-years gained while saving RM35 million (US $10.87 million). CONCLUSIONS: It is cost effective to incorporate pneumococcal vaccination in the National Immunization Programme of Malaysia. Our model suggests that PHiD-CV would be more cost saving than PCV13 from the perspective of the Ministry of Health of Malaysia. PMID- 29702921 TI - Cost-Effectiveness Analysis of Pneumococcal Vaccination with the Pneumococcal Polysaccharide NTHi Protein D Conjugate Vaccine in the Philippines. AB - OBJECTIVES: To compare the cost-effectiveness of a universal mass vaccination (UMV) program with a 2 + 1 schedule of a 10-valent pneumococcal polysaccharide nontypeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) against two strategies: 1) a no-vaccination strategy and 2) a pneumococcal 13-valent conjugate vaccine (PCV13) 2 + 1 strategy in the Philippines. METHODS: A published Markov cohort model was adapted to simulate the epidemiological and economic burden of pneumococcal diseases (meningitis, bacteremia, pneumonia, and acute otitis media) within a projected birth cohort in 2012 of 1,812,137 newborns over lifetime. Analyses were conducted at an annual discount rate of 5% from the perspective of the Philippine government. The current evaluation was updated with the best available local/regional clinical epidemiological data and published efficacy evidence. RESULTS: Compared with the no-vaccination strategy, the PHiD CV 2 + 1 UMV program was projected to prevent 3,343 deaths due to invasive pneumococcal diseases and pneumonia and 326,862 cases of pneumococcal diseases, resulting in an incremental cost-effectiveness ratio of 50,913 pesos/quality adjusted life-year gained, which was considered to be highly cost-effective according to the threshold recommended by the World Health Organization. In comparison with the PCV13 2 + 1 strategy, the PHiD-CV 2 + 1 strategy was estimated to have a substantial reduction in acute otitis media (127,680 cases) and therefore a cost saving of potential 92.5 million pesos assuming price parity between PHiD-CV and PCV13 (US $1 = 42.13 pesos in 2012). CONCLUSIONS: The PHiD-CV 2 + 1 UMV program is projected to be cost-effective, compared with no vaccination, and would provide substantial savings with higher quality-adjusted life-year gains as compared with the PCV13 2 + 1 strategy in the context of the Philippines. PMID- 29702922 TI - Analysis of a Small Group of Stakeholders Regarding Advancing Health Technology Assessment in India. AB - OBJECTIVES: This study aimed to explore and understand the perspectives of a small group of stakeholders involved in health technology assessment (HTA) for evidence-informed decision making on policy in the Indian health system. METHODS: Semi-structured interviews were conducted in April-June 2013 with policymakers, academicians, industry experts, and community representatives in India to understand their knowledge of, position regarding, and interest in HTA. A semi structured questionnaire was designed on the basis of a World Health Organization framework for evidence-informed health care policymaking. RESULTS: Seven key informant interviews were conducted to represent the various stakeholders. Although there is a good understanding of HTA among the national-level policymakers, academicians, civil society representatives, and industry experts, there is lack of knowledge about the subject among policymakers at the lower level. There is a positive perception about producing and using HTA for decision making among all the stakeholders interviewed. Nevertheless, at the national level, institutions prefer to treat the use of HTA evidence with caution because the capacity for adopting evidence-based tools in the health system is very limited. CONCLUSIONS: This small-size stakeholder analysis suggests a mixed response in implementing HTA in India. There are, however, factors involved in implementing such tools that can be dealt with using various approaches. Finally, there is a positive view on the national level toward pushing the HTA agenda forward to improve the decision-making process in health care. PMID- 29702923 TI - A Year of Significant Progress for Value in Health Regional Issues. PMID- 29702924 TI - The Drug Reimbursement Decision-Making System in Iran. AB - BACKGROUND: Previous studies of health policies in Iran have not focused exclusively on the drug reimbursement process. OBJECTIVE: The aim of this study was to describe the entire drug reimbursement process and the stakeholders, and discuss issues faced by policymakers. METHODS: Review of documents describing the administrative rules and directives of stakeholders, supplemented by published statistics and interviews with experts and policymakers. RESULTS: Iran has a systematic process for the assessment, appraisal, and judgment of drug reimbursements. The two most important organizations in this process are the Food and Drug Organization, which considers clinical effectiveness, safety, and economic issues, and the Supreme Council of Health Insurance, which considers various criteria, including budget impact and cost-effectiveness. Ultimately, the Iranian Cabinet approves a drug and recommends its use to all health insurance organizations. Reimbursed drugs account for about 53.5% of all available drugs and 77.3% of drug expenditures. Despite its strengths, the system faces various issues, including conflicting stakeholder aims, lengthy decision-making duration, limited access to decision-making details, and rigidity in the assessment process. CONCLUSIONS: The Iranian drug reimbursement system uses decision-making criteria and a structured approach similar to those in other countries. Important shortcomings in the system include out-of-pocket contributions due to lengthy decision making, lack of transparency, and conflicting interests among stakeholders. Iranian policymakers should consider a number of ways to remedy these problems, such as case studies of individual drugs and closer examination of experiences in other countries. PMID- 29702926 TI - Evaluation of the Psychometric Properties of the Malay Version of the Minnesota Nicotine Withdrawal Scale. AB - OBJECTIVES: Assessment of nicotine withdrawal symptoms is an essential part of tobacco dependence treatment. This study aimed to evaluate the psychometric properties of a Malay translated version of the Minnesota Nicotine Withdrawal Scale (MNWS). METHODS: The original scale was translated into Malay following the standard guidelines proposed for translation studies. The reliability and validity of the Malay version scale were evaluated on the basis of data collected from 133 participants. The Cronbach's alpha coefficient was calculated to assess the reliability. To validate the psychometric properties of the scale, factor analysis and construct validity were used. This study was conducted at the Quit Smoking Clinic at Penang General Hospital, Penang, Malaysia. RESULTS: The translated scale has excellent reliability, with total Cronbach's alpha of 0.91. The test-retest reliability for the scale presented an excellent reliability and stability of the translated scale with Spearman's rank correlation coefficient (r = 0.876; P < 0.001). There was a significant positive correlation between the exhaled carbon monoxide level, Fagerstrom Test for Nicotine Dependence total score, and number of cigarettes smoked per day and the MNWS total score (r = 0.72, 0.68, and 0.68, respectively; P < 0.001). A principal-components analysis with orthogonal rotation yielded a unidimensional model that includes all the items of the MNWS. CONCLUSIONS: The Malay version of the MNWS is a reliable and valid measure of withdrawal symptoms as well as the smoking urge, and it is applicable to clinical practice and research study. PMID- 29702925 TI - Cost-Effectiveness Analysis of CT Colonography for Colorectal Cancer Screening Program to Working Age in Japan. AB - OBJECTIVES: To assess the cost-effectiveness of computed tomography colonography (CTC) for a colorectal cancer screening program in a working population (aged 40 60 years) from a health care payer's perspective in Japan. METHODS: A Markov model for colorectal cancer was constructed to estimate the long-term (10-year, 20-year, and 30-year) effect of introducing CTC for three different strategies in the cohort aged 40 years on April 1, 2011. Strategy 1 (the current strategy in Japan): fecal occult blood test (FOBT) followed by optical colonoscopy (OC). In this case, 41.8% of those who were FOBT-positive did not undergo OC (uptake 58.2%). Strategy 2: All FOBT-positive cases would be offered CTC (uptake 79.1%) followed by OC. Strategy 3: Only those FOBT-positive cases who were reluctant to undergo OC (41.8%) would be offered CTC (assumed uptake 50.0%) followed by OC. Epidemiological data were obtained mainly from statistics published by the Japanese National Cancer Center. We set quality-adjusted life-year (QALY) as the primary outcome and colorectal cancer death and expected life-years as secondary ones. The discount rate for both costs and outcomes was set at 3%. RESULTS: In the base-case (20-year) analysis, total cost was increased from Japanese yen (JPY) 65,614 million (strategy 1) to JPY 69,405 million (strategy 2) but was decreased to JPY 63,878 million (strategy 3). The total QALY increased from 28,156,046 QALYs (strategy 1) to 28,158,349 (strategy 2) and 28,159,058 QALYs (strategy 3). Therefore, the incremental cost-effectiveness ratio was JPY 1,646,000 per QALY gained for strategy 2 and strategy 3 was dominant against strategy 1, both of which were well below the Japanese threshold (JPY 5-6 million per QALY gained). CONCLUSION: Adding CTC into the current colorectal cancer screening program for the working population seems to be a cost-effective option. PMID- 29702927 TI - Investigation of Evidence Sources for Health-Related Quality of Life in Cost Utility Analysis of Pharmaceuticals in Japan. AB - OBJECTIVE: To provide an overview of how current utility values were obtained in the cost-utility analysis (CUA) for pharmaceuticals in Japan on the basis of methodological guidelines developed in England and Wales, Australia, Canada, France, and Japan by conducting a systematic review of the published literature. METHODS: We searched and reviewed CUAs conducted for pharmaceuticals in Japan, reporting the results as cost per quality-adjusted life-year (QALY). The databases we used were PubMed, EconLit, Centre for Reviews and Dissemination, and the Japan Medical Abstracts Society. The search terms were "QALY" and "Japan" or "cost utility" and "Japan" in the PubMed database, Centre for Reviews and Dissemination, and EconLit. In the search on the Japan Medical Abstracts Society database, we used the term "QALY." RESULTS: In total, 41 CUA articles met the selection criteria and the most common method of obtaining utility values was derived from the published literature (31 CUAs, 168 utility values). Five CUAs were elicited by directly asking the participants regarding their own health state, and four CUAs used "mapping" techniques in which utility values were linked to clinical results. The most commonly used instrument was the EuroQol five-dimensional questionnaire followed by the time-trade-off. A few CUAs mentioned how they selected the literature for the utility values, and some utility values were combined across different sources, using different methods, and obtained from different locations. CONCLUSIONS: Practical methodological guidelines need to be developed to provide standardized methods of presenting the procedure of using utility values from the literature. Although transferability of utility values across jurisdictions has not been discussed fully, this topic should be covered in methodological guidelines and recommend best practices for evaluations. PMID- 29702928 TI - Estimating the Cost-Effectiveness of the 7-Valent Pneumococcal Conjugate Vaccine in Shanghai, China. AB - OBJECTIVE: The goal of this study was to analyze the economic benefits of introducing the 7-valent pneumococcal conjugate vaccine (PCV7) into the City Immunity Program in Shanghai. METHODS: A decision-analytic model designed for pneumococcal disease and outcomes of pneumococcal infection was populated with local, age-specific incidence and cost data to estimate the expected economic benefits from vaccinating a birth cohort of 172,183 infants in Shanghai over a 1 year period using a cross-sectional approach. The analysis was assumed to occur in a year at which time the direct and indirect effects of vaccination have reached a steady state. Costs were calculated from a payer perspective and included vaccination program costs and direct medical expenditures from pneumococcal-related disease. RESULTS: The model predicts that 112,629 cases of pneumococcal-related disease could be prevented during a given year following the introduction of the PCV7 vaccine into the City Immunity Program in Shanghai, leading to a reduction of Y187,923,359 (US $29,067,790) in direct medical costs. Overall, the inclusion of the PCV7 vaccine is estimated to have a cost-per-life year saved of Y37,468 (US $5,796) and a cost-per-quality-adjusted-life-year gained of Y41,603 (US $6,435) when both the direct and indirect effects of the vaccine resulting from herd protection are taken into account. CONCLUSIONS: Results suggest that including PCV7 into the City Immunity Program in Shanghai could be considered cost-effective under generally accepted willingness-to-pay thresholds when both the direct and indirect effects of the vaccine are considered in the analysis. PMID- 29702929 TI - Treatment Costs of Stroke Related to Nonvalvular Atrial Fibrillation Patients in India-A Multicenter Observational Study. AB - OBJECTIVE: The objective of this study was to quantify the direct medical and nonmedical costs of stroke among patients with nonvalvular atrial fibrillation in India. METHODS: An observational, multicenter cost-of-illness study was conducted within large tertiary care hospitals across three metropolitan cities in India. Medical chart records of eligible patients who were hospitalized during the study period were reviewed. A standardized data collection form was designed and used to capture resources expended in the treatment and management of stroke during the inpatient stay. In addition, direct medical and nonmedical outpatient care resources and informal care burden were captured using a detailed questionnaire, following the patients' discharge. Factors associated with acute care costs were investigated using multivariate linear regression analysis. RESULTS: Data were collected on a total of 400 patients with incident strokes. Their mean age was 61.4 +/- 9.4 years. About 84% of the patients were diagnosed with ischemic stroke. On average, patients spent 16 +/- 10 days in the hospital. Total mean direct health care costs per patient amounted to '504,973 (US $8,020) during the first year, with about 47% (mean '235,471; US $3,750) of the total costs due to the index hospitalization. The modified Rankin scale score was strongly associated with costs, whereby severely disabled patients had 32% higher costs (P = 0.001) compared with moderately disabled patients during the first 3 months postdischarge. CONCLUSIONS: Overall, the financial burden associated with medical care for patients with stroke with atrial fibrillation along with rehabilitation and long-term care costs places a significant demand on health services in India. PMID- 29702930 TI - Would It Matter to Expose Elderly Patients Who Took Digoxin to Chinese Medications? AB - OBJECTIVES: Elderly patients seem vulnerable to digoxin toxicity because of their diminished organ functions and tendency to encounter drug interactions. The aim of this research was to explore the extent of the concurrent use of digoxin with Chinese medications (CMs), its contributing factors, and the relevant consequences. METHODS: A retrospective population-based cohort study was conducted using Longitudinal Health Insurance databases in Taiwan. Those elderly patients being prescribed with digoxin in outpatient settings in 2006 were evaluated for the incidence, prevalence, and duration of concurrent use with concentrated CMs in 2006. After 1:1 random matching to select the corresponding digoxin-only elderly users, univariate and multivariate logistic regression analyses were performed to explore factors associated with concomitant incident digoxin-CM use and incident digoxin-specific CM use. The relevant clinical and economic outcomes for a 3-month follow-up period from the initial exposure of incident digoxin-CM use were compared. RESULTS: Of 185,076 elderly, 6,374 were prescribed with digoxin and 789 were CM-digoxin users in 2006. The prevalence and incidence of concomitant CM use among digoxin elderly users were 0.43% and 0.22%, respectively. Although the other factors were not statistically significantly associated with incident CM-digoxin use, patients with heart diseases and with benign prostate hypertrophy had an increased likelihood of incident CM-digoxin use of 115% and 102%, respectively. Almost all the concerned clinical and economic outcomes were not statistically significantly different between incident exposure or not, except for the use of potassium-sparing and nonsteroidal anti inflammatory drugs. CONCLUSIONS: There was a relatively low incidence of digoxin CM use among the elderly in Taiwan. Although no significant effects on clinical and economic outcomes occurred, it is necessary to monitor potential side effects of digoxin more aggressively for those vulnerable elderly using digoxin with CMs, especially for those who tended to expose to incident digoxin-CM use elderly patients. PMID- 29702931 TI - Comparative Analysis of Calendar Time-Specific and Conventional Propensity Score Analysis for Thiazolidinedione Use in Diabetes. AB - OBJECTIVES: To evaluate whether there are differences in propensity score (PS) and treatment effects estimated using conventional and calendar time-specific PS (CTS-PS) approaches. METHODS: A retrospective database analysis at a university affiliated hospital in Thailand was used. Diabetic patients receiving glucose lowering medications from July 2008 to June 2011 were included. Patients were categorized into those exposed and not exposed to thiazolidinediones (TZDs). PSs were estimated by using conventional PS and CTS-PS. In the CTS-PS, PS was separately estimated for three specific calendar time periods. Patients were matched 1:1 using caliper matching. The outcomes were cardiovascular and all cause hospitalizations. The TZD and non-TZD groups were compared with Cox proportional hazard models. RESULTS: A total of 2165 patients were included. The average conventional PS was 0.198 (95% confidence interval [CI] 0.195-0.202), while the average PS in the CTS-PS approach was 0.212 (0.206-0.218), 0.180 (0.173 0.188), and 0.205 (0.197-0.213) for July 2008 to June 2009, July 2009 to June 2010, and July 2010 to June 2011, respectively. The average difference in PS was 0.012 (P < 0.001), -0.009 (P <= 0.002), and 0.000 (P = 0.950) in the three calendar time periods. The adjusted hazard ratios of the conventional PS-matched cohort were 0.97 (95% CI 0.39-2.45) and 0.97 (95% CI 0.78-1.20) for CVD-related and all-cause hospitalizations, while the adjusted hazard ratios of the CTS-PS matched cohort were 1.11 (95% CI 0.43-2.88) and 1.12 (95% CI 0.91-1.39), respectively. CONCLUSION: CTS-PS is different from PS estimated by using the conventional approach. CTS-PS should be considered when a pattern of medication use has changed over the study period. PMID- 29702932 TI - "Socialization of Health Care" in Vietnam: What Is It and What Are Its Pros and Cons? PMID- 29702933 TI - Assessment of Preference for Hormonal Treatment-Related Health States among Patients with Breast Cancer. AB - OBJECTIVES: 1) To obtain preference scores from patients with breast cancer in Singapore for different stages of breast cancer and hormonal therapy-related adverse effects, and 2) to determine the association of patients' demographic and clinical characteristics with those preference scores. METHODS: A total of 22 health states were used to elicit preference values from 64 patients with breast cancer. At each interview, 14 health states were randomly selected and rated by the patient using the visual analogue scale and standard gamble methods to derive health state preference scores, which were recalibrated to the scale of 0 (death) and 1 (perfect health). RESULTS: Mean adjusted visual analogue scale scores ranged from 0.25 (no recurrence with ischemic cerebrovascular events) to 0.82 (no recurrence with no adverse effects). Mean adjusted standard gamble scores ranged from 0.31 (distant recurrence with chemotherapy-related adverse effects) to 0.80 (no recurrence with no adverse effects). Adverse effects ischemic cerebrovascular events and spine fracture resulted in the greatest decline in health state preference scores. Age, ethnicity, education level, and prior chemotherapy were associated with preference scores. Having children was not found to be associated with the preference scores. CONCLUSIONS: Taking into account disease progression and hormonal therapy-related adverse effects as well as their impact on health related quality of life, this study quantifies patients' preference for various breast cancer-related health states. The findings offer valuable information for future cost-utility analysis of breast cancer treatments. PMID- 29702934 TI - Economic Burden of Diabetes Mellitus on Patients with Respiratory Failure Requiring Mechanical Ventilation during Hospitalizations. AB - OBJECTIVES: To examine the economic burden of diabetes mellitus (DM) on medical expenditure among patients with respiratory failure (RF) requiring mechanical ventilation during hospitalization. METHODS: We extracted the data from Taiwan National Health Research Insurance Database for those adult patients on their first hospitalization for RF requiring mechanical ventilation between 2004 and 2010. We examined associations between medical expenditure and the presence of comorbid DM. We performed independent t tests, chi-square tests, and multivariate linear regression analysis to identify factors associated with excess medical expenditure. RESULTS: Of 347,961 patients hospitalized with first occurrence of RF requiring mechanical ventilation, 123,023 (35.36%) patients were documented to have a previous diagnosis of DM. Patients with RF and DM were sicker and consumed more health care resources than did patients with RF without DM. After adjusting for the specified covariates, mechanically ventilated patients with RF and DM consumed at least US $618 more of total inpatient medical expenditure than did patients with RF without DM. There were statistically significant interactions between age and DM on their total inpatient medical expenditure regardless of discharge status. CONCLUSIONS: DM was associated with more severe disease status and higher consumption of medical expenditure during hospitalizations among mechanically ventilated patients due to first occurrence of RF in Taiwan. These findings provide scientific evidence to facilitate appropriate resource allocation and formulate programs for higher quality of care in the future in Taiwan and other countries. PMID- 29702935 TI - Epidermal Growth Factor Receptor Mutation Testing in Thailand: A Cost-Utility Analysis. AB - OBJECTIVE: To evaluate the cost utility of epidermal growth factor receptor (EGFR) testing plus first-line gefitinib treatment in patients with activating EGFR mutations in Thailand. METHODS: The study used a decision tree model considering the provider's perspective. Direct medical costs were included and based on a local Thai database. Effectiveness was measured as quality-adjusted life-year and based on randomized controlled trials. Incremental cost effectiveness ratio was calculated and presented in 2012. A series of one-way sensitivity analyses were conducted. RESULTS: We found that the EGFR testing plus first-line gefitinib alternative gained 0.03 quality-adjusted life-year more, but 62,540 Thailand baht (US $2082.58) less total costs compared with the no-testing alternative. The results were robust when varying most variables in the model except for the duration of gefitinib treatment with activating EGFR mutation, the duration of chemotherapy treatment with activating EGFR mutation, and the utility of second-line chemotherapy. CONCLUSIONS: EGFR testing should be considered before administering EGFR tyrosine-kinase inhibitor such as gefitinib as first line treatment in patients with non-small cell lung cancer in Thailand where the incidence of EGFR mutation is high. PMID- 29702936 TI - Cost-Utility Analysis of Erythropoietin for Anemia Treatment in Thai End-Stage Renal Disease Patients with Hemodialysis. AB - OBJECTIVE: To compare the cost utility of using erythropoietin (EPO) to maintain different hemoglobin (Hb) target levels in hemodialysis patients from a societal perspective. METHODS: A Markov model was used to estimate the incremental cost and quality-adjusted life-year of five Hb levels: 9 or less, more than 9 to 10, more than 10 to 11, more than 11 to 12, and more than 12 g/dl. A systematic review of EPO treatment in hemodialysis patients was conducted to estimate transitional probabilities. Cost data were estimated on the basis of the reference price of Siriraj Hospital, the largest university hospital in Thailand. Utility scores were derived from the six-dimensional health state short form (derived from short-form 36 health survey), which were collected from 152 hemodialysis patients receiving EPO at Siriraj hospital. Probabilistic sensitivity analysis was conducted to investigate the effect of uncertain parameters. All future costs and outcomes were discounted at the rate of 3% per annum. RESULTS: The incremental cost-effectiveness ratios of Hb levels more than 9 to 10, more than 10 to 11, more than 11 to 12, and more than 12 g/dl compared with the least costly option (Hb <= 9 g/dl) were US $24,128.03, US $18,789.07, US $22,427.36, and US $28,022.33 per quality-adjusted life-year, respectively. From probabilistic sensitivity analysis, the hemoglobin level of more than 10 to 11 g/dl was appropriate when the willingness to pay was US $15,523.88 to US $46,610.17 and the probability of cost-effective was 29.32% to 95.94%. CONCLUSIONS: Providing EPO for a hemoglobin level of more than 10 to 11 g/dl had a cost-effectiveness higher than that of doing so for other hemoglobin levels. This finding will be put forward to the policy level to set up the EPO treatment guideline of the hospital for hemodialysis patients. PMID- 29702937 TI - Estimating the Incidence and Prevalence of Chronic Hepatitis C Infection in Taiwan Using Back Projection. AB - OBJECTIVE: Hepatitis C virus (HCV) infection is the leading cause of liver disease, and Taiwan has among the highest prevalence of HCV infection in the general population in Northeast Asia, estimated at between 2% and 4%. The aim of this study was to estimate the number of patients living with chronic HCV infection in Taiwan and quantify the expected numbers in each of the five Metavir fibrosis stages. METHODS: We applied a back-projection approach, using observed hepatocellular carcinoma incidence between 1979 and 2008 and a smoothed Expectation-Maximization algorithm to maximize a Poisson likelihood to estimate the previous incidence of HCV infection. The algorithm was coded in Excel and combined with the MOdelling the NAtural histoRy and Cost-effectiveness of Hepatitis model (a hepatitis C natural history markov model) to predict the past and future numbers in each Metavir fibrosis stage. RESULTS: Incident cases were predicted to have peaked in 1972 at 56,634 annually, with the prevalence peaking in 1986 at 763,737 infections and falling to 578,203 infections in 2012. It was estimated that in 2012, 127,795 (23.0%), 105,545 (19.0%), 81,211 (14.6%), 123,939 (22.3%), and 116,823 (21.1%) subjects were in fibrosis stages F0, F1, F2, F3, and F4, respectively. DISCUSSION: Our study provides HCV infection prevalence estimates, stratified by Metavir fibrosis stage, in Taiwan for 2012. This has potential implications for budget planning, particularly with the availability of emerging therapies because fibrosis stage is predictive of both rapid and sustained virological response; therefore, planning expected treatment response in a given population could be enhanced with this additional information. PMID- 29702939 TI - A Cost-Utility Analysis Comparing Standard Axillary Lymph Node Dissection with Sentinel Lymph Node Biopsy in Patients with Early Stage Breast Cancer in Thailand. AB - OBJECTIVES: In Thailand, axillary lymph node dissection (ALND) is the dominant form of treatment for breast cancer, even though the treatment often leaves patients with some degree of arm morbidity. Sentinel lymph node biopsy (SNB) is widely accepted globally as a preferable alternative procedure because of its lower rates of associated morbidity. This study compared the cost-utility of SNB and ALND in patients with early stage breast cancer in Thailand. METHODS: A decision tree with a 5-year time horizon was developed. Outcomes that were relevant to SNB and ALND were included, along with locoregional recurrence of cancer and lymphedema scenarios. The model parameters were derived from a meta analysis of international clinical trials and other relevant literature. The resources and cost data were derived from the medical records of tertiary hospitals. Health utilities were measured by using the standard gamble technique. A sensitivity analysis was performed using a set of plausible parameters. RESULTS: The incremental cost-effectiveness ratio (ICER) in the base-case analysis showed that SNB was more cost-effective than ALND. ICERs were -275,140 and -470,600 Thailand baht/quality-adjusted life-year gained from the provider perspective and the societal perspective, respectively. The most sensitive parameter was the utility score of patients with early stage breast cancer who had received breast-conserving therapy with lymphedema; the sensitivity and specificity of SNB had no impact on the ICER. CONCLUSIONS: The study confirmed that SNB was an economically viable alternative treatment to ALND. In developing countries, where resources are limited, nationwide implementation of SNB warrants widespread support from relevant stakeholders, including medical personnel and policymakers. PMID- 29702938 TI - The Patient-Related Burden of Pegylated-Interferon-alpha Therapy and Adverse Events among Patients with Viral Hepatitis C in Japan. AB - OBJECTIVES: Pegylated-interferon-alpha (IFN-alpha)-based therapies for viral hepatitis C (HCV) are effective, but they are associated with several adverse events (AEs). The primary objectives of this study were to quantify the burden of IFN-alpha-based treatment and to measure the prevalence and burden of IFN-alpha related AEs in Japan. METHODS: A cross-sectional survey was administered online to patients with HCV in 2013. Patients who were currently taking IFN-alpha-based therapy (n = 188) were compared with patients who were taking a liver protectant but not IFN-alpha-based therapy (n = 180) and with patients who were untreated (n = 365) on measures of health-related quality of life (using the Hepatitis Quality of Life Questionnaire, version 2), work productivity, and health care resource use, controlling for sociodemographic characteristics and health history. Among patients taking IFN-alpha-based therapy, the prevalence and burden of AEs was examined on the same set of health outcomes as noted above along with treatment satisfaction and adherence. RESULTS: Compared with untreated patients, patients using IFN-alpha reported poorer health-related quality of life (physical component summary score, 50.13 vs. 52.04; mental component summary score, 44.12 vs. 47.97), more overall work impairment (32.73 vs. 25.64), more physician visits in the past 6 months (14.51 vs. 8.36), and an increased likelihood of an emergency room visit (odds ratio = 7.25) and hospitalization (odds ratio = 4.05) (all P < 0.05). The mean number of AEs was 6.05 for patients using IFN-alpha. All AEs were associated with poorer health outcomes (particularly the mental component summary score), and most were also associated with lower treatment satisfaction and medication adherence. CONCLUSIONS: A significant patient burden for IFN-alpha treatment itself and various AEs was observed. The results suggest that effective, non-IFN-alpha-based treatments may reduce the societal burden. PMID- 29702940 TI - Assessment of Effect of Diabetes on Health-Related Quality of Life in Patients with Coronary Artery Disease Using the EQ-5D Questionnaire. AB - OBJECTIVE: To assess the influence of diabetes on health-related quality of life (HRQOL) in patients with coronary artery disease (CAD) and identify predictors of health status at 1-year follow-up after an acute coronary event. METHODS: A prospective cohort study in patients diagnosed with CAD at a tertiary care hospital from India. The EuroQol five-dimensional (EQ-5D) questionnaire was administered at 1-year follow-up. Multivariate stepwise liner regression was used to assess predictors of EQ visual analogue scale (VAS) and EQ-5D questionnaire utility scores. Respondents reporting problems on the EQ-5D questionnaire were stratified by the presence of diabetes at baseline for comparison. RESULTS: Of 960 (30% diabetic) patients with CAD enrolled in a main study cohort, 306 (76% males, 21% diabetic) responded to the HRQOL questionnaire at 1 year. Diabetic patients reported more difficulties/problems than did nondiabetic patients for EQ 5D questionnaire dimensions (mobility, 12.3% vs. 4.1%, P = 0.03; usual activities, 56.9% vs. 41.3%, P = 0.03; pain/discomfort, 50.8% vs. 17.8%, P < 0.001; anxiety/depression, 33.8% vs. 14.9%, P < 0.001), except for self-care (12.3% vs. 17.5%, P = 0.35). Mean +/- SD EQ VAS and EQ-5D questionnaire utility scores were significantly lower for patients with CAD with diabetes versus those without diabetes (0.75 +/- 0.15 vs. 0.83 +/- 0.15, P = 0.0002, and 67.8 +/- 8.8 vs. 73.6 +/- 5.4, P = 0.0001, respectively). Presence of diabetes, use of beta blockers on discharge, and treatment strategy significantly influenced the VAS score, whereas myocardial infarction as final diagnosis and the presence of prior CHF predicted worse EQ-5D questionnaire utility scores. CONCLUSIONS: The poorer HRQOL as assessed by the EQ-5D questionnaire among patients with CAD who had diabetes highlights the need of individualized treatment programs to improve outcomes in this most vulnerable population. PMID- 29702941 TI - Cost-Utility Analysis of Home-Based Care for Treatment of Thai Hemophilia A and B. AB - OBJECTIVE: This study aimed to evaluate the cost-utility of the home-based care policy versus the no home-based care policy of factor VIII and factor IX concentrate in Thai patients with hemophilia A and B who had no inhibitor or less than 5 Bethesda units. METHODS: A Markov model was used to evaluate the cost utility of the two policies. The first policy was "no home-based care" in which patients were treated with blood components only when admitted at the hospital but without home treatment. The second policy was "home-based care" in which factors were prescribed and infused for treatment of early bleeding episodes at home. Input parameters related to clinical and cost were obtained from primary data collection at the National Health Security Office, while patients' quality of life was surveyed from mailed questionnaires. Both costs and health outcomes were discounted at 3%. One-way analysis and probabilistic sensitivity analysis were performed to assess uncertainty surrounding model parameters. RESULTS: Based on governmental perspective, the "home-based care" policy had cost saving in patients with moderate and severe hemophilia when compared with the "no home based care" policy; in patients with mild hemophilia, the incremental cost effectiveness ratio was 80,542 Thailand baht (THB) or US $2,684.73 (US $1 = 30 THB). CONCLUSIONS: At the ceiling threshold of one time of gross domestic product per capita (120,000 THB per quality-adjusted life-year gained), the "home-based care" policy was cost-effective when compared with the "no home-based care" policy. PMID- 29702942 TI - A Systematic Review on the Extent and Quality of Pharmacoeconomic Publications for China. AB - OBJECTIVES: To evaluate the extent and quality of published pharmacoeconomic studies based in China. METHODS: A systematic literature search was conducted using PubMed, Web of Science, Google Scholar, and China National Knowledge Infrastructure to identify pharmacoeconomic studies conducted in China. The keywords included different combinations of health economics, pharmacoeconomic, cost-effectiveness, and China. The inclusion criteria for the studies were: 1) original research articles; 2) written/published in English; 3) comparing a pharmaceutical to another pharmaceutical, treatment modality, or no treatment; and 4) conducted in China. The articles were reviewed by two independent reviewers using the 100-point Quality of Health Economic Studies scale for pharmacoeconomic studies. General and economic analysis information was collected from the articles. RESULTS: A total of 20 studies were included, which were published in 11 different journals between 2006 and 2012 and had an average of 5 +/- 2 authors. The mean Quality of Health Economic Studies scale scores for pharmacoeconomic studies was 80 +/- 10. More than two-thirds of the authors resided in China (70%) and most had a medical background (90%). Most studies were published in foreign journals (not based in China) (90%), conducted cost effectiveness (65%) or cost-utility analyses (65%), and used modeling as their study design (80%). CONCLUSIONS: China-based pharmacoeconomic studies written in English are limited in number, but, on average, are of good quality. Economic evaluation of pharmaceuticals should be encouraged in China because appropriate allocation of health care resources is important in a country where, despite economic growth, resources remain scarce relative to needs. PMID- 29702943 TI - Models to Predict the Burden of Cardiovascular Disease Risk in a Rural Mountainous Region of Vietnam. AB - OBJECTIVE: To compare and identify the most appropriate model to predict cardiovascular disease (CVD) in a rural area in Northern Vietnam, using data on hypertension from the communities. METHODS: A cross-sectional survey was conducted including all residents in selected communities, aged 34 to 65 years, during April to August 2012 in Thai Nguyen province. Data on age, sex, smoking status, blood pressure, and blood tests (glucose, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol) were collected to identify the prevalence of high blood pressure and to use as input variables for the models. We compared three models, Asian, Chinese Multiple-provincial Cohort Study (CMCS), and Framingham, to estimate cardiovascular risk in the coming years in this context and compare these models and outcomes. RESULTS: The prevalence of high blood pressure in these communities was lower than reported nationally (12.3%). CVD risk differed greatly depending on the model applied: approximately 21% of the subjects according to the CMCS and Asian models, but 37% using the Framingham model, had more than 10% risk for CVD. In the group without current CVD, these numbers decreased to 9% using the CMCS and Asian models but increased to 28% according to the Framingham model. There were no significant differences between the Asian and CMCS models, but differences were highly significant when comparing Asian versus Framingham or CMCS versus Framingham model. CONCLUSIONS: The Asian and CMCS models provided similar results in predicting CVD risk in the Vietnamese population in Thai Nguyen. The Framingham model provided vastly different results. The suggestion may be that for the specific Vietnamese setting, the Asian and CMCS models provide most valid and reliable results; however, this has to be investigated in further analyses using real-life data for potential confirmation. PMID- 29702945 TI - Reviewer Acknowledgement. PMID- 29702944 TI - Cost-Effectiveness of Linezolid versus Vancomycin among Patients with Methicillin Resistant Staphylococcus aureus Confirmed Nosocomial Pneumonia in China. AB - OBJECTIVE: To estimate the cost-effectiveness of intravenous linezolid as a first line agent against intravenous vancomycin in treating methicillin-resistant Staphylococcus aureus-confirmed nosocomial pneumonia in four Chinese cities. METHODS: A decision-analytic model of 4-week time horizon was used to conduct cost-effectiveness analyses from the payer's perspective. Clinical outcomes and resource use data were derived from a head-to-head trial, supplemented with local cost estimates based on hospital data via an expert panel. A series of scenario analyses were conducted to evaluate the impact of uncertainty around model inputs. All results were reported in 2012 Chinese Renminbi. RESULTS: The predicted probability of overall treatment success was 0.629 and 0.602 for linezolid and vancomycin, respectively. Total inpatient costs varied across the four cities, ranging from Y58,835 to Y86,894 for linezolid and Y58,390 to Y87,033 for vancomycin, respectively. Linezolid was demonstrated to be a dominant treatment strategy in Guangzhou. In Beijing, Nanjing, and Xi'an, incremental cost effectiveness ratios in terms of additional successfully treated patient were Y1,861, Y163, and Y16,509, respectively. Dominance by linezolid was observed in some scenario analyses with parameters such as treatment duration, inclusion of cost of managing adverse events, and drug acquisition costs being the main drivers of cost-effectiveness results. CONCLUSIONS: Despite linezolid's higher drug acquisition cost, its superior clinical efficacy renders it a likely cost effective alternative for the treatment of methicillin-resistant Staphylococcus aureus-confirmed nosocomial pneumonia as compared with branded vancomycin from the payer perspectives of Beijing, Guangzhou, Nanjing, and Xi'an. PMID- 29702946 TI - Virtual Line Between Anterior Clinoid Process and Tuberculum Sellae on 3 Dimensional Computed Tomography Angiography to Differentiate Cavernous Sinus Aneurysms from Intradural Aneurysms. PMID- 29702947 TI - Letter to the Editor Regarding "The Likelihood of Remnant Nonfunctioning Pituitary Adenomas Shrinking Is Associated with the Lesion's Blood Supply Pattern". PMID- 29702948 TI - Letter to the Editor Regarding "Evaluation of Continuous Irrigation and Drainage with a Double-Cavity Sleeve Tube to Treat Brain Abscess". PMID- 29702949 TI - Probiotics: Novel Addition to Antiglioma Armamentarium. PMID- 29702950 TI - In Reply to the Letter to the Editor "Probiotics: Novel Addition to Antiglioma Armamentarium". PMID- 29702951 TI - Letter to the Editor Regarding "Endovascular Thrombectomy Alone versus Combined with Intravenous Thrombolysis". PMID- 29702952 TI - Postoperative Residue Pneumocephalus Progress to Tension After Observation for 9 Years. PMID- 29702953 TI - In Reply to "Postoperative Residue Pneumocephalus Progress to Tension After Observation for 9 Years". PMID- 29702954 TI - Letter to the Editor Regarding "Symptomatic Brainstem Cavernoma of Elderly Patients: Timing and Strategy of Surgical Treatment: Two Case Reports and Review of the Literature". PMID- 29702955 TI - In Reply to the Letter to the Editor Regarding "Symptomatic Brainstem Cavernoma of Elderly Patients: Timing and Strategy of Surgical Treatment: Two Case Reports and Review of the Literature". PMID- 29702956 TI - Letter to the Editor Regarding "Fluorescein-Guided Resection of Intramedullary Spinal Cord Tumors: Results from a Preliminary, Multicentric, Retrospective Study". PMID- 29702957 TI - In Reply to the Letter to the Editor Regarding ""Fluorescein-Guided Resection of Intramedullary Spinal Cord Tumors: Results from a Preliminary, Multicentric, Retrospective Study". PMID- 29702958 TI - Relationship Between Perforator Infarction and Patient Outcomes After Surgical Treatment of Ruptured Anterior Communicating Artery Aneurysms. PMID- 29702959 TI - In Reply to "Relationship Between Perforator Infarction and Patient Outcomes After Surgical Treatment of Ruptured Anterior Communicating Artery Aneurysms". PMID- 29702960 TI - Defining the Pros and Cons of AIS Surgery: Bringing Truth to the Neurosurgery Community and the Public. PMID- 29702961 TI - In Reply to "Defining the Pros and Cons of AIS Surgery: Bringing Truth to the Neurosurgery Community and the Public". PMID- 29702962 TI - Feasibility of Using Internal Thoracic Artery as Donor Vessel in High-Flow Intracranial Bypass Surgery. PMID- 29702963 TI - In Reply to "Feasibility of Using Internal Thoracic Artery as Donor Vessel in High-Flow Intracranial Bypass Surgery". PMID- 29702964 TI - In Reply to the Letter to the Editor Regarding "Aneurysm Clip Compression Technique in the Surgery of Aneurysms With Hard/Calcified Neck". PMID- 29702965 TI - Neurosurgery in East Africa: Foundations. AB - This article is the first in a series of 3 articles that seek to provide readers with an understanding of the development of neurosurgery in East Africa (Foundations), the challenges that arise in providing neurosurgical care in developing countries (Challenges), and an overview of traditional and novel approaches to overcoming these challenges to improve healthcare in the region (Innovations). We review the history and evolution of neurosurgery as a clinical specialty in East Africa. We also review Kenya, Uganda, and Tanzania in some detail and highlight contributions of individuals and local and regional organizations that helped to develop and shape neurosurgical care in East Africa. Neurosurgery has developed steadily as advanced techniques have been adopted by local surgeons who trained abroad, and foreign surgeons who have dedicated part of their careers in local hospitals. New medical schools and surgical training programs have been established through regional and international partnerships, and the era of regional specialty surgical training has just begun. As more surgical specialists complete training, a comprehensive estimation of disease burden facing the neurosurgical field is important. We present an overview with specific reference to neurotrauma and neural tube defects, both of which are of epidemiologic importance as they gain not only greater recognition, but increased diagnoses and demands for treatment. Neurosurgery in East Africa is poised to blossom as it seeks to address the growing needs of a growing subspecialty. PMID- 29702966 TI - The Growth of Neurosurgery in East Africa: Challenges. AB - As the second of 3 articles in this series, the aim of this article is to provide readers with an understanding of the development of neurosurgery in East Africa (foundations), the challenges that arise in providing neurosurgical care in developing countries (challenges), and an overview of traditional and novel approaches to overcoming these challenges and improving health care in the region (innovations). Recognizing the challenges that need to be addressed is the first step to implementing efficient and qualified surgery delivery systems in low- and middle-income countries. We reviewed the major challenges facing health care in East Africa and grouped them into 5 categories: 1) burden of surgical disease and workforce crisis; 2) global health view of surgery as "the neglected stepchild"; 3) need for recognizing the surgical system as an interdependent network and importance of organizational and equipment deficits; 4) lack of education in the community, failure of primary care systems, and net result of overwhelming tertiary care systems; 5) personal and professional burnout as well as brain drain of promising human resources from low- and middle-income countries in East Africa and similar regions across the world. Each major challenge was detailed and analyzed by authors who have worked or are currently working in the region, providing a personal perspective. PMID- 29702967 TI - Neurosurgery in East Africa: Innovations. AB - In the last 10 years, considerable work has been done to promote and improve neurosurgical care in East Africa with the development of national training programs, expansion of hospitals and creation of new institutions, and the foundation of epidemiologic and cost-effectiveness research. Many of the results have been accomplished through collaboration with partners from abroad. This article is the third in a series of articles that seek to provide readers with an understanding of the development of neurosurgery in East Africa (Foundations), the challenges that arise in providing neurosurgical care in developing countries (Challenges), and an overview of traditional and novel approaches to overcoming these challenges to improve healthcare in the region (Innovations). In this article, we describe the ongoing programs active in East Africa and their current priorities, and we outline lessons learned and what is required to create self sustained neurosurgical service. PMID- 29702968 TI - Dogma, Cost, and Health Care. PMID- 29702969 TI - Value of [18F]FDG-PET/CT and CA125, serum levels and kinetic parameters, in early detection of ovarian cancer recurrence: Influence of histological subtypes and tumor stages. AB - To assess the diagnostic accuracy of CA125, its kinetic values and positron emission tomography/computed tomography with 2-deoxy-2-[F]fluoro-D-glucose ([F]FDG-PET/CT), in relation with tumor characteristics for suspected recurrence of ovarian cancer. To evaluate the performance of CA125-related parameters as a selection criteria to perform a [F]FDG-PET/CT.A retrospective analysis of 69 [F]FDG-PET/CT for suspected recurrence of ovarian cancer was performed. All patients had 2 measurements of CA125, before PET/CT, to calculate kinetic values, as CA125vel (CA125vel = [CA125a - CA125b]/time) and CA125dt (CA125dt = [log2 * time]/[logCA125a - CA125b]). Maximum standard uptake value (SUVmax) was calculated. The diagnostic accuracy was calculated for all the variables and the optimal cut-off value of each of them by the receiver-operating characteristics (ROC) analysis. All the tests were compared with tumor characteristics and clinical-radiological evolution during follow-up of at least 6 months.Fifty-five cases were diagnosed of recurrence (11 with CA125 <35 U/mL), while 14 showed no disease (11 with CA125 < 35 U/mL). All of them were correctly cataloged by PET/CT. CA125, CA125vel, and SUVmax showed higher levels in recurrent patients (mean 129.54 U/mL, 24.58 U/mL per mo, and 8.69 g/mL, respectively) than in nonrecurrent (mean 20.35 U/mL, 0.60 U/mL per mo, and 0.64 g/mL, respectively). No statistical differences in CA125dt were found. Patients with recurrence of high grade serous carcinoma (HGSC) showed higher CA125 and CA125vel, without differences in the rest of subtypes and International Federation of Gynecology and Obstetrics stages. The ROC analyses for CA125, CA125vel, and CA125dt showed an area under the curve (AUC) of 0.873 (95% confidence interval [CI] 0.77-0.969), 0.903 (95% CI 0.813-0.994), and 0.727 (95% CI 0.542-0.913), respectively, with an optimal cut-off point of 23.95 U/mL, 4.49 U/mL per mo, and 3.36 months, respectively, while for the SUVmax the AUC was of 0.982 (95% CI 0.948-1.000), and the cut-off point of 2. Multivariate regression analysis identified CA125 and CA125vel as predictors of recurrence.[F]FDG-PET/CT is more accurate than the parameters obtained from the CA125 to detect early recurrence. CA125vel is the most suitable parameter, mainly in HGSC. Levels of CA125vel >= 4.49 U/mL per mo facilitate earlier detection by the execution of a [F]FDG-PET/CT. The calculation of these parameters is independent of tumor stage at diagnosis. PMID- 29702970 TI - A new intensive conditioning regimen for allogeneic hematopoietic stem cell transplantation in patients with refractory or relapsed acute myeloid leukemia. AB - To explore the efficacy, and safety of the intensive conditioning regimen consisting of cladribine, cytarabine (Ara-C), and granulocyte colony-stimulating factor (G-CSF) plus modified busulfan (Bu) combined with cytoxan (Cy) (BuCy), prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with refractory, or relapsed acute myeloid leukemia (R/R AML).Thirty-Six R/R AML patients scheduled to receive allo-HSCT were consecutively, enrolled in this prospective study, and treated using intensive conditioning regimen consisting of CLAG plus modified BuCy. Median follow-up duration was 11.25 (range 0.5 - 21.0) months and the last follow up date was August 15, 2017.All patients (100%) achieved white blood cell (WBC) recovery within a median time of 16.00 (13.25 - 18.00) days, and 34 of them (94%) attained platelet (PLT) recovery within a median time of 13.50 (9.25 - 19.75) days. Incidence of acute graft versus-host disease (aGVHD) was 50.00%, with median time of 71.50 (41.00 - 401.25) days. Three patients developed Grade I; nine, Grade II; 5, Grade III; and 1, Grade IV aGVHD. The incidence of chronic GVHD (cGVHD) was 44.40%, with median time of 255.00 (120.00 - 390.00) days. Four patients developed limited cGVHD, and 12, extensive cGVHD. One-year accumulating leukemia free survival (LFS), and overall survival (OS) rates between 52.9 +/- 8.8% to 69.4 +/- 7.7%, respectively. Eighteen (50%) patients were infected with cytomegalovirus; 2 (5.6%), with Epstein-Barr virus (EBV), 7 (19.4%), with hemorrhagic cystitis; 13 (36.1%), with bacteria; and 8 (22.2%), with fungus.Intensive conditioning regimen of CLAG plus modified BuCy for allo-HSCT may be effective and well-tolerated in R/R AML patients. PMID- 29702972 TI - Microsurgery for patients diagnosed with neurofibromatosis type 2 complicated by vestibular schwannomas: Clinical experience and strategy for treatments. AB - Most patients diagnosed with neurofibromatosis type 2 (NF2) have bilateral vestibular schwannomas (VS). Through reviewing surgical method and clinical outcomes, we tried to find out a strategy for treatments in NF2 patients with VS.We retrospectively reviewed patients diagnosed pathological NF2 and have had microsurgery (MS) for VS in the PLA Army General Hospital. Seventeen patients were included from January 2000 to December 2016. Fifteen patients had progressive hearing impairment, and 7 ears were totally deaf. Computed tomography and magnetic resonance imaging were used for preoperative and postoperative evaluation. House-Brackmann (H-B) classification was used to evaluate facial function, and the hearing outcome was classified according to American Academy of Otolaryngology-Head and Neck Surgery (AAO-HNS) hearing classification system. The outcomes included functional hearing, facial function, and complications.In the 17 patients, 9 were men, and the mean age was 27.2 years old. The mean duration of disease was 38.4 months. Twenty-six VS were excised. Nine patients with bilateral VS and unilateral surgery had repeated surgery for the contralateral tumor after 3 to 12 months. The hearing preservation rate was 41.6%. In the 26 excisions for VS, 24 had intact facial nerve. In the other 2 tumor excision, damaged facial nerves had head-to-head adhesion using biological fibrin glue. The rate of facial nerve function preservation was 60%. No mortality or major complication was reported. The follow-up time ranged from 11 to 78 months with a mean value of 39 months.MS is an effective treatment for NF2 patients with VS. The operation for bilateral VS should be staged according to tumor size and bilateral hearing function. However, methods on how to preserve functional hearing and facial function remain the issue. Further randomized controlled studies are needed to find out a better treatment for NF2 patients with VS according to the overall condition. PMID- 29702971 TI - Plasma rich in growth factors membrane as coadjuvant treatment in the surgery of ocular surface disorders. AB - To evaluate the safety and efficacy of the surgical use of plasma rich in growth factors fibrin membrane (mPRGF) in different ocular surface pathologies.Fifteen patients with different corneal and conjunctival diseases were included in the study. Patients were grouped according to the use of mPRGF as graft (corneal and/or conjunctival) or dressing; they were also grouped according to the surgical subgroup of intervention (persistent corneal ulcer [PCU], keratoplasty, superficial keratectomy, corneal perforation, and pterygium). Best corrected visual acuity, intraocular pressure (IOP), inflammation control time (ICT), mPRGF AT (PRGF membrane absorption time), and the healing time of the epithelial defect (HTED) were evaluated throughout the clinical follow-up time. Safety assessment was also performed reporting all adverse events.mPRGF showed a total closure of the defect in 13 of 15 patients (86.7%) and a partial closure in 2 patients (13.3%). The mean follow-up time was 11.1 +/- 4.2 (4.8-22.8) months, the mean ICT was 2.5 +/- 1.1 (1.0-4.0) months, the mean mPRGF AT was 12.4 +/- 2.0 (10.0-16.0) days, and for the global HTED the mean was 2.9 +/- 1.2 (1-4.8) months. Results showed an improvement in BCVA in all patients, with an overall improvement of 2.9 in Vision Lines. The BCVA significantly improved (P < .05) in the groups of corneal graft and dressing. In the PCU subgroup (6 patients), the healing time of epithelial defect was significantly reduced (P < .05) in patients treated only with the mPRGF in comparison to those which mPRGF therapy was associated to the amniotic membrane. The IOP remained stable (P > .05) throughout the clinical follow-up time. No adverse events were reported after mPRGF use.The mPRGF is effective and safe as coadjuvant treatment in surgeries related with ocular surface disorders, being an alternative to the use of amniotic membrane. The mPRGF accelerates tissue regeneration after ocular surface surgery thus minimizing inflammation and fibrosis. PMID- 29702974 TI - Case report of the successful treatment of lung injury caused by occupational exposure to methyl chloroformate and literature review. AB - BACKGROUND: The treatment of acute lung injuries caused by the inhalation of methyl chloroformate remains a difficult clinical problem, with a poor prognosis and a high mortality. CASE PRESENTATION: After inhalation injuries from methyl chloroformate poisoning, bronchoscopy plays an important role in the diagnosis and treatment of patients. A low tidal air volume and earlier application of steroids are also essential for successful treatment. The grading of acute exposure guideline levels (AEGLs) can direct the selection of a therapeutic regimen for patients with methyl chloroformate poisoning. CONCLUSIONS: By analyzing the reported acute methyl chloroformate inhalation poisoning cases in China during 1989 to 2017, this study aims to value occupational protection in production activities, accumulate clinical experiences, and provide guidance for the treatment of such cases in the future. PMID- 29702973 TI - Epicardial adipose tissue and carotid artery disease: Protocol for systematic review and meta-analysis. AB - BACKGROUND: Atherosclerosis is now widely recognized as a multifactorial disease with outcomes that arise from complex factors such as plaque components, blood flow, and inflammation. Epicardial adipose tissue (EAT) is a metabolically active fat depot, abundant in proinflammatory cytokines, and has been correlated with the extent and severity of carotid artery disease (CD). The locations most frequently affected by carotid atherosclerosis are the proximal internal carotid artery (ie, the origin) and the common carotid artery bifurcation. Progression of atheromatous plaque at the carotid bifurcation results in luminal narrowing, often accompanied by ulceration. However, there are no systematic analyses or well-conducted meta-analyses to evaluate the relationship between EAT and CD. The aim of this study is to examine this association of EAT with CD in different ages and sex. METHODS: This systematic review and meta-analysis will be conducted using published studies that will be identified from electronic databases (ie, PubMed, EMBASE, Web of Science, and Google Scholar. Studies that (1) examined the association between EAT and CD, (2) focus on cohort, case-control and cross sectional studies, (3) will conducted among in adults aged 40 to 70 years, (4) provided sufficient data for calculating ORs or relative risk with a 95% CI, (5) will published as original articles written in English or other languages, and (6) have been published until January 2018 will be included. Study selection, data collection, quality assessment and statistical syntheses will be conducted based on discussions among investigators. RESULTS: We propose the current protocol to evaluate the evaluation of EAT with ED. CONCLUSION: This systematic review will not need ethical approval, because it does not involve human beings. The results and findings of this study will be submitted and published in a scientific peer-reviewed journal. ETHICS AND DISSEMINATION: Ethics approval was not required for this study because it was based on published studies. The results and findings of this study will be submitted and published in a scientific peer-reviewed journal. TRIAL REGISTRATION NUMBER: PROSPERO (CRD42018083458). PMID- 29702975 TI - Primary functioning hepatic paraganglioma mimicking hepatocellular carcinoma: A case report and literature review. AB - INTRODUCTION: Hepatic paraganglioma (HPGL) originates from the sympathetic nervous tissue in the liver, and is an extremely rare type of the sympathetic paragangliomas. Till now, only 11 HPGL cases have been reported. CASE PRESENTATION: A 49-year-old woman presented to our hospital with a lesion in the right lobe of the liver, which grew from 2 to 6 cm in 2 years. In addition, she had a 6-year history of diabetes. The patient was initially diagnosed as hepatocellular carcinoma and hepatectomy was performed. Surgical resection of the liver lesion was successful, but the blood pressure rose and fell sharply when the lesion was being removed. The pathological examination of the liver lesion showed that it was HPGL. After the operation, the patient recovered uneventfully. Follow-up examination showed the blood glucose level went back to the normal range in 20 days after the operation, and MRI and I-MIBG scan showed that there was no evidence of recurrence and metastasis in >2 years. CONCLUSION: By means of reporting this case and reviewing 11 reported cases, we conclude that the incidence of HPGLs is extremely low and the clinical and radiological characteristics of HPGLs are nonspecific; thus, it is hard to diagnose HPGLs correctly. Surgical resection is curative therapy for HPGLs, whereas the removing of HPGLs may cause the releasing of catecholamine, and then lead to hypertension crisis and arrhythmia. Thus, antihypertensive therapy is necessary during the operation. Follow-ups after the operation are important for HPGL patients, for pathological examinations are not sufficient to differ malignant HPGLs from benign ones, and follow-ups are helpful for HPGL patients to find the recurrent foci or metastases timely. PMID- 29702976 TI - NUDT15 R139C variation increases the risk of azathioprine-induced toxicity in Chinese subjects: Case report and literature review. AB - INTRODUCTION: Azathioprine (AZA) is widely used as an immunosuppressive agent, and its efficacy has been recommended by many clinical studies. However, leukopenia, the most common toxicity, still restricts its clinical applications. Recent studies found that NUDT15 R139C polymorphism is strongly associated with AZA-induced leukopenia in Koreans. However, the follow-up studies available are all limited to inflammatory bowel disease (IBD). Here, we report a case of a Chinese patient with Sjogren syndrome (SS) with wild-type TPMT*3C who was diagnosed with AZA-induced severe toxicity due to NUDT15 mutation based on clinical and laboratory characteristics. CASE PRESENTATION: A 22-year-old Chinese woman with SS developed severe leukopenia after AZA administration for 21 days. Detection of 6-thioguanine nucleotides (6-TGN) showed that the erythrocyte concentration had beyond the monitoring range, indicating that severe leukopenia might be caused by AZA. Furthermore, gene sequencing showed that NUDT15 R139C (poor metabolizer) homozygosity might explain this adverse event. Based on the evidence, AZA administration was immediately stopped and supportive treatments provided, and the patient eventually recovered. CONCLUSION: In this report, we first provide detailed clinical and laboratory characteristics of AZA-induced leukopenia in a patient with SS with a mutant NUDT15 R139C genotype (TT allele) and normal TPMT activity. This case indicates that NUDT15 R139C and TPMT*3C genotypes, and more importantly, 6-TGN levels, should be routinely monitored for those administered with AZA to predict and prevent AZA-induced toxicity. PMID- 29702978 TI - Optic neuropathy causing vertical unilateral hemianopsia after pars plana vitrectomy for a macular hole: A case report. AB - INTRODUCTION: Recent progress in medical technology has resulted in improved surgical outcomes of pars plana vitrectomy (PPV); with microincision systems, the incidence of procedure-related complications during surgery has been reduced. However, unpredictable visual field defects after PPV remain an unresolved issue. A few reports have shown that damage to the retinal neurofibers owing to dry-up during air/fluid exchange or retinal neurotoxicity of the dye used to visualize the internal limiting membrane (ILM), as well as unintentional removal of retinal neurofibers during ILM peeling, are responsible for such visual field disorders. In this report, we present a case of extensive visual field defect due to optic neuropathy exhibiting vertical hemianopsia after PPV. CASE SUMMARY: A 50-year-old woman underwent PPV and cataract surgery for a macular hole and mild cataract under retrobulbar anesthesia with 3.5 mL of xylocaine. At the time of opening an infusion cannula for PPV, the intraocular lens was herniating, with an acute increase in pressure from the posterior eyeball; thus, intraocular pressure configuration level had to be decreased from the default level, whereas the other procedures including 20% SF6 injection were performed without any modification. The macular hole was closed postoperatively. However, the patient experienced nasal hemianopsia, which turned out to be optic neuropathy, as assessed via electric physiological examinations. The pattern of the visual field defect was not typical for glaucoma or anterior ischemic optic neuropathy. Her optic nerve head was pale at the temporal side soon after the surgery, and her blood pressure was low, suggesting that there may have been a congestion of the optic nerve feeder vessels because of the relatively high pressure in the orbit. The space occupancy with xylocaine and extensively stretched and plumped out eye ball with infusion during PPV may have pressed the surrounding tissue of the optic nerve and the feeder vessels. CONCLUSION: PPV is safe for most patients; however, individual variations in local and/or systemic conditions may cause complications. Future studies to optimize the surgical condition for each individual patient may be warranted. PMID- 29702977 TI - Association between ERalpha gene Pvu II polymorphism and breast cancer susceptibility: A meta-analysis. AB - BACKGROUND: Estrogen has played an important role in the development of breast cancer. ER-alpha PvuII gene polymorphism is in close association with the occurrence risk of breast cancer, but no consensus has been achieved currently. METHODS: PubMed, Embase, China National Knowledge Infrastructure (CNKI) database, Wanfang database, and VIP database were retrieved to collect the case-control studies on association between ERalpha gene Pvu II polymorphism and breast cancer risk published before September 1, 2017. Newcastle-Ottawa Scale (NOS) was used to assess the quality of the literatures, Stata 14.0 software was applied for meta analysis, and the pooled odds ratio (OR) and 95% confidence interval (95% CI) were calculated. The subgroup analysis was performed to assess the confounding factors, followed by assessment of publication bias and sensitivity analysis. RESULTS: A total of 26 studies were enrolled in the analysis based on inclusion criteria, which included 15,360 patients and 26,423 controls. The results demonstrated that ERalpha gene Pvu II polymorphism was in significant association with the decrease of breast cancer risk in 3 genetic models (C vs T, OR = 0.962, 95% CI = 0.933-0.992, P = .012; CC vs TT, OR = 0.911, 95% CI = 0.856-0.969, P = .003; CC vs TT/CT, OR = 0.923, 95% CI = 0.874-0.975, P = .004). Subgroup analysis was conducted on the basis of ethnicity and source of controls, whose results illustrated that ERalpha gene Pvu II polymorphism was in significant association with the decrease of breast cancer risk in Asians rather than in Caucasians (CC vs TT, OR = 0.862, 95% CI = 0.750-0.922, P = .038; CC vs TT/CT, OR = 0.851, 95% CI = 0.755-0.959, P = .008). In population-based subgroup rather than in hospital based subgroup, ERalpha gene Pvu II polymorphism was in significant association with the decrease of breast cancer risk in the allele model, homozygous model, dominant model, and recessive model (C vs T, OR = 0.943, 95% CI = 0.911-0.977, P = .001; CC vs TT, OR = 0.878, 95% CI = 0.817-0.944, P = .000; CC/CT vs TT, OR = 0.936, 95% CI = 0.881-0.994, P = .031; CC vs TT/CT, OR = 0.902, 95% CI = 0.847 0.960, P = .001). CONCLUSION: ERalpha gene Pvu II polymorphism exerts an important function in the progression of breast cancer. PMID- 29702979 TI - Chondroblastoma of the distal femoral metaphysis: A case report with emphasis on imaging findings and differential diagnosis. AB - Chondroblastoma is a rare benign tumor, consisting of tissue resembling foetal cartilage, and arising in the epiphyses, or apophyses of long tubular bone. However, chondroblastoma of the cortex of the long bone metaphysis is extremely rare.A 15-year-old girl presented a 10-month history of intermittent knee pain and without mobility limitation. X ray, computed tomography (CT), and magnetic resonance imaging (MRI) showed a slightly expansile lytic lesion involving the metaphyseal cortex of the left distal femur. During histological examination, typical features of chondroblastoma were observed. Chondroblastoma was definitely and histologically diagnosed. Surgical procedures included intralesional tumor curettage and allograft bone implantation. The patient was discharged without any complications 1 week after surgery and there was no recurrence during a 10-month follow-up.This report describes a case of chondroblastoma in the metaphyseal cortex of the distal femur and serves as a reminder of the atypical anatomic location of chondroblastoma. Patients in an appropriate age group with typical imaging features may be diagnosed with chondroblastoma despite its rare location. PMID- 29702980 TI - CHRNE compound heterozygous mutations in congenital myasthenic syndrome: A case report. AB - RATIONALE: Congenital myasthenic syndrome (CMSs) are a group of rare genetic disorders of the neurological junction, which can result in structural or functional weakness. Here, we characterized a case of CMS in order to clarify the diagnosis and expand the understanding of it. The molecular diagnosis had implications for choice of treatment and genetic counseling. PATIENT CONCERNS: A 3-year-old male patient with CMS had ptosis and limb weakness for 2 months after birth. Clinical course and electrophysiological, imaging, and genetic findings were assessed. Protein structure/function was predicted. A novel mutation of c.295C>T (exon 4) and another known mutation of c.442T>A (exon 5) were found in CHRNE. Both mutations localized in conserved sequences. The c.442T>A (p.C148S) missense mutation in CHRNE was predicted to be damaging/deleterious. The iterative threading assembly refinement (I-TASSER) server generated vastly different 3-dimensional (3D) atomic models based on protein sequences from wide type and novel nonsense mutation of c.295C>T (p.R99X) in CHRNE. DIAGNOSES: The diagnosis of CMS with CHRNE mutations in Han Chinese was confirmed. INTERVENTIONS: The patient was given prednisone (10 mg, once daily, taken orally) and pyridostigmine (15 mg, three times a day, taken orally). OUTCOMES: The patient had a moderate response to prednisone and pyridostigmine. LESSONS: We expanded the genotype and phenotype of CMS with CHRNE mutations in Han Chinese and provided new insights into the molecular mechanism of CMS and help to the diagnosis and treatment of CMS. PMID- 29702981 TI - Clinical analysis of lectin-like oxidized low-density lipoprotein receptor-1 in patients with in-stent restenosis after percutaneous coronary intervention. AB - In-stent restenosis (ISR) is the most common complication associated with percutaneous coronary intervention (PCI). Although some studies have reported an association between lectin-like oxidized low-density lipoprotein receptor-1 (LOX 1) and ISR, not enough clinical validation data are available to support this link. Here, we report our cross-sectional study aimed at exploring the feasibility of LOX-1 as a biomarker for the prognostic diagnosis of patients undergoing PCI.Three groups were included: ISR group, including 99 patients with ISR diagnosed with coronary arteriography (CAG) after PCI; lesion group, comprising 87 patients with coronary artery stenosis (<50%) diagnosed with CAG after PCI; and control group, consisting of 96 volunteers with no coronary artery disease. The levels of LOX-1 were measured in each patient by using an enzyme linked immunosorbent assay, and their general information as well as laboratory parameters were recorded and followed up during a period of 2 years.LOX-1 levels gradually increased after PCI along with the progression of the lesion in the 3 groups. The levels of LOX-1 were significantly higher in the ISR group than in the other 2 groups (P < .001). LOX-1 levels were correlated with the levels of uric acid (UA) (r = 0.289, P = .007), creatinine (CREA) (r = .316, P = .003), and high-density lipoprotein cholesterol (HDL-C) (r = -0.271, P = .012), whereas no statistically significant correlation was detected with the Gensini score (r = 0.157, P = .141). The sensitivity and specificity of LOX-1 were 81.5% and 55.7%, respectively, with the most optimal threshold (5.04 MUg/L). The area under curve (AUC) of the receiver operator characteristic (ROC) curve of LOX-1 was 0.720, and LOX-1 had the highest AUC compared with CREA, UA, and HDL-C, both individually and in combination.A high level of LOX-1 in the early period after PCI has a certain predictive power and diagnostic value for ISR. However, the level of LOX 1 is not related to the Gensini score of coronary artery after PCI, and CREA and UA, which are weakly related to LOX-1, have no obvious synergy in the diagnosis of ISR with LOX-1. PMID- 29702982 TI - Neonatal gastric perforation: a report of two cases and a systematic review. AB - RATIONALE: Neonatal gastric perforation is a rare and life-threatening disorder in neonates and is associated with high morbidity and mortality. However, the exact mechanisms of neonatal gastric perforation remain unknown. PATIENT CONCERNS: In this study, we reported 2 cases of neonatal gastric perforation and conducted a systematic review to analyze the prognostic factors for mortality. DIAGNOSES: Two neonates received a diagnosis of gastric perforation based on clinical presentation and imaging studies. The 2 patients underwent emergent surgery, which yielded favorable outcomes. INTERVENTIONS: We reviewed 168 cases from the literature as well as our 2 cases to analyze whether mortality in neonatal gastric perforation is associated with sex, gestational age, operation type, perforation location, or timing of perforation. OUTCOMES: The results revealed that mortality was significantly higher in preterm neonates (n = 80, P < .01) and the mortality group had a lower birth weight (n = 73, P < .05). The timing of perforation in the preterm subgroup was significantly earlier than that in the full-term subgroup (n = 90, P < .05). The outcomes about mortality of gastric perforation were significantly associated with preterm neonates (adjusted odds ratio: 4.21, 95% confidence interval: 1.28-13.88, P < .05). LESSONS: This study shows the prognostic factor of gastric perforation was significantly associated with preterm neonates. Furthermore, low-birth-weight full-term neonates had a relatively higher mortality rate than the normal-birth-weight full term neonates. In addition, preterm neonates have an earlier timing of perforation. PMID- 29702983 TI - Effect of risedronate on femoral periprosthetic bone loss following total hip replacement: A systematic review and meta-analysis. AB - BACKGROUND: Recent study has reported that risedronate was effective in reducing periprosthesis bone loss after total hip arthroplasty (THA). The meta-analysis was performed to compare the clinical outcomes of THA with oral risedronate versus placebo. METHODS: Electronic databases: PubMed (1950-March 2018), EMBASE (1974-March 2018), the Cochrane Central Register of Controlled Trials, Web of Science (1950-March 2018) were systematically searched. Two authors independently graded the methodological quality of each eligible study using the Cochrane Collaboration tool and extracted relevant data. Statistical heterogeneity among the trials were evaluated with chi-square and I-square tests. This meta-analysis was performed using STATA 14.0. RESULTS: A total of 4 randomized controlled trials (RCTs) published between 2006 and 2015 were included in our study. The meta-analysis demonstrated that risedronate was associated with a significantly reduction of periprosthetic bone mineral density after THA. No increased postoperative complications were observed. CONCLUSION: Oral risedronate might reduce the periprosthetic bone resorption after cementless THA. Additionally, no severe adverse effects were observed. High-quality RCTs with large sample size were still required. PMID- 29702984 TI - Wenxin Keli for atrial fibrillation: Protocol for a systematic review and meta analysis. AB - BACKGROUND: Atrial fibrillation (AF) is a most common cardiac arrhythmia in clinical practice. In China, Wenxin Keli (WXKL) therapy is a common treatment for AF, but its effects and safety remain uncertain. This protocol is to provide the methods used to assess the effectiveness and safety of WXKL for the treatment of patients with AF. METHODS: We will search comprehensively the 4 English databases EMBASE, the Cochrane Central Register of Controlled Trials (Cochrane Library), PubMed, and Medline and 3 Chinese databases China National Knowledge Infrastructure (CNKI), Chinese Biomedical Literature Database (CBM), and Chinese Science and Technology Periodical database (VIP) on computer on March 2018 for the randomized controlled trials (RCTs) regarding WXKL for AF. The therapeutic effects according to the sinus rhythm and p-wave dispersion (Pwd) will be accepted as the primary outcomes. We will use RevMan V.5.3 software as well to compute the data synthesis carefully when a meta-analysis is allowed. RESULTS: This study will provide a high-quality synthesis of current evidence of WXKL for AF. CONCLUSION: The conclusion of our systematic review will provide evidence to judge whether WXKL is an effective intervention for patient with AF. PROSPERO REGISTRATION NUMBER: PROSPERO CRD 42018082045. PMID- 29702985 TI - Herbal medicine (Suoquan) for treating nocturnal enuresis: A protocol for a systematic review of randomized controlled trials. AB - BACKGROUND: Suoquan is widely used to treat frequent urination, enuresis, and other diseases caused by kidney qi deficiency. Many clinical trials assessing the efficacy and safety of Suoquan for the treatment of enuresis have been reported. This review will assess the clinical evidence for and against the use of Suoquan as a treatment for enuresis. METHODS AND ANALYSIS: Fourteen databases will be searched until 2018. We will include randomized controlled trials (RCTs) examining Suoquan decoctions for any type of enuresis. All RCTs of decoctions or modified decoctions will be included. The methodological qualities of the RCTs will be assessed using the Cochrane Collaboration tool for assessing risk of bias. ETHICS AND DISSEMINATION: This systematic review will be published in a peer-reviewed journal. The review will be disseminated both electronically and in print. It will be updated to inform and guide healthcare practices. TRIAL REGISTRATION NUMBER: CRD42018087900. PMID- 29702986 TI - Banxia Xiexin tang for gastro-oesophageal reflux disease: A protocol for a systematic review of controlled trials. AB - BACKGROUND: Gastrooesophageal reflux disease (GORD) is one of the most common gastrointestinal diseases encountered in clinical practice. The aim of the present study is thus to systematically review the literature, including Asian studies, to assess the efficacy and safety of Banxia Xiexin tang (BXT) for the treatment of GORD. METHODS AND ANALYSIS: Eleven databases will be searched for studies conducted through March 2018. We will include randomized controlled trials (RCTs) of BXT as a treatment for GORD. All RCTs on BXT or related formulations will be included. The risk of bias will be assessed using the Cochrane Risk of Bias Assessment Tool, while confidence in the cumulative evidence will be evaluated using the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) tool. ETHICS AND DISSEMINATION: This systematic review will be published in a peer-reviewed journal and will also be disseminated electronically and in print. The review will be updated to inform and guide healthcare practices. REGISTRATION NUMBER: CRD42018087056. PMID- 29702987 TI - Eletromyography of abdominal muscles in different physical exercises: An update protocol for systematic review and meta-analysis. AB - BACKGROUND: The abdominal muscles are extremely important because they are directly involved in the functions of support, containment of viscera, and help in the process of expiration, defecation, urination, vomiting, and also at the time of childbirth. Many exercises and equipment are used to strengthen the abdominal muscles, and the workouts are proposed for a variety of purposes, such as preventing and rehabilitating low back pain, improving sports performance, achieving aesthetic standards, among others. Exercises that potentiate the electromyographic activity promote a greater recruitment of muscle fibers and are more effective to improve or maintain of the force. The electromyographic activity analysis allows us to reflect on the quality of the exercises proposed, consequently, to choose and order the exercises properly in a training session. METHODS: Our systematic review protocol will developed following the reporting items for the systematic review. To identify relevant studies, we sought articles on the following bases: MEDLINE, PubMed, Europubmed, SciELO, Physiotherapy Evidences Data Base (PEDro), Cochrane, and Google Scholar. The methodological quality of the studies included in the review will evaluated using a checklist and quality assessment. For intervention studies, risk of bias will estimated using the Cochrane Collaboration tool. RESULTS: The results of this study will show the electromyographic activation of the abdomen in the different types of exercises. CONCLUSION: Ethics approval was not required for this study because it was based on published studies. The results and findings of this study will be submitted and published in a scientific peer-reviewed journal. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018086172. PMID- 29702988 TI - Enteritis as initial manifestation of systemic lupus erythematosus in early pregnancy: A case report. AB - RATIONAL: Lupus enteritis is a rare, severe complication of systemic lupus erythematosus (SLE). We report of a patient who presented with enteritis as manifestation of new-onset SLE during the first trimester of pregnancy. PATIENTS CONCERNS: The 23-year nulliparous patient was admitted to a district hospital with abdominal pain, nausea, vomiting and bloody diarrhea at a gestational age (GA) of 10 weeks. Her symptoms improved with symptomatic treatment and she was discharged a few days later. At 15 weeks' of gestation she was readmitted. Her lab results revealed mild anemia and thrombocytopenia. Ascites, renal failure and proteinuria developed. An infectious cause was suspected, but stool samples and urine cultures were negative. Diagnostic work-up included abdominal ultrasound, gastro- and sigmoidoscopy, magnetic resonance imaging (MRI), and diagnostic laparoscopy. Ultrasound and MRI revealed dilated, fluid-filled small bowel loops, and increased colonic wall diameters. Mucosal edema and petechiae were detected by sigmoidoscopy, and histopathologic examination of the biopsies revealed erosive inflammation. Due to progressive deterioration she was transferred to our center. In addition to ascites, pleural and pericardial effusions had developed. DIAGNOSIS: Diagnosis of SLE was finally established at GA 16 after an autoimmune workup revealed positive antinuclear, anti- Sm, anti-dsDNA and anti-U1RNP antibodies. An interdisciplinary team was set up for her management. She was commenced on corticosteroids; response was only partial and necessitated addition of cyclosporine. The further clinical course was complicated by anemia, chest wall shingles, hypertension, and progressive cervical shortening. Serial ultrasound and Doppler examinations revealed notching of the uterine arteries with raised pulsatility indices and fetal growth restriction. INTERVENTION: At GA 35 abdominal pain reoccurred; a decision for delivery was taken. An apparently healthy fetus was delivered by cesarian section with good Apgar scores and pH (2100g, 9. percentile). The postoperative / postnatal course was unremarkable. OUTCOMES: New-onset SLE during pregnancy is rare, as is lupus enteritis. To our knowledge, our case is the first report of a combination of both. LESSONS: Diagnostic delay occurred a result of symptom overlap and limitations in diagnostic imaging. Interdisciplinary teamwork resulted in successful outcome for both, mother and fetus. PMID- 29702989 TI - The application of x-ray, computed tomography, and magnetic resonance imaging on 22 pediatric Langerhans cell histiocytosis patients with long bone involvement: A retrospective analysis. AB - The studies focusing on x-ray, computed tomography (CT), and magnetic resonance imaging (MRI) in pediatric Langerhans cell histiocytosis (LCH) patients were still rare. Therefore, we aimed to evaluate the application of x-ray, CT, and MRI in pediatric LCH patients with long bone involvement.Total 22 pediatric LCH patients were included in this study. The diagnosis of LCH was confirmed by pathological examination. All patients were followed up for 3 years. X-ray, CT, or MRI was performed and the results were recorded for further analyses.Among 22 pediatric patients, x-ray (n = 20), CT (n = 18), or MRI (n = 12) were used to scan the lesion on long bones affected by LCH. Femurs (n = 13, 38.24%), tibia (n = 11, 32.35%), humerus (n = 5, 14.71%), and radius (n = 4, 11.76%) were the most frequently affected anatomic sites. Ovoid or round radiolucent lesions, aggressive periosteal reaction, and swelling of surrounding soft tissues were characteristic image of long bones on x-ray, CT, and MRI in pediatric LCH.Femurs, tibia, humerus, and radius were the most commonly affected long bones of pediatric LCH. The application of x-ray, CT, and MRI on long bones could help with the diagnosis of pediatric LCH. PMID- 29702990 TI - Traditional cardiovascular risk factors and coronary collateral circulation: Protocol for a systematic review and meta-analysis of case-control studies. AB - BACKGROUND: Well-developed coronary collateral circulation usually results in fewer infarct size, improved cardiac function, and fewer mortality. Traditional coronary risk factors (diabetes, hypertension, and smoking) have some effects on coronary collateral circulation. However, the association between these risk factors and coronary collateral circulation are controversial. Given the confusing evidences regarding traditional cardiovascular risk factors on coronary collateral circulation, we performed this meta-analysis protocol to investigate the relationship between traditional risk factors of coronary artery disease and coronary collateral circulation. METHODS: MEDINE, EMBASE, and Science Citation Index will be searched to identify relevant studies. The primary outcomes of this meta-analysis are well-developed coronary collateral circulation. Meta-analysis was performed to calculate the odds ratio (OR) and 95% confidence interval (CI) of traditional coronary risk factors (diabetes, smoking, hypertriton). Pooled ORs were computed as the Mantel-Haenszel-weighted average of the ORs for all included studies. Sensitivity analysis, quality assessment, publication bias analysis, and the Grading of Recommendations Assessment, Development and Evaluation approach (GRADE) will be performed to ensure the reliability of our results. RESULTS: This study will provide a high-quality synthesis of current evidence of traditional risk factors on collateral circulation. CONCLUSION: This conclusion of our systematic review and meta-analysis will provide evidence to judge whether traditional risk factors affects coronary collateral circulation.Ethics and dissemination: Ethical approval is not required because our systematic review and meta-analysis will be based on published data without interventions on patients. The findings of this study will be published in a peer-reviewed journal. PMID- 29702991 TI - Intracranial hemorrhage associated with medulla oblongata dysplasia in a premature infant: A case report. AB - RATIONALE: Medulla oblongata dysplasia is an extremely rare form of neurodevelopmental immaturity in premature infants. Intracranial hemorrhage in premature infants may be closely related to neurodevelopmental immaturity. DIAGNOSES: We report a female premature infant who succumbed to intracranial hemorrhage caused by medulla oblongata dysplasia. PATIENT CONCERNS: The infant was born at 31 weeks gestation. The onset manifestation was symptomatic epilepsy associated with subependymal hemorrhage. INTERVENTIONS: Levetiracetam and sodium valproate were administered. During the hospitalization, hydrocephalus developed and the intracranial hemorrhage aggravated. OUTCOMES: The infant died on day 171 after birth. LESSONS: Early identification and prompt treatment should be emphasized. Clinicians should be aware of this condition, as it can potentially cause neonatal intracranial hemorrhage. PMID- 29702992 TI - Gender-related efficacy of pulmonary surfactant in infants with respiratory distress syndrome: A STROBE compliant study. AB - Whether gender influences the efficacy of exogenous pulmonary surfactant (PS) for replacement therapy in newborns with respiratory distress syndrome (RDS) has not been well studied yet.Retrospective cohort study design. Data on PS therapy including blood gas, oxygenation function parameters, and therapy results were collected and analyzed from 370 infants diagnosed with RDS in 20 hospitals of the Northwest China Neonatal Collaboration from January 2011 to December 2011.Female infants were more sensitive to PS treatment than males. In multivariate analysis, when adjusted for other variables, an increased initial dose of surfactant significantly reduced mortality risk (OR = 0.98, 95%CI [0.96, 0.99], P = .002). An interaction between gender and initial dose of PS was observed. In male infants, an increased initial dose of surfactant was correlated with reduced mortality risk (OR = 0.97, 95%CI [0.96, 0.99], P = 0.005), while in female infants, we failed to found a relationship between the initial dose of surfactant and the risk of mortality (OR = 0.99, 95%CI [0.96, 1.02], P = .543). Moreover, the effect of surfactant replacement therapy was better for female infants than male infants at initial PS doses <130 mg/kg.Gender influences the efficacy of PS treatment. An increased initial dose of PS should be used in RDS therapy for male infants. PMID- 29702993 TI - STARD-rapid screening for the 6 most common G6PD gene mutations in the Chinese population using the amplification refractory mutation system combined with melting curve analysis. AB - Dot-blot hybridization and high-resolution melting curve methods are used to detect G6PD gene mutations; however, the performance and throughput limitations of these methods hinder their use for screening large populations. For simple screening, we developed a novel approach called "Amplification Refractory Mutation System combined with Melting Curve Analysis (ARMS-MC)," which enables rapid and batch-based detection of the 6 most common G6PD mutations.In this method, we established 4 PCR reaction systems that can be used to detect the 6 most common G6PD mutations (c.95A>G, c.392G>T, c.871G>A, c.1024C>T, c.1376G>T, and c.1388G>A) in the Chinese population.The ARMS-MC method was evaluated with 174 cases of clinical G6PD-deficient samples, and the results were verified by direct sequencing at G6PD gene exons. The results showed that 170 samples had >=1 of the 6 mutations, which accounted for 97.70% of all mutations. These results were consistent with the results of direct sequencing with 100% accuracy and specificity. Sequencing validation revealed other mutations in the 4 samples in which no mutation was detected by the ARMS-MC method.ARMS-MC provides a rapid, simple, inexpensive, and accurate screening method for detecting the most common G6PD mutations in Chinese people. PMID- 29702994 TI - A case report regarding general anesthesia management of a patient with pulmonary vein stenosis that underwent balloon dilatation and stent implantation. AB - RATIONALE: Pulmonary vein stenosis (PVS) is a rare cardiovascular deformity that can lead to high mortality if left untreated. Patients frequently experience multiple complications such as hemoptysis, pulmonary hypertension, bronchial venous rupture and cardiac insufficiency. Currently, pulmonary vein stenosis balloon dilatation (stent implantation) is the only treatment, and this can be performed under local or general anesthesia. However, a case report on the general anesthesia management of PVS has not been previously reported. In this case report, we discuss anesthetic considerations in patients with PVS, focusing specifically on perioperative airway and circulatory management as well as the risk evaluation, and the appropriate effective management of all potential complications intraoperatively. PATIENT CONCERNS: A 58-year-old male patient was admitted because of coughing rusty sputum for during 2 years as well as experiencing dyspnea and chest distress after exertion or exercising. The difficulty breathing and chest distress had been going on for a year. This patient had undergone circumferential pulmonary vein isolation twice during the last 2 years. DIAGNOSES: Based on the transthoracic echocardiography and computed tomography, this patient's diagnosis was considered as pulmonary vein stenosis, pulmonary hypertension (secondary), and pulmonary arteriovenous thrombosis. INTERVENTIONS: We considered that such severe patients with PVS require respiratory and circulatory supports and perhaps emergency surgical interventions. Henceforth, we administered general anesthesia to the patient and had extracorporeal membrane oxygenation (ECMO) on standby. OUTCOMES: The duration of the surgery was approximately 4 hours, the intraoperative vital signs were stable, no pericardial effusion was observed postoperatively, the blood flow in the pulmonary vein stent was smooth, and the patient was discharged 7 days later following rehabilitation. LESSONS: This surgical procedure involving respiratory and circulatory supports requires the involvement of different medical personnel such as interventionists, anesthesiologists, and surgeons. Therefore, multidisciplinary cooperation under general anesthesia will undoubtedly benefit such patients. PMID- 29702995 TI - Associations between bone-alkaline phosphatase and bone mineral density in adults with and without diabetes. AB - Insufficient evidence is available to reliably compare the roles of bone alkaline phosphatase (BAP) and bone mineral density (BMD) in diabetes. This study aimed to compare associations between BAP and BMD in adults with and without diabetes to elucidate fracture risk in diabetes.Data were extracted from the National Health and Nutrition Examination Survey (NHANES), 2001-2004, including 4197 adults aged 20 to 49 years, 143 with diabetes (DM group), and 4054 without (non-DM group). Main outcome measure was BMD and regression analyses were performed to identify serum BAP and other covariates associated with total BMD.BMD decreased significantly in DM patients when BAP was increased. In the non-DM group, all BMD results were significantly decreased when BAP was increased. Factors associated with total BMD varied with DM status. Lifestyle measures such as smoking and physical activity were also associated with BMD in the non-DM group.BAP and BMD are inversely associated in DM and non-DM patients. BAP is significantly associated with BMD after controlling for other variables, suggesting that BAP may interact with other factors altering bone metabolism in DM patients. PMID- 29702997 TI - Recovery of renal function in a heart transplantation recipient with over 300 days of iatrogenic anuria: A case report. AB - RATIONALE: Anuria is a severe symptom indicating severe kidney damage. Patient recovery from prolonged anuria is rarely reported. PATIENT CONCERNS: A 15-year old boy received gender- and weight-mismatch heart transplantation (HT) due to dilated cardiomyopathy. He developed severe hypotension, and heart failure 24 hours after surgery, which were relieved by preload reduction treatments. Although, routine examinations did not show any abnormalities in renal function before surgery, anuria occurred 4 days after preload reduction treatments (24 hour urine volume was 23 mL). DIAGNOSIS: The patient was diagnosed with acute kidney injury (AKI). INTERVENTIONS: He was admitted to continuous renal replacement therapy (CRRT) or hemodialysis. OUTCOMES: Surprisingly, his urine volume was gradually, and miraculously, restored to more than 1000 mL/24 hours after over 300 days of anuria. Hemodialysis was not needed in the twentieth month after surgery. Moreover, he partially, recovered renal function. LESSONS: This case indicates the likelihood of recovery from long-term anuria. PMID- 29702996 TI - Phase I study of cord blood transplantation with intrabone marrow injection of mesenchymal stem cells: A clinical study protocol. AB - INTRODUCTION: Delayed hematological recovery, graft failure, and acute graft versus-host disease (GVHD) still remain major problems in cord blood transplantation (CBT). Mesenchymal stem cells (MSCs) are known to support bone marrow stroma and promote hematopoiesis. Additionally, MSCs possess immunomodulatory properties and are used clinically for the treatment of acute GVHD. Therefore, the use of MSCs to enhance engraftment and prevent GVHD after allogeneic hematopoietic cell transplantation has been explored. Recent clinical trials have shown the feasibility and safety of intravenous cotransplantation of MSCs with cord blood cells in pediatric patients, but not in adult patients, who are at greater risk of graft failure. As for the route of administration of MSCs, direct intrabone marrow injection of MSCs is thought to enhance the engraftment of cord blood cells more than intravenous injection. Based on these background findings, this clinical trial was designed to develop a new strategy to enhance engraftment and prevent GVHD after CBT. METHODS AND ANALYSIS: This is a single center, phase I, clinical study to evaluate the safety of CBT combined with intrabone marrow injection of ex vivo expanded MSCs from bone marrow of a third party donor. Adult patients with hematological disorders are eligible for this study. The target sample size is 5, and the registration period is 3 years. The target dose of MSCs infused is 0.5 * 10 cells/kg of patient body weight. On the day of CBT, MSCs are injected into the intrabone marrow of the patient 4 hours before the infusion of a single cord blood unit. The conditioning regimen varies according to patient age and disease. GVHD prophylaxis consists of a combination of tacrolimus and methotrexate. The primary endpoint of this study is infusional toxicity of MSCs within 14 days after transplantation. PMID- 29702998 TI - Return-to-health effect of modern combined antiretroviral therapy potentially predisposes HIV patients to hepatic steatosis. AB - Prevalence and risk factors for hepatic steatosis (HS) in the human immunodeficiency virus (HIV)-positive population of western countries are controversially discussed and potentially confounded by coinfection with viral hepatitis. Significant HS (more than 10% of hepatocytes) can be accurately assessed using controlled attenuation parameter (CAP) determination. Aim of this study was to assess prevalence and factors associated with significant HS in HIV monoinfected patients.A total of 364 HIV-infected patients (289 monoinfected) were included in this prospective, cross-sectional study. All patients underwent CAP determination. Steatosis was classified as S1 (significant steatosis) with CAP > 238 dB/m, S2 with CAP > 260 dB/m, and S3 with CAP > 292 dB/m. Multivariable logistic regression analyses were performed to assess the factors associated with HS in this cohort.Significant HS was detected in 118 monoinfected patients (149 in the total cohort). In the total cohort as well as in the monoinfected patients alone, HS grade distribution showed a similar pattern (S1:29%, S2:34%, and S3:37%). Interestingly, patients with HS had a longer history of HIV infection and combined antiretroviral therapy (cART). Interalia, age, gender, ethnicity, and metabolic factors were strongly associated with HS, while body mass index (BMI), triglyceride, and glycated hemoglobin (HbA1c) levels were independently associated with significant HS.HS is highly prevalent among HIV monoinfected patients. Although metabolic risk factors, such as obesity and poorly controlled diabetes, are independently associated with HS in HIV monoinfected patients, cART and control of HIV seem to play an indirect role in the development of HS, probably through the return-to-health effect. PMID- 29703000 TI - Rheumatological presentation of Bartonella koehlerae and Bartonella henselae bacteremias: A case report. AB - INTRODUCTION: Systemic Bartonella spp. infections are being increasingly reported in association with complex medical presentations. Individuals with frequent arthropod exposures or animal contact appear to be at risk for acquiring long standing infections with Bartonella spp. CASE REPORT: This case report describes infections with Bartonella koehlerae and Bartonella henselae in a female veterinarian whose symptoms were predominantly rheumatologic in nature. Infection was confirmed by serology, polymerase chain reaction (PCR), enrichment blood culture, and DNA sequencing of amplified B koehlerae and B henselae DNA. Long term medical management with antibiotics was required to achieve elimination of these infections and was accompanied by resolution of the patient's symptoms. Interestingly, the patient experienced substantial improvement in the acquired joint hypermobility mimicking Ehlers-Danlos Syndrome (EDS) type III. CONCLUSION: To facilitate early and directed medical interventions, systemic bartonellosis should potentially be considered as a differential diagnosis in patients with incalcitrant rheumatological symptoms and frequent arthropod exposures or extensive animal contact. PMID- 29702999 TI - Immunological markers as predictors of developing steroid-induced diabetes mellitus in pemphigus vulgaris patients: An observational study. AB - The aim of this study was to evaluate the clinical importance of autoantibodies in pemphigus vulgaris patients who developed steroid-induced diabetes mellitus (SID) because of the glucocorticoid therapy of pemphigus.A total of 137 patients with pemphigus vulgaris were studied. Patients with SID and pemphigus were compared with those that had only pemphigus. The variables recorded were: age at diagnosis, sex, body mass index, presence of diabetes mellitus (DM), cumulative cortisone dose, treatment duration, value of anti-desmoglein 1 and 3, and anti glutamic acid decarboxylase autoantibodies.A total of 31 patients (22.62%) that developed steroid-induced DM were identified. Anti-glutamic acid decarboxylase autoantibodies were positive in 20.75% of patients with pemphigus vulgaris and in 25.75% of patients with pemphigus vulgaris and SID.The overall anti-glutamic acid decarboxylase autoantibodies prevalence in pemphigus patients was high, and the risk of developing DM in patients with pemphigus remains a serious problem, being associated with increased risk of mortality. PMID- 29703001 TI - Successful diagnosis and treatment of early splenic ectopic pregnancy: A case report. AB - INTRODUCTION: Splenic ectopic pregnancy (SEP), a special abdominal pregnancy, is extremely rare but carries a high risk of potentially uncontrollable, life threatening intraperitoneal bleeding at early gestation, which is equivalent to the spontaneous rupture of the spleen. Therefore, early diagnosis of SEP is crucial and may avoid life-threatening situation. CASE PRESENTATION: A 29-year old G3P2 woman presented with 50 days of amenorrhea and positive serum beta-human gonadotropin (beta-HCG) was enrolled into the hospital due to the absence of gestational sac located in the uterine cavity. A pan-abdominal ultrasound scan revealed a 2.6 cm *1.6 cm hyperechoic mass inferior to the spleen with color Doppler signal surrounding and 0.9 cm anechoic inside. The gynecologist found the gestational sac was located in the dorsal pole of the spleen through the exploratory laparoscopy. Total splenectomy was performed uneventfully to avoid the hemorrhage shock. The patient discharged with no complications and normal 1 month follow-up. CONCLUSION: It highlights that fully understanding of the knowledge about abdominal pregnancy, especially splenic pregnancy, and early imaging study with ultrasonography could reduce or avoid the misdiagnosis and miss-diagnosis of SEP. PMID- 29703002 TI - Embolic retinal and choroidal vascular occlusion after peribulbar triamcinolone injection: A case report. AB - RATIONALE: Retinal and choroidal vascular occlusion is a vision-threatening complication of therapeutic injections in the facial region. The early identification and early treatment are necessary to reduce the risk of harm to the patient. PATIENT CONCERNS: We report an extremely rare case of embolic retinal and choroidal vascular occlusion after peribulbar triamcinolone injection in a patient with thyroid-associated ophthalmopathy. DIAGNOSES: Central retinal artery occlusion. INTERVENTIONS: First, we performed a fundus examination in the patient. Triamcinolone embolus was observed in both retinal and choroidal vessels. Anterior chamber paracentesis and ocular massage combined with venous injections of alprostadil and Ginaton as well as an acupoint injection of compound anisodine were performed immediately. Sublingual glyceryl trinitrate and intraocular pressure-lowering drugs were also administered. Fundus autofluorescence, optical coherence tomography-angiography, fundus fluorescein angiography (FFA), and indocyanine green angiography (ICGA) were also conducted to evaluate the patient's condition. OUTCOMES: One month after the onset of the situation, the triamcinolone embolus had disappeared. The retinal edema and retinal blood perfusion were also improved. The patient's visual acuity had recovered from inexact light perception to 0.02. LESSONS: Embolic retinal and choroidal vascular occlusion is vision-threatening disease. Measures such as careful aspiration before injecting in the facial region must be taken to avoid such complications. PMID- 29703003 TI - A network meta-analysis of comparison of operative time and complications of laparoscopy, laparotomy, and laparoscopic-assisted vaginal hysterectomy for endometrial carcinoma. AB - BACKGROUND: The endometrial carcinoma (EC) is the most frequently occurring female genital cancer. The authors performed this network meta-analysis to compare operative time and the incidence of bowel injury and wound infection of 3 operative approaches (laparoscopy, laparotomy, and laparoscopic-assisted vaginal hysterectomy [LAVH]) in the treatment of EC. METHODS: The Cochrane Library, PubMed, and Embase databases were searched. Randomized controlled trials (RCTs) for EC from the day of databases establishment to February 2017 were included. Direct and indirect evidences were combined to calculate the combined weighted mean difference (WMD) or odd ratio values and the surface under the cumulative ranking curve (SUCRA) value of 3 operative approaches in the treatment of EC. RESULTS: A total of 9 qualified RCTs were included into the study. The results showed that laparotomy had a shorter-operative time than LAVH (WMD = -40.36, 95% confidence interval = -75.03 to -2.57). However, there was no significant difference in the incidence of bowel injury and wound infection among 3 operative approaches. Besides, the SUCRA values indicated that laparotomy had the shortest operative time but the incidence of bowel injury and wound infection was relatively higher. CONCLUSION: The results from this study indicate that laparotomy had highest incidence of bowel injury and wound infection but shortest operative time among 3 operative approaches in the treatment of EC. PMID- 29703004 TI - A rational-emotive stress management intervention for reducing job burnout and dysfunctional distress among special education teachers: An effect study. AB - BACKGROUND: Job-related burnout and distress are adverse stress responses which affect individuals in their occupational environment. This study aimed at investigating the effect of a rational-emotive stress management program on job burnout and dysfunctional distress among special education teachers in Nigeria. METHODS: A pretest-posttest randomized control group design was used. The participants in the study were 54 special education teachers. Data were collected using self-report questionnaires. Participants were allocated to either the treatment group (n = 28 [59.1%]) or the waitlist control group (n = 26 [48.1%]), respectively. A rational-emotive stress management manual was used to deliver the intervention. We statistically analyzed the data collected at three-time points with repeated-measures analysis of variance. RESULTS: At baseline, the job related burnout symptoms and distress scores of participants were high. However, an intention-to-treat analysis showed that the rational-emotive stress management intervention program was efficacious in reducing the levels of job-related burnout symptoms and dysfunctional distress among participants assigned to the treatment group, compared to a waitlisted group at post-treatment and follow-up meetings. CONCLUSION: Our study demonstrates the effectiveness of a rational emotive stress management intervention in reducing the level of job-related burnout and distress in a sample of special education teachers in Nigeria. Occupational health counsellors and other clinicians with sufficient knowledge of rational-emotive behavior therapy framework are urged to employ this approach in assisting other employees in managing job burnout symptoms, and distress. PMID- 29703005 TI - Intravesical contrast-enhanced ultrasound (CEUS) for the diagnosis of vesicouterine fistula (VUF): A case report. AB - BACKGROUND: Vesicouterine fistula (VUF) is a very rare type of urogenital fistula, the incidence of which has increased in recent years due to increased cesarean section deliveries and other pelvic surgeries. The clinical diagnosis of VUF is typically challenging. CASE: A 31-year-old woman who presented with fever, increase urine frequency, and urinary incontinence at night, along with occasional vaginal discharge after cesarean section. The VUF was misdiagnosed on conventional ultrasound, but was successfully diagnosed by using intravesical contrast-enhanced ultrasound (CEUS) using SonoVue, which was confirmed by the subsequent cystoscopy. CONCLUSION: Intravesical CEUS provides a new effective method for diagnosing VUF, which may become the first choice for diagnosing urogenital fistulas. PMID- 29703006 TI - High 18F-fluorodeoxyglucose uptake in primary bilateral adrenal diffuse large B cell lymphomas with nongerminal center B-cell phenotype: A case report. AB - RATIONALE: Bilateral adrenal diffuse large B-cell lymphoma, nongerminal center B cell phenotype (non-GCB DLBCL), is an uncommon malignancy that exhibits rapid development. Fluorine-18-fluorodeoxyglucose position emission tomography/computed tomography (CT) is extremely sensitive in distinguishing highly malignant tumors from benign tumors. PATIENT CONCERNS: We report a case of non-GCB DLBCL showing significantly high uptake of 18F-FDG on PET/CT examination. DIAGNOSES: Histopathological and immunohistochemical examination further confirmed that the bilateral adrenal masses were non-GCB DLBCL. INTERVENTIONS: The maximal standardized uptake value (SUVmax) of the adrenal lesion was 17.2. Abnormal 18F FDG uptake was observed in a retroperitoneal lymph node, the SUVmax of which was 14.2. OUTCOMES: He was administered CHOP chemotherapy without rituximab due to high costs.His therapeutic effect and survival time could not be tracked due to patient privacy. LESSONS: non-GCB DLBCL is a rare malignancy.18F-FDG PET/CT examination can distinguish benign from malignant adrenal lesions based on increased FDG uptake. It is a noninvasive method to diagnose malignant adrenal tumors. PMID- 29703007 TI - Comparative efficacy of combination of 1 L polyethylene glycol, castor oil and ascorbic acid versus 2 L polyethylene glycol plus castor oil versus 3 L polyethylene glycol for colon cleansing before colonoscopy: Study protocol of a randomized, double-blind, single-center study. AB - Colonoscopy has been regarded as an important method of early diagnosing and treating gastrointestinal lesions; however adequate bowel preparation is critical one of many factors needed for successful colonoscopy. Although several modified or novel regimes have been developed, desired quality of bowel preparation has not yet been generated. Scattered evidences revealed that castor oil may have potential of effectively cleansing colon. It is noted that, however, prospective trial of exploring the value of castor oil in preparing bowel before colonoscopy is lacking. The aims of this study are to test the hypotheses that low dose castor oil (30 mL) may enhance potential of polyethylene glycol (PEG) and combination of low castor oil and ascorbic acid may halve the volume of PEG.This is a randomized, double-blind (endoscopist and assessor), single center trial with three-arm design. We will randomly assign 282 adult patients (>=18 years but < 75 years), who are scheduled to undergo colonoscopy, to receive either 3 L PEG alone, 2 L PEG plus 30 mL castor oil or combination of 1 L PEG, 30 mL castor oil and 5 g ascorbic acid. The bowel preparation quality based on Boston Bowel Preparation Scale (BBPS) is the primary outcome. The secondary outcomes include the first defecation time, total number of defecation, time of cecal intubation, detection rate of polyp and adenoma, willing to repeat the same regime, tolerance to regime, and adverse events.The study protocol has been approved by the Clinical Research Ethics Committees of Chongqing University Cancer Hospital & Chongqing Cancer Institute & Chongqing Cancer Hospital & Chongqing Cancer Center (2017[107]). The results from this trial will be submitted for publication in peer-reviewed journals, and will be presented at national and international conferences. PMID- 29703008 TI - Effectiveness of testosterone therapy in obese men with low testosterone levels, for losing weight, controlling obesity complications, and preventing cardiovascular events: Protocol of a systematic review of randomized controlled trials. AB - BACKGROUND: The use of testosterone replacement therapy in obese men with low testosterone levels has been controversial. This review aims to analyze the effectiveness of testosterone therapy for weight loss and preventing cardiovascular complications in obese men with low testosterone levels. METHODS: We will perform a systematic review according to Cochrane Methodology of randomized studies, including crossover studies, wherein patients are allocated into one of the two groups: testosterone therapy and control (no treatment or placebo). The primary outcomes analyzed will be: weight loss, adverse events, quality of life, improvement of libido, control of obesity complications, frequency of cardiovascular events, and deaths. Four general and adaptive search strategies have been created for the following electronic health databases: Embase, Medline, LILACS, and CENTRAL. Two reviewers will independently select the eligible studies, assess the risk of bias, and extract the data from included studies. Similar outcomes measured in at least two trials will be plotted in the meta-analysis using Review Manager 5.3. The quality of evidence of the effect estimate of the intervention for the outcomes that could be plotted in the meta analysis will be generated according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) Working Group. RESULTS: Although testosterone replacement seems to be an attractive treatment modality for obese men with low testosterone, its potential benefits has been refuted by some studies, whose results have not shown significant differences between treated and untreated patients. CONCLUSION: For obese men with low testosterone concentrations, the proposed systematic review aims to answer the following questions: When compared with no treatment or placebo: Is testosterone therapy safe? Is testosterone therapy effective in promoting weight loss, a sustained reduction in body weight and changes in body composition? Is testosterone effective in improving quality of life, libido, and erectile function? Is testosterone therapy effective in controlling obesity complications and in preventing cardiovascular events? PMID- 29703009 TI - Acute respiratory failure requiring mechanical ventilation in severe chronic obstructive pulmonary disease (COPD). AB - There are limited data on the epidemiology of acute respiratory failure necessitating mechanical ventilation in patients with severe chronic obstructive pulmonary disease (COPD). The prognosis of acute respiratory failure requiring invasive mechanical ventilation is believed to be grim in this population. The purpose of this study was to illustrate the epidemiologic characteristics and outcomes of patients with underlying severe COPD requiring mechanical ventilation.A retrospective study of patients admitted to a quaternary referral medical intensive care unit (ICU) between January 2008 and December 2012 with a diagnosis of severe COPD and requiring invasive mechanical ventilation for acute respiratory failure.We evaluated 670 patients with an established diagnosis of severe COPD requiring mechanical ventilation for acute respiratory failure of whom 47% were male with a mean age of 63.7 +/- 12.4 years and Acute physiology and chronic health evaluation (APACHE) III score of 76.3 +/- 27.2. Only seventy nine (12%) were admitted with a COPD exacerbation, 27(4%) had acute respiratory distress syndrome (ARDS), 78 (12%) had pneumonia, 78 (12%) had sepsis, and 312 (47%) had other causes of respiratory failure, including pulmonary embolism, pneumothorax, etc. Eighteen percent of the patients received a trial of noninvasive positive pressure ventilation. The median duration of mechanical ventilation was 3 days (interquartile range IQR 2-7); the median duration for ICU length of stay (LOS) was 5 (IQR 2-9) days and the median duration of hospital LOS was 12 (IQR 7-22) days. The overall ICU mortality was 25%. Patients with COPD exacerbation had a shorter median duration of mechanical ventilation (2 vs 4 days; P = .04), ICU (3 vs 5 days; P = .01), and hospital stay (10 vs 13 days; P = .01). The ICU mortality (9% vs 27%; P < .001), and the hospital mortality (17% vs 32%; P = .004) for mechanically ventilated patients with an acute exacerbation of severe COPD were lower than those with other etiologies of acute respiratory failure. A 1-unit increase in the APACHE III score was associated with a 1% decrease and having an active cancer was associated with a 45% decrease in ICU survival (P < .001). A discharge home at the time of index admission was associated an increased overall survival compared with any other discharge location (P < .001).We report good early outcomes, but significant long-term morbidity in patients with severe COPD requiring invasive mechanical ventilation for acute respiratory failure. A higher APACHE score and presence of active malignancy are associated with a decrease in ICU survival, whereas a discharge home is associated with an increase in the overall survival. PMID- 29703010 TI - Biomarkers of gastric cancer-related ischemic stroke and its underlying pathogenesis. AB - This study aimed to investigate the biomarkers and underlying pathogenesis of ischemic stroke in patients with gastric cancer (GC).Patients with active gastric cancer who had experienced acute ischemic stroke without conventional vascular risk factors (gastric cancer-related stroke [GCS] group) and visited The First Affiliated Hospital of Guangxi Medical University and First Affiliated Hospital of Sun Yat-sen University from January 2003 to December 2016 were retrospectively enrolled. The patients' clinical features and laboratory findings were compared with those of age-, sex-, and disease progression-matched patients with GC without ischemic stroke (GC group) who had been admitted to the same hospital during the same period (GCS:GC ratio = 1:2).Among the 9166 patients diagnosed with GC, 70 had experienced a cerebral infarction and were enrolled in this study. Among them, 53 (75.71%) harbored multiple lesions in multiple vascular territories. Notably, patients in the GCS group exhibited significant increases in the D-dimer and cancer antigen 125 (CA125) levels and platelet-to-neutrophil ratio (PNR), compared to their counterparts in the GC group. A multiple logistic regression analysis identified all 3 factors as independent risk factors for cerebral infarction in patients with GC (D-dimer, odds ratio [OR] = 1.006 per 1 ng/mL increase, 95% confidence interval [CI], 1.004-1.009, P = .000; CA125, OR = 1.016 per 1 U/mL increase, 95% CI, 1.005-1.027, P = .005; PNR, OR = 1.025 per 1 point increase, 95% CI: 1.003-1.048, P = .023).Elevated plasma D-dimer and CA125 levels and an increased PNR might affect the occurrence of GC-related ischemic stroke and could therefore serve as potential biomarkers. PMID- 29703011 TI - Desmoplastic small round cell tumor of the middle ear: A case report. AB - RATIONALE: Desmoplastic small round cell tumor (DSRCT) is a rare, aggressive and malignant tumor. This report describes a case involving DSRCT of the middle ear which no case has been reported in the literature till date. PATIENT CONCERN: A 59-year-old Chinese man with a 40-year history of repeated suppuration of his right ear and 1-year history of drooping of the angle of mouth. The CT of the middle ear and brain scan and enhanced MRI showed space occupying lesion in the right middle ear. DIAGNOSES: Desmoplastic small round cell tumor of the middle ear. INTERVENTIONS: After relevant examinations, radical mastoidectomy and subtotal temporal bone resection were performed on the right ear under general anesthesia. The patient underwent postoperative adjuvant chemoradiation therapy. OUTCOMES: The patient was counterchecked regularly,there was norecurrence of DSRCT of the middle ear. Four years after surgery, the CT and MRI of the middle ear mastoid showed right middle ear soft tissue shadow,but postoperative pathological results showed proliferative fibrous and vascular tissues with chronic inflammatory cell infiltration and necrosis. LESSONS: DSRCT is a relatively aggressive, malignant mesenchymal tumor, with a very poor prognosis.The diagnosis of DSRCT relies on immunohistological data. Early diagnosis, radical surgery, chemotherapy, and radiotherapy are considered a reasonable way to prolong survival. PMID- 29703012 TI - Successful treatment of left main shock syndrome induced by thrombosed coronary artery dissection: A case report. AB - RATIONALE: Left main shock syndrome (LMSS) induced by thrombosed coronary artery dissection is very rare and has a fatal prognosis. Optimal treatment strategy includes early reperfusion and hemodynamic support to prevent cardiogenic shock. However, it involves the extension of technical difficulties under different conditions. PATIENT CONCERNS: A 49-year-old woman developed symptoms of left main shock syndrome. The main clinical manifestations were retrosternal pain radiating to his back and left shoulder, heavy sweating, palpitation and brachypnea. DIAGNOSES: Acute anterioseptal myocardial infarction (Killip Class IV) with cardiogenic shock and arrhythmia including ventricular tachycardia and idionodal rhythm, and coronary artery dissection. INTERVENTIONS: A thrombus aspiration procedure was performed for the establishment of coronary flow under intra-aortic balloon pumping (IABP) support. Her coronary angiographic finding demonstrated a dissection in the mid-distal segment of the left main coronary artery where a sirolimus-eluting stent was deployed. Then, the veno-arterial extra-corporal membrane oxygenation (ECMO) was placed to improve severe cardiac dysfunction and end-organ failure. OUTCOMES: The patient had a good outcome without active symptoms. LESSONS: Thrombosis on the basis of coronary dissection is a very rare cause of LMSS. Successful team treatments, including the prompt thrombus aspiration and stent repair of artery dissection, potent IABP and ECMO support are important to improve the clinical outcome. PMID- 29703013 TI - Treatment of hemangioma of the spleen by preoperative partial splenic embolization plus laparoscopic partial splenectomy: A case report. AB - RATIONALE: Complete loss of splenic function increases infection and cardiovascular disease risks, so there is growing emphasis on spleen-preserving treatments, such as laproscopic partial splenectomy (LPS). However, LPS carries higher risk for hemorrhage. Sequential splenic embolization can obliterate the perilesional vascular bed while preserving flow through healthy tissue, substantially reducing risk of uncontrolled hemorrhage during LPS. Preoperative partial splenic embolization (PSE) may soften the spleen and reduce its size, which enhances space exposure for laparoscopic operation. Furthermore, immediate LPS guaranties these effects of PSE and prevents abscess, non-traumatic splenic rupture, post-embolization syndrome, and other complications. In light of these advantages, we conducted combined PSE and LPS for a case of hemangioma. PATIENT CONCERNS: The patient presented with left abdominal discomfort of >1 year. DIAGNOSES: Ultrasound examination at the outpatient clinic identified a space occupying lesion in the spleen. Contrast-enhanced computed tomography scan of the upper abdomen revealed a hypodense lesion, approximately 33 * 21 mm in size, located in the upper pole of the spleen, suggesting possible hemangioma. INTERVENTIONS: The patient was treated by preoperative PSE followed by LPS. OUTCOMES: Treatment resulted in only mild intraoperative hemorrhage, fast postoperative recovery, and no recurrence during follow-up. And the postoperative histopathology confirmed splenic cavernous hemangioma. LESSIONS: Preoperative PSE combined with LPS is an effective therapy for elective patients that minimizes intraoperative hemorrhage during laparoscopic surgery, reduces surgical risk, and enhances surgical safety. PMID- 29703014 TI - Sex differences in extinction to negative stimuli: Event-related brain potentials. AB - There are controversial observations regarding whether females have a longer time to extinction than men, which may be related to different levels of conditioning acquisition and/or the influence of the menstrual cycle. We explored the electrophysiological evidence of sex differences in extinction.In this study, females in the luteal phase and menstrual phase were examined for event-related potential (ERP) and evidence of attention allocation in the conditioning model using electroencephalogram recordings. A group of male participants was also included and compared.Women in the luteal phase had a higher difference waveform of P3 amplitude to conditioned stimulus (CS) in the extinction phase than women in the menstrual phase and men. There was a shorter latency of P3 to CS+ in men than in women in the extinction phase, suggesting that men react faster than women to unconditioned stimulus (US) expectation. Our study revealed that women in the luteal phase allocated more attentive resources to the expectation of a US. In contrast, men displayed faster expectation of the extinguished US than women. Our results support the superiority of ERP technology in documenting the neural mechanism of the extinction process. PMID- 29703015 TI - A case report of a very late response to 5-azacytidine in a patient with lower risk myelodysplastic syndrome: Time to update treatment guidelines for lower risk patients. AB - RATIONALE: The hypomethylating agent 5-azacytidine has been approved in Europe for patients with intermediate 2 and high (i.e., higher) risk myelodysplastic syndrome according to the International Prognostic Scoring System (IPSS). A total of 91% of all first responses in higher risk patients occur within 6 cycles of treatment; however, data regarding the time to first response in clinical trials with lower risk patients are not available. PATIENT CONCERNS: Our case describes the late response of a lower risk (intermediate 1 according to the IPSS and intermediate according to the IPSS-R) patient to 5-azacytidine treatment.Diagnosis and interventions: Once diagnosed, the patient started supportive treatment due to persistent pancytopenia and recurrent infections. The use of a hypomethylating agent was decided because the patient was transfusion dependent, and suffering from recurrent severe febrile infections due to neutropenia. Other possible causes of fever except infections in the context of his neutropenia were excluded. OUTCOMES: After the 12th cycle of 5-azacytidine the patient showed a hematologic response, with transfusion independency and with no recurrent febrile episodes. LESSONS: This case report probably indicates that a subset of patients who belong to the lower risk category according to the previous prognostic systems and to the intermediate one according to the IPSS-R, may benefit from prolonged treatment with the drug. The indication of 5 azacytidine in Europe for patients with higher risk myelodysplastic syndrome (MDS) (according to the IPSS) could possibly include a wider range of patients if updated according to the IPSS-R. PMID- 29703016 TI - A case report of life-threatening acute dysphagia in dermatomyositis: Challenges in diagnosis and treatment. AB - RATIONALE: Although dysphagia is a known complication of dermatomyositis, sudden onset of dysphagia without the notable aggravation of other symptoms can make the diagnosis and treatment challenging. PATIENT CONCERNS: A 53-year-old male diagnosed as dermatomyositis 1 month ago came to our emergency department complaining of a sudden inability to swallow solid foods and liquids. The patient showed generalized edema, but the muscle power was not different compared with 1 month ago. DIAGNOSES: Serum creatine kinase level was lower than that measured 2 weeks ago. Computed tomography scan of the larynx, chest, abdomen, and pelvis, an esophagogastroduodenoscopy, and brain magnetic resonance imaging were unremarkable. A videofluoroscopic swallowing study revealed inadequate pharyngeal contraction and slightly decreased upper esophageal sphincter opening with silent aspiration. INTERVENTION: Treatment with oral prednisolone, intravenous methylprednisolone, azathioprine, and intravenous immunoglobulins was applied. During the course of medical treatment for life-threatening dysphagia, he continued with rehabilitative therapy. OUTCOMES: He could swallow saliva at 2 months and showed normal swallowing function at 3 months from the onset of dysphagia. Dysphagia has not recurred for 3 years after recovery. LESSONS: A multidisciplinary approach is necessary to diagnose severe acute dysphagia due to exacerbation of underlying dermatomyositis rather than other structural or neurological causes. Appropriate supportive care is important because dysphagia can be life-threatening and last for a long time. PMID- 29703017 TI - Osteochondroma of ventral scapula associated with chest pain due to rib cage compression: A case report. AB - RATIONALE: The scapula is relatively rare site for osteochondroma. Scapula osteochondroma is usually asymptomatic, however it may present with features such as pseudowinging, snapping scapula, bursa formation, chronic pain, and cosmetic deformities. To our best knowledge, this is the first report in the English literature about osteochondroma of ventral scapula associated with chest pain due to rib cage compression. PATIENT CONCERNS: A 14-year-old boy was transferred to the orthopedic clinic from thoracic surgery department with a complaint of intermittent, dull, and diffuse aching pain around left chest wall and back from the past 2 months. The patient was previously diagnosed with multiple osteochondromas on another side; proximal tibia and distal femur. DIAGNOSIS: A radiopaque mass like lesion was observed on the scapula in the posteroanterior view of the chest, and compression of chest wall was also seen. In chest computed tomography (CT), pedunculated outgrowing bony mass was noted in the anterior aspect of the left scapular wing, which showed the continuity of bony cortex and medulla. This bony mass showed the mass effect on the left chest wall, causing left thoracic cavity deformity by making it narrower than the right INTERVENTIONS:: Surgery was performed under general anesthesia. After the surgery, the arm was immobilized by putting it in an abductor pillow brace for 3 weeks, and during that period pendulum exercise was permitted. OUTCOMES: The patient's symptoms resolved in the immediate postoperative period. At 1 year's follow-up, the patient was symptom free and there was no evidence of recurrence of the tumor. LESSONS: We recommend that in case of patients who have a history of osteochondroma and complaint of chest pain, surgeons should become suspicious of the presence of osteochondroma of the ventral scapula. In this situation, we recommend chest radiography, pulmonary function test, and chest CT for early detection and treatment. PMID- 29703018 TI - Multiple unexpected lesions of metachondromatosis detected by technetium-99m methylene diphosphonate SPECT/CT: A case report. AB - RATIONALE: Metachondromatosis (MC) is a very rare genetic disease, which is infrequently reported worldwide, which leads to osteochondroma and enchondromatosis. The disease has been shown to be associated with loss of function of the tumor suppressor gene "protein tyrosine phosphatase, non-receptor type 11" (PTPN11). PATIENT CONCERNS: A 12-year-old female was admitted to the hospital with pain due to an enlarged mass in her left fifth finger. DIAGNOSIS: Examination of the left hand by computed tomography (CT) revealed an expanding type of round and low-density lesion in the fifth proximal phalanx. The patient then underwent technetium-99m methylene diphosphonate single-photon emission CT/CT (Tc-MDP SPECT/CT) to assess the nature of the lesion. The SPECT/CT image revealed dilated osteopathy and increased activity of the fifth proximal phalanx on the left hand. Unexpectedly, the examination of the right hand revealed slight expanded lesions and increased activities of the third metacarpal and proximal phalange, as well as the fourth proximal phalange and the middle phalanx. On the basis of the patient's symptoms and the results of the above-mentioned examinations, we diagnosed the patient as having MC in her hands. INTERVENTION: Considering the pain of the fifth finger of the left hand, the patient underwent debridement of the fifth proximal phalanx of the left hand and internal fixation with bone graft taken from the body. OUTCOMES: The patient was discharged after a week of observation. One year later, she was admitted to the hospital again for removal of the bone healing internal fixation after osteoma surgery. Preoperative Tc-MDP SPECT/CT revealed that the left-handed lesions displayed postoperative changes, while the multiple lesions in the right hand increased in volume but remained unchanged in number. LESSONS: This case revealed the CT and Tc-MDP SPECT/CT imaging features of MC. Specifically, SPECT/CT imaging contributed to the diagnosis of clinically asymptomatic bone lesions, and the 3D SPECT/CT fusion allowed a more comprehensive and intuitive view of the lesion by combining anatomy and function. PMID- 29703019 TI - Coffee consumption and risk of esophageal cancer incidence: A meta-analysis of epidemiologic studies. AB - BACKGROUND: In epidemiologic studies, association between coffee consumption and esophageal cancer risk is inconsistent. OBJECTIVE: The aim of tjis study was to evaluate the effect of coffee on esophageal cancer by combining several similar studies. METHODS: We conducted a meta-analysis for association of coffee intake and esophageal cancer incidence. Eleven studies, including 457,010 participants and 2628 incident cases, were identified. A relative risk (RR, for cohort study) or odds ratio (OR, for case-control study) of heavy coffee drinkers was calculated, compared with light coffee drinkers or non-drinkers. The analysis was also stratified by cancer types (esophageal squamous cell carcinoma and esophageal adenocarcinoma), sex, and geographic region. RESULTS: The summarized OR of having esophageal cancer in heavy coffee drinkers was 0.93 (95% confidence interval [CI]: 0.73-1.12), compared with light coffee drinkers. When stratified by sex, pathologic type of esophageal cancer, and type of epidemiologic study, we did not find any association of coffee consumption and esophageal cancer incidence. However, an inverse association between coffee consumption and incidence of esophageal cancer was found in East Asia participants with OR of 0.64 (95% CI: 0.44-0.83), but not in Euro-America participants (OR = 1.05; 95% CI: 0.81-1.29). CONCLUSION: There is a protective role of coffee consumption against esophageal cancer in East Asians, but not in Euro-Americans. PMID- 29703020 TI - Flumazenil reduces respiratory complications during anesthesia emergence in children with preoperative upper respiratory tract infections. AB - Despite its benignity, upper respiratory infections (URIs) 1 increase the risk of postoperative respiratory complications during the perioperative and postoperative periods. Flumazenil could improve the symptoms of respiratory obstruction.To evaluate the effect of flumazenil on the occurrence of respiratory complications during anesthesia emergence of children with preoperative URI.This was a prospective study of 164 consecutive pediatric patients who underwent strabismus surgery under general anesthesia at the Tianjin Eye Hospital between August 2016 and April 2017. The patients were grouped as: normal airway (N), recent mild URI (I), normal airway and flumazenil (NF), and recent mild URI and flumazenil (group IF) (n = 41/group). An initial dose of flumazenil (0.1 mg) was administrated intravenously to groups IF and NF. The intraoperative and postoperative respiratory complications were recorded by one anesthesiologist unaware of the grouping.All patients underwent surgery uneventfully. The incidence of postoperative respiratory complications in post-anesthesia care unit (PACU) was higher in group I compared with the other 3 groups (IF: 17%; I: 41%; NF: 5%; N: 10%; P = .0147). During the PACU period, significant differences among groups were seen for cough (IF: 15%; I: 20%; NF: 2%; N: 0%; P = .004), secretion (IF: 17%; I: 29%; NF: 5%; N: 7%; P = .007), low oxygen saturation (IF: 12%; I: 32%; NF: 2%; N: 7%; P = .001), and glossocoma (IF: 15%; I: 34%; NF: 10%; N: 32%; P = .015).Respiratory complications during anesthesia emergence were higher in patients with recent preoperative URI compared to patients with healthy airways. Postoperative flumazenil could reduce the incidence of glossocoma. PMID- 29703021 TI - Rare foreign body in bladder: A case report. AB - RATIONALE: The bladder is the most common site of foreign bodies in the urinary tract. Presenting complaints in patients with a foreign body are urinary retention, dysuria, frequent urination, decreased urine volume, nocturia, hematuria, painful erection, as well as pain in the urethra and pelvis. PATIENT CONCERNS: A 50-year-old married male presented with complaints of severe lower abdominal pain and dysuria. DIAGNOSES: A plain radiograph of the pelvis showed a metallic dense foreign body that was composed of many small magnetic balls in the pelvic region. INTERVENTIONS: The foreign body was removed under cystoscopy, and 67 magnetic balls were detected without any surgical or postsurgical complications. OUTCOMES: During operation, A cystoscopic examination confirmed no residue. LESSONS: The bladder is the most common site of a foreign body in the urinary tract.Most intravesical foreign bodies can be removed transurethrally and with minimum access. The best mode of management depends on the nature of the foreign body, lodged site, expertise of the surgeon, and available instruments. PMID- 29703022 TI - Adolescent PR3-ANCA-positive hypertrophic pachymeningitis: A case report and review of the literature. AB - RATIONALE: Hypertrophic pachymeningitis (HP) is an uncommon, life-threatening disease that is seen in elderly patients with antineutrophil cytoplasmic antibody (ANCA) positivity. Proteinase-3 (PR3)-ANCA-positive HP has not been reported in adolescents. Here, we report the first case of adolescent PR3-ANCA-positive HP successfully treated with immunosuppressive therapy. PATIENT CONCERNS: A 14-year old female presented with fullness and pain in her right ear unresponsive to antibiotics. Laboratory tests showed an elevated C-reactive protein and PR3-ANCA positivity. Computed tomography and magnetic resonance imaging revealed mastoiditis in the right temporal bone. Surgical biopsy revealed severe fibrosis and prominent inflammatory-cell infiltration. She received prednisolone and methotrexate therapy, and then underwent a right mastoidectomy. Five months later, she developed headache, dysarthria, and multiple cranial nerve palsies. Further imaging revealed enhancement and thickening of the right hemispheric dura. DIAGNOSIS: PR3-ANCA-positive HP. INTERVENTIONS: She was successfully treated with steroid pulse therapy for 3 days, followed by high doses of prednisolone and intravenous cyclophosphamide. OUTCOME: The treatment resulted in significant improvement of her symptoms, laboratory data, and radiologic findings. LESSONS: PR3-ANCA-positive HP can present not only in the elderly, but also in adolescence, and prompt diagnosis and treatment with immunosuppressive therapy is vital. PMID- 29703023 TI - Serum irisin associates with breast cancer to spinal metastasis. AB - The aim of this study was to determine whether the serum level of irisin can be a candidate to predict the spinal metastasis in patients with breast cancer.In a cross-sectional study, 148 patients were recruited. Of those, 53 (35.8%) had spinal metastasis. The baseline characteristics were compared by status of spinal metastasis. Multiple logistic regression analysis was used to determine whether the serum irisin can be a candidate for predicting breast cancer to spinal metastasis. The correlation coefficient analysis was used to confirm the correlation between the serum irisin and lipid metabolic parameters and body mass index (BMI), respectively.The serum irisin was higher in patients without spinal metastasis (7.60 +/- 3.80). Multivariable analysis showed that the serum irisin was protective to the presence of spinal metastasis in patients with breast cancer after adjustments of age and BMI (odds ratio, 0.873; 95% confidence interval, 0.764-0.999). Furthermore, there was a positive correlation between the serum irisin and BMI (r = 0.263). The patients with metabolisc syndrome (MetS) had a higher level in serum irisin. In addition, the higher numbers of MetS components were associated with higher serum irisin.Higher serum irisin can be a protective factor of spinal metastasis in patients with breast cancer. The BMI is positively associated with the serum level of irisin. Furthermore, patients with MetS tended to have a higher level of serum irisin. PMID- 29703024 TI - JianPi HuaZhuo XingNao formula (Chinese herbal medicine) for the treatment of minimal hepatic encephalopathy: a protocol for a randomized, placebo-controlled pilot trial. AB - BACKGROUND: Minimal hepatic encephalopathy (MHE) is a subclinical state of hepatic encephalopathy with the possibility of developing into overt hepatic encephalopathy (OHE) and having adverse outcomes. However, no preventative medicine for MHE has been recommended so far. The aim is to evaluate the therapeutic effect of the JianPi HuaZhuo XingNao formula (JPHZXN) on MHE, specifically whether JPHZXN decreases OHE occurrence, through a randomized controlled trial. METHOD: Seventy-two patients with MHE are enrolled and allocated in a 1:1 ratio in an experimental group and a control group. JPHZXN granules and placebos are dispatched to the experimental group and control group, respectively, for 24 weeks. The primary outcome is the incidence of developing OHE. The secondary outcomes are the patients' performances in number connection test A and the digital sign test as well as results from the health survey and chronic liver disease questionnaire. RESULTS: This study will provide proof regarding the therapeutic effect of JPHZXN among patients with MHE. CONCLUSION: The outcomes could grant clinicians an alternative choice when treating potentially progressive patients with MHE. PMID- 29703025 TI - Association between perioperative hypothermia and patient outcomes after thoracic surgery: A single center retrospective analysis. AB - Hypothermia due to anaesthetic-induced impairment of thermoregulatory control and exposure to a cool environment is common in surgical patients. Peripheral vasodilation due to neuroaxial blockade may aggravate hypothermia. There is few data on perioperative hypothermia in patients undergoing thoracic surgery under combined general and regional anesthesia. We reviewed all thoracic surgical patients between 2006 and 2011 to determine the incidence and extent of hypothermia with or without an epidural anesthesia and evaluated its effect.Around 339 patients underwent lung resection procedures with intraoperative forced-air warming: 197 with general and epidural anesthesia (GA + EPI), 199 with general anesthesia alone (GA). Statistical analyses were performed to determine the association between hypothermia (T < 36 degrees C) and transfusion requirements, length of stay (LOS) in the intensive care unit (ICU), hospital LOS, and in hospital mortality.The overall incidence of hypothermia was 64.3%. Multivariate regression analysis revealed three significant risk factors for the development of hypothermia: long induction time (P = .011), small body surface area (P = .003), and application of more fluid intraoperatively (P < .001). Factors determining the extent of hypothermia were: receiving an open thoracotomy (P = .009), placement and use of an epidural catheter (P = .002), and a lower body mass index (BMI) (P < .001). Additional epidural anesthesia reduced core temperature by 0.26 degrees C (95% CI -0.414 to -0.095 degrees C, P < .05). There was no difference in transfusion requirements, ICU LOS or mortality between both groups. Hospital LOS was longer in patients with hypothermia.More than half of all thoracic patients suffered from hypothermia. A long induction time, small body surface area, and large intraoperative fluid application were independent risk factors for the development of perioperative hypothermia. Additional epidural anesthesia to general anesthesia did not increase the incidence of hypothermia but decreased body core temperature to an-albeit not clinically significant-degree. Patients scheduled for thoracic surgery will probably benefit from an additional period of prewarming prior to induction to reduce the high incidence of perioperative hypothermia. PMID- 29703026 TI - Acquired treatment response from neoadjuvant chemotherapy predicts a favorable prognosis for local advanced cervical cancer: A meta-analysis. AB - BACKGROUND: Local advanced cervical cancer (LACC) is a considerable health crisis for women, and neoadjuvant chemotherapy (NACT) followed by radical surgery has been a suggested therapy method. However, the correlation between the tumor treatment response to NACT and the prognosis of LACC remains controversial. METHODS: A comprehensive meta-analysis was performed to precisely assess the prognostic role of the clinical response and pathological response to NACT for LACC. The included studies were identified using PubMed and Web of Science up to July 2017. Hazard ratios (HR) and corresponding 95% confidence intervals (95% CI) for overall survival (OS) and disease-free survival (DFS) were determined using Review Manager (version 5.3) and Stata (version 12). RESULTS: A total of 13 publications of 4727 cases were included. The treatment clinical response rate ranged from 58.49% to 86.54%, and the pathological response rate was 7.5% to 78.81%. Our combined results suggested that a clinical response was favorable for OS (HR=3.36, 95% CI: 2.41-4.69) and DFS (HR=2.36, 95% CI: 1.82-3.06). Further, a pathological response predicts favorable OS (HR=5.45, 95% CI: 3.42-8.70) and DFS (HR=3.61, 95% CI: 2.0-6.52). CONCLUSION: The response to NACT, including the clinical and pathological response, was associated with a favorable prognosis for patients with LACC. However, the predictive value of this factor in clinical practice warrants further in-depth research. PMID- 29703027 TI - Multimodality imaging features, treatment, and prognosis of post-transplant lymphoproliferative disorder in renal allografts: A case report and literature review. AB - RATIONALE: Among patients with post-transplant lymphoproliferative disorder (PTLD), there is a high incidence of immunosuppressed transplant recipients. It is necessary to make an early diagnosis to increase the likelihood of a good prognosis. PATIENT CONCERNS: We report a case of a 54-year-old female patient who developed PTLD after liver and kidney transplantation. DIAGNOSES: We aimed to analyze the standard diagnosis and follow-up of PTLD with imaging. Radiologists need to be familiar with all imaging modalities when dealing with PTLD, including ultrasonography, computed tomography, magnetic resonance imaging, positron emission tomography/computed tomography. INTERVENTIONS: The initial treatment included both reduction of immunosuppression and rituximab. Then the treatment strategy changed to rituximab and chemotherapy. Finally, the treatment strategy combined glucocorticoid therapy. OUTCOMES: The patient was in a stable condition at the 3-month follow-up. LESSONS: Systematic evaluation of the various imaging modalities, treatment options, and prognoses of PTLD in renal allografts suggested that in cases with a poor prognosis, the proper imaging modalities provide essential information with regard to the determination of the appropriate treatment. PMID- 29703028 TI - Osteoporosis and fracture after gastrectomy for stomach cancer: A nationwide claims study. AB - This study was planned to evaluate the incidence and risk factors of osteoporosis and fracture after gastrectomy for stomach cancer using a nationwide claims database in South Korea.Data from 41,512 patients (50-79 years) who underwent gastrectomy for stomach cancer from 2008 to 2010 with at least 5 years of follow up were obtained from the Health Insurance Review and Assessment Service database. Patients diagnosed with osteoporosis and prescribed bisphosphonate or raloxifene or who experienced osteoporotic fractures after gastrectomy were operationally defined as osteoporosis. Osteoporotic fracture was defined as a fracture at common osteoporotic fracture sites (spine, pelvis, hip, forearm, or rib).In total, 37,076 patients were included in the final analysis. The incidences of postgastrectomy osteoporosis and osteoporotic fractures were 41.9 and 27.6 cases per 1000 person-years, respectively. Multivariate analysis showed that older age (hazard ratio [HR] 1.88; 95% confidence interval [CI] 1.79-1.96), female gender (HR 2.46; 2.35-2.58), total gastrectomy (HR 1.10; 1.04-1.16), and diabetes (HR 1.16; 1.11-1.22) were significantly associated with osteoporosis and that older age (HR 1.90; 95% CI 1.80-2.01), female gender (HR 1.50; 1.41-1.58), total gastrectomy (HR 1.17; 1.10-1.25), chemotherapy (HR 1.06; 1.00-1.12), and diabetes (HR 1.26; 1.19-1.33) were significantly associated with fractures. Osteoporotic fractures occurred a median 3.1 years after gastrectomy. Among the 5175 fracture patients, 780 (15.1%) experienced multisite fractures, mostly in the elderly and chemotherapy groups.The osteoporosis and osteoporotic fracture incidences are high in patients within a relatively short timeframe after gastrectomy for stomach cancer. Systematic management of osteoporosis is necessary after this surgery. PMID- 29703029 TI - Attrition rupture of ulnar nerve in a patient with rheumatoid elbow arthritis: A case report. AB - RATIONALE: Cubital tunnel syndrome has been recognized as a common pathology in rheumatoid arthritis (RA) of the elbow. We encountered a patient with RA of the elbow showing attrition rupture of the ulnar nerve. This pathology is extremely rare, and we discussed preventive measures for similar cases in the future based on our case. PATIENT CONCERNS: A 53-year-old woman, received drug treatment for RA since 30 years earlier, had numbness in the left ulnar nerve territory, dorsal interossei muscle atrophy, and resulting claw hand. DIAGNOSES: Plain x-ray examination showed bone destruction of the left elbow joint and marked osteophyte formation in the medial joint space. In nerve conduction velocity (NCV) tests, the Motor NCV was immeasurable in the ulnar nerve territory. Based on these findings, a diagnosis of left cubital tunnel syndrome was made, and anterior transposition of the ulnar nerve was planned. INTERVENTIONS: When the ulnar nerve dissection was advanced, about 80% portion of the ulnar nerve was ruptured. After the ends of the divided nerve were freshened, end-to-end anastomosis was possible by anterior transposition of the ulnar nerve. OUTCOMES: Two years after the operation, numbness and muscle atrophy also remained. There were no changes in the level of daily activities after the operation. However, motor NCV, showed improvement (22.8 m/s) after the operation. LESSONS: In patients with RA showing ulnar neuropathy symptoms, marked osteophyte formation in the medial joint space or valgus deformity may indicate attrition nerve rupture. In the future, when such patients with RA are examined, active nerve exposure and dissection should be considered in terms of ulnar nerve protection. PMID- 29703030 TI - Primary leiomyosarcoma of the fallopian tube: A case report and literature review. AB - RATIONALE: Primary leiomyosarcoma (LMS) of the fallopian tube is extremely uncommon. To the best of our knowledge, so far only 21 cases of primary fallopian tube LMS have been reported in English-language literature. No new case has been reported in the past 7 years. PATIENT CONCERNS: A 44-year-old premenopausal patient presented with a 5-day history of lower abdominal pain. DIAGNOSES: Pelvic ultrasonography detected an 8.8 * 7.8 * 6.5 cm solid and cystic mass in the left side of the pelvic cavity. The tumor was diagnosed as a primary fallopian tube LMS on paraffin section. INTERVENTIONS: The patient treated surgically followed by 4 cycles of postoperative chemotherapy with dacarbazine and DDP. OUTCOMES: The patient succumbed to the disease 27 months after the initial therapy. LESSONS: Tube LMS is a rare malignant tumor with unknown etiology, difficult early diagnosis, highly invasiveness, high local recurrence and distant metastasis rate, rapid progress, and poor prognosis. It is extremely rare so we can only summarize limited experience from limited data. Every case of tubal LMS is worth being reported. PMID- 29703031 TI - Use of low-level laser therapy on children aged 1 to 5 years with energy-protein malnutrition: A clinical trial. AB - BACKGROUND: Episodes of malnutrition in early childhood can produces alterations in the salivary glands. The investigation of mechanisms that can reduce the impact of malnutrition on the defenses of the organism is of the utmost important and interest to public health. The aim of this study is to evaluate the effect of low-level laser on the saliva of children aged 1 to 5 years with energy-protein malnutrition. METHODS: Mandatory inclusion criteria are diagnosis of malnutrition. The sample will consist of 50 men and women malnourished children aged 12 to 71 months. Saliva will be collected and the volume of saliva will be measured and the salivary flow rate will be determined (mL/min). Concentrations of salivary IgA in all samples will be measured using a commercial Enzyme-Linked Immunosorbent Assay (ELISA) kit. Low-level laser (laser diode) will be administered in the region of the parotid glands bilaterally as well as in the regions of the submandibular and sublingual glands. DISCUSSION: This study will be the first that investigate the effects of local laser therapy on the salivary glands of malnourished children. TRIAL REGISTRATION: Clinical.trials.gov as NCT03355313, first received in 21 November 2017. PMID- 29703032 TI - Acetylcholine receptor antibody-positive myasthenia gravis associated with small cell lung cancer: A case report. AB - RATIONALE: Only few cases of myasthenia gravis (MG) associated with small-cell lung cancer (SCLC) have been reported, and cases positive for acetylcholine receptor antibody (AChR-ab) are even rarer. The efficacy of standard MG treatment, such as cholinesterase inhibitor therapy, immunosuppressive therapy using steroids and immunosuppressive drugs, plasma exchange, and intravenous immune globulin (IVIg), for these cases is unclear. PATIENT CONCERNS AND DIAGNOSES: A 71-year-old man complained of bilateral eyelid ptosis. He also presented with dysphagia and masticatory muscle fatigue after chewing. The edrophonium test was positive, and the serum AChR-ab level was increased; therefore, the patient was diagnosed with MG. Computed tomography scan showed a nodule on the left upper lobe of the lung and mediastinal lymphadenopathy. Further examination revealed the lesion as SCLC. Finally, he was diagnosed with AChR-ab-positive MG associated with SCLC. INTERVENTIONS AND OUTCOMES: Oral pyridostigmine and tacrolimus were administered to treat MG; however, his symptoms worsened. Therefore, methylprednisolone and IVIg were administrated, which temporarily improved his symptoms. However, they remained uncontrolled. Meanwhile, chemotherapy with carboplatin and etoposide was administered to treat his SCLC. The lesions shrunk, and the MG symptoms and serum AChR-ab level also improved. LESSONS: AChR-ab-positive MG may develop as a comorbidity of SCLC. In such cases, management might require treatment for SCLC in addition to the standard MG treatment to stabilize the MG symptoms. PMID- 29703033 TI - Application of thoracic endovascular aortic repair (TEVAR) in treating dwarfism with Stanford B aortic dissection: A case report. AB - RATIONALE: To apply thoracic endovascular aortic repair (TEVAR) to treat dwarfism complicated with Stanford B aortic dissection. PATIENT CONCERNS: In this report, we presented a 63-year-old male patient of dwarfism complicated with Stanford B aortic dissection successfully treated with TEVAR. DIAGNOSES: He was diagnosed with dwarfism complicated with Stanford B aortic dissection. INTERVENTIONS: After conservative treatment, the male patient underwent TEVAR at 1 week after hospitalization. After operation, he presented with numbness and weakness of his bilateral lower extremities, and these symptoms were significantly mitigated after effective treatment. At 1- and 3-week after TEVAR, the aorta status was maintained stable and restored. OUTCOMES: The patient obtained favorable clinical prognosis and was smoothly discharged. During subsequent follow-up, he remained physically stable. LESSONS: TEVAR is probably an option for treating dwarfism complicated with Stanford B aortic dissection, which remains to be validated by subsequent studies with larger sample size. PMID- 29703034 TI - Usefulness of 18F-FDG PET/CT for evaluating response of ocular adnexal lymphoma to treatment. AB - The purpose of this study was to investigate the efficacy of F-fluoro deoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) for evaluating the ocular adnexal lymphoma treatment responses.We retrospectively reviewed data for 9 histologically confirmed cases of malignant lymphoma. All patients had at least one ocular adnexal tumor site and underwent FDG PET/CT before and after treatment. Patients' histological disease subtypes included diffuse large B-cell lymphoma (n = 3), mucosa-associated lymphoid tissue lymphoma (n = 2), follicular lymphoma (n = 1), NK/T-cell lymphoma (n = 1), lymphoplasmacytic lymphoma (n = 1), and Hodgkin lymphoma (n = 1). The highest FDG uptake by the ocular adnexal lesions was calculated as the maximum standardized uptake value (SUVmax). FDG uptake at ocular adnexal sites and sites of systemic disease after treatment were also assessed using the 5-point Deauville scale.In 1 of the 9 patients, a conjunctival lesion could not be detected by either pre- or posttreatment PET/CT. For 8 of the 9 patients, the SUVmax value at the ocular adnexal site significantly decreased after treatment (7.1 +/- 5.1 vs 1.6 +/- 0.58; P = .0196). For 7 of the 9 patients, the first posttreatment FDG uptake at the ocular adnexal site was considered a complete metabolic response, and these patients showed an improved clinical ophthalmic presentation with no relapse at ocular adnexal sites during follow-up.FDG PET/CT is useful for evaluation of the response of ocular adnexal lymphoma to treatment, although its usefulness may depend on the histological subtype and site of the lesion. PMID- 29703035 TI - Radiological features of azygos and hemiazygos continuation of inferior vena cava: A case report. AB - RATIONALE: Azygos and hemiazygos continuation of the inferior vena cava (IVC) is uncommon. It is rare especially when it is not associated with congenital heart disease or deep venous thrombosis. PATIENT CONCERNS: We report an interesting case of an interstitial lung disease with an interrupted IVC with azygous and hemiazygos continuation. A 67-year-old man suffered from cough and shortness of breath. DIAGNOSES: Computed tomography revealed absence of the hepatic segment of the IVC with azygos and hemiazygos continuation. The patient did not have congenital anomalies of the remaining thoracoabdominal vasculature and viscera. The diagnosis of azygos and hemiazygos continuation of IVC was made by inferior venacavography. INTERVENTIONS: There was no significant association between interstitial lung disease and expanded azygos and hemiazygos veins. The patient was treated with corticosteroids. OUTCOMES: After 6 months of follow-up, the patient was asymptomatic. LESSONS: It is important to recognize the enlarged azygos vein at the confluence with the superior vena cava and in the retrocrural space to avoid misdiagnosis as a right-sided paratracheal mass or retrocrural adenopathy. PMID- 29703036 TI - Entrapment of a metal foreign body in the cervical spinal canal during surgical procedure: A case report. AB - RATIONALE: Retention of foreign objects in spinal canal usually results from penetrating spinal trauma or failed internal instruments. However, entrapment of a foreign body in cervical spinal canal during surgery is rare, and whether such an object may cause neurological complications remains unknown in literature. PATIENT CONCERNS: A 50-year-old man underwent C5 corpectomy and instrumentation surgery due to cervical myelopathy. During the surgery, the cutting edge of a Kerrison rongeur was broken and the metal tip was retained behind C4 vertebra. DIAGNOSIS: Retention of foreign body in the cervical spinal canal. INTERVENTIONS: To remove the metal object, multiple strategies were tried but all failed. As such a metal object was thought to be dangerous to the spinal cord, a remedy C4 corpectomy was performed to remove it. Accidentally, however, the metal fragment further migrated to C2/3 canal. At last, the metal fragment had to be retained in the cervical spinal canal. OUTCOMES: At 2-year follow-up, the metal fragment remained in situ and no delayed complications occurred. LESSONS: We reported a rare case of metal object retention in cervical spinal canal due to rongeur fatigue fractures. Under certain circumstances, retention of a small foreign object in spinal canal may not lead to neurological complications. If failed to remove an entrapped foreign body, it may be safe to leave it in the spinal canal for further observation. PMID- 29703037 TI - Fatal malignant pertussis with hyperleukocytosis in a Chinese infant: A case report and literature review. AB - RATIONALE: Pertussis has re-emerged on a global scale and is an ongoing public health problem, even in countries with high rates of vaccination. Hyperleukocytosis [white blood cell (WBC) count >100 * 10/L] is a rare complication that strongly predicts mortality in cases of severe pertussis. PATIENT CONCERNS: We report a case of severe pertussis in an infant who initially presented with persistent cyanotic cough, tachypnea, and grunting. The infant's condition deteriorated rapidly, and she was transferred to the pediatric intensive care unit (PICU) during her third hour of hospitalization. On the third hospital day, her WBC count had increased to 101.85 * 10/L with a lymphocyte count of 36.76 * 10/L, and her hemoglobin level had fallen to 6.9 g/dL. Bone marrow examination found no evidence of tumor cells. Her initial echocardiogram showed no abnormal findings; however, a subsequent echocardiogram 10 days later revealed pulmonary hypertension. DIAGNOSES: The patient was diagnosed with severe pneumonia, which was confirmed to be pertussis based on a persistent cough in the infant's mother and the polymerase chain reaction and culture of the infant's nasopharyngeal secretions being positive for Bordetella pertussis. INTERVENTIONS: The infant was treated with supportive care, early macrolide antibiotics, and broad-spectrum antibiotics before being transferred to the PICU for further management, including continuous venovenous hemodiafiltration. OUTCOMES: Unfortunately, the infant died as a result of pulmonary hypertension and multiorgan failure. LESSONS: Exchange transfusion should be considered in all infants who present with severe pertussis with hyperleukocytosis. This guideline is supported by the findings of a comprehensive literature review, which is included in this article, as well as newly published criteria for exchange transfusion therapy. Finally, we hope that adults in China will be vaccinated against B. pertussis in order to prevent the infection of infants within their households. PMID- 29703038 TI - Dedifferentiated endometrioid adenocarcinoma with trophoblastic components and elevated serum alfa-fetoprotein: A case report and literature review. AB - RATIONALE: Dedifferentiated endometrioid adenocarcinoma (DEAC) consisted of a combination of undifferentiated and differentiated carcinoma is more aggressive than other conventional endometrioid adenocarcinomas. PATIENT CONCERNS: A 33-year old woman with atypical vaginal bleeding was refereed to our hospital. She had an endometrial biopsy in a local clinic which showed differentiated endometrioid carcinoma with trophoblastic components. High levels of beta-Human chorionic gonadotropin (beta-hCG) and alfa-fetoprotein (AFP) were detected in the patient's serum. INTERVENTIONS: The patient underwent total hysterectomy with bilateral salpingo-oophorectomy, total omentectomy and systemic pelvic lymphadenectomy in our center. DIAGNOSIS: Pathological investigation indicated that the tumor had well differentiated and undifferentiated adenocarcinoma as well as trophoblastic components. OUTCOMES: Serum beta-hCG and AFP dropped significantly after operation. But three weeks later, the patient had developed pulmonary metastases and elevation of serum beta-hCG. She died of the disease five months after surgery. LESSONS: DEAC with trophoblastic differentiation seems to follow an aggressive course with early metastasis and poor clinical prognosis. However, due to small number of cases, further studies are necessary. PMID- 29703039 TI - Hepatic veno-occlusive disease related to Gynura segetum: A case report. AB - INTRODUCTION: Hepatic veno-occlusive disease (HVOD), as known as hepatic sinusoidal obstruction syndrome (HSOS), is an obliterative venulitis of the terminal hepatic venules, which is responsible for considerable mortality. The potential mechanism is destruction of hepatic sinusoidal endothelial cells (SEC), with sloughing and downstream occlusion of terminal hepatic venules. Here, we report a case of HVOD who have a history of ingestion of Gynura segetum for 1 month. The patient presents for abdominal pain and distension. He was diagnosed for HVOD using computerized tomography (CT) and ultrasonography of liver. And then best supportive care was added. However, without liver transplantation for financial reason, he died in 1 month after discharged from hospital. CONCLUSIONS: We think portal flow reversal was a characteristic imaging findings of HVOD, which can be listed as a specific diagnostic criterion of HVOD. Once the condition was worsening, liver transplantation should be considered as the first choice of treatment planning. PMID- 29703040 TI - Electro-acupuncture attenuates inflammatory responses and intraabdominal pressure in septic patients: A randomized controlled trial. AB - BACKGROUND: A pathological increase in intraabdominal pressure (IAP) and inflammatory responses have negative effects on splanchnic, respiratory, cardiovascular, renal, and neurological function in septic patients with intestinal dysfunction. Electro-acupuncture (EA) has been evidenced to have a bidirectional neuron-endocrine-immune system regulating effect in patients with intestinal dysfunction. The purpose of current study was to evaluate the effects of EA at "Zusanli" (ST36) and "Shangjuxu" (ST37) on inflammatory responses and IAP in septic patients with intestinal dysfunction manifested syndrome of obstruction of the bowels Qi. METHODS: Eighty-two septic patients with intestinal dysfunction manifested syndrome of obstruction of the bowels Qi were randomly assigned to control group (n = 41) and EA group (n = 41). Patients in control group were given conventional therapies including fluid resuscitation, antiinfection, vasoactive agents, mechanical ventilation (MV), supply of enteral nutrition, and glutamine as soon as possible. In addition to conventional therapies, patients in EA group underwent 20-minutes of EA at ST36-ST37 twice a day for 5 days. At baseline, posttreatment 1, 3, and 7 days, serum levels of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) and IAP levels, were measured, respectively. And days on MV, length of stay in intensive care unit (ICU) and 28 days mortality were recorded. RESULTS: The serum levels of TNF-alpha and IL-1beta and IAP levels at posttreatment 1, 3, and 7 days were lower significantly in the EA group compared with the control group (mean [SD]; 61.03 [20.39] vs 79.28 [20.69]; P < .005, mean [SD]; 35.34 [18.75] vs 66.53 [30.43]; P < .005 and mean [SD]; 20.32 [11.30] vs 32.99 [20.62]; P = .001, respectively, TNF-alpha. Mean [SD]; 14.11 [5.21] vs 16.72 [5.59]; P = .032, mean [SD]; 9.02 [3.62] vs 12.10 [4.13]; P = .001 and mean [SD]; 5.11 [1.79] vs 8.19 [2.99]; P < .005, respectively, IL-1beta. Mean [SD]; 14.83 [5.58] vs 17.55 [3.37]; P = .009, mean [SD]; 11.20 [2.57] vs 14.85 [3.01]; P < .005 and mean [SD]; 8.62 [2.55] vs 11.25 [2.72]; P < .005, respectively, IAP). There were no significant differences in the duration of MV, length of stay in ICU, and 28d mortality between the groups. CONCLUSION: EA at ST36-ST37 attenuated inflammatory responses through reduction in serum levels of TNF-alpha and IL-1beta and IAP in septic patients with intestinal dysfunction manifested syndrome of obstruction of the bowels Qi. PMID- 29703041 TI - Effect of shape on bone cement polymerization time in knee joint replacement surgery. AB - BACKGROUND: Although many factors are known to influence the polymerization time of bone cement, it remains unclear which bone cement shape predicts the precise polymerization time. The purpose of this study was to investigate whether different cement shapes influenced polymerization time and to identify the relationship between cement shape and ambient operating theater temperature, relative humidity, and equilibration time. METHODS: Samples were gathered prospectively from 237 patients undergoing primary total knee arthroplasty. The cement components were made into 2 different shapes: lump and pan. The time at which no macroscopic indentation of both cement models was possible was recorded as the polymerization time. RESULTS: There was no significant difference between hand mixing (lump shape: 789.3 +/- 128.4 seconds, P = .591; pan shape: 899.3 +/- 152.2 seconds, P = .584) and vacuum mixing (lump shape: 780.2 +/- 131.1 seconds, P = .591; pan shape: 909.9 +/- 143.3 seconds, P = .584) in terms of polymerization time. Conversely, the polymerization time was significantly shorter for Antibiotic Simplex (lump shape: 757.4 +/- 114.9 seconds, P = .001; pan shape: 879.5 +/- 125.0 seconds, P < .001) when compared with Palacos R+G (lump shape: 829.0 +/- 139.3 seconds, P = .001; pan shape: 942.9 +/- 172.0 seconds, P < .001). Polymerization time was also significantly longer (P < .001) for the pan shape model (904 +/- 148.0 seconds) when compared with the lump shape model (785.2 +/- 129.4 seconds). In addition, the polymerization time decreased with increasing temperature (lump shape: R = 0.334, P < .001; pan shape: R = 0.375, P < .001), humidity (lump shape: R = 0.091, P < .001; pan shape: R = 0.106, P < .001), and equilibration time (lump shape: R = 0.073, P < .001; pan shape: R = 0.044, P < .001). CONCLUSIONS: The polymerization time was equally affected by temperature, relative humidity, and equilibration time regardless of bone cement shape. Furthermore, the pan shape model better reflected the cement polymerization time between implant and bone compared with the lump shape model. The current findings suggest that, clinically, constant pressure with the knee in <45 degrees of flexion needs to be applied until remaining pan shaped cement is completely polymerized. PMID- 29703042 TI - Genetic polymorphisms in very important pharmacogenomic variants in the Zhuang ethnic group of Southwestern China: A cohort study in the Zhuang population. AB - Pharmacogenomics, the study of the role of genetics in drug response, has recently become a focal point of research. Previous studies showed that genes associated with drug detoxification vary among different populations. However, pharmacogenomic information of the Zhuang ethnic group is scarce. The aim of the present study was to screen members of the Zhuang ethnicity in southwestern China for genotype frequencies of very important pharmacogenomic (VIP) variants and to determine the differences between the Zhuang ethnicity and other human populations.We genotyped 80 variants of VIP genes in 100 unrelated healthy Zhuang adults from the Yunnan province of China. Next, we analyzed the genotyping data with Structure and F-statistics (Fst).We compared our data with those of other populations using the HapMap data set, and observed that the frequency distribution of Zhuang population in Yunnan closely resembles that of JPT. Furthermore, population structure and Fst analysis showed that the Zhuang population is closely related to the Shaanxi Han population with respect to genetic background.Our study supplements existing information on Zhuang population pharmacogenomics and provides an extensive overview for developing personalized medicine. PMID- 29703043 TI - Cumulative sum analysis of the learning curve for video-assisted minilaparotomy donor nephrectomy in healthy kidney donors. AB - Video-assisted minilaparotomy surgery (VAMS) is a hybrid of open and laparoscopic surgical techniques, so has advantages of both approaches. Here, we examined the learning curve for this procedure.We retrospectively evaluated 50 consecutive patients who underwent VAMS donor nephrectomy performed by a single surgeon (YEY) between March 2015 and March 2016. The learning curve was evaluated using the cumulative sum (CUSUM) method. Measures of surgical performance included total operation time, warm ischemic time, and estimated blood loss.The mean patient age, body mass index, and body surface area were 43.5 years, 23.8 kg/m, and 1.7 m, respectively. The mean operation time and warm ischemic time were 160.0 minutes and 124.4 seconds. The learning curve of total operation time was best modeled as a second-order polynomial with equation CUSUMOT (minutes) = -0.3802 * case number + 20.315 * case number - 41.333 (R = 0.7707). The curve included 3 unique phases: phase 1 (the initial 17 cases), which is the initial learning curve; phase 2 (the middle 23 cases), expert competence, and phase 3 (the subsequent cases), mastery. In terms of warm ischemic time and estimated blood loss, the initial learning was achieved after 16 cases and after 9 to 10 cases, one could achieve competency.The VAMS donor nephrectomy learning curve is shorter than for laparoscopic or robotic hand-assisted donor nephrectomy. Surgeons can become familiar with the procedure and perform it without complications after approximately 16 to 17 operations. PMID- 29703044 TI - Effectiveness of aspiration or deroofing for blister management in patients with burns: A prospective randomized controlled trial. AB - BACKGROUND: Health care providers commonly encounter blisters when treating burn patients. The question as to whether burn blisters should be drained or deroofed has long been debated. To our knowledge, there has been no controlled, randomized clinical trial to determine which treatment is the best management option. METHODS: Between March 2016, and September 2016; 40 patients with burn blisters greater than 6-mm were enrolled in our study. Patients were randomized into 2 groups: aspiration group and deroofing group. The number of days to complete re epithelialization was noted. Patient and Observer Scar Assessment Scale data were recorded from subjects and investigators at 4 time points. Pain during dressing changes was evaluated using a visual pain scale. Bacterial cultures were also obtained. RESULTS: Average number of days to complete wound healing was 12 days in the aspiration group and 12.55 days in deroofing group. On the Patient and Observer Scar Assessment Scale, investigators found that the aspiration group scars demonstrated improvements in relief and thickness while subjects rated aspiration scars better in terms of pain. Patients with palm/sole blister in the deroofing group scored higher than aspiration group on the visual analogue pain score but it was also not statistically significant (2.66 vs 3.25). The overall incidence of colonization with microorganisms in each group was not significant (15% vs 40%). CONCLUSION: Neither aspiration nor deroofing is a superior treatment of burn blister. However, some objective indicators suggest that aspiration treatment might be more effective than deroofing treatment. PMID- 29703045 TI - A feasibility and safety study of concurrent chemotherapy based on genetic testing in patients with high-risk salivary gland tumors: Preliminary results. AB - BACKGROUND: This prospective study was conducted to evaluate the feasibility and safety of customized chemotherapy regimens based on the gene characteristics of salivary gland tumors. METHODS: Patients were enrolled with histologically confirmed intermediate or high grade, stage T3-4, N1-3 disease, and T1-2, N0 patients with a close (<=1 mm) or microscopically positive surgical margin were also enrolled in the study. All patients received radical surgery and postoperative concurrent chemoradiotherapy. To evaluate the responsiveness of therapies, the chemotherapy regimen was based on gene targets, beta-tubulin III, ABCB1, STMN1, and CYP1B1 (for docetaxel) and TYMS (for pemetrexed). The primary endpoints were treatment compliance and acute toxicities. RESULTS: A total of 20 patients were enrolled between September 2013 and January 2016. The median age was 46 years (range: 23-70 years). Genetic testing showed that 8 patients may have been sensitive to docetaxel, 5 patients may have been sensitive to pemetrexed, and 7 patients sensitive to either docetaxel or pemetrexed. All patients received the full dose of radiation. A total of 19 patients (95%) completed 2 cycles of concurrent chemotherapy (CCT). One patient treated concurrently with pemetrexed experienced grade 3 neutropenia. Three patients experienced grade 3 oral mucositis, and 2 patients experienced grade 3 dermatitis. CONCLUSION: Our study demonstrated that a CCT selecting method based on the gene targets associated with drug sensitivity was clinically feasible and safe. Further studies enrolled more patients with longer follow-up times are needed to confirm the clinical efficacy of this CCT selecting method. PMID- 29703046 TI - Creation, characterization, and assignment of opsonic values for a new pneumococcal OPA calibration serum panel (Ewha QC sera panel A) for 13 serotypes. AB - Pneumococcal conjugate vaccines (PCVs) have been very effective in reducing the disease burden caused by Streptococcus pneumoniae serotypes covered by the current vaccine formulations. However, the incidence of disease caused by serotypes not covered by the vaccine is increasing. Consequently, there are active efforts to develop new PCVs with additional serotypes in order to provide protection against the emergent serotypes. Due to costs and ethical issues associated with performing true vaccine efficacy studies, new PCVs are being licensed based on their immunogenicity, which may be assessed with 2 in vitro assays: enzyme-linked immunosorbent assay (ELISA) for quantitating antibody level and opsonophagocytic assay (OPA) for assessing protective function. While a standardized ELISA has been developed, OPA results from different laboratories can be quite disparate, even among laboratories utilizing the same platform. In order to harmonize OPA data, a recent international collaboration assigned opsonic indices to the US Food and Drug Administration (US FDA) reference serum, 007sp, as well as a panel of US FDA calibration sera. However, due to a low number of aliquots, the availability of these calibration sera is extremely limited. Because calibration sera are critical to establish the performance characteristics of an OPA, a second calibration serum panel was created, comprised of 20 sera collected from adults immunized with the 23-valent polysaccharide vaccine, with 150 to 500 aliquots prepared for each serum. In order to establish consensus OPA values of the 20 sera for the 13 serotypes in 13 valent PCV, the sera were tested by 4 laboratories in an international collaborative OPA study. The 007sp results of 1 laboratory deviated significantly from those obtained by the other laboratories, as well as from previously assigned values. Due to these discrepancies, the consensus values for the calibration sera were determined based on the data from the remaining laboratories. Thus, we were able to create a panel of sera with consensus opsonic values that could be used by outside laboratories to calibrate pneumococcal OPAs. Our results also confirmed findings of a previous study that normalization of OPA results significantly reduces interlaboratory variation, with normalization based on 007sp reducing variation by 43% to 74%, depending on serotype. PMID- 29703048 TI - Tolvaptan rescue contrast-induced acute kidney injury: A case report. AB - RATIONALE: Contrast-induced acute kidney injury is one of the most serious adverse effects of contrast media and is related to three distinct but interacting mechanisms: medullary ischemia, formation of reactive oxygen species and direct tubular cell toxicity, especially in the patients with chronic kidney disease. The strategies of treatment, including stabilization of hemodynamic parameters and maintenance of normal fluid and electrolyte balance, were similar to the management of other types of acute kidney injury. PATIENT CONCERNS: A 58 year-old woman experienced acute oligouria after complex percutaneous coronary intervention for multiple vessel coronary artery disease. DIAGNOSES: Chest radiography showed pulmonary congestion and hyponatremia was noted after fluid hydration for suspicious contrast-induced nephropathy. INTERVENTIONS: Oral tolvaptan, at 15mg per day, was used for three days. OUTCOMES: Urine output increased gradually and symptoms relieved one day later after using tolvaptan. Serum creatinine also improved to baseline level one week later after this event. LESSONS: Here, we reported an interesting case about contrast-induced acute kidney injury and hypervolemic hyponatremia, where tolvaptan was used to rescue the oliguric phase. Tolvaptan could be considered to use for contrast-induced acute kidney injury and had possibility of prevention from hemodialysis. Larger studies are still needed to investigate the role of tolvaptan in rescuing the oliguric phase in contrast-induced acute kidney injury. PMID- 29703047 TI - Gastrointestinal stromal tumors: Fibrinogen levels are associated with prognosis of patients as blood-based biomarker. AB - Improved prediction of prognosis for primary gastrointestinal stromal tumors (GISTs) after curative resection is an important goal in clinical practice. Coagulation factor of fibrinogen may inform prognosis of tumor patients as blood based biomarker. Here, we aimed to analyze the prognostic value of fibrinogen levels in patients with GIST and to explore potential threshold of fibrinogen on postoperative clinical outcome.A retrospective study was performed including data from 91 patients with newly diagnosed GISTs who underwent curative resection. Patients were followed-up for a median period of 2 years. Cox regression and competing risk analysis were applied to study the association between fibrinogen and risk of death or recurrence. Smoothing plot and threshold effect analysis were applied to learn the relationship further and explore potential threshold.High levels of fibrinogen are associated with decreased overall survival (OS) and recurrence free survival (RFS) in patients with GISTs. We discovered a nonlinear relationship between levels of fibrinogen and the risk of death or recurrence. Further, we detected a threshold for fibrinogen (3.7 g/L) on the prognosis of GISTs patients. When fibrinogen was above the inflection point, the increase in fibrinogen levels was strongly associated with increase in the risk of death or recurrence.Elevated fibrinogen can serve as an independent prognostic biomarker for a worse clinical outcome in GIST patients. PMID- 29703049 TI - Prognostic role of survivin in patients with glioma. AB - BACKGROUND: The aim of this study was to systematically evaluate the prognostic role of survivin in patients with glioma through performing a meta-analysis. METHODS: PubMed, Web of Science, Cochrane Library, and EMBASE were searched for potentially eligible literature. The study characteristics and relevant data were extracted. Hazard ratios (HRs) with 95% confidence intervals (CIs) were pooled to estimate the prognostic role of survivin in patients with glioma. RESULTS: Sixteen studies with 1260 patients were included. The pooled HR of higher survivin expression for overall survival was 1.96 (95% CI, 1.57-2.45). The pooled HRs of higher survivin expression for progression- and disease-free survival were 1.62 (95% CI, 0.91-2.90) and 2.41 (95% CI, 0.98-5.90), respectively. Subgroup analyses were also performed. CONCLUSION: Our results suggested that higher survivin expression was associated with worse overall survival in patients with glioma. The findings may assist future exploration on pathogenesis, diagnosis, anti-survivin therapy, and prognosis in glioma. However, due to the limited study number, more studies are warranted to verify our results. PMID- 29703050 TI - An observational study on the association between major dietary patterns and non alcoholic fatty liver disease in Chinese adolescents. AB - Data on the association of dietary patterns with non-alcoholic fatty liver disease (NAFLD) among adolescents are scarce. Hence, the purpose of this study was to ascertain the influence of dietary patterns and key foods on NAFLD among adolescents in Shandong, China. Data were extracted from Linyi Nutrition and Health study during 2015 to 2016. This cross-sectional study population comprised 1639 participants aged between 16 and 23 years. Dietary intake was assessed by the use of a semiquantitative food frequency questionnaire (FFQ), containing 85 food items. NAFLD diagnosis was defined as individuals whose ultrasound examination disclosed hepatic steatosis at any stage, in the absence of excess intake of alcoholic beverages. The odds ratio (OR) and 95% confidence interval (CI) were estimated for each quartile of the dietary pattern adherence scores using logistic regression analysis. Of 1639 participants, 221 (13.5%) were classified as having NAFLD. Three major dietary patterns were derived from factor analysis: traditional Chinese, Western, and high-energy dietary patterns. There were significant differences in the intake of whole grains, tuber, and vegetable across quartiles of the traditional Chinese and Western pattern (P < .05). Besides, compared with adolescents in the lowest quartile, those in the highest quartile for whole grains intake had a lower OR for NAFLD (OR = 0.72; 95%CI: 0.61 0.98; P < .05), and for red meat and soft drink consumption had greater OR for NAFLD (OR = 1.34; 95% CI: 1.06-1.72; OR = 1.69; 95% CI: 1.34-2.56; respectively, P < .05). After adjustment for several potential confounders, participants in the highest quartile of the traditional Chinese pattern scores had lower OR for NAFLD (OR = 0.726; 95% CI: 0.383-0.960, P < .05) than did those in the lowest quartile, whereas those in the highest quartile of the Western pattern score had greater OR for NAFLD (OR = 1.197; 95% CI: 1.013-1.736, P < .01) than did those in the lowest quartile. No statistically significant association was found between the high energy pattern and the risk of NAFLD.Our findings demonstrated that the traditional Chinese dietary pattern was associated with a lower risk, whereas the Western dietary pattern was associated with a higher risk of NAFLD. PMID- 29703051 TI - Balanced 10% hydroxyethyl starch compared with balanced 6% hydroxyethyl starch and balanced crystalloid using a goal-directed hemodynamic algorithm in pancreatic surgery: A randomized clinical trial. AB - BACKGROUND: While hydroxyethyl starch (HES) solutions are not recommended any longer in critically ill patients, data on efficacy and safety during surgery are still limited. METHODS: In a randomized controlled trial 63 patients were assigned to receive 10% HES (130/0.42), 6% HES (130/0.42), or crystalloid within a goal-directed hemodynamic algorithm during pancreatic surgery. The primary endpoints were intraoperative volume of HES and time until fully on oral diet. RESULTS: The trial was terminated early upon recommendation of an independent data monitoring committee due to futility for efficacy at a planned interim analysis. The intraoperative volume of HES was not different between 10% and 6% HES group (2000 [1500; 2250] vs 2250 [1750; 3000] mL, P=.059). However, considering an inhomogeneity of patient's body weight between HES groups, there was a significant difference in intraoperative volume of HES between 10% and 6% group after adjusting for patient's body weight (24.0 [21.6; 28.3] vs 33.3 [28.2; 46.2] mL kg BW, P = .002). Patients in the HES groups required less additional fluid after dose limit than those in the crystalloid group, resulting in lower intraoperative net balances. The time until fully on oral diet was not different between all study groups. Applying KDIGO oliguria criterion, patients receiving 10% HES had more AKI compared to patients receiving crystalloids (86.7 vs 45.0%, P = .010), whereas those receiving 6% HES and crystalloids did not differ (58.8 vs 45.0%, P = .253). Further explorative analyses using a gray-zone approach indicated that patients receiving 6% HES below 18.8 mL kg will not experience AKI with near certainty. CONCLUSIONS: After adjusting for patient's body weight, patients receiving 6% HES required more volume of HES than patients receiving 10% HES. The relation of 140% represents very well the volume effect of a hyperoncotic 10% HES solution. Nonetheless, both HES solutions were similarly effective in reducing intraoperative fluid administration compared with crystalloid, but this did not result into differences in gastrointestinal outcomes. Patients receiving 10% HES showed an increased rate of AKI, whereas those receiving 6% HES and crystalloid did not differ. However, 6% HES should not be applied beyond 18 mL kg during surgery. PMID- 29703052 TI - A newborn patient with both annular pancreas and Meckel's diverticulum: A case report of an unusual association. AB - RATIONALE: Annular pancreas (AP) is recognized as a cause of duodenal obstruction in children, while children with Meckel's diverticulum (MD) are usually asymptomatic. Here we present a rare case with both AP and MD, which was identified by abdominal exploration during diamond-shaped duodenoduodenostomy. PATIENT CONCERNS: A "double-bubble" sign was found by ultrasound at 35 week of pregnancy. After 39 weeks of pregnancy, the male patient was transferred to the Department of General Surgery, Children's Hospital of Soochow University because of a suspected duodenal stenosis. DIAGNOSES: Preoperative abdominal X-ray examination indicated "double-bubble" sign. AP was confirmed by exploratory surgery, with an MD located 30 cm above the ileocecal valve. INTERVENTIONS: Diamond-shaped duodenoduodenostomy and a wedge resection of the intestine with end-to-end anastomosis were performed OUTCOMES:: The patient recovered and his appetite was good without vomiting. LESSONS: Our experience demonstrates that abdominal exploration is essential for children with gastrointestinal malformations. PMID- 29703053 TI - Full-endoscopic discectomy via the interlaminar approach for disc herniation at L4-L5 and L5-S1: An observational study. AB - The purpose of this retrospective study was to investigate the clinical outcomes of full-endoscopic discectomy via the interlaminar approach in the treatment of lumbar disc herniation (LDH) at L4-L5 under general anesthesia.Eighty-four patients who underwent full-endoscopic discectomy via the interlaminar approach at L4-L5 or L5-S1 were included. Durations of surgery, intraoperative radiation, postoperative bedrest, and hospitalization as well as perioperative complications were recorded. The visual analog scale (VAS) score for leg and back pain and the Oswestry disability index (ODI) score were evaluated preoperatively and at 3, 6, and 12 months postoperatively.The mean durations of surgeries in surgeries involving L4-L5 and L5-S1 were 69.8 +/- 18.8 and 67.0 +/- 20.1 minutes, respectively. The mean durations of intraoperative radiation were 1.2 +/- 0.3 and 1.3 +/- 0.3 seconds, respectively. The mean VAS and ODI scores improved significantly postoperatively compared with the preoperative scores. The perioperative complications included intraoperative epineurium injury in 3 cases without nerve injury, cerebrospinal fluid leakage, or cauda equina syndrome. The total recurrence rate after 12 months follow-up was 1.2% (one case at L5-S1).Full endoscopic discectomy via the interlaminar approach could be considered as one of the alternative options for the treatment of LDH at L4-L5. PMID- 29703054 TI - Impact of von Willebrand factor on coronary plaque burden in coronary artery disease patients treated with statins. AB - High von Willebrand factor (VWF) levels have been reported to be associated with an increased risk of cardiovascular events. However, the relationship between VWF levels and coronary atherosclerosis in patients with coronary artery disease (CAD) who have already received stain treatment is still unclear. We examined the association between VWF levels and coronary plaque as assessed by intravascular ultrasound (IVUS) in CAD patients treated with statins. Ninety-one CAD patients who underwent percutaneous coronary intervention under IVUS guidance, and who were already receiving statin treatment based on Japanese guidelines, were included. An IVUS examination was performed for the culprit lesion, and plasma VWF antigen levels were measured using enzyme-linked immuno sorbent assay. In all of the patients, the low-density lipoprotein cholesterol levels just before the IVUS examination were low (86 +/- 26 mg/dL). The VWF levels were positively correlated with the plaque burden expressed as percent atheroma volume (PAV) (r = 0.39, P = .001), while there was no significant association between VWF and plaque composition. Multivariate stepwise regression analysis showed that higher VWF levels were independently associated with increased PAV (beta=0.26, P = .01). In CAD patients who had already been treated with statins, higher VWF levels were associated with a higher coronary plaque burden, suggesting that a high VWF level may be a marker of the residual cardiovascular risk after statin treatment. PMID- 29703055 TI - Treatment of Ramsay-Hunt's syndrome with multiple cranial nerve involvement and severe dysphagia: A case report. AB - RATIONALE: Ramsay-Hunt's syndrome (RHS) is a disorder characterized by facial paralysis, herpetic eruptions on the auricle, and otic pain due to the reactivation of latent varicella zoster virus in the geniculate ganglion. A few cases of multiple cranial nerve invasion including the vestibulocochlear nerve, glossopharyngeal nerve and vagus nerve have been reported. However, there has been no report about RHS with delayed onset multiple cranial nerve involvement causing severe aspiration, and a clinical course that improved after more than one year of dysphagia rehabilitation and percutaneous endoscopic gastrostomy (PEG). Here, we report on a 67-year old male with delayed onset swallowing difficulty after 16 days of RHS development. PATIENT CONCERN: Severe aspiration during swallowing. DIAGNOSIS: Severe dysphagia caused by RHS with multiple cranial nerve involvement. INTERVENTION: Application of percutaneous endoscopic gastrostomy (PEG) and rehabilitation therapy of dysphagia. OUTCOMES: After 13 months from symptom onset, his PAS improved from 7 to 2 in follow-up video fluoroscopic swallowing study (VFSS). Then, he was re-admitted, and the PEG tube was removed and oral feeding was started. LESSONS: This case gives us the lesson that optimal doses of acyclovir and corticosteroids are important to prevent progression of multiple cranial involvement in RHS, and swallowing difficulty in RHS patients with multiple cranial nerve involvement can be improved through long term rehabilitation even if there is no improvement for more than one year. PMID- 29703056 TI - Methylprednisolone and plasmapheresis are effective for life-threatening diffuse alveolar hemorrhage and gastrointestinal hemorrhage in granulomatosis with polyangiitis: A case report and literature review. AB - RATIONALE: The treatment of granulomatosis with polyangiitis (GPA) with life threatening complications, such as diffuse alveolar hemorrhage (DAH) and gastrointestinal hemorrhage (GIH), remains challenging. PATIENT CONCERNS: A 70 year-old female presented with a 6-month history of a productive cough and a 10 day history of arthralgia that progressed to respiratory failure and massive hematochezia. DIAGNOSES: Chest high-resolution computed tomography (HRCT) revealed multiple nodules, masses, and cavities. Urinalysis indicated microscopic hematuria. Test of proteinase3-anti-neutrophil cytoplasmic autoantibody (PR3 ANCA) was positive. INTERVENTIONS: The patient was transferred to the intensive care unit (ICU) and successfully treated with glucocorticoid pulse therapy and plasmapheresis. We combined mycophenolate mofetil (MMF) with glucocorticoid for maintenance treatment. OUTCOMES: The patient survived and is in a stable condition. We report this case that presented with a productive cough, followed by arthralgia, DAH, and GIH. LESSONS: Effective remission-induction therapy is a key to survival, while maintaining a balance between immunosuppression and avoiding infection is another challenge. PMID- 29703057 TI - Second malignancy in young early-stage breast cancer patients with modern radiotherapy: A long-term population-based study (A STROBE-compliant study). AB - Second cancer is a leading cause of death in long-term survivors of younger early stage breast cancer patients. To date, relationship of age, receipt of radiotherapy (RT), and estimated doses received by target organs have not yet been well elucidated. Using Surveillance, Epidemiology, and End Results database, patients aged 20 to 44, diagnosed with a first primary staging I-IIIA ipsilateral breast invasive ductal carcinoma, underwent surgery during 1988 to 2009 were identified, and those with a second malignancy at >=1-year follow-up were analyzed to calculate cumulative incidences (CIs) of second malignancy in whole group and each subgroup. Subgroups were dichotomized by surgery type, axillary dissection, and axillary lymph node status. With a median follow-up of 11.8 years, 22,628 women including 1495 patients (6.6%) developing second malignancies (3.7% contralateral breast cancer, 2.9% non-breast second malignancies, and 0.7% high-dose site second malignancies) were identified. Three-dimensional coordinate systems with age at primary diagnosis, time after primary breast cancer diagnosis, and CI of second malignancy as 3 axes, for endpoints including all second malignancy, second primary contralateral breast cancer, and non-breast second malignancy were presented, along with the risk in RT and non-RT groups in overall group and subgroups. Five-, 10-, 15-, and 20-year all second malignancy free survivals in RT and non-RT groups were 89.5% versus 85.4%, 80.1% versus 75.0%, 72.9% versus 67.9%, and 65.6% versus 61.8% (P < .0001). From the large national dataset, a broad visualized overview of second malignancy risk, including second contralateral breast cancer and non-breast second cancer, suggests generally beneficial therapeutic ratio for radiotherapy in young women with early-stage breast cancer. PMID- 29703058 TI - A case report about oligodendrogliomas of the fourth ventricle. AB - RATIONALE: Oligodendrogliomas are usually located in the frontal, parietal and the temporal lobe, with the ones in the fourth ventricle quite rare. Hence we want to introduce a case about the rare disease. PATIENT CONCERNS: An eight-year old boy complained of progressive headache, dizziness and vomit for about 2 months. Then the slight ataxia was found by the physical examinations, with no sensory disturbances and other motor disturbances. DIAGNOSES: Abnormal signals on the fourth ventricle were found by the preoperative brain computed tomography (CT) scan and magnetic resonance imaging (MRI) scan. So the patient accepted a gross total resection of the lesion with pathologically confirmed oligodendroglioma. INTERVENTIONS: Radiotherapy was then delivered in 27 fractions at 2Gy per fraction after the operation, with one fraction daily for five days weekly. No other therapies were used for the patient. OUTCOMES: The brain MRI was used for follow-up every three months until now when he has finished all therapies for more than one year. No progressive behaviors (for example, headache, dizziness, vomit and other symptoms about cerebellar tonsillar hernia) or images have been presented. And the follow-up will be continued. LESSONS: Although oligodendrogliomas are usually located in the frontal lobe, with the ones of fourth ventricle extremely rare, they must be kept in mind all times. Treatments applied to our case may be provided as a reference for clinicians. Furthermore, the maximal range of resection, histologically proved oligodendroglioma and the 1p/19q loss of heterozygosity are associated with favorable prognosis. PMID- 29703059 TI - Comparing the mental health of rural-to-urban migrant children and their counterparts in china: Protocol for a systematic review and meta-analysis. AB - BACKGROUND: In recent years, the issue of migrant children with peasant parents working in cities has attracted widespread attention in recent years because of the sheer number and the benefits bundled in China's household. The focus has gradually extended from early education opportunities to all aspects of physical and mental development, especially the social adaptation and mental health of migrant children. The negative impact of environment changes on migrant children' mental health is very worrying for parents and the society. Some studies have found that immigrant children's mental health is significantly lower than their peers, but there are also studies that hold the opposite view. Thus, the mental health status of migrant children is still a controversial issue, which may have a certain relationship with the potential differences in the specific problems of mental health, regions, comparison objects, and researchers. The objective of this protocol is to investigate whether mental health and subdimensions differ between rural-to-urban migrant children and their counterparts living in China and examine study characteristics that might result in differences among studies. METHODS: We will search PubMed, Embase, OVID, ERIC, Web of Science, and Chinese databases including CNKI, Chongqing VIP, and Wan Fang data from start to April 2018. Cross-sectional studies with a comparison of migrant children and their counterparts will be included. The primary outcome will be the mean and standard deviation of mental health and its sub-dimensions. Standardized mean difference is used as the main effect value. Subgroup analyses will be carried out by the location of studies and school type of. Sensitivity analyses will be conducted to assess the robustness of the findings. Analyses will be performed with RevMan and Stata software. RESULTS: This systematic review and meta-analysis will compare the mental health status of rural-to-urban migrant children and their counterparts living in China. CONCLUSION: The results of this systematic and meta analysis will be helpful to get a more reliable understanding of the mental health of rural-to-urban migrant children and the reasons for the controversy on this issue. PMID- 29703060 TI - Comparative efficacy of low volume versus traditional standard volume PEG on bowel preparation before colonoscopy: Protocol for an updated meta-analysis with trial sequential analysis. AB - INTRODUCTION: Polyethylene glycol (PEG) has been considered as the first recommendation for bowel preparation prior to colonoscopy. A previous meta analysis suggested that low volume PEG may improve the acceptability of ingesting bowel preparation solution. However, several limitations impaired the power of findings from this published meta-analysis, such as the variation in study design of included trials and adjuvant prescriptions. Moreover, some studies related to this topic have been published recently. And thus, the aim of this updated meta analysis is to further assess the comparative efficacy of low volume versus standard volume of PEG on bowel preparation before colonoscopy with trial sequential analysis (TSA). METHODS AND ANALYSIS: Systematic searches will be performed to capture any potential randomized controlled trials (RCTs) investigated the comparative efficacy of low volume versus traditional standard volume PEG on bowel preparation prior to colonoscopy in PubMed, EMBASE, and Cochrane Central Register of Controlled Trials. Moreover, we will also manually check the bibliographies of related studies and reviews so as to get additional studies. Two reviewers will independently screen the citation records, extract essential information, and appraise the risk of bias of each RCT in sequence. Finally, we will used the STATA software version 12.0 and TSA software version beta 0.9 to statistically analyze all data and test the robust of each pooled result, respectively. RESULTS: We will submit the full-text of systematic review to a peer-review journal for publication. CONCLUSION: This updated systematic review and meta-analysis with TSA will further assess the comparative efficacy and safety of low-volume versus traditional standard volume PEG for bowel preparation prior to colonoscopy. And then, a more comprehensive evidence body on low-volume compared to standard volume PEG in bowel preparation will be constructed. PMID- 29703061 TI - Endoscopically controlled flapless transcrestal sinus floor elevation with platelet-rich fibrin followed by simultaneous dental implant placement: A case report and literature review. AB - RATIONALE: In this case study, a modified transcrestal approach was applied to the patient of extremely atrophic posterior maxilla. We analysis the Implant Stability Quotient values (ISQ) to monitor implant stability, and the cone-beam computer tomography (CBCT) to evaluate the bone regeneration. PATIENT CONCERN: A 26-year-old female patient visited our hospital with no contraindications for dental implants and a loss of the maxillary right first molar. DIAGNOSE: Examination by CBCT demonstrated the posterior maxilla was extremely atrophic, the residual bone height (RBH) of #16 was 3.5 mm. INTERVENTION: Patient underwent a endoscopically controlled flapless sinus floor elevation. The maxillary sinus membrane was elevated by two-step, and an implant of 12 mm length was placed simultaneously. OUTCOMES: Twelve weeks post-surgery, the implant-level impression was finished and a full-ceramic crown was placed thereafter. LESSONS: The modified transcrestal approach can be applied to augment maxillary sinus with a residual bone height less than 4 mm. PMID- 29703062 TI - Comparison of clinical outcomes between sorafenib and hepatic artery infusion chemotherapy in advanced hepatocellular carcinoma: A STROBE-compliant article. AB - Sorafenib is the most widely used multikinase inhibitor in patients with advanced hepatocellular carcinoma (HCC). Despite its efficacy, only a small proportion of patients experience tumor regression. Hepatic artery infusion chemotherapy (HAIC) can be used as an alternative treatment for HCC.A total of 139 patients with advanced HCC, treated with HAIC (HAIC group, n = 95) or sorafenib (sorafenib group, n = 44), were retrospectively analyzed in a single hospital. We compared the efficacy and overall survival (OS) between the 2 groups, and investigated the factors affecting response rate in the HAIC group.The objective response rate (ORR) was significantly higher in the HAIC group than in the sorafenib group (23.2% vs 2.3%; P = .01). The progression-free survival time was longer in the HAIC group than in the sorafenib group (274 vs 166 days; P = .03). However, there was no significant difference in OS between the 2 groups (359 vs 223 days; P = .05). In the multivariate analysis, international normalized ratio (INR), serum bilirubin, and presence of objective response were significant prognostic factors associated with OS (P = .03, P = .01, and P = .01, respectively). In the HAIC group, INR, nonobjective response group, and < 4 HAIC cycles were identified as independent risk factors of OS (P = .03, P = .01, and P = .01, respectively).The ORR in patients treated with HAIC was found to be superior to that in advanced HCC patients treated with sorafenib. Better tumor response and prolonged OS can be expected in patients who receive >= 4 HAIC cycles. PMID- 29703063 TI - Novel method versus the Friedewald method for estimating low-density lipoprotein cholesterol in determination of the eligibility for statin treatment for primary prevention in the United States. AB - Although the Friedewald method has been used as the clinical standard to estimate low-density lipoprotein cholesterol (LDL-C) levels, a novel method with better accuracy was suggested and is now being adopted in real practice. We investigated the effect of this novel method on determining the eligibility for statin treatment for primary prevention in the United States.In this cross-sectional study, we determined the discordance in the statin-eligible population for primary prevention according to the 2 different LDL-C estimating methods based on the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guidelines. Using data from the National Health and Nutrition Examination Survey 2005-2014, we included 5302 nationally representative US adults aged between 40 and 75 years without history of atherosclerotic cardiovascular disease (ASCVD). Sampling weights were used in all statistical analyses to account for complex sampling design and nonresponse.If the Friedewald method is replaced by the novel method for analysis of the fasting samples, 0.2% (95% confidence interval [CI], 0.0-0.8) and 0.4% (95% CI, 0.3-0.6) of the population would no longer be eligible or would become newly eligible for statin treatment, respectively. Among the individuals with a TG level >=150 mg/dL and LDL-C level estimated using the Friedewald method <70 mg/dL, 11.6% (95% CI, 4.0-29.3) would become newly eligible for the statin treatment when using the novel method.The use of the novel method for estimating LDL-C instead of the Friedewald method would be associated with a small net increase in statin eligible/needed US adults for primary prevention based on the 2013 ACC/AHA guidelines. Reassessment of individuals' statin eligibility using the novel method may be beneficial, particularly when their TG level is 150 mg/dL or higher and LDL-CF level is lower than 70 mg/dL. PMID- 29703064 TI - Acupuncture for chronic prostatitis: A systematic review and meta-analysis protocol. AB - BACKGROUND: Chronic prostatitis (CP) is a prevalent genitourinary condition. Considering its safety profile, acupuncture can be an option treating CP symptoms. The aim of this review is to undertake a systematic review to estimate the effectiveness and safety of acupuncture on CP. METHODS: We will search all randomized controlled trials for CP in August 2018 in the databases of MEDLINE, Cochrane Library, Web of Science, EMBASE, Springer, WHO International Clinical Trials Registry Platform (ICTRP), China National Knowledge Infrastructure (CNKI), Wan fang, Chinese Biomedical Literature Database (CBM), PsycInfo, Chinese Scientific Journal Database (VIP), and other available resources. Languages are limited as English and Chinese. Search terms used are will "acupuncture," and "chronic prostatitis," "non-bacterial prostatitis," "abacterial prostatitis." And duplicates will be screened. The primary outcomes consisted of improvement rate and pain relief evaluated by The National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) index. Secondary outcomes include the recurrence rate and side effects, such as pneumothorax, discomforts, and infection. RESULTS: This study will demonstrate an evidence-based review of acupuncture for chronic prostatitis. CONCLUSION: The study will provide clear evidence to assess the effectiveness and side effects of acupuncture for chronic prostatitis. ETHICS AND DISSEMINATION: There is no requirement of ethical approval and it will be in print or disseminated by electronic copies. PROSPERO REGISTRATION NUMBER: CRD42018088834. PMID- 29703065 TI - Association of obstructive sleep apnea with cardiovascular outcomes after percutaneous coronary intervention: A systematic review and meta-analysis. AB - The relationship between obstructive sleep apnea (OSA) and adverse cardiovascular outcomes in patients undergoing percutaneous coronary intervention (PCI) remains unclear. We performed a systematic review and meta-analysis to assess the impact of OSA on subsequent cardiovascular events after PCI.We searched the PubMed, EMBASE, and Cochrane library from their inceptions to August 5, 2017. We included cohort studies that described the association between OSA (based on apnea hypopnea index) and cardiovascular outcomes after PCI with stenting. The primary endpoint was major adverse cardiovascular event (MACE), including all-cause or cardiovascular death, myocardial infarction, stroke, repeat revascularization, or heart failure. Outcomes data were pooled using random effects models and heterogeneity was assessed with the I statistic.We identified 9 studies with 2755 participants. The prevalence of OSA in patients treated with PCI ranged from 35.3% to 61.8%. OSA was associated with increased risk of MACE after PCI (pooled risk ratio [RR] 1.96, 95% confidence interval [CI]: 1.36-2.81, P < .001, I = 54%). Between-study heterogeneity was partially explained by sample size (2 studies with <=100 participants; RR 9.12, 95% CI: 2.69-31.00, I = 0% vs 7 studies with >100 participants; RR 1.64, 95% CI: 1.23-2.18, I = 35%). Moreover, the presence of OSA significantly increased the incidence of all-cause death (4 studies), cardiovascular death (4 studies), and repeat revascularization (7 studies) in patients undergoing PCI.Patients with OSA are at greater risk of subsequent cardiovascular events after PCI. Whether treatment of OSA prevents such events warrants further investigation. PMID- 29703067 TI - Successful mesenchymal stem cell treatment of leg ulcers complicated by Behcet disease: A case report and literature review: Erratum. PMID- 29703066 TI - Washed cell salvage in surgical patients: A review and meta-analysis of prospective randomized trials under PRISMA: Erratum. PMID- 29703068 TI - Electroacupuncture for migraine protocol for a systematic review of controlled trials. AB - BACKGROUND AND OBJECTIVE: A migraine is one of the primary headache disorders. Acupuncture has been widely used to treat migraine. Furthermore, electroacupuncture (EA) treatment has been also used to treat migraine. However, there has been no systematic review by assessing efficacy and safety of EA on migraine. This protocol is developed to conduct a systematic review and meta analysis to evaluate the evidences related to the effectiveness and safety of EA on migraine. METHODS AND ANALYSIS: This protocol follows the guideline according to the Preferred Reporting Items for Systematic reviews and Meta-Analysis Protocol and registered on the International Prospective Register of Systematic Reviews (PROSPERO). The following seven databases will be searched from their inception to September 2016: Medline, the Cochrane Central Register of Controlled Trials (CENTRAL), EMBASE, OASIS, the Korean Traditional Knowledge Portal, the Korean Medical Database and the China National Knowledge Infrastructure (CNKI). This Systemic review will include only the randomized controlled clinical trials (RCTs) of acupuncture therapy on migraine. We will perform data extraction, study selection, assessment with risk of bias and data analysis. The primary outcomes of this study are headache pain intensity and the total treatment effective rate. And this protocol study for systematic reviews, the approval of IRB was not required. ETHICS AND DISSEMINATION: This systematic review will not need ethical approval, because it doesn't involve human beings. We will publish this systematic review electronically in a peer-reviewed journal. This systematic review will give healthcare practitioners good practical guide and information for treating migraine. SYSTEMATIC REVIEW REGISTRATION: PROSPEROCRD42018085099. PMID- 29703069 TI - Analogies. PMID- 29703070 TI - Stethoscope Cleaning During Patient Care. AB - BACKGROUND: We conducted a cross-sectional survey of healthcare workers in two community teaching hospitals to better understand clinicians' beliefs and practices related to cleaning of their stethoscopes. The study was conducted from September 2015 to May 2016. PARTICIPANTS: Among the total 358 responses received, 45%, 40%, 10% and 5% were from attending physicians, medical students, nurses, and resident physicians, respectively. KEY RESULTS: Although the majority of the respondents (76%) frequently used a stethoscope at work, and almost all (93%) believed that stethoscopes can be involved in pathogen transmission, only 29% of participants reported cleaning their stethoscopes after every use. CONCLUSIONS: Hospitals should include stethoscope cleaning into their overall infection prevention efforts. PMID- 29703071 TI - To Improve Homicide Firearm Information Reporting - Rhode Island State Crime Laboratory. AB - Information on homicide firearms can be used to help state and local communities understand the problems of violence and decrease injuries and deaths. However, it is difficult to collect these data. To our knowledge, in the public health arena, the National Violent Death Reporting System (NVDRS) is the only system that collects detailed firearm information. The Rhode Island State Crime Laboratory (RISCL) can provide detailed information about the firearms and cartridge cases?bullets involved in firearm deaths. With help from the RISCL, the firearm information related to homicides in Rhode Island has improved dramatically. In 2015, information on caliber/gauge increased by 80%, the firearm type by 50%, the make by 50%, and the model by 20%. By documenting the process of using information from the RISCL, it is hoped that this process can be used as a model by other states when reporting on violent deaths. PMID- 29703072 TI - Domestic Minor Sex Trafficking: Medical Follow-up for Victimized and High-Risk Youth. AB - Domestic minor sex trafficking (DMST) has become an increasingly recognized issue associated with both immediate and long-term physical and mental health consequences. Guidelines have focused on potential risk factors, recruitment practices, and health consequences for these youth assisting in identification and intervention efforts. However, recommendations have not been established for continuous medical intervention and follow-up for this vulnerable patient population that includes both patients involved in and at high risk for DMST. Our goal is to highlight preliminary recommendations for and the importance of medical visits for these youth. A comprehensive physical examination, STI testing and treatment, and pregnancy prevention options are important to address the patients' concerns for their body and identify acute and chronic injuries. Further, collaborating with other medical and non-medical providers can provide essential resources for the multifaceted needs of DMST patients. PMID- 29703073 TI - Food Insecurity and Chronic Disease: Addressing Food Access as a Healthcare Issue. AB - Food insecurity, or lack of access to nutritionally adequate food, affects millions of US households every year. Food insecure individuals face disproportionately higher rates of chronic diseases, like diabetes mellitus and HIV/AIDS, and therefore accrue more healthcare costs. This puts into motion a cycle of disease and expense that furthers disparities between food secure and insecure patients. Our aim is to provide an overview of food insecurity, define its link to chronic disease and offer practical solutions for addressing this growing problem. PMID- 29703074 TI - Central Venous Catheters: A Closer Look at the Subclavian Vein Approach. PMID- 29703075 TI - Thrower's Fracture of the Humerus: A Case Report. AB - Humeral fractures typically occur as the result of direct, external trauma. Here however, we describe the case of a young, amateur athlete presenting with acute right, upper arm pain after throwing a ball. Examination showed right upper arm deformity and tenderness to palpation, without any distal neurovascular deficits. X-ray demonstrated a spiral fracture of the humerus. The patient had operative repair of the injury several days later, with no complications noted on outpatient visits up to 3 months later. PMID- 29703076 TI - Linking public schools and community mental health services: A model for youth suicide prevention. PMID- 29703077 TI - Surface Wetting-Driven Separation of Surfactant-Stabilized Water-Oil Emulsions. AB - Four fluorocarbon polymers including polytetrafluoroethylene and polyvinylidene fluoride were coated on a stainless steel felt to separate emulsified water droplets from ultralow sulfur diesel (ULSD) fuels. The original fuel treated with clay to remove additives was additized again with four known surfactants including pentaerythrityoleate, (octadecadienoic acid) dipolymer, (octadecadienoic acid) tripolymer, and monoolein individually. The different surfactants adsorbed on the fuel-water interface reduce the interfacial intension with different intensities. The separation efficiency at various surfactant concentrations was used to evaluate the coalescence effect exerted by these coatings. It was found the separation was both surfactant- and coating-dependent. A fluoro-polyurethane coating (FC1) stood out to counteract the adverse effect of all the surfactants. Solid free energy was then measured using acid-base and Kaelble-Uy adhesion theories for all the coatings, but its correlation with coalescence was not found at all. Coating aging in surfactant-additized fuel on the coating's water wettability was also examined to better understand how historical wetting affects separation. A tumbled model for fluorocarbons was identified that well-explained the continuous decline of the water contact angle on the FC1 coating in fuel. Subject to the challenge of the foreign environment, the fluoroalkyl chains of the polymer tilt to expose the carbonyl groups underneath, resulting in favored coalescence separation in the presence of surfactants. PMID- 29703078 TI - Advances in the Study of Aptamer-Protein Target Identification Using the Chromatographic Approach. AB - Ever since the development of the process known as the systematic evolution of ligands by exponential enrichment (SELEX), aptamers have been widely used in a variety of studies, including the exploration of new diagnostic tools and the discovery of new treatment methods. Aptamers' ability to bind to proteins with high affinity and specificity, often compared to that of antibodies, enables the search for potential cancer biomarkers and helps us understand the mechanisms of carcinogenesis. The blind spot of those investigations is usually the difficulty in the selective extraction of targets attached to the aptamer. There are many studies describing the cell SELEX for the prime choice of aptamers toward living cancer cells or even whole tumors in the animal models. However, a dilemma arises when a large number of proteins are being identified as potential targets, which is often the case. In this article, we present a new analytical approach designed to selectively target proteins bound to aptamers. During studies, we have focused on the unambiguous identification of the molecular targets of aptamers characterized by high specificity to the prostate cancer cells. We have compared four assay approaches using electrophoretic and chromatographic methods for "fishing out" aptamer protein targets followed by mass spectrometry identification. We have established a new methodology, based on the fluorescent tagged oligonucleotides commonly used for flow-cytometry experiments or as optic aptasensors, that allowed the detection of specific aptamer-protein interactions by mass spectrometry. The use of atto488-labeled aptamers for the tracking of the formation of specific aptamer-target complexes provides the possibility of studying putative protein counterparts without needing to apply enrichment techniques. Significantly, changes in the hydrophobic properties of atto488 labeled aptamer-protein complexes facilitate their separation by reverse-phase chromatography combined with fluorescence detection followed by mass-spectrometry based protein identification. These comparative results of several methodological approaches confirmed the universal applicability of this method to studying aptamer-protein interactions with high sensitivity, showing superior properties compared with pull-down techniques. PMID- 29703079 TI - Skyrmion-Mediated Voltage-Controlled Switching of Ferromagnets for Reliable and Energy-Efficient Two-Terminal Memory. AB - We propose a two-terminal nanomagnetic memory element based on magnetization reversal of a perpendicularly magnetized nanomagnet employing a unipolar voltage pulse that modifies the perpendicular anisotropy of the system. Our work demonstrates that the presence of Dzyaloshinskii-Moriya interaction can create an alternative route for magnetization reversal that obviates the need for utilizing precessional magnetization dynamics as well as a bias magnetic field that are employed in traditional voltage control of magnetic anisotropy (VCMA)-based switching of perpendicular magnetization. We show with extensive micromagnetic simulation, in the presence of thermal noise, that the proposed skyrmion-mediated VCMA switching mechanism is robust at room temperature leading to extremely low error switching while also being potentially 1-2 orders of magnitude more energy efficient than state-of-the-art spin transfer torque-based switching. PMID- 29703080 TI - One Oxygen Vacancy, Two Charge States: Characterization of Reduced alpha MoO3(010) through Theoretical Methods. AB - Molybdenum oxides are finding increasing applications that rely on their redox character. For the most common polymorph, alpha-MoO3, oxygen vacancy formation leaves two electrons on the surface that can be stored as small polarons. Detailed density functional theory calculations that properly account for the self-interaction term, Ueff = 3.5 eV, show that the vacancy generates two different configurations: either two Mo5+ centers (Mo5+? and Mo5+?O) or a single double-reduced Mo4+. These states are separated by 0.22 eV with a barrier for interconversion of 0.33 eV, and thus both are populated at catalytic temperatures, as shown by first-principles molecular dynamics. At higher reduction levels, vacancies can only be accumulated along a preferential direction and the energy difference between the 2*Mo5+ and Mo4+ configurations is reduced. These results point out the need for a revision of the experimental assignments based on our characterization that includes charges, vibrational frequencies, and XPS signatures. PMID- 29703081 TI - Mechanically Strong Polymer Sheets from Aligned Ultrahigh-Molecular-Weight Polyethylene Nanocomposites. AB - Ultrahigh-molecular-weight polyethylene (UHMWPE) is of great interest as a next generation body armor material because of its superior mechanical properties. However, such unique properties depend critically on its microscopic structure characteristics, including the degree of crystallinity, chain alignment, and morphology. Here, we present a highly aligned UHMWPE and its composite sheets containing uniformly dispersed boron nitride (BN) nanosheets. The dispersion of BN nanosheets into the UHMWPE matrix increases its mechanical properties over a broad temperature range. Experiments and simulation confirm that the alignment of chain segments in the composite matrix increases with temperature, leading to an improvement in mechanical properties at high temperature. Together with the large thermal conductivity of UHMWPE and BN, our findings serve to expand the application spectrum of highly aligned polymer nanocomposite materials for ballistic panels and body armor over a broad range of temperatures. PMID- 29703082 TI - Fabrication of a co-culture micro-bioreactor device for efficient hepatic differentiation of human induced pluripotent stem cells (hiPSCs). AB - Primary hepatocytes, as the gold standard cell type for in vitro models, lose their characteristic morphology and functions after few days. There is an urgent need to develop physiologically relevant models that recapitulate liver microenvironment to obtain mature hepatocyte from stem cells. We designed and fabricated a micro-bioreactor device mimicking the physiological shear stress and cell-cell interaction in liver sinusoid microenvironment. Induced pluripotent stem cells (iPSCs) were co-cultured with human umbilical vein endothelial cells (HUVECs) in the micro-bioreactor device with continuous perfusion of hepatic differentiation medium (100 MUL/h). Simulation results showed that flow field inside our perfusion device was uniform and shear stress was adjusted to physiological condition (<2 dyne/cm2). IPSCs-derived hepatocytes (iPSCs-Heps) that were cultured in micro-bioreactor device showed a higher level of hepatic markers compared to those in static condition. Flow cytometry and immunocytochemistry analysis revealed iPSCs cultured in the device sequentially acquired characteristics of definitive endodermal cells (SOX17 positive), hepatoblasts (AFP positive) and mature hepatocyte (ALB positive). Moreover, the albumin and urea secretion were significantly higher in micro-bioreactor device than those cultured in culture dishes during experiment. Thus, based on our results, we propose our micro-bioreactor as a beneficial device to generate mature hepatocytes for drug screening and basic research. PMID- 29703083 TI - Relationship between circulating miRNA-30e and no-reflow phenomenon in STEMI patients undergoing primary coronary intervention. AB - To investigate the relationship between miRNA-30e level in circulation and no reflow phenomenon in patients with acute ST-segment elevation myocardial infarction (STEMI) during primary percutaneous coronary intervention (pPCI). A total of 255 consecutive patients with STEMI undergoing pPCI were enrolled in this study. These patients were divided into two groups according to the occurrence of reflow during pPCI, namely normal-reflow group with 214 cases and no-reflow group with 41 cases. The plasma levels of miRNA-30e were quantified using real-time quantitative polymerase chain reaction. The plasma levels of miRNA-30e were significantly lower in the no-reflow group as compared to the normal-reflow group (p < .05). Also, miRNA-30e was positively correlated with left ventricular ejection fraction (LVEF) and negatively correlated with hs-CRP levels (p < .05). Multivariate logistic regression analyses indicated that the plasma level of miRNA-30e (OR = 0.732, 95% CI 0.674-0.851, p = .034), hs-CRP (OR = 1.353, 95% CI 1.129-1.635, p = .012) and Killip class >=2 at admission (OR = 1.263, 95% CI 1.023-1.532, p = .027), were independent risk factors for no-reflow during pPCI. When plasma miRNA-30e level was used as the test variable, the area under the curve was 0.914 (p < .05) by ROC curve analysis. Lower miRNA-30e levels at admission are associated with no-reflow in STEMI patients undergoing pPCI and may play an important role in the pathogenesis of no-reflow. Plasma miRNA-30e level was an independent predictor of no-reflow during pPCI in patients with STEMI. Therefore, early detection of plasma miRNA-30e level can be a preliminary assessment for risk of no-reflow during pPCI. PMID- 29703084 TI - Synthesis, characterization and in vitro/in vivo evaluation of novel reduction sensitive hybrid nano-echinus-like nanomedicine. AB - To remedy the problems resulting from the usage of anti-cancer drugs in cancer chemotherapy, such as deficient drug concentration in tumour cells, low water solubility and non-specific distribution of antitumour drugs, a kind of reduction sensitive polymer prodrug of curcumin (Cur) containing in the nano-echinus was synthesized and designed. The nano-echinus-like nanomedicine presented synergistic effect with glycyrrhetic acid (GA) and oligomeric hyaluronic (HA) for targeting and combating HepG2 human liver cancer cell. Firstly, a kind of small molecular prodrug of Cur, dithiodipropionic acid-Cur (-SS-Cur), was chemically conjugated onto the side chain of the conjugated glycyrrhetic acid- oligomeric hyaluronic (GA-HA) to generate an amphiphilic polymeric prodrug of Cur, GA-HA-SS Cur. The obtained GA-HA-SS-Cur prodrug and subsidiary material mPEG-DSPE could self-assemble into a sea urchin-like micelles in aqueous media and release Cur rapidly in response to glutathion (GSH). Then, Cur was loaded into the nano echinus with a particle size of (118.1 +/- 0.2 nm) and drug-loading efficiency of (8.03 +/- 2.1%). The structure of GA-HA-SS-Cur was characterized by 1H-NMR in this report. The morphology of micelles was observed with a transmission electron microscope (TEM). Subsequently, the reduction-sensitivity of the nano-echinus was confirmed by the changes in in-vitro drug release after different concentrations of GSH treatment. Besides, the cellular uptake behaviour and MTT assays of the nano-echinus were investigated, suggesting that the nano-echinus was of desirable safety and could be taken into HepG2 cells in a time-dependent manner. Later, anti-tumour efficacy in vivo revealed the effective inhibition of tumour growth. PMID- 29703085 TI - Significance of asymptomatic hyperuricemia in patients after coronary events. AB - The goal of the present study was to determine the prevalence of hyperuricemia in patients with coronary artery disease (CAD), within three months after coronary events. Also, we aimed to determine whether the presence of hyperuricemia holds correlation with severe CAD, overall heart functioning and risk factors for CAD. The study included 505 consecutive CAD patients, 385 males and 120 females, aged 60.9 +/- 9.6 years, with a mean body mass index (BMI) 28.0 +/- 3.7 kg/m2. All patients were admitted to specialized cardiovascular rehabilitation within three months post-acute myocardial infarction (AMI) without revascularization (32.6%), percutaneous coronary intervention (PCI) with myocardial infarction (32.1%) and with coronary bypass graft (35.3%). The mean value of serum acidum uricum (SUA) was 345.5 +/- 100.3 umol/L, where 115 (22.8%) patients had asymptomatic hyperuricemia. Patients with asymptomatic hyperuricemia had significantly higher average number of risk factors, lower HDL cholesterol and higher creatinine and triglycerides levels, lower ejection fraction (EF). Multivariate stepwise analysis revealed that five parameters were capable to predict SUA levels. We can conclude that in patients with CAD, SUA levels are independently associated with BMI, triglyceride and creatinine levels and negatively with EF. Thus, one can say that asymptomatic hyperuricemia is not significantly associated with the severity of CAD. PMID- 29703086 TI - Pediatric Digital Necrosis Secondary to Dressing Application: A Case Series. AB - BACKGROUND: Pediatric digital necrosis resulting in revision amputation is a devastating outcome following digital dressing application. METHODS: We report a series of 4 pediatric patients (age: 21 months-11 years) who presented for surgical consultation related to digital ischemia and irreversible necrosis following the application of Coban digital dressings. A review of the literature demonstrated that such injuries had not previously been described. RESULTS: In our case series, Coban dressing was utilized as a deterrent for thumb sucking, fingertip tuft fractures with nail bed lacerations, and a phalanx fracture secondary to crush injury. All 4 children suffered digital necrosis secondary to Coban dressings and ultimately required revision amputation. CONCLUSIONS: We discuss risks factors, application practices, and strategies to minimize complications with digital dressings in the pediatric population with the intent of creating awareness among hand surgeons to help promote safe practices and improve patient outcomes. PMID- 29703087 TI - Assessment of radiation exposure in balloon kyphoplasty using a new navigation system. AB - STUDY DESIGN: Randomized controlled trials of conventional and laser-navigated technology techniques for balloon kyphoplasty were carried out. OBJECTIVE: To evaluate the effectiveness of a new laser navigation system in reducing the radiation dose in balloon kyphoplasty procedures. MATERIAL AND METHODS: Sixty seven randomized controlled trials involving a total of 75 lumbar vertebrae were treated. Thirty-four vertebrae were treated by regular fluoroscopic imaging alone, and the other 41 vertebrae were treated using the new laser navigation system. For each procedure the fluoroscopy dosage was documented using a Hitachi Aloka Medical external dosimeter. The operation time was recorded. RESULTS: The amount of radiation exposure in the control group was 870.59 +/- 134.27 MUSv. A significant reduction of the fluoroscopy usage in the navigated group was detected (503.5 +/- 70.0 MUSv (p < .0001)). In the control group, the average procedure time was 51.47 +/- 8.30 minutes. The average procedure time in the navigated group was significantly reduced (39.26 +/- 5.87 minutes (p < .0001)). CONCLUSION: The laser positioning and navigation system is an effective solution for reducing radiation exposure in balloon kyphoplasty. The increased technical effort may lead to a significant decrease of procedure time. The clinical trial No.: ChiCTR-INR-17013051. PMID- 29703088 TI - Deliberate teaching tools for clinical teaching encounters: A critical scoping review and thematic analysis to establish definitional clarity. AB - PURPOSE AND METHOD: We conducted a scoping review of tools designed to add structure to clinical teaching, with a thematic analysis to establish definitional clarity. RESULTS: Six thousand and forty nine citations were screened, 434 reviewed for eligibility, and 230 identified as meeting study inclusion criteria. Eighty-nine names and 51 definitions were identified. Based on a post facto thematic analysis, we propose that these tools be named "deliberate teaching tools" (DTTs) and defined as "frameworks that enable clinicians to have a purposeful and considered approach to teaching encounters by incorporating elements identified with good teaching practice." We identified 46 DTTs in the literature, with 38 (82.6%) originally described for the medical setting. Forty justification articles consisted of 16 feedback surveys, 13 controlled trials, seven pre-post intervention studies with no control group, and four observation studies. Current evidence of efficacy is not entirely conclusive, and many studies contain methodology flaws. Forty-nine clarification articles comprised 12 systematic reviews and 37 narrative reviews. The most number of DTTs described by any review was four. A common design theme was identified in approximately three-quarters of DTTs. CONCLUSIONS: Applicability of DTTs to specific alternate settings should be considered in context, and appropriately designed justification studies are warranted to demonstrate efficacy. PMID- 29703090 TI - Using eye-tracking technology for communication in Rett syndrome: perceptions of impact. AB - Studies have investigated the use of eye-tracking technology to assess cognition in individuals with Rett syndrome, but few have looked at this access method for communication for this group. Loss of speech, decreased hand use, and severe motor apraxia significantly impact functional communication for this population. Eye gaze is one modality that may be used successfully by individuals with Rett syndrome. This multiple case study explored whether using eye-tracking technology, with ongoing support from a team of augmentative and alternative communication (AAC) therapists, could help four participants with Rett syndrome meet individualized communication goals. Two secondary objectives were to examine parents' perspectives on (a) the psychosocial impact of their child's use of the technology, and (b) satisfaction with using the technology. All four participants were rated by the treating therapists to have made improvement on their goals. According to both quantitative findings and descriptive information, eye-tracking technology was viewed by parents as contributing to participants' improved psychosocial functioning. Parents reported being highly satisfied with both the device and the clinical services received. This study provides initial evidence that eye-tracking may be perceived as a worthwhile and potentially satisfactory technology to support individuals with Rett syndrome in communicating. Future, more rigorous research that addresses the limitations of a case study design is required to substantiate study findings. PMID- 29703089 TI - Changes in red blood cell volume during transition of heart failure status: a reflection of cellular hydration status? AB - This study examined how changes in heart failure (HF) status induce changes in the index of erythrocyte hydration based on mean red blood cell volume (MCV). Data from 47 HF patients (32% men; 78.2 +/- 9.7 years) that experienced worsening and recovery of HF were analysed. Blood tests included measurements of MCV, albumin, serum solutes and b-type natriuretic peptide (BNP). Among a total of 47 worsening HF events, changes in MCV were positively correlated with changes in body weight (r = 0.31, p = .034), serum sodium (r = 0.417, p = .0036), and chloride (r = 0.457, p = .0012), and negatively correlated with changes in blood urea nitrogen (r= -0.389, p = .0069) and creatinine (r= -0.494, p = .0004). At recovery from worsening of HF by conventional diuretic therapy, change in MCV was positively correlated with the change in body weight (r = 0.457, p = .0012), serum sodium (r = 0.466, p = .001) and chloride (r = 0.484, p = .0006). Multivariate regression analysis demonstrated an independent association between the increase in serum chloride and MCV from stability to worsening of HF (odds ratio [OR] 6.02, 95% confidence interval [CI] 1.09-33.2, p = .039) and the increase or absence of change in serum chloride concentration and preserved MCV after decongestion (OR 11.5, 95% CI 1.53-85.9, p = .017). In conclusion, this study demonstrates that the changes in MCV under transition in HF status do not reflect a change that occurs in parallel with changes in HF-related markers, such as body weight and serum BNP level, but is independently associated with a change in the serum chloride concentration. Whether changes in MCV actually reflect the bodily cellular hydration status warrants further research. PMID- 29703091 TI - Exploring the relationship between examiners' memories for performances, domain separation and score variability. AB - BACKGROUND: OSCE examiners' scores are variable and may discriminate domains of performance poorly. Examiners must hold their observations of OSCE performances in "episodic memory" until performances end. We investigated whether examiners vary in their recollection of performances; and whether this relates to their score variability or ability to separate disparate performance domains. METHODS: Secondary analysis was performed on data where examiners had: 1/scored videos of OSCE performances showing disparate student ability in different domains; and 2/performed a measure of recollection for an OSCE performance. We calculated measures of "overall-score variance" (the degree individual examiners' overall scores varied from the group mean) and "domain separation" (the degree to which examiners separated different performance domains). We related these variables to the measure of examiners' recollection. RESULTS: Examiners varied considerably in their recollection accuracy (recognition beyond chance -5% to +75% for different examiners). Examiners' recollection accuracy was weakly inversely related to their overall score accuracy (R = -0.17, p < 0.001) and related to their ability to separate domains of performance (R = 0.25, p < 0.001). CONCLUSIONS: Examiners vary substantially in their memories for students' performances which may offer a useful point of difference to study processing and integration phases of judgment. Findings could have implication for the utility of feedback. PMID- 29703092 TI - Hearing loss and work participation: a cross-sectional study in Norway. AB - OBJECTIVE: To study work participation of persons with hearing loss, and associations with hearing disabilities, self-reported workability, fatigue and work accommodation. DESIGN: Cross-sectional internet-based survey. STUDY SAMPLE: A total of 10,679 persons with hearing loss within working-age were invited to answer the survey, where 3330 answered (35.6%). RESULTS: Degree of hearing loss was associated with low workability, fatigue and work place accommodation, while sick leave was associated with fatigue. Degree of hearing loss was positively associated with being unemployed (p < .001) and having part-time work (p < .01) (often combined with disability benefits) for women. Work place accommodation was more frequently provided among respondents working with sedentary postures, high seniority, long-term sick leave or low workability. Additional unfavourable sensory conditions were associated with decreased employment (p < .001) and workability, and an increase in sick leave (p < .01) and fatigue (p < .001). CONCLUSIONS: Hearing loss seemed to influence work participation factors negatively; particularly, for moderate hearing loss and for women, even though the degree of employment was high. A lack of work place accommodation when there was a need for such was found. This implies increased attentiveness towards individual needs concerning the experienced disability a hearing loss may produce. A more frequent use of hearing disability assessment is suggested. PMID- 29703093 TI - A cross-sectional study of learning styles among continuing medical education participants. AB - PURPOSE: Experiential learning has been suggested as a framework for planning continuing medical education (CME). We aimed to (1) determine participants' learning styles at traditional CME courses and (2) explore associations between learning styles and participant characteristics. MATERIALS AND METHODS: Cross sectional study of all participants (n = 393) at two Mayo Clinic CME courses who completed the Kolb Learning Style Inventory and provided demographic data. RESULTS: A total of 393 participants returned 241 surveys (response rate, 61.3%). Among the 143 participants (36.4%) who supplied complete demographic and Kolb data, Kolb learning styles included diverging (45; 31.5%), assimilating (56; 39.2%), converging (8; 5.6%), and accommodating (34; 23.8%). Associations existed between learning style and gender (p = 0.02). For most men, learning styles were diverging (23 of 63; 36.5%) and assimilating (30 of 63; 47.6%); for most women, diverging (22 of 80; 27.5%), assimilating (26 of 80; 32.5%), and accommodating (26 of 80; 32.5%). CONCLUSIONS: Internal medicine and psychiatry CME participants had diverse learning styles. Female participants had more variation in their learning styles than men. Teaching techniques must vary to appeal to all learners. The experiential learning theory sequentially moves a learner from Why? to What? to How? to If? to accommodate learning styles. PMID- 29703094 TI - Headphone listening habits, hearing thresholds and listening levels in Swedish adolescents with severe to profound HL and adolescents with normal hearing. AB - OBJECTIVE: Research has minimally focussed on the music listening habits and preferred sound volumes among adolescents with severe to profound congenital HL. Listening to music played at loud sound volumes and for a long duration of time could imply risks of worsening the HL. Therefore, it is important to investigate the listening habits in adolescents with HL. The aim of the present study was to describe the use of personal music devices, subjective estimated sound levels, measured sound levels, listening habits, and hearing symptoms in adolescents with severe to profound hearing loss compared with adolescents with normal hearing. DESIGN: The study was conducted in two steps. First, a questionnaire was given to students with or without hearing loss. In step two, hearing and sound level measurements were made in a subsample from both groups. STUDY SAMPLE: The study sample were based on 112 seventeen-year-old students with severe to profound hearing loss and 279 adolescents with normal hearing. Hearing thresholds and listening levels was measured on two subsamples based on 29 adolescents with severe to profound hearing loss and 50 adolescents from the group with normal hearing. RESULTS: The results showed that adolescents with severe to profound hearing loss listened to significantly louder sound levels for longer periods. For both groups, those listening at louder sound levels had poorer hearing thresholds. This finding is especially alarming for subjects with hearing loss. Among those listening above 85 dB per occasion, the sound level ranged between 85.8 dB up to 109 dB for those with hearing loss, whereas the sound level ranged between 85.5 dB and 100 dB for those with normal hearing. CONCLUSIONS: Adolescents with congenital hearing loss used portable music devices in the same manner as adolescents with normal hearing. However, adolescents with hearing loss listened to louder sound volumes most likely to compensate for their hearing loss, which significantly increases the risk of further damage to their hearing. From a hearing rehabilitation perspective it could be concluded that aspect of music listening habits should be focussed in order to prevent noise induced hearing loss among individuals with congenital hearing loss. PMID- 29703095 TI - Reproducibility, feasibility and validity of the Groningen Defecation and Fecal Continence questionnaires. AB - OBJECTIVES: Current questionnaires on defecation disorders are often brief and fail to include questions considering causative factors. Furthermore, adult and pediatric questionnaires differ, which makes it impossible to monitor defecation disorders during the transition from childhood to adulthood. With these points in mind, we developed the Groningen Defecation and Fecal Continence (DeFeC) questionnaire and its pediatric equivalent, the P-DeFeC. The aim of this paper is to introduce the questionnaires and to assess their feasibility, reproducibility and validity. MATERIALS AND METHODS: Various Rome IV criteria and scoring tools for constipation and fecal incontinence were incorporated, resulting in nine categories. Feasibility and reproducibility were assessed by performing a test retest survey in 100 adult participants. Concurrent validity was assessed in 27 patients and 18 healthy volunteers by comparing questionnaire-based diagnoses of constipation and fecal incontinence to final diagnoses based on anorectal function tests. RESULTS: There were no remarks on the understandability of any questions. The Cohen's kappa coefficient of all main questions ranged from 0.26 to 1.00, with an average of 0.57. All but one category showed moderate agreement or higher. The sensitivity of the questionnaire-based diagnosis of constipation was 75%; specificity was 100%. The sensitivity of the questionnaire-based diagnosis of fecal incontinence was 77%; specificity was 94%. CONCLUSIONS: Overall reproducibility of the Groningen DeFeC questionnaire is acceptable and its validity is good. This makes it a feasible screening tool for defecation disorders and, equally important, with these questionnaires defecation disorders can now be monitored during the transition from childhood to adulthood. PMID- 29703096 TI - A practical framework for remediating unprofessional behavior and for developing professionalism competencies and a professional identity. AB - The relatively new term "Professional Identity Formation" (PIF) complements behavior-based and attitude-based perspectives on professionalism. Unprofessional behavior and its remediation should also be addressed from this perspective. However, a framework is needed to guide discussion and remediation of unprofessional behavior, which can encompass behavior-based, attitude-based, and identity-based perspectives on professionalism. To this end, the authors propose a multi-level professionalism framework which describes, apart from professional behavior, more levels which influence professional performance: environment, competencies, beliefs, values, identity, and mission. The different levels can provide tools for educators to address and discuss unprofessional behavior with their students in a comprehensive way. By reflecting on all the different levels of the framework, educators guard themselves against narrowing the discussion to either professional behavior or professional identity. The multi-level professionalism framework can help educators and students to gain a better understanding of the root of unprofessional behavior, and of remediation strategies that would be appropriate. For despite the recent emphasis on PIF, unprofessional behavior and its remediation will remain important issues in medical education. PMID- 29703097 TI - The sex life of women surviving breast cancer. AB - The diagnosis of breast cancer elicits diverse emotional responses in patients and partners. Surviving cancer has raised new needs and caretakers must understand the medical and psychological latent effects of oncology therapy. Improving patients' well-being is crucial as 19 million survivors are expected in the next decade in the United States alone. In general, sexuality contributes to one's well-being but when it is disrupted by the occurrence of cancer, women withdraw emotionally, no longer feel desirable due to esthetic damage, and become overwhelmed by the thought of sex. Alopecia and mastectomy elicit feelings of unattractiveness affecting even some women with nipple sparing mastectomy. Couples who share the psychological distress of experiencing cancer should be logically included in survivorship interventions. Hence, any support offered to the couple improves their ability to cope significantly. Treatments causing premature ovarian failure as well as adjuvant endocrine treatments deepen the effects of hypo-estrogenism on the genital modifications of arousal. Sexual rehabilitation with vaginal dilators and sensate focus exercises help to lessen pain, and reduce the couple's anxiety toward sex. In conclusion, caregivers must realize that surviving women are often reluctant to voice their needs, thus, efficient interventions must be available to everyone. PMID- 29703098 TI - Pulmonologist evaluation on new CT visualization for guidance to lung lesions during bronchoscopy. AB - OBJECTIVE: Endoluminal visualization in virtual and video bronchoscopy lacks information about the surrounding structures, and the traditional 2 D axial, coronal and sagittal CT views can be difficult to interpret. To address this challenge, we previously introduced a novel visualization technique, Anchored to Centerline Curved Surface, for navigated bronchoscopy. The current study compares the ACCuSurf to the standard ACS CT views as planning and guiding tools in a phantom study. MATERIAL AND METHODS: Bronchoscope operators navigated in physical phantom guided by virtual realistic image data constructed by fusion of CT dataset of phantom and anonymized patient CT data. We marked four different target positions within the virtual image data and gave 12 pulmonologists the task to navigate, with either ACCuSurf or ACS as guidance, to the corresponding targets in the physical phantom. RESULTS: Using ACCuSurf reduced the planning time and increased the grade of successful navigation significantly compared to ACS. CONCLUSION: The phantom setup with virtual patient image data proved realistic according to the pulmonologists. ACCuSurf proved superior to ACS regarding planning time and navigation success grading. Improvements on visualisation or display techniques may consequently improve both planning and navigated bronchoscopy and thus contribute to more precise lung diagnostics. PMID- 29703099 TI - Hearing tests are just child's play: the sound scouts game for children entering school. AB - OBJECTIVE: To create a hearing test useable without the involvement of a clinician or calibrated equipment, suitable for children aged 5 or older. DESIGN: The tablet-based app (Sound Scouts) includes tests of speech in quiet, speech in noise and tones in noise, all embedded in game designed to maintain attention. Data were collected to intelligibility-equalize the stimuli, establish normative performance, and evaluate the sensitivity with which Sound Scouts detected known hearing problems and identified their type. STUDY SAMPLE: Participants were children from age 5 to 14 (394 with normal hearing, 97 with previously identified hearing loss) and 50 adults with normal hearing. RESULTS: With pass-fail criteria set such that 98% of children with normal hearing passed Sound Scouts, 85% of children with hearing loss failed Sound Scouts (after exclusion of children in either group who received an inconclusive result or had incomplete results). No child with four-frequency average hearing thresholds of 30 dB HL or greater in their poorer ear passed Sound Scouts. Hearing loss type was correctly identified in only two-thirds of those cases where the algorithm attempted to identify a single type of loss. CONCLUSIONS: Sound Scouts has specificity and sensitivity sufficiently high to provide hearing screening around the time children typically enter school. PMID- 29703100 TI - Insecticidal and alpha-glucosidase inhibitory activities of chemical constituents from Viburnum fordiae Hance. AB - The ethanolic extract of the stems of Viburnum fordiae Hance showed insecticidal and alpha-glucosidase inhibitory activities and then was fractionated by bioactivity-guided fractionation to obtain a rare C13-norisoprenoid (1), together with a new phenolic glycoside (2), and seven known compounds, alangionoside C (3), pisumionoside (4), koaburaside (5), 3,5-dimethoxy-benzyl alcohol 4-O-beta-d glucopyranoside (6), 3,4,5-trimethoxybenzyl-beta-d-glucopyranoside (7), arbutin (8), and salidroside (9). The previously undescribed compounds were elucidated as (3R,9R)-3-hydroxy-7,8-didehydro-beta-ionyl 9-O-alpha-d-arabinopyranosyl-(1->6) beta-d-glucopyranoside (1) and 2-(4-O-beta-d-glucopyranosyl)syringylpropane-1,3 diol (2) by spectroscopic data (1H and 13C NMR, HSQC, HMBC, 1H-1H COSY, HSQC TOCSY, HRESIMS, IR and ORD) and chemical methods. Compound 1 showed potent insecticidal effect against Mythimna separata with LD50 value of 140 MUg g-1. Compounds 2, 5, 6, 8 and 9 showed varying alpha-glucosidase inhibitory activity with IC50 values ranging from 148.2 to 230.9 MUM. PMID- 29703101 TI - Identifying developmental features in students' clinical reasoning to inform teaching. AB - BACKGROUND: There is increasing evidence that students at different levels of training may benefit from different methods of learning clinical reasoning. Two of the common methods of teaching are the "whole - case" format and the "serial cue" approach. There is little empirical evidence to guide teachers as to which method to use and when to introduce them. METHODS: We observed 23 students from different stages of training to examine how they were taking a history and how they were thinking whilst doing this. Each student interviewed a simulated patient who presented with a straightforward and a complex presentation. We inferred how students were reasoning from how they took a history and how they described their thinking while doing this. RESULTS: Early in their training students can only take a generic history. Only later in training are they able to take a focused history, remember the information they have gathered, use it to seek further specific information, compare and contrast possibilities and analyze their data as they are collecting it. CONCLUSIONS: Early in their training students are unable to analyze data during history taking. When they have started developing illness scripts, they are able to benefit from the "serial cue" approach of teaching clinical reasoning. PMID- 29703102 TI - Troponin, delta change and the evolution of cardiac biomarkers - back to the future (again). PMID- 29703103 TI - The assessment of iodine status - populations, individuals and limitations. AB - Iodine deficiency is a significant global health concern, and the single greatest cause of preventable cognitive impairment. It is also a growing public health concern in the UK particularly among pregnant women. Biomarkers such as urinary iodine concentration have clear utility in epidemiological studies to investigate population-level iodine status, but determination of iodine status in individuals is much more problematic with current assays. This article reviews the available biomarkers of iodine status and their relative utility at the level of both populations and individuals for the investigation of iodine deficiency and iodine excess. PMID- 29703104 TI - Establishment of a simpler method for measuring HDL-microRNAs. AB - Background MicroRNAs are present not only in exosomes but also in high-density lipoprotein (HDL) and have the potential as biomarkers for various diseases. Various purification methods have been developed to quantify HDL-miRNAs; however, they are unsuitable for clinical applications. Therefore, we aimed to establish a simpler analytical method to quantify HDL-miRNAs for clinical applications. Methods We purified HDL fraction from pooled plasma using a three-step protocol consisting of ultracentrifugation, phosphotungstic acid/MgCl2 precipitation and desalting/buffer exchange followed by the quantification of HDL-miRNAs by quantitative real-time PCR. In order to establish a method to quantify HDL-miRNAs by quantitative real-time PCR, we prepared standard curves for miR-223 and miR 92. The HDL-miRNAs of 10 volunteers were assessed. Results Exosomes and LDL were not detected in the purified HDL fraction. Furthermore, we confirmed that only HDL was purified and that the HDL recovery rate of our method was at least approximately 50%. The threshold cycle values of miR-223, miR-92, miR-146a and miR-150 in the same subject were 32.11 +/- 0.58, 32.50 +/- 0.35, 34.30 +/- 0.70 and 34.91 +/- 0.77, respectively ( n = 10). The coefficient of variation values for these miRNAs were 1.08-2.21%. In addition, the standard curve for the quantitative analysis of miRNAs showed high linearity (30-30,000 copies/ MUL) with a correlation coefficient of >0.99. The concentrations of HDL-miR-223 and HDL-miR-92 in the plasma of 10 subjects were 1.98 +/- 0.32 and 0.90 +/- 0.14 copies/mL (*104). Conclusions We established a simple method for quantifying HDL miRNAs and improved the sample processing capacity compared with conventional methods. PMID- 29703105 TI - Constrictive pericarditis: retrospective study of 109 patients. AB - Background Chronic constrictive pericarditis is the most common diastolic disorder of the heart. Non-elasticity of the pericardium with impaired cardiac diastolic function is constriction. Chronic constrictive pericarditis is the result of scarring and fibrosis in mid and late diastole. The clinical presentation is similar to that of right heart failure. Historically, the etiology is helpful but not diagnostic. Echocardiography and a hemodynamic study are the main diagnostic tools. A thick pericardium of more than 4 mm is not necessarily constrictive, but thickness >=7 mm is highly specific for constrictive features. Pericardiectomy is usually associated with early normalization of hemodynamics, which can be achieved via a mid-sternotomy or left anterolateral thoracotomy. Methods Data of 109 patients who underwent pericardiectomy from January 1987 to June 2016 were reviewed retrospectively. Results The outcome of our 109 cases consisted of mortality in 2 patients only. Conclusion Progressive, fibrotic, thickened, adherent inflammatory changes in response to various pathologies of the pericardium impairing diastolic filling can be treated by pericardiectomy. Pericardiectomy can be achieved by a mid sternotomy or anterolateral thoracotomy without any difference in outcome. The initial hemodynamic and clinical result may not always be dramatic but continued improvement is definite because of progressive enlargement of left ventricular dimensions. PMID- 29703106 TI - Recent trends and perspectives in enzyme based biosensor development for the screening of triglycerides: a comprehensive review. AB - Clinical manifestations of the elevated plasma triacylglycerol (TG) include a greater prevalence of atherosclerotic heart disease, acute pancreatitis, diabetes mellitus, hypertension, and ischemic vascular disease. Hence, these significant health troubles have attracted scientific attention for the precise detection of TG in biological samples. Numerous techniques have been employed to quantify TG over many decades, but biosensors hold the leading position owing to their superior traits such as highly specific recognition for target molecules, accuracy, minituarization, small sample requirement and rapid response. Enzyme based electrochemical biosensors represent an instantaneous resolution for the foremost bottlenecks constraining laboratory prototypes to reach real time bedside applications. We highlight the choice of transducers and constructive strategies to design high-performance biosensor for the quantification of triglycerides in sera and early diagnosis of health problems related to it. In the present review, a small effort has been made to emphasize the significant role of enzymes, nanostructured metal oxides, graphene, conducting polypyrrole, nanoparticles, porous silicon, EISCAP and ENFET in enabling TG biosensors more proficient and taking a revolutionary step forward. PMID- 29703107 TI - Clinical trial for development of a steerable microcatheter. AB - PURPOSE: A steerable microcatheter provided with a mechanism on the handle for changing the direction of the catheter tip was developed by Sumitomo Bakelite and evaluated in a clinical trial before introduction into clinical use. MATERIAL AND METHODS: The steerable microcatheter has a 2.4F/2.9-F external diameter (distal/proximal portion) and a 0.021-inch internal diameter with a dial on the proximal portion for moving the tip. In patients scheduled to undergo selective transarterial procedures, selective arteriography of target arterial branches chosen by the evaluator was performed using the steerable microcatheter during the procedure. Efficacy was evaluated based on operability (technical success, procedure time, use of guidewire, usefulness of tip mobility), and safety was evaluated based on defects and adverse events. RESULTS: Between September 2013 and October 2013, 20 patients were enrolled at four institutions. The success rate for guidewireless insertion of the steerable microcatheter into the target vessels was 96.7%, and operability was judged as good in all 20 patients. Poor tip movement was identified as a defect of the steerable microcatheter in one patient. There were no adverse events associated with the use of the steerable microcatheter. CONCLUSION: This trial confirmed that the steerable microcatheter had the utility required for medical device approval. Thereafter, it obtained marketing approval. PMID- 29703108 TI - Research roundup. AB - Synopses of a selection of recently published research articles of relevance to palliative care. PMID- 29703109 TI - Dying matters. PMID- 29703110 TI - Registered nurse verification of expected adult death: new guidance provides direction. AB - Despite UK national guidance on care after death, it is clear that the bereaved family can experience distress while waiting for the patient's death to be verified. This distress can escalate if there is a delay in verification. Anecdotally, such delays particularly occur out of hours and in community settings. Verification of death is a clinical task and an act of care whereby the identity of the person and death is confirmed. In addition, the subsequent providers of care to the deceased, such as families, mortuary teams, funeral directors and cremation services, have their health and safety protected by the provision of pertinent patient-specific information, for instance, infection risk and implantable devices, within the bounds of confidentiality. During this time, the bereaved family may also receive emotional support and information from the skilled clinician. Registered Nurse Verification of Expected Adult Death (RNVoEAD) guidance and associated competencies have recently been developed to ensure that the registered nurses involved in the patient's care can feel confident about their responsibilities and competent in the process of verifying death. It is hoped that this guidance will help to avoid delays that may cause additional distress to grieving families. This article sets out the rationale for the guidance, as well as discussing outstanding concerns and proposals for future considerations. PMID- 29703111 TI - Undergraduate nursing students' transformational learning during clinical training. AB - BACKGROUND: Undergraduate nursing students encounter patients at the end of life during their clinical training. They need to confront dying and death under supportive circumstances in order to be prepared for similar situations in their future career. AIM: To explore undergraduate nursing students' descriptions of caring situations with patients at the end of life during supervised clinical training. METHODS: A qualitative study using the critical incident technique was chosen. A total of 85 students wrote a short text about their experiences of caring for patients at the end of life during their clinical training. These critical incident reports were then analysed using deductive and inductive content analysis. FINDINGS: The theme 'students' transformational learning towards becoming a professional nurse during clinical training' summarises how students relate to patients and relatives, interpret the transition from life to death, feel when caring for a dead body and learn end-of-life caring actions from their supervisors. IMPLICATIONS: As a preparation for their future profession, students undergoing clinical training need to confront death and dying while supported by trained supervisors and must learn how to communicate about end-of life issues and cope with emotional stress and grief. PMID- 29703112 TI - Family members' experiences of care of the dying in residential care homes where the Liverpool Care Pathway was used. AB - BACKGROUND: Residential care homes (RCHs) are increasingly becoming a common place of death for older people. AIM: The aim of this study was to describe family members' experiences of care of the dying in RCHs where the Liverpool care pathway for the dying patient was used. METHODS: This study had a descriptive qualitative study design. Fifteen (n=15) individual interviews were analysed using qualitative content analysis. RESULTS: The analysis resulted in three themes: being confident in a familiar and warm atmosphere, being involved vs not being involved in end-of-life (EoL) care, and being consoled by witnessing the health professional's endeavour to relieve suffering. SIGNIFICANCE OF RESULTS: The results indicated that taking part in a care plan seems to increase family members' feelings of involvement in EoL care. This study also highlights the family members' needs for increased possibilities for EoL discussions with the GP. PMID- 29703113 TI - Erratum. PMID- 29703114 TI - Addressing palliative and end-of-life care needs with Native American elders. AB - BACKGROUND: Life-limiting illness plagues Native Americans, yet access to palliative and end-of-life care, including hospice care, is severely limited. AIM: This study aimed to explore palliative and hospice care with Native American elders and tribal health educators on a Northern Plains reservation in the US. METHODS: Using a community-based participatory approach, participants discussed the cultural acceptability of palliative and hospice care in their tribal community. Monthly talking circles were held over a 5-month period. RESULTS: Opportunities were present for improving cultural awareness and advance directive education to elders. Challenges raised were related to infrastructure, tribal government and the Indian Health Service. Needs identified included cultural awareness and language education for health-care providers and advance directive education. CONCLUSION: Community-based participatory research is useful when working with indigenous populations. Health professionals providing services to Native American communities must embrace cultural differences, seeking to learn from the culture itself how to best meet its people's needs. PMID- 29703115 TI - Integrating nurse-facilitated advance care planning for patients newly diagnosed with advanced lung cancer. AB - BACKGROUND: Advance care planning (ACP) is well recognised as an important component of palliative care. However, there is still a need to explore ways in which it can become a part of routine practice, ensuring a timely and person centred discussion. OBJECTIVES: To explore patients newly diagnosed with advanced lung cancer and their family members' experiences of engaging in a person-centred and structured ACP discussion facilitated by palliative care nurses in an outpatient oncology clinic at the University Hospital of Iceland. METHODS: An exploratory qualitative design employing semi-structured interviews and thematic analysis. The intervention included a structured ACP discussion, aided by a booklet. RESULTS: Key themes emerged describing families' and patients' experiences and highlighted that the timing and approach of the ACP discussion was appropriate and helpful, even though the discussion was sensitive and difficult. Using a routine approach with a flexible structure normalised the discussion and made it easier for the patients to take the lead in the discussion. CONCLUSIONS: ACP discussion can be part of an integrated palliative care and oncology service if implemented in a systematic way. PMID- 29703116 TI - Politics and palliative care: Angola. AB - Dion Smyth's review of palliative nursing on the internet. PMID- 29703117 TI - Association between T-182C, G1287A polymorphism in NET gene and suicidality in major depressive disorder in Chinese patients. AB - OBJECTIVE: Previous studies have implicated norepinephrine transporter gene (NET) polymorphisms in the etiology of major depressive disorder (MDD). A functional NET T-182C polymorphism (rs2242446) in the promoter region and a synonymous polymorphisms G1287A in the exon 9 (rs5569) were associated with MDD in different populations. However, few studies have focused on the relationship between these polymorphisms and MDD patients with suicidality. The objective of the present study was to examine whether the two polymorphisms are associated with MDD patients with suicidality in the Han Chinese population. METHODS: Two hundred and sixty-three suicidal depressed patients and 241 non-suicidal depressed patients who met DSM-IV criteria for MDD were recruited from our hospital. Three hundred and three unrelated, age- and sex-matched healthy control subjects participated in this case-control study. Suicidality was assessed using Mini International Neuropsychiatric Interview (MINI) and the Hamilton rating scale for depression (HAMD). Genotypes of T-182C polymorphism (rs2242446) and G1287A (rs5569) were screened by polymerase chain reaction. RESULTS: No statistical significant differences between patients and controls were found for any of the analysed polymorphisms, either in the genotype or allele distribution. CONCLUSIONS: Our results suggest that the investigated polymorphisms are not major susceptibility factors in the etiology of MDD with suicidality. However, the results must be verified in larger samples and different ethnicities. PMID- 29703118 TI - Endogenous testosterone does not improve prediction of incident cardiovascular disease in a community-based cohort of adult men: results from the Tehran Lipid and Glucose Study. AB - INTRODUCTION: To explore the predictive value of testosterone added to the Framingham Risk Score (FRS) for cardiovascular disease (CVD). METHODS: Among 816 men, 30-70 years/old, without prevalent CVD, from a community-based cohort (Tehran Lipid and Glucose Study), we assessed the predictive value of testosterone with incident CVD, using three multivariate Cox proportional-hazards models. Model I: FRS variables; model II: Model I plus total testosterone; model III: Model II plus Systolic blood pressure (SBP) * total testosterone (the best fit interaction-term between testosterone and FRS variables). Discriminations and goodness-of-fit were assessed by the C-statistic and the approach of Gronnesby, respectively. p Value <.05 was significant. RESULTS: During 12 years of follow up, 121 CVD events occurred. In all models, age, treated SBP, smoking, and diabetes were associated with increased CVD (p values <.05). Neither testosterone (models II and III), nor SBP * testosterone (model III) were associated with CVD (p values >.05). The C-statistics for models I, II, and III were 0.819, 0.820, and 0.821, respectively, indicating no significant improvement in the discrimination power. The models' goodness-of-fit did not improve compared with the FRS. CONCLUSION: Testosterone could not add to the predictive value of FRS for CVD in men, either directly, or through interactions with FRS variables. PMID- 29703119 TI - Individuals' experiences with brief admission during the implementation of the brief admission skane RCT, a qualitative study. AB - BACKGROUND: Brief admission (BA) is an adjunctive treatment option for individuals with self-harming behavior, having traits of borderline personality disorder (BPD). It is offered alongside outpatient psychotherapy for the purpose of strengthening autonomy, self-reflection and self-care and to increase the likelihood of being able to stay in therapy by avoiding lengthy inpatient hospitalizations. AIMS: To investigate participants' experiences with BA during the pilot phase of the Brief Admission Skane Randomized Controlled Trial (BASRCT), in order to detect possible strengths and limitations of the intervention and gain knowledge to facilitate implementation of BA at other treatment centers. METHOD: Eight participants randomized to BA were interviewed to obtain their experience of BA, or alternatively their reasons for choosing not to use BA. Thematic analysis was conducted upon their transcribed interviews. RESULTS: Reported as most helpful by the participants was the structure/routines at the ward and the positive attitudes from the staff. However, some individuals reported problems with perceived negative attitudes from the staff administering BA and negative rumination about themselves. The reported reasons to request BA were: preventing urges to self-harm from escalating; ending isolation; preventing longer admissions and forced admission; feelings of emotional exhaustion, and the need for rest and support in re-creating a daily routine. Reasons for not requesting BA were fear of rejection, questioning the method; presumed room shortage; difficulties in deciding whether one's problems are serious enough; experiencing the situation to be too clinically acute. CONCLUSION: The results from this study indicated the importance of repeated staff education on all aspects of BA when it is being newly implemented, as well as the importance of working with attitudes of staff delivering BA. These were the key ingredients in making BA implementation successful. Our findings may be of value to other treatment centers implementing BA for the first time. TRIAL REGISTRATION: NCT02985047. PMID- 29703120 TI - Workplace-based communication skills training in clinical departments: Examining the role of collegial relations through positioning theory. AB - INTRODUCTION: Studies suggest that the workplace is a key to understanding how clinical communication skills learning takes place and that medical communication skills need to be reinforced over time in order not to deteriorate. This study explored the perceptions of doctors in four hospital departments who participated in a workplace-based communication training project. Its specific focus was the relationship between collegial relations and learning communication skills. METHODS: The study applied a qualitative design using an ethnographic methodology, i.e. interviews and observations. Positioning theory was used as the theoretical framework. RESULTS: Training communication skills with colleagues in the actual workplace setting was valued by the participants who experienced more sharing of communication challenges, previously understood as something private one would not share with colleagues. However, collegial relations were also barriers for providing critical feedback, especially from junior doctors to their seniors. CONCLUSION: The position as "colleague" both reinforced the communication skills training and hindered it. The communication skills educational model had a flat, non-hierarchical structure which disturbed the hierarchical structure of the workplace, and its related positions. PMID- 29703121 TI - Validation of the Inventory of Interpersonal Problems (IIP-64): a comparison of Swedish female outpatients with anorexia nervosa or bulimia nervosa and controls. AB - AIM: The aim of the study was to explore the psychometric properties of the Inventory of Interpersonal Problems (IIP-64) and to compare levels of interpersonal distress in Swedish female outpatients with anorexia nervosa or bulimia nervosa with age- and gender-matched controls. METHODS: Totally, 401 participants were included; anorexia nervosa (n = 74), bulimia nervosa (n = 85) and controls (n = 242). All participants completed the IIP-64. The eating disorder (ED) patients also filled out the Eating Disorder Inventory-2/3 (EDI). RESULTS: Internal consistency of IIP-64 was acceptable to high. Principal component analyses with varimax rotation of the IIP-64 subscales confirmed the circumplex structure with two underlying orthogonal dimensions; affiliation and dominance. Significant correlations between EDI-3 composite scales ineffectiveness and interpersonal problems and IIP-64 were found. ED patients reported higher levels of interpersonal distress than controls on all but one subscale (intrusive/needy). CONCLUSIONS: IIP-64 can be considered to have acceptable to good reliability and validity in a Swedish ED sample. IIP-64 can be a useful complement in assessment of interpersonal problems in ED. PMID- 29703122 TI - Prevalence of prescription errors in general practice in Jeddah, Saudi Arabia. AB - PURPOSE: Prescription errors are a common cause of adverse drug events (ADEs). Recognizing ADEs can significantly contribute to the reduction of morbidity and mortality. This study aims to investigate the type and prevalence of errors in prescription writing, directed toward a needs assessment for developing educational interventions. MATERIALS AND METHODS: A cross-sectional descriptive study was conducted in Jeddah community pharmacies (January-February 2016). A random sample of 117 prescriptions were reviewed and analyzed by community pharmacists for legibility and omission of the information in the prescription. RESULTS: Results revealed that 51% of the prescriptions included diagnosis, in which 62% included the recommended drug dosage. Only 7% of drug interactions were reported between the prescribed drugs, 17% of the physicians prescribed drugs that prevented the adverse effects used for diagnosis. Prescriptions for chronic conditions were scrutinized to be 18%. It was noteworthy that 29% of the pharmacists reported difficulty in reading the handwriting of prescriptions. CONCLUSIONS: The quality of prescription writing is deficient in some elements and strategies for improvement are needed. These findings underscore a crucial requirement to upgrade the quality of prescription writing by encouraging continuous medical education programs to facilitate delivery of excellent therapeutic outcomes. PMID- 29703123 TI - Disease severity of proliferative lupus nephritis in Maghrebians. AB - Objective To study the influence of Maghrebian ethnicity on lupus nephritis. Methods We retrospectively reviewed the files of a cohort of 194 patients with proliferative lupus nephritis followed in seven lupus centres belonging to three groups: Europeans living in Belgium/France (E; n = 111); Maghrebians living in Europe, in casu Belgium/France (ME; n = 43); and Maghrebians living in Morocco (MM; n = 40). Baseline presentation was compared between these three groups but complete long-term outcome data were available only for E and ME patients. Results At presentation, the clinical and pathological characteristics of lupus nephritis did not differ between E, ME and MM patients. Renal relapses were more common in ME patients (54%) than in E patients (29%) ( P < 0.01). Time to renal flare and to end-stage renal disease was shorter in ME patients compared to E patients ( P < 0.0001 and P < 0.05, respectively). While proteinuria measured at month 12 accurately predicted a serum creatinine value of less than 1 mg/dl at 7 years in E patients, this was not the case in the ME group, in whom serum creatinine at month 12 performed better. Conclusion Despite a similar disease profile at onset, the prognosis of lupus nephritis is more severe in Maghrebians living in Europe compared to native Europeans, with a higher relapse rate. PMID- 29703124 TI - Diagnostic Accuracy of a Self-report Measure of Patellar Tendinopathy in Youth Basketball. AB - BACKGROUND: To engage clinicians in diagnosing patellar tendinopathy in large surveillance studies is often impracticable. The Oslo Sports Trauma Research Centre-patellar tendinopathy (OSTRC-P) questionnaire, a self-report measure adapted from the OSTRC questionnaire, may provide a viable alternative. OBJECTIVES: To evaluate the diagnostic accuracy of the OSTRC-P questionnaire in detecting patellar tendinopathy in youth basketball players when compared to clinical evaluation. METHODS: Following the STAndards for Reporting of Diagnostic accuracy studies guidelines, the researchers recruited 208 youth basketball players (13-18 years of age) for this prospective diagnostic accuracy validation study. Participants completed the OSTRC-P questionnaire (index test) prior to a clinical evaluation (reference standard) by a physical therapist blinded to OSTRC P questionnaire results. Sensitivity, specificity, predictive value, likelihood ratio, and posttest probability were calculated. Linear regression was used to examine the association between the OSTRC-P questionnaire severity score and the patellar tendinopathy severity rating during a single-leg decline squat. RESULTS: The final analysis included 169 players. The OSTRC-P questionnaire had a sensitivity of 79% (95% confidence interval [CI]: 65%, 90%), specificity of 98% (95% CI: 94%, 100%), positive predictive value of 95% (95% CI: 83%, 99%), negative predictive value of 92% (95% CI: 86%, 96%), positive likelihood ratio of 48 (95% CI: 12, 191), and negative likelihood ratio of 0.21 (95% CI: 0.12, 0.37). The posttest probabilities were 95% and 8%, given positive and negative results, respectively. A positive association was found between OSTRC-P questionnaire severity score and single-leg decline squat rating (beta = 0.08; 95% CI: 0.03, 0.12; P = .001). CONCLUSION: The OSTRC-P questionnaire is an acceptable alternative to clinical evaluation for self-reporting patellar tendinopathy and grading its severity in settings involving youth basketball players. LEVEL OF EVIDENCE: Diagnosis, level 1b. J Orthop Sports Phys Ther 2018;48(10):758-766. Epub 27 Apr 2018. doi:10.2519/jospt.2018.8088. PMID- 29703125 TI - Two retrievals from a single cue: A bottleneck persists across episodic and semantic memory. AB - There is evidence in the literature that two retrievals from long-term memory cannot occur in parallel. To date, however, that work has explored only the case of two retrievals from newly acquired episodic memory. These studies demonstrated a retrieval bottleneck even after dual-retrieval practice. That retrieval bottleneck may be a global property of long-term memory retrieval, or it may apply only to the case of two retrievals from episodic memory. In the current experiments, we explored whether that apparent dual-retrieval bottleneck applies to the case of one retrieval from episodic memory and one retrieval from highly overlearned semantic memory. Across three experiments, subjects learned to retrieve a left or right keypress response form a set of 14 unique word cues (e.g., black-right keypress). In addition, they learned a verbal response which involved retrieving the antonym of the presented cue (e.g., black-"white"). In the dual-retrieval condition, subjects had to retrieve both the keypress response and the antonym word. The results suggest that the retrieval bottleneck is superordinate to specific long-term memory systems and holds across different memory components. In addition, the results support the assumption of a cue-level response chunking account of learned retrieval parallelism. PMID- 29703126 TI - Twelve tips for integrating team reflexivity into your simulation-based team training. AB - Due to increasing complexity in healthcare, clinicians must often make decisions under uncertain conditions in which teams must be flexible and process emerging information "on the fly" in order to adapt to changing circumstances. A crucial strategy that helps teams to adapt, learn, and develop is team reflexivity (TR) - a team's ability to collectively reflect on group objectives, strategies, processes, and outcomes of past and current performance and to adapt accordingly. We provide 12 evidence-based tips on incorporating TR into simulation-based team training (SBTT). The first three points elaborate on basic principles of TR, when TR can take place and why it matters. The following nine tips are then organized according to three phases in which teams are able to engage in TR: pre-action, in action, and post-action. SBTT represents an ideal venue to train various TR behaviors that foster team learning and improve patient care. PMID- 29703127 TI - A systematic review of reviews to identify key research opportunities within the field of eHealth implementation. AB - Introduction This paper is a systematic review of the relevant literature surrounding the implementation and utilisation of eHealth to identify key challenges and opportunities to future eHealth applications. Methods NHS Evidence, PubMed, IEEE Explorer, Cochrane Library and JMIR Publications were all searched for reviews published between 1 January 2010 and 30 June 2017. Results A total of 47 papers met the final inclusion criterion. The published literature focused on a wide array of challenges categorised into five areas, facing the implementation and utilisation of eHealth; from this, four areas of opportunity to advance eHealth were identified. Discussion The five challenge areas are (C1) stakeholders and system users, (C2) technology and interoperability, (C3) cost effectiveness and start-up costs, (C4) legal clarity and legal framework and (C5) local context and regional differences. The four opportunity areas are (O1) participation and contribution, (O2) foundation and sustainability, (O3) improvement and productivity and (O4) identification and application. Conclusion The literature analysed in this systematic review identifies design and implementation priorities that can guide the development and utilisation of future eHealth initiatives. PMID- 29703128 TI - Relevance of Perpetrator Identity to Reporting Elder Financial and Emotional Mistreatment. AB - OBJECTIVE: The National Elder Mistreatment Study (NEMS) found that 5.2% of community older adults experienced financial abuse, and 4.6% experienced emotional mistreatment in the past year. Unfortunately, the majority of abuse was not reported to the authorities. This study investigated reasons for non reporting. METHOD: In all, 774 NEMS participants were surveyed 8 years later via telephone to assess past-year financial and emotional mistreatment, perpetrator status, and whether any of these episodes were reported to authorities. RESULTS: In total, 87.5% of financial abuse by family, friends, or acquaintances was not reported versus 33% of that perpetrated by strangers; for emotional mistreatment, 89.9% of that perpetrated by family, friends, and acquaintances was not reported, compared with 83.3% by strangers. Reasons for non-reporting of emotional abuse centered largely around with "not wanting publicity" and "not wanting to get the perpetrator in trouble," while no consistent reason emerged for failure to report stranger-perpetrated mistreatment. PMID- 29703129 TI - Lithium-incorporated deproteinized bovine bone substitute improves osteogenesis in critical-sized bone defect repair. AB - This study aimed to explore the surface modification of deproteinized bovine bone using lithium-ion and evaluate its efficacy on osteogenesis improvement and critical-sized bone defect repair. Hydrothermal treatment was performed to produce lithium-incorporated deproteinized bovine bone. In vitro study, human osteosarcoma cell MG63 (MG63) was cultured with the bone substitute to evaluate the cell viability and then calcium deposition was measured to analyze the osteogenesis. In vivo studies, male adult goats were chosen to build critical sized bone defect model and randomly divided into three groups. The goats were treated with autogenous cancellous bone, lithium-incorporated deproteinized bovine bone, and deproteinized bovine bone. Animals were evaluated using radiological analysis including X-ray, computed tomography, and Micro-CT; histological methods involving hematoxylin-eosin dyeing, Masson dyeing, and immunofluorescence detection at 4 and 12 weeks after surgery were carried out. According to the results, lithium-incorporated deproteinized bovine bone produced nano-structured surface layer. The lithium-incorporated deproteinized bovine bone could promote the osteoblast proliferation and increase the calcium deposition. In vivo studies, radiographic results revealed that lithium-incorporated deproteinized bovine bone scaffolds provided better performance in terms of mean gray values of X films, mean pixel values of computed tomography films, and bone volume and trabecular thickness of micro-computed tomography pictures when compared with the deproteinized bovine bone group. In addition, histological analysis showed that the lithium-incorporated deproteinized bovine bone group also significantly achieved larger new bone formation area. At the same time, when the expression of osteogenic factors in vivo was evaluated, runt-related transcription factor 2 (Runx2) and collagen type one (Col-1) were expressed more in lithium-incorporated deproteinized bovine bone group than those in deproteinized bovine bone group. However, the bone defect repair effect using autograft is still a little better than that of lithium-incorporated deproteinized bovine bone substitute based on our results. In conclusion, surface lithium-incorporated deproteinized bovine bone achieved improvement of osteogenesis effect and could enhance the new bone formation in critical-sized bone defects. PMID- 29703130 TI - Transcriptome profiling provides insights into dormancy release during cold storage of Lilium pumilum. AB - BACKGROUND: Bulbs of the ornamental flower Lilium pumilum enter a period of dormancy after flowering in spring, and require exposure to cold for a period of time in order to release dormancy. Previous studies focused mainly on anatomical, physiological and biochemical changes during dormancy release. There are no dormancy studies of the northern cold-hardy wild species of Lilium at the molecular level. This study observed bulb cell and starch granule ultrastructures during cold storage; and analysed the transcriptome using sequencing. The combination of morphological and transcriptomic methods provides valuable insights into dormancy release during cold storage of Lilium pumilum. RESULTS: Ultrastructural changes reflected dormancy release during cold storage of the bulbs. We compared gene expression levels among samples at 0 (S1 stage), 30 (S2 stage), 60 (S3 stage) and 90 (S4 stage) d of cold storage, with 0 d as the control. The data showed that some regulatory pathways such as carbohydrate metabolism and plant hormone signal transduction were activated to break dormancy. Some differentially expressed genes (DEGs) related to antioxidant activity, epigenetic modification and transcription factors were induced to respond to low temperature conditions. These genes constituted a complex regulatory mechanism of dormancy release. CONCLUSIONS: Cytological data related to dormancy regulation was obtained through histomorphological observation; transcriptome sequencing provided comprehensive sequences and digital gene expression tag profiling (DGE) data, and bulb cell ultrastructural changes were closely related to DEGs. The novel Lilium pumilum genetic information from this study provides a reference for the regulation of dormancy by genetic engineering using molecular biology tools. PMID- 29703131 TI - Extensive mitochondrial gene rearrangements in Ctenophora: insights from benthic Platyctenida. AB - BACKGROUND: Complete mitochondrial (mt) genomes have been sequenced for thousands of animals and represent a molecule of choice for many evolutionary studies. Nevertheless, some animal groups have remained under-sampled. Ctenophora (comb jellies) is one such example, with only two complete mt sequences determined hitherto for this phylum, which encompasses ca. 150-200 described species. This lack of data derives from the extremely fast mt evolutionary rate in this lineage, complicating primer design and DNA amplification. Indeed, in the two ctenophore mt genomes sequenced to date, i.e. those of Mnemiopsis leidyi (order Lobata) and Pleurobrachia bachei (order Cydippida), both rRNA and protein coding genes exhibit an extraordinary size reduction and have highly derived sequences. Additionally, all tRNAs, and the atp6 and atp8 genes are absent. In order to determine whether these characteristics are shared by other ctenophores, we obtained the complete mt genomes of three benthic ctenophores belonging to the so far unsampled order of Platyctenida: Coeloplana loyai, Coeloplana yulianicorum and Vallicula multiformis. RESULTS: The mt genomes of benthic ctenophores reveal the same peculiarities found in Mnemiopsis and Pleurobrachia, demonstrating that the fast evolutionary rate is a general trait of the ctenophore mt genomes. Our results also indicate that this high evolutionary rate not only affects the nucleotide substitution but also gene rearrangements. Indeed, gene order was highly rearranged among representatives of the different taxonomic orders in which it was close to random, but also quite variable within Platyctenida, in which the genera Coeloplana and Vallicula share only four conserved synteny blocks. However, the two congeneric Coeloplana species display exactly the same gene order. Because of the extreme evolutionary rate, our phylogenetic analyses were unable to resolve the phylogenetic position of ctenophores within metazoans or the relationships among the different Ctenophora orders. Comparative sequence analyses allowed us to correct the annotation of the Pleurobrachia mt genome, confirming the absence of tRNAs, the presence of both rRNA genes, and the existence of a reassignment of codon TGA from tryptophan to serine for this species. CONCLUSIONS: Since Platyctenida is an early diverging lineage among Ctenophora, our findings suggest that the mt traits described above are ancestral characteristics of this phylum. PMID- 29703132 TI - Genomic insights into natural selection in the common loon (Gavia immer): evidence for aquatic adaptation. AB - BACKGROUND: The common loon (Gavia immer) is one of five species that comprise the avian order Gaviiformes. Loons are specialized divers, reaching depths up to 60 m while staying submerged for intervals up to three minutes. In this study we used comparative genomics to investigate the genetic basis of the common loon adaptations to its ecological niche. We used Illumina short read DNA sequence data from a female bird to produce a draft assembly of the common loon (Gavia immer) genome. RESULTS: We identified 14,169 common loon genes, which based on well-resolved avian genomes, represent approximately 80.7% of common loon genes. Evolutionary analyses between common loon and Adelie penguin (Pygoscelis adeliae), red-throated loon (Gavia stellata), chicken (Gallus gallus), northern fulmar (Fulmarus glacialis), and rock pigeon (Columba livia) show 164 positively selected genes in common and red-throated loons. These genes were enriched for a number of protein classes, including those involved in muscle tissue development, immunoglobulin function, hemoglobin iron binding, G-protein coupled receptors, and ATP metabolism. CONCLUSIONS: Signatures of positive selection in these areas suggest the genus Gavia may have adapted for underwater diving by modulating their oxidative and metabolic pathways. While more research is required, these adaptations likely result in (1) compensations in oxygen respiration and energetic metabolism, (2) low-light visual acuity, and (3) elevated solute exchange. This work represents the first effort to understand the genomic adaptations of the common loon as well as other Gavia and may have implications for subsequent studies that target particular genes for loon population genetic, ecological or conservation studies. PMID- 29703133 TI - Cross-site comparison of ribosomal depletion kits for Illumina RNAseq library construction. AB - BACKGROUND: Ribosomal RNA (rRNA) comprises at least 90% of total RNA extracted from mammalian tissue or cell line samples. Informative transcriptional profiling using massively parallel sequencing technologies requires either enrichment of mature poly-adenylated transcripts or targeted depletion of the rRNA fraction. The latter method is of particular interest because it is compatible with degraded samples such as those extracted from FFPE and also captures transcripts that are not poly-adenylated such as some non-coding RNAs. Here we provide a cross-site study that evaluates the performance of ribosomal RNA removal kits from Illumina, Takara/Clontech, Kapa Biosystems, Lexogen, New England Biolabs and Qiagen on intact and degraded RNA samples. RESULTS: We find that all of the kits are capable of performing significant ribosomal depletion, though there are differences in their ease of use. All kits were able to remove ribosomal RNA to below 20% with intact RNA and identify ~ 14,000 protein coding genes from the Universal Human Reference RNA sample at >1FPKM. Analysis of differentially detected genes between kits suggests that transcript length may be a key factor in library production efficiency. CONCLUSIONS: These results provide a roadmap for labs on the strengths of each of these methods and how best to utilize them. PMID- 29703134 TI - Identification and characterization of karyotype in Passiflora hybrids using FISH and GISH. AB - BACKGROUND: A great interest exists in the production of hybrid plants of the genus Passiflora given the beauty and exotic features of its flowers which have ornamental value. Hybrid paternity confirmation is therefore important for assuring germplasm origin, and is typically carried out by molecular marker segregation. The aim of this study was to karyotypically characterize the chromosome heritance patterns of the progeny resultant from a cross of P. gardneri and P. gibertii using classical cytogenetics, chromosome banding, and molecular cytogenetics. RESULTS: All analyzed genotypes showed the same diploid chromosome number as the genitor species: 2n = 18. Classical and CMA3 and DAPI staining allowed for chromosome counting and satellite identification (secondary constrictions). Fluorescence in situ hybridization (FISH) and genomic in situ hybridization (GISH) were used to characterize subgenomes by either identifying rDNA-specific genome patterns or parental genomes, respectively. CONCLUSIONS: The heritance of chromosomal markers presenting rDNA sites from each parent for genome identification confirmed that all obtained plants were hybrids. These results will improve breeding programs involving the species of this genus. Apart from confirming hybridization, GISH allowed the visualization of recombination between the homeologous chromosome and the introgression of sequences of interest. PMID- 29703135 TI - Spectrophotometric determination of ammonia levels in tobacco fillers of and sidestream smoke from different cigarette brands in Japan. AB - BACKGROUND: The ammonia contained in tobacco fillers and mainstream and sidestream cigarette smoke accelerates nicotine dependence in cigarette smokers. Ammonia has been included in the non-exhaustive priority list of 39 tobacco components and emissions of cigarette published by the World Health Organization (WHO) Study Group on Tobacco Product Regulation. The development of a simple ammonia detection method will contribute to the establishment of tobacco product regulation under tobacco control policies and allow surveys to be conducted, even by laboratories with small research budgets. METHODS: We developed a simple colorimetric method based on the salicylate-chlorine reaction and absorption spectrometry with two reagents (sodium nitroprusside and sodium dichloroisocyanurate). To compare this method to conventional ion chromatography, we analyzed the ammonia levels in tobacco fillers extracted from 35 Japanese commercially marketed cigarette brands manufactured by four tobacco companies (Japan Tobacco (JT) Inc., British American Tobacco (BAT), Philip Morris Japan, and Natural American Spirit). We also analyzed the ammonia levels in the sidestream smoke from cigarettes of the brands that were found to contain high or low tobacco filler ammonia levels. RESULTS: The ammonia levels in the reference cigarette (3R4F) measured by our method and ion chromatography were similar and comparable to previously reported levels. The ammonia levels in tobacco fillers extracted from 35 cigarette brands ranged from 0.25 to 1.58 mg/g. The mean ammonia level of JT cigarette brands was significantly higher (0.83 +/- 0.28 mg/g) than that of Natural American Spirit cigarette brands (0.30 +/- 0.08 mg/g) and lower than those in the other two cigarette brands (1.11 +/- 0.19 mg/g for BAT and 1.24 +/- 0.15 mg/g for Philip Morris) (p < 0.001 by Bonferroni test). The ammonia levels in the sidestream smoke of CABIN, Marlboro Black Menthol, American Spirit Light, and Seven Stars were 5.89 +/- 0.28, 5.23 +/- 0.12, 6.92 +/- 0.56, and 4.14 +/- 0.19 mg/cigarette, respectively. The ammonia levels were higher in sidestream smoke than in tobacco filler. CONCLUSIONS: Our simple colorimetric could be used to analyze ammonia in tobacco fillers and sidestream smoke. There were significant differences between the ammonia levels of the 35 commercially marketed cigarette brands in Japan manufactured by four tobacco manufacturers. Over 90% of the ammonia in sidestream smoke was in gaseous phase. PMID- 29703136 TI - Whole-genome sequencing of Aspergillus tubingensis G131 and overview of its secondary metabolism potential. AB - BACKGROUND: Black Aspergilli represent one of the most important fungal resources of primary and secondary metabolites for biotechnological industry. Having several black Aspergilli sequenced genomes should allow targeting the production of certain metabolites with bioactive properties. RESULTS: In this study, we report the draft genome of a black Aspergilli, A. tubingensis G131, isolated from a French Mediterranean vineyard. This 35 Mb genome includes 10,994 predicted genes. A genomic-based discovery identifies 80 secondary metabolites biosynthetic gene clusters. Genomic sequences of these clusters were blasted on 3 chosen black Aspergilli genomes: A. tubingensis CBS 134.48, A. niger CBS 513.88 and A. kawachii IFO 4308. This comparison highlights different levels of clusters conservation between the four strains. It also allows identifying seven unique clusters in A. tubingensis G131. Moreover, the putative secondary metabolites clusters for asperazine and naphtho-gamma-pyrones production were proposed based on this genomic analysis. Key biosynthetic genes required for the production of 2 mycotoxins, ochratoxin A and fumonisin, are absent from this draft genome. Even if intergenic sequences of these mycotoxins biosynthetic pathways are present, this could not lead to the production of those mycotoxins by A. tubingensis G131. CONCLUSIONS: Functional and bioinformatics analyses of A. tubingensis G131 genome highlight its potential for metabolites production in particular for TAN-1612, asperazine and naphtho-gamma-pyrones presenting antioxidant, anticancer or antibiotic properties. PMID- 29703137 TI - Genome-wide identification of the auxin response factor gene family in Cicer arietinum. AB - BACKGROUND: Auxin Response Factors act as critical components of the auxin signaling pathway by regulating the transcription of auxin-responsive genes. The release of the chickpea reference genome provides an opportunity to identify and characterize the ARF gene family in this important legume by a data mining coupled by comparative genomics approaches. RESULTS: We performed a comprehensive characterization and analysis of 24 ARF genes in the chickpea reference genome. Comparative phylogenetic analysis of the ARF from chickpea, Medicago and Arabidopsis suggests that recent duplications have played a very limited role in the expansion of the ARF chickpea family. Gene structure analysis based on exon intron organization provides additional evidence to support the evolutionary relationship among the ARF members. Conserved motif analysis shows that most of the proteins fit into the canonical ARF structure model, but 9 proteins lack or have a truncated dimerization domain. The mechanisms underlying the diversification of the ARF gene family are based on duplications, variations in domain organization and alternative splicing. Concerning duplications, segmental, but not tandem duplications, have contributed to the expansion of the gene family. Moreover, the duplicated pair genes have evolved mainly under the influence of purifying selection pressure with restricted functional divergence. Expression profiles responding to various environmental stimuli show a close relationship between tissue and expression patterns. Promoter sequence analysis reveals an enrichment of several cis-regulatory elements related to symbiosis, and modulation of plant gene expression during the interaction with microbes. CONCLUSIONS: In conclusion, this study provides a comprehensive overview of the ARF gene family in chickpea. Globally, our data supports that auxin signaling pathway regulates a wide range of physiological processes and stress responses. Our findings could further provide new insights into the complexity of the regulation of ARF at the transcription level that may be useful to develop rational chickpea breeding strategies to improve development or stress responses. Our study also provides a foundation for comparative genomic analyses and a framework to trace the dynamic evolution of ARF genes on a large time-scale within the legume family. PMID- 29703139 TI - Identification of a novel Dlg2 isoform differentially expressed in IFNbeta producing plasmacytoid dendritic cells. AB - BACKGROUND: The murine discs large homolog 2 (DLG2; post synaptic density 93 (PSD 93); Chapsyn-110) is a member of the membrane-associated guanylate kinase (MAGUK) protein family involved in receptor assembly and associated with signaling enzymes on cell membranes. In neurons, DLG2 protein isoforms derived from alternatively spliced transcripts have been described to bind to NMDA (N-methyl aspartate) receptors and K channels and to mediate clustering of these channels in the postsynaptic membrane. In myeloid cells of the immune system, such as dendritic cells (DCs), a lack of data exists on the expression or function of DLG2. In cDNA microarray transcriptome analyses, we found Dlg2 highly expressed in a subpopulation of plasmacytoid DCs (pDCs) stimulated to produce type I interferons (IFNs) such as IFNbeta. RESULTS: Using RACE- and RT-PCR as well as immunoprecipitation followed by Western blotting we characterised the differential expression of the Dlg2 splice variants in IFNbeta-producing pDCs. Besides Dlg2gamma this cell population expressed a novel short Dlg2eta transcript we termed Dlg2eta3. Our expression data were integrated into information from genome databases to obtain a novel and comprehensive overview of the mouse Dlg2 gene architecture. To elucidate the intracellular localisation pattern of protein isoforms, ectopical expression analysis of fluorescently tagged DLG2 splice variants was performed. Here we found an enrichment of the larger isoform DLG2alpha1 at the plasma membrane while the newly identified shorter (DLG2eta) isoform as well as DLG2gamma were equally distributed throughout the cytoplasm. Additionally, DLG2eta was also found in the nucleus. Analysis of Dlg2-knockout mice previously generated by deleting exon 9 surprisingly revealed that the protein for the novel DLG2eta isoform was still expressed in the brain and in bone marrow-derived pDCs from mice carrying the homozygous deletion (Dlg2 DeltaE9/DeltaE9 ). CONCLUSION: We describe a novel splice variant of the mouse Dlg2 gene termed Dlg2eta and define the differential expression pattern of DLG2 isoforms in IFNbeta-producing pDCs. The presence of DLG2eta protein in the CNS of Dlg2 DeltaE9/DeltaE9 mice might influence the phenotype of these mice and has to be taken into account in the interpretation of results regarding the functional role of DLG2 in neuronal postsynaptic membranes. PMID- 29703138 TI - Transcriptional profiling of human bronchial epithelial cell BEAS-2B exposed to diesel and biomass ultrafine particles. AB - BACKGROUND: Emissions from diesel vehicles and biomass burning are the principal sources of primary ultrafine particles (UFP). The exposure to UFP has been associated to cardiovascular and pulmonary diseases, including lung cancer. Although many aspects of the toxicology of ambient particulate matter (PM) have been unraveled, the molecular mechanisms activated in human cells by the exposure to UFP are still poorly understood. Here, we present an RNA-seq time-course experiment (five time point after single dose exposure) used to investigate the differential and temporal changes induced in the gene expression of human bronchial epithelial cells (BEAS-2B) by the exposure to UFP generated from diesel and biomass combustion. A combination of different bioinformatics tools (EdgeR, next-maSigPro and reactome FI app-Cytoscape and prioritization strategies) facilitated the analyses the temporal transcriptional pattern, functional gene set enrichment and gene networks related to cellular response to UFP particles. RESULTS: The bioinformatics analysis of transcriptional data reveals that the two different UFP induce, since the earliest time points, different transcriptional dynamics resulting in the activation of specific genes. The functional enrichment of differentially expressed genes indicates that the exposure to diesel UFP induces the activation of genes involved in TNFalpha signaling via NF-kB and inflammatory response, and hypoxia. Conversely, the exposure to ultrafine particles from biomass determines less distinct modifications of the gene expression profiles. Diesel UFP exposure induces the secretion of biomarkers associated to inflammation (CCXL2, EPGN, GREM1, IL1A, IL1B, IL6, IL24, EREG, VEGF) and transcription factors (as NFE2L2, MAFF, HES1, FOSL1, TGIF1) relevant for cardiovascular and lung disease. By means of network reconstruction, four genes (STAT3, HIF1a, NFKB1, KRAS) have emerged as major regulators of transcriptional response of bronchial epithelial cells exposed to diesel exhaust. CONCLUSIONS: Overall, this work highlights modifications of the transcriptional landscape in human bronchial cells exposed to UFP and sheds new lights on possible mechanisms by means of which UFP acts as a carcinogen and harmful factor for human health. PMID- 29703140 TI - Molecular mechanisms of an antimicrobial peptide piscidin (Lc-pis) in a parasitic protozoan, Cryptocaryon irritans. AB - BACKGROUND: Cryptocaryon irritans is an obligate parasitic ciliate protozoan that can infect various commercially important mariculture fish species and cause high lethality and economic loss. Current methods of controlling this parasite with chemicals or antibiotics are widely considered to be environmentally harmful. Piscidins with broad spectrum antibacterial, antifungal and antiviral activities were found to have potent activity against C. irritans. Little, however, has been understood about the killing mechanisms of piscidins in parasites. RESULTS: In total, 57.12, 50.44, 55.86 and 47.87 million raw reads were generated from untreated theront and trophont, and piscidin (Lc-pis) treated theront and trophont libraries, respectively. After de novo assembly, 966,609 unigenes were generated with an average length of 420 bp: among these, 618,629 unigenes showed identity with sequences in one or more databases, with some showing to be significantly manipulated by Lc-pis treatment. The species classification showed that more than 25.8% unigenes from trophonts were homologous to the large yellow croaker (Larimichthys crocea) and less than 3.8% unigenes from theronts were matched. The homologous unigenes demonstrated that the tissue from host could exist in trophonts and might be transported to parasite via vesicular transports. Our analysis showed that regulatory transcripts were involved in vesicular trafficking. Among transcripts induced by Lc-pis, most genes up-regulated in treated and untreated theronts were involved in cell migration and apoptosis related pathways. Few transcripts were found to be down-regulated in treated and untreated trophonts related to cell structure and migration after treatment. CONCLUSIONS: This is the first transcriptome analysis of C. irritans exposed to Lc-pis, which enhanced the genomic resources and provided novel insights into molecular mechanisms of ciliates treated by cationic antimicrobial peptide. Our comprehensive transcriptome analysis can facilitate the identification of potential drug targets and vaccines candidates for controlling this devastating fish pathogen. PMID- 29703141 TI - Genome-wide identification and characterization of the SBP-box gene family in Petunia. AB - BACKGROUND: SQUAMOSA PROMOTER BINDING PROTEIN (SBP)-box genes encode a family of plant-specific transcription factors (TFs) that play important roles in many growth and development processes including phase transition, leaf initiation, shoot and inflorescence branching, fruit development and ripening etc. The SBP box gene family has been identified and characterized in many species, but has not been well studied in Petunia, an important ornamental genus. RESULTS: We identified 21 putative SPL genes of Petunia axillaris and P. inflata from the reference genome of P. axillaris N and P. inflata S6, respectively, which were supported by the transcriptome data. For further confirmation, all the 21 genes were also cloned from P. hybrida line W115 (Mitchel diploid). Phylogenetic analysis based on the highly conserved SBP domains arranged PhSPLs in eight groups, analogous to those from Arabidopsis and tomato. Furthermore, the Petunia SPL genes had similar exon-intron structure and the deduced proteins contained very similar conserved motifs within the same subgroup. Out of 21 PhSPL genes, fourteen were predicted to be potential targets of PhmiR156/157, and the putative miR156/157 response elements (MREs) were located in the coding region of group IV, V, VII and VIII genes, but in the 3'-UTR regions of group VI genes. SPL genes were also identified from another two wild Petunia species, P. integrifolia and P. exserta, based on their transcriptome databases to investigate the origin of PhSPLs. Phylogenetic analysis and multiple alignments of the coding sequences of PhSPLs and their orthologs from wild species indicated that PhSPLs were originated mainly from P. axillaris. qRT-PCR analysis demonstrated differential spatiotemperal expression patterns of PhSPL genes in petunia and many were expressed predominantly in the axillary buds and/or inflorescences. In addition, overexpression of PhSPL9a and PhSPL9b in Arabidopsis suggested that these genes play a conserved role in promoting the vegetative-to-reproductive phase transition. CONCLUSION: Petunia genome contains at least 21 SPL genes, and most of the genes are expressed in different tissues. The PhSPL genes may play conserved and diverse roles in plant growth and development, including flowering regulation, leaf initiation, axillary bud and inflorescence development. This work provides a comprehensive understanding of the SBP-box gene family in Petunia and lays a significant foundation for future studies on the function and evolution of SPL genes in petunia. PMID- 29703142 TI - Identification of new loci involved in the host susceptibility to Salmonella Typhimurium in collaborative cross mice. AB - BACKGROUND: Salmonella is a Gram-negative bacterium causing a wide range of clinical syndromes ranging from typhoid fever to diarrheic disease. Non-typhoidal Salmonella (NTS) serovars infect humans and animals, causing important health burden in the world. Susceptibility to salmonellosis varies between individuals under the control of host genes, as demonstrated by the identification of over 20 genetic loci in various mouse crosses. We have investigated the host response to S. Typhimurium infection in 35 Collaborative Cross (CC) strains, a genetic population which involves wild-derived strains that had not been previously assessed. RESULTS: One hundred and forty-eight mice from 35 CC strains were challenged intravenously with 1000 colony-forming units (CFUs) of S. Typhimurium. Bacterial load was measured in spleen and liver at day 4 post-infection. CC strains differed significantly (P < 0.0001) in spleen and liver bacterial loads, while sex and age had no effect. Two significant quantitative trait loci (QTLs) on chromosomes 8 and 10 and one suggestive QTL on chromosome 1 were found for spleen bacterial load, while two suggestive QTLs on chromosomes 6 and 17 were found for liver bacterial load. These QTLs are caused by distinct allelic patterns, principally involving alleles originating from the wild-derived founders. Using sequence variations between the eight CC founder strains combined with database mining for expression in target organs and known immune phenotypes, we were able to refine the QTLs intervals and establish a list of the most promising candidate genes. Furthermore, we identified one strain, CC042/GeniUnc (CC042), as highly susceptible to S. Typhimurium infection. CONCLUSIONS: By exploring a broader genetic variation, the Collaborative Cross population has revealed novel loci of resistance to Salmonella Typhimurium. It also led to the identification of CC042 as an extremely susceptible strain. PMID- 29703144 TI - The deregulated microRNAome contributes to the cellular response to aneuploidy. AB - BACKGROUND: Aneuploidy, or abnormal chromosome numbers, severely alters cell physiology and is widespread in cancers and other pathologies. Using model cell lines engineered to carry one or more extra chromosomes, it has been demonstrated that aneuploidy per se impairs proliferation, leads to proteotoxic as well as replication stress and triggers conserved transcriptome and proteome changes. RESULTS: In this study, we analysed for the first time miRNAs and demonstrate that their expression is altered in response to chromosome gain. The miRNA deregulation is independent of the identity of the extra chromosome and specific to individual cell lines. By cross-omics analysis we demonstrate that although the deregulated miRNAs differ among individual aneuploid cell lines, their known targets are predominantly associated with cell development, growth and proliferation, pathways known to be inhibited in response to chromosome gain. Indeed, we show that up to 72% of these targets are downregulated and the associated miRNAs are overexpressed in aneuploid cells, suggesting that the miRNA changes contribute to the global transcription changes triggered by aneuploidy. We identified hsa-miR-10a-5p to be overexpressed in majority of aneuploid cells. Hsa-miR-10a-5p enhances translation of a subset of mRNAs that contain so called 5'TOP motif and we show that its upregulation in aneuploids provides resistance to starvation-induced shut down of ribosomal protein translation. CONCLUSIONS: Our work suggests that the changes of the microRNAome contribute on one hand to the adverse effects of aneuploidy on cell physiology, and on the other hand to the adaptation to aneuploidy by supporting translation under adverse conditions. PMID- 29703143 TI - Diapause in a tropical oil-collecting bee: molecular basis unveiled by RNA-Seq. AB - BACKGROUND: Diapause is a natural phenomenon characterized by an arrest in development that ensures the survival of organisms under extreme environmental conditions. The process has been well documented in arthropods. However, its molecular basis has been mainly studied in species from temperate zones, leaving a knowledge gap of this phenomenon in tropical species. In the present study, the Neotropical and solitary bee Tetrapedia diversipes was employed as a model for investigating diapause in species from tropical zones. Being a bivoltine insect, Tetrapedia diversipes produce two generations of offspring per year. The first generation, normally born during the wet season, develops faster than individuals from the second generation, born after the dry season. Furthermore, it has been shown that the development of the progeny, of the second generation, is halted at the 5th larval instar, and remains in larval diapause during the dry season. Towards the goal of gaining a better understanding of the diapause phenomenon we compared the global gene expression pattern, in larvae, from both reproductive generations and during diapause. The results demonstrate that there are similarities in the observed gene expression patterns to those already described for temperate climate models, and also identify diapause-related genes that have not been previously reported in the literature. RESULTS: The RNA-Seq analysis identified 2275 differentially expressed transcripts, of which 1167 were annotated. Of these genes, during diapause, 352 were upregulated and 815 were downregulated. According to their biological functions, these genes were categorized into the following groups: cellular detoxification, cytoskeleton, cuticle, sterol and lipid metabolism, cell cycle, heat shock proteins, immune response, circadian clock, and epigenetic control. CONCLUSION: Many of the identified genes have already been described as being related to diapause; however, new genes were discovered, for the first time, in this study. Among those, we highlight: Niemann-Pick type C1, NPC2 and Acyl-CoA binding protein homolog (all involved in ecdysteroid synthesis); RhoBTB2 and SASH1 (associated with cell cycle regulation) and Histone acetyltransferase KAT7 (related to epigenetic transcriptional regulation). The results presented here add important findings to the understanding of diapause in tropical species, thus increasing the comprehension of diapause-related molecular mechanisms. PMID- 29703145 TI - Ginkgo biloba's footprint of dynamic Pleistocene history dates back only 390,000 years ago. AB - BACKGROUND: At the end of the Pliocene and the beginning of Pleistocene glaciation and deglaciation cycles Ginkgo biloba went extinct all over the world, and only few populations remained in China in relict areas serving as sanctuary for Tertiary relict trees. Yet the status of these regions as refuge areas with naturally existing populations has been proven not earlier than one decade ago. Herein we elaborated the hypothesis that during the Pleistocene cooling periods G. biloba expanded its distribution range in China repeatedly. Whole plastid genomes were sequenced, assembled and annotated, and sequence data was analyzed in a phylogenetic framework of the entire gymnosperms to establish a robust spatio-temporal framework for gymnosperms and in particular for G. biloba Pleistocene evolutionary history. RESULTS: Using a phylogenetic approach, we identified that Ginkgoatae stem group age is about 325 million years, whereas crown group radiation of extant Ginkgo started not earlier than 390,000 years ago. During repeated warming phases, Gingko populations were separated and isolated by contraction of distribution range and retreated into mountainous regions serving as refuge for warm-temperate deciduous forests. Diversification and phylogenetic splits correlate with the onset of cooling phases when Ginkgo expanded its distribution range and gene pools merged. CONCLUSIONS: Analysis of whole plastid genome sequence data representing the entire spatio-temporal genetic variation of wild extant Ginkgo populations revealed the deepest temporal footprint dating back to approximately 390,000 years ago. Present-day directional West-East admixture of genetic diversity is shown to be the result of pronounced effects of the last cooling period. Our evolutionary framework will serve as a conceptual roadmap for forthcoming genomic sequence data, which can then provide deep insights into the demographic history of Ginkgo. PMID- 29703146 TI - Identification of a novel fused gene family implicates convergent evolution in eukaryotic calcium signaling. AB - BACKGROUND: Both calcium signals and protein phosphorylation responses are universal signals in eukaryotic cell signaling. Currently three pathways have been characterized in different eukaryotes converting the Ca2+ signals to the protein phosphorylation responses. All these pathways have based mostly on studies in plants and animals. RESULTS: Based on the exploration of genomes and transcriptomes from all the six eukaryotic supergroups, we report here in Metakinetoplastina protists a novel gene family. This family, with a proposed name SCAMK, comprises SnRK3 fused calmodulin-like III kinase genes and was likely evolved through the insertion of a calmodulin-like3 gene into an SnRK3 gene by unequal crossover of homologous chromosomes in meiosis cell. Its origin dated back to the time intersection at least 450 million-year-ago when Excavata parasites, Vertebrata hosts, and Insecta vectors evolved. We also analyzed SCAMK's unique expression pattern and structure, and proposed it as one of the leading calcium signal conversion pathways in Excavata parasite. These characters made SCAMK gene as a potential drug target for treating human African trypanosomiasis. CONCLUSIONS: This report identified a novel gene fusion and dated its precise fusion time in Metakinetoplastina protists. This potential fourth eukaryotic calcium signal conversion pathway complements our current knowledge that convergent evolution occurs in eukaryotic calcium signaling. PMID- 29703147 TI - Characterization of recombination features and the genetic basis in multiple cattle breeds. AB - BACKGROUND: Crossover generated by meiotic recombination is a fundamental event that facilitates meiosis and sexual reproduction. Comparative studies have shown wide variation in recombination rate among species, but the characterization of recombination features between cattle breeds has not yet been performed. Cattle populations in North America count millions, and the dairy industry has genotyped millions of individuals with pedigree information that provide a unique opportunity to study breed-level variations in recombination. RESULTS: Based on large pedigrees of Jersey, Ayrshire and Brown Swiss cattle with genotype data, we identified over 3.4 million maternal and paternal crossover events from 161,309 three-generation families. We constructed six breed- and sex-specific genome-wide recombination maps using 58,982 autosomal SNPs for two sexes in the three dairy cattle breeds. A comparative analysis of the six recombination maps revealed similar global recombination patterns between cattle breeds but with significant differences between sexes. We confirmed that male recombination map is 10% longer than the female map in all three cattle breeds, consistent with previously reported results in Holstein cattle. When comparing recombination hotspot regions between cattle breeds, we found that 30% and 10% of the hotspots were shared between breeds in males and females, respectively, with each breed exhibiting some breed-specific hotspots. Finally, our multiple-breed GWAS found that SNPs in eight loci affected recombination rate and that the PRDM9 gene associated with hotspot usage in multiple cattle breeds, indicating a shared genetic basis for recombination across dairy cattle breeds. CONCLUSIONS: Collectively, our results generated breed- and sex-specific recombination maps for multiple cattle breeds, provided a comprehensive characterization and comparison of recombination patterns between breeds, and expanded our understanding of the breed-level variations in recombination features within an important livestock species. PMID- 29703149 TI - CNVs are associated with genomic architecture in a songbird. AB - BACKGROUND: Understanding variation in genome structure is essential to understand phenotypic differences within populations and the evolutionary history of species. A promising form of this structural variation is copy number variation (CNV). CNVs can be generated by different recombination mechanisms, such as non-allelic homologous recombination, that rely on specific characteristics of the genome architecture. These structural variants can therefore be more abundant at particular genes ultimately leading to variation in phenotypes under selection. Detailed characterization of CNVs therefore can reveal evolutionary footprints of selection and provide insight in their contribution to phenotypic variation in wild populations. RESULTS: Here we use genotypic data from a long-term population of great tits (Parus major), a widely studied passerine bird in ecology and evolution, to detect CNVs and identify genomic features prevailing within these regions. We used allele intensities and frequencies from high-density SNP array data from 2,175 birds. We detected 41,029 CNVs concatenated into 8,008 distinct CNV regions (CNVRs). We successfully validated 93.75% of the CNVs tested by qPCR, which were sampled at different frequencies and sizes. A mother-daughter family structure allowed for the evaluation of the inheritance of a number of these CNVs. Thereby, only CNVs with 40 probes or more display segregation in accordance with Mendelian inheritance, suggesting a high rate of false negative calls for smaller CNVs. As CNVRs are a coarse-grained map of CNV loci, we also inferred the frequency of coincident CNV start and end breakpoints. We observed frequency-dependent enrichment of these breakpoints at homologous regions, CpG sites and AT-rich intervals. A gene ontology enrichment analyses showed that CNVs are enriched in genes underpinning neural, cardiac and ion transport pathways. CONCLUSION: Great tit CNVs are present in almost half of the genes and prominent at repetitive-homologous and regulatory regions. Although overlapping genes under selection, the high number of false negatives make neutrality or association tests on CNVs detected here difficult. Therefore, CNVs should be further addressed in the light of their false negative rate and architecture to improve the comprehension of their association with phenotypes and evolutionary history. PMID- 29703148 TI - Deletion of soluble epoxide hydrolase attenuates mice Hyperoxic acute lung injury. AB - BACKGROUND: Recent studies reported that soluble epoxide hydrolase (sEH) plays an important role in lung diseases. However, the role of sEH in hyperoxia-induced ALI is unclear. METHODS: ALI was induced by exposure to 100% oxygen in an airtight cage for 72 h in wild-type (WT) and sEH gene deletion (EPHX2-/-) mice. ALI was assessed by the lung dry/wet ratio, alveolar capillary protein leak, and the infiltration of inflammatory cells in the lung. RESULTS: Hyperoxia elevated sEH activity in WT mice. Simultaneously, epoxyeicosatrienoic acids (EETs) levels were decreased in WT mice exposed to hyperoxia. However, the level of EETs was increased in EPHX2-/- mice exposed to hyperoxia. Hyperoxia induced pulmonary edema and inflammation were dampened in EPHX2-/- mice compared with WT mice. Decreased expression of Kelch-like ECH-associated protein 1 (Keap1) was found in EPHX2-/- mice exposed to hyperoxia. Hyperoxia-induced the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) was enhanced in EPHX2-/- mice compared with WT mice. Simultaneously, the activities of heme oxygenase-1 and superoxide dismutase were elevated in EPHX2-/- mice. The levels of reactive oxygen species were inhibited in EPHX2-/- mice compared with WT mice exposed to hyperoxia. CONCLUSIONS: sEH is a harmful factor for hyperoxic ALI. The beneficial effect of sEH gene deletion is associated with the elevation of EETs and regulation of Nrf2/Keap1 signal pathway. PMID- 29703150 TI - OMGene: mutual improvement of gene models through optimisation of evolutionary conservation. AB - BACKGROUND: The accurate determination of the genomic coordinates for a given gene - its gene model - is of vital importance to the utility of its annotation, and the accuracy of bioinformatic analyses derived from it. Currently-available methods of computational gene prediction, while on the whole successful, frequently disagree on the model for a given predicted gene, with some or all of the variant gene models often failing to match the biologically observed structure. Many prediction methods can be bolstered by using experimental data such as RNA-seq. However, these resources are not always available, and rarely give a comprehensive portrait of an organism's transcriptome due to temporal and tissue-specific expression profiles. RESULTS: Orthology between genes provides evolutionary evidence to guide the construction of gene models. OMGene (Optimise My Gene) aims to improve gene model accuracy in the absence of experimental data by optimising the consistency of multiple sequence alignments of orthologous genes from multiple species. Using RNA-seq data sets from plants, mammals, and fungi, considering intron/exon junction representation and exon coverage, and assessing the intra-orthogroup consistency of subcellular localisation predictions, we demonstrate the utility of OMGene for improving gene models in annotated genomes. CONCLUSIONS: We show that significant improvements in the accuracy of gene model annotations can be made, both in established and in de novo annotated genomes, by leveraging information from multiple species. PMID- 29703151 TI - Clinical features and risk factors of neurological involvement in Sjogren's syndrome. AB - BACKGROUND: To investigated distinct manifestations of Sjogren's syndrome (SS) patients with neurological complications and the potential risk factors associated with neurological complications in SS, and to produce a disease evaluation and neurological involvement prediction for SS. METHODS: 566 patients who fulfilled the 2002 classification criteria for SS from the Rheumatology Department of the First Affiliated Hospital of Wenzhou Medical University were included in the cross-sectional study. Clinical, immunological and histological characteristics were surveyed, and potential risk factors for neurological complications were examined by multivariate analysis. RESULTS: Among 566 SS patients, 184 (32.5%) patients had neurological involvement, with more than 10% got limbs pain, limbs numbness and cerebral infarction, respectively. Of these 184 SS patients with neurological complications, secondary SS (sSS) patients had a higher prevalence of peripheral nervous system (PNS) involvement than primary SS (pSS) patients (31.1 vs. 19%). And sSS patients showed higher total ESSPRI score and higher prevalence of xerostomia and low C3, C4 levels with more liver, articular involvement and saliva gland atrophy, and more severe lymphocyte infiltration in salivary glands than pSS patients. As for the specific factors associated with neurological involvement, low C3 level were found to be significant in pSS or sSS patients who were younger 50 year old, and ANA positivity, cardiac involvement, saliva gland atrophy were demonstrated to be associated in elder pSS patients. And xerophthalmia was found to be associated in sSS patients. CONCLUSION: Low complement (C3) levels, xerophthalmia, ANA positive, cardiac involvement and labial salivary gland histological result were good ways to predict neurological complications in different subgroups of SS, which might provide insight into better clinical decision-making, especially at early stages of the disease. PMID- 29703152 TI - Analysis of Theileria orientalis draft genome sequences reveals potential species level divergence of the Ikeda, Chitose and Buffeli genotypes. AB - BACKGROUND: Theileria orientalis (Apicomplexa: Piroplasmida) has caused clinical disease in cattle of Eastern Asia for many years and its recent rapid spread throughout Australian and New Zealand herds has caused substantial economic losses to production through cattle deaths, late term abortion and morbidity. Disease outbreaks have been linked to the detection of a pathogenic genotype of T. orientalis, genotype Ikeda, which is also responsible for disease outbreaks in Asia. Here, we sequenced and compared the draft genomes of one pathogenic (Ikeda) and two apathogenic (Chitose, Buffeli) isolates of T. orientalis sourced from Australian herds. RESULTS: Using de novo assembled sequences and a single nucleotide variant (SNV) analysis pipeline, we found extensive genetic divergence between the T. orientalis genotypes. A genome-wide phylogeny reconstructed to address continued confusion over nomenclature of this species displayed concordance with prior phylogenetic studies based on the major piroplasm surface protein (MPSP) gene. However, average nucleotide identity (ANI) values revealed that the divergence between isolates is comparable to that observed between other theilerias which represent distinct species. Analysis of SNVs revealed putative recombination between the Chitose and Buffeli genotypes and also between Australian and Japanese Ikeda isolates. Finally, to inform future vaccine studies, dN/dS ratios and surface location predictions were analysed. Six predicted surface protein targets were confirmed to be expressed during the piroplasm phase of the parasite by mass spectrometry. CONCLUSIONS: We used whole genome sequencing to demonstrate that the T. orientalis Ikeda, Chitose and Buffeli variants show substantial genetic divergence. Our data indicates that future researchers could potentially consider disease-associated Ikeda and closely related genotypes as a separate species from non-pathogenic Chitose and Buffeli. PMID- 29703153 TI - A comparison of weather variables linked to infectious disease patterns using laboratory addresses and patient residence addresses. AB - BACKGROUND: To understand the impact of weather on infectious diseases, information on weather parameters at patient locations is needed, but this is not always accessible due to confidentiality or data availability. Weather parameters at nearby locations are often used as a proxy, but the accuracy of this practice is not known. METHODS: Daily Campylobacter and Cryptosporidium cases across England and Wales were linked to local temperature and rainfall at the residence postcodes of the patients and at the corresponding postcodes of the laboratory where the patient's specimen was tested. The paired values of daily rainfall and temperature for the laboratory versus residence postcodes were interpolated from weather station data, and the results were analysed for agreement using linear regression. We also assessed potential dependency of the findings on the relative geographic distance between the patient's residence and the laboratory. RESULTS: There was significant and strong agreement between the daily values of rainfall and temperature at diagnostic laboratories with the values at the patient residence postcodes for samples containing the pathogens Campylobacter or Cryptosporidium. For rainfall, the R-squared was 0.96 for the former and 0.97 for the latter, and for maximum daily temperature, the R-squared was 0.99 for both. The overall mean distance between the patient residence and the laboratory was 11.9 km; however, the distribution of these distances exhibited a heavy tail, with some rare situations where the distance between the patient residence and the laboratory was larger than 500 km. These large distances impact the distributions of the weather variable discrepancies (i.e. the differences between weather parameters estimated at patient residence postcodes and those at laboratory postcodes), with discrepancies up to +/-10 degrees C for the minimum and maximum temperature and 20 mm for rainfall. Nevertheless, the distributions of discrepancies (estimated separately for minimum and maximum temperature and rainfall), based on the cases where the distance between the patient residence and the laboratory was within 20 km, still exhibited tails somewhat longer than the corresponding exponential fits suggesting modest small scale variations in temperature and rainfall. CONCLUSION: The findings confirm that, for the purposes of studying the relationships between meteorological variables and infectious diseases using data based on laboratory postcodes, the weather results are sufficiently similar to justify the use of laboratory postcode as a surrogate for domestic postcode. Exclusion of the small percentage of cases where there is a large distance between the residence and the laboratory could increase the precision of estimates, but there are generally strong associations between daily weather parameters at residence and laboratory. PMID- 29703154 TI - Familial resemblances in human whole blood transcriptome. AB - BACKGROUND: Considering the implication of gene expression in the susceptibility of chronic diseases and the familial clustering of chronic diseases, the study of familial resemblances in gene expression levels is then highly relevant. Few studies have considered the contribution of both genetic and common environmental effects to familial resemblances in whole blood gene expression levels. The objective is to quantify the contribution of genetic and common environmental effects in the familial resemblances of whole blood genome-wide gene expression levels. We also make comparisons with familial resemblances in blood leukocytes genome-wide DNA methylation levels in the same cohort in order to further investigate biological mechanisms. RESULTS: Maximal heritability, genetic heritability, and common environmental effect were computed for all probes (20.6%, 15.6%, and 5.0% respectively) and for probes showing a significant familial effect (78.1%, 60.1%, and 18.0% respectively). Pairwise phenotypic correlations between gene expression and DNA methylation levels adjusted for blood cell heterogeneity were computed for probes showing significant familial effect. A total of 78 probe pairs among the 7,618,401 possible pairs passed Bonferroni correction (corrected P-value = 6.56 * 10- 9). Significant genetic correlations between gene expression and DNA methylation levels were found for 25 probe pairs (absolute genetic correlation of 0.97). CONCLUSIONS: Familial resemblances in gene expression levels were mainly attributable to genetic factors, but common environmental effect also played a role especially in probes showing a significant familial effect. Probes and CpG sites with familial effect seem to be under a strong shared genetic control. PMID- 29703155 TI - Determinants of CD4 cell count change and time-to default from HAART; a comparison of separate and joint models. AB - BACKGROUND: HIV has the most serious effects in Sub-Saharan African countries as compared to countries in other parts of the world. As part of these countries, Ethiopia has been affected significantly by the disease, and the burden of the disease has become worst in the Amhara Region, one of the eleven regions of the country. Being a defaulter or dropout of HIV patients from the treatment plays a significant role in treatment failure. The current research was conducted with the objective of comparing the performance of the joint and the separate modelling approaches in determining important factors that affect HIV patients' longitudinal CD4 cell count change and time to default from treatment. METHODS: Longitudinal data was obtained from the records of 792 HIV adult patients at Felege-Hiwot Teaching and Specialized Hospital in Ethiopia. Two alternative approaches, namely separate and joint modeling data analyses, were conducted in the current study. Joint modeling was conducted for an analysis of the change of CD4 cell count and the time to default in the treatment. In the joint model, a generalized linear mixed effects model and Weibul survival sub-models were combined together for the repetitive measures of the CD4 cell count change and the number of follow-ups in which patients wait in the treatment. Finally, the two models were linked through their shared unobserved random effects using a shared parameter model. RESULTS: Both separate and joint modeling approach revealed a consistent result. However, the joint modeling approach was more parsimonious and fitted the given data well as compared to the separate one. Age, baseline CD4 cell count, marital status, sex, ownership of cell phone, adherence to HAART, disclosure of the disease and the number of follow-ups were important predictors for both the fluctuation of CD4 cell count and the time-to default from treatment. The inclusion of patient-specific variations in the analyses of the two outcomes improved the model significantly. CONCLUSION: Certain groups of patients were identified in the current investigation. The groups already identified had high fluctuation in the number of CD4 cell count and defaulted from HAART without any convincing reasons. Such patients need high intervention to adhere to the prescribed medication. PMID- 29703156 TI - Functional outcomes in Hirschsprung disease patients after transabdominal Soave and Duhamel procedures. AB - BACKGROUND: Several pull-through procedures have been described for Hirschsprung disease (HSCR) with varying functional outcomes. The voluntary bowel movement (VBM) and the absence of soiling or constipation after pull-through remain the most important markers of good outcome. We aimed to compare the functional outcomes in HSCR patients following Soave and Duhamel procedures. METHODS: Krickenbeck classification was utilized to determine VBM, soiling and constipation for patients who underwent Soave and Duhamel pull-through at Dr. Sardjito Hospital, Indonesia from 2013 to 2016. RESULTS: Fifty-three patients were ascertained (Soave: 23 males and 2 females vs. Duhamel: 22 males and 6 females, p = 0.26). Ninety-three and 88% patients had a VBM following Duhamel and Soave pull-through, respectively (p = 0.66). Constipation frequency was significantly higher in Soave than Duhamel groups (24% vs. 4%; p = 0.04) with OR of 8.5 (95% CI = 1.0-76.7), whereas soiling rate was similar between Duhamel (21%) and Soave (8%) groups (p = 0.26). Furthermore, the risk of constipation was increased ~ 21.7-fold in female patients after Soave procedure and was almost statistically significant (p = 0.05). CONCLUSIONS: The constipation rate is higher in patients who underwent Soave than Duhamel procedure, but the VBM and soiling frequencies are similar. The constipation risk following Soave pull through might be increased by the female gender. Furthermore, a multicenter study with a larger sample of patients is necessary to clarify and confirm our findings. PMID- 29703157 TI - A pathway from low socioeconomic status to dementia in Japan: results from the Toyama dementia survey. AB - BACKGROUND: The association between low socioeconomic status (SES) and dementia is reportedly mediated by lifestyle-related diseases (i.e., diabetes) in European countries and the United States; however, in Japan, the link between low SES and dementia has not been investigated. This study evaluated the possibility of a mediating role of lifestyle-related diseases in the relationship between low SES and dementia in Japan. METHODS: A retrospective case-control study design, with data from the Toyama Dementia Survey, Japan, was used. Individuals aged >=65 years (institutionalized and noninstitutionalized) living in Toyama prefecture were randomly selected, with a sampling rate of 0.5%. Of them, 1303 agreed to participate (response rate 84.8%). Overall, 137 cases of dementia and 1039 unimpaired controls were identified. Structured interviews with participants and family members or proxies were conducted, if necessary. Participants' history of medically diagnosed disease, lifestyle factors (i.e., smoking and alcohol drinking habits), and SES (educational attainment and occupational history) were assessed. The possibility of low SES being a risk factor for dementia via lifestyle-related diseases was investigated using the Sobel test. RESULTS: The odds ratio (OR) for dementia was higher for participants with low educational attainment (6 years or less) than for highly educated participants [age- and sex adjusted OR 3.27; 95% confidence interval (CI) 1.84-5.81]; it was also higher for participants with a blue-collar job history than a white-collar job history (age- and sex-adjusted OR 1.26; 95% CI 0.80-1.98). After adjustment for employment history, the OR for dementia for participants with low educational attainment was 3.23-3.56. Former habitual alcohol consumption and a medical history of diabetes, Parkinson's disease, stroke, and angina pectoris/cardiovascular disease were found to increase the risk of dementia. Educational attainment was not associated with alcohol consumption, smoking, diabetes, Parkinson's disease, stroke, or cardiovascular disease. Occupational history was associated with diabetes and stroke. The role of diabetes in low educational attainment and dementia was found to be extremely limited. CONCLUSIONS: In Japan, lifestyle-related diseases play a minimal role as mediators between low SES and dementia. PMID- 29703158 TI - Periprocedural anticoagulation during left atrial ablation: interrupted and uninterrupted vitamin K-antagonists or uninterrupted novel anticoagulants. AB - BACKGROUND: There is a lack of data on anticoagulation requirements during ablation of atrial fibrillation (AF). This study compares different oral anticoagulation (OAC) strategies to evaluate risk of bleeding and thromboembolic complications. METHODS: We conducted a single-centre study in patients undergoing left atrial ablation of AF. Three groups were defined: 1) bridging: interrupted vitamin-K-antagonists (VKA), INR <=2, and bridging with heparin; 2) VKA: uninterrupted VKA and INR of > 2; 3) DOAC: uninterrupted direct oral anticoagulants. Bleeding complications, thromboembolic events and peri-procedural heparin doses were assessed. RESULTS: In total, 780 patients were documented. At 48 h, major complications were more common in the bridging group compared to uninterrupted VKA and DOAC groups (OR: 3.42, 95% CI: 1.29-9.10 and OR: 3.01, 95% CI: 1.19-7.61), largely driven by differences in major pericardial effusion (OR: 4.86, 95% CI: 1.56-15.99 and OR: 4.466, 95% CI, 1.52-13.67) and major vascular events (OR: 2.92, 95% CI: 0.58-14.67 and OR: 9.72, 95% CI: 1.00-94.43). Uninterrupted VKAs and DOACs resulted in similar odds of major complications (overall OR: 1.14, 95% CI: 0.44-2.92), including cerebrovascular events (OR: 1.21, 95% CI: 0.27-5.45). However, whereas only TIAs were observed in DOAC and bridging groups, strokes also occurred in the VKA group. Rates of minor complications (pericardial effusion, vascular complications, gastrointestinal hemorrhage) and major/minor groin hemorrhage were similar across groups. CONCLUSION: Our dataset illustrates that uninterrupted VKA and DOAC have a better risk-benefit profile than VKA bridging. Bridging was associated with a 4.5* increased risk of complications and should be avoided, if possible. PMID- 29703159 TI - Clustering multilayer omics data using MuNCut. AB - BACKGROUND: Omics profiling is now a routine component of biomedical studies. In the analysis of omics data, clustering is an essential step and serves multiple purposes including for example revealing the unknown functionalities of omics units, assisting dimension reduction in outcome model building, and others. In the most recent omics studies, a prominent trend is to conduct multilayer profiling, which collects multiple types of genetic, genomic, epigenetic and other measurements on the same subjects. In the literature, clustering methods tailored to multilayer omics data are still limited. Directly applying the existing clustering methods to multilayer omics data and clustering each layer first and then combing across layers are both "suboptimal" in that they do not accommodate the interconnections within layers and across layers in an informative way. METHODS: In this study, we develop the MuNCut (Multilayer NCut) clustering approach. It is tailored to multilayer omics data and sufficiently accounts for both across- and within-layer connections. It is based on the novel NCut technique and also takes advantages of regularized sparse estimation. It has an intuitive formulation and is computationally very feasible. To facilitate implementation, we develop the function muncut in the R package NcutYX. RESULTS: Under a wide spectrum of simulation settings, it outperforms competitors. The analysis of TCGA (The Cancer Genome Atlas) data on breast cancer and cervical cancer shows that MuNCut generates biologically meaningful results which differ from those using the alternatives. CONCLUSIONS: We propose a more effective clustering analysis of multiple omics data. It provides a new venue for jointly analyzing genetic, genomic, epigenetic and other measurements. PMID- 29703160 TI - SHP2 inhibitor PHPS1 protects against atherosclerosis by inhibiting smooth muscle cell proliferation. AB - BACKGROUND: Smooth muscle cells play an important role in the development of atherosclerosis. SHP2 is known to regulate the proliferation and migration of smooth muscle cells. The purpose of this study was to determine whether the SHP2 inhibitor PHPS1 has a pro-atherosclerotic or an atheroprotective effect in vivo and in vitro. METHODS: After exposure to a high-cholesterol diet for 4 weeks, LDL receptor-deficient (Ldlr-/-) mice were exposed to the SHP2 inhibitor PHPS1 or vehicle. Body weight, serum glucose and lipid levels were determined. The size and composition of atherosclerotic plaques were measured by en face analysis, Movat staining and immunohistochemistry. The phosphorylation of SHP2 and related signaling molecules was analyzed by Western blot. Mechanistic analyses were performed in oxLDL-stimulated cultured vascular smooth muscle cells (VSMCs) with or without 10 mM PHPS1 pretreatment. Protein phosphorylation levels were detected by Western blot, and VSMC proliferation was assessed by BrdU staining. RESULTS: PHPS1 decreased the number of atherosclerotic plaques without significantly affecting body weight, serum glucose levels or lipid metabolism. Plaque composition analysis showed a significant decrease in the number of VSMCs in atherosclerotic lesions of Ldlr-/- mice treated with PHPS1. Stimulation with oxLDL induced a dose-dependent increase in the number of VSMCs and in SHP2 and ERK phosphorylation levels, and these effects were blocked by PHPS1. CONCLUSION: The SHP2 inhibitor PHPS1 exerts a protective effect against atherosclerosis by reducing VSMC proliferation via SHP2/ERK pathway activation. PMID- 29703162 TI - Decision-making process in the pre-dialysis CKD patients: do anxiety, stress and depression matter? AB - BACKGROUND: The transition from pre-dialysis chronic kidney disease (CKD) to renal replacement therapy (RRT) is a stressful event. Anxiety, depression and stress are frequent conditions in this population, and might play a role on the choice of dialysis modality. METHODS: This is a prospective study that included stages 4-5 CKD patients during a dialysis multi-disciplinary education program. Demographic, clinical, and laboratory data were evaluated. Hospital Anxiety and Depression Scale and a Perceived Stress Scale assessed levels of anxiety, depression and stress, respectively. RESULTS: A total of 67 from 190 recruited patients were included (59 +/- 15 years, 54% males). Comparing patients who chose peritoneal dialysis (PD) and hemodialysis (HD), there were no differences on anxiety (p = 0.55), and depression scores (p = 0.467), and stress (p = 0.854). Anxious (p = 0.007) and depressive (p = 0.030) patients presented lower levels of phosphate than those not affected. There was a significant correlation (p < 0.0001) between anxiety and depression scores (R2 = 0.573), anxiety and stress scores (R2 = 0.542), depression and stress scores (R2 = 0.514). At the end of study, 29.8% of patients had already started on dialysis, and scores of anxiety, depression and stress reduced significantly (all p values < 0.0001), from 5.9 +/- 3.3 to 1.8 +/- 1.8, from 7.7 +/- 4.0 to 3.8 +/- 2.9 and from 28.6 +/- 7.8 to 10.0 +/- 6.2, respectively, regardless of which therapy was chosen. CONCLUSION: Depression, anxiety and perceived stress during final stages of CKD do not seem to be related to the choice of dialysis therapy and tend to decrease after dialysis initiation. PMID- 29703161 TI - Survival and clinical outcomes of patients with melanoma brain metastasis in the era of checkpoint inhibitors and targeted therapies. AB - BACKGROUND: Melanoma brain metastasis is associated with an extremely poor prognosis, with a median overall survival of 4-5 months. Since 2011, the overall survival of patients with stage IV melanoma has been significantly improved with the advent of new targeted therapies and checkpoint inhibitors. We analyze the survival outcomes of patients diagnosed with brain metastasis after the introduction of these novel drugs. METHODS: We performed a retrospective analysis of our melanoma center database and identified 79 patients with brain metastasis between 2011 and 2015. RESULTS: The median time from primary melanoma diagnosis to brain metastasis was 3.2 years. The median overall survival duration from the time of initial brain metastasis was 12.8 months. Following a diagnosis of brain metastasis, 39 (49.4%), 28 (35.4%), and 24 (30.4%) patients were treated with anti-CTLA-4 antibody, anti-PD-1 antibody, or BRAF inhibitors (with or without a MEK inhibitor), with a median overall survival of 19.2 months, 37.9 months and 12.7 months, respectively. Factors associated with significantly reduced overall survival included male sex, cerebellar metastasis, higher number of brain lesions, and treatment with whole-brain radiation therapy. Factors associated with significantly longer overall survival included treatment with craniotomy, stereotactic radiosurgery, or with anti-PD-1 antibody after initial diagnosis of brain metastasis. CONCLUSIONS: These results show a significant improvement in the overall survival of patients with melanoma brain metastasis in the era of novel therapies. In addition, they suggest the activity of anti-PD-1 therapy specifically in the setting of brain metastasis. PMID- 29703163 TI - Development of a computational promoter with highly efficient expression in tumors. AB - BACKGROUND: Gene therapy is a potent method to increase the therapeutic efficacy against cancer. However, a gene that is specifically expressed in the tumor area has not been identified. In addition, nonspecific expression of therapeutic genes in normal tissues may cause side effects that can harm the patients' health. Certain promoters have been reported to drive therapeutic gene expression specifically in cancer cells; however, low expression levels of the target gene are a problem for providing good therapeutic efficacy. Therefore, a specific and highly expressive promoter is needed for cancer gene therapy. METHODS: Bioinformatics approaches were utilized to analyze transcription factors (TFs) from high-throughput data. Reverse transcription polymerase chain reaction, western blotting and cell transfection were applied for the measurement of mRNA, protein expression and activity. C57BL/6JNarl mice were injected with pD5-hrGFP to evaluate the expression of TFs. RESULTS: We analyzed bioinformatics data and identified three TFs, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB), cyclic AMP response element binding protein (CREB), and hypoxia-inducible factor-1alpha (HIF-1alpha), that are highly active in tumor cells. Here, we constructed a novel mini-promoter, D5, that is composed of the binding sites of the three TFs. The results show that the D5 promoter specifically drives therapeutic gene expression in tumor tissues and that the strength of the D5 promoter is directly proportional to tumor size. CONCLUSIONS: Our results show that bioinformatics may be a good tool for the selection of appropriate TFs and for the design of specific mini-promoters to improve cancer gene therapy. PMID- 29703165 TI - Incidence trends and patterns of breast cancer in Sri Lanka: an analysis of the national cancer database. AB - BACKGROUND: A gradual decline in the incidence of breast cancer is documented in developed countries especially over last two decades, while in developing countries the incidence continues to rise. We conducted this study to examine trends in incidence of breast cancer in a developing country, Sri Lanka. METHODS: A retrospective cohort evaluation of patients with breast cancer during 2001-2010 was performed using population based data from the Sri Lanka National Cancer Registry. Trends in incidence were analysed using Joinpoint regression analysis. RESULTS: The age standardized incidence of female breast cancer in Sri Lanka appears to have increased from 17.3 per 100,000 in 2001 (95% confidence interval [95% CI] 16.5-18.2) to 24.7 per 100,000 in 2010 (95% CI 23.7-25.7); a 1.4-fold increase (p < 0.05) with an estimated annual percentage change (EAPC) of 4.4 (95% CI 3.3-5.5). Highest incidence of breast cancer was seen among women of 60 to 64 year age group which has increased from 68.1 to 100.2 per 100,000 over this period (EAPC 4.6%, 95% CI 3.9-5.2, p < 0.001 for trend). A substantially greater increase was observed among women older than 50 years (from 50.4 to 76.9 per 100,000; EAPC 5.5, 95% CI 4.1-7.0, p < 0.05) compared with women younger than 50 years (from 32.0 to 39.6 per 100,000; EAPC 2.3, 95% CI 1.1-3.5, p < 0.05). CONCLUSIONS: A gradual but a significant increase in the incidence of female breast cancer is observed in Sri Lanka. A rapid rise in the breast cancer incidence among post-menopausal women appears to be the major contributor towards this increase. Improving cancer data collection appears to have been a contributor to the observed increase. However, an inherent increase is also likely as differential rates of increase were observed by age groups. Further research is needed to identify the reasons for the observed increase which may help with future cancer control efforts in Sri Lanka. PMID- 29703164 TI - Comparison between intravenous chemotherapy and intra-arterial chemotherapy for retinoblastoma: a meta-analysis. AB - BACKGROUND: Intravenous chemotherapy (IVC) and intra-arterial chemotherapy (IAC) have become the primary treatments for retinoblastoma; however, some controversy remains over which method is more effective. We conducted a meta-analysis to compare the clinical efficacy of IVC and IAC. METHODS: We systematically searched literature published on PubMed, Embase, and Cochrane Library up to May 2017. Studies containing either IAC or IVC that reported on efficacy were included. The effects estimate was expressed as a pooled rate with 95% confidence interval (CI), using a fixed-effects or random-effects model. RESULTS: Twenty-six studies were identified which included 1541 eyes (IAC: 11 trials, 445 eyes; IVC: 16 trials, 1096 eyes). The mean follow-up times were 49.4 months (range, 13.0-105.3 months) for IVC and 21.7 months (range, 8.8-38.7 months) for IAC. For the International Classification of Intraocular Retinoblastoma (ICRB) grading, the overall success rate was higher with IAC than with IVC (75.7% [95%CI: 65.7% 83.6%] vs. 69.5% [95%CI: 51.9%-82.8%], P < 0.001). The globe salvage with IAC was higher than with IVC in group D eyes (79.5% [95%CI: 71.8%-85.4%] vs. 55.1% [95%CI: 45.6%-64.2%], P < 0.001), but not in groups B (95.8% [95%CI: 57.5%-99.7%] vs. 82.5% [95%CI: 58.9%-94.0%], P = 0.163), C (91.3% [95%CI: 65.9%-98.3%] vs. 89.0% [95%CI: 69.0%-96.7%], P = 0.212), and E eyes (51.2% [95%CI: 37.0%-65.2%] vs. 43.2% [95%CI: 18.3%-72.1%], P = 0.578). IAC and IVC were not significantly different regarding the recurrence and metastasis rates (15.0% vs. 15.4%, P = 0.148 and 2.7% vs. 0.6%, P = 0.194, respectively). For Reese-Ellsworth (RE) grading, IAC had a higher globe salvage in groups IV (90.9% [95%CI: 56.0%-98.7%] vs. 66.3% [95%CI: 32.4%-89.0%], P = 0.047) and V eyes (83.2% [95%CI: 72.0%-90.5%] vs. 59.9% [95%CI: 43.1%-74.6%], P = 0.003), but not in group I-III eyes (88.6% [95%CI: 58.3%-97.7%] vs. 88.1% [95%CI: 76.6%-94.4%], P = 0.244). The overall success rate was higher in IAC than in IVC (87.1% [95%CI: 78.1%-92.7%] vs. 77.3% [95%CI: 68.1%-84.4%], P = 0.033). CONCLUSIONS: IAC may be superior to IVC for the treatment of retinoblastoma, with a higher overall success rate and higher globe salvage in group D or groups IV and V eyes. PMID- 29703167 TI - Distribution of human papilloma virus genotype prevalence in invasive cervical carcinomas and precancerous lesions in the Yangtze River Delta area, China. AB - BACKGROUND: This study aimed to provide more information for cancer prevention strategies by determining the distribution of human papilloma virus (HPV) genotype prevalence in invasive cervical carcinoma (ICC) and precancerous lesion patients in the Yangtze River Delta area in China. METHODS: This multi-centre descriptive cross-sectional study involves four university hospitals in the Jiangzhehu area. Women with histologically confirmed cervical intraepithelial neoplasia (CIN) 1, CIN2, CIN3 or ICC who were diagnosed and treated in the four selected hospitals between February 2012 and April 2014 were eligible for recruitment. The average age of the patients was 40.93 +/- 11.87 years old, among whom the youngest was 17 years old and the oldest was 76 years old.Those with immunodeficiency diseases or a previous history of cancer or CIN were excluded. HPV genotyping was performed by a central laboratory. The distribution and age and disease specificity of the HPV genotype prevalence were analysed. RESULTS: Of the 2181 collected samples, 251 were ICC and 1930 were CIN. The mean age of cervical cancer and CIN patients was 40.93 +/- 11.8 years (range, 17-76 years). The five most commonly identified HPV types in each lesion class were as follows: CIN1: 52, 58, 16, 33, and CP; CIN2: 16, 58, 52, 33, and 31; CIN3: 16, 58, 33, 52, and 31; and ICC: 16, 58, 18, 52, and 33. CIN1 had an earlier age of onset (30-40 years) than CIN2, CIN3, and cervical cancer. The age of onset of cervical cancer exhibited two peaks at 40-44 and 50-54 years of age. In all infected patients, the frequency of HPV infection with a single type was 62.9%, and with multiple types, it was 38.1%. There was no difference in the frequencies of multiple types amongst the different cervical lesions. CONCLUSIONS: The most prevalent genotypes in the investigated area (52, 58, 16 and 18) justify the necessity of anti-HPV vaccination in teenagers and young girls under 24 years old in the Yangtze River Delta area in China. Infection with multiple high-risk HPV types versus single infection does not increase the risk for >= CIN2 in ICC development. PMID- 29703166 TI - Cholesterol synthesis pathway genes in prostate cancer are transcriptionally downregulated when tissue confounding is minimized. AB - BACKGROUND: The relationship between cholesterol and prostate cancer has been extensively studied for decades, where high levels of cellular cholesterol are generally associated with cancer progression and less favorable outcomes. However, the role of in vivo cellular cholesterol synthesis in this process is unclear, and data on the transcriptional activity of cholesterol synthesis pathway genes in tissue from prostate cancer patients are inconsistent. METHODS: A common problem with cancer tissue data from patient cohorts is the presence of heterogeneous tissue which confounds molecular analysis of the samples. In this study we present a general method to minimize systematic confounding from stroma tissue in any prostate cancer cohort comparing prostate cancer and normal samples. In particular we use samples assessed by histopathology to identify genes enriched and depleted in prostate stroma. These genes are then used to assess stroma content in tissue samples from other prostate cancer cohorts where no histopathology is available. Differential expression analysis is performed by comparing cancer and normal samples where the average stroma content has been balanced between the sample groups. In total we analyzed seven patient cohorts with prostate cancer consisting of 1713 prostate cancer and 230 normal tissue samples. RESULTS: When stroma confounding was minimized, differential gene expression analysis over all cohorts showed robust and consistent downregulation of nearly all genes in the cholesterol synthesis pathway. Additional Gene Ontology analysis also identified cholesterol synthesis as the most significantly altered metabolic pathway in prostate cancer at the transcriptional level. CONCLUSION: The surprising observation that cholesterol synthesis genes are downregulated in prostate cancer is important for our understanding of how prostate cancer cells regulate cholesterol levels in vivo. Moreover, we show that tissue heterogeneity explains the lack of consistency in previous expression analysis of cholesterol synthesis genes in prostate cancer. PMID- 29703168 TI - Cross-sectional and longitudinal associations of screen time and physical activity with school performance at different types of secondary school. AB - BACKGROUND: Previous studies have already reported associations of media consumption and/or physical activity with school achievement. However, longitudinal studies investigating independent effects of physical activity and media consumption on school performance are sparse. The present study fills this research gap and, furthermore, assesses relationships of the type of secondary school with media consumption and physical activity. METHODS: The consumption of screen-based media (TV/video, game console, PC/internet, and mobile phone) and leisure physical activity (organized and non-organized) of 10 - to 17-year old adolescents participating in the LIFE Child study in Germany were related to their school grades in two major school subjects (Mathematics and German) and in Physical Education. In addition to a cross-sectional analysis at baseline (N = 850), a longitudinal analysis (N = 512) investigated the independent effects of these activities on the school grades achieved 12 months later. All associations were adjusted for age, gender, socio-economic status, year of data assessment, body-mass-index, and school grades at baseline. A further analysis investigated differences in the consumption of screen-based media and physical activity as a function of the type of secondary school (highest vs. lower secondary school). RESULTS: Adolescents of lower secondary schools reported a significantly higher consumption of TV/video and game consoles than adolescents attending the highest secondary school. Independently of the type of school, a better school performance in Mathematics was predicted by a lower consumption of computers/internet, and a better performance in Physical Education was predicted by a lower consumption of TV/video and a higher frequency of non-organized physical activity. However, the association between non-organized physical activity and subsequent grades in Physical Education was significant in girls only. CONCLUSION: The present results suggest that media consumption has a negative effect on school achievement, whereas physical activity has a positive effect, which, however, is restricted to the subject Physical Education. Future studies might explore the relationship between media consumption and school career, for example, the choice or change of the secondary school type, in more detail. TRIAL REGISTRATION: LIFE Child study: ClinicalTrials.gov, clinical trial number NCT02550236. PMID- 29703169 TI - Case series of Creutzfeldt-Jakob disease in a third-level hospital in Quito. AB - BACKGROUND: Creutzfeldt-Jakob disease is a rare and fatal neurodegenerative disorder that affects mammals and humans. The prevalence of this disease in the United States is 0.5 to 1 per million inhabitants. So far in Ecuador, we do not know what the prevalence or incidence is, and only one case report has been written. CASE PRESENTATION: We present a case series of Creutzfeldt-Jakob disease in a third-level hospital in Quito. The average age of symptom onset in our patients was 58.8 years. The male to female ratio was 1:1. Two patients began with cognitive/behavioral symptoms, while 4 patients began with focal neurological signs; 1 case with ataxia, 2 with gait disorders and 1 with vertigo and headache. All of the patients had the clinical features established by the World Health Organization. In addition, the entire cohort was positive for the 14 3-3 protein in cerebrospinal fluid, and had high signal abnormalities in caudate and putamen nucleus in DWI and FLAIR IRM. Only in one case, did we reach a definitive diagnosis through a pathological study. All other cases had a probable diagnosis. In this series of cases, 6 out of 6 patients died. The average time from the onset of the symptoms to death in this cohort was 13 months. CONCLUSION: This is the first report of a series of cases of Creutzfeldt-Jakob disease in Quito. Although definitive diagnosis must be histopathological, there are ancillary tests currently available that have allowed us to obtain a diagnosis of the disease. PMID- 29703170 TI - Factors associated with Health-Related Quality of Life in Kidney Transplant Recipients in France. AB - BACKGROUND: Health-Related Quality of Life (HRQoL) assessment after kidney transplantation has become an important tool in evaluating outcomes. This study aims to identify the associated factors with HRQoL among a representative sample size of Kidney Transplant Recipients (KTR) at the time of their inclusion in the study. METHODS: Data of this cross-sectional design is retrieved from a longitudinal study conducted in five French kidney transplant centers in 2011, and included KTR aged 18 years with a functioning graft for at least 1 year. Measures include demographic, psycho-social and clinical characteristics. To evaluate HRQoL, the Short Form-36 Health Survey (SF-36) and a HRQoL instrument for KTR (ReTransQol) were administered. Multivariate linear regression models were performed. RESULTS: A total of 1424 patients were included, with 61.4% males, and a mean age of 55.7 years (+/-13.1). Demographic and clinical characteristics were associated with low HRQoL scores for both questionnaires. New variables were found in our study: perceived poor social support and being treated by antidepressants were associated with low scores of Quality of Life (QoL), while internet access was associated with high QoL scores. CONCLUSION: The originality of our study's findings was that psycho-social variables, particularly KTR treated by antidepressants and having felt unmet needs for any social support, have a negative effect on their QoL. It may be useful to organize a psychological support specifically adapted for patients after kidney transplantation. PMID- 29703171 TI - Race is an independent predictor of survival in patients with soft tissue sarcoma of the extremities. AB - BACKGROUND: In the United States, race and socioeconomic status are well known predictors of adverse outcomes in several different cancers. Existing evidence suggests that race and socioeconomic status may impact survival in soft tissue sarcoma (STS). We investigated the National Cancer Database (NCDB), which contains several socioeconomic and medical variables and contains the largest sarcoma patient registry to date. Our goal was to determine the impact of race, ethnicity and socioeconomic status on patient survival in patients with soft tissue sarcoma of the extremities (STS-E). METHODS: We retrospectively analyzed 14,067 STS-E patients in the NCDB from 1998 through 2012. Patients were stratified based on race, ethnicity and socioeconomic status. Univariate and multivariate analyses were used to correlate specific outcomes and survival measures with these factors. Then, long-term survival between groups was evaluated using the Kaplan-Meier (KM) method with comparisons based on the log rank test. Multiple variables were analyzed between two groups. RESULTS: Of the 14,067 patients analyzed, 84.9% were white, 11% were black and 4.1% were Asian. Black patients were significantly more likely (7.18% vs 5.65% vs 4.47%) than white or Asian patients to receive amputation (p = 0.027). Black patients were also less likely to have either an above-median education level or an above median income level (p < 0.001). In addition, black patients were more likely to be uninsured (p < 0.001) and more likely to have a higher Charleson Comorbidity Score than white or Asian patients. Tumors were larger in size upon presentation in black patients than in white or Asian patients (p < 0.001). Black patients had significantly poorer overall survival than did white or Asian patients (p < 0.001) with a KM 5-year survival of 61.4% vs 66.9% and 69.9% respectively, and a 24% higher independent likelihood of dying in a multivariate analysis. CONCLUSION: This large database review reveals concerning trends in black patients with STS-E. These include larger tumors, poorer resources, a greater likelihood of amputation, and poorer survival than white and Asian patients. Future studies are warranted to help ensure adequate access to effective treatment for all patients. PMID- 29703172 TI - The accuracy of chemotherapy ascertainment among colorectal cancer patients in the surveillance, epidemiology, and end results registry program. AB - BACKGROUND: Surveillance, Epidemiology, and End Results (SEER) public research database does not include chemotherapy data due to concerns for incomplete ascertainment. To compensate for perceived lack of data quality many researchers use SEER-Medicare linked data, limiting studies to persons over age 65. We sought to determine current SEER ascertainment of chemotherapy receipt in two relatively large SEER registries compared to patient-reported receipt and to assess patterns of under-ascertainment. METHODS: In 2011-14, we surveyed patients with Stage III colorectal cancer reported to the Georgia and Metropolitan Detroit SEER registries. 1301/1909 eligible patients responded (68% response rate). Survey responses regarding treatment and sociodemographic factors were merged with SEER data. We compared patient-reported chemotherapy receipt with SEER recorded chemotherapy receipt. We estimated multivariable regression models to assess associations of under-ascertainment in SEER. RESULTS: Eighty-five percent of patients reported chemotherapy receipt. Among those, 10% (n = 104) were under ascertained in SEER (coded as not receiving chemotherapy). In unadjusted analyses, under-ascertainment was more common for older patients (11.8% age 76+ vs. < 9% for all other ages, p = 0.01) and varied with SEER registries (10.2% Detroit vs. 6.8% Georgia; p = 0.04). On multivariable analyses, chemotherapy under-ascertainment did not vary significantly by any patient attributes. CONCLUSION: We found a 10% rate of under-ascertainment of adjuvant chemotherapy for resected, stage III colorectal cancer in two SEER registries. Chemotherapy under-ascertainment did not disproportionately affect any patient subgroups. Use of SEER data from select registries is an important resource for researchers investigating contemporary chemotherapy receipt and outcomes. PMID- 29703173 TI - How to integrate proxy data from two informants in life event assessment in psychological autopsy. AB - BACKGROUND: Life event assessment is an important part in psychological autopsy, and how to integrate its proxy data from two informants is a major methodological issue which needs solving. METHODS: Totally 416 living subjects and their two informants were interviewed by psychological autopsy, and life events were assessed with Paykel's Interview for Recent Life Events. Validities of integrated proxy data using six psychological autopsy information reconstruction methods were evaluated, with living subjects' self-reports used as gold-standard criteria. RESULTS: For all the life events, average value of Youden Indexes for proxy data by type C information reconstruction method (choosing positive value from two informants) was larger than other five methods'. For family life related events, proxy data by type 1st information reconstruction method were not significantly different from living subjects' self-reports (P = 0.828). For all other life events, proxy data by type C information reconstruction method were not significantly different from the gold-standard. CONCLUSIONS: Choosing positive value is a relatively better method for integrating dichotomous (positive vs. negative) proxy data from two informants in life event assessment in psychological autopsy, except for family life related events. In that case, using information provided by 1st informants (mainly family member) is recommended. PMID- 29703174 TI - Validation of the SNACOR clinical scoring system after transarterial chemoembolisation in patients with hepatocellular carcinoma. AB - BACKGROUND: Transarterial chemoembolisation is the standard of care for intermediate stage (BCLC B) hepatocellular carcinoma, but it is challenging to decide when to repeat or stop treatment. Here we performed the first external validation of the SNACOR (tumour Size and Number, baseline Alpha-fetoprotein, Child-Pugh and Objective radiological Response) risk prediction model. METHODS: A total of 1030 patients with hepatocellular carcinoma underwent transarterial chemoembolisation at our tertiary referral centre from January 2000 to December 2016. We determined the following variables that were needed to calculate the SNACOR at baseline: tumour size and number, alpha-fetoprotein level, Child-Pugh class, and objective radiological response after the first transarterial chemoembolisation. Overall survival, time-dependent area under receiver-operating characteristic curves, Harrell's C-index, and the integrated Brier score were calculated to assess predictive ability. Finally, multivariate analysis was performed to identify independent predictors of survival. RESULTS: The study included 268 patients. Low, intermediate, and high SNACOR scores predicted a median survival of 31.5, 19.9, and 9.2 months, respectively. The areas under the receiver-operating characteristic curve for overall survival were 0.641, 0.633, and 0.609 at 1, 3, and 6 years, respectively. Harrell's C-index was 0.59, and the integrated Brier Score was 0.175. Independent predictors of survival included tumour size (P < 0.001), baseline alpha-fetoprotein level (P < 0.001) and Child Pugh class (P < 0.004). Objective radiological response (P = 0.821) and tumour number (P = 0.127) were not additional independent predictors of survival. CONCLUSIONS: The SNACOR risk prediction model can be used to identify patients with a dismal prognosis after the first transarterial chemoembolisation who are unlikely to benefit from further transarterial chemoembolisation. However, Harrell's C-index showed only moderate performance. Accordingly, this risk prediction model can only serve as one of several components used to make the decision about whether to repeat treatment. PMID- 29703175 TI - Anti-fibrotic effects of pirfenidone and rapamycin in primary IPF fibroblasts and human alveolar epithelial cells. AB - BACKGROUND: Pirfenidone, a pleiotropic anti-fibrotic treatment, has been shown to slow down disease progression of idiopathic pulmonary fibrosis (IPF), a fatal and devastating lung disease. Rapamycin, an inhibitor of fibroblast proliferation could be a potential anti-fibrotic drug to improve the effects of pirfenidone. METHODS: Primary lung fibroblasts from IPF patients and human alveolar epithelial cells (A549) were treated in vitro with pirfenidone and rapamycin in the presence or absence of transforming growth factor beta1 (TGF-beta). Extracellular matrix protein and gene expression of markers involved in lung fibrosis (tenascin-c, fibronectin, collagen I [COL1A1], collagen III [COL3A1] and alpha-smooth muscle actin [alpha-SMA]) were analyzed. A cell migration assay in pirfenidone, rapamycin and TGF-beta-containing media was performed. RESULTS: Gene and protein expression of tenascin-c and fibronectin of fibrotic fibroblasts were reduced by pirfenidone or rapamycin treatment. Pirfenidone-rapamycin treatment did not revert the epithelial to mesenchymal transition pathway activated by TGF-beta. However, the drug combination significantly abrogated fibroblast to myofibroblast transition. The inhibitory effect of pirfenidone on fibroblast migration in the scratch-wound assay was potentiated by rapamycin combination. CONCLUSIONS: These findings indicate that the combination of pirfenidone and rapamycin widen the inhibition range of fibrogenic markers and prevents fibroblast migration. These results would open a new line of research for an anti-fibrotic combination therapeutic approach. PMID- 29703176 TI - Indicators for evaluating European population health: a Delphi selection process. AB - BACKGROUND: Indicators are essential instruments for monitoring and evaluating population health. The selection of a multidimensional set of indicators should not only reflect the scientific evidence on health outcomes and health determinants, but also the views of health experts and stakeholders. The aim of this study is to describe the Delphi selection process designed to promote agreement on indicators considered relevant to evaluate population health at the European regional level. METHODS: Indicators were selected in a Delphi survey conducted using a web-platform designed to implement and monitor participatory processes. It involved a panel of 51 experts and 30 stakeholders from different areas of knowledge and geographies. In three consecutive rounds the panel indicated their level of agreement or disagreement with indicator's relevance for evaluating population health in Europe. Inferential statistics were applied to draw conclusions on observed level of agreement (Scott's Pi interrater reliability coefficient) and opinion change (McNemar Chi-square test). Multivariate analysis of variance was conducted to check if the field of expertise influenced the panellist responses (Wilk's Lambda test). RESULTS: The panel participated extensively in the study (overall response rate: 80%). Eighty indicators reached group agreement for selection in the areas of: economic and social environment (12); demographic change (5); lifestyle and health behaviours (8); physical environment (6); built environment (12); healthcare services (11) and health outcomes (26). Higher convergence of group opinion towards agreement on the relevance of indicators was seen for lifestyle and health behaviours, healthcare services, and health outcomes. The panellists' field of expertise influenced responses: statistically significant differences were found for economic and social environment (p < 0.05 in round 1 and 2), physical environment (p < 0.01 in round 1) and health outcomes (p < 0.01 in round 3). CONCLUSIONS: The high levels of participation observed in this study, by involving experts and stakeholders and ascertaining their views, underpinned the added value of using a transparent Web-Delphi process to promote agreement on what indicators are relevant to appraise population health. PMID- 29703177 TI - Functional status, pre-dialysis health and clinical outcomes among elderly dialysis patients. AB - BACKGROUND: Elderly patients comprise the fastest growing population initiating dialysis in United States. The impact of poor functional status and pre-dialysis health status on clinical outcomes in elderly dialysis patients is not well studied. METHODS: We studied a retrospective cohort of 49,645 incident end stage renal disease patients that initiated dialysis between January 1, 2008 and December 31, 2008 from the United States Renal Data System with linked Medicare data covering at least 2 years prior to dialysis initiation. Using logistic regression models adjusted for pre-dialysis health status and other cofounders, we examined the impact of poor functional status as defined from form 2728 on 1 year all-cause mortality as primary outcome, type of dialysis modality (hemodialysis vs. peritoneal dialysis), and type of initial vascular access (arteriovenous access vs. central venous catheter) among hemodialysis patients as secondary outcomes. RESULTS: Mean age was 72 +/- 11 years. At dialysis initiation, 18.7% reported poor functional status, 88.9% had at least 1 pre dialysis hospitalization, and 27.8% did not receive pre-dialysis nephrology care. In adjusted analyses, 1-year mortality was higher in patients with poor functional status (OR, 1.48; 95% CI, 1.40-1.57). Adjusted odds of being initiated on hemodialysis than peritoneal dialysis (odds ratio [OR], 1.39; 95% confidence interval [CI], 1.16-1.66) were higher in patients with poor functional status. Poor functional status decreased the adjusted odds of starting hemodialysis with arteriovenous access as compared to central venous catheter (OR, 0.79; 95% CI, 0.72-0.86). CONCLUSION: Poor functional status in elderly patients with end stage renal disease is associated with higher odds of initiating hemodialysis; increases the risk of central venous catheter use, and is an independent predictor of 1-year mortality. PMID- 29703178 TI - Extra-capsular growth of lymph node metastasis correlates with poor prognosis and high SOX9 expression in gastric cancer. AB - BACKGROUND: Extra-capsular growth (ECG) describes the extension of neoplastic cells beyond the lymph node capsule. Aim of this study was to investigate the prognostic value of ECG and its association with a stem cell like phenotype indicated by expression of the transcription factor SOX9 in gastric cancer. METHODS: By histological evaluation, 199 patients with nodal positive gastric cancer or adeoncarcinoma of the esophageal-gastric junction (AEG) were divided into two groups according to the presence (ECG) or absence (ICG) of extracapsular growth in at least one nodal metastasis. Of these, 194 patients were stained for SOX9 and SOX2 using immunohistochemistry. Seventeen nodal negative patients (pT3/4, pN0, pM0) served as controls. RESULTS: Seventy-three patients (36.7%) showed ECG. ECG was associated with lower overall survival (p < 0.0001), advanced pT- (p = 0.03) and pN- category (p < 0.0001) and lymphovascular invasion (p = 0.014). In multivariate analysis, ECG was found to be an independent prognostic factor (HR = 2.1; 95% CI 1.7-3.4; p = 0.001). SOX9 expression correlated significantly with ECG (96% SOX9 high in ECG patients vs. 79% SOX9 high in patients with ICG; p = 0.002). Controls showed significantly reduced SOX9 expression compared to nodal positive carcinomas (59% vs. 85% high SOX9 expression; p = 0.006). No significant correlation of ECG and SOX2 (59% SOX2 negative in ECG patients vs. 64% in patients with ICG, p = 0.48) could be obtained. CONCLUSIONS: Patients with ECG exhibit poorer prognosis and ECG was found to be an independent prognostic factor. Thus, ECG turns out to be a morphological biomarker for a more aggressive phenotype in gastric cancer. This is supported by the fact that ECG correlates with the expression of SOX9, which has been described in the context of pro-oncogenic properties of tumours. However, the fact that SOX2 failed to show significant results indicate that ECG is not associated with a distinct cancer stem cell phenotype in gastric cancer. PMID- 29703179 TI - Microsatellite instability testing in colorectal cancer using the QiaXcel advanced platform. AB - BACKGROUND: Microsatellite instability (MSI) is a major predictive and diagnostic marker in several cancers including colorectal carcinomas. Diagnostic testing for microsatellites is generally performed using capillary sequencers, which requires expensive high-end equipment including expensive chemistry using fluorescent dyes labelling the PCR products of interest. In this study we have modified such a diagnostic protocol and established the microsatellite testing on the QiaXcel Advanced platform. METHODS: MSI testing was based on a previously established protocol describing a multiplex PCR followed by fluorescent detection of PCR products in a capillary sequencing device. Ten microsatellites were included in the new protocol: BAT25, BAT26, BAT40, D2s123, D10s197, D13s153, D17s250, D18s58, D5s346, and MycI. In this protocol the PCR was demultiplexed and established on the QiaXcel Advanced system (Qiagen, Hilden, Germany). RESULTS: Making use of a series of FFPE control samples with known MSI status including those with and without MSI a protocol for MSI testing was successfully established on the QiaXcel Advanced platform. CONCLUSIONS: MSI testing for human colorectal cancers using the QiaXcel Advanced system could serve as an economic acceptable tool for rapid diagnostics in laboratories that do not have access to a capillary sequencing unit. PMID- 29703180 TI - Dental age estimation in southern Chinese population using panoramic radiographs: validation of three population specific reference datasets. AB - BACKGROUND: The accuracy of estimated age should depend on the reference data sets (RDS) from which the maturity scores or Ages of Attainment (AoA) were obtained. This study aimed to test the accuracy of age estimation from three different population specific dental reference datasets (RDS). METHODS: Two hundred and sixty six dental panoramic radiographs of subjects belonging to southern Chinese ethnicity were scored and dental age (DA) was estimated from three reference datasets: French-Canadian, United Kingdom (UK) Caucasian and southern Chinese. Statistical significance was set at p < 0.05 and for each method, the difference between the chronological age (CA) and dental age (CA-DA) was calculated using paired t-tests. In addition, Chi-square tests were performed to evaluate the accuracy of the age estimates within specific time interval from CA. RESULTS: The estimated age difference (CA-DA) using the French Canadian RDS was - 0.62 years for males and - 0.36 years for females. For the UK Caucasian RDS, the age difference was 0.25 years for males and 0.23 years for females. The difference observed using the southern Chinese RDS was - 0.02 years for both genders and the difference was not statistically significant (p > 0.05). The southern Chinese RDS estimated the age of 80% of subjects within +/-12 months range, and 90% of subjects within +/-18 months range (p < 0.05) showing it to be more accurate than other datasets. CONCLUSION: It is concluded that population specific Reference Data Sets improve the accuracy of dental age estimation. PMID- 29703181 TI - Disparities in risky sexual behavior among khat chewer and non- chewer college students in Southern Ethiopia: a comparative cross-sectional study. AB - BACKGROUND: Risky sexual behavior (RSB) and its consequence among school adolescents and youths have been well understood. It is still a common practice among college and university students living away from their controlling families compounded with the ever-worsening khat chewing habits. However, the relation between khat chewing and RSB is not well studied particularly among college students in Ethiopia. Hence, this study contributes to the literature by examining disparities of RSB among khat chewer and non-chewer students in Southern Ethiopia with the purpose of improving adolescent and youth health. METHODS: An institution-based comparative cross-sectional study was conducted among 1211 college students at Arba Minch town in March 2015. Respondents were selected by employing a simple random sampling technique. Data was collected by using a pre-tested, structured, self- administered questionnaire. The data was entered into Epidata version 3.1 and analyzed using IBM SPSS statistics version 21. Level of statistical significance was declared at a p- value of < 0.05. RESULTS: The prevalence of lifetime and current RSB among college students was 40.8 and 36.5% respectively. The lifetime and current prevalence of RSB among khat chewers (82.2 and 30.9%) was significantly higher than non-chewers (74.2 and 27.6%) respectively (P-value = 0.001). Male sex (AOR = 1.82; 95% CI = 1.28, 2.6), urban residence (AOR = 1.63,95% CI = 1.17, 2.28), age of students (AOR = 1.18; 95% CI = 1.09,1.28), living away from family (AOR = 2.45, 95% CI = 1.62,3.7), having high peer pressure (AOR = 2.58, 95% CI = 1.85-3.59), an increase in average grade point (AOR = 0.98, 95% CI = 0.96-0.99), regular attendance of religious institutions (AOR = 0.24, 95%CI = 0.12, 0.42), watching pornographic movies (AOR = 2.51, 95% CI = 1.79,3.51), khat chewing (AOR = 3.02, 95% CI:=1.91,4.76) and alcohol drinking (AOR = 2.26, 95% CI = 1.54,3.35) were factors associated with RSB. CONCLUSIONS: Considerable proportions of students were engaged in khat chewing and RSB. RSB was significantly higher among khat chewers as compared to non- chewers. Comprehensive sexuality education was recommended to college communities and by extension to the ministry of health and education to address the identified factors so that RSB can be reshaped. PMID- 29703182 TI - Textual health warning labels on snus (Swedish moist snuff): do they affect risk perception? AB - BACKGROUND: To strengthen the risk message on snus warning labels, the European Union in 2016 removed "can" from the warning "This tobacco product (can) damages your health and is addictive." We tested how these and other textual warnings affect risk perception. METHODS: Snus-using and non-using Norwegians aged 16-72 participated in two online survey experiments. Participants in Study 1 (N = 196) were randomized to read one of four warning labels. Outcome variables included ratings of likelihood of health damage from snus and perceived severity of such damages. Study 2 (N = 423) used similar outcome measures but added a baseline measure allowing for a pre-post comparison, as well as a control group receiving no warning label. Data were analysed using ANOVA and non-parametric tests. RESULTS: Study 1 indicated that removing "can" from the EU warning increased long term risk perception, but adding "causes cancer" had no effect on risk perception. In Study 2, risk perception increased from pre to post, regardless of label manipulation. "Causes cancer" and "damages your health" were indicated as most alarming when participants compared and ranked all warnings. CONCLUSIONS: Adding "causes cancer" or removing "can" from "damages your health" did not strengthen short-time (1 year) risk perception, but the latter increased long term (10 years) risk perception in Study 1. In the pre-post design in Study 2, risk perception increased regardless of warning label. PMID- 29703183 TI - Prevalence of excess body weight and underweight among 26 Chinese ethnic minority children and adolescents in 2014: a cross-sectional observational study. AB - BACKGROUND: Little is known regarding the nutritional burden in Chinese ethnic minority children. This study aimed to investigate the epidemiological characteristics of excess body weight and underweight for 26 ethnic groups. METHODS: Data on 80,821 participants aged 7-18 years across 26 minorities, with completed records from a large national cross-sectional survey, were obtained from Chinese National Survey on Students' Constitution and Health (CNSSCH) in 2014. Excess body weight, underweight and their components were classified according to Chinese national BMI references. RESULTS: The overall prevalence of excess body weight and underweight among ethnic groups were 12.0% and 14.5%, in which 4.4% and 4.1% of the participants were classified as obese and severe wasting, respectively. Compared with girls, boys showed a higher prevalence of underweight, severe wasting and obesity, but a lower prevalence of excess body weight (P < 0.05). Among 26 ethnic groups, Koreans had the highest prevalence of excess body weight (30.4%), while Bouyeis showed the highest prevalence of underweight (25.7%). The ethnic minority groups with high prevalence of excess body weight and underweight were more likely to show high burden of obesity and severe wasting, respectively. However, it is not the case for some groups, such as Miaos and Shuis. CONCLUSIONS: A worrying dual burden of excess body weight and underweight was recognized in Chinese ethnic minority children. Since various characteristics were found among different minorities, the ethnic-specific effort is warranted to improve their nutritional status. PMID- 29703184 TI - Knowledge, perception and practices towards sickle cell disease: a community survey among adults in Lubaga division, Kampala Uganda. AB - BACKGROUND: Worldwide, the burden of Sickle Cell disease (SCD) has not been amply addressed. In Africa, Uganda has the 5th highest burden, a situation aggravated by limited and inaccessible formal social support structures to aid patients and families cope better with the psychosocial burden of SCD. In addition, this has been coupled with stigmatization and discrimination of people living with sickle cell disease causing isolation from family and society. METHOD: This cross sectional study therefore set out to determine the attitudes, perception and level of awareness towards Sickle Cell disease in Ugandan communities. The study used an interviewer administered questionnaires to collect the data. RESULTS: Out of 110 people sampled; 91.2% of the respondents had ever heard of SCD with the highest proportion 38.7% hearing of SCD from friends and family. Close to half of the respondents 48% knew that SCD is inherited, however a large proportion 44.2% did not know the cause of SCD. However, 68.7% of the respondents said they cannot marry a person with SCD. CONCLUSION: The study results indicate that more effort needs to be done to promote sickle cell awareness in Uganda communities with emphasis on the inclusion of sickle cell in health education campaigns. PMID- 29703185 TI - Retrospective analysis of risk factors of slide positivity among febrile patients in the Salween river valley of Shan Special Region II, northern Myanmar. AB - BACKGROUND: In Myanmar, epidemiological conditions have been unclear due to a lack of accurate data. In 2014 and 2016, malaria outbreaks occurred in the Shan Special Region II (SSR2). It was reported that these outbreaks were caused by malaria patients from the Salween River Valley (SRV), but further research is needed to confirm these reports. To examine the risks of malaria infection in the SSR2 section of the SRV, this paper offers a retrospective analysis based on the data we collected in 2009. METHODS: A multivariate logistic model was utilized to analyze risk factors associated with the slide positivity of 2009. Results of the investigation in 2009 were compared with updated data. RESULTS: The number of slide positivity was 91 (24.7%, 95% confidence interval [CI], 20.3-29.4%) among 369 people who had fever 2 weeks ago of the survey, including 74 (20.1%; 95%CI, 16.1-24.5%) cases of P. falciparum, 13 (3.5%; 95%CI, 1.9-5.9%) of P.vivax and 4 (1.1%, 95%CI, 0.3-2.8%) of P. malariae. The adjusted odds ratio (OR) was 99.8 (95% CI, 24.7-887.7) for patients' age < 15 years, 6.61 (95%CI, 3.57-10.49) for people living at an altitude of < 800 m, 6.35 (95%CI, 2.45-23.27) for people lacking knowledge on malaria transmission and knowledge on symptoms, 2.10 (95%CI, 1.22-5.11) for people taking no measures against mosquito bites and 5.55 (95%CI, 2.65-13.05) for people delaying treatment. Compared with annual parasitic incidences 13.80 per 10,000 person-years (422/305733) in 2014, 2.36 per 10,000 person-years (73/309004) in 2015 and 5.25 per 10,000 person-years (164/312310) in 2015, malaria burden is reduced. CONCLUSION: Age, lower altitude, a lack of knowledge about malaria transmission and symptoms, inaction of measures against mosquito bites and delayed treatment-seeking were independent risk factors for slide positivity. These results indicate that malaria transmission was likely within housing settlements in the SRV, and that the transmission rates within the SRV are higher than in other areas. In order to eliminate malaria, it is important for people to obtain qualified treatment to contain artemisinin resistance. TRIAL REGISTRATION: Trial registration number: ChiCTR-COC-17012522 . Retrospectively registered 31 August 2017. PMID- 29703186 TI - HPV-16 E7 expression up-regulates phospholipase D activity and promotes rapamycin resistance in a pRB-dependent manner. AB - BACKGROUND: Human Papillomavirus (HPV) infection is the main risk factor for the development and progression of cervical cancer. HPV-16 E6 and E7 expression is essential for induction and maintenance of the transformed phenotype. These oncoproteins interfere with the function of several intracellular proteins, including those controlling the PI3K/AKT/mTOR pathway in which Phospolipase D (PLD) and Phosphatidic acid (PA) play a critical role. METHODS: PLD activity was measured in primary human keratinocytes transduced with retroviruses expressing HPV-16 E6, E7 or E7 mutants. The cytostatic effect of rapamycin, a well-known mTOR inhibitor with potential clinical applications, was evaluated in monolayer and organotypic cultures. RESULTS: HPV-16 E7 expression in primary human keratinocytes leads to an increase in PLD expression and activity. Moreover, this activation is dependent on the ability of HPV-16 E7 to induce retinoblastoma protein (pRb) degradation. We also show that cells expressing HPV-16 E7 or silenced for pRb acquire resistance to the antiproliferative effect of rapamycin. CONCLUSION: This is the first indication that HPV oncoproteins can affect PLD activity. Since PA can interfere with the ability of rapamycin to bind mTOR, the use of combined strategies to target mTOR and PLD activity might be considered to treat HPV-related malignancies. PMID- 29703187 TI - Trial protocol: a clustered, randomised, longitudinal, type 2 translational trial of alcohol consumption and alcohol-related harm among adolescents in Australia. AB - BACKGROUND: This cluster randomised control trial is designed to evaluate whether the Communities That Care intervention (CTC) is effective in reducing the proportion of secondary school age adolescents who use alcohol before the Australian legal purchasing age of 18 years. Secondary outcomes are other substance use and antisocial behaviours. Long term economic benefits of reduced alcohol use by adolescents for the community will also be assessed. METHODS: Fourteen communities and 14 other non-contiguous communities will be matched on socioeconomic status (SES), location, and size. One of each pair will be randomly allocated to the intervention in three Australian states (Victoria, Queensland and Western Australia). A longitudinal survey will recruit grade 8 and 10 students (M = 15 years old, N = 3500) in 2017 and conduct follow-up surveys in 2019 and 2021 (M = 19 years old). Municipal youth populations will also be monitored for trends in alcohol-harms using hospital and police administrative data. DISCUSSION: Community-led interventions that systematically and strategically implement evidence-based programs have been shown to be effective in producing population-level behaviour change, including reduced alcohol and drug use. We expect that the study will be associated with significant effects on alcohol use amongst adolescents because interventions adopted within communities will be based on evidence-based practices and target specific problems identified from surveys conducted within each community. TRIAL REGISTRATION: The trial was retrospectively registered in September, 2017 ( ACTRN12616001276448 ), as communities were selected prior to trial registration; however, participants were recruited after registration. Findings will be disseminated in peer-review journals and community fora. PMID- 29703188 TI - A structural equation model to test a conceptual framework of oral health in Japanese edentulous patients with an item weighting method using factor score weights: a cross-sectional study. AB - BACKGROUND: To investigate Locker's multidimensional model of oral health in Japanese edentulous patients with an item weighting method using factor score weights, which is more accurate than the sum scoring method. A previous study tested Locker's model in edentulous elders in the UK, using empirical evidence from the Short-Form Oral Health Impact Profile (OHIP-14). Investigating the model using the OHIP for edentulous subjects (OHIP-EDENT), which contains 19 items suitable for these patients, may complement that study. Testing Locker's model in Japanese patients may support generalization of the model. METHODS: A total of 394 patients who were edentulous in both arches and visited the Dental Hospital of Tokyo Medical and Dental University for new complete dentures were recruited. This cross-sectional study had a non-probabilistic sampling design and included the following: data collection; application of the new item weighting method that involves hierarchical confirmatory factor analysis (CFA) to derive factor score weights for each item, using the bootstrap method, to check the significance of the factor score weights; and empirical testing of Locker's conceptual model of oral health in Japanese edentulous patients, using structural equation modelling analysis with the bootstrap method for precise estimations and model generation. RESULTS: Factor score weights derived from CFA were significant. After item weighting, the initial model was analyzed and found to have an inconsistent direct path (functional limitation to disability). This path was eliminated from the model and the modified model was re-run. All effects were significant. The model showed acceptable fit on indices including the model chi-squared, standardized root-mean-square residual, root mean-square error of approximation, goodness-of-fit index, comparative fit index, and P-value. CONCLUSIONS: Our findings showed an empirical fit to Locker's model in Japanese edentulous patients when using the item weighting method, which was more accurate than the sum scoring method. These results could contribute to the generalization of Locker's model. TRIAL REGISTRATION: The experimental procedures were published in the University hospital Medical Information Network (UMIN) Center (UMINCTR Clinical Trial, Unique trial Number: UMIN000028711 ). PMID- 29703189 TI - Using participatory risk analysis to develop a song about malaria for young children in Limpopo Province, South Africa. AB - BACKGROUND: In 2015, malaria infected over 212 million people and killed over 429,000 individuals, mostly children under 5 years of age, with 90% of malaria cases occurring in sub-Saharan Africa. The aim was to develop an age and culturally appropriate song for Tshivenda-speaking children under 5 years of age to decrease the risk of malaria in Limpopo Province, South Africa. METHODS: Document review was used to identify appropriate disease determinants to decrease risk in children < 5 years old in the study area. These were used to develop lyrics and music for a song about malaria in line with the principles of participatory risk analysis. The age and cultural appropriateness of the song as well as disease determinants chosen were reviewed using a modified Delphi technique, by 10 purposively selected experts in malaria (4), Vhavenda music (3) and early childhood education (3). Thereafter, the song was translated into Tshivenda and reviewed by two focus groups living in the study area, one including female caregivers and pre-school teachers (n = 7) and a second comprising of male community based malaria control personnel (n = 5). RESULTS: The experts surveyed and both focus groups strongly supported the inclusion of knowledge about the link between mosquitoes and malaria and that children should know the signs of malaria to facilitate early diagnosis. Although the expert group felt that bed nets should not be mentioned, both focus groups suggested the inclusion of bed nets and it was observed that community members were purchasing their own nets. Focus group members also felt that young children should not be involved in internal residual spraying initiatives. CONCLUSIONS: It was concluded that although risk communication on malaria prevention and treatment in young children should be aimed at caregivers, an age and culture appropriate song about malaria could be developed to help young children protect themselves. This song focused on understanding the link between mosquitoes and malaria, preventing exposure and recognising signs of disease. PMID- 29703190 TI - Prenatal fine particulate exposure associated with reduced childhood lung function and nasal epithelia GSTP1 hypermethylation: Sex-specific effects. AB - BACKGROUND: In utero exposure to particulate matter with an aerodynamic diameter of less than 2.5 MUm (PM2.5) has been linked to child lung function. Overlapping evidence suggests that child sex and exposure timing may modify effects and associations may be mediated through glutathione S-transferase P1 (GSTP1) methylation. METHODS: We prospectively examined associations among prenatal PM2.5 exposure and child lung function and GSTP1 methylation in an urban pregnancy cohort study. We employed a validated satellite-based spatiotemporally resolved prediction model to estimate daily prenatal PM2.5 exposure over gestation. We used Baysian distributed lag interaction models (BDLIMs) to identify sensitive windows for prenatal PM2.5 exposure on child lung function and nasal epithelia GSTP1 methylation at age 7 years, and to examine effect modification by child sex. RESULTS: BDLIMs identified a sensitive window for prenatal PM2.5 exposure at 35-40 weeks gestation [cumulative effect estimate (CEE) = - 0.10, 95%CI = - 0.19 to - 0.01, per MUg/m3 increase in PM2.5] and at 36-40 weeks (CEE = - 0.12, 95%CI = - 0.20 to - 0.01) on FEV1 and FVC, respectively, in boys. BDLIMs also identified a sensitive window of exposure at 37-40 weeks gestation between higher prenatal PM2.5 exposure and increased GSTP1 percent methylation. The association between higher GSTP1 percent methylation and decreased FEV1 was borderline significant in the sample as a whole (beta = - 0.37, SE = 0.20, p = 0.06) and in boys in stratified analyses (beta = - 0.56, SE = 0.29, p = 0.05). CONCLUSIONS: Prenatal PM2.5 exposure in late pregnancy was associated with impaired early childhood lung function and hypermethylation of GSTPI in DNA isolated from nasal epithelial cells. There was a trend towards higher GSTP1 percent methylation being associated with reduced FEV1. All findings were most evident among boys. PMID- 29703191 TI - Danish translation, cultural adaption and initial psychometric evaluation of the patient feedback form. AB - AIM: No suitable Danish questionnaire exists to evaluate patient satisfaction with various patient reported outcome measures. Thus, the aim of this research project was to conduct a study on the translation and cultural adaption of an American patient reported experience measures questionnaire, "Patient Feedback Form", among Danish patients, and to examine selected psychometric properties within reliability. MATERIAL AND METHODS: In the first phase of the study, the Patient Feedback Form was forward and backward translated following the methodology of existing guidelines. Subsequently, cognitive interviewing was performed with seven cancer patients and seven healthy persons (19-86 years old/6 men and 8 women) to ensure that questions were easy to understand and made sense to Danish interviewees. In the second phase, phone interviews were carried out with 95 prostate cancer patients after they had responded to the same Patient Feedback Form. Missing data was imputed using the Expectation-Maximization technique. To examine the structure of the questionnaire, an exploratory factor analysis was conducted. Cronbach's alpha was calculated to investigate internal consistency. RESULTS: There were only minor disagreements in the translation process, and the reconciliation went smoothly (phase 1). With regard to one item, however, it was difficult to reach a consensus. Through the qualitative validation process, the right solution was found. The results from the psychometric testing (phase 2) showed that four factors had an Eigen value > 1, but only one factor was extracted as the Scree plot had a clear "elbow", showing a one factor structure that explained 46.1% of the variance. The internal consistency was high as Cronbach's alpha was 0.89. CONCLUSION: The translated, culturally adapted, and validated version of the Patient Feedback Form seems to be suitable for measuring satisfaction with patient reported outcome measures in a Danish setting. While the results should be treated with caution due to the small sample size, psychometric testing indicates that the questionnaire is a valid instrument. However, additional psychometric testing such as hypotheses testing, responsiveness, and test-retest on a larger and more diverse sample size is required to further verify the validity of the instrument. PMID- 29703193 TI - Patient house calls in Attica and Thessaloniki, Greece (2005-2015): a model for out-of-hospital multispecialty emergency medicine. AB - BACKGROUND: The SOS-doctors are a network of physicians who perform house-call visits in the areas of Attica and Thessaloniki, Greece. METHODS: Patients requesting medical services by the SOS doctors during the period 1/1/2005 - 31/12/2015 were eligible for inclusion in this retrospective analysis. RESULTS: During this period 335, 212 home visits were performed. Females used this service more frequently compared to males (60.5% versus 39.5%). Among the age-groups, patients aged over 75 years made 56.6% of all house calls. Fewer phone requests were recorded during autumn than in winter (21.1% versus 29.1%). Infections were the most common cause of house-visits (29%), followed by cardiovascular diseases (10.3%), musculoskeletal (9.1%), gastrointestinal (6.3%) and neurological disorders (3.7%). An increasing demand for radiology at home was observed, starting at 352 calls in 2009 and reaching 2230 in 2015. Finally, 9.2% of patients were advised to be admitted into a hospital. CONCLUSION: A shift towards older age, but not the oldest old (> 90 years), and acute conditions was observed during the study period. The study confirms that home visits retain a significant role in the modern health care systems. PMID- 29703192 TI - Acceptability of a herd immunity-focused, transmission-blocking malaria vaccine in malaria-endemic communities in the Peruvian Amazon: an exploratory study. AB - BACKGROUND: A transmission-blocking vaccine (TBV) to prevent malaria-infected humans from infecting mosquitoes has been increasingly considered as a tool for malaria control and elimination. This study tested the hypothesis that a malaria TBV would be acceptable among residents of a malaria-hypoendemic region. METHODS: The study was carried out in six Spanish-speaking rural villages in the Department of Loreto in the Peruvian Amazon. These villages comprise a cohort of 430 households associated with the Peru-Brazil International Centre for Excellence in Malaria Research. Individuals from one-third (143) of enrolled households in an ongoing longitudinal, prospective cohort study in 6 communities in Loreto, Peru, were randomly selected to participate by answering a pre validated questionnaire. RESULTS: All 143 participants expressed desire for a malaria vaccine in general; only 1 (0.7%) expressed unwillingness to receive a transmission-blocking malaria vaccine. Injection was considered most acceptable for adults (97.2%); for children drops in the mouth were preferred (96.8%). Acceptability waned marginally with the prospect of multiple injections (83.8%) and different projected efficacies at 70 and 50% (90.1 and 71.8%, respectively). Respondents demonstrated clear understanding that the vaccine was for community, rather than personal, protection against malaria infection. DISCUSSION: In this setting of the Peruvian Amazon, a transmission-blocking malaria vaccine was found to be almost universally acceptable. This study is the first to report that residents of a malaria-endemic region have been queried regarding a malaria vaccine strategy that policy-makers in the industrialized world often dismiss as altruistic. PMID- 29703194 TI - Relationship between movement time and hip moment impulse in the sagittal plane during sit-to-stand movement: a combined experimental and computer simulation study. AB - BACKGROUND: The association between repetitive hip moment impulse and the progression of hip osteoarthritis is a recently recognized area of study. A sit to-stand movement is essential for daily life and requires hip extension moment. Although a change in the sit-to-stand movement time may influence the hip moment impulse in the sagittal plane, this effect has not been examined. The purpose of this study was to clarify the relationship between sit-to-stand movement time and hip moment impulse in the sagittal plane. METHODS: Twenty subjects performed the sit-to-stand movement at a self-selected natural speed. The hip, knee, and ankle joint angles obtained from experimental trials were used to perform two computer simulations. In the first simulation, the actual sit-to-stand movement time obtained from the experiment was entered. In the second simulation, sit-to-stand movement times ranging from 0.5 to 4.0 s at intervals of 0.25 s were entered. Hip joint moments and hip moment impulses in the sagittal plane during sit-to-stand movements were calculated for both computer simulations. RESULTS AND CONCLUSIONS: The reliability of the simulation model was confirmed, as indicated by the similarities in the hip joint moment waveforms (r = 0.99) and the hip moment impulses in the sagittal plane between the first computer simulation and the experiment. In the second computer simulation, the hip moment impulse in the sagittal plane decreased with a decrease in the sit-to-stand movement time, although the peak hip extension moment increased with a decrease in the movement time. These findings clarify the association between the sit-to-stand movement time and hip moment impulse in the sagittal plane and may contribute to the prevention of the progression of hip osteoarthritis. PMID- 29703195 TI - Measurement of patient reported disability using WHODAS 2.0 before and after surgical intervention in Madagascar. AB - BACKGROUND: Patient reported outcomes (PRO) measure the quality of care from the patient's perspective. PROs are an important measure of surgical outcome and can be used to calculate health gains after surgical treatment. The World Health Organisation Disability Assessment Schedule (WHODAS) 2.0 is a PRO used to evaluate pre and post-operative disability across a range of surgical specialities. In this study, Mercy Ships, a non-governmental organisation (NGO), used WHODAS 2.0 to evaluate patient reported disability in 401 consecutive patients in Madagascar. We hypothesised that surgical interventions would decrease pre-operative patient reported disability across a range of specialties (maxillofacial, plastic, orthopaedic, general and obstetric fistula surgery). METHOD: WHODAS 2.0 was administered preoperatively by face-to-face interview, and at 3 months post-operatively by telephone. Demographic data, American Society of Anesthesiologists (ASA) physical classification score, duration of surgery, length of hospital stay, and in-hospital post-operative complications were collected from a separately maintained patient database. The primary outcome measure was difference in pre- and post-operative WHODAS 2.0 scores. RESULTS: No differences were seen between the two groups in preoperative disability (p = 0.25), ASA score (p = 0.46), or duration of surgery (p = 0.85). At 3 months 44% (176/401) of patients were available for telephone for postoperative evaluation. All had a significant reduction in their disability score from 8.4% to 1.0% (p < 0.001), 17 experienced a post-operative complication, but none had residual disability and there were no deaths. The group lost to follow-up were more likely to be female (65% versus 50%, p < 0.05), were younger (mean age 31 versus 35, p < 0.05), had longer hospital stays (10 versus 4 days, p < 0.001), and were more likely to have experienced post-operative complications (p < 0.05). CONCLUSION: This study demonstrates that surgical intervention in a LMIC decreases patient reported disability as measured by WHODAS 2.0. PMID- 29703196 TI - Comparison of the fecal microbiota of domestic commercial meat, laboratory, companion, and shelter rabbits (Oryctolagus cuniculi). AB - BACKGROUND: Rabbits are cecotrophic, hindgut-fermenters that rely heavily on their gastrointestinal microbiota for optimal digestion of plant-based diets. Dysbiosis, caused by disruption of the gastrointestinal microbiota, is known to predispose rabbits to rabbit enteritis complex (REC), a major cause of morbidity and mortality. The objectives of this study were to describe the fecal microbiota of domestic rabbits from a variety of settings (commercial meat, companion, laboratory, and shelter) and to identify how factors such as age, season, and routine antimicrobial use affect the fecal microbiota composition. RESULTS: A total of 86 pooled commercial meat, 54 companion, 14 pooled laboratory, and 14 shelter rabbit fecal samples were evaluated using 16S rRNA gene sequencing of the V4 region. In all sample types, the predominant bacterial phylum was Firmicutes. Other commonly identified phyla (composing >= 1% of the total microbiota composition) were Verrucomicrobia, Proteobacteria, and Bacteroidetes. Significant differences in composition were noted between commercial, companion, laboratory, and shelter rabbit samples for proportions of Verrucomicrobia (P < 0.01), Proteobacteria (P < 0.01), and Lentisphaerae (P = 0.01) within the total microbiota. Within the commercial meat rabbit samples, significant differences between the microbiota composition of growers (n = 42) and does (n = 44) were limited to one unclassified Firmicutes (P = 0.03) and no differences were identified at the phylum level. Significant differences were present between fecal samples taken from rabbits during the summer (n = 44) compared to the winter (n = 42), with Firmicutes (P = 0.04), Verrucomicrobia (P = 0.03), Proteobacteria (P = 0.02), Deinococcus-Thermus (P = 0.04), Armatimonadates (P = 0.003), and Actinobacteria (P = 0.03) forming significantly different proportions of the microbiota. The only significant difference in composition between those farms that routinely reported antimicrobial use and those that did not was in one unclassified Bacteroidetes (P < 0.05) and no differences were identified at the phylum level. CONCLUSIONS: Rabbit husbandry and diet, in addition to season, significantly influence the fecal microbiota composition of domestic rabbits, while age of the rabbit post-weaning has minimal impact. PMID- 29703197 TI - Phylogenomics resolves the evolutionary chronicle of our squirting closest relatives. AB - A recent paper in BMC Biology has resolved the family relationships of sea squirts, one of our closest invertebrate relatives, by using a large phylogenomic data set derived from available genomes and newly generated transcriptomes. The work confirms previous ideas that ascidians (the sea squirts) are not monophyletic, as they include some pelagic jelly-like relatives, and proposes a chronogram for a group that has been difficult to resolve due to their accelerated genome evolution.See research article: https://bmcbiol.biomedcentral.com/articles/10.1186/s12915-018-0499-2. PMID- 29703198 TI - A novel chimeric CYP11B2/CYP11B1 combined with a new p.L340P CYP11B1 mutation in a patient with 11OHD: case report. AB - BACKGROUND: 11beta-Hydroxylase deficiency (11OHD) is a common form of congenital adrenal hyperplasia that has been shown to result from inactivating CYP11B1 mutations, and pathogenic CYP11B2/CYP11B1 chimeras contribute to a minority of cases. Heterozygote cases (chimeras combined with missense mutation) are very rare, and genetic analysis of these cases is difficult. CASE PRESENTATION: We describe an 11OHD patient presenting with precocious pseudopuberty and hypokalemia hypertension who harbored a chimeric CYP11B2/CYP11B1 with a novel breakage point located at g.9559-9742 of CYP11B2. Interestingly, the other allele exhibited a new mutation, p.L340P, in CYP11B1. Bioinformatics and molecular dynamics simulation indicated that p.L340P decreased the stability and changed the surface configuration of 11beta-hydroxylase, indicating a disease-causing mutation. Further pedigree study, PCR and next-generation sequencing indicated that the proband carried both the chimera and p.L340P, and coexistence of the two increased the severity of 11OHD in this family. After treatment with combined medications, blood pressure and clinical parameters improved. CONCLUSIONS: Our results suggest that chimera screening and CYP11B1 mutation screening should be simultaneously conducted, and pedigree study is necessary. PMID- 29703199 TI - Unfolding the values of work - therapists' experience of addressing the return to work process in occupational rehabilitation based on Acceptance and Commitment Therapy. AB - BACKGROUND: Facilitating return to work can be challenging due to the complexity of work disability. Few studies have examined rehabilitation programs based on Acceptance and Commitment Therapy that intend to support return to work, and none have investigated therapists' experience with providing such programs. The aim of this study was therefore to explore therapists' experience of addressing the return to work process in an inpatient occupational rehabilitation program based on Acceptance and Commitment Therapy. METHODS: This was a qualitative interview study supported by participant observation. Therapists were interviewed regarding their experiences with addressing return to work in an inpatient occupational rehabilitation program based on Acceptance and Commitment Therapy. In addition, the rehabilitation program was investigated through participant observation. The interviews were analysed according to Interpretative Phenomenological Analysis and informed by an analysis of field notes from the participant observation. RESULTS: Acceptance and Commitment Therapy was experienced as a meaningful approach to facilitate return to work, as it allowed therapists to address all relevant aspects of the individual participant's life that might influence work participation. The therapists' twofold goal was to support participants in building both a meaningful life and sustainable work participation. To do so, they attempted to instil long-term and interrelated processes concerning ownership, causes of sick leave, relation to expectations, the values of work, and the scope of agency. CONCLUSION: Unfolding values connected to work participation might reconcile the tension between work and family life by integrating work with other areas of life. Providing work participation with personal meaning also seems especially commensurable with a context where economy presents a poor incentive for return to work. Therapists should, however, be attentive to the need to secure the prominence of return to work by relating participants' chosen themes explicitly to their return to work process. Therapists should also be aware of the dilemma that may arise when they attempt to refrain from providing advice while simultaneously encouraging actions they consider appropriate to facilitate sustainable work participation. In addition, having an individual-oriented approach to occupational rehabilitation may obscure the extent to which return to work is a multi-stakeholder process. PMID- 29703200 TI - Characterization of Plasmodium falciparum and Plasmodium vivax recent exposure in an area of significantly decreased transmission intensity in Central Vietnam. AB - BACKGROUND: In Vietnam, malaria transmission has been reduced to very low levels over the past 20 years, and as a consequence, the country aims to eliminate malaria by 2030. This study aimed to characterize the dynamics and extent of the parasite reservoir in Central Vietnam, in order to further target elimination strategies and surveillance. METHODS: A 1-year prospective cohort study (n = 429) was performed in three rural communities in Quang Nam province. Six malaria screenings were conducted between November 2014 and November 2015, including systematic clinical examination and blood sampling for malaria parasite identification, as well as molecular and serological analysis of the study population. Malaria infections were detected by light microscopy (LM) and quantitative real time PCR (qPCR), while exposure to Plasmodium falciparum and Plasmodium vivax was measured in the first and last survey by ELISA for PfAMA1, PfGLURP R2, PvAMA1, and PvMSP1-19. Classification and regression trees were used to define seropositivity and recent exposure. RESULTS: Four malaria infections (2 P. falciparum, 2 P. vivax) were detected in the same village by qPCR and/or LM. No fever cases were attributable to malaria. At the same time, the commune health centre (serving a larger area) reported few cases of confirmed malaria cases. Nevertheless, serological data proved that 13.5% of the surveyed population was exposed to P. falciparum and/or P. vivax parasites during the study period, of which 32.6% were seronegative at the start of the study, indicating ongoing transmission in the area. Risk factor analysis for seroprevalence and exposure to P. falciparum and/or P. vivax identified structural or economic risk factors and activity/behaviour-related factors, as well as spatial heterogeneity at the village level. CONCLUSIONS: Previous studies in Central Vietnam demonstrated high occurrence of asymptomatic and sub-microscopic infections. However, in this study very few asymptomatic infections were detected despite serological evidence of continued transmission. Nonetheless, the factors associated with spatial heterogeneity in transmission could be evaluated using serological classification of recent exposure, which supports the usefulness of serological methods to monitor malaria transmission. PMID- 29703201 TI - Factors that cause endodontic failures in general practices in Japan. AB - BACKGROUND: Bacterial biofilms that develop on root surfaces outside apical foramens have been found to be associated with refractory periapical periodontitis. However, several other factors cause endodontic failures apart from extraradicular biofilms. The aim of this study was to identify the factors causing endodontic failures in general practices in Japan. METHODS: Patients diagnosed as having refractory periapical periodontitis by general practitioners and who requested endodontic treatment at Osaka University Dental Hospital were selected by checking medical records from April 2009 to March 2013. Factors causing endodontic failures were identified. RESULTS: A total of 103 teeth were selected, and 76 teeth completed root-canal treatment. Tooth extractions were required for 18 teeth after or without endodontic treatment. Six teeth required apicoectomy after endodontic treatment. One tooth needed hemisection. One tooth needed intentional replantation. One tooth needed adhesion and replantation. The main causes of treatment failure were open apices (24 teeth), perforation (18 teeth), and root fracture (13 teeth). In six teeth with open apices that required apicoectomy or extraction, extraradicular biofilms may have been related to endodontic failure. CONCLUSIONS: Most endodontic cases diagnosed with refractory periapical periodontitis by general practitioners were compromised by any other factors rather than extraradicular biofilms. PMID- 29703202 TI - Molecular characterization of a porcine teschovirus HuN-1 isolate proliferating in PK-15 cell. AB - BACKGROUND: Porcine teschoviruses (PTVs) are small non-enveloped viruses with single-stranded, positive sense genomic RNA, belonging to the family Picornaviridae. Natural infections of teschoviruses are limited to pigs. RESULTS: In this study, a PTV HuN-1 was found that it could be proliferated in PK-15 cell, and it came from the pig fecal samples from Hunan province, in central China. The complete genome of the HuN-1 was amplified by RT-PCR and sequenced. The complete genome of HuN-1 isolate is 7098 nt, which shares the highest sequence identity (85.9%) with the PTV 8 strain of Jilin/2003/2 and Fuyu/2009/2. The HuN-1 isolate contains only one ORF (from 320 to 7039 nt) coding a 2240 amino acid polyprotein. Aligned sequences show that more mutations occurred in the structural region than in the nonstructural region. Phylogenetic analysis showed that HuN-1 isolate did not clustered with the hitherto reported strains, according to P1 sequences, forming a subgroup in the PTV cluster. CONCLUSION: In this study, complete genome of PTV HuN-1 was cloned and sequenced. Detection and characterization of further PTV strains from different geographic areas are important to understand the worldwide distribution and heterogeneity (serotype) of PTVs and their association with symptomatic infections in pigs. PMID- 29703203 TI - Effects of detraining and retraining on muscle energy-sensing network and meteorin-like levels in obese mice. AB - BACKGROUND: Increased intramuscular peroxisome proliferator-activated receptor gamma coactivator-1alpha (PGC-1alpha) with exercise directly or indirectly affects other tissues, but the effector pathway of PGC-1alpha has not been clearly elucidated. The purpose of this study was to investigate the effect of exercise and/or dietary change on the protein levels of the soleus muscle energy sensing network and meteorin-like (Metrnl), and additionally to analyze the detraining and retraining effects in high-fat diet (HFD)-induced obese mice. METHODS: One hundred male C57BL/6 mice were divided into normal-diet + sedentary (CO, n = 20) and HFD + sedentary (HF, n = 80) groups, and obesity was induced in the HF group through consumption of a 45% HFD for 6 weeks. The HF group was subdivided into HF only (n = 20), HF + training (HFT, n = 20), dietary change + sedentary (HFND, n = 20), and HFND + training (HFNDT, n = 20) groups, and the mice in the training groups underwent a treadmill training for 8 weeks, 5 times per week, 40 min per day. The HFT and HFNDT groups underwent 8-week training, 8 week detraining, and 4-week retraining. RESULTS: An 8-week training was effective in increasing the protein levels of soleus muscle AMP-activated protein kinase (AMPK), PGC-1alpha, and plasma Metrnl in the obese mice (P < 0.05). Moreover, exercise in obesity reduced body weight (P < 0.05), and exercise with dietary conversion was effective in reducing body weight (P < 0.05) and fat mass (P < 0.05) after 8-week training. 8-week detraining restored the increased protein level to the pre-exercise state, but, the previous exercise effect in body weight and fat mass (P < 0.05) of the HFNDT group remained until the end of 4-week detraining. 4-week retraining was effective in increasing the protein levels of soleus muscle AMPK, PGC-1alpha, blood Metrnl (P < 0.05), and reducing in body weight (P < 0.05) and fat mass (P < 0.05), when retraining with dietary change. CONCLUSIONS: The results of this study suggest that regular exercise is indispensable to reduce body weight and fat mass through upregulation of the muscle energy-sensing network and Metrnl protein levels, and retraining with dietary change is necessary to obtain the retraining effects more quickly. PMID- 29703204 TI - Exploring end-of-life interaction in dyads of parents and adult children: a protocol for a mixed-methods study. AB - BACKGROUND: A considerable number of terminally-ill adult children are outlived by at least one parent and receive palliative care prior to their death. At the same time, adult children continue to be confronted with their parents' terminal illnesses and end-of-life situations. The current study explores the specifics of dyadic interaction at the end of life between a) adult children suffering from a life-threatening disease and their parents, and b) terminally ill parents and their adult children. METHODS: This prospective observational study aims at filling the existing gap on adult child-parent interaction specifics at the end of life using an exploratory mixed-methods framework. The mixed-methods framework combines a qualitative face-to face interview and quantitative self-report questionnaires to study the topic at hand. The qualitative interview will focus on experiences, expectations, and wishes with regard to dyadic communication, information about illness and prognosis, expressed and perceived burden and support as well as caregiving role at the end of life. The questionnaires will cover socio-demographics, loneliness, attachment style, social support, and emotional closeness. DISCUSSION: The research group is currently adjusting a semi structured interview guide and questionnaire instructions based on the results of a multiprofessional scientific advisory board meeting (Jan. 2018). In a next step, and prior to qualitative and quantitative data collection, the questionnaires will be piloted on patients and their family members in a palliative care setting. The main expected results are i) a description of the specifics of the interaction within and between both dyads, ii) the development of hypotheses and a theoretical framework on the specifics, similarities, and differences for both study groups, and iii) clinical conclusions on specific psychosocial care needs of both groups. TRIAL REGISTRATION: The study was registered prospectively in the Health Services Research Germany register (Versorgungsforschung Deutschland - Datenbank) (Registration N degrees VfD_Dy@EoL_17_003897; date of registration: November 22, 2017) and in the German Clinical Trials Register (Deutsches Register Klinischer Studien) (Registration N degrees DRKS00013206 ; date of registration: October 27, 2017). The study is visible in the International Clinical Trials Registry Platform Search Portal of the World Health Organization under the German Clinical Trials Register number. PMID- 29703205 TI - Item reduction and validation of the Chinese version of diabetes quality-of-life measure (DQOL). AB - BACKGROUND: The Diabetes Quality-of-Life (DQOL) Measure is a 46-item diabetes specific quality of life instrument. The original English version of the DQOL has been translated into Chinese after cultural adaption, and the Chinese DQOL has been validated in the Chinese diabetic patient population and used in diabetes related studies. There are two recognized problems with the Chinese DQOL: 1) the instrument is too long, and 2) the non-response rate of certain items is relatively high. This study aimed to develop and validate a short version for the Chinese DQOL. METHODS: Item reduction was conducted based on the classical test theory (CTT) and item response theory (IRT), each combined with exploratory factor analysis (EFA). The confirmatory factor analysis (CFA) and Spearman correlation coefficient were employed in validating the short versions. RESULTS: Both the study sample (n = 2,886) and the validation sample (n = 2,286) were from a longitudinal observation study of Chinese type 2 diabetic patients. The CTT kept 32 items, and the IRT kept 24 items from the original 46-item version. The two short versions were comparable in psychometric properties. CONCLUSION: The 24 item IRT-based short version of the Chinese DQOL was selected as the preferred short version because it imposes a lower burden on patients without compromising the psychometric properties of the instrument. PMID- 29703206 TI - Equity in patient experiences of primary care in community health centers using primary care assessment tool: a comparison of rural-to-urban migrants and urban locals in Guangdong, China. AB - BACKGROUND: The equity of rural-to-urban migrants' health care utilization is already on China's agenda. The Chinese government has been embarking on efforts to improve the financial and geographical accessibility of health care for migrants by strengthening primary care services and providing universal coverage. Patient experiences are equally vital to migrants' health care utilization. To our knowledge, no studies have focused on equity in the patient experiences between migrants and locals. Based on a patient survey from Guangdong, China, which has a large number of rural-to-urban migrants, our study assessed the equity in the primary care patient experiences between rural-to-urban migrants and urban locals in the same health insurance context, since different forms of insurance can affect the patient experiences of primary care. METHODS: We stratified our samples by different insurance types into three layers. We assessed primary care patient experiences using a validated Chinese version of the Primary Care Assessment Tool (PCAT), including eight primary care attributes. A 'PCAT total score' was calculated. Data were collected through face-to-face and one-on-one surveys in 2014. Propensity score matching (PSM) was used for each layer to generate comparable samples between rural-to-urban migrants and urban locals. Based on the matched dataset, a t-test was employed to compare the primary care patient experiences of the two groups. RESULTS: Using PSM, 220 patients in the rural-to-urban migrants group were matched to 220 patients in the urban locals group. After the matching, the observed confounding variables were balanced, and the PCAT scores were almost equal between the two groups. The only slight differences existed in the Urban Employee Basic Medical Insurance layer and in the without basic medical insurance coverage layer. CONCLUSIONS: Equity in the primary care patient experiences between rural-to-urban migrants and urban locals seems to have been achieved to some extent. However, there is room for improvement in the equity of coordination of care and comprehensiveness. Policy makers should consider strengthening these two dimensions by integrating the health care system. More attention should be focused on helping migrants break down language and cultural barriers and improving the patient-physician communication process. PMID- 29703207 TI - SGLT2 inhibition via dapagliflozin improves generalized vascular dysfunction and alters the gut microbiota in type 2 diabetic mice. AB - BACKGROUND: Type 2 diabetes (T2D) is associated with generalized vascular dysfunction characterized by increases in large artery stiffness, endothelial dysfunction, and vascular smooth muscle dysfunction. Sodium glucose cotransporter 2 inhibitors (SGLT2i) represent the most recently approved class of oral medications for the treatment of T2D, and have been shown to reduce cardiovascular and overall mortality. Although it is currently unclear how SGLT2i decrease cardiovascular risk, an improvement in vascular function is one potential mechanism. The aim of the current study was to examine if dapagliflozin, a widely prescribed STLT2i, improves generalized vascular dysfunction in type 2 diabetic mice. In light of several studies demonstrating a bi-directional relation between orally ingested medications and the gut microbiota, a secondary aim was to determine the effects of dapagliflozin on the gut microbiota. METHODS: Male diabetic mice (Db, n = 24) and control littermates (Con; n = 23) were randomized to receive either a standard diet or a standard diet containing dapagliflozin (60 mg dapagliflozin/kg diet; 0.006%) for 8 weeks. Arterial stiffness was assessed by aortic pulse wave velocity; endothelial function and vascular smooth muscle dysfunction were assessed by dilatory responses to acetylcholine and sodium nitroprusside, respectively. RESULTS: Compared to untreated diabetic mice, diabetic mice treated with dapagliflozin displayed significantly lower arterial stiffness (Db = 469 cm/s vs. Db + dapa = 435 cm/s, p < 0.05), and improvements in endothelial dysfunction (area under the curve [AUC] Db = 57.2 vs. Db + dapa = 117.0, p < 0.05) and vascular smooth muscle dysfunction (AUC, Db = 201.7 vs. Db + dapa = 285.5, p < 0.05). These vascular improvements were accompanied by reductions in hyperglycemia and circulating markers of inflammation. The microbiota of Db and Con mice were distinctly different, and dapagliflozin treatment was associated with minor alterations in gut microbiota composition, particularly in Db mice, although these effects did not conclusively mediate the improvements in vascular function. CONCLUSIONS: Dapagliflozin treatment improves arterial stiffness, endothelial dysfunction and vascular smooth muscle dysfunction, and subtly alters microbiota composition in type 2 diabetic mice. Collectively, the improvements in generalized vascular function may represent an important mechanism underlying the cardiovascular benefits of SGLT2i treatment. PMID- 29703208 TI - BADGE, a synthetic antagonist for PPARgamma, prevents steroid-related osteonecrosis in a rabbit model. AB - BACKGROUND: It was indicated that inhibition of PPARgamma probably represents a novel therapy for steroid-related osteonecrosis. In this study, we investigated the preventive effects of PPARgamma inhibition on steroid-related osteonecrosis in a rabbit model. METHODS: Rabbits were randomly divided into three groups (normal group, model group and BADGE group). Osteonecrosis was induced in rabbits in the model group and the BADGE group. The BADGE group also received bisphenol a diglycidyl ether(BADGE), a PPARgamma antagonist, for 6 weeks. RESULTS: Histopathological results indicated that rabbits treated with BADGE exhibited significantly reduced osteonecrotic changes, incidence of osteonecrosis and bone marrow adiposity. Furthermore, BADGE-treated rabbits exhibited reduced intraosseous pressure and increased femoral blood perfusion. Micro-computed tomography and bone histomorphometry indicated that the BADGE group exhibited significantly improved bone quality and mineral appositional rate compared with the model group. Furthermore, the BADGE group showed a significant increase in circulating levels of the bone formation marker osteocalcin and reduced levels of the bone resorption marker TRACP. Overall, BADGE-treated rabbits exhibited reduced marrow adiposity concomitant with improved bone formation. CONCLUSIONS: In conclusion, these observations demonstrated that pharmacological inhibition of PPARgamma might represent an effective therapy for steroid-related osteonecrosis in the near future. PMID- 29703209 TI - Catastrophic healthcare expenditure and impoverishment in tropical deltas: evidence from the Mekong Delta region. AB - BACKGROUND: Universal health coverage implies that people obtain the health services they need without experiencing financial hardship. While the factors contributing to catastrophic health expenditure (CHE) among households are well understood, few studies have examined this relationship in the context of environmentally vulnerable regions, such as tropical deltas. This study aims to examine the disparities in the prevalence of CHE and impoverishment due to out-of pocket (OOP) healthcare payments in the Mekong Delta in comparison with rest of Vietnam. It also intends to investigate the associations between economic and environmental shocks, CHE and the impoverishment from healthcare payments. METHODS: Using data from the Vietnam Household Living Standards Survey 2012, the prevalence of CHE was estimated from the fraction of healthcare costs in relation to household consumption expenditure. The poverty headcount was estimated using the total household consumption expenditure considering both with and without OOP expenditure for healthcare in comparison with the national poverty-line. Simple and multiple logistic regression models were used to examine the associations between geography, health systems, environmental and demographic variables and OOP healthcare expenditure related CHE, and impoverishment respectively. RESULTS: Both the level of OOP household healthcare expenditure and the proportion of households suffering from impoverishment as the result of such payments were higher in the Mekong Delta region compared to rest of Vietnam. Although the results from the multiple regression analysis showed that households in the Mekong Delta region were significantly less likely to suffer from CHE, they were significantly more likely to be impoverished due to OOP healthcare expenditure. While health insurance membership did not have a significant effect on either outcomes, households that faced an economic or an environmental shock in past 5 years were considerably more likely to suffer from CHE and impoverishment from OOP healthcare payments. CONCLUSIONS: The findings suggest that the financial protection capacity of health insurance schemes in Vietnam should be improved and expanded to reduce impoverishment as the result of OOP healthcare payments, particularly in the Mekong Delta region. Additional investments in disaster preparedness strategies can further help to reduce the financial burden of households in this environmentally vulnerable region. PMID- 29703210 TI - Telomerase regulation by the long non-coding RNA H19 in human acute promyelocytic leukemia cells. AB - BACKGROUND: Since tumor growth requires reactivation of telomerase (hTERT), this enzyme is a challenging target for drug development. Therefore, it is of great interest to identify telomerase expression and activity regulators. Retinoids are well-known inducers of granulocytic maturation associated with hTERT repression in acute promyelocytic leukemia (APL) blasts. In a maturation-resistant APL cell line, we have previously identified a new pathway of retinoid-induced hTERT transcriptional repression independent of differentiation. Furthermore, we reported the isolation of a cell variant resistant to this repression. Those cell lines could serve as unique tools to identify new telomerase regulators. METHODS: Using a microarray approach we identified the long non-coding RNA, H19 as a potential candidate playing a role in telomerase regulation. Expression of H19, hTERT, and hTR were examined by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). Telomerase activity was quantified by quantitative telomeric repeats amplification protocol (qTRAP). In vitro and in vivo assays were performed to investigate H19 function on telomerase expression and activity. RESULTS: We showed both in retinoid-treated cell lines and in APL patient cells an inverse relationship between the expression of H19 and the expression and activity of hTERT. Exploring the mechanistic link between H19 and hTERT regulation, we showed that H19 is able to impede telomerase function by disruption of the hTERT-hTR interaction. CONCLUSIONS: This study identifies a new way of telomerase regulation through H19's involvement and thereby reveals a new function for this long non-coding RNA that can be targeted for therapeutic purpose. PMID- 29703211 TI - Factors influencing quality of life in patients followed in the neurosonology laboratory for carotid stenosis. AB - BACKGROUND: Quality of life (QoL) is one of the main endpoints in stroke prevention or acute stroke treatment studies. The aim of the current study was to identify risk factors affecting the QoL of patients with carotid stenosis in stroke prevention. METHODS: Self-sufficient patients (50-80 years of age) with >=20% carotid artery stenosis followed in the neurosonology laboratory, and without any severe illnesses within the last 12 months, dementia, or psychiatric disorders were selected for the study after signing informed consent. Patients completed two standardized QoL questionnaires (WHOQoL-BREF and EQ-5D-3 L) and a visual pain scale, provided covariate variables (medication, age, gender, education, and social situation), and the blood pressure and body mass indexes were recorded. Logistic regression (forward stepwise method) was used to identify factors affecting the individual domains of QoL questionnaires. RESULTS: Of the 584 consecutive patients, 502 met the inclusion criteria and 344 completely filled both QoL questionnaires (164 men; mean age, 69.7 +/- 7.8 years). An independent predictor of worse QoL in all domains was pain. Independent factors decreasing the QoL were lower level of education and blood pressure in the physical health domain, female gender in the psychological domain, and male gender in the social relationships domain. Independent factors decreasing satisfaction with health status were female gender and higher blood pressure. Factors negatively influencing the satisfaction with the QoL were living alone, lower level of education, and higher diastolic blood pressure (WHOQoL-BREF). Factors negatively influencing mobility were age, male gender, living alone, lower level of education, and higher body mass index (EQ-5D-3 L; p < 0.05 in all cases). CONCLUSIONS: Pain, blood pressure, body mass index, education, living alone, gender, and age were associated with the QoL in patients with carotid stenosis. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02360137 . Registered on 26 January 2015. PMID- 29703212 TI - Identification of interneurons required for the aversive response of Caenorhabditis elegans to graphene oxide. AB - BACKGROUND: So far, how the animals evade the environmental nanomaterials is still largely unclear. In this study, we employed in vivo assay system of Caenorhabditis elegans to investigate the aversive behavior of nematodes to graphene oxide (GO) and the underlying neuronal basis. RESULTS: In this assay model, we detected the significant aversive behavior of nematodes to GO at concentrations more than 50 mg/L. Loss-of-function mutation of nlg-1 encoding a neuroligin with the function in connecting pre- and post-synaptic neurons suppressed the aversive behavior of nematodes to GO. Moreover, based on the neuron-specific activity assay, we found that the NLG-1 activity in AIY or AIB interneurons was required for the regulation of aversive behavior to GO. The neuron-specific activities of NLG-1 in AIY or AIB interneurons were also required for the regulation of GO toxicity. CONCLUSIONS: Using nlg-1 mutant as a genetic tool, we identified the AIY and AIB interneurons required for the regulation of aversive behavior to GO. Our results provide an important neuronal basis for the aversive response of animals to environmental nanomaterials. PMID- 29703213 TI - Individual odour signatures that mice learn are shaped by involatile major urinary proteins (MUPs). AB - BACKGROUND: Reliable recognition of individuals requires phenotypic identity signatures that are both individually distinctive and appropriately stable over time. Individual-specific vocalisations or visual patterning are well documented among birds and some mammals, whilst odours play a key role in social recognition across many vertebrates and invertebrates. Less well understood, though, is whether individuals are recognised through variation in cues that arise incidentally from a wide variety of genetic and non-genetic differences between individuals, or whether animals evolve distinctive polymorphic signals to advertise identity reliably. As a bioassay to understand the derivation of individual-specific odour signatures, we use female attraction to the individual odours of male house mice (Mus musculus domesticus), learned on contact with a male's scent marks. RESULTS: Learned volatile odour signatures are determined predominantly by individual differences in involatile major urinary protein (MUP) signatures, a specialised set of communication proteins that mice secrete in their urine. Recognition of odour signatures in genetically distinct mice depended on differences in individual MUP genotype. Direct manipulation using recombinant MUPs confirmed predictable changes in volatile signature recognition according to the degree of matching between MUP profiles and the learned urine template. Both the relative amount of the male-specific MUP pheromone darcin, which induces odour learning, and other MUP isoforms influenced learned odour signatures. By contrast, odour recognition was not significantly influenced by individual major histocompatibility complex genotype. MUP profiles shape volatile odour signatures through isoform-specific differences in binding and release of urinary volatiles from scent deposits, such that volatile signatures were recognised from the urinary protein fraction alone. Manipulation using recombinant MUPs led to quantitative changes in the release of known MUP ligands from scent deposits, with MUP-specific and volatile-specific effects. CONCLUSIONS: Despite assumptions that many genes contribute to odours that can be used to recognise individuals, mice have evolved a polymorphic combinatorial MUP signature that shapes distinctive volatile signatures in their scent. Such specific signals may be more prevalent within complex body odours than previously realised, contributing to the evolution of phenotypic diversity within species. However, differences in selection may also result in species-specific constraints on the ability to recognise individuals through complex body scents. PMID- 29703214 TI - Ultrasound-assessed diaphragmatic impairment is a predictor of outcomes in patients with acute exacerbation of chronic obstructive pulmonary disease undergoing noninvasive ventilation. AB - BACKGROUND: Ultrasound (US) evaluation of diaphragmatic dysfunction (DD) has proved to be a reliable technique in critical care. In this single-center prospective study, we investigated the impact of US-assessed DD on noninvasive ventilation (NIV) failure in patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and its correlation with the transdiaphragmatic pressure assessed using the invasive sniff maneuver (Pdi sniff). METHODS: A population of 75 consecutive patients with AECOPD with hypercapnic acidosis admitted to our respiratory intensive care unit (RICU) were enrolled. Change in diaphragm thickness (DeltaTdi) < 20% during tidal volume was the predefined cutoff for identifying DD+/- status. Correlations between DeltaTdi < 20% NIV failure and other clinical outcomes were investigated. Correlation between DeltaTdi and Pdi sniff values was analyzed in a subset of ten patients. RESULTS: DD+ patients had a higher risk for NIV failure than DD- patients (risk ratio, 4.4; p < 0.001), and this finding was significantly associated with higher RICU, in-hospital, and 90-day mortality rates; longer mechanical ventilation duration; higher tracheostomy rate; and longer RICU stay. Huge increases in NIV failure (HR, 6.2; p < 0.0001) and 90-day mortality (HR, 4.7; p = 0.008) in DD+ patients were found by Kaplan-Meier analysis. DeltaTdi highly correlated with Pdi sniff (Pearson's r = 0.81; p = 0.004). DeltaTdi < 20% showed better accuracy in predicting NIV failure than baseline pH value and early change in both arterial blood pH and partial pressure of carbon dioxide following NIV start (AUCs 0.84 to DTdi < 20%, 0.51 to pH value at baseline, 0.56 to early change in arterial blood pH following NIV start, and 0.54 to early change in partical pressure of carbon dioxide following NIV start, respectively; p < 0.0001). CONCLUSIONS: Early and noninvasive US assessment of DD during severe AECOPD is reliable and accurate in identifying patients at major risk for NIV failure and worse prognosis. PMID- 29703215 TI - Inequalities in health and health risk factors in the Southern African Development Community: evidence from World Health Surveys. AB - BACKGROUND: Socioeconomic inequalities in health have been documented in many countries including those in the Southern African Development Community (SADC). However, a comprehensive assessment of health inequalities and inequalities in the distribution of health risk factors is scarce. This study specifically investigates inequalities both in poor self-assessed health (SAH) and in the distribution of selected risk factors of ill-health among the adult populations in six SADC countries. METHODS: Data come from the 2002/04 World Health Survey (WHS) using six SADC countries (Malawi, Mauritius, South Africa, Swaziland, Zambia and Zimbabwe) where the WHS was conducted. Poor SAH is reporting bad or very bad health status. Risk factors such as smoking, heavy drinking, low fruit and vegetable consumption and physical inactivity were considered. Other environmental factors were also considered. Socioeconomic status was assessed using household expenditures. Standardised and normalised concentration indices (CIs) were used to assess socioeconomic inequalities. A positive (negative) concentration index means a pro-rich (pro-poor) distribution where the variable is reported more among the rich (poor). RESULTS: Generally, a pro-poor socioeconomic inequality exists in poor SAH in the six countries. However, this is only significant for South Africa (CI = - 0.0573; p < 0.05), and marginally significant for Zambia (CI = - 0.0341; P < 0.1) and Zimbabwe (CI = - 0.0357; p < 0.1). Smoking and inadequate fruit and vegetable consumption were significantly concentrated among the poor. Similarly, the use of biomass energy, unimproved water and sanitation were significantly concentrated among the poor. However, inequalities in heavy drinking and physical inactivity are mixed. Overall, a positive relationship exists between inequalities in ill-health and inequalities in risk factors of ill-health. CONCLUSION: There is a need for concerted efforts to tackle the significant socioeconomic inequalities in ill-health and health risk factors in the region. Because some of the determinants of ill-health lie outside the health sector, inter-sectoral action is required. PMID- 29703216 TI - Simple paired heavy- and light-chain antibody repertoire sequencing using endoplasmic reticulum microsomes. AB - Existing methods for paired antibody heavy- and light-chain repertoire sequencing rely on specialized equipment and are limited by their commercial availability and high costs. Here, we report a novel simple and cost-effective emulsion-based single-cell paired antibody repertoire sequencing method that employs only basic laboratory equipment. We performed a proof-of-concept using mixed mouse hybridoma cells and we also showed that our method can be used for discovery of novel antigen-specific monoclonal antibodies by sequencing human CD19+ B cell IgM and IgG repertoires isolated from peripheral whole blood before and seven days after Td (Tetanus toxoid/Diphtheria toxoid) booster immunization. We anticipate broad applicability of our method for providing insights into adaptive immune responses associated with various diseases, vaccinations, and cancer immunotherapies. PMID- 29703217 TI - The release of cardioprotective humoral factors after remote ischemic preconditioning in humans is age- and sex-dependent. AB - BACKGROUND: Preclinical and proof-of-concept studies suggest a cardioprotective effect of remote ischemic preconditioning (RIPC). However, two major clinical trials (ERICCA and RIPHeart) failed to show cardioprotection by RIPC. Aging and gender might be confounding factors of RIPC affecting the inter-organ signalling. Theoretically, confounding factors might prevent the protective potency of RIPC by interfering with cardiac signalling pathways, i.e. at the heart, and/or by affecting the release of humoral factor(s) from the remote organ, e.g. from the upper limb. This study investigated the effect of age and sex on the release of cardioprotective humoral factor(s) after RIPC in humans. METHODS: Blood samples were taken from young and aged, male and female volunteers before (control) and after RIPC (RIPC). To investigate the protective potency of the different plasma groups obtained from the human volunteers, isolated perfused hearts of young rats were used as bioassay. For this, hearts were perfused with the volunteer plasma (0.5% of coronary flow) before hearts underwent global ischemia and reperfusion. In addition, to characterize the protective potency of humoral factor(s) after RIPC to initiate protection not only in young but also aged hearts, plasma from young male volunteers were transferred to isolated hearts of aged rats. At the end of the experimental protocol, infarct sizes were determined by TTC-staining (expressed as % of left ventricle). RESULTS: RIPC plasma of young male volunteers reduced infarct size in young rat hearts from 47 +/- 5 to 31 +/- 10% (p = 0.02). In contrast, RIPC plasma of aged male volunteers had no protective effect. Infarct size after application of control plasma of young female volunteers was 33 +/- 10%, and female RIPC plasma did not lead to an infarct size reduction. RIPC plasma of old female initiated no cardioprotection. RIPC plasma of young male volunteers reduced infarct size in isolated hearts from aged rats (41 +/- 5% vs. 51 +/- 5%; p < 0.001). CONCLUSIONS: The release of humoral factor(s) into the blood after RIPC in humans is affected by both age and sex. In addition, these blood borne factor(s) are capable to initiate cardioprotection within the aged heart. PMID- 29703218 TI - Physical activity and nutrition intervention for Singaporean women aged 50 years and above: study protocol for a randomised controlled trial. AB - BACKGROUND: The majority of the older Singaporean women aged 50 years and above are physically inactive and have unhealthy dietary habits, placing them at 'high risk' of non-communicable diseases (NCDs). The adoption of regular physical activity (PA) and a healthy diet are essential lifestyle behaviours to reduce this risk. This randomised controlled trial (RCT) involves the development, implementation and evaluation of a PA and nutrition programme for community dwelling Singaporean women who currently attend recreational centres (RCs are public facilities supporting social leisure activities) in their local area. The intervention will be developed after conducting formative evaluation with RC attendees and managers through focus group discussions and pilot testing of resources (i.e. surveys, accelerometers, and health booklets). Programme ambassadors (trained, certified fitness instructors and nutritionists) will deliver all sessions in English and Mandarin; implement classes to meet participants' varying needs; and conduct sessions at different times at convenient venues. Social Cognitive Theory (SCT) has been selected as the theoretical framework to inform intervention strategies as it explores the interactions of human behaviour with the environment and has been found to be valuable when developing behavioural change interventions particularly in older adults (J Gerontol B Psychol Sci Soc Sci 67B(1):18-26, 2012; Obesity Reviews 15(12):983-95, 2014). Its major construct, self-efficacy, is invaluable in achieving successful behaviour change, such as increasing levels of PA or improving dietary intake (Trials. 2017; https://doi.org/10.1186/s13063-016-1771-9 ; Psychol Health Med 18(6):714-24, 2013). METHODS: The development and implementation of the PA and nutrition intervention strategies will be guided by SCT and Motivational interviewing (MI) and implemented by trained programme ambassadors at the RCs. Sixty RCs located in Singapore will be selected from five major geographical districts and randomly allocated to the intervention (n = 30) or control (n = 30) cluster. A sample of 600 (intervention n = 300; control n = 300) women aged 50 years and above will then be recruited from these 60 centres and only the intervention group will be enrolled into the PA and nutrition intervention. It is hypothesised that by the end of the intervention, the intervention group participants compared to the control group will show significantly greater improvements in the following outcome variables: PA and dietary behaviours, health-related quality of life, objective measures of PA, anthropometric, lipid and glucose profiles. Data will be collected at baseline and 6 months and analysed using mixed regression models. DISCUSSION: It is anticipated that recruitment, retention and compliance of participants will be challenging due to the target group being unfamiliar with such community-based research programmes. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry, ACTRN12617001022358. Registered on 14 July 2017. https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=372984&isReview= rue. PMID- 29703219 TI - Primary mass casualty incident triage: evidence for the benefit of yearly brief re-training from a simulation study. AB - BACKGROUND: Triage is a mainstay of early mass casualty incident (MCI) management. Standardized triage protocols aim at providing valid and reproducible results and, thus, improve triage quality. To date, there is little data supporting the extent and content of training and re-training on using such triage protocols within the Emergency Medical Services (EMS). The study objective was to assess the decline in triage skills indicating a minimum time interval for re-training. In addition, the effect of a one-hour repeating lesson on triage quality was analyzed. METHODS: A dummy based trial on primary MCI triage with yearly follow-up after initial training using the ASAV algorithm (Amberg Schwandorf Algorithm for Primary Triage) was undertaken. Triage was assessed concerning accuracy, sensitivity, specificity, over-triage, under-triage, time requirement, and a comprehensive performance measure. A subgroup analysis of professional paramedics was made. RESULTS: Nine hundred ninety triage procedures performed by 51 providers were analyzed. At 1 year after initial training, triage accuracy and overall performance dropped significantly. Professional paramedic's rate of correctly assigned triage categories deteriorated from 84 to 71%, and the overall performance score decreased from 95 to 90 points (maximum = 100). The observed decline in triage performance at 1 year after education made it necessary to conduct re-training. A brief didactic lecture of 45 min duration increased accuracy to 88% and the overall performance measure to 97. CONCLUSIONS: To improve disaster preparedness, triage skills should be refreshed yearly by a brief re-education of all EMS providers. PMID- 29703220 TI - European principles of inhibitor management in patients with haemophilia. AB - BACKGROUND: In spite of recent major advances in the understanding and treatment of inhibitor development in patients with haemophilia, multidisciplinary management of many of these patients remains suboptimal and highly heterogenous across Europe. METHODS: Following a series of multidisciplinary meetings and a review of the literature, the European haemophilia community of health professionals and patients jointly defined practical optimum standards for ensuring and harmonizing treatment and care for patients with an inhibitor. RESULTS: Ten complementary principles for the management of inhibitors in haemophilia have been developed, emphasizing the importance and benefits of a centralized, multidisciplinary, expert and holistic approach. CONCLUSIONS: This document will serve as a benchmark to improve the multidisciplinary and practical management of patients with inhibitor. Implementation and adherence to each of these principles should have a major positive impact on the management and outcomes of patients developing an inhibitor. PMID- 29703221 TI - Conservation of the separase regulatory domain. AB - : ?: We report a protein sequence analysis of the cell cycle regulatory protease, separase. The sequence and structural conservation of the C-terminal protease domain has long been recognized, whereas the N-terminal regulatory domain of separase was reported to lack detectable sequence similarity. Here we reveal significant sequence conservation of the separase regulatory domain and report a discovery of a cysteine motif (CxCxxC) conserved in major lineages of Metazoa including nematodes and vertebrates. This motif is found in a solvent exposed linker region connecting two TPR-like helical motifs. Mutation of this motif in Caenorhabditis elegans separase leads to a temperature sensitive hypomorphic protein. Conservation of this motif in organisms ranging from C. elegans to humans suggests its functional importance. REVIEWERS: This article was reviewed by Lakshminarayan Iyer and Michael Galperin. PMID- 29703222 TI - The epidemiology of mild traumatic brain injury: the Trondheim MTBI follow-up study. AB - BACKGROUND: Mild traumatic brain injury (MTBI) is a frequent medical condition, and some patients report long-lasting problems after MTBI. In order to prevent MTBI, knowledge of the epidemiology is important and potential bias in studies should be explored. Aims of this study were to describe the epidemiological characteristics of MTBI in a Norwegian area and to evaluate the representativeness of patients successfully enrolled in the Trondheim MTBI follow up study. METHODS: During 81 weeks in 2014 and 2015, all persons aged 16-60 years, presenting with possible MTBI to the emergency department (ED) at St. Olavs Hospital, Trondheim University Hospital or to Trondheim municipal outpatient ED, were evaluated for participation in the follow-up study. Patients were identified by CT referrals and patient lists. Patients who were excluded or missed for enrolment in the follow-up study were recorded. RESULTS: We identified 732 patients with MTBI. Median age was 28 years, and fall was the most common cause of injury. Fifty-three percent of injuries occurred during the weekend. Only 29% of MTBI patients were hospitalised. Study specific exclusion criteria were present in 23%. We enrolled 379 in the Trondheim MTBI follow-up study. In this cohort, Glasgow Coma Scale score was 15 at presentation in 73%; 45% of patients were injured under the influence of alcohol. Patients missed for inclusion were significantly more often outpatients, females, injured during the weekend, and suffering violent injuries, but differences between enrolled and not enrolled patients were small. CONCLUSION: Two thirds of all patients with MTBI in the 16-60 age group were treated without hospital admission, patients were often young, and half of the patients presented during the weekend. Fall was the most common cause of injury, and patients were commonly injured under the influence of alcohol, which needs to be addressed when considering strategies for prevention. The Trondheim MTBI follow-up study comprised patients who were highly representative for the underlying epidemiology of MTBI. PMID- 29703223 TI - Comparison of exercise intensity during four early rehabilitation techniques in sedated and ventilated patients in ICU: a randomised cross-over trial. AB - BACKGROUND: In the ICU, out-of-bed rehabilitation is often delayed and in-bed exercises are generally low-intensity. Since the majority of rehabilitation is carried out in bed, it is essential to carry out the exercises that have the highest intensity. The aim of this study was to compare the physiological effects of four common types of bed exercise in intubated, sedated patients confined to bed in the ICU, in order to determine which was the most intensive. METHODS: A randomised, single-blind, placebo-controlled crossover trial was carried out to evaluate the effects of four bed exercises (passive range of movements (PROM), passive cycle-ergometry, quadriceps electrical stimulation and functional electrical stimulation (FES) cycling) on cardiac output. Each exercise was carried out for ten minutes in ventilated, sedated patients. Cardiac output was recorded using cardiac Doppler ultrasound. The secondary aims were to evaluate right heart function and pulmonary and systemic artery pressures during the exercises, and the microcirculation of the vastus lateralis muscle. RESULTS: The results were analysed in 19 patients. FES cycling was the only exercise that increased cardiac output, with a mean increase of 1 L/min (15%). There was a concomitant increase in muscle oxygen uptake, suggesting that muscle work occurred. FES cycling thus constitutes an effective early rehabilitation intervention. No muscle or systemic effects were induced by the passive techniques. CONCLUSION: Most bed exercises were low-intensity and induced low levels of muscle work. FES cycling was the only exercise that increased cardiac output and produced sufficient intensity of muscle work. Longer-term studies of the effect of FES cycling on functional outcomes should be carried out. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02920684 . Registered on 30 September 2016. Prospectively registered. PMID- 29703224 TI - Factors associated with amputation among patients with diabetic foot ulcers in a Saudi population. AB - OBJECTIVES: A prospective study was conducted at the Armed Forces Hospital, Dhahran, Saudi Arabia, between January 2015 and December 2016 to identify the risk factors associated with amputation among diabetic foot ulcers DFUs patients. RESULTS: In total, 82 patients were recruited. Fifty-five of the patients were males (67.07%), the mean (SD) age of the participants was 60 (+/- 11.4) years, the mean duration of diabetes was 8.5 (+/- 3.7) years, and the mean haemoglobin A1c was 4.8 (+/- 2.8)%. In Univariate analysis, older age and high white blood cell count (WBC) were factors associated with amputation (OR = 1.1, 95% CI = 1 1.1, P = 0.012; and OR = 383, 95% CI = 7.9-18,665, P = 0.003, respectively). On the other hand, an ischaemic ulcer was half as likely as a neuropathic ulcer to lead to amputation (OR = 0.5, 95% CI = 0.3-0.9, P = 0.036), and a higher Wagner's grade was found to be protective against amputation OR = 14.5, 95% CI = 4.3-49.4, P < 0.001. In conclusion, the current study showed that although a number of factors have been described to complicate diabetic ulcers by different researchers, none of those factors were identified in our study apart from older age and high WBC. PMID- 29703225 TI - Cardiopulmonary bypass reduces myocardial oxidative stress, inflammation and increases c-kit+CD45- cell population in newborns. AB - BACKGROUND: The aim of this study was to characterize the influence of cardiopulmonary bypass (CPB) on myocardial remodeling in newborns and children. METHODS: Biopsies from the right atrium were taken before and after CPB from 4 newborns (5-11 days old) and 7 children (8 months-16 years old). Immunostainings on 10 um heart tissue frozen sections were performed to detect c-kit+ cells, leukocytes (CD45+ cells), Ki67+ cycling cells. The percentage of 8-hydroxy guanosine (8-dOHG)+cardiomyocytes and non-cardiomyocytes [(8-dOHG)+-index] were determined to quantify oxidative stress. RESULTS: Delta c-kit+CD45- cells (resident cardiac stem cells) were increased in newborns (2.2 +/- 1.9/mm2) and decreased in children - 1.5 +/- 0.7/mm2, p < 0.01. The (8-dOHG)+-index was reduced by 43% in newborns and by 20% in children. CPB did not influence cardiac cell turnover; high cell proliferation was seen in newborns before and after CPB. Cardiopulmonary bypass significantly decreased the leucocyte infiltration in newborns to 40 +/- 8%, p < 0.05, but not in children. Infiltration with eosinophils (eosinophils/CD45%) was completely abolished in the myocardium of newborns p < 0.05 and reduced to 22 +/- 8% in children after CPB, n.s. CONCLUSIONS: Immediate response and remodeling of the myocardium to CPB differs between newborns, older infants and children. Especially an increased number of c kit expressing CD45 cells after CPB were seen in neonates in comparison to children. The clinical value of such observation needs to be further assessed in larger cohorts of patients. PMID- 29703227 TI - Revealed preferences towards the appraisal of orphan drugs in Poland - multi criteria decision analysis. AB - BACKGROUND: A Multi Criteria Decision Analysis (MCDA) technique was adopted to reveal the preferences of the Appraisal Body of the Polish HTA agency towards orphan drugs (OMPs). RESULTS: There were 34 positive and 23 negative HTA recommendations out of 54 distinctive drug-indication pairs. The MCDA matrix consisted of 13 criteria, seven of which made the most impact on the HTA process. Appraisal of clinical evidence, cost of therapy, and safety considerations were the main contributors to the HTA guidance, whilst advancement of technology and manufacturing costs made the least impact. CONCLUSIONS: MCDA can be regarded as a valuable tool for revealing decision makers' preferences in the healthcare sector. Given that only roughly half of all criteria included in the MCDA matrix were deemed to make an impact on the HTA process, there is certainly some room for improvement with respect to the adaptation of a new approach towards the value assessment of OMPs in Poland. PMID- 29703226 TI - Individualised short-term therapy for adolescents impaired by attention deficit/hyperactivity disorder despite previous routine care treatment (ESCAadol) Study protocol of a randomised controlled trial within the consortium ESCAlife. AB - BACKGROUND: Despite the high persistence rate of attention-deficit/hyperactivity disorder (ADHD) throughout the lifespan, there is a considerable gap in knowledge regarding effective treatment strategies for adolescents with ADHD. This group in particular often shows substantial psychosocial impairment, low compliance and insufficient response to psychopharmacological interventions. Effective and feasible treatments should further consider the developmental shift in ADHD symptoms, comorbidity and psychosocial adversity as well as family dysfunction. Thus, individualised interventions for adolescent ADHD should comprise a multimodal treatment strategy. The randomised controlled ESCAadol study addresses the needs of this patient group and compares the outcome of short-term cognitive behavioural therapy with parent-based telephone-assisted self-help. METHODS/DESIGN: In step 1, 160 adolescents aged 12 to 17 years with a diagnosis of ADHD will undergo a treatment as usual (TAU) observation phase of 1 month. In step 2, those still severely affected are randomised to the intervention group with an Individualised Modular Treatment Programme (IMTP) or a telephone-assisted self-help programme for parents (TASH) as an active control condition. The IMTP was specifically designed for the needs of adolescent ADHD. It comprises 10 sessions of individual cognitive behavioural therapy with the adolescents and/or the parents, for which participants choose three out of 10 available focus modules (e.g. organisational skills and planning, emotion regulation, problem solving and stress management, dysfunctional family communication). TASH combines a bibliotherapeutic component with 10 counselling sessions for the parents via telephone. Primary outcome is the change in ADHD symptoms in a clinician-rated diagnostic interview. Outcomes are assessed at inclusion into the study, after the TAU phase, after the intervention phase and after a further 12-week follow-up period. The primary statistical analysis will be by intention-to-treat, using linear regression models. Additionally, we will analyse psychometric and biological predictors and moderators of treatment response. DISCUSSION: ESCAadol compares two short-term non-pharmacological interventions as cost-efficient and feasible treatment options for adolescent ADHD, addressing the specific needs and obstacles to treatment success in this group. We aim to contribute to personalised medicine for adolescent ADHD intended to be implemented in routine clinical care. TRIAL REGISTRATION: German Clinical Trials Register (DRKS), Current Controlled Trial DRKS00008974, http://apps.who.int/trialsearch/Trial2.aspx?TrialID=DRKS00008974 ; http://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS0000 974 ; Registered on 28 December 2015. PMID- 29703228 TI - Assessment of temperatures in the vaccine cold chain in two provinces in Lao People's Democratic Republic: a cross-sectional pilot study. AB - OBJECTIVE: All childhood vaccines, except the oral polio vaccine, should be kept at 2-8 degrees C, since the vaccine potency can be damaged by heat or freezing temperature. A temperature monitoring study conducted in 2008-2009 reported challenges in cold chain management from the provincial level downwards. The present cross-sectional pilot study aimed to assess the current status of the cold chain in two provinces (Saravan and Xayabouly) of Lao People's Democratic Republic between March-April 2016. Two types of temperature data loggers recorded the temperatures and the proportions of time exposed to < 0 or > 8 degrees C were calculated. RESULTS: The temperature remained within the appropriate range in the central and provincial storages. However, the vaccines were frequently exposed to > 8 degrees C in Saravan and < 0 degrees C in Xayabouly in the district storage. Vaccines were exposed to > 8 degrees C during the transportation in Saravan and to both > 8 and < 0 degrees C in Xayabouly. Thus, challenges in managing the cold chain in the district storage and during transportation remain, despite improvements at the provincial storage. A detailed up-to-date nationwide analysis of the current situation of the cold chain is warranted to identify the most appropriate intervention to tackle the remaining challenges. PMID- 29703229 TI - Impact of an integrated control campaign on tsetse populations in Burkina Faso. AB - BACKGROUND: Tsetse flies are the sole vectors of human and animal trypanosomosis. In Burkina Faso, a project aiming to create zones free of tsetse flies and trypanosomosis was executed from June 2006 to December 2013. After the determination of tsetse distribution in the intervention area from December 2007 to November 2008, the control campaign was launched in November 2009 and ended in December 2013. The goal was to eliminate tsetse flies from 40,000 km2 of area, through an integrated control campaign including insecticide targets, traps and cattle, sequential aerial treatment (SAT) and the mass treatment of livestock using trypanocides. The campaign involved assistance of the beneficiary communities at all the steps of the control strategy with insecticide impregnated targets. METHODS: This study was carried out to assess the impact of the control project on tsetse apparent density per trap per day (ADT). To evaluate the effectiveness of tsetse control, 201 sites were selected based on the baseline survey results carried out from December 2007 to November 2008. These sites were monitored bi-monthly from January 2010 to November 2012. At the end-of-study in 2013 a generalized entomological survey was carried out in 401 infested sites found during the longitudinal survey done before the control. Barrier and tsetse persistence areas were treated by ground spraying and evaluated. Controls were also done before and after aerial spraying. RESULTS: In the insecticide impregnated target area, the control showed that ADT of tsetse flies declined from 10.73 (SD 13.27) to 0.43 (SD 2.51) fly/trap/day from the third month of campaign onwards (P < 0.0001) and remained low thereafter. At the end of the campaign in 2013, an 83% reduction of ADT was observed for Glossina palpalis gambiensis and a 92% reduction for G. tachinoides. Tsetse flies were captured only in 29% of the sites found infested in 2008. CONCLUSIONS: Tsetse flies could be suppressed efficiently but their elimination from the targeted area may require the use integrated methods including the Sterile Insect Technique, which is programmed through the development of the Pan African Tsetse and Trypanosomiasis Eradication Campaign (PATTEC Burkina) insectarium. The challenge will remain the sustainability of the achievement. PMID- 29703230 TI - Golgi tethering factor golgin-97 suppresses breast cancer cell invasiveness by modulating NF-kappaB activity. AB - BACKGROUND: Golgin-97 is a tethering factor in the trans-Golgi network (TGN) and is crucial for vesicular trafficking and maintaining cell polarity. However, the significance of golgin-97 in human diseases such as cancer remains unclear. METHODS: We searched for a potential role of golgin-97 in cancers using Kaplan Meier Plotter ( http://kmplot.com ) and Oncomine ( www.oncomine.org ) datasets. Specific functions of golgin-97 in migration and invasion were examined in golgin 97-knockdown and golgin-97-overexpressing cells. cDNA microarray, pathway analysis and qPCR were used to identify gene profiles regulated by golgin-97. The role of golgin-97 in NF-kappaB signaling pathway was examined by using subcellular fractionation, luciferase reporter assay, western blot analysis and immunofluorescence assay (IFA). RESULTS: We found that low expression of golgin 97 correlated with poor overall survival of cancer patients and was associated with invasiveness in breast cancer cells. Golgin-97 knockdown promoted cell migration and invasion, whereas re-expression of golgin-97 restored the above phenotypes in breast cancer cells. Microarray and pathway analyses revealed that golgin-97 knockdown induced the expression of several invasion-promoting genes that were transcriptionally regulated by NF-kappaB p65. Mechanistically, golgin 97 knockdown significantly reduced IkappaBalpha protein levels and activated NF kappaB, whereas neither IkappaBalpha levels nor NF-kappaB activity was changed in TGN46- or GCC185-knockdown cells. Conversely, golgin-97 overexpression suppressed NF-kappaB activity and restored the levels of IkappaBalpha in golgin-97-knockdown cells. Interestingly, the results of Golgi-disturbing agent treatment revealed that the loss of Golgi integrity was not involved in the NF-kappaB activation induced by golgin-97 knockdown. Moreover, both TGN-bound and cytosolic golgin-97 inhibited NF-kappaB activation, indicating that golgin-97 functions as an NF kappaB suppressor regardless of its subcellular localization. CONCLUSION: Our results collectively demonstrate a novel and suppressive role of golgin-97 in cancer invasiveness. We also provide a new avenue for exploring the relationship between the TGN, golgin-97 and NF-kappaB signaling in tumor progression. PMID- 29703231 TI - Predicting the distribution of Phortica variegata and potential for Thelazia callipaeda transmission in Europe and the United Kingdom. AB - BACKGROUND: Male fruitflies Phortica variegata (Drosophilidae, Steganinae) are the intermediate host of the zoonotic nematode Thelazia callipaeda (Spirurida, Thelaziidae). More than 10 years ago, when T. callipaeda was confined to remote regions of southern Italy, ecological niche models were used to predict the potential distribution of P. variegata across Europe and the likely risk of the nematode spreading through infected dogs travelling to/from endemic regions. As predicted, over the last 10 years T. callipaeda has spread rapidly across Europe. Recently, we identified the potential for its introduction to the UK through infected dogs travelling to/from endemic regions of mainland Europe. METHODS: Here updated information is used to re-evaluate the model-predicted European, and specifically, UK distribution to determine the likelihood of T. callipaeda becoming established. Additionally, the UK distribution of P. variegata was further investigated through snapshot fly trapping at model-predicted locations. RESULTS: Ecological niche modelling using Genetic Algorithm for Rule-set Prediction (GARP) analysis suggests a European range similar to that described previously, with some indication of potential spread further eastward. Finer scale UK mapping suggested that P. variegata presence was limited mostly to southern England, but highlighted regions where P. variegata has not been documented previously. The arbitrary fly trapping identified activity of P. variegata at two locations where the species has been found previously late in the season. No specimens were collected at model-predicted locations, although habitat suitable for the species was identified. CONCLUSIONS: GARP-model prediction of P. variegata distribution suggests presence of suitable conditions in previously undocumented regions of the UK and Europe and highlight the possibility for further spread of T. callipaeda across Europe, including the UK. Further work to validate the P. variegata UK model with field data will help improve its accuracy in predicting suitable areas, whilst surveillance of sylvatic definitive host species in such locations is advised to monitor for evidence of autochthonous T. callipaeda transmission. PMID- 29703232 TI - Effects of mesenchymal stem cells on solid tumor metastasis in experimental cancer models: a systematic review and meta-analysis. AB - BACKGROUND: It has been reported mesenchymal stem cells (MSCs) are recruited to and become integral parts of the tumor microenvironment. MSCs might have an active role in solid tumor progression, especially cancer metastasis. However, the contribution of MSCs in the process of cancer metastasis is still controversial. In this review, we performed a meta-analysis on the effects of MSCs administration on cancer metastasis based on published preclinical studies. METHODS: The PRISMA guidelines were used. A total of 42 publications met the inclusion criteria. Outcome data on the incidence and the number of cancer metastasis as well as study characteristics were extracted. Quality of the studies was assessed according to SYRCLE Risk of Bias tool. Random-effects meta analysis was used to pool estimates. RESULTS: Of the 42 studies included, 32 reported that MSCs administration promoted outcome events (numbers or incidences of cancer metastasis), and 39 reported data suitable for meta-analysis. The median effect size (RR) was 2.04 for the incidence of cancer metastasis (95% CI 1.57-2.65, I2 = 21%), and the median effect size (SMD) was 1.23 for the number of cancer metastasis (95% CI 0.43-2.03, I2 = 89%). Heterogeneity was observed, with the greater impact based on study length and different ways of metastasis measurement and MSCs administration. CONCLUSION: Our results suggested MSCs administration increased the number and the incidence of cancer metastasis in experimental cancer models. High heterogeneity and poor reported risk of bias limit the quality of these findings. Further preclinical studies with better design and adequate reporting are still needed. PMID- 29703233 TI - Molecular and morphological characterisation of Pharyngostrongylus kappa Mawson, 1965 (Nematoda: Strongylida) from Australian macropodid marsupials with the description of a new species, P. patriciae n. sp. AB - BACKGROUND: Pharyngostrongylus kappa Mawson, 1965 is a nematode (Strongyloidea: Cloacininae), endemic to the sacculated forestomachs of Australian macropodid marsupials (kangaroos and wallaroos). A recent study revealed genetic variation within the internal transcribed spacer region of the nuclear ribosomal DNA among P. kappa specimens collected from Macropus giganteus Shaw and Osphranter robustus (Gould). This study aimed to characterise the genetic and morphological diversity within P. kappa from four macropodid host species, including M. giganteus, O. robustus, O. antilopinus (Gould) and O. bernardus (Rothschild). METHODS: Specimens of P. kappa from M. giganteus and Osphranter spp. from various localities across Australia were examined. The first and second internal transcribed spacers (ITS1 and ITS2, respectively) were amplified using polymerase chain reaction and sequenced. Phylogenetic methods were used to determine the interspecific diversification within P. kappa and its evolutionary relationship with other congeners. RESULTS: Morphological examination revealed that P. kappa from M. giganteus, the type-host, can be distinguished from those in Osphranter spp. by the greater length and number of striations on the buccal capsules. DNA sequences showed that P. kappa from M. giganteus was genetically distinct from that in Osphranter spp., thereby supporting the morphological findings. Based on these finding, a new species from Osphranter spp., Pharyngostrongylus patriciae n. sp., is described. CONCLUSION: Pharyngostrongylus patriciae n. sp. from Osphranter spp. is distinguished from P. kappa based on molecular and morphological evidence. The study highlights the importance of combining molecular and morphological techniques for advancing the nematode taxonomy. Although ITS genetic markers have proven to be effective for molecular prospecting as claimed in previous studies, future utilisation of mitochondrial DNA to validate ITS data could further elucidate the extent of speciation among macropodid nematodes. PMID- 29703235 TI - The effects of Bifidobacterium animalis ssp. lactis B94 on gastrointestinal wellness in adults with Prader-Willi syndrome: study protocol for a randomized controlled trial. AB - BACKGROUND: Constipation is a frequent problem in adults with Prader-Willi syndrome. Certain probiotics have been shown to improve transit and gastrointestinal symptoms of adults with functional constipation. The aim of this study is to determine the effect of daily consumption of Bifidobacterium animalis ssp. lactis B94 (B. lactis B94) on stool frequency, stool form, and gastrointestinal symptoms in adults with Prader-Willi syndrome. METHODS: Adults with Prader-Willi syndrome (18-75 years old, n = 36) will be recruited and enrolled in a 20-week, randomized, double-blind, placebo-controlled, crossover study. Study subjects will be randomized to B. lactis B94 or placebo each for a 4 week period, preceded by a 4-week baseline and followed by 4-week washouts. Subjects will complete daily records of stool frequency and stool form (a proxy of transit time). Dietary intake data also will be collected. Stools, one in each period, will be collected for exploratory microbiota analyses. DISCUSSION: To our knowledge, this is the first randomized controlled trial evaluating the effectiveness of B. lactis in adults with Prader-Willi syndrome. The results of this study will provide evidence of efficacy for future clinical trials in patient populations with constipation. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT03277157 ). Registered on 08 September 2017. PMID- 29703234 TI - Bortezomib enhances radiosensitivity in oral cancer through inducing autophagy mediated TRAF6 oncoprotein degradation. AB - BACKGROUND: Oral squamous cell carcinoma (OSCC) is a malignant tumor that may occur anywhere within the oral cavity. The survival rate of OSCC patients has not improved over the past decades due to its heterogeneous etiology, genetic aberrations, and treatment outcomes. We investigated the role of tumor necrosis factor receptor-associated factor 6 (TRAF6) in OSCC cells treated with bortezomib (a proteasome inhibitor) combined with irradiation (IR) treatment. METHODS: The effects of combined treatment in OSCC cells were investigated using assays of cell viability, autophagy, apoptosis, western blotting, and immunofluorescence staining. The ubiquitination of proteins was analyzed by immunoprecipitation. Stable knockdown of TRAF6 in OSCC cells was constructed with lentivirus. The xenograft murine models were used to observe tumor growth. RESULTS: We found synergistic effects of bortezomib and IR on the viability of human oral cancer cells. The combination of bortezomib and IR treatment induced autophagic cell death. Furthermore, bortezomib inhibited IR-induced TRAF6 ubiquitination and inhibited TRAF6-mediated Akt activation. Bortezomib reduced TRAF6 protein expression through autophagy-mediated lysosomal degradation. TRAF6 played an oncogenic role in tumorigenesis of human oral cancer cells and oral tumor growth was suppressed by bortezomib and IR treatment. In addition, OSCC patients with expression of TRAF6 showed a trend towards poorer cancer-specific survival when compared with patients without TRAF6 expression. CONCLUSIONS: A combination of a proteasome inhibitor, IR treatment and TRAF6 inhibition could be a novel therapeutic strategy in OSCC. PMID- 29703236 TI - High-grade serous carcinoma with discordant p53 signature: report of a case with new insight regarding high-grade serous carcinogenesis. AB - BACKGROUND: Although p53 signature, benign-appearing epithelial cells with p53 diffuse expression, is frequently found in the fallopian tubes, the clinical and pathological significance of this lesion in the case of high-grade serous carcinoma (HGSC) patients still remains unclear. CASE PRESENTATION: A 56-year-old woman was referred to the gynecologist on account of abdominal distention. Since radiological and serological workup suggested that her illness was due to advanced ovarian cancer (FIGO Stage IVB), she received neoadjuvant chemotherapy, and the clinical evaluation of the chemotherapeutic response was a partial response. She underwent total hysterectomy with bilateral salpingo-oophorectomy, omentectomy, and intra-pelvic and para-aortic lymphadenectomy. Histologically, the cancer cells showed high-grade nuclear atypia and spread into the bilateral ovaries, omentum, uterine serosa, and left fallopian tube. The cancer cells showed complete absence of p53 but overexpressed p16, whereas some of benign appearing tubal epithelial cells overexpressed p53 but lacked p16 expression. The results of direct sequence analysis revealed that the ovarian cancer contains a 1 bp deletion in exon 8 of TP53. Finally, the histological diagnosis of HGSC with discordant p53 signature was made. Interestingly, nuclear expression of gamma H2AX, a well-known marker of DNA damage, was not only observed in both p53 aberrantly-expressing lesions but also the benign-appearing tubal epithelium without p53 overexpression. After the histological confirmation, she received adjuvant chemotherapy and has been in disease-free condition without any detectable tumor for 5 months. CONCLUSION: Recent evidence suggests that p53 signature is the putative precursor of p53 overexpression-type HGSC. Because the putative precursors of the other p53 immunophenotypical HGSC are not proposed, we presume gamma-H2AX-expressing cells without p53 overexpression may be a potent candidate of null-type TP53-mutated tubal cells, which are named "gamma-H2AX responsive foci." PMID- 29703237 TI - Optimizing a community-engaged multi-level group intervention to reduce substance use: an application of the multiphase optimization strategy. AB - BACKGROUND: Rates of alcohol and illicit drug use (AIDU) are consistently similar across racial groups (Windsor and Negi, J Addict Dis 28:258-68, 2009; Keyes et al. Soc Sci Med 124:132-41, 2015). Yet AIDU has significantly higher consequences for residents in distressed communities with concentrations of African Americans (DCAA - i.e., localities with high rates of poverty and crime) who also have considerably less access to effective treatment of substance use disorders (SUD). This project is optimizing Community Wise, an innovative multi-level behavioral health intervention created in partnership with service providers and residents of distressed communities with histories of SUD and incarceration, to reduce health inequalities related to AIDU. METHODS: Grounded in critical consciousness theory, community-based participatory research principles (CBPR), and the multiphase optimization strategy (MOST), this study employs a 2 * 2 * 2 * 2 factorial design to engineer the most efficient, effective, and scalable version of Community Wise that can be delivered for US$250 per person or less. This study is fully powered to detect change in AIDU in a sample of 528 men with a histories of SUD and incarceration, residing in Newark, NJ in the United States. A community collaborative board oversees recruitment using a variety of strategies including indigenous field worker sampling, facility-based sampling, community advertisement through fliers, and street outreach. Participants are randomly assigned to one of 16 conditions that include a combination of the following candidate intervention components: peer or licensed facilitator, group dialogue, personal goal development, and community organizing. All participants receive a core critical-thinking component. Data are collected at baseline plus five post baseline monthly follow ups. Once the optimized Community Wise intervention is identified, it will be evaluated against an existing standard of care in a future randomized clinical trial. DISCUSSION: This paper describes the protocol of the first ever study using CBPR and MOST to optimize a substance use intervention targeting a marginalized population. Data from this study will culminate in an optimized Community Wise manual; enhanced methodological strategies to develop multi-component scalable interventions using MOST and CBPR; and a better understanding of the application of critical consciousness theory to the field of health inequalities related to AIDU. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02951455 . Registered on 1 November 2016. PMID- 29703239 TI - Allogeneic transplantation of mobilized dental pulp stem cells with the mismatched dog leukocyte antigen type is safe and efficacious for total pulp regeneration. AB - BACKGROUND: We recently demonstrated that autologous transplantation of mobilized dental pulp stem cells (MDPSCs) was a safe and efficacious potential therapy for total pulp regeneration in a clinical study. The autologous MDPSCs, however, have some limitations to overcome, such as limited availability of discarded teeth from older patients. In the present study, we investigated whether MDPSCs can be used for allogeneic applications to expand their therapeutic use. METHODS: Analysis of dog leukocyte antigen (DLA) was performed using polymerase chain reaction from blood. Canine allogeneic MDPSCs with the matched and mismatched DLA were transplanted with granulocyte-colony stimulating factor in collagen into pulpectomized teeth respectively (n = 7, each). Results were evaluated by hematoxylin and eosin staining, Masson trichrome staining, PGP9.5 immunostaining, and BS-1 lectin immunostaining performed 12 weeks after transplantation. The MDPSCs of the same DLA used in the first transplantation were further transplanted into another pulpectomized tooth and evaluated 12 weeks after transplantation. RESULTS: There was no evidence of toxicity or adverse events of the allogeneic transplantation of the MDPSCs with the mismatched DLA. No adverse event of dual transplantation of the MDPSCs with the matched and mismatched DLA was observed. Regenerated pulp tissues including neovascularization and neuronal extension were quantitatively and qualitatively similar at 12 weeks in both matched and mismatched DLA transplants. Regenerated pulp tissue was similarly observed in the dual transplantation as in the single transplantation of MDPSCs both with the matched and mismatched DLA. CONCLUSIONS: Dual allogeneic transplantation of MDPSCs with the mismatched DLA is a safe and efficacious method for total pulp regeneration. PMID- 29703240 TI - Temporal phenotyping of circulating microparticles after trauma: a prospective cohort study. AB - BACKGROUND: After severe polytrauma the dynamic process of coagulation may deteriorate towards a trauma-induced coagulopathy (TIC) promoting a dramatic increase in morbidity and mortality. Recent evidence suggests that microparticles (MPs) play a pivotal role at the interface between cellular and plasmatic coagulation systems. However, the impact of MPs on functional coagulation has not been clarified yet in the setting of traumatic injuries. We assessed the temporal patterns of circulating MP concentrations including their cellular origin in the context of clinical presentation and global coagulation assays. METHODS: Blood samples from 22 consecutive polytrauma patients (ISS >=16) from 2015 were collected at hospital admission, after 24 and 72 h and compared to those from healthy individuals and minor injured patients with isolated extremity fractures. Flow cytometry (BD Accuri C6; Heidelberg/Germany) was used to determine MP concentrations and cellular origin using cell-specific markers (platelet derived (PDMP): CD42b+, CD61+, CD62p+; endothelial cell derived (EDMP): CD144+, CD62e+, CD144+/62e+). Results were correlated with clinical data and results from viscoelastic testing (ROTEM). RESULTS: Twenty two polytrauma patients (17 males, agemedian 60 yrs) with a median ISS 26.5 (IQR 14.5) were assessed. PDMP and EDMP concentrations increased significantly in polytrauma patients as compared to healthy individuals and minor injured patients. MP concentrations correlated with injury severity (CD144+: rhosp = 0.79, p < 0.001; CD42b+: rhosp = 0.61, p < 0.001). EDMP displayed a negative correlation with aPTT (CD144/62e+, rhosp = - 0.55, p < 0.05), INR (CD144/62e+, rhosp = - 0.61, p < 0.05) and ROTEM-INTEM CT (CD144/62e+, rhosp = - 0.68, p < 0.05) reflecting increased dynamics of clot formation and an overall procoagulative effect. Additionally, EDMP showed a negative association with FIBTEM values (10 min amplitude, maximum clot firmness) indicating a fibrinolytic potential. DISCUSSION: In a small cohort, analysing most severly injured patients, the association of increased MP levels and altered coagulation parameters could be demonstrated. However, these findings are based on correlation analysis, which do not enable causel evidence. Therefore, further in-vitro studies are needed analysing the underlying pathomechanisms. CONCLUSION: In conclusion, this study could demonstrate that PDMP and EDMP levels increase significantly following polytrauma correlating with injury severity. Although severe coagulopathy was not observed, EDMP levels were associated with improved coagulation parameters suggesting their essential role for regulating blood coagulation after trauma. PMID- 29703238 TI - Integrins as therapeutic targets in the organ-specific metastasis of human malignant melanoma. AB - Integrins are a large family of adhesion molecules that mediate cell-cell and cell-extracellular matrix interactions. Among the 24 integrin isoforms, many have been found to be associated with tumor angiogenesis, tumor cell migration and proliferation, and metastasis. Integrins, especially alphavbeta3, alphavbeta5 and alpha5beta1, participate in mediating tumor angiogenesis by interacting with the vascular endothelial growth factor and angiopoietin-Tie signaling pathways. Melanoma patients have a poor prognosis when the primary tumor has generated distant metastases, and the melanoma metastatic site is an independent predictor of the survival of these patients. Different integrins on the melanoma cell surface preferentially direct circulating melanoma cells to different organs and promote the development of metastases at specific organ sites. For instance, melanoma cells expressing integrin beta3 tend to metastasize to the lungs, whereas those expressing integrin beta1 preferentially generate lymph node metastases. Moreover, tumor cell-derived exosomes which contain different integrins may prepare a pre-metastatic niche in specific organs and promote organ specific metastases. Because of the important role that integrins play in tumor angiogenesis and metastasis, they have become promising targets for the treatment of advanced cancer. In this paper, we review the integrin isoforms responsible for angiogenesis and organ-specific metastasis in malignant melanoma and the inhibitors that have been considered for the future treatment of metastatic disease. PMID- 29703241 TI - Human immunodeficiency virus type 1 (HIV-1)-mediated neuroinflammation dysregulates neurogranin and induces synaptodendritic injury. AB - BACKGROUND: Human immunodeficiency virus type 1 (HIV-1)-associated neurocognitive disorder (HAND) is a common outcome of a majority of HIV-1-infected subjects and is associated with synaptodendritic damage. Neurogranin (Ng), a postsynaptic protein, and calmodulin (CaM) are two important players of synaptic integrity/functions. The biological role of Ng in the context of HAND is unknown. METHODS: We compared the expression of Ng in frontal cortex (FC) tissues from control and HIV-1-positive subjects with and without HAND by immunohistochemistry, western blot, and qRT-PCR. The interaction between Ng and CaM was analyzed by co-immunoprecipitation. Ng, microtubule-associated protein 2 (MAP2), CaM, CaM-dependent protein kinase II (CaMKII), CREB, synaptophysin (Syp), and synapsin I (Syn I) expressions were evaluated by western blot using FC tissue lysates and differentiated SH-SY5Y (dSH-SY5Y) cells. Identification of inflammatory factors related to Ng loss was accomplished by exposing dSH-SY5Y cells to HIV-1 and mock-infected monocyte-derived macrophage (MDM) supernatants or HIV-1 NLYU2 pseudotyped with VSV-G-Env. Levels of interleukin (IL)-1beta, IL 8, tumor necrosis factor (TNF)-alpha, monocyte chemoattractant protein (MCP)-1, MCP-2, and CXCL5 in MDM supernatants were measured by ELISA. Association of IL 1beta and IL-8 to Ng expression in context of HIV-1 infection was evaluated in the presence or absence of neutralizing antibodies against these cytokines. RESULTS: Expression level of Ng was reduced significantly in FC of HAND-positive (HAND+) patients compared to uninfected individuals. Although no difference was found in CaM expression, interaction between Ng and CaM was reduced in HAND+ patients, which was associated with decreased level of CaMKII, a downstream signaling molecule of CaM pathway. This in turn resulted in reduction of synaptic markers, Syp and Syn I. HIV-1 infection directly had no considerable effect on dysregulation of Ng expression in dSH-SY5Y cells, whereas high amount of pro inflammatory IL-1beta and IL-8 in HIV-1-infected MDM supernatants was associated with significant reduction in Ng expression. CONCLUSIONS: Synaptic damage in HAND+ patients could be a result of abrogation of Ng through HIV-1-induced inflammation that dysregulates Ng-CaM interaction and downstream signaling cascades associated with synaptodendritic functions. This is the first study evaluating the potential role of Ng in the context of HIV-1 neuropathogenesis. PMID- 29703242 TI - An eHealth program versus a standard care supervised health program and associated health outcomes in individuals with mobility disability: study protocol for a randomized controlled trial. AB - BACKGROUND: Young adults with mobility disability (MD) are less likely to engage in regular physical activity (PA) compared with their able-bodied peers and inactive adults with a MD are more likely to report one or more chronic diseases compared to those who are physically active. Despite the vast amount of research published in the field of PA interventions over the past decades, little attention has been focused on interventions aiming to increase PA among individuals with MD. Thus, we propose to compare the effects of an eHealth program compared to a usual care supervised health program on levels of PA and other health behaviors. METHODS: The current intervention will use a randomized controlled trial (RCT) design with two treatment groups (an eHealth program and a usual care supervised health program) in young adults with newly acquired MD. In total, 110 young adults (aged 18-40 years) with a MD, acquired within the past 3 years, will be recruited to participate in a 12-week intervention. The primary study outcome is accelerometer-measured time spent in moderate to vigorous PA. Secondary outcomes includes health-related quality of life, depression, stress, fitness, body composition, diet, musculoskeletal pain, motivation to exercise and work ability. DISCUSSION: There is a lack of RCTs investigating effective ways to increase levels of PA in young adults with MD. Increased levels of PA among this physically inactive population have the potential to substantially improve health related outcomes, possibly more so than in the general population. The trial will put strong emphasis on optimizing exercise adherence and investigating feasibility in the two treatment programs. The Ethical Review Board (EPN) at Karolinska Institutet has approved the study (2017/1206-31/1). TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN), reference number ISRCTN22387524 . Prospectively registered February 4, 2018. PMID- 29703243 TI - Re-emerging Lassa fever outbreaks in Nigeria: Re-enforcing "One Health" community surveillance and emergency response practice. AB - We evaluated the impact of man-made conflict events and climate change impact in guiding evidence-based community "One Health" epidemiology and emergency response practice against re-/emerging epidemics. Increasing evidence of emerging and re emerging zoonotic diseases including recent Lassa fever outbreaks in almost 20 states in Nigeria led to 101 deaths and 175 suspected and confirmed cases since August 2015. Of the 75 laboratory confirmed cases, 90 deaths occurred representing 120% laboratory-confirmed case fatality. The outbreak has been imported into neighbouring country such as Benin, where 23 deaths out of 68 cases has also been reported. This study assesses the current trends in re-emerging Lassa fever outbreak in understanding spatio-geographical reservoir(s), risk factors pattern and Lassa virus incidence mapping, inherent gaps and raising challenges in health systems. It is shown that Lassa fever peak endemicity incidence and prevalence overlap the dry season (within January to March) and reduced during the wet season (of May to November) annually in Sierra Leone, Senegal to Eastern Nigeria. We documented a scarcity of consistent data on rodent (reservoirs)-linked Lassa fever outbreak, weak culturally and socio-behavioural effective prevention and control measures integration, weak or limited community knowledge and awareness to inadequate preparedness capacity and access to affordable case management in affected countries. Hence, robust sub/regional leadership commitment and investment in Lassa fever is urgently needed in building integrated and effective community "One Health" surveillance and rapid response approach practice coupled with pest management and phytosanitation measures against Lassa fever epidemic. This offers new opportunities in understanding human-animal interactions in strengthening Lassa fever outbreak early detection and surveillance, warning alerts and rapid response implementation in vulnerable settings. Leveraging on Africa CDC centre, advances in cloud-sourcing and social media tools and solutions is core in developing and integrating evidence-based and timely risk communication, and reporting systems in improving contextual community-based immunization and control decision making policy to effectively defeat Lassa fever outbreak and other emerging pandemics public health emergencies in Africa and worldwide. PMID- 29703244 TI - Hunger influenced life expectancy in war-torn Sub-Saharan African countries. AB - BACKGROUND: Malnutrition is a global public health problem especially in developing countries experiencing war/conflicts. War might be one of the socio political factors influencing malnutrition in Sub-Saharan African (SSA) countries. This study aims at determining the influence of war on corruption, population (POP), number of population malnourished (NPU), food security and life expectancy (LE) in war-torn SSA countries (WTSSA) by comparing their malnutrition indicators. METHODS: Fourteen countries in WTSSA were stratified into zones according to war incidences. Countries' secondary data on population (POP), NPU, Food Security Index (FSI), corruption perceptions index (CPI), Global Hunger Index (GHI) and LE were obtained from global published data. T test, multivariate and Pearson correlation analyses were performed to determine the relationship between CPI, POP, GHI, FSI, NPU, male LE (MLE) and female LE (FLE) in WTSSA at p < .05. Data were presented in tables, means, standard deviation and percentages. RESULTS: Mean NPU, CPI, GHI, POP, FSI, MLE and FLE in WTSSA were 5.0 million, 28.3%, 18.2%, 33.8 million, 30.8%, 54.7 years and 57.1 years, respectively. GHI significantly influenced LE in both male and female POP in WTSSA. NPU, CPI, FSI, GHI and FLE were not significantly different according to zones except in MLE. CONCLUSIONS: Malnutrition indicators were similarly affected in WTSSA. Hunger influenced life expectancy. Policies promoting good governance, equity, peaceful co-existence, respect for human right and adequate food supply will aid malnutrition eradication and prevent war occurrences in Sub-Saharan African countries. PMID- 29703245 TI - D409H GBA1 mutation accelerates the progression of pathology in A53T alpha synuclein transgenic mouse model. AB - Heterozygous mutations in glucocerebrosidase 1 (GBA1) are a major genetic risk factor for Parkinson's disease and Dementia with Lewy bodies. Mutations in GBA1 leads to GBA1 enzyme deficiency, and GBA1-associated parkinsonism has an earlier age of onset and more progressive parkinsonism. To investigate a potential influence of GBA1 deficiency caused by mutations in GBA1 on the disease progression of PD, GBA1 mice carrying D409H knock-in mutation were crossbred with the human A53T (hA53T) alpha-synuclein transgenic mice. Here, we show that GBA1 enzyme activity plays a significant role in the hA53T alpha-synuclein induced alpha-synucleinopathy. The expression of D409H GBA1 markedly shortens the lifespan of hA53T alpha-synuclein transgenic mice. Moreover, D409H GBA1 expression exacerbates the formation of insoluble aggregates of alpha-synuclein, glial activation, neuronal degeneration, and motor abnormalities in the hA53T alpha-synuclein transgenic mice. Interestingly, the expression of D409H GBA1 results in the loss of dopaminergic neurons in the substantia nigra pars compacta of hA53T transgenic mice. Taken together, these results indicate that GBA1 deficiency due to D409H mutation affects the disease onset and course in hA53T alpha-synuclein transgenic mice. Therefore, strategies aimed to maintain GBA1 enzyme activity could be employed to develop an effective novel therapy for GBA1 linked-PD and related alpha-synucleinopathies. PMID- 29703246 TI - Clostridium difficile cure with fecal microbiota transplantation in a child with Pompe disease: a case report. AB - BACKGROUND: Recurrent Clostridium difficile infection is a growing problem among children due to both the increasing survival of medically fragile children with complicated chronic medical conditions resulting in prolonged antibiotic exposure and hospitalization and the emergence of strains of Clostridium difficile that are hypervirulent and associated with high rates of relapse. CASE PRESENTATION: This case describes a medically complex 21-month-old Hispanic girl with Pompe disease and B cell immunodeficiency with recurrent Clostridium difficile infection refractory to antimicrobial management. She presented with nine recurrent episodes of Clostridium difficile infection including fever, foul smelling diarrhea, and respiratory distress with failed sustained responses to compliant treatment using metronidazole and pulsed vancomycin therapy. Maternal donor fecal microbiota transplantation was performed with complete symptom resolution and produced a sustained cure, now 5 years in duration. CONCLUSIONS: This patient presented with symptomatic Clostridium difficile at an early age causing significant morbidity and reduced quality of life. After nearly one year of failed medical management, fecal microbiota transplantation provided a cure. Further evidence-based research is necessary to test the safety and efficacy of this low technology, low cost, and morbidity-sparing therapy in children. PMID- 29703247 TI - Neutral models of short-term microbiome dynamics with host subpopulation structure and migration limitation. AB - BACKGROUND: Most empirical studies tend to focus on microbiome dynamics within hosts or microbiome compositional differences between hosts over short periods. However, there is still a dearth of formal models that allow us to investigate the observed short-term dynamics of microbiomes under a unified ecological and evolutionary framework. In our previous study, we developed a computational agent based neutral framework that simulates microbiome dynamics spanning many host generations with the added dimension of a genealogy of hosts. Although this long term framework revealed interesting microbial diversity patterns under a simple but plausible evolutionary process and provided a platform for future elaboration of more complex systems, it does not allow us to explore microbiome dynamics within a single host generation. METHODS: In this paper, we developed a computational, agent-based, forward-time framework of microbiome dynamics within a single host generation. As we have done under our neutral long-term models, we incorporate neutral processes of environmental microbiome assembly and microbe acquisition from parents and environment. We also incorporate a Moran genealogical model of hosts, so that the dynamics of microbiome evolution can be studied within a single host generation. Furthermore, we allow host subpopulation structure and host migration to affect microbiome recruitment. RESULTS: We show that microbiome diversity within hosts increases monotonically with increases in environmental contribution, while microbiome diversity between hosts increases with increasing parental inheritance. Host population division and dispersal limitation under high host contribution further shaped the patterns by elevating microbiome differences between hosts and depressing microbial diversity within hosts. Microbiome diversity within the whole population showed strong temporal stability regardless of the modes of microbiome acquisition and subpopulation structures. CONCLUSIONS: We present a computational framework that integrates various processes including host genealogy, microbe recruitment, and host dispersal limitation acting on the short-term dynamics of microbiomes. Our framework demonstrates that the neutral dynamics of microbiomes within a population of hosts is strongly influenced by transmission mode and shared environment. PMID- 29703248 TI - Health-related quality of life determinants among Rwandan women after delivery: does antenatal care utilization matter? A cross-sectional study. AB - BACKGROUND: Despite the widespread use of antenatal care (ANC), its effectiveness in low-resource settings remains unclear. In this study, self-reported health related quality of life (HRQoL) was used as an alternative to other maternal health measures previously used to measure the effectiveness of antenatal care. The main objective of this study was to determine whether adequate antenatal care utilization is positively associated with women's HRQoL. Furthermore, the associations between the HRQoL during the first year (1-13 months) after delivery and socio-economic and demographic factors were explored in Rwanda. METHODS: In 2014, we performed a cross-sectional population-based survey involving 922 women who gave birth 1-13 months prior to the data collection. The study population was randomly selected from two provinces in Rwanda, and a structured questionnaire was used. HRQoL was measured using the EQ-5D-3L and a visual analogue scale (VAS). The average HRQoL scores were computed by demographic and socio-economic characteristics. The effect of adequate antenatal care utilization on HRQoL was tested by performing two multivariable linear regression models with the EQ-5D and EQ-VAS scores as the outcomes and ANC utilization and socio-economic and demographic variables as the predictors. RESULTS: Adequate ANC utilization affected women's HRQoL when the outcome was measured using the EQ-VAS. Social support and living in a wealthy household were associated with a better HRQoL using both the EQ-VAS and EQ-5D. Cohabitating, and single/unmarried women exhibited significantly lower HRQoL scores than did married women in the EQ-VAS model, and women living in urban areas exhibited lower HRQoL scores than women living in rural areas in the ED-5D model. The effect of education on HRQoL was statistically significant using the EQ-VAS but was inconsistent across the educational categories. The women's age and the age of their last child were not associated with their HRQoL. CONCLUSIONS: ANC attendance of at least four visits should be further promoted and used in low-income settings. Strategies to improve families' socio-economic conditions and promote social networks among women, particularly women at the reproductive age, are needed. PMID- 29703249 TI - miR-708-5p and miR-34c-5p are involved in nNOS regulation in dystrophic context. AB - BACKGROUND: Duchenne (DMD) and Becker (BMD) muscular dystrophies are caused by mutations in the DMD gene coding for dystrophin, a protein being part of a large sarcolemmal protein scaffold that includes the neuronal nitric oxide synthase (nNOS). The nNOS was shown to play critical roles in a variety of muscle functions and alterations of its expression and location in dystrophic muscle fiber leads to an increase of the muscle fatigability. We previously revealed a decrease of nNOS expression in BMD patients all presenting a deletion of exons 45 to 55 in the DMD gene (BMDd45-55), impacting the nNOS binding site of dystrophin. Since several studies showed deregulation of microRNAs (miRNAs) in dystrophinopathies, we focused on miRNAs that could target nNOS in dystrophic context. METHODS: By a screening of 617 miRNAs in BMDd45-55 muscular biopsies using TLDA and an in silico study to determine which one could target nNOS, we selected four miRNAs. In order to select those that targeted a sequence of 3'UTR of NOS1, we performed luciferase gene reporter assay in HEK393T cells. Finally, expression of candidate miRNAs was modulated in control and DMD human myoblasts (DMDd45-52) to study their ability to target nNOS. RESULTS: TLDA assay and the in silico study allowed us to select four miRNAs overexpressed in muscle biopsies of BMDd45-55 compared to controls. Among them, only the overexpression of miR-31, miR-708, and miR-34c led to a decrease of luciferase activity in an NOS1-3'UTR luciferase assay, confirming their interaction with the NOS1-3'UTR. The effect of these three miRNAs was investigated on control and DMDd45-52 myoblasts. First, we showed a decrease of nNOS expression when miR-708 or miR-34c were overexpressed in control myoblasts. We then confirmed that DMDd45-52 cells displayed an endogenous increased of miR-31, miR-708, and miR-34c and a decreased of nNOS expression, the same characteristics observed in BMDd45-55 biopsies. In DMDd45-52 cells, we demonstrated that the inhibition of miR-708 and miR-34c increased nNOS expression, confirming that both miRNAs can modulate nNOS expression in human myoblasts. CONCLUSION: These results strongly suggest that miR-708 and miR-34c, overexpressed in dystrophic context, are new actors involved in the regulation of nNOS expression in dystrophic muscle. PMID- 29703250 TI - A case report of giant pancreatic pseudocyst following acute pancreatitis: experience with endoscopic internal drainage. AB - BACKGROUND: Pancreatic cysts are being diagnosed more frequently because of the increasing usage of imaging techniques. A pseudocyst with the major diameter of 10 cm is termed as a giant cyst. Asymptomatic pseudo-cysts up to 6 cm in diameter can be safely observed and monitored without intervention, but larger and symptomatic pseudocysts require intervention. CASE PRESENTATION: A 27-year-old Sri Lankan male, with history of heavy alcohol use, presented with progressive abdominal distension following an episode of acute pancreatitis. Contrast enhanced CT scan of the abdomen showed a large multilocular cystic lesion almost occupying the entire abdominal cavity and displacing the liver medially and the right dome of the diaphragm superiorly. The largest locule in the right side measured as 30 cm * 15 cm * 14 cm. Endoscopic ultrasound guided drainage of the cyst was performed. The cyst was entered into with an electrocautery-assisted cystotome and a lumen-opposing metal stent was deployed under fluoroscopic vision followed by dilatation with a 10 mm controlled radial expansion balloon. Repeat endoscopic ultrasound was done a week later due to persistence of the collection and a second stent was inserted. Then 10 French gauge * 10 cm double ended pigtails were inserted through both stents. The cysts were not visualized on subsequent Ultra sound scans. Stent removal was done after 3 weeks, leaving the pigtails insitu. The patient made an uneventful recovery. CONCLUSION: Giant pancreatic pseudocysts are rare and earlier drainage is recommended before clinical deterioration. Some experts suggest that cystogastrostomy may not be appropriate for the treatment of giant pancreatic pseudocysts and in some instances external drainage of giant pancreatic pseudocysts may be safer than cystogastrostomy. Video-assisted pancreatic necrosectomy with internal drainage and laparoscopic cystogastrostomy were also tried with a good outcome. With our experience we suggest endoscopic guided internal drainage as a possible initial method of management of a giant pseudo cyst. However long-term follow up is needed with repeated imaging and endoscopy. In instances where the primary endoscopic internal drainage fails, surgical procedures may be required as a second line option. PMID- 29703251 TI - Allogeneic transplantation of programmable cells of monocytic origin (PCMO) improves angiogenesis and tissue recovery in critical limb ischemia (CLI): a translational approach. AB - BACKROUND: Employing growth factor-induced partial reprogramming in vitro, peripheral human blood monocytes can acquire a state of plasticity along with expression of various markers of pluripotency. These so-called programmable cells of monocytic origin (PCMO) hold great promise in regenerative therapies. The aim of this translational study was to explore and exploit the functional properties of PCMO for allogeneic cell transplantation therapy in critical limb ischemia (CLI). METHODS: Using our previously described differentiation protocol, murine and human monocytes were differentiated into PCMO. We examined paracrine secretion of pro-angiogenic and tissue recovery-associated proteins under hypoxia and induction of angiogenesis by PCMO in vitro. Allogeneic cell transplantation of PCMO was performed in a hind limb ischemia mouse model in comparison to cell transplantation of native monocytes and a placebo group. Moreover, we analyzed retrospectively four healing attempts with PCMO in patients with peripheral artery disease (PAD; Rutherford classification, stage 5 and 6). Statistical analysis was performed by using one-way ANOVA, Tukey's test or the Student's t test, p < 0.05. RESULTS: Cell culture experiments revealed good resilience of PCMO under hypoxia, enhanced paracrine release of pro-angiogenic and tissue recovery-associated proteins and induction of angiogenesis in vitro by PCMO. Animal experiments demonstrated significantly enhanced SO2 saturation, blood flow, neoangiogenesis and tissue recovery after treatment with PCMO compared to treatment with native monocytes and placebo. Finally, first therapeutic application of PCMO in humans demonstrated increased vascular collaterals and improved wound healing in patients with chronic CLI without exaggerated immune response, malignant processes or extended infection after 12 months. In all patients minor and/or major amputations of the lower extremity could be avoided. CONCLUSIONS: In summary, PCMO improve angiogenesis and tissue recovery in chronic ischemic muscle and first clinical results promise to provide an effective and safe treatment of CLI. PMID- 29703252 TI - Investigation of the SLC22A23 gene in laryngeal squamous cell carcinoma. AB - BACKGROUND: Laryngeal squamous cell carcinoma (LSCC) is the second most common cancer of the head and neck. In order to identify differentially expressed genes which may have a role in LSCC carcinogenesis, we performed GeneFishing Assay. One of the differentially expressed genes was the SLC22A23 (solute carrier family 22, member 23) gene. SLC22A23 belongs to a family of organic ion transporters that are responsible for the absorption or excretion of many drugs, xenobiotics and endogenous compounds in a variety of tissues. SLC22A23 is expressed in a various tissues but no substrates or functions have been identified for it. Although the exact function is unknown, single nucleotide polymorphisms (SNPs) which are located in SLC22A23 gene were associated with inflammatory bowel disease (IBD), endometriosis-related infertility and the clearance of antipsychotic drugs. On the other hand SLC22A23 is identified as a prognostic gene to predict the recurrence of triple-negative breast cancer. METHODS: To understand the role of the SLC22A23 gene in laryngeal carcinogenesis, we investigated its mRNA expression level in laryngeal tumor tissue and adjacent non-cancerous tissue samples obtained from 83 patients by quantitative real-time PCR. To understand the association between SNPs in SLC22A23 and LSCC, selected genetic variations (rs4959235, rs6923667, rs9503518) were genotyped. RESULTS: We found that SLC22A23 expression was increased in 46 of 83 tumor tissues (55.4%) and was decreased in 30 of 83 (36.1%) tumor tissues compared to normal tissues. 77.2% of patients were homozygote for genotype rs9503518-AA and they most frequently had histological grade 2 and 3 tumors. We also found that rs9503518-AA genotype is associated with increased SLC22A23 expression. CONCLUSIONS: Our results indicate that SLC22A23 may play a role in the development of laryngeal cancer. PMID- 29703253 TI - SMAD4 and NF1 mutations as potential biomarkers for poor prognosis to cetuximab based therapy in Chinese metastatic colorectal cancer patients. AB - BACKGROUND: Cetuximab, an anti-EGFR monoclonal antibody, is used in combination with chemotherapy in clinic to enhance the outcome in metastatic colorectal cancer (mCRC) patients with only ~ 20% response rate. To date only activating mutations in KRAS and NRAS have been identified as poor prognosis biomarkers in cetuximab-based treatment, which makes an urgent need for identification of novel prognosis biomarkers to precisely predict patients' response in order to maximize the benefit. METHODS: In this study, we analysed the mutation profiles of 33 Chinese mCRC patients using comprehensive next-generation sequencing (NGS) targeting 416 cancer-relevant genes before cetuximab treatment. Upon receiving cetuximab-based therapy, patients were evaluated for drug response, and the progression-free survival (PFS) was monitored. The association of specific genetic alterations and cetuximab efficacy was analyzed. RESULTS: Patients carrying SMAD4 mutations (SMAD4mut, n = 8) or NF1 mutations (NF1mut, n = 4) had significantly shorter PFS comparing to those carrying wildtype SMAD4 (SMAD4wt, n = 25) (P = 0.0081) or wildtype NF1 (NF1wt, n = 29) (P = 0.0028), respectively. None of the SMAD4mut or NF1mut patients showed response to cetuximab when assessed at 12-week post-treatment. Interestingly, two patients carrying both SMAD4mut and NF1mut showed the shortest PFS among all the patients. CONCLUSIONS: Our results demonstrated that SMAD4 and NF1 mutations can serve as potential biomarkers for poor prognosis to cetuximab-based therapy in Chinese mCRC patients. PMID- 29703254 TI - Evaluation of a novel vital sign device to reduce maternal mortality and morbidity in low-resource settings: a mixed method feasibility study for the CRADLE-3 trial. AB - BACKGROUND: The CRADLE-3 trial is a stepped-wedge randomised controlled trial aiming to reduce maternal mortality and morbidity by implementing a novel vital sign device (CRADLE Vital Sign Alert) and training package into routine maternity care in 10 low-income sites. The MRC Guidance on complex interventions proposes that interventions and implementation strategies be shaped by early phase piloting and development work. We present the findings of a three-month mixed methodology feasibility study for this trial, describe how this was informed by the MRC guidance and the study design was refined. METHODS: The fidelity, dose, feasibility and acceptability of implementation and training materials were assessed in three representative non-trial sites (Zimbabwe, Ethiopia, India) using multiple-choice questionnaires, evaluation of clinical management (action log), healthcare provider (HCP) semi-structured interviews and focus groups 4-10 weeks after implementation. Simultaneously, the 10 sites included in the main trial (eight countries) collected primary outcome data to inform the power calculation and randomisation allocation and assess the feasibility of data collection. RESULTS: The package was implemented with high fidelity (85% of HCP trained, n = 204). The questionnaires indicated a good understanding of device use with 75% of participants scoring > 75% (n = 97; 90% of those distributed). Action logs were inconsistently completed but indicated that the majority of HCP responded appropriately to abnormal results. From 18 HCP interviews and two focus groups it was widely reported that the intervention improved capacity to make clinical decisions, escalate care and make appropriate referrals. Nine of the ten main trial sites achieved ethical approval for pilot data collection. Intensive care was an inconsistent marker of morbidity and stroke an infrequent outcome and therefore they were removed from the main trial composite outcome. Tools and methods of data collection were optimized and event rates used to inform randomisation. CONCLUSIONS: This feasibility study demonstrates that the components of the intervention were acceptable, methods of implementing were successful and the main trial design would be feasible. Qualitative work identified key moderators that informed the main trial process evaluation. Changes to the training package, implementation strategy, study design and processes were identified to refine the implementation in the main trial. TRIAL REGISTRATION: ISRCTN41244132 ; Registered 24/11/2015. PMID- 29703255 TI - Fate of stable hips after prophylactic femoral varization osteotomy in patients with cerebral palsy. AB - BACKGROUND: Concurrent prophylactic femoral varization osteotomy (FVO) for stable hips has been performed in patients with cerebral palsy (CP) undergoing hip reconstructive surgery for the contralateral displaced hip. However, there is currently a lack of studies investigating the outcome after the prophylactic FVO in stable hip. This study investigated the outcomes after FVO in stable hips with CP and influencing factors. In addition, this study compared the outcomes with those after hip reconstructive surgery in the contralateral displaced hip. METHODS: This study included 119 CP patients with 224 hips (80 stable, 144 displaced) undergoing hip reconstructive surgery including FVO. Migration percentage (MP), neck-shaft angle (NSA), and head-shaft angle (HSA) were measured through preoperative and follow-up hip radiographs. All hips were divided into the stable (MP <= 33%) and displaced hip groups (MP > 33%) according to the preoperative radiographs, and the annual changes in the radiographic indices after FVO were analyzed. RESULTS: In stable hip group, MP did not significantly increase over time (p = 0.057) after prophylactic FVO. In displaced hip group, MP significantly increased over time (1.6%/year, p < 0.001). MP was significantly decreased in cases of concomitant Dega pelvic osteotomy in both stable (14.5%, p < 0.001) and displaced hips (18.9%, p < 0.001). CONCLUSIONS: Prophylactic FVO in the stable hip in patients with CP showed good surgical outcomes, without a risk of hip displacement throughout the follow-up duration, while hip reconstructive surgery in the displaced hip was associated with a risk of increased hip displacement. PMID- 29703256 TI - Manipulation of autophagy: a novelly potential therapeutic strategy for retinal neovascularization. AB - BACKGROUND: The relationship between the role of VEGF and autophagy in the process of retinal angiogenesis is still unclear. In this study, we explored this issue by using the mouse retinal vascular endothelial cell (RVEC) as a model. METHODS: RVECs were divided into the following groups: control, hypoxia (H), 3 methyladenine (3-MA) + H, VEGF + H, 3-MA + VEGF+H, anti-VEGF antibody + H, 3-MA+ anti-VEGF antibody + H. We then examined activation of autophagy by detecting formation of autophagosomes with transmission electron microscopy (TEM) and by counting the number of green fluorescent protein-positive (GFP+) puncta in RVECs. The turnover of microtubule associated protein 1 light chain 3 B (LC3B) and VEGF were examined by western blot. Cell migratory capacity was measured with wound healing assay and transwell assay. The capillary formation assay was performed to investigate the angiogenic capacity. RESULTS: Hypoxia led to an increased number of autophagosome and of the GFP+ puncta, an increased ratio of LC3B-II/I and enhanced migratory and capillary-formation capacities of RVECs. Pre-treatment with 3-MA attenuated activation of autophagy and abrogated the enhanced cell migration and capillary formation under hypoxia. Exposure to VEGF significantly increased migratory and capillary formation capacities of RVECs under hypoxia and 3-MA decreased VEGF-induced angiogenesis without its expression. Formation of autophagosome, the number of GFP+ puncta of RVECs and expression of LC3B-II/I were both elevated in cells treated with anti-VEGF antibody and these effects were partially inhibited by 3-MA pretreatment. CONCLUSION: Our present data may identify autophagic response as a novel target for enhancing the therapeutic efficacy of angiogenesis inhibitors. PMID- 29703257 TI - InsP3R-SEC5 interaction on phagosomes modulates innate immunity to Candida albicans by promoting cytosolic Ca2+ elevation and TBK1 activity. AB - BACKGROUND: Candida albicans (C. albicans) invasion triggers antifungal innate immunity, and the elevation of cytoplasmic Ca2+ levels via the inositol 1,4,5 trisphosphate receptor (InsP3R) plays a critical role in this process. However, the molecular pathways linking the InsP3R-mediated increase in Ca2+ and immune responses remain elusive. RESULTS: In the present study, we find that during C. albicans phagocytosis in macrophages, exocyst complex component 2 (SEC5) promotes InsP3R channel activity by binding to its C-terminal alpha-helix (H1), increasing cytosolic Ca2+ concentrations ([Ca2+]c). Immunofluorescence reveals enriched InsP3R-SEC5 complex formation on phagosomes, while disruption of the InsP3R-SEC5 interaction by recombinant H1 peptides attenuates the InsP3R-mediated Ca2+ elevation, leading to impaired phagocytosis. Furthermore, we show that C. albicans infection promotes the recruitment of Tank-binding kinase 1 (TBK1) by the InsP3R-SEC5 interacting complex, leading to the activation of TBK1. Subsequently, activated TBK1 phosphorylates interferon regulatory factor 3 (IRF 3) and mediates type I interferon responses, suggesting that the InsP3R-SEC5 interaction may regulate antifungal innate immune responses not only by elevating cytoplasmic Ca2+ but also by activating the TBK1-IRF-3 pathway. CONCLUSIONS: Our data have revealed an important role of the InsP3R-SEC5 interaction in innate immune responses against C. albicans. PMID- 29703258 TI - Conscientious objection to participation in abortion by midwives and nurses: a systematic review of reasons. AB - BACKGROUND: Freedom of conscience is a core element of human rights respected by most European countries. It allows abortion through the inclusion of a conscience clause, which permits opting out of providing such services. However, the grounds for invoking conscientious objection lack clarity. Our aim in this paper is to take a step in this direction by carrying out a systematic review of reasons by midwives and nurses for declining, on conscience grounds, to participate in abortion. METHOD: We conducted a systematic review of ethical arguments asking, "What reasons have been reported in the argument based literature for or against conscientious objection to abortion provision by nurses or midwives?" We particularly wanted to identify any discussion of the responsibilities of midwives and nurses in this area. Search terms were conscientious objection and abortion or termination and nurse or midwife or midwives or physicians or doctors or medics within the dates 2000-2016 on: HEIN legal, Medline, CINAHL, Psychinfo, Academic Search Complete, Web of Science including publications in English, German and Dutch. Final articles were subjected to a rigorous analysis, coding and classifying each line into reason mentions, narrow and broad reasons for or against conscientious objection. RESULTS: Of an initial 1085 articles, 10 were included. We identified 23 broad reasons, containing 116narrow reasons and 269 reason mentions. Eighty one (81) narrow reasons argued in favour of and 35 against conscientious objection. Using predetermined categories of moral, practical, religious or legal reasons, "moral reasons" contained the largest number of narrow reasons (n = 58). The reasons and their associated mentions in this category outnumber those in the sum of the other three categories. CONCLUSIONS: We identified no absolute argument either for or against conscientious objection by midwives or nurses. An invisibility of midwives and nurses exists in the whole debate concerning conscientious objection reflecting a gap between literature and practice, as it is they whom WHO recommend as providers of this service. While the arguments in the literature emphasize the need for provision of conscientious objection, a balanced debate is necessary in this field, which includes all relevant health professionals. PMID- 29703259 TI - Antischistosomal and anti-inflammatory activity of garlic and allicin compared with that of praziquantel in vivo. AB - BACKGROUND: Schistosomiasis is an acute and chronic zoonotic parasitic disease caused by trematode worms. The host inflammatory response to schistosome eggs leads to perioval granulomata formation, mainly in the liver and intestine. This study investigated the potential antischistosomal and anti-inflammatory activity of both garlic extract and allicin on liver fibrotic markers in BALB/c mice with schistosomiasis (S. mansoni infection) compared with that of the commonly used drug, praziquantel (PZQ). METHODS: In this study, 140 female BALB/c mice (7-weeks old) were divided into seven groups with 20 mice each. Six groups were infected with S. mansoni cercariae and treated with garlic, allicin, or PZQ. The seventh group was the negative control. Twenty-four hours after the final treatment, the mice were euthanised and perfused for worm recovery. The liver and intestines were harvested for parasitological and histological assessment and to analyse the proinflammatory cytokine mRNA expression. RESULTS: Prophylactic administration of garlic and allicin to the infected mice significantly reduced the worm burden. Serum concentrations of liver fibrosis markers and proinflammatory cytokines were also reduced. PZQ was the most efficacious for reduction in the number of worms. These results are similar to those normally obtained using PZQ. CONCLUSIONS: Crushed garlic homogenate and allicin are potential complementary treatments that may be used with PZQ. PMID- 29703260 TI - Adenocarcinoma arising in sigmoid colon neovagina 53 years after construction. AB - BACKGROUND: In view of the rarity of vaginal agenesis, malignancy arising in the neovagina is extremely rare. CASE PRESENTATION: Here, we report a 76-year-old female with an adenocarcinoma arising in the sigmoid colon neovagina which was constructed 53 years ago for congenital vaginal agenesis. Vaginal endoscopy to examine vaginal bleeding revealed a protruding lesion occupying three quarters of the lumen in the vicinity of anastomosis of the residual vagina and sigmoid colon. Transvaginal ultrasonography revealed the muscularis propria layer (hypoechoic fourth layer) to be interrupted. CT revealed no distant metastasis. Total pelvic exenteration was performed based on the diagnosis of neovaginal cancer at the anastomosis site. The 45-mm tumor showed well-differentiated adenocarcinoma with a mucinous adenocarcinoma component. Immunohistochemistry showed no p16-overexpressing tumor cells, suggesting the lack of human papilloma virus infection. CONCLUSIONS: Although rare, clinicians should be aware of cancer that arises in the ectopic intestine when anastomosed with other organs. PMID- 29703262 TI - Migalastat improves diarrhea in patients with Fabry disease: clinical-biomarker correlations from the phase 3 FACETS trial. AB - BACKGROUND: Fabry disease is frequently characterized by gastrointestinal symptoms, including diarrhea. Migalastat is an orally-administered small molecule approved to treat the symptoms of Fabry disease in patients with amenable mutations. METHODS: We evaluated minimal clinically important differences (MCID) in diarrhea based on the corresponding domain of the patient-reported Gastrointestinal Symptom Rating Scale (GSRS) in patients with Fabry disease and amenable mutations (N = 50) treated with migalastat 150 mg every other day or placebo during the phase 3 FACETS trial (NCT00925301). RESULTS: After 6 months, significantly more patients receiving migalastat versus placebo experienced improvement in diarrhea based on a MCID of 0.33 (43% vs 11%; p = .02), including the subset with baseline diarrhea (71% vs 20%; p = .02). A decline in kidney peritubular capillary globotriaosylceramide inclusions correlated with diarrhea improvement; patients with a reduction > 0.1 were 5.6 times more likely to have an improvement in diarrhea than those without (p = .031). CONCLUSIONS: Migalastat was associated with a clinically meaningful improvement in diarrhea in patients with Fabry disease and amenable mutations. Reductions in kidney globotriaosylceramide may be a useful surrogate endpoint to predict clinical benefit with migalastat in patients with Fabry disease. TRIAL REGISTRATION: NCT00925301 ; June 19, 2009. PMID- 29703261 TI - Biomechanical analysis of plate systems for proximal humerus fractures: a systematic literature review. AB - BACKGROUND: Proximal humerus fractures are the third most common in the human body but their management remains controversial. Open reduction and internal fixation with plates is one of the leading modes of operative treatment for these fractures. The development of technologies and techniques for these plates, during the recent decades, promise a bright future for their clinical use. A comprehensive review of in vitro biomechanical studies is needed for the comparison of plates' mechanical performance and the testing methodologies. This will not only guide clinicians with plate selection but also with the design of future in vitro biomechanical studies. This review was aimed to systematically categorise and review the in vitro biomechanical studies of these plates based on their protocols and discuss their results. The technologies and techniques investigated in these studies were categorised and compared to reach a census where possible. METHODS AND RESULTS: Web of Science and Scopus database search yielded 62 studies. Out of these, 51 performed axial loading, torsion, bending and/or combined bending and axial loading while 11 simulated complex glenohumeral movements by using tendons. Loading conditions and set-up, failure criteria and performance parameters, as well as results for each study, were reviewed. Only two studies tested four-part fracture model while the rest investigated two- and three-part fractures. In ten studies, synthetic humeri were tested instead of cadaveric ones. In addition to load-displacement data, three-dimensional motion analysis systems, digital image correlation and acoustic emission testing have been used for measurement. CONCLUSIONS: Overall, PHILOS was the most tested plate and locking plates demonstrated better mechanical performance than non-locking ones. Conflicting results have been published for their comparison with non locking blade plates and polyaxial locking screws. Augmentation with cement [calcium phosphate or poly(methyl methacrylate)] or allografts (fibular and femoral head) was found to improve bone-plate constructs' mechanical performance. Controversy still lies over the use of rigid and semi-rigid implants and the insertion of inferomedial screws for calcar region support. This review will guide the design of in vitro and in silico biomechanical tests and also supplement the study of clinical literature. PMID- 29703263 TI - Zika virus-induced hyper excitation precedes death of mouse primary neuron. AB - BACKGROUND: Zika virus infection in new born is linked to congenital syndromes, especially microcephaly. Studies have shown that these neuropathies are the result of significant death of neuronal progenitor cells in the central nervous system of the embryo, targeted by the virus. Although cell death via apoptosis is well acknowledged, little is known about possible pathogenic cellular mechanisms triggering cell death in neurons. METHODS: We used in vitro embryonic mouse primary neuron cultures to study possible upstream cellular mechanisms of cell death. Neuronal networks were grown on microelectrode array and electrical activity was recorded at different times post Zika virus infection. In addition to this method, we used confocal microscopy and Q-PCR techniques to observe morphological and molecular changes after infection. RESULTS: Zika virus infection of mouse primary neurons triggers an early spiking excitation of neuron cultures, followed by dramatic loss of this activity. Using NMDA receptor antagonist, we show that this excitotoxicity mechanism, likely via glutamate, could also contribute to the observed nervous system defects in human embryos and could open new perspective regarding the causes of adult neuropathies. CONCLUSIONS: This model of excitotoxicity, in the context of neurotropic virus infection, highlights the significance of neuronal activity recording with microelectrode array and possibility of more than one lethal mechanism after Zika virus infection in the nervous system. PMID- 29703264 TI - Cerebrospinal fluid mitochondrial DNA in neuromyelitis optica spectrum disorder. AB - BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system. Although complement-dependent astrocyte damage mediated by anti-aquaporin 4 autoantibody (AQP4-Ab) is well acknowledged to be the core of NMOSD pathogenesis, additional inflammatory cascades may contribute to the establishment of lesion formation. Thus, in this study, we investigated the possible pathogenic role of immune-reactive mitochondrial DNA (mtDNA) in cerebrospinal fluid (CSF) of NMOSD patients. METHODS: Using quantitative polymerase chain reaction, we measured extracellular mtDNA levels in CSF of NMOSD patients positive for AQP4-Ab. Patients with multiple sclerosis or other neurological diseases were examined as controls. Pre- and post-treatment extracellular mtDNA levels were also compared in the NMOSD group. Extracellular mtDNA release from human astrocytes was analyzed in vitro utilizing NMOSD sera, and interleukin (IL)-1beta production was measured in supernatants of mixed glial cells stimulated with DNA fraction of CSF derived from NMOSD patients. Furthermore, specific innate immune pathways mediating the IL-1beta production by mtDNA were investigated in peripheral blood mononuclear cells with selective inhibitors of Toll-like receptor 9 (TLR9) and NOD-like receptor protein 3 (NLRP3) inflammasomes. RESULTS: Extracellular mtDNA level was specifically elevated in acute phase of NMOSD CSF. In vitro studies provided the evidence that mtDNA is released from human astrocytes by NMOSD sera. In addition, DNA fraction isolated from NMOSD CSF promoted secretion of IL-1beta from mixed glial cells. Selective inhibition of TLR9 and NLRP3 inflammasomes revealed that mtDNA-mediated IL-1beta production depends on specific innate immune pathways. CONCLUSION: Extracellular mtDNA is specifically elevated in the CSF of patients with acute phase NMOSD, and mtDNA released by AQP4-Ab-mediated cellular damage elicits the innate immune cascades via TLR9 and NLRP3 inflammasomes pathways. Our study highlights mtDNA mediated innate immune pathways as a novel therapeutic target for future treatment of NMOSD patients. PMID- 29703265 TI - Combined CatWalk Index: an improved method to measure mouse motor function using the automated gait analysis system. AB - OBJECTIVE: Measuring motor function in mice is important for studying models of spinal cord injury (SCI) or other diseases. Several methods exist based on visual observation of mice moving in an open field. Though these methods require very little equipment, observers must be trained, and the possibility of human error or subjectivity cannot be eliminated. The Noldus CatWalk XT Automated Gait Analysis system assesses mouse motor function by taking high-resolution videos of the mice, with specialized software to measure several aspects of the animal's gait. This instrument reduces the possibility of human error, but it is not always clear what data is important for assessing motor function. This study used data collected during mouse SCI experiments to create a simple mathematical model that combines the data collected by the CatWalk system into a single score, the Combined CatWalk Index or CCI. RESULTS: The CCI system produces similar results to the Basso Mouse Scale or the CatWalk's Step Sequence Regularity Index. However, the CCI has a significantly smaller coefficient of variation than either other method. Additionally, CCI scoring shows slightly better correlation with impact force. The CCI system is likely to be a useful tool for SCI research. PMID- 29703266 TI - Statistical analysis plan for the POLAR-RCT: The Prophylactic hypOthermia trial to Lessen trAumatic bRain injury-Randomised Controlled Trial. AB - BACKGROUND: The Prophylactic hypOthermia to Lessen trAumatic bRain injury Randomised Controlled Trial (POLAR-RCT) will evaluate whether early and sustained prophylactic hypothermia delivered to patients with severe traumatic brain injury improves patient-centred outcomes. METHODS: The POLAR-RCT is a multicentre, randomised, parallel group, phase III trial of early, prophylactic cooling in critically ill patients with severe traumatic brain injury, conducted in Australia, New Zealand, France, Switzerland, Saudi Arabia and Qatar. A total of 511 patients aged 18-60 years have been enrolled with severe acute traumatic brain injury. The trial intervention of early and sustained prophylactic hypothermia to 33 degrees C for 72 h will be compared to standard normothermia maintained at a core temperature of 37 degrees C. The primary outcome is the proportion of favourable neurological outcomes, comprising good recovery or moderate disability, observed at six months following randomisation utilising a midpoint dichotomisation of the Extended Glasgow Outcome Scale (GOSE). Secondary outcomes, also assessed at six months following randomisation, include the probability of an equal or greater GOSE level, mortality, the proportions of patients with haemorrhage or infection, as well as assessment of quality of life and health economic outcomes. The planned sample size will allow 80% power to detect a 30% relative risk increase from 50% to 65% (equivalent to a 15% absolute risk increase) in favourable neurological outcome at a two-sided alpha of 0.05. DISCUSSION: Consistent with international guidelines, a detailed and prospective analysis plan has been developed for the POLAR-RCT. This plan specifies the statistical models for evaluation of primary and secondary outcomes, as well as defining covariates for adjusted analyses and methods for exploratory analyses. Application of this statistical analysis plan to the forthcoming POLAR-RCT trial will facilitate unbiased analyses of these important clinical data. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00987688 (first posted 1 October 2009); Australian New Zealand Clinical Trials Registry, ACTRN12609000764235 . Registered on 3 September 2009. PMID- 29703269 TI - Dipstick Assay for Rapid Detection of Beer Spoilage Organisms. AB - Background: Beer spoilage caused by wild yeast and bacteria is a major concern to both commercial and home brewers. Objective: To address this problem, Molecular Epidemiology Inc. (MEI, Seattle, WA) has developed a beer spoilage organism detection kit consisting of an enrichment media (BSE) and a multiplex PCR DNA dipstick that simultaneously detects these organisms within 2 h following enrichment. Methods: The kit was tested by using samples obtained from breweries located in the Greater Seattle area. Samples were spiked with the target microbes, when necessary, and used for assessing the performance characteristics of the DNA dipstick assay. Microbial enumerations were performed as per the standard microbiological plating methods. The suitability of the BSE medium to support the growth of beer spoilage microbes was compared with the industry approved NBB-C medium (Dohler, Darmstadt, Germany). Results: Inclusivity (a panel of 50 isolates) and Exclusivity (a panel of 92 isolates) testing indicated that the dipstick assay can exclusively detect the indicated target beer spoilage microbes. When compared with the NBB-C medium (Dohler, Darmstadt, Germany) approved by the European Brewers Convention for beer spoilage organisms, the BSE medium supported faster growth of critical spoilage lactic acid bacteria such as Lactobacillus brevis, L. lindneri, and Pediococcus damnosus. Conclusions: The beer spoilage organism detection kit has a detection limit of 10 cells/mL. Highlights: The kit can be used at different stages of the brewing process, thus offering a convenient, cost effective, and faster test system for brewers interested in monitoring the quality of their product. PMID- 29703267 TI - Saliva samples as a source of DNA for high throughput genotyping: an acceptable and sufficient means in improvement of risk estimation throughout mammographic diagnostics. AB - BACKGROUND: Breast cancer screening programs seem to be an insufficient tool for women at high genetic risk for breast cancer. These women are not adequately monitored yet. Genetic testing may improve clearly the quality of breast cancer prevention programs. At present, blood samples are favored for obtaining high quality DNA; however, DNA can also be obtained by collecting saliva. The aim of this study was, on the one hand, to determine whether saliva sampling is a practicable means to obtain sufficient quantity and quality of DNA and, on the other hand, whether it is accepted by patients throughout mammographic diagnostics. METHODS: 67 consecutive women with diagnostic need for mammography with or without a family history for breast cancer were asked for their basic willingness to undergo a genetic testing by saliva sample in addition to standard diagnostics. Saliva samples were analyzed in terms of DNA quantity and quality. RESULTS: 64 (95.6%) women agreed to provide a saliva sample; 3 of them denied participation. And even 63 out of 64 (98.4%) were interested in their specific results. 45 out of 64 samples contained a DNA concentration above 50 ng/ul, 12 samples were between 25 and 50 ng/ul and only 7 of them were under 25 ng/ul with the standard extraction procedure. CONCLUSION: A high number of patients seem to accept salvia samples as a risk assessment tool in breast diagnostics and are interested in their specific risk situation. At the same time, it could be demonstrated that it is an effective way to provide high-quality DNA for breast cancer gene analysis. However, it remains to be shown whether it would be possible to integrate it with the same acceptance in a nationwide breast cancer screening program. PMID- 29703268 TI - Exploring the mechanisms of resistance to Teladorsagia circumcincta infection in sheep through transcriptome analysis of abomasal mucosa and abomasal lymph nodes. AB - The present study exploited the RNA-seq technology to analyze the transcriptome of target tissues affected by the Teladorsagia circumcincta infection in two groups of adult ewes showing different statuses against gastrointestinal nematode (GIN) infection with the aim of identifying genes linked to GIN infection resistance in sheep. For this, based on the accumulated faecal egg count of 18 adult Churra ewes subjected to a first experimental infection with T. circumcincta, six ewes were classified as resistant and six others as susceptible to the infection. These 12 animals were dewormed and infected again. After humanitarian sacrifice of these 12 animals at day 7 post-infection, RNA samples were obtained from abomasal mucosa and lymph node tissues and RNA-Seq datasets were generated using an Illumina HiSeq 2000 sequencer. The distribution of the genes based on their expression level were very similar among the two different tissues and conditions. The differential expression analysis performed with two software (DESeq and EdgeR) only identified common differentially expressed genes (DEGs), a total of 106, in the lymph node samples which were considered as GIN activated. The enrichment analysis performed for these GIN-activated genes identified some pathways related to cytokine-mediated immune response and the PPARG signaling pathway as well as disease terms related to inflammation and gastro-intestinal diseases as enriched. A systematic comparison with the results of previous studies confirmed the involvement of genes such as ITLN2, CLAC1 and galectins, in the immune mechanism activated against T. circumcincta in resistant sheep. PMID- 29703270 TI - Confirmation and Identification of Salmonella spp., Cronobacter spp., and Other Gram-Negative Organisms by the Bruker MALDI Biotyper Method: Collaborative Study, First Action 2017.09. AB - The Bruker MALDI Biotyper(r) method utilizes matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS for the rapid and accurate identification and confirmation of Gram-negative bacteria from select media types. The alternative method was evaluated using nonselective and selective agars to identify Cronobacter spp., Salmonella spp., and select Gram-negative bacteria. Results obtained by the Bruker MALDI Biotyper were compared to the traditional biochemical methods as prescribed in the appropriate reference methods. Two collaborative studies were organized, one in the United States focusing on Cronobacter spp. and other Gram-negative bacteria, and one in Europe focusing on Salmonella spp. and other Gram-negative bacteria. Fourteen collaborators from seven laboratories located within the United States participated in the first collaborative study for Cronobacter spp. Fifteen collaborators from 15 service laboratories located within Europe participated in the second collaborative study for Salmonella spp. For each target organism (either Salmonella spp. or Cronobacter spp.), a total of 24 blind-coded isolates were evaluated. In each set of 24 organisms, there were 16 inclusivity organisms (Cronobacter spp. or Salmonella spp.) and 8 exclusivity organisms (closely related non-Cronobacter spp. and non-Salmonella spp. Gram-negative organisms). After testing was completed, the total percentage of correct identifications from each agar type for each strain was determined at a percentage of 100.0% to the genus level for the Cronobacter study and a percentage of 100.0% to the genus level for the Salmonella study. For both non-Cronobacter and non-Salmonella organisms, a percentage of 100.0% was correctly identified. The results indicated that the alternative method produced equivalent results when compared to the confirmatory procedures specified by each reference method. PMID- 29703271 TI - Determination of Aflatoxins and Ochratoxin A in Traditional Turkish Concentrated Fruit Juice Products by Multi-Immunoaffinity Column Cleanup and LC Fluorescence Detection: Single-Laboratory Validation. AB - Background: Pekmez and pestil are traditional Turkish foods made from concentrated grape juice, which can be contaminated with mycotoxins such as aflatoxins and ochratoxin A (OTA). Objective: To carry out a single-laboratory validation of a method to simultaneously determine aflatoxins B1, B2, G1, and G2 and ochratoxin A in pekmez and pestil. Methods: The homogenized sample is extracted with methanol-water (80 + 20) using a high-speed blender. The (sample) extract is filtered, diluted with phosphate-buffered saline solution, and applied to a multi-immunoaffinity column (AFLAOCHRA PREP(r)). Aflatoxins and ochratoxin A are removed with (neat) methanol and then directly analyzed by reversed-phase LC with fluorescence detection using post-column bromination (Kobra cell(r)). Results: Test portions of blank pekmez and pestil were spiked with a mixture of aflatoxins and ochratoxin A to give levels ranging from 2.6 to 10.4 MUg/kg and 1.0-4.0 MUg/kg, respectively. Recoveries for total aflatoxins and ochratoxin A ranged from 84 to 106% and 80-97%, respectively, for spiked samples. Based on results for spiked pekmez and pestil (30 replicates each at three levels), the repeatability RSD ranged from 1.6 to 12% and 2.7-11% for total aflatoxins and ochratoxin A, respectively. Conclusions: The method performance in terms of recovery, repeatability, and detection limits has been demonstrated to be suitable for use as an Official Method. Highlights: First immunoaffinity column method validated for simultaneous analysis of aflatoxins and ochratoxin A in pekmez and pestil. Suitability for use for official purposes in Turkey, demonstrated by single-laboratory validation. Co-occurrence of aflatoxins and OTA in mulberry and carob pekmez reported for the first time. PMID- 29703272 TI - A Validated Quantification of Sudan Red Dyes in Spicery using TLC and a 16-bit Flatbed Scanner. AB - We present a video-densitometric quantification method for Sudan red dyes in spices and spice mixtures, separated by TLC. Application was done band-wise in small dots using a 5 MUL glass pipette. For separation, the RP-18 plates (20 * 20 cm with fluorescent dye; Merck, Germany, 1.05559) were developed in a vertical developing chamber without vapor saturation from the starting point to a distance of 70 mm by using acetonitrile, methanol, and aqueous ammonia solution (25%; 8 + 1.8 + 0.2, v/v) as mobile phase. The quantification is based on direct measurements using an inexpensive 16-bit flatbed scanner for color measurements (in red, green, and blue). Evaluation of only the green channel makes the measurements very specific. For linearization, an extended Kubelka-Munk expression for data transformation was used. The range of linearity covers more than two magnitudes and lies between 20 and 500 ng. The extraction from a 2 g sample with acetonitrile, evaporation, and reconstitution to 200 MUL with methanol and the band-wise application (7 mm) of a 10 MUL sample allows a statistically defined LOD of less than 500 ppb of Sudan red dyes. To perform the analysis, a separation chamber, RP-18 plates, 5 MUL glass pipettes, and a 16-bit flatbed scanner for 105 ? are needed; therefore, the separation method is inexpensive, fast, and reliable. PMID- 29703273 TI - Confirmation and Identification of Listeria monocytogenes, Listeria spp. and Other Gram-Positive Organisms by the Bruker MALDI Biotyper Method: Collaborative Study, First Action 2017.10. AB - The Bruker MALDI Biotyper(r) method utilizes matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) MS for the rapid and accurate confirmation and identification of Gram-positive bacteria from select media types. This alternative method was evaluated using nonselective and selective agar plates to identify and confirm Listeria monocytogenes, Listeria species, and select Gram-positive bacteria. Results obtained by the Bruker MALDI Biotyper were compared with the traditional biochemical methods as prescribed in the appropriate reference method standards. Sixteen collaborators from 16 different laboratories located within the European Union participated in the collaborative study. A total of 36 blind-coded isolates were evaluated by each collaborator. In each set of 36 organisms, there were 16 L. monocytogenes strains, 12 non monocytogenes Listeria species strains, and 8 additional Gram-positive exclusivity strains. After testing was completed, the total percentage of correct identifications (to both genus and species level) and confirmation from each agar type for each strain was determined at a percentage of 99.9% to the genus level and 98.8% to the species level. The results indicated that the alternative method produced equivalent results when compared with the confirmatory procedures specified by each reference method. PMID- 29703274 TI - Romer Labs RapidChek(r)Listeria monocytogenes Test System for the Detection of L. monocytogenes on Selected Foods and Environmental Surfaces. AB - The Romer Labs RapidChek(r) Listeria monocytogenes test system (Performance Tested Method 011805) was validated against the U.S. Department of Agriculture Food Safety and Inspection Service Microbiology Laboratory Guidebook (USDA FSIS/MLG), U.S. Food and Drug Association Bacteriological Analytical Manual (FDA/BAM), and AOAC Official Methods of Analysis (AOAC/OMA) cultural reference methods for the detection of L. monocytogenes on selected foods including hot dogs, frozen cooked breaded chicken, frozen cooked shrimp, cured ham, and ice cream, and environmental surfaces including stainless steel and plastic in an unpaired study design. The RapidChek method uses a proprietary enrichment media system, a 44-48 h enrichment at 30 +/- 1 degrees C, and detects L. monocytogenes on an immunochromatographic lateral flow device within 10 min. Different L. monocytogenes strains were used to spike each of the matrixes. Samples were confirmed based on the reference method confirmations and an alternate confirmation method. A total of 140 low-level spiked samples were tested by the RapidChek method after enrichment for 44-48 h in parallel with the cultural reference method. There were 88 RapidChek presumptive positives. One of the presumptive positives was not confirmed culturally. Additionally, one of the culturally confirmed samples did not exhibit a presumptive positive. No difference between the alternate confirmation method and reference confirmation method was observed. The respective cultural reference methods (USDA-FSIS/MLG, FDA/BAM, and AOAC/OMA) produced a total of 63 confirmed positive results. Nonspiked samples from all foods were reported as negative for L. monocytogenes by all methods. Probability of detection analysis demonstrated no significant differences in the number of positive samples detected by the RapidChek method and the respective cultural reference method. PMID- 29703275 TI - Molar hypomineralization: What is the US experience? PMID- 29703276 TI - Does the new tax law benefit you? Probably? PMID- 29703277 TI - Correction. PMID- 29703278 TI - Mission of Mercy patient characteristics and dental-related emergency department use. AB - BACKGROUND: Although dental Mission of Mercy (MOM) events have existed for more than 2 decades and are held in more than 30 states, systematic data collection and reporting on patient characteristics, oral health care use patterns, and oral health care needs are lacking. METHODS: The authors surveyed patients attending the 2016 Florida MOM, asking about their reasons for seeking oral health care, oral health care use, and dental-related emergency department (ED) use. The authors conducted descriptive and multivariable analyses of survey and patient registration data to describe patient characteristics and examine associations between patient characteristics, time to last dental visit, and ED use. RESULTS: Sixty-six percent of 1,462 study participants reported having orofacial pain; one third of those were in pain for more than 1 year. Only 18% reported fair or poor overall health, whereas 75% reported fair or poor oral health. Florida MOM attendees who were younger adults, were of non-Hispanic ethnicity, had less than a college education, lived below federal poverty guidelines, and reported poorer oral health were at increased risk of having dental-related ED visits. CONCLUSIONS: Incorporating systematic data collection into dental MOM events provides important information about the characteristics and oral health care needs of clinic attendees that can be used to develop programs to address oral health care access on the basis of community-specific needs. PRACTICAL IMPLICATIONS: Community partners are using study data to develop strategies to address unmet oral health care needs. By systematically collecting information about patients who attend dental MOM events, we can obtain valuable information to create awareness about local community oral health care needs and promote efforts to develop sustainable strategies to improve oral health care access and outcomes. PMID- 29703279 TI - Assessment of inappropriate antibiotic prescribing among a large cohort of general dentists in the United States. AB - BACKGROUND: The purpose of this study was to assess dental antibiotic prescribing trends over time, to quantify the number and types of antibiotics dentists prescribe inappropriately, and to estimate the excess health care costs of inappropriate antibiotic prescribing with the use of a large cohort of general dentists in the United States. METHODS: We used a quasi-Poisson regression model to analyze antibiotic prescriptions trends by general dentists between January 1, 2013, and December 31, 2015, with the use of data from Express Scripts Holding Company, a large pharmacy benefits manager. We evaluated antibiotic duration and appropriateness for general dentists. Appropriateness was evaluated by reviewing the antibiotic prescribed and the duration of the prescription. RESULTS: Overall, the number and rate of antibiotic prescriptions prescribed by general dentists remained stable in our cohort. During the 3-year study period, approximately 14% of antibiotic prescriptions were deemed inappropriate, based on the antibiotic prescribed, antibiotic treatment duration, or both indicators. The quasi-Poisson regression model, which adjusted for number of beneficiaries covered, revealed a small but statistically significant decrease in the monthly rate of inappropriate antibiotic prescriptions by 0.32% (95% confidence interval, 0.14% to 0.50%; P = .001). CONCLUSIONS: Overall antibiotic prescribing practices among general dentists in this cohort remained stable over time. The rate of inappropriate antibiotic prescriptions by general dentists decreased slightly over time. PRACTICAL IMPLICATIONS: From these authors' definition of appropriate antibiotic prescription choice and duration, inappropriate antibiotic prescriptions are common (14% of all antibiotic prescriptions) among general dentists. Further analyses with the use of chart review, administrative data sets, or other approaches are needed to better evaluate antibiotic prescribing practices among dentists. PMID- 29703280 TI - Radiographic patterns of multiple myeloma in the jawbones of patients treated with intravenous bisphosphonates. AB - BACKGROUND: The purpose of this study was to evaluate whether intravenous (IV) bisphosphonate (BP) therapy can change the radiographic patterns of multiple myeloma (MM) in the jawbones. METHODS: The authors evaluated panoramic radiographs obtained from 188 patients with MM for the presence of solitary osteolytic lesions, multiple osteolytic lesions, diffuse osteoporosis, diffuse sclerosis, lamina dura abnormalities, nonhealing alveolar sockets, and bone sequestration. The authors compared results obtained from patients treated with IV BPs with those obtained from patients who had never been exposed to BPs. RESULTS: Multiple osteolytic lesions (P = .001), diffuse osteoporosis (P = .001), and diffuse sclerosis (P = .0036) occurred more often in the mandible in both groups. Solitary osteolytic lesions occurred less frequently in the BP group (P = .0078). Lamina dura abnormalities (P = .0006) and nonhealing alveolar sockets (P = .0021) were associated with BP treatment. CONCLUSIONS: IV BP therapy changes the radiographic patterns of MM in the jawbones. PRACTICAL IMPLICATIONS: The effect of BPs in the maxillofacial area is a matter of concern for health practitioners because this type of medication causes several alterations of the jawbones in patients with cancer. PMID- 29703281 TI - Radiolucent lesion of the anterior maxilla. PMID- 29703282 TI - Intracameral mydriatics during cataract surgery. PMID- 29703283 TI - Primary sulcus implantation of a diffractive multifocal pseudophakic piggyback intraocular lens. AB - PURPOSE: To evaluate the efficacy and safety of the combined implantation of a monofocal intraocular lens (IOL) in the capsular bag with a diffractive multifocal IOL designed for sulcus placement (Reverso). SETTING: Purpan Hospital, Toulouse, and Helios Clinic, Saint-Jean-de-Luz, France. DESIGN: Prospective case series. METHODS: The multifocal IOL piggyback IOL was implanted in the sulcus during cataract surgery. Visual acuity, defocus curve, contrast sensitivity, IOL positioning, and patient satisfaction were assessed with 1-year follow-ups. RESULTS: Fifty-four eyes of 27 patients were included. At 1-month, monocular uncorrected distance (UDVA) and near (UNVA) visual acuities were 0.13 logarithm of the minimum angle of resolution (logMAR) +/- 0.18 (SD) and 0.20 +/- 0.16 logMAR, respectively. Binocular UDVA and UNVA were 0.03 +/- 0.06 and 0.12 +/- 0.08 logMAR, respectively. At 1 year, the mean monocular logMAR UDVA, corrected distance visual acuity, UNVA, and corrected near visual acuity were 0.10 +/- 0.11, 0.02 +/- 0.06, 0.18 +/- 0.12, and 0.13 +/- 0.08, respectively. The defocus curve and contrast sensitivity values were comparable to those obtained with other multifocal IOLs. On Scheimpflug imaging, the mean distance between the sulcus multifocal IOL and the monofocal IOL was 517 +/- 141 MUm. At 1 year, ultrasound biomicroscopy showed an annular fibrosis of the anterior capsule in 94.4% of the eyes. Complications included 1 posttraumatic IOL decentration and 1 slight corectopia. Eighty-nine percent of patients reported satisfaction. CONCLUSIONS: The piggyback implantation of this multifocal IOL seemed to be safe and effective. It might provide similar results as a primary in-the-bag multifocal IOL, with the advantage of reversibility that might extend primary or secondary implantation. PMID- 29703284 TI - Evaluation of a multifunctional femtosecond laser for the creation of laser in situ keratomileusis flaps. AB - PURPOSE: To characterize the performance of a multifunctional femtosecond laser system (Lensx) for the creation of laser in situ keratomileusis (LASIK) flaps. SETTING: Two surgical sites in the United States. DESIGN: Prospective case series pilot study. METHODS: Patients with myopia or hyperopia who were eligible for femtosecond laser-initiated LASIK surgery with corrected distance visual acuities (CDVA) correctable to at least 20/25 were enrolled. Central flap thickness accuracy (desired versus achieved) and precision (flap thickness standard deviation) were measured using anterior segment optical coherence tomography. Flap dissection quality, stromal bed quality, and amount of opaque bubble layer (OBL) formation were graded during surgery, and the refractive outcomes were evaluated postoperatively at 1-month and 3-month follow-ups. RESULTS: The study comprised 30 patients (58 eyes). At 3 months postoperatively, the flap thickness accuracy was 1.3 MUm +/- 2.6 (SD). A total of 78.3% of flaps were lifted with no resistance and 16.7% were lifted with minimal resistance using a blunt instrument. All (100%) stromal beds were determined to have a very smooth surface (grade 5 on a 0 to 5 scale). No OBL was observed in 73.3% of eyes; 26.7% of eyes showed an OBL occurring on less than 24% of the stromal bed surface. At 3 months postoperatively, most eyes (84.5%) had an uncorrected distance visual acuity of 20/20 and 98% had a CDVA of 20/20. The most common ocular adverse event was punctate keratitis (11.7%). CONCLUSION: The multifunctional femtosecond laser system effectively created LASIK flaps that were high quality, accurate, and precise. PMID- 29703285 TI - Outcomes of cataract surgery in eyes with ocular melanoma treated with iodine-125 brachytherapy. AB - PURPOSE: To evaluate visual and surgical outcomes of cataract surgery in eyes with a history of iodine-125 (I125) brachytherapy for ocular melanoma. SETTING: Department of Ophthalmology, David Geffen School of Medicine at UCLA and the Stein Eye Institute, Los Angeles, California, USA. DESIGN: Retrospective case series. METHODS: Patients with ocular melanoma treated by I125 brachytherapy who subsequently had cataract surgery were evaluated. The recorded data included tumor size, location, preoperative ocular comorbidities, corrected distance visual acuity (CDVA), operative complications, and brachytherapy-related maculopathy before and after surgery. RESULTS: Thirty-two eyes of 32 patients were included. The mean age at the time of cataract surgery was 66.1 years. The median follow-up was 53.5 months. There were no intraoperative complications. Eighteen eyes (56.3%) had a history of preoperative radiation retinopathy, 10 involving the macula. Between 2 weeks and 4 weeks postoperatively, 22 eyes (68.8%) had an improvement in CDVA (>=2 lines). Seven of 10 eyes that failed to improve had radiation maculopathy. By the last follow-up examination, 13 eyes (40.6%) had improved CDVA, 9 eyes (28.1%) were worse (>=2 lines), and 10 eyes (31.3%) were unchanged (within +/-1 line). Of 15 eyes that lost CDVA gains achieved between 2 weeks and 4 weeks postoperatively, 9 eyes had new-onset or worsening maculopathy. Cataract surgery had no effect on local tumor control or distant metastasis. CONCLUSIONS: Cataract surgery after I125 brachytherapy for ocular melanoma improved CDVA in most eyes during the immediate postoperative period. Gains were often lost with further follow-up. Progression of radiation maculopathy was primarily responsible for subsequent visual decline. PMID- 29703286 TI - Transepithelial corneal crosslinking for keratoconus. AB - PURPOSE: To evaluate outcomes of corneal crosslinking (CXL) using a transepithelial technique for the treatment of keratoconus. SETTING: Cornea and refractive surgery subspecialty practice. DESIGN: Prospective case series. METHODS: Transepithelial CXL was performed in keratoconic eyes using riboflavin 0.1% and topical anesthetic containing benzalkonium chloride to facilitate riboflavin diffusion through the epithelium. Eyes were randomized to receive riboflavin administration either every 1 minute or every 2 minutes during ultraviolet-A exposure at 3mW/cm2. The principal outcome was change in maximum keratometry (K) and secondary outcomes included uncorrected (UDVA) and corrected (CDVA) distance visual acuities, mean K, and comparison of randomized groups. RESULTS: Eighty-two eyes of 56 patients were treated. At 1 year, maximum K decreased significantly by 0.45 diopters (D) +/- 1.94 (SD); it improved by 2.0 D or more in 11 eyes (13%) and worsened by 2.0 D or more in 4 eyes (5%). The mean UDVA significantly improved by 0.7 lines, whereas the CDVA improved by 0.2 lines. Two eyes showed both continued progression with loss of CDVA. Only the 1-minute subgroup showed significant improvements in maximum K (-0.73 D) and UDVA. Transient corneal erosion and epitheliopathy were reported in 21% of eyes. CONCLUSIONS: Transepithelial CXL resulted in significant improvements in maximum K and UDVA over 1 year. There was a suggestion that increased riboflavin dosing might improve procedure outcomes. Further study is required to determine the relative advantages and disadvantages of different transepithelial approaches to the standard CXL protocol with epithelial removal. PMID- 29703288 TI - Thermal capsulotomy: Initial clinical experience, intraoperative performance, safety, and early postoperative outcomes of precision pulse capsulotomy technology. AB - PURPOSE: To assess the clinical safety and performance of a new thermal capsulotomy device in patients having cataract surgery. SETTING: Launceston Eye Institute, Launceston, Tasmania, Australia. DESIGN: Prospective case series. METHODS: This single-surgeon consecutive series comprised eyes having capsulotomy with a precision pulse capsulotomy (PPC) device (Zepto). Baseline demographic information and preoperative, intraoperative, and early postoperative outcomes, including complications, intraocular pressure (IOP), flare photometry, corneal and retinal thickness, and specular microscopy were collected and analyzed. Outcomes included PPC performance, intraoperative complications, effective phacoemulsification time, IOP, postoperative inflammation, corneal edema, endothelial cell density, functional evaluation of the corneal endothelium, retinal thickness, cost-effectiveness, and early postoperative visual acuity. RESULTS: The study evaluated 100 eyes. Complete free-floating capsulotomy was achieved in 70 eyes (72%). Focal attachments were identified in 17 eyes (18%) and broad attachments in 10 eyes (10%). Intended PPC capsulotomy failed in 3 eyes due to operator or device error. Anterior capsule tears occurred in 4 eyes (4%); otherwise, there were no significant safety signals in the early postoperative period. There was no evidence of a learning curve effect; however, use of a dispersive ophthalmic viscosurgical device (OVD) is postulated as influencing capsulotomy completeness. CONCLUSIONS: The PPC device created round, reproducible, appropriately sized capsulotomies in 72% of eyes. The incidence of incomplete capsulotomy and radial tear rate was high and was possibly associated with the use of a dispersive OVD. PMID- 29703289 TI - Ability of a new crosslinked polymer ocular bandage gel to accelerate reepithelialization after photorefractive keratectomy. AB - PURPOSE: To evaluate the safety and performance of a crosslinked thiolated carboxymethyl hyaluronic acid liquid-gel (CMHA-S) ocular bandage gel in accelerating reepithelialization of corneal defects created for photorefractive keratectomy (PRK). SETTING: Three community-based clinical research sites. DESIGN: Prospective case series. METHODS: Patients scheduled for bilateral PRK had both eyes randomized immediately after PRK to Group 1 (ocular bandage gel 4 times a day for 14 days and bandage contact lens), Group 2 (ocular bandage gel 4 times a day for 14 days), or Group 3 (control; bandage contact lens and artificial tears 4 times a day for 14 days). Patients received a 9.0 mm epithelial defect for PRK and were followed through 28 days postoperatively. Safety assessments included adverse events, vision, pain, slitlamp, intraocular pressure, and fundus examinations. The primary performance endpoint was time to corneal reepithelialization after PRK. RESULTS: The study comprised 39 patients. The ocular bandage gel was well tolerated. The time to reepithelialization was 3 days for 54.5%, 80.0%, and 45.5% of patients in Group 1, Group 2, and Group 3, respectively. Compared with measurements in the control group, the mean horizontal and vertical defect lengths in Group 2 (ocular bandage gel alone) were 36.9% and 29.0% smaller, respectively, by 1 day. CONCLUSION: Crosslinked hyaluronic acid showed the ability to quickly reepithelialize the cornea and may promise a well-tolerated and effective therapy for ocular wound care after trauma, disease, or surgery. PMID- 29703287 TI - Pupil dilation dynamics with an intracameral fixed combination of mydriatics and anesthetic during cataract surgery. AB - PURPOSE: To compare the pupil dynamics of an intracameral combination of 2 mydriatics and 1 anesthetic (Mydrane) to a standard topical regimen for cataract surgery. SETTING: Sixty-two centers in Europe and 6 centers in Algeria. DESIGN: Prospective case series. METHODS: Pupil size measurements were performed in 2 randomized studies (phase 2 and phase 3) under masked conditions (recorded videography, masked reading center). The outcomes in the phase 2 study supported evaluation of the timeframe to obtain pupil dilation and the phase 3 study provided results on mydriasis stability. RESULTS: Phase 2 and phase 3 comprised 139 patients and 591 patients, respectively. After intracameral combination administration, 95% of the pupil dilation was achieved within a mean of 28.6 seconds +/- 4.6 (SD). At the beginning of capsulorhexis creation, the mean pupil diameter was larger than 7.0 mm in both groups. The intraoperative pupil diameter remained stable in the intracameral combination group and decreased in the topical group. The mean change in pupil size just before capsulorhexis to the end of surgery (just before cefuroxime injection) was -0.22 +/- 0.72 mm and -1.67 +/- 0.98 mm, respectively. No clinically significant change in pupil diameter (change <1.0 mm) occurred in the majority of the intracameral combination group (89.3%) compared with the topical group (26.8%). CONCLUSIONS: Intracameral combination of 2 mydriatics and 1 anesthetic is an alternative to topical mydriatics for cataract surgery. The prompt onset of pupil dilation and the stable mydriasis induced by this drug combination improved the intraoperative conditions during crucial steps, such as intraocular lens implantation. PMID- 29703290 TI - Quality of images with toric intraocular lenses. AB - PURPOSE: To objectively evaluate the image quality obtained with toric intraocular lenses (IOLs) when misaligned from the intended axis. SETTING: University Eye Clinic and the Department of Industrial and Information Engineering, University of Trieste, Trieste, Italy. DESIGN: Experimental study. METHODS: An experimental optoelectronic test bench was created. It consisted of a high-resolution monitor to project target images and an artificial eye. The system simulates the optical and geometric characteristics of the human eye with an implanted toric IOL. A 3.00 diopters corneal astigmatism was simulated. Images reproduced by the optical system were captured according to different IOL axis positions. The quality of each image was analyzed using the visual information fidelity (VIF) criterion. The VIF reduction was calculated at each IOL rotational step. RESULTS: A 5-degree IOL axis rotation from the intended position determined a decay in the image quality of 7.03%. Ten degrees of IOL rotation caused an 11.09% decay of relative VIF value. For a 30-degree rotation, the VIF decay value was 45.85%. Finally, the image decay with no toric correction was 56.70%. CONCLUSIONS: The more the objective quality of the image decays progressively, the further the axis of the IOL is rotated from its intended position. The reduction in image quality obtained after 30 degrees of toric IOL rotation was less than 50% and after 45 degrees, the image quality was the same as that of no toric correction. PMID- 29703291 TI - Continuous-light versus pulsed-light accelerated corneal crosslinking with ultraviolet-A and riboflavin. AB - PURPOSE: To determine whether the pulsed-light ultraviolet-A (UVA) accelerated corneal crosslinking (CXL) procedure is more efficacious and selective than its continuous-light counterpart in rabbits. SETTING: School of Ophthalmology and Optometry, Wenzhou Medical University, Wenzhou, Zhejiang, China. DESIGN: Experimental study. METHODS: Fifty-four rabbits were divided into 2 groups. Group 1 had continuous-light accelerated CXL using 9 mW/cm2 UVA for 10 minutes (5.4 J/cm2). Group 2 had pulsed-light accelerated CXL by exposing them to 9 mW/cm2 UVA for 20 minutes (1 second on/1 second off). Corneal stromal demarcation line depth, in vivo confocal microscopic analysis, biomechanical stiffness, endothelial cell density, and keratocyte apoptosis were measured after performing these CXL procedures. RESULTS: The mean stromal demarcation line depth was 254.7 MUm +/- 47.4 (SD) in Group 1 and 341.1 +/- 36.1 MUm in Group 2 (P < .01). One day after CXL, confocal analysis and histological staining identified keratocyte apoptotic fragments in the anterior stroma in the Group 2 corneas whereas all cells were obliterated in Group1. Seven days after treatment, the thicknesses in Group 1 were significantly greater than those in Group 2 (P < .05). Endothelial cell losses were reversible; however, in Group 1, some losses were still evident on day 7. Increases in both the stress-strain relationship and tangent modulus in Group 2 were greater than those in Group 1. CONCLUSION: The pulsed-light accelerated CXL protocol was less injurious and more efficacious at inducing CXL than the continuous-light accelerated CXL protocol in rabbit corneas. PMID- 29703292 TI - Cataract surgery with intraocular lens implantation in 3 brothers with megalocornea: Long-term follow-up. AB - Cataract surgery in patients with megalocornea is challenging because of the large capsular bag in which a conventional intraocular lens (IOL) does not fit and the atrophic nature of the iris. We report the procedures and outcomes of cataract surgery in 6 eyes of 3 brothers with megalocornea. In 2 eyes, a posterior chamber IOL (PC IOL) was inserted and sutured to the iris with 10-0 nylon sutures. In the other 4 eyes, an iris-clip anterior chamber IOL (AC IOL) was inserted. In all cases, the postoperative corrected distance visual acuity (CDVA) was 6/6. In the PC IOL group, 1 IOL dislocated and was replaced with an iris-clip AC IOL. In the AC IOL group, 1 IOL subluxated and was reenclavated. In both eyes with dislocation, the CDVA improved to 6/6. PMID- 29703293 TI - Unilateral corneal ectasia after small-incision lenticule extraction in a 43-year old patient. AB - Unilateral corneal ectasia developed after small-incision lenticule extraction for mild myopia in a 43-year-old man with preoperative asymmetric astigmatism. The ectasia was diagnosed 4 years postoperatively. Preoperative data showed asymmetric astigmatism with no signs of forme fruste keratoconus. Inferior anterior curvature steepening exceeded 2.00 diopters without bulging of the posterior curvature, and pachymetric thickness exceeded 515 MUm. Corneal ectasia can occur after small-incision lenticule extraction in patients older than 40 years with preoperative asymmetric astigmatism. PMID- 29703294 TI - Comparison of the neodymium:YAG rate after femtosecond laser-assisted and phacoemulsification cataract surgery. PMID- 29703295 TI - Survey of Scottish ophthalmic trainees' experiences using 3-piece IOLs in cataract surgery. PMID- 29703296 TI - Long-term recurrent flap complication after previous laser in situ keratomileusis: March consultation #1. PMID- 29703297 TI - March consultation #2. PMID- 29703299 TI - March consultation #4. PMID- 29703298 TI - March consultation #3. PMID- 29703300 TI - March consultation #7. PMID- 29703301 TI - March consultation #6. PMID- 29703302 TI - March consultation #5. PMID- 29703303 TI - March consultation #9. PMID- 29703304 TI - March consultation #8. PMID- 29703305 TI - Editor's Comment. PMID- 29703306 TI - Where to inject the triamcinolone? PMID- 29703307 TI - Markers of poor glycemic control are helpful to assess the risk of pseudophakic macular edema in diabetic cataract surgery patients. PMID- 29703308 TI - Reply. PMID- 29703309 TI - Primary descemetorhexis without endothelial keratoplasty to promote awareness and caution. PMID- 29703310 TI - Corrigendum to "Zinc oxide nanoparticles: synthesis, antiseptic activity and toxicity mechanism" Adv Colloid Interface Sci 249 (2017) 37-52. PMID- 29703311 TI - The changing face of academic nursing: Nurturing diversity, inclusivity, and equity. AB - This paper captures collective experiences of nursing and organizational leaders in creating organizational cultures attentive to diversity, inclusivity, and equity in schools of nursing. Within a cultural proficiency framework, exemplars and leadership lessons are shared. Most importantly, what it takes organizationally to start the ongoing journey towards cultural proficiency is explored. Ensuring the intentional systematic change at multiple levels facilitates sustainability when leadership changes occur. PMID- 29703312 TI - Leadership by collaboration: Nursing's bold new vision for academic-practice partnerships. AB - In 2016 the American Association of Colleges of Nursing issued a report, Advancing Healthcare Transformation: A New Era for Academic Nursing that included recommendations for more fully integrating nursing education, research, and practice. The report calls for a paradigm shift in how nursing leaders in academia and practice work together and with other leaders in higher education and clinical practice. Only by doing so can we realize the full benefits of academic nursing in this new era in which integration and collaboration are essential to success. In this paper we: 1) examine how academic nursing can contribute to healthcare innovation across environments; 2) explore leadership skills for deans of nursing to advance the goals of academic nursing in collaboration with clinical nursing partners, other health professions and clinical service leaders, academic administrators, and community members; and, 3) consider how governance structures and policy initiatives can advance this work. PMID- 29703313 TI - Transformational leadership: What every nursing dean should know. AB - Transformational leadership (TFL) has become a predominant leadership style practiced by leaders across many industries and disciplines, including nursing. As a component of the Full Range Leadership Model proposed by Bass (1985), TFL is characterized by the ability to stimulate, inspire, and motivate followers. Transformational leaders focus on building relationships with people and creating change by emphasizing values. Most TFL literature in nursing focuses on clinical practice with very little representation from academic nursing leadership. This article describes TFL, presents general findings from the literature, discusses this leadership style in the context of academic nursing leadership, makes recommendations for professional development of this leadership approach and offers suggests for future inquiry. PMID- 29703314 TI - Nursing leadership in academic nursing: The wisdom of development and the development of wisdom. AB - The purpose of this article is to discuss insights derived from adult cognitive developmental theories and relate the insights to vertical leadership development in academic nursing contexts. Equipped with developmental understanding, academic leaders are in a better position to support the vertical leadership development of one's self, faculty, peers, and colleagues. From a cognitive developmental perspective, the authors' reason as leaders develop, grow, and evolve, sense making becomes more sophisticated and nuanced resulting in the development of wisdom. Leadership wisdom is a function of horizontal (acquisition of information, skills, and competencies) and vertical development (the development of more complex and sophisticated ways of thinking). Ways to enhance vertical development, and sense making to cultivate wisdom are discussed. Principles and practices that promote vertical development in self and others deepens performance expectations of those in the academy and supports personal professional development and organizational success. PMID- 29703315 TI - Academic nursing leadership in a rural setting: Different game, same standards. AB - The call for transformation of nursing education and practice continues to be a national priority. The American Association of Colleges of Nursing recommends enhanced partnerships between academic nursing and academic health centers to advance nursing and healthcare. For academic leaders in rural settings, the context of health and healthcare means that these partnerships are vastly different from academic health centers. The purpose of this article is to describe the context of nursing education and practice in regions that are predominantly rural. The challenges and opportunities for rural academic leaders as they respond to calls for transforming the education of the future nursing workforce are described from the perspective of resources, recruitment and retention of faculty, clinical education and faculty practice, scholarship, and fundraising. Meeting rural health workforce needs is a national imperative and a priority of academic nursing leaders in rural settings. PMID- 29703316 TI - The challenges and opportunities in leading a multi-campus university. AB - Leadership in higher education on the best of days is complex and challenging due to the many competing internal and external demands and constituents. In today's climate of decreased funding, dwindling enrollments and political debate over the value of higher education, the higher education leader is often in the crossfires of debate and conflict. Nursing education leaders have the added requirement of protecting the public safety by graduating competent and safe practitioners. The role of the higher education leader is even more complex when the institution has multiple campuses, whether within one state or across states. This article addresses the unique challenges of leading across multiple college campus sites including autonomy in decision-making, communication, quality academic outcomes, consistency, culture, and knowledge management. Approaches to enhance leadership success include establishing system-wide goals and strategies; technology to facilitate knowledge management, communication and consistent policies; system wide committees or councils and a central office to provide support and consistency. By building the appropriate infrastructure and processes, multiple benefits of scale, expanded access, and efficiencies can be derived in multi campus educational institutions. PMID- 29703317 TI - Reflections on a dean's career: Lessons learned. AB - This article presents reflections of a recently retired dean of nursing on lessons learned and recommendations on the decanal role. The experience reflects a twenty-year period in dean positions at research universities in three states. The lessons learned relate to 1) forming a strategic vision, 2) using vision and strategic priorities to inform decisions and actions, and 3) communicating the vision and strategic framework. The conclusion looks to the future development of a cadre of energized and supported future leaders who will assume deanships in nursing. PMID- 29703318 TI - Preparing Academic Nursing Leaders for Today....and the Future. PMID- 29703319 TI - Pearls of wisdom for chief academic nursing leaders. AB - There is a significant shortage of executive leadership in nursing academia with large numbers of deans have retired and many more are expected in the upcoming years (AACN, 2015). This has resulted in a steady upward trend of nursing schools reporting a change in deans over the past 5 years; many of the changes in academic nursing leadership involve deans who are new to the role. The role expectations of chief academic nursing leaders are very complex and for which few new leaders are completely prepared. This article describes the role and competencies of the chief academic nursing leader and presents "pearls" for success for new leaders assuming this role. PMID- 29703320 TI - Do I take the job?: Assessing fit with the organization. AB - PURPOSE: A good 'fit' with an organization is critical to a leader's success yet when searching for a new position assessment an evaluation of many aspects may be overlooked, such as culture. This paper presents key considerations around 'fit' that applicants for leadership positions should consider prior to, during, and after the interview. Suggestions are provided on how to approach an evaluation of 'fit'. CONCLUSION: The importance of assessing individual fit with an organization prior to accepting a leadership position cannot be over-emphasized. PMID- 29703321 TI - Identifying, building, and sustaining your leadership team. AB - Effective leadership teams are important to the success of any organization, regardless of size or scope. This article uses the concepts of social capital and trust to shed light on team building skills and focuses on strategies that leaders can use to assemble, build, and sustain their leadership teams. Written from the perspective of someone who has had many years of experience in leadership roles, the article includes actual examples and tactics used to develop and mentor team members, foster social networks to build the team, and imbue trust to sustain the team. PMID- 29703322 TI - Disruptive trends in higher education: Leadership skills for successful leaders. PMID- 29703323 TI - A new funding model for nursing education through business development initiatives. AB - Public and private higher education funding models are shifting from traditional funding of schools and departments to a model in which schools increasingly rely on revenue other than tuition to fulfill and supplement activities related to their core missions. In this paper we discuss what nursing deans need to know about non tuition funding in this contemporary paradigm. We focus on how the Duke University School of Nursing created a Business Development Initiative (BDI) that provides additional revenue to help meets the financial needs of its' programs while nurturing the entrepreneurial spirit of faculty and staff. This BDI holds promise as a model that can be adapted by other schools seeking to support education, research and professional development initiatives without relying solely on tuition, tax dollars, endowments and/or grants. PMID- 29703324 TI - Label-free quantitative proteomics reveals fibrinopeptide B and heparin cofactor II as potential serum biomarkers in respiratory syncytial virus-infected mice treated with Qingfei oral liquid formula. AB - Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections. Qingfei oral liquid (QFOL), a traditional Chinese medicine, is widely used in clinical treatment for RSV-induced pneumonia. The present study was designed to reveal the potential targets and mechanism of action for QFOL by exploring its influence on the host cellular network following RSV infection. We investigated the serum proteomic changes and potential biomarkers in an RSV infected mouse pneumonia model treated with QFOL. Eighteen BALB/c mice were randomly divided into three groups: RSV pneumonia model group (M), QFOL-treated group (Q) and the control group (C). Serum proteomes were analyzed and compared using a label-free quantitative LC-MS/MS approach. A total of 172 protein groups, 1009 proteins, and 1073 unique peptides were successfully identified. 51 differentially expressed proteins (DEPs) were identified (15 DEPs when M/C and 43 DEPs when Q/M; 7 DEPs in common). Classification and interaction network showed that these proteins participated in various biological processes including immune response, blood coagulation, complement activation, and so forth. Particularly, fibrinopeptide B (FpB) and heparin cofactor II (HCII) were evaluated as important nodes in the interaction network, which was closely involved in coagulation and inflammation. Further, the FpB level was increased in Group M but decreased in Group Q, while the HCII level exhibited the opposite trend. These findings not only indicated FpB and HCII as potential biomarkers and targets of QFOL in the treatment of RSV pneumonia, but also suggested a regulatory role of QFOL in the RSV-induced disturbance of coagulation and inflammation-coagulation interactions. PMID- 29703325 TI - Constituent and effects of polysaccharides isolated from Sophora moorcroftiana seeds on lifespan, reproduction, stress resistance, and antimicrobial capacity in Caenorhabditis elegans. AB - Sophora moorcroftiana (S. moorcroftiana) is an endemic leguminous dwarf shrub in Tibet, China. Decoctions of the seeds have been used in Chinese folk medicine for dephlogistication, detoxication, and infectious diseases. The present study aimed to investigate the constituent and biological effects of polysaccharides from S. moorcroftiana seeds in Caenorhabditis elegans (C. elegans). Polysaccharides from S. moorcroftiana seeds (SMpol) were extracted with 60% ethanol and constituent was analyzed by GC-MS. SMpol was composed of glucose, galactose and inositol in the molar ratio of 35.7 : 1.3 : 17.0. Synchronized worms were treated with SMpol and then lifespan, motility, reproduction, stress resistance and antimicrobial activity were examined. Compared with the control group, the lifespan was increased to the average of 27.3 days and the number of laying eggs showed a 1.3 fold increase in nematodes treated with SMpol (4 mg.mL-1). In SMpol (4 mg.mL-1) treated worms, there was a 1.1-fold increase in 24-h survival of acute heat stress and a 1.6-fold increase in 2-h survival of oxidative stress The colonization of the bacteria in the SMpol treated nematode was significantly lower than that of the untreated group by 68.3%. In vivo studies showed SMpol significantly extended the life span, improved reproduction, increased stress resistance and antimicrobial capacity of C. elegans. In conclusion, those results indicated that the polysaccharides from S. moorcroftiana seeds were involved in a variety of biological activities leading to its modulatory effects on C. elegans which may be developed as a natural supplement agent. PMID- 29703326 TI - 1H NMR-based metabolomics approach to investigating the renal protective effects of Genipin in diabetic rats. AB - Diabetic nephropathy is one of the various complications of diabetes mellitus, affecting patients for lifetime. Earlier studies have revealed that genipin can not only improve diabetes, but also induce cytotoxicity. Therefore, it is not clear which effect of genipin on kidneys occurs, when it is used in the treatment of diabetes. In the present study, we performed nuclear magnetic resonance (NMR) based metabolomics analysis of urine and kidney tissue samples obtained from diabetic rats to explore the change of endogenous metabolites associated with diabetes and concomitant kidney disease. Nine significant differential metabolites that were closely related to renal function were screened. They were mainly related to three metabolic pathways: synthesis and degradation of ketone bodies, glycine, serine and threonine metabolism, and butanoate metabolism, which are involved in methylamine metabolism, energy metabolism and amino acid metabolism. In addition, after the intervention of genipin, the metabolic levels of all the metabolites tended to be normal, indicating a protective effect of genipin on kidneys. Our results may be helpful for understanding the antidiabetic effect of genipin. PMID- 29703327 TI - Metabolic profiling of endogenous bile acids: a novel method to assess hepatoprotective effect of Tanreqing capsule on carbon-tetrachloride-induced liver injury in rats. AB - Tanreqing (TRQ), a traditional Chinese medicine (TCM) formula, can alleviate liver injury and improve liver function. Its pharmacological mechanisms of actions are still unclear due to its complex components and multi-target natures. Metabolomic study is an effective approach to investigating drug pharmacological actions, new diagnostic markers, and potential mechanisms of actions. In the present study, a new strategy was used to evaluate the protective effect of TRQ capsule against carbon tetrachloride (CCl4)-induced hepatotoxicity in rats, by analyzing metabolic profiling of endogenous bile acids (BAs) along with biochemical and histological analyses. BAs concentrations were determined by ultra-performance liquid chromatography coupled with quadrupole mass spectrometry (UPLC-MS). Principal component analysis and partial least squares discriminant analysis were then employed to analyze the UPLC-MS results and compare the hepatoprotective effect of TRQ capsule in different groups at the doses of 0.36, 1.44, and 2.88 g.kg-1 body weight, respectively. Moreover, our results suggested that taurocholic acid (TCA) and taurohyodesoxycholic acid (THDCA) were the most important biochemical markers, which were indicative of CCl4-induced acute hepatic damage and hepatoprotective effect of TRQ capsule. Therefore, this new strategy would be an excellent alternative method for evaluating hepatoprotective effect and proposing potential mechanisms of action for other drugs as well. PMID- 29703328 TI - Cornus mas L. extract as a multifunctional material for manufacturing cosmetic emulsions. AB - Dogwood fruits are a valuable source of active ingredients, such as phenolic compounds, vitamin C, iridoids, flavonoids and anthocyanins. Plant extracts and substances derived from latin Cornus mas L. exhibit not only strong antibacterial but also antioxidant and tonicity properties, effectively preventing the development of inflammation in living organisms. In the present study, we attempted to obtain the innovative, multi-functional plant extract from the fruit of dogwood (Cornus mas L.). During the extraction process a mixture of water, glycerol, and vegetable oil were used as an extractant. The usage of such mixtures of solvents enabled us to extract a variety of active substances, soluble in both water and oils. The obtained extracts were analyzed for their physicochemical and biochemical properties, in order to apply the extract in a body nutrient lotion. The results clearly showed that such extract could be an innovative and multi-functional raw material used in cosmetics industry. PMID- 29703329 TI - Formulation development and evaluation of gastroretentive floating beads with Brucea javanica oil using ionotropic gelation technology. AB - In the present study, a gastric retention floating system for Brucea javanica oil, composed of alginate and carrageenan, was prepared using ionotropic gelation. Parameters for floatability, drug load, encapsulation efficiency, bead morphology, in vitro release, and in vivo gastric retention were evaluated. The optimized formulation via Box-Behnken design consisted of 1.7% alginate (W/V), 1.02% carrageenan (W/V), 1.4% CaCO3 (W/V), and a gelling bath of pH 0.8. The alginate-carrageenan-Brucea javanica oil beads had a porous structure and exhibited up to 24 h of in vitro floatability with a load capacity of 45%-55% and an encapsulation efficiency of 70%-80%. A 6-h sustained release was observed in vitro. The beads had a prolonged gastric retention (> 60% at 6 h) in fasted rats, compared to non-floating beads (15% at 6 h), as measured by gamma scintigraphy with single-photon emission tomography/computed tomography (SPET/CT). In conclusion, the alginate-carrageenan-Brucea javanica oil system showed enhanced oil encapsulation efficiency, excellent floating and gastric retention abilities, and a favorable release behavior. PMID- 29703330 TI - Screening and analysis of key active constituents in Guanxinshutong capsule using mass spectrum and integrative network pharmacology. AB - Guanxinshutong capsule (GXSTC) is an effective and safe traditional Chinese medicine used in the treatment of cardiovascular diseases (CVDs) for many years. However, the targets of this herbal formula and the underlying molecular mechanisms of action involved in the treatment of CVDs are still unclear. In the present study, we used a systems pharmacology approach to identify the active ingredients of GXSTC and their corresponding targets in the calcium signaling pathway with respect to the treatment of CVDs. This method integrated chromatographic techniques, prediction of absorption, distribution, metabolism, and excretion, analysis using Kyoto Encyclopedia of Genes and Genomes, network construction, and pharmacological experiments. 12 active compounds and 33 targets were found to have a role in the treatment of CVDs, and four main active ingredients, including protocatechuic acid, cryptotanshinone, eugenol, and borneol were selected to verify the effect of (GXSTC) on calcium signaling system in cardiomyocyte injury induced by hypoxia and reoxygenation. The results from the present study revealed the active components and targets of GXSTC in the treatment of CVDs, providing a new perspective to enhance the understanding of the role of the calcium signaling pathway in the therapeutic effect of GXSTC. PMID- 29703331 TI - An UPLC-MS/MS method for simultaneous determination of multiple constituents in Guizhi Fuling capsule with ultrafast positive/negative ionization switching. AB - Guizhi Fuling capsule (GFC), a traditional Chinese medicine (TCM) with effects of promoting blood circulation and dissipating blood stasis, has been widely used in the clinic. Because of the complex matrix and various chemical structure types, quality control of GFC remains great challenge. In the present study, an ultra performance liquid chromatography hybrid triple-quadrupole mass spectrometry (UPLC-QQQ MS) method with ultrafast positive/negative ionization switching was developed for simultaneous determination of 18 bioactive components in GFC, including methyl gallate, ethyl gallate, oxypaeoniflorin, benzoic acid, albiflorin, paeonolide, paeoniflorin, 1, 2, 3, 4, 6-pentagalloylglucose, mudanpioside C, benzoyloxypaeoniflorin, benzoylpaeoniflorin, pachymic acid, amygdalin, cinnamaldehyde, paeonol, cinnamic acid, 4-hydroxybenzoic acid, and gallic acid. Separation was performed on an Agilent Zorbax Extend-C18 column (2.1 mm * 50 mm, 1.8 MUm), using a gradient elution with acetonitrile and water containing 0.1% formic acid. Cholic acid was selected as the internal standard. This newly developed method was fully validated for linearity, precision, accuracy, and stability, and then applied to quality assessment of GFC. Finally, the batch-to-batch reproducibility of GFC samples was evaluated by the cosine ration and Euclidean distance method, which showed high quality consistency. The results demonstrated that the developed method pro vided a reasonable and powerful manner for quality control of GFC. PMID- 29703332 TI - Sugar, video games, and VTE: an unseen connection? PMID- 29703333 TI - Optimising initial treatment for peripheral T-cell lymphoma: a tough nut to CHOP. PMID- 29703334 TI - Analysis of big data for heparin-induced thrombocytopenia: valuable information but also some doubts. PMID- 29703336 TI - Disease burden, complication rates, and health-care costs of heparin-induced thrombocytopenia in the USA: a population-based study. AB - BACKGROUND: Heparin-induced thrombocytopenia can be a life-threatening and limb threatening complication of heparin therapy. Incidence and complication rates of this condition have been extrapolated from studies with modest sample sizes, and despite the availability of therapeutic interventions the outcomes of heparin induced thrombocytopenia are not well understood. We aimed to estimate disease burden, complication rates, and costs of heparin-induced thrombocytopenia in the USA. METHODS: In this population-based study we analysed data from 2009 to 2013 from the Nationwide (National) Inpatient Sample (NIS), a large, all-payer inpatient health-care database in the USA. To validate the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code for heparin-induced thrombocytopenia (289.84), we defined the sensitivity and specificity of this code using patient data from 2013 from a local hospital (Froedtert Memorial Lutheran Hospital, Milwaukee, WI, USA). The primary outcomes assessed were the incidence of hospital discharges with codes for heparin-induced thrombocytopenia and of discharges for heparin-induced thrombocytopenia associated with cardiopulmonary bypass, haemodialysis, hip or knee arthroplasty, trauma or injury (or both), and gingival or periodontal disease (or both). We also assessed the incidence of thrombosis, bleeding, limb or digit amputation, mortality, length of hospital stay, and associated hospital charges. FINDINGS: Between 2009 and 2013, 97 566 discharges from the NIS assigned the ICD-9-CM code for heparin-induced thrombocytopenia, and 149 911 247 discharges coded for non heparin-induced thrombocytopenia, were analysed. Overall, heparin-induced thrombocytopenia was identified in 97 566 (0.065%; SE 0.0012) of 150 008 813 discharges, corresponding to approximately one in 1500 hospital admissions. Patients undergoing cardiopulmonary bypass had the highest rates of heparin induced thrombocytopenia (7702 [0.63%; SE 0.03] of 1 230 362), followed by those undergoing haemodialysis (23 012 [0.47%; 0.01] of 4 908 100), those with gingival or periodontal disease, or both (106 [0.12%; 0.03] of 88 621), and those with trauma or injury, or both (541 [0.09%; 0.01] of 602 944); patients with hip (845 [0.04%; 0.004] of 1 943 353) and knee (676 [0.02%; 0.002] of 3 022 602) arthroplasty had the lowest rates of heparin-induced thrombocytopenia. Thrombosis (29 079 [29.8%; SE 0.4] of 97 566) and bleeding (6044 [6.2%; 0.2] of 97 566) were common complications in heparin-induced thrombocytopenia, and 1446 (23.9%; 1.2) of 6044 patients with heparin-induced thrombocytopenia who had haemorrhage died. 742 (0.76%; SE 0.06) of 97 566 patients with heparin-induced thrombocytopenia discharges underwent amputations compared with 173 043 (0.12%; 0.001) of 149 911 247 with non-heparin-induced thrombocytopenia discharges (adjusted odds ratio 5.095 [95% CI 4.309-6.023]; p<0.0001). Overall, in-hospital mortality was 9842 (10.1%; SE 0.2) of 97 508 in discharge summaries coded for heparin-induced thrombocytopenia compared with 3 206 700 (2.1%; 0.01) of 149 811 891 in discharges for non-heparin-induced thrombocytopenia (adjusted odds ratio 4.075 [95% CI 3.846-4.317]; p<0.0001). The median length of stay among live discharges was 8.9 days (IQR 4.6-17.1) and total hospital charges were US$83 072 (IQR 37 240 188 419) for heparin-induced thrombocytopenia discharges compared with 2.6 days (1.4-4.8) and $21 360 (11 426-41 917) for non-heparin-induced thrombocytopenia discharges (p<0.0001 for both). 333 discharges from a local hospital were analysed to assess the diagnostic sensitivity and specificity of the heparin induced thrombocytopenia ICD-9-CM code; sensitivity was 90.9% (95% CI 57.1-99.5) and specificity was 94.4% (91.1-96.6). INTERPRETATION: Complication rates for heparin-induced thrombocytopenia remain high and more effective preventive and treatment interventions are needed. FUNDING: None. PMID- 29703337 TI - Single or Multiple Electroacupuncture Sessions in Nonspecific Low Back Pain: Are We Low-Responders to Electroacupuncture? AB - The objective of this study was to compare the effects of one or multiple sessions of electroacupuncture (EA) in patients with chronic low back pain. The outcome measures were visual analog score (VAS), pressure pain threshold (PPT), McGill pain questionnaire (MPQ), Roland Morris disability questionnaire (RMDQ), low back skin temperature, surface electromyography of longissimus muscle (contraction/rest) and blood cytokines. After examination (AV0), patients were submitted to EA (2 Hz, 30 minutes, bilaterally at the SP6, BL23, BL31, BL32, BL33, and BL60) and were revaluated after one week (AV1). Patients with VAS <3 (VAS <3 group, n = 20) were directed to return after three weeks (AV2). Patients with VAS >3 (VAS >3 group, n = 20) were submitted to one weekly EA-treatment and revaluated after three weeks (AV2). The VAS <3 group showed a significant reduction in VAS and MPQ and increased PPT in AV1, but not in AV2. No significant differences were found in RMDQ. The VAS >3 group showed reduction in VAS and increased PPT in AV1 and a reduction in MPQ and RMDQ only in AV2. No significant differences were found in electromyography, temperature or cytokines. Thus, despite 2Hz-EA is effective reducing low back pain, some patients only experienced reduced pain intensity and improved functional capacity after full treatment. PMID- 29703338 TI - Pave the Way for Our Global Future. PMID- 29703335 TI - CHOP versus GEM-P in previously untreated patients with peripheral T-cell lymphoma (CHEMO-T): a phase 2, multicentre, randomised, open-label trial. AB - BACKGROUND: Outcomes with CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) or CHOP-like chemotherapy in peripheral T-cell lymphoma are poor. We investigated whether the regimen of gemcitabine, cisplatin, and methylprednisolone (GEM-P) was superior to CHOP as front-line therapy in previously untreated patients. METHODS: We did a phase 2, parallel-group, multicentre, open-label randomised trial in 47 hospitals: 46 in the UK and one in Australia. Participants were patients aged 18 years and older with bulky (tumour mass diameter >10 cm) stage I to stage IV disease (WHO performance status 0-3), previously untreated peripheral T-cell lymphoma not otherwise specified, angioimmunoblastic T-cell lymphoma, anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, enteropathy-associated T-cell lymphoma, or hepatosplenic gammadelta T-cell lymphoma. We randomly assigned patients (1:1) stratified by subtype of peripheral T-cell lymphoma and international prognostic index to either CHOP (intravenous cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1.4 mg/m2 [maximum 2 mg] on day 1, and oral prednisolone 100 mg on days 1-5) every 21 days for six cycles; or GEM-P (intravenous gemcitabine 1000 mg/m2 on days 1, 8, and 15, cisplatin 100 mg/m2 on day 15, and oral or intravenous methylprednisolone 1000 mg on days 1-5) every 28 days for four cycles. The primary endpoint was the proportion of patients with a CT-based complete response or unconfirmed complete response on completion of study chemotherapy, to detect a 20% superiority of GEM-P compared with CHOP, assessed in all patients who received at least one cycle of treatment and had an end-of treatment CT scan or reported clinical progression as the reason for stopping trial treatment. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov (NCT01719835) and the European Clinical Trials Database (EudraCT 2011-004146-18). FINDINGS: Between June 18, 2012, and Nov 16, 2016, we randomly assigned 87 patients to treatment, 43 to CHOP and 44 to GEM-P. A planned unmasked review of efficacy data by the independent data monitoring committee in November, 2016, showed that the number of patients with a confirmed or unconfirmed complete response with GEM-P was non-significantly inferior compared with CHOP and the trial was closed early. At a median follow-up of 27.4 months (IQR 16.6-38.4), 23 patients (62%) of 37 assessable patients assigned to CHOP had achieved a complete response or unconfirmed complete response compared with 17 (46%) of 37 assigned to GEM-P (odds ratio 0.52, 95% CI 0.21-1.31; p=0.164). The most common adverse events of grade 3 or worse in both groups were neutropenia (17 [40%] with CHOP and nine [20%] with GEM-P), thrombocytopenia (4 [10%] with CHOP and 13 [30%] with GEM-P, and febrile neutropenia (12 [29%] with CHOP and 3 [7%] with GEM-P). Two patients (5%) died during the study, both in the GEM-P group, from lung infections. INTERPRETATION: The number of patients with a complete response or unconfirmed complete response did not differ between the groups, indicating that GEM-P was not superior for this outcome. CHOP should therefore remain the reference regimen for previously untreated peripheral T-cell lymphoma. FUNDING: Bloodwise and the UK National Institute of Health Research. PMID- 29703339 TI - Helping Military Service Members Make Their Food Dollars Count. PMID- 29703341 TI - Author's Response. PMID- 29703340 TI - Malnutrition Intervention Implementation. PMID- 29703342 TI - Position of the Academy of Nutrition and Dietetics, Society for Nutrition Education and Behavior, and School Nutrition Association: Comprehensive Nutrition Programs and Services in Schools. AB - It is the position of the Academy of Nutrition and Dietetics, School Nutrition Association, and Society for Nutrition Education and Behavior that comprehensive, integrated nutrition programs in preschool through high school are essential to improve the health, nutritional status, and academic performance of our nation's children. Through the continued use of multidisciplinary teams, local school needs will be better identified and addressed within updated wellness policies. Updated nutrition standards are providing students with a wider variety of fruits, vegetables, and whole grains, while limiting sodium, calories, and saturated fat. Millions of students enjoy school meals every day in the United States, with the majority of these served to children who are eligible for free and reduced-priced meals. To maximize impact, the Academy, School Nutrition Association, and Society for Nutrition Education and Behavior recommend specific strategies in the following key areas: food and nutrition services available throughout the school campus, nutrition initiatives such as farm to school and school gardens, wellness policies, nutrition education and promotion, food and beverage marketing at school, and consideration of roles and responsibilities. PMID- 29703343 TI - Practice Paper of the Academy of Nutrition and Dietetics: Comprehensive Nutrition Programs and Services in Schools. AB - It is the position of the Academy of Nutrition and Dietetics, School Nutrition Association (SNA), and Society for Nutrition Education and Behavior (SNEB) that comprehensive, integrated nutrition programs in preschool through high school are essential to improve the health, nutritional status, and academic performance of our nation's children. To maximize impact, the Academy, SNA, and SNEB recommend specific strategies in the following key areas: food and nutrition services available throughout the school campus, nutrition initiatives such as Farm to School and school gardens, wellness policies, nutrition education and promotion, and consideration of roles and responsibilities. This paper supports the joint position paper of the Academy of Nutrition and Dietetics, SNA, and SNEB published in the May 2018 Journal of Academy of Nutrition and Dietetics. In alignment with the joint position paper, this practice paper provides registered dietitian nutritionists and nutrition and dietetics technicians, registered with an overview of current school nutrition services and opportunities for professional careers in school settings. The Academy of Nutrition and Dietetics has several position papers related to youth preschool through adolescence that cover specific nutrition needs in more detail at www.eatright.org. PMID- 29703345 TI - Erratum. PMID- 29703344 TI - Academy of Nutrition and Dietetics: Revised 2017 Standards of Practice and Standards of Professional Performance for Registered Dietitian Nutritionists (Competent, Proficient, and Expert) in Diabetes Care. AB - There are 30.3 million people with diabetes and 86 million with prediabetes in the United States, underscoring the growing need for comprehensive diabetes care and nutrition for the management of diabetes and diabetes-related conditions. Management of diabetes is also critical for the prevention of diabetes-related complications such as cardiovascular and renal disease. The Diabetes Care and Education Dietetic Practice Group along with the Academy of Nutrition and Dietetics Quality Management Committee have updated the Standards of Practice (SOP) and Standards of Professional Performance (SOPP) for Registered Dietitian Nutritionists (RDNs) in Diabetes Care. The SOP and SOPP for RDNs in Diabetes Care provide indicators that describe three levels of practice: competent, proficient, and expert. The SOP utilizes the Nutrition Care Process and clinical workflow elements for care and management of those with diabetes and prediabetes. The SOPP describes six domains that focus on professionalism: Quality in Practice, Competence and Accountability, Provision of Services, Application of Research, Communication and Application of Knowledge, and Utilization and Management of Resources. Specific indicators outlined in the SOP and SOPP depict how these standards apply to practice. The SOP and SOPP are complementary resources for RDNs caring for individuals with diabetes or specializing in diabetes care or practicing in other diabetes-related areas, including research. The SOP and SOPP are intended to be used for RDN self-evaluation for ensuring competent practice and for determining potential education and training needs for advancement to a higher practice level in a variety of settings. PMID- 29703346 TI - Why Do Practitioners Need to Read the Revised 2017 Scope/Standards Documents? PMID- 29703348 TI - May 2018 Featured Articles, Volume 226. PMID- 29703347 TI - Three-Dimensional Surgery Helps Liver Segmentectomy. PMID- 29703349 TI - Correction. PMID- 29703350 TI - Our Discoverers and Innovators-Celebrating 100 Years of the AAOMS. PMID- 29703351 TI - Improving systems of care for preterm infants. PMID- 29703352 TI - Childhood mental health conditions have substantial impact on educational dropout. PMID- 29703353 TI - 50 Years Ago in The Journal of Pediatrics: Spurious Heart Disease in Athletic Children. PMID- 29703354 TI - 50 Years Ago in The Journal of Pediatrics: Comparison of Orally Absorbable and Nonabsorbable Antibiotics in Shigellosis: A Double-Blind Study with Ampicillin and Neomycin. PMID- 29703355 TI - 50 Years Ago in The Journal of Pediatrics: Do We Know How to Treat Kwashiorkor? PMID- 29703357 TI - Universal vs targeted cholesterol screening. PMID- 29703356 TI - Hey baby, slow down-what happens now matters! PMID- 29703358 TI - Does fat or fat-free body mass drive neurodevelopment? PMID- 29703359 TI - A Cost Analysis of Universal versus Targeted Cholesterol Screening in Pediatrics. AB - OBJECTIVE: To compare the number of children needed to screen to identify a case of childhood dyslipidemia and estimate costs under universal vs targeted screening approaches. STUDY DESIGN: We constructed a decision-analytic model comparing the health system costs of universal vs targeted screening for hyperlipidemia in US children aged 10 years over a 1-year time horizon. Targeted screening was defined by family history: dyslipidemia in a parent and/or early cardiovascular disease in a first-degree relative. Prevalence of any hyperlipidemia (low-density lipoprotein [LDL] >=130 mg/dL) and severe hyperlipidemia (LDL >=190 mg/dL or LDL >=160 mg/dL with family history) were obtained from published estimates. Costs were estimated from the 2016 Maryland Medicaid fee schedule. We performed sensitivity analyses to evaluate the influence of key variables on the incremental cost per case detected. RESULTS: For universal screening, the number needed to screen to identify 1 case was 12 for any hyperlipidemia and 111 for severe hyperlipidemia. For targeted screening, the number needed to screen was 7 for any hyperlipidemia and 49 for severe hyperlipidemia. The incremental cost per case detected for universal compared with targeted screening was $1980 for any hyperlipidemia and $32 170 for severe hyperlipidemia. CONCLUSIONS: Our model suggests that universal cholesterol screening detects hyperlipidemia at a low cost per case, but may not be the most cost-efficient way to identify children with severe hyperlipidemia who are most likely to benefit from treatment. PMID- 29703360 TI - 50 Years Ago in The Journal of Pediatrics: The Genetic Basis for the Variability of the Hereditable Diseases. PMID- 29703361 TI - Childhood-Onset Systemic Lupus Erythematosus: A Review and Update. PMID- 29703362 TI - 50 Years Ago in The Journal of Pediatrics: Abuse of Tetanus Toxoid. PMID- 29703364 TI - Education of parents and providers is needed to optimize life-saving immunizations for children with sickle cell disease. PMID- 29703365 TI - Probiotic Lactobacillus reuteri effective in treating infantile colic and is associated with inflammatory marker reduction. PMID- 29703363 TI - Food Insecurity and Family Well-Being Outcomes among Households with Young Children. AB - OBJECTIVES: To investigate associations between household food insecurity and multiple family well-being variables in an effort to illuminate previously understudied, policy-amenable mechanisms through which food insecurity threatens healthy development. STUDY DESIGN: Data are drawn from the nationally representative Early Childhood Longitudinal Study-Birth Cohort. The Early Childhood Longitudinal Study-Birth Cohort contains longitudinal data on household food insecurity and several family well-being factors including maternal physical and mental health, positive parenting practices and disciplinary strategies, and frequency and severity of spousal conflict. We use regression models with lagged dependent variables to estimate associations between food insecurity and family well-being outcomes, on a subsample of low-income families (N ~ 2100-4700). RESULTS: Household food insecurity was significantly associated with poorer maternal physical health; increased depressive symptoms and use of harsh discipline strategies; and greater frequency and negativity of conflict between parents. Associations were strongest and most consistent when children were preschool aged. Transitions into food insecurity between toddlerhood and preschool were also associated with significantly worse parental physical and mental health outcomes, and more family conflict, with similar though slightly weaker and less consistent associations for transitioning into food insecurity between infancy and toddlerhood. CONCLUSIONS: Food insecurity is associated with significant decreases in family health and well-being. Clinicians and other public health officials play a critical role in assessing risk for children and families, and linking families with supportive services. Screening families experiencing or at risk for food insecurity and connecting them with resources is an avenue through which public health practitioners can support family health. PMID- 29703366 TI - Narrow-spectrum, compared with broad-spectrum, antibiotics equally effective with less adverse events. PMID- 29703367 TI - Monthly virtual asthma care at least as efficacious as routine visits. PMID- 29703369 TI - Delayed cord clamping may not be beneficial in the premature infant. PMID- 29703368 TI - Surgery highly effective for seizure cessation in drug-resistant epilepsy. PMID- 29703370 TI - Never-Ending Stories, the Loop in Pediatrics-How Many Pediatricians Need to be Trained in European Countries to Keep the Pediatric Workforce Stable? PMID- 29703371 TI - Preserving Future Generations of Pediatric Researchers. PMID- 29703372 TI - 50 Years Ago in The Journal of Pediatrics: Rash Associated with Juvenile Rheumatoid Arthritis. PMID- 29703373 TI - The Paper that Restarted Modern Central Nervous System Axon Regeneration Research. AB - Spinal cord repair research appeared to have run out of new ideas in the 1970s. In a 1981 paper, the Aguayo Laboratory revisited an experiment by Tello and Cajal that suggested that central nervous system (CNS) axons could regenerate into peripheral nerve grafts. Using modern axon tracing methods, David and Aguayo showed that axons from neurons in the spinal cord could regenerate for long distances within peripheral nervous system (PNS) grafts, but not back into the CNS. This proved that damaged CNS tissue is inhibitory to axon regeneration while PNS tissue is permissive. The experiment sparked a research revival, leading to the identification of many inhibitory molecules that block axon growth in the mature CNS. PMID- 29703374 TI - The Rough Seas of Cortical Cartography. AB - Efforts to parcellate the cortex into areas based on fine-scale anatomical signatures (e.g., cytoarchitectonics) date back to the early years of the last century. In the ensuing decades, rapidly growing knowledge of cortical connections encouraged neurobiologists to search for connectivity-based principles underlying the organization of the cerebral cortex. Using such an approach, Felleman and Van Essen presented, in their 1991 paper, a connectivity based hierarchical principle dictating the relationship between cortical areas. This helped invigorate debates on the principles underlying cortical organization, including searches for alternative, or complementary, principles. PMID- 29703375 TI - Understanding the Brain, By Default. AB - In 2001 Raichle and colleagues showed that, at rest, brain activity fluctuates near a metabolically active equilibrium: a 'default mode' of brain function. This finding broke ranks with the prevailing 'task-rest' dichotomy to position the brain as continuously active, balancing the deployment of resources according to current and anticipated needs. PMID- 29703376 TI - All in the Family: Repeats and ALS/FTD. AB - In 2011, an intronic (G4C2)*(G2C4) expansion was shown to cause the most common forms of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). This discovery linked ALS with a clinically distinct form of dementia and a larger group of microsatellite repeat diseases, and catalyzed basic and translational research. PMID- 29703378 TI - Preface. PMID- 29703379 TI - Excipient-drug pharmacokinetic interactions: Effect of disintegrants on efflux across excised pig intestinal tissues. AB - Pharmaceutical excipients were designed originally to be pharmacologically inert. However, certain excipients were found to have altering effects on drug pharmacodynamics and/or pharmacokinetics. Pharmacokinetic interactions may be caused by modulation of efflux transporter proteins, intercellular tight junctions and/or metabolic enzyme amongst others. In this study, five disintegrants from different chemical classes were evaluated for P-glycoprotein (P-gp) related inhibition and tight junction modulation effects. Bi-directional transport studies of the model compound, Rhodamine 123 (R123) were conducted in the absence (control group) and presence (experimental groups) of four concentrations of each selected disintegrant across excised pig jejunum tissue. The results showed that some of the selected disintegrants (e.g. Ac-di-sol(r) and Kollidon(r) CL-M) increased R123 absorptive transport due to inhibition of P-gp related efflux, while another disintegrant (e.g. sodium alginate) changed R123 transport due to inhibition of P-gp in conjunction with a transient opening of the tight junctions in a concentration dependent way. It may be concluded that the co-application of some disintegrants to the intestinal epithelium may lead to pharmacokinetic interactions with drugs that are susceptible to P-gp related efflux. However, the clinical significance of these in vitro permeation findings should be confirmed by means of in vivo studies. PMID- 29703380 TI - A regulatory science viewpoint on botanical-drug interactions. AB - There is a continued predisposition of concurrent use of drugs and botanical products. Consumers often self-administer botanical products without informing their health care providers. The perceived safety of botanical products with lack of knowledge of the interaction potential poses a challenge for providers and both efficacy and safety concerns for patients. Botanical-drug combinations can produce untoward effects when botanical constituents modulate drug metabolizing enzymes and/or transporters impacting the systemic or tissue exposure of concomitant drugs. Examples of pertinent scientific literature evaluating the interaction potential of commonly used botanicals in the US are discussed. Current methodologies that can be applied to advance our efforts in predicting drug interaction liability is presented. This review also highlights the regulatory science viewpoint on botanical-drug interactions and labeling implications. PMID- 29703381 TI - Activation of P-glycoprotein and CYP 3A by Coptidis Rhizoma in vivo: Using cyclosporine as a probe substrate in rats. AB - Coptidis Rhizoma (CR), the rhizome of Coptis chinensis FRANCH, is a popular Chinese herb. CR contains plenty of isoquinoline alkaloids such as berberine, coptisine and palmatine. Cyclosporine (CSP), an important immunosuppressant with narrow therapeutic window, is employed as a probe substrate of P-glycoprotein (P gp) and CYP3A4 in order to investigate the in vivo modulation effect of CR on P gp and CYP3A4. Three groups of rats were orally administered CSP without and with single dose or repeated dosing of CR in a parallel design. Blood samples were collected at specific time points and the blood CSP concentration was determined by a specific monoclonal fluorescence polarization immunoassay. The results showed that a single dose (1.0 g/kg) and the 7th dose (1.0 g/kg) of CR significantly decreased the Cmax of CSP by 56.9% and 70.4%, and reduced the AUC0 540 by 56.4% and 68.7%, respectively. Cell study indicated that CR decoction, berberine, coptisine, palmatine all activated the efflux transport of P-gp. Ex vivo study showed that the serum metabolites of CR activated CYP 3A4. In conclusion, through using CSP as an in vivo probe substrate, we have verified that oral intake of CR activated the functions of P-gp and CYP3A based on in vivo and in vitro studies. PMID- 29703382 TI - Transporter-mediated interaction of indican and methotrexate in rats. AB - Indican (indoxyl-beta-D-glucoside) is present in several Chinese herbs e.g. Isatis indigotica, Polygonum tinctorium and Polygonum perfoliatum. The major metabolite of indican was indoxyl sulfate (IS), an uremic toxin which was a known substrate/inhibitor of organic anion transporter (OAT) 1, OAT 3 and multidrug resistance-associated protein (MRP) 4. Methotrexate (MTX), an important immunosuppressant with narrow therapeutic window, is a substrate of OAT 1, 2, 3, 4 and MRP 1, 2, 3, 4. We hypothesized that IS, the major metabolite of oral indican, might inhibit the renal excretion of MTX mediated by OAT 1, OAT 3 and MRP 4. Therefore, this study investigated the effect of oral indican on the pharmacokinetics of MTX. Rats were orally given MTX with and without indican (20.0 and 40.0 mg/kg) in a parallel design. The serum MTX concentration was determined by a fluorescence polarization immunoassay. For mechanism clarification, phenolsulfonphthalein (PSP, 5.0 mg/kg), a probe substrate of OAT 1, OAT 3, MRP 2 and MRP 4, was intravenously given to rats with and without a intravenous bolus of IS (10.0 mg/kg) to measure the effect of IS on the elimination of PSP. The results indicated that 20.0 and 40.0 mg/kg of oral indican significantly increased the area under concentration-time curve0-t (AUC0 t) of MTX by 231% and 259%, prolonged the mean residence time (MRT) by 223% and 204%, respectively. Furthermore, intravenous IS significantly increased the AUC0 t of PSP by 204% and decreased the Cl by 68%. In conclusion, oral indican increased the systemic exposure and MRT of MTX through inhibition on multiple anion transporters including OAT 1, OAT 3 and MRP 4 by the major metabolite IS. PMID- 29703377 TI - The Parabrachial Nucleus: CGRP Neurons Function as a General Alarm. AB - The parabrachial nucleus (PBN), which is located in the pons and is dissected by one of the major cerebellar output tracks, is known to relay sensory information (visceral malaise, taste, temperature, pain, itch) to forebrain structures including the thalamus, hypothalamus, and extended amygdala. The availability of mouse lines expressing Cre recombinase selectively in subsets of PBN neurons and viruses for Cre-dependent gene expression is beginning to reveal the connectivity and functions of PBN component neurons. This review focuses on PBN neurons expressing calcitonin gene-related peptide (CGRPPBN) that play a major role in regulating appetite and transmitting real or potential threat signals to the extended amygdala. The functions of other specific PBN neuronal populations are also discussed. This review aims to encourage investigation of the numerous unanswered questions that are becoming accessible. PMID- 29703383 TI - PXR as a mediator of herb-drug interaction. AB - Medicinal herbs have been a part of human medicine for thousands of years. The herb-drug interaction is an extension of drug-drug interaction, in which the consumptions of herbs cause alterations in the metabolism of drugs the patients happen to take at the same time. The pregnane X receptor (PXR) has been established as one of the most important transcriptional factors that regulate the expression of phase I enzymes, phase II enzymes, and drug transporters in the xenobiotic responses. Since its initial discovery, PXR has been implicated in multiple herb-drug interactions that can lead to alterations of the drug's pharmacokinetic properties and cause fluctuating therapeutic efficacies, possibly leading to complications. Regions of the world that heavily incorporate herbalism into their primary health care and people turning to alternative medicines as a personal choice could be at risk for adverse reactions or unintended results from these interactions. This article is intended to highlight our understanding of the PXR-mediated herb-drug interactions. PMID- 29703384 TI - Risk undermined in the bilateral pharmaceutical regulatory system in Taiwan. AB - The concept of Pharmacovigilance Planning and Risk Minimization Planning (PVP/RMP), initiated by the International Conference on Harmonization (ICH), addressed an important conceptual change from monitoring the safety of individual medicine to proactively conducting risk prevention for the minimization of medication error. However, the implementation of PVP/RMP is a challenge in societies like Taiwan where irrational medication and co-medication is prevalent. It is even more difficult in Taiwan where two regulatory bodies are governing pharmaceutical affairs, namely Taiwan Food and Drug Administration (TFDA) in charge of Western Medicine (WM) and the Department of Chinese Medicine and Pharmacy (DCMP) in charge of Traditional Chinese Medicine (TCM). There are thus dual-tract drug approval panels, two GMP controls and two independent adverse drug event reporting systems. This rendered irrational co-medication of WM and TCM undetectable and the standard tools for monitoring pharmacovigilance inapplicable. The bilateral regulatory system is conceptually unscientific in accordance with PVP/RMP and unethical from humanity point of view. The first part of this review delivers (1) social aspects of polypharmacy in Taiwan; (2) regulatory aspects of pharmaceutical administration; (3) risks undermined in the bilateral regulatory system and (4) pharmacoepidemiology in relation to the risk of polypharmacy. As evidence-based medicine (EBM) forms the fundamental risk benefit assessment on medication, the second part of this review delivers (1) the scientific aspects of the beauty and the odds of biological system that governs host-xenobiotics interaction; (2) conceptual evolution from product management (pharmacovigilance) to risk management (PVP/RMP); (3) non-biased due process is essential for risk-benefit assessment on medicinal products and (4) the opinion of the authors on system building for safe medication. PMID- 29703385 TI - Transporter-mediated natural product-drug interactions for the treatment of cardiovascular diseases. AB - The growing use of natural products in cardiovascular (CV) patients has been greatly raising the concerns about potential natural product-CV drug interactions. Some of these may lead to unexpected cardiovascular adverse effects and it is, therefore, essential to identify or predict potential natural product CV drug interactions, and to understand the underlying mechanisms. Drug transporters are important determinants for the pharmacokinetics of drugs and alterations of drug transport has been recognized as one of the major causes of natural product-drug interactions. In last two decades, many CV drugs (e.g., angiotensin II receptor blockers, beta-blockers and statins) have been identified to be substrates and inhibitors of the solute carrier (SLC) transporters and the ATP-binding cassette (ABC) transporters, which are two major transporter superfamilies. Meanwhile, in vitro and in vivo studies indicate that a growing number of natural products showed cardioprotective effects (e.g., gingko biloba, danshen and their active ingredients) are also substrates and inhibitors of drug transporters. Thus, to understand transporter-mediated natural product-CV drug interactions is important and some transporter-mediated interactions have already shown to have clinical relevance. In this review, we review the current knowledge on the role of ABC and SLC transporters in CV therapy, as well as transporter modulation by natural products used in CV diseases and their induced natural product-CV drug interactions through alterations of drug transport. We hope our review will aid in a comprehensive summary of transporter-mediated natural product-CV drug interactions and help public and physicians understand these type of interactions. PMID- 29703386 TI - Organic solute carrier 22 (SLC22) family: Potential for interactions with food, herbal/dietary supplements, endogenous compounds, and drugs. AB - Many drugs, hormones, components of herbal medicines, environmental pesticides and toxins are Solute Carrier family 22 (SLC22) substrates. The last twenty years has seen great progress in determining SLC22 tissue expression profiles, membrane localization, energetics, substrate profiles and biopharmaceutical significance. However, much still remains to be answered in terms of SLC22 family member's roles in 'normal' physiology as compared to pathophysiological states, as well as in drug interactions that impact pharmacokinetics, efficacy and toxicity. This review begins with a brief synopsis of SLC22 family discovery, function and tissue expression. Subsequent sections provide examples establishing a role for SLC22 transporters in food-drug, herbal supplement-drug, endogenous substrate drug and drug-drug interactions. PMID- 29703387 TI - Food-drug interactions precipitated by fruit juices other than grapefruit juice: An update review. AB - This review addressed drug interactions precipitated by fruit juices other than grapefruit juice based on randomized controlled trials (RCTs). Literature was identified by searching PubMed, Cochrane Library, Scopus and Web of Science till December 30 2017. Among 46 finally included RCTs, six RCTs simply addressed pharmacodynamic interactions and 33 RCTs studied pharmacokinetic interactions, whereas seven RCTs investigated both pharmacokinetic and pharmacodynamic interactions. Twenty-two juice-drug combinations showed potential clinical relevance. The beneficial combinations included orange juice-ferrous fumarate, lemon juice-99mTc-tetrofosmin, pomegranate juice-intravenous iron during hemodialysis, cranberry juice-triple therapy medications for H. pylori, blueberry juice-etanercept, lime juice-antimalarials, and wheat grass juice-chemotherapy. The potential adverse interactions included decreased drug bioavailability (apple juice-fexofenadine, atenolol, aliskiren; orange juice-aliskiren, atenolol, celiprolol, montelukast, fluoroquinolones, alendronate; pomelo juice-sildenafil; grape juice-cyclosporine), increased bioavailability (Seville orange juice felodipine, pomelo juice-cyclosporine, orange-aluminum containing antacids). Unlike furanocoumarin-rich grapefruit juice which could primarily precipitate drug interactions by strong inhibition of cytochrome P450 3A4 isoenzyme and P glycoprotein and thus cause deadly outcomes due to co-ingestion with some medications, other fruit juices did not precipitate severely detrimental food drug interaction despite of sporadic case reports. The extent of a juice-drug interaction may be associated with volume of drinking juice, fruit varieties, type of fruit, time between juice drinking and drug intake, genetic polymorphism in the enzymes or transporters and anthropometric variables. Pharmacists and health professionals should properly screen for and educate patients about potential adverse juice-drug interactions and help minimize their occurrence. Much attention should be paid to adolescents and the elderly who ingest medications with drinking fruit juices or consume fresh fruits during drug treatment. Meanwhile, more researches in this interesting issue should be conducted. PMID- 29703388 TI - Update of green tea interactions with cardiovascular drugs and putative mechanisms. AB - Many patients treated with cardiovascular (CV) drugs drink green tea (GT), either as a cultural tradition or persuaded of its putative beneficial effects for health. Yet, GT may affect the pharmacokinetics and pharmacodynamics of CV compounds. Novel GT-CV drug interactions were reported for rosuvastatin, sildenafil and tacrolimus. Putative mechanisms involve inhibitory effects of GT catechins at the intestinal level on influx transporters OATP1A2 or OATP2B1 for rosuvastatin, on CYP3A for sildenafil and on both CYP3A and the efflux transporter p-glycoprotein for tacrolimus. These interactions, which add to those previously described with simvastatin, nadolol and warfarin, might lead, in some cases, to reduced drug efficacy or risk of drug toxicity. Oddly, available data on GT interaction with CV compounds with a narrow therapeutic index, such as warfarin and tacrolimus, derive from single case reports. Conversely, GT interactions with simvastatin, rosuvastatin, nadolol and sildenafil were documented through pharmacokinetic studies. In these, the effect of GT or GT derivatives on drug exposure was mild to moderate, but a high inter-individual variability was observed. Further investigations, including studies on the effect of the dose and the time of GT intake are necessary to understand more in depth the clinical relevance of GT-CV drug interactions. PMID- 29703389 TI - Association of antioxidant nutraceuticals and acetaminophen (paracetamol): Friend or foe? AB - Acetaminophen (paracetamol or APAP) is an analgesic and antipyretic drug that can induce oxidative stress-mediated hepatotoxicity at high doses. Several studies reported that antioxidant nutraceuticals, in particular phenolic phytochemicals from dietary food, spices, herbs and algae have hepatoprotective effects. Others, however, suggested that they may negatively impact the metabolism, efficacy and toxicity of APAP. The aim of this review is to discuss the pros and cons of the association of antioxidant nutraceuticals and APAP by reviewing the in vivo evidence, with particular reference to APAP pharmacokinetics and hepatotoxicity. Results from the murine models of APAP-induced hepatotoxicity showed amelioration of liver damage with nutraceuticals coadministration, as well as reductions in tissue markers of oxidative stress, and serum levels of hepatic enzymes, bilirubin, cholesterol, triglycerides and inflammatory cytokines. On the other hand, both increased and decreased APAP plasma levels have been reported, depending on the nutraceutical type and route of administration. For example, studies showed that repeated administration of flavonoids causes down-regulation of cytochrome P450 enzymes and up-regulation of uridine diphosphate glucuronosyltransferases (UGT). Moreover, nutraceuticals can alter the levels of APAP metabolites, such as mercapturate glucuronide, sulfate and cysteine conjugates. Overall, the reviewed in vivo studies indicate that interactions between APAP and nutraceuticals or plant foods exist. However, the majority of data come from animal models with doses of phytochemicals far from dietary ones. Human studies should investigate gene-diet interactions, as well as ethnic variability in order to clarify the pros and cons of co-administering antioxidant nutraceuticals and APAP. PMID- 29703390 TI - Concurrent administration of anticancer chemotherapy drug and herbal medicine on the perspective of pharmacokinetics. AB - With an increasing number of cancer patients seeking an improved quality of life, complementary and alternative therapies are becoming more common ways to achieve such improvements. The potential risks of concurrent administration are serious and must be addressed. However, comprehensive evidence for the risks and benefits of combining anticancer drugs with traditional herbs is rare. Pharmacokinetic investigations are an efficient way to understand the influence of concomitant remedies. Therefore, this study aimed to collect the results of pharmacokinetic studies relating to the concurrent use of cancer chemotherapy and complementary and alternative therapies. According to the National Health Insurance (NHI) database in Taiwan and several publications, the three most commonly prescribed formulations for cancer patients are Xiang-Sha-Liu-Jun-Zi-Tang, Jia-Wei-Xiao-Yao San and Bu-Zhong-Yi-Qi-Tang. The three most commonly prescribed single herbs for cancer patients are Hedyotis diffusa, Scutellaria barbata, and Astragalus membranaceus. Few studies have discussed herb-drug interactions involving these herbs from a pharmacokinetics perspective. Here, we reviewed Jia-Wei-Xiao-Yao San, Long-Dan-Xie-Gan-Tang, Curcuma longa and milk thistle to provide information based on pharmacokinetic evidence for healthcare professionals to use in educating patients about the risks of the concomitant use of various remedies. PMID- 29703391 TI - Effects of processing adjuvants on traditional Chinese herbs. AB - Processing of Chinese medicines is a pharmaceutical technique that transforms medicinal raw materials into decoction pieces for use in different therapies. Various adjuvants, such as vinegar, wine, honey, and brine, are used in the processing to enhance the efficacy and reduce the toxicity of crude drugs. Proper processing is essential to ensure the quality and safety of traditional Chinese medicines (TCMs). Therefore, sound knowledge of processing principles is crucial to the standardized use of these processing adjuvants and to facilitate the production and clinical use of decoction pieces. Many scientific reports have indicated the synergistic effects of processing mechanisms on the chemistry, pharmacology, and pharmacokinetics of the active ingredients in TCMs. Under certain conditions, adjuvants change the content of active or toxic components in drugs by chemical or physical transformation, increase or decrease drug dissolution, exert their own pharmacological effects, or alter drug pharmacokinetics. This review summarizes various processing methods adopted in the last two decades, and highlights current approaches to identify the effects of processing parameters on TCMs. PMID- 29703392 TI - Analysis of the activity of interconsultations conducted by the departments of internal medicine. REINA-SEMI study: Registry of Interconsultations and Shared Care of the Spanish Society of Internal Medicine. AB - OBJECTIVE: To analyse the activity of interconsultations conducted by internal medicine (IM) departments, their formal aspects and the profile of clinical care required and to quantify the workload they represent. MATERIAL AND METHOD: A multicentre, observational prospective study was conducted with consecutive hospitalised patients treated by IM departments using interconsultations between May 15 and June 15, 2016. We estimated the workload related to this activity (1time unit [TU]=10min). RESULTS: We recorded 1,141 interconsultations from 43 hospitals. The mean age of the patients involved was 69.4 years (SD: 16.2), and 51.2% were men. The mean Charlson index was 2.3 (SD: 2.2). The most common reasons for the consultations were general assessments (27.4%), fever (18.1%), dyspnoea (13.6%), metabolic disorder (9.6%), arterial hypertension (6.3%) and delirium (5.3%). The duration of the first visit was 4 TUs (SD: 5.9) and 7.3 (SD: 21.5) for the sum of all subsequent visits. The surgical patients were older (70.6 [SD, 15.9] vs. 64.4 [SD, 16.3] years; P=.0001) and required more follow-up time (5 [SD, 7.3] vs. 3.5 [SD, 4.2] days; P=.009). The following issues were more common in the interconsultation format performed by medical services: number of regular interconsultations (response >24h), specification of the reason for the interconsultation, minimal data regarding the medical history and agreement on the appropriateness of the time spent with the consultant. CONCLUSION: The patients treated through interconsultations by the IM departments represented a significant workload. The interconsultations from the medical departments were more in line with the request format. PMID- 29703393 TI - Acute coronary syndrome and anafilaxia. PMID- 29703394 TI - Male patient with chronic bronchial disease and bullous emphysema superinfection. PMID- 29703395 TI - [Up to date in hypertension in 6 topics. Proceedings of the pre-congress course at the 2016 meeting of the Spanish Society of Hypertension. Introduction]. PMID- 29703396 TI - [How and why we calculate the vascular risk in hypertensive patients?] AB - Cardiovascular risk assessment is of key importance for a global diagnosis of the hypertensive patient. Card iovascular risk stratification accord ing blood pressure levels, presence of accompanying cardiovascular risk factors, and presence of subclinical and/or clinical organ damage, constitute a systematic approach to assess risk for cardiovascular morbidity and mortality, to decide about initial antihypertensive treatment, and to promote global cardiovascular risk management. Several recent clinical practice guidelines recommend this approach, although there are no clinical trials demonstrating advantages of this management versus treating cardiovascular risk factors individually. Guidelines for management of high blood pressure and that for management of dyslipidemias constitute examples of agreement about the convenience of assessing global cardiovascular risk. Both qualitative (European guidelines for management of arterial hypertension) and quantitative (SCORE) tables are available, both useful for id entification of high-risk patients, and indicating the necessity of starting simultaneous non-pharmacological and pharmacological treatment. Family doctors should include in their usual clinical practice a systematic approach to cardiovascular risk assessment, thus diagnosing the individual cardiovascular risk burden, and consequently applying therapeutic management to reduce future risk of cardiovascular morbidity and mortality. PMID- 29703397 TI - [Should blood pressure goals be changed in hypertension treatment?] AB - Which have to be the most suitable goal for blood pressure has been an object of a debate since the publication of different guidelines of managing of arterial hypertension. Later to the publication of the last guides, the results of the SPRINT study have been known. SPRINT analyzes the differences in cardiovascular morbidity and mortality of different systolic blood pressure goals. The above mentioned study shows that a reduction to 121 mmHg in SBP is better than a SBP < 140 mmHg. Nevertheless, this study has included a low number of diabetic patients and a limited number of patients with cardiovascular disease, therefore, probably, the results are not applicable than to a limited number of hypertensive patients. In this article we analyze some of the available information with regard to this interesting aspect. PMID- 29703398 TI - [Combination for initial therapy in hypertension, is it useful?] AB - Hypertension represents the first cause of mortality worldwide because a leading role in development of cardiovascular and renal diseases. Evidence about the benefits of controlling hypertension is overwhelming, but adequate control of blood pressure is still poor even in high-income countries. At least one of 2 hypertensive patients suffers from uncontrolled blood pressure. Nearly 75% of hypertensive patients do not achieve adequate control with monotherapy. Strategies to improve control include avoiding inertia in initiating pharmacological treatment, prompt shift to combined therapy from monotherapy, initial treatment with a 2-drug combination, and use of fixed-dose combinations in a single pill. This review focuses in benefits of initiating treatment combining antihypertensive drugs. PMID- 29703399 TI - [What are the pharmacological options for treating resistant hypertension?] AB - When treating a patient with resistant hypertension therapy should be optimize in order to prescribe three antihypertensive drugs at full doses, being powerful drugs, having 24-hour coverage, and showing synergistic effects. Diuretic therapy is of special relevance. The fourth drug should be an aldosterone antagonists. In the case of intolerance, or when control is not achieved, drugs from other type of antihypertensive drugs should be, sometimes allowing adequate blood pressure control. PMID- 29703400 TI - [How to assess and to improve adherence in clinical practice?] AB - Prevalence of non-adherence of pharmacological therapy in hypertension is between 35 and 50%. In every uncontrolled hypertensive one should assess drug adherence as the cause. Several validated methods to detect noncompliance exist, being most frequently used Haynes test, pill count, and use of electronic prescription. Strategies to improve compliance should include a combination of adequate information to patients, a simplified scheme of treatment, and periodic adherence assessment. Programs for home self-measurement of blood pressure, use of double or triple drug fixed combinations, group health education, reminders, calendars, and cards enforcement, and improving doctor-patient relationship are also useful tools for compliance optimization. PMID- 29703401 TI - [Ambulatory blood pressure monitoring for hypertension diagnosis?] AB - The early and accurate diagnosis of hypertension is essential given its importance in the development of cardiovascular disease. The boundaries between normal blood pressure (BP) and hypertension are arbitrary and based on the benefits of treating exceeding those of not treating. Conventional BP measurement at the clinic only offers information of a particular time and presents multiple biases dependent on inherent variability of BP and measurement technique itself. Multiple studies have demonstrated the prognosis superiority in the development of cardiovascular disease of ambulatory blood pressure monitoring (ABPM), allows detection of white coat hypertension, avoiding overdiagnosis and overtreatment, and the detection of patients with masked hypertension who are at risk of underdetection and undertreatment. ABPM also assess nightime BP and circadian variability, providing additional prognostic value. ABPM is recognized in the diagnosis of hypertension in 2011 British NICE Guidelines, very argued at the 2013 European Society of Hypertension guidelines, and recommended in the US Preventive Services Task Force in 2015, 2016 Canadian Guidelines and the 2016 Spanish Program of Preventive Activities and Health Promotion (PAPPS). Its generalization is likely to be only a matter of time. PMID- 29703402 TI - FE analysis of conceptual hybrid composite endodontic post designs in anterior teeth. AB - OBJECTIVES: To assess conceptual designs of dental posts consisting of polyetherimide (PEI) reinforced with carbon (C) and glass (G) glass fibers in endodontically treated anterior teeth. METHODS: 3D tessellated CAD and geometric models of endodontically treated anterior teeth were generated from Micro-CT scan images. Model C-G/PEI composite posts with different Young's moduli were analyzed by Finite Element (FE) methods post A (57.7GPa), post B (31.6GPa), post C (from 57.7 to 9.0GPa in the coronal-apical direction). A load of 50N was applied at 45 degrees to the longitudinal axis of the tooth, acting on the palatal surface of the crown. The maximum principal stress distribution was determined along the post and at the interface between the post and the surrounding structure. RESULTS: Post C, with Young's modulus decreasing from 57.7 to 9.0GPa in the coronal-apical direction, reduced the maximum principal stress distribution in the restored tooth. Post C gave reduced stress and the most uniform stress distribution with no stress concentration, compared to the other C-G/PEI composite posts. SIGNIFICANCE: The FE analysis confirmed the ability of the functionally graded post to dissipate stress from the coronal to the apical end. Hence actual (physical) C-G/PEI posts could permit optimization of stress distributions in endodontically treated anterior teeth. PMID- 29703404 TI - Not everybody is going to be happy when the catheter comes out early: Can we predict who these people are? PMID- 29703403 TI - Intraventricular treatment of secondary central nervous system lymphoma - Case study and literature overview. AB - Secondary nervous system lymphoma (SCNSL) is a rare extranodal form of non Hodgkin lymphoma (NHL). This applies to a particular form of lymphoma that does not originally derive from the central nervous system (CNS); it can be both an isolated form of relapse or a systemic part of disease progression. Due to poor prognosis and a lack of established algorithms of therapeutic procedures, it is a big challenge for physicians from many specializations. In our study, we present an interesting case of a patient with a relapsed form of SCNSL for whom a unique form of treatment was used - intraventricular administration of rituximab and methotrexate. PMID- 29703405 TI - Pump the brakes: Getting ahead of ourselves with concomitant tricuspid annuloplasty? PMID- 29703406 TI - The search for the holy grail of lobectomy. PMID- 29703407 TI - Don't you want me? PMID- 29703408 TI - Cardiac involvement of Wegner granulomatosis: It's rare but not unheard of. PMID- 29703409 TI - Acknowledging the skill needed to succeed. PMID- 29703410 TI - Sweet dreams (are made of this). PMID- 29703411 TI - The importance of finding the murderer! PMID- 29703412 TI - Perfect is the enemy of good: Use of administrative databases in characterizing rare events and outcomes. PMID- 29703413 TI - Laparoscopic anterior pelvic exenteration in 10 steps. PMID- 29703414 TI - Lactotripeptide ingestion increases cerebral blood flow velocity in middle-aged and older adults. AB - The age-related decrease in cerebral blood flow velocity increases the risk of cerebrovascular disease. Milk protein-derived bioactive peptides, e.g., lactotripeptide (LTP), have been shown to inhibit angiotensin converting enzyme activities and increase vasodilator production. We hypothesized that LTP ingestion increases cerebral blood flow velocity in middle-aged and older adults. In a randomized, placebo-controlled, double-blind design, 15 healthy middle-aged and older adults were assigned to either a LTP group or a placebo group. The subjects ingested LTP or placebo orally for 8 weeks. Before and after intervention, middle cerebral blood flow velocity was measured using transcranial Doppler ultrasonography. The baseline middle cerebral blood flow velocity and most other key dependent variables did not differ between the groups. LTP ingestion significantly increased middle cerebral blood flow velocity, but there was no such improvement in the placebo groups. We concluded that 8 weeks of LTP ingestion increased middle cerebral blood flow velocity in middle-aged and older adults. PMID- 29703415 TI - Electroconvulsive therapy for depression in a patient with an Inspire hypoglossal nerve stimulator device for obstructive sleep apnea: A case report. AB - OUTCOME OBJECTIVES: METHODS: This is a case report of a patient who underwent placement and initiation of a hypoglossal nerve stimulator device in the context of receiving electroconvulsive therapy for bipolar depression between February and September 2016. To our knowledge, this has not yet been reported in the literature. Outcome measurements included successful device activation and successful device use throughout electroconvulsive therapy. RESULTS: The patient underwent successful device implantation, activation, and use without disruption throughout electroconvulsive therapy sessions. No special device deactivation was required during electroconvulsive therapy sessions. CONCLUSION: Obstructive sleep apnea is a common disorder that causes significant reduction in quality of life and is an independent risk factor for multiple comorbidities. Electroconvulsive therapy is an established treatment for medication-refractory depression with minimal risk in most patient populations. This is the first report in the literature of a patient undergoing ECT for bipolar depression with recent activation of Inspire hypoglossal nerve stimulator who had no disruption in the function of his implanted device. PMID- 29703416 TI - Cervical spine injury in rollover crashes: Anthropometry, excursion, roof deformation, and ATD prediction. AB - While rollover crashes are rare, approximately one third of vehicle occupant fatalities occur in rollover crashes. Most severe-to-fatal injuries resulting from rollover crashes occur in the head or neck region, due to head and neck interaction with the roof during the crash. While many studies have used anthropomorphic test devices (ATDs) to predict head and neck injury, the biofidelity of ATDs in rollover has not been established. This study aims to build on previous research to compare the dynamic response and injuries sustained by four post mortem human surrogates (PMHS) to those predicted by six different ATDs in full-scale rollover crash tests. Additionally, this study evaluates injuries sustained by PMHS relative to possible contributing factors including occupant kinematics, occupant anthropometry, and vehicle roof deformation. While the vehicle kinematics and roof deformation were comparable for all tests, three out of the four PMHS sustained cervical spine injury, but only the tallest specimen sustained cervical spine fracture. Neck flexion at the time of head-to roof contact appears to have affected cervical spine injury risk in these cases. Despite the injuries sustained in the PMHS, none of the six ATDs measured forces or accelerations that exceeded injury assessment reference values (IARVs), which adds to recent literature illustrating substantial differences between ATDs and PMHS in a rollover-like scenario. PMID- 29703417 TI - Next generation microbiological risk assessment-Potential of omics data for hazard characterisation. AB - According to the World Health Organization estimates in 2015, 600 million people fall ill every year from contaminated food and 420,000 die. Microbial risk assessment (MRA) was developed as a tool to reduce and prevent risks presented by pathogens and/or their toxins. MRA is organized in four steps to analyse information and assist in both designing appropriate control options and implementation of regulatory decisions and programs. Among the four steps, hazard characterisation is performed to establish the probability and severity of a disease outcome, which is determined as function of the dose of toxin and/or pathogen ingested. This dose-response relationship is subject to both variability and uncertainty. The purpose of this review/opinion article is to discuss how Next Generation Omics can impact hazard characterisation and, more precisely, how it can improve our understanding of variability and limit the uncertainty in the dose-response relation. The expansion of omics tools (e.g. genomics, transcriptomics, proteomics and metabolomics) allows for a better understanding of pathogenicity mechanisms and virulence levels of bacterial strains. Detection and identification of virulence genes, comparative genomics, analyses of mRNA and protein levels and the development of biomarkers can help in building a mechanistic dose-response model to predict disease severity. In this respect, systems biology can help to identify critical system characteristics that confer virulence and explain variability between strains. Despite challenges in the integration of omics into risk assessment, some omics methods have already been used by regulatory agencies for hazard identification. Standardized methods, reproducibility and datasets obtained from realistic conditions remain a challenge, and are needed to improve accuracy of hazard characterisation. When these improvements are realized, they will allow the health authorities and government policy makers to prioritize hazards more accurately and thus refine surveillance programs with the collaboration of all stakeholders of the food chain. PMID- 29703418 TI - Relationship between sperm motility characteristics and ATP concentrations, and association with fertility in two different pig breeds. AB - Boar fertility has a major impact on overall pig reproductive efficiency. Using accurate and objective in vitro sperm variables for predicting in vivo fertility from a single ejaculate, however, is challenging. Motility is the most widely used indicator of sperm quality, and a computer assisted sperm analysis (CASA) system is now available for objective assessment of sperm motility characteristics. In this study sperm motility characteristics and semen ATP concentrations were investigated and the effect of both were evaluated on total number of piglets born (TNB) when Norwegian Landrace (NL) and Norwegian Duroc (ND) boar semen was used for AI. In addition, breed differences for semen storage capacity were investigated. The results from CASA analysis indicated there were differences between NL and ND sperm motility variables. The percentage of motile sperm cells decreased in both NL (P = 0.01) and ND (P < 0.0001) during storage. A large proportion of sperm cells with a hyperactive motility pattern were detected in ND semen on the day of collection, with no significant changes as a result of storage. Inconsistent with this finding, there was greater degree of hyper activation in sperm motility pattern for NL because of semen storage. There was a significant decrease in semen ATP concentration during storage (P < 0.0001) in both breeds. The linearity of sperm movement at the day of collection and the wobble after storage influenced TNB in NL, while the percentage of motile cells, curvilinear velocity and lateral head amplitude on the day of semen collection and linearity after storage influenced TNB in ND. PMID- 29703419 TI - [Rich and sad topics]. PMID- 29703420 TI - Tryptophan photo-product FICZ upregulates AHR/MEK/ERK-mediated MMP1 expression: Implications in anti-fibrotic phototherapy. AB - BACKGROUND: Scleroderma is caused by aberrant transforming growth factor-beta signaling. The degradation of extracellular matrix proteins is regulated by matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs). Ultraviolet (UV) radiation has been a therapy for scleroderma. 6 Formylindolo[3,2-b]carbazole (FICZ), an endogenous aryl hydrocarbon receptor (AHR) ligand, is a tryptophan metabolite generated by UV exposure. Nonetheless, whether FICZ regulates MMPs and TIMPs has not been investigated. OBJECTIVE: To elucidate the regulatory roles of FICZ in the expression of MMPs and TIMPs in normal human dermal fibroblasts (NHDFs). METHODS: Quantitative real-time polymerase chain reaction was performed to determine the expression of MMPs or TIMPs in the NHDFs treated with FICZ or UVB. The MMPs levels were measured by enzyme-linked immunosorbent assay. The actions of FICZ on MMPs were analyzed using AHR-knockdown NHDFs or selective inhibitors of mitogen-activated protein kinases (MAPKs). Microtubule-associated protein kinase (MEK) and extracellular signal-regulated kinase (ERK) phosphorylation was examined by western blotting. RESULTS: UVB increased the mRNA and protein levels of MMP1 and MMP3 in NHDFs, while FICZ upregulated those of MMP1, but not MMP3. The effects of FICZ on TIMPs were negligible. FICZ increased MMP1 expression in an AHR-dependent manner. The FICZ-induced MMP1 upregulation was ameliorated with MEK/ERK inhibitors, whereas the effects of UVB were canceled with c-Jun N-terminal kinase (JNK) and p38-MAPK as well as MEK/ERK inhibitors. FICZ-induced ERK phosphorylation is dependent on AHR. CONCLUSION: FICZ contributes to the UV-mediated anti-fibrotic effects via the AHR/MEK/ERK signal pathway in NHDFs. FICZ is a potential therapeutic agent for scleroderma. PMID- 29703421 TI - Commentary: Long-term results of organ procurement from burn victims. Burns. 2017 Sep;43(6):1163-1167. doi: 10.1016/j.burns.2017.05.012. Epub 2017 Jun 9. PubMed PMID: 28602588. Schmauss D, Bigdeli AK, Hellmich S, Barreiros AP, Kremer T, Germann G, Kneser U, Megerle KO. PMID- 29703422 TI - New Horizons on the 50th Anniversary of Heart Transplantation in Canada: "Where There Is Death, There Is Hope". PMID- 29703423 TI - Synthesis of (E)-cinnamyl ester derivatives via a greener Steglich esterification. AB - Cinnamic acid derivatives are known antifungal, antimicrobial, antioxidant, and anticancer compounds. We have developed a facile and mild methodology for the synthesis of (E)-cinnamate derivatives using a modified Steglich esterification of (E)-cinnamic acid. Using acetonitrile as the solvent, rather than the typical chlorinated solvent, and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) as the coupling agent enables ester conversion in 45 min with mild heating (40-45 degrees C) and an average yield of 70% without need for further purification. These conditions were used to couple (E)-cinnamic acid with 1 degrees and 2 degrees aliphatic alcohols, benzylic and allylic alcohols, and phenols. This work demonstrates a facile and greener methodology for Steglich esterification reactions. PMID- 29703424 TI - Synthesis and characterization of radioiodinated 3-phenethyl-2-indolinone derivatives for SPECT imaging of survivin in tumors. AB - Survivin, overexpressed in most cancers, is associated with poor prognosis and resistance to radiation therapy and chemotherapy. Herein, we report the synthesis of three 3-phenethyl-2-indolinone derivatives and their application as in vivo imaging agents for survivin. Of these, 3-(2-(benzo[d][1,3]dioxol-5-yl)-2 oxoethyl)-3-hydroxy-5- iodoindolin-2-one (IPI-1) showed the highest binding affinity (Kd = 68.3 nM) to recombinant human survivin, as determined by quartz crystal microbalance (QCM). In vitro studies demonstrated that the [125I]IPI-1 binding in survivin-positive MDA-MB-231 cells was significantly higher than that in survivin-negative MCF-10A cells. In addition, uptake of [125I]IPI-1 by MDA-MB 231 cells decreased in a dose-dependent manner in the presence of the high affinity survivin ligand S12; this is indicative of specific binding of [125I]IPI 1 to cellular survivin protein in vitro. Biodistribution studies in MDA-MB-231 tumor-bearing mice demonstrated the moderate uptake of [125I]IPI-1 in the tumor tissue (1.37% ID/g) at 30 min that decreased to 0.32% ID/g at 180 min. Co injection of S12 (2.5 mg/kg) slightly reduced tumor uptake and the tumor/muscle ratio of [125I]IPI-1. Although further structural modifications are necessary to improve pharmacokinetic properties, our results indicate that PI derivatives may be useful as tumor-imaging probes targeting survivin. PMID- 29703426 TI - Can improving access to care help to eliminate malaria? PMID- 29703427 TI - Advances in bioleaching for recovery of metals and bioremediation of fuel ash and sewage sludge. AB - Bioleaching has been successfully used in commercial metal mining for decades. It uses microbes to biosolubilize metal-containing inorganic compounds such as metal oxides and sulfides. There is a growing interest in using bioleaching for bioremediation of solid wastes by removing heavy metals from ash and sewage sludge. This review presents the state of the art in bioleaching research for recovery of metals and bioremediation of solid wastes. Various process parameters such as reaction time, pH, temperature, mass transfer rate, nutrient requirement, pulp density and particle size are discussed. Selections of more effective microbes are assessed. Pretreatment methods that enhance bioleaching are also discussed. Critical issues in bioreactor scale-up are analyzed. The potential impact of advances in biofilm and microbiome is explained. PMID- 29703425 TI - Effect of generalised access to early diagnosis and treatment and targeted mass drug administration on Plasmodium falciparum malaria in Eastern Myanmar: an observational study of a regional elimination programme. AB - BACKGROUND: Potentially untreatable Plasmodium falciparum malaria threatens the Greater Mekong subregion. A previous series of pilot projects in Myanmar, Laos, Cambodia, and Vietnam suggested that mass drug administration was safe, and when added to provision of early diagnosis and treatment, could reduce the reservoir of P falciparum and interrupts transmission. We examined the effects of a scaled up programme of this strategy in four townships of eastern Myanmar on the incidence of P falciparum malaria. METHODS: The programme was implemented in the four townships of Myawaddy, Kawkareik, Hlaingbwe, and Hpapun in Kayin state, Myanmar. Increased access to early diagnosis and treatment of malaria was provided to all villages through community-based malaria posts equipped with rapid diagnostic tests, and treatment with artemether-lumefantrine plus single low-dose primaquine. Villages were identified as malarial hotspots (operationally defined as >40% malaria, of which 20% was P falciparum) with surveys using ultrasensitive quantitative PCR either randomly or targeted at villages where the incidence of clinical cases of P falciparum malaria remained high (ie, >100 cases per 1000 individuals per year) despite a functioning malaria post. During each survey, a 2 mL sample of venous blood was obtained from randomly selected adults. Hotspots received targeted mass drug administration with dihydroartemisinin piperaquine plus single-dose primaquine once per month for 3 consecutive months in addition to the malaria posts. The main outcome was the change in village incidence of clinical P falciparum malaria, quantified using a multivariate, generalised, additive multilevel model. Malaria prevalence was measured in the hotspots 12 months after mass drug administration. FINDINGS: Between May 1, 2014, and April 30, 2017, 1222 malarial posts were opened, providing early diagnosis and treatment to an estimated 365 000 individuals. Incidence of P falciparum malaria decreased by 60 to 98% in the four townships. 272 prevalence surveys were undertaken and 69 hotspot villages were identified. By April 2017, 50 hotspots were treated with mass drug administration. Hotspot villages had a three times higher incidence of P falciparum at malarial posts than neighbouring villages (adjusted incidence rate ratio [IRR] 2.7, 95% CI 1.8-4.4). Early diagnosis and treatment was associated with a significant decrease in P falciparum incidence in hotspots (IRR 0.82, 95% CI 0.76-0.88 per quarter) and in other villages (0.75, 0.73-0.78 per quarter). Mass drug administration was associated with a five-times decrease in P falciparum incidence within hotspot villages (IRR 0.19, 95% CI 0.13 0.26). By April, 2017, 965 villages (79%) of 1222 corresponding to 104 village tracts were free from P falciparum malaria for at least 6 months. The prevalence of wild-type genotype for K13 molecular markers of artemisinin resistance was stable over the three years (39%; 249/631). INTERPRETATION: Providing early diagnosis and effective treatment substantially decreased village-level incidence of artemisinin-resistant P falciparum malaria in hard-to-reach, politically sensitive regions of eastern Myanmar. Targeted mass drug administration significantly reduced malaria incidence in hotspots. If these activities could proceed in all contiguous endemic areas in addition to standard control programmes already implemented, there is a possibility of subnational elimination of P falciparum. FUNDING: The Bill & Melinda Gates Foundation, the Regional Artemisinin Initiative (Global Fund against AIDS, Tuberculosis and Malaria), and the Wellcome Trust. PMID- 29703428 TI - Effects of centrally administered glucagon-like peptide-2 on blood pressure and barosensitive neurons in spontaneously hypertensive rats. AB - The central administration of glucagon-like peptide-2 (GLP-2) decreases blood pressure in rats. In the present study, we investigated the hypotensive effects of GLP-2 using spontaneously hypertensive rats (SHRs), an animal model of hypertension. The central administration of GLP-2 (0.6 MUg) decreased mean arterial pressure (MAP) in SHRs (-24.1 +/- 4.5%; P < 0.05), but not in normotensive Wistar-Kyoto (WKY) rats (-10.6 +/- 7.4%; P > 0.05), whereas GLP-2 (6 MUg) decreased MAP in WKY rats (-23.5 +/- 4.2%; P < 0.05) and SHRs (-46.7 +/- 11.6%; P < 0.01) under anesthesia with urethane and alpha-chloralose. Histological analyses revealed that the central administration of GLP-2 (6 MUg) induced Fos immunoreactivity (Fos-IR) in the hypothalamic and medullary areas in WKY rats and SHRs. However, the distribution of Fos-IR in GABAergic neurons in the rostral ventrolateral medulla (RVLM) differed between WKY rats and SHRs. GLP 2 directly modulated the excitability of RVLM neurons in brainstem slices from SHRs, but not WKY rats. These results suggest that neuronal activity through the activation of GLP-2 receptors in the RVLM contributes to lowering blood pressure in SHRs. PMID- 29703429 TI - Rumination and eating disorder psychopathology: A meta-analysis. AB - Rumination is a cognitive process involving repetitive thoughts about negative experiences and emotions and is associated with psychopathology. Rumination has been implicated in mood and anxiety disorders, and there is a growing body of research on rumination in relation to eating disorder (ED) psychopathology. The current meta-analytic review focused on the literature addressing rumination and ED psychopathology. A comprehensive search process identified 38 studies, which primarily used cross-sectional designs with non-clinical samples. Results demonstrated that rumination was concurrently (r = 0.33) and prospectively (r = 0.22-0.23) associated with ED psychopathology, and that groups with ED psychopathology evidenced higher levels of rumination compared to non-ED control groups (g = 0.95), though no significant differences in rumination were observed when comparing anorexia nervosa to bulimia nervosa groups (g = 0.09). In addition, a narrative review of five experimental studies suggested that rumination in response to ED-related stimuli was related to increased negative affect and negative body-related cognitions across clinical and non-clinical samples. The type of rumination and sample population emerged as moderators of effect sizes, such that larger effects were observed among samples using ED specific measures of rumination and heterogeneous samples compared to only non clinical samples. Taken together, this literature demonstrates that rumination is a salient process in ED psychopathology, though the literature is characterized by methodological limitations and the need for more fully elaborated theories on the role of rumination in EDs. Findings are discussed in the context of existing models of rumination and ED psychopathology, with suggestions for future research in this area. PMID- 29703430 TI - Relative Bioavailability of Methylphenidate Extended-release Chewable Tablets Chewed Versus Swallowed Whole. AB - PURPOSE: Methylphenidate hydrochloride extended-release chewable tablet (MPH ERCT) is approved for treatment of attention deficit hyperactivity disorder in patients aged 6 years and older. This article evaluates the pharmacokinetic parameters and relative bioavailability of MPH ERCT when chewed versus swallowed whole. METHODS: In this open-label, single-dose, 3-period, 3-treatment crossover study, 12 healthy adult volunteers were randomly assigned to treatment sequence. In each period, subjects received a single 40-mg dose of the assigned treatment (MPH ERCT chewed, MPH ERCT swallowed whole, or methylphenidate extended-release oral suspension [MEROS]). Blood samples for pharmacokinetic analysis were collected for 24 hours postdose. Key pharmacokinetic parameters included Cmax, AUC0-t, and AUC0-infinity. FINDINGS: The geometric mean values for AUC0-t, AUC0 infinity, and Cmax were similar for MPH ERCT chewed, MPH ERCT swallowed whole, and MEROS. In all pairwise between-treatment comparisons, the 90% CIs of the geometric mean ratios for AUC0-t, AUC0-infinity, and Cmax were fully contained within the bioequivalence range of 80% to 125%. Early exposure over the first 4 hours after dosing (AUC0-4) was similar for MPH ERCT chewed versus swallowed whole; AUC0-4 was approximately 15% lower for MPH ERCT, either chewed or swallowed, compared with MEROS. Each treatment was generally well tolerated. IMPLICATIONS: There was no difference in overall rate or extent of exposure of methylphenidate when MPH ERCT was chewed versus swallowed whole by healthy volunteers. PMID- 29703431 TI - Safety Versus Tolerability. PMID- 29703432 TI - Antiviral Activity, Safety, and Tolerability of Multiple Ascending Doses of Elbasvir or Grazoprevir in Participants Infected With Hepatitis C Virus Genotype 1 or -3. AB - PURPOSE: Elbasvir (MK-8742) and grazoprevir (MK-5172; Merck & Co, Inc, Kenilworth, New Jersey) are hepatitis C virus (HCV)-specific inhibitors of the nonstructural protein 5A phosphoprotein and the nonstructural protein 3/4A protease, respectively. The aims of these studies were to evaluate the antiviral activity and safety of different doses of elbasvir or grazoprevir each administered as monotherapy to participants infected with either HCV genotype (GT) 1 or GT3. METHODS: These 2 double-blind, randomized, placebo-controlled, sequential-panel, multiple ascending dose studies were conducted to assess the safety and pharmacodynamics of 5 days of once-daily elbasvir or 7 days of once daily grazoprevir in adult male participants chronically infected with either HCV GT1 or GT3. FINDINGS: Oral administration of elbasvir or grazoprevir once daily exhibited potent antiviral activity in participants with chronic GT1 or GT3 HCV infections. HCV RNA levels declined rapidly (within 1 day for elbasvir and 2 days for grazoprevir). At 50 mg of elbasvir once daily, the mean maximum reductions in HCV RNA from baseline were 5.21, 4.17, and 3.12 log10 IU/mL for GT1b-, GT1a-, and GT3-infected participants, respectively. At 100 mg of grazoprevir once daily, the mean maximum reductions in HCV RNA from baseline were 4.74 and 2.64 log10 IU/mL for GT1- and GT3-infected participants. IMPLICATIONS: The results in the elbasvir monotherapy study showed that 10 to 50 mg of elbasvir was associated with a rapid decline in HCV viral load; the results in the grazoprevir monotherapy study suggest that doses of 50 mg of grazoprevir and higher are on the maximum response plateau of the dose-response curve for GT1-infected participants. The results of these proof-of-concept studies provided preliminary data for the selection of the dosages of elbasvir and grazoprevir to test in Phase II and III clinical studies. ClinicalTrials.gov identifiers: NCT00998985 (Protocol 5172-004) and NCT01532973 (Protocol 8742-002). PMID- 29703433 TI - Points-to-consider documents: Scientific information on the evaluation of genetic polymorphisms during non-clinical studies and phase I clinical trials in the Japanese population. AB - Pharmacotherapy shows striking individual differences in pharmacokinetics and pharmacodynamics, involving drug efficacy and adverse reactions. Recent genetic research has revealed that genetic polymorphisms are important intrinsic factors for these inter-individual differences. This pharmacogenomic information could help develop safer and more effective precision pharmacotherapies and thus, regulatory guidance/guidelines were developed in this area, especially in the EU and US. The Project for the Promotion of Progressive Medicine, Medical Devices, and Regenerative Medicine by the Ministry of Health, Labour and Welfare, performed by Tohoku University, reported scientific information on the evaluation of genetic polymorphisms, mainly on drug metabolizing enzymes and transporters, during non-clinical studies and phase I clinical trials in Japanese subjects/patients. We anticipate that this paper will be helpful in drug development for the regulatory usage of pharmacogenomic information, most notably pharmacokinetics. PMID- 29703434 TI - Screening of miRNAs in human follicular fluid reveals an inverse relationship between microRNA-663b expression and blastocyst formation. AB - RESEARCH QUESTION: Are miRNAs found in follicular fluid related to blastocyst formation from the corresponding oocytes? DESIGN: In this study, 91 individual follicular fluid samples from single follicles containing mature oocytes from 91 women were collected and classified into group 1 (n = 38) with viable blastocysts, and group 2 (n = 53) with no blastocyst. TaqMan human miRNA cards and quantitative reverse transcription polymerase chain reaction were used to identify differently expressed follicular fluid miRNAs between the two groups. RESULTS: We found MIR-663B to be significantly differentially expressed in follicular fluid of oocytes that yielded viable blastocysts versus those that did not develop into blastocysts (14.16 +/- 7.00 versus 23.68 +/- 17.02; P = 0.019), as well as for those which develop into blastocysts with good morphology versus those with poor morphology (11.69 +/- 3.49 versus 20.16 +/- 9.33; P = 0.003). CONCLUSIONS: MIR-663B expression levels in human follicular fluid samples were significantly negatively related to viable blastocyst formation and may become an objective evaluation criterion for embryo development potential after IVF. PMID- 29703435 TI - Very low anti-mullerian hormone concentrations are not an independent predictor of embryo quality and pregnancy rate. AB - RESEARCH QUESTION: Is anti-Mullerian hormone (AMH) serum concentration a useful tool to predict the outcome of assisted reproductive treatment? DESIGN: Retrospective cohort study involving 2971 patients who underwent 5570 IVF cycles. Patients were classified into six groups according to their AMH levels and analysed for associations with reproductive outcome. Several parameters of ovarian response and clinical outcome were compared between groups. RESULTS: Cancellation rate and clinical pregnancy rate varied by AMH group, with highest cancellation rates (32.8%, P = 0.021) and lowest clinical pregnancy rates (9.8%, P < 0.001) in the group with lowest AMH. When these patients achieved embryo transfer, the implantation rate (30.5%) did not significantly differ from the other groups, and retained a low, but reasonable, clinical pregnancy rate per transfer (45.9%). When this group was classified into three female age groups, the clinical pregnancy rate was found to be significantly higher in the patients younger than 37 years (58.1%) compared with patients aged between 37 and 39 years (48.9%) and those aged over 39 years (27%, P < 0.001). CONCLUSIONS: Although significant differences in pregnancy rates were observed among the different AMH groups, even in the lowest AMH level group, the probability of achieving pregnancy was reasonable, especially if the patient's age is not very advanced. PMID- 29703436 TI - Comparison of Platelet Function Guided Versus Unguided Treatment With P2Y12 Inhibitors in Patients With Acute Myocardial Infarction (from the Hungarian Myocardial Infarction Registry). AB - Evidence is conflicting regarding the clinical benefits of selecting P2Y12 inhibitors based on platelet function testing (PFT). Between March 1, 2013 and March 1, 2014, we collected clinical characteristics and platelet function data in a nationwide acute myocardial infarction (AMI) registry from 15 interventional cardiology centers in Hungary. The risk of all-cause mortality at 1 year were compared after propensity score (PS) matching between patients receiving PFT guided and unguided P2Y12-inhibitor therapies. High platelet reactivity on clopidogrel (HPRoC) was uniformly defined with the Multiplate assay. A total of 5,583 patients with AMI and coronary intervention were registered. After exclusion of cases with contraindication to prasugrel, propensity matching resulted in a sample of 2,104 patients with well-adjusted characteristics. Clopidogrel was the dominant P2Y12 inhibitor in both groups (unguided: 96% vs PFT guided: 85%, p <0.001). In the PFT-guided group, 19% of patients had HPRoC and 77% of them were switched to prasugrel. According to the adjusted analysis, all cause mortality at 1 year was significantly lower in the PFT-guided compared with the unguided group (hazard ratio 0.57 [95% confidence interval 0.43 to 0.77], p <0.001). Although prasugrel treatment was not associated with lower all-cause mortality in the overall cohort, patients with HPRoC who switched to prasugrel had significantly lower mortality when compared with those continuing clopidogrel (hazard ratio 0.33 [95% confidence interval 0.12 to 0.92], p <0.05). In conclusion, in patients with AMI, PFT-guided treatment with a high rate of switchover to prasugrel was associated with a lower risk of mortality. Prasugrel was a predictor of lower mortality in patients with HPRoC but not in the overall cohort of AMI. PMID- 29703437 TI - Incidence, Predictors, and Impact of Vascular Complications After Transfemoral Transcatheter Aortic Valve Implantation With the SAPIEN 3 Prosthesis. AB - Vascular complications (VCs) after transfemoral transcatheter aortic valve implantation (TAVI) have always been reported to occur frequently. Studies addressing VCs have been conducted with older-generation prostheses. We aimed to evaluate the incidence, predictors, and impact of VCs after transfemoral TAVI with the balloon-expandable SAPIEN 3. We report a single-center retrospective analysis of 400 consecutive patients of a prospectively acquired cohort. All patients underwent transfemoral TAVI with SAPIEN 3 between January 2014 and December 2016. VC was defined according to the Valve Academic Research Consortium. In this cohort 83 patients had VCs (20.8%), 5.8% major and 15.0% minor. Sheath-to-iliofemoral artery ratio was the only predictor of major VCs (odds ratio 7.51, 95% confidence interval 1.61 to 34.95, p = 0.010). The area under the receiver-operator characteristic curve for sheath-to-iliofemoral artery ratio was 0.63 (poor accuracy). Thirty-day mortality rates were 17.4%, 1.7%, and 0.6% for major, minor, and no VCs, respectively (log-rank p <=0.001). After adjustment, only major VCs were associated with 30-day mortality (adjusted hazard ratio 48.31, 95% confidence interval 7.80 to 299.24). Mortality from 30 days until 1 year did not differ between patients with and without VCs (log-rank p = 0.61). In conclusion we report that VCs remain an issue of transfemoral TAVI with the SAPIEN 3, and their prediction continues to be difficult, albeit the low incidence, major VCs were associated with higher 30-day mortality. However, after these first 30 days, they were not of influence on survival anymore. PMID- 29703438 TI - Etiologies, Predictors, and Economic Impact of 30-Day Readmissions Among Patients With Peripartum Cardiomyopathy. AB - Peripartum cardiomyopathy (PPCM) is a pregnancy-associated cause of heart failure. Given the significant impact of heart failure on healthcare, we sought to identify etiologies and predictive factors for readmission in PPCM. We queried the 2013 to 2014 National Readmissions Database to identify patients admitted with a diagnosis of PPCM. Patients who were readmitted within 30 days were evaluated to identify etiologies and predictors of readmission. We identified 6,977 index admissions with PPCM. Of the 6,880 (98.6%) patients who survived the index hospitalization, 30-day readmission rate was 13%. Seventy-six percent of readmitted patients were admitted once, and the other 24% were readmitted at least twice within 30 days of discharge. Length of stay was >=8 days (adjusted odds ratio [aOR] 2.80, 95% confidence interval [CI] 2.08 to 3.77), multiparity (aOR 2.07, 95% CI 1.09 to 3.92), coronary artery disease (aOR 2.28, 95% CI 1.42 to 3.67), and long-term anticoagulation use (aOR 2.51, 95% CI 1.73 to 3.64) were independently associated with increased risk of 30-day readmission. Among the readmissions, 48% were due to cardiac causes, where PPCM and related complications (24%) were the most common cardiac cause followed by heart failure (16%). The annual cost of stay for index admissions was $64.2 million (average cost for index admission was $16,892). The annual charges attributed to readmission within 30 days were ~$9 million. Cardiac etiologies were the most common cause for 30-day readmissions in PPCM patients, with a readmission rate of 13%. Long-term anticoagulation use, multiparity, coronary disease and length of stay predicted higher 30-day readmission. PMID- 29703439 TI - Left Atrial Reverse Remodeling After Catheter Ablation of Nonparoxysmal Atrial Fibrillation in Patients With Heart Failure With Reduced Ejection Fraction. AB - The efficacy of catheter ablation (CA) of nonparoxysmal atrial fibrillation (PAF) in patients with left ventricular systolic dysfunction is controversial. We investigated the outcomes of CA for non-PAF in patients with reduced left ventricular ejection fraction (LVEF) and the impact of early left atrial (LA) reverse remodeling on these outcomes. A total of 251 consecutive patients who underwent CA for non-PAF were divided into 2 groups (reduced: preoperative LVEF <=55%, LVEF: 46.5 +/- 8.7%, n = 63; normal: >55%, 65.8 +/- 5.8%, n = 188). We analyzed the 4-year atrial fibrillation- or atrial tachycardia (AT)-free survival rate and assessed changes in LVEF, hemodynamics, and LA reverse remodeling at the end of a 90-day blanking period. We also evaluated LA reverse remodeling in patients with and without recurrence. The atrial fibrillation- or AT-free survival rates were similar (reduced vs normal 48% vs 42%, p = 0.32). The reduced group exhibited significant LVEF improvement (before vs after, 46.5 +/- 8.7% vs 58.4 +/- 11.5%, p<0.001), reduced mitral regurgitation, and spectral tissue Doppler-derived index, and had greater percent maximum left atrial volume reduction (reduced vs normal 25.3 +/- 18.2% vs 19.3 +/- 16.2%, p = 0.014). Percent maximum left atrial volume reduction was greater in patients without recurrence (with recurrence vs without recurrence 17.3 +/- 16.7% vs 25.4 +/- 16.1%, p<0.001). In conclusion, the efficacy of non-PAF CA in patients with reduced LVEF was comparable with that in patients with normal LVEF. Greater LA reverse remodeling in these patients suggests an association with a reduced recurrence rate. PMID- 29703440 TI - Usefulness of Complement C1q to Predict 10-Year Mortality in Men With Diabetes Mellitus Referred for Coronary Angiography. AB - The complement system consists of a family of proteins that play a critical role in the innate immune system. Complement activation has been implicated in many chronic inflammatory diseases, including atherosclerosis. However, a number of experimental studies have highlighted a beneficial role of component C1q in early atherosclerosis and in diabetes mellitus (DM). Despite these data, there have been no studies that have specifically examined the utility of plasma complement C1q as a clinical biomarker in patients with known or suspected coronary artery disease. In this study, baseline plasma complement C1q levels were measured in 159 men with DM who were referred for coronary angiography and who were followed up prospectively for the development of all-cause mortality for 10 years. After adjustment for baseline clinical, angiographic, and laboratory parameters, reduced plasma complement C1q levels were an independent predictor of all-cause mortality at 10 years (hazard ratio 0.66, 95% confidence interval 0.52 to 0.84, p = 0.0006). In additional multivariate models that adjusted for a variety of biomarkers with established prognostic efficacy, complement C1q remained an independent predictor of all-cause mortality at 10 years. In conclusion, reduced levels of complement C1q are associated with an increased risk of all-cause mortality at 10 years in patients with DM referred for coronary angiography. Furthermore, this association is independent of a variety of clinical, angiographic, laboratory variables, including biomarkers with established prognostic efficacy in the prediction of adverse cardiovascular outcomes. PMID- 29703441 TI - Usefulness of Psoas Muscle Area and Volume and Frailty Scoring to Predict Outcomes After Transcatheter Aortic Valve Implantation. AB - Numerous scales were implemented for frailty assessment. However, limited evidence and recommendations for frailty tools for everyday clinical practice in patients who underwent transcatheter aortic valve implantation (TAVI) exist. Thus, we aimed to determine the long-term predictive value of different frailty scores and objective assessment of sarcopenia by imaging techniques in patients after TAVI. Frailty indexes according to Valve Academic Research Consortium-2 (VARC-2) recommendations, as well as other available scales of frailty, were assessed at baseline. Sarcopenia was evaluated with psoas muscle area (PSA) and psoas muscle volume (PSV) using computed tomography (CT) scans. The primary end point was 12-month all-cause mortality. We enrolled 153 patients who underwent TAVI with analyzable CT scans and complete frailty data. The median of PSA normalized for body surface area was 2,581.1 (2,214.9 to 2,654.9) mm2/m2, and the median of normalized PSV was 338.8 (288.1-365.6) cc/m2. At 12 months, all-cause mortality and new-onset atrial fibrillation were highest in the lowest tertile of normalized PSA. In the receiver operating characteristic analysis, all the tested frailty indexes, as well as PSA and PSV, were good predictors of 12-month all cause mortality after TAVI with the highest area under the curve value for PSA and PSV normalized for body surface area. In conclusion, normalized PSA and PSV values are strong predictors of long-term mortality after TAVI. CT evaluation of psoas muscles could be incorporated to preprocedural comprehensive clinical models used for prediction of outcomes in patients scheduled for TAVI. PMID- 29703442 TI - Recurrent Acute Decompensated Heart Failure Admissions for Patients With Reduced Versus Preserved Ejection Fraction (from the Atherosclerosis Risk in Communities Study). AB - Hospitals are required to report all-cause 30-day readmissions for patients discharged with heart failure. Same-cause readmissions have received less attention but may differ for heart failure with reduced ejection fraction (HFrEF) versus heart failure with preserved ejection fraction (HFpEF). The ARIC study began abstracting medical records for cohort members hospitalized with acute decompensated heart failure (ADHF) in 2005. ADHF was validated by physician review, with HFrEF defined by ejection fraction <50%. Recurrent admissions for ADHF were analyzed within 30 days, 90 days, 6 months, and 1 year of the index hospitalization using repeat-measures Cox regression models. All recurrent ADHF admissions per patient were counted rather than the more typical analysis of only the first occurring readmission. From 2005 to 2014, 1,133 cohort members survived at least 1 hospitalization for ADHF and had ejection fraction recorded. Half were classified as HFpEF. Patients with HFpEF were more often women and had more co morbidities. The overall ADHF readmission rate was greatest within 30 days of discharge but was higher for patients with HFrEF (115 vs 88 readmissions per 100 person-years). After adjustments for demographics, year of admission, and co morbidities, there was a trend for higher ADHF readmissions with HFrEF, relative to HFpEF, at 30 days (hazard ratio [HR] 1.41, 95% confidence interval [CI] 0.92 to 2.18), 90 days (HR 1.39, 95% CI 1.05 to 1.85), 6 months (HR 1.47, 95% CI, 1.18 to 1.84), and 1 year (HR 1.42, 95% CI 1.18 to 1.70) of follow-up. In conclusion, patients with HFrEF have a greater burden of short- and long-term readmissions for recurrent ADHF. PMID- 29703443 TI - How safe are carmustine wafers? PMID- 29703444 TI - Regional disparities in acute and post-acute care of stroke patients in France, 2015. AB - OBJECTIVE: The aim of this study was to assess regional variations of the hospital management of stroke patients during acute and post-acute phases in France in 2015. MATERIAL AND METHODS: Hospitalized patients coded with stroke as their main diagnosis or, if hospitalized in several different wards, any main ward diagnosis were identified in the 2015 French national hospital discharge database for acute care. Rates of hospitalization in stroke units (SUs) were assessed at a national level and in all metropolitan and overseas regions. All stroke survivors discharged at the end of the acute phase were subsequently identified in the national database for post-acute rehabilitation hospitalization (PARH) within 3 months. RESULTS: In the acute phase, half the stroke patients hospitalized for intracerebral hemorrhage, cerebral infarction or unspecified stroke were admitted to SUs. However, there were variations across metropolitan regions (from 30% to 69%) and in overseas regions (from 1% to 59%); these rates correlated with regional ratios of SU beds/100,000 inhabitants. There were also regional differences in PARH rates-in hemiplegic stroke patients, 62% were admitted for PARH (range: 58% to 67%) in metropolitan regions and, overseas, from 8% to 67%-as well as geographical discrepancies in PARH rates to specialized rehabilitation units. Hospitalization rates of hemiplegic stroke patients in neurological rehabilitation centers were 30% for the whole country, but ranged from 23% to 36% in metropolitan regions and from 2% to 45% in overseas regions. CONCLUSION: This study focused on hospital-based management of stroke patients. In spite of the creation of new SUs over the past decade in France, there are persistent regional differences in the number of SU beds/100,000 inhabitants and, consequently, in the rate of stroke patients managed in SUs. However, rates continue to improve with the creation of new SUs and the expansion of existing ones. Regional variations were also noted for post-acute hospitalization rates and PARH beds/places. PMID- 29703445 TI - First-line therapy in relapsing remitting multiple sclerosis. AB - Today, first-line treatments for multiple sclerosis include injectable immunomodulators - some of which have been on the market for nearly 25 years - as well as teriflunomide and dimethyl fumarate, which are more recent, but have opened the way for oral treatments. These drugs are considered similar in effectiveness, and their safety and side-effect profiles are generally reassuring. These treatments have been associated with a reduction in radiological and clinical disease activity, and a positive effect on patient quality of life, especially when introduced early in the disease process. This article will discuss data on first-line treatments currently available in France, their effectiveness and safety, and their place in pediatric patients and in woman who plan to become pregnant. PMID- 29703447 TI - Cognitive and functional correlates of accelerated long-term forgetting in temporal lobe epilepsy. AB - While we know that hippocampal dysfunction is responsible for the memory deficits that patients with temporal lobe epilepsy exhibit at relatively short study-test delays, the role of this region in accelerated long-term forgetting (ALF) is not yet clear. In the present study, we probed the role of the hippocampus in ALF by directly comparing memory for associations to memory that could be supported by item recognition during a forced choice recognition task over delays ranging from 15-min to 72-h. We additionally examined resting-state functional connectivity between the hippocampus and cortical regions known to be involved in processing these types of stimuli, as well as the relationship between ALF and various clinical variables including structural abnormality in the hippocampus, lateralization of epileptic focus, presence of seizures across the retention period, and standardized composite memory scores. We found evidence of accelerated forgetting for item stimuli (but not associative stimuli) by 6 h post learning, which became statistically reliable by 72-h. This finding suggests that unlike controls, patients were unable to utilize novelty to reject the incorrect object-scene pair. While none of the examined clinical variables were related to long-term forgetting, reduced resting-state functional connectivity between the affected anterior hippocampus and unaffected lateral temporal cortex predicted forgetting of item stimuli over the 72-h delay. Implications for the role of the hippocampus in accelerated long-term forgetting, and existing theories of systems consolidation in this context are discussed. PMID- 29703448 TI - Mechanisms and uncertainty in randomized controlled trials: A commentary on Deaton and Cartwright. PMID- 29703446 TI - Adding methylphenidate to prism-adaptation improves outcome in neglect patients. A randomized clinical trial. AB - : Spatial neglect is one of the main predictors of poor functional recovery after stroke. Many therapeutic interventions have been developed to alleviate this condition, but to date the evidence of their effectiveness is still scarce. OBJECTIVE: The purpose of this study was to test whether combining prism adaptation (PA) and methylphenidate (MP) could enhance the recovery of neglect patients at a functional level. METHODS: RITAPRISM is a multicentre, randomized, double-blind, placebo-controlled study comparing PA plus placebo (control) versus PA plus MP. 24 patients were prospectively enrolled (10 in the placebo group and 14 in the MP group). RESULTS: The main result is a long-term functional improvement (on the functional independence measure (FIM) and on Bergego's scale) induced by MP combined with PA. No serious adverse event occurred. CONCLUSIONS: The long-term benefit on activities of daily living (ADL) obtained in this randomized controlled trial set this intervention apart from previous attempts and supports with a high level of evidence the value of combining PA and MP in order to improve the autonomy of neglect patients. Further studies will be needed to clarify the mechanism of this improvement. Although not specifically assessed at this stage, a part of the improvement in ADL might be related to the collateral effect of MP on mood, executive functions or fatigue, and/or the combined effect of PA and MP on motor intentional bias of neglect patients. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that adding MP to PA improves the functional outcome of neglect patients. WHO TRIAL REGISTRATION ID: EUCTR2008-000325-20-FR. PMID- 29703449 TI - [Air pollution, cardiovascular risk and hypertension]. AB - Air pollution is a worrying factor and has an impact on public health. Multiple studies relate exposure to air pollutants with an increase in cardiovascular events, cardiovascular mortality and mortality for all causes. A relationship has also been demonstrated between increased pollution and high blood pressure, as well as a higher prevalence of hypertension. Pollutants that play a more relevant role in this association are particulate matters, nitrogen dioxide and sulphur dioxide. The objective of this review is to understand the mechanisms involved in this increase and to find the most recent publications that relate pollution, cardiovascular risk and hypertension. PMID- 29703450 TI - Insulin related lipodystrophic lesions and hypoglycemia: Double standards? AB - Lipohypertophy (LH) is the most common skin complication of incorrect injection technique which does not only represent an aesthetic defect but also severely disrupts insulin pharmacokinetics/pharmacodynamics. As a consequence of that, hormone release is delayed and unexplained/unpredictable hypoglycemia occurs, both deteriorating metabolic control while negatively affecting adherence to treatment and quality of life. The economic burden due to unwanted intra-LH injections is accounted for by inappropriately high insulin requirements, increased emergency-related hospitalizations, and loss of work days. Greater attention has to be paid by diabetes care teams to education programs with periodic refreshers to achieve better metabolic control and reduce the economic burden of diabetes. PMID- 29703451 TI - Osteoporosis, bone mineral density and CKD-MBD complex (I): Diagnostic considerations. AB - Osteoporosis (OP) and chronic kidney disease (CKD) independently influence bone and cardiovascular health. A considerable number of patients with CKD, especially those with stages 3a to 5D, have a significantly reduced bone mineral density leading to a high risk of fracture and a significant increase in associated morbidity and mortality. Independently of classic OP related to age and/or gender, the mechanical properties of bone are also affected by inherent risk factors for CKD ("uraemic OP"). In the first part of this review, we will analyse the general concepts regarding bone mineral density, OP and fractures, which have been largely undervalued until now by nephrologists due to the lack of evidence and diagnostic difficulties in the context of CKD. It has now been proven that a reduced bone mineral density is highly predictive of fracture risk in CKD patients, although it does not allow a distinction to be made between the causes which generate it (hyperparathyroidism, adynamic bone disease and/or senile osteoporosis, etc.). Therefore, in the second part, we will analyse the therapeutic indications in different CKD stages. In any case, the individual assessment of factors which represent a higher or lower risk of fracture, the quantification of this risk (i.e. using tools such as FRAX(r)) and the potential indications for densitometry in patients with CKD could represent an important first step pending new clinical guidelines based on randomised studies which do not exclude CKD patients, all the while avoiding therapeutic nihilism in an area of growing importance. PMID- 29703452 TI - A population-based examination of the co-occurrence and functional correlates of chronic pain and generalized anxiety disorder. AB - OBJECTIVES: This study aimed to: 1) Establish the prevalence of co-occurring chronic pain conditions (i.e., arthritis, back pain, and migraines) and generalized anxiety disorder (GAD), and 2) Examine levels of pain severity, disability, and work absenteeism among comorbid chronic pain conditions and GAD. METHODS: Data were analyzed from the 2012 Canadian Community Health Survey-Mental Health (CCHS-MH; N = 25,113). Chi-square analyses assessed whether significant differences existed in pain severity in those with comorbid chronic pain and GAD versus pain conditions alone. Multivariable regressions examined the association between comorbid chronic pain and GAD with functional outcomes. RESULTS: The weighted prevalence of GAD among those with chronic migraines, arthritis and back pain was 6.9%, 4.4%, and 6.1% respectively, compared to 2.6% among the entire sample. Severity of pain was increased among those with comorbid chronic pain and GAD compared with chronic pain conditions alone. Migraine was the only pain condition that was significantly associated with disability in our most stringent adjustment model. After controlling for other psychiatric disorders, comorbid GAD and chronic pain was not associated with work absenteeism. CONCLUSION: Chronic pain is common among the Canadian population and is associated with substantial disability. Results demonstrated that GAD is prevalent among chronic pain conditions, and comorbidity is associated with greater pain severity. GAD in the context of migraines, in particular, may represent an important treatment target to reduce disability. PMID- 29703454 TI - Wide complex tachycardia discrimination using dynamic time warping of ECG beats. AB - BACKGROUND AND OBJECTIVE: Automatic processing and accurate diagnosis of wide complex tachycardia (WCT) arrhythmia groups using electrocardiogram signals (ECG) remains a challenge. WCT arrhythmia consists of two main groups: ventricular tachycardia (VT) and supraventricular tachycardia with aberrancy (SVT-A). These two groups have similar morphologies in the realm of ECG signals. VT and SVT-A arrhythmias originate from the ventricle and atrium, respectively. Hence, inaccurate diagnosis of SVT-A instead of VT can be fatal. METHODS: In this paper, we present a novel algorithm using dynamic time warping (DTW) to discriminate between VT and SVT-A arrhythmias. This method includes pre-processing, best template search (BTS), and classifier modules. The first module, pre-processing, is responsible for filtering, R-wave detection, and beat detection of ECG signals. The second module, BTS, automatically extracts the minimum possible number of signals as a template from the entire training dataset using an intelligent algorithm. These template signals have the greatest morphological difference, which leads to accurate WCT discrimination. Finally, a 1NN classifier categorizes the test data using DTW distance. RESULTS: Our proposed method was evaluated on an ECG signal database consisting of 171 subjects. The results showed that the proposed algorithm can accurately discriminate between VT, SVT-A, and normal subjects, and appears to be suitable for future use in clinical application. The obtained accuracy, sensitivity, specificity, and positive predictive values were 93.22%, 88.68%, 96.98%, and 90.27%, respectively. CONCLUSION: The presented diagnostic method for discriminating VT and SVT-A, using only one ECG lead, is suitable for future clinical use. It can reduce needless therapeutic interventions and minimize risk for patients. PMID- 29703453 TI - Association of positive screening for dysphagia with nutritional status and long term mortality in hospitalized elderly patients. AB - OBJECTIVES: To assess the prevalence of oropharyngeal dysphagia (OD) using the Eating Assessment Tool (EAT-10) and its association with malnutrition and long term mortality. MATERIAL AND METHODS: A retrospective cohort study of patients admitted to the general internal medicine ward. In the first 48hours after hospital admission, OD was assessed using the EAT-10, and presence of malnutrition with the Mini Nutritional Assessment-Short Form (MNA-SF). Association of OD to malnutrition and long-term mortality was analyzed. RESULTS: Ninety patients with a mean age of 83 (SD: 11.8) years were enrolled. Of these, 56.7% were at risk of OD according to EAT-10. This group of patients had greater prevalence rates of malnutrition (88.2% vs. 48.7%; P=.001) and mortality (70% vs 35.9%; P=.001). During follow-up for 872.71 (SD: 642.89) days, risk of DO according to EAT-10 was an independent predictor of mortality factor in a multivariate analysis (HR: 2.8; 95%CI: 1.49-5.28; P=.001). CONCLUSIONS: The EAT 10 is a useful tool for screening OD. Adequate screening for OD is important because of its associated risks of malnutrition and long-term mortality. PMID- 29703455 TI - New concepts in macrophage ontogeny in the adult neural retina. AB - The number of neurons dedicated to vision itself is thought to be greater than the sum of the four other senses combined. Yet, little attention has been payed to the retina as compared to elsewhere in the central nervous system with respect to microglia, the macrophages of the neural parenchyma. Indeed, major advancements in the understanding of microglial ontogeny and maintenance in brain and spinal cord are now widely appreciated, whereas less notice has been given to the neural retina in this regard. The current Review covers topical concepts on adult microglia and perivascular macrophage ontogenies in the steady state retina, as well as parallels made with these macrophages in other areas of the central nervous system. The subject of recruited monocytes and their descendant monocyte-derived macrophages in degenerative diseases of the retina is also integrated into this Review. Key experiments that have led to the theories covered are highlighted throughout, as are the knowledge gaps that remain unresolved. PMID- 29703456 TI - Risk Factors for Removal of Calcaneus Screws: A Retrospective Study. AB - Although techniques using calcaneus screws have shown high union rates, posterior heel pain due to prominent hardware at the posterior and plantar aspect of the calcaneal tuberosity seems to be a significant complaint that often leads to hardware removal. The purpose of the present study was to identify the clinical and radiologic risk factors associated with calcaneus screw removal. A retrospective study of adult patients who required calcaneus screw fixation from January 2008 to December 2016 was conducted. We reviewed the medical records and radiographs to evaluate the risk factors for screw removal. Of the 123 patients included in the present study, 63 were male and 60 were female. The mean age was 55.0 +/- 6.0 years, and the mean body mass index was 31.0 +/- 6.0 kg/m2. The removal rate was 8.8% (10 of 114 evaluated) at the 1-year follow-up point and 13.6% (12 of 88 evaluated) at the 2-year follow-up point. The mean interval to removal was 1.23 +/- 1.22 years. A total of 16 screws (72.7%) were removed for heel pain. At the 1-year follow-up examination, the removal rate due to inflammatory arthritis was 25.0% (p = .07). Moreover, the proportion of screw removal was greater at 2 years in illicit drug users (p = .008). Screw sizes <=6.5 mm showed a tendency (p = .12) toward a lower rate of removal at the 2-year follow-up point. Calcaneus screws should be used with caution in specific patient populations such as illicit drug users and those with inflammatory arthritis. The use of smaller diameter calcaneus screws might be an option to lower the rate of screw removal due to heel pain. PMID- 29703457 TI - A Suture-Button Technique for Stabilization of the Plantar Plate and Lesser Metatarsophalangeal Joint. AB - We retrospectively evaluated the use of a suture-button technique to stabilize the plantar plate and lesser metatarsophalangeal joint (MTPJ) to alleviate pain and dysfunction due to failed digital surgery with lesser MTPJ dysfunction. Eight consecutive patients (8 feet, 13 rays) were studied, including 2 males (25%) and 6 females (75%). Their median age was 56.5 (range 25 to 72) years, and the median follow-up duration was 28 (range 21 to 36) months. Of the 8 patients, 7 (87.5%) underwent concomitant adjunct procedures. A 10-increment (equal intervals) pain score and the Bristol foot score (BFS) were used to assess subjective satisfaction and foot-related quality of life before and after surgery. The median preoperative pain score was 8 (range 5 to 10). Postoperatively, the median pain score was 0 (range 0), and the difference was statistically significant (p = .0106). The median preoperative and postoperative BFS was 53 (range 32 to 70) and 20 (range 18 to 34), respectively. The difference was also statistically significant (p = .018). One patient (12.5% of patients, 7.7% of rays) experienced wound dehiscence. All the patients indicated they would undergo the procedure again. From these findings, we believe the described suture-button technique is a useful method to stabilize the plantar plate and MTPJ after failed digital surgery. PMID- 29703458 TI - Operatively Treated Talus Fractures: Complications and Survivorship in a Large Patient Sample. AB - Talus fractures are relatively uncommon; however, the sequelae of talus fractures can cause significant morbidity. Although avascular necrosis has been a consistently reported complication, the reported rates of subsequent arthrodesis have varied widely. The purpose of the present study was to report the complications in a large patient sample of operatively treated talus fractures and to describe the survivorship of open reduction internal fixation (ORIF) of the talus. Patients undergoing talus ORIF for closed or open fractures from 2007 to 2011 were identified in the United Healthcare System database by International Classification of Diseases, 9th revision, code 825.21 and Current Procedural Terminology codes 28445, 28436, and 28430. Patients with a nonoperative talus fracture or isolated osteochondral defect were excluded, leaving 1527 patients in the final analysis. We also identified patients who had required subsequent subtalar, pantalar, and tibiotalocalcaneal arthrodeses using Current Procedural Terminology codes 28725, 28705, and 28715, respectively. Complications and demographic data were recorded. Of the 1527 patients, 29 (1.9%) had undergone subsequent arthrodesis within 4 years; 64 patients (4.2%) developed wound complications that did not require surgical intervention, 11 patients (0.7%) were readmitted, 204 (13.3%) presented to the emergency department (ED), and 96 (6.3%) underwent operative irrigation and debridement (I&D). The overall complication rate was 19.5%. Patients aged >34 years had a significantly greater rate of ED visits (54.7%, p = .015) and overall complications (56.8%, p < .001). In conclusion, ORIF of talus fractures has good survivorship when considering the failure of initial surgery or the requirement for secondary arthrodesis. Medical complications and hospital readmission were relatively rare; however, ED visits and infection requiring I&D were relatively common after ORIF of talus fractures. PMID- 29703459 TI - Re: Measuring Recovery After Ankle Fractures: A Systematic Review of the Psychometric Properties of Scoring Systems. PMID- 29703460 TI - Comparison and Use of Allograft Bone Morphogenetic Protein Versus Other Materials in Ankle and Hindfoot Fusions. AB - Bone grafting is a common procedure in foot and ankle surgery. Because autogenous graft use results in comorbidity to the patient, the search has been ongoing for the ideal substitute. A novel processing technique for allograft using bone marrow, which retains many of the growth factors, has shown promise in the spinal data and early reports of foot and ankle surgery. We performed a retrospective, comparative study of patients undergoing hindfoot and ankle arthrodesis, with a total of 68 patients included. Of the 68 patients, 29 (42.65%) received a bone morphogenetic protein allograft and 39 (57.35%) did not. The patient demographics and social and medical history were similar between the 2 groups and both groups had a similar time to union (p = .581). Of the 29 patients in the bone morphogenetic protein allograft group, 3 (10.3%) experienced nonunion and 4 (13.8%) developed a complication. Of the 39 patients undergoing other treatment, 7 (17.9%) experienced nonunion and 14 (35.9%) developed a complication. The difference for nonunion was not statistically significant (p = .5). However, the difference in the overall complication rate was statistically significant (p = .04). We found that this novel bone graft substitute is safe and can be used for foot and ankle arthrodesis. PMID- 29703461 TI - Validity and Reliability of Turkish Version of Olerud-Molander Ankle Score in Patients With Malleolar Fracture by Buker et al. PMID- 29703462 TI - Acute Dyspnea Caused by Achalasia. PMID- 29703463 TI - Widespread increase of empirical carbapenem use in acute care hospitals in Catalonia, Spain. AB - INTRODUCTION: The overall increase in the use of carbapenems could lead to the selection of carbapenem-resistant bacteria. The objectives of this study were to analyze carbapenem use from 2008 to 2015 and their prescription profile in 58 hospitals affiliated to the VINCat Programme (nosocomial infection vigilance system). METHODS: Retrospective, longitudinal and descriptive study of carbapenem use. Consecutive case-series study, looking for carbapenem prescription characteristics, conducted in January 2016. Use was calculated in defined daily doses (DDD)/100 patient-days (PD); prescription profiles were assessed using a standardized survey. RESULTS: Carbapenem use increased 88.43%, from 3.37 DDD/100 PD to 6.35 DDD/100-PD (p<0.001). A total of 631 patients were included in the prescription analysis. Carbapenems were prescribed empirically in 76.2% of patients, mainly for urinary tract and intra-abdominal infections due to suspicion of polymicrobial mixed infection (27.4%) and severity (25.4%). CONCLUSION: A worrying increase in carbapenem use was found in Catalonia. Stewardship interventions are required to prevent carbapenem overuse. PMID- 29703464 TI - Preface. PMID- 29703465 TI - Thrombotic microangiopathy in cancer. AB - Thrombotic microangiopathy (TMA) is clinical syndrome based on the presence of thrombocytopenia (platelet count <150 K or a reduction of the platelet count by >30% from baseline) accompanied by fragmentation hemolysis (MAHA) and evidence of organ damage. It can be seen in a variety of disorders including thrombotic thrombocytopenic purpura (TTP), atypical hemolytic uremic syndrome (aHUS), shigatoxin related hemolytic uremic syndrome (STEC-HUS). Cancer itself has long been associated with both macro and microvascular thrombosis. In addition, treatment with chemotherapy as well as hematopoetic stem cell transplantation (HCST) has been associated with atypical hemolytic uremic (aHUS) like syndrome. In this review, I will discuss the pathophysiology of TMA in cancer, chemotherapy associated HUS, and HSCT, well as new therapeutic interventions. PMID- 29703466 TI - Anti-platelet treatments in cancer: Basic and clinical research. AB - Over the past few decades the central role that platelets play in cancer development and progression, and especially in metastasis, has been elucidated. The molecular mechanisms responsible for initiating and mediating tumor cell induced platelet aggregation and secretion have been largely unravelled. Considerable mechanistic insight into how platelets contribute to tumor angiogenesis, immunoevasion and cancer cell invasion have been clarified and, consequently, platelets have been identified as potential new drug targets for cancer therapy. This article gives an overview of the platelet-targeted pharmacologic approaches that have been attempted in the prevention of cancer development, progression and metastasis, including the application of antiplatelet drugs currently used for cardiovascular disease and of new and novel strategies. PMID- 29703467 TI - Morbidity, mortality and costs associated with venous thromboembolism in hospitalized patients with cancer. AB - BACKGROUND: Venous thromboembolism (VTE) represents a leading cause of morbidity and mortality among patients with cancer. METHODS: Hospitalization data reported on adult cancer patients at US medical centers between 1995 and 2012 were analyzed. Cancer diagnosis, presence of VTE, comorbidities, and infectious complications were based on ICD-9-CM codes. RESULTS: Nearly six million hospitalizations of 3,146,388 individual patients with cancer were reported with VTE observed in 8.4%. A single hospitalization was randomly selected for each patient with VTE diagnosed in 166,537 (5.3%) of evaluated admissions. In-hospital mortality was observed in 5.5% of patients without a VTE diagnosis and in 15.0% of those with VTE including 19.4% with a pulmonary embolism. While rates of VTE increased from 3.5% in 1995 to 6.5% in 2012, no significant reported changes in VTE imaging, length of stay (LOS) or intensive care unit (ICU) admissions were observed and mortality decreased by one-third. VTE was reported in 5.2%, 5.8% and 5.4% of patients with solid tumors, lymphoma, and leukemia, respectively. Rates of VTE were greatest among patients with pancreatic, gastric or other abdominal malignancies as well as those with ovarian, lung and esophageal cancers. The risk of VTE increased progressively from 2.3% in those with no comorbidities to over 11% in those with >=3 major comorbidities. The strongest risk factors for VTE were infectious complications including sepsis, invasive candidiasis, pneumonia and IV line infections. Average costs per hospitalization adjusted to 2015 dollars for patients without and with VTE were $19,994 and $37,352, respectively. CONCLUSIONS: VTE among hospitalized patients with cancer has increased significantly with a major impact on hospital mortality and costs. Patients with major medical comorbidities and infectious complications are at particularly high risk. PMID- 29703468 TI - Antidotes for the direct oral anticoagulants: What news? AB - The direct oral anticoagulants (DOACs) are recommended as the first-choice anticoagulants for both stroke prevention in patients with non-valvular atrial fibrillation and the treatment and secondary prevention of venous thromboembolism. DOACs cause bleeding, albeit less than warfarin. Most bleeding complications can be controlled by general reversal strategies and supportive care. However, in case of life-threatening bleeding, or when urgent invasive procedures are needed, a more rapid and thorough reversal may be required. Idarucizumab, andexanet alfa and ciraparantag have been developed as reversal agents for the DOACs. To date idarucizumab is the only approved antidote and is specific for dabigatran. Andexanet alfa, a reversal agent for the factor Xa inhibitors, is still under investigation, but its approval by regulatory agencies is expected soon. Ciraparantag, a universal antidote, is in an earlier stage of development. Based on the results of clinical trials to date, these compounds appear to be breakthrough for urgent and emergency reversal. When administered at fixed doses, they ensured a rapid, efficient and safe restoration of haemostasis. From a practical perspective, all hospitals should develop local protocols to ensure safe and efficient clinical implementation of reversal strategies. Post marketing studies will be essential to assess the evolution of management strategies and to confirm the safety and effectiveness of these agents. PMID- 29703469 TI - Prothrombotic genotypes and risk of venous thromboembolism in cancer. AB - Venous thromboembolism (VTE) is a common and potentially life-threatening complication in cancer. Patients with cancer are at a higher risk of VTE-related complications such as major bleeding during anticoagulant treatment, recurrence and mortality. Therefore, it is important to identify cancer patients with high risk of VTE in order to implement targeted prevention to those with a favorable benefit-to-harm ratio for thromboprophylaxis. VTE is strongly heritable, and during the last decades, several prothrombotic genotypes associated with VTE-risk have been identified. However, most of these studies were conducted in non-cancer patients, and the role of prothrombotic genotypes in cancer-related VTE is scarcely studied. In this review, we summarize current knowledge on the role of prothrombotic genotypes in cancer-related VTE, with particular focus on factor V Leiden, the prothrombin G20210A mutation and polymorphisms in the ABO gene. In general, many of the studies were small and performed in selected cancer populations, and they showed somewhat diverging results. Results from recent, larger, studies indicated that there is an association between these prothrombotic genotypes and cancer-related VTE. However, their predictive capability has not been assessed and the clinical implications are yet unclear. Future research should be conducted in larger cancer patient populations, and should be extended to include recently identified prothrombotic genotypes and assess the predictive value of genetic risk scores. PMID- 29703470 TI - Apixaban for the prevention of venous thromboembolism in high-risk ambulatory cancer patients receiving chemotherapy: Rational and design of the AVERT trial. AB - Patients with active cancer have a heightened risk of venous thromboembolism (VTE). This risk is further increased by the initiation of chemotherapy. Although previous studies have suggested that the use of parenteral thromboprophylaxis in all ambulatory cancer patients receiving chemotherapy significantly decreases the rate of VTE, current clinical practice guidelines do not recommend routine use of thromboprophylaxis in this patient population. A major criticism of these studies has been the inclusion of patients at lower risk for VTE, which may have diluted the potential beneficial effect of the parenteral thromboprophylaxis. It is therefore imperative to appropriately risk stratify ambulatory cancer patients using a validated scoring system (e.g. Khorana risk score) in order to identify those most likely to benefit from thromboprophylaxis. Direct oral anticoagulants, such as apixaban, may offer a convenient and safe option for thromboprophylaxis. As such, AVERT will randomize 574 ambulatory cancer patients receiving chemotherapy who are at high-risk for VTE (as defined by a Khorana score of >=2) to Apixaban 2.5 mg BID versus placebo. The primary study outcome will be the first episode of objectively documented symptomatic or incidental VTE (deep vein thrombosis and/or pulmonary embolism) within the first 6 months (180 days +/- 3) following initiation of the blinded study drug for both intervention and placebo groups. The secondary safety outcomes include major bleeding, clinically relevant non-major bleeding, and overall survival rates. This study will hopefully offer evidence regarding the benefit of apixaban in ambulatory patients at high risk for VTE receiving chemotherapy. PMID- 29703472 TI - Single cell coagulomes as constituents of the oncogene-driven coagulant phenotype in brain tumours. AB - Molecular profiling of human cancers revealed a startling diversity in disease causing mechanisms superseding histological and anatomical commonalities. The emerging molecular subtypes and disease entities are often driven by distinct oncogenic pathways and their effectors, including those acting extracellularly on the vascular and coagulation systems. Indeed, several oncogenic mutations such as those affecting protein-coding genes (RAS, EGFR, PTEN, TP53) and non-coding RNA (microRNA) regulate multiple effectors of the coagulation system (coagulome), including tissue factor, protease activated receptors, clotting factors, mediators of platelet function and fibrinolysis. This is exemplified by differential coagulome profiles in the molecular subtypes of glioblastoma, medulloblastoma and other human tumours. There is mounting clinical evidence that the mutational status of cancer driver genes such as KRAS or IDH1 may influence the risk of venous thromboembolism in patients with colorectal, lung or brain cancers. Notably, single cell sequencing in glioblastoma revealed a remarkable intra-tumoural heterogeneity of cancer cell populations with regard to their individual coagulomes, suggesting a combinatorial and dynamic nature of the global pro-thrombotic phenotype. We suggest that the cellular complexity of specific cancers may define their mechanisms of interactions with the coagulation system, and the risks of thrombosis. Thus, more biologically- based, disease specific and personalized approaches may be needed to diagnose and manage cancer related thrombosis. PMID- 29703471 TI - The intersection of protein disulfide isomerase and cancer associated thrombosis. AB - The mechanisms underlying the hypercoagulability of cancer are complex and include the upregulation coagulation factors or procoagulant proteins, shedding of microparticles, and direct activation of vascular cells. Protein disulfide isomerase (PDI) is a thiol isomerase secreted from activated platelets and endothelial cells and plays a critical role in both platelet aggregation and fibrin generation. A number of potential intravascular targets of PDI have been identified including cell surface receptors (e.g. beta-integrins and glycoprotein Ib), receptor ligands (e.g. fibrinogen and von Willebrand factor), serine proteases (e.g. cathepsin G and kallekrein-14), and coagulation factors (e.g. factor XI and factor V). Recent clinical studies demonstrated that a small molecule inhibitor of PDI, isoquercetin, decreases platelet-dependent thrombin generation and PDI activity in plasma following oral administration. This review explores the mechanistic overlap between the molecular drivers of cancer associated thrombosis and the potential roles PDI plays in mediating thrombosis. These molecular insights provide rationale for clinical trials targeting PDI to prevent thrombosis in cancer patients. PMID- 29703473 TI - Tissue factor as a mediator of coagulation and signaling in cancer and chronic inflammation. AB - Thrombosis is frequently diagnosed as a first symptom in tumor patients and the clinical management of hypercoagulability in cancer patients remains challenging due to concomitant changes in risk factors for severe bleeding. It therefore remains a priority to better understand interactions of the hemostatic system with cancer biology. Specifically, further research is needed to elucidate the details and effects of new anticoagulants on extravascular coagulation and the interplay between cancer progression and chronic inflammation. In addition, it will be important to identify subgroups of cancer patients benefiting from specific modulations of the coagulation system without increasing the bleeding risk. Here, we review recent findings on tissue factor (TF) regulation, its procoagulant activity and TF signaling in the various cell types of the tumor microenvironment. PMID- 29703474 TI - Platelets, NETs and cancer. AB - In addition to the central role of platelets in hemostasis, they contribute to pathological conditions such as inflammation and tumor progression. Aberrant expression and/or exposure of pro-coagulant factors in the tumor microenvironment induce platelet activation and subsequent release of growth factors from platelet granules. Cancer patients are commonly affected by thrombotic events, as a result of tumor-induced platelet activation. A novel player potentially contributing to cancer-associated thrombosis is the formation of neutrophil extracellular traps (NETs). NETs are composed of externalized DNA of nuclear or mitochondrial origin, bound to histones and granular proteases such as neutrophil elastase (NE) and myeloperoxidase (MPO). These extracellular traps help neutrophils to catch and kill pathogens such as bacteria, virus and fungi. It is now clear that NETs form also under conditions of sterile inflammation such as cancer and autoimmunity and can promote thrombosis. Recent data show that platelets play a key role in determining when and where NETs should form. This review will highlight our current insight in the role of platelets as regulators of NET formation, both during infection and sterile inflammation. PMID- 29703475 TI - Novel strategies of coagulation inhibition for reducing tumor growth and angiogenesis. AB - Activated proteins of the coagulation system are known to enhance angiogenesis and tumor growth. Notably, the main coagulation proteins involved are those of the extrinsic and common pathways. Strategies to attenuate tumor progression by decreasing activation of the coagulation system may be compromised by an increased risk of bleeding. Currently, studies using derivatives of heparins devoid of or with low anticoagulant activity are being conducted. Heparanase protein was demonstrated to enhance tissue factor activity. In-house developed peptides, deriving from tissue factor pathway inhibitor 2 (TFPI-2) were shown to inhibit heparanase procoagulant activity by interrupting the interaction between TF and heparanase. These peptides appeared to have a non-hemostatic anti angiogenic effect. In a mouse model, the peptides caused a significant reduction in tumor growth and relapse, without predisposing to bleeding. Hence, the effects of these inhibitory peptides in cancer patients may deserve further investigation in clinical research studies. PMID- 29703476 TI - Are new anticoagulants a safe and reasonable alternative to low molecular heparins? PMID- 29703477 TI - Treatment of venous thromboembolism in patients with cancer: What news from clinical trials? AB - About 15% of patients with cancer experience one or more episodes of venous thromboembolism (VTE) during the course of their disease. In patients with cancer, VTE has a substantial impact on the quality of life and care. Current guidelines recommend low-molecular-weight heparin (LMWH) as first choice therapy for long-term anticoagulation in cancer patients with VTE. However, there are several practical issues concerning the long-term use of these anticoagulants. In the last years, several direct oral anticoagulants (DOACs) have emerged as alternatives to heparins and vitamin K antagonists for the treatment of VTE, but data regarding both efficacy and safety of DOACs in the subgroup of patients with cancer treatments were limited. The results of two studies evaluating the clinical benefit of treatment of VTE with direct oral anticoagulants in patients with cancer have been recently presented. Several studies comparing DOACs with LMWH are currently ongoing. PMID- 29703478 TI - Management of recurrent venous thromboembolism in patients with cancer: A review. AB - Venous thromboembolism (VTE) occurs in 10-20%% of patients with cancer and is associated with significant mortality and morbidity in these patients. The current standard of care recommended by international guidelines is to use low molecular-weight heparin (LMWH) for 6months for the management of cancer associated thrombosis (CAT), which is based on evidence from randomized controlled trials demonstrating that LMWH significantly reduced the risk of recurrent VTE compared with vitamin K antagonists. However, patients with CAT have a high risk of VTE recurrence of up to 20% despite receiving anticoagulation. Reasons for recurrent VTE may include non-compliance, temporary cessation of therapy due to bleeding or for procedures, inadequate dosing, cancer progression, and the presence of heparin-induced thrombocytopenia. Management of patients with CAT and recurrent VTE is not well defined. Management strategies for recurrent VTE include switching to LMWH if an oral anticoagulant is employed, dose escalation of LMWH, or as a last resort option consider insertion of a vena cava filter. In this review, we discuss the acute, long-term, and extended management of CAT, risk factors for recurrent VTE, and management of recurrent VTE. PMID- 29703479 TI - Cancer prognosis in patients with venous thromboembolism (VTE) and patients with clinical and laboratory biomarkers predictive of VTE risk. AB - Venous thromboembolism (VTE) is a well-documented complication of cancer and its treatment. While VTE contributes significant morbidity and some thrombotic mortality to cancer patients, a growing body of clinical and experimental data supports the finding that VTE is an important prognostic marker for cancer progression and mortality. This would suggest that hemostatic activation is an expression of an aggressive tumor phenotype. A number of clinical and laboratory biomarkers have been shown to be predictive of an increased risk of cancer associated VTE. In addition, it is now becoming apparent that these same biomarkers are also predictive of cancer mortality. The application of this information to reduce cancer-associated VTE and improve cancer survival await the results of ongoing prophylaxis antithrombotic studies. PMID- 29703480 TI - Arterial thrombosis and cancer. AB - Cancer-associated arterial thrombotic events (ATEs) are increasingly recognized in specific malignancies and in association with the expanding armamentarium of novel chemotherapeutic agents. The improved cancer survival led to cardiovascular complications becoming clinically relevant many years after cancer diagnosis. The pathobiology of ATEs in cancer is complex and the individual patient risk for an ATE entails a multifactorial interaction between the traditional cardiovascular risk factors and comorbidities, the specific malignancy and selected therapy. Treatment with several specific chemotherapeutic agents, immunomodulatory drugs, vascular endothelial growth factor pathway inhibitors, tyrosine kinase inhibitors, and radiotherapy, impart increased risk for ATEs that result from specific therapy-related mechanisms, often involving endothelial injury. Cancer cell-specific prothrombotic properties are important players in the pathogenesis of cancer-associated hypercoagulability. There are distinct biological and molecular processes preferentially activated in specific cancer cells which can trigger ATEs, including platelet activation, increased expression of procoagulants and suppression of fibrinolytic activity. ATEs portend adverse prognosis in cancer patients. Prevention and treatment of cancer-associated ATEs may be improved by greater awareness and careful monitoring for vascular toxicity, aggressive effort to optimize conventional cardiovascular risk factors, and use of antiplatelet and antithrombotic agents in selected patients. These issues are targets for future studies aimed to reduce ATEs in patients with cancer. PMID- 29703481 TI - Mechanisms coupling thrombin to metastasis and tumorigenesis. AB - The association of malignancy and thrombophilia is bidirectional, as evidenced by four decades of studies in animal models showing that hemostatic system components support cancer progression. Consistent with this view, clinical studies have suggested that anticoagulants not only limit thromboembolic complications associated with cancer, but also improve survival by impeding cancer progression, and may even prevent the development of cancer. In order to fully capitalize on this association, a detailed understanding of the mechanisms coupling hemostatic factors to cancer pathogenesis is required. Multiple studies have shown that thrombin-mediated procoagulant functions strongly promote metastatic potential. In particular, the platelet/fibrin(ogen) axis has been shown to protect newly formed micrometastases from innate immune surveillance, contribute to creation of a metastatic niche by recruitment of prometastatic inflammatory cells, and promote the epithelial to mesenchymal transition of metastatic cells. Thrombin-mediated functions have also been shown to support tumor growth in some contexts, and have even been linked to tumorigenesis in the setting of inflammation-driven colon cancer. Here, local thrombin-mediated extravascular fibrin deposition, and specifically fibrin-alphaMbeta2 integrin interaction, push intestinal inflammatory cells toward a pro-tumorigenic phenotype, resulting in the elaboration of key cytokines and growth factors that support the proliferation and survival of transformed intestinal epithelial cells. These studies reveal that hemostatic factors can serve as a bridge between pathological inflammation and the development of cancer. As a large proportion of cancers are caused by pathological inflammation, these studies suggest that therapies targeting the nexus between hemostasis and inflammation could be used to prevent cancer development. PMID- 29703482 TI - Anti-angiogenesis for cancer: Current status and prospects. AB - Since the establishment of tumor angiogenesis as a therapeutic target, new, effective antiangiogenic agents have been developed. Despite their demonstrable clinical benefits, these therapies often have only a short-term effect, with limited impact on the overall survival of cancer patients. A question in the development of these drugs concerns their optimal use in combination regimens with newer therapeutic strategies. Here we review the current therapeutic settings combining anti-angiogenesis inhibitors with chemotherapy, PARP inhibitors or immune checkpoint blockers, focusing on ovarian cancer as tumor model. PMID- 29703483 TI - The role of podoplanin in cancer-associated thrombosis. AB - Venous thromboembolism (VTE) is a frequent and life-threatening complication in patients with cancer. The underlying mechanisms of cancer-associated VTE are still not completely understood. However, emerging studies indicate that the mechanisms differ across tumor types. A recent study revealed that in patients with brain tumors, podoplanin overexpression is strongly correlated with intratumoral thrombotic vessels, hypercoagulability and increased VTE risk. In vitro experiments demonstrated that platelet aggregation induced by human glioblastoma cells was highly podoplanin-dependent. Podoplanin is a transmembrane glycoprotein with the ability to induce platelet activation via the platelet receptor CLEC-2. Moreover, podoplanin is a lymphatic endothelial marker and exhibits substantial functions during embryonic development. It is variously upregulated by many cancers including primary brain tumors and linked to malignant progression and poor survival. In vivo studies have indicated that the podoplanin-CLEC-2 axis might be mechanistically involved in the development of venous thrombosis. In this review, we discuss the role of podoplanin in promoting cancer-associated VTE. Since podoplanin is associated with VTE risk in brain tumor patients, it could be a useful biomarker to identify patients at very high VTE risk. Those patients may benefit from primary thromboprophylaxis. In addition, the podoplanin-CLEC-2 axis might serve as an attractive target for new therapies against cancer-associated VTE. PMID- 29703484 TI - Effects of platelets on cancer progression. AB - Platelets are small (2-4 MUm), anucleate, hematopoietic cells released by bone marrow megakaryocytes in the bloodstream. For a long time, platelets were described as the major effectors of hemostasis and thrombosis. In 1865, Armand Trousseau demonstrated a close relation between thrombosis and cancer. Subsequently, much clinical and experimental evidence supports the idea that platelets play several roles in the progression of malignancies and in cancer associated thrombosis. In this review, we will discuss the roles of tumor educated platelets (TEPs) in the progression of cancer from primary tumors to secondary metastatic outbreaks. PMID- 29703485 TI - Hemostatic biomarkers in cancer progression. AB - Malignant disease is characterized by a hemostatic imbalance, usually shifted towards a procoagulant direction, and a high incidence of thrombotic complications. The mechanisms of hemostasis that are critically involved in thrombosis are also implicated in tumor progression, angiogenesis, and metastatic spread. As there is a close relationship between cancer and the clotting system, circulating biomarkers of activation of various hemostasis compartments (i.e. coagulation, fibrinolysis, platelets, endothelium, and other blood cells) have been extensively studied to predict cancer outcomes along with predicting the thrombotic risk. In this review, we will summarize the results of published studies and will focus on ongoing research and future directions of clotting activation bioproducts as biomarkers of cancer disease and progression. PMID- 29703486 TI - Updated clinical models for VTE prediction in hospitalized medical patients. AB - Venous thromboembolism (VTE) occurring in hospitalized medical patients is associated with increased length of hospitalization, high rate of acute care hospital transfer, longer inpatient rehabilitation and multiplication of health care costs. Identification of acutely ill hospitalized medical patients eligible for thromboprophylaxis is a sophisticated process. Global VTE risk stems from the combination of predictors related with the acute medical illness, comorbidities, associated treatments and patients' intrinsic risk factors. Emerging clinical risk factors related to underlying pathologies should be considered when VTE risk is assessed. The Padua Prediction Score (PPS), the International Medical Prevention Registry on Venous Thromboembolism (IMPROVE-RAM) and the Geneva Risk Score are three robust risk assessment models (RAM) which underwent extensive external validation in cohorts of acutely ill hospitalized medical patients. The development of the IMPROVE bleeding risk assessment model and the identification of D-Dimer increase as a biomarker-predictor of VTE are some steps forward for personalized thromboprophylaxis. The beneficial impact of the RAMs in VTE prevention is already seen by the decrease of in-hospital VTE rates when RAMs are incorporated in electronic alert systems. PMID- 29703487 TI - Revisiting occult cancer screening in patients with unprovoked venous thromboembolism. AB - Unprovoked venous thromboembolism (VTE) can be the first manifestation of an unknown cancer. A recently published individual patient data meta-analysis (IPDMA) reported a prevalence of occult cancer detection of 5.2% (95% CI, 4.1% to 6.5%) over a one-year follow-up period, approximately 50% lower than the previously reported 12-month period prevalence. Although an extensive screening strategy was associated with a 2-fold higher probability of cancer detection at initial screening in the IPDMA, not enough evidence exists yet to support the routine use of these tests in patients with unprovoked VTE. It is likely that a subgroup of patients with unprovoked VTE is at higher risk of occult cancer detection and might benefit from closer clinical surveillance. A newly derived and validated clinical predictive rule seems to be able to stratify patients with unprovoked VTE accordingly to their underlying risk of occult cancer detection. The low incidence of occult cancer detection (<3%) in the low-risk group is reassuring for clinicians. Future studies are required to better define the risks and benefits of an extensive occult cancer screening strategy in high risk patients sub-group with unprovoked VTE. To date, the Scientific and Standardized Committee from the International Society of Thrombosis and Haemostasis suggests that patients with unprovoked VTE should only undergo a limited cancer screening including thorough medical history and physical examination, basic laboratory investigations, chest X-ray as well as age- and gender-specific cancer screening according to national guidelines. PMID- 29703488 TI - Clinical characteristics of disseminated intravascular coagulation in patients with solid and hematological cancers. AB - Malignant disease can be complicated by disseminated intravascular coagulation (DIC). DIC is defined as systemic intravascular triggering of coagulation (resulting in intravascular fibrin clot formation) and concurrent depletion of clotting factors and platelets (increasing the risk of hemorrhage). The clinical presentation of DIC in patients with cancer has usually a less fulminant presentation than DIC that may accompany other underlying disorders, such as sepsis and trauma. A more insidious, but also more protracted, diffuse activation of coagulation can proceed without any symptom. Ultimately this may lead to deficiency of platelets and clotting factors and hemorrhage (often at the site of the tumor or metastases) may be the first clinical symptom indicating the presence of DIC. An alternative presentation may be thrombosis, ranging from overt venous thrombo-embolism to microvascular disease and thrombotic microangiopathy. The therapeutic foundation of DIC is management of the underlying condition but in some cases supportive interventions, specifically targeting the hemostatic system may be needed. PMID- 29703489 TI - Mechanisms and management of coagulopathy in acute promyelocytic leukemia. AB - Acute promyelocytic leukemia (APL) is a subtype of leukemia which is associated with unique and distinctive coagulopathy. In the absence of treatment it is rapidly fatal and even after initiation of therapy the major cause of early mortality is related to hemorrhagic complications. The coagulopathy can be exacerbated with the start of treatment. In the absence of early hemorrhage related deaths the probability of cure exceeds 90% in low and intermediate risk patients and 80% even in high risk patients, highlighting the importance of understanding the pathophysiology of this complication and instituting prompt and appropriate management strategies. The coagulopathy in APL is complex and results from a combination of thrombocytopenia, disseminated intravascular coagulation and hyperfibronlysis. Recently the effect of all-trans retinioc acid (ATRA) induced ETosis on exacerbating coagulopathy in the first few days after starting therapy with this agent raises the potential for potentially novel strategies to reduce the risk of hemorrhage. Currently management is mainly related to rapid initiation of therapy with ATRA along with appropriate and adequate replacement of blood products to correct the coagulopathy. There is limited role for the use of low dose anti-coagulants and anti-fibrinolytic agents in the initial management of this disease. There is limited data on the use of rFVIIa or the use of global tests of hemostasis in the management of this condition. PMID- 29703490 TI - Management of thrombocytopenia in cancer. AB - Thrombocytopenia is a common finding in cancer patients and can have different and/or multifactorial pathogenesis. While in solid tumors it occurs often as a consequence of chemotherapy treatment, it is frequently observed at diagnosis in patients with hematological malignancies being aggravated to a potentially life threatening level during chemotherapy. Other associated conditions (infections, drugs, consumption coagulopathy etc.) can add to influence the degree of thrombocytopenia and the inherent risk of bleeding and they should be recognized and corrected to improve platelet count. Platelet transfusion remains the cornerstone of treatment, but its use should always be weighted taking into consideration the actual risk of bleeding to avoid inappropriate use and wasting of resources. While in hematological malignancies a threshold level of 10,000 platelets/MUL is widely accepted as the minimal level prompting prophylactic platelet transfusion, this limit is less frequently observed in patients with solid tumors and platelet transfusions are usually administered for a few days, possibly at a higher platelet level. Alternative treatments for the latter patients including thrombopoietin-mimetic agents are increasingly used and found to be promising. PMID- 29703491 TI - Thrombosis in pediatric patients with leukemia. AB - Acute lymphoblastic leukemia (ALL) is the most common type of cancer diagnosed in children. It is reportedly the most common malignancy associated with thromboembolism in the pediatric age group. Over the last 2 decades, venous thromboembolism (VTE) has been increasingly diagnosed among pediatric ALL patients with an estimated incidence ranging from about 5% (for symptomatic cases) to about 30-70% (following sequential imaging studies in asymptomatic children). The etiology is multifactorial and may stem from alterations of the hemostatic system following various chemotherapy protocols (including use of l Asparaginase), the presence of central venous lines (CVL), as well as comorbidities, e.g. inherited thrombophilia risk factors. Most symptomatic thrombotic events occur in the upper venous system or in the central nervous system (CNS). Prospective studies on the establishment of guidelines for treatment or prevention are lacking. The following review will address the epidemiology, etiology and risk factors for thrombosis, describe the currently available evidence, and address issues associated with diagnosis and treatment. PMID- 29703492 TI - Predictive factors of fatal bleeding in acute promyelocytic leukemia. AB - Acute promyelocytic leukemia (APL) is associated with a profound coagulopathy. Based on retrospective assessments, several potential risk factors for hemorrhagic morbidity and mortality have emerged. Several studies have shown elevated white blood cell (WBC) count at presentation to be a robust predictor of bleeding events. Other clinical and laboratory parameters have been evaluated with variable association with hemorrhagic morbidity or mortality. These include ECOG performance status, age, morphological subtype, platelet count, peripheral blood blast count, ethnicity, body mass index, prothrombin time, activated partial thromboplastin time, lactate dehydrogenase, d-dimers, creatinine and fibrinogen levels. Unfortunately, most of those assessments were based on a small patient sample and the results have been at times contradictory in terms of which parameters are independent predictors. More recently, two large retrospective studies have reported on the issue. They included data from several international trials of chemotherapy for APL, one on adults and the other focused on the pediatric population. Importantly, both analyses found that WBC count at presentation is the main predictor of early hemorrhagic death and early thrombo hemorrhagic death, respectively. Much remains to be done if the rate of induction mortality in APL is going to be reduced significantly. One approach would be to incorporate the known risk factors for early hemorrhagic death into a risk stratification system and devise personalized transfusion interventions to meet an individual patient's risk, which could be evaluated in future randomized trials. PMID- 29703493 TI - Supporting doctor-patient communication: Providing a question prompt list and audio recording of the consultation as communication aids to outpatients in a cancer clinic. AB - OBJECTIVE: To document the effect of a cancer specific question prompt list (QPL) on patients question asking and shared decision-making (SDM), and to evaluate the combined effect of the QPL and consultation audio recording (CAR) on patient outcomes. METHOD: This exploratory study compared two groups of patients receiving either a QPL or combined QPL/CAR, to a control group. Measurements included number/types of questions asked, and physician SDM behavior (OPTION score). Questionnaire data included anxiety/depression and quality of life (QoL). RESULTS: A total of 93 patients participated (31 Control, 30 QPL and 32 Combined). Patients in the intervention groups asked more questions concerning prognosis (p < .0001), the disease (p = .006) and quality of treatment (p < .001) than patients in the control group, but no impact was found on the OPTION score. An increase in mean consultation length was observed in the intervention groups compared to the control group (44 vs. 36 min; p = .028). Patients rated both interventions positively. CONCLUSION: Provision of the QPL facilitates patients to ask a broader range of questions, but does not increase physician SDM behavior. PRACTICAL IMPLEMENTATION: The combination of QPL and CAR seems feasible and should be tested in an implementation study following the disease trajectory. PMID- 29703494 TI - The Expanding Diversity of RNA Viruses in Vertebrates. AB - The diversity of RNA viruses in vertebrates remains largely unexplored. The discovery of 214 novel vertebrate-associated RNA viruses will likely help us to understand the diversity and evolution of RNA viruses in vertebrates. PMID- 29703495 TI - Can Broadly Neutralizing Monoclonal Antibodies Lead to a Hepatitis C Virus Vaccine? AB - While licensed vaccines elicit protective antibody responses against a variety of viral infections, an effective vaccine for hepatitis C virus (HCV) has remained elusive. The extraordinary genetic diversity of HCV and the ability of the virus to evade the immune response have hindered vaccine development efforts. However, recent studies have greatly expanded the number of well characterized broadly neutralizing human monoclonal antibodies (bNAbs) against HCV. These bNAbs target relatively conserved HCV epitopes, prevent HCV infection in animal models, and are associated with spontaneous clearance of human HCV infection. In this review, recent high-resolution bNAb epitope mapping and structural analysis of bNAb epitope complexes that may serve as a guide for vaccine development are discussed along with major obstacles. PMID- 29703497 TI - A long-awaited guideline for the delineation of primary tumor in head and neck cancer, and a few concerns about it. PMID- 29703498 TI - Automatic quantification of calcifications in the coronary arteries and thoracic aorta on radiotherapy planning CT scans of Western and Asian breast cancer patients. AB - PURPOSE: This study automatically quantified calcifications in coronary arteries (CAC) and thoracic aorta (TAC) on breast planning computed tomography (CT) scans and assessed its reproducibility compared to manual scoring. MATERIAL AND METHODS: Dutch (n = 1199) and Singaporean (n = 1090) breast cancer patients with radiotherapy planning CT scan were included. CAC and TAC were automatically scored using deep learning algorithm. CVD risk categories were based on Agatson CAC: 0, 1-10, 11-100, 101-400 and >400. Reliability between automatic and manual scoring was assessed in 120 randomly selected CT scans from each population, with linearly weighted kappa for CAC categories and intraclass correlation coefficient for TAC. RESULTS: Median age was higher in Dutch patients than Singaporean patients: 57 versus 52 years. CAC and TAC increased with age and were more present in Dutch patients than Singaporean patients: 24.2% versus 17.3% and 73.0% versus 62.2%, respectively. Reliability of CAC categories and TAC was excellent in the Netherlands (0.85 (95% confidence interval (CI) = 0.77-0.93) and 0.98 (95% CI = 0.96-0.98) respectively) and Singapore (0.90 (95% CI = 0.84-0.96) and 0.99 (95% CI = 0.98-0.99) respectively). CONCLUSIONS: CAC and TAC prevalence was considerable and increased with age. Deep learning software is a reliable method to automatically measure CAC and TAC on radiotherapy breast CT scans. PMID- 29703496 TI - Emerging Role of Retromer in Modulating Pathogen Growth. AB - Intracellular pathogens have developed elegant mechanisms to modulate host endosomal trafficking. The highly conserved retromer pathway has emerged as an important target of viruses and intravacuolar bacteria. Some pathogens require retromer function to survive. For others, retromer activity restricts intracellular growth; these pathogens must disrupt retromer function to survive. In this review, we discuss recent paradigm changes to the current model for retromer assembly and cargo selection. We highlight how the study of pathogen effectors has contributed to these fundamental insights, with a special focus on the biology and structure of two recently described bacterial effectors, Chlamydia trachomatis IncE and Legionella pneumophila RidL. These two pathogens employ distinct strategies to target retromer components and overcome restriction of intracellular growth imposed by retromer. PMID- 29703499 TI - Efficacy of thoracic radiotherapy in patients with stage IIIB-IV epidermal growth factor receptor-mutant lung adenocarcinomas who received and responded to tyrosine kinase inhibitor treatment. AB - PURPOSE: Large-scale, prospective, randomized studies of the efficacy of thoracic radiotherapy (RT) in patients with unresectable stage IIIB-IV epidermal growth factor receptor (EGFR)-mutant lung adenocarcinomas who received and responded to EGFR tyrosine kinase inhibitor (TKI) treatment are not currently available. Therefore, we designed a propensity score-matched, nationwide, population-based, cohort study for estimating the effects of thoracic RT on patients with EGFR mutant lung adenocarcinomas. PATIENTS AND METHODS: We analyzed patients with unresectable stage IIIB-IV EGFR mutant lung adenocarcinomas and categorized them into two groups according to treatment modality and compared their outcomes; groups 1 and 2 consisted of patients who received EGFR TKI treatment alone until tumor progression and those who received and responded to EGFR TKI treatment and subsequently received thoracic RT for lung tumors, respectively. The patients in groups 2 and 1 were matched at a ratio of 1:4. RESULTS: The matching process yielded a final cohort of 1475 patients (1180 and 295 patients in groups 1 and 2, respectively) who were eligible for further analysis. According to both univariate and multivariate Cox regression analyses, the adjusted hazard ratios (aHRs) (95% confidence interval [CI]) derived for thoracic RT for lung tumor after EGFR TKI use and tumor response (group 2) compared with EGFR TKI treatment alone (group 1) was 0.72 (0.60-0.85). CONCLUSIONS: Thoracic RT might be associated with overall survival in patients with unresectable stage IIIB-IV EGFR mutant lung adenocarcinomas who received and responded to EGFR TKI treatment. PMID- 29703500 TI - Overview of research and therapy facilities for radiobiological experimental work in particle therapy. Report from the European Particle Therapy Network radiobiology group. AB - Particle therapy (PT) as cancer treatment, using protons or heavier ions, can provide a more favorable dose distribution compared to X-rays. While the physical characteristics of particle radiation have been the aim of intense research, less focus has been placed on the actual biological responses arising from particle irradiation. One of the biggest challenges for proton radiobiology is the RBE, with an increasing concern that the clinically-applied generic RBE-value of 1.1 is an approximation, as RBE is a complex quantity, depending on both biological and physical parameters, such as dose, LET, cellular and tissue radiobiological characteristics, as well as the endpoints being studied. Most of the available RBE data derive from in vitro experiments, with very limited in vivo data available, especially in late-reacting tissues, which provide the main constraints and influence the quality of life endpoints in radiotherapy. There is a need for systematic, large-scale studies to thoroughly establish the biology of particle radiation in a number of different experimental models in order to refine biophysical mathematical models that can potentially be used to guide PT. The overall objective of the European Particle Therapy Network (EPTN) WP6 is to form a network of research and therapy facilities in order to coordinate and standardize the radiobiological experiments, to obtain more accurate predictive parameters than in the past. Coordinated research is required in order to obtain the most appropriate experimental data. The aim in this paper is to describe the available radiobiology infrastructure of the centers involved in EPTN WP6. PMID- 29703502 TI - Improving the modelling of irradiation-induced brain activation for in vivo PET verification of proton therapy. AB - BACKGROUND AND PURPOSES: A reliable Monte Carlo prediction of proton-induced brain tissue activation used for comparison to particle therapy positron-emission tomography (PT-PET) measurements is crucial for in vivo treatment verification. Major limitations of current approaches to overcome include the CT-based patient model and the description of activity washout due to tissue perfusion. MATERIAL AND METHODS: Two approaches were studied to improve the activity prediction for brain irradiation: (i) a refined patient model using tissue classification based on MR information and (ii) a PT-PET data-driven refinement of washout model parameters. Improvements of the activity predictions compared to post-treatment PT-PET measurements were assessed in terms of activity profile similarity for six patients treated with a single or two almost parallel fields delivered by active proton beam scanning. RESULTS: The refined patient model yields a generally higher similarity for most of the patients, except in highly pathological areas leading to tissue misclassification. Using washout model parameters deduced from clinical patient data could considerably improve the activity profile similarity for all patients. CONCLUSIONS: Current methods used to predict proton-induced brain tissue activation can be improved with MR-based tissue classification and data-driven washout parameters, thus providing a more reliable basis for PT-PET verification. PMID- 29703501 TI - Heart volume reduction during radiotherapy involving the thoracic region in children: An unexplained phenomenon. AB - BACKGROUND AND PURPOSE: Radiotherapy involving the thoracic region is associated with cardiotoxicity in long-term childhood cancer survivors. We quantified heart volume changes during radiotherapy in children (<18 years) and investigated correlations with patient and treatment related characteristics. MATERIAL AND METHODS: Between 2010 and 2016, 34 children received radiotherapy involving the thoracic region. We delineated heart contours and measured heart volumes on 114 CBCTs. Relative volume changes were quantified with respect to the volume on the first CBCT (i.e., 100%). Cardiac radiation dose parameters expressed as 2 Gy/fraction equivalent doses were calculated from DVHs. Chemotherapy was categorized as treatment with anthracyclines, alkylating agents, vinca-alkaloids, and other. RESULTS: The overall median heart volume reduction from the first to the last CBCT was 5.5% (interquartile range1.6-9.7%; p < 0.001). Heart volumes decreased significantly between the baseline measurement and the first week (Bonferroni's adjusted p = 0.002); volume changes were not significant during the following weeks. Univariate analysis showed a significant correlation between heart volume reduction and alkylating agents; however, no multivariate analyses could be done to further confirm this. CONCLUSIONS: We found a significant heart volume reduction in children during radiotherapy. Elucidation of underlying mechanisms, clinical relevance, and possible long-term consequences of early heart volume reduction require a prospective follow-up study. PMID- 29703503 TI - Fasting levels of glicentin are higher in Roux-en-Y gastric bypass patients exhibiting postprandial hypoglycemia during a meal test. AB - BACKGROUND: Post-bypass postprandial hypoglycemia (PPH) is a frequent complication of Roux-en-Y Gastric Bypass (RYGB) but predictors remain poorly identified and are needed to assess individual risk. After RYGB, exaggerated secretion of glucagon-like peptide-1 (GLP-1) and insulin could lead to PPH, but other proglucagon-derived peptides, including glicentin and glucagon, could also contribute to this phenomenon. OBJECTIVES: To identify biological hypoglycemia in relation to the secretion of proglucagon-derived peptides during a mixed-meal test (MMT) in RYGB patients. SETTING: University hospital. METHODS: Twenty RYGB patients reporting symptoms consistent with PPH were examined 36.9 +/- 5.1 months after surgery. Plasma levels of glucose, c-peptide, glucagon, GLP-1 and glicentin were assessed before and during MMT. Patients with postprandial hypoglycemia <=3 mM (54 mg/dL) during MMT were assigned to HYPO group and compared with patients not exhibiting hypoglycemia (NONHYPO group). RESULTS: Seven patients displayed hypoglycemia <=3 mM (HYPO) during the MMT. Lower fasting glycemia (4.5 mM versus 5.3 mM, P<.05) and higher fasting glicentin (22.6 pM versus 14.0 pM, P<.05) were observed in HYPO versus NONHYPO patients. Fasting glicentin was inversely correlated with postprandial nadir glucose. Examining the receiver-operating characteristics curve analysis, a cutoff of 17.2 pM for fasting glicentin identified PPH with 85.7% sensitivity and 53.8% specificity. All patients exhibited a similar increase of postprandial GLP-1, glucagon, and glicentin secretions that correlated with each other. CONCLUSIONS: These results suggest that fasting glicentin is a potential biomarker to examine in operated-obese patients at risk of developing PPH. Further studies are needed before proposing fasting glicentin as a predictive factor of PPH. PMID- 29703504 TI - Comment on: systematic assessment of decision analytic models for the cost effectiveness of bariatric surgery for morbid obesity. PMID- 29703505 TI - Patient perspectives about bariatric surgery unveil experiences, education, satisfaction, and recommendations for improvement. AB - BACKGROUND: Following bariatric surgery, up to 35% of patients struggle with strict regimens and experience weight recidivism within 2 years [1-5]. Accredited weight management centers (WMC) must provide educational programs and support patients in lifestyle changes before and after surgery. Educational programs, however, may not be evidence-based or patient-centered and may vary in curriculum, approach, and educator type [6]. OBJECTIVE: To obtain patient descriptions about the weight loss surgery (WLS) experience, including education, satisfaction, and recommendations for improvement. SETTING: Participants were recruited from a university hospital-based WMC in Pennsylvania. METHODS: This qualitative descriptive study used purposive sampling and inductive content analysis. RESULTS: A NEW ME-VERSION 2.0, encompassed themes from semistructured interviews with 11 participants (36% male). Theme 1: Programming and Tools, explained how individuals undergoing WLS found support through educational programming. Theme 2: Updates and Upgrades, identified issues surrounding quality of life and challenges before and after surgery. Theme 3: Lessons Learned and Future Considerations, identified satisfaction levels and recommendations for improving the WLS experience. Participants reported positive experiences, acknowledging educational programs and extensive WMC resources, yet also offered recommendations for improving educational programming. CONCLUSION: Patient narratives provided evidence about the WLS experience. Achievement of weight goals, adherence to rules, and improved health status contributed to perceptions of WLS success. Participants encouraged educators to identify expected outcomes of educational programming, monitor holistic transformations, foster peer support, and use technology in WMC programming. Results also validated the need for the Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program's education requirement (standard 5.1). Future educational research could help develop best practices in WLS patient education and assess associations between education and clinical outcomes. PMID- 29703506 TI - Safety and short-term outcomes of laparoscopic sleeve gastrectomy for patients over 65 years old with severe obesity. AB - BACKGROUND: Laparoscopic sleeve gastrectomy (LSG) is a widely accepted, stand alone bariatric operation. Data on elderly patients undergoing LSG are scarce. OBJECTIVES: The aim of this study was to demonstrate that LSG is safe and effective for patients>65 years old with severe obesity. SETTING: Department of Minimally Invasive Digestive Surgery, Antoine-Beclere Hospital, AP-HP, Paris Saclay University, France. METHODS: Prospectively collected data from consecutive patients undergoing LSG were retrospectively analyzed. Patients with>1-year follow-up were included in the analysis for weight loss and co-morbidities evaluation. Quality of life was evaluated using the Short-Form 36 questionnaire. RESULTS: Fifty-four patients>65 years old (range, 65-75 yr) underwent LSG. Median weight was 119 kg, and median body mass index was 43 kg/m2. Median duration of surgery was 86.5 minutes. Two patients (3.7%) suffered a gastric staple-line leak, 1 treated by pure endoscopic internal drainage and 1 by relaparoscopy with subsequent endoscopic internal drainage. Mortality was null. Median length of hospital stay was 5 days. Six, 12, and 24 months after LSG, median body mass index decreased significantly to 35, 32.9, and 30.7 kg/m2, respectively (P<.0001), with mean excess weight loss of 76.3% at 2 years. Type 2 diabetes, hypertension, dyslipidemia, obstructive sleep apnea syndrome, and arthralgia showed statistically significant remission at 1- and 2-year follow-up, while 6 of 8 SF-36 scale scores of quality of life assessment improved significantly. CONCLUSIONS: This study suggests that LSG is effective for patients>65 years old, resulting in significant weight loss, co-morbidities remission, and quality of life improvement. Careful patient selection after adequate risk versus benefit evaluation by an expert multidisciplinary team is essential for patient safety and optimal results. PMID- 29703507 TI - Validity of a simple sleep monitor for diagnosing OSA in bariatric surgery patients. AB - BACKGROUND: One third of bariatric surgery patients have an apnea-hypopnea index (AHI)>15/hr, representing moderate and severe forms of obstructive sleep apnea (OSA). Treating these forms of OSA is recommended to reduce the risk of perioperative complications. The AHI derived from poly(somno)graphy [P(S)G] is the gold standard for OSA diagnosis. However, performing P(S)G in all patients scheduled for bariatric surgery is time consuming and expensive. An accurate and simple screening tool able to rule out moderate to severe OSA would reduce the number of patients needing mandatory P(S)Gs. OBJECTIVES: To assess the validity of a simple sleep monitor (Checkme Health Monitor) as a screening tool for OSA in bariatric surgery patients. SETTING: Obesity Center Amsterdam, OLVG-West, Amsterdam, the Netherlands METHODS: Patients scheduled for bariatric surgery were prospectively enrolled in this study. All patients underwent preoperative P(S)G and simultaneously used the Checkme to assess the oxygen desaturation index. The diagnostic performance of the Checkme for AHI >=15/hr was assessed using receiver operating characteristic curve analysis. RESULTS: A total of 50 patients were analyzed. Sensitivity and negative predictive value were 100% and 100%, respectively, specificity and positive predictive value were 69% and 64%, respectively, for the optimal cutoff value of Checkme-3% oxygen desaturation index >=9/hr for P(S)G-AHI >=15. The area under the curve value expressed by the receiver operating characteristic curve was .95. CONCLUSION: The Checkme is valid for exclusion of moderate and severe OSA in bariatric surgery patients. The Checkme enables bariatric clinics not to perform P(S)G in all patients scheduled for bariatric surgery. PMID- 29703508 TI - Editorial commentary: Genetic testing of long QT syndrome: Should we go back to the future? PMID- 29703509 TI - Editorial commentary: Will the real long QT genes please stand up. PMID- 29703510 TI - Foreword: "Current trends in cancer and signalling". PMID- 29703511 TI - Validation of Musculoskeletal Ultrasound in the Assessment of Experimental Gout Synovitis. AB - The objective of this study was to validate musculoskeletal ultrasound (US) in a rabbit model of acute gout. Acute gout was induced by intra-articular injection of monosodium urate (MSU) crystals in 10 rabbits; the 3 controls received vehicle. Rabbit knees were assessed by B-mode and power Doppler (PD) US 24 and 72 h after injections. After 72 h, all rabbits were euthanized. US discriminated between the MSU-injected and control groups with respect to the different inflammatory findings at both at 24 and 72 h and for MSU crystal-related findings after 24 h of injection. US synovial thickening, intra-synovial power Doppler signal and global joint distension significantly correlated with the synovial global histopathological score (r = 0.47, p = 0.0188), tissue vascularization measured by CD31 immunohistochemical-positive staining (r = 0.46, p = 0.0172) and tissue levels of interleukin-1beta (r = 0.53, p = 0.0078), respectively. US is a valid method for assessment of synovial inflammation in experimental gouty arthritis in rabbits. PMID- 29703512 TI - Urinary metal concentrations among mothers and children in a Mexico City birth cohort study. AB - Personal care product use is a potential source of metals exposure among children, but studies have been limited. We measured urinary concentrations of 10 metals (aluminum, arsenic [As], barium [Ba], cadmium, cobalt [Co], lead [Pb], manganese [Mn], molybdenum [Mo], nickel, and zinc [Zn]) in third trimester pregnant women (n = 212) and their children at 8-14 years of age (n = 250). Demographic factors (child sex, age, socioeconomic status, and maternal education), body mass index (BMI) z-score, and child personal care product use in the 24 h prior to urine collection were examined as predictors of urinary metal concentrations. Metals were detected in 80-100% of urine samples, with significant differences in maternal versus childhood levels. However, metal concentrations were not strongly correlated within or between time points. In linear regression models including all demographic characteristics, BMI z-score, and specific gravity, age was associated with higher Co (6% [95% CI: 2, 10]), while BMI z-score was associated with lower Mo (-6% [95% CI: -11, -1). In addition, significantly higher metal concentrations were observed among users of colored cosmetics (Mo: 42% [95% CI: 1, 99]), deodorant (Ba: 28% [3, 58]), hair spray/hair gel (Mn: 22% [3, 45]), and other toiletries (As: 50% [9, 108]), as well as with an increasing number of personal care products used (As: 7% [3, 11]) after adjustment for child sex, age, total number of products used, and specific gravity. However, significantly lower metal concentrations were noted for users of hair cream (As and Zn: -20% [-36, -2] and -21% [-35, -2], respectively), shampoo (Pb: -40% [-62, -7]), and other hair products (Pb: -44% [-65, -9]). We found that personal care product use may be a predictor of exposure to multiple metals among children. Further research is recommended to inform product-specific exposure source identification and related child health risk assessment efforts. PMID- 29703513 TI - T-cell acute lymphoblastic leukemia from miRNA perspective: Basic concepts, experimental approaches, and potential biomarkers. AB - T-cell acute lymphoblastic leukemia (T-ALL) is a rare, aggressive and heterogeneous malignancy originating from T-cell precursors. The mechanisms of T ALL pathogenesis related to non-protein coding part of the genome are currently intensively studied. miRNAs are short, non-coding molecules acting as negative regulators of gene expression which shape phenotype of cells in a complex and context-specific manner. miRNAs may act as oncogenes or tumor suppressors; several miRNAs have been related to drug resistance and treatment response in various malignancies. Here we present the review of the state-of-the-art knowledge on the role of miRNAs in T-ALL pathogenesis, with detailed overview of the studies reporting on miRNAs with oncogenic and tumor suppressor potential. We discuss whether miRNAs might be considered candidate biomarkers of prognosis in T ALL and leukemia subtype-specific markers. We also describe experimental approaches and a typical workflow applied in research on the involvement of miRNAs in oncogenesis. PMID- 29703515 TI - Nutrition Environment Food Pantry Assessment Tool (NEFPAT): Development and Evaluation. AB - OBJECTIVE: To develop and evaluate a nutrition environment assessment tool to assess the consumer nutrition environment and use of recommended practices in food pantries. METHODS: The Nutrition Environment Food Pantry Assessment Tool (NEFPAT) was developed based on a literature review and guidance from professionals working with food pantries. The tool was pilot-tested at 9 food pantries, an expert panel assessed content validity, and interrater reliability was evaluated by pairs in 3 pantries. After revisions, the NEFPAT was used in 27 pantries. RESULTS: Pilot tests indicated positive appraisal for the NEFPAT and recommendations were addressed. The NEFPAT's 6 objectives and the overall tool were rated as content valid by experts, with an average section rating of 3.85 +/ 0.10. Intraclass correlation coefficients for interrater reliability were >0.90. CONCLUSIONS AND IMPLICATIONS: The NEFPAT is content valid with high interrater reliability. It provides baseline data that could be valuable for interventions within the nutrition environment of food pantries. PMID- 29703516 TI - Living Well After Traumatic Brain Injury. PMID- 29703514 TI - Lifestyle and nutritional modifiable factors in the prevention and treatment of bladder cancer. AB - Bladder cancer is one of the top 5 most common cancers diagnosed in the U.S. It is also one of the most expensive cancers to treat through the life course given its high rate of recurrence. While cigarette smoking and occupational exposures have been firmly established as risk factors, it is less certain whether modifiable lifestyle factors such as diet and physical activity play roles in bladder cancer etiology and prognosis. This literature review based on a PubMed search summarizes the research to date on key dietary factors, types of physical activity, and smoking in relation to bladder cancer incidence, and discusses the potential public health implications for formalized smoking cessation programs among recently diagnosed patients. Overall, population-based research in bladder cancer is growing, and will be a key platform to inform patients diagnosed and living with bladder cancer, as well as their treating clinicians, how lifestyle changes can lead to the best outcomes possible. PMID- 29703517 TI - The prognostic value of gray-white matter ratio on brain computed tomography in adult comatose cardiac arrest survivors. AB - BACKGROUND: Recent studies suggested that the gray-white matter ratio (GWR) determined from brain computed tomography (CT) scans may be a reliable predictor of poor neurological outcomes. The aim of study was to evaluate the association between the GWR and the outcomes in adult comatose cardiac arrest (CA) survivors in Chinese. METHODS: A total of 58 CA patients who had CT scans within 72 h of resuscitation between January 2011 and December 2015 were included in this single center retrospective study. Gray and white matter attenuations (Hounsfield units) were measured, and the GWRs were calculated according to previous studies. The study analyzed the prognostic values of the GWRs in predicting poor outcomes (Cerebral Performance Category 3-5). RESULTS: The attenuation values of gray matter were significantly higher in the good outcome group than in the poor one. All GWRs were significantly higher in the good outcome group (p < 0.05). A GWR (basal ganglia) < 1.18 predicted poor outcomes with a sensitivity and specificity of 50.0% and 87.5%, respectively (p = 0.021). GWR (cerebrum) showed the best predictive performance when CT was performed within 24-72 h (p = 0.003). No significant differences were found between GWR and poor outcomes when CT was performed within the first 24 h. CONCLUSION: Low GWRs which were obtained from brain CT scans in comatose CA patients after restoration of spontaneous circulation were associated with poor neurological outcomes. GWR from brain CT can be a useful parameter for prognostic prediction aiding to an optimal clinical decision process in comatose CA survivors. PMID- 29703518 TI - The SAFIRA study: A reflection on the prevalence and treatment patterns of atrial fibrillation and cardiovascular risk factors in 7500 elderly subjects. AB - INTRODUCTION AND AIM: Atrial fibrillation (AF) is a common arrhythmia and an important risk factor for ischemic stroke. The current ESC guidelines state that all patients aged 65 and over should be regularly screened for AF. The SAFIRA study aimed to determine the prevalence, epidemiology and clinical and therapeutic characterization of AF in the Portuguese elderly population. METHODS: The study population (7500 subjects) were recruited from all Portuguese administrative regions. Demographic, clinical and drug treatment data were collected, risk scores were calculated, and an electrocardiogram (ECG) was performed in all subjects. In those not found to have AF on the resting ECG, a randomized subset (400 subjects) underwent 24-hour Holter monitoring and 200 subjects were fitted with an event recorder for two weeks, in order to identify patients with paroxysmal AF. The primary endpoint was AF prevalence; secondary endpoints (in the AF population) included prevalence of paroxysmal AF, mean and median CHA2DS2-VASc and HAS-BLED scores, rates of anticoagulant and antiplatelet therapy, previous stroke, previous stroke/transient ischemic attack, previous bleeding, and time in therapeutic range (if on vitamin K antagonists). RESULTS: The prevalence of AF was 9.0%. Of these, 35.9% were unaware of the diagnosis and 18.6% had paroxysmal AF. Median CHA2DS2-VASc score was 3.5+/-1.2 and 56.3% of patients were not anticoagulated. In the AF subpopulation, the stroke rate was 11.2%. Overall, only 25.8% of the anticoagulated patients were considered to be adequately treated. CONCLUSIONS: This study shows the high prevalence of AF in the elderly population, as well as suboptimal rates of diagnosis, anticoagulation and effective control of cardiovascular risk factors. PMID- 29703519 TI - Proteomics and immunohistochemistry identify the expression of alpha-cardiac myosin heavy chain in the jaw-closing muscles of sooty mangabeys (order Primates). AB - OBJECTIVE: The jaw-closing muscles of humans and nonprimate mammals express alpha cardiac fibers but MyHC alpha-cardiac has not been identified in the jaw adductors of nonhuman primates. We determined whether MyHC alpha-cardiac is expressed in the superficial masseter and temporalis muscles of the sooty mangabey (Cercocebus atys), an African Old World monkey that specializes on hard seeds. DESIGN: LC-MS/MS based proteomics was used to identify the presence of MyHC Ialpha. Immunohistochemistry was used to analyze the composition and distribution of fiber types in the superficial masseter and temporalis muscles of eight C. atys. Serial sections were stained against MyHC alpha-cardiac (MYH6), as well as MyHC-1 (NOQ7.5.4D), MyHC-2 (MY-32), and MyHC-M (2F4). RESULTS: Proteomics analysis identified the presence of Myosin-6 (MyHC alpha-cardiac) in both heart atrium and superficial masseter. MyHC alpha-cardiac was expressed in abundance in the superficial masseter and temporalis muscles of all eight individuals and hybrid fibers were common. CONCLUSIONS: The identification of MyHC alpha-cardiac in the jaw adductors of sooty mangabeys is a novel finding for nonhuman primates. The abundance of MyHC alpha-cardiac indicates a fatigue-resistant fiber population characterized by intermediate speed of contraction between pure MyHC-1 and MyHC-2 isoforms. We suggest that alpha-cardiac fibers may be advantageous to sooty mangabeys, whose feeding behavior includes frequent crushing of relatively large, hard seeds during the power stroke of ingestion. Additional studies comparing jaw-adductor fiber phenotype of hard-object feeding primates and other mammals are needed to explore this relationship further. PMID- 29703520 TI - Response rates in case-control studies of cancer by era of fieldwork and by characteristics of study design. AB - PURPOSE: The purpose of this study was to describe time trends in response rates in case-control studies of cancer and identify study design factors that influence response rate. METHODS: We reviewed 370 case-control studies of cancer published in 12 journals during indicator years in each of the last four decades. We estimated time trends of response rates and reasons for nonresponse in each of the following types of study subjects: cases, medical source controls, and population controls. We also estimated response rates according to characteristics of study context. RESULTS: Median response rates among cases and population controls were between 75% and 80% in the 1970s. Between 1971 and 2010, study response rates declined by 0.31% per year for cases and 0.78% for population controls. Only a minority of studies reported reasons for nonparticipation; subject refusal was the most common reported reason. Studies conducted in North America had lower median response rates than studies conducted in Europe. In-person and telephone interviews elicited higher response rates than mail questionnaires. CONCLUSIONS: Response rates from case-control studies of cancer have declined, and this could threaten the validity of results derived from these studies. PMID- 29703521 TI - Early frailty transition predicts 15-year mortality among nondisabled older Mexican Americans. AB - PURPOSE: To investigate the effect of early frailty transitions on 15-year mortality risk. METHODS: Longitudinal data analysis of the Hispanic Established Populations for the Epidemiological Study of the Elderly involving 1171 community dwelling Mexican Americans aged >=67 years and older. Frailty was determined using the modified frailty phenotype, including unintentional weight loss, weakness, self-reported exhaustion, and slow walking speed. Participants were defined at baseline as nonfrail, prefrail, or frail and divided into nine transition groups, during a 3-year observation period. RESULTS: Mean age was 77.0 years (standard deviation [SD] = 5.3) and 59.1% were female. Participants who transitioned from prefrail to frail (hazard ratio [HR] = 1.68, 95% confidence interval [CI] = 1.23-2.28), frail to prefrail (HR = 1.54, 95% CI = 1.05-2.28); or who remained frail (HR = 1.72, 95% CI = 1.21-2.44), had significant higher 15 year mortality risk than those who remained nonfrail. Participants transitioning from frail to nonfrail had a similar 15-year mortality risk as those who remained nonfrail (HR = 0.96, 95% CI = 0.53-1.72). Weight loss and slow walking speed were associated with transitions to frailty. CONCLUSIONS: An early transition from frail to nonfrail in older Mexican Americans was associated with a 4% decrease in mortality compared with those who remained nonfrail, although this difference was not statistically significant. Additional longitudinal research is needed to understand positive transitions in frailty. PMID- 29703522 TI - Sex differences in fitness outcomes among minority youth after participation in a park-based after-school program. AB - PURPOSE: This study aimed to describe sex differences in fitness outcomes after participation in Fit2Play, a park-based after-school health and wellness program. METHODS: Youth who participated in Fit2Play for either 1, 2, or 3 school years between 2010 and 2016 (n = 2129, mean age 9.1 years, 52% Hispanic, 48% non Hispanic black, 54% male) were tested via a comprehensive fitness battery at the beginning/end of the school year(s). Effects of length of Fit2Play participation on fitness outcomes were assessed via three-level repeated measures analysis stratified by sex and adjusted for child sociodemographics, weight category, area poverty, and year. RESULTS: Significant improvements for boys and girls were found in the Progressive Aerobic Cardiovascular Endurance Run (P < .01 for girls, P < .001 for boys), 400 meter run tests (P < .001 for girls, P < .01 for boys), and push-ups (P < .01 for both), with dose-response trends for girls after up to 3 years of Fit2Play participation. From baseline to 1, 2, and 3 years of participation, girls demonstrated 8%, 14%, and 23% mean improvement in 400 meter run times versus 9%, 9%, and 17% for boys, respectively (P < .001 for all). Dose response improvements were also found in girls for PACER scores and sit-ups. CONCLUSIONS: After-school physical activity programs can improve fitness in all youth, and particularly girls with increased years of participation. Further research should examine sex differences in the effects of park-/community-based programs to reduce sex disparities in fitness, particularly in light of the current youth obesity epidemic. PMID- 29703523 TI - Four Surgical Modifications to the Classic Elastase Perfusion Aneurysm Model Enable Haemodynamic Alterations and Extended Elastase Perfusion. AB - OBJECTIVE/BACKGROUND: Abdominal aortic aneurysm (AAA) is an individual and socioeconomic burden in today's ageing society. Treatment relies on surgical exclusion of the dilated aorta by open or endovascular repair. For research purposes, animal models are necessary and the elastase induced aneurysm model closely mimics end stage human aneurysm disease. To improve the translational value of this model, four modifications to the classic elastase perfusion procedure (PPE) in relation to human aneurysm morphology were conducted. METHODS: In ten week old male C57BL/6J wild type mice the PPE procedure was modified in four ways using two different techniques. Flow alteration was simulated by partial ligation of the common iliac artery or the distal aorta. Additionally, careful exploration of the abdominal aortic branches allowed PPE induction at the suprarenal and iliac level. Molecular biology, ultrasound, and immunohistochemistry were used to evaluate these pilot results. RESULTS: Two aortic outflow obstructions simulating distal aortic or iliac stenosis significantly increase murine AAA diameter (p = .046), and affect local vascular wall remodelling. Suprarenal aortic dissection allows a juxtarenal aneurysm to be induced, similar to the angiotensin II induced aneurysm model. A separate investigation for canonical activation of transforming growth factor beta in the two embryonically distinct juxtarenal and infrarenal segments showed no distinct difference. Creating an aortoiliac bifurcated aneurysm completes the mimicry of human aneurysm morphology. CONCLUSION: The alteration of the classic PPE aneurysm by outflow modulation and further elastase perfusion to the juxtarenal and aortoiliac segment modifies morphology and diameter, and thus increases the translational value in future research. PMID- 29703524 TI - Re: "Near Infrared Spectroscopy as a Predictor for Shunt Requirement During Carotid Endarterectomy". PMID- 29703525 TI - Further Evidence for Regional Variation in Hospital Incidence of Abdominal Aortic Aneurysms: The German Data. PMID- 29703526 TI - Changes induced by co-inoculation in nitrogen-carbon metabolism in cowpea under salinity stress. AB - To mitigate the deleterious effects of abiotic stress, the use of plant growth promoting bacteria along with diazotrophic bacteria has been increasing. The objectives of this study were to investigate the key enzymes related to nitrogen and carbon metabolism in the biological nitrogen fixation process and to elucidate the activities of these enzymes by the synergistic interaction between Bradyrhizobium and plant growth-promoting bacteria in the absence and presence of salt stress. Cowpea plants were cultivated under axenic conditions, inoculated with Bradyrhizobium and co-inoculated with Bradyrhizobium sp. and Actinomadura sp., Bradyrhizobium sp. and Bacillus sp., Bradyrhizobium sp. and Paenibacillus graminis, and Bradyrhizobium sp. and Streptomycessp.; the plants were also maintained in the absence (control) and presence of salt stress (50mmolL-1 NaCl). Salinity reduced the amino acids, free ammonia, ureides, proteins and total nitrogen content in nodules and increased the levels of sucrose and soluble sugars. The co-inoculations responded differently to the activity of glutamine synthetase enzymes under salt stress, as well as glutamate synthase, glutamate dehydrogenase aminating, and acid invertase in the control and salt stress. Considering the development conditions of this experiment, co-inoculation with Bradyrhizobium sp. and Bacillus sp. in cowpea provided better symbiotic performance, mitigating the deleterious effects of salt stress. PMID- 29703527 TI - Cost-effective production of bacterial cellulose using acidic food industry by products. AB - To reduce the cost of obtaining bacterial cellulose, acidic by-products of the alcohol and dairy industries were used without any pretreatment or addition of other nitrogen sources. Studies have shown that the greatest accumulation of bacterial cellulose (6.19g/L) occurs on wheat thin stillage for 3 days of cultivation under dynamic conditions, which is almost 3 times higher than on standard Hestrin and Schramm medium (2.14g/L). The use of whey as a nutrient medium makes it possible to obtain 5.45g/L bacterial cellulose under similar conditions of cultivation. It is established that the pH of the medium during the growth of Gluconacetobacter sucrofermentans B-11267 depends on the feedstock used and its initial value. By culturing the bacterium on thin stillage and whey, there is a decrease in the acidity of the waste. It is shown that the infrared spectra of bacterial cellulose obtained in a variety of environments have a similar character, but we found differences in the micromorphology and crystallinity of the resulting biopolymer. PMID- 29703529 TI - Editorial Comment. PMID- 29703530 TI - Editorial Comment. PMID- 29703528 TI - Replication of a Gene-Diet Interaction at CD36, NOS3 and PPARG in Response to Omega-3 Fatty Acid Supplements on Blood Lipids: A Double-Blind Randomized Controlled Trial. AB - BACKGROUND: Modulation of genetic variants on the effect of omega-3 fatty acid supplements on blood lipids is still unclear. METHODS: In a double-blind randomized controlled trial, 150 patients with type 2 diabetes (T2D) were randomized into omega-3 fatty acid group (n = 56 for fish oil and 44 for flaxseed oil) and control group (n = 50) for 180 days. All patients were genotyped for genetic variants at CD36 (rs1527483), NOS3 (rs1799983) and PPARG (rs1801282). Linear regression was used to examine the interaction between omega-3 fatty acid intervention and CD36, NOS3 or PPARG variants for blood lipids. FINDINGS: Significant interaction with omega-3 fatty acid supplements was observed for CD36 on triglycerides (p-interaction = 0.042) and PPAGR on low-density lipoprotein cholesterol (p-interaction = 0.02). We also found a significant interaction between change in erythrocyte phospholipid omega-3 fatty acid composition and NOS3 genotype on triglycerides (p-interaction = 0.042), total cholesterol (p interaction = 0.013) and ratio of total cholesterol to high-density lipoprotein cholesterol (p-interaction = 0.015). The T2D patients of CD36-G allele, PPARG-G allele and NOS3-A allele tended to respond better to omega-3 fatty acids in improving lipid profiles. The interaction results of the omega-3 fatty acid group were mainly attributed to the fish oil supplements. INTERPRETATION: This study suggests that T2D patients with different genotypes at CD36, NOS3 and PPARG respond differentially to intervention of omega-3 supplements in blood lipid profiles. PMID- 29703531 TI - Author Reply. PMID- 29703533 TI - Reply from the Editors to a Letter to the Editor Re: 'An evaluation of cause-of death trends from recent decades based on registered deaths in Turkey'. PMID- 29703532 TI - The effect of cigarette smoking on the clinical and serological phenotypes of polymyositis and dermatomyositis. AB - OBJECTIVE: Cigarette smoking is associated with immune-mediated disorders. We explored the contribution of smoking to polymyositis (PM) and dermatomyositis (DM) phenotypes and attempted to determine whether cigarette smoking effects differ by race and genotype. METHODS: Associations of tobacco smoking with disease features, autoantibodies, HLA types, and race were evaluated using multiple logistic regressions in 465 patients. RESULTS: Caucasian ever-smokers (n = 140) were more likely to have PM (adjusted OR = 2.24, 95% CI: 1.41-3.57), anti synthetase (adjusted OR = 1.93, 95% CI: 1.12-3.34) and anti-Jo-1 autoantibodies (adjusted OR = 1.94, 95% CI: 1.08-3.46) and less likely to have anti-p155/140 autoantibodies (adjusted OR = 0.36, 95% CI: 0.14-0.92). In Caucasians, ever smokers had a greater interstitial lung disease (ILD) frequency than never smokers, while in African-Americans this relationship was inverted, but neither trend reached statistical significance. Pack-years of cigarette smoking showed significant positive associations with PM (adjusted OR = 1.02, 95% CI: 1.002 1.04) and ILD (adjusted OR = 1.02, 95% CI: 1.001-1.03) and was inversely associated with anti-p155/140 autoantibodies (adjusted OR = 0.93, 95% CI: 0.87 0.99) in Caucasians. Caucasian heavy smokers (>=20 pack-years) were more likely to have PM (adjusted OR = 2.52, 95% CI: 1.25-5.09), ILD (adjusted OR = 2.48, 95% CI: 1.23-5.00) and anti-Jo-1 autoantibodies (adjusted OR = 2.65, 95% CI: 1.16 6.08) than never-smokers. In Caucasians, compared to never-smokers without HLA DRB1*03:01 allele, ever-smokers with HLA-DRB1*03:01 allele had the highest odds of PM, ILD, ASA, and anti-Jo-1 autoantibodies. Risks for those with only one of these two factors were intermediate. An inverse pattern was observed regarding anti-p155/140 autoantibodies. CONCLUSION: Tobacco smoking was associated with clinical and autoantibody phenotypes in Caucasians. Our findings also suggest possible interactions among HLA-DRB1*03:01 and smoking on the risk of PM and ILD, as well as, anti-synthetase, anti-Jo-1, and anti-p155/140 autoantibodies in Caucasians. PMID- 29703534 TI - Anticipating the Next Step in the Management of ALK-Positive NSCLC. PMID- 29703535 TI - The Tradition of the Rising Sun: When Geography Counts. PMID- 29703536 TI - Heritable Germline Variation and Lung Cancer Susceptibility: One Size Does not Fit All. PMID- 29703537 TI - "Teachable Moment" Interventions in Lung Cancer: Why Action Matters. PMID- 29703538 TI - ROS-1 Rearrangements in Circulating Tumor Cells. PMID- 29703539 TI - VIT-ALK, a Novel Alectinib-Sensitive Fusion Gene in Lung Adenocarcinoma. PMID- 29703540 TI - Pulmonary Lymphoepithelioma-like Carcinoma Disguised as Squamous Cell Carcinoma. PMID- 29703541 TI - Massive Hemoptysis after the First Administration of Pembrolizumab in a Strongly Positive, Centrally Located NSCLC. PMID- 29703543 TI - Correlation between 22C3-PD-L1 Expression and EGFR Mutations in Japanese Patients with Advanced Lung Adenocarcinoma. PMID- 29703542 TI - Prolonged Partial Response to Osimertinib after Disease Progression to Rociletinib in Metastasic EGFR T790M-Positive Non-Small Cell Lung Cancer. PMID- 29703544 TI - Updated Correlation of 22C3-PD-L1 >=50% Expression with Driver Oncogene Mutations and Response to Pembrolizumab in the Kinase Inhibitor-Resistant Setting. PMID- 29703545 TI - Comments on Cost-Effectiveness of Osimertinib for EGFR Mutation-Positive Non Small-Cell Lung Cancer after Progression during First-Line EGFR Tyrosine Kinase Inhibitor Therapy. PMID- 29703546 TI - Response: Comments on Cost-Effectiveness of Osimertinib for EGFR Mutation Positive Non-Small Cell Lung Cancer after Progression following First-Line EGFR Tyrosine Kinase Inhibitor Therapy. PMID- 29703547 TI - Peripheral Blood Biomarkers Associated with Clinical Outcome in Non-Small Cell Lung Cancer Patients Treated with Nivolumab: Methodological Issues. PMID- 29703548 TI - In Reply. PMID- 29703549 TI - The rice rat Euryoryzomys russatus, a competent amplifying host of Rickettsia parkeri strain Atlantic rainforest for the tick Amblyomma ovale. AB - Rickettsia parkeri strain Atlantic rainforest (SAR) is the etiological agent of a spotted fever group rickettsiosis in Brazil, where it is transmitted to humans by the tick Amblyomma ovale. A previous study demonstrated that R. parkeri SAR was successfully maintained in A. ovale ticks by transstadial and transovarial passages; however, because this agent induced lower reproduction rates in A. ovale, the participation of a vertebrate amplifier host, yet to be determined, was speculated. Since the rice rat Euryoryzomys russatus was demonstrated to be the most important host for immature stages of A. ovale in a focus of R. parkeri SAR transmission, the present study evaluated the competence of rice rats to act as amplifying host of R. parkeri SAR for A. ovale ticks. Rice rats were infested with R. parkeri SAR-infected A. ovale nymphs, and four days later with uninfected A. ovale larvae. Rickettsial transmission to rats was confirmed by seroconversion to R. parkeri antigens. Detached engorged larvae were allowed to molt to nymphs, in which rickettsial DNA was detected in up to 60% (mean: 20%) of the specimens. When part of these nymphs was allowed to feed on susceptible rice rats, rickettsial transmission was confirmed by seroconversion, indicating that there was successful horizontal transmission of R. parkeri SAR from infected nymphs to uninfected larvae in the previous acquisition infestations. Because we used naive, susceptible rats, we infer that this horizontal transmission occurred via a systemic infection (rickettsemia) in the rat. Our results, coupled with previous epidemiological studies, suggest that under natural conditions rice rats could be acting as amplifying hosts of R. parkeri SAR to A. ovale ticks. PMID- 29703550 TI - Valproic Acid Attenuates Postoperative Psychosis Following Aggressive Resection of a Intracardiac Carcinoid Neuroendocrine Tumor: A Case Report. PMID- 29703551 TI - Clozapine Discontinuation and Malignant Catatonia: A Case Report. PMID- 29703552 TI - Incidence and predictors of 30-day readmissions in patients hospitalized with chronic pancreatitis: A nationwide analysis. AB - BACKGROUND: Patients with chronic pancreatitis are prone to frequent readmissions. The aim of this study is to evaluate the rate and predictors of 30 day readmissions in patients with chronic pancreatitis using the Nationwide Readmission Database (NRD). METHODS: We performed a retrospective analysis of all adult patients with the principal discharge diagnosis of chronic pancreatitis from 2010 through 2014. We excluded patients who died during the hospitalization. Multivariate Cox proportional hazard regression was performed to identify demographic, clinical, and hospital factors that associated with 30-day unplanned readmissions. RESULTS: During the study period, 25,259 patients had the principal discharge diagnosis of chronic pancreatitis and survived the index hospitalization. Of these, 6477 (26.7%) were readmitted within 30 days. Younger age group, males, length of stay >5 days, admission to a large, metropolitan hospital, and several comorbidities (renal failure, rheumatic disease, chronic anemia, heart failure, depression, drug abuse, psychosis, and diabetes) were independently associated with increased risk of 30-day readmission. ERCP, pancreatic surgery, and obesity were associated with lower risk. The most common reasons for readmissions were acute pancreatitis (30%), chronic pancreatitis (17%), pseudocyst (2%), and abdominal pain (6%). CONCLUSIONS: One in four patients with chronic pancreatitis is readmitted within 30 days (26.7%). Pancreatic disease accounts for at least half of all readmissions. Several baseline comorbidities and characteristics are associated with 30-day readmission risk after index admission. Knowledge of these predictors can help design interventions to target high-risk patients and reduce readmissions and costs of care. PMID- 29703553 TI - Trends in the prevalence of type 2 diabetes and its association with mortality rates in Asians vs. Whites: Results from the United States National Health Interview Survey from 2000 to 2014. AB - AIMS: To identify the prevalence and mortality of type 2 diabetes in Asian Americans (Asians) vs. non-Hispanic whites (Whites). METHODS: We analyzed a nationally representative sample of 237,354 U.S. adults aged >=30 years using National Health Interview Survey data from 2000 to 2014 to estimate the prevalence and trends of type 2 diabetes. Additionally, 144,638 Asians and Whites represented in surveys from 2000 to 2009 were included in the mortality analysis with follow-up to 2011. RESULTS: Type 2 diabetes was higher in Asians than Whites (7.0-11.2 vs. 5.6-8.3%) and increased over time. Prevalence rates increased from 8.1 (2000-2002) to 9.6% (2012-2014) in Asians and from 6.0 (2000-2002) to 7.9% (2012-2014) in Whites (both P < 0.05). The age-standardized mortality rates were 72.7 and 138.8 per 1000 person-years in Asians and Whites with diabetes, respectively, and 58.1 and 77.8 per 1000 person-years, respectively, in those without diabetes. Among Asians and Whites with diabetes, hazard ratios for total and CVD mortality were 0.7 (95% CI: 0.5-0.9) and 0.3 (95% CI: 0.1-0.6), respectively, with no difference in cancer mortality. Asians and Whites without diabetes exhibited no differences in total or cause-specific mortality. CONCLUSIONS: Type 2 diabetes was more prevalent in Asians, with a significant upward trend since 2000, but overall mortality was lower in Asians than Whites with diabetes. Asians are susceptible to type 2 diabetes; thus, prevention programs are still needed. PMID- 29703554 TI - The biological basis and prevention of preterm birth. AB - The time of birth is a critical determinant of perinatal and long-term outcomes. Preterm birth is still the first cause of infant mortality and morbidity; unfortunately, rates of preterm birth remain high in both high- and low-resource countries, ranging from 5% to 18%. Preterm parturition is a syndrome, which can be induced by various factors such as infection, cervical pathology, uterine overdistension, progesterone deficiency, vascular alterations (utero-placental ischemia, decidual hemorrhage), maternal and fetal stress, allograft reaction, allergic phenomena, and probably other several unknown factors. These various etiologies can lead to the pathological activation of a common pathway of decidua/fetal membranes, which causes uterine contractility, cervical ripening, and rupture of membranes. Moreover, the mechanisms responsible for these processes have been identified, which involve receptors, chemokines, and inflammatory cytokines. It is very important to understand the cellular and biochemical pathways responsible for preterm labor to identify, treat, and prevent negative outcome in a timely manner. Clinicians and researchers play a key role in improving biochemical knowledge on preterm delivery, identifying risk factors, and shaping interventions that can address this complex syndrome. PMID- 29703555 TI - [The importance of social relationships as a mechanism to improve the health and quality of life of the elderly, from an interdisciplinary perspective]. AB - INTRODUCTION: This study presents an analysis on the effects of positive social relationships as determining factors on the health status of the elderly, from an interdisciplinary point of view. MATERIALS AND METHODS: A survey was carried out on a total of 2,332 subjects in the province of Toledo, Spain, using several scales related to the study objectives. For the multivariable analysis of the data, the linear regression, along with goodness of fit, as well as the tests of Cox, Snell and R-squared of Nagelkerke, were calculated to determine the correlation between the networks and the social contacts with the health. RESULTS: Good social relationships result in better health, because they allow us to feel good and add life to the years. The size of the social network, and the frequency of contacts, although decreasing with age, become vitally important at this stage of life. All these factors constitute stimuli to improve the perception of health, to provide social support in activities of daily living, as well as for instrumental or disease management. CONCLUSIONS: The main outcome of this study is that positive social relationships can be considered as a determining factor in the health of the elderly, but not all these interactions influence the same extent. The factor of the human relationship in terms of emotional proximity, together with the frequency or quantity of these encounters, are also correlated with health, due to the emotional impact they imply. PMID- 29703556 TI - Flu vaccination communication in Europe: What does the government communicate and how? AB - INTRODUCTION: The Flu vaccine is the most effective measure to prevent influenza. Yet, vaccination rates remain at sub-optimal levels, with 10%-29% coverage rates in the general population of the EU. As mistrust in vaccines has increased, effective strategies are needed and one is communication. The aim of this research is to identify vaccination recommendations of the health ministries in 5 European Member States and to investigate the communication strategies used. METHODS: Two methods were employed in this study. A review of flu vaccination recommendations in the European Union and five Members States (Austria, Germany, Malta, Ireland and United Kingdom). Next a content analysis was conducted of flu vaccination communication in those six contexts. RESULTS AND DISCUSSION: All countries recommend flu vaccination as a primary protection tool, but they differed in their recommendations for various target audiences. Channels for communication included seven websites and 42 other materials. The main messages used were gained framed promoting protection, either for oneself, family or patients. Most communications provided basic information replying on providing facts and knowledge about the flu and the benefits of vaccination. No information on the development of the communication or its effects were found. CONCLUSION: Communicating flu vaccination as a protective tool is common across countries and is consistent with the benefits of vaccination. Furthermore, the communications in the countries were not consistent with their recommendations. As the recommendations vary across and within countries, communication becomes a challenge. They should, at a minimum, be consistent with EU and country specific recommendations. PMID- 29703557 TI - Italian Registry of Therapeutic Apheresis. AB - Since the 80s the Italian Society of Apheresis and Cell Manipulation (SIdEM) started to monitor the adverse events of therapeutic apheresis (TA) procedures. In subsequent years other variables were added and a national TA registry was created, with a fluctuating adhesion over the years. From 2010 to 2013 the Registry was shared with the Italian Society of Nephrology (SIN): the collection method required data of each patient and a lack of adhesion was observed, mainly because of a heavy workload needed to fill out all the fields. SIdEM was then forced to simplify the form by collecting aggregated data. At the same time, the Italian Privacy Authority (IPA) gave a negative opinion on the use of the SIdEM SIN registry because it did not prevent the possibility to identify the patients and raised the question whether a national registry could be managed by a scientific society or if it should be under the control of the Regulatory Authority (CNS - National Blood Centre). Since 2015 SIdEM has continued to collect aggregated data, with a simple form sent to each Italian TA unit. Today the main limitation of our Registry is the absence of informatic and financial support and the main limit of all TA Registries is represented by the voluntary adhesion, which can be limited by lack of time and interest or reluctance to show and share own data. In the last year SIdEM has started to work with the CNS in order to implement and integrate the Registry into the Information System of the Transfusion Units (SISTRA), a system that monitors the activities of the whole Italian blood system.The hypothesis of a Global Registry is fascinating. In order to have the greatest adhesion it should be easy and fast to fill in and, possibly, based on aggregated data. PMID- 29703558 TI - [Cutaneous manifestations in an infant with hyper-IgE syndrome]. PMID- 29703559 TI - Personalized weight change prediction in the first week of life. AB - BACKGROUND & AIMS: Almost all neonates show physiological weight loss and consecutive weight gain after birth. The resulting weight change profiles are highly variable as they depend on multiple neonatal and maternal factors. This limits the value of weight nomograms for the early identification of neonates at risk for excessive weight loss and related morbidities. The objective of this study was to characterize weight changes and the effect of supplemental feeding in late preterm and term neonates during the first week of life, to identify and quantify neonatal and maternal influencing factors, and to provide an educational online prediction tool. METHODS: Longitudinal weight data from 3638 healthy term and late preterm neonates were prospectively recorded up to 7 days of life. Two thirds (n = 2425) were randomized to develop a semi-mechanistic model characterizing weight change as a balance between time-dependent rates of weight gain and weight loss. The dose-dependent effect of supplemental feeding on weight gain was characterized. A population analysis applying nonlinear mixed-effects modeling was performed using NONMEM 7.3. The model was evaluated on the remaining third of neonates (n = 1213). RESULTS: Key population characteristics (median [range]) of the whole sample were gestational age 39.9 [34.4-42.4] weeks, birth weight 3400 [1980-5580] g, maternal age 32 [15-51] years, cesarean section 26%, and girls 50%. The model demonstrated good predictive performance (bias 0.01%, precision 0.56%), and is able to accurately predict individual weight change (bias 0.15%, precision 1.43%) and the dose-dependent effects of supplemental feeding up to 1 week after birth based on weight measurements during the first 3 days of life, including birth weight, and the following characteristics: gestational age, gender, delivery mode, type of feeding, maternal age, and parity. CONCLUSIONS: We present the first mathematical model not only to describe weight change in term and late preterm neonates but also to provide an educational online tool for personalized weight prediction in the first week of life. PMID- 29703561 TI - Tension hydrothorax: Emergency decompression of a pleural cause of cardiac tamponade. AB - INTRODUCTION: A tension hydrothorax is defined as a massive pleural effusion presenting with hemodynamic abnormalities secondary to mediastinal compression. In these patients pleural volume increases intrathoracic pressure to the point of compromising diastolic filling and cardiac output simulating a cardiac tamponade physiology. This is an uncommon yet potentially fatal medical emergency that if left untreated may progress to cardiac arrest. Early detection and rapid intervention of these patients prevents cardiorespiratory collapse. CASE PRESENTATION: We present a two-case report of patients presenting with malignant tension hydrothoraxes decompressed with ultrasound-guided thoracentesis and tube thoracostomy in the ED. CONCLUSION: Although these life-saving decompressive interventions appear simple, not having proper training is an independent factor for chest tube and thoracentesis complications. Courses and simulation training can benefit physicians to minimize potential complications when managing emergency conditions such as tension hydrothoraxes which continue to be a medical challenge. Whether thoracentesis or thoracostomy is superior in managing this condition remains in debate and a clinical dilemma. PMID- 29703560 TI - Recruiting the ABCD sample: Design considerations and procedures. AB - The ABCD study is a new and ongoing project of very substantial size and scale involving 21 data acquisition sites. It aims to recruit 11,500 children and follow them for ten years with extensive assessments at multiple timepoints. To deliver on its potential to adequately describe adolescent development, it is essential that it adopt recruitment procedures that are efficient and effective and will yield a sample that reflects the nation's diversity in an epidemiologically informed manner. Here, we describe the sampling plans and recruitment procedures of this study. Participants are largely recruited through the school systems with school selection informed by gender, race and ethnicity, socioeconomic status, and urbanicity. Procedures for school selection designed to mitigate selection biases, dynamic monitoring of the accumulating sample to correct deviations from recruitment targets, and a description of the recruitment procedures designed to foster a collaborative attitude between the researchers, the schools and the local communities, are provided. PMID- 29703562 TI - D-dimer levels in VTE patients with distal and proximal clots. AB - OBJECTIVES: There is growing evidence that venous thromboembolism (VTE) patients with distal clots (distal calf deep vein thrombosis [DVT] and sub-segmental pulmonary embolism [PE]) may not routinely benefit from anticoagulation. We compared the D-dimer levels in VTE patients with distal and proximal clots. METHODS: We conducted a multinational, prospective observational study of low-to intermediate risk adult patients presenting to the emergency department (ED) with suspected VTE. Patients were classified as distal (calf DVT or sub-segmental PE) or proximal (proximal DVT or non-sub-segmental PE) clot groups and compared with univariate and multivariate analyses. RESULTS: Of 1752 patients with suspected DVT, 1561 (89.1%) had no DVT, 78 (4.4%) had a distal calf DVT, and 113 (6.4%) had a proximal DVT. DVT patients with proximal clots had higher D-dimer levels (3760 vs. 1670 mg/dL) than with distal clots. Sensitivity and negative predictive value (NPV) for proximal DVT at an optimal D-dimer cutoff of 5770 mg/dL were 40.7% and 52.1% respectively. Of 1834 patients with suspected PE, 1726 (94.1%) had no PE, 7 (0.4%) had isolated sub-segmental PE, and 101 (5.5%) had non-sub-segmental PE. PE patients with proximal clots had higher D-dimer levels (4170 vs. 2520 mg/dL) than those with distal clots. Sensitivity and NPV for proximal PE at an optimal D dimer cutoff of 3499 mg/dL were 57.4% and 10.4% respectively. CONCLUSIONS: VTE patients with proximal clots had higher D-dimer levels than patients with distal clots. However, D-dimer levels cannot be used alone to discriminate between VTE patients with distal or proximal clots. PMID- 29703563 TI - Refractory ventricular fibrillation in patient taking Lamictal. AB - Refractory ventricular fibrillation occurs when there are three or more episodes of ventricular fibrillation within a 24-hour period. We report the first case of a 35-year-old woman without prior medical or family cardiac history who sustained refractory ventricular fibrillation while taking Lamictal for bipolar depression. She presented to the Emergency Department (ED) after a syncopal episode at work. She then sustained a cardiac arrest and required defibrillation in the ED multiple times due to recurrent ventricular fibrillation. The patient received a Subcutaneous Implantable Cardio-Defibrillator and was discharged home. There was no identifiable cardiac or medical cause of her ventricular fibrillation and the electrophysiologist suspected Lamictal caused her refractory ventricular fibrillation. PMID- 29703564 TI - Right atrial pressure predicts worsening renal function in patients with acute right ventricular myocardial infarction. AB - BACKGROUND: Right ventricular myocardial infarction (RVMI) is associated with serious complications in the short-term. Worsening renal function (WRF) is a frequent and dangerous complication. We investigated if right atrial pressure (RAP) predicts WRF in these patients. METHODS: We prospectively studied patients with RVMI. RAP was obtained invasively at admission to coronary care unit. Blood samples were extracted from patients at baseline and every 24h for creatinine measurements for seven days. We defined WRF as an increase of 25% or 0.5mg/dl in serum creatinine during the first seven days compared to baseline creatinine. RESULTS: We included forty-five patients (age 68+/-10years, male 71%). WRF occurred in 51%. The best cut-off value of RAP for WRF prediction was 11mmHg. RAP >=11mmHg was associated with WRF at univariate analysis (OR 5.5, 95% CI 1.27 24.3, p=0.023) and multivariate analysis (OR 6.1, 95% CI 1.07-35.4, p=0.042). RAP >=11mmHg improved reclassification and discrimination after usual prediction with the Mehran score (net reclassification improvement 64.8%, p=0.030; integrated discrimination improvement 7.5%, p=0.037). CONCLUSION: In patients with RVMI, RAP >=11mmHg predicted WRF and improved discrimination. PMID- 29703565 TI - Dispatcher-assisted bystander cardiopulmonary resuscitation and survival in out of-hospital cardiac arrest. AB - INTRODUCTION: Bystander cardiopulmonary resuscitation (CPR) is critical to the survival of patients with out-of-hospital cardiac arrest (OHCA). However, it is unknown whether bystander CPR with or without dispatcher assistance is more effective or why. Thus, we evaluated the association between dispatcher-assisted bystander CPR (vs. bystander CPR without dispatcher assistance) and survival of patients with OHCA. METHODS: This is a retrospective, nonrandomized, observational study using national registry data for all OHCAs. We performed a propensity analysis. Patients with OHCA of cardiac origin were 18-100 years of age and received bystander chest compression in Japan between 2005 and 2014. Outcome measures were bystander rescue breathing, return of spontaneous circulation (ROSC) before hospital arrival, and survival and Cerebral Performance Category (CPC) 1 or 2 at 1 month after the event. RESULTS: During the study period, 1,176,351 OHCAs occurred, and 87,400 cases met the inclusion criteria. Among propensity-matched patients, a negative association was observed between dispatcher-assisted bystander CPR and outcome measures in a fully-adjusted model [odds ratio (OR) (95% CI) for ROSC = 0.87 (0.78-0.97), P < 0.05; OR (95% CI) for 1-month survival = 0.81 (0.65-1.00), P < 0.05; OR (95% CI) for CPC 1 or 2 = 0.64 (0.43-0.93), P < 0.05]. OR of survival for dispatcher-assisted bystander CPR tended to decrease as the emergency medical services response time increased. CONCLUSIONS: Survival benefit was less for dispatcher-assisted bystander CPR with dispatcher assistance than without dispatcher assistance. Low quality is hypothesized to be the cause of the reduced benefit. PMID- 29703566 TI - Management and neurodevelopmental outcomes of the tiniest babies. PMID- 29703567 TI - A new formula for estimating endotracheal tube insertion depth in neonates. PMID- 29703568 TI - Role of long noncoding RNA ZFAS1 in proliferation, apoptosis and migration of chondrocytes in osteoarthritis. AB - OBJECTIVE: This study aimed to investigate the role of long noncoding RNA (lncRNA) ZFAS1 in the development of osteoarthritis (OA) as well as to explore the potential molecular mechanisms. MATERIAL AND METHODS: The expression of lncRNA ZFAS1 in OA chondrocytes was determined. After cell transfection, the effects of ZFAS1 overexpression on the viability, proliferation, apoptosis and migration of OA chondrocytes were detected. Additionally, the expression levels of Bcl-2, Bax, Caspase-3, and matrix metalloproteinases (MMP1 and MMP13) were determined. The expressions of Wnt3a signaling proteins, and the relationship between ZFAS1 and Wnt3a were detected as well. RESULTS: The expression of ZFAS1 was down-regulated in OA chondrocytes compared with normal chondrocytes. Overexpression of ZFAS1 promoted the viability, proliferation and migration, and inhibited apoptosis and matrix synthesis of OA chondrocytes. Additionally, overexpressed ZFAS1 significantly decreased Wnt3a factors. The effects of ZFAS1 on OA chondrocytes were achieved by regulating Wnt3a signaling. CONCLUSIONS: Our study demonstrates that ZFAS1 may promote chondrocyte proliferation, and migration, and decrease apoptosis and matrix synthesis in OA possible via targeting Wnt3a signaling. ZFAS1 provides a potential therapeutic target for OA treatment. PMID- 29703570 TI - [French and worldwide epidemiology of obesity]. AB - Obesity is a disease characterized by an excessive fat deposition. It is associated to the development of several comorbidities. The worldwide prevalence of obesity has been rising in the past 30 years. Recent results published in 2015 show a global prevalence of 12% in adults, which amounts to 604 million obese adults in the world. The prevalence of obesity has also increased in children since the 1980s to reach 5% globally. Social categories are differently affected by obesity with the most impoverished ones having the highest rate of obesity and obesity increase. In the French ESTEBAN study of 2015, the prevalence of overweight and obesity was the highest among adults with the lowest education level and among children whose caregiver was without diploma. PMID- 29703569 TI - Anti-invasion and anti-metastasis effects of Valjatrate E via reduction of matrix metalloproteinases expression and suppression of MAPK/ERK signaling pathway. AB - Valjatrate E is an iridoid compound extracted from Valeriana jatamansi Jones herb and is the active ingredient in antitumor activity. Here, we reported its action on tumor invasion and metastasis in the human hepatocellular carcinoma HepG2, aiming at a better understanding of the potential mechanism of action of Valjatrate E. HepG2 cells were treated with Valjatrate E at different concentrations. Wound healing assay and transwell chamber assay were used to determine the effects of Valjatrate E on the migration and invasiveness of HepG2 cells, respectively. Moreover, homogeneity and heterotypic adhesion experiments evaluated the adhesion property of HepG2 cells. The molecular mechanisms by which Valjatrate E inhibited the invasion and migration of HepG2 cells were investigated by gelatin zymography experiment and western blot. Treatment with Valjatrate E inhibited the migration and invasion of HepG2 cells. It achieved this by reducing the expression of matrix metalloprotease 2 (MMP-2) and matrix metalloprotease 9 (MMP-9), by inhibition of heterogeneous adhesion ability, by blocking mitogen-activated protein kinase (MAPK) signaling via inhibiting the phosphorylation of extracellular signal-regulated kinases (p-ERK). Taken together, these findings provide new evidence that mitogen-activated protein kinase/extracellular signal regulated kinase (MAPK/ERK) signaling pathway plays an important role in promoting invasion and metastasis in HepG2 cells through p ERK, and MAPK/ERK signaling pathway may be a therapeutic target for tumor. PMID- 29703571 TI - [Complications after bariatric surgery]. AB - Bariatric surgery became consensual after the NIH consensus of 1991 and the appearance of laparoscopic approach. This type of operation has a functional role (improvement of quality of life, locomotion and digestive symptoms as gastro esophageal reflux disease), a prevention role (increase in life expectancy, reduction of risk of cancer and cardiovascular disease) and a curative role (remission of diabetes mellitus, obstructive sleep apnea syndrome and arterial hypertension). The laparoscopic approach for bariatric surgery led to a major reduction of postoperative morbi-mortality. Types and rates of complications after bariatric surgery vary according to the procedure. The efficiency of each technique is closely related to its morbi-mortality rate. This concept explains the disparity concerning the choice of the adequate procedure for the patient according to the bariatric team. The risk/benefits balance evaluation must be analyzed case-by-case by each specialist of the multidisciplinary bariatric staff and explained to the patients before final decision. This preoperative period (6 to 12 months) is crucial to select good candidates for bariatric surgery and contributes to the reduction of postoperative complications. A multidisciplinary surveillance for life is mandatory to prevent and treat late complications of bariatric surgery. PMID- 29703572 TI - [Probiotics: Don't through baby with the bath water]. PMID- 29703573 TI - IL-8 negatively regulates ABCA1 expression and cholesterol efflux via upregulating miR-183 in THP-1 macrophage-derived foam cells. AB - OBJECTIVE: Previous studies suggest that IL-8 has an important role in the regulation of cholesterol efflux, but whether miRNAs are involved in this process is still unknown. The purpose of this study is to explore whether IL-8 promotes cholesterol accumulation by enhancing miR-183 expression in macrophages and its underlying mechanism. METHODS AND RESULTS: Treatment of THP-1 macrophage-derived foam cells with IL-8 decreased ABCA1 expression and cholesterol efflux. Using bioinformatics analyses and dual-luciferase reporter assays, we found that miR 183 was highly conserved during evolution and directly inhibited ABCA1 protein and mRNA expression by targeting ABCA1 3'UTR. MiR-183 directly regulated endogenous ABCA1 expression levels. Furthermore, IL-8 enhanced the expression of miR-183 and decrease ABCA1 expression. Cholesterol transport assays confirmed that IL-8 dramatically inhibited apolipoprotein AI-mediated ABCA1-dependent cholesterol efflux by increasing miR-183 expression. In contrast, treatment with anti-IL-8 antibody reversed these effects. CONCLUSION: IL-8 enhances the expression of miR-183, which then inhibits ABCA1 expression and cholesterol efflux. Our studies suggest that the IL-8-miR-183-ABCA1 axis may play an intermediary role in the development of atherosclerosis. PMID- 29703574 TI - Closer to Universal Newborn Screening for Congenital Cytomegalovirus Infection but Far Away from Antiviral Therapy in All Infected Infants. PMID- 29703575 TI - Learning and Encouragement Effects on Six-Minute Walking Test in Children. AB - OBJECTIVES: To evaluate learning and encouragement effects on the 6-minute walk test in children between 6 and 12 years of age. STUDY DESIGN: Two 6-minute walk tests separated by a 10-minute resting period were performed by healthy children between 6 and 12 years of age to evaluate the learning (part 1) and encouragement effects (part 2; randomization with and without encouragement). Distance and cardiorespiratory variables were used as outcomes. RESULTS: 148 children were recruited. The intraclass correlation coefficient estimates were 0.927 (95% CI, 0.893-0.951; part 1) and 0.844 (95% CI, 0.744-0.907; part 2). The test-retest agreement was verified for distance (P = .679) with a bias of 1.1 m (95% CI, -4 to 6), but the increase in distance with encouragement was significantly and clinically relevant (P < .001; +41 m; 95% CI, 33-50). CONCLUSION: No training is required for the 6-minute walk test in children, in contrast with adults, but there was an encouragement effect on the walked distance in these children. Guidelines should take these results into account. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03276299. PMID- 29703576 TI - Neonatal Intensive Care Unit Length of Stay Reduction by Heart Rate Characteristics Monitoring. AB - OBJECTIVE: To examine the effect of heart rate characteristics (HRC) monitoring on length of stay among very low birth weight (VLBW; <1500 g birth weight) neonates in the HeRO randomized controlled trial (RCT). STUDY DESIGN: We performed a retrospective analysis of length of stay metrics among 3 subpopulations (all patients, all survivors, and survivors with positive blood or urine cultures) enrolled in a multicenter, RCT of HRC monitoring. RESULTS: Among all patients in the RCT, infants randomized to receive HRC monitoring were more likely than controls to be discharged alive and prior to day 120 (83.6% vs 80.1%, P = .014). The postmenstrual age at discharge for survivors with positive blood or urine cultures was 3.2 days lower among infants randomized to receive HRC monitoring when compared with controls (P = .026). Although there were trends in other metrics toward reduced length of stay in HRC-monitored patients, none reached statistical significance. CONCLUSIONS: HRC monitoring is associated with reduced mortality in VLBW patients and a reduction in length of stay among infected surviving VLBW infants. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00307333. PMID- 29703577 TI - Enhancing Parent Talk, Reading, and Play in Primary Care: Sustained Impacts of the Video Interaction Project. AB - OBJECTIVE: To determine the early impacts of pediatric primary care parenting interventions on parent cognitive stimulation in low socioeconomic status families and whether these impacts are sustained up to 1.5 years after program completion. STUDY DESIGN: This randomized controlled trial included assignment to 1 of 2 interventions (Video Interaction Project [VIP] or Building Blocks) or to a control group. Mother-newborn dyads were enrolled postpartum in an urban public hospital. In VIP, dyads met with an interventionist on days of well-child visits; the interventionist facilitated interactions in play and shared reading through provision of learning materials and review of videotaped parent-child interactions. In Building Blocks, parents were mailed parenting pamphlets and learning materials. We compare the trajectories of cognitive stimulation for parents in VIP and control from 6 to 54 months. RESULTS: There were 546 families that contributed data. VIP was associated with enhanced reading, parent verbal responsivity, and overall stimulation at all assessment points, with analyses demonstrating a 0.38 standard deviation increase in cognitive stimulation overall. Trajectory models indicated long-term persistence of VIP impacts on reading, teaching, and verbal responsivity. CONCLUSIONS: VIP is associated with sustained enhancements in cognitive stimulation in the home 1.5 years after completion of the program and support expansion of pediatric interventions to enhance developmental trajectories of children of low socioeconomic status. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00212576. PMID- 29703578 TI - Early in vivo experience with the pediatric continuous-flow total artificial heart. AB - BACKGROUND: Heart transplantation in infants and children is an accepted therapy for end-stage heart failure, but donor organ availability is low and always uncertain. Mechanical circulatory support is another standard option, but there is a lack of intracorporeal devices due to size and functional range. The purpose of this study was to evaluate the in vivo performance of our initial prototype of a pediatric continuous-flow total artificial heart (P-CFTAH), comprising a dual pump with one motor and one rotating assembly, supported by a hydrodynamic bearing. METHODS: In acute studies, the P-CFTAH was implanted in 4 lambs (average weight: 28.7 +/- 2.3 kg) via a median sternotomy under cardiopulmonary bypass. Pulmonary and systemic pump performance parameters were recorded. RESULTS: The experiments showed good anatomical fit and easy implantation, with an average aortic cross-clamp time of 98 +/- 18 minutes. Baseline hemodynamics were stable in all 4 animals (pump speed: 3.4 +/- 0.2 krpm; pump flow: 2.1 +/- 0.9 liters/min; power: 3.0 +/- 0.8 W; arterial pressure: 68 +/- 10 mm Hg; left and right atrial pressures: 6 +/- 1 mm Hg, for both). Any differences between left and right atrial pressures were maintained within the intended limit of +/-5 mm Hg over a wide range of ratios of systemic-to-pulmonary vascular resistance (0.7 to 12), with and without pump-speed modulation. Pump-speed modulation was successfully performed to create arterial pulsation. CONCLUSION: This initial P CFTAH prototype met the proposed requirements for self-regulation, performance, and pulse modulation. PMID- 29703579 TI - Monochorionic twin with neovascularization proven on collagenized fibrotic amniotic membrane after fetoscopic laser photocoagulation. PMID- 29703580 TI - Nitric Oxide in Cardiac Surgery: A Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVES: To investigate the efficacy and safety of perioperative administration of nitric oxide in cardiac surgery. DESIGN: Meta-analysis of randomized controlled trials (RCTs). PARTICIPANTS: Cardiac surgery patients. INTERVENTIONS: A search of Cochrane Central Register of Controlled Trials (CENTRAL), Embase, and MEDLINE for RCTs that compared nitric oxide with placebo or other comparators. MEASUREMENTS AND MAIN RESULTS: The primary outcome was intensive care unit (ICU) stay, and secondary outcomes were mortality, duration of mechanical ventilation, and reduction of mean pulmonary artery pressure. The study included 18 RCTs comprising 958 patients. The authors calculated the pooled odds ratio (OR) and the mean difference (MD) with random-effects model. Quantitative synthesis of data demonstrated a clinically negligible reduction in the length of ICU stay (MD -0.38 days, confidence interval CI [-0.65 to -0.11]; p = 0.005) and mechanical ventilation duration (MD -4.81 hours, CI [-7.79 to 1.83]; p = 0.002) compared with all control interventions with no benefit on mortality. CONCLUSIONS: Perioperative delivery of inhaled nitric oxide resulted to be of no or minimal benefit in patients with pulmonary hypertension undergoing cardiac surgery. Large, randomized trials are needed to further assess its effect on major clinical outcomes and its cost-effectiveness. PMID- 29703581 TI - In Reply to "Continuous Erector Spinae Plane (ESP) Block: Optimizing the Analgesia Technique". PMID- 29703582 TI - A New Phase in Applied Biology. PMID- 29703583 TI - Nanoparticle-Mediated Delivery towards Advancing Plant Genetic Engineering. AB - Genetic engineering of plants has enhanced crop productivity in the face of climate change and a growing global population by conferring desirable genetic traits to agricultural crops. Efficient genetic transformation in plants remains a challenge due to the cell wall, a barrier to exogenous biomolecule delivery. Conventional delivery methods are inefficient, damaging to tissue, or are only effective in a limited number of plant species. Nanoparticles are promising materials for biomolecule delivery, owing to their ability to traverse plant cell walls without external force and highly tunable physicochemical properties for diverse cargo conjugation and broad host range applicability. With the advent of engineered nuclease biotechnologies, we discuss the potential of nanoparticles as an optimal platform to deliver biomolecules to plants for genetic engineering. PMID- 29703584 TI - [Medulloblastoma. Pathology]. AB - Medulloblastomas, embryonal neuroepithelial tumors developed in the cerebellum or brain stem, are mainly observed in childhood. The treatment of WHO-Grade IV tumors depends on stratifications that are usually based on postoperative data, histopathological subtype, tumor extension and presence of MYC or NMYC amplifications. Recently, molecular biology studies, based on new technologies (i.e. sequencing, transcriptomic, methylomic) have introduced genetic subtypes integrated into the latest WHO-2016 neuropathological classification. According to this classification, the three genetic groups WNT, SHH, with or without mutated TP53 gene, and non-WNT/non-SHH, comprising subgroups 3 and 4, are recalled in this review. The contribution of immunohistochemistry to define these groups is specified. The four histopathological groups are detailed in comparison to the WHO-2007 classification and the molecular data: classic medulloblastoma, desmoplastic/nodular medulloblastoma, medulloblastoma with extensive nodularity, and large cell/anaplastic medulloblastoma. The groups defined on genetic and histopathological grounds are not strictly concordant. Depending on the age of the patients, their correlations are different, as well as their role in the management and prognosis of these tumors. Other embryonal tumors, for which new classifications are in progress and gliomas may be confused with a medulloblastoma and the elements of the differential diagnosis of these entities are discussed. This evolution in classification fully justifies ongoing structuring procedures such as histopathological review (RENOCLIP) and the organization of molecular biology platforms. PMID- 29703585 TI - Predictive factors for progression through the difficulty levels of Pilates exercises in patients with low back pain: a secondary analysis of a randomized controlled trial. AB - BACKGROUND: The progression through the difficulty levels of Pilates exercises is a subjective criterion, that depends on the therapist's experience and ability to identify the best moment to progress to the next level. OBJECTIVE: To identify the factors that interfere in the progression through the difficulty levels of the Pilates exercises in patients with chronic nonspecific low back pain. METHODS: Data from 139 patients with chronic nonspecific low back pain from a randomized controlled trial were used for statistical analysis using binary logistic regression. The dependent variable was the progression through the difficulty levels, and the independent variables were age, gender, educational level, low back pain duration, pain intensity, general disability, kinesiophobia, previous physical activity, and number of absences. RESULTS: The factors that interfered in the progression through the difficulty levels were previous physical inactivity (odds ratio [OR]=5.14, 95% confidence interval [CI]: 1.53 17.31), low educational level (OR=2.62, 95% CI: 1.12-6.10), more advanced age (OR=0.95, 95% CI: 0.92-0.98) and more absences (OR=0.63, 95% CI: 0.50-0.79). These variables explain 41% of the non-progression through the difficulty level of the exercises. CONCLUSION: Physical inactivity, low educational level, more advanced age and greater number of absences can be interfering factors in the progression through the difficulty levels of the Pilates exercises in patients with chronic nonspecific low back pain. PMID- 29703586 TI - Exosome-Mediated Pathogen Transmission by Arthropod Vectors. AB - Recent molecular and cellular studies have highlighted a potentially important role for tick exosomes in parasite transmission. Here we summarize evolving hypotheses about the largely unknown cellular events that may take place at the tick-host-pathogen interface, focusing on a potential role for arthropod exosomes in this tripartite interaction. PMID- 29703587 TI - The Genome of Artemisia annua Provides Insight into the Evolution of Asteraceae Family and Artemisinin Biosynthesis. AB - Artemisia annua, commonly known as sweet wormwood or Qinghao, is a shrub native to China and has long been used for medicinal purposes. A. annua is now cultivated globally as the only natural source of a potent anti-malarial compound, artemisinin. Here, we report a high-quality draft assembly of the 1.74 gigabase genome of A. annua, which is highly heterozygous, rich in repetitive sequences, and contains 63 226 protein-coding genes, one of the largest numbers among the sequenced plant species. We found that, as one of a few sequenced genomes in the Asteraceae, the A. annua genome contains a large number of genes specific to this large angiosperm clade. Notably, the expansion and functional diversification of genes encoding enzymes involved in terpene biosynthesis are consistent with the evolution of the artemisinin biosynthetic pathway. We further revealed by transcriptome profiling that A. annua has evolved the sophisticated transcriptional regulatory networks underlying artemisinin biosynthesis. Based on comprehensive genomic and transcriptomic analyses we generated transgenic A. annua lines producing high levels of artemisinin, which are now ready for large scale production and thereby will help meet the challenge of increasing global demand of artemisinin. PMID- 29703588 TI - Newborn screening for proximal urea cycle disorders: Current evidence supporting recommendations for newborn screening. AB - Current newborn screening (NBS) for urea cycle disorders (UCD) is incomplete as only distal UCDs are included in most NBS programs by measuring elevated amino acid concentrations. NBS for the proximal UCDs involves the detection in NBS spots of low citrulline values, a finding which is often overlooked because it is considered to be inadequate. We retrospectively analyzed NBS blood spots from known UCD patients comparing the utility of the Region 4 Stork (R4S) interpretive tools to conventional cutoff based interpretation. This study shows the utility of R4S tools in detecting all UCDs, and provides evidence to support the nomination to add proximal UCDs to the recommended uniform screening panel. PMID- 29703589 TI - Increased GPNMB, phospho-ERK1/2, and MMP-9 in cystic fibrosis in association with reduced arylsulfatase B. AB - BACKGROUND: GPNMB was increased in a CF gene array and in Arylsulfatase B (ARSB; N-acetylgalactosamine-4-sulfatase)-null mice, consistent with previous reports that ARSB is reduced in cystic fibrosis (CF). Implications of GPNMB increase in CF are unknown. METHODS: GPNMB levels were determined in serum and circulating leukocytes from CF patients and healthy controls. GPNMB binding with beta-1 integrin and measurements of phospho-ERK1/2 and MMP-9 in CFTR-uncorrected, CFTR corrected, and normal human bronchial epithelial cells (BEC) were determined, following ARSB and GPNMB knockdown, and treatment with RGD peptide, and ERK phosphorylation inhibitor. RESULTS: GPNMB was markedly increased in CF patients compared to controls (p < 0.0001, unpaired t-test, two-tailed). Silencing GPNMB, treatment with excess RGD peptide, and treatment with ERK phosphorylation inhibitor blocked ARSB silencing-induced increases in MMP-9 in the normal BEC. CONCLUSIONS: Findings suggest that decline in ARSB activity caused by decline in CFTR function leads to increased GPNMB, which may contribute to organ dysfunction in CF by increased MMP-9 expression. PMID- 29703590 TI - How effective is trauma simulation as an educational process for healthcare providers within the trauma networks? A systematic review. AB - BACKGROUND: Major trauma is a significant public health problem and a leading cause of death for several age groups. To address this issue, Major Trauma Networks were introduced in the UK from 2010, consisting of Major Trauma Centres (MTCs) and a network of linked Trauma Units (TUs). OBJECTIVE: The aim is to undertake a systematic review to examine how effective is trauma simulation as an educational process for healthcare providers within trauma networks. METHODS: The databases searched included Medline, Embase and Cinahl from 2010 to 2016. This time frame was chosen to reflect more contemporaneous research into simulation training since the advent of trauma networks in 2010 and the publication of national trauma guidelines (NICE). Seven observational studies were selected for narrative review. The screening and selection process followed the PRISMA guidance. The method used to assess the selected studies is based on the Scottish Intercollegiate Guidelines Network (SIGN) handbook. RESULTS: Overall, the studies showed benefits of simulation in trauma training, with some statistical evidence that non-technical skills and overall trauma team performance improved after simulation training, which appears to be effective. Although no studies found any specific correlation of simulation- based learning in trauma to wider effects such as patient outcomes, length of stay or morbidity. Some studies have found that time to diagnosis and treatment arising from improved non-technical trauma team skills from simulation, are a valid surrogate indicator of improved patient outcomes. CONCLUSION: Overall, it is evident from this review that trauma simulation is an effective educational tool, which can aid trauma learning, develop team's non-technical skills and increase task completion, having a positive impact on the trauma network. Trauma units should therefore benefit from increased trauma simulation training and accessibility to repeated simulation based courses or workshops. PMID- 29703591 TI - Nurse-initiated radiographic-test protocol for ankle injuries: A randomized controlled trial. AB - INTRODUCTION: Nurse-initiated radiographic-test protocol was compared with usual practice in reducing unnecessary ankle and foot radiographic-test requests and shortening patients' length of stay (LOS) in an emergency department (ED) by reducing their waiting time for physician reassessment. METHODS: Patients with ankle injuries were enrolled in an unblinded randomized controlled trial. Participants were randomized to receive either the protocol (n = 56) or usual practice (n = 56). Primary outcome was the proportion of radiographic-test requests. Secondary outcomes were the proportion of fractures detected and patients' LOS and waiting times. RESULTS: The proportions of ankle and foot radiographic tests requested by triage nurses implementing the Ottawa Ankle Rules (OARs) in protocol group were smaller than those requested by physicians using their expertise in usual practice group. The proportions of malleolar and midfoot fractures detected by triage nurses implementing the OARs in protocol group were higher than those detected by physicians using their expertise in usual practice group. Patients' LOS and waiting time from consultation to discharge in protocol group were shorter than those in usual practice group. CONCLUSIONS: Implementing the nurse-initiated radiographic-test protocol reduced unnecessary ankle and foot radiographic-test requests and shortened patients' LOS in the ED by reducing their waiting time for physician reassessment. PMID- 29703593 TI - Ball milling of eggshell waste as a green and sustainable approach: A review. AB - Eggshell waste belongs to the most abundant natural waste in nature and is created in huge amounts by everyday consumption of eggs. The majority of this material is being discarded, despite the fact that it has multidisciplinary applications. In this review, the possibility of utilizing the method of ball milling to further broaden the application potential of this material is discussed. The particular application fields include the formation of nanophases, bioceramics synthesis, formation of composites and preparation of material with increased sorption ability. In addition, some other specific applications, like the utilization of ball-milled eggshell as a drug delivery agent, or for the formation of antibacterially active species, are also mentioned. The review provides a critical mechanochemical insight into this topic and aims to emphasize the green and sustainable way of utilizing eggshell waste by environmentally friendly method. PMID- 29703592 TI - Personalized Intrinsic Network Topography Mapping and Functional Connectivity Deficits in Autism Spectrum Disorder. AB - BACKGROUND: Recent advances in techniques using functional magnetic resonance imaging data demonstrate individually specific variation in brain architecture in healthy individuals. To our knowledge, the effects of individually specific variation in complex brain disorders have not been previously reported. METHODS: We developed a novel approach (Personalized Intrinsic Network Topography, PINT) for localizing individually specific resting-state networks using conventional resting-state functional magnetic resonance imaging scans. Using cross-sectional data from participants with autism spectrum disorder (ASD; n = 393) and typically developing (TD) control participants (n = 496) across 15 sites, we tested: 1) effect of diagnosis and age on the variability of intrinsic network locations and 2) whether prior findings of functional connectivity differences in persons with ASD compared with TD persons remain after PINT application. RESULTS: We found greater variability in the spatial locations of resting-state networks within individuals with ASD compared with those in TD individuals. For TD persons, variability decreased from childhood into adulthood and increased in late life, following a U-shaped pattern that was not present in those with ASD. Comparison of intrinsic connectivity between groups revealed that the application of PINT decreased the number of hypoconnected regions in ASD. CONCLUSIONS: Our results provide a new framework for measuring altered brain functioning in neurodevelopmental disorders that may have implications for tracking developmental course, phenotypic heterogeneity, and ultimately treatment response. We underscore the importance of accounting for individual variation in the study of complex brain disorders. PMID- 29703594 TI - Early operative management of complicated appendicitis is associated with improved surgical outcomes in adults. AB - BACKGROUND: There is no consensus on the ideal management of complicated appendicitis. METHODS: The New York State Planning and Research Cooperative database was used to identify all patients admitted with complicated appendicitis and undergoing appendectomy within 1-year. Primary outcome was any complication. Secondary outcomes included length of stay (LOS), hospital charges, and laparoscopy use. Outcomes were compared in appendectomy before or after 48h from admission. RESULTS: 31,167 patients >=18yo were identified for analysis, 28,015(89.9%) underwent early appendectomy. Early appendectomy patients were more likely to be White (69.8% vs. 64.2% p < 0.01), and commercially insured (53.1% vs. 45.4%, p < 0.01). Of the 3152 undergoing delayed surgery, 1610(51.1%) had surgery later during the index admission, 715(22.7%) were readmitted urgently and underwent appendectomy, and 827(26.2%) had elective appendectomy. Patients undergoing delayed surgery had more complications (OR 1.34 95%CI 1.23-1.45), readmissions (OR 1.55 95%CI 1.42-1.70), high hospital charges (OR 4.79 95%CI 4.35 5.27), and prolonged LOS (OR 6.12 95%CI 5.61-6.68). CONCLUSIONS: In this population-level study of complicated appendicitis we found more complications, longer LOS, and higher charges in patients undergoing delayed surgery. PMID- 29703595 TI - Go with your gut: Digestibility and digestive function of two arid-zone Australian murids, Pseudomys australis and Notomys alexis. AB - Spinifex hopping-mice (Notomys alexis) and plains mice (Pseudomys australis) are able to successfully occupy arid zones of Australia. We studied the digestive parameters and energy assimilation of captive spinifex hopping-mice and plains mice. The experiment consisted of six diets fed to the animals for periods of 12days per food type. On a dry matter basis, the plains mice consumed between 2.5 and 7.2% and the hopping-mice between 5.8 and 9.3% of their body mass in food per day. The body mass of the spinifex hopping-mice increased significantly on the sunflower seed diet, while body mass did not change significantly for the plains mice on any diet. Apparent digestibility of macronutrients was similar in the hopping-mice and plains mice when maintained on the same diet, however digestibility of total micronutrients differed. Maintenance energy requirements for the plains mice were 529kJkg-0.75d-1 and spinifex hopping-mice 550kJkg-0.75d 1. Spinifex hopping-mice and plains mice are able to exploit a range of food items and efficiently digest macronutrients, to ensure they meet their nutritional needs, an ability they require in the variable arid environment. The information gained in this study increases the paucity of information on Australian native murids, specifically their digestive function and energy requirements, and will aid captive murid management. The study will allow future expansion into field studies, to aid the conservation of wild rodent diets and nutrition of arid zone murids. PMID- 29703596 TI - How to warn drivers in various safety-critical situations - Different strategies, different reactions. AB - Technological advances allow supporting drivers in a multitude of occasions, ranging from comfort enhancement to collision avoidance, for example through driver warnings, which are especially crucial for traffic safety. This psychological driving simulator experiment investigated how to warn drivers visually in order to prevent accidents in various safety-critical situations. Collision frequencies, driving behavior and subjective evaluations of situation criticality, warning understandability and helpfulness of sixty drivers were measured in two trials of eight scenarios each (within-subjects factors). The warning type in the head-up display (HUD) varied (between-subjects) in its strategy (attention-/reaction-oriented) and specificity (generic/specific) over four warning groups and a control group without a warning. The results show that the scenarios differed in their situation criticality and drivers adapted their reactions accordingly, which underlines the importance of testing driver assistance systems in diverse scenarios. Besides some learning effects over the trials, all warned drivers showed faster and stronger brake reactions. Some warning concepts were understood better than others, but all were accepted. Generic warnings were effective, yet the warning strategy should adapt to situation requirements and/or driver behavior. A stop symbol as reaction generic warning is recommendable for diverse kinds of use cases, leading to fast and strong reactions. However, for rather moderate driver reactions an attention generic approach with a caution symbol might be more suitable. Further research should investigate multi-stage warnings with adaptive strategies for application to various situations including other modalities and false alarms. PMID- 29703597 TI - A simple one-step ultrasonic-assisted extraction and derivatization method coupling to high-performance liquid chromatographyfor the determination of epsilon-aminocaproic acid and amino acids in cosmetics. AB - Nowadays, the safety of cosmetics is a widespread concern. Amines are common cosmetic additives. Some of them such as amino acids are beneficial. Another kind of amines, however, epsilon-aminocaproic acid (EACA) is prohibited to add into cosmetics for its adverse reactions. In this study, a simple, rapid, sensitive and eco-friendly one-step ultrasonic-assisted extraction and derivatization (UAE D) method was developed for determination of EACA and amino acids in cosmetics by coupling with high-performance liquid chromatography (HPLC). By using this sample preparation method, extraction and derivatization of EACA and amino acids were finished in one step in ultrasound field. During this procedure, 4-fluoro-7 nitrobenzofurazan (NBD-F)was applied as derivatization reagent. The extraction conditions including the amount of NBD-F, extraction and derivatization temperature, the ultrasonic vibration time and pH value of the aqueous phase were evaluated. Meanwhile, the extraction mechanism was investigated. Under optimized conditions, the method detection limits were 0.086-0.15 MUg/L, and method quantitation limits were 0.29-0.47 MUg/L with RSDs less than 3.7% (n = 3). The recoveries of EACA and amino acids obtained from cosmetic samples were in range from 76.9% to 122.3%. Amino acids were found in all selected samples and quantified in range from 1.9 +/- 0.9 to 677.2 +/- 17.9 MUg/kg. And EACA was found and quantified with the contents of 1284.3 +/- 22.1 MUg/kg in a toner sample. This UAE-D-HPLC method shortened and simplified the sample pretreatment as well as enhanced the sensitivity of analytical method. In our record, only 10 min was needed for the total sample preparation process. And the method detection limits were two orders of magnitude less than literature reports. Furthermore, we reduced the consumption of solvent and minimized the usage of organic solvents, which made our method moving towards green analytical chemistry. In brief, our UAE-D-HPLC method is a simple, rapid, sensitive and eco-friendly analytical method for the determination of EACA and amino acids in cosmetics. PMID- 29703598 TI - Biomass production in the Lower Mississippi River Basin: Mitigating associated nutrient and sediment discharge to the Gulf of Mexico. AB - A watershed model was developed using the Soil and Water Assessment Tool (SWAT) that simulates nitrogen, phosphorus, and sediment loadings in the Lower Mississippi River Basin (LMRB). The LMRB SWAT model was calibrated and validated using 21 years of observed flow, sediment, and water-quality data. The baseline model results indicate that agricultural lands within the Lower Mississippi River Basin (LMRB) are the dominant sources of nitrogen and phosphorus discharging into the Gulf of Mexico. The model was further used to evaluate the impact of biomass production, in the presence of riparian buffers in the LMRB, on suspended sediment and nutrient loading discharge from the Mississippi River into the Gulf of Mexico. The interplay among land use, riparian buffers, crop type, land slope, water quality, and hydrology were anlyzed at various scales. Implementing a riparian buffer in the dominant agricultural region within the LMRB could reduce suspended sediment, nitrogen, and phosphorus loadings at the regional scale by up to 65%, 38%, and 39%, respectively. Implementation of this land management practice can reduce the suspended-sediment content and improve the water quality of the discharge from the LMRB into the Gulf of Mexico and support the potential production of bioenergy and bio-products within the Mississippi River Basin. PMID- 29703599 TI - Opinions on the swine model for the surgical prevention of lymphedema. PMID- 29703601 TI - Nonnarcotic analgesics reduce average pain up to 24 hours after endodontic treatment compared with placebo. PMID- 29703603 TI - Phytotherapy as adjunct to scaling and root planing may have negligible benefits in probing depth and clinical attachment in the short term. PMID- 29703602 TI - Pit-and-fissure sealants may have better retention rates than resin-based sealants. PMID- 29703600 TI - Vascular toxicities with VEGF inhibitor therapies-focus on hypertension and arterial thrombotic events. AB - The vascular endothelial growth factor (VEGF) signaling pathway (VSP) fulfills a cardinal role in endothelial cells and its inhibition has profound cardiovascular impact. This is true not only for the normal vasculature but also for the tumor vasculature when VSP inhibitors are used as anti-angiogenic therapies. Generalized endothelial dysfunction predisposes to vasoconstriction, atherosclerosis, platelet activation, and thrombosis (arterial more than venous). All of these have been reported with VSP inhibitors and collectively give rise to vascular toxicities, the most concerning of which are arterial thromboembolic events (ATE). VSP inhibitors include antibodies, acting extracelluarly on VEGF, such as bevacizumab and tyrosine kinases inhibitors, acting intracellularly on the kinase domain of VEGF receptors, such as sunintib and sorafenib. The addition of bevacizumab and VSP tyrosine kinase inhibitor therapy to the cancer treatment regimen is associated with a 1.5-2.5-fold and 2.3-4.6-fold increase risk of ATEs, respectively. Risk factors for ATEs while on VSP inhibitor therapy include age older than 65 years, previous thromboembolic events, history of atherosclerotic disease, and duration of VSP inhibitor therapy. In clinical practice, hypertension remains the most commonly noted vascular manifestation of VSP inhibition. Optimal blood pressure goals and preferred therapeutic strategies toward reaching these goals are not defined at present. This review summarizes current data on this topic and proposes a more intensive management approach to patients undergoing VSP inhibitor therapy including Systolic Blood PRessure Intervention Trial (SPRINT) blood pressure goals, pleiotropic vasoprotective agents such as angiotensin converting enzyme inhibitors, amlodipine, and carvedilol, high-dose statin therapy, and aspirin. PMID- 29703604 TI - Restoring teeth with moderate and severe tooth wear with direct composite resin restorations had a high success and a high survival rate after 3.5 years. PMID- 29703605 TI - A paradigm for emulating the early learning stage of handwriting: Performance comparison between healthy controls and Parkinson's disease patients in drawing loop shapes. AB - We present a novel paradigm, aimed at emulating the early stage of handwriting learning in proficient writers, by asking them to produce a familiar shape through a novel (unfamiliar) motor plan. Handwriting of beginner writers is characterized by slower movements, reduced spatial precision, lower fluency and reduced force regulation compared to those observed in the handwriting production of proficient writers. Features observed in the ink trace obtained with the novel motor plan and performance comparison of the handwriting obtained by familiar and unfamiliar motor plan suggest that the proposed paradigm is able to elicit non automated movements in proficient writers. As that produced by beginner writers, handwriting of Parkinson's disease (PD) patients is characterized by lack of fluency, slowness and abrupt changes of direction. Furthermore, PD patients show impaired performance in learning novel motor behaviors, as well as in executing motor behaviors acquired before the onset of the disease. We used the proposed paradigm for comparing the performance achieved by healthy controls in writing a familiar shape through a novel motor plan with those obtained by PD patients performing a well-known motor plan for drawing the same shape. Our analysis points out some similarities between performance obtained by healthy controls and those obtained by PD patients, sustaining the hypothesis that the fine tuning of the motor plan parameters involved in the handwriting production is impaired by PD. PMID- 29703606 TI - Final Analysis of Outcomes and RAS/BRAF Status in a Randomized Phase 3 Study of Panitumumab and Best Supportive Care in Chemorefractory Wild Type KRAS Metastatic Colorectal Cancer. AB - INTRODUCTION: Tumor rat sarcoma gene (RAS) status is a negative predictive biomarker for anti-epidermal growth factor receptor (EGFR) therapy in metastatic colorectal cancer (mCRC). We analyzed outcomes according to RAS and v-Raf murine sarcoma viral oncogene homolog B (BRAF) mutational status, and evaluated early tumor shrinkage (ETS) and depth of response (DpR) for patients with wild type RAS. PATIENTS AND METHODS: Patients with confirmed metastatic colon or rectum adenocarcinoma, wild type Kristen rat sarcoma gene tumor exon 2 status, clinical/radiologic disease progression or toxicity during irinotecan or oxaliplatin treatment, and no previous anti-EGFR therapy were randomized 1:1 to receive best supportive care (BSC) with or without panitumumab (6.0 mg/kg, intravenously, on day 1 of each 14-day cycle) in this open-label, multicenter, phase III study (20100007). RAS and BRAF mutation status were determined using Sanger sequencing. ETS was evaluated as maximum percentage change from baseline to week 8; DpR was calculated as the percentage change for tumor shrinkage at nadir versus baseline. RESULTS: Overall, 270 patients had RAS wild type mCRC (panitumumab with BSC, n = 142; BSC, n = 128). For patients with wild type RAS tumors, median overall survival (OS; hazard ratio [HR], 0.72; P = .015) and progression-free survival (PFS; HR, 0.45; P < .0001) were improved with panitumumab with BSC versus BSC. Similar improvements were seen for patients with wild type RAS, and wild type BRAF tumors (OS: HR, 0.75; P = .04; PFS: HR, 0.45; P < .0001). Median DpR was 16.9% for the evaluable panitumumab with BSC wild type RAS population. Overall, 69.5% experienced any type of tumor shrinkage at week 8; 38.2% experienced >= 20% shrinkage. Similar improvements in OS and PFS were seen with stratification according to ETS. CONCLUSION: This analysis showed that panitumumab improved outcomes in wild type RAS mCRC and indicated that ETS and DpR could be used as additional efficacy markers. PMID- 29703607 TI - Progression beyond nivolumab: Stop or repeat? Dramatic responses with salvage chemotherapy. PMID- 29703608 TI - Influence of SNPs in Genes that Modulate Lung Disease Severity in a Group of Mexican Patients with Cystic Fibrosis. AB - BACKGROUND: The variation in cystic fibrosis (CF) lung disease not always is explained by the CFTR genotype, so it has become apparent that modifier genes must play a considerable role in the phenotypic heterogeneity of CF, so we investigated the association of allelic variants in modifier genes that modulate the severity of lung function in a group of Mexican patients diagnosed with CF. METHODS: We included 140 CF patients classified according to lung phenotype and analyzed 17 single nucleotide polymorphisms (SNPs) by TaqMan(r) allelic discrimination. RESULTS: We demonstrated that patients with GG or GC genotype of the allelic variant rs11003125 (MBL2-550) of the MBL2 gene exhibit most of the lung manifestations at an earlier age; and the rs1042713 allelic variant of ADRB2 gene, showed statistical difference only with the age of first spirometry. When we used the dominant model, the MBL2 allele rs11003125 (MBL2-550; p = 0.022, Odds Ratio (OR) 2.87, 95% CI 1.14-7.27) was significantly associated with CF patients as risk factor, and the ADRB2 allele rs1042713 (p.Arg16Gly; p = 0.005, Odds Ratio (OR) 0.37, 95% CI 0.19-0.75) was significantly associated with CF patients as protect factor. CONCLUSIONS: Our findings suggest that the MBL2 and ADRB2 genes exerts an important genetic influence on the lung disease in our patients. Taking into account our results, we insist on not leaving aside this type of studies, since having techniques such as GWAS or WES will be able to advance in achieving a better quality of life for CF patients with severe lung disease. PMID- 29703609 TI - Persistent Arthralgia and Related Risks Factors: A Cohort Study at 12 Months from Laboratory-Confirmed Chikungunya Infection. AB - AIM OF THE STUDY: To assess the cumulative incidence and clinical markers associated with persistent arthralgia (PA) at 12 months from acute chikungunya virus (CHIKV) infection. METHODS: A multicenter retrospective cohort study was conducted in the state of Colima, Mexico, and 217 serologically confirmed cases of CHIKV infection were enrolled. Participants aged 15 years and older were interviewed on 6 months basis from acute illness onset and the main binary outcome was self-reported PA at 12 months. To assess clinical markers associated with PA we used a generalized linear model. The 2-item Patient Health Questionnaire (PHQ-2) was used to screen for depressive symptoms among PA positive individuals. RESULTS: The cumulative incidence of PA was 31.8%. In the generalized linear model, individuals >=40 years of age (risk ratio (RR) = 1.68; 95% confidence interval (CI), 1.10-2.55) and those with 8 or more arthralgia sites (RR = 2.91, 95% CI 1.87-4.53) at acute disease had a significantly increased risk of PA at 12 months from CHIKV infection. Self-reported arthralgia (any site) at 3 months post-infection, a sub-chronic clinical marker, was also associated with a significantly increased risk of long-term articular manifestations (RR = 7.06, 95% CI 2.97-16.81). Depressive symptoms (PHQ-2 score >=3) were reported by 33.3% of PA-positive participants. CONCLUSIONS: Our findings suggest that chronic CHKV-related articular manifestations were a frequent event in the study sample and the impact on functional status was potential. These results may be useful in health care settings in the risk stratification of PA after CHIKV infection. PMID- 29703610 TI - [Hepatic abnormalities]. PMID- 29703611 TI - [Amoebosis: May sexual transmission be an underestimated way of contamination?] AB - INTRODUCTION: Amoebiasis is a cosmopolitan disease and the third most deadly of parasitic diseases. Entamoeba histolytica is the only one to be pathogenic. Its transmission is not only related to the faecal peril but also sexual, with cases described among men who have sex with men. A case of unusual sexual transmission is described in this article, aiming to discuss the impact of these ways of transmitting amoebiasis on patient management. CASE REPORT: We describe the case of an amebic liver abscess in a 27-years-old man who did not travel in endemic areas. After patient interrogation, it seems that the contamination mode was sexual, related to a heterosexual relationship with a new female partner 4 months before the diagnosis. HIV and hepatitis B serologies were negative. CONCLUSION: The diagnosis of amoebiasis should be suspected in case of dysentery or liver abscess even if there is no history of travel in endemic areas or of sexual intercourse between men. PMID- 29703612 TI - Trends of obesity prevalence among Spanish adults with diabetes, 1987-2012. AB - INTRODUCTION AND OBJECTIVE: Our aim was to examine the secular trends in obesity prevalence among Spanish adults with diabetes. MATERIAL AND METHODS: Data were collected from 8 waves (from 1987 to 2012) of the National Health Surveys (NHS). NHS are cross-sectional studies conducted in representative samples of the Spanish adult population. Data of 7378 adults (>=16 years) who reported having been diagnosed of diabetes were analyzed. Previously validated self-reported weight and height were used to estimate body mass index (BMI). Obesity was defined as a BMI of 30kg/m2 or greater. Age-adjusted obesity prevalence for each wave was calculated by the direct standardization method. RESULTS: From 1987 to 2012 age-adjusted prevalence of obesity among persons with diabetes increased from 18.2% (95% confidence interval [CI]: 14.2-22.2%) to 39.8% (95% CI: 36.8 42.8%). Age-adjusted prevalence of obesity in males with diabetes increased from 13.2% (95% CI: 7.3-19.1%) to 38.0% (95% CI: 33.8-42.1%) and in females from 23.0% (95% CI: 17.6-28.4%) to 42.3% (95% CI: 38.0-46.6%). CONCLUSIONS: Between 1987 and 2012 the prevalence of obesity markedly increased in Spain among adults with diabetes. PMID- 29703613 TI - Noonan syndrome: Severe phenotype and PTPN11 mutations. AB - INTRODUCTION AND OBJECTIVE: Noonan syndrome (NS) is a genetic disorder characterized by a wide range of distinctive features and health problems. It caused in 50% of cases by missense mutations in PTPN11 gene. It has been postulated that it is possible to predict the disease course based into the impact of mutations on the protein. PATIENTS AND METHODS: We report two cases of severe NS phenotype including hydrops fetalis. PTPN11 gene was studied in germinal cells of both patients by sequencing. RESULTS: Two different mutations (p.Gly503Arg and p.Met504Val) was detected in PTPN11 gene. DISCUSSION: These mutations have been reported previously, and when they were germinal variants, patients presented classic NS, NS with other malignancies and recently, p.Gly503Arg has been also observed in a patient with severe NS and hydrops fetalis, as our cases. Therefore, these observations shade light on that it is not always possibly to determine the genotype-phenotype relation based into the impact of mutations on the protein in NS patients with PTPN11 mutations. PMID- 29703614 TI - Reply. PMID- 29703615 TI - Scleral Lenses Reduce the Need for Corneal Transplants in Severe Keratoconus. PMID- 29703616 TI - ?DNA assembly technique simplifies the construction of infectious clone of fowl adenovirus. AB - Plasmid bearing adenovirus genome is generally constructed with the method of homologous recombination in E. coli BJ5183 strain. Here, we utilized Gibson gene assembly technique to generate infectious clone of fowl adenovirus 4 (FAdV-4). Primers flanked with partial inverted terminal repeat (ITR) sequence of FAdV-4 were synthesized to amplify a plasmid backbone containing kanamycin-resistant gene and pBR322 origin (KAN-ORI). DNA assembly was carried out by combining the KAN-ORI fragment, virus genomic DNA and DNA assembly master mix. E. coli competent cells were transformed with the assembled product, and plasmids (pKFAV4) were extracted and confirmed to contain viral genome by restriction analysis and sequencing. Virus was successfully rescued from linear pKFAV4 transfected chicken LMH cells. This approach was further verified in cloning of human adenovirus 5 genome. Our results indicated that DNA assembly technique simplified the construction of infectious clone of adenovirus, suggesting its possible application in virus traditional or reverse genetics. PMID- 29703617 TI - Hazards of Improper Dispensary: Literature Review and Report of an Accidental Chloroform Injection. AB - Several clear, transparent solutions are used in endodontics. Inappropriate dispensing methods can lead to accidental injection or accidental irrigation. These accidents can cause permanent tissue damage including damage to the bone, periodontium, nerves, and vasculature. This article reports on the consequences of an accidental chloroform injection. Nonsurgical retreatment of tooth #8 was planned as part of a restorative treatment plan in a 69-year-old woman. The dentist accidentally injected chloroform instead of local anesthesia because chloroform was loaded into the anesthetic syringe. The patient experienced severe pain and swelling and soft tissue necrosis and suffered permanent sensory and motor nerve damage. A review of the literature was performed on accidents caused by improper dispensary, namely accidental injections and accidental irrigations. The data were extracted and summarized. Sodium hypochlorite, chlorhexidine, formalin, formocresol, 1:1000 adrenaline, benzalkonium chloride, and lighter fuel were accidentally injected as an intraoral nerve block or as infiltration injections. Bone and soft tissue necrosis, tooth loss, and sensory nerve damage (anesthesia and paresthesia) were the most common consequences reported. Such disastrous events can be prevented by appropriate labeling and separate dispensing methods for each solution. There is a need for disseminating information on toxicity and biocompatibility of materials/solutions used in endodontics. The authors recommend training dental students and endodontic residents on immediate and long-term therapeutic management of patients when an accidental injection or accidental irrigation occurs. PMID- 29703618 TI - Biological Analysis of Simvastatin-releasing Chitosan Scaffold as a Cell-free System for Pulp-dentin Regeneration. AB - INTRODUCTION: The improvement of biomaterials capable of driving the regeneration of the pulp-dentin complex mediated by resident cells is the goal of regenerative dentistry. In the present investigation, a chitosan scaffold (CHSC) that released bioactive concentrations of simvastatin (SIM) was tested, aimed at the development of a cell-free tissue engineering system. METHODS: First, we performed a dose-response assay to select the bioactive dose of SIM capable of inducing an odontoblastic phenotype in dental pulp cells (DPCs); after which we evaluated the synergistic effect of this dosage with the CHSC/DPC construct. SIM at 1.0 MUmol/L (CHSC-SIM1.0) and 0.5 MUmol/L were incorporated into the CHSC, and cell viability, adhesion, and calcium deposition were evaluated. Finally, we assessed the biomaterials in an artificial pulp chamber/3-dimensional culture model to simulate the cell-free approach in vitro. RESULTS: SIM at 0.1 MUmol/L was selected as the bioactive dose. This drug was capable of strongly inducing an odontoblastic phenotype on the DPC/CHSC construct. The incorporation of SIM into CHSC had no deleterious effect on cell viability and adhesion to the scaffold structure. CHSC-SIM1.0 led to significantly higher calcium-rich matrix deposition on scaffold/dentin disc assay compared with the control (CHSC). This biomaterial induced the migration of DPCs from a 3-dimensional culture to its surface as well as stimulated significantly higher expressions of alkaline phosphatase, collagen type 1 alpha 1, dentin matrix acidic phosphoprotein 1, and dentin sialophosphoprotein on 3-dimensional-cultured DPCs than on those in contact with CHSC. CONCLUSIONS: CHSC-SIM1.0 scaffold was capable of increasing the chemotaxis and regenerative potential of DPCs. PMID- 29703619 TI - The Accuracy of a New Cone-beam Computed Tomographic Software in the Preoperative Working Length Determination Ex Vivo. AB - INTRODUCTION: This study investigates the accuracy of 3D Endo software (Dentsply Sirona, Salzburg, Austria) to determine the working length when using preoperative cone-beam computed tomographic (CBCT) scans of extracted teeth, compared with conventional CBCT software and an electronic apex locator (EAL). METHODS: CBCT scans of 30 premolars were obtained. Using OnDemand3D software (Cybermed, Seoul, Korea), the measurement obtained from the coronal reference to the apical foramen (AF) was recorded as the conventional CBCT length. Then, using 3D Endo software (Dentsply Sirona), the suggested length (3D-SL) and the operator adjusted length (3D-OL) were obtained. Teeth were accessed, and the actual length was measured. Finally, the teeth were embedded in alginate to obtain the electronic length (EL) using the EAL Root ZX (J Morita, Tokyo, Japan). The means of the absolute values and the percentages of distribution of the tested measurement methods were compared to the actual length. RESULTS: No difference was found regarding the mean measurements (analysis of variance, P > .05). All the CBCT measurements presented a high reliability (Dahlberg's formula). The measurements within a +/-0.5-mm range from the AF were 86.6% for the 3D-SL, 80% for the 3D-OL and EL, and 73.3% for the CBCT length. The EL presented significantly fewer underestimated measurements (P < .05). The 3D-OL and 3D-SL presented significantly fewer measurements beyond the AF (P < .05). CONCLUSIONS: The preoperative working length determination using 3D Endo was reliable and similar to conventional CBCT software. However, the combined use of CBCT with an EAL is required to increase the accuracy in the location of the AF. PMID- 29703620 TI - A Comparative Evaluation of Concentrated Growth Factor and Platelet-rich Fibrin on the Proliferation, Migration, and Differentiation of Human Stem Cells of the Apical Papilla. AB - INTRODUCTION: Concentrated growth factor (CGF) is considered to be a natural biomaterial that is better than platelet-rich fibrin (PRF) in bone regeneration, but there is little information acquired in regenerative endodontics. Therefore, the purpose of this study was to evaluate their effects on the proliferation, migration, and differentiation of human stem cells of the apical papilla (SCAPs). METHODS: CGF- and PRF-conditioned medium were prepared using the freeze-dried method. SCAPs were isolated and identified. The proliferative potential of SCAPs was investigated using the Cell Counting Kit-8 (KeyGen Biotech, Nanjing, China). The migration capacity was analyzed using transwell assays, and the mineralization ability was determined by alizarin red S staining. The expression levels of alkaline phosphatase, bone sialoprotein, dentin matrix protein 1, and dentin sialophosphoprotein were determined by quantitative polymerase chain reaction. RESULTS: The cultured cells exhibited mesenchymal stem cell characteristics. The growth rate and migratory cell numbers of the CGF and PRF groups were significantly greater than those of the control group. The mineralized areas in the CGF and PRF groups were significantly larger than those in the control group after incubation for 7 days and 14 days. The expression levels of osteogenic/odontoblast-related genes were reduced on day 7, but they were dramatically enhanced on day 14, and the related gene expression levels in the PRF group were higher than those in the CGF group. CONCLUSIONS: Both CGF and PRF can promote the proliferation, migration, and differentiation of SCAPs. CGF may be a promising alternative in regenerative endodontics. PMID- 29703621 TI - [PKHD1 mutations in autosomal recessive polycystic kidney disease (ARPKD): Genotype-phenotype correlations from a series of 308 cases to improve prenatal counselling]. AB - OBJECTIVES: ARPKD is a recessive rare disease due to PKHD1 mutation. The main objective of the study was to characterize the phenotypic variability according to the different types of PKHD1 mutations. METHODS: This study was performed in 308 ARPKD patients with a genetic diagnosis from our genetic center. Related physicians provided minimal clinical and biological data. RESULTS: Patients were divided into three genotypic groups: the first group (G1; n=65) consisted of patients with two truncating mutations, the second group (G2; n=117) of patients with one truncating and one non-truncating mutation, and the third group (G3; n=126) of patients with two non-truncating mutations. In the entire cohort, the outcomes consisted of 31% of pregnancy termination, 18% of neonatal deaths and 51% of patient survival after the neonatal period. The proportion of severe ARPKD (pregnancy termination or neonatal death) was significantly greater in G1: 94% versus 47% in G2 and 27% in G3 (P<0.001). CONCLUSION: The presence of two truncating mutations in PKHD1 is associated with the most severe perinatal phenotype. However, the phenotypic variability observed in the other genotypic groups requires caution for prenatal counseling. PMID- 29703623 TI - WASP (Write a Scientific Paper) using Excel - 12: Odds ratio and relative risk. AB - The calculation of odds ratios and relative risks may be required as part of a data analysis exercise. This paper explains how to set up these calculations in Microsoft Excel from a two by two contingency table. PMID- 29703622 TI - Multicystic mesothelioma: Operative and long-term outcomes with cytoreductive surgery and hyperthermic intra peritoneal chemotherapy. AB - BACKGROUND: Multicystic peritoneal mesothelioma (MCPM) is an extremely rare disease with 40-50% rate of recurrence after surgical debulking. Due to the recurrent nature of the disease, the option of cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) was offered for this condition. In the present study we aimed to describe the outcomes of this strategy in a single center cohort. METHODS: We retrospectively reviewed a prospectively collected database of all patients with MCPM that underwent the combined procedure in our center. Clinical presentation, operative procedures and outcomes were reviewed. RESULTS: Between August 1997 and October 2017, 19 patients with MCPM underwent 20 cytoreduction and HIPEC procedures in our center. The majority of the patients were females (n = 17, 89%), and mean age was 42, as reported in other series. Disease extent, as measured by mean peritoneal carcinomatosis index (PCI) was 15.5 +/- 9.9 and total number of procedures performed 6.7 +/- 2.6. Major complications occurred in 3 (15%) patients, with no perioperative mortality. After a median of follow-up of 69 months (range 4-220) all patients were alive and 4 patients had recurrence (21%). Patients with high PCI (defined by median PCI) had shorter recurrence free survival (RFS) than patient with low PCI (mean RFS = 106.4 +/- 6.6 for high PCI vs. 125.6 +/- 34.1 for low PCI, p = 0.03). CONCLUSION: Cytoreduction and HIPEC offer low recurrence rate and prolonged mean RFS for patients with MCPM. The combined procedure can be offered with acceptable morbidity in specialized centers. PMID- 29703624 TI - A modern documented Italian identified skeletal collection of 2127 skeletons: the CAL Milano Cemetery Skeletal Collection. AB - The CAL Milano Cemetery Skeletal Collection is a modern and continuously growing identified osteological collection of 2127 skeletons under study in the Laboratorio di Antropologia e Odontologia Forense (LABANOF) in the Department of Biomedical Sciences for Health of the University of Milan (Italy), and part of the Collezione Antropologica LABANOF (CAL). The collection presents individuals of both sexes and of all age groups with a high representation of the elderly and an interesting sample of infants. Each individual is associated with a documentation that includes sex, age-at-death, dates of birth and death, and a death certificate that specifies the exact cause of death and the chain of events that led to it (related pathological conditions or traumatic events). It was also possible to recover for several individuals the autopsy reports and antemortem photographs. This documented osteological collection is of crucial interest in physical and forensic anthropology: it provides unique teaching opportunities and more importantly considerable research possibilities to test and develop sex and age estimation methods, investigate key subjects of forensic relevance and discuss pathological markers, among others. The aim of this paper is to introduce the CAL Milano Cemetery Skeletal Collection as a new identified skeletal collection and present its research and teaching potential. PMID- 29703625 TI - Elevated lipoprotein(a) and low-density lipoprotein cholesterol as predictors of the severity and complexity of angiographic lesions in patients with premature coronary artery disease. AB - BACKGROUND: Elevated lipoprotein(a) (Lp[a]) and low-density lipoprotein (LDL) cholesterol are important inheritable risk factors for premature coronary artery disease (CAD). Lp(a) mediates cardiovascular risk through prothrombotic, proinflammatory, and proatherogenic properties. The association of Lp(a) and LDL cholesterol with angiographic disease severity and complexity in patients with premature CAD has yet to be established. OBJECTIVE: To investigate the relationship of Lp(a) and LDL cholesterol with the severity and complexity of coronary artery lesions using the SYNergy between percutaneous coronary intervention with TAXUS and Cardiac Surgery (SYNTAX) and Gensini scores, in patients with premature CAD. METHODS: Plasma Lp(a) levels were consecutively measured by an automated latex-enhanced immunoassay in 147 patients with premature coronary events (aged <60 years). Elevated Lp(a) was defined as >0.5 g/L, and elevated LDL cholesterol as an untreated LDL cholesterol of >5.0 mmol/L (>193 mg/dL). Demographical, biochemical, and clinical data were retrospectively collected from medical records. SYNTAX and Gensini scores were independently assessed by 2 investigators. RESULTS: Patients were subdivided into tertiles using SYNTAX scores. The proportion of patients with elevated Lp(a) and elevated LDL cholesterol were significantly higher in patients with higher SYNTAX and Gensini scores (P < .05). In multivariate analysis (adjusting for age, diabetes, hypertension, and previous coronary event), elevated Lp(a) and elevated LDL cholesterol remained significant, independent predictors of higher SYNTAX and Gensini scores (P < .05). Patients with both elevated Lp(a) and elevated LDL cholesterol constituted most of the patients in the highest SYNTAX tertile, while patients with nonelevated Lp(a) and nonelevated LDL cholesterol were predominantly in the lowest SYNTAX tertile (P < .05). CONCLUSION: In patients with premature CAD, elevated Lp(a) and LDL cholesterol (in a range consistent with familial hypercholesterolemia) were significant, independent predictors of the severity of CAD. Both lipid disorders should be routinely screened for in younger patients presenting to the coronary care unit. PMID- 29703626 TI - Temporal changes in statin prescription and intensity at discharge and impact on outcomes in patients with newly diagnosed atherosclerotic cardiovascular disease Real-world experience within a large integrated health care system: The IMPRES study. AB - BACKGROUND: Statins are indicated for secondary atherosclerotic cardiovascular disease (ASCVD) prevention; however, multiple surveys have found treatment gaps in clinical application. OBJECTIVE: To determine trends over 15 years in the prevalence and impact of a statin prescription and dose intensity at discharge after a first ASCVD event. METHODS: The Intermountain Enterprise Data Warehouse was searched to identify all adults with a first encounter for ASCVD between January 1, 1999 and December 31, 2013, including coronary artery disease, cerebrovascular disease, and peripheral arterial disease, who survived the index event and were followed for >=3 years or until death. Major adverse cardiovascular events (MACE) were assessed overall and in 5-year increments. RESULTS: A total of 62,070 patients met inclusion criteria. Mean age was 65.9 +/- 13.7 years, and most of them were male (64.7%). Increases in any statin (59.3% to 72.6% to 80.8%) and high-intensity prescription (3.1% to 14.2% to 28.1%) occurred over consecutive 5-year intervals and were greatest in coronary artery disease patients. Statin therapy was associated with a reduced risk of 3-year MACE (multivariable hazard ratio = 0.75 [0.72, 0.78], P < .0001), with a significant linear trend across dose intensities. CONCLUSION: In a real-world experience within a large, integrated health care system, significant reductions in MACE were found in association with both any and high-intensity statin prescriptions following an ASCVD event. Temporal trends indicated progressive improvement in guideline-recommended prescriptions. However, treatment gaps remain in receipt of both any statin and, especially, a high-intensity statin prescription, and these represent prime opportunities for further improvement in secondary ASCVD prevention. PMID- 29703627 TI - The impact of nurse practitioner regulations on population access to care. AB - BACKGROUND: By 2025, experts estimate a significant shortage of primary care providers in the United States, and expansion of the nurse practitioner (NP) workforce may reduce this burden. However, barriers imposed by state NP regulations could reduce access to primary care. PURPOSE: The objectives of this study were to examine the association between three levels of NP state practice regulation (independent, minimum restrictive, and most restrictive) and the proportion of the population with a greater than 30-min travel time to a primary care provider using geocoding. METHODS: Logistic regression models were conducted to calculate the adjusted odds of having a greater than 30-min drive time. FINDINGS: Compared with the most restrictive NP states, states with independent practice had 19.2% lower odds (p = .001) of a greater than 30-min drive to the closest primary care provider. DISCUSSION: Allowing NPs full autonomy to practice may be a relatively simple policy mechanism for states to improve access to primary care. PMID- 29703628 TI - Fuzzy logic for plant-wide control of biological wastewater treatment process including greenhouse gas emissions. AB - The application of control strategies is increasingly used in wastewater treatment plants with the aim of improving effluent quality and reducing operating costs. Due to concerns about the progressive growth of greenhouse gas emissions (GHG), these are also currently being evaluated in wastewater treatment plants. The present article proposes a fuzzy controller for plant-wide control of the biological wastewater treatment process. Its design is based on 14 inputs and 6 outputs in order to reduce GHG emissions, nutrient concentration in the effluent and operational costs. The article explains and shows the effect of each one of the inputs and outputs of the fuzzy controller, as well as the relationship between them. Benchmark Simulation Model no 2 Gas is used for testing the proposed control strategy. The results of simulation results show that the fuzzy controller is able to reduce GHG emissions while improving, at the same time, the common criteria of effluent quality and operational costs. PMID- 29703629 TI - Benzofuran-pyran hybrids: A new class of potential bone anabolic agents. AB - Benzofuran moiety is an important pharmacophore showing positive effects on bone health. In the present study, sixteen benzofuran-pyran hybrids were synthesized and were evaluated for their osteogenic effects on primary osteoblast cells isolated from calvaria. Compounds 22 and 24 were found potent in stimulating osteoblast differentiation as assessed by the alkaline phosphatase activity. These compounds were also found to be nontoxic to osteoblast cells as compared to the control cells in MTT assay. Further, Alizarin Red-S staining for visualization of calcium nodules demonstrated compounds 22 and 34 as active in enhancing mineralization in osteoblast cells. Additionally, transcriptional analysis of these compounds on osteoblast cells revealed that compound 22 up regulated the expression of osteogenic genes RUNX2, BMP-2, COL-1, thus substantiating that compound 22 having two geminal methyl groups in its R3 position is a potent osteogenic agent. Additionally, compound 22 enhanced the ability of bone marrow stromal cells to differentiate towards osteoblast lineage and therefore can be further studied in vivo in bone loss model. PMID- 29703630 TI - Mid- to long-term survivorship of oxidised zirconium total knee replacements performed in patients under 50years of age. AB - BACKGROUND: Oxidised zirconium has the wear properties of ceramic with the breakage resistance of metal. This results in less wear and is of benefit to younger, higher demand patients. We report the short- to mid-term survival of 103 Profix zirconium total knee replacements performed in patients under 50years of age at time of surgery. METHODS: Data was collected prospectively and survival analysis undertaken with strict end points used. SF (Short Form) 12 and WOMAC (Western Ontario and McMaster University) scores were recorded at pre-operatively and at twelve months, one, three, five, seven and ten years. RESULTS: The average age at operation was 43.21years (range 20-50years) with a mean follow-up of 8.56years (range five to 15years). No patients died with one patient lost to follow-up after seven year review. The mean WOMAC score improved from 53 to 29, and the mean SF12 physical component improved from 29 to 36. The five year survivorship for implant related complications was 99.03% (95% CI 94.64-100.0) due to tibial component aseptic loosening at year one. Reoperation for any cause at five years including stiffness was 94.09% (95% CI 88.69-98.11). Forty-four patients were at least ten years post-operative at the time of analysis, with no aseptic loosening of either component giving 10year femoral component survival of 100% and all cause revision of 95.4%. The only zirconium femoral failure was at 12years. CONCLUSIONS: Our data shows excellent mid-term survivorship of oxidised zirconium total knee replacements in younger, higher demand patients. PMID- 29703631 TI - Features and roles of T helper 9 cells and interleukin 9 in immunological diseases. AB - T helper 9 (TH9) cells are considered as newly classified helper T cells that have an important role in the regulation of immune responses. Since these cells preferentially produce IL-9, these cells are termed TH9 cells. Recently, the role of TH9 and its signature cytokine (IL-9) has been investigated in a wide range of diseases, including autoimmunity, allergy, infections, cancer and immunodeficiency. Herein, we review the most recent data concerning TH9 cells and IL-9 as well as their roles in disease. These insights suggest that TH9 cells are a future target for therapeutic intervention. PMID- 29703632 TI - Plasma n-6 Polyunsaturated Fatty Acid Levels and Survival in Renal Transplantation. AB - OBJECTIVE: The major n-6 polyunsaturated fatty acids linoleic acid (LA) and arachidonic acid (AA) play a role in inflammation and glucose metabolism, which could affect patient and renal transplant survival. DESIGN AND METHODS: In this single center cohort study of 1988 Norwegian renal transplant recipients, we assessed associations between plasma levels of LA and AA at baseline, measured by gas chromatography, and patient and graft survival, as well as inflammation and cardiovascular risk markers. RESULTS: During follow-up (median of 9.6 years), 595 patients died and 805 renal transplants were lost, either due to recipient death or graft failure. In multivariable survival analysis, we found no associations with mortality for plasma levels of LA (hazard ratios: 0.99, 95% confidence intervals: 0.96-1.01) or AA (hazard ratios: 1.01, 95% confidence intervals: 0.96 1.06). No associations were found for cardiovascular mortality, overall graft loss, or death-censored graft loss. Plasma glucose, proglycemic marker chemerin, and proinflammatory marker growth differentiation factor 15 were inversely associated with plasma LA and positively associated with plasma AA levels in multivariable analysis. CONCLUSIONS: We found no associations between plasma levels of LA or AA and patient or graft survival. Plasma levels of LA and proglycemic indices were inversely associated, signaling a possible beneficial effect of LA consumption for prevention of posttransplantation diabetes mellitus. PMID- 29703633 TI - Oral Versus Intravenous Iron Supplementation for the Treatment of Iron Deficiency Anemia in Patients on Maintenance Hemodialysis-Effect on Fibroblast Growth Factor 23 Metabolism. AB - OBJECTIVE: Iron administration affects serum levels of intact (I-) fibroblast growth factor-23 (FGF23) and its cleavage product C-terminal (C-) FGF23 in iron deficient patients on maintenance hemodialysis (MHD). The objective of this study was to compare the effect of oral or intravenous iron administration on serum levels of I-FGF23 and C-FGF23 in iron-deficient patients on MHD. DESIGN AND METHODS: A prospective randomized study. SUBJECTS: Participants on MHD with severe iron deficiency (n = 61). INTERVENTION: Participants were randomized to receive oral iron (50 mg of sodium ferrous citrate daily; oral group, n = 29) or intravenous iron (40 mg of saccharated ferric oxide weekly; IV group, n = 32). MAIN OUTCOME MEASURE: Changes in I-FGF23 and C-FGF23 after 10 weeks of treatment. RESULTS: Iron supplementation significantly increased hemoglobin, mean corpuscular volume, ferritin, and transferrin saturation rate, and decreased erythropoiesis-stimulating agent dose and erythropoiesis-stimulating agent resistance index value. Serum phosphate, calcium, and intact parathyroid hormone levels did not change significantly during the study. I-FGF23 levels increased significantly in the IV group and did not change in the oral group, whereas C FGF23 levels were significantly reduced in both groups. Serum interleukin-6 and tumor necrosis factor-alpha levels were increased in both groups. Multiple regression analysis indicated the relationship between iron or erythropoiesis and FGF23 metabolism. CONCLUSION: Iron administration to patients on MHD with severe iron deficiency decreased C-FGF23 levels, whereas intravenous iron increased I FGF23 levels though oral iron did not. If the target of chronic kidney disease mineral and bone disorder therapy is reducing I-FGF23 levels, we suggest the use of oral iron. PMID- 29703634 TI - Human mast cell neutral proteases generate modified LDL particles with increased proteoglycan binding. AB - BACKGROUND AND AIMS: Subendothelial interaction of LDL with extracellular matrix drives atherogenesis. This interaction can be strengthened by proteolytic modification of LDL. Mast cells (MCs) are present in atherosclerotic lesions, and upon activation, they degranulate and release a variety of neutral proteases. Here we studied the ability of MC proteases to cleave apoB-100 of LDL and affect the binding of LDL to proteoglycans. METHODS: Mature human MCs were differentiated from human peripheral blood-derived CD34+ progenitors in vitro and activated with calcium ionophore to generate MC-conditioned medium. LDL was incubated in the MC-conditioned medium or with individual MC proteases, and the binding of native and modified LDL to isolated human aortic proteoglycans or to human atherosclerotic plaques ex vivo was determined. MC proteases in atherosclerotic human coronary artery lesions were detected by immunofluorescence and qPCR. RESULTS: Activated human MCs released the neutral proteases tryptase, chymase, carboxypeptidase A3, cathepsin G, and granzyme B. Of these, cathepsin G degraded most efficiently apoB-100, induced LDL fusion, and enhanced binding of LDL to isolated human aortic proteoglycans and human atherosclerotic lesions ex vivo. Double immunofluoresence staining of human atherosclerotic coronary arteries for tryptase and cathepsin G indicated that lesional MCs contain cathepsin G. In the lesions, expression of cathepsin G correlated with the expression of tryptase and chymase, but not with that of neutrophil proteinase 3. CONCLUSIONS: The present study suggests that cathepsin G in human atherosclerotic lesions is largely derived from MCs and that activated MCs may contribute to atherogenesis by enhancing LDL retention. PMID- 29703636 TI - Mobilisation is feasible in intensive care patients receiving vasoactive therapy: An observational study. AB - BACKGROUND: Mobilisation of intensive care unit (ICU) patients reduces ICU acquired weakness and is associated with better functional outcomes. However, the prevalence of mobilisation of ICU patients remains low. A known barrier to mobilisation is haemodynamic instability, frequently with patients requiring vasoactive therapy. There is a lack of published data to guide clinicians about the safety and feasibility of mobilising patients receiving vasoactive therapy. OBJECTIVES: To describe our mobilisation practice in ICU patients receiving vasoactive therapy and identify factors associated with mobilisation and adverse events. METHODS: Retrospective cohort study of patients undergoing vasoactive therapy in a 31-bed tertiary ICU (October-December, 2016). Details of vasoactive drug dosage, mobilisation, and adverse events were extracted from databases, including mobilisation intensity (ICU Mobility Scale [IMS]). Two generalised linear mixed models were used: first, to describe factors associated with mobilisation and second, to describe factors associated with adverse events during mobilisation, adjusting for age, gender, and acute physiology and chronic health evaluation II score as co-variates. RESULTS: In 119 patients undergoing vasoactive therapy on 371 cumulative vasoactive days, 195 mobilisation episodes occurred (37.5% of vasoactive days). Low (76.8%) and moderate (13.7%) dose vasoactive therapies were associated with a higher probability of mobilisation relative to high (9.4%) dose therapy (odds ratio = 5.50, 95% confidence interval = 2.23-13.59 and odds ratio = 2.50, 95% confidence interval = 0.95-6.59, respectively). For patients who mobilised on vasoactive therapy (n = 72), maximum mobilisation intensity was low (IMS = 1-2) in 31%, moderate (IMS = 3-5) in 51%, and high (IMS = 6-10) in 18% of vasoactive days. While no serious adverse events occurred, there were 14 occurrences of reversible hypotension requiring transient escalation of vasoactive therapy (7.3%), associated with lower mean arterial pressure (p = 0.001). CONCLUSION: In our ICU, patients mobilised on approximately one-third of vasoactive days. Clinicians should anticipate a higher risk of hypotension during mobilisation in patients receiving vasoactive therapy, which may require transient escalation of vasoactive therapy. PMID- 29703637 TI - A research agenda for infection prevention in home healthcare. PMID- 29703635 TI - Differences in the association of total versus local coronary artery calcium with acute coronary syndrome and culprit lesions in patients with acute chest pain: The coronary calcium paradox. AB - BACKGROUND AND AIMS: Total coronary artery calcium (CAC) burden is associated with an increased cardiovascular risk, while local CAC may represent stable plaques. We determined differences in relationship of total CAC with acute coronary syndrome (ACS) and local CAC with culprit lesions in patients with suspected ACS. METHODS: We performed computed tomography (CT) for CAC and CT angiography to assess the presence of significant stenosis and high-risk plaque (positive remodeling, low CT attenuation, napkin-ring sign, spotty calcium) in 37 patients with ACS and 223 controls. Total and segmental Agatston scores were measured. Culprit lesions were assessed in subjects with ACS. RESULTS: Patients (n = 260) with vs. without ACS had higher total CAC score (median 229, 25th-75th percentile 75-517 vs. 27, 25th-75th percentile 0-99, p<0.001), higher prevalence of significant stenosis (78% vs. 7%, p<0.001) and high-risk plaque (95% vs. 59%, p<0.001). In those with ACS, culprit (n = 41) vs. non-culprit (n = 200) lesions, had similar segmental CAC score (median 22, 25th-75th percentile 4-71 vs. 14, 25th-75th percentile 0-51; p=0.37), but higher prevalence of significant stenosis (81% vs. 11%, p<0.001) and high-risk plaque (76% vs. 51%, p=0.005). Significant stenosis (odds ratio 40.2, 95%CI 15.6-103.9, p<0.001) and high-risk plaque (odds ratio 3.4, 95%CI 1.3-9.1, p=0.02), but not segmental CAC score (odds ratio 1.0, 95%CI 1.0-1.0, p=0.47), were associated with culprit lesions of ACS. CONCLUSIONS: Total CAC burden was associated with ACS but segmental CAC was not associated with culprit lesions. Our findings suggest that total but not local CAC is a marker of ACS risk and support the hypothesis that extensive local CAC is a marker of plaque stability. PMID- 29703638 TI - [Skin hydration and hydrating products]. AB - One of the skin's principal functions is to protect the body against its environment by maintaining an effective epidermal barrier, not only against external factors, but also to prevent water loss from the body. Indeed, water homeostasis is vital for the normal physiological functioning of skin. Hydration levels affect not only visible microscopic parameters such as the suppleness and softness of skin, but also molecular parameters, enzyme activities and cellular signalling within the epidermis. The body is continually losing some of its water, but this phenomenon is limited and the optimal hydration gradient in skin is ensured via a set of sophisticated regulatory processes that rely on the functional and dynamic properties of the uppermost level of the skin consisting of the stratum corneum. The present article brings together data recently acquired in the fields of skin hydration and the characterisation of dehydrated or dry skin, whether through study of the regulatory processes involved or as a result of changes in the techniques used for in situ measurement, and thus in optimisation of management. PMID- 29703639 TI - [Angiosarcoma of the head and neck treated with bevacizumab and paclitaxel]. PMID- 29703640 TI - [Treatment of patients with inoperable stage III or stage IV melanoma. Societe francaise de dermatologie]. PMID- 29703641 TI - [Cyproterone acetate and meningioma: The latest findings]. PMID- 29703642 TI - Oleanolic acid exerts bone protective effects in ovariectomized mice by inhibiting osteoclastogenesis. AB - Postmenopausal osteoporosis (POP) is quite prevalent and many new drugs are under development to obtain better therapeutic outcomes. Oleanolic acid (OA) has been reported to prevent bone loss in ovariectomized (OVX) rats by stimulating osteoblastogenesis. One previous study has demonstrated that acetate of OA suppressed lipopolysaccharides (LPS)-induced bone loss in mice. However, the role of OA in the receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated osteoclastogenesis is still not elucidated. Here we show that OA dose-dependently inhibits RANKL-mediated osteoclastogenesis and the formation of functional osteoclasts without impairing the viability and osteoclastic potential in bone marrow macrophages (BMMs). Moreover, OA administration attenuates bone loss in OVX mice by inhibiting osteoclast's densities. Mechanistically, OA does not affect RANKL-induced activation of the NF-kB, JNK, p38, ERK and Akt pathways, but inhibits the expression of the nuclear factor of activated T-cells c1(NFATc1) and c-Fos. Moreover, OA significantly suppresses the expression of RANKL-activated osteoclast genes encoding matrix metalloproteinase 9 (MMP9), Cathepsin K(Ctsk), tartrate-resistant acid phosphatase (TRAP) and carbonic anhydrase II (Car2). This work has elucidated the molecular mechanism of OA in RANKL-mediated osteoclastogenesis and revealed the promising potential of OA to be further developed as a new drug to prevent and treat POP. PMID- 29703643 TI - Medaka as a model for ECG analysis and the effect of verapamil. AB - The heart of the medaka, a small fish native to East Asia, has electrophysiological aspects similar to mammalian hearts. We found that the heart rates of medaka were more similar to humans than mice or rats. Medaka exhibited similar electrocardiogram patterns to those of humans, suggesting a similarity in cardiac impulse formation and propagation. Their hearts also exhibited similar responsiveness to verapamil, a calcium channel antagonist; atropine, a parasympathetic nerve blocker; propranolol, a sympathetic beta-adrenergic blocker; and isoproterenol, a sympathetic beta-adrenergic agonist. We successfully analyzed action potentials and cardiac contractile forces in vivo. Verapamil affected action potential duration and reduced heart rate, suggesting the importance of voltage-dependent calcium channels in determining the heart rhythm of medaka. We also analyzed the expression of the voltage-dependent calcium channel beta2 subunit, which participates in channel formation in cardiac myocytes, and found that splice variant type-2 was the only major transcript in the heart. Our results indicate that medaka could be an appropriate animal model for studying cardiovascular pharmacology. PMID- 29703644 TI - Comparison of two motor subtype classifications in de novo Parkinson's disease. AB - BACKGROUND: Clinical subtypes of Parkinson's disease (PD) have been empirically defined based on the prominent motor symptoms. The aim of this study was to compare the prevalence of non-motor symptoms across PD motor subtypes in patients with PD. METHODS: A total of 192 patients with de novo PD were included. The patients were classified into the tremor-dominant/mixed/akinetic-rigid (TD/mixed/AR) and tremor-dominant/mixed/postural instability and gait disturbance (TD/mixed/PIGD) subtypes, according to previous reports. RESULTS: In the TD/mixed/AR classification, scores for scales related to motor symptoms and activities of daily living (ADL) were significantly different among the groups, and patients with the AR subtype demonstrated more severe scores than patients with the TD subtype. In the TD/mixed/PIGD classification, age, age at symptom onset, scores on motor-related scales, ADL, and non-motor symptoms were significantly different among the groups. Scores including the modified Hoehn and Yahr stages, the motor and ADL subscores of the Unified Parkinson's Disease Rating Scale, the Beck Depression Inventory, and the Non-Motor Symptom Assessment Scale were significantly different after adjustments for age and age at symptom onset, and patients with the PIGD subtype obtained more severe scores than patients with the TD subtype. CONCLUSION: The TD/mixed/PIGD classification seems to be more suitable for identifying non-motor abnormalities than the TD/mixed/AR classification. PMID- 29703645 TI - Psilocybin modulates functional connectivity of the amygdala during emotional face discrimination. AB - Recent studies suggest that the antidepressant effects of the psychedelic 5-HT2A receptor agonist psilocybin are mediated through its modulatory properties on prefrontal and limbic brain regions including the amygdala. To further investigate the effects of psilocybin on emotion processing networks, we studied for the first-time psilocybin's acute effects on amygdala seed-to-voxel connectivity in an event-related face discrimination task in 18 healthy volunteers who received psilocybin and placebo in a double-blind balanced cross over design. The amygdala has been implicated as a salience detector especially involved in the immediate response to emotional face content. We used beta-series amygdala seed-to-voxel connectivity during an emotional face discrimination task to elucidate the connectivity pattern of the amygdala over the entire brain. When we compared psilocybin to placebo, an increase in reaction time for all three categories of affective stimuli was found. Psilocybin decreased the connectivity between amygdala and the striatum during angry face discrimination. During happy face discrimination, the connectivity between the amygdala and the frontal pole was decreased. No effect was seen during discrimination of fearful faces. Thus, we show psilocybin's effect as a modulator of major connectivity hubs of the amygdala. Psilocybin decreases the connectivity between important nodes linked to emotion processing like the frontal pole or the striatum. Future studies are needed to clarify whether connectivity changes predict therapeutic effects in psychiatric patients. PMID- 29703646 TI - Striatal dopamine release and impaired reinforcement learning in adults with 22q11.2 deletion syndrome. AB - 22q11.2 deletion syndrome (22q11DS) is a genetic disorder caused by a microdeletion on chromosome 22q11.2 and associated with an increased risk for developing psychosis. The catechol-O-methyltransferase (COMT) gene is located in the deleted region and involved in dopamine (DA) breakdown. Impaired reinforcement learning (RL) is a recurrent feature in psychosis and thought to be related to abnormal striatal DA function. This study aims to examine RL and the potential association with striatal DA-ergic neuromodulation in 22q11DS. Twelve non-psychotic adults with 22q11DS and 16 healthy controls (HC) were included. A dopamine D2/3 receptor [18F]fallypride positron emission tomography (PET) scan was acquired while participants performed a modified version of the probabilistic stimulus selection task. RL-task performance was significantly worse in 22q11DS compared to HC. There were no group difference in striatal nondisplaceable binding potential (BPND) and task-induced DA release. In HC, striatal task induced DA release was positively associated with task performance, but no such relation was found in 22q11DS subjects. Moreover, higher caudate nucleus task induced DA release was found in COMT Met hemizygotes relative to Val hemizygotes. This study is the first to show impairments in RL in 22q11DS. It suggests that potentially motivational impairments are not only present in psychosis, but also in this genetic high risk group. These deficits may be underlain by abnormal striatal task-induced DA release, perhaps as a consequence of COMT haplo insufficiency. PMID- 29703647 TI - Adeno-Associated Virus Gene Therapy: Translational Progress and Future Prospects in the Treatment of Heart Failure. AB - Despite advances in treatment over the past decade, heart failure remains a significant public health burden and a leading cause of death in the developed world. Gene therapy provides a promising approach for preventing and reversing cardiac abnormalities, however, clinical application has shown limited success to date. A substantial effort is being invested into the development of recombinant adeno-associated viruses (AAVs) for cardiac gene therapy as AAV gene therapy offers a high safety profile and provides sustained and efficient transgene expression following a once-off administration. Due to the physiological, anatomical and genetic similarities between large animals and humans, preclinical studies using large animal models for AAV gene therapy are crucial stepping stones between the laboratory and the clinic. Many molecular targets selected to treat heart failure using AAV gene therapy have been chosen because of their potential to regulate and restore cardiac contractility. Other genes targeted with AAV are involved with regulating angiogenesis, beta-adrenergic sensitivity, inflammation, physiological signalling and metabolism. While significant progress continues to be made in the field of AAV cardiac gene therapy, challenges remain in overcoming host neutralising antibodies, improving AAV vector cardiac transduction efficiency and selectivity, and optimising the dose, route and method of delivery. PMID- 29703648 TI - Analysis of Test-Retest Reliability, Construct Validity, and Internal Consistency of the Brazilian Version of the Pelvic Girdle Questionnaire. AB - OBJECTIVE: The purpose of this study was to evaluate test-retest reliability, construct validity, and internal consistency of the Brazilian version of the Pelvic Girdle Questionnaire (PGQ-Brazil). METHODS: Analysis of the measurement properties was carried out in 4 steps. Step 1 was the pilot study, on which basis 4 hypotheses were formulated. These hypotheses were tested during the next step (construct validity, step 2) by completion of the questionnaire by the 2 groups (in pain [n = 105] and not in pain [n = 52]). For implementation of the PGQ Brazil in the group with pain, we calculated the internal consistency (step 3) and, 7 days later, test-retest reliability (step 4) by re-application of the instrument in this group. RESULTS: First, the PGQ-Brazil was able to discriminate between these groups (construct validity). Second, test-retest reliability (intraclass correlation coefficients for Activities subscale [0.97 with 95% confidence interval of 0.95-0.98] and Symptoms subscale [0.98 with 95% confidence interval of 0.97-0.98] and kappa coefficient between 0.50 and 0.89 for the items) was found to be good; the Bland-Altman test indicated satisfactory agreement. The Rasch analysis indicated good internal consistency, and the instrument's ability to divide the participants into at least 3 levels of skills was confirmed. In contrast, a ceiling effect was observed, as 24% of pregnant women exhibited skills superior to what the PGQ-Brazil could evaluate. CONCLUSIONS: The PGQ Brazil had good internal consistency, test-retest reliability, and construct validity in assessment of limitations in activities and symptoms of pregnant women with pelvic girdle pain. PMID- 29703649 TI - Index versus delayed cholecystectomy in mild gallstone pancreatitis: results of a randomized controlled trial. AB - BACKGROUND: Delayed cholecystectomy is associated with increased risk of biliary events. The objectives of the study were to confirm the superiority of index cholecystectomy over delayed operation in mild gallstone pancreatitis. METHODS: Patients with mild gallstone pancreatitis were randomized into index-or delayed cholecystectomy (IC vs. DC). IC was performed within 48 h from randomization provided a stable or improved clinical condition. The primary outcome was gallstone-related events. Secondary outcomes were rates of cholecystectomy complications, common bile duct stones (CBDS) detected at cholecystectomy and patient reported quality-of-life and pain. RESULTS: Sixty-six patients were randomized into IC (n = 32) or DC (n = 34) between May 2009 and July 2017. There were significantly higher rates of gallstone-related events in the DC compared with the IC group (nine patients vs. one patient, p = 0.013). No statistically significant differences could be demonstrated in cholecystectomy complications (p = 0.605) and CBDS discovered during cholecystectomy (p = 0.302) between the groups. Pain and emotional well-being measured by SF-36 were improved significantly in the IC group at follow-up. CONCLUSIONS: Delayed cholecystectomy in mild gallstone pancreatitis can no longer be recommended since it is associated with an increased risk for recurrent gallstone-related events and impaired patient's reported outcomes. TRIAL REGISTRATION NUMBER: clinicaltrials.gov (ID: NCT02630433). PMID- 29703650 TI - Lung abscess following bronchoscopy due to multidrug-resistant Capnocytophaga sputigena adjacent to lung cancer with high PD-L1 expression. AB - Lung abscess following flexible bronchoscopy is a rare and sometimes fatal iatrogenic complication. Here, we report the first case of a lung abscess caused by multidrug-resistant Capnocytophaga sputigena following bronchoscopy. A 67-year old man underwent bronchoscopy to evaluate a lung mass. Seven days after transbronchial lung biopsy, he presented with an abscess formation in a lung mass. Empirical antibiotic therapy, including with garenoxacin, ampicillin/sulbactam, clindamycin and cefepime, was ineffective. Percutaneous needle aspiration of lung abscess yielded C. sputigena resistant to multiple antibiotics but remained susceptible to carbapenem. He was successfully treated by the combination therapy with surgery and with approximately 6 weeks of intravenous carbapenem. Finally he was diagnosed with a lung abscess with adenocarcinoma expressing high levels of programmed cell death ligand 1. The emergence of multidrug-resistant Capnocytophaga species is a serious concern for effective antimicrobial therapy. Clinicians should consider multidrug-resistant C. sputigena as a causative pathogen of lung abscess when it is refractory to antimicrobial treatment. PMID- 29703651 TI - Sound-localization performance of patients with single-sided deafness is not improved when listening with a bone-conduction device. AB - An increased number of treatment options has become available for patients with single sided deafness (SSD), who are seeking hearing rehabilitation. For example, bone-conduction devices that employ contralateral routing of sound (CROS), by transmitting acoustic bone vibrations from the deaf side to the cochlea of the hearing ear, are widely used. However, in some countries, cochlear implantation is becoming the standard treatment. The present study investigated whether CROS intervention, by means of a CROS bone-conduction device (C-BCD), affected sound localization performance of patients with SSD. Several studies have reported unexpected moderate to good unilateral sound-localization abilities in unaided SSD listeners. Listening with a C-BCD might deteriorate these localization abilities because sounds are transmitted, through bone conduction to the contralateral normal hearing ear, and could thus interfere with monaural level cues (i.e. ambiguous monaural head-shadow cues), or with the subtle spectral localization cues, on which the listener has learned to rely on. The present study included nineteen SSD patients who were using their C-BCD for more than five months. To assess the use of the different localization cues, we investigated their localization abilities to broadband (BB, 0.5-20 kHz), low-pass (LP, 0.5-1.5 kHz), and high-pass filtered noises (HP, 3-20 kHz) of varying intensities. Experiments were performed in complete darkness, by measuring orienting head-movement responses under open-loop localization conditions. We demonstrate that a minority of listeners with SSD (5 out of 19) could localize BB and HP (but not LP) sounds in the horizontal plane in the unaided condition, and that a C-BCD did not deteriorate their localization abilities. PMID- 29703652 TI - Looking back and moving forward: On the application of proportional shortfall in healthcare priority setting in the Netherlands. AB - The increasing demand for healthcare and the resulting pressure on available budgets render priority setting inevitable. If societies aim to improve health and distribute health(care) fairly, equity-efficiency trade-offs are necessary. In the Netherlands, proportional shortfall (PS) was introduced to quantify necessity of care, allowing a direct equity-efficiency trade-off. This study describes the history and application of PS in the Netherlands and examines the theoretical and empirical support for PS as well as its current role in healthcare decision making. We reviewed the international literature on PS from 2001 onwards, along with publicly accessible meeting reports from the Dutch appraisal committee, Adviescommissie Pakket (ACP), from 2013 to 2016. Our results indicate that there is support for the decision model in which necessity is quantified and incremental cost-effectiveness ratios are evaluated against associated monetary reference values. The model enables a uniform framework for priority setting across all healthcare sectors. Although consensus about the application of PS has not yet been reached and alternative ways to quantify necessity were found in ACP reports, PS has increasingly been applied in decision making since 2015. However, empirical support for PS is limited and it may insufficiently reflect societal preferences regarding age and reducing lifetime health inequalities. Hence, further investigation into refining PS-or exploration of another approach-appears warranted for operationalising the equity-efficiency trade-off. PMID- 29703653 TI - Testing a new taxonomic model for the assessment of medical devices: Is it plausible and applicable? Insights from HTA reports and interviews with HTA institutions in Europe. AB - OBJECTIVE: Medical devices (MDs) encompass a broad and heterogeneous range of technologies. While practices vary considerably across countries, MDs often find application in patient care with little or no evaluation of their effectiveness and safety following market approval. A recently proposed taxonomy of MDs considered devices from the viewpoint of Health Technology Assessment (HTA). The aim of the work presented here was to test its plausibility and applicability by considering real-world HTA practices. METHODS: HTA reports on MDs from European institutions were collected in a systematic manner and the evaluated devices and/or related procedures were matched to a position on the taxonomy. Following this, representatives from 16 European HTA institutions were asked about the usefulness of the taxonomy in semi-structured interviews. RESULTS: 1237 HTA reports (2004-2015) from 33 European institutions were included in the sample. The majority of reports was on technologies from the taxonomic positions initially estimated as having high relevance. Most of the experts interviewed stated that they found the taxonomy useful, particularly regarding its potential to aid in selecting technologies for assessment and to highlight potential methodological particularities per taxonomic position. CONCLUSIONS: Overall, the distribution of identified reports on the matrix confirmed that the initial estimation of the relevance and necessity of HTA provided in the taxonomic model is plausible. In addition, interviews with representatives of European HTA institutions showed that the taxonomy could be useful. PMID- 29703655 TI - Techniques of Impella removal while preserving arterial access. AB - Preservation of the arterial access site after removal of large caliber mechanical circulatory devices (MCD) can be challenging. In this paper, we describe two novel techniques and review the current literature focusing on the maintenance of arterial access after Impella removal. PMID- 29703654 TI - Should interventions to reduce variation in care quality target doctors or hospitals? AB - Interventions to reduce variation in care quality are increasingly targeted at both individual doctors and the organisations in which they work. Concerns remain about the scope and consequences for such performance management, the relative contribution of individuals and organisations to observed variation, and whether performance can be measured reliably. This study explores these issues in the context of the English National Health Service by analysing comprehensive administrative data for all patients treated for four clinical conditions (acute myocardial infarction, hip fracture, pneumonia, ischemic stroke) and two surgical procedures (coronary artery bypass, hip replacement) during April 2010-February 2013. Performance indicators are defined as 30-day mortality, 28-day emergency readmission and inpatient length of stay. Three-level hierarchical generalised linear mixed models are estimated to attribute variation in case-mix adjusted indicators to individual doctors and hospital organisations. Except for length of stay after hip replacement, no more than 11% of variation in case-mix adjusted performance indicators can be attributed to doctors and organisations with the rest reflecting random chance and unobserved patient factors. Doctor variation exceeds hospital variation by a factor of 1.2 or more. However, identifying poor performance amongst doctors is hampered by insufficient numbers of cases per doctor to reliably estimate their individual performances. Policy makers and regulators should therefore be cautious when targeting individual doctors in performance improvement initiatives. PMID- 29703656 TI - A systematic review of pharmacy health coaching and an evaluation of patient outcomes. AB - BACKGROUND: Pharmacy health coaching is a nascent topic offering promise on several fronts. There is considerable benefit to discerning the contributions thus far and future directions of pharmacy health coaching and research of the topic. OBJECTIVE: The objective of this review was to synthesize the available empirical evidence regarding pharmacy health coaching and to define it. METHODS: This systematic review followed the PRISMA guidelines. CINHAL, EMBASE, PubMed, PsychINFO and SCOPUS) were searched (2000-2017) to identify sources related to pharmacy health coaching. Included articles were reviewed for their definition and outcomes of health coaching as well as recurring terms/themes pertaining to health coaching. RESULTS: Ten papers met the eligibility criteria. The results of each empirical study as well as the definitions were used to identify the key outcomes associated with pharmacy health coaching and were then cross tabulated. The most commonly occurring outcome of health coaching was an improvement in a health outcome of a target population. An improvement in medication management/adherence and the relationship between health professionals was equally evident. Lastly, an improved attitude towards drug therapy was referred to more often than the cost-effectiveness of health coaching. CONCLUSIONS: The evaluations enabled the formulation of a grounded definition of health coaching. PMID- 29703657 TI - Using the Behaviour Change Wheel to explore potential strategies for minimising harms from non-recreational prescription medicine sharing. AB - INTRODUCTION: Non-recreational sharing of prescribed medicines can have positive outcomes under some circumstances, but can also result in negative health outcomes. This paper describes a theoretically underpinned and systematic approach to exploring potential interventions to reduce harm. METHODS: Individual, semi-structured, face-to-face interviews were conducted with purposively sampled pharmacists (n = 8), doctors (n = 4), nurses (n = 6) and patients (n = 17) from Auckland, New Zealand. Thematic analysis of suggested interventions was undertaken, and these were linked to relevant intervention functions of the Behaviour Change Wheel (BCW). Analysis of previously defined factors influencing sharing were mapped onto the "Capability, Opportunity, Motivation - Behaviour" (COM-B) model of the BCW. RESULTS: COM-B analysis of the factors influencing sharing behaviour revealed: (i) 'Capability'-related factors, such as patient misconceptions about the safety of certain medicines, forgetting to refill or to carry around own medicines, and lack of knowledge about safe disposal of leftover/unused medicines; (ii) 'Opportunity'-related factors included lack of access to health facilities, lack of time to see a doctor, linguistic and cultural barriers, lack of information from healthcare providers about risks of sharing, and having leftover/unused medicines, and (iii) 'Motivation'-related factors included altruism, illness denial, embarrassment about seeing a doctor, not carrying around own medicines, habit, and fear of negative health consequences from missing a few doses of medicines. Five intervention functions of the BCW appear to be the most likely candidates for targeting the factors which relate to medicine sharing. These are education, persuasion, enablement, environmental restructuring and restriction. CONCLUSIONS: A variety of personal and external factors which influence sharing behaviours were identified, and the BCW provided a means by which theoretically underpinned interventions to reduce potential harms from this behaviour could be proposed. The findings can help with the design of approaches to reduce harm associated with non-recreational medicine sharing. PMID- 29703658 TI - Lean Soft Tissue Mass Measured Using Dual-Energy X-Ray Absorptiometry Is an Effective Index for Assessing Change in Leg Skeletal Muscle Mass Following Exercise Training. AB - It is difficult to precisely and easily estimate the changes in skeletal muscle mass (SMM) following exercise training. We aimed to assess whether the change in lean soft tissue mass measured using dual-energy X-ray absorptiometry (DXA) reflects the change in SMM measured using magnetic resonance imaging (MRI) following exercise training in both the leg and trunk regions. Anthropometry, DXA, and MRI measurements of the trunk and leg regions were obtained in 10 male college sumo wrestlers before and after exercise training (mean duration between measurements: ~2 yr). Contiguous magnetic resonance images with 1-cm slice thickness and without gap were obtained from the first cervical vertebra to the ankle joints as reference data. Skeletal muscle volume was calculated from the summation of the digitized cross-sectional areas. The volume measurements were converted into mass by using an assumed skeletal muscle density (1.041 g/cm3). Trunk and leg areas, using DXA regional computer-generated lines, were adjusted to coincide with each discrete region by using MRI. Although the change in the DXA-measured lean soft tissue mass in the trunk region was significantly different from that of the MRI-measured SMM (Cohen's d = -1.3145, concordance correlation coefficient = 0.26, p < 0.01), the changes were similar in the leg region (Cohen's d = 0.07, concordance correlation coefficient = 0.87, p = 0.88). The exercise training-induced change in lean soft tissue mass significantly correlated with that in SMM, both in the leg (r = 0.88, p < 0.01) and trunk (r = 0.64, p < 0.05) regions. Bland-Altman analysis did not indicate a bias for the changes in leg lean soft tissue mass and SMM following exercise training. These results suggest that lean soft tissue mass measured using DXA is an effective index for assessing change in leg SMM following exercise training. PMID- 29703660 TI - Endoscopic treatment of anastomotic leaks - A tailored approach. PMID- 29703659 TI - Comparison of different electrotherapy methods and exercise therapy in shoulder impingement syndrome: A prospective randomized controlled trial. AB - OBJECTIVE: The aim of this study was to assess and compare the effects of different electrotherapy methods and exercise therapy on pain, function and quality of life in shoulder impingement syndrome. METHODS: Eighty-three patients (66 females, 17 males; mean age: 48.2 +/- 7.33 years) with shoulder impingement syndrome were selected and 79 of them were randomly allocated into four groups. Group 1 (n = 19, mean age: 47.89 +/- 7.12 years) was given hot pack and exercises, Group 2 (n = 20, mean age: 47.70 +/- 6.51 years) was given hot packs, exercises and interferential current, Group 3 (n = 20, mean age: 48.50 +/- 8.34 years) was given hot packs, exercises and TENS and Group 4 (n = 20, mean age: 48.55 +/- 7.89 years) was given hot packs, exercises and ultrasound three times a week for four weeks. Assessments were made before treatment, right after it and three months after that using the visual analog scale (VAS), Short Form-36 (SF 36) and the Disabilities of the Arm, Shoulder and Hand (DASH) outcome measures. RESULTS: At the fourth week and third month assessments, all groups showed significant improvements in terms of pain, DASH and SF-36 physical component scores (p < 0.05). In intragroup comparisons, a significant difference between pre- and post-treatment results was found only in SF-36 mental component scores of Group 2. No significant difference was observed between the groups in any stage of the study period (p > 0.05). CONCLUSION: Application of ultrasound, interferential current and TENS in addition to exercise therapy in shoulder impingement syndrome treatment had similar improvements in terms of pain, function and physical component of quality of life. However, interferential current treatment showed significantly better outcomes for the mental component of quality of life. LEVEL OF EVIDENCE: Level I, Therapeutic study. PMID- 29703661 TI - Inflammatory biomarkers in individuals at clinical high risk for psychosis (CHR P): State or trait? AB - BACKGROUND: Studies linking neuro-inflammation to psychotic episodes has been rapidly expanding. Assessments of changes in inflammatory biomarkers in prodromal patients who subsequently convert to psychosis may help in predicting those likely to transition to psychosis. METHODS: We reviewed the literature for original studies that measured inflammatory biomarkers in individuals at clinical high risk for psychosis (CHR-P), and compared pro-inflammatory biomarker data between converters and non-converters to psychosis as well as in healthy controls. RESULTS: Our search yielded 15 studies. Our findings suggest a possible role of plasma levels of Interleukins-1beta, 7, 8, matrix metalloproteinase (MMP) 8, cortisol, albumin and salivary cortisol, measured at baseline, as predictors of psychotic transition. Both baseline C-reactive protein (CRP) and Interleukin-6 levels were not shown to discriminate between converters and non-converters to psychosis. The dearth of longitudinal biomarker measures, before and after treating the psychotic episodes, was a limitation for assessing inflammatory biomarkers as trait vs state marker properties of biomarkers. DISCUSSION: Gaps of data in published studies prevent confirming whether inflammatory biomarkers are state or trait indicators of transition to psychosis in the CHR-P populations. Future investigations should be designed to longitudinally measure inflammatory biomarkers in order to navigate the extensive heterogeneity of the schizophrenia syndrome and its prodrome. PMID- 29703662 TI - Dysregulation of auditory neuroplasticity in schizophrenia. AB - Schizophrenia is a complex brain syndrome characterized by an array of positive symptoms (delusions, hallucinations, disorganized speech), negative symptoms (alogia, apathy, avolition) and cognitive impairments (memory, executive functions). Although investigations of the cognitive deficits in schizophrenia have primarily concentrated on disturbances affecting higher-order cognitive processes, there is an increasing realization that schizophrenia also affects early sensory processing, which might, in fact, play a significant role in the development of higher-order cognitive impairments. Recent evidence suggests that many of these early sensory processing impairments possibly arise from a dysregulation of plasticity regulators in schizophrenia, resulting in either reduced plasticity or excessive unregulated plasticity. The purpose of the present manuscript is to provide a concise overview of how the dysregulation of cortical plasticity mechanisms contributes to schizophrenia symptoms with an emphasis on auditory dysplasticity and to discuss its relevance for treatment outcomes. The idea that plasticity mechanisms are not constrained only within sensitive periods suggests that many functional properties of sensory neurons can be altered throughout the lifetime. PMID- 29703663 TI - Malaria elimination in Indonesia: halfway there. PMID- 29703664 TI - Malaria in pregnancy: a call for a safe, efficient, and patient-centred approach to first-trimester treatment. PMID- 29703665 TI - Does the instrument used for the implant site preparation influence the bone implant interface? A systematic review of clinical and animal studies. AB - This systematic review evaluates the influence of the instrument used for the implant site preparation on the bone-implant interface. Any type of clinical or animal study were searched for in MEDLINE/PubMed, ISI Web of Science, and SciVerse Scopus. Two independent reviewers screened titles/abstracts of articles and the full-text of potentially eligible studies. Comparisons of bone to implant contact and crestal bone loss were estimated using pairwise meta-analysis. Twenty nine studies met the inclusion criteria. The instruments identified in the articles were conventional drills (CDs), osteotome (OT), piezoelectric device (PD), Er:YAG LASER (LS) and osseodensification drills (ODs). The meta-analysis on bone to implant contact suggested no difference between CDs and other techniques and the meta-analysis on crestal bone loss suggested no difference between CDs and PD. The survival of implants in sites prepared with CDs vs. OT or PD presented no significant differences. The use of PD provided lower inflammatory response and earlier bone formation when compared to CDs. ODs provided significant biomechanical improvement in comparison to CDs. LS did not provide any relevant improvement in comparison to CDs or PD. The influence of the instrument used for implant site preparation depended on the property evaluated. PMID- 29703666 TI - Combining midfacial degloving, LeFort-I osteotomy and inferiorly extended lateral orbitotomy (Kronlein) for removal of an orbital cavernous haemangioma: a new approach. AB - Orbital tumours, located in the medial extraconal and intraconal compartment of the orbit, represent a challenge, with regard to surgical exposure. In the present paper removal of a cavernous haemangioma, located in the medial intraconal compartment was accomplished by combining lateral orbitotomy, midfacial degloving and LeFort-I osteotomy. Resection of the tumour could be performed under direct vision. Surgical exposure and removal of the lesion were obtained, without causing damage to surrounding tissues. Aesthetical results and postoperative eye function proved to be highly satisfactorily. With regard to limitations, concerning the combination of these methods, extended surgery duration and invasiveness have to be named. According to the technical feasibility and postoperative results, this new surgical approach represents a reliable and fully viable alternative method for the removal of medial orbital tumours. PMID- 29703667 TI - Entering the Next Dimension: Plant Genomes in 3D. AB - After linear sequences of genomes and epigenomic landscape data, the 3D organization of chromatin in the nucleus is the next level to be explored. Different organisms present a general hierarchical organization, with chromosome territories at the top. Chromatin interaction maps, obtained by chromosome conformation capture (3C)-based methodologies, for eight plant species reveal commonalities, but also differences, among them and with animals. The smallest structures, found in high-resolution maps of the Arabidopsis genome, are single genes. Epigenetic marks (histone modification and DNA methylation), transcriptional activity, and chromatin interaction appear to be correlated, and whether structure is the cause or consequence of the function of interacting regions is being actively investigated. PMID- 29703668 TI - A technique to record the gingival configuration of an interim implant-supported fixed partial denture. AB - Transferring the soft tissue around an interim implant-supported fixed partial denture to the definitive cast is difficult. A technique that can accurately record the soft tissue configuration when making an impression for an implant supported fixed partial denture is described. PMID- 29703669 TI - Biomechanical behavior of 2-implant- and single-implant-retained mandibular overdentures with conventional or mini implants. AB - STATEMENT OF PROBLEM: The use of single or mini dental implants to retain mandibular overdentures is still questionable. PURPOSE: The purpose of this finite element analysis (FEA) study was to investigate the biomechanical behavior of 2- and single-implant-retained mandibular overdentures with conventional or mini implants. MATERIAL AND METHODS: Four 3-dimensional (3D) finite element models were constructed with the following designs of mandibular overdentures: 2 (group 2-C) and single (group 1-C) conventional external hexagon implants with ball or O-ring attachment and 2 (group 2-M) and single (group 1-M) 1-piece mini implants. A 150-N axial load was applied bilaterally and simultaneously on the first molar. Overdenture displacement, von Mises equivalent stress (implants and/or prosthetic components), and maximum principal stresses (peri-implant bone) were recorded numerically and then color-coded and compared among the groups. RESULTS: The overdenture displacement (in mm) was higher for the 1-M (0.16) and 2 M (0.17) groups when compared with 1-C (0.09) and 2-C (0.08). Irrespective of the type of implant, the single-implant groups presented higher values of stress (in MPa) on the implants than did the 2-implant groups (1-C=52.53; 1-M=2.95; 2 C=34.66; 2-M=2.37), ball attachment (1-C=201.33; 2-C=159.06), housing or O-ring (1-C=125.01; 1-M=1.96; 2-C=88.84; 2-M=1.27), and peri-implant cortical bone (1 C=19.37; 1-M=1.47; 2-C=15.70; 2-M=1.06). The mini implant overdentures presented lower stress values on the implants, housing or O-ring, and peri-implant bone than did the conventional implant overdentures, regardless of the number of implants. CONCLUSIONS: The 2-implant-retained overdentures exhibited lower stresses than the single- implant-retained overdentures, irrespective of the type of implant. The mini implants demonstrated higher overdenture displacement and lower stresses than did conventional implant overdentures for single- and 2 implant-retained overdentures. PMID- 29703670 TI - Immediate versus early loading of single dental implants: A systematic review and meta-analysis. AB - STATEMENT OF PROBLEM: Patients prefer to be rehabilitated as soon as possible if the risk of implant failure is not increased. However, whether immediate loading of single implants is riskier than early loading is not clear. PURPOSE: This systematic review and meta-analysis investigated whether the immediate loading protocol has more clinical disadvantages than the early loading protocol for single dental implants in terms of the marginal bone loss and survival rate of single implant crowns. MATERIAL AND METHODS: Two reviewers conducted an advanced electronic database search, with no language or date restriction, in Medline/PubMed, Embase, and the Cochrane Library up to May 2016. Studies were chosen by title and abstract for screening in accordance with the following inclusion criteria: dental implants studies; cohort studies (prospective and retrospective) and randomized controlled trials; samples involving partially edentulous patients; immediate loading implants; early loading implants; and n>=10 participants. RESULTS: Of the 5710 studies initially identified, 5 fulfilled the inclusion criteria. A meta-analysis yielding risk differences (RD) and mean differences (MD) with a 95% confidence interval (CI) was performed. The trials included showed no significant differences between early and immediate loading protocols in single implant crowns with regard to survival rate at 1 and 3 years (RD, -0.00; 95% CI, -0.04 to 0.04; P=.990 for 1 year and P=.980 for 3 years) or marginal bone loss at 1 year (MD, 0.09; 95% CI, -0.02 to 0.19; P=.110) and 3 years (MD, -0.23; 95% CI, -0.47 to 0.01; P=.060). CONCLUSIONS: This systematic review showed no significant differences between early and immediate loading protocols in single implant crowns with regard to survival rate or marginal bone loss at 1 or 3 years. PMID- 29703671 TI - Dental implants with fixed prosthodontics in oligodontia: A retrospective cohort study with a follow-up of up to 25 years. AB - STATEMENT OF PROBLEM: Long-term assessments of implant survival and treatment outcome in patients with oligodontia are lacking. PURPOSE: The purpose of this retrospective clinical study was to assess which factors determine a long-term implant survival and treatment outcome of up to 25 years in a cohort of patients with oligodontia. MATERIAL AND METHODS: The medical records of all patients with oligodontia treated with fixed implant prosthodontics between January 1991 and December 2015 in the Department of Oral and Maxillofacial Surgery at the University Medical Center Groningen, the Netherlands, were assessed. Specifically, this involved the retrieval of records on the need for and mode of bone augmentation, implant survival, and survival of and adverse events associated with the prosthodontics. The Kaplan-Meier estimator was used to analyze implant and superstructure survival. Log-rank tests were used to compare the survival of subgroups. RESULTS: A total of 126 patients with oligodontia were treated with dental implants. Of the 777 implants in total, 56 were lost, resulting in a 5-year cumulative survival of 95.7% (95% confidence interval [CI], 94.2% to 97.2%) and a 10-year cumulative survival of 89.2% (95% CI, 86.2% to 92.2%). The survival of implants placed in regions where bone augmentation surgery had been performed was significantly lower. The 5-year cumulative superstructure survival was 90.5% (95% CI, 87.6% to 93.5%), and the 10-year cumulative superstructure survival was 80.3% (95% CI, 75.3% to 85.3%). The performance of the screw-retained and cemented superstructures was comparable, but the survival of single crowns was significantly higher than the survival of fixed partial dentures (P<.001). CONCLUSIONS: Implant treatment is a predictable treatment option for patients with oligodontia with a favorable long-term outcome. Survival of implants in augmented areas is lower. PMID- 29703672 TI - Color change of CAD-CAM materials and composite resin cements after thermocycling. AB - STATEMENT OF PROBLEM: The color of resin cements and computer-aided-design and computer-aided-manufacturing (CAD-CAM) restorations may change with aging. PURPOSE: The purpose of this in vitro study was to analyze the influence of thermocycling on the color of CAD-CAM materials with underlying resin cement. MATERIAL AND METHODS: Seven different CAD-CAM materials, composite resins and glass-ceramics were cut into 0.7-mm and 1.2-mm thicknesses (n=10) and cemented with a dual-polymerizing resin cement, a light-polymerizing resin cement, and a preheated composite resin (N=420). Color values were measured by using spectrophotometry. Specimens were subjected to thermocycling (5 degrees C and 55 degrees C; 5000 cycles). The measured color difference (DeltaE) data were analyzed by using descriptive statistics. Normality of data distribution was tested by using the Kolmogorov-Smirnov test. Three-way and 1-way ANOVA followed by the Scheffe post hoc test and unpaired 2-sample Student t test were computed to determine the significant differences among the tested parameters (alpha=.05). RESULTS: DeltaE values were significantly influenced by the CAD-CAM material (etap2=0.85, P<.001) and the resin composite cement (etaP2=0.03, P=.003) but were not influenced by thickness (P=.179). Significant interactions were present among thickness, cement, and CAD-CAM materials (P<.001). Vita Suprinity and GC Cerasmart showed significantly the lowest DeltaE values (P<.001). The highest DeltaE values were observed for IPS Empress CAD. The dual-polymerizing resin cement showed significantly lower DeltaE values than the preheated composite resin (P=.003). CONCLUSIONS: Restoration materials and composite resin cement types used for cementation influence the amount of color change due to aging. PMID- 29703673 TI - Positional accuracy of a prosthetic treatment plan incorporated into a cone beam computed tomography scan using surface scan registration. AB - STATEMENT OF PROBLEM: The registration of surface scans onto cone beam computed tomography (CBCT) scans has been proposed as a method of visualizing different anatomic structures and the prosthetic treatment plan simultaneously. This method also overcomes some of the problems associated with conventional radiographic templates. However, it has not been thoroughly investigated or validated for use in implant dentistry. PURPOSE: The purpose of this in vitro study was to evaluate the accuracy of a prosthetic treatment plan surface scan incorporated into a CBCT scan and to compare it to conventional radiographic templates for single tooth replacement. MATERIAL AND METHODS: Direct surface scans of a completely dentate master model with removable radiopaque teeth were made using an intraoral scanner, and indirect surface scans of a stone duplicate of the master model were made using a laboratory scanner. To simulate a clinical scenario, the mandibular left first molar was removed. A CBCT scan of the clinical scenario was made. The surface scans were registered onto the CBCT scans. Radiographic templates for the clinical scenario were fabricated, and the master model was subsequently scanned using the same CBCT scanner with each radiographic template seated. Metrology software was used to assess the accuracy of each method by measuring the 3 dimensional deviation on standard tessellation language (STL) files generated from the CBCT scans against an STL file of the completely dentate master model generated from a CBCT scan. One-way ANOVA and the Tukey HSD test were used for statistical analysis (alpha=.05). RESULTS: The incorporation technique had a significant effect on deviation from the master model (P=.004). The overall mean 3-dimensional deviation was 0.04 mm for direct surface scan registrations, 0.03 mm for indirect surface scan registrations, and 0.33 mm for radiographic templates. Radiographic templates were significantly less accurate compared with both surface scan registration methods (P<.001), whereas no statistically significant difference in accuracy was found between the registration of a laboratory scan and that of an intraoral scan (P=.94). CONCLUSIONS: Intraoral and laboratory surface scan registration on CBCT scans were more accurate than radiographic templates for prosthetic treatment plan incorporation. The accuracy of the registration of an intraoral scan and a laboratory scan was comparable. PMID- 29703674 TI - Effects of an etching solution on the adhesive properties and surface microhardness of zirconia dental ceramics. AB - STATEMENT OF PROBLEM: Conventional approaches to adhesive bonding are not applicable to zirconia restorations. Recently, an etching solution, Zeta Etching Solution (ZES), has been introduced for etching the surface of zirconia. The effects of this etching solution on the bond strength and mechanical properties of zirconia are unknown. PURPOSE: The purpose of this in vitro study was to examine the effects of ZES on the bond strength and surface hardness of zirconia. MATERIAL AND METHODS: Two different types of partially stabilized tetragonal polycrystalline zirconia (TZP), Prettau zirconia (group P) and anterior Prettau (group AP), were evaluated with and without ZES etching. Each group was bonded to a zirconia substrate by using an adhesive resin cement. After 24 hours of storage in distilled water, the bond strength of the zirconia was analyzed. Vickers hardness was determined by using a microhardness tester. Scanning electron microscopy was used to analyze the surface microstructure and determine the mode of failure for each specimen. Results were analyzed and compared using 1-way ANOVA and Student t tests (alpha=.05). RESULTS: Scanning electron microscopy analysis showed that etching the surface of zirconia with ZES etching solution for 60 minutes changed the morphological characteristics and microstructure of zirconia, making the surface more irregular. The changes were more pronounced for AP specimens. Etching with ZES significantly increased the shear bond strength of zirconia (P<.05) in AP specimens. The bond strength of Prettau (P group) specimens after ZES etching did not increase significantly (P>.05). An adhesive failure mode was observed for P zirconia specimens, whereas zirconia specimens exhibited a cohesive mode of failure. No significant decrease (P>.05) was observed in the mean Vickers hardness numbers. CONCLUSIONS: Within the limitations of this in vitro study, it was concluded that etching in ZES for 30 minutes significantly enhanced the shear bond strength of highly translucent anterior Prettau (AP) zirconia restorations. Moreover, etching with ZES did not adversely affect the surface hardness of the zirconia specimens tested. PMID- 29703675 TI - Accuracy and reproducibility of virtual edentulous casts created by laboratory impression scan protocols. AB - STATEMENT OF PROBLEM: Although computer-aided design and computer-aided manufacturing (CAD-CAM) complete removable dental prostheses (CRDPs) have gained popularity, conventional impressions are still common for CAD-CAM CRDP treatment. These need to be digitized and converted into virtual edentulous casts with a laboratory impression scan protocol during prosthesis fabrication. How this can best be accomplished is unclear. PURPOSE: The purpose of this in vitro study was to compare the accuracy and reproducibility of virtual edentulous casts created by a dental laboratory laser scanner and a cone beam computed tomography (CBCT) scanner with a digitized master cast. MATERIAL AND METHODS: A master cast was digitized as the virtual reference cast. Ten polyvinyl siloxane impressions were made on the master cast and scanned with the dental laboratory laser scanner and CBCT scanner. The impressions were sprayed with antiglare spray and rescanned. Four groups of virtual study casts (N=40) were created from the impression scans. All virtual study casts and the reference cast were registered with surface matching software, and the root mean square (RMS) values (representation of overall accuracy) and percentage of measurement data points within 1 standard deviation (SD) of mean RMS values (%, representation of overall reproducibility) among the 4 study groups were measured. Additionally, 95 numeric distance differences (representation of accuracy at each region) were measured in 5 distinct regions: the apex of the denture border, 6 mm from denture border, crest of the ridge, palate, and posterior palatal seal. The repeated-measures ANOVA and post hoc test (t grouping) were used to determine statistical differences (alpha=.05). RESULTS: The laboratory scanner group had a significantly larger RMS value (4.0 +/-0.3 MUm, P<.001) and smaller percentage of measurement data points within 1 SD of mean RMS value (77.5 +/-1.0%, P<.001). The RMS values between the CBCT scanner (1.2 +/-0.3 MUm) and CBCT scanner-spray (1.1 +/-0.2 MUm) groups were not significantly different (P=.968), and the percentage of measurement data points within 1 SD of mean RMS values (90.1 +/-1.1% versus 89.5 +/-0.8%) were also not significantly different (P=.662). The numeric distance differences across 5 regions were affected by the scanning protocols (P<.001). The laboratory scanner and laboratory scanner-spray groups had significantly higher numeric distance differences at the apex of the denture border and crest of the ridge regions (P<.001). CONCLUSIONS: The CBCT scanner created more accurate and reproducible virtual edentulous casts, and the antiglare spray only significantly improved the accuracy and reproducibility of virtual edentulous casts created by the dental laboratory laser scanner. The accuracy of the virtual edentulous casts was different across 5 regions and was affected by the scanning protocols. PMID- 29703677 TI - Concomitant CALR and LNK mutations leading to essential thrombocythemia with erythrocytosis. PMID- 29703676 TI - Exposure to brominated and organophosphate ester flame retardants in U.S. childcare environments: Effect of removal of flame-retarded nap mats on indoor levels. AB - We assessed exposure to 39 brominated and 16 organophosphate ester flame retardants (FRs) from both dust and indoor air at seven childcare centres in Seattle, USA, and investigated the importance of nap mats as a source of these chemicals. Many childcare centres serving young children use polyurethane foam mats for the children's naptime. Until recently, the vast majority of these mats sold in the United States contained flame-retarded polyurethane foam to meet California Technical Bulletin 117 (TB117) requirements. With the 2013 update of TB117, allowing manufacturers to meet flammability standards without adding FRs to filling materials, FR-free nap mats have become widely available. We conducted an intervention study by actively switching out FR-treated nap mats with FR-free nap mats and measuring FR levels in indoor air and dust before and after the switch-out. The predominant FRs found in dust and indoor air were 2-ethylhexyl tetrabromobenzoate (EHTBB) and tris(1-chloro-2-propyl) phosphate (TCIPP), respectively. Nap mat samples analysed from four of the six centres contained a Firemaster(r) mixture, while one mat was predominantly treated with tris(1,3 dichloroisopropyl) phosphate (TDCIPP) and the other contained no detectable target FRs. After replacement, there was a significant decrease (p = 0.03-0.09) in median dust concentrations for bis(2-ethylhexyl) tetrabromophthalate (BEHTBP), EHTBB, tris(4-butylphenyl) phosphate (TBPP), and TDCIPP with reductions of 90%, 79%, 65%, and 42%, respectively. These findings suggest that the nap mats were an important source of these FRs to dust in the investigated childcare environments and that a campaign of swapping out flame-retarded mats for FR-free ones would reduce exposure to these chemicals. While calculated exposure estimates to the investigated FRs via inhalation, dust ingestion, and dermal absorption were below established reference dose values, they are likely underestimated when considering the toddlers' direct contact to the mats and personal cloud effects. PMID- 29703678 TI - Using a Tibial Short Extension Stem Reduces Tibial Component Loosening After Primary Total Knee Arthroplasty in Severely Varus Knees: Long-term Survival Analysis With Propensity Score Matching. AB - BACKGROUND: Patients with severe preoperative varus deformity have been reported to have high rates of loosening after total knee arthroplasty (TKA), primarily on the tibial side. This study investigated whether a short extension stem for the tibial component in severely varus knees would reduce the failure rate due to loosening on the tibial side. METHODS: Patients who underwent TKA, performed by a single surgeon using a single implant between November 1998 and January 2009, were retrospectively evaluated. Patients diagnosed with primary osteoarthritis, having a hip-knee-ankle axis greater than varus 8 degrees on preoperative long film radiographs, and postoperatively followed up for more than 2 years were included. Patients were divided into "stem" and "nonstem" groups, followed by 1:1 propensity score matching according to age, gender, body mass index, preoperative mechanical axis, and postoperative alignment. Tibial loosening rates in the 2 groups were compared. RESULTS: The study cohort included 602 patients, divided into "stem" and "nonstem" groups. Propensity score matching yielded 88 pairs of patients. Mean follow-up duration was similar in the stem and nonstem groups (109.22 vs 103.81 months, P = .451). None of the patients in the stem group, compared with 5 in the nonstem group, experienced aseptic loosening. The overall implant survival rate was significantly higher in the stem group than in the nonstem group (P = .0201). CONCLUSION: Using a short extension stem for the tibial component in primary TKA in patients with severe varus deformity greater than 8 degrees may reduce the rate of loosening of the tibial side and increase the longevity of the implant. LEVEL OF EVIDENCE: Level III. PMID- 29703679 TI - A Network Neuroscience Approach to Typical and Atypical Brain Development. AB - Human brain networks based on neuroimaging data have already proven useful in characterizing both normal and abnormal brain structure and function. However, many brain disorders are neurodevelopmental in origin, highlighting the need to go beyond characterizing brain organization in terms of static networks. Here, we review the fast-growing literature shedding light on developmental changes in network phenotypes. We begin with an overview of recent large-scale efforts to map healthy brain development, and we describe the key role played by longitudinal data including repeated measurements over a long period of follow up. We also discuss the subtle ways in which healthy brain network development can inform our understanding of disorders, including work bridging the gap between macroscopic neuroimaging results and the microscopic level. Finally, we turn to studies of three specific neurodevelopmental disorders that first manifest primarily in childhood and adolescence/early adulthood, namely psychotic disorders, attention-deficit/hyperactivity disorder, and autism spectrum disorder. In each case we discuss recent progress in understanding the atypical features of brain network development associated with the disorder, and we conclude the review with some suggestions for future directions. PMID- 29703680 TI - The greater tuberosity angle: a new predictor for rotator cuff tear. AB - BACKGROUND: The implication of scapular morphology in rotator cuff tears has been extensively studied. However, the role of the greater tuberosity (GT) should be of equal importance. The aim of this study was to propose a new radiographic marker, the GT angle (GTA), which measures the position of the GT in relation to the center of rotation of the humeral head. The hypothesis was that a higher angle value would be associated with a higher likelihood in detecting a rotator cuff tear. METHODS: During 1 year, patients were prospectively recruited from a single institution specialized shoulder clinic in 2 different groups. The patient group consisted of individuals with a degenerative rotator cuff tear involving at least the supraspinatus. The control group consisted of individuals with no rotator cuff pathology. Individuals in both groups with congenital, post traumatic, or degenerative alterations of the proximal humerus were excluded. The GTA was measured on an anteroposterior shoulder x-ray image with the arm in neutral rotation by 3 observers at 2 different times. RESULTS: The study recruited 71 patients (33 patients, 38 controls). Mean GTA value was 72.5 degrees (range, 67.6 degrees -79.2 degrees ) in patients and 65.2 degrees (range, 55.8 degrees -70.5 degrees ) for controls (P <.001). A value above 70 degrees resulted in 93-fold higher odds of detecting a rotator cuff tear (P <.001). Interobserver and intraobserver reliability were high. CONCLUSIONS: GT morphology is implicated in rotator cuff tears. The GTA is a reliable radiographic marker, with more than 70 degrees being highly predictive in detecting such lesions. PMID- 29703681 TI - The influence of preoperative opioid use on inpatient opioid requirements and discharge prescriptions after primary shoulder arthroplasty. AB - BACKGROUND: Active opioid users experience more pain and require more opioids after primary shoulder arthroplasty than non-opioid users. However, it is unknown whether discharge prescription regimens are tailored to these different postoperative opioid requirements. METHODS: We performed a retrospective analysis of a prospectively collected cohort of patients who underwent primary shoulder replacement over a 15-month period. Demographic and operative variables were collected and compared between prior opioid users and non-opioid users. Inpatient opioid requirements, daily discharge prescription regimens, total prescription quantities, and rates of persistent opioid use 6 weeks after surgery were also compared between these cohorts. RESULTS: A total of 119 patients were analyzed (mean age, 68 years; 53% men; 39.5% prior opioid users). Prior opioid users required considerably more opioids on the first (60 oral morphine equivalents [OMEs] vs 45 OMEs, P = .01) and last (42 OMEs vs 15 OMEs, P < .001) hospitalization days but were discharged with similar daily opioid regimens (90 OMEs vs 90 OMEs, P = .3), total opioid quantities (600 OMEs vs 600 OMEs, P = .24), and total pills (80 vs 60, P = .27) compared with non-opioid users. Persistent opioid use 6 weeks after surgery was 7-fold higher for prior opioid users than nonusers (71.0% vs 9.1%, P < .001). CONCLUSIONS: Daily and total opioid regimens prescribed after primary shoulder arthroplasty were similar between prior opioid users and nonusers despite large differences in their inpatient opioid requirements. Tailoring discharge opioid prescription regimens to inpatient use appears feasible and warrants further study. PMID- 29703682 TI - Case-Cohort Studies: Design and Applicability to Hand Surgery. AB - Observational studies are common research strategies in hand surgery. The case cohort design offers an efficient and resource-friendly method for risk assessment and outcomes analysis. Case-cohorts remain underrepresented in upper extremity research despite several practical and economic advantages over case control studies. This report outlines the purpose, utility, and structure of the case-cohort design and offers a sample research question to demonstrate its value to risk estimation for adverse surgical outcomes. The application of well designed case-cohort studies is advocated in an effort to improve the quality and quantity of observational research evidence in hand and upper extremity surgery. PMID- 29703683 TI - Treatment of Recurrent and Persistent Carpal Tunnel Syndrome: The Fasciocutaneous Dorsal Ulnar Artery Flap. AB - Surgical treatment of recurrent and persistent carpal tunnel syndrome by repeat carpal tunnel release combined with soft tissue nerve coverage results in a higher success rate for symptomatic relief in the presence of a scarred median nerve. Several techniques, including local pedicled flaps, transposition flaps from the distal forearm, and free flaps, have been described, but consensus regarding a preferred technique has not been reached. The dorsal ulnar artery flap or Becker flap is a local fasciocutaneous flap based on a dorsal perforating branch of the ulnar artery that can be used for soft tissue coverage of the median nerve. Advantages of this technique are the quick and easy dissection and low donor site morbidity. Studies of its use for the treatment of recurrent carpal tunnel syndrome are limited. PMID- 29703684 TI - Surgical Treatment for Chronic Tendon Mallet Injury. AB - A variety of surgical options for chronic tendon mallet fingers have been reported. There are advantages and disadvantages to current surgical approaches. We introduce a surgical treatment for chronic tendon mallet injury that involves anatomical reconstruction of the terminal tendon and lateral band with palmaris longus (PL) tendon grafting. Harvested PL tendon is folded in 2 or divided into 2 slips. The graft is attached to a remnant of the original terminal tendon at the distal interphalangeal joint. Both half-slip tendons are passed under the transverse retinacular ligament and sutured side to side to the lateral band at the level of the proximal phalanx. This surgical technique has these advantages: (1) it provides anatomical reconstruction of the terminal tendon; (2) it is indicated regardless of the condition of the terminal tendon and the interval from the initial injury; and (3) it is easy to determine the tension of the grafted tendon. Anatomical reconstruction of the terminal tendon and both lateral bands with PL tendon grafting is useful for chronic tendon mallet injury. PMID- 29703685 TI - Sex Bias in Hand Surgery Research. AB - It has been long recognized that sex-based biases related to participant inclusion exist in research. To help address inequities in research participation, the National Institutes of Health Revitalization Act was passed into law in 1993. Although this act was primarily designed to increase inclusion of females and minorities in research funded by National Institutes of Health, it has also helped raise global awareness of the value of routinely including females and minority groups in research. Subsequent work has demonstrated a continued gap in inclusion of females in medical and surgical research and female animals and cell lines in basic science research. Hand surgeons have recognized that certain conditions have greater incidence in one sex over the other, but there has been no widespread discussion on whether, when, and how sex should be used as an outcomes variable. This review investigated the recent hand surgery literature to assess for equity in inclusion of both sexes in research as well as whether outcomes were analyzed based on sex. PMID- 29703686 TI - Risks and Benefits of Adjuvant Radiotherapy After Inguinal Lymphadenectomy in Node-positive Penile Cancer: A Systematic Review by the European Association of Urology Penile Cancer Guidelines Panel. AB - CONTEXT: Management of men with penile squamous cell carcinoma (PSCC) who have high-risk features following radical inguinal lymphadenectomy (ILND) remains controversial. European Association of Urology guidelines state that adjuvant inguinal radiotherapy (AIRT) is "not generally recommended". Despite this, many centres continue to offer AIRT to a subset of men. OBJECTIVE: To undertake a systematic review of the evidence on AIRT in node-positive men with PSCC. EVIDENCE ACQUISITION: A systematic review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, with no language or date restriction. Inclusion criteria were men with PSCC, pathologically staged inguinal node positive after ILND. The intervention included ILND with AIRT compared with ILND alone. Primary outcomes were relapse-free survival and toxicity. Risk of bias assessment was undertaken. EVIDENCE SYNTHESIS: A total of 913 abstracts were identified and screened independently by two reviewers. Seven studies were eligible for inclusion: six full-text manuscripts and one conference abstract. All were retrospective series and at a high risk of bias. The selected studies included 1605 men. Indications for AIRT varied but were typically involvement of two or more inguinal nodes or extranodal extension. Regional recurrence rate following AIRT was reported at 10 91.7%. Only one study reported on toxicity. Two studies compared recurrence and survival between men who received and who did not receive AIRT, with no significant difference (p>0.05). CONCLUSIONS: The evidence indicates that men treated with AIRT do not gain benefit with respect to relapse or survival. Uncertainty remains due to the retrospective nature and high risks of bias across the evidence. Given the lack of evidence supporting AIRT, it cannot be recommended for routine practice. PATIENT SUMMARY: Men with penile cancer who have involvement of the inguinal lymph nodes are at a high risk of cancer recurrence and death. We reviewed the literature to see if radiation treatment after removal of the nodes provided benefit. We did not find any good-quality evidence supporting this treatment, and hence it cannot be recommended. PMID- 29703687 TI - Social Frailty Has a Stronger Impact on the Onset of Depressive Symptoms than Physical Frailty or Cognitive Impairment: A 4-Year Follow-up Longitudinal Cohort Study. AB - OBJECTIVES: To examine the association between each type of frailty status and the incidence rate of depressive symptoms among community-dwelling older adults. DESIGN: Prospective cohort study. SETTING: General communities in Japan. PARTICIPANTS: Participants comprised 3538 older Japanese adults. MEASUREMENTS: We assessed our participants in terms of frailty status (physical frailty, cognitive impairment, and social frailty), depressive symptoms (geriatric depression scale >=6), and other covariates, and excluded those who showed evidence of depression. Then, after a 4-year interval, we again assessed the participants for depressive symptoms. Physical frailty was defined by the Fried criteria, showing 1 or more of these were physical frailty. To screen for cognitive impairment, receiving a score below an age-education adjusted reference threshold in 1 or more tests was cognitive impairment. Finally, social frailty was defined using 5 questions, and those who answered positively to 1 or more of these were considered to have social frailty. RESULTS: After multiple imputations, the incidence rate of depressive symptoms after 4 years of follow-up was 7.2%. The incidence rates of depressive symptoms for each frailty status were as follows: 9.6% for physical frailty vs 4.6% without, 9.3% for cognitive impairment vs 6.5% without, and 12.0% for social frailty vs 5.1% without. Finally, through the application of multivariable logistic regression analysis, the incidence of depressive symptoms was found to have a significant association with social frailty (odds ratio 1.55; 95% confidence interval 1.10-2.20) but not with physical frailty or cognitive impairment. CONCLUSIONS: This study revealed that social frailty, in comparison with physical frailty and cognitive impairment, is more strongly associated with incidences of depressive symptoms among elderly. PMID- 29703688 TI - Histological and morphological characteristics of the prepuce of penis skin structure in different age groups. AB - BACKGROUND: Hypospadias is one of the most common congenital abnormalities in childhood. The number of cases has rapidly grown in recent years. OBJECTIVES: The purpose of this research was to analyze the histological and morphological differences of the foreskin samples taken from boys in three age groups. STUDY DESIGN: A total of 30 Asian patients participated in the research. Clinical materials obtained via biopsy were divided into three age groups. The first group included 10 biopsy materials of preputial skin taken from boys aged <3 years. The second included 10 similar biopsy materials from boys aged 3-5 years. The third included 10 biopsy materials taken from boys aged 5-7 years. The skin areas were taken from the dorsal, two lateral and the ventral surfaces (closer to the bridle) with dimensions of 1.0 * 1.0 cm. All removed foreskins underwent histological examination. RESULTS: Obtained results showed that the number of vein clusters in the prepuce and the cases of vessel wall fibrosis grew with age. It is worth noting that no such discoveries were made in younger boys (aged <3 years). Sample analysis showed that the number of nerve, vessel, and collagen fibers increased with age. DISCUSSION: It is believed that it is important to continue investigating the prepuce in hypospadias, in order to gain a better understanding of the abnormality depending on type. CONCLUSION: Peculiarities of prepuce in hypospadias discovered in different age groups allowed a full understanding of the pathology development processes. PMID- 29703689 TI - Comparing Accuracy of Mammography and Magnetic Resonance Imaging for Residual Calcified Lesions in Breast Cancer Patients Undergoing Neoadjuvant Systemic Therapy. AB - BACKGROUND: Neoadjuvant systemic therapy (NST) is performed to increase the rate of breast-conserving surgery in advanced breast cancer patients. Although magnetic resonance imaging (MRI) is accurate in predicting residual cancer, if calcification remains, the issue of whether to perform the surgery on the basis of the residual tumor prediction range in mammography (MMG) or MRI has not yet been elucidated. This study aimed to estimate the accuracy of predicting residual tumor after NST for residual microcalcification on mammographic and enhancing lesion on MRI. PATIENTS AND METHODS: This was a single-center, retrospective study. We included breast cancer patients who underwent NST, had microcalcifications in the post-NST MMG, and underwent surgery from January 2, 2013 to December 30, 2014 at Asan Medical Center. Patients with post-NST MMG as well as MRI were included. Final pathologic tumor size with histopathology and biomarker status were obtained postoperatively. RESULTS: In total, 151 patients were included in this study. Overall, MRI correlated better than MMG in predicting the tumor size (intraclass correlation coefficient [ICC], 0.769 vs. 0.651). For hormone receptor (HR)-positive (HR+)/HER2- subtype, MMG had higher correlation than MRI (ICC = 0.747 vs. 0.575). In HR- subtype, MRI had a strong correlation with pathology (HR-/HER2+ or triple negative (TN), ICC = 0.939 vs. 0.750), whereas MMG tended to overestimate the tumor size (HR-/HER2+ or TN, ICC = 0.543 vs. 0.479). CONCLUSION: Post-NST residual microcalcifications on MMG have a lower correlation with residual tumor size than MRI. Other than HR+/HER2- subtype, the extent of calcifications on preoperative evaluation might not be accurate in evaluating the residual extent of the tumor after NST. PMID- 29703691 TI - Hypoalbuminemia is related to inflammation rather than malnutrition in sarcoidosis. PMID- 29703690 TI - Quality-Adjusted Survival With nab-Paclitaxel Versus Standard Paclitaxel in Metastatic Breast Cancer: A Q-TWiST Analysis. AB - BACKGROUND: In this analysis we compared quality-adjusted survival outcomes between nab-paclitaxel (nab-P) and standard paclitaxel (Pac) using data from the nab-P phase III registration trial in metastatic breast cancer. PATIENTS AND METHODS: Quality-adjusted overall survival was estimated using the quality adjusted time without symptoms or toxicity (Q-TWiST) approach. Overall survival was partitioned into time without progression/Grade >= 3 adverse events (AEs) toxicity (TWiST), time with Grade >= 3 AE toxicity (TOX), and time after relapse (REL). Q-TWiST was calculated by multiplying mean time in each health state by its assigned utility (base-case utility values: time without symptoms of disease progression or toxicity of Grade >= 3 adverse events [TWiST] = 1.0, TOX = 0.5, and REL = 0.5). In threshold analyses, TOX and REL varied from 0.0 to 1.0 whereas TWiST was maintained at 1.0. Comparisons were made for the intent-to-treat population and the subset of patients initiating the study drugs as second or subsequent lines (2L+) of chemotherapy (per approved nab-P indication; 2L+ subpopulation). A >= 15% relative Q-TWiST gain (vs. mean Pac overall survival) was considered clearly clinically important. RESULTS: In the intent-to-treat population, nab-P (n = 229) versus Pac (n = 225) resulted in nonsignificant gains of 1.4 months of mean Q-TWiST (11.6 vs. 10.2 months; 95% confidence interval [CI], -0.03 to 2.8). In the 2L+ subpopulation, nab-P (n = 132) versus Pac (n = 136) resulted in a statistically significant gain of 2.2 months of mean Q-TWiST (10.5 vs. 8.4 months; 95% CI, 0.6-3.8), with a 17.1% relative Q-TWiST gain (threshold analysis range, 14.0%-19.5%, both figures significant). CONCLUSION: In its approved indication for metastatic breast cancer, nab-P showed a statistically significant and clearly clinically important improvement in quality adjusted survival time versus Pac in the 2L+ subpopulation. PMID- 29703692 TI - New and developing therapies in spinal muscular atrophy. AB - Great progress has been made in the clinical translation of several therapeutic strategies for spinal muscular atrophy (SMA), including measures to selectively address Survival Motor Neuron (SMN) protein deficiency with SMN1 gene replacement or modulation of SMN2 encoded protein levels, as well as neuroprotective approaches and supporting muscle strength and function. This review highlights these novel therapies. This is particularly vital with the advent of the first disease modifying therapy, which has brought to the fore an array of questions surrounding who, how and when to treat, and stimulated challenges in resource limited healthcare systems to streamline access for those eligible for drug therapy. The overhaul of the landscape for all those involved in SMA extends to the design of further drug trials and the necessity of multidisciplinary supportive care to potentiate the effects of disease modifying medications. The impact of respiratory complications in SMA is central to management in the current era of emerging novel therapies. These fundamental changes in our knowledge and management approach to those with SMA are explored further in this review. PMID- 29703693 TI - Hypersensitivity reactions to intravenous antibiotics in cystic fibrosis. AB - Hypersensitivity reactions to intravenous antibiotics are common in cystic fibrosis (CF). As well as causing immediate morbidity, the need for future avoidance of the causative antibiotic can have a long-term negative impact on CF management. This paper reviews the epidemiology and clinical presentation of hypersensitivity reactions in CF patients, and using an illustrative case describes a rare but severe form of delayed drug reaction for which a high index of suspicion is required. PMID- 29703694 TI - Expression of Siglec-8 is regulated by interleukin-5, and serum levels of soluble Siglec-8 may predict responsiveness of severe eosinophilic asthma to mepolizumab. PMID- 29703695 TI - The role of adenosine for IgE receptor-dependent degranulation of human peripheral basophils and skin mast cells. PMID- 29703696 TI - Evaluation of matrix factorisation approaches for muscle synergy extraction. AB - The muscle synergy concept provides a widely-accepted paradigm to break down the complexity of motor control. In order to identify the synergies, different matrix factorisation techniques have been used in a repertoire of fields such as prosthesis control and biomechanical and clinical studies. However, the relevance of these matrix factorisation techniques is still open for discussion since there is no ground truth for the underlying synergies. Here, we evaluate factorisation techniques and investigate the factors that affect the quality of estimated synergies. We compared commonly used matrix factorisation methods: Principal component analysis (PCA), Independent component analysis (ICA), Non-negative matrix factorization (NMF) and second-order blind identification (SOBI). Publicly available real data were used to assess the synergies extracted by each factorisation method in the classification of wrist movements. Synthetic datasets were utilised to explore the effect of muscle synergy sparsity, level of noise and number of channels on the extracted synergies. Results suggest that the sparse synergy model and a higher number of channels would result in better estimated synergies. Without dimensionality reduction, SOBI showed better results than other factorisation methods. This suggests that SOBI would be an alternative when a limited number of electrodes is available but its performance was still poor in that case. Otherwise, NMF had the best performance when the number of channels was higher than the number of synergies. Therefore, NMF would be the best method for muscle synergy extraction. PMID- 29703697 TI - Plaque Erosion Stabilized by Intense Antiplatelet Therapy. PMID- 29703698 TI - Accuracy of general hospital dementia diagnoses in England: Sensitivity, specificity, and predictors of diagnostic accuracy 2008-2016. AB - INTRODUCTION: Recognizing dementia in general hospitals allows for tailored care. We aimed to assess hospital dementia diagnosis accuracy, changes over time, and predictors of correct identification. METHOD: Retrospective cohort study of people over 65 years, using data from a large mental health care database as gold standard, linked to 2008-2016 English hospital data. RESULTS: In 21,387 people who had 138,455 admissions, we found sensitivity and specificity of dementia recording, respectively, to be 78.0% and 92.0% for each person's complete records, and 63.3% and 96.6% for each nonelective admission. Diagnostic sensitivity increased between 2008 and 16. Accurate general hospital recording of the presence of dementia was lower in ethnic minority groups, younger, single people, and those with physical illness. DISCUSSION: Dementia diagnosis recording in general hospitals is increasing but remains less likely in some groups. Clinicians should be aware of this inequity and have a higher index of clinical suspicion in these groups. PMID- 29703700 TI - Improved Patency of ePTFE Grafts as a Hemodialysis Access Site by Seeding Autologous Endothelial Cells Expressing Fibulin-5 and VEGF. AB - Small caliber synthetic vascular grafts used for dialysis access sites have high failure rates due to neointima formation and thrombosis. Seeding synthetic grafts with endothelial cells (ECs) provides a biocompatible surface that may prevent graft failure. We tested the use of ePTFE grafts seeded with autologous ECs expressing fibulin-5 and vascular endothelial growth factor (VEGF), as a dialysis access site in a porcine model. We connected the carotid arteries and jugular veins of 12 miniature pigs using 7-mm ePTFE grafts; five grafts were seeded with autologous venous ECs modified to express fibulin-5 and VEGF, and seven unseeded grafts were implanted at the same location and served as controls. At 6 months, after completion of angiography, the carotid arteries and jugular veins with the connecting grafts were excised and fixed. Autologous EC isolation and transduction and graft seeding were successful in all animals. At 3 months, 4 of 5 seeded grafts and 3 of 7 control grafts were patent. At 6 months, 4 of 5 (80%) seeded grafts and only 2 of 7 (29%) control grafts were patent. Seeding ePTFE vascular grafts with genetically modified ECs improved long term small caliber graft patency. The biosynthetic grafts offer a novel therapeutic modality for vascular access in hemodialysis. PMID- 29703699 TI - Oncolytic Virus Combination Therapy: Killing One Bird with Two Stones. AB - Over the last 60 years an eclectic collection of microbes has been tested in a variety of pre-clinical models as anti-cancer agents. At the forefront of this research are a number of virus-based platforms that have shown exciting activity in a variety of pre-clinical models and are collectively referred to as oncolytic viruses. Our true understanding of the potential and limitations of this therapeutic modality has been substantially advanced through clinical studies carried out over the last 25 years. Perhaps not surprising, as with all other cancer therapeutics, it has become clear that current oncolytic virus therapeutics on their own are unlikely to be effective in the majority of patients. The greatest therapeutic gains will therefore be made through thoughtful combination strategies built upon an understanding of cancer biology. PMID- 29703702 TI - Stimulation-induced reversed plus-minus syndrome: Insights into eyelid physiology. PMID- 29703701 TI - Robust Revascularization in Models of Limb Ischemia Using a Clinically Translatable Human Stem Cell-Derived Endothelial Cell Product. AB - Pluripotent stem cell-derived differentiated endothelial cells offer high potential in regenerative medicine in the cardiovascular system. With the aim of translating the use of a human stem cell-derived endothelial cell product (hESC ECP) for treatment of critical limb ischemia (CLI) in man, we report a good manufacturing practice (GMP)-compatible protocol and detailed cell tracking and efficacy data in multiple preclinical models. The clinical-grade cell line RC11 was used to generate hESC-ECP, which was identified as mostly endothelial (60% CD31+/CD144+), with the remainder of the subset expressing various pericyte/mesenchymal stem cell markers. Cell tracking using MRI, PET, and qPCR in a murine model of limb ischemia demonstrated that hESC-ECP was detectable up to day 7 following injection. Efficacy in several murine models of limb ischemia (immunocompromised/immunocompetent mice and mice with either type I/II diabetes mellitus) demonstrated significantly increased blood perfusion and capillary density. Overall, we demonstrate a GMP-compatible hESC-ECP that improved ischemic limb perfusion and increased local angiogenesis without engraftment, paving the way for translation of this therapy. PMID- 29703703 TI - Assessing the utility of the spinal instability neoplastic score (SINS) to predict fracture after conventional radiation therapy (RT) for spinal metastases. AB - PURPOSE: Assessing the stability of spinal metastases is critical for making treatment decisions. The spinal instability neoplastic score (SINS) was developed by the Spine Oncology Study Group to categorize tumor-related lesions; however, data describing its utility in predicting fractures in patients with spinal metastases are limited. The purpose of this study is to assess the validity of SINS in predicting new or worsening fracture after radiation therapy (RT) to spine metastases. METHODS AND MATERIALS: This is a retrospective analysis of patients treated with conventional RT alone (median total dose, 30 Gy; range, 8 47 Gy; median number of fractions, 10; range, 1-25) for spinal metastasis at Dana Farber/Brigham and Women's Cancer Center from 2006 to 2013. SINS was calculated for each lesion (range, 0-18). The primary endpoint was time from RT start to radiographically documented new or worsening fracture or last disease assessment. RESULTS: A total of 203 patients and 250 lesions were included in analysis. The percentages of lesions with SINS of 0 to 6, 7 to 12, and 13 to 18 were 38.8%, 54.8%, and 6.4%, respectively. Of 250 lesions, 20.4% developed new or worsening fractures; 14.4% for SINS 0 to 6, 21.2% for SINS 7 to 12, and 50.0% for SINS 13 to 18. Multivariate analysis adjusted for sex, age, Eastern Cooperative Oncology Group, histology, and total dose indicated that, compared with stable lesions (SINS 0-6), potentially unstable lesions (SINS 7-12) demonstrated a greater likelihood of new or worsening fracture that was not statistically significant (hazard ratio, 1.66; 95% confidence interval, 0.85-3.22; P = .14), and unstable lesions (SINS 13-18) were significantly more likely to develop to new or worsening fracture (hazard ratio, HR,4.37, 95% confidence interval, 1.80-10.61; P = .001). CONCLUSIONS: In this study of patients undergoing RT for spinal metastases, 20.4% developed new or worsening vertebral fractures. SINS is demonstrated to be a useful tool to assess fracture risk after RT. PMID- 29703704 TI - Dosimetric analysis of stereotactic body radiation therapy for pancreatic cancer using MR-guided Tri-60Co unit, MR-guided LINAC, and conventional LINAC-based plans. PMID- 29703705 TI - Integration of radiobiological modeling and indices in comparative plan evaluation: A study comparing VMAT and 3D-CRT in patients with NSCLC. AB - PURPOSE: The purpose of this article was to generate an algorithm to calculate radiobiological endpoints and composite indices and use them to compare volumetric modulated arc therapy (VMAT) and 3-dimensional conformal radiation therapy (3D-CRT) techniques in patients with locally advanced non-small cell lung cancer. METHODS AND MATERIALS: The study included 25 patients with locally advanced non-small cell lung cancer treated with 3D-CRT at our center between January 1, 2010, and December 31, 2014. The planner generated VMAT plans using clones of the original computed tomography scans and regions of interest volumes, which did not include the original 3D plans. Both 3D-CRT and VMAT plans were generated using the same dose-volume constraint worksheet. The dose-volume histogram parameters for planning target volume and relevant organs at risk (OAR) were reviewed. The calculation engine was written in the R programming language; the user interface was developed with the "shiny" R Web library. Dose-volume histogram data were imported into the calculation engine and tumor control probability (TCP), normal tissue complication probability (NTCP), composite cardiopulmonary toxicity index (CPTI), morbidity index: MI = ?j = 1#ofrelevantOARs(wj * NTCPj), uncomplicated TCP (UTCP=TCP*?k=1#ofOARs1-NTCPK100, and therapeutic gain (TG): ie, TG = TCP * (100 - MI) were calculated. RESULTS: TCP was better with 3D-CRT (12.62% vs 11.71%, P < .001), whereas VMAT demonstrated superior NTCP esophagus (4.45% vs 7.39%, P = .02). NTCP spinal cord (0.001% vs 0.009%, P = .001), and NTCP heart/perfusion defect (44.57% vs 56.42%, P = .016). There was no difference in NTCP lung (6.27% vs 7.62%, P = .221) and NTCP heart/pericarditis (0.001% vs 0.15%, P = .129) between 2 techniques. VMAT showed substantial improvement in morbidity index (11.06% vs. 14.31%, P = 0.01), CPTI (47.59% vs 59.41%, P = .03), TG (P = .035), and trend toward superiority in UTCP (5.89 vs 4.75, P=.057). CONCLUSION: The study highlights the utility of the radiobiological algorithm and summary indices in comparative plan evaluation and demonstrates benefits of VMAT over 3D-CRT. PMID- 29703706 TI - Accelerating epidemic control: the role of HIV self-testing. PMID- 29703708 TI - Frontal sinus schwannoma. AB - INTRODUCTION: Nasal sinus schwannomas are rare tumors, particularly in the frontal sinus. CASE REPORT: The authors report the case of a woman with left frontal sinus schwannoma discovered in a context of frontal sinusitis with orbital and ocular complications. The surgical procedure consisted of endonasal tumor resection and external drainage. DISCUSSION: The pathogenesis of frontal sinus schwannomas remains unclear. These tumors can present with a wide range of clinical and radiological signs, making them difficult to diagnosis. Surgical resection of these tumors is also complex. PMID- 29703707 TI - Reliability of HIV rapid diagnostic tests for self-testing compared with testing by health-care workers: a systematic review and meta-analysis. AB - BACKGROUND: The ability of individuals to use HIV self-tests correctly is debated. To inform the 2016 WHO recommendation on HIV self-testing, we assessed the reliability and performance of HIV rapid diagnostic tests when used by self testers. METHODS: In this systematic review and meta-analysis, we searched PubMed, PopLine, and Embase, conference abstracts, and additional grey literature between Jan 1, 1995, and April 30, 2016, for observational and experimental studies reporting on HIV self-testing performance. We excluded studies evaluating home specimen collection because patients did not interpret their own test results. We extracted data independently, using standardised extraction forms. Outcomes of interest were agreement between self-testers and health-care workers, sensitivity, and specificity. We calculated kappa to establish the level of agreement and pooled kappa estimates using a random-effects model, by approach (directly assisted or unassisted) and type of specimen (blood or oral fluid). We examined heterogeneity with the I2 statistic. FINDINGS: 25 studies met inclusion criteria (22 to 5662 participants). Quality assessment with QUADAS-2 showed studies had low risk of bias and incomplete reporting in accordance with the STARD checklist. Raw proportion of agreement ranged from 85.4% to 100%, and reported kappa ranged from fair (kappa 0.277, p<0.001) to almost perfect (kappa 0.99, n=25). Pooled kappa suggested almost perfect agreement for both types of approaches (directly assisted 0.98, 95% CI 0.96-0.99 and unassisted 0.97, 0.96 0.98; I2=34.5%, 0-97.8). Excluding two outliers, sensitivity and specificity was higher for blood-based rapid diagnostic tests (4/16) compared with oral fluid rapid diagnostic tests (13/16). The most common error that affected test performance was incorrect specimen collection (oral swab or finger prick). Study limitations included the use of different reference standards and no disaggregation of results by individuals taking antiretrovirals. INTERPRETATION: Self-testers can reliably and accurately do HIV rapid diagnostic tests, as compared with trained health-care workers. Errors in performance might be reduced through the improvement of rapid diagnostic tests for self-testing, particularly to make sample collection easier and to simplify instructions for use. FUNDING: The Bill & Melinda Gates Foundation and Unitaid. PMID- 29703709 TI - Effectiveness of Japanese encephalitis SA 14-14-2 live attenuated vaccine among Indian children: Retrospective 1:4 matched case-control study. AB - OBJECTIVES: We estimate the effectiveness of Japanese encephalitis (JE) SA 14-14 2 live-attenuated vaccination single dose campaign among children aged 1-15 years in India during 2006-07. METHODS: Acute encephalitis syndrome (AES) cases hospitalized following vaccination campaigns during the years 2006-08 were investigated retrospectively. The laboratory-confirmed JE cases were detected from the surveillance laboratories based on anti-JE IgM antibody by ELISA or viral RNA detection by RT-PCR in sera or cerebrospinal fluid. Consent was sought from parents or guardians. Four community controls were chosen randomly per case during house-to-house survey employing individual matching on age, gender and residence during the risk period. Vaccination history was enquired from the child's guardian and verified from vaccination card at home or records at health centre. Conditional logistic regression was conducted on matched case-control sets. RESULTS: We studied 149 cases and matched 596 controls. Vaccination effectiveness was 43.8% (95% CI, 1.9-67.8) based on vaccination card or record. However, effectiveness was 72.2% (95% CI, 56.2-82.4) based on parental history or card/record. Vaccination effectiveness in Assam state was higher than in Uttar Pradesh state. CONCLUSIONS: We concluded that the single subcutaneous dose of SA 14-14-2 JE vaccine provided moderate effectiveness in Indian children. PMID- 29703710 TI - Co-infection ZIKV and HSV-1 associated with meningoencephalitis: Case report and literature review. AB - A man, 26years-old, presented fever, mental confusion and a progressively worsening headache 6days prior to admission. The CSF study was suggestive of meningoencephalitis, the PCR study revealed presence of HSV-1 and ZIKV, while other immunology tests were negative. ZIKV was also identified in serum. The MRI showed temporal lobe hyper-intensity in FLAIR-weight sequence with areas of contrast enhancement and the electroencephalogram showed slow wave activity in such region. Patient was treated with acyclovir and supportive measures and had good clinical outcome at evaluation after 6 months. Neurological spectrum of ZIKV manifestations is wide, but meningoencephalitis is not frequent. Co-infection HSV 1 plus ZIKV was not yet related in humans, but there is increased cellular damage caused by association of ZIKV and herpes virus family infection. ZIKV may facilitate infection or recrudescence by other viruses or cause concurrently neuronal injury by direct or indirect mechanisms. We suggest that clinicians attempt new manifestations related to ZIKV and include this agent in differential diagnosis of neurological diseases even when other agents were identified. PMID- 29703711 TI - The prevalence of transfusion-transmitted infections and nucleic acid testing among blood donors in Majmaah, Saudi Arabia. AB - BACKGROUND: Few studies discussed the prevalence of TTIs in Saudi donor blood samples. Thus, this study investigated the prevalence of hepatitis B virus (HBV), hepatitis C virus (HCV), human immunodeficiency virus (HIV), human T-lymphotropic virus (HTLV), syphilis and malaria in such samples to determine the efficacy of conducting serological and NATs on blood donors at King Khalid General Hospital in Majmaah, Saudi Arabia. METHODS: A total of 3028 donated blood units were collected from August 2015 to March 2017. Serum samples were screened for hepatitis B surface antigens (HBsAgs), HBsAbs, total anti-core antibodies (HBcAbs), HCV antigens and HIV Ab/Ag combinations. Additionally, plasma was screened for syphilis (TPHA) and HTLV. Samples were also tested for malaria with rapid malaria antigen tests. Finally, NATs were performed for the simultaneous direct detection of HBV, HCV and HIV in each sample. RESULTS: Out of the 3028 blood samples, 10 (0.33%) reacted to HBsAgs; 12 (0.40%) reacted to HCV antigens; 4 (0.13%) reacted to HIV Ab/Ag combinations; 6 (0.20%) reacted to HTLV antibodies; 297 (9.81%) reacted to HBcAbs and 236 (7.80%) reacted to HBsAbs. Additionally, NATs showed that 14 (0.46%) reacted to NAT-HBV; 20 (0.66%) samples were reacted to NAT-HCV and 2 (0.07%) samples reacted to NAT-HIV. Finally, 16 (0.53%) were positive for syphilis. No samples were positive for malaria. CONCLUSIONS: The results indicated that NATs are more effective than serology tests for detecting TTIs. Moreover, correlations between standard serology tests and NATs indicated that using NATs could improve test sensitivities and decrease residual risks of TTIs and ensure safe blood transfusions. PMID- 29703712 TI - Combined Topical Growth Factor and Protease Inhibitor in Chronic Wound Healing: Protocol for a Randomized Controlled Proof-of-Concept Study. AB - BACKGROUND: Leg ulcers due to venous disease are chronic wounds that can take 6 or more months to heal. Growth factors have been used to try and improve this healing; however, many such studies have failed, and that is thought to be due to enzymes in the wound that degrade the growth factors and prevent them from working. OBJECTIVE: This is a proof-of-concept study that will evaluate the treatment of chronic leg ulcers with topically applied growth factors that are combined with a therapy to prevent their inactivation in the wound. This combined therapy has the potential to speed up the healing of these wounds and thereby improve the quality of life of patients and reduce the costs to the health system. METHODS: This will be a double-blind, placebo-controlled, randomized controlled proof-of-concept study comparing growth factor with protease inhibitor wound dressings to growth factors with standard wound dressings. RESULTS: The project was funded by the Canadian Institutes for Health Research and enrollment is expected to be initiated in 2018. It is expected that results will be available in 2021. CONCLUSIONS: It is expected that the results of this trial will inform as to whether modifying the wound environment through the use of protease inhibitors increases the effectiveness of topically applied growth factors in the healing of chronic wounds. TRIAL REGISTRATION: ClinicalTrials.gov NCT02845466; https://clinicaltrials.gov/ct2/show/NCT02845466 (Archived by WebCite at http://www.webcitation.org/6yOPhSBUA) PMID- 29703713 TI - The Effect of Occupational Lifting on Hypertension Risk: Protocol for a Project Using Data From the Copenhagen City Heart Study. AB - BACKGROUND: Hypertension is a major risk factor for cardiovascular disease and is responsible for 14% of all annual deaths globally. The prevalence of hypertension varies across occupational groups, possibly affected by differences in the working environment. One work-related factor that might impose a risk for hypertension is lifting due to the acute large increases in blood pressure (BP) during lifting. OBJECTIVE: The aim of this study is to explore associations between heavy occupational lifting and hypertension in the Copenhagen City Heart Study. METHODS: This study will use data from the third, fourth, and fifth examination of the Copenhagen City Heart Study. The dataset contains person-based information on health as well as a large variety of biological, environmental, and lifestyle-related factors. Using a cross-sectional design, we will investigate the association between heavy occupational lifting and hypertension, defined as using antihypertensive drugs or having a measured systolic BP (SBP) >=140 mm Hg or diastolic BP (DBP) >=90 mm Hg. Furthermore, in a prospective design, we will investigate the association between heavy occupational lifting and risk of becoming an SBP case, defined as the shift from not using antihypertensive drugs in examination n to use of antihypertensive drugs in examination n+1 or an above median delta value of SBP (SBP in examination n+1-SBP in examination n). RESULTS: In the third examination in 1991-1994, 10,135 out of 16,560 participants attended (61.20%), in the fourth examination in 2001-2003, 6237 out of 12,599 participants attended (49.50%), and in the fifth examination in 2011-2015, 4550 out of 9765 participants attended (46.59%). On the basis of the inclusion criteria of answering to the level of occupational physical activity, 5031 observations were excluded from examination 3, 2600 from examination 4, and 1621 from examination 5. Hence, the final populations for the cross-sectional and prospective analysis are assumed to include less than 7166 participants in the cross-sectional analysis and less than 1850 participants in the prospective analysis due to the additional inclusion criteria of measured BP and use of antihypertensive drugs. CONCLUSIONS: One-third of the workforce in Europe reports to carry or move heavy loads regularly during working hours (6th survey in Eurofound). Thus, if this study shows occupational lifting to increase the risk for hypertension, the prevention for hypertension can be improved. PMID- 29703714 TI - Tailored Versus Generic Knowledge Brokering to Integrate Mood Management Into Smoking Cessation Interventions in Primary Care Settings: Protocol for a Cluster Randomized Controlled Trial. AB - BACKGROUND: Both tobacco smoking and depression are major public health problems associated with high morbidity and mortality. In addition, individuals with depression are almost twice as likely to smoke and less likely to achieve smoking cessation. In the Smoking Treatment for Ontario Patients program, an established smoking cessation program in Ontario, Canada, 38% of smokers in primary care settings have current or past depression with 6-month quit rates that are significantly lower than those without depression (33% versus 40%, P<.001). Integrating self-help mood management (eg, relaxation exercises and mood monitoring) with smoking cessation treatment increases long-term quit rates by 12%-20%. However, integration in real-world settings has not been reported. It is unclear which knowledge translation strategy would be more effective for motivating clinicians to provide resources on mood management to eligible patients. OBJECTIVE: The objectives of this study are to investigate the following comparisons among depressed smokers enrolled in a smoking cessation program: 1) the effectiveness of generalized, exclusively email-based prompts versus a personalized knowledge broker in implementing mood management interventions; 2) the effectiveness of the two knowledge translation strategies on smoking quit rates; and 3) the incremental costs of the two knowledge translation strategies on the implementation of mood management interventions. METHODS: The study design is a cluster randomized controlled trial of Family Health Teams participating in the Smoking Treatment for Ontario Patients program. Family Health Teams will be randomly allocated 1:1 to receive either generalized messages (related to depression and smoking) exclusively via email (group A) or be assigned a knowledge broker who provides personalized support through phone- and email-based check-ins (group B). The primary outcome, measured at the site level, is the proportion of eligible baseline visits that result in the provision of the mood management intervention to eligible patients. RESULTS: Recruitment for the primary outcome of this study will be completed in 2018/2019. Results will be reported in 2019/2020. CONCLUSIONS: This study will address the knowledge gap in the implementation strategies (ie, email-based prompts versus a knowledge broker) of mood management interventions for smokers with depression in primary care settings. TRIAL REGISTRATION: ClinicalTrials.gov NCT03130998; https://clinicaltrials.gov/ct2/show/NCT03130998 (Archived on WebCite at www.webcitation.org/6ylyS6RTe) PMID- 29703715 TI - The Use of Virtual Reality in Patients with Eating Disorders: Systematic Review. AB - BACKGROUND: Patients with eating disorders are characterized by pathological eating habits and a tendency to overestimate their weight and body shape. Virtual reality shows promise for the evaluation and management of patients with eating disorders. This technology, when accepted by this population, allows immersion in virtual environments, assessment, and therapeutic approaches, by exposing users to high-calorie foods or changes in body shape. OBJECTIVE: To better understand the value of virtual reality, we conducted a review of the literature, including clinical studies proposing the use of virtual reality for the evaluation and management of patients with eating disorders. METHODS: We searched PubMed, PsycINFO, ScienceDirect, the Cochrane Library, Scopus, and Web of Science up to April 2017. We created the list of keywords based on two domains: virtual reality and eating disorders. We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses to identify, select, and critically appraise relevant research while minimizing bias. RESULTS: The initial database searches identified 311 articles, 149 of which we removed as duplicates. We analyzed the resulting set of 26 unique studies that met the inclusion criteria. Of these, 8 studies were randomized controlled trials, 13 were nonrandomized studies, and 5 were clinical trials with only 1 participant. Most articles focused on clinical populations (19/26, 73%), with the remainder reporting case-control studies (7/26, 27%). Most of the studies used visual immersive equipment (16/26, 62%) with a head-mounted display (15/16, 94%). Two main areas of interest emerged from these studies: virtual work on patients' body image (7/26, 27%) and exposure to virtual food stimuli (10/26, 38%). CONCLUSIONS: We conducted a broad analysis of studies on the use of virtual reality in patients with eating disorders. This review of the literature showed that virtual reality is an acceptable and promising therapeutic tool for patients with eating disorders. PMID- 29703716 TI - CIP2A- and SETBP1-mediated PP2A inhibition reveals AKT S473 phosphorylation to be a new biomarker in AML. PMID- 29703718 TI - Bcl-2 Protein Targeting by the p53/p21 Complex-Response. PMID- 29703717 TI - Fifty years of preventing and treating childhood behaviour disorders: a systematic review to inform policy and practice. AB - QUESTION: Oppositional defiant and conduct disorders (ODD and CD) start early and persist, incurring high individual and collective costs. To inform policy and practice, we therefore asked: What is the best available research evidence on preventing and treating these disorders? STUDY SELECTION AND ANALYSIS: We sought randomised controlled trials (RCTs) evaluating interventions addressing the prevention or treatment of behaviour problems in individuals aged 18 years or younger. Our criteria were tailored to identify higher-quality RCTs that were also relevant to policy and practice. We searched the CINAHL, ERIC, MEDLINE, PsycINFO and Web of Science databases, updating our initial searches in May 2017. Thirty-seven RCTs met inclusion criteria-evaluating 15 prevention programmes, 8 psychosocial treatments and 5 medications. We then conducted narrative synthesis. FINDINGS: For prevention, 3 notable programmes reduced behavioural diagnoses: Classroom-Centered Intervention; Good Behavior Game; and Fast Track. Five other programmes reduced serious behaviour symptoms such as criminal activity. Prevention benefits were long term, up to 35 years. For psychosocial treatment, Incredible Years reduced behavioural diagnoses. Three other interventions reduced criminal activity. Psychosocial treatment benefits lasted from 1 to 8 years. While 4 medications reduced post-test symptoms, all caused important adverse events. CONCLUSIONS: Considerable RCT evidence favours prevention. CLINICAL IMPLICATIONS: Effective prevention programmes should therefore be made widely available. Effective psychosocial treatments should also be provided for all children with ODD/CD. But medications should be a last resort given associated adverse events and given only short-term evidence of benefits. Policymakers and practitioners can help children and populations by acting on these findings. PMID- 29703719 TI - Sialic Acid Blockade Suppresses Tumor Growth by Enhancing T-cell-Mediated Tumor Immunity. AB - Sialic acid sugars on the surface of cancer cells have emerged as potent immune modulators that contribute to the immunosuppressive microenvironment and tumor immune evasion. However, the mechanisms by which these sugars modulate antitumor immunity as well as therapeutic strategies directed against them are limited. Here we report that intratumoral injections with a sialic acid mimetic Ac53FaxNeu5Ac block tumor sialic acid expression in vivo and suppress tumor growth in multiple tumor models. Sialic acid blockade had a major impact on the immune cell composition of the tumor, enhancing tumor-infiltrating natural killer cell and CD8+ T-cell numbers while reducing regulatory T-cell and myeloid regulatory cell numbers. Sialic acid blockade enhanced cytotoxic CD8+ T-cell mediated killing of tumor cells in part by facilitating antigen-specific T-cell tumor cell clustering. Sialic acid blockade also synergized with adoptive transfer of tumor-specific CD8+ T cells in vivo and enhanced CpG immune adjuvant therapy by increasing dendritic cell activation and subsequent CD8+ T-cell responses. Collectively, these data emphasize the crucial role of sialic acids in tumor immune evasion and provide proof of concept that sialic acid blockade creates an immune-permissive tumor microenvironment for CD8+ T-cell-mediated tumor immunity, either as single treatment or in combination with other immune based intervention strategies.Significance: Sialic acid sugars function as important modulators of the immunosuppressive tumor microenvironment that limit potent antitumor immunity.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3574/F1.large.jpg Cancer Res; 78(13); 3574-88. (c)2018 AACR. PMID- 29703720 TI - From MGUS to Multiple Myeloma, a Paradigm for Clonal Evolution of Premalignant Cells. AB - Multiple myeloma (MM) is a treatable, but incurable, malignancy of plasma cells (PC) in the bone marrow (BM). It represents the final stage in a continuum of PC dyscrasias and is consistently preceded by a premalignant phase termed monoclonal gammopathy of undetermined significance (MGUS). The existence of this well defined premalignant phase provides the opportunity to study clonal evolution of a premalignant condition into overt cancer. Unraveling the mechanisms of malignant transformation of PC could enable early identification of MGUS patients at high risk of progression and may point to novel therapeutic targets, thereby possibly delaying or preventing malignant transformation. The MGUS-to-MM progression requires multiple genomic events and the establishment of a permissive BM microenvironment, although it is generally not clear if the various microenvironmental events are causes or consequences of disease progression. Advances in gene-sequencing techniques and the use of serial paired analyses have allowed for a more specific identification of driver lesions. The challenge in cancer biology is to identify and target those lesions that confer selective advantage and thereby drive evolution of a premalignant clone. Here, we review recent advances in the understanding of malignant transformation of MGUS to MM. Cancer Res; 78(10); 2449-56. (c)2018 AACR. PMID- 29703721 TI - Bcl-2 Protein Targeting by the p53/p21 Complex-Letter. PMID- 29703722 TI - MYD88 L265P Mutation in Lymphoid Malignancies. AB - Next-generation sequencing has revealed cancer genomic landscapes, in which over 100 driver genes that, when altered by intragenic mutations, can promote oncogenesis. MYD88 is a driver gene found in hematologic B-cell malignancies. A missense mutation (L265P) changing leucine at position 265 to proline in MYD88 is found in ~90% of Waldenstrom macroglobulinemia (WM) cases and in significant portions of activated B-cell diffuse large B-cell lymphomas and IgM monoclonal gammopathy of undetermined significance. Few cancers such as WM have a single amino acid substitution in one gene like MYD88 L265P that occurs in ~90% of cases, making WM paradigmatic for study of a single causative mutation in oncogenesis. In this review, we summarize the frequency and cancer spectrum of MYD88 L265P and its downstream effects in lymphoid cancers. Malignant B cells with MYD88 L265P are likely transformed from IgM-producing B cells either in response to T-cell-independent antigens or in response to protein antigens before class switching. We also discuss therapeutic strategies that include targeting Bruton tyrosine kinase and other kinases, interfering with the assembly of MYD88 and its interacting partners, and MYD88 L265P-specific peptide-based immunotherapy. Cancer Res; 78(10); 2457-62. (c)2018 AACR. PMID- 29703723 TI - The BMJ Awards 2018: Primary Care Team of the Year. PMID- 29703725 TI - Allocating healthcare resources-seriously ill people should have priority. PMID- 29703726 TI - Government is too slow to act on NHS sustainability recommendations, say peers. PMID- 29703724 TI - Outcomes at 18 Months From a Community Health Worker and Peer Leader Diabetes Self-Management Program for Latino Adults. AB - OBJECTIVE: This study evaluated the effectiveness of a community health worker (CHW) diabetes self-management education (DSME) program, followed by two different approaches to maintain improvements in HbA1c and other clinical and patient-centered outcomes over 18 months. RESEARCH DESIGN AND METHODS: The study randomized 222 Latino adults with type 2 diabetes and poor glycemic control from a federally qualified health center to 1) a CHW-led, 6-month DSME program or 2) enhanced usual care (EUC). After the 6-month program, participants randomized to the CHW-led DSME were further randomized to 1) 12 months of CHW-delivered monthly telephone outreach (CHW-only) or 2) 12 months of weekly group sessions delivered by peer leaders (PLs) with telephone outreach to those unable to attend (CHW+PL). The primary outcome was HbA1c. Secondary outcomes were blood pressure, lipid levels, diabetes distress, depressive symptoms, understanding of diabetes self management, and diabetes social support. Assessments were conducted at baseline and at 6, 12, and 18 months. RESULTS: Participants in the CHW intervention at the 6-month follow-up had greater decreases in HbA1c (-0.45% [95% CI -0.87, -0.03]; P < 0.05) and in diabetes distress (-0.3 points [95% CI -0.6, -0.03]; P < 0.05) compared with EUC. CHW+PL participants maintained HbA1c improvements at 12 and 18 months, and CHW-only participants maintained improvements in diabetes distress at 12 and 18 months. CHW+PL participants also had significantly fewer depressive symptoms at 18 months compared with EUC (-2.2 points [95% CI -4.1, -0.3]; P < 0.05). Participants in CHW-led DSME had significant improvements in diabetes social support and in understanding of diabetes self-management at 6 months relative to EUC, but these intervention effects were not sustained at 18 months. CONCLUSIONS: This study demonstrates the effectiveness of a 6-month CHW intervention on key diabetes outcomes and of a volunteer PL program in sustaining key achieved gains. These are scalable models for health care centers in low resource settings for achieving and maintaining improvements in key diabetes outcomes. PMID- 29703728 TI - Social aetiologies of type 2 diabetes. PMID- 29703727 TI - NKG2D-based chimeric antigen receptor therapy induced remission in a relapsed/refractory acute myeloid leukemia patient. PMID- 29703729 TI - NICE recommends prostate artery embolisation as a treatment option for BPH symptoms. PMID- 29703730 TI - Screening for germline KCNQ1 and KCNE2 mutations in a set of somatotropinoma patients. AB - OBJECTIVE: Recently, mutations in KCNQ1, a potassium channel gene usually linked to long QT syndrome, were reported to cause maternally inherited gingival fibromatosis and growth hormone deficiency (GHD). Expression of the mutated KCNQ1 with the auxiliary potassium channel subunit KCNE2 was shown to reduce pituitary hormone secretion in functional experiments. Here, we investigated if germline mutations in KCNQ1 and KCNE2 were present in patients with somatotropinomas, which represent a model of growth hormone excess. DESIGN AND METHODS: KCNQ1 and KCNE2 were screened for germline mutations in 53 patients with acromegaly by Sanger sequencing. Effects of the variants were predicted by in silico tools. RESULTS: Only deep intronic and synonymous polymorphisms were detected in KCNQ1. These findings were likely insignificant based on in silico predictions and the variants' frequencies in the general population. In KCNE2, a heterozygous c.22A>G, p.(Thr8Ala) mutation with unknown significance was found in three patients. It was present in the database controls with a frequency of 0.0038. CONCLUSIONS: KCNQ1 or KCNE2 mutations do not appear to account for somatotropinoma formation, although larger patient series are needed to validate the findings. PMID- 29703731 TI - Dysregulation of sphingolipid metabolism contributes to bortezomib-induced neuropathic pain. AB - The development of chemotherapy-induced painful peripheral neuropathy is a major dose-limiting side effect of many chemotherapeutics, including bortezomib, but the mechanisms remain poorly understood. We now report that bortezomib causes the dysregulation of de novo sphingolipid metabolism in the spinal cord dorsal horn to increase the levels of sphingosine-1-phosphate (S1P) receptor 1 (S1PR1) ligands, S1P and dihydro-S1P. Accordingly, genetic and pharmacological disruption of S1PR1 with multiple S1PR1 antagonists, including FTY720, blocked and reversed neuropathic pain. Mice with astrocyte-specific alterations of S1pr1 did not develop neuropathic pain and lost their ability to respond to S1PR1 inhibition, strongly implicating astrocytes as a primary cellular substrate for S1PR1 activity. At the molecular level, S1PR1 engaged astrocyte-driven neuroinflammation and altered glutamatergic homeostasis, processes blocked by S1PR1 antagonism. Our findings establish S1PR1 as a target for therapeutic intervention and provide insight into cellular and molecular pathways. As FTY720 also shows promising anticancer potential and is FDA approved, rapid clinical translation of our findings is anticipated. PMID- 29703732 TI - Regulation of the Synthesis and Secretion of the Iron Chelator Cyclodipeptide Pulcherriminic Acid in Bacillus licheniformis. AB - The cyclodipeptide pulcherriminic acid synthesized by Bacillus licheniformis is an iron chelator and antagonizes certain pathogens by removing iron from the environment. But as the insoluble Fe-pulcherriminic acid complex cannot act as an iron carrier like siderophores, so excessive synthesized pulcherriminic acid causes iron starvation for the producer cells. At present, regulation of pulcherriminic acid synthesis and the mechanism by which B. licheniformis strikes a balance between biocontrol and self-protection from excessive iron removal remain unclear. This study provides insights into the regulation network and explained the decision mechanism of pulcherriminic acid biosynthesis. The synthetic gene cluster yvmC-cypX was directly negatively regulated by three regulators, AbrB, YvnA and YvmB. Inside the regulation network, YvnA expression was not only repressed by AbrB but also repressed by iron-limiting environments, while YvmB expression was repressed by YvnA. The transporter gene yvmA is repressed by YvmB and required for pulcherriminic acid secretion. The biosynthesis window was determined by the combined concentration of the three regulators in iron rich environment. In iron-limiting conditions, cells close the pulcherriminic acid synthesis pathway by down regulating the YvnA expression.IMPORTANCE The cyclodipeptides are widespread in nature, and exhibit a broad variety of biological and pharmacological activities. The cyclodipeptide scaffold is synthesized by non-ribosomal peptide synthetases (NRPSs) and cyclodipeptide synthases (CDPSs). At present, it is clear that CDPSs use aminoacyl tRNAs as substrates to synthesize the two peptide bonds, and the pulcherriminic acid synthase YvmC is a member of the eight identified CDPSs. However, little is known about the regulation of cyclodipeptide synthesis and secretion. In this study, we showed that the AbrB, which is considered to be the main regulator of NRPS-dependent pathways, is also involved in the regulation of CDPS genes. But AbrB is not the decisive factor of pulcherrimin acid synthesis, the expression of YvnA determines the fate of pulcherriminic acid synthesis. With this information on how CDPS gene transcription was regulated, a clearer understanding of cyclodipeptides synthesis can be developed for B. licheniformis Similar approaches could be used to augment our knowledge on CDPS in other bacteria. PMID- 29703733 TI - Glycine Betaine Monooxygenase, an Unusual Rieske-Type Oxygenase System, Catalyzes the Oxidative N-Demethylation of Glycine Betaine in Chromohalobacter salexigens DSM 3043. AB - Although some bacteria, including Chromohalobacter salexigens DSM 3043, can use glycine betaine (GB) as a sole source of carbon and energy, little information is available about the genes and their encoded proteins involved in the initial step of the GB degradation pathway. In the present study, the results of conserved domain analysis, construction of in-frame deletion mutants, and an in vivo functional complementation assay suggested that the open reading frames Csal_1004 and Csal_1005, designated bmoA and bmoB, respectively, may act as the terminal oxygenase and the ferredoxin reductase genes in a novel Rieske-type oxygenase system to convert GB to dimethylglycine in C. salexigens DSM 3043. To further verify their function, BmoA and BmoB were heterologously overexpressed in Escherichia coli, and 13C nuclear magnetic resonance analysis revealed that dimethylglycine was accumulated in E. coli BL21(DE3) expressing BmoAB or BmoA. In addition, His-tagged BmoA and BmoB were individually purified to electrophoretic homogeneity and estimated to be a homotrimer and a monomer, respectively. In vitro biochemical analysis indicated that BmoB is an NADH-dependent flavin reductase with one noncovalently bound flavin adenine dinucleotide (FAD) as its prosthetic group. In the presence of BmoB, NADH, and flavin, BmoA could aerobically degrade GB to dimethylglycine with the concomitant production of formaldehyde. BmoA exhibited strict substrate specificity for GB, and its demethylation activity was stimulated by Fe2+ Phylogenetic analysis showed that BmoA belongs to group V of the Rieske nonheme iron oxygenase (RO) family, and all the members in this group were able to use quaternary ammonium compounds as substrates.IMPORTANCE GB is widely distributed in nature. In addition to being accumulated intracellularly as a compatible solute to deal with osmotic stress, it can be utilized by many bacteria as a source of carbon and energy. However, very limited knowledge is presently available about the molecular and biochemical mechanisms for the initial step of the aerobic GB degradation pathway in bacteria. Here, we report the molecular and biochemical characterization of a novel two-component Rieske-type monooxygenase system, GB monooxygenase (BMO), which is responsible for oxidative demethylation of GB to dimethylglycine in C. salexigens DSM 3043. The results gained in this study extend our knowledge on the catalytic reaction of microbial GB degradation to dimethylglycine. PMID- 29703734 TI - An ATP-Dependent Ligase with Substrate Flexibility Involved in Assembly of the Peptidyl Nucleoside Antibiotic Polyoxin. AB - Polyoxin (POL) is an unusual peptidyl nucleoside antibiotic, in which the peptidyl moiety and nucleoside skeleton are linked by an amide bond. However, their biosynthesis remains poorly understood. Here, we report the deciphering of PolG as an ATP-dependent ligase responsible for the assembly of POL. A polG mutant is capable of accumulating multiple intermediates, including the peptidyl moiety (carbamoylpolyoxamic acid [CPOAA]) and the nucleoside skeletons (POL-C and the previously overlooked thymine POL-C). We further demonstrate that PolG employs an ATP-dependent mechanism for amide bond formation and that the generation of the hybrid nucleoside antibiotic POL-N is also governed by PolG. Finally, we determined that the deduced ATP-binding sites are functionally essential for PolG and that they are highly conserved in a number of related ATP dependent ligases. These insights have allowed us to propose a catalytic mechanism for the assembly of peptidyl nucleoside antibiotic via an acyl phosphate intermediate and have opened the way for the combinatorial biosynthesis/pathway engineering of this group of nucleoside antibiotics.IMPORTANCE POL is well known for its remarkable antifungal bioactivities and unusual structural features. Actually, elucidation of the POL assembly logic not only provides the enzymatic basis for further biosynthetic understanding of related peptidyl nucleoside antibiotics but also contributes to the rational generation of more hybrid nucleoside antibiotics via synthetic biology strategy. PMID- 29703735 TI - The catabolite repressor/activator, Cra, bridges a connection between carbon metabolism and host colonization in the plant drought resistance-promoting bacterium Pantoea alhagi LTYR-11Z. AB - Efficient root colonization is a prerequisite for application of plant growth promoting (PGP) bacteria in improving health and yield of agricultural crops. We have recently identified an endophytic bacterium Pantoea alhagi LTYR-11Z with multiple PGP properties that effectively colonizes the root system of wheat and improves its growth and drought tolerance. To identify novel regulatory genes required for wheat colonization, we screened a LTYR-11Z transposon (Tn) insertion library and found cra to be a colonization-related gene. By using RNA-seq analysis, we found that transcriptional levels of an eps operon, the ydiV gene encoding an anti-FlhD4C2 factor and the yedQ gene encoding an enzyme for synthesis of cyclic dimeric GMP (c-di-GMP) were significantly downregulated in the mutant Deltacra. Further studies demonstrated that Cra directly binds to the promoters of the eps operon, ydiV and yedQ and activates their expression, thus inhibiting motility and promoting exopolysaccharides (EPS) production and biofilm formation. Consistent with previous findings that Cra plays a role in transcriptional regulation in response to carbon source availability, the activating effects of Cra were much more pronounced when LTYR-11Z was grown within a gluconeogenic environment than when it was grown within a glycolytic environment. We further demonstrate that the ability of LTYR-11Z to colonize wheat roots is modulated by the availability of carbon sources. All together, these results uncover a novel strategy utilized by LTYR-11Z to achieve host colonization in response to carbon nutrition in the environment, in which Cra bridges a connection between carbon metabolism and colonization capacity of LTYR 11Z.IMPORTANCE Rapid and appropriate response to environmental signals is crucial for bacteria to adapt to competitive environments and to establish interactions with their hosts. Efficient colonization and persistence within the host is controlled by various regulatory factors that respond to specific environmental cues. The most common is nutrient availability. In this work, we unraveled the pivotal role of Cra in regulation of colonization ability of Pantoea alhagi LTYR 11Z in response to carbon source availability. Moreover, we identified three novel members of the Cra regulon involved in EPS synthesis, regulation of flagellar biosynthesis, and synthesis of c-di-GMP, and propose a working model to explain the Cra-mediated regulatory mechanism that links carbon metabolism to host colonization. This study elucidates the regulatory role of Cra in bacterial attachment and colonization of plants, which raises the possibility to extend our studies to other bacteria associated with plant and human health. PMID- 29703736 TI - Distribution and Diversity of Rhodopsin-Producing Microbes in the Chesapeake Bay. AB - Although sunlight is an abundant source of energy in surface environments, less than 0.5% of the available photons are captured by (bacterio)chlorophyll dependent photosynthesis in plants and bacteria. Metagenomic data indicate that 30 to 60% of the bacterial genomes in some environments encode rhodopsins, retinal-based photosystems found in heterotrophs, suggesting that sunlight may provide energy for more life than previously suspected. However, quantitative data on the number of cells that produce rhodopsins in environmental systems are limited. Here, we use total internal reflection fluorescence microscopy to show that the number of free-living microbes that produce rhodopsins increases along the salinity gradient in the Chesapeake Bay. We correlate this functional data with environmental data to show that rhodopsin abundance is positively correlated with salinity and with indicators of active heterotrophy during the day. Metagenomic and metatranscriptomic data suggest that the microbial rhodopsins in the low-salinity samples are primarily found in Actinobacteria and Bacteroidetes, while those in the high-salinity samples are associated with SAR-11 type AlphaproteobacteriaIMPORTANCE Microbial rhodopsins are common light-activated ion pumps in heterotrophs, and previous work has proposed that heterotrophic microbes use them to conserve energy when organic carbon is limiting. If this hypothesis is correct, rhodopsin-producing cells should be most abundant where nutrients are most limited. Our results indicate that in the Chesapeake Bay, rhodopsin gene abundance is correlated with salinity, and functional rhodopsin production is correlated with nitrate, bacterial production, and chlorophyll a We propose that in this environment, where carbon and nitrogen are likely not limiting, heterotrophs do not need to use rhodopsins to supplement ATP synthesis. Rather, the light-generated proton motive force in nutrient-rich environments could be used to power energy-dependent membrane-associated processes, such as active transport of organic carbon and cofactors, enabling these organisms to more efficiently utilize exudates from primary producers. PMID- 29703738 TI - Yeast Cell Wall Chitin Reduces Wine Haze Formation. AB - Protein haze formation in bottled wines is a significant concern for the global wine industry, and wine clarification before bottling is therefore a common but expensive practice. Previous studies have shown that wine yeast strains can reduce haze formation through the secretion of certain mannoproteins, but it has been suggested that other yeast-dependent haze protective mechanisms exist. On the other hand, the addition of chitin has been shown to reduce haze formation, likely because grape chitinases have been shown to be the major contributors to haze. In this study, Chardonnay grape must fermented by various yeast strains resulted in wines with different protein haze levels, indicating differences in haze-protective capacities of the strains. The cell wall chitin levels of these strains were determined, and a strong correlation between cell wall chitin levels and haze protection capability was observed. To further evaluate the mechanism of haze protection, Escherichia coli-produced green fluorescent protein (GFP)-tagged grape chitinase was shown to bind efficiently to yeast cell walls in a cell wall chitin concentration-dependent manner, while commercial chitinase was removed from synthetic wine in quantities that also correlated with the cell wall chitin levels of the strains. Our findings suggest a new mechanism of reducing wine haze, and we propose a strategy for optimizing wine yeast strains to improve wine clarification.IMPORTANCE In this study, we establish a new mechanism by which wine yeast strains can impact the protein haze formation of wines, and we demonstrate that yeast cell wall chitin binds grape chitinase in a chitin concentration-dependent manner. We also show that yeast can remove this haze forming protein from wine. Chitin has in the past been shown to efficiently reduce wine haze formation when added to the wine in high concentration as a clarifying agent. Our data suggest that the selection of yeast strains with high levels of cell wall chitin can reduce protein haze. We also investigate how yeast cell wall chitin levels are affected by environmental conditions. PMID- 29703737 TI - Quantification of Leptospira interrogans Survival in Soil and Water Microcosms. AB - Leptospira interrogans is the etiological agent of leptospirosis, a globally distributed zoonotic disease. Human infection usually occurs through skin exposure with water and soil contaminated with the urine of chronically infected animals. In this study, we aimed to quantitatively characterize the survival of Leptospira interrogans serovar Copenhageni in environmental matrices. We constructed laboratory microcosms to simulate natural conditions and determined the persistence of DNA markers in soil, mud, spring water and sewage using a quantitative PCR (qPCR) and a propidium monoazide (PMA)-qPCR assay. We found that L. interrogans does not survive at high concentrations in the tested matrices. No net growth was detected in any of the experimental conditions and in all cases the concentration of the DNA markers targeted decreased from the beginning of the experiment following an exponential decay with a decreasing decay rate over time. After 12 and 21 days of incubation the spiked concentration of 106L. interrogans cells/ml or g decreased to approximately 100 cells/ml or g in soil and spring water microcosms, respectively. Furthermore, culturable L. interrogans persisted at concentrations under the limit of detection by PMA-qPCR or qPCR for at least 16 days in soil and 28 days in spring water. Altogether, our findings suggest that the environment is not a multiplication reservoir but a temporary carrier of L. interrogans Copenhageni, although the observed prolonged persistence at low concentrations may still enable the transmission of the disease.IMPORTANCE Leptospirosis is a zoonotic disease caused by spirochetes of the genus Leptospira that primarily affects impoverished populations worldwide. Although leptospirosis is transmitted by contact with water and soil, little is known about the ability of the pathogen to survive in the environment. In this study, we quantitatively characterized the survival of L. interrogans in environmental microcosms and found that although it cannot multiply in water, soil or sewage, it survives for extended time periods (days to weeks depending on the matrix). The survival parameters obtained here may help to better understand the distribution of pathogenic Leptospira in the environment and improve the predictions of human infection risks in areas where such infections are endemic. PMID- 29703739 TI - tuf Gene Sequence Variation in Bifidobacterium longum subsp. infantis Detected in the Fecal Microbiota of Chinese Infants. AB - Members of the bacterial genus Bifidobacterium generally dominate the fecal microbiota of infants. The species Bifidobacterium longum is prevalent, but the B. longum subsp. longum and B. longum subsp. infantis strains that are known to colonize the infant bowel are not usually differentiated in microbiota investigations. These subspecies differ in their capacities to metabolize human milk oligosaccharides (HMO) and may have different ecological and symbiotic roles in humans. Quantitative PCR provides a quick analytical method by which to accurately ascertain the abundances of target species in microbiotas and microcosms. However, amplification targets in DNA extracted from samples need to be dependably differential. We evaluated the tuf gene sequence as a molecular target for quantitative PCR measurements of the abundances of B. longum subsp. infantis and B. longum subsp. longum in fecal microbiotas. This approach resulted in the detection of a tuf gene variant (operational taxonomic unit 49 [OTU49]) in Chinese infants that has sequence similarities to both B. longum subsp. infantis and B. longum subsp. longum We compared the genome sequence and growth and transcriptional characteristics of an OTU49 isolate cultured in HMO medium to those of other B. longum subsp. infantis cultures. We concluded from these studies that OTU49 belongs to B. longum subsp. infantis, that dependable quantitative PCR (qPCR) differentiation between the B. longum subspecies cannot be achieved by targeting tuf gene sequences, and that functional genes involved in carbohydrate metabolism might be better targets because they delineate ecological functions.IMPORTANCE High-throughput DNA sequencing methods and advanced bioinformatics analysis have revealed the composition and biochemical capacities of microbial communities (microbiota and microbiome), including those that inhabit the gut of human infants. However, the microbiology and function of natural ecosystems have received little attention in recent decades, so an appreciation of the dynamics of gut microbiota interactions is lacking. With respect to infants, rapid methodologies, such as quantitative PCR, are needed to determine the prevalences and proportions of different bifidobacterial species in observational and microcosm studies in order to obtain a better understanding of the dynamics of bifidobacterial nutrition and syntrophy, knowledge that might be used to manipulate the microbiota and perhaps ensure the better health of infants. PMID- 29703740 TI - Free-Chlorine Disinfection as a Selection Pressure on Norovirus. AB - Human noroviruses are excreted in feces from infected individuals and included in wastewater. It is critical to remove/inactivate them in wastewater treatment processes, particularly in the disinfection step, before release to aquatic environments. However, the high mutation rates of human noroviruses raise concerns about the emergence of strains that are less susceptible to disinfectants and can survive even after wastewater treatment. This study aimed to demonstrate the strain-dependent susceptibility of norovirus to free chlorine. A population originated from the murine norovirus strain S7-PP3, a surrogate for human noroviruses in environmental testing, was exposed to free chlorine and then propagated in a host cell. This cycle of free chlorine exposure followed by propagation in cells was repeated 10 times, and populations with lower susceptibility to free chlorine were obtained from two independent trials of chlorine exposure cycles. Open reading frame 2 (ORF2) and ORF3 of the murine norovirus genome were analyzed by next-generation sequencing, and a unique nonsynonymous mutation (corresponding to a change from phenylalanine to serine) at nucleotide (nt) 7280 in ORF3, which encodes the minor capsid protein VP2, was found in chlorine-exposed populations from both trials. It was confirmed that all of the clones from the chlorine-treated population had lower susceptibility to free chlorine than those from the control population. These results indicate that exposure to free chlorine and dilution exert different driving forces to form murine norovirus (MNV) quasispecies, and that there is a selective force to form MNV quasispecies under free chlorine exposure.IMPORTANCE This study showed that free chlorine disinfection exerted a selection pressure for murine norovirus (MNV). The strain-dependent viral susceptibility to the disinfectant elucidated in this study highlights the importance of employing less susceptible strains as representative viruses in disinfection tests, because the disinfection rate values obtained from more susceptible strains would be less useful in predicting the virus inactivation efficiency of circulating strains under practical disinfection conditions. PMID- 29703742 TI - A 31-Year-Old Woman with Consecutive Pregnancy Losses. PMID- 29703741 TI - Hyperpolarised magnetic resonance for in vivo real-time metabolic imaging. AB - Although non-invasive perfusion and viability imaging often provide the gateway to coronary revascularisation, current non-invasive imaging methods only report the surrogate markers of inducible hypoperfusion and presence or absence of myocardial scar, rather than actually visualising areas of ischaemia and/or viable myocardium. This may lead to suboptimal revascularisation decisions. Normally respiring (viable) cardiomyocytes convert pyruvate to acetyl-CoA and CO2/bicarbonate (via pyruvate dehydrogenase), but under ischaemic conditions characteristically shift this conversion to lactate (by lactate dehydrogenase). Imaging pyruvate metabolism thus has the potential to improve upon current imaging techniques. Using the novel hyperpolarisation technique of dynamic nuclear polarisation (DNP), the magnetic resonance signal of injected [1 13C]pyruvate can be transiently magnified >10 000 times over that seen in conventional MR spectroscopy, allowing the characteristic metabolic signatures of ischaemia (lactate production) and viability (CO2/bicarbonate production) to be directly imaged. As such DNP imaging of the downstream metabolism of [1 13C]pyruvate could surpass the diagnostic capabilities of contemporary ischaemia and viability testing. Here we review the technique, and with brief reference to the salient biochemistry, discuss its potential applications within cardiology. These include ischaemia and viability testing, and further characterisation of the altered metabolism seen at different stages during the natural history of heart failure. PMID- 29703743 TI - Commentary. PMID- 29703744 TI - Commentary. PMID- 29703745 TI - Correction. PMID- 29703746 TI - Serine Deficiency in a Child with Neurological Presentation, Hearing Loss, and Multiple Congenital Anomalies. PMID- 29703747 TI - Case of the Improbably High TSH. PMID- 29703748 TI - Beautiful Terraced Rice Fields in China. PMID- 29703749 TI - Rationale and Design of the CONCERT-HF Trial (Combination of Mesenchymal and c kit+ Cardiac Stem Cells As Regenerative Therapy for Heart Failure). AB - RATIONALE: Autologous bone marrow mesenchymal stem cells (MSCs) and c-kit+ cardiac progenitor cells (CPCs) are 2 promising cell types being evaluated for patients with heart failure (HF) secondary to ischemic cardiomyopathy. No information is available in humans about the relative efficacy of MSCs and CPCs and whether their combination is more efficacious than either cell type alone. OBJECTIVE: CONCERT-HF (Combination of Mesenchymal and c-kit+ Cardiac Stem Cells As Regenerative Therapy for Heart Failure) is a phase II trial aimed at elucidating these issues by assessing the feasibility, safety, and efficacy of transendocardial administration of autologous MSCs and CPCs, alone and in combination, in patients with HF caused by chronic ischemic cardiomyopathy (coronary artery disease and old myocardial infarction). METHODS AND RESULTS: Using a randomized, double-blinded, placebo-controlled, multicenter, multitreatment, and adaptive design, CONCERT-HF examines whether administration of MSCs alone, CPCs alone, or MSCs+CPCs in this population alleviates left ventricular remodeling and dysfunction, reduces scar size, improves quality of life, or augments functional capacity. The 4-arm design enables comparisons of MSCs alone with CPCs alone and with their combination. CONCERT-HF consists of 162 patients, 18 in a safety lead-in phase (stage 1) and 144 in the main trial (stage 2). Stage 1 is complete, and stage 2 is currently randomizing patients from 7 centers across the United States. CONCLUSIONS: CONCERT-HF will provide important insights into the potential therapeutic utility of MSCs and CPCs, given alone and in combination, for patients with HF secondary to ischemic cardiomyopathy. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02501811. PMID- 29703750 TI - Identification of substrates of the small RNA methyltransferase Hen1 in mouse spermatogonial stem cells and analysis of its methyl-transfer domain. AB - Small noncoding RNAs (sncRNAs) regulate many genes in eukaryotic cells. Hua enhancer 1 (Hen1) is a 2'-O-methyltransferase that adds a methyl group to the 2' OH of the 3'-terminal nucleotide of sncRNAs. The types and properties of sncRNAs may vary among different species, and the domain composition, structure, and function of Hen1 proteins differ accordingly. In mammals, Hen1 specifically methylates sncRNAs called P-element-induced wimpy testis-interacting RNAs (piRNAs). However, other types of sncRNAs that are methylated by Hen1 have not yet been reported, and the structures and the substrates of mammalian Hen1 remain unknown. Here, we report that mouse Hen1 (mHen1) performs 3'-end methylation of classical piRNAs, as well as those of most noncanonical piRNAs derived from rRNAs, small nuclear RNAs and tRNAs in murine spermatogonial stem cells. Moreover, we found that a distinct class of tRNA-derived sncRNAs are mHen1 substrates. We further determined the crystal structure of the putative methyltransferase domain of human Hen1 (HsHen1) in complex with its cofactor AdoMet at 2.0 A resolution. We observed that HsHen1 has an active site similar to that of plant Hen1. We further found that the putative catalytic domain of HsHen1 alone exhibits no activity. However, an FXPP motif at its N terminus conferred full activity to this domain, and additional binding assays suggested that the FXPP motif is important for substrate binding. Our findings shed light on its methylation substrates in mouse spermatogonial stem cells and the substrate recognition mechanism of mammalian Hen1. PMID- 29703751 TI - Gating modifier toxins isolated from spider venom: Modulation of voltage-gated sodium channels and the role of lipid membranes. AB - Gating modifier toxins (GMTs) are venom-derived peptides isolated from spiders and other venomous creatures and modulate activity of disease-relevant voltage gated ion channels and are therefore being pursued as therapeutic leads. The amphipathic surface profile of GMTs has prompted the proposal that some GMTs simultaneously bind to the cell membrane and voltage-gated ion channels in a trimolecular complex. Here, we examined whether there is a relationship among spider GMT amphipathicity, membrane binding, and potency or selectivity for voltage-gated sodium (NaV) channels. We used NMR spectroscopy and in silico calculations to examine the structures and physicochemical properties of a panel of nine GMTs and deployed surface plasmon resonance to measure GMT affinity for lipids putatively found in proximity to NaV channels. Electrophysiology was used to quantify GMT activity on NaV1.7, an ion channel linked to chronic pain. Selectivity of the peptides was further examined against a panel of NaV channel subtypes. We show that GMTs adsorb to the outer leaflet of anionic lipid bilayers through electrostatic interactions. We did not observe a direct correlation between GMT amphipathicity and affinity for lipid bilayers. Furthermore, GMT lipid bilayer interactions did not correlate with potency or selectivity for NaVs. We therefore propose that increased membrane binding is unlikely to improve subtype selectivity and that the conserved amphipathic GMT surface profile is an adaptation that facilitates simultaneous modulation of multiple NaVs. PMID- 29703752 TI - Reassignment of the human aldehyde dehydrogenase ALDH8A1 (ALDH12) to the kynurenine pathway in tryptophan catabolism. AB - The kynurenine pathway is the primary route for l-tryptophan degradation in mammals. Intermediates and side products of this pathway are involved in immune response and neurodegenerative diseases. This makes the study of enzymes, especially those from mammalian sources, of the kynurenine pathway worthwhile. Recent studies on a bacterial version of an enzyme of this pathway, 2 aminomuconate semialdehyde (2-AMS) dehydrogenase (AMSDH), have provided a detailed understanding of the catalytic mechanism and identified residues conserved for muconate semialdehyde recognition and activation. Findings from the bacterial enzyme have prompted the reconsideration of the function of a previously identified human aldehyde dehydrogenase, ALDH8A1 (or ALDH12), which was annotated as a retinal dehydrogenase based on its ability to preferentially oxidize 9-cis-retinal over trans-retinal. Here, we provide compelling bioinformatics and experimental evidence that human ALDH8A1 should be reassigned to the missing 2-AMS dehydrogenase of the kynurenine metabolic pathway. For the first time, the product of the semialdehyde oxidation by AMSDH is also revealed by NMR and high-resolution MS. We found that ALDH8A1 catalyzes the NAD+-dependent oxidation of 2-AMS with a catalytic efficiency equivalent to that of AMSDH from the bacterium Pseudomonas fluorescens Substitution of active-site residues required for substrate recognition, binding, and isomerization in the bacterial enzyme resulted in human ALDH8A1 variants with 160-fold increased Km or no detectable activity. In conclusion, this molecular study establishes an additional enzymatic step in an important human pathway for tryptophan catabolism. PMID- 29703753 TI - Imaging mycobacterial growth and division with a fluorogenic probe. AB - Control and manipulation of bacterial populations requires an understanding of the factors that govern growth, division, and antibiotic action. Fluorescent and chemically reactive small molecule probes of cell envelope components can visualize these processes and advance our knowledge of cell envelope biosynthesis (e.g., peptidoglycan production). Still, fundamental gaps remain in our understanding of the spatial and temporal dynamics of cell envelope assembly. Previously described reporters require steps that limit their use to static imaging. Probes that can be used for real-time imaging would advance our understanding of cell envelope construction. To this end, we synthesized a fluorogenic probe that enables continuous live cell imaging in mycobacteria and related genera. This probe reports on the mycolyltransferases that assemble the mycolic acid membrane. This peptidoglycan-anchored bilayer-like assembly functions to protect these cells from antibiotics and host defenses. Our probe, quencher-trehalose-fluorophore (QTF), is an analog of the natural mycolyltransferase substrate. Mycolyltransferases process QTF by diverting their normal transesterification activity to hydrolysis, a process that unleashes fluorescence. QTF enables high contrast continuous imaging and the visualization of mycolyltransferase activity in cells. QTF revealed that mycolyltransferase activity is augmented before cell division and localized to the septa and cell poles, especially at the old pole. This observed localization suggests that mycolyltransferases are components of extracellular cell envelope assemblies, in analogy to the intracellular divisomes and polar elongation complexes. We anticipate QTF can be exploited to detect and monitor mycobacteria in physiologically relevant environments. PMID- 29703755 TI - Mass-correlated rotational Raman spectra with high resolution, broad bandwidth, and absolute frequency accuracy. AB - We present mass-correlated rotational alignment spectroscopy, based on the optical excitation of a coherent rotational quantum wave and the observation of temporal wave interferences in a mass spectrometer. Combined electronic and opto mechanical delays increased the observation time and energy resolution by an order of magnitude compared with preceding time-domain measurements. Rotational transition frequencies were referenced to an external clock for accurate absolute frequency measurements. Rotational Raman spectra for six naturally occurring carbon disulfide isotopologues were resolved with 3 MHz resolution over a spectral range of 500 GHz. Rotational constants were determined with single kilohertz accuracy, competitive with state-of-the-art frequency domain measurements. PMID- 29703754 TI - KIF15 nanomechanics and kinesin inhibitors, with implications for cancer chemotherapeutics. AB - Eg5, a mitotic kinesin, has been a target for anticancer drug development. Clinical trials of small-molecule inhibitors of Eg5 have been stymied by the development of resistance, attributable to mitotic rescue by a different endogenous kinesin, KIF15. Compared with Eg5, relatively little is known about the properties of the KIF15 motor. Here, we employed single-molecule optical trapping techniques to define the KIF15 mechanochemical cycle. We also studied the inhibitory effects of KIF15-IN-1, an uncharacterized, commercially available, small-molecule inhibitor, on KIF15 motility. To explore the complementary behaviors of KIF15 and Eg5, we also scored the effects of small-molecule inhibitors on admixtures of both motors, using both a microtubule (MT)-gliding assay and an assay for cancer cell viability. We found that (i) KIF15 motility differs significantly from Eg5; (ii) KIF15-IN-1 is a potent inhibitor of KIF15 motility; (iii) MT gliding powered by KIF15 and Eg5 only ceases when both motors are inhibited; and (iv) pairing KIF15-IN-1 with Eg5 inhibitors synergistically reduces cancer cell growth. Taken together, our results lend support to the notion that a combination drug therapy employing both inhibitors may be a viable strategy for overcoming chemotherapeutic resistance. PMID- 29703756 TI - Hyping health effects: a news analysis of the 'new smoking' and the role of sitting. PMID- 29703757 TI - Telomerase promoter mutations and copy number alterations in solitary fibrous tumours. AB - AIMS: Solitary fibrous tumour (SFT) is an infrequently metastasising mesenchymal tumour defined by the NAB2-STAT6 fusion gene. Activating mutations in the telomerase reverse transcriptase (hTERT) gene promoter has been reported to associate with adverse patient outcome in SFTs. METHODS: We analysed the hTERT gene for promoter mutations and copy number alterations in 43 primary extrameningeal SFTs (9 malignant and 34 benign tumours according to WHO 2013 criteria), six local recurrences and three metastatic lesions. RESULTS: Activating -124 C>T (n=12) or -148 C>T (n=2) mutations were found in 33% of the tumours and associated with older age (P=0.006), necrosis (P=0.009), higher mitotic rate (P=0.003), nuclear atypia (P=0.002), malignant histological diagnosis (P=0.04) and worse progression-free survival (P=0.023). We also observed frequent (24%) hTERT promoter mutations in histologically benign tumours without metastasis (mean follow-up >9 years), and in 14%-18% of low-risk SFTs as determined by three risk-stratification models. Mutations were seen in 2/6 metastatic tumours and metastatic lesions. hTERT copy number gain was seen in 11/28 hTERT promoter wild-type cases. CONCLUSIONS: Activating hTERT promoter mutations associate with aggressive histopathological features, indicating a role in tumour progression. Given the comparatively high prevalence of hTERT promoter mutations in low-risk and non-metastasising lesions, further studies are required to clarify the prognostic value of hTERT promoter analysis before implementing the analysis in clinical diagnostics. PMID- 29703758 TI - Immune checkpoint inhibitor-induced gastrointestinal and hepatic injury: pathologists' perspective. AB - Immune checkpoint inhibitors (CPIs) are a relatively new class of 'miracle' dugs that have revolutionised the treatment and prognosis of some advanced-stage malignancies, and have increased the survival rates significantly. This class of drugs includes cytotoxic T lymphocyte antigen-4 inhibitors such as ipilimumab; programmed cell death protein-1 inhibitors such as nivolumab, pembrolizumab and avelumab; and programmed cell death protein ligand-1 inhibitors such as atezolizumab. These drugs stimulate the immune system by blocking the coinhibitory receptors on the T cells and lead to antitumoural response. However, a flip side of these novel drugs is immune-related adverse events (irAEs), secondary to immune-mediated process due to disrupted self-tolerance. The irAEs in the gastrointestinal (GI) tract/liver may result in diarrhoea, colitis or hepatitis. An accurate diagnosis of CPI-induced colitis and/or hepatitis is essential for optimal patient management. As we anticipate greater use of these drugs in the future given the significant clinical response, pathologists need to be aware of the spectrum of histological findings that may be encountered in GI and/or liver biopsies received from these patients, as well as differentiate them from its histopathological mimics. This present review discusses the clinical features, detailed histopathological features, management and the differential diagnosis of the luminal GI and hepatic irAEs that may be encountered secondary to CPI therapy. PMID- 29703759 TI - Evaluation of the correlation between KRAS mutated allele frequency and pathologist tumorous nuclei percentage assessment in colorectal cancer suggests a role for zygosity status. AB - Evaluation of molecular tumour heterogeneity relies on the tumorous nuclei percentage (TNP) assessment by a pathologist, which has been criticised for being inaccurate and suffering from interobserver variability. Based on the 'Big Bang theory' which states that KRAS mutation in colorectal cancer is mostly homogeneous, we investigated this issue by performing a critical analysis of the correlation of the KRAS mutant allele fraction with the TNP in 99 colorectal tumour samples with a positive KRAS mutation status as determined by next generation sequencing. Our results yield indirect evidence that the KRAS zygosity status influences the correlation between these parameters and we show that a well-trained pathologist is indeed capable of accurately assessing TNP. Our findings indicate that tumour zygosity, a feature which has largely been neglected until now, should be taken into account in future studies on (colorectal) molecular tumour heterogeneity. PMID- 29703760 TI - Peribronchial tertiary lymphoid structures persist after rituximab therapy in patients with cystic fibrosis. PMID- 29703762 TI - New links between lipid accumulation and cancer progression. AB - Individuals with elevated lipid levels are at risk for developing cardiovascular disease as well as cancer. Sterol regulatory element-binding protein transcription factors (SREBPs) are inducers of lipid synthesis. Elevated SREBPs levels are linked to cell proliferation and metastasis. Using biochemical and mouse models of cancer, Zhao et al. have discovered that nuclear SREBP-1a dependent transcription is activated by pyruvate kinase M2 in cancer cells, which promotes tumor growth. Targeting the lipogenesis pathway may therefore be a promising avenue for cancer treatment. PMID- 29703761 TI - Clonal T cell receptor gene rearrangements in coeliac disease: implications for diagnosing refractory coeliac disease. AB - AIMS: Refractory coeliac disease type II (RCDII), a rare complication of coeliac disease (CD) associated with high morbidity, requires identification of a clonal population of phenotypically aberrant intraepithelial lymphocytes (IELs) for diagnosis. However, data regarding the frequency and significance of clonal T cell receptor (TCR) gene rearrangements (TCR-GRs) in small bowel (SB) biopsies of patients without RCDII are limited. METHODS: We analysed results of TCR-GR analyses performed on SB biopsies at our institution over a 3-year period, which were obtained from eight active CD, 172 CD on gluten-free diet (GFD), 33 RCDI, and three RCDII patients and 14 patients without CD. TCR-GR patterns were divided into clonal, polyclonal and prominent clonal peaks (PCPs) and these patterns were correlated with clinical and pathological features. RESULTS: Clonal TCR-GR products were detected in biopsies from 67% of patients with RCDII, 17% of patients with RCDI and 6% of patients with GFD. PCPs were observed in all disease phases (range 12%-33%). There was no significant difference in the TCR-GR patterns between the non-RCDII disease categories (p=0.39). A higher frequency of surface CD3(-) IELs was noted in cases with clonal TCR-GR, but the PCP pattern did not show associations with any clinical or pathological feature. Persistence of clonal or PCP pattern on repeat biopsy was seen for up to 2 years without evidence of RCDII. CONCLUSIONS: Clonal TCR-GRs are not infrequent in cases lacking features of RCDII, while PCPs are frequent in all disease phases. TCR-GR results should be assessed in conjunction with immunophenotypic, histological and clinical findings for appropriate diagnosis and classification of RCD. PMID- 29703763 TI - Association of Coffee and Tea Intake with the Oral Microbiome: Results from a Large Cross-Sectional Study. AB - Background: The oral microbiota play a central role in oral health, and possibly in carcinogenesis. Research suggests that coffee and tea consumption may have beneficial health effects. We examined the associations of these common beverages with the oral ecosystem in a large cross-sectional study.Methods: We assessed oral microbiota in mouthwash samples from 938 participants in two U.S. cohorts using 16S rRNA gene sequencing. Coffee and tea intake were assessed from food frequency questionnaires. We examined associations of coffee and tea intake with overall oral microbiota diversity and composition using linear regression and permutational MANOVA, respectively, and with taxon abundance using negative binomial generalized linear models; all models adjusted for age, sex, cohort, body mass index, smoking, ethanol intake, and energy intake.Results: Higher tea intake was associated with greater oral microbiota richness (P = 0.05) and diversity (P = 0.006), and shifts in overall community composition (P = 0.002); coffee was not associated with these microbiome parameters. Tea intake was associated with altered abundance of several oral taxa; these included Fusobacteriales, Clostridiales, and Shuttleworthia satelles (higher with increasing tea) and Bifidobacteriaceae, Bergeyella, Lactobacillales, and Kingella oralis (lower with increasing tea). Higher coffee intake was only associated with greater abundance of Granulicatella and Synergistetes.Conclusions: In the largest study to date of tea and coffee consumption in relation to the oral microbiota, the microbiota of tea drinkers differed in several ways from nondrinkers.Impact: Tea-driven changes to the oral microbiome may contribute to previously observed associations between tea and oral and systemic diseases, including cancers. Cancer Epidemiol Biomarkers Prev; 27(7); 814-21. (c)2018 AACR. PMID- 29703765 TI - Role of Epidermal Growth Factor Receptor (EGFR) Inhibitors and Radiation in the Management of Brain Metastases from EGFR Mutant Lung Cancers. AB - : The growth of genotype-directed targeted therapies, such as inhibitors of the epidermal growth factor receptor (EGFR), has revolutionized treatment for some patients with oncogene-addicted lung cancer. However, as systemic control for these patients has improved, brain metastases remain an important source of morbidity and mortality. Traditional treatment for brain metastases has been radiotherapy, either whole-brain radiation or stereotactic radiosurgery. The growing availability of drugs that can cross the blood-brain barrier and have activity in the central nervous system (CNS) has led to many studies investigating whether targeted therapy can be used in combination with or in lieu of radiation. In this review, we summarize the key literature about the incidence and nature of EGFR-mutant brain metastases (EGFR BMs), the data about the activity of EGFR inhibitors in the CNS, and whether they can be used as front line therapy for brain metastases. Although initial use of tyrosine kinase inhibitors for EGFR BMs can often be an effective treatment strategy, multidisciplinary evaluation is critical, and prospective studies are needed to clarify which patients may benefit from early radiotherapy. IMPLICATIONS FOR PRACTICE: Management of brain metastases in epidermal growth factor receptor (EGFR) mutant lung cancer is a common clinical problem. The question of whether to start initial therapy with an EGFR inhibitor or radiotherapy (either whole brain radiotherapy or stereotactic radiosurgery) is controversial. The development of novel EGFR inhibitors with enhanced central nervous system (CNS) penetration is an important advance in the treatment of CNS disease. Multidisciplinary evaluation and evaluation of extracranial disease status are critical to choosing the best treatment option for each patient. PMID- 29703766 TI - Immuno-Oncology Biomarkers for Gastric and Gastroesophageal Junction Adenocarcinoma: Why PD-L1 Testing May Not Be Enough. AB - PURPOSE: The treatment of patients with advanced gastric and gastroesophageal junction (G/GEJ) adenocarcinomas has been transformed by the U.S. Food and Drug Administration approval of pembrolizumab. Tumor and adjacent tissue must stain positively for the programmed cell death ligand 1 (PD-L1) protein by companion diagnostic testing. However, some patients with PD-L1-negative tumors also benefit from pembrolizumab. High microsatellite instability (MSI) and tumor mutational load (TML) are positive predictive biomarkers for immune checkpoint inhibition (ICI) in other tumors. We sought to identify more patients who could benefit from ICI using alternative PD-L1 thresholds, MSI, and TML. METHODS: Tumor specimens underwent next-generation sequencing (NGS) and PD-L1 testing using immunohistochemistry. NGS was used to determine TML and MSI. RESULTS: We profiled 581 G/GEJ adenocarcinoma specimens. PD-L1 staining was scored for intensity (0, none; 1+, weak; 2+, moderate; 3+, strong). Using 2+ staining at a 5% threshold, 9.3% of tumors were PD-L1 positive, and using 1+ staining at 1%, 16.2% were PD-L1 positive. 6.9% of tumors had high MSI. High TML (>=17 mutations per megabase) was seen in 6.9%, and medium TML (>=7) was seen in 56.5% of tumors. Thirty (5.2%) PD L1-negative tumors at the 1+, 1% threshold had high TML or high MSI. Primary tumors had higher rates of high TML (8.8% vs. 3.9%; p = .0377) and high MSI (8.5% vs. 3.9%; p = .0471) than metastases. CONCLUSION: PD-L1 testing alone fails to detect patients who may benefit from ICI. Lower PD-L1 thresholds and TML testing should be considered in future clinical trials. IMPLICATIONS FOR PRACTICE: Pembrolizumab is approved by the U.S. Food and Drug Administration for patients with refractory gastric and gastroesophageal cancers if the tumor and adjacent tissue stain positively for the programmed cell death ligand 1 (PD-L1) protein by companion diagnostic testing. Tumor mutational load, microsatellite instability (MSI), and alternative PD-L1 testing thresholds may serve as predictive biomarkers for response to immune checkpoint inhibition, and standard PD-L1 testing will not identify all patients who may benefit from this therapy. PMID- 29703764 TI - Emerging Gene Fusion Drivers in Primary and Metastatic Central Nervous System Malignancies: A Review of Available Evidence for Systemic Targeted Therapies. AB - : Primary and metastatic tumors of the central nervous system present a difficult clinical challenge, and they are a common cause of disease progression and death. For most patients, treatment consists primarily of surgery and/or radiotherapy. In recent years, systemic therapies have become available or are under investigation for patients whose tumors are driven by specific genetic alterations, and some of these targeted treatments have been associated with dramatic improvements in extracranial and intracranial disease control and survival. However, the success of other systemic therapies has been hindered by inadequate penetration of the drug into the brain parenchyma. Advances in molecular characterization of oncogenic drivers have led to the identification of new gene fusions driving oncogenesis in some of the most common sources of intracranial tumors. Systemic therapies targeting many of these alterations have been approved recently or are in clinical development, and the ability to penetrate the blood-brain barrier is now widely recognized as an important property of such drugs. We review this rapidly advancing field with a focus on recently uncovered gene fusions and brain-penetrant systemic therapies targeting them. IMPLICATIONS FOR PRACTICE: Driver gene fusions involving receptor tyrosine kinases have been identified across a wide range of tumor types, including primary central nervous system (CNS) tumors and extracranial solid tumors that are associated with high rates of metastasis to the CNS (e.g., lung, breast, melanoma). This review discusses the systemic therapies that target emerging gene fusions, with a focus on brain-penetrant agents that will target the intracranial disease and, where present, also extracranial disease. PMID- 29703767 TI - Encephalitis with mGluR5 antibodies: Symptoms and antibody effects. AB - OBJECTIVE: To report the clinical features of 11 patients with metabotropic glutamate receptor 5 (mGluR5) antibody-associated encephalitis, immunoglobulin G (IgG) subclass, and effects of the antibodies on neuronal mGluR5 clusters. METHODS: Clinical information was retrospectively obtained from referring physicians. Antibodies to mGluR5 and IgG subclasses were determined with brain immunohistochemistry and cell-based assays. The effects of the antibodies were examined on rat hippocampal neurons with reported techniques. RESULTS: From January 2005 to May 2017, 11 patients (median age 29 years, range 6-75 years, 5 female) were identified. The main clinical features were psychiatric (10), cognitive (10), movement disorders (7), sleep dysfunction (7), and seizures (6). Median modified Rankin Scale score at the peak of the disease was 4; 4 patients required intensive care. Five patients had Hodgkin lymphoma, and 1 had small cell lung cancer. CSF showed pleocytosis (median white blood cell count 22 mm3) in all patients; brain MRI was abnormal in 5, involving limbic (1) or extralimbic (4) regions. Treatments included immunotherapy and/or oncologic therapy; at the last follow-up (median 48 months), 6 patients had complete and 5 had partial recovery. Neurologic relapse occurred in 2 patients. Antibodies were IgG1 alone (4 of 9) or in combination with IgG2 (1 of 9), IgG3 (3 of 9), or both (1). Patients' IgG caused a significant and specific decrease of cell-surface synaptic and extrasynaptic mGluR5 without altering the levels of postsynaptic density protein 95. CONCLUSIONS: Anti-mGluR5 encephalitis associates with a complex neuropsychiatric syndrome, not restricted to limbic encephalitis, and can occur without tumor. Patients respond to treatment, but relapses can occur. The antibodies have pathogenic effects altering the levels of cell-surface mGluR5. PMID- 29703769 TI - Pattern of polyphenol intake and the long-term risk of dementia in older persons. AB - OBJECTIVE: To investigate the optimal combination of dietary polyphenols associated with the long-term risk of dementia in a large prospective French cohort of older persons, the Three-City (3C) Study. METHODS: We included 1,329 older adults without dementia from the 3C study with assessment of intake of 26 polyphenol subclasses who were followed up for 12 years for dementia. Using partial least squares for Cox models, we identified a pattern of polyphenol intake associated with dementia risk. RESULTS: The pattern combined several flavonoids (dihydroflavonols, anthocyanins, isoflavonoids, flavanones), stilbenes (including resveratrol), lignans, and other subclasses (hydroxybenzaldehydes, naphthoquinones, furanocoumarins). Compared with participants in the lower quintile of pattern score, those in the higher quintile had a 50% lower risk of dementia (95% confidence interval 20%-68%, p for trend <0.01) in multivariate models. CONCLUSIONS: In this French cohort, a polyphenol pattern provided by a diet containing specific plant products (nuts, citrus, berries, leafy vegetables, soy, cereals, olive oil) accompanied by red wine and tea was associated with lower dementia risk. PMID- 29703768 TI - Long-term neuropsychological outcome following pediatric anti-NMDAR encephalitis. AB - OBJECTIVE: To provide detailed long-term outcome data of children and adolescents following pediatric anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis, to identify neuropsychological impairments, and to evaluate the influence of these factors on quality of life (QoL). METHODS: All Dutch children diagnosed with anti-NMDAR encephalitis were identified. Patients currently aged 4 years or older were included in the follow-up study, consisting of a visit to our clinic for a detailed interview and a standardized neuropsychological assessment. The following domains were included: attention, memory, language, executive functioning, QoL, and fatigue. Primary outcome measures were z scores on sustained attention, long-term verbal memory, QoL, fatigue, and working memory. RESULTS: Twenty-eight patients were included. Median Pediatric Cerebral Performance Category at last visit was 1 (interquartile range 1-2, range 1-4), and 64% (18/28) of patients returned consistently to their previous school level. Twenty-two patients were included in the cross-sectional part of the long-term follow-up study. Median follow-up time was 31 months (interquartile range 15-49, range 5-91). There were problems with sustained attention (z = -2.10, 95% confidence interval = -2.71 to -1.46, p < 0.0001) and fatigue (z = -0.96, 95% confidence interval = -1.64 to -0.28, p = 0.008). Cognitive deficits were not correlated with QoL, while fatigue was strongly correlated with QoL (r = 0.82, p < 0.0001). CONCLUSIONS: Although follow-up is often reported as "good" following pediatric anti-NMDAR encephalitis, many patients have cognitive problems and fatigue, even up until adolescence, resulting in academic achievement problems and lower QoL. For physicians, it is essential to be aware of these problems, to provide valuable advice to patients and caregivers in the acute and follow-up phase, and to consider early neuropsychological counseling. PMID- 29703770 TI - Visual stimulation leads to activation of the nociceptive trigeminal nucleus in chronic migraine. AB - OBJECTIVE: The visual system has often been described to be sensitized in migraineurs, with light being perceived as aversive or even painful. One possible explanation for this altered perception is crosslinks between the visual and the trigeminonociceptive system. Visual stimulation in chronic migraineurs on the level of the brainstem might lead to enhanced activity within the spinal trigeminal nucleus (sTN) as the main site of trigeminal pain processing within this area. METHODS: Eighteen episodic migraineurs (EM), 17 chronic migraineurs (CM), and 19 healthy controls (HC) underwent one session of high-resolution brainstem imaging during which a rotating checkerboard was presented repeatedly as a visual stimulus. Data were analyzed using SPM12 and MATLAB with the classic first-level-second-level approach of SPM. Analyses of variance were used for group comparisons. RESULTS: CM showed enhanced activation within the sTN as compared to HC. In addition, we observed enhanced activity within the right superior colliculus in CM as compared to HC. When comparing all migraineurs with headaches during scanning with all migraineurs without headaches during scanning and HC, we also found the sTN to be more strongly activated during headaches. CONCLUSION: Our data provide evidence for the existence of visual-nociceptive integration on brainstem level in chronic migraineurs. PMID- 29703771 TI - Sex differences in stroke outcomes: A case for better health care for older women. PMID- 29703772 TI - COL4A1/2 CNVs and cerebral small vessel disease: Narrowing in on the critical chromosomal region. PMID- 29703773 TI - Factors contributing to sex differences in functional outcomes and participation after stroke. AB - OBJECTIVE: To examine factors contributing to the sex differences in functional outcomes and participation restriction after stroke. METHODS: Individual participant data on long-term functional outcome or participation restriction (i.e., handicap) were obtained from 11 stroke incidence studies (1993-2014). Multivariable log-binomial regression was used to estimate the female:male relative risk (RR) of poor functional outcome (modified Rankin Scale score >2 or Barthel Index score <20) at 1 year (10 studies, n = 4,852) and 5 years (7 studies, n = 2,226). Multivariable linear regression was used to compare the mean difference (MD) in participation restriction by use of the London Handicap Scale (range 0-100 with lower scores indicating poorer outcome) for women compared to men at 5 years (2 studies, n = 617). For each outcome, study-specific estimates adjusted for confounding factors (e.g., sociodemographics, stroke-related factors) were combined with the use of random-effects meta-analysis. RESULTS: In unadjusted analyses, women experienced worse functional outcomes after stroke than men (1 year: pooled RRunadjusted 1.32, 95% confidence interval [CI] 1.18 1.48; 5 years: RRunadjusted 1.31, 95% CI 1.16-1.47). However, this difference was greatly attenuated after adjustment for age, prestroke dependency, and stroke severity (1 year: RRadjusted 1.08, 95% CI 0.97-1.20; 5 years: RRadjusted 1.05, 95% CI 0.94-1.18). Women also had greater participation restriction than men (pooled MDunadjusted -5.55, 95% CI -8.47 to -2.63), but this difference was again attenuated after adjustment for the aforementioned factors (MDadjusted -2.48, 95% CI -4.99 to 0.03). CONCLUSIONS: Worse outcomes after stroke among women were explained mostly by age, stroke severity, and prestroke dependency, suggesting these potential targets to improve the outcomes after stroke in women. PMID- 29703774 TI - [11C]PK11195 binding in Alzheimer disease and progressive supranuclear palsy. AB - OBJECTIVE: We tested whether in vivo neuroinflammation relates to the distinctive distributions of pathology in Alzheimer disease (AD) and progressive supranuclear palsy (PSP). METHODS: Sixteen patients with symptomatic AD (including amnestic mild cognitive impairment with amyloid-positive PET scan), 16 patients with PSP Richardson syndrome, and 13 age-, sex-, and education-matched healthy controls were included in this case-control study. Participants underwent [11C]PK11195 PET scanning, which was used as an in vivo index of neuroinflammation. RESULTS: [11C]PK11195 binding in the medial temporal lobe and occipital, temporal, and parietal cortices was increased in patients with AD, relative both to patients with PSP and to controls. Compared to controls, patients with PSP showed elevated [11C]PK11195 binding in the thalamus, putamen, and pallidum. [11C]PK11195 binding in the cuneus/precuneus correlated with episodic memory impairment in AD, while [11C]PK11195 binding in the pallidum, midbrain, and pons correlated with disease severity in PSP. CONCLUSIONS: Together, our results suggest that neuroinflammation has an important pathogenic role in the 2 very different human neurodegenerative disorders of AD and PSP. The increase and distribution of microglial activation suggest that immunotherapeutic strategies may be useful in slowing the progression of both diseases. PMID- 29703775 TI - Correction for Belouzard et al., "Entry and Release of Hepatitis C Virus in Polarized Human Hepatocytes". PMID- 29703776 TI - Correction for Borozan et al., "Analysis of Epstein-Barr Virus Genomes and Expression Profiles in Gastric Adenocarcinoma". PMID- 29703777 TI - Prehospital neurological deterioration in stroke. AB - BACKGROUND AND PURPOSE: Patients with stroke can experience neurological deterioration in the prehospital setting. We evaluated patients with stroke to determine factors associated with prehospital neurological deterioration (PND). METHODS: Among the Greater Cincinnati/Northern Kentucky region (population ~1.3 million), we screened all 15 local hospitals' admissions from 2010 for acute stroke and included patients aged >=20. The GCS was compared between emergency medical services (EMS) arrival and hospital arrival, with decrease >=2 points considered PND. Data obtained retrospectively included demographics, medical history and medication use, stroke subtype (eg, ischaemic stroke (IS), intracerebral haemorrhage (ICH), subarachnoid haemorrhage (SAH)) and IS subtype (eg, small vessel, large vessel, cardioembolic), seizure at onset, time intervals between symptom onset, EMS arrival and hospital arrival, EMS level of training, and blood pressure and serum glucose on EMS arrival. RESULTS: Of 2708 total patients who had a stroke, 1092 patients (median (IQR) age 74 (61-83) years; 56% women; 21% black) were analysed. PND occurred in 129 cases (12%), including 9% of IS, 24% of ICH and 16% of SAH. In multivariable analysis, black race, atrial fibrillation, haemorrhagic subtype and ALS level of transport were associated with PND. CONCLUSION: Haemorrhage and atrial fibrillation is associated with PND in stroke, and further investigation is needed to establish whether PND can be predicted. Further studies are also needed to assess whether preferential transport of patients with deterioration to hospitals equipped with higher levels of care is beneficial, identify why race is associated with deterioration and to test therapies targeting PND. PMID- 29703778 TI - Brentuximab vedotin plus bendamustine: a highly active first salvage regimen for relapsed or refractory Hodgkin lymphoma. AB - Autologous stem cell transplantation (ASCT) is standard of care for patients with Hodgkin lymphoma (HL) who have relapsed/refractory disease after frontline chemotherapy. Achievement of complete remission (CR) with pre-ASCT salvage chemotherapy predicts favorable outcomes post-ASCT. This phase 1/2 study evaluated the combination of brentuximab vedotin (BV) plus bendamustine as a first salvage regimen in relapsed/refractory HL. A total of 55 patients (28 primary refractory and 27 relapsed) were enrolled. Patients received BV (1.8 mg/kg) on day 1 and bendamustine (90 mg/m2) on days 1 and 2 of a 21-day cycle for up to 6 cycles. Patients could undergo ASCT any time after cycle 2. Following ASCT or completion of combination therapy if not proceeding to ASCT, patients could receive BV monotherapy for up to 16 cycles of total therapy. After a median of 2 cycles of combination therapy (range, 1-6), the objective response rate among 53 efficacy-evaluable patients was 92.5%, with 39 patients (73.6%) achieving CR. Forty patients underwent ASCT. Thirty-one patients (25 of whom underwent ASCT) received BV monotherapy (median, 10 cycles; range, 1-14). After a median of 20.9 months of follow-up, the estimated 2-year progression-free survival was 69.8% and 62.6% for patients who received ASCT and all patients, respectively. Thirty-one patients (56.4%) experienced infusion-related reactions (IRRs), with a majority occurring during cycle 2 of combination therapy. A protocol amendment requiring premedication reduced IRR severity. BV plus bendamustine as first salvage therapy in relapsed/refractory HL is highly active with a manageable toxicity profile. This trial was registered at www.clinicaltrials.gov as #NCT01874054. PMID- 29703779 TI - Impact of Revascularization on Absolute Myocardial Blood Flow as Assessed by Serial [15O]H2O Positron Emission Tomography Imaging: A Comparison With Fractional Flow Reserve. AB - BACKGROUND: The main goal of coronary revascularization is to restore myocardial perfusion in case of ischemia, causing coronary artery disease. Yet, little is known on the effect of revascularization on absolute myocardial blood flow (MBF). Therefore, the present prospective study assesses the impact of coronary revascularization on absolute MBF as measured by [15O]H2O positron emission tomography and fractional flow reserve (FFR) in patients with stable coronary artery disease. METHODS AND RESULTS: Fifty-three patients (87% men, mean age 58.7+/-9.0 years) with suspected coronary artery disease were included prospectively. All patients underwent serial [15O]H2O positron emission tomography perfusion imaging at baseline and after revascularization by either percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery. FFR was routinely measured at baseline and directly post-PCI. After revascularization, regional rest and stress MBF improved from 0.77+/-0.16 to 0.86+/-0.25 mL/min/g and from 1.57+/-0.59 to 2.48+/-0.91 mL/min/g, respectively, yielding an increase in coronary flow reserve from 2.02+/-0.69 to 2.94+/-0.94 (P<0.01 for all). Mean FFR at baseline improved post-PCI from 0.61+/-0.17 to 0.89+/-0.08 (P<0.01). After PCI, an increase in FFR paralleled improvement in absolute myocardial perfusion as reflected by stress MBF and coronary flow reserve (r = 0.74 and r = 0.71, respectively, P<0.01 for both). PCI demonstrated a greater improvement of regional stress MBF as compared with coronary artery bypass graft surgery (1.14+/-1.11 versus 0.66+/-0.69 mL/min/g, respectively, P=0.02). However, patients undergoing bypass grafting had a more advanced stage of coronary artery disease and more incomplete revascularizations. CONCLUSION: Successful coronary revascularization has a significant and positive impact on absolute myocardial perfusion as assessed by serial quantitative [15O]H2O positron emission tomography. Notably, improvement of FFR after PCI was directly related to the increase in hyperemic MBF. PMID- 29703780 TI - Prenatal Diagnosis of Distal Aortopulmonary Window With Type A Aortic Arch Interruption With 4-Dimensional Spatiotemporal Image Correlation Rendering. PMID- 29703782 TI - Adipose and skeletal muscle thermogenesis: studies from large animals. AB - The balance between energy intake and energy expenditure establishes and preserves a 'set-point' body weight. The latter is comprised of three major components including metabolic rate, physical activity and thermogenesis. Thermogenesis is defined as the cellular dissipation of energy via heat production. This process has been extensively characterised in brown adipose tissue (BAT), wherein uncoupling protein 1 (UCP1) creates a proton leak across the inner mitochondrial membrane, diverting protons away from ATP synthesis and resulting in heat dissipation. In beige adipocytes and skeletal muscle, thermogenesis can occur independent of UCP1. Beige adipocytes have been shown to produce heat via UCP1 as well as via both futile creatine and calcium cycling pathways. On the other hand, the UCP1 homologue UCP3 is abundant in skeletal muscle and post-prandial thermogenesis has been associated with UCP3 and the futile calcium cycling. This review will focus on the differential contributions of adipose tissue and skeletal muscle in determining total thermogenic output and energy expenditure in large mammals. Sheep and pigs do not have a circumscribed brown fat depot but rather possess white fat depots that contain brown and beige adipocytes interspersed amongst white adipose tissue. This is representative of humans, where brown, beige and white adipocytes have been identified in the neck and supraclavicular regions. This review will describe the mechanisms of thermogenesis in pigs and sheep and the relative roles of skeletal muscle and adipose tissue thermogenesis in controlling body weight in larger mammals. PMID- 29703781 TI - Simultaneous sequencing of coding and noncoding RNA reveals a human transcriptome dominated by a small number of highly expressed noncoding genes. AB - Comparing the abundance of one RNA molecule to another is crucial for understanding cellular functions but most sequencing techniques can target only specific subsets of RNA. In this study, we used a new fragmented ribodepleted TGIRT sequencing method that uses a thermostable group II intron reverse transcriptase (TGIRT) to generate a portrait of the human transcriptome depicting the quantitative relationship of all classes of nonribosomal RNA longer than 60 nt. Comparison between different sequencing methods indicated that FRT is more accurate in ranking both mRNA and noncoding RNA than viral reverse transcriptase based sequencing methods, even those that specifically target these species. Measurements of RNA abundance in different cell lines using this method correlate with biochemical estimates, confirming tRNA as the most abundant nonribosomal RNA biotype. However, the single most abundant transcript is 7SL RNA, a component of the signal recognition particle. Structured noncoding RNAs (sncRNAs) associated with the same biological process are expressed at similar levels, with the exception of RNAs with multiple functions like U1 snRNA. In general, sncRNAs forming RNPs are hundreds to thousands of times more abundant than their mRNA counterparts. Surprisingly, only 50 sncRNA genes produce half of the non-rRNA transcripts detected in two different cell lines. Together the results indicate that the human transcriptome is dominated by a small number of highly expressed sncRNAs specializing in functions related to translation and splicing. PMID- 29703783 TI - A High-Quality Reference Genome for the Invasive Mosquitofish Gambusia affinis Using a Chicago Library. AB - The western mosquitofish, Gambusia affinis, is a freshwater poecilid fish native to the southeastern United States but with a global distribution due to widespread human introduction. Gambusia affinis has been used as a model species for a broad range of evolutionary and ecological studies. We sequenced the genome of a male G. affinis to facilitate genetic studies in diverse fields including invasion biology and comparative genetics. We generated Illumina short read data from paired-end libraries and in vitro proximity-ligation libraries. We obtained 54.9* coverage, N50 contig length of 17.6 kb, and N50 scaffold length of 6.65 Mb. Compared to two other species in the Poeciliidae family, G. affinis has slightly fewer genes that have shorter total, exon, and intron length on average. Using a set of universal single-copy orthologs in fish genomes, we found 95.5% of these genes were complete in the G. affinis assembly. The number of transposable elements in the G. affinis assembly is similar to those of closely related species. The high-quality genome sequence and annotations we report will be valuable resources for scientists to map the genetic architecture of traits of interest in this species. PMID- 29703784 TI - Ancestral State Reconstruction of the Apoptosis Machinery in the Common Ancestor of Eukaryotes. AB - Apoptotic cell death is a type of eukaryotic cell death. In animals, it regulates development, is involved in cancer suppression, and causes cell death during pathological aging of neuronal cells in neurodegenerative diseases such as Alzheimer's. Mitochondrial apoptotic-like cell death, a form of primordial apoptosis, also occurs in unicellular organisms. Here, we ask the question why the apoptosis machinery has been acquired and maintained in unicellular organisms and attempt to answer it by performing ancestral state reconstruction. We found indications of an ancient evolutionary arms race between protomitochondria and host cells, leading to the establishment of the currently existing apoptotic pathways. According to this reconstruction, the ancestral protomitochondrial apoptosis machinery contained both caspases and metacaspases, four types of apoptosis induction factors (AIFs), both fungal and animal OMI/HTR proteases, and various apoptotic DNases. This leads to the prediction that in extant unicellular eukaryotes, the apoptotic factors are involved in mitochondrial respiration and their activity is needed exclusively in aerobic conditions. We test this prediction experimentally using yeast and find that a loss of the main apoptotic factors is beneficial under anaerobic conditions yet deleterious under aerobic conditions in the absence of lethal stimuli. We also point out potential medical implications of these findings. PMID- 29703785 TI - A Cloning-Free Method for CRISPR/Cas9-Mediated Genome Editing in Fission Yeast. AB - The CRISPR/Cas9 system, which relies on RNA-guided DNA cleavage to induce site specific DNA double-strand breaks, is a powerful tool for genome editing. This system has been successfully adapted for the fission yeast Schizosaccharomyces pombe by expressing Cas9 and the single-guide RNA (sgRNA) from a plasmid. In the procedures published to date, the cloning step that introduces a specific sgRNA target sequence into the plasmid is the most tedious and time-consuming. To increase the efficiency of applying the CRISPR/Cas9 system in fission yeast, we here developed a cloning-free procedure that uses gap repair in fission yeast cells to assemble two linear DNA fragments, a gapped Cas9-encoding plasmid and a PCR-amplified sgRNA insert, into a circular plasmid. Both fragments contain only a portion of the ura4 or bsdMX marker so that only the correctly assembled plasmid can confer uracil prototrophy or blasticidin resistance. We show that this gap-repair-based and cloning-free CRISPR/Cas9 procedure permits rapid and efficient point mutation knock-in, endogenous N-terminal tagging, and genomic sequence deletion in fission yeast. PMID- 29703787 TI - Dissociation between CSD-Evoked Metabolic Perturbations and Meningeal Afferent Activation and Sensitization: Implications for Mechanisms of Migraine Headache Onset. AB - The onset of the headache phase during attacks of migraine with aura, which occur in ~30% of migraineurs, is believed to involve cortical spreading depression (CSD) and the ensuing activation and sensitization of primary afferent neurons that innervate the intracranial meninges, and their related large vessels. The mechanism by which CSD enhances the activity and mechanosensitivity of meningeal afferents remains poorly understood, but may involve cortical metabolic perturbations. We used extracellular single-unit recording of meningeal afferent activity and monitored changes in cortical blood flow and tissue partial pressure of oxygen (tpO2) in anesthetized male rats to test whether the prolonged cortical hypoperfusion and reduction in tissue oxygenation that occur in the wake of CSD contribute to meningeal nociception. Suppression of CSD-evoked cortical hypoperfusion with the cyclooxygenase inhibitor naproxen blocked the reduction in cortical tpO2, but had no effect on the activation of meningeal afferents. Naproxen, however, distinctly prevented CSD-induced afferent mechanical sensitization. Counteracting the CSD-evoked persistent hypoperfusion and reduced tpO2 by preemptively increasing cortical blood flow using the ATP-sensitive potassium [K(ATP)] channel opener levcromakalim did not inhibit the sensitization of meningeal afferents, but prevented their activation. Our data show that the cortical hypoperfusion and reduction in tpO2 that occur in the wake of CSD can be dissociated from the activation and mechanical sensitization of meningeal afferent responses, suggesting that the metabolic changes do not contribute directly to these neuronal nociceptive responses.SIGNIFICANCE STATEMENT Cortical spreading depression (CSD)-evoked activation and mechanical sensitization of meningeal afferents is thought to mediate the headache phase in migraine with aura. We report that blocking the CSD-evoked cortical hypoperfusion and reduced tissue partial pressure of oxygen by cyclooxygenase inhibition is associated with the inhibition of the afferent sensitization, but not their activation. Normalization of these CSD-evoked metabolic perturbations by activating K(ATP) channels is, however, associated with the inhibition of afferent activation but not sensitization. These results question the contribution of cortical metabolic perturbations to the triggering mechanism underlying meningeal nociception and the ensuing headache in migraine with aura, further point to distinct mechanisms underlying the activation and sensitization of meningeal afferents in migraine, and highlight the need to target both processes for an effective migraine therapy. PMID- 29703786 TI - Drift in Neural Population Activity Causes Working Memory to Deteriorate Over Time. AB - Short-term memories are thought to be maintained in the form of sustained spiking activity in neural populations. Decreases in recall precision observed with increasing number of memorized items can be accounted for by a limit on total spiking activity, resulting in fewer spikes contributing to the representation of each individual item. Longer retention intervals likewise reduce recall precision, but it is unknown what changes in population activity produce this effect. One possibility is that spiking activity becomes attenuated over time, such that the same mechanism accounts for both effects of set size and retention duration. Alternatively, reduced performance may be caused by drift in the encoded value over time, without a decrease in overall spiking activity. Human participants of either sex performed a variable-delay cued recall task with a saccadic response, providing a precise measure of recall latency. Based on a spike integration model of decision making, if the effects of set size and retention duration are both caused by decreased spiking activity, we would predict a fixed relationship between recall precision and response latency across conditions. In contrast, the drift hypothesis predicts no systematic changes in latency with increasing delays. Our results show both an increase in latency with set size, and a decrease in response precision with longer delays within each set size, but no systematic increase in latency for increasing delay durations. These results were quantitatively reproduced by a model based on a limited neural resource in which working memories drift rather than decay with time.SIGNIFICANCE STATEMENT Rapid deterioration over seconds is a defining feature of short-term memory, but what mechanism drives this degradation of internal representations? Here, we extend a successful population coding model of working memory by introducing possible mechanisms of delay effects. We show that a decay in neural signal over time predicts that the time required for memory retrieval will increase with delay, whereas a random drift in the stored value predicts no effect of delay on retrieval time. Testing these predictions in a multi-item memory task with an eye movement response, we identified drift as a key mechanism of memory decline. These results provide evidence for a dynamic spiking basis for working memory, in contrast to recent proposals of activity-silent storage. PMID- 29703788 TI - Primary Tactile Thalamus Spiking Reflects Cognitive Signals. AB - Little is known about whether information transfer at primary sensory thalamic nuclei is modified by behavioral context. Here we studied the influence of previous decisions/rewards on current choices and preceding spike responses of ventroposterior medial thalamus (VPm; the primary sensory thalamus in the rat whisker-related tactile system). We trained head-fixed rats to detect a ramp-like deflection of one whisker interspersed within ongoing white noise stimulation. Using generative modeling of behavior, we identify two task-related variables that are predictive of actual decisions. The first reflects task engagement on a local scale ("trial history": defined as the decisions and outcomes of a small number of past trials), whereas the other captures behavioral dynamics on a global scale ("satiation": slow dynamics of the response pattern along an entire session). Although satiation brought about a slow drift from Go to NoGo decisions during the session, trial history was related to local (trial-by-trial) patterning of Go and NoGo decisions. A second model that related the same predictors first to VPm spike responses, and from there to decisions, indicated that spiking, in contrast to behavior, is sensitive to trial history but relatively insensitive to satiation. Trial history influences VPm spike rates and regularity such that a history of Go decisions would predict fewer noise-driven spikes (but more regular ones), and more ramp-driven spikes. Neuronal activity in VPm, thus, is sensitive to local behavioral history, and may play an important role in higher-order cognitive signaling.SIGNIFICANCE STATEMENT It is an important question for perceptual and brain functions to find out whether cognitive signals modulate the sensory signal stream and if so, where in the brain this happens. This study provides evidence that decision and reward history can already be reflected in the ascending sensory pathway, on the level of first order sensory thalamus. Cognitive signals are relayed very selectively such that only local trial history (spanning a few trials) but not global history (spanning an entire session) are reflected. PMID- 29703789 TI - Bacteria profile and antibiogram of the bacteria isolated from the exposed pulp of dog canine teeth. AB - Twenty-seven microbiological samples were taken from root canals (RC) of the canine teeth of 20 dogs where the pulps were non-vital and exposed due to complicated crown fractures. These pulps were cultured for aerobic/anaerobic bacteria. Antimicrobial susceptibility of isolates was determined using the Kirby Bauer diffusion test. A total of 49 cultivable isolates, belonging to 27 different microbial species and 18 different genera, were recovered from the 27 RCs sampled. Twenty (40.81 per cent) of the cultivable isolates were Gram positive while 29 (59.19 per cent) were Gram negative. Facultative anaerobes were the most common bacteria (77.56 per cent). Aerobic isolates represented 18.36 per cent, and strict anaerobes 4.08 per cent. The antimicrobials with the highest in vitro efficacy were gentamicin (100 per cent) and enrofloxacin (93.32 per cent). PMID- 29703790 TI - Impact of sustained virological response on the extrahepatic manifestations of chronic hepatitis C: a meta-analysis. AB - BACKGROUND AND AIMS: Extrahepatic manifestations of HCV are responsible for morbidity and mortality in many chronically infected patients. New, interferon free antiviral treatment regimens, which present the opportunity to treat all HCV infected patients, call for a better understanding of the benefits of treating non-cirrhotic chronically infected individuals. METHODS: A systematic review was conducted. Identified studies from targeted database searches on Embase and Medline were screened. The methodological quality of the included publications was evaluated. Random-effect model meta-analyses were performed. Strength of evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. RESULTS: Data were extracted from a total of 48 identified studies. Achieving sustained virological response (SVR) was associated with reduced extrahepatic mortality (vs no SVR, OR 0.44 (95% CI 0.28 to 0.67)). SVR was associated with higher complete remissions in patients with cryoglobulinemia vasculitis (OR 20.76 (6.73 to 64.05)) and a higher objective response in those with malignant B-cell lymphoproliferative diseases (OR 6.49 (2.02 to 20.85)). Achieving SVR was also associated with reduced insulin resistance at follow-up (OR 0.42 (0.33 to 0.53)) and a significant protective effect on the incidence of diabetes (OR 0.34 (0.21 to 0.56)). Lack of randomised data comparing SVR versus non-SVR patients for the relevant extrahepatic indications attenuated these analyses. CONCLUSION: Antiviral therapy can reduce extrahepatic manifestations related to HCV when SVR is achieved. Higher quality data, and reporting over longer follow-up periods, will be required to thoroughly explore comprehensive HCV treatment strategies. PMID- 29703791 TI - Human gastric cancer modelling using organoids. AB - OBJECTIVE: Gastric cancer is the second leading cause of cancer-related deaths and the fifth most common malignancy worldwide. In this study, human and mouse gastric cancer organoids were generated to model the disease and perform drug testing to delineate treatment strategies. DESIGN: Human gastric cancer organoid cultures were established, samples classified according to their molecular profile and their response to conventional chemotherapeutics tested. Targeted treatment was performed according to specific druggable mutations. Mouse gastric cancer organoid cultures were generated carrying molecular subtype-specific alterations. RESULTS: Twenty human gastric cancer organoid cultures were established and four selected for a comprehensive in-depth analysis. Organoids demonstrated divergent growth characteristics and morphologies. Immunohistochemistry showed similar characteristics to the corresponding primary tissue. A divergent response to 5-fluoruracil, oxaliplatin, irinotecan, epirubicin and docetaxel treatment was observed. Whole genome sequencing revealed a mutational spectrum that corresponded to the previously identified microsatellite instable, genomic stable and chromosomal instable subtypes of gastric cancer. The mutational landscape allowed targeted therapy with trastuzumab for ERBB2 alterations and palbociclib for CDKN2A loss. Mouse cancer organoids carrying Kras and Tp53 or Apc and Cdh1 mutations were characterised and serve as model system to study the signalling of induced pathways. CONCLUSION: We generated human and mouse gastric cancer organoids modelling typical characteristics and altered pathways of human gastric cancer. Successful interference with activated pathways demonstrates their potential usefulness as living biomarkers for therapy response testing. PMID- 29703792 TI - The APOL1 Long-Term Kidney Transplantation Outcomes Network-APOLLO. PMID- 29703794 TI - TIRADS score is of limited clinical value for risk stratification of indeterminate cytological results. AB - CONTEXT: Thyroid nodules with cytological indeterminate results represent a daily and recurrent issue for patient management. OBJECTIVE: The primary aim of our study was to determine if TIRADS (Thyroid Imaging Reporting and Data System) could be used to stratify the malignancy risk of these nodules and to help in their clinical management. Secondary objective was to estimate if this risk stratification would change after reclassification of encapsulated non-invasive follicular variant of papillary carcinomas (FVPTC) as non-invasive follicular thyroid neoplasm (NIFTP). PATIENTS AND METHODS: Single-center retrospective study of a cohort of 602 patients who were referred for ultrasound-guided fine-needle aspiration from January 2010 to December 2016 with an indeterminate cytological result and in whom histological results after surgery were available. TIRADS score was prospectively determined for all patients included. Nodules that had been classified as FVPTC were submitted to a rereading of histological report and reclassified as NIFTP when judged relevant. A table of malignancy risk crossing Bethesda and TIRADS results was built before and after this reclassification. RESULTS: The study included 602 cytologically indeterminate nodules. TIRADS score was positively correlated with the malignancy rate (P < 0.0001). Risk stratification with TIRADS was significant only in Bethesda V nodules (P = 0.0004). However, the risk of malignancy in this Bethesda V category was always above 45%, whatever the TIRADS score. CONCLUSION: For a clinician facing an indeterminate cytological result for a thyroid nodule, return to TIRADS score is of limited value in most conditions to rule in or rule out malignancy and to guide subsequent management of patients. PMID- 29703793 TI - Liraglutide increases IVF pregnancy rates in obese PCOS women with poor response to first-line reproductive treatments: a pilot randomized study. AB - OBJECTIVE: Glucagon-like peptide-1 (GLP-1) has been investigated in regulation of reproductive system in animal models. The potential impact of short-term preconception intervention with liraglutide on fertility potential in polycystic ovary syndrome (PCOS) has not been evaluated yet. DESIGN: A prospective randomized open-label study was conducted in 28 infertile obese PCOS patients (age: 31.07 +/- 4.75, BMI: 36.7 +/- 3.5 kg/m2, mean +/- s.d.). They were assigned to metformin (MET) 1000 mg BID or to MET 1000 mg BID combined with low-dose liraglutide 1.2 mg QD s.c. (COMBI) for 12 weeks. Ovarian stimulation protocol was started after a 4-week medication-free period. METHODS: The in vitro fertilization pregnancy rate (PR) was defined as the number of clinical pregnancies confirmed by ultrasound visualization of the fetal cardiac activity, divided by the total number of cycles performed or embryo transfers (ET). The spontaneous PR was followed for 12 months. RESULTS: Patients in the MET group on average lost 7.0 +/- 6.0 kg (P = 0.001) compared with 7.5 +/- 3.9 kg in the COMBI group (P < 0.001) with no significant between-treatment difference (P = 0.246). The PR per ET was significantly higher in the COMBI (85.7%) compared with the MET (28.6%) group (P = 0.03). The cumulative PR in the time frame of 12 months was 69.2% in the COMBI group compared to 35.7% in the MET group. CONCLUSIONS: Preconception intervention with low-dose liraglutide added to metformin is superior to metformin alone in increasing PRs per ET and cumulative PRs in infertile obese women with PCOS, despite comparable weight reduction in both groups. A potential impact of liraglutide on the reproductive system needs further exploration, in particular the GLP-1 impact on endometrial quality and receptivity. PMID- 29703795 TI - Is Less More or Is It a Call for Evidence-Based Guidance? PMID- 29703796 TI - Limiting Gastric Inflation. PMID- 29703798 TI - Editor's Commentary. PMID- 29703797 TI - Interprofessional Education: Making Our Way Out of the Silos. PMID- 29703800 TI - Comparing standard office-based follow-up with text-based remote monitoring in the management of postpartum hypertension: a randomised clinical trial. AB - BACKGROUND: Monitoring blood pressure at 72 hours and 7-10 days post partum in women with hypertensive disorders is recommended to decrease morbidity. However, there are no recommendations as to how to achieve this. OBJECTIVE: To compare the effectiveness of text-based blood pressure monitoring to in-person visits for women with hypertensive disorders of pregnancy in the immediate postpartum period. METHODS: Randomised clinical trial among 206 postpartum women with pregnancy-related hypertension diagnosed during the delivery admission between August 2016 and January 2017. Women were randomised to 2 weeks of text-based surveillance using a home blood pressure cuff and previously tested automated platform or usual care blood pressure check at their prenatal clinic 4-6 days following discharge. The primary study outcome was a single recorded blood pressure in the first 10 days post partum. The ability to meet American Congress of Obstetricians and Gynecologists (ACOG) guidelines, defined as having a blood pressure recorded on postpartum days 3-4 and 7-10 was evaluated in the text message group. The study was powered to detect a 1.4-fold increase in a single recorded blood pressure using text messaging. All outcomes were analysed as intention to treat. RESULTS: 206 women were randomised (103 in each arm). Baseline characteristics were similar. There was a statistically significant increase in a single blood pressure obtained in the texting group in the first 10 days post partum as compared with the office group (92.2% vs 43.7%; adjusted OR 58.2 (16.2-208.1), p<0.001). Eighty-four per cent of patients undergoing text based surveillance met ACOG criteria for blood pressures at both recommended points. CONCLUSIONS: Text-based monitoring is more effective in obtaining blood pressures and meeting current clinical guidelines in the immediate postdischarge period in women with pregnancy-related hypertension compared with traditional office-based follow-up. TRIAL REGISTRATION NUMBER: NCT03185455, Remote Surveillance of Postpartum Hypertension (TextBP), https://clinicaltrials.gov. PMID- 29703801 TI - Successful Management of Chylothorax With Etilefrine: Case Report in 2 Pediatric Patients. AB - Chylothorax is defined as the accumulation of chyle within the pleural space. Originally described in 1917 by Pisek, it is the most common cause of pleural effusion in the neonatal period. The leading cause of chylothorax is laceration of the thoracic duct during surgery, which occurs in 0.85% to 6.6% of children undergoing cardiothoracic surgery. Few authors of reports in the literature have looked at etilefrine, a relatively unknown sympathomimetic, as an option for the medical treatment of chylothorax. In this case report, we review the clinical course of 2 infants with type III esophageal atresia who developed chylothorax after thoracic surgery and were successfully treated with intravenous etilefrine after failing initial dietary and pharmacological management. PMID- 29703802 TI - A Multicomponent Early Intervention Program and Trajectories of Behavior, Cognition, and Health. AB - OBJECTIVES: To investigate the developmental impact of a prenatal-to-age-5 multicomponent early intervention program targeting families living in low socioeconomic conditions. METHODS: Pregnant women from a disadvantaged Irish community were randomly assigned into a treatment group (home visits, baby massage, and parenting program; n = 115) or control group (n = 118). Children's behavioral problems (externalizing, internalizing), cognitive skills (general, vocabulary), and health service use (number of health clinic visits), were regularly assessed (6 months to 4 years of age). Children's developmental trajectories were modeled by using latent class growth analyses to test whether certain subgroups benefited more than others. RESULTS: High and low developmental trajectories were identified for each outcome. Treated children were more likely to follow the high-level trajectory for cognition (odds ratio = 2.89; 95% confidence interval = 1.55-5.50) and vocabulary skills (odds ratio = 2.02; 95% confidence interval = 1.08-3.82). There were no differences by treatment condition in the risk of belonging to a high externalizing or high health clinic visit trajectory. However, within the high externalizing trajectory, treated children had lower scores than controls (Hedges' g range (2-4 years) = 0.45-0.58; P < .05) and, within the high health clinic visit trajectory, only children in the control group experienced an increasing number of visits. CONCLUSIONS: This program revealed moderate positive impacts on trajectories of cognitive development and number of health clinic visits for all children, whereas positive impacts on externalizing behavior problems were restricted to children with the most severe problems. PMID- 29703804 TI - Opioids versus non-opioids for chronic musculoskeletal pain. PMID- 29703803 TI - Antidepressants: modest effect after 8 weeks. PMID- 29703805 TI - Value of brief alcohol interventions in primary care. PMID- 29703806 TI - Strategies for reducing medication-related harm. PMID- 29703807 TI - Self-monitoring and telemonitoring titration of antihypertensive treatment. PMID- 29703808 TI - Esmya (ulipristal acetate) - safety update. PMID- 29703809 TI - Association of aortic aneurysm with fluoroquinolones. PMID- 29703811 TI - Relationship Between Emergency Medical Services Response Time and Bystander Intervention in Patients With Out-of-Hospital Cardiac Arrest. AB - BACKGROUND: The response time of emergency medical services (EMS) is an important determinant of survival after out-of-hospital cardiac arrest. We sought to identify upper limits of EMS response times and bystander interventions associated with neurologically intact survival. METHODS AND RESULTS: We analyzed the records of 553 426 patients with out-of-hospital cardiac arrest in a Japanese registry between 2010 and 2014. The primary study end point was 1-month neurologically intact survival (Cerebral Performance Category scale 1 or 2). Increased EMS response time was associated with significantly decreased adjusted odds of 1-month neurologically intact survival (adjusted odds ratio [aOR] for each 1-minute increase, 0.89; 95% confidence interval [CI], 0.89-0.90), although this relationship was modified by bystander interventions. The bystander interventions and the ranges of EMS response times that were associated with increased adjusted 1-month neurologically intact survival were as follows: bystander defibrillation, from <=2 minutes (aOR, 3.10 [95% CI, 1.25-7.31]) to 13 minutes (aOR, 5.55 [95% CI, 2.66-11.2]); bystander conventional cardiopulmonary resuscitation, from 3 minutes (aOR 1.48 [95% CI, 1.02-2.12]) to 11 minutes (aOR 2.41 [95% CI, 1.61-3.56]); and bystander chest-compression-only cardiopulmonary resuscitation, from <=2 minutes (aOR 1.57 [95% CI, 1.01-2.25]) to 11 minutes (aOR 1.92 [95% CI, 1.45-2.56]). However, the increase in neurologically intact survival of those receiving bystander interventions became statistically insignificant compared with no bystander interventions when the EMS response time was outside these ranges. CONCLUSIONS: The upper limits of the EMS response times associated with improved 1-month neurologically intact survival were 13 minutes when bystanders provided defibrillation (typically with cardiopulmonary resuscitation) and 11 minutes when bystanders provided cardiopulmonary resuscitation without defibrillation. PMID- 29703810 TI - Association Between Work-Related Stress and Coronary Heart Disease: A Review of Prospective Studies Through the Job Strain, Effort-Reward Balance, and Organizational Justice Models. PMID- 29703812 TI - Time to Compress the Time to First Compression. PMID- 29703813 TI - A 23-month-old girl with chronic 'seborrhoeic' dermatitis, dehydration and failure to thrive. PMID- 29703814 TI - Floppy neonate with feeding difficulties. PMID- 29703815 TI - Neonate with mirror image of double bubble sign. PMID- 29703816 TI - Brainstem and thalamic haemorrhage following cannabis consumption. PMID- 29703817 TI - Comprehensive viral enrichment enables sensitive respiratory virus genomic identification and analysis by next generation sequencing. AB - Next generation sequencing (NGS) technologies have revolutionized the genomics field and are becoming more commonplace for identification of human infectious diseases. However, due to the low abundance of viral nucleic acids (NAs) in relation to host, viral identification using direct NGS technologies often lacks sufficient sensitivity. Here, we describe an approach based on two complementary enrichment strategies that significantly improves the sensitivity of NGS-based virus identification. To start, we developed two sets of DNA probes to enrich virus NAs associated with respiratory diseases. The first set of probes spans the genomes, allowing for identification of known viruses and full genome sequencing, while the second set targets regions conserved among viral families or genera, providing the ability to detect both known and potentially novel members of those virus groups. Efficiency of enrichment was assessed by NGS testing reference virus and clinical samples with known infection. We show significant improvement in viral identification using enriched NGS compared to unenriched NGS. Without enrichment, we observed an average of 0.3% targeted viral reads per sample. However, after enrichment, 50%-99% of the reads per sample were the targeted viral reads for both the reference isolates and clinical specimens using both probe sets. Importantly, dramatic improvements on genome coverage were also observed following virus-specific probe enrichment. The methods described here provide improved sensitivity for virus identification by NGS, allowing for a more comprehensive analysis of disease etiology. PMID- 29703819 TI - New Insights from Studies of Clonal Hematopoiesis. AB - Clonal hematopoiesis (CH) describes an asymptomatic expansion of blood cells descended from a single hematopoietic stem cell. Recent studies have shown that CH increases in frequency with aging and is often driven by somatic mutations in genes that are recurrently mutated in hematologic malignancies. When CH is associated with a mutation in a leukemia-associated gene at a variant allele frequency of 0.02 or greater, it is termed "clonal hematopoiesis of indeterminate potential" (CHIP). CHIP has a 0.5% to 1% risk per year of progression to hematologic neoplasia, and increases both all-cause mortality and the risk of myocardial infarction and ischemic stroke due to a proinflammatory interaction between clonally derived leukocytes and vascular endothelium. CH frequently emerges in the context of immune-mediated marrow failure syndromes such as aplastic anemia, whereas CH emerging after cytotoxic cancer therapy is strongly associated with subsequent development of a therapy-related myeloid neoplasm, especially if a TP53 mutation is present. However, risk factors for developing CH other than aging, marrow failure, and cytotoxic radiotherapy or chemotherapy are poorly defined. In this review, we discuss the epidemiology, molecular mechanisms, and clinical consequences of this common and clinically important biological state. Clin Cancer Res; 24(19); 4633-42. (c)2018 AACR. PMID- 29703818 TI - Paclitaxel Plasma Concentration after the First Infusion Predicts Treatment Limiting Peripheral Neuropathy. AB - Purpose: Paclitaxel exposure, specifically the maximum concentration (Cmax) and amount of time the concentration remains above 0.05 MUmol/L (Tc>0.05), has been associated with the occurrence of paclitaxel-induced peripheral neuropathy. The objective of this study was to validate the relationship between paclitaxel exposure and peripheral neuropathy.Experimental Design: Patients with breast cancer receiving paclitaxel 80 mg/m2 * 12 weekly doses were enrolled in an observational clinical study (NCT02338115). Paclitaxel plasma concentration was measured at the end of and 16-26 hours after the first infusion to estimate Cmax and Tc>0.05 Patient-reported peripheral neuropathy was collected via CIPN20 at each dose, and an 8-item sensory subscale (CIPN8) was used in the primary analysis to test for an association with Tc>0.05 Secondary analyses were conducted using Cmax as an alternative exposure parameter and testing each parameter with a secondary endpoint of the occurrence of peripheral neuropathy induced treatment disruption.Results: In 60 subjects included in the analysis, the increase in CIPN8 during treatment was associated with baseline CIPN8, cumulative dose, and relative dose intensity (P < 0.05), but neither Tc>0.05 (P = 0.27) nor Cmax (P = 0.99). In analyses of the secondary endpoint, cumulative dose (OR = 1.46; 95% confidence interval (CI), 1.18-1.80; P = 0.0008) and Tc>0.05 (OR = 1.79; 95% CI, 1.06-3.01; P = 0.029) or Cmax (OR = 2.74; 95% CI, 1.45-5.20; P = 0.002) were associated with peripheral neuropathy-induced treatment disruption.Conclusions: Paclitaxel exposure is predictive of the occurrence of treatment-limiting peripheral neuropathy in patients receiving weekly paclitaxel for breast cancer. Studies are warranted to determine whether exposure-guided dosing enhances treatment effectiveness and/or prevents peripheral neuropathy in these patients. Clin Cancer Res; 24(15); 3602-10. (c)2018 AACR. PMID- 29703820 TI - Insulin-Like Growth Factor 2 mRNA-Binding Protein 3 is a Novel Post Transcriptional Regulator of Ewing Sarcoma Malignancy. AB - Purpose: Large-scale sequencing studies have indicated that besides genomic alterations, the posttranscriptional regulation of gene expression or epigenetic mechanisms largely influences the clinical behavior of Ewing sarcoma. We investigated the significance of the RNA-binding protein IGF2BP3 in the regulation of Ewing sarcoma aggressiveness.Experimental Design: Explorative study was performed in 14 patients with localized Ewing sarcoma using RNA sequencing. Next, 128 patients with localized Ewing sarcoma were divided into two cohorts. In the training set, 29 Ewing sarcoma samples were analyzed using Affymetrix GeneChip arrays. In the validation set, 99 Ewing sarcoma samples were examined using qRT-PCR. Patient-derived cell lines and experimental models were used for functional studies.Results:Univariate and multivariate analyses indicated IGF2BP3 as a potent indicator of poor prognosis. Furthermore, ABCF1 mRNA was identified as a novel partner of IGF2BP3. Functional studies indicated IGF2BP3 as an oncogenic driver and ABCF1 mRNA as a sponge that by binding IGF2BP3, partly repressed its functions. The combined evaluation of IGF2BP3 and ABCF1 could identify different patient outcomes-high IGF2BP3 and low ABCF1 levels indicated poor survival (25%), whereas low IGF2BP3 and high ABCF1 levels indicated favorable survival (85.5%). The bromodomain and extraterminal domain inhibitor (BETi) JQ1 decreased IGF2BP3 expression, modified the expression of its validated targets and inhibited the capability of Ewing sarcoma cells to grow under anchorage-independent conditions.Conclusions: The combined assessment of IGF2BP3 and ABCF1 predicts recurrence in Ewing sarcoma patients. Thus, for patients with high expression of IGF2BP3 and poor probability of survival, the use of BETis should be clinically evaluated. Clin Cancer Res; 24(15); 3704-16. (c)2018 AACR. PMID- 29703822 TI - Blinatumomab Approval Expanded Based on MRD. AB - The FDA recently expanded the approval of blinatumomab using minimal residual disease (MRD) as a regulatory endpoint, which could signal more such approvals to come. The drug can now be used to treat adults and children with B-cell precursor acute lymphoblastic leukemia who are in remission and have MRD. PMID- 29703823 TI - Everolimus Enhances the Efficacy of Fulvestrant in ER+ Breast Cancer. AB - mTOR inhibition with everolimus extends progression-free survival in combination with fulvestrant. PMID- 29703821 TI - A Rationally Designed Fully Human EGFRvIII:CD3-Targeted Bispecific Antibody Redirects Human T Cells to Treat Patient-derived Intracerebral Malignant Glioma. AB - Purpose: Conventional therapy for malignant glioma fails to specifically target tumor cells. In contrast, substantial evidence indicates that if appropriately redirected, T cells can precisely eradicate tumors. Here we report the rational development of a fully human bispecific antibody (hEGFRvIII-CD3 bi-scFv) that redirects human T cells to lyse malignant glioma expressing a tumor-specific mutation of the EGFR (EGFRvIII).Experimental Design: We generated a panel of bispecific single-chain variable fragments and optimized design through successive rounds of screening and refinement. We tested the ability of our lead construct to redirect naive T cells and induce target cell-specific lysis. To test for efficacy, we evaluated tumor growth and survival in xenogeneic and syngeneic models of glioma. Tumor penetrance following intravenous drug administration was assessed in highly invasive, orthotopic glioma models.Results: A highly expressed bispecific antibody with specificity to CD3 and EGFRvIII was generated (hEGFRvIII-CD3 bi-scFv). Antibody-induced T-cell activation, secretion of proinflammatory cytokines, and proliferation was robust and occurred exclusively in the presence of target antigen. hEGFRvIII-CD3 bi-scFv was potent and target-specific, mediating significant lysis of multiple malignant glioma cell lines and patient-derived malignant glioma samples that heterogeneously express EGFRvIII. In both subcutaneous and orthotopic models, well-engrafted, patient-derived malignant glioma was effectively treated despite heterogeneity of EGFRvIII expression; intravenous hEGFRvIII-CD3 bi-scFv administration caused significant regression of tumor burden (P < 0.0001) and significantly extended survival (P < 0.0001). Similar efficacy was obtained in highly infiltrative, syngeneic glioma models, and intravenously administered hEGFRvIII-CD3 bi-scFv localized to these orthotopic tumors.Conclusions: We have developed a clinically translatable bispecific antibody that redirects human T cells to safely and effectively treat malignant glioma. On the basis of these results, we have developed a clinical study of hEGFRvIII-CD3 bi-scFv for patients with EGFRvIII positive malignant glioma. Clin Cancer Res; 24(15); 3611-31. (c)2018 AACR. PMID- 29703824 TI - Germline IKZF1 Variants Predispose Children to Developing B-ALL. AB - Germline DNA sequencing of 4,963 B-ALLs identified 28 IKZF1 variants, with 22 determined to be damaging. PMID- 29703825 TI - SAMHD1 Mutations Disrupt Replication Fork Progression to Induce IFN. AB - SAMHD1 activates MRE11 exonuclease activity to prevent release of ssDNA from stalled replication forks. PMID- 29703826 TI - Neoadjuvant Endpoints, Response Criteria Proposed. AB - Lung cancer experts propose using immune-related pathologic response criteria to evaluate lung tumors in neoadjuvant trials of checkpoint inhibitors, and suggest using major pathologic response as a surrogate endpoint for all preoperative lung cancer studies. PMID- 29703827 TI - Single-Cell RNA Sequencing Reveals H3K27M Glioma Oncogenic Programs. AB - H3K27M+ gliomas display a unique oncogenic program and are driven by OPC-like glioma cells. PMID- 29703828 TI - Anti-GD2 CAR T Cells Are Potent in H3-K27M+ Diffuse Midline Gliomas. AB - The disialoganglioside GD2 is an immunotherapeutic target in H3-K27M+ diffuse midline gliomas. PMID- 29703830 TI - Junior doctor whistleblowers need protection they can trust, says Robert Francis. PMID- 29703831 TI - The patients who decide what makes a good doctor. PMID- 29703829 TI - Old gene, new phenotype: splice-altering variants in CEACAM16 cause recessive non syndromic hearing impairment. AB - BACKGROUND: Hearing loss is a genetically and phenotypically heterogeneous disorder. OBJECTIVES: The purpose of this study was to determine the genetic cause underlying the postlingual progressive hearing loss in two Iranian families. METHODS: We used OtoSCOPE, a next-generation sequencing platform targeting >150 genes causally linked to deafness, to screen two deaf probands. Data analysis was completed using a custom bioinformatics pipeline, and variants were functionally assessed using minigene splicing assays. RESULTS: We identified two homozygous splice-altering variants (c.37G>T and c.662-1G>C) in the CEACAM16 gene, segregating with the deafness in each family. The minigene splicing results revealed the c.37G>T results in complete skipping of exon 2 and loss of the AUG start site. The c.662-1G>C activates a cryptic splice site inside exon 5 resulting in a shift in the mRNA reading frame. CONCLUSIONS: These results suggest that loss-of-function mutations in CEACAM16 result in postlingual progressive hearing impairment and further support the role of CEACAM16 in auditory function. PMID- 29703832 TI - Complete resolution of extensive thrombosis of atheromatous non-aneurysmal descending aorta and pulmonary embolism with warfarin therapy. AB - A 54-year-old man underwent decompressive craniectomy following a stroke. He further developed right lower limb ischaemia, and CT aortography revealed extensive aortic atherosclerotic disease. Urgent embolectomy prevented him from having a major amputation. He subsequently developed pulmonary embolism. This was initially treated with heparin followed by warfarin apart from antiplatelets and statin. A follow-up aortography at 3 months interval showed near complete resolution of atheromatous disease of the aorta. This report raises the possibility that apart from antiplatelets and lipid-lowering agents, anticoagulation may be responsible for resolution of such an extensive atheromatous disease and whether this can be considered as part of regular treatment. PMID- 29703833 TI - Streptococcus anginosus endocarditis and multiple liver abscesses in a splenectomised patient. AB - An unusual case of infective endocarditis and concurrent multiple liver abscesses both caused by Streptococcus anginosus in a splenectomised patient is reported. The microorganism is a very rare cause of endocarditis and its presentation with multiple liver abscesses is highly unusual. It was initially misdiagnosed as Streptococcus sanguinis and issues relating to the different clinical presentations of S. anginosus including the rare cases of endocarditis, the role of the patient's splenectomy and problems that may contribute to its potential laboratory misidentifications are discussed. PMID- 29703834 TI - Type 1 cryoglobulinaemia presenting as digital ischaemia in chronic lymphocytic leukaemia. PMID- 29703835 TI - Fever of unknown origin, bilateral sensorineural hearing loss with canal paresis and uveitis with iridocyclitis and episcleritis: a case of Cogan's syndrome. PMID- 29703836 TI - Bordetella bronchiseptica pneumonia: beware of the dog! AB - We report the case of a 35-year-old quadriplegic male with confirmed Bordetella bronchiseptica pneumonia, manifesting with acute hypoxic respiratory failure on a background of chronic hypercarbia requiring mechanical ventilation in intensive care.B. bronchiseptica are known to colonise the upper respiratory tracts of many mammals but are very rarely responsible for acute respiratory tract infections in humans.A review of the literature suggests preponderance for immunocompromised or immunoincompetent patients who have experienced environmental exposure to colonised animals. The disease pattern of B. bronchiseptica infection is non uniform and while it is rarely described as a commensal or colonising organism, very few case reports describe severe respiratory infections. PMID- 29703837 TI - Herpes simplex virus type 1: an atypical presentation of primary infection. PMID- 29703838 TI - Structural insights into the molecular mechanism of mouse TRPA1 activation and inhibition. AB - Pain, though serving the beneficial function of provoking a response to dangerous situations, is an unpleasant sensory and emotional experience. Transient receptor potential ankyrin 1 (TRPA1) is a member of the transient receptor potential (TRP) cation channel family and is localized in "nociceptors," where it plays a key role in the transduction of chemical, inflammatory, and neuropathic pain. TRPA1 is a Ca2+-permeable, nonselective cation channel that is activated by a large variety of structurally unrelated electrophilic and nonelectrophilic chemical compounds. Electrophilic ligands are able to activate TRPA1 channels by interacting with critical cysteine residues on the N terminus of the channels via covalent modification and/or disulfide bonds. Activation by electrophilic compounds is dependent on their thiol-reactive moieties, accounting for the structural diversity of the group. On the other hand, nonelectrophilic ligands do not interact with critical cysteines on the channel, so the structural diversity of this group is unexplained. Although near-atomic-resolution structures of TRPA1 were resolved recently by cryo-electron microscopy, in the presence of both agonists and antagonists, detailed mechanisms of channel activation and inhibition by these modulators could not be determined. Here, we investigate the effect of both electrophilic and nonelectrophilic ligands on TRPA1 channel conformational rearrangements with limited proteolysis and mass spectrometry. Collectively, our results reveal that channel modulation results in conformational rearrangements in the N-terminal ankyrin repeats, the pre-S1 helix, the TRP-like domain, and the linker regions of the channel. PMID- 29703839 TI - The Complexity and Heterogeneity of Monoclonal Immunoglobulin-Associated Renal Diseases. AB - Monoclonal gammopathies are characterized by the overproduction of monoclonal Ig (MIg) detectable in the serum or urine resulting from a clonal proliferation of plasma cells or B lymphocytes. The underlying hematologic conditions range from malignant neoplasms of plasma cells or B lymphocytes, including multiple myeloma and B-cell lymphoproliferative disorders, to nonmalignant small clonal proliferations. The term MGUS implies presence of an MIg in the setting of a "benign" hematologic condition without renal or other end organ damage. The term MGRS was recently introduced to indicate monoclonal gammopathy with MIg associated renal disease in the absence of hematologic malignancy. Most MIg associated renal diseases result from the direct deposition of nephrotoxic MIg or its light- or heavy-chain fragments in various renal tissue compartments. Immunofluorescence microscopy is essential to identify the offending MIg and define its tissue distribution. Mass spectrometry is helpful in difficult cases. Conditions caused by direct tissue deposition of MIg include common disorders, such as cast nephropathy, amyloidosis, and MIg deposition diseases, as well as uncommon disorders, such as immunotactoid glomerulopathy, proliferative GN with MIg deposits, light-chain proximal tubulopathy, and the rare entities of crystal storing histiocytosis and crystalglobulinemia. Indirect mechanisms of MIg-induced renal disease can cause C3 glomerulopathy or thrombotic microangiopathy without tissue MIg deposits. Treatment of MIg-associated renal disease is aimed at eliminating the clonal plasma cell or B-cell population as appropriate. Both the renal and the underlying hematologic disorders influence the management and prognosis of MIg-associated renal diseases. PMID- 29703841 TI - A HER2-Targeting Antibody-Drug Conjugate, Trastuzumab Deruxtecan (DS-8201a), Enhances Antitumor Immunity in a Mouse Model. AB - Trastuzumab deruxtecan (DS-8201a), a HER2-targeting antibody-drug conjugate with a topoisomerase I inhibitor exatecan derivative (DX-8951 derivative, DXd), has been reported to exert potent antitumor effects in xenograft mouse models and clinical trials. In this study, the immune system-activating ability of DS-8201a was assessed. DS-8201a significantly suppressed tumor growth in an immunocompetent mouse model with human HER2-expressing CT26.WT (CT26.WT-hHER2) cells. Cured immunocompetent mice rejected not only rechallenged CT26.WT-hHER2 cells, but also CT26.WT-mock cells. Splenocytes from the cured mice responded to both CT26.WT-hHER2 and CT26.WT-mock cells. Further analyses revealed that DXd upregulated CD86 expression on bone marrow-derived dendritic cells (DC) in vitro and that DS-8201a increased tumor-infiltrating DCs and upregulated their CD86 expression in vivo DS-8201a also increased tumor-infiltrating CD8+ T cells and enhanced PD-L1 and MHC class I expression on tumor cells. Furthermore, combination therapy with DS-8201a and anti-PD-1 antibody was more effective than either monotherapy. In conclusion, DS-8201a enhanced antitumor immunity, as evidenced by the increased expression of DC markers, augmented expression of MHC class I in tumor cells, and rejection of rechallenged tumor cells by adaptive immune cells, suggesting that DS-8201a enhanced tumor recognition by T cells. Furthermore, DS-8201a treatment benefited from combination with anti-PD-1 antibody, possibly due to increased T-cell activity and upregulated PD-L1 expression induced by DS-8201a. Mol Cancer Ther; 17(7); 1494-503. (c)2018 AACR. PMID- 29703840 TI - Transcription factor ID2 prevents E proteins from enforcing a naive T lymphocyte gene program during NK cell development. AB - All innate lymphoid cells (ILCs) require the small helix-loop-helix transcription factor ID2, but the functions of ID2 are not well understood in these cells. We show that mature natural killer (NK) cells, the prototypic ILCs, developed in mice lacking ID2 but remained as precursor CD27+CD11b- cells that failed to differentiate into CD27-CD11b+ cytotoxic effectors. We show that ID2 limited chromatin accessibility at E protein binding sites near naive T lymphocyte associated genes including multiple chemokine receptors, cytokine receptors, and signaling molecules and altered the NK cell response to inflammatory cytokines. In the absence of ID2, CD27+CD11b- NK cells expressed ID3, a helix-loop-helix protein associated with naive T cells, and they transitioned from a CD8 memory precursor-like to a naive-like chromatin accessibility state. We demonstrate that ID3 was required for the development of ID2-deficient NK cells, indicating that completely unfettered E protein function is incompatible with NK cell development. These data solidify the roles of ID2 and ID3 as mediators of effector and naive gene programs, respectively, and revealed a critical role for ID2 in promoting a chromatin state and transcriptional program in CD27+CD11b- NK cells that supports cytotoxic effector differentiation and cytokine responses. PMID- 29703842 TI - Targeting the Proteasome-Associated Deubiquitinating Enzyme USP14 Impairs Melanoma Cell Survival and Overcomes Resistance to MAPK-Targeting Therapies. AB - Advanced cutaneous melanoma is one of the most challenging cancers to treat because of its high plasticity, metastatic potential, and resistance to treatment. New targeted therapies and immunotherapies have shown remarkable clinical efficacy. However, such treatments are limited to a subset of patients and relapses often occur, warranting validation of novel targeted therapies. Posttranslational modification of proteins by ubiquitin coordinates essential cellular functions, including ubiquitin-proteasome system (UPS) function and protein homeostasis. Deubiquitinating enzymes (DUB) have been associated to multiple diseases, including cancer. However, their exact involvement in melanoma development and therapeutic resistance remains poorly understood. Using a DUB trap assay to label cellular active DUBs, we have observed an increased activity of the proteasome-associated DUB, USP14 (Ubiquitin-specific peptidase 14) in melanoma cells compared with melanocytes. Our survey of public gene expression databases indicates that high expression of USP14 correlates with melanoma progression and with a poorer survival rate in metastatic melanoma patients. Knockdown or pharmacologic inhibition of USP14 dramatically impairs viability of melanoma cells irrespective of the mutational status of BRAF, NRAS, or TP53 and their transcriptional cell state, and overcomes resistance to MAPK-targeting therapies both in vitro and in human melanoma xenografted mice. At the molecular level, we find that inhibition of USP14 rapidly triggers accumulation of poly ubiquitinated proteins and chaperones, mitochondrial dysfunction, ER stress, and a ROS production leading to a caspase-independent cell death. Our results provide a rationale for targeting the proteasome-associated DUB USP14 to treat and combat melanomas. Mol Cancer Ther; 17(7); 1416-29. (c)2018 AACR. PMID- 29703843 TI - MKAD-21 Suppresses the Oncogenic Activity of the miR-21/PPP2R2A/ERK Molecular Network in Bladder Cancer. AB - Bladder cancer represents a disease associated with significant morbidity and mortality. MiR-21 has been found to have oncogenic activity in multiple cancers, including bladder cancer, whereas inhibition of its expression suppresses tumor growth. Here, we examine the molecular network regulated by miR-21 in bladder cancer and evaluate the effects of i.v. and i.p. administration of a novel miR-21 chemical inhibitor in vivo LNA miR-21 reduced the oncogenic potential of bladder cancer cells, whereas the MKAD-21 chemically modified antisense oligo against miR 21 dose-dependently blocked xenograft growth. I.v. administration of LNA miR-21 was more effective in suppressing tumor growth than was i.p. administration. Integration of computational and transcriptomic analyses in a panel of 28 bladder cancer lines revealed a 15-gene signature that correlates with miR-21 levels. Protein Phosphatase 2 Regulatory Subunit Balpha (PPP2R2A) was one of these 15 genes and was experimentally validated as a novel miR-21 direct target gene. Gene network and molecular analyses showed that PPP2R2A is a potent negative regulator of the ERK pathway activation and bladder cancer cell proliferation. Importantly, we show that PPP2R2A acts as a mediator of miR-21-induced oncogenic effects in bladder cancer. Integrative analysis of human bladder cancer tumors and a large panel of human bladder cancer cell lines revealed a novel 15-gene signature that correlates with miR-21 levels. Importantly, we provide evidence that PPP2R2A represents a new miR-21 direct target and regulator of the ERK pathway and bladder cancer cell growth. Furthermore, i.v. administration of the MKAD-21 inhibitor effectively suppressed tumor growth through regulation of the PPP2R2A ERK network in mice. Mol Cancer Ther; 17(7); 1430-40. (c)2018 AACR. PMID- 29703845 TI - MCP-1 Feedback Loop Between Adipocytes and Mesenchymal Stromal Cells Causes Fat Accumulation and Contributes to Hematopoietic Stem Cell Rarefaction in the Bone Marrow of Patients With Diabetes. AB - Fat accumulates in bone marrow (BM) of patients with diabetes. In this study, we investigated the mechanisms and consequences of this phenomenon. BM mesenchymal stromal cells (BM-MSCs) from patients with type 2 diabetes (T2D) constitutively express adipogenic markers and robustly differentiate into adipocytes (ADs) upon in vitro induction as compared with BM-MSCs from subjects without diabetes. Moreover, BM-ADs from subjects with T2D (T2D BM-ADs) paracrinally stimulate a transcriptional adipogenic program in BM-MSCs. Antagonism of MCP-1, a chemokine pivotally expressed in T2D BM-ADs, prevented the T2D BM-AD secretome from converting BM-MSCs into ADs. Mechanistic validation of human data was next performed in an obese T2D mouse model. Systemic antagonism of MCP-1 improved metabolic control, reduced BM fat, and increased osteocyte density. It also indirectly re-established the abundance of long-term versus short-term hematopoietic stem cells. We reveal a diabetic feedback loop in which 1) BM-MSCs are constitutively inclined to make ADs, and 2) mature BM-ADs, via secreted MCP 1, relentlessly fuel BM-MSC determination into new fat. Pharmacological inhibition of MCP-1 signaling can contrast this vicious cycle, restoring, at least in part, the balance between adipogenesis and hematopoiesis in BM from subjects with T2D. PMID- 29703846 TI - LPA Variants Are Associated With Residual Cardiovascular Risk in Patients Receiving Statins. AB - BACKGROUND: Coronary heart disease (CHD) is a leading cause of death globally. Although therapy with statins decreases circulating levels of low-density lipoprotein cholesterol and the incidence of CHD, additional events occur despite statin therapy in some individuals. The genetic determinants of this residual cardiovascular risk remain unknown. METHODS: We performed a 2-stage genome-wide association study of CHD events during statin therapy. We first identified 3099 cases who experienced CHD events (defined as acute myocardial infarction or the need for coronary revascularization) during statin therapy and 7681 controls without CHD events during comparable intensity and duration of statin therapy from 4 sites in the Electronic Medical Records and Genomics Network. We then sought replication of candidate variants in another 160 cases and 1112 controls from a fifth Electronic Medical Records and Genomics site, which joined the network after the initial genome-wide association study. Finally, we performed a phenome-wide association study for other traits linked to the most significant locus. RESULTS: The meta-analysis identified 7 single nucleotide polymorphisms at a genome-wide level of significance within the LPA/PLG locus associated with CHD events on statin treatment. The most significant association was for an intronic single nucleotide polymorphism within LPA/PLG (rs10455872; minor allele frequency, 0.069; odds ratio, 1.58; 95% confidence interval, 1.35-1.86; P=2.6*10 10). In the replication cohort, rs10455872 was also associated with CHD events (odds ratio, 1.71; 95% confidence interval, 1.14-2.57; P=0.009). The association of this single nucleotide polymorphism with CHD events was independent of statin induced change in low-density lipoprotein cholesterol (odds ratio, 1.62; 95% confidence interval, 1.17-2.24; P=0.004) and persisted in individuals with low density lipoprotein cholesterol <=70 mg/dL (odds ratio, 2.43; 95% confidence interval, 1.18-4.75; P=0.015). A phenome-wide association study supported the effect of this region on coronary heart disease and did not identify noncardiovascular phenotypes. CONCLUSIONS: Genetic variations at the LPA locus are associated with CHD events during statin therapy independently of the extent of low-density lipoprotein cholesterol lowering. This finding provides support for exploring strategies targeting circulating concentrations of lipoprotein(a) to reduce CHD events in patients receiving statins. PMID- 29703847 TI - Evaluating the long-term consequences of air pollution in early life: geographical correlations between coal consumption in 1951/1952 and current mortality in England and Wales. AB - OBJECTIVE: To evaluate associations between early life air pollution and subsequent mortality. DESIGN: Geographical study. SETTING: Local government districts within England and Wales. EXPOSURE: Routinely collected geographical data on the use of coal and related solid fuels in 1951-1952 were used as an index of air pollution. MAIN OUTCOME MEASURES: We evaluated the relationship between these data and both all-cause and disease-specific mortality among men and women aged 35-74 years in local government districts between 1993 and 2012. RESULTS: Domestic (household) coal consumption had the most powerful associations with mortality. There were strong correlations between domestic coal use and all cause mortality (relative risk per SD increase in fuel use 1.124, 95% CI 1.123 to 1.126), and respiratory (1.238, 95% CI 1.234 to 1.242), cardiovascular (1.138, 95% CI 1.136 to 1.140) and cancer mortality (1.073, 95% CI 1.071 to 1.075). These effects persisted after adjustment for socioeconomic indicators in 1951, current socioeconomic indicators and current pollution levels. CONCLUSION: Coal was the major cause of pollution in the UK until the Clean Air Act of 1956 led to a rapid decline in consumption. These data suggest that coal-based pollution, experienced over 60 years ago in early life, affects human health now by increasing mortality from a wide variety of diseases. PMID- 29703848 TI - Should empiric antibiotic therapy be withheld when aetiology of preterm birth is non-infectious? A protocol for a systematic review. AB - INTRODUCTION: Preterm birth (PTB) at <37 weeks of gestation is the leading cause of perinatal morbidity and mortality in developed countries. The traditional approach has been based on the assumption that PTB is primarily a result of intrauterine infection, which triggers preterm labour and puts the newborn at risk of early onset sepsis (EOS). We are currently experiencing a rise in prematurity that results from maternal and fetal diseases unrelated to infection. We have designed a systematic review to assess whether chemoprophylaxis should be withheld when the aetiology of preterm birth is non-infectious. METHODS AND ANALYSIS: Our study will focus on studies evaluating EOS in preterm infants. We will conduct a comprehensive search of literature available up to 28 February 2018. An information specialist will search for eligible studies in Medline (Ovid interface, 1948 and onwards), Embase (Ovid interface, 1980 onwards) and the Cochrane Central Register of Controlled Trials (Wiley interface, current issue). We will search databases and registries including records of ongoing research, conference proceedings and thesis (clinical trials, WHO International Clinical Trials Registry Platform). Two authors will independently extract data from eligible studies and assess risk of bias. For continuous outcomes, which follow discrete distribution, mean difference will be calculated. Dichotomous data will be presented using risk ratios, while count data will be expressed using rate ratios. Time-to-event outcomes will be reported as HRs. All estimates will be presented together with 95% CI. Studies comparable with respect to methodology and reporting the same outcomes will be combined in a meta-analysis. ETHICS AND DISSEMINATION: Our systematic review does not require approval from the research and ethics board. We will use the findings to prepare a future multicentre randomised control trial in order to establish safe and adequate antibiotics policies for preterm infants, based on the aetiology of PTB. PROSPERO REGISTRATION NUMBER: CRD42016029707. PMID- 29703849 TI - Financial impact of injury in older workers: use of a national retrospective e cohort to compare income patterns over 3 years in a universal injury compensation scheme. AB - OBJECTIVE: The study aims to quantify the impact of injury on the financial well being of older workers. The hypothesis was that injured older workers have substantially reduced income from work following injury, but that New Zealand's (NZ) universal injury compensation scheme mitigates the difference for total income. DESIGN, SETTING AND PARTICIPANTS: An e-cohort of 617 722 workers aged 45 64 years old was created using de-identified linked administrative data in NZ's Integrated Data Infrastructure. Person-level data from numerous government agencies were used to compare 21 639 with an injury-related entitlement claim in 2009 with the remaining 596 133. Event date was the date of injury, or for the comparison group, a randomly selected date in 2009. PRIMARY AND SECONDARY OUTCOME MEASURES: Geometric mean ratios (GMRs) were used to compare income from work and total income from all taxable sources between those injured and the comparison group. Adjusted GMRs estimated income differences up to 36 months following the event date. RESULTS: Differences in total income increased over time. In the third year, those injured received 6.7% less (adjusted GMR 0.933 (95% CI 0.925 to 0.941)) than the comparison group, equivalent to an average loss of $NZ2628. Restricting to income from work, those injured received 29.2% less than the comparison group at 3 years (adjusted GMR 0.708 (95% CI 0.686 to 0.730)). For both men and women, those injured at 45-49 years consistently had the greatest relative income loss compared with those aged 50-54, 55-59 or 60-64 years. CONCLUSIONS: Although the substantial impacts of injury on income were mainly mitigated by public income transfers, relative losses in income in those aged 45 64 years increased in the 3 years following injury. Policies focused on adequate compensation and reducing the time away from employment could reduce these financial impacts in older workers. PMID- 29703850 TI - Hospitalisation cost analysis on hip fracture in China: a multicentre study among 73 tertiary hospitals. AB - OBJECTIVE: To describe and analyse the hospitalisation cost of patients with hip fracture under the influence of various factors and to provide references for Chinese national medical insurance policy. MATERIALS AND METHODS: All data were collected from the Chinese National Medical Data Centre database, which contained the hospitalisation data of 73 tertiary hospitals from 24 provinces. The included patients were first hospitalised with the main diagnosis of femoral neck or intertrochanteric fracture, and were discharged between 1 January 2014 and 31 December 2015. Secondary hospitalisation, multiple trauma or pathologic fracture (except for osteoporotic fracture) patients or patients with missing data were excluded. The impact of various factors on the cost was investigated using analysis of variance and multivariable linear regression analysis. The Gross Domestic Product per capita and average annual disposable income were obtained from the website of the National Bureau of Statistics. RESULTS: 27 205 cases were included in the study. The mean cost of all patients was Y53 440. 60-69 years age group had a significantly higher cost compared with 80 years and above age group. The mean cost of femoral neck fractures was lower than that of the patients with intertrochanteric fractures; the mean cost of hip replacement was higher than that of internal fixation, which showed a strong effect of the surgical approach to the cost. Patients in low-income provinces spent less than those in high income provinces, while the gap between high-income and middle-income provinces were relatively small. CONCLUSION: The hospitalisation cost of hip fracture has become a great burden to the patients' families. The Chinese medical insurance policy may need further consideration of the demographic and economic factors. PMID- 29703852 TI - Evaluation of the feasibility and performance of early warning scores to identify patients at risk of adverse outcomes in a low-middle income country setting. AB - OBJECTIVE: This study describes the availability of core parameters for Early Warning Scores (EWS), evaluates the ability of selected EWS to identify patients at risk of death or other adverse outcome and describes the burden of triggering that front-line staff would experience if implemented. DESIGN: Longitudinal observational cohort study. SETTING: District General Hospital Monaragala. PARTICIPANTS: All adult (age >17 years) admitted patients. MAIN OUTCOME MEASURES: Existing physiological parameters, adverse outcomes and survival status at hospital discharge were extracted daily from existing paper records for all patients over an 8-month period. STATISTICAL ANALYSIS: Discrimination for selected aggregate weighted track and trigger systems (AWTTS) was assessed by the area under the receiver operating characteristic (AUROC) curve.Performance of EWS are further evaluated at time points during admission and across diagnostic groups. The burden of trigger to correctly identify patients who died was evaluated using positive predictive value (PPV). RESULTS: Of the 16 386 patients included, 502 (3.06%) had one or more adverse outcomes (cardiac arrests, unplanned intensive care unit admissions and transfers). Availability of physiological parameters on admission ranged from 90.97% (95% CI 90.52% to 91.40%) for heart rate to 23.94% (95% CI 23.29% to 24.60%) for oxygen saturation. Ability to discriminate death on admission was less than 0.81 (AUROC) for all selected EWS. Performance of the best performing of the EWS varied depending on admission diagnosis, and was diminished at 24 hours prior to event. PPV was low (10.44%). CONCLUSION: There is limited observation reporting in this setting. Indiscriminate application of EWS to all patients admitted to wards in this setting may result in an unnecessary burden of monitoring and may detract from clinician care of sicker patients. Physiological parameters in combination with diagnosis may have a place when applied on admission to help identify patients for whom increased vital sign monitoring may not be beneficial. Further research is required to understand the priorities and cues that influence monitoring of ward patients. TRIAL REGISTRATION NUMBER: NCT02523456. PMID- 29703853 TI - A modified Delphi study towards developing a guideline to inform policy on fetal alcohol spectrum disorders in South Africa: a study protocol. AB - INTRODUCTION: Maternal alcohol consumption during pregnancy can result in mental and physical birth defects in individuals. These birth defects are usually described as fetal alcohol spectrum disorders (FASDs). With an estimated 183-259 per 1000 children born with FASDs, South Africa is identified to have the highest prevalence of FASDs in the world. Nevertheless, there is a lack of appropriate policies, guidelines and interventions addressing the issues around FASDs. This protocol outlines a proposed process for developing a guideline to inform policies on FASDs. METHODS AND ANALYSIS: This process will have three phases. Phase I will be carried out in three steps; we plan to conduct a document review of available policies on the prevention and management of FASDs and update the existing systematic review on FASDs interventions. The aim of the two reviews is to explore the availability and content of existing policies and global interventions on FASDs. In addition, we will conduct two exploratory qualitative studies to obtain the perspectives of various stakeholders on the existing or possible guidelines and policies for the management of FASDs and available interventions and services. In phase II, we will aggregate the findings of the previous phase to develop a prototype guideline. In phase III, using the developed prototype, we will apply the Delphi approach with experts on FASDs, soliciting their opinions on the nature and content of the proposed guidelines for policies. The information gathered will be used to modify the prototype to formulate a policy guideline on FASDs. The data will be analysed using thematic analysis and narrative synthesis. ETHICS AND DISSEMINATION: Ethical clearance has been obtained from the ethics committee of the university and governmental departments. The findings will be disseminated through publications and the guideline will be submitted to relevant departments. PMID- 29703851 TI - Efficacy and safety of faecal microbiota transplantation in patients with psoriatic arthritis: protocol for a 6-month, double-blind, randomised, placebo controlled trial. AB - INTRODUCTION: An unbalanced intestinal microbiota may mediate activation of the inflammatory pathways seen in psoriatic arthritis (PsA). A randomised, placebo controlled trial of faecal microbiota transplantation (FMT) infused into the small intestine of patients with PsA with active peripheral disease who are non responsive to methotrexate (MTX) treatment will be conducted. The objective is to explore clinical aspects associated with FMT performed in patients with PsA. METHODS AND ANALYSIS: This trial is a randomised, two-centre stratified, double blind (patient, care provider and outcome assessor), placebo-controlled, parallel group study. Eighty patients will be included and randomised (1:1) to either placebo (saline) or FMT provided from an anonymous healthy donor. Throughout the study, both groups will continue the weekly self-administered subcutaneous MTX treatment, remaining on the preinclusion dosage (15-25 mg/week). The clinical measures of psoriasis and PsA disease activity used include the Short (2-page) Health Assessment Questionnaire, the Dermatology Quality of Life Index, the Spondyloarthritis Research Consortium of Canada Enthesitis Index, the Psoriasis Area Severity Index, a dactylitis digit count, a swollen/tender joint count (66/68), plasma C reactive protein as well as visual analogue scales for pain, fatigue and patient and physician global assessments. The primary end point is the proportion of patients who experience treatment failure during the 6-month trial period. The number of adverse events will be registered throughout the study. ETHICS AND DISSEMINATION: This is a proof-of-concept clinical trial and will be performed in agreement with Good Clinical Practice standards. Approvals have been obtained from the local Ethics Committee (DK-S-20150080) and the Danish Data Protection Agency (15/41684). The study has commenced in May 2017. Dissemination will be through presentations at national and international conferences and through publications in international peer-reviewed journal(s). TRIAL REGISTRATION NUMBER: NCT03058900; Pre-results. PMID- 29703854 TI - Evaluation of plasma microRNA-122, high-mobility group box 1 and keratin-18 concentrations to stratify acute gallstone disease: a pilot observational cohort study in an emergency general surgery unit. AB - OBJECTIVE: To obtain pilot data to evaluate the discriminatory power of biomarkers microRNA-122 (miR-122), high-mobility group box 1 (HMGB1), full-length keratin-18 (flk-18) and caspase-cleaved keratin-18 (cck-18) in plasma to identify potential biliary complications that may require acute intervention. DESIGN: An observational biomarker cohort pilot study. SETTING: In a Scottish University teaching hospital for 12 months beginning on 3 September 2014. PARTICIPANTS: Blood samples were collected from adults (>=16 years old) referred with acute biliary-type symptoms who have presented to hospital within 24 hours prior were recruited. Patients unable or refused to give informed consent or were transferred from a hospital outside the National Health Service regional trust were excluded. PRIMARY OUTCOME MEASURES: To evaluate whether circulating miR-122, HMGB1, flk-18 and cck-18 can discriminate between people with and without gallstone disease and uncomplicated from complicated gallstone disease during the first 24 hours of hospital admission. RESULTS: 300 patients were screened of which 285 patients were included. Plasma miR-122, cck-18 and flk-18 concentrations were increased in patients with gallstones compared with those without (miR-122: median: 2.89*104 copies/mL vs 0.90*104 copies/mL (p<0.001); cck 18: 121.2 U/L vs 103.5 U/L (p=0.031); flk-18: 252.4 U/L vs 145.1 U/L (p<0.001)). Uncomplicated gallstone disease was associated with higher miR-122 and cck-18 concentrations than complicated disease (miR-122: 5.72*104 copies/mL vs 2.26*104 copies/mL (p=0.023); cck-18: 139.7 U/L vs 113.6 U/L (p=0.047)). There was no significant difference in HMGB1 concentration between patients with and without gallstones (p=0.559). Separation between groups for all biomarkers was modest. CONCLUSION: miR-122 and keratin-18 plasma concentrations are elevated in patients with gallstones. However, this result is confounded by the association between biomarker concentrations, age and gender. In this pilot study, miR-122 and keratin-18 were not sufficiently discriminatory to be progressed as clinically useful biomarkers in this context. PMID- 29703855 TI - Public performance reporting and hospital choice: a cross-sectional study of patients undergoing cancer surgery in the Australian private healthcare sector. AB - OBJECTIVES: National mandatory public performance reporting (PPR) for Australian public hospitals, including measures of cancer surgery waiting times, was introduced in 2011. PPR is voluntary for private hospitals. The aims of this study were to assess whether PPR of hospital data is used by patients with breast, bowel or lung cancer when selecting a hospital for elective surgery and how PPR could be improved to meet their information needs. DESIGN: A national cross-sectional postal questionnaire. SETTING: Australian private healthcare sector. PARTICIPANTS: Private patients with breast, bowel or lung cancer who attended a public or private hospital for elective surgery (n=243) in 2016. OUTCOME MEASURES: Patients' choice of hospital, use of PPR information and preferred areas of PPR information. Descriptive and conventional qualitative content analyses were conducted. RESULTS: Two hundred and twenty-eight respondents (94%) attended a private hospital. Almost half could choose a hospital. Choice of hospital was not influenced by PPR data (92% unaware) but by their specialist (90%). Respondents considered PPR to be important (71%) but they did not want to see the information, preferring their general practitioners (GPs) to tell them about it (40%). Respondents considered surgery costs (59%), complications (58%) and recovery success rates (57%) to be important areas of information that should be publicly reported. Almost half suggested that quality indicators should be reported at the individual clinician level. Analysis of the open-ended questions identified four themes: (1) decision-making factors; (2) data credibility; (3) unmet information needs and (4) unintended consequences. CONCLUSIONS: PPR of hospital data had no substantial impact on patients' choice of hospital. Nonetheless, many respondents expressed interest in using it in future. To increase PPR awareness and usability, personalised and integrated information on cost and quality of hospitals is required. Dissemination of PPR information via specialists and GPs could assist patients to interpret the data and support decision-making. PMID- 29703856 TI - Decline of adolescent smoking in Ireland 1995-2015: trend analysis and associated factors. AB - OBJECTIVES: The study examines trends in smoking among Irish adolescents aged 15 16 years between 1995 and 2015 and the factors associated with their smoking behaviours between 2007 and 2015. METHODS: Data were obtained from the European School Survey Project on Alcohol and Other Drugs Ireland between 1995 and 2015. To examine the gender gap, two-sample proportion tests were used. Multivariate logistic regression was performed to examine the factors associated with smoking behaviours. Dependent variable is whether a respondent is a smoker in last 30 days. Independent variables include gender, survey years, perceived ease of access to cigarettes, perceived risk of smoking, perceived relative wealth, parental monitoring, maternal relationship, family structure, truancy and peer smoking. RESULTS: Smoking prevalence has dropped from 41% in 1995 to 13% in 2015. The prevalence was much higher among girls than boys in 1995. The gender gap was closed by 2015. Multivariate regression results show that peer smoking, perceived access to cigarettes, perceived risks of smoking, parental monitoring, truancy, maternal relationship, perceived relative wealth and family structure were all significantly associated with adolescent smoking, and some of the factors had different effects for female and male students. CONCLUSION: Ireland has successfully achieved a considerable decrease of adolescent smoking from 1995 to 2015, during which various tobacco control policies have been implemented. In addition, the gender gap on adolescent smoking has been closed during the period. Adolescent smoking could be further improved through strengthening enforcement on adolescent access to cigarettes and maintaining a high-intensity tobacco control media campaign targeting adolescents. Parents could also contribute by enhancing monitoring. PMID- 29703858 TI - Incidence of major complications after percutaneous native renal biopsies in adults from low-income to middle-income countries: a protocol for systematic review and meta-analysis. AB - INTRODUCTION: Kidney biopsy is an essential tool for guiding clinicians towards diagnoses, treatment and determining prognosis in renal disease. However, the procedure can be marred by various complications. The reported occurrence of complications varies among countries or regions and is also affected by several clinical and technical factors. This systematic review and meta-analysis aims to evaluate the incidence of major complications after percutaneous native renal biopsy in low-income to middle-income countries (LMICs). METHODS AND ANALYSIS: We will include studies of populations from LMIC as per World Bank 2017 country list. Relevant abstracts published from 1 January 1980 to 30 December 2017 will be searched in PubMed, Cochrane, Excerpta Medica Database (Embase) and African Journals Online, without language restriction. Two reviewers will independently screen, select studies, extract data and assess the risk of bias in each study. A third reviewer will arbitrate in cases of disagreements. The study-specific estimates will be pooled through a random-effects model meta-analysis to obtain an overall summary estimate of the incidence of major complications across studies. Clinical and statistical heterogeneity will be evaluated by Cochrane's Q statistic. Funnel-plot analysis and Egger's test will be used to assess publication bias. Results will be presented by geographical region and income group. ETHICS AND DISSEMINATION: This study will use published data. Therefore, there is no requirement for ethical approval. This systematic review and meta analysis is expected to inform healthcare workers and providers about the occurrence of major complications following renal biopsies and highlight possible actions needed to improve the safety of the procedure in LMICs. The final report will be published as an original article in a peer-reviewed journal. Findings will also be presented at a conference and submitted to relevant health authorities. PROSPERO REGISTRATION NUMBER: CRD42017077656. PMID- 29703857 TI - The relationship between sleep duration and fruit/vegetable intakes in UK adults: a cross-sectional study from the National Diet and Nutrition Survey. AB - OBJECTIVES: There is increasing evidence to suggest an association between sleep and diet. The aim of the present study was to examine the association between sleep duration and fruit/vegetable (FV) intakes and their associated biomarkers in UK adults. DESIGN: Cross-sectional. SETTING: Data from The National Diet and Nutrition Survey. PARTICIPANTS: 1612 adults aged 19-65 years were included, pregnant/breastfeeding women were excluded from the analyses. OUTCOME MEASURES: Sleep duration was assessed by self-report, and diet was assessed by 4-day food diaries, disaggregation of foods containing FV into their components was conducted to determine total FV intakes. Sleep duration was divided into: short (<7 hours/day), reference (7-8 hours/day) and long (>8 hours/day) sleep periods. Multiple regression adjusting for confounders was used for analyses where sleep duration was the exposure and FV intakes and their associated biomarkers were the outcomes. Restricted cubic spline models were developed to explore potential non linear associations. RESULTS: In adjusted models, long sleepers (LS) consumed on average 28 (95% CI -50 to -6, p=0.01) g/day less of total FV compared to reference sleepers (RS), whereas short sleepers (SS) consumed 24 g/day less (95% CI -42 to -6, p=0.006) and had lower levels of FV biomarkers (total carotenoids, beta-carotene and lycopene) compared to RS. Restricted cubic spline models showed that the association between sleep duration and FV intakes was non-linear (p<0.001) with RS having the highest intakes compared to SS and LS. The associations between sleep duration and plasma total carotenoids (p=0.0035), plasma vitamin C (p=0.009) and lycopene (p<0.001) were non-linear with RS having the highest levels. CONCLUSIONS: These findings show a link between sleep duration and FV consumption. This may have important implications for lifestyle and behavioural change policy. PMID- 29703859 TI - Characteristics of value-based health and social care from organisations' perspectives (OrgValue): a mixed-methods study protocol. AB - INTRODUCTION: Health and social care systems are under pressure to organise care around patients' needs with constrained resources. Several studies reveal that care is constantly challenged by balancing economic requirements against individual patients' preferences and needs. Therefore, value-based health and social care aims to facilitate patient-centredness while taking the resources spent into consideration. The OrgValue project examines the implementation of patient-centredness while considering the health and social care organisations' resource orientation in the model region of the city of Cologne, Germany. METHODS AND ANALYSIS: First, the implementation status of patient-centredness as well as its facilitators and barriers-also in terms of resource orientation-will be assessed through face-to-face interviews with decision-makers (at least n=18) from health and social care organisations (HSCOs) in Cologne. Second, patients' understanding of patient-centredness and their preferences and needs will be revealed by conducting face-to-face interviews (at least n=15). Third, the qualitative results will provide the basis for a quantitative survey of decision makers from all HSCOs in Cologne, which will include questions on patient centredness, resource orientation and determinants of implementation. Fourth, qualitative interviews with decision-makers from different types of HSCOs will be conducted to develop a uniform measurement instrument on the cost and service structure of HSCOs. ETHICS AND DISSEMINATION: For all collected data, the relevant data protection regulations will be adhered to. Consultation and a positive vote from the ethics committee of the Medical Faculty of the University of Cologne have been obtained. All personal identifiers (eg, name, date of birth) will be pseudonymised. Dissemination strategies include a feedback report as well as research and development workshops for the organisations with the aim of initiating organisational learning and organisational development, presenting results in publications and at conferences, and public relations. TRIAL REGISTRATION NUMBER: DRKS00011925. PMID- 29703860 TI - Thinking clearly about the FIRST trial: addressing ethical challenges in cluster randomised trials of policy interventions involving health providers. AB - The ethics of the Flexibility In duty hour Requirements for Surgical Trainees (FIRST) trial have been vehemently debated. Views on the ethics of the FIRST trial range from it being completely unethical to wholly unproblematic. The FIRST trial illustrates the complex ethical challenges posed by cluster randomised trials (CRTs) of policy interventions involving healthcare professionals. In what follows, we have three objectives. First, we critically review the FIRST trial controversy, finding that commentators have failed to sufficiently identify and address many of the relevant ethical issues. The 2012 Ottawa Statement on the Ethical Design and Conduct of Cluster Randomized Trials provides researchers and research ethics committees with specific guidance for the ethical design and conduct of CRTs. Second, we aim to demonstrate how the Ottawa Statement provides much-needed clarity to the ethical issues in the FIRST trial, including: research participant identification; consent requirements; gatekeeper roles; benefit-harm analysis and identification of vulnerable participants. We nonetheless also find that the FIRST trial raises ethical issues not adequately addressed by the Ottawa Statement. Hence, third and finally, we raise important questions requiring further ethical analysis and guidance, including: Does clinical equipoise apply to policy interventions with little or no evidence-base? Do healthcare providers have an obligation to participate in research? Does the power-differential in certain healthcare settings render healthcare providers vulnerable to duress and coercion to participant in research? If so, what safeguards might be implemented to protect providers, while allowing important research to proceed? PMID- 29703861 TI - Comparison of Heterosubtypic Protection in Ferrets and Pigs Induced by a Single Cycle Influenza Vaccine. AB - Influenza is a major health threat, and a broadly protective influenza vaccine would be a significant advance. Signal Minus FLU (S-FLU) is a candidate broadly protective influenza vaccine that is limited to a single cycle of replication, which induces a strong cross-reactive T cell response but a minimal Ab response to hemagglutinin after intranasal or aerosol administration. We tested whether an H3N2 S-FLU can protect pigs and ferrets from heterosubtypic H1N1 influenza challenge. Aerosol administration of S-FLU to pigs induced lung tissue-resident memory T cells and reduced lung pathology but not the viral load. In contrast, in ferrets, S-FLU reduced viral replication and aerosol transmission. Our data show that S-FLU has different protective efficacy in pigs and ferrets, and that in the absence of Ab, lung T cell immunity can reduce disease severity without reducing challenge viral replication. PMID- 29703862 TI - Integrin Activation Controls Regulatory T Cell-Mediated Peripheral Tolerance. AB - Maintenance of the regulatory T (Treg) cell pool is essential for peripheral tolerance and prevention of autoimmunity. Integrins, heterodimeric transmembrane proteins consisting of alpha and beta subunits that mediate cell-to-cell and cell to-extracellular matrix interactions, play an important role in facilitating Treg cell contact-mediated suppression. In this article, we show that integrin activation plays an essential, previously unappreciated role in maintaining murine Treg cell function. Treg cell-specific loss of talin, a beta integrin binding protein, or expression of talin(L325R), a mutant that selectively abrogates integrin activation, resulted in lethal systemic autoimmunity. This dysfunction could be attributed, in part, to a global dysregulation of the Treg cell transcriptome. Activation of integrin alpha4beta1 led to increased suppressive capacity of the Treg cell pool, suggesting that modulating integrin activation on Treg cells may be a useful therapeutic strategy for autoimmune and inflammatory disorders. Taken together, these results reveal a critical role for integrin-mediated signals in controlling peripheral tolerance by virtue of maintaining Treg cell function. PMID- 29703844 TI - A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes. AB - Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 * 10-8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD. PMID- 29703863 TI - Antibodies Encoded by FCRL4-Bearing Memory B Cells Preferentially Recognize Commensal Microbial Antigens. AB - FCRL4, a low-affinity IgA Ab receptor with strong immunoregulatory potential, is an identifying feature of a tissue-based population of memory B cells (Bmem). We used two independent approaches to perform a comparative analysis of the Ag receptor repertoires of FCRL4+ and FCRL4- Bmem in human tonsils. We determined that FCRL4+ Bmem displayed lower levels of somatic mutations in their Ag receptors compared with FCRL4- Bmem but had similar frequencies of variable gene family usage. Importantly, Abs with reactivity to commensal microbiota were enriched in FCRL4+ cells, a phenotype not due to polyreactive binding characteristics. Our study links expression of the immunoregulatory FCRL4 molecule with increased recognition of commensal microbial Ags. PMID- 29703865 TI - A Specific Glycogen Mobilization Strategy Enables Rapid Awakening of Dormant Cyanobacteria from Chlorosis. AB - Many organisms survive stressful conditions via entry into a dormant state that can be rapidly exited when the stressor disappears; this ability provides a strong selective advantage. In the cyanobacterium Synechocystis sp. PCC 6803, the exit from nitrogen chlorosis takes less than 48 h and is enabled by the impressive metabolic flexibility of these cyanobacteria, which pass through heterotrophic and mixotrophic phases before reentering photoautotrophic growth. Switching between these states requires delicate coordination of carbohydrate oxidation, CO2 fixation, and photosynthesis. Here, we investigated the contribution of the different carbon catabolic routes by assessing mutants of these pathways during nitrogen chlorosis and resuscitation. The addition of nitrate to nitrogen-starved cells rapidly starts the awakening program. Metabolism switches from maintenance metabolism, characterized by residual photosynthesis and low cellular ATP levels, to an initial heterotrophic phase, characterized by respiration and an immediate increase in ATP levels. This respiration relies on glycogen breakdown catalyzed by the glycogen phosphorylase GlgP2. In the following transient mixotrophic phase, photosynthesis and CO2 fixation restart and glycogen is consumed. During the mixotrophic phase, parallel operation of the oxidative pentose phosphate cycle and the Entner-Doudoroff pathway is required for resuscitation to proceed; the glycolytic route via the Embden-Meyerhof-Parnas pathway has minor importance. Our data suggest that, during resuscitation, only the Entner-Doudoroff and oxidative pentose phosphate pathways supply the metabolic intermediates necessary for the anabolic reactions required to reconstitute a vegetative cell. Intriguingly, the key enzymes for glycogen catabolism are already expressed during the preceding chlorotic phase, in apparent preparation for rapid resuscitation. PMID- 29703864 TI - Farnesyltransferase Inhibition Exacerbates Eosinophilic Inflammation and Airway Hyperreactivity in Mice with Experimental Asthma: The Complex Roles of Ras GTPase and Farnesylpyrophosphate in Type 2 Allergic Inflammation. AB - Ras, a small GTPase protein, is thought to mediate Th2-dependent eosinophilic inflammation in asthma. Ras requires cell membrane association for its biological activity, and this requires the posttranslational modification of Ras with an isoprenyl group by farnesyltransferase (FTase) or geranylgeranyltransferase (GGTase). We hypothesized that inhibition of FTase using FTase inhibitor (FTI) 277 would attenuate allergic asthma by depleting membrane-associated Ras. We used the OVA mouse model of allergic inflammation and human airway epithelial (HBE1) cells to determine the role of FTase in inflammatory cell recruitment. BALB/c mice were first sensitized then exposed to 1% OVA aerosol or filtered air, and half were injected daily with FTI-277 (20 mg/kg per day). Treatment of mice with FTI-277 had no significant effect on lung membrane-anchored Ras, Ras protein levels, or Ras GTPase activity. In OVA-exposed mice, FTI-277 treatment increased eosinophilic inflammation, goblet cell hyperplasia, and airway hyperreactivity. Human bronchial epithelial (HBE1) cells were pretreated with 5, 10, or 20 MUM FTI 277 prior to and during 12 h IL-13 (20 ng/ml) stimulation. In HBE1 cells, FTase inhibition with FTI-277 had no significant effect on IL-13-induced STAT6 phosphorylation, eotaxin-3 peptide secretion, or Ras translocation. However, addition of exogenous FPP unexpectedly augmented IL-13-induced STAT6 phosphorylation and eotaxin-3 secretion from HBE1 cells without affecting Ras translocation. Pharmacological inhibition of FTase exacerbates allergic asthma, suggesting a protective role for FTase or possibly Ras farnesylation. FPP synergistically augments epithelial eotaxin-3 secretion, indicating a novel Ras independent farnesylation mechanism or direct FPP effect that promotes epithelial eotaxin-3 production in allergic asthma. PMID- 29703866 TI - Structure-Function Analysis of Chloroplast Proteins via Random Mutagenesis Using Error-Prone PCR. AB - Site-directed mutagenesis of chloroplast genes was developed three decades ago and has greatly advanced the field of photosynthesis research. Here, we describe a new approach for generating random chloroplast gene mutants that combines error prone polymerase chain reaction of a gene of interest with chloroplast complementation of the knockout Chlamydomonas reinhardtii mutant. As a proof of concept, we targeted a 300-bp sequence of the petD gene that encodes subunit IV of the thylakoid membrane-bound cytochrome b6f complex. By sequencing chloroplast transformants, we revealed 149 mutations in the 300-bp target petD sequence that resulted in 92 amino acid substitutions in the 100-residue target subunit IV sequence. Our results show that this method is suited to the study of highly hydrophobic, multisubunit, and chloroplast-encoded proteins containing cofactors such as hemes, iron-sulfur clusters, and chlorophyll pigments. Moreover, we show that mutant screening and sequencing can be used to study photosynthetic mechanisms or to probe the mutational robustness of chloroplast-encoded proteins, and we propose that this method is a valuable tool for the directed evolution of enzymes in the chloroplast. PMID- 29703867 TI - Plant Hormonomics: Multiple Phytohormone Profiling by Targeted Metabolomics. AB - Phytohormones are physiologically important small molecules that play essential roles in intricate signaling networks that regulate diverse processes in plants. We present a method for the simultaneous targeted profiling of 101 phytohormone related analytes from minute amounts of fresh plant material (less than 20 mg). Rapid and nonselective extraction, fast one-step sample purification, and extremely sensitive ultra-high-performance liquid chromatography-tandem mass spectrometry enable concurrent quantification of the main phytohormone classes: cytokinins, auxins, brassinosteroids, gibberellins, jasmonates, salicylates, and abscisates. We validated this hormonomic approach in salt-stressed and control Arabidopsis (Arabidopsis thaliana) seedlings, quantifying a total of 43 endogenous compounds in both root and shoot samples. Subsequent multivariate statistical data processing and cross-validation with transcriptomic data highlighted the main hormone metabolites involved in plant adaptation to salt stress. PMID- 29703868 TI - Primary care barriers to cataract surgery in the eastern zone of Peninsular Malaysia: an interpretative phenomenological analysis. AB - OBJECTIVE: Cataract is the leading cause of blindness in Malaysia. There is an alarming backlog of cataract extraction surgery as the majority believes they did not require surgery. This study aimed to explore the barriers at the primary care level to cataract surgery from the perspective of patients with severe cataract blindness. METHODS: Eleven participants were involved in this qualitative research which utilised the interpretative phenomenological analysis approach more renowned in health psychology research. All interviews conducted at their home. The interviews were recorded, typed verbatim, and the transcripts were analysed using NVivo software version 8.0. RESULTS: The main barriers identified at the primary care level were 1) nondisclosure of their visual problems originated from their belated needs for better sight, delayed awareness of their visual status and social stigma and 2) patient-provider-related issues namely miscommunication and delayed referral. The first main theme explains their belief for not requiring surgery. This has led to their delayed awareness and impeded disclosure of their visual problems to family members or primary care providers. The second main theme reflects the provider-patient-related issues which retarded cataract detection and referral process required for earlier cataract extraction surgery. CONCLUSION: Thus, the appropriate approach targeting these specific barriers at primary care level will be able to detect, motivate and assist patients for early uptake of cataract extraction surgery to improve their vision and prevent severe blindness. PMID- 29703869 TI - A 10-years retrospective study on Severe Cutaneous Adverse Reactions (SCARs) in a tertiary hospital in Penang, Malaysia. AB - INTRODUCTION: Severe cutaneous adverse drug reactions (SCARs) are not uncommon and potentially lifethreatening. Our objective is to study the patient characteristics, the pattern of implicated drugs and treatment outcome among patients with SCARs. METHODS: A 10-year retrospective analysis of SCARs cases in Penang General Hospital was carried out from January 2006 to December 2015. Data collection is based on the Malaysian Adverse Drug Reactions Advisory Committee registry and dermatology clinic records. RESULTS: A total of 189 cases of SCARs were encountered (F:M ratio; 1.2:1.0; mean age of 45 year). The commonest manifestation was Stevens-Johnson Syndrome [SJS] (55.0%), followed by toxic epidermal necrolysis [TEN] (23.8%), drug rash with eosinophilia and systemic symptoms [DRESS] (12.7%), acute generalised exanthematous pustulosis [AGEP] (4.8%), SJS/TEN overlap syndrome (2.6%) and generalised bullous fixed drug eruptions [GBFDE] (1.1%). Mean time to onset for TEN/SJS/Overlap syndrome was 10.5+/-13 days; AGEP, three days; GBFDE, 2.5+/-0.7 days, and DRESS, 29.4+/-5.7 days. The most common drugs implicated were antibiotics (33.3%), followed by allopurinol (18.9%) and anticonvulsant (18.4%). Out of 154 cases of SJS/TEN/overlap syndrome, allopurinol was the commonest causative agents (20.1%). In DRESS, allopurinol accounts for 45.8% of the cases. The mortality rate in SJS, TEN and DRESS were 1.9%, 13.3% and 12.5% respectively. No mortality was observed in AGEP and GBFDE. CONCLUSION: The commonest manifestations of SCARs in our setting were SJS, TEN and DRESS. Allopurinol was the most common culprit. Thus, judicious allopurinol use is advocated and pre-emptive genetic screening for HLAB *5801 should be considered. PMID- 29703870 TI - The epidemiology of chronic myeloid leukaemia in southern Sarawak, Borneo Island. AB - OBJECTIVES: There are very few published chronic myeloid leukaemia (CML) epidemiology studies in South-East Asia and no representative from Malaysia. METHODS: This is a cross-sectional study of adult CML patients (citizen) in a single but representative centre in southern Sarawak. RESULTS: Total 79 patients (Malay 39%, Chinese 30.4%, Iban 17.7%, Bidayuh 12.7%) were identified from the databases. Median age at diagnosis was younger, 40, compared to developed countries due to population structure. M:F ratio was higher, 2.6:1 compared to other countries 1.3-1.7:1. Majority presented at chronic phase (89.5%), low/intermediate risk score (80%) and started imatinib (96%) as first line tyrosine kinase inhibitor (TKI), which 40% of them switched to other TKI due to intolerance (17%) and failure (including disease progression)/not achieving major molecular response (83%). Quantitative polymerase chain reaction (qPCR) assessment after three months of TKI treatment had higher positive predictive value to predict Imatinib failure, 75%, than qPCR assessment after six months of TKI treatment, 58%. Presenting phase, symptoms, signs and laboratory data were like most countries. Estimated prevalence and incidence of CML in southern Sarawak was 69.2/1,000,000 population at the Year 2016 (similar to most developing countries) and 8.0/1,000,000 population per year at the Year 2011-2016 (similar to most countries), respectively. The incidence increased with age and was lowest among Iban, 12.8 and highest among Chinese, 19.5, which was 4x higher than Chinese in China. The prevalence of different BCR-ABL1 transcript type was like other Asia countries CONCLUSION: Significant epidemiological differences on M:F ratio and ethnic groups compared to other countries warrant further study. PMID- 29703871 TI - Epidemiology of Inflammatory Bowel Disease in Southern Peninsular Malaysia. AB - AIM: To record the incidence and prevalence of inflammatory bowel disease (IBD), its social demographics, clinical characteristics and treatment, in the state of Johor, Malaysia. METHODS: Hospital Sultanah Aminah, Johor Bahru, is the only public hospital in Johor with a Gastroenterology service. Data on all existing and new IBD patients managed by the Gastroenterology Unit in 2016 were collected. Incidence and prevalence of IBD in 2016 were then calculated based on the estimated population of Johor and Johor Bahru. RESULTS: Twenty-five new cases of IBD were diagnosed in 2016. Among the 25 cases, 13 cases were Crohn's disease (CD), 10 were ulcerative colitis (UC) and two were IBD Unclassified (IBDU). The crude incidence of IBD, CD, UC and IBDU were 0.68, 0.36, 0.27, and 0.05 per 100,000 population respectively. Ethnic Indians had the highest incidence of IBD at 4.21 followed by Malays and Chinese at 0.56 and 0.18 per 100,000 population respectively. A total of 156 IBD cases were captured. Amongst them, 85 cases were UC, 68 cases were CD and three cases were IBDU, hence the prevalence of IBD, UC, CD and IBDU were 4.27, 2.33, 1.86 and 0.08 per 100,000 population respectively. Similarly, Indians had the highest prevalence at 16.84, followed by Chinese at 4.06 and Malays at 3.44 per 100,000 population. CONCLUSIONS: The incidence of IBD in Johor is comparable to that of a previous study in northern Peninsular Malaysia. The ethnicity preponderance is similar to the previous studies conducted in Malaysia. PMID- 29703872 TI - Prevalence, risk factors and secondary prevention of stroke recurrence in eight countries from south, east and southeast asia: a scoping review. AB - INTRODUCTION: In most Asian countries, stroke is one of the major causes of mortality. A stroke event is life-changing for stroke survivors, which results in either mortality or disability. Therefore, this study comprehensively focuses on prevalence, risk factors, and secondary prevention for stroke recurrence identified in South, East, and Southeast Asian countries. METHODS: This scoping review uses the methodological framework of Arksey and O'Malley. A comprehensive search of academic journals (English) on this topic published from 2007 to 2017 was conducted. A total of 22 studies were selected from 585 studies screened from the electronic databases. RESULTS: First-year stroke recurrence rates are in the range of 2.2% to 25.4%. Besides that, modifiable risk factors are significantly associated with pathophysiological factors (hypertension, ankle-brachial pressure index, atherogenic dyslipidaemia, diabetes mellitus, metabolic syndrome, and atrial fibrillation) and lifestyle factors (obesity, smoking, physical inactivity, and high salt intake). Furthermore, age, previous history of cerebrovascular events, and stroke subtype are also significant influence risk factors for recurrence. A strategic secondary prevention method for recurrent stroke is health education along with managing risk factors through a combination of appropriate lifestyle intervention and pharmacological therapy. CONCLUSION: To prevent recurrent stroke, health intervention should be geared towards changing lifestyle to embody a healthier approach to life. This is of great importance to public health and stroke survivors' quality of life. PMID- 29703873 TI - Juara Sihat: assessing the sustained impact of a school-based obesity intervention. AB - INTRODUCTION: Obesity and physical inactivity among school children are among the most challenging health problems in Malaysia. The present study aimed to evaluate the sustained impact of Juara Sihat programme on physical activity level and anthropometric status at 18-month post-intervention. METHOD: Participants of Juara Sihat (n=55) were followed-up at 18 months after completion of the intervention. Juara Sihat intervention was implemented over 12 weeks and focused on four key components: (i) five one-hour nutrition education classes, (ii) four one-hour physical activity education sessions, (iii) family involvement, and (iv) empowerment of Parents and Teachers Association. Anthropometric variables (body mass index, body fat percentage and waist circumference) were measured and physical activity level was evaluated by using Physical Activity Questionnaire for Children (PAQ-C) at baseline (P0), immediately upon completion of intervention (P1), at three-month post-intervention (P2), and at 18-month postintervention (P3). Analyses of repeated measures analysis of covariance (ANCOVA) with intention-to-treat principle were applied. RESULTS: Sustained effects were found in BMI-for-age z-score which showed a reduction (P0 2.41+/ 0.84 vs P3 2.27+/-0.81) and physical activity level which showed positive improvements (P0 2.46+/-0.62 vs P3 2.87+/-0.76) at 18 months after intervention was completed. Body fat and waist circumference had increased over the same time period. CONCLUSION: Overall, this study successfully demonstrated sustained intervention effects of Juara Sihat intervention on BMI-for-age z-score and physical activity, but not on body fat percentage and waist circumference. PMID- 29703874 TI - Cytokine profile of patients with leptospirosis in Sabah, Malaysia. AB - BACKGROUND: Leptospirosis is a zoonotic disease with symptoms ranging from a mild, febrile illness to a severe form with multiorgan failure. Severe leptospirosis may require medical interventions in the form of dialysis and/or mechanical ventilation and often leads to mortality. An exaggerated host immune response-in particular, a "cytokine storm"-that causes endothelial and organ damage is associated with the disease severity and mortality. METHODS: Microscopic agglutination test (MAT)-positive and MAT-negative human serum samples (n=30) from patients with leptospirosis were obtained from the Public Health Laboratory, Kota Kinabalu, Sabah, Malaysia and control serum samples (n=10) were obtained from healthy student volunteers. We estimated the levels of IL-1beta, IL-6, IL-8, IL-10, and TNF-alpha in serum samples by a Luminex assay. RESULTS: The levels of IL-6, IL-8, and IL1-beta were significantly higher in 13% of the patients with leptospirosis compared to the healthy controls, while the levels of IL-10 and TNF-alpha were not elevated in either group. CONCLUSION: Our data suggest that elevated levels of IL-6, IL- 8, and IL1-beta may be associated with leptospirosis disease severity, which requires patient follow-up for confirmation. PMID- 29703875 TI - Mesenteric bones: Intra-abdominal heterotopic ossification. AB - Intra-abdominal heterotopic ossification usually develops after abdominal surgery and can cause complications such as bowel obstruction and even intestinal perforation. Bisphosphonates, NSAIDs and even local radiation is used as prophylaxis or treatment. Surgeons must consider heterotopic ossification and its complications as a differential when managing complex polytrauma patients with suspicious radiographic densities. PMID- 29703876 TI - The use of facial artery musculomucosal (FAMM) readvancement flap in closure of recurrent oronasal fistula. AB - High failure rate for recurrent palatal fistulas closure pose a great challenge to plastic surgeons. Tongue and facial artery musculomucosal (FAMM) flaps are the more commonly used flaps for closure of these recurrent fistulas. We report a case of a formerly inset FAMM flap to effectively close a previously repaired oronasal fistula. PMID- 29703877 TI - Ancient schwannoma of cervical sympathetic chain masquerading as carotid body tumour. AB - Schwannoma of cervical sympathetic chain is a rare cause of neck swelling. We report a 73- year-old male presented with anterior neck triangle swelling mimicking a carotid body tumour. Surgical excision was done, and the histopathological examination reported as ancient schwannoma. We would like to discuss the important differential diagnoses and highlight the possibility of an ancient schwannoma of cervical sympathetic chain masquerading as carotid body tumour. Also, to emphasise the importance of imaging for pre-operative planning and counselling. PMID- 29703878 TI - Lumbosacral osteosarcoma with dural spread, skip lesions and intravascular extension: A case report. AB - Primary osteosarcoma of the spine is indeed rare and only several sporadic cases have been reported. It tends to occur in a slightly older age group than those with appendicular skeleton tumours. We present here an unusual case of aggressive lumbosacral osteosarcoma in a young teenager complicated by extensive dural spread, skip lesions and intravascular extension. Although a histopathological examination is mandatory to establish the diagnosis, this case emphasises the need of imaging to ascertain the full extent of disease spread especially in deciding the type of treatment to be instituted and to evaluate the response to the treatment. PMID- 29703879 TI - Progressive pulmonary vein stenosis in Down syndrome infant: a rare cause of pulmonary hypertension. AB - Pulmonary veins stenosis in a Down Syndrome infant with normal connection pulmonary vein is rare and precise incidence of this disease is unknown. We report a case of progressive multiple pulmonary vein stenosis in a Down Syndrome infant with congenital heart disease and transient myeloproliferative leukaemia. This case-report aims to improve awareness among physicians and sonographers of this disease and the importance of pulmonary vein assessment in congenital heart disease with unexplained pulmonary hypertension. PMID- 29703880 TI - Intradermal Naevi of External Auditory Canal: Unusual location with a unique presentation. AB - The incidence of intradermal nevus in the external auditory canal is uncommon. We herein are describing a case of 60-year-old lady who presented with foreign body sensation in the right external ear canal (EAC) with mild discomfort and ear bleed during ear picking. Otoscopic examination revealed hyperpigmented mass on the floor of the outer two third of EAC. Complete excisional biopsy of the mass resulted in histopathology findings of intradermal nevus. Despite the fact that the disease is not alarming, the possibilities of benign melanocytic nevi transformation into malignant lesions such as melanoma need to be ruled out. PMID- 29703881 TI - The association of factor V G1961A (factor V Leiden), prothrombin G20210A, MTHFR C677T and PAI-1 4G/5G polymorphisms with recurrent pregnancy loss in Bosnian women. AB - Aim To investigate association of factor V Leiden, prothrombin G20210A, MTHFR C677T and PAI-1 4G/5G polymorphisms with recurrent pregnancy loss in Bosnian women. Methods A total of 60 women with two or more consecutive miscarriages before 20 weeks of gestation with the same partners and without history of known causes or recurrent pregnancy loss were included. A control group included 80 healthy women who had one or more successful pregnancies without history of any complication which could be associated with miscarriages. Genotyping of factor V Leiden, prothrombin G20210A, MTHFR C677T and PAI-1 4G/5G polymorphisms were performed by polymerase chain reaction/restriction fragments length polymorphism method (PCR/RFLP). Results Both factor V Leiden and MTHFR C677T polymorphisms were significantly associated with recurrent pregnancy loss (RPL) in Bosnian women while prothrombin G20210A and PAI-1 4G/5G polymorphisms did not show strongly significant association. Conclusion The presence of thrombophilic polymorphisms may predispose women to recurrent pregnancy loss. Future investigation should be addressed in order to find when carriers of those mutations, polymorphisms should be treated with anticoagulant therapy. PMID- 29703882 TI - Unusual Association of Aniridia with Aicardi-Goutieres Syndrome-Related Congenital Glaucoma in a Tertiary Care Center. AB - BACKGROUND Aicardi-Goutieres syndrome (AGS) is a rare autosomal recessive encephalopathy of early onset. AGS visual dysfunction range from nystagmus and optic atrophy to cortical blindness in affected individuals; however, congenital glaucoma has been recently noticed among AGS pediatric patients. According to the literature, aniridia has never been recognized among AGS patients. CASE REPORT We report the case of a 4-year-old boy with AGS who had multiple congenital anomalies in the eyes. He was found to have congenital glaucoma, nystagmus, spherophakia with shallow chambers, and aniridia in both eyes. Family history was positive for glaucoma, with consanguineously married parents. According to the genetics report, both parents are carriers of congenital glaucoma genes. A whole exome sequencing identified IFIH1 heterozygous missense mutation of the patient, which is associated with AGS Type 7. Also, he was diagnosed as having congenital glaucoma with CYP1B1 mutation, homozygous recessive. This case demonstrates the unusual coexistence of bilateral aniridia, a feature not previously reported in ocular findings of AGS. CONCLUSIONS In summary, this is the first reported case of aniridia with AGS-related congenital glaucoma in the literature. This paper summarizes the usual ocular manifestation of AGS, also it highlights atypical ocular features in both; AGS as well as congenital glaucoma. The aim of this paper is to lay the foundation for a national database on AGS in Saudi Arabia, which will help create a bridge between genetic data and clinical findings of AGS patients. PMID- 29703883 TI - Interactions Among Polymorphisms of Susceptibility Loci for Alzheimer's Disease or Depressive Disorder. AB - BACKGROUND Several genetic susceptibility loci for major depressive disorder (MDD) or Alzheimer's disease (AD) have been described. Interactions among polymorphisms are thought to explain the differences between low- and high-risk groups. We tested for the contribution of interactions between multiple functional polymorphisms in the risk of MDD or AD. MATERIAL AND METHODS A genetic association case-control study was performed in 68 MDD cases, 84 AD cases (35 of them with comorbid depression), and 90 controls. The contribution of 7 polymorphisms from 5 genes (APOE, HSPA1A, SLC6A4, HTR2A, and BDNF) related to risk of MDD or AD development was analyzed. RESULTS Significant associations were found between MDD and interactions among polymorphisms in HSPA1A, SLC6A4, and BDNF or HSPA1A, BDNF, and APOE genes. For polymorphisms in the APOE gene in AD, significant differences were confirmed on the distributions of alleles and genotype rates compared to the control or MDD. Increased probability of comorbid depression was found in patients with AD who do not carry the epsilon4 allele of APOE. CONCLUSIONS Assessment of the interactions among polymorphisms of susceptibility loci in both MDD and AD confirmed a synergistic effect of genetic factors influencing inflammatory, serotonergic, and neurotrophic pathways at these heterogenous complex diseases. The effect of interactions was greater in MDD than in AD. A presence of the epsilon4 allele was confirmed as a genetic susceptibility factor in AD. Our findings indicate a role of APOE genotype in onset of comorbid depression in a subgroup of patients with AD who are not carriers of the APOE epsilon4 allele. PMID- 29703884 TI - The Ustilago maydis repetitive effector Rsp3 blocks the antifungal activity of mannose-binding maize proteins. AB - To cause disease in maize, the biotrophic fungus Ustilago maydis secretes a large arsenal of effector proteins. Here, we functionally characterize the repetitive effector Rsp3 (repetitive secreted protein 3), which shows length polymorphisms in field isolates and is highly expressed during biotrophic stages. Rsp3 is required for virulence and anthocyanin accumulation. During biotrophic growth, Rsp3 decorates the hyphal surface and interacts with at least two secreted maize DUF26-domain family proteins (designated AFP1 and AFP2). AFP1 binds mannose and displays antifungal activity against the rsp3 mutant but not against a strain constitutively expressing rsp3. Maize plants silenced for AFP1 and AFP2 partially rescue the virulence defect of rsp3 mutants, suggesting that blocking the antifungal activity of AFP1 and AFP2 by the Rsp3 effector is an important virulence function. Rsp3 orthologs are present in all sequenced smut fungi, and the ortholog from Sporisorium reilianum can complement the rsp3 mutant of U. maydis, suggesting a novel widespread fungal protection mechanism. PMID- 29703885 TI - Bayesian nonparametric discovery of isoforms and individual specific quantification. AB - Most human protein-coding genes can be transcribed into multiple distinct mRNA isoforms. These alternative splicing patterns encourage molecular diversity, and dysregulation of isoform expression plays an important role in disease etiology. However, isoforms are difficult to characterize from short-read RNA-seq data because they share identical subsequences and occur in different frequencies across tissues and samples. Here, we develop BIISQ, a Bayesian nonparametric model for isoform discovery and individual specific quantification from short read RNA-seq data. BIISQ does not require isoform reference sequences but instead estimates an isoform catalog shared across samples. We use stochastic variational inference for efficient posterior estimates and demonstrate superior precision and recall for simulations compared to state-of-the-art isoform reconstruction methods. BIISQ shows the most gains for low abundance isoforms, with 36% more isoforms correctly inferred at low coverage versus a multi-sample method and 170% more versus single-sample methods. We estimate isoforms in the GEUVADIS RNA-seq data and validate inferred isoforms by associating genetic variants with isoform ratios. PMID- 29703886 TI - Plasma cell differentiation is controlled by multiple cell division-coupled epigenetic programs. AB - The genomic loci associated with B cell differentiation that are subject to transcriptional and epigenetic regulation in vivo are not well defined, leaving a gap in our understanding of the development of humoral immune responses. Here, using an in vivo T cell independent B cell differentiation model, we define a cellular division-dependent cis-regulatory element road map using ATAC-seq. Chromatin accessibility changes correlate with gene expression and reveal the reprogramming of transcriptional networks and the genes they regulate at specific cell divisions. A subset of genes in naive B cells display accessible promoters in the absence of transcription and are marked by H3K27me3, an EZH2 catalyzed repressive modification. Such genes encode regulators of cell division and metabolism and include the essential plasma cell transcription factor Blimp-1. Chemical inhibition of EZH2 results in enhanced plasma cell formation, increased expression of the above gene set, and premature expression of Blimp-1 ex vivo. These data provide insights into cell-division coupled epigenetic and transcriptional processes that program plasma cells. PMID- 29703887 TI - Supramolecular latching system based on ultrastable synthetic binding pairs as versatile tools for protein imaging. AB - Here we report ultrastable synthetic binding pairs between cucurbit[7]uril (CB[7]) and adamantyl- (AdA) or ferrocenyl-ammonium (FcA) as a supramolecular latching system for protein imaging, overcoming the limitations of protein-based binding pairs. Cyanine 3-conjugated CB[7] (Cy3-CB[7]) can visualize AdA- or FcA labeled proteins to provide clear fluorescence images for accurate and precise analysis of proteins. Furthermore, controllability of the system is demonstrated by treating with a stronger competitor guest. At low temperature, this allows us to selectively detach Cy3-CB[7] from guest-labeled proteins on the cell surface, while leaving Cy3-CB[7] latched to the cytosolic proteins for spatially conditional visualization of target proteins. This work represents a non-protein based bioimaging tool which has inherent advantages over the widely used protein based techniques, thereby demonstrating the great potential of this synthetic system. PMID- 29703888 TI - Manipulation of insulin signaling phenocopies evolution of a host-associated polyphenism. AB - Plasticity, the capacity of an organism to respond to its environment, is thought to evolve through changes in development altering the integration of environmental cues. In polyphenism, a discontinuous plastic response produces two or more phenotypic morphs. Here we describe evolutionary change in wing polyphenism and its underlying developmental regulation in natural populations of the red-shouldered soapberry bug, Jadera haematoloma (Insecta: Hemiptera: Rhopalidae) that have adapted to a novel host plant. We find differences in the fecundity of morphs in both sexes and in adult expression of insulin signaling components in the gonads. Further, the plastic response of ancestral-state bugs can be shifted to resemble the reaction norm of derived bugs by the introduction of exogenous insulin or RNA interference targeting the insulin signaling component encoded by FoxO. These results suggest that insulin signaling may be one pathway involved in the evolution of this polyphenism, allowing adaptation to a novel nutritional environment. PMID- 29703889 TI - Necroptosis promotes cell-autonomous activation of proinflammatory cytokine gene expression. AB - Necroptosis, a form of regulated necrotic cell death, is mediated by receptor interacting protein 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL). However, the mechanism by which necroptosis promotes inflammation is still unclear. Here we report that the expression of cytokines is robustly upregulated in a cell-autonomous manner during necroptosis induced by tumor necrosis factor alpha (TNFalpha). We demonstrate that TNFalpha-induced necroptosis leads to two waves of cytokine production. The first wave, more transient and weaker than the second, is in response to TNFalpha alone; whereas the second wave depends upon the necroptotic signaling. We show that necroptosis promotes the transcription of TNFalpha-target genes in a cell-intrinsic manner. The activation of both NF-kappaB and p38 by the necroptotic machinery, RIPK1, RIPK3, and MLKL, is involved in mediating the robust induction of cytokine expression in the second wave. In contrast, necroptosis induced by direct oligomerization of MLKL promotes cytokine production at much lower levels than that of necroptosis induced with TNFalpha. Thus, we conclude that TNFalpha induced necroptosis signaling events mediated by RIPK1 and RIPK3 activation, in addition to the MLKL oligomerization, promotes the expression of cytokines involving multiple intracellular signaling mechanisms including NF-kappaB pathway and p38. These findings reveal that the necroptotic cell death machinery mounts an immune response by promoting cell-autonomous production of cytokines. Our study provides insights into the mechanism by which necroptosis promotes inflammation in human diseases. PMID- 29703890 TI - An enrichment method based on synergistic and reversible covalent interactions for large-scale analysis of glycoproteins. AB - Protein glycosylation is ubiquitous in biological systems and essential for cell survival. However, the heterogeneity of glycans and the low abundance of many glycoproteins complicate their global analysis. Chemical methods based on reversible covalent interactions between boronic acid and glycans have great potential to enrich glycopeptides, but the binding affinity is typically not strong enough to capture low-abundance species. Here, we develop a strategy using dendrimer-conjugated benzoboroxole to enhance the glycopeptide enrichment. We test the performance of several boronic acid derivatives, showing that benzoboroxole markedly increases glycopeptide coverage from human cell lysates. The enrichment is further improved by conjugating benzoboroxole to a dendrimer, which enables synergistic benzoboroxole-glycan interactions. This robust and simple method is highly effective for sensitive glycoproteomics analysis, especially capturing low-abundance glycopeptides. Importantly, the enriched glycopeptides remain intact, making the current method compatible with mass spectrometry-based approaches to identify glycosylation sites and glycan structures. PMID- 29703892 TI - Interaction of the primordial germ cell-specific protein C2EIP with PTCH2 directs differentiation of embryonic stem cells via HH signaling activation. AB - Although many marker genes for germ cell differentiation have been identified, genes that specifically regulate primordial germ cell (PGC) generation are more difficult to determine. In the current study, we confirmed that C2EIP is a PGC marker gene that regulates differentiation by influencing the expression of pluripotency-associated genes such as Oct4 and Sox2. Knockout of C2EIP during embryonic development reduced PGC generation efficiency 1.5-fold, whereas C2EIP overexpression nearly doubled the generation efficiency both in vitro and in vivo. C2EIP encodes a cytoplasmic protein that interacted with PTCH2 at the intracellular membrane, promoted PTCH2 ubiquitination, activated the Hedgehog (HH) signaling pathway via competitive inhibition of the GPCR-like protein SMO, and positively regulated PGC generation. Activation and expression of C2EIP are regulated by the transcription factor STAT1, histone acetylation, and promoter methylation. Our data suggest that C2EIP is a novel, specific indicator of PGC generation whose gene product regulates embryonic stem cell differentiation by activating the HH signaling pathway via PTCH2 modification. PMID- 29703891 TI - Targeting of NAT10 enhances healthspan in a mouse model of human accelerated aging syndrome. AB - Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare, but devastating genetic disease characterized by segmental premature aging, with cardiovascular disease being the main cause of death. Cells from HGPS patients accumulate progerin, a permanently farnesylated, toxic form of Lamin A, disrupting the nuclear shape and chromatin organization, leading to DNA-damage accumulation and senescence. Therapeutic approaches targeting farnesylation or aiming to reduce progerin levels have provided only partial health improvements. Recently, we identified Remodelin, a small-molecule agent that leads to amelioration of HGPS cellular defects through inhibition of the enzyme N-acetyltransferase 10 (NAT10). Here, we show the preclinical data demonstrating that targeting NAT10 in vivo, either via chemical inhibition or genetic depletion, significantly enhances the healthspan in a Lmna G609G HGPS mouse model. Collectively, the data provided here highlights NAT10 as a potential therapeutic target for HGPS. PMID- 29703893 TI - Artemether attenuates LPS-induced inflammatory bone loss by inhibiting osteoclastogenesis and bone resorption via suppression of MAPK signaling pathway. AB - Osteolysis is an osteolytic lesion featured by enhanced osteoclast formation and potent bone erosion. Lacking of effective regimen for treatment of the pathological process highlights the importance of identifying agents that can suppress the differentiation and function of osteoclast. Artemether is a natural compound derived from Artemisia annua L. and it is popularized for the treatment of malaria. In present study, we demonstrated that artemether could suppress RANKL-induced osteoclastogenesis and expression of osteoclast marker genes such as tartrate-resistant acid phosphatase, cathepsin K, matrix metalloproteinase 9, nuclear factor of activated T-cell cytoplasmic 1, and dendritic cell-specific transmembrane protein. It inhibited the osteoclastic bone resorption in a dose dependent manner in vitro. Furthermore, artemether attenuated RANKL-induced MAPKs (ERK, JNK, p-38) activity. In addition, we have showed that artemether was able to mitigate bone erosion in a murine model of LPS-induced inflammatory bone loss. Taken together, these findings suggest that artemether reduces inflammatory bone loss via inhibition of MAPKs activation during osteoclast differentiation, and it might be a potential candidate for the treatment of osteoclast-related disorders. PMID- 29703894 TI - A somatic role for the histone methyltransferase Setdb1 in endogenous retrovirus silencing. AB - Subsets of endogenous retroviruses (ERVs) are derepressed in mouse embryonic stem cells (mESCs) deficient for Setdb1, which catalyzes histone H3 lysine 9 trimethylation (H3K9me3). Most of those ERVs, including IAPs, remain silent if Setdb1 is deleted in differentiated embryonic cells; however they are derepressed when deficient for Dnmt1, suggesting that Setdb1 is dispensable for ERV silencing in somatic cells. However, H3K9me3 enrichment on ERVs is maintained in differentiated cells and is mostly diminished in mouse embryonic fibroblasts (MEFs) lacking Setdb1. Here we find that distinctive sets of ERVs are reactivated in different types of Setdb1-deficient somatic cells, including the VL30-class of ERVs in MEFs, whose derepression is dependent on cell-type-specific transcription factors (TFs). These data suggest a more general role for Setdb1 in ERV silencing, which provides an additional layer of epigenetic silencing through the H3K9me3 modification. PMID- 29703895 TI - Limits on determining the skill of North Atlantic Ocean decadal predictions. AB - The northern North Atlantic is important globally both through its impact on the Atlantic Meridional Overturning Circulation (AMOC) and through widespread atmospheric teleconnections. The region has been shown to be potentially predictable a decade ahead with the skill of decadal predictions assessed against reanalyses of the ocean state. Here, we show that the prediction skill in this region is strongly dependent on the choice of reanalysis used for validation, and describe the causes. Multiannual skill in key metrics such as Labrador Sea density and the AMOC depends on more than simply the choice of the prediction model. Instead, this skill is related to the similarity between the nature of interannual density variability in the underlying climate model and the chosen reanalysis. The climate models used in these decadal predictions are also used in climate projections, which raises questions about the sensitivity of these projections to the models' innate North Atlantic density variability. PMID- 29703896 TI - Population size changes and selection drive patterns of parallel evolution in a host-virus system. AB - Predicting the repeatability of evolution remains elusive. Theory and empirical studies suggest that strong selection and large population sizes increase the probability for parallel evolution at the phenotypic and genotypic levels. However, selection and population sizes are not constant, but rather change continuously and directly affect each other even on short time scales. Here, we examine the degree of parallel evolution shaped through eco-evolutionary dynamics in an algal host population coevolving with a virus. We find high degrees of parallelism at the level of population size changes (ecology) and at the phenotypic level between replicated populations. At the genomic level, we find evidence for parallelism, as the same large genomic region was duplicated in all replicated populations, but also substantial novel sequence divergence between replicates. These patterns of genome evolution can be explained by considering population size changes as an important driver of rapid evolution. PMID- 29703897 TI - The signalling game between plants and pollinators. AB - Plants can send floral signals to advertise their reward for pollinators. Based on the presence or absents of such signals, pollinators can determine whether to visit plants. Plants can send dishonest signals but foraging behaviours of pollinators can limit the cheating strategies of plants. We model the plant pollinator interactions by the two-type Spence signalling game and investigate the conditions under which honest signalling can be established. In our model, plants either send costly signal or they do not. The cost of signal is dependent on the quality of plant. Pollinators can learn from the interactions with plants and can update their willingness to visit plants' flowers to maximize their foraging efficiency. We find three general conditions that are required for the evolutionary stability of honest signaling. Those conditions are satisfied if there is (a) a high frequency of high-yield signalling plants in the population, (b) the balance between cost and benefit of signalling, and (c) high cost of dishonest signalling. Our model also predicts that other factors contributing to the establishment of honest signaling are the low abundance of pollinators, and the positive density-dependent and positive frequency-dependent relationship between plants and pollinators. PMID- 29703898 TI - TAK1 activation of alpha-TAT1 and microtubule hyperacetylation control AKT signaling and cell growth. AB - Acetylation of microtubules (MT) confers mechanical stability necessary for numerous functions including cell cycle and intracellular transport. Although alphaTAT1 is a major MT acetyltransferase, how this enzyme is regulated remains much less clear. Here we report TGF-beta-activated kinase 1 (TAK1) as a key activator of alphaTAT1. TAK1 directly interacts with and phosphorylates alphaTAT1 at Ser237 to critically enhance its catalytic activity, as mutating this site to alanine abrogates, whereas a phosphomimetic induces MT hyperacetylation across cell types. Using a custom phospho-alphaTAT1-Ser237 antibody, we screen various mouse tissues to discover that brain contains some of the highest TAK1-dependent alphaTAT1 activity, which, accordingly, is diminished rapidly upon intra-cerebral injection of a TAK1 inhibitor. Lastly, we show that TAK1 selectively inhibits AKT to suppress mitogenic and metabolism-related pathways through MT-based mechanisms in culture and in vivo. Collectively, our findings support a fundamental new role for TGF-beta signaling in MT-related functions and disease. PMID- 29703899 TI - Mitochondria-targeted Probes for Imaging Protein Sulfenylation. AB - Mitochondrial reactive oxygen species (ROS) are essential regulators of cellular signaling, metabolism and epigenetics underlying the pathophysiology of numerous diseases. Despite the critical function of redox regulation in mitochondria, currently there are limited methods available to monitor protein oxidation in this key subcellular organelle. Here, we describe compounds for imaging sulfenylated proteins in mitochondria: DCP-NEt2-Coumarin (DCP-NEt2C) and rhodamine-based DCP-Rho1. Side-by-side comparison studies are presented on the reactivity of DCP-NEt2C and DCP-Rho1 with a model protein sulfenic acid (AhpC SOH) and mitochondrial localization to identify optimized experimental conditions for labeling and visualization of protein sulfenylation that would be independent of mitochondria membrane potential and would not impact mitochondrial function. These probes are applied to image mitochondrial protein sulfenylation under conditions of serum starvation and in a cell culture model of lung cancer exposed to ionizing radiation and silver nanoparticles, agents serving dual functions as environmental stressors and cancer therapeutics. PMID- 29703900 TI - Three-dimensional Cardiomyocytes Structure Revealed By Diffusion Tensor Imaging and Its Validation Using a Tissue-Clearing Technique. AB - We characterized the microstructural response of the myocardium to cardiovascular disease using diffusion tensor imaging (DTI) and performed histological validation by intact, un-sectioned, three-dimensional (3D) histology using a tissue-clearing technique. The approach was validated in normal (n = 7) and ischemic (n = 8) heart failure model mice. Whole heart fiber tracking using DTI in fixed ex-vivo mouse hearts was performed, and the hearts were processed with the tissue-clearing technique. Cardiomyocytes orientation was quantified on both DTI and 3D histology. Helix angle (HA) and global HA transmurality (HAT) were calculated, and the DTI findings were confirmed with 3D histology. Global HAT was significantly reduced in the ischemic group (DTI: 0.79 +/- 0.13 degrees /% transmural depth [TD] and 3D histology: 0.84 +/- 0.26 degrees /%TD) compared with controls (DTI: 1.31 +/- 0.20 degrees /%TD and 3D histology: 1.36 +/- 0.27 degrees /%TD, all p < 0.001). On direct comparison of DTI with 3D histology for the quantitative assessment of cardiomyocytes orientation, significant correlations were observed in both per-sample (R2 = 0.803) and per-segment analyses (R2 = 0.872). We demonstrated the capability and accuracy of DTI for mapping cardiomyocytes orientation by comparison with the intact 3D histology acquired by tissue-clearing technique. DTI is a promising tool for the noninvasive characterization of cardiomyocytes architecture. PMID- 29703901 TI - CVD-grown monolayer MoS2 in bioabsorbable electronics and biosensors. AB - Transient electronics represents an emerging technology whose defining feature is an ability to dissolve, disintegrate or otherwise physically disappear in a controlled manner. Envisioned applications include resorbable/degradable biomedical implants, hardware-secure memory devices, and zero-impact environmental sensors. 2D materials may have essential roles in these systems due to their unique mechanical, thermal, electrical, and optical properties. Here, we study the bioabsorption of CVD-grown monolayer MoS2, including long-term cytotoxicity and immunological biocompatibility evaluations in biofluids and tissues of live animal models. The results show that MoS2 undergoes hydrolysis slowly in aqueous solutions without adverse biological effects. We also present a class of MoS2-based bioabsorbable and multi-functional sensor for intracranial monitoring of pressure, temperature, strain, and motion in animal models. Such technology offers specific, clinically relevant roles in diagnostic/therapeutic functions during recovery from traumatic brain injury. Our findings support the broader use of 2D materials in transient electronics and qualitatively expand the design options in other areas. PMID- 29703902 TI - Snail promotes ovarian cancer progression by recruiting myeloid-derived suppressor cells via CXCR2 ligand upregulation. AB - Snail is a major transcriptional factor that induces epithelial-mesenchymal transition (EMT). In this study, we explore the effect of Snail on tumor immunity. Snail knockdown in mouse ovarian cancer cells suppresses tumor growth in immunocompetent mice, associated with an increase of CD8+ tumor-infiltrating lymphocytes and a decrease of myeloid-derived suppressor cells (MDSCs). Snail knockdown reduces the expression of CXCR2 ligands (CXCL1 and CXCL2), chemokines that attract MDSCs to the tumor via CXCR2. Snail upregulates CXCR ligands through NF-kB pathway, and most likely, through direct binding to the promoters. A CXCR2 antagonist suppresses MDSC infiltration and delays tumor growth in Snail expressing mouse tumors. Ovarian cancer patients show elevated serum CXCL1/2, which correlates with Snail expression, MDSC infiltration, and short overall survival. Thus, Snail induces cancer progression via upregulation of CXCR2 ligands and recruitment of MDSCs. Blocking CXCR2 represents an immunological therapeutic approach to inhibit progression of Snail-high tumors undergoing EMT. PMID- 29703903 TI - IL-31 is crucial for induction of pruritus, but not inflammation, in contact hypersensitivity. AB - IL-31, which is a member of the IL-6 family of cytokines, is produced mainly by activated CD4+ T cells, in particular activated Th2 cells, suggesting a contribution to development of type-2 immune responses. IL-31 was reported to be increased in specimens from patients with atopic dermatitis, and IL-31-transgenic mice develop atopic dermatitis-like skin inflammation, which is involved in the pathogenesis of atopic dermatitis. However, the role of IL-31 in development of contact dermatitis/contact hypersensitivity (CHS), which is mediated by hapten specific T cells, including Th2 cells, is not fully understood. Therefore, we investigated this using IL-31-deficient (Il31-/-) mice, which we newly generated. We demonstrated that the mice showed normal migration and maturation of skin dendritic cells and induction of hapten-specific T cells in the sensitization phase of FITC-induced CHS, and normal induction of local inflammation in the elicitation phase of FITC- and DNFB-induced CHS. On the other hand, those mice showed reduced scratching frequency and duration during FITC- and/or DNFB-induced CHS. Our findings suggest that IL-31 is responsible for pruritus, but not induction of local skin inflammation, during CHS induced by FITC and DNFB. PMID- 29703904 TI - Thymol nanoemulsion exhibits potential antibacterial activity against bacterial pustule disease and growth promotory effect on soybean. AB - An antibacterial and plant growth promoting nanoemulsion was formulated using thymol, an essential oil component of plant and Quillaja saponin, a glycoside surfactant of Quillaja tree. The emulsion was prepared by a sonication method. Fifty minutes of sonication delivered a long term stable thymol nanoemulsion which was characterized by dynamic light scattering (DLS), transmission electron microscopy (TEM), cryogenic-field emission scanning electron microscopy (Cryo FESEM) and fourier transform infra-red (FTIR) spectroscopy. Creaming index, pH and dilution stability were also studied for deliberation of its practical applications. The nanoemulsion (0.01-0.06%, v/v) showed substantial in vitro growth inhibition of Xanthomonas axonopodis pv. glycine of soybean (6.7-0.0 log CFU/ml). In pot experiments, seed treatment and foliar application of the nanoemulsion (0.03-0.06%, v/v) significantly lowered the disease severity (DS) (33.3-3.3%) and increased percent efficacy of disease control (PEDC) (54.9-95.4%) of bacterial pustule in soybean caused by X. axonopodis pv. glycine. Subsequently, significant enhancements of plant growth were also recorded in plants treated with thymol nanoemulsion. This is the first report of a thymol based nanoemulsion obtained using Quillaja saponin as a surfactant. Our study claims that nano scale thymol could be a potential antimicrobial and plant growth promoting agent for agriculture. PMID- 29703905 TI - Local administration of curcumin-loaded nanoparticles effectively inhibits inflammation and bone resorption associated with experimental periodontal disease. AB - There is evidence indicating that curcumin has multiple biological activities, including anti-inflammatory properties. In vitro and in vivo studies demonstrate that curcumin may attenuate inflammation and the connective tissue destruction associated with periodontal disease. Most of these studies use systemic administration, and considering the site-specific nature of periodontal disease and also the poor pharmacodynamic properties of curcumin, we conducted this proof of principle study to assess the biological effect of the local administration of curcumin in a nanoparticle vehicle on experimental periodontal disease. We used 16 rats divided into two groups of 8 animals according to the induction of experimental periodontal disease by bilateral injections of LPS or of the vehicle control directly into the gingival tissues 3*/week for 4 weeks. The same volume of curcumin-loaded nanoparticles or of nanoparticle vehicle was injected into the same sites 2*/week. uCT analysis showed that local administration of curcumin resulted in a complete inhibition of inflammatory bone resorption and in a significant decrease of both osteoclast counts and of the inflammatory infiltrate; as well as a marked attenuation of p38 MAPK and NF-kB activation. We conclude that local administration of curcumin-loaded nanoparticles effectively inhibited inflammation and bone resorption associated with experimental periodontal disease. PMID- 29703907 TI - MicroRNA 199a-5p induces apoptosis by targeting JunB. AB - MicroRNAs participate in a variety of physiological and pathophysiological processes in various organs including the heart. Our previous work revealed that the level of miR-199a-5p was significantly higher in failing hearts than in control hearts. However, whether it is associated with the progression of heart failure (HF) and mediates cardiomyocyte apoptosis remained unclear. In the present study, we used various biochemical and molecular biological approaches to investigate the changes in miR-199a-5p levels in failing hearts in a rat model induced by acute myocardial infarction. We found that miR-199a-5p levels in the heart increased with the progression of HF, and overexpression of miR-199a-5p significantly increased apoptosis in untreated H9C2 cells and potentiated angiotensin II-induced apoptosis. Thus, our results indicate that miR-199a-5p is involved in the progression of HF and mediates cardiomyocyte apoptosis. We also confirmed that JunB, a member of the activator protein-1 transcription factor family, is one of direct targets of miR-199a-5p via a dual-luciferase reporter assay and mutagenesis on the 3' untranslated region of the JunB gene. Consistent with the above findings, overexpression of JunB in H9c2 cells suppressed cell apoptosis. Based on our findings, miR-199a-5p induces apoptosis by targeting JunB. PMID- 29703906 TI - Dietary patterns and chronic kidney disease: a cross-sectional association in the Irish Nun Eye Study. AB - Associations between dietary patterns and chronic kidney disease are not well established, especially in European populations. We conducted a cross-sectional study of 1033 older Irish women (age range 56-100 years) with a restricted lifestyle. Dietary intake was assessed using a food frequency questionnaire. Renal function was determined by estimated glomerular filtration rate. Two dietary patterns were identified within the study population using factor analysis. A significant negative association was found between unhealthy dietary pattern adherence and renal function in both unadjusted and adjusted models controlling for potential confounding variables (p for trend <0.001), with a mean difference in estimated glomerular filtration rate of -6 ml/min/1.73 m2 between those in the highest fifth of adherence to the unhealthy dietary pattern compared to the lowest, in the fully adjusted model. Chronic kidney disease risk was significantly greater for the highest fifth, compared to the lowest fifth of unhealthy dietary pattern adherence in adjusted models (adjusted odds ratio = 2.62, p < 0.001). Adherence to the healthy dietary pattern was not associated with renal function or chronic kidney disease in adjusted models. In this cohort, an unhealthy dietary pattern was associated with lower renal function and greater prevalence of chronic kidney disease. PMID- 29703908 TI - A side-effect free method for identifying cancer drug targets. AB - Identifying effective drug targets, with little or no side effects, remains an ever challenging task. A potential pitfall of failing to uncover the correct drug targets, due to side effect of pleiotropic genes, might lead the potential drugs to be illicit and withdrawn. Simplifying disease complexity, for the investigation of the mechanistic aspects and identification of effective drug targets, have been done through several approaches of protein interactome analysis. Of these, centrality measures have always gained importance in identifying candidate drug targets. Here, we put forward an integrated method of analysing a complex network of cancer and depict the importance of k-core, functional connectivity and centrality (KFC) for identifying effective drug targets. Essentially, we have extracted the proteins involved in the pathways leading to cancer from the pathway databases which enlist real experimental datasets. The interactions between these proteins were mapped to build an interactome. Integrative analyses of the interactome enabled us to unearth plausible reasons for drugs being rendered withdrawn, thereby giving future scope to pharmaceutical industries to potentially avoid them (e.g. ESR1, HDAC2, F2, PLG, PPARA, RXRA, etc). Based upon our KFC criteria, we have shortlisted ten proteins (GRB2, FYN, PIK3R1, CBL, JAK2, LCK, LYN, SYK, JAK1 and SOCS3) as effective candidates for drug development. PMID- 29703909 TI - Interaction of the GntR-family transcription factor Sll1961 with thioredoxin in the cyanobacterium Synechocystis sp. PCC 6803. AB - Changes in the redox state of the photosynthetic electron transport chain act as a signal to trigger acclimation responses to environmental cues and thioredoxin has been suggested to work as a key factor connecting the redox change with transcriptional regulation in the cyanobacterium Synechocystis sp. PCC 6803. We screened for redox-dependent transcription factors interacting with thioredoxin M (TrxM) and isolated the GntR-type transcription factor Sll1961 previously reported to be involved in acclimation responses of the photosynthetic machinery. Biochemical analyses using recombinant Sll1961 proteins of wild type and mutants of three cysteine residues, C124, C229 and C307, revealed that an intramolecular disulfide bond is formed between C229 and C307 under oxidizing conditions and TrxM can reduce it by attacking C307. Sll1961 exists in a dimeric form of about 80 kDa both under reducing and oxidizing conditions. C124 can form an intermolecular disulfide bond but it is not essential for dimerization. Based on these observations, tertiary structure models of the Sll1961 homodimer and the Sll1961-TrxM complex were constructed. PMID- 29703910 TI - Recent strengthening of the stratospheric Arctic vortex response to warming in the central North Pacific. AB - The stratospheric Arctic vortex (SAV) plays a critical role in forecasting cold winters in northern mid-latitudes. Its influence on the tropospheric mid- and high-latitudes has attracted growing attention in recent years. However, the trend in the SAV during the recent two decades is still unknown. Here, using three reanalysis datasets, we found that the SAV intensity during 1998-2016 has a strengthening trend, in contrast to the weakening trend before that period. Approximately 25% of this strengthening is contributed by the warming of sea surface temperature (SST) over the central North Pacific (CNP). Observational analysis and model experiments show that the warmed CNP SST tends to weaken the Aleutian low, subsequently weakening the upward propagation of wavenumber-1 planetary wave flux, further strengthening the SAV. This strengthened SAV suggests important implications in understanding the Arctic warming amplification and in predicting the surface temperature changes over the northern continents. PMID- 29703911 TI - Hydrogen-mediated magnetic domain formation and domain wall motion in Co30Pd70 alloy films. AB - In this study, the microscopic origin of the hydrogen effect on magnetic materials was explored through the characterization of time-dependent magnetic domain evolution. We prepared 25-nm Co30Pd70 alloy films with canted magnetic moment on SiO2/Si(001) substrates. From macroscopic Kerr hysteresis loops, considerable hydrogen-induced reduction of magnetic coercivity by a factor of 1/5 in a longitudinal direction and enhancement of magnetic remanence to saturation ratio from 60% to 100% were observed. The magnetic reversal behavior of the Co30Pd70 alloy films gradually transformed from nucleation- to domain-wall-motion dominance when H2 pressure was increased from a vacuum of 1 * 10-5 mbar to 0.8 bar. Domain size also increased considerably with H2 pressure. When H2 pressure was above 0.4 bar, the domain wall (DW) motion was clear to observe and the DW velocity was approximately 10-6-10-5 m/s. Greater hydrogen content in the Co30Pd70 alloy films promoted DW motion that was closer to the behavior of a thermally activated model. The hydrogen effects on magnetism were observed to be reversible and could have valuable future application in spintronic devices for hydrogen sensing. PMID- 29703912 TI - Iron(III)-Tannic Molecular Nanoparticles Enhance Autophagy effect and T1 MRI Contrast in Liver Cell Lines. AB - Herein, a new molecular nanoparticle based on iron(III)-tannic complexes (Fe-TA NPs) is presented. The Fe-TA NPs were simply obtained by mixing the precursors in a buffered solution at room temperature, and they exhibited good physicochemical properties with capability of inducing autophagy in both hepatocellular carcinoma cells (HepG2.2.15) and normal rat hepatocytes (AML12). The Fe-TA NPs were found to induce HepG2.2.15 cell death via autophagic cell death but have no effect on cell viability in AML12 cells. This is possibly due to the much higher uptake of the Fe-TA NPs by the HepG2.2.15 cells via the receptor-mediated endocytosis pathway. As a consequence, enhancement of the T1 MRI contrast was clearly observed in the HepG2.2.15 cells. The results demonstrate that the Fe-TA NPs could provide a new strategy combining diagnostic and therapeutic functions for hepatocellular carcinoma. Additionally, because of their autophagy-inducing properties, they can be applied as autophagy enhancers for prevention and treatment of other diseases. PMID- 29703913 TI - Inflammatory breast cancer biology: the tumour microenvironment is key. AB - Inflammatory breast cancer (IBC) is a rare and aggressive disease that accounts for ~2-4% of all breast cancers. However, despite its low incidence rate, IBC is responsible for 7-10% of breast cancer-related mortality in Western countries. Thus, the discovery of robust biological targets and the development of more effective therapeutics in IBC are crucial. Despite major international efforts to understand IBC biology, genomic studies have not led to the discovery of distinct biological mechanisms in IBC that can be translated into novel therapeutic strategies. In this Review, we discuss these molecular profiling efforts and highlight other important aspects of IBC biology. We present the intrinsic characteristics of IBC, including stemness, metastatic potential and hormone receptor positivity; the extrinsic features of the IBC tumour microenvironment (TME), including various constituent cell types; and lastly, the communication between these intrinsic and extrinsic components. We summarize the latest perspectives on the key biological features of IBC, with particular emphasis on the TME as an important contributor to the aggressive nature of IBC. On the basis of the current understanding of IBC, we hope to develop the next generation of translational studies, which will lead to much-needed survival improvements in patients with this deadly disease. PMID- 29703914 TI - The fungus Aspergillus niger consumes sugars in a sequential manner that is not mediated by the carbon catabolite repressor CreA. AB - In nature, the fungus Aspergillus niger degrades plant biomass polysaccharides to monomeric sugars, transports them into its cells, and uses catabolic pathways to convert them into biochemical building blocks and energy. We show that when grown in liquid cultures, A. niger takes up plant-biomass derived sugars in a largely sequential manner. Interestingly, this sequential uptake was not mediated by the fungal general carbon catabolite repressor protein CreA. Furthermore, transcriptome analysis strongly indicated that the preferential use of the monomeric sugars is arranged at the level of transport, but it is not reflected in transcriptional regulation of sugar catabolism. Therefore, the results indicate that the regulation of sugar transport and catabolism are separate processes in A. niger. PMID- 29703915 TI - Nivolumab-ipilimumab - exploiting the mutation burden of NSCLCs. PMID- 29703917 TI - Spin polarized semimagnetic exciton-polariton condensate in magnetic field. AB - Owing to their integer spin, exciton-polaritons in microcavities can be used for observation of non-equilibrium Bose-Einstein condensation in solid state. However, spin-related phenomena of such condensates are difficult to explore due to the relatively small Zeeman effect of standard semiconductor microcavity systems and the strong tendency to sustain an equal population of two spin components, which precludes the observation of condensates with a well defined spin projection along the axis of the system. The enhancement of the Zeeman splitting can be achieved by introducing magnetic ions to the quantum wells, and consequently forming semimagnetic polaritons. In this system, increasing magnetic field can induce polariton condensation at constant excitation power. Here we evidence the spin polarization of a semimagnetic polaritons condensate exhibiting a circularly polarized emission over 95% even in a moderate magnetic field of about 3 T. Furthermore, we show that unlike nonmagnetic polaritons, an increase on excitation power results in an increase of the semimagnetic polaritons condensate spin polarization. These properties open new possibilities for testing theoretically predicted phenomena of spin polarized condensate. PMID- 29703916 TI - A Plasma Biomarker Panel of Four MicroRNAs for the Diagnosis of Prostate Cancer. AB - Prostate cancer is diagnosed in over 1 million men every year globally, yet current diagnostic modalities are inadequate for identification of significant cancer and more reliable early diagnostic biomarkers are necessary for improved clinical management of prostate cancer patients. MicroRNAs (miRNAs) modulate important cellular processes/pathways contributing to cancer and are stably present in body fluids. In this study we profiled 372 cancer-associated miRNAs in plasma collected before (~60% patients) and after/during commencement of treatment (~40% patients), from age-matched prostate cancer patients and healthy controls, and observed elevated levels of 4 miRNAs - miR-4289, miR-326, miR-152 3p and miR-98-5p, which were validated in an independent cohort. The miRNA panel was able to differentiate between prostate cancer patients and controls (AUC = 0.88). Analysis of published miRNA transcriptomic data from clinical samples demonstrated low expression of miR-152-3p in tumour compared to adjacent non malignant tissues. Overexpression of miR-152-3p increased proliferation and migration of prostate cancer cells, suggesting a role for this miRNA in prostate cancer pathogenesis, a concept that was supported by pathway analysis of predicted miR-152-3p target genes. In summary, a four miRNA panel, including miR 152-3p which likely targets genes with key roles in prostate cancer pathogenesis, has the potential to improve early prostate cancer diagnosis. PMID- 29703918 TI - Author Correction: Normothermic Microwave Irradiation Induces Death of HL-60 Cells through Heat-Independent Apoptosis. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29703919 TI - Lifestyle index for mortality prediction using multiple ageing cohorts in the USA, UK and Europe. AB - Current mortality prediction indexes are mainly based on functional morbidity and comorbidity, with limited information for risk prevention. This study aimed to develop and validate a modifiable lifestyle-based mortality predication index for older adults. Data from 51,688 participants (56% women) aged >=50 years in 2002 Health and Retirement Study, 2002 English Longitudinal Study of Ageing and 2004 Survey of Health Ageing and Retirement in Europe were used to estimate coefficients of the index with cohort-stratified Cox regression. Models were validated across studies and compared to the Lee index (having comorbid and morbidity predictors). Over an average of 11-year follow-up, 10,240 participants died. The lifestyle index includes smoking, drinking, exercising, sleep quality, BMI, sex and age; showing adequate model performance in internal validation (C statistic 0.79; D-statistic 1.94; calibration slope 1.13) and in all combinations of internal-external cross-validation. It outperformed Lee index (e.g. differences in C-statistic = 0.01, D-statistic = 0.17, P < 0.001) consistently across health status. The lifestyle index stratified participants into varying mortality risk groups, with those in the top quintile having 13.5% excess absolute mortality risk over 10 years than those in the bottom 50th centile. Our lifestyle index with easy-assessable behavioural factors and improved generalizability may maximize its usability for personalized risk management. PMID- 29703920 TI - Prevalent metabolic derangement and severe thrombocytopenia in ABO-incompatible liver recipients with pre-transplant plasma exchange. AB - Desensitisation with therapeutic plasma exchange (TPE) is essential for ABO incompatible (ABO-I) liver transplants (LTs). However, excessive citrate load and coagulation disturbances after TPE have been poorly studied, in particular in cirrhotic patients with hypocapnic alkalosis, metabolic compensation and electrolyte imbalances. We retrospectively evaluated 1123 consecutive LT recipients (923 ABO-compatible [ABO-C], 200 ABO-I) from November 2008 to May 2015. TPE was generally performed a day before LT and blood sampling was performed before anaesthesia induction. We performed propensity score matching (PSM) and inverse probability treatment weighting (IPTW) analyses. In 199 PSM pairs, metabolic alkalosis was prevalent in ABO-I LT recipients (expectedly due to citrate conversion) with higher pH >= 7.50 (IPTW-adjusted odds ratio [aOR] = 2.23) than in ABO-C LT recipients. With increasing cirrhosis severity, the arterial pH and bicarbonate levels showed dose-dependent relationships, whereas mild hypoxaemia was more prevalent in ABO-I LT recipients. ABO-I LT recipients exhibited worsened hypokalaemia <=3.0 mmol/l (17.6%, aOR = 1.44), hypomagnesaemia <=1.7 mg/dl (27.6%, aOR = 3.43) and thrombocytopenia <30,000/ul (19.1%, aOR = 2.26) confirmed by lower maximal clot firmness (P = 0.001) in rotational thromboelastometry (EXTEM), which necessitated platelet transfusions. Preoperative identification of these change may prevent worsening of severe electrolyte disturbances and thrombocytopenia for optimal LT anaesthesia. PMID- 29703922 TI - Anisotropic diamond etching through thermochemical reaction between Ni and diamond in high-temperature water vapour. AB - Diamond possesses excellent physical and electronic properties, and thus various applications that use diamond are under development. Additionally, the control of diamond geometry by etching technique is essential for such applications. However, conventional wet processes used for etching other materials are ineffective for diamond. Moreover, plasma processes currently employed for diamond etching are not selective, and plasma-induced damage to diamond deteriorates the device-performances. Here, we report a non-plasma etching process for single crystal diamond using thermochemical reaction between Ni and diamond in high-temperature water vapour. Diamond under Ni films was selectively etched, with no etching at other locations. A diamond-etching rate of approximately 8.7 MUm/min (1000 degrees C) was successfully achieved. To the best of our knowledge, this rate is considerably greater than those reported so far for other diamond-etching processes, including plasma processes. The anisotropy observed for this diamond etching was considerably similar to that observed for Si etching using KOH. PMID- 29703921 TI - Mutations in VP1 and 5'-UTR affect enterovirus 71 virulence. AB - Enterovirus 71 (EV71) is a major cause of hand, foot and mouth disease (HFMD). The current EV71 propagating in Vero (EV-V) or sub-passaged in RD (EV-R) cells was used as a pathogen. Interestingly, EV-R exhibited differential virulence; challenging human scavenger receptor class B2-expressing (hSCARB2-Tg) mice with EV71 revealed that EV-V was more virulent than EV-R: 100% of mice that received lethal amounts of EV-V died, while all the mice that received EV-R survived. Severe pathogenesis correlated with viral burdens and proinflammatory cytokine levels were observed in EV-V-challenged mice, but controversy in EV-R-challenged mice. Consensus sequence analysis revealed EV-R rapidly acquired complete mutations at E145G and S241L and partial mutations at V146I of VP1, and acquired a T to C substitution at nucleotide 494 of the 5'-UTR. EV-R exhibited higher binding affinity for another EV71 receptor, human P-selectin glycoprotein ligand 1 (hPSGL-1), than EV-V. Both EV71s exhibited no significant difference in binding to hSCARB2. The molecular modelling indicate that these mutations might influence EV71 engagement with PSGL-1 and in vivo virulence. PMID- 29703923 TI - In situ full-field measurement of surface oxidation on Ni-based alloy using high temperature scanning probe microscopy. AB - We use in situ scanning probe microscopy (SPM) to investigate the high temperature oxidation of Ni-based single crystal alloys at the micro-/nanoscale. SiO2 micro-pillar arrays were pre-fabricated on the alloy surface as markers before the oxidation experiment. The SPM measurement of the oxidized surface in the vicinity of SiO2 micro-pillars was conducted real time at temperatures from 300 degrees C to 800 degrees C. The full-field evolution of oxide film thickness is quantitatively characterized by using the height of SiO2 micro pillars as reference. The results reveal the non-uniform oxide growth featuring the nucleation and coalescence of oxide islands on the alloy surface. The outward diffusion of Ni and Co is responsible for the formation and coalescence of first stage single-grain oxide islands. The second-stage of oxidation involves the formation and coalescence of poly-grain oxide islands. PMID- 29703924 TI - Author Correction: HDAC3 inhibition ameliorates spinal cord injury by immunomodulation. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29703925 TI - An Innovative Approach for The Integration of Proteomics and Metabolomics Data In Severe Septic Shock Patients Stratified for Mortality. AB - In this work, we examined plasma metabolome, proteome and clinical features in patients with severe septic shock enrolled in the multicenter ALBIOS study. The objective was to identify changes in the levels of metabolites involved in septic shock progression and to integrate this information with the variation occurring in proteins and clinical data. Mass spectrometry-based targeted metabolomics and untargeted proteomics allowed us to quantify absolute metabolites concentration and relative proteins abundance. We computed the ratio D7/D1 to take into account their variation from day 1 (D1) to day 7 (D7) after shock diagnosis. Patients were divided into two groups according to 28-day mortality. Three different elastic net logistic regression models were built: one on metabolites only, one on metabolites and proteins and one to integrate metabolomics and proteomics data with clinical parameters. Linear discriminant analysis and Partial least squares Discriminant Analysis were also implemented. All the obtained models correctly classified the observations in the testing set. By looking at the variable importance (VIP) and the selected features, the integration of metabolomics with proteomics data showed the importance of circulating lipids and coagulation cascade in septic shock progression, thus capturing a further layer of biological information complementary to metabolomics information. PMID- 29703926 TI - Long non-coding RNAs involved in the regulatory network during porcine pre implantation embryonic development and iPSC induction. AB - Long non-coding RNAs (lncRNA) play a key role in the orchestration of transcriptional regulation during development and many other cellular processes. The importance of the regulatory co-expression network was highlighted in the identification of the mechanism of these processes in humans and mice. However, elucidation of the properties of porcine lncRNAs involved in the regulatory network during pre-implantation embryonic development and fibroblast reprogramming to induced pluripotent stem cell (iPSC) has been limited to date. Using a weighted gene co-expression network analysis, we constructed the regulatory network and determined that the novel lncRNAs were functionally involved in key events of embryonic development during the pre-implantation period; moreover, reprogramming could be delineated by a small number of potentially functional modules of co-expressed genes. These findings indicate that lncRNAs may be involved in the transcriptional regulation of zygotic genome activation, first lineage segregation and somatic reprogramming to pluripotency. Furthermore, we performed a conservation and synteny analysis with the significant lncRNAs involved in these vital events and validated the results via experimental assays. In summary, the current findings provide a valuable resource to dissect the protein coding gene and lncRNA regulatory networks that underlie the progressive development of embryos and somatic reprogramming. PMID- 29703927 TI - Relationships between digestive efficiency and metabolomic profiles of serum and intestinal contents in chickens. AB - The increasing cost of conventional feedstuffs has bolstered interest in genetic selection for digestive efficiency (DE), a component of feed efficiency, assessed by apparent metabolisable energy corrected to zero nitrogen retention (AMEn). However, its measurement is time-consuming and constraining, and its relationship with metabolic efficiency poorly understood. To simplify selection for this trait, we searched for indirect metabolic biomarkers through an analysis of the serum metabolome using nuclear magnetic resonance (1H NMR). A partial least squares (PLS) model including six amino acids and two derivatives from butyrate predicted 59% of AMEn variability. Moreover, to increase our knowledge of the molecular mechanisms controlling DE, we investigated 1H NMR metabolomes of ileal, caecal, and serum contents by fitting canonical sparse PLS. This analysis revealed strong associations between metabolites and DE. Models based on the ileal, caecal, and serum metabolome respectively explained 77%, 78%, and 74% of the variability of AMEn and its constitutive components (utilisation of starch, lipids, and nitrogen). In our conditions, the metabolites presenting the strongest associations with AMEn were proline in the serum, fumarate in the ileum and glucose in caeca. This study shows that serum metabolomics offers new opportunities to predict chicken DE. PMID- 29703928 TI - The effect of attention and working memory on the estimation of elapsed time. AB - Psychological models of time perception involve attention and memory: while attention typically regulates the flow of events, memory maintains timed events or intervals. The precise, and possibly distinct, roles of attention and memory in time perception remain debated. In this behavioral study, we tested 48 participants in a prospective duration estimation task while they fully attended to time or performed a working memory (WM) task. We report that paying attention to time lengthened perceived duration in the range of seconds to minutes, whereas diverting attention away from time shortened perceived duration. The overestimation due to attending to time did not scale with durations. To the contrary, increasing WM load systematically decreased subjective duration and this effect scaled with durations. Herein, we discuss the dissociation between attention and WM in timing and scalar variability from the perspective of Bayesian models of time estimations. PMID- 29703929 TI - Non-contact identification and differentiation of illicit drugs using fluorescent films. AB - Sensitive and rapid identification of illicit drugs in a non-contact mode remains a challenge for years. Here we report three film-based fluorescent sensors showing unprecedented sensitivity, selectivity, and response speed to the existence of six widely abused illicit drugs, including methamphetamine (MAPA), ecstasy, magu, caffeine, phenobarbital (PB), and ketamine in vapor phase. Importantly, for these drugs, the sensing can be successfully performed after 5.0 * 105, 4.0 * 105, 2.0 * 105, 1.0 * 105, 4.0 * 104, and 2.0 * 102 times dilution of their saturated vapor with air at room temperature, respectively. Also, presence of odorous substances (toiletries, fruits, dirty clothes, etc.), water, and amido-bond-containing organic compounds (typical organic amines, legal drugs, and different amino acids) shows little effect upon the sensing. More importantly, discrimination and identification of them can be realized by using the sensors in an array way. Based upon the discoveries, a conceptual, two-sensor based detector is developed, and non-contact detection of the drugs is realized. PMID- 29703930 TI - Whole exome sequencing reveals rare variants linked to congenital pouch colon. AB - We demonstrate the application of whole exome sequencing to discover the rare variants for congenital pouch colon, acronymed CPC. For 18 affected individuals in a total of 64 samples, we sequenced coding regions to a mean coverage of 100*. A sufficient depth of ca. 94% of targeted exomes was achieved. Filtering against the public SNP/variant repositories, we identified a host of candidate genes, EPB41L4A and CTC1 associated with colon, neural/brain muscles and Dyskeratosis Congenita maladies. Furthermore, the stop gain mutations in the form of JAG1,OR5AR1,SLC22A24,PEX16,TSPAN32,TAF1B,MAP2K3 and SLC25A19 appears to be localized to Chromosomes 2, 11, 17 and 20 in addition to the three stop lost mutants across three genes, viz. OAS2, GBA3 and PKD1L2 affecting the colon tissue. While our results have paved way for transcendence of monogenic traits in identifying the genes underlying rare genetic disorders, it will provide helpful clues for further investigating genetic factors associated with anorectal anomalies, particularly CPC. PMID- 29703931 TI - Transient peak-strain matching partially recovers the age-impaired mechanoadaptive cortical bone response. AB - Mechanoadaptation maintains bone mass and architecture; its failure underlies age related decline in bone strength. It is unclear whether this is due to failure of osteocytes to sense strain, osteoblasts to form bone or insufficient mechanical stimulus. Mechanoadaptation can be restored to aged bone by surgical neurectomy, suggesting that changes in loading history can rescue mechanoadaptation. We use non-biased, whole-bone tibial analyses, along with characterisation of surface strains and ensuing mechanoadaptive responses in mice at a range of ages, to explore whether sufficient load magnitude can activate mechanoadaptation in aged bone. We find that younger mice adapt when imposed strains are lower than in mature and aged bone. Intriguingly, imposition of short-term, high magnitude loading effectively primes cortical but not trabecular bone of aged mice to respond. This response was regionally-matched to highest strains measured by digital image correlation and to osteocytic mechanoactivation. These data indicate that aged bone's loading response can be partially recovered, non invasively by transient, focal high strain regions. Our results indicate that old murine bone does respond to load when the loading is of sufficient magnitude, and bones' age-related adaptation failure may be due to insufficient mechanical stimulus to trigger mechanoadaptation. PMID- 29703932 TI - Author Correction: L1-associated genomic regions are deleted in somatic cells of the healthy human brain. AB - In the version of this article initially published, NIH grant U01 MH106882 to F.H.G. was missing from the Acknowledgments. The error has been corrected in the HTML and PDF versions of the article. PMID- 29703934 TI - Author Correction: Nanostructured laminar tungsten alloy with improved ductility by surface mechanical attrition treatment. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29703935 TI - Effects of litter feeders on the transfer of 137Cs to plants. AB - The effects of the Japanese horned beetle larvae on the transfer of 137Cs from a contaminated leaf litter to the leaf vegetable, komatsuna (Brassica rapa var. perviridis) was studied. Feces of the larvae which were fed 137Cs-contaminated leaf litter were added to a potting mix in which komatsuna plants were cultivated. The presence of feces increased the harvest yield of komatsuna, suggesting that feces provided nutrients for the plant growth. In addition, the amount of exchangeable 137Cs in leaf litter was experimentally confirmed to be enhanced by the presence of feces which were excreted by larvae feeding. However, there was no difference in the soil-to-plant transfer factor of 137Cs for the presence and absence of feces. Interactions between clay minerals and exchangeable 137Cs in the soil beneath the litter layer may diminish the root uptake of 137Cs. From these results, it was concluded that the effect of exchangeable 137Cs released from feces was limited for the transfer of 137Cs to plants if plant roots were not present in litter layers. PMID- 29703933 TI - The cysteine-reactive small molecule ebselen facilitates effective SOD1 maturation. AB - Superoxide dismutase-1 (SOD1) mutants, including those with unaltered enzymatic activity, are known to cause amyotrophic lateral sclerosis (ALS). Several destabilizing factors contribute to pathogenicity including a reduced ability to complete the normal maturation process which comprises folding, metal cofactor acquisition, intra-subunit disulphide bond formation and dimerization. Immature SOD1 forms toxic oligomers and characteristic large insoluble aggregates within motor system cells. Here we report that the cysteine-reactive molecule ebselen efficiently confers the SOD1 intra-subunit disulphide and directs correct SOD1 folding, depopulating the globally unfolded precursor associated with aggregation and toxicity. Assisted formation of the unusual SOD1 cytosolic disulphide bond could have potential therapeutic applications. In less reducing environments, ebselen forms a selenylsulphide with Cys111 and restores the monomer-dimer equilibrium of A4V SOD1 to wild-type. Ebselen is therefore a potent bifunctional pharmacological chaperone for SOD1 that combines properties of the SOD1 chaperone hCCS and the recently licenced antioxidant drug, edaravone. PMID- 29703936 TI - Ketogenic diet enhances neurovascular function with altered gut microbiome in young healthy mice. AB - Neurovascular integrity, including cerebral blood flow (CBF) and blood-brain barrier (BBB) function, plays a major role in determining cognitive capability. Recent studies suggest that neurovascular integrity could be regulated by the gut microbiome. The purpose of the study was to identify if ketogenic diet (KD) intervention would alter gut microbiome and enhance neurovascular functions, and thus reduce risk for neurodegeneration in young healthy mice (12-14 weeks old). Here we show that with 16 weeks of KD, mice had significant increases in CBF and P-glycoprotein transports on BBB to facilitate clearance of amyloid-beta, a hallmark of Alzheimer's disease (AD). These neurovascular enhancements were associated with reduced mechanistic target of rapamycin (mTOR) and increased endothelial nitric oxide synthase (eNOS) protein expressions. KD also increased the relative abundance of putatively beneficial gut microbiota (Akkermansia muciniphila and Lactobacillus), and reduced that of putatively pro-inflammatory taxa (Desulfovibrio and Turicibacter). We also observed that KD reduced blood glucose levels and body weight, and increased blood ketone levels, which might be associated with gut microbiome alteration. Our findings suggest that KD intervention started in the early stage may enhance brain vascular function, increase beneficial gut microbiota, improve metabolic profile, and reduce risk for AD. PMID- 29703937 TI - A photochemical diode artificial photosynthesis system for unassisted high efficiency overall pure water splitting. AB - The conversion of solar energy into chemical fuels can potentially address many of the energy and environment related challenges we face today. In this study, we have demonstrated a photochemical diode artificial photosynthesis system that can enable efficient, unassisted overall pure water splitting without using any sacrificial reagent. By precisely controlling charge carrier flow at the nanoscale, the wafer-level photochemical diode arrays exhibited solar-to-hydrogen efficiency ~3.3% in neutral (pH ~ 7.0) overall water splitting reaction. In part of the visible spectrum (400-485 nm), the energy conversion efficiency and apparent quantum yield reaches ~8.75% and ~20%, respectively, which are the highest values ever reported for one-step visible-light driven photocatalytic overall pure water splitting. The effective manipulation and control of charge carrier flow in nanostructured photocatalysts provides critical insight in achieving high efficiency artificial photosynthesis, including the efficient and selective reduction of CO2 to hydrocarbon fuels. PMID- 29703938 TI - Publisher Correction: A smartphone app to reduce excessive alcohol consumption: Identifying the effectiveness of intervention components in a factorial randomised control trial. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29703939 TI - Juggling resistance mutations. PMID- 29703942 TI - Comparative transcriptomic analysis identifies genes responsible for fruit count and oil yield in the oil tea plant Camellia chekiangoleosa. AB - Fruit yield is an important trait for horticultural crops. However, the limited fruit yield of Camellia chekiangoleosa, a novel promising oil tree, restricts the production of oil. The breeding improvement is little due to its long generation time and lack of available genomic sequence. We identified distinct fruit count phenotypes, high-yield (HY) and low-yield (LY). To understand the underlying genetic basis, we focused on global gene discovery and expression levels in floral buds, which affect fruit count. A total of 140,299 de novo assembled unigenes were obtained using RNA-seq technology, and more genes were expressed in HY than in LY. 2395 differentially expressed genes (DEGs) were identified and enriched in membrane, energy metabolism, secondary metabolism, fatty acid biosynthesis and metabolism, and 18 other metabolic pathways. Of the DEGs, twelve identified transcription factors, including AP2, mostly involve in inflorescence and flower development and in hormone networks. Key DEGs in fatty acid biosynthesis (Fab) FabB, FabF, FabZ, and AccD were highly expressed in floral buds and associated with high oil yield in fruits. We hypothesized that a potential link exists between fruit count and its oil yield. These findings help to elucidate the molecular cues affecting fruit count and oil yield. PMID- 29703940 TI - The genetic architecture of floral traits in the woody plant Prunus mume. AB - Mei (Prunus mume) is an ornamental woody plant that has been domesticated in East Asia for thousands of years. High diversity in floral traits, along with its recent genome sequence, makes mei an ideal model system for studying the evolution of woody plants. Here, we investigate the genetic architecture of floral traits in mei and its domestication history by sampling and resequencing a total of 351 samples including 348 mei accessions and three other Prunus species at an average sequencing depth of 19.3*. Highly-admixed population structure and introgression from Prunus species are identified in mei accessions. Through a genome-wide association study (GWAS), we identify significant quantitative traits locus (QTLs) and genomic regions where several genes, such as MYB108, are positively associated with petal color, stigma color, calyx color, and bud color. Results from this study shed light on the genetic basis of domestication in flowering plants, particularly woody plants. PMID- 29703943 TI - Skillful prediction of hot temperature extremes over the source region of ancient Silk Road. AB - The source region of ancient Silk Road (SRASR) in China, a region of around 150 million people, faces a rapidly increased risk of extreme heat in summer. In this study, we develop statistical models to predict summer hot temperature extremes over the SRASR based on a timescale decomposition approach. Results show that after removing the linear trends, the inter-annual components of summer hot days and heatwaves over the SRASR are significantly related with those of spring soil temperature over Central Asia and sea surface temperature over Northwest Atlantic while their inter-decadal components are closely linked to those of spring East Pacific/North Pacific pattern and Atlantic Multidecadal Oscillation for 1979 2016. The physical processes involved are also discussed. Leave-one-out cross validation for detrended 1979-2016 time series indicates that the statistical models based on identified spring predictors can predict 47% and 57% of the total variances of summer hot days and heatwaves averaged over the SRASR, respectively. When the linear trends are put back, the prediction skills increase substantially to 64% and 70%. Hindcast experiments for 2012-2016 show high skills in predicting spatial patterns of hot temperature extremes over the SRASR. The statistical models proposed herein can be easily applied to operational seasonal forecasting. PMID- 29703941 TI - Couple serostatus patterns in sub-Saharan Africa illuminate the relative roles of transmission rates and sexual network characteristics in HIV epidemiology. AB - HIV prevalence has surpassed 30% in some African countries while peaking at less than 1% in others. The extent to which this variation is driven by biological factors influencing the HIV transmission rate or by variation in sexual network characteristics remains widely debated. Here, we leverage couple serostatus patterns to address this question. HIV prevalence is strongly correlated with couple serostatus patterns across the continent; in particular, high prevalence countries tend to have a lower ratio of serodiscordancy to concordant positivity. To investigate the drivers of this continental pattern, we fit an HIV transmission model to Demographic and Health Survey data from 45,041 cohabiting couples in 25 countries. In doing so, we estimated country-specific HIV transmission rates and sexual network characteristics reflective of pre-couple and extra-couple sexual contact patterns. We found that variation in the transmission rate could parsimoniously explain between-country variation in both couple serostatus patterns and prevalence. In contrast, between-country variation in pre-couple or extra-couple sexual contact rates could not explain the observed patterns. Sensitivity analyses suggest that future work should examine the robustness of this result to between-country variation in how heterogeneous infection risk is within a country, or to assortativity, i.e. the extent to which individuals at higher risk are likely to partner with each other. PMID- 29703944 TI - An integrative analysis of non-coding regulatory DNA variations associated with autism spectrum disorder. AB - A number of genetic studies have identified rare protein-coding DNA variations associated with autism spectrum disorder (ASD), a neurodevelopmental disorder with significant genetic etiology and heterogeneity. In contrast, the contributions of functional, regulatory genetic variations that occur in the extensive non-protein-coding regions of the genome remain poorly understood. Here we developed a genome-wide analysis to identify the rare single nucleotide variants (SNVs) that occur in non-coding regions and determined the regulatory function and evolutionary conservation of these variants. Using publicly available datasets and computational predictions, we identified SNVs within putative regulatory regions in promoters, transcription factor binding sites, and microRNA genes and their target sites. Overall, we found that the regulatory variants in ASD cases were enriched in ASD-risk genes and genes involved in fetal neurodevelopment. As with previously reported coding mutations, we found an enrichment of the regulatory variants associated with dysregulation of neurodevelopmental and synaptic signaling pathways. Among these were several rare inherited SNVs found in the mature sequence of microRNAs predicted to affect the regulation of ASD-risk genes. We show a paternally inherited miR-873-5p variant with altered binding affinity for several risk-genes including NRXN2 and CNTNAP2 putatively overlay maternally inherited loss-of-function coding variations in NRXN1 and CNTNAP2 to likely increase the genetic liability in an idiopathic ASD case. Our analysis pipeline provides a new resource for identifying loss-of function regulatory DNA variations that may contribute to the genetic etiology of complex disorders. PMID- 29703945 TI - Critical period inhibition of NKCC1 rectifies synapse plasticity in the somatosensory cortex and restores adult tactile response maps in fragile X mice. AB - Sensory perturbations in visual, auditory and tactile perception are core problems in fragile X syndrome (FXS). In the Fmr1 knockout mouse model of FXS, the maturation of synapses and circuits during critical period (CP) development in the somatosensory cortex is delayed, but it is unclear how this contributes to altered tactile sensory processing in the mature CNS. Here we demonstrate that inhibiting the juvenile chloride co-transporter NKCC1, which contributes to altered chloride homeostasis in developing cortical neurons of FXS mice, rectifies the chloride imbalance in layer IV somatosensory cortex neurons and corrects the development of thalamocortical excitatory synapses during the CP. Comparison of protein abundances demonstrated that NKCC1 inhibition during early development caused a broad remodeling of the proteome in the barrel cortex. In addition, the abnormally large size of whisker-evoked cortical maps in adult Fmr1 knockout mice was corrected by rectifying the chloride imbalance during the early CP. These data demonstrate that correcting the disrupted driving force through GABAA receptors during the CP in cortical neurons restores their synaptic development, has an unexpectedly large effect on differentially expressed proteins, and produces a long-lasting correction of somatosensory circuit function in FXS mice. PMID- 29703946 TI - Cleavage of potassium channel Kv2.1 by BACE2 reduces neuronal apoptosis. AB - Potassium channel Kv2.1 regulates potassium current in cortical neurons and potassium efflux is necessary for cell apoptosis. As a major component of delayed rectifier current potassium channels, Kv2.1 forms clusters in the membrane of hippocampal neurons. BACE2 is an aspartyl protease to cleave APP to prevent the generation of Abeta, a central component of neuritic plaques in Alzheimer's brain. We now identified Kv2.1 as a novel substrate of BACE2. We found that BACE2 cleaved Kv2.1 at Thr376, Ala717, and Ser769 sites and disrupted Kv2.1 clustering on cell membrane, resulting in decreased Ik of Kv2.1 and a hyperpolarizing shift in primary neurons. Furthermore, we discovered that the BACE2-cleaved Kv2.1 forms, Kv2.1-1-375, Kv2.1-1-716, and Kv2.1-1-768, depressed the delayed rectifier Ik surge and reduced neuronal apoptosis. Our study suggests that BACE2 plays a neuroprotective role by cleavage of Kv2.1 to prevent the outward potassium currents, a potential new target for Alzheimer's treatment. PMID- 29703947 TI - Human brain arousal in the resting state: a genome-wide association study. AB - Arousal affects cognition, emotion, and behavior and has been implicated in the etiology of psychiatric disorders. Although environmental conditions substantially contribute to the level of arousal, stable interindividual characteristics are well-established and a genetic basis has been suggested. Here we investigated the molecular genetics of brain arousal in the resting state by conducting a genome-wide association study (GWAS). We selected N = 1877 participants from the population-based LIFE-Adult cohort. Participants underwent a 20-min eyes-closed resting state EEG, which was analyzed using the computerized VIGALL 2.1 (Vigilance Algorithm Leipzig). At the SNP-level, GWAS analyses revealed no genome-wide significant locus (p < 5E-8), although seven loci were suggestive (p < 1E-6). The strongest hit was an expression quantitative trait locus (eQTL) of TMEM159 (lead-SNP: rs79472635, p = 5.49E-8). Importantly, at the gene-level, GWAS analyses revealed significant evidence for TMEM159 (p = 0.013, Bonferroni-corrected). By mapping our SNPs to the GWAS results from the Psychiatric Genomics Consortium, we found that all corresponding markers of TMEM159 showed nominally significant associations with Major Depressive Disorder (MDD; 0.006 <= p <= 0.011). More specifically, variants associated with high arousal levels have previously been linked to an increased risk for MDD. In line with this, the MetaXcan database suggests increased expression levels of TMEM159 in MDD, as well as Autism Spectrum Disorder, and Alzheimer's Disease. Furthermore, our pathway analyses provided evidence for a role of sodium/calcium exchangers in resting state arousal. In conclusion, the present GWAS identifies TMEM159 as a novel candidate gene which may modulate the risk for psychiatric disorders through arousal mechanisms. Our results also encourage the elaboration of the previously reported interrelations between ion-channel modulators, sleep wake behavior, and psychiatric disorders. PMID- 29703948 TI - Computational psychiatry: a report from the 2017 NIMH workshop on opportunities and challenges. PMID- 29703949 TI - Uses of selection strategies in both spectral and sample spaces for classifying hard and soft blueberry using near infrared data. AB - In the current work, we attempt to leverage the fewer wavelengths and samples to develop a classification model for classifying hard and soft blueberries using near infrared (NIR) data. To do this, random frog selection and active learning approaches are used in the spectral space and the sample queue, respectively. To reduce the spectral number, a random frog spectral selection approach was applied to collect wavelengths informative with hardness. Prediction model based on 22 selected spectra gave slightly better results than that based on the full spectra. In terms of the selection operation in the sample space, the query by committee was validated to be suitable for blueberry hardness classification with the accuracy, precision and recall of 78%, 74% and 98% when taking only 25 sample queries. Its standard deviation curves of performance metrics are also located in regions of low values (around 0.05) and fluctuated steadily in shape, winning over those of the other 4 active learning strategies and random method. In summary, the respective uses of random frog and query by committee in the NIR spectral vector and the sample queue showed the considerable potential for establishing a simple but robust classifier for hard and soft blueberries with very low labeling cost. PMID- 29703950 TI - Human rhinovirus internal ribosome entry site element enhances transgene expression in transfected CHO-S cells. AB - Chinese hamster ovary (CHO) cells are mainly used for recombinant protein production. However, the unstable transgene expression and lower transgene copy numbers are the major issues need to be resolved. Here, eleven internal ribosome entry site (IRES) elements from viral and cellular IRES were evaluated for foreign gene expression in CHO-S cells. We constructed eleven fusing plasmids containing different IRES sequences downstream of the enhanced green fluorescent protein (EGFP) gene. EGFP expression was detected by flow cytometry and the transgene copy number was evaluated by quantitative PCR. The erythropoietin (EPO) protein was also used to assess the stronger IRES. The results showed that IRES from human rhinovirus (HRV) exhibited the highest EGFP expression level under transient and stable transfections. The EGFP expression level of vector with IRES from HRV was related to the gene copy number in stably transfected CHO-S cells. Moreover, IRES from HRV induced higher expression level of EPO compared with one mutant IRES from EMCV in transfected cells. In conclusion, IRES from HRV can function as a strong IRES element for stable expression in CHO-S cells, which could potentially guide more effective foreign gene expression in CHO-S cells. PMID- 29703951 TI - Acceptability, tolerability, and potential efficacy of cognitive behavioural therapy for Insomnia Disorder subtypes defined by polysomnography: A retrospective cohort study. AB - In this retrospective cohort study, we describe acceptability, tolerability and potential efficacy of cognitive behavioural therapy (CBT) in Insomnia Disorder subtypes, derived from polysomnography (PSG): insomnia with normal-sleep duration (I-NSD) and insomnia with short-sleep duration (I-SSD). All research volunteers were offered access to digital CBT, single component sleep restriction therapy and face-to-face group CBT. Follow-up occurred at three months post-treatment using the insomnia severity index (ISI). 96 participants (61 females, mean age of 41 years) were grouped into either normal-sleep (n = 53) or short-sleep (n = 43). CBT was acceptable to 63% of participants (normal-sleep = 31, short-sleep = 29), with 28 completing therapy (tolerability: normal-sleep = 11, short-sleep = 17). For potential efficacy, 39 (normal-sleep = 20, short-sleep = 19) out of 96 participants (41%) completed a follow-up ISI assessment. In this reduced sample, mean (SD) ISI scores decreased across both groups (normal-sleep: 18.0 (4.0) to 10.7 (4.6); short-sleep: 16.5 (5.5) to 11.0 (6.3); both P < 0.01). Those with normal-sleep were more likely to respond (>=6-point ISI reduction) to CBT compared to short-sleep (70%, n = 14/20 vs. 37%, n = 7/19 respectively, P = 0.038). In this cohort, 60 (63%) of participants attempted CBT and of those 28 (47%) completed therapy. Results may be comparable to clinical participants with implications for the successful translation of CBT for insomnia. PMID- 29703952 TI - The Genomics ADvISER: development and usability testing of a decision aid for the selection of incidental sequencing results. AB - Guidelines recommend patients be informed of their incidental results (IR) when undergoing genomic sequencing (GS), yet there are limited tools to support patients' decisions about learning IR. The aim of this study is to develop and test the usability of a decision aid (DA) to guide patients' selection of IR, and to describe patients' preferences for learning IR following use of the DA. We developed and evaluated a DA using an iterative, mixed-methods process consisting of (1) prototype development, (2) feasibility testing, (3) cognitive interviews, (4) design and programming, and (5) usability testing. We created an interactive online DA called the Genomics ADvISER, a genomics decision AiD about Incidental SEquencing Results. The Genomics ADvISER begins with an educational whiteboard video, and then engages users in a values clarification exercise, knowledge quiz and final choice step, based on a 'binning' framework. Participants found the DA acceptable and intuitive to use. They were enthusiastic towards GS and IR; all selected multiple categories of IR. The Genomics ADvISER is a new patient centered tool to support the clinical delivery of incidental GS results. The Genomics ADvISER fills critical care gaps, given the health care system's limited genomics expertise and capacity to convey the large volume of IR and their myriad of implications. PMID- 29703953 TI - Structural analysis of human ARS2 as a platform for co-transcriptional RNA sorting. AB - ARS2 is a highly conserved metazoan protein involved in numerous aspects of nuclear RNA metabolism. As a direct partner of the nuclear cap-binding complex (CBC), it mediates interactions with diverse RNA processing and transport machineries in a transcript-dependent manner. Here, we present the human ARS2 crystal structure, which exhibits similarities and metazoan-specific differences to the plant homologue SERRATE, most notably an additional RRM domain. We present biochemical, biophysical and cellular interactome data comparing wild type and mutant ARS2 that identify regions critical for interactions with FLASH (involved in histone mRNA biogenesis), NCBP3 (a putative cap-binding protein involved in mRNA export) and single-stranded RNA. We show that FLASH and NCBP3 have overlapping binding sites on ARS2 and that CBC-ARS2-NCBP3 form a ternary complex that is mutually exclusive with CBC-ARS-PHAX (involved in snRNA export). Our results support that mutually exclusive higher-order CBC-ARS2 complexes are critical in determining Pol II transcript fate. PMID- 29703954 TI - Unexpected behaviors in molecular transport through size-controlled nanochannels down to the ultra-nanoscale. AB - Ionic transport through nanofluidic systems is a problem of fundamental interest in transport physics and has broad relevance in desalination, fuel cells, batteries, filtration, and drug delivery. When the dimension of the fluidic system approaches the size of molecules in solution, fluid properties are not homogeneous and a departure in behavior is observed with respect to continuum based theories. Here we present a systematic study of the transport of charged and neutral small molecules in an ideal nanofluidic platform with precise channels from the sub-microscale to the ultra-nanoscale (<5 nm). Surprisingly, we find that diffusive transport of nano-confined neutral molecules matches that of charged molecules, as though the former carry an effective charge. Further, approaching the ultra-nanoscale molecular diffusivities suddenly drop by up to an order of magnitude for all molecules, irrespective of their electric charge. New theoretical investigations will be required to shed light onto these intriguing results. PMID- 29703955 TI - Predator and prey biodiversity relationship and its consequences on marine ecosystem functioning-interplay between nanoflagellates and bacterioplankton. AB - The importance of biodiversity effects on ecosystem functioning across trophic levels, especially via predatory-prey interactions, is receiving increased recognition. However, this topic has rarely been explored for marine microbes, even though microbial biodiversity contributes significantly to marine ecosystem function and energy flows. Here we examined diversity and biomass of bacteria (prey) and nanoflagellates (predators), as well as their effects on trophic transfer efficiency in the East China Sea. Specifically, we investigated: (i) predator diversity effects on prey biomass and trophic transfer efficiency (using the biomass ratio of predator/prey as a proxy), (ii) prey diversity effects on predator biomass and trophic transfer efficiency, and (iii) the relationship between predator and prey diversity. We found higher prey diversity enhanced both diversity and biomass of predators, as well as trophic transfer efficiency, which may arise from more balanced diet and/or enhanced niche complementarity owing to higher prey diversity. By contrast, no clear effect was detected for predator diversity on prey biomass and transfer efficiency. Notably, we found prey diversity effects on predator-prey interactions; whereas, we found no significant diversity effect on biomass within the same trophic level. Our findings highlight the importance of considering multi-trophic biodiversity effects on ecosystem functioning in natural ecosystems. PMID- 29703956 TI - Author Correction: Double MgO-based Perpendicular Magnetic-Tunnel-Junction Spin valve Structure with a Top Co2Fe6B2 Free Layer using a Single SyAF [Co/Pt]n Layer. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29703957 TI - Enhancement of UV Second-Harmonic Radiation at Nonlinear Interfaces with Discontinuous Second-order Susceptibilities. AB - We investigate the generation of ultraviolet (UV) second-harmonic radiation at the boundary of a UV transparent crystal, which is derived from the automatic partial phase matching of the incident wave and the total internal reflection. By adhering to another UV non-transparent crystal with a larger second-order nonlinear coefficient chi(2), a nonlinear interface with large disparity in chi(2) is formed and the enhancement of UV second-harmonic radiation is observed experimentally. The intensity of enhanced second harmonic wave generated at the nonlinear interface is up to 11.6 times that at the crystal boundary. As a tunable phase-matching method, it may suggest potential applications in the UV, and even vacuum-UV region. PMID- 29703958 TI - A modular synthetic approach for band-gap engineering of armchair graphene nanoribbons. AB - Despite the great promise of armchair graphene nanoribbons (aGNRs) as high performance semiconductors, practical band-gap engineering of aGNRs remains an unmet challenge. Given that width and edge structures are the two key factors for modulating band-gaps of aGNRs, a reliable synthetic method that allows control of both factors would be highly desirable. Here we report a simple modular strategy for efficient preparation of N = 6 aGNR, the narrowest member in the N = 3p (p: natural number) aGNR family, and two unsymmetrically edge-functionalized GNRs that contain benzothiadiazole and benzotriazole moieties. The trend of band-gap transitions among these GNRs parallels those in donor-acceptor alternating conjugated polymers. In addition, post-functionalization of the unsymmetrical heterocyclic edge via C-H borylation permits further band-gap tuning. Therefore, this method opens the door for convenient band-gap engineering of aGNRs through modifying the heteroarenes on the edge. PMID- 29703959 TI - A cryptic cycle in haematopoietic niches promotes initiation of malaria transmission and evasion of chemotherapy. AB - Blood stage human malaria parasites may exploit erythropoietic tissue niches and colonise erythroid progenitors; however, the precise influence of the erythropoietic environment on fundamental parasite biology remains unknown. Here we use quantitative approaches to enumerate Plasmodium infected erythropoietic precursor cells using an in vivo rodent model of Plasmodium berghei. We show that parasitised early reticulocytes (ER) in the major sites of haematopoiesis establish a cryptic asexual cycle. Moreover, this cycle is characterised by early preferential commitment to gametocytogenesis, which occurs in sufficient numbers to generate almost all of the initial population of circulating, mature gametocytes. In addition, we show that P. berghei is less sensitive to artemisinin in splenic ER than in blood, which suggests that haematopoietic tissues may enable origins of recrudescent infection and emerging resistance to antimalarials. Continuous propagation in these sites may also provide a mechanism for continuous transmission and infection in malaria endemic regions. PMID- 29703960 TI - The State of the World's Beaches. AB - Coastal zones constitute one of the most heavily populated and developed land zones in the world. Despite the utility and economic benefits that coasts provide, there is no reliable global-scale assessment of historical shoreline change trends. Here, via the use of freely available optical satellite images captured since 1984, in conjunction with sophisticated image interrogation and analysis methods, we present a global-scale assessment of the occurrence of sandy beaches and rates of shoreline change therein. Applying pixel-based supervised classification, we found that 31% of the world's ice-free shoreline are sandy. The application of an automated shoreline detection method to the sandy shorelines thus identified resulted in a global dataset of shoreline change rates for the 33 year period 1984-2016. Analysis of the satellite derived shoreline data indicates that 24% of the world's sandy beaches are eroding at rates exceeding 0.5 m/yr, while 28% are accreting and 48% are stable. The majority of the sandy shorelines in marine protected areas are eroding, raising cause for serious concern. PMID- 29703961 TI - Genetic variants in chemokine CC subfamily genes influence hepatitis C virus viral clearance. AB - Chemokine genes may influence both hepatitis C virus (HCV) spontaneous clearance in acute infection and treatment response in chronic infection. We conducted this study to evaluate whether the genetic variants in several CC family genes influence HCV spontaneous clearance and treatment response. The current research genotyped eight SNPs, including CCR1 rs3733096, rs13096371, CCR5 rs746492, rs1800874, CCL3 rs1130371, CCL5 rs3817656, CCL8 rs1133763, CCL14 rs854625, to explore their associations with HCV spontaneous clearance and response to treatment in two populations. We identified that the CCR1 rs3733096 (dominant model: adjusted OR = 2.29, 95% CI = 1.49-3.53, additive model: adjusted OR = 2.21, 95% CI = 1.50-3.25) and CCL5 rs3817656 (dominant model: OR = 1.37, 95% CI = 1.10-1.70, additive model: OR = 1.33, 95% CI = 1.12-1.58) were associated with HCV spontaneous clearance in Chinese Han population, while we found no association with treatment response. Moreover, the expression quantitative trait loci (eQTL) analysis showed that the risk alleles of rs3817656 were significantly associated with downregulated expression of CCL5 in whole blood (P < 0.001). The polymorphism of CCR1 rs3733096 and CCL5 rs3817656 are associated with spontaneous clearance of HCV in Chinese Han population. PMID- 29703962 TI - Truncating mutations of HIBCH tend to cause severe phenotypes in cases with HIBCH deficiency: a case report and brief literature review. AB - 3-hydroxyisobutryl-CoA hydrolase (HIBCH) deficiency is a rare inborn error of valine metabolism characterized by neurodegenerative symptoms and caused by recessive mutations in the HIBCH gene. In this study, utilizing whole exome sequencing, we identified two novel splicing mutations of HIBCH (c.304+3A>G; c.1010_1011+3delTGGTA) in a Chinese patient with characterized neurodegenerative features of HIBCH deficiency and bilateral syndactyly which was not reported in previous studies. Functional tests showed that both of these two mutations destroyed the normal splicing and reduced the expression of HIBCH protein. Through a literature review, a potential phenotype-genotype correlation was found that patients carrying truncating mutations tended to have more severe phenotypes compared with those with missense mutations. Our findings would widen the mutation spectrum of HIBCH causing HIBCH deficiency and the phenotypic spectrum of the disease. The potential genotype-phenotype correlation would be profitable for the treatment and management of patients with HIBCH deficiency. PMID- 29703963 TI - Determination of dehydroepiandrosterone and its biologically active oxygenated metabolites in human plasma evinces a hormonal imbalance during HIV-TB coinfection. AB - An estimated one third of the world's population is affected by latent tuberculosis (TB), which once active represents a leading cause of death among infectious diseases. Human immunodeficiency virus (HIV) infection is a main predisposing factor to TB reactivation. Individuals HIV-TB co-infected develop a chronic state of inflammation associated with hypothalamic-pituitary-adrenal (HPA) axis dysregulation. This results in a hormonal imbalance, disturbing the physiological levels of cortisol and dehydroepiandrosterone (DHEA). DHEA and its oxygenated metabolites androstenediol (AED), androstenetriol (AET) and 7-oxo-DHEA are immunomodulatory compounds that may regulate physiopathology in HIV-TB co infection. In order to study possible changes in plasma levels of these hormones, we developed an approach based on high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS). To our knowledge, this represents the first report of their simultaneous measurement in HIV-TB individuals and the comparison with healthy donors, obtaining statistically higher plasma levels of DHEA, AET and 7-oxo-DHEA in patients. Moreover, we found that concentrations of 7-oxo-DHEA positively correlated with absolute CD4+ T cell counts, nadir CD4+ T cell values and with individuals who presented TB restricted to the lungs. This research contributes to understanding the role of these hormones in HIV-TB and emphasizes the importance of deepening their study in this context. PMID- 29703964 TI - Opto-mechanical lab-on-fibre seismic sensors detected the Norcia earthquake. AB - We have designed and developed lab-on-fibre seismic sensors containing a micro opto-mechanical cavity on the fibre tip. The mechanical cavity is designed as a double cantilever suspended on the fibre end facet and connected to a proof mass to tune its response. Ground acceleration leads to displacement of the cavity length, which in turn can be remotely detected using an interferometric interrogation technique. After the sensors characterization, an experimental validation was conducted at the Italian National Institute of Geophysics and Volcanology (INGV), which is responsible for seismic surveillance over the Italian country. The fabricated sensors have been continuously used for long periods to demonstrate their effectiveness as seismic accelerometer sensors. During the tests, fibre optic seismic accelerometers clearly detected the seismic sequence that culminated in the severe Mw6.5 Norcia earthquake that struck central Italy on October 30, 2016. The seismic data provided by the optical sensors were analysed by specialists at the INGV. The wave traces were compared with state-of-the-art traditional sensors typically incorporated into the INGV seismic networks. The comparison verifies the high fidelity of the optical sensors in seismic wave detection, indicating their suitability for a novel class of seismic sensors to be employed in practical scenarios. PMID- 29703965 TI - Lenalidomide vs bortezomib maintenance choice post-autologous hematopoietic cell transplantation for multiple myeloma. AB - Maintenance therapy post-autologous hematopoietic cell transplantation (AHCT) with either lenalidomide or bortezomib for multiple myeloma (MM) have separately been shown to improve progression-free survival (PFS), but have never been directly compared. We performed a retrospective study to investigate progression free and overall survival outcomes and toxicities of lenalidomide maintenance therapy compared with bortezomib maintenance in MM patients post-AHCT. This study included 156 patients who received post-AHCT lenalidomide or bortezomib maintenance therapy for MM. The primary outcome was PFS. Ninety-two patients received lenalidomide maintenance and 64 received bortezomib maintenance post AHCT. By multivariable analysis, maintenance therapy choice and cytogenetics risk did not impact PFS or OS. Staging by International Staging System and pre maintenance disease response were the greatest predictors for PFS. Treatment related toxicities were as anticipated with 5.4% of patients receiving maintenance lenalidomide experiencing secondary primary malignancies (SPMs) compared with 3% for bortezomib. These findings suggest there were no differences in PFS or OS between lenalidomide and bortezomib maintenance therapy options for post-transplantation MM patients. These data should be validated in a larger, prospective cohort to determine if maintenance choice should be guided by side effect profile and patient anticipated tolerance rather than by disease biology alone. PMID- 29703966 TI - CD3+ graft cell count influence on chronic GVHD in haploidentical allogeneic transplantation using post-transplant cyclophosphamide. AB - The effects of graft or donor characteristics in haploidentical hematopoietic cell transplantation (HCT) using post-transplant cyclophosphamide (PT-Cy) are largely unknown. In this multicenter retrospective study we analyzed the correlations between graft cell composition (CD34+, CD3+) and donor features on transplant outcomes in 234 patients who underwent HCT between 2010 and 2016. On multivariate analysis, the use of peripheral blood stem cells (PBSC) was associated with an increased incidence of grade 2-4 acute GVHD [HR 1.94, 95% confidence Interval (CI) = 1.01-3.98, p = 0.05]. An elevated CD3+ graft content was associated with an increased incidence of all-grade chronic GVHD [HR 1.36 (95% CI = 1.06-1.74), p = 0.01]. This effect was confirmed only for the PBSC graft group. A higher CD34+ graft content had a protective role on non-relapse mortality [HR 0.78 (95% CI = 0.62-0.96), p = 0.02] but this was confirmed only for the bone marrow (BM)-derived graft cohort. Donor characteristics did not influence any outcomes. GVHD prophylaxis should be modulated accordingly to CD3+ graft content, especially when a PBSC graft is used. These results need further validation in prospective trials. PMID- 29703968 TI - Similar survival but increased toxicity with a sequential versus concurrent FluBu4 regimen. PMID- 29703967 TI - Adalimumab for treatment of hemophagocytic syndrome following unrelated bone marrow transplantation in a boy with Behcet's disease and secondary myelodysplastic syndrome. PMID- 29703969 TI - Role of one, two and three doses of high-dose chemotherapy with autologous transplantation in the treatment of high-risk or relapsed testicular cancer: a systematic review. AB - Approximately 20-30% of patients with metastatic germ cell cancers (GCCs) can develop relapsed or refractory (RR) disease, about 40-50% of patients who relapse after salvage chemotherapy may reach long-term remission. The goal of this review was to identify patients who appear to benefit from high-dose chemotherapy (HDCT) and autologous stem cell transplant (ASCT). To access this, we performed a systematic medical literature review to evaluate the effectiveness of HDCT in the frontline setting, as well as in patients with RR testicular cancer. We searched databases for interventional clinical studies and identified 5883 studies. We selected 49 studies for inclusion, which included a total of 5985 patients. Seventeen studies reported results of newly diagnosed poor-risk GCC patients and 32 studies reported results of RR patients. For newly diagnosed patients with poor prognostic predictors, a risk adjusted strategy using unfavorable tumor marker decline with initial standard chemotherapy regimen and upfront HDCT demonstrated improved outcomes. Our data suggest a minimum of two HDCT cycles with ASCT should be standard of care for patients with RR GCC. Failure of HDCT results in a poor prognosis with only 10% of patients achieving lasting remission with salvage therapy. PMID- 29703970 TI - Automated washing of long-term cryopreserved peripheral blood stem cells promotes cell viability and preserves CD34+ cell numbers. PMID- 29703971 TI - A case-series of Toxoplasmosis in hematopoietic stem cell transplantation: still a concern for endemic countries. PMID- 29703972 TI - Critically ill allogenic HSCT patients in the intensive care unit: a systematic review and meta-analysis of prognostic factors of mortality. AB - Outcome of patients undergoing allogenic hematopoietic stem cell transplantation (allo-HSCT) has improved. To investigate if this improvement can be transposed to the ICU setting, we conducted a systematic review and meta-analysis to assess short-term mortality of critically ill allo-HSCT patients admitted to the ICU and to identify prognostic factors of mortality. Public-domain electronic databases, including Medline via PubMed and the Cochrane Library were searched. All full text articles written-English studies published from 2006 to 2016, including allo HSCT adults transferred to the ICU were included. Eighteen studies were selected, including 2342 patients. Overall estimated ICU mortality was 51.7%. Prognostic factors associated with an increased ICU mortality were mechanical ventilation (OR = 12.2, 95% CI = 6.2-23.7), vasopressors (OR = 6.3, 95% CI = 3.6-11.1), renal replacement therapy (OR = 4.2, 95% CI = 2.8-6.2), ICU admission for acute respiratory failure (OR = 2.2, 95% CI = 1.1-4.4), acute kidney injury (OR = 2.2, 95% CI = 1.3-4), and acute graft-versus-host disease (OR = 1.6, 95% CI = 1.1 2.3). Factors associated with an increased ICU survival were a single-organ failure (OR = 0.2, 95% CI = 0.1-0.4), neurological failure (OR = 0.4, 95% CI = 0.2-0.8), and reduced-intensity conditioning regimens (OR = 0.7, 95% CI = 0.5 0.9). Septic shock, underlying malignancy, disease status, donor, and graft source did not impact prognosis. Outcome has improved, supporting the usefulness of ICU management. Organ failures at ICU admission, organ support requirement, and GVHD are the main prognostic factors. PMID- 29703973 TI - RNA-sequencing reveals long-term effects of silver nanoparticles on human lung cells. AB - Despite a considerable focus on the adverse effects of silver nanoparticles (AgNPs) in recent years, studies on the potential long-term effects of AgNPs are scarce. The aim of this study was to explore the effects of AgNPs following repeated low-dose, long-term exposure of human bronchial epithelial cells. To this end, the human BEAS-2B cell line was exposed to 1 ug/mL AgNPs (10 nm) for 6 weeks followed by RNA-sequencing (RNA-Seq) as well as genome-wide DNA methylation analysis. The transcriptomics analysis showed that a substantial number of genes (1717) were differentially expressed following AgNP exposure whereas only marginal effects on DNA methylation were observed. Downstream analysis of the transcriptomics data identified several affected pathways including the 'fibrosis' and 'epithelial-mesenchymal transition' (EMT) pathway. Subsequently, functional validation studies were performed using AgNPs of two different sizes (10 nm and 75 nm). Both NPs increased collagen deposition, indicative of fibrosis, and induced EMT, as evidenced by an increased invasion index, anchorage independent cell growth, as well as cadherin switching. In conclusion, using a combination of RNA-Seq and functional assays, our study revealed that repeated low-dose, long-term exposure of human BEAS-2B cells to AgNPs is pro-fibrotic, induces EMT and cell transformation. PMID- 29703976 TI - Searching for superstool: maximizing the therapeutic potential of FMT. PMID- 29703974 TI - The ng_zeta1 toxin of the gonococcal epsilon/zeta toxin/antitoxin system drains precursors for cell wall synthesis. AB - Bacterial toxin-antitoxin complexes are emerging as key players modulating bacterial physiology as activation of toxins induces stasis or programmed cell death by interference with vital cellular processes. Zeta toxins, which are prevalent in many bacterial genomes, were shown to interfere with cell wall formation by perturbing peptidoglycan synthesis in Gram-positive bacteria. Here, we characterize the epsilon/zeta toxin-antitoxin (TA) homologue from the Gram negative pathogen Neisseria gonorrhoeae termed ng_E1 / ng_zeta1. Contrary to previously studied streptococcal epsilon/zeta TA systems, ng_E1 has an epsilon unrelated fold and ng_zeta1 displays broader substrate specificity and phosphorylates multiple UDP-activated sugars that are precursors of peptidoglycan and lipopolysaccharide synthesis. Moreover, the phosphorylation site is different from the streptococcal zeta toxins, resulting in a different interference with cell wall synthesis. This difference most likely reflects adaptation to the individual cell wall composition of Gram-negative and Gram-positive organisms but also the distinct involvement of cell wall components in virulence. PMID- 29703975 TI - Transporter gene acquisition and innovation in the evolution of Microsporidia intracellular parasites. AB - The acquisition of genes by horizontal transfer can impart entirely new biological functions and provide an important route to major evolutionary innovation. Here we have used ancient gene reconstruction and functional assays to investigate the impact of a single horizontally transferred nucleotide transporter into the common ancestor of the Microsporidia, a major radiation of intracellular parasites of animals and humans. We show that this transporter provided early microsporidians with the ability to steal host ATP and to become energy parasites. Gene duplication enabled the diversification of nucleotide transporter function to transport new substrates, including GTP and NAD+, and to evolve the proton-energized net import of nucleotides for nucleic acid biosynthesis, growth and replication. These innovations have allowed the loss of pathways for mitochondrial and cytosolic energy generation and nucleotide biosynthesis that are otherwise essential for free-living eukaryotes, resulting in the highly unusual and reduced cells and genomes of contemporary Microsporidia. PMID- 29703977 TI - Deconvolution of subcellular protrusion heterogeneity and the underlying actin regulator dynamics from live cell imaging. AB - Cell protrusion is morphodynamically heterogeneous at the subcellular level. However, the mechanism of cell protrusion has been understood based on the ensemble average of actin regulator dynamics. Here, we establish a computational framework called HACKS (deconvolution of heterogeneous activity in coordination of cytoskeleton at the subcellular level) to deconvolve the subcellular heterogeneity of lamellipodial protrusion from live cell imaging. HACKS identifies distinct subcellular protrusion phenotypes based on machine-learning algorithms and reveals their underlying actin regulator dynamics at the leading edge. Using our method, we discover "accelerating protrusion", which is driven by the temporally ordered coordination of Arp2/3 and VASP activities. We validate our finding by pharmacological perturbations and further identify the fine regulation of Arp2/3 and VASP recruitment associated with accelerating protrusion. Our study suggests HACKS can identify specific subcellular protrusion phenotypes susceptible to pharmacological perturbation and reveal how actin regulator dynamics are changed by the perturbation. PMID- 29703978 TI - Time efficient whole-brain coverage with MR Fingerprinting using slice interleaved echo-planar-imaging. AB - Magnetic resonance fingerprinting (MRF) is a promising method for fast simultaneous quantification of multiple tissue parameters. The objective of this study is to improve the coverage of MRF based on echo-planar imaging (MRF-EPI) by using a slice-interleaved acquisition scheme. For this, the MRF-EPI is modified to acquire several slices in a randomized interleaved manner, increasing the effective repetition time of the spoiled gradient echo readout acquisition in each slice. Per-slice matching of the signal-trace to a precomputed dictionary allows the generation of T1 and T2* maps with integrated B1+ correction. Subsequent compensation for the coil sensitivity profile and normalization to the cerebrospinal fluid additionally allows for quantitative proton density (PD) mapping. Numerical simulations are performed to optimize the number of interleaved slices. Quantification accuracy is validated in phantom scans and feasibility is demonstrated in-vivo. Numerical simulations suggest the acquisition of four slices as a trade-off between quantification precision and scan-time. Phantom results indicate good agreement with reference measurements (Difference T1: -2.4 +/- 1.1%, T2*: -0.5 +/- 2.5%, PD: -0.5 +/- 7.2%). In-vivo whole-brain coverage of T1, T2* and PD with 32 slices was acquired within 3:36 minutes, resulting in parameter maps of high visual quality and comparable performance with single-slice MRF-EPI at 4-fold scan-time reduction. PMID- 29703979 TI - Structural defects in a nanomesh of bulk MoS2 using an anodic aluminum oxide template for photoluminescence efficiency enhancement. AB - Two-dimensional (2D) materials beyond graphene have attracted considerable interest because of the zero bandgap drawbacks of graphene. Transition metal dichalcogenides (TMDs), such as MoS2 and WSe2, are the potential candidates for next 2D materials because atomically thin layers of TMDs exhibit unique and versatile electrical and optical properties. Although bulk TMDs materials have an indirect bandgap, an indirect-to-direct bandgap transition is observed in monolayers of TMDs (MoS2, WSe2, and MoSe2). Optical properties of TMD films can be improved by the introduction of structural defects. For example, large-area spatial tuning of the optical transition of bulk MoS2 films is achieved by using an anodic aluminum oxide (AAO) template to induce structural defects such as edge and terrace-terminated defects in a nanomesh structure. Strong photoluminescence emission peaks with a band gap of 1.81 eV are observed, possibly because of radiative transition at the defect sites. This work shows that the AAO template lithography method has potential for the production of homogenous large-scale nanomesh structures for practical semiconductor processing applications in future MoS2-based electronic and optical devices. PMID- 29703980 TI - Towards ultrafast dynamics with split-pulse X-ray photon correlation spectroscopy at free electron laser sources. AB - One of the important challenges in condensed matter science is to understand ultrafast, atomic-scale fluctuations that dictate dynamic processes in equilibrium and non-equilibrium materials. Here, we report an important step towards reaching that goal by using a state-of-the-art perfect crystal based split-and-delay system, capable of splitting individual X-ray pulses and introducing femtosecond to nanosecond time delays. We show the results of an ultrafast hard X-ray photon correlation spectroscopy experiment at LCLS where split X-ray pulses were used to measure the dynamics of gold nanoparticles suspended in hexane. We show how reliable speckle contrast values can be extracted even from very low intensity free electron laser (FEL) speckle patterns by applying maximum likelihood fitting, thus demonstrating the potential of a split-and-delay approach for dynamics measurements at FEL sources. This will enable the characterization of equilibrium and, importantly also reversible non equilibrium processes in atomically disordered materials. PMID- 29703981 TI - Transmission events revealed in tuberculosis contact investigations in London. AB - Contact tracing is a key part of tuberculosis prevention and care, aiming to hasten diagnosis and prevent transmission. The proportion of case-contact pairs for which recent transmission occurred and the typical timespans between the index case and their contact accessing care are not known; we aimed to calculate these. We analysed individual-level TB contact tracing data, collected in London from 20/01/2011-31/12/2015, linked to tuberculosis surveillance and MIRU-VNTR 24 locus strain-typing information. Of pairs of index cases and contacts diagnosed with active tuberculosis, 85/314 (27%) had strain typing data available for both. Of these pairs, 79% (67/85) shared indistinguishable isolates, implying probable recent transmission. Of pairs in which both contact and the index case had a social risk factor, 11/11 (100%) shared indistinguishable isolates, compared to 55/75 (75%) of pairs in which neither had a social risk factor (P = 0.06). The median time interval between the index case and their contact accessing care was 42 days (IQR: 16, 96). As over 20% of pairs did probably not involve recent transmission between index case and contact, the effectiveness of contact tracing is not necessarily limited to those circumstances where the index case has transmitted disease to their close contacts. PMID- 29703982 TI - Whole-exome sequencing of cell-free DNA and circulating tumor cells in multiple myeloma. AB - Liquid biopsies including circulating tumor cells (CTCs) and cell-free DNA (cfDNA) have enabled minimally invasive characterization of many cancers, but are rarely analyzed together. Understanding the detectability and genomic concordance of CTCs and cfDNA may inform their use in guiding cancer precision medicine. Here, we report the detectability of cfDNA and CTCs in blood samples from 107 and 56 patients with multiple myeloma (MM), respectively. Using ultra-low pass whole genome sequencing, we find both tumor fractions correlate with disease progression. Applying whole-exome sequencing (WES) to cfDNA, CTCs, and matched tumor biopsies, we find concordance in clonal somatic mutations (~99%) and copy number alterations (~81%) between liquid and tumor biopsies. Importantly, analyzing CTCs and cfDNA together enables cross-validation of mutations, uncovers mutations exclusive to either CTCs or cfDNA, and allows blood-based tumor profiling in a greater fraction of patients. Our study demonstrates the utility of analyzing both CTCs and cfDNA in MM. PMID- 29703983 TI - Calibrating facial morphs for use as stimuli in biological studies of social perception. AB - Studies of human social perception become more persuasive when the behavior of raters can be separated from the variability of the stimuli they are rating. We prototype such a rigorous analysis for a set of five social ratings of faces varying by body fat percentage (BFP). 274 raters of both sexes in three age groups (adolescent, young adult, senior) rated five morphs of the same averaged facial image warped to the positions of 72 landmarks and semilandmarks predicted by linear regression on BFP at five different levels (the average, +/-2 SD, +/-5 SD). Each subject rated all five morphs for maturity, dominance, masculinity, attractiveness, and health. The patterns of dependence of ratings on the BFP calibration differ for the different ratings, but not substantially across the six groups of raters. This has implications for theories of social perception, specifically, the relevance of individual rater scale anchoring. The method is also highly relevant for other studies on how biological facial variation affects ratings. PMID- 29703984 TI - Author Correction: Unravelling the effects of mechanical physiological conditioning on cardiac adipose tissue-derived progenitor cells in vitro and in silico. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29703985 TI - Application of droplet digital PCR in the analysis of genome integration and organization of the transgene in BAC transgenic mice. AB - Transgenic (Tg) mice containing bacterial artificial chromosome (BAC) DNA are widely used for gene expression analysis and gene therapy models because BAC transgenes provide gene expression at physiological levels with the same developmental timing as endogenous genes. To ensure correct interpretation of transgene functions, investigation of the genomic organisation and integration of the BAC transgene is required. Here, we describe a reliable method based on droplet digital PCR (ddPCR) and inverse PCR to estimate copy number, genomic organisation and insertion sites of BAC transgenes in the mouse genome. We generated BAC Tg mice containing fragments of BAC clone RP23-59P20. ddPCR and iPCR analysis showed that the transgene consisted of five fragments of the BAC clone containing the Mkrn3 gene region, and that the transgene was inserted into Bckdhb, homozygous deletion of which causes the maple syrup urine disease phenotype. The ddPCR method described here should prove useful for analysis of genomic organisation and integration of BAC transgenes. PMID- 29703986 TI - Improved method for estimating adlayer thickness and bulk RI change for gold nanocrescent sensors. AB - This paper presents a novel method employing the maximum likelihood estimation (MLE) technique alongside a nonlinear sensor response model to improve and extract more quantitative sensing results for localized surface plasmon resonance biosensors. The nonlinear response model treats the sensor response as a nonlinear function of the biomolecular adlayer thickness. This method makes use of the multiple resonance characteristic of nanocrescent structures in order to estimate the adlayer thickness and bulk refractive index (RI) change. Nanoimprint lithography is used here to fabricate the nanostructures. The finite element method (FEM) is used to model the nanocrescents and numerically validate the nonlinear-MLE method. Comparing to the established linear model, the proposed nonlinear-MLE method achieves 75% improvement in the limit of detection based on the estimated adlayer thickness and improves the bulk RI resolution by two orders of magnitude. PMID- 29703987 TI - Staphylococcus aureus enterotoxins modulate IL-22-secreting cells in adults with atopic dermatitis. AB - Atopic dermatitis (AD) is a chronic inflammatory immune-mediated skin disease characterized by skin colonization by Staphylococcus aureus. Interleukin (IL)-22, in cooperation with IL-17, triggers antimicrobial peptide elaboration and enhances certain immunological responses. In AD, IL-22 is related to epidermal hyperplasia, keratinocyte apoptosis, and inhibition of antimicrobial peptide (AMP) production. We aimed to evaluate the impact of staphylococcal enterotoxins on the Tc22/Th22 induction in the peripheral blood of AD patients and on CD4+/CD8+ T cells expressing IL-22 in AD skin. Our study showed inhibition of the staphylococcal enterotoxins A and B (SEA and SEB) response by Th22 (CD4+IL-22+IL 17A-IFN-gamma-) cells in AD patients. In contrast, Tc22 (CD8+IL-22+IL-17A-IFN gamma-) cells were less susceptible to the inhibitory effects of staphylococcal enterotoxins and exhibited an enhanced response to the bacterial stimuli. In AD skin, we detected increased IL-22 transcript expression and T lymphocytes expressing IL-22. Together, our results provide two major findings in response to staphylococcal enterotoxins in adults with AD: dysfunctional CD4+ IL-22 secreting T cells and increased Tc22 cells. Our hypothesis reinforces the relevance of CD8 T cells modulated by staphylococcal enterotoxins as a potential source of IL-22 in adults with AD, which is relevant for the maintenance of immunological imbalance. PMID- 29703988 TI - Artisanal shark fishing in Milne Bay Province, Papua New Guinea: biomass estimation from genetically identified shark and ray fins. AB - Our study is the first detailed examination of species composition using DNA COI barcoding of elasmobranchs from an artisanal fishery of Papua New Guinea. The study is the first in the region to provide biomass estimates based on species confirmation following examination of dried fins. Over 20 species of elasmobranchs were identified from 623 fins from the artisanal fishery in Milne Bay Province of PNG, with Carcharhinus amblyrhynchos and Carcharhinus melanopterus the most abundant species in the catches. Of concern, 21% of fins examined were from IUCN listed threatened species (Vulnerable or Endangered) with 8% of fins from the Endangered scalloped hammerhead (Sphyrna lewini). Following species identifications and use of species-specific length and weight extrapolations, we estimated over 9 t of elasmobranchs contributed to the fin batch. Importantly, the vast majority of the elasmobranchs in this batch were from immature animals. Genetic identification has an important role to play in the ongoing sustainable management of elasmobranchs in artisanal fisheries in PNG and more widely. However in the absence of ongoing genetic testing, recording the species (if known) at the time of catch is more achievable and would provide more robust data for fisheries managers in PNG over the longer term. PMID- 29703989 TI - Personality traits affecting judgement bias task performance in dogs (Canis familiaris). AB - Certain personality traits (e.g. anxiousness, fearfulness), are known to affect the cognitive processing of environmental stimuli, such as the judgement of ambiguous stimuli (judgement bias). Our aim was to assess if personality traits are predictive of a more or less 'pessimistic' or 'optimistic' judgement bias in the domestic dog. We assessed dog personality (N = 31) using two validated protocols: the Dog Mentality Assessment (standardised battery test) and the CBARQ (owner-based survey). We used a common task based on the animals' latency to approach a bowl placed in one of three ambiguous positions (Near Positive, Middle, Near Negative) between a baited (Positive) and a non-baited food bowl (Negative) to assess judgement bias. Linear Mixed Model analyses revealed that dogs scoring higher on sociability, excitability and non-social-fear had shorter response latencies to bowls in an ambiguous location, indicating a more 'optimistic' bias. In contrast, dogs scoring higher on separation-related behaviour and dog-directed-fear/aggression traits were more likely to judge an ambiguous stimulus as leading to a negative outcome, indicating a more 'pessimistic' bias. Results, partially consistent with previous findings in humans, indicate that personality plays a role in the cognitive processing of environmental stimuli in the domestic dog. PMID- 29703990 TI - Topical pharyngeal anesthesia provides no additional benefit to propofol sedation for esophagogastroduodenoscopy: a randomized controlled double-blinded clinical trial. AB - Propofol sedation has been applied during esophagogastroduodenoscopy procedures, but whether topical pharyngeal anesthesia should be administered at the same time has rarely been reported. Our study examined the role of topical pharyngeal anesthesia in sedated endoscopies in a randomized controlled double-blinded clinical trial. A total of 626 patients who underwent sedated esophagogastroduodenoscopy were randomized into the experimental group (n = 313) or the control group (n = 313). The discomfort score, immediately and one day after the procedure, was not statistically significant [7.2 (5-9) vs. 7.5 (6-9), P = 0.210; 2.3 (0-3) vs. 2.6 (0-4), P = 0.095, respectively]. Two patients in the experimental group and three patients in the control group needed oral medication for pharyngeal discomfort (P = 0.354). The satisfaction score was 9.2 (8-10) in the experimental group and 8.9 (7-10) in the control group (P = 0.778). Lidocaine topical pharyngeal anesthesia in propofol-sedated esophagogastroduodenoscopy did not further reduce the pharyngeal discomfort or improve the satisfaction. This clinical trial was registered at ClinicalTrials.gov (ClinicalTrials.gov ID: NCT03070379). PMID- 29703991 TI - Development of a Click-Chemistry Reagent Compatible with Mass Cytometry. AB - The recent development of mass cytometry has allowed simultaneous detection of 40 or more unique parameters from individual single cells. While similar to flow cytometry, which is based on detection of fluorophores, one key distinguishing feature of mass cytometry is the detection of atomic masses of lanthanides by mass spectrometry in a mass cytometer. Its superior mass resolution results in lack of signal overlap, thereby allowing multiparametric detection of molecular features in each single cell greater than that of flow cytometry, which is limited to 20 parameters. Unfortunately, most detection in mass cytometry relies on lanthanide-tagged antibodies, which is ideal to detect proteins, but not other types of molecular features. To further expand the repertoire of molecular features that are detectable by mass cytometry, we developed a lanthanide chelated, azide-containing probe that allows click-chemistry mediated labeling of target molecules. Following incorporation of the thymidine analog 5-ethynyl-2' deoxyuridine (EdU) during DNA synthesis in S-phase of the cell cycle, we demonstrate that the probe introduced here, tagged with Terbium-159 (159Tb), reacts via copper-catalyzed azide-alkyne Huisgen cycloaddition (click-chemistry) with Edu. Thus, detection of 159Tb makes it possible to measure DNA synthesis in single cells using mass cytometry. The approach introduced here shows similar sensitivity (true positive rate) to other methods used to measure DNA synthesis in single cells by mass cytometry and is compatible with the parallel antibody based detection of other parameters in single cells. Due to its universal nature, the use of click-chemistry in mass cytometry expands the types of molecular targets that can be monitored by mass cytometry. PMID- 29703992 TI - Dynamic tuneable G protein-coupled receptor monomer-dimer populations. AB - G protein-coupled receptors (GPCRs) are the largest class of membrane receptors, playing a key role in the regulation of processes as varied as neurotransmission and immune response. Evidence for GPCR oligomerisation has been accumulating that challenges the idea that GPCRs function solely as monomeric receptors; however, GPCR oligomerisation remains controversial primarily due to the difficulties in comparing evidence from very different types of structural and dynamic data. Using a combination of single-molecule and ensemble FRET, double electron electron resonance spectroscopy, and simulations, we show that dimerisation of the GPCR neurotensin receptor 1 is regulated by receptor density and is dynamically tuneable over the physiological range. We propose a "rolling dimer" interface model in which multiple dimer conformations co-exist and interconvert. These findings unite previous seemingly conflicting observations, provide a compelling mechanism for regulating receptor signalling, and act as a guide for future physiological studies. PMID- 29703993 TI - Cortical inhibitory markers of lifetime suicidal behavior in depressed adolescents. AB - Although suicide is the second-leading cause of death in adolescents and young adults worldwide, little progress has been made in developing reliable biological markers of suicide risk and suicidal behavior. Converging evidence suggests that excitatory and inhibitory cortical processes mediated by the neurotransmitters glutamate and gamma-aminobutyric acid (GABA) are dysregulated in suicidal individuals. This study utilized single- and paired-pulse transcranial magnetic stimulation (TMS) to assess excitatory and inhibitory cortical functioning in healthy control adolescents (n = 20), depressed adolescents without any history of suicidal behavior ("Depressed", n = 37), and depressed adolescents with lifetime history of suicidal behavior ("Depressed+SB", n = 17). In a fixed effects general linear model analysis, with age, sex, and depression severity as covariates, no significant group main effects emerged for resting motor threshold, intracortical facilitation, short-interval intracortical inhibition, or cortical silent period. However, group main effects were significant for long interval intracortical inhibition (LICI) at interstimulus intervals (ISIs) of 100 ms and 150 ms, but not 200 ms. Depressed+SB adolescents demonstrated impaired LICI compared to healthy control and Depressed adolescents, while healthy control and Depressed participants did not differ in LICI. Multiple linear robust regression revealed significant positive linear relationships between lifetime suicidal behavior severity and impairment in LICI at 100-ms and 150-ms ISIs. In a post hoc receiver operating characteristic analysis, LICI significantly discriminated Depressed from Depressed+SB youth in 100-ms and 150-ms paradigms. These findings suggest that GABAB receptor-mediated inhibition is distinctly dysregulated in depressed adolescents with histories of suicidal behavior. Further research is warranted to establish the utility of cortical inhibition in the assessment of suicide risk and as a target for treatment interventions. PMID- 29703995 TI - Opportunities and needs in digital phenotyping. PMID- 29703997 TI - Neural cell adhesion molecule peptide mimetics modulate emotionality: pharmacokinetic and behavioral studies in rats and non-human primates. AB - Recent evidence highlights the fibroblast growth factor (FGF) family in emotion modulation. Although ligands that activate FGF receptors have antidepressant and anxiolytic effects in animal models, FGF ligands have a broad range of actions both in the brain and the periphery. Therefore, identifying molecular partners that may function as allosteric modulators could offer new avenues for drug development. Since neural cell adhesion molecule (NCAM) activates FGF receptors, we asked whether peripherally administered NCAM peptide mimetics penetrate the brain and alter the behavior of standardized tests that have predictive validity for drug treatments of anxiety or depression. The NCAM peptide mimetic, plannexin, acutely increased and chronically decreased anxiety, but did not have antidepressant effects in rats. Another NCAM peptide mimetic, FGLL, had acute anxiogenic effects and chronic antidepressant effects in rats. A related NCAM peptide mimetic, FGLS, had antidepressant effects without modulating anxiety-like behavior, and these antidepressant effects were blocked by an AMPA receptor antagonist. Cisternal cerebrospinal fluid (CSF) levels of FGLs correlated with blood plasma levels in rats and non-human primates, and CSF-to-blood ratios of FGLS were comparable in both species. Results indicate that NCAM peptide mimetics penetrate the brain and support the suggestion that FGLS may be a candidate for further development as a novel treatment for major depressive disorder in humans. PMID- 29703994 TI - Behavioral and neurobiological mechanisms of punishment: implications for psychiatric disorders. AB - Punishment involves learning about the relationship between behavior and its adverse consequences. Punishment is fundamental to reinforcement learning, decision-making and choice, and is disrupted in psychiatric disorders such as addiction, depression, and psychopathy. However, little is known about the brain mechanisms of punishment and much of what is known is derived from study of superficially similar, but fundamentally distinct, forms of aversive learning such as fear conditioning and avoidance learning. Here we outline the unique conditions that support punishment, the contents of its learning, and its behavioral consequences. We consider evidence implicating GABA and monoamine neurotransmitter systems, as well as corticostriatal, amygdala, and dopamine circuits in punishment. We show how maladaptive punishment processes are implicated in addictions, impulse control disorders, psychopathy, anxiety, and depression and argue that a better understanding of the cellular, circuit, and cognitive mechanisms of punishment will make important contributions to next generation therapeutic approaches. PMID- 29703998 TI - Oxytocin reduces a chemosensory-induced stress bias in social perception. AB - Social transmission of fear is not restricted to visual or auditory cues, but extends to the phylogenetically more ancient olfactory domain. Anxious individuals exhibit heightened sensitivity towards chemosensory stress signals in sweat; however, it is still unknown whether endogenous neuromodulators such as the peptide hormone oxytocin (OXT) influence the chemosensory communication of stress. Here, we investigated whether OXT selectively diminishes behavioral and neural responses to social chemosensory stress cues utilizing a randomized, double-blind, placebo (PLC)-controlled, within-subject functional MRI study design. Axillary sweat was obtained from 30 healthy male donors undergoing the Trier Social Stress Test (stress) and bicycle ergometer training (sport). Subsequently, 58 healthy participants (30 females) completed a forced-choice emotional face recognition task with stimuli of varying intensities (neutral to fearful) while they were exposed to both sweat stimuli and a non-social control odor following intranasal OXT or PLC administration, respectively. OXT diminished stress-induced recognition accuracy and response time biases towards fear. On the neural level, OXT reduced stress-evoked responses in the amygdala in both sexes, the anterior cingulate cortex (ACC) in females, and the hippocampus in males. Furthermore, OXT reinstated the functional connectivity between the ACC and the fusiform face area that was disrupted by stress odors under PLC. Our findings reveal a new role for OXT signaling in the modulation of chemosensory communication of stress in humans. Mechanistically, this effect appears to be rooted in a downregulation of stress-induced limbic activations and concomitant strengthening of top-down control descending from the ACC to the fusiform face area. PMID- 29703996 TI - Knockdown of hypocretin attenuates extended access of cocaine self-administration in rats. AB - The hypocretin/orexin (HCRT) neuropeptide system regulates feeding, arousal state, stress responses, and reward, especially under conditions of enhanced motivational relevance. In particular, HCRT neurotransmission facilitates drug seeking behavior in circumstances that demand increased effort and/or motivation to take the drug. The present study used a shRNA-encoding adeno-associated viral vector to knockdown Hcrt expression throughout the dorsal hypothalamus in adult rats and determine the role of HCRT in cocaine self-administration. Chronic Hcrt silencing did not impact cocaine self-administration under short-access conditions, but robustly attenuated cocaine intake under extended access conditions, a model that mimics key features of compulsive cocaine taking. In addition, Hcrt silencing decreased motivation for both cocaine and a highly palatable food reward (i.e., sweetened condensed milk; SCM) under a progressive ratio schedule of reinforcement, but did not alter responding for SCM under a fixed ratio schedule. Importantly, Hcrt silencing did not affect food or water consumption, and had no consequence for general measures of arousal and stress reactivity. At the molecular level, chronic Hcrt knockdown reduced the number of neurons expressing dynorphin (DYN), and to a smaller extent melanin-concentrating hormone (MCH), in the dorsal hypothalamus. These original findings support the hypothesis that HCRT neurotransmission promotes operant responding for both drug and non-drug rewards, preferentially under conditions requiring a high degree of motivation. Furthermore, the current study provides compelling evidence for the involvement of the HCRT system in cocaine self-administration also under low effort conditions in rats allowed extended access, possibly via functional interactions with DYN and MCH signaling. PMID- 29703999 TI - Amphetamine maintenance differentially modulates effects of cocaine, methylenedioxypyrovalerone (MDPV), and methamphetamine on intracranial self stimulation and nucleus accumbens dopamine in rats. AB - Amphetamine maintenance is effective clinically to reduce the consumption of the monoamine uptake inhibitor cocaine but not of the monoamine releaser methamphetamine, and its effectiveness in treating the abuse of other psychostimulants is not known. The mechanisms for differential amphetamine maintenance effectiveness to treat different types of psychostimulant abuse are also not known. Accordingly, the present study compared the effects of amphetamine maintenance on abuse-related behavioral and neurochemical effects of cocaine, methamphetamine, and the "bath salts" constituent 3,4 methylenedioxypyrovalerone (MDPV) in rats. In behavioral studies, rats were trained to lever press for electrical brain stimulation in an intracranial self stimulation (ICSS) procedure. In neurochemical studies, nucleus accumbens (NAc) levels of dopamine (DA) and serotonin (5-HT) were monitored by in vivo microdialysis. Cocaine, methamphetamine, and MDPV each produced dose-dependent ICSS facilitation and increases in NAc DA; cocaine and methamphetamine also increased NAc 5-HT. Amphetamine maintenance (0.32 mg/kg/h * 7 days) produced (1) sustained increases in basal ICSS and NAc DA with no change in NAc 5-HT, (2) blockade of cocaine but not methamphetamine effects on ICSS and NAc DA, and (3) no blockade of cocaine- or methamphetamine-induced increases in NAc 5-HT. Amphetamine maintenance blocked the increases in NAc DA produced by the selective DA uptake inhibitor MDPV, but it did not block MDPV-induced ICSS facilitation. These results show different effects of amphetamine maintenance on behavioral and neurochemical effects of different psychostimulants. The selective effectiveness of amphetamine maintenance to treat cocaine abuse may reflect attenuation of cocaine-induced increases in NAc DA while preserving cocaine-induced increases in NAc 5-HT. PMID- 29704000 TI - Glutamatergic and gabaergic ventral BNST neurons differ in their physiological properties and responsiveness to noradrenaline. AB - The bed nucleus of the stria terminalis (BNST) regulates defensive responses to threats and its anteroventral portion (BNST-AV) is involved. BNST-AV contains a minority of glutamatergic neurons scattered among a dominant population of GABAergic cells. There is evidence that these two cell types might exert opposite influences, the former promoting and the latter reducing anxiety. Although GABAergic cells greatly outnumber glutamatergic neurons in BNST-AV, in some circumstances the influence of glutamatergic cells appears to predominate. Related to this, BNST-AV receives a very strong noradrenaline (NA) input and negative emotional states are associated with a marked rise of NA concentration in BNST-AV. However, it is currently unclear whether NA differentially alters the excitability of glutamatergic and GABAergic BNST-AV neurons. Thus, to shed light on how BNST-AV regulates negative emotional states, the present study compared the physiological properties and NA responsiveness of glutamatergic and GABAergic BNST-AV neurons using whole-cell recordings in transgenic mice that express a fluorescent reporter in either cell group. We found that glutamatergic cells had a slightly more complex morphology than the GABAergic cells, a higher intrinsic excitability, and a different responsiveness to NA. Indeed, while NA inhibited EPSPs in both cell types through alpha1 and alpha2 adrenoreceptors, the EPSP reduction seen in glutamatergic cells had a lower amplitude and a shorter duration than in GABAergic cells. These differences were due to the presence of a beta-receptor-mediated EPSP enhancement in the glutamatergic cells. Together, our results suggest that multiple properties contribute to the disproportionate influence of glutamatergic BNST-AV neurons. PMID- 29704001 TI - Cognitive deficit in methamphetamine users relative to childhood academic performance: link to cortical thickness. AB - Individuals with cognitive problems may be predisposed to develop substance use disorders; therefore, differences in cognitive function between methamphetamine users and control participants may be attributable to premorbid factors rather than methamphetamine use. The goal of this study was to clarify the extent to which this is the case. Childhood academic transcripts were obtained for 37 methamphetamine-dependent adults and 41 control participants of similar educational level and premorbid IQ. Each participant completed a comprehensive cognitive battery and received a structural magnetic resonance imaging scan. Data from control participants and linear regression were used to develop a normative model to describe the relationship between childhood academic performance and scores on the cognitive battery. Using this model, cognitive performance of methamphetamine users was predicted from their premorbid academic scores. Results indicated that methamphetamine users' childhood grade point average was significantly lower than that of the control group (p < 0.05). Further, methamphetamine users' overall cognitive performance was lower than was predicted from their grade point average prior to methamphetamine use (p = 0.001), with specific deficits in attention/concentration and memory (ps < 0.01). Memory deficits were associated with lower whole-brain cortical thickness (p < 0.05). Thus, in addition to having an apparent premorbid weakness in cognition, methamphetamine users exhibit subsequent cognitive function that is significantly lower than premorbid estimates would predict. The results support the view that chronic methamphetamine use causes a decline in cognition and/or a failure to develop normative cognitive abilities, although aside from methamphetamine use per se, other drug use and unidentified factors likely contribute to the observed effects. PMID- 29704002 TI - Selective far-field addressing of coupled quantum dots in a plasmonic nanocavity. AB - Plasmon-emitter hybrid nanocavity systems exhibit strong plasmon-exciton interactions at the single-emitter level, showing great potential as testbeds and building blocks for quantum optics and informatics. However, reported experiments involve only one addressable emitting site, which limits their relevance for many fundamental questions and devices involving interactions among emitters. Here we open up this critical degree of freedom by demonstrating selective far-field excitation and detection of two coupled quantum dot emitters in a U-shaped gold nanostructure. The gold nanostructure functions as a nanocavity to enhance emitter interactions and a nanoantenna to make the emitters selectively excitable and detectable. When we selectively excite or detect either emitter, we observe photon emission predominantly from the target emitter with up to 132-fold Purcell enhanced emission rate, indicating individual addressability and strong plasmon exciton interactions. Our work represents a step towards a broad class of plasmonic devices that will enable faster, more compact optics, communication and computation. PMID- 29704003 TI - Pilot study with IBAT inhibitor A4250 for the treatment of cholestatic pruritus in primary biliary cholangitis. AB - Pruritus is a common complication of cholestatic liver diseases. Inhibition of the ileal bile acid transporter (IBAT/ASBT) may emerge as treatment option. Our aim was to assess tolerability and effect on pruritus of the selective IBAT inhibitor A4250 in patients with primary biliary cholangitis (PBC). Ten patients with PBC and bile acid sequestrant treatment of cholestatic pruritus were after a two-week wash out of the bile acid sequestrant treated with either 0.75 mg (n = 4) or 1.5 mg (n = 5) of A4250 for four weeks. Patients' pruritus was assessed by Visual Analogue Scale (VAS), 5-D itch scale and the pruritus module of the PBC40 questionnaire. Plasma bile acids and 7alpha-hydroxy-4-cholesten-3-one were measured by UPLC-MS/MS, plasma fibroblast growth factor 19 by ELISA, and serum autotaxin activity by homemade assay. All nine patients exposed to A4250 reported a remarkable improvement in pruritus, until none or mild according to 5-D itch, VAS and PBC40 pruritus. Five patients finished the study prematurely due to abdominal pain (5/5) and diarrhoea (4/5). The high incidence of probably bile acid malabsorption-related diarrhoea and abdominal pain in the bile acid sequestrant pre-treated population indicates that the start dose of A4250 may have been too high for adult patients. PMID- 29704004 TI - The transcription factor Spores Absent A is a PKA dependent inducer of Dictyostelium sporulation. AB - Sporulation in Dictyostelium fruiting bodies evolved from amoebozoan encystation with both being induced by cAMP acting on PKA, but with downstream components still being unknown. Using tagged mutagenesis to find missing pathway components, we identified a sporeless mutant defective in a nuclear protein, SpaA. Expression of prespore genes was strongly reduced in spaA- cells, while expression of many spore stage genes was absent. Chromatin immunoprecipitation (ChIP) of a SpaA-YFP gene fusion showed that (pre)spore gene promoters bind directly to SpaA, identifying SpaA as a transcriptional regulator. SpaA dependent spore gene expression required PKA in vivo and was stimulated in vitro by the membrane permeant PKA agonist 8Br-cAMP. The PKA agonist also promoted SpaA binding to (pre)spore promoters, placing SpaA downstream of PKA. Sequencing of SpaA-YFP ChIPed DNA fragments revealed that SpaA binds at least 117 (pre)spore promoters, including those of other transcription factors that activate some spore genes. These factors are not in turn required for spaA expression, identifying SpaA as the major trancriptional inducer of sporulation. PMID- 29704005 TI - Multidrug-resistant Pseudomonas aeruginosa aggravates inflammatory responses in murine chronic colitis. AB - The World Health Organization has rated multidrug-resistant (MDR) Gram-negative bacteria including Pseudomonas aeruginosa (Psae) as serious threat to human health. We here addressed whether chronic murine gut inflammation facilitates intestinal MDR Psae colonization and whether bacterial infection subsequently worsens colonic immunopathology. Converse to wildtype counterparts, Psae colonized the intestines of IL-10-/- mice with chronic colitis following peroral challenge, but did not lead to changes in intestinal microbiota composition. Psae infection accelerated both macroscopic (i.e. clinical) and microscopic disease (i.e. colonic epithelial apoptosis), that were accompanied by increased intestinal pro-inflammatory immune responses as indicated by elevated colonic numbers of innate and adaptive immune cell subsets and enhanced secretion of pro inflammatory cytokines such as TNF and IFN-gamma in mesenteric lymph nodes of Psae-infected as compared to unchallenged IL-10-/- mice. Remarkably, Psae-induced pro-inflammatory immune responses were not restricted to the gut, but could also be observed systemically as indicated by increased TNF and IFN-gamma concentrations in sera upon Psae-infection. Furthermore, viable commensals originating from the intestinal microbiota translocated to extra-intestinal compartments such as liver, kidney and spleen of Psae-infected IL-10-/- mice with chronic colitis only. Hence, peroral MDR Psae-infection results in exacerbated colonic as well as systemic pro-inflammatory immune responses during chronic murine colitis. PMID- 29704006 TI - Intracellular glycolysis in brown adipose tissue is essential for optogenetically induced nonshivering thermogenesis in mice. AB - Release of fatty acids from lipid droplets upon activation of the sympathetic nervous system (SNS) is a key step in nonshivering thermogenesis in brown adipose tissue (BAT). However, intracellular lipolysis appears not to be critical for cold-induced thermogenesis. As activation of the SNS increases glucose uptake, we studied whether intracellular glycolysis plays a role in BAT thermogenesis. To stimulate BAT-innervating sympathetic nerves in vivo, we expressed channelrhodopsin-2 (ChR2) in catecholaminergic fibers by crossbreeding tyrosine hydroxylase-Cre mice with floxed-stop ChR2 mice. Acute optogenetic stimulation of sympathetic efferent fibers of BAT increased body temperature and lowered blood glucose levels that were completely abolished by the beta-adrenergic receptor antagonist. Knockdown of the Ucp1 gene in BAT blocked the effects of optogenetic stimulation on body temperature and glucose uptake. Inhibition of glucose uptake in BAT and glycolysis abolished optogenetically induced thermogenesis. Stimulation of sympathetic nerves upregulated expression of the lactate dehydrogenase-A and -B genes in BAT. Optogenetic stimulation failed to induce thermogenesis following treatment with the LDH inhibitor. Pharmacological blockade and genetic deletion of the monocarboxylate transporter 1 completely abolished the effects of sympathetic activation. Our results suggest that intracellular glycolysis and lactate shuttle play an important role in regulating acute thermogenesis in BAT. PMID- 29704007 TI - Contribution of multidrug and toxin extrusion protein 1 (MATE1) to renal secretion of trimethylamine-N-oxide (TMAO). AB - Trimethylamine-N-oxide (TMAO) gained considerable attention because of its role as a cardiovascular risk biomarker. Organic cation transporter 2 (OCT2) mediates TMAO uptake into renal proximal tubular cells. Here we investigated the potential role of multidrug and toxin extrusion protein 1 (MATE1) for translocation of TMAO across the luminal membrane of proximal tubular cells. HEK293 cells stably expressing OCT2 (HEK-OCT2) or MATE1 (HEK-MATE1) were used for uptake studies. Transcellular transport of TMAO was investigated using monolayers of MDCK control cells (MDCK-Co) as well as single- (MDCK-OCT2, MDCK-MATE1) and double-transfected cells (MDCK-OCT2-MATE1). In line with previous studies, HEK-OCT2 cells revealed a 2.4-fold uptake of TMAO compared to control cells (p < 0.001), whereas no significant uptake was observed in HEK-MATE1. In monolayers of MDCK cells, polarised TMAO transcellular transport was not significantly different between MDCK-Co and MDCK-OCT2 cells, but significantly increased in MDCK-MATE1 (p < 0.05) and MDCK-OCT2-MATE1 cells (p < 0.001). The OCT/MATE inhibitor trimethoprim abolished TMAO translocation in MDCK-OCT2-MATE1 cells (p < 0.05). The present data suggest that MATE1 contributes to renal elimination of TMAO. For selected MATE substrates, such as TMAO, uptake studies using non-polarised MATE-expressing cells can reveal false negative results compared to studies using polarised monolayers. PMID- 29704008 TI - Impact of late-onset Alzheimer's genetic risk factors on beta-amyloid endocytic production. AB - The increased production of the 42 aminoacids long beta-amyloid (Abeta42) peptide has been established as a causal mechanism of the familial early onset Alzheimer's disease (AD). In contrast, the causal mechanisms of the late-onset AD (LOAD), that affects most AD patients, remain to be established. Indeed, Abeta42 accumulation has been detected more than 30 years before diagnosis. Thus, the mechanisms that control Abeta accumulation in LOAD likely go awry long before pathogenesis becomes detectable. Early on, APOE4 was identified as the biggest genetic risk factor for LOAD. However, since APOE4 is not present in all LOAD patients, genome-wide association studies of thousands of LOAD patients were undertaken to identify other genetic variants that could explain the development of LOAD. PICALM, BIN1, CD2AP, SORL1, and PLD3 are now with APOE4 among the identified genes at highest risk in LOAD that have been implicated in Abeta42 production. Recent evidence indicates that the regulation of the endocytic trafficking of the amyloid precursor protein (APP) and/or its secretases to and from sorting endosomes is determinant for Abeta42 production. Thus, here, we will review the described mechanisms, whereby these genetic risk factors can contribute to the enhanced endocytic production of Abeta42. Dissecting causal LOAD mechanisms of Abeta42 accumulation, underlying the contribution of each genetic risk factor, will be required to identify therapeutic targets for novel personalized preventive strategies. PMID- 29704010 TI - Timing is everything: intraperitoneal chemotherapy after primary or interval debulking surgery for advanced ovarian cancer. AB - PURPOSE: To evaluate the outcomes of intraperitoneal chemotherapy (IP) compared with those of intravenous chemotherapy (IV) in patients with advanced ovarian cancer after neoadjuvant chemotherapy (NACT) and interval debulking surgery (IDS) or primary debulking surgery (PDS). METHODS: Patients with advanced epithelial ovarian carcinoma treated with PDS or NACT and IDS from 2006 to 2015 were identified. Comparative statistics were used to evaluate covariates, and survival rates were calculated using the Kaplan-Meier method and compared with log-rank tests. RESULTS: Sixty-six patients received NACT followed by IDS with residual disease of <= 1 cm; 42 of these patients (63.6%) received IP therapy; and 24 patients (36.3%) had IV therapy only after IDS. The median progression-free survival (PFS) was 16.0 months in the IP group and 13.5 months in the IV group (p = 0.13). The estimated median overall survival (OS) was 64.0 months with IP and 50.0 months with IV (p = 0.44). During the same study period, 149 patients underwent optimal PDS after which 93 patients (62.4%) received IP and 56 patients (37.6%) were given IV chemotherapy. Patients after IP demonstrated improved survival outcomes when compared to patients after IV therapy. The median PFS was 28.0 months after IP and 16.5 months after IV (p = 0.0006), and the median OS was not reached for IP and 50.0 months after IV (p < 0.0001). CONCLUSIONS: Although IP chemotherapy after PDS is associated with improved survival, IP therapy after NACT and IDS, despite high rates of completion, may not have the same degree of survival advantage over IV therapy. PMID- 29704009 TI - Attendance to cervical cancer screening among Roma and non-Roma women living in North-Western region of Romania. AB - OBJECTIVES: Romania has Europe's highest incidence and mortality rates of cervical cancer. Participation in the national cervical cancer-screening programme is low, especially among minority Roma women. METHODS: We conducted a cross-sectional study, using a structured questionnaire aiming to quantify reasons for screening attendance among women in North-Western region of Romania. RESULTS: 980 women were enrolled in this study. Data were analysed using logistic regression, estimating odds ratios (OR) and 95% confidence intervals (CI). This study revealed that Roma women (46%) attended screening less frequently that non Roma women (63%),; however, ethnicity in itself was not associated with screening attendance. Instead we found that attendance to the cervical cancer screening programme was determined by having ever heard about a screening opportunity (OR 5.90, 95% CI 3.76-9.27) and having three or more sex partners (OR 5.99, 95% CI 1.71-21.04). CONCLUSIONS: We concluded that information about the screening programme's existence and its rationale does not reach the women targeted for screening sufficiently and argue that a process of user involvement aiming to build contact, interaction and cooperation between the programme and its potential participants is warranted. PMID- 29704011 TI - [CEUS-diagnosis of benign liver lesions]. AB - CLINICAL/METHODICAL ISSUE: Focal liver lesions are commonly seen during routine ultrasound examinations. STANDARD RADIOLOGICAL METHODS: With native ultrasound there are lesions that cannot be sufficiently characterized. In these cases additional imaging might be necessary. METHODICAL INNOVATIONS: With contrast enhanced ultrasound (CEUS), focal liver lesions can be characterized with high diagnostic accuracy. After the ultrasound contrast agent has been injected into a peripheral vein, the examiner saves video loops of the arterial, portal venous and late contrast phases. Combing the findings of native and contrast-enhanced ultrasound allows not only assessment of the etiology as benign or malignant but also detailed characterization of the focal liver lesion in most cases. PERFORMANCE: Using CEUS, focal liver lesions can be characterized with a sensitivity of over 95% and a specificity of about 83%. ACHIEVEMENTS: The advantages of CEUS include that there is no radiation exposure and that the ultrasound contrast agent has no effects on the function of the liver, kidneys or the thyroid gland. The main limiting factors for CEUS are bowel gas and obesity of the patient. PRACTICAL RECOMMENDATIONS: CEUS can visualize micro- and macrovascularization of benign focal liver lesions in real time. It is a useful imaging modality in unclear cases. PMID- 29704012 TI - [CEUS-Use in testicular pathologies]. AB - BACKGROUND: The work-up of scrotal diseases forms an essential part of daily work in urology. Sonography plays an important role in the diagnostic process, due to its wide availability and feasibility. OBJECTIVES: Advantages of modern contrast enhanced ultrasound (CEUS) are illustrated using examples of common testicular pathologies. MATERIALS AND METHODS: Relevant studies regarding the application of CEUS on testicular pathologies are evaluated. PubMed and Medline were screened for reviews and clinical trials. RESULTS: In the differentiation of benign and malignant testicular lesions, contrast medium uptake, e. g. can exclude a hemorrhagic testicular cyst. A differentiation between benign and malignant testicular lesions due to pure enhancement is currently not possible. Evaluation of testicular abscesses, infarctions and infections depends on the assessment of vascularization. Following a scrotal trauma, evaluation of enhancement can distinguish between vital and non-vital areas. A complete absence of perfusion may support the diagnosis of testicular torsion. CONCLUSION: CEUS is a feasible instrument in the diagnostic work-up of testicular pathologies. Results from previous studies are promising. Regarding the application in cases of scrotal trauma, the method could play an essential role in the future. With regard to a classification of unclear testicular lesions, further studies with a larger number of patients are needed in order to confirm previously described perfusion patterns. PMID- 29704014 TI - Kirklin sign. PMID- 29704013 TI - [CEUS-Diagnostic of malignant liver lesions]. AB - CLINICAL/METHODICAL ISSUE: Cross-sectional modalities or conventional ultrasound are not always able to sufficiently identify and characterize malignant liver lesions. STANDARD RADIOLOGICAL METHODS: The evaluation of malignant liver lesions in conventional ultrasound relies on echostructure, shape and borders, but often warrants additional contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) studies. METHODICAL INNOVATIONS: Contrast-enhanced ultrasound (CEUS) is a relatively safe imaging technique used for the detection and characterization of malignant liver lesions. The use of a second-generation contrast agent in dynamic real-time imaging allows the visualization of vascularization in any kind of liver lesion as well as liver perfusion during the arterial, portal venous and late phase. PERFORMANCE: Due to the different enhancement patterns, it is possible to differentiate a liver lesion with high diagnostic accuracy (over 90%). ACHIEVEMENTS: CEUS is a helpful complementary technique to cross-sectional imaging for the evaluation of unclear liver lesions and may frequently obviate additional contrast-enhanced MRI or CT studies. PRACTICAL RECOMMENDATIONS: CEUS enables the detection and characterization of liver lesions in real time. PMID- 29704015 TI - Reverse rim sign: acute renal cortical necrosis. PMID- 29704016 TI - Function of low back muscle exercise : Preventive effect of refracture analysis of postoperative vertebral fractures. AB - BACKGROUND: Low back muscles exercise reportedly influence the risk of osteoporotic vertebral fractures. The exact relationship between the low back muscles exercise and the incidence of vertebral refractures remain unclear. OBJECTIVE: To investigate the ability of exercise to strengthen the low back muscles to prevent vertebral refracture after surgery, through clinical analysis of the vertebral fracture risk reduction program. METHODS: In total 152 patients with vertebral fractures who had undergone percutaneous vertebroplasty (PVP) and anti-osteoporosis treatment were randomly divided into observation and control groups. The observation group performed exercises to strengthen the back muscles after surgery. The clinical efficacy and incidence of re-fractures were compared between groups. RESULTS: The observation group had reduced physical dysfunction and pain following surgery. After 3 months, the vertebral body height had significantly decreased (P < 0.05) in the control group but not in the observation group (P > 0.05). In the observation and control groups, the incidence of vertebral refractures was 9.2% (7/76) and 17.1% (13/76), respectively (P < 0.05). CONCLUSION: Postoperative exercise to strengthen the back muscles can improve physical function, relieve pain and promote the recovery of vertebral height; it can also assist in maintaining bone density, thereby significantly reducing the risk of refracture. This approach is safe and effective and can help improve the quality of life in patients with vertebral fractures. PMID- 29704017 TI - Toxic Tales-Recent Histories of Pollution, Poisoning, and Pesticides (ca. 1800 2010). PMID- 29704019 TI - Role of minimal residual disease in the management of acute myeloid leukemia-a case-based discussion. AB - AML is stratified into risk-categories based on cytogenetic and molecular features that prognosticate survival and facilitate treatment algorithms, though there is still significant heterogeneity within risk groupings with regard to risk of relapse and prognosis. The ambiguity regarding prognosis is due in large part to the relatively outdated criteria used to determine response to therapy. Whereas risk assessment has evolved to adopt cytogenetic and molecular profiling, response criteria are still largely determined by bone marrow morphologic assessment and peripheral cell count recovery. Minimal residual disease refers to the detection of a persistent population of leukemic cells below the threshold for morphologic CR determination. MRD assessment represents standard of care for ALL and PML, but concerns over prognostic capability and standardization have limited its use in AML. However, recent advancements in MRD assessment and research supporting the use of MRD assessment in AML require the reconsideration and review of this clinical tool in this disease entity. This review article will first compare and contrast the major modalities used to assess MRD in AML, such as RQ-PCR and flow cytometry, as well as touching upon newer technologies such as next-generation sequencing and digital droplet PCR. The majority of the article will discuss the evidence supporting the use of MRD assessment to prognosticate disease at various time points during treatment, and review the limited number of studies that have incorporated MRD assessment into novel treatment algorithms for AML. The article concludes by discussing the current major limitations to the implementation of MRD assessment in this disease. The manuscript is bookended by a clinical vignette that highlights the need for further research and refinement of this clinical tool. PMID- 29704020 TI - Role of Chicoric Acid and 13-Cis Retinoic Acid in Mycobacterium tuberculosis Infection Control by Human U937 Macrophage. AB - Mycobacterium tuberculosis (Mtb) survives and proliferates within the main cells of the innate immune system, macrophages. The goal of our study was to investigate the immunostimulatory effects of 13-cis retinoic acid (RA) and chicoric acid (CA) in human U937 macrophages against H37Ra Mtb infection by evaluating its potential role in the cell surface expression of HLA-DR, CD14 molecules as well as nitric oxide (NO) production and prevention of the Mtb growth within macrophages. In this study, we investigated the effects of 13-cis RA and CA on Mtb-infected macrophages using flowcytometry and Griess methods, respectively. Moreover, inhibitory effect of 13-cis RA and CA on Mtb growth within macrophages were assessed using colony-forming unit. 13-Cis RA and CA enhanced the cell surface expression of HLA-DR and CD14 molecules on U937 macrophages and prevented the growth of Mtb within macrophages. In addition, 13 cis RA and CA, have increased NO generation compared to untreated control macrophages, significantly (p < 0.001). Both drugs have a significant inhibitory effect on Mtb growth but CA at the highest concentration was more potent than 13 cis RA (p < 0.05). The results of our study showed that infected U937 macrophages treated with 13-cis RA and CA represented significant increases in NO production, CD14 and HLA-DR expression and also prevents intracellular survival of Mtb. Therefore, 13-cis RA and CA may have a significant therapeutic approach in the control of Mtb infection. PMID- 29704018 TI - Consensus statement for cancer patients requiring intensive care support. AB - This consensus statement is directed to intensivists, hematologists, and oncologists caring for critically ill cancer patients and focuses on the management of these patients. PMID- 29704021 TI - Cytotoxic Assessment of Chromium and Arsenic Using Chromosomal Behavior of Root Meristem in Allium cepa L. AB - A study was performed for phyto-genotoxic assay of chromium (Cr) and arsenic (As) through Allium cepa. Various concentrations (0, 1, 3, 6 and 12 mg L-1) of Cr and As for 48 and 168 h time points exposed to A. cepa. The phytotoxic effects of metal(loid) were evident through inhibited root length and root protein. Metal(loid) toxicity also lead to genotoxic effects, which included depression of mitotic index and increased frequency of chromosomes aberrations like break, fragments, c-metaphase, multipolar arrangements etc. Genotoxic endpoint as progressive frequency of micronuclei in interphase of root meristem cells in treated plants was also observed. This genotoxic endpoint revealed carcinogenic nature of both aforementioned metal(loid). Along with inhibition in root length and protein content, depression in mitotic index as well as stimulation of various abnormality in mitotic cell division indicated that both metal(loid) are hazardous in nature and causing harmful effect on the environment. PMID- 29704022 TI - Quality of life and social functioning of former long-stay psychiatric patients transferred into the community: a 10 year follow up study. AB - PURPOSE: Deinstitutionalisation in Ireland began following the impetus of the successful transfer of psychiatric patients into the community in other countries. This study sought to evaluate the quality of life (QoL) and social functioning (SF) of former long-stay institutionalised patients with severe and enduring mental illness who had been relocated into local community settings and followed up 10 years later. METHOD: One month prior to hospital closure, 87 former long-stay psychiatric patients, the majority of whom had a diagnosis of schizophrenia, were assessed on a range of QoL and SF measures. Patients were followed-up 10 years later in the community, to evaluate baseline predictors of quality of life and social functioning. RESULTS: Study completers (n = 35) improved significantly on a range of QoL and SF measures over the 10 year period. Specific improvements were noted in domestic skills (t = - 2.8, p < 0.0008), community skills (t = - 4.9, p < 0.001), as well as the activity and social relations measure (t = - 4.1, p < 0.001). Increased social function (t = - 6.3, p < 0.001) and improvement on the social behaviour scale (t = 7.6, p < 0.001) were noted at follow-up. Linear regression analysis found that less social behaviour problems at baseline predicted QoL 10 years later (t = - 2.6, p < 0.02). CONCLUSION: This study demonstrated that transfer into the community from an institutional environment was associated with long-term improvements in quality of life and social functioning, even in those who spent many years in the institution. Those who demonstrated the greatest improvement in QoL had less social behavioural problems at baseline assessment, providing further evidence of the success of community living for former long-stay patients. PMID- 29704023 TI - Radiological analysis of cystic lesion in osteonecrosis of the femoral head. AB - PURPOSE: Cystic lesions are a common complication in osteonecrosis of the femoral head (ONFH). This study will discuss the cause of cystic lesion formation and the feature of cystic lesion distribution in ONFH. According to the feature of cystic lesion in ONFH, we will discuss the possible mechanisms of cystic lesions and their influence on collapse of the femoral head. MATERIALS AND METHODS: We retrospectively gathered 102 ONFH patients (168 hips) from November in 2015 to August in 2016 on China-Japan Friendship Hospital. Three categories of patients' medical information were collected: demographic characteristics, bone cystic lesion location, and pathological finding on CT and MRI imaging (microfracture, collapse, crescent sign). On mid-coronal and mid-axial CT section, the femoral head was divided into four quadrants for locating the cystic lesion. And we classified the location relationship of cystic lesion and sclerosis rim as G1 type, G2 type, and G3 type on coronal CT section. RESULTS: A significant difference was found between ONFH group with cystic lesion and ONFH group without cystic lesion in terms of microfracture (P < 0.001), collapse (P < 0.001), and crescent sign (P < 0.001). Forty-four cystic lesions (70%) are located in anterior hip area and 19 cystic lesions (30%) are located in posterior hip area. There were 14, 24, and seven cystic lesions (31, 53, 16%) locating in lateral, central, and medial pillars of the femoral head. G2 type was the most common pattern of location relationship between cystic lesion and sclerosis rim. CONCLUSION: Cystic lesions are often found near sclerosis rim in ONFH. The femoral head with osteonecrosis complicating by cystic lesions is more likely to accompany microfracture, collapse, and crescent sign which indicate structural instability in the femoral head. Cystic lesion in ONFH plays an important role in aggravating the progression of femoral head collapse. The peak stress from sclerosis rim may be a main factor inducing the formation of cystic lesion in ONFH via an OA-like mechanism. PMID- 29704024 TI - The relationship of pelvic incidence to post-operative total hip arthroplasty dislocation in patients with lumbar fusion. AB - PURPOSE: To determine if lumbar fusion increases the risk of dislocation following total hip arthroplasty (THA) via a posterior approach and to investigate anatomic variables associated with this increased risk. METHODS: Five year retrospective review of THAs performed through a posterior approach identifying cases of post-operative dislocation. Patients were grouped into those with or without previous lumbar spine fusion. Lumbar fusion patients were then further analyzed in terms of cup position, pelvic incidence, sacral slope, and pelvic tilt to determine if there were specific variables associated with the increased risk of dislocation. RESULTS: Five hundred nine primary THAs in 460 patients (non-simultaneous bilateral THAs in 41 patients) met inclusion criteria with a dislocation rate of 5.5%. Thirty-one patients were identified as having prior lumbar fusions. The dislocation rate was significantly higher in fusion patients (29 vs 4%; p = 0.009) yielding a relative risk (RR) of dislocation of 4.77 (p = < 0.0001). Additionally, cup anteversion was significantly different between groups (26.8 vs 21.42; p = 0.009). Dislocators in the fusion group were also at greater risk of requiring subsequent revision (RR = 3.24; p = 0.003). Subgroup analysis of fusion patients revealed that dislocators had lower pelvic incidence and sacral slope compared to non-dislocators (45.2 vs 58.6 [p = 0.0029] and 26.3 vs 35.6 [p = 0.0384] respectively). CONCLUSIONS: Patients with lumbar fusion are at increased risk for post-operative dislocations requiring revision. Together, lower pelvic incidence and decreased sacral slope are associated with increased risk of dislocation in these patients. PMID- 29704025 TI - Effect of glycerol on photobleaching of cytochrome Raman lines in frozen yeast cells. AB - We applied a Raman spectroscopy approach to investigate the effect of a cryoprotectant on the redox state of cytochromes on freezing yeast cells. The redox activity of cytochromes was studied using time-resolved photobleaching of the resonance Raman lines. It is found that ice formation causes a drastic change in the redox state of cytochromes in cells frozen without cryoprotectant, whereas in the presence of glycerol the effects of ice formation are more gradual. The photobleaching rate of cells frozen in glycerol solution shows a gradual slowing with temperature decrease and an abrupt slowdown below - 48 degrees C. This abrupt decrease was interpreted as originating from changes in protein conformational dynamics. Our findings provide important new insights into the transition from active to inactive cytochrome states as cells undergo freezing in the presence and absence of cryoprotectant. PMID- 29704026 TI - The relation of low levels of bone mineral density with coronary artery calcium and mortality. AB - : Osteoporosis and atherosclerosis are two prevalent major healthcare concerns that frequently coexist. The clinical outcome of 5590 consecutive subjects who underwent coronary artery calcium (CAC) scanning and thoracic bone mineral density (BMD) measurement was assessed. A significant link between low BMD levels and CAC with increased risk of mortality in both genders across ethnicities noted. INTRODUCTION: While a relation of CAC with lower levels of BMD reported previously; it is unclear whether low levels of BMD would be an independent risk factor for CAC and mortality. This study investigated the relation of BMD levels with CAC and mortality in both genders across ethnicities. METHODS: This study consisted of 5590 consecutive at-risk subjects without known coronary artery disease (CAD), age 57 +/- 12, and 69% male, who underwent non-enhanced cardiac computed tomography, and were followed for mean of 8 years. The subjects' CAC (Agatston score) and thoracic BMD levels (mg/cm3) were measured. CAC stratified based on the severity to CAC 0, 1-100, 101-400, and 400+. Low-BMD levels defined as BMD levels below median (180 mg/cm3). Physician verified that all-cause mortality was assessment hard-endpoint. Multivariate regression analysis, adjusted for age, gender, and other cardiovascular risk factors, was used to assess the relationship between BMD and CAC. RESULTS: The BMD levels were proportionally lowering with the severity of CAC in both genders, especially in postmenopausal women (p < 0.05). The risk of each standard deviation reduce in BMD levels increased with the severity of CAC, as compared to CAC = 0 across ethnicities (p < 0.05). Low BMD levels were an independent predictor of mortality and event-free survival rate decreased from 99% in those within normal BMD levels to 93% in those with low BMD levels (p = 0.0001). Furthermore, a significant link between low BMD levels and CAC > 0 with increased risk of mortality was noted (p = 0.0001). The relative risk of death was 2.8, 5.9, and 14.3-folds higher in CAC 1-100, 101-400, and 400+ with low BMD levels, compared to CAC = 0 and within normal BMD levels, respectively (p < 0.05). CONCLUSIONS: The lower BMD levels are independently associated with the severity of CAC that predicts mortality. PMID- 29704027 TI - Implementation of the Western Australian Osteoporosis Model of Care: a fracture liaison service utilising emergency department information systems to identify patients with fragility fracture to improve current practice and reduce re fracture rates: a 12-month analysis. AB - : Fracture liaison service linked to an emergency department database effectively identifies patients with OP, improves best practice care, reduces recurrent fractures, and improves quality of life (QoL). The next step is to establish cost effectiveness. This should be seen as the standard model of care. INTRODUCTION: The Western Australian Osteoporosis Model of Care recommends implementation of a fracture liaison service (FLS) to manage patients with minimal trauma fractures (MTFs). This study evaluates the efficacy of a FLS linked to a tertiary hospital emergency department information system (EDIS) in reducing recurrent fractures. METHODS: Patients aged >= 50 years with MTF identified from EDIS were invited to the FLS. Patient outcomes were compared to routine care (retrospective group-same hospital, and prospective group-other hospital) at 3- and 12-month follow-up. RESULTS: Two hundred forty-one of 376 (64.1%) eligible patients participated in the FLS with 12 months of follow-up. Absolute risk of recurrent MTF at 12 months was reduced by 9.2 and 10.2% compared with the prospective and retrospective controls, respectively. After age/sex adjustment, FLS participants had less MTF at 12 months vs. the retrospective controls, OR 0.38 (95%CI 0.18-0.79), but not the prospective controls, OR 0.40 (95%CI 0.16-1.01). FLS patients were more likely to receive the 'best practice' care, i.e. awareness of osteoporosis, investigations, and treatment (all p < 0.05). 'Fallers' (OR 0.48 (95%CI 0.24, 0.96)) and fall rates were lower in the FLS (p = 0.001) compared to the prospective control. FLS experienced the largest improvement in QoL from 3 to 12 months as measured by the EuroQoL 5-domain (EQ-5D) UK weighted score (+ 15 vs. - 11 vs. - 16%, p < 0.001) and EQ-5D Health State visual analogue scale (+ 29 vs. - 2 vs. + 1%, p < 0.001). CONCLUSION: Patients managed in a linked EDIS-FLS were more likely to receive the 'best practice' care and had lower recurrent MTF and improved QoL. PMID- 29704028 TI - Contractile responses in intact and mucosa-denuded human ureter-a comparison with urinary bladder detrusor preparations. AB - Human proximal and distal ureter tissues were studied to clarify whether the presence of mucosa affects contractile responses. In histological studies, human ureter was compared with urinary bladder (detrusor). Contractions in response to high KCl solution, phenylephrine, and carbachol were measured in intact and mucosa-denuded strips of human ureter. Tissue sections of human bladder and ureter were used for histological staining. Thirty-four percent of the ureter strips contracted spontaneously with highly variable patterns, and this was affected neither by mucosa nor by proximal or distal tissue origin. Upon stimulation with 40 mM KCl, ureter strips exhibited strong phasic and weak tonic contractions. In intact strips, normalized tonic force was lower than in denuded strips, but no consistent effect of mucosa was observed with phasic contractions. Absolute force values of phasic contractions were weaker in proximal than distal ureter strips, but similar when normalized to tissue wet weight. Stimulation with 80 mM KCl enhanced tonic contraction fourfold; phasic contractions occurred rarely. Phenylephrine produced no statistically significant stronger tonic contraction in distal compared with proximal ureter strips; nevertheless, in some strips, pre-existing spontaneous contractions increased. Carbachol did not influence ureter contractions. In the bladder, a suburothelial cell layer stained positive with alpha-smooth muscle actin (alpha-SMA)-specific antibodies could be further differentiated with vimentin- and desmin-specific antibodies. alpha-SMA positive cells were absent in suburothelial ureter tissue. Like in detrusor, the mucosa inhibits KCl-stimulated tonic ureter contractions. The mucosa of detrusor and ureter tissue exhibits distinct staining patterns for alpha-SMA, vimentin, and desmin. This suggests a different distribution of smooth muscle cells, fibroblasts, and myofibroblasts, which could be a target for pharmacological therapy of pathologic contractile processes. PMID- 29704029 TI - Ion concentration in micro and nanoscale electrospray emitters. AB - Solution-phase ion transport during electrospray has been characterized for nanopipettes, or glass capillaries pulled to nanoscale tip dimensions, and micron sized electrospray ionization emitters. Direct visualization of charged fluorophores during the electrospray process is used to evaluate impacts of emitter size, ionic strength, analyte size, and pressure-driven flow on heterogeneous ion transport during electrospray. Mass spectrometric measurements of positively- and negatively-charged proteins were taken for micron-sized and nanopipette emitters under low ionic strength conditions to further illustrate a discrepancy in solution-driven transport of charged analytes. A fundamental understanding of analyte electromigration during electrospray, which is not always considered, is expected to provide control over selective analyte depletion and enrichment, and can be harnessed for sample cleanup. Graphical abstract Fluorescence micrographs of ion migration in nanoscale pipettes while solution is electrosprayed. PMID- 29704030 TI - Nanospray desorption electrospray ionization mass spectrometry of untreated and treated probiotic Lactobacillus reuteri cells. AB - Mass spectrometry has proven to be a useful technique for rapid identification of bacterial cells. Among various ionization techniques in mass spectrometry, matrix assisted laser desorption/ionization (MALDI) has been commonly used for the identification of bacterial cells. Recently, MALDI mass spectrometry has also been utilized to distinguish cellular responses. Ambient ionization techniques do support whole bacterial cell analysis, which include desorption electrospray ionization (DESI). Nanospray DESI (nDESI) is a new variant of DESI, and its application to whole-cell mass spectrometry is limited. In this project, the use of nDESI mass spectrometry to measure probiotic Lactobacillus reuteri (LR) cells is explored. A unique and reproducible mass spectral pattern of untreated LR cells was obtained by using 50% methanol/water as nDESI solvent. The use of nDESI mass spectrometry is further extended to distinguish untreated LR cells from treated LR cells that have been exposed to low pH. These findings demonstrate the feasibility of using nDESI in whole-cell mass spectrometry. Graphical abstract ?. PMID- 29704031 TI - Rapid detection of the neonicotinoid insecticide imidacloprid using a quenchbody assay. AB - Contamination of the land and water by neonicotinoid insecticide residues is currently a severe environmental problem. However, the traditional methods for pesticide residue analysis are time consuming and laborious. To tackle this problem, here we describe a novel quenchbody (Q-body) immunoassay reagent that allows the rapid and sensitive detection of imidacloprid, one of the most frequently used neonicotinoid pesticides, in aqueous solution. A Q-body comprises an antibody Fab fragment that is site-specifically labeled with a fluorescent dye. The Fab fragment quenches the dye with its internal tryptophan residues via photoinduced electron transfer. The subsequent addition of imidacloprid stabilizes the antibody structure and displaces the quenched dye to the outside of the protein, resulting in increased fluorescence. The constructed Q-body assay exhibited a high dynamic range and a low limit of detection (10 ng mL-1), and the entire assay procedure could be completed in a few minutes. The assay showed a low cross-reactivity with possible interfering analogous compounds, indicating that it has a good selectivity. Hence, the developed Q-body assay has excellent potential as a universal technology for monitoring neonicotinoid residues in environmental and food samples. Graphical abstract A novel quenchbody (Q-body) immunoassay reagent that allows the rapid and sensitive detection of imidacloprid, one of the most frequently used neonicotinoid pesticides, in aqueous solution was developed. The addition of imidacloprid stabilizes the Q body structure and displaces the quenched dye to the outside of the protein, resulting in increased fluorescence. The constructed Q-body assay exhibited a high dynamic range and a low limit of detection (10 ng mL-1), and completed in a few minutes. PMID- 29704032 TI - Preconcentration of DNA using magnetic ionic liquids that are compatible with real-time PCR for rapid nucleic acid quantification. AB - Nucleic acid extraction and purification represents a major bottleneck in DNA analysis. Traditional methods for DNA purification often require reagents that may inhibit quantitative polymerase chain reaction (qPCR) if not sufficiently removed from the sample. Approaches that employ magnetic beads may exhibit lower extraction efficiencies due to sedimentation and aggregation. In this study, four hydrophobic magnetic ionic liquids (MILs) were investigated as DNA extraction solvents with the goal of improving DNA enrichment factors and compatibility with downstream bioanalytical techniques. By designing custom qPCR buffers, we directly incorporated DNA-enriched MILs including trihexyl(tetradecyl)phosphonium tris(hexafluoroacetylaceto)nickelate(II) ([P6,6,6,14+][Ni(hfacac)3-]), [P6,6,6,14+] tris(hexafluoroacetylaceto)colbaltate(II) ([Co(hfacac)3-]), [P6,6,6,14+] tris(hexafluoroacetylaceto)manganate(II) ([Mn(hfacac)3-]), or [P6,6,6,14+] tetrakis(hexafluoroacetylaceto)dysprosate(III) ([Dy(hfacac)4-]) into reaction systems, thereby circumventing the need for time-consuming DNA recovery steps. Incorporating MILs into the reaction buffer did not significantly impact the amplification efficiency of the reaction (91.1%). High enrichment factors were achieved using the [P6,6,6,14+][Ni(hfacac)3-] MIL for the extraction of single-stranded and double-stranded DNA with extraction times as short as 2 min. When compared to a commercial magnetic bead-based platform, the [P6,6,6,14+][Ni(hfacac)3-] MIL was capable of producing higher enrichment factors for single-stranded DNA and similar enrichment factors for double-stranded DNA. The MIL-based method was applied for the extraction and direct qPCR amplification of mutation prone-KRAS oncogene fragment in plasma samples. Graphical abstract Magnetic ionic liquid solvents are shown to preconcentrate sufficient KRAS DNA template from an aqueous solution in as short as 2 min without using chaotropic salts or toxic organic solvents. By using custom-designed qPCR buffers, DNA can be directly amplified and quantified from four MILs examined in this study. PMID- 29704033 TI - Multi-component identification and target cell-based screening of potential bioactive compounds in toad venom by UPLC coupled with high-resolution LTQ Orbitrap MS and high-sensitivity Qtrap MS. AB - Traditional Chinese medicines (TCMs) are undoubtedly treasured natural resources for discovering effective medicines in treating and preventing various diseases. However, it is still extremely difficult for screening the bioactive compounds due to the tremendous constituents in TCMs. In this work, the chemical composition of toad venom was comprehensively analyzed using ultra-high performance liquid chromatography (UPLC) coupled with high-resolution LTQ Orbitrap mass spectrometry and 93 compounds were detected. Among them, 17 constituents were confirmed by standard substances and 8 constituents were detected in toad venom for the first time. Further, a compound database of toad venom containing the fullest compounds was further constructed using UPLC coupled with high-sensitivity Qtrap MS. Then a target cell-based approach for screening potential bioactive compounds from toad venom was developed by analyzing the target cell extracts. The reliability of this method was validated by negative controls and positive controls. In total, 17 components in toad venom were discovered to interact with the target cancer cells. Further, in vitro pharmacological trials were performed to confirm the anti-cancer activity of four of them. The results showed that the six bufogenins and seven bufotoxins detected in our research represented a promising resource to explore bufogenins/bufotoxins based anticancer agents with low cardiotoxic effect. The target cell-based screening method coupled with the compound database of toad venom constructed by UPLC-Qtrap-MS with high sensitivity provide us a new strategy to rapidly screen and identify the potential bioactive constituents with low content in natural products, which was beneficial for drug discovery from other TCMs. ? Graphical abstract. PMID- 29704034 TI - The effect of concurrent hand movement on estimated time to contact in a prediction motion task. AB - In many activities, we need to predict the arrival of an occluded object. This action is called prediction motion or motion extrapolation. Previous researchers have found that both eye tracking and the internal clocking model are involved in the prediction motion task. Additionally, it is reported that concurrent hand movement facilitates the eye tracking of an externally generated target in a tracking task, even if the target is occluded. The present study examined the effect of concurrent hand movement on the estimated time to contact in a prediction motion task. We found different (accurate/inaccurate) concurrent hand movements had the opposite effect on the eye tracking accuracy and estimated TTC in the prediction motion task. That is, the accurate concurrent hand tracking enhanced eye tracking accuracy and had the trend to increase the precision of estimated TTC, but the inaccurate concurrent hand tracking decreased eye tracking accuracy and disrupted estimated TTC. However, eye tracking accuracy does not determine the precision of estimated TTC. PMID- 29704036 TI - Evaluation of articular cartilage following rotational acetabular osteotomy for hip dysplasia using T2 mapping MRI. AB - BACKGROUND: Rotational acetabular osteotomy (RAO) is one of the surgical treatments for acetabular dysplasia, and satisfactory results have been reported. We evaluated the postoperative changes of articular cartilage and whether the pre operative condition of the articular cartilage influences the clinical results using T2 mapping MRI. METHODS: We reviewed 31 hips with early stage osteoarthritis in 31 patients (mean age, 39.6 years), including three men and 28 women who underwent RAO for hip dysplasia. Clinical evaluations including Japanese Orthopedic Association (JOA) score and Japanese Orthopedic Association Hip Disease Evaluation Questionnaire (JHEQ), and radiographical evaluations on X ray were performed. Longitudinal qualitative assessment of articular cartilage was also performed using 3.0-T MRI with T2 mapping technique preoperatively, 6 months, and at 1 and 2 years postoperatively. RESULTS: There was no case with progression of osteoarthritis. The mean JOA score improved from 70.1 to 93.4 points, the mean postoperative JHEQ score was 68.8 points, and radiographical data also improved postoperatively. We found that the T2 values of the cartilage at both femoral head and acetabulum increased at 6 months on coronal and sagittal views. However, they significantly decreased 1 and 2 years postoperatively. The T2 values of the center to anterolateral region of acetabulum negatively correlated with postoperative JHEQ score, particularly in pain score. CONCLUSIONS: This study suggests that biomechanical and anatomical changes could apparently cause decreased T2 values 1-2 years postoperatively compared with those preoperatively. Furthermore, preoperative T2 values of the acetabulum can be prognostic factors for the clinical results of RAO. PMID- 29704038 TI - Quantitative evaluation of tau PET tracers 18F-THK5351 and 18F-AV-1451 in Alzheimer's disease with standardized uptake value peak-alignment (SUVP) normalization. AB - PURPOSE: Off-target binding in the reference region is a challenge for recent tau tracers 18F-AV-1451 and 18F-THK5351. The conventional standardized uptake value ratio (SUVR) method relies on the average uptake from an unaffected tissue sample, and therefore is susceptible to biases from off-target binding as well as variability among individuals in the reference region. We propose a new method, standardized uptake value peak-alignment (SUVP), to reduce the bias of the SUVR, and improve the quantitative assessment of tau deposition. METHODS: The SUVP normalizes uptake values by their mode and standard deviation. Instead of using a reference region, the SUVP derives the contrast from unaffected voxels over the whole brain. Using SUVP and SUVR methods, we evaluated the global and regional tau binding of 18F-THK5351 and 18F-AV-1451 on two independent cohorts (N = 18 and 32, respectively), each with cognitively normal (NL) subjects and Alzheimer's disease (AD) subjects. RESULTS: Both tracers showed significantly increased binding for AD in the targeted cortical areas. In the temporal cortex, SUVP had a higher classification success rate (CSR) than SUVR (0.96 vs 0.89 for 18F-THK5351; 0.86 vs 0.75 for 18F-AV-1451), as well as higher specificity under fixed sensitivity around 0.80 (0.70 vs 0.45 specificity for 18F-THK5351; 1.00 vs 0.78 for 18F-AV-1451). In the cerebellar cortex, an AD-NL group difference with effect size (Cohen's d) of 0.62 was observed for AV-1451, confirming the limitation of the SUVR approach using this region as a reference. A smaller cerebellar effect size (0.09) was observed for THK5351. CONCLUSION: The SUVP method reduces the bias of the reference region and improves the NL-AD classification compared to the SUVR approach. PMID- 29704037 TI - Clinical utility of FDG-PET for the clinical diagnosis in MCI. AB - PURPOSE: We aim to report the quality of accuracy studies investigating the utility of [18F]fluorodeoxyglucose (FDG)-PET in supporting the diagnosis of prodromal Alzheimer's Disease (AD), frontotemporal lobar degeneration (FTLD) and prodromal dementia with Lewy bodies (DLB) in mild cognitive impairment (MCI) subjects, and the corresponding recommendations made by a panel of experts. METHODS: Seven panellist, four from the European Association of Nuclear Medicine, and three from the European Academy of Neurology, produced recommendations taking into consideration the incremental value of FDG-PET, as added on clinical neuropsychological examination, to ascertain the aetiology of MCI (AD, FTLD or DLB). A literature search using harmonized population, intervention, comparison, and outcome (PICO) strings was performed, and an evidence assessment consistent with the European Federation of Neurological Societies guidance was provided. The consensual recommendation was achieved based on Delphi rounds. RESULTS: Fifty four papers reported the comparison of interest. The selected papers allowed the identification of FDG patterns that characterized MCI due to AD, FTLD and DLB. While clinical outcome studies supporting the diagnosis of MCI due to AD showed varying accuracies (ranging from 58 to 100%) and varying areas under the receiver operator characteristic curves (0.66 to 0.97), no respective data were identified for MCI due to FTLD or for MCI due to DLB. However, the high negative predictive value of FDG-PET and the existence of different disease-specific patterns of hypometabolism support the consensus recommendations for the clinical use of this imaging technique in MCI subjects. CONCLUSIONS: FDG-PET has clinical utility on a fair level of evidence in detecting MCI due to AD. Although promising also in detecting MCI due to FTLD and MCI due to DLB, more research is needed to ultimately judge the clinical utility of FDG-PET in these entities. PMID- 29704039 TI - Correction to: 18F-FDG PET in drug-resistant epilepsy due to focal cortical dysplasia type 2: additional value of electroclinical data and coregistration with MRI. AB - The original version of this article has added numbers in the text which are unnecessary. Correct line should be: "We also performed PET/MRI based surgical resections in an increasing number of MRI negative/ doubtful cases with favourable outcome." PMID- 29704040 TI - Medicinal components in Termitomyces mushrooms. AB - Termitomyces is a genus of edible mushrooms commonly consumed in Africa and Asia among the mushrooms collected from the wild. Termitomyces mushrooms grow as symbionts in the termite nests, where they produce various enzymes to help termites digest lignocellulosic substrates. Many species of Termitomyces are used by different ethnic groups with ethnomedicinal knowledge. Bioactive components that Termitomyces mushrooms contain have potential uses as antioxidants, immunomodulators, antitumors, and antimicrobials. Termitomyces also has a potential for treating neurodegenerative disorders. Here, we review the bioactive compounds from Termitomyces species that have been isolated and assayed in vitro and/or in vivo for their medicinal properties. PMID- 29704041 TI - Contrasting beneficial and pathogenic microbial communities across consecutive cropping fields of greenhouse strawberry. AB - Soil weakness across consecutive cropping fields can be partially explained by the changes in microbial community diversity and structure. Succession patterns and co-occurrence mechanisms of bacteria and fungi, especially beneficial or pathogenic memberships in continuous cropping strawberry fields and their response to edaphic factors remained unclear. In this study, Illumina sequencing of bacterial 16S ribosomal RNA and fungal internal transcribed spacer genes was applied in three time-course (1, 5, and 10 years) fields across spring and winter. Results showed that the richness and diversity of bacterial and fungal communities increased significantly (p < 0.05) in 1-year field and decreased afterwards across two seasons. Network analysis revealed beneficial bacterial and fungal genus (Bacillus and Trichoderma) dominated under 1-year field whereas Fusarium accumulated under 10-year field at either season. Moreover, Trichoderma harzianum and Bacillus subtilis that have been reported to effectively control Fusarium wilt in strawberries accumulated significantly under 1-year field. Canonical correspondence analysis showed that beneficial bacterial Rhodospirillales and Rhizobiales and fungal Glomerales accumulated in 1-year field and their distributions were significantly affected by soil pH, microbial biomass C (MBC), and moisture. On the contrary, fungal pathogenic species Fusarium oxysporum strongly increased under 10-year field at the winter sample and the abundance was positively (p < 0.01) correlated with soil moisture. Our study suggested that the potential of microcosm under 1-year field stimulates the whole microbial diversity and favors different beneficial taxa across two seasons. Soil pH, moisture, and MBC were the most important edaphic factors leading to contrasting beneficial and pathogenic memberships across consecutive strawberry cropping fields. PMID- 29704042 TI - Robust signal peptides for protein secretion in Yarrowia lipolytica: identification and characterization of novel secretory tags. AB - Upon expression of a given protein in an expression host, its secretion into the culture medium or cell-surface display is frequently advantageous in both research and industrial contexts. Hence, engineering strategies targeting folding, trafficking, and secretion of the proteins gain considerable interest. Yarrowia lipolytica has emerged as an efficient protein expression platform, repeatedly proved to be a competitive secretor of proteins. Although the key role of signal peptides (SPs) in secretory overexpression of proteins and their direct effect on the final protein titers are widely known, the number of reports on manipulation with SPs in Y. lipolytica is rather scattered. In this study, we assessed the potential of ten different SPs for secretion of two heterologous proteins in Y. lipolytica. Genomic and transcriptomic data mining allowed us to select five novel, previously undescribed SPs for recombinant protein secretion in Y. lipolytica. Their secretory potential was assessed in comparison with known, widely exploited SPs. We took advantage of Golden Gate approach, for construction of expression cassettes, and micro-volume enzymatic assays, for functional screening of large libraries of recombinant strains. Based on the adopted strategy, we identified novel secretory tags, characterized their secretory capacity, indicated the most potent SPs, and suggested a consensus sequence of a potentially robust synthetic SP to expand the molecular toolbox for engineering Y. lipolytica. PMID- 29704043 TI - Antioxidant enzymes and their contributions to biological control potential of fungal insect pathogens. AB - Filamentous fungal insect pathogens represent a source of biological insecticides and acaricides formulated using intact cells, such as conidia or other spores. These mycoinsecticides infect arthropod pests through cuticular penetration. In field application, formulated fungal cells are exposed to environmental stresses, including solar UV irradiation, high temperature, and applied chemical herbicides and fungicides, as well as stress from host immune defenses. These stresses often result in accumulation of toxic reactive oxygen species (ROS), generating oxidative stress to the fungal cells and hence affecting the efficacy and persistency of fungi formulated for pest control. In response, fungi have evolved effective antioxidant mechanisms that include enzyme families that act as ROS scavengers, e.g., superoxide dismutases, catalases, peroxidases, thioredoxins /thioredoxin reductases, and glutaredoxins/glutathione reductases. Over two dozen antioxidant enzymes dispersed in different families have been characterized in Beauveria bassiana in recent years. This mini-review focuses on the progress detailed in the studies of these enzymes and provides an overview of their antioxidant activities and contributions to conidial thermotolerance, UV resistance and virulence. These activities are crucial for the biological control potential of mycoinsecticide formulation and have significantly advanced our understanding of how these organisms work. Several potent antioxidant genes have been exploited for successful genetic engineering of entomopathogenic fungi aimed at enhancing their potential against arthropod pests. PMID- 29704044 TI - Using Cluster Analysis to Compartmentalize a Large Managed Wetland Based on Physical, Biological, and Climatic Geospatial Attributes. AB - Hierarchical and partitional cluster analyses were used to compartmentalize Water Conservation Area 1, a managed wetland within the Arthur R. Marshall Loxahatchee National Wildlife Refuge in southeast Florida, USA, based on physical, biological, and climatic geospatial attributes. Single, complete, average, and Ward's linkages were tested during the hierarchical cluster analyses, with average linkage providing the best results. In general, the partitional method, partitioning around medoids, found clusters that were more evenly sized and more spatially aggregated than those resulting from the hierarchical analyses. However, hierarchical analysis appeared to be better suited to identify outlier regions that were significantly different from other areas. The clusters identified by geospatial attributes were similar to clusters developed for the interior marsh in a separate study using water quality attributes, suggesting that similar factors have influenced variations in both the set of physical, biological, and climatic attributes selected in this study and water quality parameters. However, geospatial data allowed further subdivision of several interior marsh clusters identified from the water quality data, potentially indicating zones with important differences in function. Identification of these zones can be useful to managers and modelers by informing the distribution of monitoring equipment and personnel as well as delineating regions that may respond similarly to future changes in management or climate. PMID- 29704045 TI - Recommended care received by geriatric hip fracture patients: where are we now and where are we heading? AB - INTRODUCTION: Despite the availability of clinical guidelines on the prevention and treatment of geriatric hip fractures, the percentage of recommended care received by patients is low. We conducted an importance-performance analysis for prioritizing interventions to improve the in-hospital management of these patients. MATERIALS AND METHODS: A secondary data analysis was conducted on the in-hospital treatment of 540 geriatric hip fracture patients in 34 hospitals in Belgium, Italy, and Portugal. First, we assessed the level of expert consensus on the process indicators composing international guidelines on hip fracture treatment. Second, guideline adherence on in-hospital care was evaluated within and across hospitals. Third, an importance-performance analysis was conducted, linking expert consensus to guideline adherence. RESULTS: Level of expert consensus was high (above 75%) for 12 of 22 process indicators identified from the literature. There is large between and within hospital variation in guideline adherence for these indicators and for none of the 540 patients were all 22 process indicators adhered to. Importance-performance analysis demonstrated that three indicators that had a high level of expert consensus also had a high level of adherence (above 80%). Nine indicators, most of which have been previously linked to patient outcomes, had a high level of expert consensus but a consistently low level of adherence across hospitals and are identified as priority areas for improvement. CONCLUSIONS: Guideline adherence for the treatment of geriatric hip fracture patients is remarkably suboptimal. Importance performance analysis is a useful strategic approach to assist practitioners and healthcare managers to improve the quality of care. PMID- 29704046 TI - [Implementation of the "Digital Pathology in Diagnostics" guideline : Support systems and their functionality]. AB - BACKGROUND: The "Digital Pathology in Diagnostics - Assessment of Digital Images" guideline describes the technical and legal framework under which the use of this digital technology is justifiable for the individual pathologist. The focus is on conducting a validation study, defining minimum requirements for the generation and management of whole slide images, and ensuring the functionality and quality of the virtual microscopy solution used. By establishing a special web-based service, supportive services can be provided to assist the pathologist in the introduction of virtual microscopy and quality assurance. AIM: Presentation of the Digitale-Pathologie.de server and description of its services in the context of the guideline. RESULTS AND DISCUSSION: In the context of several scanner contests at the Charite in Berlin, as well as with the introduction of virtual microscopy in practice, many experiences were collected, which will be presented systematically. Essentially, this will provide support for the application of the guideline in practice. The following fields are discussed: implementation of the guideline recommendations, planning and evaluation of the validation study, and ensuring the correct color calibration of the slide scanner being used. Via the Digitale-Pathologie.de server, the possibility for self-monitoring and anonymously benchmarking will be offered. For example, errors in setup can be detected quickly and optimal settings can be identified. PMID- 29704048 TI - Long-range interactions of Chara chloroplasts are sensitive to plasma-membrane H+ flows and comprise separate photo- and dark-operated pathways. AB - Local illumination of the characean internode with a 30-s pulse of white light was found to induce the delayed transient increase of modulated chlorophyll fluorescence in shaded cell parts, provided the analyzed region is located downstream in the cytoplasmic flow at millimeter distances from the light spot. The fluorescence response to photostimulation of a remote cell region indicates that the metabolites produced by source chloroplasts in an illuminated region are carried downstream with the cytoplasmic flow, thus ensuring long-distance communications between anchored plastids in giant internodal cells. The properties of individual stages of metabolite signaling are not yet well known. We show here that the export of assimilates and/or reducing equivalents from the source chloroplasts into the flowing cytoplasm is largely insensitive to the direction of plasma-membrane H+ flows, whereas the events in sink regions where these metabolites are delivered to the acceptor chloroplasts under dim light are controlled by H+ fluxes across the plasma membrane. The fluorescence response to local illumination of remote cell regions was best pronounced under weak background light and was also observed in a modified form within 1-2 min after the transfer of cell to darkness. The fluorescence transients in darkened cells were suppressed by antimycin A, an inhibitor of electron transfer from ferredoxin to plastoquinone, whereas the fluorescence response under background light was insensitive to this inhibitor. We conclude that the accumulation of reduced metabolites in the stroma leads to the reduction of photosystem II primary quinone acceptor (QA) via two separate (photochemical and non-photochemical) pathways. PMID- 29704047 TI - Genome-wide evolutionary characterization and expression analyses of major latex protein (MLP) family genes in Vitis vinifera. AB - The major latex protein/ripening-related protein (MLP/RRP) subfamily is known to be involved in a wide range of biological processes of plant development and various stress responses. However, the biological function of MLP/RRP proteins is still far from being clear and identification of them may provide important clues for understanding their roles. Here, we report a genome-wide evolutionary characterization and gene expression analysis of the MLP family in European Vitis species. A total of 14 members, was found in the grape genome, all of which are located on chromosome 1, where are predominantly arranged in tandem clusters. We have noticed, most surprisingly, promoter-sharing by several non-identical but highly similar gene members to a greater extent than expected by chance. Synteny analysis between the grape and Arabidopsis thaliana genomes suggested that 3 grape MLP genes arose before the divergence of the two species. Phylogenetic analysis provided further insights into the evolutionary relationship between the genes, as well as their putative functions, and tissue-specific expression analysis suggested distinct biological roles for different members. Our expression data suggested a couple of candidate genes involved in abiotic stresses and phytohormone responses. The present work provides new insight into the evolution and regulation of Vitis MLP genes, which represent targets for future studies and inclusion in tolerance-related molecular breeding programs. PMID- 29704049 TI - Extrafloral nectaries of four varieties of Chamaecrista ramosa (Vogel) H.S.Irwin & Barneby (Fabaceae): anatomy, chemical nature, mechanisms of nectar secretion, and elimination. AB - Considering the importance of extrafloral nectaries (EFNs) in Fabaceae, the objectives of this research were to analyze (1) the anatomical and histochemical characteristics of the EFNs of Chamaecrista ramosa var. ramosa, C. ramosa var. curvifoliola, C. ramosa var. parvifoliola, and C. ramosa var. lucida and (2) the ultrastructure of the EFNs of C. ramosa var. ramosa. Standard techniques in plant anatomy and transmission electron microscopy were used. The anatomical analyses confirmed the characteristics described for extrafloral nectaries, evidencing three well-defined regions: epidermis, nectariferous, and subnectariferous parenchymas. Carbohydrates, proteins, pectins/mucilages, and lipids were detected by histochemical analyzes in all varieties. The ultrastructure of the EFNs of C. ramosa var. ramosa allowed the observation of microchannels at the external periclinal cell walls of the epidermis covering the secretory region. The nectariferous and subnectariferous parenchyma cells have periplasmic spaces, large plastids containing starch grains and plastoglobules, mitochondria, developed endoplasmic reticulum, large vacuoles with electron-dense contents, and membrane residues may be associated with the vacuole, suggesting the occurrence of autophagic processes. The anatomical, histochemical, and ultrastructural patterns revealed characteristics that confirm the glands of C. ramosa as extrafloral nectaries and suggest the eccrine mechanism of secretion. PMID- 29704050 TI - The Pringle maneuver reduces the infusion rate of rocuronium required to maintain surgical muscle relaxation during hepatectomy. AB - INTRODUCTION: We investigated the continuous infusion rates of rocuronium necessary to obtain the surgical muscle relaxation before, during, and after the Pringle maneuver on patients who underwent hepatectomy. METHODS: Fifteen patients were induced by total intravenous anesthesia with propofol. After obtaining the calibration of acceleromyography, the patient was intubated with rocuronium 0.6 mg/kg. Fifteen minutes after initial rocuronium injection, the continuous infusion was started at 7.5 ug/kg/min. The infusion rate was adjusted every 15 min so that the first twitch height (% T1) might become from 3 to 10% of control. The infusion rates at the time when the state of surgical muscle relaxation was achieved for more than 15 min were recorded before, during and after the Pringle maneuver. The 25% recovery time was measured after discontinuing the continuous infusion. RESULTS: The infusion rate of rocuronium before, during, and after the Pringle maneuver was 7.2 +/- 1.8, 4.2 +/- 1.4, and 4.7 +/- 1.5 ug/kg/min (mean +/ SD), respectively. The rocuronium infusion rate during the Pringle maneuver was decreased about 40% compared to that before this maneuver, and that after completion of the Pringle maneuver was not recovered to that before the Pringle maneuver. The 25% recovery time was 20 +/- 7 min. CONCLUSION: In case of continuous administration of rocuronium during surgery performing the Pringle maneuver, it was considered necessary to regulate the administration of rocuronium using muscle relaxant monitoring in order to deal with the decrease in muscle relaxant requirement by the Pringle maneuver. PMID- 29704051 TI - Correction to: Evaluation of pharmacokinetic models of intravenous dexmedetomidine in sedated patients under spinal anesthesia. AB - Inadvertently, the reference [8] was published incorrectly in the original publication of the article. The correct reference [8] is provided below. PMID- 29704053 TI - A comparative study of eubacterial communities by PCR-DGGE fingerprints in anoxic and aerobic biotrickling filters used for biogas desulfurization. AB - Biological desulfurization has proven to be a process that is technically and economically feasible on using biotrickling filters that can be performed under aerobic and anoxic conditions. However, microbial communities are different mainly due to the use of different final electron acceptors. The analysis of microbial communities in these systems has not been addressed with regard to the anoxic process. The aim of the work reported here was to analyse the eubacterial community in the two types of bioreactor along the packed bed and during the operation time. The analysis was carried out using the 16S PCR-DGGE molecular fingerprint technique. The microbial profile analysis in the aerobic bioreactor revealed that the community was more diverse and stratified compared to those obtained in the two anoxic bioreactors, influenced by environmental factors. The main OTU involved in this process is genus Thiobacillus, although different species were detected depending on each operational condition. PMID- 29704052 TI - Regulation of kinetochore configuration during mitosis. AB - Successful proliferation and function of an organism relies on the equal segregation of its genetic material during cell division. Duplicate sister chromatids need to accurately segregate at mitosis. Precise segregation depends on a multicomplex protein structure called the kinetochore. The kinetochore assembles at centromeres and attaches to microtubules to segregate sister chromatids. Even though the kinetochore structure was first observed nearly a century ago, many aspects of the regulation, function and assembly of this large 100 + protein structure remain to be determined. Improved microscopy and proteomics techniques over the years have helped to reveal the structure, composition and localization of sub-modules of the kinetochore. Recent work suggests that the configuration of the kinetochore is plastic, with extra submodules being added during anaphase to support microtubule tracking and chromosome segregation. We discuss our perspective of how this process might be regulated. PMID- 29704054 TI - Restricted working hours in Austrian residency programs : Survey results. AB - BACKGROUND: New regulations for working hours of medical doctors have been implemented in Austria based on the European directive 2003/88/EG, limiting on duty working hours to 48 h per week. Clinical work is, therefore, substantially reduced compared to previous decades, and little is known on physician and students' opinions on this matter. We illustrate survey results concerning on-job training, its difficulties, and implications for restricted working hours. METHODS: We conducted an internal survey among M.D. and Ph.D. students and medical staff members at the Medical University of Vienna using the MedCampus system (CAMPUSOnline, Graz, Austria) and SPSS (V.21, IBM Corp, Armonk, NY, USA). RESULTS: Participants were 36.5% staff members and 63.5% students. Students rated continuous education of physicians high at 9.19 +/- 1.76 and staff members at 8.90 +/- 2.48 on a 1-10 (1 unimportant, 10 most important) scale. Students rated limited time resources, while staff considered financial resources as the greatest challenge for in-hospital education. Overall, 28.85% thought that restricted working hours can positively influence education, while 19.04% thought the opposite and 52.11% were undecided. DISCUSSION: Considering the limited available time and financial resources, education of tomorrow's medical doctors remains an important but difficult task. While participants of our survey rated education as very important despite its many challenges, the opinions towards limited working hours were not as clear. Given that over 50% are still undecided whether reduced work hours may also positively influence medical education, it clearly presents an opportunity to include the next generations of physicians in this undertaking. PMID- 29704055 TI - The ethylene response factor SmERF6 co-regulates the transcription of SmCPS1 and SmKSL1 and is involved in tanshinone biosynthesis in Salvia miltiorrhiza hairy roots. AB - MAIN CONCLUSION: The SmERF6, which recognizes the GCC-box of SmCPS1 and SmKSL1 promoter in nucleus, regulates the tanshinone biosynthesis in Salvia miltiorrhiza hairy roots. Tanshinone, an important medicinal ingredient in Salvia miltiorrhiza, is best known for its use in medicine. However, the transcription factor regulation of tanshinone biosynthesis is unclear. Here, we isolated and identified a transcription factor in the ERF family of S. miltiorrhiza, SmERF6, which was screened from an S. miltiorrhiza cDNA library by the promoters of two key tanshinone synthesis genes (SmKSL1 and SmCPS1); this factor regulated tanshinone biosynthesis. The gene was highly expressed in the root and responded to ethylene treatment. SmERF6 modulated tanshinone biosynthesis by directly binding to an ethylene-responsive element (GCC-box) of the SmKSL1 and SmCPS1 promoters and activating their transcription. Overexpression of SmERF6 in the hairy roots increased their tanshinone accumulation, and SmERF6 silencing by RNAi led to a lower tanshinone content. Furthermore, tanshinone accumulation maintained homeostasis with the total phenolic acid and flavonoid contents in S. miltiorrhiza. These findings elucidated how SmERF6 directly co-regulates the transcription of SmCPS1 and SmKSL1 and modulates tanshinone synthesis to accelerate the metabolic flux of tanshinone accumulation in S. miltiorrhiza. PMID- 29704056 TI - Application of flow cytometry with a fluorescent dye to measurement of intracellular nitric oxide in plant cells. AB - MAIN CONCLUSION: A simple and rapid method involving flow cytometry and NO specific probe (DAF-FM DA) proved useful for detection and determination of intracellular NO production in Medicago truncatula suspension cells and leaves as well as in cells of Avena fatua, Amaranthus retroflexus embryos and leaves. The measurement of nitric oxide (NO) in plant material is important for examining the regulatory roles of endogenous NO in various physiological processes. The possibility of detecting and determining intracellular NO production by flow cytometry (FCM) with 4-amino-5-methylamino-2',7'-difluorofluorescein (DAF-FM DA), an NO-specific probe in Medicago truncatula cells in suspension and leaves as well as in cells of embryos and leaves of Avena fatua L. or Amaranthus retroflexus L. was explored. To detect and measure NO production by cell suspension or embryos and leaves, the recommended DAF-FM DA concentration is 5 or 10 uM, respectively, applied for 30 min. Exogenous NO increased the intensity of the fluorescent signal in embryos and leaves of both plants, while carboxy-PTIO (cPTIO), an NO scavenger, decreased it. Thus, these results demonstrate that NO can be detected and an increase and a decrease of its intracellular level can be estimated. Wounding was observed to increase the fluorescence signal, indicating an increase in the intracellular NO level. In addition, the levels of exogenous and endogenous ascorbic acid were demonstrated to have no effect on the NO related fluorescence signal, indicating the signal's specificity only in relation with NO. The applicability of the proposed method for detection and determination of NO was confirmed (1) by in situ NO imaging in cell suspensions and (2) by determining the NO concentration in embryos and leaves using the Griess reagent. In view of the data obtained, FCM is recommended as a rapid and simple method with which to detect and determine intracellular NO production in plant cells. PMID- 29704057 TI - Cardiorespiratory fitness and academic performance association is mediated by weight status in adolescents: DADOS study. AB - : The aim of our study was to examine the mediation effect of weight status on the association between cardiorespiratory fitness (CRF) and academic performance (AP). Two hundred sixty-nine adolescents (140 boys) aged 13.9 +/- 0.3 years old from the DADOS study were included in this cross-sectional analysis. CRF was assessed by the 20-m shuttle run test and estimated maximum oxygen uptake was used in the analysis. AP was assessed through the final academic grades and the Science Research Associates Test of Educational Abilities for assessing reasoning, verbal, and numeric abilities. Weight status was assessed by body mass index (kg/m2). Boot-strapped mediation procedures were performed and indirect effects (IE) with confidence intervals (CI) not including zero were considered statistically significant. Mediation analysis revealed that weight status acted as a mediator of the relationship of CRF with reasoning ability (IE = 0.039; CI = 0.001; 0.091) and the final grades in Math (IE = 0.011; CI = 0.002; 0.025), Language (IE = 0.013; CI = 0.004; 0.027), and GPA (IE = 0.011; CI = 0.003; 0.023). CONCLUSIONS: Our data show that the influence of CRF on academic performance is mediated by weight status in adolescents. We suggest that our data could be considered by educators, families, and policy makers, so that active lifestyles might be promoted when designing programs aimed to improve AP among adolescents. What is Known: * Academic performance is associated with both, cardiorespiratory fitness and weight status. * The role of weight status in the association between cardiorespiratory fitness and academic performance is poorly understood. What is New: * We support the scarce research investigating the mediating role of weight status as mechanism in the association between fitness and academic performance in youth. * Previous knowledge is expanded by suggesting that cardiorespiratory fitness is related to weight status which in turn may positively influence academic performance in adolescents. PMID- 29704058 TI - Do longer or shorter cores yield more cancer? PMID- 29704059 TI - Contemporary rates of adherence to international guidelines for pelvic lymph node dissection in radical cystectomy: a population-based study. AB - OBJECTIVE: To examine the rates of adherence to guidelines for pelvic lymph node dissection (PLND) in patients treated with radical cystectomy (RC) and to identify predictors of omitting PLND. MATERIALS AND METHODS: We relied on 66,208 patients treated with RC between 2004 and 2013 within the National Inpatients Sample (NIS) database. We examined the rates of PLND according to year of surgery, patient and hospital characteristics. Univariate and multivariate logistic regression analyses assessed the probability of PLND use, after adjusting for year of surgery, age, gender, race, comorbidities, hospital location, teaching status and hospital surgical volume. RESULTS: Overall, PLND was performed on 54,223 (81.9%) RC patients. The rates PLND at RC significantly increased over the study period from 72.3% in 2004 to 85.9% in 2013, (p < 0.001). Barriers to PLND at RC consisted of female gender (OR: 1.31; 95% CI 1.25-1.38; p < 0.001), African American race (OR: 1.21; 95% CI 1.10-1.32; p < 0.001), intermediate (OR: 1.78; 95% CI 1.68-1.88; p < 0.001) or low surgical volume institutions (OR: 2.59; 95% CI 2.44-2.74; p < 0.001), non-teaching institution status (OR: 1.21; 95% CI 1.15-1.27; p < 0.001) and rural hospital location (OR: 1.13; 95% CI 1.01-1.25; p = 0.03). CONCLUSIONS: It is encouraging to note increasing rates of PLND at RC over time. Both patients and hospital characteristics influence PLND rates. More efforts should be aimed at reducing inequalities in PLND at RC due to these highly modifiable variables. PMID- 29704060 TI - Breast cancer patients' satisfaction with individual therapy goals and treatment in a standardized integrative medicine consultancy service. AB - PURPOSE: Complementary medicine services are nowadays usually quite heterogeneous, and little information is available on standards for running an integrative medicine consultancy service. This study aimed to assess patients' satisfaction with a standardized treatment service on integrative medicine. METHODS: Using a cross-sectional design, 75 breast cancer patients from the integrative medicine consultancy service at the University Breast Center for Franconia were evaluated between January 2016 and March 2017. At primary consultation, patients answered a standardized questionnaire on their medical history and treatment goals regarding integrative medicine. In a subsequent interview, patients evaluated their satisfaction with the treatment service and individual treatment goals. RESULTS: 72% of the patients (n = 54) reported high satisfaction with the overall approach of the treatment service. 76% of the patients (n = 57) were very satisfied or satisfied with their individual treatment plans. The most frequently reported goals were to slow tumor progression (n = 64, 85.3%), reducing the side effects of conventional cancer treatments (n = 60, 80%), and a desire to participate actively in the treatment of breast cancer (n = 64, 85.3%). CONCLUSIONS: Using a standardized procedure in integrative medicine allows a high quality level to be offered to patients. Overall, breast cancer patients report very high satisfaction with the integrative medicine consultancy service and state long-term treatment goals. Hence, long-term treatment with integrative medicine methods should be taken into consideration. PMID- 29704062 TI - Body sway during quiet standing post-stroke: effects of individual and interpersonal light touch. PMID- 29704061 TI - On the neuronal circuitry mediating L-DOPA-induced dyskinesia. AB - With the advent of rodent models of L-DOPA-induced dyskinesia (LID), a growing literature has linked molecular changes in the striatum to the development and expression of abnormal involuntary movements. Changes in information processing at the striatal level are assumed to impact on the activity of downstream basal ganglia nuclei, which in turn influence brain-wide networks, but very little is actually known about systems-level mechanisms of dyskinesia. As an aid to approach this topic, we here review the anatomical and physiological organisation of cortico-basal ganglia-thalamocortical circuits, and the changes affecting these circuits in animal models of parkinsonism and LID. We then review recent findings indicating that an abnormal cerebellar compensation plays a causal role in LID, and that structures outside of the classical motor circuits are implicated too. In summarizing the available data, we also propose hypotheses and identify important knowledge gaps worthy of further investigation. In addition to informing novel therapeutic approaches, the study of LID can provide new clues about the interplay between different brain circuits in the control of movement. PMID- 29704063 TI - Effects of competition and herbivory over woody seedling growth in a temperate woodland trump the effects of elevated CO2. AB - A trend of increasing woody plant density, or woody thickening, has been observed across grassland and woodland ecosystems globally. It has been proposed that increasing atmospheric [CO2] is a major driver of broad scale woody thickening, though few field-based experiments have tested this hypothesis. Our study utilises a Free Air CO2 Enrichment experiment to examine the effect of elevated [CO2] (eCO2) on three mechanisms that can cause woody thickening, namely (i) woody plant recruitment, (ii) seedling growth, and (iii) post-disturbance resprouting. The study took place in a eucalypt-dominated temperate grassy woodland. Annual assessments show that juvenile woody plant recruitment occurred over the first 3 years of CO2 fumigation, though eCO2 did not affect rates of recruitment. Manipulative experiments were established to examine the effect of eCO2 on above-ground seedling growth using transplanted Eucalyptus tereticornis (Myrtaceae) and Hakea sericea (Proteaceae) seedlings. There was no positive effect of eCO2 on biomass of either species following 12 months of exposure to treatments. Lignotubers (i.e., resprouting organs) of harvested E. tereticornis seedlings that were retained in situ for an additional year were used to examine resprouting response. The likelihood of resprouting and biomass of resprouts increased with lignotuber volume, which was not itself affected by eCO2. The presence of herbaceous competitors and defoliation by invertebrates and pathogens were found to greatly reduce growth and/or resprouting response of seedlings. Our findings do not support the hypothesis that future increases in atmospheric [CO2] will, by itself, promote woody plant recruitment in eucalypt-dominated temperate grassy woodlands. PMID- 29704064 TI - The legacy of Jules Gonin: one hundred years of identifying and treating retinal breaks. PMID- 29704065 TI - Time trends of Finnish adolescents' mental health and use of alcohol and cigarettes from 1998 to 2014. AB - This study reports time-trend changes in self-reported mental health problems, smoking, and alcohol habits among Finnish adolescents over a 16-year period using three cross-sectional studies with similar designs, methodologies, and geographical recruitment areas. There were 4508 participants with a mean age of 14.4 years (range 13-18) in 1998 (n = 1449), 2008 (n = 1560), and 2014 (n = 1499). The information they provided on their mental health was measured with the Strengths and Difficulties Questionnaire and they were also asked questions about their alcohol and smoking habits. The findings showed that from 1998 to 2014 females reported less hyperactivity and conduct problems and males reported fewer peer problems and better prosocial skills. The only mental health problem that showed a significant increase was emotional symptoms among females. Smoking and alcohol use consistently decreased in males and females during the 16-year period. Our findings suggest that overall adolescent's self-reported mental health problems were either stable or falling, indicating increased well-being. The decreased smoking indicates that anti-smoking campaigns have been successfully changing teenagers' attitudes towards smoking. The important finding is that self-reported emotional symptoms had increased in females. This may indicate an increase or earlier onset of affective disorders. PMID- 29704066 TI - Current Status of Extended Adjuvant Endocrine Therapy in Early Stage Breast Cancer. AB - OPINION STATEMENT: In the past decade, several endocrine treatment regimens have been developed for the adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer, including tamoxifen, aromatase inhibitors (AI), or a combination of these. The standard duration of adjuvant endocrine treatment has been 5 years for a long time. Nevertheless, the high number of recurrences occurring after 5 years suggested that extended endocrine therapy could further improve outcome, which led to the start of several randomized clinical trials investigating the effects of extended use of endocrine therapy. The extended duration of tamoxifen has been shown to improve disease-free survival and overall survival in the ATLAS and aTTom trials. However, in postmenopausal women, AIs have been shown to be more effective when compared with tamoxifen. Based hereon, it is recommended that adjuvant endocrine therapy in postmenopausal women with early breast cancer should include an AI. Recently, the DATA, IDEAL, and NSABP B42 trials showed that extended adjuvant endocrine therapy with AIs beyond 5 years in postmenopausal women with early breast cancer did reduce the occurrence of secondary breast tumors, but had no or only a small impact on distant metastasis free survival. Furthermore, toxicity of adjuvant AIs led to gradually decreasing compliance rates and long-term toxicities to non breast cancer-related deaths. Therefore, we suggest considering extended adjuvant treatment only in women with high-risk early breast cancer who tolerate treatment well. PMID- 29704067 TI - Microbial community and diversity in the feces of Sichuan takin (Budorcas taxicolor tibetana) as revealed by Illumina Miseq sequencing and quantitative real-time PCR. AB - The Sichuan takin (Budorcas taxicolor tibetana) is a rare and endangered ruminant distributed in the eastern Himalayas. However, little information is available regarding the intestinal microbiota of the takin. In this study, Illumina Miseq platform targeting the V4 region of the 16S rRNA was employed to characterize microbial community and diversity in the feces of wild (n = 6) and captive takins (n = 6). The takin exhibited an intestinal microbiota dominated by three phyla: Firmicutes (57.4%), Bacteroidetes (24.2%) and Proteobacteria (12.3%). At family/genus level, Ruminococcaceae, Bacteroidaceae, Acinetobacter, Clostridium, Lachnospiraceae, Rikenellaceae, Bacillus, Comamonas and Spirochaetaceae were dominant. Distinctive microbiotas between wild and captive takins were observed based on microbial community structure, captive takins having significantly higher community diversity. Quantitative real-time PCR were also utilized to monitor predominant bacteria in three Sichuan takin individuals housed in Chengdu Zoo over a half-year period, which showed that microbial communities of the three takins were relatively similar to each other and stable during our study period. Our results suggested that diet was a major driver for shaping microbial community composition. PMID- 29704068 TI - LED phototherapy in full-thickness burns induced by CO2 laser in rats skin. AB - Many studies have been conducted on the treatment of burns because they are important in morbidity and mortality. These studies are mainly focused on improving care and quality of life of patients. The aim of this study was evaluate the LED phototherapy effects in rats skin full-thickness burns induced by CO2 laser. The animals were divided in NT group that did not received any treatment and LED group that received LED irradiation at 685 nm, 220 mW, and 4.5 J/cm2 during 40 s by burned area. Biopsies were obtained after 7, 14, and 21 days of treatment and submitted to histological and immunohistochemical analysis. The LED phototherapy shows anti-inflammatory effects, improves angiogenesis, and stimulates the migration and proliferation of fibroblasts. The T CD8+ lymphocytes were more common in burned areas compared to T CD4+ lymphocytes since statistically significant differences were observed in the LED group compared to the NT group after 7 days of treatment. These results showed that LED phototherapy performs positive influence in full-thickness burns repair from the healing process modulated by cellular immune response. The obtained results allowed inferring that burns exhibit a characteristic cell immune response and this cannot be extrapolated to other wounds such as incision and wounds induced by punch, among others. PMID- 29704069 TI - A nanocomposite prepared from FeOOH and N-doped carbon nanosheets as a peroxidase mimic, and its application to enzymatic sensing of glucose in human urine. AB - A method is described for the synthesis of a nanocomposite containing FeOOH and N doped carbon nanosheets. The nanocomposite was synthesized by a hydrothermal method using a Fe3O4/chitosan nanocomposite as the precursor. The nanocomposite displays peroxidase-like activity and catalyzes the oxidation of 3,3',5,5' tetramethylbenzidine (TMB) by H2O2. This results in the formation of a blue colored product with an absorption maximum at 652 nm in the UV-vis spectra. Based on these findings, colorimetric assays were worked out for both hydrogen peroxide and glucose. The H2O2 assay works in the 5 to 19 MUM concentration range, and the limit of detection is 5 nM. The glucose assay works in the 8 MUM to 0.8 mM concentration range and has a 0.2 MUM detection limit. The method was successfully applied to the determination of glucose in human urine. Graphical abstract Schematic of the hydrothermal synthesis of a FeOOH/N-doped carbon nanocomposite. It was used to replace peroxidase enzyme for the catalytic oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) in a visual colorimetric test for glucose in human urine. PMID- 29704070 TI - Hydroxyapatite nanoparticle based fluorometric determination and imaging of cysteine and homocysteine in living cells. AB - Fluorescent hydroxyapatite nanoparticles (HAP-NPs) were prepared by reacting calcium ion with phosphate in the presence of Eu(III) ion. The HAP-NPs display large Stokes' shift and two strong fluorescence emissions with peaks at 590 nm and 615 nm when excited at 250 nm. The HAP-NPs also have good photostability and water solubility. The HAP-NPs combined with Cu(II) were applied to fluorometric determination of cysteine and homocysteine in biological samples and in living cells. In this detection scheme, the fluorescence of HAP-NPs is initially quenched by Cu(II). The addition of biothiols results in the formation of Cu(II) thiol complexes and leads to fluorescence recovery. The assay allows cysteine to be detected with a 110 nM detection limit, and homocysteine with a 160 nM detection limit. The assay was successfully applied to the analysis of cysteine in spiked human serum samples and to imaging of cysteine in HeLa cells, and this demonstrates its potential for clinical testing and in biomedical research. Graphical abstract Fluorescent hydroxyapatite nanoparticles were synthesized and combined with Cu2+ for fluorescence sensing of biothiols (cysteine and homocysteine) in complex biological samples and in living cells. PMID- 29704071 TI - Variation of nanoparticle fraction and compositions in two-stage double peaks aging precipitation of Al-Zn-Mg alloy. AB - Atom probe tomography (APT) coupling high-resolution transmission electron microscopy (HRTEM) was used to analyze the fraction and compositions of different nanoparticles in two-stage double peaks aging process of Al-Zn-Mg alloy. Al content is found to be closely related to the size of nanoparticles and it can be greater than ~ 50.0 at. % in the nanoparticle with the equivalent radius under ~ 3.0 nm. Correspondingly, Al content of the nanoparticle, with the equivalent radius over ~ 5.0 nm, is measured under ~ 40.0 at. %. Evolution from Guinier Preston (G.P.) zone to eta phase is a growing process where Mg and Zn atoms enter the nanoparticle, therefore rejecting Al atoms. G.P. zones can take up a number fraction of ~ 85.0 and ~ 22.7% of nanoparticles in the first and second peak-aged samples, respectively, and even in the over-aged (T73) sample, they can still be found. As aging time increases, fraction of eta' phases monotonically rises to the peak value (~ 54.5%) in the second peak-aged state and then drops, which is significant for the second hardness peak and directly proves their function as the transitional medium. In T73 state, ~ 63.3% nanoparticles compose of eta phases, which were measured to still contain ~ 10.2 to ~ 36.4 at. % Al atoms. PMID- 29704072 TI - Understanding the Growth Mechanism of GaN Epitaxial Layers on Mechanically Exfoliated Graphite. AB - The growth mechanism of GaN epitaxial layers on mechanically exfoliated graphite is explained in detail based on classic nucleation theory. The number of defects on the graphite surface can be increased via O-plasma treatment, leading to increased nucleation density on the graphite surface. The addition of elemental Al can effectively improve the nucleation rate, which can promote the formation of dense nucleation layers and the lateral growth of GaN epitaxial layers. The surface morphologies of the nucleation layers, annealed layers and epitaxial layers were characterized by field-emission scanning electron microscopy, where the evolution of the surface morphology coincided with a 3D-to-2D growth mechanism. High-resolution transmission electron microscopy was used to characterize the microstructure of GaN. Fast Fourier transform diffraction patterns showed that cubic phase (zinc-blend structure) GaN grains were obtained using conventional GaN nucleation layers, while the hexagonal phase (wurtzite structure) GaN films were formed using AlGaN nucleation layers. Our work opens new avenues for using highly oriented pyrolytic graphite as a substrate to fabricate transferable optoelectronic devices. PMID- 29704073 TI - Humate-assisted Synthesis of MoS2/C Nanocomposites via Co Precipitation/Calcination Route for High Performance Lithium Ion Batteries. AB - A facile, cost-effective, non-toxic, and surfactant-free route has been developed to synthesize MoS2/carbon (MoS2/C) nanocomposites. Potassium humate consists of a wide variety of oxygen-containing functional groups, which is considered as promising candidates for functionalization of graphene. Using potassium humate as carbon source, two-dimensional MoS2/C nanosheets with irregular shape were synthesized via a stabilized co-precipitation/calcination process. Electrochemical performance of the samples as an anode of lithium ion battery was measured, demonstrating that the MoS2/C nanocomposite calcinated at 700 degrees C (MoS2/C-700) electrode showed outstanding performance with a high discharge capacity of 554.9 mAh g- 1 at a current density of 100 mA g- 1 and the Coulomb efficiency of the sample maintained a high level of approximately 100% after the first 3 cycles. Simultaneously, the MoS2/C-700 electrode exhibited good cycling stability and rate performance. The success in synthesizing MoS2/C nanocomposites via co-precipitation/calcination route may pave a new way to realize promising anode materials for high-performance lithium ion batteries. PMID- 29704074 TI - The Italian validation of the minimal assessment of cognitive function in multiple sclerosis (MACFIMS) and the application of the Cognitive Impairment Index scoring procedure in MS patients. AB - Cognitive dysfunction occurs in almost 50-60% of patients with multiple sclerosis (MS) even in early stages of the disease and affects different aspects of patient's life. Aims of the present study were (1) to introduce and validate an Italian version of the minimal assessment of cognitive functions in MS (MACFIMS) battery and (2) to propose the use of the Cognitive Impairment Index (CII) as a scoring procedure to define the degree of impairment in relapsing-remitting (RRMS) and secondary-progressive (SPMS) patients. A total of 240 HC and 123 MS patients performed the Italian version of the MACFIMS composed by the same tests as the original except for the Paced Auditory Serial Addition Test. The CII was derived for each score of the 11 scales for participants of both groups. The results of the study show that cognitive impairment affects around 50% of our sample of MS patients. In RRMS group, only the 15.7% of patients reported a severe impairment, while in the group of SPMS, the 51.4% of patients felt in the "severely impaired" group. Results are in line with previously reported percentages of impairment in MS patients, showing that the calculation of the CII applied to the Italian version of the MACFIMS is sensitive and reliable in detecting different degrees of impairment in MS patients. PMID- 29704075 TI - Influence of fluoride varnish on shear bond strength of a universal adhesive on intact and demineralized enamel. AB - The aim was to evaluate the effect of fluoride varnish on the shear bond strength (SBS) on polished and non-polished intact and demineralized enamel. Bovine incisors (half demineralized) were used. Bifluorid 12TM was applied. Bonding was made with Futurabond(r)M + and GrandioSO, 24 h and 7 days after varnishing. In some groups, varnish was removed by polishing before bonding. SBS was measured. Fracture type was determined by stereomicroscopy and scanning electron microscope (SEM) observations of the enamel surface were made. Between-group differences were determined by one-way ANOVA and the Tukey test. Associations between study factors and fracture modes were analysed using contingency tables and Pearson's chi-squared test. For intact enamel, SBS on varnished enamel at 24 h was significantly less than in the other groups. SBS recovered 7 days after varnishing. Varnish elimination after 24 h significantly increased the SBS. However, removal at 7 days did not modify SBS. SBS on demineralized enamel groups was significantly less than in intact enamel, except for demineralized enamel varnished and removed at 7 days. Demineralized enamel was associated with cohesive enamel fractures and intact enamel with cohesive fractures of the composite and adhesive fractures. SEM of varnish surfaces showed a homogenous layer scattered with amorphous precipitate. In conclusion, on intact enamel fluoride varnish had a negative effect on SBS at 24 h, which disappeared after 7 days. On demineralized enamel, varnish did not reduce SBS at either time. Polishing the varnished enamel surface showed a similar SBS to intact enamel after 7 days. PMID- 29704076 TI - Spatio-temporal Reconstruction of Neural Sources Using Indirect Dominant Mode Rejection. AB - Adaptive minimum variance based beamformers (MVB) have been successfully applied to magnetoencephalogram (MEG) and electroencephalogram (EEG) data to localize brain activities. However, the performance of these beamformers falls down in situations where correlated or interference sources exist. To overcome this problem, we propose indirect dominant mode rejection (iDMR) beamformer application in brain source localization. This method by modifying measurement covariance matrix makes MVB applicable in source localization in the presence of correlated and interference sources. Numerical results on both EEG and MEG data demonstrate that presented approach accurately reconstructs time courses of active sources and localizes those sources with high spatial resolution. In addition, the results of real AEF data show the good performance of iDMR in empirical situations. Hence, iDMR can be reliably used for brain source localization especially when there are correlated and interference sources. PMID- 29704079 TI - Leptomeningeal disease in uveal melanoma: a case series. PMID- 29704077 TI - Executive Functions in Children and Adolescents with Turner Syndrome: A Systematic Review and Meta-Analysis. AB - Turner syndrome (TS) is a genetic disorder, affecting 1/2500 to 1/3000 live female births, induced by partial or total deletion of one X chromosome. The neurocognitive profile of girls with TS is characterized by a normal Verbal IQ and weaknesses in visual-spatial, mathematics, and social cognitive domains. Executive functions (EFs) impairments have also been reported in these young patients. However, methodological differences across studies do not allow determination of which EFs are impaired and what is the magnitude of these impairments. The aim of this review was to clarify the EF profile of children and adolescents with TS. Sixteen samples, from thirteen studies, were included in the current meta-analysis. EFs measures used in these studies were classified into working memory, inhibitory control, cognitive flexibility, or higher-order EFs tasks in accordance with Diamond's model, Annual Review of Psychology, 64, 135 168 (2013). Results confirmed that girls with TS had significant executive impairments with effect sizes varying from small (inhibitory control) to medium (cognitive flexibility) and large (working memory, higher-order EFs). Analyses by task revealed that cognitive inhibition may be more impaired than the other inhibitory control abilities. Heterogeneity across cognitive flexibility measures was also highlighted. Between-sample heterogeneity was observed for three tasks and the impact of participants' characteristics on EFs was discussed. This meta analysis confirms the necessity to assess, in patients living with TS, each EF by combining both visual and verbal tasks. Results also underline that, when studying girls with TS' executive profile, it is important to explore the impact of moderator variables, such as IQ, parental socio-economic status, TS karyotype, psychiatric comorbidities, and hormonal treatment status. PMID- 29704078 TI - Health-related quality of life of African-American female breast cancer survivors, survivors of other cancers, and those without cancer. AB - PURPOSE: The purpose of this study was to compare differences in health-related quality of life (HRQOL) between African-American female breast cancer survivors, African-American female survivors of other cancers, and African-American women with no history of cancer. METHODS: Using data from the 2010 National Health Interview Survey (NHIS), the HRQOL of African-American women aged 35 years or older was compared by cancer status. Physical and mental health items from the Patient-Reported Outcomes Measurement Information System (PROMIS) global health scale were used to assess differences in HRQOL. RESULTS: For summary physical and mental health measures, no significant differences were found between breast cancer survivors and women with no history of cancer; survivors of other cancers reported poorer physical and mental health than did women with no history of cancer. Similar differences were found at the item level. When we examined the two African-American female cancer survivor groups, we found that cancer survivors whose cancer was being treated reported substantially poorer physical health and mental health than did those whose cancer was not being treated. Survivors who had private insurance and were cancer free reported better physical and mental health than did those who did not have private insurance and those who were not cancer free. Breast cancer survivors reported slightly better physical and mental health than did survivors of other cancers. CONCLUSIONS: Our findings highlight the need for public health agencies to adopt practices to improve the mental and physical health of African-American female survivors of cancer. PMID- 29704081 TI - Antidepressant and anxiolytic like effects of Urtica dioica leaves in streptozotocin induced diabetic mice. AB - The present study was aimed to investigate the effect of Urtica dioica Linn. (UD) extract against chronic diabetes mediated anxiogenic and depressive like behavior in mice. Streptozotocin (STZ) (50 mg/kg, i.p.) for 5 consecutive days was used to induce diabetes followed by treatment with UD leaves extract (50 mg/kg, p.o.) and rosiglitazone (ROSI) (5 mg/kg, p.o.) for 8 weeks. STZ induced chronic diabetes significantly induced anxiety and depressive like behavior in mice. Chronic diabetes significantly downregulated BDNF (p < 0.001), TrKB (p < 0.001), Cyclin D1 (p < 0.001), Bcl2 (p < 0.05) and autophagy7 (p < 0.001), while upregulated iNOS (p < 0.05) mRNA expression in the hippocampus as compared to control mice. In addition, chronic diabetes significantly increased the expression of TNF-alpha in CA1 (p < 0.001), CA2 (p < 0.01), CA3 (p < 0.001) and DG (p < 0.001) regions of hippocampus as compared to control mice. Chronic diabetes mediated neuronal damage in the CA2, CA3 and DG regions of hippocampus. Chronic administration of UD leaves extract significantly reversed diabetes mediated anxiogenic and depressive like behavior in mice. Further, UD treatment significantly upregulated BDNF (p < 0.01), TrKB (p < 0.001), Cyclin D1 (p < 0.001), Bcl2 (p < 0.01), autophagy5 (p < 0.01) and autophagy7 (p < 0.001), while downregulated iNOS (p < 0.05) mRNA expression in the hippocampus of diabetic mice. Concomitantly, UD administration significantly decreased the expression of TNF-alpha in hippocampal CA1 (p < 0.001), CA2 (p < 0.01), CA3 (p < 0.001) and DG (p < 0.001) regions of diabetic mice. Diabetes mediated neuronal damage and DNA fragmentation in the hippocampus was substantially attenuated following UD treatment. UD leaves extract might prove to be effective for diabetes mediated anxiety and depressive like behavior. PMID- 29704080 TI - MR-spectroscopic imaging of glial tumors in the spotlight of the 2016 WHO classification. AB - BACKGROUND: The purpose of this study is to map spatial metabolite differences across three molecular subgroups of glial tumors, defined by the IDH1/2 mutation and 1p19q-co-deletion, using magnetic resonance spectroscopy. This work reports a new MR spectroscopy based classification algorithm by applying a radiomics analytics pipeline. MATERIALS: 65 patients received anatomical and chemical shift imaging (5 * 5 * 20 mm voxel size). Tumor regions were segmented and registered to corresponding spectroscopic voxels. Spectroscopic features were computed (n = 860) in a radiomic approach and selected by a classification algorithm. Finally, a random forest machine-learning model was trained to predict the molecular subtypes. RESULTS: A cluster analysis identified three robust spectroscopic clusters based on the mean silhouette widths. Molecular subgroups were significantly associated with the computed spectroscopic clusters (Fisher's Exact test p < 0.01). A machine-learning model was trained and validated by public available MRS data (n = 19). The analysis showed an accuracy rate in the Random Forest model by 93.8%. CONCLUSIONS: MR spectroscopy is a robust tool for predicting the molecular subtype in gliomas and adds important diagnostic information to the preoperative diagnostic work-up of glial tumor patients. MR spectroscopy could improve radiological diagnostics in the future and potentially influence clinical and surgical decisions to improve individual tumor treatment. PMID- 29704082 TI - Flexor pollicis longus tendon rupture by sandwiched underlying volar locking plate and distal radius. AB - Flexor pollicis longus (FPL) tendon rupture is a major complication of volar locking plate fixation for distal radius fractures. The tendon rupture is usually caused by friction between the distal edge of the plate and the FPL tendon, and has been well detected recently with ultrasonography. Rarely, the volar locking plate itself entraps the FPL tendon, leading to its rupture. A 63-year-old man was consistently unable to flex his right thumb after previous surgery for a distal radius fracture at another hospital. Ultrasonography demonstrated loss of tendon gliding and unusual patterns of the FPL tendon. The tendon was sandwiched between the plate and the distal radius, and was penetrated by the distal locking screw, which was comparable to intraoperative findings of complete entrapment and rupture of the FPL tendon from the underlying plate. The tendon defects were repaired using a palmaris longus tendon graft after removing the screws and plate. Finally, he could flex his thumb actively with satisfaction. Unusual patterns of FPL tendon rupture buried under inadequate plate positioning must be recognized, as in this case. Ultrasonographic assessment is routinely recommended to visibly determine any FPL tendon damage after volar locking plate fixation for distal radius fractures. PMID- 29704083 TI - Does Affective Theory of Mind Contribute to Proactive Aggression in Boys with Conduct Problems and Psychopathic Tendencies? AB - Adolescent psychopathic tendencies are associated with phenotypic increases in proactive aggression. However, the extent to which an understanding of others' affective mental states, or affective theory of mind (ToM), contributes to proactive aggression remains unknown. We examined how performance on a well-known test of affective ToM, based on cropped images of the eye region, contributes to reactive and proactive types of aggression in a mixed ethnicity sample of 80 incarcerated adolescent boys. A hierarchical regression model showed that affective ToM predicted proactive aggression over and above the influence of clinically rated psychopathic tendencies. Importantly, affective ToM was unrelated to reactive aggression. Our results suggest that being able to recognize others' affective mental states may be an important factor in aggressing against others for personal gain. These findings have implications for interventions designed to enhance ToM in youth with conduct problems. PMID- 29704086 TI - Automated Quality Assessment of Colour Fundus Images for Diabetic Retinopathy Screening in Telemedicine. AB - Fundus images obtained in a telemedicine program are acquired at different sites that are captured by people who have varying levels of experience. These result in a relatively high percentage of images which are later marked as unreadable by graders. Unreadable images require a recapture which is time and cost intensive. An automated method that determines the image quality during acquisition is an effective alternative. To determine the image quality during acquisition, we describe here an automated method for the assessment of image quality in the context of diabetic retinopathy. The method explicitly applies machine learning techniques to access the image and to determine 'accept' and 'reject' categories. 'Reject' category image requires a recapture. A deep convolution neural network is trained to grade the images automatically. A large representative set of 7000 colour fundus images was used for the experiment which was obtained from the EyePACS that were made available by the California Healthcare Foundation. Three retinal image analysis experts were employed to categorise these images into 'accept' and 'reject' classes based on the precise definition of image quality in the context of DR. The network was trained using 3428 images. The method shows an accuracy of 100% to successfully categorise 'accept' and 'reject' images, which is about 2% higher than the traditional machine learning method. On a clinical trial, the proposed method shows 97% agreement with human grader. The method can be easily incorporated with the fundus image capturing system in the acquisition centre and can guide the photographer whether a recapture is necessary or not. PMID- 29704085 TI - Associations between Oxytocin Receptor (OXTR) Genotype and Elementary School Children's Likability, Dis-likability and Friendship among Classroom Peers: A Longitudinal Study. AB - The single nucleotide polymorphism rs53576 of the oxytocin receptor (OXTR) gene is involved in forming and maintaining relationships in various social contexts. However, this has not been studied in the childhood peer context. The present study followed 359 children (51.6% girls) from age 9 to 12 to explore associations between OXTR rs53576 genotype (i.e., AA, AG or GG genotype) and three indicators of children's relationships with peers: likability and dis likability among, and friendship with, classroom peers. Our results showed that OXTR rs53576 was associated with likability among boys, but not with dis likability and friendship or among girls. Boys with an A and a G allele (i.e., AG genotype) became increasingly more liked by their peers across the four-year studied period than those with two A alleles or two G alleles (i.e., AA and GG genotype). This study indicates that OXTR rs53576 genotype might influence children's peer relationships, particularly their likeability among peers. Associations between OXTR rs53576 and peer relationships may differ depending on children's sex and the specific type of peer-relationship under scrutiny. PMID- 29704087 TI - Focus Group in Community Mental Health Research: Need for Adaption. AB - The article presents an analysis of the use of focus groups in researching community mental health users, starting with the reasons for using them, their implementation in mental health service users' research, and the adaptations of focus group use when researching the experiences of users. Based on personal research experience and a review of scientific publications in the Google Scholar, Web of Science, ProQuest, EBSCOhost, and Scopus databases, 20 articles published between 2010 and 2016 were selected for targeted content analysis. A checklist for reporting on the use of focus groups with community mental health service users, aiming to improve the comparability, verifiability and validity was developed. Adaptations of the implementation of focus groups in relation to participants' characteristics were suggested. Focus groups are not only useful as a scientific research technique, but also for ensuring service users' participation in decision-making in community mental health and evaluating the quality of the mental health system and services . PMID- 29704088 TI - Housing for People with Substance Use Disorders: One Size Does Not Fit All Tenants-Assessment of 16 Housing Services and Suggestions for Improvement Based on Real World Experience. AB - Housing is an important factor for individuals addressing substance use disorders (SUD). This work compared aims and outcomes for new housing services and made suggestions for improvement. 16 new services were assessed over 6 months activity against factors identified as important. Services defined expected standards including (1) engagement with treatment for SUD, (2) restrictions on continuing substance use by tenants. After 6 months, 9 (56%) housing projects did not achieve planned standards and lowered criteria for inclusion. When setting up housing for people with SUD it is important to define clearly the nature of the intended service. Different types of housing programs in a network are needed to meet the evolving behaviour of tenants. One size does not fit all. Stable housing is important for people addressing SUD and these suggestions may increase the chance of providing a suitable foundation for people in need. PMID- 29704089 TI - Bartenders' and Rum Shopkeepers' Knowledge of and Attitudes Toward "Problem Drinking" in Saint Vincent and the Grenadines. AB - Harmful alcohol use encompasses a spectrum of habits, including heavy episodic drinking (HED) which increases the risk of acute alcohol-related harms. The prevalence of HED in Saint Vincent and the Grenadines (SVG) is 5.7% among the overall population aged 15 years and older and 10.2% among drinkers. Responsible Beverage Service interventions train alcohol servers to limit levels of intoxication attained by customers and decrease acute alcohol-related harms. The objectives of this study were to determine bar tenders' and rum shopkeepers' knowledge of and attitudes toward problem drinking and willingness to participate in server training. Researchers used convenience and purposive sampling to recruit 30 participants from Barraouile, Kingstown, and Calliaqua to participate in semi-structured interviews designed to explore study objectives. Results and conclusions were derived from grounded theory analysis. Heavy episodic drinking is common but not stigmatized. Heavy drinking is considered a "problem" if the customer attains a level of disinhibition causing drunken and disruptive or injurious behavior. Bartenders and rum shopkeepers reported intervening with visibly intoxicated patrons and encouraging cessation of continued alcohol consumption. Participants cited economic incentives, prevention of alcohol related harms, and personal morals as motivators to prevent drunkenness. Respondents acknowledged that encouraging responsible drinking was a legitimate part of their role and were favorable to server training. However, there were mixed opinions about the intervention's perceived efficacy given absent community wide standards on preventing intoxication and limitations of existing alcohol policy. Given respondents' motivation and lack of standardized alcohol server training in SVG, mandated server training can be an effective strategy when promoted as one piece of a multi-component alcohol policy. PMID- 29704090 TI - Association between bovine digital dermatitis and annual periods of lower pluviometric precipitation in Central Brazil. AB - We aimed to follow the epidemiologic evolution of bovine digital dermatitis (BDD) and other podal diseases grouped in a dairy farm in Central Brazil between the years 2010 and 2016. This study was carried out in a farm in Jatai, Goias, Central Brazil, where the prevalence data of bovine digital dermatitis (BDD) and other podal diseases, as well as the composition, history, and management of the herd, was collected. We analyzed the collected data into the two annual pluviometric precipitation values in Central Brazil: rainy season and dry season. The cumulative frequency for comparison of prevalence between seasons throughout the years was calculated from 2011 to 2016. The comparison was carried out by post hoc chi-square test with the Bonferroni correction adopting a level of significance of 5% (p < 0.05). BDD was not diagnosed at the property in 2010; however, the disease became endemic from 2011, which coincides with the arrival of new animals to the herd. The comparison of the accumulated frequencies for prevalence of the diseases in the herd between 2011 and 2016 revealed BDD, as well as the grouped nutritional and metabolic foot diseases, has the highest prevalence in the period of lower annual precipitation in Central Brazil, which occurs between May and October. For a better control of BDD, we recommend greater attention in cattle management in the dry season of the year in Brazil, as well as in any other place in the world in which rainfall is seasonal. PMID- 29704091 TI - Cross-sectional prevalence of gastrointestinal helminth parasites in cattle in Lira District, Uganda. AB - The prevalence of gastrointestinal helminth parasite infections and associated risk factors was studied in traditionally reared East African short-horned zebu cattle in Lira District, Uganda. Fecal samples were collected from 205 cattle and coprologically examined for the presence of helminth parasites using the simple salt flotation method complemented with the sedimentation method. The overall prevalence of gastrointestinal helminth parasites (GITPs) in cattle in Adekokwok, Lira District, was 32.2%. Of these, 12 (18.18%) were cases of mixed infections mainly of Amphistomes and other GITPs. Paramphistomum was the most prevalent parasite contributing up to 45.5% of infections, followed by Fasciola, Toxocara, strongyles, Trichuris, and Nematodirus, in descending order of abundance. GITP infections were not influenced by the sex of cattle, while infection with Toxocara was associated with cattle age. The mean body condition score (BCS) for all animals studied was 2.37 +/- 0.07. A low BCS was associated with gastrointestinal helminth infections. Nevertheless, other factors such as nutritional stress are likely to augment the effects of parasites in the traditional agro-pastoral system particularly in the dry season and should therefore be considered when using the cattle body condition as an indicator of parasitism. PMID- 29704092 TI - New protocol for dissociating visuospatial working memory ability in reaching space and in navigational space. AB - Several studies have demonstrated that the processing of visuospatial memory for locations in reaching space and in navigational space is supported by independent systems, and that the coding of visuospatial information depends on the modality of the presentation (i.e., sequential or simultaneous). However, these lines of evidence and the most common neuropsychological tests used by clinicians to investigate visuospatial memory have several limitations (e.g., they are unable to analyze all the subcomponents of this function and are not directly comparable). Therefore, we developed a new battery of tests that is able to investigate these subcomponents. We recruited 71 healthy subjects who underwent sequential and simultaneous navigational tests by using an innovative sensorized platform, as well as comparable paper tests to evaluate the same components in reaching space (Exp. 1). Consistent with the literature, the principal-component method of analysis used in this study demonstrated the presence of distinct memory for sequences in different portions of space, but no distinction was found for simultaneous presentation, suggesting that different modalities of eye gaze exploration are used when subjects have to perform different types of tasks. For this purpose, an infrared Tobii Eye-Tracking X50 system was used in both spatial conditions (Exp. 2), showing that a clear effect of the presentation modality was due to the specific strategy used by subjects to explore the stimuli in space. Given these findings, the neuropsychological battery established in the present study allows us to show basic differences in the normal coding of stimuli, which can explain the specific visuospatial deficits found in various neurological conditions. PMID- 29704093 TI - Trends in the treatment of chronic kidney disease-associated anaemia in a cohort of haemodialysis patients: the Irish experience. AB - BACKGROUND: Anaemia among haemodialysis patients is treated with iron and erythropoietin-stimulating agents (ESAs). ESAs reduce requirements for blood transfusions but are also expensive and overzealous use may be associated with adverse outcomes. Recent international trends have been characterised by reduced ESA doses and a greater reliance on intravenous (IV) iron. We determined trends in prescribing patterns of ESAs and IV iron for the treatment of anaemia in two representative Irish dialysis centres and correlated with current guidelines and international trends. METHODS: Patient data was accessed from the Kidney Disease Clinical Patient Management System (KDCPMS) for the period 2012 to 2014. We generated reports on ESA and iron doses, lab data (haemoglobin (Hb), transferrin saturation (TSAT) and ferritin) and patient population characteristics. We mapped the trends in ESA, iron dosing and lab parameters achieved. A linear mixed model determined the significance of these trends over time. RESULTS: ESA dosing became lower in the second, third and fourth quarters of 2014. Dosing of iron increased throughout but a large increase was seen in the third and fourth quarters of 2014. Ferritin levels decreased and TSAT and haemoglobin levels increased. Changes in iron dosing were significant with p value of < 0.05. CONCLUSIONS: Our findings are consistent with recent global trends toward increasing iron use. Such trends may have economic implications given the high cost of ESAs and the relative affordability of iron. In addition, the potential harm of excessive iron dosing may need to be considered. PMID- 29704094 TI - Fake snakes uncover chimpanzees' mind-reading ability. AB - Crockford et al. (2017, Science Advances, 3(11), e1701742) conducted experimental studies in the wild in Africa to investigate the ability of chimpanzees to understand the mental states of other conspecific individuals. Their findings suggest that chimpanzees understand whether or not other individuals are aware of dangers, and they behave differently according to their understanding about the mental states of other individuals. PMID- 29704096 TI - Letter to the Editor Regarding: Practical Treatment of Lewy Body Disease in the Clinic: Patient and Physician Perspectives. PMID- 29704095 TI - Pharmacokinetic Profiling of Butylidenephthalide and Alisol B in Danggui-Shaoyao San in Rats. AB - BACKGROUND AND OBJECTIVE: Danggui-Shaoyao-San (DSS), a famous Chinese formula, has been widely used to treat gynecological disorders since ancient times and has recently showed efficacy in treating Alzheimer's disease. Butylidenephthalide (BDPH) and alisol B (ALI) are recognized as the primary active ingredients of DSS. The objectives of the present study were to evaluate the pharmacokinetic comparative study of BDPH and ALI in herbal extracts and their purified forms. METHOD: A sensitive and specific high-performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) methodology was developed to determine the concentration level of BDPH and ALI in rat plasma. This approach enables a real time pharmacokinetics profiling of BDPH and ALI in DSS extracts as well as their purified forms in rats after oral administration. RESULTS: The validated method showed an evident linearity over a wide range of dosages (r > 0.99) with sensitivity down to 1.0 ng/mL for each analyte. The extraction recovery of the analyte ranged from 80.8 to 99.1%. The pharmacokinetic parameters were significantly different in herbal extracts and their purified forms. The results showed that the absorption of both BDPH and ALI from DSS extracts was significantly greater compared with their purified forms. CONCLUSIONS: A highly specific, sensitive and rapid HPLC-MS/MS method was developed and applied for the determination of BDPH and ALI in rat plasma. It was found that BDPH and ALI had higher bioavailability in the DSS extract compared with their purified forms. PMID- 29704097 TI - Editorial Regarding: Practical Treatment of Lewy Body Disease in the Clinic: Patient and Physician Perspectives. PMID- 29704098 TI - Author's Response to the Letter to the Editor Regarding: Practical Treatment of Lewy Body Disease in the Clinic: Patient and Physician Perspectives. PMID- 29704099 TI - Usefulness of scoring right ventricular function for assessment of prognostic factors in patients with chronic thromboembolic pulmonary hypertension. AB - Right ventricular (RV) function is associated with prognosis in chronic thromboembolic pulmonary hypertension (CTEPH). This study aimed to establish an RV dysfunction score using RV echocardiographic parameters to clarify the clinical characteristics in patients with CTEPH and to compare RV dysfunction score with parameters such as World Health Organization (WHO) functional class, hemodynamics, exercise capacity, and plasma BNP level. We enrolled 35 inpatients with CTEPH (mean age, 62 +/- 15 years, 15 males). We constructed 'an RV dysfunction score' calculated as the summation of each point awarded for the presence of four parameters: tricuspid annular plane systolic excursion (TAPSE) < 16 mm, 1 point; tissue Doppler-derived tricuspid lateral annular systolic velocity (S') < 10 cm/s, 1 point; right ventricular fractional area change (RVFAC) < 35%, 1 point; and right ventricular myocardial performance index (RV MPI) > 0.4, 1 point. TAPSE, S', RVFAC, and RV-MPI was 18.7 +/- 4.8 mm, 11.9 +/- 3.1 cm/s, 33.5 +/- 13.9%, and 0.39 +/- 0.2, respectively. The RV dysfunction score was associated with symptom [WHO functional class (p = 0.026)], hemodynamics [mean PAP (p = 0.01), cardiac index (p = 0.009), pulmonary vascular resistance (p = 0.001), and SvO2 (p = 0.039)], exercise capacity [6-min walk distance (p = 0.046), peakVO2 (p = 0.016), and VE/VCO2 slope (p = 0.031)], and plasma BNP level (p = 0.005). This RV dysfunction score using the four RV echocardiographic parameters could be a simple and useful scoring system to evaluate prognostic factors in patients with CTEPH. PMID- 29704100 TI - Downregulation of miR-34a promotes endothelial cell growth and suppresses apoptosis in atherosclerosis by regulating Bcl-2. AB - Several miRNAs have been demonstrated to be involved in endothelial dysfunction during atherosclerosis (AS). However, the detailed roles and underlying mechanisms of miR-34a in AS-associated endothelial cell apoptosis are far from being addressed. Apolipoprotein E-deficient (ApoE-/-) mice fed with high-fat diet (HFD) were used as in vivo model of AS. Oxidized low-density lipoprotein (ox-LDL) treated human aortic endothelial cells (HAECs) were applied as in vitro model of AS. The effects of miR-34a on atherosclerotic lesions were evaluated by hematoxylin-eosin (HE) and Oil Red O staining. Pecam-1+ endothelial cells were isolated from the aortic arch with flow cytometry. qRT-PCR and western blot were employed to measure gene and protein expression. The effects of miR-34a on cell viability, cell cycle distribution, and apoptosis were assessed by Cell counting kit (CCK)-8 and flow cytometry analysis. The relationship between miR-34a and Bcl 2 was confirmed by online softwares, luciferase reporter assay, and RNA immunoprecipitation (RIP). miR-34a was upregulated in HFD-induced ApoE-/- mice and ox-LDL-treated HAECs. Anti-miR-34a decreased atherosclerotic lesions and inhibited Pecam-1+ endothelial cells apoptosis in HFD-induced ApoE-/- mice. Moreover, anti-miR-34a significantly promoted cell viability, alleviated cell cycle arrest, and restrained apoptosis in ox-LDL-treated HAECs. Furthermore, Bcl 2 was identified as a target of miR-34a, and miR-34a inhibited Bcl-2 expression via binding to its 3'UTR. Rescue experiments demonstrated that Bcl-2 overexpression dramatically reversed miR-34a-mediated inhibition of cell growth and promotion of apoptosis in ox-LDL-exposed HAECs. Depletion of miR-34a facilitated endothelial cell growth and blocked apoptosis in AS by upregulating Bcl-2, offering a promising avenue for AS therapy. PMID- 29704101 TI - Clinical impact of thrombus aspiration on in-hospital mortality in each culprit lesion in the setting of ST-segment elevation myocardial infarction. AB - Recent randomized clinical trials have questioned the clinical benefits of thrombus aspiration (TA) in ST-segment elevation myocardial infarction (STEMI). Real-world data on TA and the efficacy of TA for various culprit lesions have not been sufficiently evaluated. This study mainly aimed to evaluate whether the clinical impact of TA depends on culprit lesions in the setting of STEMI. We surveyed the Tokyo Coronary Care Unit Network Registry, a prospective cohort study, between 2010 and 2014, which included 10,232 patients with STEMI. In hospital deaths occurred in 538 patients (5.3%). Improved Thrombolysis in Myocardial Infarction flow was more frequently observed in patients who underwent TA than in those who did not (87 vs. 80%; p < 0.001). Univariate logistic regression analysis revealed that TA was associated with a lower in-hospital mortality rate [odds ratio (OR), 0.80; 95% confidential interval (CI), 0.66-0.96; p = 0.016]. However, the difference was not significant after multivariate logistic regression analysis (OR 0.95; 95% CI 0.71-1.17; p = 0.355). Only TA for the left circumflex (LCx) lesions was associated with a better prognosis (OR 0.38; 95% CI 0.21-0.72; p = 0.003). The effect persisted after adjustment (OR 0.50; 95% CI 0.25-0.99; p = 0.049) but was attenuated after analysis using inverse probability weighting (OR 0.97; 95% CI 0.93-0.99; p = 0.048). On the basis of the findings in a large Japanese cohort, a prognostic benefit of TA on in-hospital mortality was not observed. The effect of TA on the LCx lesions was marginally significant and limited. Therefore, TA is not recommended in Japanese patients with STEMI. PMID- 29704103 TI - Minimally invasive bunionette correction. AB - OBJECTIVE: Bunionette or 'tailor's bunion' is a deformity of the fifth ray, which comes along with a metatarsus quintus valgus and a varus deformity of the fifth toe with subluxation of the metatarsophalangeal joint. A minimally invasive osteotomy of the fifth metatarsal without internal fixation using burrs is an increasingly used alternative for symptomatic tailor's bunion deformity. Similar to open surgery procedures the type of osteotomy complies with the underlying pathology. Minimally invasive surgical (MIS) procedures allow comprehensive treatment of various types of tailor's bunion deformities. INDICATIONS: Symptomatic tailor's bunion deformity, failed conservative treatment, a closed epiphyseal gap. CONTRAINDICATIONS: Osteoporotic bone, poor patient compliance. SURGICAL TECHNIQUE: The technique comprises percutaneous resection of the lateral exostosis of the fifth metatarsal head with a straight burr and an osteotomy of the fifth metatarsal, either distally, diaphyseal or proximally with a conical burr due to the shape of the deformity, usually without internal fixation. POSTOPERATIVE MANAGEMENT: Redressive wrapping, partial pain-adapted weight bearing. Non-steroidal anti-inflammatory drugs for 3-5 days, lymphatic drainage, intermittent cooling. Radiographic assessment on postoperative day 1; radiographic follow-up 6 weeks postoperatively. Thromboembolic prophylaxis. RESULTS: The clinical outcome is comparable to standard surgical procedures with the advantages of MIS. Based on our results and the current literature, the minimally invasive distal metatarsal osteotomy without fixation is becoming a reliable treatment for tailor's bunion. PMID- 29704102 TI - Diastolic dysfunction predicts the risk of contrast-induced nephropathy and outcome post-emergency percutaneous coronary intervention in AMI patients with preserved ejection fraction. AB - Patients with acute myocardial infarction (AMI) and reduced left ventricular ejection fraction (LVEF) are at high risk of contrast-induced nephropathy (CIN). However, the risk factors of CIN in AMI patients with preserved LVEF remain largely unknown now. The present study explored the relationship between LV diastolic function and CIN in this patient cohort. The present prospective cohort study enrolled 379 AMI patients with preserved LVEF (>= 50%) who underwent emergency percutaneous coronary interventions (PCI). Transthoracic echocardiography was performed before PCI using a portable echocardiography system. Diastolic function was graded as normal, indeterminate and diastolic dysfunction according to the current recommendation of the American Society of Echocardiography and the European Association of Cardiovascular Imaging. A total of 88 patients (23.2%) developed CIN. Multivariate logistic regression analysis showed that both diastolic dysfunction (DD) and the mitral E velocity to mitral annular tissue Doppler E' velocity ratio (E/E') were independent predictors of CIN (P < 0.001). Other independent risk factors of CIN included increased Mehran score, ST-segment-elevation myocardial infarction, higher HbA1c and left anterior descending lesion, as well as the use of diuretics. Multivariate Cox regression analysis found that CIN, DD, higher N-terminal pro-B-type natriuretic peptide and HbA1c were independent predictors of MACE 2 years after AMI. Diastolic dysfunction determined before emergency PCI is linked with increased risk of CIN in AMI patients with preserved LVEF. CIN and diastolic dysfunction are independent predictors of MACE at 2 years in this patient cohort. PMID- 29704104 TI - Total Endovascular Iliocaval Reconstruction Using Polytetrafluoroethylene Stent Graft Placement for the Treatment of Inferior Vena Cava Resection. AB - Resection of the inferior vena cava (IVC) is a rare surgical technique that is occasionally combined with nephrectomy in the setting of renal malignancy with intravascular tumor extension. While this may be fairly well tolerated in some patients due to extensive collateralization in the venous system, there is a clear potential for lower extremity venous insufficiency and deep vein thrombosis (DVT). This report describes a patient who underwent right nephrectomy and segmental IVC resection from the subhepatic space to the iliac confluence, which was complicated by profoundly symptomatic lower extremity DVT and gastrointestinal hemorrhage due to system-to-portal shunting. After performing sharp recanalization through the retroperitoneum, iliocaval reconstruction was accomplished utilizing covered stent-grafts, with complete resolution of symptoms.Level of Evidence Case Report, Level 5. PMID- 29704105 TI - Branched Thoraco-Abdominal Aortic Aneurysm Repair with Branch Access Through a Transapical Left Ventricular Approach. AB - Branched thoracic aortic aneurysm repair requires arterial access from above the diaphragm in order to insert the visceral branches. This is routinely performed from the subclavian, axillary or carotid arteries and less commonly direct thoracic aorta puncture. The left ventricular apex is an alternative access route which is commonly used for percutaneous aortic valve replacement and rarely used for EVAR, FEVAR and TEVAR access. Here we describe two patients for which the left ventricular apex was the most suitable available access to the visceral branches during a branched thoracic aortic aneurysm repair. This access should be considered as an alternative approach if conventional arterial access is not available. PMID- 29704106 TI - Applications of Mossbauer Spectroscopy in Biomedical Research. AB - A brief review on the applications of Mossbauer spectroscopy in biomedical research discusses the results of more than fifty years of experience in this field. Basing on the numerous results the main directions of biomedical applications of Mossbauer spectroscopy are considered as follows: 1) studies of the quantitative changes of iron-containing biomolecules related to pathological processes; 2) studies of the qualitative changes in iron-containing biomolecules related to pathological processes; 3) studies of the effect of various environmental factors (physical, chemical, and biological) on iron-containing biomolecules; 4) studies of metabolic processes by means of analysis of the Mossbauer nuclides pathways in organisms; 5) studies of dynamic processes; 6) studies of pharmaceutical compounds and blood substitutes containing Mossbauer nuclides; 7) miscellaneous studies. Some examples of biomedical research using 57Fe, 57Co, 119Sn, 153Sm, and 197Au Mossbauer nuclides are presented. PMID- 29704107 TI - Choosing the Allometric Exponent in Covariate Model Building. AB - BACKGROUND: Allometric scaling is often used to describe the covariate model linking total body weight (WT) to clearance (CL); however, there is no consensus on how to select its value. OBJECTIVES: The aims of this study were to assess the influence of between-subject variability (BSV) and study design on (1) the power to correctly select the exponent from a priori choices, and (2) the power to obtain unbiased exponent estimates. METHODS: The influence of WT distribution range (randomly sampled from the Third National Health and Nutrition Examination Survey, 1988-1994 [NHANES III] database), sample size (N = 10, 20, 50, 100, 200, 500, 1000 subjects), and BSV on CL (low 20%, normal 40%, high 60%) were assessed using stochastic simulation estimation. A priori exponent values used for the simulations were 0.67, 0.75, and 1, respectively. RESULTS: For normal to high BSV drugs, it is almost impossible to correctly select the exponent from an a priori set of exponents, i.e. 1 vs. 0.75, 1 vs. 0.67, or 0.75 vs. 0.67 in regular studies involving < 200 adult participants. On the other hand, such regular study designs are sufficient to appropriately estimate the exponent. However, regular studies with < 100 patients risk potential bias in estimating the exponent. CONCLUSION: Those study designs with limited sample size and narrow range of WT (e.g. < 100 adult participants) potentially risk either selection of a false value or yielding a biased estimate of the allometric exponent; however, such bias is only relevant in cases of extrapolating the value of CL outside the studied population, e.g. analysis of a study of adults that is used to extrapolate to children. PMID- 29704108 TI - Can early palliative care with anticancer treatment improve overall survival and patient-related outcomes in advanced lung cancer patients? A review of the literature. AB - PURPOSE: Metastatic non-small-cell lung cancer (NSCLC), the leading cause of death from cancer worldwide, is a debilitating disease that results in a high burden of symptoms and poor quality of life; the estimated prognosis after the diagnosis has been established was less than 1 year until some years ago. At the present, the new targeted therapies and immunotherapy are changing the course of the disease. However, advanced NSCLC remains an incurable disease, with a poor prognosis for the majority of the affected patients, so that quality of life and relief from symptoms are primary objectives of treatment. Some evidences suggest that early palliative care (EPC) for these patients can improve quality of life and even survival. DESIGN: A systematic review of the studies evaluating the impact on objective and on patient-reported outcomes of the introduction of EPC in opposition to standard care (SC), for advanced lung cancer patients, was performed. Because of the small number of studies conducted in this area, retrospective studies were also considered for the review. RESULTS: Five studies were included because they matched the inclusion criteria previously defined as relevant for the study. The review found that both survival and quality of life were better for patients included in EPC groups. CONCLUSIONS: While results of the studies included in this review are not always comparable because different methods and scales have been used, there is enough evidence for clinical oncologists to implement the use of EPC in clinical practice for advanced lung cancer patients. PMID- 29704109 TI - Out-of-pocket expenses experienced by rural Western Australians diagnosed with cancer. AB - PURPOSE: Out-of-pocket expenses (OOPE) can have a significant impact on patients' experiences of cancer treatment. This cross-sectional study sought to quantify the OOPEs experienced by rural cancer patients in Western Australia (WA), and determine factors that contributed to higher OOPE. METHODS: Four hundred people diagnosed with breast, lung, colorectal or prostate cancer who resided in selected rural regions of WA were recruited through the WA Cancer Registry and contacted at least 3 months after diagnosis to report the medical OOPE (such as surgery or chemotherapy, supportive care, medication and tests) and non-medical OOPE (such as travel costs, new clothing and utilities) they had experienced as a result of accessing and receiving treatment. Bootstrapped t tests identified demographic, financial and treatment-related factors to include in multivariate analysis, performed using log-linked generalised linear models with gamma distribution. RESULTS: After a median 21 weeks post-diagnosis, participants experienced an average OOPE of AU$2179 (bootstrapped 95% confidence interval $1873-$2518), and 45 (11%) spent more than 10% of their household income on these expenses. Participants likely to experience higher total OOPE were younger than 65 years (p = 0.008), resided outside the South West region (p = 0.007) and had private health insurance (PHI) (p < 0.001). CONCLUSIONS: Rural WA cancer patients experience significant OOPE following their diagnosis. The impact these expenses have on patient wellbeing and their treatment decisions need to be further explored. PMID- 29704110 TI - Systematic review and meta-analysis investigating the efficacy and safety of probiotics in people with cancer. AB - BACKGROUND/OBJECTIVES: Probiotics are living microorganisms that confer a health benefit on the host when administered. This systematic review and meta-analysis investigates the efficacy and safety of probiotics in adult and paediatric patients diagnosed with cancer. METHODS: A systematic review and meta-analysis was undertaken (PROSPERO registration: CRD42016050252). Randomised controlled trials (RCT), identified through screening multiple databases were included for analysis of efficacy. Non-randomised controlled trials and case reports were included for safety analysis. Outcomes included the reduction in the incidence and severity of diarrhoea, and adverse events. Where possible, data were combined for meta-analysis using a random-effects model. Planned subgroup analyses were not possible through marked heterogeneity of study characteristics. RESULTS: Twenty one studies (N = 2982 participants) were included for assessment of efficacy. Probiotics may reduce the incidence of diarrhoea in patients with cancer [odds ratio (OR) = 0.52, 95% confidence interval (CI) 0.34-0.78, 95% prediction interval (PI) 0.3-0.92, I-sq 36.9%, 5 studies] and the duration of pyrexia [standardised mean difference 0.39 days, 95% CI 0.35-0.43, I-sq 0.01%, 5 studies]. Twenty five studies (N = 2242) were included in the safety analysis. Five case reports showed probiotic-related bacteraemia/fungaemia/positive blood cultures. Definitions and reporting of adverse events were variable and inconsistent. CONCLUSIONS: There remain insufficient studies to assess the true effect of probiotics in people with cancer. Meta-analysis suggests probiotics may be beneficial but further studies are still required. Improved reporting of outcomes and adverse events in clinical trials are required to improve accuracy and confidence of conclusions drawn in future updates. PMID- 29704112 TI - In memoriam Hans Heinrich Passler 1940-2018. PMID- 29704111 TI - Chemosensory changes and quality of life in patients undergoing hematopoietic stem cell transplantation. AB - PURPOSE: To assess magnitude and characteristics of changes in chemosensory function and quality of life (QOL) for patients receiving hematopoietic stem cell transplantation (HSCT). METHODS: Patients (aged 18 years and above) scheduled to undergo HSCT at the Seattle Cancer Care Alliance were tested for chemosensory function at three time points: pre-transplant (baseline), 30 +/- 5 days (day 30), and 80 +/- 5 days (day 80) post-HSCT. Gustatory function was assessed following procedures developed at the Monell-Jefferson Taste and Smell Clinic. Olfactory testing was conducted using the National Institute of Health Toolbox Odor Identification test. QOL was also assessed. RESULTS: Twenty-nine patients were enrolled in the study between August 2014 and March 2015. Twenty-three patients were included in the analysis, with 16 tested at all three time points (baseline, day 30, and day 80). The primary finding is decreased taste sensitivity for 0.32 M NaCl, 0.0056 M citric acid, and 0.018 M citric acid on day 30 following HSCT. Increased taste sensitivity for 0.32 M sucrose at day 30 was also observed. Taste sensitivity largely recovered by day 80. Olfactory identification scores were unchanged from baseline to day 30. QOL was reduced at day 30 but was restored to an acceptable level of functioning and symptoms by day 80. However, some areas remain impaired. CONCLUSIONS: Alterations in taste perception were confirmed in the early post-transplant period. This was largely resolved within 2.5 months. No obvious impairments were observed in olfactory function. QOL improved by day 80, though some oral symptoms lingered. PMID- 29704113 TI - Repair of the lateral posterior meniscal root improves stability in an ACL deficient knee. AB - PURPOSE: To investigate the stabilizing effect of a lateral meniscus posterior root repair in an ACL and root deficient knee. METHODS: The hypothesis of the current study was that a sequential transection of the posterior root and the meniscofemoral ligaments in an ACL-deficient knee increases rotational instability, and conversely, a repair of the meniscus root reduces the internal tibial rotation. Therefore, eight human knee joints were tested in a robotic setup (5 N m internal torque, 50 N m anterior translation load). Five conditions were tested: intact, ACL cut, ACL cut + lateral meniscus posterior root tear (LMRT), ACL cut + LMRT + transection of the MFL and ACL cut + lateral meniscus root repair. The angles of internal tibial rotation as well as anterior tibial translation were recorded. RESULTS: Transection of the lateral meniscus posterior root increased the internal tibial instability as compared to the ACL insufficient state. A significant increase was detected in 60 degrees and 90 degrees of flextion. Sectioning of the meniscofemoral ligament further destabilized the knees significantly at all flexion angles as compared to the ACL deficient state. Even in 30 degrees , 60 degrees and 90 degrees a significant difference was detected as compared to the isolated root tear. A tibial fixation of the lateral meniscus root reduced the internal tibial rotation in all flexion angles and led to a significant decrease of internal tibial rotation in 30 degrees and 90 degrees as compared to the transection of the root and the MFL. The anterior tibial translation was increased in all conditions as compared to the native state. CONCLUSION: A lateral meniscus root repair can reduce internal tibial rotation in the ACL-deficient knee. To check the condition of the lateral posterior meniscus root attachment is clinical relevant as a lateral meniscus root repair might improve rotational stability. PMID- 29704114 TI - Ankle strength is not strongly associated with postural stability in patients awaiting surgery for chronic lateral ankle instability. AB - PURPOSE: (1) To describe ankle strength and postural stability in patients with chronic lateral ankle instability and (2) to analyse the correlation between deficits in ankle strength and postural stability. METHODS: Results of preoperative isokinetic and balance tests in 203 patients whose contralateral ankle was normal were retrospectively reviewed. Isokinetic peak torque values of eversion and inversion at 2 angular velocities (30 degrees /s and 120 degrees /s) were measured in the injured and normal ankles. In the balance test, the percent differences of 3 actual scores (overall, anterior-posterior, and medial-lateral) between the injured and normal ankles were calculated. Additional statistical analyses were performed to evaluate weakness of ankle strength, postural stability deficits, and their correlation. RESULTS: Significant differences in 4 peak torque values and 4 relative peak torque values (peak torque/body weight) were found between the injured and normal ankles. All 8 values were significantly lower in the injured ankles. Weakness was severe during inversion and at 30 degrees /s. In the balance test, 49 subjects (24.1%) had significant deficits in postural stability and 109 (53.7%) had favourable results. No strong association was found between weakness of ankle strength and deficits in postural stability. CONCLUSIONS: Strength measurement alone is insufficient to evaluate preoperative functional deficits, and other functional tests are required to measure postural stability. The results of this study provide further evidence for a rehabilitation programme consisting of proprioceptive training as well as strengthening. The proprioceptive training must be an integral part of the rehabilitation programme in addition to strengthening exercise. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 29704116 TI - Protocols for Full Thickness Skin Wound Repair Using Prevascularized Human Mesenchymal Stem Cell Sheet. AB - Split thickness skin grafts (STSGs) are one of the standard treatments available for full thickness wound repair when full thickness grafts (FTGs) are not viable, such as in the case of wounds with large surface areas. The donor sites of STSGs may be harvested repeatedly, but STSG transplants are still limited by insufficient blood supply at the early stages of wound healing. Prevascularized human mesenchymal stem cell (hMSC) sheets may accelerate wound healing and improve regeneration by providing preformed vessel structures and angiogenic factors to overcome this limitation. This book chapter provides the protocol of co-culturing hMSCs and endothelial cells to attain a prevascularized hMSC cell sheet (PHCS). The protocols for implantation of the prevascularized stem cell sheet for full thickness skin wound repair in a rat autologous skin graft model as well as the evaluation of the wound healing effects are also provided. PMID- 29704115 TI - BDNF/TrkB Pathway Mediates the Antidepressant-Like Role of H2S in CUMS-Exposed Rats by Inhibition of Hippocampal ER Stress. AB - Our previous works have shown that hydrogen sulfide (H2S) significantly attenuates chronic unpredictable mild stress (CUMS)-induced depressive-like behaviors and hippocampal endoplasmic reticulum (ER) stress. Brain-derived neurotrophic factor (BDNF) generates an antidepressant-like effect by its receptor tyrosine protein kinase B (TrkB). We have previously found that H2S upregulates the expressions of BDNF and p-TrkB in the hippocampus of CUMS-exposed rats. Therefore, the present work was to explore whether BDNF/TrkB pathway mediates the antidepressant-like role of H2S by blocking hippocampal ER stress. We found that treatment with K252a (an inhibitor of BDNF/TrkB pathway) significantly increased the immobility time in the forced swim test and tail suspension test and increased the latency to feed in the novelty-suppressed feeding test in the rats cotreated with sodium hydrosulfide (NaHS, a donor of H2S) and CUMS. Similarly, K252a reversed the protective effect of NaHS against CUMS-induced hippocampal ER stress, as evidenced by increases in the levels of ER stress-related proteins, glucose-regulated protein 78, CCAAT/enhancer binding protein homologous protein and cleaved caspase-12. Taken together, our results suggest that BDNF/TrkB pathway plays an important mediatory role in the antidepressant-like action of H2S in CUMS-exposed rats, which is by suppression of hippocampal ER stress. These data provide a novel mechanism underlying the protection of H2S against CUMS-induced depressive-like behaviors. PMID- 29704117 TI - Regeneration of Mouse Skin Melanocyte Stem Cells In Vivo and In Vitro. AB - Coordinated regeneration of melanocyte stem cells (McSCs) and hair follicle stem cells (HSCs) contributes to generation of pigmented hairs. Synchronous regeneration of McSCs with activation of HSCs occurs not only during initiation of a new hair cycle in vivo but also during reconstitution of hair follicles in vitro. The duration of the quiescent state of these stem cells becomes longer and longer in lifespan of mammals, leading to a decreased regenerative ability to form hair follicles. Here, we describe methods to activate McSCs during hair follicle regeneration in vivo, and isolate melanocytes from neonatal mouse skin to generate an immortalized cell line of melanocyte progenitors in vitro, aiming to use them for studying melanogenesis and future clinical application. PMID- 29704118 TI - Insights uncovered from experiencing a rise in the incidence of gestational diabetes at a Melbourne hospital. PMID- 29704119 TI - Investigation of rubidium(I) ion solvation in liquid ammonia using QMCF-MD simulation and NBO analysis of first solvation shell structure. AB - Rb(I) ion solvation in liquid ammonia has been studied by an ab initio quantum mechanical charge field molecular dynamics simulation, and the first solvation shell structure has been analyzed using natural bond orbital. The simulation was performed for an ion and 593 ammonia molecules in a box with a length of 29.03 A corresponding to a liquid ammonia density of 0.69 g/mL at 235.16 K. The quantum mechanical calculation was carried out for atomic interactions in the radius of 6.4 A from the ion using LANL2DZ ECP and DZP (Dunning) basis sets for Rb(I) ion and ammonia respectively. The trajectories of the simulation were analyzed in terms of radial, angular, and coordination number distribution functions, vibration, and mean residence time (MRT). Two solvation shell regions are observed for the Rb(I)-N as well as the Rb(I)-H. The maximum distance of Rb(I)-N in the first solvation shell is in accordance with experimental data where a coordination number of 8 is favorable. A non-single coordination number of the first and second shell indicates dynamic solvation structure. It is confirmed by frequent exchange ligand processes observed within a simulation time of 15 ps. The low stabilization energy of donor acceptor ion-ligand interaction with a small Wiberg bond index affirms that the Rb(I)-NH3 interaction is weak electrostatically. PMID- 29704120 TI - Metazoan parasites of Micropterus salmoides (Lacepede 1802) (Perciformes, Centrarchidae): a review with evidences of spillover and spillback. AB - Among the topics related to invasion science, the least studied are parasite co introduction and spillback. This leads to an uncertainty in invasion ecology theories and applications to management. Therefore, the present study brings a systematic review of published information on the metazoan parasite fauna of Micropterus salmoides, a widely introduced fish, with the aim of comparing information about the composition and richness of the associated parasite communities in its native and introduced regions. This review demonstrates that there were twice as many studies of M. salmoides in its native region in comparison with introduced regions, although most of the studies focused on the analysis of a single species or taxon of parasite. This bias impacts the number of parasite species observed and, consequently, the apparent importance of enemy release in introduced regions. The composition of the parasite community in the two regions showed high similarity, which indicates the introduction and acquisition of parasites in introduced regions. Otherwise, there was no pattern related to the geographic distance, highlighting the influence of the propagule pressure and vector strength on the introduction of novel parasites. This illustrates the importance of vector strength on fish-parasite co-introduction and the necessity of new research examining host-parasite interactions with the parasite community of the invaded ecosystems. We still do not know the major influences of the composition of the parasite fauna of M. salmoides or how we can manage to develop a more restrictive vector pathway of introduction. The future of our ecosystems depends on how to account for current and future interactions among novel interactions, habitat, and climate change. PMID- 29704121 TI - Immunodetection of hepatic stellate cells in dogs with visceral leishmaniasis. AB - Hepatic stellate cells (HSC), or Ito cells, store vitamin A when at rest but undergo phenotypic changes in situations of liver injury, which may induce fibrosis, and they may participate in the immune response in the liver. The objective of the present study was to investigate the role of HSC in the livers of dogs with visceral leishmaniasis (VL). Twenty-eight livers from dogs infected with VL that were living in an area endemic for the disease were evaluated, among which 13 were asymptomatic (A) and 15 were symptomatic (S). A control group (C) was formed by five dogs from an area that was not endemic for VL. These organs were subjected to histopathological analysis (Masson's trichrome for fibrosis) and immunohistochemical analysis (Leishmania, smooth-muscle alpha-actin and TGF beta). In the livers from the symptomatic dogs, a moderate to severe granulomatous inflammatory reaction was observed in the capsule and in the portal, centrilobular and intralobular regions. In the asymptomatic dogs, there was slight to moderate presence of granulomas, and these were even absent in some dogs. The intensity of hepatic fibrosis was predominantly low in the infected dogs (A and S), and fibrosis was absent in the control group. The immunomarking of HSC in the infected groups (A and S) differed significantly (P = 0.0153) from that of the control group. The symptomatic dogs presented the largest number of positive cells. This group also presented a larger number of parasitized macrophages, but did not differ statistically from the asymptomatic group (P > 0.05). The cytokine TGF-beta was only detected at low levels, and only in the infected animals, but this did not differ from the control group. Immunomarking for HSC was observed mainly in the nuclei of cells present in the hepatic granulomas of symptomatic dogs and in the sinusoids of the asymptomatic dogs. It was concluded that in the livers of dogs with VL, the HSC are activated and participate in the hepatic response to the parasite. The cytokine TGF-beta may be involved in this activation, but in the chronic phase of the infection, this cytokine was detected at lower proportions. It is possible that HSC may also contribute towards chemotaxis of leukocytes for the hepatic compartment, along with other cell types such as Kupffer cells. PMID- 29704122 TI - Vasospasm-related complications after subarachnoid hemorrhage: the role of patients' age and sex. AB - BACKGROUND: Outcome of aneurysmal subarachnoid hemorrhage (SAH) depends strongly on occurrence of symptomatic vasospasm (SV) leading to delayed cerebral ischemia (DCI). Various demographic, radiographic, and clinical predictors of SV have been reported so far, partially with conflicting results. The aim of this study was to analyze the role of patients' age and sex on SV/DCI risk, especially to identify age and sex-specific risk groups. METHODS: All patients admitted with acute SAH during a 14-year-period ending in 2016 were eligible for this study. The study endpoints were the following: SV requiring spasmolysis, occurrence of DCI in follow-up computed tomography scans and unfavorable outcome at 6 months (modified Rankin scale > 2). RESULTS: Nine hundred ninety-four patients were included in this study. The majority was female (666; 67%). SV, DCI, and unfavorable outcomes were observed in 21.5, 21.8, and 43.6% of the patients, respectively. Younger age (p < 0.001; OR = 1.03 per year decrease) and female sex (p = 0.025; OR = 1.510) were confirmed as independent predictors of SV. Regarding the sex differences, there were three age groups for SV/DCI risk <= 54, 55-74, and >= 75 years. Male patients showed earlier decrease in SV risk (at >= 55 vs. >= 75 years in females). Therefore, SAH females aged between 55 and 74 years were at the highest risk for DCI and unfavorable outcome, as compared to younger/older females (p = 0.001, OR = 1.77/p = 0.001, OR = 1.80). In contrast, their male counterparts did not show these risk alterations (p = 0.445/p = 0.822). CONCLUSION: After acute SAH, female and male patients seem to show different age patterns for the risk of SV and DCI. Females aged between 55 and 74 years are at particular risk of vasospasm-related SAH complications, possibly due to onset of menopause. CLINICAL TRIAL REGISTRATION NUMBER: DRKS, Unique identifier: DRKS00008749. PMID- 29704123 TI - Specific features of colorectal cancer in patients with metabolic syndrome: a matched case-control analysis of 772 patients. AB - PURPOSE: Although association between colorectal cancer (CRC) and metabolic syndrome (MetS) is established, specific features of CRC arising in patients presenting with MetS have not been clearly identified. METHOD: All patients who underwent colectomy for CRC from January 2005 to December 2014 at Institut Mutualiste Montsouris were identified from a prospectively collected database and characteristics were compared in the entire population and in a 1:2 matched case control analysis [variables on which matching was performed were CRC localization (right- or left-sided) and AJCC stage (0 to IV)]. RESULTS: Out of the 772 identified patients, 98 (12.7%) presented with MetS. Entire population analysis revealed that CRC associated with MetS was more frequent in men (71.4 vs. 47.8%, p < 0.001), more often right-sided (71.4 vs. 50.4%, p < 0.001) and presented with less synchronous liver metastasis (4.1 vs. 8.7%, p = 0.002). Case-control analysis confirmed the gender association (p < 0.001) and showed HNPCC (p < 0.001) and history family of CRC (p = 0.010) to be significantly more frequent in Non-MetS patients. CONCLUSIONS: CRC associated with MetS is more frequent in men, more often right-sided, and presents with fewer synchronous metastasis. Further investigations should be designed in order to confirm these results and to enhance our knowledge of carcinogenesis related to MetS. PMID- 29704124 TI - Growth and Cell Properties of Modified Lactobacillus plantarum CICC21001 with Supplementing C18-FFAs to Growth Medium in vitro. AB - Fatty acids (FAs) are one of the important factors that can influence cell growth and membrane composition. The aim of this study was to investigate the influence of supplementing MLM+ growth medium with C18 free fatty acids (C18-FFAs), including stearic (C18:0), oleic (C18:1), linoleic (C18:2), and linolenic (C18:3) acid, on the growth of Lactobacillus plantarum CICC21001 by forming ion pairs with lysine to increase the solubility of FAs in liquid medium. The utilization of C18-FFAs was further confirmed by GC-FID. The investigation of cell properties, including cell surface hydrophobicity and zeta potential, was carried out for the modified L. plantarum and control group (non-supplementation). Furthermore, cell survival was measured in real time under heat (at 55 and 62 degrees C for 5 min), acid (pH 2.2), and bile salt stress. Our results indicated that the action of L. plantarum was modulated by assimilating C18-FFAs. This study suggested that C18-FFAs altered the life cycles and physiochemical properties of L. plantarum, which provided a guideline for probiotics production and their medical application. PMID- 29704125 TI - Enlargement of sacral subcutaneous meningocele associated with retained medullary cord. AB - BACKGROUND: A retained medullary cord (RMC) is a rare closed spinal dysraphism with a robust elongated neural structure continuous from the conus and extending to the dural cul-de-sac. Four cases of RMC extending down to the base of an associated subcutaneous meningocele at the sacral level have been reported. CLINICAL PRESENTATION: We report an additional case of RMC, in whom serial MRI examination revealed an enlargement of the meningocele associated with RMC over a 3-month period between 8 and 11 months of age, when he began to stand. At the age of 12 months, untethering of the cord was performed. Histologically, the presence of ependyma-lined central canals in the dense neuroglial cores was noted in all cord-like structures in the intradural and intrameningocele sacs and at the attachment to the meningocele. CONCLUSION: It is conceivable that the hydrodynamic pressure with standing position and the check valve phenomenon were involved in meningocele enlargement. We should be mindful of these potential morphological changes. PMID- 29704126 TI - Dermal white adipose tissue undergoes major morphological changes during the spontaneous and induced murine hair follicle cycling: a reappraisal. AB - In murine skin, dermal white adipose tissue (DWAT) undergoes major changes in thickness in synchrony with the hair cycle (HC); however, the underlying mechanisms remain unclear. We sought to elucidate whether increased DWAT thickness during anagen is mediated by adipocyte hypertrophy or adipogenesis, and whether lipolysis or apoptosis can explain the decreased DWAT thickness during catagen. In addition, we compared HC-associated DWAT changes between spontaneous and depilation-induced hair follicle (HF) cycling to distinguish between spontaneous and HF trauma-induced events. We show that HC-dependent DWAT remodelling is not an artefact caused by fluctuations in HF down-growth, and that dermal adipocyte (DA) proliferation and hypertrophy are HC-dependent, while classical DA apoptosis is absent. However, none of these changes plausibly accounts for HC-dependent oscillations in DWAT thickness. Contrary to previous studies, in vivo BODIPY uptake suggests that increased DWAT thickness during anagen occurs via hypertrophy rather than hyperplasia. From immunohistomorphometry, DWAT thickness likely undergoes thinning during catagen by lipolysis. Hence, we postulate that progressive, lipogenesis-driven DA hypertrophy followed by dynamic switches between lipogenesis and lipolysis underlie DWAT fluctuations in the spontaneous HC, and dismiss apoptosis as a mechanism of DWAT reduction. Moreover, the depilation-induced HC displays increased DWAT thickness, area, and DA number, but decreased DA volume/area compared to the spontaneous HC. Thus, DWAT shows additional, novel HF wounding related responses during the induced HC. This systematic reappraisal provides important pointers for subsequent functional and mechanistic studies, and introduces the depilation-induced murine HC as a model for dissecting HF-DWAT interactions under conditions of wounding/stress. PMID- 29704127 TI - Correlation between femoral offset loss and dynamic hip screw cut-out complications after pertrochanteric fractures: a case-control study. AB - BACKGROUND: Screw-plates disassembly incidence after pertrochanteric fracture (PF) amounts to 1 and 16% among the elderly population. The main occurrence is early cervical screw cut-out. The population at highest risk of disassembly remains difficult to identify. The correlation between femoral offset loss and disassembly occurrence has never been surveyed. OBJECTIVES: A radiological prognosis score for screw plate disassembly was defined to reflect trochanteric impaction (TI); it was based on a femoral offset ratio. STUDY DESIGN AND METHODS: Our single-centre retrospective case-control study surveyed patients suffering from Dynamic Hip Screw (DHS, Synthes(r)) disassembly following osteosynthesis of non-pathological osteoporotic PF between 2004 and 2014. All cases were categorised by age and gender and paired to three patients in the control group. The primary endpoint was TI measurement, corresponding to offset loss on the operated hip compared to healthy hip offset and expressed as a percentage. The measurement was done on an immediate postoperative X-ray. The secondary endpoints were tip apex distance (TAD) measurement, Ender and AO classifications, as well as postoperative weight-bearing prescription. RESULTS: Twenty-three cases and 69 controls were surveyed. The case group's average age was 87; 70% of the cases were women. The main disassembly occurrence delay was after 27 days. Average TI was 26% within the patients global group and 12% within the control group (p < 10 5). Over a 21% impaction percentage, disassembly occurrence represents a greater risk: OR = 21.95% CI [5.4-104.3], p < 10-5. Ender 3 type fractures were the most frequent indication for surgery within the case group. Average TAD was 20 mm within the case group, and 17 mm within the control group (p = 0.03). The weight bearing prescription rate was 52% within the control group and 21% within the case group (p = 0.014). 14.5% of the control group had a TI > 21%. CONCLUSIONS: Using the offset ratio tool, TI measurement was associated with a greater risk of DHS disassembly when it was higher than 21%. The exclusive use of a DHS device does not seem optimal for a TI > 21%. Weight-bearing may be prescribed for all the patients with a TI < 21%, provided good implant positioning is secured. PMID- 29704128 TI - Prompting with electronic checklist improves clinician performance in medical emergencies: a high-fidelity simulation study. AB - BACKGROUND: Inefficient processes of care delivery during acute resuscitation can compromise the "Golden Hour," the time when quick interventions can rapidly determine the course of the patient's outcome. Checklists have been shown to be an effective tool for standardizing care models. We developed a novel electronic tool, the Checklist for Early Recognition and Treatment of Acute Illness (CERTAIN) to facilitate standardized evaluation and treatment approach for acutely decompensating patients. The checklist was enforced by the use of a "prompter," a team member separate from the leader who records and reviews pertinent CERTAIN algorithms and verbalizes these to the team. Our hypothesis was that the CERTAIN model, with the use of the tool and a prompter, can improve clinician performance and satisfaction in the evaluation of acute decompensating patients in a simulated environment. METHODS: Volunteer clinicians with valid adult cardiac life support (ACLS) certification were invited to test the CERTAIN model in a high-fidelity simulation center. The first session was used to establish a baseline evaluation in a standard clinical resuscitation scenario. Each subject then underwent online training before returning to a simulation center for a live didactic lecture, software knowledge assessment, and practice scenarios. Each subject was then evaluated on a scenario with a similar content to the baseline. All subjects took a post-experience satisfaction survey. Video recordings of the pre-and post-test sessions were evaluated using a validated method by two blinded reviewers. RESULTS: Eighteen clinicians completed baseline and post-education sessions. CERTAIN prompting was associated with reduced omissions of critical tasks (46 to 32%, p < 0.01) and 12 out of 14 general assessment tasks were completed in a more timely manner. The post-test survey indicated that 72% subjects felt better prepared during an emergency scenario using the CERTAIN model and 85% would want to be treated with the CERTAIN if they were critically ill. CONCLUSION: Prompting with electronic checklist improves clinicians' performance and satisfaction when dealing with medical emergencies in high-fidelity simulation environment. PMID- 29704130 TI - Recurrent corneal erosion caused by retained sutures in blepharoplasty. AB - PURPOSE: To present recurrent corneal erosion (RCE) caused by late suture exposure after blepharoplasty. METHODS: Four patients who have unilateral RCE were found to have previous blepharoplasty. The RCE was associated with late suture exposure. The clinical courses, characteristics, methods to identify the suture exposure and treatment were presented. RESULTS: The clinical presentations including local erosion of upper bulbar conjunctiva, corneal abrasion lines, local corneal epithelial defects with rough border, and subepithelial opacity were noticed in all four patients. RCE symptoms exaggerated in eye blinking and did not respond to artificial tears treatment. Erosion recurred soon after the removal of therapeutic contact lenses. They underwent blepharoplasty 1-10 years before RCE emerged, and the RCE lasted 1-8 months before suture exposure was found. RCE healed within 1 week after suture removal. CONCLUSIONS: Suture exposure may occur several years after blepharoplasty and could cause RCE. Thorough exploration of the fornix by double eyelid eversion can identify the hidden sutures in such patients. PMID- 29704129 TI - Integrative Pharmacology: Advancing Development of Effective Immunotherapies. AB - With the recent advances in cancer immunotherapy, it is now evident that the antigen-specific activation of the patients' immune responses can be utilized for achieving significant therapeutic benefits. Novel molecules have been developed and promising advances have been achieved in cancer therapy. The recent success of cancer immunotherapy clearly reflects the novelty of the approach and importance of this class of therapeutics. Due to the nature of immunotherapy, i.e., harnessing the patient's immune system, it becomes critical to evaluate the important variables that can guide preclinical development, translational strategies, patient selection, and effective clinical dosing paradigms following single and combination therapies. To further boost the durability and efficacy profiles of IO (immuno-oncology) drugs following single agent therapy, novel combination therapies are being sought. Combination strategies have become critical for enhancing the anti-tumor immunity in broader cancer indications. Comprehensive methods are being developed to quantify the synergistic combination effect profiles at various development phases. Further evaluation of the signaling and pathway components can potentially establish a unique "signature" characteristic for specific combination therapies following modulation of various immunomodulatory pathways. In this article, critical topics related to preclinical, translational, and clinical development of IO agents are discussed. PMID- 29704131 TI - Factors influencing stereopsis in patients with both refractive accommodative esotropia and amblyopia. AB - PURPOSE: Potential factors influencing stereopsis were investigated in patients with both refractive accommodative esotropia (RAE) and amblyopia. MATERIALS AND METHODS: A retrospective chart review was performed to find out all patients with the diagnosis of both RAE and amblyopia. Patients are classified into two groups: group 1 (with stereopsis) and group 2 (without stereopsis). Onset age of RAE, history of strabismus in family members, time of amblyopia treatment, mean spherical equivalent, anisometropia, ocular movement disorders, especially, overaction of inferior oblique (IO) muscle, visual acuity difference (VAD) between eyes, best-corrected visual acuity (BCVA) levels of amblyopic and normal eyes and the presence of alternation of fixation (AOF) were investigated as possible factors. These factors were compared statistically between groups. RESULTS: Groups 1 and 2 consisted of 21 and 26 patients, respectively. There was no statistical significant difference in terms of onset age of RAE, family history, amblyopia treatment, BCVA of normal eyes and anisometropia. IO overaction and higher VAD were found to be statistically different between groups (p: 0.019, p: 0.022, respectively). Besides, there was significant difference in terms of AOF and better BCVA in amblyopic eyes (p: 0.000, p: 0.009, respectively). CONCLUSION: IO overaction, BCVA in amblyopic eyes, VAD and AOF were found to be potential risk factors for the development of stereopsis in patients with both RAE and amblyopia. PMID- 29704132 TI - Hook and flip technique: for phacoemulsification in non-rotating nuclei and posterior polar cataracts. AB - PURPOSE: We put forward a physical levitation method to hook and flip the chopped nuclear fragments that could not be solely drawn by vacuum during phacoemulsification, due to various reasons such as a non-rotating nuclei or posterior polar cataracts where hydrodissection was unsuccessful or contra indicated, respectively. METHOD: A Sinskey hook is insinuated through the crack of the divided nuclei into a plane behind the nuclear pie to 'hook and flip' the chopped piece, heading it towards the phacoemulsification probe. This simple step disassembles the nuclear chunk, thereby creating space to facilitate the dismantling of the rest of the fragments. The remnant epinuclear cushion guards the posterior capsule, mitigating the chances of serious intra-operative complications. RESULT: We have employed this technique in 17 eyes during similar situations. No specific intra-operative complications were observed; all surgeries were uneventful. A Sinskey hook utilised for this step ensures safety and familiarity, none encountered posterior capsular rent. This technique not only eases the surgery, but also decreases the anticipated intra-operative and post-operative complications. CONCLUSION: 'Hook and flip technique' thus proves useful whenever dismantling difficulties are encountered during phacoemulsification. PMID- 29704137 TI - Bonding to new CAD/CAM resin composites: influence of air abrasion and conditioning agents as pretreatment strategy. AB - OBJECTIVES: Because of their industrially standardized process of manufacturing, CAD/CAM resin composites show a high degree of conversion, making a reliable bond difficult to achieve. PURPOSE: The purpose of this experiment was to investigate the tensile bond strength (TBS) of luting composite to CAD/CAM resin composite materials as influenced by air abrasion and pretreatment strategies. MATERIAL AND METHODS: The treatment factors of the present study were (1) brand of the CAD/CAM resin composite (Brilliant Crios [Coltene/Whaledent], Cerasmart [GC Europe], Shofu Block HC [Shofu], and Lava Ultimate [3M]); (2) air abrasion vs. no air abrasion; and (3) pretreatment using a silane primer (Clearfil Ceramic Primer, Kuraray) vs. a resin primer (One Coat 7 Universal, Coltene/Whaledent). Subsequently, luting composite (DuoCem, Coltene/Whaledent) was polymerized onto the substrate surface using a mold. For each combination of the levels of the three treatment factors (4 (materials) * 2 (air abrasion vs. no air abrasion; resin) * 2 (primer vs. silane primer)), n = 15, specimens were prepared. After 24 h of water storage at 37 degrees C and 5000 thermo-cycles (5/55 degrees C), TBS was measured and failure types were examined. The resulting data was analyzed using Kaplan-Meier estimates of the cumulative failure distribution function with Breslow-Gehan tests and non-parametric ANOVA (Kruskal-Wallis test) followed by the multiple pairwise Mann-Whitney U test with alpha-error adjustment using the Benjamini-Hochberg procedure and chi-square test (p < 0.05). RESULTS: The additional air abrasion step increased TBS values and lowered failure rates. Specimens pretreated using a resin primer showed significantly higher TBS and lower failure rates than those pretreated using a silane primer. The highest failure rates were observed for groups pretreated with a silane primer. Within the Shofu Block HC group, all specimens without air abrasion and pretreatment with a silane primer debonded during the aging procedure. CONCLUSIONS: Before fixation of CAD/CAM resin composites, the restorations should be air abraded and pretreated using a resin primer containing methyl-methacrylate to successfully bond to the luting composite. The pretreatment of the CAD/CAM resin composite using merely a silane primer results in deficient adhesion. CLINICAL RELEVANCE: For a reliable bond of CAD/CAM resin composites to the luting composite, air abrasion and a special pretreatment strategy are necessary in order to achieve promising long-term results. PMID- 29704133 TI - The Role of Environmental Contamination in the Transmission of Nosocomial Pathogens and Healthcare-Associated Infections. AB - PURPOSE OF REVIEW: The aim of this review is to highlight the role of environmental contamination in healthcare-associated infections (HAIs) and to discuss the most commonly implicated nosocomial pathogens. RECENT FINDINGS: Recent studies suggest that environmental contamination plays a significant role in HAIs and in the unrecognized transmission of nosocomial pathogens during outbreaks, as well as ongoing sporadic transmission. Several pathogens can persist in the environment for extended periods and serve as vehicles of transmission and dissemination in the hospital setting. Cross-transmission of these pathogens can occur via hands of healthcare workers, who become contaminated directly from patient contact or indirectly by touching contaminated environmental surfaces. Less commonly, a patient could become colonized by direct contact with a contaminated environmental surface. This review describes the role of environmental contamination in HAIs and provides context for reinforcing the importance of hand hygiene and environmental decontamination for the prevention and control of HAIs. PMID- 29704138 TI - Novel Automated Approach to Predict the Outcome of Laser Peripheral Iridotomy for Primary Angle Closure Suspect Eyes Using Anterior Segment Optical Coherence Tomography. AB - Develop an algorithm to predict the success of laser peripheral iridotomy (LPI) in primary angle closure suspect (PACS), using pre-treatment anterior segment optical coherence tomography (ASOCT) scans. A total of 116 eyes with PACS underwent LPI and time-domain ASOCT scans (temporal and nasal cuts) were performed before and 1 month after LPI. All the post-treatment scans were classified to one of the following categories: (a) both angles open, (b) one of two angles open and (c) both angles closed. After LPI, success is defined as one or more angles changed from close to open. In this proposed method, the pre and post-LPI ASOCT scans were registered at the corresponding angles based on similarities between the respective local descriptor features and random sample consensus technique was used to identify the largest consensus set of correspondences between the pre and post-LPI ASOCT scans. Subsequently, features such as correlation co-efficient (CC) and structural similarity index (SSIM) were extracted and correlated with the success of LPI. We included 116 eyes and 91 (78.44%) eyes fulfilled the criteria for success after LPI. Using the CC and SSIM index scores from this training set of ASOCT images, our algorithm showed that the success of LPI in eyes with narrow angles can be predicted with 89.7% accuracy, specificity of 95.2% and sensitivity of 36.4% based on pre-LPI ASOCT scans only. Using pre-LPI ASOCT scans, our proposed algorithm showed good accuracy in predicting the success of LPI for PACS eyes. This fully-automated algorithm could aid decision making in offering LPI as a prophylactic treatment for PACS. PMID- 29704140 TI - Correction to: Antenatal Management for Women with Inflammatory Bowel Disease: Experience from Our 'IBD MOM' Clinic. AB - The original version of the article unfortunately contained tagging error in first and family name of authors Ariella Bar-Gil Shitrit and Ami Ben Ya'acov. This has been corrected with this erratum. PMID- 29704139 TI - Anti-fibrogenic Potential of Mesenchymal Stromal Cells in Treating Fibrosis in Crohn's Disease. AB - BACKGROUND: Intestinal fibrosis is a major complication of CD and may result in stricture formation leading to intestinal obstruction. MSCs play multiple roles in active CD and fibrosis-associated diseases. AIMS: This study was designed to investigate the role of MSCs in CD-associated intestinal fibrosis. METHODS: Intestinal fibrosis was induced over 7 weeks of enema with increasing doses of TNBS and assessed by Masson's trichrome staining. Transcriptome sequencing and gene set enrichment analysis were conducted to reveal the transcriptome changes among groups at the mRNA level. Immunofluorescence assays were used to validate the role of EMT in intestinal fibrosis. Quantitative real-time PCR and immunohistochemistry analyses were performed to clarify the association between the anti-fibrogenic properties of MSCs and the immune microenvironment. Western blotting was used to verify the potential signaling pathways. RESULTS: Fibrotic tissue accumulation and inflammatory cell infiltration were detected in the colon tissue after TNBS induction treatment. Prophylactic MSCs treatment inhibited colon shortening, while therapeutic treatment decreased colon weight. Prophylactic treatment with MSCs inhibited the accumulation of fibrotic tissue, the expression of fibrotic proteins and EMT. Therapeutic MSCs treatment reversed the established intestinal fibrosis and reduced EMT. The secretion of the fibrogenic factors IL-1beta, IL-6 and IL-13 was down-regulated after both MSCs treatment approaches, while IL-10, an anti-fibrogenic factor, was up-regulated. Both MSCs therapies inhibited the expression of TGF-beta and the phosphorylation of Smad2 and Smad3 after TNBS induction. CONCLUSION: MSCs exert anti-fibrogenic activity against CD-associated fibrosis by regulating the inflammatory environment, inhibiting the TGF-beta/Smad signaling pathway and ameliorating EMT. PMID- 29704141 TI - 2D:4D Ratio in Neurodevelopmental Disorders: A Twin Study. AB - The second to fourth digit (2D:4D) ratio is of interest in autism spectrum disorder (ASD). Studies on the relationship of this ratio with other neurodevelopmental disorders (NDDs) are lacking. Investigating the association between the ratio and NDDs in twins can provide insight into genetic and/or environmental factors driving the ratio. Hand images were collected in N = 238 twins with NDDs or typical development from 70 monozygotic and 49 dizygotic pairs to examine ratios and their associations to DSM-5 defined categorical NDDs, autistic traits, zygosity, and sex. There were small associations for males between the ratios and any NDD and ADHD diagnoses. Males had lower ratios than females. Future studies exploring the ratio alongside physical anomalies could provide etiological insight into NDDs. PMID- 29704142 TI - Systematic Review of Problem Behavior Interventions: Outcomes, Demographics, and Settings. AB - Interventions designed to decrease problem behavior for students with ASD are critical and may be differentially important for students from minority groups as those students tend to be assigned more negative outcomes related to problem behavior (e.g., suspensions). School-based interventions intended to decrease problem behavior for individuals with ASD were reviewed; 46 articles including 84 single case designs and 87 participants were analyzed regarding participant demographics, settings and implementers, intervention components, and study characteristics. We assessed outcomes for 55 demonstration designs with adequate rigor. Most research was conducted with students in segregated settings and, although race and ethnicity were rarely reported, proportions were different from other reviews in that children from some minority groups were overrepresented. PMID- 29704144 TI - Does this patient have takotsubo syndrome? PMID- 29704143 TI - Sufentanil Alleviates Intrathecal Lidocaine Induced Prolonged Sensory and Motor Impairments but not the Spinal Histological Injury in Rats. AB - Spinal anesthesia has evolved into a safe and widely accepted method of anesthesia. Synergy between opioids and local anesthetics further increases the quality of analgesia and decreases the dose requirement of both local anesthetics and opioids. However, over the last decades compelling evidence suggested that lidocaine could be more neurotoxic than other commonly used local anesthetics. Whether opioids can modify the local anesthetics-induced neurotoxicity is largely unexplored. Here, we investigated the effect of sufentanil on the neurotoxicity induced by intrathecal lidocaine in a rat model. Our data showed that 5 ug/ml sufentanil didn't deteriorate nor reduce the histopathological injuries induced by intrathecal application of 10% lidocaine in a rat model. However, it did alleviate sensory and motor function impairments induced by 10% lidocaine. Repeated intrathecal injection of 5 ug/ml sufentanil also decreased the paw withdraw threshold compared to the baseline. An increase in expression of activating transcription factor 3, a stress response gene, as a marker for injured neurons, was also detected in lidocaine-induced neurotoxicity, while 5 ug/ml sufentanil inhibited lidocaine-induced the upregulation of activating transcription factor 3. These results suggest that sufentanil alleviates lidocaine induced sensory and motor impairments, and did not worsen histopathological injury induced by intrathecal lidocaine. PMID- 29704145 TI - Cardiac tamponade. PMID- 29704146 TI - Paediatric sequential organ failure assessment score (pSOFA): a plea for the world-wide collaboration for consensus. PMID- 29704147 TI - Associations Between Marijuana Use Trajectories and Educational and Occupational Success in Young Adulthood. AB - Adolescence and young adulthood is a critical stage when the economic foundations for life-long health are established. To date, there is little consensus as to whether marijuana use is associated with poor educational and occupational success in adulthood. We investigated associations between trajectories of marijuana use from ages 15 to 28 and multiple indicators of economic well-being in young adulthood including achievement levels (i.e., educational attainment and occupational prestige), work characteristics (i.e., full vs part-time employment, hours worked, annual income), financial strain (i.e., debt, trouble paying for necessities, delaying medical attention), and perceived workplace stress. Data were from the Victoria Healthy Youth Survey, a 10-year prospective study of a randomly recruited community sample of 662 youth (48% male; Mage = 15.5), followed biennially for six assessments. Models adjusted for baseline age, sex, SES, high school grades, heavy drinking, smoking, and internalizing and oppositional defiant disorder symptoms. Chronic users (our highest risk class) reported lower levels of educational attainment, lower occupational prestige, lower income, greater debt, and more difficulty paying for medical necessities in young adulthood compared to abstainers. Similarly, increasers also reported lower educational attainment, occupational prestige, and income. Decreasers, who had high early use but quit over time, showed resilience in economic well-being, performing similar to abstainers. Groups did not differ on employment status or perceived workplace stress. The findings indicate that early onset and persistent high or increasingly frequent use of marijuana in the transition from adolescent to young adulthood is associated with risks for achieving educational and occupational success, and subsequently health, in young adulthood. PMID- 29704148 TI - Clinical lipidomics: a new way to diagnose human diseases. AB - Lipidomics is a measurement of a large scale of lipid species to understand roles of their carbon atoms, dual bonds, or isomerism in the lipid molecule. Clinical lipidomics was recently defined "as a new integrative biomedicine to discover the correlation and regulation between a large scale of lipid elements measured and analyzed in liquid biopsies from patients with those patient phenomes and clinical phenotypes". The first step to translate lipidomics into clinical lipidomics is to settle a number of standard operation procedures and protocols of lipidomics performance and measurement. Clinical lipidomics is the part of clinical trans-omics which was coined as a new emerging scientific discipline where clinical phenomes are integrated with molecular multiomics. We believe it is the time to translate lipid science and lipidomics into clinical application and to understand the importance of clinical lipidomics as one of the most helpful approaches during the design and decision-making of therapeutic strategies for individuals. We emphasize here that clinical lipidomics should be merged with clinical phenomes, e.g. patient signs and symptoms, biomedical analyses, pathology, images, and responses to therapies, although it is difficult to integrate and fuse the information of clinical lipidomics with clinical phenomes. It will be a great achievement if we can draw the networks of lipidomic species fused with networks of genes and proteins to describe the molecular mechanisms of the disease in multi-dimensions. PMID- 29704149 TI - The small GTPase ARF-1.2 is a regulator of unicellular tube formation in Caenorhabditis elegans. AB - The membrane trafficking events that regulate unicellular tube formation and maintenance are not well understood. Here, using an RNAi screen, we identified the small GTPase ARF1 homolog ARF-1.2 as a regulator of excretory tube formation in Caenorhabditis elegans. RNAi-mediated knockdown and knockout of the arf-1.2 gene resulted in the formation of large intracellular vacuoles at the growth sites (varicosities) of the excretory canals. arf-1.2 mutant animals were sensitive to hyperosmotic conditions. arf-1.2 RNAi affected the localization of the anion transporter SULP-8, which is expressed in the basal plasma membrane of the excretory canals, but did not affect the expression of SULP-4, which is expressed in the apical membrane. The phenotype of arf-1.2 mutants was suppressed by mutation of the small Rho GTPase CDC-42, a regulator of apical/basal traffic balance. These results suggest that ARF-1.2 plays an essential role in basal membrane traffic to regulate the formation of the unicellular excretory tube. PMID- 29704150 TI - Protective and Therapeutic Effects of Engeletin on LPS-Induced Acute Lung Injury. AB - Acute lung injury (ALI) is a serious disease with morbidity and mortality in patients. Engeletin (dihydrokaempferol 3-rhamnoside) is a flavanonol glycoside. It can be found in the skin of white grapes and white wine and is widely distributed in southeast Asia. In our study, we evaluated the protective and therapeutic effects of engeletin on lipopolysaccharide (LPS)-induced ALI in animal model. We determined the level of peroxisome proliferator-activated receptor-gamma (PPAR-gamma), nuclear factor kappaB (NF-kappaB), and IkappaBalpha by western blotting. The myeloperoxidase (MPO) activity and lung wet/dry (W/D) ratio in lung tissues were also detected. Histopathological changes and the pro inflammatory cytokines TNF-alpha, IL-6, and IL-1beta were determined by H&E staining and ELISA. The MPO activity and lung W/D ratio induced by LPS were attenuated by engeletin. The numbers of inflammatory cells and the levels of inflammatory cytokines in bronchoalveolar lavage fluid (BALF) were ameliorated by engeletin. Furthermore, the results also showed that engeletin significantly suppressed LPS-induced NF-kappaB activation. The expression of PPAR-gamma was upregulated by treatment of engeletin. In conclusion, we found that engeletin had protective and therapeutic effects against LPS-induced ALI by activating PPAR gamma. Engeletin is a potentially effective agent for the treatment of lung injury. PMID- 29704152 TI - Racialized economic segregation and stage at diagnosis of colorectal cancer in the United States. AB - PURPOSE: In order to improve colorectal cancer outcomes in the United States, there is an urgent need for research on the drivers of geographic disparities in stage at diagnosis. Our objective was to determine the effects of racialized economic segregation on the odds of late diagnosis. METHODS: Among 187,843 adults (>= 18 years old) with new diagnoses of colorectal cancer reported to the Surveillance, Epidemiology and End-Results program between 1st January 2009 and 31st December 2013, exposure to racialized economic segregation was measured at the county-level using Index of Concentration at the Extremes metrics. Multilevel logistic regression models including registry and county random effects were fit to examine the association between racialized economic segregation and odds of metastatic disease at time of diagnosis. RESULTS: Odds of late diagnosis were greatest in counties with the lowest compared to highest quintile for racial and economic privilege (OR 1.14; 95% CI 1.09-1.20). In multilevel models adjusting for individual-level covariates, odds of late diagnosis were greater for all patients except those living in counties with the highest concentration of white high-income individuals. There was significant effect modification of this relationship by age, with greater adverse effects for younger adults (OR 1.16; 95% CI 1.02-1.32) than older adults (OR 1.06; 95% CI 1.00-1.11). Racialized economic segregation was strongly associated with access to affordable healthcare. CONCLUSIONS: Spatial social polarization, quantified in relation to racialized economic segregation, increases the odds of late diagnosis of colorectal cancer for persons residing in the least compared to most privileged counties. PMID- 29704151 TI - Extracellular Matrix Remodeling and Modulation of Inflammation and Oxidative Stress by Sulforaphane in Experimental Diabetic Peripheral Neuropathy. AB - The peripheral nervous system is one of many organ systems that can be profoundly impacted in diabetes mellitus. Diabetic peripheral neuropathy has a significant negative effect on patients' quality of life as it begins with loss of limbs' sensation and may result in lower limb amputation. This investigation aimed at exploring the effect of sulforaphane on peripheral neuropathy in diabetic rats. Experimental diabetes was induced through single intraperitoneal injections of nicotinamide (50 mg/kg) and streptozotocin (52.5 mg/kg). Rats were divided into five groups. Two groups were treated with saline or sulforaphane (1 mg/kg, p.o.). Three diabetic groups were either untreated or given sulforaphane (1 mg/kg, p.o.) or pregabalin (10 mg/kg, i.p.). Two weeks after drugs' administration, biochemical, behavioral, histopathological, and immunohistochemical investigations were carried out. Treatment with sulforaphane restored animals' body weight, reduced blood glucose, glycated hemoglobin, and increased insulin levels. In parallel, it normalized motor coordination and the latency withdrawal time of tail flick test, increased the latency withdrawal time of cold allodynia test, and ameliorated histopathological changes. Treatment of sulforaphane, likewise, decreased sciatic nerve malondialdehyde, nitric oxide, interleukin-6, and matrix metalloproteinase-2 and -9 contents. Similarly, it reduced sciatic nerve DNA fragmentation and expression of cyclooxygenase-2 and nuclear factor kappa-B p65. Meanwhile, it increased sciatic nerve superoxide dismutase and interleukin-10 contents. These results reveal the neuroprotective effect of sulforaphane against peripheral neuropathy in diabetic rats possibly through modulating oxidative stress, inflammation, and extracellular matrix remodeling. Graphical Abstract Diagram that illustrates the effects of sulforaphane in treating experimental diabetic peripheral neuropathy. In NA-STZ model of diabetes mellitus, sulforaphane, restored animals' body weight, reduced blood glucose, glycated hemoglobin and increased insulin levels. In parallel, it normalized motor coordination and the latency withdrawal time of tail flick test, increased the latency withdrawal time of cold allodynia test and ameliorated histopathological changes. Treatment of sulforaphane, likewise, decreased sciatic nerve malondialdehyde, nitric oxide, interleukin-6, matrix metalloproteinase-2 and -9 contents. Similarly, it reduced sciatic nerve DNA fragmentation and expression of cyclooxygenase-2 and nuclear factor kappa-B p65. Meanwhile, it increased sciatic nerve superoxide dismutase and interleukin-10 contents. PMID- 29704153 TI - Gastrokine 1 protein is a potential theragnostic target for gastric cancer. AB - BACKGROUND: Gastrokine 1 (GKN1) plays important roles in maintaining mucosal homeostasis, and in regulating cell proliferation and differentiation. Here, we determined whether GKN1 is a potential theragnostic marker for gastric cancer. METHODS: We identified GKN1 binding proteins using the protein microarray assay and investigated whether GKN1 is one of the exosomal cargo proteins by western blot, immunoprecipitation, and immunofluorescent assays. Cell proliferation and apoptosis were analyzed by MTT, BrdU incorporation, flow cytometry, and western blot assays. We further validated the functional relevance of exosomal GKN1 in MKN1-injected xenograft mice. The possibility of serum GKN1 as a diagnostic marker for gastric cancer was determined by ELISA assay. RESULTS: In protein microarray assay, GKN1 binding to 27 exosomal proteins was clearly observed. GKN1 was expressed in exosomes derived from HFE-145 gastric epithelial cells by western blot and immunofluorescent assays, but not in exosomes from AGS and MKN1 gastric cancer cells. Exosomes carrying GKN1 inhibited cell proliferation and induced apoptosis in both AGS and MKN1 cells, and exosomes carrying GKN1-treated nude mice-bearing MKN1 xenograft tumors exhibited significantly reduced tumor volume and tumor weight. Silencing of clathrin markedly down-regulated the internalization of exosomal GKN1. Interestingly, serum GKN1 concentrations in patients with gastric cancer were significantly lower than those in healthy individuals and patients with colorectal and hepatocellular carcinomas. CONCLUSIONS: The GKN1 is secreted and internalized in the gastric epithelium by exosome-driven transfer, which inhibits gastric tumorigenesis and supports the clinical application of GKN1 protein in gastric cancer diagnosis and treatment. PMID- 29704154 TI - Pharmacological effect of human melanocortin-2 receptor accessory protein 2 variants on hypothalamic melanocortin receptors. AB - PURPOSE: Melanocortin-3 receptor (MC3R), melanocortin-4 receptor (MC4R), and a recently identified melanocortin-2 receptor accessory protein 2 (MRAP2), are highly expressed in hypothalamus and coordinately regulate energy homeostasis, but the single cellular transcriptome of melanocortin system remains unknown. Several infrequent MRAP2 variants are reported from severe obese human patients but the mechanisms on how they affect melanocortin signaling are unclear. METHODS: First, we performed in silico analysis of mouse hypothalamus RNA sequencing datasets at single-cell resolution from two independent studies. Next, we inspected the three-dimensional conformational alteration of three mutations on MRAP2 protein. Finally, the influence of MRAP2 variants on MC3R and MC4R signaling was analyzed in vitro. RESULTS: (1) We confirmed the actual co expression of Mrap2 with Mc3r and Mc4r, and demonstrated more broad distribution of Mrap2-positive neuronal populations than Mc3r or Mc4r in mouse hypothalamus. (2) Compared with wild-type MRAP2, MRAP2N88Y, and MRAP2R125C showed impaired alpha-MSH-induced MC4R or MC3R stimulation. (3) MRAP2N88Yexhibited enhanced interaction with MC4R protein and its own. CONCLUSIONS: This is the first dedicated description of single-cell transcriptome signature of Mrap2, Mc3r, and Mc4r in the central nerve system and the first evidence describing the unique dimer formation, conformational change, and pharmacological effect of MRAP2 mutations on MC3R signaling. PMID- 29704155 TI - Acute pancreatitis as the first manifestation in a young boy with primary hyperparathyroidism. PMID- 29704156 TI - Lactate induces expression and secretion of fibroblast growth factor-21 by muscle cells. PMID- 29704157 TI - Fast and effective: Intuitive processes in complex decisions. AB - Is it possible to carry out complex multi-attribute decisions (which require an estimation of the weighted average) intuitively, without resorting to simplifying heuristics? Over the course of 600 trials, 26 participants had to choose the better-suiting job-candidate, a task requiring comparison of two alternatives over three/four/five dimensions with specified importance weights, with a time constraint forcing intuitive decisions. Participants performed the task fast (mean reaction time (RT) ~ 1.5 s) and with high accuracy (~86%). The participants were classified as users of one of three strategies: Weighted Additive Utility (WADD), Equal Weight rule and Take-The-Best heuristic (TTB). Fifty-nine percent of the participants were classified as users of the compensatory WADD strategy and 29% as users of the non-compensatory TTB. Moreover, the WADD users achieved higher task accuracy without showing time costs. The results provide support for the existence of an automatic compensatory mechanism in weighted average estimations. PMID- 29704158 TI - Production of N-acetyl-D-neuraminic Acid by Recombinant Single Whole Cells Co expressing N-acetyl-D-glucosamine-2-epimerase and N-acetyl-D-neuraminic Acid Aldolase. AB - N-acetyl-D-neuraminic acid (Neu5Ac) is a costly precursor for many drugs such as anti-influenza antivirals. In a previous study, a whole-cell process for Neu5Ac production was developed using a combination of two Escherichia coli cells expressing Anabaena sp. CH1 N-acetyl-D-glucosamine-2-epimerase (bage) and E. coli N-acetyl-D-neuraminic acid aldolase (nanA), respectively. In this study, we constructed a bAGE and NanA co-expression system to improve Neu5Ac production. Two recombinant E. coli strains, E. coli BL21 (DE3) pET-bage-nanA (HA) and E. coli BL21 (DE3) pET-bage-2nanA (HAA), synchronously expressing bAGE and NanA were used as biocatalysts to generate Neu5Ac from N-acetyl-D-glucosamine (GlcNAc) and pyruvate. The HA biocatalysts produced 187.5 mM Neu5Ac within 8 h. The yield of GlcNAc was 15.6%, and the Neu5Ac production rate was 7.25 g/L/h. The most active HAA biocatalysts generated 412.6 mM Neu5Ac and a GlcNAc yield of 34.4%. HAA achieved a Neu5Ac production rate of 15.9 g/L/h, which surpassed those for all reported Neu5Ac production processes so far. The present study demonstrates that using recombinant E. coli cells synchronously expressing bAGE and NanA as biocatalysts could potentially be used in the industrial mass production of Neu5Ac. PMID- 29704161 TI - [Being young with rheumatism]. PMID- 29704160 TI - There is more to septic shock than arterial hypotension and elevated lactate levels: another appeal to rethink current resuscitation strategies! PMID- 29704162 TI - A Comparison of Motivations for Marijuana Use in HIV-Positive and HIV-Negative Adults. AB - While medicinal marijuana use is common among persons with HIV, it is not known whether persons with HIV are more motivated to use marijuana medically compared to HIV-negative counterparts. This study examined motivations for marijuana use in a sample of 94 HIV+ and HIV- adults. Participants used marijuana 21.27 days in the last 30 days on average. HIV+ participants reported using marijuana for medical reasons more often than HIV- participants, but HIV+ and HIV- participants did not differ in other domains. Problematic marijuana use was associated with motives, regardless of HIV status. Motives were associated with mental and physical health functioning, but there were no interactions between motivations and HIV status. Overall this study found that motivations were similar for HIV+ and HIV- participants. Future research including qualitative work to further understand motivations would benefit the field, as would research examining the effectiveness of marijuana in treating physical symptoms. PMID- 29704159 TI - Diversity of Immunoglobulin (Ig) Isotypes and the Role of Activation-Induced Cytidine Deaminase (AID) in Fish. AB - The disparate diversity in immunoglobulin (Ig) repertoire has been a subject of fascination since the emergence of prototypic adaptive immune system in vertebrates. The carboxy terminus region of activation-induced cytidine deaminase (AID) has been well established in tetrapod lineage and is crucial for its function in class switch recombination (CSR) event of Ig diversification. The absence of CSR in the paraphyletic group of fish is probably due to changes in catalytic domain of AID and lack of cis-elements in IgH locus. Therefore, understanding the arrangement of Ig genes in IgH locus and functional facets of fish AID opens up new realms of unravelling the alternative mechanisms of isotype switching and antibody diversity. Further, the teleost AID has been recently reported to have potential of catalyzing CSR in mammalian B cells by complementing AID deficiency in them. In that context, the present review focuses on the recent advances regarding the generation of diversity in Ig repertoire in the absence of AID-regulated class switching in teleosts and the possible role of T cell-independent pathway involving B cell activating factor and a proliferation inducing ligand in activation of CSR machinery. PMID- 29704164 TI - Regulation of excitation energy in Nannochloropsis photosystem II. AB - Recently, we isolated a complex consisting of photosystem II (PSII) and light harvesting complexes (LHCs) from Nannochloropsis granulata (Umetani et al. Photosynth Res 136:49-61, 2017). This complex contained stress-related protein, Lhcx, as a major component of LHC (Protein ID is Naga_100173g12.1), suggesting that non-photochemical quenching activities may be taking place in the PSII-LHC complex. In this study, we examined the energy transfer dynamics in the isolated LHCs and PSII-LHC complexes, and found substantial quenching capacity. In addition, the LHCs contained low-energy chlorophylls with fluorescence maxima at approximately 710 nm, which may enhance the quenching efficiency in the PSII-LHC. Delayed fluorescence analysis suggested that there was an approximately 50% reduction in energy trapping at the PSII reaction center in the PSII-LHC supercomplex under low-pH condition compared to neutral pH condition. Enhanced quenching may confer a survival advantage in the shallow-water habitat of Nannochloropsis. PMID- 29704163 TI - Respiratory sinus arrhythmia in the immediate post-exercise period: correlation with breathing-specific heart rate. AB - BACKGROUND: Although the absolute values of pulmonary ventilation and cardiac output are similar, the designs of the respiratory and cardiovascular systems imply major differences in flow patterns, airflow being intermittent by comparison to the quasi-continuous pulmonary blood flow. PURPOSE: We hypothesized that respiratory sinus arrhythmia (RSA, difference in heart rate (fH) between inspiration and expiration, as percent of mean fH) ameliorates the inevitable differences between air- and blood-flow patterns. Specifically, we hypothesized RSA to correlate more closely to the ratio between fH and breathing frequency (fR) (fH/fR "breathing-specific heart rate", a proxy for cardio-respiratory coupling) than to either fH or fR alone. Hence, we designed protocols to change independently fH or fR. METHODS: We measured RSA breath-by-breath in 145 young men and women during spontaneous breathing, breathing under cues at different fR (to modify the denominator of fH/fR) and immediately post-exercise while breathing freely or by keeping fR as at rest (to modify the nominator of fH/fR). RESULTS: RSA had no significant correlation with fH, and a better correlation with fH/fR (r2 = 0.92) than with fR alone (r2 = 0.75); the variance of the Y values of the fH/fR-RSA correlation was ~ half that of the fR/RSA correlation (P < 0.002). CONCLUSIONS: We propose that the fH/fR-RSA relationship reflects a central process that ameliorates gas exchange against the difference between air- and blood-flow patterns. The neurological mechanisms are still conjectural. Measurements of RSA could offer a glimpse of the degree of cardio-respiratory central compensation in face of the inequality between blood flow and airflow. PMID- 29704165 TI - Genetic Creutzfeldt-Jakob disease with an 8-year disease course. PMID- 29704166 TI - Lies, damned lies, and statistics. PMID- 29704167 TI - Context and clinical reasoning : Understanding the medical student perspective. AB - INTRODUCTION: Studies have shown that a physician's clinical reasoning performance can be influenced by contextual factors. We explored how the clinical reasoning performance of medical students was impacted by contextual factors in order to expand upon previous findings in resident and board certified physicians. Using situated cognition as the theoretical framework, our aim was to evaluate the verbalized clinical reasoning processes of medical students in order to describe what impact the presence of contextual factors has on their reasoning performance. METHODS: Seventeen medical student participants viewed three video recordings of clinical encounters portraying straightforward diagnostic cases in internal medicine with explicit contextual factors inserted. Participants completed a computerized post-encounter form as well as a think-aloud protocol. Three authors analyzed verbatim transcripts from the think-aloud protocols using a constant comparative approach. After iterative coding, utterances were analyzed and grouped into categories and themes. RESULTS: Six categories and ten associated themes emerged, which demonstrated overlap with findings from previous studies in resident and attending physicians. Four overlapping categories included emotional disturbances, behavioural inferences about the patient, doctor patient relationship, and difficulty with closure. Two new categories emerged to include anchoring and misinterpretation of data. DISCUSSION: The presence of contextual factors appeared to impact clinical reasoning performance in medical students. The data suggest that a contextual factor can be innate to the clinical scenario, consistent with situated cognition theory. These findings build upon our understanding of clinical reasoning performance from both a theoretical and practical perspective. PMID- 29704168 TI - Crystallizations of constructs : Lessons learned from a literature review. PMID- 29704169 TI - How are competency frameworks perceived and taught? : An exploratory study in the context of pharmacy education. AB - INTRODUCTION: Faculties of Pharmacy worldwide have to adapt their curriculum to accreditation criteria. The present study explored how the Association of Faculties of Pharmacy of Canada's (AFPC's) 2010 Educational Outcomes are perceived and taught at the Leslie Dan Faculty of Pharmacy (LDFP). These outcomes were adapted from the CanMeds Physician Competency Framework which describes both medical expert and non-expert roles. METHODS: We wondered if pharmacy would struggle, as medicine has, to integrate these roles into curricula in meaningful ways, given the absence of previous studies from Pharmacy. We conducted an exploratory interview study with 10 core faculty members in charge of courses where non-expert roles were taught. Data were analysed using conventional content analysis. RESULTS: Faculty members understood that the AFPC Outcomes are important for students, patients, and the profession of pharmacy, and some saw the roles as knowledge-based and teachable using content from academic disciplines. However, most saw them as skills taught informally or through clinical experience. They used the roles as a framing device to legitimize their course content and relied on informal role modelling to do most of the teaching. The few faculty members who taught content related to these roles had postgraduate education in a social science or humanities discipline. DISCUSSION: Similar to studies of Faculties of Medicine, our study highlights the difficulty of translating a role-based, competency framework into concrete, integrated curricula for students. Competency development should be explicitly embedded into the curriculum and cannot be left to individual instructors. PMID- 29704170 TI - Comparison of Hematologic and Other Prognostic Markers in Metastatic Colorectal Cancer. AB - BACKGROUND: Associations of thrombocytosis, neutrophilia, and lymphopenia with prognosis have been confirmed in many cancers. This study aims at comparing various prognostic indices based on blood counts in metastatic colorectal adenocarcinomas. PATIENTS AND METHODS: Records from 152 patients with metastatic colorectal cancer who were treated in our center were reviewed. Demographic and disease characteristics and hematologic parameters data were extracted and patients were stratified according to their scores of several hematologic ratios. Hematologic ratios and parameters considered included the platelet-neutrophil to lymphocyte ratio (PNLR), the platelet to lymphocyte ratio (PLR), the neutrophil to lymphocyte ratio (NLR), the Abnormal Hematological Markers Index (AHMI), and the neutrophil-platelet score (NPS). Optimal cutoffs were defined with the aid of an online tool. Baseline parameters of the two groups derived for each tool were evaluated and compared with the chi2 test. Univariate and multivariate Cox proportional-hazards regression analyses were performed on variables of interest. RESULTS: Progression-Free Survival (PFS) hazard ratios (HR) between the high-risk and low-risk groups derived from the multivariate analyses for each index were as follows: for PNLR 2.0 (95% CI 1.28-3.13), for PLR 1.74 (95% CI 1.13-2.67), for NLR 1.54 (95% CI 1.04-2.29), for AHMI 1.62 (95% CI 1.06-2.46), and for NPS 1.47 (95% CI 1.1-1.96). Overall Survival (OS) hazard ratios (HR) derived from the multivariate analyses for each index were as follows: for PNLR 2.23 (95% CI 1.36 3.66), for PLR 1.68 (95% CI 1.03-2.75), for NLR 1.62 (95% CI 1.06-2.49), for AHMI 1.7 (95% CI 1.07-2.69), and for NPS 1.53 (95% CI 1.11-2.11). Another prognostic index called PRONOPALL, which is based on ECOG PS (0-1 versus 2-3 versus 4), number of metastatic sites (<= 1 versus >= 2), LDH (< 600 U/L versus >= 600 U/L), and albumin (>= 33 g/L versus < 33 g/L), had HRs of 1.75 and 2.20 for PFS and OS, respectively, with a cutoff of < 4 versus >= 4. This score has a range of 0 to 10 and points are attributed for the presence of each of the four prognostic factors. CONCLUSION: In this analysis of metastatic colorectal cancer patients, several ratios and other prognostic tools had prognostic value for both OS and PFS. While other variables held significance for poorer prognosis, PNLR had the highest HR and the highest significance in multivariate analysis for both PFS and OS. Thus, it represents a valid prognostic tool in metastatic colorectal cancer among the spectrum of hematologic parameter-constructed tools. PMID- 29704171 TI - Efficacy of Scorpion Antivenom in Grade III and IV Scorpion Envenomation. PMID- 29704172 TI - A direct oral factor Xa inhibitor edoxaban ameliorates neointimal hyperplasia following vascular injury and thrombosis in apolipoprotein E-deficient mice. AB - Vascular injury activates the coagulation cascade. Some studies report that coagulation factor Xa and thrombin are implicated in proliferation of vascular smooth muscle cells and neointimal hyperplasia after vascular injury. The aim of this study was to determine the effect of an oral direct factor Xa inhibitor, edoxaban, on neointimal hyperplasia following the carotid artery injury in apolipoprotein E (ApoE)-deficient mice. Vascular injury was induced by the application of 10% ferric chloride to the carotid artery for 3 min in ApoE deficient mice. After vascular injury, all animals were fed with high-cholesterol chow for 6 weeks. Edoxaban at 15 mg/kg was orally administered to the mice 1 h before (n = 10) or 1 h after (n = 9) ferric chloride injury, and thereafter 10 mg/kg edoxaban was orally administered b.i.d. for 6 weeks. Thrombus formation and neointimal hyperplasia were evaluated. Treatment with 15 mg/kg edoxaban before vascular injury almost completely inhibited thrombus formation, and following chronic administration of edoxaban significantly suppressed neointimal hyperplasia. In the mice treated with edoxaban after vascular injury, there was wide interindividual variability. In some mice (four out of nine) the neointimal hyperplasia was inhibited like in edoxaban-pretreated mice, but there was no statistical difference compared with control. This study demonstrated that inhibition of the coagulation and thrombosis by edoxaban ameliorated neointimal hyperplasia caused by vascular injury and high-cholesterol diets in ApoE deficient mice. This suggests that factor Xa has a crucial role in the formation of neointima following vascular injury.The abstract should be followed by 3-4 bullet points that highlight major findings. The final bullet point should emphasize future directions for research. PMID- 29704173 TI - Infection following percutaneous vertebral augmentation with polymethylmethacrylate. AB - : Although the incidence of infection following vertebroplasty or kyphoplasty is rare, postoperative infection and cement augmentation in preexistent spondylitis can cause life-threatening complications in frail patients with notable comorbidities. In such cases, urgent culture and biopsy and the long-term use of proper antibiotics are necessary. PURPOSE: Infection following vertebral augmentation with polymethylmethacrylate (PMMA) is rare. We aimed to analyze 11 cases of pyogenic spondylitis and spondylodiscitis that occurred after vertebroplasty or kyphoplasty and to review similar cases in the literature. METHODS: All cases of postoperative spinal infections in our institution between January 2005 and November 2016 that primarily underwent percutaneous vertebroplasty or kyphoplasty were retrospectively reviewed. Eleven patients (mean age 76.3 years) were included. RESULTS: The incidence of infection following vertebroplasty/kyphoplasty was 0.36%. Postoperative infection occurred in 3 of 826 cases. All patients underwent combined surgical and antibiotic treatment because of neurologic deficit on the initial diagnosis of the infection or failure of prior medical treatment of the infection. The surgical procedure was thorough debridement of infected tissue and material including PMMA following anterior column reconstruction via anterior/posterior/combined approach in 10 patients and percutaneous pedicle screw fixation alone in 1 patient aged 96 years. The mean follow-up period was 21.1 months after the revision operation, excluding one patient who died 17 days after revision surgery. Ten patients recovered from infection. CONCLUSIONS: Although the incidence of infection following vertebroplasty or kyphoplasty is rare, postoperative infection and cement augmentation in preexisting spondylitis can develop into a life threatening complication in frail patients with notable comorbidities. In treating infected vertebroplasty and kyphoplasty, immediate culture and biopsy and the long-term use of proper antibiotics are critical. Prompt surgical treatment should be considered in case of significant neurologic deficit, severe instability due to infected fracture, and resistance to antibiotics. PMID- 29704174 TI - Predictors of 90-day mortality in patients with severe alcoholic hepatitis: Experience with 183 patients at a tertiary care center from India. AB - BACKGROUND: Severe alcoholic hepatitis (AH) is not an uncommon indication for hospital admission in India. However, there is limited data from India on predictors of mortality in patients of severe AH. We analyzed the data on patients with severe AH admitted to our institute and compared various parameters and severity scores in predicting 90-day mortality. METHODS: In this prospective study, we analyzed patients with severe AH (defined as discriminant function >= 32) admitted from January 2015 to February 2017 to our institute. All patients were administered standard treatment according to various guidelines, and their 90-day mortality was determined. Various hematologic, biochemical factors, and severity scores were compared between survivors and patients who died. RESULTS: A total of 183 patients (98% males, median age 41 years [range 20-70 years]) were included in our study. The median model for end-stage liver disease (MELD) was 26 (15-40). Ascites were present in 83% and hepatic encephalopathy in 38%. Only 21 (12%) could be offered steroid therapy, due to contraindications in the remaining. By 90 days, only 103 (56%) patients survived while 80 (44%) died. All patients died due to progressive liver failure and its complications. On multivariate analysis, presence of ascites, hepatic encephalopathy, high bilirubin, low albumin, high creatinine, high INR, and low potassium independently predicted 90-day mortality. All the scores performed significantly in predicting 90-day mortality with no statistically significant difference between them. MELD score had a maximum area under the curve 0.76 for 90-day mortality. A combination of Child class and presence of acute kidney injury (creatinine >= 1.35) was good in predicting 90-day mortality. CONCLUSION: Our patients had severe AH characterized by a median MELD score of 26 and had a 90 day mortality of 44%. Most patients were not eligible to receive corticosteroids. Presence of Child C status and high serum creatinine value (>= 1.35 mg/dL) accurately predicted mortality. Newer treatment options need to be explored for these patients. PMID- 29704175 TI - Biochemical responses of the Protaetia brevitarsis Lewis larvae to subchronic copper exposure. AB - Copper (Cu) is one of the most commonly detected heavy metals in livestock manure pollution. Protaetia brevitarsis Lewis larvae are widely used in the decomposition of livestock manure. During decomposition, heavy metals in livestock manure can accumulate in P. brevitarsis larvae and affect normal growth and reproduction. Therefore, this research focused on characterizing the toxic effects of Cu to P. brevitarsis Lewis larvae. Larvae were exposed to Cu concentrations of 0, 100, 200, 400, and 800 mg kg-1 in edible fungi residue for 7, 14, 21, and 28 days. Results showed that the soluble protein content was markedly increased in 200 and 400 mg kg-1 treatment groups on day 28. Compared to the control group, superoxide dismutase (SOD) and glutathione S-transferase (GST) activities were significantly stimulated on day 7 and then decreased as exposure length was increased (e.g., after 14, 21, and 28 days). Catalase (CAT) activity was also significantly increased after 7 days of exposure. Malondialdehyde (MDA) levels were markedly increased in the 100, 200, and 400 mg kg-1 treatment groups on day 7. However, as time and Cu concentration were increased, MDA levels gradually decreased. These results indicate that Cu has biochemical effects on P. brevitarsis Lewis larvae, and both time and dose affect this biochemical response. PMID- 29704176 TI - Litter breakdown as a tool for assessment of the efficiency of afforestation and ash-aided phytostabilization on metal-contaminated soils functioning in Northern France. AB - The main objective of the study was to assess the efficiency of phytoremediation methods implemented for 14 years on highly metal-contaminated soils. The different experimental strategies were plots planted with a tree mix or with a single tree species coupled or not with the use of fly-ashes as an amendment to limit metals mobility in soil. The breakdown of poplar litter on the four plots was monitored during 10 months. In parallel, colonization of litter bags by functional groups of mesofauna (Collembola and Acari) was followed. Two mesh sized litter bags were used to allow distinguishing microbial and mesofaunal actions on the litter breakdown. We observed the breakdown of litter in four studied plots. Litter breakdown occurred faster in 3-mm litter bags than 250 MUm ones during summer demonstrating the importance of mesofauna. Mixed plantation allowed faster litter breakdown than mono-specific plantation. A higher abundance of mesofauna and/or better abiotic conditions (moisture, shading...) could explain this result. Regarding litter breakdown and mesofauna, no significant difference was observed between the amended plots and those subjected to soil phytomanagement. However, communities of the studied area are disturbed since a low abundance of detritivores was observed. This could explain also the slower litter breakdown than expected in our study. To conclude, among the phytomanagement methods tested, mixed plantations could provide a benefit for the restoration of degraded soils. By contrast, the use of fly-ashes does not seem to have any effect on the functionality of ecosystem neither on the litter breakdown process nor on the abundance of mesofauna. PMID- 29704177 TI - Effect of single and mixed polycyclic aromatic hydrocarbon contamination on plant biomass yield and PAH dissipation during phytoremediation. AB - Polycyclic aromatic hydrocarbon (PAH)-contaminated sites have a mixture of PAH of varying concentration which may affect PAH dissipation differently to contamination with a single PAH. In this study, pot experiments investigated the impact of PAH contamination on Medicago sativa, Lolium perenne, and Festuca arundinacea biomass and PAH dissipation from soils spiked with phenanthrene (Phe), fluoranthene (Flu), and benzo[a]pyrene (B[a]P) in single and mixed treatments. Stimulatory or inhibitory effects of PAH contamination on plant biomass yields were not different for the single and mixed PAH treatments. Results showed significant effect of PAH treatments on plant growth with an increased root biomass yield for F. arundinacea in the Phe (175%) and Flu (86%) treatments and a root biomass decrease in the mixed treatment (4%). The mean residual PAHs in the planted treatments and unplanted control for the single treatments were not significantly different. B[a]P dissipation was enhanced for single and mixed treatments (71-72%) with F. arundinacea compared to the unplanted control (24-50%). On the other hand, B[a]P dissipation was inhibited with L. perenne (6%) in the single treatment and M. sativa (11%) and L. perenne (29%) in the mixed treatment. Abiotic processes had greater contribution to PAH dissipation compared to rhizodegradation in both treatments. In most cases, a stimulatory effect of PAH contamination on plant biomass yield without an enhancement of PAH dissipation was observed. Plant species among other factors affect the relative contribution of PAH dissipation mechanisms during phytoremediation. These factors determine the effectiveness and suitability of phytoremediation as a remedial strategy for PAH-contaminated sites. Further studies on impact of PAH contamination, plant selection, and rhizosphere activities on soil microbial community structure and remediation outcome are required. PMID- 29704178 TI - Structural characterization of Bacillus licheniformis Dahb1 exopolysaccharide antimicrobial potential and larvicidal activity on malaria and Zika virus mosquito vectors. AB - Microbial polysaccharides produced by marine species play a key role in food and cosmetic industry, as they are nontoxic and biodegradable polymers. This investigation reports the isolation of exopolysaccharide from Bacillus licheniformis Dahb1 and its biomedical applications. Bacillus licheniformis Dahb1 exopolysaccharide (Bl-EPS) was extracted using the ethanol precipitation method and structurally characterized. FTIR and 1H-NMR pointed out the presence of various functional groups and primary aromatic compounds, respectively. Bl-EPS exhibited strong antioxidant potential confirmed via DPPH radical, reducing power and superoxide anion scavenging assays. Microscopic analysis revealed that the antibiofilm activity of Bl-EPS (75 MUg/ml) was higher against Gram-negative (Pseudomonas aeruginosa and Proteus vulgaris) bacteria over Gram-positive species (Bacillus subtilis and Bacillus pumilus). Bl-EPS led to biofilm inhibition against Candida albicans when tested at 75 MUg/ml. The hemolytic assay showed low cytotoxicity of Bl-EPS at 5 mg/ml. Besides, Bl-EPS achieved LC50 values < 80 MUg/ml against larvae of mosquito vectors Anopheles stephensi and Aedes aegypti. Overall, our findings pointed out the multipurpose bioactivity of Bl-EPS, which deserves further consideration for pharmaceutical, environmental and entomological applications. PMID- 29704179 TI - Neonicotinoid detection in wild turkeys (Meleagris gallopavo silvestris) in Ontario, Canada. AB - The use of neonicotinoid insecticides in agriculture is now recognized for the health risks it poses to non-target wildlife, with associated honey bee mortality especially concerning. Research directed toward the presence and effects of these pesticides on terrestrial vertebrates that consume neonicotinoid-coated seeds, such as wild turkeys (Meleagris gallopavo silvestris), is lacking. This study used liquid chromatography attached to a tandem mass spectrometer to assess the liver from 40 wild turkeys for neonicotinoid and other pesticide residues and compared detected levels of these contaminants across the southern Ontario, Canada. Nine (22.5%) wild turkeys had detectible levels of neonicotinoid residues clothianidin in eight, and thiamethoxam in three. Two (5.0%) of these turkeys had detectable levels of both clothianidin and thiamethoxam. Fuberidazole was detected in two (5.0%) wild turkeys. The highest level of thiamethoxam detected was 0.16 ppm, while clothianidin was detected at 0.12 ppm, and fuberidazole at 0.0094 ppm. Knowledge of exposure in free-ranging wildlife is critical for better understanding the effects of neonicotinoids on wildlife health; thus, these data help establish baseline data for southern Ontario wild turkeys and provide context for reference values in future analyses. PMID- 29704180 TI - The impact of occupational exposure to traffic-related air pollution among professional motorcyclists from Porto Alegre, Brazil, and its association with genetic and oxidative damage. AB - Vehicles play an important role in modern life; however, they also generate hazards. Occupational exposed subjects are in long-term contact with harmful products, which sets these professionals in a susceptible group to air pollutant damage. The aims of this study were to quantify individual exposure to pollutant gases and chemical elements and to evaluate oxidative and genetic damage in professional motorcyclists and office workers. We recruited professional motorcyclists and office workers from Porto Alegre, Brazil, between January and December 2016. Individual exposure to air pollutants was assessed by passive monitoring. Fingernail trace elements were determined by using inductively coupled plasma mass spectrometry. Oxidative stress biomarkers were quantified spectrophotometrically, and genotoxicity was evaluated by micronuclei assay. Individual exposure to NO2 and O3, trace element content (Sb, Pt, As, Cd, V, Mn, and Co), oxidative stress factors, and genetic damage were statistically higher in professional motorcyclists (p < 0.05). Moreover, NO2 and O3 levels showed very strong positive correlation with plasmatic lipid peroxidation (p < 0.001 and r = 0.8849 and 0.8995) and strong positive correlation with micronuclei frequency (p < 0.001 and r = 0.7683 and 0.7280). Results suggest that professional motorcyclists are at high risk due to long-term air pollution exposure, which implies in the onset of several harmful effects and worsening of pre-existent diseases. PMID- 29704181 TI - Influence of temperature fluctuations on one-stage deammonification systems in northern cold region. AB - Cold and fluctuant temperatures are still a bottleneck for the application of one stage deammonification in mainstream anammox (anaerobic ammonium oxidation). In this study, to simulate the practical but critical operational condition under rapidly fluctuant temperatures between April and May in cold northern area, two deammonification reactors with anammox granular sludge and nitritation flocculent sludge were tested under the cold shock with temperature fluctuations (11-18 degrees C). Under the controlled temperature (32 degrees C), good performances were obtained in both reactors. However, after the cold shock (ca. 13 degrees C), both reactors deteriorated similarly. The ammonia removal efficiencies decreased by half, while total nitrogen (TN) removal efficiencies decreased by two thirds. Nitrite accumulated in both reactors, while nitrate production was not disturbed although its contributions from nitrite oxidizing bacteria (NOB) increased. In the stage with increasing wastewater temperatures (17.5 +/- 2.2 degrees C), several operational conditions were tested to recover the performances, including limited dissolved oxygen, long hydraulic retention time (HRT), high nitrogen loading with elevated pH, and low NH4+-N (60 mg/L), which did not significantly improve the performances, while the phenomena of heterotrophic nitrate reduction dramatically improved the nitrogen removal performances under limited aeration. During the cold temperature shock, insufficient anammox activity, and nitrate overproduction were the main problems. PMID- 29704182 TI - Early Childhood Obesity Risk Factors: Socioeconomic Adversity, Family Dysfunction, Offspring Distress, and Junk Food Self-Medication. AB - PURPOSE OF REVIEW: To explore the sequence and interaction of infancy and early childhood risk factors, particularly relating to disturbances in the social environment, and how the consequences of such exposures can promote weight gain and obesity. RECENT FINDINGS: This review will argue that socioeconomic adversity is a key upstream catalyst that sets the stage for critical midstream risk factors such as family strain and dysfunction, offspring insecurity, stress, emotional turmoil, low self-esteem, and poor mental health. These midstream risk factors, particularly stress and emotional turmoil, create a more or less perfect foil for calorie-dense junk food self-medication and subtle addiction, to alleviate uncomfortable psychological and emotional states. Disturbances in the social environment during infancy and early childhood appear to play a critical role in weight gain and obesity, through such mechanisms as insecurity, stress, and emotional turmoil, eventually leading to junk food self-medication and subtle addiction. PMID- 29704183 TI - Collaborative Care for Depression and Posttraumatic Stress Disorder: Evaluation of Collaborative Care Fidelity on Symptom Trajectories and Outcomes. AB - BACKGROUND: Despite the growing consensus that collaborative care is effective, limited research has focused on the importance of collaborative care fidelity as it relates to mental health clinical outcomes. OBJECTIVE: To assess the relationship of collaborative care fidelity on symptom trajectories and clinical outcomes among military service members enrolled in a multi-site randomized controlled trial for the treatment of depression and posttraumatic stress disorder (PTSD). DESIGN: Study data for our analyses came from a two-parallel arm randomized trial that evaluated the effectiveness of a centralized collaborative care model compared to the existing collaborative care model for the treatment of PTSD and depression. All patients were included in the analyses to evaluate how longitudinal trajectories of PTSD and depression scores differed across various collaborative care fidelity groupings. PARTICIPANTS: A total of 666 US Military Service members screening positive for probable PTSD or depression through primary care. MAIN MEASURES: Disease registry data from a web-based clinical management support tool was used to measure collaborative care fidelity for patients enrolled in the trial. Participant depression and PTSD symptoms were collected independently from research survey assessments at four time points across the 1-year trial period. Treatment utilization records were acquired from the Military Health System administrative records to determine mental health service use. KEY RESULTS: Consistent and late fidelity to the collaborative care model predicted an improving symptom trajectory over the course of treatment. This effect was more pronounced for patients with depression than for patients with PTSD. CONCLUSIONS: Long-term fidelity to key collaborative care elements throughout care episodes may improve depression outcomes, particularly for patients with elevated symptoms. More controlled research is needed to further understand the influence of collaborative care fidelity on clinical outcomes. TRIAL REGISTRATION: Clinicaltrials.gov Identifier NCT01492348. PMID- 29704184 TI - Venous thromboembolism prophylaxis in mental health in-patient services: a qualitative study. AB - Background Venous thromboembolism (VTE) is an important and potentially preventable cause of morbidity and mortality in hospitalised patients. It is a significant, international patient safety issue affecting medical, surgical and mental health in-patients. There is a paucity of published evidence on the incidence of VTE, and the role of VTE risk-assessment and prophylaxis, in mental healthcare settings. Epidemiological evidence indicates that antipsychotic medications are an independent risk factor for VTE. Objective To explore healthcare practitioners' experiences and perspectives regarding VTE prophylaxis for in-patients in mental health services in Ireland. Setting This study was conducted in two national teaching hospitals in Dublin, Ireland. Method This experiential, qualitative study was conducted using face-to-face, semi-structured interviews. Purposive sampling was used to allow strategic selection of participants from the pharmacy, medical and nursing disciplines. Data was analysed using inductive thematic analysis. Consolidated criteria for reporting qualitative studies guidelines were used as a reporting framework. Main outcome measure Participants' views on VTE prophylaxis for mental health in-patients. Results Five key themes were derived: risk factors in mental health, attitudes to risk-assessment, challenges with VTE prophylaxis, lack of awareness, and lack of evidence in mental health. Conclusion The results indicate considerable diversities in perceived risk of VTE, and in experiences with VTE risk-assessment and prophylaxis. VTE risk was considered in practice specifically for immobile, older adults and eating disorder patients on bed rest. Specific research is required to address this area of clinical uncertainty in mental health. PMID- 29704185 TI - The Effect of Heated CO2 Insufflation in Minimising Surgical Wound Contamination During Open Surgery. AB - The primary source of infections in open surgeries has been found to be bacteria and viruses carried into the surgical wound on the surfaces of skin particles shed by patients and surgical staff. In open cardiac surgeries, insufflation of the wound with carbon dioxide is used to limit the quantity of air able to enter into the heart, avoiding air embolisms when the heart is restarted. This surgical technique has been evaluated as a method of limiting the number of skin particles able to enter into the wound, using computational fluid dynamics (CFD) simulations and experimental testing. Spherical particles of 5.0 and 13.5 MUm in diameter were used to simulate skin particles falling above a wound, travelling in air ventilation velocities of either 0.2 or 0.4 m/s, and with or without CO2 insufflation. The CFD simulations with CO2 included a diffuser placed in the wound and supplied with CO2 at a rate of 10 L/min. Experimental testing was completed under similar conditions. The results of CFD simulations and experimental testing showed CO2 insufflation can significantly limit the number of particles able to enter into the wound. PMID- 29704186 TI - Immersive Virtual Reality to Improve Walking Abilities in Cerebral Palsy: A Pilot Study. AB - Immersive virtual reality (IVR) offers new possibilities to perform treatments in an ecological and interactive environment with multimodal online feedbacks. Sixteen school-aged children (mean age 11 +/- 2.4 years) with Bilateral CP diplegia, attending mainstream schools were recruited for a pilot study in a pre post treatment experimental design. The intervention was focused on walking competences and endurance and performed by the Gait Real-time Analysis Interactive Lab (GRAIL), an innovative treadmill platform based on IVR. The participants underwent eighteen therapy sessions in 4 weeks. Functional evaluations, instrumental measures including GAIT analysis and parental questionnaire were utilized to assess the treatment effects. Walking pattern (stride length left and right side, respectively p = 0.001 and 0.003; walking speed p = 0.001), endurance (6MWT, p = 0.026), gross motor abilities (GMFM-88, p = 0.041) and most kinematic and kinetic parameters significantly improved after the intervention. The changes were mainly predicted by age and cognitive abilities. The effect could have been due to the possibility of IVR to foster integration of motor/perceptual competences beyond the training of the walking ability, giving a chance of improvement also to older and already treated children. PMID- 29704187 TI - Torso-Tank Validation of High-Resolution Electrogastrography (EGG): Forward Modelling, Methodology and Results. AB - Electrogastrography (EGG) is a non-invasive method for measuring gastric electrical activity. Recent simulation studies have attempted to extend the current clinical utility of the EGG, in particular by providing a theoretical framework for distinguishing specific gastric slow wave dysrhythmias. In this paper we implement an experimental setup called a 'torso-tank' with the aim of expanding and experimentally validating these previous simulations. The torso tank was developed using an adult male torso phantom with 190 electrodes embedded throughout the torso. The gastric slow waves were reproduced using an artificial current source capable of producing 3D electrical fields. Multiple gastric dysrhythmias were reproduced based on high-resolution mapping data from cases of human gastric dysfunction (gastric re-entry, conduction blocks and ectopic pacemakers) in addition to normal test data. Each case was recorded and compared to the previously-presented simulated results. Qualitative and quantitative analyses were performed to define the accuracy showing [Formula: see text] 1.8% difference, [Formula: see text] 0.99 correlation, and [Formula: see text] 0.04 normalised RMS error between experimental and simulated findings. These results reaffirm previous findings and these methods in unison therefore present a promising morphological-based methodology for advancing the understanding and clinical applications of EGG. PMID- 29704188 TI - Mucolipidosis type III, a series of adult patients. AB - BACKGROUND: Mucolipidosis type III alpha/beta or gamma (MLIII) are rare autosomal recessive diseases, in which reduced activity of the enzyme UDP-N-acetyl glucosamine-1-phosphotransferase (GlcNAc-PTase) leads to intra-lysosomal accumulation of different substrates. Publications on the natural history of MLIII, especially the milder forms, are scarce. This study provides a detailed description of the disease characteristics and its natural course in adult patients with MLIII. METHODS: In this retrospective chart study, the clinical, biochemical and molecular findings in adult patients with a confirmed diagnosis of MLIII from three treatment centres were collected. RESULTS: Thirteen patients with MLIII were included in this study. Four patients (31%) were initially misdiagnosed with a type of mucopolysaccharidosis (MPS). Four patients (31%) had mild cognitive impairment. Six patients (46%) needed help with activities of daily living (ADL) or were wheelchair-dependent. All patients had dysostosis multiplex and progressive secondary osteoarthritis, characterised by cartilage destruction and bone lesions in multiple joints. All patients underwent multiple orthopaedic surgical interventions as early as the second or third decades of life, of which total hip replacement (THR) was the most common procedure (61% of patients). Carpal tunnel syndrome (CTS) was found in 12 patients (92%) and in eight patients (61%), CTS release was performed. CONCLUSIONS: Severe skeletal abnormalities, resulting from abnormal bone development and severe progressive osteoarthritis, are the hallmark of MLIII, necessitating surgical orthopaedic interventions early in life. Future therapies for this disease should focus on improving cartilage and bone quality, preventing skeletal complications and improving mobility. PMID- 29704190 TI - Tissue Engineering in Osteoarthritis: Current Status and Prospect of Mesenchymal Stem Cell Therapy. AB - Osteoarthritis (OA) is the most common form of arthritis. Over the last 20 years, attempts have been made to regenerate articular cartilage to overcome the limitations of conventional treatments. As OA is generally associated with larger and diffuse involvement of articular surfaces and alteration of joint homeostasis, a tissue engineering approach for cartilage regeneration is more difficult than in simple chondral defects. Autologous and allogeneic mesenchymal stem cells (MSCs) have rapidly emerged as investigational products for cartilage regeneration. This review outlines points to consider in MSC-based approaches for OA treatment, including allogeneic MSCs, sources of MSCs, dosages, feasibility of multiple injections, indication according to severity of OA lesion and patient age, and issues regarding implantation versus injection. We introduce possible mechanisms of action of implanted or injected MSCs as well as the immunological aspects of MSC therapy and provide a summary of clinical trials of MSCs in the treatment of OA. Given current knowledge, it is too early to draw conclusions on the ultimate effectiveness of intra-articular application of MSCs in terms of regenerative effects. Further radiological and histological data will be needed, with a larger pool of patients, before this question can be answered. PMID- 29704189 TI - Periodic Health Examination and Injury Prediction in Professional Football (Soccer): Theoretically, the Prognosis is Good. AB - In professional soccer and other elite sports, medical and performance screening of athletes (also termed periodic health examination or PHE) is common practice. The purposes of this are: (1) to assist in identifying prevalent conditions that may be a threat to safe participation, (2) to assist in setting benchmark targets for rehabilitation or performance purposes and (3) to assist clinicians in determining which athletes may be at risk of future injury and selecting appropriate injury prevention strategies to reduce the perceived risk. However, when using PHE as an injury prevention tool, are clinicians seeking to identify potential causes of injury or to predict future injury? This Current Opinion aims to examine the conceptual differences between aetiology and prediction of injury while relating these areas to the capabilities of PHE in practice. We also introduce the concept of prognosis-a broader approach that is closely related to prediction-and why this may have greater applicability to PHE of professional athletes. PMID- 29704191 TI - Morning Stiffness in Elderly Patients with Rheumatoid Arthritis: What is Known About the Effect of Biological and Targeted Agents? AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease that affects all age groups, but the prevalence appears to increase with age. Elderly-onset RA (after the age of 60 years) has distinct clinical patterns. Treatment of RA in older individuals is confounded by the presence of medical comorbidities, concurrent medications, drug interactions, and the altered pharmacokinetics and pharmacodynamics related to aging and organ dysfunction. Patients with RA commonly experience morning stiffness, which is associated with reduced quality of life and work disability. However, despite its importance, morning stiffness is seldom assessed in clinical practice and usually only its duration is measured in the research setting. Whether the intensity, timing, location and impact of this symptom should be assessed in future clinical trials requires further evaluation. The biologic and newer targeted synthetic disease-modifying anti rheumatic drugs have been shown to be effective in reducing the duration of morning stiffness in patients with RA. Glucocorticoids are a double-edged sword in RA. Although they can effectively reduce inflammation and retard radiological damage (disease modifying), the long-term use of glucocorticoids is associated with numerous adverse effects. Thus, glucocorticoids should be used for short term treatment of RA only. Night-time administration of glucocorticoids has been shown to alleviate morning stiffness and should be considered in patients with serious morning joint stiffness symptoms. PMID- 29704192 TI - SGLT2 inhibition and heart failure-current concepts. AB - Type 2 diabetes mellitus (T2DM) is a major risk factor for several cardiovascular (CV) conditions, including heart failure (HF). However, until recently, no therapy to treat patients with diabetes could also reduce CV risks related to HF. The EMPA-REG OUTCOME trial with empagliflozin was the first to demonstrate significant cardioprotective benefits in this population. Its impressive 35% reduction in hospitalizations for HF drew the attention of the scientific community to the possibility that pharmacologic sodium-glucose cotransporter 2 (SGLT2) inhibition could be part of the armamentarium for treating patients with HF, with and without diabetes. The recently published CANVAS Program (with canagliflozin) and real-life data from the CVD-Real Study (using dapagliflozin, empagliflozin, and canagliflozin) further strengthened this hypothesis, suggesting that the observed benefit is not restricted to a particular drug, but is rather a class effect. This review explores the effects of pharmacologic SGLT2 inhibitors' use in cardiac function and discusses the potential role of this class of medication as a treatment for HF. PMID- 29704193 TI - Health Selection, Migration, and HIV Infection in Malawi. AB - Despite its importance in studies of migrant health, selectivity of migrants-also known as migration health selection-has seldom been examined in sub-Saharan Africa (SSA). This neglect is problematic because several features of the context in which migration occurs in SSA-very high levels of HIV, in particular-differ from contextual features in regions that have been studied more thoroughly. To address this important gap, we use longitudinal panel data from Malawi to examine whether migrants differ from nonmigrants in pre-migration health, assessed via SF 12 measures of mental and physical health. In addition to overall health selection, we focus on three more-specific factors that may affect the relationship between migration and health: (1) whether migration health selection differs by destination (rural-rural, rural-town, and rural-urban), (2) whether HIV infection moderates the relationship between migration and health, and (3) whether circular migrants differ in pre-migration health status. We find evidence of the healthy migrant phenomenon in Malawi, where physically healthier individuals are more likely to move. This relationship varies by migration destination, with healthier rural migrants moving to urban and other rural areas. We also find interactions between HIV-infected status and health: HIV-infected women moving to cities are physically healthier than their nonmigrant counterparts. PMID- 29704194 TI - Qualitative Assessment of Clerkship Students' Perspectives of the Topics of Pain and Addiction in their Preclinical Curriculum. AB - OBJECTIVE: A majority of physicians feel poorly trained in the treatment of chronic pain and addiction. As such, it is critical that medical students receive appropriate education in both pain management and addiction. The purpose of this study was to assess the pre-clinical curriculum in pain medicine and addiction from the perspective of students after they had completed their pre-clinical training and to assess what they perceived as the strengths and weaknesses of their training. METHODS: The authors conducted focused interviews among clinical medical students who had completed at least 6 months of clerkships. The interviews targeted the students' retrospective opinions about the pre-clinical curriculum and their preparedness for clinical encounters with either pain or addiction-related issues during their rotations. Coders thematically analyzed the de-identified interview transcripts, with consensus reached through discussion and code modification. RESULTS: Themes that emerged through the focused interviews included: fragmented curricular structure (and insufficient time) for pain and addiction medicine, not enough specific treatment strategies for pain or addiction, especially for complex clinical scenarios, and lack of a trained work force to provide guidance in the management of pain and addiction. CONCLUSION: This study demonstrated the feasibility of gathering student perspectives to inform changes to improve the pre-clinical curriculum in pain and addiction medicine. Students identified multiple areas for improvement at the pre-clerkship level, which have informed updates to the curriculum. More research is needed to determine if curricular changes based on student feedback lead to improved learning outcomes. PMID- 29704195 TI - A Four-Week Reflective Writing Program in the Psychiatry Clerkship: Testing Effects on Reflective Capacity. AB - OBJECTIVE: Reflective capacity is the ability to review and reconstruct the importance, emotional impact, and outcomes of an experience to give it added meaning and context. In medicine, greater reflective capacity is associated with greater empathy and diagnostic accuracy. This project implemented a four-week reflective writing curriculum for third-year medical students during their psychiatric clerkship. METHODS: A single class of medical students participated in a pilot reflective writing program during their four-week Psychiatry Care Block. Students were provided with weekly writing prompts, and the reflective capacity of their writing assignments was assessed using the REFLECT rubric. RESULTS: Medical students who participated in the reflective writing course demonstrated a significant increase in Wald Rubric reflective writing scores across the four-week clerkship. CONCLUSIONS: These results suggest a short, four week reflective writing curriculum can enhance reflective capacity in a class of third-year medical students. PMID- 29704197 TI - Impaired Bioenergetics in Mutant Mitochondrial DNA Determines Cell Fate During Seizure-Like Activity. AB - Mutations in genes affecting mitochondrial proteins are increasingly recognised in patients with epilepsy, but the factors determining cell fate during seizure activity in these mutations remain unknown. Fluorescent dye imaging techniques were applied to fibroblast cell lines from patients suffering from common mitochondrial mutations and to age-matched controls. Using live cell imaging techniques in fibroblasts, we show that fibroblasts with mutations in the mitochondrial genome had reduced mitochondrial membrane potential and NADH pools and higher redox indices, indicative of respiratory chain dysfunction. Increasing concentrations of ferutinin, a Ca2+ ionophore, led to oscillatory Ca2+ signals in fibroblasts resembling dynamic Ca2+ changes that occur during seizure-like activity. Co-monitoring of mitochondrial membrane potential (DeltaPsim) changes induced by ferutinin showed accelerated membrane depolarisation and cell collapse in fibroblasts with mutations in the mitochondrial genome when compared to controls. Ca2+ flash photolysis using caged Ca2+ confirmed impaired Ca2+ handling in fibroblasts with mitochondrial mutations. Findings indicate that intracellular Ca2+ levels cannot be compensated during periods of hyperexcitability, leading to Ca2+ overload and subsequent cell death in mitochondrial diseases. PMID- 29704196 TI - Exploiting the potential of unlabeled endoscopic video data with self-supervised learning. AB - PURPOSE: Surgical data science is a new research field that aims to observe all aspects of the patient treatment process in order to provide the right assistance at the right time. Due to the breakthrough successes of deep learning-based solutions for automatic image annotation, the availability of reference annotations for algorithm training is becoming a major bottleneck in the field. The purpose of this paper was to investigate the concept of self-supervised learning to address this issue. METHODS: Our approach is guided by the hypothesis that unlabeled video data can be used to learn a representation of the target domain that boosts the performance of state-of-the-art machine learning algorithms when used for pre-training. Core of the method is an auxiliary task based on raw endoscopic video data of the target domain that is used to initialize the convolutional neural network (CNN) for the target task. In this paper, we propose the re-colorization of medical images with a conditional generative adversarial network (cGAN)-based architecture as auxiliary task. A variant of the method involves a second pre-training step based on labeled data for the target task from a related domain. We validate both variants using medical instrument segmentation as target task. RESULTS: The proposed approach can be used to radically reduce the manual annotation effort involved in training CNNs. Compared to the baseline approach of generating annotated data from scratch, our method decreases exploratively the number of labeled images by up to 75% without sacrificing performance. Our method also outperforms alternative methods for CNN pre-training, such as pre-training on publicly available non medical (COCO) or medical data (MICCAI EndoVis2017 challenge) using the target task (in this instance: segmentation). CONCLUSION: As it makes efficient use of available (non-)public and (un-)labeled data, the approach has the potential to become a valuable tool for CNN (pre-)training. PMID- 29704198 TI - Extracellular Galectin-3 Induces Accelerated Oligodendroglial Differentiation Through Changes in Signaling Pathways and Cytoskeleton Dynamics. AB - Galectin-3 (Gal-3) is a chimeric protein structurally composed of unusual tandem repeats of proline and short glycine-rich segments fused onto a carbohydrate recognition domain. Our studies have previously demonstrated that Gal-3 drives oligodendrocyte (OLG) differentiation to control myelin integrity and function. The cytoskeleton plays a key role in OLG maturation: the initial stage of OLG process extension requires dynamic actin filament assembly, while subsequent myelin wrapping coincides with the upregulation of actin disassembly proteins which are dependent on myelin basic protein (MPB) expression. In this context, the aim of the present work was to elucidate the mechanism by which recombinant Gal-3 (rGal-3) induces OLG maturation, giving special attention to the actin cytoskeleton. Our results show that rGal-3 induced early actin filament assembly accompanied by Erk signaling deactivation, which led to a decrease in the number of platelet-derived growth factor receptor alpha (PDGFRalpha)+ cells concomitantly with an increase in the number of 2',3'-cyclic-nucleotide 3' phosphodiesterase (CNPase)+ cells at 1 day of treatment (TD1), and Akt signaling activation at TD1 and TD3. Strikingly, rGal-3 induced an accelerated shift from polymerized to depolymerized actin between TD3 and TD5, accompanied by a significant increase in MBP, gelsolin, Rac1, Rac1-GTP, and beta-catenin expression at TD5. These results were strongly supported by assays using Erk 1/2 and Akt inhibitors, indicating that both pathways are key to rGal-3-mediated effects. Erk 1/2 inhibition in control-treated cells resembled an rGal-3 like state characterized by an increase in MBP, beta-catenin, and gelsolin expression. In contrast, Akt inhibition in rGal-3-treated cells reduced MBP, beta-catenin, and gelsolin expression, indicating a blockade of rGal-3 effects. Taken together, these results indicate that rGal-3 accelerates OLG maturation by modulating signaling pathways and protein expression which lead to changes in actin cytoskeleton dynamics. PMID- 29704199 TI - Inactivation of Basolateral Amygdala Prevents Stress-Induced Astroglial Loss in the Prefrontal Cortex. AB - Repeated stress causes cognitive decline and decreases the expression of glial fibrillary acidic protein (GFAP)+ astroglial cells in the prefrontal cortex (PFC). The stress-induced alterations in astroglial density and morphology might significantly contribute to cognitive impairments. Apart from PFC, a key region involved in modulation of repercussions of stress is basolateral amygdala (BLA), which undergoes hypertrophy following chronic immobilization stress (CIS) and has intense reciprocal connections to the PFC. Interestingly, inactivation of BLA precludes stress-induced learning deficits. However, the modulatory role of BLA on CIS-induced alterations in GFAP+ astroglial density and associated learning deficits are presently unknown. Accordingly, we present two sets of experiments evaluating the effects of BLA inactivation either permanently or temporarily on CIS-induced changes in learning and astroglial expression in the PFC. CIS causes impairment in novel object recognition memory and astroglial loss in the PFC. In experiment I, we permanently inactivated the BLA by ibotenate lesion prior to CIS and observed a significant improvement in learning. Surprisingly, BLA lesion also prevented the stress-induced astroglial loss in the PFC. Furthermore, in the experiment II, we analyzed whether the effects of permanent inactivation could be mirrored by the temporary blockage of BLA specifically during stress. Interestingly, temporary inactivation of BLA mimics the effects of lesion. There was a notable prevention of learning impairment and astroglial loss in the PFC following BLA inactivation during stress. The present study emphasizes that stress-induced astroglial loss might contribute to cognitive deficits and modulation of BLA activity might be a viable strategy for management of stress related PFC dysfunctions. PMID- 29704200 TI - Identification of Alprenolol Hydrochloride as an Anti-prion Compound Using Surface Plasmon Resonance Imaging. AB - Prion diseases are transmissible neurodegenerative disorders of humans and animals, which are characterized by the aggregation of abnormal prion protein (PrPSc) in the central nervous system. Although several small compounds that bind to normal PrP (PrPC) have been shown to inhibit structural conversion of the protein, an effective therapy for human prion disease remains to be established. In this study, we screened 1200 existing drugs approved by the US Food and Drug Administration (FDA) for anti-prion activity using surface plasmon resonance imaging (SPRi). Of these drugs, 31 showed strong binding activity to recombinant human PrP, and three of these reduced the accumulation of PrPSc in prion-infected cells. One of the active compounds, alprenolol hydrochloride, which is used clinically as a beta-adrenergic blocker for hypertension, also reduced the accumulation of PrPSc in the brains of prion-infected mice at the middle stage of the disease when the drug was administered orally with their daily water from the day after infection. Docking simulation analysis suggested that alprenolol hydrochloride fitted into the hotspot within mouse PrPC, which is known as the most fragile structure within the protein. These findings provide evidence that SPRi is useful in identifying effective drug candidates for neurodegenerative diseases caused by abnormal protein aggregation, such as prion diseases. PMID- 29704201 TI - Targeted Gene Editing of Glia Maturation Factor in Microglia: a Novel Alzheimer's Disease Therapeutic Target. AB - Alzheimer's disease (AD) is a devastating, progressive neurodegenerative disorder that leads to severe cognitive impairment in elderly patients. Chronic neuroinflammation plays an important role in the AD pathogenesis. Glia maturation factor (GMF), a proinflammatory molecule discovered in our laboratory, is significantly upregulated in various regions of AD brains. We have previously reported that GMF is predominantly expressed in the reactive glial cells surrounding the amyloid plaques (APs) in the mouse and human AD brain. Microglia are the major source of proinflammatory cytokines and chemokines including GMF. Recently clustered regularly interspaced short palindromic repeats (CRISPR) based genome editing has been recognized to study the functions of genes that are implicated in various diseases. Here, we investigated if CRISPR-Cas9-mediated GMF gene editing leads to inhibition of GMF expression and suppression of microglial activation. Confocal microscopy of murine BV2 microglial cell line transduced with an adeno-associated virus (AAV) coexpressing Staphylococcus aureus (Sa) Cas9 and a GMF-specific guide RNA (GMF-sgRNA) revealed few cells expressing SaCas9 while lacking GMF expression, thereby confirming successful GMF gene editing. To further improve GMF gene editing efficiency, we developed lentiviral vectors (LVs) expressing either Streptococcus pyogenes (Sp) Cas9 or GMF-sgRNAs. BV2 cells cotransduced with LVs expressing SpCas9 and GMF-sgRNAs revealed reduced GMF expression and the presence of indels in the exons 2 and 3 of the GMF coding sequence. Lipopolysaccharide (LPS) treatment of GMF-edited cells led to reduced microglial activation as shown by reduced p38 MAPK phosphorylation. We believe that targeted in vivo GMF gene editing has a significant potential for developing a unique and novel AD therapy. PMID- 29704203 TI - Safety and efficacy of synchronous robotic surgery for colorectal cancer with liver metastases. AB - Timing of resection and treatment of colorectal cancer (CRC) with liver metastases varies based on patient characteristics and center protocols. Concerns of increased morbidity and mortality (M&M) related to anesthetic time and blood loss have limited widespread adaptation of synchronous colorectal and liver resections. Furthermore, technical challenges have made minimally invasive synchronous resections less common. We present our series of synchronous robotic surgery for CRC with liver metastases. Retrospective review of prospectively collected data of patients with stage IV CRC with liver metastases treated at a tertiary center from February 2013 to June 2014. Patients who underwent synchronous robotic surgery for CRC with liver metastasis(es) were included and selected by a multidisciplinary cancer committee. Data included patient demographics, disease stage, OR time, EBL, and complications. All resections were performed robotically by the same well-experienced surgeons. A radiologist was present for intraoperative ultrasound. Liver treatment was performed first in consideration of intraoperative bleeding risk. Sixty-six patients with Stage IV CRC were seen at the tertiary center during the study period. Six patients met inclusion criteria (2 male, 4 female). Mean age was 59.3 years and mean BMI was 23.46. Mean of 2.25 liver segments were resected and mean of 1.75 liver segments were ablated. Four patients underwent metastatectomy; three with concurrent microwave ablation. One patient had ablation without resection and another had no identifiable lesion on ultrasound. The colonic resections included 3 low anterior resections, 2 abdominal perineal resections (APR), and 1 right hemicolectomy. Mean operative time was 401 min (349-506 min) with mean EBL of 316 mL (150-1000 mL). No conversions to an open approach occurred. Median length of stay (LOS) was 4.5 days (3-10 days). Complications included delayed wound healing after an APR and a delayed rectal anastomotic failure after ileostomy reversal. There was no 30-day mortality. At a mean follow-up of 19 months, one death occurred at 26 months and the remaining patients had documented metastatic disease. Synchronous resection for metastatic CRC carries risks. We report our series of synchronous robotic surgery for CRC with liver metastases. The robotic approach contributed to low blood loss, appropriate LOS, and no 30-day mortality. Morbidity experienced was consistent with the procedures and not related to the robotic technique. This series supports the potential benefits of synchronous resection from a technical standpoint. Further data are required to determine treatment and survival benefits. Limitations include small number and retrospective review of data. PMID- 29704202 TI - Role of HPA and the HPG Axis Interaction in Testosterone-Mediated Learned Helpless Behavior. AB - Affective disorders show sex-specific differences in prevalence, symptoms, and complications. One hypothesis for this discrepancy is the interaction between the hypothalamic-pituitary-adrenal (HPA) axis and hypothalamic-pituitary-gonadal (HPG) axis. The present study investigates the influence of androgen on the behavioral phenotype and explores how it interacts with HPA axis genes. Gonadectomized (GDX) and GDX rats treated with testosterone propionate (T) were tested for learned helplessness (LH) behavior and compared with tested controls (TC). Prefrontal cortex was used for analyses of HPG- axis-related genes (androgen receptor, (Ar); estrogen receptor-beta (Er-beta)) and HPA axis-related genes (corticotropin-releasing hormone, (Crh); glucocorticoid receptor, (Nr3c1); corticotropin-releasing hormone receptor 1, (Crhr1); corticotropin-releasing hormone receptor 2, (Crhr2); FK506 binding protein 5, (Fkbp5)). Promoter-specific CpG methylation in the Crh gene was determined by bisulfite sequencing. Chromatin immunoprecipitation (ChIP) assay was used for determining ER-beta binding on the proximal promoter region of Crh gene. Serum testosterone levels confirmed a testosterone-depleted GDX group, a group with supraphysiological levels of testosterone (T) and another group with physiological levels of testosterone (control (C)). Unlike GDX rats, T group exhibited significantly higher LH score when compared with any other group. Crh and Fkbp5 genes were significantly upregulated in GDX group compared with controls, whereas Er-beta showed a significant downregulation in the same group. Methylation analysis showed no significant differences in-between groups. ChIP assay was unable to determine a significant change in ER-beta binding but revealed a notable contrast in Crh promoter occupancy between T and GDX groups. Altogether, the present study reveals an increased susceptibility to depression-like behavior due to chronic supraphysiological level of androgen via HPA axis inhibition. PMID- 29704204 TI - Tissue Trace Elements and Lipid Peroxidation in Breeding Female Bank Voles Myodes glareolus. AB - Recent studies have demonstrated that reproduction reduces oxidative damage in various tissues of small mammal females. The present work was designed to determine whether the reduction of oxidative stress in reproductive bank vole females was associated with changes in tissue trace elements (iron, copper, zinc) that play an essential role in the production of reactive oxygen species. Lipid peroxidation (a marker of oxidative stress) and iron concentration in liver, kidneys, and skeletal muscles of reproducing bank vole females that weaned one litter were significantly lower than in non-reproducing females; linear regression analysis confirmed a positive relation between the tissue iron and lipid peroxidation. The concentrations of copper were significantly lower only in skeletal muscles of reproductive females and correlated positively with lipid peroxidation. No changes in tissue zinc were found in breeding females when compared with non-breeding animals. These data indicate that decreases in tissue iron and copper concentrations may be responsible for the reduction of oxidative stress in reproductive bank vole females. PMID- 29704205 TI - Analysis of the Relationship Between Hemorheologic Parameters, Aluminum, Manganese, and Selenium in Smokers. AB - Smoking is a significant risk factor in fatal pathologies including cardio cerebrovascular and respiratory diseases. Aluminum (Al) is a toxic element without known biological function, but with recognized toxic effects. Manganese (Mn) and selenium (Se) are essential trace elements involved in cellular antioxidant defense mechanisms. Al, Mn, and Se carry out their metabolic activities via blood flow and tissue oxygenation. The structure and number of red blood cells (RBC) play important role in tissue oxygenation throughout blood flow. Increased hematocrit (Hct) as a result of probable hypoxia induces disturbed blood flow, RBC aggregation (RBC Agg), RBC deformability index (Tk), and oxygen delivery index (ODI). Therefore, we aimed to investigate the effects of altered Al, Mn, and Se levels on number, structure, and function of RBCs (Hct, blood and plasma viscosity (BV and PV, respectively), RBC Agg, Tk, ODI) in smokers without diagnosis of chronic obstructive pulmonary disease (COPD) in a study group (n = 128) categorized as ex-smokers (ES), smokers (S), and healthy controls (HC). Elements were analyzed in serum using ICP-OES. BV and PV were measured via Brookfield and Harkness viscometers at 37 degrees C, respectively. Smokers had statistically higher serum Al and Mn levels, BV, RBC, Hgb, Hct, PV, fibrinogen, RBC Agg, Tk45, and pulmonary blood flow rate, but lower serum Se levels and ODI45 values versus HC. In conclusion, increased Al, Mn, and hemorheological parameters and decreased Se and ODI45 might result from inflammatory response in defense mechanism in smokers without diagnosis of COPD. Our results point out that serum Al, Mn, and Se with hemorheological parameters may be beneficial markers of tissue oxygenation and defense mechanism before the clinic onset of COPD in smokers. PMID- 29704206 TI - Protective Effect of Rosa damascena Against Aluminum Chloride-Induced Oxidative Stress. AB - Aluminum is considered an essential element endowed with toxicity potentials in human and animal. Thus, intoxication with aluminum can lead to oxidative stress, which is associated with oxidative damage to various macromolecules. Moreover, antioxidants from natural sources can play an important role in human health. Accordingly, the purpose of this study was to investigate the protective effect of Rosa damascena extract against aluminum-induced oxidative stress. In this study, 60 male rats were randomly divided into six groups and then they were given daily aluminum chloride and Rosa damascena extract. After 8 weeks of treatment, the levels of total antioxidant and malondialdehyde, as well as antioxidant enzymes including catalase, glutathione S-transferase, and myeloperoxidase, were measured in all experimental groups in this study. A significant increase was found in the total antioxidant level in the rats treated with aluminum, Rosa damascena extract, and aluminum plus Rosa damascena extract compared with those in the control group. Also, malondialdehyde levels were not significantly different in all the studied groups. Glutathione S-transferase activity levels in rats receiving the Rosa damascena extract as well as rats taking aluminum with Rosa damascena extract increased significantly compared with the ones in the control group. Catalase activity in the aluminum-treated group also increased significantly compared with the rates in the control group (31.34 +/- 4.50 U/gHb vs. 14.04 +/- 6.17 U/gHb, p = 0.014). Furthermore, myeloperoxidase activity in the aluminum-treated group increased significantly compared with the control group (49.47 +/- 5.12 U/L vs. 25.28 +/- 2.18 U/L, p < 0.001). The Rosa damascena extract could improve antioxidant capacity and reduce oxidative conditions in rats receiving aluminum chloride as evidenced by assays of the ferric reducing ability of plasma and activity of antioxidant enzymes. According to the findings of this study, it can be concluded that the Rosa damascena extract with its high antioxidant content is able to exert a protective effect against aluminum-induced oxidative stress. PMID- 29704207 TI - Effects of Selenium- and Chromium-Enriched Diets on Growth Performance, Lipid Profile, and Mineral Concentration in Different Tissues of Growing Rabbits. AB - The aim of this study was to investigate the effect of dietary supplementation with different sources of selenium and/or organic chromium on the growth performance, digestibility, lipid profile, and mineral content of hair, liver, and fore and hind limb of growing rabbits. A total of 150 weanling New Zealand White (NZW) male rabbits were randomly allotted to six dietary treatment groups: (1) basal diet (control group), (2) basal diet + 0.6 mg sodium selenite/kg diet, (3) basal diet + 0.6 mg selenium yeast/kg diet, (4) basal diet + 0.3 mg sodium selenite/kg diet + 0.3 mg selenium yeast/kg diet, (5) basal diet + 0.6 mg chromium yeast/kg diet + 0.6 mg selenium yeast/kg diet, (6) basal diet + 0.6 mg chromium yeast/kg diet. Only the combination between inorganic and organic selenium led to significant improvement in body weight, body weight gain, and feed conversion ratio. Carcass traits were not different in all groups. Selenium (Se) and chromium (Cr) were deposited in the tissues of rabbits fed diets supplemented with Se and Cr, respectively. Blood serum in both of selenium- and chromium-supplemented groups showed declined total cholesterol, triglycerides, and low-density lipoprotein (LDL). Group supplemented with organic chromium showed higher high-density lipoprotein (HDL) than the other groups. It could be concluded that using a mixture of inorganic and organic Se has a positive effect on the growth performance of growing rabbits. Both Se and Cr have hypocholesterolemic effect. Both of Se and Cr can be deposited in the meat and other tissues of rabbits and that improves meat quality which positively reflects on human acceptance. The combination between inorganic (0.3 mg sodium selenite/kg diet) and organic selenium (0.6 mg selenium yeast/kg diet) improved growth performance traits of growing rabbits. PMID- 29704208 TI - Neuroimaging Neuroinformatics: Sample Size and Other Evolutionary Topics. PMID- 29704209 TI - Neurologic manifestations of elderly patients with cancer. AB - BACKGROUND: The incidence of cancer is an age-related phenomenon; therefore, the interest on clinical manifestations, diagnostic approach and treatment strategies for older patients diagnosed with cancer has increased lately. Neurologic symptoms are one of the main reasons for consultation and a common cause of decreased quality of life among cancer patients. AIMS: To identify the neurologic manifestations of patients >= 65 years of age diagnosed with cancer and compare them to those presented by a younger population. METHODS: Cross-sectional study of cancer patients referred to neuro-oncologic consultation at a Cancer Center. Sociodemographic, health and oncologic characteristics were obtained through clinical interviews. Clinical symptoms and final diagnoses were also recorded. Bivariate logistic regression analyses were carried out. RESULTS: More than 17,000 neuro-oncologic consultations in 3015 patients were given, 27% (n = 811) of them were >= 65 years of age. Most frequent primary neoplasms in elderly patients were: breast cancer, hematologic neoplasms, gynecological, urologic, skin and head and neck cancers. Elderly patients had an increased risk of having the following diagnoses: abnormal movements, stroke, peripheral vertigo, dementia, degenerative spine disorder, and delirium. DISCUSSION: Elderly patients are considered a vulnerable population. The present study found that the main neoplasms associated with neurological manifestations are similar to the reported previously. We described the main symptoms that led to a neuro-oncological assessment. Moreover, we enlisted the final diagnoses made on elderly patients and compared them with others reports. To the best of our knowledge, this study provides valuable information, since there is scarce evidence in the literature about this topic. CONCLUSION: Identifying the frequency and correlation of neurologic manifestations in older cancer patients will allow for the implementation of timely multidisciplinary care in an attempt to improve these patients' health-related quality of life. PMID- 29704210 TI - Epicardial adipose tissue: new parameter for cardiovascular risk assessment in high risk populations. AB - Epicardial adipose tissue (EAT) is localized between the myocardial surface and visceral layer of the pericardium. It is a metabolically active organ that secretes several cytokines which modulate cardiovascular morphology and function. EAT may interact locally with coronary arteries through paracrine secretion mechanisms. Cytokines from peri-adventitial EAT may pass through the coronary wall by diffusion from the outside to the inside, interacting with cells. An additional potential mechanism by which EAT interacts locally with coronary arteries may be the vasocrine secretion.EAT may play a significant role as a modulator of cardiac functions. In physiologic conditions, EAT has biochemical cardio-protective properties, secreting anti-atherosclerosis substances; in metabolic disease states, EAT secretes bioactive molecules that may play an important role in the pathogenesis of coronary artery disease and cardiac arrhythmias by promoting atherosclerosis. EAT has been evaluated both in the general population and in metabolic disease states that are characterized by inflammation, such as cardiovascular diseases and chronic kidney disease.This review focuses on the current state of knowledge on EAT as a reliable new parameter for cardiovascular risk stratification in high risk populations. PMID- 29704211 TI - [Occupational skin cancer : Prevention and recommendations for UV protection as part of the treatment approved by the public statutory employers' liability insurance]. AB - In Germany, approximately 2 to 3 million employees work in outdoor professions. They are exceptionally exposed to solar ultraviolet (UV) radiation for a large part of their daily working time. Cumulative UV exposure is associated with a significantly increased risk of skin cancer for outdoor workers from various occupational groups (e. g. landscape and horticulture, agriculture and forestry, fisheries and seafaring, construction and trade, as well as sports teachers, lifeguards and mountain guides). Since 1 January 2015, squamous cell carcinoma and multiple actinic keratosis due to natural UV radiation can be recognised as occupational disease No. 5103 by the German statutory social accident insurance. Reducing cumulative UV exposure is the main prevention aspect of this type of skin damage. Therefore, technical, organisational and personal UV protection measures should be implemented in the professional and private environment. Moreover, they have to be regularly used in an appropriate way. In addition to guideline-oriented therapy, training and counselling of patients with already existing actinic skin damage or a recognised occupational disease No. 5103 is therefore of particular importance. The focus should be on improving the individual UV protection behaviour. This article gives an overview of current recommendations for UV protection in the professional environment. It outlines possible solutions for patient counselling in terms of UV protection in everyday practice. PMID- 29704212 TI - Recent developments in biocatalysis in multiphasic ionic liquid reaction systems. AB - Ionic liquids are well known and frequently used 'designer solvents' for biocatalytic reactions. This review highlights recent achievements in the field of multiphasic ionic liquid-based reaction concepts. It covers classical biphasic systems including supported ionic liquid phases, thermo-regulated multi-component solvent systems (TMS) and polymerized ionic liquids. These powerful concepts combine unique reaction conditions with a high potential for future applications on a laboratory and industrial scale. The presence of a multiphasic system simplifies downstream processing due to the distribution of the catalyst and reactants in different phases. PMID- 29704213 TI - alpha-Synuclein strains and seeding in Parkinson's disease, incidental Lewy body disease, dementia with Lewy bodies and multiple system atrophy: similarities and differences. AB - Several age-related neurodegenerative disorders are characterized by the deposition of aberrantly folded endogenous proteins. These proteins have prion like propagation and amplification properties but so far appear nontransmissible between individuals. Because of the features they share with the prion protein, PrP, the characteristics of pathogenic protein aggregates in several progressive brain disorders, including different types of Lewy body diseases (LBDs), such as Parkinson's disease (PD), multiple system atrophy (MSA) and dementia with Lewy bodies (DLB), have been actively investigated. Even though the pleomorphic nature of these syndromes might suggest different underlying causes, alpha-synuclein (alphaSyn) appears to play an important role in this heterogeneous group of diseases (the synucleinopathies). An attractive hypothesis is that different types of alphaSyn protein assemblies have a unique and causative role in distinct synucleinopathies. We will discuss the recent research progress on alphaSyn assemblies involved in PD, MSA and DLB; their behavior as strains; current spreading hypotheses; their ability to seed centrally and peripherally; and their implication for disease pathogenesis. PMID- 29704215 TI - Population Pharmacokinetic Modeling to Describe the Total Plasma and Free Brain Levels of Fluconazole in Healthy and Cryptococcus neoformans Infected Rats: How Does the Infection Impact the Drug's Levels on Biophase? AB - PURPOSE: The present work aimed to evaluate the influence of experimental meningitis caused by C. neoformans on total plasma and free brain concentrations of fluconazole (FLC) in Wistar rats. METHOD: The infection was induced by the administration of 100 MUL of inoculum (1.105 CFU) through the tail vein. Free drug in the brain was assessed by microdialisys (MUD). Blood and MUD samples were collected at pre-determined time points up to 12 h after intravenous administration of FLC (20 mg/kg) to healthy and infected rats. The concentration time profiles were analyzed by non-compartmental and population pharmacokinetics approaches. RESULTS: A two-compartmental popPK model was able to simultaneously describe plasma and free drug concentrations in the brain for both groups investigated. Analysis of plasma and MUD samples showed a better FLC distribution on the brain of infected than healthy animals (1.04 +/- 0.31 vs 0.69 +/- 0.14, respectively). The probability of target attainment was calculated by Monte Carlo simulations based on the developed popPK model for 125 mg/kg dose for rats and 400-2000 mg for humans. CONCLUSIONS: FLC showed a limited use in monotherapy to the treatment of criptoccocosis in rats and humans to value of MIC >8 MUg/mL. PMID- 29704214 TI - Expert opinion paper on atrial fibrillation detection after ischemic stroke. AB - This expert opinion paper on atrial fibrillation detection after ischemic stroke includes a statement of the "Heart and Brain" consortium of the German Cardiac Society and the German Stroke Society. This paper was endorsed by the Stroke Unit Commission of the German Stroke Society and the German Atrial Fibrillation NETwork. In patients with ischemic stroke, detection of atrial fibrillation should usually lead to a change in secondary stroke prevention, since oral anticoagulation is superior to antiplatelet drugs. The detection of previously undiagnosed atrial fibrillation can be improved in patients with ischemic stroke to optimize stroke prevention. This paper summarizes the present knowledge on atrial fibrillation detection after ischemic stroke. We propose an interdisciplinary standard for a "structured analysis of ECG monitoring" on the stroke unit as well as a staged diagnostic scheme for the detection of atrial fibrillation. Since the optimal duration and mode of ECG monitoring has not yet been finally established, this paper is intended to give advice to physicians who are involved in stroke care. In line with the nature of an expert opinion paper, labeling of classes of recommendations is not provided, since many statements are based on the expert opinion, reported case series and clinical experience. Therefore, this paper is not intended as a guideline. PMID- 29704216 TI - Attentional capacities prior to drug exposure predict motivation to self administer nicotine. AB - RATIONALE: Nicotine can enhance attention and attribution of incentive salience to nicotine-associated stimuli. However, it is not clear whether inter-individual differences in attentional capacities prior to any exposure could play a role in vulnerability to nicotine self-administration. We further explored this vulnerability through pre-existing inter-individual differences in attention to a reward-predictive cue in drug-free animals. METHODS: A cued version of the Fixed Consecutive Number schedule (FCN16cue) of reinforcement task was used to assess attention. This task consists in completing a long chain of sequential lever presses to obtain a reward, and examines the rats' ability to pay attention to a cue light that signals its availability. Rats were then trained to self administer nicotine intravenously (30 MUg/kg/0.1 mL). Drug-taking and seeking behaviors were investigated. RESULTS: Our results showed important inter individual differences in response for nicotine during the progressive ratio schedule of reinforcement. By comparing rats in the lower and upper quartiles of the mean breaking point, we showed that high-motivated rats were also more sensitive to the reinforcing properties of nicotine than low-motivated ones. We found that while both groups did not differ in premature responding in the FCN16cue task, high-motivated rats were more efficient in taking the cue light into account than low-motivated rats as shown by a higher proportion of optimal chains, indicating a higher level of attention to the reward-predictive cue. Moreover, it was positively correlated with higher motivation for nicotine, a hallmark of nicotine addiction. CONCLUSIONS: These results suggest that higher attention to reward-associated cues prior to drug taking predicts vulnerability to nicotine-reinforcing properties. PMID- 29704217 TI - Momentary changes in craving predict smoking lapse behavior: a laboratory study. AB - RATIONALE: Current research on factors that predict smoking lapse behavior is limited in its ability to fully characterize the critical moments leading up to decisions to smoke. OBJECTIVES: We used a validated and widely used experimental analogue for smoking lapse to assess how moment-to-moment dynamics of craving relate to decisions to smoke. METHODS: Heavy smokers (N = 128, M age = 35.9) participated in a 50-min laboratory delay to smoking task on 2 consecutive days, earning money for each 5 min they remained abstinent or ending the task by choosing to smoke. Participants rated craving and negative affect levels immediately prior to each choice. Participants were randomized to smoking as usual (n = 50) or overnight abstinence (n = 50 successfully abstained, n = 22 failed abstaining) prior to session 2. Discrete-time hazard models were used to examine craving and negative affect as time-varying predictors of smoking. RESULTS: Higher craving levels prior to smoking opportunities predicted increased risk of smoking. When controlling for craving levels, incremental increases in craving predicted increased smoking risk. Increases in negative affect incrementally predicted increased smoking risk at session 2 only. Smokers who failed to abstain were at a higher risk of smoking than those who successfully abstained, whereas abstinent and non-abstinent smokers did not differ in smoking risk. CONCLUSIONS: Findings demonstrate an extension of the smoking lapse paradigm that can be utilized to capture momentary changes in craving that predict smoking behavior. Evaluations of nuanced craving experiences may inform clinical and pharmacological research on preventing smoking lapse and relapse. PMID- 29704218 TI - Correction to: Clozapine-related neutropenia, myocarditis and cardiomyopathy adverse event reports in Australia 1993-2014. AB - The authors would like to change the statement found in the results section of the abstract from "There were five reported deaths from neutropenia and cardiomyopathy." to "There were five, 13, and two reported deaths from neutropenia, myocarditis, and cardiomyopathy, respectively." PMID- 29704220 TI - Therapeutic applications of CRISPR/Cas9 system in gene therapy. AB - Gene therapy is based on the principle of the genetic manipulation of DNA or RNA for treating and preventing human diseases. The clustered regularly interspaced short palindromic repeats/CRISPR associated nuclease9 (CRISPR/Cas9) system, derived from the acquired immune system in bacteria and archaea, has provided a new tool for accurate manipulation of genomic sequence to attain a therapeutic result. The advantage of CRISPR which made it an easy and flexible tool for diverse genome editing purposes is that a single protein (Cas9) complex with 2 short RNA sequences, function as a site-specific endonuclease. Recently, application of CRISPR/Cas9 system has become popular for therapeutic aims such as gene therapy. In this article, we review the fundamental mechanisms of CRISPR Cas9 function and summarize preclinical CRISPR-mediated gene therapy reports on a wide variety of disorders. PMID- 29704219 TI - Receptor/gene/protein-mediated signaling connects methylprednisolone exposure to metabolic and immune-related pharmacodynamic actions in liver. AB - A multiscale pharmacodynamic model was developed to characterize the receptor mediated, transcriptomic, and proteomic determinants of corticosteroid (CS) effects on clinically relevant hepatic processes following a single dose of methylprednisolone (MPL) given to adrenalectomized (ADX) rats. The enhancement of tyrosine aminotransferase (TAT) mRNA, protein, and enzyme activity were simultaneously described. Mechanisms related to the effects of MPL on glucose homeostasis, including the regulation of CCAAT-enhancer binding protein-beta (C/EBPbeta) and phosphoenolpyruvate carboxykinase (PEPCK) as well as insulin dynamics were evaluated. The MPL-induced suppression of circulating lymphocytes was modeled by coupling its effect on cell trafficking with pharmacogenomic effects on cell apoptosis via the hepatic (STAT3-regulated) acute phase response. Transcriptomic and proteomic time-course profiles measured in steroid-treated rat liver were utilized to model the dynamics of mechanistically relevant gene products, which were linked to associated systemic end-points. While time-courses of TAT mRNA, protein, and activity were well described by transcription-mediated changes, additional post-transcriptional processes were included to explain the lack of correlation between PEPCK mRNA and protein. The immune response model quantitatively discerned the relative roles of cell trafficking versus gene mediated lymphocyte apoptosis by MPL. This systems pharmacodynamic model provides insights into the contributions of selected molecular events occurring in liver and explores mechanistic hypotheses for the multi-factorial control of clinically relevant pharmacodynamic outcomes. PMID- 29704221 TI - Erratum to: EG-VEGF Maintenance Over Early Gestation to Develop a Pregnancy Induced Hypertensive Animal Model. PMID- 29704222 TI - Canadian Anesthesia Incident Reporting System (CAIRS): The Canadian Anesthesiologists' Society's National Patient Safety Initiative. PMID- 29704223 TI - Low thoracic erector spinae plane block for perioperative analgesia in lumbosacral spine surgery: a case series. AB - PURPOSE: Severe postoperative pain following spine surgery is a significant cause of morbidity, extended length of facility stay, and marked opioid usage. The erector spinae plane (ESP) block anesthetizes the dorsal rami of spinal nerves that innervate the paraspinal muscles and bony vertebra. We describe the use of low thoracic ESP blocks as part of multimodal analgesia in lumbosacral spine surgery. CLINICAL FEATURES: We performed bilateral ESP blocks at the T10 or T12 level in six cases of lumbosacral spine surgery: three lumbar decompressions, two sacral laminoplasties, and one coccygectomy. Following induction of general anesthesia, single-injection ESP blocks were performed in three patients while bilateral continuous ESP block catheters were placed in the remaining three. All six patients had minimal postoperative pain and very low postoperative opioid requirements. There was no discernible motor or sensory block in any of the cases and no interference with intraoperative somatosensory evoked potential monitoring used in two of the cases. CONCLUSIONS: The ESP block can contribute significantly to a perioperative multimodal opioid-sparing analgesic regimen and enhance recovery after lumbosacral spine surgery. PMID- 29704224 TI - Ensuring all falling trees are heard: the importance of publishing all research. PMID- 29704225 TI - Neural substrates of fear-induced hypophagia in male and female rats. AB - Cessation of eating under fear is an adaptive response that aids survival by prioritizing the expression of defensive behaviors over feeding behavior. However, this response can become maladaptive when persistent. Thus, accurate mediation of the competition between fear and feeding is important in health and disease; yet, the underlying neural substrates are largely unknown. The current study identified brain regions that were recruited when a fear cue inhibited feeding in male and female rats. We used a previously established behavioral paradigm to elicit hypophagia with a conditioned cue for footshocks, and Fos imaging to map activation patterns during this behavior. We found that distinct patterns of recruitment were associated with feeding and fear expression, and that these patterns were similar in males and females except within the medial prefrontal cortex (mPFC). In both sexes, food consumption was associated with activation of cell groups in the central amygdalar nucleus, hypothalamus, and dorsal vagal complex, and exposure to food cues was associated with activation of the anterior basolateral amygdalar nucleus. In contrast, fear expression was associated with activation of the lateral and posterior basomedial amygdalar nuclei. Interestingly, selective recruitment of the mPFC in females, but not in males, was associated with both feeding and freezing behavior, suggesting sex differences in the neuronal processing underlying the competition between feeding and fear. This study provided the first evidence of the neural network mediating fear-induced hypophagia, and important functional activation maps for future interrogation of the underlying neural substrates. PMID- 29704226 TI - A novel mutation in the TUBB8 gene is associated with complete cleavage failure in fertilized eggs. AB - PURPOSE: Cleavage of the zygote during human reproduction is a key event of early embryonic development. The genetic events associated with idiopathic embryonic cleavage failure are not certain. Mutations in the tubulin beta 8 class VIII (TUBB8) gene have been reported to be associated with oocyte maturation, fertilization, and developmental arrest. Here, we aimed to assess the clinical and genetic characteristics of complete cleavage failure in fertilized eggs. METHODS: We have characterized a patient with a 9-year history of primary infertility in a non-consanguineous family from China. The patient presented complete cleavage failure in all two-pronuclear (2PN) fertilized oocytes after 2 cycles of in vitro fertilization (IVF). We performed Sanger sequencing of the TUBB8 gene in the patient, and further bioinformatics analysis to identify pathogenesis of gene. RESULTS: A novel homozygous mutation, c.322G > A (p.Glu108Lys), was detected, and this change was absent from 179 control subjects. Glutamic acid is highly conserved at this position, and replacement by lysine was predicted to be repelled by the alpha-tubulin positive region, disrupting the alpha-beta tubulin interaction. CONCLUSIONS: Our findings presented a homozygous mutation of TUBB8 associated with complete cleavage failure in fertilized eggs and provided new data for the genotype-phenotype of TUBB8-related diseases. PMID- 29704227 TI - Low estradiol responses in oocyte donors undergoing gonadotropin stimulation do not influence clinical outcomes. AB - PURPOSE: To examine the effect of low and very low estradiol responses in oocyte donors receiving gonadotropins on clinical outcomes of donor in vitro fertilization (IVF) cycles and to identify possible mechanisms responsible for low estradiol response. METHODS: This is a retrospective cohort study of oocyte donors undergoing antagonist IVF cycles with progression to oocyte retrieval between January 2010 and December 2016 at a single urban academic fertility center. Oocyte yield, fertilization rate, blastocyst rate, percentage of normal embryos on preimplantation genetic screening (PGS), pregnancy outcomes, and follicular fluid steroid profiles were compared between donors with normal estradiol response and those with low estradiol response. RESULTS: Three hundred sixty-six antagonist oocyte donor IVF cycles were identified: 42 cycles had a normal estradiol response (NE2), defined as peak serum estradiol (E2) of over 200 pg/mL per retrieved oocyte; 140 cycles had an intermediate estradiol response (iE2), defined as peak serum E2 between 100 and 200 pg/mL per retrieved oocyte; 110 cycles had a low estradiol response (LE2), defined as peak serum E2 between 50 and 100 pg/mL per retrieved oocyte; and 74 cycles had a very low estradiol response (vLE2), defined as peak serum E2 less than 50 pg/mL per retrieved oocyte. LE2 cycles resulted in a greater number of mature oocytes (22.4 vs. 13.6, p < 0.017), and fertilizations versus NE2 donors (18.5 vs. 10.7, p < 0.017), although the number of transferred or cryopreserved blastocysts were similar between groups (8.6, 6.9 vs. 4.8, p = 0.095, p = 1). The percentage of chromosomally normal embryos after PGS was similar between LE2, vLE2, and NE2 cycles (66.4, 71.8 vs. 63.1%, p = 0.99, p = 1). Pregnancy outcomes were similar between LE2, vLE2, and NE2 cycles. Serum AMH obtained on the day of peak E2 was similar to baseline serum AMH and did not differ between LE2 versus NE2 cycles. Follicular fluid E2 levels paralleled serum E2 levels and were lower in LE2 cycles versus NE2 cycles. CONCLUSION: The prevalence of very low E2 responses in donors appears to be high (20.2%). In contrast to autologous IVF cycles, LE2 does not portend poor outcomes in oocyte donors. PMID- 29704228 TI - A Prospective Randomized Controlled Trial of the Metabolic Effects of Sleeve Gastrectomy with Transit Bipartition. AB - PURPOSE: To compare the effects of the sleeve gastrectomy with transit bipartition (SG + TB) procedure with standard medical therapy (SMT) in mildly obese patients with type II diabetes (T2D). METHODS: This is a prospective, randomized, controlled trial. Twenty male adults, <= 65 years old, with T2D, body mass index (BMI) > 28 kg/m2 and < 35 kg/m2, and HbA1c level > 8% were randomized to SG + TB or to SMT. Outcomes were the remission in the metabolic and cardiovascular risk variables up to 24 months. RESULTS: At 24 months, SG + TB group showed a significant decrease in HbaA1c values (9.3 +/- 2.1 versus 5.5 +/- 1.1%, P = < 0.05) whereas SMT group maintained similar levels from baseline (8.0 +/- 1.5 versus 8.3 +/- 1.1%, P = NS). BMI values were lower in the SG + TB group (25.3 +/- 2.8 kg/m2 versus 30.9 +/- 2.5 kg/m2; P = < 0.001). At 24 months, none patient in SG + TB group needed medications for hyperlipidemia/hypertension. HDL cholesterol levels increased in the SG + TB group (33 +/- 8 to 45 +/- 15 mg/dL, P < 0.001). After 24 months, the area under the curve (AUC) of GLP1 increased and in the SG + TB group and the AUC of the GIP concentrations was lower in the SG + TB group than in the SMT. At 3 months, SG + TB group showed a marked increase in FGF19 levels (74.1 +/- 45.8 to 237.3 +/- 234 pg/mL; P = 0.001). CONCLUSIONS: SG + TB is superior to SMT and was associated with a better metabolic and cardiovascular profile. PMID- 29704229 TI - Roux-en-Y Gastric Bypass: Does the Direction of Staples Matter? AB - PURPOSE: Mechanical gastro-intestinal anastomosis using stapler is a critical step in laparoscopic Roux-en-Y gastric bypass (RYGB). To date the effect of the direction of staples on anastomotic leak has not been investigated. The study aim was to investigate the impact of the direction of staples on the integrity of the gastro-jejunal anastomosis. MATERIALS AND METHODS: Eight gastro-jejunostomy (GJ) models were performed using porcine stomach and small intestine. Specimens were divided into group A where the cartridge was in the gastric lumen with the anvil in the jejunal lumen and vice versa in group B. Enterotomy was closed and gastric and jejunal ends were stapled off. Burst pressure (BP) was measured by infusion of methylene blue saline into the GJ model until leak occurred. Site of leak, BP, and total volume (TV) infused were recorded. Compliance (C) was calculated from the equation DeltaTV/DeltaBP. RESULTS: The BP was greater in group A compared to group B (18 mmHg (range 15-25) versus 11 mmHg (range 8-15); p = 0.045) despite similar TV between the groups 60.00 mL (range 55.00-65.00) versus 51.25 mL (range 40.00-60.00); p = 0.11). The compliance did not significantly differ between groups A and B (6.38 mL/mmHg (range 4.34-8.59) versus 5.61 mL/mmHg (range 3.93 7.21); p = 0.48). CONCLUSION: BP recorded when the stapler cartridge was introduced in the gastric lumen was higher than when it was introduced from the jejunal lumen. The lack of difference in compliance between groups suggests that the difference in BP was due to the difference in the direction of staples. PMID- 29704230 TI - Application of HARM Score to Measure Surgical Quality and Outcomes in Bariatric Patients. AB - BACKGROUND: The HospitAl stay, Readmission, and Mortality rates (HARM) score is a quality indicator that is easily determined from routine administrative data. However, the HARM score has not yet been applied to patients undergoing bariatric surgery. OBJECTIVE: The aims of the present study were to adjust the HARM score to the bariatric population and to validate the ability of the modified HARM score to serve as an inexpensive tool to measure the quality of bariatric surgery. METHODS: A MBSAQIP 2015 PUF database was reviewed. For each discharge, a 1 to 10 score was calculated on the basis of length of stay (LOS), discharge status, and 30-day readmissions. We adjusted the LOS categories to the distribution of LOS in the MBSQIP database. The new LOS categories were used to calculate the modified HARM score, referred to as the BARiatric HARM (BAR-HARM) score. The association between HARM and BAR-HARM scores and complication rate was assessed. RESULTS: A total of 197,141 cases were evaluated: 98.8% were elective and 1.2% were emergent admissions. The mean individual patient BAR-HARM score was 1.75 +/- 1.04 for elective cases, and 2.02 +/- 1.45 for emergency cases. The complication rates for the respective BAR-HARM categories <= 2, > 2 to 3, > 3 to 4, and > 4 were 3.95, 27.53, 40.14, and 79.97% (p < 0.001). CONCLUSIONS: The quality of bariatric surgery can be reliably and validly assessed using the BAR HARM score, which is a modification of the HARM score. PMID- 29704231 TI - Management of extravasation of oxaliplatin by mimicking its biotransformation. AB - Although oxaliplatin (Oxali) plays a key role in the treatment of many types of cancer and has been reported to be an irritant, there is no specific and effective method for its extravasation and failure in Oxali extravasation management results in the need for plastic surgery. In the body, Oxali bio transforms upon dilution in chloride-containing buffer salts to its di-chloro derivative and loses an oxalate molecule. Consequently, the chloride ions exchange with water molecules in the intracellular environment to produce the di aqua derivative, which is the most active biotransformation product of Oxali in terms of forming the DNA adducts. Thus, inhibiting transformation of di-chloro to di-aqua derivatives by accumulating chloride ions at the site of extravasation and saturating the Oxali molecule with these ions is a strategy that could help manage extravasation. Injecting normal saline at this site is a simple yet effective way to achieve this goal. PMID- 29704232 TI - Prognostic and microRNA profile analysis for CD44 positive expression pediatric posterior fossa ependymoma. AB - BACKGROUND: Ependymoma is the third most common pediatric brain tumor and occurs most frequently in the posterior fossa. However, the lack of immortalized cell lines, xenografts, or animal models has significantly hindered the study of pediatric posterior fossa ependymoma (P-PF-EPN) pathogenesis. This prompted us to use clinical big data to study this rare disease. METHODS: Application of the robust rank aggregation method revealed CD44 as a reliable biomarker in P-PF-EPN. 120 P-PF-EPN samples after surgical resection were selected for Kaplan-Merier and Cox proportion hazard regression survival analysis. Immunohistochemical analysis was performed to assess CD44 expression in the tumor samples. The miRNA profile was determined using a whole-genome miRNA microarray. The expression patterns of related mRNAs, miRNAs and proteins were validated by qRT-PCR or Western blotting. RESULTS: CD44 was found to be an independent predictor of prognosis in survival analysis. It improved the accuracy of using LAMA2/NELL2 for classifying P-PF-EPN molecular subgroups. Fourteen miRNAs were underexpressed, and one miRNA was overexpressed in CD44-positive P-PF-EPNs. miR-543, miR-495-3p, miR-299-3p, miR 139-5p and miR-128-3p were identified to have CD44 positively co-regulated potential target oncogenes. Two PI3K-Akt signaling pathway related potential target oncogenes (VEGFA, CSF1) for miR-299-3p and miR-495-3p were validated overexpression in CD44 positive P-PF-EPNs. Abnormal activation of the PI3K-Akt pathway was confirmed in CD44-positive cases. CONCLUSIONS: CD44 is of great clinical significance as a prognostic biomarker. The survival difference between CD44 positive and negative P-PF-EPN is determined by a complex functional miRNA mRNA-signaling pathway regulatory network. PMID- 29704233 TI - The mutational analysis in the diagnostic work-up of thyroid nodules: the real impact in a center with large experience in thyroid cytopathology. AB - PURPOSE: Fine-needle aspiration (FNA) cytology is a mainstay in the evaluation of thyroid nodules, but fails to reach reliable results in 25-30% of cases. The role of molecular markers in helping clinical decisions has been investigated for the last years, but their clinical usefulness is still unsettled. METHODS: Mutation analysis of BRAF, RAS genes and TERT promoter was performed in a series of 617 consecutive cytological specimens undergoing FNA. RESULTS: The 617 nodules had the following cytological diagnosis: non diagnostic 22 (3.6%), benign 425 (68.9%), indeterminate 114 (18.5%), suspicious 11 (1.8%) and malignant 45 (7.3%). BRAF mutations were found in 31 cases (5.0%), all but two in suspicious and malignant nodules. RAS mutations were detected in 47 samples (7.6%): 25 benign (5.9%) and 19 indeterminate nodules (16.7%). TERT promoter mutation alone was detected in three samples. Histological outcome was available for 167 nodules, 81 of which proved malignant: all the 48 with suspicious or malignant cytology; 25 out of 56 (44.6%) with indeterminate and 8 out of 57 (14%) with benign cytology. BRAF mutations were associated with worse tumors pathological features. The presence of RAS mutations was indicative of follicular-patterned malignancies in 5 out of 8 benign nodules and 9 out of 11 indeterminate nodules. CONCLUSIONS: Our study established mutational rates for BRAF and RAS genes in a large series of FNA specimens. BRAF mutations were confirmed as highly specific but not able to improve cytological diagnosis, while RAS testing proved effective in assessing malignancy in nodules with indeterminate and benign cytology. PMID- 29704234 TI - Diagnosis and treatment of lipodystrophy: a step-by-step approach. AB - AIM: Lipodystrophy syndromes are rare heterogeneous disorders characterized by deficiency of adipose tissue, usually a decrease in leptin levels and, frequently, severe metabolic abnormalities including diabetes mellitus and dyslipidemia. PURPOSE: To describe the clinical presentation of known types of lipodystrophy, and suggest specific steps to recognize, diagnose and treat lipodystrophy in the clinical setting. METHODS: Based on literature and in our own experience, we propose a stepwise approach for diagnosis of the different subtypes of rare lipodystrophy syndromes, describing its more frequent co morbidities and establishing the therapeutical approach. RESULTS: Lipodystrophy is classified as genetic or acquired and by the distribution of fat loss, which can be generalized or partial. Genes associated with many congenital forms of lipodystrophy have been identified that may assist in diagnosis. Because of its rarity and heterogeneity, lipodystrophy may frequently be unrecognized or misdiagnosed, which is concerning because it is progressive and its complications are potentially life threatening. A basic diagnostic algorithm is proposed. Effective management of lipodystrophy includes lifestyle changes and aggressive, evidence-based treatment of comorbidities. Leptin replacement therapy (metreleptin) has been found to improve metabolic parameters in many patients with lipodystrophy. Metreleptin is approved in the United States as replacement therapy to treat the complications of leptin deficiency in patients with congenital or acquired generalized lipodystrophy and has been submitted for approval in Europe. CONCLUSIONS: Here, we describe the clinical presentation of known types of lipodystrophy, present an algorithm for differential diagnosis of lipodystrophy, and suggest specific steps to recognize and diagnose lipodystrophy in the clinical setting. PMID- 29704235 TI - Dissonance among treatment algorithms for hyperglycemia in type 2 diabetes: an egalitarian dialog. PMID- 29704236 TI - Are reflective models appropriate for very short scales? Proofs of concept of formative models using the Ten-Item Personality Inventory. AB - OBJECTIVE: Because of their length and objective of broad content coverage, very short scales can show limited internal consistency and structural validity. We argue that it is because their objectives may be better aligned with formative investigations than with reflective measurement methods that capitalize on content overlap. As proofs of concept of formative investigations of short scales, we investigate the Ten-Item Personality Inventory (TIPI). METHOD: In Study 1, we administered the TIPI and the Big Five Inventory (BFI) to 938 adults and fitted a formative Multiple Indicators Multiple Causes model, which consisted of the TIPI items forming five latent variables, which in turn predicted the five BFI scores. These results were replicated in Study 2 on a sample of 759 adults, but this time with the Revised NEO Personality Inventory (NEO-PI-R) as the external criterion. RESULTS: The models fit the data adequately, and moderate to strong significant effects (.37 < |beta| < .69, all ps < .001) of all five latent formative variables on their corresponding BFI and NEO-PI-R scores were observed. CONCLUSIONS: This study presents a formative approach that we propose to be more consistent with the aims of scales with broad content and short length like the TIPI. PMID- 29704237 TI - Biochemical composition and antioxidant activity affected by spraying potassium sulfate in black grape (Vitis vinifera L. cv. Rasha). AB - BACKGROUND: The physiological and metabolic processes involved with grapevine growth and production are influenced by key macro- and micronutrients. Potassium is an essential plant nutrient that affects growth and fruit quality. In this study, the impact of foliar spraying of potassium sulfate (K2 SO4 ) on qualitative characteristics of grape berries was evaluated in the cultivar 'Rasha', a commonly cultivated cultivar in Kurdistan province of Iran. Leaves of the fully grown vines were sprayed with each of the 1.5 and 3 g L-1 K2 SO4 solutions once (1 month after petal senescence) and twice (15 days after first spraying). The control plants were sprayed with distilled water. Various biochemical contents and enzyme activities on the ripe berries were analyzed. RESULTS: Significant increases in anthocyanin, total protein content, and antioxidant enzyme activities were observed in the berries treated twice with 3 g L-1 K2 SO4 . Concentrations of total carbohydrate, phenol, and antioxidant activity in berries sprayed with K2 SO4 were higher than in the controls. We observed a strong correlation between antioxidant activity and different phenolic compounds. CONCLUSION: These findings suggest that K2 SO4 treatment influences biosynthesis of phenolic compounds and antioxidant enzymes. Thus, treatment by K2 SO4 could improve nutritional and qualitative attributes of grape. (c) 2018 Society of Chemical Industry. PMID- 29704238 TI - MicroRNA-3064-3p regulates the differentiation of cementoblasts through targeting DKK1. AB - BACKGROUND AND OBJECTIVE: MicroRNAs (miRNAs) are short, noncoding RNAs that interfere with translation of target mRNAs and thereby play a pivotal role in a variety of biological processes. Cementoblasts are the cells that build up cementum. They share a similar gene expression pattern with osteoblasts. Recent studies have suggested that miRNAs are able to control osteoblast-mediated bone formation. However, the effects of miRNA on cementoblast differentiation still remain unsolved. Herein, we wanted to elucidate the role of miR-3064-3p in cementoblast differentiation. MATERIAL AND METHODS: A miRNA microarray was operated to explore the miRNA expression patterns during cementoblast differentiation. miR-3064-3p agomir/antagomir was used to promote or inhibit, respectively, the expression of miR-3064-3p. In order to measure the differentiation level of cementoblasts, quantitative RT-PCR (qRT-PCR), Alizarin red staining, and assessment of alkaline phosphatase activity were performed. Luciferase assays, qRT-PCR, and western blotting were used to identify the target gene of miR-3064-3p. RESULTS: miR-3064-3p showed persistently decreased expression during cementoblast differentiation. Overexpression of miR-3064-3p suppressed cementoblast differentiation, while inhibition of miR-3064-3p promoted cementoblast differentiation. Target prediction-analysis tools and dual luciferase assay identified Dickkopf WNT signaling pathway inhibitor 1 (DKK1) as a direct target of miR-3064-3p. Results from qRT-PCR and western blotting showed that inhibition of miR-3064-3p led to a remarkable increase in DKK1/Dickkopf related protein 1 (Dkk-1) expression. In addition, pretreatment with recombinant Dickkopf related protein 1 (Dkk-1) rescued the miR-3064-3p-mediated suppression of cementoblast differentiation. CONCLUSION: This study demonstrates, for the first time, that miR-3064-3p suppresses cementoblast differentiation via the regulation of DKK1. PMID- 29704239 TI - CD97 Promotes Tumor Aggressiveness Through the Traditional G Protein-Coupled Receptor-Mediated Signaling in Hepatocellular Carcinoma. AB - Cluster of differentiation 97 (CD97) is a member of the epidermal growth factor seven-transmembrane family belonging to the class B G protein-coupled receptors (GPCRs). The protein affects tumor aggressiveness through its cellular ligand CD55 stimulation and exhibits adhesive properties. Studies have demonstrated the involvement of CD97 in dedifferentiation, migration, invasiveness, and metastasis of tumors. However, little information is currently available on the specific role of CD97 in hepatocellular carcinoma (HCC). Here, we have shown that CD97 up regulation in HCCs is positively correlated with tumor metastasis. Functionally, CD97 promoted cell migration and invasion in vitro. In an in vivo mouse model, overexpression of CD97 in HCC cells led to accelerated lung metastasis. Mechanistically, CD97 cooperated with the altered regulator, GPCR kinase 6 (GRK6), to mediate GPCR desensitization and internalization. Down-regulation of GRK6 suppressed CD97 internalization and promoted CD97 expression. Integrated regulatory interactions between CD97 and GRK6 stimulated downstream matrix metalloproteinase 2/9 secretion and, consequently, HCC metastasis. Conclusion: Our collective findings support the utility of CD97 as an effective potential prognosticator and therapeutic target for HCC. PMID- 29704240 TI - Accurate O2 delivery enabled benzene biodegradation through aerobic activation followed by denitrification-coupled mineralization. AB - Although benzene can be biodegraded when dissolved oxygen is sufficient, delivering oxygen is energy intensive and can lead to air stripping the benzene. Anaerobes can biodegrade benzene by using electron acceptors other than O2 , and this may reduce costs and exposure risks; the drawback is a remarkably slower growth rate. We evaluated a two-step strategy that involved O2 -dependent benzene activation and cleavage followed by intermediate oxidation coupled to NO3- respiration. We employed a membrane biofilm reactor (MBfR) featuring nonporous hollow fibers as the means to deliver O2 directly to a biofilm at an accurately controlled rate. Benzene was mineralized aerobically when the O2 -supply rate was more than sufficient for mineralization. As the O2 -supply capacity was systematically lowered, O2 respiration was gradually replaced by NO3- respiration. When the maximum O2 -supply capacity was only 20% of the demand for benzene mineralization, O2 was used almost exclusively for benzene activation and cleavage, while respiration was almost only by denitrification. Analyses of microbial community structure and predicted metagenomic function reveal that Burkholderiales was dominant and probably utilized monooxygenase activation, with subsequent mineralization coupled to denitrification; strict anaerobes capable of carboxylative activation were not detected. These results open the door for a promising treatment strategy that simultaneously ameliorates technical and economic challenges of aeration and slow kinetics of anaerobic activation of aromatics. PMID- 29704241 TI - Enhancement of mitochondrial biogenesis and paradoxical inhibition of lactate dehydrogenase mediated by 14-3-3eta in oncocytomas. AB - Oncocytomas represent a subset of benign pituitary adenomas that are characterized by significant mitochondrial hyperplasia. Mitochondria are key organelles for energy generation and metabolic intermediate production for biosynthesis in tumour cells, so understanding the mechanism underlying mitochondrial biogenesis and its impact on cellular metabolism in oncocytoma is vital. Here, we studied surgically resected pituitary oncocytomas by using multi omic analyses. Whole-exome sequencing did not reveal any nuclear mutations, but identified several somatic mutations of mitochondrial DNA, and dysfunctional respiratory complex I. Metabolomic analysis suggested that oxidative phosphorylation was reduced within individual mitochondria, and that there was no reciprocal increase in glycolytic activity. Interestingly, we found a reduction in the cellular lactate level and reduced expression of lactate dehydrogenase A (LDHA), which contributed to mitochondrial biogenesis in an in vitro cell model. It is of note that the hypoxia-response signalling pathway was not upregulated in pituitary oncocytomas, thereby failing to enhance glycolysis. Proteomic analysis showed that 14-3-3eta was exclusively overexpressed in oncocytomas, and that 14-3 3eta was capable of inhibiting glycolysis, leading to mitochondrial biogenesis in the presence of rotenone. In particular, 14-3-3eta inhibited LDHA by direct interaction in the setting of complex I dysfunction, highlighting the role of 14 3-3eta overexpression and inefficient oxidative phosphorylation in oncocytoma mitochondrial biogenesis. These findings deepen our understanding of the metabolic changes that occur within oncocytomas, and shine a light on the mechanism of mitochondrial biogenesis, providing a novel perspective on metabolic adaptation in tumour cells. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 29704242 TI - Association between glutathione S-transferase gene M1 and T1 polymorphisms and chronic obstructive pulmonary disease risk: A meta-analysis. AB - Chronic obstructive pulmonary disease (COPD) is a severe lung disease characterized by long-term breathing problems. A series of studies have indicated that the glutathione S-transferase genes M1 and T1 are associated with COPD susceptibility; however, the result still remains inconclusive. This meta analysis was performed to estimate the effect of GSTM1 and GSTT1 polymorphisms in COPD risk. Eligible case-control studies published between January 2000 and December 2017 was searched and retrieved. A total of 37 articles were screened out, including 4674 COPD patients and 5006 controls. Overall, our results found that GSTM1 and GSTT1 null genotypes significantly increased the risk of COPD (GSTM1: odds ratio [OR] = 1.52, 95% confidence interval [CI] = 1.31-1.77, P <.00001; GSTT1: OR = 1.28, 95% CI = 1.09-1.50, P = .003). Subgroup analysis by ethnicity suggested that there was a close association between GSTM1 null polymorphism and COPD susceptibility in each studied ethnicity, while GSTT1 null polymorphism only showed association with Asian COPD patients. Moreover, we also found that joint GSTM1/GSTT1 null genotypes showed a high association with increased COPD susceptibility (OR = 1.42, 95% CI = 1.21-1.66, P < .0001). In conclusion, our results indicated that GSTM1 null, GSTT1 null, and the combined GSTM1/GSTT1 null genotypes might be risk factors in the development of COPD. However, future case-control studies with large-scale participants are still required to further estimate these associations. PMID- 29704243 TI - Absent metaboreflex-induced increases in sympathetic outflow to contracting muscle. PMID- 29704244 TI - Age-related trends in cardiometabolic disease among adults with cerebral palsy. AB - AIM: To examine the longitudinal trends of cardiometabolic diseases in a large sample of adults with cerebral palsy (CP). METHOD: The Optum Clinformatics Data Mart is a de-identified nationwide claims database of beneficiaries from a single private payer. Beneficiaries were included if they had an International Classification of Diseases, Ninth Revision, Clinical Modification code for a diagnosis of CP. Adults with at least 3 years of continuous enrollment on a single plan between 2002 and 2009 were included in the final analyses (n=2659). We examined the longitudinal trends of incident diabetes mellitus, hypercholesterolemia, hypertension, cardiac dysrhythmias, and atherosclerosis, stratified by age categories: 18 to 39 years, 40 to 59 years, and 60 years and over. Kaplan-Meier product-limit survival curves were compared across age categories for each of the cardiometabolic outcomes, and a Cox proportional hazards regression was run to determine adjusted hazard ratios. RESULTS: The cumulative incidence of each of the cardiometabolic diseases ranged from 6.0% for atherosclerosis to 34.4% for hypercholesterolemia at 3 years and over. Risk adjusted Cox proportional hazard models revealed that age was a robust predictor of survival for each outcome, with higher hazard ratio ranges in middle age (hazard ratio 1.41-2.72) and older adults (hazard ratio 2.20-5.93) compared with young adults. INTERPRETATION: Adults with CP have high rates of cardiometabolic diseases; and disease-free survival shortens significantly with higher ages. WHAT THIS PAPER ADDS: Adults with cerebral palsy have high rates of cardiometabolic diseases. Disease-free survival of all cardiometabolic diseases shortens significantly with higher ages. The highest rates were for hypercholesterolemia and hypertension. PMID- 29704245 TI - MaBZR1/2 act as transcriptional repressors of ethylene biosynthetic genes in banana fruit. AB - Banana fruit (Musa acuminate L.) ripening is a complex genetical process affected by multiple phytohormones and expression of various genes. However, whether plant hormone brassinosteroid (BR) is involved in this process remains obscure. In this work, three genes that encode BR core signaling components brassinazole resistant (BZR) proteins, namely MaBZR1 to MaBZR3, were characterized from banana fruit. MaBZR1-MaBZR3 exhibited both nuclear and cytoplasmic localization and behaved as transcription inhibitors. Expression analysis showed that MaBZR1/2/3 were continuously decreased as fruit ripening proceeded, indicating their negative roles in banana ripening. Moreover, gel shift and transient expression assays demonstrated that MaBZR1/2 could suppress the transcription of ethylene biosynthetic genes, including MaACS1, MaACO13 and MaACO14, which increased gradually during the banana ripening, via specifically binding to CGTGT/CG sequence in their promoters. Importantly, exogenous application of BRs promotes banana ripening, which is presumably due to the accelerated expression of MaACS1 and MaACO13/14, and consequently the ethylene production. Our study indicates that MaBZR1/2 act as transcriptional repressors of ethylene biosynthetic genes during banana fruit ripening. PMID- 29704246 TI - Sugars en route to the roots. Transport, metabolism and storage within plant roots and towards microorganisms of the rhizosphere. AB - In plants, the root is a typical sink organ that relies exclusively on the import of sugar from the aerial parts. Sucrose is delivered by the phloem to the most distant root tips and, en route to the tip, is used by the different root tissues for metabolism and storage. Besides, a certain portion of this carbon is exuded in the rhizosphere, supplied to beneficial microorganisms and diverted by parasitic microbes. The transport of sugars toward these numerous sinks either occurs symplastically through cell connections (plasmodesmata) or is apoplastically mediated through membrane transporters (MST, mononsaccharide tranporters, SUT/SUC, H+/sucrose transporters and SWEET, Sugar will eventually be exported transporters) that control monosaccharide and sucrose fluxes. Here, we review recent progresses on carbon partitioning within and outside roots, discussing membrane transporters involved in plant responses to biotic and abiotic factors. PMID- 29704247 TI - Clinical and molecular characterization and response to acitretin in three families with Sjogren-Larsson syndrome. AB - INTRODUCTION: Sjogren-Larsson syndrome (SLS) is a rare congenital disorder characterized by the triad of ichthyosis, spasticity, and mental retardation. Patients are usually referred to dermatology clinics during infancy. As paraplegia becomes the most debilitating symptom of the disease within a few years, ichthyosis, although a major burden for the patient, takes a back seat. Optimum treatment of ichthyosis in these children and the effect of treatment on different aspects such as severity of the ichthyosis, pruritus, or quality of life of the patients' and their caregivers is not well established. MATERIALS AND METHODS: Genetic background of eight patients from three families diagnosed clinically with SLS was determined with whole-exome and Sanger sequencing. Clinical phenotypes, laboratory findings, magnetic resonance imaging (MRI), and treatment of the ichthyosis with acitretin were assessed. RESULTS: All patients had the classical triad of Sjogren-Larsson syndrome. Genetic analysis revealed that one patient had a novel c.799-1 (+/+) homozygous splicing mutation in the ALDH3A2 gene. Other patients had the c.683G>A p.R228H (NM_000382.2) mutation in the same gene. Other manifestations included skeletal anomalies, enamel hypoplasia, bilateral T2-hyperintensities in white matter, and moderate-severe pruritus. Acitretin treatment in a maintenance dose of 0.25 mg/kg/day decreased the severity of ichthyosis in all children. It increased quality of life significantly in all of the children and their caregivers. CONCLUSION: We conclude that ichthyosis can be treated effectively with low-dose acitretin in children with Sjogren-Larsson syndrome, and this treatment is associated with a significant improvement in the quality of life. PMID- 29704248 TI - Cementum protein 1 transfection does not lead to ultrastructural changes in nucleolar organization of human gingival fibroblasts. AB - BACKGROUND AND OBJECTIVE: Transfection of cementum protein 1 (CEMP1) into human gingival fibroblasts (HGFs) notably increases cell metabolism and results in overexpression of molecules related to biomineralization at transcriptional and protein levels. Therefore, HGF-CEMP1 cells are considered as putative cementoblasts. This represents a significant advance in periodontal research because cementum neoformation is a key event in periodontal regeneration. In addition, it is well known that important changes in cell metabolism and protein expression are related to nucleolar structure and the function of this organelle, which is implicated in ribosome biogenesis. The aim of this study was to determine the effect of transfecting CEMP1 gene in human HGF on the ultrastructure of the nucleolus. MATERIAL AND METHODS: Cells were processed using the conventional technique for transmission electron microscopy, fixed with glutaraldehyde, postfixed with osmium tetraoxide, and embedded in epoxy resin. Semi-thin sections were stained with Toluidine blue and observed by light microscopy. Thin sections were stained with uranyl acetate and lead citrate. For ribonucleoprotein detection, the staining method based on the regressive effect of EDTA was used. In addition, the osmium ammine technique was used for specific staining of DNA. RESULTS: The results obtained in this study suggest that transfection of CEMP1 into HGFs does not produce changes in the general nucleolar ultrastructure because the different components of the organelle are present as fibrillary centers, and dense fibrillar and granular components compared with the control. CONCLUSION: The transfection of CEMP1 into HGFs allows these cells to perform cementoblast-like functions without alteration of the ultrastructure of the nucleolus, evaluated by the presence of the different compartments of this organelle involved in ribosomal biogenesis. PMID- 29704249 TI - Do UV-A radiation and blue light during growth prime leaves to cope with acute high light in photoreceptor mutants of Arabidopsis thaliana? AB - We studied how plants acclimated to growing conditions that included combinations of blue light (BL) and ultraviolet (UV)-A radiation, and whether their growing environment affected their photosynthetic capacity during and after a brief period of acute high light (as might happen during an under-canopy sunfleck). Arabidopsis thaliana Landsberg erecta wild-type were compared with mutants lacking functional blue light and UV photoreceptors: phototropin 1, cryptochromes (CRY1 and CRY2) and UV RESISTANT LOCUS 8 (uvr8). This was achieved using light emitting-diode (LED) lamps in a controlled environment to create treatments with or without BL, in a split-plot design with or without UV-A radiation. We compared the accumulation of phenolic compounds under growth conditions and after exposure to 30 min of high light at the end of the experiment (46 days), and likewise measured the operational efficiency of photosystem II (phiPSII, a proxy for photosynthetic performance) and dark-adapted maximum quantum yield (Fv /Fm to assess PSII damage). Our results indicate that cryptochromes are the main photoreceptors regulating phenolic compound accumulation in response to BL and UV A radiation, and a lack of functional cryptochromes impairs photosynthetic performance under high light. Our findings also reveal a role for UVR8 in accumulating flavonoids in response to a low UV-A dose. Interestingly, phototropin 1 partially mediated constitutive accumulation of phenolic compounds in the absence of BL. Low-irradiance BL and UV-A did not improve phiPSII and Fv /Fm upon our acute high-light treatment; however, CRYs played an important role in ameliorating high-light stress. PMID- 29704250 TI - A new sequential injection analysis-capillary electrophoresis system with amperometric detection. AB - A novel and fully automated sequential injection analysis manifold coupled to a capillary electrophoresis apparatus with amperometric detection, is described. The sequential injection manifold was isolated from the high voltage by inserting an air plug into the circuit. Small buffer reservoirs were used to avoid the need to pump fresh buffer to the interface during the electrophoretic separation. No decoupling device was used to mitigate the interference from the high voltage electric field, instead the potential shift induced by the separation voltage, was accounted for. The new hydrodynamic injection method presented is based on the overpressure created in the circuit when a pinch valve is closed for a predetermined time. The injection method yields RSD values of peak height and area below 2.55 and 1.82%, respectively, at different durations of valve closure (n = 5). The capillary and working electrode alignment was achieved by adapting a commercial available capillary union. When the electrode was replaced, the alignment method proved to be very reliable, yielding RSD values of peak height and area lower than 2.64 and 2.08%, respectively (n = 8). Using this system with a gold microelectrode, dopamine, and epinephrine could be quantified within the concentration range of 1-500 MUM and detected at a concentration of 0.3 MUM. The methods here presented could be applied for the development of new capillary electrophoresis systems with amperometric detection and/or to the design of fully automated systems for online process monitoring purposes. PMID- 29704251 TI - Forensic applicability of multi-allelic InDels with mononucleotide homopolymer structures. AB - Insertion/deletion polymorphisms (InDels), which possess the characteristics of low mutation rates and a short amplicon size, have been regarded as promising markers for forensic DNA analysis. InDels can be classified as bi-allelic or multi-allelic, depending on the number of alleles. Many studies have explored the use of bi-allelic InDels in forensic applications, such as individual identification and ancestry inference. However, multi-allelic InDels have received relatively little attention. In this study, InDels with 2-6 alleles and a minor allele frequency >=0.01, in Chinese Southern Han (CHS), were retrieved from the 1000 Genomes Project Phase III. Based on the structural analysis of all retrieved InDels, 17 multi-allelic markers with mononucleotide homopolymer structures were selected and combined in one multiplex PCR reaction system. Sensitivity, species specificity and applicability in forensic case work of the multiplex were analyzed. A total of 218 unrelated individuals from a Chinese Han population were genotyped. The combined discriminatory power (CDP), the combined match probability (CMP) and the cumulative probability of exclusion (CPE) were 0.9999999999609, 3.91E-13 and 0.9956, respectively. The results demonstrated that this InDel multiplex panel was highly informative in the investigated population and most of the 26 populations of the 1000 Genomes Project. The data also suggested that multi-allelic InDel markers with monomeric base pair expansions are useful for forensic applications. PMID- 29704253 TI - Quality evaluation of six bioactive constituents in goji berry based on capillary electrophoresis field amplified sample stacking. AB - Goji berry, fruits of the plant Lycium barbarum L., has long been used as traditional medicine and functional food in China. In this work, a simple and easy-operation on-line concentration capillary electrophoresis (CE) for detection flavonoids in goji berry was developed by coupling of field amplified sample stacking (FASS) with an electroosmotic (EOF) pump driving water removal process. Due to the EOF pump and electrokinetic injection showing different influence on the concentration, the analytes injection condition should be systemically studied. Thereafter, the verification of the analytes injection conditions was achieved using response surface experimental design. Under the optimum conditions, 86-271 folds sensitivity enhancement upon normal capillary zone electrophoresis (CZE, 50 mbar * 5 s) were achieved for six flavonoids, and the detection limits ranged from 0.35 to 1.82 ng/mL; the LOQ ranged from 1.20 to 6.01 ng/mL. Eventually, the proposed method was applied to detect flavonoids in 30 goji berry samples from different habitats of China; and the results indicated that the flavonoids were rich in the eluent of 30-60% methanol, which provided a reference for extraction of goji berry flavonoids. PMID- 29704252 TI - Baseline Intrahepatic and Peripheral Innate Immunity are Associated with Hepatitis C Virus Clearance During Direct-Acting Antiviral Therapy. AB - Hepatitis C virus (HCV) infection induces interferon (IFN)-stimulated genes (ISGs) and downstream innate immune responses. This study investigated whether baseline and on-treatment differences in these responses predict response versus virological breakthrough during therapy with direct-acting antivirals (DAAs). Thirteen HCV genotype 1b-infected patients who had previously failed a course of pegylated IFN/ribavirin were retreated with asunaprevir/daclatasvir for 24 weeks. After pretreatment biopsy, patients were randomized to undergo a second biopsy at week 2 or 4 on therapy. Microarray and NanoString analyses were performed on paired liver biopsies and analyzed using linear mixed models. As biomarkers for peripheral IFN responses, peripheral blood natural killer cells were assessed for phosphorylated signal transducer and activator of transcription 1 (pSTAT1) and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) expression and degranulation. Nine of 13 (69%) patients achieved sustained virological response at 12 weeks off therapy (SVR12), and 4 experienced virological breakthroughs between weeks 4 and 12. Patients who achieved SVR12 displayed higher ISG expression levels in baseline liver biopsies and a higher frequency of pSTAT1 and TRAIL-expressing, degranulating natural killer cells in baseline blood samples than those who experienced virological breakthrough. Comparing gene expression levels from baseline and on-therapy biopsies, 408 genes (+/-1.2-fold, P < 0.01) were differentially expressed. Genes down-regulated on treatment were predominantly ISGs. Down-regulation of ISGs was rapid and correlated with HCV RNA suppression. Conclusion: An enhanced IFN signature is observed at baseline in liver and blood of patients who achieve SVR12 compared to those who experience a virological breakthrough; the findings suggest that innate immunity may contribute to clearance of HCV during DAA therapy by preventing the emergence of resistance-associated substitutions that lead to viral breakthrough during DAA therapy. PMID- 29704254 TI - Intrahepatic T-Cell Receptor beta Immune Repertoire Is Essential for Liver Regeneration. AB - T lymphocytes synergize with the cellular immune system to promote hepatocyte regeneration. The T-cell receptor (TCR) immune repertoire is closely associated with the host immune response and regenerative proliferation. High-throughput sequencing of TCR provides deep insight into monitoring the immune microenvironment. Here, we aimed to determine the role of the TCRbeta immune repertoire in liver regeneration (LR). We investigated hepatic regeneration in TCRbeta chain-deficient (tcrb-/- ) mice by two-thirds partial hepatectomy (PHx) method. Our results demonstrated that tcrb-/- mice revealed a reduced capacity for LR, which was characterized by impaired hepatocyte proliferation and enhanced hepatocyte apoptosis. Dysregulation of inflammatory signaling activation and inflammatory factors was observed in regenerated tcrb-/- livers. Simultaneously, significantly altered immunocyte levels and aberrant cytokine levels were observed during hepatic regeneration. In addition, we first determined the profile of the TCRbeta immune repertoire during LR, indicating that PHx resulted in remarkably lower TCRbeta diversity in intrahepatic T lymphocytes. Conclusion: Taken together, our data suggest that TCRbeta deficiency gives a rise to aberrant intrahepatic immune microenvironment that impairs LR, and the TCRbeta reconstitution is required for hepatic immunocyte recruitment and activation during LR. PMID- 29704256 TI - Multi-Objective Optimization of Managed Aquifer Recharge. AB - This study demonstrates the utilization of a multi-objective hybrid global/local optimization algorithm for solving managed aquifer recharge (MAR) design problems, in which the decision variables included spatial arrangement of water injection and abstraction wells and time-variant rates of pumping and injection. The objective of the optimization was to maximize the efficiency of the MAR scheme, which includes both quantitative and qualitative aspects. The case study used to demonstrate the capabilities of the proposed approach is based on a published report on designing a real MAR site with defined aquifer properties, chemical groundwater characteristics as well as quality and volumes of injected water. The demonstration problems include steady state and transient scenarios. The steady state scenario demonstrates optimization of spatial arrangement of multiple injection and recovery wells, whereas the transient scenario was developed with the purpose of finding optimal regimes of water injection and recovery at a single location. Both problems were defined as multi-objective problems. The scenarios were simulated by applying coupled numerical groundwater flow and solute transport models: MODFLOW-2005 and MT3D-USGS. The applied optimization method was a combination of global (the non-dominated sorting genetic algorithm [NSGA-2]) and local (the Nelder-Mead downhill simplex search algorithms). The analysis of the resulting Pareto optimal solutions led to the discovery of valuable patterns and dependencies between the decision variables, model properties, and problem objectives. Additionally, the performance of the traditional global and the hybrid optimization schemes were compared. PMID- 29704255 TI - Subungual exostosis and subungual osteochondromas: a description of 25 cases. AB - BACKGROUND: Subungual exostosis (SE) and subungual osteochondroma (SO) are an uncommon, benign tumor of the distal phalanx. The purpose of this retrospective study was to evaluate clinical, demographical, and radiological features; treatment modalities; and follow-up results in SE and SO cases. METHODS: Twenty five cases were confirmed histopathologically as SE or SO. At the time of admission, clinical data were obtained on the age and sex of the patient, duration of symptoms, presence of pain, previous diagnoses and treatments, concomitant systemic diseases, family history, lesional localization, clinical and radiological features of the lesion, surgical treatment methods, and duration of follow-up. RESULTS: There were 14 patients in the SE group and 11 patients in the SO group. There was no statistically significant difference in gender, age, duration of symptoms, or pain between the two groups. Regarding the locations of the lesions, two (14.28%) were on the hands, 12 (85.72%) lesions were on the toes, 11 (91.67%) of which were on the great toe, and one (8.33%) was on the small toe of the left foot in the SE group. All the osteochondroma lesions were located on the toes. In five (45%) cases, the lesion was on the great toe. Two patients had residual lesions in the SE group. Recurrence occurred in one case in the SO group. CONCLUSIONS: Clinically and histopathologically, SE and SO appear to be two different entities. When diagnosed correctly and treated appropriately, the lesions have good functional and cosmetic results, as well as a very low recurrence rate. PMID- 29704257 TI - Fibroblast Growth Factor Receptor Inhibition for Cholangiocarcinoma: Looking Through a Door Half-Opened. PMID- 29704258 TI - Potential role of periodontal pathogens in compromising epithelial barrier function by inducing epithelial-mesenchymal transition. AB - BACKGROUND AND OBJECTIVE: Epithelial-mesenchymal transition (EMT) is a process by which epithelial cells acquire a mesenchymal-like phenotype and this may be induced by exposure to gram-negative bacteria. It has been proposed that EMT is responsible for compromising epithelial barrier function in the pathogenesis of several diseases. However, the possible role of EMT in the pathogenesis of periodontitis has not previously been investigated. The aim of this study therefore was to investigate whether gram-negative, anaerobic periodontal pathogens could trigger EMT in primary oral keratinocytes in vitro. MATERIAL AND METHODS: Primary oral keratinocytes were harvested from labial mandibular mucosa of Wistar Han rats. Cells were exposed to heat-killed Fusobacterium nucleatum and Porphyromonas gingivalis (100 bacteria/epithelial cell) and to 20 MUg/mL of Escherichia coli lipopolysaccharide over an 8-day period. Exposure to bacteria did not significantly change epithelial cell number or vitality in comparison with unstimulated controls at the majority of time-points examined. Expression of EMT marker genes was determined by semiquantitative RT-PCR at 1, 5, and 8 days following stimulation. The expression of EMT markers was also assessed by immunofluorescence (E-cadherin and vimentin) and using immunocytochemistry to determine Snail activation. The loss of epithelial monolayer coherence, in response to bacterial challenge, was determined by measuring trans-epithelial electrical resistance. The induction of a migratory phenotype was investigated using scratch-wound and transwell migration assays. RESULTS: Exposure of primary epithelial cell cultures to periodontal pathogens was associated with a significant decrease in transcription (~3-fold) of E-cadherin and the upregulation of N-cadherin, vimentin, Snail, matrix metalloproteinase-2 (~3-5 fold) and toll-like receptor 4. Bacterial stimulation (for 8 days) also resulted in an increased percentage of vimentin-positive cells (an increase of 20% after stimulation with P. gingivalis and an increase of 30% after stimulation with F. nucleatum, compared with controls). Furthermore, periodontal pathogens significantly increased the activation of Snail (60%) and cultures exhibited a decrease in electrical impedance (P < .001) in comparison with unexposed controls. The migratory ability of the cells increased significantly in response to bacterial stimulation, as shown by both the number of migrated cells and scratch-wound closure rates. CONCLUSION: Prolonged exposure of primary rat oral keratinocyte cultures to periodontal pathogens generated EMT-like features, which introduces the possibility that this process may be involved in loss of epithelial integrity during periodontitis. PMID- 29704259 TI - TRUSS Exacerbates NAFLD Development by Promoting IkappaBalpha Degradation in Mice. AB - There is no effective treatment method for nonalcoholic fatty liver disease (NAFLD), the most common liver disease. The exact mechanism underlying the pathogenesis of NAFLD remains to be elucidated. Here, we report that tumor necrosis factor receptor-associated ubiquitous scaffolding and signaling protein (TRUSS) acts as a positive regulator of NAFLD and in a variety of metabolic disorders. TRUSS expression was increased in the human liver specimens with NAFLD or nonalcoholic steatohepatitis, and in the livers of high-fat diet (HFD)-induced and genetically obese mice. Conditional knockout of TRUSS in hepatocytes significantly ameliorated hepatic steatosis, insulin resistance, glucose intolerance, and inflammatory responses in mice after HFD challenge or in spontaneous obese mice with normal chow feeding. All of these HFD-induced pathological phenotypes were exacerbated in mice overexpressing TRUSS in hepatocytes. We show that TRUSS physically interacts with the inhibitor of nuclear factor kappaB alpha (IkappaBalpha) and promotes the ubiquitination and degradation of IkappaBalpha, which leads to aberrant activation of nuclear factor kappaB (NF-kappaB). Overexpressing IkappaBalphaS32A/S36A , a phosphorylation resistant mutant of IkappaBalpha, in the hepatocyte-specific TRUSS overexpressing mice almost abolished HFD-induced NAFLD and metabolic disorders. Conclusion: Hepatocyte TRUSS promotes pathological stimuli-induced NAFLD and metabolic disorders, through activation of NF-kappaB by promoting ubiquitination and degradation of IkappaBalpha. Our findings may provide a strategy for the prevention and treatment of NAFLD by targeting TRUSS. PMID- 29704260 TI - Comments to: skin findings of twenty-first-century movie response. PMID- 29704261 TI - Further evidence for causation of ischiospinal dysostosis by a pathogenic variant in BMPER and expansion of the phenotype. PMID- 29704263 TI - Allergic contact dermatitis caused by laurel fruit oil. PMID- 29704262 TI - Self-esteem and peer-perceived social status in early adolescence and prediction of eating pathology in young adulthood. AB - OBJECTIVE: Self-esteem is implied as a factor in the development of eating disorders. In adolescence peers have an increasing influence. Support for the role of self-esteem in eating disorders is ambiguous and little is known about the influence of social status as judged by others. The present study investigates whether self-esteem and peer status in early adolescence are associated with eating pathology in young adulthood. METHOD: This study is part of TRAILS, a longitudinal cohort study on mental health and social development from preadolescence into adulthood. At age 11, participants completed the Self Perception Profile for Children, assessing global self-esteem and self perceptions regarding social acceptance, physical appearance, and academic competence. At age 13, peer status among classmates was assessed regarding likeability, physical attractiveness, academic performance, and popularity in a subsample of 1,007 participants. The Eating Disorder Diagnostic Scale was administered at age 22. The present study included peer-nominated participants with completed measures of self-perception at age 11 and eating pathology at age 22 (N = 732; 57.8% female). RESULTS: In a combined model, self-perceived physical attractiveness at age 11 and peer popularity at age 13 were inversely correlated with eating pathology at 22 years, while likeability by peers at age 13 was positively related to eating pathology. DISCUSSION: Both self-perceptions and peer status in early adolescence are significant predictors of eating pathology in young adults. Specific measures of self-esteem and peer-perceived status may be more relevant to the prediction of eating pathology than a global measure of self-esteem. PMID- 29704264 TI - NF-Y-dependent regulation of glutamate receptor 4 expression and cell survival in cells of the oligodendrocyte lineage. AB - Glutamate receptor subunit 4 (GluA4) is highly expressed by neural cells sensitive to excitotoxicity, and is the predominant subunit expressed by oligodendrocyte precursor cells (OPC) during a key period of vulnerability to hypoxic-ischemic injury. Therefore, transcriptional networks downstream of excitotoxic GluA4 activation represent a promising area for therapeutic intervention. In this work, we identify the CCAAT binding transcription factor NF Yb as a novel transcriptional regulator of Gria4 (GluA4 gene), and a controller of excitotoxic death in the oligodendroglial lineage. We describe a novel regulatory region within Gria4 containing CCAAT sequences whose binding by NF-Yb is regulated by excitotoxicity. Excitotoxicity-induced alterations in NF-Yb binding are associated with changes in Gria4 transcription, while knockdown of NF Yb alters the transcription of reporter constructs containing this regulatory region. Data from immortalized and primary OPC reveal that RNAi and pharmacological disruption of NF-Yb alter Gria4 transcription, with the latter inducing apoptosis and influencing a set of apoptotic genes similarly regulated during excitotoxicity. These data provide the first definition of a trans-acting mechanism regulating Gria4, and identify the NF-Y network as a potential source of pharmacological targets for promoting OPC survival. PMID- 29704266 TI - The role of interleukins in vitiligo: a systematic review. AB - Vitiligo is a disorder of the skin that causes depigmentation and asymptomatic macules whose exact cause is still unclear. Although its aetiology is not fully elucidated, the main theory of its pathomechanism is that it is associated with the autoimmune process. There is few summarized information about the role of inflammatory mediators, as interleukins, in vitiligo, so our aim was to present a systematic review of the role of interleukins in vitiligo, focusing on interleukins. In this review, we included all studies assessing interleukin levels in vitiligo patients conducted up to June 2017. Quality assessment of these studies was performed using the Newcastle-Ottawa Scale (NOS). The interleukins mainly involved were IL-2, IL-4, IL-6, IL-10 and IL-17. The studies highlight the crucial role of IL-17 in the onset and progression of the disease, and its synergistic action with IL-2, IL-6 and IL-33. Dysregulated levels of the interleukins were also correlated with the stage of disease, the affected skin surface area, and indicated as the main factor for lymphocyte infiltration found in depigmented regions. These findings illustrate the growing need for new therapies targeting vitiligo and further research into the role of interleukins as an area of particular interest. PMID- 29704265 TI - Comparison of PCR-based methods for the diagnosis of cutaneous leishmaniasis in two different epidemiological scenarios: Spain and Morocco. AB - BACKGROUND: Cutaneous leishmaniasis (CL) is a disfiguring and stigmatising disease occurring in more than 70 countries across the world including Spain and Morocco. The use of sensitive tests that can differentiate Leishmania species is advised. OBJECTIVE: To evaluate the influence of the epidemiological scenario on the reliability of the PCR techniques and contribute to the selection of the most efficient one for CL diagnosis. METHODS: The sensitivities of parasitological methods and four PCRs were compared in cutaneous samples from 77 patients from Spanish (PSH) and Moroccan hospitals (PMH). Exudates and fresh or paraffin embedded tissue biopsies were used. RESULTS: None of the PCRs used in this study allowed the diagnosis of all CL cases, showing also some drawbacks. Lmj4/Uni21 PCR displayed the best sensitivity with PMH, but it did not provide positive results in PSH with CL confirmed by other PCRs. Conversely, JW13/JW14-PCR and L. infantum-PCR-ELISA displayed good sensitivities with PSH that were not achieved with PMH. Nested-ITS-1-PCR did not show enough sensitivity with paraffin-embedded tissue biopsies. False-negative results were obtained in 19% of PSH due to unspecific hybridizations of ITS-1 primers with human chromosome1. CONCLUSIONS: PCR should be routinely used in patients with cutaneous lesions compatible with CL and furthermore, the combination of two PCR techniques is advisable. The selection of these PCRs will be influenced by the epidemiological scenario: In areas where L. infantum is endemic, the use of the PCR-ELISA joint with JW13/JW14 PCR seems an appropriate choice, whereas in areas such as Morocco, Lmj4/Uni21 and ITS-1 provide satisfactory results. PMID- 29704267 TI - Bullous complex regional pain syndrome: A description of the clinical and histopathologic features. PMID- 29704268 TI - Characteristics of hemostasis during experimental Ehrlichia canis infection. AB - BACKGROUND: Ehrlichia canis infection in dogs can cause thrombocytopenia and clinical evidence of bleeding. It is unknown why some dogs show signs of bleeding whereas others do not despite clinically relevant thrombocytopenia. HYPOTHESIS/OBJECTIVES: Activated platelets, decreased fibrinolysis or both mitigate bleeding tendency. Assess standard hemostatic variables, platelet dynamics, and specialized coagulation testing in dogs experimentally infected with E. canis to evaluate this clinical discrepancy. ANIMALS: Four healthy laboratory beagles. METHODS: Dogs were given blood infected with E. canis IV. Platelet indices of activation, platelet aggregometry, antiplatelet antibodies (percent IgG), complete coagulation panel, and thromboelastography (TEG) were measured before inoculation and on weeks 1-8. Dogs were treated with doxycycline at approximately 5 mg/kg PO q12h between weeks 3 and 4 (day 24). For each variable, 1-way repeated measures analysis (1-way ANOVA) with post-hoc analysis was performed with statistical significance set at P < .05. RESULTS: Dogs had significantly lower platelet counts, evidence of activated platelets, and antiplatelet antibodies during E. canis infection. Dogs also appeared hypercoagulable and hypofibrinolytic using TEG as compared with baseline, changes that persisted for variable amounts of time after doxycycline administration. No overt signs of bleeding were noted during the study. CONCLUSIONS AND CLINICAL IMPORTANCE: Activated platelets and a hypercoagulable, hypofibrinolytic state could explain the lack of a bleeding phenotype in some dogs despite clinically relevant thrombocytopenia. Findings from our pilot study indicate that additional studies are warranted. PMID- 29704270 TI - Favre-Racouchot syndrome: report of a case treated by plasma exeresis. PMID- 29704269 TI - Genotype-guided warfarin dosing vs. conventional dosing strategies: a systematic review and meta-analysis of randomized controlled trials. AB - AIMS: Previous trials on the effectiveness of genotype-guided warfarin dosing vs. conventional dosing have been inconclusive. We conducted a systematic review and meta-analysis of randomized trials comparing genotype-guided to conventional dosing strategies. METHODS: PubMed and the Cochrane Library were searched up to 23 October 2017. RESULTS: A total of 76 and 94 entries were retrieved were retrieved from PubMed and the Cochrane Library, respectively. A total of 2626 subjects in the genotype-guided dosing (mean age 63.3 +/- 5.8 years; 46% male) and 2604 subjects in the conventional dosing (mean age 64.7 +/- 6.1 years; 46% male) groups (mean follow-up duration 64 days) from 18 trials were included. Compared with conventional dosing, genotype-guided dosing significantly shortened the time to first therapeutic international normalized ratio (INR) (mean difference 2.6 days, standard error 0.3 days; P < 0.0001; I2 0%) and time to first stable INR (mean difference 5.9 days, standard error 2.0 days; P < 0.01; I2 94%). Genotype-guided dosing also increased the time in therapeutic range (mean difference 3.1%, standard error 1.2%; P < 0.01; I2 80%) and reduced the risks of both excessive anticoagulation, defined as INR >=4 [risk ratio (RR) 0.87; 95% confidence interval (CI) 0.78, 0.98; P < 0.05; I2 : 0%), and bleeding (RR 0.82; 95% CI 0.69, 0.98; P < 0.05; I2 31%). No difference in thromboembolism (RR 0.84; 95% CI 0.56, 1.26; P = 0.40; I2 0%) or mortality (RR 1.16; 95% CI 0.46, 2.91; P = 0.76; I2 0%) was observed between the two groups. CONCLUSIONS: Genotype-guided warfarin dosing offers better safety with less bleeding compared with conventional dosing strategies. No significant benefit on thromboembolism or mortality was evident. PMID- 29704271 TI - Commentary on 'Gender differences in clinical registration trials; is there a real problem?' by Labots et al. PMID- 29704272 TI - Targeted Therapies for Parkinson's Disease: From Genetics to the Clinic. AB - The greatest unmet medical need in Parkinson's disease (PD) is treatments that slow the relentless progression of symptoms. The discovery of genetic variants causing and/or increasing the risk for PD has provided the field with a new arsenal of potential therapies ready to be tested in clinical trials. We highlight 3 of the genetic discoveries (alpha-synuclein, glucocerebrosidase, and leucine-rich repeat kinase) that have prompted new therapeutic approaches now entering the clinical stages. We are at an exciting juncture in the journey to developing disease-modifying treatments based on knowledge of PD genetics and pathology. This review focuses on therapeutic paradigms that are under clinical development and highlights a wide range of key outstanding questions in PD. (c) 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 29704273 TI - Alitretinoin can be a good treatment option for idiopathic recalcitrant trachyonychia in adults: an open-label study. AB - BACKGROUND: Trachyonychia can be refractory to conventional treatments including topical, intralesional or systemic corticosteroids, as well as cyclosporine and retinoids. Therefore, new treatment options are needed for recalcitrant trachyonychia. OBJECTIVE: To evaluate the efficacy and safety of oral alitretinoin for idiopathic recalcitrant trachyonychia. METHODS: A total of 21 adult patients with 210 nails affected by idiopathic recalcitrant trachyonychia were evaluated in this open-label prospective study. All patients took 30 mg of alitretinoin daily for at least 3 months. Clinical outcomes were assessed using the Physician Global Assessment (PGA) scale proposed by Park et al. (degree of roughness: 0, clear; 1, mild; 2, moderate; 3, marked; 4, severe) at baseline and 1, 3 and 6 months after treatment. RESULTS: After 1, 3 and 6 months of treatment, 74.3% (123/210), 98.1% (206/210) and 99.2% (119/120) of nails showed clinical improvement, respectively; 0% (0/210), 22.9% (48/210) and 69.2% (83/120) were completely free from nail abnormalities. The mean PGA score at baseline was 3.4, decreasing significantly to 2.7, 1.3 and 0.7 at 1, 3 and 6 months following treatment, respectively. LIMITATIONS: A small number of participants and lack of a control group were limitations. CONCLUSIONS: For the first time, this study evaluated the efficacy and safety of oral alitretinoin for idiopathic recalcitrant trachyonychia in adults. The results suggest that oral alitretinoin can be a good treatment option for adult patients with recalcitrant trachyonychia. PMID- 29704274 TI - Saccadic oscillations in 4 dogs and 1 cat. AB - Disorders affecting the control of saccadic eye movements result in involuntary saccadic oscillations and are widely reported in human medicine. Information regarding the occurrence and potential importance of saccadic oscillations in veterinary medicine is currently limited. The clinical histories of three dogs and one cat displaying involuntary eye movements consistent with opsoclonus are presented, with final diagnoses including idiopathic generalized tremor syndrome and neuronal ceroid lipofuscinosis (NCL). A dog with eye movements closely resembling macrosaccadic oscillations is also presented, for which a final diagnosis of NCL was made. All animals had clinical signs of cerebellar disease. As in human medicine, recognition of these forms of involuntary eye movement might suggest a cerebellar neuroanatomic localization. Opsoclonus and macrosaccadic oscillations are forms of involuntary saccadic eye movement that are both unrecognized and under-reported in veterinary medicine. PMID- 29704275 TI - The smart approach: feasibility of lentigo maligna superficial margin assessment with hand-held reflectance confocal microscopy technology. AB - BACKGROUND: Lentigo maligna may be challenging to clear surgically. OBJECTIVE: To evaluate feasibility of using superficial skin cuts as RCM imaging anchors for attaining negative surgical margins in lentigo maligna. METHODS: Included patients presented with lentigo maligna near cosmetically sensitive facial structures. We evaluated, with hand-held-RCM, microscopic clearance of melanoma beyond its dermoscopically detected edges. Evaluated margins were annotated using shallow skin cuts. If a margin was positive at 'first-step' RCM evaluation, we sequentially advanced the margin radially outward at that segment by 2-mm intervals until an RCM-negative margin was identified. Prior to final surgical excision, we placed sutures at the outmost skin cuts to allow comparison of RCM and histopathological margin assessments. Primary outcome measure was histopathological verification that RCM-negative margins were clear of melanoma. RESULTS: The study included 126 first-step margin evaluations in 23 patients, median age 70 years (range: 43-91). Seventeen patients (74%) had primary in-situ melanoma and six (26%) invasive melanoma, mean thickness 0.3 mm (range 0.2-0.4 mm). Six cases (26%) showed complete negative RCM margins on 'first-step', 11 (48%) were negative at 'second-step', and four (17%) at 'third-step'. In two additional cases (9%), margins clearance could not be determined via RCM due to widespread dendritic cells proliferation. The RCM-negative margins in all 21 cases proved clear of melanoma on histopathology. Of the 15 cases that returned at 1-year follow-up, none showed any residual melanoma on dermoscopic and RCM examinations. Interobserver reproducibility showed fair agreement between bedside RCM reader and blinded remote-site reader, with Spearman's rho of 0.48 and Cohen's kappa of 0.43; using bedside reader as reference, the remote reader's sensitivity was 92% and specificity 57% in positive margin detection. CONCLUSIONS: Margin mapping of lentigo maligna with hand-held-RCM, using superficial skin cuts, appears feasible. This approach needs validation by larger studies. PMID- 29704276 TI - Twenty-first-century skin findings response. PMID- 29704278 TI - Pemphigus and smoking - insights from a big data analysis. PMID- 29704277 TI - Prediction and prevention of small-for-gestational-age neonates: evidence from SPREE and ASPRE. AB - OBJECTIVES: To examine the effect of first-trimester screening for pre-eclampsia (PE) on the prediction of delivering a small-for-gestational-age (SGA) neonate and the effect of prophylactic use of aspirin on the prevention of SGA. METHODS: The data for this study were derived from two multicenter studies. In SPREE, we investigated the performance of screening for PE by a combination of maternal characteristics and biomarkers at 11-13 weeks' gestation. In ASPRE, women with a singleton pregnancy identified by combined screening as being at high risk for preterm PE (> 1 in 100) participated in a trial of aspirin (150 mg/day from 11-14 until 36 weeks' gestation) compared to placebo. In this study, we used the data from the ASPRE trial to estimate the effect of aspirin on the incidence of SGA with birth weight < 10th , < 5th and < 3rd percentile for gestational age. We also used the data from SPREE to estimate the proportion of SGA in the pregnancies with a risk for preterm PE of > 1 in 100. RESULTS: In SPREE, screening for preterm PE by a combination of maternal factors, mean arterial pressure, uterine artery pulsatility index and serum placental growth factor identified a high-risk group that contained about 46% of SGA neonates < 10th percentile born at < 37 weeks' gestation (preterm) and 56% of those born at < 32 weeks (early); the overall screen-positive rate was 12.2% (2014 of 16 451 pregnancies). In the ASPRE trial, use of aspirin reduced the overall incidence of SGA < 10th percentile by about 40% in babies born at < 37 weeks' gestation and by about 70% in babies born at < 32 weeks; in babies born at >= 37 weeks, aspirin did not have a significant effect on incidence of SGA. The aspirin-related decrease in incidence of SGA was mainly due to its incidence decreasing in pregnancies with PE, for which the decrease was about 70% in babies born at < 37 weeks' gestation and about 90% in babies born at < 32 weeks. On the basis of these results, it was estimated that first-trimester screening for preterm PE and use of aspirin in the high-risk group would potentially reduce the incidence of preterm and early SGA by about 20% and 40%, respectively. CONCLUSION: First trimester screening for PE by the combined test identifies a high proportion of cases of preterm SGA that can be prevented by the prophylactic use of aspirin. (c) 2018 Crown copyright. Ultrasound in Obstetrics & Gynecology (c) 2018 ISUOG. PMID- 29704279 TI - Brazilin blocks catabolic processes in human osteoarthritic chondrocytes via inhibition of NFKB1/p50. AB - This study aimed to evaluate the chondroprotective and anti-inflammatory activity of brazilin in human osteoarthritic (OA) cartilage and chondrocytes with particular focus on the nuclear factor-kappa B (NF-kappaB) pathway. Therefore, brazilin was isolated from Caesalpinia sappan and identified using high performance liquid chromatography (HPLC). The effect of brazilin was assessed in cartilage explants treated with 10 ng/ml interleukin (IL)-1beta and 10 ng/ml tumor necrosis factor (TNF)-alpha using histological and biochemical glycosaminoglycan (GAG) analyses and in primary chondrocytes treated with 10 ng/ml IL-1beta using RT-qPCR, ELISA, and Western blot. The involvement of NF kappaB signaling was examined using a human NF-kappaB signaling array and in silico pathway analysis. Brazilin was found to reduce the GAG loss from cartilage explants stimulated with IL-1beta and TNF-alpha. NF-kappaB pathway analysis in chondrocytes revealed NFKB1/p50 as a central player regulating the anti inflammatory activities of brazilin. Brazilin suppressed the IL-1beta-mediated up regulation of OA markers and the induction of NFKB1/p50 in chondrocytes. In conclusion, brazilin effectively attenuates catabolic processes in human OA cartilage and chondrocytes-at least in part due to the inhibition of NFKB1/p50 which indicates a chondroprotective potential of brazilin in OA. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2431-2438, 2018. PMID- 29704280 TI - Prediction of adverse pregnancy outcome in monochorionic- diamniotic twin pregnancies complicated by selective fetal growth restriction. AB - OBJECTIVE: To identify key factors implicated in adverse perinatal outcome in monochorionic twin pregnancies complicated by selective fetal growth restriction. METHODS: This is a retrospective cohort study conducted in a single tertiary referral centre included all monochorionic diamniotic (MCDA) twin pregnancies complicated by selective fetal growth restriction (sFGR). The presence of co existing twin to twin transfusion syndrome (TTTS) was noted. Fetal biometry and Doppler indices, including the umbilical artery (UA) and ductus venosus (DV), were recorded at the time of diagnosis. The type of sFGR was diagnosed according to the pattern of end-diastolic flow (EDF) in the UA of the smaller twin. DV pulsatility indices were converted to z-scores and estimated fetal weight (EFW) values to centiles, to correct for gestational age (GA). Cox proportional hazards model was used to examine for independent predictors of adverse perinatal outcome. Adverse perinatal outcome was defined according to survival and included both intra-uterine fetal demise and neonatal death of the FGR twin. RESULTS: We analysed 104 pregnancies complicated by sFGR. Sixty-six (63.5%) were diagnosed with type I and 38 (36.5%) with type II at initial presentation. Pregnancies complicated by type II sFGR were diagnosed (median GA 19.6 weeks' vs 21.5 weeks, p=0.012) and delivered (median GA 30.4 weeks' vs 32.57 weeks; p=0.055) earlier and are associated with increased risk of adverse perinatal outcomes (intrauterine demise of the smaller twin 19.7% vs 10.6%, p=0.001), when compared to type I sFGR. Twin pregnancies complicated by sFGR, whether type I or II, resulting in intrauterine demise have a significantly earlier onset of diagnosis (p<0.001), earlier GA at delivery (p<0.05), higher DV pulsatility index (p<0.05), and lower birth weight (BW) centile of the smaller twin (p<0.01) when compared to pregnancies resulting in livebirth. Co-existing TTTS had no significant impact on the perinatal outcome of pregnancies diagnosed with either type I or type II sFGR (p>0.05 for both). Earlier GA at diagnosis (HR 0.70, 95% CI 0.56-0.88; p=0.002), type II sFGR (HR 3.53, 95% CI 1.37-9.07; p=0.008) and higher DV PI z scores (HR 1.36, 95% CI 1.12-1.65; p=0.001) were significantly associated with increased risk of adverse perinatal outcome of the smaller twin. CONCLUSION: Pregnancies complicated by type II sFGR are diagnosed significantly earlier and are associated with increased risk of adverse perinatal outcomes when compared to type I. Co-existing TTTS has no significant impact on the perinatal outcome of pregnancies diagnosed with either type I or type II sFGR. Earlier GA at diagnosis, type II sFGR and higher DV PI z scores are significantly associated with increased risk of adverse perinatal outcome for the smaller twin. PMID- 29704281 TI - Granulomatous dermatitis associated with ipilimumab therapy (ipilimumab associated granulomatous dermatitis). PMID- 29704282 TI - Amyloid fibrils induce dysfunction of hippocampal glutamatergic silent synapses. AB - Silent glutamatergic synapses lacking functional AMPA (alpha-amino-3-hydroxy-5 methyl-4-isoxazoleproprionate) receptors exist in several brain regions including the hippocampus. Their involvement in the dysfunction of hippocampal glutamatergic transmission in the setting of Alzheimer's disease (AD) is unknown. This study demonstrated a decrease in the percentage of silent synapses in rats microinjected with amyloid fibrils (Abeta1-40 ) into the hippocampal CA1. Also, pairing low-frequency electric stimuli failed to induce activation of the hippocampal silent synapses in the modeled rats. Immunoblotting studies revealed a decreased expression of GluR1 subunits in the hippocampal CA1 synaptosomal preparation, indicating a potential reduction in the GluR1 subunits anchoring in postsynaptic density in the modeled rats. We also noted a decreased expression of phosphorylated cofilin, which regulates the function of actin cytoskeleton and receptor trafficking, and reduced expression of the scaffolding protein PSD95 in the hippocampal CA1 synaptosome in rats injected with Abeta1-40 . Taken together, this study illustrates dysfunction of hippocampal silent synapse in the rodent model of AD, which might result from the impairments of actin cytoskeleton and postsynaptic scaffolding proteins induced by amyloid fibrils. PMID- 29704283 TI - Selective dopamine D3 receptor antagonism significantly attenuates stress-induced immobility in a rat model of post-traumatic stress disorder. AB - Post-traumatic stress disorder (PTSD) is a debilitating psychiatric syndrome that occurs in individuals exposed to extremely threatening or traumatic events. In both animals and humans, dopamine (DA) function appears to be dysregulated in brain areas involved in the conditioned fear response(s) that underlie PTSD. In this study, we determined the effect of the selective DA D3 receptor antagonists YQA14A (6.25, 12.5 and 25 mg/kg i.p.) and SB-277011A (6 mg/kg i.p.) on tone induced fear (assessed by measuring freeze time) in a modified version of the single-prolonged stress (SPS) model of PTSD in adult male Sprague-Dawley rats. Rats pretreated with vehicle and then subjected to restraint stress, forced swim and random foot shock (SPS) in the presence of a distinctive tone, displayed a significantly increased tone-induced contextual freeze time and fecal pellet mass following re-exposure to the tone. Rats pretreated with a single i.p. injection of 6.25 or 12.5 mg/kg of YQA14 or 6 mg/kg of SB-277011A showed significantly attenuated contextual freeze time in the presence of the tone when tested 14 days after exposure to SPS. Overall, our results indicate that selectively antagonizing DA D3 receptors significantly decreases freezing time caused by an environment previously associated with stress. If our findings can be extrapolated to humans with PTSD, they suggest that DA D3 receptors may play a role in the pathophysiology of PTSD, and may have therapeutic utility for the clinical management of PTSD. PMID- 29704285 TI - Walking velocity and step length adjustments affect knee joint contact forces in healthy weight and obese adults. AB - Knee osteoarthritis is a major public health problem and adults with obesity are particularly at risk. One approach to alleviating this problem is to reduce the mechanical load at the joint during daily activity. Adjusting temporospatial parameters of walking could mitigate cumulative knee joint mechanical loads. The purpose of this study was to determine how adjustments to velocity and step length affects knee joint loading in healthy weight adults and adults with obesity. We collected three-dimensional gait analysis data on 10 adults with a normal body mass index and 10 adults with obesity during over ground walking in nine different conditions. In addition to preferred velocity and step length, we also conducted combinations of 15% increased and decreased velocity and step length. Peak tibiofemoral joint impulse and knee adduction angular impulse were reduced in the decreased step length conditions in both healthy weight adults (main effect) and those with obesity (interaction effect). Peak knee joint adduction moment was also reduced with decreased step length, and with decreased velocity in both groups. We conclude from these results that adopting shorter step lengths during daily activity and when walking for exercise can reduce mechanical stimuli associated with articular cartilage degenerative processes in adults with and without obesity. Thus, walking with reduced step length may benefit adults at risk for disability due to knee osteoarthritis. Clinical Significance: Adopting a shorter step length during daily walking activity may reduce knee joint loading and thus benefit those at risk for knee cartilage degeneration. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2679-2686, 2018. PMID- 29704286 TI - Lipase-Catalyzed Dynamic Kinetic Resolution of C1 - and C2 -Symmetric Racemic Axially Chiral 2,2'-Dihydroxy-1,1'-biaryls. AB - We have discovered that the racemization of configurationally stable, axially chiral 2,2'-dihydroxy-1,1'-biaryls proceeds with a catalytic amount of a cyclopentadienylruthenium(II) complex at 35-50 degrees C. Combining this racemization procedure with lipase-catalyzed kinetic resolution led to the first lipase/metal-integrated dynamic kinetic resolution of racemic axially chiral biaryl compounds. The method was applied to the synthesis of various enantio enriched C1 - and C2 -symmetric biaryl diols in yields of up to 98 % and enantiomeric excesses of up to 98 %, which paves the way for new developments in the field of asymmetric synthesis. PMID- 29704284 TI - Prognostic importance of plasma total magnesium in a cohort of cats with azotemic chronic kidney disease. AB - BACKGROUND: Hypomagnesemia is associated with increased mortality and renal function decline in humans with chronic kidney disease (CKD). Magnesium is furthermore inversely associated with fibroblast growth factor 23 (FGF23), an important prognostic factor in CKD in cats. However, the prognostic significance of plasma magnesium in cats with CKD is unknown. OBJECTIVES: To explore associations of plasma total magnesium concentration (tMg) with plasma FGF23 concentration, all-cause mortality, and disease progression in cats with azotemic CKD. ANIMALS: Records of 174 client-owned cats with IRIS stage 2-4 CKD. METHODS: Cohort study. Cats with azotemic CKD were identified from the records of two London-based first opinion practices (1999-2013). Possible associations of baseline plasma tMg with FGF23 concentration and risks of death and progression were explored using, respectively, linear, Cox, and logistic regression. RESULTS: Plasma tMg (reference interval, 1.73-2.57 mg/dL) was inversely associated with plasma FGF23 when controlling for plasma creatinine and phosphate concentrations (partial correlation coefficient, -0.50; P < .001). Hypomagnesemia was observed in 12% (20/174) of cats, and independently associated with increased risk of death (adjusted hazard ratio, 2.74; 95% confidence interval [CI], 1.35-5.55; P = .005). The unadjusted associations of hypermagnesemia (prevalence, 6%; 11/174 cats) with survival (hazard ratio, 2.88; 95% CI, 1.54-5.38; P = .001), and hypomagnesemia with progressive CKD (odds ratio, 17.7; 95% CI, 2.04-154; P = .009) lost significance in multivariable analysis. CONCLUSIONS AND CLINICAL IMPORTANCE: Hypomagnesemia was associated with higher plasma FGF23 concentrations and increased risk of death. Measurement of plasma tMg augments prognostic information in cats with CKD, but whether these observations are associations or causations warrants further investigation. PMID- 29704287 TI - Subliminal encoding and flexible retrieval of objects in scenes. AB - Our episodic memory stores what happened when and where in life. Episodic memory requires the rapid formation and flexible retrieval of where things are located in space. Consciousness of the encoding scene is considered crucial for episodic memory formation. Here, we question the necessity of consciousness and hypothesize that humans can form unconscious episodic memories. Participants were presented with subliminal scenes, that is, scenes invisible to the conscious mind. The scenes displayed objects at certain locations for participants to form unconscious object-in-space memories. Later, the same scenes were presented supraliminally, that is, visibly, for retrieval testing. Scenes were presented absent the objects and rotated by 90 degrees -270 degrees in perspective to assess the representational flexibility of unconsciously formed memories. During the test phase, participants performed a forced-choice task that required them to place an object in one of two highlighted scene locations and their eye movements were recorded. Evaluation of the eye tracking data revealed that participants remembered object locations unconsciously, irrespective of changes in viewing perspective. This effect of gaze was related to correct placements of objects in scenes, and an intuitive decision style was necessary for unconscious memories to influence intentional behavior to a significant degree. We conclude that conscious perception is not mandatory for spatial episodic memory formation. PMID- 29704288 TI - Colocating an accredited practising dietitian to an adult community mental health service: An exploratory study. AB - For people with severe mental illness, accredited practising dietitians may assist with a nutrition care plan that considers the medical, psychiatric, psychological, social, spiritual, and pharmacological aspects of their care. However, consumers' access to care has been limited by difficulties attending appointments and suboptimal interface between nutritional and mental health services. Therefore, the objectives of this exploratory study were to describe access to, and key stakeholder perspectives of, the accredited practising dietitian role colocated in a community mental health service. A total of 16 key stakeholders participated in one-to-one interviews. Two main themes with subthemes were derived from analysis of interviews: (i) 'building empowerment and collaboration' and included the subthemes, (a) nutrition awareness and education and (b) healthy lifestyle changes, and (ii) 'overcoming challenges to optimal nutrition and effective health care'. In addition, improved access to the role was demonstrated with 124 (79%) consumers attending at least one appointment with an accredited practising dietitian. A total of 15 (12%) consumers attended more than 10 appointments during their outpatient admission to the community mental health service. Colocating an accredited practising dietitian was perceived to build empowerment and collaboration, and overcome challenges to optimal nutrition and effective health care for consumers, carers, and clinicians. The colocation of a dietitian can empower consumers' to make health-informed decisions and support their willingness to engage with physical healthcare provision when it is prioritized alongside mental healthcare provision. PMID- 29704289 TI - A precisely targeted application strategy of dipping young cucumber fruit in fungicide to control cucumber gray mold. AB - BACKGROUND: Gray mold is a ubiquitous destructive plant disease found worldwide. To avoid the shortcomings of conventional spraying systems for controlling this disease, such as high selection pressure on Botrytis cinerea for resistance and fungicide waste resulting from spray drift, a precisely targeted application strategy of dipping young cucumber fruit in a mixture of fungicide and forchlorfenuron (plant growth regulator, PGR) during the bloom period to control cucumber gray mold was developed in the current study. RESULTS: Without leaving above-limit residues in cucumber fruits, dipping in fludioxonil at 30 mg L-1 provided a greater efficacy (85.4%) against cucumber gray mold than did spraying at 100 mg L-1 (76.4%). Importantly, fludioxonil mixed with forchlorfenuron from 25 to 35 mg L-1 increased the yield of cucumbers by 26.2-36.7% compared to dipping fruit only in forchlorfenuron. The increased yield may be a benefit of controlling gray mold. CONCLUSION: Dipping fruit in fungicides and PGRs seems to be a potential precisely targeted application strategy to not only control cucumber gray mold effectively but also, through the action of PGRs, to increase the cucumber yield. This novel application method is believed to have a bright prospect in cucumber production in Chinese solar glasshouses. (c) 2018 Society of Chemical Industry. PMID- 29704290 TI - Engineering the Frontier Orbitals of a Diazadiborinine for Facile Activation of H2 , NH3 , and an Isonitrile. AB - An annulated 1,3,2,5-diazadiborinine with 14 pi electrons has been synthesized and fully characterized. Experimental and computational studies revealed that this compound features a rather small HOMO-LUMO gap, which leads to enhanced reactivity towards small molecules. Thus, the 1,3,2,5-diazadiborinine readily cleaves the H-H bond of dihydrogen and an N-H bond of ammonia under mild conditions. Moreover, it reacts with 2,6-dimethylphenylisonitrile in a [4+1] cycloaddition at room temperature. PMID- 29704291 TI - A missense mutation in EBF2 was segregated with imperforate anus in a family across three generations. AB - The etiology of imperforate anus, a major phenotype of anorectal malformation (ARM), is still unknown and not a single gene has been reported to be associated with it. We studied a Korean family with six affected members with imperforate anus across three generations by whole exome sequencing and identified a missense mutation in the EBF2 gene (c.215C > T; p.Ala72Val). This mutation is completely segregated with the disease phenotype in the family and is evolutionarily highly conserved among diverse vertebrates. Also, this mutation was predicted to be functionally damaging. These results support that missense mutation in the EBF2 c.215C > T (p.Ala72Val) is very likely to contribute to the pathogenesis of ARM in this family. PMID- 29704292 TI - Modulation of hippocampal excitability via the hydroxycarboxylic acid receptor 1. AB - In addition to its prominent role as an energetic substrate in the brain, lactate is emerging as a signaling molecule capable of controlling neuronal excitability. The finding that the lactate-activated receptor (hydroxycarboxylic acid receptor 1; HCA1) is widely expressed in the brain opened up the possibility that lactate exerts modulation of neuronal activity via a transmembranal receptor-linked mechanism. Here, we show that lactate causes biphasic modulation of the intrinsic excitability of CA1 pyramidal cells. In the low millimolar range, lactate or the HCA1 agonist 3,5-DHBA reduced the input resistance and membrane time constant. In addition, activation of HCA1 significantly blocked the fast inactivating sodium current and increased the delay from inactivation to a conducting state of the sodium channel. As the observed actions occurred in the presence of 4-CIN, a blocker of the neuronal monocarboxylate transporter, the possibility that lactate acted via neuronal metabolism is unlikely. Consistently, modulation of the intrinsic excitability was abolished when CA1 pyramidal cells were dialyzed with pertussis toxin, indicating the dependency of a Galphai/o -protein-coupled receptor. The activation of HCA1 appears to serve as a restraining mechanism during enhanced network activity and may function as a negative feedback for the astrocytic production of lactate. PMID- 29704294 TI - A cryptic diapause strategy in Halotydeus destructor (Tucker) (Trombidiformes: Penthaleidae) induced by multiple cues. AB - BACKGROUND: The polyphagous mite pest, Halotydeus destructor, typically has three generations during the cool moist season in Australia and produces over-summering diapause eggs in spring. Diapause eggs have a distinct thick and dark chorion and can survive heat, desiccation and the application of pesticides. Farmers suppress mites producing diapause eggs by a carefully timed spring pesticide application using Timerite(r) , which predicts the onset of diapause egg production based largely on day length. We investigated the association between diapause induction and other environmental factors that may complicate diapause predictions. RESULTS: Diapause in H. destructor induction was influenced by three interacting environmental factors, namely day length, temperature and soil moisture. A cryptic type of diapause egg that lacked a thick chorion and was instead morphologically similar to non-diapause eggs was also discovered. Like diapause eggs, this newly discovered egg type could also survive hot and dry summer conditions. CONCLUSIONS: There is an opportunity to refine the Timerite(r) spring spray by incorporating knowledge of other environmental factors inducing diapause in H. destructor. Compared with typical diapause eggs, the production of cryptic diapause eggs could reflect a strategy to deal with diversifying environmental stresses and/or represent a bet-hedging strategy to adapt to unpredictable environments. (c) 2018 Society of Chemical Industry. PMID- 29704295 TI - An Assembled Nanocomplex for Improving both Therapeutic Efficiency and Treatment Depth in Photodynamic Therapy. AB - Photodynamic therapy (PDT) shows unique selectivity and irreversible destruction toward treated tissues or cells, but still has several problems in clinical practice. One is limited therapeutic efficiency, which is attributed to hypoxia in tumor sites. Another is the limited treatment depth because traditional photosensitizes are excited by short wavelength light (<700 nm). An assembled nano-complex system composed of oxygen donor, two-photon absorption (TPA) species, and photosensitizer (PS) was synthesized to address both problems. The photosensitizer is excited indirectly by two-photon laser through intraparticle FRET mechanism for improving treatment depth. The oxygen donor, hemoglobin, can supply extra oxygen into tumor location through targeting effect for enhanced PDT efficiency. The mechanism and PDT effect were verified through both in vitro and in vivo experiments. The simple system is promising to promote two-photon PDT for clinical applications. PMID- 29704296 TI - Rtt109-dependent histone H3 K56 acetylation and gene activity are essential for the biological control potential of Beauveria bassiana. AB - BACKGROUND: Rtt109 is a histone acetyltransferase that catalyzes histone H3K56 acetylation required for genomic stability, DNA damage repair and virulence related gene activity in yeast-like human pathogens but remains functionally unknown in fungal insect pathogens. This study seeks to elucidate the catalytic activity of a Rtt109 orthologue and its possible role in sustaining the biological control potential of Beauveria bassiana, a fungal entomopathogen. RESULTS: Deletion of rtt109 in B. bassiana abolished histone H3K56 acetylation and triggered histone H2A-S129 phosphorylation. Consequently, the deletion mutant showed increased sensitivity to the stresses of DNA damage, oxidation, cell wall perturbation, high osmolarity and heat shock during colony growth, severe conidiation defects under normal culture conditions, reduced conidial hydrophobicity, decreased conidial UV-B resistance, and attenuated virulence through normal cuticle infection. These phenotypic changes correlated well with reduced transcript levels of many genes that encode the families of H2A-S129 dephosphorylation-related protein phosphatases, DNA damage-repairing factors, antioxidant enzymes, heat-shock proteins, key developmental activators, hydrophobins and cuticle-degrading Pr1 proteases respectively. CONCLUSION: Rtt109 can acetylate H3K56 and dephosphorylate H2A-S129 in direct and indirect ways respectively, and hence has an essential role in sustaining the genomic stability and global gene activity required for conidiation capacity, environmental fitness and pest control potential in B. bassiana. (c) 2018 Society of Chemical Industry. PMID- 29704297 TI - Renal safety of short-term empiric gentamicin therapy in aged patients. AB - OBJECTIVE: To determine the incidence of acute kidney injury (AKI) in aged patients receiving empiric gentamicin therapy. METHODS: Patients aged >=65 years receiving gentamicin upon admission between 2013 and 2015 at two Australian hospitals were retrospectively studied. AKI was defined as a rise in creatinine by >=50% and/or >=26.5 MUmol/L. RESULTS: Most patients (95%) received a single dose of gentamicin. The incidence of AKI was 15% (36/242 patients). A composite outcome of persistent kidney injury, requirement for renal replacement therapy or inpatient death in a patient with AKI occurred in 10 (4%) patients. Patients who developed AKI were older (median 80.5 vs 78 years, P = 0.03), had higher Charlson Co-morbidity Index (median 7 vs 5, P = 0.0004) and had more advanced chronic kidney disease at baseline (Stages IV and V) (OR 4.38, 95% confidence interval 1.45-13.2, P = 0.01). CONCLUSION: Empiric gentamicin use in patients with advancing age is associated with low rates of predominantly transient renal impairment. PMID- 29704298 TI - A Universal Organic Cathode for Ultrafast Lithium and Multivalent Metal Batteries. AB - Low-cost multivalent battery chemistries (Mg2+ , Al3+ ) have been extensively investigated for large-scale energy storage applications. However, their commercialization is plagued by the poor power density and cycle life of cathodes. A universal polyimides@CNT (PI@CNT) cathode is now presented that can reversibly store various cations with different valences (Li+ , Mg2+ , Al3+ ) at an extremely fast rate. The ion-coordination charge storage mechanism of PI@CNT is systemically investigated. Full cells using PI@CNT cathodes and corresponding metal anodes exhibit long cycle life (>10000 cycles), fast kinetics (>20 C), and wide operating temperature range (-40 to 50 degrees C), making the low-cost industrial polyimides universal cathodes for different multivalent metal batteries. The stable ion-coordinated mechanism opens a new foundation for the development of high-energy and high-power multivalent batteries. PMID- 29704300 TI - Can we minimize wait-list mortality in young children with Biliary atresia? PMID- 29704299 TI - Current status of chirality in agrochemicals. AB - The agrochemical industry is searching continuously for new pesticides to develop products that have optimal efficacy, lower application rates in the field, increased selectivity, favourable toxicological and environmental safety, enhanced user friendliness and better economic viability. One strategy by which to achieve these ambitious goals makes use of the unique properties of molecules containing asymmetric centres. In the past, many natural products and their congeners have been a source of inspiration in the design of new active ingredients, and the molecular structures of the resulting compounds have become increasingly complex; some 30% contain fragments with asymmetric centres. However, despite enormous progress in catalytic asymmetric processes over the past decade, few agrochemicals are produced in an enantiomerically pure or enriched form on an industrial scale. Since 2007, ~ 43% of the 44 products launched (insecticides, acaricides, fungicides, nematicides and herbicides) contain one or more asymmetric centres in the molecule (~ 47%) and most have been launched as racemic mixtures of enantiomers or diastereomers. This review provides an overview of the current status of chiral agrochemicals launched over the past 10 years and describes the inherently connected challenges of modern agricultural chemistry by managing important aspects resulting from the stereochemistry of these innovative products. (c) 2018 Society of Chemical Industry. PMID- 29704302 TI - Familial autosomal dominant severe ankyloglossia with tooth abnormalities. AB - Ankyloglossia is a congenital oral anomaly characterized by the presence of a hypertrophic and short lingual frenulum. Mutations in the gene encoding the transcription factor TBX22 have been involved in isolated ankyloglossia and X linked cleft palate. The knockout of Lgr5 in mice results in ankyloglossia. Here, we report a five-generation family including patients with severe ankyloglossia and missing lower central incisors. Two members of this family also exhibited congenital anorectal malformations. In this report, male-to-male transmission was in favor of an autosomal dominant inheritance, which allowed us to exclude the X linked TBX22 gene. Linkage analysis using short tandem repeat markers located in the vicinity of LGR5 excluded this gene as a potential candidate. These results indicate genetic heterogeneity for ankyloglossia. Further investigations with additional families are required in order to identify novel candidate genes. PMID- 29704303 TI - Atypical presentations associated with non-polyalanine repeat PHOX2B mutations. AB - Congenital central hypoventilation syndrome (CCHS) is a disorder of ventilatory control and autonomic dysregulation that can be caused by mutations in the paired like homeobox 2B (PHOX2B) gene. The majority of CCHS cases are caused by polyalanine repeat mutations (PARMs) in PHOX2B; however, in rare cases, non polyalanine repeat mutations (NPARMs) have been identified. Here, we report two patients with NPARMs in PHOX2B. Patient 1 has a mild CCHS phenotype seen only on polysomnogram, which was performed for desaturations and stridor following a bronchiolitis episode, and characterized by night-time hypoventilation and a history of ganglioneuroblastoma. She carried a novel de novo missense variant, p.R102S (c.304C > A), in exon 2. Patient 2 has an atypical CCHS phenotype including micrognathia, gastroesophageal reflux, stridor, hypopnea, and intermittent desaturations. Sleep study demonstrated that Patient 2 had daytime and night-time hypercarbia with obstructive sleep apnea, requiring tracheostomy. On PHOX2B sequencing, she carried a recently identified nonsense variant, p.Y78* (c.234C > G), in exon 1. In summary, we present two patients with CCHS and identified NPARMs in PHOX2B who have distinct differences in phenotype severity, further elucidating the range of clinical outcomes in CCHS and illustrating the necessity of considering PHOX2B mutations when encountering atypical CCHS presentations. PMID- 29704304 TI - Loss of function IFT27 variants associated with an unclassified lethal fetal ciliopathy with renal agenesis. AB - Ciliopathies comprise a group of clinically heterogeneous and overlapping disorders with a wide spectrum of phenotypes ranging from prenatal lethality to adult-onset disorders. Pathogenic variants in more than 100 ciliary protein encoding genes have been described, most notably those involved in intraflagellar transport (IFT) which comprises two protein complexes, responsible for retrograde (IFT-A) and anterograde transport (IFT-B). Here we describe a fetus with an unclassified severe ciliopathy phenotype including short ribs, polydactyly, bilateral renal agenesis, and imperforate anus, with compound heterozygosity for c.118_125del, p.(Thr40Glyfs*11) and a c.352 +1G > T in IFT27, which encodes a small GTPase component of the IFT-B complex. We conclude that bilateral renal agenesis is a rare feature of this severe ciliopathy and this report highlights the phenotypic overlap of Pallister-Hall syndrome and ciliopathies. The phenotype in patients with IFT27 gene variants is wide ranging from Bardet-Biedl syndrome to a lethal phenotype. PMID- 29704305 TI - Exponential Isothermal Amplification of Nucleic Acids and Assays for Proteins, Cells, Small Molecules, and Enzyme Activities: An EXPAR Example. AB - Isothermal exponential amplification techniques, such as strand-displacement amplification (SDA), rolling circle amplification (RCA), loop-mediated isothermal amplification (LAMP), nucleic acid sequence based amplification (NASBA), helicase dependent amplification (HDA), and recombinase polymerase amplification (RPA), have great potential for on-site, point-of-care, and in situ assay applications. These amplification techniques eliminate the need for temperature cycling, as required for the polymerase chain reaction (PCR), while achieving comparable amplification yields. We highlight here recent advances in the exponential amplification reaction (EXPAR) for the detection of nucleic acids, proteins, enzyme activities, cells, and metal ions. The incorporation of fluorescence, colorimetric, chemiluminescence, Raman, and electrochemical approaches enables the highly sensitive detection of a variety of targets. Remaining issues, such as undesirable background amplification resulting from nonspecific template interactions, must be addressed to further improve isothermal and exponential amplification techniques. PMID- 29704306 TI - Recessive variants of MuSK are associated with late onset CMS and predominant limb girdle weakness. AB - Congenital myasthenic syndrome (CMS) is a heterogeneous disorder that causes fatigable muscle weakness. CMS has been associated with variants in the MuSK gene and, to date, 16 patients have been reported. MuSK-CMS patients present a different phenotypic pattern of limb girdle weakness. Here, we describe four additional patients and discuss the phenotypic and clinical relationship with those previously reported. Two novel damaging missense variants are described: c.1742T > A; p.I581N found in homozygosis, and c.1634T > C; p.L545P found in compound heterozygosis with p.R166*. The reported patients had predominant limb girdle weakness with symptom onset at 12, 17, 18, and 30 years of age, and the majority exhibited a good clinical response to Salbutamol therapy, but not to esterase inhibitors. Meta-analysis including previously reported variants revealed an increased likelihood of a severe, respiratory phenotype with null alleles. Missense variants exclusively affecting the kinase domain, but not the catalytic site, are associated with late onset. These data refine the phenotype associated with MuSK-related CMS. PMID- 29704308 TI - A sibling pair with cardiofaciocutaneous syndrome (CFC) secondary to BRAF mutation with unaffected parents-the first cases of gonadal mosaicism in CFC? AB - Cardiofaciocutaneous (CFC) syndrome is a RASopathy characterized by intellectual disability, congenital heart defects, a characteristic facial appearance, gastro intestinal complications, ectodermal abnormalities and growth failure. The RASopathies result from germline mutations in the Ras/Mitogen-activated-protein kinase (MAPK) pathway. CFC is associated with mutations in BRAF, KRAS, MEK1 and MEK2. CFC has been considered a "sporadic" disorder, with minimal recurrence risk to siblings. In recent years, vertical transmission of CFC has been seen in mutations involving the MEK2 and KRAS genes, but has not previously been reported with BRAF mutations. Two brothers with clinical features of CFC and mutations in BRAF (c.770A > G, p.Gln257Arg) are described. Neither parent (both phenotypically normal) had the BRAF mutation in their leukocyte DNA. Although this mutation is one of the most common mutations in CFC, to our knowledge, this is the first molecularly confirmed BRAF mutation causing CFC in siblings. This observation also likely represents the first description of germ cell mosaicism in CFC and so it is important to provide optimal genetic counselling to families regarding the risk of reoccurrence. PMID- 29704307 TI - MECP2 variation in Rett syndrome-An overview of current coverage of genetic and phenotype data within existing databases. AB - Rett syndrome (RTT) is a monogenic rare disorder that causes severe neurological problems. In most cases, it results from a loss-of-function mutation in the gene encoding methyl-CPG-binding protein 2 (MECP2). Currently, about 900 unique MECP2 variations (benign and pathogenic) have been identified and it is suspected that the different mutations contribute to different levels of disease severity. For researchers and clinicians, it is important that genotype-phenotype information is available to identify disease-causing mutations for diagnosis, to aid in clinical management of the disorder, and to provide counseling for parents. In this study, 13 genotype-phenotype databases were surveyed for their general functionality and availability of RTT-specific MECP2 variation data. For each database, we investigated findability and interoperability alongside practical user functionality, and type and amount of genetic and phenotype data. The main conclusions are that, as well as being challenging to find these databases and specific MECP2 variants held within, interoperability is as yet poorly developed and requires effort to search across databases. Nevertheless, we found several thousand online database entries for MECP2 variations and their associated phenotypes, diagnosis, or predicted variant effects, which is a good starting point for researchers and clinicians who want to provide, annotate, and use the data. PMID- 29704309 TI - The neuroprotective and antidepressant-like effects of Hcyb1, a novel selective PDE2 inhibitor. AB - AIMS: Depression is currently the most common mood disorder. Regulation of intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP) signaling by phosphodiesterase (PDE) inhibition has been paid much attention for treatment of depression. This study aimed to investigate the neuroprotective effects of Hcyb1, a novel PDE2 inhibitor, in HT-22 cells and antidepressant-like effects in mouse models of depression. METHODS: Hcyb1 was synthesized and its selectivity upon PDE2 was tested. Moreover, HT-22 hippocampal cells were used to determine the effects of Hcyb1 on cell viability, cyclic nucleotide levels, and the downstream molecules related to cAMP/cGMP signaling by neurochemical, enzyme-linked immunosorbent, and immunoblot assays in vitro. The antidepressant-like effects of Hcyb1 were also determined in the forced swimming and tail suspension tests in mice. RESULTS: Hcyb1 had a highly selective inhibition of PDE2A (IC50 = 0.57 +/- 0.03 MUmol/L) and over 250-fold selectivity against other recombinant PDE family members. Hcyb1 at concentrations of 10-10 and 10-9 mol/L significantly increased cell viability after treatment for 24 hours. At concentrations of 10-9 ~10-7 mol/L, Hcyb1 also increased cGMP levels by 1.7~2.3 folds after 10-minute treatment. Furthermore, Hcyb1 at the concentrations of 10-9 mol/L increased both cGMP and cAMP levels 24 hours after treatment. The levels of phosphorylation of CREB and BDNF were also increased by Hcyb1 treatment in HT-22 cells for 24 hours. Finally, in the in vivo tests, Hcyb1 (0.5, 1, and 2 mg/kg, i.g.) decreased the immobility time in both forced swimming and tail suspension tests, without altering locomotor activity. CONCLUSION: These results suggest that the novel PDE2 inhibitor Hcyb1 produced neuroprotective and antidepressant-like effects most likely mediated by cAMP/cGMP-CREB-BDNF signaling. PMID- 29704310 TI - Bifunctional Ligand Enables Efficient Gold-Catalyzed Hydroalkenylation of Propargylic Alcohol. AB - Using the previously designed biphenyl-2-ylphosphine ligand, featuring a remote tertiary amino group, the first gold-catalyzed intermolecular hydroalkenylation of alkynes has been developed. Synthetically valuable conjugated dienyl alcohols are formed in moderate to good yields. A range of alkenyltrifluoroborates are allowed as the alkenyl donor, and no erosion of alkene geometry and/or the propargylic configuration are detected. DFT calculations confirm the critical role of the remote basic group in the ligand as a general-base catalyst for promoting this novel gold catalysis with good efficiency. PMID- 29704311 TI - Sleep disturbances in Rett syndrome: Impact and management including use of sleep hygiene practices. AB - Sleep disturbances are debilitating for individuals with Rett syndrome (RTT) and their families yet the evidence base for management is poor. We investigated management strategies and their relationships with sleep problems. Data were provided by 364/461 (79%) families with a child with RTT and registered with the International RTT Phenotype Database. Logistic regression models were used to investigate relationships between impacts of sleep problems on the child and family with age group, mutation type, medication type, and sleep hygiene score. Linear regression models were used to estimate the association of disorders of initiating and maintaining sleep (DIMS) with age group, mutation type, medication type, and sleep hygiene. Among those who ever had difficulty falling asleep or night waking, use of any medication was associated with higher odds of moderate/major impact sleep problems (relative to minor/no impact) for the affected child and the family, as well as higher DIMS scores, when compared with the no treatment/nonmedication group accounting for the effects of age, mutation type, and sleep hygiene score. Better use of sleep hygiene practices was associated with lower odds of moderate/major impact on the family (odds ratio 0.60, 95% confidence intervals [CIs] 0.37, 0.98) and lower DIMS scores (geometric mean ratio 0.86, 95%CI 0.80, 0.92) compared with poorer use after adjusting for covariates. Attention to sleep hygiene remains an important management strategy for sleep problems in RTT. Further prospective research is required to investigate efficacy of pharmaceutical treatments. PMID- 29704312 TI - Self-expandable tubular collagen implants. AB - Collagen has been extensively used as a biomaterial, yet for tubular organ repair, synthetic polymers or metals (e.g., stents) are typically used. In this study, we report a novel type of tubular implant solely consisting of type I collagen, suitable to self-expand in case of minimal invasive implantation. Potential benefits of this collagen scaffold over conventional materials include improved endothelialization, biodegradation over time, and possibilities to add bioactive components to the scaffold, such as anticoagulants. Implants were prepared by compression of porous scaffolds consisting of fibrillar type I collagen (1.0-2.0% (w/v)). By applying carbodiimide cross-linking to the compressed scaffolds in their opened position, entropy-driven shape memory was induced. The scaffolds were subsequently crimped and dried around a guidewire. Upon exposure to water, crimped scaffolds deployed within 15-60 s (depending on the collagen concentration used), thereby returning to the original opened form. The scaffolds were cytocompatible as assessed by cell culture with human primary vascular endothelial and smooth muscle cells. Compression force required to compress the open scaffolds increased with collagen content from 16 to 32 mN for 1.0% to 2.0% (w/v) collagen scaffolds. In conclusion, we report the first self expandable tubular implant consisting of solely type I collagen that may have potential as a biological vascular implant. PMID- 29704313 TI - HLA-DQB1*03:01:40, an HLA-DQB1*03:01 variant, identified in a Taiwanese individual. AB - One nucleotide substitution at codon 106 of HLA-DQB1*03:01:01:01 results in a new allele, HLA-DQB1*03:01:40. PMID- 29704314 TI - Bioactive bacterial cellulose sulfate electrospun nanofibers for tissue engineering applications. AB - Cellulosic materials have been of tremendous importance to mankind since its discovery due to its superior properties and its abundance in nature. Recently, an increase in demand for alternate green materials has rekindled the interest for cellulosic materials. Here, bacterial cellulose has been functionalized with sulfate groups through acetosulfation to gain solubility in aqueous media, which provides access to several applications. The cell viability, antioxidant, and hemocompatibility assays have verified the biocompatible and antioxidant characteristics of bacterial cellulose sulfate (BCS) in both in vitro and ex vivo conditions. Further, novel BCS/polyvinyl alcohol nanofibers were fabricated by simple electrospinning route to engineer ultrafine nanoscale fibers. The biological evaluation of BCS/polyvinyl alcohol nanofiber scaffolds was done using L929 mouse fibroblast cells, which confirmed that these nanofibers are excellent matrices for cell adhesion and proliferation. PMID- 29704315 TI - Epigenetics and autism spectrum disorder: A report of an autism case with mutation in H1 linker histone HIST1H1E and literature review. AB - Genetic mutations in genes encoding proteins involved in epigenetic machinery have been reported in individuals with autism spectrum disorder (ASD), intellectual disability, congenital heart disease, and other disorders. H1 histone linker protein, the basic component in nucleosome packaging and chromatin organization, has not been implicated in human disease until recently. We report a de novo deleterious mutation of histone cluster 1 H1 family member e (HIST1H1E; c.435dupC; p.Thr146Hisfs*50), encoding H1 histone linker protein H1.4, in a 10 year-old boy with autism and intellectual disability diagnosed through clinical whole exome sequencing. The c.435dupC at the 3' end of the mRNA leads to a frameshift and truncation of the positive charge in the carboxy-terminus of the protein. An expression study demonstrates the mutation leads to reduced protein expression, supporting haploinsufficiency of HIST1H1E protein and loss of function as an underlying mechanism of dysfunction in the brain. Taken together with other recent cases with mutations of HIST1H1E in intellectual disability, the evidence supporting the link to causality in disease is strong. Our finding implicates the deficiency of H1 linker histone protein in autism. The systematic review of candidate genes implicated in ASD revealed that 42 of 215 (19.5%) genes are directly involved in epigenetic regulations and the majority of these genes belong to histone writers, readers, and erasers. While the mechanism of how haploinsufficiency of HIST1H1E causes autism is entirely unknown, our report underscores the importance of further study of the function of this protein and other histone linker proteins in brain development. PMID- 29704316 TI - Genome-wide and digital polymerase chain reaction epigenetic assessments of alcohol consumption. AB - The lack of readily employable biomarkers of alcohol consumption is a problem for clinicians and researchers. In 2014, we published a preliminary DNA methylation signature of heavy alcohol consumption that remits as a function of abstinence. Herein, we present new genome-wide methylation findings from a cohort of additional subjects and a meta-analysis of the data. Using DNA from 47 consecutive heavy drinkers admitted for alcohol detoxification in the context of alcohol treatment and 47 abstinent controls, we replicate the 2014 results and show that 21,221 CpG residues are differentially methylated in active heavy drinkers. Meta-analysis of all data from the 448,058 probes common to the two methylation platforms shows a similarly profound signature with confirmation of findings from other groups. Principal components analyses show that genome-wide methylation changes in response to alcohol consumption load on two major factors with one component accounting at least 50% of the total variance in both smokers and nonsmoking alcoholics. Using data from the arrays, we derive a panel of five methylation probes that classifies use status with a receiver operator characteristic area under the curve (AUC) of 0.97. Finally, using droplet digital polymerase chain reaction (PCR), we convert these array-based findings to two marker assays with an AUC of 0.95 and a four marker set AUC of 0.98. We conclude that DNA methylation assessments are capable of quantifying alcohol use status and suggest that readily employable digital PCR approaches for substance consumption may find widespread use in alcohol-related research and patient care. PMID- 29704317 TI - Development of GMP-1 a molecular chaperone network modulator protecting mitochondrial function and its assessment in fly and mice models of Alzheimer's disease. AB - Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD) and may play an important role in the pathogenesis of disease. It has been shown that amyloid beta peptide (Abeta) and amyloid precursor protein (APP) interact with mitochondria contributing to the mitochondrial dysfunction in AD. Prevention of abnormal protein targeting to mitochondria can protect normal mitochondrial function, increase neuronal survival and at the end, ameliorate symptoms of AD and other neurodegenerative disorders. First steps of mitochondrial protein import are coordinated by molecular chaperones Hsp70 and Hsp90 that bind to the newly synthesized mitochondria-destined proteins and deliver them to the protein import receptors on the surface of organelle. Here, we have described the development of a novel compound named GMP-1 that disrupts interactions between Hsp70/Hsp90 molecular chaperones and protein import receptor Tom70. GMP-1 treatment of SH-SY5Y cells results in decrease in mitochondria-associated APP and protects SH-SY5Y cells from toxic effect of Abeta1-42 exposure. Experiments in drosophila and mice models of AD demonstrated neuroprotective effect of GMP-1 treatment, improvement in memory and behaviour tests as well as restoration of mitochondrial function. PMID- 29704318 TI - Roles of microglia in nervous system development, plasticity, and disease. PMID- 29704319 TI - A molecule-based genetic association approach implicates a range of voltage-gated calcium channels associated with schizophrenia. AB - Traditional genome-wide association studies (GWAS) have successfully detected genetic variants associated with schizophrenia. However, only a small fraction of heritability can be explained. Gene-set/pathway-based methods can overcome limitations arising from single nucleotide polymorphism (SNP)-based analysis, but most of them place constraints on size which may exclude highly specific and functional sets, like macromolecules. Voltage-gated calcium (Cav ) channels, belonging to macromolecules, are composed of several subunits whose encoding genes are located far away or even on different chromosomes. We combined information about such molecules with GWAS data to investigate how functional channels associated with schizophrenia. We defined a biologically meaningful SNP set based on channel structure and performed an association study by using a validated method: SNP-set (sequence) kernel association test. We identified eight subtypes of Cav channels significantly associated with schizophrenia from a subsample of published data (N = 56,605), including the L-type channels (Cav 1.1, Cav 1.2, Cav 1.3), P-/Q-type Cav 2.1, N-type Cav 2.2, R-type Cav 2.3, T-type Cav 3.1, and Cav 3.3. Only genes from Cav 1.2 and Cav 3.3 have been implicated by the largest GWAS (N = 82,315). Each subtype of Cav channels showed relatively high chip heritability, proportional to the size of its constituent gene regions. The results suggest that abnormalities of Cav channels may play an important role in the pathophysiology of schizophrenia and these channels may represent appropriate drug targets for therapeutics. Analyzing subunit-encoding genes of a macromolecule in aggregate is a complementary way to identify more genetic variants of polygenic diseases. This study offers the potential of power for discovery the biological mechanisms of schizophrenia. PMID- 29704320 TI - siRNA release from gold nanoparticles by nanosecond pulsed laser irradiation and analysis of the involved temperature increase. AB - Nanosecond pulsed laser irradiation can trigger a release of nucleic acids from gold nanoparticles, but the involved nanoeffects are not fully understood yet. Here we investigate the release of coumarin labeled siRNA from 15 to 30 nm gold particles after nanosecond pulsed laser irradiation. Temperatures in the particle and near the surface were calculated for the different radiant exposures. Upon irradiation with laser pulses of 4 nanosecond duration release started for both particle sizes at a calculated temperature increase of approximately 500 K. Maximum coumarin release was observed for 15 nm particles after irradiation with radiant exposure of 80 mJ cm-2 and with 32 mJ cm-2 for 30 nm particles. This corresponds to a temperature increase of 815 and 900 K, respectively. Our results show that the molecular release by nanosecond pulsed irradiation is based on a different mechanism compared to continuous or femtosecond irradiation. Local temperatures are considerably higher and it is expected that bubble formation plays a crucial role in release and damage to cellular structures. PMID- 29704321 TI - On the influence of surface patterning on tissue self-assembly and mechanics. AB - Extracellular matrix assembly and composition influence the biological and mechanical functions of tissues. Developing strategies to control the spatial arrangement of cells and matrix is of central importance for tissue engineering related approaches relying on self-assembling and scaffoldless processes. Literature reports demonstrated that signals patterned on material surfaces are able to control cell positioning and matrix orientation. However, the mechanisms underlying the interactions between material signals and the structure of the de novo synthesized matrix are far from being thoroughly understood. In this work, we investigated the ordering effect provided by nanoscale topographic patterns on the assembly of tissue sheets grown in vitro. We stimulated MC3T3-E1 preosteoblasts to produce and assemble a collagen-rich matrix on substrates displaying patterns with long- or short-range order. Then, we investigated microstructural features and mechanical properties of the tissue in uniaxial tension. Our results demonstrate that patterned material surfaces are able to control the initial organization of cells in close contact to the surface; then cell-generated contractile forces profoundly remodel tissue structure towards mechanically stable spatial patterns. Such a remodelling effect acts both locally, as it affects cell and nuclear shape and globally, by affecting the gross mechanical response of the tissue. Such an aspect of dynamic interplay between cells and the surrounding matrix must be taken into account when designing material platform for the in vitro generation of tissue with specific microstructural assemblies. PMID- 29704322 TI - Macrophage phenotype in the epigallocatechin-3-gallate (EGCG)-modified collagen determines foreign body reaction. AB - Collagen has been widely used in guided bone regeneration, and the implantation of collagen membranes will elicit the foreign body reaction (FBR). The imbalance of FBR often leads to failure of dental implants. Therefore, modulation of the FBR after implantation of collagen membranes becomes increasingly important. Macrophages, pivotal in FBR, have been distinguished into pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes. Epigallocatechin-3-gallate (EGCG)-modified collagen membranes have been previously shown to regulate secretion of inflammatory factors. In this study, immunohistochemistry of CD31 showed that areas of blood vessels were significantly enlarged after implantation of EGCG modified collagen membranes compared with those treated with pure collagen membranes. Besides, haematoxylin-eosin staining and immunofluorescence showed an increased number of M2 macrophages after implantation of EGCG-modified collagen membranes. In addition, quantitative real-time polymerase chain reaction showed that after implantation of EGCG-modified collagen membranes, expression of CXCL1 (predominant chemoattractants to neutrophils and inflammation promotors) was significantly downregulated, whereas expressions of STAB1, CCR2, CCR3, CCL2, and CCL3 (related to M2 macrophages) were significantly upregulated. From these findings, we conclude that EGCG-modified collagen membranes were able to regulate the recruitment and polarization of macrophages, so that ameliorate FBR. PMID- 29704323 TI - Machine learning in schizophrenia genomics, a case-control study using 5,090 exomes. AB - Our hypothesis is that machine learning (ML) analysis of whole exome sequencing (WES) data can be used to identify individuals at high risk for schizophrenia (SCZ). This study applies ML to WES data from 2,545 individuals with SCZ and 2,545 unaffected individuals, accessed via the database of genotypes and phenotypes (dbGaP). Single nucleotide variants and small insertions and deletions were annotated by ANNOVAR using the reference genome hg19/GRCh37. Rare (predicted functional) variants with a minor allele frequency <=1% and genotype quality >=90 including missense, frameshift, stop gain, stop loss, intronic, and exonic splicing variants were selected. A file containing all cases and controls, the names of genes with variants meeting our criteria, and the number of variants per gene for each individual, was used for ML analysis. The supervised machine learning algorithm used the patterns of variants observed in the different genes to determine which subset of genes can best predict that an individual is affected. Seventy percent of the data was used to train the algorithm and the remaining 30% of data (n = 1,526) was used to evaluate its efficiency. The supervised ML algorithm, gradient boosted trees with regularization (eXtreme Gradient Boosting implementation) was the best performing algorithm yielding promising results (accuracy: 85.7%, specificity: 86.6%, sensitivity: 84.9%, area under the receiver-operator characteristic curve: 0.95). The top 50 features (genes) of the algorithm were analyzed using bioinformatics resources for new insights about the pathophysiology of SCZ. This manuscript presents a novel predictor which could potentially enable studies exploring disease-modifying intervention in the early stages of the disease. PMID- 29704324 TI - Voxel-wise brain-wide functional connectivity abnormalities in first-episode, drug-naive patients with major depressive disorder. AB - Due to different foci and single sample across studies, abnormal functional connectivity (FC) has been implicated in the pathophysiology of major depressive disorder (MDD) with inconsistent results. The inconsistency may reflect a combination of clinical and methodological variability, which leads to limited reproducibility of these findings. The samples included 59 patients with MDD and 31 controls from Sample 1, 29 patients with MDD and 24 controls from Sample 2, and 31 patients with schizophrenia and 37 controls from Sample 3. Global-brain FC (GFC) and an overlapping technique were applied to analyze the imaging data. Compared with healthy controls, patients with MDD in Samples 1 and 2 showed increased GFC in the overlapped brain areas, including the bilateral insula, right inferior parietal lobule (IPL), and right supramarginal gyrus/IPL. By contrast, decreased GFC in the overlapped brain areas, including the bilateral posterior cingulate cortex/presuneus and left calcarine cortex, was found in patients with MDD. In addition, patients with schizophrenia in Sample 3 did not show any GFC abnormalities in the overlapped areas from the results of Samples 1 and 2. The present study is the first to examine voxel-wise brain-wide FC in MDD with two independent samples by using an overlapping technique. The results indicate that aberrant FC patterns of insula-centered sensorimotor circuit may account for the pathophysiology of MDD. PMID- 29704325 TI - Transcytosis of Junonia coenia densovirus VP4 across the gut epithelium of Spodoptera frugiperda (Lepidoptera: Noctuidae). AB - The Junonia coenia densovirus rapidly traverses the gut epithelium of the host lepidopteran without replicating in the gut cells. The ability of this virus to transcytose across the gut epithelium is of interest for the potential use of virus structural proteins as delivery vehicles for insecticidal peptides that act within the insect hemocoel, rather than in the gut. In this study, we used fall armyworm, Spodoptera frugiperda to examine the binding of the virus to brush border membrane vesicle proteins by two-dimensional ligand blot analysis. We also assessed the rate of flux of the primary viral structural protein, VP4 fused to eGFP with a proline-rich linker (VP4-P-eGFP) through the gut epithelium ex vivo in an Ussing chamber. The mechanisms involved with transcytosis of VP4-P-eGFP were assessed by use of inhibitors. Bovine serum albumin (BSA) and eGFP were used as positive and negative control proteins, respectively. In contrast to BSA, which binds to multiple proteins on the brush border membrane, VP4-P-eGFP binding was specific to a protein of high molecular mass. Protein flux was significantly higher for VP4-P-eGFP after 2 h than for albumin or eGFP, with rapid transcytosis of VP4-P-eGFP within the first 30 min. In contrast to BSA which transcytosed following clathrin-mediated endocytosis, the movement of VP4-P-eGFP was vesicle mediated but clathrin-independent. The specificity of binding combined with the efficiency of transport across the gut epithelium suggest that VP4 will provide a useful carrier for insecticidal peptides active within the hemocoel of key lepidopteran pests including S. frugiperda. PMID- 29704326 TI - Polyclonal B-cell lymphocytosis: Report of three cases. AB - BACKGROUND: Persistent polyclonal B-cell lymphocytosis (PPBL) is a rare benign condition characterized by a polyclonal B-cell lymphocytosis with binucleated lymphocytes. We hereby report three cases of PPBL. METHODS: Flow cytometry immunophenotyping was performed in peripheral blood samples from three patients with clinical suspicion of lymphoproliferative disease. RESULTS: Case 1 was a female middle-aged smoker; Case 2 was an elderly male; and Case 3 was a non smoker female. Flow cytometry evaluation of all cases revealed an expansion of mature B-cells, with a normal Kappa/Lambda light chain ratio; B-cell lymphocytes of Cases 2 and 3 had CD5 coexpression; Case 3 also had monocytosis. CONCLUSIONS: Diagnose of PPBL is important in order to avoid unnecessary diagnostic procedures and therapy. (c) 2018 International Clinical Cytometry Society. PMID- 29704327 TI - Morphological characterization of chronic antibody-mediated rejection in ABO identical or ABO-compatible pediatric liver graft recipients. AB - This study aims to define the morphological profile associated with the presence of donor-specific antibodies (DSAs) and/or C4d immunostaining in ABO-identical or compatible pediatric liver grafts. Ten-year protocol liver graft biopsies performed at 131.3 +/- 15.3 months after transplantation in 53 pediatric liver graft recipients were reviewed. Immunostaining for C4d was systematically performed and semiquantitatively analyzed. DSAs were concurrently quantified, and results were available for 44 patients. All biopsies demonstrated fibrotic changes with a mean liver allograft fibrosis score (LAFSc) of 5.1 +/- 2.2. A total of 31 (58%) biopsies exhibited C4d positivity. DSAs were detected in 20 (45%) patients, and mean maximal mean fluorescence intensity was 12,977 +/- 6731. LAFSc (6.3 +/- 1.3 versus 3.9 +/- 2.2; P = 0.008), perivenular fibrosis (2.7 +/- 0.5 versus 1.3 +/- 1.0; P < 0.001), and portal inflammation (1.4 +/- 0.8 versus 0.3 +/- 0.5; P = 0.009) were significantly higher in the double-DSA and C4d positive group versus the double-negative group. We defined a histological scoring system from these results, which was integrated with the 2016 Banff definition and allowed reclassifying patients for the diagnosis of chronic active antibody-mediated rejection (cAMR; 11/53 versus 13/53). Diagnoses of probable cAMR according to Banff 2016 (n = 4) were unchanged, but 2 among the 9 patients classified as possible cAMR according to the 2016 Banff definition were excluded for this diagnostic when using our histological score. In conclusion, our results confirmed that perivenular fibrosis and portal inflammation in late pediatric liver graft biopsies are features of cAMR. Our histological score could improve the accuracy of the 2016 Banff definition for the diagnosis of cAMR. Liver Transplantation 24 897-907 2018 AASLD. PMID- 29704328 TI - Complex regression Doppler optical coherence tomography. AB - We introduce a new method to measure Doppler shifts more accurately and extend the dynamic range of Doppler optical coherence tomography (OCT). The two-point estimate of the conventional Doppler method is replaced with a regression that is applied to high-density B-scans in polar coordinates. We built a high-speed OCT system using a 1.68-MHz Fourier domain mode locked laser to acquire high-density B-scans (16,000 A-lines) at high enough frame rates (~100 fps) to accurately capture the dynamics of the beating embryonic heart. Flow phantom experiments confirm that the complex regression lowers the minimum detectable velocity from 12.25 mm / s to 374 MUm / s, whereas the maximum velocity of 400 mm / s is measured without phase wrapping. Complex regression Doppler OCT also demonstrates higher accuracy and precision compared with the conventional method, particularly when signal-to-noise ratio is low. The extended dynamic range allows monitoring of blood flow over several stages of development in embryos without adjusting the imaging parameters. In addition, applying complex averaging recovers hidden features in structural images. PMID- 29704329 TI - Real-time biodetection using a smartphone-based dual-color surface plasmon resonance sensor. AB - We proposed a compact and cost-effective red-green dual-color fiber optic surface plasmon resonance (SPR) sensor based on the smartphone. Inherent color selectivity of phone cameras was utilized for real-time monitoring of red and green color channels simultaneously, which can reduce the chance of false detection and improve the sensitivity. Because there are no external prisms, complex optical lenses, or diffraction grating, simple optical configuration is realized. It has a linear response in a refractive index range of 1.326 to 1.351 (R2 = 0.991) with a resolution of 2.3 * 10 - 4 RIU. We apply it for immunoglobulin G (IgG) concentration measurement. Experimental results demonstrate that a linear SPR response was achieved for IgG concentrations varying from 0.02 to 0.30 mg / ml with good repeatability. It may find promising applications in the fields of public health and environment monitoring owing to its simple optics design and applicability in real-time, label-free biodetection. PMID- 29704330 TI - [Responses of plant community structure and species composition to warming and N addition in an alpine meadow, northern Tibetan Plateau, China]. AB - Global climate warming and increasing nitrogen (N) deposition, as controversial global environmental issues, may distinctly affect the functions and processes of terrestrial ecosystems. It has been reported that the Qinghai-Tibet Plateau has been experiencing significant warming in recent decades, especially in winter. Previous studies have mainly focused on the effects of warming all the year round; however, few studies have tested the effects of winter warming. To investigate the effects of winter warming and N addition on plant community structure and species composition of alpine meadow, long-term N addition and simulated warming experiment was conducted in alpine meadow from 2010 in Damxung, northern Tibet. The experiment consisted of three warming patterns: Year-round warming (YW), winter warming (WW) and control (NW), crossed respectively with five N gradients: 0, 10, 20, 40, 80 kg N.hm-2.a-1. From 2012 to 2014, both warming and N addition significantly affected the total coverage of plant community. Specifically, YW significantly decreased the total coverage of plant community. Without N addition, WW remarkably reduced the vegetation coverage. However, with N addition, the total vegetation coverage gradually increased with the increase of N level. Warming and N addition had different effects on plants from different functional groups. Warming significantly reduced the plant coverage of grasses and sedges, while N addition significantly enhanced the plant coverage of grasses. Regression analyses showed that the total coverage of plant community was positively related to soil water content in vigorous growth stages, indicating that the decrease in soil water content resulted from warming during dry seasons might be the main reason for the decline of total community coverage. As soil moisture in semi-arid alpine meadow is mainly regulated by rainfalls, our results indicated that changes in spatial and temporal patterns of rainfalls under the future climate change scenarios would dramatically influence the vegetation coverage and species composition. Additionally, the effects of increasing atmospheric N deposition on vegetation community might also depend on the change of rainfall patterns. PMID- 29704331 TI - [Carbon storage of forest vegetation and allocation for main forest types in the east of Da-xing'an Mountains based on additive biomass model]. AB - Based on the biomass investigation data of main forest types in the east of Daxing'an Mountains, the additive biomass models of 3 main tree species were developed and the changes of carbon storage and allocation of forest community of tree layer, shrub layer, herb layer and litter layer from different forest types were discussed. The results showed that the carbon storage of tree layer, shrub layer, herb layer and litter layer for Rhododendron dauricum-Larix gmelinii forest was 71.00, 0.34, 0.05 and 11.97 t.hm-2, respectively. Similarly, the carbon storage of the four layers of Ledum palustre-L. gmelinii forest was 47.82, 0.88, 0, 5.04 t.hm-2, 56.56, 0.44, 0.04, 8.72 t.hm-2 for R. dauricum-mixed forest of L. gmelinii-Betula platyphylla, 46.21, 0.66, 0.07, 6.16 t.hm-2 for L. palustre mixed forest of L. gmelinii-B. platyphylla, 40.90, 1.37, 0.04, 3.67 t.hm-2 for R. dauricum-B. platyphylla forest, 36.28, 1.12, 0.18, 4.35 t.hm-2 for L. palustre-B. platyphylla forest. The carbon storage of forest community for the understory vegetation of R. dauricum was higher than that of the forest with L. palustre. In the condition of similar circumstances for the understory, the order of carbon storage for forest community was L. gmelinii forest > the mixed forest of L. gmelinii-B. platyphylla > B. platyphylla forest. The carbon storage of different forest types was different with the order of R. dauricum-L. gmelinii forest (83.36 t.hm-2)> R. dauricum-mixed forest of L. gmelinii-B. platyphylla (65.76 t.hm-2) > L. palustre-L. gmelinii forest (53.74 t.hm-2)> L. palustre-mixed forest of L. gmelinii-B. platyphylla (53.10 t.hm-2)> R. dauricum-B. platyphylla forest (45.98 t.hm-2) > L. palustre-B. platyphylla forest (41.93 t.hm-2). The order of carbon storage for the vertical distribution in forest communities with diffe rent forest types was the tree layer (85.2%-89.0%) > litter layer (8.0%-14.4%) > shrub layer (0.4%-2.7%) > herb layer (0-0.4%). PMID- 29704332 TI - [Biomass, carbon storage and nutrient characteristics in Larix kaempferi plantations at diffe-rent stand ages]. AB - Based on 7-, 17-, 30-, and 40-year-old Larix kaempferi plantations, this paper studied the influence of tree age on biomass, carbon storage and nutrient characteristics. There was significant difference in biomass and nutrient concentration of stem, bark, needle, branch and root at different development stages at individual tree level. The biomass of each organ showed a trend of increase with the increasing age. The concentrations of N, P, K decreased, Mg concentration increased at first and then decreased, and Ca concentration continued to rise with the increasing age. There was significant difference in biomass of each organ for dominant, intermediate and suppressed trees, but no significant difference in nutrient concentration. It indicated that nutrient concentration of each organ was not affected by competition. At stand level, the total biomass, carbon storage and nutrient accumulation increased with the increasing age. Compared with young stand, the growth rate of biomass, carbon storage and nutrient accumulation were increased by 217%, 218% and 56% in mature stand, respectively. It indicated L. kaempferi had a high nutrient use efficiency, and could utilize less nutrient to produce more dry matter. Except that the accumulation of P and K had a slight decrease in pre-mature stand (30 years old), other elements increased with the increasing age. N mainly concentrated in needle, Ca concentrated in stem, K and Mg concentrated in root and P was distributed evenly in different organs. The annual accumulation rates of biomass, carbon and nutrient of L. kaempferi stands decreased with the increasing age, from 7.16 t.hm-2, 3.40 t.hm-2 and 104.64 kg.hm-2 for young stand to 3.99 t.hm-2, 1.89 t.hm-2and 28.64 kg.hm-2 for mature stand, respectively. It indicated that L. kaempferi plantations had great carbon sequestration potential and high nutrient consumption during young and middle ages. PMID- 29704333 TI - [Water repellency and its influencing factors in Manas River Basin, China]. AB - Soil water repellency (SWR) impedes the processes of soil water infiltration and redistribution. Although water repellent soils exist extensively in the world, its causes were not very clear. In this research, three measurement methods including the water droplet penetration time (WDPT), the molarity of ethanol drop (MED) and the contact angle (denoted as theta below) methods, were applied to obtain different SWR indices for the tested soils collected in Manas River Basin, Xinjiang Uygur Autonomous Region, China. The height method and the mass method were conducted to measure theta values. WDPT values of different soil samples were compared to investigate whether WDPT values were affected after being oven dried or by different bulk densities. The relationships among three SWR indices (WDPT, MED and theta) were compared, and the major soil physico-chemical properties which influenced SWR were analyzed to discuss the intrinsic mechanism that caused SWR. The results showed that WDPT values of higher bulk density were larger than those of lower bulk density, and WDPT values of oven-dried soils were larger than those of air-dried soils. There were correlations between the three SWR indices of WDPT, MED and theta, but MED was insignificantly related to theta, which showed the differences among various SWR indices, although they were related to each other. When measuring theta values of soil-water, theta values obtained using the height method were larger than those obtained using the mass method, and the differences of theta for the three replications with the height method were smaller than those with the mass method. When using octane as the reference liquid for measuring theta values of soil-water, the differences of the three replications were small, being lower than those using ethyl alcohol. Among the studied multi-physico-chemical properties, clay content affected WDPT and theta values more significantly than other soil physico-chemical properties. Concentrations of K+ and Na+ were both positively correlated to theta va-lues, while the content of montmorillonite was negatively correlated to WDPT and MED values. In summary, among the three SWR measurement methods, the WDPT method was quite simple in operation but was susceptible, the MED method shortened the infiltration time but was time-consuming in operation, and the contact angle method was complicated in operation but the results were relatively accurate. When using octane as the reference liquid for the height method, it was more reliable than using the other liquids. Because each index had its inherent nature, it was suggested to use multiple indices to characterize SWR comprehensively. PMID- 29704334 TI - [Evaluation of the forest ecosystem service values in Qinling, China]. AB - Landsat TM images of Mt. Qinling in 1984, 2000, 2005, and 2014 were used to extract land use and land cover type by a supervised classification method in ERDAS software. Equivalent factor of ecosystem service value per unit area was revised regionally in temporal and spatial dimensions, and then was modified pixel by pixel using the vegetation coverage. Forest ecosystem service values from 1984 to 2014 were calculated with RS and GIS techniques, and the results were tested by the sensitivity index. The results showed that from 1984 to 2014, forest area accounted for 77% of the study area, and the area changes in cultivated land and construction land were the most obvious. The total ecosystem service value of Mt. Qinling increased annually and by a total of 1.68*1017 yuan during the study period. The forest ecosystem service value (its growth rate was the biggest) contributed 93.8% of the overall ecosystem service value, while water and grass ecosystem service value contributed 1.6% and 1.3%, respectively. The ecosystem service value tended to increase with increasing distance from the study area boundary, which was consistent with the spatial distribution and per unit ecosystem service value of land use types in Mt. Qinling. The annual rate of change of each ecosystem service value was insignificant. Among the four ecosystem functions, the service value of regulation accounted for 62.7%-65.8% of the total ecosystem service value, and the service value of climate regulation showed the most dramatic increase by 4.91*1016 yuan over the study period. The sensitivity index was <1, which indicated that the modified service value index was stable and the calculated results were reliable. Overall, the forest ecosystem service value in Mt. Qinling was very large, and strengthening forest protection would be an effective measure for maintaining the stability of the Mt. Qinling ecosystem. PMID- 29704335 TI - [Spatial-temporal evolvement of ecosystem service value of Dongting Lake area influenced by changes of land use]. AB - With the technology of geographic information system (GIS), the ecosystem service va-lue (ESV) coefficient of different types of land use in Dongting Lake area was estimated in this paper by interpreting the remote-sensing image for years and combining its economic development statistics. Meanwhile, the temporal-spatial evolvement characteristics of the ESV were investigated by employing the methods of spatial statistics analysis such as spatial autocorrelation, highland clustering analysis and hotspot analysis. The results showed that the ESV of Dongting Lake area increased slightly during 2000-2013, from 3868.39 billion yuan to 3886.62 billion yuan due to the increase of wetland in the area. The areas with high ESV and low ESV were infiltrated into each other, while the areas with second high ESV embraced those areas with high and low ESV. The characteristics of ESV and its dynamic evolvement in Dongting Lake area were obviously of spatial autocorrelation and high and low value clustering, but the trend was weakened. The focus of ESV hotspot of Dongting Lake area moved to northwest slightly with a "S" track in a obviously phased manner of "quick-slow-quick". PMID- 29704336 TI - [Simulating of carbon fluxes in bamboo forest ecosystem using BEPS model based on the LAI assimilated with Dual Ensemble Kalman Filter]. AB - LAI is one of the most important observation data in the research of carbon cycle of forest ecosystem, and it is also an important parameter to drive process-based ecosystem model. The Moso bamboo forest (MBF) and Lei bamboo forest (LBF) were selected as the study targets. Firstly, the MODIS LAI time series data during 2014-2015 was assimilated with Dual Ensemble Kalman Filter method. Secondly, the high quality assimilated MBF LAI and LBF LAI were used as input dataset to drive BEPS model for simulating the gross primary productivity (GPP), net ecosystem exchange (NEE) and total ecosystem respiration (TER) of the two types of bamboo forest ecosystem, respectively. The modeled carbon fluxes were evaluated by the observed carbon fluxes data, and the effects of different quality LAI inputs on carbon cycle simulation were also studied. The LAI assimilated using Dual Ensemble Kalman Filter of MBF and LBF were significantly correlated with the observed LAI, with high R2 of 0.81 and 0.91 respectively, and lower RMSE and absolute bias, which represented the great improvement of the accuracy of MODIS LAI products. With the driving of assimilated LAI, the modeled GPP, NEE, and TER were also highly correlated with the flux observation data, with the R2 of 0.66, 0.47, and 0.64 for MBF, respectively, and 0.66, 0.45, and 0.73 for LBF, respectively. The accuracy of carbon fluxes modeled with assimilated LAI was higher than that acquired by the locally adjusted cubic-spline capping method, in which, the accuracy of mo-deled NEE for MBF and LBF increased by 11.2% and 11.8% at the most degrees, respectively. PMID- 29704337 TI - [Hyperspectral inversion of soil water and salt content in soils with different textures]. AB - In order to monitor soil water and salt content of saline soil conveniently and quickly, this paper took the typical salinization irrigation district of Xinjiang as the research object, obtained the spectral curve of soil water and salt content by using portable spectrometers based on the hyperspectral technology, transformed the original spectra of soil using the first order differential, second order differential and continuum removal methods. The results showed that the transformation of the original spectral data was beneficial to fingerprint band extraction of soil properties, and the method was not same in soils with different textures. In loam soil, continuum removal analysis was the best method for extraction of characteristic bands when the soil water content was 0% and 10%, first order differential equations were the best method when the soil water content was 15%, and second order differential equations were the best method when the soil water content was 19%. In sandy soil, continuum removal analysis was the best method for extraction of characteristic bands when the soil water content was 0%, whereas second order differential equations were the best method when soil water content was 10%, 15% or 19%. The transformed data were screened for inversion models of soil water and salt content by using the partial least squares regression method. When thesalinity was < 6.38 mS.cm-1 in loam soil and < 5.94 mS.cm-1 in sandy soil, the decision coefficients (Rcal2), internal cross validation (Rcv2), and external validation (Rval2) were greater than 0.65 (P<0.05). When the soil moisture content was less than 16% in loam soil and 12% in sandy soil, the inversion accuracy of model was higher. The results would provide a reference threshold for si-multaneously monitoring soil water and salt content in salinized areas. PMID- 29704338 TI - [Variation in delta13C and water use efficiency of plant leaf at different slopes in an alpine mea-dow]. AB - Through the systematical measurements of delta13C values of samples representing 25 families and 86 C3 herb species along the slope aspects in an alpine meadow, the responses of delta13C va-lues and water use efficiency (WUE) for C3 plants to slope aspect changes and influence of environmental factors were analyzed and main environmental factors related to plant delta13C values change were revealed. Along the north-facing to south-facing slope, soil water content decreased gradually, the soil temperature and light intensity increased gradually, and plant community structure also had corresponding change. The delta13C values of C3 plant species in 5 slope aspects were from -31.190/00 to -21.80/00, with an average value of (-27.18+/-0.13)0/00. The average delta13C value was the highest along the south-facing slope, followed by that along the southwest slope, west slope and northwest slope, with the lowest along the north slope during the whole growing season. The difference of delta13C values among the different slope aspects were caused by discrepancy in soil water content, soil temperature and light intensity. Soil water content was the main limiting factor. From north slope to south slope, plant delta13C value increased with the increasing soil temperature, light intensity and the reducing soil water content, which suggested that different species had different strategies to adapt to environmental changes of drought stress in different slope aspects, and water use efficiency was improved gradually in order to adapt to the environment of drought stress. PMID- 29704339 TI - [Ecological stoichiometry characteristics of leaf-litter-soil in different plantations on the Loess Plateau, China]. AB - In order to research into the influence of Grain to Green Project in Ziwuling forest region, this paper took three typical plantations which were Robinia pseudoacacia plantation, Pinus tabuliformis plantation, and Platycladus orientalis plantation in the Ziwuling forest region of Shaanxi Province as research objects and analyzed the carbon, nitrogen and phosphorus contents of leaf, litter and soil among the three plantations. The results showed that the contents of C, N and P in the three plantations were in order of leaf > litter > soil, the contents of N and P in leaf of R. pseu-doacacia plantation were significantly higher than that of P. tabuliformis plantation and P. orientalis. Leaf N:P was 12.21, 5.36 and 6.09 in R. pseudoacacia plantation, P. tabuliformis plantation and P. orientalis plantation, respectively. It was indicated that the three species were all subject to N deficiency. C:N and C:P showed the trend of litter > leaf > soil, and N:P demonstrated the trend of leaf > litter > soil. There were highly significant positive relationships in C:N between leaf and litter in P. tabuliformis plantation. N and P in the leaf development process of R. pseu-doacacia plantation were proportionally absorbed, and proportionally remained in the litter after N and P resorption. R. pseudoacacia was the better plantation species than P. tabuliformis and P. orientalis in the south fo-rest zone on the Loess Plateau. PMID- 29704340 TI - [Climate change risk of nature reserve and its assessment: A case study of Dalinuoer National Nature Reserve in Inner Mongolia Autonomous Region]. AB - According to the theoretical framework of addressing climate change based on risk mana-gement and the challenge to nature reserve management under climate change, climate change risk of nature reserve was analyzed and defined. Focus on birds and water habitat, grassland habitat, forest habitat, wetland habitat in Dalinuoer Nature Reserve, risk assessment method of nature reserve under climate change was formulated, climate change risks to Dalinuoer Nature Reserve and its habitats were assessed and predicted. The results showed that, during the period from 1997 to 2010, there was significant volatility in dynamic changes of climate change risks to Dalinuoer Nature Reserve and waterbody, grassland, forest, wetland in the region, Dalinuoer Nature Reserve and its habitats were in status of risk in 1999, 2001, 2005 and 2008, wetland habitat was also in status of risk in 2002 and 2004. Under scenario A, B and C, climate change risks to Dalinuoer Nature Reserve and waterbody, grassland, forest, wetland in the region would be more serious in 2020 and 2030, compared with the 2010 level. Climate change risks to different habitats were different significantly, with most serious climate change risk to wetland habitat due to its sensitivity to climate change and rich bird resources. The effect of climate change on nature reserve and related risk would be aggravated by excess utilization of water resource and grassland resource. As climate change risks had appeared in Dalinuoer Nature Reserve, risk management associated with climate change could greatly help to maintain and enhance biodiversity protection function of nature reserves. PMID- 29704341 TI - [Effects of thinning intensities on reproductive modules of Quercus liaotungensis in Huanglong and Qiaoshan Mountains, Northwest China]. AB - Taking the Quercus liaotungensis middle-aged forests in Huanglong and Qiaoshan Mountains as study objects, the average size of individual trees of Q. liaotungensis, yield and rate of its reproductive modules, as well as their spatial distribution characteristics were investigated in five years after thinning at different intensities (CK, 10%, 20% and 30%), in order to demonstrate the impact of thinning intensity on reproductive modules of Q. liaotungensis. Thinning intensity had no significant effect on average height and average DBH, while it had significant positive correlation with crown area and crown volume. The yield of generative shoots, young fruits and mature fruits increased with thinning intensity, but vegetative shoots, staminate inflorescence, staminate flowers and pistillate flowers of Q. liaotungensis had little change. The yield of generative shoots, young fruits and mature fruits had raised significantly under 20% thinning, and reached the maximum under 30% thinning intensity. The rate of generative shoots and fruit setting rate increased with thinning intensity, and reached significant level under 20% or 30% thinning compared with the control. About three-quarters of the generative shoots, female and male flowers centered in the upper canopy, and the rest were in the lower part. Numbers of reproductive modules at sunny side accounted for about 65% of the total. The lower crown, shaded generative shoots, pistillate flowers and staminate inflorescence increased with the increasing thinning intensity, and the upper crown, sunny generative shoots, pistillate flowers and staminate inflorescence showed a decreasing trend with the increasing thinning intensity. Thinning at the intensity of 30% (canopy density 0.6) was the best, which could greatly improve the fruit set percentage of Q. liaotungensis and its mature rate, so as to improve the seed yield and quality, providing the guarantee for the seed collection and natural regeneration of Q. liaotungensis forests. PMID- 29704342 TI - [Response of seed germination and seedling growth of Chinese fir to different light intensities]. AB - The effect of light intensity on the seed germination and seedling growth of Chinese fir under different light intensities (100%, 40%, 20%, 10%, 5% of full light, and the PPFD was 201.3, 77.0, 37.5, 19.2, 9.8 MUmol.m-2.s-1, respectively) was investigated, and the adaptive strategy of seed germination, seedling survival, growth, morphological plasticity, biomass accumulation and allocation under different light intensities was explored in this paper. The results showed that light intensity significantly affected the germination rate, survival rate, establishment rate and germination index. Germination rate reached the maximum under 40% light intensity, while survival rate and establishment rate reached the maximum at 100% light intensity. With the light intensity decreased, the stem length increased, while the root length, cotyledon length, cotyledon thickness and euphylla number declined, and basal stem diameter had no significant difference among diffe-rent light intensities. The total biomass, root biomass, stem biomass and leaf biomass were the highest under 100% light intensity. With the light intensity decreased, the photosynthesis non-photosynthesis biomass ratio and leaf biomass ratio declined, while stem biomass ratio increased, the root to shoot ratio and root biomass ratio had no significant difference among different light intensities. Low light promoted seed germination, but seedlings grew slowly with high mortality under low light. The accumulation of biomass in stem increased the plant tolerance to low light. PMID- 29704343 TI - [Impacts of rapid warming on radial growth of Larix gmelinii on two typical micro topographies in the recent 30 years]. AB - Ravine and slope are the two typical micro-topographies in the Great Xing'an Mountains. Permafrost in the two micro-topographies is extremely sensitive to global warming. To compare the differences in responses of Larix gmelinii radial growth to rapid warming in the recent 30 years, tree-ring samples were collected from northern part of Great Xing'an Mountains in Inner Mongolia and tree ring width chronologies were developed. The results showed that the divergence between tree growth and temperature occurred in 1980 in Mo'erdaoga and in 2000 in Hanma, respectively. Since 2000, tree growth on ravine sites was greater than that on the slope stands. Chronology of two topographies reached significant level by t test in 1984-2008, the Euclidean distance was 0.937-2.742 between chronologies, and far greater than the average (0.809-1.304). The rapid warming caused a significant radial growth response in L. gmelinii to hydrothermal conditions. On the slope sites, tree growth was mainly controlled by temperature and declined gradually in recent years, while the trees growing in ravines showed an accelerating growth rate with permafrost degeneration. L. gmelinii was undergoing profound environmental pressures caused by rapid warming, and it would experience a complex growth and development process. More seriously, L. gmelinii might disappear in China with a warming climate and permafrost degeneration. PMID- 29704344 TI - [Comparison of three stand-level biomass estimation methods]. AB - At present, the forest biomass methods of regional scale attract most of attention of the researchers, and developing the stand-level biomass model is popular. Based on the forestry inventory data of larch plantation (Larix olgensis) in Jilin Province, we used non-linear seemly unrelated regression (NSUR) to estimate the parameters in two additive system of stand-level biomass equations, i.e., stand-level biomass equations including the stand variables and stand biomass equations including the biomass expansion factor (i.e., Model system 1 and Model system 2), listed the constant biomass expansion factor for larch plantation and compared the prediction accuracy of three stand-level biomass estimation methods. The results indicated that for two additive system of biomass equations, the adjusted coefficient of determination (Ra2) of the total and stem equations was more than 0.95, the root mean squared error (RMSE), the mean prediction error (MPE) and the mean absolute error (MAE) were smaller. The branch and foliage biomass equations were worse than total and stem biomass equations, and the adjusted coefficient of determination (Ra2) was less than 0.95. The prediction accuracy of a constant biomass expansion factor was relatively lower than the prediction accuracy of Model system 1 and Model system 2. Overall, although stand-level biomass equation including the biomass expansion factor belonged to the volume-derived biomass estimation method, and was different from the stand biomass equations including stand variables in essence, but the obtained prediction accuracy of the two methods was similar. The constant biomass expansion factor had the lower prediction accuracy, and was inappropriate. In addition, in order to make the model parameter estimation more effective, the established stand-level biomass equations should consider the additivity in a system of all tree component biomass and total biomass equations. PMID- 29704345 TI - [Three dimensional fluorescent characteristics of soil dissolved organic matter (DOM) in Jiaozhou Bay coastal wetlands, China]. AB - In order to elucidate the structure characteristics of soil dissolved organic matter (DOM) and analyze the sources in Jiaozhou Bay coastal wetlands, four typical types of wetlands around Jiaozhou Bay were chosen, including Spartina anglica wetland, the barren wetland, Suaeda glauca wetland and Phragmites australis wetland. The soil samples were collected in January 2014. The contents of soil DOM were determined and the spectral analysis was made by three dimensional fluorescent technology. The results showed that the contents of soil dissolved organic carbon (DOC) in four types of wetlands all decreased with the increasing soil depth, and S. anglica wetland ranked the first in the contents of soil DOC, followed by the barren wetland, S. glauca wetland and P. australis wetland. Five fluorescence peaks including B, T, A, D and C were found in the three-dimensional fluorescence spectrum (3DEEMs), indicating tyrosine-like, tryptophan-like, phenol-like, soluble microbial byproduct-like and humic acid like- substances, respectively. Fluorescence integration (FRI) was applied in the qualitative analysis of five components. The results showed that tryptophan-like, phenol-like and tyrosine-like substances ranked in top three in content, followed by soluble microbial byproduct-like and humic acid-like substances which were not significantly different. Pearson correlation analysis demonstrated that a positive correlation existed between any two of the five components of DOM, and they were all positively related to DOC content. In addition, there existed different correlations between the five components of DOM and total phosphorus (TP), available phosphorus (AP) and total nitrogen (TN). The soil DOM in the four types of wetlands was mainly produced by biotic interactions, and the degree of humification was relatively low. PMID- 29704346 TI - [Diversity and distribution character of wood-rotting fungi in the secondary forest ecosystem of Liaodong areas, Northeast China]. AB - During July to September of 2013, field investigations and specimen collections on wood-rotting fungi were carried from three sites in the secondary forests (Qingyuan forest farm, Laotudingzi National Nature Reserve and Baishilaizi Nature Reserve) of eastern Liaoning Province. A total of 1062 specimens were collected and recorded, and 92 species were identified, belonging to48 genera. Among the three studying sites, Baishilaizi Nature Reserve had the most abundant polypore species and the Shannon diversity index was 4.04. The species biogeography of eastern Liaoning could be divided into 4 groups at genus level. The main elements were North temperate element and cosmopolitan element, and floristic analysis showed a distinct north temperate character. White rot species were the dominant decomposers here. Most species distributed in the fallen wood with decay stages 2 and 3. The wood dominant hosts of wood-rotting fungi were the Acer genus in the secondary forests of eastern Liaoning Province, and 243 specimens were collected from maples, occupying 23.2% of the total. PMID- 29704347 TI - [Effects of mushroom residue compost on growth and nutrient accumulation of Larix principis-rupprechtii containerized transplants]. AB - Excessive use of peat may cause some environmental problems. To alleviate the negative effect, an experiment was conducted with the mushroom residue compost to replace peat in Larix principis-rupprechtii containerized transplant production, and the proportion of mushroom residue compost was 0% (T0, control), 15% (T1), 18.75% (T2), 25% (T3), 37.50% (T4), 50% (T5), 56.25% (T6) and 60% (T7), respectively. The physical and chemical features of the substrates and its effect on the vegetative growth and nutrient accumulation of L. principis-rupprechtii containerized transplants were studied. The results showed when the proportion of mushroom residue compost in the substrate accounted for 50% or less, there was no significant difference in the transplant height, diameter, and biomass compared with the control, and the nutrient concentration in T2, T4, T5 treatments was significantly higher than in T0. The pH value was sub-acidic to neutral which was suitable to the transplant growth. When the compost proportion accounted for more than 50%, the pH value was altered to alkali and was not suitable to the transplant growth. When the proportion of mushroom residue compost accounted for 15%, the plant grew best, and the height, diameter, and total biomass got the highest. Therefore, using mushroom residue compost to replace peat in L. principis-rupprechtii containerized transplants cultivation was feasible and the maximum replacement ratio could reach 50%. The high quality transplants could be obtained when the compost replacement ratio was 15%. PMID- 29704348 TI - [Relationship between leaf anatomical structure and heat resistance of 15 Rhododendron cultivars]. AB - In this study, 17 anatomical structure indexes of 15 Rhododendron cultivars were mea-sured by scanning electron microscope (SEM). Leaf anatomical structure indexes were screened via coefficient of variation, analysis of correlation and hierarchical cluster analysis, and comprehensive evaluation on heat resistance for each cultivar was conducted by the subordinate function. The results showed that the leaves of Rhododendron cultivars were typical bifacial leaf and the epidermal anticlinal walls showed slightly sinuate. The stomata only distributed in the lower epidermis and the shape was ruleless. The anatomical structure indexes all reached a significant level difference among 15 cultivars (P<0.01), except for lower epidermis thickness (P<0.05). Thickness of lamina corneum, stomatal density, stomatal width, the thickness palisade tissue and looseness of leaf spongy tissue were the main factors related to the hardness, while other indexes, such as stomatal length, stoma aperture, stomatal opening, length and thickness of upper epidermis, length and thickness of lower epidermis, thickness of spongy tissue, the ratio of the palisade tissue to spongy tissue, tightness of leaf palisade tissue, leaf thickness and media thickness didn't show much effect on heat resistance. There were some differences among 15 cultivars in heat resistance, and the order was Rhododendron 'Song Jiang Da Tao Hong' > Rhododendron 'Zhuang Yuan Hong' > Rhododendron 'Lv Se Guang Hui' > Rhododendron 'Fen Zhen Zhu' > Rhododendron 'Wai Guo Hong' > Rhododendron 'Lan Yin' > Rhododendron 'Bi Zhi' >Rhododendron 'Da He Zhi Chun' > Rhododendron 'Guo Qi Hong' > Rhododendron 'Yu Ling Long' > Rhododendron 'Hong Shan Hu' > Rhododendron 'Ning Bo Hong' > Rhododendron 'Tao Ban Zhu Sha' > Rhododendron 'Ai Ding Bao' > Rhododendron 'Liu Qiu Hong'. According to the heat hardiness, the cultivars could be divided into 4 groups: R. 'Song Jiang Da Tao Hong', R. 'Zhuang Yuan Hong' and R. 'Lv Se Guang Hui' with high heat resistance, R. 'Fen Zhen Zhu', R. 'Wai Guo Hong', R. 'Lan Yin', R. 'Bi Zhi', R. 'Da He Zhi Chun', R. 'Guo Qi Hong' and R. 'Yu Ling Long' with medium heat resistance, R. 'Hong Shan Hu', R. 'Ning Bo Hong', R. 'Tao Ban Zhu Sha' and R. 'Ai Ding Bao' with lower heat resistance, R. 'Liu Qiu Hong' without heat resistance. However, the accurate heat hardiness evaluation of Rhododendron still needs to consider other factors, including morphological structure, physiological and biochemical indicators and genetic factor of heat resistance, the harmfulness of Rhododendron, and the recovery state after being injured by high temperature. PMID- 29704349 TI - [Spatial characteristics analysis of Huizhou-Styled Village based on ideal ecosystem model and 3D landscape indices: A case in Chengkan, China]. AB - Huizhou-Styled Village is a typical representative of the traditional Chinese ancient villages. It preserves plentiful information of the regional culture and ecological connotation. The Huizhou-Style is the apotheosis of harmony between the Chinese ancient people and nature. The research and protection of Huizhou Styled Village plays a very important role in fields of ecology, geography, architecture and esthetics. This paper took Chengkan Village of Anhui Province as an exa-mple, and proposed a new model of ideal ecosystem oriented in theories of Feng-shui and psychological field. The new method of characterizing 3D landscape index was introduced to explore the spatial patterns of Huizhou-Styled Village and the functionality of the composited landscape components in a quantitative way. The results indicated that, Chengkan Village showed a spatially composited pattern of "mountain-forest-village-river-forest". It formed an ideal settlement ring structure with human architecture in the center and natural landscape around in the horizontal and vertical horizons. The traditional method based on the projection distance caused the deviation of the landscape index, such as underestimating the area and distance of landscape patch. The 3D landscape index of average patch area was 6.7% higher than the 2D landscape index. The increasing rate ofarea proportion in 3D index was 1.0% higher than that of 2D index in forest lands. Area proportion of the other landscapes decreased, especially the artificial landscapes like construction and cropland landscapes. The area and perimeter metric were underestimated, whereas the shape metric and the diversity metric were overestimated. This caused the underestimation of the dominance of natural patches was underestimated and the overestimation of the dominance of artificial patches during the analysis of landscape pattern. The 3D landscape index showed that the natural elements and their combination in Chengkan Village ecosystem reflected better ecological function, the key elements and the composited landscape ecosystem preserved higher stability, connectivity and aggregation. The quantitative confirmation showed that the Huizhou-Styled Village represented by Chengkan Village is an ideal ecosystem. PMID- 29704350 TI - [Dynamic monitoring and analysis of ecological environment in Weinan City, Northwest China based on RSEI model]. AB - Based on the data of remote sensing images from Landsat in 1995 and 2015, this paper used the principal component analysis (PCA) method to determine the weights of four ecological indexes (greenness, dryness, wetness and heat), and then selected a evaluation model of remote sensing based ecological index (RSEI) to monitor and analyze the ecological environment quality of Weinan City from 1995 to 2015. The results showed that the mean values of RSEI in Weinan City increased from 0.489 to 0.556 during 1995-2015, which indicated the ecological environment qua-lity had been improved. The improved area of ecological quality was mainly distributed in the central area of Weinan City and its proportion was 49.6%. While the proportion of ecological environment degradation was 15.4%, and such areas were mainly distributed in some mine areas of Hancheng City and the southern Weinan (Weinan Section in North Qinling Mountains). The quality of ecolo gical environment was greatly influenced by the urban planning and construction in the study area. Generally, the ecological condition of Weinan City had been improved, which benefited from the attention and investment of government. PMID- 29704351 TI - [Fractional vegetation cover of invasive Spartina alterniflora in coastal wetland using unmanned aerial vehicle (UAV)remote sensing]. AB - The effective management and utilization of resources and ecological environment of coastal wetland require investigation and analysis in high precision of the fractional vegetation cover of invasive species Spartina alterniflora. In this study, Sansha Bay was selected as the experimental region, and visible and multi spectral images obtained by low-altitude UAV in the region were used to monitor the fractional vegetation cover of S. alterniflora. Fractional vegetation cover parameters in the multi-spectral images were then estimated by NDVI index model, and the accuracy was tested against visible images as references. Results showed that vegetation covers of S. alterniflora in the image area were mainly at medium high level (40%-60%) and high level (60%-80%). Root mean square error (RMSE) between the NDVI model estimation values and true values was 0.06, while the determination coefficient R2 was 0.92, indicating a good consistency between the estimation value and the true value. PMID- 29704352 TI - [Effects of drought stress on biosynthesis of isoflavones in soybean seedling]. AB - In this present study, two soybean cultivars with different drought tolerance in serial number of JP-6 (high drought-tolerant species) and JP-16 (low drought tolerant species) were researched. The HPLC and real-time PCR analyses were used to determine the isoflavone contents and relative expression levels of key genes, which encoded isoflavone synthesis relative enzymes in lea-ves and roots under different drought stress levels, respectively. The results indicated that the isoflavone contents in roots were significantly higher than that in leaves, whereas the relative expression of isoflavone synthetic enzyme related genes in leaves was significantly higher than that in roots. Analysis of isoflavone accumulation by comparing two different drought tolerance soybean cultivars found that the isoflavone accumulation in roots of JP-6 was greater than that in others. With increa-sing levels of the drought stress, there were significant differences in both isoflavone synthesis and accumulation between JP-6 and JP-16 soybean cultivars. In JP-6, the isoflavone accumulation in root and leaf increased after slight decreasing, while the opposite result was obtained in JP 16, in which the isoflavone accumulation in different parts were decreased after slight increasing. The expression of isoflavone synthesis relative enzyme genes presented a trend that decreased and then gradually increased with the increasing level of drought stress, except C4H, 4CL and IFS2 which were synthesis genes upstream of isoflavones in leaves of JP-6. Soybean isoflavones were mainly synthesized in leaves, little was synthesized in roots. The isoflavone synthesis and accumulation of low drought-tolerant species were scare, while those of high drought-resistant variety were relatively higher. The variety with high isoflavone accumulation in the root was more drought-resistant. PMID- 29704353 TI - [Climatic suitability of spring maize planted in the "sickle bend" area of China and regulation suggestion]. AB - The "sickle bend" area is a typical dry farming and excellent livestock development area, with fragile ecological environment. It includes 13 provinces (autonomous regions) in the north and the southwest of China. The climate suitability and the climatic potential productivity of spring maize from 1981 to 2010 in this area were quantitatively assessed. The daily data from 650 meteorological stations and grid data (1 km*1 km) in the "sickle bend" area from 1981 to 2010, and recognized indicators of agricultural meteorology were used in this study. The agro-ecological zoning mo-del (AEZ) which was currently very popular in estimating crop climatic potential productivity internationally was also applied, as well as land use classification information monitoring from satellite remote sensing. Then, based on biological characteristics of spring maize and agricultural climate resources, scientific countermeasures on reasonably adjusting agricultural production structure in subsuitable and unsuitable areas were proposed. The results showed that: 1) the climatic potential productivity of spring maize in the northern growing areas showed the "big-medium-smaller-small" distribution pattern from the east to the west from 1981 to 2010. However, the climatic potential productivity of spring maize in the southern growing areas had no significant distribution law, fluctuating between "smaller" and " medium " in general. 2) It presented the "most suitable-suitable subsuitable-unsuitable" distribution pattern from the southeast to the northwest in the northern maize growing region of the "sickle bend" area on the whole from 1981 to 2010. In contrast, the southern planting area showed the "unsuitable subsuitable-suitable-most suitable" distribution pattern from the southeast to the northwest. The most suitable and suitable planting areas of spring maize were mainly located in the most areas of Northeast China and North China, and the southeastern areas of Northwest China. The subsuitable or unsuitable regions mainly included Inner Mongolia, northern Xinjiang, western Gansu and Guangxi. 3) The most suitable planting area of spring maize was the largest (47%), followed by subsuitable area (23%), unsuitable area (17%) and suitable area (13%). 4) According to the analysis of climatic conditions, we proposed to mainly decrease the spring maize planting in the subsuitable and unsuitable areas. These subsuitable and unsuitable regions were low climatic potential productivity areas, including the arid windstorm region of Northwest, the cold area of Northeast, agro-pastoral area and the rocky desertification region of Southwest. PMID- 29704354 TI - [Effects of cotton straw returning on soil organic carbon, nitrogen, phosphorus and potas-sium contents in soil aggregates]. AB - To clarify the effects of cotton straw returning on the composition and contents of nu-trients in different particle sizes of aggregates, two treatments with or without cotton straw returning were tested in continuous three years. After three years straw treatments, we collected undisturbed soil within 0-5, 5-10, 10-20 and 20-30 cm soil layers, and to measure the composition, soil organic carbon, nitrogen, phosphorus and potassium contents in different particle sizes of aggregates classified using dry sieving. Returning cotton straw into the field significantly increased particle contents of 2-5 mm and >5 mm aggregates in 0-5 cm soil layer, while the content of <0.25 mm micro-aggregates was decreased. Cotton straw returning significantly improved soil organic carbon, nitrogen, and potassium contents by 19.2%, 14.2% and 17.3%, respectively, compared to no returning control. In 5-10 cm soil layer, cotton straw returning increased the contents of 2-5 mm and >5 mm aggregates, reduced the content of <0.25 mm micro aggregate, but significantly increased contents of soil organic carbon, available nitrogen and potassium by 19.6%, 12.6% and 23.4%, compared to no straw returning control. In 10-20 cm soil layer, cotton straw returning significantly reduced the content of <0.25 mm micro-aggregates, and significantly enhanced soil organic carbon, nitrogen, and potassium contents by 8.4%, 10.9% and 11.5%, compared to the control. However, in 20-30 cm soil layer, cotton straw returning only increased soil available potassium content by 12.0%, while there were no significant changes in particle size, organic carbon, nitrogen and phosphorus contents. We concluded that cotton straw returning could significantly improve the structure of surface soil by increasing the number of macro-aggregates, contents of organic carbon, available nitrogen and potassium in aggregates, while decreasing micro-aggregate content. The enhancement of the contribution of macro aggregates to soil fertility by returning cotton straw could improve soil physical structure, fertility and then increase cotton yield. PMID- 29704355 TI - [Effects of postponed basal nitrogen application with reduced nitrogen rate on grain yield and nitrogen use efficiency of south winter wheat]. AB - Excessive nitrogen (N) fertilizer application has led to a reduction of nitrogen use efficiency and environmental problems. It was of great significance for high yield and high-efficiency cultivation to reduce N fertilizer application with modified application strategies. A two-year field experiment was conducted to study effects of different N application rates at basal and seedling application stages on grain yield and nitrogen use efficiency. Taking the conventional nitrogen application practice (240 kg N.hm-2 with application at basal, jointing, and booting stages at ratios of 5:3:2, respectively) as control, a field trial was conducted at different N application rates (240, 180 and 150 kg N.hm-2, N240, N180 and N150, respectively) and different application times [basal (L0), fourth (L4) and sixth leaf stage (L6)] to investigate the effects on grain yield and nitrogen use efficiency. The results indicated that grain yield decreased along with reducing the N application rate, but it had no significant difference between N240 and N180 while decreased significantly under N150. Nitrogen agronomy and recovery efficiency were all highest under N180. Among different N application stages, grain yield and nitrogen use efficiency were highest under L4. N180L4 had no signifi-cant difference with control in grain yield, but its nitrogen use efficiency was significantly higher. The leaf area index, flag leaf photosynthesis rate, leaf nitrogen content, activity of nitrogen reductase and glutamine synthase in flag leaf, dry matter and N accumulation after jointing of N180L4 had no significant difference with control. In an overall view, postponing basal N fertilizer application at reduced nitrogen rate could maintain high yield and improve nitrogen use efficiency through improving photosynthetic production capacity and promoting nitrogen uptake and assimilation. PMID- 29704357 TI - [Effect of tobacco straw incorporation on rice yield and nutrient absorption and its substitute for potassium fertilizer]. AB - Field trails were carried to study the effects of tobacco straw incorporation and potassium (K) fertilizer on rice yield, K uptake and use efficiency, and its substitute for K fertilizer under different paddy soil K levels in tobacco-rice rotation areas. Results showed that both tobacco straw incorporation (2250 kg.hm 2) and K fertilizer application (75 kg K2O .hm-2) could increase grain yield and aboveground K uptake of rice. The treatment of tobacco straw incorporation with K fertilizer (St+NPK) got the best effect on rice yield compared with the control (NP). In this treatment (St+NPK), rice yields were increased by 13.3%, 17.1% and 13.5% for low-K soil (available potassium content < 100 mg.kg-1), middle-K soil (available potassium content 100-150 mg.kg-1) and high-K soil (available potassium content > 150 mg.kg-1), respectively, compared with NP. Tobacco straw incorporation (St+NP) could increase K fertilizer recovery efficiency and K fertilizer agronomic efficiency. Under the current practice of applying 75 kg K2O.hm-2, St+NPK showed no significant effect on K fertilizer recovery efficiency and K fertilizer agronomic efficiency, demonstrating that the recommended rate of K fertilizer might be more than the actual demand of rice growth. More importantly, data of tobacco straw substitute for K fertilizer showed that tobacco straw incorporation could replace 10%-22% K fertilizer during rice growing season, i.e. K fertilizer could be reduced by 7.2-16.5 kg.hm-2 for rice under the condition of tobacco straw incorporation. Therefore, it was suggested that straw incorporation could reduce the rate of K fertilizer for high-K soil, but the current K fertilizer inputs (75 kg K2O.hm-2) should be supplied to get high rice yield and maintain the soil potassium balance for low-K soil and middle K soil. PMID- 29704356 TI - [Effects of enhanced-efficiency nitrogen fertilizers on nitrous oxide emissions from cotton field under plastic mulched drip irrigation in Xinjiang,China]. AB - The effect of enhanced-efficiency nitrogen (N) fertilizers on emissions of nitrous oxide (N2O) from the grey desert agricultural soils of Xinjiang is uncertain. In this study, the enhanced-efficiency fertilizers, polymer-coated urea (ESN), and stabilized urea with urease and nitrification inhibitors (U+I) were compared to conventional urea (U) for N2O emissions from cotton under plastic mulch drip irrigation near Urumqi, Xinjiang. ESN was added once at planting but the other treatments were added multiple times with drip irrigation during the growing season. Gas samples were collected and analyzed twice per week during the growing season, using the static chamber-chromatography methodology. The results showed that generally, ESN significantly increased soil cumulative N2O emissions during the growing season by 47%-73% compared to other treatments. In the first four months after fertilization, soil ammonium (NH4+-N) and nitrate (NO3--N) concentrations under ESN treatment were generally higher than under other treatments. Thereafter, NH4+-N and NO3--N concentrations under all treatments gradually decreased to similar levels. ESN all added at planting was likely responsible for high NH4+-N and NO3--N concentrations and highest N2O emissions. The U+I treatment reduced soil N2O emission by 9.9% in comparison with U, whereas the difference was not statistically significant. In addition, soil NO3--N contents of the U+I treatments were generally lower than those of the ESN and the U treatments. The cumulative N2O emissionsover the growing season ranged from 300 to 500 g N2O-N.hm-2, generally lower than emissions reported for other agricultural ecosystems. Drip irrigation successfully kept moisture conditions below levels for appreciable N2O emissions. Multiple applications of N via drip irrigation seemed to be effective to lower emissions than all N applied at planting. Therefore, for cotton field under plastic mulch drip irrigation in arid land of Northwest China, the benefit of enhanced efficiency N ferti-lizers on N2O mitigation is limited. PMID- 29704358 TI - [Differences in nitrogen utilization characteristics of different peanut genotypes in high fertility soils]. AB - A total of twenty genotypes of peanut (Arachis hypogaea) were used to investigate the differences in nitrogen (N) utilization characteristics in a pot experiment with 15N isotope tracing analysis. Results showed the main N sources for peanut in high fertility soils following as soil N source > N fixed by root nodule source > fertilizer N source. The N uptake and accumulation in peanut from total N and the three N supplied sources (fertilizer N, soil N and N fixation) varied among the different genotypes. N fixation source had the largest genetic variation among the twenty genotypes while genetic variation for fertilizer N source and soil N source were lower and similar. Significant differences showed among the twenty genotypes in pod producing efficiency of N and N use efficiency, and the highest values were respectively 3.6 and 2.1 times of the lowest values. There were also significant differences among the twenty genotypes in the harvest indexes of total N, fertilizer N source, soil N source and N fixation source, and the largest variation showed in the harvest index of N fixation source. The pod yields significantly or extremely significantly corrected with N accumulation amounts from different N sources, N harvest index, pod producing efficiency of N, and N use efficiency. According to N uptake and accumulation and pod yield, four major types of peanut were classified, namely high total N accumulation high yield type, high fertilizer N source high yield type, high soil N source high yield type, and high N fixation source high yield type. Four of the twenty genotypes had all characteristics of the four major types. PMID- 29704359 TI - [Effect of exogenous gamma-aminobutyric acid on NO3--N assimilation in muskmelon under Ca(NO3)2 stress]. AB - The effect of exogenous gamma-aminobutyric acid (GABA) on NO3--N assimilation in muskmelon under Ca(NO3)2 stress was investigated in ' Yipintianxia 208', a salt sensitive melon variety cultured under deep flow hydroponics which simulated soil salinization. The results showed that under Ca(NO3)2 stress, the activities of nitrate reductase (NR), glutamate synthetase (GS) and glutamate amino transferase (GOGAT) in muskmelon seedlings were significantly reduced, while the activities of glutamate dehydrogenase (GDH), glutamate oxaloacetate transaminase (GOT) and glutamate pyruvate aminotransferase (GPT) were enhanced, leading to increased contents of NH4+-N and total amino acids, and decreased contents NO3--N and soluble protein in muskmelon, which further severely inhibited plant growth and photosynthesis of muskmelon seedlings. Exogenous GABA effectively improved the absorption of NO3--N in muskmelon roots and its transportation from root to shoot under Ca(NO3)2 stress, and improved NH4+-N assimilation by enhancing NR, GS and GOGAT activities in muskmelon seedlings. Exogenous GABA also reduced NH4+ release by limiting GDH deamination, thus further alleviated the toxication of NH4+-N induced by Ca(NO3)2 stress. In addition, foliage spraying of GABA could regulate amino acids metabolic pathways and promote protein synthesis. The results suggested that exogenous GABA could improve NO3--N assimilation and regulate amino acids metabolism to alleviate Ca(NO3)2 stress damage in muskmelon seedlings. PMID- 29704360 TI - [Effects of calcium and ABA on photosynthesis and related enzymes activities in cucumber seedlings under drought stress]. AB - To investigate the effect of calcium and ABA on photosynthesis and the activities of antioxidant enzymes in cucumber seedlings under drought stress, the cucumber was used as the expe-riment materials, normal nutrient solution culture was considered as the control, and PEG-6000 application in the nutrient solution simulated the drought stress. There were five different treatments which were spraying water, ABA, CaCl2+ABA, LaCl3(calcium channel inhibitor)+ABA and EGTA (calcium ion chelating agent)+ABA under drought stress. The results showed that drought stress inhibited the growth of cucumber seedlings, and reduced the activities of antioxidant enzymes, nitrate reductase, net photosynthetic rate and fluorescence parameters of the cucumber seedlings leaves. The application of ABA reduced the inhibition of activities of superoxide dismutase (SOD), peroxidase (POD), catalase (CAT) and ascorbate peroxidase (APX), photosynthesis (Pn, gs) and the fluorescence parameters (Fv'/Fm', qP and ETR), and decreased the damage of drought stress on plant. Spraying CaCl2+ABAsignificantly promoted the positive effect of ABA, while EGTA+ABA and LaCl3 +ABA didn't show the promoting effect. PMID- 29704362 TI - [Effects of As stress on contents of saponin and flavonoid, key enzymes activities of Panax notoginseng and its proteomic analysis]. AB - Field plot experiments were conducted to study the effect of two-year consecutive As stress [As(V): 0, 20, 80, 140, 200 and 260 mg.kg-1] on contents of As, saponin and flanovoids, the enzyme activities of phenylalanine ammonia lyase (PAL), chalcone synthase (CHS), and squalene synthase (SS) in main root, fibrous root and rhizome and shoot, and proteome of three-year old Panax notoginseng in Wenshan prefecture, Yunnan Province, China. The results showed that total saponin content of fibrous root decreased with increase in As treatment concentration. Total saponin contents of shoot and rhizome increased with 140 mg.kg-1 As treatment compared with control. SS activity of rhizome was higher than that of shoot. Flavonoid contents of diffe-rent plant parts decreased with increase in As treatment concentration. With 140 mg.kg-1 As treatment, activities of PAL and CHS in rhizome were higher than that in shoot. CHS activities in shoot and rhizome were lower, and PAL activities were higher than those of the control. As contents in different plant parts of P. notoginseng increased with increase in As treatment concentration. The highest As content was observed in fibrous root. With 140 mg.kg-1 As treatment, twenty-one diffe-rential proteins (ratio >2, P<0.05) were identified in the inoculated compared to the control. The down regulated proteins included phosphoribulokinase, heat shock protein, NAD(P) binding rossmann-fold superfamily proteinisoform, monodehydroascorbate reductase and cytochrome b6-f complex iron-sulfur subunit. The up-regulated proteins included CDC27 family protein, acidic endochitinase isoform, symbiosis receptor like kinase precursor, isoflavone reductase-like protein, phospho-2-dehydro-3 deoxyheptonate aldolase, putative protein kinase superfamily protein, malate dehydrogenase, glyoxalase I isoform and glutamine synthetase cytosolic isozyme. In general, with two-year consecutive As stress, As contents in different plant parts of P. notoginseng increased, which not only affected the photosynthesis and energy, but also decreased the antioxidation and resilience, and induced the increased expression of protein involved in detoxication, resulted in decrease in the contents of flavonoid and saponin. The tolerant threshold value of P. notoginseng for As was 140 mg.kg-1. PMID- 29704361 TI - [Influence of a new phosphoramide urease inhibitor on urea-N transformation in different texture soil]. AB - Addition of urease inhibitors is one of the important measures to increase nitrogen (N) use efficiency of crop, due to retardant of urea hydrolysis and reduction of ammonia volatilization loss. An incubation experiment was conducted to investigate the urease inhibition effect of a new phosphoramide urease inhibitor, NPPT (N-(n-propyl) thiophosphoric triamide) in different texture soils under dark condition at 25 C, and NBPT (N-(n-butyl) thiophosphoric triamide) was obtained to compare the inhibition effect on urease in different soil textures by different dosages of urea adding. Results showed that the effective reaction time of urea was less than 9 d in the loamy and clay soil. Addition of inhibitors for retardation of urea hydrolysis was more than 3 d. In sandy soil, urea decomposition was relatively slow, and adding inhibitor significantly inhibited soil urease acti-vity, and reduced NH4+-N content. During the incubation time, the inhibition effect of high dosage urea in the soil was better than that of low dosage. At day 6, the urease inhibition rate of NBPT and NPPT (N 250 mg.kg-1) were 56.3% and 53.0% in sandy soil, 0.04% and 0.3% in loamy soil, 4.1% and 6.2% in clay soil; the urease inhibition rate of NBPT and NPPT (N 500 mg.kg-1) were 59.4% and 65.8% in sandy soil, 14.5% and 15.1% in loamy soil, 49.1% and 48.1% in clay soil. The urease inhibition effects in different texture soil were in order of sandy soil > clay soil> loamy soil. The soil NH4+-N content by different inhibitors during incubation time increased at first and then decreased, while soil NO3--N content and apparent nitrification rate both showed rising trends. Compared with urea treatment, addition of urease inhibitors (NBPT and NPPT) significantly increased urea-N left in the soil and reduced NH4+-N content. In short, new urease inhibitor NPPT in different texture is an effective urease inhibitor. PMID- 29704363 TI - [Colonization of grape leaves by endophytic Bacillus subtilis JL4 and its control of grape downy mildew]. AB - In order to understand the colonization pattern of Bacillus subtilis JL4 both on and inside grape leaves, and its control of grape downy mildew, a shuttle vector pGFP78, carrying the GFP gene, was transformed into B. subtilis JL4, and a GFP labelled transformant designated as JL4-gfp was obtained successfully. The stability of the marker and antagonistic activity to Plasmopara viticola of JL4 gfp were tested. JL4-gfp was spray inoculated on grape leaves in a vine yard and colonization of the leaves was investigated by dilution plating on selective medium. Leaves treated with JL4-gfp were collected and taken to the laboratory for inoculation of a sporangial suspension of P. viticola, to determine its control effect on grape downy mildew. The green fluorescence of the marked strain was stable for at least 10 subcultures, and JL4-gfp maintained wild type antagonistic activity against P. viticola. JL4-gfp was recovered from the grape leaves by dilution plating on medium supplemented with antibiotics. Numbers recovered from the leaf surface of grape leaves were 3.6*105, 2.7*105 and 3.1*103 CFU.g-1 at 0, 3 and 7 days after inoculation, and the population density inside the leaf tissue reached a maximum of 9.6*104 CFU.g-1 at 3 days after inoculation, but could not be recovered after 14 days. The efficiency of downy mildew control by the marked strain was more than 88.0% at 3 days after inoculation, but no significant control effect was observed after 7 days. Our results suggested that there was a positive correlation between the JL4-gfp population density and control efficiency of grape downy mildew, and a threshold colonization level at 105 CFU.g-1 was a prerequisite for this Bacillus strain to present efficient control effects. PMID- 29704364 TI - [Rhizosphere microbial impacts of alleviating faba bean Fusarium wilt with inoculating AM fungi]. AB - Greenhouse pot trials were conducted to investigate the effects of arbuscular mycorrhizal fungus (Glomus mosseae, Glomus tortuosum, Glomus intraradices and Glomus etunicatum) inoculation on the seedling growth, occurance of Fusarium wilt, population of Fusarium oxysporum and rhizosphere microbial community functional diversity in faba bean rhizosphere soil. Results showed that after inoculation of G. mosseae, G. tortuosum, G. intraradices and G. etunicatum, the shoot and root fresh mass of faba bean seedlings increased significantly, the disease index of faba bean fusarium wilt decreased significantly by 94.0%, 60.0%, 64.0% and 94.0%, respectively, the amount of F. oxysporum of faba bean rhizosphere decreased significantly by 98.6%, 74.3%, 77.8% and 90.4%, respectively. The best inhibitory effects to Fusarium wilt were with G. mosseae and G. etunicatum treatments. Inoculation of G. mosseae, G. tortuosum and G. etunicatum significantly increased carbon sources utilization ability of carbohydrates, amino acids, carboxylic acids and phenolic acids, with the average well color development (AWCD) value being increased by 34.4%, 31.5% and 50.8% respectively, but such significant differences were not observed with inoculation of G. intraradice. Principal component analyses showed that inoculation of G. mosseae, G. tortuosum and G. etunicatum fungi changed the rhizospheric microbial community composition. Correlation analyses showed that the utilization of carbohydrates carbon sources (beta-Methyl-D-glucoside, D-Galacturonic acid, D Mannitol, N-Acetyl-D-Glucosamine, D-Cellobiose,) and carboxylic acids carbon sources (D-Galactonic acid-gamma-Lactone) were significantly increased after inoculation of G. tortuosum, and the utilization of L-Arginine and 4-Hydroxy benzoic acid significantly increased after inoculation of G. mosseae and G. etunicatum. Carbohydrates, carboxylic acids were main carbon sources utilized by rhizosphere microbes after G. tortuosum and G. intraradices inoculation, and amino acids and phenolic acids were main carbon sources utilized by rhizosphere microbes after G. mosseae and G. etunicatum inoculation. Inoculation of AM fungi significantly increased the activities of rhizosphere microbes, changed soil microbe community functional diversity, and thus inhibited the growth of F. oxysporum. The inhibitory impacts of AM fungi inoculations depended on the changes of microbes utilizing carbon sources. PMID- 29704365 TI - [SSR analysis on stress effect of transgenic hybrid poplar 741 on Clostera anachoreta (Fabricius) (Lepidoptera: Notodontidae)]. AB - The genetic differentiation of the experimental population of Clostera anachoreta fed on different resistant transgenic 741 poplar leaves was analyzed by SSR molecular marker technique to investigate stress effect of transgenic poplar Bt gene as food on target insect. The experimental population of C. anachoreta fed on transgenic 741 poplar high resistant strains 'Pb29', medium resis-tant strains 'Pb17' and non-transgenic poplar (CK), and the screened ten pairs of SSR primers were used. The results showed that 76 alleles were observed in ten pairs of primers. The average allele was 7.6, the average effective number of alleles was 2.2, the average observed heterozygosity was 0.5167, the average expected heterozygosity was 0.5167, and the average percentage of polymorphic loci was 96.7%. The genetic diversity level of C. anachoreta experimental population fed on transgenic poplar 741 was significantly higher than that fed on non-transgenic populations, and C. anachoreta fed on high resistance had the lowest genetic similarity with CK samples, which showed an increasing trend of the genetic diversity of the experimental population fed on transgenic Bt poplar. It was thus clear that transgenic hybrid poplar 741 had stress effects on genetic differentiation of C. anachoreta experimental population by SSR. PMID- 29704366 TI - [Effects of cadmium on protein tyrosine phosphorylation of mouse spermatozoa and the protective role of EGTA]. AB - In this study, we explored the effects of cadmium (Cd) on mouse sperm motility parame-ters, protein tyrosine phosphorylation and the location of tyrosine phosphorylated targets using computer-assisted sperm analysis (CASA), western blot (WB) and immunofluorescence technique coupled to sperm in vitro culture method, respectively. The results showed sperm motility was inhibi-ted by Cd in a dose-dependent manner and when Cd increased to 1.0 MUmol.L-1, sperm motility was inhibited significantly (P<0.05). Simultaneously, protein tyrosine phosphorylation was enhanced by Cd and in particular, the tyrosine phosphorylation of ~55 kDa proteins was greatly promoted when Cd concentrations were greater or equal to 1.0 MUmol.L-1 (P<0.05). Importantly, these tyrosine phosphorylated proteins were mainly localized in the middle piece of mouse sperm. However, when sperm was incubated with 30 MUmol.L-1 ethylene glycol tetraacetic acid (EGTA) and 10 MUmol.L-1 Cd concurrently, both the tyrosine phosphorylation of ~55 kDa proteins and sperm motility were not changed obviously (P>0.05). These results suggested that Cd may inhibit sperm motility by inducing the tyrosine phosphorylation of ~55 kDa proteins in the middle piece and EGTA could chelate Cd ions to relieve its toxicity. This study demonstrated that Cd induced the tyrosine phosphorylation of a specific subset of proteins and thus decreased sperm motility. Interes-tingly, EGTA acted as an inhibitor to block Cd from entering the sperm, which provided a novel research method for revealing the molecular mechanisms of reproductive toxicity caused by Cd. PMID- 29704367 TI - [Spatial point patterns of Antarctic krill fishery in the northern Antarctic Peninsula]. AB - As a key species in the Antarctic ecosystem, the spatial distribution of Antarctic krill (thereafter krill) often tends to present aggregation characteristics, which therefore reflects the spatial patterns of krill fishing operation. Based on the fishing data collected from Chinese krill fishing vessels, of which vessel A was professional krill fishing vessel and Vessel B was a fishing vessel which shifted between Chilean jack mackerel (Trachurus murphyi) fishing ground and krill fishing ground. In order to explore the characteristics of spatial distribution pattern and their ecological effects of two obvious different fishing fleets under a high and low nominal catch per unit effort (CPUE), from the viewpoint of spatial point pattern, the present study analyzed the spatial distribution characteristics of krill fishery in the northern Antarctic Peninsula from three aspects: (1) the two vessels' point pattern characteristics of higher CPUEs and lower CPUEs at different scales; (2) correlation of the bivariate point patterns between these points of higher CPUE and lower CPUE; and (3) correlation patterns of CPUE. Under the analysis derived from the Ripley's L function and mark correlation function, the results showed that the point patterns of the higher/lo-wer catch available were similar, both showing an aggregation distribution in this study windows at all scale levels. The aggregation intensity of krill fishing was nearly maximum at 15 km spatial scale, and kept stably higher values at the scale of 15-50 km. The aggregation intensity of krill fishery point patterns could be described in order as higher CPUE of vessel A > lower CPUE of vessel B >higher CPUE of vessel B > higher CPUE of vessel B. The relationship of the higher and lo-wer CPUEs of vessel A showed positive correlation at the spatial scale of 0-75 km, and presented stochastic relationship after 75 km scale, whereas vessel B showed positive correlation at all spatial scales. The point events of higher and lower CPUEs were synchronized, showing significant correlations at most of spatial scales because of the dynamics nature and complex of krill aggregation patterns. The distribution of vessel A's CPUEs was positively correlated at scales of 0-44 km, but negatively correlated at the scales of 44-80 km. The distribution of vessel B's CPUEs was negatively correlated at the scales of 50-70 km, but no significant correlations were found at other scales. The CPUE mark point patterns showed a negative correlation, which indicated that intraspecific competition for space and prey was significant. There were significant differences in spatial point pattern distribution between vessel A with higher fishing capacity and vessel B with lower fishing capacity. The results showed that the professional krill fishing vessel is suitable to conduct the analysis of spatial point pattern and scientific fishery survey. PMID- 29704368 TI - [Relationship between morphological traits and body mass of Miichthys miiuy]. AB - Miichthys miiuy Basilewsky is a commercially important marine fish in China. To understand the relationship between body mass and morphometric traits of M. miiuy, body mass (Y, g) and other eight morphometric traits (cm), e.g., total length (X1), body length (X2), head length (X3), trunk length (X4), tail length (X5), tail handle length (X6), tail handle height (X7), and body height (X8) of 524 individuals of about 12-month-old M. miiuy were measured in this study. The methods of correlation analysis, multiple regression analysis, and path ana-lysis were used to analyze the data. Also, the best model reflecting the relationship between morphometric traits and body mass were obtained through model fitting screening. The results showed that the correlation coefficients between every two traits ranged from 0.834 to 0.941, and all reached significance level (P<0.01). And body length was ruled out from the multiple regression analysis by the method of multicollinearity diagnosis. We established a regression equation using the rest morphologi-cal traits as variables and body mass as dependent variable, in which direct and indirect path coefficients and determinant coefficients were calculated. Four morphometric traits achieved highly significant levels (P<0.01), and they were the main decisive morphometric traits linked to body mass. The multiple linear regression model equation was established as Y=-444.188 +7.943X1+12.861X4 +38.254X7 + 42.722X8. Among them, the trait with the strongest direct effect on body mass was the body height (0.351), then the total length (0.335). In addition, the best model fitted for the individuals was y=0.013 x2.891 for total length, y=2.028 x2.751 for body height. The method of model fit test showed the accuracy of total length estimated body mass was higher than that of body height. This research may provide an important reference for the effective use of morphological traits for breeding of M. miiuy. PMID- 29704369 TI - [Selenium (Se)uptake and transformation mechanisms and physiological function in plant: A review]. AB - Selenium (Se) is an essential nutrient for many organisms, including microbe, animal and human, but the Se uptake and transformation mechanisms and physiological roles in plant still are controversial until now. Se could improve the growth and tolerance of plant at an appropriate le-vel, but could be toxic at higher levels. Research concerning Se uptake and metabolism in plant were promoted by Se biofortification and Se phytoremediation induced by the issues of Se deficiency in food and Se pollution in special areas. Recently, the results of Se uptake and transformation in plant have indicated that there are significant differences of Se accumulation and physiological roles in various plants and significant influence of soil conditions on Se uptake of plant. In addition, the process of Se metabolism in Se hyperaccumulators and its regulation were revealed gradually with the studies on improvement of Se uptake in plant. According to the results of Se biofortification in crop and Se phytoremediation so far, we summarized the advances in the studies with the reference to Se distribution in environment, the detail process of Se uptake, key regulators of transformation and its physiological roles in plant. We hope this can provide a novel insight to further research upon Se in plant. PMID- 29704370 TI - Evaluation of Healthy Fit: A Community Health Worker Model to Address Hispanic Health Disparities. AB - INTRODUCTION: Hispanics in the United States have disproportionately high rates of obesity, hypertension, and diabetes and poorer access to preventive health services. Healthy Fit uses community health workers to extend public health department infrastructure and address Hispanic health disparities related to cardiovascular disease and access to preventive health services. We evaluated the effectiveness of Healthy Fit in 1) reaching Hispanic Americans facing health disparities, and 2) helping participants access preventive health services and make behavior changes to improve heart health. METHODS: Community health workers recruited a sample of predominantly low-income Hispanic immigrant participants (N = 514). Following a health screening, participants received vouchers for breast, cervical, and colorectal cancer screening, and received vaccinations as needed for influenza, pneumonia, and human papillomavirus. Participants who were overweight or had high blood pressure received heart health fotonovelas and referrals to community-based exercise activities. Community health workers completed follow-up phone calls at 1, 3, and 6 months after the health screening to track participant uptake on the referrals and encourage follow-through. RESULTS: Participants faced health disparities related to obesity and screening for breast, cervical, and colorectal cancer. Postintervention completion rates for breast, cervical, and colorectal cancer screening were 54%, 43%, and 32%, respectively, among participants who received a voucher and follow-up phone call. Among participants with follow-up data who were overweight or had high blood pressure, 70% read the fotonovela, 66% completed 1 or more heart health activities in the fotonovela, 21% attended 1 or more community-based exercise activities, and 79% took up some other exercise on their own. CONCLUSION: Healthy Fit is a feasible and low-cost strategy for addressing Hispanic health disparities related to cancer and cardiovascular disease. PMID- 29704371 TI - Technical Assistance and Changes in Nutrition and Physical Activity Practices in the National Early Care and Education Learning Collaboratives Project, 2015-2016. AB - PURPOSE AND OBJECTIVES: The National Early Care and Education Learning Collaboratives Project (ECELC) aims to improve best practices in early care and education (ECE) programs in topic areas of the Nutrition and Physical Activity Self-Assessment in Child Care (NAP SACC). Technical assistance is a component of the ECELC, yet its effect on outcomes is unclear. Beyond dose and duration of technical assistance, limited research exists on characteristics of technical assistance that contribute to outcomes. The objective of this study was to identify and describe technical assistance characteristics and explore associations with NAP SACC outcomes. INTERVENTION APPROACH: We collected data from 10 collaboratives comprising 84 ECE programs in 2 states in 2015-2016. The objective of technical assistance was to support programs in improving best practices. Technical assistance was provided to programs via on-site, telephone, or email and was tailored to program needs. EVALUATION METHODS: We used a mixed methods design to examine associations between technical assistance and NAP SACC outcomes. We used multiple regression analysis to assess quantitative data and qualitative comparative analysis to determine necessary and sufficient technical assistance conditions supporting NAP SACC outcomes. We also conducted a document review to describe technical assistance that referred conditions identified by the qualitative comparative analysis. RESULTS: Regression analyses detected an inverse relationship between changes in NAP SACC scores and hours of technical assistance. No clear pattern emerged in the qualitative comparative analysis, leaving no necessary and sufficient conditions. However, the qualitative comparative analysis identified feedback as a potentially important component of technical assistance, whereas resource sharing and frequent email were characteristics that seemed to reduce the likelihood of improved outcomes. Email and resource sharing were considered primarily general information rather than tailored technical assistance. IMPLICATIONS FOR PUBLIC HEALTH: Technical assistance may be used in programs and made adaptable to program needs. The inclusion and evaluation of technical assistance, especially tailored approaches, is warranted for environmental interventions, including ECE settings. PMID- 29704372 TI - [Systematic discovery of novel prokaryotic defense systems: progress and prospects]. AB - Microbial defense systems provide fundamental elements for biotechnology development. For example, molecular cloning techniques greatly depend on the discovery of the bacterial restriction-modification system, and similarly, deciphering the CRISPR adaptive immunity gives rise to the revolutionary genome editing technique CRISPR-Cas9. Therefore, exploring novel microbial defense systems has attracted world-wide attention, and new systems like prokaryotic Argonautes (pAgos) and the defense island system associated with restriction modification (DISARM) were successively discovered and investigated. Recently, Sorek et al. reported a systematic strategy to predict novel defense systems within the vast microbial genomes and validated the antivirus or anti-plasmid capability of 10 candidates using synthetic biology procedures. Here, we introduce the systematic analysis pipeline developed by Sorek et al., summarize the characteristics of the novel microbial defense systems, and prospect the research trends and challenges in this rising field. PMID- 29704373 TI - [Applications of the CRISPR/Cas9 system in insects]. AB - The CRISPR/Cas9 (clustered regularly interspaced short palindromic repeat/CRISPR associated) system guides Cas9 to specific genomic locations by a short RNA search string. This technology enables the systematic interrogation of mammalian genome editing, repairing damaged genes, silencing harmful genes and improving quality traits. In recent years, with the introduction of the CRISPR/Cas9 system for easy, fast and efficient genetic modification, it has been possible to conduct meaningful functional studies in a broad array of insect species, such as Drosophila, Bombyx mori, Aedes aegypti and butterflies et al. In this review, we summarize the application of CRISPR/Cas9 in different insect species, discuss methods for its promotion, and consider its application for future insect studies. PMID- 29704374 TI - [Research progress on the asymmetric division in mammalian oocytes]. AB - The mammalian oocyte maturation process consists of two consecutive asymmetric divisions, and produces three daughter cells of vastly different sizes: one larger egg cell and two smaller polar bodies. Asymmetric division is a typical feature of mammalian oocyte meiosis that results in a highly polar egg cell. The mitosis of the cell after fertilization exhibits restored symmetric division, but the polarity characteristics formed during meiosis of oocytes are preserved and affect the polarity of early embryos. In this review, we summarize the research progress on asymmetric division of mammalian oocytes in recent years, and mainly focus on the asymmetric division of cytoplasmic and the asymmetric division of nucleus, including the functions of chromosome and cytoskeleton in asymmetric division of mammalian oocytes, the redistribution of cytoplasmic organelles occurring in oocyte maturation, and chromosome nonrandom separation. We aim to demonstrate the main mechanism of asymmetry division in mammalian oocytes from both cellular and molecular levels. PMID- 29704375 TI - [Regulatory mechanism for lncRNAs in skeletal muscle development and progress on its research in domestic animals]. AB - Skeletal muscle is an essential tissue to maintain the normal functions of an organism. It is also closely associated with important economic performance, such as carcass weight, of domestic animals. In recent years, studies using high throughput sequencing techniques have identified numerous long non-coding RNAs (lncRNAs) with myogenic functions involved in regulation of gene expression at multiple levels, including epigenetic, transcriptional and post-transcriptional regulation. These lncRNAs target myogenic factors, which participate in all processes of skeletal muscle development, including proliferation, migration and differentiation of skeletal muscle stem cells, proliferation, differentiation and fusion of myocytes, muscle hypertrophy and conversion of muscle fiber types. In this review, we summarize the functional roles of lncRNAs in regulation of myogenesis in humans and mice, describe the methods for the analysis of lncRNA function, discuss the progress of lncRNA research in domestic animals, and highlight the current problems and challenges in lncRNA research on livestock production. We hope to provide a useful reference for research on lncRNA in domestic animals, thereby further identifying the molecular regulatory mechanisms in skeletal muscle growth and development. PMID- 29704376 TI - [Estimating genomic breed composition of individual animals using selected SNPs]. AB - Natural and artificial selection, geographical segregation and genetic drift can result in differentiation of allelic frequencies of single nucleotide polymorphism (SNP) at many loci in the animal genome. For individuals whose ancestors originated from different populations, their genetic compositions exhibit multiple components correlated with the genotypes or allele frequencies of these breeds or populations. Therefore, by using an appropriate statistical method, one can estimate the genomic contribution of each breed (ancestor) to the genome of each individual animal, which is referred to as the genomic breed composition (GBC). This paper reviews the principles, statistical methods and steps for estimating GBC of individual animals using SNP genotype data. Based on a linear regression model and an admixture model respectively, the protocols were demonstrated by the breed characterization of 198 purported Akaushi cattle, which included selection of reference SNPs and reference individual animals, and computing GBC for animals to be evaluated. The reference populations consist of 36 574 cattle from five cattle breeds (Akaushi, Angus, Hereford, Holstein and Jersey), each genotyped on either a 40K or 50K SNP chip. Four common SNP panels scanned from commercial chips for estimating GBC of individual animals are optimally selected, thereby expanding the functionalities of the currently available commercial SNP chips. It remains to be explored in future studies as to how estimated GBC can be incorporated to improve the accuracies on genomic prediction in purebred animals and crossbreds as well. PMID- 29704377 TI - [Progress on salt resistance in autopolyploid plants]. AB - Polyploidization is a key driving force that plays a vital role in the evolution of higher plants. Autopolyploid plants often demonstrate altered physiology phenomena due to the different genome composition and gene expression patterns. For example, autopolyploid plants are more resistant to stresses than their homologous diploid ancestors. Soil salinity and secondary salinization are two vital factors affecting crop production which severely limit the sustainable development of agriculture in China. Polyploid plants are important germplasm resources in crop genetic improvement due to their higher salt tolerance. Revealing the mechanism of salt tolerance in homologous plants will provide a foundation for breeding new plants with improved salt resistance. In this review, we describe the existing and ongoing characterization of the mechanism of salt tolerance in autopolyploid plants, including the salt tolerance evolution, physiology, biochemistry, cell structure and molecular level researches. Finally, we also discuss the prospects in this field by using polyploid watermelon as an example, which will be helpful in polyploid research and plant breeding. PMID- 29704378 TI - [MYB-like transcription factor SiMYB42 from foxtail millet (Setaria italica L.) enhances Arabidopsis tolerance to low-nitrogen stress]. AB - Myeloblastosis (MYB) transcription factors are one of the largest families of transcription factors in higher plants. They play an important role in plant development, defense response processes, and non-biological stresses, i.e., drought stress. Foxtail millet (Setaria italica L.), originated in China, is resistant to drought and low nutrition stresses and has been regarded as an ideal material for studying abiotic stress resistance in monocotyledon. In this study, we ran a transcription profile analysis of zheng 204 under low-nitrogen conditions and identified a MYB-like transcription factor SiMYB42, which was up regulated under low-nitrogen stress. Phylogenetic tree analysis showed that SiMYB42 belongs to R2R3-MYB subfamily and has two MYB conserved domains. Expression pattern analysis showed that SiMYB42 was significantly up-regulated under various stress conditions, including low-nitrogen stress, high salt, drought and ABA conditions. The results of subcellular localization, quantitative real-time PCR and transcriptional activation analysis indicated that SiMYB42 protein localizes to the nucleus and cell membrane of plant cells, mainly expressed in the leaf or root of foxtail millet, and has transcription activation activity. Functional analysis showed that there was no significant difference between transgenic SiMYB42 Arabidopsis and wild-type (WT) Arabidopsis under normal conditions; however, under low-nitrogen condition, the root length, surface area and seedling fresh weight in transgenic SiMYB42 Arabidopsis, were significantly higher than their counterparts in WT. These results suggest that SiMYB42 transgenic plants exhibit higher tolerance to low-nitrogen stress. Expression levels of nitrate transporters genes NRT2.1, NRT2.4 and NRT2.5, which are the transcriptional targets of SiMYB42, were higher in transgenic SiMYB42 Arabidopsis plants than those in WT; the promoter regions of NRT2.1, NRT2.4 and NRT2.5 all have MYB binding sites. These results indicate that SiMYB42 might enhance foxtail millet tolerance to low-nitrogen condition through regulating the expression of nitrate transporter genes. This study reveals the possible functions of SiMYB42 in a low-nitrogen stress response pathway, and provides a foundation for further understanding the entire regulation network of foxtail millet in response to low-nitrogen stress. PMID- 29704379 TI - Mechanical profiles of murder and murderers: An extensive review. AB - INTRODUCTION: Murder is an extreme form of violent crime which occurs across all social, cultural, and ethnic spheres. It is therefore, crucial to understand the nature and the extent of mechanical profiles of murder and murderers. The purpose of this article is to review such critical aspects of murder in a nutshell. METHODS: An archival research methodology was employed in this study where relevant search for literatures on these mechanical aspects related to murder was made across search engines such as Google Scholar and Elsevier with relevant articles selected for this review. RESULTS AND DISCUSSION: This review discusses in an in-depth manner, pivotal mechanical profiles which include motives, methods of killing, choice of weapon, settings, targeted body parts, and murder victim concealment. In-depth understanding of each mechanical aspect offers an opportunity to the public at large to expand their knowledge on murder prevention manners which is vital for crime prevention efforts in the future. PMID- 29704380 TI - The spectrum of pathological findings of tonsils in children: A clinicopathological review. AB - Tonsillectomy is among the most commonly performed operations in children. Although follicular lymphoid hyperplasia is usually the main and only pathologic finding at microscopic examination, a variety of other rare but important pathologic changes may be encountered. This review aims to provide an inclusive practical resource and reference for both training and practising pathologists. It discusses the spectrum of pathologic findings, including both neoplastic and non-neoplastic conditions and provides illustrative images. PMID- 29704381 TI - Study on ABO and RhD blood grouping: Comparison between conventional tile method and a new solid phase method (InTec Blood Grouping Test Kit). AB - INTRODUCTION: 'InTec Blood Grouping Test kit' using solid-phase technology is a new method which may be used at outdoor blood donation site or at bed side as an alternative to the conventional tile method in view of its stability at room temperature and fulfilled the criteria as point of care test. This study aimed to compare the efficiency of this solid phase method (InTec Blood Grouping Test Kit) with the conventional tile method in determining the ABO and RhD blood group of healthy donors. METHODS: A total of 760 voluntary donors who attended the Blood Bank, Penang Hospital or offsite blood donation campaigns from April to May 2014 were recruited. The ABO and RhD blood groups were determined by the conventional tile method and the solid phase method, in which the tube method was used as the gold standard. RESULTS: For ABO blood grouping, the tile method has shown 100% concordance results with the gold standard tube method, whereas the solid-phase method only showed concordance result for 754/760 samples (99.2%). Therefore, for ABO grouping, tile method has 100% sensitivity and specificity while the solid phase method has slightly lower sensitivity of 97.7% but both with good specificity of 100%. For RhD grouping, both the tile and solid phase methods have grouped one RhD positive specimen as negative each, thus giving the sensitivity and specificity of 99.9% and 100% for both methods respectively. CONCLUSION: The 'InTec Blood Grouping Test Kit' is suitable for offsite usage because of its simplicity and user friendliness. However, further improvement in adding the internal quality control may increase the test sensitivity and validity of the test results. PMID- 29704382 TI - Establishing the cut off values of androgen markers in the assessment of polycystic ovarian syndrome. AB - INTRODUCTION: Hyperandrogenism remains as one of the key features in Polycystic Ovarian Syndrome (PCOS) and can be assessed clinically or determined by biochemical assays. Hirsutism is the most common clinical manifestation of hyperandrogenism. The clinical assessment is subjected to wide variability due to poor interobserver agreement and multiple population factors such as ethnic variation, cosmetic procedures and genetic trait. The difficulty in resolving the androgen excess biochemically is due to a lack of consensus as to which serum androgen should be measured for the diagnosis of PCOS. The aim of the study was to compare and establish the diagnostic cut off value for different androgen biomarker for the diagnosis of PCOS. MATERIALS AND METHODS: A total of 312 patients classified to PCOS (n = 164) and non PCOS (n = 148) cohorts were selected from the Laboratory Information System (LIS) based on serum total testosterone (TT) and sex hormone binding globulin (SHBG) from the period of 1st April 2015 to 31st March 2016. PCOS was diagnosed based on Rotterdam criteria. Clinical hyperandrogenism and ultrasound polycystic ovarian morphology were obtained from the clinical records. The other relevant biochemical results such as serum luteinizing hormone (LH), follicle stimulating hormone (FSH) and albumin were also obtained from LIS. Free androgen index (FAI), calculated free testosterone (cFT) and calculated bioavailable testosterone (cBT) were calculated for these patients. Receiver Operating Characteristic (ROC) curve analysis were performed for serum TT, SHBG, FAI, cFT, cBT and LH: FSH ratio to determine the best marker to diagnose PCOS. RESULTS: All the androgen parameters (except SHBG) were significantly higher in PCOS patients than in control (p<0.0001). The highest area under curve (AUC) curve was found for cBT followed by cFT and FAI. TT and LH: FSH ratio recorded a lower AUC and the lowest AUC was seen for SHBG. cBT at a cut off value of 0.86 nmol/L had the highest specificity, 83% and positive likelihood ratio (LR) at 3.79. This is followed by FAI at a cut off value of 7.1% with specificity at 82% and cFT at a cut off value of 0.8 pmol/L with specificity at 80%. All three calculated androgen indices (FAI, cFT and cBT) showed good correlation with each other. Furthermore, cFT, FAI and calculated BT were shown to be more specific with higher positive likelihood ratio than measured androgen markers. CONCLUSIONS: Based on our study, the calculated testosterone indices such as FAI, cBT and cFT are useful markers to distinguish PCOS from non-PCOS. Owing to ease of calculation, FAI can be incorporated in LIS and can be reported with TT and SHBG. This will be helpful for clinician to diagnose hyperandrogenism in PCOS. PMID- 29704383 TI - Plasma-derived microparticles in polycythaemia vera. AB - INTRODUCTION: Microparticles are membrane bound vesicles, measuring less than 1.0 um, which are released during cellular activation or during apoptosis. Studies have shown that these circulating microparticles play a role in coagulation, cell signaling and cellular interactions. Increased levels of circulating microparticles have been observed in a number of conditions where there is vascular dysfunction, thrombosis and inflammation. The objective of this study was to determine the various plasma-derived microparticles in patients with polycythaemia vera (PV) in Universiti Kebangsaan Malaysia Medical Centre and to compare them with normal control. METHODS: A total of 15 patients with PV and 15 healthy volunteers were included in this cross-sectional descriptive study. Plasma samples from both patients and healthy volunteers were prepared and further processed for isolation of microparticles. Flow cytometry analyses were then carried out in all samples to determine the cellular origin of the microparticles. Full blood count parameters for both groups were also collected. Data collected were analyzed using SPSS version 12.0. RESULTS: Patients with PV had a significantly higher percentage of platelet derived microparticles compared to healthy controls (P <0.05). The control group had a higher level of endothelial derived microparticles but the differences were not statistically significant (P > 0.05). CONCLUSION: The median percentage of positive events for platelet derived microparticles was higher in patients with PV compared to normal healthy controls. PMID- 29704384 TI - Epstein-Barr virus infection in B-cell Non-Hodgkin's Lymphomas of the oral and maxillofacial region: Is there any evidence? AB - INTRODUCTION: Epstein-Barr virus (EBV) might be an aetiological agent involved in the pathogenesis of certain Non-Hodgkin's Lymphomas (NHLs). EBV infection has been diagnosed by serologic testing within the tumour biopsies of patients with NHL. However, the association between EBV and NHL is inconsistent with a preference for certain anatomic sites, histologic subtypes and immunosuppressed patients. The objective of this study was to characterise the B-cell NHLs of the oral cavity and maxillofacial region using histological and immunophenotypical techniques and to determine its association with EBV infection. MATERIALS AND METHODS: This was a descriptive cross-sectional study that included 14 cases of B cell NHLs of the oral cavity and maxillofacial region. The haematopoietic and lymphoid tissue tumours classification of WHO was used to categorize the cases. In-situ hybridisation for EBV-encoded RNA was performed to confirm the EBV infection. RESULTS: The average age of the patients included in the study was found to be 48.8 +/- 23 years with a higher female to male ratio (1.3:1). Our study suggested that diffuse large B-cell lymphomas (DLBCLs) and Burkitt's lymphomas (BLs) constitute the predominant subtypes of lymphomas affecting the oral cavity and maxillofacial regions. CONCLUSION: The findings from our study support the view that at least a relatively smaller proportion of B-cell NHLs that occur in the oral cavity and maxillofacial region do not have a pathogenic association with EBV. PMID- 29704385 TI - CD10 expression pattern in prostatic adenocarcinoma: Elucidation of differences between Gleason's grades. AB - CD10, a transmembrane endopeptidase, has been shown to be lost as an early event in prostate cancer. We aimed at evaluating the pattern of expression of CD10 in various Gleason's grades of prostatic adenocarcinoma in comparison with nodular hyperplasia of prostate. This retrospective study included 30 cases of nodular hyperplasia and 30 of prostatic adenocarcinoma of various Gleason's grades. Immunohistochemical staining for CD10 was performed on all cases and positivity evaluated as percentage of cells as well as location (membranous or cytoplasmic or both). Of prostatic adenocarcinomas, grade 3 was seen in 10 foci, grade 4 in 28 and grade 5 in 22 foci. CD10 positivity in carcinoma was lower than in nodular hyperplasia, with the lowest positivity in grade 5. The pattern of expression of CD10 also changed from membranous in grade 3 to cytoplasmic in grade 5. Loss of CD10 expression appears to be associated with increasing tumour grade in carcinoma prostate and this can potentially be useful in stratification of such patients. PMID- 29704386 TI - Autologous mononuclear cells from different sources are seen to improve wound healing in patients with haematological malignancies. AB - INTRODUCTION: Immunosuppressive state due to haematological malignancies and chemotherapy may cause disruption to wound healing despite optimum conventional treatment and standard wound dressing. Non-healing wounds are predisposed to infection whereas chemotherapy dose reductions or interruptions are associated with poor survival. BACKGROUND: Mononuclear cells contain progenitor cells including haematopoietic and mesenchymal stem cells, endothelial progenitor cells and fibroblasts which facilitate wound healing through cytokines, growth factor secretions, cell-cell interactions and provision of extracellular matrix scaffolding. Clinical applications of autologous mononuclear cells therapy in wound healing in non-malignant patients with critical limb ischaemia have been reported with remarkable outcome. METHODS: We report three patients with haematological malignancies undergoing chemotherapy, who received autologous mononuclear cells implantation to treat non-healing wound after optimum conventional wound care. The sources of mononuclear cells (MNC) were from bone marrow (BM), peripheral blood (PB) and mobilised PB cells (mPB-MNC) using granulocyte colony stimulating factor (G-CSF). The cells were directly implanted into wound and below epidermis. Wound sizes and adverse effects from implantation were assessed at regular intervals. RESULTS: All patients achieved wound healing within three months following autologous mononuclear cells implantation. No implantation adverse effects were observed. CONCLUSIONS: Autologous mononuclear cells therapy is a feasible alternative to conventional wound care to promote complete healing in non-healing wounds compounded by morbid factors such as haematological malignancies, chemotherapy, diabetes mellitus (DM), infections and prolonged immobility. PMID- 29704387 TI - The crucial role of molecular testing to facilitate the diagnosis of pneumocystis pneumonia during pregnancy. AB - Pneumocystis pneumonia is an important human immunodeficiency virus (HIV) associated opportunistic infection, and especially so in pregnant HIV-positive patients. We report a case of a 40-year-old woman in her first trimester of pregnancy who initially presented with acute gastroenteritis symptoms but due to a history of high-risk behaviour and the observation of oral thrush, she was worked up for HIV infection. Her retroviral status was positive and her CD4+ T cell count was only 8 cells/uL. She was also worked up for pneumocystis pneumonia due to the presence of mild resting tachypnoea and a notable drop in oxygen saturation (from 100% to 88%) following brief ambulation. Her chest radiograph revealed bilaterally symmetrical lower zone reticular opacities and Giemsa staining of her bronchoalveolar lavage (BAL) was negative for Pneumocystis jirovecii cysts. However, real-time P. jirovecii polymerase chain reaction (PCR) testing on the same BAL specimen revealed the presence of the organism. A course of oral co-trimoxazole plus prednisolone was commenced and her clinical condition improved. PMID- 29704388 TI - Unrecognised IgG4 association in progressively transformed germinal centers of lymph nodes with subsequent full-blown IgG4-related chronic fibrosing pancreatitis: A case report. AB - Progressively transformed germinal centers (PTGC) is a benign process characterised by a morphological variant of reactive follicular hyperplasia in lymph nodes. It was recently shown that some cases of PTGC are associated with IgG4-related disease (IgG4-RD) or increased IgG4 plasma cells. Five years ago, a 57-year-old woman presented with enlargement of multiple lymph nodes in the left parotid, submandibular, and neck areas, pathologically diagnosed as PTGC after excisional biopsy. Since then, she has experienced numbness in her extremities, especially the left shoulder and arm, pruritus on the left side of the face and intermittent facial palsy, for which she has been receiving regular symptomatic treatment. Recently the patient developed diabetes mellitus (approximately seven months ago). In routine follow-up scans, a mass was detected in left kidney and magnetic resonance imaging of the abdomen prior to surgery revealed a slightly enhanced bulky mass replacing the pancreatic tail and uncinate process. The mass in left kidney was diagnosed as clear cell renal cell carcinoma, and the pathological features of the pancreatic lesion were those of IgG4-related chronic fibrosing pancreatitis. Retrograde examination of the neck lymph node diagnosed as PTGC showed increased deposition of IgG4-positive plasma cells. PMID- 29704389 TI - Recommended parameters for pathology reporting of gastroenteropancreatic neuroendocrine tumours (GEP-NETs). AB - No abstract available. PMID- 29704390 TI - Abstracts of the 16th Annual Scientific Meeting of the College of Pathologists, Academy of Medicine of Malaysia. AB - No abstract available. PMID- 29704391 TI - WITHDRAWN Monocyte chemoattractant protein-1 promoter-2518 G allele increases renal damage in systemic lupus erythematosus patients: result from a meta analysis. AB - Ahead of Print article withdrawn by publisher. Not clarified suspected conflict of interest. PMID- 29704393 TI - Correlation between herpes zoster and stroke-A case-control study. AB - Cerebrovascular accident is the second most common cause of death in the world. Herpes zoster (HZ) is reported to be a major trigger of the stroke syndrome. Considering the high prevalence of stroke in Iran, we carried out a study to assess the correlation between stroke and HZ. This is one of the very few studies carried out on this correlation in Asian nations. One hundred and five cases and 105 controls were included in this study. The cases had been diagnosed with stroke by a neurologist and confirmed by brain imaging. The controls had never had any type of stroke. Both groups were between 30 and 90 years of age. We looked for the HZ infection in both groups. Logistic regression analysis was used to evaluate the association between stroke and HZ. The mean age of the cases was 63.95 +/- 12.24 years and the man age of the controls was 66.99 +/- 14.58 years. There was a significant difference in the HZ infection between the cases and the controls (P < .0001). Head zoster (including ophthalmic zoster) was significantly higher in the case group than the control group (P < .0001). The risk of stroke was the highest 2-4 weeks after the onset of HZ and the incidences of ischemic stroke were higher than those of hemorrhagic stroke (P < .0001). In an analysis adjusted for the age, sex, and hypertension, HZ was found to be associated with an increased risk of stroke (odds ratio, 5.84; 95% confidence interval, 1.98 8.23). Close monitoring is suggested for cerebrovascular diseases in patients who have had the head zoster, especially in the first month after the infection. PMID- 29704392 TI - The Nephroprotective Effect of MS-275 on Lipopolysaccharide (LPS)-Induced Acute Kidney Injury by Inhibiting Reactive Oxygen Species (ROS)-Oxidative Stress and Endoplasmic Reticulum Stress. AB - BACKGROUND Histone deacetylase (HDAC) inhibitors can attenuate acute kidney injury (AKI)-mediated damage and reduce fibrosis in kidney disease models. The aim of the present study was to investigate the effects of the HDAC inhibitor MS 275 on lipopolysaccharide (LPS)-induced AKI and the associated mechanisms. MATERIAL AND METHODS A LPS-induced model in 6-8 weeks-old mice was established by intraperitoneal injection of LPS (10 mg/kg), with pre-treatment of MS-275 (2 mg/kg/day) administered intraperitoneally for five days. In addition, HK-2 cells were exposed to LPS (1 MUg/mL) at 0.1 nM, 1 nM, 10 nM, and 100 nM. For our in vitro MS-275 study, detection programs included histology, biochemical, immunohistochemistry, mRNA and protein expression as well as apoptosis. RESULTS MS-275 ameliorated renal damage, enhanced the survival rate of the LPS-induced sepsis model, decreased the expressions of TNF-alpha, IL-1beta, IL-6, COX-2, and NF-kappaBp65 nucleus translocation, suppressed the HDAC activity which was enhanced in septic AKI mice, and enhanced the acetylation of histone H3 and H4. Reactive oxygen species (ROS) production was enhanced in the kidney of LPS mice compared to control mice, while MS-275 suppressed the production of ROS in kidney tissue. In the in vitro studies, MS-275 reduced the LPS-induced apoptosis of HK-2 cells, inhibited ROS and MDA production, increased the production GSH and SOD activity, decreased the expressions of CHOP, GRP78, caspase3, and capase12, which was related to endoplasmic reticulum stress in LPS stimulated HK-2 cells. CONCLUSIONS MS-275 pre-treatment improved renal function and ameliorated histological alterations, inflammation, and ROS production in LPS-induced AKI mice and may act through inhibiting ROS-oxidative stress and endoplasmic reticulum stress. PMID- 29704394 TI - Identification of uterine pacemaker regions at the myometrial-placental interface in the rat. AB - KEY POINTS: Coordinated contraction of the uterine smooth muscle is essential to parturition. Histologically and physiologically defined pacemaker structures have not been identified in uterine smooth muscle. Here we report combined electrophysiological and histological evidence of zones associated with pacemaker activity in the rat myometrium. Our method relies crucially on the integration of histological and electrophysiological data in an in silico three-dimensional reconstruction of the rat myometrium at 10 MUm resolution. We find that myometrial/placental pacemaking zones are closely related with placental sites and the area of disruptive myometrial remodelling surrounding such sites. If analogues of the myometrial/placental pacemaking zone are present in the human, defining their histology and physiology will be important steps towards treatment of pre-term birth, pre-eclampsia, and postpartum haemorrhage. ABSTRACT: Coordinated uterine contractions are essential for delivering viable offspring in mammals. In contrast to other visceral smooth muscles, it is not known where excitation within the uterus is initiated, and no defined pacemaking region has hitherto been identified. Using multi-electrode array recordings and high resolution computational reconstruction of the three-dimensional micro-structure of late pregnant rat uterus, we demonstrate that electrical potentials are initiated in distinct structures within the placental bed of individual implantation sites. These previously unidentified structures represent modified smooth muscle bundles that are derived from bridges between the longitudinal and circular layers. Coordinated implantation and encapsulation by invading trophoblast give rise to isolated placental/myometrial interface bundles that directly connect to the overlying longitudinal smooth muscle layer. Taken together, these observations imply that the anatomical structure of the uterus, combined with site-specific implantation, gives rise to emergent patterns of electrical activity that drive effective contractility during parturition. PMID- 29704395 TI - Measuring public knowledge, attitudes, and behaviors related to radon to inform cancer control activities and practices. AB - Radon exposure is the second leading risk factor for lung cancer among smokers and the leading risk factor among non-smokers. Radon concentrated in lower levels of homes/buildings can be reduced if found, thus lowering lung cancer risk. The objective of this study was to measure radon knowledge in diverse populations, with varying radon-related laws, to inform radon-related cancer control practices and activities. A survey was mailed to 3000 homebuyers who purchased single family homes; 995 responses (33%) were received. Overall, 86% of respondents heard of radon-related health issues. Real estate agents (69%) or home inspectors (65%) were the most common sources of information. Respondents were more likely to test their home for radon if they reported previously hearing of radon-related health issues or understanding of how radon-related health issues affect the home buying process. Respondents in states with notification policies were twice as likely as those without policies to have heard about radon-related health issues (OR 2.01, 95% CI: 1.27-3.17). This study provides useful information for cancer control activities including that education is positively associated with home testing for radon. It also suggests partnering with real estate agents to further radon education and testing efforts to reduce radon exposure and lung cancer risk. PMID- 29704397 TI - Association of the hypha-related protein Pra1 and zinc transporter Zrt1 with biofilm formation by the pathogenic yeast Candida albicans. AB - Bloodstream infection by the pathogenic fungus Candida albicans is a major health problem. Candidemia is often associated with medical devices, which can act as substrates for biofilm development. Biofilm-related infections are relatively difficult to treat because of their resistance to antimicrobial agents. It is therefore important to explore the mechanisms of biofilm formation. Dimorphism is a major contributor to biofilm formation in C. albicans. To determine whether the hypha-related proteins Pra1 (pH-regulated antigen) and Zrt1 (zinc transporter) are responsible for biofilm formation, the ability of pra1 and zrt1 deletion mutants to form biofilms was investigated. Biofilm formation by both deletion mutants was less than that of the wild-type strain. Because Pra1 and Zrt1 are also related to the zinc homeostasis system, the effects of adding zinc on biofilm formation were also examined. Biofilm formation was increased in the presence of zinc. These data suggest that Pra1 and Zrt1 regulate biofilm formation through zinc homeostasis. PMID- 29704398 TI - The effect of ischaemic preconditioning on central and peripheral fatiguing mechanisms in humans following sustained maximal isometric exercise. AB - NEW FINDINGS: What is the central question of this study? Does ischaemic preconditioning (IPC) influence central and peripheral fatiguing mechanisms during sustained maximal isometric exercise? What is the main finding and its importance? Voluntary activation and pre- to postexercise reductions in resting twitch torque values were unchanged by IPC. However, an effect on tissue oxygenation was observed within the IPC trials, where greater concentrations of deoxyhaemoglobin were recorded with concurrent upward trends of total haemoglobin concentrations. Using a direct assessment of neural drive, we found that IPC had no influence on either central or peripheral fatiguing pathways after maximal isometric exercise. ABSTRACT: Ischaemic preconditioning (IPC) is thought to inhibit neural feedback from metabolically sensitive muscle afferents during exercise. It was hypothesized that IPC could affect mechanisms associated with centrally mediated fatigue after a maximally fatiguing protocol. Eleven resistance-trained men completed three 2 min maximal voluntary contractions (MVCs) via an isometric leg extension preceded by treatments of IPC (three bouts of 5 min bilateral leg occlusions at 220 mmHg), SHAM (three bouts of 5 min at 20 mmHg) or CON (30 min passive rest). Femoral nerve stimulation was used to explore central and peripheral fatigue pathways. These pathways were profiled at baseline (BL), before the 2 min MVC (Pre) and 10 s afterwards (Post). Tissue oxygenation was measured throughout the 2 min MVCs via near-infrared spectroscopy. The Pre to Post MVC (-71 +/- 56 Nm; d = 1.33 +/- 0.51, P < 0.01) and twitch torque (-51 +/- 20 Nm; d = 3.76 +/- 0.84, P < 0.01) levels declined without differences between conditions (MVC, P = 0.67; twitch torque, P = 0.39). Voluntary activation was also unaffected by condition (P = 0.80). Peak deoxyhaemoglobin concentrations were elevated in the IPC trials relative to CON (3.7 +/- 3.0 MUmol l-1 ; d = 1.02 +/- 0.46, P < 0.01) and SHAM (3.0 +/- 3.7 MUmol l-1 ; d = 0.82 +/- 0.57, P < 0.05). These findings demonstrate that IPC does not affect central or peripherally mediated mechanisms of fatigue during a sustained 2 min maximal effort isometric leg-extension task. PMID- 29704396 TI - Protective immunity induced by an intranasal multivalent vaccine comprising 10 Lactococcus lactis strains expressing highly prevalent M-protein antigens derived from Group A Streptococcus. AB - Streptococcus pyogenes (group A Streptococcus) causes diseases ranging from mild pharyngitis to severe invasive infections. The N-terminal fragment of streptococcal M protein elicits protective antibodies and is an attractive vaccine target. However, this N- terminal fragment is hypervariable: there are more than 200 different M types. In this study, an intranasal live bacterial vaccine comprising 10 strains of Lactococcus lactis, each expressing one N terminal fragment of M protein, has been developed. Live bacterial-vectored vaccines cost less to manufacture because the processes involved are less complex than those required for production of protein subunit vaccines. Moreover, intranasal administration does not require syringes or specialized personnel. Evaluation of individual vaccine types (M1, M2, M3, M4, M6, M9, M12, M22, M28 and M77) showed that most of them protected mice against challenge with virulent S. pyogenes. All 10 strains combined in a 10-valent vaccine (M*10) induced serum and bronchoalveolar lavage IgG titers that ranged from three- to 10-fold those of unimmunized mice. After intranasal challenge with M28 streptococci, survival of M*10-immunized mice was significantly higher than that of unimmunized mice. In contrast, when mice were challenged with M75 streptococci, survival of M*10 immunized mice did not differ significantly from that of unimmunized mice. Mx-10 immunized mice had significantly less S. pyogenes in oropharyngeal washes and developed less severe disease symptoms after challenge than did unimmunized mice. Our L. lactis-based vaccine may provide an alternative solution to development of broadly protective group A streptococcal vaccines. PMID- 29704399 TI - Design, synthesis chalcone derivatives as AdipoR agonist for type 2 diabetes. AB - Two structurally novel series of chalcone derivatives were designed and synthesized as potential agents against type 2 diabetes. As a result of the antidiabetic biological evaluation in streptozotocin (STZ)-induced type 2 diabetes animal model, 13e, 13g, and 19f showed more significant reduction in serum Glu, TG, TC levels by contrast to the positive control AdipoRon. In addition to upregulating the expression of AdipoR1 and AdipoR2, 13e and 19f treatment also increased expression of AMPK and PPAR-alpha. Taken together, these results suggested that 13e and 19f might be a promising compound for type 2 diabetes treatment. PMID- 29704400 TI - Ligand-Unsupported Cuprophilicity in the Preparation of Dodecacopper(I) Complexes and Raman Studies. AB - Synthesis and characterization of two dodecacopper(I) extended metal atom chains (EMAC) assembled by two hexadentate bis(pyridylamido)amidinate-supported hexacopper(I) string complexes (monomers) via the ligand-unsupported cuprophilicity are described. In addition to short unsupported Cu-Cu contacts, two hexacopper fragments in these two dodecacopper EMACs show a bent conformation based on X-ray crystallography. Compared with their THF-bound hexacopper(I) monomers and protonated ligands, these ligand-unsupported cuprophilic interactions are shown to be weak by Raman spectroscopy. DFT calculations suggest the ligand-unsupported cuprophilicity originate from weak attractive orbital interactions, and the strength is estimated to be 2.4 kcal mol-1 . PMID- 29704401 TI - Leaf stage-associated resistance is correlated with phytohormones in a pathosystem-dependent manner. AB - It has been reported in several pathosystems that disease resistance can vary in leaves at different stages. However, how general this leaf stage-associated resistance is, and the molecular mechanism(s) underlying it, remain largely unknown. Here, we investigated the effect of leaf stage on basal resistance, effector-triggered immunity (ETI) and nonhost resistance, using eight pathosystems involving the hosts Arabidopsis thaliana, Nicotiana tabacum, and N. benthamiana and the pathogens Sclerotinia sclerotiorum, Pseudomonas syringae pv. tabaci, P. syringae pv. tomato DC3000, and Xanthomonas oryzae pv. oryzae (Xoo). We show evidence that leaf stage-associated resistance exists ubiquitously in plants, but with varying intensity at different stages in diverse pathosystems. Microarray expression profiling assays demonstrated that hundreds of genes involved in defense responses, phytohormone biosynthesis and signaling, and calcium signaling, were differentially expressed between leaves at different stages. The Arabidopsis mutants sid1, sid2-3, ein2, jar1-1, aba1 and aao3 lost leaf stage-associated resistance to S. sclerotiorum, and the mutants aba1 and sid2-3 were affected in leaf stage-associated RPS2/AvrRpt2+ -conferred ETI, whereas only the mutant sid2-3 influenced leaf stage-associated nonhost resistance to Xoo. Our results reveal that the phytohormones salicylic acid, ethylene, jasmonic acid and abscisic acid likely play an essential, but pathosystem-dependent, role in leaf stage-associated resistance. PMID- 29704402 TI - Association of tumor necrosis factor alpha gene polymorphisms with Helicobacter pylori infection in dyspeptic patients in Sri Lanka. AB - Single nucleotide polymorphisms present on the promoter sequence of the TNF-alpha gene may affect production of TNF-alpha, a pro-inflammatory cytokine, during immune responses. The presence of TNF-alpha polymorphisms is also reportedly associated with more severe manifestations of Helicobacter pylori infection. However, the frequency of TNF-alpha polymorphisms and the associated disease severity vary between different patient groups. In this study, gastric biopsies and blood specimens were collected from 138 patients with dyspepsia undergoing routine upper gastrointestinal endoscopy. Our institution's Ethics Review Committee approved the study and written informed consent was obtained from all participants. The presence of H. pylori was confirmed histologically in all patients. The frequency of TNF-alpha polymorphisms in the study cohort was investigated using PCR-restriction fragment length polymorphism and expression of serum TNF-alpha quantitated using a commercial ELISA assay. The proportions of selected TNF-alpha polymorphisms (TNF-alpha -238, -308 and -863) were similar in H. pylori-positive and -negative patients. Homozygous mutations of TNF-alpha polymorphisms were rarely detected in the study group. There was a significant difference in TNF-alpha concentrations between patients with mild chronic gastritis and TNF-alpha -308 GG genotype and patients with moderate to severe chronic gastritis (P = 0.008). It was not possible to identify an association between these genotypes and disease severity because of the low frequency of heterozygous and homozygous mutated genes in Sri Lankan patients with dyspepsia. PMID- 29704403 TI - Green Tea Polyphenols Mitigate Gliadin-Mediated Inflammation and Permeability in Vitro. AB - SCOPE: Green tea, a polyphenol-rich beverage, has been reported to mitigate a number of inflammatory and hypersensitivity disorders in laboratory models, and has been shown to moderate pathways related to food allergies in vitro. The present study investigates the impact of decaffeinated green tea extract (GTE) on the digestion of gliadin protein in vitro and the effect of physical interactions with GTE on the ability of gliadin to stimulate celiac disease-related symptoms in vitro. METHODS AND RESULTS: Complexation of GTE and gliadin in vitro is confirmed by monitoring increases in turbidity upon titration of GTE into a gliadin solution. This phenomenon is also observed during in vitro digestion when gliadin is exposed to the digestive proteases pepsin and trypsin. SDS-PAGE and enzymatic assays reveal that GTE inhibits digestive protease activity and gliadin digestion. In differentiated Caco-2 cell monolayers as a model of the small intestinal epithelium, complexation of gliadin with GTE reduces gliadin stimulated monolayer permeability and the release of interleukin (IL)-6 and IL-8. CONCLUSION: There are potential beneficial effects of GTE as an adjuvant therapy for celiac disease through direct interaction between gliadin proteins and green tea polyphenols. PMID- 29704404 TI - Can David topple Goliath again? The 'simple' perianal abscess could provide a key to identifying early Crohn's disease. PMID- 29704405 TI - Hospital readmissions in diabetic kidney transplant recipients with peripheral vascular disease. AB - BACKGROUND: The benefits of kidney transplantation in diabetic patients with peripheral vascular disease (PVD) are unclear. While patients may have improved survival compared to dialysis, the burden of care after transplant has not been assessed. METHODS: We performed a retrospective review of adult diabetic kidney only transplant recipients with and without PVD transplanted from January 2012 until June 30, 2015. RESULTS: Of 203 diabetic kidney transplant recipients, 56 (27.6%) had PVD and 147 (72.4%) had no PVD. At a median of 3.14 years follow-up, there were no significant differences in 30-, 90-, or 1-year readmission rates. At 1 year after transplant, PVD patients were significantly more likely to have a greater sum of unplanned inpatient days (44.6% vs 27.9% with >=10 inpatient days, P = .03) and at least 1 reoperation (28.6% vs. 8.7%, P < .01). At 1 year post transplant, there were similar rates of graft-related reoperations; however, patients with PVD had significantly increased rates of non-graft-related operations of which 31.2% were PVD-related. CONCLUSIONS: Diabetic patients with PVD utilize more resources after kidney transplant, spending more time in the hospital and undergoing more post-transplant operations. The causes of readmission are predominantly related to progression of PVD rather than allograft complications. PMID- 29704406 TI - Robotic complete mesocolic excision in right hemicolectomy - a video vignette. PMID- 29704407 TI - Design of Interactions Between Nanomaterials and Proteins: A Highly Affine Peptide Tag to Bare Iron Oxide Nanoparticles for Magnetic Protein Separation. AB - Superparamagnetic nanoparticles have recently gained much attention due to their broad range of applicability including medical in vivo technologies, sensors, and as supports for catalysts. As magnetic affinity materials, they can be utilized for the development of new purification strategies for pharmaceuticals and other target molecules from crude lysates. Here, a short peptide tag based on a glutamate sequence is introduced and the adsorption of pure protein as well as protein from crude cell lysate at different conditions is demonstrated. Fused to a model protein this tag can be used to recognize and purify this protein from a fermentation broth by bare iron oxide nanoparticles (BIONs). Binding of up to 0.2 g protein per g nanoparticles can be achieved and recovered easily by switching to a citrate buffered system. For a deeper understanding of the separation process, the aggregation and agglomeration of the nanoparticle protein systems were monitored for binding and elution steps. Furthermore, an upscaling of the process to the liter scale and the separation of a green fluorescent protein (GFP) containing the affinity tag to purities of 70% from Escherichia coli fermentation broth was possible in a one step process by means of high gradient magnetic separation (HGMS). PMID- 29704409 TI - Editorial. AB - no summary. PMID- 29704408 TI - Relevance of a Mobile Internet Platform for Capturing Inter- and Intrasubject Variabilities in Circadian Coordination During Daily Routine: Pilot Study. AB - BACKGROUND: Experimental and epidemiologic studies have shown that circadian clocks' disruption can play an important role in the development of cancer and metabolic diseases. The cellular clocks outside the brain are effectively coordinated by the body temperature rhythm. We hypothesized that concurrent measurements of body temperature and rest-activity rhythms would assess circadian clocks coordination in individual patients, thus enabling the integration of biological rhythms into precision medicine. OBJECTIVE: The objective was to evaluate the circadian clocks' coordination in healthy subjects and patients through simultaneous measurements of rest-activity and body temperature rhythms. METHODS: Noninvasive real-time measurements of rest-activity and chest temperature rhythms were recorded during the subject's daily life, using a dedicated new mobile electronic health platform (PiCADo). It involved a chest sensor that jointly measured accelerations, 3D orientation, and skin surface temperature every 1-5 min and relayed them out to a mobile gateway via Bluetooth Low Energy. The gateway tele-transmitted all stored data to a server via General Packet Radio Service every 24 hours. The technical capabilities of PiCADo were validated in 55 healthy subjects and 12 cancer patients, whose rhythms were e monitored during their daily routine for 3-30 days. Spectral analyses enabled to compute rhythm parameters values, with their 90% confidence limits, and their dynamics in each subject. RESULTS: All the individuals displayed a dominant circadian rhythm in activity with maxima occurring from 12:09 to 20:25. This was not the case for the dominant temperature period, which clustered around 24 hours for 51 out of 67 subjects (76%), and around 12 hours for 13 others (19%). Statistically significant sex- and age-related differences in circadian coordination were identified in the noncancerous subjects, based upon the range of variations in temperature rhythm amplitudes, maxima (acrophases), and phase relations with rest-activity. The circadian acrophase of chest temperature was located at night for the majority of people, but it occurred at daytime for 26% (14/55) of the noncancerous people and 33% (4/12) of the cancer patients, thus supporting important intersubject differences in circadian coordination. Sex, age, and cancer significantly impacted the circadian coordination of both rhythms, based on their phase relationships. CONCLUSIONS: Complementing rest activity with chest temperature circadian e-monitoring revealed striking intersubject differences regarding human circadian clocks' coordination and timing during daily routine. To further delineate the clinical importance of such finding, the PiCADo platform is currently applied for both the assessment of health effects resulting from atypical work schedules and the identification of the key determinants of circadian disruption in cancer patients. PMID- 29704410 TI - Are we able to evaluate suicide risk? AB - Suicide is not only a medical but also a social problem. It seems important to be able to evaluate the risk of suicide in ordertointroduce appropriate preventive actions.Several instruments (scales) for the evaluation of the suicide risk may be of a help to the physician, however, they do not allow for a more precise measurement of such a risk. For the evaluation of suicide risk the following factors seemto play important role:severe depressive symptoms coexisting with substance abuse, feeling that there is no escape (entrapment), more arguments for suicide that against it, earlier suicidal thoughts / tendencies / attempts, active preparations for a suicide. PMID- 29704411 TI - Are suicide risk factors gender specific? AB - OBJECTIVES: Suicide is an important clinical problem in psychiatric patients. The highest risk of suicide attempts is noted in affective disorders. In this study we tested 20 factors described in the literature (sociodemographic and clinical factors as well as family burden) in association with suicidal behavior and we analyzed whether the significance of those factors differs between males and females. METHODS: In the study we included patients with major depressive disorder (MDD; n = 249) and bipolar affective disorder (BP; n = 582). The Structured Clinical Interview for DSM-IV Axis I (SCID I), the Operational Criteria Diagnostic Checklist (OPCRIT) and a questionnaire of family history were used. RESULTS: In the study population we observed an association between suicidal attempts and the following factors: family history of psychiatric disorders, affective disorders and psychoactive substance abuse/dependence; family history of attempted/completed suicide; occurrence of specific symptoms in the course of depressive episode (inappropriate guilt, sense of worthlessness, early morning awakening); and psychotic symptoms. Having children was also associated with suicide attempts. The risk factors of suicide attempt differ between males and females. The age of onset of MDD and coexistence of substance abuse/dependence with affective disorder were significant for lifetime risk of attempted suicide only in female group. Having children was associated with suicide attempts in the whole group and in the male subgroup, but not in the female subgroup. CONCLUSIONS: Suicide attempts are significantly associated with 10 out of 20 analyzed clinical factors in our group of affective patients, however, the significance (or lack of it) of these factors differed in female and male groups in half the cases. PMID- 29704412 TI - Evaluation of the relationship between cognitive functioning in patients with borderline personality disorder and their general functioning. AB - OBJECTIVES: The purpose of the study was to examine the relation between cognitive functioning in people with borderline personality disorder and their overall functioning level, as well as psychopathology intensification specific for this type of disorders. METHODS: 64 patients aged 18-55 (M = 30.09) with borderline personality disorder (emotionally unstable personality - borderline type in the ICD-10) were examined. The study used: demographic-descriptive questionnaire, SCID II, Borderline Symptom Checlist-23, and Global Assessment of Functioning (GAF). For cognitive assessment, The Rey Auditory Verbal Learning Test, The Rey-Osterrieth Complex Figure test, TMTA, TMTB, verbal fluency test, Stroop test and Frontal Assessment Battery (FAB) were used. RESULTS: The average GAF score in the sample was M =43.65. Significant differences between the comorbidity group and non-comorbidity group were observed with respect to the GAF scores (Mann-Whitney U = 300.500, p = 0.008) as well as a number of significant (p < 0.05) correlations between the level of cognitive functions and functioning in patients with no co-morbidity. CONCLUSIONS: Clinically significant disturbances in general and social functioning persisted in the group of subjects with borderline personality disorder. The obtained data seem to suggest that the cognitive functions affect the overall functioning only in patients with psychiatric co-morbidity. In people without psychiatric co-morbidity there is a relationship of cognitive functions only with certain aspects of psychopathology specific to BPD. PMID- 29704413 TI - Difficulties to differentiate mood disorders co-occurring with compulsive gambling. Discussion based on a case study. AB - Contemporary literature does not take a clear position on the issue of determining civil and criminal liability of persons diagnosed with pathological gambling, and all the more so in case of possible comorbidity of or interference with other mental disorders. Diagnostic difficulties are demonstrated by a clinical picture of a patient with problem gambling who underwent forensic and psychiatric assessments to evaluate the process of making informed (and independent) decisions in view of numerous concluded civil law (mainly financial) agreements. The patient had been examined 5 times by expert psychiatrists who, in 4 opinions, diagnosed her with bipolar affective disorder, including 1 diagnosis of rapid cycling of episodes. Based on the current state of scientific knowledge about the relationship between problem gambling and mood disorders, bipolar affective disorder was not confirmed. Diagnostic difficulties, resulting both from diagnostic haziness and unreliable information obtained during patient interview, that emerged in the course of case study point to the need for multi dimensional clinical diagnosis of persons with suspected mood disorders and behavioral addictions. PMID- 29704414 TI - Level of personality integration in psychopathy. AB - OBJECTIVES: Aim of this research was to determine whether differences in clinical picture of psychopathy (on the basis of which subtypes of psychopathy are identified) reflect differences in pathology of personality organization (integration) according to O. Kernberg. METHODS: The research was conducted on 417 subjects, of whom 88.5% were criminals, 11.5% - non-criminals. Psychopathic Personality Inventory-Revised (PPI-R), developed by S.O. Lilienfeld, was used to assess level of psychopathy while personality organization level was assessed by Borderline Personality Inventory (BPI) developed by F. Leichsenring. K-means cluster analysis was supported by AUC. RESULTS: Cluster analysis allowed for differentiation of two groups: cluster 1 - fearlessly dominating psychopaths and cluster 2 - egocentrically-impulsive psychopaths. Egocentrically-impulsive psychopaths are significantly more frequently characterized by borderline personality organization than psychopaths from cluster 1. In addition to symptoms of psychopathy they show evidence of deeper identity disorders, apply primitive defense mechanisms more frequently, experience fear of fusion and severe problems in reality testing. CONCLUSIONS: Differences in picture of psychopathy reflect different pathology of personality organization. Results confirm the thesis of distinctive nature of coldheartedness and its invariant presence in picture of psychopathy regardless of configuration of other traits in both subtypes. PMID- 29704415 TI - Ways of understanding of religious delusions associated with a change of identity on the example of identification with Jesus Christ. AB - Identification with Christ among psychiatric patients is an example of a complex and multifaceted phenomenon. As a delusion it includes a misidentification (change of identity) in the layer of content and, usually, grandiosity and/or paranoid traits in the formal aspect. What is more, it fits in the category of religious delusions, which are perhaps the most controversial type of delusions and as such require special sensitivity as well as knowledge beyond psychology or psychiatry. The aim of the articleis to show the phenomenon of identification with Christ among psychiatric patients, taking into account different ways of its explaining and understanding. Papers relating to the topic, both theoretical considerations and case studies, found in the EBSCO database were analyzed. Searching for the articles the following key words were used: identity, identification, delusion, Jesus/Christ/Messiah, psychosis, schizophrenia. The analysis included all (actually not numerous) articles except for the one linked to cognitive approach which did not significantly contribute to the issue. Given the multiplicity of ways of explaining and understanding the experience of identification with the figure of the Messiah, it seems to be a mistake to hold both objectivist and one-sided, based on one theory, attitude towards it. Such an experience should be recognized in the context of the history of patient's life and the all possible mechanisms leading to its occurrence, as well as the meanings hidden beneath the symptom, should be take into account. It is also important to be well-oriented in the system of religious beliefs and spiritual needs of the patient. PMID- 29704416 TI - Kleptomania or common theft - diagnostic and judicial difficulties. AB - First descriptions of kleptomania as a mental disorder date back to the nineteenth century. For the first time, kleptomania as an accompanying symptom rather than a formal diagnosis was included in the classification of psychiatric disorders of the American Psychiatric Association DSM-I in 1952. It was included in the International Classification of Diseases ICD-10 and classified under "habit and impulse disorders". Kleptomania is a serious disorder, as numerous thefts are impulsively carried out, carrying the risk of detection and consequently criminal liability. In Poland, we lack epidemiological data, however, it is estimated that 5% of those who commit theft are affected by kleptomania. People suffering from this disorder often do not seek a medical opinion so reviewing such cases is challenging for expert psychiatrists. The authors have proposed the term "kleptomania spectrum" for defining cases in which patients have an intense urge to steal, experienced a sense of tension from such an action, and relief following it, however, the criterion of theft of a superfluous object, without a profitable motive for themselves or others is not met. PMID- 29704417 TI - Areas of stigma and discrimination of mentally ill people among Internet respondents in Poland. AB - OBJECTIVES: The aim of this study was to investigate the public perception of mentally ill people, stigma of the mentally ill and distance towards them in Poland. METHODS: The study group was composed of 1,309 respondents who were interviewed using an authors' own survey, which was spread with the use of online media. RESULTS: The results indicate a high level of stigma of psychiatric patients in the subjective assessment of their appearance, intellect as well as respondents' sense of superiority over the patients. The stigma of a psychiatric patient is also resolutely demonstrated in the economic aspect, which results from respondents' unwillingness to employ, or even work with people affected by a disorder from the mental illness group. CONCLUSIONS: Undoubtedly, the fight against the phenomenon of stigma and discrimination against people affected by mental health problems is becoming one of the priorities in the field of mental health. PMID- 29704418 TI - The analysis of the phenomenon of violence in psychiatric patients. AB - OBJECTIVES: Domestic violence is a phenomenon stemming from various social issues. One of such issues, which arouses much interest, is the behavior of psychiatric patients using violence in their family. The aim of the following work was the analysis of the phenomenon of violence with reference to perpetrators-psychiatric patients from the Szczecin area in the years 2012-2013. In addition, the authors'aim was also to indicate that the beliefs held by society on aggression of psychiatric patients are not confirmed by the actual state. METHODS: The research was conducted with the research tool prepared on the basis of the "Blue Cards" - part A questionnaire. For data gathering, the document analysis method -survey-was used. 141 psychiatric patients constituted the research group. These people have already used violence against adults, and they already had the Blue Card. The members of the group were examined on the basis of several variables, such as sex, age, and the form of the violence used. RESULTS: Men were the ones most frequently using violence, and with regard to the forms of violence, it was most often hitting and pushing. As far as psychic violence is concerned, most perpetrators admitted they used to humiliate, criticize and bother their victims. Regarding other types of behaviors among the psychiatric patients using violence, as many as 96 respondents admitted that they used punishable threats and insults, and 71 respondents admitted they destroyed and damaged property. CONCLUSIONS: On the basis of the conducted analysis, the authors claim that the obtained data do not confirm the common belief that psychiatric patients indicate an increased level of aggression. PMID- 29704419 TI - Changes in ego strength in patients with neurotic and personality disorders treated with a short-term comprehensive psychodynamic psychotherapy. AB - OBJECTIVES: Analysis of changes in ego strength in the course of group psychotherapy in patients treated with neurotic and selected personality disorders (F40-F61, ICD-10). METHODS: 82 patients (61 women and 21 men) participated in the study. They underwent intensive short-term group psychotherapy treatment in a day hospital for neurotic and behavioural disorders. The assessment of the patients' personality functioning was carried out at the onset and the end of the psychotherapy. The assessment was reported as a value on the ego strength scale by means of the MMPI-2 questionnaire. RESULTS: The comparative analysis with the use of the t-Student test for related measurements, which was carried out for the measurement of ego strength values at the onset and the end of the therapy, demonstrated a statistically significant positive change both for the entire examined group and the groups which considered the gender and diagnosis distribution. CONCLUSIONS: Short-term intensive comprehensive group psychotherapy with elements of individual psychotherapy results in obtaining the desired changes in the personality functioning manifested through the increase in ego strength. PMID- 29704420 TI - Patient mental adjustment to selected types of cancer. AB - OBJECTIVES: Physical symptoms related to cancer are associated with various mental conditions. An adopted attitude towards pain and disease affects the quality of life of patients and may even decide about the final outcome of therapy. The objective of the study was to assess the degree of mental adjustment of patients diagnosed with breast, lung, colorectal and prostate cancer. The analysis also covered the effect of socioeconomic factors on mental adjustment in patients in the above groups. METHODS: The study included 902 patients treated on an outpatient basis at the Center of Oncology, the Maria Sklodowska-Curie Institute in Warsaw, in the year 2013. The study participants were patients diagnosed with breast, lung, colorectal and prostate carcinoma. The Paper and Pencil Interview (PAPI) technique was applied. The questionnaire interview included demographic-type questions (socioeconomic variables) and the Mini-Mental Adjustment to Cancer (mini-MAC) scale, which measures the degree of mental adjustment to disease. RESULTS: The highest scores in the anxious preoccupation and helplessness-hopelessness subclasses were those of the lung, colorectal, breast and prostate cancer patients. In breast and lung cancer study participants, differences between individual categories distinguished due to socioeconomic features proved statistically insignificant. However, significant dependencies were observed between mental adjustment to disease and chemotherapy in the past year; though, the results differ with respect to the primary site. CONCLUSIONS: The primary site affects patient adjustment to disease. Socioeconomic factors in the area of mental adaptation differentiate colorectal carcinoma patients. PMID- 29704421 TI - Functioning of the various forms of mental health care in Poland in the years 2010-2013. Organizational, economic and financial aspects. AB - OBJECTIVES: The main objective of the study was to verify the hypothesis about the high growth rate of expenditure on the provision of mental health in the past few years. High dynamics of the expenditure increase will result in the development of a model of community psychiatry and a gradual move away from the hospital psychiatric treatment towards mental health care in the open system, including the community one. METHODS: This research is based on data on the implementation of services for mental health care in the framework of agreements with the National Health Fund, which has been collected in the NFZ IT system. Some information is from 2010, which was adopted as the base date for the implementation of the principles of the National Mental Health Program in 2011. The data from the implementation of individual benefits in 2013 were used for the comparison. In addition, other selected organizational, economic and financial elements of the psychiatric care system were analyzed. RESULTS: In 2013, compared to 2010, increased the number of mental health care organizations: outpatient mental health clinics (an increase of 37 clinics), outpatient mental health day hospital wards (an increase of 25 wards) and community psychiatric treatment teams (an increase of 74 teams). The largest increase in the value of contracts (approx. 150%) was related to community treatment teams. CONCLUSIONS: Between 2010 and 2013 there was an increase in the value of cleared contracts in psychiatric care, in general and in each of the three forms of psychiatric care (i.e., in day wards, outpatient mental health clinics and in community teams). The highest increase in investments included community treatment teams, to a lesser extent day wards and outpatient clinics. The adopted organizational, economic and financial solutions in the mental health care system are in line with the objectives of the National Mental Health Program, including the assumed structure of Mental Health Centers. PMID- 29704422 TI - The "PsychoZak" program - an example of using positive concepts of mental health in practice. AB - For years experts have been advocating the need to develop an individual's health potential, which enables him/her to maintain health and improve his/her effective functioning in difficult situations. A number of positive mental health models have been created, among others: the functional model of mental health, the complete state model of health, the salutogenic model and the model of psychological well-being. They cover both optimal and unfavorable aspects of human functioning. The article presents an authorial program for mental health promotion - "PsychoZak", which is based on the positive concepts of mental health, a review of empirical reports concerning health promotion and on the target group's expectations. The program is addressed to young adults studying at universities as well as final-year secondary school students. Its aim is to strengthen students' psychological, emotional, somatic, and social well-being. It can be used by higher education institutions and thus be a tool satisfying the demand for mental health promotion at universities. PMID- 29704423 TI - Revision of Antoni Kepinski's concept of information metabolism. AB - Information metabolism is a key model for describing psychiatric life in the works of a Polish psychiatrist, Antoni Kepinski. Due to the significance of Kepinski's writings on the psychiatric environment in Poland, and also its influence on the cultural life, a significant interpretative trend of this concept was subject to a critical analysis, a trend which relies on identifying information metabolism with the so-called biological model. The biological model is a postulate appearing in Kepinski's writings to describe issues concerning psyche in analogy to the somatic structures of an organism, especially the biology of a cell. This fragment of Kepinski's work was the main reason for his subsequent criticism. This article proves that the concept of information metabolism itself does not include the biological model. Eventually, an example has been provided to show the topicality of the system of Kepinski's information metabolism in relation to the concept of somatic markers of Antonio Damasio. PMID- 29704424 TI - The role of corticostriatal-hypothalamic neural circuits in feeding behaviour: implications for obesity. AB - Emerging evidence from human imaging studies suggests that obese individuals have altered connectivity between the hypothalamus, the key brain region controlling energy homeostasis, and cortical regions involved in decision-making and reward processing. Historically, animal studies have demonstrated that the lateral hypothalamus is the key hypothalamic region involved in feeding and reward. The lateral hypothalamus is a heterogeneous structure comprised of several distinct types of neurons which are scattered throughout. In addition, the lateral hypothalamus receives inputs from a number of cortical brain regions suggesting that it is uniquely positioned to be a key integrator of cortical information and metabolic feedback. In this review, we summarize how human brain imaging can inform detailed animal studies to investigate neural pathways connecting cortical regions and the hypothalamus. Here, we discuss key cortical brain regions that are reciprocally connected to the lateral hypothalamus and are implicated in decision-making processes surrounding food. PMID- 29704425 TI - PHBV-TiO2 mats prepared by electrospinning technique: Physico-chemical properties and cytocompatibility. AB - One of the most important challenges in tissue engineering research is the development of biomimetic materials. In this present study, we have investigated the effect of the titanium dioxide (TiO2 ) nanoparticles on the properties of electrospun mats of poly (hydroxybutyrate-co-3-hydroxyvalerate) (PHBV), to be used as scaffold. The morphology of electrospun fibers was observed by scanning electron microscopy (SEM). Both pure PHBV and nanocomposites fibers were smooth and uniform. However, there was an increase in fiber diameter with the increase of TiO2 concentration. Thermal properties of PHBV and nanocomposite mats were characterized by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). DSC analysis showed that the crystallization temperature for PHBV shifts to higher temperature in the presence of the nanoparticles, indicating that TiO2 nanoparticles change the process of crystallization of PHBV due to heterogeneous nucleation effect. TGA showed that in the presence of the nanoparticles, the curves are shifted to lower temperatures indicating a decreasing in thermal stability of nanocomposites compared to pure PHBV. To produce scaffolds for tissue engineering, it is important to evaluate the biocompatibility of the material. Cytotoxicity assay showed that TiO2 nanoparticles were not cytotoxic for cells at the concentration used to synthesize the mats. The proliferation of cells on the mats was evaluated by the MTT assay. Results showed that the nanocomposite samples increased cell proliferation compared to the pure PHBV. These results indicate that continuous electrospun fibrous scaffolds may be a good substrate for tissue regeneration. PMID- 29704426 TI - Epidemiological and molecular investigation of a measles outbreak in Punjab, Pakistan, 2013-2015. AB - Despite the availability of an effective vaccine, the measles virus continues to cause significant morbidity and mortality in children worldwide. Molecular characterization of wild-type measles strains is an invaluable component of epidemiological studies or surveillance systems that provides important information pertinent to outbreak linkages and transmission pathways. Serum samples and throat swabs were collected from suspected measles cases from the Punjab province of Pakistan (2013-2015) and further tested for measles immunoglobulin M (IgM) through enzyme-linked immunosorbent assay and reverse transcriptase polymerase chain reaction for molecular characterization. Among the total of 5415 blood samples, 59% tested positive for measles IgM. Males had a higher infection rate (55%) than females (45%), and the highest frequency of positive cases (63%) was found in the age group of 0 to 5 years. Partial sequencing of the nucleoprotein gene showed that 27 strains belonged to the B3 genotype, whereas 2 viruses were identified as D4. On phylogenetic analysis, Pakistani B3 strains were found to be closely related to previously reported indigenous strains and those from neighboring countries of Iran and Qatar. This is the first report on the detection of the measles B3 genotype from Punjab, Pakistan. The current study shows a high burden of measles infections in Punjab province owing to poor routine immunization coverage in major cities. It is imperative that national health authorities adopt strategic steps on an urgent basis for improvement of routine immunization coverage. Molecular epidemiology of the measles viruses circulating in different parts of the country can provide useful data to manage future outbreaks. PMID- 29704428 TI - Sleep disturbance in psoriasis: a case-controlled study. AB - BACKGROUND: Sleep is essential for daytime functioning and health. Given the physical symptoms of psoriasis, a higher prevalence of sleep disorders can be expected. So far, the studies examining sleep disturbance in psoriasis have been of less-than-optimal methodological quality and with mixed results. OBJECTIVES: To examine the prevalence of sleep disturbance in patients with plaque psoriasis compared with a control group, to evaluate associations with health-related quality of life (HRQoL) and examine possible disease-related predictors of disturbed sleep. METHODS: We used a cross-sectional, case-controlled design. Participants included 179 consecutively recruited patients with plaque psoriasis and 105 controls. Measures included psoriasis severity (Psoriasis Area and Severity Index); HRQoL (Dermatology Life Quality Index); insomnia severity [Insomnia Severity Index (ISI)]; sleep quality [Pittsburgh Sleep Quality Index (PSQI)]; stress (Perceived Stress Scale); itch (Itch Severity Scale); and depressive symptoms (Beck Depression Inventory). Analyses included group comparisons and regression analyses to identify predictors of sleep disturbance. RESULTS: A total of 25% of patients with psoriasis reported clinical insomnia (ISI > 15), compared with 10.5% of controls. In all, 53.6% of patients with psoriasis were poor sleepers (PSQI > 5), compared with 21.9% of controls. Itch was statistically significantly associated with all sleep-related outcomes. CONCLUSIONS: A higher proportion of patients with psoriasis experience poor sleep than controls from the general population. Itch was the main predictor of impaired sleep. Improved control of psoriasis with decreased itch may improve sleep disturbance in psoriasis. PMID- 29704427 TI - Cancer/testis antigen-Plac1 promotes invasion and metastasis of breast cancer through Furin/NICD/PTEN signaling pathway. AB - Placenta-specific protein 1 (Plac1) is a cancer/testis antigen that plays a critical role in promoting cancer initiation and progression. However, the clinical significance and mechanism of Plac1 in cancer progression remain elusive. Here, we report that Plac1 is an important oncogenic and prognostic factor, which physically interacts with Furin to drive breast cancer invasion and metastasis. We have shown that Plac1 expression positively correlates with clinical stage, lymph node metastasis, hormone receptor status, and overall patient survival. Overexpression of Plac1 promoted invasion and metastasis of breast cancer cells in vitro and in vivo. Co-immunoprecipitation and immunofluorescence cell staining assays revealed that interaction of Plac1 and Furin degraded Notch1 and generated Notch1 intracellular domain (NICD) that could inhibit PTEN activity. These findings are consistent with the results of microarray study in MDA-MB-231 cells overexpressing Plac1. A rescue study showed that inhibition of Furin and overexpression of PTEN in Plac1 overexpression cells blocked Plac1-induced tumor cell progression. Taken together, our findings suggest that functional interaction between Plac1 and Furin enhances breast cancer invasion and metastasis and the Furin/NICD/PTEN axis may act as an important therapeutic target for breast cancer treatment. PMID- 29704429 TI - Insights into optic pathway glioma vision loss from mouse models of neurofibromatosis type 1. AB - Neurofibromatosis type 1 (NF1) is a common cancer predisposition syndrome caused by mutations in the NF1 gene. The NF1-encoded protein (neurofibromin) is an inhibitor of the oncoprotein RAS and controls cell growth and survival. Individuals with NF1 are prone to developing low-grade tumors of the optic nerves, chiasm, tracts, and radiations, termed optic pathway gliomas (OPGs), which can cause vision loss. A paucity of surgical tumor specimens and of patient derived xenografts for investigative studies has limited our understanding of human NF1-associated OPG (NF1-OPG). However, mice genetically engineered to harbor Nf1 gene mutations develop optic gliomas that share many features of their human counterparts. These genetically engineered mouse (GEM) strains have provided important insights into the cellular and molecular determinants that underlie mouse Nf1 optic glioma development, maintenance, and associated vision loss, with relevance by extension to human NF1-OPG disease. Herein, we review our current understanding of NF1-OPG pathobiology and describe the mechanisms responsible for tumor initiation, growth, and associated vision loss in Nf1 GEM models. We also discuss how Nf1 GEM and other preclinical models can be deployed to identify and evaluate molecularly targeted therapies for OPG, particularly as they pertain to future strategies aimed at preventing or improving tumor associated vision loss in children with NF1. PMID- 29704431 TI - Transanal total mesorectal excision with retro-ileal colorectal anastomosis: combining old and new techniques. PMID- 29704430 TI - Calcium/calmodulin-dependent kinase II and memory destabilization: a new role in memory maintenance. AB - In this review, we discuss the poorly explored role of calcium/calmodulin dependent protein kinase II (CaMKII) in memory maintenance, and its influence on memory destabilization. After a brief review on CaMKII and memory destabilization, we present critical pieces of evidence suggesting that CaMKII activity increases retrieval-induced memory destabilization. We then proceed to propose two potential molecular pathways to explain the association between CaMKII activation and increased memory destabilization. This review will pinpoint gaps in our knowledge and discuss some 'controversial' observations, establishing the basis for new experiments on the role of CaMKII in memory reconsolidation. The role of CaMKII in memory destabilization is of great clinical relevance. Still, because of the lack of scientific literature on the subject, more basic science research is necessary to pursue this pathway as a clinical tool. PMID- 29704432 TI - Secukinumab shows high efficacy irrespective of HLA-Cw6 status in patients with moderate-to-severe plaque-type psoriasis: SUPREME study. AB - BACKGROUND: Understanding genetic variations is important in predicting treatment response and forms the basis for identifying new pharmacogenetic and pharmacogenomic targets for psoriasis treatment. There are limited data on the efficacy of secukinumab in relation to genetic markers. OBJECTIVES: To evaluate the efficacy and safety of secukinumab 300 mg in HLA-Cw6-positive (Cw6-POS) and HLA-Cw6-negative (Cw6-NEG) patients with moderate-to-severe chronic plaque-type psoriasis. METHODS: SUPREME was a 24-week, phase IIIb study with an extension period up to 72 weeks. Primary end point was Psoriasis Area Severity Index (PASI) 90 response rate after 16 weeks. RESULTS: In total, 434 patients were recruited: 185 (42.6%) were Cw6-POS and 246 (56.7%) were Cw6-NEG (three not assessed). Mean +/- SD age was 45.2 +/- 13.2 years (Cw6-POS 42.7 +/- 13.1; Cw6-NEG 47.2 +/- 12.9). The baseline PASI score was comparable between the cohorts [Cw6-POS 20.7 +/- 8.99; Cw6-NEG 21.5 +/- 9.99 (P = 0.777)]. At week 16, PASI 90 was achieved in 80.4% of Cw6-POS and 79.7% of Cw6-NEG patients (difference 0.76; 95% confidence interval -7.04 to 8.23). No differences in absolute PASI at week 16 (Cw6-POS 1.36 +/- 3.58; Cw6-NEG 1.18 +/- 2.29) were observed. The overall safety profile of secukinumab was consistent with that previously reported. No statistically significant difference was detected in the rate of treatment-emergent adverse events [Cw6-POS 42.7%; Cw6-NEG 49.6% (P = 0.295)]. A high PASI 90 response was achieved with secukinumab with a fast reduction in absolute PASI. CONCLUSIONS: Determination of HLA-Cw6 status for secukinumab therapy is unnecessary, as it is highly effective regardless of HLA-Cw6 status. PMID- 29704434 TI - Diagnostic accuracy of SCCA and SCCA-IgM for hepatocellular carcinoma: A meta analysis. AB - BACKGROUND & AIMS: Squamous cell carcinoma antigen (SCCA) and its immune complex (SCCA-IgM) have been proposed for use in the screening of hepatocellular carcinoma (HCC). We conducted a meta-analysis to evaluate the diagnostic performance of SCCA and SCCA-IgM and of both combined with alpha-foetoprotein. METHODS: After a systematic review of the relevant studies, the sensitivity, specificity, positive and negative likelihood ratios, diagnostic odds ratio (DOR) and area under curve (AUC) for the diagnosis of HCC were pooled using bivariate meta-analysis. Hierarchic summary receiver operating characteristic curves were used to summarize the overall test performance. Bivariate boxplots were used to confirm whether the threshold effect existed. A Fagan nomogram was used to assess the clinical utility. Heterogeneity was explored by sensitivity analysis, univariable meta-regression and subgroup analysis. RESULTS: Eleven studies that had HCC diagnosis as their purpose were ultimately included in the quantitative analysis. The summary estimates were as follows: SCCA (AUC: 0.80 [95% CI: 0.76 0.83]) and SCCA-IgM (AUC: 0.77 [95% CI: 0.74-0.83]) demonstrated similar diagnostic performance, while a combination of AFP and SCCA-IgM had an AUC of 0.90 (95% CI: 0.87-0.92) and a DOR of 22.87 (95% CI: 8.38-62.40). Meta-regression showed that patient selection, cut-off values, reference standards and tumour biopsy as the diagnostic method significantly influenced the heterogeneity of the included studies. CONCLUSIONS: Both SCCA and SCCA-IgM showed a moderate diagnostic accuracy for HCC screening; the combination of SCCA-IgM and AFP is the best diagnostic option. PMID- 29704433 TI - Retrievable hydrogels for ovarian follicle transplantation and oocyte collection. AB - Cancer survivorship rates have drastically increased due to improved efficacy of oncologic treatments. Consequently, clinical concerns have shifted from solely focusing on survival to quality of life, with fertility preservation as an important consideration. Among fertility preservation strategies for female patients, ovarian tissue cryopreservation and subsequent reimplantation has been the only clinical option available to cancer survivors with cryopreserved tissue. However, follicle atresia after transplantation and risk of reintroducing malignant cells have prevented this procedure from becoming widely adopted in clinics. Herein, we investigated the encapsulation of ovarian follicles in alginate hydrogels that isolate the graft from the host, yet allows for maturation after transplantation at a heterotopic (i.e., subcutaneous) site, a process we termed in vivo follicle maturation. Survival of multiple follicle populations was confirmed via histology, with the notable development of the antral follicles. Collected oocytes (63%) exhibited polar body extrusion and were fertilized by intracytoplasmic sperm injection and standard in vitro fertilization procedures. Successfully fertilized oocytes developed to the pronucleus (14%), two-cell (36%), and four-cell (7%) stages. Furthermore, ovarian follicles cotransplanted with metastatic breast cancer cells within the hydrogels allowed for retrieval of the follicles, and no mice developed tumors after removal of the implant, confirming that the hydrogel prevented seeding of disease within the host. Collectively, these findings demonstrate a viable option for safe use of potentially cancer-laden ovarian donor tissue for in vivo follicle maturation within a retrievable hydrogel and subsequent oocyte collection. Ultimately, this technology may provide novel options to preserve fertility for young female patients with cancer. PMID- 29704435 TI - Impaired oxidative status as a potential predictor in clinical manifestations of herpes zoster. AB - Oxidative stress, caused by an imbalance between reactive oxygen species and antioxidants, is related to many dermatologic diseases. Increased reactive oxygen species is also associated with various decreased T-cell immune responses. The incidence and severity of herpes zoster (HZ), which is caused by the reactivation of varicella-zoster virus, increase with age because of declining cell-mediated immunity. The main purpose of this study was to assess the levels of oxidative stress biomarkers in patients with HZ compared with control subjects. In this case-control study, the serum levels of total antioxidant capacity (TAC), total oxidant status (TOS), oxidative stress index, glutathione, superoxide dismutase, and total polyphenol content (TPC) in 43 patients with HZ and 47 age-matched controls were determined, and their biomarker patterns were compared. TAC and TPC levels were significantly lower in patients with HZ; however, TOS and oxidative stress index levels were significantly higher in comparison with the control (P < .001). In addition, a significantly strong negative correlation was found between TAC and TPC with TOS levels in patients with HZ (r = -.79, P < .001; r = -.81, P < .001, respectively). Our findings showed an oxidative stress imbalance in HZ. Whether this change correlates with HZ pathogenesis or is a consequence of the inflammatory response to HZ needs more investigation. PMID- 29704436 TI - Interaction with SP1, but not binding to the E-box motifs, is responsible for BHLHE40/DEC1-induced transcriptional suppression of CLDN1 and cell invasion in MCF-7 cells. AB - Basic helix-loop-helix family member e40 (BHLHE40) is located in 3p26.1 and acts as a transcriptional repressor of the circadian rhythm by suppressing the expression of the clock genes and clock-controlled genes. Recent research indicated that BHLHE40 may be involved in regulating tumor cell progression. However the mechanism by which BHLHE40 regulates the invasion and metastasis of tumor cells is unclear. Our in vitro assays showed that BHLHE40 promoted tumor cell invasion while BHLHE40 silencing by siRNA suppressed tumor cell invasion of MCF-7 cells. BHLHE40 suppressed the mRNA and protein expression of CLDN1 CLDN4 and CDH1 and promoted the expression of SNAI1 and SNAI2. Reporter assays demonstrated that BHLHE40 suppressed CLDN1 transcription but not through direct binding to the E-box motifs in the CLDN1 promoter. Further studies demonstrated BHLHE40 suppressed CLDN1 transcription by preventing the interaction between SP1 and a specific motif within the promoter region of CLDN1. BHLHE40 could not further suppress CLDN1 transactivation after SP1 siRNA transfection that is, BHLHE40-induced suppression of CLDN1 relied on SP1. Furthermore our data indicated that SP1 was a major regulator of CLDN1 transcription by binding to a specific motif that was located at -233 to -61 bp upstream of the transcription start site. Immunoprecipitation and co-localization data revealed an interaction between BHLHE40 and SP1. By constructing deletion mutants we found that the BHLH and Orange regions are both essential for the BHLHE40-SP1 interaction. BHLHE40 probably acts as an inhibitory nuclear cofactor or perhaps recruits other inhibitory cofactors to inhibit the SP1-mediated CLDN1 transactivation. These results suggest that BHLHE40 facilitates cell invasion and may be used as a novel target for breast cancer prevention and treatment. PMID- 29704437 TI - A Randomized Controlled Trial of Subcutaneous Nerve Stimulation for Back Pain Due to Failed Back Surgery Syndrome: The SubQStim Study. AB - OBJECTIVES: To compare the effectiveness of peripheral nerve stimulation utilizing a subcutaneous lead implant technique-subcutaneous nerve stimulation (SQS) plus optimized medical management (SQS + OMM arm) vs. optimized medical management alone (OMM arm) in patients with back pain due to failed back surgery syndrome. PATIENTS AND METHODS: Patients were recruited from 21 centers, in Europe, Israel, and Australia. Eligible patients were randomized (1:1) to SQS + OMM or OMM arms. Those in the SQS arm were implanted with a neurostimulator and up to two subcutaneous percutaneous cylindrical leads in the area of pain. Patients were evaluated pre-randomization and at one, three, six, and nine months post-randomization. The primary endpoint was the proportion of subjects with a >=50% reduction in back pain intensity ("responder") from baseline to nine months. Secondary outcomes included proportion of responders with a >=50% reduction in back pain intensity at six months and >=30% reduction at nine months, and the mean change from baseline in back pain intensity at six and nine months between the two arms. RESULTS: Due to the slow rate of recruitment, the study was terminated early with 116 subjects randomized. A total of 33.9% (19/56, missing: n = 20 [36%]) of subjects in the SQS + OMM arm and 1.7% (1/60, missing: n = 24 [40%]) in the OMM arm were responders at Month 9 (p < 0.0001). Secondary objectives showed a significant difference in favor of SQS + OMM arm. CONCLUSION: The results indicate that the addition of SQS to OMM is more effective than OMM alone in relieving low back pain at up to nine months. PMID- 29704438 TI - CRISPR interference-mediated metabolic engineering of Corynebacterium glutamicum for homo-butyrate production. AB - Combinatorial metabolic engineering enabled the development of efficient microbial cell factories for modulating gene expression to produce desired products. Here, we report the combinatorial metabolic engineering of Corynebacterium glutamicum to produce butyrate by introducing a synthetic butyrate pathway including phosphotransferase and butyrate kinase reactions and repressing the essential acn gene-encoding aconitase, which has been targeted for downregulation in a genome-scale model. An all-in-one clustered regularly interspaced short palindromic repeats interference system for C. glutamicum was used for tunable downregulation of acn in an engineered strain, where by-product forming reactions were deleted and the synthetic butyrate pathway was inserted, resulting in butyrate production (0.52 +/- 0.02 g/L). Subsequently, biotin limitation enabled the engineered strain to produce butyrate (0.58 +/- 0.01 g/L) without acetate formation for the entire duration of the culture. These results demonstrate the potential homo-production of butyrate using engineered C. glutamicum. This method can also be applied to other industrial microorganisms. PMID- 29704439 TI - Histone deacetylase inhibitor chidamide promotes reactivation of latent human immunodeficiency virus by introducing histone acetylation. AB - Highly active antiretroviral therapy can reduce the human immunodeficiency virus (HIV) viral load in the plasma to undetectable levels. However, because of the presence of latent HIV reservoirs, it is difficult to completely eradicate HIV in infected patients. Our objective was to assess the potency of chidamide, a novel histone deacetylase inhibitor recently approved for cancer treatment by the China Food and Drug Administration, to reactivate latent HIV-1 via histone acetylation. Viral reactivities of chidamide were accessed in 2 latent HIV pseudotype virus cell reporter systems (J-Lat Tat-green fluorescent protein clone A72 and TZM-bl), a latently infected full-length HIV virus cell system (U1/HIV), and resting CD4+ T cells from 9 HIV-infected patients under highly active antiretroviral therapy with undetectable viral load. Chidamide was able to increase HIV expression in each cell line, as evidenced by green fluorescent protein, luciferase activity, and p24, as well as to reactivate latent HIV-1 in primary CD4+ T cells of HIV infected patients. Histone acetylation adjacent to the HIV promoter in A72 cells was determined by chromatin immunoprecipitation. Chidamide was able to increase histone H3 and H4 acetylation at the HIV promoter. In brief, chidamide induced the reactivation of latent HIV in pseudotype virus reporter cells, latently infected cells, and primary CD4+ T cells, making this compound an attractive option for future clinical trials. PMID- 29704440 TI - Development and implementation of EPID-based quality assurance tests for the small animal radiation research platform (SARRP). AB - PURPOSE: Although small animal image-guided radiotherapy (SA-IGRT) systems are used increasingly in preclinical research, tools for performing routine quality assurance (QA) have not been optimized and are not readily available. Robust, efficient, and reliable QA tools are needed to ensure the accuracy and reproducibility of SA-IGRT systems. Several investigators have reported custom made phantoms and protocols for SA-IGRT systems QA. These are typically time and resource intensive and are therefore not well suited to the preclinical radiotherapy environment, in which physics support is limited and routine QA is performed by technical staff. We investigated the use of the inbuilt electronic portal imaging device (EPID) to develop and validate routine QA tests and procedures. In this work, we focus on the Xstrahl Small Animal Radiation Research Platform (SARRP) EPID. However, the methodology and tests developed here are applicable to any SA-IGRT system that incorporates an EPID. METHODS: We performed a comprehensive characterization of the dosimetric properties of the camera-based EPID at kilovoltage energies over a 11-month period, including detector warm-up time, radiation dose history effect, stability and short- and long-term reproducibility, gantry angle dependency, output factor, and linearity of the EPID response. We developed a test to measure the constancy of beam quality in terms of half-value layer and tube peak potential using the EPID. We verified the SARRP daily output and beam profile constancy using the imager. We investigated the use of the imager to monitor beam-targeting accuracy at various gantry and couch angles. RESULTS: The EPID response was stable and reproducible, exhibiting maximum variations of <=0.3% and <=1.9% for short and long terms, respectively. The detector showed no dependence on response at different gantry angles, with a maximum variation <=0.5%. We found close agreement in output factor measurement between the portal imager and reference dosimeters, with maximum differences <=3% for ionization chamber and <=1.7% for Gafchromic EBT3 dosimetry film, respectively. We have shown that the EPID response is linear with tube current (mA) for the entire range of tube kilovoltage peak. Notably, a close relationship was seen between the detector response vs mA slope, and the kilovoltage peak, allowing an independent verification of kilovoltage peak stability based solely on EPID response. In addition to dosimetry tests, according to the beam-targeting measurement using portal images, maximum displacement of the central axis of the x-ray beam (due to sag) was 0.76 +/- 0.09 mm at gantry 135 degrees /couch 0 degrees and 0.89 +/- 0.06 mm at gantry 0 degrees /couch -135 degrees . CONCLUSION: We performed the first comprehensive analysis on the dosimetric properties of an EPID operating at kilovoltage x-ray energies. We characterized the detector performance over a 11-month period. Our results indicate that the imager is a stable and convenient tool for SARRP routine QA tests. We then developed EPID-based tests to perform routine SA-IGRT systems QA tasks, such as verifying constancy of beam quality, energy, output, and profile measurements, relative output factors, and beam targeting. PMID- 29704441 TI - Improving culture performance and antibody production in CHO cell culture processes by reducing the Warburg effect. AB - Lactate is one of the key waste metabolites of mammalian cell culture. High lactate levels are caused by high aerobic glycolysis, also known as the Warburg effect, and are usually associated with adverse culture performance. Therefore, reducing lactate accumulation has been an ongoing challenge in the cell culture development to improve growth, productivity, and process robustness. The pyruvate dehydrogenase complex (PDC) plays a crucial role for the fate of pyruvate, as it converts pyruvate to acetyl coenzyme A (acetyl-CoA). The PDC activity can be indirectly increased by inhibiting the PDC inhibitor, pyruvate dehydrogenase kinase, using dichloroacetate (DCA), resulting in less pyruvate being available for lactate formation. Here, Chinese hamster ovary cells were cultivated either with 5 mM DCA or without DCA in various batch and fed-batch bioreactor processes. In all cultures, DCA increased peak viable cell density (VCD), culture length and final antibody titer. The strongest effect was observed in a fed batch with media and glucose feeding in which peak VCD was increased by more than 50%, culture length was extended by more than 3 days, and the final antibody titer increased by more than twofold. In cultures with DCA, lactate production and glucose consumption during exponential growth were on average reduced by approximately 40% and 35%, respectively. Metabolic flux analysis showed reduced glycolytic fluxes, whereas fluxes in the tricarboxylic acid (TCA) cycle were not affected, suggesting that cultures with DCA use glucose more efficiently. In a proteomics analysis, only few proteins were identified as being differentially expressed, indicating that DCA acts on a posttranslational level. Antibody quality in terms of aggregation, charge variant, and glycosylation pattern was unaffected. Subsequent bioreactor experiments with sodium lactate and sodium chloride feeding indicated that lower osmolality, rather than lower lactate concentration itself, improved culture performance in DCA cultures. In conclusion, the addition of DCA to the cell culture improved culture performance and increased antibody titers without any disadvantages for cell-specific productivity or antibody quality. PMID- 29704442 TI - Factors affecting residual/recurrent cervical intraepithelial neoplasia after cervical conization with negative margins. AB - To identify factors for predicting residual or recurrent cervical intraepithelial neoplasia (CIN) after cervical conization with negative margins. A total of 172 patients with histologically verified high-grade squamous intraepithelial lesions who underwent conization with negative margins were recruited at the General Hospital of Tianjin Medical University from December 2006 to January 2016. Follow up comprised clinical examination, a liquid-based cytology test, a human papillomavirus (HPV) DNA genotyping test, colposcopy assessment, and if indicated, colposcopy-directed punch biopsy. The Kaplan-Meier method was used to analyze the median recurrent time, whereas log-rank tests and Cox regression models were used to determine the predictors of residual/recurrent CIN. Fourteen residual/recurrent cases (8.1%) were identified in 172 patients. In univariate analysis, cytologic abnormalities on follow-up (P = .000), conization method (P = .017), HPV positivity at any visit (P = .000), persistent HPV infection postconization (P = .000), persistent infection with the same HPV genotype (P = .000), and HPV positivity at 18 months after conization (P = .000) were predictive factors of residual/recurrent CIN. The results of multivariate analysis further revealed that persistent HPV infection postconization (P = .035), HPV positivity at 18 months after conization (P = .017), and cytologic abnormalities on follow-up (P = .000) had an increased risk of residual/recurrent CIN. During follow-up, patients with persistent HPV infection or cytologic abnormalities were at high risk of residual/recurrent CIN and should be identified for close surveillance and monitoring. Meanwhile, patients with HPV who became negative within 18 months after treatment had a low risk of recurrence. PMID- 29704443 TI - Is the mixture of human cytomegalovirus genotypes frequent in infants with congenital infection at birth in a high seroprevalence population? AB - It is still not well known, in a population with high human cytomegalovirus (HCMV) seroprevalence, whether a child with congenital infection harbors multiple viral strains at birth, and whether the prolonged viral excretion in these children is secondary to the persistence of the same viral strain. To verify the genomic diversity of HCMV detected in congenitally infected children, the nucleotide viral sequences from urine and/or saliva obtained at birth from 14 newborns with congenital infection and breast milk obtained from mothers of 5 of these children were analyzed. Among the 14 children, 10 had sequential samples until the median age of 10 months. The viral nucleotide sequences in the breast milk were compared with those identified in the respective children at birth. The differentiation of viral strains was based on the variability of 3 regions of viral genes (UL55/gB, UL144, and UL73/gN). In 13/14 children (92.8%), a single genotype was observed at birth. Different viral genotypes were found in 1 child (7.2%). Among the sequential samples from 10 children, the same genotype obtained at birth was detected in 9/10 (90%), and in 1 of them (10%), a genotype change in the urine was found. More than 1 HCMV strain in milk was observed in 2 mothers (2/5, 40%). In a population with high seroprevalence, a single genotype was found in the majority of infected children. Reinfection did not frequently occur in the first months of life. Maternal reinfection does not seem to be a rare event in transmitter mothers. PMID- 29704444 TI - Chromosome-level assembly, genetic and physical mapping of Phalaenopsis aphrodite genome provides new insights into species adaptation and resources for orchid breeding. AB - The Orchidaceae is a diverse and ecologically important plant family. Approximately 69% of all orchid species are epiphytes, which provide diverse microhabitats for many small animals and fungi in the canopy of tropical rainforests. Moreover, many orchids are of economic importance as food flavourings or ornamental plants. Phalaenopsis aphrodite, an epiphytic orchid, is a major breeding parent of many commercial orchid hybrids. We provide a high quality chromosome-scale assembly of the P. aphrodite genome. The total length of all scaffolds is 1025.1 Mb, with N50 scaffold size of 19.7 Mb. A total of 28 902 protein-coding genes were identified. We constructed an orchid genetic linkage map, and then anchored and ordered the genomic scaffolds along the linkage groups. We also established a high-resolution pachytene karyotype of P. aphrodite and completed the assignment of linkage groups to the 19 chromosomes using fluorescence in situ hybridization. We identified an expansion in the epiphytic orchid lineage of FRS5-like subclade associated with adaptations to the life in the canopy. Phylogenetic analysis further provides new insights into the orchid lineage-specific duplications of MADS-box genes, which might have contributed to the variation in labellum and pollinium morphology and its accessory structure. To our knowledge, this is the first orchid genome to be integrated with a SNP based genetic linkage map and validated by physical mapping. The genome and genetic map not only offer unprecedented resources for increasing breeding efficiency in horticultural orchids but also provide an important foundation for future studies in adaptation genomics of epiphytes. PMID- 29704445 TI - Technical Note: A feasibility study of using the flat panel detector on linac for the kV x-ray generator test. AB - PURPOSE: To investigate the feasibility of using kV flat panel detector on linac for consistency evaluations of kV x-ray generator performance. METHODS: An in house designed aluminum (Al) array phantom with six 9 * 9 cm2 square regions having various thickness was proposed and used in this study. Through XML script driven image acquisition, kV images with various acquisition settings were obtained using the kV flat panel detector. Utilizing pre-established baseline curves, the consistency of x-ray tube output characteristics, including tube voltage accuracy, exposure accuracy and exposure linearity was assessed through image quality assessment metrics including ROI mean intensity, ROI standard deviation (SD), and noise power spectrums (NPS). The robustness of this method was tested on two linacs for a 3-month period. RESULTS: With the proposed method, tube voltage accuracy can be verified through conscience check with a 2% tolerance and 2 kVp intervals for forty different kVp settings. The exposure accuracy can be tested with a 4% consistency tolerance for three mAs settings over forty kVp settings. The exposure linearity tested with 3 mAs settings achieved a coefficient of variation (CV) of 0.1. CONCLUSION: We proposed a novel approach that uses the kV flat panel detector available on linac for x-ray generator test. This approach eliminates the inefficiencies and variability associated with using third-party QA detectors while enabling an automated process. PMID- 29704446 TI - Decreased protein C function predicts mortality in patients with cirrhosis. AB - INTRODUCTION: Protein C (PrC), a physiological anticoagulant, regulates inflammation and cell death and has known predictive/therapeutic roles in sepsis. Accumulating evidences suggest plasma hypercoagulability results in progression of fibrosis and formation of microclots causing end-organ dysfunction. We investigated a possible association between natural anticoagulants-PrC, protein S (PrS) and antithrombin III (AT)-and clinical outcomes in cirrhotics. METHODS: Functional PrC, PrS and AT were analysed in 515 cirrhotic patients and compared with 229 noncirrhotics. Among those with cirrhosis, we conducted multivariable predictive model on 3-month survival to assess the prognostic ability of anticoagulants. RESULTS: Protein C (P < .001), PrS (P < .001) and AT (P < .001) levels were lower in cirrhotics compared with noncirrhotics. In addition, patients with Child-Pugh (CP)-C had significantly lower (P < .05) functional PrC, PrS and AT levels than CP-B, CP-A and noncirrhotic patients. Low PrC function correlated with markers of liver dysfunction and inflammation: INR(r = -.72, P < .001), bilirubin (r = -.620, P < .001), albumin (r = .539, P < .001), creatinine (r = -.417, P < .001), ferritin (r = -.68, P = .035), procalcitonin (r = -.79, P = .01), raised ESR (r = .56, P < .001) and liver fibrosis (r = -.840, P < .001). Patients who died (n = 160) had significantly lower median PrC function (23.8%, 16.3-33.0]) compared with those who remained alive (74.9%, [59.7-92.5]); P < .001. In a multivariable predictive model using PrC, and MELD score, we found a significant impact of low PrC levels on survival (P < .001, IRR = 0.97, 95% CI = 0.96-0.98). Receiver operating characteristic (ROC) curve analysis revealed that functional PrC levels <52% were associated with increased mortality (P < .001). CONCLUSION: Low functional protein C level correlated with markers of liver dysfunction, inflammation and sepsis and independently predicted mortality at 3 months in cirrhotics, especially if functional levels were <52%. PMID- 29704447 TI - Spatial analysis of reported new cases and local risk of leprosy in hyper-endemic situation in Northeastern Brazil. AB - OBJECTIVE: To analyse the spatial distribution of the incidence of leprosy and identify areas at risk for occurrences of hyper-endemic disease in Northeastern Brazil. METHODS: Ecological study using municipalities as the analysis unit. Data on new cases of leprosy came from the Health Hazard Notification System (SINAN). This study focused on Pernambuco and covered the years 2005 to 2014. Indicators for monitoring were calculated per 100 000 inhabitants. The local empirical Bayes method was used to minimise rate variance, and spatial autocorrelation maps were used for spatial pattern analysis (box maps and Moran maps). RESULTS: A total of 28 895 new cases were registered in the study period. The average incidence was 21.88/100 000; the global Moran's I index was 0.36 (P < 0.01), thus indicating the existence of spatial dependence; and the Moran map identified 20 municipalities with high priority for attention. The average incidence rate among individuals under 15 years of age was 8.78/100 000; the global Moran's I index showed the presence of positive spatial autocorrelation (0.43; P < 0.01), and the Moran map showed a main cluster of 15 hyper-endemic municipalities. The average rate of grade 2 physical disability at the time of diagnosis was 1.12/100 000; the global Moran index presented a positive spatial association (0.17; P < 0.01); and the Moran map located clusters of municipalities (high-high) in three mesoregions. CONCLUSION: Application of different spatial analysis methods made it possible to locate areas that would not have been identified by epidemiological indicators alone. PMID- 29704448 TI - Establishment of new complete blood count reference values for healthy Thai adults. AB - INTRODUCTION: Laboratory reference ranges are essential for diagnostic orientation and treatment decision. As complete blood count parameters are influenced by various factors, including gender, geographic origin, and ethnic origin, it is important to establish specific hematologic reference values for specific populations. METHODS: This study was conducted at the Department of Clinical Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand. Blood samples were taken from healthy adults aged 18-60 years that attended a health check-up program at our hospital during February 2015 to July 2015. Hematologic and routine chemistry analysis were performed. Participants were determined to be healthy based on medical history and routine medical examinations. Serum vitamin B12, folate, ferritin, and hemoglobin typing were also analyzed to exclude the possible presence of anemia. RESULTS: A statistically significant difference was observed between males and females for Hb level, hematocrit level, red blood cell count, mean corpuscular hemoglobin concentration, percentage neutrophils, monocytes and eosinophils, and absolute neutrophil, lymphocyte, basophil, and platelet counts. Accordingly, gender specific reference intervals were established for all complete blood count parameters in healthy Thai adult population. CONCLUSIONS: The reference value ranges established in this study reflect significant differences between genders. It is possible that these reference ranges may be generalizable to adults living in Thailand. The findings of this study emphasize the importance of establishing specific hematologic reference values for specific populations. PMID- 29704449 TI - Contribution of sea ice microbial production to Antarctic benthic communities is driven by sea ice dynamics and composition of functional guilds. AB - Organic matter produced by the sea ice microbial community (SIMCo) is an important link between sea ice dynamics and secondary production in near-shore food webs of Antarctica. Sea ice conditions in McMurdo Sound were quantified from time series of MODIS satellite images for Sept. 1 through Feb. 28 of 2007-2015. A predictable sea ice persistence gradient along the length of the Sound and evidence for a distinct change in sea ice dynamics in 2011 were observed. We used stable isotope analysis (delta13 C and delta15 N) of SIMCo, suspended particulate organic matter (SPOM) and shallow water (10-20 m) macroinvertebrates to reveal patterns in trophic structure of, and incorporation of organic matter from SIMCo into, benthic communities at eight sites distributed along the sea ice persistence gradient. Mass-balance analysis revealed distinct trophic architecture among communities and large fluxes of SIMCo into the near-shore food web, with the estimates ranging from 2 to 84% of organic matter derived from SIMCo for individual species. Analysis of patterns in density, and biomass of macroinvertebrate communities among sites allowed us to model net incorporation of organic matter from SIMCo, in terms of biomass per unit area (g/m2 ), into benthic communities. Here, organic matter derived from SIMCo supported 39 to 71 per cent of total biomass. Furthermore, for six species, we observed declines in contribution of SIMCo between years with persistent sea ice (2008-2009) and years with extensive sea ice breakout (2012-2015). Our data demonstrate the vital role of SIMCo in ecosystem function in Antarctica and strong linkages between sea ice dynamics and near-shore secondary productivity. These results have important implications for our understanding of how benthic communities will respond to changes in sea ice dynamics associated with climate change and highlight the important role of shallow water macroinvertebrate communities as sentinels of change for the Antarctic marine ecosystem. PMID- 29704450 TI - Medical resident training in China. PMID- 29704451 TI - Opportunities and challenges in the current era of global medical education. PMID- 29704452 TI - Neuroprotective Effect of omega-3 Polyunsaturated Fatty Acids on Bilirubin Encephalopathy In Vitro and In Vivo. AB - BACKGROUND Bilirubin encephalopathy is a serious complication in neonatal jaundice and is associated with high mortality and disability in newborns. The present study aimed to investigate the neuroprotective effects of omega-3 polyunsaturated fatty acids (omega-3 PUFA) on bilirubin encephalopathy in vitro and in vivo. MATERIAL AND METHODS The cytotoxicity of unconjugated bilirubin (UCB) to neurons and neuroprotection of omega-3 PUFA were investigated using MTT assays and apoptosis evaluations. Superoxide dismutase (SOD) and catalase (CAT) enzyme activity were measured to investigate the anti-oxidative effect of omega-3 PUFA. The differences between eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) were also compared. The in vivo neuroprotective effect of DHA was demonstrated in neonatal rats with bilirubin encephalopathy by bilirubin monitoring, neuron-specific enolase (NSE) monitoring, H&E staining of brain tissue, and apoptosis rate evaluations. RESULTS Omega-3 PUFA reduced the rate of apoptosis induced by UCB and increased SOD and CAT enzyme activity for anti oxidation. DHA did not reduce the bilirubin in the serum of neonatal rats with bilirubin encephalopathy, but did reduce the damage caused by bilirubin with decreased NSE and apoptosis rate as well as improved neuron morphology. CONCLUSIONS Omega-3 PUFA, particularly DHA, can reduce neurological damage in neonatal rats with bilirubin encephalopathy by increasing anti-apoptosis and anti oxidation effects against UCB, providing a theoretical basis for the clinical treatment of bilirubin encephalopathy in newborns. PMID- 29704453 TI - Elevated total serum IgE in vitiligo might be protective for other autoimmune diseases. PMID- 29704454 TI - Accumulation of 24 nucleotide transgene-derived siRNAs is associated with crinivirus immunity in transgenic plants. AB - RNA silencing is a conserved antiviral defence mechanism that has been used to develop robust resistance against plant virus infections. Previous efforts have been made to develop RNA silencing-mediated resistance to criniviruses, yet none have given immunity. In this study, transgenic Nicotiana benthamiana plants harbouring a hairpin construct of the Lettuce infectious yellows virus (LIYV) RNA dependent RNA polymerase (RdRp) sequence exhibited immunity to systemic LIYV infection. Deep sequencing analysis was performed to characterize virus-derived small interfering RNAs (vsiRNAs) generated on systemic LIYV infection in non transgenic N. benthamiana plants as well as transgene-derived siRNAs (t-siRNAs) derived from the immune-transgenic plants before and after LIYV inoculation. Interestingly, a similar sequence distribution pattern was obtained with t-siRNAs and vsiRNAs mapped to the transgene region in both immune and susceptible plants, except for a significant increase in t-siRNAs of 24 nucleotides in length, which was consistent with small RNA northern blot results that showed the abundance of t-siRNAs of 21, 22 and 24 nucleotides in length. The accumulated 24-nucleotide sequences have not yet been reported in transgenic plants partially resistant to criniviruses, and thus may indicate their correlation with crinivirus immunity. To further test this hypothesis, we developed transgenic melon (Cucumis melo) plants immune to systemic infection of another crinivirus, Cucurbit yellow stunting disorder virus (CYSDV). As predicted, the accumulation of 24-nucleotide t-siRNAs was detected in transgenic melon plants by northern blot. Together with our findings and previous studies on crinivirus resistance, we propose that the accumulation of 24-nucleotide t-siRNAs is associated with crinivirus immunity in transgenic plants. PMID- 29704455 TI - New insights on the functional role of URG7 in the cellular response to ER stress. AB - BACKGROUND INFORMATION: Up-regulated Gene clone 7 (URG7) is an ER resident protein, whose expression is up-regulated in the presence of hepatitis B virus X antigen (HBxAg) during HBV infection. In virus-infected hepatocytes, URG7 shows an anti-apoptotic activity due to the PI3K/AKT signalling activation, does not seem to have tumorigenic properties, but it appears to promote the development and progression of fibrosis. However, the molecular mechanisms underlying URG7 activity remain largely unknown. RESULTS: To shed light on URG7 activity, we first analysed its interactome in HepG2 transfected cells: this analysis suggests that URG7 could have a role in affecting protein synthesis, folding and promoting proteins degradation. Moreover, keeping into account its subcellular localisation in the ER and that several viral infections give rise to ER stress, a panel of experiments was performed to evaluate a putative role of URG7 in ER stress. Our main results demonstrate that in ER-stressed cells URG7 is able to modulate the expression of Unfolded Protein Response (UPR) markers towards survival outcomes, up-regulating GRP78 protein and down-regulating the pro-apoptotic protein CHOP. Furthermore, URG7 reduces the ER stress by decreasing the amount of unfolded proteins, by increasing both the total protein ubiquitination and the AKT activation and reducing Caspase 3 activation. CONCLUSIONS: All together these data suggest that URG7 plays a pivotal role as a reliever of ER stress-induced apoptosis. SIGNIFICANCE: This is the first characterisation of URG7 activity under ER stress conditions. The results presented here will help to hypothesise new strategies to counteract the antiapoptotic activity of URG7 in the context of the viral infection. PMID- 29704456 TI - Tretinoin (0.05% cream vs. 5% peel) for photoaging and field cancerization of the forearms: randomized, evaluator-blinded, clinical trial. AB - BACKGROUND: Topical tretinoin cream is the gold standard treatment for skin ageing, particularly photoaging. The purpose of tretinoin peel was to obtain similar results, but in a shorter time, however, there have been few controlled trials on its effectiveness. OBJECTIVE: To compare efficacy and safety of tretinoin 0.05% cream and 5% as a peeling agent on photoaging and field cancerization of the forearms. METHODS: Clinical trial with therapeutic intervention, prospective, randomized (computer-generated randomization list), parallel, comparative (intrasubject) and evaluator-blinded (except for histology and immunohistochemistry), including 24 women (48 forearms) aged over 60 years who have not undergone hormone replacement and categorized as Fitzpatrick skin phototype II or III. The forearms of the participants were randomized for treatment with 0.05% tretinoin cream three nights a week, or 5% tretinoin peel every 2 weeks. The opinion of the participant, severity of photoaging, corneometry, profilometry, high-frequency ultrasound, histology (haematoxylin eosin and Verhoeff stainings) and immunohistochemistry (p53, bcl-2, Ki67 and collagen I) were assessed. RESULTS: One participant dropped out. The mean photoaging score reduced 20% and the mean actinic keratosis (AK) count reduced 60% with no difference between treatments. Three efficacy parameters showed opposite effects between the tretinoin treatments (P < 0.05%): (i) thickness of the corneal layer decreased with 0.05% tretinoin and increased by 5%; (ii) dermis echogenicity increased by 0.05% and decreased by 5% and (iii) Ki67 expression increased by 0.05% and decreased by 5%. There was good tolerability for both regimens. CONCLUSION: Tretinoin as a cream 0.05% or peeling (5%) is safe and effective for the treatment of moderate photoaging and forearm field cancerization. The cream was superior in improving ultrasonographic parameters of ageing. Peeling was shown a superior performance in the stabilization of field cancerization. PMID- 29704457 TI - Substitution of sodium chloride by salt microspheres in dough: Effect on dough rheological properties. AB - : This research aimed to evaluate the impact of different salts on dough rheology parameters and gas cell development during dough preparation. Three types of salts in four concentrations each were used in dough preparation and following analyses were conducted: sodium content, salt structure analysis, dough hardness, dough stickiness and dough image analysis. The research showed how significantly (p < .05) the measured properties of dough can be influenced by the used type of salt, salt concentrations and fermentation time. The emphasis is put on salt substitutes of hollow microsphere salt (Hs) substitutes due to its special physical characteristics. The uniqueness of Hs physical characteristics was confirmed by electron microscope photomicrographs. The gained results are indicating that even low changes in salt concentration (0.40; 0.30; 0.25; and 0.15) make noticeable changes in dough characteristics. The usage of salt substitutes in food industry has been constantly growing and it makes the research a valuable source of information for further application of this salts. PRACTICAL APPLICATIONS: The different salt types (table-Ts, sea-Ss and hollow microsphere-Hs) which were studied in our work differ just slightly. However, an important issue in choosing salt should also be the nutritive perspective, in particular low sodium content as a preventive measure against cardio-vascular diseases. Hs and Ss are therefore suitable alternatives to typical Ts. PMID- 29704458 TI - GM-CSF and IL-4 are not involved in IVIG-mediated amelioration of ITP in mice: a role for IL-11 cannot be ruled out. AB - Previously, we have reported that interleukin (IL)-4, granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-11, but not IL-33, are up-regulated in two strains of mice with immune thrombocytopenia (ITP) that are responsive to intravenous immunoglobulin (IVIg) treatment. Previously, IL-4 was ruled out in the mechanism of IVIg; however, other publications have suggested this cytokine as a major player in the mechanism of IVIg action. Thus, we sought to further investigate a role for IL-4 and, in addition, GM-CSF and IL-11 in the mechanism of action of IVIg using a murine model of ITP. A passive platelet antibody model was used to generate ITP in IL-4 receptor knock-out (IL-4R-/- ), IL-11 receptor knock-out (IL-11Ralpha-/- ) and GM-CSF knock-out (Csf2-/- ) mice. We also used a neutralizing antibody to IL-11 and recombinant human IL-11 (rhIL-11) in addition to depleting basophils in vivo to study the effect of IVIg to ameliorate ITP. Our results showed that basophils, IL-4 and GM-CSF were unimportant in both ITP induction and its amelioration by IVIg. The role of IL-11 in these processes was less clear. Even though IL-11Ralpha-/- mice with ITP responded to IVIg similarly to wild-type (WT) mice, treatment of ITP WT mice with rhIL-11 instead of IVIg showed an increase in platelet numbers and WT mice administered anti-IL-11 showed a significant reduction in the ability of IVIg to ameliorate the ITP. Our findings indicate that neither IL-4, basophils or GM-CSF have roles in IVIg amelioration of ITP; however, a role for IL-11 requires further study. PMID- 29704460 TI - Melanoma diagnosis during periodic surveillance of patients with multiple atypical naevi. PMID- 29704459 TI - A reference genome of the Chinese hamster based on a hybrid assembly strategy. AB - Accurate and complete genome sequences are essential in biotechnology to facilitate genome-based cell engineering efforts. The current genome assemblies for Cricetulus griseus, the Chinese hamster, are fragmented and replete with gap sequences and misassemblies, consistent with most short-read-based assemblies. Here, we completely resequenced C. griseus using single molecule real time sequencing and merged this with Illumina-based assemblies. This generated a more contiguous and complete genome assembly than either technology alone, reducing the number of scaffolds by >28-fold, with 90% of the sequence in the 122 longest scaffolds. Most genes are now found in single scaffolds, including up- and downstream regulatory elements, enabling improved study of noncoding regions. With >95% of the gap sequence filled, important Chinese hamster ovary cell mutations have been detected in draft assembly gaps. This new assembly will be an invaluable resource for continued basic and pharmaceutical research. PMID- 29704461 TI - Non-Newtonian rheology in suspension cell cultures significantly impacts bioreactor shear stress quantification. AB - The fields of regenerative medicine and tissue engineering require large-scale manufacturing of stem cells for both therapy and recombinant protein production, which is often achieved by culturing cells in stirred suspension bioreactors. The rheology of cell suspensions cultured in stirred suspension bioreactors is critical to cell growth and protein production, as elevated exposure to shear stress has been linked to changes in growth kinetics and genetic expression for many common cell types. Currently, little is understood on the rheology of cell suspensions cultured in stirred suspension bioreactors. In this study, we present the impact of three common cell culture parameters, serum content, cell presence, and culture age, on the rheology of a model cell line cultured in stirred suspension bioreactors. The results reveal that cultures containing cells, serum, or combinations thereof are highly shear thinning, whereas conditioned and unconditioned culture medium without serum are both Newtonian. Non-Newtonian viscosity was modeled using a Sisko model, which provided insight on structural mechanisms driving the rheological behavior of these cell suspensions. A comparison of shear stress estimated by using Newtonian and Sisko relationships demonstrated that assuming Newtonian viscosity underpredicts both mean and maximum shear stress in stirred suspension bioreactors. Non-Newtonian viscosity models reported maximum shear stresses exceeding those required to induce changes in genetic expression in common cell types, whereas Newtonian models did not. These findings indicate that traditional shear stress quantification of cell or serum suspensions is inadequate and that shear stress quantification methods based on non-Newtonian viscosity must be developed to accurately quantify shear stress. PMID- 29704462 TI - Perinevoid alopecia: a case report and literature review. PMID- 29704463 TI - Skin microbiome changes in patients with interdigital tinea pedis. PMID- 29704464 TI - Administration of activated lymphocyte-derived DNA accelerates and aggravates lupus nephritis in B6/lpr mice: a new approach to modify a lupus murine model. AB - B6/lpr mouse strain is a well-known systemic lupus erythematosus murine model characterized by uncontrolled lymphoproliferation and autoantibody production. However, it displays a delayed and mild development of lupus nephritis (LN), which is not conducive to the research of the pathogenesis and therapeutic strategies of this condition. Our previous study demonstrated that activated lymphocyte-derived DNA (ALD-DNA) could induce high urine protein levels and severe glomerulonephritis (GN) in BALB/c mice. In the present study, we tried to remedy delayed urine protein production and mild GN in B6/lpr mice via ALD-DNA immunization. We found that urine protein levels were enhanced significantly in B6/lpr mice 4 weeks after ALD-DNA immunization compared with those in unactivated lymphocyte-derived (UnALD)-DNA- and phosphate-buffered saline (PBS)-treated controls. Moreover, more serious GN and glomerular immune complex were observed in ALD-DNA-immunized B6/lpr mice. We further explored the mechanism, and found that ALD-DNA immunization promoted T helper type 17 (Th17) cell enrichment remarkably, which enhanced the proportion of autoantibody-secreting plasma cells and promoted the production of anti-dsDNA autoantibodies, leading to accelerated and aggravated LN. Our data demonstrated that ALD-DNA immunization could remedy delayed urine protein production and mild GN in B6/lpr mouse, which makes it more suitable for studies on the pathogenesis of and therapeutic strategies against LN. PMID- 29704465 TI - Association of manual or engine-driven glide path preparation with canal centring and apical transportation: a systematic review. AB - The role and effect of glide path preparation in root canal treatment remain controversial. This systematic review aims to compare apical transportation and canal centring of different glide path preparation techniques, with or without subsequent engine-driven root canal preparation. A database search in PubMed, PubMed Central, Embase, Scopus, EBSCO Dentistry & Oral Sciences Source and Virtual Health Library was conducted, using appropriate key words to identify the effect of glide path preparation (or its absence) on apical transportation and canal centring. An assessment for the risk of bias in included studies was carried out. Amongst 2146 studies, 18 satisfied the inclusion criteria. Nine studies assessed glide path preparation per se, comparing apical transportation and canal centring of rotary systems and/or manual files; eleven further investigations examined the efficacy of the glide path prior to final canal preparation with different engine-driven systems. Risk of bias and other study design features with potential influence on study outcomes and clinical implications were assessed. Based on the available evidence, and within the limitation of the studies included, preparation of a glide path using rotary sequences performs similarly (in most of the component studies) or significantly better than manual preparation when assessing apical transportation or canal centring. When compared to the absence of a glide path, canal shaping following glide path preparation was of similar, or significantly better quality, in regard to apical transportation or canal centring. PMID- 29704466 TI - External cervical resorption-part 1: histopathology, distribution and presentation. AB - External cervical resorption (ECR) is the loss of dental hard tissue as a result of odontoclastic action. It is a dynamic process that involves periodontal, dental and in later stages pulpal tissues. Over the last two decades, ECR has attracted increased interest; this is in part due to novel micro-CT and histopathological techniques for its assessment and also improved radiographic detection using CBCT. This literature review will cover the aetiology, potential predisposing factors, histopathology and diagnosis of ECR. Part 2 will cover the management of ECR. PMID- 29704467 TI - Xanthomonas oryzae pv. oryzae TALE proteins recruit OsTFIIAgamma1 to compensate for the absence of OsTFIIAgamma5 in bacterial blight in rice. AB - Xanthomonas oryzae pv. oryzae (Xoo), the causal agent of bacterial blight (BB) of rice, uses transcription activator-like effectors (TALEs) to interact with the basal transcription factor gamma subunit OsTFIIAgamma5 (Xa5) and activates the transcription of host genes. However, how OsTFIIAgamma1, the other OsTFIIAgamma protein, functions in the presence of TALEs remains unclear. In this study, we show that OsTFIIAgamma1 plays a compensatory role in the absence of Xa5. The expression of OsTFIIAgamma1, which is activated by TALE PthXo7, increases the expression of host genes targeted by avirulent and virulent TALEs. Defective OsTFIIAgamma1 rice lines show reduced expression of the TALE-targeted susceptibility (S) genes, OsSWEET11 and OsSWEET14, which results in increased BB resistance. Selected TALEs (PthXo1, AvrXa7 and AvrXa27) were evaluated for interactions with OsTFIIAgamma1, Xa5 and xa5 (naturally occurring mutant form of Xa5) using biomolecular fluorescence complementation (BiFC) and microscale thermophoresis (MST). BiFC and MST demonstrated that the three TALEs bind Xa5 and OsTFIIAgamma1 with a stronger affinity than xa5. These results provide insights into the complex roles of OsTFIIAgamma1 and OsTFIIAgamma5 in TALE-mediated host gene transcription. PMID- 29704468 TI - Renal ischemia/reperfusion-induced mitophagy protects against renal dysfunction via Drp1-dependent-pathway. AB - Autophagy is upregulated under stress conditions to degrade superfluous proteins and recycle damaged organelles including damaged mitochondria. However, the occurrence of mitochondrial autophagy and its contribution remain to be elucidated during renal ischemia/reperfusion injury (IRI). In this study, mitophagosomes and engulfed mitochondria were frequently observed by electron microscopy after renal IRI vs. control. Meanwhile, the increase of lipidated microtubule associated protein light chain 3 (LC3-II) and decrease of mitochondrial proteins were detected by western blot, suggesting the presence of mitophagy. Drp1 translocated to mitochondria and was phosphorylated at S616 in response to IRI. Interestingly, we found that inhibiting drp1 phosphorylation with mdivi-1 significantly suppressed IRI-induced mitophagy without affecting general autophagy. Furthermore, our results showed that downregulation of mitophagy significantly exacerbated cell apoptosis and markedly aggravated kidney dysfunction induced by IRI. Taken together, these data indicate that mitophagy was activated via Drp1-dependent pathway and such mitophagic clearance of damaged mitochondria protects cells from IRI-induced apoptosis. PMID- 29704469 TI - Current treatment of ocular toxoplasmosis in immunocompetent patients: a network meta-analysis. AB - Ocular toxoplasmosis (OT) is the most frequent form of infectious posterior uveitis caused by the protozoan parasite Toxoplasma gondii. To evaluate the available evidence in peer-reviewed publications about the most effective therapy for OT in immunocompetent patients, herein a systematic literature search was conducted using Embase, PubMed, Google Scholar, and the Cochrane Central Register of Controlled Trials (CENTRAL) database from January 1987 to October 2017, with search terms "OT", "retinochoroiditis", "treatment", and "immunocompetent"; search filters "controlled clinical trial", "randomized clinical trial", and "clinical trial". The included studies were performed to evaluate the various treatment modalities of OT. Different treatment regimens were compared with regard to the improvement of visual acuity, the resolution of vitreous inflammation, recurrence, and side-effects. We independently extracted data and assessed eligibility and risk of bias using the preferred reporting items for systematic reviews and meta-analysis, and resolved any disagreement through discussion. A Bayesian network meta-analysis model was used to evaluate the interesting outcomes of all the interventions. Total 10 trials of treatments for OT were found to meet the inclusion criteria. Six trials of treatments including clindamycin, azithromycin, and trimethoprim-sulfamethoxazole (TMP-SMX) were compared with conventional therapy (the combination of pyrimethamine, sulfadiazine, and corticosteroids) for evaluation of the effect on visual acuity, vitreous inflammation, recurrence of OT, and side-effects. Two trials were compared TMP-SMX with placebo. One trial was compared azithromycin with TMP-SMX. And another trial was compared among treatments with clindamycin, P-S, TMP-SMX, and placebo. Based on our network meta-analysis, therapy with TMP-SMX seems to be an alternative treatment of OT in immunocompetent patients. PMID- 29704470 TI - Temperature preference of cave and surface populations of Astyanax mexicanus. AB - Little is known about the genetic basis of behavioral choice, such as temperature preference, especially in natural populations. Thermal preference can play a key role in habitat selection, for example in aquatic species. Examining this behavior on a genetic level requires access to individuals or populations of the same species that display distinct temperature preferences. Caves provide a uniquely advantageous setting to tackle this problem, as animals colonizing caves encounter an environment that generally has a different, and far more stable, annual temperature than what is encountered on the outside. Here, we focus on cave and surface populations of Astyanax mexicanus, the Mexican tetra, and examine temperature preference and strength of temperature preference (reflected in the percent of time spent at the optimal temperature). We used a tank with a stable temperature gradient and automated tracking software to follow individual fish from each population. We found that distinct populations of A. mexicanus display differences in both temperature preference and strength of preference. Hybrid crosses established that these are multigenic traits that segregate independently from one another. Temperature preference in many aquatic animals is known to shift towards warmer temperatures following infection with parasites (akin to a fever response in humans). While surface fish infected by the ectoparasite Gyrodactylus turnbulli (a gill fluke) displayed a strong fever response, cavefish showed a significantly attenuated fever response. This work establishes A. mexicanus as a genetically tractable system in which differences in temperature preference can be studied in naturally evolved populations. PMID- 29704471 TI - Transplantation of autologous esophageal mucosa to prevent stricture after circumferential endoscopic submucosal dissection of early esophageal cancer (with video). AB - BACKGROUND AND AIMS: Esophageal stricture is a common adverse event after endoscopic submucosal dissection (ESD) when it involves the entire circumference of the esophagus. We aimed to assess the effectiveness and safety of endoscopic transplantation of autologous esophageal mucosa in preventing stricture formation after circumferential ESD. METHODS: Nine patients who underwent circumferential ESD for early esophageal cancer were enrolled. After the patients underwent ESD, autologous esophageal mucosal patches were attached to the ulcer surface by using hemoclips and were then fixed with a covered metal mesh stent. The stent was removed 7 days after the procedure. The patients were followed up with endoscopy at scheduled times. RESULTS: Epithelialization occurred within a median of 7.1 days, with a graft survival rate of 96.5%. Strictures occurred at a mean of 24.7 days (range 18-34 days) after the procedure. The median number of endoscopic balloon dilatation sessions was 2.7 (range 0-6). CONCLUSIONS: Transplantation of autologous esophageal mucosa could be a safe way of relieving the severity of esophageal stricture after circumferential ESD. PMID- 29704472 TI - Visual detection of miRNA using peroxidase-like catalytic activity of DNA-CuNCs and methylene blue as indicator. AB - In this study, we developed a colorimetric method which is primarily based on the limited amount of redox in response to the miRNA target analyte binding for the determination of the miRNA, which is used as a biomarker to confirm the clinical diagnosis of cancers such as breast cancer. This method is on the basis of the peroxidase-like property of DNA templated copper nanoclusters (DNA-CuNCs). In this research, it was found that the DNA (poly T) stabilized green emitting CuNCs which exhibited enzyme-like peroxidase activity. After hybridization of miRNA with DNA-CuNCs probe and duplex formation, CuNCs catalyzed the oxidation of the methylene blue (MB) substrate, which can interact easily with DNA/miR-155 heteroduplex. Applying the optimal conditions, the absorbance of MB decreased by increasing the target miRNA-155 with in a dynamic range from 1.0 pM to 10.0 nM down to a detection limit (LOD) of 0.6 pM. The DNA-CuNCs/MB complex was designed to develop a facile, cheap, and fast colorimetric assay for detection of miRNA through MB oxidation by DNA stabilized CuNCs. PMID- 29704473 TI - Levels of serum high mobility group box 1 were independently associated with cardiovascular risk in patients undergoing coronary angiography. AB - BACKGROUND: We aimed to examine the association of serum high mobility group box 1 (HMGB1) level with cardiovascular risk in patients undergoing coronary angiography with no history of diabetes. METHODS: We enrolled patients with no history of diabetes who had been admitted for coronary angiography due to suspected or known coronary artery disease. Two to four weeks after the patients were discharged from the hospital, an oral glucose tolerance test (OGTT) was conducted and serum HMGB1 level was measured. Patients' 10-year coronary heart disease (CHD) risk was assessed using the Framingham Risk Scoring. RESULTS: A total of 476 patients were enrolled. Overall, mean serum HMGB1 level was 6.1 +/- 1.3 pg/ml. Using linear regression analysis, high-density lipoprotein cholesterol was negatively associated with serum HMGB1 (beta coefficient - 0.033, 95% CI 0.063 to -0.003, p = 0.033) after adjustment for several confounders. With regard to cardiovascular risk, levels of serum HMGB1 were positively associated with 10 year CHD risk (beta coefficient 0.506, 95% CI 0.030 to 0.983, p = .037), independent of patients' undiagnosed abnormal glucose regulation. CONCLUSIONS: In patients undergoing coronary angiography with no history of diabetes, levels of serum HMGB1 were positively associated with 10-year CHD risk, independent of patients' undiagnosed abnormal glucose regulation. PMID- 29704474 TI - New insights about the peculiar role of the 28-38 C-terminal segment and some selected residues in PACAP for signaling and neuroprotection. AB - The pituitary adenylate cyclase-activating polypeptide (PACAP), which exists in two isoforms of 27 and 38 amino acids, can induce neuronal protection in vitro and in vivo following the activation of PAC1, a class B G protein-coupled receptor (GPCR). With its potent neuroprotective and anti-inflammatory effects, this peptide represents a promising avenue for the development of therapeutic strategies to potentially cure or at least slow the progression of neurodegenerative disorders. Beyond the canonical G protein signal effectors, GPCRs are also coupled to a multitude of intracellular signaling pathways that can be independently activated by biased ligands, thereby expanding vastly the potential for discovering new drugs. Interestingly, some studies have demonstrated distinct signaling features for the PACAP isoforms. With this observation in mind, we assessed the impact of chemical and structural modifications introduced into specific regions of the PACAP isoforms on their neuroprotective effects, and determined the role played by these physico-chemical and structural features on their signaling signatures. Each compound was also evaluated for its ability to bind the PACAP receptors, promote cell survival in a cellular model of Parkinson's disease and stimulate the signaling partners associated with PAC1 activation, including Gs and Gq, as well as beta-arrestin 1 and 2. Our results demonstrate that PACAP38 and its related analogs exert a more potent neuroprotective action than their 27-amino acid counterparts and that this neuroprotective effect is dependent on both Gq and Gs-dependent signaling. This study will definitely improve our understanding of the molecular and cellular mechanisms associated with PACAP neuroprotection. PMID- 29704476 TI - iPhosT-PseAAC: Identify phosphothreonine sites by incorporating sequence statistical moments into PseAAC. AB - Among all the post-translational modifications (PTMs) of proteins, Phosphorylation is known to be the most important and highly occurring PTM in eukaryotes and prokaryotes. It has an important regulatory mechanism which is required in most of the pathological and physiological processes including neural activity and cell signalling transduction. The process of threonine phosphorylation modifies the threonine by the addition of a phosphoryl group to the polar side chain, and generates phosphothreonine sites. The investigation and prediction of phosphorylation sites is important and various methods have been developed based on high throughput mass-spectrometry but such experimentations are time consuming and laborious therefore, an efficient and accurate novel method is proposed in this study for the prediction of phosphothreonine sites. The proposed method uses context-based data to calculate statistical moments. Position relative statistical moments are combined together to train neural networks. Using 10-fold cross validation, 94.97% accurate result has been obtained whereas for Jackknife testing, 96% accurate results have been obtained. The overall accuracy of the system is 94.4% to sensitivity value 94% and specificity 94.6%. These results suggest that the proposed method may play an essential role to the other existing methods for phosphothreonine sites prediction. PMID- 29704475 TI - Chronic Cough Related to Acute Viral Bronchiolitis in Children: CHEST Expert Panel Report. AB - BACKGROUND: Acute bronchiolitis is common in young children, and some children develop chronic cough after their bronchiolitis. We thus undertook systematic reviews based on key questions (KQs) using the PICO (Population, Intervention, Comparison, Outcome) format. The KQs were: Among children with chronic cough (> 4 weeks) after acute viral bronchiolitis, how effective are the following interventions in improving the resolution of cough?: (1) Antibiotics. If so what type and for how long? (2) Asthma medications (inhaled steroids, beta2 agonist, montelukast); and (3) Inhaled osmotic agents like hypertonic saline? METHODS: We used the CHEST expert cough panel's protocol and the American College of Chest Physicians (CHEST) methodological guidelines and GRADE framework. Data from the systematic reviews in conjunction with patients' values and preferences and the clinical context were used to form these suggestions. Delphi methodology was used to obtain consensus. RESULTS: Several studies and systematic reviews on the efficacy of the three types of interventions listed in the introduction were found but no data were relevant to our KQs. Thus, no recommendations on using the interventions above could be formulated. CONCLUSIONS: The panel made several consensus-based suggestions and identified directions for future studies to advance the field of managing chronic cough post-acute bronchiolitis in children. PMID- 29704477 TI - Reactive oxygen species dynamics in roots of salt sensitive and salt tolerant cultivars of rice. AB - Salinity stress is one of the major constraints for growth and survival of plants that affects rice productivity worldwide. Hence, in the present study, roots of two contrasting salinity sensitive cultivars, IR64 (IR64, salt sensitive) and Luna Suvarna (LS, salt tolerant) were compared with regard to the levels of reactive oxygen species (ROS) to derive clues for their differential salt stress adaptation mechanisms. In our investigation, the tolerant cultivar exhibited longer primary roots, more lateral roots, higher root number leading to increased root biomass, with respect to IR64. It was observed that LS roots maintained higher level of H2O2 in comparison to IR64. The activities of various enzymes involved in enzymatic antioxidant defense mechanism (SOD, CAT, GPX, DHAR and MDHAR) were found to be greater in LS roots. Further, the higher transcript level accumulation of genes encoding ROS generating (RbohA, RbohD and RbohE) and scavenging enzymes (Fe-SOD, Chloroplastic Cu/Zn-SOD, CAT and DHAR) were noticed in the roots of tolerant cultivar, LS. Moreover, the content of other stress markers such as total protein and proline were also elevated in LS roots. While, the expression of proline biosynthesis gene (P5CS) and proline catabolism gene (PDH) was observed to be lower in LS. PMID- 29704478 TI - Impact of rearing temperature on encapsulation and the accumulation of transcripts putatively involved in capsule formation in a parasitized lepidopteran host. AB - Encapsulation and melanisation are innate immune reactions of insects against foreign intruders such as parasitoids. In an earlier study, we observed that immature life stages of the endoparasitoid Tranosema rostrale (Hymenoptera: Ichneumonidae) parasitizing Choristoneura fumiferana (Lepidoptera: Tortricidae) larvae experienced higher mortality due to encapsulation and melanisation when reared at high (30 degrees C) than at lower (10 degrees C, 20 degrees C) temperatures. Downregulation of T. rostrale polydnavirus genes in parasitized hosts and upregulation of two genes involved in the spruce budworm's melanisation process were identified as likely contributors to parasitoid mortality at high temperature. However, levels of transcripts of genes involved in the spruce budworm's cellular encapsulation process were not measured inasmuch as candidate genes, in the spruce budworm, had not yet been identified. In addition, our assessment of temperature-dependent encapsulation and melanisation of foreign objects in spruce budworm larvae was only partial. To fill these knowledge gaps, we injected SephadexTM beads into unparasitized spruce budworm larvae and assessed their encapsulation/melanisation after the insects had been held at three different temperatures (10, 20, and 30 degrees C), and we identified spruce budworm genes putatively involved in the encapsulation process and quantified their transcripts at the same three temperatures, using a qPCR approach. As expected, both encapsulation and melanisation of SephadexTM beads increased as a function of temperature. At the molecular level, three of the five genes examined (Integrin beta1, Hopscotch, Stat92E) clearly displayed temperature dependent upregulation. The results of this study further support the hypothesis that a temperature-dependent increase in the encapsulation response of C. fumiferana against T. rostrale is due to the combined effects of reduced expression of polydnavirus genes and enhanced expression of host immune genes. PMID- 29704479 TI - Robotic-Assisted Versus Thoracoscopic Lobectomy Outcomes From High-Volume Thoracic Surgeons. AB - BACKGROUND: Reports of surgical outcomes comparing proficient surgeons who perform either robotic-assisted or video-assisted thoracoscopic lobectomy are lacking. We evaluate the comparative effectiveness of robotic-assisted and video assisted thoracoscopic lobectomies by surgeons who performed 20 or more annual surgical procedures in a national database. METHODS: Patients 18 years or older, who underwent elective lobectomy by surgeons who performed 20 or more annual lobectomies by robotic-assisted or thoracoscopic approach from January 2011 through September 2015, were identified in the Premier Healthcare database with the use of codes from the ninth revision of the International Statistical Classification of Diseases and Related Health Problems. Propensity-score matching based on patient and hospital characteristics and by year was performed 1:1 to identify comparable cohorts for analysis (n = 838 in each cohort). All tests were two-sided, with statistical significance set at p less than 0.05. RESULTS: A total of 23,779 patients received an elective lobectomy during the study period: 9,360 were performed by video-assisted thoracoscopic approach and 2,994 were by robotic-assisted approach. Propensity-matched comparison of lobectomies performed by surgeons who performed 20 or more procedures annually (n = 838) showed that robotic-assisted procedures had a longer mean operative time by 25 minutes (mean 247.1 minutes vs 222.6 minutes, p < 0.0001) but had a lower conversion-to-open rate (4.8% vs 8.0%, p = 0.007) and a lower 30-day complication rate (33.4% vs 39.2%, p = 0.0128). Transfusion rates and 30-day mortality rates were similar between the two cohorts. CONCLUSIONS: When surgical outcomes are limited to surgeons who perform 20 or more annual procedures, the robotic-assisted approach is associated with a lower conversion-to-open rate and lower 30-day complication rate when than video-assisted thoracoscopic surgeons, with a mean operative time difference of 25 minutes. PMID- 29704480 TI - Protective effect and mechanism of injection of glutamate into cerebellum fastigial nucleus on chronic visceral hypersensitivity in rats. AB - AIMS: We investigated the effects of chemical stimulation of cerebellum fastigial nucleus (FN) on the chronic visceral hypersensitivity (CVH) and its possible mechanism in rats. MAIN METHODS: We stimulated the FN by microinjecting glutamate into the FN, in order to explore whether the cerebellum fastigial nucleus played a role on CVH in rat. The model of CVH was established by colorectal distension (CRD) in neonatal rats. Abdominal withdrawal reflex (AWR) scores, pain threshold, and amplitude of electromyography (EMG) were used to assess the hyperalgesia. KEY FINDINGS: We showed that microinjection of l-glutamate (Glu) into the FN markedly attenuated hyperalgesia. The protective effect of FN was prevented by pretreatment with the glutamate decarboxylase inhibitor, 3-mercaptopropionic acid (3-MPA) into the FN or GABAA receptor antagonist, bicuculline (Bic) into the LHA (lateral hypothalamic area). The expressions of protein Bax, caspase-3 were decreased, but the expression of protein Bcl-2 was increased after chemical stimulation of FN. These results indicated that the FN participated in regulation of CVH, and was a specific area in the CNS for exerting protective effects on the CVH. In addition, LHA and GABA receptor may be involved in this process. SIGNIFICANCE: Our findings might provide a new and improved understanding of the FN function, and might show an effective treatment strategy for the chronic visceral hypersensitivity. PMID- 29704481 TI - Grewia tiliaefolia and its active compound vitexin regulate the expression of glutamate transporters and protect Neuro-2a cells from glutamate toxicity. AB - AIM: Glutamate is a major neurotransmitter involved in several brain functions and glutamate excitotoxicity is involved in Alzheimer's disease (AD). In the current study, the neuroprotective effect of the Indian medicinal plant Grewia tiliaefolia (GT) and its active component vitexin was evaluated in Neuro-2a cells against glutamate toxicity. MATERIALS AND METHODS: Neuro-2a cells were exposed to glutamate to cause excitotoxicity and the neuroprotective effect of GT and vitexin were evaluated using biochemical studies (estimation of reactive oxygen species, reactive nitrogen species, protein carbonyl content, lipid peroxidation level, mitochondrial membrane potential and caspase-3 activity), molecular docking studies, gene expression and western blot analysis. KEY FINDINGS: Glutamate exposure to Neuro-2a cells induced oxidative stress, loss of membrane potential, suppressed the expression of antioxidant response genes (Nrf-2, HO-1, NQO-1), glutamate transporters (GLAST-1, GLT-1) and induced the expression of NMDAR, Calpain. However, pre-treatment of cells with GT/vitexin inhibited oxidative stress mediated damage by augmenting the expression of Nrf-2/HO-1 pathway, inducing the expression of glutamate transporters and downregulating Calpain, NMDAR. Molecular docking showed that vitexin effectively binds to NMDAR and GSK-3beta and thereby can inhibit their activation. GT/vitexin also inhibited glutamate induced Bax expression. SIGNIFICANCE: Methanol extract of G. tiliaefolia and its active component vitexin can act in an antioxidant dependent mechanism as well as by regulating glutamate transporters in mitigating the toxicity exerted by glutamate in Neuro-2a cells. Our results conclude that GT/vitexin can act as potential drug leads for the therapeutic intervention of AD. PMID- 29704482 TI - New HSF1 inducer as a therapeutic agent in a rodent model of Parkinson's disease. AB - Molecular chaperone HSP70 (HSPA1A) has therapeutic potential in conformational neurological diseases. Here we evaluate the neuroprotective function of the chaperone in a rat model of Parkinson's disease (PD). We show that the knock-down of HSP70 (HSPA1A) in dopaminergic neurons of the Substantia nigra causes an almost 2-fold increase in neuronal death and multiple motor disturbances in animals. Conversely, pharmacological activation of HSF1 transcription factor and enhanced expression of inducible HSP70 with the echinochrome derivative, U-133, reverses the process of neurodegeneration, as evidenced by a increase in the number of tyrosine hydroxylase-containing neurons, and prevents the motor disturbances that are typical of the clinical stage of the disease. The neuroprotective effect caused by the elevation of HSP70 in nigral neurons is due to the ability of the chaperone to prevent alpha-synuclein aggregation and microglia activation. Our findings support the therapeutic relevance of HSP70 induction for the prevention and/or deceleration of PD-like neurodegeneration. PMID- 29704483 TI - The potent insulin secretagogue effect of betulinic acid is mediated by potassium and chloride channels. AB - Betulinic acid (BA) has been described as an insulin secretagogue which may explain its potent antihyperglycemic effect; however, the exact role of BA as an insulinogenic agent is not clear. The aim of this study was to investigate the mechanism of BA on calcium influx and static insulin secretion in pancreatic islets isolated from euglycemic rats. We found that BA triggers calcium influx by a mechanism dependent on ATP-dependent potassium channels and L-type voltage dependent calcium channels. Additionally, the voltage-dependent and calcium dependent chloride channels are also involved in the mechanism of BA, probably due to an indirect stimulation of calcium entry and increased intracellular calcium. Additionally, the downstream activation of PKC, which is necessary for the effect of BA on calcium influx, is involved in the full stimulatory response of the triterpene. BA stimulated the static secretion of insulin in pancreatic islets, indicating that the abrupt calcium influx may be a key step in its secretagogue effect. As such, BA stimulates insulin secretion through the activation of electrophysiological mechanisms, such as the closure of potassium channels and opening of calcium and chloride channels, inducing cellular depolarization associated with metabolic-biochemical effects, in turn activating PKC and ensuring the secretion of insulin. PMID- 29704485 TI - BML-111 alleviates acute lung injury through regulating the expression of lncRNA MALAT1. AB - BML-111 is a lipoxin receptor agonist that plays a vital role on inflammation. MALAT1 is reported to mediate lung injury. ALI rat model was established using the method of venous cannula. Pulmonary microvascular endothelial cells (PMVEC) of rats were isolated using immunomagnetic separation method. Hematoxylin-eosin (HE) staining was performed to observe the lung injury degree. Real-time PCR and western blot were performed to detect the genes expression. ELIAS was used to determine the level of TNF-alpha and IL-6. RNA pull-down and RIP were carried out to affirm the relationship between MALAT1 and TLR4. The lung injury score and lung wet/dry weight ratio was significantly increased in ALI rats, while BML-111 treatment significantly decreased it, the HE staining directly revealed the lung injury. The expression of MALAT1 was decreased, while TLR4 was increased in ALI rats, BML-111 stimulation significantly reversed it. MALAT1 targets TLR4 to regulate its expression. TLR4 regulated the inflammation and cell apoptosis of PMVEC via NF-kappaB and p38 MAPK signaling pathway. The down-regulated MALAT1 mediates the mechanism of ALI by regulating of NF-kappaB and p38 MAPK signaling pathways via TLR4, while BML-111 stimulation significantly alleviated the ALI by regulating the expression of MALAT1. PMID- 29704484 TI - Role of the C-terminus mobile domain of cardiac troponin I in the regulation of thin filament activation in skinned papillary muscle strips. AB - The C-terminus mobile domain of cTnI (cTnI-MD) is a highly conserved region which stabilizes the actin-cTnI interaction during the diastole. Upon Ca2+-binding to cTnC, cTnI-MD participates in a regulatory switching that involves cTnI to switch from interacting with actin toward interacting with the Ca2+-regulatory domain of cTnC. Despite many studies targeting the cTnI-MD, the role of this region in the length-dependent activation of cardiac contractility is yet to be determined. The present study investigated the functional consequences of losing the entire cTnI MD in cTnI(1-167) truncation mutant, as it was exchanged for endogenous cTnI in skinned rat papillary muscle fibers. The influence of cTnI-MD truncation on the extent of the N-domain of cTnC hydrophobic cleft opening and the steady-state force as a function of sarcomere length (SL), cross-bridge state, and [Ca2+] was assessed using the simultaneous in situ time-resolved FRET and force measurements at short (1.8 MUm) and long (2.2 MUm) SLs. Our results show the significant role of cTnI-MD in the length dependent thin filament activation and the coupling between thin and thick filament regulations affected by SL. Our results also suggest that cTnI-MD transmits the effects of SL change to the core of troponin complex. PMID- 29704486 TI - Identification of experimental bladder sensitivity among dysmenorrhea sufferers. AB - BACKGROUND: Dysmenorrhea is a common risk factor for chronic pain conditions including bladder pain syndrome. Few studies have formally evaluated asymptomatic bladder pain sensitivity in dysmenorrhea, and whether this largely reflects excess pelvic symptom reporting due to comorbid psychological dysfunction. OBJECTIVE: We sought to determine whether bladder hypersensitivity is more common among women reporting moderate or greater dysmenorrhea, without chronic pain elsewhere, after accounting for anxiety and depression. Demonstrating this would suggest that dysmenorrhea might be an early clue for visceral or widespread pain hypersensitivity and improve understanding of potential precursors to bladder pain syndrome. STUDY DESIGN: We compared cohorts of regularly menstruating women, without symptoms of chronic pain elsewhere, reporting (1) moderate-to-severe dysmenorrhea (n = 98) and (2) low levels or no menstrual pain (n = 35). Participants underwent rapid bladder filling following a standard water ingestion protocol, serially rating bladder pain and relative urgency during subsequent distension. Potential differences in bladder volumes were controlled for by sonographic measurement at standard cystometric thresholds. Bladder sensitivity was also measured with complementary measures at other times separately including a simplified rapid filling test, palpation of the bladder wall, and through ambulatory self-report. Anxiety and depression were evaluated with the National Institutes of Health Patient-Reported Outcomes Measurement Information System measures. RESULTS: Women with moderate-to-severe dysmenorrhea reported more urinary symptoms than controls and had a lower maximum capacity (498 +/- 18 mL vs 619 +/- 34 mL, P < .001) and more evoked bladder filling pain (0-100 visual analog scale: 25 +/- 3 vs 12 +/- 3, P < .001). The dysmenorrhea-bladder capacity relationship remained significant irrespective of menstrual pain severity, anxiety, depression, or bladder pain (R2 = 0.13, P = .006). Severity of menstrual pain predicted evoked bladder pain (R2 = 0.10, P = .008) independent of anxiety (P = .21) and depression (P = .21). Women with moderate-to-severe dysmenorrhea exhibiting provoked bladder pain (24/98, 24%) also reported higher pain during the screening rapid bladder test (P < .001), in response to transvaginal bladder palpation (P < .015), and on prospective daily diaries (P < .001) than women with dysmenorrhea without provoked bladder pain. CONCLUSION: Women experiencing moderate-to-severe dysmenorrhea also harbor a higher pain response to naturally evoked bladder distension. Noninvasive bladder provocation needs to be tested further longitudinally in those with dysmenorrhea to characterize the course of visceral sensitivity and determine if it may help predict individuals at risk for developing subsequent pain in the bladder or elsewhere. PMID- 29704487 TI - Cervical pessary to reduce preterm birth <34 weeks of gestation after an episode of preterm labor and a short cervix: a randomized controlled trial. AB - BACKGROUND: To date, no intervention has proved effective in reducing the spontaneous preterm birth rate in singleton pregnancies following an episode of threatened preterm labor and short cervix remaining. OBJECTIVE: This study was designed to ascertain whether cervical pessaries could be useful in preventing spontaneous preterm birth in women with singleton pregnancies and a short cervix after a threatened preterm labor episode. STUDY DESIGN: This open randomized controlled trial was conducted in 357 pregnant women (between 240-336 weeks) who had not delivered 48 hours after a threatened preterm labor episode and had a short cervix remaining (<=25 mm at 240-296 weeks; <=15 mm at 300-336 weeks). Patients were randomly assigned to cervical pessary (179) or routine management (178). The primary outcome was the spontaneous preterm birth rate <34 weeks. Spontaneous preterm birth <28 and 37 weeks and neonatal morbidity and mortality were also evaluated in an intention-to-treat analysis. RESULTS: No significant differences between the pessary and routine management groups were observed in the spontaneous preterm birth rate <34 weeks (19/177 [10.7%] in the pessary group vs 24/175 [13.7%] in the control group; relative risk, 0.78; 95% confidence interval, 0.45-1.38). Spontaneous preterm birth <37 weeks occurred less frequently in the pessary group (26/175 [14.7%] vs 44/175 [25.1%]; relative risk, 0.58; 95% confidence interval, 0.38-0.90; P = .01). Preterm premature rupture of membranes rate was significantly lower in pessary carriers (4/177 [2.3%] vs 14/175 [8.0%]; relative risk, 0.28; 95% confidence interval, 0.09-0.84; P = .01). The pessary group less frequently required readmission for new threatened preterm labor episodes (8/177 [4.5%] vs 35/175 [20.0%]; relative risk, 0.23; 95% confidence interval, 0.11-0.47; P < .0001). No serious adverse maternal events occurred; neonatal morbidity and mortality were similar in both groups. CONCLUSION: Pessary use did not significantly lower the spontaneous preterm birth rate <34 weeks in women with a short cervix remaining after a threatened preterm labor episode but did significantly reduce the spontaneous preterm birth rate <37 weeks, threatened preterm labor recurrence, and the preterm premature rupture of membranes rate. PMID- 29704488 TI - Bribery games on interdependent complex networks. AB - Bribe demands present a social conflict scenario where decisions have wide ranging economic and ethical consequences. Nevertheless, such incidents occur daily in many countries across the globe. Harassment bribery constitute a significant sub-set of such bribery incidents where a government official demands a bribe for providing a service to a citizen legally entitled to it. We employ an evolutionary game-theoretic framework to analyse the evolution of corrupt and honest strategies in structured populations characterized by an interdependent complex network. The effects of changing network topology, average number of links and asymmetry in size of the citizen and officer population on the proliferation of incidents of bribery are explored. A complex network topology is found to be beneficial for the dominance of corrupt strategies over a larger region of phase space when compared with the outcome for a regular network, for equal citizen and officer population sizes. However, the extent of the advantage depends critically on the network degree and topology. A different trend is observed when there is a difference between the citizen and officer population sizes. Under those circumstances, increasing randomness of the underlying citizen network can be beneficial to the fixation of honest officers up to a certain value of the network degree. Our analysis reveals how the interplay between network topology, connectivity and strategy update rules can affect population level outcomes in such asymmetric games. PMID- 29704489 TI - Evaluation of the whole body physiologically based pharmacokinetic (WB-PBPK) modeling of drugs. AB - The Physiologically based pharmacokinetic (PBPK) modeling is a supporting tool in drug discovery and improvement. Simulations produced by these models help to save time and aids in examining the effects of different variables on the pharmacokinetics of drugs. For this purpose, Sheila and Peters suggested a PBPK model capable of performing simulations to study a given drug absorption. There is a need to extend this model to the whole body entailing all another process like distribution, metabolism, and elimination, besides absorption. The aim of this scientific study is to hypothesize a WB-PBPK model through integrating absorption, distribution, metabolism, and elimination processes with the existing PBPK model.Absorption, distribution, metabolism, and elimination models are designed, integrated with PBPK model and validated. For validation purposes, clinical records of few drugs are collected from the literature. The developed WB PBPK model is affirmed by comparing the simulations produced by the model against the searched clinical data. . It is proposed that the WB-PBPK model may be used in pharmaceutical industries to create of the pharmacokinetic profiles of drug candidates for better outcomes, as it is advance PBPK model and creates comprehensive PK profiles for drug ADME in concentration-time plots. PMID- 29704490 TI - Mathematical modeling of atherosclerotic plaque destabilization: Role of neovascularization and intraplaque hemorrhage. AB - Observational studies have identified angiogenesis from the adventitial vasa vasorum and intraplaque hemorrhage (IPH) as critical factors in atherosclerotic plaque progression and destabilization. Here we propose a mathematical model incorporating intraplaque neovascularization and hemodynamic calculation with plaque destabilization for the quantitative evaluation of the role of neoangiogenesis and IPH in the vulnerable atherosclerotic plaque formation. An angiogenic microvasculature is generated by two-dimensional nine-point discretization of endothelial cell proliferation and migration from the vasa vasorum. Three key cells (endothelial cells, smooth muscle cells and macrophages) and three key chemicals (vascular endothelial growth factors, extracellular matrix and matrix metalloproteinase) are involved in the plaque progression model, and described by the reaction-diffusion partial differential equations. The hemodynamic calculation of the microcirculation on the generated microvessel network is carried out by coupling the intravascular, interstitial and transvascular flow. The plasma concentration in the interstitial domain is defined as the description of IPH area according to the diffusion and convection with the interstitial fluid flow, as well as the extravascular movement across the leaky vessel wall. The simulation results demonstrate a series of pathophysiological phenomena during the vulnerable progression of an atherosclerotic plaque, including the expanding necrotic core, the exacerbated inflammation, the high microvessel density (MVD) region at the shoulder areas, the transvascular flow through the capillary wall and the IPH. The important role of IPH in the plaque destabilization is evidenced by simulations with varied model parameters. It is found that the IPH can significantly speed up the plaque vulnerability by increasing necrotic core and thinning fibrous cap. In addition, the decreased MVD and vessel permeability may slow down the process of plaque destabilization by reducing the IPH dramatically. We envision that the present model and its future advances can serve as a valuable theoretical platform for studying the dynamic changes in the microenvironment during the plaque destabilization. PMID- 29704492 TI - Synergistic Amyloid Switch Triggered by Early Heterotypic Oligomerization of Intrinsically Disordered alpha-Synuclein and Tau. AB - Amyloidogenic intrinsically disordered proteins, alpha-synuclein and tau are linked to Parkinson's disease and Alzheimer's disease, respectively. A body of evidence suggests that alpha-synuclein and tau, both present in the presynaptic nerve terminals, co-aggregate in many neurological ailments. The molecular mechanism of alpha-synuclein-tau hetero-assembly is poorly understood. Here we show that amyloid formation is synergistically facilitated by heterotypic association mediated by binding-induced misfolding of both alpha-synuclein and tau K18. We demonstrate that the intermolecular association is largely driven by the electrostatic interaction between the negatively charged C-terminal segment of alpha-synuclein and the positively charged tau K18 fragment. This heterotypic association results in rapid formation of oligomers that readily mature into hetero-fibrils with a much shorter lag phase compared to the individual proteins. These findings suggested that the critical intermolecular interaction between alpha-synuclein and tau can promote facile amyloid formation that can potentially lead to efficient sequestration of otherwise long-lived lethal oligomeric intermediates into innocuous fibrils. We next show that a well-known familial Parkinson's disease mutant (A30P) that is known to aggregate slowly via accumulation of highly toxic oligomeric species during the long lag phase converts into amyloid fibrils significantly faster in the presence of tau K18. The early intermolecular interaction profoundly accelerates the fibrillation rate of A30P alpha-synuclein and impels the disease mutant to behave similar to wild type alpha-synuclein in the presence of tau. Our findings suggest a mechanistic underpinning of bypassing toxicity and suggest a general strategy by which detrimental amyloidogenic precursors are efficiently sequestered into more benign amyloid fibrils. PMID- 29704491 TI - Artificial Anti-Tumor Opsonizing Proteins with Fibronectin Scaffolds Engineered for Specificity to Each of the Murine FcgammaR Types. AB - We have engineered a panel of novel Fn3 scaffold-based proteins that bind with high specificity and affinity to each of the individual mouse Fcgamma receptors (mFcgammaR). These binders were expressed as fusions to anti-tumor antigen single chain antibodies and mouse serum albumin, creating opsonizing agents that invoke only a single mFcgammaR response rather than the broader activity of natural Fc isotypes, as well as all previously reported Fc mutants. This panel isolated the capability of each of the four mFcgammaRs to contribute to macrophage phagocytosis of opsonized tumor cells and in vivo tumor growth control with these monospecific opsonizing fusion proteins. All activating receptors (mFcgammaRI, mFcgammaRIII, and mFcgammaRIV) were capable of driving specific tumor cell phagocytosis to an equivalent extent, while mFcgammaRII, the inhibitory receptor, did not drive phagocytosis. Monospecific opsonizing fusion proteins that bound mFcgammaRI alone controlled tumor growth to an extent similar to the most active IgG2a murine isotype. As expected, binding to the inhibitory mFcgammaRII did not delay tumor growth, but unexpectedly, mFcgammaRIII also failed to control tumor growth. mFcgammaRIV exhibited detectable but lesser tumor-growth control leading to less overall survival compared to mFcgammaRI. Interestingly, in vivo macrophage depletion demonstrates their importance in tumor control with mFcgammaRIV engagement, but not with mFcgammaRI. This panel of monospecific mFcgammaR-binding proteins provides a toolkit for isolating the functional effects of each mFcgammaR in the context of an intact immune system. PMID- 29704493 TI - Co-translational Folding Intermediate Dictates Membrane Targeting of the Signal Recognition Particle Receptor. AB - Much of our knowledge on the function of proteins is deduced from their mature, folded states. However, it is unknown whether partially synthesized nascent protein segments can execute biological functions during translation and whether their premature folding states matter. A recent observation that a nascent chain performs a distinct function, co-translational targeting in vivo, has been made with the Escherichia coli signal recognition particle receptor FtsY, a major player in the conserved pathway of membrane protein biogenesis. FtsY functions as a membrane-associated entity, but very little is known about the mode of its targeting to the membrane. Here we investigated the underlying structural mechanism of the co-translational FtsY targeting to the membrane. Our results show that helices N2-4, which mediate membrane targeting, form a stable folding intermediate co-translationally that greatly differs from its fold in the mature FtsY. These results thus resolve a long-standing mystery of how the receptor targets the membrane even when deleted of its alleged membrane targeting sequence. The structurally distinct targeting determinant of FtsY exists only co translationally. Our studies will facilitate further efforts to seek cellular factors required for proper targeting and association of FtsY with the membrane. Moreover, the results offer a hallmark example for how co-translational nascent intermediates may dictate biological functions. PMID- 29704494 TI - Metformin, a first-line drug for type 2 diabetes mellitus, disrupts the MALAT1/miR-142-3p sponge to decrease invasion and migration in cervical cancer cells. AB - The molecular mechanisms underlying the anti-neoplastic properties of metformin, a first-line drug for type 2 diabetes, remain elusive. To explore the novel anti neoplastic mechanisms of metformin, the transwell chamber and wound-healing assays were used to evaluate its effects on the migration and invasion of human cervical cancer cells. Real-time PCR and Western blotting were used to measure the gene and protein expression, respectively, of microRNA (miRNA) miR-142-3p, long non-coding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1), and high-mobility group AT-hook 2 (HMGA2). The dual-luciferase reporter assay system was used to examine the direct interaction between miR-142 3p and lncRNA MALAT1 and HMGA2. Immunofluorescence was used to detect the protein expression of HMGA2. In addition, tumor xenografts in a nude mouse model were developed to evaluate the anti-tumor efficacy of metformin. We found that metformin could suppress cervical cancer migration and invasion. During the process of tumor metastasis, miR-142-3p was significantly upregulated, whereas lncRNA MATAL1 and HMGA2 were suppressed by metformin. The binding site that allow the direct interaction between miR-142-3p and MALAT1 were located in the 3' untranslated region (3' UTR) of lncRNA MATAL1 and HMGA2 at base pairs (bp) 4452 5255, while that between miR-142-3p and HMGA2 was located at bp 1562-2521 of HMGA2. Metformin markedly inhibited the growth and angiogenesis of SiHa xenografts in nude mice. In conclusion, this study provides evidence that metformin can prevent the MALAT1/miR-142-3p sponge from developing anti neoplastic properties in human cervical cancer cells and cervical cancer cell xenografts in nude mice. Thus, our findings demonstrate the novel anti-tumor effects of metformin in cervical cancer. PMID- 29704495 TI - FOXM1 regulates radiosensitivity of lung cancer cell partly by upregulating KIF20A. AB - Forkhead box protein M1 (FOXM1), an important regulator of tumorigenesis in various human tumors, has recently been reported to play a role in the modulation of radiosensitivity in glioma and breast cancer cells. The present study aimed to investigate the effects of FOXM1 on radiotherapy resistance in human lung cancer and to explore the related molecular mechanisms. The results revealed that FOXM1 expression was upregulated in A549 and H1299 cells after IR (Ionizing radiation). FOXM1 inhibition impeded survival fractions, impeded proliferation, and triggered apoptosis after IR. Moreover, the silencing of FOXM1 dampened cell migration, invasion, and EMT (epithelial-mesenchyman transition) in A549 and H1299 cells treated by IR. In addition, KIF20A was also highly expressed in IR-treated A549 cells and downregulated by FOXM1 inhibition. Knockdown of KIF20A inhibited the survival fraction. Reintroduction of KIF20A partly reversed the effects of FOXM1 on the proliferation, apoptosis, and metastasis of A549 cells. Taken together, these results indicated that FOXM1 might enhance radioresistance partly through the induction of KIF20A expression. PMID- 29704496 TI - Salusin-alpha attenuates hepatic steatosis and atherosclerosis in high fat diet fed low density lipoprotein receptor deficient mice. AB - Salusin-alpha is an endogenous bioactive peptide and likely to prevent atherosclerosis. But its protective effect against atherosclerosis in vivo remains poorly understood. The aim of the present study was to determine the potential effects of salusin-alpha on atherosclerosis and its associated metabolic disorders in high fat diet (HFD)-fed low density lipoprotein receptor deficient (LDLr-/-) mice, and also explore the possible underlying mechanisms involved. Our data showed that after 12 weeks treatment, salusin-alpha ameliorated HFD-induced weight gain, hyperlipidemia, and serum levels of interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha). Salusin-alpha suppressed HFD-induced hepatic steatosis and regulated gene expression of fatty acid synthase, acetyl coenzyme A carboxylase-alpha, peroxisome proliferator activated receptor-alpha, camitine palmitoyltransferase-1alpha and CYP7A1 in liver. Salusin-alpha reduced atherosclerotic plaque area and macrophage foam cell formation. Salusin-alpha prevented hepatic and aortic inflammation as evidenced by the reduced macrophage recruitment and mRNA expression of IL-6 and TNF-alpha in both liver and aorta. Salusin-alpha also reduced hepatic and aortic oxidative stress by normalizing activities of antioxidant enzymes in liver and suppressing reactive oxygen species generation and protein expressions of NADPH-oxidase (NOX) 2 and NOX4 in both liver and aorta. Our present data suggest that salusin-alpha could reduce hepatic steatosis and atherosclerosis via its pleiotropic effects, including amelioration of lipid profiles, regulation of some key molecules involved in lipid metabolism in liver, anti-oxidative effect and anti inflammatory action. PMID- 29704497 TI - Structural heterogeneity leads to functional homogeneity in A. marina phycocyanin. AB - The major light harvesting antenna in all cyanobacterial species is the phycobilisome (PBS). The smallest PBS identified to date is that of Acaryochloris marina (A. marina), composed of a single four-hexamer rod. We have determined the crystal structure of phycocyanin (AmPC), the major component of the A. marina PBS (AmPBS) to 2.1 A. The basic unit of the AmPC is a heterodimer of two related subunits (alpha and beta), and we show that the asymmetric unit contains a superposition of two alpha and two beta isoforms, the products of the simultaneous expression of different genes. This is the first time to our knowledge that isolated proteins crystallized with such identifiable heterogeneity. We believe that the presence of the different isoforms allows the AmPBS to have a significant bathochromic shift in its fluorescence emission spectrum, allowing, in the total absence of allophycocyanin, a better overlap with absorption of the chlorophyll d-containing reaction centers. We show that this bathochromic shift exists in intact AmPBS as well as in its disassembled components, thus suggesting that AmPC can efficiently serve as the AmPBS terminal emitter. PMID- 29704498 TI - The cytochrome bc1 complex inhibitor Ametoctradin has an unusual binding mode. AB - Ametoctradin is an agricultural fungicide that selectively inhibits the cytochrome bc1 complex of oomycetes. Previous spectrophotometric studies using the purified cytochrome bc1 complex from Pythium sp. showed that Ametoctradin binds to the Qo-site of the enzyme. However, as modeling studies suggested a binding mode like that of the substrate ubiquinol, the possibility for a dual Qo- and Qi-site binding mode was left open. In this work, binding studies and enzyme assays with mitochondrial membrane preparations from Pythium sp. and an S. cerevisiae strain with a modified Qi-site were used to investigate further the binding mode of Ametoctradin. The results obtained argue that the compound could bind to both the Qo- and Qi-sites of the cytochrome bc1 complex and that its position or binding pose in the Qi-site differs from that of Cyazofamid and Amisulbrom, the two Qi-site-targeting, anti-oomycetes compounds. Furthermore, the data support the argument that Ametoctradin prefers binding to the reduced cytochrome bc1 complex. Thus, Ametoctradin has an unusual binding mode and further studies with this compound may offer the opportunity to better understand the catalytic cycle of the cytochrome bc1 complex. PMID- 29704499 TI - Spectral components of detergent-solubilized bovine cytochrome oxidase. AB - Cytochrome oxidase is the terminal oxidase of the mitochondrial electron transport chain and pumps 4 protons per oxygen reduced to water. Spectral shifts in the alpha-band of heme a have been observed in multiple studies and these shifts have the potential to shed light on the proton pumping intermediates. Previously we found that heme a had two spectral components in the alpha-band during redox titrations in living RAW 264.7 mouse macrophage cells, the classical 605 nm form and a blue-shifted 602 nm form. To confirm these spectral changes were not an artifact due to the complex milieu of the living cell, redox titrations were performed in the isolated detergent-solubilized bovine enzyme from both the Soret- and alpha-band using precise multiwavelength spectroscopy. This data verified the presence of the 602 nm form in the alpha-band, revealed a similar shift of heme a in the Soret-band and ruled out the reversal of calcium binding as the origin of the blue shift. The 602 nm form was found to be stabilized at high pH or by binding of azide, which is known to blue shift the alpha-band of heme a. Azide also stabilized the 602 nm form in the living cells. It is concluded there is a form of cytochrome oxidase in which heme a undergoes a blue shift to a 602 nm form and that redox titrations can be successfully performed in living cells where the oxidase operates in its authentic environment and in the presence of a proton motive force. PMID- 29704500 TI - Corrigendum to 'Morphological Changes in Different Populations of Bladder Afferent Neurons Detected by Herpes Simplex Virus (HSV) Vectors with Cell-type specific Promoters in Mice with Spinal Cord Injury' [Neuroscience 364 (2017) 190 201]. PMID- 29704501 TI - Molecular identification of BrHAB2a, one of the two AtHAB2-like proteins in Brassica rapa, is an important component of ABA signaling. AB - Abscisic acid (ABA) signaling is a vital physiological step that is used by many land plants to fight against environmental stress. As components of the linear ABA signaling pathway, clade A protein phosphatases type 2C (PP2C-As) are mainly inhibited by PYRABACTIN RESISTANCE1/PYR1-LIKE/REGULATORY COMPONENTS OF ABA RECEPTORS (PYLs)-type receptors upon their binding to ABA. Here, we show that the genome of Brassica rapa encodes 14 putative clade A PP2C-like proteins (BrPP2C As). Two of these BrPP2C-As, Bra025964 and Bra016595, show high similarity to the HAB2 (Homology to ABI2) protein in Arabidopsis. RNAseq data reveal that nearly all BrPP2C-As, like BrHAB2a (Bra025964) and BrHAB2b (Bra016595), were highly expressed in at least one tissue. Overexpression of BrHAB2a conferred ABA insensitivity to Arabidopsis thaliana seedlings. Furthermore, the phosphatase activity of BrHAB2a could be inhibited by AtPYL1 or BrPYL1 in the presence of ABA. Overall, these results suggest that BrHAB2a is a functional PP2C-A like protein phosphotase and a key component of ABA signaling in Brassica rapa. PMID- 29704502 TI - Analysis of metastasis associated signal regulatory network in colorectal cancer. AB - Metastasis is a key factor that affects the survival and prognosis of colorectal cancer patients. To elucidate molecular mechanism associated with the metastasis of colorectal cancer, genes related to the metastasis time of colorectal cancer were screened. Then, a network was constructed with this genes. Data was obtained from colorectal cancer expression profile. Molecular mechanism elucidated the time of tumor metastasis and the expression of genes related to colorectal cancer. We found that metastasis-promoting and metastasis-inhibiting networks included protein hubs of high connectivity. These protein hubs were components of organelles. Some ribosomal proteins promoted the metastasis of colorectal cancer. In some components of organelles, such as proteasomes, mitochondrial ribosome, ATP synthase, and splicing factors, the metastasis of colorectal cancer was inhibited by some sections of these organelles. After performing survival analysis of proteins in organelles, joint survival curve of proteins was constructed in ribosomal network. This joint survival curve showed metastasis was promoted in patients with colorectal cancer (P = 0.0022939). Joint survival curve of proteins was plotted against proteasomes (P = 7 e-07), mitochondrial ribosome (P = 0.0001157), ATP synthase (P = 0.0001936), and splicing factors (P = 1.35e 05). These curves indicate that metastasis of colorectal cancer can be inhibited. After analyzing proteins that bind with organelle components, we also found that some proteins were associated with the time of colorectal cancer metastasis. Hence, different cellular components play different roles in the metastasis of colorectal cancer. PMID- 29704503 TI - Different roles of circular RNAs with protein coding potentials. AB - Circular RNAs are a class of recently identified long non-coding RNAs. Various experiments reveled that they are covalently closed molecules and are resistant to attack by exonucleases. These RNA molecules are linked to various diseases. Interestingly, though they belong to the class of non-coding RNAs, some of them are experimentally verified to code for protein products. Till date there are no reports regarding the structural aspects of the protein products from these circular RNA molecules. In this work, an attempt has been made to analyze the structural details of the proteins obtained from the circular RNA molecules. Only those circular RNAs were selected for which there was direct experimental evidences of generation of protein products. The work for the first time elucidates the molecular details of the protein products obtained from circular RNA molecules. PMID- 29704504 TI - Inhibition of mTOR ameliorates bleomycin-induced pulmonary fibrosis by regulating epithelial-mesenchymal transition. AB - Epithelial-mesenchymal transition (EMT) plays a pivotal role in idiopathic pulmonary fibrosis (IPF). In bleomycin-induced pulmonary fibrosis mice, we observed that inhibition of mTOR (mammalia target of rapamycin) attenuated IPF. Rapamycin suppressed the down-regulation of E-cadherin and up-regulation of fibronectin in bleomycin-induced pulmonary fibrosis mice. In addition, dual immunofluorescence staining for E-cadherin and fibronectin demonstrated that rapamycin pretreatment decreased the proportions of AECs undergoing EMT in bleomycin-induced pulmonary fibrosis, indicating that mTOR inhibition suppressed EMT in vivo. In the setting of transforming growth factor (TGF)-beta1-induced EMT in AECs, we found that mTOR inhibitor attenuated TGF-beta1-induced EMT in AECs. This EMT was characterized by morphology and cell skeleton changes and the expression of EMT phenotype markers. Finally, mTOR blockade decreased S6k and TGF beta1-induced Smad2/3 phosphorylation. Bleomycin induced pulmonary fibrosis and EMT in mice, while mTOR repression inhibited bleomycin-induced pulmonary fibrosis and attenuated EMT in vivo. Hence, our study provided evidence of a novel mechanism by which mTOR inhibitor ameliorates pulmonary fibrosis. Suppression of mTOR and EMT may be a target for treatment of pulmonary fibrosis. PMID- 29704505 TI - Research on epigenetic mechanism of SFRP2 in advanced chronic myeloid leukemia. AB - Secreted frizzled-related protein 2 (SFRP2) has been reported to act as a tumor suppressors. This study aims to detect the biological role of SFRP2 in advanced chronic myeloid leukemia (CML). In this study we examined bone marrow samples from 45 CML patients and 10 healthy donors. K562 and KCL22 cells were cultured and treated with demethylation drug and histone deacetylase inhibitor (HDACi). KCL22 and K562 cells were transfected with lentiviral vector (LV)-SFRP2, LV control. The cells were then subjected to proliferation and apoptosis assays, real time polymerase chain reaction (PCR), Methylation-specific PCR (MSP), Western blotting, co-immunoprecipitation (CoIP) and Chromatin immunoprecipitation (ChIP), We found that SFRP2 was down-regulated in the accelerated and blast phase of CML, whereas, the levels of WNT1, WNT3 and WNT5A were up-regulated in the accelerated and blast phase of CML. Overexpression SFRP2 inhibited proliferation, promoted apoptosis and activated the WNT pathway. CoIP-MS results showed that SFRP2 interacted with WNT1 and WNT5A. ChIP-seq result indicated that the promoter of H3K4me3 and H3K27me3 were able to interact with SFRP2. In conclusion, our findings demonstrated the SFRP2 act as a potential therapeutic target for advanced CML. Furthermore, our results support the use of demethylation drugs and HDACi as a potential CML treatment strategy. PMID- 29704506 TI - Resveratrol alleviates LPS-induced injury in human keratinocyte cell line HaCaT by up-regulation of miR-17. AB - BACKGROUND: Resveratrol (RSV), an edible polyphenolic phytoalexin, plays an important role in ameliorating inflammation, including skin inflammation after burn injury. However, the specific molecular mechanism underlying its anti inflammation effect is still unclear. Herein, the effect and the mechanism underlying the protection of HaCaT cells by RSV against inflammation were examined. METHODS: Lipopolysaccharide (LPS)-induced inflammation and the cytoprotection of RSV were evaluated by detecting viability, apoptosis, expressions of apoptosis-associated proteins and the productions of pro inflammatory factors by CCK-8 assay, flow cytometer, Western blot, and qRT-PCR. miR-17 expression in RSV-treated HaCaT cells was determined by qRT-PCR. The role of miR-17 in protective effect of RSV was investigated after altering its expression using transfection assay. The main ingredients in PTEN/PI3K/AKT and mTOR pathways were quantified by Western blot. RESULTS: LPS-induced HaCaT cell injury was inhibited by RSV administration. RSV promoted viability, inhibited apoptotic cell rate, increased Bcl-2 expression, decreased Bax, cleaved-Caspase 3, and cleaved-Caspase-9 expressions. RSV also inhibited inflammation injury of HaCaT cells by reducing productions of IL-6, IL-8, and TNF-alpha. miR-17 was up regulated in LPS and RSV-co-treated cells. The protective effect of RSV might contribute to overexpression of miR-17. In the mechanism study, RSV-miR-17 axis was found to activate PTEN/PI3K/AKT and mTOR pathways in LPS-treated cells. CONCLUSION: RSV alleviated LPS-induced injury in human keratinocyte cell line HaCaT through activations of PTEN/PI3K/AKT and mTOR pathways, which were modulated by miR-17. PMID- 29704507 TI - Development and Psychometric Evaluation of a Fatigability Index for Full-Time Wheelchair Users With Spinal Cord Injury. AB - OBJECTIVE: To develop and evaluate psychometrically a self-reported instrument assessing physical fatigability (PF) and mental fatigability (MF) in adults with spinal cord injury (SCI). DESIGN: Cross-sectional. SETTING: Peer-support groups at rehabilitation centers, online support groups. PARTICIPANTS: Adults with SCI (N=464) in the United States. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The dimensional structure was assessed by confirmatory factor analysis. The relationship between item responses and fatigability was measured with item response theory (graded response model). Reliability was measured with test information functions. Differential item functioning was evaluated with Wald chi square tests and the weighted area between the curves. Construct validity was assessed using the known groups method. RESULTS: An 82-item pool was developed from prior qualitative research and consultations with rehabilitation experts. A non-probability sample (N=464) was used to evaluate the psychometric properties of the PF and MF scales. The item pool was reduced to 75 based on factor loadings and R2. Both scales are primarily unidimensional, despite moderate multidimensionality. There is good discrimination overall: 18 PF items and 26 MF items have high or very high discrimination power (slopes > 1.35). The measurement precision in the theta range -2.0 to 2.5 is the equivalent of 0.94 reliability for PF and 0.91 for MF. For both measures, F statistics P values were significant at P<.01, and means were higher for those with paraplegia vs quadriplegia, and for those with incomplete paraplegia. CONCLUSIONS: The Fatigability Index is the first instrument designed to assess physical and mental fatigability in adults with SCI. The index highlights causes of fatigue and areas requiring immediate intervention. Development of short-forms and further research on representative samples are necessary. PMID- 29704508 TI - Does Psychological Health Influence Hospital Length of Stay Following Total Knee Arthroplasty? A Systematic Review. AB - OBJECTIVE: To systematically review the literature to determine if preoperative psychological health affected hospital length of stay among adults following primary unilateral total knee arthroplasty. DATA SOURCES: Systematic review. We searched 6 online databases for original research published before December 31, 2016, that investigated adults undergoing primary unilateral total knee arthroplasty. STUDY SELECTION: We included studies that used any measure of preoperative psychological health and reported length of stay, irrespective of study design. We excluded studies that considered participants with cognitive impairment or substance abuse; studies that considered participants who experienced revision, bilateral or hip surgery; and studies that did not have full text available in English. DATA EXTRACTION: One review author screened 438 titles and abstracts for inclusion. Another author reviewed a 10% sample of excluded studies for adherence to the review protocol, with no violations observed. For all included studies, 2 authors independently extracted data from each study using a form designed a priori and independently assessed study quality according to the Joanna Briggs Checklist for Cohort Studies. DATA SYNTHESIS: In view of the heterogeneity of the included studies, we present a narrative synthesis . Of the 7 included studies, 5 reported statistically significant increases in hospital length of stay among those with worse preoperative psychological health. These differences were often <1 calendar day, and, therefore, the clinical significance of these results remains unknown, but the potential to reduce health care costs may still be significant. CONCLUSIONS: Adults experiencing worse preoperative psychological health before total knee arthroplasty may have a longer hospital stay compared to those with unremarkable psychological health. PMID- 29704509 TI - Free fatty acid receptor 1 as a novel therapeutic target for type 2 diabetes mellitus-current status. AB - The incidence of type 2 diabetes mellitus (T2DM) has been on the increase in recent times. Although several oral treatments for T2DM are available, some of them have been found to elicit undesirable side effects. This therefore underscores the need for new treatment options with lesser side effects than the existing ones for people with T2DM. Free fatty acid receptor 1 (FFAR1), also known as GPR40, belongs to a class of G-protein coupled receptors that are encoded by FFAR1 genes in humans. It is expressed in the pancreatic beta-cells and it is activated by medium- and long-chain saturated and unsaturated fatty acids. Thus it responds to endogenous medium and long chain unsaturated fatty acids, resulting in enhancement of insulin secretion during increased glucose levels. The glucose dependency of insulin secretion has made this receptor a very good target for developing therapies that could be efficacious with fewer side effects than the existing therapies for the treatment of T2DM. Given that tremendous efforts have been made in recent times in developing novel FFAR1 agonists with antidiabetic potentials, this article provides a current status of knowledge on the efforts made so far in developing novel FFAR1 agonists that would be of relevance in the management of T2DM. PMID- 29704510 TI - RNA interference against stromal interacting molecule-1 (STIM1) ameliorates ethanol-induced hepatotoxicity. AB - Previously we have demonstrated that stromal interacting molecule-1 (STIM1) was involved in ethanol induced liver injury. However, the exact pathogenic mechanism of STIM1 in alcoholic liver disease (ALD) is still unknown. We constructed plasmid vectors encoding short-hairpin RNA against STIM1 to investigate its role in ALD in the rat liver cell line BRL and in Sprague-Dawley rats. The results showed that STIM1 targeted sh-RNA (Sh-STIM1) significantly ameliorated ethanol induced BRL cells injury and liver injury in rats with 20 weeks-induced alcoholic liver disease. Inhibition of STIM1 also reduced intracellular calcium ion concentration, reactive oxygen species (ROS) production, lipid peroxidation, NF kappa B activation and TNF-alpha production under ethanol exposure. STIM1 may play an important role in the pathogenesis of alcoholic liver disease. Silencing STIM1 may be effective in preventing alcoholic liver disease. PMID- 29704511 TI - NGAL attenuates renal ischemia/reperfusion injury through autophagy activation and apoptosis inhibition in rats. AB - Ischemia/reperfusion (I/R) injury is a main cause of acute kidney injury (AKI), and currently lacks effective therapies. This study is to investigate the level of Neutrophil gelatinase-associated lipocalin (NGAL) and autophagy status during renal I/R injury, so as to determine whether the exogenous NGAL protein could exert a protective effect for I/R injury and explore the potential mechanisms. Forty male Wistar rats were randomly divided into the following four groups: Sham, I/R, pre-treated with NGAL before I/R (I/R + pre-N), treated with NGAL after I/R (I/R + post-N). All rats were subjected to clamping the left renal pedicle for 45 min after right nephrectomy, followed by 24 h of reperfusion. Serum creatinine (SCr) and blood urea nitrogen (BUN) were used for renal function, tubular cell apoptosis and autophagy were measured by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) method, histological examination and electron microscope, respectively. The tubular cell proliferation was assessed by the protein expression of proliferating cell nuclear antigen (PCNA). Western blotting was used to quantitate the levels of LC3, Beclin-1, Bcl-2 and Bax in kidney tissues. Exogenous NGAL protein intervention significantly improved renal function, reduced tubular cell apoptosis, increased tubular cell proliferation and promoted autophagy activation after renal I/R injury. Further, the efficacy in pre-N was significantly better than post-N. The mechanisms were involved in the regulation of several autophagy and apoptosis-related genes. Our study demonstrated that exogenous NGAL protein play a protective role during I/R injury, which may offer a novel may for prevention and treatment of renal I/R injury. PMID- 29704512 TI - The effect of the anodal transcranial direct current stimulation over the cerebellum on the motor cortex excitability. AB - This study was designed to investigate whether the cerebellum has an inhibitory effect on motor cortical excitability. Sixteen healthy adults (age range, 25-50 years, five female) participated in the study. Anodal cerebellar transcranial direct current stimulation (a-cTDCS) was used to modulate cerebellar excitability. A-cTDCS was given for 20 min at 1 mA intensity. The automatic threshold tracking method was used to investigate cortical excitability. Resting motor threshold (RMT), short interval intracortical inhibition (SICI), short interval intracortical facilitation (SICF), intracortical facilitation (ICF), and the input output curve (I-O curve) were motor cortical excitability parameters. a cTDCS caused a reduction in overall SICI and the reduced SICF for interstimulus intervals (ISIs) to 2.4-4.4 ms. a-cTDCS has no effect on ICF, RMT, and the I-O curve. There were no significant changes in any of these cortical excitability parameters after sham cTDCS. Results of the study indicate that a-cTDCS has a dual (both inhibitory and excitatory) effect on motor cortical excitability, rather than a simple inhibitory effect. The cerebellum modulates both the inhibitory and facilitatory activities of motor cortex (M1) and suggest that cerebello-cerebral motor connectivity is more complex than solely inhibitory or facilitatory connections. PMID- 29704513 TI - Outcomes of sequential treatment with sorafenib followed by regorafenib for HCC: Additional analyses from the phase III RESORCE trial. AB - BACKGROUND & AIMS: The RESORCE trial showed that regorafenib improves overall survival (OS) in patients with hepatocellular carcinoma progressing during sorafenib treatment (hazard ratio [HR] 0.62, 95% confidence interval [CI] 0.50 0.78; p <0.0001). This exploratory analysis describes outcomes of sequential treatment with sorafenib followed by regorafenib. METHODS: In RESORCE, 573 patients were randomized 2:1 to regorafenib 160 mg/day or placebo for 3 weeks on/1 week off. Efficacy and safety were evaluated by last sorafenib dose. The time from the start of sorafenib to death was assessed. Time to progression (TTP) in RESORCE was analyzed by TTP during prior sorafenib treatment. RESULTS: HRs (regorafenib/placebo) for OS by last sorafenib dose were similar (0.67 for 800 mg/day; 0.68 for <800 mg/day). Rates of grade 3, 4, and 5 adverse events with regorafenib by last sorafenib dose (800 mg/day vs. <800 mg/day) were 52%, 11%, and 15% vs. 60%, 10%, and 12%, respectively. Median times (95% CI) from the start of sorafenib to death were 26.0 months (22.6-28.1) for regorafenib and 19.2 months (16.3-22.8) for placebo. Median time from the start of sorafenib to progression on sorafenib was 7.2 months for the regorafenib arm and 7.1 months for the placebo arm. An analysis of TTP in RESORCE in subgroups defined by TTP during prior sorafenib in quartiles (Q) showed HRs (regorafenib/placebo; 95% CI) of 0.66 (0.45-0.96; Q1); 0.26 (0.17-0.40; Q2); 0.40 (0.27-0.60; Q3); and 0.54 (0.36-0.81; Q4). CONCLUSIONS: These exploratory analyses show that regorafenib conferred a clinical benefit regardless of the last sorafenib dose or TTP on prior sorafenib. Rates of adverse events were generally similar regardless of the last sorafenib dose. LAY SUMMARY: This analysis examined characteristics and outcomes of patients with hepatocellular carcinoma who were treated with regorafenib after they had disease progression during sorafenib treatment. Regorafenib provided clinical benefit to patients regardless of the pace of their disease progression during prior sorafenib treatment and regardless of their last sorafenib dose. The sequence of sorafenib followed by regorafenib for hepatocellular carcinoma may extend survival beyond what has been previously reported. ClinicalTrials.gov NCT01774344. PMID- 29704514 TI - The coalescent of a sample from a binary branching process. AB - At time 0, start a time-continuous binary branching process, where particles give birth to a single particle independently (at a possibly time-dependent rate) and die independently (at a possibly time-dependent and age-dependent rate). A particular case is the classical birth-death process. Stop this process at time T>0. It is known that the tree spanned by the N tips alive at time T of the tree thus obtained (called a reduced tree or coalescent tree) is a coalescent point process (CPP), which basically means that the depths of interior nodes are independent and identically distributed (iid). Now select each of the N tips independently with probability y (Bernoulli sample). It is known that the tree generated by the selected tips, which we will call the Bernoulli sampled CPP, is again a CPP. Now instead, select exactly k tips uniformly at random among the N tips (a k-sample). We show that the tree generated by the selected tips is a mixture of Bernoulli sampled CPPs with the same parent CPP, over some explicit distribution of the sampling probability y. An immediate consequence is that the genealogy of a k-sample can be obtained by the realization of k random variables, first the random sampling probability Y and then the k-1 node depths which are iid conditional on Y=y. PMID- 29704515 TI - Ancestral inference from haplotypes and mutations. AB - We consider inference about the history of a sample of DNA sequences, conditional upon the haplotype counts and the number of segregating sites observed at the present time. After deriving some theoretical results in the coalescent setting, we implement rejection sampling and importance sampling schemes to perform the inference. The importance sampling scheme addresses an extension of the Ewens Sampling Formula for a configuration of haplotypes and the number of segregating sites in the sample. The implementations include both constant and variable population size models. The methods are illustrated by two human Y chromosome datasets. PMID- 29704517 TI - DUOXA1-mediated ROS production promotes cisplatin resistance by activating ATR Chk1 pathway in ovarian cancer. AB - The acquisition of resistance is a major obstacle to the clinical use of platinum drugs for ovarian cancer treatment. Increase of DNA damage response is one of major mechanisms contributing to platinum-resistance. However, how DNA damage response is regulated in platinum-resistant ovarian cancer cells remains unclear. Using quantitative high throughput combinational screen (qHTCS) and RNA sequencing (RNA-seq), we show that dual oxidase maturation factor 1 (DUOXA1) is overexpressed in platinum-resistant ovarian cancer cells, resulting in over production of reactive oxygen species (ROS). Elevated ROS level sustains the activation of ATR-Chk1 pathway, leading to resistance to cisplatin in ovarian cancer cells. Moreover, using qHTCS we identified two Chk1 inhibitors (PF-477736 and AZD7762) that re-sensitize resistant cells to cisplatin. Blocking this novel pathway by inhibiting ROS, DUOXA1, ATR or Chk1 effectively overcomes cisplatin resistance in vitro and in vivo. Significantly, the clinical studies also confirm the activation of ATR and DOUXA1 in ovarian cancer patients, and elevated DOUXA1 or ATR-Chk1 pathway correlates with poor prognosis. Taken together, our findings not only reveal a novel mechanism regulating cisplatin resistance, but also provide multiple combinational strategies to overcome platinum-resistance in ovarian cancer. PMID- 29704518 TI - Inhibition of MAPKAPK2/MK2 facilitates DNA replication upon cancer cell treatment with gemcitabine but not cisplatin. AB - The signaling pathway driven by p38 and MAPKAPK2 alias MK2 is activated as part of stress responses, and these kinases represent attractive drug targets for cancer therapy. However, seemingly conflicting results were obtained when assessing the role of MK2 in chemotherapy. MK2 inhibitors were reported to either enhance or diminish the chemosensitivity of cancer cells. Here we show that this strongly depends on the particular chemotherapeutic drug. Two different MK2 inhibitors increased the proliferating fraction of pancreatic cancer-derived cells upon treatment with gemcitabine, whereas no consistent protection against cisplatin was observed. Both drugs enhanced, rather than attenuated, the toxicity of another DNA crosslinking agent, mitomycin C. Gemcitabine and cisplatin were each capable of activating MK2, and we did not observe differences in the intracellular localization of MK2 upon treatment. However, DNA replication fork progression, as determined by fiber assays, was restored by MK2 inhibition upon treatment with gemcitabine, but not when cisplatin was used. Thus, MK2 is required for the reduction in DNA replication in response to gemcitabine but not to cisplatin. These observations raise the need to carefully evaluate synergisms and antagonisms with conventional chemotherapeutics when taking MK2 inhibitors to the clinics. PMID- 29704519 TI - Hemocyanin-derived phenoloxidase reaction products display anti-infective properties. AB - Hemocyanin is a multi-functional protein located in the hemolymph (blood) of certain arthropods and molluscs. In addition to its well-defined role in oxygen transport, hemocyanin can be converted into a phenoloxidase-like enzyme. Herein, we tested the antimicrobial properties of horseshoe crab (Limulus polyphemus) hemocyanin-derived phenoloxidase reaction products using broad ranges of phenolic substrates (e.g. l-DOPA) and microbial targets (Gram-positive/negative bacteria, yeast). The enzyme-catalysed turnover of several substrates generated (by)products that reduced significantly the number of colony forming units. Microbicidal effects of hemocyanin-derived phenoloxidase were thwarted by the inhibitor phenylthiourea. Data presented here further support a role for hemocyanin in invertebrate innate immunity. PMID- 29704520 TI - Trends in the incidence and outcome of paediatric out-of-hospital cardiac arrest: A 17-year observational study. AB - BACKGROUND: System-based improvements to the chain of survival have yielded increases in survival from out-of-hospital cardiac arrest (OHCA) in adults. Comparatively little is known about the long-term trends in incidence and survival following paediatric OHCA. METHODS: Between 2000 and 2016, we included children aged <=16 years who suffered a non-traumatic OHCA in the state of Victoria, Australia. Trends in incidence and unadjusted outcomes were assessed using linear regression and a non-parametric test for trend. Multivariable logistic regression with multiple imputation was used to identify arrest factors associated with event survival and survival to hospital discharge. RESULTS: Of the 1301 paediatric OHCA events attended by emergency medical services (EMS), 948 (72.9%) received an attempted resuscitation. The overall incidence of EMS attended and EMS-treated events was 6.7 and 4.9 cases per 100,000 person-years, with no significant changes in trend. Although the proportion of cases with OHCA identified in the call and receiving bystander CPR increased over time, EMS response times also increased. Unadjusted event survival rose from 23.3% in 2000 to 33.3% in 2016 (p trend = .007), and survival to hospital discharge rose from 9.4% to 17.7% over the same period (p trend = .04). Increases in survival to hospital discharge were largely driven by initial shockable arrests, which rose from 33.3% in 2000 to 60.0% in 2016 (p trend = .005). Survival after initial shockable arrests was higher if the first shock was delivered by either first responder or public AED compared with paramedics (83.3% vs. 40.0%, p = .04). After adjustment, the odds of event survival and survival to hospital discharge increased independent of baseline characteristics, by 7% (OR 1.07, 95% CI: 1.03, 1.11; p = .001) and 8% (OR 1.08, 95% CI: 1.01, 1.15; p = .02) per study year, respectively. CONCLUSIONS: Survival following paediatric OHCA increased in our region over a 17 year period. This was driven, in part, by improving outcomes for initial shockable arrests. PMID- 29704516 TI - The neuroanatomic complexity of the CRF and DA systems and their interface: What we still don't know. AB - Corticotropin-releasing factor (CRF) is a neuropeptide that mediates the stress response. Long known to contribute to regulation of the adrenal stress response initiated in the hypothalamic-pituitary axis (HPA), a complex pattern of extrahypothalamic CRF expression is also described in rodents and primates. Cross talk between the CRF and midbrain dopamine (DA) systems links the stress response to DA regulation. Classically CRF + cells in the extended amygdala and paraventricular nucleus (PVN) are considered the main source of this input, principally targeting the ventral tegmental area (VTA). However, the anatomic complexity of both the DA and CRF system has been increasingly elaborated in the last decade. The DA neurons are now recognized as having diverse molecular, connectional and physiologic properties, predicted by their anatomic location. At the same time, the broad distribution of CRF cells in the brain has been increasingly delineated using different species and techniques. Here, we review updated information on both CRF localization and newer conceptualizations of the DA system to reconsider the CRF-DA interface. PMID- 29704521 TI - Including experimental uncertainty on the independent variables when modelling microbial dynamics: The combined effect of pH and acetic acid on the growth rate of E. coli K12. AB - Modelling methods applied in predictive microbiology generally neglect the importance of uncertainty on the measurement of the independent variables. The Ordinary Least Squares (OLS) method that is commonly applied in predictive microbiology is only applicable if the experimental error on the inputs of the model are insignificant. However, this does not apply for many types of experimental measurements of the independent variables. Therefore, a parameter estimation method was adapted in this research for the estimation of the parameters of secondary models, taking into account uncertainty on the measurement of the influencing food characteristics. This parameter estimation method was based on the work of Stortelder (1996) and is referred to as the Weighted Total Least Squares method (WTLS). The method is formulised as an extension of the commonly used OLS method. Consequently the current WTLS method (i) is easily implemented using similar numerical methods, (ii) reduces to an OLS method when the measurement error on the model inputs is negligible and (iii) enables the evaluation of the accuracy of the model parameter estimates based on the same approximations. PMID- 29704522 TI - Mapping functional brain organization: Rethinking lesion symptom mapping and advanced neuroimaging methods in the understanding of human cognition. PMID- 29704523 TI - Uncanny valley as a window into predictive processing in the social brain. AB - Uncanny valley refers to humans' negative reaction to almost-but-not-quite-human agents. Theoretical work proposes prediction violation as an explanation for uncanny valley but no empirical work has directly tested it. Here, we provide evidence that supports this theory using event-related brain potential recordings from the human scalp. Human subjects were presented images and videos of three agents as EEG was recorded: a real human, a mechanical robot, and a realistic robot in between. The real human and the mechanical robot had congruent appearance and motion whereas the realistic robot had incongruent appearance and motion. We hypothesize that the appearance of the agent would provide a context to predict her movement, and accordingly the perception of the realistic robot would elicit an N400 effect indicating the violation of predictions, whereas the human and the mechanical robot would not. Our data confirmed this hypothesis suggesting that uncanny valley could be explained by violation of one's predictions about human norms when encountered with realistic but artificial human forms. Importantly, our results implicate that the mechanisms underlying perception of other individuals in our environment are predictive in nature. PMID- 29704524 TI - Differential effects of high-frequency transcranial random noise stimulation (hf tRNS) on contrast sensitivity and visual acuity when combined with a short perceptual training in adults with amblyopia. AB - Amblyopia is a neuro-developmental disorder characterised by several functional impairments in spatial vision even with the best optical correction. There is evidence that extensive perceptual training can improve visual acuity (VA) and contrast sensitivity (CS) in adults with amblyopia. In the present study, we assessed the efficacy of a recently developed neuro-modulatory technique (i.e., high-frequency transcranial random noise stimulation; hf-tRNS) combined with a short perceptual training in adults with amblyopia. One group of ten participants underwent a short (8 sessions) monocular training in a contrast detection task with concurrent hf-tRNS, whereas another group of ten participants underwent the same training protocol but with Sham stimulation (control group). The training consisted of a two-interval forced choice (2IFC) contrast detection task in which participants had to detect the presence of a central Gabor patch flanked by two high-contrast collinear Gabors (lateral masking). The results showed a significant and similar improvement of CS for both groups, suggesting that hf tRNS is not crucial for the improvement of CS. However, for VA, a significant improvement was only observed in the hf-tRNS group with a mean VA improvement of 0.19 LogMAR in the amblyopic eye. Most notably, this improvement was achieved after eight training sessions. The results are discussed in terms of the influence of hf-tRNS on short-term neural plasticity. PMID- 29704525 TI - Opportunities and challenges for using the zebrafish to study neuronal connectivity as an endpoint of developmental neurotoxicity. AB - Chemical exposures have been implicated as environmental risk factors that interact with genetic susceptibilities to influence individual risk for complex neurodevelopmental disorders, including autism spectrum disorder, schizophrenia, attention deficit hyperactivity disorder and intellectual disabilities. Altered patterns of neuronal connectivity represent a convergent mechanism of pathogenesis for these and other neurodevelopmental disorders, and growing evidence suggests that chemicals can interfere with specific signaling pathways that regulate the development of neuronal connections. There is, therefore, a growing interest in developing screening platforms to identify chemicals that alter neuronal connectivity. Cell-cell, cell-matrix interactions and systemic influences are known to be important in defining neuronal connectivity in the developing brain, thus, a systems-based model offers significant advantages over cell-based models for screening chemicals for effects on neuronal connectivity. The embryonic zebrafish represents a vertebrate model amenable to higher throughput chemical screening that has proven useful in characterizing conserved mechanisms of neurodevelopment. Moreover, the zebrafish is readily amenable to gene editing to integrate genetic susceptibilities. Although use of the zebrafish model in toxicity testing has increased in recent years, the diverse tools available for imaging structural differences in the developing zebrafish brain have not been widely applied to studies of the influence of gene by environment interactions on neuronal connectivity in the developing zebrafish brain. Here, we discuss tools available for imaging of neuronal connectivity in the developing zebrafish, review what has been published in this regard, and suggest a path forward for applying this information to developmental neurotoxicity testing. PMID- 29704526 TI - A novel gene expression analytics-based approach to structure aided design of rexinoids for development as next-generation cancer therapeutics. AB - Rexinoids are powerful ligands that bind to retinoid-X-receptors (RXRs) and show great promise as therapeutics for a wide range of diseases, including cancer. However, only one rexinoid, bexarotene (Targretin TM) has been successfully transitioned from the bench to the clinic and used to treat cutaneous T-cell lymphoma (CTCL). Our goal is to develop novel potent rexinoids with a less untoward side effect profile than bexarotene. To this end, we have synthesized a wide array of rexinoids with EC50 values and biological activity similar to bexarotene. In order to determine their suitability for additional downstream analysis, and to identify potential candidate analogs for clinical translation, we treated human CTCL cells in culture and employed microarray technology to assess gene expression profiles. We analyzed twelve rexinoids and found they could be stratified into three distinct categories based on their gene expression: similar to bexarotene, moderately different from bexarotene, and substantially different from bexarotene. Surprisingly, small changes in the structure of the bexarotene parent compound led to marked differences in gene expression profiles. Furthermore, specific analogs diverged markedly from our hypothesis in expression of genes expected to be important for therapeutic promise. However, promoter analysis of genes whose expression was analyzed indicates general regulatory trends along structural frameworks. Our results suggest that certain structural motifs, particularly the basic frameworks found in analog 4 and analog 9, represent important starting points to exploit in generating additional rexinoids for future study and therapeutic applications. PMID- 29704528 TI - Plant selenium hyperaccumulation- Ecological effects and potential implications for selenium cycling and community structure. AB - BACKGROUND: Selenium (Se) hyperaccumulation occurs in ~50 plant taxa native to seleniferous soils in Western USA. Hyperaccumulator tissue Se levels, 1000-15,000 mg/kg dry weight, are typically 100 times higher than surrounding vegetation. Relative to other species, hyperaccumulators also transform Se more into organic forms. SCOPE OF REVIEW: We review abiotic and biotic factors influencing soil Se distribution and bioavailability, soil being the source of the Se in hyperaccumulators. Next, we summarize the fate of Se in plants, particularly hyperaccumulators. We then extensively review the impact of plant Se accumulation on ecological interactions. Finally, we discuss the potential impact of Se hyperaccumulators on local community composition and Se cycling. MAJOR CONCLUSIONS: Selenium (hyper)accumulation offers ecological advantages: protection from herbivores and pathogens and competitive advantage over other plants. The extreme Se levels in and around hyperaccumulators create a toxic environment for Se-sensitive ecological partners, while offering a niche for Se resistant partners. Through these dual effects, hyperaccumulators may influence species composition in their local environment, as well as Se cycling. GENERAL SIGNIFICANCE: The implied effects of Se hyperaccumulation on community assembly and local Se cycling warrant further investigations into the contribution of hyperaccumulators and general terrestrial vegetation to global Se cycling and may serve as a case study for how trace elements influence ecological processes. Furthermore, understanding ecological implications of plant Se accumulation are vital for safe implementation of biofortification and phytoremediation, technologies increasingly implemented to battle Se deficiency and toxicity. PMID- 29704527 TI - Tacrine derivatives stimulate human glioma SF295 cell death and alter important proteins related to disease development: An old drug for new targets. AB - Glioblastoma is the most common and aggressive glioma, characterized by brain invasion capability. Being very resistant to the current therapies, since even under treatment, surgery, and chemotherapy with temozolomide (TMZ), patients achieve a median survival of one year. In the search for more effective therapies, new molecules have been designed. For nervous system cancers, molecules able to cross the blood-brain barrier are handled with priority. Accordingly, tacrine was chosen for this study and the inclusion of spiro heterocyclic rings was done in its structure resulting in new compounds. Cytotoxic activity of tacrine derivatives was assayed using glioblastoma cell line (SF295) as well as analyzing cell death mechanism. Increased caspases activities were observed, confirming apoptosis as cell death type. Some derivatives also increased reactive oxygen species formation and decreased the mitochondrial membrane potential. Moreover, compounds acted on several glioblastoma-related proteins including p53, HLA-DR, beta-catenin, Iba-1, MAP2c, Olig-2, and IDH1. Therefore, tacrine derivatives presented promising results for the development of new glioblastoma therapy, particularly to treat those patients resistant to TMZ. PMID- 29704529 TI - Modeling relationships of achievement motivation and physical fitness with academic performance in Japanese schoolchildren: Moderation by gender. AB - The aim of this study was to determine, using structural equation modeling, the comprehensive relationships of achievement motivation (self-fulfillment achievement motivation [SFAM] and competitive achievement motivation [CAM]), daily behaviors (exercise habits, screen time, and learning duration), body mass index [BMI], and cardiorespiratory fitness [CRF]) with academic performance among schoolchildren. Three hundred twenty-five schoolchildren (172 males and 153 females; 12-13 years old) were recruited. Academic performance was assessed using the total grade points in 8 academic subjects (GP8); CRF using the 20-m shuttle run; and achievement motivation, daily behaviors, and socioeconomic status using questionnaires. Socioeconomic status was included as a control variable. In males, two cascade associations of achievement motivation to GP8 were detected: (1) SFAM -> screen time/learning duration -> GP8, and (2) CAM -> exercise habit > CRF -> GP8 (chi2 = 8.72, p = .19, AGFI = .92). In females, two cascade associations were also detected: (1) SFAM -> screen time/learning habit -> GP8, and (2) exercise habit -> BMI2 -> GP8 (chi2 = 6.17, p = .41, AGFI = .93). Our results suggest that greater achievement motivation is associated with academic success via various physiological/behavioral factors, and that these associations differ by gender. PMID- 29704530 TI - How social factors and behavioural strategies affect feeding and social interaction patterns in pigs. AB - Animals living in groups compete for food resources and face food conflicts. These conflicts are affected by social factors (e.g. competition level) and behavioural strategies (e.g. avoidance). This study aimed to deepen our understanding of the complex interactions between social factors and behavioural strategies affecting feeding and social interaction patterns in animals. We focused on group-housed growing pigs, Sus scrofa, which typically face conflicts around the feeder, and of which patterns in various competitive environments (i.e. pig:feeder ratio) have been documented soundly. An agent-based model was developed to explore how interactions among social factors and behavioural strategies can affect various feeding and social interaction patterns differently under competitive situations. Model results show that pig and diet characteristics interact with group size and affect daily feeding patterns (e.g. feed intake and feeding time) and conflicts around the feeder. The level of competition can cause a turning point in feeding and social interaction patterns. Beyond a certain point of competition, meal-based (e.g. meal frequency) and social interaction patterns (e.g. displacements) are determined mainly by behavioural strategies. The average daily feeding time can be used to predict the group size at which this turning point occurs. Under the model's assumptions, social facilitation was relatively unimportant in the causation of behavioural patterns in pigs. To validate our model, simulated patterns were compared with empirical patterns in conventionally housed pigs. Similarities between empirical and model patterns support the model results. Our model can be used as a tool in further research for studying the effects of social factors and group dynamics on individual variation in feeding and social interaction patterns in pigs, as well as in other animal species. PMID- 29704531 TI - Biologically active fungal depsidones: Chemistry, biosynthesis, structural characterization, and bioactivities. AB - Fungi produce a wide range of structurally unique metabolites. Depsidones represent one of the most interesting classes of metabolites, consisting of two 2,4-dihydroxybenzoic acid rings linked together by both ether and ester bonds. Naturally occurring depsidones are produced by lichen, fungi, and plants. They possessed a wide array of bioactivities, including antioxidant, antiproliferative, antimalarial, cytotoxic, antibacterial, radical scavenging, antihypertensive, anti-inflammatory, antifungal, and aromatase and protein kinase inhibitory. In order to point out the potential of this class of compounds, the present review focuses only on the depsidones that have been isolated from fungal source and published from 1978 to 2018. This review outlined the research on the biosynthesis, source, isolation, spectral and physical data, and bioactivities of the naturally occurring fungal depsidones. On the basis of 88 references, > 80 compounds have been described. PMID- 29704532 TI - MDM2 controls NRF2 antioxidant activity in prevention of diabetic kidney disease. AB - Oxidative stress and P53 contribute to the pathogenesis of diabetic kidney disease (DKD). Nuclear factor erythroid 2-related factor 2 (NRF2) is a master regulator of cellular antioxidant defense system, is negatively regulated by P53 and prevents DKD. Recent findings revealed an important role of mouse double minute 2 (MDM2) in protection against DKD. However, the mechanism remained unclear. We hypothesized that MDM2 enhances NRF2 antioxidant signaling in DKD given that MDM2 is a key negative regulator of P53. The MDM2 inhibitor nutlin3a elevated renal P53, inhibited NRF2 signaling and induced oxidative stress, inflammation, fibrosis, DKD-like renal pathology and albuminuria in the wild-type (WT) non-diabetic mice. These effects exhibited more prominently in nutlin3a treated WT diabetic mice. Interestingly, nutlin3a failed to induce greater renal injuries in the Nrf2 knockout (KO) mice under both the diabetic and non-diabetic conditions, indicating that NRF2 predominantly mediates MDM2's action. On the contrary, P53 inhibition by pifithrin-alpha activated renal NRF2 signaling and the expression of Mdm2, and attenuated DKD in the WT diabetic mice, but not in the Nrf2 KO diabetic mice. In high glucose-treated mouse mesangial cells, P53 gene silencing completely abolished nutlin3a's inhibitory effect on NRF2 signaling. The present study demonstrates for the first time that MDM2 controls renal NRF2 antioxidant activity in DKD via inhibition of P53, providing MDM2 activation and P53 inhibition as novel strategies in the management of DKD. PMID- 29704533 TI - Sphingolipid-mediated calcium signaling and its pathological effects. AB - Metabolites of sphingomyelin, as well as calcium ion fluxes, have a profound role in cellular signaling in almost all cell types. In addition, metabolites of sphingomyelin often modulate calcium signaling, either directly or indirectly. This is an interesting aspect on how lipids may wield their physiological role, as calcium is probably one of the most versatile signaling molecules in the cell, and as modulation of calcium signaling has profound effects on cellular physiology. The aim of this review is to discuss the mechanisms by which metabolites of sphingomyelin, especially the sphingolipids sphingosine and sphingosine 1-phosphate (S1P), modulate calcium fluxes, and how this may affect cellular function. In addition, the pathological aspects of sphingolipid-evoked modulation of calcium fluxes will be discussed. PMID- 29704534 TI - Toxin-resolved antivenomics-guided assessment of the immunorecognition landscape of antivenoms. AB - Snakebite envenoming represents a major issue in rural areas of tropical and subtropical regions across sub-Saharan Africa, South to Southeast Asia, Latin America and Oceania. Antivenoms constitute the only scientifically validated therapy for snakebite envenomings, provided they are safe, effective, affordable, accessible and administered appropriately. However, the lack of financial incentives in a technology that has remained relatively unchanged for more than a century, has contributed to some manufacturers leaving the market and others downscaling production or increasing the prices, leading to a decline in the availability and accessibility for these life-saving antidotes to millions of rural poor most at risk from snakebites in low income countries. The shortage of antivenoms can be significantly alleviated by optimizing the use of current antivenoms (through the assessment of their specific and paraspecific efficacy against the different medically relevant homologous and heterologous snake venoms) and by generating novel polyspecific antivenoms exhibiting broad clinical spectrum and wide geographic distribution range. Research on venoms has been continuously enhanced by advances in technology. Particularly, the last decade has witnessed the development of omics strategies for unravelling the toxin composition of venoms ("venomics") and to assess the immunorecognition profile of antivenoms ("antivenomics"). Here, we review recent developments and reflect on near future innovations that promise to revolutionize the mutually enlightening relationship between evolutionary and translational venomics. PMID- 29704536 TI - Binocular contrast-gain control for natural scenes: Image structure and phase alignment. AB - In the context of natural scenes, we applied the pattern-masking paradigm to investigate how image structure and phase alignment affect contrast-gain control in binocular vision. We measured the discrimination thresholds of bandpass filtered natural-scene images (targets) under various types of pedestals. Our first experiment had four pedestal types: bandpass-filtered pedestals, unfiltered pedestals, notch-filtered pedestals (which enabled removal of the spatial frequency), and misaligned pedestals (which involved rotation of unfiltered pedestals). Our second experiment featured six types of pedestals: bandpass filtered, unfiltered, and notch-filtered pedestals, and the corresponding phase scrambled pedestals. The thresholds were compared for monocular, binocular, and dichoptic viewing configurations. The bandpass-filtered pedestal and unfiltered pedestals showed classic dipper shapes; the dipper shapes of the notch-filtered, misaligned, and phase-scrambled pedestals were weak. We adopted a two-stage binocular contrast-gain control model to describe our results. We deduced that the phase-alignment information influenced the contrast-gain control mechanism before the binocular summation stage and that the phase-alignment information and structural misalignment information caused relatively strong divisive inhibition in the monocular and interocular suppression stages. When the pedestals were phase-scrambled, the elimination of the interocular suppression processing was the most convincing explanation of the results. Thus, our results indicated that both phase-alignment information and similar image structures cause strong interocular suppression. PMID- 29704537 TI - Testosterone and FSH modulate Sertoli cell extracellular secretion: Proteomic analysis. AB - Spermatogenesis is a highly complicated biological process that occurs in the epithelium of the seminiferous tubules. It is regulated by a complex network of endocrine and paracrine factors and by juxtacrine testicular cross-talk. Sertoli cells (SC) play a key role in spermatogenesis due to their production of trophic, differentiation and immune-modulating factors, but many of the molecular pathways of SC action remain controversial and unclear. Over the last two decades, research has focused on extracellular vesicles as an important mechanism of intercellular communication. The aim of this study was to investigate the presence of extracellular vesicles (EVs) in SC and the modulation of their content in SC after FSH and testosterone stimulation. Highly purified porcine pre pubertal Sertoli cells were isolated according to previously established methods. After 48 h of culture with FSH or FSH + testosterone stimulation, we identified sertolian EVs containing specific mRNAs. Proteomic analysis of EVs content identified 29 proteins under non-stimulatory conditions, most of which were related to receptor binding activity. FSH stimulation induced increases in inhibin-alpha, inhibin-beta, plakoglobin, haptoglobin, D-3-phosphoglycerate dehydrogenase and sodium/potassium-transporting ATPase in sertolian EVs. Testosterone stimulation enhanced the abundance of inhibin-alpha, inhibin-beta, tissue-type plasminogen activator, epidermal growth factor-like protein 8, elongating factor 1-gamma and D-3-phosphoglycerate dehydrogenase. These results are likely to help determine the unknown molecular secretion of Sertoli cells. PMID- 29704538 TI - In vitro oxidized HDL and HDL from type 2 diabetes patients have reduced ability to efflux oxysterols from THP-1 macrophages. AB - Oxidized LDL (OxLDL) that are enriched in products of lipid peroxidation including oxysterols have been shown to induce cellular oxidative stress and cytotoxicity therefore accelerating atheroma plaque formation. Upon oxLDL exposure of THP-1 macrophages, intracellular oxidation of LDL derived-cholesterol as well as endogenous cholesterol was increased. The oxysterols intracellularly produced were efficiently exported to HDL whereas apolipoprotein A1 was inefficient. These findings prompted us to investigate the consequences of modification of HDL by oxidation and glycation as observed in type 2 diabetes with respect to oxysterol and cholesterol efflux. We show that efflux of oxysterols was significantly impaired after in vitro oxidation and glycoxidation of HDL whereas glycation alone had no impact. Cholesterol efflux was only slightly decreased by oxHDL or glycoxidized HDL and not changed with glycated HDL. The defect of HDL towards oxysterol efflux was also observed with HDL isolated from diabetic subjects as compared to healthy controls. These findings support a deleterious cellular retention of oxysterols due to dysfunctional HDL in type 2 diabetes. PMID- 29704539 TI - Identification of Pseudomonas mosselii BS011 gene clusters required for suppression of Rice Blast Fungus Magnaporthe oryzae. AB - Pseudomonas is a Gram-negative, rod-shaped bacteria. Many members of this genus displayed remarkable physiological and metabolic activity against different plant pathogens. However, Pseudomonas mosselii has not yet been characterized in biocontrol against plant disease. Here we isolated a strain of P. mosselii BS011 from the rhizosphere soil of rice plants, and the isolate showed strong inhibitory activity against the rice blast fungus Magnaporthe oryzae. Further we sequenced the complete genome of BS011, which consist of 5.75 Mb with a circular chromosome, 5,170 protein-coding genes, 23 rRNA and 78 tRNA operons. Bioinformatic analysis revealed that seven gene clusters may be involved in the biosynthesis of metabolites. Gene deletion experiments demonstrated that the gene cluster c-xtl is required for inhibitory activity against M. oryzae. Bioassay showed that the crude extract from BS011 fermentation sample significantly inhibited the development of M. oryzae at a concentration of 10 MUg/ml. Besides, we illustrated that the crude extract of BS011 impaired the appressorial formation in a dose dependent manner. Collectively our results revealed that P. mosselii BS011 is a promising biocontrol agent and the gene cluster c-xtl is essential for inhibiting the development of M. oryzae. PMID- 29704540 TI - "A bumpy road": Kindergarten staff's experiences with an intervention to promote healthy diets in toddlers. AB - : This study explores the experiences of kindergarten staff with a multi component kindergarten-based intervention, the aims of which were to reduce levels of food neophobia and to promote healthy diets in toddlers (aged 2-3 years). A qualitative design was chosen for the study, and the data are based on three focus group interviews. Altogether, 15 kindergarten staff were interviewed using a semi-structured interview guide. The focus group interviews were analyzed using qualitative content analysis. Five main themes emerged from the interviews: i) Successful development of sensory knowledge, ii) Food neophobia, iii) Implementing new routines, a challenge for some, iv) Lack of cooking skills, and v) Inspired to continue. A main finding was that all kindergarten staff perceived the sensory education sessions as successful and reported that both toddlers and staff expanded their food vocabulary and increased their attention to sensory impressions of food. However, the staff reported that some toddlers were less willing to taste new lunch dishes than to taste new foods in the sensory education sessions. The staff also noted that the guidelines for feeding practices resulted in unfamiliar situations at the lunch table. The staff agreed that cooking novel foods was time consuming and left less time for other tasks. Finally, all kindergarten staff expressed that they would like to continue with portions of the food intervention. Our main interpretation is that the intervention presented several challenges, especially regarding cooking and feeding practices. If kindergartens are to be a place to promote healthy eating habits in the early years, sufficient time and resources for cooking seem to be needed and food and feeding practices included in the curriculum of kindergartens and higher education for kindergarten teachers. TRIAL REGISTRATION: ISRCTN74823448. PMID- 29704541 TI - Towards more sustainable diets: Insights from the food philosophies of "gourmets" and their relevance for policy strategies. AB - Food has become a central focus for the achievement of sustainability objectives. One of the current challenges is that promoting food sustainability requires much more attention to cultural and social contexts and the food philosophies of specific groups of consumers. The present paper focuses on those consumers in the Netherlands who intrinsically appreciate the taste and the quality of food (hereafter "gourmets"). Our expectation was that, due to their respect for the origin of food and their distance from mainstream food culture, the gourmets may be able to reveal practices and cultural assumptions that help to find entry points for promoting more sustainable food choices among the general population. Drawing on literature about gastronomy, Slow Food and craft consumption, fifteen in-depth interviews were held to examine the food philosophies of individual gourmets from a health and sustainability perspective. The results demonstrated how the values of pleasure of taste, food competences and social relatedness may contribute to the extent of complementarity between culinary and ethical principles. Entry points for promoting change in a more sustainable direction include a shift from quantity to quality, such as meals with less but better meat, a shift towards making meals less focused on meat and a general open mindedness towards other eating styles (a new look at vegetables), a shift to planning for a competent use of leftovers and a shift in willingness to accept limitations on food choices, such as the seasonal unavailability of food. PMID- 29704542 TI - Ambulatory Blood Pressure and Endothelial Dysfunction in Hematopoietic Cell Transplantation Recipients. AB - Hematopoietic cell transplantation (HCT) is a common treatment for many disorders. Albuminuria post-HCT, which may represent endothelial injury or inflammation from graft- versus-host disease, increases the risk of chronic kidney disease and nonrelapse mortality at 1 year. HCT recipients also have abnormal blood pressure (BP) and increased rates of cardiovascular complications. We sought to determine the relationships among albuminuria, endothelial dysfunction, and BP in HCT recipients. Patients age >=12 years who underwent their first allogeneic HCT between 2012 and 2015 and survived through day 80 post HCT were eligible. Peripheral endothelial function was assessed using the EndoPAT2000 device at day 80 along with 24-hour ambulatory BP monitoring (ABPM). Clinical and laboratory data were collected along with a urine sample for calculation of the albumin-to-creatinine ratio. Both logistic and linear regression analyses were used to identify associations between EndoPAT score and clinical variables. Sixty patients (median age, 48 years; range, 14 to 69 years) completed the study. The median EndoPAT score was 2.05 (range, 1.02 to 4.45), and 17 patients (28%) had abnormal endothelial function. Forty-two patients (72%) had ambulatory hypertension (HTN), and 38 (63%) had blunted nocturnal dipping. HTN on ABPM (P = .045) and blunted nocturnal dipping (P = .04) were associated with a lower EndoPAT score. Albuminuria was not associated with EndoPAT score. There was a lack of agreement between our clinical definition of HTN (office BP and/or use of medications) and ABPM results (P = .04). We did not find an association between lower EndoPAT scores and albuminuria, but did find an association between an abnormal nocturnal dip and HTN diagnosed by ABPM. This suggests that albuminuria may reflect local endothelial injury and inflammation rather than a systemic process. Office BP readings do not accurately reflect true BP, suggesting that 24-hour ABPM studies are needed to diagnose and treat HTN appropriately. PMID- 29704543 TI - Allogeneic Hematopoietic Stem Cell Transplantation to Cure Transfusion-Dependent Thalassemia: Timing Matters! PMID- 29704544 TI - Prenatal exposure to benzophenone-3 (BP-3) induces apoptosis, disrupts estrogen receptor expression and alters the epigenetic status of mouse neurons. AB - Current evidence indicates that benzophenone-3 (BP-3) can pass through the placental and blood-brain barriers and thus can likely affect infant neurodevelopment. Despite widespread exposure, data showing the effects of BP-3 on the developing nervous system are scarce. This study revealed for the first time that prenatal exposure to BP-3 led to apoptosis and neurotoxicity, altered the levels of estrogen receptors (ERs) and changed the epigenetic status of mouse neurons. In the present study, subcutaneous injections of pregnant mice with BP-3 at 50 mg/kg, which is an environmentally relevant dose, evoked activation of caspase-3 and lactate dehydrogenase (LDH) release as well as substantial loss of mitochondrial membrane potential in neocortical cells of their embryonic offspring. Apoptosis-focused microarray analysis of neocortical cells revealed up regulation of 22 genes involved in apoptotic cell death. This effect was supported by increased BAX and CASP3 mRNA and protein levels, as evidenced by qPCR, ELISAs and western blots. BP-3-induced apoptosis and neurotoxicity were accompanied by decreases in the mRNA and protein expression levels of ESR1 and ESR2 (also known as ERalpha and ERbeta), with a simultaneous increase in GPER1 (also known as GPR30) expression. In addition to the demonstration that treatment of pregnant mice with BP-3 induced apoptosis, caused neurotoxicity and altered ERs expression levels in neocortical cells of their embryonic offspring, we showed that prenatal administration of BP-3 inhibited global DNA methylation as well as reduced DNMTs activity. BP-3 also caused specific hypomethylation of the genes Gper1 and Bax, an effect that was accompanied by increased mRNA and protein expression levels. In addition, BP-3 caused hypermethylation of the genes Esr1, Esr2 and Bcl2, which could explain the reduced mRNA and protein levels of the estrogen receptors. This study demonstrated for the first time that prenatal exposure to BP-3 caused severe neuronal apoptosis that was accompanied by impaired ESR1/ESR2 expression, enhanced GPER1 expression, global DNA hypomethylation and altered methylation statuses of apoptosis-related and ERs genes. We suggest that the effects of BP-3 in embryonic neurons may be the fetal basis of the adult onset of nervous system disease. PMID- 29704545 TI - Polychlorinated biphenyl 138 exposure-mediated lipid droplet enlargement endows adipocytes with resistance to TNF-alpha-induced cell death. AB - Although epidemiological reports have shown the association between polychlorinated biphenyls (PCBs) and obesity, the molecular mechanism of PCB induced obesity is mostly unknown. The aim of the present study was to further dissect the significance of lipid droplet (LD) enlargement in PCB-induced obesity. For this aim, we hypothesized that PCB-induced LD enlargement endows adipocytes with resistance to cell death, inhibiting the natural loss of adipocytes. Four types of PCBs were screened, and the detailed molecular mechanism was investigated by using PCB-138. We observed that PCB-138-conferred cell death resistance to hypertrophic adipocytes with enlarged LDs. We further observed that PCB-138 prevents Tumour necrosis factor-alpha (TNF-alpha)-induced apoptosis and necroptosis in 3T3-L1 adipocytes and increases the expression of anti-apoptotic proteins, including survivin, in vitro and in vivo. In addition, we demonstrated that fat-specific protein 27 (Fsp27), perilipin, and survivin endow adipocytes with resistance to TNF-alpha-induced cell death through sustaining enlarged LDs. Thus, the present study suggests that PCB-138-induced LD enlargement endows adipocytes with resistance to TNF-alpha-induced cell death and that Fsp27, perilipin, and survivin, at least in part, help adipocytes to sustain enlarged LDs, contributing to the induction of obesity. PMID- 29704546 TI - Adaptive changes in global gene expression profile of lung carcinoma A549 cells acutely exposed to distinct types of AhR ligands. AB - Exposure to persistent ligands of aryl hydrocarbon receptor (AhR) has been found to cause lung cancer in experimental animals, and lung adenocarcinomas are often associated with enhanced AhR expression and aberrant AhR activation. In order to better understand the action of toxic AhR ligands in lung epithelial cells, we performed global gene expression profiling and analyze TCDD-induced changes in A549 transcriptome, both sensitive and non-sensitive to CH223191 co-treatment. Comparison of our data with results from previously reported microarray and ChIP seq experiments enabled us to identify candidate genes, which expression status reflects exposure of lung cancer cells to TCDD, and to predict processes, pathways (e.g. ER stress, Wnt/beta-cat, IFNgamma, EGFR/Erbb1), putative TFs (e.g. STAT, AP1, E2F1, TCF4), which may be implicated in adaptive response of lung cells to TCDD-induced AhR activation. Importantly, TCDD-like expression fingerprint of selected genes was observed also in A549 cells exposed acutely to both toxic (benzo[a]pyrene, benzo[k]fluoranthene) and endogenous AhR ligands (2 (1H-Indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester and 6 formylindolo[3,2-b]carbazole). Overall, our results suggest novel cellular candidates, which could help to improve monitoring of AhR-dependent transcriptional activity during acute exposure of lung cells to distinct types of environmental pollutants. PMID- 29704547 TI - Predictive performance of a gentamicin population pharmacokinetic model in two western populations of critically ill patients. AB - : External validation of population pharmacokinetic (PK) models is warranted before they can be clinically applied to aid in antibiotic dose selection. The primary objective of this study was to assess the predictive performance of a gentamicin population PK model in intensive care unit (ICU) patients in two independent western populations of critically ill patients. METHODS: Data were collected from the ICU where the model was developed (Academic Medical Centre, Amsterdam [AMC]) and from the Centre Hospitalier Universitaire de Nimes (CHU Nimes). Primary endpoints were bias and accuracy. The model was regarded as valid if bias was not significantly different from 0 and accuracy was equal to or less than 2.5 mg/L. Non-linear mixed-effects modelling (NONMEM) was used for data analysis. RESULTS: The AMC validation dataset consisted of 192 samples from 66 ICU patients and the CHU Nimes dataset of 230 gentamicin samples from 50 ICU patients. The structural model predicted the gentamicin plasma concentrations in the AMC population with a non-significant bias (0.35, 95%CI: -0.11-0.81) and a sufficient accuracy of 2.5 mg/L (95%CI: 2.3-2.8). The gentamicin plasma concentrations were overpredicted in the CHU Nimes population with a significant bias of 4.8 mg/L (95%CI: 4.00-5.62) and an accuracy of 5.5 mg/L (95%CI: 4.7-6.2). CONCLUSION: The model is valid for use in the AMC ICU population but not in the CHU Nimes ICU population. This illustrates that caution is needed when using a population PK model in an external population. PMID- 29704548 TI - Toxicity and aggregation of the polyglutamine disease protein, ataxin-3 is regulated by its binding to VCP/p97 in Drosophila melanogaster. AB - Among the nine dominantly inherited, age-dependent neurodegenerative diseases caused by abnormal expansion in the polyglutamine (polyQ) repeat of otherwise unrelated proteins is Spinocerebellar Ataxia Type 3 (SCA3). SCA3 is caused by polyQ expansion in the deubiquitinase (DUB), ataxin-3. Molecular sequelae related to SCA3 remain unclear. Here, we sought to understand the role of protein context in SCA3 by focusing on the interaction between this DUB and Valosin-Containing Protein (VCP). VCP is bound directly by ataxin-3 through an arginine-rich area preceding the polyQ repeat. We examined the importance of this interaction in ataxin-3-dependent degeneration in Drosophila melanogaster. Our assays with new isogenic fly lines expressing pathogenic ataxin-3 with an intact or mutated VCP binding site show that disrupting the ataxin-3-VCP interaction delays the aggregation of the toxic protein in vivo. Importantly, early on flies that express pathogenic ataxin-3 with a mutated VCP-binding site are indistinguishable from flies that do not express any SCA3 protein. Also, reducing levels of VCP through RNA-interference has a similar, protective effect to mutating the VCP binding site of pathogenic ataxin-3. Based on in vivo pulse-chases, aggregated species of ataxin-3 are highly stable, in a manner independent of VCP-binding. Collectively, our results highlight an important role for the ataxin-3-VCP interaction in SCA3, based on a model that posits a seeding effect from VCP on pathogenic ataxin-3 aggregation and subsequent toxicity. PMID- 29704550 TI - Tau hyperphosphorylation and P-CREB reduction are involved in acrylamide-induced spatial memory impairment: Suppression by curcumin. AB - Acrylamide (ACR) is an axonal toxicant that produces peripheral neuropathy in laboratory animals and humans. Epidemiological study found that diet ACR exposure was associated with a mild cognitive decline in men. However, limited information is available as regards its potential and underlying mechanism to cause memory alterations. Curcumin is a polyphenol with neuroprotective and cognitive enhancing properties. In this study, we aimed to investigate the mechanism of ACR induced spatial memory impairment and the beneficial effect of curcumin. ACR exposure at 10 mg/kg/d for 7 weeks caused slight gait abnormality and spatial memory deficits, which was associated with an activation of glial cells, a reduction of phosphorylated cAMP response elements binding protein (P-CREB) and an aggregation of hyperphosphorylated tau including p-tau (Ser262), AT8 (p-tau Ser202/Thr205) and PHF1 (p-tau Ser396/404) in the hippocampus and cortex. ACR markedly regulate the expression of glycogen synthase kinase-3beta (GSK-3beta) and cyclin-dependent kinase-5 (cdk5) to accelerate tau hyperphosphorylation. ACR inhibited the protein phosphatase 2A (PP2A) and lysosomal protease cathepsin D to decrease the p-tau dephosphorylation and degradation. The P-CREB and brain derived neurotrophic factor (BDNF) were significantly decreased by ACR. The upstream signalings of P-CREB, extracellular signal-related kinase (ERK) and Akt were markedly inhibited. The protein kinase RNA-like endoplasmic reticulum kinase (PERK) -eukaryotic initiation factor-2alpha (eIF2alpha) - activating transcription factor 4 (ATF4) signaling which negatively regulate memory processes by suppressing CREB was activated by ACR. Curcumin alleviated ACR induced spatial memory impairment through reversing tau abnormalities and P-CREB reduction in the hippocampus. These results offered deeper insight into the mechanisms of and presented a potential new treatment for ACR-induced neurotoxicity. PMID- 29704549 TI - The role of autophagy in acute brain injury: A state of flux? AB - It is established that increased autophagy is readily detectable after various types of acute brain injury, including trauma, focal and global cerebral ischemia. What remains controversial, however, is whether this heightened detection of autophagy in brain represents a homeostatic or pathologic process, or an epiphenomenon. The ultimate role of autophagy after acute brain injury likely depends upon: 1) the degree of brain injury and the overall autophagic burden; 2) the capacity of individual cell types to ramp up autophagic flux; 3) the local redox state and signaling of parallel cell death pathways; 4) the capacity to eliminate damage associated molecular patterns and toxic proteins and metabolites both intra- and extracellularly; and 5) the timing of the pro- or anti-autophagic intervention. In this review, we attempt to reconcile conflicting studies that support both a beneficial and detrimental role for autophagy in models of acute brain injury. PMID- 29704551 TI - Reducing impulsive choice: V. The role of timing in delay-exposure training. AB - Impulsive decision-making is common in addiction-related disorders, with some research suggesting it plays a causal role in their development. Therefore, reducing impulsive decision-making may prevent or reduce addiction-related behaviors. Recent research shows that prolonged experience with response contingent delayed reward (delay exposure [DE] training) reduces impulsive choice in rats, but it is unclear what behavioral mechanisms underlie this effect. The present study evaluated whether improvements in interval timing mediate the effects of DE training on impulsive choice. Thirty-nine Long-Evans rats were randomly assigned to groups completing DE, immediacy-, or no-exposure training, followed by impulsive-choice and timing tasks (temporal bisection). Despite replicating the DE effect on impulsive choice, timing accuracy and precision were unaffected by DE training and unrelated to impulsive choice. The present findings did not replicate previous reports that timing precision and impulsive choice are related, which may be due to between-laboratory differences in impulsive choice tasks. Continued research to identify candidate behavioral mechanisms of DE training may assist in improving training efficacy and facilitating translational efforts. PMID- 29704552 TI - Effects of sucrose concentration on choice in an adjusting-magnitude schedule. AB - Rats were trained under a discrete-trials adjusting-magnitude schedule in which a response on lever A delivered either a larger or a smaller sucrose reinforcer (qA1 = 8 MUl, qA2 = 64 MUl) with equal probability, while a response on B delivered a reinforcer whose size qB was adjusted according to the rats' choices. When A was preferred in a given block of trials, qB was increased in the following block; when B was preferred, qB was reduced in the following block. The oscillating changes in qB, analysed by the Fourier transform, could be described by a power spectrum whose dominant frequency corresponded to a period of 40-50 trial blocks. The equilibrium value of qB (qB(50)) was inversely related to sucrose concentration; it significantly exceeded the arithmetic mean of qA1 and qA2 when the concentration was 0.2 or 0.4 M, but not when it was 0.8 or 1.6 M. Analysis by mixed-effects modelling revealed a trend for the power of oscillation of qB to increase monotonically with sucrose concentration; the period of oscillation was not systematically related to sucrose concentration. These results are consistent with predictions derived from a revised version of the multiplicative hyperbolic model of intertemporal choice. PMID- 29704553 TI - Changes in natural haemolytic complement activity induced by stress in gilthead seabream (Sparus aurata L.). AB - In aquaculture, animals can be continually exposed to environmental stress factors that put their health and even survival at risk. Two experiments were performed to evaluate the impact of different stress conditions (acute crowding and anaesthetic) on the natural haemolytic complement activity in serum and skin mucus of gilthead seabream (Sparus aurata L.). In the first experiment, fish were subjected to 10 kg m-3 (low density, control group) and 50 kg m-3 (high density, crowding group) during 2, 24 and 48 h. In the second experiment, fish were unexposed (control) or exposed to 40 ppm of MS-222 or 5 ppm or 10 ppm of clove oil for 1 h. In fish maintained in acute crowding conditions only an increase of the haemolytic complement activity was observed in the skin mucus after 24 h of exposure. However, a similar statistically significant increase was observed in serum and skin mucus of fish exposed for 1 h to the lowest concentration of clove oil (5 ppm) tested. The results point to a new and alternative way to assess stress in farmed fish by using skin mucus instead of blood serum and confirm that the measurement of natural haemolytic complement activity serves as an indicator of stress in fish. PMID- 29704554 TI - Growth, physiological, antioxidants, and immune response of African catfish, Clarias gariepinus (B.), to dietary clove basil, Ocimum gratissimum, leaf extract and its susceptibility to Listeria monocytogenes infection. AB - Clove basil, Ocimum gratissimum, is a native plant to Africa and grows virtually in tropical and subtropical regions. It has good aroma and its leaves have become used as a spicy and in traditional medicine. The use of plant leaves in fish diets may deteriorate their growth because it may content anti-nutritional factors. Thus, it is better to use plants leaves extract. In the current study, clove basil leaves extract (CBLE) was administrated to African catfish, Clarias gariepinus (B.) to evaluate its effect on growth performance, physiological, antioxidants, and innate immunity variables. Fish (10.7 +/- 0.5 g) were fed on diets enriched with 0.0, 5, 10, or 15 g CBLE/kg diet for 12 weeks. After the feeding trial, fish were further exposed to pathogenic bacteria (Listeria monocytogenes) for 14 days. Fish performance and feed intake were significantly enhanced with increasing CBLE levels and its optimum level is found to be 12 g/kg diet. It is noticed that the dietary CBLE in African catfish diets increased significantly the intestinal villi length, villi width, and absorption area in a dose-dependent manner and fish weight was highly correlated with villi length, villi width, and absorption area (R2 = 0.91, 0.91, and 0.92, respectively). On the other side, Dietary CBLE has significant modulatory effect on hemato- and physiological variables of African catfish in a dose-dependent manner. In this regard, blood glucose and cholesterol levels decreased significantly; mean while total protein, albumin, and globulin increased significantly in fish fed high CBLE levels (10-15 g/kg diet). Furthermore, activities of aspartate aminotransferase and alanine aminotransferase, alkaline phosphatase, urea, and creatinine levels were significantly elevated with increasing dietary CBLE levels and their maximum values were detected in fish fed 15 g CBLE/kg diet. Antioxidants and immunity variables were significantly enhanced by CBLE supplementation. Additionally, fish mortality after bacterial challenge was highest in fish fed the control diet (85%) than those fed CBLE-enriched diets. The lowest fish mortality was observed in fish fed 15 g CBLE/kg diet (13.5%). This study evoked that CBLE administration enhanced the performance, feed utilization, antioxidant, and innate immunity properties of African catfish with optimum level of 12 g/kg diet. Also, its supplementation enhanced fish challenge against L. monocytogenes. PMID- 29704555 TI - The G-protein gamma subunit of Phytophthora infestans is involved in sporangial development. AB - The oomycete Phytophthora infestans is a notorious plant pathogen with potato and tomato as its primary hosts. Previous research showed that the heterotrimeric G protein subunits Galpha and Gbeta have a role in zoospore motility and virulence, and sporangial development, respectively. Here, we present analyses of the gene encoding a Ggamma subunit in P. infestans, Pigpg1. The overall similarity of PiGPG1 with non-oomycete Ggamma subunits is low, with only the most conserved amino acids maintained, but similarity with its homologs in other oomycetes is high. Pigpg1 is expressed in all life stages and shows a similar expression profile as the gene encoding the Gbeta subunit, Pigpb1. To elucidate its function, transformants were generated in which Pigpg1 is silenced or overexpressed and their phenotypes were analyzed. Pigpg1-silenced lines produce less sporangia, which are malformed. Altogether, the results show that PiGPG1 is crucial for proper sporangia development and zoosporogenesis. PiGPG1 is a functional Ggamma, and likely forms a dimer with PiGPB1 that mediates signaling. PMID- 29704556 TI - National characteristics and trends in antiretroviral treatment in Australia can be accurately estimated using a large clinical cohort. AB - OBJECTIVES: Cohort studies are often used as a national surveillance tool to monitor trends in HIV treatment and morbidity outcomes. However, there are limited studies validating the accuracy of using cohorts as a representation of the overall HIV-positive population. We compared data from a large Australian HIV positive cohort study (Australian HIV Observational Database [AHOD]) and a 10% longitudinal sample from Australia's subsidized prescription medication scheme (Pharmaceutical Benefits Scheme [PBS]) to assess the use of cohorts for providing representative data for surveillance and monitoring purposes. STUDY DESIGN AND SETTING: Basic demographics and treatment information from July 1, 2013, to March 31, 2016, were divided into half-yearly periods to compare HIV trends between AHOD (n = 2,488) and PBS (n = 18,409) patients. RESULTS: In both data sets, most patients were men, aged above 50 years, and primarily resided in New South Wales. Both data sets revealed a significant shift toward the increased use of integrase strand transfer inhibitors and a gradual decline in the use of protease inhibitors and nonnucleoside reverse-transcriptase inhibitors among the treated population in Australia. Similarly, a substantial increase in the use of once daily, single-tablet, fixed-dose combination regimens was also observed. CONCLUSION: Our results show that observational cohort studies can serve as useful surrogate surveillance tools for monitoring patient characteristics and HIV treatment trends. PMID- 29704557 TI - Mabfilin and Fabfilin - New antibody-scaffold fusion formats for multispecific targeting concepts. AB - Protein based binding molecules have a broad applicability from therapeutic to technical use. Monoclonal antibodies represent the major class of this type of agents complemented by innovative approaches using scaffold proteins with tailor made properties. Various concepts for new formats combining antibody chains or antibody fragments and fusions with other entities have been developed recently. This strategy opens up options to design molecules with biophysical, biochemical and pharmacological characteristics in a broad range while simultaneously addressing several targets or epitopes. The demand for such compounds is still growing as reflected by the literature and further new ideas are expected. In this context we developed so called Mabfilin and Fabfilin molecules. The formats synergistically bring together the classical antibody or fragments thereof supplemented with additional binding moieties, the Affilin(r) molecules. These are based on the scaffold ubiquitin endowed with novel targeting properties by local randomization and selection from combinatorial libraries. Mab-/Fabfilin variants show advantageous biochemical properties and open a new route for the development of multispecific compounds for flexible applications. PMID- 29704558 TI - Genome-wide association studies in kidney transplantation: Advantages and constraints. AB - Since the discovery of the human leukocyte antigen (HLA) system, the role of HLA molecules in the field of transplantation has been appreciated: better matching leads to better graft function. Since then, the association of other genetic polymorphisms with clinical outcome has been investigated in many studies. Genome wide association studies (GWAS) represent a powerful tool to identify causal genetic variants, by simultaneously analyzing millions of single nucleotide polymorphisms scattered across the genome. GWAS in transplantation may indeed be useful to reveal novel markers that may potentially be involved in the mechanism of allograft rejection and graft failure. However, the relevance of GWAS for risk stratification or donor selection for an individual patient is limited as is already reflected by the fact that many parameters, significant in one study, cannot be confirmed in another one. PMID- 29704559 TI - Quantitative measurement of cartilage volume is possible using two-dimensional magnetic resonance imaging data sets. AB - PURPOSE: 3D Magnetic resonance imaging (MRI) scans are generally used for quantitative cartilage measurements in knee osteoarthritis. However, a great deal of MRI data is from 2D scans, often thought to be unsuitable for quantitative cartilage assessment. The goal of our study was to demonstrate that mLACS, a modified version of the Local Area Cartilage Segmentation (LACS) method, could be used to measure cartilage volume on 2D MRI images. METHODS: We studied 301 randomly selected subjects from the OA Biomarkers Consortium FNIH Study, a nested case-control study within the Osteoarthritis Initiative (OAI). The study comprised four subgroups based on radiographic and pain progression. We compared mLACS applied to 2D TSE scans to LACS on 3D DESS data. The Pearson's correlation coefficient was used to establish agreement between LACS and mLACS, standardized response means (SRMs) for responsiveness, and intra-class correlation coefficients (ICCs) to measure reader precision. Logistic regression in a case/control analysis was used to compare the clinical validity between the two methods. RESULTS: We found R2 = 0.76 for the correlation between LACS and mLACs. For LACS, the responsiveness was SRM = 0.49 compared to 0.39 for mLACS. The odds ratios (OR) for the primary case/control analyses were 1.62 for LACS and 1.78 for mLACS. The intra and inter reader reproducibility values for mLACS were ICC = 0.90 and 0.86, respectively. CONCLUSION: This study has demonstrated that a reproducible, responsive, and clinically valid quantitative measurement of cartilage volume can be made using 2D TSE scans with a modest loss of responsiveness compared to 3D scans. PMID- 29704560 TI - Identification of an optimal threshold for detecting human brown adipose tissue using receiver operating characteristic analysis of IDEAL MRI fat fraction maps. AB - PURPOSE: Lower fat fraction (FF) in brown adipose tissue (BAT) than white adipose tissue (WAT) has been exploited using Dixon-based Magnetic Resonance Imaging (MRI) to differentiate these tissues in rodents, human infants and adults. We aimed to determine whether an optimal FF threshold could be determined to differentiate between BAT and WAT in adult humans in vivo. METHODS: Sixteen volunteers were recruited (9 females, 7 males; 44.2 +/- 19.2 years) based on BAT uptake on 18F-FDG PET/CT. Axial 3-echo TSE IDEAL sequences were acquired (TR(ms)/TE(ms)/matrix/NEX/FoV(cm) = 440/10.7-11.1/512 * 512/3/30-40), of the neck/upper thorax on a 3T HDxt MRI scanner (GE Medical Systems, Milwaukee, USA), and FF maps generated from the resulting water- and fat-only images. BAT depots were delineated on PET/CT based on standardized uptake values (SUV) >2.5 g/ml, and transposed onto FF maps. WAT depots were defined manually within subcutaneous fat. Receiver operating characteristic (ROC) analyses were performed, and optimal thresholds for differentiating BAT and WAT determined for each subject using Youden's J statistic. RESULTS: There was large variation in optimal FF thresholds to differentiate BAT and WAT between subjects (0.68-0.85), with great variation in sensitivity (0.26-0.84) and specificity (0.62-0.99). FF was excellent or good at separating BAT and WAT in four cases (area under the curve [AUC] 0.84-0.92), but poor in 10 (AUC 0.25-0.68). CONCLUSION: Although this technique was effective at differentiating BAT and WAT in some cases, no universal cut-off could be identified to reliably differentiate BAT and WAT in vivo in adult humans on the basis of FF. PMID- 29704561 TI - Oral carcinoma: Clinical evaluation using diffusion kurtosis imaging and its correlation with histopathologic findings. AB - PURPOSE: In this study, we aimed to determine the usefulness of diffusion kurtosis imaging (DKI) as a noninvasive method for evaluation of the histologic grade and lymph node metastasis in patients with oral carcinoma. MATERIALS AND METHODS: Twenty-seven patients with oral carcinoma were examined with a 3-T MR system and 16-channel coil. DKI data were obtained by a single-shot echo-planar imaging sequence with repetition time, 10,000 ms; echo time, 94 ms; field of view, 250 * 204.25 ms; matrix, 120 * 98; section thickness, 4 mm; four b values of 0, 500, 1000, and 2000 s/mm2; and motion-probing gradients in three orthogonal directions. Diffusivity (D) and kurtosis (K) were calculated using the equation: S = S0 ? exp(-b ? D + b2 ? D2 ? K/6). Conventional apparent diffusion coefficient (ADC) was also calculated. The MR images were compared with the histopathologic findings. RESULTS: Relative to the histologic grades (Grades 1, 2, and 3) of the 27 oral carcinomas, D values showed a significant inverse correlation (r = 0.885; P < 0.001) and K values showed a significant positive correlation (r = 0.869; P < 0.001), whereas ADC values showed no significant correlation (r = 0.311; P = 0.115). When comparing between metastatic and non-metastatic lymph nodes, significant differences in the D values (P < 0.001) and K values (P < 0.001), but not the ADC values (P = 0.110) became apparent. CONCLUSIONS: In patients with oral carcinoma, DKI seems to be clinically useful for the evaluation of histologic grades and lymph node metastasis. PMID- 29704562 TI - A survey to identify the breach between evidence and practice in the prevention of surgical infection: Time to take action. AB - BACKGROUND: The knowledge of the grade of implementation of preventative measures for surgical site infection (SSI) is crucial prior to planning dissemination strategies. METHODS: Online survey among the members of the Spanish Association of Surgeons (AEC) to know the actual application of measures, and to compare them with new recommendations issued by international organizations. RESULTS: Most of the 835 responding surgeons work in National Health Service Hospitals (91.3%). Surgeons of all super-specialties answered. 90.4% of responders recommend a preoperative shower, with normal soap or chlorhexidine. 60% recommend hair removal, preferably clipping, although 30% still recommend shaving. Povidone iodine in aqueous solution or chlorhexidine in alcohol are used for skin preparation. Only 51.9% of surgeons allow solution to air drying before applying surgical drapes. In 83.2% of cases surgeons operate with a single pair of gloves. Perioperative normothermia and hyperoxia were used in 92% and 27.9% of cases, respectively. At the end of the procedure, peritoneal and wound lavage are used, in most cases with saline. Antimicrobial impregnated sutures are rarely used (85.7%) by surgeons, and 32% occasionally use negative pressure therapy on the closed wound. CONCLUSIONS: There is great variability in the level of awareness and application of the main measures of SSI prevention among Spanish surgeons. Several areas for improvement have been detected, as core prevention measures are not in common use, and discontinued practices are continued to be used. These practices should be addressed by the AEC by drafting specific recommendations for the prevention of SSI in Spanish hospitals. PMID- 29704564 TI - The Mediterranean and the DASH dietary patterns: Insights into their role in cardiovascular disease prevention. PMID- 29704563 TI - Building a model for day case hiatal surgery - Lessons learnt over a 10 year period in a high volume unit: A case series. AB - BACKGROUND: Laparoscopic anti-reflux surgery has become the standard treatment for symptomatic gastro-oesophageal reflux disease refractory to medical therapy. Successful anti-reflux surgery involves safe, minimally invasive surgery, resulting in symptom resolution with minimal side effects. This study aims to assess the feasibility and safety of day case anti-reflux surgery focussing on peri- and post-operative outcomes as a measure of success. METHODS: Data was collected from the hospital database from 2003 to 2012. Data collection included demographics, surgeon, mode of admission, length of stay and complications. Electronic records were independently scrutinised for all patients with a length of stay of more than two nights. RESULTS: 723 patients underwent laparoscopic fundoplication +/- small hiatus hernia repair (<5 cm) with a day case rate of 67.1%. The 30 day readmission rate in these patients was 2.9% (21/723 patients). Nine patients had a failure of their initial laparoscopic fundoplication (defined as recurrence of symptoms). Three patients required a re-operation within 12 months of their initial procedure (re-operation rate = 0.41% (3/723 patients)). CONCLUSION: Laparoscopic hiatal surgery can be performed safely as a day case in high volume specialist centres with good outcomes. Raising the national standard for day case fundoplication promotes good practice and should be the model for future commissioning. PMID- 29704565 TI - Antithrombotic treatment in patients with acute coronary syndromes and atrial fibrillation. What is established and what is missing. PMID- 29704566 TI - Cryoballoon ablation under transesophageal echocardiographic guidance in dextrocardia. PMID- 29704567 TI - Physiological activation and deactivation of soluble guanylate cyclase. AB - Soluble guanylate cyclase (sGC) is responsible for transducing the gaseous signaling molecule nitric oxide (NO) into the ubiquitous secondary signaling messenger cyclic guanosine monophosphate in eukaryotic organisms. sGC is exquisitely tuned to respond to low levels of NO, allowing cells to respond to non-toxic levels of NO. In this review, the structure of sGC is discussed in the context of sGC activation and deactivation. The sequence of events in the activation pathway are described into a comprehensive model of in vivo sGC activation as elucidated both from studies with purified enzyme and those done in cells. This model is then used to discuss the deactivation of sGC, as well as the molecular mechanisms of pathophysiological deactivation. PMID- 29704568 TI - The reaction between GSNO and H2S: On the generation of NO, HNO and N2O. AB - Several recent reports suggest that HNO may be produced endogenously by reaction of H2S and S-nitrosoglutathione (GSNO). This hypothesis was tested using deoxymyoglobin (MbFeII) to trap the expected HNO released from the target reaction, which should generate the stable HNO adduct, HNO-Mb, under anaerobic conditions. Under numerous experimental conditions, the sole globin product was NO-Mb, as characterized by absorbance, EPR, and NMR spectroscopies. Analogous reactions of GSNO with other biological reductants such as ascorbic acid, dithiothreitol, glutathione, and dithionite also yielded NO-Mb as the sole globin product; however, whereas analogous reduction of GSNO using NaBH4 generates HNO Mb in high yield. Quantitative GC/MS analyses of reactions of GS15NO with H2S showed that the main reaction product was 15NO, with 15N2 produced at a comparable level to 15N2O. Overall yield of N2O is unchanged by the presence of MbFeII, discounting the intermediacy of either NO or HNO in its formation. Taken together, these results argue against the generation of free HNO as a major pathway in the reactions of GSNO with H2S, and instead imply some as yet uncharacterized intermediates generate the nitrogenic gases. PMID- 29704569 TI - Protein biomarkers associated with pain mechanisms in osteoarthritis. AB - Osteoarthritis (OA) is the most common arthritic disease in the world, leading to debilitating pain and destruction of joint tissues. While pain is the hallmark symptom of osteoarthritis, clear associations between pain and disease processes involved in joint deterioration are lacking. OA pain is multifactorial and may arise from multiple distinct or concurrent mechanisms, and may thus present as different pain sub-types. Several biomarkers developed to reflect important pathological processes are available, and associations between such biomarkers and OA pain may give hints to important pathological features, which have not been possible to assess using clinical, radiographic or magnetic resonance imaging techniques. This review highlights a selection of important, protein derived biomarkers measured in body fluids from OA patients, which have been associated with different types and aspects of OA pain, and discusses the potential mechanisms behind the associations. SIGNIFICANCE: Osteoarthritis (OA) is a heterogenous disease affecting the entire joint, including cartilage, bone and synovium. While pain is the hallmark symptom of osteoarthritis, clear associations between pain and disease processes involved in joint deterioration are lacking. Thus, there is clear need for biomarkers that can accurately describe the underlying processes and distinguish between different disease and pain pathologies. In this review we discuss a selected number of biomarkers which have been directly or indirectly associated with pain mechanisms and development of pain in OA either via structural correlates or as molecular sensitizing agents. We further evaluate the challenges that the OA field faces in the development and application of biomarkers for OA pain. PMID- 29704570 TI - Proteomic analysis of the effect of plant-derived smoke on soybean during recovery from flooding stress. AB - : Flooding negatively affects the growth of soybean, whereas the plant-derived smoke enhances seedling growth of crops. To clarify the mechanism underlying the recovery from flooding stress, proteomic analysis was performed based on morphological results. Growth of soybean seedlings was inhibited under flooding stress, but it recovered after water removal following treatment with plant derived smoke. Sucrose/starch metabolism and glycolysis were suppressed in smoke treated flooded soybean compared to flooded soybean. The protein abundance and gene expression of O-fucosyltransferase family proteins related to the cell wall were higher in smoke-treated flooded soybean than in flooded soybean. Protein abundance and gene expression of peptidyl-prolyl cis-trans isomerase and Bowman Birk proteinase isoinhibitor D-II were lower in smoke-treated flooded soybean than in flooded soybean. Taken together, these results suggest that plant-derived smoke enhances soybean growth during recovery from flooding stress through the balance of sucrose/starch metabolism and glycolysis. Furthermore, the accumulation of cell-wall related protein might be an important factor contributing to recovery of soybean from flooding stress. BIOLOGICAL SIGNIFICANCE: Flooding negatively affects the growth of soybean, whereas the plant-derived smoke enhances the seedling growth of crops. To clarify the mechanism underlying the recovery from flooding stress, proteomic analysis of soybean with different treatments including normal conditions, flooding stress, and flooding stress in the presence of plant-derived smoke was performed in this study. Growth of soybean seedlings was inhibited under flooding stress, however, it recovered with plant-derived smoke treatment during recovery from flooding stress. Sucrose/starch metabolism and glycolysis were suppressed in smoke-treated flooded soybean compared to flooded soybean, which suggests altered sucrose/starch metabolism and glycolysis contribute to soybean growth recovery from flood stress. Furthermore, the protein abundance and gene expression of O fucosyltransferase family proteins related to the cell wall was higher in smoke treated flooded soybean than in flooded soybean, which might be an important factor contributing to the recovery of soybean from flooding stress. PMID- 29704571 TI - Detection of EGFR Variants in Plasma: A Multilaboratory Comparison of a Real-Time PCR EGFR Mutation Test in Europe. AB - Molecular testing of EGFR is required to predict the response likelihood to targeted therapy in non-small cell lung cancer. Analysis of circulating tumor DNA in plasma may complement limitations of tumor tissue. This study evaluated the interlaboratory performance and reproducibility of a real-time PCR EGFR mutation test (cobas EGFR Mutation Test v2) to detect EGFR variants in plasma. Fourteen laboratories received two identical panels of 27 single-blinded plasma samples. Samples were wild type or spiked with plasmid DNA to contain seven common EGFR variants at six predefined concentrations from 50 to 5000 copies per milliliter. The circulating tumor DNA was extracted by a cell-free circulating DNA sample preparation kit (cobas cfDNA Sample Preparation Kit), followed by duplicate analysis with the real-time PCR EGFR mutation test (Roche Molecular Systems, Pleasanton, CA). Lowest sensitivities were obtained for the c.2156G>C p.(Gly719Ala) and c.2573T>G p.(Leu858Arg) variants for the lowest target copies. For all other variants, sensitivities varied between 96.3% and 100.0%. All specificities were 98.8% to 100.0%. Coefficients of variation indicated good intralaboratory and interlaboratory repeatability and reproducibility but increased for decreasing concentrations. Prediction models revealed a significant correlation for all variants between the predefined copy number and the observed semiquantitative index values, which reflect the samples' plasma mutation load. This study demonstrates an overall robust performance of the real-time PCR EGFR mutation test kit in plasma. Prediction models may be applied to estimate the plasma mutation load for diagnostic or research purposes. PMID- 29704572 TI - What does the functional organization of cortico-hippocampal networks tell us about the functional organization of memory? AB - Historically, research on the cognitive processes that support human memory proceeded, to a large extent, independently of research on the neural basis of memory. Accumulating evidence from neuroimaging, however, has enabled the field to develop a broader and more integrative perspective. Here, we briefly outline how advances in cognitive neuroscience can potentially shed light on concepts and controversies in human memory research. We argue that research on the functional properties of cortico-hippocampal networks informs us about how memories might be organized in the brain, which, in turn, helps to reconcile seemingly disparate perspectives in cognitive psychology. Finally, we discuss several open questions and directions for future research. PMID- 29704573 TI - Cortical modulation of brainstem circuits is abnormal in cervical dystonia. AB - OBJECTIVE: In healthy subjects, magnitude of hand-evoked blink reflex (BR) is increased if the stimulated hand is positioned in the peripersonal space. Here, we aimed to investigate the modulation of hand-evoked BR in peripersonal space to understand alterations of cortical modulations of subcortical structures in cervical dystonia. PATIENTS AND METHOD: We recruited 23 patients with idiopathic cervical dystonia and 21 healthy subjects, all of whom had hand-evoked BR. The reflex was recorded while stimulated hand was close to face ('peripersonal space) and far away from face (extrapersonal space). Comparisons were done between two conditions in each group. RESULTS: In extrapersonal space, magnitude of the reflex was bigger in patients compared to healthy subjects. In peripersonal space, magnitude of the reflex was increased in healthy subjects whereas it was reduced in patients. Comparisons of patients with and without sensory trick disclosed reflex magnitude was reduced in peripersonal space in patients with sensory trick whereas it did not change between two conditions in patients without sensory trick. DISCUSSION: Enhancement of hand-evoked BR is a normal phenomenon that provides evidence for top-down modulation of its neural circuitry. In cervical dystonia, the normal modulation is lost which suggests abnormal modulatory effect of higher-order centers upon brainstem circuits. The pattern of alteration also differs if there is no sensory trick. PMID- 29704575 TI - The glutamate clearance function of adipose stromal cells-derived astrocytes. AB - ADSCs-derived astrocytes qualify the morphology, ultrastructure and membrane electrical potential, which are all unique to astrocytes. But whether they have the glutamate clearance function like mature astrocytes is under exploration. ADSCs were extracted, cultured and induced into astrocytes for 48 h, 7d, 14d and 21d in vitro. Inverted phase contrast microscope was used to observe the morphology of the cells in each group. Immunocytochemistry assay, immunofluorescence assay and Western blotting were used to detect the expression of GFAP, EAAT2 and GS of the cells in each group. The cells were cultured in glutamate solution for 1, 2, 3 and 4 h respectively before the solution collected. The glutamate concentration of the solution was detected using Glutamate Colorimetric Assay Hit. ADSCs-derived astrocytes expressed GFAP, EAAT2 and GS, all of which increased gradually and reached peak when induced for 14 days. In induction for 48 h, 7d and 14d groups, the extracellular glutamate concentration decreased gradually during the cells cultured in glutamate solution for 1, 2, 3 and 4 h, among which the decrease extent was most prominent in 14d group, while the extracellular glutamate concentration had no change in uninduction and induction for 21d group. ADSCs-derived astrocytes expressed EAAT2 and GS, meanwhile had the function of clearing glutamate, which was prominent when induced into astrocytes for 7-14 days. PMID- 29704574 TI - The intersection of lysosomal and endoplasmic reticulum calcium with autophagy defects in lysosomal diseases. AB - The lysosomal storage disorders (LSDs) encompass a group of more than 50 inherited diseases characterized by the accumulation of lysosomal substrates. Two thirds of patients experience significant neurological symptoms, but the mechanisms of neurodegeneration are not well understood. Interestingly, a wide range of LSDs show defects in both autophagy and Ca2+ homeostasis, which is notable as Ca2+ is a key regulator of autophagy. The crosstalk between these pathways in the context of LSD pathogenesis is not well characterized, but further understanding of this relationship could open up promising therapeutic targets. This review discusses the role of endoplasmic reticulum and lysosomal Ca2+ in autophagy regulation and highlights what is known about defects in autophagy and Ca2+ homeostasis in two LSDs, Niemann-Pick type C disease and Gaucher disease. PMID- 29704576 TI - Bone impairment caused by AlCl3 is associated with activation of the JNK apoptotic pathway mediated by oxidative stress. AB - Exposure to aluminum (Al) inhibits bone formation, the principal mechanism possibly due to oxidative stress. However, little data is available that establishes the precise relationship. In this study, Wistar rats were exposed to 0 (GC), 0.4 (GL), 0.8 (GM) or 1.6 (GH) mg/L aluminum trichloride (AlCl3) in drinking water for 90 days, respectively. The concentrations of Al in serum and bone, serum markers of bone metabolism, bone mineral density (BMD) and body weight were measured. Histological changes within femurs were observed by H&E, ALP, and TRACP staining. Oxidative stress markers and JNK apoptotic pathway were detected in bone. The results indicate that AlCl3 exposure decreased BMD, numbers of ALP-positive osteoblasts and serum levels of bone formation markers (B-ALP, PICP and BGP), and caused damaged to the trabecular structure. Serum levels of bone resorption markers (TRACP-5b, CTX-I) and numbers of TRACP-positive osteoclasts increased in GL, but conversely, they decreased in GM and GH. In addition, AlCl3 caused oxidative stress, up-regulated expression of c-Jun and pro apoptotic factors with increased p-JNK/JNK ratio and down-regulated expression of anti-apoptotic factor Bcl-2 in bone. Taken together, these results indicate that bone impairment caused by AlCl3 is associated with activation of the oxidative stress-mediated JNK apoptotic pathway. PMID- 29704577 TI - Food-drug interaction: Anabolic steroids aggravate hepatic lipotoxicity and nonalcoholic fatty liver disease induced by trans fatty acids. AB - Remains unknown if dietary lipids and anabolic steroids (AS) can interact to modify energy metabolism, hepatic structure and function. We investigated the impact of AS on gene expression, lipid profile, redox status and the development of nonalcoholic fatty liver disease (NAFLD) in mice treated with a diet rich in trans fatty acids. Seventy-two C57BL/6 mice were equally randomized into six groups and treated with a standard diet (SD) or high-fat diet (HFD) alone or combined with testosterone cypionate (10 or 20 mg/kg) for 12 weeks. When combined with a HFD, AS reduced plasma HDL cholesterol levels. It also upregulated SREBP 1, PPARalpha, SCD-1 and ACOX1 gene expression; plasma and hepatic triglyceride levels; oxidative stress; circulating hepatic transaminase levels and NAFLD severity. Our finding indicated that the activity of antioxidant enzymes such as catalase, glutathione-s-transferase and superoxide dismutase was attenuated by HFD, an effect whose implications for AS-induced hepatotoxicity requires further investigation. Increased lipid, protein and DNA oxidative damage as well as worsening NAFLD in response to the interaction of HFD and AS were also potentially associated with the ability of AS to amplify the activation of regulatory lipid metabolism genes that are also involved in the control of cellular redox balance. PMID- 29704578 TI - Current standing of plant derived flavonoids as an antidepressant. AB - Depression, a multifactorial brain disorder, is one of the most prevalent diseases worldwide. Several strategies have been developed to counteract the main symptoms and disorders. However, the treatments are usually associated with different side effects or poor effect. For that reason, new necessary approaches are emerging; among them, natural products are good alternatives since no interactions have been described up to now. Flavonoids have been related to antidepressant effects in cell lines and animal models by their action on the amine mechanisms protecting the neuroendocrine and immune systems. The current review includes an approach of some of the main results related to the action of flavonoids on depression found in the literature and a short view of the possible mechanisms involved. Thus, it highlights the potential emerging candidates with strong antidepressant effects which could be effective new compounds. PMID- 29704579 TI - Safety assessment of biotechnologically produced 2'-Fucosyllactose, a novel food additive. PMID- 29704580 TI - Differential effects of uncertainty on LPP responses to emotional events during explicit and implicit anticipation. AB - Previous studies have investigated whether uncertainty influences neural responses to emotional events. The findings of such studies, particularly with respect to event-related potentials (ERPs), have been controversial due to several factors, such as the stimuli that serve as cues and the emotional content of the events. However, it is still unknown whether the effects of uncertainty on ERP responses to emotional events are influenced by anticipation patterns (e.g., explicit or implicit anticipation). To address this issue, participants in the present study were presented with anticipatory cues and then emotional (negative and neutral) pictures. The cues either did or did not signify the emotional content of the upcoming picture. In the inter-stimulus intervals between cues and pictures, participants were asked to estimate the expected probability of the occurrence of a specific emotional category of the subsequent picture based on a scale in the explicit anticipation condition, while in the implicit condition, participants were asked to indicate, using a number on a scale, which color was different from the others. The results revealed that in the explicit condition, uncertainty increased late positive potential (LPP) responses, particularly for negative pictures, whereas LPP responses were larger for certain negative pictures than for uncertain negative pictures in the implicit condition. The findings in the present study suggest that the anticipation pattern influences the effects of uncertainty when evaluation of negative events. PMID- 29704581 TI - Individual differences in combat experiences and error-related brain activity in OEF/OIF/OND veterans. AB - Increased error-related negativity (ERN) has been implicated in the pathophysiology of multiple forms of psychopathology. Although there is increasing evidence that the ERN can be shaped by environment and experience, no studies to date have examined this question in a clinical sample. In the current study, we examined the influence of combat exposure on the ERN using electroencephalogram (EEG) in a sample of military veterans with a high prevalence of psychopathology. Participants included sixty-seven U.S. military veterans from Operations Enduring Freedom, Iraqi Freedom, and New Dawn (OEF/OIF/OND). The degree of combat exposure was assessed using the Deployment Risk and Resilience Inventory-2 (DRRI-2) and Combat Exposure Scale (CES). A well validated flanker task was used to elicit the ERN during continuous EEG recording. Results revealed that veterans who reported experiencing greater combat exposure exhibited a more enhanced ERN, even when adjusting for broad anxiety and posttraumatic stress disorder (PTSD) symptoms. The association between combat exposure and ERN was not moderated by PTSD symptom severity. The current study demonstrates that greater combat exposure is associated with a more enhanced ERN among OEF/OIF/OND veterans. This enhanced ERN may be one mechanism that places veterans at greater risk for developing psychiatric disorders following exposure to combat. Future longitudinal studies are needed to directly test whether the ERN mediates the relation between level of combat exposure and the development of internalizing disorders. PMID- 29704582 TI - Robotic Single-port Partial Prostatectomy for Anterior Tumors: Transvesical Approach. AB - OBJECTIVE: To evaluate the feasibility of a single-port transvesical robotic approach for anterior partial prostatectomy in a cadaver model. MATERIALS AND METHODS: The cadavers were placed in a lithotomy position and secured to the operating table. A 3-cm midline incision was made in the suprapubic skin fold. After opening the Retzius space, a single-port mini device (GelPOINT, Rancho Margarita, CA) was introduced percutaneously directly into the bladder. The da Vinci Si robotic platform (Intuitive Surgical, Sunnyvale, CA) was docked to the GelPOINT by inserting 2 8-mm (robotic arms) and 1 12-mm (camera) trocar through the GelSeal Cap. The surgical steps for en bloc anterior prostatectomy were performed in the following order: (1) retrograde dissection of transition zone at the bladder neck, (2) lateral excision of the peripheral zone, and (3) urethrovesical anastomosis. Primary outcomes such as intraoperative complications, rate of conversion to standard techniques, and operative times were recorded. RESULTS: Single-port transvesical robotic approach for anterior partial prostatectomy was technically completed in 2 male cadavers. Both cases were completed successfully using the da Vinci Si surgical system without conversion or the need for additional ports. There were no intraoperative complications. The total operative time was 124.1 and 81.3 minutes. Step-specific times are listed in Table 1. CONCLUSION: Transvesical robotic partial prostatectomy is technically feasible using a single-port approach in a preclinical model. Further studies are needed for evaluation on patients with anterior localized prostate cancer. Prospective comparison with standard surgical techniques and focal therapy are warranted. Refinement of this technique may potentially expand the role of single-site surgery in the clinical practice. PMID- 29704583 TI - Precise Clamping of Renal Artery With Endovascular Stents During Robotic Partial Nephrectomy: Technical Hints to Optimize Outcomes. AB - OBJECTIVE: To describe our surgical technique for robotic partial nephrectomy,1 focusing on specific technical hints for vascular clamping on patients with renal masses and endovascular stent (ES) in the renal artery. METHODS: We reviewed the records of 3 patients that underwent robotic partial nephrectomy in our institution with precise clamping of renal arteries due to previous placement of ES. Perioperative outcomes were recorded. In our video, we present the case of 73 year-old Caucasian with a 10-cm left renal neoplasm and associated fenestrated endograft due to endovascular aorta repair. After preoperative imaging was reviewed, a robotic approach was planned. RESULTS: Key hints for outcomes optimization during nephron sparing surgery on patients with ES on the renal arteries: (1) preoperative computed tomography scan is crucial for surgical planning on dissection of the renal pedicle,2 (2) an additional multiplanar volume rendering of the computed tomography scan may allow better 3-dimensional visualization and orientation of the renal vasculature and anatomy, (3) precise renal artery clamping distal from the renal artery stent is required to avoid renal stent occlusion, (4) extensive and meticulous dissection of the renal pedicle is mandatory to dictate correct clamping, and (5) an intraoperative Doppler ultrasound after clamping release confirms the blood flow through the renal arteries.3 From the patients analyzed, median age was 69.6 years, median body mass index was 31.3, and mean estimated glomerular filtration rate was 36.6 mL/min. No cases were converted to open procedures. Perioperative outcomes are described in Table 1. CONCLUSION: Partial nephrectomy in patients with renal artery stents requires distal dissection of the renal artery beyond the stent. Our described technique provides feasible, reproducible, and valuable surgical suggestions for outcomes optimization during nephron-sparing surgery on patients with endovascular graft stents. PMID- 29704584 TI - Concurrent Robotic Pyelolithotomy and Partial Nephrectomy: Tips and Tricks. AB - OBJECTIVE: With the evolution of robot-assisted surgery in the urology field, this technology is being applied to treat many genitourinary conditions.1 Although incidence of urolithiasis and renal neoplasm has increased, encountering both entities in a single kidney is noteworthy. Our video exhibits the concurrent management of a renal calculus and an ipsilateral renal neoplasm using a robotic platform. MATERIALS AND METHODS: A 53-year-old man was diagnosed with a 1.7-cm left renal pelvis calculus and a 4.7-cm enhancing ipsilateral upper pole renal mass (R.E.N.A.L score 8a) after an episode of flank pain. After reviewing preoperative imaging, a single-setting approach using a robotic platform was planned. Main steps of our robotic technique on the case included (1) kidney defatting and mobilization, (2) hilum and ureter dissection up to the renal pelvis, (3) intraoperative ultrasound for tumor demarcation and stone localization, (4) anterior robotic pyelolithotomy,2 (5) double J stent placement and pyelotomy closure, (6) excision of renal mass, and (7) renorrhaphy. Perioperative outcomes were recorded. RESULTS: The operative time was 180 minutes and the estimated blood loss was 100 mL. Warm ischemia time was 17 minutes. There were no intra- or postoperative complications. The patient was discharged home on postoperative day 3. Final pathology reported a 3.4-cm mass consistent with a clear cell renal carcinoma, with a tumor, nodes, metastases (TNM) staging pT1aNx and negative surgical margin. The double J stent was removed after 4 weeks, and the patient remained asymptomatic at 1 month postoperatively. CONCLUSION: Pyelolithotomy and robotic partial nephrectomy can be performed effectively when treating patients with concurrent kidney mass and renal stone using the same surgical access. This minimally invasive approach should be contemplated as an option when managing patients with both conditions in an ipsilateral kidney. Furthermore, it will diminish the necessity of various surgeries while preserving renal function and maintaining oncological outcomes. We underline that the association of both procedures increases the likelihood of technical complications and risk for clot-related or stone-related ureteral obstruction, infection, and urine leak. PMID- 29704585 TI - The Role of Human Acellular Dermis in Preventing Fistulas After Bladder Neck Transection in the Exstrophy-epispadias Complex. AB - OBJECTIVE: To evaluate human acellular dermis (HAD) as an adjunct during bladder neck transection (BNT) by comparing surgical outcomes with other types of tissue interposition. METHODS: A prospectively maintained institutional database of exstrophy-epispadias complex (EEC) patients was reviewed for those who underwent a BNT with at least 6 months follow-up. The primary outcome was the occurrence of BNT-related fistulas. RESULTS: In total, 147 EEC patients underwent a BNT with a mean follow-up time of 6.9 years (range 0.52-23.35 years). There were 124 (84.4%) classic exstrophy patients, 22 (15.0%) cloacal exstrophy patients, and 1 (0.7%) penopubic epispadias patient. A total of 12 (8.2%) BNTs resulted in fistulization, including 4 vesicoperineal fistulas, 7 vesicourethral fistulas, and 1 vesicovaginal fistula. There were 5 (22.7%) fistulas in the cloacal exstrophy cohort and 7 (5.6%) fistulas in the classic bladder exstrophy cohort (P = .019). Using either HAD or native tissue flaps resulted in a lower fistulization rate than using no interposed layers (5.8% vs 20.8%; P = .039). Of those with HAD, the use of a fibrin sealant did not decrease fistulization rates when compared to HAD alone (6.5% vs 8.8%, P = .695). There was no statistical difference in surgical complications between the use of HAD and native flaps (8.6% vs 5%, P = .716). CONCLUSION: Use of soft tissue flaps and HAD is associated with decreased fistulization rates after BNT. HAD is a simple option and an effective adjunct that does not require harvesting of tissues in patients where a native flap is not feasible. PMID- 29704586 TI - Histologic and Oncologic Outcomes Following Liver Mass Resection With Retroperitoneal Lymph Node Dissection in Patients With Nonseminomatous Germ Cell Tumor. AB - OBJECTIVE: To evaluate the oncologic outcomes and histologic concordance of postchemotherapy residual liver mass resection with postchemotherapy retroperitoneal lymph node dissection (PC-RPLND). METHODS: Retrospective review of our prospectively maintained germ cell tumor (GCT) surgical database identified patients with nonseminomatous GCT who underwent both postchemotherapy residual liver mass resection and PC-RPLND between 1990 and 2015. RESULTS: A total of 36 patients were identified, of whom 29 (81%) presented with a liver mass at initial diagnosis and 17 (47%) received second-line chemotherapy before liver resection. Teratoma was found in 8 (22%) and 5 (14%) of PC-RPLND and liver resection specimens, respectively. Viable GCT was found in 5 (14%) and 4 (11%) of PC-RPLND and liver resection specimens, respectively. Histologic discordance was observed in 4 of 19 patients (21%; 95% confidence interval [CI] 6.1%-46%); in all cases, liver resection specimens contained teratoma or viable GCT while PC-RPLND revealed only fibrosis or necrosis. At 3 years after surgical intervention, the Kaplan-Meier estimated probability of cancer-specific survival was 75% (95% CI 55%-85%) and the probability of progression-free survival was 75% (95% CI 56% 87%). CONCLUSION: In this contemporary cohort, clinically significant discordance was observed between the histology of metastatic liver masses and that of retroperitoneal lymph nodes. The benefit of postchemotherapy liver mass resection for patients with advanced nonseminomatous GCT is supported by favorable survival outcomes. Until more reliable predictors of postchemotherapy histology exist, complete surgical resection of all sites of residual disease should be performed whenever feasible. PMID- 29704587 TI - Do Urodynamic Findings Other Than Outlet Obstruction Influence the Decision to Perform a Transurethral Resection of Prostate? AB - OBJECTIVE: To determine if urodynamic findings other than high-pressure voiding influence the decision to perform a transurethral resection of prostate (TURP). METHODS: Four clinical scenarios were created featuring a healthy 65-year-old man. An electronic survey was distributed to members of the International Continence Society and the Society for Urodynamics, Female Pelvic Medicine and Urogenital Reconstruction. RESULTS: Eighty-six urologists responded (median age was 45-54 years, 62% described their practice as academic). Scenario 1: an incidental residual urine >1 L with detrusor underactivity. The majority (76%) would offer a TURP; however, the estimated chance that the residual volume would improve was only 57%. Scenario 2: retention with detrusor overactivity but no voluntary voiding contraction. The majority (72%) would offer a TURP; however, the average chance quoted that he would void was only 48%. Scenario 3: catheter dependent retention and an underactive detrusor. The majority (89%) would offer a TURP; however, the average chance quoted that he would void was only 53%. Scenario 4: a man with only frequency and urgency, but urodynamic bladder outlet obstruction. The majority (90%) would offer him a TURP; however, the average chance that his frequency and urgency would improve was only 64%, and the average estimated postoperative risk of urgency incontinence was 33%. Willingness to offer TURP did not correlate with physician characteristics. CONCLUSION: Urodynamic findings other than bladder outlet obstruction were associated with modest perceived outcomes after TURP; however, despite this, urologists are still willing to offer this intervention. PMID- 29704588 TI - Case Report: Nephron-sparing Surgery in a Patient With Bilateral Multifocal Wilms Tumor. AB - We present a case of bilateral multifocal Wilms tumor in a nonsyndromic 12-month old male. Our management approach included 12 weeks of preoperative chemotherapy for maximal tumor shrinkage and, despite the central location of the tumors, successful staged bilateral nephron-sparing surgery. We advocate for a broader application of nephron-sparing surgery in Wilms tumor cases with the goal of preserving renal function without compromising oncologic outcomes. PMID- 29704589 TI - Mitochondrial alterations in Parkinson's disease human samples and cellular models. AB - Mitochondrial impairment is one of the most important hallmarks of Parkinson's disease (PD) pathogenesis. In this work, we wanted to verify the molecular basis of altered mitochondrial dynamics and disposal in Substantia nigra specimens of sporadic PD patients, by the comparison with two cellular models of PD. Indeed, SH-SY5Y cells were treated with either dopamine or 1-methyl-4-phenylpyridinium (MPP+) in order to highlight the effect of altered dopamine homeostasis and of complex I inhibition, respectively. As a result, we found that fusion impairment of the inner mitochondrial membrane is a common feature of both PD human samples and cellular models. However, the effects of dopamine and MPP+ treatments resulted to be different in terms of the mitochondrial damage induced. Opposite changes in the levels of two mitochondrial protein markers (voltage-dependent anion channels (VDACs) and cytochrome c oxidase subunit 5beta (COX5beta)) were observed. In this case, dopamine treatment better recapitulated the molecular picture of patients' samples. Moreover, the accumulation of PTEN-induced putative kinase 1 (PINK1), a mitophagy marker, was not observed in both PD patients samples and cellular models. Eventually, in transmission electron microscopy images, small electron dense deposits were observed in mitochondria of PD subjects, which are uniquely reproduced in dopamine-treated cells. In conclusion, our study suggests that the mitochondrial molecular landscape of Substantia nigra specimens of PD patients can be mirrored by the impaired dopamine homeostasis cellular model, thus supporting the hypothesis that alterations in this process could be a crucial pathogenetic event in PD. PMID- 29704590 TI - Protective influences of N-acetylcysteine against alcohol abstinence-induced depression by regulating biochemical and GRIN2A, GRIN2B gene expression of NMDA receptor signaling pathway in rats. AB - Evidences have indicated a high degree of comorbidity of alcoholism and depression. N-acetylcysteine (NAC) has shown its clinical efficiency in the treatment of several psychiatric disorders and is identified as a multi-target acting drug. The ability of NAC to prevent alcohol abstinence-induced depression like effects and underlying mechanism(s) have not been adequately addressed. This study was aimed to investigate the beneficial effects of NAC in the alcohol abstinence-induced depression developed following long-term voluntary alcohol intake. For evaluation of the effects of NAC, Sprague-Dawley rats were enabled to voluntary drinking of 4.5%, 7.5% and 9% v/v alcohol for fifteen days. NAC (25, 50, and 100 mg/kg) and fluoxetine (5 mg/kg) were injected intraperitoneally for three consecutive days during the alcohol abstinence period on the days 16, 17, 18. The behavioral studies were conducted employing forced swim test (FST), and tail suspension test (TST) on day 18 to determine the effects of N-acetylcysteine and fluoxetine in the ethanol withdrawal induced-depression. Blood alcohol concentration, alcohol biomarkers like SGPT, SGOT, ALP, GGT, and MCV were estimated by using commercially available kits. Serotonin concentrations were measured in the plasma, hippocampus and pre-frontal cortex using the rat ELISA kit. The expression of GRIN1, GRIN2A, GRIN2B genes for the N-methyl d-aspartate receptors (NMDAR) subunits in the hippocampus and the prefrontal cortex were also examined by reverse-transcription quantitative polymerase chain reaction. The results revealed that alcohol abstinence group depicted increased immobility time in FST and TST. Further, NAC exerted significant protective effect at the doses 50 mg/kg and 100 mg/kg, but 25 mg/kg showed insignificant protection against alcohol abstinence-induced depression. The increased level of biochemical parameters following ethanol abstinence were also reversed by NAC at the dose of 100 mg/kg. The significant reversal effect of NAC on the serotonin level following alcohol abstinence was greater in the hippocampus as compared to the third-day alcohol withdrawal group. The increased expression levels of GRIN2A and GRIN2B following ethanol abstinence were reversed with a higher dose of NAC (100 mg/kg) treatment. In conclusion, the results of the study reveal that NAC has remarkable protective effects in the alcohol abstinence-induced depression by modulating alcohol markers, serotonin levels and GRIN2A, GRIN2B gene expression of NMDAR signaling pathway in rats. PMID- 29704591 TI - Antimycobacterial and hypolipemiant activities of Bidens odorata (Cavanilles). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Bidens odorata Cavanilles is a medicinal and edible plant known as "mozote blanco, aceitilla, acahual, mozoquelite" which is traditionally used in Mexico as a diuretic, hypoglycaemic, anti-inflammatory, antipyretic, antitussive, to treat gastrointestinal disorders, kidney pain, and lung or respiratory diseases. AIM OF THE STUDY: This research study was aimed at phytochemical analysis of aerial extracts of B. odorata for antimycobacterial and lipid-lowering activities. MATERIALS AND METHODS: Compounds 1 (((2R, 3R, 4S, 5S, 6R)-3,4,5-Tryhidroxy-6-(((E)-3-(4-hydroxyphenyl) acryloyl) oxy) tetrahydro-2H pyran-2-yl) methyl-4-hydroxybenzoate) and 2 (3,5-Dihydroxybenzoic acid) were isolated from B. odorata aerial shoots and their structural elucidation was carried out using 1 and 2D NMR, infrared spectroscopy (IR) and mass spectrometry (ESI-MS). The antimycobacterial activity of various extracts and compounds 1 and 2 was determined using the Microplate Alamar Blue Assay (MABA). The evaluation of the hypolipidemic effect of the ethanolic extract and the glycosylated compound 1 was tested in a murine model of hypercholesterolemia induced by diet and by Triton WR-1339. On the other hand, the LD50 of the ethanolic extract was evaluated in ICR mice by the OECD protocol TG 423. RESULTS: Antimycobacterial assay of hexane, CH2Cl2, EtOAc, ethanolic and aqueous extracts, as well as the new glycosidic compound 1 and benzoic acid derivative 2 isolated from B. odorata showed minimal inhibitory concentrations (MIC) of 100, 12.5, 12.5, 12.5, >=200, 3.125 and 50 MUg/mL, respectively, against Mycobacterium tuberculosis H37Rv. Only hexane and CH2Cl2 extracts were observed to be active against Mycobacterium smegmatis mc2155 at a concentration of 50 and 100 MUg/mL, respectively. The ethanolic extract showed lipid-lowering activity at doses of 100 and 1000 mg/kg, while glycosidic compound 1 was active at doses of 50 and 100 mg/kg. In addition, the LD50 of the ethanolic extract was >2000 mg/kg, meaning that this extract does not cause lethality or adverse effects, and no signs of organs alterations or tissue damage were observed. CONCLUSION: The hexane, CH2Cl2, EtOAc, and ethanolic extracts of B. odorata, as well as their components 1 and 2, displayed antimycobacterial activity against M. tuberculosis. Moreover, the ethanolic extract and glycosidic compound 1 showed an important lipid-lowering effect, without lethality or secondary effect. The results of this study support the documented traditional use for B. odorata. PMID- 29704592 TI - Cytoprotective, antioxidant and anti-inflammatory mechanism related to antiulcer activity of Cissampelos sympodialis Eichl. in animal models. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The leaves and roots of Cissampelos sympodialis (Menispermaceae) are used by indian tribes and in folk medicine to treat genitourinary infections, inflammation, asthma and gastrointestinal disorders. MATERIAL AND METHODS: The standardized ethanolic extract (Cs-EtOHE) and alkaloids total fraction (Cs-TAF) obtained from aerial parts of C. sympodialis were evaluated in several models of acute gastric ulcers. The antisecretory and/or neutralizing mechanisms of the gastric acid secretion, cytoprotective, antioxidant and immunoregulatory mechanisms were also evaluated. RESULTS: Cs EtOHE and Cs-TAF presented a reduction in gastric mucosa lesions against ethanol, NSAIDs, hypothermic restraint-stress and gastric juice containment induced ulcer models. This activity is related to alkaloids present in the extract, and involves the participation of sulfhydryl compounds, nitric oxide, KATP channels, prostaglandins, decreased levels of IL-1beta and TNF-alpha and increased levels of GSH and IL-10. CONCLUSION: The data indicate gastroprotective activity, due to the participation of the cytoprotective, antioxidant and immunoregulatory mechanisms. PMID- 29704593 TI - Regulatory T-cell dysfunction induces autoantibodies to bullous pemphigoid antigens in mice and human subjects. AB - BACKGROUND: Regulatory T (Treg) cells play a crucial role in peripheral immune tolerance in multiple organs, including the skin. Thus far, the effect of peripheral immune tolerance failure on autoantibody-related autoimmune reactions to the skin is unclear. OBJECTIVE: We sought to elucidate the target autoantigens in the skin under the condition of Treg cell dysfunction caused by forkhead box P3 (Foxp3) gene mutations in scurfy mice and patients with immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. METHODS: Sera and skin from scurfy mice and sera from patients with IPEX syndrome were analyzed to detect target autoantigens by using immunofluorescence studies, ELISAs, and immunoblotting. The pathogenicity of scurfy IgG was examined by using a passive transfer experiment. CD4+ T cells from scurfy mice were transferred to immunodeficient mice to examine their pathogenicity. Signal transducer and activator of transcription 6 (Stat6)-/- scurfy mice were analyzed to further clarify the molecular pathway of autoantibody production. Follicular helper T cell counts are measured in Stat6-/- scurfy mice and scurfy mice. RESULTS: Scurfy mice spontaneously generated IgG autoantibodies to the dermal-epidermal junction, which had been class-switched from IgM within 12 days after birth. The target autoantigens were murine BP230 and type XVII collagen (COL17). The scurfy polyclonal autoantibodies did not induce skin fragility in neonatal mice. Autoantibody production was induced by CD4+ T cells from scurfy mice and was ameliorated by Stat6 gene knockout in association with a decrease of follicular helper T cells. We also identified autoantibodies to COL17 and BP230 in patients with IPEX syndrome and found an association between production of autoantibodies to COL17 and an eczematous skin phenotype. CONCLUSIONS: Dysregulation of Treg cells generates autoantibodies to COL17 and BP230 in vivo. PMID- 29704594 TI - Hypoallergenic casein hydrolysate for peptide-based oral immunotherapy in cow's milk allergy. PMID- 29704595 TI - Regulatory T-cell deficiency leads to pathogenic bullous pemphigoid antigen 230 autoantibody and autoimmune bullous disease. AB - BACKGROUND: Autoimmune bullous diseases/dermatoses (AIBDs) are severe autoantibody-mediated skin diseases. The pathogenic relevance of autoreactive CD4+ T cells for the induction of autoantibody production remains to be fully evaluated. Scurfy mice lack functional regulatory T (Treg) cells, experience spontaneous activation of autoreactive CD4+ T cells, and display severe erosive skin lesions suggestive of AIBDs. OBJECTIVE: We sought to determine whether AIBDs develop in Treg cell-deficient scurfy mice. METHODS: Histology, indirect immunofluorescence (IF) microscopy, direct IF, and ELISA were used to prove the presence of AIBDs in scurfy mice. Monoclonal autoantibodies from sera of scurfy mice were screened by using indirect IF on murine skin, and immunoprecipitation and mass spectrometry were used for target antigen identification, followed by confirmation in modified human embryonic kidney cells and murine keratinocytes. Pathogenicity was determined by injecting the autoantibody into neonatal mice and transferring scurfy CD4+ T cells into nu/nu mice. RESULTS: Autoantibodies against different known autoantigens of AIBDs spontaneously develop in scurfy mice. Histology reveals subepidermal blisters, and direct IF of skin of scurfy mice shows a predominant linear staining pattern. The mAb 20B12 shows a linear staining pattern in indirect IF, recognizes the murine hemidesmosomal protein bullous pemphigoid antigen 230 (BP230) as the target antigen, and cross-reacts with human BP230. Purified mAb 20B12 induces subepidermal blisters in neonatal mice. Transfer of scurfy CD4+ T cells is sufficient to induce antibodies with reactivity to AIBD autoantigens and subepidermal blisters in the skin of recipient T cell-deficient nu/nu mice. CONCLUSION: We show that the absence of Treg cells leads to AIBDs by pathogenic autoantibodies targeting BP230. PMID- 29704597 TI - Modelling fragile X syndrome in the laboratory setting: A behavioral perspective. AB - Fragile X syndrome is the most common form of inherited mental retardation and the most frequent monogenic cause of syndromic autism spectrum disorders. The syndrome is caused by the loss of the Fragile X Mental Retardation Protein (FMRP), a key RNA-binding protein involved in synaptic plasticity and neuronal morphology. Patients show intellectual disability, social deficits, repetitive behaviors and impairments in social communication. The aim of this review is to outline the importance of behavioral phenotyping of animal models of FXS from a developmental perspective, by showing how the behavioral characteristics of FXS at the clinical level can be translated into effective, developmentally-specific and clinically meaningful behavioral readouts in the laboratory setting. After introducing the behavioral features, diagnostic criteria and off-label pharmacotherapy of FXS, we outline how FXS-relevant behavioral features can be modelled in laboratory animals in the course of development: we review the progress to date, discuss how behavioral phenotyping in animal models of FXS is essential to identify potential treatments, and discuss caveats and future directions in this research field. PMID- 29704596 TI - Locomotor sensitization to cocaine in adolescent and adult female Wistar rats. AB - Adolescent stress exposure is a risk factor for drug abuse, and sex differences contribute to psychostimulant responses. Although many studies have utilized the Wistar rat strain in adolescent stress paradigms, the impact of adolescent stress exposure on addiction-like outcomes has not been rigorously tested in female Wistar rats. In this study, locomotor sensitization was assessed in adolescent and adult female Wistar rats following either chronic stress during adolescence (CAS) or no stress (NS). Adolescent, but not adult, female Wistar rats developed locomotor sensitization to 15 mg/kg cocaine over 5 days of treatment, regardless of stress history. CAS reduced the initial locomotor response to novelty in both adolescent and adult rats compared to NS controls but had no effect on locomotor sensitization to cocaine in adolescents or adult female rats. These studies expand our understanding of age and adolescent stress on cocaine-induced behavioral plasticity in female Wistar rats. PMID- 29704598 TI - Gene expression of Dio2 (thyroid hormone converting enzyme) in telencephalon is linked with predisposed biological motion preference in domestic chicks. AB - Filial imprinting leads to the formation of social attachment if training is performed during a brief sensitive period after hatching. We found that thyroid hormone (3,5,3'-triiodothyronine, T3) acts as a critical determining factor of the sensitive period in domestic chicks. Imprinting upregulates gene expression of the converting enzyme (Dio2, type 2 iodothyronine deiodinase) in the telencephalon, leading to increased brain T3 content. If systemically applied, T3 facilitates imprinting in aged chicks even after the sensitive period is over. Imprinting is also associated with the rapid development of visual perception. Exposure to motion pictures induces a predisposed preference to Johansson's biological motion (BM), and those individuals with higher BM preference are more easily imprinted. Here, we examined whether Dio2 expression is also linked with BM predisposition. Chicks were trained by a rotating red block, and tested for imprinting (experiment 1) and BM preference (experiment 2). To examine the time courses of behavioural and physiological processes, Dio2 expression in telencephalon was compared among three groups: naive control chicks, and chicks trained for a short (0.5 h) or long period (2 h). In experiment 1, higher Dio2 expression appeared in the 2-h group than in the 0.5-h/control groups, but it was not correlated with the individual imprinting score. In experiment 2, a significant positive correlation appeared between Dio2 expression and BM preference in 2-h-trained chicks. Memory priming by T3 is therefore functionally linked to BM preference induction, leading to successful imprinting to natural objects even when they are initially exposed to artificial objects. PMID- 29704599 TI - Erysodine, a competitive antagonist at neuronal nicotinic acetylcholine receptors, decreases ethanol consumption in alcohol-preferring UChB rats. AB - Alcohol abuse is a worldwide health problem with high economic costs to health systems. Emerging evidence suggests that modulation of brain nicotinic acetylcholine receptors (nAChRs) may be a therapeutic target for alcohol dependence. In this work, we assess the effectiveness of four doses of erysodine (1.5, 2.0, 4.0 or 8.0 mg/kg/day, i.p.), a competitive antagonist of nAChRs, on voluntary ethanol consumption behavior in alcohol-preferring UChB rats, administered during three consecutive days. Results show that erysodine administration produces a dose-dependent reduction in ethanol consumption respect to saline injection (control group). The highest doses of erysodine (4 and 8 mg/kg) reduce (45 and 66%, respectively) the ethanol intake during treatment period and first day of post-treatment compared to control group. While, the lowest doses of erysodine (1.5 and 2 mg/kg) only reduce ethanol intake during one day of treatment period. These effective reductions in ethanol intake were 23 and 29% for 1.5 and 2 mg/kg erysodine, respectively. Locomotor activity induced by a high dose of erysodine (10 mg/kg) was similar to those observed with saline injection in control rats, showing that the reduction in ethanol intake was not produced by hypolocomotor effect induced by erysodine. This is the first report showing that erysodine reduces ethanol intake in UChB rats in a dose-dependent manner. Our results highlight the role of nAChRs in the reward effects of ethanol and its modulation as a potentially effective pharmacological alternative for alcohol dependence treatment. PMID- 29704601 TI - Biodegradable lignocellulosic porous materials: Fabrication, characterization and its application in water processing. AB - Biodegradable porous materials based on natural lignocellulosic biomass have multiple advantages of low cost, lightweight, non-toxicity, and the potential in place of non-biodegradable petrochemical products. However, the fabrication process for the porous materials was complicated by the slow and costly prefreeze or supercritical drying methods. Herein, a facile and green/clean strategy was presented to fabricate corncob and willow wood porous materials in ambient conditions. The effect of biomass solution concentration and preparation condition on porous material morphology structure was investigated systematically by scanning electron microscope (SEM). Further, X-ray diffraction (XRD), Fourier transform infrared (FTIR), Brunauer-Emmet-Teller (BET) and thermogravimetric analysis (TGA) were used to estimate the structure and thermostability of the porous materials. Furthermore, the adsorptive properties of the biomass porous materials towards dye methylene blue and oil were evaluated. The biomass porous materials with a fluffy and porous structure were readily obtained via this procedure and showed effective adsorption capacity for dye methylene blue and oil. PMID- 29704600 TI - Effects of internal and external factors on the budgeting between defensive and non-defensive responses in Aplysia. AB - Following exposure to aversive stimuli, organisms budget their behaviors by augmenting defensive responses and reducing/suppressing non-defensive behaviors. This budgeting process must be flexible to accommodate modifications in the animal's internal and/or external state that require the normal balance between defensive and non-defensive behaviors to be adjusted. When exposed to aversive stimuli, the mollusk Aplysia budgets its behaviors by concurrently enhancing defensive withdrawal reflexes (an elementary form of learning known as sensitization) and suppressing feeding. Sensitization and feeding suppression are consistently co-expressed following different training protocols and share common temporal domains, suggesting that they are interlocked. In this study, we attempted to uncouple the co-expression of sensitization and feeding suppression using: 1) manipulation of the animal's motivational state through prolonged food deprivation and 2) extended training with aversive stimuli that induces sensitization lasting for weeks. Both manipulations uncoupled the co-expression of the above behavioral changes. Prolonged food deprivation prevented the expression of sensitization, but not of feeding suppression. Following the extended training, sensitization and feeding suppression were co-expressed only for a limited time (i.e., 24 h), after which feeding returned to baseline levels as sensitization persisted for up to seven days. These findings indicate that sensitization and feeding suppression are not interlocked and that their co expression can be uncoupled by internal (prolonged food deprivation) and external (extended aversive training) factors. The different strategies, by which the co expression of sensitization and feeding suppression was altered, provide an example of how budgeting strategies triggered by an identical aversive experience can vary depending on the state of the organism. PMID- 29704602 TI - Implication of sulfonylurea derivatives as prospective inhibitors of human carbonic anhydrase II. AB - Selective carbonic anhydrase (CA) inhibitors have gained a lot of importance owing to the implication of specific isoforms of CA in certain diseases like glaucoma, leukemia, cystic fibrosis, and epilepsy. A novel class of sulfonylurea derivatives was synthesized from corresponding sulfonyl chlorides and amines. Compounds with different pendant moieties in the sulfonylurea derivatives show significant interactions with human carbonic anhydrase II (CAII). In vitro evaluation of the sulfonylurea derivatives revealed that three compounds possess admirable inhibitory activity against CAII. Compounds containing methyl (G2), isopropyl (G4) and o-tosyl (G5) groups displayed IC50 (109-137 MUm) for CAII. Fluorescence binding and cytotoxicity studies revealed that these compounds are showing good binding affinity (18-34 MUM) to CAII and non- toxic to human cells. Further, molecular docking studies of G2, G4 and G5 with CAII showed that these compounds fit nicely in the active site of CAII. Molecular dynamics simulation studies of these compounds complexed with CAII showed that essential interactions were maintained up to 50 ns of simulation. These results indicate the promising nature of the sulfonylurea scaffold towards CAII inhibition and opens scope of hit to-lead optimization for discovery of effective drugs against CAII-associated disorders. PMID- 29704603 TI - Structural characterization and antiviral activity of lentinan from Lentinus edodes mycelia against infectious hematopoietic necrosis virus. AB - A novel lentinan (LNT-I) was extracted from Lentinus edodes mycelia, and purified by an anion-exchange DEAE cellulose column and Sephadex G-200 gel. The structural characterization of LNT-I was determined by gas chromatography-mass spectrometry, high performance gel permeation chromatography, Fourier transform infrared spectrometry and 1D-nuclear magnetic resonance spectroscopy. The results showed that LNT-I was a beta-(1 -> 3)-glucan backbone with -(1 -> 6)-glucosyl side branching units terminated by mannosyl and galactosyl residues, and its molecular weight was 3.79 * 105 Da. LNT-I consisted of glucose, mannose and galactose with the molar ratio of 19.26:1.20:1.00. LNT-I represented the prominent antiviral activity to IHNV at MOI of 0.05 and 0.10, respectively. Direct inactivation and the antiviral ability in pre-addition, co-addition and post-addition to IHNV (MOI of 0.05) were 62.34%, 39.60%, 53.63% and 82.38%, respectively under 100 MUg/mL of LNT-I. Antiviral mechanisms of LNT-I mainly involved in the direct inactivation and the inhibition of viral replication. Moreover, LNT-I significantly down regulated the expression level of TNF-alpha, IL-2 and IL-11, and up-modulated the expression levels of IFN-1 and IFN-gamma after challenging with IHNV. The results indicated that the inhibitory effects of LNT-I on IHNV infection were possibly attributed to its regulation of the innate immune responses and specific immunity. PMID- 29704604 TI - Functional importance of the TGF-beta1/Smad3 signaling pathway in oxygen-glucose deprived (OGD) microglia and rats with cerebral ischemia. AB - We investigated the transforming growth factor-b1 (TGF-beta1)/Smad3 signaling pathway in rats with cerebral ischemia and oxygen-glucose-deprived (OGD) microglia. Cerebral ischemia is a clinical condition that occurs when insufficient blood flows to the brain to maintain metabolic activity. TGF-beta1 is a well-known functional peptide that regulates cell differentiation, migration, proliferation, and apoptosis. In the current study, we determined the infarct size and TGF-beta1/Smad3 protein expression in stroke-induced rats. Apoptosis and TGF-beta1/Smad3 mRNA and protein expression were determined in transfected OGD human microglial cells. TGF-beta1 treatment resulted in smaller infarct regions than in control cells, whereas TGF-beta1 inhibitor treatment resulted in larger infarcts. The TGF-beta1-treated groups showed substantial TGF beta1 and Smad3 expression by immunofluorescence compared to the controls. Apoptosis was significantly reduced in TGF-beta1- and Smad3-transfected cells, and an increased rate of apoptosis was observed in Smad3 or TGF-beta1 siRNA transfected cells. TGF-beta1 and Smad3 mRNA and protein expression increased following TGF-beta1 and Smad3 transfection. Taken together, our experimental results show that Smad3 and TGF-beta1 play a protective role against ischemic stroke, as demonstrated by the reduced infarct size. Smad3 and TGF-beta1 expression was increased in cells transfected with TGF-beta1, whereas Smad3 and TGF-beta1 expression was increased in TGF-beta1 inhibitor-transfected cells. PMID- 29704605 TI - Studies on immunological and degranulation properties of a galectin-1 purified from goat (Capra hircus) heart. AB - Galectins are mammalian lectins characterized by affinity for beta-galactosides and the presence of a conserved carbohydrate recognition domain (CRD). Galectins play crucial role in the causation and progression of deadly human diseases like cancer, neurodegenerative disorders and cardiovascular disorders. Available literature reports relevant roles of galectins in innate as well as adaptive immune responses, along with the modulation of acute inflammatory response. In the current study, we purified the goat heart galectin-1 (GHG-1) and carried out its extensive immunological studies. Immunodiffusion studies revealed that anti GHG-1 antibodies recognize the GHG-1 more readily as compared to the other galectins, suggesting its preferred utilization in various recognition studies. Antigenic cross-reactivity between galectins isolated from different tissues and species suggest their evolutionary preserved fundamental biological roles. A gradual increase in the lysozyme release was evident when the neutrophils were treated with various neutrophil activating agents. The findings of the present study confirm the increase in lysozyme production under the presence of various neutrophil activators, and thus add new information on GHG-1 induced degranulation. PMID- 29704606 TI - Characterisation of bare and tannase-loaded calcium alginate beads by microscopic, thermogravimetric, FTIR and XRD analyses. AB - Incorporating enzymes into calcium alginate beads is an effective method to immobilise them and to preserve, at the same time, their catalytic activity. Sodium alginate was mixed with Aspergillus ficuum tannase in aqueous solution, and tannase-loaded calcium alginate beads were prepared using a simple droplet based microfluidic system. Extensive experimental analysis was carried out to characterise the samples. Microscopic imaging revealed morphological differences between the surfaces of bare alginate matrix and tannase-loaded alginate beads. Thermal analysis allowed assessing the hydration contents of alginate and revealed the presence of tannase entrapped in the loaded beads, which was confirmed by vibrational spectroscopy. X-ray diffraction allowed us to conclude that alginate of tannase-loaded beads is not crystalline, which would make them suitable as carriers for possible controlled release. Moreover, they could be used in food applications to improve tea quality or clarify juices. PMID- 29704607 TI - Studies on European eel skin sulfated glycosaminoglycans: Recovery, structural characterization and anticoagulant activity. PMID- 29704608 TI - Comparison of one- and three-lead ECG to measure cardiac intervals and differentiate drug-induced multi-channel block. AB - INTRODUCTION: FDA has established initiatives to characterize clinical and non clinical biomarkers to enable more precise prediction of proarrhythmia risk based upon knowledge of drug effect on multiple cardiac ion channels (Colatsky et al., 2016). The FDA has recently demonstrated superiority of early ventricular repolarization interval (JTp) in differentiating pure hERG block from multi channel block in human subjects. Preclinical studies often acquire a single lead ECG, whereas FDA measurements of JTp were derived from a spatial vectorcardiogram computed using multiple leads. This study compares QT subintervals derived from single lead vs. spatial magnitude (SM) ECG and contrasts information obtained from multilead and single lead ECGs in the canine model. METHODS: Four beagle dogs were instrumented with 3-lead Holter monitors to acquire continuous surface ECG recordings for three consecutive days. A 24-h baseline recording was obtained on day 1 followed by administration of dofetilide on day 2 and atropine and dofetilide on day 3. Lead II and SM ECGs were automatically analyzed using the AE 1010 Rhythm ExpressTM (RE) software (VivaQuant, St. Paul, MN USA) without manual intervention or editing of the results (auto). Five-minute averages of beat-to beat intervals measured on each lead were compared for agreement assessed by Bland-Altman (BA) statistics and consistency measured as the repeatability standard deviation (SD) from 5-min intervals. The fully automated results were screened by an operator (semi-automated) and compared to automated results. RESULTS: JTp and TpTe measured using SM lead are less sensitive to changes in posture and respiration related changes in T-wave morphology. The 24-h repeatability SD of 5-min subintervals for JTp and TpTe over the three days was improved by 15.4% and 15.5% respectively with the highest improvements of 23.3% for JTp on day 2 and 25.3% for TpTe on day 3. Drug induced changes in QTcV, QRS, RR, and PR intervals were qualitatively similar between the SM lead and Lead II and in close agreement based on BA statistics. Semi-automated and automated measurements from SM Lead were in close agreement based on BA statistics. DISCUSSION: Single lead ECG is adequate for PR, RR, QRS, and QT, but produces different and more variable results when assessing QT subintervals relative to the SM lead. Close agreement between automated and semi-automated measurements demonstrates Rhythm Express accuracy and the potential to streamline interval analysis. PMID- 29704609 TI - Complex-learning Induced Modifications in Synaptic Inhibition: Mechanisms and Functional Significance. AB - Following training in a difficult olfactory-discrimination (OD) task rats acquire the capability to perform the task easily, with little effort. This new acquired skill, of 'learning how to learn' is termed 'rule learning'. At the single-cell level, rule learning is manifested in long-term enhancement of intrinsic neuronal excitability of piriform cortex (PC) pyramidal neurons, and in excitatory synaptic connections between these neurons to maintain cortical stability, such long-lasting increase in excitability must be accompanied by paralleled increase in inhibitory processes that would prevent hyper-excitable activation. In this review we describe the cellular and molecular mechanisms underlying complex learning-induced long-lasting modifications in GABAA-receptors and GABAB-receptor mediated synaptic inhibition. Subsequently we discuss how such modifications support the induction and preservation of long-term memories in the in the mammalian brain. Based on experimental results, computational analysis and modeling, we propose that rule learning is maintained by doubling the strength of synaptic inputs, excitatory as well as inhibitory, in a sub-group of neurons. This enhanced synaptic transmission, which occurs in all (or almost all) synaptic inputs onto these neurons, activates specific stored memories. At the molecular level, such rule-learning-relevant synaptic strengthening is mediated by doubling the conductance of synaptic channels, but not their numbers. This post synaptic process is controlled by a whole-cell mechanism via particular second messenger systems. This whole-cell mechanism enables memory amplification when required and memory extinction when not relevant. PMID- 29704610 TI - Thirst-Dependent Activity of the Insular Cortex Reflects its Emotion-Related Subdivision: A Cerebral Blood Flow Study. AB - Recent studies investigating neural correlates of human thirst have identified various subcortical and telencephalic brain areas. The experience of thirst represents a homeostatic emotion and a state that slowly evolves over time. Therefore, the present study aims at systematically examining cerebral perfusion during the parametric progression of thirst. We measured subjective thirst ratings, serum parameters and cerebral blood flow in 20 healthy subjects across four different thirst stages: intense thirst, moderate thirst, subjective satiation and physiological satiation. Imaging data revealed dehydration-related perfusion differences in previously identified brain areas, such as the anterior cingulate cortex, the middle temporal gyrus and the insular cortex. However, significant differences across all four thirst stages (including the moderate thirst level), were exclusively found in the posterior insular cortex. The subjective thirst ratings over the different thirst stages, however, were associated with perfusion differences in the right anterior insula. These findings add to our understanding of the insular cortex as a key player in human thirst - both on the level of physiological dehydration and the level of the subjective thirst experience. PMID- 29704611 TI - Functional characterization of MODY2 mutations in the nuclear export signal of glucokinase. AB - Glucokinase (GCK) plays a key role in glucose homeostasis. Heterozygous inactivating mutations in the GCK gene cause the familial, mild fasting hyperglycaemia named MODY2. Besides its particular kinetic characteristics, glucokinase is regulated by subcellular compartmentation in hepatocytes. Glucokinase regulatory protein (GKRP) binds to GCK, leading to enzyme inhibition and import into the nucleus at fasting. When glucose concentration increases, GCK GKRP dissociates and GCK is exported to the cytosol due to a nuclear export signal (NES). With the aim to characterize the GCK-NES, we have functionally analysed nine MODY2 mutations located within the NES sequence. Recombinant GCK mutants showed reduced catalytic activity and, in most cases, protein instability. Most of the mutants interact normally with GKRP, although mutations L306R and L309P impair GCK nuclear import in cotransfected cells. We demonstrated that GCK-NES function depends on exportin 1. We further showed that none of the mutations fully inactivate the NES, with the exception of mutation L304P, which likely destabilizes its alpha-helicoidal structure. Finally, we found that residue Glu300 negatively modulates the NES activity, whereas other residues have the opposite effect, thus suggesting that some of the NES spacer residues contribute to the low affinity of the NES for exportin 1, which is required for its proper functioning. In conclusion, our results have provided functional and structural insights regarding the GCK-NES and contributed to a better knowledge of the molecular mechanisms involved in the nucleo-cytoplasmic shuttling of glucokinase. Impairment of this regulatory mechanism by some MODY2 mutations might contribute to the hyperglycaemia in the patients. PMID- 29704612 TI - Dynamic functional connectivity and its behavioral correlates beyond vigilance. AB - Fluctuations in resting-state functional connectivity and global signal have been found to correspond with vigilance fluctuations, but their associations with other behavioral measures are unclear. We evaluated 52 healthy adolescents after a week of adequate sleep followed by five nights of sleep restriction to unmask inter-individual differences in cognition and mood. Resting state scans obtained at baseline only, analyzed using sliding window analysis, consistently yielded two polar dynamic functional connectivity states (DCSs) corresponding to previously reported 'low arousal' and 'high arousal' states. We found that the relative temporal preponderance of two dynamic connectivity states (DCS) in well rested participants, indexed by a median split of participants, based on the relative time spent in these DCS, revealed highly significant group differences in vigilance at baseline and its decline following multiple nights of sleep restriction. Group differences in processing speed and working memory following manipulation but not at baseline suggest utility of DCS in predicting cognitive vulnerabilities unmasked by a stressor like sleep restriction. DCS temporal predominance was uninformative about mood and sleepiness speaking to specificity in its behavioral predictions. Global signal fluctuation provided information confined to vigilance. This appears to be related to head motion, which increases during periods of low arousal. PMID- 29704613 TI - Regional brain volume changes following chronic antipsychotic administration are mediated by the dopamine D2 receptor. AB - BACKGROUND: Neuroanatomical alterations are well established in patients suffering from schizophrenia, however the extent to which these changes are attributable to illness, antipsychotic drugs (APDs), or their interaction is unclear. APDs have been extremely effective for treatment of positive symptoms in major psychotic disorders. Their therapeutic effects are mediated, in part, through blockade of D2-like dopamine (DA) receptors, i.e. the D2, D3 and D4 dopamine receptors. Furthermore, the dependency of neuroanatomical change on DA system function and D2-like receptors has yet to be explored. METHODS: We undertook a preclinical longitudinal study to examine the effects of typical (haloperidol (HAL)) and atypical (clozapine (CLZ)) APDs in wild type (WT) and dopamine D2 knockout (D2KO) mice over 9-weeks using structural magnetic resonance imaging (MRI). RESULTS: Chronic typical APD administration in WT mice was associated with reductions in total brain (p = 0.009) and prelimbic area (PL) (p = 0.02) volumes following 9-weeks, and an increase in striatal volume (p = 0.04) after six weeks. These APD-induced changes were not present in D2KOs, where, at baseline, we observed significantly smaller overall brain volume (p < 0.01), thinner cortices (q < 0.05), and enlarged striata (q < 0.05). Stereological assessment revealed increased glial density in PL area of HAL treated wild types. Interestingly, in WT and D2KO mice, chronic CLZ administration caused more limited changes in brain structure. CONCLUSIONS: Our results present evidence for the role of D2 DA receptors in structural alterations induced by the administration of the typical APD HAL and that chronic administration of CLZ has a limited influence on brain structure. PMID- 29704614 TI - Contribution of systemic vascular effects to fMRI activity in white matter. AB - To investigate a potential contribution of systemic physiology to recently reported BOLD fMRI signals in white matter, we compared photo-plethysmography (PPG) and whole-brain fMRI signals recorded simultaneously during long resting state scans from an overnight sleep study. We found that intermittent drops in the amplitude of the PPG signal exhibited strong and widespread correlations with the fMRI signal, both in white matter (WM) and in gray matter (GM). The WM signal pattern resembled that seen in previous resting-state fMRI studies and closely tracked the location of medullary veins. Its temporal cross-correlation with the PPG amplitude was bipolar, with an early negative value. In GM, the correlation was consistently positive. Consistent with previous studies comparing physiological signals with fMRI, these findings point to a systemic vascular contribution to WM fMRI signals. The PPG drops are interpreted as systemic vasoconstrictive events, possibly related to intermittent increases in sympathetic tone related to fluctuations in arousal state. The counter-intuitive polarity of the WM signal is explained by long blood transit times in the medullary vasculature of WM, which cause blood oxygenation loss and a substantial timing mismatch between blood volume and blood oxygenation effects. A similar mechanism may explain previous findings of negative WM signals around large draining veins during both task- and resting-state fMRI. PMID- 29704615 TI - Short- and long-term reliability of language fMRI. AB - When using functional magnetic resonance imaging (fMRI) for mapping important language functions, a high test-retest reliability is mandatory, both in basic scientific research and for clinical applications. We, therefore, systematically tested the short- and long-term reliability of fMRI in a group of healthy subjects using a picture naming task and a sparse-sampling fMRI protocol. We hypothesized that test-retest reliability might be higher for (i) speech-related motor areas than for other language areas and for (ii) the short as compared to the long intersession interval. 16 right-handed subjects (mean age: 29 years) participated in three sessions separated by 2-6 (session 1 and 2, short-term) and 21-34 days (session 1 and 3, long-term). Subjects were asked to perform the same overt picture naming task in each fMRI session (50 black-white images per session). Reliability was tested using the following measures: (i) Euclidean distances (ED) between local activation maxima and Centers of Gravity (CoGs), (ii) overlap volumes and (iii) voxel-wise intraclass correlation coefficients (ICCs). Analyses were performed for three regions of interest which were chosen based on whole-brain group data: primary motor cortex (M1), superior temporal gyrus (STG) and inferior frontal gyrus (IFG). Our results revealed that the activation centers were highly reliable, independent of the time interval, ROI or hemisphere with significantly smaller ED for the local activation maxima (6.45 +/ 1.36 mm) as compared to the CoGs (8.03 +/- 2.01 mm). In contrast, the extent of activation revealed rather low reliability values with overlaps ranging from 24% (IFG) to 56% (STG). Here, the left hemisphere showed significantly higher overlap volumes than the right hemisphere. Although mean ICCs ranged between poor (ICC<0.5) and moderate (ICC 0.5-0.74) reliability, highly reliable voxels (ICC>0.75) were found for all ROIs. Voxel-wise reliability of the different ROIs was influenced by the intersession interval. Taken together, we could show that, despite of considerable ROI-dependent variations of the extent of activation over time, highly reliable centers of activation can be identified using an overt picture naming paradigm. PMID- 29704616 TI - Clearance of intracellular Klebsiella pneumoniae infection using gentamicin loaded nanoparticles. AB - Klebsiella pneumoniae is a foremost gram-negative pathogen that can induce life threatening nosocomial pulmonary infections. Although it can be phagocytosed successfully by lung resident macrophages, this pathogen remains viable within vacuolar compartments, resulting in chronic infection and limiting therapeutic treatment with antibiotics. In this study, we aimed to generate and evaluate a cell-penetrant antibiotic poly(lactide-co-glycolide) (PLGA)-based formulation that could successfully treat intracellular K. pneumoniae infection. Screening of formulation conditions allowed the generation of high drug loaded nanoparticles through a water-in-oil-in-water approach. We demonstrated the therapeutic usefulness of these gentamicin-loaded nanoparticles (GNPs), showing their ability to improve survival and provide extended prophylactic protection towards K. pneumoniae using a Galleria mellonella infection model. We subsequently showed that the GNPs could be phagocytosed by K. pneumoniae infected macrophages, and significantly reduce the viability of the intracellular bacteria without further stimulation of pro-inflammatory or pro-apoptotic effects on the macrophages. Taken together, these results clearly show the potential to use antibiotic loaded NPs to treat intracellular K. pneumoniae infection, reducing bacterial viability without concomitant stimulation of inflammatory or pyroptotic pathways in the treated cells. PMID- 29704617 TI - The role of small molecule Kit protein-tyrosine kinase inhibitors in the treatment of neoplastic disorders. AB - The Kit proto-oncogene was found as a consequence of the discovery of the feline v-kit sarcoma oncogene. Stem cell factor (SCF) is the Kit ligand and it mediates Kit dimerization and activation. The Kit receptor contains an extracellular segment that is made up of five immunoglobulin-like domains (D1/2/3/4/5), a transmembrane segment, a juxtamembrane segment, a protein-tyrosine kinase domain that contains an insert of 77 amino acid residues, and a carboxyterminal tail. Activating somatic mutations in Kit have been documented in various neoplasms including gastrointestinal stromal tumors (GIST), mast cell overexpression (systemic mastocytosis), core-binding factor acute myeloid leukemias (AML), melanomas, and seminomas. In the case of gastrointestinal stromal tumors, most activating mutations occur in the juxtamembrane segment and these mutants are initially sensitive to imatinib. As with many targeted anticancer drugs, resistance to Kit antagonists occurs in about two years and is the result of secondary KIT mutations. An activation segment exon 17 D816V mutation is one of the more common resistance mutations in Kit and this mutant is resistant to imatinib and sorafenib. Type I protein kinase inhibitors interact with the active enzyme form with DFG-D of the proximal activation segment directed inward toward the active site (DFG-Din). In contrast, type II inhibitors bind to their target with the DFG-D pointing away from the active site (DFG-Dout). Based upon the X ray crystallographic structures, imatinib, sunitinib, and ponatinib are Type II Kit inhibitors. We used the Schrodinger induced fit docking protocol to model the interaction of midostaurin with Kit and the result indicates that it binds to the DFG-Din conformation of the receptor and is thus classified as type I inhibitor. This medication inhibits the notoriously resistant Kit D816V mutant and is approved for the treatment of systemic mastocytosis and is effective against tumors bearing the D816V activation/resistance mutation. PMID- 29704618 TI - Themes Addressed by Couples With Advanced Cancer During a Communication Skills Training Intervention. AB - CONTEXT: Couple-based communication interventions have beneficial effects for patients with cancer and their partners. However, few studies have targeted patients with advanced stages of disease, and little is known about how best to assist couples in discussing issues related to life-limiting illness. OBJECTIVES: The purpose of the present study was to identify themes addressed by couples during a Couples Communication Skills Training intervention and the frequency with which they discussed issues related to end of life. METHODS: Content analyses were conducted on recordings of 72 sessions from 12 couples facing advanced gastrointestinal cancer. Coding was based on six themes identified a priori from the framework for understanding what patients and family value at end of life. The percent of couples addressing each theme was calculated to gauge level of importance and acceptability of these topics. RESULTS: The majority of couples addressed topics previously identified as salient at end of life, including clear decision making, affirmation of the whole person, pain and symptom management, contributing to others, and preparation for death. In addition, novel aspects to these themes emerged in the context of couples' conversations, illustrating the importance of the couple relationship in adjusting to life with a life-limiting illness and anticipating the transition to end of life. CONCLUSION: Findings suggest that couples likely would be receptive to an intervention that combines training in communication skills with guidance in focusing on issues related to life completion to assist with transitions at end of life. Such interventions might enhance both individuals' abilities to cope with illness-related symptoms and demands, enjoy the time they have together, and derive meaning from the experience. PMID- 29704619 TI - Factors Associated With Adherence to 14-Day Office Appointments After Heart Failure Discharge. AB - BACKGROUND: Follow-up within 14 days after hospital discharge for heart failure (HF) may prevent 30-day hospital readmission, but adherence varies. The purpose of this study was to determine predictors of nonadherence to scheduled appointments. METHODS AND RESULTS: A medical record review included patients hospitalized for decompensated HF at 3 health system hospitals who had a scheduled 14-day office appointment. Patient demographics, and social, HF, and hospital factors were studied for association with appointment adherence. Multivariable modeling was used to determine the odds of missing scheduled appointments. Of 701 cases, mean (standard deviation) age was 73.5 (13.8) years, 46.4% were female and 38.9% were nonwhite. Appointment nonadherence was 16.2%. In multivariate analyses, 4 factors predicted missed appointments: drug use history (odds ratio [OR], 3.95; 95% confidence interval [CI], 1.70-9.20; P < .001), nonwhite race (OR, 1.85; 95% CI, 1.08-3.16; P = .024), pulmonary disease (OR, 1.80; 95% CI, 1.12-2.87; P = .014), and anemia (OR, 1.58; 95% CI, 1.01-2.46; P = .044). Scheduling appointments postdischarge vs predischarge was not associated with missed appointments (OR, 0.72; 95% CI, 0.45-1.15; P = .17). CONCLUSIONS: Findings may help practitioners identify patients who are likely to miss a follow up visit; all 4 predictors were easily retrievable from medical records during hospitalization. PMID- 29704620 TI - WITHDRAWN:Mitochondrial targeting of HIF-1alpha inhibits hypoxia-induced apoptosis independently of its transcriptional activity. PMID- 29704621 TI - Electron transfer kinetics of the mitochondrial outer membrane protein mitoNEET. AB - Increasing evidence suggests that the mitochondrial outer membrane protein mitoNEET is a key regulator of energy metabolism, iron homeostasis, and production of reactive oxygen species in mitochondria. Previously, we reported that mitoNEET is a redox enzyme that catalyzes electron transfer from the reduced flavin mononucleotide (FMNH2) to oxygen or ubiquinone via its unique [2Fe-2S] clusters. Here, we explore the reduction and oxidation kinetics of the mitoNEET [2Fe-2S] clusters under anaerobic and aerobic conditions. We find that the mitoNEET [2Fe-2S] clusters are rapidly reduced by a catalytic amount of FMNH2 which is reduced by flavin reductase and an equivalent amount of NADH under anaerobic conditions. When the reduced mitoNEET [2Fe-2S] clusters are exposed to air, the [2Fe-2S] clusters are slowly oxidized by oxygen at a rate constant of about 6.0 M-1 s-1. Compared with oxygen, ubiquinone-2 has a much higher activity to oxidize the reduced mitoNEET [2Fe-2S] clusters at a rate constant of about 3.0 * 103 M-1 s-1 under anaerobic conditions. Under aerobic conditions, the mitoNEET [2Fe-2S] clusters can still be reduced by FMNH2 in the presence of flavin reductase and excess NADH. However, when NADH is completely consumed, the reduced mitoNEET [2Fe-2S] clusters are gradually oxidized by oxygen. Addition of ubiquinone-2 also rapidly oxidizes the pre-reduced mitoNEET [2Fe-2S] clusters and effectively prevents the FMNH2-mediated reduction of the mitoNEET [2Fe-2S] clusters under aerobic conditions. The results suggest that ubiquinone may act as an intrinsic oxidant of the reduced mitoNEET [2Fe-2S] clusters in mitochondria under aerobic and anaerobic conditions. PMID- 29704622 TI - Hypothermia augments stress response in mammalian cells. AB - Mild hypothermia (32 degrees C) is routinely used in medical practice to alleviate hypoxic ischemic damage, however, the mechanisms that underlie its protective effects remain uncertain. Using a systems approach based on genome wide expression screens, reporter assays and biochemical studies, we find that cellular hypothermia response is associated with the augmentation of major stress inducible transcription factors Nrf2 and HIF1Alpha affecting the antioxidant system and hypoxia response pathways, respectively. At the same time, NF-kappaB, a transcription factor involved in the control of immune and inflammatory responses, was not induced by hypothermia. Furthermore, mild hypothermia did not trigger unfolded protein response. Lower temperatures (27 degrees C and 22 degrees C) did not activate Nrf2 and HIF1A pathways as efficiently as mild hypothermia. Current findings are discussed in the context of the thermodynamic hypothesis of therapeutic hypothermia. We argue that the therapeutic effects are likely to stem both from metabolic suppression (inhibitory component) and augmentation of stress tolerance (activating component). We argue that systems coping with cellular stressors are plausible targets of therapeutic hypothermia and deserve more attention in clinical hypothermia research. PMID- 29704623 TI - Fluorescent probes for the detection of nitroxyl (HNO). AB - Nitroxyl (HNO), which according to the IUPAC recommended nomenclature should be named azanone, is the protonated one-electron reduction product of nitric oxide. Recently, it has gained a considerable attention due to the interesting pharmacological effects of its donors. Although there has been great progress in the understanding of HNO chemistry and chemical biology, it still remains the most elusive reactive nitrogen species, and its selective detection is a real challenge. The development of reliable methodologies for the direct detection of azanone is essential for the understanding of important signaling properties of this reactive intermediate and its pharmacological potential. Over the last decade, there has been considerable progress in the development of low-molecular weight fluorogenic probes for the detection of HNO, and therefore, in this review, we have focused on the challenges and limitations of and perspectives on nitroxyl detection based on the use of such probes. PMID- 29704624 TI - Positive allosteric modulators of alpha7* or beta2* nicotinic acetylcholine receptors trigger different kinase pathways in mitochondria. AB - Mitochondrial nicotinic acetylcholine receptors (nAChRs) regulate the early stage of mitochondria-driven apoptosis, including cytochrome c release. Mitochondrial nAChR signaling is mainly mediated by intra-mitochondrial kinases, in an ion independent manner. To determine the relationship between specific nAChR subtypes and mitochondrial kinases, the effects of a set of nAChR subtype-selective positive allosteric modulators (PAMs) on cytochrome c release from mouse liver mitochondria stimulated by 0.9 MUM Ca2+, 0.5 mM H2O2 or 1.0 MUM wortmanin is studied. The results indicate that Ca2+-stimulated cytochrome c release from wild type, but not alpha7-/-, mice mitochondria is attenuated by the potent agonist PNU-282987 or type II PAMs (PNU-120596, 4BP-TQS, and PAM-2-4), but not by NS 1738, a type I PAM. In contrast, wortmannin-stimulated cytochrome c release from wild-type and, to a lesser extent, alpha7-/- mice mitochondria is efficiently attenuated by the beta2-selective PAM desformylfrustrabromine. In conclusion, the ligand-evoked alpha7* nAChR conformational changes required to induce intra mitochondrial signaling can be triggered through orthosteric (agonists) and transmembrane (type II PAMs) sites, but not by the interaction with type I PAMs. The alpha7 and beta2 nAChR subunits are responsible for the engagement of distinct kinase pathways, supporting the concept that multiple heteromeric nAChR subtypes ensure mitochondria resistance to various exogenous and endogenous apoptogenic agents. PMID- 29704625 TI - Tricyclic antidepressants inhibit hippocampal alpha7* and alpha9alpha10 nicotinic acetylcholine receptors by different mechanisms. AB - The activity of tricyclic antidepressants (TCAs) at alpha7 and alpha9alpha10 nicotinic acetylcholine receptors (AChRs) as well as at hippocampal alpha7 containing (i.e., alpha7*) AChRs is determined by using Ca2+ influx and electrophysiological recordings. To determine the inhibitory mechanisms, additional functional tests and molecular docking experiments are performed. The results established that TCAs (a) inhibit Ca2+ influx in GH3-alpha7 cells with the following potency (IC50 in MUM) rank: amitriptyline (2.7 +/- 0.3) > doxepin (5.9 +/- 1.1) ~ imipramine (6.6 +/- 1.0). Interestingly, imipramine inhibits hippocampal alpha7* AChRs (42.2 +/- 8.5 MUM) in a noncompetitive and voltage dependent manner, whereas it inhibits alpha9alpha10 AChRs (0.53 +/- 0.05 MUM) in a competitive and voltage-independent manner, and (b) inhibit [3H]imipramine binding to resting alpha7 AChRs with the following affinity rank (IC50 in MUM): imipramine (1.6 +/- 0.2) > amitriptyline (2.4 +/- 0.3) > doxepin (4.9 +/- 0.6), whereas imipramine's affinity was no significantly different to that for the desensitized state. The molecular docking and functional results support the notion that imipramine noncompetitively inhibits alpha7 AChRs by interacting with two overlapping luminal sites, whereas it competitively inhibits alpha9alpha10 AChRs by interacting with the orthosteric sites. Collectively our data indicate that TCAs inhibit alpha7, alpha9alpha10, and hippocampal alpha7* AChRs at clinically relevant concentrations and by different mechanisms of action. PMID- 29704626 TI - Understanding dengue virus evolution to support epidemic surveillance and counter measure development. AB - Dengue virus (DENV) causes a profound burden of morbidity and mortality, and its global burden is rising due to the co-circulation of four divergent DENV serotypes in the ecological context of globalization, travel, climate change, urbanization, and expansion of the geographic range of the Ae.aegypti and Ae.albopictus vectors. Understanding DENV evolution offers valuable opportunities to enhance surveillance and response to DENV epidemics via advances in RNA virus sequencing, bioinformatics, phylogenetic and other computational biology methods. Here we provide a scoping overview of the evolution and molecular epidemiology of DENV and the range of ways that evolutionary analyses can be applied as a public health tool against this arboviral pathogen. PMID- 29704627 TI - Newly emerged porcine enteric alphacoronavirus in southern China: Identification, origin and evolutionary history analysis. AB - Coronaviruses have a wide host range and can cause a variety of diseases with varying severity in different animals. Several enteric coronaviruses have been identified that are associated with diarrhea in swine and that have caused substantial economic losses. In this study, a newly emerged porcine enteric alphacoronavirus (PEAV), PEAV-GD-CH/2017, was identified from suckling piglets with diarrhea in southern China, and a full-length genome sequence of PEAV was obtained for systematic analysis. The novel PEAV sequence was most identical to that of bat-HKU2, and the differences between them were comprehensively compared, especially the uniform features of the S protein, which was shown to have a close relationship with betacoronaviruses and to perhaps represent unrecognized betacoronaviruses. In addition, Bayesian analysis was conducted to address the origin of PEAV, and the divergence time between PEAV and bat-HKU2 was estimated at 1926, which indicates that PEAV is not newly emerged and may have circulated in swine herds for several decades since the interspecies transmission of this coronavirus from bat to swine. The evolutionary rate of coronaviruses was estimated to be 1.93 * 10-4 substitutions per site per year for the RdRp gene in our analysis. For the origin of PEAV, we suspect that it is the result of the interspecies transmission of bat-HKU2 from bat to swine. Our results provide valuable information about the uniform features, origin and evolution of the novel PEAV, which will facilitate further investigations of this newly emerged pathogen. PMID- 29704628 TI - 42nd Annual Meeting of the Developmental Neurotoxicology Society: Held in conjunction with the 58th annual meeting of the Teratology Society, Hilton Clearwater Beach Resort Clearwater Beach, FL June 23-27, 2018. PMID- 29704629 TI - Cytotoxicity of CeO2 nanoparticles using in vitro assay with Mytilus galloprovincialis hemocytes: Relevance of zeta potential, shape and biocorona formation. AB - Over the last decades, the growth in nanotechnology has provoked an increase in the number of its applications and consumer products that incorporate nanomaterials in their formulation. Metal nanoparticles are released to the marine environment and they can interact with cells by colloids forces establish a nano-bio interface. This interface can be compatible or generate bioadverse effects to cells. The daily use of CeO2 nanoparticles (CeO2 NPs) in industrial catalysis, sunscreen, fuel cells, fuel additives and biomedicine and their potential release into aquatic environments has turned them into a new emerging pollutant of concern. It is necessary to assess of effects of CeO2 NPs in aquatic organisms and understand the potential mechanisms of action of CeO2 NP toxicity to improve our knowledge about the intrinsic and extrinsic characteristic of CeO2 NPs and the interaction of CeO2 NPs with biomolecules in different environment and biological fluids. The conserved innate immune system of bivalves represents a useful tool for studying immunoregulatory responses when cells are exposed to NPs. In this context, the effects of two different CeO2 NPs with different physico-chemical characteristics (size, shape, zeta potential and Ce+3/Ce+4 ratio) and different behavior with biomolecules in plasma fluid were studied in a series of in vitro assays using primary hemocytes from Mytilus galloprovincialis. Different cellular responses such as lysosome membrane stability, phagocytosis capacity and extracellular reactive oxygen species (ROS) production were evaluated. Our results indicate that the agglomeration state of CeO2 NPs in the exposure media did not appear to have a substantial role in particle effects, while differences in shape, zeta potential and biocorona formation in NPs appear to be important in provoking negative impacts on hemocytes. The negative charge and the rounded shape of CeO2 NPs, which formed Cu, Zn-SOD biocorona in hemolymph serum (HS), triggered higher changes in the biomarker of stress (LMS) and immunological parameters (ROS and phagocytosis capacity). On the other hand, the almost neutral surface charge and well-faceted shape of CeO2 NPs did not show either biocorona formation in HS under tested conditions or significant responses. According to the results, the most relevant conclusion of this work is that not only the physicochemical characterization of CeO2 NPs plays an important role in NPs toxicity but also the study of the interaction of NPs with biological fluids is essential to know it behavior and toxicity at cellular level. PMID- 29704630 TI - Knockdown of NUP160 inhibits cell proliferation, induces apoptosis, autophagy and cell migration, and alters the expression and localization of podocyte associated molecules in mouse podocytes. AB - Genetic mutations in dozens of monogenic genes can lead to serious podocyte dysfunction, which is a major cause of steroid-resistant nephrotic syndrome (SRNS). The NUP160 gene is expressed in both human kidney and mouse kidney. However, whether knockdown of NUP160 impairs podocytes has not yet been established. Therefore, we knocked down NUP160 by targeted short hairpin RNA (shRNA) in conditionally immortalized mouse podocytes and observed the effect of NUP160 knockdown on the proliferation, apoptosis, autophagy and cell migration of podocytes. We also investigated the effect of NUP160 knockdown on the expression and localization of podocyte associated molecules, such as nephrin, podocin, CD2AP and alpha-actinin-4. The knockdown of NUP160 significantly inhibited the proliferation of podocytes by decreasing the expression of both cyclin D1 and CDK4, increasing the expression of p27, and inducing S phase arrest. The knockdown of NUP160 promoted the apoptosis and autophagy of podocytes, and enhanced cell migration. The knockdown of NUP160 decreased the expression of nephrin, podocin and CD2AP in podocytes, and increased the expression of alpha actinin-4. The knockdown of NUP160 also altered the subcellular localization of nephrin, podocin and CD2AP in podocytes. These results suggest that the knockdown of NUP160 impairs mouse podocytes, i.e. inhibiting cell proliferation, inducing apoptosis, autophagy and cell migration of mouse podocytes, and altering the expression and localization of podocyte associated molecules, including nephrin, podocin, CD2AP and alpha-actinin-4. PMID- 29704631 TI - CircRNF13 regulates the invasion and metastasis in lung adenocarcinoma by targeting miR-93-5p. AB - Circular RNAs (circRNAs) are a group of non-protein-coding RNAs that are generated from back-splicing. Recent evidence indicates that circRNAs play important roles in tissue development, gene regulation, and carcinogenesis. It was recently demonstrated that circular RNAs can function as sponges for miRNAs. In our study, the clinical implications of circRNF13 were assessed in 50 pathologically diagnosed lung adenocarcinoma samples and their paired peripheral normal lung tissues by using quantitative polymerase chain reaction. We validated that circRNF13 was almost 2.98-fold down-regulated in cancer tissues. The expression level of circRNF13 was significantly negatively correlated with TNM staging and lymph node metastasis. In vitro experiments indicated that circRNF13 repressed the invasion and metastasis of lung adenocarcinoma cell lines. Cell fraction analyses and fluorescence in situ hybridization detected that circRNF13 was mostly located in the cytoplasm. Bioinformatic analyses and RIP experiments revealed that circRNF13 could interact with Ago2, an RNA binding protein, and could function as sponge for miR-93-5p. Our data suggest that circRNF13 represents a potential novel biomarker and a therapeutic target of lung adenocarcinoma. PMID- 29704632 TI - Comparative profiling of differentially expressed microRNAs in estrous ovaries of Kazakh sheep in different seasons. AB - Seasonal estrus is a critical limiting factor for animal fecundity. However, estrus occurs in some seasonally estrous sheep in the non-breeding season, and this phenomenon involves changes in ovarian biology. Previous studies indicated that small RNAs, such as microRNAs (miRNAs), play important regulatory roles in ovarian biology. Differentially expressed miRNAs in the ovaries of estrous sheep were identified using Solexa sequencing technology. A total of 423 known miRNAs were identified in ovaries of estrous sheep in the breeding season and non breeding season. In the comparison of these two groups, 48 miRNAs were identified that were differentially expressed between the two groups (including 5 up regulated and 43 down-regulated miRNAs). KEGG pathway analysis revealed that the target genes of some differentially expressed miRNAs were involved in pathways related to reproductive hormone signaling and follicular development. Furthermore, the levels of estradiol (E2), progesterone (P4), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were lower in anestrus sheep than in sheep during the breeding season. Upon combining the pathway enrichment analysis, target gene expression and hormone measurement results, we suggest that these differentially expressed miRNAs might influence ovarian activity in the non breeding season by regulating the above pathways. The identification of miRNAs that are differentially expressed between ovines in the breeding season and non breeding season will contribute to our understanding of the role of miRNAs in estrus regulation, and these data may provide a basis for regulating estrus in sheep during the non-breeding season. PMID- 29704633 TI - MYB - A regulatory factor in hematopoiesis. AB - MYB is a transcription factor which was identified in birds as a viral oncogene (v-MYB). Its cellular counterpart was subsequently isolated as c-MYB which has three functional domains - DNA binding domain, transactivation domain and negative regulatory domain. c-MYB is essential for survival, and deletion of both alleles of the gene results in embryonic death. It is highly expressed in hematopoietic cells, thymus and neural tissue, and required for T and B lymphocyte development and erythroid maturation. Additionally, aberrant MYB expression has been found in numerous solid cancer cells and human leukemia. Recent studies have also implicated c-MYB in the regulation of expression of fetal hemoglobin which is highly beneficial to the beta-hemoglobinopathies (beta thalassemia and sickle cell disease). These findings suggest that MYB could be a potential therapeutic target in leukemia, and possibly also a target for therapeutic increase of fetal hemoglobin in the beta-hemoglobinopathies. PMID- 29704634 TI - Computer navigation for total knee arthroplasty achieves better postoperative alignment compared to conventional and patient-specific instrumentation in a low volume setting. AB - BACKGROUND: Procedure volume is an important determinant of total knee arthroplasty (TKA) outcomes. We aimed to determine whether computer navigation or patient-specific instrumentation (PSI) would improve postoperative alignment in a low-volume setting. HYPOTHESIS: PSI for TKA achieves better limb and implant alignment compared to conventional TKA and to computer navigated TKA. MATERIALS AND METHODS: This is a retrospective cohort study of 385 primary TKAs (Women=59%. Mean age=67years. Mean BMI=30.1kg/m2), which were performed using conventional instrumentation (n=117; 30%), computer navigation (n=209; 54%), or patient specific instrumentation (n=59; 15%) in a low-volume center (<50 TKAs/year). The risk of postoperative leg and implant mechanical alignment outliers in the coronal plane (>3 degrees from neutral), average alignment and operation time were assessed. RESULTS: The risk of postoperative mechanical alignment outliers (>3 degrees ) was reduced by 89% in the navigated group (4% outliers) compared to the conventional group (35%) (RR=0.11; p<0.0001). No significant improvement was observed in the PSI group (27%) (RR=0.91; p=0.772). The risk of postoperative femoral component coronal alignment outliers was reduced by 63% in the navigated group (11%) compared to the conventional group (31%) (RR=0.37; p=0.018). No significant reduction in outliers was observed in the PSI group (32%) (RR=1.08; p=0.816). There was a reduction in the risk of tibial component coronal malalignment of 66% in the navigated group (5%) compared to the conventional group (13%) (RR=0.33; p=0.070). There was a two-fold increase in the risk of tibial component alignment outliers in the PSI group (29%) (RR=1.94; p=0.110). DISCUSSION: Computer navigation improved postoperative alignment in TKA. No evidence of improved alignment was seen with patient-specific instrumentation. The routine use of patient-specific instrumentation in low-volume centers is not supported by the currently available data. TYPE OF STUDY: Retrospective cohort study. Level IV. PMID- 29704635 TI - Plasma of argon enhances the adhesion of murine osteoblasts on different graft materials. AB - OBJECTIVE: Plasma of argon treatment was demonstrated to increase material surface energy leading to stronger and faster interaction with cells. The aim of the present in vitro study was to test the effect of plasma treatment on different graft materials. MATERIALS AND METHODS: Synthetic hydroxyapatite (Mg HA), biphasic calcium phosphate (BCP), cancellous and cortical xenogeneic bone matrices (CaBM, CoBM) were used representing commonly used classes of bone substitute materials. Fifty serially numbered disks with a 10mm-diameter from each graft material were randomly divided into two groups: test group (argon plasma treatment) and control group (absence of treatment). Cell morphology (using pre-osteoblastic murine cells) and protein adsorption were analyzed at all samples from both the test and control group. Differences between groups were analyzed using the Mann-Whitney test setting the level of significance at p<0.05. RESULTS: Plasma treatment significantly increased the protein adsorption at all samples. Similarly, plasma treatment significantly increased cell adhesion in all groups. CONCLUSIONS: Data confirmed that non-atmospheric plasma of argon treatment led to an increase of protein adsorption and cell adhesion in all groups of graft material to a similar extent. CLINICAL RELEVANCE: Plasma of argon is able to improve the surface conditions of graft materials. PMID- 29704636 TI - Decreased microglial numbers in Vav1-Cre+:dicer knock-out mice suggest a second source of microglia beyond yolk sac macrophages. AB - Microglia represent the resident macrophages of the central nervous system (CNS). While it is clear that microglia recruitment is established by differentiation of primitive yolk sac (YS) macrophages and consecutive invasion of the brain, starting around E8 in rodents (Ginhoux et al., 2010), more recent studies suggest that a non-YS contribution to the microglia population should not entirely be dismissed (Swinnen et al., 2013; Xu et al., 2015). Therefore, we used Vav1 Cre+:dicer knock-out mice in order to study the effect of the post-YS hematopoiesis on the definitive microglial population in late prenatal (E16.5, E18.5) and early postnatal brains (P0, P1). Since Vav1 is thereby exclusively expressed in hematopoietic cells starting at E11, the depletion of the micro RNA processing enzyme dicer in Vav1-positive cells allows interfering with post-YS microglia recruitment. Using this approach, analysis of the number of Iba-1 positive microglia revealed a reduction of microglial numbers by 40% in knock-out mice at P1 compared to their individual control littermates. Noteworthy, immunolabeling for Ki-67 and active caspase 3 confirmed that the differences in the microglial numbers are not related to differential rates of proliferation or apoptosis. Therefore, our data demonstrates that interfering with the definitive hematopoiesis highly impacts on the microglial population, implicating an important role of post-YS hematopoiesis on microglial development and recruitment. PMID- 29704637 TI - Effects of creatine supplementation on cognitive function of healthy individuals: A systematic review of randomized controlled trials. AB - BACKGROUND AND AIMS: Creatine is a supplement used by sportsmen to increase athletic performance by improving energy supply to muscle tissues. It is also an essential brain compound and some hypothesize that it aids cognition by improving energy supply and neuroprotection. The aim of this systematic review is to investigate the effects of oral creatine administration on cognitive function in healthy individuals. METHODS: A search of multiple electronic databases was performed for the identification of randomized clinical trials (RCTs) examining the cognitive effects of oral creatine supplementation in healthy individuals. RESULTS: Six studies (281 individuals) met our inclusion criteria. Generally, there was evidence that short term memory and intelligence/reasoning may be improved by creatine administration. Regarding other cognitive domains, such as long-term memory, spatial memory, memory scanning, attention, executive function, response inhibition, word fluency, reaction time and mental fatigue, the results were conflicting. Performance on cognitive tasks stayed unchanged in young individuals. Vegetarians responded better than meat-eaters in memory tasks but for other cognitive domains no differences were observed. CONCLUSIONS: Oral creatine administration may improve short-term memory and intelligence/reasoning of healthy individuals but its effect on other cognitive domains remains unclear. Findings suggest potential benefit for aging and stressed individuals. Since creatine is safe, future studies should include larger sample sizes. It is imperative that creatine should be tested on patients with dementias or cognitive impairment. PMID- 29704638 TI - Mild cognitive impairment and sedentary behavior: A multinational study. AB - BACKGROUND: Sedentary behavior (SB) is associated with poor cognitive performance. However, the contribution of sedentary time to risk of mild cognitive impairment (MCI) remains unclear. This study assessed the association of SB with MCI in six low- and middle-income countries. METHODS: The Study on Global Ageing and Adult Health (SAGE) survey included 34,129 adults aged >=50 years [mean (SD) age 62.1 (15.6) years; 51.7% females]. SB was self-reported and expressed as a categorical variable [<8 or >=8 h per day (high SB)]. The definition of MCI was based on the recommendations of the National Institute on Ageing-Alzheimer's Association. Multivariable logistic regression analysis was conducted to assess the association between SB and MCI. RESULTS: The overall prevalence (95%CI) of MCI and high SB (i.e., >=8 h/day) were 15.3% (14.4%-16.3%) and 10.1% (9.0%-11.3%), respectively. After adjustment for potential confounders, being sedentary for >=8 h/day was associated with a 1.56 (95%CI = 1.27-1.91) times higher odds for MCI. A one-hour increase in SB was associated with a 1.08 (95%CI = 1.05-1.11) times higher odds for MCI. CONCLUSION: Our study results highlight the need to further explore a sedentary lifestyle as a potential risk factor for MCI or subsequent dementia. Longitudinal and intervention studies are warranted to confirm/refute the current findings. PMID- 29704639 TI - Proteomic analysis of age-related changes in ovine cerebrospinal fluid. AB - Cerebrospinal fluid (CSF) circulates through the brain and has a unique composition reflecting the biological processes of the brain. Identifying ageing CSF biomarkers can aid in understanding the ageing process and interpreting CSF protein changes in neurodegenerative diseases. In this study, ovine CSF proteins from young (1-2 year old), middle aged (3-6 year old) and old (7-10 year old) sheep were systemically studied. CSF proteins were labelled with iTRAQ tagging reagents and fractionated by 2-dimensional high performance, liquid chromatography. Tryptic peptides were identified using MS/MS fragmentation ions for sequencing and quantified from iTRAQ reporter ion intensities at m/z 114, 115, 116 and 117. Two hundred thirty one peptides were detected, from which 143 proteins were identified. There were 52 proteins with >25% increase in concentrations in the old sheep compared to the young. 33 of them increased >25% but <50%, 13 increased >50% but <1 fold, 6 increased >1 fold [i.e. haptoglobin (Hp), haemoglobin, neuroendocrine protein 7B2, IgM, fibrous sheath interacting protein 1, vimentin]. There were 18 proteins with >25% decrease in concentrations in the old sheep compared to the young. 17 of them decreased >25% but <50%, and histone deacetylase 7 (HDAC7) was gradually decreased for over 80%. Glutathione S transferase was decreased in middle aged CSF compared to both young and old CSF. The differential expressions of 3 proteins (Hp, neuroendocrine protein 7B2, IgM) were confirmed by immunoassays. These data expand our current knowledge regarding ovine CSF proteins, supply the necessary information to understand the ageing process in the brain and provide a basis for diagnosis of neurodegenerative diseases. PMID- 29704640 TI - Homocysteine levels are associated with bone resorption in pre-frail and frail Spanish women: The Toledo Study for Healthy Aging. AB - BACKGROUND: Homocysteine (Hcy) high levels are associated with fractures, bone resorption and an early onset of osteoporosis in elderly persons; a relationship between Hcy and bone formation has also been suggested but is still controversial. Frailty, an independent predictor of fractures and decreased bone mineral density is associated with altered bone metabolism in women. However, no previous works have studied the relationship among frailty, Hcy levels and bone turnover. METHODS: We studied the association among Hcy, osteoporosis and N terminal propeptide of type I procollagen (PINP), C-terminal telopeptide of type I collagen (beta-CTX), parathyroid hormone (PTH), calcium and 25-hydroxyvitamin D (25(OH)D) in 631 Spanish women between the ages of 65-78 from the Toledo Study for Healthy Aging (TSHA) cohort, who were classified as highly functional (robust subjects) or non-robust (pre-frail or frail subjects) according to Fried's criteria. RESULTS: Hcy was independently associated with beta-CTX in the entire population (B = 0.22; 95% CI, 0.09-0.34; p = 0.001) and in the non-robust group (B = 0.24; 95% CI, 0.09-0.39; p = 0.002). Hcy was also associated with PINP in the entire and non-robust populations, but the association was lost after including the levels of beta-CTX, but not the other bone biomarkers, in the multivariate analysis. This suggests that the controversial relationship between Hcy and bone formation might be explained, at least to a certain extent, by the confounding effects of beta-CTX. CONCLUSIONS: This work highlights the important implication of frailty status in the association between Hcy and increased bone turnover in older women. PMID- 29704641 TI - Chronically raised C-reactive protein is inversely associated with cortical beta amyloid in older adults with subjective memory complaints. AB - BACKGROUND: Inflammation promotes amyloidogenesis in animals and markers of inflammation are associated with beta-amyloid (Abeta) in humans. Hence, we sought to examine the cross-sectional associations between chronically elevated plasma C reactive protein (CRP) and cortical Abeta in 259 non-demented elderly individuals reporting subjective memory complaints from the Multidomain Alzheimer Preventive Trial (MAPT). METHODS: Cortical-to-cerebellar standard uptake value ratios were obtained using [18F] florbetapir positron emission tomography (PET). CRP was measured in plasma using immunoturbidity. Chronically raised CRP was defined as having 2 consecutively high CRP readings (>3 mg/l <= 10 mg/l) between study baseline and the 1 year visit (visits were performed at baseline, 6 months, 1 year and then annually). Associations were explored using adjusted multiple linear regression. RESULTS: Chronically raised CRP was found to be inversely associated with cortical Abeta (B-coefficient: -0.054, SE: 0.026, p = 0.040) and this association seemed to be specific to apolipoprotein E (Apo E) epsilon4 carriers (B-coefficient: -0.130, SE: 0.058, p = 0.027). CRP as an isolated reading measured closest to PET scan was also inversely associated with cortical Abeta when CRP was treated as a dichotomized variable (high CRP > 3 mg/l <= 10 mg/l, B-coefficient: -0.048, SE: 0.023, p = 0.043). CONCLUSIONS: Our preliminary findings suggest that inflammation might be beneficial in the early stages of Alzheimer's disease as the immune systems attempts to combat Abeta pathology particularly in ApoE epsilon4 carriers. Investigating the temporal relationships between cerebral Abeta and a panel of inflammatory markers would provide further evidence as to whether chronic inflammation might modulate amyloidogenesis in vivo. PMID- 29704642 TI - Verapamil and riluzole cocktail liposomes overcome pharmacoresistance by inhibiting P-glycoprotein in brain endothelial and astrocyte cells: A potent approach to treat amyotrophic lateral sclerosis. AB - Riluzole is currently one of two approved medications for the treatment of amyotrophic lateral sclerosis (ALS). However, brain disposition of riluzole, as a substrate of P-glycoprotein (P-gp), is limited by the efflux transporters at the blood-brain barrier (BBB). We propose to develop a liposomal co-delivery system that could effectively transport riluzole to brain cells by reducing efflux pumps with a P-gp inhibitor, verapamil. Riluzole and verapamil cocktail liposomes were prepared by lipid film hydration. The average particle size of cocktail liposomes was 194.3 +/- 6.0 nm and their polydispersity index (PDI) was 0.272 +/- 0.017. The encapsulation efficiencies of verapamil and riluzole in the cocktail liposomes were 86.0 +/- 1.4% and 85.6 +/- 1.1%, respectively. The drug release from cocktail liposomes after 8 h in PBS at 37 degrees C was 78.4 +/- 6.2% of riluzole and 76.7 +/- 3.8% of verapamil. The average particle size of liposomes did not show significant changes at 4 degrees C after three months. Verapamil cocktail liposomes inhibited P-gp levels measured by western blotting in dose and time-dependent manners in brain endothelial bEND.3 cells. Increased drug efflux transporters were detected in bEND.3 and astrocytes C8D1A cells, promoted by tumor necrosis factor (TNF-alpha) or hydrogen peroxide (H2O2). Restored accumulations of riluzole and fluorescent dye rhodamine 123 were observed in bEND.3 cells after treatments with cocktail liposomes. It indicated that inhibitory potential of co-delivery liposome system towards P-gp could mediate the transport of both P-gp substrates. Verapamil and riluzole co-loaded liposomes may be used to overcome pharmacoresistance of riluzole for improving ALS therapy. PMID- 29704643 TI - Co-existing colloidal phases in artificial intestinal fluids assessed by AF4/MALLS and DLS: A systematic study into cholate & (lyso-) phospholipid blends, incorporating celecoxib as a model drug. AB - Colloidal phases (self-assemblies) in aqueous dispersions of selected binary bile salt/phospholipid blends were studied utilizing the combined analytical approach of asymmetrical flow field-flow fractionation (AF4) and multi-angle laser light scattering (MALLS) in order to resolve the co-existence of different colloidal assemblies. The binary blends were prepared by freeze-drying from tert butanol/water co-solvent solutions. The blends contained one of two bile salts (sodium taurocholate (TC) or sodium glycodeoxycholate (GDX)) and a mono- or di acyl phospholipid (lyso-phosphatidylcholine (L-PC) and phosphatidylcholine (PC), respectively). Bile salt and phospholipid (PL) concentrations and their respective ratios were varied systematically within the physiological range found in human intestinal fluids. Furthermore, the BCS class II drug Celecoxib was incorporated in selected blends to assess its potential impact on colloidal phases. To further investigate the smallest self-assemblies observed in AF4/MALLS analysis, dispersions of TC and GDX, respectively, were prepared and analyzed by dynamic light scattering (DLS). AF4/MALLS analysis revealed that binary bile salt/phospholipid blends form three distinct particle fractions, when the concentration of bile-salt was sufficiently high (>=3.5 mM). Those fractions were assumed to be very small pure bile-salt dimeric/oligomeric self-assemblies (O ~ 2 3 nm), mid-sized mixed micelles (O ~ 10-50 nm) and large liposomes/aggregates (O ~ 150-280 nm). If present, Celecoxib was found solubilized within the structures, but at the lowest TC concentration triggered the formation of an additional (vesicular) phase. PMID- 29704644 TI - Effect of beta-elemene on the kinetics of intracellular transport of d-luciferin potassium salt (ABC substrate) in doxorubicin-resistant breast cancer cells and the associated molecular mechanism. AB - In order to explore the mechanism of the reversing multidrug resistance (MDR) phenotypes by beta-elemene (beta-ELE) in doxorubicin (DOX)-resistant breast cancer cells (MCF-7/DOX), both the functionality and quantity of the ABC transporters in MCF-7/DOX were studied. Bioluminescence imaging (BLI) was used to study the efflux of d-luciferin potassium salt, the substrate of ATP-binding cassette transporters (ABC transporters), in MCF-7/DOX cells treated by beta-ELE. At the same time three major ABC transport proteins and genes-related MDR, P glycoprotein (P-gp, ABCB1) and multidrug resistance-associated protein 1 (MRP, ABCC1) as well as breast cancer resistance protein (BCRP, ABCG2) were analyzed by q-PCR and Western blot. To investigate the efflux functionality of ABC transporters, MCF-7/DOXFluc cell line with stably-overexpressed luciferase was established. BLI was then used to real-time monitor the efflux kinetics of d luciferin potassium salt before and after MCF-7/DOXFluc cells being treated with beta-ELE or not. The results showed that the efflux of d-luciferin potassium salt from MCF-7/DOXFluc was lessened when pretreated with beta-ELE, which means that beta-ELE may dampen the functionality of ABC transporters, thus decrease the efflux of d-fluorescein potassium or other chemotherapies which also serve as the substrates of ABC transporters. As the effect of beta-ELE on the expression of ABC transporters, the results of q-PCR and Western blot showed that gene and protein expression of ABC transporters such as P-gp, MRP, and BCRP were down regulated after the treatment of beta-ELE. To verify the efficacy of beta-ELE on reversing MDR, MCF-7/DOX cells were treated with the combination of DOX and beta ELE. MTT assay showed that beta-ELE increased the inhibitory effect of DOX on the proliferation of MCF-7/DOX, and the IC50 of the combination group was much lower than that of the single DOX or beta-ELE treatment. In all, beta-ELE may reverse MDR through the substrates of ABC transporters by two ways, to lessen the ABC protein efflux by weakening their functionality, or to reduce the quantity of ABC gene and protein expression. PMID- 29704645 TI - Cadmium effects on embryo growth of pea seeds during germination: Investigation of the mechanisms of interference of the heavy metal with protein mobilization related factors. AB - This work aims to give more insight into mechanisms of action of cadmium (Cd) on germinating pea seeds (Pisum sativum L. var. douce province), specifically the different ways by which Cd cations may interfere with the principal factors involved during germination process, notably storage proteins mobilization, amino acids freeing and proteolytic activities. Obtained results revealed that the process of hydrolysis of main storage proteins showed a significant disruption, which resulted in the decrease of the release of free amino acids, thus imposing a lack in nitrogen supply of essential nutrients to growing embryo under Cd stress. This hypothesis was evidenced by Cd-induced changes occurring in main purified protein fractions; Albumins, Legumins and Vicilins, during their breakdown. Besides, at enzymatic level, the activities of main proteases responsible for this hydrolysis were altered. Indeed, assays using synthetic substrates and specific protease inhibitors followed by protease activity measurements demonstrated that Cd inhibited drastically the total azocaseinolytic activity (ACA) and activities of different proteolytic classes: cysteine-, aspartic-, serine- and metallo-endopeptidases (EP), leucine- and proline aminopeptidases (LAP and PAP, respectively), and glycine-carboxypeptidases (Gly CP). The data here presented may suggest that the vulnerability of the embryonic axes towards Cd toxicity could be explained as a result of eventual disruption of metabolic pathways that affect mobilization of reserves and availability of nutrients. In vitro studies suggest that Cd cations may act either directly on the catalytic sites of the proteolytic enzymes, which may cause their deactivation, or indirectly via the generation of oxidative stress and overproduction of free radicals that can interact with enzymes, by altering their activity and structure. PMID- 29704646 TI - KT-HAK-KUP transporters in major terrestrial photosynthetic organisms: A twenty years tale. AB - Since their discovery, twenty years ago, KT-HAK-KUP transporters have become a keystone to understand how alkali cation fluxes are controlled in major land dwelling photosynthetic organisms. In this review we focus on their discovery, phylogeny, and functions, as well as the regulation of its canonical member, AtHAK5. We also address issues related to structure-function studies, and the technological possibilities opened up by recent findings. Available evidence suggests that this family of transporters underwent an early divergence into major groups following the conquest of land by embryophytes. KT-HAK-KUPs are necessary to accomplish several major developmental and growth processes, as well as to ensure plant responses to environmental injuries. Although the primary function of these transporters is to mediate potassium (K+) fluxes, some of them can also mediate sodium (Na+) and cesium (Cs+) transport, and contribute to maintenance of K+ (and Na+) homeostasis in different plant tissues. In addition, there is evidence for a role of some members of this family in auxin movement and in adenylate cyclase activity. Recent research, focusing on the regulation of the canonical member of this family, AtHAK5, revealed the existence of a complex network that involves transcriptional and post-transcriptional phenomena which control the enhancement of AtHAK5-mediated K+ uptake when Arabidopsis thaliana plants are faced with low K+ supply. In spite of the formidable advances made since their discovery, important subjects remain to be elucidated to gain a more complete knowledge of the roles and regulation of KT-HAK-KUPs, as well as to improve their use for innovative procedures in crop breeding. PMID- 29704648 TI - Shades of white: diffusion properties of T1- and FLAIR-defined white matter signal abnormalities differ in stages from cognitively normal to dementia. AB - The underlying pathology of white matter signal abnormalities (WMSAs) is heterogeneous and may vary dependent on the magnetic resonance imaging contrast used to define them. We investigated differences in white matter diffusivity as an indicator for white matter integrity underlying WMSA based on T1-weighted and fluid-attenuated inversion recovery (FLAIR) imaging contrast. In addition, we investigated which white matter region of interest (ROI) could predict clinical diagnosis best using diffusion metrics. One hundred three older individuals with varying cognitive impairment levels were included and underwent neuroimaging. Diffusion metrics were extracted from WMSA areas based on T1 and FLAIR contrast and from their overlapping areas, the border surrounding the WMSA and the normal appearing white matter (NAWM). Regional diffusivity differences were calculated with linear mixed effects models. Multinomial logistic regression determined which ROI diffusion values classified individuals best into clinically defined diagnostic groups. T1-based WMSA showed lower white matter integrity compared to FLAIR WMSA-defined regions. Diffusion values of NAWM predicted diagnostic group best compared to other ROI's. To conclude, T1- or FLAIR-defined WMSA provides distinct information on the underlying white matter integrity associated with cognitive decline. Importantly, not the "diseased" but the NAWM is a potentially sensitive indicator for cognitive brain health status. PMID- 29704647 TI - Preferential consolidation of emotionally salient information during a nap is preserved in middle age. AB - Sleep preferentially preserves aspects of memory that are most salient and valuable to remember at the expense of memory for less relevant details. Daytime naps and nocturnal sleep enhance this emotional memory trade-off effect, with memory for emotional components correlated with slow-wave sleep during the day and rapid eye movement sleep overnight. However, these studies have primarily sampled from young adult populations. Sleep and memory are altered by middle age, and the aim of the present study was to examine how age affects sleep-based mechanisms of emotional memory prioritization, using a daytime nap protocol to compare young to middle-aged adults. In both age groups, a nap soon after encoding scenes that contained a negative or neutral object on a neutral background led to superior retention of emotional object memory at the expense of memory for the related backgrounds. Sleep spindle activity during slow-wave sleep was related to memory for this emotionally salient information across the age range. PMID- 29704650 TI - Quality of Care for Children With Medical Complexity: An Analysis of Continuity of Care as a Potential Quality Indicator. AB - OBJECTIVE: To examine the relationship between continuity of care for children with medical complexity (CMC) and emergency department (ED) utilization, care coordination quality, and family effects related to care coordination. METHODS: We measured ED utilization and primary care continuity with the Bice-Boxerman continuity of care index for 1477 CMC using administrative data from Minnesota and Washington state Medicaid agencies. For a subset of 186 of these CMC a caregiver survey was used to measure care coordination quality (using items adapted from the Consumer Assessment of Healthcare Providers and System Adult Health Plan Survey) and family impact (using items adapted from the National Survey of Children with Special Health Care Needs). Multivariable regression was used to examine the relationship between continuity, entered as a continuous variable ranging from 0 to 1, and the outcomes. RESULTS: The median continuity was 0.27 (interquartile range [IQR], 0.12-0.48) in the administrative data cohort and 0.27 (IQR, 0.14-0.43) in the survey cohort. Compared with children with a continuity score of 0, children with a score of 1 had lower odds of having >=1 ED visit (odds ratio, 0.65; 95% confidence interval [CI], 0.46-0.93; P = .017) and their caregivers reported higher scores for the measure of receipt of care coordination (beta = 35.2 on a 0-100 scale; 95% CI, 11.5-58.9; P = .004). There was no association between continuity and family impact. CONCLUSIONS: Continuity of care holds promise as a quality measure for CMC because of its association with lower ED utilization and more frequent receipt of care coordination. PMID- 29704649 TI - Preparation of a robust immobilized biocatalyst of beta-1,4-endoxylanase by surface coating with polymers for production of xylooligosaccharides from different xylan sources. AB - Xylooligosaccharides display interesting prebiotic effects on human health. The endoxylanase Xys1Delta, from Streptomyces halstedii JM8, was immobilized and stabilized on glyoxyl-agarose beads by multipoint covalent attachment using a novel strategy based on surface coating with a multilayer of polymers. The optimal modification consisted of surface coating with a bilayer formed by a layer of derived dextran polymers and a layer of polyethylenimine. The optimized biocatalyst was 550-fold more stable than one-point covalent immobilized Xys1Delta (at 70 degrees C, pH 7). This biocatalyst was tested for the production of xylooligosaccharides from soluble xylans from various sources. Hydrolysis of beechwood, wheat straw and corncob xylans was 93% in 4 h, 44% in 5 h and 100% in 1 h, respectively. Maximum values of xylooligosaccharides were found for beechwood at 20.6 mg/mL, wheat at 12.5 mg/mL and corncob at 30.4 mg/mL. The optimized biocatalyst was reused for 15 reaction cycles without affecting its catalytic activity. PMID- 29704652 TI - Adolescent predictors of social and coping drinking motives in early adulthood. AB - Although motivations to use alcohol have been shown to predict alcohol use and alcohol-related problems, little is known about how drinking motives develop. This study identified antecedents in adolescence of social and coping motives for drinking in early adulthood. Data came from a longitudinal study of youths in the eastern U.S. (N = 451) followed from secondary school into early adulthood (52.4% female; Mage = 23.01; SD = 1.03). In a structural equation analysis, frequency of drunkenness and peer alcohol use positively predicted young adult social motives, whereas only frequency of drunkenness predicted coping motives. These findings indicate that alcohol use behaviors and social relationships in adolescence may contribute to the development of adult drinking motives. PMID- 29704651 TI - Pediatric Program Director Minimum Milestone Expectations Before Allowing Supervision of Others and Unsupervised Practice. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education requires semiannual Milestone reporting on all residents. Milestone expectations of performance are unknown. OBJECTIVE: To determine pediatric program director (PD) minimum Milestone expectations for residents before being ready to supervise and before being ready to graduate. METHODS: Mixed methods survey of pediatric PDs on their programs' Milestone expectations before residents are ready to supervise and before they are ready to graduate, and in what ways PDs use Milestones to make supervision and graduation decisions. If programs had no established Milestone expectations, PDs indicated expectations they considered for use in their program. Mean minimum Milestone level expectations were adjusted for program size, region, and clustering of Milestone expectations by program were calculated for before supervise and before graduate. Free-text questions were analyzed using thematic analysis. RESULTS: The response rate was 56.8% (113 of 199). Most programs had no required minimum Milestone level before residents are ready to supervise (80%; 76 of 95) or ready to graduate (84%; 80 of 95). For readiness to supervise, minimum Milestone expectations PDs considered establishing for their program were highest for humanism (2.46; 95% confidence interval [CI], 2.21-2.71) and professionalization (2.37; 95% CI, 2.15-2.60). Minimum Milestone expectations for graduates were highest for help-seeking (3.14; 95% CI, 2.83-3.46). Main themes included the use of Milestones in combination with other information to assess learner performance and Milestones are not equally weighted when making advancement decisions. CONCLUSIONS: Most PDs have not established program minimum Milestones, but would vary such expectations according to competency. PMID- 29704653 TI - Exceeding the theoretical fermentation yield in mixotrophic Rubisco-based engineered Escherichia coli. AB - Rubisco-based engineered Escherichia coli MZLFB (E. coli BL21(DE3) Deltazwf, Deltaldh, Deltafrd) containing heterologous phosphoribulokinase (Prk) and Ribulose-1,5- bisphosphate carboxylase/oxygenase (Rubisco) was constructed for the mixotrophic growth. However, in situ CO2 recycling was hindered by clogs of pyruvate during glucose metabolism, which consequently resulted in an insufficient regeneration of NAD+ through the pflB-mediated ethanol production. Recombinant plasmid pLOI295 (encodes pyruvate decarboxylase and alcohol dehydrogenase II, referred to as the Pdc-based carbon tap valve (CTV) for convenience) was introduced into E. coli MZLFB + CTV to bypass the pflB-mediated ethanol production. Results show that while the C-2/C-1 ratio (i.e., the molar ratio of ethanol and acetate to formate and total CO2) for parental strain MZLFB was 1.0 +/- 0.1, the C-2/C-1 for MZLFB + CTV increased to 1.6 +/- 0.1. This indicates that the Pdc-based CTV enhanced the performance of in situ CO2 recycling. By simultaneously utilizing glucose and CO2, the fermentation product yield of MZLFB + CTV exceeded the normal theoretical yield and reached 2.2 +/- 0.0 (mol/mol). In silico analysis shows that 61% of the glucose consumption went through the Rubisco-based engineered pathway when the CTV was equipped. Also shown are the average CO2 consumption rate of 55.3 mg L-1.h-1 and an average ethanol production rate of 144.8 mg L-1.h-1. The conversion of CO2 to ethanol through the Rubisco-based engineered pathway and the Pdc-based carbon tap valve is important for mixotrophic growth, since these two modules serve as the energy sink to achieve intracellular energy balance. Also, during mixotrophic growth, ATP production from a certain percentage (39% in this study) of the EMP pathway activity is needed for mixotrophic growth. PMID- 29704654 TI - Metabolic engineering of Pichia pastoris. AB - Besides its use for efficient production of recombinant proteins the methylotrophic yeast Pichia pastoris (syn. Komagataella spp.) has been increasingly employed as a platform to produce metabolites of varying origin. We summarize here the impressive methodological developments of the last years to model and analyze the metabolism of P. pastoris, and to engineer its genome and metabolic pathways. Efficient methods to insert, modify or delete genes via homologous recombination and CRISPR/Cas9, supported by modular cloning techniques, have been reported. An outstanding early example of metabolic engineering in P. pastoris was the humanization of protein glycosylation. More recently the cell metabolism was engineered also to enhance the productivity of heterologous proteins. The last few years have seen an increased number of metabolic pathway design and engineering in P. pastoris, mainly towards the production of complex (secondary) metabolites. In this review, we discuss the potential role of P. pastoris as a platform for metabolic engineering, its strengths, and major requirements for future developments of chassis strains based on synthetic biology principles. PMID- 29704655 TI - Hippocampus volume alterations and the clinical correlates in medication naive obsessive compulsive disorder. AB - BACKGROUND: Converging evidence suggests the role of hippocampus in the pathophysiology of Obsessive-Compulsive Disorder (OCD). The role of hippocampus, which might have a cardinal role in the neurobiology of OCD through its mediating effect on various cognitive and affective processes, needs further investigation. This study is a region-of-interest analysis of hippocampal volume and its clinical correlates in a medication-naive sample with low comorbidity rate. METHOD: T1 weighted MRI (1.5T) was analysed for medication-naive DSM IV OCD patients (n = 26) patients and 20 age and sex matched healthy controls (HC) using a region-of-interest (ROI) method separately for the anterior and posterior subdivisions of hippocampus. RESULTS: We found significantly greater left hippocampus volume compared to healthy controls. Furthermore, the severity of the compulsion score and the left posterior hippocampus volume demonstrated a significant negative correlation among the OCD patients. LIMITATION: Modest sample size precludes examination of the effect of symptom dimensions on hippocampal volume. CONCLUSIONS: The study results highlight the role of hippocampus in the neurobiological basis of OCD and in mediation of the illness severity. PMID- 29704656 TI - Person-centered analysis of psychological traits to explain heterogeneity in patient-reported outcomes of coronary artery disease- the THORESCI study. AB - BACKGROUND: Heterogeneity in the prognosis of coronary artery disease (CAD) patients may be explained by relatively stable individual psychological differences. Therefore, we studied multiple personality and coping traits using a person-centered approach, and examined the predictive value of this approach for patient-reported outcomes. METHOD: 657 CAD patients (age = 66.39 +/- 10.6; 79% men) completed multiple self-report questionnaires focusing on demographics, negative affectivity and social inhibition (DS14), neuroticism and extraversion (EPQ), resilience (DRS-15), and coping styles (CISS) after undergoing percutaneous coronary intervention. Depressive symptoms (PHQ-9), anxiety (GAD-7), and treatment adherence (MOS) were assessed at 6 months follow-up. Clinical information was extracted from patients' medical records. RESULTS: A step-3 latent class analysis identified four subgroup profiles: Low distress (31%), Passive coping (21%), Active coping (20%), and High distress (28%). For all patient-reported outcomes, overall significant differences between the subgroups were observed (p-values < .05). The High distress profile was associated with the highest levels of emotional distress (d's > .94), and lowest levels of positive mood (d = -1.02) and treatment adherence (d = -2.75) at follow-up. Patients with an Active coping profile also experienced increased emotional distress (d's > .50), but participated in cardiac rehabilitation most often (d = .13), and reported high levels of positive mood (d = -1.02). Patients with a Passive coping profile displayed few emotional problems after six months (d's < .30), but participation to cardiac rehabilitation was relatively low (d = .04). CONCLUSIONS: This study revealed four distinct psychological latent subgroups, which were predictive of patient-reported outcomes. The results indicate that a person-centered approach is useful in explaining heterogeneity in recovery from PCI, and may enhance personalized medicine in patients with CAD. PMID- 29704657 TI - Rumination in relation to suicide risk, ideation, and attempts: Exacerbation by poor sleep quality? AB - BACKGROUND: Rumination, particularly brooding rumination, is associated with suicide risk, ideation and attempts; however, findings are inconsistent with respect to reflective rumination. Recent research suggests reflective rumination might be associated with increased suicide risk specifically among vulnerable individuals. Poor sleep quality is related to both suicide risk and rumination, yet no research has examined whether reflective rumination and sleep quality interact in relation to suicidal risk. This study, therefore, examined whether sleep quality moderates the link between ruminative subtypes and (a) suicide risk overall, and (b) suicidal ideation and (c) history of suicide attempts, specifically. METHODS: Participants were 1696 college students (ages 18-29 years; 65% female) who completed measures assessing rumination, sleep, and suicidal ideation and behavior. Hierarchical linear and logistic regressions were performed regressing overall suicide risk (linear), suicidal ideation (linear) and history of attempts (logistic) on ruminative subtypes controlling for demographics. Sleep quality was examined as a moderator of the rumination-suicide risk/ideation/attempts link. RESULTS: Brooding rumination was significantly associated with increased suicide risk, ideation, and attempts but these associations were not moderated by sleep quality. Sleep quality exacerbated the association of reflective rumination with overall suicide risk and suicidal ideation specifically. Reflective rumination was not itself, or in interaction with sleep quality, significantly associated with a history of suicide attempts. LIMITATIONS: The study is cross-sectional and utilizes a college student sample. CONCLUSIONS: This study adds to the literature that suggests reflective rumination is associated with suicide risk and ideation in certain cases, such as in individuals with lower sleep quality. In addition, the study adds continued support for an association between brooding rumination and suicidal behaviors. More studies that examine the relations between ruminative subtypes and attempts are needed. Interventions that target sleep problems and rumination may be beneficial for suicide prevention and intervention. PMID- 29704658 TI - Cost-Effectiveness of Sorafenib Monotherapy and Selected Combination Therapy with Sorafenib in Patients with Advanced Hepatocellular Carcinoma. AB - OBJECTIVES: To evaluate the cost-effectiveness of sorafenib treatment in combination with other therapies versus sorafenib monotherapy among patients with advanced hepatocellular carcinoma (HCC) who are enrolled in Taiwan's National Health Insurance. METHODS: A Markov model was constructed to simulate treatment outcomes and direct medical costs of sorafenib combination therapy and monotherapy from the perspective of the healthcare payer in Taiwan. Both life years (LYs) and quality-adjusted life-years (QALYs) were used to measure treatment outcomes, and all costs were expressed in 2014 New Taiwan dollars (NT$). Model parameters were acquired primarily using data from population-based administrative databases: the Cancer Registry, National Health Insurance Research Database, and the Death Registry. Willingness-to-pay (WTP) threshold was set at three times the per capita gross domestic product at NT$2,133,930. Deterministic and probabilistic sensitivity analyses were conducted. RESULTS: For advanced HCC patients, sorafenib combined with other treatments might not be a cost-effective option when compared with sorafenib therapy alone. In the base-case analysis, combination treatment with sorafenib was estimated to increase costs by NT$434,788 compared with monotherapy, with a gain of 0.1595 QALYs. The resulting incremental cost-effectiveness ratio (ICER) was NT$2,725,943 per QALY gained. Results were sensitive to health utility values and monthly costs accrued in the progression-free survival state of the combination therapy group. CONCLUSIONS: Our evidence from Taiwan demonstrated that while sorafenib in combination with other therapeutic approaches might improve treatment outcome when compared with sorafenib monotherapy, its ICER exceeded the WTP threshold and was considered not cost-effective. PMID- 29704659 TI - New Drug Reimbursement and Pricing Policy in Taiwan. AB - BACKGROUND: Taiwan has implemented a national health insurance system for more than 20 years now. The benefits of pharmaceutical products and new drug reimbursement scheme are determined by the Expert Advisory Meeting and the Pharmaceutical Benefit and Reimbursement Scheme (PBRS) Joint Committee in Taiwan. OBJECTIVES: To depict the pharmaceutical benefits and reimbursement scheme for new drugs and the role of health technology assessment (HTA) in drug policy in Taiwan. METHODS: All data were collected from the Expert Advisory Meeting and the PBRS meeting minutes; new drug applications with HTA reports were derived from the National Health Insurance Administration Web site. Descriptive statistics were used to analyze the timeline of a new drug from application submission to reimbursement effective, the distribution of approved price, and the approval rate for a new drug with/without local pharmacoeconomic study. RESULTS: After the second-generation national health insurance system, the timeline for a new drug from submission to reimbursement effective averages at 436 days, and that for an oncology drug reaches an average of 742 days. New drug approval rate is 67% and the effective rate (through the approval of the PBRS Joint Committee and the acceptance of the manufacturer) is 53%. The final approved price is 53.6% of the international median price and 70% of the proposed price by the manufacturer. Out of 95 HTA reports released during the period January 2011 to February 2017, 28 applications (30%) conducted an HTA with a local pharmacoeconomic study, and all (100%) received reimbursement approval. For the remaining 67 applications (70%) for which HTA was conducted without a local pharmacoeconomic analysis, 54 cases (81%) were reimbursed. CONCLUSIONS: New drug applications with local pharmacoeconomic studies are more likely to get reimbursement. PMID- 29704661 TI - How can native mass spectrometry contribute to characterization of biomacromolecular higher-order structure and interactions? AB - Native mass spectrometry (MS) is an emerging approach for characterizing biomacromolecular structure and interactions under physiologically relevant conditions. In native MS measurement, intact macromolecules or macromolecular complexes are directly ionized from a non-denaturing solvent, and key noncovalent interactions that hold the complexes together can be preserved for MS analysis in the gas phase. This technique provides unique multi-level structural information such as conformational changes, stoichiometry, topology and dynamics, complementing conventional biophysical techniques. Despite the maturation of native MS and greatly expanded range of applications in recent decades, further dissemination is needed to make the community aware of such a technique. In this review, we attempt to provide an overview of the current body of knowledge regarding major aspects of native MS and explain how such technique contributes to the characterization of biomacromolecular higher-order structure and interactions. PMID- 29704660 TI - Genetic and epigenetic control of adipose development. AB - White adipose tissue (WAT) is the primary energy storage organ and its excess contributes to obesity, while brown adipose tissue (BAT) and inducible thermogenic (beige/brite) adipocytes in WAT dissipate energy via Ucp1 to maintain body temperature. BAT and subcutaneous WAT develop perinatally while visceral WAT forms after birth from precursors expressing distinct markers, such as Myf5, Pref 1, Wt1, and Prx1, depending on the anatomical location. In addition to the embryonic adipose precursors, a pool of endothelial cells or mural cells expressing Ppargamma, Pdgfrbeta, Sma and Zfp423 may become adipocytes during WAT expansion in adults. Several markers, such as Cd29, Cd34, Sca1, Cd24, Pdgfralpha and Pref-1 are detected in adult WAT SVF cells that can be differentiated into adipocytes. However, potential heterogeneity and differences in developmental stage of these cells are not clear. Beige cells form in a depot- and condition specific manner by de novo differentiation of precursors or by transdifferentiation. Thermogenic gene activation in brown and beige adipocytes relies on common transcriptional machinery that includes Prdm16, Zfp516, Pgc1alpha and Ebf2. Moreover, through changing the chromatin landscape, histone methyltransferases, such as Mll3/4 and Ehmt1, as well as demethylases, such as Lsd1, play an important role in regulating the thermogenic gene program. With the presence of BAT and beige/brite cells in human adults, increasing thermogenic activity of BAT and BAT-like tissues may help promote energy expenditure to combat obesity. PMID- 29704662 TI - Functional microbiomics: Evaluation of gut microbiota-bile acid metabolism interactions in health and disease. AB - There is an ever-increasing recognition that bile acids are not purely simple surfactant molecules that aid in lipid digestion, but are a family of molecules contributing to a diverse range of key systemic functions in the host. It is now also understood that the specific composition of the bile acid milieu within the host is related to the expression and activity of bacterially-derived enzymes within the gastrointestinal tract, as such creating a direct link between the physiology of the host and the gut microbiota. Coupled to the knowledge that perturbation of the structure and/or function of the gut microbiota may contribute to the pathogenesis of a range of diseases, there is a high level of interest in the potential for manipulation of the gut microbiota-host bile acid axis as a novel approach to therapeutics. Much of the growing understanding of the biology of this area reflects the recent development and refinement of a range of novel techniques; this study applies a number of those techniques to the analysis of human samples, aiming to illustrate their strengths, drawbacks and biological significance at all stages. Specifically, we used microbial profiling (using 16S rRNA gene sequencing), bile acid profiling (using liquid chromatography-mass spectrometry), bsh and baiCD qPCR, and a BSH enzyme activity assay to demonstrate differences in the gut microbiota and bile metabolism in stool samples from healthy and antibiotic-exposed individuals. PMID- 29704663 TI - Contemporary hydrogen deuterium exchange mass spectrometry. AB - Hydrogen/deuterium exchange (HDX) mass spectrometry (MS) emerged as a tool for biochemistry and structural biology around 25 years ago. It has since become a key approach for studying protein dynamics, protein-ligand interactions, membrane proteins and intrinsically disordered proteins (IDPs). In HDX labeling, proteins are exposed to deuterated solvent (usually D2O) for a variable 'labeling time', resulting in isotope exchange of unprotected labile protons on the amide backbone and amino acid side chains. By comparing the levels of deuterium uptake in different regions of a protein, information on conformational and dynamic changes in the system can be acquired. When coupled with MS, HDX is suitable for probing allosteric effects in catalysis and ligand binding, epitope mapping, validation of biosimilars, drug candidate screening and mapping membrane-protein interactions among many other bioanalytical applications. This review introduces HDX-MS via a brief description of HDX-MS development, followed by an overview of HDX theory and ultimately an outline of methods and procedures involved in performing HDX-MS experiments. PMID- 29704664 TI - Mass spectrometry approaches to metabolic profiling of microbial communities within the human gastrointestinal tract. AB - The interaction between microbial communities and their environment, such as the human gastrointestinal tract, has been an area of microbiology rapidly advanced, by developments in sequencing technology. However, these techniques are largely limited to the detection of the taxonomic composition of a microbial community and/or its genetic functional capacity. Here, we discuss a range of mass spectrometry-based approaches which researchers can employ to explore the host microbiome interactions at the metabolic level. Traditional approaches to mass spectrometry are detailed, alongside new developments in the field, namely ambient ionisation mass spectrometry and imaging mass spectrometry, which we believe will prove to be important to future work in this field. We further discuss considerations for experimental workflows, data analysis options and propose a methodology for the establishment of causal relationships between functional host-microbiome interactions with regards to health and disease in the human gastrointestinal tract. PMID- 29704666 TI - Resolving biomolecular motion and interactions by R2 and R1rho relaxation dispersion NMR. AB - Among the tools of structural biology, NMR spectroscopy is unique in that it not only derives a static three-dimensional structure, but also provides an atomic level description of the local fluctuations and global dynamics around this static structure. A battery of NMR experiments is now available to probe the motions of proteins and nucleic acids over the whole biologically relevant timescale from picoseconds to hours. Here we focus on one of these methods, relaxation dispersion, which resolves dynamics on the micro- to millisecond timescale. Key biological processes that occur on this timescale include enzymatic catalysis, ligand binding, and local folding. In other words, relaxation-dispersion-resolved dynamics are often closely related to the function of the molecule and therefore highly interesting to the structural biochemist. With an astounding sensitivity of ~0.5%, the method detects low-population excited states that are invisible to any other biophysical method. The kinetics of the exchange between the ground state and excited states are quantified in the form of the underlying exchange rate, while structural information about the invisible excited state is obtained in the form of its chemical shift. Lastly, the population of the excited state can be derived. This diversity in the information that can be obtained makes relaxation dispersion an excellent method to study the detailed mechanisms of conformational transitions and molecular interactions. Here we describe the two branches of relaxation dispersion, R2 and R1rho, discussing their applicability, similarities, and differences, as well as recent developments in pulse sequence design and data processing. PMID- 29704665 TI - Synthesis of multi-omic data and community metabolic models reveals insights into the role of hydrogen sulfide in colon cancer. AB - Multi-omic data and genome-scale microbial metabolic models have allowed us to examine microbial communities, community function, and interactions in ways that were not available to us historically. Now, one of our biggest challenges is determining how to integrate data and maximize data potential. Our study demonstrates one way in which to test a hypothesis by combining multi-omic data and community metabolic models. Specifically, we assess hydrogen sulfide production in colorectal cancer based on stool, mucosa, and tissue samples collected on and off the tumor site within the same individuals. 16S rRNA microbial community and abundance data were used to select and inform the metabolic models. We then used MICOM, an open source platform, to track the metabolic flux of hydrogen sulfide through a defined microbial community that either represented on-tumor or off-tumor sample communities. We also performed targeted and untargeted metabolomics, and used the former to quantitatively evaluate our model predictions. A deeper look at the models identified several unexpected but feasible reactions, microbes, and microbial interactions involved in hydrogen sulfide production for which our 16S and metabolomic data could not account. These results will guide future in vitro, in vivo, and in silico tests to establish why hydrogen sulfide production is increased in tumor tissue. PMID- 29704668 TI - Cytomegalovirus aggravates the autoimmune phenomenon in systemic autoimmune diseases. AB - BACKGROUND: Human Cytomegalovirus (CMV), because of its ability to extensively manipulate host immunity during active infection, has been suggested to be involved in autoimmunity. However, its influence on T-cells and cytokines in systemic autoimmune diseases like systemic lupus erythematosus (SLE) and systemic sclerosis (SSc) is indistinct. METHODS: We investigated the in-vitro response of T lymphocytes from SLE and SSc patients to CMV antigen. Functional activity of T lymphocytes was determined by estimating Th1 (IL-2 and IFN-gamma) and Th2 (IL-4 and IL-10) cytokines. RESULTS: We observed that CMV antigen stimulation in-vitro resulted in significant increase in CD4:CD8 T-cell ratio in peripheral blood mononuclear cells (PBMCs) from SLE and SSc patients; response dominated by CD4+ than CD8+ memory T-cells. SSc T-cell response was differentiated by aberrant increase in CD4+CD25+ T-cells. CMV antigen caused elevation in IL-4 and IFN-gamma production in both patient PBMCs, whereas IL-2 was also raised in SLE PBMCs. The development of large pool of memory T-cells and overproduction of IFN-gamma may result in flare-up of autoimmunity in these patients. CONCLUSION: Our study provides an insight into the immunopathological potential of CMV-reactive immune cells to develop new potential strategies for targeted therapeutic intervention. PMID- 29704669 TI - 18S and 28S rDNA identity and phylogeny of two novel myxosporeans infecting gills of cyprinid carps inhabiting a cold water wetland in northern India. AB - The sequences of 18S and 28S rDNA have been extensively used as molecular markers to resolve phylogenetic relationships among various myxosporeans infecting fishes. Two novel myxosporeans have been identified during the present study namely, Henneguya latiusii sp. nov. infecting gills of Crossocheilus latius and Myxobolus atkinsoni sp. nov. infecting gills of Labeo rohita inhabiting Ranjit Sagar Wetland, Punjab (India). These myxosporeans formed plasmodia in the gill arch and gill lamellae respectively and infection was moderate (gill plasmodium index, GPI: 2). Myxospores of both the species possessed distinct morphological and morphometric characteristics hence validated as new species. Phylogenetically, H. latiusii sp. nov. was closest to H. doneci infecting gill filaments of Carassius auratus gibelio, with 96% and 74% similarity in 18S and 28S rDNA respectively. Similarly, M. atkinsoni sp. nov. showed close homogeneity of 90% with M. turpisrotundus and 83% with M. nielii infecting gills of Carassius auratus. The phylogenetic analyses of species of Myxobolus and Henneguya showed a tendency to cluster according to the order or family of the host, tissue and geographical location. This study is the first report on LSU gene marker (28S rDNA) standardized on myxozoans infecting fresh water fishes from Indian subcontinent. PMID- 29704667 TI - Gene expression profiling of primary human type I alveolar epithelial cells exposed to Bacillus anthracis spores reveals induction of neutrophil and monocyte chemokines. AB - The lung is the entry site for Bacillus anthracis in inhalation anthrax, the most deadly form of the disease. Spores must escape through the alveolar epithelial cell (AEC) barrier and migrate to regional lymph nodes, germinate and enter the circulatory system to cause disease. Several mechanisms to explain alveolar escape have been postulated, and all these tacitly involve the AEC barrier. In this study, we incorporate our primary human type I AEC model, microarray and gene enrichment analysis, qRT-PCR, multiplex ELISA, and neutrophil and monocyte chemotaxis assays to study the response of AEC to B. anthracis, (Sterne) spores at 4 and 24 h post-exposure. Spore exposure altered gene expression in AEC after 4 and 24 h and differentially expressed genes (+/-1.3 fold, p <= 0.05) included CCL4/MIP-1beta (4 h), CXCL8/IL-8 (4 and 24 h) and CXCL5/ENA-78 (24 h). Gene enrichment analysis revealed that pathways involving cytokine or chemokine activity, receptor binding, and innate immune responses to infection were prominent. Microarray results were confirmed by qRT-PCR and multiplex ELISA assays. Chemotaxis assays demonstrated that spores induced the release of biologically active neutrophil and monocyte chemokines, and that CXCL8/IL-8 was the major neutrophil chemokine. The small or sub-chemotactic doses of CXCL5/ENA 78, CXCL2/GRObeta and CCL20/MIP-3alpha may contribute to chemotaxis by priming effects. These data provide the first whole transcriptomic description of the human type I AEC initial response to B. anthracis spore exposure. Taken together, our findings contribute to an increased understanding of the role of AEC in the pathogenesis of inhalational anthrax. PMID- 29704670 TI - Anti-inflammatory effects of isorhamnetin on LPS-stimulated human gingival fibroblasts by activating Nrf2 signaling pathway. AB - Periodontitis is a highly prevalent infective and inflammatory disease with an adverse impact on systemic health. Isorhamnetin, a flavonoid mainly isolated from Hippophae fhamnoides L. fruit, has been reported to have anti-inflammatory effect. This study aimed to investigate the anti-inflammatory effects and mechanism of isorhamnetin on lipopolysaccharide (LPS)-induced inflammatory response in human gingival fibroblasts (HGFs). The production of inflammatory mediators and the expression of proteins were measured by ELISA and western blot analysis. The results demonstrated that isorhamnetin attenuated LPS-induced release of PGE2, NO, IL-6, and IL-8 in HGFs. Isorhamnetin also inhibited LPS induced NF-kappaB activation. The expression of Nrf2 and HO-1 were up-regulated by treatment of isorhamnetin. Furthermore, knockdown of Nrf2 by siRNA reversed the anti-inflammatory effects of isorhamnetin. In conclusion, these results suggested that isorhamnetin inhibited LPS-induced inflammation in HGFs by activating Nrf2 signaling pathway. PMID- 29704671 TI - Apathy in Alzheimer's disease and frontotemporal dementia: Distinct clinical profiles and neural correlates. AB - OBJECTIVE: Apathy is the most prevalent and disabling non-cognitive symptom of dementia and affects 90% of patients across the disease course. Despite its pervasiveness, how apathy manifests across dementia syndromes and the neurobiological mechanisms driving these symptoms are poorly understood. Here, we applied the multidimensional ABC model of apathy, which recognizes Affective, Behavioural and Cognitive apathy, in Alzheimer's disease (AD) and behavioural variant frontotemporal dementia (bvFTD). METHODS: One hundred and twenty-two patients (53 AD; 69 bvFTD) were included. Informants completed the Neuropsychiatric Inventory (NPI), Cambridge Behavioral Inventory and Disability and Dementia scale to quantify Affective, Behavioural and Cognitive apathy. All patients underwent structural magnetic resonance imaging (MRI) and voxel-based morphometry (VBM) was employed to identify brain regions correlated with increased Affective, Behavioural and Cognitive apathy. RESULTS: On the NPI, 60% of AD and 84% of bvFTD patients had some degree of apathy, but bvFTD had more severe and more frequent symptoms than AD. Importantly, bvFTD patients had higher affective and cognitive apathy whereas AD had higher cognitive apathy only. Neuroimaging analyses revealed that affective apathy was associated with the ventral prefrontal cortex; behavioural apathy with the basal ganglia; and cognitive apathy with the dorsomedial prefrontal cortex. Finally, affective and behavioural apathy significantly predicted carer burden. CONCLUSIONS: Our results support the notion that apathy is multidimensional and manifests differently across dementia syndromes. Thus, novel interventions which target these divergent mechanisms will be necessary to improve motivation and goal-directed behaviour in people with dementia. PMID- 29704672 TI - Environmental noise pollution and risk of preeclampsia. AB - BACKGROUND: Environmental noise exposure is associated with a greater risk of hypertension, but the link with preeclampsia, a hypertensive disorder of pregnancy, is unclear. OBJECTIVES: We sought to determine the relationship between environmental noise pollution and risk of preeclampsia during pregnancy. METHODS: We analyzed a population-based cohort comprising 269,263 deliveries on the island of Montreal, Canada between 2000 and 2013. We obtained total environmental noise pollution measurements (LAeq24, Lden, Lnight) from land use regression models, and assigned noise levels to each woman based on the residential postal code. We computed odds ratios (OR) and 95% confidence intervals (CI) for the association of noise with preeclampsia in mixed logistic regression models with participants as a random effect, and adjusted for air pollution, neighbourhood walkability, maternal age, parity, multiple pregnancy, comorbidity, socioeconomic deprivation, and year of delivery. We assessed whether noise exposure was more strongly associated with severe or early onset preeclampsia than mild or late onset preeclampsia. RESULTS: Prevalence of preeclampsia was higher for women exposed to elevated environmental noise pollution levels (LAeq24h >= 65 dB(A) = 37.9 per 1000 vs. <50 dB(A) = 27.9 per 1000). Compared with 50 dB(A), an LAeq24h of 65.0 dB(A) was not significantly associated the risk of preeclampsia (OR 1.09, 95% CI 0.99-1.20). Associations were however present with severe (OR 1.29, 95% CI 1.09-1.54) and early onset (OR 1.71, 95% CI 1.20-2.43) preeclampsia, with results consistent across all noise indicators. The associations were much weaker or absent for mild and late preeclampsia. CONCLUSIONS: Environmental noise pollution may be a novel risk factor for pregnancy-related hypertension, particularly more severe variants of preeclampsia. PMID- 29704673 TI - PAHs sensitivity of picophytoplankton populations in the Red Sea. AB - In this study, we investigated the in situ responses of Red Sea picophytoplankton, the dominant phytoplankton group in the oligotrophic ocean, to two toxic polycyclic aromatic hydrocarbons (PAHs), phenanthrene and pyrene. The experiments were conducted across a latitudinal gradient of the Saudi Arabian Red Sea, an area sensitive to oil pollution. We observed significant adverse effects on the growth and abundance of the picocyanobacteria Synechococcus and picoeukaryotes, at all stations sampled. Prochlorococcus, which was abundant only at one of the stations, also appeared to be affected. Pyrene was found to be more toxic to phytoplankton at all stations. In general, picoeukaryotes exhibited higher sensitivity to PAHs than Synechococcus. Populations in the highly oligotrophic Northern region of the Red Sea were more tolerant to PAHs, presumably influenced by the natural selection of more resistant strains of phytoplankton due to the prolonged exposure to PAHs. Toxicity threshold values estimated here are higher than those reported for picophytoplankton from other oligotrophic marine waters and exceed by far the natural levels of PAHs in many oceans. Our findings reveal a possible adaptation of picophytoplankton populations to oil-related contaminants, which may clearly influence their spatial distribution patterns in the Red Sea. PMID- 29704674 TI - PD-L1 Expression Heterogeneity in Non-Small Cell Lung Cancer: Defining Criteria for Harmonization between Biopsy Specimens and Whole Sections. AB - INTRODUCTION: Determination of programmed death ligand 1 (PD-L1) expression defines eligibility for treatment with pembrolizumab in patients with advanced NSCLC. This study was designed to better define which value across core biopsy specimens from the same case more closely reflects the PD-L1 expression status on whole sections and how many core biopsy specimens are needed for confident classification of tumors in terms of PD-L1 expression. METHODS: We built tissue microarrays as surrogates of biopsies collecting five cores per case from 268 cases and compared PD-L1 staining results obtained by using the validated clone SP263 with the results obtained by using whole tumor sections. RESULTS: We found an overall positivity in 39% of cases at a cutoff of 1% and in 10% of cases at a cutoff of 50%. The maximum value across cores was associated with high concordance between cores and whole sections and the lowest number of false negative cases overall. To reach high concordance with whole sections, four and three cores are necessary at cutoffs of 1% and 50%, respectively. Importantly, with 20% as the cutoff for core biopsy specimens, fewer than three cores showed high sensitivity and specificity in identifying cases with 50% or more of tumor cells positive for PD-L1 on whole sections. Specifically, for PD-L1 expression values of 20% to 49% on cores, the probabilities of a tumor specimen expressing PD-L1 in at least 50% of cells on a whole section were 46% and 24% with one and two biopsy specimens, respectively. CONCLUSIONS: An accurate definition of the criteria to determine the PD-L1 status of a given tumor may greatly help in selecting those patients who could benefit from anti-programmed cell death 1/PD L1 treatment. PMID- 29704675 TI - Efficacy of Crizotinib among Different Types of ROS1 Fusion Partners in Patients with ROS1-Rearranged Non-Small Cell Lung Cancer. AB - INTRODUCTION: ROS1 rearrangement-positive NSCLC can be treated effectively with an anaplastic lymphoma kinase/ROS1/mesenchymal-epithelial transition factor inhibitor such as crizotinib; however, the rate of response remains variable. Although several ROS1 fusion partners have been identified, the efficacy of crizotinib in patients with different types of ROS1 fusion partners is poorly understood. METHODS: We reviewed clinicopathological data of patients with ROS1 rearrangement who received crizotinib therapy at our institution between April 2014 and December 2016. ROS1 fusion partners were evaluated by using Sanger sequencing for available tumor tissue. RESULTS: During the study, 49 patients were found to have ROS1 rearrangement and were subsequently treated with crizotinib. Tumor specimens were available for 36 patients, of whom 19 were found to have CD 74 molecule gene (CD74)-ROS1 fusion partners. Before therapy, those in the CD74-ROS1 group were found to have a higher rate of brain metastases (six versus 0 [p = 0.020]). The objective response rate for crizotinib was 83.3% in all patients, whereas it was 94.11% and 73.68% in the non-CD74-ROS1 and CD74-ROS1 groups, respectively. As compared with the CD74-ROS1 group, the non-CD74-ROS1 group had both a significantly longer progression-free survival (17.63 months versus 12.63 months [p = 0.048]) and a significantly longer overall survival (44.50 months versus 24.33 months [p = 0.036]). On multivariable analysis, the only factor associated with overall survival was presence of brain metastases before therapy (p = 0.010). There were no significant factors associated with progression-free survival in the multivariable analysis. CONCLUSIONS: These findings suggests that patients with CD74-ROS1 fusion partners are more likely to present with brain metastases. Although not independently significant, a trend toward improved survival was observed in patients in the non-CD74-ROS1 group when they were treated with crizotinib. PMID- 29704676 TI - Afatinib in Osimertinib-Resistant EGFR ex19del/T790M/P794L Mutated NSCLC. PMID- 29704677 TI - Laparoscopic Resection of Post-Cesarean Section Scar Uterine Cyst. AB - STUDY OBJECTIVE: To demonstrate a technique of performing laparoscopic resection of a post-cesarean section scar uterine cyst. DESIGN: Technical video (Canadian Task Force classification III). SETTING: University Hospital. PATIENT: A 38-year old woman. INTERVENTION: Laparoscopic excision of a uterine cyst within a cesarean section scar. MEASUREMENTS AND MAIN RESULTS: A 38-year-old woman presented with secondary subfertility requesting removal of a cesarean section scar defect to prepare the uterine cavity for in vitro fertilization. Preoperative ultrasound demonstrated a 17.7 * 12.2 mm scar defect. At rigid hysteroscopy the anterior uterine wall cyst was observed and noted to be narrowing the uterine cavity. A laparoscopic approach was used to excise the uterine cyst. We carefully mobilized the bladder from its adhesions at the site of the previous cesarean section scar. The uterine cyst was located and margins of the defect identified. An ultrasonic-energy device was used to enucleate and excise the cyst. A uterine manipulator helped to identify the cervical canal and protect the posterior wall from inadvertent suture placement. The defect was closed with 1 vicryl interrupted sutures, being careful to incorporate the full thickness of the uterine wall to an able maximal opposition. An adhesion barrier was applied to the area. Transvaginal ultrasound scanning performed 6 weeks postoperatively demonstrated full healing with no residual defect. CONCLUSION: Niches are recognized complications of cesarean sections resulting from incomplete healing of the scar and more likely in single-layer closures [1]. They can be associated with postmenstrual spotting, dysmenorrhea, chronic pain, subfertility, and poorer reproductive and obstetric outcomes [1-5]. Laparoscopic resection of niches is well established, showing symptomatic relief and an increase in residual myometrium [6]. Although cesarean section scar defects have been described as niches, we presented a further variety of defect that has not been previously described, a uterine cyst. PMID- 29704678 TI - Coexistence of a Tubal Ectopic Pregnancy and Tubal Leiomyoma. PMID- 29704679 TI - Evaluating the longer-term cognitive effects of adjunctive perampanel compared to lacosamide in a naturalistic outpatient setting. AB - PURPOSE: This retrospective longitudinal study aims to compare the longer-term cognitive and behavioral side effects of adjunctive antiepileptic treatment with perampanel (PER) and lacosamide (LCM), two third generation antiepileptic drugs with suggested favorable cognitive profiles. The two drugs were monitored according to a previously established routine diagnostic protocol (Helmstaedter et al. E&B 2013;26:182-7) which facilitates the retrospective comparison of antiepileptic drug tolerability in a naturalistic outpatient setting. METHODS: Records from 94 patients were evaluated who underwent neuropsychological assessment before and under adjunctive treatment with either PER (n = 57) or LCM (n = 37). Cognition was assessed using the EpiTrack screening for executive functions and a VLMT short form for verbal memory. Subjective assessments included a German QOLIE-10 adaptation (quality of life) and an extended Adverse Events Profile (AEP). The median follow-up interval was 36 weeks. RESULTS: Multivariate repeated measures statistics revealed a non-significant trend towards an interaction effect "time - treatment arm" on both executive function and memory. When analyzed separately executive functions and memory scores significantly improved under LCM (t = -2.76 p < 0.01 and t = -2.44 p < 0.05 respectively). Subjectively, PER was associated with improvements in 2/18 physiological domains and in the LCM group 1/9 cognitive domains deteriorated. Seizure freedom was achieved for five patients treated with LCM (14%) and 15 treated with PER (26%, chi2 = 2.2, n.s.). CONCLUSION: In a naturalistic outpatient setting, chronic adjunctive treatment with PER and LCM did not negatively affect cognition and LCM may even improve cognition. Neither drug increased self-reported irritability or aggression. This suggests favorable longer-term tolerability. PMID- 29704680 TI - Evidence to Support Monitoring of Vedolizumab Trough Concentrations in Patients With Inflammatory Bowel Diseases. AB - BACKGROUND & AIMS: Trough concentrations of vedolizumab were found to correlate with clinical response in phase 3 studies of patients with ulcerative colitis (UC) or Crohn's disease (CD). Nevertheless, there are no solid data to support monitoring of vedolizumab trough concentrations in treated patients. We investigated the correlation between vedolizumab exposure and response in a real world population and aimed to identify patient factors that affect exposure and response. METHODS: We performed a retrospective cohort study of 179 consecutive patients (66 with UC and 113 with CD) who began vedolizumab therapy from September 1, 2015, through October 1, 2016, at University Hospitals Leuven, Belgium. Serum concentrations of vedolizumab were measured before all infusions up to week 30. Effectiveness endpoints included endoscopic healing (UC, Mayo endoscopic sub-score <=1; CD, absence of ulcers), clinical response (physicians' global assessment), and biologic response or remission (based on level of C reactive protein) and were assessed at week 14 (for patients with UC) and week 22 (for patients with CD). A stepwise forward addition-backward elimination modeling approach was performed to identify factors independently associated with vedolizumab exposure and response. RESULTS: Vedolizumab trough concentrations >30.0 MUg/mL at week 2, >24.0 MUg/mL at week 6, and >14.0 MUg/mL during maintenance therapy associated with a higher probability of attaining the effectiveness endpoints for patients with UC or CD (P < .05). Higher body mass and more severe disease (based on high level of C-reactive protein and low level of albumin and/or hemoglobin) at the start of vedolizumab therapy associated with lower trough concentrations of vedolizumab over the 30-week period and a lower probability of achieving mucosal healing (P < .05). Mucosal healing was achieved in significantly more patients with UC than patients with CD, even though a diagnosis of UC was not an independent predictor of higher vedolizumab trough concentrations. CONCLUSIONS: In a retrospective study of 179 patients with CD or UC, we observed a correlation between vedolizumab exposure and response. These findings support monitoring of vedolizumab trough concentrations to predict patients' outcome. PMID- 29704681 TI - Fulminant Emphysematous Pancreatitis. PMID- 29704682 TI - Outcomes of Endoscopic Submucosal Dissection vs Esophagectomy for T1 Esophageal Squamous Cell Carcinoma in a Real-World Cohort. AB - BACKGROUND & AIMS: Esophagectomy is the standard treatment for early-stage esophageal squamous cell carcinoma (EESCC), but patients who undergo this procedure have high morbidity and mortality. Endoscopic submucosal dissection (ESD) is a less-invasive procedure for treatment of EESCC, but is considered risky because this tumor frequently metastasizes to the lymph nodes. We aimed to directly compare outcomes of patients with EESCC treated with ESD vs esophagectomy. METHODS: We performed a retrospective cohort study of patients with T1a-m2/m3, or T1b EESCCs who underwent ESD (n = 322) or esophagectomy (n = 274) from October 1, 2011 through September 31, 2016 at Zhongshan Hospital in Shanghai, China. The primary outcome was all-cause mortality at the end of follow up (minimum of 6 months). Secondary outcomes included operation time, hospital stay, cost, perioperative mortalities/severe non-fatal adverse events, requirement for adjuvant therapies, and disease-specific mortality and cancer recurrence or metastasis at the end of the follow up period. RESULTS: Patients who underwent ESD were older (mean 63.5 years vs 62.3 years for patients receiving esophagectomy; P = .006) and a greater proportion was male (80.1% vs 70.4%; P = .006) and had a T1a tumor (74.5% vs 27%; P = .001). A lower proportion of patients who underwent ESD had perioperative mortality (0.3% vs 1.5% of patients receiving esophagectomy; P = .186) and non-fatal severe adverse events (15.2% vs 27.7%; P = .001)-specifically lower proportions of esophageal fistula (0.3% of patients receiving ESD vs 16.4% for patients receiving esophagectomy; P = .001) and pulmonary complications (0.3% vs 3.6%; P = .004). After a median follow-up time of 21 months (range, 6-73 months), there were no significant differences between treatments in all-cause mortality (7.4% for ESD vs 10.9%; P = .209) or rate of cancer recurrence or metastasis (9.1% for ESD vs 8.9%; P = .948). Disease-specific mortality was lower among patients who received ESD (3.4%) vs patients who patients who received esophagectomy (7.4%) (P = .049). In Cox regression analysis, depth of tumor invasion was the only factor associated with all-cause mortality (T1a-m3 or deeper vs T1a-m2: hazard ration, 3.54; P = .04). CONCLUSION: In a retrospective study of patients with T1am2/m3 or T1b EESCCs treated with ESD (n = 322) or esophagectomy (n = 274), we found lower proportions of patients receiving ESD to have perioperative adverse events or disease specific mortality after a median follow up time of 21 months. We found no difference in overall survival or cancer recurrence or metastasis in patients with T1a or T1b ESCCs treated with ESD vs esophagectomy. PMID- 29704683 TI - Rates of Hospital Readmission Among Medicare Beneficiaries With Gastrointestinal Bleeding Vary Based on Etiology and Comorbidities. AB - BACKGROUND & AIMS: Gastrointestinal bleeding results in significant morbidity, mortality, and healthcare costs in the United States. The Center for Medicare and Medicaid Services' payment reform programs assess quality and value based on rates of hospital readmission for patients with gastrointestinal bleeding, but they identify these patients using Medicare Severity Diagnosis Related Groups (MS DRGs), which include many types of gastrointestinal bleeding and do not account for the clinical heterogeneity among these patients. We aimed to characterize heterogeneity in outcomes of subgroups of patients with gastrointestinal bleeding. METHODS: We performed was a cross-sectional, claims-based retrospective analysis of Medicare fee for service beneficiaries hospitalized for gastrointestinal bleeding in 2014 (159,000 hospitalizations). The primary outcome was unplanned readmission within 30 days of discharge from the hospital (30-day readmission). Secondary outcomes included length of stay, inpatient mortality, and death within 30 days of admission to the hospital (30-day mortality). Analyses were adjusted for age, sex, race, and Elixhauser comorbidities using logistic and Poisson regression, adjusting for clustering within hospitals. RESULTS: The 30-day readmission rate was 16.0%. Readmission rates varied among patients with different types of gastrointestinal bleeding, ranging from 13.5% for diverticular bleeding to 18.6% for small bowel bleeding. The mean length of stay was 4.2 days and 30-day mortality was 6.9% (ranging from 3.4% for diverticular bleeding to 12.1% for upper gastrointestinal bleeding not otherwise specified). When hospitalizations were stratified by MS-DRGs, the main source of variation in rates of readmission and mortality was MS-DRGs. CONCLUSIONS: In a retrospective analysis of Medicare fee for service beneficiaries hospitalized for gastrointestinal bleeding, we found that 16% of these patients are readmitted to the hospital. Rates of hospital readmission, length of stay, and mortality vary with type of gastrointestinal bleeding, but MS-DRGs account for the largest source of variation. Policies focused on quality and value should account for this heterogeneity. PMID- 29704684 TI - Improved molecular platform for the gene therapy of rare diseases by liver protein secretion. AB - Many rare monogenic diseases are treated by protein replacement therapy, in which the missing protein is repetitively administered to the patient. However, in several cases, the missing protein is required at a high and sustained level, which renders protein therapy far from being adequate. As an alternative, a gene therapy treatment ensuring a sustained effectiveness would be particularly valuable. Liver is an optimal organ for the secretion and systemic distribution of a therapeutic transgene product. Cutting edge non-viral gene therapy tools were tested in order to produce a high and sustained level of therapeutic protein secretion by the liver using the hydrodynamic delivery technique. The use of S/MAR matrix attachment region provided a slight, however not statistically significant, increase in the expression of a reporter gene in the liver. We have selected the von Willebrand Factor (vWF) gene as a particularly challenging large gene (8.4 kb) for liver delivery and expression, and also because a high vWF blood concentration is required for disease correction. By using the optimized miniplasmid pFAR free of antibiotic resistance gene together with the Sleeping Beauty transposon and the hyperactive SB100X transposase, we have obtained a sustainable level of vWFblood secretion by the liver, at 65% of physiological level. Our results point to the general use of this plasmid platform using the liver as a protein factory to treat numerous rare disorders by gene therapy. PMID- 29704685 TI - Is it research or is it clinical? Revisiting an old frontier through the lens of next-generation sequencing technologies. AB - As next-generation sequencing technologies (NGS) are increasingly used in the clinic, one issue often pointed out in the literature is the fact that their implementation "blurs the line" between research and healthcare. Indeed, NGS data obtained through research study may have clinical significance, and patients may consent that their data is shared in international databases used in research. This blurred line may increase the risk of therapeutic misconception, or that of over-reporting incidental findings. The law has been used to impose a distinction between the two contexts, but this distinction may not always be as clear in the practice of clinical genomics. To illustrate this, we reviewed the legal frameworks in France and Quebec on the matter, and asked the opinion of stakeholders who use NGS to help cancer and rare disease patients in practice. We found that while there are clear legal distinctions between research and clinical care, bridges between the two contexts exist, and the law focuses on providing appropriate protections to persons, whether they are patients or research participants. The technology users we interviewed expressed that their use of NGS was designed to help patients, but harbored elements pertaining to research as well as care. We hence saw that NGS technologies are often used with a double objective, both individual care and the creation of collective knowledge. Our results highlight the importance of moving towards research-based care, where clinical information can be progressively enriched with evolutive research results. We also found that there can be a misalignment between scientific experts' views and legal norms of what constitutes research or care, which should be addressed. Our method allowed us to shed light on a grey zone at the edge between research and care, where the full benefits of NGS can be yielded. We believe that this and other evidence from the realities of clinical research practice can be used to design more stable and responsible personalized medicine policies. PMID- 29704686 TI - A novel NKX3-2 mutation associated with perinatal lethal phenotype of spondylo megaepiphyseal-metaphyseal dysplasia in a neonate. AB - Spondylo-megaepiphyseal-metaphyseal dysplasia (SMMD) is an autosomal recessive skeletal dysplasia, characterized by disproportionate short stature with a short and stiff neck and trunk. SMMD is caused by inactivating mutations in NKX3-2, which encodes a homeobox-containing protein. Because of the rarity of the disorder, the diagnostic feature has not been fully established yet. We describe an affected newborn with dysmorphic facial features and severe short trunk. The patient required immediate intubation at the delivery room and duodenal atresia was detected during his course in neonatal intensive care unit. Skeletal survey revealed total absence of the ossification of the vertebral bodies, pubis, and ischia. Mainly the femora was short and broad with mild flaring of the metaphyses. The downward sloping or tented appearance of the ribs was distinctive. A diagnosis of SMMD was made on clinical and radiological grounds. Molecular analysis revealed homozygosity for a novel mutation, c.507-508delCA (p.Gly171Cysfs*55) in exon 2 of NKX3-2. The patient was operated on postnatal day 7 for duodenal atresia. In the post-operative period he developed sepsis and respiratory failure and he died on postnatal day 14. Although no neuroradiologic imaging could be performed, the findings of clubfoot, neuromuscular respiratory insufficiency requiring invasive mechanical ventilation and downward sloping or tented appearance of the ribs were suggestive of very early cervical cord compression leading to perinatal mortality. To our knowledge this patient yet represents one of the most severe postnatal phenotypes of SMMD. PMID- 29704687 TI - Clinical Experience of Autologous Blood Transfusion in Neurosurgery: Prospective Study in Central India. AB - OBJECTIVE: To evaluate the benefits of intraoperative autologous blood transfusion in intracranial procedures and to conserve precious homologous blood due to shortage of donor and associated complications. METHODS: This was a prospective study performed at Bansal Hospital, Bhopal. Predetermined autologous blood was collected in a well-labeled bag containing citrate phosphate dextrose adenine solution after induction of general anesthesia. Then appropriate amount of crystalloid solution was transfused in to the body. All collected autologous blood was transfused back to the patient at the end of the surgery or during the surgery if excessive blood loss occurred. Demographic data, hemodynamic changes (mean arterial pressure, heart rate) before and after donation, complications, and any additional homologous blood requirement were noted. Pre- and postoperative hemoglobin and hematocrit values were compared. RESULTS: In total, 32 patients were included in this study. In our study, mean age was 48.87 years; male-to-female ratio was 1:1.4. The mean amount of autologous blood collected was 461 mL, and the mean amount of blood loss during surgery was 1048 mL. In our study, there was no statistically significant difference was found in mean arterial pressure and heart rate before and after autologous blood collection (P > 0.05). When we compared pre- and postoperative mean hemoglobin and hematocrit levels, there was a statistically significant difference present (P < 0.05); this was due to the fact that many patients had meningiomas (15 of 32). Additional homologous blood was required only in 25% of cases (8/32). Of 8 patients, 5 were again cases of deep-seated meningiomas. No complications were observed during or after autologous blood collection. CONCLUSIONS: Autologous blood transfusion is a safe, effective, and affordable method of blood transfusion in patients undergoing intracranial surgery. Complications associated with homologous blood transfusion can be avoided with autologous blood transfusion. PMID- 29704688 TI - Diffusely Infiltrating Cerebellar Anaplastic Astrocytoma Effectively Controlled with Bevacizumab: Case Report and Literature Review. AB - BACKGROUND: Gliomas that show extensive diffuse infiltration from the cerebellum to the brainstem without masslike expansion are extremely rare. The efficacy of bevacizumab treatment for diffusely infiltrating gliomas remains uncertain. CASE DESCRIPTION: A 75-year-old man presented with a cerebellar anaplastic astrocytoma showing diffuse infiltration to the brainstem without a definite mass. He had experienced rapidly progressive nausea and dysarthria, as well as vertigo and headache for 2 months. Magnetic resonance imaging (MRI) revealed a poorly demarcated T2 high-intensity area in the right cerebellum and brainstem. The tumor in the right cerebellum showed sparse enhancement with gadolinium (Gd). Suboccipital decompressive craniotomy and partial removal of the tumor was emergently performed because of the rapid progression of symptoms and severe tonsillar herniation demonstrated on MRI. The pathologic diagnosis was anaplastic astrocytoma, and genomic analyses revealed no mutation in IDH1, H3F3A, or BRAF. During concomitant chemoradiotherapy with temozolomide, rapid worsening of the neurologic symptoms developed and significant enlargement of the T2 high intensity area extending to the cerebral peduncle was seen, as well as a new Gd enhancing lesion in the midbrain. After administration of bevacizumab, the neurologic symptoms gradually improved, the T2 high-intensity area decreased, and the Gd-enhancing lesion disappeared. At follow-up 2 years after the operation, no worsening of neurologic symptoms was seen and the residual T2 high-intensity area remained unchanged on MRI. CONCLUSIONS: Bevacizumab treatment may be a salvage treatment option for patients with diffusely infiltrating cerebellar gliomas that exhibits rapid progression during standard treatment. PMID- 29704689 TI - Postictal Delirium and Violent Behavior in Patients with Post-Neurosurgical Epilepsy. AB - BACKGROUND: Neurosurgical brain interventions may result in lesions that can cause epilepsy. Diagnosis may be delayed in some situations. Meanwhile, violent behavior can occur during postictal delirium states. Although benign behavioral manifestations are well documented in literature, violent offenses in post neurosurgical epilepsy have been rarely reported. Here we describe 2 such cases, focusing on management and emphasizing the need for prevention. CASE DESCRIPTION: Both patients were suffering from post-neurosurgical epilepsy and offended during postictal delirium states. The first patient had generalized epilepsy and committed an attempted rape. The second patient had temporal lobe epilepsy and committed an attempted homicide. Both patients were well managed using anticonvulsant medication after the offenses. CONCLUSIONS: Early diagnosis and regular follow-up are measures to take into consideration to prevent violent behavior in patients with post-neurosurgical epilepsy. PMID- 29704690 TI - A Systematic Review of the Semi-Sitting Position in Neurosurgical Patients with Patent Foramen Ovale: How Frequent Is Paradoxical Embolism? AB - BACKGROUND: The semi-sitting position is preferred in some surgeries of the posterior fossa and the cervical spine. At the same time, it is associated with a risk of air embolism. In the presence of a patent foramen ovale (PFO) with an intracardial right-to-left shunt, an air embolism can result in a paradoxical embolism to the heart or brain. It is unclear whether the risk-benefit ratio favors the semi-sitting position in this scenario. METHODS: We conducted a systematic review of the relevant studies published after 2007 by searching the PubMed, Science Direct, and Cochrane Database of Systematic Reviews databases. Studies in which the presence of PFO was stated and the occurrence of paradoxical embolism was evaluated in patients who underwent neurosurgical procedures in the semi-sitting position were included in our analysis. RESULTS: We identified 4 observational studies with a total of 977 patients who underwent surgery of the posterior fossa or cervical spine in the semi-sitting position; among these, 82 had a PFO. Air embolism occurred in 33 of these 82 patients (40.2%). No paradoxical embolisms were detected. CONCLUSIONS: In experienced medical centers, neurosurgery in the semi-sitting position is feasible with acceptable risk even in patients with PFO. If the PFO is large, or if a permanent right-to-left shunt is present in a patient with a history of paradoxical embolism, it may be reasonable to repair the PFO before surgery if the semi-sitting position is strongly preferred. The risk analysis must be done on a case-by-case basis. PMID- 29704691 TI - A Comparative Report on Intracranial Tumor-to-Tumor Metastasis and Collision Tumors. AB - BACKGROUND: The incidence of 2 distinct tumor types occupying the same anatomic location is rarely observed and may be accounted for by 2 separate mechanisms: tumor-to-tumor metastasis and collision tumors, where 2 adjacent tumors invade one another. These rare phenomena arise from distinct mechanisms, which may affect their preoperative recognition, surgical approach, and postoperative care. We review 2 cases, highlighting their identification and perioperative management. CASE DESCRIPTIONS: In case 1, a 71-year-old patient with a history of sphenoid wing meningioma presented with headache, nausea, and vomiting and was found to have a mass with meningioma and glioblastoma (GBM) characteristics. In case 2, a 61-year-old man with worsening dysmetria in the setting of unintentional weight loss presented with multiple masses in the pelvis, abdomen, lung, and brain. The brain masses were classified as meningioma with intratumoral metastatic adenocarcinoma foci. CONCLUSIONS: Preoperative recognition of collision tumor and tumor-to-tumor metastasis is imperative for surgical planning, including selecting regions for tissue biopsy and goals of care. Meticulous evaluation of history and imaging and thorough pathologic analysis allow for effective diagnosis and optimal patient outcomes. PMID- 29704692 TI - Calcifying Pseudoneoplasm of the Neuraxis (CAPNON) in Lateral Cerebellomedullary Junction: Clinical Image with Surgical Video. AB - Calcifying pseudoneoplasms of the neuraxis are rare, benign, slow-growing lesions, which occur anywhere in the central nervous system without any age or sex predilection. The lesion's clinical course is variable and poorly understood because a limited number of cases have been reported in the literature. In this report, we present a case of calcifying pseudoneoplasms of the neuraxis in the lateral cerebello-medullary junction, which was removed via a far-lateral approach. To best of our knowledge, this is the first report demonstrating actual lesions in a real-time surgical video, which may make the readers and viewers aware of such a pathology if they encounter this rare lesion. PMID- 29704693 TI - Cardiac Arrest During Spine Surgery in the Prone Position: Case Report and Review of the Literature. AB - OBJECTIVE: Intraoperative cardiac arrest (CA) is usually attributable to pre existing disease or intraoperative complications. In rare cases, intraoperative stress can demask certain genetic diseases, such as catecholaminergic polymorphic ventricular tachycardia (CPVT). It is essential that neurosurgeons be aware of the etiologies, risk factors, and initial management of CA during surgery with the patient in the prone position. METHODS: We present a case of CA directly after spinal fusion for lumbar spondylolisthesis and review the literature on cardiac arrests during spinal neurosurgery in the prone position. We focus on etiologies of CA in patients with structurally normal hearts. RESULTS: After resuscitation, a 53-years-old female patient achieved return of spontaneous circulation after 17 minutes, without any neurologic deficits and with substantial improvement of functional disability and pain scores. Extensive imaging, stress testing, and genetic screening ruled out common etiologies of CA. In this patient with a structurally normal heart, CPVT was established as the most likely cause. We identified 18 additional cases of CA associated with spinal neurosurgery in the prone position. Most cases occurred during deformity or fusion procedures. Commonly reported etiologies of CA were air embolism, hypovolemia, and dural traction leading to vasovagal response. In patients with structurally normal hearts, inherited arrhythmia syndromes including CPVT, Brugada syndrome, and long QT syndrome should be included in the differential diagnosis and specifically included in testing. CONCLUSIONS: Although intraoperative CA is rare during spine surgery, neurosurgeons should be aware of the etiologies and the specific difficulties in the management associated with the prone position. PMID- 29704694 TI - Flexible Endoscopic-Assisted Microsurgical Radical Resection of Intracanalicular Vestibular Schwannomas by a Retrosigmoid Approach: Operative Technique. AB - The efficacy of endoscopic techniques in the surgical management of intracanalicular vestibular schwannomas (ICVSs) has been underlined in recent studies. An endoscopic- assisted retrosigmoid approach (EARSA) appears to be particularly suitable for achieving complete resection of an ICVS. In this study, we describe the surgical treatment of 3 cases of ICVS with an EARSA, highlighting the advantages and limitations of flexible endoscopy in accomplishing a safe radical resection with hearing preservation. Three patients with an ICVS underwent surgery via a flexible endoscopic-assisted microneurosurgical retrosigmoid approach. Flexible endoscopic assistance allowed the identification of residual tumor located in the most lateral portion of the fundus of the internal auditory canal in all cases. Endoscopic controls and further microsurgical resection were attempted, and complete surgical resection was achieved in all cases without the occurrence of postoperative facial or auditory nerve dysfunction. Flexible endoscopy appears to be particularly useful and safe in the surgical management of ICVS by microneurosurgery via an EARSA. PMID- 29704695 TI - Endoscopic Strategy in Surgical Treatment of Adult Idiopathic Bilateral Occlusion of the Foramen of Monro and Review of the Literature. AB - BACKGROUND: Endoscopic approach has been used increasingly for the surgical treatment of adult idiopathic bilateral occlusion of the foramen of Monro (AIOFM). The aim of this study is to assess and compare the results of this strategy with other surgical methods of treating AIOFM. METHODS: A retrospective study was performed to identify patients with AIOFM treated in our department from 2012 to 2017. We also performed a search of the literature to detect any case of AIOFM reported from 1980 to 2017 to provide a comprehensive assessment of the treatment of this condition. AIOFM was classified as 4 groups, including bilateral true stenosis of the foramen of Monro (FM), bilateral membrane occlusion of the FM, unilateral true FM stenosis with septum deviation, and unilateral membrane occlusion of the FM with septum deviation all assessed and discussed separately. RESULTS: We found four patients with AIOFM surgically treated with endoscopic procedures in our department between the years of 2012 to 2017 with an excellent outcome. Fourteen studies were also detected during our review of the literature, most of which involved treatment with neuroendoscopy and excellent outcomes. We found that neuroendoscopy could be the first-line strategy to treat all 4 types of AIOFM. CONCLUSIONS: Endoscopic strategy is associated with excellent outcomes and fewer risks in treatment of all types of AIOFM; it is also less invasive compared with ventriculoperitoneal shunt insertion. PMID- 29704696 TI - Evaluation of cross-sectional and longitudinal changes in volumetric bone mineral density in postmenopausal women using single- versus dual-energy quantitative computed tomography. AB - Central quantitative computed tomography (QCT) is increasingly used in clinical trials and practice to assess bone mass or strength and to evaluate longitudinal changes in response to drug treatment. Current studies utilize single-energy (SE) QCT scans, which may be confounded both by the amount of bone marrow fat at baseline and changes in marrow fat over time. However, the extent to which marrow fat changes either underestimate volumetric BMD (vBMD) measurements at baseline or under-/overestimate longitudinal changes in vivo in humans remains unclear. To address this issue, 197 early postmenopausal women [median age (IQR) 56.7 (54.4 58.7) years] underwent spine and hip QCT scans at baseline and 3 years using a 128-slice dual-source dual-energy (DE) scanner. The scans were analyzed as either SE scans (100 kVp) or DE scans (100 kVp and 140 kVp), with the latter accounting for bone marrow fat. At baseline, vertebral trabecular vBMD was (median) 17.6% lower (P < 0.001) while femur neck (FN) cortical vBMD was only 3.2% lower (P < 0.001) when assessed by SE vs DE scanning. SE scanning overestimated the 3 year rate of bone loss for trabecular bone at the spine by 24.2% (P < 0.001 vs DE rates of loss) but only by 8.8% for changes in FN cortical vBMD (P < 0.001 vs DE rates of loss). The deviation between SE and DE rates of bone loss in trabecular vBMD became progressively greater as the rate of bone loss increased. These findings demonstrate that SE QCT scans underestimate trabecular vBMD and substantially overestimate rates of age-related bone loss due to ongoing conversion of red to yellow marrow. Further, the greater the rate of bone loss, the greater the overestimation of bone loss by SE scans. Although our findings are based on normal aging, recent evidence from animal studies demonstrates that the skeletal anabolic drugs teriparatide and romosozumab may markedly reduce marrow fat, perhaps accounting for the disproportionate increases in trabecular vBMD by SE QCT as compared to dual-energy X-ray absorptiometry with these agents. As such, future studies using recently available DE scanning technology that has satisfactory precision and radiation exposure are needed to evaluate changes in trabecular vBMD independent of changes in marrow fat with aging and drugs that may alter marrow fat composition. PMID- 29704697 TI - Imaging methods used to study mouse and human HSC niches: Current and emerging technologies. AB - Bone marrow contains numerous different cell types arising from hematopoietic stem cells (HSCs) and non-hematopoietic mesenchymal/skeletal stem cells, in addition to other cell types such as endothelial cells- these non-hematopoietic cells are commonly referred to as stromal cells or microenvironment cells. HSC function is intimately linked to complex signals integrated by their niches, formed by combinations of hematopoietic and stromal cells. Studies of hematopoietic cells have been significantly advanced by flow cytometry methods, enabling the quantitation of each cell type in normal and perturbed situations, in addition to the isolation of these cells for molecular and functional studies. Less is known, however, about the specific niches for distinct developing hematopoietic lineages, or the changes occurring in the niche size and function in these distinct anatomical sites in the bone marrow under stress situations and ageing. Significant advances in imaging technology during the last decade have permitted studies of HSC niches in mice. Additional imaging technologies are emerging that will facilitate the study of human HSC niches in trephine BM biopsies. Here we provide an overview of imaging technologies used to study HSC niches, in addition to highlighting emerging technology that will help us to more precisely identify and characterize HSC niches in normal and diseased states. PMID- 29704698 TI - An osteopenic/osteoporotic phenotype delays alveolar bone repair. AB - Aging is associated with a function decline in tissue homeostasis and tissue repair. Aging is also associated with an increased incidence in osteopenia and osteoporosis, but whether these low bone mass diseases are a risk factor for delayed bone healing still remains controversial. Addressing this question is of direct clinical relevance for dental patients, since most implants are performed in older patients who are at risk of developing low bone mass conditions. The objective of this study was to assess how an osteopenic/osteoporotic phenotype affected the rate of new alveolar bone formation. Using an ovariectomized (OVX) rat model, the rates of tooth extraction socket and osteotomy healing were compared with age-matched controls. Imaging, along with molecular, cellular, and histologic analyses, demonstrated that OVX produced an overt osteoporotic phenotype in long bones, but only a subtle phenotype in alveolar bone. Nonetheless, the OVX group demonstrated significantly slower alveolar bone healing in both the extraction socket, and in the osteotomy produced in a healed extraction site. Most notably, osteotomy site preparation created a dramatically wider zone of dying and dead osteocytes in the OVX group, which was coupled with more extensive bone remodeling and a delay in the differentiation of osteoblasts. Collectively, these analyses demonstrate that the emergence of an osteoporotic phenotype delays new alveolar bone formation. PMID- 29704699 TI - Molecular diversity underlying cortical excitatory and inhibitory synapse development. AB - The complexity and precision of cortical circuitries is achieved during development due to the exquisite diversity of synapse types that is generated in a highly regulated manner. Here, we review the recent increase in our understanding of how synapse type-specific molecules differentially regulate the development of excitatory and inhibitory synapses. Moreover, several synapse subtype-specific molecules have been shown to control the targeting, formation or maturation of particular subtypes of excitatory synapses. Because inhibitory neurons are extremely diverse, a similar molecular diversity is likely to underlie the development of different inhibitory synapses making it a promising topic for future investigation in the field of the synapse development. PMID- 29704700 TI - Quality of life of nursing students from nine countries: A cross-sectional study. AB - BACKGROUND: Nursing student life is stressful as a result of the work they exert to learn concepts ranging from basic to complicated issues and health concerns for maintaining overall human health. Hence, assessing the quality of life (QOL) of nursing students is important to determine if they have excellent well-being levels as they go through the learning process. OBJECTIVES: This study measured and compared QOL of respondents by country of residence, and identified the QOL predictors of students. DESIGN: Descriptive, cross-sectional design. SETTINGS: A multi-country study conducted in Chile, Egypt, Greece, Hong Kong, India, Kenya, Oman, Saudi Arabia, and the United States of America. PARTICIPANTS: A convenience sample of 2012 Bachelor of Science in Nursing (BSN) students. METHODS: A self administered questionnaire containing demographic characteristic items and the World Health Organization QOL-BREF (WHOQOL-BREF) was used to gather data from respondents. RESULTS: The highest overall QOL was recorded in the physical health domain, whereas the lowest was in the social health domain. The perceived highest and lowest QOL dimension varied between countries. Age, country of residence, and monthly family income showed statistically significant multivariate effect on the aspects of QOL. CONCLUSIONS: Considering their stressful lives, the present study underscores the importance of ensuring the highest level of well-being among nursing students. The maintenance of high levels of well-being among nursing students should also be prioritized to maximize their learning and ensure their satisfaction in their student life. PMID- 29704701 TI - Incivility in nursing education: An intervention. AB - Incivility in nursing education is an unfortunate phenomenon affecting nursing students in all aspects of their educational experience. Students and their instructors are often ill equipped to deal with academic incivility and their lack of ability to handle such behaviors has proven detrimental to the future of the nursing profession. Nursing instructors need tools to help educate nursing students on how to recognize uncivil behaviors within themselves as well as others and ways to combat it. This research project addressed these aspects of academic incivility and implemented an e-learning module that was developed to educate students on incivility. The data was collected through a pre-test, post test model with resulting statistical analysis using the McNemar's test. Results showed the nursing students obtained increased self-efficacy in regards to their ability to define, detect, and combat academic incivility after viewing the e learning module. In conclusion, the successful implementation of the e-learning module provides further incentive for schools of nursing to consider implementing incivility education in their curriculums. PMID- 29704702 TI - Simulation with standardized patients to prepare undergraduate nursing students for mental health clinical practice: An integrative literature review. AB - OBJECTIVE: To evaluate the available evidence supporting the efficacy of using simulation with standardized patients to prepare nursing students for mental health clinical practice. DESIGN: Integrative literature review. DATA SOURCES: A systematic search of the electronic databases CINAHL (EBSCOhost), Embase, MEDLINE, PsycINFO, and SveMed+ was conducted to identify empirical studies published until November 2016. Multiple search terms were used. Original empirical studies published in English and exploring undergraduate nursing students' experiences of simulation with standardized patients as preparation for mental health nursing practice were included. A search of reference lists and gray literature was also conducted. In total, 1677 studies were retrieved; the full texts of 78 were screened by 2 of the authors, and 6 studies reminded in the review. REVIEW METHODS: The authors independently reviewed the studies in three stages by screening the titles, abstracts, and full texts, and the quality of the included studies was assessed in the final stage. Design-specific checklists were used for quality appraisal. The thematic synthesizing method was used to summarize the findings of the included studies. RESULTS: The studies used four different research designs, both qualitative and quantitative. All studies scored fairly low in the quality appraisal. The five themes identified were enhanced confidence, clinical skills, anxiety regarding the unknown, demystification, and self-awareness. CONCLUSIONS: The findings of this study indicate that simulation with standardized patients could decrease students' anxiety level, shatter pre assumptions, and increase self-confidence and self-awareness before entering clinical practice in mental health. More high-quality studies with larger sample sizes are required because of the limited evidence provided by the six studies in the present review. PMID- 29704703 TI - Quality assurance of the clinical learning environment in Austria: Construct validity of the Clinical Learning Environment, Supervision and Nurse Teacher Scale (CLES+T scale). AB - BACKGROUND: Within nursing education, the clinical learning environment is of a high importance in regards to the development of competencies and abilities. The organization, atmosphere, and supervision in the clinical learning environment are only a few factors that influence this development. In Austria there is currently no valid instrument available for the evaluation of influencing factors. OBJECTIVES: The aim of the study was to test the construct validity with principal component analysis as well as the internal consistency of the German Clinical Learning Environment, Supervision and Teacher Scale (CLES+T scale) in Austria. METHOD: The present validation study has a descriptive-quantitative cross-sectional design. The sample consisted of 385 nursing students from thirteen training institutions in Austria. The data collection was carried out online between March and April 2016. Starting with a polychoric correlation matrix, a parallel analysis with principal component extraction and promax rotation was carried out due to the ordinal data. RESULTS: The exploratory ordinal factor analysis supported a four-component solution and explained 73% of the total variance. The internal consistency of all 25 items reached a Cronbach's alpha of 0.95 and the four components ranged between 0.83 and 0.95. CONCLUSION: The German version of the CLES+T scale seems to be a useful instrument for identifying potential areas of improvement in clinical practice in order to derive specific quality measures for the practical learning environment. PMID- 29704704 TI - Effect of each component of a LINAC therapy head on neutron and photon spectra. AB - Linear accelerators (LINACs) are widely applied in radiotherapy for their versatility and flexibility. Monte Carlo simulations were made to find the neutron and photon spectra at the isocenter (IC) of a LINAC operating at 10, 15, 18, and 24 MV by the MCNPX code. A detailed model of the LINAC head, consisting of flattening filter, secondary collimator, primary collimator, and multi-leaf collimator were used in the calculations. The effect of eliminating any of these components on contamination of a neutron spectrum and a photon spectrum was assessed. Photon and neutron ambient equivalent doses were found, and comparisons were made for the various structures. Lethargy neutron spectra at the IC were compared with spectra computed with the function reported by Tosi et al., which describes well neutron spectra for the energy region beyond 1 MeV, although tending to undervalue energy spectra below 1 MeV. The findings show that the photon and neutron fluences are enhanced when eliminating a LINAC component. The neutron and photon doses increased except when removing the primary collimator. PMID- 29704705 TI - Neutron production in the interaction of 12 and 18 MeV electrons with a scattering foil inside a simple LINAC head. AB - The characteristics of photons and neutrons produced during the interaction between a monoenergetic (12 and 18 MeV) electron beam and a tungsten scattering foil enclosed into a 10 cm-thick tungsten shell have been determined using Monte Carlo methods. This model was used aiming to represent a linac head working in electron-mode for cancer treatment. Photon and neutron spectra were determined around the scattering foil and to 50 and 100 cm below the electron source. Induced photons are mainly produced along the direction of the incoming electron beam. On the other hand, neutrons are produced in two sites, mainly in the inner surface of the linac head and in less extent in the scattering foil. The neutron spectra are evaporation neutrons which are emitted isotropically from the site where are produced leaking out from the linac head, reaching locations were the patient is allocated. PMID- 29704706 TI - A Monte Carlo study on the performance evaluation of a parallel hole collimator for a HiReSPECT: A dedicated small-animal SPECT. AB - Collimator geometry has an important contribution on the image quality in SPECT imaging. The purpose of this study was to investigate the effect of parallel hole collimator hole-size on the functional parameters (including the spatial resolution and sensitivity) and the image quality of a HiReSPECT imaging system using SIMIND Monte Carlo program. To find a proper trade-off between the sensitivity and spatial resolution, the collimator with hole diameter ranges of 0.3-1.5 mm (in steps of 0.3 mm) were used with a fixed septal and hole thickness values (0.2 mm and 34 mm, respectively). Lead, Gold, and Tungsten as the LEHR collimator material were also investigated. The results on a 99mTc point source scanning with the experimental and also simulated systems were matched to validate the simulated imaging system. The results on the simulation showed that decreasing the collimator hole size, especially in the Gold collimator, improved the spatial resolution to 18% and 3.2% compared to the Lead and the Tungsten, respectively. Meanwhile, the Lead collimator provided a good sensitivity in about of 7% and 8% better than that of Tungsten and Gold, respectively. Overall, the spatial resolution and sensitivity showed small differences among the three types of collimator materials assayed within the defined energy. By increasing the hole size, the Gold collimator produced lower scatter and penetration fractions than Tungsten and Lead collimator. The minimum detectable size of hot rods in micro Jaszczak phantom on the iterative maximum-likelihood expectation maximization (MLEM) reconstructed images, were determined in the sectors of 1.6, 1.8, 2.0, 2.4 and 2.6 mm for scanning with the collimators in hole sizes of 0.3, 0.6, 0.9, 1.2 and 1.5 mm at a 5 cm distance from the phantom. The Gold collimator with hole size of 0.3 mm provided a better image quality with the HiReSPECT imaging. PMID- 29704707 TI - Unravelling the reactivity of bifenazate in water and on vegetables: Kinetics and byproducts. AB - In this study, we aimed to better understand the transformation mechanisms of bifenazate, a biphenyl hydrazine derivative insecticide poorly studied up to now. For this, we compared its reactivity in the dark and under simulated solar light irradiation in different media (water, non-aqueous polar solvent, surface of apolar wax films, skin of vegetable). In air-saturated pH = 5.7 water, bifenazate underwent both autoxidation in the dark (t1/2 = 34 h) and photolysis (t1/2 = 17 h). In an aprotic polar solvent such as acetonitrile, bifenazate was stable in the dark but was quickly photodegraded in the presence of oxygen (t1/2 = 2 h). The phototransformation of bifenazate was due to the oxidation of excited states by oxygen and to the cleavage of the NN bond, while the autoxidation in water started by the initial oxidation of the molecule by oxygen and involved the superoxide anion as chain carrier. On paraffinic wax film, photodegradation (t1/2 = 365 h) and dark autoxidation (t1/2 = 1600 h) were very slow. On green pepper skin, bifenazate disappeared both in the dark (t1/2 = 34 h) and through photolysis (t1/2 = 23 h) at rates close to those measured in water. This shows that on green pepper skin, bifenazate is affected by water contained in the vegetable and possibly released by transpiration. Bifenazate diazene was the major degradation product in all studied conditions. Minor byproducts were detected too. They depended on the experimental conditions showing that degradation pathways are governed by the nature and properties of the medium. In particular, on green pepper one found byproducts generated in acetonitrile and on wax by photolysis and in water by autoxidation. This finding highlights the need for a better model than wax to mimic photolysis on plant surfaces. PMID- 29704708 TI - Are stormwater pollution impacts significant in life cycle assessment? A new methodology for quantifying embedded urban stormwater impacts. AB - Current life cycle assessment (LCA) models do not explicitly incorporate the impacts from urban stormwater pollution. To address this issue, a framework to estimate the impacts from urban stormwater pollution over the lifetime of a system has been developed, laying the groundwork for subsequent improvements in life cycle databases and LCA modelling. The proposed framework incorporates urban stormwater event mean concentration (EMC) data into existing LCA impact categories to account for the environmental impacts associated with urban land occupation across the whole life cycle of a system. It consists of five steps: (1) compilation of inventory of urban stormwater pollutants; (2) collection of precipitation data; (3) classification and characterisation within existing midpoint impact categories; (4) collation of inventory data for impermeable urban land occupation; and (5) impact assessment. The framework is generic and can be applied to any system using any LCA impact method. Its application is demonstrated by two illustrative case studies: electricity generation and production of construction materials. The results show that pollutants in urban stormwater have an influence on human toxicity, freshwater and marine ecotoxicity, marine eutrophication, freshwater eutrophication and terrestrial ecotoxicity. Among these, urban stormwater pollution has the highest relative contribution to the eutrophication potentials. The results also suggest that stormwater pollution from urban areas can have a substantial effect on the life cycle impacts of some systems (construction materials), while for some systems the effect is small (e.g. electricity generation). However, it is not possible to determine a priori which systems are affected so that the impacts from stormwater pollution should be considered routinely in future LCA studies. The paper also proposes ways to incorporate stormwater pollution burdens into the life cycle databases. PMID- 29704709 TI - Deposition of sulfur and nitrogen components in Louisiana in August, 2011. AB - Dry and wet deposition of sulfur and nitrogen contained air pollutants lead to increase of sulfur and nitrogen to the surface, causing acidification of surface water bodies and subsequent damage to aquatic and terrestrial ecosystems. Louisiana has abundant water resources and it is important to protect water resources from excessive atmospheric deposition of sulfur and nitrogen. However, the information for understanding sulfur and nitrogen deposition and adverse effects in Louisiana is limited. In this study, a source-oriented version of the Community Multi-scale Air Quality (CMAQ) model was used to simulate emission, formation, transport, and deposition of sulfur and nitrogen species in Louisiana in August 2011 to understand the forms and quantities of sulfur and nitrogen deposition due to wet and dry processes in Louisiana, to show the spatial and temporal variations of deposition fluxes, and to quantify the contributions of different sources to sulfur and nitrogen deposition. Aerosol phase sulfate (AeroSO4) has the highest monthly total flux of 6 kg S/ha in wet deposition of sulfur. Major forms of sulfur dry depositions are AeroSO4 (~1 kg S/ha) and SO2 (~3 kg S/ha). Nitrogen deposition is mainly in forms of NO2, HNO3, NH3, and aerosol phase nitrate (AeroNO3). Electric generating utilities (EGU) are the largest contributor to sulfur depositions with monthly total flux of 1.6 kg S/ha, followed by industry (1 kg S/ha) and upwind sources. On-road vehicles and industry are important to nitrogen (except ammonia) depositions with maximum contributions of 0.6 kg N/ha and 0.8 kg N/ha, respectively. The dominate source of ammonia is "Other" implicit sector including agricultural activities. PMID- 29704710 TI - Predicting trace metal bioavailability to chironomids in sediments by diffusive gradients in thin films. AB - The technique of diffusive gradients in thin films (DGT) has been developed as a promising tool to assess metal bioavailability in sediment. However, it has yet to be determined whether the DGT-labile metal in sediment is representative of bioavailable fraction for benthic organisms. In this study, the performance of DGT for predicting metal bioavailability was evaluated by exposing DGT and chironomids Chironomus tentans to a series of metal-contaminated natural sediments in the laboratory. Conventional methods, including acid-volatile sulfides and simultaneously extracted metals method, and total recoverable and dilute-acid extractable metal concentrations were also used to assess the availability of Zn, Cu and Pb to chironomids. The bioassay results showed that >70% of the larvae (73 +/- 1.7%-98 +/- 0.5%) survived in all sediment samples, however, an enhanced uptake of Zn, Cu and Pb by C. tentans in contaminated sediments was observed compared to control sediments. The correlation analyses indicated that the total recoverable metal concentrations and DGT-metal fluxes in the surficial sediment (-1 cm) were all significantly associated with metal bioaccumulation in C. tentans (p < 0.01). Given the advantages of DGT devices for in situ and time-averaged measurement of the potentially bioavailable fraction, DGT-metal fluxes were proved to be a better surrogate to predict C. tentans response to metal contamination. The results further supported the applicability of the DGT technique as an alternative method to assess the bioavailability of metals in sediment to benthic invertebrates. PMID- 29704711 TI - The effects of short term, long term and reapplication of biochar on soil bacteria. AB - Biochar has been shown to affect soil microbial diversity and abundance. Soil microbes play a key role in soil nutrient cycling, but there is still a dearth of knowledge on the responses of soil microbes to biochar amendments, particularly for longer-term or repeated applications. We sampled soil from a field trial to determine the individual and combined effects of newly applied (1 year ago), re applied (1 year ago into aged biochar) and aged (9 years ago) biochar amendments on soil bacterial communities, with the aim of identifying the potential underlying mechanisms or consequences of these effects. Soil bacterial diversity and community composition were analysed by sequencing of 16S rRNA using a Miseq platform. This investigation showed that biochar in soil after 1 year significantly increased bacterial diversity and the relative abundance of nitrifiers and bacteria consuming pyrogenic carbon (C). We also found that the reapplication of biochar had no significant effects on soil bacterial communities. Mantel correlation between bacterial diversity and soil chemical properties for four treatments showed that the changes in soil microbial community composition were well explained by soil pH, electrical conductivity (EC), extractable organic C and total extractable nitrogen (N). These results suggested that the effects of biochar amendment on soil bacterial communities were highly time-dependent. Our study highlighted the acclimation of soil bacteria on receiving repeated biochar amendment, leading to similar bacterial diversity and community structure among 9-years old applied biochar, repeated biochar treatments and control. PMID- 29704712 TI - A gradual change between methanogenesis and sulfidogenesis during a long-term UASB treatment of sulfate-rich chemical wastewater. AB - The competition between methane-producing archaea and sulfate-reducing bacteria is an important topic in anaerobic wastewater treatment. In this study, an Up flow Anaerobic Sludge Blanket Reactor (UASB) was operated for 330 days to evaluate the treatment performance of sulfate-rich wastewater. The effects of competition change between methane production and sulfate reduction on the organic removal efficiency, methane production, and electrons allocation were investigated. Synthetic wastewater was composed of ethanol and acetate with a chemical oxygen demand (COD)/SO42- of 1.0. As a result, the COD removal efficiency achieved in long-term treatment was higher than 90%. During the initial stage, methane production was the dominant reaction. Sulfate-reducing bacteria (SRB) could only partially oxidize ethanol to acetate, and methane producing archaea (MPA) utilized acetate for methane production. Methane production declined gradually over the long-term operation, whereas the sulfate reducing efficiency increased. However, UASB performed well throughout the experiment because there was no significant inhibition. After the complete reduction of the sulfate, MPA converted the remaining COD into methane. PMID- 29704713 TI - The relative contribution of peat compaction and oxidation to subsidence in built up areas in the Rhine-Meuse delta, The Netherlands. AB - An increasing number of people lives in coastal zones with a subsurface consisting of heterogenic soft-soil sequences. Many of these sequences contain substantial amounts of peat. While population growth and urbanization continues in coastal zones, they are threatened by global sea-level rise and land subsidence. Peat compaction and oxidation, caused by loading and drainage, are important contributors to land subsidence, and hence relative sea-level rise, in peat-rich coastal zones. Especially built-up areas, having densely-spaced urban assets, are heavily impacted by land subsidence, in terms of livelihoods and damage-related costs. Yet, built-up areas have been largely avoided in peat compaction and oxidation field studies. Consequently, essential information on the relative contributions of both processes to total subsidence and underlying mechanisms, which is required for developing effective land use planning strategies, is lacking. Therefore, we quantified subsidence due to peat compaction and oxidation in built-up areas in the Rhine-Meuse delta, The Netherlands, using lithological borehole data and measurements of dry bulk density, organic matter, and CO2 respiration. We reconstructed subsidence over the last 1000 years of up to ~4 m, and recent subsidence rates of up to ~140 mm.yr-1 averaged over an 11-year time span. The amount and rate of subsidence due to peat compaction and oxidation is variable in time and space, depending on the Holocene sequence composition, overburden thickness, loading time, organic-matter content, and groundwater-table depth. In our study area, the potential for future subsidence due to peat compaction and oxidation is substantial, especially where the peat layer occurs at shallow depth and is relatively uncompacted. We expect this is the case for many peat-rich coastal zones worldwide. We propose to use subsurface-based spatial planning, using specific subsurface information mentioned above, to inform land use planners about the most optimal building sites in organo-clastic coastal zones. PMID- 29704714 TI - Strengthening insurance partnerships in the face of climate change - Insights from an agent-based model of flood insurance in the UK. AB - Multisectoral partnerships are increasingly cited as a mechanism to deliver and improve disaster risk management. Yet, partnerships are not a panacea and more research is required to understand the role that they can play in disaster risk management and particularly disaster risk reduction. This paper investigates how partnerships can incentivise flood risk reduction by focusing on the UK public private partnership on flood insurance. Developing the right flood insurance arrangements to incentivise flood risk reduction and adaptation to climate change is a key challenge. In the face of rising flood risks due to climate change and socio-economic development insurance partnerships can no longer afford to focus only on the risk transfer function. However, while expectations of the insurance industry have traditionally been high when it comes to flood risk management, the insurance industry alone will not provide the solution to the challenge of rising risks. The case of flood insurance in the UK illustrates this: even national government and industry together cannot fully address these risks and other actors need to be involved to create strong incentives for risk reduction. Using an agent-based model focused on surface water flood risk in London we analyse how other partners could strengthen the insurance partnership by reducing flood risk and thus helping to maintain affordable insurance premiums. Our findings are relevant for wider discussions on the potential of insurance schemes to incentivise flood risk management and climate adaptation in the UK and also internationally. PMID- 29704715 TI - Acute effects of ambient particulate matter pollution on hospital admissions for mental and behavioral disorders: A time-series study in Shijiazhuang, China. AB - Until now, few epidemiological studies have focused on the association between ambient particulate matter pollution and mental and behavioral disorders, especially in developing countries. Thus, a time-series study on the short-term association between both fine and inhalable particles (PM2.5 and PM10) and daily hospital admissions for mental and behavioral disorders in Shijiazhuang, China was conducted, from 2014 to 2016. An over-dispersed, generalized additive model was used to analyze the associations after controlling for time trend, weather conditions, day of the week, and holidays. In addition, the modification effects of age, sex, and season were estimated. A total of 9156 cases of hospital admissions for mental and behavioral disorders were identified. A 10 MUg/m3 increase in a 3-day average concentration (lag02) of PM2.5 and PM10 correspond to an increase of 0.48% (95% confidence interval (CI): 0.18-0.79%) and 0.32% (95% CI: 0.03-0.62%) in daily hospital admission for mental and behavioral disorders, respectively. We found stronger associations of PM2.5 and PM10 with mental and behavioral disorders in male and elder individuals (>=45 years) than in female and younger individuals (<45 years). Further, results indicated a generally stronger association of PM2.5 with mental and behavioral disorders in the cool season than in the warm season. This research found a significant association between ambient PM2.5 and PM10 and hospital admission for mental and behavioral disorders in Shijiazhuang, China. PMID- 29704716 TI - Dissipation of polyoxyethylene tallow amine (POEA) and glyphosate in an agricultural field and their co-occurrence on streambed sediments. AB - The environmental fate of polyoxyethylene tallow amine (POEA), an additive in glyphosate herbicide formulations, has not been studied. This study examined the dissipation of POEA; glyphosate; and aminomethylphosphonic acid (AMPA), a degradation product of glyphosate, in the top 45 cm of soil from an agricultural field where glyphosate was applied. The concentration of these compounds was also analyzed in bed sediment samples from watersheds in agricultural and urban areas from six states (Georgia, Hawaii, Iowa, Mississippi, North Carolina, South Carolina). The field studies show that POEA, glyphosate, and AMPA persist on the soil from planting season to planting season but dissipate over time with little migration into deeper soil. POEA, glyphosate, and AMPA were found on the bed sediment samples in urban and agricultural watersheds. PMID- 29704717 TI - Mussel digestive gland as a model tissue for assessing xenobiotics: An overview. AB - Control strategies and routine biomonitoring programs are commonly performed worldwide using sentinel marine invertebrates, such as mussels of the genus Mytilus, for assessing the "health status" of the aquatic environment. Those species can accumulate and tolerate xenobiotics at levels higher than those being present into the aquatic environment, thus providing accurate and reliable biological endpoints (e.g. physiological, behavioral, cellular, biochemical and molecular indices) that can be measured in their tissues. Taking under consideration the significance of bivalves for assessing the environmental hazard of xenobiotics being present into the water medium, as well as the key role of digestive gland as a target-tissue for the compounds ingested in the organism, the present study aimed to summarize available data on the effects of different categories of xenobiotic compounds, previously characterized as a potential threat for the marine ecosystems. In this context, different types of pharmaceuticals and personal care products (PPCPs), biocides, microplastics (MPs) and nanoparticles (NPs), currently investigated in mussels' digestive gland, using a battery of experimental approaches and analytical methods, as well as stress indices evaluation, are briefly described and further discussed in order to elucidate not only the presence and the toxic mode of action of xenobiotics, but also the important role of the digestive gland as a reliable target-tissue for investigating the effects of xenobiotics at cellular, biochemical, and molecular levels. PMID- 29704718 TI - Pharmaceutical manufacturing facility discharges can substantially increase the pharmaceutical load to U.S. wastewaters. AB - Discharges from pharmaceutical manufacturing facilities (PMFs) previously have been identified as important sources of pharmaceuticals to the environment. Yet few studies are available to establish the influence of PMFs on the pharmaceutical source contribution to wastewater treatment plants (WWTPs) and waterways at the national scale. Consequently, a national network of 13 WWTPs receiving PMF discharges, six WWTPs with no PMF input, and one WWTP that transitioned through a PMF closure were selected from across the United States to assess the influence of PMF inputs on pharmaceutical loading to WWTPs. Effluent samples were analyzed for 120 pharmaceuticals and pharmaceutical degradates. Of these, 33 pharmaceuticals had concentrations substantially higher in PMF influenced effluent (maximum 555,000 ng/L) compared to effluent from control sites (maximum 175 ng/L). Concentrations in WWTP receiving PMF input are variable, as discharges from PMFs are episodic, indicating that production activities can vary substantially over relatively short (several months) periods and have the potential to rapidly transition to other pharmaceutical products. Results show that PMFs are an important, national-scale source of pharmaceuticals to the environment. PMID- 29704719 TI - A study of cadmium remediation and mechanisms: Improvements in the stability of walnut shell-derived biochar. AB - Biochar has been recognized as an efficient soil amendment for cadmium remediation in recent years. In the present study, biochar was prepared using walnut shell, and it was incubated in Cd(NO3)2 and kaolin for 15 days. Different chemical forms of cadmium in kaolin and biochar were determined, and the stability of biochar was evaluated by R50 using TGA analysis. It was found that walnut shell derived biochar could reduce the mobility of cadmium. After incubation, the R50, biochar value increased from 61.31% to 69.57%-72.24%, indicating that the stability of biochar was improved. The mechanisms that initiated improvements in biochar stability were investigated by XPS, XRD and SEM EDS analysis. The result showed that the enhanced biochar stability is likely due to physical isolation and the formation of precipitates and complexes, formed on the surface or interior of the biochar. The results suggested that walnut shell derived biochar can be used as a cadmium sorbent for soil remediation. PMID- 29704720 TI - Hydrogeochemical behavior of an anthropogenic mine aquifer: Implications for potential remediation measures. AB - This study characterizes the hydrogeochemical behavior of one of the most pollutant sources in the Iberian Pyrite Belt, namely, the Poderosa adit outflow. This artificial spring arises from an anthropogenic mine aquifer with a similar hydrogeological behavior to karstic systems, where the infiltration area is an endorheic zone and the aquifer shows allogenic recharge. Recent mining has markedly increased the contaminant levels. The pollutant load released from the adit to the receiving water body is very high, with average loads of 280 kg/day of Fe, 47 kg/day of Al, 17 kg/day of Cu and so on. However, a high variability is observed related to hydrological and geochemical factors, especially during intense rainy episodes. Thus, the pollutant load during these events suffers a dramatic increase, i.e., from ~100-200 kg/day of Fe during base flow to almost 2200 kg/day during the flow peak. These data highlight the importance of short but intense rainy events on metal fluxes from mining areas, which has been previously reported in surface waters but scarcely reported in mine adits, with expected lower response times to rainfall. The pollutant load released by non point sources, i.e., spoil heaps, is lower than that released from the adit most of the year, although it increased noticeably during intense rainy events. Some remediation measures were adopted during the 1990s without a suitable hydrogeological characterization and were shown to be ineffective. On the basis of the obtained results, potential restoration measures are discussed. PMID- 29704721 TI - Hydraulic reliability of a horizontal wetland for wastewater treatment in Sicily. AB - The purpose of this study was to evaluate how the hydraulic behavior of a horizontal subsurface wetland (HF), that is part of the hybrid wetland (hybrid TW) of the IKEA(r) store in Eastern Sicily (Italy), influences the overall wastewater treatment performance. The HF unit experiences frequent overloading peaks due to the extreme variability in the number of visitors at the store, and after 2 years of operation it showed signals of partial clogging at the inlet area. The hydraulics of the HF unit has been monitored through measurements of hydraulic conductivity at saturation (Ks), tracer tests, and geophysical (i.e. electrical resistivity tomography-ERT) measurements carried out during the years 2016 and 2017. Results indicated a general good agreement between the performed measurement techniques, thus their combination, if adequately performed and calibrated, might be a reliable tool for detecting those wetland areas mainly affected by clogging conditions. The results also indicated that partial clogging had no significant effect on the quality of the discharged water. PMID- 29704722 TI - Substituted 1,5-naphthyridine derivatives as novel antileishmanial agents. Synthesis and biological evaluation. AB - Visceral leishmaniasis is a parasitic disease that affects, among other areas, both sides of the Mediterranean Basin. The drugs classically used in clinical practice are pentavalent antimonials (SbV) and amphotericin B, which are nephrotoxic, require parenteral administration, and increasing drug resistance in visceral leishmaniasis has been observed. These circumstances justify the search of new families of compounds to find effective drugs against the disease. Eukaryotic type I DNA topoisomerase (TopIB) has been found essential for the viability of the parasites, and therefore represents a promising target in the development of an antileishmanial therapy. In this search, heterocyclic compounds, such as 1,5-naphthyridines, have been prepared by cycloaddition reaction between N-(3-pyridyl)aldimines and acetylenes and their antileishmanial activity on promastigotes and amastigote-infected splenocytes of Leishmania infantum has been evaluated. In addition, the cytotoxic effects of newly synthesized compounds were assessed on host murine splenocytes in order to calculate the corresponding selective indexes (SI). Excellent antileishmanial activity of 1,5-naphthyridine 19, 21, 22, 24 and 27 has been observed with similar activity than the standard drug amphotericin B and higher selective index (SI > 100) towards L. infantum amastigotes than amphotericin B (SI > 62.5). Special interest shows the 1,5-naphthyridine 22 with an IC50 value (0.58 +/- 0.03 MUM) similar to the standard drug amphotericin B (0.32 +/- 0.05 MUM) and with the highest selective index (SI = 271.5). In addition, this compound shows remarkable inhibition on leishmanial TopIB. However, despite these interesting results, further studies are needed to disclose other potential targets involved in the antileishmanial effect of these novel compounds. PMID- 29704723 TI - Identification of novel beta-lactams and pyrrolidinone derivatives as selective Histamine-3 receptor (H3R) modulators as possible anti-obesity agents. AB - Four series of structurally related beta-lactams, 2,5-pyrrolidinediones, azaspirodecatrienediones (ASDT) and dihydropyrroloquinoxalinetriones (DPQT) were synthesized by utilizing post-Ugi modifications in one-pot, and their activity towards human histamine-3 receptor (H3R) was evaluated. Out of 94 compounds, screened against histamine-3 receptor (H3R), 21 compounds showed high H3R selective agonist property with EC50 values ranging from 187 nM to 0.1 nM, whereas none of the compound was found to have the affinity towards other receptors of histamine family such as histamine H1, H2, and H4 receptor. All active compounds have no assay interference activity as determined by in-silico analysis and receptor independent luciferase assay and cell cytotoxicity assay. Given the important role of H3R in hypophagia, we also evaluated the in vivo effect of the representative compound 6k on the cumulative food intake in diet induce obese C57BL6/J mice. Interestingly, we observed that single dose administration (20 mg/kg, intraperitoneal injection) of 6k significantly suppressed cumulative food intake, while no significant effect was observed at 10 mg/kg. These results suggest that beta-lactams, 2,5-pyrrolidinediones, azaspirodecatrienediones (ASDT) and dihydropyrroloquinoxalinetriones (DPQT) could be useful for the development of anti-obesity candidate drugs. PMID- 29704724 TI - Both-sided native valve infective endocarditis in a drug addict with incidental pneumoconiosis. AB - Involvement of both right and left heart chambers with infective endocarditis is extremely rare. In this case report, we aimed to present a rare case of Infective endocarditis (IE) in an intravenous & inhalational drug misuse involving both cardiac chambers with incidental pneumoconiosis. PMID- 29704725 TI - External foam and the post-mortem period: Only the positive finding counts. PMID- 29704726 TI - Drug Policy in Romania. AB - OBJECTIVES: The objectives of this article were to describe the characteristics of the drug policy in Romania in the last 10 years and to present the consequences in terms of patient accessibility to drugs. METHODS: The Romanian health care system with pricing and reimbursement legislation was studied while considering the evolution of pricing and reimbursement processes, the key stakeholders, and the reasons behind changes. A critical appraisal was done covering published materials on the effects of pricing and reimbursement decisions. RESULTS: Romania uses an external reference pricing model considering the lowest price from 12 European Union countries. The result is the visible list price, which is used by the payer as the basis for the reimbursement prices. The reimbursed price depends on the type of drug and the therapeutic area. The claw back taxation reduces the reimbursement prices by another 12% to 75%, depending on the type of reimbursement for each drug: unconditional (more than 4000 drugs) or conditional (19 drugs) reimbursement. As a consequence, the Romanian prices are one of the cheapest in the European Union, some drugs are leaving the country subject to intracommunity trade and more than 2000 drugs have disappeared from the market in the last 5 years. CONCLUSIONS: The drug policy in Romania is centered on price reduction using different techniques and no value-based criteria are used. The pricing is not included in the health technology assessment system, managed entry agreements are not used, and the main effect visible at the patient level is the lack of drugs for some therapeutic areas. PMID- 29704727 TI - How do skeletons with HIV present? A study on the identified CAL Milano Cemetery Skeletal Collection. AB - With the Human Immunodeficiency Virus (HIV) infection and Acquired Immune Deficiency Syndrome (AIDS) pandemic, the study of HIV/AIDS on bones has become of pivotal interest for research in bone pathologies, forensic applications (especially in the matter of identification when confronted to antemortem data) and medical purposes. In this paper, we document and discuss the macroscopic lesions found on the skeletons of nine individuals with known HIV, including four with known AIDS, coming from the identified CAL Milano Cemetery Skeletal Collection. As a result, several types of lesions were observed on bones: periosteal new bone formation, dental lesions, thickening of the frontal diploe, destructive localized porosity and evidence of trauma. None of the lesions reported can be directly linked to HIV because the virus does not directly affect bones in a macroscopic way. However, HIV/AIDS-induced infections and inflammations and HIV-related risk factors may leave bone markers. The differential diagnosis of each of the lesions noted in this research and its potential link to HIV or AIDS was discussed. Although it is not possible to diagnose HIV on bare bones, this was not the focus of this study. To our knowledge, no anthropological study has ever been performed on known HIV individuals. With this paper, we present for the first time skeletons with known HIV. PMID- 29704728 TI - Atomic force microscope scanning head with 3-dimensional orthogonal scanning to eliminate the curved coupling. AB - An atomic force microscopy (AFM) scanning head is designed with the probe orthogonal scanning mode for metrological AFM to eliminate the curvature distortion. The AFM probe is driven by piezostage and the scanning trajectory of the probe in 3 directions are orthogonal to reduce the cross coupling. A new optical lever amplification optical path is developed to eliminate the coupling error. The tracing lens and probe tip are moved as an integrated part. The AFM is operated at contacting mode. The step approach process of the probe tip is tested to the sample surface and the noise of the AFM head is analyzed. The response of the probe demonstrates a 0.5 nm resolution of the probe head in the z direction. Finally, the planar scanning performance of the scanning head is demonstrated compared with tube scanning AFM. PMID- 29704729 TI - An analytical formula for predicting R-branch high-lying transition lines of BiLi molecule. AB - A concise and convenient analytical formula without any spectral constant is derived from the conventional expression of R-branch transitional energies for calculating the R-branch high-lying rovibrational emission spectral lines of diatomic molecule. This is based on the thought of Sun's difference converging method (DCM) in 2011. This formula can correctly predict the high-lying transitional emission spectral lines only using 11 known experimental transition lines and a set of physical criteria when any spectral constants of the system are not available. Furthermore, a new method for analyzing the accuracy of prediction with the improved formula is proposed, which point out the core problem of the predicted spectrum and give a quantitative conclusion on the reliability of our work. In this work, the new method is applied to study the R branch transitional emission spectra of the (0-0) band of the A20+ -> X10+ and A20+ -> X21 transition systems of BiLi molecule. A series of experimental and theoretical comparisons and discussions show that under the condition of lack of any spectral constants, our method can still use 11 known experimental transition spectral data to reproduce the R-branch emission spectral lines reliably including the high excited rovibrational transition spectral lines. PMID- 29704730 TI - Calix[4]arene containing thiourea and coumarin functionality as highly selective fluorescent and colorimetric chemosensor for fluoride ion. AB - A novel calix[4]arene based chemosensor L which contains coumarin and thiourea group has been synthesized and characterized. Interestingly, probe L exhibits both fluorescent and colorimetric response to fluoride anion with high selectivity and sensitivity. The addition of F- to a solution of probe L resulted in obvious naked-eye color change from colorless to orange under daylight and prominent fluorescence quenching. Further studies showed that the recognition process was less affected by other anions. The binding property of L with F- was studied by a combination of combination of various spectroscopic techniques, such as absorption spectra, fluorescence titration, Job's plot and 1H NMR titration. We are anticipating that this architecture with functional group attached to upper rim of calix[4]arene platform may provide a new approach for the development of F- chemosensor. PMID- 29704731 TI - Fluorescence chemodosimeter for dopamine based on the inner filter effect of the in situ generation of silver nanoparticles and fluorescent dye. AB - A new strategy for the sensitive and selective detection of dopamine (DA) was proposed. The chemodosimeter design was based on the measurement of the fluorescent quenching of fluorescein dye caused by the in situ generation of silver nanoparticles (AgNPs). The AgNPs can be simply generated by a reaction between DA and Ag+ in the presence of polymethacrylic acid (PMAA). In addition, the generated AgNPs possess the maximum surface plasmon resonance (SPR) at 440 nm and an increase in the SPR intensity with an increasing DA concentration. Basically, fluorescein dye can emit the fluorescent intensity maximum at 513 nm with excitation at 487 nm. Thus, fluorescent quenching was achieved due to an inner filter effect from the overlap between the excitation spectrum of the fluorescein dye and the SPR spectrum of the generated AgNPs. The degree of fluorescent quenching linearly depends on the number of generated AgNPs that can be directly related to the concentration of DA. The proposed chemodosimeter can be used to detect DA in a working linear concentration range of 1.0-5.0 MUM at a detection limit of 10.6 nM. This chemodosimeter was successfully applied to determine DA in a real urine sample and a dopamine injection formulation with satisfactory results. PMID- 29704732 TI - Paeonol alleviated acute alcohol-induced liver injury via SIRT1/Nrf2/NF-kappaB signaling pathway. AB - In this study, the beneficial effect of paeonol on acute alcohol-induced liver injury and the basic mechanisms were investigated. in vitro, HepG2 cells were treated with paeonol for 24 h before it were exposed to alcohol for 24 h. in vivo, male C57BL/6 mice were used to establish alcohol-induced liver injury models by oral gavage of alcohol (5 g/kg BW). Paeonol pretreatment showed statistically significant reduction in alcohol-induced ROS, MDA, IL-1beta, IL-6, TNF-alpha, and nitric oxide, while GSH content was retained (P < 0.05). Furthermore, paeonol treatment resulted in the increase of Nrf2 nuclear translocation, the increase of NQO-1 and HO-1 expression, and the suppression of NF-kappaB p65 nuclear translocation. However, pretreatment with NAM (inhibitor of SIRT1) not only inhibited the effect of paeonol on reducing nuclear translocation of NF-kappaBp65, but also inhibited the effect of paeonol on promoting the expression of nuclear Nrf2, NQO1 and HO-1. Besides, paeonol pretreatment at test doses significantly ameliorated alcohol-induced edema, hepatocyte necrosis and hepatic cord irregular. These results demonstrated that paeonol has the high potential for relieving acute alcohol-induced liver injury. PMID- 29704733 TI - Evaluation of the national laboratory-based surveillance system for respiratory syncytial virus in Sweden, 2015-2016. AB - BACKGROUND: Most laboratories use RSV PCR but near-patient tests (NPT) performed at paediatric clinics are believed to be increasingly used. Anonymised data on RSV infections has been collected since 1990 in Sweden. No evaluation of Swedish RSV surveillance or use of laboratory testing had previously been performed. OBJECTIVES: Swedish RSV data and methods used for RSV laboratory testing and reporting were evaluated in order to improve RSV surveillance in a forthcoming vaccine era. STUDY DESIGN: RSV data obtained in Sweden 2015-2016 were reviewed. Data on methods used for the RSV laboratory detection and reporting were collected via on-line questionnaires submitted to laboratories (n = 26) and clinics (n = 4) known to perform virological testing. Swedish Quality Control Program reports from 2013 to 2015 on the performance of RSV testing were also evaluated. RESULTS: Over 60% of RSV infections were diagnosed in children under 5 years (1917/2925), but infections were also common in those 65 years and older (n = 607). Two laboratories limited RSV testing to children only. RSV NPT was utilised in eight clinics; four participated in RSV surveillance. RSV NPTs evaluated could only detect 50% of RSV positive samples. Reporting was complete and timely, but took too much time (18 min/week/laboratory). CONCLUSIONS: Although most common in children, RSV infections are also common in the elderly, and testing should not be limited to children only. The poor performance of RSV NPT and importance of confirming results should be communicated to all relevant laboratories and clinics. All clinics should be encouraged to participate in surveillance. Automated case-based reporting should be considered. PMID- 29704734 TI - Molecular epidemiology of human adenovirus infections in Denmark, 2011-2016. AB - BACKGROUND: Human adenoviruses (HAdVs) can cause respiratory tract infections, conjunctivitis, diarrhoea and outbreaks have been reported. However, little is known about the disease burden and the molecular epidemiology of HAdV. OBJECTIVES: To retrospectively perform a molecular characterization of HAdV positive samples received at Statens Serum Institut during the period 2011-2016 and to compare this with demographic information, geographic location, sample collection date and type and co-infection with other viral pathogens. STUDY DESIGN: 152 HAdV positive samples were genotyped by Sanger sequencing of a fragment of the hexon gene using published primers along with a newly developed primer set for enhanced genotyping of HAdV D. Phylogenetic analysis was used for genotyping and genotypes were compared with epidemiological information. In addition, HAdV burden and co-infection was evaluated for samples tested in laboratory analysis packages. RESULTS: Six out of seven HAdV species were identified and represented by 13 types. Young children (<5 years old) were more likely to be positive for HAdV and co-infections with other gastrointestinal or respiratory viruses were common. Possible outbreaks of ocular infections due to HAdV D could not be confirmed. CONCLUSION: A diverse set of HAdV species were circulating in Denmark in the study period and although possible transmission clusters were identified, this could not be verified with current genotyping methods Young children were commonly affected by HAdV infection and co-infections with other viral pathogens were frequent suggesting a possible underestimation of the real HAdV burden. PMID- 29704735 TI - Heterophilic interference in specimens yielding false-reactive results on the Abbott 4th generation ARCHITECT HIV Ag/Ab Combo assay. AB - BACKGROUND: False-reactivity in HIV-negative specimens has been detected in HIV fourth-generation antigen/antibody or 'combo' assays which are able to detect both anti-HIV-1/HIV-2 antibodies and HIV-1 antigen. OBJECTIVES: We sought to characterize these specimens and determine the effect of heterophilic interference. STUDY DESIGN: Specimens previously testing as false-reactive on the Abbott ARCHITECT HIV Ag/Ab combo assay and re-tested on a different (Siemens ADVIA Centaur HIV Ag/Ab) assay. A subset of these specimens were also pre-treated with heterophilic blocking agents and re-tested on the Abbott assay. RESULTS: Here we report that 95% (252/264) of clinical specimens that were repeatedly reactive on the Abbott ARCHITECT HIV Ag/Ab combo assay (S/Co range, 0.94-678) were negative when re-tested on a different fourth generation HIV combo assay (Siemens ADVIA Centaur HIV Ag/Ab). All 264 samples were subsequently confirmed to be HIV negative. On a small subset (57) of specimens with available volume, pre treatment with two different reagents (HBT; Heterophilic Blocking Tube, NABT; Non Specific Blocking Tube) designed to block heterophilic antibody interference either eliminated (HBT) or reduced (NABT) the false reactivity when re-tested on the ARCHITECT HIV Ag/Ab combo assay. CONCLUSIONS: Our results suggest that the Abbott ARCHITECT HIV Ag/Ab combo assay can be prone to heterophilic antibody interference. PMID- 29704736 TI - Viral bronchiolitis management in hospitals in the UK. AB - BACKGROUND: Viral bronchiolitis is the leading cause of hospitalisation in infants less than a year old. The United Kingdom (UK) National Institute for Health and Care Excellence (NICE) published a guideline for the management of viral bronchiolitis in June 2015. OBJECTIVES: This study aimed to prospectively survey the management of viral bronchiolitis in hospital Trusts in the UK to provide a baseline of practice prior to the publication of the 2015 NICE bronchiolitis guideline against which future practice can be assessed. STUDY DESIGN: An electronic, structured questionnaire was sent to hospital paediatricians in the UK prior to the publication of the NICE bronchiolitis guideline via the Royal College of Paediatrics and Child Health e-portfolio system to assess the quality of Trust's viral bronchiolitis management guidelines. RESULTS: Paediatricians from 111 (65% of all) UK Trusts completed an electronic questionnaire. 91% of Trusts had a bronchiolitis guideline. Overall only 18% of Trusts would be fully compliant with the NICE guideline. Between 43 100% of Trusts would be compliant with different sections of the guideline. There was variation in hospital admission criteria with respect to the need for supplemental oxygen (oxygen saturations <88% to <95%). 'Unnecessary' medications (especially bronchodilators, nebulised hypertonic saline and antibiotics) and investigations (chest x-ray and blood gas) were regularly advised. 72% of Trusts advised respiratory virus testing in all hospitalised infants and 64% created bronchiolitis bays to cohort infants. CONCLUSIONS: There was wide variation in the management of infants with bronchiolitis in Trusts. Most bronchiolitic infants are not managed optimally in hospitals. Future guidelines should include advice on virus testing and isolation/cohorting. PMID- 29704737 TI - Laparoscopic and percutaneous repair of a large midline incisional hernia extending to the bilateral subcostal region: A case report. AB - INTRODUCTION: Optimal surgery for a midline incisional hernia extending to the subcostal region remains unclear. We report successful hybrid laparoscopic and percutaneous repair for such a complex incisional hernia. PRESENTATION OF CASE: An 85-year-old woman developed a symptomatic incisional hernia after open cholecystectomy. Computed tomography revealed a 14 * 10 cm fascial defect. Four trocars were placed under general anesthesia. Percutaneous defect closure was performed using multiple non-absorbable monofilament threads, i.e., a "square stitch." Each thread was inserted into the abdominal cavity from the right side of the defect and pulled out to the left side. The right side of the thread was subcutaneously introduced anterior to the hernia sac. The threads were sequentially tied in a cranial to caudal direction. A multifilament polyester mesh with resorbable collagen barrier was selected and fixed using absorbable tacks with additional full-thickness sutures. The cranial-most limit of mesh fixation was at the level of the subcostal margin, and the remaining part was draped over the liver surface. The postoperative course was uneventful, with no seroma, mesh bulge, or hernia recurrence at 1, 3, 6, and 12 months of follow-up. DISCUSSION: The advantages of our technique are the minimal effect on the scar in the midline during defect closure, the minimal damage to the ribs and obtaining more overlap during mesh fixation. The disadvantage is the postoperative pain. CONCLUSION: Our proposed hybrid surgical approach may be considered as the treatment of choice for a large midline incisional hernia extending to the bilateral costal region. PMID- 29704738 TI - Case-report: Metastases in a low-stage middle-graded HCC in cleared HCV infection, non-cirrhotic liver: Surgical therapy. AB - INTRODUCTION: Hepatocellular carcinoma (HCC) is rare in non-cirrhotic liver. Achievement of sustained virological response (SVR) reduces even more the risk. PRESENTATION OF CASE: Liver resection for small HCC was performed in cleared HCV infection non-cirrhotic 62-year-old man. Methacronous oligometastatic recurrences in intolerant to Nexavar(r) side-effects patient, were treated by multiple innovative microinvasive approaches: bilateral laparoscopic adrenalectomy, thoracic wall resection, laparoscopic sacrum cryoablation combined with hadron therapy. DISCUSSION: Therapies allowed the patient to lead 6 years satisfying QoL with only a small residual presacral disease stable at 8 months. CONCLUSION: Microinvasive surgery may be a valid resource of therapy in indolent HCC limited distant recurrences. PMID- 29704739 TI - Silastic band erosion in the bypassed stomach after Fobi-Pouch operation for obesity: Case report. AB - INTRODUCTION: Worldwide, one of the most commonly performed bariatric surgeries is the laparoscopic Roux-en-Y gastric bypass (LRYGP). Access to the bypassed stomach in patients who have undergone this procedure, for evaluation and/or management in different clinical situations remains a challenge for the physician. In order to facilitate the entrance to the gastric remnant, a silastic marker is left in place during the Fobi-Pouch operation, a modified laparoscopic gastric bypass surgery technique. PRESENTATION OF CASE: We present the case of a 56-year old female who presented 10 years after a Fobi-pouch operation, complaining of severe upper gastrointestinal bleeding. An enteroscopy revealed several marginal ulcers and erosion of the silastic ring marker in the excluded stomach. A partial gastric sleeve resection including the silastic ring was performed without any complications, preventing further bleeding due to the eroded ring. DISCUSSION: Physicians must be familiarized with the different bariatric procedures in order to associate the patient's symptomatology and possible surgery-related complications. Gastric ulceration and bleeding related to the presence of a foreign body have been previously described; however, to the best of our knowledge this is the first article reporting the concomitant erosion and bleeding of the silastic marker in the excluded stomach. CONCLUSION: Silastic marker erosion in the bypassed stomach is a rare but possible complication not reported in the literature before. Different approaches for this complication are possible including laparoscopic management, with excellent results. PMID- 29704740 TI - Tanshinone IIA protects against subclinical lipopolysaccharide induced cardiac fibrosis in mice through inhibition of NADPH oxidase. AB - Myocardial fibrosis plays a central role in the development of heart failure. It has been shown that recurrent exposure to subclinical lipopolysaccharide (LPS) increases mortality and induces cardiac fibrosis in mice, which is not mediated by the common renin-angiotensin system. LPS increased NADPH oxidase2 (NOX2) in isolated adult mouse cardiac fibroblasts and NOX2 may mediate LPS-induced cardiac fibrosis. Therefore, the current study was designed to delineate the role of NOX2 in LPS-induced fibrosis model and to investigate the preventive role of Tanshinone IIA (TIIA) on the development of cardiac fibrosis. The protective mechanism of TIIA was determined to be associated with the inhibition of NOX2, by comparing its effects with the NADPH oxidase inhibitor, apocynin. The results revealed remarkable effects of apocynin and TIIA on attenuating the development of myocardial fibrosis and fibrosis-related genes and mediators. Furthermore, TIIA and apocynin decreased the expression of NADPH oxidase subunits (NOX2 and P67phox) expression and the ROS levels. The anti-fibrotic effect of apocynin suggested that NOX2 inhibition may be a potential preventive strategy for attenuating the progression of LPS-induced cardiac fibrosis. Our results demonstrate that TIIA may be a potent agent against subclinical LPS-induced cardiac fibrosis in mice partially via inhibition of NADPH oxidase 2. PMID- 29704741 TI - Stepwise-acid-active organic/inorganic hybrid drug delivery system for cancer therapy. AB - Due to the difference of pH values between normal tissues, tumor tissues and intracellular environments, DOX@MSN-CD-PEG, a stepwise-acid-active organic/inorganic hybrid drug delivery system (DDS) was reported in this article. The inorganic mesoporous silica nanoparticle (MSN) was introduced for loading of doxorubicin hydrochloride (DOX). Then organic components were applied to achieve the stepwise-acid-active intracellular drug release: MSN was capped with a beta cyclodextrine (beta-CD) based host-guest system via pH-sensitive epoxy bond. Then PEG was grafted outside of the carriers through pH-sensitive benzoic imine bond. With the protection of PEG layer, the carriers were difficult cellular uptake by normal cells but could be "acid-activated" for cytophagy by cancer cells in the slightly acidic environments in tumor tissues because of the abscission of PEG. Inside the cells, the more acidic environments could further "activate" the carriers to release DOX as the leaving of the host-guest system. The fabrication processes of DOX@MSN-CD-PEG were monitored. And the stepwise-acid-active property of which was investigated by acid-triggered PEG abscission studies and in vitro drug release studies at pH 7.4 and 6.5, respectively. The in vitro cellular cytotoxicity and cellular uptake behavior were also investigated. In summary, the stepwise-acid-active hybrid DDS should be considerable for cancer therapy. PMID- 29704742 TI - Magnetic hydrogels for levodopa release and cell stimulation triggered by external magnetic field. AB - Magnetic responsive hydrogels composed of alginate (Alg) and xanthan gum (XG), crosslinked with Ca2+ ions, were modified by in situ magnetic nanoparticles (MNP) formation. In comparison to magnetic Alg hydrogels, magnetic Alg-XG hydrogels presented superior mechanical and swelling properties, due to the high charge density and molecular weight of XG. The loading efficiency of levodopa (LD), an important antiparkinson drug, in the Alg-XG/MNP hydrogels was the highest (64%), followed by Alg/MNP (56%), Alg-XG (53%) and Alg (28%). A static external magnetic field (EMF) of 0.4 T stimulated the release of LD from Alg-XG/MNP hydrogels achieving 64 +/- 6% of the initial loading after 30 h. The viability, proliferation and expression of dopaminergic markers of human neuroblastoma SH SY5Y cell on the LD loaded magnetic hydrogels were successful, particularly under EMF, which stimulated the release of LD. Overall, the results of this study provided the rational design of magnetic hydrogels for the delivery of drugs, which combined with external magnetic stimulus, might improve cell proliferation and specific differentiation. PMID- 29704743 TI - On the effects of regional accents on memory and credibility. AB - The information we obtain from how speakers sound-for example their accent affects how we interpret the messages they convey. A clear example is foreign accented speech, where reduced intelligibility and speaker's social categorization (out-group member) affect memory and the credibility of the message (e.g., less trustworthiness). In the present study, we go one step further and ask whether evaluations of messages are also affected by regional accents-accents from a different region than the listener. In the current study, we report results from three experiments on immediate memory recognition and immediate credibility assessments as well as the illusory truth effect. These revealed no differences between messages conveyed in local-from the same region as the participant-and regional accents-from native speakers of a different country than the participants. Our results suggest that when the accent of a speaker has high intelligibility, social categorization by accent does not seem to negatively affect how we treat the speakers' messages. PMID- 29704744 TI - The role of psychological distancing in appreciation of art: Can native versus foreign language context affect responses to abstract and representational paintings? AB - Our work examines the role of psychological distancing in responses to art. We argued that the context of a foreign (vs native) language may distance the individual away from the pragmatic everyday perception style and enhance appreciation of paintings. We established the distinction between the sets of abstract and representational paintings in terms of perceptual-cognitive features and affective responses (Study 1). Then, we examined the influence of language context on appreciation of paintings. When examined separately, abstract paintings were better appreciated within a foreign (than native) language context (Study 2a), whereas appreciation of representational paintings was not significantly enhanced by a foreign language (Study 2b). The combined analysis of Studies 2a and 2b suggests, however, that distance induced by the foreign language similarly enhances appreciation of abstract and representational art. PMID- 29704745 TI - Trends and determinants of weight gains among OECD countries: an ecological study. AB - OBJECTIVES: Obesity has become a global issue with abundant evidence to indicate that the prevalence of obesity in many nations has increased over time. The literature also reports a strong association between obesity and economic development, but the trend that obesity growth rates may converge over time has not been examined. We propose a conceptual framework and conduct an ecological analysis on the relationship between economic development and weight gain. We also test the hypothesis that weight gain converges among countries over time and examine determinants of weight gains. STUDY DESIGN: This is a longitudinal study of 34 Organisation for Economic Cooperation and Development (OECD) countries in the years 1980-2008 using publicly available data. METHODS: We apply a dynamic economic growth model to test the hypothesis that the rate of weight gains across countries may converge over time. We also investigate the determinants of weight gains using a longitudinal regression tree analysis. RESULTS: We do not find evidence that the growth rates of body weight across countries converged for all countries. However, there were groups of countries in which the growth rates of body weight converge, with five groups for males and seven groups for females. The predicted growth rates of body weight peak when gross domestic product (GDP) per capita reaches US$47,000 for males and US$37,000 for females in OECD countries. National levels of consumption of sugar, fat and alcohol were the most important contributors to national weight gains. CONCLUSION: National weight gains follow an inverse U-shape curve with economic development. Excessive calorie intake is the main contributor to weight gains. PMID- 29704746 TI - Examining upper limb kinematics and dysfunction of breast cancer survivors in functional dynamic tasks. AB - BACKGROUND: Comorbidities within the breast cancer population can reduce quality of life. Current breast cancer survivor upper limb kinematic strategies unfortunately lack robust connection with performing important activities of daily living. METHODS: Accordingly, fifty breast cancer survivors performed 88 dynamic tasks (divided into range of motion-reach, range of motion-rotate, activity of daily living, and work tasks). Humerothoracic and scapulothoracic angles were extracted from motion capture data. Bilateral differences existed for range of motion, and maximal and minimal scapulothoracic and humerothoracic angles. FINDINGS: Generally, the affected side used less range of motion across task types. Humerothoracic angles on the affected side experienced 6.7 degrees less range of motion in plane of elevation in range of motion-reach (p < 0.01), 2.3 degrees less elevation angle range of motion in range of motion-rotate (p = 0.01), and 7.1 degrees more internal rotation range of motion in range of motion rotate (p < 0.01). Scapulothoracic angles on the affected side had 2 degrees more anterior/posterior tilt range of motion in work tasks (p = 0.03), 3.4 degrees less maximal protraction in activity of daily living tasks (p = 0.01), and 3.5 degrees less minimum downward rotation in range of motion-rotate (p < 0.01). INTERPRETATION: A reduced range of motion on the affected side suggests the breast cancer population had less varied movement strategies, keeping movements in narrower ranges to avoid disability, pain, or subacromial impingement. This investigation produced an unprecedentedly diverse collection of three-dimensional humerothoracic and scapulothoracic kinematics for a breast cancer population. Documentation of physical capability, dysfunction, and adaptive strategies is a crucial step towards developing targeted strategies for enhancing functional recovery in breast cancer survivors. PMID- 29704748 TI - Developmental interactions between thalamus and cortex: a true love reciprocal story. AB - The developmental programs that control the specification of cortical and thalamic territories are maintained largely as independent processes. However, bulk of evidence demonstrates the requirement of the reciprocal interactions between cortical and thalamic neurons as key for the correct development of functional thalamocortical circuits. This reciprocal loop of connections is essential for sensory processing as well as for the execution of complex sensory motor tasks. Here, we review recent advances in our understanding of how mutual collaborations between both brain regions define area patterning and cell differentiation in the thalamus and cortex. PMID- 29704749 TI - Personalized brain network models for assessing structure-function relationships. AB - Many recent efforts in computational modeling of macro-scale brain dynamics have begun to take a data-driven approach by incorporating structural and/or functional information derived from subject data. Here, we discuss recent work using personalized brain network models to study structure-function relationships in human brains. We describe the steps necessary to build such models and show how this computational approach can provide previously unobtainable information through the ability to perform virtual experiments. Finally, we present examples of how personalized brain network models can be used to gain insight into the effects of local stimulation and improve surgical outcomes in epilepsy. PMID- 29704750 TI - Active mechanosensory feedback during locomotion in the zebrafish spinal cord. AB - The investigation of mechanosensory feedback to locomotion has been hindered by the challenge of recording neurons in motion. Genetic accessibility and optical transparency of zebrafish larvae provide means to revisit this question. Glutamatergic Rohon-Beard (RB) and GABAergic CSF-contacting neurons (CSF-cNs) are spinal mechanosensory neurons. Recent studies combining bioluminescence, silencing and optogenetic activation show that mechanosensory neurons enhance speed and stabilize posture during locomotion. RB neurons can modulate speed by projecting onto glutamatergic premotor V2a interneurons during fast swimming, while CSF-cNs inhibit V0-v interneurons sustaining slow swimming. Sensory gating, either through inhibition of sensory interneurons (CoPA) or though the direct inhibition of primary motor neurons by CSF-cNs, mediates postural control. Advanced optical methods have shed light on the dynamics of sensorimotor integration during active locomotion unraveling implications for translational research. PMID- 29704751 TI - Exposure to ambient PM2.5 concentrations and cognitive function among older Mexican adults. AB - BACKGROUND: Recent epidemiological research has shown that exposure to fine particulate pollution (PM2.5) is associated with a reduction in cognitive function in older adults. However, primary evidence comes from high-income countries, and no specific studies have been conducted in low and middle-income countries where higher air pollution levels exist. OBJECTIVES: To estimate the association between the exposure to PM2.5 and cognitive function in a nationally representative sample of older Mexican adults and the associated effect modifiers. METHODS: Data for this study were taken from the National Survey of Health and Nutrition in Mexico carried out in 2012. A total of 7986 older adults composed the analytical sample. Cognitive function was assessed using two tests: semantic verbal fluency and three-word memory. The annual concentration of PM2.5 was calculated using satellite data. Association between exposure to PM2.5 and cognitive function was estimated using two-level logistic and linear regression models. RESULTS: In adjusted multilevel regression models, each 10 MUg/m3 increase in ambient PM2.5 raised the odds of a poorer cognitive function using the three-word memory test (OR = 1.37, 95% CI: 1.08, 1.74), and reduced the number of valid animal named in the verbal fluency test (beta = -0.72, 95% CI: 1.05, -0.40). Stratified analyses did not yield any significant modification effects of age, sex, indoor pollution, urban/rural dwelling, education, smoking and other factors. CONCLUSIONS: This study supports an association between exposure to PM2.5 concentrations and cognitive function in older adults. This is particularly relevant to low- and middle-income countries, which are marked by a rapid growth of their aging population and high levels of air pollution. PMID- 29704747 TI - Non-viral delivery systems for CRISPR/Cas9-based genome editing: Challenges and opportunities. AB - In recent years, CRISPR (clustered regularly interspaced short palindromic repeat)/Cas (CRISPR-associated) genome editing systems have become one of the most robust platforms in basic biomedical research and therapeutic applications. To date, efficient in vivo delivery of the CRISPR/Cas9 system to the targeted cells remains a challenge. Although viral vectors have been widely used in the delivery of the CRISPR/Cas9 system in vitro and in vivo, their fundamental shortcomings, such as the risk of carcinogenesis, limited insertion size, immune responses and difficulty in large-scale production, severely limit their further applications. Alternative non-viral delivery systems for CRISPR/Cas9 are urgently needed. With the rapid development of non-viral vectors, lipid- or polymer-based nanocarriers have shown great potential for CRISPR/Cas9 delivery. In this review, we analyze the pros and cons of delivering CRISPR/Cas9 systems in the form of plasmid, mRNA, or protein and then discuss the limitations and challenges of CRISPR/Cas9-based genome editing. Furthermore, current non-viral vectors that have been applied for CRISPR/Cas9 delivery in vitro and in vivo are outlined in details. Finally, critical obstacles for non-viral delivery of CRISPR/Cas9 system are highlighted and promising strategies to overcome these barriers are proposed. PMID- 29704752 TI - Are the existing guideline values adequate to protect soil health from inorganic mercury contamination? AB - Currently, data that guide safe concentration ranges for inorganic mercury in the soil are lacking and subsequently, threaten soil health. In the present study, a species sensitivity distribution (SSD) approach was applied to estimate critical mercury concentration that has little (HC5) or no effect (PNEC) on soil biota. Recently published terrestrial toxicity data were incorporated in the approach. Considering total mercury content in soils, the estimated HC5 was 0.6 mg/kg, and the PNEC was 0.12-0.6 mg/kg. Whereas, when only water-soluble mercury fractions were considered, these values were 0.04 mg/kg and 0.008-0.04 mg/kg, respectively. PMID- 29704753 TI - Does exposure to PM10 decrease age at menarche? AB - BACKGROUND: There has been a consistent decrease in age at menarche in South Korea. A potential risk factor for early menarche is exposure to particulate matter (PM), because endocrine-disrupting compounds emitted into air from anthropogenic sources may be incorporated into PM. The objective of this study was to examine the association between pre-menarcheal exposure to PM <= 10 MUm in diameter (PM10) and age at menarche in adolescents of South Korea using Korea National Health and Nutrition Examination Survey (KNHANES) 2010-2012 data. METHODS: We used self-reported age at menarche of 639 girls aged 13-17 years in this study. The cut-off age for early menarche was set to 12 years. Based on each subject's address, 1-year, 2-year, and 3-year averages of annual mean PM10 concentrations (models 1-3) were linked to KNHANES. Models were adjusted for body mass index (BMI), city size, household income level, maternal age at menarche, and second-hand smoke exposure at home. SURVEYREG and SURVEYLOGISTIC procedures were used to address the complex survey design of KNHANES. RESULTS: Overall analysis showed that exposure to PM10 has a significant effect on decreasing age at menarche. Multiple linear regression results suggested that each 1 MUg/m3 increase in 1-year, 2-year, 3-year averages of annual mean PM10 concentrations accelerated age at menarche by 0.046 years (95% CI: -0.064, -0.027; p < .0001), 0.038 years (95% CI: -0.059, -0.018; p = 0.0003),and 0.031 years (95% CI: -0.047, -0.015; p = 0.0002), respectively. Adjusted ORs for a 1 MUg/m3 increase in PM10 concentration were 1.08 (95% CI: 1.04 -1.12) for model 1, 1.06 (95% CI: 1.02 1.10) for model 2, and 1.05 (95% CI: 1.01 -1.09) for model 3. CONCLUSION: Our findings suggest that elevated PM10 concentration can decrease age at menarche. This is the first study that investigates the association between exposure to PM10 and age at menarche using a nationally representative sample of Koreans. PMID- 29704754 TI - Correlation between objective semen analysis and fertility in Japanese quail. AB - This study investigated the relationship between sperm kinematics and egg fertility in Japanese quail in an attempt to identify a semen trait that could be used to predict male fertility. Males (n=45) and females (n=180) from five strains (A, B, C, D, E) were used. Ejaculates (n=720) were collected from 8 to 38 weeks of male age. Semen volume and sperm concentration were recorded and sperm motility was analyzed using Sperm Class Analyzer (SCA(r)-CASA). At the time of ejaculate collection, males were allowed to mate with females in order to obtain egg fertility data: percent fertile eggs and the numbers of sperm (SpermOPVL) and sperm-holes (HolesIPVL) present on the egg perivitelline membranes. Sperm concentration was positively correlated with ejaculate volume (r=0.35; P < 0.01) and percent fertile eggs (r=0.08; P < 0.05). There were high correlations (P < 0.01) among the sperm kinematic parameters: percent motile (MOT%), percent rapid (Rapid%), percent progressive (PROG%), percent medium (Medium%), velocity curvilinear (VCL), velocity straight line (VSL), and velocity average path (VAP), linearity (LIN%), straightness of trajecotry (STR%) and beat cross frequency (BCF). The strains differed with respect to the correlations for sperm kinematics and egg fertility: SpermOPVL was correlated (P < 0.05) with VSL (r=0.18), VAP (r=0.18), and BCF (r=0.23) for Strain A, with PROG% (r=0.17) for Strain B, and with Medium% (r=0.18) for Strain C. When the data were adjusted for the effects of strain and age, Medium% was correlated with HolesIPVL (r=0.36; P < 0.01) and percent fertile eggs (r=0.31; P < 0.01), whereas PROG% was correlated with SpermOPVL (r=0.30; P < 0.01) and HolesIPVL (r=0.30; P < 0.01). Males could be ranked into high and low fertility categories based on initial (i.e. Week 8) and the life-time (i.e. Weeks 8-38) data for sperm kinematics and egg fertility. Of the males classified as poorly fertile by Week 8 sperm kinematics, 30% were also confirmed as poor on the basis of life-time sperm kinematics. Of the males classified as poorly fertile by Week 8 egg fertility, 47% were confirmed as poor on the basis of life time-data of egg fertility. We concluded that sperm concentration, Medium%, PROG%, VAP, VSL and BCF are important determinants of egg fertility in quail, and that these relationships depend on genotype. PMID- 29704755 TI - It's not going to be that fun: negative experiences can add meaning to life. AB - People seek to spend time in positive experiences, enjoying and savoring. Yet there is no escaping negative experiences, from the mundane (e.g. arguing) to the massive (e.g. death of a child). Might negative experiences confer a hidden benefit to well-being? We propose that they do, in the form of enhanced meaning in life. Research suggests that negative experiences can serve to boost meaning because they stimulate comprehension (understanding how the event fits into a broader narrative of the self, relationships, and the world), a known pillar of meaning in life. Findings on counterfactual thinking, reflecting on events' implications, and encompassing experiences into broad-based accounts of one's identity support the role of comprehension in contributing to life's meaning from unwanted, unwelcome experiences. PMID- 29704756 TI - Sampling in schools and large institutional buildings: Implications for regulations, exposure and management of lead and copper. AB - Legacy lead and copper components are ubiquitous in plumbing of large buildings including schools that serve children most vulnerable to lead exposure. Lead and copper samples must be collected after varying stagnation times and interpreted in reference to different thresholds. A total of 130 outlets (fountains, bathroom and kitchen taps) were sampled for dissolved and particulate lead as well as copper. Sampling was conducted at 8 schools and 3 institutional (non-residential) buildings served by municipal water of varying corrosivity, with and without corrosion control (CC), and without a lead service line. Samples included first draw following overnight stagnation (>8h), partial (30 s) and fully (5 min) flushed, and first draw after 30 min of stagnation. Total lead concentrations in first draw samples after overnight stagnation varied widely from 0.07 to 19.9 MUg Pb/L (median: 1.7 MUg Pb/L) for large buildings served with non-corrosive water. Higher concentrations were observed in schools with corrosive water without CC (0.9-201 MUg Pb/L, median: 14.3 MUg Pb/L), while levels in schools with CC ranged from 0.2 to 45.1 MUg Pb/L (median: 2.1 MUg Pb/L). Partial flushing (30 s) and full flushing (5 min) reduced concentrations by 88% and 92% respectively for corrosive waters without CC. Lead concentrations were <10 MUg Pb/L in all samples following 5 min of flushing. However, after only 30 min of stagnation, first draw concentrations increased back to >45% than values in 1st draw samples collected after overnight stagnation. Concentrations of particulate Pb varied widely (>=0.02-846 MUg Pb/L) and was found to be the cause of very high total Pb concentrations in the 2% of samples exceeding 50 MUg Pb/L. Pb levels across outlets within the same building varied widely (up to 1000X) especially in corrosive water (0.85-851 MUg Pb/L after 30MS) confirming the need to sample at each outlet to identify high risk taps. Based on the much higher concentrations observed in first draw samples, even after a short stagnation, the first 250mL should be discarded unless no sources of lead are present. Results question the cost-benefit of daily or weekly flushing as a remediation strategy. As such, current regulatory requirements may fail to protect children as they may not identify problematic taps and effective mitigation measures. PMID- 29704757 TI - Metagenomic binning reveals the functional roles of core abundant microorganisms in twelve full-scale biogas plants. AB - The aim of this work was to elucidate the microbial ecology in twelve mesophilic and thermophilic full-scale biogas plants using a genome-centric metagenomic approach. In this study both biogas plants treating manure and those treating sludge from waste water treatment plants were considered. The identification of 132 Metagenome-Assembled Genomes (MAGs) and analysis of their abundance profile in different samples allowed the identification of the most abundant core members of the anaerobic digestion microbiome. Canonical correspondence analysis was used to determine the influence of biotic and environmental factors on MAGs abundance and to investigate the methanogenic performance of the biogas plants. Prediction of the functional properties of MAGs was obtained analyzing their KEGG pathways and their carbohydrate active domains. Network analysis allowed investigation of species-species associations and shed light on syntrophic interactions between members belonging to the anaerobic digestion dark matter (phylum Fermentibacteria). By stratifying and comparing different levels of information, it was predicted that some MAGs have a crucial role in the manure-supplemented thermophilic biogas plants and it was highlighted the importance of the glycine cleavage system in complementing the "truncated" Wood-Ljungdahl pathway. PMID- 29704758 TI - Impact of ageing on the fate of molybdate-zerovalent iron nanohybrid and its subsequent effect on cyanobacteria (Microcystis aeruginosa) growth in aqueous media. AB - Nanoscale zerovalent iron (nZVI) has been proposed to remediate heavy metal ions in the subsurface. However, the fate of metal-nZVI hybrid has not been fully investigated. In this study, we investigated (1) the long-term removal performance of nZVI for molybdate (Mo(VI)); (2) the relationship between the ageing of Mo-nZVI hybrid in specific solution chemistries and the remobilization of Mo(VI) from the hybrid; and (3) the effects of Mo-nZVI hybrid on cyanobacteria (Microcystis aeruginosa). Results showed that although common ions have limited influence on the removal ratio of Mo(VI) by nZVI, they do impact the structure evolution and transformation of the Mo-nZVI nanohybrid formed thereafter. Ageing time was crucial for the chemical stabilization of Mo-nZVI hybrid, but common groundwater ions retarded the stabilizing process, which may lead to a significant remobilization of Mo(VI) from the hybrid after exposure to water bodies. While low levels of Mo(VI) ions could stimulate the growth of M. aeruginosa, aged Mo-nZVI hybrid inhibited the growth of M. aeruginosa, except when ageing occurred in the presence of HPO42-/CO32- (which also retarded hybrid stabilization). This study shows that nZVI can immobilize Mo(VI) ions in groundwater, and the derived metal-nZVI hybrid can effectively suppress the potential growth of M. aeruginosa in river water. PMID- 29704759 TI - Autocatalytic degradation of perfluorooctanoic acid in a permanganate-ultrasonic system. AB - An autocatalytic system, permanganate-ultrasonic (PM-US) system, was applied to degrade perfluorooctanoic acid (PFOA) in aqueous solutions. After a 120-min ultrasonication, a PM dosage of 6 mM increased the pseudo first-order rate constant (k1) for PFOA decomposition from 3.5 * 10-3 to 13.0 * 10-3 min-1 and increased the pseudo zeroth-order rate constant (k2) for PFOA defluorination from 1.5 * 10-3 to 7.9 * 10-3 mM.min-1, respectively. The PFOA degradation rates increased proportionally with the enhanced production rates of MnO2 particles. An initial pH 4 condition was optimal for the PFOA degradation compared to highly acidic and neutral conditions. PFOA degradation could be significantly facilitated by increasing power density of ultrasonication from 60 to 180 W.L-1. While increasing solution temperature to 50 degrees C only slightly promoted the PFOA decomposition and defluorination to 1.15 and 1.07 times of that at 30 degrees C, respectively. The solution saturated with argon was more favorable for the PFOA degradation in the PM-US system than that saturated with air and oxygen. Co-dissolved Cu(II), Fe(II) and Fe(III) ions inhibited the PFOA degradation by forming metal-PFOA complexes. Based on the experimental results and intermediates analysis, mechanisms and pathways of PFOA decomposition and defluorination in the PM-US system were proposed. PMID- 29704760 TI - Microbial community response to influent shift and lowering temperature in a two stage mainstream deammonification process. AB - The effects of influent shift from synthetic wastewater to anaerobically pretreated actual sewage coupling with lowering temperature on microbial community of a two-stage partial nitritation (PN)-anammox process were evaluated through high-throughput sequencing. Venn diagrams and Hill numbers showed the significantly increased bacterial diversity both in the PN and anammox reactor. However, taxonomic analysis indicated that outstanding enrichment of heterotrophic bacteria and reduction of autotrophic species mainly occurred in the PN reactor, while nearly all of the dominant bacteria in the anammox reactor only slightly decreased in abundance. Moreover, immigrant bacteria from the PN reactor to the following anammox reactor had no negative effect on the anammox function. These results implied the positive role of the first-stage PN in maintaining the stability of the following anammox community. Nitrosomonas europaea (17.9-52.9%) and one cluster (19.2-27.7%) within Candidatus Brocadia remained as the dominant functional species in the PN and anammox reactor, respectively. PMID- 29704761 TI - Anaerobic digestion of soft drink beverage waste and sewage sludge. AB - Soft drink beverage waste (BW) was evaluated as a potential substrate for anaerobic co-digestion with sewage sludge to increase biogas production. Results from this study show that the increase in biogas production is proportional to the increase in organic loading rate (OLR) rate due to BW addition. The OLR increase of 86 and 171% corresponding to 10 and 20% BW by volume in the feed resulted in 89 and 191% increase in biogas production, respectively. Under a stable condition, anaerobic co-digestion with BW did not lead to any significant impact on digestate quality (in terms of COD removal and biosolids odour) and biogas composition. The results suggest that existing nutrients in sewage sludge can support an increase in OLR by about 2 kg COD/m3/d from a carbon rich substrate such as soft drink BW without inhibition or excessive impact on subsequent handling of the digestate. PMID- 29704762 TI - Long-term high-solids anaerobic digestion of food waste: Effects of ammonia on process performance and microbial community. AB - A long-term high solids anaerobic digestion of food waste was conducted to identify microbial mechanisms of ammonia inhibition during digestion and to clarify correlations between ammonia accumulation, microbial community dynamics (diversity, composition, and interactions), and process stability. Results show that the effects of ammonia on process performance and microbial community were indirectly caused by volatile fatty acid accumulation. Excess free ammonia blocked acetate metabolism, leading to process instability. Accumulated acetate caused feedback inhibition at the acetogenesis stage, which resulted in considerable accumulation of propionate, valerate, and other long-chain fatty acids. This high concentration of volatile fatty acids reduced the abundance of syntrophic acetogenic bacteria and allowed hydrolytic fermentative bacteria to dominate. The normally interactive and orderly metabolic network was broken, which further exacerbated the process instability. These results improve the understanding of microbial mechanisms which contribute to process instability and provide guidance for the microbial management of anaerobic digesters. PMID- 29704763 TI - Process design and economic analysis of a biorefinery co-producing itaconic acid and electricity from sugarcane bagasse and trash lignocelluloses. AB - Itaconic acid has economic potential as a commodity biochemical for the sugar industry, but its production is limited due to high production costs. Using cheaper and alternative lignocellulosic feedstocks together with achieving higher product titres have been identified as potential strategies for viable IA production. Consequently the use of sugarcane bagasse and trash for the production of itaconic acid (IA) and electricity have been investigated for an integrated biorefinery, where the production facility is annexed to an existing sugar mill and new combined heat and power (CHP) plant. Three IA biorefinery scenarios were designed and simulated in Aspen Plus(r). Subsequent economic analyses indicated that cheaper feedstocks reduced the IA production cost from 1565.5 US$/t for glucose to 616.5 US$/t, but coal supplementation was required to sufficiently lower the production cost to 604.3 US$/t for a competitive IA selling price of 1740 US$/t, compared to the market price of 1800 US$/t. PMID- 29704765 TI - Lymphatic endothelial progenitor cells: origins and roles in lymphangiogenesis. AB - How are lymphatic vessels built? What are the sources of progenitor cells employed to construct lymphatic vessels during embryogenesis and in pathological situations? Are lymphatic vessels in different tissues built the same way? These questions have been highly topical and actively debated in the field of lymphangiogenesis research for more than 100 years. While embryonic veins and cells of mesenchymal origin have been recognised as sources of embryonic lymphatic endothelial cells for many years, recent advances in technology have revealed the existence of additional sources of lymphatic endothelial cells important for embryonic lymphangiogenesis. Intriguingly, distinct progenitor cell sources appear to be employed in a tissue specific manner during development. Gaining further insight into the identity of lymphatic endothelial progenitor cells and the signals that direct their assembly, both during development and in disease, has the potential to enable the design of therapeutics able to selectively target specific lymphatic vessel beds, a feature likely to prove valuable for the treatment of human disorders including cancer, lymphoedema and inflammatory disease. PMID- 29704764 TI - Antibody-based vaccine strategies against intracellular pathogens. AB - Historically, antibody-mediated immunity was considered effective against toxins, extracellular pathogens and viruses, while control of intracellular pathogens was the domain of cellular immunity. However, numerous observations in recent decades have conclusively shown that antibody can protect against intracellular pathogens. This paradigmatic shift has tremendous implications for immunology and vaccine design. For immunology the observation that antibody can protect against intracellular pathogens has led to the discovery of new mechanisms of antibody action. For vaccine design the knowledge that humoral immunity can be effective in protection means that the knowledge acquired in more than a century of antibody studies can be applied to make new vaccines against this class of pathogens. PMID- 29704766 TI - Validating the Chinese version of the PEmb-QoL questionnaire: A measure for quality of life assessment after pulmonary embolism. AB - PURPOSE: The purpose of the study was to test the psychometrical properties of the Chinese version of the Pulmonary Embolism Quality of Life (PEmb-QoL) questionnaire. METHODS: We translated the English version of the PEmb-QoL into Chinese. Patients at various periods after pulmonary embolism diagnosed at Peking Union Medical College Hospital between May 2016 and Dec 2017 were invited to complete the questionnaire. Standard psychometrical tests and criteria were used to evaluate the acceptability, reliability and validity of the Chinese version of the PEmb-QoL. RESULTS: A total of 108 participants completed the questionnaire and were included for further analysis. The Chinese version of the PEmb-QoL showed good internal consistency (Crohnbach's alpha ranging from 0.643 to 0.930), inter-item correlations (0.369-0.599), and item-total correlations (0.341-0.893). Test-retest reliability was also good (0.759-0.896). Moderate correlations between PEmb-QoL and SF-36 dimensions, and low correlations between PEmb-QoL and clinical characteristics supported convergent and discriminant validity. Exploratory factor analysis suggested four underlying dimensions: work-related problems, daily activity limitations, emotional complaints and frequency and intensity of complaints. CONCLUSIONS: The Chinese version of the PEmb-QoL questionnaire is both valid and reliable for measuring quality of life in patients at various periods after pulmonary embolism, proving the universality of this disease-specific questionnaire. PMID- 29704767 TI - Management of cancer-associated upper extremity deep vein thrombosis with and without venous catheters at a tertiary care center. AB - INTRODUCTION: Data on management of upper extremity deep vein thrombosis (UEDVT) in patients with cancer is limited. The objective of this study was to determine risk factors for UEDVT and the rates of recurrence and bleeding in a real-world setting. METHODS: Retrospective review of consecutive patients assessed for cancer-associated UEDVT. Outcome measures were recurrent venous thromboembolism (VTE), and major and clinically relevant non-major bleeding (CRNMB). Risk factors for recurrent VTE and bleeding were assessed. RESULTS: Mean duration of follow-up was 7.2 months. Two hundred cases were identified; 69% were associated with a central line. Non-line associated UEDVT occurred more frequently in the setting of breast cancer, lung cancer and documented local mass effect. The incidence of recurrent VTE was 18.5%, of which 14 (37.8%) were ipsilateral UEDVT. The risk of recurrence is higher with male gender (HR 2.0, 95% CI; 1.0-4.0). Major and CRNMB occurred in 1% and 11.5%, respectively. Concurrent use of an antiplatelet agent was associated with a higher risk of CRNMB compared to anticoagulant therapy alone (HR 3.9, 95% CI; 1.4-10.7). CONCLUSIONS: Presence of a venous catheter was the primary risk factor for UEDVT, however, extrinsic compression by local tumour may be just as important for some cancer types. Furthermore, the majority of recurrent events did not occur in the same upper limb suggesting that UEDVT may be predictive of increased thrombotic risk rather than just a local effect of catheters. PMID- 29704768 TI - Management of treatment-related toxicities in advanced medullary thyroid cancer. AB - Progress in the treatment of advanced medullary thyroid cancer (MTC) has resulted from the approval of 2 drugs within the past 5 years, vandetanib and cabozantinib. These multikinase inhibitors (MKIs) possess overlapping specificities for multiple kinase targets implicated in the progression of MTC. Both drugs are associated with toxicities, including hypertension, hemorrhage/perforation, diarrhea and other gastrointestinal events, several dermatologic events, and hypothyroidism. In addition, vandetanib is uniquely associated with QTc prolongation through interaction with myocardial potassium channels, and cabozantinib is uniquely associated with hand-foot skin reaction. Treatment-related toxicities occur frequently and can be severe or life threatening, and patients undergoing long-term treatment will likely experience adverse events (AEs). Here we offer specific practical recommendations for managing AEs commonly occurring with vandetanib and cabozantinib. The recommended approach relies on early recognition and palliation of symptoms, dose interruption, and dose reduction as necessary in order for the patient to maintain the highest tolerable dose for as long as possible and optimal quality of life. Treatment guidelines do not specify a recommended sequence for treating with vandetanib and cabozantinib; however, most patients will receive both drugs during their lifetime. The choice for first-line therapy is individualized after a risk-benefit assessment and depends on physician preference and patient-related factors, such as comorbid conditions. Because most generalist practices may not be familiar with the intricacies of agents such as vandetanib and cabozantinib, we commend that patients with advanced MTC be managed and treated by a thyroid cancer specialist with coordination of care within a multidisciplinary team. PMID- 29704769 TI - Generation of the induced pluripotent stem cell line CSSi006-A (3681) from a patient affected by advanced-stage Juvenile Onset Huntington's Disease. AB - Juvenile Onset Huntington's Disease (JOHD) is a rare variant of HD withage of onset <=20 years, accounting for 3-10% of all HD patients. The rarity occurrence of JOHD cases, who severely progress towards mental and physical disability with atypical clinical manifestations compared to classical HD, are responsible of general lack of knowledge about this variant. We obtained a fully reprogrammed iPS cell line from fibroblasts of a JOHD patient carrying 65 CAG repeats and age at onset at age 15. At the biopsy time, the patient showed an advanced stage after 10 years of disease. PMID- 29704770 TI - Physical principles and new applications of comet assay. AB - The comet assay is a sensitive method to assess DNA damages in single cells. The approach consists of an analysis of electrophoretic migration of DNA from nucleoids obtained after cell lysis in a thin layer of agarose. Although the method is widely used the physical mechanisms of DNA track formation remained to be rather elusive for a long time. This review is devoted to our recent results pertaining to this subject, using an original approach based on the kinetic measurements of the comet formation. We argue that linear DNA fragments give an essential contribution into the tail formation in the alkaline conditions and, at neutral pH, when the level of DNA damages is very high. On the other hand, in the neutral comet assay at low levels of DNA damages (and also in the case of undamaged cells) the tail is formed by extended DNA loops. These loops are about the same as chromatin loops in the cell nuclei. Kinetic measurements in the comet assay give an opportunity to investigate the topology of the loops and large scale features of the loop domain organization (and re-organization) in nucleoids obtained from different cell types. PMID- 29704771 TI - New approach based on immunochemical techniques for monitoring of selective estrogen receptor modulators (SERMs) in human urine. AB - Antiestrogenic compounds such as tamoxifen, toremifen and chlomifen are used illegally by athletes to minimize physical impacts such as gynecomastia resulting from the secondary effects of anabolic androgenic steroids, used to increase athletic efficiency unlawfully. The use of these compounds is banned by the World Anti-Doping Agency (WADA) and controls are made through analytical methodologies such as HPLC-MS/MS, which do not fulfil the sample throughput requirements. Moreover, compounds such as tamoxifen are also used to treat hormone receptor positive breast cancer (ER + ).Therapeutic drug monitoring (TDM) of tamoxifen may also be clinically useful for guiding treatment decisions. An accurate determination of these drugs requires a solid phase extraction of patient serum followed by HPLC-MS/MS. In the context of an unmet need of high-throughput screening (HTS) and quantitative methods for antiestrogenic substances we have approached the development of antibodies and an immunochemical assay for the determination of these antiestrogenic compounds. The strategy applied has taken into consideration that these drugs are metabolized and excreted in urine as the corresponding 4-hydroxylated compounds. A microplate-based ELISA procedure has been developed for the analysis of these metabolites in urine with a LOD of 0.15, 0.16 and 0.63 MUg/L for 4OH-tamoxifen, 4OH-toremifen and 4OH-clomifen, respectively, much lower than the MRPL established by WADA (20 MUg/L). PMID- 29704772 TI - Mass spectrometry characterization of DOTA-Nimotuzumab conjugate as precursor of an innovative beta- tracer suitable in radio-guided surgery. AB - The aim of the present work has been the mass spectrometry characterization of the Nimotuzumab (NIM) antibody chemically modified with the bifunctional chelating agent para-S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraaza cyclododecanetetraacetic acid (p-SCN-Bn-DOTA). The conjugate, upon labeling with the pure beta--emitter 90Y3+, could represent a promising candidate as radiotracer for an innovative radio-guided surgery (RGS) technique, developed and patented by researchers of our group, which uses a probe system for intraoperative detection of tumor residues exploiting the selective uptake of beta--emitting tracers. The results reported in this study show that multiple DOTA molecules bind to lysine residues of both light and heavy chains of the antibody and, probably, some of them are linked to the variable region of antibody. Moreover, the new mass spectrometric analysis highlights the presence of unreacted NIM in the final product. The information obtained by this work is of fundamental importance in the perspective to utilize this conjugate as a radiocompound after its labeling with 90Y3+ radioisotope. Indeed, the conjugation efficiency and the presence of unreacted NIM affect the specific activity of the final radiotracer which binds specific receptor. PMID- 29704773 TI - Escalation from normal appearance related intrusive cognitions to clinical preoccupations in Body Dysmorphic Disorder: A cross-sectional study. AB - Current cognitive approaches to Body Dysmorphic Disorder (BDD) assume that appearance-related intrusive cognitions and their functional consequences characterize the disorder, in a similar way that obsessive intrusive thoughts characterize the Obsessive-Compulsive Disorder (OCD). This study explores whether normal but unwanted appearance-related intrusive thoughts (AITs), escalate to clinical AITs when they are dysfunctionally appraised and instigate counterproductive neutralizing strategies. From a sample of 344 non-clinical individuals who reported a highly upsetting AIT during the past three months two subgroups were extracted according to their high (n = 68) and low (n = 276) vulnerability to BDD. The subjects in the high-risk group obtained significantly higher scores on the frequency of the most disturbing AIT and its emotional impact, interference, and appraisals evaluated with the Appearance Intrusions Questionnaire (AIQ). Additionally, two subgroups of 15 subjects each, with high and low risk to BDD, were formed and their scores were compared to 10 patients with BDD. The AIT had a greater emotional negative impact and more severe consequences on individuals with BDD compared to individuals at high-risk of BDD, which in turn, reported worse consequences of the AIT than those at low-risk. These results empirically support the similarities between BDD and OCD regarding their functional and phenomenological characteristics. PMID- 29704774 TI - Efficacy of "HLE"-a multidrug efflux-pump inhibitor-as a disinfectant against surface bacteria. AB - We evaluated the efficacy of a new disinfectant product, HLE, to inhibit multiple species of planktonic and biofilm bacterial cultures. The HLE disinfectant comprised of EDTA, lactic acid and hydrogen peroxide, and our data indicated that the disinfectant had effective antimicrobial and anti-biofilm activity even at low concentrations (0.15% to 0.4% HLE, v/v). Furthermore, the HLE disinfectant destabilized biofilm structures eradicated them due to the synergistic effect of EDTA and both antimicrobials (lactic acid and hydrogen peroxide), as revealed by confocal laser scanning microscopy. Additionally, sub-inhibitory concentrations of HLE disinfectant, with EDTA as an efflux pump inhibitor, inhibited the expression of multidrug EfrAB, NorE and MexCD efflux pumps in both planktonic and biofilm cultures. This could provide an alternative way to disinfect surfaces to avoid spreading multi-drug resistant strains in the food chain and the environment by decreasing efflux pump expression and consequently reducing the antibiotic selective pressure caused by systemic antibiotics and disinfectant use. PMID- 29704775 TI - Metal(loid) bioaccessibility and inhalation risk assessment: A comparison between an urban and an industrial area. AB - The content of metal(loid)s in particulate matter (PM) is of special concern due to their contribution to overall (PM) toxicity. In this study, the bioaccessibility and human health risk of potentially toxic metal(loid)s associated with PM10 were investigated in two areas of the Cantabrian region (northern Spain) with different levels of exposure: an industrial area mainly influenced by a ferromanganese alloy plant; and an urban area consisting mainly of residential and commercial activities, but also affected, albeit to a lesser extent by the ferroalloy plant. Total content and bioaccessible fractions in simulated lung fluids (SLFs) of Fe, Mn, Zn, Ni, Cu, Sb, Mo, Cd and Pb were determined by ICP-MS. Gamble's solution and artificial lysosomal fluid (ALF) were used to mimic different conditions inside the human respiratory system. A health risk assessment was performed based on the United States Environmental Protection Agency's (USEPA) methodology. Most metal(loid)s showed moderate and high bioaccessibility in Gamble's solution and ALF, respectively. Despite the high variability between the samples, metal(loid) bioaccessibility was found to be higher on average at the industrial site, suggesting a greater hazard to human health in the proximity of the main metal(loid) sources. Based on the results of the risk assessment, the non-carcinogenic risk associated with Mn exposure was above the safe limit (HQ> 1) under all the studied scenarios at the industrial site and under some specific scenarios at the urban location. The estimated carcinogenic inhalation risk for Cd exposure at the industrial site was found to be within the range between 1.0 * 10-6 to 1.0 * 10-4 (uncertainty range) under some scenarios. The results obtained in this study indicate that Mn and Cd inhalation exposure occurring in the vicinities of the studied areas may pose a human health risk. PMID- 29704776 TI - Recall of mobile phone usage and laterality in young people: The multinational Mobi-Expo study. AB - OBJECTIVE: To study recall of mobile phone usage, including laterality and hands free use, in young people. METHODS: Actual mobile phone use was recorded among volunteers aged between 10 and 24 years from 12 countries by the software application XMobiSense and was compared with self-reported mobile phone use at 6 and 18 months after using the application. The application recorded number and duration of voice calls, number of text messages, amount of data transfer, laterality (% of call time the phone was near the right or left side of the head, or neither), and hands-free usage. After data cleaning, 466 participants were available for the main analyses (recorded vs. self-reported phone use after 6 months). RESULTS: Participants were on average 18.6 years old (IQR 15.2-21.8 years). The Spearman correlation coefficients between recorded and self-reported (after 6 months) number and duration of voice calls were 0.68 and 0.65, respectively. Number of calls was on average underestimated by the participants (adjusted geometric mean ratio (GMR) self-report/recorded = 0.52, 95% CI = 0.47 0.58), while duration of calls was overestimated (GMR=1.32, 95%, CI = 1.15-1.52). The ratios significantly differed by country, age, maternal educational level, and level of reported phone use, but not by time of the interview (6 vs. 18 months). Individuals who reported low mobile phone use underestimated their use, while individuals who reported the highest level of phone use were more likely to overestimate their use. Individuals who reported using the phone mainly on the right side of the head used it more on the right (71.1%) than the left (28.9%) side. Self-reported left side users, however, used the phone only slightly more on the left (53.3%) than the right (46.7%) side. Recorded percentage hands-free use (headset, speaker mode, Bluetooth) increased with increasing self-reported frequency of hands-free device usage. Frequent (>=50% of call time) reported headset or speaker mode use corresponded with 17.1% and 17.2% of total call time, respectively, that was recorded as hands-free use. DISCUSSION: These results indicate that young people can recall phone use moderately well, with recall depending on the amount of phone use and participants' characteristics. The obtained information can be used to calibrate self-reported mobile use to improve estimation of radiofrequency exposure from mobile phones. PMID- 29704777 TI - Promoting evaluation capacity building in a complex adaptive system. AB - This study provides results from an NSF funded, four year, case study about evaluation capacity building in a complex adaptive system, the Nanoscale Informal Science Education Network (NISE Net). The results of the Complex Adaptive Systems as a Model for Network Evaluations (CASNET) project indicate that complex adaptive system concepts help to explain evaluation capacity building in a network. The NISE Network was found to be a complex learning system that was supportive of evaluation capacity building through feedback loops that provided for information sharing and interaction. Participants in the system had different levels of and sources of evaluation knowledge. To be successful at building capacity, the system needed to have a balance between both centralized and decentralized control, coherence, redundancy, and diversity. Embeddedness of individuals within the system also provided support and moved the capacity of the system forward. Finally, success depended on attention being paid to the control of resources. Implications of these findings are discussed. PMID- 29704778 TI - Lessons learned: Evaluating the program fidelity of UNWomen Partnership for Peace domestic violence diversion program in the Eastern Caribbean. AB - To date, there have been a plethora of punitive and diversion programs to address domestic violence around the world. However, the evaluative scholarship of such programs overwhelmingly reflects studies in developed countries while barely showcasing the realities of addressing domestic violence in developing countries. This paper features a multi-year (2008-2011) evaluation study that measured the fidelity of the United Nations Partnership for Peace (PfP) domestic violence diversion program in the Eastern Caribbean country of Grenada. Our findings illuminate organic engagement strategies that were built within existing multi sectoral partnerships that included magistrate court judges, law enforcement officials, and social service agencies. Furthermore, we documented how the locally-devised implementation strategies ensured the program's fidelity within a resource-limited context. This paper contributes to the global evaluative scholarship, highlighting the lessons learned about implementing culturally adapted and theoretically-driven domestic violence diversion within a developing country. PMID- 29704780 TI - Modeling of the capillary wicking of flax fibers by considering the effects of fiber swelling and liquid absorption. AB - We propose a new model for the capillary rise of liquid in flax fibers whose diameter is changed by liquid absorption. Liquid absorption into the flax fibers is taken into account in a new modified Washburn equation by considering the mass of the liquid absorbed inside the fibers as well as that imbibed between the fibers. The change of permeability and hydraulic radius of pores in a fibrous medium due to the fiber swelling is modeled by a statistical approach considering a non-uniform distribution of flax fiber diameter. By comparisons between capillary rise test results and modeling results, we prove the validity of the proposed modified Washburn model to take into account the effects from fiber swelling and liquid absorption on the decrease of capillary rise velocity. The experimental observation of long-term capillary rise tests show that the swelling behavior of the fibers highly packed in a closed volume and its influence on the capillary wicking are different from those of an individual single fiber in a free space. The current approach was useful to characterize the swelling of fibers highly packed in a closed volume and its influence of the long-term behavior of capillary wicking. PMID- 29704779 TI - Effect of pyrolysis temperature on phosphate adsorption characteristics and mechanisms of crawfish char. AB - The purpose of this study was to investigate the characteristics of crawfish char (CFC) derived at different pyrolysis temperature and to evaluate its adsorption characteristics on phosphate. Phosphate adsorption by CFC occurred rapidly at the beginning of the reaction, and the time to reach equilibrium was dependent on the pyrolysis temperature. Maximum adsorption capacities of phosphate by CFC at different pyrolysis temperatures were high in order of CFC800 (70.9 mg/g) > CFC600 (56.8 mg/g) > CFC400 (47.2 mg/g) ? CFC200 (9.5 mg/g) ~ uncharred crawfish feedstock (CF) (7.1 mg/g). Spectroscopic analyses using SEM-EDS and FTIR showed that the phosphate present in the CFC itself was associated with carbon, while the phosphate adsorbed on the CFC was closely related to calcium. The adsorption of phosphate by CFC is dominantly affected by pH. Phosphate adsorption of CFC600 primarily occurred at acid and neutral pH which is related to dissolved calcium from surface and phosphate hydrolysis product (H2PO4-), while phosphate adsorption of CFC800 mainly took place at alkaline pH, with precipitation mechanism between PO43- and calcium dissolved from free CaO and Ca(OH)2. Overall, CFC derived at pyrolysis temperatures above 400 degrees C is effective for waste reduction and phosphate treatment in wastewater. PMID- 29704781 TI - Platinum69-cobalt31 alloyed nanosheet nanoassemblies as advanced bifunctional electrocatalysts for boosting ethylene glycol oxidation and oxygen reduction. AB - Pt-based bimetallic nanocrystals are feasible to dramatically improve the catalytic performances in fuel cells via morphology- and composition-engineering. Herein, bimetallic platinum69-cobalt31 nanosheet nanoassemblies (Pt69Co31 NSNSs) were facilely synthesized through a one-pot co-reduction solvothermal strategy in oleylamine (OAm), using cetyltrimethylammonium chloride (CTAC) and allantoin as the directing agents. The current synthesis highly depended on the critical concentrations of Pt and Co precursors, the combined use of allantoin to OAm as the co-reductant, and the use of proper allantoin concentration. The obtained nanocatalyst exhibited largely enhanced electrocatalytic activity and durable ability towards ethylene glycol oxidation reaction (EGOR) and oxygen reduction reaction (ORR) relative to home-made Pt85Co15 nanoparticles (NPs), Pt19Co81 NPs and Pt black catalysts due to its much larger electrochemically active surface area than the contrasts. PMID- 29704782 TI - Shape-dependent adsorption of CeO2 nanostructures for superior organic dye removal. AB - Highly efficient removal of dye pollutants from water resources remains a great challenge. Herein, we demonstrate a new approach for the efficient removal of anionic organic dyes from wastewater using shape-dependent CeO2 nanostructures. It was found that the volume stoichiometry ratio of ethanol to water (EtOH/H2O) was a key factor affecting the CeO2 nanostructures. Accordingly, the adsorption capacity of the spindle CeO2 nanostructure for Congo red reached 162.4 mg g-1, which is much higher than that of octahedral and spherical CeO2 or other adsorbents previously reported. The superior adsorption performance may be mainly attributed to the peculiar structure and presence of electrostatic interactions between the sample surface and dye molecules. This finding will provide new avenues for using promising adsorbent materials for dye removal in water treatments. PMID- 29704783 TI - Detection of Bisphenol A in aqueous medium by screen printed carbon electrodes incorporating electrochemical molecularly imprinted polymers. AB - Electrochemical molecularly imprinted polymers (e-MIPs) were for the first time introduced in screen-printed carbon electrodes (SPCE) as the sensing element for the detection of an organic pollutant. To play this sensing role, a redox tracer was incorporated inside the binding cavities of a cross-linked MIP, as a functional monomer during the synthesis step. Ferrocenylmethyl methacrylate was used for this purpose. It was associated with 4-vinylpyridine as a co-functional monomer and ethylene glycol dimethacrylate as cross-linker for the recognition of the endocrine disruptor, Bisphenol A (BPA), as a target. Microbeads of e-MIP and e-NIP (corresponding non-imprinted polymer) were obtained via precipitation polymerization in acetonitrile. The presence of ferrocene inside the polymers was assessed via FTIR and elemental analysis and the polymers microstructure was characterized by SEM and nitrogen adsorption/desorption experiments. Binding isotherms and batch selectivity experiments evidenced the presence of binding cavities inside the e-MIP and its high affinity for BPA compared to carbamazepine and ketoprofen. e-MIP (and e-NIP) microbeads were then incorporated in a graphite hydroxyethylcellulose composite paste to prepare SPCE. Electrochemical properties of e-MIP-SPCE revealed a high sensitivity in the presence of BPA in aqueous medium compared to e-NIP-SPCE with a limit of detection (LOD) of 0.06 nM. Selectivity towards carbamazepine and ketoprofen was also observed with the e-MIP SPCE. PMID- 29704784 TI - Geometric screening of core/shell hydrogel microcapsules using a tapered microchannel with interdigitated electrodes. AB - Core/shell hydrogel microcapsules attract increasing research attention due to their potentials in tissue engineering, food engineering, and drug delivery. Current approaches for generating core/shell hydrogel microcapsules suffer from large geometric variations. Geometrically defective core/shell microcapsules need to be removed before further use. High-throughput geometric characterization of such core/shell microcapsules is therefore necessary. In this work, a continuous flow device was developed to measure the geometric properties of microcapsules with a hydrogel shell and an aqueous core. The microcapsules were pumped through a tapered microchannel patterned with an array of interdigitated microelectrodes. The geometric parameters (the shell thickness and the diameter) were derived from the displacement profiles of the microcapsules. The results show that this approach can successfully distinguish all unencapsulated microparticles. The geometric properties of core/shell microcapsules can be determined with high accuracy. The efficacy of this method was demonstrated through a drug releasing experiment where the optimization of the electrospray process based on geometric screening can lead to controlled and extended drug releasing profiles. This method does not require high-speed optical systems, simplifying the system configuration and making it an indeed miniaturized device. The throughput of up to 584 microcapsules per minute was achieved. This study provides a powerful tool for screening core/shell hydrogel microcapsules and is expected to facilitate the applications of these microcapsules in various fields. PMID- 29704785 TI - 2'-Fluoro ribonucleic acid modified DNA dual-probe sensing strategy for enzyme amplified electrochemical detection of double-strand DNA of PML/RARalpha related fusion gene. AB - In the study, a novel sensing strategy based on dual-probe mode, which involved two groups of 2'-fluoro ribonucleic acid (2'-F RNA) modified probes, was designed for the detection of synthetic target double-strand DNA (dsDNA) of PML/RARalpha fusion genes in APL. And each pair of probes contained a thiolated capture probe (C1 or C2) immobilized on one of electrode surfaces in the dual-channel electrochemical biosensor and a biotinylated reporter probe (R1 or R2). The two groups of 2'-F RNA modified probes were separately complementary with the corresponding strand (Sa or Sb) from target dsDNA in order to prevent renaturation of target dsDNA. Through flanking target dsDNA, two "sandwitch" complexes (C1/Sa/R1 and C2/Sb/R2) were separately shaped by capture probes (C1 and C2) and free reporter probes (R1 and R2) in hybridization solution on the surfaces of different electrodes after the thermal denaturation. The biotin modified enzyme which produced the measurable electrochemical current signal was localized to the surface by affinity binding between biotin with streptavidin. Under the optimal condition, the biosensor was able to detect 84 fM target dsDNA and showed a good specificity in PBS hybridization solution. Otherwise, the investigations of the specificity and sensitivity of the biosensor were carried out further in the mixed hybridization solution containing different kinds of mismatch sequences as interference background. It can be seen that under a certain interference background, the method still exhibited excellent selectivity and specificity for the discrimination between the fully-complementary and the mismatch sequences. The results of our research laid a good basis of further detection research in practical samples. PMID- 29704786 TI - Two-dimensional mesoporous ZnCo2O4 nanosheets as a novel electrocatalyst for detection of o-nitrophenol and p-nitrophenol. AB - Novel mesoporous ZnCo2O4 (meso-ZnCo2O4) nanosheets were synthesized by a simple hydrothermal method for detection of o-nitrophenol (ONP) and p-nitrophenol (PNP). The resultant meso-ZnCo2O4 nanosheets possess more catalytic active sites than other structures, which enhance the catalysis properties for the electrochemical detection of nitrophenol. This sensor exhibits a wide linear detection range (1 4000 and 1-4000 MUM) and high sensitivity (0.256 and 0.318 MUA MUM-1 cm-2), as well as low detection limit (0.3 and 0.3 MUM), for ONP and PNP, respectively. In addition, the fabricated sensor reveals excellent reproducibility, stability and selectivity. PMID- 29704787 TI - The effect of epoch length on time and frequency domain parameters of electromyographic and mechanomyographic signals. AB - The selection of epoch lengths affects the time and frequency resolution of electromyographic (EMG) and mechanomyographic (MMG) signals, as well as decisions regarding the signal processing techniques to use for determining the power density spectrum. No previous studies, however, have examined the effects of epoch length on parameters of the MMG signal. The purpose of this study was to examine the differences between epoch lengths for EMG amplitude, EMG mean power frequency (MPF), MMG amplitude, and MMG MPF from the VL and VM muscles during MVIC muscle actions as well as at each 10% of the time to exhaustion (TTE) during a continuous isometric muscle action of the leg extensors at 50% of MVIC. During the MVIC trial, there were no significant (p > 0.05) differences between epoch lengths (0.25, 0.50, 1.00, and 2.00-s) for mean absolute values for any of the EMG or MMG parameters. During the submaximal, sustained muscle action, however, absolute MMG amplitude and MMG MPF were affected by the length of epoch. All epoch related differences were eliminated by normalizing the absolute values to MVIC. These findings supported normalizing EMG and MMG parameter values to MVIC and utilizing epoch lengths that ranged from 0.25 to 2.00-s. PMID- 29704788 TI - Clinical Audit of the Radiotherapy Process in Rectal Cancer: Clinical Practice Guidelines and Quality Certification Do Not Avert Variability in Clinical Practice. AB - BACKGROUND: The therapeutic approach to cancer is complex and multidisciplinary. Radiotherapy is among the essential treatments, whether used alone or in conjunction with other therapies. This study reports a clinical audit of the radiotherapy process to assess the process of care, evaluate adherence to agreed protocols and measure the variability to improve therapeutic quality for rectal cancer. METHODS: Multicentre retrospective cohort study in a representative sample of patients diagnosed with rectal cancer in the Institut Catala d'Oncologia, a comprehensive cancer centre with three different settings. We developed a set of indicators to assess the key areas of the radiotherapy process. The clinical audit consisted of a review of a random sample of 40 clinical histories for each centre. RESULTS: The demographic profile, histology and staging of patients were similar between centres. The MRI reports did not include the distance from tumour to mesorectal fascia (rCRM) in 38.3% of the cases. 96.7% of patients received the planned dose, and 57.4% received it at the planned time. Surgery followed neoadjuvant treatment in 96.7% of the patients. Among this group, postoperative CRM was recorded in 65.5% of the cases and was negative in 93.4% of these. With regard to the 34.5% (n = 40) of cases where no CRM value was stated, there were differences between the centres. Mean follow-up was 3.4 (SD 0.6) years, and overall survival at four years was 81.7%. CONCLUSIONS: The audit revealed a suboptimal degree of adherence to clinical practice guidelines. Significant variability between centres exists from a clinical perspective but especially with regard to organization and process. PMID- 29704789 TI - Coordinative structuring of gait kinematics during adaptation to variable and asymmetric split-belt treadmill walking - A principal component analysis approach. AB - Gait adaptation is a task that requires fine-tuned coordination of all degrees of freedom in the lower limbs by the central nervous system. However, when individuals change their gait it is unknown how this coordination is organized, and how it can be influenced by contextual interference during practice. Such knowledge could provide information about measurement of gait adaptation during rehabilitation. Able-bodied individuals completed an acute bout of asymmetric split-belt treadmill walking, where one limb was driven at a constant velocity and the other according to one of three designed practice paradigms: serial practice, where the variable limb belt velocity increased over time; random blocked practice, where every 20 strides the variable limb belt velocity changed randomly; random practice, where every stride the variable limb belt velocity changed randomly. On the second day, subjects completed one of two different transfer tests; one with a belt asymmetry close to that experienced on the acquisition day (transfer 1; 1.5:1), and one with a greater asymmetry (transfer 2; 2:1) . To reduce this inherently high-dimensional dataset, principal component analyses were used for kinematic data collected throughout the acquisition and transfer phases; resulting in extraction of the first two principal components (PCs). For acquisition, PC1 and PC2 were related to sagittal and frontal plane control. For transfer 1, PC1 and PC2 were related to frontal plane control of the base of support and whole-body center of mass. For transfer 2, PC1 did not have any variables with high enough coefficients deemed to be relevant, and PC2 was related to sagittal plane control. Observations of principal component scores indicate that variance structuring differs among practice groups during acquisition and transfer 1, but not transfer 2. These results demonstrate the main kinematic coordinative structures that exist during gait adaptation, and that control of sagittal plane and frontal plane motion are perhaps a trade-off during acquisition of a novel asymmetric gait pattern. PMID- 29704790 TI - The effects of a fatiguing lifting task on postural sway among males and females. AB - Lifting and falls comprise a large proportion of work related injuries. Repetitive lifting to the point of fatigue can affect postural sway, which is associated with fall risk. To investigate the effects of lifting and fatigue on postural sway in males and females, 35 participants (18 male, 17 female) were asked to lift a weighted box in sets of 25 lifts at 5 different incremental weights (10, 15, 20, 25, and 30 kg) until fatigue. Before and after each lifting set, participants performed a single leg balance test on a force platform to assess postural sway by means of center of pressure mean velocity. Analysis of pre-fatigue to post-fatigue postural sway measurements indicated that there were no significant differences in mean velocity when males and females were grouped together. However, when analyzed as separate groups, mean postural sway center of pressure velocity increased for males but did not for females, indicating that males and females use different strategies to maintain balance when fatigued. PMID- 29704791 TI - Comparison of elemental composition in two wild and cultured marine fish and potential risks to human health. AB - Among all available species, fish are a powerful model for risk-benefit assessments to study the effects of contaminants on human health. Gilthead seabream (Sparus aurata, Linnaeus 1758) and european seabass (Dicentrarchus labrax, Linnaeus 1758) are two species of great economic importance, representing very large production volumes in the Mediterranean. The objective of this study is (1) to analyze the concentrations of Trace Elements (TE) between wild and cultured seabream and seabass specimens, (2) to compare the determined concentrations with other studies, and (3) to increase the data about the potential risks to human health. Our results point to significant intra- and interspecies-specific differences between wild and cultured fish for several trace elements. Several strong and moderate inter-elemental correlations in fish muscle were observed through correlation analysis. In our study, the mean levels of trace elements were still below the standard safety values for fish intended for human consumption. The same results were reached for all the parameters analyzed (international legal limits, estimated weekly intake, provisional tolerable weekly intake, target hazard quotient, target cancer risk), with trace element levels in fish below those that could pose a risk to human health. Consequently, these fish can be considered safe for human consumption. A better understanding of the levels of trace elements in fish would also better inform consumers about the potential risks of exposure to contaminants. PMID- 29704792 TI - Aluminum-responsive genes revealed by RNA-Seq and related physiological responses in leaves of two Citrus species with contrasting aluminum-tolerance. AB - Little is known about the physiological and molecular responses of leaves to aluminum (Al)-toxicity. Seedlings of Al-intolerant Citrus grandis and Al-tolerant Citrus sinensis were supplied daily with nutrient solution containing 0 mM (control) and 1.0 mM (Al-toxicity) AlCl3.6H2O for 18 weeks. We found that Al treatment only decreased CO2 assimilation in C. grandis leaves, and that the Al induced alterations of gene expression profiles were less in C. sinensis leaves than those in C. grandis leaves, indicating that C. sinensis seedlings were more tolerant to Al-toxicity than C. grandis ones. Al concentration was similar between Al-treated C. sinensis and C. grandis roots, but it was higher in Al treated C. grandis stems and leaves than that in Al-treated C. sinensis stems and leaves. Al-treated C. sinensis seedlings accumulated relatively more Al in roots and transported relatively little Al to shoots. This might be responsible for the higher Al-tolerance of C. sinensis. Further analysis showed that the following several aspects might account for the higher Al-tolerance of C. sinensis, including: (a) Al-treated C. sinensis leaves had higher capacity to maintain the homeostasis of energy and phosphate, the stability of lipid composition and the integrity of cell wall than did Al-treated C. grandis leaves; (b) Al-triggered production of reactive oxygen species (ROS) and the other cytotoxic compounds was less in Al-treated C. sinensis leaves than that in Al-treated C. grandis leaves, because Al-toxicity decreased CO2 assimilation only in C. grandis leaves; accordingly, more upregulated genes involved in the detoxifications of ROS, aldehydes and methylglyoxal were identified in Al-treated C. grandis leaves; in addition, flavonoid concentration was increased only in Al-treated C. grandis leaves; (c) Al-treated C. sinensis leaves could keep a better balance between protein phosphorylation and dephosphorylation than did Al-treated C. grandis leaves; and (d) both the equilibrium of hormones and hormone-mediated signal transduction were greatly disrupted in Al-treated C. grandis leaves, but less altered in Al-treated C. sinensis leaves. Finally, we discussed the differences in Al-responsive genes between Citrus roots and leaves. PMID- 29704794 TI - Going at the heart of social cognition: is there a role for interoception in self other distinction? AB - Interoception describes the processing and awareness of bodily signals arising from visceral organs, essential for the organism's homeostatic needs. Beyond homeostasis, the integration of exteroceptive and interoceptive signals is required for the coherence of bodily self-awareness. Here, we suggest that interoception also plays a critical role in social cognition. Relating to others as individuals who are distinct from one's self requires the simultaneous yet distinct co-representation of self and others. We propose that interoceptive awareness appears to stabilise the mental representation of one's self as distinct from others. A more nuanced understanding of the role of interoception in the representation of others in relation to ourselves is vital to determine its importance in social cognition. PMID- 29704793 TI - Lane change warning threshold based on driver perception characteristics. AB - Lane Change Warning system (LCW) is exploited to alleviate driver workload and improve the safety performance of lane changes. Depending on the secure threshold, the lane change warning system could transmit caution to drivers. Although the system possesses substantial benefits, it may perturb the conventional operating of the driver and affect driver judgment if the warning threshold does not conform to the driver perception of safety. Therefore, it is essential to establish an appropriate warning threshold to enhance the accuracy rate and acceptability of the lane change warning system. This research aims to identify the threshold that conforms to the driver perception of the ability to safely change lanes with a rear vehicle fast approaching. We propose a theoretical warning model of lane change based on a safe minimum distance and deceleration of the rear vehicle. For the purpose of acquiring the different safety levels of lane changes, 30 licensed drivers are recruited and we obtain the extreme moments represented by driver perception characteristics from a Front Extremity Test and a Rear Extremity Test implemented on the freeway. The required deceleration of the rear vehicle corresponding to the extreme time is calculated according to the proposed model. In light of discrepancies in the deceleration in these extremity experiments, we determine two levels of a hierarchical warning system. The purpose of the primary warning is to remind drivers of the existence of potentially dangerous vehicles and the second warning is used to warn the driver to stop changing lanes immediately. We use the signal detection theory to analyze the data. Ultimately, we confirm that the first deceleration threshold is 1.5 m/s2 and the second deceleration threshold is 2.7 m/s2. The findings provide the basis for the algorithm design of LCW and enhance the acceptability of the intelligent system. PMID- 29704795 TI - Silica micro- and nanoparticles reduce the toxicity of surfactant solutions. AB - In this work, the toxicity of hydrophilic fumed silica micro- and nanoparticles of various sizes (7 nm, 12 nm, and 50 MUm) was evaluated using the luminescent bacteria Vibrio fischeri. In addition, the toxicity of an anionic surfactant solution (ether carboxylic acid), a nonionic surfactant solution (alkyl polyglucoside), and a binary (1:1) mixture of these solutions all containing these silica particles was evaluated. Furthermore, this work discusses the adsorption of surfactants onto particle surfaces and evaluates the effects of silica particles on the surface tension and critical micellar concentration (CMC) of these anionic and nonionic surfactants. It was determined that silica particles can be considered as non-toxic and that silica particles reduce the toxicity of surfactant solutions. Nevertheless, the toxicity reduction depends on the ionic character of the surfactants. Differences can be explained by the different adsorption behavior of surfactants onto the particle surface, which is weaker for nonionic surfactants than for anionic surfactants. Regarding the effects on surface tension, it was found that silica particles increased the surface activity of anionic surfactants and considerably reduced their CMC, whereas in the case of nonionic surfactants, the effects were reversed. PMID- 29704796 TI - Application of carbon dots as efficient catalyst for the green oxidation of phenol: Kinetic study of the degradation and optimization using response surface methodology. AB - The reactivity of bio-polymer based nano carbon dots (NCDs) was studied for catalyzing the decomposition of H2O2 to generate free hydroxyl radicals and consequently its applicability in the removal of phenol. To the best of our knowledge, for the first time, this work reports that bio-polymer based NCDs could activate H2O2 and yielding more than 99% phenol degradation within 20 min in the presence of 12 mmol H2O2. Herein, a simple hydrothermal carbonization route was employed for the synthesis of NCDs. The surface morphology, functional groups and crystallinity of the NCDs are studied. SEM images show the NCDs with spherical shape. The graphitic nature of the NCDs was evident from the XRD pattern. The presence of many surface functional groups is confirmed by FT-IR spectra. The influences of three independent operating parameters involving hydrogen peroxide concentration (4-12 mmol), reaction time (10-20 min) and catalyst amount (50-1000 ppm) on the phenol oxidation rate by two NCDs were examined using response surface methodology (RSM). Terephthalic acid (TA) dosimetry demonstrates that the as-prepared NCDs can produce hydroxyl radicals from H2O2, and hence catalyze the oxidation of phenol. Finally, the reusability of the NCDs catalysts was examined and the produced catalysts exhibit good recyclability. PMID- 29704797 TI - Enhanced degradation of 2,4-dichlorophenoxyacetic acid by pre-magnetization Fe-C activated persulfate: Influential factors, mechanism and degradation pathway. AB - 2,4-dichlorophenoxyacetic acid (2,4-D) is one of the most applicable herbicides in the world, its residue in aquatic environment threatens the human health and ecosystems. In this study, for the first time, inexpensive Fe-C after pre magnetization (Pre-Fe-C) was used as the heterogeneous catalyst to activate persulfate (PS) for 2,4-D degradation, proving that Pre-Fe-C could significantly improve the degradation and dechlorination. The results indicated the stability and reusability of Pre-Fe-C were much better than pre-magnetization Fe0 (Pre Fe0), while the leaching iron ion was lower, indicating that using Pre-Fe-C not only reduced the post-treatment cost, but also enhanced the removal and dechlorination efficiency of 2,4-D. Several important parameters including initial pH, Fe-C dosage, PS concentration affecting 2,4-D degradation and dechlorination by Pre-Fe-C/PS were investigated and compared with that of Fe C/PS, observing a 1.2-2.7 fold enhancement in the degradation rate of 2,4-D. The Fe-C and Pre-Fe-C were characterized by scanning electron microscopy (SEM), energy dispersive X-ray (EDX) and SEM-EDX-mapping, suggesting that the content of Fe and O changed more obviously after magnetization. The degradation intermediates, such as chloroquinol, 2-chlorophenol, were identified by a gas chromatography mass spectrometry (GC/MS) and an ion chromatography (IC), and a possible degradation pathway was proposed. PMID- 29704798 TI - Validation of an LC-MS/MS method for simultaneous quantification of venlafaxine and its five metabolites in rat plasma and its application in a pharmacokinetic study. AB - A sensitive, selective, and reliable LC-MS/MS method was developed and validated for simultaneous quantification of venlafaxine (VEN) and its 5 metabolites (ODV, NDV, NNDDV, OHV and NODDV) in rat plasma. The calibration ranges are 15.0 to 6000 ng/mL for VEN, 1.00 to 400 ng/mL for ODV, 5.00 to 2000 ng/mL for NDV, 1.00 to 400 ng/mL for NNDDV, 10.0 to 4000 ng/mL for OHV, and 0.200 to 20.0 ng/mL for NODDV. Briefly, 50 MUL of rat plasma was extracted using liquid-liquid extraction (LLE) with methyl tert-butyl ether (MTBE). The analytes were separated on an Agilent SB Phenyl (50 mm * 4.6 mm, 3.5 MUm) column using a binary gradient of 0.1% formic acid in water versus 0.1% formic acid in acetonitrile at a flow rate of 0.8 mL/min. The method was validated following FDA guidance for bioanalytical method validation. Validated method was successfully applied to a pharmacokinetic study of VEN orally administered to rats. PMID- 29704799 TI - Simultaneous determination of cyclosporine and tacrolimus in human whole blood by ultra-high performance liquid chromatography tandem mass spectrometry and comparison with a chemiluminescence microparticle immunoassay. AB - Overestimation of immunoassays for cyclosporine (CsA) and tacrolimus (TAC) analysis in human whole blood is a problem. The liquid chromatography tandem mass spectrometry is recommended as a golden method for CsA and TAC analysis. The aim of the study is to develop and validate an ultra-high performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) method for simultaneous determination of CsA and TAC in human whole blood and evaluate its agreement with a chemiluminescence microparticle immunoassay (CMIA). The UHPLC-MS/MS method for simultaneous determination of CsA and TAC in human whole blood was developed and validated according to the guidelines. A total of 177 CsA and 220 TAC samples were determined by UHPLC-MS/MS and CMIA, and the agreement of the two methods was evaluated by Bland-Altman plot. The calibration range of UHPLC-MS/MS method was 5 to 2000 ng/mL for CsA and 0.2 to 80 ng/mL for TAC. The inaccuracy and imprecision were -13.33% to 11.80% and <11.74% for CsA and -8.94% to 6.53% and <10.84% for TAC, respectively. Evaluated by Bland-Altman plot, the mean overestimation of CMIA compared to UHPLC-MS/MS was 53.7% for CsA and 48.1% for TAC. PMID- 29704800 TI - Does building resilience in undergraduate nursing students happen through clinical placements? A qualitative study. AB - BACKGROUND: The shortage of nurses has become a global phenomenon, and methods of decreasing the attrition rate of nurses have been explored. Resilience was one of the important factors that increased the retention rate of nurses who stayed in this highly stressful profession. OBJECTIVES: To understand how undergraduate nursing students perceive and experience their clinical placements and to identify the factors that helped them build resilience. DESIGN: A qualitative design utilizing focus group interviews was adopted for this study. PARTICIPANTS: Nineteen third- and fourth-year undergraduate nursing students in a Bachelor of Nursing program participated in this study. SETTING: This study was conducted at a local university in Singapore. METHOD: Four audio-taped focus group interviews were conducted. RESULTS: Students reported that they were stressed while facing challenges head-on during their first clinical placements, mainly due to a lack of peer and clinical support. Gradually, students built resilience overtime and were able to adapt to the ward culture through peer support and reframing coping strategies. CONCLUSION: Nursing students gradually built resilience after accumulating experiences from their clinical placements. Although they eventually adapted well, peer, clinical, and informational support during clinical placements were lacking. Resilience programs that teach positive coping strategies and mindfulness training could be implemented in the undergraduate nursing curriculum. PMID- 29704801 TI - Effect of noise stimulation below and above sensory threshold on postural sway during a mildly challenging balance task. AB - BACKGROUND: Mechanical and electrical sub-sensory noise stimulation applied to the sensory receptors has been shown to improve performance during postural balance tasks. This improvement has been linked with the Stochastic Resonance (SR) phenomenon. It is not clear if noise levels above sensory threshold can also lead to a reduction in postural sway. RESEARCH QUESTION: The aim of this study was to investigate the different effects of sub- and super-sensory electrical noise stimulation applied to the Tibialis Anterior muscle during several repetitions of a mildly challenging single-leg postural balance task. METHODS: Fifteen healthy individuals participated in this study. Participants performed 25 repetitions of a balance tasks where they leaned forward and maintained a pre determined position for 20 s. Each participant experienced 5 different stimulation levels (no-stimulation, 70%, 90%, 110% and 130% of their sensory threshold ST) for 5 times in a randomized order. Optimal stimulation (OS) was defined as the stimulation intensity minimizing the standard deviation of postural sway in the anteroposterior direction. RESULTS: ~57% of the participants presented levels of OS below ST. We did not observe a clear SR-effect, characterized by a U-shaped relationship between the performance metric and the stimulation intensity. OS led to a selective improvement in all the anteroposterior posturographic parameters analyzed. Stimulation below ST led to an improvement in most of the balance features, while stimulation above ST led to an increase in postural sway. SIGNIFICANCE: Our results suggest that OS can be found both below and above ST although stimulation below ST appears to be more effective in reducing postural sway. PMID- 29704802 TI - Frequent retinal ganglion cell damage after acute optic neuritis. AB - BACKGROUND: To identify the extent of ganglion cell damage after first-time optic neuritis (ON) using the inter-ocular difference between affected and fellow eyes, and whether this approach is able to detect more patients suffering from ganglion cell damage than using absolute values. METHODS: Thirty-four patients with first time unilateral ON were followed for a median 413 days. Patients underwent optical coherence tomography testing to determine ganglion cell plus inner plexiform layer thickness (GCIP). Ganglion cell loss was quantified as GCIP difference between ON-affected and fellow eyes (inter-GCIP) and was compared against measurements from 93 healthy controls (HC). Visual function was assessed with high contrast visual acuity; and standard automated perimetry-derived measures of mean deviation and foveal threshold. RESULTS: At clinical presentation after median 19 days from symptom onset, 47.1% of patients showed early GCIP thinning in the ON-affected eye based on inter-GCIP. At the last visit acute ON was associated with 16.1 +/- 10.0 um GCIP thinning compared to fellow eyes (p = 3.669e-06). Based on inter-GCIP, 84.9% of ON patients sustained GCIP thinning in their affected eye at the last visit, whereas using absolute values only 71.0% of patients suffered from GCIP thinning (p = 0.002076). Only 32.3% of these patients had abnormal visual function. The best predictor of GCIP thinning as a measure of ON severity at the last visit was worse visual field mean deviation at clinical presentation. CONCLUSION: Inter-ocular GCIP identifies significantly more eyes suffering damage from ON than absolute GCIP, visual fields or visual acuity loss. Effective interventional options are needed to prevent ganglion cell loss. PMID- 29704803 TI - Identification of cis-regulatory elements by chromatin structure. AB - The systematic identification of cis-regulatory elements (CREs) in plant genomes is critically important in understanding transcriptional regulation during development and in response to environmental cues. Several genome-wide structure based methods have been successfully applied to plant genomes in the past few years. Here, we review recent results on the identification and characterization of CREs in multiple plant species and in different biological processes and discuss future applications of chromatin accessibility data to understand the mechanism, function and evolution of transcriptional regulation networks. PMID- 29704804 TI - Selective concentration for ciprofloxacin resistance in Escherichia coli grown in complex aquatic bacterial biofilms. AB - There is concern that antibiotics in the environment can select for and enrich bacteria carrying acquired antibiotic resistance genes, thus increasing the potential of those genes to emerge in a clinical context. A critical question for understanding and managing such risks is what levels of antibiotics are needed to select for resistance in complex bacterial communities. Here, we address this question by examining the phenotypic and genotypic profiles of aquatic communities exposed to ciprofloxacin, also evaluating the within-species selection of resistant E. coli in complex communities. The taxonomic composition was significantly altered at ciprofloxacin exposure concentrations down to 1 MUg/L. Shotgun metagenomic analysis indicated that mobile quinolone resistance determinants (qnrD, qnrS and qnrB) were enriched as a direct consequence of ciprofloxacin exposure from 1 MUg/L or higher. Only at 5-10 MUg/L resistant E.coli increased relative to their sensitive counterparts. These resistant E. coli predominantly harbored non-transferrable, chromosomal triple mutations (gyrA S83 L, D87N and parC S80I), which confer high-level resistance. In a controlled experimental setup such as this, we interpret effects on taxonomic composition and enrichment of mobile quinolone resistance genes as relevant indicators of risk. Hence, the lowest observed effect concentration for resistance selection in complex communities by ciprofloxacin was 1 MUg/L and the corresponding no observed effect concentration 0.1 MUg/L. These findings can be used to define and implement discharge or surface water limits to reduce risks for selection of antibiotic resistance in the environment. PMID- 29704805 TI - Advanced data mining approaches in the assessment of urinary concentrations of bisphenols, chlorophenols, parabens and benzophenones in Brazilian children and their association to DNA damage. AB - Human exposure to endocrine disrupting chemicals (EDCs) has received considerable attention over the last three decades. However, little is known about the influence of co-exposure to multiple EDCs on effect-biomarkers such as oxidative stress in Brazilian children. In this study, concentrations of 40 EDCs were determined in urine samples collected from 300 Brazilian children of ages 6-14 years and data were analyzed by advanced data mining techniques. Oxidative DNA damage was evaluated from the urinary concentrations of 8-hydroxy-2' deoxyguanosine (8OHDG). Fourteen EDCs, including bisphenol A (BPA), methyl paraben (MeP), ethyl paraben (EtP), propyl paraben (PrP), 3,4-dihydroxy benzoic acid (3,4-DHB), methyl-protocatechuic acid (OH-MeP), ethyl-protocatechuic acid (OH-EtP), triclosan (TCS), triclocarban (TCC), 2-hydroxy-4-methoxybenzophenone (BP3), 2,4-dihydroxybenzophenone (BP1), bisphenol A bis(2,3-dihydroxypropyl) glycidyl ether (BADGE.2H2O), 2,4-dichlorophenol (2,4-DCP), and 2,5-dichlorophenol (2,5-DCP) were found in >50% of the urine samples analyzed. The highest geometric mean concentrations were found for MeP (43.1 ng/mL), PrP (3.12 ng/mL), 3,4-DHB (42.2 ng/mL), TCS (8.26 ng/mL), BP3 (3.71 ng/mL), and BP1 (4.85 ng/mL), and exposures to most of which were associated with personal care product (PCP) use. Statistically significant associations were found between urinary concentrations of 8OHDG and BPA, MeP, 3,4-DHB, OH-MeP, OH-EtP, TCS, BP3, 2,4-DCP, and 2,5-DCP. After clustering the data on the basis of i) 14 EDCs (exposure levels), ii) demography (age, gender and geographic location), and iii) 8OHDG (effect), two distinct clusters of samples were identified. 8OHDG concentration was the most critical parameter that differentiated the two clusters, followed by OH-EtP. When 8OHDG was removed from the dataset, predictability of exposure variables increased in the order of: OH-EtP > OH-MeP > 3,4-DHB > BPA > 2,4-DCP > MeP > TCS > EtP > BP1 > 2,5-DCP. Our results showed that co-exposure to OH-EtP, OH-MeP, 3,4 DHB, BPA, 2,4-DCP, MeP, TCS, EtP, BP1, and 2,5-DCP was associated with DNA damage in children. This is the first study to report exposure of Brazilian children to a wide range of EDCs and the data mining approach further strengthened our findings of chemical co-exposures and biomarkers of effect. PMID- 29704806 TI - Thyroid function, phthalate exposure and semen quality: Exploring associations and mediation effects in reproductive-aged men. AB - BACKGROUND: A normal thyroid physiology is crucial for the maintenance of male reproductive health. Changes in thyroid hormones may represent an intermediate biological mechanism linking phthalate exposure and potential adverse health effects on male reproduction. OBJECTIVE: To investigate the mediating role of thyroid function on the association between phthalate exposure and semen quality. METHOD: Serum thyroid hormones, semen quality and repeated measures of urinary phthalate metabolites were determined among 509 reproductive-aged men in Wuhan, China. Cross-sectional associations between urinary phthalate metabolites, serum thyroid hormones and semen quality were explored using multivariable linear regressions. A mediation analysis was conducted to explore the role of thyroid function on the association of phthalate exposure with semen quality. RESULTS: Significant dose-dependent relationships were found across quartiles of monoethyl phthalate (MEP) with decreasing serum free thyroxine (FT4), which, in turn, was negatively associated with percentage of normal morphology (p for trend = 0.04). Also, we found that the proportions of di-(2-ethylhexyl)-phthalate metabolites excreted as mono-(2-ethylhexyl) phthalate (%MEHP) were negatively associated with serum thyroid-stimulating hormone (TSH) (all p for trends <0.05), which, in turn, was positively associated with progressive and total sperm motility (p for trends = 0.04 and 0.03, respectively). The mediation analysis indicated that higher urinary MEP was significantly associated with a decreasing percentage of normal morphology after controlling for thyroid hormones, and 17% of the association was mediated by serum FT4. CONCLUSIONS: Higher urinary MEP and %MEHP were associated with decreasing serum thyroid hormones, which in turn were associated with altered semen quality. Mediation analysis indicated that serum FT4 was a possible mediator of the association between urinary MEP and proportion of normal sperm morphology. PMID- 29704808 TI - Lobular capillary hemangioma of the mandible: A case report. AB - Lobular capillary hemangiomas are acquired benign vascular neoplasms which typically affect the skin and mucous membranes. While these lesions commonly involve the head and neck, particularly the oral cavity, there are no reports in the literature of lobular capillary hemangioma arising from the mandible. The diagnosis of such a rare entity can therefore be challenging, especially as it may mimic more aggressive lesions, including malignancy. We present a rare case of an 8-year-old male with a lobular capillary hemangioma of the mandible, highlighting its imaging features and discussing the differential diagnosis of primary mandibular lesions in the pediatric population. PMID- 29704807 TI - Applications of low-cost sensing technologies for air quality monitoring and exposure assessment: How far have they gone? AB - Over the past decade, a range of sensor technologies became available on the market, enabling a revolutionary shift in air pollution monitoring and assessment. With their cost of up to three orders of magnitude lower than standard/reference instruments, many avenues for applications have opened up. In particular, broader participation in air quality discussion and utilisation of information on air pollution by communities has become possible. However, many questions have been also asked about the actual benefits of these technologies. To address this issue, we conducted a comprehensive literature search including both the scientific and grey literature. We focused upon two questions: (1) Are these technologies fit for the various purposes envisaged? and (2) How far have these technologies and their applications progressed to provide answers and solutions? Regarding the former, we concluded that there is no clear answer to the question, due to a lack of: sensor/monitor manufacturers' quantitative specifications of performance, consensus regarding recommended end-use and associated minimal performance targets of these technologies, and the ability of the prospective users to formulate the requirements for their applications, or conditions of the intended use. Numerous studies have assessed and reported sensor/monitor performance under a range of specific conditions, and in many cases the performance was concluded to be satisfactory. The specific use cases for sensors/monitors included outdoor in a stationary mode, outdoor in a mobile mode, indoor environments and personal monitoring. Under certain conditions of application, project goals, and monitoring environments, some sensors/monitors were fit for a specific purpose. Based on analysis of 17 large projects, which reached applied outcome stage, and typically conducted by consortia of organizations, we observed that a sizable fraction of them (~ 30%) were commercial and/or crowd-funded. This fact by itself signals a paradigm change in air quality monitoring, which previously had been primarily implemented by government organizations. An additional paradigm-shift indicator is the growing use of machine learning or other advanced data processing approaches to improve sensor/monitor agreement with reference monitors. There is still some way to go in enhancing application of the technologies for source apportionment, which is of particular necessity and urgency in developing countries. Also, there has been somewhat less progress in wide-scale monitoring of personal exposures. However, it can be argued that with a significant future expansion of monitoring networks, including indoor environments, there may be less need for wearable or portable sensors/monitors to assess personal exposure. Traditional personal monitoring would still be valuable where spatial variability of pollutants of interest is at a finer resolution than the monitoring network can resolve. PMID- 29704809 TI - Causative factors, imaging findings, and CT course of round atelectasis. AB - OBJECTIVE: To assess causative factors, associated imaging findings, and CT course of round atelectasis (RA). MATERIALS AND METHODS: We retrospectively reviewed CT reports for "round" or "rounded atelectasis" over a 5-year time frame. Patients with at least 2 CT scans a minimum of 6 months apart were included. Electronic medical records and clinical and imaging follow-up was reviewed for all cases. RESULTS: Study population included 50 individuals with mean age of 63 years, and 59 unique instances of RA. The most commonly associated etiologies were hepatic hydrothorax (26%, n = 13) and asbestos exposure (26%), followed by post-infectious pleural inflammation (22%), congestive heart failure (12%), and end stage renal disease (8%). RA was found in the right lower lobe in over half of cases (n = 30). Association with one or more pleural abnormality was identified in all cases, including thickening (88%), fluid (60%), or calcification (40%). Nearly one third (n = 19) demonstrated intra-lesional calcification. In those who underwent PET/CT (20%), lesions demonstrated an average SUV of 2.2 (range 0-7.8). CT course over mean follow up of 32 months (range 6-126 months), demonstrated RA to remain stable (n = 26) or decrease (n = 26) in size in the majority (88%) of cases. CONCLUSION: Round atelectasis may arise from diverse etiologies beyond asbestos, and will most often decrease or remain stable in size over serial exams. Accurate identification may obviate the need for added diagnostic interventions. PMID- 29704810 TI - Differentiation of benign and metastatic axillary lymph nodes in breast cancer: additive value of shear wave elastography to B-mode ultrasound. AB - OBJECTIVES: The purpose of this study is to evaluate the additive value of shear wave elastography (SWE) for differentiating benign and metastatic axillary lymph nodes (LNs) in breast cancer. MATERIALS AND METHODS: The area under the receiver operating characteristic curve, sensitivity, and specificity of B-mode US, SWE, and combined modality were compared for 54 suspicious LNs. RESULTS: After combining information from SWE, sensitivity was significantly higher for combined modality than for B-mode US alone (94.12% vs. 82.35%, p = 0.046) without a decrease in specificity. CONCLUSION: Combined B-mode US and SWE may improve detection of metastatic axillary LNs in patients with breast cancer. PMID- 29704811 TI - Involvement of ion channels in allergy. AB - Allergic asthma is a complex disease, often characterized by an inappropriate Th2 response to normally harmless allergens. Epithelial cells damaged or activated by the allergen produce IL-33, TSLP and IL-25, activating ILC2 and dendritic cells. The latter migrate into lymph nodes where they induce Th2-cell commitment. Th2 and other type 2 innate inflammatory cells trigger inflammation and airway hyper reactivity. The toolbox consisting of the ion channels varies from one cellular type to another and depends on its activation state, offering the possibility to design novel drugs in the field of allergy. We will discuss about some channels as calcium, nonselective cation, potassium and chloride channels that appear as good candidates in allergy. PMID- 29704812 TI - A theoretical study on ionization of sartans in aqueous media and on interactions with surfactant micelles. AB - The ionization order of sartans in aqueous media and possible way of interactions between their equilibrium forms and surfactant micelles have been theoretically investigated. The examined sartans are ampholytes (irbesartan and losartan) and a diacid (valsartan) with the close values of ionization constants. In order to get a better insight in the overlapped protolytic equilibria of sartans and to predict an affinity of the equilibrium forms interacting with micelles as biomembrane mimetic systems, the theoretical study was performed. Energy calculation of the optimized structures of the equilibrium forms was performed at the B3LYP/6-31G (d,p) level of the Density Functional Theory (DFT). The results of the theoretical study helped to assign the experimentally determined pKa values to the corresponding ionizable centers and confirmed that in all examined compounds, the higher pKa values can be attributed to ionization of tetrazole. The molecular descriptor values showed that sartans interact predominantly with the micelle surfaces. The equilibrium forms of ampholytes demonstrate higher affinity to the micelles, as compared to the forms of the diprotic acid. Additionally, it was shown that the uncharged molecular forms of ampholytes are more lipophylic then their zwitterionic forms. PMID- 29704813 TI - Opportunistic prophylactic salpingectomy for prevention of ovarian cancer: What do national societies advise? AB - OBJECTIVE: To determine how many FIGO (International Federation of Obstetrics and Gynecology) member societies have statements regarding opportunistic (incidental, prophylactic, risk-reducing) salpingectomy at the time of benign gynecologic surgery and to categorize statements as positive, negative or ambivalent. STUDY DESIGN: The websites of the 130 FIGO member societies were searched for statements on opportunistic salpingectomy. We looked for separate statements and statements embedded in other documents such as clinical guidelines as well as statements by national societies of gynecologic oncology. If nothing was found on the websites we contacted societies by Email or fax. RESULTS: As of early 2018, 13 FIGO member societies representing 14 countries have statements regarding opportunistic salpingectomy. Nine were separate, stand-alone statements, four were embedded in other documents. Nine of the 13 statements (from Canada, Finland, U.S.A., Great Britain, Australia and New Zealand, Denmark, Austria, Turkey, and Japan) support consideration of opportunistic salpingectomy in appropriate women and four (from Germany, Sweden, Norway, and France) are ambivalent; there are no statements recommending against opportunistic salpingectomy. CONCLUSION: In 2018 only a small minority of FIGO members have statements on opportunistic prophylactic salpingectomy. These statements are ambivalent or supportive, none is negative. PMID- 29704814 TI - Developing and validating a prognostic index predicting re-hospitalization of patients with Hyperemesis Gravidarum. AB - OBJECTIVE: Hyperemesis Gravidarum (HG) can have adverse effects on pregnant women's quality of life and is the main cause for hospitalization in the first half of the pregnancy. Between 19%-30% of the women admitted to hospital return for a second hospitalization during their pregnancy. These hospitalizations create a burden on the health system and are associated with high health care costs. The aim of this study was to develop a prediction tool that predicts re hospitalization of women with HG and to validate it. STUDY DESIGN: A retrospective cohort study was conducted. The data was retrieved from the computerized information systems of two medical centers in Israel and included all women who were hospitalized between 2010 and 2012 with HG. Two thirds formed the training set and one third formed the validation set. Risk factors for re hospitalization were determined based on a logistic regression model. Using the regression coefficient of each risk factor, a total score was calculated for each woman. The index was validated using logistic regression, c-statistic and Chi square for trend test. RESULTS: 282 women were included in the study, 37.6% of which were re-hospitalized. Three risk factors were included in the final index and were given a score: gestational age (2); length of hospitalization (1) and HG during previous pregnancies/first pregnancy (1). Each subject received a total score between 0 and 4. Re-hospitalization rates in the training set increased from 13.6% to 65% for scores 0 and 4, respectively. Validation testing showed: c statistic-0.678 and Chi-square for trend, p < 0.001 (training set); c-statistic 0.622 and Chi-square for trend p = 0.036 (validation set). CONCLUSIONS: The developed index is a simple tool, based on few parameters and has a high level of accuracy. It potentially helps reduce hospitalization costs, assists in identifying women at risk of re-hospitalization, improves their treatment plan and prevents another admission to the hospital. PMID- 29704815 TI - Thoracic endometriosis syndrome: Comparison between catamenial pneumothorax or endometriosis-related pneumothorax and catamenial hemoptysis. AB - OBJECTIVES: To evaluate the clinical features of thoracic endometriosis syndrome (TES) represented by catamenial pneumothorax (CP), endometriosis-related pneumothorax (ERP), and catamenial hemoptysis (CH). STUDY DESIGN: In this retrospective study, we enrolled 25 patients with TES, 18 of whom had CP/ERP and 7 had CH, to investigate the clinical presentation, effectiveness of treatment, and recurrence rates in these disorders. RESULTS: The age at onset was significantly lower in patients with CH than in patients with CP/ERP (P < 0.05). In 94.4% of patients with CP/ERP, pneumothorax was observed on either the right side or bilaterally, however there was no tendency toward laterality of CH among our cases. In our study, patients with CP/ERP predominantly underwent surgical management and the recurrence rate during treatment was higher in patients with CP/ERP than in those with CH. We found that the recurrence frequency of CP/ERP was lowest under the combination therapy with thoracic surgery and postoperative hormonal therapy. CONCLUSION: Our findings suggest that CP/ERP and CH are different pathological conditions and CP/ERP is more difficult to manage than CH. PMID- 29704816 TI - The role of macroplastique implantation in the management of occult urinary stress incontinence. AB - OBJECTIVE: Pelvic floor disorders, in particular pelvic organ prolapse (POP) and stress urinary incontinence (SUI), are common in women. There is a described higher risk to develop postoperative SUI also in preoperatively continent women: this happens because in 30% of women the relief of the urethral obstruction caused by prolapse, unmasks a pre-existing compromised urethral function and thus an "occult" or potential SUI. The aims of this study were to evaluate the role of Macroplastique(r) implant, TVT-O or surgery alone in the management of occult urinary stress incontinence during prolapse surgery in terms of success rate and adverse events. STUDY DESIGN: We enrolled 47 consecutive patients scheduled to vaginal prolapse surgery who did not report symptoms of stress incontinence. We collected surgical data, success and complication rates. Moreover we compared all the data with retrospective ones regarding surgery plus concomitant TVT-O (39 pts) and surgery alone (41 pts). RESULTS: At 12-months follow-up, we reported a success rate of 87,2% in the "macroplastique group", comparable to the "surgery plus TVT-O group", with a statistically significant difference in comparison to the "surgery alone" group. "Surgery + TVT-O" group reported a higher rate of major complications (p<0,01) in comparison to the other groups. CONCLUSIONS: Postoperative SUI prevention at the time of prolapse repair remains a challenging issue. In selected patients, Macroplastique may play an interesting role having a good success rate and a low complication rate and for these reasons it may be proposed as A concomitant procedure during POP surgery. PMID- 29704818 TI - Serum C1q/TNF-related protein 9 is not related to nonalcoholic fatty liver disease. AB - AIMS: C1q/TNF-related protein 9 (CTRP9) is an adipokine mainly secreted by white adipose tissue and plays protective roles in energy metabolism. However, information regarding the role of CTRP9 in nonalcoholic fatty liver disease (NAFLD) is scarce. Here we aimed to ascertain the clinical relevance between circulating CTRP9 levels and NAFLD through a cross-sectional study. METHODS: The study enrolled 82 NAFLD adults and 79 sex- and age-matched non-NAFLD controls. Serum CTRP9 was measured via ELISA method. Metabolic parameters were also determined. RESULTS: Although serum CTRP9 level seems to be higher in NAFLD adults, there was no significant difference among the ultrasonographic degrees of NAFLD (P = 0.275). Further, after adjustment for BMI in the multinomial logistic regression model, no significant odds ratio difference was observed for NAFLD among the CTRP9 tertiles. Moreover, binary logistic regression models demonstrated that, body mass index (BMI) and alanine aminotransferase (ALT) but not CTRP9 were independent factors related to NAFLD. Besides, serum CTRP9 was positively correlated with BMI, waist circumference, Fasting insulin, HbA1c, and HOMA-IR in all subjects. BMI was the independent factor associated with serum CTRP9. CONCLUSIONS: Serum CTRP9 is not independently related to NAFLD. The association between serum CTRP9 and NAFLD might be due to the influence of obesity. PMID- 29704817 TI - Association between interleukin-6, C-reactive protein and adiponectin with adiposity: Findings from the 1993 pelotas (Brazil) birth cohort at 18 and 22 years. AB - BACKGROUND: Most of the literature has shown a direct association between adiposity, interleukin-6 (IL-6) and C-reactive protein (CRP), and an inverse association with adiponectin. The aim of this paper was to assess the association of obesity measurements and IL-6, CRP and adiponectin. METHODS: We performed cross-sectional/longitudinal analysis in the 1993 Birth Cohort in Brazil. Associations between IL-6 (pg/mL), CRP (mg/L) and adiponectin (ug/Ml) with body mass index (BMI), waist circumference (WC), percentage total fat mass (FM) (BODPOD) and trunk FM (DXA) were verified. Four trajectory variables were generated: (a) highest tertile/obesity according to BMI in both follow-ups; (b) highest tertile/obesity only at 18 years; (c) highest tertile/obesity only at 22 years; (d) not in the highest tertile/not obese at both ages. RESULTS: We found a direct association for IL-6 and CRP and an inverse association for adiponectin with measures of adiposity. For instance, for females, the highest mean IL-6 and CRP, respectively, was for those who had been in the obese category at 18-22 years (2.49; 3.75), in the highest tertile of WC (2.11; 3.08), in the highest % of FM (1.56; 3.30 l), and in the highest tertile of trunk FM (2.07; 3.26) (p < 0.001 for all these results in the adjusted analysis). Adiponectin showed an inverse association for the above variables, with lower mean values for males than females. CONCLUSION: There was a longitudinal and direct association between adiposity and IL-6 and CRP, and an inverse association with adiponectin at 22 years. PMID- 29704819 TI - Comprehensive cytokine profiling provides evidence for a multi-lineage Th responses in Guillain Barre Syndrome. AB - Guillain Barre Syndrome (GBS) is one of the commonest acquired immune-mediated neuropathies, often preceded by infections. Although cellular immune responses are shown to substantially account for the pathophysiology of GBS, the precise mechanistic basis of risk and disease course remains enigmatic till date. Cytokines are best known for their abilities to drive cellular immunity and inflammation through their co-ordinated actions. Data obtained from clinical and animal model studies suggest important implications of some of the cytokines in the progression and recovery of GBS. However, these studies were performed on few cytokines and small set of GBS patients, thereby lacking a complete understanding of the patterns of association of cytokines representing Th1, Th2, and Th17 responses with GBS. We studied 65 well-characterized GBS patients and 73 age- and sex-matched healthy controls. A panel of 15 cytokines representing Th1, Th2 and Th17 pathways was assayed using Multiplex Suspension Array platform. Plasma levels of five cytokines were found to be altered in GBS patients compared to healthy control subjects: (i) IL-1beta exhibited reduced levels, and (ii) IFN gamma, IL-4, IL-21 and IL-33 were elevated in GBS patients. The most important finding of this study was up-regulated expression of IL-21 and IL-33 in patients with GBS. Given the role of IL-33 as an alarmin, the elevated level of this cytokine provides important indication about a much broader role of cytokines in GBS. This study also provides evidence towards a multi-lineage Th cells (Th1, Th2 and Th17) associated cytokine responses in the pathophysiology of GBS. PMID- 29704820 TI - Upregulation of osteopontin expression via the interaction of macrophages and fibroblasts under IL-1b stimulation. AB - BACKGROUND: Fibrosis is attributed to dysregulation of tissue-remodeling. In remodeling areas, fibroblasts and macrophages actively make contact with each other. Osteopontin (OPN) is a pro-fibrotic molecule, whose expression is upregulated by interleukin (IL)-1beta via secretion of its downstream cytokines, such as IL-6. Here, we investigated the effect of interaction between fibroblasts and macrophages under IL-1beta stimulation on the expression of OPN. METHODS: We used human lung fibroblasts and THP-1 macrophages differentiated from THP-1 cells using phorbol 12-myristate 13-acetate. These cells were either cultured alone or co-cultured under IL-1beta stimulation. Secretion of OPN and IL-6 were examined by enzyme-linked immunosorbent assay, and mRNA expression was assessed by quantitative real-time PCR. The effects of siRNA against IL-6 or OPN on OPN expression were evaluated. RESULTS: OPN expression increased when fibroblasts and THP-1 macrophages were co-cultured under IL-1beta stimulation. The siRNA against IL-6 in fibroblasts suppressed the upregulation of OPN expression during co culture, whereas siRNA against IL-6 in THP-1 macrophages did not. The upregulation of expression of OPN mRNA in fibroblasts or THP-1 macrophages when co-cultured under IL-1beta stimulation was mediated by IL-6 from fibroblasts. OPN from THP-1 macrophages was involved in the increase of OPN expression in fibroblasts. CONCLUSIONS: The present study revealed the crosstalk between fibroblasts and THP-1 macrophages under IL-1beta stimulation, where IL-6 from fibroblasts, stimulated by IL-1beta, upregulated OPN expression in fibroblasts themselves via increase in OPN from THP-1 macrophages. The fibroblasts/macrophages network may induce activation or qualitative changes in both cells, which contributes to inflammation-associated fibrosis. PMID- 29704821 TI - Chemokine receptor antagonist block inflammation and therapy Japanese encephalitis virus infection in mouse model. AB - Japanese encephalitis (JE) is a viral encephalitis disease caused by infection with the Japanese encephalitis virus (JEV). The virus can cross the blood-brain barrier and cause death or long-term sequela in infected humans or animals. In this study, we first investigated the distribution of JEV infection in brain and further analyzed the dynamic change in inflammation related genes, chemokines, as well as pathological characteristics. Results demonstrated that CCR2 and CCR5 antagonist could significantly inhibit the inflammation. The mice treated with CCR2 and CCR5 antagonists had a higher survival rate between 60% and 70%, respectively. In summary, our study thoroughly illustrated the characteristics of the dynamic change in inflammation related genes and chemokines induced by JEV infection. We further indicated that CCR5 and CCR2 are potential targets for treatment of JE. PMID- 29704822 TI - Development of a novel radiobromine-labeled sigma-1 receptor imaging probe. AB - INTRODUCTION: Sigma-1 receptor is a target for tumor imaging. In a previous study, we synthesized a vesamicol analog, (+)-2-[4-(4 bromophenyl)piperidino]cyclohexanol [(+)-pBrV], with a high affinity for sigma-1 receptor, and synthesized radiobrominated (+)-pBrV. This radiobrominated (+)-pBrV showed high tumor uptake in tumor-bearing mice; however, radioactivity accumulation in normal tissues, such as the liver, was high. We assumed that the accumulation of (+)-pBrV in the non-target tissues was partially derived from its high lipophilicity; therefore, we synthesized and evaluated (+)-4-[1-(2 hydroxycyclohexyl)piperidine-4-yl]-2-bromophenol [(+)-BrV-OH], which is a more hydrophilic compound. Although we aimed to develop a PET tracer using 76Br, in these initial studies, we used 77Br because of its longer half-life. METHODS: (+) [77Br]BrV-OH was synthesized using the chloramine-T method with a radiochemical purity of 95%. Lipophilicity and affinity for sigma-1 receptor of (+)-[77Br]BrV OH were determined, and biodistribution experiments were performed. We also performed an in vivo blocking study by co-injecting excess amounts of the sigma-1 receptor ligand, SA4503, into mice. RESULTS: The lipophilicity and affinity for sigma-1 receptor of (+)-[77Br]BrV-OH were lower than those of (+)-[77Br]pBrV. (+) [77Br]BrV-OH also showed high tumor uptake in biodistribution experiments in DU 145 tumor-bearing mice,. Although (+)-[77Br]pBrV was retained in most tissues, (+)-[77Br]BrV-OH was cleared from these tissues. In blocking studies, the co injection of SA4503 significantly decreased the tumor uptake of (+)-[77Br]BrV-OH. CONCLUSION: These results indicate that (+)-[76Br]BrV-OH has potential as a PET probe for sigma-1 receptor imaging. PMID- 29704823 TI - 13C-labelled yeast as internal standard for LC-MS/MS and LC high resolution MS based amino acid quantification in human plasma. AB - Extracts from isotopically labelled organisms can be a versatile source for isotopically labelled chemical compounds providing ideal internal standards in mass spectrometry based assays. In this work, the application of 13C enriched yeast (Pichia pastoris) for accurate absolute metabolite quantification in human samples was investigated. >99% 13C enriched Pichia pastoris was produced via fermentation and extracted employing established protocols. Quantitative assays based on LC-triple quadrupole mass spectrometry (QQQ-MS) and LC-high resolution mass spectrometry (HRMS) were validated using the Standard Reference Material, SRM 1950 - metabolites in frozen human plasma. 14 amino acids (as given in the certificate) were quantified using separations by reversed phase liquid chromatography (RPLC) and hydrophilic interaction liquid chromatography (HILIC). The latter chromatographic separation provided retention and selectivity for the amino acid panel, while the studied approaches employing RPLC relied on the selectivity of the MS detection. Cross-validation using the different MS platforms showed that in all cases the application of in-vivo labelled standards resulted in a significant improvement of trueness and precision. LODs and LOQs ranged, regardless of the detection system and addition of internal standards, in the same order of magnitude. The linear dynamic range of the employed detection systems was enhanced at least for one order of magnitude for several analytes when the internal standards were applied. PMID- 29704824 TI - The mitochondrial oxidoreductase CHCHD4 is present in a semi-oxidized state in vivo. AB - Disulfide formation in the mitochondrial intermembrane space is an essential process catalyzed by a disulfide relay machinery. In mammalian cells, the key enzyme in this machinery is the oxidoreductase CHCHD4/Mia40. Here, we determined the in vivo CHCHD4 redox state, which is the major determinant of its cellular activity. We found that under basal conditions, endogenous CHCHD4 redox state in cultured cells and mouse tissues was predominantly oxidized, however, degrees of oxidation in different tissues varied from 70% to 90% oxidized. To test whether differences in the ratio between CHCHD4 and ALR might explain tissue-specific differences in the CHCHD4 redox state, we determined the molar ratio of both proteins in different mouse tissues. Surprisingly, ALR is superstoichiometric over CHCHD4 in most tissues. However, the levels of CHCHD4 and the ratio of ALR over CHCHD4 appear to correlate only weakly with the redox state, and although ALR is present in superstoichiometric amounts, it does not lead to fully oxidized CHCHD4. PMID- 29704825 TI - Respiratory analysis of coupled mitochondria in cryopreserved liver biopsies. AB - The aim of this work was to develop a cryopreservation method of small liver biopsies for in situ mitochondrial function assessment. Herein we describe a detailed protocol for tissue collection, cryopreservation, high-resolution respirometry using complex I and II substrates, calculation and interpretation of respiratory parameters. Liver biopsies from cow and rat were sequentially frozen in a medium containing dimethylsulfoxide as cryoprotectant and stored for up to 3 months at -80 degrees C. Oxygen consumption rate studies of fresh and cryopreserved samples revealed that most respiratory parameters remained unchanged. Additionally, outer mitochondrial membrane integrity was assessed adding cytochrome c, proving that our cryopreservation method does not harm mitochondrial structure. In sum, we present a reliable way to cryopreserve small liver biopsies without affecting mitochondrial function. Our protocol will enable the transport and storage of samples, extending and facilitating mitochondrial function analysis of liver biopsies. PMID- 29704826 TI - Premenstrual syndrome and sleep disturbances: Results from the Sao Paulo Epidemiologic Sleep Study. AB - The aim of this study is to compare sleep characteristics between women with premenstrual syndrome (PMS) and a control group. The data were extracted from an epidemiologic survey conducted in Sao Paulo (EPISONO), Brazil, which used subjective assessments and objective polysomnography records to analyze subjects' sleep pattern. Subjective questionnaires used in this study were Women's Questionnaire, Pittsburgh Sleep Quality Index, Epworth sleepiness scale, Insomnia Severity Index and the general sleep questionnaire. The presence of PMS was obtained by a direct question in the Women's Questionnaire. The survey included 230 women, of whom 72.6% reported PMS. The PMS group had poorer sleep quality, a higher perception of unrefreshing sleep and more subthreshold insomnia. Participants with PMS had an increased total sleep time recorded by polysomnography and a lower saturation of peripheral oxygen. It is still unkown the mechanism behind PMS and the sleep-wake cycle. In the other hand, it is clear that PMS play a role in sleep, since women with this disorder has a poor quality of sleep and it is not refreshing. Better knowledge about this syndrome and its outcomes can help to improve their well-being and develop more precise therapeutic approaches. PMID- 29704827 TI - Development and clinical verification of numerical simulation for laser in situ keratomileusis. AB - To develop and validate numerical models of the laser in situ keratomileusis (LASIK) procedure through considering its effect on corneal biomechanical behavior. 3D finite element models of the human eye were developed to simulate LASIK. The models' predictions of post-operative corneal elevation, corneal refractive power with vector decomposition (M-c-pos, J0-c-pos, J45-c-pos) and refractive error correction (M-rec, J0-rec, J45-rec) were compared against clinical data obtained for 28 eyes of 28 patients. A parallel exercise was conducted to estimate the post-operative corneal shape using a shape subtraction method (SSM) - which does not consider the effects of LASIK on corneal mechanical behavior - and the results are compared with the finite element method (FEM). A significant decrease in elevation differences between FEM predictions and clinical data was found compared with the differences between SSM results and clinical data (p = 0.000). In addition, there were no significant differences in post-operative equivalent sperical corneal refractive power between FEM results and corresponding clinical data (M-c-pos: p = 0.501), while SSM showed significant differences with clinical data (M-c-pos: p = 0.000). Further, FEM achieved a predicted value of M-c-pos within +/- 1.00D accuracy in 100% of cases, compared with 57% achieved by the SSM. M-rec predicted by FEM was not significantly different from clinical results (p = 0.085), while SSM overestimated it (p = 0.000). The match between LASIK numerical model predictions with clinical measurements improved significantly when the procedure's effect on corneal biomechanical behavior was considered. This outcome has important implications on efforts to develop planning tools for refractive surgery. PMID- 29704828 TI - A computational parametric study on edge loading in ceramic-on-ceramic total hip joint replacements. AB - Edge loading in ceramic-on-ceramic total hip joint replacement is an adverse condition that occurs as the result of a direct contact between the head and the cup rim. It has been associated with translational mismatch in the centres of rotation of the cup and head, and found to cause severe wear and early failure of the implants. Edge loading has been considered in particular in relation to dynamic separation of the cup and head centres during a gait cycle. Research has been carried out both experimentally and computationally to understand the mechanism including the influence of bearing component positioning on the occurrence and severity of edge loading. However, it is experimentally difficult to measure both the load magnitude and duration of edge loading as it occurs as a short impact within the tight space of hip joints. Computationally, a dynamic contact model, for example, developed using the MSC ADAMS software for a multi body dynamics simulation can be particularly useful for calculating the loads and characterising the edge loading. The aim of the present study was to further develop the computational model, and improve the predictions of contact force and the understanding of mechanism in order to provide guidance on design and surgical factors to avoid or to reduce edge loading and wear. The results have shown that edge loading can be avoided for a low range of translational mismatch in the centres of rotation of the cup and head during gait at the level of approximately 1.0 mm for a cup at 45 degrees inclination, keeping a correct cup inclination at 45 degrees is important to reduce the edge loading severity, and edge loading can be avoided for a certain range of translational mismatch of the cup and head centres with an increased swing phase load. PMID- 29704829 TI - Where does Munch flow begin? Sucrose transport in the pre-phloem path. AB - Current conceptions of sucrose export largely neglect the effect of transpiration induced water potential gradients within leaf mesophyll, even as the mix of convection and diffusion in the pre-phloem path remains uncertain. It is also generally held that the relative importance of convection and diffusion in the pre-phloem path is controlled by the ratio of their respective mass transfer coefficients. Here, we consider pre-phloem sucrose transport in the presence of adverse water potential gradients, finding that whether convection impedes or aids sucrose delivery to the phloem is independent of the permeability of the plasmodesmata to bulk flow, and depends only on assimilation rate, path-length, and the diffusivity. For most tissues subject to transpiration, convection through plasmodesmata pushes sugar away from the phloem. PMID- 29704830 TI - The rendez-vous of mobile sieve-element and abundant companion-cell proteins. AB - Thousands of sieve tube exudate proteins (STEP) have now been identified and predicted to fulfill a diversity of functions. However, most STEPs should be considered putative, since methods to collect sieve tube exudates have many technical drawbacks, and advanced functional characterization will be required to distinguish contaminant from bonafide proteins, and determine the latter's location and activity in sieve elements (SE). One major challenge is to develop new approaches to elucidate the function of these SE proteins, which in turn, is expected to shed light on intriguing aspects of SE cell biology. PMID- 29704831 TI - The first sustainable material designed for air particulate matter capture: An introduction to Azure Chemistry. AB - This work presents a new porous material (SUNSPACE) designed for air particulate matter (PM) capture. It was developed in answer to the European Commission request of an innovative, affordable, and sustainable solution, based on design driven material, to reduce the concentration of air particulate matter in urban areas. SUNSPACE material was developed from by-products and low-cost materials, such as silica fume and sodium alginate. Its capability to catch ultrafine PM was evaluated by different ad-hoc tests, considering diesel exhaust fumes and incense smoke PM. Despite the fact that procedures and materials can be designed for remediation, the high impact on the environment, for example in terms of natural resources consumption and emissions, are not usually considered. Instead, we believe that the technologies must be always evaluated in terms of material embodied energy (EE) and carbon footprint (CF). We define our approach to solve environment problems by a sustainable methodology "Azure Chemistry". For the SUNSPACE synthesis, the multi-criteria decision analysis was performed to select the best sustainable solution. The emissions and the energies involved in the synthesis of SUNSPACE material were evaluated with the Azure Chemistry approach, showing that this could be the best available technology to face the problem of capturing the PM in urban area. PMID- 29704832 TI - Fabrication of novel sandwich nanocomposite as an efficient and regenerable adsorbent for methylene blue and Pb (II) ion removal. AB - An adsorbent, which is easy to be separated and reused after adsorption, is very important for the removal of pollutants in aqueous solution. Hence, a novel nanofibrous sandwich structured adsorbent of silica nanofiber/magnetite nanoparticles/porous silica (SNF/MNP/PS) was designed and synthesized for the first time. The magnetite nanoparticles with diameter less than 10 nm were evenly distributed on the surface of silica nanofiber, which was subsequently fully covered by a layer of porous silica. The novel adsorbent was proved possessing good adsorption capacity for both methylene blue (MB) and Pb (II) ion (Pb2+), and the adsorption equilibrium could be well described by the Langmuir-isotherm model with the maximum adsorption capacity of 103.1 mg/g for MB and 243.9 mg/g for Pb2+ at 288 K. Moreover, in MB-Pb2+ mixed system the measured adsorption capacity reached 74.5 mg/g for MB and 202.4 mg/g for Pb2+, respectively. The saturated adsorbent could be readily magnetically separated from the solution and then efficiently regenerated by heterogeneous Fenton-like reaction (for MB) or acidic desorption process (for Pb2+), respectively. After 5 cycles of adsorption regeneration, the adsorption capacity of the reused adsorbent still reached 81.0% (for MB) and 70.9% (for Pb2+) of the initial value. The SNF/MNP/PS behaves good adsorption properties for different types of pollutants, high magnetic recoverability and regeneration efficiency, which make it applicable to different contaminants removal. PMID- 29704833 TI - Regeneration of Salicaceae riparian forests in the Northern Hemisphere: A new framework and management tool. AB - Human activities on floodplains have severely disrupted the regeneration of foundation riparian shrub and tree species of the Salicaceae family (Populus and Salix spp.) throughout the Northern Hemisphere. Restoration ecologists initially tackled this problem from a terrestrial perspective that emphasized planting. More recently, floodplain restoration activities have embraced an aquatic perspective, inspired by the expanding practice of managing river flows to improve river health (environmental flows). However, riparian Salicaceae species occupy floodplain and riparian areas, which lie at the interface of both terrestrial and aquatic ecosystems along watercourses. Thus, their regeneration depends on a complex interaction of hydrologic and geomorphic processes that have shaped key life-cycle requirements for seedling establishment. Ultimately, restoration needs to integrate these concepts to succeed. However, while regeneration of Salicaceae is now reasonably well-understood, the literature reporting restoration actions on Salicaceae regeneration is sparse, and a specific theoretical framework is still missing. Here, we have reviewed 105 peer reviewed published experiences in restoration of Salicaceae forests, including 91 projects in 10 world regions, to construct a decision tree to inform restoration planning through explicit links between the well-studied biophysical requirements of Salicaceae regeneration and 17 specific restoration actions, the most popular being planting (in 55% of the projects), land contouring (30%), removal of competing vegetation (30%), site selection (26%), and irrigation (24%). We also identified research gaps related to Salicaceae forest restoration and discuss alternative, innovative and feasible approaches that incorporate the human component. PMID- 29704834 TI - Ecological research and environmental management: We need different interfaces based on different knowledge types. AB - The role of ecological science in environmental management has been discussed by many authors who recognize that there is a persistent gap between ecological science and environmental management. Here we develop theory through different perspectives based on knowledge types, research categories and research management interface types, which we combine into a common framework. To draw out insights for bridging this gap, we build our case by:We point out the complementarities as well as the specificities and limitations of the different types of ecological research, ecological knowledge and research-management interfaces, which is of major importance for environmental management and research policies. PMID- 29704835 TI - Competing pathways to sustainability? Exploring conflicts over mine establishments in the Swedish mountain region. AB - Natural resource (NR) exploitation often gives rise to conflict. While most actors intend to manage collectively used places and their NRs sustainably, they may disagree about what this entails. This article accordingly explores the origin of NR conflicts by analysing them in terms of competing pathways to sustainability. By comparing conflicts over mine establishments in three places in northern Sweden, we specifically explore the role of place-based perceptions and experiences. The results indicate that the investigated conflicts go far beyond the question of metals and mines. The differences between pathways supporting mine establishment and those opposing it refer to fundamental ideas about human-nature relationships and sustainable development (SD). The study suggests that place-related parameters affect local interpretations of SD and mobilisation in ways that explain why resistance and conflict exist in some places but not others. A broader understanding of a particular conflict and its specific place-based trajectory may help uncover complex underlying reasons. However, our comparative analysis also demonstrates that mining conflicts in different places share certain characteristics. Consequently, a site-specific focus ought to be combined with attempts to compare, or map, conflicts at a larger scale to improve our understanding of when and how conflicts evolve. By addressing the underlying causes and origins of contestation, this study generates knowledge needed to address NR management conflicts effectively and legitimately. PMID- 29704836 TI - BaP-metals co-exposure induced tissue-specific antioxidant defense in marine mussels Mytilus coruscus. AB - Both benzo(alpha)pyrene (BaP) and metals are frequently found in marine ecosystem and can cause detrimental effects in marine organism, especially the filter feeder-marine mussels. Although the biological responses in mussels have been well-studied upon the single metal or BaP exposure, the information about antioxidant defense, especially in different tissues of mussels, are still limited. Considering the variety of contaminants existing in the actual marine environment, single BaP (56 MUg/L) and the co-exposure with Cu, Cd and Pb (50 MUg/L, 50 MUg/L and 3 mg/L respectively) were applied in a 6 days exposure followed by 6 days depuration experiment. The alterations of superoxide dismutase (SOD), catalase (CAT) activities and total antioxidant capacity (TAC) level were assessed in haemolymph, gills and digestive glands of marine mussels, Mytilus coruscus. An unparalleled change in antioxidant biomarkers was observed in all cells/tissues, with the SOD activity showing higher sensitivity to exposure. A tissue-specific response showing unique alteration in gill was investigated, indicating the different function of tissues during stress responses. Depressed antioxidant effects were induced by BaP-metals co-exposure, indicating the interaction may alter the intact properties of BaP. To our knowledge, this is the first research to explore the antioxidant defense induced by combined exposure of BaP-metals regarding to tissue-specific responses in marine mussels. The results and experimental model will provide valuable information and can be utilized in the investigation of stress response mechanisms, especially in relation to tissue functions in marine organism in the future. PMID- 29704837 TI - Degradation of Acid Orange 7 by peroxymonosulfate activated with the recyclable nanocomposites of g-C3N4 modified magnetic carbon. AB - Carbon-based catalysts have attracted high attention since they are greener and cheaper, while magnetic nanomaterials are very useful in environmental application because of the easy recovery and operation given by the magnetic separability. Therefore, graphitic carbon nitride modified magnetic carbon nanocomposites Fe3O4@C/g-C3N4 was prepared herein for the first time as a new carbon-based catalyst for the activation of peroxymonosulfate (PMS). The catalytic properties of Fe3O4@C/g-C3N4 in activating PMS for the degradation of Acid Orange 7 (AO 7), a model organic pollutant, were investigated. AO 7 degradation efficiency was significantly enhanced after modification of Fe3O4@C with g-C3N4, and the composite Fe3O4@C/g-C3N4 from loading of 5 wt% g-C3N4 and calcined at 300 degrees C for 30 min exhibited the best performance. AO 7 could be efficiently decolorized using the "Fe3O4@C/C3N4 (5%) + PSM" system within the pH range of 2-6, and 97% of AO 7 could be removed in 20 min without pH adjustment (pH = 4). Radical quenching and EPR studies confirmed that both sulfate and hydroxyl radicals produced from PMS activation were the active species responsible for the oxidation of AO 7. The degradation mechanism was suggested based on the experimental results and XPS analyses. It was proposed that the CO groups on the carbon surface of Fe3O4@C rather than the CO in g-C3N4 played a key role as the active sites for PMS activation. The catalyst was magnetically separable and displayed good stability and reusability, thus providing a potentially green catalyst for sustainable remediation of organic pollutants. PMID- 29704839 TI - Mineralogical controls on mobility of rare earth elements in acid mine drainage environments. AB - Rare earth elements (REE) were analyzed in river waters, acid mine waters, and extracts of secondary precipitates collected in the Iberian Pyrite Belt. The obtained concentrations of the REE in river water and mine waters (acid mine drainage - AMD) were in the range of 0.57 MUg/L (Lu) and 2579 MUg/L (Ce), which is higher than previously reported in surface waters from the Iberian Pyrite Belt, but are comparable with previous findings from AMD worldwide. Total REE concentrations in river waters were ranged between 297 MUg/L (Cobica River) and 7032 MUg/L (Trimpancho River) with an average of 2468 MUg/L. NASC (North American Shale Composite) normalized REE patterns for river and acid mine waters show clear convex curvatures in middle-REE (MREE) with respect to light- and heavy REE. During the dissolution experiments of AMD-precipitates, heavy-REE and middle REE generate the most enriched patterns in the solution. A small number of precipitates did not display MREE enrichment (an index Gdn/Lun < 1.0) in NASC normalized pattern and produced relatively lower REE concentrations in extracts. Additionally, very few samples, which mainly contained aluminum sulfates, e.g., pickeringite and alunogen, displayed light-REE enrichment relative to heavy-REE (HREE). In general, the highest retention of REE occurs in samples enriched in magnesium (epsomite or hexahydrite) and aluminum sulfates, mainly pickeringite. PMID- 29704838 TI - Long-term impact of a tetracycline concentration gradient on the bacterial resistance in anaerobic-aerobic sequential bioreactors. AB - Wastewater treatment systems are considered as hotspots for release of antibiotic resistance genes (ARGs) into the environment. Anaerobic-aerobic sequential (AAS) bioreactors now are intensively used for wastewater treatment worldwide. However, the occurrence of ARGs in wastewater treatment systems exposed to low-level (i.e., sub-inhibitory) antibiotic is poorly known. Here, we studied the distribution patterns of seven tetracycline resistance genes (tet genes) including tet(A), tet(C), tet(G), tet(X), tet(M), tet(O), and tet(W), as well as one mobile element [class 1 integron (intI1)] in AAS bioreactors under exposure to tetracycline from 50 MUg/L to 500 MUg/L. Additionally, effect on the removal performance of nutrients and tetracycline in both anaerobic and aerobic units was also investigated. A tetracycline concentration gradient selected for bacterial resistance in the anaerobic reactor, with the exception of tet(A) and tet(W), and the tetracycline removal deteriorated by 47%. However, the abundance of tet and intI1 genes reduced in the subsequent aerobic unit, and the removal of tetracycline, soluble COD, and NH4+-N maintained at average efficiencies of 91%, 90%, and 93%, respectively. The level of tet(X) was largely unaffected by AAS treatment. It is notable that intI1 genes probably played a crucial role on the horizontal dissemination of tet genes. The tetracycline levels and intI1 genes appear to be the primary factors influencing the occurrence of tet genes in AAS bioreactors. Nonetheless, AAS treatments still show promise for reducing antibiotics, ARGs and mobile elements without affecting nutrient removal, and need further research for practical applications. PMID- 29704840 TI - Body lipid composition modulates acute cadmium toxicity in Daphnia magna adults and juveniles. AB - Long chain polyunsaturated fatty acids (LC-PUFAs) such as eicosapentaenoic acid (EPA, 20:5n-3) affect zooplankton fitness and ability to cope with environmental stressors. However, the impact of LC-PUFAs on zooplankton sensitivity to chemical stressors is unknown. Here, we aimed to document the interaction between EPA and cadmium (Cd), as model chemical stressor, in Daphnia magna. A life-history experiment was performed in which daphnid neonates were raised into adulthood on three diets of different lipid composition: (i) algae mix; (ii) algae mix supplemented with control liposomes; (iii) algae mix supplemented with liposomes containing EPA. Juveniles (3rd, 4th and 5th brood) released by daphnids during this life-history experiment were sampled, challenged with Cd during 48 h and their immobility was assessed. At the end of this life-history experiment, another immobilisation test was performed with adults from each treatment. Daphnids absorbed, incorporated and transferred ingested EPA to their offspring. Liposome feeding increased adult tolerance to Cd. The presence of EPA in liposomes did not increase adult tolerance to Cd. Offspring's tolerance to Cd was influenced by the brood number and the maternal diet. It was positively correlated with the PUFA level in body neutral lipids, especially alpha-linolenic acid (ALA, 18:3n-3) and negatively correlated with the saturated fatty acid level in body neutral lipids, especially stearic acid (18:0). Overall, these results emphasize the importance of dietary lipids and maternal transfer of body lipids in D. magna sensitivity to Cd and highlight the need to take into account these parameters in ecotoxicological studies and risk assessment. PMID- 29704841 TI - Performance of biomarkers metallothionein and ethoxyresorufin O-deethylase in aquatic environments: A meta-analytic approach. AB - The preservation of natural environments guarantees the conservation of biodiversity and ecosystem processes. Biomonitoring programs in preserved sites can be carried out using molecular biomarkers, which reflect possible stresses that exist in the monitored location. The metallothionein (MT) proteins and isoenzyme Cytochrome P4501A (CYP4501A) are among the most used biomarkers and reflect the detoxification of metal and organic xenobiotics, respectively. This study aimed to assess the performance of these biomarkers in natural aquatic environments using a meta-analytic approach. The data search was conducted in ISI Web of ScienceTM, considering papers published until August 2016. Studies included in this research needed to compare reference or control sites and sites under stress and be conducted in situ. In general, both biomarkers were useful when comparing control sites with sites under stress. Moreover, when the data were categorized into groups of organisms, mainly bivalves and fishes, there were differences between the groups and between the monitored environments, marine or freshwater. The use of these biomarkers in fish is suitable for freshwater environments, and bivalves are suitable for marine environments. We concluded that the concomitant use of vertebrate and invertebrate bioindicators is useful to develop an effective biomonitoring program and to avoid biases due the physiology of the selected bioindicator. PMID- 29704842 TI - Effects of ZnSO4 and Zn-EDTA broadcast or banded to soil on Zn bioavailability in wheat (Triticum aestivum L.) and Zn fractions in soil. AB - Human Zn deficiency is prevalent in developing countries, and staple grains are commonly bio-fortified to increase their Zn contents. We measured Zn content, distribution, and bioavailability in calcareous soil and in wheat plants (Triticum aestivum L.) in Shaanxi Province, China, when either an organic Zn ethylenediaminetetraacetate (Zn-EDTA) or an inorganic zinc sulfate heptahydrate (ZnSO4.7H2O) Zn source was banded below the seedbed or broadcasted into soil. Compared with ZnSO4.7H2O, Zn-EDTA fertilization produced higher Zn concentration and uptake in wheat plants. However, Zn bioavailability in grain remained low, with [phytate]/[Zn] ratio >15 and the resulting estimated dietary total absorbed zinc (TAZ) < 3 mg Zn/d. ZnSO4 banded into soil had little short-term effect on grain Zn concentration but had a high residual effect and promoted the maintenance of a high concentration of the Zn fraction bound to loose organic matter (LOM-Zn) in rhizosphere soil. Both ZnSO4 and Zn-EDTA were more efficient if uniformly mixed through the soil than if banded to soil. Both ZnSO4 and Zn EDTA had limited effects on Zn bioavailability in wheat plants due to the high rate of Zn fixation in this calcareous soil. PMID- 29704844 TI - Efficient enhancement of ozonation performance via ZVZ immobilized g-C3N4 towards superior oxidation of micropollutants. AB - A functional organic-metal composite material zero-valent zinc immobilized graphitic carbon nitride (ZVZ-g-C3N4) was prepared by a fast and facile two-step synthetic approach with an optimal ZVZ content of 5.4 wt%. The structure, surface morphology and chemical composition of the as-synthesized ZVZ-g-C3N4 were characterized by BET surface area, XRD, FT-IR, SEM, TEM, and XPS, respectively. ZVZ-g-C3N4 composite exhibited superior catalytic ozonation activity with an improvement of 61.2% on atrazine (ATZ) degradation efficiency in 1.5 min reaction, more than 12 times of the pseudo-first-order rate constant, and almost 16-fold of the Rct value obtained in O3/ZVZ-g-C3N4 process compared to O3 alone. Meanwhile, the ATZ degradation efficiency was gradually enhanced with increasing ZVZ-g-C3N4 dosage and initial solution pH in the range from 3.0 to 9.0, and a higher amount of ATZ was degraded when the initial concentration of ATZ rose from 1 to 10 mg L-1. The enhanced catalytic ozonation activity of ZVZ-g-C3N4 is attributed to the synergistic effects among ZVZ, ZnO and g-C3N4, as well as the improved dispersibility, increased surface area, and intensive electron-transfer ascribed to the electronic and surface properties modification. The radical scavengers experiments demonstrated that O2-, OH, and 1O2 were the dominant reactive radical species in the multifunctional processes. Moreover, an empirical kinetic model was proposed to predict ATZ degradation. The results indicated that the ZVZ-g-C3N4 composite was a highly efficient, recoverable, and durable catalyst, which would provide a promising alternative in catalytic ozonation. PMID- 29704843 TI - Maximization of current efficiency for organic pollutants oxidation at BDD, Ti/SnO2-Sb/PbO2, and Ti/SnO2-Sb anodes. AB - Whereas electrochemical oxidation is noted for its ability to degrade bio refractory organics, it has also been incorrectly criticized for excessive energy consumption. The present paper rectifies this misunderstanding by demonstrating that the energy actually consumed in the degradation process is much less than that wasted in the side reaction of oxygen evolution. To minimize the side reaction, the possible highest instantaneous current efficiency (PHICE) for electrochemical oxidation of phenol at Boron-doped Diamond (BDD), Ti/SnO2-Sb/PbO2 (PbO2), and Ti/SnO2-Sb (SnO2) anodes has been investigated systematically, and found to reach almost 100% at the BDD anode compared with 23% at the PbO2 anode and 9% at the SnO2 anode. The significant discrepancy between PHICE values at the various anodes is interpreted in terms of different existing forms of hydroxyl radicals. For each anode system, the PHICEs are maintained experimentally using a computer-controlled exponential decay current mode throughout the electrolysis process. For applications, the minimized energy consumption is predicted by response surface methodology, and demonstrated for the BDD anode system. Consequently, almost 100% current efficiency is achieved (for a relatively meagre energy consumption of 17.2 kWh kgCOD-1) along with excellent COD degradation efficiency by optimizing the initial current density, flow rate, electrolysis time, and exponential decay constant. Compared with galvanostatic conditions, over 70% of the energy is saved in the present study, thus demonstrating the great potential of electrochemical oxidation for practical applications. PMID- 29704845 TI - Effect of human pharmaceuticals common to aquatic environments on hepatic CYP1A and CYP3A-like activities in rainbow trout (Oncorhynchus mykiss): An in vitro study. AB - This study examined the ability of several human pharmaceuticals to modulate hepatic piscine CYP-mediated monooxygenase activities. Effects of six pharmaceuticals: diclofenac, sulfamethoxazole, tramadol, carbamazepine, venlafaxine and nefazodone, were investigated in vitro in rainbow trout hepatic microsomes. The reactions of 7-ethoxyresorufin-O-deethylase (EROD) and benzyloxy 4-trifluoromethylcoumarin-O-debenzyloxylase (BFCOD), were used as markers for hepatic CYP1A and CYP3A-like activities, respectively. Our results showed that EROD and BFCOD activities were both affected by nefazodone. Nefazodone inhibited EROD in a dose dependent manner and was found to be a potent non-competitive inhibitor of EROD with a Ki value of 6.6 MUM. BFCOD activity was inhibited non competitively in the presence of nefazadone with Ki value of 30.7 MUM. BFCOD activity was slightly reduced only by the highest concentration of carbamazepine. Diclofenac, sulfamethoxazole, tramadol, and venlafaxine did not affect the activity of either EROD or BFCOD. We further exposed microsomal fraction to mixtures of six pharmaceuticals to investigate potential inhibition. The results showed that EROD and BFCOD activity was inhibited on 94% and 80%, respectively at higher tested concentration. To our knowledge, this is the first report to demonstrate an inhibitory effect of nefazodone on hepatic CYP1A and CYP3A-like proteins in rainbow trout. PMID- 29704846 TI - Geochronology and sources of heavy metal pollution in sediments of Istanbul Strait (Bosporus) outlet area, SW Black Sea, Turkey. AB - Geochemical and sedimentological analyses and radionuclide (210Pb and 137Cs) dating of three cores from the Bosporus outlet area of the Black Sea, north of Istanbul, were conducted to assess the sources and history of heavy metal pollution. The sedimentary succession in the shelf core KD12-01 consists mainly of clay (49-80%) and silt (15-41%). Radionuclide dating of the core indicates that it consists of old sediments that are uncontaminated with heavy metals. In contrast, cores KD12-04 and KD12-07 recovered from -350 m and -304 mm in the upper slope area represent sediments consisting of silt and clay that were deposited since at least the last 120 years and 60 years, respectively. The latter core contains two mass-flow units represented by relatively old sedimentary material according to the low 210Pb activity and relatively low heavy metal contents. The upper 40 and 48 cm of cores KD 12-04 and KD 12-07 represent sediments deposited since 1970s and 1980s that are significantly polluted with Cu, Ni, Zn, Mo, Pb and Cr, Cu, Co, Ni, Mo, Pb, Zn, respectively. However, high Pb and Cr concentrations with high TOC contents date back to early part of the 20th century in core KD 12-04. The geochemical data, together with the high 137Cs concentrations of the contaminated sediments, strongly suggest that the pollution is mainly delivered to the western and north western Black Sea by the large European rivers, from there transported to the study area by the rim current, and deposited in the sediments under anoxic conditions. PMID- 29704847 TI - One-step construction of heterostructured metal-organics@Bi2O3 with improved photoinduced charge transfer and enhanced activity in photocatalytic degradation of sulfamethoxazole under solar light irradiation. AB - A facile one-step assembly method was developed for the preparation of metal organics @Bi2O3 composites for photocatalysis. Two kinds of metal-organics (Ti bdc and Cu-btc)@Bi2O3 composites were synthesized via the coordination of btc3 /bdc2- and metal ions (Ti4+/Cu2+) as well as OH on the surface of Bi2O3. Compared with pure Bi2O3, Ti-bdc@Bi2O3 shows a 1.7 times higher photocatalytic activity in the degradation of sulfamethoxazole (SMX) under a simulated solar irradiation with a cumulative removal of 62% within 60 min. The high photocatalytic activity could be attributed to the high charge separation, enhanced electron transfer as well as the low recombination rate of photo-generated electrons and holes due to the construction of hetero-structures. The stability test showed that Ti bdc@Bi2O3 is more stable in water than Cu-btc@Bi2O3. Furthermore, through the radical-trapping experiments and main intermediates detection, it is demonstrated that the photo-generated holes as well as the OH and O2- formed dominate the photocatalytic decomposition of SMX. These findings demonstrate the potential usage of a facile method to synthesize metal-organics and metal oxides composites, some of which possess high water stability and thus could be employed for water treatment. PMID- 29704848 TI - Trichloroethene (TCE) hydrodechlorination by NiFe nanoparticles: Influence of aqueous anions on catalytic pathways. AB - Amending bulk and nanoscale zero-valent iron (ZVI) with catalytic metals significantly accelerates hydrodechlorination of groundwater contaminants such as trichloroethene (TCE). The bimetallic design benefits from a strong synergy between Ni and Fe in facilitating the production of active hydrogen for TCE reduction, and it is of research and practical interest to understand the impacts of common groundwater solutes on catalyst and ZVI functionality. In this study, TCE hydrodechlorination reaction was conducted using fresh NiFe bimetallic nanoparticles (NiFe BNPs) and those aged in chloride, sulfate, phosphate, and humic acid solutions with concurrent analysis of carbon fractionation of TCE and its daughter products. The apparent kinetics suggest that the reactivity of NiFe BNPs is relatively stable in pure water and chloride or humic acid solutions, in contrast to significant deactivation observed of PdFe bimetallic particles in similar media. Exposure to phosphate at greater than 0.1 mM led to a severe decrease in TCE reaction rate. The change in kinetic regimes from first to zeroth order with increasing phosphate concentration is consistent with consumption of reactive sites by phosphate. Despite severe kinetic effect, there is no significant shift in TCE 13C bulk enrichment factor between the fresh and the phosphate-aged particles. Instead, pronounced retardation of TCE reaction by NiFe BNPs in deuterated water (D2O) points to the importance of hydrogen spillover in controlling TCE reduction rate by NiFe BNPs, and such process can be strongly affected by groundwater chemistry. PMID- 29704849 TI - Simultaneous suppression of acid mine drainage formation and arsenic release by Carrier-microencapsulation using aluminum-catecholate complexes. AB - Pyrite (FeS2), the most common sulfide mineral in nature, plays an important role in the formation of acid mine drainage (AMD), one of the most serious environmental problems after the closure of mines and mineral processing operations. Likewise, arsenopyrite (FeAsS) is an important sulfide mineral because its dissolution releases toxic arsenic (As) into the environment. To mitigate the serious environmental problems caused by pyrite and arsenopyrite, this study investigated carrier-microencapsulation (CME) using Al-catecholate complexes, a technique that selectively forms protective coatings on the surfaces of sulfide minerals, by electrochemical techniques and batch leaching experiments coupled with surface sensitive characterization techniques. Cyclic voltammetry (CV) of Al-catecholate complexes (mono-, bis-, tris-catecholate) suggest that these three species could be oxidatively decomposed in this order: [Al(cat)3]3- >[Al(cat)2]-->[Al(cat)]+->Al3+, and these reactions were irreversible. Among these three species, [Al(cat)]+ was the most effective in suppressing pyrite and arsenopyrite oxidations because it requires less steps for complete decomposition than the other two complexes. Analyses of CME treated minerals by scanning electron microscopy with energy dispersive X-ray spectroscopy (SEM-EDX) and diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) indicated that they were covered with Al-oxyhydroxide (gamma-AlO(OH)), which became more extensive at higher [Al(cat)]+ concentrations. In addition, this coating was stable even at relatively high applied potentials that simulated surface oxidizing conditions. Based on these results, a detailed mechanism of Al-based CME is proposed: (1) adsorption of [Al(cat)]+ on the surface of mineral, (2) oxidative decomposition of [Al(cat)]+ and release of "free" Al3+, and (3) precipitation and formation of Al-oxyhydroxide coating. PMID- 29704850 TI - Supercritical water oxidation of 2-, 3- and 4-nitroaniline: A study on nitrogen transformation mechanism. AB - Supercritical water oxidation (SCWO) of 2-, 3- and 4-nitroaniline (NA) was investigated under residence time of 1-6 min, pressure of 18-26 MPa, temperature of 350-500 degrees C, with initial concentration of 1 mM and 300% excess oxygen. Among these operating conditions, temperature and residence time played a more significant role in decomposing TOC and TN than pressure. Moreover, the products of N-containing species were mainly N2, ammonia and nitrate. When temperature, pressure and retention time enhanced, the yields of NO3- and org-N were reduced, the amount of N2 was increasing, the proportion of NH4+, however, presented a general trend from rise to decline in general. The experiment of aniline/nitrobenzene indicated that TN removal behavior between amino and nitro groups would prefer to happen in the molecule rather than between the molecules, therefore, the smaller interval between the amino and nitro group was the more easily to interreact. This might explain the reason why TN removal efficiency was in an order that 2-NA > 3-NA > 4-NA. The NH4+/NO3- experiment result demonstrated that ammonia and nitrate did convert into N2 during SCWO, however, the formation of N2 was little without auxiliary fuel. Density functional theory (DFT) method was used to calculate the molecular structures of 2-, 3- and 4-NA to further explore reaction mechanism, which verified that amino group was more easily to be attacked than nitro group. Based on these results, the conceivable reaction pathways of 2-, 3- and 4-NA were proposed, which contained three parts, namely denitrification, ring-open and mineralization. PMID- 29704851 TI - Republic of Georgia estimates for prevalence of drug use: Randomized response techniques suggest under-estimation. AB - BACKGROUND: Validity of responses in surveys is an important research concern, especially in emerging market economies where surveys in the general population are a novelty, and the level of social control is traditionally higher. The Randomized Response Technique (RRT) can be used as a check on response validity when the study aim is to estimate population prevalence of drug experiences and other socially sensitive and/or illegal behaviors. AIM: To apply RRT and to study potential under-reporting of drug use in a nation-scale, population-based general population survey of alcohol and other drug use. METHODS: For this first-ever household survey on addictive substances for the Country of Georgia, we used the multi-stage probability sampling of 18-to-64-year-old household residents of 111 urban and 49 rural areas. During the interviewer-administered assessments, RRT involved pairing of sensitive and non-sensitive questions about drug experiences. RESULTS: Based upon the standard household self-report survey estimate, an estimated 17.3% [95% confidence interval, CI: 15.5%, 19.1%] of Georgian household residents have tried cannabis. The corresponding RRT estimate was 29.9% [95% CI: 24.9%, 34.9%]. The RRT estimates for other drugs such as heroin also were larger than the standard self-report estimates. DISCUSSION AND CONCLUSIONS: We remain unsure about what is the "true" value for prevalence of using illegal psychotropic drugs in the Republic of Georgia study population. Our RRT results suggest that standard non-RRT approaches might produce 'under-estimates' or at best, highly conservative, lower-end estimates. PMID- 29704852 TI - Prevalence of alcohol use in pregnant women with substance use disorder. AB - BACKGROUND: Prenatal care programs for women with opioid use disorder (OUD) often focus treatment/counseling plans around illicit substances, while concurrent use of alcohol might present an equal or greater risk to the fetus. METHODS: This study evaluated self-reported prevalence of alcohol use in patients participating in a comprehensive prenatal care program for women with substance use disorder (SUD; n = 295), of which 95% are treated for OUD, and pregnant women being served through general obstetrical clinics at the University of New Mexico (n = 365). During the screening phase of a prospective study, patients were asked to report alcohol use in the periconceptional period, and between the last menstrual period and pregnancy recognition. RESULTS: The screening interview was conducted at 22.3 (median = 22; Q1 = 16; Q3 = 29) gestational weeks. Among patients screened at the SUD clinic, 28.8% and 24.1% reported at least one binge drinking episode in the periconceptional period and in early pregnancy, respectively. The prevalence of binge drinking was similar in the general obstetrics population (24.7% and 24.4%, respectively). Among those who reported drinking in early pregnancy, median number of binge drinking episodes was higher among patients screened at the SUD clinic (median = 3; Q1 = 1; Q3 = 10) compared to the general obstetrics group (median = 1; Q1 = 1; Q3 = 3; p < 0.001). CONCLUSIONS: This study demonstrates a high prevalence of prenatal alcohol use in early pregnancy in both groups, while patients with SUD/OUD consume more alcohol. These findings underscore the need for targeted screening and intervention for alcohol use in all pregnant women, especially those with SUD/OUD. PMID- 29704853 TI - Postmortem blood alcohol content among late-middle aged and older suicide decedents: Associations with suicide precipitating/risk factors, means, and other drug toxicology. AB - BACKGROUND: This study examined blood alcohol content (BAC) among suicide decedents aged 50+ and its associations with suicide precipitating/risk factors, means, and other drug toxicology. METHODS: The National Violent Death Reporting System, 2005-2015, provided data (N = 56,118 for all suicide decedents and N = 29,115 with alcohol test results). We used logistic regression models, with BAC > 0.0 (BAC positive) and BAC > = 0.08 (intoxication) as the dependent variables. RESULTS: Almost a third of decedents who were tested for alcohol were BAC positive, and almost two-thirds of those who were positive had a BAC > = 0.08. Alcohol problems prior to suicide (AOR = 6.71, 95% CI = 6.24-7.21), relationship problems (AOR = 1.53, 95% CI = 1.44-1.63), and death/suicide of family/friends (AOR = 1.22, 95% CI = 1.11-1.35) were associated with greater odds of a positive BAC, but suicide means were not significantly associated with a positive BAC. Alcohol problems (AOR = 2.98, 95% CI = 2.68-3.31), relationship problems (AOR = 1.18, 95% CI = 1.06-1.30), firearm use (AOR = 1.85, 95% CI = 1.59-2.16), and hanging/suffocation (AOR = 1.38, 95% CI = 1.16-1.64) were associated with greater odds of a BAC > = 0.08. A toxicology positive for antidepressants, marijuana, cocaine, or amphetamines was associated with greater odds of a positive BAC; however, a toxicology positive for antidepressants, opiates, or amphetamines was associated with lower odds of a BAC > = 0.08. BAC > = 0.08 rates increased over the study period. CONCLUSIONS: Alcohol intoxication may have contributed to using more violent suicide means. The significant association between relationship problems and intoxication before suicide calls for restricting access to alcohol and suicide means for individuals with these problems. Suicide prevention may require crisis counseling/support for acute life stressors and ongoing emotional support. PMID- 29704854 TI - Cognitive behavioral therapy for post-stroke depression: A meta-analysis. AB - BACKGROUND: Cognitive behavioral therapy (CBT) has been widely used for post stroke depression (PSD), but the findings have been inconsistent. This is a meta analysis of randomized controlled trials (RCTs) of CBT for PSD. METHODS: Both English (PubMed, PsycINFO, Embase) and Chinese (WanFang Database, Chinese National Knowledge Infrastructure and SinoMed) databases were systematically searched. Weighted and standardized mean differences (WMDs/SMDs), and the risk ratio (RR) with their 95% confidence intervals (CIs) were calculated using the random effects model. RESULTS: Altogether 23 studies with 1,972 participants with PSD were included and analyzed. Of the 23 RCTs, 39.1% (9/23) were rated as high quality studies, while 60.9% (14/23) were rated as low quality. CBT showed positive effects on PSD compared to control groups (23 arms, SMD = -0.83, 95% CI: -1.05 to -0.60, P < 0.001). Both CBT alone (7 arms, SMD = -0.76, 95% CI: -1.22 to -0.29, P = 0.001) and CBT with antidepressants (14 arms, SMD = -0.95, 95% CI: 1.20 to -0.71, P < 0.00001) significantly improved depressive symptoms in PSD. CBT had significantly higher remission (6 arms, RR = 1.76, 95% CI: 1.37-2.25, P < 0.00001) and response rates (6 arms, RR = 1.41, 95% CI: 1.22-1.63, P < 0.00001), with improvement in anxiety, neurological functional deficits and activities of daily living. CBT effects were associated with sample size, mean age, proportion of male subjects, baseline depression score, mean CBT duration, mean number of CBT sessions, treatment duration in each session and study quality. CONCLUSION: Although this meta-analysis found positive effects of CBT on depressive symptoms in PSD, the evidence for CBT is still inconclusive due to the limitations of the included studies. Future high-quality RCTs are needed to confirm the benefits of CBT in PSD. PMID- 29704855 TI - Intersentential coreference expectations reflect mental models of events. AB - Comprehenders' perception of the world is mediated by the mental models they construct. During discourse processing, incoming information allows comprehenders to update their model of the events being described. At the same time, comprehenders use these models to generate expectations about who or what will be mentioned next. The temporal dynamics of this interdependence between language processing and mental event representation has been difficult to disentangle. The present visual world eye-tracking experiment measures listeners' coreference expectations during an intersentential pause between a sentence about a transfer of-possession event and a continuation mentioning either its Source or Goal. We found a temporally dispersed but sustained preference for fixating the Goal that was significantly greater when the event was described as completed rather than incomplete (passed versus was passing). This aligns with reported offline sensitivity to event structure, as conveyed via verb aspect, and provides new evidence that our mental model of an event leads to early and, crucially, proactive expectations about subsequent mention in the upcoming discourse. PMID- 29704856 TI - Fast mapping word meanings across trials: Young children forget all but their first guess. AB - Do children learn a new word by tracking co-occurrences between words and referents across multiple instances ("cross-situational learning" models), or is word-learning a "one-track" process, where learners maintain a single hypothesis about the possible referent, which may be verified or falsified in future occurrences ("propose-but-verify" models)? Using a novel word-learning task, we ask which learning procedure is utilized by preschool-aged children. We report on findings from three studies comparing the word-learning strategies across different populations of child learners: monolingual English learners, Spanish - English dual language learners, and learners at risk for language-delay. In all three studies, we ask what, if anything, is retained from prior exposures and whether the amount of information retained changes as children get older. The ability to make a good initial hypothesis was a function of various factors, including language ability and experience, but across-the-board, children were no better than chance after a wrong initial hypothesis. This suggests that children do not retain multiple meaning hypotheses across learning instances, lending support to the propose-but-verify models. PMID- 29704857 TI - Visual short-term memory guides infants' visual attention. AB - Adults' visual attention is guided by the contents of visual short-term memory (VSTM). Here we asked whether 10-month-old infants' (N = 41) visual attention is also guided by the information stored in VSTM. In two experiments, we modified the one-shot change detection task (Oakes, Baumgartner, Barrett, Messenger, & Luck, 2013) to create a simplified cued visual search task to ask how information stored in VSTM influences where infants look. A single sample item (e.g., a colored circle) was presented at fixation for 500 ms, followed by a brief (300 ms) retention interval and then a test array consisting of two items, one on each side of fixation. One item in the test array matched the sample stimulus and the other did not. Infants were more likely to look at the non-matching item than at the matching item, demonstrating that the information stored rapidly in VSTM guided subsequent looking behavior. PMID- 29704858 TI - Body builder: from synthetic cells to engineered tissues. AB - It is estimated that 18 Americans die every day waiting for an organ donation. And even if a patient receives the organ that s/he needs, there is still >10% chance that the new organ will not work. The field of tissue engineering and regenerative medicine aims to actively use a patient's own cells, plus biomaterials and factors, to grow specific tissues for replacement or to restore normal functions of that organ, which would eliminate the need for donors and the risk of alloimmune rejection. In this review, we summarized recent advances in fabricating synthetic cells, with a specific focus on their application to cardiac regenerative medicine and tissue engineering. At the end, we pointed to challenges and future directions for the field. PMID- 29704859 TI - Differential sensitivity of the human sperm cell to near infrared radiation. PMID- 29704860 TI - Morphological and genetical changes of endothelial progenitor cells after in vitro conversion into photoreceptors. AB - BACKGROUND: Retinal degeneration is a condition ensued by various ocular disorders such as artery occlusion, diabetic retinopathy, retrolental fibroplasia and retinitis pigmentosa which cause abnormal loss of photoreceptor cells and lead to eventual vision impairment. No efficient treatment has yet been found, however, the use of stem cell therapy such as bone marrow and embryonic stem cells has opened a new treatment modality for retinal degenerative diseases. The major goal of this study is to analyze the potential of endothelial progenitor cells derived from bone marrow to differentiate into retinal neural cells for regenerative medicine purposes. METHODS: In this study, endothelial progenitor cells were induced in-vitro with photoreceptor growth factor (taurine) for 21 days. Subsequently, the morphology and gene expression of CRX and RHO of the photoreceptors-induced EPCs were examined through immunostaining assay. FINDINGS: The results indicated that the induced endothelial progenitor cells demonstrated positive gene expression of CRX and RHO. Our findings suggested that EPC cells may have a high advantage in cell replacement therapy for treating eye disease, in addition to other neural diseases, and may be a suitable cell source in regenerative medicine for eye disorders. PMID- 29704861 TI - Development of facile drug delivery platform of ranibizumab fabricated PLGA PEGylated magnetic nanoparticles for age-related macular degeneration therapy. AB - The present anti-angiogenic therapies for neovascular age-related macular degeneration require effective drug delivery systems for transfer drug molecules. Ranibizumab is an active humanized monoclonal antibody that counteracts active forms of vascular endothelial growth factor A in the neovascular age-related macular degeneration therapy. The development of ranibizumab-related therapies, we have designed the effective drug career with engineered magnetic nanoparticles (Fe3O4) as a facile platform of ranibizumab delivery for the treatment of neovascular age-related macular degeneration. Ranibizumab conjugated iron oxide (Fe3O4)/PEGylated poly lactide-co-glycolide (PEG-PLGA) was successfully designed and the synthesized materials are analyzed different analytical techniques. The microscopic techniques (Scanning Electron Microscopy (SEM) & Transmission Electron Microscopy (TEM)) are clearly displayed that spherical nanoparticles into the PEG-PLGA matrix and presence of elements and chemical interactions confirmed by the results of energy dispersive X-ray analysis (EDX) and Fourier trans-form infrared (FTIR) spectroscopic methods. The in vitro anti-angiogenic evaluation of Fe3O4/PEG-PLGA polymer nanomaterial efficiently inhibits the tube formation in the Matrigel-based assay method by using human umbilical vein endothelial cells. Ranibizumab treated Fe3O4/PEG-PLGA polymer nanomaterials not disturbed cell proliferation and the results could not display the any significant differences in human endothelial cells. The present investigated results describe that Fe3O4/PEG-PLGA polymer nanomaterials can be highly favorable and novel formulation for the treatment of neovascular age-related macular degeneration. PMID- 29704862 TI - A nonrestrictive, weight loss diet focused on fiber and lean protein increase. AB - OBJECTIVE: We examined the feasibility and acceptability of a non-restrictive diet that was focused on increasing dietary fiber and lean protein intake for weight loss. METHODS: Dietary intake was assessed using three randomly selected 24-h dietary recalls. Fifteen obese adults enrolled in a 12-wk study that included six biweekly individual dietary counseling sessions to attain a daily goal of higher fiber (35 g/d) and lean protein (0.8 g/kg/d of individual's ideal body weight) intake. Feasibility was determined by retention and attendance and dietary adherence was measured. RESULTS: One participant dropped out of the study before the 12-wk assessment visit. Fourteen participants completed all six counseling sessions and one participant completed five sessions. At week 12, 93% of participants approved of the diet and 92% of participants did not feel hungry while on the diet. Mean fiber intake increased by 6.8 g/d (95% confidence interval [CI], 3.2 to 10.5 g/d) and total protein intake increased by 5.7 g/d (95% CI, -3.7 to 15.0 g/d). The mean change in energy intake was -265.5 kcal/d (95% CI, -454.8 to -76.2 kcal/d). The dietary quality score as measured by the Alternative Healthy Eating Index increased by 6.1 (95% CI, 1.5 to 10.7). The mean change in weight was -2.2% (95% CI, -3.6 to -0.7%). CONCLUSIONS: A diet that promotes increased fiber and lean protein intake demonstrates feasibility and high acceptability ratings, which resulted in calorie and weight reductions and an improvement of the dietary quality. PMID- 29704863 TI - Adherence to the Mediterranean dietary pattern and incidence of anorexia and bulimia nervosa in women: The SUN cohort. AB - OBJECTIVE: To our knowledge, no study has yet assessed the association between dietary patterns and incidence of eating disorders. This study aimed to assess the association between adherence to the Mediterranean dietary pattern (MDP) and incident risk of anorexia (AN) and bulimia nervosa (BN). METHODS: We conducted a prospective cohort study of 11 800 women from the Seguimiento Universidad de Navarra follow-up project. Participants were classified as having incident AN or BN if they were free of AN or BN at baseline and reported a physician-made diagnosis of AN or BN during the follow-up period. Nutritional status, lifestyle, and behavioral variables were investigated and used as covariates. A validated 136-item food frequency questionnaire and the Trichopoulou score were used to assess adherence to the MDP. RESULTS: After a median follow-up time of 9.4 y, 100 new cases of AN and BN were identified. The multivariate hazard ratio of AN and BN for the two upper categories of adherence to the MDP were 0.39 (95% CI: 0.20 0.75) and 0.32 (95% CI: 0.14-0.70; Ptrend = 0.021). Inverse dose-response relationships were found for the consumption of cereals and olive oil and marginally for polyunsaturated fatty acid intake. To address reverse causation, multivariable linear regressions were run using a cross-sectional approach between adherence to the MDP and risk of AN and BN at baseline. No difference in adherence was found between participants with and without eating disorders. CONCLUSIONS: Our results suggest a potential inverse association between the MDP and the risk of AN and BN. Additional longitudinal studies and trials are needed. PMID- 29704864 TI - From Autotransplantation to Allotransplantation: A Perspective on the Future of Reconstructive Microsurgery. AB - It has been half a century since Susumu Tamai reported on the first thumb replantation. The evolution of reconstructive microsurgery has continually added new applications of the operating microscope for reconstructive surgery and has had profound impact on countless patients. From the time of Harold Gillies until today, the reconstructive ladder has evolved to a reconstructive elevator with the "penthouse" floor being represented by vascularized composite allotransplantation. PMID- 29704865 TI - Platelet-Rich Fibrin and Its Contradictory Effect on Peripheral Nerve Repair after Malignant Tumor Resection: Nerve Regeneration versus Cancer Proliferation. PMID- 29704866 TI - Effects of Transfusion on Free Flap Survival: Searching for an Optimal Hemoglobin Threshold for Transfusion. AB - BACKGROUND: Microsurgical free tissue transfer is a popular technique nowadays. Because of its considerably exquisite procedure, various risk factors can affect surgical outcome. However, current key practices, especially those in blood transfusion, are in contention due to the lack of enough evidence. Therefore, the objective of this study was to investigate the impact of perioperative blood transfusion on microsurgical complication. METHODS: Data of a total of 168 patients who underwent microvascular free tissue transfer from 2013 through 2016 were retrospectively reviewed. Age, comorbidity, anatomical surgical site, preoperative and postoperative lowest hemoglobin (Hb) level, estimated blood volume loss, and final clinical flap outcome were compared between patients with and without transfusion treatment. Factors with a significance of p < 0.05 in univariate analysis were included in the multivariate logistic regression model to identify independent risk factors. RESULTS: Of 168 patients, 72 (43%) were in the transfusion group. Cross analysis statistics showed that flap failure in the transfusion group was 3.6 times higher (p = 0.018) than that in the control group. Multivariable analysis revealed that age (p = 0.083) and perioperative lowest Hb level (p = 0.021) remained as significant predictors of flap failure. Receiver-operating characteristic curve analysis showed that the appropriate lower limit of transfusion commencement of Hb was 8.75 g/dL (area under the curve: 0.721). CONCLUSION: A transfusion during perioperative period of free flap did not increase its failure rate. Rather than appropriate transfusion strategy, perioperative lowest Hb level, and age were significant predictors of flap failure. Therefore, transfusion can be confidently used in patients who undergo free flap without any hesitation. Results of this study provide practical evidence of performing perioperative transfusion for free tissue transfer patients. PMID- 29704867 TI - Azathioprine-induced alopecia and leukopenia associated with NUDT15 polymorphisms. PMID- 29704869 TI - Risk of skin cancer in people with vitiligo: a systematic review and meta analysis. PMID- 29704870 TI - Immune-regulatory genes as possible modifiers of familial pityriasis rubra pilaris - lessons from a family with PRP and psoriasis. PMID- 29704868 TI - Inter-laboratory comparison of channelized hotelling observer computation. AB - PURPOSE: The task-based assessment of image quality using model observers is increasingly used for the assessment of different imaging modalities. However, the performance computation of model observers needs standardization as well as a well-established trust in its implementation methodology and uncertainty estimation. The purpose of this work was to determine the degree of equivalence of the channelized Hotelling observer performance and uncertainty estimation using an intercomparison exercise. MATERIALS AND METHODS: Image samples to estimate model observer performance for detection tasks were generated from two dimensional CT image slices of a uniform water phantom. A common set of images was sent to participating laboratories to perform and document the following tasks: (a) estimate the detectability index of a well-defined CHO and its uncertainty in three conditions involving different sized targets all at the same dose, and (b) apply this CHO to an image set where ground truth was unknown to participants (lower image dose). In addition, and on an optional basis, we asked the participating laboratories to (c) estimate the performance of real human observers from a psychophysical experiment of their choice. Each of the 13 participating laboratories was confidentially assigned a participant number and image sets could be downloaded through a secure server. Results were distributed with each participant recognizable by its number and then each laboratory was able to modify their results with justification as model observer calculation are not yet a routine and potentially error prone. RESULTS: Detectability index increased with signal size for all participants and was very consistent for 6 mm sized target while showing higher variability for 8 and 10 mm sized target. There was one order of magnitude between the lowest and the largest uncertainty estimation. CONCLUSIONS: This intercomparison helped define the state of the art of model observer performance computation and with thirteen participants, reflects openness and trust within the medical imaging community. The performance of a CHO with explicitly defined channels and a relatively large number of test images was consistently estimated by all participants. In contrast, the paper demonstrates that there is no agreement on estimating the variance of detectability in the training and testing setting. PMID- 29704871 TI - When passion hurts: adverse cutaneous reaction to tattoo in a FC Barcelona soccer fan ('Cule Dermatitis'). PMID- 29704873 TI - The early days of a blood vessel. PMID- 29704872 TI - Inhibition of interleukin-12 and/or interleukin-23 for the treatment of psoriasis: What is the evidence for an effect on malignancy? AB - Immune cells and cytokines play an important role in the pathogenesis of psoriasis. Interleukin-12 (IL-12) and IL-23 promote cellular responses mediated by T cells, which contribute to an inflammatory loop responsible for the induction and maintenance of psoriatic plaques. Antibodies that inhibit IL-12/23 or IL-23 are key treatment options for patients with psoriasis. IL-12 and IL-23 also play a key role in immune responses to infections and tumors. A growing body of information from clinical trials, cohort studies, postmarketing reports, genetic studies and animal models provides insights into the potential biological relationships between IL-12/23 inhibition and malignancies. We summarize this information in tables and provide some context for the interpretation of these data with the goal of informing dermatologists who are using IL-12/23 or IL-23 inhibitors to treat patients with psoriasis. PMID- 29704875 TI - Frequency-dependent top-down modulation of temporal summation by anodal transcranial direct-current stimulation of the primary motor cortex in healthy adults. AB - BACKGROUND: Transcranial direct-current stimulation (tDCS) applied over the primary motor cortex has been shown to be effective in the treatment of a number of chronic pain conditions. However, there is a lack of understanding of the top down analgesic mechanisms involved. METHOD: In this study, we investigated the effects of tDCS on the facilitation of subjective sensory and pain scores using a transcutaneous electrically evoked measure of temporal summation. In this randomized, blinded, cross-over study healthy subjects received a single stimulus given at 0.9* pain threshold (pTh) over the L5 dermatome on the lateral aspect of the right leg, followed by a train of 5 stimuli given at 0.5, 1, 5 and 20 Hz before and after 20 min of sham or anodal tDCS (2 mA) applied over the primary motor cortex. Ratings of sensation and pain intensity were scored on a visual analogue scale (VAS). RESULTS: Temporal summation leading to pain only occurred at higher frequencies (5 and 20 Hz). Sham or real tDCS had no effect over temporal summation evoked at 5 Hz; however, there was a significant analgesic effect at 20 Hz. Sham or real tDCS had no effect over acute, single stimuli evoked responses. CONCLUSION: These results indicate that anodal tDCS applied to the primary motor cortex preferentially modulates temporal summation induced by high-frequency electrical stimulation-induced pain. The inhibitory effects of tDCS appear to be dynamic and dependent on the degree of spinal cord excitability and may explain the higher analgesic efficacy in patients with moderate to severe chronic pain symptoms. SIGNIFICANCE: The analgesic effects of tDCS are dependent on spinal cord excitability. This work provides insight into top-down modulation during acute pain and temporal summation. This knowledge may explain why tDCS has a higher analgesic efficacy in chronic pain patients. PMID- 29704876 TI - Katharsis of the skin: peeling applications and agents of chemical peelings in Greek medical textbooks of Graeco-Roman antiquity. AB - BACKGROUND: Recipes for peelings date back to medical texts of old Egypt. The oldest medical papyri contain recipes for 'improving beauty of the skin' and 'removing wrinkles' by use of agents such as salt and soda. The Egyptian Queen Cleopatra (69-30 BC) is said to have taken bathes in donkey's milk to improve the beauty of her skin. However, little is known about other agents and peeling applications in later Greek medical textbooks. OBJECTIVE: We will discover new agents and describe ancient peeling applications. First, we will have to identify ancient Greek medical terms for the modern terms 'peeling' and 'chemical peeling'. Second, on the basis of the identified terms, we will perform a systematic full-text search for agents in original sources. Third, we will categorize the results into three peeling applications: (i) cleansing, (ii) aesthetical improvement of the skin and (iii) therapy of dermatological diseases. METHODS: We performed a full systematic keyword search with the identified Greek terms in databases of ancient Greek texts. Our keywords for peeling and chemical peeling are 'smexis' and 'tripsis'. Our keywords for agents of peeling and chemical peeling are 'smegmata', 'rhymmata', 'kathartika' and 'trimmata'. RESULTS: Diocles (4th century BC) was the first one who mentioned 'smexis' and 'tripsis' as parts of daily cleansing routine. Criton (2nd century AD) wrote about peeling applications, but any reference to the agents is lost. Antyllus (2nd century AD) composed three lists of peeling applications including their agents. CONCLUSION: Greek medical textbooks of Graeco-Roman antiquity report several peeling applications such as cleansing, brightening, darkening, softening and aesthetical improvement of the skin by use of peeling and chemical peeling, as well as therapy of dermatological diseases. There are 27 ancient agents for what is contemporarily called peeling and chemical peeling. We discovered more specific agents than hitherto known to research. PMID- 29704877 TI - Failure of rituximab in refractory erosive lichen planus. PMID- 29704878 TI - Neuraminidase A from Streptococcus pneumoniae has a modular organization of catalytic and lectin domains separated by a flexible linker. AB - Neuraminidase A (NanA) of the pathogen Streptococcus pneumoniae cleaves receptors of the human respiratory epithelial surface during bacterial colonization. The full-size structure of NanA that contains one lectin and one catalytic domain within a single polypeptide chain remains unresolved. Both domains are crucial for the microorganism's virulence and considered as promising antimicrobial targets. Methods of bioinformatics and molecular dynamics have been implemented to model NanA's structure and study interaction between the lectin and catalytic domains in three neuraminidases NanA, NanB, and NanC from Streptococcus pneumoniae. A significant difference in spatial organization of these homologous enzymes has been revealed. The lectin and catalytic domains of NanB and NanC form rigid globules stabilized by multiple interdomain interactions, whereas in NanA, the two domains are separated by a 16 amino acids long flexible linker - a characteristic of proteins that require conformational flexibility for their functioning. The biological role of this structural adaptation of NanA as a key virulence enzyme is discussed. PMID- 29704879 TI - Topical retinol attenuates stress-induced ageing signs in human skin ex vivo, throughEGFR activation viaEGF, but notERK andAP-1 activation. AB - Stress-induced oxidative damage and the inflammatory response lead to degradation of collagen and elastic fibres and wrinkle formation. Topical retinol (or vitamin A) can be a strategy to attenuate the effects of stress in skin as it promotes collagen and elastic fibre production and reduces protease synthesis. This study investigated the effect of topical retinol in stressed human skin using in vitro and ex vivo models. Human skin explants were treated with high levels of epinephrine (as observed in stressed patients) and topically with retinol for 13 days. Human dermal fibroblasts were treated with conditioned medium of ex vivo retinol-treated and non-stressed (without epinephrine) human skin for 24 hours. In ex vivo human skin, retinol reversed the epinephrine-induced reduction in epidermal proliferation and differentiation, normalizing epidermal thickness. Retinol also inhibited the epinephrine-induced reduction in elastic fibre deposition and organization, restoring dermal thickness. In addition, retinol reversed the epinephrine-induced increase in c-JUN protein expression, but it did not alter extracellular signal-regulated kinase 1/2 (ERK) phosphorylation in ex vivo human skin. Conditioned medium of ex vivo retinol-treated and non-stressed human skin presented an increased protein expression of epidermal growth factor (EGF). In human dermal fibroblasts, conditioned medium of ex vivo retinol-treated and non-stressed human skin increased protein and gene expression of fibrillin-1 and protein expression of EGF receptor (EGFR). In conclusion, topical retinol attenuates stress-induced skin ageing signs in human skin ex vivo, probably through EGFR activation via EGF, but not by the stress-activated ERK 1/2 and c JUN pathways. PMID- 29704874 TI - The convergence theory for vitiligo: A reappraisal. AB - Vitiligo is characterized by progressive loss of skin pigmentation. The search for aetiologic factors has led to the biochemical, the neurologic and the autoimmune theory. The convergence theory was then proposed several years ago to incorporate existing theories of vitiligo development into a single overview of vitiligo aetiology. The viewpoint that vitiligo is not caused only by predisposing mutations, or only by melanocytes responding to chemical/radiation exposure, or only by hyperreactive T cells, but rather results from a combination of aetiologic factors that impact melanocyte viability, has certainly stood the test of time. New findings have since informed the description of progressive depigmentation. Understanding the relative importance of such aetiologic factors combined with a careful selection of the most targetable pathways will continue to drive the next phase in vitiligo research: the development of effective therapeutics. In that arena, it is likewise important to acknowledge that pathways affected in some patients may not be altered in others. Taken together, the convergence theory continues to provide a comprehensive viewpoint of vitiligo aetiology. The theory serves to intertwine aetiologic pathways and will help to define pathways amenable to disease intervention in individual patients. PMID- 29704880 TI - Feasibility randomized-controlled trial of online Acceptance and Commitment Therapy for patients with complex chronic pain in the United Kingdom. AB - BACKGROUND: Acceptance and Commitment Therapy (ACT) has growing support for chronic pain. However, more accessible treatment delivery is needed. This study evaluated the feasibility of online ACT for patients with complex chronic pain in the United Kingdom to determine whether a larger trial is justified. METHODS: Participants with chronic pain and clinically meaningful disability and distress were randomly assigned to ACT online plus specialty medical pain management, or specialty medical management alone. Participants completed questionnaires at baseline, and 3- and 9-month post-randomization. Primary feasibility outcomes included recruitment, retention and treatment completion rates. Secondary outcomes were between-groups effects on treatment outcomes and psychological flexibility. RESULTS: Of 139 potential participants, 63 were eligible and randomized (45% recruitment rate). Retention rates were 76-78% for follow-up assessments. Sixty-one per cent of ACT online participants completed treatment. ACT online was less often completed by employed (44%) compared to unemployed (80%) participants. Fifty-six per cent of ACT online participants rated themselves as 'much improved' or better on a global impression of change rating, compared to only 20 per cent of control participants. Three-month effects favouring ACT online were small for functioning, medication and healthcare use, committed action and decentring, medium for mood, and large for acceptance. Small to-medium effects were maintained for functioning, healthcare use and committed action at 9 months. CONCLUSIONS: Online ACT for patients with chronic pain in the United Kingdom appears feasible to study in a larger efficacy trial. Some adjustments to treatment and trial procedures are warranted, particularly to enhance engagement among employed participants. SIGNIFICANCE: This study supports the feasibility of online Acceptance and Commitment Therapy for chronic pain in the United Kingdom and a larger efficacy trial. Refinements to treatment delivery, particularly to better engage employed patients, may improve treatment completion and outcomes. PMID- 29704881 TI - Transgene-independent heredity of RdDM-mediated transcriptional gene silencing of endogenous genes in rice. AB - To induce transcriptional gene silencing (TGS) of endogenous genes of rice (Oryza sativa L.), we expressed double-strand RNA of each promoter region and thus induced RNA-directed DNA methylation (RdDM). We targeted constitutively expressed genes encoding calnexin (CNX), protein disulphide isomerase (PDIL1-1) and luminal binding protein (BiP1); an endoplasmic reticulum stress-inducible gene (OsbZIP50); and genes with seed-specific expression encoding alpha-globulin (Glb 1) and glutelin-B4 (GluB4). TGS of four genes was obtained with high efficiency (CNX, 66.7% of regenerated plants; OsBiP1, 67.4%; OsbZIP50, 63.4%; GluB4, 66.1%), whereas the efficiency was lower for PDIL1-1 (33.3%) and Glb-1 TGS lines (10.5%). The heredity of TGS, methylation levels of promoter regions and specificity of silencing of the target gene were investigated in some of the TGS lines. In progeny of CNX and OsbZIP50 TGS lines, suppression of the target genes was preserved (except in the endosperm) even after the removal of trigger genes (T DNA) by segregation. TGS of CNX was reverted by demethylation treatment, and a significant difference in CG and CHG methylation levels in the -1 to -250 bp region of the CNX promoter was detected between the TGS and revertant lines, suggesting that TGS is closely related to the methylation levels of promoter. TGS exhibited specific suppression towards the target gene compared with post transcriptional gene silencing when GluB4 gene from glutelin multigene family was targeted. Based on these results, future perspectives and problems to be solved in the application of RdDM to new plant breeding techniques in rice are discussed. PMID- 29704882 TI - Screening of white-rot fungi for bioprocessing of wheat straw into ruminant feed. AB - AIM: In this study, the biological variation for improvement of the nutritive value of wheat straw by 12 Ceriporiopsis subvermispora, 10 Pleurotus eryngii and 10 Lentinula edodes strains was assessed. Screening of the best performing strains within each species was made based on the in vitro degradability of fungal-treated wheat straw. METHODS AND RESULTS: Wheat straw was inoculated with each strain for 7 weeks of solid state fermentation. Weekly samples were evaluated for in vitro gas production (IVGP) in buffered rumen fluid for 72 h. Out of the 32 fungal strains studied, 17 strains showed a significantly higher (P < 0.05) IVGP compared to the control after 7 weeks (227.7 ml g-1 OM). The three best Ceriporiopsis subvermispora strains showed a mean IVGP of 297.0 ml g-1 OM, while the three best P. eryngii and L. edodes strains showed a mean IVGP of 257.8 and 291.5 ml g-1 OM, respectively. CONCLUSION: Ceriporiopsis subvermispora strains show an overall high potential to improve the ruminal degradability of wheat straw, followed by L. edodes and P. eryngii strains. SIGNIFICANCE AND IMPACT OF THE STUDY: Large variation exists within and among different fungal species in the valorization of wheat straw, which offers opportunities to improve the fungal genotype by breeding. PMID- 29704883 TI - EPS production by Propionibacterium freudenreichii facilitates its immobilization for propionic acid production. AB - AIMS: Immobilization of microbial cells is a useful strategy for developing high cell density bioreactors with improved stability and productivity for production of different chemicals. Functionalization of the immobilization matrix or biofilm forming property of some strains has been utilized for achieving cell attachment. The aim of the present study was to investigate the production of exopolysaccharide (EPS) by Propionibacterium freudenreichii C.I.P 59.32 and utilize this feature for immobilization of the cells on porous glass beads for production of propionic acid. METHODS AND RESULTS: Propionibacterium freudenreichii was shown to produce both capsular and excreted EPS during batch cultivations using glucose as carbon source. Different electron microscopy techniques confirmed the secretion of EPS and formation of cellular aggregates. The excreted EPS was mainly composed of mannose and glucose in a 5.3 : 1 g g-1 ratio. Immobilization of the cells on untreated and polyethyleneimine (PEI) treated Poraver beads in a bioreactor was evaluated. Higher productivity and yield of propionic acid (0.566 g l-1 h-1 and 0.314 g g-1 , respectively) was achieved using cells immobilized to untreated beads and EPS production reached 617.5 mg l-1 after 48 h. CONCLUSION: These results suggest an important role of EPS-producing strains for improving cell immobilization and propionic acid production. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates the EPS producing microbe to be easily immobilized on a solid matrix and to be used in a bioprocess. Such a system could be optimized for achieving high cell density in fermentations without the need for functionalization of the matrix. PMID- 29704884 TI - Molecular basis of the skin barrier structures revealed by electron microscopy. AB - The barrier function of skin is indispensable for terrestrial animals. This function is mainly carried out by the epidermis, more specifically by its granular and cornified layers. The major structural components associated with this function are the intercellular lipid layer, desmosomes, corneodesmosomes, tight junctions, cornified cell envelope and keratin filaments. In this review, we discuss the current knowledge of their ultrastructure, their molecular basis and their relevance to skin disease. PMID- 29704885 TI - Parental chronic widespread pain and the association with chronic widespread pain in adult offspring: Family-linkage data from the Norwegian HUNT Study. AB - BACKGROUND: Individuals experiencing chronic widespread pain (CWP) have greater disability and poorer quality of life compared to those with other chronic painful conditions; although research identifying risk factors for CWP is lacking. We aimed to investigate whether parental CWP increases the risk of offspring CWP, and if offspring body mass index (BMI) and leisure time physical activity modify this association. METHODS: We included 6589 parent-offspring trios participating in the Norwegian HUNT Study in 1995-1997 and 2006-2008. Logistic regression was used to calculate adjusted odd ratios (ORs) (95% confidence intervals, CIs) as estimates of relative risk for offspring CWP. We analysed the joint effect of parental CWP and offspring BMI or leisure time physical activity on offspring risk of CWP and calculated the relative excess risk due to interaction (RERI). RESULTS: In total, 886 (13.5%) offspring developed CWP during follow-up. Having one (OR = 1.23, 95% CI, 1.05-1.44) or both parents with CWP (OR = 1.89, 95% CI, 1.50-2.38) increased the risk of offspring CWP. In analyses of joint effects, ORs were 1.84 (95% CI, 1.31-2.56) and 3.35 (95% CI, 1.94-5.77) in normal weight and obese offspring, respectively, when both parents had CWP. The estimate of RERI suggested some synergistic effect (RERI = 1.19, 95% CI, -0.68 to 3.05), although precision was low. Risk of CWP was similar in active (OR = 2.05, 95% CI, 1.56-2.70) and inactive (OR = 1.96, 95% CI, 1.31 2.91) offspring when both parents had CWP. CONCLUSION: Parental CWP increases the risk of CWP in adult offspring, particularly if both parents have CWP and offspring are obese. This highlights a familial predisposition for CWP and an important target group for preventive measures. SIGNIFICANCE: The parent offspring transmission of CWP is stronger in obese offspring (particularly when both parents have CWP). This study is the first to investigate the interaction between modifiable lifestyle factors, familial factors and CWP. PMID- 29704886 TI - Physiological role of Kvbeta2 (AKR6) in murine skeletal muscle growth and regulation. AB - AIM: Potassium channel accessory subunits (Kvbeta) play a key role in cardiac electrical activity through ion channel modulation. In this study, we hypothesize that Kvbeta2 regulates skeletal muscle growth and fibre phenotype via protein protein interactions. METHODS: Kvbeta2 knockout mouse model was used for morphometric, immunohistochemical and biochemical analysis to evaluate the role of Kvbeta2 in skeletal muscle physiology. RESULTS: Deletion of Kvbeta2 gene in mice (Kvbeta2 knockout, KO) leads to significant decrease in body weight along with skeletal muscle size. Key hindlimb muscles such as biceps, soleus and gastrocnemius were significantly smaller in size in KO mice compared to that of wild type. Morphometric measurements and histological analysis clearly point that the fibre size is decreased in each of the muscle type in KO compared with wild type mice. In addition, Kvbeta2 deletion contributes to fibre-type switching from fast to slow fibre as indicated by more abundant MHCI-expressing fibres in gastrocnemius and soleus muscles, which may underscore the smaller muscle size alongside increase in U3 ubiquitin ligase; NEDD4 expression. Using targeted siRNA knockdown approach, we identified that Kvbeta2 knockdown does not affect the myoblasts proliferation. However, Pax7 expression was significantly decreased in 4-week-old gastrocnemius muscle, suggesting that cellular reserve for growth may be deficient in KO mice. This is further supported by decreased migratory capacity of C2C12 cells upon siRNA-targeted Kvbeta2 knockdown. CONCLUSION: Overall, this is the first report identifying that genetic deletion of Kvbeta2 leads to decreased skeletal muscle size along with isotype switching. PMID- 29704887 TI - The siRNA-mediated downregulation of PD-1 alone or simultaneously with CTLA-4 shows enhanced in vitro CAR-T-cell functionality for further clinical development towards the potential use in immunotherapy of melanoma. AB - Chimeric antigen receptor (CAR)-T cells have been used successfully for cancer immunotherapy. While substantial tumor regression was observed in leukaemia and lymphoma, CAR therapy of solid tumors needs further improvement. A major obstacle to the efficiency of engineered T cells is posed by triggering of inhibitory receptors, for example programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte-associated protein 4 (CTLA-4), leading to an impaired antitumor activity. To boost CAR-T-cell function, we co-electroporated T cells with both, mRNA encoding a CAR specific for chondroitin sulphate proteoglycan 4 (CSPG4) and small-interfering RNAs (siRNAs) to downregulate PD-1 (siPD-1) and CTLA-4 (siCTLA 4). Flow cytometry revealed that activation-induced upregulation of both PD-1 and CTLA-4 was suppressed when compared to CAR-T cells electroporated with negative control siRNA. The siRNA transfection showed no influence on CAR expression of engineered T cells. Functionality assays were performed using PD-L1- and CD80 transfected melanoma cells endogenously expressing CSPG4. CAR-T cells transfected with siPD-1 alone showed improvement in cytokine secretion. Additionally, CAR-T cells transfected with either siPD-1 alone or together with siCTLA-4 exhibited a significantly increased cytotoxicity. No or only little effects were observed when CAR-T cells were co-transfected with siCTLA-4 only. Taken together, it is feasible to optimize CAR-T cells by co-transfection of CAR-encoding mRNA and siRNAs to downregulate inhibitory receptors. Our in vitro data indicate an improvement of the functionality of these CAR-T cells, suggesting that this strategy could represent a novel method to enhance CAR-T-cell immunotherapy of cancer. PMID- 29704889 TI - From spaceflight to blood doping: Devices for assessing haemoglobin mass and intravascular volumes. PMID- 29704888 TI - Alteration of S-adenosylhomocysteine levels affects lignin biosynthesis in switchgrass. AB - Methionine (Met) synthesized from aspartate is a fundamental amino acid needed to produce S-adenosylmethionine (SAM) that is an important cofactor for the methylation of monolignols. As a competitive inhibitor of SAM-dependent methylation, the effect of S-adenosylhomocysteine (SAH) on lignin biosynthesis, however, is still largely unknown in plants. Expression levels of Cystathionine gamma-synthase (PvCGS) and S-adenosylhomocysteine hydrolase 1 (PvSAHH1) were down regulated by RNAi technology, respectively, in switchgrass, a dual-purpose forage and biofuel crop. The transgenic switchgrass lines were subjected to studying the impact of SAH on lignin biosynthesis. Our results showed that down-regulation of PvCGS in switchgrass altered the accumulation of aspartate-derived and aromatic amino acids, reduced the content of SAH, enhanced lignin biosynthesis and stunted plant growth. In contrast, down-regulation of PvSAHH1 raised SAH levels in switchgrass, impaired the biosynthesis of both guaiacyl and syringyl lignins and therefore significantly increased saccharification efficiency of cell walls. This work indicates that SAH plays a crucial role in monolignol methylation in switchgrass. Genetic regulation of either PvCGS or PvSAHH1 expression in switchgrass can change intracellular SAH contents and SAM to SAH ratios and therefore affect lignin biosynthesis. Thus, our study suggests that genes involved in Met metabolism are of interest as new valuable targets for cell wall bioengineering in future. PMID- 29704890 TI - PIK3CA Mutation Analysis in Iranian Patients with Gastric Cancer AB - Backgrounda: Aberrant activation of phosphatidylinositol-3 kinases (PI3K)/AKT/mTOR (mammalian target of rapamycin) pathway is a critical event during gastric cancer progression. Selective function of AKT inhibitor AZD5363 in PI3KCA mutant gastric cancer necessitates the assessment of PI3KCA mutations in these patients. Methods: The study included 100 patients with gastric cancer who underwent surgical resection at Imam Reza Hospital, Tehran, Iran, between January 2009 and December 2016. Mutations in codon 1047 of PIK3CA were evaluated by tetra primer ARMS-PCR and direct sequencing methods. Results: We detected p.H1047R and p.H1047L in eight and three samples, respectively. Also, a significant association was found between PIK3CA mutations and lymphatic invasion. Kaplan Meier analysis demonstrated no significant differences in overall survival between patients with and without mutations. Conclusion: Our study detected gain of-function mutations in exon 20 of PI3KCA gene in 11% of gastric cancer patients. Future studies are needed to assess the mutation rate in other regions of this gene to find eligible patients for targeted therapies. PMID- 29704891 TI - An Association Study between Longitudinal Changes of Leukocyte Telomere and the Risk of Azoospermia in a Population of Iranian Infertile Men AB - Background: Telomeres are evolutionary, specialized terminal structures at the ends of eukaryotic chromosomes containing TTAGGG repeats in human. Several human diseases have been known to be associated with dramatic changes in telomere length. The aim of the present study was to assess the correlation between the relative leukocyte telomere length (LTL) and infertility in a group of Iranian azoospermic males. Methods: : In this case-control pilot study, relative telomere length (RTL) of peripheral blood leukocytes from a total of 30 idiopathic non obstructive azoospermic males and 30 healthy fertile males was evaluated using real-time PCR. RTL was calculated as T (telomere)/S (single copy gene) ratio and compared between infertile and fertile groups. Results: Patients with azoospermia showed significantly shorter RTL than fertile males (0.54 vs. 0.84, p < 0.05). The area under the receiver operating characteristic (ROC) curve was estimated to be 99.8%, suggesting LTL as a potential marker for the diagnosis of azoospermia. Conclusion: Our findings demonstrated a probable association between telomere shortening and azoospermia in a population of Iranian infertile men affected by idiopathic azoospermia. PMID- 29704892 TI - Fluid outflow in the rat spinal cord: the role of perivascular and paravascular pathways. AB - BACKGROUND: Cerebrospinal fluid (CSF) is thought to flow into the brain via perivascular spaces around arteries, where it mixes with interstitial fluid. The precise details concerning fluid outflow remain controversial. Although fluid dynamics have been studied in the brain, little is known about spinal cord fluid inflow and outflow. Understanding the normal fluid physiology of the spinal cord may give insight into the pathogenesis of spinal cord oedema and CSF disorders such as syringomyelia. We therefore aimed to determine the fluid outflow pathways in the rat spinal cord. METHODS: A fluorescent tracer, Alexa-Fluor(r)-647 Ovalbumin, was injected into the extracellular space of either the cervicothoracic lateral white matter or the grey matter in twenty-two Sprague Dawley rats over 250 s. The rats were sacrificed at 20 or 60 min post injection. Spinal cord segments were sectioned and labelled with vascular antibodies for immunohistochemistry. RESULTS: Fluorescent tracer was distributed over two to three spinal levels adjacent to the injection site. In grey matter injections, tracer spread radially into the white matter. In white matter injections, tracer was confined to and redistributed along the longitudinal axonal fibres. Tracer was conducted towards the pial and ependymal surfaces along vascular structures. There was accumulation of tracer around the adventitia of the intramedullary arteries, veins and capillaries, as well as the extramedullary vessels. A distinct layer of tracer was deposited in the internal basement membrane of the tunica media of arteries. In half the grey matter injections, tracer was detected in the central canal. CONCLUSIONS: These results suggest that in the spinal cord interstitial fluid movement is modulated by tissue diffusivity of grey and white matter. The central canal, and the compartments around or within blood vessels appear to be dominant pathways for fluid drainage in these experiments. There may be regional variations in fluid outflow capacity due to vascular and other anatomical differences between the grey and white matter. PMID- 29704893 TI - The behavioural variant frontotemporal dementia phenocopy syndrome is a distinct entity - evidence from a longitudinal study. AB - BACKGROUND: This study aimed to i) examine the frequency of C9orf72 expansions in a cohort of patients with the behavioural variant frontotemporal dementia (bvFTD) phenocopy syndrome, ii) observe outcomes in a group of phenocopy syndrome with very long term follow-up and iii) compare progression in a cohort of patients with the phenocopy syndrome to a cohort of patients with probable bvFTD. METHODS: Blood was obtained from 16 phenocopy cases. All met criteria for possible bvFTD and were labeled as phenocopy cases if they showed no functional decline, normal cognitive performance on the Addenbrooke's Cognitive Examination-Revised (ACE-R) and a lack of atrophy on brain imaging, over at least 3 years of follow-up. In addition, we obtained very long term follow-up data in 6 cases. A mixed model analysis approach determined the pattern of change in cognition and behaviour over time in phenocopy cases compared to 27 probable bvFTD cases. RESULTS: All 16 patients were screened for the C9orf72 expansion that was present in only one (6.25%). Of the 6 cases available for very long-term follow-up (13 - 21 years) none showed progression to frank dementia. Moreover, there was a decrease in the caregiver ratings of behavioural symptoms over time. Phenocopy cases showed significantly slower rates of progression compared to probable bvFTD patients (p < 0.006). CONCLUSION: The vast majority of patients with the bvFTD phenocopy syndrome remain stable over many years. An occasional patient can harbor the C9orf72 expansion. The aetiology of the remaining cases remains unknown but it appears very unlikely to reflect a neurodegenerative syndrome due to lack of clinical progression or atrophy on imaging. PMID- 29704895 TI - Mobile population dynamics and malaria vulnerability: a modelling study in the China-Myanmar border region of Yunnan Province, China. AB - BACKGROUND: The China-Myanmar border region presents a great challenge in malaria elimination in China, and it is essential to understand the relationship between malaria vulnerability and population mobility in this region. METHODS: A community-based, cross-sectional survey was performed in five villages of Yingjiang county during September 2016. Finger-prick blood samples were obtained to identify asymptomatic infections, and imported cases were identified in each village (between January 2013 and September 2016). A stochastic simulation model (SSM) was used to test the relationship between population mobility and malaria vulnerability, according to the mechanisms of malaria importation. RESULTS: Thirty-two imported cases were identified in the five villages, with a 4-year average of 1 case/year (range: 0-5 cases/year). No parasites were detected in the 353 blood samples from 2016. The median density of malaria vulnerability was 0.012 (range: 0.000-0.033). The average proportion of mobile members of the study population was 32.56% (range: 28.38-71.95%). Most mobile individuals lived indoors at night with mosquito protection. The SSM model fit the investigated data (chi2 = 0.487, P = 0.485). The average probability of infection in the members of the population that moved to Myanmar was 0.011 (range: 0.0048-0.1585). The values for simulated vulnerability increased with greater population mobility in each village. CONCLUSIONS: A high proportion of population mobility was associated with greater malaria vulnerability in the China-Myanmar border region. Mobile population-specific measures should be used to decrease the risk of malaria re-establishment in China. PMID- 29704894 TI - Virulent duck enteritis virus infected DEF cells generate a unique pattern of viral microRNAs and a novel set of host microRNAs. AB - BACKGROUND: Duck enteritis virus (DEV) belongs to the family Herpesviridae and is an important epornitic agent that causes economic losses in the waterfowl industry. The Chinese virulent (CHv) and attenuate vaccines (VAC) are two different pathogenic DEV strains. MicroRNAs (miRNAs) are a class of non-coding RNAs that regulate gene expression in viral infection. Nonetheless, there is little information on virulent duck enteritis virus (DEV)-encoded miRNAs. RESULTS: Using high-throughput sequencing, we identified 39 mature viral miRNAs from CHv-infected duck embryo fibroblasts cells. Compared with the reported 33 VAC-encoded miRNAs, only 13 miRNA sequences and 22 "seed sequences" of miRNA were identical, and 8 novel viral miRNAs were detected and confirmed by stem-loop RT qPCR in this study. Using RNAhybrid and PITA software, 38 CHv-encoded miRNAs were predicted to target 41 viral genes and formed a complex regulatory network. Dual luciferase reporter assay (DLRA) confirmed that viral dev-miR-D8-3p can directly target the 3'-UTR of CHv US1 gene (p < 0.05). Gene Ontology analysis on host target genes of viral miRNAs were mainly involved in biological regulation, cellular and metabolic processes. In addition, 598 novel duck-encoded miRNAs were detected in this study. Thirty-eight host miRNAs showed significant differential expression after CHv infection: 13 miRNAs were up-regulated, and 25 miRNAs were down-regulated, which may affect viral replication in the host cell. CONCLUSIONS: These data suggested that CHv encoded a different set of microRNAs and formed a unique regulatory network compared with VAC. This is the first report of DEF miRNAs expression profile and an analysis of these miRNAs regulatory mechanisms during DEV infection. These data provide a basis for further exploring miRNA regulatory roles in the pathogenesis of DEV infection and contribute to the understanding of the CHv-host interaction at the miRNA level. PMID- 29704896 TI - Platelet activation and aggregation after aneurysmal subarachnoid hemorrhage. AB - BACKGROUND: Endovascular techniques have proven beneficial in the treatment of aneurysmal subarachnoid hemorrhage (aSAH), but with high risk of arterial clotting, emboli and dissection. Platelet activation and alterations in hemostasis may contribute to these complications. We investigated platelet activation and aggregation pathways in aSAH patients who underwent endovascular treatment. METHODS: Two blood samples were taken, in the early days after bleeding and during the period at risk of vasospasm. We studied platelet activation through the expression of GpIIbIIIa and P-selectin as well as aggregation rate in the presence of agonists. Platelets from aSAH patients were compared with those from orthopedic postoperative patients (POSTOP). RESULTS: Platelets in aSAH were initially spontaneously activated and remained so over time. aSAH platelets were further activated with rapid aggregation in the presence of agonists, particularly ADP, with behavior comparable to POSTOP platelets. CONCLUSIONS: aSAH platelets showed prolonged increases in activation and aggregation. Therapies targeting the ADP pathway might reduce the risk of clotting and ischemic events in this context among patients requiring multiple endovascular procedures. TRIAL REGISTRATION: Not applicable. PMID- 29704897 TI - Occurrence of anembryonic pregnancy with use of levonorgestrel subdermal implant (JADELLE(r)): a case report. AB - BACKGROUND: Progestin-only subdermal implants are one of the most effective contraceptive methods. Anembryonic pregnancy is not reported as a possible outcome in cases of contraceptive failure of these products. We present a rare case of anembryonic pregnancy occurring in a woman with levonorgestrel-releasing implant (JADELLE(r)). CASE PRESENTATION: A 31-year-old Cameroonian (black African) housewife with a JADELLE(r) implant for 13 months, consulted at our hospital for a 1-month history of pelvic pain, prolonged menstrual bleeding, and spotting. She had a last normal menstrual period 8 weeks 1 day prior to presentation. On examination, there was suprapubic tenderness and blood trickling from her cervix. Despite a negative qualitative urine pregnancy test, an empty intrauterine gestational sac with mean sac diameter of 28 mm was visualized on pelvic ultrasound. Dilation and curettage with suction was done and she had complete relief from symptoms. CONCLUSION: This case report highlights the possibility of anembryonic pregnancy occurring in women using the levonorgestrel releasing subdermal implant (JADELLE(r)). PMID- 29704898 TI - Implementation of a mechanical CPR device in a physician staffed HEMS - a prospective observational study. AB - In this prospective, observational study we describe the incidence and characteristics of out of hospital cardiac arrest (OHCA) cases who received mechanical CPR, after the implementation of a mechanical CPR device (LUCAS 2; Physio Control, Redmond, WA, USA) in a physician staffed helicopter emergency medical service (HEMS) in South Tyrol, Italy. During the study period (06/2013 04/2016), 525 OHCA cases were registered by the dispatch centre, 271 (51.6%) were assisted by HEMS. LUCAS 2 was applied in 18 (6.6%) of all HEMS-assisted OHCA patients; ten were treated with LUCAS 2 at the scene only, and eight were transported to hospital with ongoing CPR. Two (11.1%) of the 18 patients survived long term with full neurologic recovery. In seven of eight patients transferred to hospital with ongoing CPR, CPR was ceased in the emergency room without further intervention. Retrospectively, all HEMS-assisted OHCA cases were screened for proposed indication criteria for prolonged CPR. Thirteen patients fulfilled these criteria, but only two of them were transported to hospital. Based on these results, we propose a standard operating procedure for HEMS-assisted patients with refractory OHCA in a region without hospitals with ECLS capacity. PMID- 29704900 TI - The development of temperament and character during adolescence: The processes and phases of change. AB - We studied the pattern of personality development in a longitudinal population based sample of 752 American adolescents. Personality was assessed reliably with the Junior Temperament and Character Inventory at 12, 14, and 16 years of age. The rank-order stability of Junior Temperament and Character Inventory traits from age 12 to 16 was moderate (r = .35). Hierarchical linear modeling of between group variance due to gender and within-group variance due to age indicated that harm avoidance and persistence decreased whereas self-directedness and cooperativeness increased from age 12 to 16. Novelty seeking, reward dependence, and self-transcendence increased from age 12 to 14 and then decreased. This biphasic pattern suggests that prior to age 14 teens became more emancipated from adult authorities while identifying more with the emergent norms of their peers, and after age 14 their created identity was internalized. Girls were more self directed and cooperative than boys and maintained this advantage from age 12 to 16. Dependability of temperament at age 16 was mainly predicted by the same traits at earlier ages. In contrast, maturity of character at age 16 was predicted by both temperament and character at earlier ages. We conclude that character develops rapidly in adolescence to self-regulate temperament in accord with personally valued goals shaped by peers. PMID- 29704901 TI - Do the plant host origins of Helicoverpa (Lepidoptera: Noctuidae) moth populations reflect the agricultural landscapes within which they are caught? AB - The use of Bt cotton varieties has greatly reduced the amount of conventional insecticides required to control lepidopteran pests, Helicoverpa armigera and Helicoverpa punctigera, in Australia, but the possibility that these moths might become resistant to Bt remains a threat. Consequently, a Resistance Management Plan, which includes the mandatory growing of refuge crops (pigeon pea and non-Bt cotton; both C3 plants), has been established for Bt cotton farmers. However, knowledge of the relative contributions made to overall moth populations from the many host origins (both C3 and C4 plants) available to these insects throughout cotton production regions remains limited, as do the scales of movement and spatial mixing of moths within and between these areas. This study used stable isotope signatures (in particular delta13C) to help identify where moths fed as larvae within separate cotton production regions which differed in their proportions of C3 and C4 host crops (e.g. cotton and sorghum, respectively). C3 derived moths predominated in the early season, but C4-derived moths increased in frequency later. The overall proportion of C4 moths was higher in H. armigera than in H. punctigera. Whilst the relative proportions of C3 and C4 moths differed between regions, no differences in such proportiorns were found at smaller spatial scales, nor were there significant correlations between crop composition and isotope signatures in moths. Overall, these results suggest that C4 host plants are likely to be very important in offsetting the development of Bt resistance in these insects and such influences may operate across multiple regions within a single growing season. PMID- 29704899 TI - The enigmatic seminal plasma: a proteomics insight from ejaculation to fertilization. AB - BACKGROUND: The 'omics' approach for a noninvasive diagnosis of male reproductive system disorders has gained momentum during the last decade, particularly from a screening and prognosis point of view. Due to the rapid development in assisted reproductive technologies (ART) over the years, the major focus of proteomic studies has been around the ejaculated spermatozoa. Although seminal plasma is not a requirement for ART, the question arose whether the role of seminal plasma is merely to transport spermatozoa. MAIN BODY: Seminal plasma (SP) contains a large diversity of proteins that are essential not only for sperm transport, but also for sperm protection and maturation. Most of the proteins bind to sperm surface through exosomes (epididymosomes and prostasomes), modulating sperm function, interaction with the female reproductive tract and finally fertilization. This review focuses on the state-of-art discoveries regarding SP proteome and its role in fertilization. CONCLUSION: Tissue-specific proteins in the SP have emerged as fundamental contributors for protein biomarker discovery. This is important for a noninvasive diagnosis of male infertility and development of new therapeutic approaches. Moreover, ART success rates may be improved by taking into account the critical role of seminal proteome in fertilization. PMID- 29704902 TI - Administrative health databases for addressing emerging issues in adults with CHD: a systematic review. AB - The need for population-based studies of adults with CHD has motivated the growing use of secondary analyses of administrative health data in a variety of jurisdictions worldwide. We aimed at systematically reviewing all studies using administrative health data sources for adult CHD research from 2006 to 2016. Using PubMed and Embase (1 January, 2006 to 1 January, 2016), we identified 2217 abstracts, from which 59 studies were included in this review. These comprised 12 different data sources from six countries. Of these, 55% originated in the United States of America, 28% in Canada, and 17% in Europe and Asia. No study was published before 2007, after which the number of publications grew exponentially. In all, 41% of the studies were cross-sectional and 25% were retrospective cohort studies with a wide variation in the availability of patient-level compared with hospitalisation-level episodes of care; 58% of studies from eight different data sources linked administrative data at a patient level; and 37% of studies reported validation procedures. Assessing resource utilisation and temporal trends of relevant epidemiological and outcome end points were the most reported objectives. The median impact factor of publication journals was 4.04, with an interquartile range of 3.15, 7.44. Although not designed for research purposes, administrative health databases have become powerful data sources for studying adult CHD populations because of their large sample sizes, comprehensive records, and long observation periods, providing a useful tool to further develop quality of care improvement programmes. Data linkage with electronic records will become important in obtaining more granular life-long adult CHD data. The health services nature of the data optimises the impact on policy and public health. PMID- 29704903 TI - When Natural Disaster Follows Economic Downturn: The Incremental Impact of Multiple Stressor Events on Trajectories of Depression and Posttraumatic Stress Disorder. AB - OBJECTIVE: To determine whether there were incremental mental health impacts, specifically on depression trajectories, as a result of the 2008 economic crisis (the Great Recession) and subsequent Hurricane Sandy. METHOD: Using latent growth mixture modeling and the ORANJ BOWL dataset, we examined prospective trajectories of depression among older adults (mean age, 60.67; SD, 6.86) who were exposed to the 2 events. We also collected community economic and criminal justice data to examine their impact upon depression trajectories. Participants (N=1172) were assessed at 3 times for affect, successful aging, and symptoms of depression. We additionally assessed posttraumatic stress disorder (PTSD) symptomology after Hurricane Sandy. RESULTS: We identified 3 prospective trajectories of depression. The majority (83.6%) had no significant change in depression from before to after these events (resilience), while 7.2% of the sample increased in depression incrementally after each event (incremental depression). A third group (9.2%) went from high to low depression symptomology following the 2 events (depressive improving). Only those in the incremental depression group had significant PTSD symptoms following Hurricane Sandy. CONCLUSION: We identified a small group of individuals for whom the experience of multiple stressful events had an incremental negative effect on mental health outcomes. These results highlight the importance of understanding the perseveration of depression symptomology from one event to another. (Disaster Med Public Health Preparedness. 2018;page 1 of 10). PMID- 29704904 TI - General practitioner referral of older patients to Improving Access to Psychological Therapies (IAPT): an exploratory qualitative study. AB - : Aims and methodTo understand general practitioner (GP) reticence to refer older patients to a local Improving Access to Psychological Therapies (IAPT) service providing mostly cognitive-behavioural therapy (CBT)-based interventions. Semi structured, hour-long interviews were conducted with eight GPs and then analysed by modified grounded theory and thematic analysis. RESULTS: GP views regarding the treatability of older adults with CBT influenced their willingness to refer to a CBT-based IAPT service. Perceptions of local IAPT assessment processes being distressing and onerous to older patients also motivated referral inaction. GPs expressed a preference to treat depressed older patients themselves (with medication and psychological approaches such as watchful waiting).Clinical implicationsAny strategy to increase referral rates of older adults to CBT-based IAPT services should address local GP concerns regarding assessment processes and the effectiveness of offered treatments.Declaration of interestNone. PMID- 29704906 TI - Contemporary challenges to iodine status and nutrition: the role of foods, dietary recommendations, fortification and supplementation. AB - Iodine deficiency (ID) in women of childbearing age remains a global public health concern, mainly through its impact on fetal and infant neurodevelopment. While iodine status is improving globally, ID is still prevalent in pregnancy, when requirements increase. More than 120 countries have implemented salt iodisation and food fortification, strategies that have been partially successful. Supplementation during pregnancy is recommended in some countries and supported by the WHO when mandatory salt iodisation is not present. The UK is listed as one of the ten countries with the lowest iodine status globally, with approximately 60 % of pregnant women not meeting the WHO recommended intake. Without mandatory iodine fortification or recommendation for supplementation in pregnancy, the UK population depends on dietary sources of iodine. Both women and healthcare professionals have low knowledge and awareness of iodine, its sources or its role for health. Dairy and seafood products are the richest sources of iodine and their consumption is essential to support adequate iodine status. Increasing iodine through the diet might be possible if iodine-rich foods get repositioned in the diet, as they now contribute towards only about 13 % of the average energy intake of adult women. This review examines the use of iodine-rich foods in parallel with other public health strategies, to increase iodine intake and highlights the rare opportunity in the UK for randomised trials, due to the lack of mandatory fortification programmes. PMID- 29704905 TI - The development of a consensus-based nutritional pathway for infants with CHD before surgery using a modified Delphi process. AB - : IntroductionDespite improvements in the medical and surgical management of infants with CHD, growth failure before surgery in many infants continues to be a significant concern. A nutritional pathway was developed, the aim of which was to provide a structured approach to nutritional care for infants with CHD awaiting surgery.Materials and methodsThe modified Delphi process was development of a nutritional pathway; initial stakeholder meeting to finalise draft guidelines and develop questions; round 1 anonymous online survey; round 2 online survey; regional cardiac conference and pathway revision; and final expert meeting and pathway finalisation. RESULTS: Paediatric Dietitians from all 11 of the paediatric cardiology surgical centres in the United Kingdom contributed to the guideline development. In all, 33% of participants had 9 or more years of experience working with infants with CHD. By the end of rounds 1 and 2, 76 and 96% of participants, respectively, were in agreement with the statements. Three statements where consensus was not achieved by the end of round 2 were discussed and agreed at the final expert group meeting. CONCLUSIONS: Nutrition guidelines were developed for infants with CHD awaiting surgery, using a modified Delphi process, incorporating the best available evidence and expert opinion with regard to nutritional support in this group. PMID- 29704907 TI - Illness Perceptions Predict Cognitive Performance Validity. AB - OBJECTIVES: The aim of this study was to investigate the relationship of psychological variables to cognitive performance validity test (PVT) results in mixed forensic and nonforensic clinical samples. METHODS: Participants included 183 adults who underwent comprehensive neuropsychological examination. Criterion groups were formed, that is, Credible Group or Noncredible Group, based upon their performance on the Word Memory Test and other stand-alone and embedded PVT measures. RESULTS: Multivariate logistic regression analysis identified three significant predictors of cognitive performance validity. These included two psychological constructs, for example, Cogniphobia (perception that cognitive effort will exacerbate neurological symptoms), and Symptom Identity (perception that current symptoms are the result of illness or injury), and one contextual factor (forensic). While there was no interaction between these factors, elevated scores were most often observed in the forensic sample, suggesting that these independently contributing intrinsic psychological factors are more likely to occur in a forensic environment. CONCLUSIONS: Illness perceptions were significant predictors of cognitive performance validity particularly when they reached very elevated levels. Extreme elevations were more common among participants in the forensic sample, and potential reasons for this pattern are explored. (JINS, 2018, 24, 735-745). PMID- 29704908 TI - Latent trajectories of internalizing symptoms from preschool to school age: A multi-informant study in a high-risk sample. AB - Recent proposals suggest early adversity sets in motion particularly chronic and neurobiologically distinct trajectories of internalizing symptoms. However, few prospective studies in high-risk samples delineate distinct trajectories of internalizing symptoms from preschool age onward. We examined trajectories in a high-risk cohort, oversampled for internalizing symptoms, several preschool risk/maintenance factors, and school-age outcomes. Parents of 325 children completed the Strengths and Difficulties Questionnaire on up to four waves of data collection from preschool (3-5 years) to school age (8-9 years) and Preschool Age Psychiatric Assessment interviews at both ages. Multi-informant data were collected on risk factors and symptoms. Growth mixture modelling identified four trajectory classes of internalizing symptoms with stable low, rising low-to-moderate, stable moderate, and stable high symptoms. Children in the stable high symptom trajectory manifested clinically relevant internalizing symptoms, mainly diagnosed with anxiety disorders/depression at preschool and school age. Trajectories differed regarding loss/separation experience, maltreatment, maternal psychopathology, temperament, and stress-hormone regulation with loss/separation, temperament, maternal psychopathology, and stress-hormone regulation (trend) significantly contributing to explained variance. At school age, trajectories continued to differ on symptoms, disorders, and impairment. Our study is among the first to show that severe early adversity may trigger a chronic and neurobiologically distinct internalizing trajectory from preschool age onward. PMID- 29704909 TI - Gut immunity: its development and reasons and opportunities for modulation in monogastric production animals. AB - The intestine performs the critical roles of nutrient acquisition, tolerance of innocuous and beneficial microorganisms, while retaining the ability to respond appropriately to undesirable microbes or microbial products and preventing their translocation to more sterile body compartments. Various components contribute to antimicrobial defenses in the intestine. The mucus layer(s), antimicrobial peptides and IgA provide the first line of defense, and seek to trap and facilitate the removal of invading microbes. If breached, invading microbes next encounter a single layer of epithelial cells and, below this, the lamina propria with its associated immune cells. The gut immune system has developmental stages, and studies from different species demonstrate that innate capability develops earlier than acquired. In addition, various factors may influence the developmental process; for example, the composition and activity of the gut microbiota, antimicrobials, maternally derived antibodies, host genetics, and various stressors (e.g. feed deprivation). Therefore, it is clear that particularly younger (meat-producing) animals are reliant on innate immune responses (as well as passive immunity) for a considerable period of their productive life, and thus focusing on modulating appropriate innate responses should be an intervention priority. The gut microbiota is probably the most influential factor for immune development and capability. Interventions (e.g. probiotics, prebiotics, antibodies, etc.) that appropriately modulate the composition or activity of the intestinal microbiota can play an important role in shaping the desired functionality of the innate (and acquired) response. In addition, innate immune mediators, such as toll-like receptor agonists, cytokines, etc., may provide more specific ways to suitably modulate the response. A better understanding of mucosal immunology, signaling pathways, and processes, etc., will provide even more precise methods in the future to boost innate immune capability and minimize any associated (e.g. nutrient) costs. This will provide the livestock industry with more effective options to promote robust and efficient productivity. PMID- 29704910 TI - Hearing loss and the risk of dementia in later life. AB - Dementia is a major source of disability worldwide and there are currently no available disease-modifying treatments. Hearing loss may be associated with increased risk of dementia in later life and therefore could be a modifiable risk factor, given the availability of efficacious interventions. We investigated the association of hearing loss and dementia through two complementary approaches: a prospective, cohort study of 37,898 older men (mean age 72.5 +/- 4.6 years) with a mean follow-up of 11.1 years, and a systematic review and meta-analysis of prospective studies. In our cohort, men with hearing loss were more likely to develop dementia (n = 6948, 18.3%) than men free of significant hearing impairment - adjusted hazard ratio 1.69, 95% CI = 1.54-1.85. In our review, the aggregated hazard of dementia was 1.49 (95% CI 1.30-1.67) in those with hearing impairment (14 included studies). Study quality, duration and dementia type did not alter the results considerably. We found an increased risk of incident dementia with hearing impairment in both our novel data and the meta-analysis. This is an important finding, particularly in light of recent suggestions that mid-life hearing loss may account for up to 9.1% of dementia cases worldwide, and efforts to reduce its impact should continue to be explored. PMID- 29704911 TI - Vegans report less bothersome vasomotor and physical menopausal symptoms than omnivores. AB - OBJECTIVES: Lifestyle modifications that may reduce menopausal symptoms have generated much interest. The vegetarian diet has been associated with a lower risk of chronic disease as well as a more healthy hormonal milieu. Our objective in this cross-sectional study was to survey peri- and postmenopausal women to investigate menopausal symptoms and dietary pattern. STUDY DESIGN: Survey distribution in 2015-2016 was aimed at female vegans, vegetarians, and omnivores between the ages of 45 and 80 years, who were active on senior and vegetarian social networking websites and at vegan restaurants and events. MAIN OUTCOME MEASURES: We investigated vasomotor and physical symptoms as measured by the Menopause-specific Quality of Life Questionnaire (MENQOL) and dietary pattern classified by animal protein intakes reported in response to food frequency questions. RESULTS: Out of 754 participants who completed the survey, 604 reported they were perimenopausal (n = 121) or postmenopausal (n = 483), of whom 539 also completed the food frequency questions. We compared vasomotor and physical symptoms in omnivores (n = 304, consumed meat and/or poultry at least monthly) and vegans (n = 125, abstained from all animal proteins) using general linear models; covariates included age, exercise, hormone replacement therapy, presence of reproductive organs, and age at menopause. Among perimenopausal women, vegans reported less bothersome vasomotor (p < 0.01) and physical symptoms (p < 0.01) than omnivores. For both symptom types, more vegetables and less flesh food were associated with less bothersome symptoms (p values < 0.05). CONCLUSION: Eating a plant-based diet may be helpful for women in menopausal transition who prefer a natural means to manage their symptoms. PMID- 29704912 TI - Religiosity and faith in relation to time to metabolic syndrome for Hispanic women in a multiethnic cohort of women-Findings from the Study of Women's Health Across the Nation (SWAN). AB - OBJECTIVES: We investigated whether faith was associated with a difference in time to incident metabolic syndrome (MetS) among midlife Hispanic women vs women of other ethnicities. STUDY DESIGN: The Study of Women's Health Across the Nation (SWAN) is a community-based, longitudinal study of a cohort of midlife women. Social, demographic, psychosocial, anthropometric, medical, and physiological measures, and incident MetS were assessed in near-annual intervals using questionnaires and assays. Each participant answered key questions related to religion and meaning in her life. Differences in time to MetS were modeled by Hispanic ethnicity (vs. otherwise) among women reporting low and high levels of faith. MAIN OUTCOME MEASURE: Incident MetS in the 7 years after the SWAN baseline assessment. RESULTS: Among 2371 women, average baseline age 46, Hispanic women (n = 168) were more likely to have higher perceived stress and financial strain than non-Hispanic women (n = 2203). Nevertheless, Hispanic women were far more likely than non-Hispanic women to report that faith brought them strength and comfort in times of adversity, that they prayed often, and that their faith was sustaining for them. Hispanic women had the highest incidence rate of MetS of any racial/ethnic group. However, among women with high levels of faith, the incidence rate of MetS was similar in the Hispanic and non-Hispanic groups. Conversely, among women with low levels of faith, Hispanic women had a faster progression to MetS than did non-Hispanic women. CONCLUSIONS: Faith might be associated with a different risk of MetS among women of Hispanic vs other ethnicities. Among women who are not part of a faith community, Hispanic ethnicity might be a risk factor for MetS. PMID- 29704913 TI - Effects of oral contraceptives on rheumatoid arthritis in Korean menopausal women: A nationwide cross-sectional study. AB - Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease with a multifactorial etiology. The higher prevalence of RA in women than in men may originate from differences in sex hormone levels or types. Ethnicity may interact with hormonal factors to produce various observed differences in the prevalence of RA. Oral contraceptives (OCs) are a source of exogenous sex hormones and can affect the prevalence of RA. We investigated the effects of OCs on RA in Korean menopausal women using a national data set. Data were collected from a cross sectional study of 8789 eligible participants who completed the 2008-2012 Korea National Health and Nutrition Examination Survey. To balance the distribution of baseline characteristics between those participants who had ever used OCs and those who had not, we employed propensity score matching to adjust for differences. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) for the effects of OCs on the incidence of RA. The development of RA in Korean women rapidly increased during the perimenopause. After propensity score matching, the use of OCs was associated with RA (OR 1.24, 95% CI 1.01-1.51, P = 0.04). However, hormone replacement therapy (HRT) was not associated with RA regardless of whether OCs had been used (OR 0.80, 95% CI 0.62-1.04, P = 0.09, and OR 1.00, 95% CI 0.66-1.52, P = 0.99, respectively). Our findings suggest that factors associated with sex hormones influence the prevalence of RA. PMID- 29704914 TI - Celiac disease and non-celiac gluten or wheat sensitivity and health in later life: A review. AB - Celiac disease (CD) and non-gluten (or wheat) sensitivity (NCGS) are two gluten related disorders, the treatment of which relies on dietary withdrawal of gluten (absolute and lifelong in the case of CD patients). However, these conditions differ in their pathophysiology and impact on health. CD is an autoimmune disorder of the intestine, and is associated with a wide range of disorders, pre- and post-diagnosis. Its autoimmune and inflammatory nature raises concerns about its potential effects on mortality and morbidity. Here we review the data on the health impact CD or NCGS may have prospectively, and report on the role of a gluten-free diet (GFD) in this respect. Since study designs have been heterogeneous, we focus on studies of treated patients with a biopsy-proven diagnosis of CD, to eliminate possible bias from misdiagnosis. The review revealed a moderately increased mortality risk among CD patients, mainly attributed to cardiovascular disease and malignancy. Other long-term morbidities of CD include autoimmune disorders, nutritional deficiencies, impaired bone health, reproductive abnormalities, and neurologic and neuropsychiatric disorders, which are substantially improved, and some of them even completely treated, after strict adherence to a GFD. For NCGS, the literature is too limited and its long-term complications are unknown. PMID- 29704915 TI - Optimizing nutrition in older people. AB - Older adults are at increased risk of malnutrition, for a variety of physiological and psychological reasons. This has implications for health, quality of life, independence and economic circumstances. Improvements in nutrition are known to bring tangible benefits to older people and many age related diseases and conditions can be prevented, modulated or ameliorated by good nutrition. However, practical and realistic approaches are required to optimize diet and food intake in older adults. One area where improvements can be made relates to appetite. Encouraging older adults to prepare meals can increase appetite and food intake, and providing opportunities for older adults to eat a wide variety of foods, in company, is a simple strategy to increase food intake. The protein requirement of older adults is subject to controversy and although considered the most satiating macronutrient, it appears that protein does not elicit as great a satiating effect in older adults as it does in younger individuals. This indicates that there is potential to increase protein intake without impacting on overall energy intake. Other areas where simple practical improvements can be made include both packaging of foods that are easy to prepare and the education of older adults on the safe storage and preparation of food. Research into improving the diets and nutritional status of older adults has indicated that many of the strategies can be easily and cost-effectively undertaken. PMID- 29704916 TI - Social exclusion in adult informal carers: A systematic narrative review of the experiences of informal carers of people with dementia and mental illness. AB - Social exclusion has a negative impact on quality of life. People living with dementia or mental health disorders as well as informal carers have been separately described as socially excluded. The objective of this systematic narrative review was to examine the extent to which social exclusion experienced by adult informal carers of people living with dementia or severe mental health disorders has been identified and described in research literature. It synthesised qualitative and quantitative evidence and included the perspectives of carers themselves and of professionals. Eight electronic databases (1997-2017) were searched. Five relevant studies published between 2010 and 2016 were identified. All were qualitative and used interviews and focus groups. Study quality was variable and most were European. Two focused on carers of people living with dementia and three on carers of people with mental health disorders. Four investigated carers' perspectives and experiences of social exclusion directly (total of 137 carer participants, predominantly parents, spouses and adult children), while the fifth focused on the perceptions of 65 participants working in health and social care. Stigma, financial difficulties and social isolation were highlighted in four studies and the challenges for carers in engaging in leisure activities were described in the fifth. Most conceptualised social exclusion as a form of stigma, or as resulting from stigma. One presented social exclusion as an element of carer burden. Two explicitly discussed the negative effects of social exclusion on carers. The dearth of research and the lack of specificity about social exclusion in carers was surprising. Future research should investigate aspects of social exclusion that may adversely affect carer wellbeing. PMID- 29704917 TI - Testosterone and sexual function in men. AB - Testosterone (T) is deeply involved in every step of the male sexual response. However, the occurrence of sexual disorders cannot be automatically related to a decline in T levels. In fact, this relationship is complicated by organic, relational and psychological factors, which can independently impair sexual function. For example, it is recognized that erectile dysfunction (ED) can result from vascular damage as well as from low levels of T. T therapy (TTh) can improve sexual function but meta-analyses show that it improves erectile function only in men with ED and overt hypogonadism. Similarly, impaired sexual desire can result from a wide range of organic, relational and psychological factors, although it is recognized as one of the most specific symptoms of hypogonadism. Accordingly, low desire is improved by TTh in men with overt hypogonadism. The association between low T levels and delayed ejaculation has not been well studied and needs further confirmation, as does the role of TTh in such cases. Meta-analyses have found that TTh can improve orgasmic function in hypogonadal men. Clinicians should bear in mind that sexual dysfunctions have multifactorial causes and hypogonadism represents only one of these. Only hypogonadal men are likely to improve their sexual symptoms when treated with TTh. The assessment of serum T levels is mandatory before patients are prescribed TTh, as are the assessment and possible treatment of other concomitant conditions. PMID- 29704918 TI - Microbiota-drug interactions: Impact on metabolism and efficacy of therapeutics. AB - The microbiome not only represents a vital modifier of health and disease, but is a clinically important drug target. Therefore, study of the impact of the human microbiome on drug metabolism, toxicity and efficacy is urgently needed. This review focuses on gut and vaginal microbiomes, and the effect of those microbiomes or components thereof on the pharmacokinetics of specific chemotherapeutic agents, immunotherapies, anti-inflammatory and antimicrobial drugs. In some cases, the presence of specific bacterial species within the microbiome can alter the metabolism of certain drugs, such as chemotherapeutic agents and antiviral drugs. These microbiota-drug interactions are identified mostly through studies using germ-free or microbiome-depleted animal models, or by the administration of specific bacterial isolates. The biotransformation of drugs can cause drug-related toxicities; however, biotransformation also provides a mechanism by which drug developers could exploit host microbiota to create more site-specific drugs. Within this review we consider the importance of the route of drug administration and interactions with microbiota at various mucosal sites. Notably, we discuss the potential utility of bacterial therapeutics in altering the microbiome to enhance therapeutic efficacy and clinical outcomes in a personalized fashion. Based on the data to date, there is a clinically important relationship between microbiota and drug metabolism throughout the lifespan; therefore, profiling of the human microbiome will be essential in order to understand the mechanisms by which these microbiota-drug interactions occur and the degree to which this complex interplay affects drug efficacy. PMID- 29704919 TI - The characteristics, management and outcomes of older women with breast cancer in New Zealand. AB - The aim of this study was to understand the characteristics of older women with breast cancer and to describe the current patterns of treatment and outcomes. The study included data from the combined Auckland and Waikato breast cancer registers, which hold information for 12, 372 women diagnosed with stage I-IV breast cancer between June 2000 and May 2013. Of these women, 2671 (21.6%) were over 70 years of age. Patient characteristics, treatment type and survival were compared across four-year age groups (70-74, 75-79, 80-84, 85+) and hormone receptor status. Of the women aged over 70 years, 2485 (93.0%) had stage I-III disease. Increasing age was significantly associated with decreasing use of surgery, adjuvant radiotherapy, endocrine therapy and chemotherapy, even after adjustment for stage and level of co-morbidity. Nine hundred and one women (33.7%) had co-morbidities at the time of diagnosis. The 5-year breast cancer specific survival rate for women aged 70-74 and that for women aged 75-79 were similar, but was worse in women aged over 80. Generally, older women are treated as per guidelines, although chemotherapy may be under-used. However, age is a significant factor influencing whether women are treated or not. PMID- 29704920 TI - Hypertension in patients with type 2 diabetes mellitus: Targets and management. AB - Two-thirds of patients with type 2 diabetes mellitus (T2DM) have arterial hypertension. Hypertension increases the incidence of both micro- and macrovascular complications in these patients, while the co-existence of these two major risk factors leads to a four-fold increased risk for cardiovascular disease (CVD) compared with normotensive non-diabetic controls. The aim of this article is to comprehensively review the literature and present updated information on targets for blood pressure (BP) and on the management of hypertension in patients with T2DM. A BP target of <140/90 mmHg applies to most patients, but individualization is always important. All classes of antihypertensive drugs can be used in the management of hypertension in patients with T2DM, as long as they are effective and safe and after taking co-morbidities into account. Angiotensin-converting-enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) are the ideal choice for initial or early treatment of hypertension in patients with T2DM and albuminuria. Combination of two or more drugs seems to be inevitable as most of these patients demonstrate resistant hypertension. The combination of ACE inhibitors with ARBs should be avoided. Thiazide and thiazide-like diuretics might be beneficial, alone or in a fixed dose combination with ACE inhibitors or ARBs. Calcium channel blockers (CCBs) constitute an ideal option as a second- or third-line agent. Beta-blockers are not considered as first-line antihypertensive agents, except for those patients with heart failure or previous myocardial infarction. The addition of mineralocorticoid receptor antagonists to a triple-drug therapy seems the next ideal step. Gender-specific characteristics regarding BP, T2DM and CVD should be taken into consideration, even if different recommendations do not exist yet. PMID- 29704921 TI - Assistive technologies to overcome sarcopenia in ageing. AB - Sarcopenia is an age-related decline in skeletal muscle mass and function that results in disability and loss of independence. It affects up to 30% of older adults. Exercise (particularly progressive resistance training) and nutrition are key strategies in preventing and reversing declines in muscle mass, strength and power during ageing, but many sarcopenic older adults fail to meet recommended levels of both physical activity and dietary nutrient intake. Assistive technology (AT) describes devices or systems used to maintain or improve physical functioning. These may help sarcopenic older adults to maintain independence, and also to achieve adequate physical activity and nutrition. There is a paucity of research exploring the use of AT in sarcopenic patients, but there is evidence that AT, including walking aids, may reduce functional decline in other populations with disability. Newer technologies, such as interactive and virtual reality games, as well as wearable devices and smartphone applications, smart homes, 3D printed foods, exoskeletons and robotics, and neuromuscular electrical stimulation also hold promise for improving engagement in physical activity and nutrition behaviours to prevent further functional declines. While AT may be beneficial for sarcopenic patients, clinicians should be aware of its potential limitations. In particular, there are high rates of patient abandonment of AT, which may be minimised by appropriate training and monitoring of use. Clinicians should preferentially prescribe AT devices which promote physical activity. Further research is required in sarcopenic populations to identify strategies for effective use of current and emerging AT devices. PMID- 29704922 TI - The validity and reliability of consumer-grade activity trackers in older, community-dwelling adults: A systematic review. AB - OBJECTIVE: To understand the validity and reliability of consumer-grade activity trackers (consumer wearables) in older, community-dwelling adults. METHODS: A systematic review of studies involving adults aged over 65 years who underwent physical activity monitoring with consumer wearables. A total of 7 observational studies qualified, identified from electronic databases: MEDLINE, EMBASE, Cochrane Library and others (2014-2018). Validity was interpreted using correlation coefficients (CC) and percentage error for agreement between reference devices or gold-standard validation methods Reliability was compared using mean differences or ranges (under- or overestimation) of step count and activity time. RESULTS: Total sample size was 290 adults, mean age of 70.2 +/- 4.8 years and females constituting 46.7 +/- 26.1%. The studies evaluated eight different consumer wearables used by community-dwelling adults with a range of co morbidities. Daily step count for all consumer wearables correlated highly with validation criterion, especially the ActiGraph device: intraclass correlation coefficients (ICC) were 0.94 for Fitbit One, 0.94 for Zip, 0.86 for Charge HR and 0.96 for Misfit Shine. Slower walking pace and impaired ambulation reduced the levels of agreement. Daily step count captured by Fitbit Zip was on average 7117 (+/-5,880.6), which was overestimated by five of the eight consumer wearables compared with reference devices (range 167.6-2,690.3 steps/day). Measurement of activity duration was accurate compared with reference devices, yet less so than step count. CONCLUSION: In older, community-dwelling adults, consumer wearables accurately measure step count and activity duration, as confirmed by reference devices and validation methods Further research is required to understand how co morbidities, gait and activity levels interact with monitoring in free-living environments. PMID- 29704925 TI - Correction in Article by Cano et al. "Spanish Pacemaker Registry. 14th Official Report of the Spanish Society of Cardiology Working Group on Cardiac Pacing (2016)", Rev Esp Cardiol. 2017;70:1083-1097. PMID- 29704926 TI - Language as an Application of Mindfulness. PMID- 29704927 TI - Can Bisphosphonates Prevent Recurrent Fragility Fractures? A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - OBJECTIVES: Although a few trials have explored whether bisphosphonates (BPs) prevented recurrent fragility fractures (FFs), little is known about the secondary preventative effects of BPs. Thus, we performed a meta-analysis to examine the effects of BPs on prevention of subsequent fractures, mortality, and on bone metabolic and functional parameters related to FF. We compared BP and control groups. DESIGN: A meta-analysis of randomized controlled trials was conducted. SETTING AND PARTICIPANTS: Twelve randomized controlled trials that included 5670 participants investigating the effects of BPs following FF were retrieved from PubMed, Embase, and the Cochrane Library. MEASURES: We performed a pairwise meta-analysis using fixed- and random-effects models. RESULTS: BPs exhibited significant secondary preventative effects after FF compared with controls [overall standardized mean difference = 0.766; 95% confidence interval (CI) 0.493-1.038; P < .001]. The risks of subsequent fracture (odds ratio = 0.499; 95% CI 0.418-0.596; P < .001) and mortality (odds ratio = 0.662; 95% CI 0.511-0.858; P = .002) decreased in the BP groups. Bone mineral density, bone turnover marker levels, pain at the fracture site, and health-related quality of life also differed significantly between the groups. CONCLUSIONS/IMPLICATIONS: Our meta-analysis revealed that BPs administered after FF potentially prevented subsequent fractures and reduced mortality. Positive effects in terms of pain, quality of life, and increased bone mineral density and bone metabolism were also verified regardless of the fracture sites and the administration types (oral or intravenous). Therefore, more active BPs use is recommended to prevent recurrent fragility fractures. LEVEL OF EVIDENCE: Level I, meta-analysis. PMID- 29704928 TI - A Pilot Randomized Trial of Asynchronous and Synchronous Telepsychiatry in Skilled Nursing Facilities. PMID- 29704929 TI - Socially Assistive Robots and Their Potential in Enhancing Older People's Activity and Social Participation. PMID- 29704931 TI - [Novel strategy in oncoimmunology]. AB - Recent advances in immuno-oncology with the development of anti-PD1/PD-L1 antibodies are revolutionizing oncological management. Immuno-oncology I currently developing in most histological types of cancer. However, the rate of success of anti-PD1/PD-L1 antibodies in monotherapy is limited by a limited to a subpopulation of patients accounting for about 25-30 % of patients in most indications. The development of new strategies is based on this observation with the aim to predict response or enhancing response rate. Thus, we note the development of different strategies aimed at better selecting patients or combining inhibitory checkpoints with other therapies in order to increase their effectiveness. This review will study therapeutic test strategies to validate these new associations. PMID- 29704933 TI - Face validity of a proposed tool for staging canine osteoarthritis: Canine OsteoArthritis Staging Tool (COAST). PMID- 29704934 TI - Liver enhancement in healthy dogs after gadoxetic acid administration during dynamic contrast-enhanced magnetic resonance imaging. AB - Dynamic contrast enhanced (DCE)-magnetic resonance imaging (MRI) consists of acquisition of native baseline images, followed by a series of acquisitions performed during and after administration of a contrast medium. DCE-MRI, in conjunction with hepatobiliary-specific contrast media, such as gadoxetic acid (GD-EOB-DTPA), allows for precise characterisation of the enhancement pattern of the hepatic parenchyma following administration of the contrast agent. The aim of the study was to assess the pattern of temporal resolution contrast enhancement of the hepatic parenchyma following administration of GD-EOB-DTPA and to determine the optimal time window for post-contrast assessment of the liver. The study was carried out on eight healthy beagle dogs. MRI was performed using a 1.5T scanner. The imaging protocol included T1 weighted (T1-W) gradient echo (GRE), T2 weighted (T2-W) turbo spin echo (TSE) and dynamic T1-W GRE sequences. The dynamic T1-W sequence was performed using single 10mm thick slices. Regions of interest (ROIs) were chosen and the signal intensity curves were calculated for quantitative image analysis. The mean time to peak for all dogs was 26min. The plateau phase lasted on average 21min. A gradual decrease in the signal intensity of the hepatic parenchyma was observed in all dogs. A DCE-MRI enhancement pattern of the hepatic parenchyma was evident in dogs following the administration of a GD-EOB-DTPA, establishing baseline data for an optimal time window between 26 and 41min after administration of the contrast agent. PMID- 29704935 TI - Epidemiology of pituitary pars intermedia dysfunction: A systematic literature review of clinical presentation, disease prevalence and risk factors. AB - Pituitary pars intermedia dysfunction (PPID) is caused by an age-related degenerative disease of dopaminergic neurones. Despite its importance in equine practice, available information regarding its epidemiology is limited. This systematic review aimed to assess published literature to evaluate available evidence regarding the clinical presentation, prevalence and risk factors for PPID in horses and ponies. Electronic database searches were undertaken using a range of terms, and English language publications published prior to August 2016 were included. Both authors independently reviewed screened papers for inclusion, extracted data, and assessed the quality of reporting using predefined criteria. Data were extracted using modified critically appraised topic data collection forms. Meta-analysis was not undertaken due to marked between-study variations. Following removal of duplicate records, of 358 published papers yielded by the search, 97 abstracts were screened for eligibility and 29 publications meeting inclusion criteria were included in the review. Most studies reviewed were case series or cross-sectional studies, with considerable variation in study populations and PPID case definition. Hypertrichosis and/or other hair coat abnormalities, laminitis and epaxial muscle wastage or muscle atrophy are the most frequently reported clinical signs, with prevalence of these signs increasing with increasing horse age. The most robust prevalence estimates for PPID were 21.2% in horses and ponies aged >=15 years and 2.9% amongst the general equine population. Findings regarding breed and sex predispositions were equivocal and only increasing age has been identified as a significant risk factor for PPID. PMID- 29704936 TI - Associations between single nucleotide polymorphisms in the calcium sensing receptor and chronic kidney disease-mineral and bone disorder in cats. AB - Feline chronic kidney disease (CKD) is associated with high variability in severity of CKD-mineral and bone disorder (CKD-MBD). The calcium sensing receptor (CaSR) regulates circulating parathyroid hormone (PTH) and calcium concentrations. Single nucleotide polymorphisms (SNPs) in the CaSR are associated with severity of secondary renal hyperparathyroidism and total calcium concentrations in human patients receiving haemodialysis. The objective of this study was to explore associations between polymorphisms in the feline CaSR (fCaSR) and biochemical changes observed in CKD-MBD. Client owned cats (>=9years) were retrospectively included. SNP discovery was performed in 20 cats with azotaemic CKD and normal or dysregulated calcium concentrations. Non-pedigree cats (n=192) (125 with azotaemic CKD and 66 healthy), Persians (n=40) and Burmese (n=25) were genotyped for all identified SNPs using KASP. Biochemical parameters from the date of CKD diagnosis or from first visit to the clinic (healthy cats) were used. Associations between genotype and ionized calcium, total calcium, phosphate, PTH and FGF-23 were performed for non-pedigree cats using logistic regression. Sequence alignment against the fCaSR sequence revealed eight novel exonic SNPs. KASP genotyping had high accuracy (99.6%) and a low failure rate (<6%) for all SNPs. Allele frequencies varied between breeds. In non-pedigree cats, one synonymous SNP CaSR:c.1269G>A was associated with logPTH concentration (adjusted for plasma creatinine concentration), with a recessive model having the best fit (G/G vs A/A-G/A, P=0.031). Genetic variation in the fCaSR is unlikely to explain the majority of the variability in presence and severity of CKD-MBD in cats. PMID- 29704937 TI - A retrospective cohort study investigating risk factors for the failure of Thoroughbred racehorses to return to racing after superficial digital flexor tendon injury. AB - A retrospective cohort study was conducted to investigate risk factors for the failure of Thoroughbred racehorses to return to racing after an injury of the superficial digital flexor tendon (SDFT). Successful return was defined as the completion of five or more races after SDFT injury. The official Japan Racing Association (JRA) medical records of racehorses with a core-type SDFT injury were reviewed for clinical variables related to the characteristics of the horse and the severity of SDFT injuries at the time of diagnosis. Data on racing outcomes were obtained from the official JRA racing database. Risk factors were screened using univariable logistic regression and subsequent multivariable model building. Forty-nine of 346 (14.2%) horses successfully returned to racing after SDFT injuries. Multivariable model building revealed that an increase in the total number of injured zones (defined as the total number of zones in which the injured hypoechoic area was observed at the time of ultrasonographic diagnosis of SDFT injury) was associated with an increased risk of failure to return to racing after SDFT injury. Horse characteristics, such as age, body mass and sex, were not associated with a successful return to racing. In the rehabilitation of cases with larger (longer) lesions, more effective and careful medical management may be needed for an improvement in the athletic outcomes. PMID- 29704938 TI - Evaluation of the humoral immune response to a multicomponent recombinant vaccine against S. aureus in healthy pregnant heifers. AB - Staphylococcus aureus is a worldwide pathogen that causes mastitis in dairy herds. Shortcomings in control programs have encouraged the development of vaccines against this pathogen. This study evaluated the vaccine candidate VacR, which included recombinant S. aureus protein clumping factor A (rClf), fibronectin binding protein A (rFnBP) and hemolysin beta (rBt), formulated with a novel immune-stimulating complex. Comparisons were made between healthy pregnant heifers that received either VacR (n=8; VacR group) or phosphate buffered saline (PBS) plus adjuvant (control group) SC in the supramammary lymph node area on days 45 and 15 before the expected calving date. Blood and foremilk samples were collected from 7 to 60days post-calving. After calving, heifers in the VacR group produced higher total IgG (IgGtotal) titers against each component, in both serum (rBt, 3.4*105; rClf, 3.1*105; rFnBP, 2.3*105) and milk (rBt, 2.6*104; rClf, 1.3*104; rFnBP, 1.1*104), than control heifers (P<0.0001). There were increased concentrations of IgG1 and IgG2 in VacR group (P<0.05), in both serum and milk. Humoral responses remained high throughout the period most susceptible to intramammary infections (P<0.01). Antibodies produced against S. aureus rClf and rFnBP reduced bacterial adherence to fibronectin and fibrinogen by 73% and 67%, respectively (P<0.001). Milk antibodies against these adhesins inhibited S. aureus invasion of a mammary epithelial cell line (MAC-T), resulting in 15.7% of bacteria internalized (P<0.0001). There was an approximately 6-fold reduction in the hemolysis titer for the native hemolysin in the VacR group compared to the control group (P<0.0001) and a significantly increase in the proportion of positive neutrophils (VacR, 29.7%; PBS, 13.1%) and the mean fluorescent index (VacR, 217.4; PBS, 152.6; P<0.01) in the VacR group. The results suggest that VacR is a valuable vaccine candidate against S. aureus infections, and merits further field trials and experimental challenges. PMID- 29704939 TI - Canonical discriminant analysis and meat quality analysis as complementary tools to detect the illicit use of dexamethasone as a growth promoter in Friesian bulls. AB - A screening method based on meat quality parameters and production traits for detecting the effects of illegal administration of dexamethasone in Friesian bulls was assessed. Twenty finishing bulls were divided into an untreated control group (n=8) and two treatment groups receiving dexamethasone orally at dosages of 1.4 (n=6) or 0.7 (n=6)mg per head per day for 60 days. The animals were slaughtered 26days after cessation of treatment. Thirty-six parameters were measured on live animals, carcasses and samples of the longissimus thoracis muscle. The production traits were similar between groups, but there were significant differences in meat quality between treatment groups. The higher dosage of dexamethasone improved meat tenderness, while the lower dosage resulted in more saturated red meat, with increased meat cooking shrinkage and cooking loss. The use of a portable 'electronic nose' as a screening tool was not successful in discriminating between treated and untreated meat. These results indicate that a multivariable approach using canonical discriminant analysis may be a complementary tool to identify meat from animals illegally treated with dexamethasone, based on several parameters (meat flavour, cooking and thawing loss, tenderness, colour and live weight gain), which are part of the normal analysis of meat quality. PMID- 29704940 TI - Fecal strongyle egg counts in horses with suspected pre-clinical pituitary pars intermedia dysfunction before and after treatment with pergolide. AB - Pituitary pars intermedia dysfunction (PPID) has been associated with diminished immune response in aged horses. This prospective study hypothesised that this may result in increased strongyle egg shedding in affected animals and that horses treated with pergolide would have reduced fecal egg counts (eggs per gram, EPG) compared to placebo-treated animals. Adrenocorticotropic hormone (ACTH) concentrations and EPG were tested in 48 horses. There were no significant differences in baseline EPG between horses with pre-clinical PPID and healthy controls. There was no significant difference in EPG between horses with PPID after treatment with pergolide and placebo-treated animals. Using EPG as a marker of immune function, these results did not support a proposed decrease in immune function in horses with pre-clinical PPID. PMID- 29704941 TI - Geographical characteristics influencing the risk of poisoning in pet dogs: Results of a large population-based epidemiological study in Italy. AB - Pets can act as sentinels for human health and thus surveillance of pet dogs has the potential to improve awareness of emerging risks for animal and public health. The aim of this study was to investigate factors associated with the risk of canine poisoning. In a large population-based epidemiological investigation in Italy performed from January 2015 to January 2016 and April 2016 to April 2017, descriptive statistics were acquired and analysed to determine variables associated with poisoning events in pet dogs. Results were validated in a test population and forecast analysis of risk was performed. The cumulative incidence of poisoning events was low (10.2/1000 dogs/year). Anticoagulant rodenticides, organophosphate pesticides, metaldehyde and strychnine were the most frequent causes of intoxications. Territory characteristics significantly modulated both the frequency and the nature of the involved substances. The seashore area was associated with poisoning by rodenticides (odds ratio, OR, 1.81, 95% confidence interval, CI, 1.54-2.13) and metaldehyde (OR 1.61, 95% CI 1.16-2.28). The hill country area was associated with poisoning by organophosphate pesticides (OR 1.73, 95% CI 1.38-2.15), metaldehyde (OR 2.26, 95% CI 1.53-3.25) and strychnine (OR 1.86, 95% CI, 1.34-2.57). The mountain area was associated with strychnine poisoning (OR 3.79, 95% CI 2.84-5.06). The prospective cumulative incidence of poisoning over 10 years was 9.74% (95% CI 9.57-9.91). These results may be useful for predicting the risk of poisoning and for estimating the risk index related to specific toxic compounds in specific territories. This study suggests that poisoning events in dogs may represent a problem of public health with the potential to affect wildlife and human beings. PMID- 29704942 TI - Identification of Staphylococcus epidermidis with transferrable mupirocin resistance from canine skin. AB - Resistance to mupirocin was analysed in Staphylococcus spp. isolated from healthy dogs (n=21) and dogs with pyoderma (n=47) or otitis externa (n=52). Isolates were identified to species level by MALDI-TOF and PCR-RFLP of the groEL gene. One isolate of Staphylococcus epidermidis from the skin of a healthy dog, which harboured a plasmid carrying the mupA gene, was resistant to mupirocin. PMID- 29704943 TI - What has changed in canine pyoderma? A narrative review. AB - Canine pyoderma is a common presentation in small animal practice and frequently leads to prescription of systemic antimicrobial agents. A good foundation of knowledge on pyoderma was established during the 1970s and 1980s, when treatment of infection provided relatively few challenges. However, the ability to treat canine pyoderma effectively is now limited substantially by the emergence of multidrug-resistant, methicillin-resistant staphylococci (MRS) and, in some countries, by restrictions on antimicrobial prescribing for pets. The threat from rising antimicrobial resistance and the zoonotic potential of MRS add a new dimension of public health implications to the management of canine pyoderma and necessitate a revisit and the search for new best management strategies. This narrative review focusses on the impact of MRS on how canine pyoderma is managed and how traditional treatment recommendations need to be updated in the interest of good antimicrobial stewardship. Background information on clinical characteristics, pathogens, and appropriate clinical and microbiological diagnostic techniques, are reviewed in so far as they can support early identification of multidrug-resistant pathogens. The potential of new approaches for the control and treatment of bacterial skin infections is examined and the role of owner education and hygiene is highlighted. Dogs with pyoderma offer opportunities for good antimicrobial stewardship by making use of the unique accessibility of the skin through cytology, bacterial culture and topical therapy. In order to achieve long term success and to limit the spread of multidrug resistance, there is a need to focus on identification and correction of underlying diseases that trigger pyoderma in order to avoid repeated treatment. PMID- 29704944 TI - Insulinaemic and glycaemic responses to three forages in ponies. AB - Reduction of the hyperinsulinaemic response to feeding is central to the management of insulin dysregulation (ID). The aim of this study was to compare insulinaemic and glycaemic responses to soaked hay, dry hay and haylage in ponies. Twelve ponies of mixed breeds were maintained under identical management conditions. A randomised four-way crossover trial was conducted, in which fasted animals were fed a meal of 0.25% body weight as dry matter intake soaked hay, dry hay or haylage, or administered an oral glucose test (OGT). Blood glucose and serum insulin concentrations were measured before and at 2h following OGT, and regularly for 5h following forage meals. Median and interquartile range (IQR) area under the curve (AUC) for insulin (AUCi) was greater for haylage (median 6495; IQR 17352) vs. dry hay (2932; IQR 5937; P=0.019) and soaked hay (1066; IQR 1753; P=0.002), and greater for dry hay vs. soaked hay (P=0.002). The AUC for glucose (AUCg) was lower for soaked hay (1021; IQR 99) vs. dry hay (1075; IQR 105; P=0.002) and haylage (1107; IQR 221; P=0.003). Six ponies were classified as having ID based on the OGT. AUCi was greater in ID vs. non-ID ponies after all forages. In contrast, there was no detectable effect of ID status on AUCg. On an equivalent dry matter basis, soaked hay produced the lowest insulinaemic and glycaemic responses to feeding, while haylage produced the highest responses. The insulinaemic effects of all forages were greater in ponies with ID. These data support the practice of soaking hay with water to reduce postprandial insulinaemic responses in ponies. PMID- 29704945 TI - Inconsistent MHC class II association in Beagles experimentally infected with Leishmania infantum. AB - The clinical outcome of Leishmania infantum infection in dogs varies from subclinical infection to severe disease. Researchers attribute this variability in clinical manifestations to the ability of the immune response to limit pathogen multiplication and dissemination, which is, in part, likely determined by the immune response genes. The aim of this study was to test the hypothesis that MHC class II genes are associated with disease outcome of experimental L. infantum infection in Beagles. Dog leukocyte antigen (DLA) class II haplotypes were characterised by sequence-based typing of Beagle dogs experimentally infected with L. infantum during vaccine challenge studies. Variability of response to infection was determined by clinical score, serology and quantification of L. infantum DNA in the bone marrow over the study period. Dogs showed limited DLA diversity and the DLA profiles of dogs recruited for the different vaccine challenge studies differed. There were variable responses to infection, despite the apparent restriction in genetic diversity. One haplotype DLA-DRB1*001:02-DQA1*001:01-DQB1*002:01 was associated with increased anti Leishmania antibodies in one infection model, but no DLA associations were found in other groups or with parasite load or clinical score. Examination of this particular DLA haplotype in a larger number of dogs is required to confirm whether an association exists with the immune or clinical responses to L. infantum infection. PMID- 29704946 TI - Development of a deep convolutional neural network to predict grading of canine meningiomas from magnetic resonance images. AB - An established deep neural network (DNN) based on transfer learning and a newly designed DNN were tested to predict the grade of meningiomas from magnetic resonance (MR) images in dogs and to determine the accuracy of classification of using pre- and post-contrast T1-weighted (T1W), and T2-weighted (T2W) MR images. The images were randomly assigned to a training set, a validation set and a test set, comprising 60%, 10% and 30% of images, respectively. The combination of DNN and MR sequence displaying the highest discriminating accuracy was used to develop an image classifier to predict the grading of new cases. The algorithm based on transfer learning using the established DNN did not provide satisfactory results, whereas the newly designed DNN had high classification accuracy. On the basis of classification accuracy, an image classifier built on the newly designed DNN using post-contrast T1W images was developed. This image classifier correctly predicted the grading of 8 out of 10 images not included in the data set. PMID- 29704947 TI - Drowsiness measures for commercial motor vehicle operations. AB - Timely detection of drowsiness in Commercial Motor Vehicle (C MV) operations is necessary to reduce drowsiness-related CMV crashes. This is relevant for manual driving and, paradoxically, even more so with increasing levels of driving automation. Measures available for drowsiness detection vary in reliability, validity, usability, and effectiveness. Passively recorded physiologic measures such as electroencephalography (EEG) and a variety of ocular parameters tend to accurately identify states of considerable drowsiness, but are limited in their potential to detect lower levels of drowsiness. They also do not correlate well with measures of driver performance. Objective measures of vigilant attention performance capture drowsiness reliably, but they require active driver involvement in a performance task and are prone to confounds from distraction and (lack of) motivation. Embedded performance measures of actual driving, such as lane deviation, have been found to correlate with physiologic and vigilance performance measures, yet to what extent drowsiness levels can be derived from them reliably remains a topic of investigation. Transient effects from external circumstances and behaviors - such as task load, light exposure, physical activity, and caffeine intake - may mask a driver's underlying state of drowsiness. Also, drivers differ in the degree to which drowsiness affects their driving performance, based on trait vulnerability as well as age. This paper provides a broad overview of the current science pertinent to a range of drowsiness measures, with an emphasis on those that may be most relevant for CMV operations. There is a need for smart technologies that in a transparent manner combine different measurement modalities with mathematical representations of the neurobiological processes driving drowsiness, that account for various mediators and confounds, and that are appropriately adapted to the individual driver. The research for and development of such technologies requires a multi-disciplinary approach and significant resources, but is technically within reach. PMID- 29704948 TI - Re: Characterization of Clinical Cases of Advanced Papillary Renal Cell Carcinoma via Comprehensive Genomic Profiling. PMID- 29704949 TI - Corrigendum to "Impact of intense rains and flooding on mercury riverine input to the coastal zone" [Mar. Pollut. Bull. 127 (2018) 593-602]. PMID- 29704950 TI - Special Issue Dedicated to Dr. Timothy J Bartness. PMID- 29704951 TI - Lower C-reactive protein and IL-6 associated with vegetarian diets are mediated by BMI. AB - BACKGROUND AND AIMS: The mechanism by which vegetarian diets are associated with less inflammation is not clear. We investigated the role of BMI as a mediator in the relationship between vegetarian diet and concentrations of C-reactive protein (CRP), and the cytokines IL-6, IL-10 and TNF-alpha. METHODS AND RESULTS: We used data from participants of the Adventist Health Study 2 (AHS-2) Calibration (n = 893) and Biological Manifestations of Religion (n = 478) sub-studies. Vegetarian diet variations were determined based on reported intake of animal products assessed by FFQ. Combining all participants, the proportion of non-vegetarians (NVs), partial vegetarians (PVs), lacto-ovo vegetarians (LOVs), and strict vegetarians (SVs) was 44%, 16%, 31%, and 9%, respectively. NV and PV participants were older than other dietary groups, and non-vegetarians had the highest BMI. Mediation analyses supported the mediating effect of BMI in associations of vegetarian diet with CRP (p < 0.001 each for PV, LOV and SV), and with IL-6 (p < 0.05 each for PV, LOV and SV). Mediation by BMI was not evident between vegetarian diet and the biomarkers IL-10 and TNF-alpha. A direct pathway was significant only in the association between strict vegetarians and CRP (p = 0.017). CONCLUSION: The lower CRP and IL-6 concentrations among vegetarians may be mediated by BMI. PMID- 29704952 TI - Physician Assistants and Nurse Practitioners in Ophthalmology-Has the Time Come? PMID- 29704953 TI - Risk factors associated with amputation in civilian popliteal artery trauma. AB - Popliteal artery trauma is uncommon but is associated with a high risk of limb loss depending on the scenario involving blunt or penetrating trauma as well as the severity and extent of injury that has occurred. In our setting there is a significant amount of gang and civilian warfare resulting in Vascular Trauma. There were 32 patients over a decade who sustained traumatic injury to the popliteal artery consisting of 30 males (94%) and 2 females with an age range 16 59 years with a mean of 32. There were 20 cases of penetrating trauma (63%) and 12 cases of blunt trauma (37%). Of the penetrating trauma, 18 were due to gunshot wounds (GSWs) (90%) and 2 stabs. The majority (7/12; 58%) of blunt trauma was due to falls, and 42% (5/12) secondary to motor vehicular accidents (MVAs). In terms of extent of injury, 21 of 32 patients (65%) sustained an isolated popliteal artery injury, whilst 6 (19%) had injury to both the popliteal artery and vein and another 5 (16%) had combined popliteal artery, vein and nerve injuries. There were 14 cases with associated orthopaedic injuries: 7 posterior knee dislocations, 1 fracture/dislocation of the knee, 2 femoral fractures, 2 tibial plateau fractures and 2 tibia/fibula fracture. Methods of repair included 14 reversed vein grafts, 16 polytetrafluoroethylene (PTFE) grafts and 2 primary. The overall amputation rate was 28% (9 patients). Of the penetrating trauma patients 25% required amputations composed of 5 GSWs, 33% of the blunt trauma patients required amputations. It was noted that factors associated with (but not statistically significant) poor outcomes included combined artery/vein injury, artery/vein/nerve injury, concomitant fracture/dislocation and delayed transfer to a Vascular Surgery Unit. The type of graft or repair did not affect outcome. The incidence of popliteal artery trauma was calculated at 2.46 per 100,000 population per year. PMID- 29704954 TI - A systematic review of opioid use after extremity trauma in orthopedic surgery. AB - BACKGROUND: The United States is in a prescription opioid crisis. Orthopedic surgeons prescribe more opioid narcotics than any other surgical specialty. The purpose of this study was to evaluate the state of opioid use after extremity trauma in orthopedic surgery. METHODS: A computerized literature search of PubMed/MEDLINE was conducted to evaluate the status of opioids after extremity fractures. Six articles were identified and included in the review. RESULTS: Patients who consume more opioids communicate greater pain intensity and less satisfaction with pain control. Intraoperative multimodal drug injection and nerve blockade are viable alternatives for postoperative pain control and can help decrease systemic opioid use. Orthopedic surgeons are overprescribing opioids. Compared to other countries, the United States consumes more opioids with no better satisfaction with pain control. CONCLUSION: Orthopedic trauma surgeons should tailor their postoperative opioid prescriptions to the individual patient and utilize alternative options in order to control postoperative pain. Patients should be counseled regarding narcotic addiction and dependence. Patients unable to manage pain postoperatively should be followed closely and receive the proper chronic pain management, mental and social health services referrals. PMID- 29704955 TI - Comparison of plate osteosynthesis versus non-operative management for mid-shaft clavicle fractures-A prospective study. AB - INTRODUCTION: Treatment for mid-shaft clavicle fractures has recently seen a paradigm shift towards surgical management. The aim of the study was to compare clinical and functional outcome between plate osteosynthesis and conservative line of management in middle-third clavicle fractures. MATERIAL AND METHODS: A prospective randomized study was conducted on 69 patients with closed displaced clavicle fractures between May 2014 and May 2016. Patients with medial or lateral third clavicle fractures, polytrauma and compound fractures were excluded from the study. Patients treated with plating were in group A (n = 36) while those treated with arm pouch were in group B (n = 33). RESULTS: The mean age of the patient in group A was 32.4 +/- 43 and group B was 31.7 +/- 26 years. 48 (69.9%) females were involved in the study. History of fall was the most common mechanism of injury affecting 51 (73.9%) patients. All the patients were type 2 B as per the Robinson classification system. The average operative duration was 78.3 +/- 12.4 min. Union was seen at 15.6 +/- 0.8 in group A and 22.8 +/- 0.4 in group B (p < 0.0001). Two (6%) of the patients in group B had non-union. One (2.7%) patient in group A had mal-union. Two (5.5%) patients had plate prominence. One (2.7%) patient had superficial infection. The Constant and Murley scoring at 24 months was 89.42 and 76.24 in group A and group B respectively. CONCLUSION: Plating for displaced mid-shaft clavicle fractures is can lead to better functional and radiological outcomes with minimal complications as compared to the conservative modality of treatment. PMID- 29704956 TI - The prevalence and characteristics of overweight and obesity among students in Qatar. AB - OBJECTIVES: To estimate the prevalence of overweight and obesity using World Health Organisation (WHO) cut-offs for the body mass index (BMI) among students of the general population living in Qatar in the period 2015-2016. STUDY DESIGN: Cross-sectional study. METHODS: The study includes 164,963 students aged 5-19 years. The body weight and height were measured to calculate the BMI. The WHO standard cut-offs were used to categorise the BMI into severe thinness (BMI z score <-3), thinness (BMI z-score >=-3 to <-2), normal (BMI z-score >=-2 to <1), overweight (BMI z-score >=+1 to <+2) and obese (BMI z-score >+2). RESULTS: Overweight and obesity prevalence was 44.8% and 40.4% among males and females and 45.6% and 40.9% among Qatari and non-Qatari students, respectively. Odds of obesity and overweight status were significantly higher among 10-14 and 15-19 age groups than 5-9 years age group (P < 0.001). By sex, males had 1.48 times higher odds of having obesity than females (P < 0.001), and Qatari nationals had 1.4 times higher odds of obesity than non-Qataris (P < 0.001). Although non-Qatari males also had higher odds of being overweight than females (odds ratio [OR] = 1.05, P = 0.0006), the opposite was seen among Qatari students (OR = 0.95, P = 0.01). CONCLUSION: The result of this survey provides evidence of a high prevalence of overweight and obese students living in Qatar. Therefore, preventive strategies are essential in this population to lower the incidence of being overweight and obesity. PMID- 29704957 TI - Prevalence of physical activity and sedentary-related behaviors among adolescents: data from the Qatar National School Survey. AB - OBJECTIVES: To investigate the prevalence of physical activity (PA) and sedentary behaviors among adolescents in Qatar by selected demographic characteristics. STUDY DESIGN: Cross-sectional study. METHODS: A total of 5862 students (2938 boys and 2924 girls) in the age group 12-17 years were included in the analyses. PA and sedentary-related measures were obtained from the self-reported survey questions. RESULTS: Only 35.4% of students were performing 60 min of PA >=3 days/week. The proportion of students with >2 hr screentime ranged from 43% to 57% (weekdays) and 50% to 62.5% (weekends). Girls had less odds of being physically active than the boys (odds ratio [OR] = 0.61, P < 0.001). Qatari students were less likely to be physically active than non-Qataris (OR = 0.79, P < 0.001). Age was inversely correlated with PA ([r = -0.113, P < 0.001 for participation with sports team] and [r = -0.139, P < 0.001 for school physical education classes]). Participation in sports teams positively correlated with 60 min of PA number of days in a week (r = 0.317, P < 0.001). CONCLUSIONS: The study describes insufficient PA among youth as a public health issue of concern in the State of Qatar that requires multipronged health promotion initiatives. PMID- 29704958 TI - [Misdiagnosis of hidradenitis suppurativa continues to be a major issue. The R ENS Verneuil study]. AB - OBJECTIVE: To provide physicians with an understanding of the factors behind significant delays in the diagnosis of hidradenitis suppurativa (HS) in France. PATIENTS AND METHODS: This prospective multicentre national study conducted from October 2015 to March 2016 included all patients consulting for HS. Patient data were collected by means of a standardized questionnaire. Univariate and multivariate analyses were conducted to collect factors associated with a significant time to diagnosis of at least 5.5years, defined as the period between the onset of initial clinical signs and the time of formal diagnosis. RESULTS: The 16 participating centres enrolled 312 patients (62% women), of average age 35years. The average age at onset of HS was 22years. Before formal diagnosis by a dermatologist (64% of cases), 170 (54%), 114 (37%) and 45 (15%) patients had previously consulted at least 3, 5 and 10 general physicians, respectively. The average time between the initial clinical signs of HS, the first dermatology visit and the definitive diagnosis was 6.2 and 8.4 years, respectively. Active smoking (OR adjusted 1.85; P=0.027) and disease onset at a younger age (adjusted OR 0.92; P<0.001) were both associated with significant delays in diagnosis. CONCLUSION: These results emphasized misdiagnosis among HS patients but did not evidence any association between either sociodemographic or economic characteristics and the existence of significant times to diagnosis. PMID- 29704960 TI - After the experimental turn: A commentary on Deaton and Cartwright. PMID- 29704959 TI - ? AB - Behcet's disease is a rare multisystemic vasculitis with an etiology that is still unknown. Neurological manifestations may be seen in approximately 5-15% of patients, and both parenchymal and extraparenchymal neurological involvement has been described. When cerebral venous thrombosis (CVT) is the main extraparenchymal manifestation of Behcet's disease, the condition is then dubbed "angio-Behcet's syndrome". However, arterial involvement is extremely rare, with only one reported case of vasculo-neuro-Behcet's disease, characterized by both venous and intracranial arterial involvement - until now. This report is of two patients diagnosed with Behcet's disease characterized by the concomitant presence of both cerebral arterial manifestations and CVT. PMID- 29704961 TI - Challenging the hegemony of randomized controlled trials: A commentary on Deaton and Cartwright. PMID- 29704962 TI - New Directions in the Cognitive-Behavioral Treatment of OCD: Theory, Research, and Practice. AB - The beneficial effects of cognitive-behavioral interventions (particularly exposure and response prevention) for OCD are among the most consistent research findings in the mental health literature. Nevertheless, even after an adequate trial, many individuals experience residual symptoms, and others never receive adequate treatment due to limited access. These and other issues have prompted clinicians and researchers to search for ways to improve the conceptual and practical aspects of existing treatment approaches, as well as look for augmentation strategies. In the present article, we review a number of recent developments and new directions in the psychological treatment of OCD, including (a) the application of inhibitory learning approaches to exposure therapy, (b) the development of acceptance-based approaches, (c) involvement of caregivers (partners and parents) in treatment, (d) pharmacological cognitive enhancement of exposure therapy, and (e) the use of technology to disseminate effective treatment. We focus on both the conceptual/scientific and practical aspects of these topics so that clinicians and researchers alike can assess their relative merits and disadvantages. PMID- 29704963 TI - A Multimethod Examination of the Effect of Insomnia Symptoms on Anxious Responding to a Social Stressor. AB - A growing number of studies identify insomnia symptoms as a potential risk factor for the development of anxiety disorders. However, little research has examined potential mechanisms through which insomnia could confer increased risk for anxiety. A separate line of literature suggests sleep is necessary for adaptive emotional and behavioral responding to stressors, a potential mechanism linking insomnia symptoms to anxiety risk. To test whether insomnia symptoms affect emotional and behavioral responding to an anxiety-relevant stressor, the current study recruited a sample of 99 undergraduates with varying levels of insomnia symptoms. Participants completed self-report and psychophysiological measures before, during, and after an impromptu speech task. Results indicated that, after covarying for negative affectivity, increased insomnia symptoms were significantly associated with elevated anticipatory anxiety and skin conductance response prior to the speech, and increased skin conductance response, emotion regulation difficulties, and safety aid use during the speech. Taken together, results provide evidence for the notion that insomnia symptoms are associated with maladaptive emotional and behavioral responding to an anxiety-relevant stressor. PMID- 29704964 TI - The Long-Term Effects of Group-Based Psychological Interventions for Children With Tourette Syndrome: A Randomized Controlled Trial. AB - This randomized controlled trial examined the long-term effects of group-based psychological interventions on measures of tic severity, self-reported quality of life (QOL), and school attendance. Children (n = 28) with Tourette syndrome (TS) were assessed 12 months after completing a course of either group-based Habit Reversal Training (HRT) or Education. Both groups demonstrated long-term improvement in tic severity and QOL, which included significant continued improvement during the follow-up (FU) period. Both groups also showed significant posttreatment improvement in school attendance. Further research is required to explore potential therapeutic mechanisms, independent or mutual, which may underlie long-term symptom improvements. PMID- 29704965 TI - Changes in Problematic Anger, Shame, and Disgust in Anxious and Depressed Adults Undergoing Treatment for Emotion Dysregulation. AB - Emotion dysregulation, the pervasive difficulty managing negative emotions, is a core problem across mood and anxiety disorders. Anger, shame, and disgust are particularly problematic emotions, impacting both disorder severity and treatment outcome. We previously found that a 16-week dialectical behavior therapy skills training group (DBT-ST) was superior to an activities-based support group (ASG) in decreasing emotion dysregulation in 44 adults with high emotion dysregulation who met diagnostic criteria for an anxiety or depressive disorder. We presently examine these participants' changes in anger, shame, disgust, and distress using self-reports collected over 6 months during and after treatment. Hierarchical linear modeling analyses show that DBT-ST was superior to ASG in decreasing anger suppression (d = 0.93) and distress (d = 1.04). Both conditions significantly reduced shame, disgust propensity, and disgust sensitivity, but neither was superior for these outcomes. The treatments did not significantly reduce anger expression. Mediation analyses suggest that condition indirectly influenced 4 month anger suppression, shame, and distress through its effect on 2-month emotion dysregulation. These findings suggest that DBT-ST is efficacious for certain problematic emotions and distress in depressed and anxious adults and that common factors may account for some, but not all, of its benefits. PMID- 29704966 TI - The Use of Acceptance and Commitment Therapy to Promote Mental Health and School Engagement in University Students: A Multisite Randomized Controlled Trial. AB - The aim of this multisite randomized controlled trial was to determine whether an intervention based on Acceptance and Commitment Therapy (ACT) was efficacious in improving university students' psychological flexibility, mental health, and school engagement. Students were recruited in four Canadian universities and randomly assigned to an intervention (n = 72) or a wait-list control group (n = 72). Students in the intervention group took part in four 2.5-hour workshops during a 4-week period and were asked to do exercises at home (e.g., meditation, observation grids). Wait-list students received the intervention soon after the post measurements. MANCOVAs and ANCOVAs revealed that students in the intervention group showed greater psychological flexibility at postintervention than those in the control group. They also reported greater well-being and school engagement, and lower stress, anxiety, and depression symptoms. Taken together, results of this study suggest that an ACT-based intervention offers a valuable way to promote mental health and school engagement in postsecondary settings. PMID- 29704967 TI - Social Anxiety and the Quality of Everyday Social Interactions: The Moderating Influence of Alcohol Consumption. AB - Most research on the link between social anxiety and alcohol consumption has examined problematic outcomes without consideration of potential adaptive functions. Alcohol is an anxiolytic that has the short-term benefit of reducing anxiety; consumption may act as a social lubricant that facilitates higher quality social interactions. Using experience-sampling methodology, we examined how consuming alcohol attenuates the adverse effects of social anxiety in naturally occurring social interactions. Participants (N = 160) completed demographic and trait measures, then completed daily assessments for 14 consecutive days. Results from multilevel model analyses revealed that during face-to-face social interactions, state social anxiety was inversely related to 10 indicators of healthy social interactions (e.g., enjoyment, laughter, feelings of acceptance). Alcohol consumption moderated seven of these associations, such that when participants consumed alcohol in social situations, state social anxiety was no longer associated with social interaction quality. The quantity of alcoholic drinks consumed moderated two of these associations. Furthermore, we found evidence for directionality, such that social anxiety in a given social interaction predicted alcohol consumption in a subsequent social interaction, but not the reverse (i.e., alcohol consumption did not prospectively predict state social anxiety). In social situations that involved alcohol, experiences of social anxiety no longer thwarted one's ability to derive social benefits. These results should be interpreted in the context of a participant sample with relatively low levels of trait social anxiety and frequency of alcohol use. Nonetheless, obtaining social rewards may be a reinforcement mechanism that maintains the link between social anxiety and alcohol consumption. PMID- 29704968 TI - Body Image-Acceptance and Action Questionnaire-5: An Abbreviation Using Genetic Algorithms. AB - Body image concerns are typically linked with negative outcomes such as disordered eating and diminished well-being, but some people can exhibit psychological flexibility and remain committed to their valued goals despite being dissatisfied about their bodies. Such flexibility is most frequently measured by the Body Image-Acceptance and Action Questionnaire (BI-AAQ). This study used a recently validated, fully automated method based on genetic algorithms (GAs) on data from an American community sample (N1=538, 71.5% female, Age: M = 40.87, SD = 13.5) to abbreviate the 12-item BI-AAQ to a 5-item short form, BI-AAQ-5. Validation tests were conducted on data from an independent community sample (N2= 762, 44.6% female, Age: M = 40.65, SD = 13.06). The short form performed comparably to the long form in terms of its factor structure and correlations with theoretically relevant constructs, including body image dissatisfaction, stigma, internalization of societal norms of appearance, self compassion, and poor mental health. Further, preliminary analyses using structural equation modeling showed that body image flexibility, as measured by either the long or short form, was associated with almost all the criterion variables, even while controlling for a highly related construct of body image dissatisfaction. These results demonstrate the potential discriminant validity of both the long and short form of the BI-AAQ, and show that the BI-AAQ-5 is a suitable alternative to its long form. We discuss how psychological flexibility with respect to body image dissatisfaction can be conducive to positive functioning. PMID- 29704969 TI - A Pilot Study of Emotion Regulation Therapy for Generalized Anxiety and Depression: Findings From a Diverse Sample of Young Adults. AB - Emotion regulation therapy (ERT) for generalized anxiety disorder (GAD) and accompanying major depressive disorder (MDD) is a theoretically derived, evidence based treatment that integrates principles from traditional and contemporary cognitive-behavioral and experiential approaches with basic and translational findings from affect science to offer a blueprint for improving intervention by focusing on the motivational responses and corresponding self-referential regulatory characteristics. Preliminary evidence supports the efficacy of a 20 session version of ERT. However, previous trials of ERT and other traditional and contemporary cognitive-behavioral therapies have often utilized relatively homogeneous samples. Various contextual and demographic factors may be associated with challenges that increase risk for negative mental and social outcomes for young adults ages 18-29, particularly for individuals from diverse backgrounds. The aim of this pilot study was to examine the effectiveness of a briefer 16 session version of ERT in a racially and ethnically diverse sample of young adults. Participants (N = 31) were enrolled at an urban-based, commuter college who consented to treatment for anxiety, worry, or depression at an on-campus counseling center. Open-trial results demonstrate strong ameliorative changes in worry, rumination, self-reported and clinician-rated GAD and MDD severity, social disability, quality of life, attentional flexibility, decentering/distancing, reappraisal, trait mindfulness, and negative emotionality from pre- to posttreatment. These gains were maintained throughout a 3- and 9-month follow-up. These findings provide preliminary evidence for the efficacy of ERT in treating a racially and ethnically heterogeneous population. Further, this study highlights comparable effectiveness of a briefer 16-session version of ERT. PMID- 29704970 TI - Working Memory and Motor Activity: A Comparison Across Attention Deficit/Hyperactivity Disorder, Generalized Anxiety Disorder, and Healthy Control Groups. AB - Converging findings from recent research suggest a functional relationship between attention-deficit/hyperactivity disorder (ADHD)-related hyperactivity and demands on working memory (WM) in both children and adults. Excessive motor activity such as restlessness and fidgeting are not pathognomonic symptoms of ADHD, however, and are often associated with other diagnoses such as generalized anxiety disorder (GAD). Further, previous research indicates that anticipatory processing associated with anxiety can directly interfere with storage and rehearsal processes of WM. The topographical similarity of excessive motor activity seen in both ADHD and anxiety disorders, as well as similar WM deficits, may indicate a common relationship between WM deficits and increased motor activity. The relationship between objectively measured motor activity (actigraphy) and PH and visuospatial WM demands in adults with ADHD (n = 21), adults with GAD (n = 21), and healthy control adults (n = 20) was examined. Although all groups exhibited significant increases in activity from control to WM conditions, the ADHD group exhibited a disproportionate increase in activity, while activity exhibited by the GAD and healthy control groups was not different. Findings indicate that ADHD-related hyperactivity is uniquely related to WM demands, and appear to suggest that adults with GAD are no more active relative to healthy control adults during a cognitively demanding laboratory task. PMID- 29704971 TI - Experiential Avoidance: An Examination of the Construct Validity of the AAQ-II and MEAQ. AB - Experiential avoidance (also referred to as acceptance or psychological flexibility) is a core construct of third-wave behavior therapies. It is the tendency to avoid uncomfortable thoughts or feelings, even when doing so has negative long-term consequences. In order for developments in experiential avoidance and third-wave behavior therapies to continue, it is imperative to examine the construct validity of the most widely used measures of this construct, the Acceptance and Action Questionnaire-II (AAQ-II) and the Multidimensional Experiential Avoidance Questionnaire (MEAQ). In Amazon's Mechanical Turk (N = 1,052) and college (N = 364) samples, we evaluated the construct validity of these measures. The AAQ-II demonstrated suboptimal patterns of convergent and discriminant validity with measures of neuroticism/negative affect (Big Five Inventory, Big Five Aspects Scale, Positive and Negative Affect Schedule), the MEAQ, and mindfulness (Five Factor Mindfulness Questionnaire). In contrast, the MEAQ demonstrated optimal convergent and discriminant validity. Factor analyses at the scale, subscale, and item levels demonstrated that the AAQ II loads with indicators of neuroticism/negative affect and not with other constructs at the core of third-wave behavior therapies. In contrast, the MEAQ loads on factors with mindfulness or forms its own factors. These findings suggest the AAQ-II functions as a measure of neuroticism/negative affect, whereas the MEAQ functions as an indicator of experiential avoidance. These findings have substantial implications for research on experiential avoidance and third-wave behavior therapies. Therefore, in order to improve the theory, research, and practice of third-wave behavior therapies, we recommend using the MEAQ to assess experiential avoidance. PMID- 29704972 TI - Safety Behavior After Extinction Triggers a Return of Threat Expectancy. AB - Safety behavior is involved in the maintenance of anxiety disorders, presumably because it prevents the violation of negative expectancies. Recent research showed that safety behavior is resistant to fear extinction. This fear conditioning study investigated whether safety behavior after fear extinction triggers a return of fear in healthy participants. Participants learned that two stimuli (A and C) were followed by an aversive loud noise ("threat"), and one stimulus (B) was not. Participants then learned to use safety behavior that prevented the loud noise. Next, A and C were no longer followed by the loud noise, which typically led to extinction of threat expectancy. Safety behavior then became available again for C, but not for A and B. All participants used safety behavior on these C trials. In a final test phase, A, B, and C were presented once without the availability to use safety behavior. At each stimulus presentation, participants rated threat expectancy by indicating to what extent they expected that the loud noise would follow. Compared with the last extinction trial, threat expectancy increased for C in the test phase, whereas it did not increase for A and B. Hence, safety behavior after the extinction of classically conditioned fear caused a partial return of fear. The findings suggest that safety behavior may be involved in relapse after exposure-based therapy for anxiety disorders. PMID- 29704973 TI - The Efficacy and Acceptability of Third-Wave Behavioral and Cognitive eHealth Treatments: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - eHealth is an innovative method of delivering therapeutic content with the potential to improve access to third-wave behaviural and cognitive therapies. This systematic review and meta-analysis aimed to determine the efficacy and acceptability of third-wave eHealth treatments in improving mental health outcomes. A comprehensive search of electronic bibliographic databases including PubMed, PsycINFO, Web of Science, and CENTRAL was conducted to identify randomized controlled trials of third-wave treatments in which eHealth was the main component. Twenty-one studies were included in the review. Meta-analyses revealed that third-wave eHealth significantly outperformed inactive control conditions in improving anxiety, depression, and quality-of-life outcomes and active control conditions in alleviating anxiety and depression with small to medium effect sizes. No statistically significant differences were found relative to comparison interventions. Findings from a narrative synthesis of participant evaluation outcomes and meta-analysis of participant attrition rates provided preliminary support for the acceptability of third-wave eHealth. Third-wave eHealth treatments are efficacious in improving mental health outcomes including anxiety, depression, and quality of life, but not more so than comparison interventions. Preliminary evidence from indices of participant evaluation and attrition rates supports the acceptability of these treatments. PMID- 29704975 TI - 1000 consecutive liver transplants. Descriptive analysis and evolution of a single center. AB - Between 1991 and 2013, 1,000 liver transplantations were performed at Virgen del Rocio Hospital (Seville, Spain). A retrospective study was conducted, analyzing the characteristics of recipients and donors, indications, surgical technique, complications and survival in 2 different stages (1991-2002 vs. 2003-2013) coinciding with the implementation of the MELD scale as a prioritization model. The most frequent indication were of hepatopathy of hepatocellular origin in 48.8%. There was a significant increase in the indications for hepatocarcinoma (8.6% and 24.1% P=0.03), and the rate of retransplantation (5.9% vs 9.6%, P=0.04). There was a change in the age of donation, going from 27.7 years in 1990 to 62.9 years in 2012 (P=0.001). The percentage of patients who did not require blood transfusion doubled (6.16 vs. 14.31%, P=.001). Survival of all patients after one, 5 and 10 years was 77, 63.5 and 51.3%, respectively. PMID- 29704976 TI - Acral ischemia secondary to pheochromocytoma. PMID- 29704977 TI - Outcomes of an Innovative Evidence-Based Practice Project: Building a Difficult Access Team in the Emergency Department. AB - PROBLEM: Difficult venous access is a common problem in health care-especially in the emergency setting-that relies on quick diagnostics to differentiate patient acuities and administer critical medications. The creation of a dedicated team to address difficult venous access (DVA) is a possible solution to the problems of delayed venous access, yet no studies have been published on implementing such a team in the emergency department. METHODS: This was a quasi-experimental study in an urban emergency department. Researchers performed chart audits of staff identified patients with DVA to gather baseline data. A DVA team was subsequently implemented 16 hours a day, 7 days a week. Data were recorded on patients referred to the team and included time, number of IV attempts, and patient characteristics. RESULTS: Baseline data were collected on 53 patients, and postintervention data included 135 patients. The implementation of a DVA team decreased the mean lab order-to-lab completion time by 115 minutes (P < 0.0001). Decreases in the number of attempts were not statistically significant. Patients requiring increased numbers of IV attempts also had many common characteristics including history of multiple attempts, poor skin quality, and IV drug use. DISCUSSION: The use of a dedicated team for DVA reduces the lag time from physician orders to actionable diagnostics or administration of medication. A dedicated DVA technician is a concrete solution to threats of patient safety, as well as ED crowding, and has the potential to affect both patient- and department level care. PMID- 29704978 TI - Counseling Suicidal Patients About Access to Lethal Means: Attitudes of Emergency Nurse Leaders. AB - INTRODUCTION: For ED patients at risk of suicide, counseling to reduce access to lethal means (including firearms) is recommended yet not routine. To enhance practice uptake, we sought to examine the attitudes and beliefs of emergency nurse leaders concerning the acceptability and effectiveness of lethal-means counseling. METHODS: We invited a nurse leader (ED nurse manager or Chief Nursing Officer [CNO]) at each hospital-based emergency department in the 8-state Mountain West region of the United States to complete a closed-ended telephone survey. Questions assessed current practices and leaders' views on suicide prevention and lethal-means counseling. Reponses were weighted to all eligible hospitals to adjust for nonresponse. RESULTS: From 363 eligible hospitals, 190 emergency nurse leaders responded (overall response rate: 52%). Emergency nurse leaders thought providers at their emergency departments did an excellent job of safety counseling (74%) for suicidal patients. Most respondents believed that talking about firearms with suicidal patients is acceptable to patients (77%), supported by hospital administration (64%), effective in preventing suicide (69%), and something that providers should do (91%). However, the majority also had doubts about whether suicide is preventable (60%). DISCUSSION: Despite expressing high levels of support for the acceptability and effectiveness of lethal-means counseling, high proportions of emergency nurse leaders expressed skepticism regarding the preventability of suicide, a finding consistent with previous work. Our results support the need to address and modify misperceptions about prevention of suicide in any efforts for widespread implementation and dissemination of lethal-means counseling. PMID- 29704979 TI - Improving Emergency Health Care Workers' Knowledge, Competency, and Attitudes Toward Lesbian, Gay, Bisexual, and Transgender Patients Through Interdisciplinary Cultural Competency Training. AB - INTRODUCTION: Emergency staff members have a unique role in providing episodic care to marginalized populations. The lesbian, gay, bisexual, and transgender (LGBT) community is a marginalized population that is routinely encountered by ED staff. Implicit prejudice may influence emergency staff interactions and contribute to distrust of health care providers by some members of the LGBT community. The purpose of our study is to evaluate aggregate ED health care team member's knowledge and attitudes toward lesbian, gay, bisexual, and transgender people pre- and post-cultural competency training education. METHODS: A pre-/post intervention design was used to assess the impact of LGBT cultural competency training. The Ally Identity Measure (AIM) was administered to an unmatched sample of ED nurses, nurse practitioners, unit secretaries, and physicians. Consisting of 3 domains- knowledge and skills, openness and support, and awareness of oppression experienced by the LGBT community (Cronbach's alphas of 0.76 to 0.88) the AIM assessed for aggregate differences among our staff pre- and post-cultural competency training. RESULTS: Pre-survey data revealed 85.3 % (n = 81) of staff had no previous LGBT education specific to the needs of the population. Post survey data collected between 3 to 5 months after the education intervention demonstrated a total index mean increase of 8.8% (P < 0.001) in the areas of knowledge and skills, openness and support, and awareness of oppression regarding the LGBT community. DISCUSSION: Status post-cultural competency training, the AIM results indicated that our team's collective knowledge about challenges facing the LGBT community increased, and the aggregate scores reflected more openness, support, and awareness of oppression by our staff. This elevated self-awareness and increased knowledge may aid in creating a more open, supportive patient experience for the LGBT community members seeking care at our facility. PMID- 29704980 TI - Emergency Department Crowding and Time at the Bedside: A Wearable Technology Feasibility Study. AB - INTRODUCTION: ED crowding is a public health crisis, limiting quality and access to lifesaving care. The purpose of this study was to (1) evaluate the feasibility of radio-frequency identification tags to measure clinician-patient contact and (2) to test the relationship between ED occupancy and clinician-patient contact time. METHODS: In this 4-week observational study, radio-frequency identification tags were worn by emergency clinicians in a 21-bay urban teaching hospital emergency department. The time-motion data were merged with electronic medical repository patient information (N = 3,237) to adjust for occupancy, age, gender, and acuity. Qualitative themes were generated from focus group (N = 39) debriefings of the quantitative results. RESULTS: Data were collected on 56,342 total clinician events. Adjusting for patient age, increasing ED occupancy increased the number of times the attending physician entered and left the patient room (b = 0 .008, 95% confidence interval [CI] = [0.001-0.016], P = 0.03). There was no relationship for patient gender, triage acuity, shift at arrival, disposition to home, or discharge diagnosis category with either total minutes or number of encounters per patient visit. No time-motion and occupancy associations were observed for nurses, residents, or nurse practitioners/physician assistants. Debriefings indicated occupancy influenced the quality of care, despite maintaining the same quantity of contact time. DISCUSSION: The physical environment and clinician privacy concerns limit the feasibility of wearable tracking technology in the emergency setting. Attending physician care becomes more fragmented with increasing ED occupancy. Other clinicians report changes in the quality of care, whereas the quantity of time and encounters were unchanged with occupancy rates. PMID- 29704981 TI - Ub and Down: Ubiquitin Exercise for the Elderly. AB - Conjugation of ubiquitin onto proteins generates a degradation signal or exerts degradation-independent regulatory functions. Ubiquitylation is governed by the antagonistic action of ubiquitin ligases and deubiquitylating enzymes (DUBs). Several recent publications illustrate a balanced interplay of ligases and DUBs at signaling hubs that are central to longevity and protein homeostasis (proteostasis). In addition, stress-induced alterations of ubiquitin conjugation are emerging as key events that drive aging and contribute to the pathology of age-related diseases. This physiological role of dynamic ubiquitylation further extends its well-known function in protein regulation and quality control at the cellular level. Recent work thus significantly advances our understanding of the aging process both at the molecular and organismal level. PMID- 29704982 TI - Cellular Senescence in Postmitotic Cells: Beyond Growth Arrest. AB - In mitotic cells, cellular senescence is a permanent state of G1 arrest, that may have evolved in parallel to apoptosis, to limit proliferation of damaged cells and oncogenesis. Recent studies have suggested that postmitotic cells are also capable of entering a state of senescence, although the repercussions of postmitotic cellular senescence (PoMiCS) on tissue health and function are currently ill-defined. In tissues made largely of post-mitotic cells, it is evolutionary advantageous to preserve cellular integrity and cellular senescence of post-mitotic cells may prevent stressor-induced tissue degeneration and promote tissue repair. Paradoxically, PoMiCS may also contribute to disease progression through the generation of inflammatory mediators, termed the senescence-associated secretory phenotype. Here, we discuss the potential roles of PoMiCS and propose to enlarge the current definition of cellular senescence to postmitotic terminally differentiated cells. PMID- 29704983 TI - Intermittent stimulation in the nucleus basalis of meynert improves sustained attention in rhesus monkeys. AB - Sustained attention is essential in important behaviors in daily life. Many neuropsychiatric disorders are characterized by a compromised ability to sustain attention, making this cognitive domain an important therapeutic target. In this study, we tested a novel method of improving sustained attention. Monkeys were engaged in a continuous performance task (CPT) while the nucleus basalis of Meynert (NB), the main source of cholinergic innervation of the neocortex, was stimulated. Intermittent NB stimulation improved the animals' performance by increasing the hit rate and decreasing the false alarm rate. Administration of the cholinesterase inhibitor donepezil or the muscarinic antagonist scopolamine alone impaired performance, whereas the nicotinic antagonist mecamylamine alone improved performance. Applying NB stimulation while mecamylamine or donepezil were administered impaired CPT performance. Methylphenidate, a monoaminergic psychostimulant, was applied in conjunction with intermittent stimulation as a negative control, as it does not directly modulate cholinergic output. Methylphenidate also improved performance, and it produced further improvement when combined with NB stimulation. The additive effect of the combination suggested NB stimulation altered behavior independently from methylphenidate effects. We conclude that basal forebrain projections contribute to sustained attention, and that intermittent NB stimulation is an effective way of improving performance. PMID- 29704984 TI - Antibacterial activity of extracted bioactive molecules of Schinus terebinthifolius ripened fruits against some pathogenic bacteria. AB - The aim of this work is to identify the chemical constituents and the bioactivity of essential oil (EO), acetone extract (ACE) and n-hexane extract (HexE) of S. terebinthifolius ripened fruits using GC-MS. Total phenolic content and antioxidant activity of extracts were determined using the Folin-Ciocalteu and 1,1-diphenyl-2-picryl-hydrazyl (DPPH) assays, respectively. The toxicity against the growth of Acinetobacter baumannii, Bacillus subtilis, Escherichia coli, Micrococcus flavus, Pseudomonas aeruginosa, Sarcina lutea, and Staphylococcus aureus was determined with measuring the inhibition zones (IZs) using the disc diffusion method at the concentrations from 125 to 2000 MUg/mL, also, the minimum inhibitory concentrations (MICs) using 96-well micro-plates and ranged from 4 to 2000 MUg/mL. The major components in EO were alpha-pinene (36.9%), and alpha phellandrene (32.8%). The major components in ACE were oleic acid (38.7%), alpha phellandrene (13.33%), and delta-cadinene (11.1%), while the major methyl esters of fatty acids detected in HexE were oleic (12.8%), and palmitic (10.9%). The EO showed good activity against the growth of Staph. aureus and P. aeruginosa with MIC values of 16 MUg/mL and 32 MUg/mL, the ACE showed broad activity against the studied bacterial pathogens with MIC values ranged from of 4-128 MUg/mL against the studied bacterial isolates, while HexE, however, showed weak antibacterial activity. The IC50 values of EO, ACE and HexE were 15.11 +/- 0.99, 118.16 +/- 1.7 and 324.26 +/- 2.45 MUg/mL, respectively, compared to IC50 of Tannic acid (23.83 +/- 1.9 MUg/mL) and butylated hydroxytoluene (BHT, 2.9 +/- 0.1 MUg/mL). Data suggested that the ripened fruits of S. terebinthifolius have potent antioxidant and antibacterial activities. PMID- 29704985 TI - Effects of the probiotics Lactococcus lacttis (MTCC-440) on Salmonella enteric serovar Typhi in co-culture study. AB - Lactococcus lactis (L. lactis)a probiotics microorganism having wide range of benefits on human health, and also protects the body from pathogenic microorganism. This study was conducted to determine the co-culture effect with the probiotic strain L. lactis (MTCC440) on Salmonella enterica serovar Typhi (S.Typhi). The existing problem was to determine the individual growth of both strains during co-culture. Growth kinetics study was performed and observed for 28 h and used to determine specific growth rate of S. Typhi under co-culture study. In growth kinetics study maximum specific growth rate (MU) of S. Typhi under monoculture and co-culture study was achieved 0.695 h-1 and 0.35 h-1 respectively. The maximum cell mass of L. lactis and S. Typhi was obtained 0.15 g/L and 0.18 g/L respectively. In co-culture study, L. lactis was found effective for the inhibition of 73% growth of S. Typhi due to lactic acid production. PMID- 29704986 TI - Beliefs About Dementia: Development and Validation of the Representations and Adjustment to Dementia Index (RADIX). AB - OBJECTIVES: The Self-Regulation Model (SRM) identifies that the beliefs people hold about an illness can influence their responses to that illness. Although there are generic measures of illness representations, there is a need for a brief tailored measure to use with people with dementia. The aim of this study was to develop and validate a brief measure called the Representations and Adjustment to Dementia Index (RADIX). The RADIX contains questions on the SRM elements: Identity, Cause, Timeline, Control, and Consequences. METHODS: The RADIX validation was conducted with a sample of 385 community-dwelling people with mild to moderate dementia who were taking part in the IDEAL cohort study. Test-retest reliability was conducted over a 4-week period with a separate sample of 20 people with dementia. RESULTS: The validation process resulted in a reduction in the number of items in the Timeline, Control, and Consequences items. The resulting RADIX demonstrated good acceptability, internal reliability, and test-retest reliability. All the RADIX items had low missing data, indicating good acceptability. The factor analysis confirmed that the Consequences items formed two subscales (practical and emotional consequences) that had Cronbach's alpha of 8 and 0.91 respectively. Test-retest reliability indicated that the Identity, Timeline, and Control items had moderate reliability and the practical and emotional consequences scales had good reliability. CONCLUSIONS: The RADIX demonstrates acceptable psychometric properties, proves to be a useful measure for exploring people's beliefs about dementia, and could aid the provision of tailored information and support to people with dementia. PMID- 29704987 TI - Impaired Identification of Specific Odors and Cognition in Older Adults. PMID- 29704988 TI - Genetic polymorphisms of IL17A, TLR4 and P2RX7 and associations with the risk of chronic obstructive pulmonary disease. AB - We investigated the association between genetic polymorphisms of IL17A, TLR4 and P2RX7 genes and chronic obstructive pulmonary disease (COPD) in a Han population. We performed a case-control study with 152 COPD subjects from the Third People's Hospital of Nantong in 2015. Healthy controls were selected from a group of people attending the physical examination and were frequency-matched to the cases by sex and age. Genotyping was performed using TaqMan allelic discrimination technology. A logistic regression model was used to calculated odds ratios (OR) and 95% confidence intervals (CI). After Bonferroni correction, polymorphisms rs2275913 and rs763780 in the IL17A gene, rs10759932 and rs2737190 in the TLR4 gene, and rs1718119 in the P2RX7 gene were significantly associated with altered risk for COPD. Individuals carrying rs2275913 allele A had a reduced risk (OR 0.62; 95% CI: 0.46-0.86). Individuals carrying rs763780 allele C had an increased risk (OR 1.96; 95% CI: 1.29-2.98). Individuals carrying rs10759932 allele C had a reduced risk (OR 0.49; 95% CI: 0.34-0.73). Individuals carrying rs2737190 allele G had a reduced risk (OR 0.51; 95% CI: 0.37-0.71). Individuals carrying rs1718119 allele A had a reduced risk (OR 0.69; 95% CI: 0.45-1.06).Genetic polymorphisms in IL17A, TLR4 and P2RX7 genes were significantly associated with altered risks for COPD. PMID- 29704989 TI - Genotoxicity assessment of the novel antitussive agent Benzonatate and its major metabolite. AB - Benzonatate (TESSALON(r)) is a peripherally acting oral antitussive. It undergoes rapid ester hydrolysis producing 4-(butylamino) benzoic acid (BBA) and methylated polyethylene glycol (MPG) metabolites, which are eliminated in urine and feces. The nonclinical and clinical efficacy of Benzonatate has been demonstrated over the last 60 years, but its safety was not fully assessed. In this study, we tested the genotoxicity of Benzonatate and its major metabolite BBA in an in vitro bacterial reverse mutation and in vivo micronucleus assays. A chromosomal aberration assay was also performed on Benzonatate and BBA. In the reverse mutation assay, Benzonatate and BBA doses 1.5-5000 MUg/plate +/- S9 metabolic activation were used and the numbers of revertants/plate were compared to various controls. Chromosomal aberration assays with human peripheral blood lymphocytes used Benzonatate and BBA concentrations 25-2000 and 62.5-1930 MUg/mL, respectively. A CByB6F1 mouse bone marrow micronucleus assay was performed as part of a 28-day oral toxicology study at up to 250 mg/kg/day. The frequencies of micronuclei in polychromatic erythrocytes in treated groups were compared with the control group. Neither Benzonatate nor BBA induced significant mutagenicity in any of the bacterial strains, with or without metabolic activation. They also did not produce any biologically relevant structural or numerical aberrations in human chromosomes. Benzonatate and its BBA and MPG metabolites rapidly produced from esterase activity did not produce any significant increase in the incidence of micronucleated polychromatic erythrocytes. In conclusion, Benzonatate and its major metabolite BBA were not mutagenic and did not cause numerical or structural chromosome alterations. While the MPG metabolite was not tested, studies on structural analogues indicated it was also unlikely to be genotoxic. This was supported by oral rodent carcinogenicity assays showing no increase in malignancies. PMID- 29704990 TI - The metabolism of imidacloprid by aldehyde oxidase contributes to its clastogenic effect in New Zealand rabbits. AB - Imidacloprid (IMI) is a systemic, chloro-nicotinyl insecticide classified in Regulation N degrees 1272/2008 of the European Commision as "harmful if swallowed and very toxic to aquatic life, with long-lasting effects". IMI is metabolized in vitro both by aldehyde oxidase (AOX) (reduction) and by cytochrome P450s enzymes (CYPs). In the present study, the AOX inhibitor sodium tungstate dihydrate (ST) was used to elucidate the relative contribution of CYP 450 and AOX metabolic pathways on IMI metabolism, in male rabbits exposed to IMI for two months. To evaluate the inhibition effectiveness, various metabolite concentrations in the IMI and IMI + ST exposed groups were monitored. DNA damage was also evaluated in micronucleus (MN) and single cell electrophoresis (SCGC) assays in both groups, along with oxidative stress (OS) with the inflammatory status of the exposed animals, in order to clarify which metabolic pathway is more detrimental in this experimental setting. A significant increase in the frequency of binucleated cells with MN (BNMN, 105%) and micronuclei (MN, 142%) was observed after exposure to IMI (p < 0.001). The increase in the ST co-exposed animals was less pronounced (BNMN 75%, MN 95%). The Cytokinesis Block Proliferation Index (CBPI) showed no significant difference between controls and exposed animals at any time of exposure (p > 0.05), which indicates no cytotoxic effect. Similarly, comet results show that the IMI group exhibited the highest achieved tail intensity, which reached 70.7% over the control groups, whereas in the IMI + ST groups the increase remained at 48.5%. No differences were observed between all groups for oxidative-stress biomarkers. The results indicate that the AOX metabolic pathway plays a more important role in the systemic toxicity of IMI. PMID- 29704991 TI - Roasting has a distinct effect on the antimutagenic activity of coffee varieties. AB - Coffee is a highly consumed beverage throughout the world. Its popularity derives from its organoleptic properties that are a result of the roasting process. Roasting greatly alters a coffee bean's composition and possibly its bioactivity. In the current study, green as well as roasted extracts from both Coffea arabica (Brazil and Decaf) and Coffea canephora (Robusta) species were tested for their antimutagenic activity using the Ames test. In addition, a compositional analysis was conducted to identify the main components, mainly Chlorogenic acid isomers (CGA) and derivatives present in the extracts using UHPLC-ESI(+/-) and HRMS/MS methods According to the results, all extracts exhibited strong antimutagenic activity against the oxidizing factor tert-Butyl hydroperoxide, a Reactive Oxygen Species-producing compound. Roasting had a distinct effect on the antimutagenic activity of coffee, enhancing it in the Brazil variety and having no effect in the Decaf and Robusta varieties. In addition, all coffee extracts exhibited reducing activity as well as the ability to scavenge (albeit differentially) both the superoxide and hydroxyl radicals, implying that their potential antimutagenic effect can be partially attributed to their free radical scavenging activity. PMID- 29704992 TI - Opposing roles of Y-family DNA polymerases in lipid peroxide mutagenesis at the hisG46 target in the Ames test. AB - DNA polymerases play a key role in mutagenesis by performing translesion DNA synthesis (TLS). The Y-family of DNA polymerases comprises several evolutionarily conserved families, specializing in TLS of different DNA adducts. Exocyclic etheno and propano DNA adducts are among the most common endogenous DNA lesions induced by lipid peroxidation reactions triggered by oxidative stress. We have investigated the participation of two enterobacterial representatives of the PolIV and PolV branches of Y-family DNA polymerases in mutagenesis by two model lipid peroxidation derived genotoxins, glyoxal and crotonaldehyde. Mutagenesis by the ethano adduct (glyoxal-derived) and the propano adduct (crontonaldehyde derived) at the GC target in the Ames test depended exclusively on PolV type DNA polymerases such as PolRI. In contrast, PolIV suppressed glyoxal and, even more, crotonaldehyde mutagenesis, as detected by enzyme overexpression and gene knockout approaches. We propose that DNA polymerase IV, which is the mammalian DNA polymerase kappa ortholog, acts as a housekeeper protecting the genome from lipoxidative stress. PMID- 29704993 TI - Dose-dependent proliferative and cytotoxic effects of melatonin on human epidermoid carcinoma and normal skin fibroblast cells. AB - New in vitro studies have demonstrated that N-acetyl-5-methoxytryptamine (Melatonin) has cytotoxic and apoptotic effects on various cell types although most of the previous investigations document that it is a potent antioxidant. However, the precise molecular mechanism(s) of its effects are not fully elucidated. In this study, we examined dose-dependent cytotoxic, genotoxic, apoptotic and reactive oxygen species (ROS) generating effects of melatonin in human epidermoid carcinoma cells (A-431) and human normal skin fibroblastic cells (CCD-1079Sk). The cells were incubated with different doses of melatonin (0.031-5 mM) for 24 h. Cell viability was assessed based on luminometric ATP cell viability assay. Intracellular ROS was detected using 2,7 dichlorodihydrofluorescein-diacetate (H2DCF-DA) fluorescent probes. Genotoxicity was evaluated by alkaline single cell gel electrophoresis assay (Comet Assay). Apoptosis was evaluated by western blotting, DAPI staining, acridine orange/ethidium bromide and Annexin V-FITC/propidium iodide double staining methods Mitochondrial membrane potentials were measured by flow cytometry. Although lower doses of melatonin (0.031-0.06 mM) increased cell proliferation and decreased ROS generation, higher doses (0.125-5 mM) markedly inhibited the cell viability, induced DNA damage, apoptosis and ROS generation. Cytotoxic, genotoxic, apoptotic and ROS generating effects were significantly higher in cancer cells than those observed in normal cells. Melatonin-induced cell death, and ROS generating activity were effectively inhibited by N-acetyl-l-cysteine (NAC) In conclusion, at low doses, melatonin has proliferative effects on both cancer and normal cells, whereas high concentrations have cytotoxic effects. Cytotoxic, genotoxic and apoptotic effects at higher doses of melatonin may be due to its ROS production capacity. PMID- 29704994 TI - gammaH2AX is increased in peripheral blood lymphocytes of Alzheimer's disease patients in the South Australian Neurodegeneration, Nutrition and DNA Damage (SAND) study of aging. AB - An early cellular response to DNA double-strand breaks is the phosphorylation of histone H2AX to form gammaH2AX. Although increased levels of gammaH2AX have been reported in neuronal nuclei of Alzheimer's disease (AD) patients, gammaH2AX responses in the lymphocytes of individuals with mild cognitive impairment (MCI) and AD remain unexplored. In this study, the endogenous gammaH2AX level was measured, using laser scanning cytometry (LSC) and visual scoring, in lymphocyte nuclei from MCI (n = 18), or AD (n = 20) patients and healthy controls (n = 40). Levels were significantly elevated in nuclei of the AD group compared to the MCI and control groups, and there was a concomitant increase, with a significant trend, from the control group through MCI to the AD group. A significant negative correlation was seen between gammaH2AX and the mini mental state examination (MMSE) score, when the analysis included all subjects. Receiver Operation Characteristic curves were carried out for different gammaH2AX parameters; visually scored percent cells containing overlapping gammaH2AX foci displayed the best area under the curve value of 0.9081 with 85% sensitivity and 92% specificity for the identification of AD patients versus control. Plasma homocysteine, creatinine, and chitinase-3-like protein 1 (CHI3L1) were positively correlated with lymphocyte gammaH2AX signals, while glomerular filtration rate (GFR) was negatively correlated. Finally, there was a diminished gammaH2AX response to X-rays in lymphocytes of the MCI and AD groups compared to the control group. Our results indicate that lymphocyte gammaH2AX levels are a potential marker for identifying individuals at increased risk of developing AD. Prospective studies with normal healthy individuals are needed to test whether there is indeed a link between gammaH2AX levels and AD risk. PMID- 29704995 TI - Genome-wide mutation detection by interclonal genetic variation. AB - Genetic toxicology assays estimate mutation frequencies by phenotypically screening for the activation or inactivation of endogenous or exogenous reporter genes. These reporters can only detect mutations in narrow areas of the genome and their use is often restricted to certain in vitro and in vivo models. Here, we show that Interclonal Genetic Variation (ICGV) can directly identify mutations genome-wide by comparing sequencing data of single-cell clones derived from the same source or organism. Upon ethyl methanesulfonate (EMS) exposure, ICGV detected greater levels of mutation in a dose- and time-dependent manner in E. coli. In addition, ICGV was also able to identify a ~20-fold increase in somatic mutations in T-cell clones derived from an N-ethyl-N-nitrosourea (ENU)-treated rat vs. a vehicle-treated rat. These results demonstrate that the genetic differences of single-cell clones can be used for genome-wide mutation detection. PMID- 29704996 TI - p53 and K-ras mutations in lung tissues and sputum samples of individuals exposed to smoky coal emissions in Xuan Wei County, China. AB - Lung cancer mortality in Xuan Wei County (XWC) is among the highest in China. Lung cancer in XWC is associated with exposure, in poorly vented homes, to coal smoke containing high levels of polycyclic aromatic hydrocarbons (PAHs). We have previously investigated mutations in the p53 tumor suppressor gene and the K-ras oncogene in lung carcinomas and in sputum samples from individuals exposed to smoky coal emissions in XWC. This paper summarizes the results concerning p53 and K-ras mutations from these studies, in relation to mutations found in lung cancer patients not exposed to smoky coal emissions. PMID- 29704997 TI - Successful proof of concept of a micronucleus genotoxicity assay on reconstructed epidermis exhibiting intrinsic metabolic activity. AB - We investigated the commercially available Episkin LMTM reconstructed epidermis test system as a potential 3D model for human genotoxicity assessment by cytokinesis-block micronucleus assay to mitigate limitations of the currently accepted micronucleus test. We established appropriate culture conditions for cytokinesis-block micronucleus assay in maximizing the frequency of binucleated cells by choice of culture medium and calibration of the system exposure to the cytokinesis inhibitor Cytochalasin B, without affecting the basal frequency of micronuclei in the model. We confirmed that the application of the classic solvents had no significant effect on this basal level of micronuclei. We determined the performance of cytokinesis-block micronucleus assay in Episkin LMTM reconstructed epidermis to predict in vivo genotoxins by testing the genotoxicity potential of 17 well known in vivo genotoxic, progenotoxic and non genotoxic reference chemicals over a 48 h and 72 h exposure period. We found that cytokinesis-block micronucleus assays in EpiskinTM reconstructed epidermis following the 48 h-topical regimen had a specificity of 60-75% and a sensitivity of 83-85%, resulting in an overall accuracy of 76-82% for genotoxicity assessment in tissues depending on the assessment of the reference chemicals with equivocal genotoxic profiles in the literature. The positive micronucleus test results obtained without addition of any exogenous metabolic activation system confirmed the ability of Episkin LMTM reconstructed epidermis to intrinsically bioactivate progenotoxic chemicals. The evidence showed that the 72-h exposure protocol significantly improved the detection of progenotoxins. Taken together, our data demonstrated that the Episkin LMTM reconstructed epidermis system is a relevant in vitro tool in the study of genetic toxicology. PMID- 29704998 TI - Selenoprotein P as the major transporter for mercury in serum from methylmercury poisoned rats. AB - Selenium (Se) has been found to promote weight gain, decrease hepatic damage, but redistribute mercury (Hg) in brains and livers in methylmercury (MeHg)-poisoned rats. The aims of the present work were to examine the effects of Se on the levels of Hg in serum and the role of serum selenoproteins in binding with Hg in MeHg-poisoned rats. The concentration of Se, Hg and MeHg were studied using ICP MS and CVAFS. The Hg- and Se-binding selenoproteins were separated and quantified using affinity chromatography with post-column isotope dilution analysis using both enriched 78Se and 199Hg. It was found that Se treatment reduced Hg levels in serum in MeHg-poisoned rats. Among the three separated selenoproteins, the amounts of SelP-bound Hg and Se increased to 73% and 93.6%, from 64.4% and 89.3% of the total Hg and Se, respectively after Se treatment, suggesting that SelP acts as a major transporter for Hg and pool for Se in serum. Over 90% of the total Hg was MeHg in serum, and the molar ratios of MeHg to Se as 1:4 and 1:9 in the formed MeHg-Se-SelP complex in the control and the Se treatment group, respectively. The elevated Se level binding with SelP facilitated the Hg extraction from tissues and organs, as well as its redistribution in brains and livers through blood circulation in the MeHg-poisoned rats. Together, our findings provide direct evidence that serum SelP is the major Hg transporter in MeHg-poisoned rats. PMID- 29704999 TI - Early Childhood Media Exposure and Self-Regulation: Bidirectional Longitudinal Associations. AB - OBJECTIVE: To investigate: 1) prospective associations between media exposure (television viewing, computers, and electronic games) at 2 years and self regulation at 4 and 6 years, and 2) bidirectional associations between media exposure and self-regulation at 4 and 6 years. We hypothesized that media exposure and self-regulation would show a negative prospective association and subsequent bidirectional inverse associations. METHODS: Data from the nationally representative Longitudinal Study of Australian Children when children were aged 2 years (n = 2786) and 4/6 years (n = 3527) were used. Primary caregivers reported children's weekly electronic media exposure. A composite measure of self regulation was computed from caregiver-, teacher-, and observer-report data. Associations were examined using linear regression and cross-lagged panel models, accounting for covariates. RESULTS: Lower television viewing and total media exposure at 2 years were associated with higher self-regulation at 4 years (both beta = -0.02; 95% confidence interval [CI], -0.03 to -0.01). Lower self regulation at 4 years was also significantly associated with higher television viewing (beta = -0.15; 95% CI, -0.21 to -0.08), electronic game use (beta = 0.05; 95% CI, -0.09 to -0.01), and total media exposure (beta = -0.19; 95% CI, 0.29 to -0.09) at 6 years. However, media exposure at 4 years was not associated with self-regulation at 6 years. CONCLUSIONS: Although media exposure duration at 2 years was associated with later self-regulation, and self-regulation at 4 years was associated with later media exposure, associations were of small magnitude. More research is needed to examine content quality, social context, and mobile media use and child self-regulation. PMID- 29705000 TI - Near-infrared light-controlled regulation of intracellular calcium to modulate macrophage polarization. AB - Macrophages are multifunctional immune cells with diverse physiological functions such as fighting against infection, influencing progression of pathologies, maintaining homeostasis, and regenerating tissues. Macrophages can be induced to adopt distinct polarized phenotypes, such as classically activated pro inflammatory (M1) phenotypes or alternatively activated anti-inflammatory and pro healing (M2), to execute diverse and dynamic immune functions. However, unbalanced polarizations of macrophage can lead to various pathologies, such as atherosclerosis, obesity, tumor, and asthma. Thus, the capability to remotely control macrophage phenotypes is important to the success of treating many pathological conditions involving macrophages. In this study, we developed an upconversion nanoparticle (UCNP)-based photoresponsive nanocarrier for near infrared (NIR) light-mediated control of intracellular calcium levels to regulate macrophage polarization. UCNP was coated with mesoporous silica (UCNP@mSiO2), into which loaded calcium regulators that can either supply or deplete calcium ions. UCNP@mSiO2 was chemically modified through serial coupling of photocleavable linker and Arg-Gly-Asp (RGD) peptide-bearing molecular cap via cyclodextrin-adamantine host-guest complexation. The RGD-bearing cap functioned as the photolabile gating structure to control the release of calcium regulators and facilitated the cellular uptake of UCNP@mSiO2 nanocarrier. The upconverted UV light emission from the UCNP@mSiO2 under NIR light excitation triggered the cleavage of cap and intracellular release of calcium regulators, thereby allowing temporal regulation on the intracellular calcium levels. Application of NIR light through skin tissue promoted M1 or M2 polarization of macrophages, by elevating or depleting intracellular calcium levels, respectively. To the best of our knowledge, this is the first demonstration of NIR light-mediated remote control on macrophage polarization. This photoresponsive nanocarrier offers the potential to remotely manipulate in vivo immune functions, such as inflammation or tissue regeneration, via NIR light-controlled macrophage polarization. PMID- 29705001 TI - Dendritic peptide bolaamphiphiles for siRNA delivery to primary adipocytes. AB - Obesity is a major risk factor for diabetes, heart disease and other health problems. Adipose tissue plays a central role in the development of obesity and obesity-associated diseases. Gene therapy targeting adipose tissue may provide a promising strategy for obesity treatment. However, nucleic acid delivery to adipose tissue or even cultured adipocytes is challenging due to low delivery efficacy and high toxicity of the current cationic lipid based delivery systems, or monoamphiphiles. Herein, we report using dendritic peptide bolaamphiphiles (bolas) to deliver siRNA to primary adipocytes and hepatocytes. The bola consists of two l-Lysine dendrons connected to a fluorocarbon core through disulfide linkages. The Lysine dendrons are functionalized with l-histidine and l tryptophan to promote endosomal escape and cellular uptake. The bola exhibited over 70% knockdown of GAPDH gene in both primary adipocytes and hepatocytes. Importantly, different from Lipofectamine that significantly reduced genes involved in lipolysis, lipogenesis, fatty acid oxidation and ketogenesis, the bolas had little to no effect on these genes. These results demonstrate the bola as a promising new vector for clinical and experimental applications for delivery of siRNA to metabolic organs. PMID- 29705002 TI - Validation of Peripheral Quantitative Computed Tomography-Derived Thigh Adipose Tissue Subcompartments in Young Girls Using a 3 T MRI Scanner. AB - The ability to assess skeletal muscle adipose tissue is important given the negative clinical implications associated with greater fat infiltration of the muscle. Computed tomography and magnetic resonance imaging (MRI) are highly accurate for measuring appendicular soft tissue and muscle composition, but have limitations. Peripheral quantitative computed tomography (pQCT) is an alternative that investigators find valuable because of its low radiation, fast scan time, and comparatively lower costs. The present investigation sought to assess the accuracy of pQCT-derived estimates of total, subcutaneous, skeletal muscle, intermuscular, and calculated intramuscular adipose tissue areas, and muscle density in the midthigh of young girls using the gold standard, 3 T MRI, as the criterion. Cross-sectional data were analyzed for 26 healthy girls aged 9-12 years. Midthigh soft tissue composition was assessed by both pQCT and 3 T MRI. Mean tissue area for corresponding adipose compartments by pQCT and MRI was compared using t tests, regression analysis, and Bland-Altman plots. Muscle density was regressed on MRI skeletal muscle adipose tissue, intermuscular adipose tissue, and intramuscular adipose tissue, each expressed as a percentage of total muscle area. Correlations were high between MRI and pQCT for total adipose tissue (r2 = 0.98), subcutaneous adipose tissue (r2 = 0.95), skeletal muscle adipose tissue (r2 = 0.83), and intermuscular adipose tissue (r2 = 0.82), and pQCT muscle density correlated well with both MRI skeletal muscle adipose tissue (r2 = 0.70) and MRI intermuscular adipose tissue (r2 = 0.70). There was a slight, but statistically significant underestimation by pQCT for total and subcutaneous adipose tissue, whereas no significant difference was observed for skeletal muscle adipose tissue. Both pQCT-estimated intramuscular adipose tissue and muscle density were weakly correlated with MRI-intramuscular adipose tissue. We conclude that pQCT is a valid measurement technique for estimating all adipose subcompartments, except for intramuscular adipose tissue, for the midthigh region in young/adolescent girls. PMID- 29705003 TI - An integrated approach to uncover quality marker underlying the effects of Alisma orientale on lipid metabolism, using chemical analysis and network pharmacology. AB - BACKGROUND: Quality control of traditional Chinese medicines is currently a great concern, due to the correlation between the quality control indicators and clinic effect is often questionable. According to the "multi-components and multi targets" property of TCMs, a new special quality and bioactivity evaluation system is urgently needed. PURPOSE: Present study adopted an integrated approach to provide new insights relating to uncover quality marker underlying the effects of Alisma orientale (AO) on lipid metabolism. METHODS: In this paper, guided by the concept of the quality marker (Q-marker), an integrated strategies "effect compound-target-fingerprint" was established to discovery and screen the potential quality marker of AO based on network pharmacology and chemical analysis. Firstly, a bioactivity evaluation was performed to screen the main active fractions. Then the chemical compositions were rapidly identified by chemical analysis. Next, networks were constructed to illuminate the interactions between these component and their targets for lipid metabolism, and the potential Q-marker of AO was initially screened. Finally, the activity of the Q-markers was validated in vitro. RESULTS: 50% ethanol extract fraction was found to have the strongest lipid-lowering activity. Then, the network pharmacology was used to clarify the unique relationship between the Q-markers and their integral pharmacological action. CONCLUSION: Combined with the results obtained, five active ingredients in the 50% ethanol extract fraction were given special considerations to be representative Q-markers: Alisol A, Alisol B, Alisol A 23 acetate, Alisol B 23-acetate and Alisol A 24-acetate, respectively. The chromatographic fingerprints based Q-marker was establishment. The integrated Q marker screen may offer an alternative quality assessment of herbal medicines. PMID- 29705004 TI - Patients participating to neurobiological research in early psychosis: A selected subgroup? AB - AIM: Selection bias could be an important limiting factor in psychiatric neurobiological research. The study aim was to compare, within an early psychosis program, patients who agreed to participate to neurobiological research with patients who refused. METHODS: 284 patients with early psychosis were assessed at baseline on a large set of socio-demographic and clinical variables and were followed-up over 36 months. RESULTS: There were no differences between groups, except regarding forensic/psychiatric history, lifetime substance abuse and social-occupational level during follow-up. CONCLUSIONS: While patients participating to neurobiological research seem representative of our clinical cohort, the few differences identified may deserve attention. PMID- 29705005 TI - Plasma cytokines in minimally treated schizophrenia. AB - In schizophrenia, plasma cytokines abnormalities offer vital support for immunopathogenetic basis. However, most of the previous studies on plasma cytokines are confounded by examination of antipsychotic-treated schizophrenia patients. In this study, we examined a large sample of antipsychotic-naive/free schizophrenia patients (N = 75) in comparison with healthy controls (N = 102). Plasma cytokines (Interleukins ([IL] 2, 4, 6, 10, 17), Tumor necrosis factor [TNF] and Interferon gamma [IFN-g]) were assessed using cytometric bead array assay. Schizophrenia patients showed significantly greater levels of IL-6 and lower levels of IL-17 as well as IFN-g in comparison to healthy controls. However, after taking censoring into account and adjusting for potential confounders (sex, age, BMI and smoking), only IL-6 was found to be elevated in patients. Cytokine profile showed differential and pathogenetically relevant correlation with clinical symptoms. Together, these observations offer further support to immunological component in schizophrenia pathogenesis. PMID- 29705006 TI - Modified cariprazine relapse prevention clinical trial results. PMID- 29705008 TI - Repeatability of automatic measurements by a new anterior segment optical coherence tomographer combined with Placido topography and agreement with 2 Scheimpflug cameras. AB - PURPOSE: To evaluate the repeatability of automatic measurements by a new anterior segment optical coherence tomographer (AS-OCT) combined with Placido topography and their agreement with those provided by 2 rotating Scheimpflug cameras. SETTING: G.B. Bietti Foundation IRCCS, Rome, Italy. DESIGN: Evaluation of a diagnostic test instrument. METHODS: Unoperated eyes and eyes with previous myopic excimer laser surgery were analyzed. Three consecutive scans were acquired with an AS-OCT device (MS-39) and 1 with 2 rotating Scheimpflug cameras (Pentacam HR and Sirius). The following parameters were evaluated: simulated keratometry, posterior and total corneal power, total corneal astigmatism, corneal asphericity, thinnest corneal thickness, central epithelial thickness, corneal diameter, and aqueous depth. Repeatability was assessed using test-retest variability, the coefficient of variation (CoV), and the intraclass correlation coefficient; agreement was assessed by the 95% limits of agreement. RESULTS: The study comprised 96 unoperated eyes and 43 eyes with previous myopic excimer laser surgery. High repeatability was achieved in both groups, as shown by a CoV less than 1.0% for most parameters. The repeatability of epithelial thickness was slightly lower than that of the whole corneal thickness, although the CoV was still good (1.87% in unoperated eyes; 3.28% in post-refractive surgery eyes). Moderate repeatability was found for total corneal astigmatism measurements, with a CoV greater than 20.0%. Agreement with Scheimpflug cameras was high for aqueous depth and thinnest corneal thickness and moderate for most other parameters. CONCLUSION: The high repeatability of automatic measurements by the new AS-OCT device supports its use in clinical practice. PMID- 29705007 TI - Altered brain cannabinoid 1 receptor mRNA expression across postnatal development in the MAM model of schizophrenia. AB - Altered cannabinoid 1 receptor (CB1R) expression has been reported in the brain of subjects with schizophrenia, a developmental mental illness that usually emerges in late adolescence/early adulthood. However, the developmental period at which changes in the CB1R expression appear in schizophrenia is unknown. To gain insight into this factor, we assessed the postnatal developmental trajectory of CB1R expression in the methylazoxymethanol (MAM) model of schizophrenia. Using in situ hybridization with film and grain analyses, CB1R messenger RNA (mRNA) levels were quantified in multiple brain regions, including the medial prefrontal cortex (mPFC), secondary motor cortex, dorsomedial and dorsolateral striatum, dorsal subregions and ventral subiculum of the hippocampus, of MAM-treated rats and normal controls at three developmental periods [juvenile - postnatal day (PD) 30; adolescence - PD45; and adulthood - PD85]. In all brain regions studied, CB1R mRNA levels were highest in juveniles and then decreased progressively toward adolescent and adult levels in control and MAM-treated rats. However, in MAM treated rats, CB1R mRNA levels were lower in the mPFC at PD85 and higher in the dorsolateral striatum at PD45 and PD85 relative to controls. Cellular analyses confirmed the changes in CB1R mRNA expression in MAM-treated rats. These findings are in accordance with previous studies showing a decrease in the CB1R mRNA expression from juvenile period to adolescence to adulthood in cortical, striatal, and hippocampal regions. Additionally, similar to most of the schizophrenia-like signs observed in the MAM model, embryonic exposure to MAM leads to schizophrenia-related changes in CB1R mRNA expression that only emerge later in development. PMID- 29705009 TI - Cataract surgery after deep anterior lamellar keratoplasty and penetrating keratoplasty in age- and disease-matched eyes. AB - PURPOSE: To assess the efficacy and safety of cataract surgery after deep anterior lamellar keratoplasty (DALK) and penetrating keratoplasty (PKP). SETTING: Tokyo Dental College Ichikawa General Hospital, Chiba, Japan. DESIGN: Retrospective case series. METHODS: Age-matched and disease-matched eyes that had phacoemulsification and intraocular lens insertion after DALK or PKP were studied. Graft clarity was assessed at the final follow-up. The difference in the endothelial cell density (ECD), corrected distance visual acuity (CDVA), spherical equivalence, and refractive error between the expected values and values 1, 3, 6, and 12 months after cataract surgery were compared between the 2 groups. RESULTS: Indications for keratoplasty were corneal stromal scar (22 eyes), lattice dystrophy (2 eyes), keratoconus (2 eyes), and postherpetic keratitis (4 eyes). All 30 eyes in each group had successful cataract surgery after keratoplasty. Graft clarity rates were 90.0% and 80.0% in the DALK group and PKP group, respectively (P = .47). The decrease in ECD at 12 months was significantly greater in the PKP group than in the DALK group (8.7% [SD] +/- 21.7% versus 26.3% +/- 27.8%) (P = .043). The CDVA was significantly improved in both groups. At 1 month, the mean refractive error was -0.5 diopter (D) +/- 2.4 (SD) in the DALK and -0.4 +/- 1.9 D in the PKP groups and remained stable thereafter. CONCLUSIONS: Cataract surgery was successfully performed in eyes that had DALK or PKP, providing excellent visual and refractive outcomes. In cases of combined cataract and corneal pathology, and in the absence of endothelial involvement, DALK followed by cataract surgery might cause less endothelial damage. PMID- 29705010 TI - Changes in macular vasculature after uncomplicated phacoemulsification surgery: Optical coherence tomography angiography study. AB - PURPOSE: To use optical coherence tomography (OCT) angiography and a split spectrum amplitude-decorrelation angiography algorithm to evaluate the changes in the macular vascular system after uncomplicated phacoemulsification. SETTING: Department of Ophthalmology, Eye and and Ear, Nose, and Throat Hospital of Fudan University, Shanghai, China. DESIGN: Prospective case series. METHODS: Patients with senile cataracts were included. Retinal vessel density and thickness at the macular area were checked by OCT at baseline and at 1 week, 1 month, and 3 months after cataract surgery. RESULTS: Thirty-two eyes (32 patients) were included in the final analysis. There was a significant increase in retinal vessel density, a decrease in the foveal avascular zone at the macular area after the cataract surgery (all P < .05, repeated-measures analysis of variance), and an increase in full and inner macular thickness, all of which extended to the end of the follow up period. At 3 months postoperatively, there was a mean 6% and 3% increase in vessel density at the parafoveal and perifoveal regions, respectively, and a mean 27% reduction in the foveal avascular zone. The mean increase in inner retinal thickness was 15%, 10%, and 7% at the fovea, parafovea, and perifovea, respectively. Compared with the parafovea and perifovea, the fovea had a much higher percentage of change in retinal vasculature and inner retinal thickness (all P < .001). CONCLUSIONS: Macular vessel density and thickness increased after cataract surgery. Whether these changes will persist over a longer period still needs to be studied. PMID- 29705011 TI - Brinzolamide-brimonidine fixed combination to prevent intraocular pressure elevation after neodymium:YAG laser posterior capsulotomy. PMID- 29705012 TI - An Alternative Thumb Reconstruction by Double Microsurgical Transfer From the Great and Second Toe for a Carpometacarpal Amputation. AB - Thumb amputation at the carpometacarpal level is very incapacitating. Pollicization may be considered. We describe an alternate technique for thumb reconstruction at the level of the metacarpal base using a trimmed great toe along with a vascularized second metatarsophalangeal joint, including the second metatarsal, all supplied on a single vascular pedicle. Two patients who had a combined soft tissue defect and amputation of the thumb close to the carpometacarpal joint were reconstructed with this method. A transposition of the second toe was performed on top of the remaining proximal phalanx of the great toe to decrease donor site morbidity. This technique provides adequate length to the thumb without compromising another finger by creating a new thumb using a double microsurgical toe transfer on a single vascular pedicle. We minimize donor site morbidity by transposing the second toe onto the great toe. PMID- 29705014 TI - Posterior interval tear after superior capsule reconstruction: a case report. PMID- 29705013 TI - Incidence of recurrence after shoulder dislocation: a nationwide database study. AB - BACKGROUND: The reported incidence of shoulder redislocation varies among different reports. This was a nationwide study to investigate the recurrence rate of shoulder dislocation after closed reduction. METHODS: We performed a cohort study to analyze the incidence of first dislocation as well as second and third repeated dislocations in a nationwide dataset from the National Health Insurance Research Database of Taiwan. Patients who had any shoulder dislocation event and received closed reduction from 2000 to 2013 were included. RESULTS: From this dataset of 1 million persons, we identified 1074 patients who had a shoulder dislocation. Of these, 210 had a second shoulder dislocation and 93 had a third shoulder dislocation. The shoulder redislocation rates were 9.4%, 12.7%, and 17.0% at 1 year, 2 years, and 5 years, respectively, after the first shoulder dislocation and 19.6% at overall follow-up. Patients in the youngest age group and male patients had higher risks of redislocation (adjusted hazard ratios, 3.28 and 1.41, respectively). The mean time to recurrence was 13.1 months. However, the patients who had a second shoulder dislocation had a shorter time to recurrence and a higher risk of redislocation (44%), with no statistical differences in risk among any age or sex groups. CONCLUSIONS: After the first shoulder dislocation, male patients and younger patients had higher shoulder redislocation rates. However, after the second shoulder dislocation, all groups shared a similar high shoulder redislocation rate regardless of age or sex. Surgical treatment should be considered for patients with multiple episodes of shoulder dislocation. PMID- 29705015 TI - Evaluation of postural tachycardia syndrome (POTS). AB - The diagnostic evaluation of a patient with suspected postural tachycardia syndrome (POTS) requires a thoughtful diagnostic approach utilizing a careful clinical history and examination, laboratory, and autonomic testing. This article outlines the importance of a thorough history in identifying mechanism of symptom onset, clinical features, associated clinical conditions or disorders, and factors that may result in symptom exacerbation. The clinical examination involves an assessment of pupillary responses, an evaluation for sudomotor and vasomotor signs, and an assessment for joint hypermobility. Laboratory testing helps to exclude mimics of autonomic dysfunction, recognize conditions that may exacerbate symptoms, and to identify conditions that may cause or be associated with autonomic nervous system disease. The purpose of autonomic testing is to confirm a POTS diagnosis, exclude other causes of orthostatic intolerance, and may provide for characterization of POTS into neuropathic and hyperadrenergic subtypes. Other diagnostic studies, such as epidermal skin punch biopsy, exercise testing, radiographic studies, sleep studies, gastrointestinal motility studies, and urodynamic studies should be considered when clinically appropriate. PMID- 29705016 TI - Oral Azithromycin: A Treatment Option for Papulopustular Rosacea. PMID- 29705017 TI - Treatment Satisfaction of Patients With Advanced Non-Small-cell Lung Cancer Receiving Platinum-based Chemotherapy: Results From a Prospective Cohort Study (PERSONAL). AB - INTRODUCTION: In patients with advanced non-small-cell lung cancer, the treatment benefits and risks need to be constantly weighed. We explored patient-reported satisfaction with therapy (SWT) and assessed its value in addition to quality of life (QoL) and adverse events (AEs). PATIENTS AND METHODS: In a prospective multicenter cohort study, patients with stage IIIB/IV non-small-cell lung cancer received platinum-pemetrexed chemotherapy. They completed the World Health Organization Quality of Life-BREF (WHOQoL-BREF) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ C30) before and during chemotherapy. After the last cycle, patients reported on SWT, expectations of therapy, and feelings about side effects (FSE) using the Cancer Therapy Satisfaction Questionnaire. The explained variance (R2) of QoL after treatment by SWT was calculated. Using multivariable linear regression, we examined the association of SWT with patient- and treatment-related variables, FSE, and AEs. RESULTS: Eighty-nine patients finished 4 cycles of chemotherapy, 65 of whom completed the Cancer Therapy Satisfaction Questionnaire. Fifty-six patients (86.2%) would probably or definitely decide to undergo the same treatment again, regardless of deterioration or improvement in QoL or a high or low frequency of AEs during chemotherapy. The explained variance of QoL by SWT was greatest for the EORTC QLQ C-30 global health status/QoL scale (R2 = 0.170). Patient age (beta = 0.43; 95% confidence interval [CI], 0.05-0.82), FSE (beta = 0.17; 95% CI, 0.06-0.29), and tumor response (beta = 7.93; 95% CI (1.64 to 14.22)) were independently associated with SWT. CONCLUSION: SWT could provide important supplementary information in addition to QoL assessments and treatment toxicities. Tumor response, older age, and FSE score were associated with better SWT. These insights could affect decision-making during palliative chemotherapy. PMID- 29705018 TI - Cardiovascular calcification: The emerging role of micronutrients. PMID- 29705019 TI - Turning parasites into friends not foes. PMID- 29705020 TI - Imaging of hemifacial spasm. AB - Almost all primary hemifacial spasms are associated with one or more neurovascular conflicts, most often at the root exit zone in the immediate vicinity of the brainstem. Imaging has first to exclude a secondary hemifacial spasm and secondly to search for and characterize the responsible neurovascular conflict(s). Magnetic resonance imaging should include high-resolution anatomical hyper T2-weighted sequences and magnetic resonance angiography by using 1.5 or even better 3 Tesla magnets. The most frequent vascular compressions are from the anterior-inferior cerebellar artery, the posterior-inferior cerebellar artery and the vertebrobasilar artery; venous conflicts are very rare. Conflicts are often multiple; also, the same vessel may compress the facial nerve in two places. Also, conflicts may be aided by particular anatomical circumstances, including arterial dolichoectasia, posterior fossa with a small volume or bony malformations. PMID- 29705021 TI - Endoscope-assisted decompression of facial nerve for treatment of hemifacial spasm. AB - Microvascular decompression has become the sole method for a curative treatment of primary hemifacial spasm. Finding the responsible conflicting artery is not always easy as its location can be deeply situated within the cerebellopontine/medullary fissure at the facial root exit zone. Sole or additional offending vessel(s) may be at the meatus of the internal auditory canal (5% of the cases). Identifying the compressive vessel(s) and performing decompression is in most cases possible without cerebellar retraction by classical microsurgical techniques. However, in a number of patients the neurovascular conflict may be hidden in spite of the direct illumination of the operative microscope. Therefore, assistance by endoscopy can be useful and contribute as a minimally invasive approach. The author reports his own experience in a series of 553 patients operated on over the past three decades. A total of 93.6% had complete relief of their spasm (11% after repeated surgery). Relief was delayed in 20.8% of these patients. Recurrence was rare (0.3%). There was no mortality and morbidity was low: deafness occurred in 0.6%. There was no permanent postoperative facial palsy. CSF leakage amounted to 1% in the last period of surgery. In conclusion, the author advocates combining the use of both the endoscopy for exploration and the microscope for decompression. PMID- 29705022 TI - Comorbid thyroid disease in patients with major depressive disorder - results from the European Group for the Study of Resistant Depression (GSRD). AB - This multicenter study of the European Group for the Study of Resistant Depression (GSRD) aimed to explore the association between major depressive disorder (MDD) and comorbid thyroid disease. A total number of 1410 patients' characteristics in terms of demographic and clinical information were compared between MDD subjects with and without concurrent thyroid disease using descriptive statistics, analyses of covariance (ANCOVA) and binary logistic regression analyses. We determined a point prevalence rate for comorbid hypothyroidism of 13.2% and 1.6% for comorbid hyperthyroidism respectively. Patients with MDD+comorbid hypothyroidism were significantly older, more likely to be female, inpatient and suffering from other comorbid chronic somatic conditions. Furthermore, MADRS score at onset of the current depressive episode was significantly higher, psychotic features of depression were more likely pronounced. Overall, patients in the MDD+comorbid hypothyroidism group were rather treated with a combination of drugs, for example, pregabalin, antipsychotic drugs and mood stabilizers. In the MDD+comorbid hyperthyroidism group patients were significantly older, of Caucasian origin and diagnosed with other somatic comorbidities. In conclusion, our analyses suggest that abnormal thyroid function, especially hypothyroidism, is linked to depression severity and associated with distinct psychopathologic features of depression. However, comorbid thyroid disease has no influence on treatment response. A combination or augmentation of psychopharmacological drugs, especially with antipsychotics, mood stabilizers and pregabalin is more likely in patients with hypothyroid conditions. Thyroid disorder is frequently found in combination with other chronic somatic diseases including hypertension and heart disease. PMID- 29705023 TI - Lower dopamine tone in the striatum is associated with higher body mass index. AB - Existing literature suggests that striatal dopamine (DA) tone may be altered in individuals with higher body mass index (BMI), but evidence accrued so far only offers an incomplete view of their relationship. Here, we characterized striatal DA tone using more comprehensive measures within a larger sample than previously reported. In addition, we explored if there was a relationship between striatal DA tone and disinhibited eating. 60 healthy participants underwent a 6 [18F]fluoro-L-3,4-dihydroxyphenylalanine (18F-DOPA) positron emission tomography (PET) scan. Disinhibited eating was measured with the Three-Factor Eating Questionnaire on a baseline visit. Individual whole-brain PET parameter estimates, namely 18F-DOPA influx rate constant (kocc i.e. DA synthesis capacity), 18F-DA washout rate (kloss) and effective distribution volume ratio (EDVR= kocc/ kloss), were derived with a reversible-tracer graphical analysis approach. We then computed parameter estimates for three regions-of-interests (ROIs), namely the ventral striatum, putamen and caudate. Overweight/mildly obese individuals had lowered EDVR than normal weight individuals in all three ROIs. The most prominent of these associations, driven by lowered kocc (r = -.28, p = .035) and heightened kloss (r = .48, p < .001), was found in the ventral striatum (r = -.46, p < .001). Disinhibition was greater in higher-BMI individuals (r = .31, p = .015), but was unrelated to PET measures and did not explain the relationship between PET measures and BMI. In sum, our findings resonate with the notion that overweight/mildly obese individuals have lower striatal DA tone and suggest new avenues for investigating their underlying mechanisms. PMID- 29705024 TI - Impact of Adjuvant Anthracycline-Based and Taxane-Based Chemotherapy on Plasma VEGF Levels and Cognitive Function in Breast Cancer Patients: A Longitudinal Study. AB - BACKGROUND: Vascular endothelial growth factor (VEGF) has been shown to induce neurogenesis in the brain and yield neuroprotective effects. It is hypothesized that chemotherapy reduces circulating VEGF levels and leads to cognitive decline among patients. This multicenter longitudinal study aimed to evaluate the impact of chemotherapy on VEGF levels and the association between VEGF levels and cognitive function. PATIENTS AND METHODS: A total of 145 early-stage breast cancer patients were recruited and assessed before chemotherapy (T1), during chemotherapy (T2), and at the end of chemotherapy (T3). At each time point, plasma VEGF levels were assessed using a multiplex immunoassay. Cognitive function was assessed using both Functional Assessment of Cancer Therapy Cognitive Function, Version 3 (FACT-Cog), and Headminder (a computerized, web based neuropsychologic battery). RESULTS: Generally, we observed higher-than baseline plasma VEGF levels after the start of chemotherapy (P < .001). Among patients receiving anthracycline-based chemotherapy, the median plasma VEGF levels were significantly higher at T2 (T2: 37.3 pg/mL vs. T1: 21.3 pg/mL; P < .001) and T3 (T3: 35.5 pg/mL vs. T1: 21.3 pg/mL; P < .001) than at baseline. Plasma VEGF levels were not associated with chemotherapy-associated cognitive impairment. CONCLUSION: Breast cancer patients experience an increasing trend in plasma VEGF levels during chemotherapy, and the regimen types may have a differential effect on circulating VEGF levels. Furthermore, changes in plasma VEGF levels during chemotherapy were not associated with cognitive impairment. VEGF may play a minor role in mediating the occurrence of chemotherapy-associated cognitive impairment. PMID- 29705025 TI - Linking stress and immunity: Immunoglobulin A as a non-invasive physiological biomarker in animal welfare studies. AB - As the animal welfare community strives to empirically assess how care and management practices can help maintain or even enhance welfare, the development of tools for non-invasively measuring physiological biomarkers is essential. Of the suite of physiological biomarkers, Immunoglobulin A (IgA), particularly the secretory form (Secretory IgA or SIgA), is at the forefront because of its crucial role in mucosal immunity and links to physical health, stress, and overall psychological well-being. While interpretation of changes in SIgA concentrations on short time scales is complex, long-term SIgA patterns are consistent: conditions that create chronic stress lead to suppression of SIgA. In contrast, when welfare is enhanced, SIgA is predicted to stabilize at higher concentrations. In this review, we examine how SIgA concentrations are reflective of both physiological stress and immune function. We then review the literature associating SIgA concentrations with various metrics of animal welfare and provide detailed methodological considerations for SIgA monitoring. Overall, our aim is to provide an in-depth discussion regarding the value of SIgA as physiological biomarker to studies aiming to understand the links between stress and immunity. PMID- 29705026 TI - Current status and future developments in preparation and application of nonspherical polymer particles. AB - Nonspherical polymer particles (NPPs) are nano/micro-particulates of macromolecules that are anisotropic in shape, and can be designed anisotropic in chemistry. Due to shape and surface anisotropies, NPPs bear many unique structures and fascinating properties which are distinctly different from those of spherical polymer particles (SPPs). In recent years, the research on NPPs has surprisingly blossomed in recent years, and many practical materials based on NPPs with potential applications in photonic device, material science and biomedical engineering have been generated. In this review, we give a systematic, balanced and comprehensive summary of the main aspects of NPPs related to their preparation and application, and propose perspectives for the future developments of NPPs. PMID- 29705027 TI - The chemical (not mechanical) paradigm of thermodynamics of colloid and interface science. AB - In the most influential monograph on colloid and interfacial science by Adamson three fundamental equations of "physical chemistry of surfaces" are identified: the Laplace equation, the Kelvin equation and the Gibbs adsorption equation, with a mechanical definition of surface tension by Young as a starting point. Three of them (Young, Laplace and Kelvin) are called here the "mechanical paradigm". In contrary it is shown here that there is only one fundamental equation of the thermodynamics of colloid and interface science and all the above (and other) equations of this field follow as its derivatives. This equation is due to chemical thermodynamics of Gibbs, called here the "chemical paradigm", leading to the definition of surface tension and to 5 rows of equations (see Graphical abstract). The first row is the general equation for interfacial forces, leading to the Young equation, to the Bakker equation and to the Laplace equation, etc. Although the principally wrong extension of the Laplace equation formally leads to the Kelvin equation, using the chemical paradigm it becomes clear that the Kelvin equation is generally incorrect, although it provides right results in special cases. The second row of equations provides equilibrium shapes and positions of phases, including sessile drops of Young, crystals of Wulff, liquids in capillaries, etc. The third row of equations leads to the size-dependent equations of molar Gibbs energies of nano-phases and chemical potentials of their components; from here the corrected versions of the Kelvin equation and its derivatives (the Gibbs-Thomson equation and the Freundlich-Ostwald equation) are derived, including equations for more complex problems. The fourth row of equations is the nucleation theory of Gibbs, also contradicting the Kelvin equation. The fifth row of equations is the adsorption equation of Gibbs, and also the definition of the partial surface tension, leading to the Butler equation and to its derivatives, including the Langmuir equation and the Szyszkowski equation. Positioning the single fundamental equation of Gibbs into the thermodynamic origin of colloid and interface science leads to a coherent set of correct equations of this field. The same provides the chemical (not mechanical) foundation of the chemical (not mechanical) discipline of colloid and interface science. PMID- 29705028 TI - Food, microbiome and colorectal cancer. AB - You are what you eat. This adage has been confirmed by many studies demonstrating the high impact of nutrition on risk of cardiovascular diseases, many malignancies and other diseases. Dietary factors are of major relevance in the evolution of colorectal carcinoma. Various aspects are involved in colorectal carcinoma pathogenesis including genetics, lifestyle, age, chronic inflammation and others. It has only recently been recognized that the gut microbiota might reflect an important missing link in the interaction between diet and subsequent colorectal carcinoma development. Dietary factors are a major confounding factor affecting the composition of the intestinal microbiota. Several preclinical and clinical studies have recently suggested a role for the intestinal microbiota in potentially initiating and driving colorectal carcinoma. Therefore it is increasingly acknowledged that dietary factors might favor carcinogenesis via manipulation of the gut microbiota via potential outgrowth of certain bacterial populations, such as Fusobacterium nucleatum, Escherichia coli or Bacteroides fragilis. Excitingly, recent large clinical studies also highlighted a role for the gut microbiota and in particular Akkermansia muciniphila in tumor response toward chemotherapeutic agents and immune checkpoint inhibitors. This review will concentrate on the role of dietary factors in affecting the microbiota and implications in colorectal carcinoma. PMID- 29705030 TI - Adherence to quality criteria improves concordance between transient elastography and ElastPQ for liver stiffness assessment-A multicenter retrospective study. AB - BACKGROUND: Assessment of liver stiffness provides important diagnostic and prognostic information in patients with chronic liver disease. AIMS: To investigate whether the use of quality criteria (i) improves the concordance between transient elastography (TE) and a novel point shear wave elastography technique (ElastPQ(r)) and (ii) impacts on the performance of ElastPQ(r) for liver fibrosis staging using TE as the reference standard. METHODS: In this multicenter retrospective study, data of patients undergoing liver stiffness measurements (LSM) in five European centers were collected. TE was performed with FibroScan(r) (Echosens, France) and ElastPQ(r) with EPIQ(r) or Affiniti(r) systems (Philips, The Netherlands). The agreement between TE and ElastPQ(r) LSMs was assessed with Lin's concordance correlation coefficient (CCC). Diagnostic performance of ElastPQ(r) was assessed by the area under receiver operating characteristic (AUROC) curves. RESULTS: Overall, 664 patients were included: mean age: 54.8(13.5) years, main etiologies: viral hepatitis (83.1%) and NAFLD (7.5%). CCC increased significantly when LSMs with ElastPQ(r) were obtained with IQR/M <= 30% (p < 0.001). The diagnostic performance of ElastPQ(r) for fibrosis staging also increased if LSM values were obtained with IQR/M <= 30%. CONCLUSION: Quality criteria should be followed when using ElastPQ(r) for LSM, since the concordance with TE fibrosis staging was better at an ElastPQ(r) IQR/M <= 30. PMID- 29705029 TI - Usefulness of contrast-enhanced ultrasound (CEUS) in Inflammatory Bowel Disease (IBD). AB - Intestinal ultrasonography has emerged as a cheap, non-invasive and readily accessible modality for the assessment of a number of gastroenterological diseases. Over the last decade, particularly due to the widespread use of biological agents in Inflammatory Bowel Disease (IBD), guidelines regarding management and follow-up advise more regular disease assessment and surveillance in order to guide treatment adjustments, and provide more personalised care. Given the young age of the majority of patients with IBD the availability of an alternative modality to harmful radiation or the risks of endoscopy for this indication offers an appealing advantage. Intestinal ultrasonography has been shown to be as sensitive and specific for detecting IBD as both computed tomography and magnetic resonance enterography, and endoscopic evaluation. More recent developments in the technology of ultrasonography equipment and the use of intravenous contrast agents (contrast enhanced ultrasonography, known as CEUS), have significantly increased the ability to both detect disease location, determine the disease activity and also potentially the difference between fibrotic and inflammatory segments. This review focusses specifically on the value of CEUS for the diagnosis of both Crohn's disease and Ulcerative Colitis, in determining disease activity, extraintestinal complications, determination of fibrosis as well as its more recent use in assessing and predicting response to biological and immunosuppressive therapies. PMID- 29705031 TI - 3He diffusion MRI in human lungs. AB - Hyperpolarized 3He gas allows the air spaces of the lungs to be imaged via MRI. Imaging of restricted diffusion is addressed here, which allows the microstructure of the lung to be characterized through the physical restrictions to gas diffusion presented by airway and alveolar walls in the lung. Measurements of the apparent diffusion coefficient (ADC) of 3He at time scales of milliseconds and seconds are compared; measurement of acinar airway sizes by determination of the microscopic anisotropy of diffusion is discussed. This is where Dr. JJH Ackerman's influence was greatest in aiding the formation of the Washington University 3He group, involving early a combination of physicists, radiologists, and surgeons, as the first applications of 3He ADC were to COPD and its destruction/modification of lung microstructure via emphysema. The sensitivity of the method to early COPD is demonstrated, as is its validation by direct comparison to histology. More recently the method has been used broadly in adult and pediatric obstructive lung diseases, from severe asthma to cystic fibrosis to bronchopulmonary dysplasia, a result of premature birth. These applications of the technique are discussed briefly. PMID- 29705032 TI - Diagnosis of multiple sclerosis through the lens of ultra-high-field MRI. AB - The long-standing relationship between ultra-high-field (7 T) MRI and multiple sclerosis (MS) has brought new insights to our understanding of lesion evolution and its associated pathology. With the recent FDA approval of a commercially available scanner, 7 T MRI is finally entering the clinic with great expectations about its potential added value. By looking through the prism of MS diagnosis, this perspective article discusses current limitations and prospects of 7 T MRI techniques relevant to helping clinicians diagnose patients encountered in daily practice. PMID- 29705033 TI - Biophysics of BOLD fMRI investigated with animal models. AB - The widely-used BOLD fMRI signal depends on various anatomical, physiological, and imaging parameters. Thus, it is important to examine its biophysical and physiological source in order to optimize, model and accurately interpret fMRI. Animal models have been used to investigate these issues to take systematic measurements and combine with conventional invasive approaches. Here, we reviewed and discussed multiple issues, including the echo time-dependent intravascular contribution and extravascular contributions, gradient-echo vs. spin-echo fMRI, the physiological source of BOLD fMRI, arterial vs. venous cerebral blood volume change, cerebral oxygen consumption change, and arterial oxygen saturation change. We then discuss future directions of animal fMRI and translation to human fMRI. Systematic biophysical BOLD fMRI studies provide insight into the modeling and interpretation of BOLD fMRI in animals and humans. PMID- 29705034 TI - Preclinical MRI: Studies of the irradiated brain. AB - Radiation therapy (RT) plays a central role in the treatment of primary brain tumors. However, despite recent advances in RT treatment, local recurrences following therapy remain common. Radiation necrosis (RN) is a severe, late complication of radiation therapy in the brain. RN is a serious clinical problem often associated with devastating neurologic complications. Therapeutic strategies, including neuroprotectants, have been described, but have not been widely translated in routine clinical use. We have developed a mouse model that recapitulates all of the major pathologic features of late-onset RN for the purposes of characterizing the basic pathogenesis of RN, identifying non-invasive (imaging) biomarkers of RN that might allow for the radiologic discernment of tumor and RN, systematic testing of tumor and RN therapeutics, and exploring the complex interplay between RN pathogenesis and tumor recurrence. Herein, we describe the fundamental clinical challenges associated with RN and the progress made towards addressing these challenges by combining our novel mouse model of late-onset RN and magnetic resonance imaging (MRI). MRI techniques discussed include conventional T1- and T2-weighted imaging, diffusion-weighted imaging, magnetization transfer, and measures of tissue oxygenation. Studies of RN mitigation and neuroprotection are described, including the use of anti-VEGF antibodies, and inhibitors of GSK-3beta, HIF-1alpha, and CXCR4. We conclude with some future perspectives on the irradiated brain and the study and treatment of recurrent tumor growing in an irradiated tumor microenvironment. PMID- 29705035 TI - RF pulse methods for use with surface coils: Frequency-modulated pulses and parallel transmission. AB - The first use of a surface coil to obtain a 31P NMR spectrum from an intact rat by Ackerman and colleagues initiated a revolution in magnetic resonance imaging (MRI) and spectroscopy (MRS). Today, we take it for granted that one can detect signals in regions external to an RF coil; at the time, however, this concept was most unusual. In the approximately four decade long period since its introduction, this simple idea gave birth to an increasing number of innovations that has led to transformative changes in the way we collect data in an in vivo magnetic resonance experiment, particularly with MRI of humans. These innovations include spatial localization and/or encoding based on the non-uniform B1 field generated by the surface coil, leading to new spectroscopic localization methods, image acceleration, and unique RF pulses that deal with B1 inhomogeneities and even reduce power deposition. Without the surface coil, many of the major technological advances that define the extraordinary success of MRI in clinical diagnosis and in biomedical research, as exemplified by projects like the Human Connectome Project, would not have been possible. PMID- 29705037 TI - Perspectives: MRI of angiogenesis. AB - Angiogenesis, the expansion of the vascular bed, is an important component in remodeling of tissues and organs. Such remodeling is essential for coping with substantial and sustained increase in the demands for supply of oxygen and nutrients and the timely removal of waste products. The vasculature, and its effectiveness in systemic delivery to all parts of the body, regulates the distribution of immune cells and the delivery of therapeutics as well as the dissemination of disease. Therefore, the vascular bed is possibly one of the key organs involved in homeostasis, in health and disease. The critical role of the vasculature in health, and the accessibility to non invasive probing by MRI, renders MRI as a modality of choice for monitoring the vasculature and its adaption to challenges. PMID- 29705036 TI - Oxidative stress measured in vivo without an exogenous contrast agent using QUEST MRI. AB - Decades of experimental studies have implicated excessive generation of reactive oxygen species (ROS) in the decline of tissue function during normal aging, and as a pathogenic factor in a vast array of fatal or debilitating morbidities. This massive body of work has important clinical implications since many antioxidants are FDA approved, readily cross blood-tissue barriers, and are effective at improving disease outcomes. Yet, the potential benefits of antioxidants have remained largely unrealized in patients because conventional methods cannot determine the dose, timing, and drug combinations to be used in clinical trials to localize and decrease oxidative stress. To address this major problem and improve translational success, new methods are urgently needed that non invasively measure the same ROS biomarker both in animal models and patients with high spatial resolution. Here, we summarize a transformative solution based on a novel method: QUEnch-assiSTed MRI (QUEST MRI). The QUEST MRI index is a significant antioxidant-induced improvement in pathophysiology, or a reduction in 1/T1 (i.e., R1). The latter form of QUEST MRI provides a unique measure of uncontrolled production of endogenous, paramagnetic reactive oxygen species (ROS). QUEST MRI results to-date have been validated by gold standard oxidative stress assays. QUEST MRI has high translational potential because it does not use an exogenous contrast agent and requires only standard MRI equipment. Summarizing, QUEST MRI is a powerful non-invasive approach with unprecedented potential for (i) bridging antioxidant treatment in animal models and patients, (ii) identifying tissue subregions exhibiting oxidative stress, and (iii) coupling oxidative stress localization with behavioral dysfunction, disease pathology, and genetic vulnerabilities to serve as a marker of susceptibility. PMID- 29705038 TI - In vivo NMR investigations of glyphosate influences on plant metabolism. AB - Glyphosate is the world's most widely used herbicide; popular due to its relative low cost, low toxicity, and high efficacy in controlling most common weed species. Genetic engineering of crop seeds to be glyphosate-tolerant has facilitated the modern global agricultural practice whereby both weeds and crops are treated with herbicide, while only the crops survive. However, due to extreme selective pressure, glyphosate-resistant (GR) weed species are now found with increasing frequency in nature, threatening the dominant weed management system used in large-scale agriculture across much of the globe. In vivo NMR studies of plants have facilitated the discovery and understanding of the glyphosate resistance mechanism of the multi-continent, highly invasive weed species, GR horseweed Conyza canadensis (L.) Cronq. and GR ryegrass (Lolium spp.). This study exemplifies how in vivo NMR spectroscopy can be used to better understandherbicide-associated metabolic alterations observed in living plants, which poses a significant threat to modern agriculture as it is currently practiced. PMID- 29705039 TI - Using diffusion anisotropy to study cerebral cortical gray matter development. AB - Diffusion-weighted magnetic resonance imaging (diffusion MRI) is being used to characterize morphological development of cells within developing cerebral cortical gray matter. Abnormal morphology is a shared characteristic of cerebral cortical neurons for many neurodevelopmental disorders, and therefore diffusion MRI is potentially of high value for monitoring growth-related anatomical changes of relevance to brain function. Here, the theoretical framework for analyzing diffusion MRI data is summarized. An overview of quantitative methods for validating the interpretations of diffusion MRI data using light microscopy is then presented. These theoretical modeling and validation methods have been used to precisely characterize changes in water diffusion anisotropy with development in the context of several animal model systems. Further, in diffusion MRI studies of several preclinical models of neurodevelopmental disorders, the ability is demonstrated of diffusion MRI to detect abnormal morphological neural development. These animal model studies are reviewed along with recent initial efforts to translate the findings into an approach for studies of human subjects. This body of data indicates that diffusion MRI has the requisite sensitivity to detect abnormal cellular development in the context of several models of neurodevelopmental disorders, and therefore may provide a new strategy for detecting abnormalities in early stages of brain development in humans. PMID- 29705040 TI - Theranostics and metabolotheranostics for precision medicine in oncology. AB - Most diseases, especially cancer, would significantly benefit from precision medicine where treatment is shaped for the individual. The concept of theragnostics or theranostics emerged around 2002 to describe the incorporation of diagnostic assays into the selection of therapy for this purpose. Increasingly, theranostics has been used for strategies that combine noninvasive imaging-based diagnostics with therapy. Within the past decade theranostic imaging has transformed into a rapidly expanding field that is located at the interface of diagnosis and therapy. A critical need in cancer treatment is to minimize damage to normal tissue. Molecular imaging can be applied to identify targets specific to cancer with imaging, design agents against these targets to visualize their delivery, and monitor response to treatment, with the overall purpose of minimizing collateral damage. Genomic and proteomic profiling can provide an extensive 'fingerprint' of each tumor. With this cancer fingerprint, theranostic agents can be designed to personalize treatment for precision medicine of cancer, and minimize damage to normal tissue. Here, for the first time, we have introduced the term 'metabolotheranostics' to describe strategies where disease-based alterations in metabolic pathways detected by MRS are specifically targeted with image-guided delivery platforms to achieve disease specific therapy. The versatility of MRI and MRS in molecular and functional imaging makes these technologies especially important in theranostic MRI and 'metabolotheranostics'. Our purpose here is to provide insights into the capabilities and applications of this exciting new field in cancer treatment with a focus on MRI and MRS. PMID- 29705041 TI - White matter biomarkers from diffusion MRI. AB - As part of an issue celebrating 2 decades of Joseph Ackerman editing the Journal of Magnetic Resonance, this paper reviews recent progress in one of the many areas in which Ackerman and his lab has made significant contributions: NMR measurement of diffusion in biological media, specifically in brain tissue. NMR diffusion signals display exquisite sensitivity to tissue microstructure, and have the potential to offer quantitative and specific information on the cellular scale orders of magnitude below nominal image resolution when combined with biophysical modeling. Here, I offer a personal perspective on some recent advances in diffusion imaging, from diffusion kurtosis imaging to microstructural modeling, and the connection between the two. A new result on the estimation accuracy of axial and radial kurtosis with axially symmetric DKI is presented. I moreover touch upon recently suggested generalized diffusion sequences, promising to offer independent microstructural information. We discuss the need and some methods for validation, and end with an outlook on some promising future directions. PMID- 29705042 TI - Pre-clinical MR elastography: Principles, techniques, and applications. AB - Magnetic resonance elastography (MRE) is a method for measuring the mechanical properties of soft tissue in vivo, non-invasively, by imaging propagating shear waves in the tissue. The speed and attenuation of waves depends on the elastic and dissipative properties of the underlying material. Tissue mechanical properties are essential for biomechanical models and simulations, and may serve as markers of disease, injury, development, or recovery. MRE is already established as a clinical technique for detecting and characterizing liver disease. The potential of MRE for diagnosing or characterizing disease in other organs, including brain, breast, and heart is an active research area. Studies involving MRE in the pre-clinical setting, in phantoms and artificial biomaterials, in the mouse, and in other mammals, are critical to the development of MRE as a robust, reliable, and useful modality. PMID- 29705043 TI - Using 1H2O MR to measure and map sodium pump activity in vivo. AB - The cell plasma membrane Na+,K+-ATPase [NKA] is one of biology's most [if not the most] significant enzymes. By actively transporting Na+ out [and K+ in], it maintains the vital trans-membrane ion concentration gradients and the membrane potential. The forward NKA reaction is shown in the Graphical Abstract [which is elaborated in the text]. Crucially, NKA does not operate in isolation. There are other transporters that conduct K+ back out of [II, Graphical Abstract] and Na+ back into [III, Graphical Abstract] the cell. Thus, NKA must function continually. Principal routes for ATP replenishment include mitochondrial oxidative phosphorylation, glycolysis, and creatine kinase [CrK] activity. However, it has never been possible to measure, let alone map, this integrated, cellular homeostatic NKA activity in vivo. Active trans-membrane water cycling [AWC] promises a way to do this with 1H2O MR. Inthe Graphical Abstract, the AWC system is characterized by active contributions totheunidirectional rate constants for steady-state water efflux and influx, respectively, kio(a) and koi(a). The discovery, validation, and initial exploration of active water cycling are reviewed here. Promising applications in cancer, cardiological, and neurological MRI are covered. This initial work employed paramagnetic Gd(III)chelate contrast agents [CAs]. However, the significant problems associated with in vivo CA use are also reviewed. A new analysis of water diffusion-weighted MRI [DWI] is presented. Preliminary results suggest a non invasive way to measure the cell number density [rho (cells/MUL)], the mean cell volume [V (pL)], and the cellular NKA metabolic rate [cMRNKA(fmol(ATP)/s/cell)] with high spatial resolution. These crucial cell biology properties have not before been accessible invivo. Furthermore, initial findings indicate their absolute values can be determined. PMID- 29705044 TI - Co-biodrying of sewage sludge and organic fraction of municipal solid waste: Role of mixing proportions. AB - This study investigated the performance of co-biodrying sewage sludge and organic fraction of municipal solid waste (OFMSW) at different proportions. Cornstalk was added at 15% (of total wet weight) as the bulking agent. Results show that increasing OFMSW percentage promoted the biodegradation of organic matter, thus enhancing the temperature integration value and water removal to above 75% during sludge and OFMSW co-biodrying. In particular, adding more OFMSW accelerated the biodegradation of soluble carbohydrates, lignins, lipids, and amylums, resulting in more organic loss and thus lower biodrying index (3.3-3.7 for 55-85% OFMSW). Water balance calculation indicated that evaporation was the main mechanism for water removal. Heat used for water evaporation was 37.7-48.6% of total heat consumption during co-biodrying. Our results suggest that sludge and OFMSW should be mixed equally for their efficient co-biodrying. PMID- 29705045 TI - Combined processes of ozonation and supercritical water oxidation for landfill leachate degradation. AB - Leachate is a highly variable, heterogeneous and recalcitrant wastewater generated in landfills which may contain high concentrations of many organic and inorganic compounds, hampering the application of a single technique in its treatment. Therefore, this paper assessed leachate degradation through supercritical water oxidation (ScWO) as well as combined processes of ozonation and supercritical water oxidation (O3/ScWO and ScWO/O3), a yet innovative combination. Ozonation was carried out at different reaction times (30-120 min). ScWO was developed at 600 degrees C, 23 MPa, and spatial time (tau) from 29 to 52 s. A combination of ozonation (30 min) and supercritical water oxidation process (O3-30'/ScWO) was the most efficient technique for the degradation of the leachate assessed. These conditions enabled to remove high values of apparent and true color (92% and 97%, respectively), biochemical oxygen demand (BOD5,20) (95%), chemical oxygen demand (COD) (92%), total organic carbon (TOC) (79%), nitrite (78%), nitrate (84%), total (96%), dissolved (96%) and suspended (94%) solids. In addition, the combined process presented significant decrease in electric conductivity (EC) (68%) and less leachate turbidity removal (43%). Except for ammonia and nitrite, all parameters of the leachate treated by O3 30'/ScWO met the specifications of Brazilian legislation (CONAMA Resolutions No. 357/2005 and No. 430/2011) for the disposal of wastewater in water bodies. Besides, both processes are considered to be clean technologies. This shows the great possibility of applying the O3/ScWO combination to landfills leachates. PMID- 29705046 TI - Estimating degradation-related settlement in two landfill-reclaimed soils by sand salt analogues. AB - Landfill reclaimed soil here refers to largely degraded materials excavated from old landfill sites, which after processing can be reinstated as more competent fill, thereby restoring the former landfill space. The success of the process depends on the presence of remaining degradable particles and their influence on settlement. Tests on salt-sand mixtures, from which the salt is removed, have been used to quantify the impact of particle loss on settlement. Where the amount of particle loss is small, say 10% by mass or less, settlements are small and apparently independent of lost particle size. A conceptual model is presented to explain this behaviour in terms of nestling particles and strong force chains. At higher percentages of lost particles, greater rates of settlement together with some sensitivity to particle size were observed. The conceptual model was then applied to two landfill reclaimed soils, the long-term settlements of which were found to be consistent with the conceptual model suggesting that knowledge of particle content and relative size are sufficient to estimate the influence of degradable particles in landfill reclaimed soils. PMID- 29705047 TI - Investigating impact of waste reuse on the sustainability of municipal solid waste (MSW) incineration industry using emergy approach: A case study from Sichuan province, China. AB - China has become the largest generator of municipal solid waste (MSW) in the world with its rapid urbanization, population growth and raising living standard. Among diverse solid waste disposal technologies, MSW incineration has been becoming an attractive choice. In terms of systematic point, an integrated MSW incineration system should include an incineration subsystem and a bottom ash (BA) disposal subsystem. This paper employed an extend emergy assessment method with several improved indicators, which considers the emissions' impact, to evaluate the comprehensive performances of an integrated MSW incineration system. One existing incineration plant in Yibin City, Sichuan Province, China, as a case study, is evaluated using the proposed method. Three alternative scenarios (scenario A: the incineration subsystem + the BA landfill subsystem; scenario B: the incineration subsystem + the concrete paving brick production subsystem using BA as raw material; scenario C: the incineration subsystem + the non-burnt wall brick production subsystem using BA as raw material) were compared. The study results reveal that the ratio of positive output is 1.225, 2.861 and 1.230, the improved environmental loading ratio is 2.715, 2.742 and 1.533, and the improved environmental sustainability index is 0.451, 1.043 and 0.803 for scenario A, B and C respectively. Therefore, reuse of BA can enhance the sustainability level of this integrated system greatly. Comparatively, scenario B has the best comprehensive performance among the three scenarios. Finally, some targeted recommendations are put forward for decision-making. PMID- 29705048 TI - ERK activation is required for the antiepileptogenic effect of low frequency electrical stimulation in kindled rats. AB - INTRODUCTION: The signaling pathways involved in the antiepileptogenic effect of low frequency electrical stimulation (LFS) have not been fully understood. In the present study the role of extracellular signal-regulated kinase (ERK) signaling cascade was investigated in mediating the inhibitory effects of LFS on kindled seizures. METHODS: Animals received kindling stimulations for seven days (the mean number of stimulation days for achieving stage 5 seizure) according to semi rapid perforant path kindling protocol (12 stimulations per day at 10 min intervals). LFS (0.1 ms pulse duration at 1 Hz, 800 pulses) was applied at 5 min after the last kindling stimulation every day. During the kindling procedure, FR180204 (inhibitor of ERK) was daily microinjected (1 MUg/MUl; intracerebroventricular) immediately after the last kindling stimulation and before LFS application. The expression of activated ERK (p-ERK) in the dentate gyrus was also investigated using immunohistochemistry technique. RESULTS: Application of LFS at 5 min after the last kindling stimulation had inhibitory effect on kindling rate. FR180204 had no significant effect on seizure parameters when administered at the dose of 1 MUg/MUl in kindled group of animals. However, microinjection of FR180204 before LFS application reduced the inhibitory effect of LFS on seizure severity and field potential parameters (i.e. the slope of population field excitatory postsynaptic potentials and population spike amplitude) during kindling. FR180204 also blocked the preventing effects of LFS on kindling-induced increase in early (at 10-40 ms intervals) and late (at 300 1000 ms intervals) paired pulse depression. In addition, application of LFS following kindling stimulations increased the expression of p-ERK in the dentate gyrus. CONCLUSION: Obtained results showed ERK signaling pathway had important role in mediating the antiepileptogenic effect of LFS in perforant path kindling. These findings represent a promising opportunity to gain insight about LFS mechanism in epilepsy therapy. PMID- 29705049 TI - Proficiency-based cervical cancer brachytherapy training. AB - PURPOSE: Although brachytherapy increases the local control rate for cervical cancer, there has been a progressive decline in its use. Furthermore, the training among residency programs for gynecologic brachytherapy varies considerably, with some residents receiving little to no training. This trend is especially concerning given the association between poor applicator placement and decline in local control. Considering the success of proficiency-based training in other procedural specialties, we developed and implemented a proficiency-based cervical brachytherapy training curriculum for our residents. METHODS AND MATERIALS: Each resident placed tandem and ovoid applicators with attending guidance and again alone 2 weeks later using a pelvic model that was modified to allow for cervical brachytherapy. Plain films were taken of the pelvic model, and applicator placement quality was evaluated. Other evaluated metrics included retention of key procedural details, the time taken for each procedure and presession and postsession surveys to assess confidence. RESULTS: During the initial session, residents on average met 4.5 of 5 placement criteria, which improved to 5 the second session. On average, residents were able to remember 7.6 of the 8 key procedural steps. Execution time decreased by an average of 10.5%. Resident confidence with the procedure improved dramatically, from 2.6 to 4.6 of 5. Residents who had previously never performed a tandem and ovoid procedure showed greater improvements in these criteria than those who had. All residents strongly agreed that the training was helpful and wanted to participate again the following year. CONCLUSIONS: Residents participating in this simulation training had measurable improvements in the time to perform the procedure, applicator placement quality, and confidence. This curriculum is easy to implement and is of great value for training residents, and would be particularly beneficial in programs with low volume of cervical brachytherapy cases. Simulation programs could also be created for other technically challenging radiation oncology procedures. PMID- 29705050 TI - Prevalence of metabolic syndrome-like in the follow-up of very low birth weight preterm infants and associated factors. AB - OBJECTIVE: To assess the prevalence of metabolic syndrome-like symptoms in a population of preterm infants with very low birth weight (<1500g) at 2 years of corrected age and identify the occurrence of associated risk factors. METHODS: Cross-sectional study during a five-year period, including preterm infants born with very low birth weight evaluated at 2 years of corrected age. Metabolic syndrome-like symptoms was defined by the presence of three or more of these criteria: abdominal circumference>=90th percentile, fasting blood glucose>=100mg/dL, triglycerides>=110mg/dL, HDL cholesterol<=40mg/dL, and blood pressure>=90th percentile. RESULTS: A total of 214 preterm infants with birth weight<1500g were evaluated. The prevalence of metabolic syndrome-like symptoms at 2 years of corrected age was 15.1%. Arterial hypertension was present in 57.5%, HDL<=40mg/dL in 29.2%, hypertriglyceridemia in 22.6%, and abdominal circumference above the 90th percentile in 18.8%. Only 3.7% had hyperglycemia. The presence of periventricular leukomalacia was an independent risk factor for arterial hypertension at this age (OR 2.34, 95% CI: 0.079-0.69, p=0.008). Overweight and obesity at 2 years of corrected age were independently associated with metabolic syndrome-like symptoms (OR 2.75, 95% CI: 1.19-6.36, p=0.018). CONCLUSION: Metabolic syndrome-like symptoms can be observed in very low birth weight preterm infants as early as 2 years of corrected age. Overweight and early onset obesity are significant risk factors for metabolic syndrome-like symptoms, which deserves appropriate intervention for this high-risk population. PMID- 29705051 TI - Intra-abdominal fat measurement by ultrasonography: association with anthropometry and metabolic syndrome in adolescents. AB - OBJECTIVE: To associate intra-abdominal fat thickness measured by ultrasonography to the factors related to metabolic syndrome and to determine cutoff points of intra-abdominal fat measurement associated with a greater chance of metabolic syndrome in adolescents. METHODS: This was a cross-sectional study, with 423 adolescents from public schools. Intra-abdominal fat was measured by ultrasonography. Anthropometric data were collected, and biochemical analyses were performed. RESULTS: Intra-abdominal fat was measured by ultrasonography, showing a statistically significant association with the diagnosis of metabolic syndrome (p=0.037), body mass index (p<0.001), elevated triglyceride levels (p=0.012), decreased plasma HDL levels (p=0.034), and increased systemic blood pressure values (p=0.023). Cutoff values of intra-abdominal fat thickness measurements were calculated by ultrasound to estimate the individuals most likely to develop metabolic syndrome. In the logistic regression models, the cutoff values that showed the highest association with metabolic syndrome in males were 4.50, 5.35, 5.46, 6.24, and 6.50cm for the ages of 14, 15, 16, 17, and 18/19 years, respectively. In the female gender, the cutoff values defined for the same age groups were 4.46, 4.55, 4.45, 4.90, and 6.46cm. In an overall analysis using the ROC curve, without gender and age stratification, the cut-off of 3.67cm showed good sensitivity, but low specificity. CONCLUSION: Ultrasonography is a useful method to estimate intra-abdominal adipose tissue in adolescents, which is associated with the main factors related to obesity and metabolic syndrome. PMID- 29705052 TI - Malignant middle cerebral artery (MCA) infarction in people over 85 years old - Diagnosis, management and risk factors. AB - INTRODUCTION: Malignant ischemic stroke of the middle cerebral artery (MCA) territory causes neurological deterioration due to the effects of space occupying cerebral edema. The prognosis is poor, and death usually occurs as a result of brainstem compression. There is no information on ischemic stroke, especially the malignant ones, in patients over 85 years old. AIM: The aim of this retrospective study was to evaluate the disease course, risk factors, survival rate and treatment of MCA malignant infarction in people over 85 years old. METHOD: The medical history of 66 patients with malignant MCA stroke was analyzed. The frequency of the occurrence of the risk factors like hypertension, hyperlipidemia, atrial fibrillation, heart failure, diabetes was evaluated. Disability was measured with the use of the National Institutes of Health Stroke Scale (NIHSS). Safety and effectiveness of the anticoagulants used in the group of patients with atrial fibrillation were analyzed. Chi-quadrat test and Mann Whitney U test were used for statistical analysis of data. We also described 85 year-old patient with malignant brain stroke who was treated neurosurgically with a positive effect. RESULTS: Atrial fibrillation was diagnosed in 65% of patients of the investigated group. There were no statistically significant changes in the survival rate between the group of patients treated with the use of mannitol and patients without this treatment. CONCLUSION: The key risk factor in this group is the atrial fibrillation. The elderly patients require an intensive monitoring of the health condition by reference to brain stroke risk factors, especially atrial fibrillation. PMID- 29705053 TI - Rural-metropolitan disparities in ovarian cancer survival: a statewide population based study. AB - PURPOSE: To investigate rural-metropolitan disparities in ovarian cancer survival, we assessed ovarian cancer mortality and differences in prognostic factors by rural-metropolitan residence. METHODS: The Utah Population Database was used to identify ovarian cancer cases diagnosed between 1997 and 2012. Residential location information at the time of cancer diagnosis was used to stratify rural-metropolitan residence. All-cause death and ovarian cancer death risks were estimated using Cox proportional hazard regression models. RESULTS: Among 1661 patients diagnosed with ovarian cancer, 11.8% were living in rural counties of Utah. Although ovarian cancer patients residing in rural counties had different characteristics compared with metropolitan residents, we did not observe an association between rural residence and risk of all-cause nor ovarian cancer-specific death after adjusting for confounders. However, among rural residents, ovarian cancer mortality risk was very high in older age at diagnosis and for mucinous carcinoma, and low in overweight at baseline. CONCLUSIONS: Rural residence was not significantly associated with the risk of ovarian cancer death. Nevertheless, patients residing in rural-metropolitan areas had different factors affecting the risk of all-cause mortality and cancer-specific death. Further research is needed to quantify how mortality risk can differ by residential location accounting for degree of health care access and lifestyle-related factors. PMID- 29705054 TI - Steroids versus No Steroids in Nonarteritic Anterior Ischemic Optic Neuropathy: A Randomized Controlled Trial. AB - PURPOSE: To examine the role of oral steroid therapy in the treatment of nondiabetic cases of acute nonarteritic anterior ischemic optic neuropathy (NAAION). DESIGN: Randomized double-blind clinical trial. PARTICIPANTS: Thirty eight patients with acute nondiabetic NAAION divided into 2 arms of 19 patients each. One arm constituted the cases and the other constituted the controls. METHODS: Cases received oral steroid therapy and were designated the steroid group, whereas controls received placebo and were designated the nonsteroid group. Best-corrected visual acuity (BCVA), visual evoked response (VER), and OCT were performed at baseline, 1 month, 3 months, and 6 months after recruitment into the trial. MAIN OUTCOME MEASURES: Best-corrected visual acuity, VER, and retinal nerve fiber layer changes on OCT. RESULTS: Both groups showed significant improvement in BCVA, VER latency, and resolution of disc edema on OCT parameters over 6 months. Final outcome showed no statistically significant difference with regard to visual acuity, although VER was better in the steroid group (P = 0.011). Best-corrected visual acuity, VER amplitude, and VER latency (P = 0.02, P = 0.02, and P = 0.04, respectively) showed a greater percentage improvement in the steroid group, which also saw a faster resolution of disc edema on OCT (1 month follow-up). CONCLUSIONS: Oral steroids in acute NAAION did not improve the visual acuity significantly at 6 months. However, they improved resolution of disc edema significantly and enabled a greater improvement in VER parameters. This subtle benefit of oral steroids in NAAION is clinically unimportant and does not provide support for its use. PMID- 29705055 TI - Effects of Prolonged Reading on Dry Eye. AB - PURPOSE: To demonstrate the effects of prolonged silent reading on tear film and ocular surface parameters. DESIGN: Prospective, observational clinical study. PARTICIPANTS: A total of 177 patients with dry eye and 34 normal controls aged 50 years and older. METHODS: After evaluating symptoms using the Ocular Surface Disease Index (OSDI) questionnaire, the following tests were performed in consecutive order: automated noninvasive tear break-up time (TBUT), surface asymmetry and regularity indices, Schirmer's testing without anesthesia, corneal staining using fluorescein, and conjunctival staining using lissamine green. The participants were then asked to read a 30-minute validated passage silently. The tests were repeated after the reading task. MAIN OUTCOME MEASURES: Changes in tear film and ocular surface parameters after reading. RESULTS: All parameters, with the exception of surface asymmetry index, worsened after the reading task in patients with dry eye and in controls. The worsening reached a statistical significance for corneal and conjunctival staining in the dry eye group (P < 0.001) and for corneal staining in the control group (P < 0.01). At baseline, OSDI scores correlated only with corneal and conjunctival staining scores (r = 0.19, P = 0.006 and r = 0.27, P < 0.001). Among postreading measurements, baseline OSDI scores correlated with TBUT (r = -0.15, P = 0.03) in addition to corneal and conjunctival staining (r = 0.25, P < 0.001 and r = 0.22, P = 0.001). Changes in TBUT and Schirmer's test correlated significantly with their respective baseline values (r = -0.61, P < 0.001 and r = -0.44, P < 0.001), indicating that the more unstable the tear film and the lower the aqueous tear secretion, the worse they became after the prolonged reading task. Worsening in corneal staining directly correlated with the baseline conjunctival staining (r = 0.17, P = 0.02) and surface regularity index (r = 0.21, P = 0.01). CONCLUSIONS: Evaluating tear film and ocular surface parameters at rest may miss clinical findings brought about by common everyday tasks such as reading, leading to discordance between patient-reported symptoms and clinician-observed signs. Quantifying dry eye after visually straining activities such as prolonged silent reading may help better understand patient symptomatology. PMID- 29705056 TI - Long-Term Metastatic Risk after Biopsy of Posterior Uveal Melanoma. AB - PURPOSE: Biopsy of posterior uveal melanoma continues to be intensely debated in terms of the clinical benefits and safety profile. Although several studies have reported a low frequency of ocular complications after tumor biopsy, the potential long-term risk of iatrogenic dissemination remains unresolved. The purpose of this study was to assess the risk of metastatic disease after biopsy of posterior uveal melanoma. DESIGN: Retrospective nationwide cohort study linking clinical and histopathologic records to pathology, cancer, and mortality registries. PARTICIPANTS: All patients with posterior uveal melanoma treated in Denmark between January 1985 and December 2016. METHODS: For each patient, we recorded detailed information on age, gender, tumor characteristics, and diagnostic and therapeutic measures, including tumor biopsy, if any, and the primary treating hospital. Absolute risk of melanoma-specific death was presented by cumulative incidence curves that accounted for competing risks. Cox regression models were used to estimate crude and adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and melanoma-specific mortality of patients who underwent biopsy during primary treatment compared with nonbiopsied patients through November 1, 2017. Fine and Gray risk regression was used as a sensitivity analysis to evaluate the impact of competing risks. MAIN OUTCOME MEASURES: All-cause and melanoma-specific mortality. RESULTS: Among 1637 patients, 567 (35%) underwent biopsy during primary treatment. At diagnosis, biopsied patients exhibited better prognostic characteristics, including smaller tumor size (P < 0.001) and younger age (P < 0.001), than nonbiopsied patients. In the adjusted analyses, we observed no apparent differences in all-cause mortality (HR, 1.07; 95% CI, 0.89-1.26; P = 0.47) or melanoma-specific mortality (HR, 1.11; 95% CI, 0.89-1.39; P = 0.35) among biopsied patients compared with nonbiopsied patients. CONCLUSIONS: All-cause and melanoma-specific mortality after primary treatment were similar among biopsied and nonbiopsied patients with posterior uveal melanoma. Our findings do not support an increased metastatic risk after intraocular tumor biopsy. PMID- 29705057 TI - Patterns of Progressive Ganglion Cell-Inner Plexiform Layer Thinning in Glaucoma Detected by OCT. AB - PURPOSE: To investigate the spatial characteristics and patterns of progressive macular ganglion cell-inner plexiform layer (GCIPL) thinning in glaucomatous eyes assessed by OCT Guided Progression Analysis (GPA). DESIGN: Longitudinal, retrospective, observational study. PARTICIPANTS: Two hundred ninety-two eyes of 192 patients with primary open-angle glaucoma with a mean follow-up of 6.0 years (range, 3.2-8.1 years) were included. METHODS: Macular GCIPL imaging and visual field (VF) examination were performed at 6-month intervals for 3 years or more. Progressive GCIPL thinning was evaluated by a Cirrus HD-OCT (Carl Zeiss Meditec, Dublin, CA) GPA device. Spatial characteristics of progressive GCIPL thinning were assessed by the GCIPL thickness change map. The pattern of progressive GCIPL thinning was evaluated by comparing the baseline GCIPL thickness deviation map and the final GCIPL thickness change map. Visual field progression was determined by Early Manifest Glaucoma Trial criteria and linear regression of the VF index. MAIN OUTCOME MEASURES: Spatial characteristics and patterns of progressive GCIPL thinning. RESULTS: Seventy-two eyes of 62 participants (24.7% [72/292]) showed progressive GCIPL thinning in the GCIPL thickness change map. Progressive GCIPL thinning was detected most frequently (25.0%) at 2.08 mm from the fovea, and it extended in an arcuate shape in the inferotemporal region (250 degrees -339 degrees ). Compared with the baseline GCIPL defects, the progressive GCIPL thinning extended toward the fovea and optic disc. The most common pattern of progressive GCIPL thinning was widening of GCIPL defects (42 eyes [58.3%]), followed by deepening of GCIPL defects (19 eyes [26.4%]) and newly developed GCIPL defects (15 eyes [20.8%]). Visual field progression was accompanied by progressive GCIPL thinning in 41 of 72 eyes (56.9%). Progressive GCIPL thinning preceded (61.0% [25/41]) or occurred concomitantly with (21.9% [9/41]) VF progression. CONCLUSIONS: The use of OCT GPA maps offers an effective approach to evaluate the topographic patterns of progressive GCIPL thinning in glaucomatous eyes. Progression of GCIPL thinning occurred before apparent progression on standard automated perimetry in most glaucomatous eyes. Understanding specific patterns and sequences of macular damage may provide important insights in the monitoring of glaucomatous progression. PMID- 29705058 TI - Molecular, physiological and behavioral responses of honey bee (Apis mellifera) drones to infection with microsporidian parasites. AB - Susceptibility to pathogens and parasites often varies between sexes due to differences in life history traits and selective pressures. Nosema apis and Nosema ceranae are damaging intestinal pathogens of European honey bees (Apis mellifera). Nosema pathology has primarily been characterized in female workers where infection is energetically costly and accelerates worker behavioral maturation. Few studies, however, have examined infection costs in male honey bees (drones) to determine if Nosema similarly affects male energetic status and sexual maturation. We infected newly emerged adult drones with Nosema spores and conducted a series of molecular, physiological, and behavioral assays to characterize Nosema etiology in drones. We found that infected drones starved faster than controls and exhibited altered patterns of flight activity in the field, consistent with energetic distress or altered rates of sexual maturation. Moreover, expression of candidate genes with metabolic and/or hormonal functions, including members of the insulin signaling pathway, differed by infection status. Of note, while drone molecular responses generally tracked predictions based on worker studies, several aspects of infected drone flight behavior contrasted with previous observations of infected workers. While Nosema infection clearly imposed energetic costs in males, infection had no impact on drone sperm numbers and had only limited effects on antennal responsiveness to a major queen sex pheromone component (9-ODA). We compare Nosema pathology in drones with previous studies describing symptoms in workers and discuss ramifications for drone and colony fitness. PMID- 29705059 TI - [Result of treatment of urinary lithiasis for professional aptitude]. AB - INTRODUCTION: Military people are inapt for presence of urinary stones. In this specific population, the treatment of stones is even more aggressive than for the general population without recommendation. The final decision about aptitude is the responsibility of the military doctor. Whereas, ureteroscopy has its place there and must done by any urologist. METHODS: The purpose of this study was to estimate the results of treatments by ureteroscopy in this population. Success was defined by the complete absence of fragment visualized in the imaging of control operating comment and so the end of the inaptitude time. RESULTS: Between 2009 and 2016, forty-two were treated for ureteral or renal calculi. The population comprises of 93% men, 35 years old on average. The stones were mainly multiple (more 2) and the medium size is 5mm; sixteen (42.9%) was at the left and eight (19%) was bilateral. In 78.8% (78) of the cases there was a stone in renal position whose 50% (39) still at the lower calyx. In total, 5% of the patients were stone-free in 2 sessions on average. The average deadline of inaptitude of the initial consultation in the resumption of work was of 6 months. In 4% of the cases there was a complication operating rank 4. CONCLUSION: This study confirms the feasibility, the weak harmlessness of ureteroscopy and the lesser deadline of inaptitude. Every urologist can treat this specific population. The patient must be informed and accept the treatment because of excluding referential. LEVEL OF EVIDENCE: 4. PMID- 29705060 TI - Use of Vessel-Sealing Devices during Vaginal Hysterectomy. AB - STUDY OBJECTIVE: To demonstrate the proper use of vessel-sealing devices during vaginal hysterectomy. DESIGN: Educational video (Canadian Task Force classification level III). SETTING: University hospital. INTERVENTION: The video reviews the principles on the use of energy in minimally invasive surgery. We focus on how vessel-sealing devices function and the benefits of their use in difficult vaginal hysterectomy. The video explains the 2 major types of complications, inadequate vessel sealing and undesired thermal injury, and demonstrates techniques to avoid these complications. MEASUREMENTS AND MAIN RESULTS: Laboratory, intraoperative, and cadaveric recordings demonstrate proper use and the complications that may arise in the setting of improper use. CONCLUSION: Vessel-sealing devices may be a useful tool for surgeons performing vaginal hysterectomy. This video demonstrates their use and underlines the importance of understanding the principles of energy devices and their proper usage in surgery. PMID- 29705061 TI - Dietary inflammatory potential and risk of mortality in metabolically healthy and unhealthy phenotypes among overweight and obese adults. AB - BACKGROUND & AIMS: This study was designed to investigate the association between the dietary inflammatory index (DII(r)) scores, metabolic phenotypes, and risk of mortality risk in overweight/obese individuals from a representative sample of the U.S. POPULATION: METHODS: Data from 3733 overweight/obese adults (BMI >= 25 kg/m2) aged 20-90 years from the National Health and Nutrition Examination Survey III, 1988-1994 were analyzed; these participants were followed for mortality through December 31, 2011. DII scores were computed based on baseline dietary intake using 24-h dietary recalls. Metabolically unhealthy status was defined as having 2 or more of these metabolic abnormalities: high glucose, insulin resistance, elevated blood pressure, triglycerides, C-reactive protein levels, or low high-density lipoprotein-cholesterol values. RESULTS: In metabolically unhealthy overweight/obese (MUO) individuals, DII score was associated with increased risk of all-cause mortality (HRTertile 3 vs Tertile 1 1.44; 95% CI 1.11 1.86 Ptrend = 0.008; HR1SD increase 1.08; 95% CI 0.99-1.18). Additionally, a stronger association with cardiovascular mortality was observed (HRT3 vs T1 3.29; 95% CI 2.01-5.37 Ptrend < 0.001; HR1SD increase 1.40; 95% CI 1.18-1.66), after adjusting for potential confounders. Furthermore, when analyses were restricted to obese individuals (BMI >= 30 kg/m2), the association was more pronounced, especially for cardiovascular mortality (HRT3 vs T1 5.55; 95% CI 2.11-14.57 Ptrend = 0.006; HR1SD increase 1.74; 95% CI 1.21-2.50). No association was observed between DII score and risk of mortality in individuals with metabolically healthy overweight/obese (MHO) phenotype, or for cancer mortality in either MHO or MUO phenotype. CONCLUSIONS: A pro-inflammatory diet appears to increase risk of all-cause and cardiovascular mortality in the MUO phenotype, but not among the MHO phenotype. PMID- 29705062 TI - Ecological change points: The strength of density dependence and the loss of history. AB - Change points in the dynamics of animal abundances have extensively been recorded in historical time series records. Little attention has been paid to the theoretical dynamic consequences of such change-points. Here we propose a change point model of stochastic population dynamics. This investigation embodies a shift of attention from the problem of detecting when a change will occur, to another non-trivial puzzle: using ecological theory to understand and predict the post-breakpoint behavior of the population dynamics. The proposed model and the explicit expressions derived here predict and quantify how density dependence modulates the influence of the pre-breakpoint parameters into the post-breakpoint dynamics. Time series transitioning from one stationary distribution to another contain information about where the process was before the change-point, where is it heading and how long it will take to transition, and here this information is explicitly stated. Importantly, our results provide a direct connection of the strength of density dependence with theoretical properties of dynamic systems, such as the concept of resilience. Finally, we illustrate how to harness such information through maximum likelihood estimation for state-space models, and test the model robustness to widely different forms of compensatory dynamics. The model can be used to estimate important quantities in the theory and practice of population recovery. PMID- 29705063 TI - LipiDex: An Integrated Software Package for High-Confidence Lipid Identification. AB - State-of-the-art proteomics software routinely quantifies thousands of peptides per experiment with minimal need for manual validation or processing of data. For the emerging field of discovery lipidomics via liquid chromatography-tandem mass spectrometry (LC-MS/MS), comparably mature informatics tools do not exist. Here, we introduce LipiDex, a freely available software suite that unifies and automates all stages of lipid identification, reducing hands-on processing time from hours to minutes for even the most expansive datasets. LipiDex utilizes flexible in silico fragmentation templates and lipid-optimized MS/MS spectral matching routines to confidently identify and track hundreds of lipid species and unknown compounds from diverse sample matrices. Unique spectral and chromatographic peak purity algorithms accurately quantify co-isolation and co elution of isobaric lipids, generating identifications that match the structural resolution afforded by the LC-MS/MS experiment. During final data filtering, ionization artifacts are removed to significantly reduce dataset redundancy. LipiDex interfaces with several LC-MS/MS software packages, enabling robust lipid identification to be readily incorporated into pre-existing data workflows. PMID- 29705064 TI - Corrigendum to "A whole genome bioinformatic approach to determine potential latent phase specific targets in Mycobacterium tuberculosis" [Tuberculosis 97 (March 2016) 181-192]. PMID- 29705065 TI - Anticipation of a mentally effortful task recruits Dorsolateral Prefrontal Cortex: An fNIRS validation study. AB - Preparing for a mentally demanding task calls upon cognitive and motivational resources. The underlying neural implementation of these mechanisms is receiving growing attention because of its implications for professional, social, and medical contexts. While several fMRI studies converge in assigning a crucial role to a cortico-subcortical network including Anterior Cigulate Cortex (ACC) and striatum, the involvement of Dorsolateral Prefrontal Cortex (DLPFC) during mental effort anticipation has yet to be replicated. This study was designed to target DLPFC contribution to anticipation of a difficult task using functional Near Infrared Spectroscopy (fNIRS), as a more cost-effective tool measuring cortical hemodynamics. We adapted a validated mental effort task, where participants performed easy and difficult mental calculation, and measured DLPFC activity during the anticipation phase. As hypothesized, DLPFC activity increased during anticipation of a hard task as compared to an easy task. Besides replicating previous fMRI work, these results establish fNIRS as an effective tool to investigate cortical contributions to anticipation of effortful behavior. This is especially useful if one requires testing large samples (e.g., to target individual differences), populations with contraindication for functional MRI (e.g., infants or patients with metal implants), or subjects in more naturalistic environments (e.g., work or sport). PMID- 29705067 TI - Correction. PMID- 29705066 TI - Manipulating memory efficacy affects the behavioral and neural profiles of deterministic learning and decision-making. AB - When making a decision, we have to identify, collect, and evaluate relevant bits of information to ensure an optimal outcome. How we approach a given choice can be influenced by prior experience. Contextual factors and structural elements of these past decisions can cause a shift in how information is encoded and can in turn influence later decision-making. In this two-experiment study, we sought to manipulate declarative memory efficacy and decision-making in a concurrent discrimination learning task by altering the amount of information to be learned. Subjects learned correct responses to pairs of items across several repetitions of a 50- or 100-pair set and were tested for memory retention. In one experiment, this memory test interrupted learning after an initial encoding experience in order to test for early encoding differences and associate those differences with changes in decision-making. In a second experiment, we used fMRI to probe neural differences between the two list-length groups related to decision-making across learning and assessed subsequent memory retention. We found that a striatum-based system was associated with decision-making patterns when learning a longer list of items, while a medial cortical network was associated with patterns when learning a shorter list. Additionally, the hippocampus was exclusively active for the shorter list group. Altogether, these behavioral, computational, and imaging results provide evidence that multiple types of mnemonic representations contribute to experienced-based decision-making. Moreover, contextual and structural factors of the task and of prior decisions can influence what types of evidence are drawn upon during decision-making. PMID- 29705068 TI - Sperm chromatin alterations in fertile and subfertile bulls. AB - Alterations in sperm chromatin have been related with subfertility in several mammals. In this study, chromatin alteration types (Base, Basal half, Central axis, Dispersed, and Whole) were assessed by toluidine blue (TB) staining, 6 diamidino-2-fenilindole (DAPI) and anti-protamine 1 antibody (anti-PR1) labeling in sperm samples of fertile and subfertile bulls. Semen samples were obtained from bulls kept in Artificial Insemination Center (fertile bulls) or from bulls subjected to scrotal insulation (subfertile bulls). The percentage of chromatin alterations identified by TB was similar (P > 0.05) in semen samples of fertile and subfertile bulls. In contrast, a greater (P < 0.01) chromatin decondensation and heterogeneity were recorded in semen samples of subfertile bulls. In DAPI and anti-PR1 methods, the subfertile bulls samples had a higher (P < 0.05) percentage of alteration in the base as well as overall chromatin alterations (P < 0.05). Moreover, the chromatin alterations recorded with TB, DAPI, and anti-PR1 were compared in semen samples of fertile and subfertile bulls. In fertile bulls, the overall chromatin alterations were similar (P > 0.05) among the methods In contrast, semen samples of subfertile bulls had a higher (P < 0.05) percentage of overall chromatin alterations when labeled with DAPI. In conclusion, our findings shown that all dye tested had specific sperm stainability and can be feasible to monitor subfertility condition in bulls. Also, different chromatin alteration types in sperm samples of fertile and suberftile bulls were recorded. PMID- 29705069 TI - Methodological issue re. validating a new predictive equation for resting metabolic rate. PMID- 29705070 TI - Novel Insights into Cell Entry of Emerging Human Pathogenic Arenaviruses. AB - Viral hemorrhagic fevers caused by emerging RNA viruses of the Arenavirus family are among the most devastating human diseases. Climate change, global trade, and increasing urbanization promote the emergence and re-emergence of these human pathogenic viruses. Emerging pathogenic arenaviruses are of zoonotic origin and reservoir-to-human transmission is crucial for spillover into human populations. Host cell attachment and entry are the first and most fundamental steps of every virus infection and represent major barriers for zoonotic transmission. During host cell invasion, viruses critically depend on cellular factors, including receptors, co-receptors, and regulatory proteins of endocytosis. An in-depth understanding of the complex interaction of a virus with cellular factors implicated in host cell entry is therefore crucial to predict the risk of zoonotic transmission, define the tissue tropism, and assess disease potential. Over the past years, investigation of the molecular and cellular mechanisms underlying host cell invasion of human pathogenic arenaviruses uncovered remarkable viral strategies and provided novel insights into viral adaptation and virus-host co-evolution that will be covered in the present review. PMID- 29705071 TI - S-Nitrosylation of STIM1 by Neuronal Nitric Oxide Synthase Inhibits Store Operated Ca2+ Entry. AB - Store-operated Ca2+ entry (SOCE) mediated by stromal interacting molecule-1 (STIM1) and Orai1 represents a major route of Ca2+ entry in mammalian cells and is initiated by STIM1 oligomerization in the endoplasmic or sarcoplasmic reticulum. However, the effects of nitric oxide (NO) on STIM1 function are unknown. Neuronal NO synthase is located in the sarcoplasmic reticulum of cardiomyocytes. Here, we show that STIM1 is susceptible to S-nitrosylation. Neuronal NO synthase deficiency or inhibition enhanced Ca2+ release-activated Ca2+ channel current (ICRAC) and SOCE in cardiomyocytes. Consistently, NO donor S nitrosoglutathione inhibited STIM1 puncta formation and ICRAC in HEK293 cells, but this effect was absent in cells expressing the Cys49Ser/Cys56Ser STIM1 double mutant. Furthermore, NO donors caused Cys49- and Cys56-specific structural changes associated with reduced protein backbone mobility, increased thermal stability and suppressed Ca2+ depletion-dependent oligomerization of the luminal Ca2+-sensing region of STIM1. Collectively, our data show that S-nitrosylation of STIM1 suppresses oligomerization via enhanced luminal domain stability and rigidity and inhibits SOCE in cardiomyocytes. PMID- 29705072 TI - Comparative aspects and evolutionary perspectives of behavioral fever: Or what can we learn from fish? PMID- 29705073 TI - Antithrombotic Therapy in Acute Coronary Syndrome: Striking a Happy Medium. PMID- 29705074 TI - Kidney Transplantation in HIV-Positive Patients: A Single-Center, 16-Year Experience. AB - Hahnemann University Hospital has performed 120 kidney transplantations in human immunodeficiency virus (HIV)-positive individuals during the last 16 years. Our patient population represents ~10% of the entire US population of HIV-positive kidney recipients. In our earlier years of HIV transplantation, we noted increased rejection rates, often leading to graft failure. We have established a multidisciplinary team and over the years have made substantial protocol modifications based on lessons learned. These modifications affected our approach to candidate evaluation, donor selection, perioperative immunosuppression, and posttransplantation monitoring and resulted in excellent posttransplantation outcomes, including 100% patient and graft survival at 1 year and patient and graft survival at 3 years of 100% and 96%, respectively. We present key clinical data, including a granular patient-level analysis of the associations of antiretroviral therapy regimens with long-term survival, cellular and antibody mediated rejection rates, and the causes of allograft failures. In summary, we provide details on the evolution of our approach to HIV transplantation during the last 16 years, including strategies that may improve outcomes among HIV positive kidney transplantation candidates throughout the United States. PMID- 29705075 TI - Effectiveness of continuous versus single injection femoral nerve block for total knee arthroplasty: A double blinded, randomized trial. AB - BACKGROUND: Effective analgesia following total knee arthroplasty (TKA) is important for maximizing patient satisfaction, early participation in physical therapy and reducing the hospital stay. This trial compared continuous catheter femoral nerve block (cFNB) to single injection femoral nerve block (sFNB) in terms of analgesia, opioid consumption, and participation in physical therapy and associated side effects. METHODS: This randomized, double blinded trial was conducted in a non-university hospital setting, without major changes to anesthesia or surgical clinical pathways. A total of 85 patients scheduled for primary TKA were randomized to receive either cFNB (n=44) or sFNB (n=41). All patients had FNB with 0.5% ropivacaine bolus followed by subarachnoid block for surgery. Postoperatively, 0.2% ropivacaine infusion was commenced in cFNB group and a sham catheter was taped to the skin in sFNB group. All patients received a structured multimodal analgesia regimen throughout hospital stay. The primary outcomes were peak resting visual analogue scale (VAS) scores and morphine consumption at 48h postoperatively. RESULTS: VAS scores (Mean difference 0.25, 95% Confidence Interval (CI) -0.56 to 1.06; [P=0.196]) and morphine consumption (Mean difference 0.95mg, 95% CI -9.99 to 11.89; [P=0.863]) were not significantly different among patients who received cFNB versus sFNB at 48h. There was no difference in hospital stay (P=0.517) or long-term functional recovery between the two groups (P=0.385). CONCLUSIONS: sFNB block provides equal pain relief compared with cFNB, after TKA with no significant difference in opioid consumption, hospital stay, physical therapy outcomes or associated side effects. PMID- 29705076 TI - Stereophotogrammetric surface anatomy of the anterior cruciate ligament's tibial footprint: Precise osseous structure and distances to arthroscopically-relevant landmarks. AB - BACKGROUND: While femoral tunnel malposition is widely recognized as the main technical error of failed anterior cruciate ligament (ACL) surgery, tibial tunnel malposition is likely underrecognized and underappreciated. PURPOSE: To describe more precisely the qualitative and quantitative anatomy of the ACL's tibial attachment in vitro using widely available technology for stereophotogrammetric surface reconstruction, and to test its applicability in vivo. METHODS: Stereophotogrammetric surface reconstruction was obtained from fourteen proximal tibias of cadaver donors. Measurements of areas and distances from the center of the ACL footprint and the footprint of the obtained bundles to selected arthroscopically-relevant anatomic landmarks were carried out using a three dimensional design software program, and means and 95% confidence intervals were calculated for these measurements. Reference landmarks were tested in three dimensional models obtained with arthroscopic videos. MAIN FINDINGS: The osseous footprint of the ACL was described in detail, including its precise elevated limits, size, and shape, with its elevation pattern described as a quarter-turn staircase-like ridge. Its internal indentations were related to inter-spaces identified as bundle divisions. Distances from the footprint center to arthroscopically relevant landmarks were obtained and compared to its internal structure, yielding a useful X-like landmark pointing to the most accurate placeholder for the ACL footprint's "anatomic" center. Certain structures and reference landmarks described were readily recognized in three-dimensional models from arthroscopic videos. CONCLUSIONS: Stereophotogrammetric surface reconstruction is an accessible technique for the investigation of anatomic structures in vitro, offering a detailed three-dimensional depiction of the ACL's osseous footprint. PMID- 29705077 TI - Do joint mobilizations assist in the recovery of lateral elbow tendinopathy? A systematic review and meta-analysis. AB - STUDY DESIGN: Systematic review. INTRODUCTION: No consensus exists as to which are the most effective methods to treat the symptoms associated with lateral elbow tendinopathy (LET). Research has suggested that joint mobilizations may assist in the recovery of patients with LET. PURPOSE OF THE STUDY: To determine if joint mobilizations are effective in improving pain, grip strength, and disability in adults with LET. METHODS: Searches in 3 databases were performed to identify relevant clinical trials. Reviewers independently extracted data and assessed the methodological quality. Summary measures of quantitative data were extracted or calculated where possible. Appropriate data were pooled for meta analysis using a random-effects model. RESULTS: A total of 20 studies met the inclusion criteria; 7 were included in the meta-analysis. Studies were broadly classified into 3 groups: mobilization with movement (MWM), Mill's manipulation, and regional mobilization techniques. Pooled data across all time periods demonstrated a mean effect size of 0.43 (95% confidence interval [CI]: 0.15-0.71) for MWM on improving pain rating, and 0.31 (95% CI: 0.11-0.51) for MWM on improving grip strength, 0.47 (95% CI: 0.11-0.82) for Mill's manipulation on improving pain rating. A mean effect size of -0.01 (95% CI: -0.27 to -0.26) shows Mill's manipulation did not improve pain free grip strength. Functional outcomes varied considerably among studies. Pain, grip strength, and functional outcomes were improved with regional mobilizations. CONCLUSION: There is compelling evidence that joint mobilizations have a positive effect on both pain and/or functional grip scores across all time frames compared to control groups in the management of LET. PMID- 29705078 TI - Therapist's practice patterns for subsequent fall/osteoporotic fracture prevention for patients with a distal radius fracture. AB - STUDY DESIGN: Cross-sectional survey. INTRODUCTION: Multifactorial risk factor screening and treatment is needed for subsequent falls/osteoporotic fractures prevention (SFOFP), given the elevated risk among patients with distal radius fracture (DRF). PURPOSE OF THE STUDY: The primary objective was to describe hand therapists' knowledge and clinical practice patterns for assessment, treatment, referral, and education with respect to SFOFP for patients with DRF older than 45 years. Secondary objective was to explore therapist's preferences in content and delivery of knowledge translation tools that would support implementation of SFOFP. METHODS: A cross-sectional multinational (Canada, the United States, and India) survey was conducted among 272 therapists from August to October 2014. Completed surveys were analyzed descriptively. RESULTS: Surveys were completed by 157 therapists. Most respondents were from the United States (59%), certified hand therapists (54%), and females (87%). Although 65%-90% believed that they had knowledge about SFOFP assessment, treatment, and referral options, 55% did not include it in their routine practice for patients with DRF. Most assessed medication history (82%) and never used a Fracture Risk Assessment Tool (90%) or lower extremity muscle strength testing (54%) to identify those at risk of secondary fractures. With respect to treatment, approximately 33% always used upper extremity muscle strengthening exercises. Most reported rarely (sometimes to never) using balance (79%), lower extremity muscle strengthening (85%), bone strengthening (54%), or community-based physical activity (72%) programs. Similarly, when surveyed about patient education, therapists rarely (sometimes to never) advised patients about web-based resources (94%), regular vision testing (92%), diet for good bone health (87%), bone density evaluation (86%), footwear correction (73%), and hazard identification (67%). Most hand therapists were interested to receive more information on SFOFP for patients with DRF. Nearly one half preferred to have Web sites for patients, and two-fifth were in favor of pamphlets for patients. CONCLUSION: Current practice patterns reveal care gaps and limited implementation with respect to SFOFP for patients with DRF. Future research should focus on web-based educational/knowledge translation strategies to promote implementation of multifactorial fall risk screening and hand therapist's engagement in SFOFP for patients with DRF. PMID- 29705079 TI - Gold nanoparticles induce serum amyloid A 1-Toll-like receptor 2 mediated NF-kB signaling in lung cells in vitro. AB - Gold nanoparticles (AuNPs) have emerging applications in biomedicine and the industry. Exposure to AuNPs has previously been shown to alter the transcriptional activity of nuclear factor kappa B (NF-kB), which is known to mediate physiological and pathological processes. This study seeks to provide mechanistic insights into AuNP-induced NF-kB activation in Small Airway Epithelial Cells (SAECs) in vitro. Increased NF-kB transcriptional activity (quantified by the luciferase reporter assay) was observed in AuNP-treated SAECs. Transcriptomic analysis revealed differential expression of 42 genes, which regulate functional processes that include cellular response to stimulus, chemicals and stress as well as immune response. Notably, the gene expression of serum amyloid A1 (SAA1), an acute phase protein and Toll-like receptor 2 (TLR2) were found to be up-regulated. As TLR2 is known to be a functional receptor of SAA1, a co-immunoprecipitation assay was performed. SAA1 was observed to be co immunoprecipitated with the TLR2 protein and this protein-protein interaction was further supported by in silico computer based protein modeling. The present study suggests that AuNPs may potentially induce SAA1-TLR2-mediated NF-kB transcription factor activation in lung epithelial cells, highlighting that nano-bio interactions could result in biological effects that may affect cells. PMID- 29705080 TI - No relationship between mild limb length discrepancy and spine, hip or knee degenerative disease in a large cadaveric collection. AB - BACKGROUND: Although asymptomatic mild limb length discrepancy (LLD) in children is generally treated non-operatively, there is limited high quality follow up data to support this recommendation. HYPOTHESIS: We hypothesized that there would be no association between LLD and arthritic changes with mild limb length discrepancy. MATERIALS AND METHODS: We studied 576 well-preserved cadaveric skeletons ranging from 40 to 79 years of age. Limb length discrepancy was based on combined femoral and tibial lengths measured using digital calipers. Degenerative disease was hand graded in the spine, hips and knees using a previously described classification system. Power was set at 90%. RESULTS: Average age was 56+/-10 years and average LLD was 4.8+/-4.0mm. Multiple regression analysis did not demonstrate any correlation between LLD and degenerative disease. After screening to find 26 additional specimens with LLD 10mm or greater, and assessing a potentially quadratic relationship, we still did not find any detrimental effects of LLD. DISCUSSION: Our data support the general clinical recommendation of observation for mild asymptomatic LLD. These results do not apply to larger LLD nor LLD associated with other deformities or clinical symptoms. LEVEL OF EVIDENCE: Not applicable, anatomic basic science study. PMID- 29705081 TI - Should we avoid shoulder surgery in wheelchair users? A systematic review of outcomes and complications. AB - INTRODUCTION: The prevalence of shoulder pathology in wheelchair dependent patients is high. The shoulder joint is critical for maintaining independence but traditionally there has been reluctance to offer surgical intervention in view of perceived poor outcomes. The aim of this study was to provide patients and surgeons with a realistic overview of outcomes following surgical intervention for shoulder pathology in wheelchair dependent patients. METHODS: A systematic review of the online databases Medline and Embase was performed in September 2017. Studies reporting functional outcomes, complications or rate of revision surgery after shoulder surgery in patients' dependent on wheelchair for mobility were included. A narrative synthesis of the studies and appraisal using the MINORS tool was performed. RESULTS: The search strategy identified 11 eligible studies; 7 assessed rotator cuff repair and 4-shoulder arthroplasty. Six of the seven studies reporting on rotator cuff repairs demonstrated improvement in pain, range of motion and functional outcomes with a retear rate between 12 and 39%. Although total shoulder arthroplasty and hemiarthroplasty reportedly improved pain and function, the subsequent risk of rotator cuff failure was reported up to 100%. The two studies assessing reverse arthroplasty demonstrated significant improvement in function and pain with the largest series reporting a 15.8% failure rate. CONCLUSION: Rotator cuff repairs and reverse shoulder arthroplasties performed in wheelchair users are associated with significant functional improvement and a slightly higher complication profile to those performed in ambulatory patients. This review provides a resource to aid surgeons and patients in holding realistic expectations following shoulder surgery in wheelchair users. PMID- 29705082 TI - Transvenous extraction of advisory implantable cardioverter defibrillator leads with a relatively long implant duration. AB - BACKGROUND: Optimal management of advisory implantable cardioverter defibrillator (ICD) leads has not been established. Several studies were reported concerning the lead extraction of advisory ICD leads, but the implant duration of those studies was short. We estimated the efficacy of lead extractions of advisory ICD leads with a relatively longer duration in Japanese patients. METHODS: We retrospectively analyzed 28 patients who underwent a lead extraction at Kokura Memorial Hospital and Tokyo Medical and Dental University Hospital [Fidelis (Medtronic, Minneapolis, MN, USA): n=19, Riata (St. Jude Medical, Sylmar, CA, USA): n=8, Isoline (SORIN CRM SAS, Clamart, France): n=1]. The mean implant duration was 63.3+/-19.3 months. The indications were device related infections in 3, electrical lead failures in 18, electrical lead failures and venous obstructions in 3, and prophylactic reasons in 4 patients. Inappropriate shocks because of electrical lead failures were observed in 9 patients. RESULTS: Complete removals were achieved of all 28 advisory leads. In 23 out of 28 patients, new ICD leads were implanted during the same procedure. In one patient, open chest surgery was performed for a hemothorax that occurred during a new ICD lead implantation just after successfully removing the advisory ICD lead. There were no other major or minor complications. CONCLUSION: Transvenous extractions of advisory ICD leads with relatively long implant duration were performed with a high success rate and low complication and mortality rate in Japanese patients. PMID- 29705083 TI - Cochineal dye-induced immediate allergy: Review of Japanese cases and proposed new diagnostic chart. AB - BACKGROUND: Cochineal dye is used worldwide as a red coloring in foods, drinks, cosmetics, quasi-drugs, and drugs. The main component of the red color is carminic acid (CA). Carmine is an aluminum- or calcium-chelated product of CA. CA and carmine usually contain contaminating proteins, including a 38-kDa protein thought to be the primary allergen. Severe allergic reactions manifest as anaphylaxis. The aim of this study was to review all Japanese reported cases and propose useful diagnostic chart. METHODS: All reported Japanese cases of cochineal dye-induced immediate allergy were reviewed, and newly registered cases were examined by skin prick test (SPT) with cochineal extract (CE) and measurement of CE and carmine-specific serum IgE test. Two-dimensional (2D) western blotting using patient serum was conducted to identify the antigen. RESULTS: Twenty-two Japanese cases have been reported. SPT and the level of specific IgE test indicated that six cases should be newly registered as cochineal dye allergy. All cases were adult females, and all cases except three involved anaphylaxis; 13 cases involved past history of local symptoms associated with cosmetics use. Japanese strawberry juice and fish-meat sausage, and European processed foods (especially macarons made in France) and drinks were recent major sources of allergen. 2D western blotting showed that patient IgE reacted to the 38-kDa protein and other proteins. Serum from healthy controls also weakly reacted with these proteins. CONCLUSIONS: SPT with CE and determination of the level of CE and carmine-specific IgE test are useful methods for the diagnosis of cochineal dye allergy. PMID- 29705084 TI - Action memory and knowledge-based cuing in school-aged children: The effect of object presentation and semantic integration. AB - Research into memory has found that declarative knowledge provides rich information about the world and improved memory performance. The present research investigates the effects of knowledge-based cues on memory for action events and on the enactment effect. Cued recall of action phrases was examined in four groups of 8-14-year-olds (410 children in total). The object cues (i.e., real vs. imaginary objects) and semantic relational cues (i.e., well-integrated vs. poorly integrated items) were manipulated in three encoding conditions: verbal tasks, experimenter-performed tasks, and subject-performed tasks. Results indicate that enacted encoding has a recall advantage over verbal encoding regardless of the cue manipulations, though presenting objects and semantic-integrated items can moderate the enactment effect. In addition, providing further information about prior knowledge can directly influence memory performance across age groups. These results are discussed in relation to the effect of knowledge-based information in facilitating memory strategies and cognitive processing in school aged children. PMID- 29705085 TI - Interobserver and intraobserver variability in measuring the tortuosity of the thoracic aorta on computed tomography. AB - OBJECTIVE: The variability in measuring the tortuosity of the thoracic aorta has not been previously studied. This study evaluated the interobserver and intraobserver variability of major methods used for measuring the tortuosity of the thoracic aorta in patients with aortic arch or descending thoracic aortic aneurysm. METHODS: This retrospective study enrolled 66 patients with aortic arch or descending thoracic aortic aneurysm who had undergone thoracic endovascular aortic repair. Two radiologists used preoperative computed tomography images to measure the tortuosity of the thoracic aorta at multiple segments by using the fitting circle diameter, tortuosity index, and centerline angle methods; these measurements were repeated after an interval of >28 days. The variability of the methods was analyzed for interobserver and intraobserver reliability and agreement. The estimated intraclass correlation coefficient (ICC) was used to analyze the reliability. The Bland-Altman plot was used to analyze the interobserver and intraobserver agreement. The association between aortic characteristics, including calcification, luminal irregularity, shape, and diameter, and the variability of the measurements was also analyzed. RESULTS: The interobserver ICC estimates for the tortuosity index at multiple aortic segments, centerline angle methods at the supra-aortic branch orifices, and fitting circle diameter on the greater and lesser curvature sides were 0.97 to 0.98, 0.39 to 0.75, and 0.82 to 0.84, respectively. The corresponding intraobserver ICC estimates were 0.98 to 1.00, 0.44 to 0.75, and 0.82 to 0.85, respectively. In the agreement analysis, the 95% limits of agreement for the tortuosity index, centerline angle, and fitting circle diameter were -5.5% to 5.6%, -10.9% to 10.9%, and -18.0% to 24.0%, respectively. The tortuosity index had the highest ICC estimate and narrowest 99.5% limits of agreement of the three methods. Aortic characteristics, including calcification, grade of atheroma, aneurysm shape, and diameter, were not associated with the variability of the tortuosity index method in the thoracic aorta. CONCLUSIONS: The tortuosity index method has low interobserver and intraobserver variability in measuring the tortuosity of the thoracic aorta in patients with thoracic aortic aneurysm. The characteristics of the aorta and aneurysm are not associated with the interobserver or intraobserver variability of the tortuosity index. PMID- 29705086 TI - Transaxillary decompression of thoracic outlet syndrome patients presenting with cervical ribs. AB - OBJECTIVE: The transaxillary approach to thoracic outlet decompression in the presence of cervical ribs offers the advantage of less manipulation of the brachial plexus and associated nerves. This may result in reduced incidence of perioperative complications, such as nerve injuries. Our objective was to report contemporary data for a series of patients with thoracic outlet syndrome (TOS) and cervical ribs managed through a transaxillary approach. METHODS: We reviewed a prospectively maintained database for all consecutive patients who underwent surgery for TOS and who had a cervical rib. Symptoms, preoperative evaluation, surgical details, complications, and postoperative outcomes form the basis of this report. RESULTS: Between 1997 and 2016, there were 818 patients who underwent 1154 procedures for TOS, including 873 rib resections. Of these, 56 patients underwent 70 resections for first and cervical ribs. Cervical ribs were classified according to the Society for Vascular Surgery reporting standards: 25 class 1, 17 class 2, 5 class 3, and 23 class 4. Presentations included neurogenic TOS in 49 patients and arterial TOS in 7. Operative time averaged 141 minutes, blood loss was 47 mL, and hospital stay averaged 2 days. No injuries to the brachial plexus, long thoracic, or thoracodorsal nerves were identified. One patient had partial phrenic nerve dysfunction that resolved. No hematomas, lymph leak, or early rehospitalizations occurred. Average follow-up was 591 days. Complete resolution or minimal symptoms were noted in 52 (92.8%) patients postoperatively. Significant residual symptoms requiring ongoing evaluation or pain management were noted in four (7.1%) at last follow-up. Somatic pain scores were reduced from 6.9 (preoperatively) to 1.3 (at last visit). Standardized evaluation using shortened Disabilities of the Arm, Shoulder, and Hand scores indicated improvement from 60.4 (preoperatively) to 31.3 (at last visit). CONCLUSIONS: This series of transaxillary cervical and first rib resections demonstrates excellent clinical outcomes with minimal morbidity. The presence of cervical ribs, a positive response to scalene muscle block, and abnormalities on electrodiagnostic testing are reliable indicators for surgery. A cervical rib in a patient with TOS suggests that there is excellent potential for improvement after first and cervical rib excision. PMID- 29705087 TI - Long-term outcomes after repair of symptomatic abdominal aortic aneurysms. AB - OBJECTIVES: Previous studies have reported increased perioperative mortality of nonruptured symptomatic abdominal aortic aneurysms (Sx-AAA) compared with asymptomatic elective AAA (E-AAA) repairs, but no long-term-outcomes have been reported. We sought to compare long-term outcomes of Sx-AAA and E-AAA after repair at a single academic institution. METHODS: Patients receiving AAA repair for Sx-AAA and E-AAA from 1995 through 2015 were included. Ruptured AAA and suprarenal or thoracoabdominal AAA were excluded. Demographics, comorbidities, and operative approach were collected. Long-term mortality was the primary outcome, determined by chart review or link to Social Security Death Index. Additionally, long-term mortality and reinterventions were compared after groups were matched with nearest neighbor propensity to reduce bias. RESULTS: AAA repair was performed for 1054 E-AAA (383 open repair [36%], 671 endovascular aneurysm repair [EVAR] [64%]), and 139 symptomatic aneurysms (60 open repair [43%], 79 EVAR [57%]). Age (73 years vs 74 years; P = .13) and aneurysm diameter were similar between Sx-AAA and E-AAA (6.0 cm vs 5.8 cm; P = .5). The proportion of women was higher for Sx-AAA (26% vs 16%; P = .003), as was the proportion of non Caucasians (40% vs 29%; P = .009). After propensity matching, there were no differences between groups for patient characteristics, AAA diameter, treatment modality, or comorbidities, including hypertension, coronary artery disease, congestive heart failure, diabetes, hyperlipidemia, lung disease, diabetes, renal disease, and smoking history. Women were treated for Sx-AAA at significantly smaller aortic diameters; however, compared with men (5.1 cm vs 6.3 cm; P < .001). Perioperative mortality was 5.0% for Sx-AAA and 2.3% for E-AAA (P = .055). By life-table analysis, Sx-AAA had lower 5-year (62% vs 71%) and 10-year (39% vs 51%) survivals (P = .01) compared with E-AAA for the entire cohort. Similar trends were observed for 5-year and 10-year mortality after propensity matching (63% and 40% vs 71% and 52%; P = .05). When stratified by repair type 5-year and 10-year survivals trended lower after open surgery (68% and 42% Sx-AAA vs 84% and 59% E-AAA; P = .08) but not EVAR (59% and 40% Sx-AAA vs 61% and 49% E-AAA; P = .4). Aneurysm-related reinterventions were similar for Sx-AAA and E-AAA (15% vs 14%; P = .8). Reinterventions were more common after EVAR compared with open repair (22% vs 7%, Sx-AAA P = .015; 20% vs 4% E-AAA; P = .007). CONCLUSIONS: Patients with Sx-AAA had lower long-term survival and similar aneurysm-related reinterventions compared with patients with E-AAA undergoing repair. Women also underwent repair for Sx-AAA at a significantly smaller size when compared with men, which emphasizes the role of gender in AAA symptomatology. Differences in long-term survival may be only partially explained by measured patient, aneurysm, and operative factors, and may reflect unmeasured social factors or suggest inherent differences in pathophysiology of Sx-AAAs. PMID- 29705088 TI - Time Is Brain: The Stroke Theory of Relativity. AB - BACKGROUND: Since the introduction of the philosophical tenet "Time is Brain!," multiple lines of research have demonstrated that other factors contribute to the degree of ischemic injury at any one point in time, and it is now clear that the therapeutic window of acute ischemic stroke is more protracted than it was first suspected. To define a more realistic relationship between time and the ischemic process, we used computational modeling to assess how these 2 variables are affected by collateral circulatory competence. METHODS: Starting from the premise that the expression "Time=Brain" is mathematically false, we reviewed the existing literature on the attributes of cerebral ischemia over time, with particular attention to relevant clinical parameters, and the effect of different variables, particularly collateral circulation, on the time-ischemia relationship. We used this information to construct a theoretical computational model and applied it to categorically different yet abnormal cerebral perfusion scenarios, allowing comparison of their behavior both overall (i.e., final infarct volume) and in real-time (i.e., instantaneous infarct growth rate). RESULTS: Optimal collateral circulatory competence was predictably associated with slower infarct growth rates and prolongation of therapeutic window. Modeling of identifiable specific types of perfusion maps allows forecasting of the fate of the ischemic process over time. CONCLUSIONS: Distinct cerebral perfusion map patterns can be readily identified in patients with acute ischemic stroke. These patterns have inherently different behaviors relative to the time-ischemia construct, allowing the possibility of improving parsing and treatment allocation. It is clearly evident that the effect of time on the ischemic process is relative. PMID- 29705089 TI - Effective ventilation: The most critical intervention for successful delivery room resuscitation. AB - Lung aeration is the critical first step that triggers the transition from fetal to postnatal cardiopulmonary physiology after birth. When an infant is apneic or does not breathe sufficiently, intervention is needed to support this transition. Effective ventilation is therefore the cornerstone of neonatal resuscitation. In this article, we review the physiology of cardiopulmonary transition at birth, with particular attention to factors the caregiver should consider when providing ventilation. We then summarize the available clinical evidence for strategies to monitor and perform positive pressure ventilation in the delivery room setting. PMID- 29705090 TI - Alterations in the expression of DNA damage response-related molecules in potentially preneoplastic oral epithelial lesions. AB - OBJECTIVES: The aim of this study was to evaluate the expression levels of DNA damage response (DDR) markers in potentially preneoplastic oral epithelial lesions (PPOELs). STUDY DESIGN: Immunohistochemical expression of DDR markers (gammaEta2 AlphaChi, pChk2, 53 BP1, p53, and phosphorylated at Ser 15 p53) was assessed in 41 oral leukoplakias, ranging from hyperplasia (H) to dysplasia (D) and in comparison with oral squamous cell carcinoma (OSCC) and normal mucosa (NM). Statistical and receiver operating characteristic curve analysis were performed. RESULTS: gammaH2 AX immunoexpression demonstrated a gradual increase and upper layer extension from NM to H to higher D degrees to OSCC. pChk2 expression was minimal in NM, relatively low in PPOELs, with an increasing tendency from H to D, and higher in OSCC. 53 BP1 demonstrated higher levels in OSCC than in NM, whereas its expression in PPOELs was heterogeneous, gradually increasing according to D. p53 demonstrated progressively higher levels and upper layer extension from H to D to OSCC. Phosphorylated p53 was absent in NM and relatively low in PPOELs and OSCC. CONCLUSIONS: DDR markers' expression is variable in PPOELs, showing a tendency to increase along with dysplasia. Activated DDR mechanisms may play an important protective role at early stages of oral carcinogenesis, but probably suffer progressive deregulation, eventually failing to suppress malignant transformation. PMID- 29705091 TI - Albuminuric and non-albuminuric chronic kidney disease in type 1 diabetes: Association with major vascular outcomes risk and all-cause mortality. AB - AIMS: Albuminuric and non-albuminuric phenotypes of chronic kidney disease (CKD) may have different cardiovascular risk and survival in type 1 diabetes (T1DM). Herein we estimated risk of major vascular outcomes by the EURODIAB PCS score and determined all-cause mortality rate in 774 T1DM according to CKD phenotypes. METHODS: We evaluated the distribution of CKD phenotypes [no CKD, stages 1-2, non albuminuric stage >=3 (Alb-CKD), albuminuric stage >=3 (Alb+CKD)], the EURODIAB risk score for major vascular outcomes [low- (LS), intermediate- (IS), and high- (HS) risk] and all-cause mortality over a follow-up of 8.25 +/- 2.34 years. RESULTS: Out of 774 subjects, 692 (89.4%) had no CKD, 53 (6.8%) CKD stages 1-2, 17 (2.2%) Alb-CKD and 12 (1.6%) Alb+CKD; 466 (60.2%) had LS, 205 (26.5%) IS and 103 (13.3%) HS. Distribution of HS was: no CKD, 9.1%; CKD stages 1-2, 34.0%; Alb CKD, 64.7%; Alb+CKD, 91.7% (P < 0.0001). Mortality increased from no CKD, 3.0%; to stages 1-2, 15.1% (HR 4.504); Alb-CKD, 29.4% (8.573); Alb+CKD, 50.0% (20.683, P < 0.0001). Accounting for age and sex, HRs for mortality compared to no CKD were: CKD stages 1-2, 3.84 (P = 0.001); Alb-CKD, 2.97 (P = 0.046); Alb+CKD, 7.44 (P < 0.0001). Adjusting for sex and the EURODIAB score, HRs for mortality compared to no CKD were: CKD stages 1-2, 2.57 (P = 0.027); Alb-CKD, 2.77 (P = 0.058); Alb+CKD, 4.58 (P = 0.003). CONCLUSIONS: In our T1DM cohort, one fifth of those with CKDs were non-albuminuric. This phenotype was associated with higher risk of major outcomes and similar rate of mortality as compared to CKD stages 1 2. The greatest risk and highest mortality occur in patients with Alb+CKD. PMID- 29705092 TI - Randomized controlled trials in pediatric patients had higher completion rates than adult trials: a cross-sectional study. AB - OBJECTIVE: Conduct of clinical trials is perceived to be more challenging in children than in adults. This study aimed to evaluate the impact of the age of participants on completion rates of randomized controlled trials (RCTs). STUDY DESIGN AND SETTING: A cross-sectional study on RCTs registered in the ClinicalTrials.gov database. All RCTs registered up to December 31, 2016, were extracted and were classified according to their recruitment status: active, completed, or discontinued and according to the age of participants: children (<17 years), adults (>=18 years), and mixed-age population. A logistic regression model was applied to assess the impact of participant's age category on trial completion while controlling for other relevant trial features. RESULTS: A total of 65,095 registered RCTs were identified. Among pediatric trials, 49.9% were completed and 8.5% were discontinued. Among adult and mixed age RCTs, respectively, 49.7% and 47.9% were completed whereas, 10.2% and 9.4% were discontinued. Overall, pediatric and mixed age RCTs were more likely to be registered as completed than adult RCTs (odds ratio: 1.16, 95% CI: 1.02-1.30; odds ratio: 1.15, 95% CI: 1.04-1.27, respectively). Also, funding source, type of intervention under evaluation, primary trial purpose, use of a blinding procedure, use of a placebo, and participants' assignment model were identified as independent predictors of RCT completion. CONCLUSION: Contrary to current perceptions and despite several specific challenges, recruitment of children and adolescents is not a limiting factor to completing a RCT. Other study features such as funding source, impact completeness and should be carefully considered before initiating research. PMID- 29705093 TI - No firm evidence that lack of blinding affects estimates of mortality in randomized clinical trials of intensive care interventions: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the effect of blinding on mortality effect estimates in randomized clinical trials (RCTs) in adult intensive care unit (ICU) patients. STUDY DESIGN AND SETTING: A systematic review and meta-analysis of RCTs reporting mortality effect estimates of ICU interventions in adult ICU patients. We assessed differences in summarized risk ratios with 95% confidence intervals between blinded and unblinded RCTs. P < 0.10 was considered statistically significant (test of interaction). RESULTS: We included 22 ICU interventions assessed in 269 RCTs enrolling a total of 42,007 adult ICU patients in the primary analyses. We observed statistically significant differences between blinded and unblinded RCTs for all-cause mortality at longest follow-up in one of 22 interventions (5%), for in-hospital mortality in one of 12 interventions (8%) but not for in-ICU mortality. Combining all interventions, unblinded trials reported larger summary effect estimates on all-cause mortality at longest follow up compared to blinded trials (test of interaction, P = 0.09). However, the difference was not statistically significant following adjustment for other risk of bias domains. CONCLUSIONS: We observed no firm evidence that lack of blinding affects estimates of mortality in RCTs of ICU interventions. PMID- 29705094 TI - Registered trials report less beneficial treatment effects than unregistered ones: a meta-epidemiological study in orthodontics. AB - OBJECTIVES: Clinical trial registration is widely recommended because it allows tracking of trials that helps ensure full and unbiased reporting of their results. The aim of the present overview was to provide empirical evidence on bias associated with trial registration via a meta-epidemiological approach. STUDY DESIGN AND SETTINGS: Six databases were searched in September 2017 for randomized clinical trials and systematic reviews thereof assessing the effects of orthodontic clinical interventions. After duplicate study selection and data extraction, statistical analysis included a two-step meta-epidemiological approach within- and across-included meta-analyses with a Paule-Mandel random effects model to calculate differences in standardized mean differences (DeltaSMD) between registered and unregistered trials and their 95% confidence intervals (CI), followed by subgroup and sensitivity analyses. RESULTS: A total of 16 meta-analyses with 83 trials and 4,988 patients collectively were finally included, which indicated that registered trials reported less beneficial treatment effects than unregistered trials (DeltaSMD = -0.36; 95% CI = -0.60, 0.12). Although some small-study effects were identified, sensitivity analyses according to precision and risk of bias indicated robustness. CONCLUSION: Signs of bias from lack of trial protocol registration were found with nonregistered trials reporting more beneficial intervention effects than registered ones. Caution is warranted by the interpretation of nonregistered randomized trials or systematic reviews thereof. PMID- 29705095 TI - Investigation of the "m" in the cmRCT (cohort multiple randomized controlled trial) design revealed dependence between trial results. PMID- 29705096 TI - Trajectory-guided biopsy of orbital tumor - Technology, principal considerations and clinical implementation. AB - Intraorbital space-occupying lesions always pose a challenge, both in terms of definite surgical removal as well as preoperative sampling for histopathological examination. Despite the use of modern high-resolution imaging techniques, the dignity of orbital lesions can often not be determined with sufficient certainty preoperatively. As the amount and complexity of treatment possibilities continue to increase, detailed diagnostics in advance of treatment choice are essential. Histological classification of orbital lesions can still be considered the gold standard for reliable diagnoses, leading to appropriate treatment. Over recent years minimally invasive surgical approaches have gained more importance in the treatment and diagnosis of cranio-maxillo-facial tumor and trauma. The aim of our study was to adapt and establish a precise procedure for orbital biopsies. 23 patients suffering from space-occupying lesions of unknown dignity were included. Trajectory-guided procedures were pre-planned for all cases. In most cases minimally invasive procedures were suitable for taking biopsies of the orbit. For only two patients a conventional, non-minimally invasive, lateral orbitotomy had to be performed. Further evaluation of the presented procedure demonstrates clearly that trajectory-guided biopsies of the orbit can be performed correctly and effectively, regardless of the suspected lesion's size. PMID- 29705097 TI - Ascites: A marker for increased surgical risk unaccounted for by the model for end-stage liver disease (MELD) score for general surgical procedures. AB - BACKGROUND: Ascites and the Model for End-Stage Liver Disease score have both been shown to independently correlate with surgical morbidity and mortality. We evaluated if incorporating the presence of ascites changed postoperative risk as assessed by the Model for End-Stage Liver Disease score. METHODS: Data originated from the National Surgical Quality Improvement Program database from 2005-2014. Patients undergoing hernia repair, adhesiolysis, and cholecystectomy were included. Univariate analysis and logistic regression stratified by Model for End Stage Liver Disease score and presence of ascites was performed. RESULTS: A total of 30,391 patients were analyzed. When compared to low Model for End-Stage Liver Disease stratum without ascites, the presence of ascites predicted increased risk for complications (low Model for End-Stage Liver Disease with ascites odds ratio 3.22, 95% confidence interval [2.00-5.18], moderate Model for End-Stage Liver Disease with ascites odds ratio 3.70, 95% confidence interval [2.64-5.19], high Model for End-Stage Liver Disease with ascites odds ratio 6.38, 95% confidence interval [4.39-9.26]). These findings hold true for mortality as well (low Model for End-Stage Liver Disease with ascites odds ratio 9.40 95% confidence interval [3.53-25.01], moderate Model for End-Stage Liver Disease with ascites odds ratio 15.24 95% confidence interval [8.17-28.45], high Model for End-Stage Liver Disease with ascites odds ratio 28.56 95% confidence interval [15.43-52.88]). CONCLUSIONS: Ascites increased the risk of morbidity and mortality across multiple general surgery operations. Model for End-Stage Liver Disease may underestimate surgical risk in patients with ascites. Predictive models inclusive of ascites may more accurately predict the perioperative risk of these complex patients. PMID- 29705099 TI - Ultraviolet radiation exposure triggers neurokinin-1 receptor upregulation in ocular tissues in vivo. AB - The purpose of this study was to investigate the neurokinin receptor-1 (NKR-1) protein expression in ocular tissues before and after supra-cataract threshold ultraviolet radiation (UVR-B peak at 312 nm) exposure in vivo in a mouse model. Six-week-old C57Bl/6 mice were unilaterally exposed to a single (2.9 kJ/m2) and an above 3-fold UVR-B cataract threshold dose (9.4 kJ/m2) of UVR. UVR-exposure (lambdapeak = 312 nm) was performed in mydriasis using a Bio-Spectra exposure system. After latency periods of 3 and 7 days, eyes were fixed in 4% paraformaldehyde, embedded in paraffin, sectioned and stained with fluorescence coupled antibody for NKR-1 and DAPI for cell nuclei staining. Control animals received only anesthesia but no UVR-exposure. Cataract development was documented with a Leica dark-field microscope and quantified as integrated optical density (IOD). NKR-1 is ubiquitously present in ocular tissues. An above 3-fold cataract threshold dose of UV-radiation induced NKR-1 upregulation after days 3 and 7 in the epithelium and endothelium of the cornea, the endothelial cells of the iris vessels, the pigmented epithelium/stroma of the ciliary body, the lens epithelium, pronounced in the nuclear bow region and the inner plexiform layer of the retina. A significant upregulation of NKR-1 could not be provoked with a single cataract threshold dose (2.9 kJ/m2 UVR-B) ultraviolet irradiation. All exposed eyes developed anterior subcapsular cataracts. Neurokinin-1 receptor is present ubiquitously in ocular tissues including the lens epithelium and the nuclear bow region of the lens. UV-radiation exposure to an above 3-fold UVR-B cataract threshold dose triggers NKR-1 upregulation in the eye in vivo. The involvement of inflammation in ultraviolet radiation induced cataract and the role of neuroinflammatory peptides such as substance P and its receptor, NKR-1, might have been underestimated to date. PMID- 29705098 TI - Contemporary concepts in hernia prevention: Selected proceedings from the 2017 International Symposium on Prevention of Incisional Hernias. AB - Incisional hernia is a frequent complication of midline laparotomy and enterostomal creation and is associated with high morbidity, decreased quality of life, and high costs. The International Symposium on Incisional Hernia Prevention was held October 19-20, 2017, at the InterContinental Hotel in San Francisco, CA, hosted by the Department of Surgery, University of California, San Francisco. One hundred and three attendees included general and plastic surgeons from 9 countries, including principal participants for several of the seminal studies in the field. Over the course of the 2-day meeting, there were 38 oral presentations, 3 keynote lectures, and 2 panel discussions. The Symposium was a combination of new information but also a comprehensive review of the existing data so as to assess the current state of the field and to set the stage for future research. Further, the Symposium sought to increase awareness and thus emphasize the importance of preventing the formation of incisional and enterostomal hernias. PMID- 29705100 TI - Event-triggered Hinfinity filtering of discrete-time switched linear systems. AB - In this paper, the event-triggered Hinfinity filtering problem for discrete-time switched linear systems is addressed. The filter and the system are connected via a communication network, and the transmitted information of system output and switching signal is determined by an event-triggered transmission scheme, which contains system mode dependent parameters. Consequently, the asynchronous switching between the filter and the system occurs, and the filtering error system is modeled as a switched system with augmented switching signal by using the merging switching signal technique. Then, by the multiple Lyapunov function method, a new sufficient condition is obtained such that the filtering error system is exponentially asymptotically stable and satisfies the weighted Hinfinity performance. Finally, the design method for the filter and event triggered parameters is proposed by solving a set of linear matrix inequalities. Numerical simulations illustrate the effectiveness of the proposed approach. PMID- 29705101 TI - How close is the dose? Manipulation of 10 mg hydrocortisone tablets to provide appropriate doses to children. AB - This study explores the methodology advised by healthcare professionals and the methods used by parents/carers to identify whether there is a best practice method for manipulation of 10 mg hydrocortisone tablets to provide an accurate dose to children. Bespoke surveys were used to identify methods recommended and used in manipulation of tablets. Hydrocortisone tablets were manipulated to provide a specified dose by both naive participants and parents/carers. The accuracy of manipulation was assessed using HPLC analysis. Competed surveys were received from 159 parent/carers reporting doses that ranged from 0.25 to 15 mg. Parents/carers most commonly reported splitting the tablet and administering the solid fraction; however more than 30% of those reporting physically splitting tablets were preparing doses that were not simply halving or quartering tablets. In a naive population the dose accuracy, defined as percent of doses within 20% of the theoretical dose ranged from 57 to 58% depending on the tablet brand and the method of manipulation used. Almost three-quarters (74.1%) of parent/carers (n = 27) were able to produce a dose within 20% of the theoretical value and the most accurate method was to split tablets and administer the solid fraction. This study shows that a lack of age-appropriate medicines results in children being at risk of sub-optimal dosing. PMID- 29705102 TI - Comparative analyses of flow and compaction properties of diverse mannitol and lactose grades. AB - Appropriate selection of excipient grade during tablet formulation development depends on thorough knowledge in their compaction and flow properties. Each chemically unique pharmaceutical excipient is usually available in several commercial grades that are widely different in powder properties, which influence their performance for a specific formulation application. In this work, 11 grades of mannitol were systematically characterized, in terms of their particulate, flow and tableting properties, and compared against 5 grades of lactose. Principal component analysis (PCA) identified significant correlations among selected variables, such as particle size, surface area, flowability, wall friction, plasticity parameter, tensile strength, and tablet brittleness. PCA also revealed similar grades of the two excipients, which may be used to select replacement grade, if needed, based on similarity in their overall properties. PMID- 29705103 TI - An EPR spin probe study of the interactions between PC liposomes and stratum corneum membranes. AB - The electron paramagnetic resonance (EPR) spin labeling methodology was used to analyze the interactions of phosphatidylcholine (PC) liposomal formulations that are commonly used as transepidermal drug delivery systems with stratum corneum (SC) membranes. The lipid dynamics of five liposome formulations were evaluated to study the influences of sorbitan monooleate (Span80), cholesterol, and cholesterol with the charged lipids 2-dioleoyl-3-trimethylammonium-propane (DOTAP) and 1,2-distearoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DSPG) on the molecular dynamics of PC vesicles. The EPR spectra of 5-doxyl-stearic acid (5 DSA) showed that the addition of Span80 to the liposomes increased the lipid fluidity, whereas cholesterol had the opposite effect, and the combination of charged lipids and cholesterol did not additionally influence the lipid bilayer dynamics. Fatty acid spin-labeled SC membranes were treated with the liposome formulations, leading to migration of the spin label to the molecular environment of the formulation and the presence of two spectral components representing distinct mobility states. In terms of molecular dynamics, these environments correspond to the lipid domains of the untreated SC and the liposome, indicating a poor interaction between the liposome and SC membranes. However, the contact was sufficient to allow a pronounced exchange of the spin-labeled fatty acid. Our data suggest that flexible liposomes may access the inner intercellular membranes of the SC and facilitate mutual lipid exchange without losing their relative liposomal integrity. PMID- 29705104 TI - Low temperature fused deposition modeling (FDM) 3D printing of thermolabile drugs. AB - Fused deposition modelling (FDM) is the most commonly investigated 3D printing technology for the manufacture of personalized medicines, however, the high temperatures used in the process limit its wider application. The objective of this study was to print low-melting and thermolabile drugs by reducing the FDM printing temperature. Two immediate release polymers, Kollidon VA64 and Kollidon 12PF were investigated as potential candidates for low-temperature FDM printing. Ramipril was used as the model low melting temperature drug (109 degrees C); to the authors' knowledge this is the lowest melting point drug investigated to date by FDM printing. Filaments loaded with 3% drug were obtained by hot melt extrusion at 70 degrees C and ramipril printlets with a dose equivalent of 8.8 mg were printed at 90 degrees C. HPLC analysis confirmed that the drug was stable with no signs of degradation and dissolution studies revealed that drug release from the printlets reached 100% within 20-30 min. Variable temperature Raman and solid state nuclear magnetic resonance (SSNMR) spectroscopy techniques were used to evaluate drug stability over the processing temperature range. These data indicated that ramipril did not undergo degradation below its melting point (which is above the processing temperature range: 70-90 degrees C) but it was transformed into the impurity diketopiperazine upon exposure to temperatures higher than its melting point. The use of the excipients Kollidon VA64 and Kollidon 12PF in FDM was further validated by printing with the drug 4 aminosalicylic acid (4-ASA), which in previous work was reported to undergo degradation in FDM printing, but here it was found to be stable. This work demonstrates that the selection and use of new excipients can overcome one of the major disadvantages in FDM printing, drug degradation due to thermal heating, making this technology suitable for drugs with lower melting temperatures. PMID- 29705105 TI - Photocurable poly(ethylene glycol) as a bioink for the inkjet 3D pharming of hydrophobic drugs. AB - Binder jetting and material extrusion are the two most common additive manufacturing techniques used to create pharmaceutical tablets. However, their versatility is limited since the powder component is present throughout the dosage forms fabricated by binder jet 3D printing and material extrusion 3D printing requires high operating temperatures. Conversely, material jetting allows for compositional control at a voxel level and can dispense material at room temperature. Unfortunately, there are a limited number of materials that are both printable and biocompatible. Therefore, the aim of this study was to engineer photocurable bioinks that are suitable for hydrophobic active pharmaceutical ingredients and have rapid gelation times upon visible light exposure. The resulting bioinks were comprised of poly(ethylene glycol) diacrylate (250 Da) as the crosslinkable monomer, Eosin Y as the photoinitiator, and methoxide-poly(ethylene glycol)-amine as the coinitiator. Additionally, poly(ethylene glycol) (200 Da) was added as a plasticizer to modulate the drug release profiles, and Naproxen was used as the model drug due to its high hydrophobicity. Various bioink formulations were dispensed into the bottom half of blank preform tablets - made via direct compression - using a piezoelectric nozzle, photopolymerized, and capped with the top half of the preform tablet to complete the pharmaceutical dosage form. Results from the release studies showed that drug release can be modulated by both the percent of poly(ethylene glycol) diacrylate in the formulation and the light exposure time used to cure the bioinks. These bioinks have the potential to expand the library of materials available for creating pharmaceutical tablets via inkjet printing with personalized drug dosages. PMID- 29705106 TI - Corrigendum to "Exposure to school violence at school and mental health of victimized adolescents: The mediation role of social support" [Child Abuse Negl. 76C (2018) 342-352]. PMID- 29705107 TI - Polysaccharides from Diaphragma juglandis fructus: Extraction optimization, antitumor, and immune-enhancement effects. AB - This study discusses the optimization of the microwave-assisted extraction of polysaccharides from Diaphragma juglandis (DJPs). One main fraction (DJP-2) was successfully purified by ion-exchange chromatography and gel-permeation chromatography. The results showed that the optimal extraction conditions with DJP extraction yield of 4.7 +/- 0.28% were water to raw material ratio of 20 mL/g, extraction time of 40 min, and microwave extraction power of 400 W. Bioassays indicated that DJP-2 could effectively suppress the proliferation of HepG2 and BGC-82 cell lines. In addition, DJP-2 could significantly enhance phagocytosis; stimulate the production of NO, tumor necrosis factor-alpha (TNF alpha), and interleukins (IL-6 and IL-1beta); and promote their corresponding mRNA expression levels in a dose-dependent manner. Meanwhile, CR3, MR, and TLR2 were confirmed to be the major membrane receptors of DJP-2 on RAW 264.7. All these results indicated that DJP-2 could be a potential antitumor and immunomodulatory agent in the field of pharmacology. PMID- 29705109 TI - Proteomic analysis and food-grade enzymes of Moringa oleifer Lam. a Lam. flower. AB - Moringa oleifer Lam. flower contain high-proteins and function nutrients. Many advances have been made to it, but there is still no proteomic information of this species. Total protein from the flowers applied shotgun 2DLC-MS/MS proteomic identified 9443 peptides corresponding to 4004 high-confidence proteins by Proteome DiscovererTM Software 2.1. These proteins were mostly distributed ranging between 40 and 70 kDa. Gene Ontology (GO) analysis indicated that the largest of the proteins were cytoplasm 72.7%, catalytic activity 61.5% and macromolecule metabolism 43.7%, and KEGG analysis revealed that the largest group of 129 proteins was involved in Ribosome to directing protein synthesis (translation). Moreover, a number of commercially important food-grade enzymes were commented, 261 proteins were annotated as carbohydrate-active enzymes, 16 protease, 22 proteins are assigned to the citrate cycle, which the top proteins were assigned to GH family, cysteine synthase and serine/threonine-protein phosphatase. These enzymes indicated that is a new source with potential use for fermentation and brewing industry, fruit and vegetable storage and the development of function peptides. PMID- 29705108 TI - Facile preparation of antibacterial chitosan/graphene oxide-Ag bio-nanocomposite hydrogel beads for controlled release of doxorubicin. AB - The present project describes the facile preparation of novel pH-sensitive bio nanocomposite hydrogel beads based on chitosan (CH) and GO-Ag nanohybrid particles for controlled release of anti-cancer drugs such as doxorubicin (DOX). The loading efficiency of doxorubicin into test beads was measured via UV-vis spectroscopy analysis and was found to be high. The formation of silver nanoparticles on the GO sheets and structural characteristics were evaluated via FT-IR, TEM, XRD, and SEM techniques. In addition, the antibacterial activity, swelling and drug release profiles of prepared nanocomposite beads were evaluated. Also, in vitro drug release test was performed in order to investigate the efficiency of CH/GO-Ag nanocomposite hydrogel beads as a drug carrier for controlled release of anti-cancer drugs such as doxorubicin (DOX). A more sustained and controlled drug release profile was observed for CH/GO-Ag nanocomposite hydrogel beads that enhanced by increasing the GO-Ag nanohybrid particles content. PMID- 29705110 TI - Development of biopolymers based interpenetrating polymeric network of capecitabine: A drug delivery vehicle to extend the release of the model drug. AB - The research aims the development and optimization of capecitabine loaded interpenetrating polymeric network by ionotropic gelation method using polymers locust bean gum and sodium alginate by QbD approach. FMEA was performed to recognize the risks influencing CQAs. BBD was applied to study the effect of factors (polymer ratio, amount of cross-linker and curing time) on responses (particle size, % drug entrapment and % drug release). Polynomial equations and 3 D graphs were plotted to relate between factors and responses. The results of the optimized batch viz. particle size (457.92 +/- 1.6 MUm), % drug entrapment (74.11 +/- 3.1%) and % drug release (90.23 +/- 2.1%) were close to the predicted values generated by Minitab(r) 17. Characterization techniques SEM, EDX, FTIR, DSC and XRD were also performed for the optimized batch. To study the water transport inside IPN microbeads, swelling study was done. In vitro drug release of optimized batch showed controlled drug release for 12 h. Pharmacokinetic study carried out following oral administration in Albino Wistar rats exhibited that optimized microbeads had better PK parameters than free drug. In vitro cytotoxicity against HT-29 cells revealed significant reduction of the cell growth when treated with optimized formulation indicating IPN microbeads as effective dosage form for treating colon cancer. PMID- 29705111 TI - Preparation of bergenin - Poly (lactic acid) polymers and in vitro controlled release studies. AB - The efficacy of bergenin prepared with osmotic-pump-controlled release is much lower than expected. In this study, biodegradable polylactic acid is used to modify bergenin and immobilize it with chemical methods. Bergenin-PLA obtained by this method has low molecular weight and good thermal stability, as well as prolonged in vitro release time along with increased molecular weight. Biocompatibility tests and in vitro antitumor tests showed that bergenin-PLA at a ratio of 1:30 has good biological properties and low cytotoxicity at t three concentrations, and its antitumor activity was significantly increased compared to bergenin. The chemical immobilization of bergenin not only provides a good mode of administration for patients but also provides a good foundation for the sustained release of drugs over time. PMID- 29705113 TI - Loose Anagen Hair Syndrome. PMID- 29705112 TI - A Brain Marker for Developmental Speech Disorders. AB - OBJECTIVE: To characterize the organization of speech- and language-related white matter tracts in children with developmental speech and/or language disorders. STUDY DESIGN: We collected magnetic resonance diffusion-weighted imaging data from 41 children, ages 9-11 years, with developmental speech and/or language disorders, and compared them with 45 typically developing controls with the same age range. We used probabilistic tractography of diffusion-weighted imaging to map language (3 segments of arcuate fasciculus, extreme capsule system) and speech motor (corticobulbar) tracts bilaterally. The corticospinal and callosal tracts were used as control regions. We compared the mean fractional anisotropy and diffusivity values between atypical and control groups, covarying for nonverbal IQ. We then examined differences between atypical subgroups: developmental speech disorder (DSD), developmental language disorder, and co occurring developmental speech and language disorder. RESULTS: Fractional anisotropy in the left corticobulbar tract was lower in the DSD than in the control group. Radial and mean diffusivity were higher in the DSD than the developmental language disorder, co-occurring developmental speech and language disorder, or control groups. There were no group differences for any metrics in the language or control tracts. CONCLUSIONS: Atypical development of the left corticobulbar tract may be a neural marker for DSD. This finding is in line with reports of speech disorder after left corticobulbar damage in children and adults with brain injury. By contrast, we found no association between diffusion metrics in language-related tracts in developmental language disorder, and changes for language disorders are likely more complex. PMID- 29705114 TI - Review of Interventions and Radiation Exposure from Chest Computed Tomography in Children with Blunt Trauma. AB - OBJECTIVE: To determine the radiation risk to a child undergoing trauma evaluation with chest computed tomography (CCT) for every clinically actionable injury identified. STUDY DESIGN: This observational, cross-sectional study included all blunt trauma patients under 18 years of age undergoing CCT in a single urban emergency department. Via a retrospective chart review, therapeutic interventions done exclusively for chest injuries identified on CCT scan were identified. Effective radiation from each CCT was calculated and averaged and the dose required to diagnose 1 management-changing chest injury was determined. RESULTS: Of 209 children undergoing CCT over a 19-month period, 168 were victims of blunt trauma. Ten required an intervention specifically for a chest injury identified on CCT (suggesting development of 1 malignancy per 37 actionable injures identified). None required an intervention for an injury exclusively noted on CCT, as all 10 actionable injuries were apparent via other modalities (radiograph, ultrasound examination, clinical examination). CONCLUSION: Although 10 uniquely actionable injuries were identified on CCT, none were found only on CCT. Because CCTs rarely modified management, the amount of radiation administered per management change was sufficiently high to recommend reconsideration of current imaging practice in this single-center study. PMID- 29705115 TI - Suction Mask vs Conventional Mask Ventilation in Term and Near-Term Infants in the Delivery Room: A Randomized Controlled Trial. AB - OBJECTIVE: To compare the suction mask, a new facemask that uses suction to create a seal between the mask and the infant's face, with a conventional soft, round silicone mask during positive pressure ventilation (PPV) in the delivery room in newborn infants >34 weeks of gestation. STUDY DESIGN: Single-center randomized controlled trial in the delivery room. The primary outcome was mask leak. RESULTS: Forty-five infants were studied at a median gestational age of 38.1 weeks (IQR, 36.4-39.0 weeks); 22 were randomized to the suction mask and 23 to the conventional mask. The suction mask did not reduce mask leak (49.9%; IQR, 11.0%-92.7%) compared with the conventional mask (30.5%; IQR, 10.6%-48.8%; P = .51). The suction mask delivered lower peak inspiratory pressure (27.2 cm H2O [IQR, 25.0-28.7 cm H2O] vs 30.4 cm H2O [IQR, 29.4-32.5 cm H2O]; P < .05) and lower positive end expiratory pressure (3.7 cm H2O [IQR, 3.1-4.5 cm H2O] vs 5.1 cm H2O [IQR, 4.2-5.7 cm H2O ]; P < .05). There was no difference in the duration of PPV or rates of intubation or admission to the neonatal intensive care unit. In 5 infants (23%), the clinician switched from the suction to the conventional mask, 2 owing to intermittently low peak inspiratory pressure, 2 owing to failure to respond to PPV, and 1 owing to marked facial bruising after 6 minutes of PPV. CONCLUSIONS: The use of the suction mask to provide PPV in newborn infants did not reduce facemask leak. Adverse effects such as the inability to achieve the set pressures and transient skin discoloration are concerning. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry ACTRN12616000768493. PMID- 29705116 TI - Environmental or Nasal Cannula Supplemental Oxygen for Preterm Infants: A Randomized Cross-Over Trial. AB - OBJECTIVE: To test the hypothesis that environmental compared with nasal cannula oxygen decreases episodes of intermittent hypoxemia (oxygen saturations <85% for >=10 seconds) in preterm infants on supplemental oxygen by providing a more stable hypopharyngeal oxygen concentration. STUDY DESIGN: This was a single center randomized crossover trial with a 1:1 parallel allocation to order of testing. Preterm infants on supplemental oxygen via oxygen environment maintained by a servo-controlled system or nasal cannula with flow rates <=1.0 L per kg per minute were crossed over every 24 hours for 96 hours. Data were collected electronically to capture real time numeric and waveform data from patient monitors. RESULTS: Twenty-five infants with gestational age of 27 +/- 2 weeks (mean +/- SD) and a birth weight of 933 +/- 328 g were studied at postnatal day 36 +/- 26. The number of episodes of intermittent hypoxemia per 24 hours was 117 +/- 77 (median, 98; range, 4-335) with oxygen environment vs 130 +/- 63 (median, 136; range, 16-252) with nasal cannula (P = .002). Infants on oxygen environment compared with nasal cannula also had decreased episodes of severe intermittent hypoxemia (P = .005). Infants on oxygen environment compared with nasal cannula had a lower proportion of time with oxygen saturations <85% (.05 +/- .03 vs .06 +/- .03, P < .001), and a lower coefficient of variation of oxygen saturation (P = .02). CONCLUSIONS: In preterm infants receiving supplemental oxygen, servo controlled oxygen environment decreases hypoxemia compared with nasal cannula. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02794662. PMID- 29705117 TI - Parental Perspectives Regarding Outcomes of Very Preterm Infants: Toward a Balanced Approach. AB - OBJECTIVES: To explore parental perspectives regarding their preterm child at 18 months corrected age and to investigate whether reported answers correlate with level of neurodevelopmental impairment (NDI) as defined by clinicians. We hypothesized that parents would report more negative concerns with increasing level of NDI. STUDY DESIGN: This study included 190 infants born <29 weeks of gestational age in 2009-2012 at 1 tertiary university health center. Infants underwent detailed developmental assessment at 18 months corrected age, and were classified into either absence or presence of mild to moderate or severe NDI. Parents were asked 2 open-ended questions: "What concerns you most about your child?" and "Please describe the best things about your child." Open-ended questions were analyzed using qualitative methodology. RESULTS: In this cohort, 49%, 43%, and 8% of participants had no, mild to moderate, and severe NDI. The majority of parents (72.8%) had both positive and negative aspects to report; 26.8% only had positive ones. The main positive themes invoked by parents included their child's personality (61%), happiness (40%), developmental outcome/progress (40%), and physical health (11%). The main themes regarding parental concerns included neurodevelopment (56%), notably language and behavior, and physical health (24%), particularly growth/nutrition and physical fragility. There was no association between positive themes and categories of NDI, but parents of children with mild to moderate NDI reported more concerns about development. CONCLUSIONS: Neonatal outcome research would benefit from incorporating parental perspectives regarding their child, including negative and positive aspects, enabling physicians to provide complete and balanced information to parents of all preterm infants. PMID- 29705118 TI - Multi-Stakeholder Informed Guidelines for Direct Admission of Children to Hospital. AB - OBJECTIVES: To develop pediatric direct admission guidelines and prioritize outcomes to evaluate the safety and effectiveness of hospital admission processes. STUDY DESIGN: We conducted deliberative discussions at 1 children's hospital and 2 community hospitals, engaging parents of hospitalized children and inpatient, outpatient, and emergency department physicians and nurses to identify shared and dissenting perspectives regarding direct admission processes and outcomes. Discussions were audio-recorded, professionally transcribed, and analyzed using a general inductive approach. We then convened a national panel to prioritize guideline components and outcome measures using a RAND/UCLA Modified Delphi approach. RESULTS: Forty-eight stakeholders participated in 6 deliberative discussions. Emergent themes related to effective multistakeholder communication, resources needed for high quality direct admissions, written direct admission guidelines, including criteria to identify children appropriate for and inappropriate for direct admission, and families' needs. Building on these themes, Delphi panelists endorsed 71 guideline components as both appropriate and necessary at children's hospitals and community hospitals and 13 outcomes to evaluate hospital admission systems. Guideline components include (1) pre admission communication, (2) written guidelines, (3) hospital resources to optimize direct admission processes, (4) special considerations for pediatric populations that may be at particular risk of nosocomial infection and/or stress in emergency departments, (5) communication with families referred for direct admission, and (6) quality reviews to evaluate admission systems. CONCLUSIONS: These direct admission guidelines can be adapted by hospitals and health systems to inform hospital admission policies and protocols. Multistakeholder engagement in evaluation of hospital admission processes may improve transitions of care and health system integration. PMID- 29705119 TI - Relationship between Epigenetic Maturity and Respiratory Morbidity in Preterm Infants. AB - OBJECTIVE: To assess associations between epigenetic maturity of extremely preterm babies (born at less than 28 weeks of gestation), neonatal interventions, and respiratory outcomes, including the administration of surfactant and postnatal corticosteroids, duration of assisted ventilation, and development of bronchopulmonary dysplasia (BPD). STUDY DESIGN: DNA was extracted from neonatal blood spots collected after birth from 143 extremely preterm infants born 1991 1992 in Victoria, Australia and used to determined DNA methylation (DNAm). A DNAm based gestational age was determined using our previously published method. The residual of DNAm gestational age and clinically estimated gestational age (referred to as "gestational age acceleration") was used as a measure to assess developmental maturity. Associations between gestational age acceleration and respiratory interventions and morbidities were determined. RESULTS: Infants with higher gestational age acceleration were less likely to receive surfactant (P = .009) or postnatal corticosteroids (P = .008), had fewer days of assisted ventilation (P = .01), and had less BPD (P = .02). Respiratory measures are known to correlate with gestational age; however, models comparing each with clinically estimated gestational age were improved by the addition of the gestational age acceleration measure in the model. CONCLUSIONS: Gestational age acceleration correlates with respiratory interventions and outcomes of extremely preterm babies. Surfactant and postnatal corticosteroid use, assisted ventilation days, and BPD rates were all lower in babies who were epigenetically more mature than their obstetrically estimated gestational age. This suggests that gestational age acceleration is a clinically relevant metric of developmental maturity. PMID- 29705120 TI - Incidence of reactive hyperplastic lesions in the oral cavity: a 10 year retrospective study in Santa Catarina, Brazil. AB - INTRODUCTION: Reactive hyperplastic lesions develop in response to a chronic injury simulating an exuberant tissue repair response. They represent some of the most common oral lesions including inflammatory fibrous hyperplasia, oral pyogenic granuloma, giant cell fibroma, peripheral ossifying fibroma, and peripheral giant cell lesions. OBJECTIVE: The incidence of those lesions was investigated in an oral pathology service, and the clinical characteristics, associated etiological factors, concordance between the clinical and histopathological diagnostic was determined. METHODS: A total of 2400 patient records were screened from 2006 to 2016. Clinical features were recorded from biopsy reports and patients' files. RESULTS: A total of 534 cases of reactive hyperplastic lesions were retrieved and retrospectively studied, representing 22.25% of all diagnoses. The most frequent lesion was inflammatory fibrous hyperplasia (72.09%), followed by oral pyogenic granuloma (11.79%), giant cell fibroma (7.30%), peripheral ossifying fibroma (5.24%), and peripheral giant cell lesions (3.55%). Females were predominantly affected (74.19%), the gingiva and alveolar ridge were the predominant anatomical site (32.89%), and chronic traumatism was presented as the main etiological factor. The age widely ranges from the 1st decade of life to the 7th. Clinically, the reactive hyperplastic lesions consisted of small lesions (0.5-2cm) and shared a strong likeness in color to the oral mucosa. The concordance between the clinical and histopathological diagnostic was high (82.5%). CONCLUSION: Reactive hyperplastic lesions had a high incidence among oral pathologies. The understanding of their clinical features helps to achieve a clearer clinical and etiological diagnosis, and the knowledge of factors related to their development. This may contribute to adequate treatment and positive prognosis. PMID- 29705121 TI - Dysbiosis of gut microbiota and microbial metabolites in Parkinson's Disease. AB - Gut microbial dysbiosis and alteration of microbial metabolites in Parkinson's disease (PD) have been increasingly reported. Dysbiosis in the composition and abundance of gut microbiota can affect both the enteric nervous system and the central nervous system (CNS), indicating the existence of a microbiota-gut-brain axis and thereby causing CNS diseases. Disturbance of the microbiota-gut-brain axis has been linked to specific microbial products that are related to gut inflammation and neuroinflammation. Future directions should therefore focus on the exploration of specific gut microbes or microbial metabolites that contribute to the development of PD. Microbiota-targeted interventions, such as antibiotics, probiotics and fecal microbiota transplantation, have been shown to favorably affect host health. In this review, recent findings regarding alterations and the role of gut microbiota and microbial metabolites in PD are summarized, and potential molecular mechanisms and microbiota-targeted interventions in PD are discussed. PMID- 29705122 TI - Measurement of endocrine disrupting and asthma-associated chemicals in hair products used by Black women. AB - BACKGROUND: Personal care products are a source of exposure to endocrine disrupting and asthma-associated chemicals. Because use of hair products differs by race/ethnicity, these products may contribute to exposure and disease disparities. OBJECTIVE: This preliminary study investigates the endocrine disrupting and asthma-associated chemical content of hair products used by U.S. Black women. METHODS: We used gas chromatography/mass spectrometry (GC/MS) to test 18 hair products in 6 categories used by Black women: hot oil treatment, anti-frizz/polish, leave-in conditioner, root stimulator, hair lotion, and relaxer. We tested for 66 chemicals belonging to 10 chemical classes: ultraviolet (UV) filters, cyclosiloxanes, glycol ethers, fragrances, alkylphenols, ethanolamines, antimicrobials, bisphenol A, phthalates, and parabens. RESULTS: The hair products tested contained 45 endocrine disrupting or asthma-associated chemicals, including every targeted chemical class. We found cyclosiloxanes, parabens, and the fragrance marker diethyl phthalate (DEP) at the highest levels, and DEP most frequently. Root stimulators, hair lotions, and relaxers frequently contained nonylphenols, parabens, and fragrances; anti-frizz products contained cyclosiloxanes. Hair relaxers for children contained five chemicals regulated by California's Proposition 65 or prohibited by EU cosmetics regulation. Targeted chemicals were generally not listed on the product label. CONCLUSIONS: Hair products used by Black women and children contained multiple chemicals associated with endocrine disruption and asthma. The prevalence of parabens and DEP is consistent with higher levels of these compounds in biomonitoring samples from Black women compared with White women. These results indicate the need for more information about the contribution of consumer products to exposure disparities. A precautionary approach would reduce the use of endocrine disrupting chemicals in personal care products and improve labeling so women can select products consistent with their values. PMID- 29705123 TI - The association of CCL3 and CCL4 polymorphisms with HCV clearance in Chinese Han population. AB - AIM: To explore the association of CCL3 (rs1063340) and CCL4 (rs1049807) polymorphisms with hepatitis C virus (HCV) clearance and sustained virologic response (SVR). METHODS: Two populations were enrolled in the current study; one was a general population including 1585 untreated individuals, with HCV infection and the other was a treatment population comprising 353 HCV-infected patients treated with pegylated interferon-alpha and ribavirin (pegIFN-alpha/RBV). Two single nucleotide polymorphisms (SNPs) were genotyped, and the relationship between HCV clearance and treatment outcome was analysed. RESULTS: The general population comprised 995 persistent HCV cases (both HCV RNA and anti-HCV were positive) and 590 spontaneous clearance cases (HCV RNA was negative, but anti-HCV was positive). An association between the SNPs and HCV clearance was not found in our study. The treatment population consisted of 235 patients who achieved SVR and 118 non-responders. Variants of both SNPs (rs1063340-C and rs1049807-G) were associated with a reduction in SVR following IFN treatment (dominant model: P = 0.026 for rs1063340 and P = 0.048 for rs1049807). In addition, the ancestral alleles of rs1063340 and rs1049807 increased the likelihood of virus clearance by 62% compared to both the derived and minor alleles of the two SNPs (P = 0.040).The interaction analysis showed that the level of glucose interacted with the association of rs1063340 and SVR. CONCLUSIONS: Our results suggested that genetic variants at the CCL3 and CCL4 loci may be marker SNPs for risk of HCV treatment outcome. PMID- 29705124 TI - Taxonomic profiles in metagenomic analyses of free-living microbial communities in the Ofunato Bay. AB - The Ofunato Bay in Iwate Prefecture, Japan is a deep coastal bay located at the center of the Sanriku Rias Coast and considered an economically and environmentally important asset. Here, we describe the first whole genome sequencing (WGS) study on the microbial community of the bay, where surface water samples were collected from three stations along its length to cover the entire bay; we preliminarily sequenced a 0.2 MUm filter fraction among sequentially size fractionated samples of 20.0, 5.0, 0.8 and 0.2 MUm filters, targeting the free living fraction only. From the 0.27-0.34 Gb WGS library, 0.9 * 106-1.2 * 106 reads from three sampling stations revealed 29 bacterial phyla (~80% of assigned reads), 3 archaeal phyla (~4%) and 59 eukaryotic phyla (~15%). Microbial diversity obtained from the WGS approach was compared with 16S rRNA gene results by mining WGS metagenomes, and we found similar estimates. The most frequently recovered bacterial sequences were Proteobacteria, predominantly comprised of 18.0-19.6% Planktomarina (Family Rhodobacteraceae) and 13.7-17.5% Candidatus Pelagibacter (Family Pelagibacterales). Other dominant bacterial genera, including Polaribacter (3.5-6.1%), Flavobacterium (1.8-2.6%), Sphingobacterium (1.4-1.6%) and Cellulophaga (1.4-2.0%), were members of Bacteroidetes and likely associated with the degradation and turnover of organic matter. The Marine Group I Archaea Nitrosopumilus was also detected. Remarkably, eukaryotic green alga Bathycoccus, Ostreococcus and Micromonas accounted for 8.8-15.2%, 3.6-4.9% and 2.1-3.1% of total read counts, respectively, highlighting their potential roles in the phytoplankton bloom after winter mixing. PMID- 29705125 TI - Systematically analyses of the common dysregulated networks to understand the common pathologies between T2D and atherosclerosis. AB - BACKGROUND: Diabetic macroangiopathy, atherosclerosis secondary to diabetes mellitus, causes cerebro-cardiovascular diseases (CVD), which increase the risk of death in patients with DM and significantly reduce their quality of life. Therefore, mechanisms underlying the common shared pathologies between type 2 diabetes (T2D) and atherosclerosis are key to prevention and treatment of diabetic macroangiopathy. However, the common shared pathological links between T2D and atherosclerosis are not fully understood. METHODS: We constructed a T2D and atherosclerosis associated protein interaction sub-network (TAN) to investigate common shared mechanisms between T2D and atherosclerosis. In addition, MCODE plugin of Cytoscape was applied to TAN to identify most significant functional modules. The network modules were further mapped to KEGG pathway enrichment analysis. Finally, we established a miRNA-gene regulatory network by searching disease associated miRNAs and integrated them into miRNA gene interaction network for each module. RESULTS: TAN contains 1230 nodes which represent the union of T2D and atherosclerosis related genes and 3683 edges which represent the interactions of gene pairs. MCODE plugin was applied and five most significant modular clusters were identified. KEGG analysis of functional modules showed these genes were involved in several pathways including type 2 diabetes mellitus, ErbB and neurotrophin signaling pathway. miRNAgene interaction network was established and these miRNA-gene interactions mediated common shared pathologies between T2D and atherosclerosis. CONCLUSIONS: Analysis of TAN demonstrated that modular organization of the interaction network elucidates shared pathologies of T2D and atherosclerosis. Furthermore, the disease associated miRNA-gene interaction network enriched our insight into role of miRNAs in mediating common shared pathologies between T2D and atherosclerosis. Thus, miRNAs constitute attractive targets for the development of novel therapies for treating both T2D and atherosclerosis. PMID- 29705127 TI - Genomic methylation and transcriptomic profiling provides insights into heading depression in inbred Brassica rapa L. ssp. pekinensis. AB - Inbreeding depression is the reduction in fitness observed in inbred populations. In plants, it leads to disease, weaker resistance to adverse environmental conditions, inhibition of growth, and decrease of yield. To elucidate molecular mechanisms behind inbreeding depression, we compared global DNA methylation and transcriptome profiles of a normal and a highly inbred heading degenerated variety of the Chinese cabbage (Brassica rapa L. ssp. pekinensis). DNA methylation was reduced in inbred plants, suggesting a change in the epigenetic landscape. Transcriptome analysis by RNA-Seq revealed that genes in auxin response and synthesis pathways were differentially expressed in the inbreeding depression lines. Interestingly, methylation levels of some of those genes were also changed. Furthermore, endogenous IAA content was decreased in inbred plants, in agreement with expression and methylation data. Chemical inhibition of auxin also replicated the degenerated phenotype in normal plants, while exogenous IAA application had no effect in inbred depression plants, suggesting a more complex mechanism. These data indicate DNA methylation-regulated auxin pathways play a role in establishing inbred depression phenotypes in plants. Our findings reveal new insights into inbreeding depression and leafy head development in Chinese cabbage. PMID- 29705126 TI - The mre11A470T mutation and homeologous interactions increase error-prone BIR. AB - In the absence of the RNA-templated reverse transcriptase, telomerase, the predominant means of terminal addition, arises from break-induced replication (BIR) at multiple homologous subtelomeric Y' loci and among internal homeologous (imperfect) (polyG1-3T) tracts. These last tracts are interspersed between subtelomeric Y' direct repeats. One major survivor class contains very short (~50 bp) terminal telomere repeats. This size is sufficient for slow growth and partial telomere functionality and cell viability. However, in cells carrying the mre11A470T allele, adjacent to the predicted Rad50/Mre11 junction, cells thrive at wild-type rates, with small, but reproducible, increases in telomere length. We have proposed that the increase in telomere size and growth rate are causally linked. To understand the BIR process at the telomere, we initiated studies of large-tract (RAD51-sensitive) homologous BIR in MRE11 and mre11A470T cells in a model color assay coupled with CHEF gel analysis and marker retention. Wild-type and mutant homologous BIR rates are maintained at the same level as the rates between wild-type and mutant homeologous BIR. However, the fidelity of BIR products was severely altered in mre11A470T cells. We find that 95% of homologous BIR in MRE11 cells gives rise to the expected product size, while 25% of BIR products in mre11A470T cells were of unpredicted size (error-prone), most of which initiated at an aberrant site. However, ~25% of homeologous MRE11 cells and 1/7 of homeologous mre11A470T cells underwent error-prone BIR. This class is initiated erroneously, followed by secondary events that elongate or truncate the telomere. We conclude that error-prone BIRs are increased in homeologous recombination in wild-type and in mre11A470T cells. This finding may explain the bypass of senescence in telomerase-negative cells. PMID- 29705128 TI - Identifying causal variants at the interferon lambda locus in case-control studies: Utilizing non-synonymous variant rs117648444 to probe the role of IFN lambda4. AB - Genetic variants at the interferon lambda (IFNL) locus have been associated with several human phenotypes in both disease and health. In chronic hepatitis C virus (HCV) infections, where the IFNL variants were first identified to be associated with response to interferon-alpha-ribavirin therapy, the available data clearly suggests that the causal variant could be the dinucleotide polymorphism rs368234815 that causes an open reading frame-shift in the IFNL4 gene resulting in expression of a functional IFN-lambda4, a new type III IFN. In other human diseases/phenotypes where IFNL variants have been recently associated with, the causal mechanism remains unclear. In vitro evidence has shown that other IFNL variants (rs28416813, rs4803217) may regulate expression of another type III IFN, IFN-lambda3. Therefore, expression of a functional IFN-lambda4 and quantitative differences in IFN-lambda3 expression are two potential causal mechanisms behind the observed phenotypes. Since these two potential causal mechanisms involve features of mutual exclusivity and overlapping functions, it is difficult to differentiate one from the other, in vivo, in absence of other implicating evidences. In addition, the strong linkage disequilibrium (LD) observed in many populations at the IFNL locus makes it difficult to tease out the actual functional/causal variants responsible for the phenotypes. The non-synonymous single nucleotide polymorphism rs117648444 that alters the activity of IFN lambda4 and the LD structure in the IFNL region which leads to a confounding effect of rs117648444 on other IFNL variants, provide us with additional tools in case-control studies to probe the role of IFN-lambda4. PMID- 29705129 TI - Basin-scale seasonal changes in marine free-living bacterioplankton community in the Ofunato Bay. AB - The Ofunato Bay in the northeastern Pacific Ocean area of Japan possesses the highest biodiversity of marine organisms in the world and has attracted much attention due to its economic and environmental importance. We report here a shotgun metagenomic analysis of the year-round variation in free-living bacterioplankton collected across the entire length of the bay. Phylogenetic differences among spring, summer, autumn and winter bacterioplankton suggested that members of Proteobacteria tended to decrease at high water temperatures and increase at low temperatures. It was revealed that Candidatus Pelagibacter varied seasonally, reaching as much as 60% of all sequences at the genus level in the surface waters during winter. This increase was more evident in the deeper waters, where they reached up to 75%. The relative abundance of Planktomarina also rose during winter and fell during summer. A significant component of the winter bacterioplankton community was Archaea (mainly represented by Nitrosopumilus), as their relative abundance was very low during spring and summer but high during winter. In contrast, Actinobacteria and Cyanobacteria appeared to be higher in abundance during high-temperature periods. It was also revealed that Bacteroidetes constituted a significant component of the summer bacterioplankton community, being the second largest bacterial phylum detected in the Ofunato Bay. Its members, notably Polaribacter and Flavobacterium, were found to be high in abundance during spring and summer, particularly in the surface waters. Principal component analysis and hierarchal clustering analyses showed that the bacterial communities in the Ofunato Bay changed seasonally, likely caused by the levels of organic matter, which would be deeply mixed with surface runoff in the winter. PMID- 29705130 TI - Seasonal changes in the abundance of bacterial genes related to dimethylsulfoniopropionate catabolism in seawater from Ofunato Bay revealed by metagenomic analysis. AB - Ofunato Bay is located in the northeastern Pacific Ocean area of Japan, and it has the highest biodiversity of marine organisms in the world, primarily due to tidal influences from the cold Oyashio and warm Kuroshio Currents. Our previous results from performing shotgun metagenomics indicated that Candidatus Pelagibacter ubique and Planktomarina temperata were the dominant bacteria (Reza et al., 2018a, 2018b). These bacteria are reportedly able to catabolize dimethylsulfoniopropionate (DMSP) produced from phytoplankton into dimethyl sulfide (DMS) or methanethiol (MeSH). This study was focused on seasonal changes in the abundances of bacterial genes (dddP, dmdA) related to DMSP catabolism in the seawater of Ofunato Bay by BLAST+ analysis using shotgun metagenomic datasets. We found seasonal changes among the Candidatus Pelagibacter ubique strains, including those of the HTCC1062 type and the Red Sea type. A good correlation was observed between the chlorophyll a concentrations and the abundances of the catabolic genes, suggesting that the bacteria directly interact with phytoplankton in the marine material cycle system and play important roles in producing DMS and MeSH from DMSP as signaling molecules for the possible formation of the scent of the tidewater or as fish attractants. PMID- 29705131 TI - Effect of carp pituitary homogenate (CPH) and sGnRHa (Ovaprim) on northern pike (Esox lucius) spermiation stimulation and its effect on quantity and quality of sperm. AB - The effect of carp pituitary homogenate (CPH, n = 7) at a dose of 2.0 mg kg-1 and (D-Arg6, Pro9NET)-sGnRH + domperidone (Ovaprim, n = 7) at a dose of 0.5 ml kg-1 in northern pike (Esox lucius) sperm maturation under controlled conditions was examined. On the control group, 0.9% NaCl at a dose of 1.0 ml kg-1 (n = 7) was used. Sperm was collected 48 h following injection. Sperm quantity (total sperm volume, total sperm production and sperm concentration), sperm motility using the Computer-assisted sperm analysis (CASA) system and sperm and seminal plasma quality (sperm pH, seminal plasma osmotic pressure and seminal plasma pH) were determined for each male separately in each group. The results of the present study demonstrate that hormonal treatment had a positive effect on sperm maturation in northern pike, regardless of the hormonal preparation used. However, even though no differences were found in total sperm volume and total sperm production between fish injected with either CPH or Ovaprim, it should be highlighted that the highest progressive motile sperm (PRG), straight-linear velocity (VSL) and movement linearity (LIN) was noted in fish treated with Ovaprim. It was also found that it is possible to collect sperm from non hormonally manipulated fish. However, in such a case, only a small sperm volume (around 0.1 ml) characterised by lowered PRG (below 40%) was noted. Considering the fact that only after Ovaprim application sperm motility with progressive movement of sperm above 50% was observed, the hatchery practice of collection of sperm 48 h after its application (at a dose of 0.5 ml kg-1) may be recommended. PMID- 29705133 TI - Determination of the binding properties of p-cresyl glucuronide to human serum albumin. AB - p-Cresyl glucuronide (p-CG) is a by-product of tyrosine metabolism that accumulates in patients with end-stage renal disease. p-CG binding to human serum albumin in physiological conditions (37 degrees C, pH 7.40) was studied by ultrafiltration (MWCO 10 kDa) and data were analyzed assuming one binding site. The estimated value of the association constant was 2.77 * 103 M-1 and a maximal stoichiometry of 3.80 mol per mole. At a concentration relevant for end-stage renal patients, p-CG was 23% bound to albumin. Competition experiments, using fluorescent probes, demonstrated that p-CG did not bind to Sudlow's site I or site II. The p-CG did not interfere with the binding of p-cresyl-sulfate or indoxyl sulfate to serum albumin. PMID- 29705132 TI - Ophiopogonin D improves osteointegration of titanium alloy implants under diabetic conditions by inhibition of ROS overproduction via Wnt/beta-catenin signaling pathway. AB - A high failure rate of titanium implants in diabetic patients has been indicated in clinical evidences. Excessive oxidative stress at the bone-implant interface plays an important role in the impaired osteointegration under diabetic conditions. While the underlying mechanisms remain unknown and the targeted treatments are urgently needed. Ophiopogonin D (OP-D), isolated from Chinese herbal Radix Ophiopogon japonicus, is generally reported to be a potent antioxidant agent. In the present study, we hypothesized that OP-D exerted promotive effects on osteointegration against oxidative stress, and investigated the underlying mechanisms associated with alteration of Wnt/beta-catenin signaling pathway. Rabbit osteoblasts incubated on titanium alloy implant were co cultured with normal serum (NS), diabetic serum (DS), DS + OP-D, DS + NAC (a potent ROS inhibitor) and DS + OP-D + Dkk1 (a Wnt inhibitor) for examinations of osteoblast behaviors. For in vivo study, titanium alloy implants were implanted into the femoral condyle defects on diabetic rabbits. Results demonstrated that diabetes-induced oxidative stress resulted in osteoblast dysfunctions and apoptotic injury at the bone-implant interface, concomitant with the inactivation of Wnt/beta-catenin signaling. Importantly, OP-D administration attenuated oxidative stress, directly reactivating Wnt/beta-catenin signaling. Osteoblast dysfunctions were thus reversed as evidenced by improved osteoblast adhesion, proliferation and differentiation, and ameliorated apoptotic injury, exerting similar effects to NAC treatment. In addition, the positive effects afforded by OP-D were confirmed by improved osteointegration and oetogenesis within the titanium alloy implants in vivo by Micro-CT and histological analyses. Furthermore, the pro-osteogenic effects of OP-D were almost completely abolished by the Wnt inhibitor Dkk1. These results demonstrated, for the first time, OP-D administration alleviated the damaged osteointegration of titanium alloy implants under diabetic conditions by means of inhibiting oxidative stress via a Wnt/beta catenin-dependent mechanism. The OP-D administration would become a reliable treatment strategy for implant failure therapy in diabetics due to the optimal anti-oxidative and pro-osteogenic properties. PMID- 29705134 TI - Increase in liver cytosolic lipases activities and VLDL-TAG secretion rate do not prevent the non-alcoholic fatty liver disease in cafeteria diet-fed rats. AB - We have previously shown that the cafeteria diet increases body fat mass, plasma triacylglycerol (TAG) and insulin levels, glucose uptake by white and brown adipose tissues, as well as the sympathetic activity to both adipose tissues in Wistar rats. The metabolic pathways responsible for the development of non alcoholic fatty liver disease (NAFLD) were examined in cafeteria diet-fed rats. After 3 weeks offering cafeteria diet, we evaluated: (i) activity of the sympathetic nervous system by norepinephrine turnover rates; (ii) de novo fatty acid synthesis in vivo using 3H2O; (iii) secretion of very low density lipoprotein (VLDL)-TAG secretion measuring serum TAG levels after administration of lipase lipoprotein inhibitor, (iv) liver cytosolic lipases activities and (v) liver mRNA expression of enzymes involved in lipids secretion and oxidation by RT PCR. The cafeteria diet induced an increase in TAG (120%) and cholesterol (30%) liver contents. Cafeteria diet did not change the sympathetic nervous system activity to liver, but induced a marked increase in the lipogenesis (approximately four-fold) and significant increase in cytosolic lipases activities (46%) and VLDL-TAG secretion (22%) compared to control diet-fed rats. The cafeteria diet also increased the microsomal triglyceride transfer protein (30%) and carnitine palmitoyltransferase I (130%) mRNA expression but decreased the apolipoprotein B100 (26%) mRNA expression. Our findings demonstrate that the increase in the cytosolic lipases activities and VLDL-TAG secretion rates were not able to compensate for the increased lipogenesis rates induced by the cafeteria diet, resulting in NAFLD. PMID- 29705135 TI - Multiple roles of the splicing complex SF3B in DNA end resection and homologous recombination. AB - The appropriate repair of DNA double strand breaks is critical for genome maintenance. Thus, several cellular pathways collaborate to orchestrate a coordinated response. These include the repair of the breaks, which could be achieved by different mechanisms. A key protein involved in the regulation of the repair of broken chromosomes is CtIP. Here, we have found new partners of CtIP involved in the regulation of DNA break repair through affecting DNA end resection. We focus on the splicing complex SF3B and show that its depletion impairs DNA end resection and hampers homologous recombination. Functionally, SF3B controls CtIP function at, as least, two levels: by affecting CtIP mRNA levels and controlling CtIP recruitment to DNA breaks, in a way that requires ATM mediated phosphorylation of SF3B2 at serine 289. Indeed, overexpression of CtIP rescues the resection defect caused by SF3B downregulation. Strikingly, other SF3B depletion phenotypes, such as impaired homologous recombination or cellular sensitivity to DNA damaging agents, are independent of CtIP levels, suggesting a more general role of SF3B in controlling the response to chromosome breaks. PMID- 29705136 TI - Does translucency influence cure efficiency and color stability of resin-based composites? AB - OBJECTIVE: To determine if material's translucency influences the cure efficiency and color stability of resin-based composites (RBCs). METHODS: Four commercially available RBCs indicated for aesthetic restorations were selected in different translucent/opaque shades: IPS Empress Direct (IED) A3 Dentin, A3 Enamel, Trans 20, and Trans 30; Filtek Z350 XT (FZX) A3D, A3B, A3E, and CT; Estelite ? Quick (EQ) OA3, A3, and CE; and Opallis (OP) DA3, EA3, and T-Neutral. Color was obtained in the L'C'h' system at three distinct periods: 24h after photoactivation (baseline), after 30d of water storage (WS), and after 30d of coffee storage (CS). The translucency parameter (TP) of each RBC was calculated at baseline. The degree of CC conversion (DC) was obtained by Fourier-transform infrared spectroscopy at 0.05mm (top) and 2mm (bottom) surfaces; the cure efficiency considered the bottom/top ratio. The CIEDE2000 color difference (DeltaE00) was calculated considering the WS-baseline and CS-baseline values. Data were submitted to two-way ANOVA and Tukey's post-hoc test (alpha=0.05). Pearson's tests were used to analyze the correlations between TP and DC, and between TP and DeltaE00. RESULTS: For all RBCs, cure efficiency was not affected by materials' translucency. A positive, significant correlation was observed between TP and DC at the bottom surface for FZX only. For all RBCs, the higher the TP, the higher the DeltaE00. The DeltaE00 was higher after CS than after WS, except for EQ A3. Positive correlation between TP and DeltaE00 were observed for all materials. CONCLUSION: The translucency did not influence the cure efficiency but affected the color stability for all RBCs. CLINICAL SIGNIFICANCE: High translucent RBCs presented lower color stability and should be used carefully. PMID- 29705137 TI - Clinical Outcome and Molecular Analysis of a Chinese Patient With Lung Adenocarcinoma Harboring Rare EGFR Mutation V834L. PMID- 29705138 TI - What is the risk of local recurrence after laparoscopic transperitoneal radical nephrectomy in children with Wilms tumours? Analysis of a local series and review of the literature. AB - BACKGROUND: To reduce long-term morbidity (adhesions-related complications and impaired quality of life due to scars), laparoscopy has been used as an alternative to open surgery in Wilms tumours (WTs). However, concerns have been raised on the risk of local recurrence after this type of resection. OBJECTIVE: The aim was to determine the incidence of local recurrence after laparoscopic transperitoneal radical nephrectomy (LTRN). STUDY DESIGN: We analysed 18 local cases and conducted a review of the English literature in Pubmed from 2004 to 2017 with the following keywords: (Wilms OR nephroblastoma) AND (laparoscopy OR minimally invasive surgery) AND 2004:3000. The review was conducted according to PRISMA guidelines. Data were collected independently in duplicate in a preformed Excel database. Review articles and duplicated case reports were excluded. Patients with retroperitoneoscopic or nephron-sparing surgery were also excluded. RESULTS: One hundred and four LTRNs have been performed for WT with neoadjuvant chemotherapy in 93 cases. Tumour was ruptured preoperatively in three cases but never intraoperatively. The median volume of the tumour was 229.4 mL (3.8-776 mL). Local stage was specified in 86 cases: 49 stage I, 28 stage II, and nine stage III. Lymph nodes were sampled in 48 patients (median 2.3 [0-14] nodes). Histology was reported in 90 cases: 27 favourable and two unfavourable histology (COG); and six low, 50 intermediate, and five high-risk tumours (International Society of Paediatric Oncology). With a median follow-up of 20.5 months (1-114 months), there were four local recurrences (3.8%) at a median of 8.5 (7-9) months after surgery. Three tumours were initial local stage I (2 intermediate and 1 high risk) and one stage III. The results are presented in the Figure. DISCUSSION: The incidence of local recurrence after LTRN is 3.8%. This is lower than previously reported after open resection. However, tumours amenable to minimally invasive surgery are smaller, with higher numbers of low stage and standard histology. Additionally, the quality of the reports is suboptimal and follow-up is relatively short. CONCLUSION: LTRN does not seem to increase the incidence of local recurrence in WT but inclusion of patients in international protocols with prolonged and systematic follow-up is of utmost importance to carefully evaluate this risk. PMID- 29705139 TI - Characteristics, treatment decisions and outcomes of prepubertal testicular germ cell tumor: A descriptive analysis from a large Chinese center. AB - INTRODUCTION: Prepubertal testicular tumors are fundamentally distinct from their postpubertal and adult counterparts. Racial and ethnic differences contribute to the incidence, characteristics, and histological distribution of prepubertal testicular germ cell tumors (PTGCTs). OBJECTIVE: To elucidate the characteristics and treatment outcomes of PTGCTs in a Chinese cohort. STUDY DESIGN: Data were retrospectively reviewed from consecutive PTGCT patients aged <12 years who received treatment at the current institution from January 2007 to December 2015. Exclusion criteria were: patients aged >12 years, non-primary testicular germ cell tumors, and para-testicular tumors. RESULTS: A total of 167 patients qualified for the study (Table). The median age at diagnosis was 20 months (range 1-142). Pathology revealed 87 (50.9%) teratomas, 50 (29.2%) yolk sac tumors (YSTs), 33 (19.3%) epidermoid cysts, and one (0.6%) mixed germ cell tumor. Of the teratomas, 70 (80.5%) mature teratomas (MTs) and 17 (19.5%) immature teratomas (ITs) were detected. ITs manifested at a younger age and were larger in size compared with MTs (P < 0.001). Testis-sparing surgery (TSS) was performed for all MTs and 10 ITs. Radical orchiectomy (RO) was performed for seven ITs. No metastatic or local recurrence was detected in benign tumors during follow-up. Obviously elevated alpha fetoprotein (AFP) levels were detected in all the YSTs. Of these, 47 (94%) were diagnosed as Stage I, one (2%) as Stage II, and two (4%) as Stage IV. After RO, recurrence was detected in one Stage I patient with a median follow-up of 46 months. One Stage II and two Stage IV patients died due to tumor progression. DISCUSSION: Racial and ethnic differences were detected in PTGCTs. It is believed that the present study is the largest study detailing the clinicopathologic characteristics and treatment outcomes of PTGCTs in a Chinese cohort. CONCLUSIONS: Teratoma was the most common subtype of PTGCTs, followed by YST. ITs manifested as benign behavior and were more likely to be present at a younger age and have a larger tumor size compared with MTs. TSS was reliable for benign lesions. For Stage I YST, RO alone was valid. Salvage chemotherapy was effective and preventative retroperitoneal lymph node dissection may not be necessary for YST. The prognosis of PTGCTs was favorable. PMID- 29705140 TI - Modified Heitz-Boyer-Hovelacque rectal bladder in children: Reassuring histology after median follow-up of 10.5 years. PMID- 29705141 TI - Krohnke pyridines: Rapid and facile access to Mcl-1 inhibitors. AB - The tumorigenic activity of upregulated Mcl-1 is manifested by binding the BH3 alpha-helical death domains of opposing Bcl-2 family members, neutralizing them and preventing apoptosis. Accordingly, the development of Mcl-1 inhibitors largely focuses on synthetic BH3 mimicry. The condensation of alpha-pyridinium methyl ketone salts and alpha,beta-unsaturated carbonyl compounds in the presence of a source of ammonia, or the Krohnke pyridine synthesis, is a simple approach to afford highly functionalized pyridines. We adapted this chemistry to rapidly generate low-micromolar inhibitors of Mcl-1 wherein the 2,4,6-substituents were predicted to mimic the i, i + 2 and i + 7 side chains of the BH3 alpha-helix. PMID- 29705143 TI - Convoluted history and confusing morphology: Molecular phylogenetic analysis of dicrocoeliids reveals true systematic position of the Anenterotrematidae Yamaguti, 1958 (Platyhelminthes, Digenea). AB - The Dicrocoeliidae is a highly diverse family of digeneans parasitic in amniotic tetrapods. Detailed molecular phylogenetic analysis of dicrocoeliids is lacking and only a few dicrocoeliids from mammals have been included in previous studies. Sequence data were previously absent for the Anenterotrematidae that shares several morphological characteristics with dicrocoeliids. We examined phylogenetic affinities of several newly sequenced (nuclear 28S rDNA) taxa of dicrocoeliids and anenterotrematids collected from small mammals in Ecuador, Panama, Peru, USA and Vietnam. Our analyses demonstrated that the two anenterotrematid genera (Anenterotrema, Apharyngotrema) belong to the Dicrocoeliidae, placing the Anenterotrematidae into synonymy with the Dicrocoeliidae. Molecular data combined with morphological examination of type and new specimens provided evidence that Parametadelphis and Apharyngotrema are junior synonyms of Metadelphis, with all Metadelphis species lacking a digestive system. Phylogenetic analysis demonstrates that reduction of the alimentary tract in Lutztrema and its loss in Anenterotrema and Metadelphis represent at least two independent evolutionary events. Genera Brachylecithum, Brachydistomum, and Lyperosomum proved to be non-monophyletic, each likely representing more than a single genus. Furthermore, phylogenetic analysis did not support monophyly of the two largest subfamilies of the Dicrocoeliidae (Dicrocoeliinae and Leipertrematinae) with the other two subfamilies not included in this study. Therefore, we propose to abandon the current subfamily division of the Dicrocoeliidae. Analysis of host associations indicates multiple host-switching events throughout evolution of dicrocoeliids. Lastly, analysis of dicrocoeliid geographic distribution revealed that nearly all major clades included taxa from more than a single zoogeographic realm with the exception of the clade Anenterotrema + Metadelphis, found only in the Neotropics. PMID- 29705142 TI - Discovery of 6-(pyrimidin-5-ylmethyl)quinoline-8-carboxamide negative allosteric modulators of metabotropic glutamate receptor subtype 5. AB - Based on previous work that established fused heterocycles as viable alternatives for the picolinamide core of our lead series of mGlu5 negative allosteric modulators (NAMs), we designed a novel series of 6-(pyrimidin-5 ylmethyl)quinoline-8-carboxamide mGlu5 NAMs. These new quinoline derivatives also contained carbon linkers as replacements for the diaryl ether oxygen atom common to our previously published chemotypes. Compounds were evaluated in a cell-based functional mGlu5 assay, and an exemplar analog 27 was >60-fold selective versus the other seven mGlu receptors. Selected compounds were also studied in metabolic stability assays in rat and human S9 hepatic fractions and exhibited a mixture of P450- and non-P450-mediated metabolism. PMID- 29705144 TI - Brachylaima asakawai sp. nov. (Trematoda: Brachylaimidae), a rodent intestinal fluke in Hokkaido, Japan, with a finding of the first and second intermediate hosts. AB - In the 1970's and 1980's, an unknown species of the genus Brachylaima (Trematoda: Brachylaimidae) had been recorded from the intestines of Rattus norvegicus and Apodemus speciosus in Hokkaido, Japan. The rodent fluke was characteristic in extending a bilateral vitellarium till the level of posterior margin of anterior testis and in keeping almost the same-sized spherical ovary and testes. In this study, the rodent fluke was rediscovered from A. speciosus, Apodemus argenteus, and Myodes rufocanus in Hokkaido. The resultant parasite collection enabled us to make a mitochondrial DNA (mtDNA) barcode for tracking its intermediate hosts. The metacercaria of the rodent fluke was detected frequently from the kidney of three species of land snails (Discus pauper, Succinea lauta, and Ainohelix editha). However, its sporocyst with cercariae was found only from the hepatopancreas of D. pauper, a fairly small snail. The wide-spectrum of the second intermediate host seems to increase the chance of transmitting the parasite to various mammals and birds. The use of indigenous land snails as the first and second intermediate hosts, the distinctiveness of the mtDNA sequence, and the characteristic morphology of all the developmental stages prompted us to propose Brachylaima asakawai sp. nov. for the rodent intestinal fluke in Hokkaido. The present field survey suggests that the life cycle of the new species is primarily dependent on a predator-prey relationship between rodents and D. pauper. PMID- 29705145 TI - Paralytic shellfish toxin producing Aphanizomenon gracile strains isolated from Lake Iznik, Turkey. AB - Aphanizomenon gracile is one of the most widespread Paralytic Shellfish Toxin (PST) producing cyanobacteria in freshwater bodies in the Northern Hemisphere. It has been shown to produce various PST congeners, including saxitoxin (STX), neosaxitoxin (NEO), decarbamoylsaxitoxin (dcSTX) and gonyautoxin 5 (GTX5) in Europe, North America and Asia. Three cyanobacteria strains were isolated in Lake Iznik in northwestern Turkey. Morphological characterization of these strains suggested all three strains conformed to classical taxonomic identification of A. gracile with some differences such as clumping of filaments, partially hyaline cells in some filaments and longer than usual vegetative cells. Sequences of 16S rRNA gene of these strains were placed within an A. gracile cluster including the majority of PST producing strains, confirming the identification of these strains as A. gracile. These new strains possessed saxitoxin biosynthesis genes sxtA, sxtG and their sequences clustered with those of other A. gracile. Liquid chromatography tandem mass spectrometry (LC-MS/MS) analysis demonstrated the presence of NEO, STX, dcSTX and decarbamoylneosaxitoxin (dcNEO) in all strains. This is the first report of a PST producer in any water body in Turkey and first observation of dcNEO in an A. gracile culture. PMID- 29705146 TI - Diversity of cyanobacteria and the presence of cyanotoxins in the epilimnion of Lake Yerevan (Armenia). AB - This paper presents the first report of cyanobacteria and cyanotoxins from the South Caucasus region, in particular from Lake Yerevan (Armenia). Microcystis, Dolichospermum and Planktothrix were the key genera identified during the growing season. A trend of a remarkable increase in cyanobacterial densities was observed from 2012 to 2013 exhibiting bloom formation in June (by Nostoc linckia) with the highest values in June and August 2013, reaching up to 695.9*103 cells mL-1. Seasonal dependence of cyanobacterial density on temperature, and temperature as a driver for cyanobacterial cells growth and development were suggested. Biogenic nutrients were identified as co-drivers determining species richness and dominance, as well as the distribution of phytoplankton in different parts of the reservoir. Cyanotoxin concentrations in the filtered biomass were reported during July 2012 for both stations of the reservoir (left and right bank). Microcystin RR (MC-RR) was the most abundant and the most frequently observed cyanotoxin. Lower MC-LR concentrations were identified in all samples from both stations, with the highest values observed at the right bank in July 2012. [D-Asp3]MC-RR, MC-YR, MC-HtyR, [D-Asp3]MC-LR, MC-HilR, MC-WR, MC-LY and MC-LW were also identified in trace levels. Anatoxin-a (ANA) was reported in the samples from both stations during August 2012. Cylindrospermopsin (CYN) was present in trace concentrations in samples from both stations during July and in the sample from the left bank during September. PMID- 29705147 TI - Anti-neoplastic activity of Amblyomma sculptum, Amblyomma parvum and Rhipicephalus sanguineus tick saliva on breast tumor cell lines. AB - Cancer is one of the most troubling diseases and is becoming increasingly common. Breast cancer has a high cure rate when diagnosed early, but when diagnosed late, treatment is frequently painful, devastating and unsuccessful. The search for new treatments that are more effective and less harmful has led to several substances and biomolecules from plants and animals with potential anti-tumor activity. Within this context, ticks have emerged as an excellent source of new molecules with a wide array of therapeutic properties. Various molecules in tick saliva have immunomodulatory, anticoagulant, anti-inflammatory and anti-tumor effects across different tumor cell lines. Our study evaluates the effect of saliva from three widespread and important tick species in Brazil (Amblyomma sculptum, Amblyomma parvum and Rhipicephalus sanguineus) on MCF-7, MDA-MB-231 breast cancer cell lines and on the non-neoplastic MCF-10A cell line. We found that tick saliva from all three tick species showed cytotoxicity to tumor cells (MCF-7, MDA-MB 231) but not to the non-tumor cells (MCF-10A). Morphological changes on the surface of MCF-7 and MDA-MB-231 tumor cells did not occur on the MCF-10A cells. We also demonstrated that tumor cells die by apoptosis induced by caspase-3 and caspase 7 activity, suggesting that intrinsic pathway apoptosis may be triggered by tick saliva. These changes were not observed in MCF10A cells, which remained broadly unchanged even after exposure to diverse types of saliva. These results suggest that tick saliva from these tick species is a source of molecules, or biomolecules, useful for the potential source for the development of new breast cancer drugs. PMID- 29705148 TI - Use of the receptor binding assay for determination of paralytic shellfish poisoning toxins in bivalve molluscs from Great Britain and the assessment of method performance in oysters. AB - A receptor binding assay (RBA) for the determination of paralytic shellfish poisoning toxicity is formally validated through collaborative study and approved for regulatory monitoring use in the US for mussels and clams. However, to date, the method has not been tested on bivalve molluscs originating from European waters and no validation studies have been conducted for oysters, a shellfish species of great importance globally. This study firstly reports the work conducted to assess the performance of the assay in comparison with a regulatory chemical detection method for a range of shellfish species originating from Great Britain. Data obtained showed a complete absence of false negative RBA results, with a tendency to over-estimate PSP toxicity for some shellfish species in comparison with liquid chromatography with fluorescence detection. Secondly, the performance of the RBA was assessed for oysters, with the analysis of a dilution series of oyster matrix certified reference materials. Method trueness, sensitivity and precision were found to compare well with results reported previously for other species. In addition, the RBA analysis of untreated and demetallated oyster extracts, provided good evidence that the RBA is not suppressed in the presence of high concentrations of zinc as reported previously for the mouse bioassay. Consequently, there is strong evidence from this study, that the RBA would be suitable for determination of PSP toxicity in bivalve molluscs from GB, with acceptable method performance in oysters. Further validation studies would be required for other shellfish species of interest before the method can be considered suitable for implementation in Europe. PMID- 29705149 TI - Assessment of the potential toxicological hazard of the Green Parrot Snake (Leptophis ahaetulla marginatus): Characterization of its venom and venom delivery system. AB - Snakes are the major group of venomous vertebrates, and the rear-fanged snakes represent the vast majority of species and occur worldwide; however, relatively few studies have characterized their venoms and evaluated their potential hazards for humans. Herein we explore the protein composition and properties of the venom of the rear-fanged Green Parrot Snake, Leptophis ahaetulla marginatus, the most common snake found in the Iguazu National Park (Argentina), as well as the main features of its venom delivery system. This species has venom reminiscent of elapid venoms, composed mainly of components such as 3FTxs, CRiSPs and AChE, but it shows low toxicity toward mammals (LD50 > 20 MUg/g mouse). The histology of its Duvernoy's venom gland is similar to that of other colubrids, with serous secretory cells arranged in densely packed secretory tubules. The posterior end of its maxilla exhibits 1-3 blade-shaped and slightly recurved fangs but without grooves. This study provides an initial analysis of the biological role of venom in Leptophis, with implications for potential symptoms that might be anticipated from bites by this species. PMID- 29705150 TI - A myotoxic Lys49 phospholipase A2-homologue is the major component of the venom of Bothrops cotiara from Misiones, Argentina. AB - Bothrops cotiara is a pitviper found in Southeastern Brazil and, scarcely, in the Misiones province of Argentina. In contrast to considerable information available on the venom of the Brazilian snake population, that of Misiones has received little attention. While exploring the chromatographic venom profile of Argentinean B. cotiara, a major protein peak was found which, according to a previous study, is not present in the venom of Brazilian origin. The corresponding protein was isolated by RP-HPLC, and characterized by electrophoresis, mass spectrometry, phospholipase A2 (PLA2) assay, and myotoxic activities. Representing nearly 15% of B. cotiara venom from Misiones, this protein was identified as a Lys49 PLA2 homologue. In accordance with the characteristics of this toxin family, the protein induced myotoxicity in mice and was devoid of PLA2 activity. Since previous work reported that no PLA2 or PLA2 homologues occur in B. cotiara venom of Brazilian origin, the presence of an abundant Lys49 PLA2 homologue in the venom from Misiones highlights a striking phenotypic variation in toxin expression within two populations of a single snake species inhabiting different geographic areas. The considerable proportion of B. cotiara Lys49 PLA2 homologue myotoxin in the venom alerts that skeletal muscle necrosis might be a potentially relevant consequence of eventual envenomings by this species in Misiones. PMID- 29705151 TI - Extraction and preliminary chemical characterization of the venom of the spider wasp Pepsis decorata (Hymenoptera: Pompilidae). AB - Arthropod venoms may be considered important sources of bioactive molecules; however, technical difficulties, such as venom extraction and homogeneity may impair the biochemical identification of new molecules. In this context, we have developed a method to maintain wasps in captivity that allows the collection of the venom, without use of chemical, mechanical or electrical stimuli. The crude venom was analyzed by RP-HPLC-ESIQ-ToF and 20 peptides were identified by de novo peptide sequencing, among them Eumenine-Mastoparan and a Ponericin-G2-simile peptide. PMID- 29705152 TI - Evaluation of diffuse large B-cell lymphoma patients with 64-slice multidetector computed tomography versus 18FDG positron emission tomography/computed tomography in initial staging and restaging after treatment. AB - BACKGROUND AND OBJECTIVES: To prospectively compare the accuracy in initial staging and end-of-treatment restaging of diffuse large B-cell lymphoma (DLBCL) between 64-slice multidetector computed tomography (64MDCT) and 18FDG positron emission tomography/computed tomography (18FGD PET/CT) with intravenous contrast injection. MATERIAL AND METHODS: Randomised and blind controlled clinical multicentric trial that included biopsy-proven DLBCL patients. Seventy-two patients from five different hospitals in the region of Madrid, Spain, were enrolled in the study between January 2012 and June 2015. Thirty-six were randomly allocated to 18FDG PET/TC and the other 36 to 64MDCT for initial staging and end-of-treatment restaging. A nuclear medicine physician and a radiologist independently analysed 18FDG PET/TC images and reached an agreement post-hoc. 64MDCT images were separately evaluated by a different radiologist. Every set of images was compared to the reference standard that included clinical data, complementary tests and follow-up. The study was approved by participating centres' ethics committees and written informed consent was obtained from all the participants. RESULTS: A good agreement was observed between both diagnostic techniques and the reference standard in initial staging [18FDG PET/CT (k=0.5) and 64MDCT (k=0.6)], although only the 18FDG PET/TC showed a good agreement with the reference standard for the end-of-treatment restaging (k=0.7). CONCLUSION: In DLBCL, both 18FDG PET/TC and 64MDCT have shown good agreement with the reference standard in initial staging. Nevertheless, 18FDG PET/CT has shown to be superior to 64MDCT in end-of-treatment response assessment. PMID- 29705153 TI - Visceral leishmania-associated hemophagocytic lymphohistiocytosis. PMID- 29705154 TI - Genetic mutations in young patients admitted to an emergency department for syncope during sport practice. AB - BACKGROUND AND OBJECTIVES: To study the frequency of genetic mutations related to genetic heart disease among young patients admitted for syncope during sport practice. PATIENTS AND METHODS: A case series study that included patients<=45 years admitted for syncope during sport practice during 2010-2011. We collected demographic and clinical variables, genetic tests mutations and final clinical diagnosis. RESULTS: A genetic test was performed in 46 (76.7%) of 60 patients evaluated. The genetic test was positive in 12 (26%; 95% CI 15.6-40.3) patients; 10 (21.7%) had PKP2 mutation related to arrhythmogenic right ventricular dysplasia mutation, one (2.2%) KCNQ1 mutation and one (2.2%) SCN5A mutation related to channelopathies. The genetic test was positive in 11 (35.5%) cases of undetermined syncope and one (50%) case of cardiac syncope, being negative in all cases with neuromediated syncopes (P=.037). CONCLUSIONS: Gene mutations are common in young patients suffering from syncope during sports, especially in those with cardiac or undetermined aetiology. PMID- 29705155 TI - The effect of telehealth, telephone support or usual care on quality of life, mortality and healthcare utilization in elderly high-risk patients with multiple chronic conditions. A prospective study. AB - BACKGROUND AND OBJECTIVE: To assess the effect of home based telehealth or structured telephone support interventions with respect to usual care on quality of life, mortality and healthcare utilization in elderly high-risk multiple chronic condition patients. PATIENTS AND METHODS: 472 elderly high-risk patients with plurimorbidity in the region of Valencia (Spain) were recruited between June 2012 and May 2013, and followed for 12 months from recruitment. Patients were allocated to either: (a) a structured telephone intervention, a nurse-led case management program with telephone follow up every 15 days; (b) telehealth, which adds technology for remote self-management and the exchange of clinical data; or (c) usual care. Main outcome measures was quality of life measured by the EuroQol (EQ-5D) instrument, cognitive impairment, functional status, mortality and healthcare resource use. Inadequate randomization process led us to used propensity scores for adjusted analyses to control for imbalances between groups at baseline. RESULTS: EQ-5D score was significantly higher in the telehealth group compared to usual care (diff: 0.19, 0.08-0.30), but was not different to telephone support (diff: 0.04, -0.05 to 0.14). In adjusted analyses, inclusion in the telehealth group was associated with an additional 0.18 points in the EQ-5D score compared to usual care at 12 months (p<0.001), and with a gain of 0.13 points for the telephone support group (p<0.001). No differences in mortality or utilization were found, except for a borderline significant increase in General Practitioner visits. CONCLUSIONS: Telehealth was associated with better quality of life. Important limitations of the study and similarity of effects to telephone intervention call for careful endorsement of telemedicine. Clinicaltrials.gov (identifier: NCT02447562). PMID- 29705156 TI - Value of testosterone in saliva in the diagnosis of Alzheimer's disease. PMID- 29705157 TI - Community acquired pneumonia by Legionella pneumophila: Study of 136 cases. AB - OBJECTIVE: Most of the data on Legionella pneumonia in our country come from the Mediterranean area, and there are few studies from the Northwest area. This study tries to assess the situation of this infection in this area. METHOD: Retrospective study of all patients with positive Legionella antigenuria treated at the University Hospital Lucus Augusti in Lugo (Spain) from 2001, the year in which this test was introduced in our centre, until 2015. We analysed epidemiological data, risk factors, clinical, radiological and biochemical findings, and clinical outcome. RESULTS: The sampled included 136 patients. When comparing the first five years of the study with the last five, the incidence increased from 10.9 to 64.5 cases/1,000,000; the number of antigenuria requests increased 3.4 times, and compared to other pneumonia aetiologies Legionella increased from 0.9% to 15%. The mean age was 64.1years and 84.6% were males; 74.3% had comorbidities. Males were significantly younger (62.7+/-16.6 vs 71.9+/ 17.3) and consumed more alcohol (26.1% vs 0%) and tobacco (67.8% vs 14.3%). Diagnosis was established within the first 72hours in 88.9% of cases and most received levofloxacin (95.6%). Hospitalisation was needed in 85% of cases, 11.7% in ICU and 4.4% died. CONCLUSIONS: After the introduction of antigenuria there was an increase in the incidence of Legionella pneumonia recorded in our health area. Its rate in recent years has been one of the highest in our country. Despite the fact that the patients had advanced age and comorbidities, mortality was low. PMID- 29705158 TI - Efficacy of combined electrostimulation in patients with acute exacerbation of COPD: randomised clinical trial. AB - INTRODUCTION AND OBJECTIVE: Muscle dysfunction is very common in patients with chronic obstructive pulmonary disease (COPD). Muscular strength depletion is a result of numerous hospitalisations and this causes an increase in the symptomatology. Numerous interventions have been used in these patients, but there is no consensus on the best. The main objective of this study is to compare the effectiveness of two physiotherapy interventions during hospitalisation in COPD patients. PATIENTS AND METHODS: In this clinical trial, we included 39 patients who were randomised into three groups. A control group received standard medical treatment (oxygen therapy and pharmacotherapy), and two groups received, in addition to standard medical treatment, a physiotherapy intervention, one with functional electrostimulation and one with calisthenic exercises. The main variables were the ability to exercise using the Five-time sit-to-stand test as well as the functionality associated with symptomatology, as measured by the London Chest Activity of Daily Living Scale. RESULTS: After comparing the results, there was a significant improvement in dyspnea on discharge versus admission in all three groups. In addition, we found significant differences in functionality, exercise capacity, and fatigue in both intervention groups, being better in the electrostimulation with calisthenic exercises group than in the functional group. CONCLUSION: An electrostimulation treatment improves the exercise capacity, functionality and fatigue in hospitalised AECOPD patients. PMID- 29705159 TI - Intrathoracic pancreatic herniation: A rare cause of acute pancreatitis. PMID- 29705160 TI - Percutaneous Closure of a Fistulous Giant Coronary Aneurysm. AB - Giant coronary artery aneurysms larger than 50 mm are rare and associated with important complications: namely, rupture. Its workup requires comprehensive imaging and standard treatment is surgical exclusion. We present a 60-year-old patient with previous ostium secundum atrial septal defect surgical closure diagnosed with a giant proximal right coronary artery aneurysm (70 x 62 mm) fistulizing into the right atrium. Percutaneous closure of its aortic origin with an atrial septal occluder was successfully performed, and thrombosis of the aneurysm confirmed on angiography and echocardiogram. This case depicts an innovative, minimally invasive approach to this worrisome entity. PMID- 29705161 TI - Ca2+ Entry Through Reverse Mode Na+/Ca2+ Exchanger Contributes to Store Operated Channel-Mediated Neointima Formation After Arterial Injury. AB - BACKGROUND: Na+/Ca2+ exchange (NCX) reversal-mediated Ca2+ entry is a critical pathway for stimulating proliferation in many cell lines. However, the role of reverse-mode NCX1 in neointima formation and atherosclerosis remains unclear. The aims of the present study were to investigate the functional role of NCX1 in the pathogenesis of atherosclerosis and vascular smooth muscle cell (VSMC) proliferation, and to determine the interaction between NCX1 and store depletion in VSMCs. METHODS: A rat balloon injury model was established to examine the effect of the knockdown of NCX1 on neointima formation after injury. VSMCs were cultured to verify that NCX1 knockdown suppressed serum-induced VSMC proliferation. RESULTS: The results showed that balloon injury induced neointima formation and upregulated NCX1 expression at 7 and 14 days after injury in rat carotid arteries (1.18- and 1.45-fold, respectively). A lentivirus vector expressing short hairpin (sh)RNA against rat NCX1 dramatically downregulated NCX1, proliferating cell nuclear antigen (PCNA) and Ki-67 expression, and suppressed neointima formation in vivo (62% at 7 days and 70% at 14 days). KB R7943 (an inhibitor of reverse-mode NCX1) and NCX1 knockdown significantly inhibited serum-induced VSMC proliferation (65% at 72 hours and 41% at 72 hours, respectively), determined according to PCNA and Ki-67 expression and cell counting in vitro, and markedly suppressed store depletion-mediated Ca2+ entry and peripheral cytosolic Na+ transients in VSMCs. CONCLUSIONS: Reverse-mode NCX1 is activated by store depletion and is required for proliferative VSMC proliferation and neointima formation after arterial injury. PMID- 29705162 TI - Streptomyces globosus DK15 and Streptomyces ederensis ST13 as new producers of factumycin and tetrangomycin antibiotics. AB - Fifty seven soil-borne actinomycete strains were assessed for the antibiotic production. Two of the most active isolates, designed as Streptomyces ST-13 and DK-15 exhibited a broad range of antimicrobial activity and therefore they were selected for HPLC fractionation against the most suppressed bacteria Staphylococcus aureus (ST-13) and Chromobacterium violaceum (DK-15). LC/MS analysis of extracts showed the presence of polyketides factumycin (DK15) and tetrangomycin (ST13). The taxonomic position of the antibiotic-producing actinomycetes was determined using a polyphasic approach. Phenotypic characterization and 16S rRNA gene sequence analysis of the isolates matched those described for members of the genus Streptomyces. DK-15 strain exhibited the highest 16S rRNA gene sequence similarity to Streptomyces globosus DSM-40815 (T) and Streptomyces toxytricini DSM-40178 (T) and ST-13 strain to Streptomyces ederensis DSM-40741 (T) and Streptomyces phaeochromogenes DSM-40073 (T). For the proper identification, MALDI-TOF/MS profile of whole-cell proteins led to the identification of S. globosus DK-15 (accession number: KX527570) and S. ederensis ST13 (accession number: KX527568). To our knowledge, there is no report about the production of these antibiotics by S.globosus and S. ederensis, thus isolates DK15 and ST13 identified as S. globosus DK-15 and S.ederensis ST-13 can be considered as new sources of these unique antibacterial metabolites. PMID- 29705163 TI - Free fatty acids reduce metabolic stress and favor a stable production of heterologous proteins in Pichia pastoris. AB - The growth of yeasts in culture media can be affected by many factors. For example, methanol can be metabolized by other pathways to produce ethanol, which acts as an inhibitor of the heterologous protein production pathway; oxygen concentration can generate aerobic or anaerobic environments and affects the fermentation rate; and temperature affects the central carbon metabolism and stress response protein folding. The main goal of this study was determine the implication of free fatty acids on the production of heterologous proteins in different culture conditions in cultures of Pichia pastoris. We evaluated cell viability using propidium iodide by flow cytometry and thiobarbituric acid reactive substances to measure cell membrane damage. The results indicate that the use of low temperatures and low methanol concentrations favors the decrease in lipid peroxidation in the transition phase from glycerol to methanol. In addition, a temperature of 14 degrees C+1%M provided the most stable viability. By contrast, the temperature of 18 degrees C+1.5%M favored the production of a higher antibody fragment concentration. In summary, these results demonstrate that the decrease in lipid peroxidation is related to an increased production of free fatty acids. PMID- 29705165 TI - The Possible Effect of Oxytocin in Postpartum Recovery From a Stroke: A Case Report. AB - Pregnancy is a risk factor for stroke in young women, but the effect of delivery on recovery and rehabilitation after stroke has not been elucidated in pregnant patients with stroke. This case report presents a pregnant patient with stroke who recovered successfully after cesarean delivery during rehabilitation. The possible effect of oxytocin is discussed as a factor promoting recovery from stroke. PMID- 29705164 TI - Saccharomyces cerevisiae populations and other yeasts associated with indigenous beers (chicha) of Ecuador. AB - Chicha, a type of beer made mainly with maize or cassava, is a traditional fermented beverage of the Andean region. There have only been a few studies on yeasts associated with chicha fermentation, and the species diversity occurring during the production of this beverage is not known. The objective of this study was to determine the biodiversity of yeasts in chicha, and to characterize the Saccharomyces cerevisiae populations associated with the production of chicha de jora, seven-grain chicha, chicha de yuca, and chicha de morocho in Ecuador. The molecular diversity of S. cerevisiae populations was determined by restriction polymorphism mitochondrial profiles. The beverages were characterized based on their physicochemical parameters. Twenty-six species were identified, and the most prevalent species were S. cerevisiae and Torulaspora delbrueckii. Other yeast species were isolated at low frequencies. Among 121 isolates of S. cerevisiae, 68 different mtDNA molecular profiles were identified. These results showed that chichas are fermented by a high number of different strains of S. cerevisiae. Some other species provided a minor contribution to the fermentation process. The chicha presented generally similar physicochemical parameters to those observed for other traditional fermented beverages, and can be considered as an acid fermented beverage. PMID- 29705166 TI - Differences in Knee and Hip Adduction and Hip Muscle Activation in Runners With and Without Iliotibial Band Syndrome. AB - BACKGROUND: Iliotibial band syndrome has been associated with altered hip and knee kinematics in runners. Previous studies have recommended further research on neuromuscular factors at the hip. The frontal plane hip muscles have been a strong focus in strength comparison but not for electromyography investigation. OBJECTIVE: To compare hip surface electromyography, and frontal plane hip and knee kinematics, in runners with and without iliotibial band syndrome. DESIGN: Observational cross-sectional study. SETTING: Biomechanics research laboratory within a university. PARTICIPANTS: Thirty subjects were recruited consisting of 15 injured runners with iliotibial band syndrome and 15 gender-, age-, and body mass index-matched controls. In each group, 8 were male runners and 7 were female runners. Inclusion criteria for the injured group were pain within 2 months related to iliotibial band syndrome and a positive Noble compression test. Participants were excluded if they reported other lower extremity diagnoses within the last year or active lower extremity or low back pain not related to iliotibial band syndrome. Controls were excluded if they reported a history of iliotibial band syndrome. Convenience sampling was used based on referrals from local running clinics and orthopedic clinics. METHODS: Three-dimensional motion capture was performed with 10 high-speed cameras synchronized with wireless surface electromyography during a 30-minute run. The first data point was at 3 minutes, using a constant speed of 2.74 meters per second. A second data point was at 30 minutes, using a self-selected pace by the participant to allow for a challenging run until completion at 30 minutes. MAIN OUTCOME MEASUREMENTS: Motion capture was reported as peak kinematic values from heel strike to peak knee flexion for hip adduction and knee adduction. Surface electromyography was reported as a percentage of maximal voluntary contraction for the gluteus maximus, gluteus medius and tensor fascia latae muscles. RESULTS: Injured runners demonstrated increased knee adduction compared with control runners at 30 minutes (P = .002, control = -1.48 degrees , injured = 3.74 degrees ). Tensor fasciae latae muscle activation in injured runners was increased compared with control runners at 3 minutes (P = .017, control = 7% maximal voluntary isometric contraction, injured = 11% maximal voluntary isometric contraction). CONCLUSION: The results of this study suggest that lateral knee pain in runners localized to the distal iliotibial band is associated with increased knee adduction at 30 minutes. Increased tensor fasciae latae muscle activation at 3 minutes is noted, but more investigation is needed to better understand the clinical meaning. These findings are consistent with but not conclusive evidence supporting the theory that neuromuscular factors of the hip muscles may contribute to increased knee adduction in runners with iliotibial band syndrome. We advise caution using these findings to support treatments intended to modify tensor fasciae latae activation, given the small differences of 4% in muscle activation. Increased knee adduction in runners at 30 minutes was over 5 degrees and beyond the minimal detectable difference. Additional research is needed to confirm whether the degree of knee adduction changes earlier versus later in a run and whether fatigue is a clinically relevant factor. LEVEL OF EVIDENCE: III. PMID- 29705167 TI - Stiff Person Syndrome With Evidence of Nonspecific Focal Myositis Secondary to Sustained Muscle Contraction: A Case Report. AB - Stiff person syndrome (SPS) is a rare neuroimmunological disorder characterized by progressive muscular rigidity and spasms that affect axial and limb muscles. There have been a few reports that patients with SPS had evidences of polymyositis. There have been no clear explanations about the characteristics of polymyositis in SPS. We report the case of a 36-year-old woman with SPS in association with nonspecific focal myositis secondary to sustained muscle contraction. She presented with stiffness and pain in her extremities, and diazepam and baclofen were ineffective. With immunotherapy, her serum creatinine kinase levels reduced; however, her clinical symptoms progressively worsened. PMID- 29705168 TI - Stenosis and Neurologic Level Discrepancies in Cervical Spondylotic Myelopathy. AB - BACKGROUND: Cervical spondylotic myelopathy (CSM) is the most common cause of cord dysfunction in older individuals. CSM involves either the upper motor neuron or lower motor neuron (LMN) in the cervical spine. The neurologic level of the LMN lesion does not usually correspond with the structural level detected via magnetic resonance imaging (MRI). OBJECTIVE: To examine the relationship between the structural level of stenosis and the neurologic level of LMN involvement in patients with CSM. DESIGN: Retrospective descriptive study. SETTING: Tertiary hospital. PATIENTS: Patients with cervical spondylotic myelopathy, aged 41-79 years. METHODS: We reviewed electromyography (EMG) and magnetic resonance imaging (MRI) findings from 17 patients with CSM to objectively show the relation between the structural level of stenosis and the neurologic level with LMN involvement. MAIN OUTCOME MEASUREMENTS: The structural level was defined by spinal canal stenosis with definite cord compression on MRI. The neurologic level was determined by myotomes with abnormal spontaneous activity on EMG. RESULTS: In all patients but one, myotomes with abnormal spontaneous EMG activity were one to 4 levels lower than the stenotic canal shown on MRI. CONCLUSIONS: LMN involvement in CSM is usually not concordant with the structural lesion. For accurate diagnosis and treatment, physicians should recognize that myotomal involvement in CSM is often due to canal stenosis one to 4 levels above the lesion. LEVEL OF EVIDENCE: III. PMID- 29705169 TI - Lumbar Epidural Varix Causing Radicular Pain: A Case Report and Differential Diagnosis of Lumbar Cystic Lesions. AB - Lumbar epidural varices are a rare cause of radicular pain mimicking lumbar disc herniation or other cyst-like masses including sequestrated disc herniation, facet joint synovial cyst, or perineural cyst. We report a case of a 36-year-old woman presenting with lumbar radicular pain caused by a lumbar epidural varix. Lumbar magnetic resonance imaging (MRI) revealed a cystic lesion in the ventral epidural space posterior to the right L4 body. Surgery was conducted and histopathology confirmed the diagnosis of an epidural varix. Lumbar epidural varices and other lumbar cystic lesions can commonly cause radicular pain. Physicians will benefit from increased awareness of epidural varices as a cause of lumbosacral radicular pain and the associated radiologic findings supporting differential diagnosis. In particular, careful interpretation of MRI scans may help ensure proper diagnosis of an epidural varix versus other cystic lesions. LEVEL OF EVIDENCE: V. PMID- 29705170 TI - An Incidental Periscapular Lipoma With Marked Bone Erosion in an Elderly Woman With Contralateral Shoulder Pain. PMID- 29705171 TI - Prevalence and Risk Factors for Musculoskeletal Pain in Keyboard Musicians: A Systematic Review. AB - OBJECTIVE: To identify the prevalence and risk factors for musculoskeletal pain in keyboard musicians. DESIGN: Systematic review METHODS: A systematic review was conducted according to the MOOSE recommendations and it was registered with the PROSPERO database under registration number CRD42016042913. We included observational studies through the electronic databases PubMed, Scopus, ScienceDirect, Web of Science, Repertoire International de Litterature Musicale (RILM), Retrospective Index to Music Periodicals (RIPM), Scielo, and Google Scholar, with combinations of the keywords pianists, keyboard players, musculoskeletal pain, muscular disease, tendinitis, tendinopathy, observational, case-control, prevalence, and risk factors. Data from population, information about pain, and risk factors were extracted from studies that fulfilled the eligibility criteria. The methodological quality of the studies was classified through the Newcastle-Ottawa Scale. The risk of bias and quality of evidence was assessed using the GRADE system. RESULTS: Twelve articles (case-controls) were included for the qualitative synthesis. The quality of the studies was classified as fair (n = 6) and good (n = 6). Prevalence was observed between 25.8% and 77.0% of musculoskeletal pain among keyboard musicians, with a higher prevalence in wrists and hands (13.8%-65.8%), neck (9.8%-64.2%), and shoulders (9.8%-59.8%). The only consistent risk factor found in the 4 studies was being female, with OR ranging from 1.05-1.90. Age greater than 18 years; weekly training more than 20 hours; training for more than 60 minutes without a rest break; not having a habit of practicing sports; and playing despite the pain were also described as risks factors for musculoskeletal pain. It was not possible to perform the meta analysis due to the heterogeneity of the studies. CONCLUSION: Keyboard musicians presented a high prevalence of musculoskeletal pain, especially in the upper extremity regions of the body. Female, ageing, playing behaviors, and sedentary lifestyle showed an increased likelihood to report musculoskeletal pain. LEVEL OF EVIDENCE: II. PMID- 29705172 TI - The Effect of Arch Drop on Tibial Rotation and Tibiofemoral Contact Stress in Postpartum Women. AB - BACKGROUND: Women are at greater risk for knee osteoarthritis and numerous other lower limb musculoskeletal disorders. Arch drop during pregnancy and the resultant excessive pronation of the feet may alter loading patterns and contribute to the greater prevalence of knee osteoarthritis in women. OBJECTIVE: To determine the effect of arch drop on tibial rotation and tibiofemoral contact stress. DESIGN: Interventional study with internal control. SETTING: Biomechanics laboratory. PARTICIPANTS: Eleven postpartum women (age 33.4 +/- 5.3 years, body mass 76.1 +/- 13.5 kg) who had lost arch height with pregnancy in a previous study. METHODS: Subjects underwent standing computed tomography (SCT) with their knees in a 20 degrees fixed-flexed position with and without semirigid arch supports to reconstitute prepregnancy arch height. Magnetic resonance imaging of the knee was acquired at a flexion angle equivalent to that of SCT. Bone and cartilage were manually segmented on the magnetic resonance images and segmented surfaces were registered to the 3-dimensional SCT image sets for the arch supported and -unsupported conditions. These models were used to measure changes in tibial rotation, as well as to estimate contact stress in the medial and lateral tibiofemoral compartments, using computational methods. MAIN OUTCOME MEASURES: Change in tibial rotation and tibiofemoral contact stress with arch drop. RESULTS: Arch drop resulted in a mean tibial internal rotation of 0.75 +/- 1.33 degrees (P = .02). Changes in mean or peak contact stress were not detected. CONCLUSIONS: Arch drop causes internal tibial rotation, resulting in a shift in the tibiofemoral articulation. An associated increase in contact stress was not detected. Internal rotation of the tibia increases stress on the anterior cruciate ligament and menisci, potentially explaining the greater prevalence of knee disorders in postpartum women. LEVEL OF EVIDENCE: NA. PMID- 29705173 TI - Ultrasonographic prenatal imaging of fetal ocular and orbital abnormalities. AB - Technological progress in medicine has provided earlier diagnosis, even into the prenatal period. We address ultrasonographic imaging of the prenatal eye and orbit. During development of these structures, multiple pathologies and diseases can arise. Orbital anomalies can be detected prenatally using ultrasound or magnetic resonance imaging. Some of these include congenital cataracts, hypertelorism, hypotelorism, dacryocystocele, microphthalmia, anophthalmia, orbital tumors/masses, and septo-optic dysplasia. We describe characteristic ultrasound findings of these diseases. Prenatal ocular and orbital diagnosis is best facilitated by a team approach between ophthalmology, radiology, obstetrics, neonatology, and genetic counselors to optimize diagnostic accuracy, familial expectations, and early treatment. PMID- 29705174 TI - A sticky situation. AB - An 81-year-old man with bilateral progressively blurry vision and optic disc swelling was referred for evaluation. Examination and ancillary testing confirmed a diagnosis of bilateral vitreopapillary traction accompanied by unilateral tractional retinoschisis in the right eye. Pars plana vitrectomy was performed to release the traction in both the eyes. Visual acuity improved in the right eye and stabilized in the left eye. Retinoschisis in the right eye resolved. The visual field improved in both the eyes although the left eye demonstrated a persistent hemifield defect likely attributable to a prior optic neuropathy. Distinguishing vitreopapillary traction optic neuropathy from nonarteritic anterior ischemic optic neuropathy is discussed. PMID- 29705175 TI - Ischemic retinal vein occlusion: characterizing the more severe spectrum of retinal vein occlusion. AB - Retinal vein occlusion (RVO)-including central RVO, branch RVO, and hemicentral and hemispheric RVO-is the second most common vascular cause of visual loss, surpassed only by diabetic retinopathy. The presence and extent of retinal ischemia in RVO is associated with a worse prognosis. On this basis, most previously conducted studies considered ischemic retinal vein occlusion (iRVO) and non-iRVO as separate entities based on set thresholds of existing retinal ischemia as determined by fundus fluorescein angiography. Other diagnostic technologies have been used specifically in the differentiation of ischemic central retinal vein occlusion and nonischemic central retinal vein occlusion. To date, there is no fully accepted definition for iRVO. Some clinicians and researchers may favor establishing a clear differentiation between these forms of RVO; others may prefer not to consider iRVO as a separate entity. Whatever the case, retinal ischemia in RVO confers a higher risk of visual loss and neovascular complications; thus, it should be determined as accurately as possible in patients with this disease and be considered in clinical and experimental studies. Most recently conducted clinical trials evaluating new treatments for macular edema secondary to RVO included none or only few patients with iRVO based on previous definitions (i.e., few patients with sizeable areas of retinal ischemia were recruited in these trials), and thus it is unclear whether the results observed in recruited patients could be extrapolated to those with retinal ischemia. There has been scant research aiming at developing and/or testing treatments for retinal ischemia, as well as to prevent new vessel formation as a result of RVO. We provide a detailed review of the knowledge gathered over the years on iRVO, from controversies on its definition and diagnosis to the understanding of its epidemiology, risk factors and pathogenesis, the structural and functional effects of this disease in the eye and its complications, natural history, and outcomes after treatment. In each section, the definition of iRVO used is given so, independently of whether iRVO is considered a separate clinical entity or a more severe end of the spectrum of RVO, the information will be useful to clinicians to determine patient's risk, guide therapeutic decisions, and counsel patients and for researchers to design future studies. PMID- 29705176 TI - Natural history of scoliosis in cerebral palsy and risk factors for progression of scoliosis. AB - BACKGROUND: Scoliosis in cerebral palsy (CP) often occurs and causes a disturbance in daily life. The purpose of this study was to investigate the natural history of scoliosis in cerebral palsy and determine risk factors for the progression of scoliosis using multivariate analyses. METHODS: We revised 113 patients with CP (47 males and 66 females) who had scoliosis with a curve of at least 10 degrees were reviewed and retrospectively investigated these cases of scoliosis and analyzed the risk factors for the progression of this condition. RESULTS: The mean follow-up period was 16.5 years and the mean age at onset of scoliosis was 6.6 years (range: 1-16 years). In 59 patients (52%), the age at onset of scoliosis was under 6 years. On the final radiographs, the mean Cobb angle was 55.1 degrees (range: 10 degrees to 169 degrees ). After the age of 20 years, 13 of 40 patients (32.5%) had a progression of over 10 degrees in scoliosis. Multivariate analyses showed the risk factors for the progression of scoliosis to be hip displacement (p = 0.0038), the onset of scoliosis before the age of 6 years (p = 0.0024), and 30 degrees of the Cobb angle before the age of 10 years (p < 0.001). A subtype of CP (spastic quadriplegia) was identified as a potential risk factor. CONCLUSIONS: After the age of 20 years, 32.5% patients had a progression of over 10 degrees in scoliosis. Risk factors for the progression of scoliosis in CP included hip displacement, early-onset scoliosis, and Cobb angle of 30 degrees before the age of 10 years. LEVEL OF EVIDENCE: Prognostic level IV - case series. PMID- 29705177 TI - The impact of exercise and vitamin D supplementation on physical function in community-dwelling elderly individuals: A randomized trial. AB - BACKGROUND: We investigated the impact of exercise and vitamin D supplementation on physical function and locomotor dysfunction in community-dwelling elderly individuals. METHODS: In total, 148 community-dwelling elderly individuals (aged >=60 years) who were not taking osteoporosis medications participated in a 24 week intervention. The participants were randomly divided into an exercise group, vitamin D group, and exercise and vitamin D group. The participants and outcome assessing staff were not blinded to group assignment. Exercise comprised three daily sets each of single-leg standing (1 min/leg/set) and squatting (5-6 repetitions/set); vitamin D supplementation was 1000 IU/day. Participants were contacted every 2 weeks to check on their condition and encourage continued participation. The primary outcome was lower limb muscle strength and mass; secondary outcomes were several physical function measurements, serum 25 hydroxyvitamin D levels, and results of a self-assessment questionnaire completed pre- and post-intervention. RESULTS: We analyzed data from 45, 42, and 43 participants in the exercise, vitamin D, and exercise and vitamin D groups, respectively, who completed the intervention. Locomotive syndrome, which involves reduced mobility due to locomotive organ impairment, was diagnosed in 99 participants (76.2%). Many physical function measurements improved in all groups. Lower limb muscle mass increased significantly in all three groups, with no significant differences between the groups in the degree of change. The average serum 25-hydroxyvitamin D of all vitamin D-supplemented participants increased from 28.1 ng/ml to 47.3 ng/ml after vitamin D supplementation. CONCLUSIONS: Both exercise and vitamin D supplementation independently improved physical function and increased muscle mass in community-dwelling elderly individuals. Moreover, the combination of exercise and vitamin D supplementation might further enhance these positive effects. CLINICAL TRIAL REGISTRY: UMIN Clinical Trial, UMIN000028229. PMID- 29705178 TI - Three-dimensional model based navigation-assisted bone recontouring of the distal end of the humerus: A case report. PMID- 29705179 TI - Redesigning primary care with health coaches: An interview with Iora Health CEO Rushika Fernandopulle. PMID- 29705180 TI - [Activity of Erwinia-asparaginase after anaphylactic reaction to Peg asparaginase]. PMID- 29705181 TI - [Natural progression of premature pubarche and underlying diseases]. AB - INTRODUCTION: Premature pubarche (PP) is generally thought to be a benign condition, but it can also be the first sign of underlying disease. OBJECTIVE: To analyse the aetiology and the evolution of the anthropometric, analytical and metabolic risk parameters of a group of patients with PP. MATERIAL AND METHODS: A descriptive and analytical retrospective study of 92 patients affected by PP. Anthropometry, analyses, bone age and indicators of lipid metabolism were all evaluated. RESULTS: The sample included 92 patients with PP (67 female and 25 male), with a mean age of 7.1+/-0.6 for girls and 8.3+/-0.7 for boys. Small for gestational age was recorded in 7.7%. There was an accelerated bone age (1.20+/ 0.1 years). A total of 21 patients were classified as idiopathic (23%), 60 as idiopathic premature adrenarche (65%), and 11 with non-classic congenital adrenal hyperplasia (12%). Puberty was reached early (11+0.9 years old in boys and 9.9+/ 0.8 in girls), as was menstruation age (11.8+1.1 years old), P<.001. The stature finally reached was close to their genetic stature. There is a positive correlation between body mass index, blood glucose and LDL cholesterol, as well as a tendency towards hyperinsulinaemia. CONCLUSIONS: The present study shows that PP is a benign condition in the majority of cases, but non-classic congenital adrenal hyperplasia (12%) is not uncommon. Menstruation and puberty started early and bone age was accelerated. Growth was normal, and more or less in line with genetic size. PP associated with obesity is linked with analytical variations of metabolic risks. PMID- 29705182 TI - Inhibition of NF-kappaB results in anti-glioma activity and reduces temozolomide induced chemoresistance by down-regulating MGMT gene expression. AB - The introduction of temozolomide (TMZ) has improved chemotherapy for malignant gliomas. However, many gliomas are refractory to TMZ, so there is a pressing need for more effective therapeutic options. Here we demonstrated that glioma specimens and cell lines have constitutively high levels of nuclear factor kappaB (NF-kappaB) activity. Notably, the expression levels of this transcription factor correlated with malignant grades in glioblastoma multiforme (GBM) and inversely correlated with overall survival. Conversely, knockdown of NF-kappaB inhibits glioma cell proliferation and treating a panel of established glioma cell lines with pharmacological NF-kappaB inhibitors markedly decreased glioma viability, led to S cell cycle arrest, and induced apoptosis. We also found a significant correlation between NF-kappaB expression and O6-methylguanine-DNA methyltransferase (MGMT) expression in gliomas with different origins, and immunohistochemistry confirmed these findings. Genetic or pharmacological (especially parthenolide) inhibition of NF-kappaB activity down-regulated MGMT gene expression and substantially restored TMZ chemosensitivity in vitro and in vivo. Importantly, the TMZ sensitizing effect of siNF-kappaB(p65) or parthenolide were rescued by MGMT cDNA expression. These findings suggest that NF-kappaB is a potential target for inducing cell death in gliomas. A targeted combination strategy in which the response to TMZ is synergistically enhanced by the addition of parthenolide which may be useful, especially in chemoresistant gliomas with high MGMT expression. PMID- 29705183 TI - Equipment-free recombinase polymerase amplification assay using body heat for visual and rapid point-of-need detection of canine parvovirus 2. AB - A visible and equipment-free recombinase polymerase amplification assay combined with a lateral flow strip (LFS RPA) was developed to detect canine parvovirus type 2 (CPV-2), which is the etiological agent of canine parvovirus disease. The CPV-2 LFS RPA assay was developed based on the VP2 gene and is performed in a closed fist using body heat for 15 min; the products are visible to the naked eye on the LFS within 5 min. The assay could detect CPV-2a, CPV-2b and CPV-2c, and there was no cross-reaction with the other viruses tested. Using the standard CPV 2 DNA as a template, the analytical sensitivity was 1.0 * 102 copies per reaction, which was the same result as that of a real-time PCR. The assay performance was further evaluated by testing 60 canine fecal samples, and CPV-2 DNA was detected in 46 samples (76.7%, 46/60) by LFS RPA, which was the same result as that of the real-time PCR assay and higher than that of the SNAP method (48.3%, 29/60). The novel CPV-2 LFS RPA assay is an attractive and promising tool for rapid and convenient diagnosis of CPV disease, especially cage side and in underequipped laboratories. PMID- 29705184 TI - Homogeneous vs. patient specific breast models for Monte Carlo evaluation of mean glandular dose in mammography. AB - PURPOSE: To compare, via Monte Carlo simulations, homogeneous and non-homogenous breast models adopted for mean glandular dose (MGD) estimates in mammography vs. patient specific digital breast phantoms. METHODS: We developed a GEANT4 Monte Carlo code simulating four homogenous cylindrical breast models featured as follows: (1) semi-cylindrical section enveloped in a 5-mm adipose layer; (2) semi elliptical section with a 4-mm thick skin; (3) semi-cylindrical section with a 1.45-mm skin layer; (4) semi-cylindrical section in a 1.45-mm skin layer and 2-mm subcutaneous adipose layer. Twenty patient specific digital breast phantoms produced from a dedicated CT scanner were assumed as reference in the comparison. We simulated two spectra produced from two anode/filter combinations. An additional digital breast phantom was produced via BreastSimulator software. RESULTS: With reference to the results for patient-specific breast phantoms and for W/Al spectra, models #1 and #3 showed higher MGD values by about 1% (ranges [ 33%; +28%] and [-31%; +30%], respectively), while for model #4 it was 2% lower (range [-34%; +26%]) and for model #2 -11% (range [-39%; +14%]), on average. On the other hand, for W/Rh spectra, models #1 and #4 showed lower MGD values by 2% and 1%, while for model #2 and #3 it was 14% and 8% lower, respectively (ranges [ 43%; +13%] and [-41%; +21%]). The simulation with the digital breast phantom produced with BreastSimulator showed a MGD overestimation of +33%. CONCLUSIONS: The homogeneous breast models led to maximum MGD underestimation and overestimation of 43% and 28%, respectively, when compared to patient specific breast phantoms derived from clinical CT scans. PMID- 29705185 TI - Plasma alpha-synuclein and cognitive impairment in the Parkinson's Associated Risk Syndrome: A pilot study. AB - Plasma total and nervous system derived exosomal (NDE) alpha-synuclein have been determined as potential biomarkers of Parkinson's disease (PD). To explore the utility of plasma alpha-synuclein in the prodromal phase of PD, plasma total and NDE alpha-synuclein were evaluated in baseline and 2-year follow-up samples from 256 individuals recruited as part of the Parkinson's Associated Risk Syndrome (PARS) study. The results demonstrated that baseline and longitudinal increases in total alpha-synuclein predicted progression of cognitive decline in hyposmic individuals with dopamine transporter (DAT) binding reduction. On the other hand, a longitudinal decrease in NDE alpha-synuclein predicted worsening cognitive scores in hyposmic individuals with DAT binding reduction. Finally, in individuals with faster DAT progression, decreasing NDE/total alpha-synuclein ratio was associated with a larger reduction in DAT from baseline to follow-up. These results suggest that, though underlying mechanisms remain to be defined, alterations in plasma total and NDE alpha-synuclein concentrations are likely associated with PD progression, especially in the aspect of cognitive impairment, at early stages of the disease. PMID- 29705187 TI - Seizure-induced reduction in glucose utilization promotes brain hypometabolism during epileptogenesis. AB - Brain glucose hypometabolism is an early symptom of acquired epilepsy, its causative mechanism yet unclear. We suggest that a bidirectional positive feedback linking seizures and hypometabolism (hypometabolism induces seizures while seizures disrupt glucose metabolism) may be a primary cause for acquired epileptogenesis. We reported recently that chronic partial inhibition of brain glycolysis triggers epileptogenesis in healthy rats. Here, by monitoring dynamic electrical and multiple metabolic parameters before and following seizure generation in mouse hippocampal slices using the 4-aminopyridine model of epileptiform activity, we show that in turn seizures are followed by a long lasting glucose hypometabolism, indicating possible existence of a positive feedback in the mechanism of epileptogenesis. Seizures were associated with acute oxidative stress that may contribute to the subsequent glucose metabolism impairment, since exogenous application of H2O2 replicated the post-seizure metabolic effects. Exogenous pyruvate, the principal mitochondrial energy substrate with a broad spectrum of neuroprotective properties, effectively normalized the post-seizure glucose consumption. We have shown recently that pyruvate exhibited a strong antiepileptic action in three rodent chronic epilepsy models, while in the present study we find that pyruvate effectively normalizes impaired glucose metabolism following seizures. Together, our results provide the mechanistic basis for the metabolic concept of acquired epileptogenesis and an efficient treatment strategy. PMID- 29705186 TI - Fibronectin EDA forms the chronic fibrotic scar after contusive spinal cord injury. AB - Gliosis and fibrosis after spinal cord injury (SCI) lead to formation of a scar that is an impediment to axonal regeneration. Fibrotic scarring is characterized by the accumulation of fibronectin, collagen, and fibroblasts at the lesion site. The mechanisms regulating fibrotic scarring after SCI and its effects on axonal elongation and functional recovery are not well understood. In this study, we examined the effects of eliminating an isoform of fibronectin containing the Extra Domain A domain (FnEDA) on both fibrosis and on functional recovery after contusion SCI using male and female FnEDA-null mice. Eliminating FnEDA did not reduce the acute fibrotic response but markedly diminished chronic fibrotic scarring after SCI. Glial scarring was unchanged after SCI in FnEDA-null mice. We found that FnEDA was important for the long-term stability of the assembled fibronectin matrix during both the subacute and chronic phases of SCI. Motor functional recovery was significantly improved, and there were increased numbers of axons in the lesion site compared to wildtype mice, suggesting that the chronic fibrotic response is detrimental to recovery. Our data provide insight into the mechanisms of fibrosis after SCI and suggest that disruption of fibronectin matrix stability by targeting FnEDA represents a potential therapeutic strategy for promoting recovery after SCI. PMID- 29705188 TI - Pregnancy after bariatric surgery: risks and benefits. PMID- 29705189 TI - Did the maternal pulse mask the fetal heart rate of acidemic infants with no explanatory features? PMID- 29705190 TI - Reply. PMID- 29705191 TI - Mild fetal ventriculomegaly: diagnosis, evaluation, and management. AB - Ventriculomegaly is defined as dilation of the fetal cerebral ventricles and is a relatively common finding on prenatal ultrasound. The purpose of this document is to review the diagnosis, evaluation, and management of mild fetal ventriculomegaly. When enlargement of the lateral ventricles (>=10 mm) is identified, a thorough evaluation should be performed, including detailed sonographic evaluation of fetal anatomy, amniocentesis for karyotype and chromosomal microarray analysis, and a workup for fetal infection. In some cases, fetal magnetic resonance imaging may identify other central nervous system abnormalities and should be considered when this technology as well as expert interpretation is available. Follow-up ultrasound examination should be performed to assess for progression of the ventricular dilation. In the setting of isolated ventriculomegaly of 10-12 mm, the likelihood of survival with normal neurodevelopment is >90%. With moderate ventriculomegaly (13-15 mm), the likelihood of normal neurodevelopment is 75-93%. The following are Society for Maternal-Fetal Medicine recommendations: We suggest that ventriculomegaly be characterized as mild (10-12 mm), moderate (13-15 mm), or severe (>15 mm) for the purposes of patient counseling, given that the chance of an adverse outcome and potential for other abnormalities are higher when the ventricles measure 13-15 mm vs 10-12 mm (GRADE 2B); we recommend that diagnostic testing (amniocentesis) with chromosomal microarray analysis should be offered when ventriculomegaly is detected (GRADE 1B); we recommend testing for cytomegalovirus and toxoplasmosis when ventriculomegaly is detected, regardless of known exposure or symptoms (GRADE 1B); we suggest that magnetic resonance imaging be considered in cases of mild or moderate fetal ventriculomegaly when this modality and expert radiologic interpretation are available; magnetic resonance imaging is likely to be of less value if the patient has had a detailed ultrasound performed by an individual with specific experience and expertise in sonographic imaging of the fetal brain (GRADE 2B); we recommend that timing and mode of delivery be based on standard obstetric indications (GRADE 1C); we recommend that with isolated mild ventriculomegaly of 10-12 mm, after a complete evaluation, women be counseled that the outcome is favorable, and the infant is likely to be normal (GRADE 1B); we recommend that with isolated moderate ventriculomegaly of 13-15 mm, after a complete evaluation, women be counseled that the outcome is likely to be favorable but that there is an increased risk of neurodevelopmental disabilities (GRADE 1B). PMID- 29705192 TI - Needs assessment survey of obstetrics and gynecology subspecialty fellowship program directors. PMID- 29705193 TI - Reply. PMID- 29705194 TI - Apparently conflicting meta-analyses on prophylactic negative pressure wound therapy after cesarean delivery. PMID- 29705195 TI - Two Lys-vasopressin-like peptides, EFLamide, and other phasmid neuropeptides. AB - Phasmid neuropeptide genes were identified in the genomes of two phasmids, Timema cristinae and Clitarchus hookeri. The two species belong to two sisters groups, the Timematodea and Euphasmatodea respectively. Neuropeptide genes were identified using the BLAST+ program on the genome assemblies and the absence of some neuropeptides was confirmed by the concomitant absence of their G-protein coupled receptors. Both genomes were assembled using short reads and the average coverage of the genome is more than 166 times for both species. This makes it virtually impossible that there would not be a single short read for at least one of the conserved transmembrane regions of a GPCR coded by such a genome. Hence, when not a single read can be found for a specific GPCR, it can be concluded that the particular gene is absent from that species. Most previously identified insect neuropeptides are used by these two species. Of the three arthropod allatostatin C related peptides, only allatostatins CC and CCC are present. Both species lack leucokinin, while sulfakinin and dilp8 signaling is absent from Clitarchus, but present in Timema. Interestingly, whereas Timema has lost a vasopressin-related peptide, the gene coding such a peptide is amplified in the Clitarchus genome. Furthermore, while Clitarchus has a specific tryptopyrokinin gene, Timema does not and in this species tryptopyrokinin is coded only by the pyrokinin and periviscerokinin genes. Finally, both species have genes coding EFLamide and its GPCR; in phasmids these genes codes for one (Clitarchus) or two (Timema) EFLamide paracopies. PMID- 29705196 TI - Automatic address validation and health record review to identify homeless Social Security disability applicants. AB - OBJECTIVE: Homeless patients face a variety of obstacles in pursuit of basic social services. Acknowledging this, the Social Security Administration directs employees to prioritize homeless patients and handle their disability claims with special care. However, under existing manual processes for identification of homelessness, many homeless patients never receive the special service to which they are entitled. In this paper, we explore address validation and automatic annotation of electronic health records to improve identification of homeless patients. MATERIALS AND METHODS: We developed a sample of claims containing medical records at the moment of arrival in a single office. Using address validation software, we reconciled patient addresses with public directories of homeless shelters, veterans' hospitals and clinics, and correctional facilities. Other tools annotated electronic health records. We trained random forests to identify homeless patients and validated each model with 10-fold cross validation. RESULTS: For our finished model, the area under the receiver operating characteristic curve was 0.942. The random forest improved sensitivity from 0.067 to 0.879 but decreased positive predictive value to 0.382. DISCUSSION: Presumed false positive classifications bore many characteristics of homelessness. Organizations could use these methods to prompt early collection of information necessary to avoid labor-intensive attempts to reestablish contact with homeless individuals. Annually, such methods could benefit tens of thousands of patients who are homeless, destitute, and in urgent need of assistance. CONCLUSION: We were able to identify many more homeless patients through a combination of automatic address validation and natural language processing of unstructured electronic health records. PMID- 29705197 TI - Label-indicator morpheme growth on LSTM for Chinese healthcare question department classification. AB - BACKGROUND: Current Chinese medicine has an urgent demand for convenient medical services. When facing a large number of patients, understanding patients' questions automatically and precisely is useful. Different from the high professional medical text, patients' questions contain only a small amount of descriptions regarding the symptoms, and the questions are slightly professional and colloquial. OBJECT: The aim of this paper is to implement a department classification system for patient questions. Patients' questions will be classified into 11 departments, such as surgery and others. METHODS: This paper presents a morpheme growth model that enhances the memories of key elements in questions, and later extracts the "label-indicators" and germinates the expansion vectors around them. Finally, the model inputs the expansion vectors into a neural network to assign department labels for patients' questions. RESULTS: All compared methods are validated by experiments on three datasets that are composed of real patient questions. The proposed method has some ability to improve the performance of the classification. CONCLUSIONS: The proposed method is effective for the departments classification of patients questions and serves as a useful system for the automatic understanding of patient questions. PMID- 29705198 TI - Xenopus laevis oocyte as a model for the study of the cytoskeleton. AB - At the beginning of diplotene, the oocyte of Xenopus laevis is a cell of about 10 20 microns destined to increase 10,000-fold its size when the oocyte becomes filled with yolk platelets and has accumulated a great number of pigment granules in a half of its periphery. Its internal architecture is gradually accomplished during growth because of several factors, especially because of cytoskeletal changes. In the fully-grown oocyte, the cytoskeleton appears to sustain the eccentrically located germinal vesicle through arms radiating from the cortex to the germinal vesicle, a unique organization not to be found in other Amphibians. In this report, we summarized and analysed steps of cytoskeletal proteins and related mRNAs organization and function throughout diplotene stage, highlighting our studies in this animal model. The cytoskeletal proteins appear to exploit their activity with respect to ribosomal 60S subunit maturation and during translation. Most importantly, the polarity of the oocyte is achieved through a sophisticated and highly organized localization of mRNAs and cytoskeletal proteins in one side of the cell. This asymmetry will start the construction of the oocyte polarity that is instrumental for determining the characteristic of this cell, which will become an embryo. Moreover, in the same time membrane composition, conditioned by the underlying cytoskeletal organization, will acquire the prerequisites for sperm binding and fusion. PMID- 29705199 TI - Determination of the Stoichiometry between alpha- and gamma1 Subunits of the BK Channel Using LRET. AB - Two families of accessory proteins, beta and gamma, modulate BK channel gating and pharmacology. Notably, in the absence of internal Ca2+, the gamma1 subunit promotes a large shift of the BK conductance-voltage curve to more negative potentials. However, very little is known about how alpha- and gamma1 subunits interact. In particular, the association stoichiometry between both subunits is unknown. Here, we propose a method to answer this question using lanthanide resonance energy transfer. The method assumes that the kinetics of lanthanide resonance energy transfer-sensitized emission of the donor double-labeled alpha/gamma1 complex is the linear combination of the kinetics of the sensitized emission in single-labeled complexes. We used a lanthanide binding tag engineered either into the alpha- or the gamma1 subunits to bind Tb+3 as the donor. The acceptor (BODIPY) was attached to the BK pore-blocker iberiotoxin. We determined that gamma1 associates with the alpha-subunit with a maximal 1:1 stoichiometry. This method could be applied to determine the stoichiometry of association between proteins within heteromultimeric complexes. PMID- 29705200 TI - Thermal liquid biopsy for monitoring melanoma patients under surveillance during treatment: A pilot study. AB - BACKGROUND: Differential Scanning Calorimetry (DSC) is a technique traditionally used to study thermally induced macromolecular transitions, and it has recently been proposed as a novel approach for diagnosis and monitoring of several diseases. We report a pilot study applying Thermal Liquid Biopsy (TLB, DSC thermograms of plasma samples) as a new clinical approach for diagnostic assessment of melanoma patients. METHODS: Multiparametric analysis of DSC thermograms of patient plasma samples collected during treatment and surveillance (63 samples from 10 patients) were compared with clinical and diagnostic imaging assessment to determine the utility of thermograms for diagnostic assessment in melanoma. Nine of the ten patients were stage 2 or 3 melanoma subjects receiving adjuvant therapy after surgical resection of their melanomas. The other patient had unresectable stage 4 melanoma and was treated with immunotherapy. Two reference groups were used: (A) 36 healthy subjects and (B) 13 samples from 8 melanoma patients who had completed successful surgical management of their disease and were determined by continued clinical assessment to have no evidence of disease. RESULTS: Plasma thermogram analysis applied to melanoma patients generally agrees with clinical evaluation determined by physical assessment or diagnostic imaging (~80% agreement). No false negatives were obtained from DSC thermograms. Importantly, this methodology was able to detect changes in disease status before it was identified clinically. CONCLUSIONS: Thermal Liquid Biopsy could be used in combination with current clinical assessment for the earlier detection of melanoma recurrence and metastasis. GENERAL SIGNIFICANCE: TLB offers advantages over current diagnostic techniques (PET/CT imaging), limited in frequency by radiation burden and expense, in providing a minimally-invasive, low risk, low-cost clinical test for more frequent personalized patient monitoring to assess recurrence and facilitate clinical decision-making. PMID- 29705201 TI - Fungal communities associated with Evernia prunastri, Ramalina fastigiata and Pleurosticta acetabulum: Three epiphytic lichens potentially active against Candida biofilms. AB - Fungal communities associated to three epiphytic lichens active against Candida, were investigated using culture-based methods We hypothetized that associated fungi would contribute to lichens activities. The ability of specific fungi to grow inside or outside lichens was investigated. To detect biogenesis pathways involved in the production of secondary metabolites, genes coding for nonribosomal peptide synthetase (NRPS) and polyketide synthase I (PKS I) were screened by PCR from fungal DNA extracts. Both endo and epilichenic communities were isolated from two fructicose (Evernia prunastri and Ramalina fastigiata) and one foliose (Pleurosticta acetabulum) lichens. A total of 86 endolichenic and 114 epilichenic isolates were obtained, corresponding to 18 and 24 phylogenetic groups respectively suggesting a wide diversity of fungi. The communities and the species richness were distinct between the three lichens which hosted potentially new fungal species. Additionally, the endo- and epilichenic communities differed in their composition: Sordariomycetes were particularly abundant among endolichenic fungi and Dothideomycetes among epilichenic fungi. Only a few fungi colonized both habitats, such as S. fimicola, Cladosporium sp1 and Botrytis cinerea. Interestingly, Nemania serpens (with several genotypes) was the most abundant endolichenic fungus (53% of isolates) and was shared by the three lichens. Finally, 12 out of 36 phylogenetic groups revealed the presence of genes coding for nonribosomal peptide synthetase (NRPs) and polyketide synthase I (PKS I). This study shows that common lichens are reservoirs of diverse fungal communities, which could potentially contribute to global activity of the lichen and, therefore, deserve to be isolated for further chemical studies. PMID- 29705202 TI - Subterranean infestation by Holotrichia parallela larvae is associated with changes in the peanut (Arachis hypogaea L.) rhizosphere microbiome. AB - Rhizosphere microorganisms contribute to the health and development of crops and these beneficial microbes are recruited to the root-zone when plants experience biotic/abiotic stress. The subterranean pests Holotrichia parallela cause severe crop loss in peanut (Arachis hypogaea L.) fields. Hypothesizing that infestation by H. parallela larva may influence the composition of rhizosphere microbial communities, deep sequencing of V3 and V4 hypervariable regions of 16S rRNA gene was used to characterize the rhizosphere bacteria of infested and uninfested peanuts. A total of 2,673,656 reads were generated and an average of 2558 OTUs were obtained for each sample. Comparisons of rhizosphere bacterial community structure of peanuts with those infested by H. parallela larva revealed that the relative abundance of Proteobacteria and Bacteroidetes increased, while that of Actinobacteria decreased in the rhizosphere with infestation. A significant shift in bacterial communities was observed within 24 h after infestation by principal coordinate analysis. For the 332 genera identified in 24 h treatment, infestation of white grubs led to the significant changes of abundance of 67 genera. An increase in the Pseudomonas genus of infested-samples for 24 h was verified by real-time qPCR. Our results indicate H. parallela larvae infestation can quickly leads to the change of peanut rhizosphere microbiome and enrichment of specific bacterial species. But the effects were not persistent. This study provides the insight into the function of rhizosphere microbiome in the interaction between subterranean pests and crops. PMID- 29705203 TI - Biocontrol of Sclerotinia sclerotiorum (Lib.) de Bary on common bean by native lipopeptide-producer Bacillus strains. AB - Bacillus sp. B19, Bacillus sp. P12 and B. amyloliquefaciens B14 were isolated from soils of Salta province, and PGPR properties on the common bean (Phaseolus vulgaris L.) cv. Alubia and antagonistic activity against Sclerotinia sclerotiorum were studied. It was determined that B19 and P12 increased crop germination potential (GP) from the common bean by 14.5% compared to control seeds; these strains also increased root length (10.4 and 15%, respectively) and stem length (20.2 and 30%, respectively) compared to the control; however, as for the B14 strain, no increases in growth parameters were detected. In addition, all the treatments that combined two bacilli: B14 + B19, B14 + P12 and B19 + P12, generated beneficial effects on GP and seedling growth compared to control seeds, but not compared to a single inoculant. B19 and P12 strains synthesized auxins at concentrations of 5.71 and 4.90 mg/mL, respectively, and it was qualitatively determined that they synthesize siderophores. In addition, previous studies have determined that B14 produces auxins in a concentration of 10.10 mg/mL, and qualitatively synthesizes siderophores. The phytosanitary state of the white bean cv. Alubia control seeds revealed bacterial contamination in 87% of all the evaluated seeds and different fungi such as Cladosporium sp., Fusarium sp., and Rhizopus sp. Bean seeds treated with B14, B19 or P12 showed no growth of contaminating bacteria or of pathogenic fungi; in fact, bacilli inoculum development was observed in all seeds. Additionally, B19, P12 and B14 strains inhibited in vitro the development of 9 native S. sclerotiorum strains isolated from the Salta region, with FI ranging between 60 and 100%. The three Bacillus strains synthesized different isoforms of the lipopeptides: surfactin, iturin, and fengycin in the presence of S. sclerotiorum, as determined by MALDI-TOF. In the in vivo trials, when common bean seeds were grown in soils contaminated with S. sclerotiorum, an incidence of 100% was determined when the seeds were not treated with any Bacillus. Seeds treated with the chemical fungicide and sown in S. sclerotiorum-infested soil did not produce seed emergence, while the inoculation of the seeds with B14 + P12, B14 + B19 or B19 + P12 reduced the effect of the pathogen by 46, 43 and 25%, respectively. Disease progression in B14 + P12 and B14 + B19 treatments was significantly lower than in the remaining treatments, with an AUDPC of 873.75 and 1071, respectively. PMID- 29705204 TI - Comparison of genomic islands in cyanobacteria: Evidence of bacteriophage mediated horizontal gene transfer from eukaryotes. AB - A number of examples of putative eukaryote-to-prokaryote horizontal gene transfer (HGT) have been proposed in the past using phylogenetic analysis in support of these claims but none have attempted to map these gene transfers to the presence of genomic islands (GIs) in the host. Two of these cases have been examined in detail, including an ATP sulfurylase (ATPS) gene and a class I fructose bisphosphate aldolase (FBA I) gene that were putatively transferred to cyanobacteria of the genus Prochlorococcus from either green or red algae, respectively. Unlike previous investigations of HGT, parametric methods were initially used to detect genomic islands, then more traditional phylogenomic and phylogenetic methods were used to confirm or deny the HGT status of these genes. The combination of these three methods of analysis- detection of GIs, the determination of genomic neighborhoods, as well as traditional phylogeny, lends strong support to the claim that trans-domain HGT has occurred in only one of these cases and further suggests a new insight into the method of transmission of FBA I, namely that cyanophage-mediated transfer may have been responsible for the HGT event in question. The described methods were then applied to a range of prochlorococcal genomes in order to characterize a candidate for eukaryote-to prokaryote HGT that had not been previously studied by others. Application of the same methodology used to confirm or deny HGT for ATPS and FBA I identified a ?12 fatty acid desaturase (FAD) gene that was likely transferred to Prochlorococcus from either green or red algae. PMID- 29705205 TI - Phenotypic and genotypic characterisation of an unique indigenous hypersaline unicellular cyanobacterium, Euhalothece sp.nov. AB - A novel halotolerant species of cyanobacterium of the order Chroococcales was isolated from hypersaline estuary in Kwa-Zulu Natal, South Africa. A comprehensive polyphasic approach viz., cell morphology, pigment composition and complete genome sequence analysis was conducted to elucidate the taxonomic position of the isolated strain. The blue-green oval to rod-shaped cells were 14 18 MUm in size, and contained a high amount of phycocyanin pigments. The strain was moderate thermotolerant/alkalitolerant halophile with the optimum conditions for growth at 35 degrees C, pH 8.5 and 120 g/l of NaCl. Based on 16S rRNA gene sequence phylogeny, the strain was related to members of the 'Euhalothece' subcluster (99%). The whole genome sequence was determined, and the annotated genes showed a 90% sequence similarity to the gas-vacuolate, spindle-shaped Dactylococcopsis salina PCC 8305. The size of the genome was determined to be 5,113,178 bp and contained 4332 protein-coding genes and 69 RNA genes with a G + C content of 46.7%. Genes encoding osmoregulation, oxidative stress, heat shock, persister cells, and UV-absorbing secondary metabolites, among others, were identified. Based on the phylogenetic analysis of the 16S rRNA gene sequences, physiological data, pigment compositions and genomic data, the strain is considered to represent a novel species of Euhalothece. PMID- 29705207 TI - Retraction notice to Marine actinobacterial metabolites: current status and future perspectives MICRES_168_6(2013)311-322. PMID- 29705206 TI - Tissue age and plant genotype affect the microbiota of apple and pear bark. AB - Plant tissues host complex fungal and bacterial communities, and their composition is determined by host traits such as tissue age, plant genotype and environmental conditions. Despite the importance of bark as a possible reservoir of plant pathogenic microorganisms, little is known about the associated microbial communities. In this work, we evaluated the composition of fungal and bacterial communities in the pear (Abate and Williams cultivars) and apple (Golden Delicious and Gala cultivars) bark of three/four-year-old shoots (old bark) or one-year-old shoots (young bark), using a meta-barcoding approach. The results showed that both fungal and bacterial communities are dominated by genera with ubiquitous attitudes, such as Aureobasidium, Cryptococcus, Deinococcus and Hymenobacter, indicating intense microbial migration to surrounding environments. The shoot age, plant species and plant cultivar influenced the composition of bark fungal and bacterial communities. In particular, bark communities included potential biocontrol agents that could maintain an equilibrium with potential plant pathogens. The abundance of fungal (e.g. Alternaria, Penicillium, Rosellinia, Stemphylium and Taphrina) and bacterial (e.g. Curtobacterium and Pseudomonas) plant pathogens was affected by bark age and host genotype, as well as those of fungal genera (e.g. Arthrinium, Aureobasidium, Rhodotorula, Sporobolomyces) and bacterial genera (e.g. Bacillus, Brevibacillus, Methylobacterium, Sphingomonas and Stenotrophomonas) with possible biocontrol and plant growth promotion properties. PMID- 29705208 TI - Basic experiments in 2H static NMR for the characterization of protein side-chain dynamics. AB - The focus of this review is the basic methodology for applications of static deuteron NMR for studies of dynamics in the side chains of proteins. We review experimental approaches for the measurements of static line shapes and relaxation rates as well as signal enhancement strategies using the multiple echo acquisition scheme. Further, we describe computational strategies for modeling jump and diffusive motions underlying experimental data. Applications are chosen from studies of amyloid fibrils comprising the amyloid-beta protein. PMID- 29705209 TI - High-dimensional NMR methods for intrinsically disordered proteins studies. AB - Intrinsically disordered proteins (IDPs) are getting more and more interest of the scientific community. Nuclear magnetic resonance (NMR) is often a technique of choice for these studies, as it provides atomic-resolution information on structure, dynamics and interactions of IDPs. Nonetheless, NMR spectra of IDPs are typically extraordinary crowded, comparing to those of structured proteins. To overcome this problem, high-dimensional NMR experiments can be used, which allow for a better peak separation. In the present review different aspects of such experiments are discussed, from data acquisition and processing to analysis, focusing on experiments for resonance assignment. PMID- 29705211 TI - Assessment of microbiota:host interactions at the vaginal mucosa interface. AB - There is increasing appreciation of the role that vaginal microbiota play in health and disease throughout a woman's lifespan. This has been driven partly by molecular techniques that enable detailed identification and characterisation of microbial community structures. However, these methods do not enable assessment of the biochemical and immunological interactions between host and vaginal microbiota involved in pathophysiology. This review examines our current knowledge of the relationships that exist between vaginal microbiota and the host at the level of the vaginal mucosal interface. We also consider methodological approaches to microbiomic, immunologic and metabolic profiling that permit assessment of these interactions. Integration of information derived from these platforms brings the potential for biomarker discovery, disease risk stratification and improved understanding of the mechanisms regulating vaginal microbial community dynamics in health and disease. PMID- 29705210 TI - Multiplex confounding factor correction for genomic association mapping with squared sparse linear mixed model. AB - Genome-wide Association Study has presented a promising way to understand the association between human genomes and complex traits. Many simple polymorphic loci have been shown to explain a significant fraction of phenotypic variability. However, challenges remain in the non-triviality of explaining complex traits associated with multifactorial genetic loci, especially considering the confounding factors caused by population structure, family structure, and cryptic relatedness. In this paper, we propose a Squared-LMM (LMM2) model, aiming to jointly correct population and genetic confounding factors. We offer two strategies of utilizing LMM2 for association mapping: 1) It serves as an extension of univariate LMM, which could effectively correct population structure, but consider each SNP in isolation. 2) It is integrated with the multivariate regression model to discover association relationship between complex traits and multifactorial genetic loci. We refer to this second model as sparse Squared-LMM (sLMM2). Further, we extend LMM2/sLMM2 by raising the power of our squared model to the LMMn/sLMMn model. We demonstrate the practical use of our model with synthetic phenotypic variants generated from genetic loci of Arabidopsis Thaliana. The experiment shows that our method achieves a more accurate and significant prediction on the association relationship between traits and loci. We also evaluate our models on collected phenotypes and genotypes with the number of candidate genes that the models could discover. The results suggest the potential and promising usage of our method in genome-wide association studies. PMID- 29705212 TI - Variable selection in heterogeneous datasets: A truncated-rank sparse linear mixed model with applications to genome-wide association studies. AB - A fundamental and important challenge in modern datasets of ever increasing dimensionality is variable selection, which has taken on renewed interest recently due to the growth of biological and medical datasets with complex, non i.i.d. structures. Naively applying classical variable selection methods such as the Lasso to such datasets may lead to a large number of false discoveries. Motivated by genome-wide association studies in genetics, we study the problem of variable selection for datasets arising from multiple subpopulations, when this underlying population structure is unknown to the researcher. We propose a unified framework for sparse variable selection that adaptively corrects for population structure via a low-rank linear mixed model. Most importantly, the proposed method does not require prior knowledge of sample structure in the data and adaptively selects a covariance structure of the correct complexity. Through extensive experiments, we illustrate the effectiveness of this framework over existing methods. Further, we test our method on three different genomic datasets from plants, mice, and human, and discuss the knowledge we discover with our method. PMID- 29705213 TI - Multi-kinetic release of benznidazole-loaded multiparticulate drug delivery systems based on polymethacrylate interpolyelectrolyte complexes. AB - Interpolyelectrolyte complexes (IPEC) formulated as multiparticulate drug delivery systems (MDDS) are interesting carriers to improve drug' performance. Benznidazole (BZ) is the first-line drug for Chagas treatment; however, it presents side effects and toxicity, conditioning its efficacy and safety. The goal of this work was to obtain novel MDDS composed by IPEC based on different polymethacrylate carriers loaded with BZ and to investigate in vitro drug delivery performance for oral administration. Physicochemical characterizations were studied and preclinical studies in a murine model of acute Chagas disease were also performed. The MDDS composed by BZ-loaded IPEC based on polymethacrylates were obtained by casting solvent followed by wet granulation methods with yields >83%. FT-IR demonstrated ionic interaction between the polyelectrolytes. Confocal microscopy, DSC and PXRD revealed a fraction uniformly distributed of free BZ on the multiparticles. The rheological evaluation of the MDDS showed adequate flow features for their formulation in hard gelatin capsules. The type and composition of IPEC conditioned the modulation of BZ release and fluid uptake results. MDDS based on more hydrophylic Eudragit(r) showed very fast dissolution (Q15min > 85%), while an extended release (Q120min <= 40%) for the hydrophobic ones was observed. Capsules containing a combination of two MDDS with different release profile of BZ showed promising properties to improve Chagas disease pharmacotherapy in the preliminary in vivo assay performed, in which the BZ-loaded MDDS exhibited efficacy to reduce parasitemia, while decreasing the levels of liver injury markers in comparison to BZ conventional treatment. Multi-kinetic BZ delivery systems developed are interesting pharmaceutical alternatives to improve the treatment of Chagas disease. PMID- 29705214 TI - Preclinical characterization and clinical evaluation of tacrolimus eye drops. AB - Severe allergic ocular diseases as atopic keratoconjunctivitis can induce corneal damage due to inflammatory substances released from giant papillae. Tacrolimus eye drops are one of the current therapeutic alternatives for its treatment. This work is aimed at developing and characterizing a 0.03% tacrolimus ophthalmic formulation, which was introduced in three types of vehicles (BBS, PVA and Hyaluronic Acid). For this, we have performed in vitro (stability studies) and in vivo assays (corneal permanence time measured directly by Positron Emission Tomography) of three potential formulations. Next, the best formulation was selected, and its toxicological profile and clinical effectiveness have been evaluated. The biopermanence studies (direct measurements and PET/CT) showed that the formulations with PVA and Hyaluronic Acid present more retention time on the ocular surface of rats than PBS. From the stability study, we have determined that tacrolimus with PVA in cold storage is the best option. Tacrolimus with PVA has shown lower cytotoxicity than cyclosporine at early times. On the other hand, the pilot study performed has shown significant improvements in patients, with no noticeable adverse reactions. Based on stability, biopermanence, safety and clinical effectiveness studies, we concluded that tacrolimus-PVA eye drops are a suitable candidate for its clinical application in inflammatory ophthalmology diseases. PMID- 29705215 TI - Relationship between exposure to treosulfan and its monoepoxytransformer - An insight from population pharmacokinetic study in pediatric patients before hematopoietic stem cell transplantation. AB - Treosulfan (TREO), a structural analog of busulfan, is currently studied as a myeloablative agent in conditioning regimens before hematopoietic stem cell transplantation in pediatric patients. High exposure to TREO (>1650 mg*h/mL) might be related to early toxicity, especially skin toxicity and mucositis. The aim of the present study was to investigate a potential relationship between exposure to TREO and its monoepoxytransformer (S,S-EBDM), as well as variability of the pharmacokinetics of these entities by means of a population pharmacokinetic approach with a non-linear mixed-effects analysis. The study included data from 14 children with malignant and non-malignant diseases treated with TREO in daily doses 10-14 g/m2. The parent-metabolite population pharmacokinetic model was developed in NONMEM 7.3 software. Upon the constructed model, an extensive simulation was performed to assess the correlation between exposure to TREO and S,S-EBDM. It was found that TREO and S,S-EBDM pharmacokinetics was best described with 2-compartmental and 1-compartmental linear models, respectively. The vast majority (>65%) of TREO was transformed to S,S-EBDM. Overall, a considerable interpatient variability of pharmacokinetic parameters was observed, especially the clearance of S,S-EBDM. A weak correlation was found between the exposure to TREO and S,S-EBDM (r = 0.1681, p < 0.0001). Also, patients with an exposure to TREO above 1650 mg*h/mL were most likely to have also a high exposure to S,S-EBDM (35.38 MUM*h vs. 43.14 MUM*h, p < 0.0001). In summary, a parent-metabolite population pharmacokinetic model for TREO and S,S EBDM was developed for the first time. It was shown that there is a weak correlation between exposure to TREO and S,S-EBDM. Therefore therapeutic drug monitoring of not only prodrug but also its active epoxide might be needed. PMID- 29705216 TI - Effect of minimally invasive endotracheal tube suctioning on physiological indices in adult intubated patients: An open-labelled randomised controlled trial. AB - BACKGROUND: Endotracheal tube suctioning (ETS) is one of the most frequent procedures performed by nurses in intensive care units. Nevertheless, some suctioning practices are still being performed that do not provide any benefit for patients. OBJECTIVES: To investigate the effects of minimally invasive ETS (MIETS) versus routine ETS (RETS) on physiological indices in adult intubated patients. METHODS: In this single centre parallel randomised controlled, open label trial, 64 adult intubated patients in the four intensive care units of Alzahra University hospital, Isfahan, Iran, were randomly allocated to a MIETS or a RETS group. Physiological indices including systolic blood pressure, diastolic blood pressure, mean arterial pressure, heart rate, and peripheral oxygen saturation were assessed immediately before, immediately after, and 10 min after ETS in both groups. The chi-square test, independent t-test, and repeated measures analysis of variance were used to analyse the data. RESULTS: Sixty-four patients were randomised and analysed. There were no significant differences in mean heart rate between the both groups across the three time points. However, there was a significant drop in peripheral oxygen saturation across the three time points in the RETS group compared to the MIETS group. Furthermore, there was a significant increase in systolic blood pressure, diastolic blood pressure, and mean arterial pressure across the three time points in the RETS group compared to the MIETS group. CONCLUSION: The results of this study indicate that the use of MIETS has less effect on the alterations of physiological indices and consequently fewer adverse effects than RETS. PMID- 29705217 TI - Lower Glucose Target Is Associated With Improved 30-Day Mortality in Cardiac and Cardiothoracic Patients. AB - BACKGROUND: Practice guidelines recommend against intensive insulin therapy in patients who are critically ill based on trials that had high rates of severe hypoglycemia. Intermountain Healthcare uses a computerized IV insulin protocol that allows choice of blood glucose (BG) targets (80-110 vs 90-140 mg/dL) and has low rates of severe hypoglycemia. We sought to study the effects of BG target on mortality in adult patients in cardiac ICUs that have very low rates of severe hypoglycemia. METHODS: Critically ill patients receiving IV insulin were treated with either of two BG targets (80-110 vs 90-140 mg/dL). We created a propensity score for BG target using factors thought to have influenced clinicians' choice, and then we performed a propensity score-adjusted regression analysis for 30-day mortality. RESULTS: There were 1,809 patients who met inclusion criteria. Baseline patient characteristics were similar. Median glucose was lower in the 80 110 mg/dL group (104 vs 122 mg/dL, P < .001). Severe hypoglycemia occurred at very low rates in both groups (1.16% vs 0.35%, P = .051). Unadjusted 30-day mortality was lower in the 80-110 mg/dL group (4.3% vs 9.2%, P < .001). This remained after propensity score-adjusted regression (OR, 0.65; 95% CI, 0.43-0.98; P = .04). CONCLUSIONS: Tight glucose control can be achieved with low rates of severe hypoglycemia and is associated with decreased 30-day mortality in a cohort of largely patients in cardiac ICUs. Although such findings should not be used to guide clinical practice at present, the use of tight glucose control should be reexamined using a protocol that has low rates of severe hypoglycemia. PMID- 29705218 TI - Acute Tetrahydrobiopterin Improves Endothelial Function in Patients With COPD. AB - BACKGROUND: Cardiovascular diseases represent a hallmark characteristic in COPD, and endothelial dysfunction has been observed in these patients. Tetrahydrobiopterin (BH4) is an essential cofactor for nitric oxide (NO) synthesis and a regulator of endothelial function. The goal of this study was to test the hypothesis that a single dose of BH4 would improve endothelial function in patients with COPD via an increase in NO bioavailability. METHODS: Seventeen patients with COPD completed a randomized, double-blind, placebo (PLC) controlled, crossover trial with an acute dose of either BH4 (Kuvan; BioMarin Pharmaceutical Inc) or PLC. Flow-mediated dilation (FMD), a bioassay of endothelial function, was completed prior to and 3 h following each treatment. Phospho- and total endothelial NO synthase (NOS3) protein was evaluated after incubating endothelial cells with plasma from the patients prior to and following treatment. Fifteen demographically matched control subjects were tested at baseline for case control comparisons. RESULTS: Treatment with BH4 significantly (P <= .004) increased FMD, improving endothelial function in patients compared to control values (P >= .327). BH4 increased (P = .013) the ratio of phospho-NOS3 to total NOS3 protein. No changes in FMD (P >= .776) or the protein ratio (P = .536) were observed following PLC. CONCLUSIONS: An acute dose of BH4 was able to improve endothelial function in patients with COPD to values similar to control subjects. The improvement in endothelial function was accompanied by an increase in NOS3 phosphorylation. BH4 may represent a potential novel therapy to improve endothelial function and reduce cardiovascular disease risk in patients with COPD. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01398943; URL: www.clinicaltrials.gov. PMID- 29705220 TI - Psychometric Validation of the Pulmonary Arterial Hypertension-Symptoms and Impact (PAH-SYMPACT) Questionnaire: Results of the SYMPHONY Trial. AB - BACKGROUND: Disease-specific patient-reported outcome (PRO) instruments are important in assessing the impact of disease and treatment. The Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire is the first instrument for quantifying pulmonary arterial hypertension (PAH) symptoms and impacts developed according to the 2009 US Food and Drug Administration PRO guidance; previous qualitative research in patients with PAH supported its initial content validity. METHODS: Content finalization and psychometric validation were conducted by using data from A Study of Macitentan in Pulmonary Arterial Hypertension to Validate the PAH-SYMPACT (SYMPHONY), a single-arm, 16-week trial with macitentan 10 mg in US patients with PAH. Item performance, Rasch analysis, and factor analyses were used to select the final item content of the PRO and to define its domain structure. Internal consistency, test-retest reliability, known group and construct validity, sensitivity to change, and influence of oxygen on item performance were evaluated. RESULTS: Data from 278 patients (79% female; mean age: 60 years) were analyzed. Following removal of redundant/misfitting items, the final questionnaire has 11 symptom items across two domains (cardiopulmonary and cardiovascular symptoms) and 11 impact items across two domains (physical and cognitive/emotional impacts). Differential item function analysis confirmed that PRO scoring is unaffected by oxygen use. For all four domains, internal consistency reliability was high (Cronbach's alpha > 0.80), and scores were highly reproducible in stable patients (intraclass correlation coefficient: 0.84-0.94). Correlations with the Cambridge Pulmonary Hypertension Outcome Review questionnaire and the 36-item Medical Outcomes Study Short Form Survey were moderate to high ([r] = 0.34-0.80). The questionnaire differentiated well between patients with varying disease severity levels and was sensitive to improvements in clinician- and patient-reported disease severity. CONCLUSIONS: The Pulmonary Arterial Hypertension-Symptoms and Impact Questionnaire is a brief, disease-specific PRO instrument possessing good psychometric properties that can be administered in clinical practice and clinical studies. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01841762; URL: www.clinicaltrials.gov. PMID- 29705219 TI - Multicentric Standardized Flow Cytometry Routine Assessment of Patients With Sepsis to Predict Clinical Worsening. AB - BACKGROUND: In this study, we primarily sought to assess the ability of flow cytometry to predict early clinical deterioration and overall survival in patients with sepsis admitted in the ED and ICU. METHODS: Patients admitted for community-acquired acute sepsis from 11 hospital centers were eligible. Early (day 7) and late (day 28) deaths were notified. Levels of CD64pos granulocytes, CD16pos monocytes, CD16dim immature granulocytes (IGs), and T and B lymphocytes were assessed by flow cytometry using an identical, cross-validated, robust, and simple consensus standardized protocol in each center. RESULTS: Among 1,062 patients screened, 781 patients with confirmed sepsis were studied (age, 67 +/- 48 years; Simplified Acute Physiology Score II, 36 +/- 17; Sequential Organ Failure Assessment, 5 +/- 4). Patients were divided into three groups (sepsis, severe sepsis, and septic shock) on day 0 and on day 2. On day 0, patients with sepsis exhibited increased levels of CD64pos granulocytes, CD16pos monocytes, and IGs with T-cell lymphopenia. Clinical severity was associated with higher percentages of IGs and deeper T-cell lymphopenia. IG percentages tended to be higher in patients whose clinical status worsened on day 2 (35.1 +/- 35.6 vs 43.5 +/- 35.2, P = .07). Increased IG percentages were also related to occurrence of new organ failures on day 2. Increased IG percentages, especially when associated with T-cell lymphopenia, were independently associated with early (P < .01) and late (P < .01) death. CONCLUSIONS: Increased circulating IGs at the acute phase of sepsis are linked to clinical worsening, especially when associated with T cell lymphopenia. Early flow cytometry could help clinicians to target patients at high risk of clinical deterioration. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01995448; URL: www.clinicaltrials.gov. PMID- 29705221 TI - Early Corticosteroids for Pneumocystis Pneumonia in Adults Without HIV Are Not Associated With Better Outcome. AB - BACKGROUND: Evidence supporting adjunctive corticosteroids during the treatment of Pneumocystis jirovecii pneumonia (PcP) in adults without HIV is minimal and controversial. METHODS: This retrospective cohort study included P jirovecii pneumonia-positive, hospitalized patients without HIV admitted to the Mayo Clinic from 2006 to 2016. Change from baseline in the respiratory component of the Sequential Organ Failure Assessment score (SOFAresp) at day 5 was compared between early (within 48 h) steroid recipients and nonrecipients by using multivariable logistic regression and in a propensity-matched analysis. RESULTS: Among the 323 included patients (early steroids, n = 258; no steroids, n = 65), the median (interquartile range) age was 65 (53, 73) years, 63% were male, and 92% were white. Severity-adjusted regression and propensity-matched analyses found that early administration of steroids was associated with less improvement in SOFAresp at day 5 compared with no steroids (P = .001 and P = .017, respectively). No differences were observed in the odds of having at least a one point improvement in SOFAresp at day 5 compared with baseline between groups (adjusted OR, 0.76 [95% CI, 0.24-2.28]; P = .61). Overall 30-day mortality was 22.9% (95% CI, 18.2-27.4). No differences in mortality, length of stay, admission to the ICU, or need for mechanical ventilation were found between early steroid recipients and nonrecipients. CONCLUSIONS: The addition of early corticosteroids to anti-Pneumocystis therapy in patients without HIV was not associated with improved respiratory outcomes. PMID- 29705222 TI - Combination therapy for chronic hepatitis B: The future and beyond. PMID- 29705223 TI - Emergence of azithromycin resistance mediated by the mph(A) gene in Salmonella Typhimurium clinical isolates in Latin America. PMID- 29705224 TI - Translumbar Infusion of N-Butyl Cyanoacrylate for the Treatment of Type II Endoleaks. AB - PURPOSE: To evaluate long-term efficacy of translumbar embolization of type II endoleaks exclusively supplied by the lumbar arteries in patients with growing abdominal aortic aneurysm sacs using N-butyl cyanoacrylate (NBCA) instilled via percutaneous needle access. MATERIALS AND METHODS: The study included 25 patients who developed type II endoleak after endovascular aneurysm repair. Inclusion criteria for intervention were defined as sac expansion > 5 mm detected with CT angiography at 6-month follow-up or later. Translumbar infusion of NBCA directly into the patent portion of the aneurysm sac was performed in all cases. Duplex US was performed the day after the intervention, and CT angiography was performed within the first month. Subsequently, duplex US was performed at 3, 6, and 9 months, and CT angiography or CT was performed at 12 months and annually thereafter. RESULTS: Translumbar embolization was achieved in all 25 patients. The endoleak resolved in 22 patients (88%) on duplex US performed 1 day after the embolization procedure. Three patients with persistent endoleak (12%) required repeat embolization. Two complications were detected and were managed conservatively. CONCLUSIONS: This study demonstrates the safety and efficacy of NBCA injection for treatment of type II endoleaks. This technique provides another option for the management of type II endoleaks. PMID- 29705225 TI - A Comparison of Concomitant Tributary Laser Ablation and Foam Sclerotherapy in Patients Undergoing Truncal Endovenous Laser Ablation for Lower Limb Varicose Veins. AB - PURPOSE: To compare outcomes of patients who received simultaneous tributary endovenous laser ablation (EVLA) or foam sclerotherapy (FS) with EVLA of the great saphenous vein (GSV) trunk. METHODS AND MATERIALS: This study recruited 418 patients (542 legs) with diagnosed varicose veins. Patients in the EVLA/FS group (255 patients, 327 legs) received concomitant FS for the tributaries with truncal lasering. For the EVLA-alone group (163 patients, 215 legs), tributaries (8W) were ablated with EVLA in addition to the GSV trunk (14W). Complications, Aberdeen Varicose Vein Questionnaire (AVVQ), EuroQol Group 5-Dimension Self Report Questionnaire (EQ-5D), numerical rating scale (NRS) scores, and condition of residual varicosities were assessed at 3 days, 4 weeks, and 6 months after procedure. All residual varicosities were identified and treated with a staged FS at 6 months. RESULTS: Except for ecchymosis, incidence of other complications was not significantly different between both groups at 6 months. Pain NRS scores of the EVLA/FS group were remarkably elevated at 4 weeks and then, at 6 months, declined to a level similar to the EVLA-alone group. The EVLA/FS group exhibited more significant improvement in both AVVQ and EQ-5D scales than the EVLA group at 6 months, while exhibiting poor improvement at 4 weeks. The EVLA/FS group had a significantly lower rate of residual varicosities than the EVLA group, thus reducing the need for the staged FS. CONCLUSIONS: These results confirm the feasibility and safety of simultaneous tributary EVLA and FS. In addition, they indicate better early quality-of-life improvement and a reduced reoperation rate of simultaneously combined truncal EVLA and tributary FS. PMID- 29705226 TI - Contralateral Deep Vein Thrombosis after Iliac Vein Stent Placement in Patients with May-Thurner Syndrome. AB - PURPOSE: To investigate the incidence and potential causes of contralateral deep vein thrombosis (DVT) after common iliac vein (CIV) stent placement in patients with May-Thurner syndrome (MTS). MATERIALS AND METHODS: Data of 111 patients (women: 73%) who had CIV stent implantation for symptomatic MTS at a single center were retrospectively analyzed. Mean patient age was 63.1 +/- 15.2 years. Median follow-up was 36 months (range, 1-142 months). Stent location was determined by venogram and classified as extended to the inferior vena cava (IVC), covered the confluence, or confined to the iliac vein. Potential causes of contralateral DVT were presumed based on venographic findings. The relationship between stent location and contralateral DVT was analyzed. RESULTS: Ten patients (9%, men/women: 4/6) exhibited contralateral DVT at a median timing of 40 months (range, 6-98 months). Median age was 69 years (range, 42-85 years). Median follow up was 73.5 months (range, 20-134 months). Potential causes were venous intimal hyperplasia (VIH) (n = 7), "jailing" (n = 2), and indeterminate (n = 1). All patients with VIH had previous CIV stents overextended to the IVC. Overextension of CIV stent was associated with contralateral DVT (P < .001). The primary patency rate of the contralateral CIV stent was 70% at 20 months. CONCLUSIONS: Contralateral DVT after CIV stent implantation has a relatively high incidence and often occurs late during follow-up. Overextension of the CIV stent to the IVC is associated with development of contralateral DVT, and VIH should be considered a potential cause. PMID- 29705227 TI - Anatomic Recanalization of Hepatic Vein and Inferior Vena Cava versus Direct Intrahepatic Portosystemic Shunt Creation in Budd-Chiari Syndrome: Overall Outcome and Midterm Transplant-Free Survival. AB - PURPOSE: To assess overall outcome and midterm transplant-free survival of patients with Budd-Chiari syndrome (BCS) undergoing radiologic interventions including anatomic recanalization of the hepatic vein (HV) and inferior vena cava (IVC) and direct intrahepatic portosystemic shunt (DIPS) creation, both as combined and as independent groups. MATERIALS AND METHODS: From November 2010 to October 2014, 136 patients with BCS were treated with HV/IVC recanalization (group 1) or DIPS creation (group 2). Both groups were periodically analyzed for stent patency on Doppler ultrasound, clinical outcome, biochemical parameters, and survival until death, liver transplantation, or last clinical evaluation. RESULTS: Actuarial transplant-free survival for the entire cohort was 94% at 1 year and 5 years with no significant difference in overall survival. There was significant biochemical improvement in group 1 with decrease in mean serum bilirubin level (1.8 mg/dL to 1.4 mg/dL, P < .011), mean serum aspartate aminotransferase (48.6 IU/L to 33.2 IU/L, P < .05), and mean serum alanine aminotransferase (38.7 IU/L to 28.5 IU/L) and increase in mean serum albumin level (3.2 g/dL to 3.45 g/dL, P < .001) after 3 and 24 months. There were 4 deaths in each group at 1-year follow-up; all 4 patients had acute fulminant BCS at presentation. CONCLUSIONS: Radiologic interventions for BCS lead to remarkable improvement of liver function and a good overall outcome and midterm transplant free survival. Patients receiving anatomic recanalization show improved liver synthetic functions compared with patients treated with DIPS. PMID- 29705228 TI - Physical therapists' perceptions and experiences about barriers and facilitators of therapeutic patient-centred relationships during outpatient rehabilitation: a qualitative study. AB - BACKGROUND: Over recent years there has been a paradigm shift towards a patient centred biopsychosocial care model in physical therapy. This new paradigm features a growing interest in understanding the contextual factors that influence the patient's experience of disease, pain and recovery. This includes generalized consensus regarding the importance of establishing a therapeutic relationship that is centred on the patient. OBJECTIVE: To explore physical therapists' perceptions and experiences regarding barriers and facilitators of therapeutic patient-centred relationships in outpatient rehabilitation settings. METHODS: This is a qualitative study with four focus groups including twenty-one physical therapists. Two researchers conducted the focus groups, using a topic guide with predetermined questions. The focus group discussions were audiotaped and videotaped, transcribed verbatim and analysed thematically using a modified grounded theory approach. RESULTS: Physical therapists perceived that the therapeutic patient-centred relationship not only depends on the personal qualities of the professional, but also on the patient's attitudes and the characteristics of the context, including the organization and team coordination. CONCLUSIONS: Although being more linked towards the patients' contextual factors and needs than towards the practice of the profession, a therapeutic relationship is worth considering by physical therapists. Furthermore this study highlights the need for physical therapists and administrators to rethink the situation and propose strategies for improvement. PMID- 29705229 TI - Primary Spinal Lymphoma Masquerading as Meningioma: Preoperative and Postoperative Magnetic Resonance Imaging Findings. AB - A 55-year-old male who complained of frequent back pain accompanied by increasing weakness in the lower extremities was admitted to our hospital's Neurosurgery Department. No additional disease was in his history. Magnetic resonance imaging of the thoracic area, anterior epidural space, and paravertebral area revealed an approximately 55 * 9 mm lymphoma pressuring the spinal cord from the anterior. It was fusiformed with a dural tail, hypointense on sagittal T1-weighted imaging series, and hypointense on sagittal T2-weighted imaging series compared with the spinal cord, showing contrast enhancement. After gadolinium application, an extra axial mass lesion was detected. The lesion was surgically removed from the patient, whom we thought had meningioma on the basis of radiology. However, histopathology resulted in the diagnosis of diffuse large B-cell non-Hodgkin lymphoma. PMID- 29705230 TI - Risk Factor Analysis for the Outcomes of Indirect Traumatic Optic Neuropathy with No Light Perception at Initial Visual Acuity Testing. AB - BACKGROUND: The optimal management of indirect traumatic optic neuropathy (TON) is controversial. We aimed to compare the differences in visual improvement by treatment option in patients presenting with TON and no light perception (NLP). We also wanted to identify any patient-related factors that might favor the use of steroid pulse therapy or optic nerve decompression (OND). METHODS: We retrospectively identified 46 consecutive patients with indirect TON treated at Chang Gung Memorial Hospital between 2007 and 2015. The outcome was the improvement in visual acuity by improvement rate and degree of improvement. RESULTS: Females had a better improvement rate than did males. Compared with delayed treatment, patients receiving steroid pulse therapy within 14 hours or receiving OND within 26 hours had a better improvement rate/degree. In patients with an initial intraocular pressure (IOP) of 17-23 mm Hg, the improvement rate/degree was significantly better than for patients with an IOP outside this range. For patients treated by OND, an initially normal IOP (11-21 mm Hg) suggested a significantly better prognosis in the improvement rate/degree. CONCLUSIONS: For patients with indirect TON, initial NLP implies a poor prognosis, but steroid pulse therapy or OND are both feasible treatment options. These results emphasize the importance of timely treatment for patients with indirect TON and NLP. Females and patients with an initial IOP of 17-23 mm Hg were more likely to recover. The results of our study indicate that normal initial IOP (11-21 mm Hg) is good prognostic factor for patients with indirect TON treated with OND. PMID- 29705231 TI - Efficacy and Safety of Microvascular Decompression and Gamma Knife Surgery Treatments for Patients with Primary Trigeminal Neuralgia: A Prospective Study. AB - PURPOSE: To compare efficacy and safety of microvascular decompression (MVD) and Gamma Knife surgery (GKS) treatments for trigeminal neuralgia. METHOD: Patients with primary trigeminal neuralgia were randomly divided into 2 groups to undergo either MVD or GKS. All patients were followed for 2 years to evaluate efficacy, recurrence rates, and complications of treatment. RESULTS: Of 441 enrolled patients, 220 were in the MVD group, and 221 were in the GKS group. There were no deaths in either group. At the 2-year follow-up, 183 patients (83%) in the MVD group reported complete pain relief, 5 (2%) had obvious pain relief, and 20 (9%) had no relief. In the GKS group, 55 patients (25%) reported complete pain relief, 106 (48%) had obvious pain relief, and 37 (17%) had no relief. There was no significant difference in the recurrence rate (0.45% vs. 0.9%) between the 2 groups. The most common complications in the MVD group were chemical meningitis (6%), cerebrospinal fluid leakage (4%), and facial palsy (4%). Loss of corneal reflex (6%) and facial numbness (5%) were the most common complications in the GKS group. CONCLUSIONS: Both MVD and GKS are effective surgical treatments for trigeminal neuralgia. The rate of complete pain relief in the MVD group was significantly superior to the rate of complete pain relief in the GKS group. There was no significant difference in recurrence rates between the groups; however, there were more severe complications in the MVD group than in the GKS group. PMID- 29705232 TI - Dexamethasone Administration and Mortality in Patients with Brain Abscess: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Dexamethasone has been used to treat cerebral edema associated with brain abscess. Whereas some argue that dexamethasone might aid antibiotic treatment, others believe that because of its immunosuppressive characteristics, it might have a negative impact on outcomes. How corticosteroid use affects overall mortality of brain abscess patients remains unclear. METHODS: A systematic search of the literature was conducted in accordance with PRISMA guidelines. PubMed, Embase, and Cochrane databases were utilized to identify all studies related to patients diagnosed with a brain abscess treated with dexamethasone. The main outcome of interest was mortality. Pooled effect estimates were calculated using fixed-effects (FE) and random-effects (RE) models. RESULTS: After removal of duplicates, 1681 articles were extracted from the literature of which 11 were included. These included 7 cohort studies and 4 case series. Indications to administer dexamethasone were either hospital brain abscess protocol or clinical presentation of cerebral edema. The 7 cohort studies involving 571 patients with brain abscesses comprised of 330 patients treated with standard of care (SOC) plus dexamethasone and 241 patients treated with SOC alone, after aspiration or surgical management of the abscess in either group. Pooling results from all seven cohort studies demonstrated a nonsignificant mortality benefit comparing SOC and dexamethasone patients to SOC patients (FE: risk ratio [RR], 0.94; 95% confidence interval [CI], 0.64-1.37; RE: RR, 0.95; 95% CI, 049-1.82; I2 = 53.9%; P for heterogeneity = 0.04). CONCLUSIONS: In patients with a brain abscess treated with antibiotics, the use of dexamethasone was not associated with increased mortality. PMID- 29705233 TI - Association of Vitamin D Receptor Gene TaqI, BsmI, FokI, and ApaI Polymorphisms and Susceptibility to Hallux Valgus in the Chinese Population. AB - Previous studies have indicated that vitamin D receptor (VDR) TaqI, BsmI, FokI and ApaI gene polymorphisms are associated with the risk of skeletal malformations with inflammation. However, the potential association of VDR gene polymorphisms with the susceptibility to hallux valgus remains unclear. To clarify this association, we compared the genotypes of 228 patients with hallux valgus with those of 200 controls using the Multiplex SNaPshot system. The chi2 test was used to compare the allele and genotype frequencies between groups, and p <= .05 was considered statistically significant. The frequencies of the mutant allele C in TaqI (p= .036; odds ratio [OR] 1.57; 95% confidence interval [CI] 1.03-2.39) and mutant allele A in BsmI (p= .036; OR 1.33; 95% CI 1.02-1.74) were significantly greater in the patients than in the controls. In addition, after adjusting for sex and age, TaqI (p= .047; OR 1.61; 95% CI 1.00-2.58) and BsmI (p= .025; OR 1.67; 95% CI 1.06-2.61) were associated with the risk of hallux valgus through a dominant genetic model. A homozygous genetic model of BsmI was also significantly associated with the risk of hallux valgus (p= .033; OR 1.81; 95% CI 1.05-2.57). However, neither ApaI nor FokI were associated with increased susceptibility. To the best of our knowledge, we have reported for the first time that VDR gene TaqI and BsmI polymorphisms might contribute to the increased risk of hallux valgus in Chinese population. PMID- 29705234 TI - Syndesmosis Fixation in Unstable Ankle Fractures Using a Partially Threaded 5.0 mm Cannulated Screw. AB - The present study evaluated the radiographic outcomes of syndesmosis injuries treated with a partially threaded 5.0-mm cannulated screw. The present study included 58 consecutive patients with syndesmosis injuries concurrent with ankle fractures who had undergone operative fixation with a partially threaded 5.0-mm cannulated screw to repair the syndesmosis injury. Radiographic indexes, including the medial clear space, tibiofibular overlap, tibiofibular clear space, and fibular position on the lateral radiograph, were measured on the preoperative, immediate postoperative, and final follow-up radiographs. The measurements were compared between the injured and intact ankles. All preoperative radiographic indexes, including the medial clear space (p < .001), tibiofibular overlap (p < .001), tibiofibular clear space (p < .001), and fibular position on the lateral radiograph (p = .026), were significantly different between the injured and intact ankles. The medial clear space of the injured ankle was significantly wider than that of the intact ankle preoperatively (p < .001) and had become significantly narrower immediately postoperatively (p < .001). Finally, the medial clear space was not significantly different between the injured and intact ankles at the final follow-up examination (p = .522). No screw breakage or repeat fractures were observed. A 5.0-mm partially threaded cannulated screw effectively restored and maintained the normal relationship between the tibia and fibula within the ankle mortise with a low risk of complications. This appears to be an effective alternative technique to treat syndesmosis injuries concurrent with ankle fractures. PMID- 29705235 TI - Authors' Reply to Letter to the Editor. PMID- 29705236 TI - Comparison of the Complication Incidence in Open Versus Endoscopic Gastrocnemius Recession: A Retrospective Medical Record Review. AB - Gastrocnemius recession is a practical and effective procedure to address gastrocnemius equinus. It has been shown that an equinus deformity can lead to the development of plantar fasciitis, osteoarthritis, and foot ulcerations. The 2 approaches to gastrocnemius recession are open and endoscopic. Both are viable options; however, both also have associated complications. We compared and evaluated the postoperative complications associated with these procedures. The electronic database of our orthopedics division at the University of Florida College of Medicine, Jacksonville, was retrospectively searched to identify all cases of gastrocnemius recession (Current Procedural Terminology [CPT] code 27687), and unlisted arthroscopy (CPT code 29999) from February 2006 to February 2016. The difference in the outcome variable, the incidence of postoperative complications, was assessed using Fisher's exact test. A total of 39 patients (41 procedures) were in the open gastrocnemius recession group and 35 (39 procedures) were in the endoscopic gastrocnemius recession group. The median follow-up time was shorter in the open gastrocnemius recession group than in the endoscopic gastrocnemius recession group (9 versus 12 months; p < .001). Postoperative complications developed after 12 of the 80 procedures (15%), with a greater incidence after open than endoscopic procedures (26.8% versus 2.6%; p = .003). The complications associated with the open technique included 1 case of scar pain (2.4%), 5 of dehiscence (12.2%), 1 of infection (2.4%), 2 of calf abscess (4.9%), and 2 cases of nerve injury (4.9%). A single complication occurred with the endoscopic technique-1 case of dehiscence (2.6%). To the best of our knowledge, ours is the first study to compare the postoperative complications between these 2 techniques. We found the incidence of postoperative complications was significantly lower in the endoscopic group, emphasizing the benefit of using the endoscopic approach. These findings could prove invaluable when addressing gastrocnemius equinus in those with a greater risk of postoperative complications. PMID- 29705238 TI - HCV modifies EGF signalling and upregulates production of CXCR2 ligands: Role in inflammation and antiviral immune response. AB - BACKGROUND & AIMS: To affect immune response and inflammation, the hepatitis C virus (HCV) substantially influences intercellular communication pathways that are decisive for immune cell recruitment. The present study investigates mechanisms by which HCV modulates chemokine-mediated intercellular communication from infected cells. METHODS: Chemokine expression was studied in HCVcc-infected cell lines or cell lines harbouring a subgenomic replicon, as well as in serum samples from patients. Expression or activity of mediators and signalling intermediates was manipulated using knockdown approaches or specific inhibitors. RESULTS: HCV enhances expression of CXCR2 ligands in its host cell via the induction of epidermal growth factor (EGF) production. Knockdown of EGF or of the p65 subunit of the NF-kappaB complex results in a substantial downregulation of HCV-induced CXCR2 ligand expression, supporting the involvement of an EGF dependent mechanism as well as activation of NF-kappaB. Furthermore, HCV upregulates expression of CXCR2 ligands in response to EGF stimulation via downregulation of the T-cell protein tyrosine phosphatase (TC-PTP [PTPN2]), activation of NF-kappaB, and enhancement of EGF-inducible signal transduction via MEK1 (MAP2K1). This results in the production of a cytokine/chemokine pattern by the HCV-infected cell that can recruit neutrophils but not monocytes. CONCLUSIONS: These data reveal a novel EGF-dependent mechanism by which HCV influences chemokine-mediated intercellular communication. We propose that this mechanism contributes to modulation of the HCV-induced inflammation and the antiviral immune response. LAY SUMMARY: In most cases hepatitis C virus (HCV) results in chronic infection and persistent viral replication, taking decades until development of overt disease. To achieve such a course, the respective virus must have developed mechanisms to circumvent antiviral response, to modulate the inflammatory response and to utilise the infrastructure of its host with moderate effect on its viability. The present study provides novel data indicating that HCV induces epidermal growth factor production in its host cell, enhancing epidermal growth factor-inducible expression of chemokines that bind to the CXCR2 receptor and recruit neutrophile granulocytes. Importantly, chemokines are critical mediators determining the pattern of immune cells recruited to the site of injury and thereby the local inflammatory and immunological milieu. These data strongly suggest that HCV triggers mechanisms that enable the virus to influence the inflammatory and immunological processes of its host. PMID- 29705239 TI - Reply to: "Validation of response to yttrium-90 radioembolization for hepatocellular carcinoma with portal vein invasion". PMID- 29705237 TI - beta-Hydroxybutyrate protects from alcohol-induced liver injury via a Hcar2-cAMP dependent pathway. AB - BACKGROUND & AIMS: Sterile inflammation resulting in alcoholic hepatitis (AH) occurs unpredictably after many years of excess alcohol intake. The factors responsible for the development of AH are not known but mitochondrial damage with loss of mitochondrial function are common features. Hcar2 is a G-protein coupled receptor which is activated by beta-hydroxybutyrate (BHB). We aimed to determine the relevance of the BHB-Hcar2 pathway in alcoholic liver disease. METHODS: We tested if loss of BHB production can result in increased liver inflammation. We further tested if BHB supplementation is protective in AH through interaction with Hcar2, and analyzed the immune and cellular basis for protection. RESULTS: Humans with AH have reduced hepatic BHB, and inhibition of BHB production in mice aggravated ethanol-induced AH, with higher plasma alanine aminotransferase levels, increased steatosis and greater neutrophil influx. Conversely supplementation of BHB had the opposite effects with reduced alanine aminotransferase levels, reduced steatosis and neutrophil influx. This therapeutic effect of BHB is dependent on the receptor Hcar2. BHB treatment increased liver Il10 transcripts, and promoted the M2 phenotype of intrahepatic macrophages. BHB also increased the transcriptional level of M2 related genes in vitro bone marrow derived macrophages. This skewing towards M2 related genes is dependent on lower mitochondrial membrane potential (Deltapsi) induced by BHB. CONCLUSIONS: Collectively, our data shows that BHB production during excess alcohol consumption has an anti-inflammatory and hepatoprotective role through an Hcar2 dependent pathway. This introduces the concept of metabolite-based therapy for AH. LAY SUMMARY: Alcoholic hepatitis is a life-threatening condition with no approved therapy that occurs unexpectedly in people who consume excess alcohol. The liver makes many metabolites, and we demonstrate that loss of one such metabolite beta-hydroxybutyrate occurs in patients with alcoholic hepatitis. This loss can increase alcohol-induced liver injury, and beta-hydroxybutyrate can protect from alcohol-induced liver injury via a receptor on liver macrophages. This opens the possibility of metabolite-based therapy for alcoholic hepatitis. PMID- 29705241 TI - Hepatitis E blood donor screening - More than a mere drop in the ocean? PMID- 29705240 TI - CD36 palmitoylation disrupts free fatty acid metabolism and promotes tissue inflammation in non-alcoholic steatohepatitis. AB - BACKGROUND AND AIMS: Fatty acid translocase CD36 (CD36) is a membrane protein with multiple immuno-metabolic functions. Palmitoylation has been suggested to regulate the distribution and functions of CD36, but little is known about its significance in non-alcoholic steatohepatitis (NASH). METHODS: Human liver tissue samples were obtained from patients undergoing liver biopsy for diagnostic purposes. CD36 knockout mice were injected with lentiviral vectors expressing wild-type CD36 or CD36 with mutated palmitoylation sites. Liver histology, immunofluorescence, mRNA expression profile, subcellular distributions and functions of CD36 protein were assessed. RESULTS: The localization of CD36 on the plasma membrane of hepatocytes was markedly increased in patients with NASH compared to patients with normal liver and those with simple steatosis. Increased CD36 palmitoylation and increased localization of CD36 on the plasma membrane of hepatocytes were also observed in livers of mice with NASH. Furthermore, inhibition of CD36 palmitoylation protected mice from developing NASH. The absence of palmitoylation decreased CD36 protein hydrophobicity reducing its localization on the plasma membrane as well as in lipid raft of hepatocytes. Consequently, a lack of palmitoylation decreased fatty acid uptake and CD36/Fyn/Lyn complex in HepG2 cells. Inhibition of CD36 palmitoylation not only ameliorated intracellular lipid accumulation via activation of the AMPK pathway, but also inhibited the inflammatory response through the inhibition of the JNK signaling pathway. CONCLUSIONS: Our findings demonstrate the key role of palmitoylation in regulating CD36 distributions and its functions in NASH. Inhibition of CD36 palmitoylation may represent an effective therapeutic strategy in patients with NASH. LAY SUMMARY: Fatty acid translocase CD36 (CD36) is a multifunctional membrane protein which contributes to the development of liver steatosis. In the present study, we demonstrated that the localization of CD36 on the plasma membrane of hepatocytes is increased in patients with non-alcoholic steatohepatitis. Blocking the palmitoylation of CD36 reduces CD36 distribution in hepatocyte plasma membranes and protects mice from non-alcoholic steatohepatitis. The inhibition of CD36 palmitoylation not only improved fatty acid metabolic disorders but also reduced the inflammatory response in vitro and in vivo. The present study suggests that CD36 palmitoylation is important for non-alcoholic steatohepatitis development and inhibition of CD36 palmitoylation could be used to cure non-alcoholic steatohepatitis. PMID- 29705242 TI - Epithelial barrier dysfunction in desmoglein-1 deficiency. PMID- 29705244 TI - Matrix protein tenascin-C expands and reversibly blocks maturation of murine eosinophil progenitors. PMID- 29705243 TI - A kindred with mutant IKAROS and autoimmunity. PMID- 29705245 TI - Role of human forkhead box P3 in early thymic maturation and peripheral T-cell homeostasis. AB - BACKGROUND: Forkhead box P3 (FOXP3) is a key transcription factor in regulatory T (Treg) cell function. FOXP3 gene mutations cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome, a fatal autoimmune syndrome. FOXP3 has also been proposed to act in effector T (Teff) cells, but to date, this role has not been confirmed. OBJECTIVE: We sought to evaluate the effect of reduced FOXP3 expression on human Treg and Teff cell development and correlate it with IPEX syndrome immune pathology. METHODS: We developed a model of humanized mice (huMice) in which the human hematopoietic system is stably knocked down or knocked out for the FOXP3 gene (knockdown [KD]/knockout [KO] huMice). RESULTS: Because FOXP3-KD/KO was not 100% effective, residual FOXP3 expression in hematopoietic stem progenitor cells was sufficient to give rise to Treg cells with normal expression of FOXP3. However, numerous defects appeared in the Teff cell compartment. Compared with control mice, FOXP3-KD/KO huMice showed altered thymocyte differentiation, with KD/KO thymocytes displaying significantly reduced T-cell receptor (TCR) signaling strength and increased TCR repertoire diversity. Peripheral KD/KO Teff cells were expanded and showed signs of homeostatic proliferation, such as a significantly contracted TCR repertoire, a severely reduced naive compartment, decreased telomeric repeat-binding factor 2 expression, and a skew toward a TH2 profile, resembling an aged immune system. Consistent with results in FOXP3-KD/KO huMice, analysis of patients with IPEX syndrome provided evidence of defects in the Teff cell compartment at both the thymic and peripheral levels. CONCLUSIONS: These findings support an intrinsic role for human FOXP3 in controlling thymocyte maturation and peripheral expansion of Teff cells and reveal a previously undescribed pathogenic mechanism through an altered Teff cell compartment in patients with IPEX syndrome. PMID- 29705246 TI - Profilin-mediated food-induced allergic reactions are associated with oral epithelial remodeling. AB - BACKGROUND: In areas of high exposure to grass pollen, allergic patients are frequently sensitized to profilin, and some experience severe profilin-mediated food-induced reactions. This specific population of patients is ideal to study the relationship between respiratory and food allergies. OBJECTIVE: We sought to determine the role of oral mucosal epithelial barrier integrity in profilin mediated allergic reactions. METHODS: Thirty-eight patients with profilin allergy stratified into mild or severe according to their clinical history and response to a profilin challenge test and 6 nonallergic subjects were recruited. Oral mucosal biopsies were used for measurement of CD11c, CD3, CD4, tryptase, claudin 1, occludin, E-cadherin, and vascular endothelial growth factor A levels; Masson trichrome staining; and POSTN, IL33, TPSAB, TPSB, and CMA gene expression analysis by using quantitative RT-PCR. Blood samples were used for basophil activation tests. RESULTS: Distinct features of the group with severe allergy included the following: (1) impaired epithelial integrity with reduced expression of claudin-1, occludin, and E-cadherin and decreased numbers of epithelial cells, which is indicative of acanthosis, higher collagen deposition, and angiogenesis; (2) inflammatory immune response in the mucosa, with an increased number of CD11c+ and CD4+ infiltrates and increased expression of the cytokine genes POSTN and IL33; and (3) a 10-fold increased sensitivity of basophils to profilin. CONCLUSIONS: Patients with profilin allergy present with significant damage to the oral mucosal epithelial barrier, which might allow profilin penetration into the oral mucosa and induction of local inflammation. Additionally, severely allergic patients presented with increased sensitivity of effector cells. PMID- 29705248 TI - Prognostic implications of peripheral artery disease in coronary artery disease. AB - Prevalence of peripheral arterial disease in patients with coronary artery disease is considerably higher than in the general population. A graded increase in the risk of major cardiovascular events in a variety of clinical settings is associated with the number of arterial beds affected by peripheral arterial disease. This is not surprising, considering that both coronary artery disease and peripheral arterial disease are linked to a higher prevalence of cardiovascular risk factors and a greater incidence of atherosclerotic burden. Aggressive lipid lowering therapy is associated with less coronary and peripheral arterial disease progression and greater regression. On the contrary, blood pressure therapy should be carefully managed, considering the association of both high and low values of pressure with adverse outcomes. PMID- 29705247 TI - Transfer of gene-corrected T cells corrects humoral and cytotoxic defects in patients with X-linked lymphoproliferative disease. AB - BACKGROUND: X-linked lymphoproliferative disease 1 arises from mutations in the SH2D1A gene encoding SLAM-associated protein (SAP), an adaptor protein expressed in T, natural killer (NK), and NKT cells. Defects lead to abnormalities of T-cell and NK cell cytotoxicity and T cell-dependent humoral function. Clinical manifestations include hemophagocytic lymphohistiocytosis, lymphoma, and dysgammaglobulinemia. Curative treatment is limited to hematopoietic stem cell transplantation, with outcomes reliant on a good donor match. OBJECTIVES: Because most symptoms arise from defective T-cell function, we investigated whether transfer of SAP gene-corrected T cells could reconstitute known effector cell defects. METHODS: CD3+ lymphocytes from Sap-deficient mice were transduced with a gammaretroviral vector encoding human SAP cDNA before transfer into sublethally irradiated Sap-deficient recipients. After immunization with the T-dependent antigen 4-hydroxy-3-nitrophenylacetly chicken gammaglobulin (NP-CGG), recovery of humoral function was evaluated through germinal center formation and antigen specific responses. To efficiently transduce CD3+ cells from patients, we generated an equivalent lentiviral SAP vector. Functional recovery was demonstrated by using in vitro cytotoxicity and T follicular helper cell function assays alongside tumor clearance in an in vivo lymphoblastoid cell line lymphoma xenograft model. RESULTS: In Sap-deficient mice 20% to 40% engraftment of gene modified T cells led to significant recovery of germinal center formation and NP specific antibody responses. Gene-corrected T cells from patients demonstrated improved cytotoxicity and T follicular helper cell function in vitro. Adoptive transfer of gene-corrected cytotoxic T lymphocytes from patients reduced tumor burden to a level comparable with that seen in healthy donor cytotoxic T lymphocytes in an in vivo lymphoma model. CONCLUSIONS: These data demonstrate that autologous T-cell gene therapy corrects SAP-dependent defects and might offer an alternative therapeutic option for patients with X-linked lymphoproliferative disease 1. PMID- 29705249 TI - Corrections. PMID- 29705250 TI - Corrections. PMID- 29705251 TI - The Clive Ballard energy equation. PMID- 29705252 TI - Editorial Comment. PMID- 29705253 TI - Reply by Authors. PMID- 29705255 TI - Editorial Comment. PMID- 29705254 TI - Editorial Comment. PMID- 29705256 TI - Reply by Authors. PMID- 29705257 TI - Reply by Authors. PMID- 29705258 TI - Subclinical Volume Overload Across the Spectrum of Heart Failure: Lessons From Total Blood Volume Measurements. PMID- 29705259 TI - Fat deposits as manifestation of alcohol use disorder: Madelung's Disease. PMID- 29705260 TI - Should Distal Attachment Devices be Routinely Added for Colonoscopy? PMID- 29705262 TI - Characteristics and Outcomes Reported by Patients With Primary Sclerosing Cholangitis Through an Online Registry. AB - BACKGROUND AND AIMS: Primary sclerosing cholangitis (PSC) is a fibrostenosing disease of the bile ducts associated with inflammatory bowel disease (IBD) for which the only treatment is liver transplantation. PSC progression has been defined in cohorts from referral centers or single-nation population databases. However, observations made from these cohorts have limited applicability due to referral bias and demographic confounders. We analyzed data from the worldwide PSC Partners Patient Registry, an international online database established in 2014 to obtain information from individuals with PSC or their caretakers and compare symptoms, disease progression, and treatments of PSC in the Unites States (US) and other countries. METHODS: We analyzed demographic and clinical characteristics, symptoms, and clinical outcomes of patients with PSC using the PSC Partners Patient Registry. Participants completed an online standardized questionnaire and electronic case report, providing information on age, age of symptom onset, age of PSC diagnosis, methods of diagnosis, concurrent diagnoses, family history, and medication use. RESULTS: Of 873 registrants, 811 had completed questionnaires and 528 (65.1%) had their PSC diagnosis confirmed; we found no significant demographic or clinical differences between patients with vs without a confirmed diagnosis. In contrast to other studies, we found a higher proportion of individuals with PSC to be female (52.5%). However, mean age of PSC diagnosis (32.4 + 14.7 years) and proportion of individuals with PSC and IBD (67.1%) were similar to those from prior reports. Most cases in the database were from the US (74.9%). More than half of the participants reported having pruritus, abdominal pain, fatigue, or sleep disturbances; rates were not significantly different among participants within vs outside the US. There was no significant difference in treatment with ursodeoxycholic acid between participants within vs outside the US (50.0% and 57.8%, P = 0.07). Median time of transplant-free survival was 21 years; transplant-free survival associated with female sex and Crohn's disease. CONCLUSIONS: Our findings from an analysis of data from the PSC Partners Patient Registry confirm those from previous studies, although we found a higher proportion of individuals with PSC to be female. In addition to allowing efficient collection of patient-reported outcomes, the patient-driven registry allows for inclusion of previously under-represented cases of PSC. PMID- 29705261 TI - Vibration-Controlled Transient Elastography to Assess Fibrosis and Steatosis in Patients With Nonalcoholic Fatty Liver Disease. AB - BACKGROUND & AIMS: Vibration-controlled transient elastography (VCTE), which measures liver stiffness, has become an important tool for evaluating patients with nonalcoholic fatty liver disease (NAFLD). We aimed to determine the diagnostic accuracy of VCTE in detection of NAFLD in a multicenter cohort of patients. METHODS: We performed a prospective study of 393 adults with NAFLD who underwent VCTE within 1 year of liver histology analysis (median time, 49 d; interquartile range, 25-78 d), from July 1, 2014, through July 31, 2017. Liver stiffness measurement (LSM) cut-off values for pairwise fibrosis stage and controlled attenuation parameter cut-off values for pairwise steatosis grade were determined using cross-validated area under the receiver operating characteristics curve (AUROC) analyses. Diagnostic statistics were computed at a sensitivity fixed at 90% and a specificity fixed at 90%. RESULTS: LSM identified patients with advanced fibrosis with an AUROC of 0.83 (95% CI, 0.79- 0.87) and patients with cirrhosis with an AUROC of 0.93 (95% CI, 0.90-0.97). At a fixed sensitivity, a cut-off LSM of 6.5 kPa excluded advanced fibrosis with a negative predictive value of 0.91, and a cut-off LSM of 12.1 kPa excluded cirrhosis with a negative predictive value of 0.99. At a fixed specificity, LSM identified patients with advanced fibrosis with a positive predictive value of 0.71 and patients with cirrhosis with a positive predictive value of 0.41. Controlled attenuation parameter analysis detected steatosis with an AUROC of 0.76 (95% CI, 0.64-0.87). In contrast, the VCTE was less accurate in distinguishing lower fibrosis stages, higher steatosis grades, or the presence of NASH. CONCLUSIONS: In a prospective study of adults with NAFLD, we found VCTE to accurately distinguish advanced vs earlier stages of fibrosis, using liver histology as the reference standard. PMID- 29705263 TI - Previous Use of Antithrombotic Agents Reduces Mortality and Length of Hospital Stay in Patients With High-risk Upper Gastrointestinal Bleeding. AB - BACKGROUND & AIMS: Anti-thrombotic agents are risk factors for upper gastrointestinal bleeding (UGIB). However, few studies have evaluated their effects on patient outcomes. We assessed the effects of anti-thrombotic agents on outcomes of patients with high-risk UGIB. METHODS: We performed a prospective study of 619 patients with acute UGIB (defined by hematemesis, coffee-ground vomit or melena) who required intervention and underwent endoscopy at 8 centers in North America, Asia, and Europe, from March 2014 through March 2015. We collected data recorded on use of anti-thrombotic agents, clinical features, and laboratory test results to calculate AIMS65, Glasgow-Blatchford Score, and full Rockall scores. We also collected and analyzed data on co-morbidities, endoscopic findings, blood transfusion, interventional radiology results, surgeries, length of hospital stay, rebleeding, and mortality. RESULTS: Of the 619 patients who required endoscopic therapy, data on use of anti-thrombotic agents was available for 568; 253 of these patients (44%) used anti-thrombotic agents. Compared to patients not taking anti-thrombotic agents, patients treated with anti thrombotics were older (P < .001), had a higher mean American Society of Anesthesiologists classification score (P < .0001), had a higher mean Rockall score (P < .0001), a higher mean AIMS65 score (P < .0001), and more frequently bled from ulcers (P < .001). There were no differences between groups in sex, systolic blood pressure, level of hemoglobin at hospital admission, frequency of malignancies, Glasgow-Blatchford Score, need for surgery or interventional radiology, number of rebleeding events, or requirement for transfusion. All-cause mortality was lower in patients who took anti-thrombotic drugs (11 deaths, 4%) than in patients who did not (37 deaths, 12%) (P = .002); this was due to lower bleeding-related mortality in patients taking anti-thrombotic drugs (3 deaths, 1%) than in patients who were not (19 deaths, 6%) (P = .003). Patients taking anti-thrombotic drugs had mean hospital stays of 6.9 days (95% CI, 2-23 days) compared to 7.9 days for non-users of anti-thrombotic agents (95% CI, 2-26 days) (P = .04). CONCLUSIONS: Despite being older, with higher American Society of Anesthesiologists classification, AIMS65, and Rockall scores, patients who have UGIB that requires endoscopic therapy and take anti-thrombotic drugs have lower mortality due to GI bleeding and shorter hospital stays, with similar rates of rebleeding, surgery, and transfusions, compared with those not taking anti thrombotic drugs. PMID- 29705264 TI - Neutrophil-to-Lymphocyte Ratio Associates Independently With Mortality in Hospitalized Patients With Cirrhosis. AB - BACKGROUND & AIMS: The neutrophil to lymphocyte ratio (NLR) is a biomarker of immune dysregulation in patients with cirrhosis and is inexpensive to measure. We investigated the association between NLR and mortality in hospitalized patients with cirrhosis at 4 liver transplant centers, controlling for severity of acute on-chronic liver failure (ACLF). METHODS: We performed a retrospective study using data from the North American Consortium for the Study of End-stage Liver Disease on patients with index hospitalizations for cirrhosis from December 2011 through December 2016. We collected data on patient demographics, NLR, model for end-stage liver disease (MELD) scores, serum levels of Na, cirrhosis stages, infections, hepatocellular carcinomas, and ACLF severity (based on number of organ failures). Competing risk regression analysis evaluated mortality within 1 year after hospital discharge, accounting for competing events (liver transplant). RESULTS: At admission, the patients' mean age was 57 years, mean MELD score was 21, and mean serum level of Na was 134 mmol/L. Sixty-eight patients had no organ failure, 21 patients had 1 organ failures, 7 patients had 2 organ failures, 4 patients had 3 organ failures, and 1 patient had 4 organ failures; 36% of the patients had confirmed or suspected infections. In univariate models, risk of death associated with increasing NLR, up to a value of 8 (hazard ratio [HR]= 1.14; 95% CI, 1.07-1.20; P < .001), and NLR quartile (for NLR range of 3-5, HR = 2.17; for NLR range of >5-9, HR=2.46; for NLR quartile >9, HR=2.84 vs the lowest quartile [NLR<3]) (P <= .001). The NLR remained statistically significant in multivariable models, adjusting for age, MELD score, hepatocellular carcinoma, and ACLF severity. Additionally, NLR was a statistically significant independent predictor of length of index hospital stay and mortality within 90 days after discharge. CONCLUSION: In a retrospective analysis of patients with cirrhosis, we found NLR to associate with death within 1 year after non-elective hospitalization. In these patients, the risk of death associated with acute immune dysregulation persists long after their initial hospitalization. PMID- 29705265 TI - Acetyl-CoA Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and Steatosis in Patients With Nonalcoholic Steatohepatitis. AB - BACKGROUND & AIMS: Increased de novo lipogenesis (DNL) contributes to the pathogenesis of nonalcoholic steatohepatitis (NASH). Acetyl-CoA carboxylase catalyzes the rate-limiting step in DNL. We evaluated the safety and efficacy of GS-0976, a small molecule inhibitor of acetyl-CoA carboxylase, in patients with NASH. METHODS: In an open-label prospective study, patients with NASH (n = 10) received GS-0976 20 mg orally once daily for 12 weeks. NASH was diagnosed based on a proton density fat fraction estimated by magnetic resonance imaging (MRI PDFF) >=10% and liver stiffness by magnetic resonance elastography (MRE) >=2.88 kPa. The contribution from hepatic DNL to plasma palmitate was measured by 14 days of heavy water labeling before and at the end of treatment. We performed the same labelling protocol in an analysis of healthy volunteers who were not given DNL (controls, n = 10). MRI-PDFF and MRE at baseline, and at weeks 4 and 12 of GS 0976 administration, were measured. We analyzed markers of liver injury and serum markers of fibrosis. RESULTS: The contribution of hepatic DNL to plasma palmitate was significantly greater in patients with NASH compared with controls (43% vs 18%) (P = .003). After 12 weeks administration of GS-0976, the median hepatic DNL was reduced 22% from baseline in patients with NASH (P = .004). Compared with baseline, reductions in MRI-PDFF at week 12 (15.7% vs 9.1% at baseline; P = .006), liver stiffness by MRE (3.4 kPa vs 3.1 kPa at baseline; P = .049), TIMP metallopeptidase inhibitor 1 (275 ng/mL vs 244 ng/mL at baseline; P = .049), and serum level of alanine aminotransferase (101 U/L vs 57 U/L at baseline; P = .23) were consistent with decreased hepatic lipid content and liver injury. At week 12, 7 patients (70%) had a >=30% decrease in MRI-PDFF. CONCLUSION: In an open label study, patients with NASH given GS-0976 for 12 weeks had reduced hepatic DNL, steatosis, and markers of liver injury. ClinicalTrials.gov no: NCT02856555. PMID- 29705266 TI - Elevated serum BDNF levels are associated with favorable outcome in CLL patients: Possible link to CXCR4 downregulation. AB - Increased chemokine C-X-C receptor 4 (CXCR4) expression is related to unfavorable outcome in chronic lymphocytic leukemia (CLL). Brain-derived neurotrophic factor (BDNF) is a neuronal growth factor that has been shown previously to interact with CXCR4 in neuronal cells. Here, we studied the in vitro effect of BDNF on CXCR4 expression and chemotaxis toward stromal derived factor-1 (SDF-1) in freshly isolated CLL cells. We also explored the correlations between serum BDNF levels in CLL patients and disease characteristics and clinical course. Incubation of CLL cells with recombinant BDNF (50 ng/mL) resulted in a downregulation of CXCR4 surface expression and atenuated chemotaxis toward SDF-1. Higher serum BDNF levels were associated with a mutated immunoglobulin heavy chain variable (IGHV) gene, an early clinical stage, and a stable clinical course. Our findings suggest that increased circulating blood BDNF may be associated with a favorable effect in CLL. However, the exact mechanism of this favorable effect should be investigated further. PMID- 29705268 TI - Aberrant determination of phenotypic markers in chronic lymphocytic leukemia (CLL) lymphocytes after cryopreservation. AB - The cryopreservation of peripheral blood mononuclear cells (PBMCs) is a routine research laboratory process, enabling long-term storage of primary patient blood samples. Retrospective analysis of these samples has the potential to identify markers that may be associated with prognosis and response to treatment. To draw valid biological conclusions from this type of analysis, it is essential to ensure that any observed changes are directly related to the pathology of the disease rather than the preservation process itself. Therefore, we have investigated 15 cell surface markers that are relevant to chronic lymphocytic leukemia (CLL) on matched fresh and thawed samples to determine the effect of cryopreservation on their detection. We found that the number of CLL cells positive for the markers CD22, CD40, CD49d, CD54, CD69, and CXCR3 was decreased significantly after cryopreservation. In addition, the mean fluorescence intensity of 10 of the 15 markers changed significantly after cryopreservation. These findings demonstrate that care must be taken when interpreting this type of analysis on thawed samples. PMID- 29705267 TI - Branched-chain amino acid depletion conditions bone marrow for hematopoietic stem cell transplantation avoiding amino acid imbalance-associated toxicity. AB - Hematopoietic stem cells (HSCs) are used clinically in bone marrow (BM) transplantation due to their unique ability to reform the entire hematopoietic system. Recently, we reported that HSCs are highly sensitive to valine, one of the three branched-chain amino acids (BCAAs) in addition to isoleucine and leucine. Dietary depletion of valine could even be used as a conditioning regimen for HSC transplantation. Here, we report that HSCs are highly sensitive to the balance of BCAAs, with both proliferation and survival reduced by BCAA imbalance. However, low but balanced BCAA levels failed to rescue HSC maintenance. Importantly, in vivo depletion of all three BCAAs was significantly less toxic than depletion of valine only. We demonstrate that BCAA depletion can replace valine depletion as a safer alternative to BM conditioning. In summary, by determining HSC metabolic requirements, we can improve metabolic approaches to BM conditioning. PMID- 29705269 TI - Structure and dynamics of neurosteroid binding to the alpha1beta2gamma2 GABAA receptor. AB - Neurosteroids are the principal endogenous modulators of the gamma-Aminobutyric acid receptors (GABAARs), pentameric membrane-bound proteins that can be assembled from at least 19 subunits. In the most abundant GABAAR arrangement (alpha1beta2gamma2), neurosteroids can potentiate the GABA action as well as produce a direct activation of the channel. The recent crystal structures of neurosteroids bound to alpha homopentameric GABAAR reveal binding to five equivalent sites. However, these results have been obtained using receptors that are not physiologically relevant, suggesting a need to investigate neurosteroid binding to heteropentameric receptors that exist in the central nervous system. In a previous work, we predicted the neurosteroid binding site by applying molecular modeling methods on the beta3 homopentamer. Here we construct a homology model of the transmembrane domain of the heteropentameric alpha1beta2gamma2 receptor and then, by combining docking and molecular dynamics simulations, we analyzed neurosteroid binding. Results show that the five neurosteroid cavities are conserved in the alpha1beta2gamma2 receptor and all of them are able to bind neurosteroids. Two different binding modes were detected depending on the identity of the residue at position 241 in the transmembrane helix 1. These theoretical findings provide microscopic insights into neurosteroid binding at the heteropentameric GABAAR. The existence of two classes of sites may be associated with how neurosteroids modulate GABAAR. Our finding would represent the essential first step to reach a comprehensive understanding of how these endogenous molecules regulate the central nervous system. PMID- 29705270 TI - Nuclear progestin receptor (Pgr) knockouts resulted in subfertility in male tilapia (Oreochromis niloticus). AB - It was documented that 17alpha, 20beta-dihydroxy-4-pregnen-3-one (DHP), a fish specific progestin, might play critical roles in spermatogenesis, sperm maturation and spermiation partially through activating nuclear receptor (Pgr). However, no direct evidence is available to demonstrate the functions of DHP in fish spermatogenesis. To further elucidate the roles of DHP in teleosts, we generated a pgr homozygous mutant line in XY Nile tilapia (Oreochromis niloticus). Pgr gene mutation resulted in the development of a smaller, thinner testis and a lower GSI compared with normal testis. Pgr gene knockout led to irregular arrangement of spermatogenic cysts, decline of sperm count and sperm motility. Significant decrease of spermatocytes and spermatozoa was observed, which was further proved by the PCNA and Ph3 staining. Real-time PCR analysis demonstrated that mutation of pgr gene resulted in a significant up-regulation of steroidogenesis-related genes of cyp17a, cyp11b2, StAR, scc, 20beta-HSD, and sf1, and down-regulation of fshb, fshr, oct4, sycp3, cdk1, prm, cyclinB1, cyclinB2 and cdc25 genes. Furthermore, both Immunohistochemistry and Western blotting experiments revealed a remarkable increase of Cyp17a1, Cyp17a2 and Cyp11b2 expressions in the pgr-/- testis. EIA measurement showed that an evident increase of 11-KT level was found in the pgr-/- XY fish. There was a significant increase in the mortality of offspring when crossing pgr-/- XY fish with wild type XX fish. Increased TUNEL staining and enhanced apoptosis maker gene (bax) expressions were also observed. Taken together, our data suggested that DHP activated physiology via pgr is crucial for the fertility in the XY tilapia. PMID- 29705271 TI - Effects of human SULT1A3/SULT1A4 genetic polymorphisms on the sulfation of acetaminophen and opioid drugs by the cytosolic sulfotransferase SULT1A3. AB - Sulfoconjugation has been shown to be critically involved in the metabolism of acetaminophen (APAP), morphine, tapentadol and O-desmethyl tramadol (O-DMT). The objective of this study was to investigate the effects of single nucleotide polymorphisms (SNPs) of human SULT1A3 and SULT1A4 genes on the sulfating activity of SULT1A3 allozymes toward these analgesic compounds. Twelve non-synonymous coding SNPs (cSNPs) of SULT1A3/SULT1A4 were investigated, and the corresponding cDNAs were generated by site-directed mutagenesis. SULT1A3 allozymes, bacterially expressed and purified, exhibited differential sulfating activity toward each of the four analgesic compounds tested as substrates. Kinetic analyses of SULT1A3 allozymes further revealed significant differences in binding affinity and catalytic activity toward the four analgesic compounds. Collectively, the results derived from the current study showed clearly the impact of cSNPs of the coding genes, SULT1A3 and SULT1A4, on the sulfating activity of the coded SULT1A3 allozymes toward the tested analgesic compounds. These findings may have implications in the pharmacokinetics as well as the toxicity profiles of these analgesics administered in individuals with distinct SULT1A3 and/or SULT1A4 genotypes. PMID- 29705272 TI - hsa-miR-93 regulates MUCIN family gene expression via WNT/beta-catenin pathway in intrahepatic stone disease. AB - BACKGROUND: Mucin plays an essential role in the intrahepatic stone formation, but the mechanism of mucin regulation is unclear. OBJECTIVE: To investigate the potential implication of miR-93 and WNT pathway in the regulation of intrahepatic bile duct mucin expression. METHODS: Thirty patients with or without intrahepatic bile duct stones are involved; Reverse-transcription polymerase chain reaction was performed to evaluate the expression of MUC3, MUC4, MUC5B, MUC5AC mRNA and miR-93 levels. miR-NC or miR-93 mimics was transfected into intrahepatic biliary epithelial cells. Then mucins and Wnt pathway proteins were detected by the immunoblotting, and the target gene TCF7 were validated using the dual luciferase assay. beta-catenin, wnt4, and mucins were an immunohistochemical stain of the intrahepatic biliary epithelial tissues. RESULTS: The expression levels of MUC3, MUC4, MUC5B, and MUC5AC in patients with intrahepatic bile duct stones are higher than control, as well as Wnt pathway proteins (especially beta-catenin and wnt4). Mucins levels increased in wnt4, wnt5a or SB216763-treated HIBECs, and reduced by miR-93 mimics transfection. miR-93 directly targeted TCF7 and repressed Wnt pathway protein expression, which reversed the upregulation of mucin levels induced by wnt4 or wnt5a, but not SB216763. CONCLUSION: These results suggest a new potential mechanism in intrahepatic stones, regulating by miR-93/TCF7, non canonical Wnt pathway, and mucins. PMID- 29705273 TI - Cold snare protrusion. PMID- 29705274 TI - Early onset lysosomal acid lipase deficiency presenting as secondary hemophagocytic lymphohistiocytosis: Two infants treated with sebelipase alfa. AB - Two unrelated infants were diagnosed with and initially treated for hemophagocytic lymphohistiocytosis (HLH), but progressed to cholestasis and liver failure. Early onset lysosomal acid lipase deficiency (EO-LAL-D) was suspected due to lymphocytes with cytoplasmic vacuolation and/or adrenal calcifications and confirmed by enzymatic and genetic analysis. Enzyme replacement therapy with sebelipase alfa was implemented, but both children died, despite initial improvement. Since this inborn error of metabolism progresses rapidly in infants, early diagnosis is crucial, and appropriate treatment should be started as soon as possible. The authors suggest that the diagnosis of EO-LAL-D should be considered in infants with symptoms of HLH. PMID- 29705275 TI - Conformational studies of Gram-negative bacterial quorum sensing acyl homoserine lactone (AHL) molecules: The importance of the n -> pi* interaction. AB - A 1H NMR study shows the presence of intermolecular hydrogen bonds for AHLs in CDCl3 solution. A detailed computational study of the structure of AHLs and the relative stability between the extended conformations (X) and those showing n -> pi* interactions (np) have been carried out by means of DFT calculations. Solvent effects have been shown to be very important when stabilising np conformations, particularly with polar solvents. This was shown by the shortening of C?O intramolecular distances and the increase in the relative energies favouring the np conformation with the dielectric constant of the solvent. The charge transfer between the O donor and the acceptor carbonyl group, assessed by second order perturbation energies, E(2), also shows an increase in the E(2) values with the dielectric constant of the solvent. PMID- 29705276 TI - Biophysical evaluation of cardiolipin content as a regulator of the membrane lytic effect of antimicrobial peptides. AB - Cardiolipin is an anionic tetra-acyl chained glycerophospholipid that increases lipid packing levels and induces intrinsic negative curvature in membranes. Cardiolipin is found in Staphylococcus aureus (S. aureus) membranes, where increased levels of this lipid are induced at the expense of diacyl phosphatidylglycerol in response to stress. We investigate cardiolipin as an inhibitor of the lytic activity of the cationic antimicrobial peptides LL-37 and ?M2 in model systems with varying phosphatidylglycerol/cardiolipin ratios. Using HPTLC, we show that S. aureus (RN4220), under different growth conditions, has a phosphatidylglycerol/cardiolipin ratio of 80:20. From this, we chose three model systems to evaluate (100:0, 80:20, 60:40). ?M2 presents higher binding affinity towards all mixtures compared to LL-37. This correlates with the higher antimicrobial activity of ?M2 compared to LL-37 in S. aureus (MIC90 of 14 MUM for ?M2 and 57.7 MUM for LL-37). Laurdan GP shows that Cardiolipin decreases lipid headgroup spacing. We find that cardiolipin does not affect ?M2 or LL-37 binding to phosphatidylglycerol/cardiolipin liposomes. Instead, cardiolipin inhibits the ability of both peptides to induce calcein leakage in model liposomes. In conclusion, cardiolipin can reduce cAMP activity by inhibiting lysis but not binding. PMID- 29705277 TI - Endotoxin Metabolism Reflects Hepatic Functional Reserve in End-Stage Liver Disease. AB - BACKGROUND: The hepatic clearance of endotoxin (Et) may reflect hepatic functional reserve and ischemic injury to hepatocytes. Therefore, we examined the relationships between Et activity (EA) and the metrics Pediatric End-Stage Liver Disease (PELD)/Model of End-Stage Liver Disease (MELD) score and alanine transaminase (ALT) levels in the postoperative period. METHODS: We performed 8 living-donor liver transplantations (LDLTs) for biliary atresia at our center from April 2012 to December 2012. EA was measured by means of an Et activity assay (EAA) in samples collected from a vein 1 day before LDLT, from the portal vein during the intraoperative anhepatic phase, from an artery 1 hour after reperfusion, from an artery on postoperative day (POD) 1, and from an artery or vein at PODs 7 and 14. RESULTS: EAs generally remained at low levels. EA at the reperfusion period was significantly lowest. The correlation coefficient for the preoperative MELD/PELD score and the EAA was 0.837, and the corresponding P value was .009; thus, there was a significant relationship between the preoperative MELD/PELD score and the EAA. The correlation coefficients for ALT at POD 1 and EA during the anhepatic phase, at 1 hour after reperfusion, and at POD 1 were 0.64, 0.43, and 0.38, respectively, and the P values for these correlations were .08, .67, and .34. Thus, we observed that ALT and EA generally tended to be somewhat directly correlated, but no significant relationships between these 2 metrics were observed. CONCLUSIONS: Endotoxin metabolism reflects the hepatic functional reserve capacity of end-stage liver disease. PMID- 29705278 TI - Diagnostic Usefulness of APRI and FIB-4 for the Prediction of Liver Fibrosis After Liver Transplantation in Patients Infected with Hepatitis C Virus. AB - BACKGROUND: Aspartate transaminase-to-platelet ratio index (APRI) and fibrosis-4 (FIB-4) are well known as representative indirect serum biomarkers related to liver fibrosis. The usefulness of these markers for the diagnosis of liver fibrosis after liver transplantation (LT) in hepatitis C virus (HCV)-infected patients and the influence of splenectomy were investigated. METHODS: From June 2003 to May 2014, 31 HCV-infected patients who underwent LT and postoperative follow-up liver biopsies were included in this study. The association between liver fibrosis and serum biomarkers and the influence of splenectomy on APRI and FIB-4 were also investigated. RESULTS: A total of 195 biopsy specimens were collected, and liver fibrosis was identified as: F0, 59.7%; F1, 34.1%; and F2, 6.3%. Both APRI and FIB-4 were significantly higher in patients who showed F1 and F2 in liver biopsy specimen than F0 (P values, .009 and .022, respectively); sensitivity and specificity of APRI were, respectively, 63.4% and 66.7%, and those of FIB-4 were 57.7% and 69.6%. In 11 patients (35.5%) who underwent splenectomy at the time of LT, the cutoff values for APRI and FIB-4 were 0.61 and 1.41, which were significantly lower than the corresponding values (1.00 and 3.64) of patients without splenectomy. CONCLUSIONS: APRI and FIB-4 could effectively estimate liver fibrosis after LT for HCV-related liver disease. For LT patients with splenectomy, APRI and FIB-4 were also useful to estimate liver fibrosis, but the standard values should be adjusted lower than those for patients without splenectomy. PMID- 29705279 TI - Effects of Subnormothermic Perfusion Before Transplantation for Liver Grafts from Donation After Cardiac Death: A Simplified Dripping Perfusion Method in Pigs. AB - BACKGROUND: Liver transplantation from donors after cardiac death (DCD) provides a solution to the donor shortage. However, DCD liver grafts are associated with a high incidence of primary graft nonfunction. We investigated the effectiveness of subnormothermic porcine liver perfusion, before transplantation from DCD, on graft viability. METHODS: Landrace pigs (25-30 kg) were randomly allocated to 3 groups (5 per group): heart-beating (HB) graft, transplanted after a 4-hour period of cold storage (CS); DCD graft, retrieved 20 minutes after apnea-induced cardiac arrest (respiratory withdrawal) and transplanted after a 4-hour period of CS; and subnormothermic ex vivo liver perfusion (SELP) graft, retrieved in the same manner as the DCD graft but perfused with a subnormothermic oxygenated Krebs Henseleit buffer (21-25 degrees C, 10-15 cm H2O) for 30 minutes in a simplified dripping manner, without a machine perfusion system, after the 4-hour period of CS, and subsequently transplanted. RESULTS: Although all animals in the HB group survived for >7 days, all animals in the DCD group died within 12 hours after transplantation. In the SELP group, 2 recipients survived for >7 days and another 2 recipients were killed on day 5. The survival rate was significantly better for SELP than for DCD grafts (P = .0016). The values of tumor necrosis factor alpha were not significantly different between the SELP and HB groups. Preserved structure of the parenchyma was observed in the SELP group on histologic examination. CONCLUSIONS: A simplified subnormothermic perfusion before liver transplantation is expected to improve graft viability and survival. PMID- 29705280 TI - Comparison of T1 Mapping and T1rho Values with Conventional Diffusion-weighted Imaging to Assess Fibrosis in a Rat Model of Unilateral Ureteral Obstruction. AB - RATIONALE AND OBJECTIVES: The aim of this study was to investigate the potential of magnetic resonance imaging (MRI) T1 mapping and T1 relaxation time in the rotating frame (T1rho) for assessment of renal fibrosis in a rat model of unilateral ureteral obstruction (UUO). MATERIALS AND METHODS: UUO was created in 36 rats. Six rats were scanned at each of the six time points (on days 0, 1, 3, 5, 10, and 15 after UUO). The contralateral kidneys were examined as controls. Hematoxylin-eosin, Masson's trichrome, and alpha-smooth muscle actin (alpha-SMA) antibody staining assays were performed. MRI data obtained with a 3.0T scanner were analyzed with alpha-SMA expression and Masson's staining. RESULTS: The T1 relaxation times and T1rho values increased, and the mean apparent diffusion coefficient (ADC) values decreased with time after UUO. Simple regression analysis indicated that the mean ADCs, T1 relaxation times, and T1rho values had strong correlations with the alpha-SMA expression levels (R2 = 0.34, R2 = 0.66, R2 = 0.71, respectively; P <.001) and positive Masson's staining (R2 = 0.38, R2 = 0.67, R2 = 0.65, respectively; P <.001). CONCLUSIONS: The T1 mapping and T1rho parameters had better correlations with alpha-SMA expression and Masson's staining than ADC values. PMID- 29705282 TI - Is Urodynamics Necessary when Assessing a Patient with Male Lower Urinary Tract Symptoms? AB - Urodynamics can distinguish bladder outlet obstruction from detrusor underactivity. Clear identification of the mechanism of a man's voiding symptoms can help give the best chance of good outcome from surgery. Publication of results from the UPSTREAM study will help in establishing the exact place for urodynamic testing in male lower urinary tract symptoms. PMID- 29705281 TI - A Multireader Exploratory Evaluation of Individual Pulse Sequence Cancer Detection on Prostate Multiparametric Magnetic Resonance Imaging (MRI). AB - RATIONALE AND OBJECTIVES: To determine independent contribution of each prostate multiparametric magnetic resonance imaging (mpMRI) sequence to cancer detection when read in isolation. MATERIALS AND METHODS: Prostate mpMRI at 3-Tesla with endorectal coil from 45 patients (n = 30 prostatectomy cases, n = 15 controls with negative magnetic resonance imaging [MRI] or biopsy) were retrospectively interpreted. Sequences (T2-weighted [T2W] MRI, diffusion-weighted imaging [DWI], and dynamic contrast-enhanced [DCE] MRI; N = 135) were separately distributed to three radiologists at different institutions. Readers evaluated each sequence blinded to other mpMRI sequences. Findings were correlated to whole-mount pathology. Cancer detection sensitivity, positive predictive value for whole prostate (WP), transition zone, and peripheral zone were evaluated per sequence by reader, with reader concordance measured by index of specific agreement. Cancer detection rates (CDRs) were calculated for combinations of independently read sequences. RESULTS: 44 patients were evaluable (cases median prostate specific antigen 6.83 [ range 1.95-51.13] ng/mL, age 62 [45-71] years; controls prostate-specific antigen 6.85 [2.4-10.87] ng/mL, age 65.5 [47-71] years). Readers had highest sensitivity on DWI (59%) vs T2W MRI (48%) and DCE (23%) in WP. DWI-only positivity (DWI+/T2W-/DCE-) achieved highest CDR in WP (38%), compared to T2W-only (CDR 24%) and DCE-only (CDR 8%). DWI+/T2W+/DCE- achieved CDR 80%, an added benefit of 56.4% from T2W-only and of 42% from DWI-only (P < .0001). All three sequences interpreted independently positive gave highest CDR of 90%. Reader agreement was moderate (index of specific agreement: T2W = 54%, DWI = 58%, DCE = 33%). CONCLUSIONS: When prostate mpMRI sequences are interpreted independently by multiple observers, DWI achieves highest sensitivity and CDR in transition zone and peripheral zone. T2W and DCE MRI both add value to detection; mpMRI achieves highest detection sensitivity when all three mpMRI sequences are positive. PMID- 29705283 TI - What's New in TIND? AB - CONTEXT: There is growing interest in minimally invasive (MI) treatment options for male lower urinary tract symptoms (LUTS). Among these options, the temporary implantable nitinol device (TIND; Medi-Tate, Or Akiva, Israel) is a novel instrument used to alleviate symptoms by creating incisions in the prostate via mechanical stress. OBJECTIVE: To review recent data for TIND as an MI procedure to improve LUTS. EVIDENCE ACQUISITION: Medline, PubMed, the Cochrane Database, and Embase were screened for clinical trials, randomized controlled trials, and review articles on the use of TIND in patients with male LUTS. EVIDENCE SYNTHESIS: There are currently two studies available, one being a follow-up of the first pilot study. Both 12-mo and 36-mo results suggest at least medium-term effects of TIND in terms of symptom improvement (International Prostate Symptom Score, IPSS) and maximum urinary flow (Qmax). IPSS was improved by 41% after 12mo (p<0.001) and worsened only insignificantly after 36mo compared to baseline values. Qmax increased by 4.4ml/s after 12mo (p<0.001) and did not decrease significantly after 36mo. Postoperative complications were mild and included urinary tract infection and urinary retention. CONCLUSIONS: Preliminary data suggest that TIND is a safe and effective MI technique for patients with male LUTS. Symptom relief and increase in urinary flow after 36mo are promising. However, long-term results are needed. PATIENT SUMMARY: Various treatment options for male patients suffering from urinary voiding symptoms are emerging. TIND, a temporary implantable nitinol device, appears to be a safe option that improves symptoms without affecting sexuality. PMID- 29705284 TI - Number of lymph nodes assessed has no prognostic impact in node-negative rectal cancers after neoadjuvant therapy. Results of the "Italian Society of Surgical Oncology (S.I.C.O.) Colorectal Cancer Network" (SICO-CCN) multicentre collaborative study. AB - INTRODUCTION: We retrospectively investigated the impact of number or complete absence of nodes retrieved on survival of patients with rectal cancer (RC) treated with neoadjuvant radiation-therapy (NAT). METHODS: All patients with RC treated with NAT followed by curative surgery from 2000 to 2014 in 14 Italian referral Centres for Colorectal Surgery were enrolled. Information about number of nodes harvested, node ratio, type of radiation therapy schedule and tumour stage were recorded. Impact of number or complete absence of nodes retrieved on overall survival (OS) and on cumulative incidence of death for disease (CIDD) was assessed and factors influencing node yield were investigated. RESULTS: In total, 1407 patients were included. Mean number of nodes retrieved was 12.9, while no lymph nodes were found in only 32 patients (2%, ypNnull). Definite nodal stage was ypN0 in 1001 patients (71%) and ypN+ in 372 patients (27%). In multivariable analysis ypNnull patients showed worse OS and CIDD compared to both ypN0 and ypN+. In ypN0 patients, number of nodes assessed, stratified in 4 groups (<5, 5 10, 11-15 and > 15), did not significantly influence OS and CIDD. Long-course radiation schedule and early T stages negatively affected node assessment. CONCLUSION: Complete absence of nodes assessed was associated with worse prognosis compared to node-negative and node-positive patients. In node-negative patients number of nodes was not associated to OS and CIDD. Based on data from this large population of irradiated RC, number of nodes assessed has no prognostic impact in node-negative patients. PMID- 29705285 TI - Contribution of lymph node staging method and prognostic factors in malignant ovarian sex cord-stromal tumors: A world wide database analysis. AB - OBJECTIVE: To investigate the clinicopathologic prognostic factors in patients with malignant sex cord-stromal tumors (SCSTs) with lymph node dissection, and at the same time, to evaluate the influence of the log odds of positive lymph nodes (LODDS) on their survival. METHODS: Patients diagnosed with malignant SCSTs who underwent lymph node dissection were extracted from the 1988-2013 Surveillance, Epidemiology, and End Results (SEER) database. Overall survival (OS) and cancer specific survival (CSS) were estimated by Kaplan-Meier curves. The Cox proportional hazards regression model was used to identify independent predictors of survival. RESULTS: 576 patients with malignant SCSTs and with lymphadenectomy were identified, including 468 (81.3%) patients with granulosa cell tumors (GCTs) and 80 (13.9%) patients with Sertoli-Leydig cell tumors (SLCTs). 399 (69.3%) patients and 118 (20.5%) patients were in the LODDS < -1 group and -1 <= LODDS < 0.5 group, respectively. The 10-year OS rate was 80.9% and CSS was 87.2% in the LODDS < -0.5 group, whereas the survival rates for other groups were 68.5% and 73.3%. On multivariate analysis, age 50 years or less (p < 0.001), tumor size of 10 cm or less (p < 0.001), early-stage disease (p < 0.001), and GCT histology (p <= 0.001) were the significant prognostic factors for improved survival. LODDS < 0.5 was associated with a favorable prognosis (OS: p = 0.051; CSS:P = 0.055). CONCLUSIONS: Younger age, smaller tumor size, early stage, and GCT histologic type are independent prognostic factors for improved survival in patients with malignant SCST with lymphadenectomy. Stratified LODDS could be regarded as an effective value to assess the lymph node status, and to predict the survival status of patients. PMID- 29705286 TI - Preoperative predictors of high and low axillary nodal burden in Z0011 eligible breast cancer patients with a positive lymph node needle biopsy result. AB - BACKGROUND: Z0011 trial showed that early breast cancer patients with low axillary nodal burden, may be spared an axillary lymph node dissection with no survival compromise. Axillary lymph node dissection can be reserved for patients with a high axillary nodal burden. We aim to determine the preoperative factors that could distinguish between low and high axillary nodal burden in Z0011 eligible patients with a needle biopsy proven metastatic node. METHOD: Patients who fulfilled Z0011 trial criteria with a positive lymph node needle biopsy and had axillary lymph node dissection (ALND) were recruited. These patients were classified into low and high nodal burden subgroups, defined as having 1-2 and >=3 metastatic lymph nodes, respectively. The clinical, radiological and pathological features between the 2 subgroups were compared. RESULTS: 70 (40%) and 105 (60%) patients had low and high nodal burden respectively. The high nodal burden subgroup was more likely to have on ultrasound >=3 abnormal lymph nodes (37.14% versus 4.29%) (P < 0.0001) and maximum cortical thickness >4 mm (31.43% versus 10.0%) (P = 0.0036). Multivariate analysis revealed abnormal lymph nodes >=3 to have an odds ratio of 20.72 (95% CI 5.91-72.65) P < 0.0001. CONCLUSION: >=3 abnormal lymph nodes on ultrasound was the most significant predictor of high nodal burden subgroup in Z0011 eligible patients with a positive lymph node needle biopsy. This information could allow this subgroup to proceed to an upfront ALND and avoid the need of a sentinel lymph node biopsy in the post Z0011 trial era. PMID- 29705287 TI - A population-based audit of surgical practice and outcomes of oncoplastic breast conservations in Scotland - An analysis of 589 patients. AB - INTRODUCTION: Current evidence for oncoplastic breast conservation (OBC) is based on single institutional series. Therefore, we carried out a population-based audit of OBC practice and outcomes in Scotland. METHODS: A predefined database of patients treated with OBC was completed retrospectively in all breast units practicing OBC in Scotland. RESULTS: 589 patients were included from 11 units. Patients were diagnosed between September 2005 and March 2017. High volume units performed a mean of 19.3 OBCs per year vs. low volume units who did 11.1 (p = 0.012). 23 different surgical techniques were used. High volume units offered a wider range of techniques (8-14) than low volume units (3-6) (p = 0.004). OBC was carried out as a joint operation involving a breast and a plastic surgeon in 389 patients. Immediate contralateral symmetrisation rate was significantly higher when OBC was performed as a joint operation (70.7% vs. not joint operations: 29.8%; p < 0.001). The incomplete excision rate was 10.4% and was significantly higher after surgery for invasive lobular carcinoma (18.9%; p = 0.0292), but was significantly lower after neoadjuvant chemotherapy (3%; p = 0.031). 9.2% of patients developed major complications requiring hospital admission. Overall the complication rate was significantly lower after neoadjuvant chemotherapy (p = 0.035). The 5 year local recurrence rate was 2.7%, which was higher after OBC for DCIS (8.3%) than invasive ductal cancer (1.6%; p = 0.026). 5-year disease-free survival was 91.7%, overall survival was 93.8%, and cancer-specific survival was 96.1%. CONCLUSION: This study demonstrated that measured outcomes of OBC in a population-based multi-centre setting can be comparable to the outcomes of large volume single centre series. PMID- 29705288 TI - Endogenous acetylcholine regulates neuronal and astrocytic vascular endothelial growth factor expression levels via different acetylcholine receptor mechanisms. AB - Vascular endothelial growth factor (VEGF), a signaling molecule involved in angiogenesis, plays an important role in neuroprotection and neurogenesis. In the present study, we aimed to elucidate the mechanisms underlying endogenous acetylcholine (ACh)-induced VEGF expression in neurons and astrocytes, and identify the neuronal cells contributing to its expression in the medial septal area, a nuclear origin of cholinergic neurons mainly projecting to the hippocampus. The mRNA expression and secretion of VEGF were measured by RT-PCR and ELISA using mouse primary cultured cortical neurons and astrocytes. VEGF expression in the medial septal area was assessed by RT-PCR and immunostaining using mice treated with tacrine [9-amino-1,2,3,4-tetrahydro-acridine HCl (THA); 2.5 mg/kg, i.p.] once daily for 7 days. The THA treatment increased VEGF mRNA expression in neurons in a manner that was reversed by mecamylamine, a nicotinic ACh receptor (AChR) antagonist, whereas in mouse primary cultured astrocytes, carbachol, but not THA dose-dependently increased VEGF mRNA expression and secretion in a manner that was inhibited by scopolamine, a muscarinic AChR inhibitor. In in vivo studies, the administration of THA significantly increased the expression of VEGF in medial septal cholinergic neurons and the effects of THA were significantly blocked by mecamylamine. THA also significantly increased the expression levels of a phosphorylated form of VEGF receptor 2 (p-VEGFR2), an activated form of VEGFR2. The present results suggest that endogenous ACh plays an up-regulatory role for VEGF expression in neurons and astrocytes via different mechanisms. Moreover, endogenous ACh-induced increases in VEGF levels appear to activate VEGFR2 on medial septal cholinergic neurons via an autocrine mechanism. PMID- 29705289 TI - Generativity affects fear of death through ego integrity in German, Czech, and Cameroonian older adults. AB - This cross-cultural study examined a potential direct effect of generativity and indirect effect through ego integrity on fear of death. In sum, 617 adults aged 60-86 from Germany, the Czech Republic, and Cameroon provided self-report information on their generative concern, ego integrity, and fear of death. Whereas it had no direct effect, generativity had an indirect effect on fear of death: It was associated with increased ego integrity which, in turn, was associated with reduced fear of death. This pattern was verified for the three cultural groups via structural equation modeling. Results suggest that generativity is not sufficient in coming to terms with one's mortality. Instead, generativity contributes to ego integrity which then helps to face death relatively unafraid. PMID- 29705290 TI - Investigation of the role of ion channels in human pancreatic beta-cell hubs: A mathematical modeling study. AB - In many cellular networks, the structure of the network follows a scale-free organization, where a limited number of cells are strongly coupled to other cells. These cells are called hub cells and their critical roles are well accepted. Despite their importance, there have been only a few studies investigating the characteristic features of these cells. In this paper, a computational approach is proposed to study the possible role of different ion channels in distinguishing between the hub and non-hub cells. The results show that the P/Q-type and T-type calcium channels may have an especial role in the beta-cell hubs because the high-level expressions of these channels make a pancreatic beta-cell more potent to force other coupled cells to follow it. In addition, in order to consider the variation of the coupling strength with voltage, a novel mathematical model is proposed for the gap junction coupling between the pancreatic beta-cells. The proposed approach is validated based on the data from the literature. PMID- 29705291 TI - Macrophages Promote Wound-Induced Hair Follicle Regeneration in a CX3CR1- and TGF beta1-Dependent Manner. AB - Hair follicle stem cells are regulated by intrafollicular and extrafollicular niche signals. Appropriate hair follicle regeneration relies on the coordinated release and integration of these signals. How immune cells, particularly cutaneous macrophages, influence the hair follicle stem cell niche and regeneration is not well understood. We took advantage of wound-induced hair growth (WIHG) to explore the relationship between wound macrophages and hair follicle regeneration. First, we showed that WIHG is dependent on CD11b+F4/80+ macrophages at 7-11 days after injury. Next, using CX3CR1gfp/+:CCR2rfp/+ mice to capture the dynamic spectrum of macrophage phenotypes during wound healing, we showed that wound macrophages transition from a CX3CR1lo/med to a CX3CR1hi phenotype at the onset of WIHG. Finally, WIHG is abolished in mice deficient for CX3CR1, delayed with pharmacological inhibition of transforming growth factor beta receptor type 1, and rescued with exogenous transforming growth factor beta1. Overall, we propose a model in which transforming growth factor-beta1 and CX3CR1 are critical for recruiting and maintaining the CCR2+CX3CR1hiLy6CloTNFalpha+ macrophages critical for stimulating WIHG. PMID- 29705292 TI - EphA2 Transmembrane Domain Is Uniquely Required for Keratinocyte Migration by Regulating Ephrin-A1 Levels. AB - EphA2 receptor tyrosine kinase is activated by ephrin-A1 ligand, which harbors a glycosylphosphatidylinositol anchor that enhances lipid raft localization. Although EphA2 and ephrin-A1 modulate keratinocyte migration and differentiation, the ability of this cell-cell communication complex to localize to different membrane regions in keratinocytes remains unknown. Using a combination of biochemical and imaging approaches, we provide evidence that ephrin-A1 and a ligand-activated form of EphA2 partition outside of lipid raft domains in response to calcium-mediated cell-cell contact stabilization in normal human epidermal keratinocytes. EphA2 transmembrane domain swapping with a shorter and molecularly distinct transmembrane domain of EphA1 resulted in decreased localization of this receptor tyrosine kinase at cell-cell junctions and increased expression of ephrin-A1, which is a negative regulator of keratinocyte migration. Accordingly, altered EphA2 membrane distribution at cell-cell contacts limited the ability of keratinocytes to seal linear scratch wounds in vitro in an ephrin-A1-dependent manner. Collectively, these studies highlight a key role for the EphA2 transmembrane domain in receptor-ligand membrane distribution at cell cell contacts that modulates ephrin-A1 levels to allow for efficient keratinocyte migration with relevance for cutaneous wound healing. PMID- 29705293 TI - Cytotoxicity of radiocontrast dyes in human umbilical cord mesenchymal stem cells. AB - Radiocontrast dyes are used for a wide range of diagnostic procedures for enhancing the image of anatomical structures, pain targets, and vascular uptake. While some of these dyes show toxicity to primary cells, their effect on stem cells, particularly mesenchymal stem cells (MSCs), is unknown. This study investigates the cytotoxic effects of two clinically used radiocontrast dyes, iohexol and iopamidol, on bone marrow and human umbilical cord MSCs. Exposure to these dyes significantly affected morphology of MSCs from both sources, as treated cells appeared transparent and no longer fibroblastoid. Cell viability decreased as determined by trypan blue and Annexin-V/PI staining, in a dose dependent manner with simultaneous loss of CD90 and CD105 concurrent with spontaneous differentiation in MSCs treated with iohexol and iopamidol. In addition, significantly higher cell death was observed in MSCs exposed to iopamidol than iohexol. At a concentration of 1:1, iohexol and iopamidol induced apoptosis in 19% and 92% (<.01) of MSCs, respectively. Global transcriptome analysis of treated MSCs revealed 139 and 384 differentially expressed genes in iohexol vs control and iopamidol vs control at p <= .01 and 1.5-fold, respectively. This suggested that iopamidol had more significant effect on the transcription of MSCs. Based on these results a molecular mechanism of radiocontast dye induced cell death via intrinsic apoptosis pathway mediated by p53 was proposed. Since iopamidol was significantly more toxic than iohexol in human MSCs, a more careful examination of safety of radiocontrast dyes for clinical use is warranted. PMID- 29705294 TI - Standardized methods for preparation and bi-variate length & diameter counting/sizing of aerosol and tissue digestion fiber samples. AB - Most fiber length distributions fit a log-normal distribution with their being many more shorter fibers present as compared to the longer fibers. As the longer fibers have been suggested to be more important for possible pathogenesis giving equal weight to all fiber lengths when sizing fibers will under sample the longer fibers. The methods described here, are based upon the optimization of fiber counting/sizing rules over a number years of experience and have been developed to provide a stable estimate of the mean number of particles and fibers present in the size ranges: particles, fibers < 5 MUm; 5-20 MUm; and >20 MUm. These methods were first applied using TEM, however, with the development of high resolution SEM, it was found that higher reproducibility could be obtained with SEM. PMID- 29705295 TI - Evaluation of the dose-response and fate in the lung and pleura of chrysotile containing brake dust compared to chrysotile or crocidolite asbestos in a 28-day quantitative inhalation toxicology study. AB - This study provides an understanding of the biokinetics and potential toxicology in the lung and pleura following inhalation of brake-dust (brakes manufactured with chrysotile). The design included a 28-day repeated multi-dose inhalation exposure (6 h/d, 5 d/wk, 4 wks) followed by 28-days without exposure. Fiber control groups included a similar grade chrysotile as used in the brakes and a commercial crocidolite asbestos. Aerosol fiber distributions of the chrysotile and crocidolite were similar (fiber-length > 20 MUm/cm3: Chrysotile-low/high 42/62; Crocidolite-low/high 36/55; WHO-fibers/cm3: Chrysotile-low/high 192/219; Crocidolite-low/high 211/255). The total number of aerosol particles/cm3 in the brake-dust was similar to that in the chrysotile (Brake-dust 710-1065; Chrysotile 532-1442). Brake-dust at particle exposure levels equal to or greater than chrysotile or crocidolite caused no indication of microgranulomas, epithelial hyperplasia, or fibrosis (Wagner score < 1.7) or changes in bronchoalveolar lavage (BAL) indices from the air control. Chrysotile BAL indices did not differ from the air control. Pathologically, there was low level of inflammation and epithelial hyperplasia, but no fibrosis (Wagner score <= 3). Crocidolite induced elevated neutrophils and cell damage (BAL), persistent inflammation, microgranulomas, and fibrosis (Wagner scores 4) which persisted through the post exposure period. Confocal microscopy of snap-frozen chestwalls showed no difference between control, brake-dust and chrysotile-HD groups or in thickness of visceral or parietal pleural. The crocidolite exposure resulted in extensive inflammatory response, collagen development and adhesions between the visceral and parietal surfaces with double the surface thickness. These results provide essential information for the design of a subsequent subchronic study. PMID- 29705296 TI - Glyphosate affects the secretion of regulators of uterine contractions in cows while it does not directly impair the motoric function of myometrium in vitro. AB - The effects of pure glyphosate and its most popular product (brand name: Roundup) on the secretion of hormones involved in the regulation of myometrial contractions as well as their direct effects on myometrial contractions were examined. Myometrial strips as well as uterine and ovarian cells were taken from cows during the oestrous cycle and they were treated with both compounds at concentrations from their environmental range. Glyphosate stimulated the secretion of oestradiol from granulosa cells while both herbicides increased and decreased oxytocin (OT) and progesterone secretion from luteal cells respectively. However only Roundup stimulated mRNA expression of the precursor of OT. Both compounds decreased the secretion of prostaglandins from endometrial cells while they exerted no effect on the basal and OT-stimulated force of myometrial contractions. The studied herbicides did not directly impair the motoric function of the myometrium. However our data indicate the potential of these compounds to disturb the secretory functions of the ovaries and uterus which can lead to the deregulation of uterine contractions and to the impairment of fertilisation or to difficulties in the maintenance of gestation. PMID- 29705297 TI - Effect of PLIF and TLIF on sagittal spinopelvic balance of patients with degenerative spondylolisthesis. AB - OBJECTIVE: The aim of this study was to evaluate the effects of PLIF and TLIF on sagittal spinopelvic balance and to compare radiological results of two surgical procedures with regard to spinopelvic parameters. METHODS: Thirty-five patients (34 female and 1 male; mean age: 52.29 +/- 13.08 (range: 35-75)) with degenerative spondylolisthesis cases were included in the study. Patients were divided into two groups according to surgical technique: PLIF and TLIF. The level and the severity of listhesis according to Meyerding classification were assessed and spinopelvic parameters including sacral slope, pelvic tilt, pelvic incidence (PI), lumbar lordosis, and segmental lumbar lordosis were measured on digital X rays. All preoperative and postoperative parameters and the results were compared between two groups. RESULTS: The age distribution was similar in both groups (p = 0.825) and there was no difference between the mean PI of the groups (p = 0.616). In 15 patients, spondylolisthesis level were at the L5-S1 level (PLIF: 8, TLIF: 7), in 16 patients at the L4-L5 level (PLIF: 6, TLIF: 10) and in 4 patients at the L3-L4 level (PLIF: 2, TLIF: 2). According to Meyerding classification, before the operation, the sliding grades were 0 in 4 patients, 1 in 21 patients, 2 in 7 patients, and 3 in 3 patients. The grades changed into 0 in 28 patients, 1 in 5 patients, and 2 in 2 patients after surgery. There were no differences in the grade of listhesis between PLIF and TLIF groups preoperatively (p = 0.190) and postoperatively (p = 0.208). In both groups, the spondylolisthesis-related deformities of patients were significantly corrected after surgery (p < 0.001). CONCLUSION: PLIF and TLIF techniques have similar radiological results in restoring the sagittal spinopelvic balance in patients with degenerative spondylolisthesis. Both techniques are good options to achieve reduction and fusion in patients with degenerative spondylolisthesis, but have no advantage over each other for restoring spinopelvic balance. LEVEL OF EVIDENCE: Level III, Therapeutic study. PMID- 29705298 TI - How accurate is visual estimation of perioperative blood loss in adolescent idiopathic scoliosis surgery? AB - OBJECTIVE: The aim of this study was to assess whether the visual estimation method for perioperative blood loss is accurate in adolescent idiopathic scoliosis surgery. METHODS: Sixty-five consecutive patients, who were operated on from 2012 to 2015 and had a diagnosis of AIS, were included into the study. Gender, age, preoperative weight and height, preoperative major curve magnitude and T5-T12 kyphosis angles, the fusion level, and the time of surgery were recorded. Perioperative blood loss was estimated by the same anesthesiologist for all patients. Then, an experienced surgeon estimated the perioperative blood loss by a gravimetric method, and the results were compared. RESULTS: Seventeen (26.2%) of the patients were male and 48 (73.8%) were female. The mean age was 15.8 +/- 1.9. The mean height of the patients was 162.1 +/- 8.9 cm and the mean weight was 52.6 +/- 8.9 kg. The mean preoperative major curve magnitude and kyphosis angles were 49.5 +/- 9.2 and 47.1 +/- 12.7 respectively. The mean estimate of the surgeon was 1009 +/- 404.5 ml and the mean estimate of the anesthesiologist was 434 +/- 217.6 ml and the difference was statistically significant (p < 0.05). Moreover, if blood loss was high during the operation, the difference between the estimates of the surgeon and anesthesiologist was also higher. CONCLUSIONS: Even in operations where most of the blood goes into a suction canister, such as for AIS, a visual estimation method is not accurate. A short training regarding optimizing the amount of blood contained in sponges that are not fully soaked may be sufficient to improve this method. PMID- 29705299 TI - Planarian regeneration between 1960s and 1990s: From skilful baffled ancestors to bold integrative descendants. A personal account. AB - Scientific fields grow by accretion of knowledge brought up by succesive generations of scientists. With the field of planarian regeneration as a general background, here I give a personal account of it from the late 1960s until the late 1990s when new research groups, namely Americans, broke into it. After a short historical summary, I report how I got into regeneration, why I choose planarians, and most especially the finding and description of the current model organism Schmidtea mediterranea. Next, I concentrate on the quantitative cellular approaches to regeneration, growth, and degrowth undertaken in our lab in Barcelona, and the long struggle to set neoblasts as a totipotent/pluripotent heterogeneous population of mitotic and non-mitotic cells for homeostatic somatic cell renewal, reproduction, and blastema formation during regeneration. Finally, the first attempts by several labs to analyze regeneration in molecular terms (RNAs, proteins, mAbs, gene detection, cloning and expression) are also covered. Along this essay, I am honoured to pay due tribute to our forebears (ancestors) from Morgan and Child to the French School researchers. In spite of being often baffled by planarian 'tricks', they struggled hard to find new techniques, new ways, and new ideas to tackle the main problems of regeneration, paving the way to those (descendants) that followed suit. PMID- 29705300 TI - Post-translational regulation of planarian regeneration. AB - Most mammals cannot easily overcome degenerative disease or traumatic injuries. In contrast, an innate ability to regenerate is observed across animal phyla. Freshwater planarians are amongst the organisms that are capable of stem cell mediated whole-body regeneration and have served as an exemplary model to study how pluripotency is maintained and regulated in vivo. Here, we review findings on the role of post-translational modifications and the genes regulating phosphorylation, ubiquitylation, and chromatin remodeling in planarian regeneration. Furthermore, we discuss how technological advances for identifying cellular targets of these processes will fill gaps in our knowledge of the signaling mechanisms that underlie regeneration in planarians, which should inform how tissue repair can be stimulated in non-regenerative model organisms and in humans. PMID- 29705301 TI - It is not all about regeneration: Planarians striking power to stand starvation. AB - All living forms, prokaryotes as eukaryotes, have some means of adaptation to food scarcity, which extends the survival chances under extreme environmental conditions. Nowadays we know that dietary interventions, including fasting, extends lifespan of many organisms and can also protect against age-related diseases including in humans. Therefore, the capacity of adapting to periods of food scarcity may have evolved billions of years ago not only to allow immediate organismal survival but also to be able to extend organismal lifespan or at least to lead to a healthier remaining lifespan. Planarians have been the center of attention since more than two centuries because of their astonishing power of full body regeneration that relies on a large amount of adult stem cells or neoblasts. However, they also present an often-overlooked characteristic. They are able to stand long time starvation. Planarians have adapted to periods of fasting by shrinking or degrowing. Here we will review the published data about starvation in planarians and conclude with the possibility of starvation being one of the processes that rejuvenate the planarian, thus explaining the historical notion of non-ageing planarians. PMID- 29705302 TI - Effect of ultrasound and chemical treatment on total phenol, flavonoids and antioxidant properties on carrot-grape juice blend during storage. AB - Ultrasonics is one of the developing technologies which is being studied extensively on different food commodities. Our aim was to study the effect of sonication and chemical (Potassium metabisulfite, K2S2O5,) preservation method on grape-carrot juice blend. Sonication/ultrasound treatments (20 kHz frequency, 70% amplitude level (525 W power), and pulse duration 5 s on and 5 s off, 5 min at 15 degrees C) of all the samples (250 mL) were performed by using an ultrasonic processor with 0.5 in. probe at 2 in. depth of the sample. Additionally, impact of sonication on 90 days of storage period at refrigerated temperature was also measured. It was observed that sonication had a positive effect on nutritional status of juice blend as it enhanced the total phenolic, flavonoid, reducing power and antioxidant properties of juice significantly (p < 0.05) with increase in sonication time. Sonication can be employed successfully for treatment of juice with better nutritional attributes from consumers' point of view. PMID- 29705303 TI - Silver-choline chloride modified graphene oxide: Novel nano-bioelectrochemical sensor for celecoxib detection and CCD-RSM model. AB - In this study, silver nanoparticles modified choline chloride functionalized graphene oxide (AgNPs-ChCl-GO) was synthesized using sonochemical method and utilized as a bioelectrochemical sensor for detection of celecoxib (CEL). The characterization studies were ultimately performed in order to acheive a more complete understanding of the morphological and structural features of the AgNPs ChCl-GO using different techniques including FT-IR, AFM, FE-SEM, EDX, and XRD. AgNPs-ChCl-GO demonstrated a significant improvement in the reduction activity of CEL due to the enhancement in the current response compared to the bare carbon paste electrode (CPE). The optimum experimental conditions, were optimized using central composite design (CCD) methodology. The differential pulse voltammetry (DPVs) showed an expanded linear dynamic ranges of 9.6 * 10-9-7.4 * 10-7 M for celecoxib in Britton-Robinson buffer in pH 5.0 with. LOD (S/N = 3) and LOQ (S/N = 10) were obtained 2.51 * 10-9 M and 6.58 * 10-9 M respectively. AgNPs-ChCl-GO carbon paste electrode exhibited suitable properties and high accuracy determination of celecoxib in the human plasma sample. PMID- 29705304 TI - Ultrasound assisted synthesis of WO3-ZnO nanocomposites for brilliant blue dye degradation. AB - The present work deals with the preparation of WO3 and WO3-ZnO nanocomposites in presence of ultrasonic irradiation, and its use in the sonocatalytic degradation of brilliant blue dye. WO3-ZnO nanocomposite is prepared using one step in-situ ultrasound assisted method. The successfully prepared WO3 and WO3-ZnO nanocomposites were characterized using different characterization techniques such as XRD, Raman, BET, FE-SEM and EDS. The XRD pattern reveals that the formation of monoclinic and hexagonal crystal structures of WO3 and ZnO respectively. BET study shows that WO3-ZnO nanocomposite have maximum surface area than that of the WO3. EDS study confirms the formation of WO3-ZnO nanocomposites. Further the use of the prepared WO3 and WO3-ZnO nanocomposites as a sonocatalyst for the degradation of brilliant blue dye. The rate constant (k) was evaluated as a function of the initial concentration of brilliant blue dye. It is found that WO3-ZnO nanocomposites exhibits maximum sonocatalytic activity as compared to WO3 photocatalyst. PMID- 29705305 TI - Investigation of the visible light photocatalytic activity of BiVO4 prepared by sol gel method assisted by ultrasonication. AB - Visible light induced photocatalyst BiVO4 with monoclinic scheelite structure has been synthesised via sol gel method assisted by ultrasonication. The prepared samples were characterised using X-ray diffraction (XRD), scanning electron microscope (SEM), UV-Vis diffused reflectance spectroscopy (DRS) techniques. The photocatalytic efficiency was evaluated by decolourisation of MB under visible light irradiation. The effect of ultrasound output power on the properties of BiVO4 during and after preparation by sol-gel method has been compared with normal agitated sample (As prepared). The power of ultrasonic vibration has been varied and an ideal output power which yields better catalytic efficiency is determined. BiVO4 sonicated with 80 W during preparation 80 W (D) exhibited relatively high surface area, better surface morphology and better catalytic efficiency compared to other samples which were sonicated with 100, 160 and 200 W. The results signify that the photodegradation rate of BiVO4 80 W (D) sample is high up to 96% in 90 min compared to other samples. Change in morphology leading to better catalytic efficiency was obtained just by exposing the sample to ultrasonic radiation without addition of any surfactant. The recovery test showed that the sample was stable for four consecutive cycles. Using radical test, a reasonable mechanism for photodegradation has been proposed. PMID- 29705306 TI - Investigation of tip sonication effects on structural quality of graphene nanoplatelets (GNPs) for superior solvent dispersion. AB - The exceptional properties of graphene and its structural uniqueness can improve the performance of nanocomposites if it can attain the uniform dispersion. Tip sonication assisted graphene solvent dispersion has been emerged as an efficient approach but it can cause significant degradation of graphene structure. This study aimed to evaluate the parametric influence of tip sonication on the characteristics of sp2 carbon structure in graphene nanoplatelets by varying the sonication time and respective energy at three different amplitudes (60%, 80% and 100%). The study is essential to identify appropriate parameters so as to achieve high-quality and defect-free graphene with a highly desirable aspect ratio after solvent dispersion for composite reinforcement. Quantitative approach via Raman spectroscopy is used to find the defect ratio and lateral size of graphene evolved under the effect of tip sonication parameters. Results imply that the defect ratio is steady and increases continually with GNPs, along with the transformation to the nano-crystalline stage I up to 60 min sonication at all amplitudes. Exfoliation was clearly observed at all amplitudes together with sheet re-stacking due to considerable size reduction of sheets with large quantity. Finally, considerable GNPs fragmentation occurred during sonication with increased amplitude and time as confirmed by the reduction of sp2 domain (La) and flake size. This also validates the formation of edge-type defect in graphene. Convincingly, lower amplitude and time (up to 60 min) produce better results for a low defect content and larger particle size as quantified by Raman analysis. PMID- 29705307 TI - A novel Z-scheme sonocatalyst system, Er3+:Y3Al5O12@Ni(Fe0.05Ga0.95)2O4-Au-BiVO4, and application in sonocatalytic degradation of sulfanilamide. AB - A novel Z-scheme coated composite, Er3+:Y3Al5O12@Ni(Fe0.05Ga0.95)2O4-Au-BiVO4, was designed for sonocatalytic degradation of sulfanilamide and fabricated by sol hydrothermal and calcination methods. The prepared sample was characterized by X ray diffractometer (XRD), transmission electron microscopy (TEM), scanning electron microscopy (SEM), X-ray photoelectron spectroscopy (XPS), energy dispersive X-ray spectroscopy (EDX), UV-vis diffuse reflectance spectra (DRS), fourier transform infrared (FT-IR) spectra, Raman spectra and photoluminescence (PL) spectra. In Er3+:Y3Al5O12@Ni(Fe0.05Ga0.95)2O4-Au-BiVO4, Ni(Fe0.05Ga0.95)2O4 and BiVO4 form a Z-scheme sonocatalytic system, Er3+:Y3Al5O12 as an up-conversion luminescence agent (from visible-light to ultraviolet-light) provides the ultraviolet-light for satisfying the energy demand of wide band-gap Ni(Fe0.05Ga0.95)2O4 and Au nanoparticles as co-catalyst forms more active sites to enrich electrons. Also, Au nanoparticles as conductive channels promotes the electrons (e-) from conduction band of BiVO4 to transfer to valence band of Ni(Fe0.05Ga0.95)2O4. Due to the characteristics of valence state diversity, the Fe3+ and V5+ constitute a redox reaction recombination system, which can also push electrons (e-) on conduction band of BiVO4 to quickly transfer to valence band of Ni(Fe0.05Ga0.95)2O4. The sonocatalytic activity of Er3+:Y3Al5O12@Ni(Fe0.05Ga0.95)2O4-Au-BiVO4 nanocomposite was detected through degradation of sulfanilamide under ultrasonic irradiation. A high sonocatalytic degradation ratio (95.64%) of sulfanilamide can be obtained when the conditions of 10.00 mg/L sulfanilamide, 1.00 g/L Er3+:Y3Al5O12@Ni(Fe0.05Ga0.95)2O4-Au-BiVO4, 300 min ultrasonic irradiation and 100 mL total volume were adopted. Some factors such as ultrasonic irradiation time and cycle number on the sonocatalytic degradation efficiency are also investigated by using TOC and UV-vis spectroscopy. Subsequently, the effects of hydroxyl radicals (OH) and hole scavengers were investigated to elaborate the mechanism. The researches show that the prepared Z-scheme Er3+:Y3Al5O12@Ni(Fe0.05Ga0.95)2O4-Au-BiVO4 coated composite displayed an excellent sonocatalytic activity in degradation of sulfanilamide under ultrasonic irradiation. PMID- 29705308 TI - One-pot sonochemical synthesis of magnetite@reduced graphene oxide nanocomposite for high performance Li ion storage. AB - In this research, we introduce a one-pot sonochemical method for the fabrication of magnetite@reduced graphene oxide (Fe3O4@rGO) nanocomposite as anode material for Li-ion batteries. Fe3O4@rGO is synthesized under ultrasonic irradiations by using iron (II) salt and GO as raw materials. An in-situ oxidation-reduction occurs between GO and Fe2+ during the ultrasonic chemical reaction process. Fe3O4 particles with the size of ~20 nm are uniformly deposited on the surface of rGO nanosheets. The electrochemical activity of Fe3O4@rGO is systematically evaluated as an anode material in Li-ion battery. Li-ion cells using Fe3O4@rGO as electrode deliver high discharge and charge capacities of 1433.6 and 907.8 mAh g-1 in the initial cycle at 200 mA g-1. Even performed at 500 and 5000 mA g-1, it is able to deliver reversible capacities of 846.4 and 355.6 mAh g-1, respectively, demonstrating outstanding Li-ion storage performance. This research presents a straightforward and efficient method for the fabrication of Fe3O4@rGO, which holds great potential in synthesis of other metal oxides on graphene sheets. PMID- 29705309 TI - Modeling of sonochemistry in water in the presence of dissolved carbon dioxide. AB - CO2 capture and utilization (CCU) is a process that captures CO2 emissions from sources such as fossil fuel power plants and reuses them so that they will not enter the atmosphere. Among the various ways of recycling CO2, reduction reactions are extensively studied at lab-scale. However, CO2 reduction by standard methods is difficult. Sonochemistry may be used in CO2 gas mixtures bubbled through water subjected to ultrasound waves. Indeed, the sonochemical reduction of CO2 in water has been already investigated by some authors, showing that fuel species (CO and H2) are obtained in the final products. The aim of this work is to model, for a single bubble, the close coupling of the mechanisms of bubble dynamics with the kinetics of gas phase reactions in the bubble that can lead to CO2 reduction. An estimation of time-scales is used to define the controlling steps and consequently to solve a reduced model. The calculation of the concentration of free radicals and gases formed in the bubble is undertaken over many cycles to look at the effects of ultrasound frequency, pressure amplitude, initial bubble radius and bubble composition in CO2. The strong effect of bubble composition on the CO2 reduction rate is confirmed in accordance with experimental data from the literature. When the initial fraction of CO2 in the bubble is low, bubble growth and collapse are slightly modified with respect to simulation without CO2, and chemical reactions leading to CO2 reduction are promoted. However, the peak collapse temperature depends on the thermal properties of the CO2 and greatly decreases as the CO2 increases in the bubble. The model shows that initial bubble radius, ultrasound frequency and pressure amplitude play a critical role in CO2 reduction. Hence, in the case of a bubble with an initial radius of around 5 MUm, CO2 reduction appears to be more favorable at a frequency around 300 kHz than at a low frequency of around 20 kHz. Finally, the industrial application of ultrasound to CO2 reduction in water would be largely dependent on sonochemical efficiency. Under the conditions tested, this process does not seem to be sufficiently efficient. PMID- 29705310 TI - Ultrasound assisted process intensification of uricase and alkaline protease enzyme co-production in Bacillus licheniformis. AB - Low energy ultrasound irradiation was used to enhance co-production of enzymes uricase and alkaline protease using Bacillus licheniformis NRRL 14209. Production of uricase and alkaline protease was evaluated for different ultrasound parameters such as ultrasound power, time of irradiation, duty cycle and growth stage of organisms at which irradiation is carried out. Maximum uricase production of 0.825 U/mL and alkaline protease of 0.646 U/mL have been obtained when fermentation broth was irradiated at 6 h of growth stage with 60 W power for 15 min of duration having 40% of duty cycle. The enzyme yield was found to be enhanced by a factor of 1.9-3.8 and 1.2-2.2 for uricase and alkaline protease respectively. Nevertheless, intracellular uricase was also observed in a fermentation broth after ultrasonic process intensification. The results indicate the effectiveness of low frequency ultrasound in improving enzyme yields with a vision of commercial applicability of the process. PMID- 29705311 TI - Sonochemical fabrication of Cu(II) and Zn(II) metal-organic framework films on metal substrates. AB - In this article, we demonstrate a rapid and facile method for in-situ growth of metal-organic framework (MOF) films on Cu or Zn metal substrates by sonochemical techniques. The substrates were first treated with a strong oxidizing agent to convert the metal to the corresponding metal hydroxide. Ultrasonic irradiation provided the energy to drive the reaction between the metal ion sources and organic ligands. Four MOF films (Cu-BTC, Cu-BDC, ZIF-8 and MOF-5) were successfully fabricated by this approach. The produced films were characterized by scanning electron microscopy and X-ray diffraction analysis. The effects of organic ligand concentration and ultrasonic irradiation time on MOF film synthesis were also systematically investigated. The rapid and facile fabrication method presented in this article could serve a new route to grow MOF films on various gas sensor surfaces. Of the MOF films, ZIF-8 film was tested as a potential methane sensor. PMID- 29705312 TI - Sonochemical synthesis of terbium tungstate for developing high power supercapacitors with enhanced energy densities. AB - Sonochemically prepared nanoparticles of terbium tungstate (TWNPs) were evaluated through scanning electron microscopy (SEM), thermogravimetric analysis (TGA), X ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR), UV-Vis spectroscopy, and the optimal products were further characterized in terms of their electrochemical properties using conventional and continuous cyclic voltammetry (CV, and CCV), galvanostatic charge/discharge technique, and electrochemical impedance spectroscopy (EIS). The CV studies indicated the TWNPs to have specific capacitance (SC) values of 336 and 205 F g-1 at 1 and 200 mV s 1, and galvanostatic charge-discharge tests revealed the SC of the TWNP-based electrodes to be 300 F g-1 at 1 Ag-1. Also continuous cyclic voltammetry evaluations proved the sample as having a capacitance retention value of 95.3% after applying 4000 potential cycles. In the light of the results TWNPs were concluded as favorable electrode materials for use in hybrid vehicle systems. PMID- 29705313 TI - Ultrasound-assisted synthesis and characterization of a new metal-organic framework based on azobenzene-4,4-dicarboxylic acid: Precursor for the fabrication of Co3O4 nano-particles. AB - Azobenzene groups are widely known as photochromic ligands thus are particularly interesting building blocks for designing receptors for neutral or charged guests. A new metal-organic framework, [Co3(adc)3(DMF)4].2DMF (compound 1) (adc = azobenzene-4,4-dicarboxylic acid, DMF = N,N-dimethylformamide), was synthesized by solvothermal methods and structurally characterized using X-ray crystallography and a range of spectroscopic techniques. Also, nanorods of compound 1 have been synthesized by a sonochemical process and characterized by field emission scanning electron microscopy (FE-SEM) and powder X-ray diffraction (PXRD). The effect of sonication time and concentration of the initial reagents on the size and morphology of the MOF have been optimized. Results indicate that decreasing of initial concentration and increasing ultrasound radiation time lead to small size nanorods of compound 1. Thus, ultrasound radiation affects the size of nanorods. After heat treatment, the cobalt ion-based metal organic framework nanorods can be converted into porous Co3O4 nanoparticles. PMID- 29705314 TI - Experimental investigation on the effect of ultrasonic waves on reducing asphaltene deposition and improving oil recovery under temperature control. AB - A well-known complication in the oil reservoir during oil production is asphaltene deposition in and around the production wellbore. Deposition of asphaltene around the production wellbore may cause a significant pressure drop and in turn loss of efficiency in the production process. Various mechanical and chemical methods have been employed in order to reduce asphaltene formation or to eliminate the precipitate. A novel technique which presented a great potential for prevention or elimination of asphaltene is spreading out the high energy ultrasound wave within the oil reservoir. In this study, in a glass micro-model, asphaltene precipitation was first simulated in a transparent porous medium and its removal by application of high energy ultrasound wave was then investigated. To simulate asphaltene precipitation, the micro-model was first saturated with oil and then a normal-pentane was injected. This was followed by flooding the porous media with brine while propagating ultrasound waves (30 kHz and 100 W) to eliminate asphaltene precipitation. The experiment setup was equipped with a temperature controller. The results indicate a significant reduction in asphaltene precipitation in the oil reservoir may be achieved by application of ultrasound energy. Asphaltene particle deposition has been solved reversibly in the oil layer of porous medium and with the oil layering mechanism, the rate of oil production has been increased. In some spots, water/oil emulsion has been formed because of the ultrasonic vibration on the wall. Both the crude and synthetic oils were examined. PMID- 29705315 TI - Sono-chemical treatment of per- and poly-fluoroalkyl compounds in aqueous film forming foams by use of a large-scale multi-transducer dual-frequency based acoustic reactor. AB - Aqueous film-forming foams (AFFFs) contain a mixture of organic chemicals, including per- and poly-fluorinated, alkyl sulfonate substances (PFAS) (1-5%, w/w). Some longer-chain PFAS can be toxic, moderately bioaccumulative and persistent in the environment. In the present work, decomposition of PFAS present in two commercially available AFFFs (ANSUL- and 3M-) was investigated using a sono-chemical reactor of volume 91 L. The reactor consists of 12 transducers with operating frequencies of 1 MHz or 500 kHz and total input power of 12 kW. Degradation of PFASs performed using various dilutions of AFFF revealed that release of F- and SO4-2 ions was inversely proportional to initial pH of up to 4. Defluorination of ANSUL-AFFF resulted in an increase in the concentration of F- released from 55.6 +/- 0.3 uM (500* dilution) to 58.6 +/- 0.6 (25* dilution), while for 3M AFFF it increased from 19.9 +/- 0.7 uM (500* dilution) to 217.1 +/- 2.4 uM (25* dilution). Though amounts of F- released were less for ANSUL-AFFF than for 3M-AFFF, there was a considerable increase in removal of TOC and release of SO4-2 present in ANSUL-AFFF. Approximately 90.5% and 26.6% reduction of perfluoroalkyl sulfonates (PFSA) and perfluoroalkyl carboxylates (PFCA) in 3M, respectively, and 38.4% reduction of fluorotelomer sulfonates in ANSUL-AFFF were achieved in 13 h. Estimated costs of energy for the treatment of ANSUL-AFFF and 3M-AFFF at a 500* dilution were $0.015 +/- 0.0001/L and $0.019 +/- 0.0002/L, respectively. PMID- 29705316 TI - Ultrasonic soldering of Cu alloy using Ni-foam/Sn composite interlayer. AB - In this study, Cu alloy joints were fabricated with a Ni-foam reinforced Sn-based composite solder with the assistance of ultrasonic vibration. Effects of ultrasonic soldering time on the microstructure and mechanical properties of Cu/Ni-Sn/Cu joints were investigated. Results showed that exceptional metallurgic bonding could be acquired with the assistance of ultrasonic vibration using a self-developed Ni-foam/Sn composite solder. For joint soldered for 5 s, a (Cu,Ni)6Sn5 intermetallic compound (IMC) layer was formed on the Cu substrate surface, Ni skeletons distributed randomly in the soldering seam and a serrated (Ni,Cu)3Sn4 IMC layer was formed on the Ni skeleton surface. Increasing the soldering time to 20 s, the (Ni,Cu)3Sn4 IMC layer grew significantly and exhibited a loose porous structure on the Ni skeleton surface. Further increase the soldering time to 30 s, Ni skeletons were largely dissolved in the Sn base solder, and micro-sized (Ni,Cu)3Sn4 particles were formed and dispersed homogeneously in the soldering seam. The formation of (Ni,Cu)3Sn4 particles was mainly ascribed to acoustic cavitations induced erosion and grain refining effects. The joint soldered for 30 s exhibited the highest shear strength of 64.9 +/- 3.3 MPa, and the shearing failure mainly occurred at the soldering seam/Cu substrate interface. PMID- 29705317 TI - Ultrasound-accelerated synthesis of biphenyl compounds using novel Pd(0) nanoparticles immobilized on bio-composite. AB - This study describes (i) an eco-friendly approach for design of Pd(0) nanoparticles on a natural composite, which is composed of carboxymethyl cellulose/agar polysaccharides (CMC/AG), without using any toxic reducing agents and (ii) development of ultrasound assisted simple protocol for synthesis of biphenyl compounds. Chemical characterization studies of Pd(0) nanoparticles (Pd NPs@CMC/AG) revealed that size of the particles were in the range of 37-55 nm. Catalytic performance of Pd NPs@CMC/AG was evaluated in synthesis of various biphenyl compounds by using the ultrasound-assisted method that was developed in this study. Pd NPs@CMC/AG exhibited excellent catalytic performance by producing high reaction yields. In addition, Pd NPs@CMC/AG was successfully used up to six reaction cycles without losing its catalytic activity, indicating high reproducibility of Pd NPs@CMC/AG. Additionally, compared to conventional the methods, new ultrasound-assisted synthesis technique that was followed in this study exhibited some advantages such as shorter reaction time, greener reaction conditions, higher yields and easier work-up. PMID- 29705318 TI - Chiral betulin-imino-chitosan hydrogels by dynamic covalent sonochemistry. AB - A series of chiral hydrogels was prepared from a homogeneous mixture of chitosan and betulinic aldehyde in different molar ratios, under the effect of ultrasound. The hydrogelation mechanism has been investigated by FTIR and CD spectroscopy, wide angle X-ray diffraction and polarized light microscopy. The morphology of hydrogels was examined by SEM. The swelling ability has been tested in three media of different pH. It was concluded that hydrogelation occurred by different pathways, closely related to the peculiarities of the chitosan-betulin systems. Circular dichroism measurements revealed chiroptical properties of the hydrogels, correlated to their content and crosslinking pathway. PMID- 29705319 TI - Wastewater treatment for Amoxicillin removal using magnetic adsorbent synthesized by ultrasound process. AB - In this study, the effect of magnetic adsorbent prepared from Olive kernel (MA OK) was studied in the Amoxicillin (AMX) removal. The synthesized adsorbent, under a sonochemical method, were characterized using Field emission scanning electron microscope (FESEM), Fourier transform infrared spectroscopy (FTIR), Brunauer-Emmett-Teller (BET) and X-ray diffraction (XRD). The absorption functions in the batch experiments were studied using the expected parameters for the maximum absorption capacities (qm) such as pH, contact time, the dosage adsorbent, and the initial concentration of AMX. The residual amount of AMX were recorded after injection into the HPLC. The proportion of the mobile phase was methanol to water (40:60) at a flow rate of 1 ml/min. Adsorption experimental results indicated that the removal efficiency reaches its maximum using 0.5 g/L of the adsorbent, concentration of AMX (200 mg/L) at contact time of 90 min and pH of 6. The kinetics of the reaction and the adsorption isotherm could be well described by the pseudo-second order equation and the Langmuir adsorption isotherm with a regression coefficient of 0.9981 and 0.9979, respectively. The maximum adsorption capacity obtained from the Langmuir model was to be 238.1 mg/g. The ionic strength of the solution has no significant effect on increasing the AMX removal efficiency. Eventually, application of this adsorbent was successfully performed for removing AMX from aqueous and hospital wastewater solutions. PMID- 29705320 TI - Highly effective degradation of selected groups of organic compounds by cavitation based AOPs under basic pH conditions. AB - Cavitation has become on the most often applied methods in a number of industrial technologies. In the case of oxidation of organic pollutants occurring in the aqueous medium, cavitation forms the basis of numerous advanced oxidation processes (AOPs). This paper presents the results of investigations on the efficiency of oxidation of the following groups of organic compounds: organosulfur, nitro derivatives of benzene, BTEX, and phenol and its derivatives in a basic model effluent using hydrodynamic and acoustic cavitation combined with external oxidants, i.e., hydrogen peroxide, ozone and peroxone. The studies revealed that the combination of cavitation with additional oxidants allows 100% oxidation of the investigated model compounds. However, individual treatments differed with respect to the rate of degradation. Hydrodynamic cavitation aided by peroxone was found to be the most effective treatment (100% oxidation of all the investigated compounds in 60 min). When using hydrodynamic and acoustic cavitation alone, the effectiveness of oxidation was diversified. Under these conditions, nitro derivatives of benzene and phenol and its derivatives were found to be resistant to oxidation. In addition, hydrodynamic cavitation was found to be more effective in degradation of model compounds than acoustic cavitation. The results of investigations presented in this paper compare favorably with the investigations on degradation of organic contaminants using AOPs under conditions of basic pH published thus far. PMID- 29705321 TI - A novel two-step ultrasound post-assisted lye peeling regime for tomatoes: Reducing pollution while improving product yield and quality. AB - In this paper, the effects and mechanisms of a novel two-step tomato peeling method, hot lye with a post-assistance of ultrasound, were investigated. The present work aims to improve the environmental friendliness of the conventional hot lye tomato peeling method (10% w/v, 97 degrees C, 45 s). The results showed that 4% (w/v) lye treatment at 97 degrees C for 30 s with a post-assistance of a 31.97 W/L ultrasound treatment at 70 degrees C for 50 s achieved a 100% peelability. In this scenario, the peeling yield and lycopene content in the peeled product were significantly higher than the peeling yield and lycopene content with the conventional hot lye peeling method. The present two-step peeling method was concluded with a mechanism of chemico-mechanical synergism, in which the hot lye functions mainly in a chemical way while the ultrasound is a mechanical process. Especially from the lye side, this work first demonstrated that the lye penetrated across the tomato skin via a pitting model rather than evenly. The findings reported in this paper not only provide a novel tomato peeling method with significant environmental benefits but also discover new clues to the peeling mechanism using hot lye. PMID- 29705322 TI - Sono-photocatalytic production of hydrogen by interface modified metal oxide insulators. AB - Dielectric oxide materials are well-known insulators that have many applications in catalysis as well as in device manufacturing industries. However, these dielectric materials cannot be employed directly in photochemical reactions that are initiated by the absorption of UV-Vis photons. Despite their insensitivity to solar energy, dielectric materials can be made sono-photoactive even for low energy IR photons by modifications of the interfacial properties of dielectric materials by noble metals and metal oxides. In this investigation, by way of interface modification of dielectric MgO nanoparticles by Ag metal and Ag2O nanoparticles, IR photon initiated sono-photocatalytic activity of MgO is reported. The observed photocatalytic activity is found to be the synergic action of both IR light and sonication effect and sonication assisted a multi-step, sub bandgap excitation of electrons in the MgO is proposed for the observed catalytic activity of Ag/Ag2O coated MgO nanoparticles. Our investigation reveals that other dielectric materials such as silver coated SiO2 and Al2O3 also exhibit IR active sono-photocatalytic activity. PMID- 29705323 TI - A review on heterogeneous sonocatalyst for treatment of organic pollutants in aqueous phase based on catalytic mechanism. AB - Heterogeneous sonocatalysis, as an emerging advanced oxidation process (AOP), has shown immense potential in water treatment and been widely demonstrated to remove persistent organic compounds in the past decade. The present article aims to provide a comprehensive review on the development of a heterogeneous catalyst for enhancing the ultrasonic degradation rate of organic pollutants from a viewpoint of sonocatalytic mechanism. The rational design and fundamentals for preparing sonocatalysts are presented in the context of facilitating the heterogeneous nucleation and photo-thermal-catalytic effects as well as considering the mechanical stability and separation capacity of the heterogeneous catalyst. In addition, some new trends, ongoing challenges and possible methods to overcome these challenges are also highlighted and proposed. PMID- 29705324 TI - Sonochemical synthesis and structural characterization of a new Zn(II) nanoplate metal-organic framework with removal efficiency of Sudan red and Congo red. AB - A 3-D Zn(II) based metal-organic framework (MOF) of [Zn4(oba)3(DMF)2] was synthesized using the nonlinear dicarboxylate ligand, 4,4'-oxybis(benzoic acid) (H2oba) via sonochemical and solvothermal routes. IR spectroscopy, single-crystal X-ray crystallography, scanning electron microscopy, and X-ray powder diffraction were used to characterize these MOF samples. The effect of different times of irradiation and various concentrations of primary reagents were experimented for obtaining monotonous morphology. The results show that uniform nanoplates can be achieved by increasing the time of irradiation and decreasing the concentration. N2 adsorption was applied to examine the effect of synthesis method on porosity of the framework. Also Congo red and Sudan red dyes were employed to explore the efficiency of this MOF in removal of the dye pollutants. PMID- 29705325 TI - Efficient and controllable thermal ablation induced by short-pulsed HIFU sequence assisted with perfluorohexane nanodroplets. AB - A HIFU sequence with extremely short pulse duration and high pulse repetition frequency can achieve thermal ablation at a low acoustic power using inertial cavitation. Because of its cavitation-dependent property, the therapeutic outcome is unreliable when the treatment zone lacks cavitation nuclei. To overcome this intrinsic limitation, we introduced perfluorocarbon nanodroplets as extra cavitation nuclei into short-pulsed HIFU-mediated thermal ablation. Two types of nanodroplets were used with perfluorohexane (PFH) as the core material coated with bovine serum albumin (BSA) or an anionic fluorosurfactant (FS) to demonstrate the feasibility of this study. The thermal ablation process was recorded by high-speed photography. The inertial cavitation activity during the ablation was revealed by sonoluminescence (SL). The high-speed photography results show that the thermal ablation volume increased by ~643% and 596% with BSA-PFH and FS-PFH, respectively, than the short-pulsed HIFU alone at an acoustic power of 19.5 W. Using nanodroplets, much larger ablation volumes were created even at a much lower acoustic power. Meanwhile, the treatment time for ablating a desired volume significantly reduced in the presence of nanodroplets. Moreover, by adjusting the treatment time, lesion migration towards the HIFU transducer could also be avoided. The SL results show that the thermal lesion shape was significantly dependent on the inertial cavitation in this short-pulsed HIFU mediated thermal ablation. The inertial cavitation activity became more predictable by using nanodroplets. Therefore, the introduction of PFH nanodroplets as extra cavitation nuclei made the short-pulsed HIFU thermal ablation more efficient by increasing the ablation volume and speed, and more controllable by reducing the acoustic power and preventing lesion migration. PMID- 29705326 TI - Acoustic cavitation induced synthesis of zirconium impregnated activated carbon for effective fluoride scavenging from water by adsorption. AB - Environmental concern associated with the side effects of high fluoride content in ground water and surface water has prompted the researchers to look for an efficient, convenient and easy method. Considering the potential of a good adsorbent, present study reports the synthesis of a composite by impregnating zirconium on powdered activated carbon (AC) using ultrasound as the tool for synthesis and applying it for fluoride adsorption from water. The nature of the composite was determined through characterization by scanning electron microscopy (SEM), energy dispersive Xray (EDX), Xray diffraction (XRD), N2 adsorption analysis (BET) and Fourier Transform Infrared Spectroscopy (FTIR) analysis. The pHpzc (point of zero charge) of the adsorbent was found to be 5.03; with the optimum pH obtained at 4 for adsorption of strong electronegative fluoride ions. The initial fluoride concentration was varied from 2.5 up to 20 mg.L-1 and the maximum adsorption capacity of 5 mg.g-1 was obtained. A maximum fluoride removal of 94.4% was obtained for an initial concentration of 2.5 mg.L-1 within an equilibrium time of 180 min. The adsorption isotherm followed the Langmuir isotherm model indicating a monolayer adsorption process and the adsorption kinetics followed pseudo second order model. The effects of various coexisting ions (HCO3-, NO3-, SO42-, Cl-) commonly present in the water were found to have negligible impact on the process performance. Conducting the adsorption desorption studies for five consecutive cycles for an initial fluoride concentration of 10 mg.L-1, the removal efficiency reduced from 86.2 to 32.6%. The ultrasonic method provided an easy route to synthesize the composite in less time and significantly reduced energy consumption by more than 96% compared to the conventional method. PMID- 29705327 TI - Numerical modelling of acoustic pressure fields to optimize the ultrasonic cleaning technique for cylinders. AB - Fouling build up is a well-known problem in the offshore industry. Accumulation of fouling occurs in different structures, e.g. offshore pipes, ship hulls, floating production platforms. The type of fouling that accumulates is dependent on environmental conditions surrounding the structure itself. Current methods deployed for fouling removal span across hydraulic, chemical and manual, all sharing the common disadvantage of necessitating halting production for the cleaning process to commence. Conventionally, ultrasound is used in ultrasonic baths to clean a submerged component by the generation and implosion of cavitation bubbles on the fouled surface; this method is particularly used in Reverse Osmosis applications. However, this requires the submersion of the fouled structure and thus may require a halt to production. Large fouled structures such as pipelines may not be accommodated. The application of high power ultrasonics is proposed in this work as a means to remove fouling on a structure whilst in operation. The work presented in this paper consists of the development of a finite element analysis model based on successful cleaning results from a pipe fouled with calcite on the inner pipe wall. A Polytec 3D Laser Doppler Vibrometer was used in this investigation to study the fouling removal process. Results show the potential of high power ultrasonics for fouling removal in pipe structures from the wave propagation across the structure under excitation, and are used to validate a COMSOL model to determine cleaning patterns based on pressure and displacement distributions for future transducer array design and optimization. PMID- 29705328 TI - Nakagami-m parametric imaging for characterization of thermal coagulation and cavitation erosion induced by HIFU. AB - Nowadays, both thermal and mechanical ablation techniques of HIFU associated with cavitation have been developed for noninvasive treatment. A specific challenge for the successful clinical implementation of HIFU is to achieve real-time imaging for the evaluation and determination of therapy outcomes such as necrosis or homogenization. Ultrasound Nakagami-m parametric imaging highlights the degrading shadowing effects of bubbles and can be used for tissue characterization. The aim of this study is to investigate the performance of Nakagami-m parametric imaging for evaluating and differentiating thermal coagulation and cavitation erosion induced by HIFU. Lesions were induced in basic bovine serum albumin (BSA) phantoms and ex vivo porcine livers using a 1.6 MHz single-element transducer. Thermal and mechanical lesions induced by two types of HIFU sequences respectively were evaluated using Nakagami-m parametric imaging and ultrasound B-mode imaging. The lesion sizes estimated using Nakagami-m parametric imaging technique were all closer to the actual sizes than those of B mode imaging. The p-value obtained from the t-test between the mean m values of thermal coagulation and cavitation erosion was smaller than 0.05, demonstrating that the m values of thermal lesions were significantly different from that of mechanical lesions, which was confirmed by ex vivo experiments and histologic examination showed that different changes result from HIFU exposure, one of tissue dehydration resulting from the thermal effect, and the other of tissue homogenate resulting from mechanical effect. This study demonstrated that Nakagami-m parametric imaging is a potential real-time imaging technique for evaluating and differentiating thermal coagulation and cavitation erosion. PMID- 29705329 TI - Ultrasound-induced liquid/solid interfacial reaction between Zn-3Al alloy and Zr based bulk metallic glasses. AB - Ultrasound-assisted fluxless brazing of Zr based Bulk metallic glasses (Zr-BMG) joint using Zn-3Al filler metal was performed in this study. The effect of ultrasonic vibration time on the microstructure and mechanical properties of Zr BMG joints were investigated. Results showed that excellent metallurgic bonding could be obtained in ultrasonically brazed Zr-BMG joints. The interfacial reaction between liquid Zn-3Al filler metal and Zr-BMG substrate showed a mutation characteristic, which could be distinguished into incubation period and acceleration period. In the incubation period, Zn50Zr25Al25 intermetallic compounds (IMCs) with small ellipsoidal shape were slowly formed and distributed randomly on Zr-BMG surface. However, in the acceleration period, Zn50Zr25Al25 ellipsoids developed rapidly into a wavy-structured IMCs layer with a thickness of 17 MUm, which was comprised of alternate Zn50Zr25Al25 and Zn22Zr sublayers. The microstructure evolution of Zn-3Al/Zr-BMG interface was ascribed to the combined effects of acoustic cavitations and Al element controlled interfacial metallurgic reactions. The average shear strength of joint was increased firstly then decreased slightly with increasing ultrasonic vibration time, and a highest strength value of approximately 100 MPa was obtained for joints brazed for 96 s. The shearing failure was inclined to occur at the Zn-3Al/Zr-BMG interface then transferred into the interfacial IMCs layer with increasing ultrasonic vibration time. PMID- 29705330 TI - Optimizing dewaterability of drinking water treatment sludge by ultrasound treatment: Correlations to sludge physicochemical properties. AB - Sludge dewatering has proven to be an effective method to reduce the volume of sludge. In this study, drinking water treatment sludge (DWTS) was treated by ultra-sonication under variable conditions comparing two sonoreactor types (bath and probe), four frequencies (25, 40, 68, 160 kHz) and four energy density levels (0.03, 1, 3, 5 W/mL). The effects of these conditions were studied using specific resistance to filtration and capillary suction time as measures of dewaterability, and floc size, the Brunauer, Emmett and Teller (BET) specific surface area and Zeta potential to determine treated sludge characteristics. The results indicated that the dewaterability of sonicated sludge improved at relatively low energy densities of 0.03 and 1.0 W/mL, while an optimum for sonication duration (within 10 min) was also identified. Higher frequencies (tested up to 160 kHz) with acoustic energy density of 0.03 W/mL also reduced the dewatering property. At higher energy densities of 3.0 and 5.0 W/mL, dewaterability of sludge deteriorated regardless of ultra-sonication time, with an increase of solubilized organic matter content and severely changed floc characteristics. The deterioration of the dewatering capacity was closely related to the considerably reduced floc sizes, dissolution of proteins and polysaccharides, and to the Zeta potential of sonicated sludge flocs. The dewaterability was not correlated with BET specific surface area. Mechanistic explanations for the observations were discussed by analyzing corrosion patterns of aluminum foil as a measure for cavitation field distribution. PMID- 29705331 TI - Disparate levels of beta-catenin activity determine nephron progenitor cell fate. AB - Formation of a functional kidney depends on the balance between renewal and differentiation of nephron progenitors. Failure to sustain this balance can lead to kidney failure or stem cell tumors. For nearly 60 years, we have known that signals from an epithelial structure known as the ureteric bud were essential for maintaining this balance. More recently it was discovered that one molecule, Wnt9b, was necessary for both renewal and differentiation of the nephron progenitor cells. How one ligand signaling through one transcription factor promoted two seemingly contradictory cellular processes was unclear. In this study, we show that Wnt9b/beta-catenin signaling alone is sufficient to promote both renewal and differentiation. Moreover, we show that discrete levels of beta catenin can promote these two disparate fates, with low levels fostering progenitor renewal and high levels driving differentiation. These results provide insight into how Wnt9b regulates distinct target genes that balance nephron progenitor renewal and differentiation. PMID- 29705334 TI - Modulation of TGFbeta/Smad signaling by the small GTPase RhoB. AB - We have shown previously that the small GTPases RhoA and RhoB play important roles in early TGFbeta-induced actin cytoskeleton reorganization and that RhoB is transcriptionally activated by TGFbeta and its signaling effectors, the Smad proteins. However, this long-term impact of RhoB gene upregulation by TGFbeta on cellular functions is not known. We now show that increased levels of RhoB, but not of RhoA, inhibit the TGFbeta/Smad-mediated transcriptional induction of the cell cycle inhibitor p21WAF1/Cip1 gene as well as of a generic Smad-responsive promoter suggesting that RhoB could be part of an auto-inhibitory loop in TGFbeta signaling by inhibiting the genomic responses to TGFbeta. We show that RhoB blocks the interaction of Smad3 with the type I TGFbeta receptor which prohibits its phosphorylation by this receptor and its translocation to the nucleus. Using in vivo GST pull-down and co-immunoprecipitation assays we show that Smad3 physically interacts with RhoB but not with RhoA. We show that RhoB, but not RhoA, potently regulates actin cytoskeleton reorganization by inducing stress fiber formation in a Smad-dependent manner. Finally we show that Smad3 downregulates the expression of the epithelial adherens junctions protein E Cadherin and upregulates the fibronectin gene in Smad3-/- JEG3 cells only in the presence of RhoB suggesting that RhoB/Smad3 complexes in the cytoplasm may be involved in epithelial to mesenchymal transitions. In summary, our data propose a novel mechanism of TGFbeta/Smad signaling modulation by the small GTPase RhoB and show that this TGFbeta/RhoB signaling cross talk affects the nuclear and cytoplasmic responses to TGFbeta in opposite ways. PMID- 29705333 TI - Shh signaling influences the phenotype of Pitx1-/- hindlimbs. AB - Forelimbs (FLs) and hindlimbs (HLs) develop under the instructive and integrated guidance of signaling centers and transcription factor (TF) action. The development of structures specific to each limb type depends on the limb-specific modulation of these integrated components. Pitx1 is a transcription factor gene expressed in HL, absent in FL, and required for HL-specific patterning and development, in particular for formation of anterior HL skeletal elements. Pitx1 achieves this function by direct TF action on the core limb program, which is largely shared between FL and HL. Shh signaling plays a crucial role in anterior posterior (AP) patterning in both FL and HL. The present work assessed the relationship between Shh signaling and Pitx1 action for AP patterning. We found that reducing the gene dosage of Shh in the context of the Pitx1-/- HL decreases the severity of the Pitx1-/- phenotype, in particular, the loss of anterior limb structures and the shortening of femur length. However, this did not rescue HL specific patterning features. Thus, Pitx1 action integrates Shh signaling but not for limb-type-specific patterning. PMID- 29705332 TI - Transcriptional profiling of the CAM plant Agave salmiana reveals conservation of a genetic program for regeneration. AB - In plants, the best characterized plant regeneration process is de novo organogenesis. This type of regeneration is characterized by the formation of a multicellular structure called callus. Calli are induced via phytohormone treatment of plant sections. The callus formation in plants like Agave species with Crassulacean Acid Metabolism (CAM) is poorly studied. In this study, we induced callus formation from Agave salmiana leaves and describe cell arrangement in this tissue. Moreover, we determined and analyzed the transcriptional program of calli, as well as those of differentiated root and leaf tissues, by using RNA seq. We were able to reconstruct 170,844 transcripts of which 40,644 have a full Open Reading Frame (ORF). The global profile obtained by Next Generation Sequencing (NGS) reveals that several callus-enriched protein coding transcripts are orthologs of previously reported factors highly expressed in Arabidopsis calli. At least 62 genes were differentially expressed in Agave calli, 50 of which were up-regulated. Several of these are actively involved in the perception of, and response to, auxin and cytokinin. Not only are these the first results for the A. salmiana callus, but they provide novel data from roots and leaves of this Agave species, one of the largest non-tree plants in nature. PMID- 29705335 TI - Molecular mechanisms of platelet activation and aggregation induced by breast cancer cells. AB - Tumor cell-induced platelet aggregation represents a critical process both for successful metastatic spread of the tumor and for the development of thrombotic complications in cancer patients. To get further insights into this process, we investigated and compared the molecular mechanisms of platelet aggregation induced by two different breast cancer cell lines (MDA-MB-231 and MCF7) and a colorectal cancer cell line (Caco-2). All the three types of cancer cells were able to induce comparable platelet aggregation, which, however, was observed exclusively in the presence of CaCl2 and autologous plasma. Aggregation was supported both by fibrinogen binding to integrin alphaIIbbeta3 as well as by fibrin formation, and was completely prevented by the serine protease inhibitor PPACK. Platelet aggregation was preceded by generation of low amounts of thrombin, possibly through tumor cells-expressed tissue factor, and was supported by platelet activation, as revealed by stimulation of phospholipase C, intracellular Ca2+ increase and activation of Rap1b GTPase. Pharmacological inhibition of phospholipase C, but not of phosphatidylinositol 3-kinase or Src family kinases prevented tumor cell-induced platelet aggregation. Tumor cells also induced dense granule secretion, and the stimulation of the P2Y12 receptor by released ADP was found to be necessary for complete platelet aggregation. By contrast, prevention of thromboxane A2 synthesis by aspirin did not alter the ability of all the cancer cell lines analyzed to induce platelet aggregation. These results indicate that tumor cell-induced platelet aggregation is not related to the type of the cancer cells or to their metastatic potential, and is triggered by platelet activation and secretion driven by the generation of small amount of thrombin from plasma and supported by the positive feedback signaling through secreted ADP. PMID- 29705336 TI - Does intrawound vancomycin powder reduce surgical site infection after posterior instrumented spinal surgery? A propensity score-matched analysis. AB - BACKGROUND CONTEXT: Recent reports suggested that placing vancomycin powder into surgical wounds before closure can prevent surgical site infections (SSIs) in spinal surgery. PURPOSE: The present study aimed to evaluate if intrawound vancomycin powder could prevent SSIs after spinal surgery with posterior instrumentation. STUDY DESIGN: This is a multicenter retrospective cohort study using propensity score matching. PATIENT SAMPLE: We reviewed all spinal surgeries performed with posterior instrumentation from July 2012 to December 2014 at 11 institutions among patients aged >=15 years. OUTCOME MEASURES: The incidence of SSIs was compared between patients who received intrawound vancomycin powder (vancomycin group) and those who did not (control group). METHODS: Demographic and operative data and microbiological findings of SSI cases were analyzed. After a preliminary whole-cohort analysis, we performed one-to-one propensity score matching to adjust for the differences between the two groups and then compared the incidence of SSIs between the matched groups. No funds were received in support of this work. No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript. RESULTS: A total of 2,859 patients were included in the study. In the vancomycin and control groups (n=694 and n=2165, respectively), 12 (1.73%) and 21 (0.97%) patients developed SSIs, respectively, but the difference was not statistically significant (p=.10, chi-square test). During the propensity score matched analysis, 507 pairs were analyzed. No significant change in the rate of SSIs was seen between the vancomycin and control groups (8 SSIs [1.58%] vs. 9 SSIs [1.78%], respectively; p=.81, chi-square test). Microbiological analysis revealed that 5 of 12 (42%) and 11 of 21 (52%) SSIs in the vancomycin and control groups, respectively, were caused by Staphylococcus (p=.72, Fisher exact test). CONCLUSIONS: Intrawound application of vancomycin powder was not associated with a significant decrease in the incidence of SSIs after posterior instrumented spinal surgeries in a propensity score-matched analysis. However, the rate of infections caused by Staphylococcus species was lower in the vancomycin group. PMID- 29705337 TI - Cost-effectiveness of circumferential fusion for lumbar spondylolisthesis: propensity-matched comparison of transforaminal lumbar interbody fusion with anterior-posterior fusion. AB - BACKGROUND CONTEXT: Transforaminal lumbar interbody fusion (TLIF) and dual approach anteroposterior (AP) are common techniques to achieve circumferential fusion for lumbar spondylolisthesis. It is unclear which approach is more cost effective. PURPOSE: Our goal was to determine the incremental cost-effectiveness ratio (ICER) by calculating the cost per quality-adjusted life year (QALY) for each approach. STUDY DESIGN/SETTING: This study is a propensity-matched cost effectiveness comparison. PATIENT SAMPLE: Patients with lumbar spondylolisthesis undergoing single-level AP fusion or TLIF and enrolled in a prospective observational surgical database were included in this study. OUTCOME MEASURES: The outcome measures in this study were the Oswestry Disability Index (ODI) and the Short Form-6D (SF-6D). METHODS: From a prospective surgical database, patients with lumbar spondylolisthesis undergoing single-level AP fusion were propensity matched to a TLIF cohort based on age, gender, body mass index, smoking status, workers compensation, preoperative ODI, and back and leg pain numeric scores. Quality-adjusted life years gained were determined using baseline and 1- and 2-yearpostoperative SF-6D scores. Cost was calculated from actual, direct hospital costs and included subsequent postsurgical costs (epidural spinal injections, spine-related emergency department visits, readmissions, and revision surgery). RESULTS: Thirty-one cases of AP fusions were identified and propensity matched to 31 TLIF patients. Patients undergoing TLIF had a shorter mean operative time (270 vs. 328 minutes, p=.039) but no difference in estimated blood loss (526 vs. 548 cc, p=.804) or hospital length of stay (4.5 vs. 6.1 days, p=.146). Quality-adjusted life years gained at 2 years were also similar (0.140 vs. 0.130, p=.672). The mean index surgery and the total 2-year costs were lower for TLIF compared with AP (index: $29,428 vs. $31,466; final: $30,684 vs. $331,880). As overall costs were lower and QALYs gained were similar for TLIF compared with AP fusion, TLIF was the dominant intervention with an ICER of $116,327. CONCLUSIONS: Under our study parameters, surgical treatment of lumbar spondylolisthesis with TLIF is more cost-effective compared with AP fusion. Because of the short-term follow-up, the longevity of this should be further investigated. PMID- 29705338 TI - Correcting sample drift using Fourier harmonics. AB - During image acquisition of crystalline materials by high-resolution scanning transmission electron microscopy, the sample drift could lead to distortions and shears that hinder their quantitative analysis and characterization. In order to measure and correct this effect, several authors have proposed different methodologies making use of series of images. In this work, we introduce a methodology to determine the drift angle via Fourier analysis by using a single image based on the measurements between the angles of the second Fourier harmonics in different quadrants. Two different approaches, that are independent of the angle of acquisition of the image, are evaluated. In addition, our results demonstrate that the determination of the drift angle is more accurate by using the measurements of non-consecutive quadrants when the angle of acquisition is an odd multiple of 45 degrees . PMID- 29705339 TI - Pseudoallergic conjunctivitis induced by tamsulosin, a selective alpha-1 adrenergic receptor antagonist. PMID- 29705340 TI - Demographic, social, economic and geographic factors associated with long-term outcomes in a cohort of cardiac arrest survivors. AB - BACKGROUND: Demographic, social, economic and geographic factors are associated with increased short-term mortality after cardiac arrest. We sought to determine if these factors are additionally associated with long-term outcome differences using a detailed clinical database linked to state-wide administrative data. METHODS: We included cardiac arrest patients surviving to hospital discharge from five hospitals in the United States from 2005 to 2013, with follow-up through 2015. We obtained information on sex, race, arrest location, initial rhythm, median ZIP code income, post-arrest illness severity, cardiac catheterization, internal cardioverter-defibrillator insertion, rural residence and drive time from residence to the nearest acute care hospital. We used Cox proportional hazard models identify predictors of mortality. RESULTS: We included 891 patients followed for 2081 patient-years. There were 340 deaths with median survival 6 years. In adjusted models we identified an interaction effect between median ZIP code income and cardiac catheterization. Among patients who had cardiac catheterization there was an attenuated benefit from cardiac catheterization at progressively lower neighborhood incomes (adjusted HR: 0.21 to 0.46 to 0.56). Residence more than 20 min from the nearest acute care hospital was associated with increased hazard of death (adjusted HR: 1.48; 95%CI: 1.35-1.62), after controlling for rural residence and residence in a Medically Underserved Area/Population. Female patients showed less benefit following ICD placement (male adjusted HR: 0.49; female adjusted HR: 0.66). CONCLUSIONS: There are persistent long-term outcome differences in cardiac arrest survival based on sex, income, and geographic access acute care. PMID- 29705341 TI - Reply letter: Neurocognitive and behavioral outcomes in a nearly drowned child with cardiac arrest and hypothermia resuscitated after 43 min of no flow-time: A case study. PMID- 29705342 TI - miR-145 via targeting ERCC2 is involved in arsenite-induced DNA damage in human hepatic cells. AB - Arsenic, an established human carcinogen, causes genetic toxicity. However, the molecular mechanisms involved remain unknown. MicroRNAs (miRNAs) are regulators that participate in fundamental cellular processes. In the present investigation, we selected, as research subjects, patients with arsenic poisoning caused by burning of coal in Guizhou Province, China. For these patients, the plasma levels of miR-145 were up-regulated. In L-02 cells, arsenite, an active form of arsenic, induced up-regulation of miR-145 and down-regulation of ERCC1 and ERCC2, and caused DNA damage. For L-02 cells, transfection with an miR-145 inhibitor prevented arsenite-induced DNA damage and decreased ERCC2 levels. Luciferase reporter assays showed that miR-145 regulated ERCC2 expression by targeting the 3'-UTR of ERCC2, but not that for ERCC1. The present results demonstrate that arsenite induces the over-expression of miR-145 and inhibits DNA repair via targeting ERCC2, thus promoting DNA damage. The information provides a new mechanism for arsenic-induced liver injury. PMID- 29705344 TI - Postoperative complications as a predictor for survival after liver transplantation - proposition of a prognostic score. AB - BACKGROUND: Liver transplantation is major surgery with a high risk of complications. Existing scoring systems for evaluating complications after surgery are not specific for liver transplantation. Nor are they designed to evaluate the relation to recipient survival or graft loss. We wished to uncover the relation between postoperative complications and one-year risk of death or retransplantation, and to develop a prognostic score for complications based on our findings. METHOD: The study was a retrospective cohort study including 253 adult liver recipients. Thirty-days postoperative complications were registered using the Clavien-Dindo classification. A prognostic score was developed based on types, severity, and quantity of complications. RESULTS: A total of 1113 complications occurred in 233 (92.1%) of the patients. One-year mortality or graft loss was associated with graft, biliary, surgical, systemic, pulmonary, cardiovascular, renal, and infectious complication but not with neurologic or gastrointestinal complications. The developed score was more accurate in predicting the outcome than both the modified Clavien-Dindo score and the Comprehensive Complication Index. CONCLUSION: Types, severity, and quantity of different postoperative complications after liver transplantation are not equally important. The proposed score may focus attention on treating or preventing complications with strong relation to recipient mortality or graft loss. PMID- 29705343 TI - CDK5-mediated tau accumulation triggers methamphetamine-induced neuronal apoptosis via endoplasmic reticulum-associated degradation pathway. AB - Overexposure to methamphetamine (METH) causes apoptosis in a number of cell types, particularly neuronal cells. However, the underlying mechanisms of METH induced neuronal apoptosis remain to be elucidated. Accumulation of microtubule associated protein Tau can lead to activation of multiple neurotoxic pathways, which is closely correlated with neuronal apoptosis. The aim of this study was to determine the role of Tau in METH-induced neuronal apoptosis. We determined the expression of two phosphorylated Tau proteins (serine 396 and threonine 231) in the human neuroblastoma SH-SY5Y cells and in the hippocampus of Sprague-Dawley rats treated with vehicle or METH using western blotting, immunohistochemical staining and immunofluorescence staining. We also measured the expression levels of the phosphorylated Tau protein, ubiquitination proteins, the intermediate products of proteasome degradation pathway, CD3-delta (a substrate of proteasome degradation pathway), endoplasmic reticulum stress signal molecule phosphorylated PERK (pPERK), and endoplasmic reticulum stress-specific apoptotic signal molecule caspase-12 in SH-SY5Y cells and in rats after inhibiting the expression of an upstream regulatory factor of phosphorylated Tau protein (CDK5) using siRNA or virus transfection. The results showed that exposure to METH significantly up regulated the expression of phosphorylated Tau protein in vivo and in vitro and silencing the expression of CDK5 inhibited the up-regulation of phosphorylated Tau induced by METH exposure. METH exposure also significantly increased the expression of ubiquitination protein and CD3-delta and these effects were blocked by CDK5 silencing. In addition, METH exposure significantly elevated the levels of phosphorylated PERK and caspase-12 and these effects were suppressed after CDK5 silencing, which indicates that blockade of CDK5 expression can mitigate METH-induced neuronal apoptosis. These results suggest that METH can impair the endoplasmic reticulum-associated degradation (ERAD) pathway and induce neuronal apoptosis through endoplasmic reticulum stress, which is mainly mediated by abnormal CDK5-regulated Tau phosphorylation. PMID- 29705345 TI - Does blood group affect survival following pancreatoduodenectomy for periampullary malignancy? AB - BACKGROUND: Blood group is reported to have an effect upon survival following pancreatoduodenectomy for pancreatic ductal adenocarcinoma. The effect of blood group is not known, however, among patients with other periampullary cancers. This study sought to review this. METHODS: Data were collected for a range of factors and survival outcomes from patients treated at two centres. Those with blood groups B and AB were excluded, due to small numbers. Patient survival was compared between patients with blood groups O and A using multivariable analysis which accounted for confounding factors. RESULTS: Among 431 patients, 235 (54.5%) and 196 (45.5%) were of blood groups A and O respectively. Baseline comparisons found a significant difference in the distribution of tumour types (p = 0.011), with blood group O patients having more ampullary carcinomas (33.2% vs 23.4%) and less pancreatic ductal adenocarcinomas (45.4 vs 61.3%) than group A. On multivariable analysis, after accounting for confounding factors including pathologic variables, survival was found to be significantly shorter in those with blood group A than group O (p = 0.047, HR 1.30 [95%CI: 1.00-1.69]). CONCLUSIONS: There is a difference in the distribution of blood groups across the different types of periampullary cancers. Survival is shorter among blood group A patients. PMID- 29705346 TI - Pancreatoduodenectomy with colon resection for pancreatic cancer: a systematic review. AB - BACKGROUND: Radical resection of advanced pancreatic cancer may occasionally require a simultaneous colon resection. The risks and benefits of this combined procedure are largely unknown. This systematic review aimed to assess short and long term outcome after pancreatoduodenectomy with colon resection (PD-colon) for pancreatic ductal adenocarcinoma (PDAC). METHODS: A systematic literature search was performed in PubMed, Embase, and the Cochrane Library for studies published between 1994 and 2017 concerning PD-colon for PDAC. RESULTS: After screening 2038 articles, 5 articles with a total of 181 patients undergoing PD-colon were eligible for inclusion. Included studies showed a relatively low risk of bias. The pooled complication rate was 73% (95% CI 61-84) including a pooled colonic anastomotic leak rate of 5.5%. Pooled mortality was 10% (95% CI 6-15). Pooled mean survival (data from 86 patients) was 18 months (95% CI 13-23) with pooled 3- and 5-year survival of 31% (95% CI 20-72) and 19% (95% CI 6-38). CONCLUSION: Based on the available data, PD-colon for PDAC seems to be associated with an increased morbidity and mortality but with survival comparable with standard PD in selected patients. Future large series are needed to allow for better patient selection for PD-colon. PMID- 29705347 TI - Prevalence and Correlates of Low Pain Interference Among Patients With High Pain Intensity Who Are Prescribed Long-Term Opioid Therapy. AB - : The pain experience may vary greatly among individuals reporting equally high levels of pain. We sought to examine the demographic and clinical characteristics associated with pain interference in patients with high pain intensity. Among patients with chronic musculoskeletal pain who were prescribed long-term opioid therapy and who were recruited from 2 health care systems, we identified a subset who reported high pain intensity (n = 189). All individuals completed self-report assessments of clinical and demographic factors. Analyses examined characteristics associated with pain interference. Within this group of patients with high reported pain intensity, 16.4% (n = 31) had low pain interference, 39.2% (n = 74) had moderate pain interference, and 44.4% (n = 84) had high pain interference. In bivariate analyses, patients with lower pain interference had fewer symptoms of depression and anxiety, less pain catastrophizing, a better quality of life, and greater self-efficacy for managing pain. In multivariate analyses, variables most strongly associated with low pain interference, relative to high interference, were depression severity (odds ratio 0.90; 95% confidence interval 0.82-0.99) and pain self-efficacy (odds ratio 1.07; 95% confidence interval 1.02-1.12). Study results suggest that chronic pain treatments that address symptoms of depression and enhance pain self-efficacy may be prioritized, particularly among patients who are prescribed long-term opioid therapy. PERSPECTIVE: This article describes the prevalence and correlates of pain interference categories (low, medium, and high) among patients with high pain intensity who are prescribed long-term opioid therapy. Findings reveal that 16.4% of participants with high pain intensity had low impairment. Multivariate analyses indicate that variables significantly associated with low pain interference were lower depression scores and greater pain self-efficacy. PMID- 29705348 TI - Proteoglycans contribute locally to swelling, but globally to compressive mechanics, in intact cervine medial meniscus. AB - Loss of charged proteoglycans in the knee meniscus, which aid in the support of compressive loads by entraining water, is an effect of degeneration and is often associated with osteoarthritis. In healthy menisci, proteoglycan content is highest in the inner white zone and decreases towards the peripheral red zone. We hypothesized that loss of proteoglycans would reduce both osmotic swelling and compressive stiffness, spatially localized to the avascular white zone of the meniscus. This hypothesis was tested by targeted enzymatic digestion of proteoglycans using hyaluronidase in intact cervine medial menisci. Mechanics were quantified by creep indentation on the femoral surface. Osmotic swelling changes were assessed by measuring collagen fiber crimp period in the radial axial plane in the lamellar layer along both the tibial and femoral contacting surfaces. All measurements were made in the inner, middle, and outer zones of the anterior, central, and posterior regions. Mechanical measurements showed variation in creep behavior with anatomical location, along with spatially uniform decreases in viscosity (average of 21%) and creep stiffness (average of 15%) with hyaluronidase treatment. Lamellar collagen crimp period was significantly decreased (average of 27%) by hyaluronidase, indicating a decrease in osmotic swelling, with the largest decreases seen in locations with the highest proteoglycan content. Taken together, these results suggest that while proteoglycans have localized effects on meniscus swelling, the resulting effect on compressive properties is distributed throughout the tissue. PMID- 29705349 TI - The control structure of the nematode Caenorhabditis elegans: Neuro-sensory integration and proprioceptive feedback. AB - We develop a biophysically realistic model of the nematode C. elegans that includes: (i) its muscle structure and activation, (ii) key connectomic activation circuitry, and (iii) a weighted and time-dynamic proprioception. In combination, we show that these model components can reproduce the complex waveforms exhibited in C. elegans locomotive behaviors, chiefly omega turns. This is achieved via weighted, time-dependent suppression of the proprioceptive signal. Though speculative, such dynamics are biologically plausible due to the presence of neuromodulators which have recently been experimentally implicated in the escape response, which includes an omega turn. This is the first integrated neuromechanical model to reveal a mechanism capable of generating the complex waveforms observed in the behavior of C. elegans, thus contributing to a mathematical framework for understanding how control decisions can be executed at the connectome level in order to produce the full repertoire of observed behaviors. PMID- 29705350 TI - miRNA-150-5p associate with antihypertensive effect of epigallocatechin-3-gallate revealed by aorta miRNome analysis of spontaneously hypertensive rat. AB - AIMS: The antihypertensive mechanism (s) of the epigallocatechin-3-gallate (EGCG), a major effective component in green tea, might associate with microRNAs (miRNAs). Here, we aimed to investigate which microRNA in aorta of spontaneously hypertensive rats (SHRs) were modulated by administration of EGCG and its mechanism. MAIN METHODS: The pharmacokinetic behaviors of EGCG and epigallocatechin (EGC) in Sprague-Dawley rats were analyzed by HPLC and DRUG AND STATISTICS software. Blood pressure of SHRs was monitored by the tail-cuff method, the miRNomes of aorta from SHRs was analyzed with deep sequencing, and expression of hypertension-associated miRNAs with significant change and their host genes and target genes were validated by real-time PCR and Western blot. KEY FINDINGS: The plasma deposition of EGCG and EGC best fitted a mono-compartmental model with maximum plasma concentration post-dose (Cmax, 6.65 vs 4.45 MUg/ml) and the corresponding time (Tmax, 15 vs 10 min). Systolic blood pressure (SBP) of SHRs decreased to the lowest point by 34.04 mmHg and recovered by 23.39 mmHg after 15 and 30 min of administration at dose of 300 mg/kg BW EGCG, respectively, and it decreased again at 60 min and recovered at time 2 h. Total 35 upregulated and 18 downregulated miRNAs were identified compared to the control group (p < .01) after EGCG administration. Expression of hypertension-associated miRNA-126a 3p and miRNA-150-5p were further validated. In turn, their host gene and target genes were up-regulated and down-regulated, respectively. SIGNIFICANCE: Our results indicated that miRNA-150-5p might be involved in the antihypertensive effect of EGCG through SP1/AT1R pathway. PMID- 29705351 TI - Stimulation of nitric oxide-sensitive soluble guanylate cyclase in monocrotaline induced pulmonary hypertensive rats. AB - AIMS: In this study, we examined whether a disruption in the balance between nitric oxide (NO)-sensitive and -insensitive soluble guanylate cyclase (sGC) is observed in pulmonary hypertension (PH) and whether treatment with NO-enhancing drugs can halt disease progression. MAIN METHODS: Rats were injected subcutaneously with saline or 60 mg/kg monocrotaline (MCT). At 14 days after injection, the vascular reactivity of isolated extralobar pulmonary arteries was assessed by organ chamber technique. In a separate experiment, isosorbide mononitrate (0.3 or 1 g/L) or sodium nitrite (30 or 300 mg/L) was administered in drinking water for the last 14 days (from day 15 to day 28), and their therapeutic potential was evaluated. KEY FINDINGS: The NO-sensitive sGC stimulant BAY 41-2272 and the NO-insensitive sGC stimulant BAY 60-2770 both relaxed the pulmonary arteries, which was comparable between saline- and MCT-injected rats. Treatment with isosorbide mononitrate suppressed the MCT-induced right ventricular systolic pressure (RVSP) elevation and pulmonary arterial medial thickening but not right ventricular hypertrophy. However, the beneficial effects on RVSP and pulmonary vascular remodeling were not observed when a high dose was administered. The same results were obtained following the sodium nitrite treatment. Interestingly, NO-enhancing drugs did not increase plasma nitrite plus nitrate levels at a dose that provided the greatest therapeutic advantage. SIGNIFICANCE: These findings suggest that the balance between NO-sensitive and insensitive sGC is not disrupted in the early stage of MCT-induced PH. Furthermore, supplementation with an adequate amount of NO may be a useful therapy to prevent the progression of PH. PMID- 29705352 TI - Apigenin-7-O-beta-d-(-6"-p-coumaroyl)-glucopyranoside pretreatment attenuates myocardial ischemia/reperfusion injury via activating AMPK signaling. AB - AIMS: Apigenin-7-O-beta-d-(-6"-p-coumaroyl)-glucopyranoside (APG) was considered as the major active compound derived from Clematis tangutica. Though we have demonstrated that APG exerts cardioprotective effects, the mechanism of APG mediated cardioprotection remains largely unknown. Numerous studies indicate that endoplasmic reticulum stress (ERS) is a vital injury factor in myocardial ischemia reperfusion (MI/R). In this study, we mainly investigated whether modulation of the ERS and AMPK were involved in the cardioprotective action of APG during MI/R injury. MAIN METHODS: The perfused isolated rat heart or primary neonatal rat cardiomyocytes which exposed to APG with or else without the AMPK inhibitor Compound C was then subject to MI/R. After reperfusion, the degree of myocardial injury was assessed by using lactate dehydrogenase (LDH) release, creatine kinase (CK) release, histological examination, and TTC staining. The protein expressions of p-AMPK, AMPK, p-PERK, PERK, p-eIF2alpha, eIF2alpha, CHOP, Bax, Bcl2 and Cleaved Caspase 3 were analyzed by western blot. The cell viability was assessed by CCK-8 kit while apoptosis assessed by using TUNEL assay. KEY FINDINGS: Pretreatment of APG significantly improved cardiac function and suppressed ERS through activating the AMPK signaling pathway, which could simultaneously improve cardiac function, alleviate myocardial injury, increase the cell viability and decrease apoptosis. SIGNIFICANCE: To conclude, APG ameliorates MI/R injury by activating the AMPK signaling pathway and relieving endoplasmic reticulum stress. APG may be a natural product with pharmacological preconditioning activity, which could do us a favor to develop more novel therapy methods to against MI/R injury in the future. PMID- 29705353 TI - Apoptosis induction in human breast cancer cell lines by synergic effect of raloxifene and resveratrol through increasing proapoptotic genes. AB - AIMS: Breast cancer is the most common cancer of women. The aim of this study was to investigate the synergic effect of raloxifene (Ral) and resveratrol (Res) on apoptosis of breast cancer cell lines (MCF7 and MDA-MB-231). MAIN METHODS: Cells were treated with Ral and Res alone and in combination. Cell viability (MTT assay), apoptosis (TUNEL assay) and nitric oxide (NO) production (Griess method) were investigated. Expression of proapoptotic gene (Bax and p53), anti-apoptotic gene (Bcl2) and caspases-3, caspase -8 were evaluated. One-way ANOVA test was used for data analysis. KEY FINDINGS: The viabilities of MCF7 and MDA-MB-231 cells treated by Ral (1 MUM) and Res (20 MUM) decreased significantly (p = 0.000) and their synergic use showed more reduction. Nitric oxide production by MCF7 and MDA-MB-231 cells exposed upon each drug alone and in combination showing a significant reduction (p = 0.000). There was also an increase in apoptosis in the cells treated with combination use of Ral and Res in both cell lines. Moreover, reduced expression of Bcl2 and increased expression of Bax and p53 genes were observed. SIGNIFICANCE: The synergic effects of Ral and Res through increased ratio of Bcl2/Bax and expressions of p53, caspase-3 and caspase-8 genes indicating a better therapeutic effect on breast cancer cells relative to each drug alone. Combination of Res and Ral via increased expression of apoptotic genes including Bax, p53 and caspase-3 and caspase-8 is able to promote apoptosis as a mitochondrial dependent pathway in MCF7 and MDA-MB-231. The synergic effect was more potent in MCF7 estrogen receptor positive cell line. PMID- 29705354 TI - Effect of TET2 on the pathogenesis of diabetic nephropathy through activation of transforming growth factor beta1 expression via DNA demethylation. AB - AIMS: Transforming growth factor beta1 (TGFbeta1) plays a pivotal role in the pathogenesis of diabetic nephropathy (DN). However, the mechanism of its expression and activation induced by high glucose (HG) is still unclear. We mainly explored the role of ten-eleven translocation enzyme-2 (TET2) in regulating TGFbeta1 expression in the process of DN. MAIN METHODS: Human mesangial cells (HMCs) and db/db mice were used to analyze the biological effects of hyperglycemia both in vivo and in vitro. Gene expression levels, cell proliferation, protein recruitment levels to TGFbeta1 regulatory region, DNA methylation statues and pathological changes in kidney were tested in different groups. Short hairpin RNA(shRNA) and oral inhibitor were used to knock down or inhibit TET2 expression. KEY FINDINGS: Our study demonstrated that TET2 expression was increased in the renal cortex of db/db mice and in HMCs inducing by HG. We also found that TET2 binding was increased while DNA methylation of CpG islands was reduced in the TGFbeta1 regulation region in HG, resulting in the increased expression level of TGFbeta1 and cell phenotype transformation. More importantly, clinical research revealed that gradually decreased DNA methylation in the TGFbeta1 regulatory region was also present in patients with diabetes and DN. SIGNIFICANCE: Our work suggests that TET2 plays an important role in the pathogenesis of DN by activating TGFbeta1 expression through demethylation of CpG islands in the TGFbeta1 regulatory region. This may provide a potential new therapeutic target for DN. PMID- 29705355 TI - [Patient perspective of the importance of asthma- and COPD-specific rehabilitation components: A secondary data analysis]. AB - Little is known about the importance that patients attribute to individual rehabilitation components (RCs) and about which factors influence the patients' perspective and the impact of this judgment on the perceived success of the rehabilitation process. To address these questions, the data of 759 patients with chronic obstructive pulmonary disease (COPD) or bronchial asthma, who were interviewed at the end of their rehabilitation about the subjective importance of various RCs, were analysed retrospectively. The patients were pooled from our previous studies "Prospektive Katamnesestudie zur Asthma-Rehabilitation" (ProKAR) and "Routinemabetaiges Inspirationsmuskeltraining in der COPD-Rehabilitation" (RIMTCORE). Asthma patients and COPD patients differed in their assessments. Their evaluation was also affected by personal parameters such as sex, comorbidities, quality of life and the perceived effectiveness of the "rehabilitation as a whole". Patients considered all RCs to be essential, with minor differences. However, the patients' assessment of the importance of the RCs was in the closest possible agreement with the evidence available for the effectivity of multimodal rehabilitation. The added value of the proposed study is to generate further insight into the upcoming scientific field of personal rating of therapy components. PMID- 29705356 TI - Corrigendum to "Two-day fasting evokes stress, but does not affect mood, brain activity, cognitive, psychomotor, and motor performance in overweight women" [Behav. Brain Res. 338 (2018) 166-172]. PMID- 29705358 TI - Abdominal pain of cardiovascular origin. AB - Infective endocarditis is a microbial infection of the endocardium and it is rare in the pediatric population. In children, congenital heart disease is one of the most important risk factors for developing infective endocarditis and can involve other structures in addition to cardiac valves. The prognosis is generally better than in other forms of endocarditis, although the average mortality rate in the pediatric population is 15-25%. Clinical manifestations can mimic other diseases such as meningitis and collagen-vascular disease or vasculitis. Therefore, a high degree of suspicion is required to make an early diagnosis. Gram-positive bacteria, specifically alpha-hemolytic streptococci, Staphylococcus aureus and coagulase-negative staphylococci, are the most commonly involved bacteria. Diagnosis is based on the modified Duke criteria, which rely mostly on clinical assessment, echocardiography and blood cultures. Antibacterial treatment should ideally be targeted. However, if no specific bacteria have been identified, patients should promptly be treated empirically with multiple drug regimens based on local resistance and the most common etiologies. The authors describe a case of a seven-year-old girl with classic clinical signs of endocarditis, with a clinical twist. PMID- 29705357 TI - Low doses of DNA damaging agents extend Saccharomyces cerevisiae chronological lifespan by promoting entry into quiescence. AB - A variety of mild stresses have been shown to extend lifespan in diverse species through hormesis, which is a beneficial response to a stress or toxin that would cause a negative response at a higher exposure. Whether particular stresses induce hormesis can vary with genotype for a given species, and the underlying mechanisms of lifespan extension are only partly understood in most cases. We show that low doses of the DNA damaging or replication stress agents hydroxyurea, methyl methanesulfonate, 4-nitroquinoline 1-oxide, or Zeocin (a phleomycin derivative) lengthened chronological lifespan in Saccharomyces cerevisiae if cells were exposed during growth, but not if they were exposed during stationary phase. Treatment with these agents did not change mitochondrial activity, increase resistance to acetic acid, ethanol, or heat stress, and three of four treatments did not increase resistance to hydrogen peroxide. Stationary phase yeast populations consist of both quiescent and nonquiescent cells, and all four treatments increased the proportion of quiescent cells. Several mutant strains with deletions in genes that influence quiescence prevented Zeocin treatment from extending lifespan and from increasing the proportion of quiescent stationary phase cells. These data indicate that mild DNA damage stress can extend lifespan by promoting quiescence in the absence of mitohormesis or improved general stress responses that have been frequently associated with improved longevity in other cases of hormesis. Further study of the underlying mechanism may yield new insights into quiescence regulation that will be relevant to healthy aging. PMID- 29705360 TI - Bioinformatics analysis of ROP8 protein to improve vaccine design against Toxoplasma gondii. AB - Rhoptry proteins (ROPs) are involved in the different stages of Toxoplasma gondii (T. gondii) invasion and are also critical for survival within host cells. ROP8 is expressed in the early stages of infection and have a key role in the parasitophorous vacuole (PV) formation. In this paper, we have combined several bioinformatics online servers for immunogenicity prediction of ROP8 protein. In this study, several bioinformatics approaches were used to analyze the different aspects of ROP8 protein, including the physico-chemical properties, transmembrane domain, subcellular localization, secondary and tertiary structure, B and T-cell potential epitopes, and other important characteristics of this protein. The findings showed that ROP8 protein had 60 potential post-translational modification sites. Also, only one transmembrane domain was recognized for this protein. The secondary structure of ROP8 protein comprises 33.04% alpha-helix, 18.26% extended strand, and 48.70% random coil. Moreover, several potential B and T-cell epitopes were identified for ROP8. In addition, the obtained findings from antigenicity and allergenicity evaluation remarked that this protein is immunogenic and non-allergen. Based on the results of Ramachandran plot, 94.8%, 4.1%, and 1.1% of amino acid residues were incorporated in the favored, allowed, and outlier regions, respectively. This paper provides a foundation for further investigations, and laid a theoretical basis for the development of an appropriate vaccine against toxoplasmosis. More studies are needed experimentally using the ROP8 alone or in combination with other antigens in the future. PMID- 29705359 TI - Blood pressure is associated with body adiposity indicators in children aged 4 to 7 years. AB - INTRODUCTION AND OBJECTIVE: Studies in adults have shown an association between increased adiposity and hypertension, but few studies have analyzed this association in childhood. The aim of this study was to investigate the association between blood pressure (BP) and body adiposity indicators in children, controlling for the variables of birth conditions, sociodemographics, lifestyle and diet. METHODS: In this cross-sectional study of 399 children aged 4 to 7 years, the dependent variable was BP, measured according to the protocol established by the 7th Brazilian Guidelines on Hypertension. The explanatory variables of the study were waist-to-height ratio (WHtR) and body mass index (BMI). Multiple linear regression was used to assess the independent association between adiposity and BP indicators adjusted for the variables of birth conditions, sociodemographics, lifestyle and diet. Statistical significance was set as alpha=5%. RESULTS: BMI for age and WHtR correlated positively with systolic (SBP) and diastolic blood pressure (DBP). After multivariate analysis, higher values of BMI (model 1) and WHtR (model 2) were associated with increased SBP and DBP. CONCLUSION: Increased body adiposity, as assessed by BMI and WHtR, was associated with increased SBP and DBP among the children studied. Thus, we suggest the use of BMI and WHtR in the nutritional assessment of children to detect changes in BP and other cardiometabolic risk factors in this population. PMID- 29705361 TI - Diversity and prevalence of gastrointestinal parasites in two wild Galago species in Gabon. AB - In this study, we characterize the diversity and estimated infection levels of gastrointestinal parasites circulating in two galago species, Galago demidoff and G. thomasi in two sites situated in the Southeastern forests of Gabon. Our study reveals that eleven parasites including nine helminthes (Ascaris spp., Ankylostoma spp., Dicrocoelium spp., Gongylonema spp., Oesophagostomum spp., Lemuricola spp., Strongyloides spp. Trichostrongylus spp. and Trichuris spp.) and two protozoans (Balantidium spp. and Entamoeba spp.) may infect Galago spp. with high infection rates. The results show that: a very similar parasite spectrum is found in both host species; all the taxa identified were previously observed in other Primate species and/or Man. They also show that age, gender and forest type may influence infection rates and/or parasite diversity found in a particular host and/or geographic area. PMID- 29705362 TI - Detection of reassortant H5N6 clade 2.3.4.4 highly pathogenic avian influenza virus in a black-faced spoonbill (Platalea minor) found dead, Taiwan, 2017. AB - A H5N6 highly pathogenic avian influenza virus (HPAIV) was detected in a black faced spoonbill (Platalea minor) found dead in Taiwan during December 2017. Genome sequencing and phylogenetic analyses suggest the hemagglutinin gene belongs to H5 clade 2.3.4.4 Group B. All genes except neuraminidase gene shared high levels of nucleotide identity with H5N8 HPAIV identified from Europe during 2016-2017. Genetically similar H5N6 HPAIV was also identified from Japan during November 2017. Enhanced surveillance is required in this region. PMID- 29705363 TI - Contrast-induced encephalopathy and diagnostic modalities - Can it make a difference? PMID- 29705364 TI - A preliminary study on classification and therapeutic strategies for spontaneous perirenal hemorrhage. AB - BACKGROUND: The aim of our study was to report our experience in the classification and therapeutic management strategies for spontaneous perirenal hemorrhage (SPH). METHODS: From September 2005 to April 2015, 20 patients with SPH were newly diagnosed in our hospital. Their clinical features, image findings, identification of underlying causes, and therapeutic management were retrospectively analyzed, and relevant literature was reviewed. In this study, patients were classified according to the degree of severity of the disease or emergency imaging diagnosis of underlying causes. On the basis of the former, patients were classified as critical and noncritical, and on the basis of the latter, patients were classified as renal cell carcinoma (RCC), undefined solid neoplasm, angioleiomyolipoma (AML), and unknown cause. RESULTS: In the acute stage, contrast-enhanced computed tomography (CT) was superior to ultrasonography for both diagnostic accuracy of SPH (p = 0.02) and etiology discovery power (p = 0.004). The results of contrast-enhanced magnetic resonance imaging (MRI) were identical to those of contrast-enhanced CT. We summarized a flowchart in the whole classification and therapeutic strategies of SPH. According to the imaging diagnosis of underlying causes, all the patients with undefined solid neoplasm or RCC underwent emergency operation. Patients with AML or unknown cause underwent selective arterial embolization (SAE) or conservative management according to the critical degree. Acute hemorrhage was controlled in 19 cases, of which 14 were cured by the operation and only one critical patient with severe shock died shortly despite rescue efforts. CONCLUSIONS: Contrast-enhanced CT or MRI is the first choice of imaging examination, which could not only accurately diagnose SPH but also detect the underlying causes. Choice of therapeutic strategies for SPH should vary according to the identification of critical patients and imaging diagnosis of underlying cause. PMID- 29705366 TI - Permanent Pacemaker Implantation After Rapid Deployment Aortic Valve Replacement. AB - BACKGROUND: Expandable, rapid deployment aortic valves may interfere with the cardiac conduction system, which can lead to permanent pacemaker implantation (PPI). We sought to characterize PPI after rapid deployment aortic valve replacement with the Edwards Intuity valve system (Edwards Lifesciences, Irvine, CA) and investigate associated factors. METHODS: We analyzed 708 patients from 29 centers in the Multicenter Experience With Rapid Deployment Edwards Intuity Valve System for Aortic Valve Replacement (TRANSFORM) trial undergoing rapid deployment aortic valve replacement with or without coronary artery bypass graft surgery without preexisting pacemakers. Intrinsic conduction status was recorded as well as PPI incidence through 1 year. The PPI indications were categorized based on expert review of patient PPI source documents. Multivariate analysis was conducted to identify characteristics associated with PPI. RESULTS: After rapid deployment aortic valve replacement, the PPI incidence through 30 days (PPI30) was 13.6%, with 10.9% due to atrioventricular block. In the 423 of 708 patients (59.7%) without any baseline conduction abnormalities, all-cause PPI30 was 8%, 5% for atrioventricular block. For PPIs inserted before discharge, the median time to PPI was 5 days, with 22% placed within 48 hours. Independent predictors of PPI30 were baseline right bundle branch block (odds ratio 7.35, p < 0.0001), female gender (2.62, p = 0.004), larger valve size (1.20, p = 0.016), and atrioventricular block (1.80, p = 0.062). Subset analysis revealed a greater than twofold difference in PPI30 among the largest enrolling centers. CONCLUSIONS: Patient factors associated with PPI after rapid deployment aortic valve replacement were right bundle branch block, atrioventricular block, female gender, and larger valve size. Interestingly, a strong center-level effect was associated with PPI. This effect may reflect differences in practice patterns, such as postoperative drug management or timing to PPI. These findings provide a deeper understanding of PPI after rapid deployment aortic valve replacement and help guide clinical practice and patient management. PMID- 29705367 TI - Reply. PMID- 29705365 TI - Progesterone Receptor Regulation of Uterine Adaptation for Pregnancy. AB - Progesterone acts through the progesterone receptor to direct physiological adaption of the uterus in preparation and completion of pregnancy. Genome-wide transcriptome and cistrome analyses have uncovered new members and novel modifiers of the progesterone signaling pathway. Genetically engineered mice allow functional assessment of newly identified genes in vivo and provide insights on the impact of progesterone receptor-dependent molecular mechanisms on pregnancy at the organ system level. Progesterone receptor isoforms collectively mediate progesterone signaling via their distinct and common downstream target genes, which makes the stoichiometry of isoforms relevant in modifying the progesterone activity. This review discusses recent advances on the discovery of the progesterone receptor network, with special focus on the endometrium at early pregnancy and myometrium during parturition. PMID- 29705368 TI - Novel T-Shaped Linear-Stapled Intrathoracic Esophagogastric Anastomosis With a Little Improvement. PMID- 29705369 TI - Essential Thrombocythemia and Cardiac Surgery: A Case Series and Review of the Literature. AB - BACKGROUND: Essential thrombocythemia (ET) is a rare myeloproliferative disorder characterized by an unexplained thrombocytosis (>450 * 109/L) and associated vasomotor, thrombotic, and hemorrhagic manifestations. Although the literature detailing the perioperative management of patients with ET undergoing cardiac operations is sparse, major perioperative complications have been reported, particularly in poorly controlled patients presenting with platelet counts of 800 * 109/L or higher. The purpose of this study was to provide the experience at a large tertiary medical center in managing patients with ET undergoing cardiac operation and to summarize the available literature. METHODS: Patients with ET undergoing cardiac operations between January 1, 2006, and May 1, 2016, were identified. Perioperative data were exhaustively reviewed and recorded. An extensive literature search for "essential thrombocythemia" and "cardiac surgery" was performed. RESULTS: During the study period, 25 patients with ET underwent cardiac operations, and 24 had immediate preoperative platelet counts of less than 800 * 109/L. Perioperative complications related to ET occurred in 1 of 25 patients (4%). The immediate preoperative platelet count was 181 * 109/L. A literature search identified 18 patients who underwent cardiac operations, with major perioperative complications occurring in 5 (28%), of which 4 of 5 had an immediate preoperative platelet count of 800 * 109/L or higher. CONCLUSIONS: Patients with ET undergoing cardiac operations represent a complex cohort at risk for perioperative thrombotic or hemorrhagic complications, or both. Although not currently an indication for platelet reduction therapy by risk stratification criteria, preoperative cytoreduction to platelet counts of less than 800 * 109/L and perhaps lower should be considered in patients undergoing cardiac operations. PMID- 29705370 TI - Clinical Outcomes of VasoRing Connector in Patients With Acute Type A Aortic Dissection. AB - BACKGROUND: Outcomes of acute type A aortic dissection repair may be improved when VasoRing connectors (VRC [Sunwei Technology, Taipei, Taiwan]) are used to facilitate aortic anastomosis. In the present study, we compared the results of acute type A aortic dissection repair using VRC and conventional suture technique. METHODS: A total of 68 patients who underwent acute type A aortic dissection repair by total arch replacement and antegrade frozen elephant trunk procedure at our institution were enrolled. Records of patients receiving aorta anastomosis with VRC (n = 33) and conventional suture (n = 35) were retrospectively compared. All the surgical results were collected and analyzed. RESULTS: The results showed that the VRC group exhibited significance in total operative time (326 +/- 80 minutes versus 362 +/- 34 minutes, p = 0.023), cardiopulmonary bypass time (97 +/- 10 minutes versus 134 +/- 15 minutes, p < 0.001), aortic cross-clamp time (97 +/- 10 minutes versus 134 +/- 15 minutes, p < 0.001), and circulatory arrest time (15 +/- 4 minutes versus 50 +/- 8 minutes, p < 0.001) compared with the suture group. Use of VRC for aortic anastomosis led to significantly less perioperative blood loss (442 +/- 75 mL versus 849 +/- 419 mL, p < 0.001) compared with conventional suture for aortic anastomosis There was no reoperation for postoperative bleeding in the VRC group whereas reoperation for postoperative bleeding occurred in 20% of the suture group (0% versus 20%, p = 0.011). Postoperative blood loss, amount of blood transfusion, and acute kidney injury requiring hemodialysis were also significantly less in the VRC group than the suture group. CONCLUSIONS: Use of VRC shortened operative time and improved bleeding control incorporating standard methods for aortic anastomoses during acute type A aortic dissection repair by total arch replacement and antegrade frozen elephant trunk procedure. Long-term follow-up and randomized comparison are needed to confirm VRC efficacy. PMID- 29705371 TI - Effect of probiotic supplement on aflatoxicosis and gene expression in the liver of broiler chicken. AB - The present study aimed to investigate the toxic effect of aflatoxin B1 (AFB1) and the effectiveness of a biological mycotoxin binder (Nutritox(r)) in detoxifying aflatoxicosis. Ninety one-day-old chicks were chosen and divided into 3 groups. The first group received standard basal diet only, the second group received a basal diet with AFB1 (0.25 mg/kg diet), and the third group received a basal diet with AFB1 (0.25 mg/kg diet) and Nutritox(r) (1 kg/ton diet). AFB1 feed contamination significantly reduced growth performance and deteriorated FCR. Moreover, it significantly increased serum AST, ALT, and malondialdehyde and significantly decreased serum total protein, albumin, globulin, SOD, CAT activities and glutathione peroxidase gene expression as well. Aflatoxin residues were detected in the liver tissues. Furthermore, the liver and kidney of AFB1 treated group showed pathological changes. The supplementation of Nutritox(r) significantly reduced aflatoxin levels in the liver and counteracted the negative effects of AFB1. PMID- 29705372 TI - Kaempferol protects against gamma radiation-induced mortality and damage via inhibiting oxidative stress and modulating apoptotic molecules in vivo and vitro. AB - To investigate the potential protective effect of kaempferol, a representative flavonoid, against radiation induced mortality and injury in vivo and vitro.C57BL/6 male mice and human umbilical venous endothelial cells (HUVECs) were pretreated with kaempferol before radiation. We found that kaempferol can effectively increase 30-day survival rate after 8.5 Gy lethal total body irradiation (TBI). Mice were sacrificed at 7th day after 7 Gy TBI, we found kaempferol against radiation-induced tissues damage, by inhibiting the oxidative stress, and attenuating morphological changes and cell apoptosis. In vitro, kaempferol increased HUVECs cell viability and decrease apoptosis. It also mitigated oxidative stress and restored the abnormal expression of prx-5, Cyt-c, Caspase9 and Caspase3 in mRNA and protein level in HUVECs after radiation. Taken together, it suggests kaempferol can protect against gamma-radiation induced tissue damage and mortality. The present study is the first report of the radioprotective role of kaempferol in vivo and vitro. PMID- 29705373 TI - Proactive behavior in midwifery: A qualitative overview from midwifery student's perspective. AB - In the process of continuing developments and contemporary working conditions, this study provides an in depth exploration of proactive behavior in midwifery. Exploring 55 midwifery students' perceptions on facilitators and/or barriers of proactive behavior in midwifery practice, this study uncloses additional insights of proactive behavior in midwifery and aims to confirm and/or supplement previous results. Four key themes were identified: 1) Nature-nurture, supported by good communication and lifelong learning. 2) Willingness, regulated by the midwife's norms and values and the organizational culture of the midwifery team. 3) The impact of awareness and feedback on the reflective tendencies to strengthen the midwife's beliefs and convictions to behave proactively. 4) Time was identified as something gained in the presence of proactive behavior as well as a barrier if time was limited. Providing midwives with knowledge of the key factors required to successfully effect proactive behavior in midwifery, this study has merit for future midwifery education, policy and practice. Strengthening intrinsic motivation of midwives integrated into midwifery education, focus on feedback as part of the daily routine of the midwife and the gaining of time as an effect of proactive behavior, needs clear attention in midwifery practice. PMID- 29705374 TI - Predictors of Obstructive Coronary Disease and Mortality in Adults Having Cardiac Arrest. AB - Coronary angiography is a key component of systematic, multi-disciplinary post cardiac arrest (CA) care, however, coronary angiogram is not routinely performed in the setting of CA. We sought to identify the predictors of obstructive coronary artery disease (CAD) and mortality in adults with CA undergoing coronary angiogram. The study population included 208 consecutive patients hospitalized with CA who underwent resuscitation and subsequent coronary angiogram at an academic tertiary medical center. The primary outcome of interest was presence of obstructive CAD, defined as >1 coronary artery with >70% stenosis or >1 coronary bypass graft with >70% stenosis. The secondary outcome of interest was in hospital mortality. Of the 208 patients studied, 160 (76.9%) had obstructive CAD while 48 (23.1%) did not. In-hospital mortality occurred in 47 patients (22.6%). In multivariate analysis, ST-elevation myocardial infarction (STEMI) (OR 7.69, 95% CI 2.89 to 20.51), defibrillation (OR 4.90, 95% CI 1.19 to 20.17), vasopressors (OR 3.53, 95% CI 1.15 to 10.81), and absence of therapeutic hypothermia (OR 0.38, 95% CI 0.15 to 0.98) were independently associated with presence of obstructive CAD while STEMI (OR 3.21, 95% CI 1.01 to 10.24), vasopressors (OR 4.92, 95% CI 1.78 to 13.62), therapeutic hypothermia (OR 3.89, 95% CI 1.47 to 10.31), and admission blood urea nitrogen (OR 1.06, 95% CI 1.00 to 1.11) were independently associated with higher rates of in-hospital mortality. In this observational contemporary study, predictors of obstructive CAD and mortality exist in adults with CA undergoing coronary angiogram. Such risk models may aid in identification of CA patients who will benefit from early angiography and percutaneous coronary intervention. PMID- 29705375 TI - Three-Year Impact of Immediate Invasive Strategy in Patients With Non-ST-Segment Elevation Myocardial Infarction (from the RIDDLE-NSTEMI Study). AB - Previous studies compared clinical outcomes of early versus delayed invasive strategy in patients with non-ST-elevation acute coronary syndrome up to 1-year follow-up, but long-term data remain scarce. Our aim was to evaluate the long term effects of immediate invasive intervention in patients with Non-ST-Segment Elevation Myocardial Infarction (NSTEMI). The Randomized Study of Immediate Versus Delayed Invasive Intervention in Patients With Non-ST-Segment Elevation Myocardial Infarction (RIDDLE-NSTEMI) was a randomized, investigator-initiated, parallel-group trial that assigned 323 patients with NSTEMI (1:1) to either immediate (median time to intervention 1.4 hours) or delayed invasive strategy (61.0 hours). The primary end point was the composite of death or new myocardial infarction (MI). At 3 years, immediate invasive intervention was associated with a lower rate of death or new MI, compared with a delayed invasive strategy (12.3% vs 22.5%, hazard ratio 0.50, 95% confidence interval 0.29 to 0.87, p = 0.014). The observed benefit of immediate intervention was mainly driven by an increased early reinfarction risk in delayed strategy, with similar new MI rates beyond 30 days (4.4% in the immediate and 5.6% in the delayed group, p = 0.61). Three-year mortality was 9.3% in the immediate invasive strategy, and 10.0% in the delayed strategy (p = 0.83). High baseline Global Registry of Acute Coronary Events score (>140) was associated with a significant increase in long-term mortality, regardless of the timing of invasive intervention. In conclusion, whereas immediate invasive intervention significantly reduced the early risk of new MI, the timing of invasive intervention appears to have no significant impact on clinical outcomes beyond 30 days, which seem to mostly be related to the baseline clinical risk profile. PMID- 29705376 TI - Synthesis and biological evaluation of 2,4-disubstituted phthalazinones as Aurora kinase inhibitors. AB - A series of 2,4-disubstituted phthalazinones were synthesized and their biological activities, including antiproliferation, inhibition against Aurora kinases and cell cycle effects were evaluated. Among them, N-cyclohexyl-4-((4-(1 methyl-1H-pyrazol-4-yl)-1-oxophthalazin-2(1H)-yl) methyl) benzamide (12c) exhibited the most potent antiproliferation against five carcinoma cell lines (HeLa, A549, HepG2, LoVo and HCT116 cells) with IC50 values in range of 2.2-4.6 MUM, while the IC50 value of reference compound VX-680 was 8.5-15.3 MUM. Moreover, Aurora kinase assays exhibited that compound 12c was potent inhibitor of AurA and AurB kinase with the IC50 values were 118 +/- 8.1 and 80 +/- 4.2 nM, respectively. Molecular docking studies indicated that compound 12c forms better interaction with both AurA and AurB. Furthermore, compound 12c induced G2/M cell cycle arrest in HeLa cells by regulating protein levels of cyclinB1 and cdc2. These results suggested that 12c is a promising pan-Aurora kinase inhibitor for the potential treatment of cancer. PMID- 29705377 TI - Structure-activity relationship investigation of Phe-Arg mimetic region of human glutaminyl cyclase inhibitors. AB - Glutamyl cyclase (QC) is a promising therapeutic target because of its involvement in the pathogenesis of Alzheimer's disease. In this study, we developed novel QC inhibitors that contain 3-aminoalkyloxy-4-methoxyphenyl and 4 aminoalkyloxyphenyl groups to replace the previously developed pharmacophore. Several potent inhibitors were identified, showing IC50 values in a low nanomolar range, and were further studied for in vitro toxicity and in vivo activity. Among these, inhibitors 51 and 53 displayed the most potent AbetaN3pE-40-lowering effects in in vivo acute model with reasonable BBB penetration, without showing cytotoxicity and hERG inhibition. The molecular modeling analysis of 53 indicated that the salt bridge interaction and the hydrogen bonding in the active site provided a high potency. Given the potent activity and favorable BBB penetration with low cytotoxicity, we believe that compound 53 may serve as a potential candidate for anti-Alzheimer's agents. PMID- 29705378 TI - Intervertebral disc regeneration: From cell therapy to the development of novel bioinspired endogenous repair strategies. AB - Low back pain (LBP), frequently associated with intervertebral disc (IVD) degeneration, is a major public health concern. LBP is currently managed by pharmacological treatments and, if unsuccessful, by invasive surgical procedures, which do not counteract the degenerative process. Considering that IVD cell depletion is critical in the degenerative process, the supplementation of IVD with reparative cells, associated or not with biomaterials, has been contemplated. Recently, the discovery of reparative stem/progenitor cells in the IVD has led to increased interest in the potential of endogenous repair strategies. Recruitment of these cells by specific signals might constitute an alternative strategy to cell transplantation. Here, we review the status of cell based therapies for treating IVD degeneration and emphasize the current concept of endogenous repair as well as future perspectives. This review also highlights the challenges of the mobilization/differentiation of reparative progenitor cells through the delivery of biologics factors to stimulate IVD regeneration. PMID- 29705379 TI - Modeling the hydrogen sulfide binding to heme. AB - The binding of hydrogen sulfide to a model heme compound is investigated by coupled-cluster singles-doubles augmented by a perturbative triple excitations, CCSD(T), and density functional theory, DFT. The minimum energy path for the H2S addition to an isolated heme center of the heme protein is evaluated by adopting as a model the heme compound FeP(Im) (P = porphyrin; Im = imidazole). The FeP(Im) H2S aduct is bound by 13.7 kcal/mol at the CCSD(T) level of theory. Relaxed potential energy curves for the lowest lying spin states of the H2S to FeP(Im) binding using DFT reveal that the binding process is associated with a "double spin-crossover" reaction with the existence of long-distance van der Waals minima only 5-7 kcal/mol above the FeP(Im)-H2S ground state. The fact that the energy of the singlet ground state of FeP(Im)-H2S is so close in energy to the dissociation products FeP(Im) + H2S points towards the reversibility of the H2S adsorption/desorption process in biochemical reactions. PMID- 29705380 TI - Allergic skin diseases. PMID- 29705381 TI - High dimensional immune biomarkers demonstrate differences in phenotypes and endotypes in food allergy and asthma. PMID- 29705382 TI - Increasing patient mobility through an individualized goal-centered hospital mobility program: A quasi-experimental quality improvement project. AB - BACKGROUND: Hospital-acquired functional decline due to decreased mobility has negative impacts on patient outcomes. Current nurse-directed mobility programs lack a standardized approach to set achievable mobility goals. PURPOSE: We aimed to describe implementation and outcomes from a nurse-directed patient mobility program. METHOD: The quality improvement mobility program on the project unit was compared to a similar control unit providing usual care. The Johns Hopkins Mobility Goal Calculator was created to guide a daily patient mobility goal based on the level of mobility impairment. FINDINGS: On the project unit, patient mobility increased from 5.2 to 5.8 on the Johns Hopkins Highest Level of Mobility score, mobility goal attainment went from 54.2% to 64.2%, and patients exceeding the goal went from 23.3% to 33.5%. All results were significantly higher than the control unit. DISCUSSION: An individualized, nurse-directed, patient mobility program using daily mobility goals is a successful strategy to improve daily patient mobility in the hospital. PMID- 29705383 TI - Endosulfan causes the alterations of DNA damage response through ATM-p53 signaling pathway in human leukemia cells. AB - Exposure to pesticides results in DNA damage and genomic instability. We previously predicted that endosulfan might be associated with leukemia, but the role of endosulfan in leukemia cells has been unexplored. The aim of this study is to elucidate molecular mechanism of endosulfan-induced DNA damage response in human leukemia cells. We performed endosulfan exposure experiments in K562 cells with varying concentrations of endosulfan for 48 h and found that endosulfan lowered cell viability in a dose-dependent manner. We observed the dramatic DNA damage using comet assay and the increase of micronucleus in 75 MUM endosulfan exposed cells. Endosulfan at 75 MUM caused the expression alterations of ATM and DNA repair genes such as FANCD2, and BRCA1/2 at different exposure time points (12, 24, 48 h), which was reversed by ATM inhibitor KU-55933. Endosulfan significantly increased the mRNA expression levels of p53 and GADD45A, and decreased PCNA and XRCC2 at 48 h after exposure. Flow cytometric analysis showed that endosulfan at 50 and 75 MUM induced cell cycle G1 arrest, a response attributed to down-regulation of CDK6 and up-regulation of p21. We also observed that endosulfan at 50 and 75 MUM induced a considerable percentage of cells to undergo apoptosis, as detected by Annexin-V binding assays. Endosulfan resulted in the activation of caspase-3, and elevated the expression levels of PUMA and the ratio of BAX/Bcl-2. These findings suggest that endosulfan caused DNA damage response throughATM-p53 signaling pathway, implicating the potential correlation between endosulfan and leukemia. PMID- 29705384 TI - Trends in the Utilisation and In-Hospital Mortality Associated With Short-Term Mechanical Circulatory Support for Heart Failure With Reduced Ejection Fraction. AB - Heart failure with reduced ejection fraction (HFrEF) is a systolic dysfunction with an ejection fraction below 40% and the prevalence of it is substantially increasing in the United States. Mechanical circulatory support (MCS) devices have increasingly been used for the management of HFrEF and are associated with improved outcomes. The National Inpatient Sample database was used to identify hospitalisations with mechanical circulatory support for HFrEF from 2005 to 2014. This study observed a reduction in the utilisation of intra-aortic balloon pump (IABP), which is partially replaced by percutaneous left ventricular assist device (pLVAD) and extracorporeal membrane oxygenation (ECMO) for the management of HFrEF. In-hospital mortality in IABP and ECMO recipients decreased during the study period while mortality with pLVAD did not change. Finally, technology for the short-term MCS in HFrEF hospitalisations continues to improve, however, there is still some space for updated technology in future. PMID- 29705385 TI - Diagnosis of Arrhythmogenic Right Ventricular Cardiomyopathy: Progress and Pitfalls. AB - Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy that predominantly affects the right ventricle. With a prevalence in the range of 1:5000 to 1:2000 persons, ARVC is one of the leading causes of sudden cardiac death in young people and in athletes. Although early detection and treatment is important, the diagnosis of ARVC remains challenging. There is no single pathognomonic diagnostic finding in ARVC; rather, current international task force criteria specify diagnostic major and minor criteria in six categories: right ventricular imaging (including echocardiography and cardiac magnetic resonance imaging (MRI)), histology, repolarisation abnormalities, depolarisation and conduction abnormalities, arrhythmias and family history (including genetic testing). Combining findings from differing diagnostic modalities can establish a "definite", "borderline" or "possible" diagnosis of ARVC. However, there are limitations inherent in the current task force criteria, including the lack of specificity for ARVC; future iterations may be improved, for example, by enhanced imaging protocols able to detect subtle changes in the structure and function of the right ventricle, incorporation of electro anatomical data, response to adrenergic challenge, and validated criteria for interpreting genetic variants. PMID- 29705386 TI - Gender is Not a Predictor of Mortality or Major Adverse Cardiovascular Events in Patients Undergoing Percutaneous Coronary Intervention for Acute Coronary Syndromes. AB - BACKGROUND: Historically, studies of percutaneous coronary intervention (PCI) for acute coronary syndrome (ACS) have reported worse outcomes for women. We sought to determine if contemporary PCI techniques eliminate gender differences in PCI outcomes. METHODS: This was a retrospective study of 4776 consecutive patients who underwent PCI for acute coronary syndromes between January 2008 and July 2015. Primary outcomes studied were major adverse cardiovascular events (MACE) and death at 1year. RESULTS: Percutaneous coronary intervention success was similar in men and women (97.8% v 97.7%, p=0.76). There was no significant gender difference in the number of vessels attempted (1.14 vs 1.12, p=0.25), mean number of lesions treated (1.34 vs 1.32, p=0.21) or the mean number of stents used (1.32 vs 1.30, p=0.31). There was equivalent use of drug eluting stents (38.2% vs 38.3%, p=0.94). Women with ST-elevation myocardial infarction STEMI had longer median symptom-to-door time (111 vs 90 mins, p=0.0411) but there was no gender difference in door-to-balloon time or symptom-to-balloon time. There was no significant difference in percentages of women and men <75years treated with prasugrel or ticagrelor (11.1% vs 13.4%, p=0.092). Unadjusted 1-year mortality was 6.4% for women and 4% for men (p=0.0012), but on multivariate analysis, female sex was not a predictor of death. There was no significant gender difference in the overall incidence of unadjusted 1-year MACE (11.6% vs 10.8%, p=0.434). CONCLUSIONS: When contemporary PCI techniques are applied equally to men and women with ACS there is no gender difference in mortality or MACE at 1year. PMID- 29705387 TI - Sudden Cardiac Death in Athletes. AB - Sudden cardiac death (SCD) in athletes is a rare but tragic complication of a number of cardiovascular diseases. Inherited causes such as the structural and arrhythmogenic genetic heart conditions are often found or suspected to be the underlying cause of death at post mortem examination. Physical activity and intense exercise may trigger cardiac arrhythmias in individuals with these conditions leading to SCD. Prevention and treatment strategies include individual athlete management strategies, coupled with public health measures such as universal cardiopulmonary resuscitation (CPR) training and availability of automatic external defibrillators (AEDs) in public places, thereby preventing SCD in both athletes and the general population. Where an athlete is known to have a cardiac condition, some restrictions from participation may be prudent, however, new evidence is emerging that perhaps current restrictions are too strict and could be relaxed in some cases. An athlete-centred model of care is essential to ensure the clinical implications and athlete preferences are balanced providing the best outcome for all concerned. PMID- 29705388 TI - The Translation of Knowledge into Practice in the Management of Atrial Fibrillation in Singapore. AB - BACKGROUND: Atrial fibrillation (AF) is a clinically significant cardiac arrhythmia known to increase the risk of stroke by at least four times. Stroke risk assessment and thromboprophylaxis are vital components in AF management. Guidelines are available to standardise AF management, but physicians' adherence to the recommended guidelines has been low. The aims were to: 1. Examine and compare the level of knowledge and current practice in AF management between cardiologists and non-cardiologist physicians in Singapore; 2. Identify physicians' perceived barriers to prescribing oral anticoagulants (OACs) when indicated; 3. Identify strategies to optimise AF management. METHODS: From June 2017 to August 2017, a cross-sectional online survey involving physicians was conducted in Singapore. The survey instrument was adapted from a previously developed instrument, and validated locally by five cardiologists. It explored the physicians' stroke-risk assessment practices, estimation of stroke risk and benefits of anticoagulation, likelihood of prescribing anticoagulation when indicated, perceived barriers to anticoagulation, and strategies to optimise AF management. RESULTS: Sixty-three physicians completed the survey (14 cardiologists and 49 non-cardiologist physicians). No significant difference was found between cardiologists and non-cardiologist physicians in their assessment and estimation of stroke risk for stable AF patients. However, when presented with an AF patient with stroke risk, cardiologists were more likely than non cardiologist physicians to prescribe novel OACs (93% vs. 51%; chi2=7.933, p=0.004). Compared to cardiologists, the majority of the non-cardiologist physicians thought the risk of falls were usually or always barriers to prescribing OACs (29% vs 69%; chi2=7.579, p=0.006). Among the suggested strategies to support them in AF management, physicians have overwhelmingly rated two as "quite useful" and "very useful": the establishment of clinics for monitoring anticoagulated patients (100%); and involvement of pharmacists in managing patients on warfarin (98.4%). CONCLUSIONS: Physicians possess good knowledge about stroke-risk assessment in AF patients yet it is not translated into effective measures for stroke prevention. Physicians, especially non cardiologist ones, were not anticoagulating AF patients when indicated. Although novel OACs are safer alternatives to warfarin, non-cardiologist physicians were less inclined to use them for stroke prevention. All physicians opined that establishing anticoagulation clinics and collaborating with pharmacists were useful strategies to optimise AF management. Existing barriers to anticoagulation impeded the translation of knowledge into practice in the management of AF patients in Singapore, for which optimal strategies to optimise AF management are ascertained. PMID- 29705389 TI - [The pictogram "Drug and Pregnancy" : Good intentions but difficulties in sight]. PMID- 29705390 TI - Automated EEG background analysis to identify neonates with hypoxic-ischemic encephalopathy treated with hypothermia at risk for adverse outcome: A pilot study. AB - BACKGROUND: To improve the objective assessment of continuous video-EEG (cEEG) monitoring of neonatal brain function, the aim was to relate automated derived amplitude and duration parameters of the suppressed periods in the EEG background (dynamic Interburst Interval= dIBIs) after neonatal hypoxic-ischemic encephalopathy (HIE) to favourable or adverse neurodevelopmental outcome. METHODS: Nineteen neonates (gestational age 36-41 weeks) with HIE underwent therapeutic hypothermia and had cEEG-monitoring. EEGs were retrospectively analyzed with a previously developed algorithm to detect the dynamic Interburst Intervals. Median duration and amplitude of the dIBIs were calculated at 1 h intervals. Sensitivity and specificity of automated EEG background grading for favorable and adverse outcomes were assessed at 6 h-intervals. RESULTS: Dynamic IBI values reached the best prognostic value between 18 and 24 h (AUC of 0.93). EEGs with dIBI amplitude >=15 MUV and duration <10 s had a specificity of 100% at 6-12 h for favorable outcome but decreased subsequently to 67% at 25-42 h. Suppressed EEGs with dIBI amplitude <15 MUV and duration >10 s were specific for adverse outcome (89-100%) at 18-24 h (n = 10). Extremely low voltage and invariant EEG patterns were indicative of adverse outcome at all time points. CONCLUSIONS: Automated analysis of the suppressed periods in EEG of neonates with HIE undergoing TH provides objective and early prognostic information. This objective tool can be used in a multimodal strategy for outcome assessment. Implementation of this method can facilitate clinical practice, improve risk stratification and aid therapeutic decision-making. A multicenter trial with a quantifiable outcome measure is warranted to confirm the predictive value of this method in a more heterogeneous dataset. PMID- 29705391 TI - Stability of benzylpenicillin potassium and ampicillin in an elastomeric infusion pump. AB - Some infectious diseases, such as infective endocarditis, osteomyelitis, and abscesses, require treatment with long-term intravenous antimicrobial treatment. Therefore, the patient is required to stay in the hospital to receive therapy, which lowers their quality of life. Establishing an outpatient parenteral antimicrobial therapy (OPAT) by continuous infusion pump is desired in Japan to overcome these issues. However, the 24-h stability of antimicrobial agents dissolved in infusion solutions is unclear. Thus, we investigated the stability of antimicrobial agents in five different infusion solutions in a clinical setting. Benzylpenicillin potassium (PCG) and ampicillin (ABPC) were dissolved separately in five different infusion solutions and kept at 25 or 31.1 degrees C for 24 h. The residual ratios were determined by high-performance liquid chromatography (HPLC). Dissolved PCG in acetate ringer solution remained stable for 24 h at temperatures of 25 and 31.1 degrees C (101.7 +/- 1.4% and 92.9 +/- 1.3%, respectively). In addition, the PCG solution did not adsorb onto the elastomeric infusion pump after 24 h at 31.1 degrees C. PCG dissolved in acetate ringer solution was also stable for 10 days after being kept in an elastomeric infusion pump at 4 degrees C (99.7 +/- 0.5%). ABPC was unstable in all of the tested infusion solutions and temperatures. Based on our results, PCG in acetate ringer solution can be used in OPAT with continuous infusion pumps. PMID- 29705392 TI - Risk stratification for the development of chronic pulmonary aspergillosis in patients with Mycobacterium avium complex lung disease. AB - BACKGROUND: The number of patients with pulmonary nontuberculous mycobacterial disease complicated by chronic pulmonary aspergillosis (CPA) has been increasing. Additionally, CPA is reportedly associated with mortality in patients with Mycobacterium avium complex lung disease (MAC-LD). In the present study, we aimed to identify risk factors for developing CPA and stratify the risk for CPA development in patients with MAC-LD. METHODS: We retrospectively examined 361 patients newly diagnosed with MAC-LD. Risk factors for CPA development were examined using multivariate Cox proportional hazards regression analyses. A risk stratification system was established using the risk factors and receiver operating characteristic curve analyses. RESULTS: CPA developed in 20 (5.5%) of the 361 patients. Independent risk factors for CPA development included the presence of pulmonary emphysema, baseline steroid use, a serum albumin level <3.5 g/dL, and the presence of MAC-LD cavities. A 4-point scoring system was established to stratify patients into low-risk (0-1 point) and high-risk (2-4 points) groups. The 5-year incidence rates of CPA were 2.2% and 31% in the low- and high-risk groups, respectively (P < 0.001). CONCLUSIONS: We identified independent predictors of CPA development and established a simple risk stratification system for identifying patients with MAC-LD who were at a high risk of developing CPA. PMID- 29705393 TI - Diagnostic scoring system for tuberculous meningitis among adult patients with non-suppurative and non-bacterial meningitis. AB - Tuberculous meningitis (TBM) is the most severe form of extra-pulmonary tuberculosis. The definite diagnosis of this disease is difficult and can result in delayed treatment. Conventional culture yields low sensitivity while high sensitivity diagnostic techniques are costly and unpractical. Adenosine deaminase (ADA) is used to diagnose several settings of extra-pulmonary tuberculosis but it is limited in TBM especially among HIV-infected patients. We retrospectively reviewed the data of patients with non-suppurative meningitis and compared the patient data with TBM and other causes including carcinomatous, lymphomatous, lymphocytic and fungal meningitis. We found that HIV infection, diabetes mellitus, duration of symptoms <14 days, radiologic findings of hydrocephalus, and CSF ADA level >10 IU were associated with TBM. The scoring system based on these parameters and their coefficients in the final model achieved an area under the receiver operating characteristic curve of 0.95,625. The indices were HIV infection = 5, diabetes mellitus = 3, duration of symptoms <14 days = 5, hydrocephalus = 4, and ADA in CSF >10 IU = 5. Based on the assumed costs of the patients with false negative and false positive, an appropriate cut off value of 10 was selected and the sensitivity was 92% and specificity was 89%. PMID- 29705394 TI - Functional flexibility of electron flow between quinol oxidation Qo site of cytochrome bc1 and cytochrome c revealed by combinatory effects of mutations in cytochrome b, iron-sulfur protein and cytochrome c1. AB - Transfer of electron from quinol to cytochrome c is an integral part of catalytic cycle of cytochrome bc1. It is a multi-step reaction involving: i) electron transfer from quinol bound at the catalytic Qo site to the Rieske iron-sulfur ([2Fe-2S]) cluster, ii) large-scale movement of a domain containing [2Fe-2S] cluster (ISP-HD) towards cytochrome c1, iii) reduction of cytochrome c1 by reduced [2Fe-2S] cluster, iv) reduction of cytochrome c by cytochrome c1. In this work, to examine this multi-step reaction we introduced various types of barriers for electron transfer within the chain of [2Fe-2S] cluster, cytochrome c1 and cytochrome c. The barriers included: impediment in the motion of ISP-HD, uphill electron transfer from [2Fe-2S] cluster to heme c1 of cytochrome c1, and impediment in the catalytic quinol oxidation. The barriers were introduced separately or in various combinations and their effects on enzymatic activity of cytochrome bc1 were compared. This analysis revealed significant degree of functional flexibility allowing the cofactor chains to accommodate certain structural and/or redox potential changes without losing overall electron and proton transfers capabilities. In some cases inhibitory effects compensated one another to improve/restore the function. The results support an equilibrium model in which a random oscillation of ISP-HD between the Qo site and cytochrome c1 helps maintaining redox equilibrium between all cofactors of the chain. We propose a new concept in which independence of the dynamics of the Qo site substrate and the motion of ISP-HD is one of the elements supporting this equilibrium and also is a potential factor limiting the overall catalytic rate. PMID- 29705395 TI - Imperatorin ameliorates lipopolysaccharide induced memory deficit by mitigating proinflammatory cytokines, oxidative stress and modulating brain-derived neurotropic factor. AB - BACKGROUND: Lipopolysaccharide (LPS), an endotoxin from the outer membrane of Gram negative bacteria has been reported to cause neuroinflammation and learning and memory deficits. There are reports describing the beneficial effects of Imperatorin (IMP), a naturally occurring furanocoumarin in central nervous system (CNS) disorders such as anxiety and epilepsy. OBJECTIVE: In the current study, we investigated whether IMP protects against LPS mediated memory deficits and neuroinflammation. METHODS: Mice pretreated with IMP (5, 10 mg/kg po) were administered LPS (250 MUg/kg ip) for 7 days. Memory was evaluated in the Morris water maze (MWM) and Y maze. The mice were euthanised and different biochemical assessments were carried out to measure oxidative stress and acetyl choline esterase (AChE). Further, evaluation of proinflammatory cytokines such as tumor necrosis factor (TNF-alpha) and interleukin-6 (IL-6) levels and brain derived neurotrophic factor (BDNF) in hippocampus and cortex of brain were performed. RESULTS: LPS administration caused poor memory retention in both, MWM and Y maze, and caused distinct oxidative stress since decrease in superoxide dismutase (SOD), reduced glutathione (GSH) levels and increased lipid peroxidation were observed. Also, a significant rise was observed in the levels of AChE. Moreover, a rise in TNF-alpha and IL-6 levels and depleted levels of BDNF were noted. IMP pretreatment reversed LPS induced behavioral and memory disturbances and significantly decreased the oxidative stress and AChE levels. It also reduced TNF alpha and IL-6 levels and caused a significant upregulation of BDNF levels. CONCLUSION: Present study highlights the potential neuroprotective role of IMP against LPS mediated cognitive impairment and neuroinflammation. PMID- 29705396 TI - Acute physical exercise increases the adaptor protein APPL1 in the hypothalamus of obese mice. AB - Adiponectin is considered an adipokine that has essential anti-inflammatory and insulin-sensitivity actions. The adaptor protein containing the pleckstrin homology domain, the phosphotyrosine-binding domain, and leucine zipper motif 1 (APPL1) is a protein involved in adiponectin signaling that plays a role in many physiological and pathophysiological processes. In the central nervous system, adiponectin can potentiate the effects of leptin in the arcuate proopiomelanocortin (POMC) neurons. However, the role of APPL1 in the hypothalamus is not well understood. Therefore, in this study, we explored the effects of acute physical exercise on APPL1 protein content in the hypothalamus and food intake control in leptin stimulated-obese mice. Here we show that acute exercise increased serum adiponectin levels and APPL1 content in the hypothalamus, which were followed by reduced food intake in obese mice. Further, at the molecular level, the exercised obese mice increased the protein kinase B (Akt) signaling in the hypothalamus and attenuated the mammalian homolog of Drosophila tribbles protein 3 (TRB3) levels. In conclusion, the results indicate physical exercise is capable of increasing APPL1 protein content in the hypothalamus of leptin stimulated-obese mice and modulating food intake. PMID- 29705397 TI - Autocrine CCL5 promotes tumor progression in esophageal squamous cell carcinoma in vitro. AB - The pro-tumoral effects of CCL5 have been identified in numerous cancer types. We successfully cultivated 4 esophageal squamous cell carcinoma (ESCC) cell lines, including TWES-1, TWES-3 and a pair of cell lines derived from primary lesion (TWES-4PT) and metastatic lymph node (TWES-4LN) of the same patient. Whole genome screening showed that TWES-4LN expressed higher levels of CCL5 compared to that of TWES-4PT; quantification of protein secretion displayed comparable results, suggesting that CCL5 could be associated with lymph node metastasis in ESCC. CCL5 knockdown by siRNA significantly reduced basal growth rate, tumor migration and invasiveness in the paired cell lines; whereas this treatment induced cell apoptosis in TWES-1 and TWES-3. CCR5 antagonist maraviroc significantly inhibited tumor migration and invasion in the paired cell lines without affecting tumor growth. Collectively, these results suggest that CCL5 autocrine loop may promote ESCC progression; targeting the CCL5/CCR5 axis could be a potential therapeutic strategy for this deadly disease. PMID- 29705398 TI - A systematic review and meta-analysis of comparison between autologous costal cartilage and alloplastic materials in rhinoplasty. AB - BACKGROUND: Both autologous costal cartilage (ACC) and alloplastic materials are widely used in rhinoplasty. However, there is controversy regarding which material can offer the ideal outcome and fewer complications. OBJECTIVE: The authors review current literature to evaluate complication and satisfaction rates with different materials used in rhinoplasty. METHODS: A comprehensive literature search of articles was conducted in Embase and PubMed published through April 14, 2017. We included only articles that used ACC, silicone, Medpor, Gore-Tex, or a combination of autologous and alloplastic materials in rhinoplasty. The primary outcomes analyzed were complications and postoperative satisfaction. After data extraction, meta-analysis using the random effect model was performed to summarize outcome parameters among different implant types. RESULTS: Fifty-three articles met inclusion criteria and were included in the meta-analysis. The overall complication rate of ACC was 14%, which was higher than that of other implants. However, ACC was more commonly used in revision rhinoplasty. Medpor was associated with low overall complication rates (6%) and good aesthetic and functional outcomes. CONCLUSIONS: Our analysis of available evidence suggests that ACC is preferred in revision rhinoplasty, which may explain its association with higher complication rates. In primary rhinoplasty, Medpor offered versatility in addition to low complication rates and good aesthetic and function outcomes. But its potential dramatic damage to the nasal tissue made secondary surgery extremely difficult. Our findings were limited by lack of high-quality evidence. Future studies with rigorous study design for head-to-head comparisons and longer follow-up are needed to establish clear guidelines for choosing the appropriate rhinoplasty graft material. PMID- 29705399 TI - Mollie Lentaigne, the nurse who drew McIndoe's Guinea pigs: Exploring the role of a medical artist at the Queen Victoria Hospital, 1940-1945. AB - Mollie Lentaigne was a medical artist who worked at the Queen Victoria Hospital in East Grinstead during the Second World War alongside Archibald McIndoe and his dedicated team. She drew hundreds of medical illustrations for McIndoe and his fellow surgeons during the years between 1940 and 1945. Her illustrations depict the plastic surgery that was carried out in that hospital on the badly burnt RAF servicemen injured during the war that took place in the skies over Europe, which included many aircrew injured during the Battle of Britain. This project looks at the career of Lentaigne and her role within the surgical team in East Grinstead during that era and explores a number of Lentaigne's illustrations whilst providing context as to the procedures and patients depicted. An examination of Lentaigne's story, using an interview conducted by the author with the artist offers an alternative perspective with which to observe the events that unfolded in East Grinstead during that conflict. An analysis of these images shows the ability of this artist to portray relatively complex operations with a series of simple pencil or ink diagrams whilst also skilfully engaging the observer's sense of touch. The ability of a medical artist to be selective with her illustrations allowed them to provide clearer, less cluttered images that were preferred by McIndoe when recording the specific surgical procedures for use in the patient's medical records. PMID- 29705400 TI - Associations between TV viewing and depressive symptoms among 60,202 Brazilian adults: The Brazilian national health survey. AB - BACKGROUND: Our aim was to examine associations between depression and time spent in TV viewing in a representative sample of Brazilian adults. METHODS: Data from the Brazilian National Health Survey (Pesquisa Nacional de Saude - PNS in Portuguese) (n =60,202; >=18 years) were used. Time spent TV viewing (h/day) was elicited via interview. Depression was evaluated through the Patient Health Questionnaire-9. Chronological age, educational status, employment status, alcohol use, tobacco smoking and body mass index were covariates. Descriptive statistics (mean and 95% confidence interval) and adjusted logistic regression models were applied. RESULTS: Five or more hours as well as less than 1 h of TV viewing was associated with increased depression (men: <1 h OR = 1.89, 95%CI = 1.40-2.54; >=5 h OR = 2.69, 95%CI = 1.88-3.83; women: <1 h OR = 1.50, 95%CI = 1.25-1.81; >=5 h OR = 1.65, 95%CI = 1.35-2.03) when compared to 2-2.99 h of TV viewing. CONCLUSION: More than 5 h/day seems to be associated with a higher risk for depression among Brazilian adults (except for older adults). Less than 1 h TV viewing might be a measure-of-proxy for a lower socio-economic status, which is a known risk factor for depression. PMID- 29705401 TI - Initial hazard assessment of 4-benzylphenol, a structural analog of bisphenol F: Genotoxicity tests in vitro and a 28-day repeated-dose toxicity study in rats. AB - 4-Benzylphenol (CAS No. 101-53-1), a structural analog of bisphenol F, has estrogenic activity in vitro and in vivo, as is the case with bisphenol F. 4 Benzylphenol is used in plastics and during organic synthesis. Since its safety is largely unknown, we conducted toxicity tests as part of screening risk assessment in an existing chemical safety survey program. Based on results of the Ames test and the chromosomal aberration test using Chinese hamster lung cells (OECD TG 471 and 473), 4-benzylphenol was determined to be non-genotoxic in vitro. In a 28-day repeated-dose toxicity study, Crl:CD (SD) rats were administrated 4-benzylphenol by gavage at 0, 30, 150, or 750 mg/kg/day (OECD TG 407). Consequently, body weight was lower in males at 750 mg/kg/day. In the liver, relative organ weights were increased in both sexes at 750 mg/kg/day, and centrilobular hepatocellular hypertrophy was observed in males at 150 and 750 mg/kg/day. In the forestomach, hyperkeratosis and hyperplasia of squamous cells were observed in males at 150 and 750 mg/kg/day, and in females at 750 mg/kg/day. Based on these results, we identified the NOAEL for 4-benzylphenol as 30 mg/kg/day, with a hazard assessment value (D-value) of 0.05 mg/kg/day corresponding to hazard class 3. PMID- 29705402 TI - Gene co-expression analysis identifies gene clusters associated with isotropic and polarized growth in Aspergillus fumigatus conidia. AB - Aspergillus fumigatus is a saprophytic fungus that extensively produces conidia. These microscopic asexually reproductive structures are small enough to reach the lungs. Germination of conidia followed by hyphal growth inside human lungs is a key step in the establishment of infection in immunocompromised patients. RNA-Seq was used to analyze the transcriptome of dormant and germinating A. fumigatus conidia. Construction of a gene co-expression network revealed four gene clusters (modules) correlated with a growth phase (dormant, isotropic growth, polarized growth). Transcripts levels of genes encoding for secondary metabolites were high in dormant conidia. During isotropic growth, transcript levels of genes involved in cell wall modifications increased. Two modules encoding for growth and cell cycle/DNA processing were associated with polarized growth. In addition, the co expression network was used to identify highly connected intermodular hub genes. These genes may have a pivotal role in the respective module and could therefore be compelling therapeutic targets. Generally, cell wall remodeling is an important process during isotropic and polarized growth, characterized by an increase of transcripts coding for hyphal growth and cell cycle/DNA processing when polarized growth is initiated. PMID- 29705403 TI - A refined rat primary neonatal microglial culture method that reduces time, cost and animal use. AB - BACKGROUND: Primary microglial cultures have been used extensively to facilitate the development of therapeutic strategies for a variety of CNS disorders including neurodegeneration and neuropathic pain. However, existing techniques for culturing these cells are slow and costly. NEW METHOD: Here, we report a refined protocol based on our previously published methods described by Clark et al., which reduces in the time, reagents and the number of animals used for each culture whilst yielding high number and excellent quality microglial cells. RESULTS: Our refined protocol offers an isolation of >96% microglia from a mixed glial culture after only four days of incubation. It results in a high yield of microglia, in excess of one million cells per cortex with predominantly resting morphology and a low level of cell activation. COMPARISON WITH EXISTING METHOD(S): Compared to conventional procedures our refined protocol requires only one third of the time to prepare high quality microglial cultures, cuts the cost more than four-fold, and significantly reduces the number of animals used per culture. CONCLUSION: Our consistent, reliable, and time/cost effective microglial culture protocol is crucial for efficient in vitro screening of potential therapeutics. By dramatically reducing the culture time from 2 weeks to just 4 days and increasing the laboratory research output it has implications for the Reduction, Refinement and Replacement policies endorsed by many government funding agencies and animal research regulatory bodies. PMID- 29705404 TI - Oral lichen sclerosus: an overview and report of three cases. AB - Lichen sclerosus is an unusual, chronically relapsing mucocutaneous disease that usually afflicts the anogenital region. Oral lesions of lichen sclerosus are rare, with only 36 histologically verified cases reported to date. The classic histopathologic findings of oral lichen sclerosus include: an area of subepithelial hyalinization, loss of elastic fibres, and band-like mononuclear inflammatory infiltrate. Despite its rarity, oral lichen sclerosus should be included in the differential diagnosis of porcelain- or ivory-white macules. Here we present three new cases of oral lichen sclerosus. A review of these cases and the previously reported cases revealed that oral lichen sclerosus is slightly more common in women and can affect individuals of any age. Oral lesions of lichen sclerosus usually do not require treatment, except when there are significant symptoms or aesthetic complaint. Almost 50% of the patients with oral lichen sclerosus present with extraoral manifestations. Thus, referral to a dermatologist and a gynaecologist is advised. Although no cases of malignant transformation of oral lichen sclerosus have been reported, regular, long-term follow-up of patients with oral lichen sclerosus is indicated. PMID- 29705405 TI - Three-dimensional surface models of the facial soft tissues acquired with a low cost scanner. AB - Although there has been an increase in three-dimensional (3D) scanning methods available on the market, they are generally expensive. The DI3D system is considered a good scanner for the acquisition of soft tissue surface images. The Microsoft Kinect scanner is a much more affordable alternative for acquiring 3D models. The aim of this study was to determine whether the precision and accuracy of Kinect are similar to those of DI3D. To verify the accuracy, 10 patients were scanned with both methods The models of each patient acquired from the two scanners were superimposed using a surface-to-surface registration technique, and the distances between the models were recorded for 10 different anatomical regions of interest. For the evaluation of precision, one patient was scanned 11 different times with the Kinect scanner, and these models were compared using the same superimposition method. It was found that the average difference between the two methods was 0.3+/-2.03mm. The assessment of reproducibility showed an average difference between the images taken with Kinect of 0.1+/-0.6mm (P<0.05, one sample t-test). Thus, Kinect showed good precision and reasonable accuracy, and appears to be an interesting and promising resource for facial analysis. PMID- 29705406 TI - Bleeding during and after dental extractions in patients with liver cirrhosis. AB - Little is known about the prevention and management of acquired coagulopathies, such as those affecting cirrhotic patients. The objective of this analytic retrospective observational study was to evaluate patients on the liver transplant waiting list according to the following outcomes: (1) presence of unusual intraoperative bleeding (>10min after routine haemostatic procedures); and (2) presence of postoperative haemorrhagic complications. The outcomes were analysed according to clinical and laboratory variables. A total of 190 visits were performed for extraction of 333 teeth (ranging from 1 to 9 teeth per visit), with platelet count ranging from 16,000 to 216,000 and international normalized ratio (INR) below 3. Twelve cases (6.31%) had unusual intraoperative bleeding and 12 had postoperative haemorrhagic complications. All the events were controlled by local measures. Intraoperative bleeding was associated with low count of platelets (P=0.026). However, this counting could explain only 16% (adjusted R2=0.16) of the cases of bleeding (P=0.44), meaning that platelet function changes might be involved. Our results show that cirrhotic patients presenting platelet count above 16,000 and INR below 3 need no previous blood transfusion, with local measures being enough to manage haemorrhagic events. PMID- 29705407 TI - Does the clinical frailty score improve the accuracy of the SOFA score in predicting hospital mortality in elderly critically ill patients? A prospective observational study. AB - PURPOSE: To determine whether the addition of the frailty status assessed by the clinical frailty scale (CFS) to the SOFA score (SOFA-CFS) improves the performance of the SOFA score alone in predicting the hospital mortality of elderly critically ill patients. METHODS: A prospective observational study performed between February 2015 and February 2016 including 189 patients aged >=65 years and hospitalized >=24 h in the intensive care unit (ICU). RESULTS: The SOFA-CFS score did not improve the performance of the SOFA score alone in predicting hospital mortality (AUC = 0.66, 95% CI 0.58-0.74 vs AUC = 0.63, 95% CI 0.55-0.72, respectively, p = 0.082). The AUC of the CFS score was 0.62 (95% CI 0.53-0.71). In the multivariable analysis, age (OR: 1.09, 95% CI 1.03-1.16, p = 0.006), McCabe score C vs A (reference) and B vs A (reference) (OR: 8.28, 95% CI 2.83-24.27and OR: 2.29, 95% CI 1.02-5.12, p = 0.006, respectively), Glasgow coma score at admission (OR: 0.31, 95% CI 0.14-0.48, p = 0.003), and SOFA score (OR: 1.11, 95% CI 1.01-1.23, p = 0.037) were risk factors for hospital mortality. CONCLUSIONS: The performance of the SOFA score in predicting hospital mortality was low, although it was an independent risk factor for mortality. The combination of frailty status with the SOFA score did not improve the performance of the SOFA score alone. PMID- 29705408 TI - Factors associated with delayed rapid response team activation. AB - Delayed activation of the rapid response team (RRT) is common and has been associated with adverse outcomes. However, little is known about the factors associated with delayed activation. This was an observational study from two hospitals in Ottawa, Canada, including adult inpatients with experiencing an activation of the RRT. Data was collected between May 1, 2012 and May 31, 2016 and groups were divided between those with activation within 1 h of meeting call criteria and those with >1 h (delayed activation). The primary outcome was in hospital mortality. There were 6131 patients included in the study, of which 1441 (26.0%) experienced a delay. The reasons for RRT call were significantly different (P < 0.001) with respiratory distress (29.3% versus 24.8%), and hypotension (17.4% versus 13.2%) being more common in the delayed group, and dysrhythmias (15.9% versus 18.5%) and altered level of consciousness (13.5% versus 18.7%) being less common. RRT activation was more delayed on non-surgical services (P < 0.001). Delayed activation was associated with increased mortality (Adjusted odds ratio [OR] 1.23, 95% CI 1.07-1.41), ICU admission (Adjusted OR 1.72, 95% CI 1.51-1.96), and hospital length of stay (13 versus 15 days, P < 0.001). PMID- 29705409 TI - Optical activities of steroid ketones - Elucidation of the octant rule. AB - Theoretical calculations of optical activities in steroid ketones are presented by using modern semi-empirical PM7 wavefunctions. Both circular dichroism (CD) and specific rotation, which is proportional to optical rotation dispersion (ORD), are well simulated, and signs of the Cotton effect at the most long wavelength region are fully in accordance with the experimental results. The good accordance is related to the octant rule, which is deduced within the framework of the perturbation theory. Our treatment is promising to predict the signs of the Cotton effect of large molecules, and thus, the absolute configurations can also be grasped without demanding procedures. PMID- 29705410 TI - Spectroscopic investigation and DFT modelling studies of Eu3+ complex with 1-(2,6 dihydroxyphenyl)ethanone. AB - Eu3+ complex with 1-(2,6-dihydroxyphenyl)ethanone in the solid state has been synthesized and characterized by elemental analysis, UV-visible, FT-IR and FT Raman spectroscopies, powder X-ray diffraction, electron emission under femtosecond laser excitation. The stoichiometry and the formula of the studied complex have been proposed. Its physicochemical properties have been analyzed in terms of the structure and DFT calculations performed for the ligand. The luminescence and dynamics of the excited states depopulation have been studied using femtosecond laser excitation. Spectral and energetic transformation of femtosecond light impulses has been studied and possibility of the energy transfer between the ligand and the Eu3+ electron levels has been analyzed. PMID- 29705411 TI - Short communication: Identifying challenges and opportunities for improved nutrient management through the USDA's Dairy Agroecosystem Working Group. AB - Nutrient management on US dairy farms must balance an array of priorities, some of which conflict. To illustrate nutrient management challenges and opportunities across the US dairy industry, the USDA Agricultural Research Service Dairy Agroecosystems Working Group (DAWG) modeled 8 confinement and 2 grazing operations in the 7 largest US dairy-producing states using the Integrated Farm System Model (IFSM). Opportunities existed across all of the dairies studied to increase on-farm feed production and lower purchased feed bills, most notably on large dairies (>1,000 cows) with the highest herd densities. Purchased feed accounted for 18 to 44% of large dairies' total operating costs compared with 7 to 14% on small dairies (<300 milk cows) due to lower stocking rates. For dairies with larger land bases, in addition to a reduction in environmental impact, financial incentives exist to promote prudent nutrient management practices by substituting manure nutrients or legume nutrients for purchased fertilizers. Environmental priorities varied regionally and were principally tied to facility management for dry-lot dairies of the semi-arid western United States (ammonia-N emissions), to manure handling and application for humid midwestern and eastern US dairies (nitrate-N leaching and P runoff), and pasture management for dairies with significant grazing components (nitrous oxide emissions). Many of the nutrient management challenges identified by DAWG are beyond slight modifications in management and require coordinated solutions to ensure an environmentally and economically sustainable US dairy industry. PMID- 29705412 TI - Use of beta-glucan from spent brewer's yeast as a thickener in skimmed yogurt: Physicochemical, textural, and structural properties related to sensory perception. AB - Powdered beta-glucan extracted from brewer's yeast (Yestimun, Leiber GmbH, Bramsche, Germany) was incorporated into skimmed-milk yogurt at varying concentrations (0.2-0.8% wt/wt) to investigate its potential application as a thickener. The effect of beta-glucan fortification on the nutritional profile, microstructure, physicochemical properties, and texture of freshly prepared yogurts was investigated. Sensory evaluation was also conducted and was correlated with instrumental analysis. The addition of Yestimun significantly reduced the fermentation time of the yogurt mix from 4 h to 3 h. Scanning electron microscopy revealed that beta-glucan particles formed small spherical clusters within the yogurt matrix. The majority of the physicochemical properties (syneresis, viscosity, color, and titratable acidity) remained unaffected by the incorporation of Yestimun in the recipe. Textural properties showed a gradual increment with increasing beta-glucan concentration. Hardness, total work done, adhesive force, and adhesiveness increased by 19.27, 23.3, 21.53, and 20.76%, respectively, when using the highest amount of Yestimun powder. Sensory analysis (n = 40) indicated that fortifying yogurt with Yestimun at 0.8% (wt/wt) concentration may affect overall acceptance ratings, which was attributed to adverse flavor and aftertaste effects. However, the overall liking score of the yogurt (5.0/9.0) shows potential for commercialization of the product. PMID- 29705413 TI - The effect of ultrasound treatment on microbial and physicochemical properties of Iranian ultrafiltered feta-type cheese. AB - Pasteurization failures in the dairy industry have been reported in many previous studies. Hence, ultrasound, as a nonthermal alternative to pasteurization, has been studied in recent years. In this research, retentate of ultrafiltered milk was pasteurized, inoculated with Escherichia coli O157:H7, Staphylococcus aureus, Penicillium chrysogenum, or Clostridium sporogenes, and then treated with ultrasound for 20 min at frequencies of 20, 40, and 60 kHz and intensity of 80%. Microbial and physicochemical properties of the subsequently produced ultrafiltered white cheeses were investigated throughout 60 d of ripening. Sonication at 20, 40, and 60 kHz reduced counts of E. coli O157:H7, S. aureus, P. chrysogenum, and Cl. sporogenes by 4.08, 4.17, and 4.28 log; 1.10, 1.03, and 1.95 log; 1.11, 1.07, and 1.11 log; and 2.11, 2.03, and 2.17 log, respectively. Sonication improved the acidity of ripened cheese, and sonicated samples had lower pH values than control samples at the end of storage. Sonication did not affect fat in dry matter or the protein content of cheese during ripening, but it did accelerate lipolysis and proteolysis; the highest rates of lipolysis index (free fatty acid content) and proteolysis index (water-soluble nitrogen) were observed on d 60 of ripening for samples sonicated at 60 kHz. Sonication did not affect cohesiveness or springiness of cheese samples, but hardness and gumminess increased in the first 30 d and then decreased until 60 d of storage. Furthermore, ultrasound treatment improved organoleptic properties of the cheese. In terms of overall acceptance, samples sonicated at 60 kHz received the highest sensorial scores. Results showed that sonication can improve microbial, physicochemical, and sensorial properties of ultrafiltered white cheese. PMID- 29705414 TI - Genome-wide association study for milking speed in French Holstein cows. AB - Using a combination of data from the BovineSNP50 BeadChip SNP array (Illumina, San Diego, CA) and a EuroGenomics (Amsterdam, the Netherlands) custom single nucleotide polymorphism (SNP) chip with SNP pre-selected from whole genome sequence data, we carried out an association study of milking speed in 32,491 French Holstein dairy cows. Milking speed was measured by a score given by the farmer. Phenotypes were yield deviations as obtained from the French evaluation system. They were analyzed with a linear mixed model for association studies. We identified SNP on 22 chromosomes significantly associated with milking speed. As clinical mastitis and somatic cell score have an unfavorable genetic correlation with milking speed, we tested whether the most significant SNP on these 22 chromosomes associated with milking speed were also associated with clinical mastitis or somatic cell score. Nine hundred seventy-one genome-wide significant SNP were associated with milking speed. Of these, 86 were associated with clinical mastitis and 198 with somatic cell score. The most significant association signals for milking speed were observed on chromosomes 7, 8, 10, 14, and 18. The most significant signal was located on chromosome 14 (ZFAT gene). Eleven novel milking speed quantitative trait loci (QTL) were observed on chromosomes 7, 10, 11, 14, 18, 25, and 26. Twelve candidate SNP for milking speed mapped directly within genes. Of these, 10 were QTL lead SNP, which mapped within the genes HMHA1, POLR2E, GNB5, KLHL29, ZFAT, KCNB2, CEACAM18, CCL24, and LHPP. Limited pleiotropy was observed between milking speed QTL and clinical mastitis. PMID- 29705415 TI - Rapid baso-apical translocation of Mycobacterium avium ssp. paratuberculosis in mammary epithelial cells in the presence of Escherichia coli. AB - Infection of mammary gland cells with bacterial pathogens begins with adhesion, invasion, and persistence within the cells or systemic distribution. Some bacteria, such as Escherichia coli, are known to causes bovine mastitis, resulting in acute proinflammatory responses in the mammary tissue. Mycobacterium avium ssp. paratuberculosis (MAP), the etiological agent of paratuberculosis, is able to spread to distant organs after crossing intestinal cells, reaching the mammary gland and potentially being released in milk, infecting calves during suckling. Its exit from systemic sites may be influenced by preexisting inflammation such as that caused by E. coli mastitis. Interactions between E. coli and MAP in mammary epithelial cells have not yet been described. In this study, we posited that E. coli-infected bovine mammary epithelial cells would facilitate baso-apical translocation of MAP in an ex vivo model. We showed that the presence of E. coli in a bovine mammary epithelial cell line (MAC-T) increased baso-apical translocation of MAP to the apical side of the cells. Levels were significantly higher 30 min post-infection and decreased at 120 min post-infection. Cells previously infected with E. coli and MAP or with E. coli alone showed a significant increase in IL1B mRNA expression at 120 min. We detected no significant expression of p38 mitogen-activated protein kinase (mapkp38) or IL10, regardless of treatment. Thereby, the presence of E. coli in MAC-T cells alters the translocation of MAP through epithelial cells, enabling its rapid translocation to the cellular surface. Expression of IL1B was shown to influence the apical-basal translocation of MAP at 120 min. Findings from the current study suggest that MAP translocation into milk is likely enhanced by inflammatory states such as those induced during E. coli mastitis. This is the first report demonstrating the effect of E. coli under MAP coinfection in bovine mammary epithelial cells under experimental conditions. PMID- 29705416 TI - Use of MALDI-TOF to characterize staphylococcal intramammary infections in dairy goats. AB - The most common pathogens causing intramammary infections (IMI) in dairy goats are staphylococci. Gene sequencing has been the reference method for identification of staphylococcal species, but MALDI-TOF mass spectrometry could represent a rapid and cost-effective alternative method. The objectives were to evaluate the typeability and accuracy of partial gene sequencing and MALDI-TOF for identifying staphylococci isolated from caprine milk samples, and to evaluate the relationship between staphylococcal species IMI, milk somatic cell score (SCS), and milk yield (MY). A composite (goat-level) milk sample was collected from all 940 lactating goats in a single herd. Dairy Herd Information Association test-day data for parity, days in milk, SCS, and MY were retrieved from Dairy Herd Information Association records. Milk samples were cultured on Columbia blood agar, and isolates from samples that yielded a single colony type of a presumptively identified Staphylococcus spp. were identified by PCR amplification and partial sequencing of rpoB, tuf, or 16S-rRNA, and MALDI-TOF. Mixed linear models were used to evaluate the relationship between staphylococcal IMI, SCS, and MY. The goat-level prevalence of staphylococcal IMI based on isolation of a single colony type was 24.4% (213/874). Seventeen goats had a contaminated sample. Among the remaining goats (n = 857), the most common species causing single colony-type IMI were Staphylococcus simulans (7.9%), Staphylococcus xylosus (3.5%), Staphylococcus caprae (3.6%), Staphylococcus chromogenes (2.9%), and Staphylococcus epidermidis (2.2%). The typeability of staphylococcal isolates with partial housekeeping gene sequence analysis (rpoB, complemented by tuf and 16S as needed) was 97.7%. The typeability and accuracy of MALDI-TOF were 84 and 100%, respectively. Overall, only Staphylococcus chromogenes IMI was associated with a higher SCS than goats with no growth. After adjusting for parity and stage of lactation, staphylococcal IMI status was not significantly associated with MY. For the staphylococci isolated from goats in this herd, MALDI-TOF proved an accurate method of speciation with a relatively high typeability. An association between staphylococcal IMI, SCS, and MY was not defined using goat-level data with the exception of S. chromogenes IMI, which was associated with a higher SCS than goats with no growth. PMID- 29705417 TI - Milk fat depression in dairy ewes fed fish oil: Might differences in rumen biohydrogenation, fermentation, or bacterial community explain the individual variation? AB - Dairy ewes show large individual variation in the extent of diet-induced milk fat depression (MFD) but reasons behind this variability remain uncertain. Previous results offered no convincing support for these differences being related to relevant changes in the milk fatty acid (FA) profile, including potentially antilipogenic FA, or in the transcript abundance of candidate genes involved in mammary lipogenesis. Therefore, we hypothesized that alterations in the processes of rumen biohydrogenation and fermentation, as well as in the bacterial community structure, might account for individual variation in fish oil-induced MFD severity. To test this explanation, 15 ewes received a total mixed ration without lipid supplementation (control; n = 5) or supplemented with 20 g of fish oil/kg of dry matter [10 animals divided into those showing a strong (RESPON+; -25.4%; n = 5) or a mild (RESPON-; -7.7%; n = 5) decrease in milk fat concentration] for 5 wk. Rumen fermentation parameters, biohydrogenation metabolites, and bacterial structure and diversity were analyzed in rumen samples collected before and after treatments. Although the fish oil supplementation increased the concentration of demonstrated or putative antilipogenic FA (e.g., cis-9 16:1, cis-11 18:1, or trans-10,cis-12 CLA), surprisingly, none of them differed significantly in relation to the extent of MFD (i.e., between RESPON- and RESPON+), and this was the case only for a few minor FA (e.g., cis-6+7 16:1 or 17:0 anteiso). Changes in total volatile FA, acetate, and propionate concentrations were associated with MFD severity, with higher decreases in more susceptible animals. Individual responses were not related to shifts in rumen bacterial structure but some terminal restriction fragments compatible with Clostridiales, Ruminococcaceae, Lachnospiraceae, and Succiniclasticum showed greater abundances in RESPON-, whereas some others that may correspond to Prevotella, Mogibacterium, and Quinella-related spp. were more abundant in RESPON+. Overall, the results suggest that individual variation in MFD severity in dairy ewes fed fish oil cannot be fully explained by differences in the processes of rumen biohydrogenation and fermentation or in the bacterial community, and further research would be necessary to elucidate the large variability in the responsiveness to MFD inducing marine lipids. PMID- 29705418 TI - Short communication: Serum osteoprotegerin concentrations in periparturient dairy cows. AB - Dairy cows experience hypocalcemia at the onset of lactation; however, the contribution of bone metabolism to circulating Ca concentrations during the periparturient period is not well understood. Osteoprotegerin (OPG) protects against loss of skeletal mass by regulating osteoclastogenesis. We previously reported that the bone resorption increased around parturition in dairy cows from the perspective of bone markers in blood. The aim of this study was to explore osteoclastic bone resorption in periparturient dairy cows by measuring changes in serum OPG concentrations around calving. The OPG concentrations were evaluated in primiparous (n = 9) and multiparous (n = 9) cows at 21 d precalving and over 5 d after calving. Based on mixed model analyses, the multiparous cows had a higher serum OPG concentration than primiparous cows at precalving and exhibited a significant decline in serum OPG and Ca concentrations after calving. In contrast to multiparous cows, primiparous cows did not exhibit these changes. Therefore, we hypothesized that multiparous cows preserve their bone mineral content during late pregnancy and activate the osteoclastic bone resorption after calving. Based on our serum OPG data, we identified the different periparturient osteoclastic bone resorption patterns in healthy primiparous and multiparous dairy cows. PMID- 29705419 TI - Comparison of performance and quantitative descriptive analysis sensory profiling and its relationship to consumer liking between the artisanal cheese producers panel and the descriptive trained panel. AB - The aim of this research was to compare the performance and sensory profiling of a panel of artisanal cheese producers against a trained panel and their relationship to consumer liking (external preference mapping). Performance was analyzed statistically at an individual level using the Fisher's test (F) for discrimination, the mean square error for repeatability, and Manhattan plots for visualizing the intra-panel homogeneity. At group level, performance was evaluated using ANOVA. External preference mapping technique was applied to determine the efficiency of each sensory profile. Results showed that the producers panel was discriminant and repetitive with a performance similar to that of the trained panel. Manhattan plots showed that the performance of artisanal cheese producers was more homogeneous than trained panelists. The correlation between sensory profiles (Rv = 0.95) demonstrated similarities in the generation and use of sensory profiles. The external preference maps generated individually with the profiles of each panel were also similar. Recruiting individuals familiar with the production of artisanal cheeses as panelists is a viable strategy for sensory characterization of artisanal cheeses within their context of origin because their results were similar to those from the trained panel and can be correlated with consumer liking data. PMID- 29705420 TI - Short communication: In vitro rumen gas production and starch degradation of starch-based feeds depend on mean particle size. AB - Our objective was to model the effect of mean particle size (mPS) on in vitro rumen starch degradation (IVSD) and the kinetics of gas production for different starch-based feeds. For each feed, 2 batches of the same grains were separately processed through 2 different mills (cutter or rotor speed mills), with or without different screens to achieve a wide range of mPS (0.32 to 3.31 mm for corn meals; 0.19 to 2.81 mm for barley meals; 0.16 to 2.13 mm for wheat meals; 0.28 to 2.32 mm for oat meals; 0.21 to 2.36 mm for rye meals; 0.40 to 1.79 for sorghum meals; 0.26 to 4.71 mm for pea meals; and 0.25 to 4.53 mm for faba meals). The IVSD data and gas production kinetics, obtained by fitting to a single-pool exponential model, were analyzed using a completely randomized design, in which the main tested effect was mPS (n = 6 for all tested meals, except n = 7 for corn meals and n = 5 for sorghum meals). Rumen inocula were collected from 2 fistulated Holstein dairy cows that were fed a total mixed ration consisting of 16.2% crude protein, 28.5% starch, and 35.0% neutral detergent fiber on a dry matter basis. The IVSD, evaluated after 7 h of rumen incubation, decreased linearly with increasing mPS for corn, barley, wheat, rye, pea, and faba meals, and decreased quadratically with increasing mPS for the other meals. The y-axis intercept for 7-h IVSD was below 90% starch for corn, barley, and rye feeds and greater than 90% for the other tested feeds. The mPS adjustment factors for the rate of rumen starch degradation varied widely among the different tested feeds. We found a linear decrease in starch degradation with increasing mPS for barley, wheat, rye, and pea meals, whereas we noted a quadratic decrease in starch degradation for the other tested meals. Further, we observed a linear decrease in the rate of gas production with increasing mPS in each tested feed, except for pea meal, which had a quadratic relationship. For each 1 mm increase in mPS, the gas production was adjusted by -0.009 h-1 for corn, -0.011 h-1 for barley, -0.008 h-1 for wheat, and -0.006 h-1 for faba, whereas numerically greater adjustments were needed for oat (-0.022 h-1), rye ( 0.017 h-1), and sorghum (-0.014 h-1). These mPS adjustment factors could be used to modify the starch-based feed energy values as a function of mean particle size, although in vivo validation is required. PMID- 29705421 TI - Genetic variability in the humoral immune response to bovine herpesvirus-1 infection in dairy cattle and genetic correlations with performance traits. AB - Bovine herpesvirus-1 (BoHV-1) is a viral pathogen of global significance that is known to instigate several diseases in cattle, the most notable of which include infectious bovine rhinotracheitis and bovine respiratory disease. The genetic variability in the humoral immune response to BoHV-1 has, to our knowledge, not ever been quantified. Therefore, the objectives of the present study were to estimate the genetic parameters for the humoral immune response to BoHV-1 in Irish female dairy cattle, as well as to investigate the genetic relationship between the humoral immune response to BoHV-1 with milk production performance, fertility performance, and animal mortality. Information on antibody response to BoHV-1 was available to the present study from 2 BoHV-1 sero-prevalence research studies conducted between the years 2010 to 2015, inclusive; after edits, BoHV-1 antibody test results were available on a total of 7,501 female cattle from 58 dairy herds. National records of milk production (i.e., 305-d milk yield, fat yield, protein yield, and somatic cell score; n = 1,211,905 milk-recorded cows), fertility performance (i.e., calving performance, pregnancy diagnosis, and insemination data; n = 2,365,657 cows) together with animal mortality data (i.e., birth, farm movement, death, slaughter, and export events; n = 12,853,257 animals) were also available. Animal linear mixed models were used to quantify variance components for BoHV-1 as well as to estimate genetic correlations among traits. The estimated genetic parameters for the humoral immune response to BoHV 1 in the present study (i.e., heritability range: 0.09 to 0.16) were similar to estimates previously reported for clinical signs of bovine respiratory disease in dairy and beef cattle (i.e., heritability range: 0.05 to 0.11). Results from the present study suggest that breeding for resistance to BoHV-1 infection could reduce the incidence of respiratory disease in cattle while having little or no effect on genetic selection for milk yield or milk constituents (i.e., genetic correlations ranged from -0.13 to 0.17). Moreover, even though standard errors were large, results also suggest that breeding for resistance to BoHV-1 infection may indirectly improve fertility performance while also reducing the incidence of mortality in older animals (i.e., animals >182 d of age). Results can be used to inform breeding programs of potential genetic gains achievable for resistance to BoHV-1 infection in cattle. PMID- 29705422 TI - Influence of Bactrian camel milk on the gut microbiota. AB - Bactrian camel milk has become popular in the market as an important source of nutrients with diverse functional effects. In this study, the influence of Bactrian camel milk on the gut microbiota of mice was studied using metagenomic based sequencing of the V3 and V4 hypervariable regions of the 16S rRNA gene. Bioinformatics analysis showed that Firmicutes and Bacteroidetes were the predominant phyla, accounting for more than 80% of the bacteria present. At the genus level, Allobaculum, Akkermansia, Romboutsia, Bifidobacterium, and Lactobacillus were most abundant in the gut microbiota; of these, Allobaculum and Akkermansia were the predominant genera, representing 40.42 and 7.85% of all the bacteria present, respectively. Camel milk was found to reduce relative abundance of Romboutsia, Lactobacillus, Turicibacter, and Desulfovibrio (decreased by 50.88, 34.78, 26.67, and 54.55%, respectively) in the gut microbiota compared with the control. However, some genera such as Allobaculum, Akkermansia, and Bifidobacterium in the gastrointestinal flora increased in abundance in the presence of camel milk; these genera are correlated with beneficial effects for organisms. Our research suggests that the gut microbiota should be taken into account when conducting functional studies on camel milk, and this work provides a useful foundation for further study on functions of camel milk. PMID- 29705423 TI - The cost-benefit of genomic testing of heifers and using sexed semen in pasture based dairy herds. AB - Recent improvements in dairy cow fertility and female reproductive technologies offer an opportunity to apply greater selection pressure to females. This means there may be greater incentive to obtain genomic breeding values for females. We modeled the impact of changes to key parameters on the net benefit from genomic testing of heifer calves with and without usage of sexed semen. This paper builds on earlier cost-benefit studies but uses parameters relevant to pasture-based systems. A deterministic model was used to evaluate the effect on net benefit due to changes in (1) reproduction rate, (2) genomic test costs, (3) availability of parent-derived breeding values (EBVPA), and (4) replacement rate. When the use of sexed semen was included, we also considered (1) the proportion of heifers and cows mated to sexed semen, (2) decreases in conception rate in inseminations with sexed semen, and (3) the marginal return for surplus heifers. Scenarios with lower replacement rates and no availability of EBVPA had the largest net benefits. Under current Australian parameters, the net benefit of genomic testing realized over the lifetime of genotyped heifers is expected to range from A$204 to A$1,124 per 100 cows for a herd with median reproductive performance. The cost of a genomic test, a perceived barrier to many farmers, had only a small effect on net benefit. Genomic testing alone was always more profitable than using sexed semen and genomic testing together if the only benefit considered was increased genetic gain in heifer replacements. When other benefits (i.e., the higher sale price of a surplus heifer compared with a male calf) were considered, there were combinations of parameters where net benefit from using sexed semen and genomic testing was higher than the equivalent scenario with genomic testing only. Using sexed semen alongside genomic testing is most likely to be profitable when (1) used in heifers, (2) the marginal return for selling surplus heifers (sale price minus rearing costs) is greater than A$400, and (3) conception rates of no more than 10 percentage points lower than those achieved using conventional semen can be realized. Net benefit was highly dependent on the marginal return. Demonstrating that the initial investment in genomic testing can be recouped within the lifetime of the heifers tested may assist in the development of extension messages to explain the value of genomic testing females at the herd level. PMID- 29705424 TI - Proteome profiling of exosomes derived from plasma of heifers with divergent genetic merit for fertility. AB - The current study evaluated exosomes isolated from plasma of heifers bred to have high or low fertility through developing extreme diversity in fertility breeding values, however, key animal traits (e.g., body weight, milk production, and percentage of North American genetics) remained similar between the 2 groups. The exosomes were isolated by a combined ultracentrifugation and size exclusion chromatography approach and characterized by their size distribution (nanoparticle tracking analysis), morphology (transmission electron microscopy), and presence of exosomal markers (immunoblotting). In addition, a targeted mass spectrometry approach was used to confirm the presence of 2 exosomal markers, tumor susceptibility gene 101 and flotillin 1. The number of exosomes from plasma of high fertility heifers was greater compared with low fertility heifers. Interestingly, the exosomal proteomic profile, evaluated using mass spectrometry, identified 89 and 116 proteins in the high and low fertility heifers respectively, of which 4 and 31 were unique, respectively. These include proteins associated with specific biological processes and molecular functions of fertility. Most notably, the tetratricopeptide repeat protein 41-related, glycodelin, and kelch-like protein 8 were identified in plasma exosomes unique to the low fertility heifers. These proteins are suggested to play a role in reproduction; however, the role of these proteins in dairy cow reproduction remains to be elucidated. Their identification underscores the potential for proteins within exosomes to provide information on the fertility status and physiological condition of the cow. This may potentially lead to the development of prognostic tools and interventions to improving dairy cow fertility. PMID- 29705425 TI - In vitro ruminal biohydrogenation of eicosapentaenoic (EPA), docosapentaenoic (DPA), and docosahexaenoic acid (DHA) in cows and ewes: Intermediate metabolites and pathways. AB - A great deal of uncertainty still exists about intermediate metabolites and pathways explaining the biohydrogenation (BH) of 20- and 22-carbon polyunsaturated fatty acids (PUFA). Therefore, this study was conducted to provide further insight into the ruminal metabolism of 20:5 n-3 (EPA), 22:5 n-3 (DPA), and 22:6 n-3 (DHA), the main n-3 PUFA present in the marine lipids used in dairy ruminant feeding, and to examine potential differences between bovine and ovine. To meet this aim, we investigated the 20- and 22-carbon metabolites accumulated during in vitro incubation of EPA, DPA, and DHA with rumen inocula from cows and ewes. The PUFA were added at a dose of 2% incubated dry matter and digesta samples were analyzed after 24 h of incubation using complementary gas liquid chromatography of fatty acid methyl esters and gas chromatography-mass spectrometry of 4,4-dimethyloxazoline derivatives. Results suggested that the main BH pathway of EPA and DPA would proceed via the reduction of the double bond closest to the carboxyl group (cis-5 in EPA and cis-7 in DPA); curiously, this mechanism seemed of much lower importance for DHA. Thus, DPA would not be a major intermediate product of DHA and their BH might actually follow separate pathways, with the accumulation of numerous unique metabolites in each case. A principal component analysis supported this hypothesis, with a clear separation between PUFA treatments in the score and loading plots. Within EPA and DPA groups, cow and ewe samples loaded separately from each other but not distant. No conjugated 20:5, 22:5, or 22:6 isomer compatible with the initial product of EPA, DPA, or DHA metabolism, respectively, was identified in the ruminal digesta, although this would not unequivocally exclude their transient formation. In this regard, results from DPA incubations provided the first indication that the metabolism of this very long chain PUFA may involve the formation of conjugated double bond structures. The BH of EPA, DPA, and DHA resulted in the appearance of several tentative trans-10-containing metabolites, showing a general trend to be more abundant in the digesta of ewes than in that of cows. This finding was speculated to have some relationship with the susceptibility of dairy sheep to marine lipid induced milk fat depression. Differences in the relative proportion of intermediate products would also suggest an influence of ruminant species on BH kinetics, with a process that would likely be slower and less complete in cows than in ewes. PMID- 29705426 TI - Potential probiotic characterization of Lactobacillus reuteri from traditional Chinese highland barley wine and application for room-temperature-storage drinkable yogurt. AB - The aim of this study was to select probiotic strains that could be used in drinkable yogurt to yield viable cells following storage at room temperature (RT). The uniquely high altitude conditions in Tibet and the alcoholic environment of certain products, such as the highland barley wine homemade in Tibet, may induce unusual characteristics of microbial strains. A total of 27 lactic acid bacteria were isolated from homemade highland barley wines. One strain, Lactobacillus reuteri WHH1689, demonstrated no ability for lactose utilization, exhibited a high survival rate during storage at RT in drinkable yogurts, and produced very weak post-acidification. This strain showed great resistance to conditions simulating the gastrointestinal tract, including strong adherence to HT-29 cells and inhibitory activity against Escherichia coli, Shigella flexneri, Salmonella paratyphi beta, and Staphylococcus aureus. A dextran sulfate sodium (DSS)-induced mouse model was used to evaluate the in vivo influence of Lb. reuteri WHH1689 on the intestinal flora and showed that strain WHH1689 increased viable counts of bifidobacteria in feces of mice. The probiotic strain selected in this study-with its high survival at RT and lack of serious post-acidification problems-may provide significant improvements for dairy industry products by extending the storage time of dairy products with living cells. PMID- 29705427 TI - Use of novel sensors combining local positioning and acceleration to measure feeding behavior differences associated with lameness in dairy cattle. AB - Time constraints for dairy farmers are an important factor contributing to the under-detection of lameness, resulting in delayed or missed treatment of lame cows within many commercial dairy herds. Hence, a need exists for flexible and affordable cow-based sensor systems capable of monitoring behaviors such as time spent feeding, which may be affected by the onset of lameness. In this study a novel neck-mounted mobile sensor system that combines local positioning and activity (acceleration) was tested and validated on a commercial UK dairy farm. Position and activity data were collected over 5 consecutive days for 19 high yield dairy cows (10 lame, 9 nonlame) that formed a subset of a larger (120 cow) management group housed in a freestall barn. A decision tree algorithm that included sensor-recorded position and accelerometer data was developed to classify a cow as doing 1 of 3 categories of behavior: (1) feeding, (2) not feeding, and (3) out of pen for milking. For each classified behavior the mean number of bouts, the mean bout duration, and the mean total duration across all bouts was determined on a daily basis, and also separately for the time periods in between milking (morning = 0630-1300 h; afternoon = 1430-2100 h; night = 2230 0500 h). A comparative analysis of the classified cow behaviors was undertaken using a Welch t-test with Benjamini-Hochberg post-hoc correction under the null hypothesis of no differences in the number or duration of behavioral bouts between the 2 test groups of lame and nonlame cows. Analysis showed that mean total daily feeding duration was significantly lower for lame cows compared with non-lame cows. Behavior was also affected by time of day with significantly lower mean total duration of feeding and higher total duration of nonfeeding in the afternoons for lame cows compared with nonlame cows. The results demonstrate how sensors that measure both position and acceleration are capable of detecting differences in feeding behavior that may be associated with lameness. Such behavioral differences could be used in the development of predictive algorithms for the prompt detection of lameness as part of a commercially viable automated behavioral monitoring system. PMID- 29705428 TI - ADSA Foundation Scholar Award: A role for serotonin in lactation physiology-Where do we go from here? AB - Lactation is a physiological event that is exclusive to mammals. Lactation evolved as a strategy to improve the survival of the young by providing them with the complete nutrition that is required for survival upon birth as well as maternal-offspring bonding. Typically, milk production by the dam matches the demand of the young. The dairy cow is a unique exception in which the discoveries and genetic selection related to lactation physiology have been applied and resulted in a dramatic increase in milk yield of dairy cows. Studies on the role of mammary-derived serotonin and the coordination of various aspects of milk production and maternal metabolism have revealed novel mechanisms by which milk production and maternal metabolism can be improved. Furthermore, the investigation into molecular and cellular mechanisms regulating mammary gland function has revealed the importance of epigenetics on mammary gland function. Understanding mammary gland function at the cellular and physiological levels will be important for improving mammary gland control of maternal metabolism during early lactation. The early lactation period is a critical time for a dairy cow as that is when she is most susceptible to disease and metabolic disorders that can lead to negative effects on her productive capacity and overall health. Our research in the area of serotonin physiology has illustrated the importance of serotonin on the regulation of lactation and maternal homeostasis. Future research in the area of lactation physiology should be targeted at improving maternal health and longevity in the herd through manipulation of the signals the mammary gland sends to coordinate maternal metabolism and synthesize milk. Specifically, we believe that serotonin will play a central role in understanding the communication between the mammary gland and the maternal physiology during lactation. PMID- 29705429 TI - Technical note: Evaluation of a wireless pulse oximeter for measuring arterial oxygen saturation and pulse rate in newborn Holstein Friesian calves. AB - Pulse oximetry is a well-established technique in human and veterinary medicine. In farm animals, it could also be a useful tool for the detection of critical conditions relating to oxygen supply and the cardiovascular system. Among other uses, an innovative application could be the monitoring of fetuses during birth. This could help in the early identification of critical situations and support farmers and veterinarians in their decision to start obstetric or life-support interventions. Until now, however, its use in ruminant medicine was still limited to experimental applications. The objective of this study was to evaluate the accuracy of the Radius-7 Wearable Pulse CO-Oximeter (Masimo Corporation, Irvine, CA) for monitoring vital parameters in newborn calves. All measurements were conducted on animals in the lying down position. The sensor of the pulse oximeter was placed in the interdigital space of the calves' front legs and fixed with a homemade latex hoof cover. The pulsoximetric measurements of arterial oxygen saturation (SpO2) in 40 newborn calves were compared with the corresponding results (SaO2) from a portable blood gas analyzer (VetScan iStat1, Abaxis Inc., Union City, CA), which served as the reference. For this, an arterial blood sample was taken from the medial intermediate branch of the caudal auricular artery. In addition, the pulse rate was measured in 10 calves aged between 0 and 7 d with the pulse oximeter and simultaneously with a heart rate belt (Polar Equine Belt, Polar Electro Oy, Kempele, Finland) to determine their level of agreement. Spearman correlation coefficient for oxygen saturation was 93.8% for the pulse oximeter and the blood gas analyzer, and 97.7% for the pulse rate measured with the pulse oximeter and the heart rate belt. Bland-Altman plots revealed an overestimation of SaO2 by 2.95 +/- 6.39% and an underestimation of the pulse rate by -0.41 +/- 3.18 beats per minute compared with the corresponding reference methods. In summary, the pulse oximeter is suitable for continuous monitoring of arterial oxygen saturation and pulse in newborn Holstein Friesian calves. For practical use, purpose-built technical equipment is required to attach the sensor to the calves' legs. PMID- 29705430 TI - Technical note: Evaluation of the diagnostic accuracy of 2 point-of-care beta hydroxybutyrate devices in stored bovine plasma at room temperature and at 37 degrees C. AB - The use of point-of-care (POC) devices to measure blood metabolites, such as beta hydroxybutyrate (BHB), on farm have become an important diagnostic and screening tool in the modern dairy industry. The POC devices allow for immediate decision making and are often more economical than the use of laboratory-based methods; however, precision and accuracy may be lower when measurements are performed in an uncontrolled environment. Ideally, the advantages of the POC devices and the standardized laboratory environment could be combined when measuring samples that do not require an immediate result-for example, in research applications or when immediate intervention is not the goal. The objective of this study was to compare the capability of 2 POC devices (TaiDoc, Pharmadoc, Lubeck, Germany; Precision Xtra, Abbott Diabetes Care, Abingdon, UK) to measure BHB concentrations either at room temperature (RT; 20-22 degrees C) or at 37 degrees C compared with the gold standard test in stored plasma samples. Whole blood from multiparous Holstein dairy cows (n = 113) was sampled from the coccygeal vessels between 28 d before expected calving and 42 DIM. Whole-blood BHB concentrations were determined cow-side using the TaiDoc POC device. Plasma was separated within 1 h of collection and stored until analysis. A subset of stored plasma samples (n = 100) consisting of 1 sample per animal was chosen retrospectively based on the BHB concentrations in whole blood within the range of 0.2 to 4.0 mmol/L. The samples were analyzed for BHB plasma concentration using an automated chemistry analyzer (Hitachi 917, Hitachi, Tokyo, Japan), which was considered the gold standard. On the same day, the samples were also measured with the 2 POC devices, with samples either at RT or heated up to 37 degrees C. Our study showed high Spearman correlation coefficients (>0.99) using either device and with samples at both temperatures compared with the gold standard. Passing-Bablok regression revealed a very strong correlation (>0.99), indicating good agreement between both POC devices and the gold standard method. For hyperketonemia detection, defined as BHB concentration >=1.2 mmol/L, the sensitivity for both POC devices at RT and 37 degrees C was equally high at 100%. Specificity was lowest (67.4%) for the TaiDoc used with plasma at RT and was highest (86.5%) when plasma was measured at 37 degrees C with the Precision Xtra meter. Bland-Altman plots revealed a mean bias of 0.25 and 0.4 mmol/L for the Precision Xtra meter and TaiDoc, respectively, when tested on plasma at 37 degrees C. Our data showed that both POC devices are suitable for measuring BHB concentration in stored bovine plasma, and accuracy was highest when samples were heated to 37 degrees C compared with RT. PMID- 29705431 TI - Effect of straw particle size on the behavior, health, and production of early lactation dairy cows. AB - The objective of this study was to determine the effect of reducing the particle size of wheat straw in a total mixed ration (TMR) on cow behavior, health, and production in early lactation. For 28 d after calving, 41 multiparous Holstein cows were individually provided either 1 of 2 TMR with 9% wheat straw (dry matter basis) chopped (1) using a 2.54-cm screen (short; n = 21) or (2) using a 5.08-cm screen (long; n = 20). Cows were housed in freestall pens during both the dry and lactating period. Enrollment in the trial was on a rolling basis and cows were evenly distributed by parity and milk production between treatments. Wireless telemetry boluses were used to measure reticulorumen pH. Automated systems recorded TMR dry matter intake, milk yield, and rumination activity. The TMR and orts samples were collected every 3 d to determine feed sorting. A particle separator was used to separate feed samples into 4 fractions: long (>19 mm), medium (<19 mm, >8 mm), short (<8 mm, >4 mm), and fine (<4 mm) particles. Feed sorting was calculated as actual intake of each particle fraction expressed as a percentage of its predicted intake. Cows sorted the longest TMR particles differently by treatment; on the long treatment cows sorted against long particles (94.2 +/- 1.9%), whereas on the short treatment cows did not sort for or against these particles (99.7 +/- 1.9%). Data were analyzed in mixed-effect linear regression models and fitted with polynomial functions over the 28 d of observations. The fitted data indicated treatment differences in linear coefficients, quadratic coefficients, and cubic coefficients for mean time (min/d) below a reticulorumen pH of 5.8 and milk yield. Rumination time (min/d) differed between treatments for quadratic and cubic coefficients. Cows on the short treatment linearly increased in dry matter intake at a greater rate than cows on the long treatment. Mean reticulorumen pH decreased at a greater rate for cows on the long treatment than for cows on the short, as indicated by differences between linear coefficients. Cows on the short treatment tended to produce 75 kg more milk cumulatively during the first 28 d in milk than cows on long treatment. These results suggest that cows fed a diet with longer straw particles selected against physically effective fiber, which may have contributed to greater fluctuations in rumination time, reticulorumen pH, dry matter intake, and milk production in early lactation. PMID- 29705432 TI - An agent-based model evaluation of economic control strategies for paratuberculosis in a dairy herd. AB - This paper uses an agent-based simulation model to estimate the costs associated with Mycobacterium avium ssp. paratuberculosis (MAP), or Johne's disease, in a milking herd, and to determine the net benefits of implementing various control strategies. The net present value (NPV) of a 1,000-cow milking herd is calculated over 20 yr, parametrized to a representative US commercial herd. The revenues of the herd are generated from sales of milk and culled animals. The costs include all variable and fixed costs necessary to operate a representative 1,000-cow milking herd. We estimate the NPV of the herd with no MAP infection, under an expected endemic infection distribution with no controls, and under an expected endemic infection distribution with various controls. The initial number of cows in a herd with an endemic MAP infection is distributed as 75% susceptible, 13% latent, 9% low MAP shedding, and 3% high MAP shedding. Control strategies include testing using ELISA and fecal culture tests and culling of cows that test positive, and culling based on observable milk production decrease. Results show that culling cows based on test results does not increase the herd's NPV and in most cases decreases NPV due to test costs as well as false positives and negatives with their associated costs (e.g., culling healthy cows and keeping infected cows). Culling consistently low producing cows when MAP is believed to be present in the herd produces higher NPV over the strategy of testing and culling MAP infected animals, and over the case of no MAP control. PMID- 29705433 TI - Outcomes of deviation from treatment guidelines in status epilepticus: A systematic review. AB - OBJECTIVE: Due to a gap between published clinical guidelines on status epilepticus SE and clinician management of SE, a systematic review was performed to investigate treatment adherence to SE guidelines and its impact on patient outcomes. METHODS: Medline and Embase searches were conducted for studies appraising adherence to SE guidelines (from 1970 and 1st April 2018). The quality of eligible studies was assessed by QUADAS- 2 criteria. Comparison was made between patients where guidelines were followed and not followed. Various patient outcomes including intubation, ICU admission, morbidity and mortality were compared. A Forest plot was used to investigate the effect of adherence on outcome. RESULTS: A total of 3424 titles and abstracts were screened from the initial search after removal of duplicates. A total of 441 full text articles were reviewed in detail, and 22 articles were included in this study. The proportion of deviations ranged from 10.7% to 66.1%. Four studies were descriptive. Eighteen studies looked at the adverse effects of non-adherence. Eight studies showed respiratory depression and intubation were associated with excessive benzodiazepine use. A subset analysis showed 5.79 times higher odds of respiratory depression and intubation], if excessive benzodiazepines were given. The next most common variations were delayed management and insufficient treatment. These variations from the guidelines were associated with prolonged seizures. CONCLUSIONS: This review provides preliminary evidence that non adherence to SE guidelines negatively impacts on patient outcomes. Appropriate and timely treatment is imperative for rapid seizure termination and improving outcomes. PMID- 29705434 TI - Urbanization and climate change implications in flood risk management: Developing an efficient decision support system for flood susceptibility mapping. AB - The effects of urbanization and climate change impact to the flood risk of two governorates in Egypt were analyzed. Non-parametric change point and trend detection algorithms were applied to the annual rainfall, rainfall anomaly, and temperature anomaly of both study sites. Next, change points and trends of the annual and monthly surface runoff data generated by the Curve Number method over 1948-2014 were also analyzed to detect the effects of urbanization on the surface runoff. Lastly, a GIS decision support system was developed to delineate flood susceptibility zones for the two governorates. The significant decline in annual rainfall and rainfall anomaly after 1994 at 8.96 and 15.3 mm/decade respectively was likely due to climate change impact, especially significant warming trend since 1976 at 0.16 degrees C/decade, though that could partly be attributed to rapid urbanization. Since 1970, effects of urbanization to flood risk are clear, because despite a decline in rainfall, the annual surface runoff and runoff anomaly show positive trends of 12.7 and of 14.39 mm/decade, respectively. Eleven flood contributing factors have been identified and used in mapping flood susceptibility zones of both sites. In the El-Beheira governorate, 9.2%, 17.9%, 32.3%, 28.3% and 12.3% of its area are categorized as very high, high, moderate, low and very low susceptibility to flooding, respectively. Similarly, in Alexandria governorate, 15.9%, 33.5%, 41%, 8.8% and 0.8% of its area are categorized as very high, high, moderate, low and very low susceptibility to flooding, respectively. Very high and high susceptible zones are located in the northern, northwestern and northeastern parts of the Beheira governorates, and in the northeastern and northwestern parts of Alexandria. The flood related information obtained in this study will be useful to assist mitigating potential flood damages and future land use planning of both governorates of Egypt. PMID- 29705435 TI - Mechanism of the influence of hydrodynamics on Microcystis aeruginosa, a dominant bloom species in reservoirs. AB - Hydrodynamic conditions play a key role in algal blooms, which have become an increasing threat to aquatic environments, especially reservoirs. Microcystis aeruginosa is a dominant species in algal blooms in reservoirs and releases large amounts of algal toxins during algal bloom events. The algal growth characteristics and the corresponding mechanism of the influence of hydrodynamic conditions were explored using custom hydraulic rotating devices. The long-term experimental results were as follows: (1) a moderate flow velocity increased the algal growth rate and prolonged algal lifetime relative to static water; (2) moderate water turbulence promoted energy metabolism and nutrient absorbance in algal cells; (3) moderate shear stress reduced oxidation levels in algal cells and improved algal cell morphology; (4) under hydrodynamic treatment, algal cell deformation was confirmed by scanning electron microscopy (SEM), and a high shear stress of 0.0104 Pa induced by a flow of 0.5 m/s may have destroyed cell morphology and disturbed reactive oxygen species (ROS) metabolism; (5) algal cell morphology evaluation (including circle ratio, eccentricity, diameter increasing rate, and deformation rate) was established; (6) based on algal growth status and specific effects, five independent intervals (including 'positive-promotion', 'middle-promotion', 'negative-promotion', 'transition', and 'inhibition') and the hydrodynamic threshold system (including flow velocity, turbulent dissipation, and shear stress) were established; and (7) for M. aeruginosa, the optimum flow velocity was 0.24 m/s, and the static-equivalent flow velocity was 0.47 m/s. These results provide a basic summary of the hydrodynamic effects on algal growth and a useful reference for the control of M. aeruginosa blooms in reservoirs. PMID- 29705436 TI - Effects of the exposure of TiO2 nanoparticles on basil (Ocimum basilicum) for two generations. AB - There is a lack of information about the transgenerational effects of titanium dioxide nanoparticles (nano-TiO2) in plants. This study aimed to evaluate the impacts of successive exposure of nano-TiO2 with different surface properties to basil (Ocimum basilicum). Seeds from plants exposed or re-exposed to pristine, hydrophobic, or hydrophilic nano-TiO2 were cultivated for 65 days in soil unamended or amended with 750 mg.kg-1 of the respective particles. Plant growth, concentration of titanium and essential elements, as well as content of carbohydrates and chlorophyll were evaluated. There were no differences on Ti concentration in roots of plants sequentially exposed to pristine or hydrophobic nano-TiO2, or in roots of plants exposed to the corresponding particle, only in the second cycle. However, sequential exposure to hydrophilic particles resulted in 65.2% less Ti in roots, compared to roots of plants exposed the same particles, only in the second cycle. The Ti concentrations in shoots were similar in all treatments. On the other hand, pristine and hydrophilic particles reduced Mg in root by 115% and 81%, respectively, while pristine and hydrophobic particles reduced Ni in shoot by 84% and 75%, respectively, compared to unexposed plants in both cycles. Sequential exposure to pristine nano-TiO2 increased stomatal conductance (214%, p <= 0.10), compared to plants that were never exposed. Hydrophobic and hydrophilic nano-TiO2 reduced chlorophyll b (52%) and total chlorophyll (30%) but increased total sugar (186%) and reducing sugar (145%), compared to unexposed plants in both cycles. Sequential exposure to hydrophobic or hydrophilic nano-TiO2 resulted in more adverse effects on photosynthesis but in positive effects on plant growth, compared to pristine nano TiO2. PMID- 29705437 TI - Influences of the alternation of wet-dry periods on the variability of chromophoric dissolved organic matter in the water level fluctuation zone of the Three Gorges Reservoir area, China. AB - Dissolved organic matter (DOM) is a crucial driver of various biogeochemical processes in aquatic systems. Thus, many lakes and streams have been investigated in the past several decades. However, fewer studies have sought to understand the changes in DOM characteristics in the waters of the Three Gorges Reservoir (TGR) areas, which are the largest artificial reservoir areas in the world. Thus, a field investigation of dissolved organic carbon (DOC) concentrations and of chromophoric dissolved organic matter (CDOM) properties was conducted from 2013 to 2015 to track the spatial-temporal variability of DOM properties in the TGR areas. The results showed that the alternations of wet and dry periods due to hydrological management have a substantial effect on the quantity and quality of aquatic DOM in TGR areas. Increases in DOC concentrations in the wet period show an apparent "dilution effect" that decreases CDOM compounds with relatively lower aromaticity (i.e., SUVA254) and molecular weight (i.e., SR). In contrast to the obvious temporal variations of DOM, significant spatial variability was not observed in this study. Additionally, DOM showed more terrigenous characteristics in the dry period but weak terrigenous characteristics in the wet period. Furthermore, the positive correlation between SUVA254 and CDOM suggests that the aromatic component controls the CDOM dynamics in TGR areas. The first attempt to investigate the DOM dynamics in TGR areas since the Three Gorges Dam was conducted in 2012, and the unique patterns of spatial-temporal variations in DOM that are highlighted in this study might provide a new insight for understanding the role of DOM in the fates of contaminants and may help in the further management of flow loads and water quality in the TGR area. PMID- 29705438 TI - Dating groundwater with dissolved silica and CFC concentrations in crystalline aquifers. AB - Estimating intermediate water residence times (a few years to a century) in shallow aquifers is critical to quantifying groundwater vulnerability to nutrient loading and estimating realistic recovery timelines. While intermediate groundwater residence times are currently determined with atmospheric tracers such as chlorofluorocarbons (CFCs), these analyses are costly and would benefit from other tracer approaches to compensate for the decreasing resolution of CFC methods in the 5-20 years range. In this context, we developed a framework to assess the capacity of dissolved silica (DSi) to inform residence times in shallow aquifers. We calibrated silicate weathering rates with CFCs from multiple wells in five crystalline aquifers in Brittany and in the Vosges Mountains (France). DSi and CFCs were complementary in determining apparent weathering reactions and residence time distributions (RTDs) in shallow aquifers. Silicate weathering rates were surprisingly similar among Brittany aquifers, varying from 0.20 to 0.23 mg L-1 yr-1 with a coefficient of variation of 7%, except for the aquifer where significant groundwater abstraction occurred, where we observed a weathering rate of 0.31 mg L-1 yr-1. The silicate weathering rate was lower for the aquifer in the Vosges Mountains (0.12 mg L-1 yr-1), potentially due to differences in climate and anthropogenic solute loading. Overall, these optimized silicate weathering rates are consistent with previously published studies with similar apparent ages range. The consistency in silicate weathering rates suggests that DSi could be a robust and cheap proxy of mean residence times for recent groundwater (5-100 years) at the regional scale. This methodology could allow quantification of seasonal groundwater contributions to streams, estimation of residence times in the unsaturated zone and improve assessment of aquifer vulnerability to anthropogenic pollution. PMID- 29705439 TI - Perfluoroalkyl phosphonic acids adsorption behaviour and removal by wastewater organisms. AB - In this study we have experimentally assessed different physicochemical parameters such as the distribution constant between octanol - water and between water and sludge for three perfluoroakyl substances (PFASs) widely used in waxes and coating materials: perfluorohexane (PFHxPA), perfluorooctane (PFOPA) and perfluorodecane (PFDPA) phosphonic acids. Distribution coefficients were assessed based on the procedures described in the OECD guideline 123 for partition coefficients while the studies of adsorption-desorption in sludge based on the indirect method of the OECD guideline 106. Besides, the removal behaviour of selected compounds has been evaluated using the green algae Desmodesmus subspicatus and microorganisms present in an effluent wastewater. These last experiments were carried out using laboratory scale bioreactors under aerobic conditions according to the OECD guideline 309. The main results of this study showed the resistance to biodegradation of selected compounds by both treatments, <5% was eliminated using D. subspicatus and similar results were obtained by aerobic degradation with wastewater microorganisms. However, it was observed that PFDPA induced changes in algae colour while it was detected to be accumulated in a floccula generated by the microorganisms present in wastewater. According to distribution coefficients the three compounds have values of logDow below 3, indicating their capability to be present in both phases. Finally, the results of the adsorption/desorption experiments showed that PFOPA and PFDPA reach the equilibrium after 10 days of contact with a sorption percentage higher than 40% and 70%, respectively. PMID- 29705440 TI - The association between quality of life and complementary and alternative medicine use in patients with diabetes mellitus. AB - AIM: In the current study, we aimed to evaluate the relationship between life quality and use of complementary and alternative medicine (CAM) in patients with diabetes mellitus. METHODS: The Audit of Diabetes-Dependent Quality of Life (ADDQOL-19) scale was applied to 453 diabetic patients. Socio-demographic characteristics of the patients and their CAM usage were recorded. RESULTS: The rate of CAM use among diabetic patients was 46.1%. The most preferred practices were herbal medicine, including black cumin (26.6%), cinnamon (23.3%) and olive leaf (12.5%). 'Freedom to eat' (p = 0.002), 'drinking freedom' (p = 0.001) and 'physical health' (p = 0.001) were the most negatively affected items that may drive patients to use CAM. CONCLUSIONS: In this sampling, the use of CAM among patients with diabetes mellitus is high. The association between CAM usage and eating and drinking freedom and physical health should be studied in detail in further studies. PMID- 29705441 TI - What motivates arrangements of dog visits in nursing homes? Experiences by dog handlers and nurses. AB - INTRODUCTION: Dog visits to nursing homes are used as a structured approach for enhancing residents' well-being. Few studies have emphasized the perspectives of the organizers. The purpose of the present study was to gain insight into the experiences of volunteer dog handlers and nurses involved in dog visits to nursing homes, focusing on what motivated them to contribute and identifying possible factors to successful dog visits. METHODS: Individual, in-depth interviews with eight dog handlers and group interviews with 10 nurses from four nursing homes. RESULTS: Feelings of meaningfulness and joy motivated both the dog handlers and nurses to arrange dog visits to nursing homes. Successful visits depended on shared information and collaboration. CONCLUSION: Both groups were motivated by the positive impact of dog visits on nursing home residents. Dog visits may be health-promoting not only for residents, but for the volunteer dog handlers as well. PMID- 29705442 TI - The effects of training and the use of cranberry capsule in preventing urinary tract infections after urostomy. AB - PURPOSE: The study was conducted to investigate the effects of training provided by researcher and the use of cranberry capsule in preventing late term UTIs after urostomy. METHODS: The study included 60 patients who underwent ileal conduit diversion between June 2013 and November 2014. The participants were randomly divided into three groups. First group used cranberry capsule, second group received training about UTIs and the other control group. The patients were assessed for a UTI by laboratory analysis at 2, 3, and 4 months after discharge. RESULTS: When the effect of cranberry capsule use and training on the prevention of urinary tract infections were compared, we found that there was a significant difference between the group that used and didn't use cranberry capsules, favoring the cranberry capsule (log-rank test; p < 0.05). CONCLUSION: We found that the use of cranberry capsules is effective in the prevention of urinary tract infections. PMID- 29705443 TI - A prospective research study to investigate the impact of complementary therapies on patient well-being in palliative care. AB - Complementary therapies are being used more in the UK over the last two decades and yet very little evidence of their benefit is available. The aim of this study was to investigate, through face to face interviews with patients, using a phenomenological approach the perceived benefits of the different therapies in terms of their overall patient well-being. Eight patients; mean age 52.87years, range 40-64years presenting in the palliative care phase for life limiting conditions comprising one male and seven females agreed to participate in the study between March and September 2015. All eight participants reported perceived benefited from the therapies and that their identified concerns had been ameliorated. Participants reported feeling relaxed, calmer and being able to carry on with their daily lives and refocussing on themselves and what is important in life. Complementary therapies played a positive role, and therefore, an acceptable model of supporting palliative care patients. PMID- 29705444 TI - Effect of hand and foot surface stroke massage on anxiety and vital signs in patients with acute coronary syndrome: A randomized clinical trial. AB - BACKGROUND AND OBJECTIVES: Anxiety affects various body systems, which leads to an increase in respiratory rate, heart rate, blood pressure, and myocardial oxygen demand. The aim of this study was to investigate the effect of hand and foot surface stroke massage on the level of anxiety and vital signs in patients with acute coronary syndrome (ACS). MATERIALS AND METHODS: The single-blind clinical trial was performed on 70 patients with ACS. The patients were randomly assigned to the case and control groups. Anxiety levels were controlled 30 min before and 15 min after the intervention. The vital signs were checked in the two groups before, immediately after, 60 min, and 90 min after the intervention. The data were analyzed using SPSS software, descriptive statistics (mean +/- standard deviation), independent t-test, paired t-test, and chi-square test. RESULTS: No significant difference was observed in the patients' levels of anxiety, systolic blood pressure, diastolic blood pressure, respiratory rate, and pulse rate before the intervention. However, after the intervention, the mean changes in the levels of anxiety, blood pressure, heart rate, and respiratory rate were significant. CONCLUSION: Hand and foot massage can be a useful nursing intervention in attenuating anxiety levels and improving the vital signs in patients. PMID- 29705445 TI - Comparison of the effect of lavender and bitter orange on anxiety in postmenopausal women: A triple-blind, randomized, controlled clinical trial. AB - INTRODUCTION: This trial compared the effects of lavender and bitter orange on anxiety in postmenopausal women. METHODS: This trial was conducted in 2015. Eligible postmenopausal women were allocated into one of two intervention groups or a control group (n = 52 per group) in a 1:1:1 ratio using a randomized block design. Intervention groups received 500 mg capsules containing only bitter orange or lavender flower powder, and the control group received 500 mg capsules containing starch. The Spielberger's State -Trait Anxiety Inventory (STAI) was used before and eight weeks after starting the intervention. Data analyses were based on intention to treat. RESULTS: A one-way ANOVA showed no significant difference in mean state anxiety (P = 0.254) and trait anxiety (p = 0.972) score among the three groups before the intervention. The general linear model, adjusted for baseline state and trait anxiety scores and confounding factors, showed significant differences among the groups in the mean state anxiety (P = 0.010) and trait anxiety (p = 0.041) score after eight weeks of treatment. Bitter orange significantly reduced the mean state-anxiety scores compared with the control group [Adjusted Mean Difference (aMD): -1.99 (95% Confidence Interval, 3.64 to -0.34)]. Lavender significantly reduced the mean state-anxiety scores compared with the control group as well [aMD: -2.45 (95% CI -4.13 to -0.77)] and Bitter orange significantly reduced the mean trait-anxiety scores compared with the control group [aMD: -1.76 (95% CI -3.45 to -0.06)]. Lavender significantly reduced the mean trait-anxiety scores compared with the control group as well [aMD: -2.05 (95% CI -3.76 to -0.33)]. There was no significant difference between bitter orange and lavender groups after intervention in the mean trait-anxiety (p = 0.731) or state-anxiety (p = 0.578) scores. CONCLUSION: The positive effect of bitter orange and lavender on anxiety in postmenopausal women suggests that they can be used to decrease anxiety in such women. PMID- 29705446 TI - The effects of different combinations of perceptual-motor exercises, music, and vitamin D supplementation on the nerve growth factor in children with high functioning autism. AB - The present study investigated the effects of different combinations of perceptual-motor exercises, music, and Vitamin D consumption on the nerve growth factor (NGF) in children with high-functioning autism. 48 children with autism, aged between six and nine years, were divided into four groups: Group A- perceptual-motor activities along with music (n = 12); Group B-Vitamin D supplementation (n = 12); Group C-perceptual-motor activities along with music and Vitamin D (n = 12); and Group D-control (n = 12). Participants' blood NGF level was measured before and after the intervention. The results showed a significant improvement in the NGF levels in Groups B and C due to the interventions. Also, in Group A, the NGF levels increased compared to Group D, although this increase was not significant. In addition, the intake of Vitamin D along with perceptual-motor exercises resulted in a significant increase in the levels of NGF compared to Groups A, B and D. These findings suggest that perceptual-motor exercises along with music as well as taking Vitamin D may provide two appropriate interventions for improving NGF in children with autism. PMID- 29705447 TI - Knowledge, attitude and use of complementary and alternative medicine among nurses: A systematic review. AB - OBJECTIVES: The purpose of this study was to systematically review the literature to describe the knowledge, attitude and practice of CAM by nurses. METHODS: Three databases were searched for relevant studies from launch through September of 2017 and included MEDLINE, Scopus and Web of science. RESULTS: The average knowledge of CAM therapies by nurses was 62.2% with attitude about use averaging 65.7%. Close to two-thirds (65.9%) reported use of CAM therapies with patients. The primary reasons nurses suggested use of CAM were for stress and anxiety reduction and health improvement. CONCLUSION: Current evidence demonstrates the need for nurse education programs to integrate and strengthen CAM content into existing curricula. Similarly, documentation of the nature and extent of nurse use of CAM therapies in the clinical setting, as well as patient-reported use and preferences for CAM therapies, would provide valuable prospective data. PMID- 29705448 TI - The effect of different types of music on patients' preoperative anxiety: A randomized controlled trial. AB - OBJECTIVE: The purpose of this study was to determine effect of three different types of music on patients' preoperative anxiety. METHOD: This randomized controlled trial included 180 patients who were randomly divided into four groups. While the control group didn't listen to music, the experimental groups respectively listened to natural sounds, Classical Turkish or Western Music for 30 min. The State Anxiety Inventory (STAI-S), systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR) and cortisol levels were checked. FINDINGS: The post-music STAI-S, SBP, DBP, HR and cortisol levels of the patients in music groups were significantly lower than pre-music time. All types of music decreased STAI-S, SBP, and cortisol levels; additionally natural sounds reduced DBP; Classical Turkish Music also decreased DBP, and HR. CONCLUSIONS: All types of music had an effect on reducing patients' preoperative anxiety, and listening to Classical Turkish Music was particularly the most effective one. PMID- 29705449 TI - Of Dodo birds and common factors: A scoping review of direct comparison trials in adventure therapy. AB - BACKGROUND: Adventure therapy (AT) is a term that includes therapies such as wilderness therapy and adventure-based counseling. With growing empirical support for AT, the diversity of studies make it difficult to attribute outcomes to specific treatment factors. OBJECTIVES: Researchers explored whether AT, often perceived as an alternative therapy, works because of AT's unique components, or whether factors shared by all therapies were responsible. METHODS: A scoping review was undertaken utilizing a search of major databases, unpublished dissertations, and a hand search for direct comparison trials matching AT with another therapeutic intervention. RESULTS: 881 publications were identified. 105 quantitative studies were included following a title and abstract review. Only 13 met the full inclusion criteria. Little to no differences were found to isolate specific therapeutic factors. CONCLUSIONS: We discuss the implications of these results considering the movement toward evidence-based practice and recommend future research to eclipse our current understanding of AT. PMID- 29705450 TI - The determination of Complementary and Alternative Medicine use in patients presenting at the emergency room. AB - OBJECTIVE: The aim of this study was to determine CAM use in patients presenting at the emergency room. METHOD: This cross-sectional study was conducted with the participation of 385 patients presenting at the emergency room. Data was collected with a questionnaire between the dates 02.01.2016-31.03.2016. RESULTS: The reasons for the presentation at the emergency room were found to be stomach ache (17.2%), vomiting nausea (14.8%), headache (11.2%), shortness of breath (10.9%), and urinary problems (9.6%). 94% of the patients presenting at the emergency room were found to use CAM methods with the methods used being prayer (82.3%), herbal medicine/tea (48.6%), and diets supplementary (9.4%). 80.9% of the patients were found not to share their CAM usage with health professionals. CONCLUSION: In order to ensure patient safety and prevent patients from coming to harm, it is thought that encouraging patients to share their CAM use with health care professionals is very important. PMID- 29705451 TI - The barberry juice effects on metabolic factors and oxidative stress in patients with type 2 diabetes: A randomized clinical trial. AB - AIM: The aim of this study was to investigate the effect of barberry juice (BJ) on cardiovascular risk factors in patients with type 2 diabetes (T2DM). METHODS: 46 diabetic Patients were randomly allocated to either the BJ group (n = 23) who consumed 200 ml of BJ daily for eight weeks, or the control group (n = 23) with no intervention. At the baseline and the end of 8-week intervention, blood pressure and biochemical markers were measured. RESULTS: forty-two Patients completed the study. After intervention systolic blood pressure (SBP), diastolic blood pressure (DBP), Fasting Blood Sugar (FBS) Total Cholesterol significantly decreased (P < 0.05 for treatment effect) also Triglyceride (TG) decrease significantly in BJ group. Paraoxonase-1(PON1) concentrations significantly increased in Bj group and have a significant difference (P < 0.0001 for treatment effect) compared with control group. CONCLUSIONS: This study revealed that BJ might decrease the risk of cardiovascular diseases in patients with diabetes. PMID- 29705452 TI - Aromatherapy for the management of cancer complications: A narrative review. PMID- 29705453 TI - Participant characteristics of users of holistic movement practices in Australia. AB - OBJECTIVES: The aim of this study was to compare the characteristics of users of holistic movement practices in Australia to people who were physically active but not using holistic movement practices. A second aim was to compare characteristics of users of specific holistic movement practices (yoga/Pilates and t'ai chi/qigong). DESIGN: We performed a secondary data analysis on pooled data of a nationally-representative physical activity survey conducted yearly 2001-2010 (n = 195,926). SETTING: Australia-wide Exercise, Recreation, and Sport Survey (ERASS). MAIN OUTCOME MEASURES: A range of socio-demographic and participation characteristics were documented and compared between users and non users of holistic movement practices and between yoga/Pilates and t'ai chi/qigong users, employing descriptive statistics, chi square, and multiple logistic regression analyses. RESULTS: Users of holistic movement practices (n = 6826) were significantly more likely than non-users to be female, older, have fewer children at home, and have higher levels of education, socio-economic background, and physical activity involvement (p < 0.001). Yoga/Pilates (n = 5733) and t'ai chi/qigong (n = 947) users were also found to differ on a number of characteristics, including age, sex, socioeconomic background, and marital status. CONCLUSION: As a group, Australian users of holistic movement practices differ on a range of characteristics from those Australians active in other types of physical activities. However, differences between yoga/Pilates and t'ai chi/qigong users suggest these practices attract somewhat different sub populations. To what extent these differences are due to characteristics inherent to the practices themselves or to differences in delivery-related parameters needs to be examined in future research. PMID- 29705454 TI - Effects of a hippotherapy intervention on muscle spasticity in children with cerebral palsy: A randomized controlled trial. AB - OBJECTIVE: The aim of the present study is to evaluate the effect of a 12 weeks hippotherapy intervention protocol on hip adductors spasticity in children with spastic cerebral palsy. DESIGN: Randomized controlled trial. SETTINGS/LOCATION: The intervention was conducted in an Equestrian and Therapeutic Association. Patients were recruited from a Rehabilitation Unit of Cerebral Palsy. SUBJECTS: A total of 44 children with spastic cerebral palsy (Gross Motor Function Classification System [GMFCS] levels IV-V; 28 boys and 16 girls; aged 8 years 10 months, SD 3 months) were assigned to a treatment (n = 22; mean age 9 years 6 months, SD 3 months) or a control group (n = 22; mean age 8 years 3 months, SD 3 months). INTERVENTIONS: The control group received conventional therapy, and the treatment group received hippotherapy in addition to their conventional treatment. The intervention consisted of a 12-weeks hippotherapy program (1 time/week, 45 min). OUTCOME MEASURES: Both groups were assessed before and after the full program with the Modified Ashworth Scale (MAS). RESULTS: There were significant differences in the MAS scores between the treatment and the control group in both adductors (left adductors: p = 0,040; right adductors: p = 0,047), after a 12-weeks hippotherapy intervention. CONCLUSIONS: A hippotherapy based treatment in addition to conventional therapy, in children with cerebral palsy, produces statistically significant changes in hip adductors spasticity after a 12 weeks intervention. Thus, it seems to produce benefits in the short-term. PMID- 29705455 TI - The design of visitation facilities to engage patients with their own cats and dogs. AB - There are voluminous data acknowledging the validity of the animal/human bond. Pharmacologic, endocrinologic, immunologic, and psychologic studies have clearly documented the impact of the companion animal on the health and well-being of patients and families, especially in the medical setting. Our paper is, to our knowledge, the first study outlining the mechanics, engineering concepts, and background of providing the appropriate facility to connect the hospitalized patient with their companion animal. We have summarized the peer-reviewed research in this critical area. PMID- 29705456 TI - Investigation into complementary and integrative medicine practitioners' clinical experience of intestinal permeability: A cross-sectional survey. AB - BACKGROUND: This study aims to explore the conditions complementary and integrative medicine (CIM) practitioners associate with increased intestinal permeability (IP) and the methods they employ to assess IP. METHODS: A cross sectional survey of naturopaths, nutritionists and Western herbal medicine practitioners was undertaken (n = 227) through the Practitioner Research and Collaboration Initiative (PRACI) network. RESULTS: CIM practitioners (n = 36, response rate 15.9%) associate IP with gastrointestinal (100.0%), autoimmune (91.7%), skin (91.7%), neurological (80.6%), respiratory (55.6%) and liver related conditions (44.4%). CIM practitioners frequently treat IP (72.7%); observing a minimum 3 months of treatment is required to resolve IP. Patient's signs and symptoms were the main reasons CIM practitioners suspected IP (94.1%). CONCLUSION: CIM practitioners observe a clinical link between IP and a wide range of conditions, including those not yet recognised within the literature. The clinical experience of CIM practitioners holds substantial value to the advancement of research and the clinical management of IP. PMID- 29705457 TI - Comparing the effects of relaxation technique and inhalation aromatherapy on fatigue in patients undergoing hemodialysis. AB - This study aimed to compare the effects of relaxation techniques on fatigue in hemodialysis patients. This clinical trial study was conducted on 105 hemodialysis patients. The subjects were categorized into three groups as: relaxation, aromatherapy and control. In the relaxation group, Benson muscle relaxation techniques were employed; in the aromatherapy group, the inhalation of two drops of 5% lavender essential oil used and the control group only received regular healthcare actions. Data collected by using brief fatigue inventory, before and after the intervention. Results of the current study indicated significant differences in the mean of changes in fatigue scores before and after the intervention between the relaxation and aromatherapy groups, but the difference was insignificant in the control group. Aromatherapy with lavender essential oil can decrease the level of fatigue in the patients undergoing hemodialysis compared to Benson relaxation techniques. PMID- 29705458 TI - Integrative medicine in anxiety disorders. AB - Anxiety disorders are a current public health issue, as an estimated 16.5% of the Portuguese population suffers from this condition. The goal of this descriptive study was to analyze the efficiency of the treatment of integrative medicine (acupuncture and therapeutic massage) to reduce anxiety disorders and to describe the sociodemographic characteristics of Integrative Medicine Institute (IMI) patients. To this end, a documental analysis from the data base of the clinical reports of IMI was performed, with the approval of the Ethics Committee of the Health Sciences Research Unit with informed consents being signed by all patients. Between January and August 2017, 259 IMI patients were treated. Of these, 30,5% had been diagnosed with an anxiety disorder. Ten sessions of Integrative Medicine (IM) using acupuncture techniques combined with therapeutic massage were applied. Each session consisted of an initial treatment of acupuncture for 30 min, followed by a therapeutic massage for another 30 min. Before starting all 10 treatments, anxiety levels were measured by a self perception 5 points scale. Anxiety levels were also assessed at the end of the 5th and the 10th treatment. It was found that 75.29% of the patients looking for IM were female and 34.4% were professionals working in intellectual and scientific activities. Patients taking anxiolytic medication presented higher levels of anxiety in comparison with non-medicated ones (p = 0.000). After a maximum of ten treatments (acupuncture combined with massage), the levels of anxiety were reduced (98.39% after five sessions). Women at their tenth treatment reached lower anxiety levels than those of men. The therapies used are proved to be efficient and can be used as a complementary care to treat and relief the symptoms of anxiety disorders. This research is the basis for designing a future randomized control trial study of acupuncture efficiency in the treatment of anxiety disorders. PMID- 29705459 TI - Effects of foot reflexology on anxiety and physiological parameters in patients undergoing coronary artery bypass graft surgery: A clinical trial. AB - INTRODUCTION: This study aimed to investigate the effect of foot reflexology on anxiety and physiological parameters in patients after CABG surgery. METHOD: This was a single-blind, three-arm, parallel-group, randomized controlled trial with three groups of 40 male patients undergoing CABG. Participants were placed in three groups, named intervention, placebo, and control. Physiological parameters were measured including systolic and diastolic blood pressure, mean arterial pressure, heart rate, respiratory rate, percutaneous oxygen saturation, and anxiety of participants. RESULTS: Results showed a statistically significant difference between intervention and control groups in terms of the level of anxiety (p < 0.05). Also, results showed a statistically significant effect on all physiological parameters except heart rate (p < 0.05). CONCLUSION: This study indicated that foot reflexology may be used by nurses as an adjunct to standard ICU care to reduce anxiety and stabilize physiological parameters such as systolic, diastolic, mean arterial pressure, and heart rate. PMID- 29705460 TI - Behavioural typologies of experienced benefit of psychomotor therapy in patients with chronic shoulder pain: A grounded theory approach. AB - In this study we aimed to develop a theoretical account of the experienced benefit of psychomotor therapy in addition to treatment as usual in patients with chronic shoulder pain. The qualitative study design was based on a grounded theory approach. Open-ended face-to-face interviews were conducted after treatment was completed. We generated data and performed analyses by constant comparative analysis and theoretical sampling that focused on the patients' behavioural characteristics related to the experienced benefit of psychomotor therapy. We conducted 12 interviews, eight of which were with men. "Regaining capability" emerged as representative of the pattern of behaviour. Through this pattern, the patients resolved concern about losing capability. Regaining capability involved three behavioural typologies: taking advice, minding the body, and encompassing life changes. The patients' behavioural typologies revealed different levels of life changes. Psychomotor therapy offered the patients in our study new and better ways of coping with their shoulder pain. PMID- 29705461 TI - Principal component analysis of synthetic adulterants in herbal supplements advertised as weight loss drugs. AB - OBJECTIVE: Obesity is one of the major problems in many countries. Herbal drugs are widely used to treat obesity. Unfortunately the majority of herbal weight loss drugs are adulterated with active pharmaceutical ingredients. The purpose of the present study was to analyse herbal weight loss drugs for the general search for pharmaceuticals. METHODS: sixty one herbal weight loss drugs that were collected from herb shops and internet in Kermanshah, Iran were analysed qualitatively using gas chromatography/mass spectrometry. RESULTS: Of the 61 weight loss products sampled, 72% were found to be adulterated with tramadol, caffeine, fluoxetine, rizatriptan, venlafaxine and methadone. CONCLUSION: Herbal weight loss products were adulterated with controlled and legitimate drugs. Patients should be aware of the danger of using adulterated supplements. PMID- 29705462 TI - Opinions and observations of caregivers of children with cerebral palsy about changes seen after reflexology: A qualitative study. AB - The aim of this research was to examine the effect of reflexology on the problems of children with cerebral palsy from perspective of caregivers. Qualitative study was made after 24-session reflexology program. 12 caregivers who have 2-18 year old children with spastic type cerebral palsy receiving special education and received reflexology. The thematic questions were determined and in-depth interviews were conducted. Themes of the study were determined as; the caregiver's views on reflexology, the effect of reflexology on health of children with CP and the caregivers' observations on child after reflexology therapy, positive and negative aspects and causes of reflexology treatment. As a results; the caregivers expressed that there were increases in self-confidence of children, improvement in walking, reduced spasticity, relaxation, decreases in constipation, and increases in communication, speech and perception after reflexology. PMID- 29705463 TI - Modern postural yoga as a mental health promoting tool: A systematic review. AB - Yoga has been gaining popularity as a complementary therapy for mental health conditions, but research on the efficacy of yoga is still in its beginnings. The aim of this systematic review is to investigate the effects of modern postural yoga (strong focus on physical postures) on positive mental health (PMH) indicators in clinical and nonclinical populations. The most common PMH indicators were mindfulness, affect, resilience and well-being, followed by satisfaction with life, self-compassion, empathy and others. Diverse results were found across the 14 studies analysed, including significant positive effects of yoga practice on outcome variables, to no significant effects, both in relation to baseline levels and in relation to control groups. Nonetheless, most studies observed ameliorations in PMH indicators due to yoga practice. Given that yoga interventions pose serious methodological concerns, more research and better experimental designs are needed to properly assess the effects of yoga on PMH indicators. PMID- 29705464 TI - Management of psoriasis with nutraceuticals: An update. AB - Psoriasis is a chronic skin disorder that speeds up the life cycle of skin cells, typically on the surface of the skin. Additional skin cells form thick scales and red fixes which are awfully itchy and sometimes painful. Although there are many therapeutic systems available to get symptomatic relief, unfortunately replete cure for psoriasis is not yet reported. Moreover, poor treatment outcomes as well as high toxicity profile of drugs makes these therapies more inconvenient to treat psoriasis. In search of alternative and complementary therapy for this disease, the focus has been shifted to nutraceuticals, few of them were reported since ages. It includes vitamins, herbal extracts, phytochemicals and dietary supplements. In this review, the attempt has been made to highlight key nutraceuticals for better management of psoriasis. Supplementation of appropriate nutraceutical may improve the quality of patient's life and have positive impact on overall state of disease. PMID- 29705465 TI - Trunk and hip muscle activation during yoga poses: Do sex-differences exist? AB - OBJECTIVE: To compare core activation during yoga between males and females. METHODS: Surface electromyography was used to quantify rectus abdominis (RA), abdominal obliques (AO), lumbar extensors (LE), and gluteus maximus (GMX) activation during four yoga poses. Data were expressed as 100% of a maximum voluntary isometric contraction. Mixed-model 2 * 2 analyses of variance with repeated measures were used to determine between-sex differences in muscle activity. RESULTS: Females generated greater RA activity than males during the High Plank (P < 0.0001) and Dominant-Side Warrior 1 (P = 0.017). They generated greater AO (P < 0.0001) and GMX (P = 0.004) activity during the High Plank (P < 0.0001). No between-sex EMG activity differences existed for the Chair and Upward Facing Dog. CONCLUSION: Findings have provided preliminary evidence for between sex differences in muscle activation during yoga poses. Clinicians should consider such differences when prescribing yoga to improve muscle strength and endurance. PMID- 29705466 TI - Effectiveness of yoga and educational intervention on disability, anxiety, depression, and pain in people with CLBP: A randomized controlled trial. AB - OBJECTIVE: The current study investigates the effects of an 8-week yoga program with educational intervention compared with an informational pamphlet on disability, anxiety, depression, and pain, in people affected by chronic low back pain (CLBP). METHODS: Thirty individuals (age 34.2 +/- 4.52 yrs) with CLBP were randomly assigned into a Yoga Group (YG, n = 15) and a Pamphlet Group (PG, n = 15). The YG participated in an 8-week (2 days per week) yoga program which included education on spine anatomy/biomechanics and the management of CLBP. MAIN OUTCOME MEASURES: Monitoring response to intervention, the Oswestry Low Back Pain Disability Questionnaire (ODI-I), Zung self-Rating Depression Scale (SDS), Zung Self-Rating Anxiety Scale (SAS) and Numeric Rating Scale for Pain (NRS 0-10) were used to collect data. RESULTS: After intervention, the YG showed a significant decrease (p < 0.05) in the mean score in all assessed variables when compared with baseline data. In addition, statistically significant (p < 0.05) differences were observed among groups at the end of intervention in depression, anxiety, and pain, but not in disability. CONCLUSIONS: The yoga program and education together appear to be effective in reducing depression and anxiety, which can affect perception of pain. PMID- 29705467 TI - Effects of Gua Sha therapy on perimenopausal syndrome: A systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVE: In East Asia, Gua Sha therapy is widely used in patients with perimenopausal syndrome. The goal of this systematic review was to evaluate the available evidence from randomized controlled trials (RCTs) of Gua Sha therapy for the treatment of patients with perimenopausal syndrome. METHODS: Databases searched from inception until June 2017 included: PubMed, Embase, the Cochrane Central Register of Controlled Trials and four Chinese databases [WanFang Med Database, Chinese BioMedical Database, Chinese WeiPu Database, and the China National Knowledge Infrastructure (CNKI)]. Only the RCTs related to the effects of Gua Sha therapy on perimenopausal syndrome were included in this systematic review. A quantitative analysis of RCTs was employed using RevMan 5.3 software. Study selection, data extraction, and validation were performed by two independent reviewers. Cochrane criteria for risk-of-bias were used to evaluate the methodological quality of the trials. RESULTS: A total of 6 RCTs met the inclusion criteria, and most were of low methodological quality. When compared with Western medicine therapy alone, meta-analysis of 5 RCTs indicated favorable statistically significant effects of Gua Sha therapy plus Western medicine on the Kupperman Menopausal Index (KMI) Score [mean difference (MD) = -4.57, 95% confidence interval (CI) (-5.37, -3.77), p < 0.01; heterogeneity: Chi2 = 29.57 p < 0.01, I2 = 86%]. Moreover, study participants who received Gua Sha therapy plus Western medicine therapy showed significantly greater improvements in serum levels of follicle-stimulating hormone (FSH) [MD = -5.00, 95% CI (-9.60, -0.40), p = 0.03], luteinizing hormone (LH) [MD = -4.00, 95% CI (-7.67, -0.33), p = 0.03], and E2 [MD = -6.60, 95% CI (-12.32, -0.88), p = 0.02] compared to participants in the Western medicine therapy group, with a low heterogeneity (Chi2 = 0.12, p = 0.94, I2 = 0% in FSH; Chi2 = 0.19 p = 0.91, I2 = 0% in LH; Chi2 = 0.93, p = 0.63, I2 = 0% in E2). In addition, the pooled results displayed favorable significant effects of Gua Sha therapy plus the Western medicine therapy on the MENQOL scale when compared with the Western medicine therapy alone [MD = -5.13, 95% CI (-7.45, -2.81), p < 0.01] with low heterogeneity (Chi2 = 0.66, p = 0.42, I2 = 0%). CONCLUSION: Preliminary evidence supported the hypothesis that Gua Sha therapy effectively improved the treatment efficacy in patients with perimenopausal syndrome. Additional studies will be required to elucidate optimal frequency and dosage of Gua Sha. PMID- 29705468 TI - The short-term effects of TENS plus therapeutic ultrasound combinations in chronic neck pain. AB - INTRODUCTION: To investigate the effects of TENS plus therapeutic ultrasound combinations on symptom relief, physical functionality, perceived stress levels, daytime sleepiness and neck mobility in patients with chronic neck pain (CNP). METHODS: A total of 64 patients were divided into two groups as the TENS plus ultrasound group (n = 39) and the control CNP group (n = 25). The therapy comprised TENS and therapeutic ultrasound applications for 10 sessions. The control subjects were discouraged from using analgesics but were allowed to use paracetamol daily, if necessary. The Neck Disability Index (NDI), Epworth Sleepiness Scale (ESS), Perceived Stress Scale (PSS), visual analog scale (VAS) and tragus-wall/chin-manubrium distances were recorded at the baseline and after therapy. RESULTS: Significant improvements were detected in the TENS plus ultrasound group compared to the control CNP subjects in respect of VAS, PSS and NDI scores after the TENS plus therapeutic ultrasound therapies (all p < 0.05). DISCUSSION: The combination of therapeutic ultrasound plus TENS can be an effective modality for relieving pain/stress levels and improving functionality in the short-term of CNP. PMID- 29705469 TI - Auricular acupressure is an alternative in treating constipation in leukemia patients undergoing chemotherapy: A systematic review and meta-analysis. AB - OBJECTIVE: Auricular acupressure (AA) therapy has been widely used in Eastern Asia and Europe to prevent constipation in leukemia patients undergoing chemotherapy. The aim of this systematic review was to review data from randomized controlled trials (RCTs) of auricular acupressure therapy for preventing constipation in leukemia patients undergoing chemotherapy. METHODS: Databases that were searched from their inception until August 2017 included: MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, as well as four Chinese databases [Chinese BioMedical Database, China National Knowledge Infrastructure, Wan-Fang Data, and the Chinese WeiPu Database]. In this systematic review, only RCTs that were related to the effects of auricular acupressure therapy on preventing constipation in leukemia patients undergoing chemotherapy were included. Study selection, data extraction, and validation were performed independently by two reviewers. Quantitative analyses of RCTs were performed using RevMan 5.3 software, and cochrane criteria for risk-of-bias were used to assess the methodological quality of the trials. RESULTS: A total of 5 RCTs met the inclusion criteria, and most were of low methodological quality. Participants in the AA plus routine care group showed significantly greater improvements in the Bristol Stool Form (BSF) [MD = 0.55, 95% CI (0.39, 0.71), p < 0.01] with low heterogeneity (Chi2 = 5.01, p = 0.29, I2 = 20%). Moreover, when compared with routine care alone, meta-analysis of three RCTs indicated favorable statistically significant effects of AA plus routine care on the Constipation Assessment Scale (CAS) [MD = -1.51, 95% CI (-1.89, -1.14), p < 0.01] with low heterogeneity (Chi2 = 1.63, p = 0.44, I2 = 0%). Furthermore, when compared with routine care alone, meta-analysis of two RCTs demonstrated statistically significant effects of AA plus routine care on the Patient Assessment of Constipation-Quality Of Life (PAC-QOL) [MD = -1.28, 95% CI (-1.44, -1.13), p < 0.01], with low heterogeneity (Chi2 = 0.19, p = 0.67, I2 = 0%). CONCLUSION: Taken together, as a potential safety therapy, only weak evidence supported the hypothesis that AA effectively prevented constipation in leukemia patients undergoing chemotherapy. PMID- 29705470 TI - Investigation of the effect of black cumin oil on pain in osteoarthritis geriatric individuals. AB - PURPOSE: This study has been carried out to investigate the analgesic effect of black cumin oil on individuals with knee pain. METHOD: The experimental group (n = 30) and control group (n = 30) have been randomly selected. The control group patients have continued their routine prescription. For the experimental group, black cumin oil has been applied by rubbing to their knees 3 times a week for 1 month. FINDINGS: As a result of the study, the mean VAS values of the patients in the experimental group has changed to 7.50 +/- 0.97 on the 1st day and 6.30 +/- 1.14 on the 30th day and there has been a significant decrease in pain severity in this group (p < 0.001). RESULTS: This study has shown that the pain relieving properties of black cumin oil is effective on geriatric individuals living with knee pain. PMID- 29705471 TI - Acute responses of cytokines and adipokines to aerobic exercise in relapsing vs. remitting women with multiple sclerosis. AB - OBJECTIVE: To examine the acute effect of exercise on cytokines and adipokines during relapse and the remitting phase of multiple sclerosis (MS). METHODS: Thirty women with MS in the relapsing or remitting phase were matched with fifteen healthy controls. Participants performed a single-bout of aerobic exercise at 60-70% maximal heart rate. Furthermore, five women in the relapsing phase were enrolled (control relapse) and did not receive any intervention. Blood samples were taken before, immediately after, 1-h and 6-h after the exercise. RESULTS: Levels of IL-10 and TNF-alpha in response to exercise were similar in healthy and MS remitting subjects. Compared to baseline, TNF-alpha levels in relapsing subjects were significantly decreased immediately after exercise. Immediately following exercise, leptin levels significantly decreased in relapsing subjects. Adiponectin and IL-6 showed no significant difference between groups. CONCLUSION: After relapse, exercise does not induce inflammatory cytokine response and temporarily improves both cytokine and adipokine balance. PMID- 29705472 TI - Efficacy of topical Linum usitatissimum L. (flaxseed) oil in knee osteoarthritis: A double-blind, randomized, placebo-controlled clinical trial. PMID- 29705473 TI - Self-efficacy and embodiment associated with Alexander Technique lessons or with acupuncture sessions: A longitudinal qualitative sub-study within the ATLAS trial. AB - BACKGROUND AND PURPOSE: A large randomised controlled trial found that the provision of either Alexander Technique lessons or acupuncture, for those with chronic neck pain, resulted in significantly increased self-efficacy when compared with usual care alone. In turn, enhanced self-efficacy was associated with significant reductions in neck pain at 6 and 12 months. In this analysis we explore the perspectives of participants within the trial, with the aim of gaining a better understanding of how these interventions had an impact. METHODS: We used a longitudinal qualitative approach; in-depth interviews, informed by a topic guide, were conducted with a sample of the trial population. Participants were interviewed twice: at around six months (n = 30) and twelve months (n = 26) after trial entry. Analysis was guided by the principles of grounded theory, and key themes were developed. RESULTS: Five key themes emerged: pre-trial experiences of biomedical treatment against which subsequent interventions were compared; emergence of tangible benefits from the interventions; factors that contributed to the observed benefits, notably growing self-care and self efficacy; a developing sense of embodiment as an integral part of the transformative process; and contribution of these factors to sustaining benefits over the longer term. CONCLUSIONS: In-depth interviews revealed a rich array of experiences. They gave insight into the positive impact of the interventions on development of self-care, self-efficacy and embodiment. These findings complement the quantitative trial data, providing a more nuanced understanding of the factors that underpin the previously quantified improvement in self-efficacy and its association with longer-term reductions in pain. PMID- 29705474 TI - Acupuncture and electroacupuncture for anxiety disorders: A systematic review of the clinical research. AB - Anxiety disorders are one of the most common mental health concerns with a major contribution to the global burden of disease. When not treated, anxiety can be aggravated to more serious and complicated health problems. Pharmacology and psychotherapy stand for the conventional treatment for anxiety disorders but these present limited efficacy, especially in the case of chronic anxiety, with high relapse rates and often causing adverse side effects. Clinical research studies render acupuncture as a valid treatment therapy for anxiety disorders without significant adverse effects. The objective of this paper is to review the literature on the effectiveness of acupuncture and electroacupuncture for the treatment of patients with anxiety disorders in order to find strong scientific evidence for its regular practice in Western culture. The systematic review of the clinical research was focused on published clinical trials (controlled, randomized and non-randomized) regarding the treatment of anxiety with acupuncture. Only clinical trials where anxiety was treated as the therapeutic target, and not as a secondary measurement or being associated with other health condition or disease, were considered. Two authors extracted the data independently and exclusion and inclusion criteria were set. The search rendered 1135 papers addressing anxiety as a primary therapeutic target. After review, 13 papers were identified to match exclusion and inclusion criteria and were selected for this analysis. Methodology, design, and quality of the research were highly variable and are discussed and compared. Overall, there is good scientific evidence encouraging acupuncture therapy to treat anxiety disorders as it yields effective outcomes, with fewer side effects than conventional treatment. More research in this area is however needed. PMID- 29705475 TI - The effects of reflexology on pain and sleep deprivation in patients with rheumatoid arthritis: A randomized controlled trial. AB - OBJECTIVE: This study was intended to examine the effect of foot reflexology on RA patients' pain and sleep quality. METHODS: This is a randomized controlled trial and was held at the "Rheumatology Follow-up Polyclinic" in Turkey between January-July 2015. A total of 60 patients were included in the research. A sociodemographic data form, the Pittsburgh Sleep Quality Index (PSQI) and the Visual Analogue Scale (VAS) were used. Foot Reflexology was administered to the experimental group. RESULTS: The research found that the pain scores of the experimental group were statistically more significant than those of the control group (p < .01). The experimental group's average pain was reduced by the six weeks of foot reflexology. The total PSQI score of the experimental group was lowered. CONCLUSIONS: Foot reflexology is a non-pharmacological nursing intervention that may reduce the pain and sleep deprivation symptoms of RA patients. PMID- 29705476 TI - Pain-related encephalic regions influenced by yoga meditation: An integrative review. AB - INTRODUCTION: The mechanisms underlying the use of yoga in pain relief are still unclear. This study reviewed literature reports on encephalic activity related to analgesia induced by yoga meditation practice. METHODS: This integrative review examined studies published in the Pubmed, LILACS and MEDLINE databases without restriction of the year of publication. The research involved 16 descriptors related to the words: yoga, pain and neuroimaging methods. Inclusion criteria involved only the publications available online, with free access and written in English. RESULTS: 2 case studies and 1 pilot study met the criteria. Yoga meditation practice induces analgesia primarily through attenuation of the medial pain perception system including the Anterior Cingulate Cortex and Insula regions, as well as the lateral system including the Secondary Sensory Cortex and Thalamus. CONCLUSION: Yoga induced analgesia is a potentially important adjunct to current pain management. This integrative review revealed that there is a need for further research that analyzes the encephalic regions related to analgesia induced by yoga practice. PMID- 29705477 TI - Evidence-informed massage therapy - an Australian practitioner perspective. AB - Massage therapy (MT) is the most popular complementary and alternative medicine therapy used by the Australian public. With the growing emphasis by the Australian health authority on evidence-informed healthcare decision-making, there is an increasing demand for massage therapists to move towards the evidence informed practice (EIP). With MT research gaining significant attention over the last 30 years, clinical evidence exists to support the efficacies of MT on many health conditions, including chronic low back pain. This growing body of research supports MT to become an evidence-informed therapeutic modality. The evidence utilization process of asking clinical questions, searching for available research evidence, and appraising the evidence critically can be incorporated into the clinical practice of MT. Moreover, integrating practitioners' skills and experience with research evidence enables the best treatment plan to address the clients' needs and stated goals. No dichotomy exists between scientific research and the humanistic client care of MT. A massage therapist can gain greater confidence in practice, improve critical thinking and decision-making skills, and increase career satisfaction through EIP. Despite its high public utilization, massage therapists in Australia remain a low-paying profession dominated by part time workers who rarely utilize research evidence in practice. Professional associations of massage therapists in Australia need to play a key role in promoting EIP through continuing professional education, providing the access to research information and resources, as well as fostering a culture of EIP. PMID- 29705478 TI - Evidence based practice in traditional & complementary medicine: An agenda for policy, practice, education and research. AB - OBJECTIVE: To develop a policy, practice, education and research agenda for evidence-based practice (EBP) in traditional and complementary medicine (T&CM). METHODS: The study was a secondary analysis of qualitative data, using the method of roundtable discussion. The sample comprised seventeen experts in EBP and T&CM. The discussion was audio-recorded, and the transcript analysed using thematic analysis. RESULTS: Four central themes emerged from the data; understanding evidence and EBP, drivers of change, interpersonal interaction, and moving forward. Captured within these themes were fifteen sub-themes. These themes/sub themes translated into three broad calls to action: (1) defining terminology, (2) defining the EBP approach, and (3) fostering social movement. These calls to action formed the framework of the agenda. CONCLUSIONS: This analysis presents a potential framework for an agenda to improve EBP implementation in T&CM. The fundamental elements of this action plan seek clarification, leadership and unification on the issue of EBP in T&CM. PMID- 29705479 TI - Bibliometric analysis of apitherapy in complementary medicine literature between 1980 and 2016. AB - Apitherapy is the medical use and the application of honey bee products and in recent years there has been a growing interest in studies of this field. We aimed to perform a bibliometric study in the apitherapy literature. We used Web of Science database in this study and our search retrieved a total of 6917 documents of which great majority (82.4%) was original articles. Brazil was found to ranked first on the publication number with 889 papers followed by the USA, China, Japan and Turkey. We measured a productivity score for each country and the most productive countries in apitherapy field were Switzerland (2.978), Croatia (2.074), and Bulgaria (1.840). Propolis was the most used keyword followed by bee venom, flavonoids, apis mellifera and apoptosis. A moderate correlation was detected between number of publications and GDP. To the best of our knowledge our study was the first in this area and we proposed that further studies should be supported in this field. PMID- 29705480 TI - Use and toxicity of traditional and complementary medicine among patients seeking care at an emergency department of a teaching hospital in Malaysia. AB - OBJECTIVE: Traditional and Complementary Medicines (TCM) are widely used worldwide, and many of them have the potential to cause toxicity, interaction with conventional medications and non-adherence to prescribed medications due to patients' preference for the TCM use. However, information regarding their use among patients seeking care at emergency departments (ED) of a healthcare facility is limited. The study aimed to evaluate the TCM use among patients attending the ED of a teaching hospital in Malaysia. STUDY DESIGN: A sub-analysis of data from a prevalence study of medication-related visits among patients at the ED of Hospital Universiti Sains Malaysia was conducted. The study took place over a period of six weeks from December 2014 to January 2015 involving 434 eligible patients. Data on demography, conventional medication, and TCM uses were collected from patient interview and the medical folders. RESULTS: Among this cohort, 66 patients (15.2%, 95%CI 12.0, 19.0) reported concurrent TCM use. Sixteen (24.2%) of the TCM users were using more than one (1) type of TCM, and 17 (25.8%) came to the ED for medication-related reasons. Traditional Malay Medicine (TMM) was the most frequently used TCM by the patients. Five patients (7.6%) sought treatment at the ED for medical problems related to use of TCM. CONCLUSION: Patients seeking medical care at the ED may be currently using TCM. ED-physicians should be aware of these therapies and should always ask patients about the TCM use. PMID- 29705481 TI - Feasibility evaluation of a mindfulness-based intervention for primary care professionals: Proposal of an evaluative model. AB - A critical issue in the contemporary field of public health is the organizational stress experienced by healthcare professionals. An integrative and complementary therapy that research has shown as efficacious in helping healthcare professionals to cope with stress is mindfulness meditation. An intervention, however, can't merely be efficacious, it also needs to be feasible to be implemented in a specific political and organizational context. This paper proposes a theoretical logical model and evaluation matrix of the feasibility of a mindfulness-based stress reduction program for primary care professionals. The literature review about the topic was the source for the construction of the theoretical logical model and evaluation matrix, and the validation of those was given by consensus methods, gathering data from experts in the field. PMID- 29705482 TI - The effect of progressive muscle relaxation on the management of fatigue and quality of sleep in patients with chronic obstructive pulmonary disease: A randomized controlled clinical trial. AB - OBJECTIVE: To assess the effect of progressive muscle relaxation (PMR) on fatigue and sleep quality of patients with chronic obstructive pulmonary disease (COPD) stages 3 and 4. MATERIALS AND METHODS: The pretest posttest clinical trial recruited 91 patients COPD grades 3 and 4. Following random assignment of subjects, the treatment group (n = 45) performed PMR for eight weeks and the control group (n = 46) received routine cares. At baseline and after the intervention, fatigue and sleep quality was assessed. Data obtained were analyzed in SPSS. RESULTS: It was determined that PMR decreased patients' fatigue level and improved some sleep quality subscales including subjective sleep quality, sleep latency, sleep duration and habitual sleep efficiency, but no improvement was found in global sleep quality and other sleep subscales. CONCLUSION: An eight week home-based PMR program can be effective in reducing fatigue and improving certain subscales of sleep quality in patients with COPD stages 3,4. (IRCT2016080124080N3). PMID- 29705483 TI - Herbal medicine use among hypertensive patients attending public and private health facilities in Freetown Sierra Leone. AB - OBJECTIVE: This study aimed to determine the prevalence, determinants and pattern of herbal medicine use among hypertensive patients in Freetown. METHODS AND MATERIALS: We conducted a cross-sectional study among hypertensive patients attending public and private health facilities in Freetown, Sierra Leone between August and October 2016. We analyzed the data using SPSS version 24. We used Chi square, Fisher exact two-tailed test and regression analysis for data analysis. A p-value less than 0.05 was considered statistically significant. RESULTS: Out of 260 study participants, over half (n = 148, 56.9%) reported using herbal medicine for the treatment of hypertension alone or together with comorbid condition(s). The most commonly used herbal medicine among users were honey (n = 89, 33.3%), moringa (n = 80, 30.0%) and garlic (n = 73, 27.3%). No significant difference existed between users and non-users of herbal medicine with regards to socio demographic and health-related factors. The majority (n = 241, 92.7%) of respondents considered herbal medicine beneficial if it was recommended by a healthcare provider yet 85.1% (n = 126) did not disclose their herbal medicine use to their health care provider. CONCLUSION: There is a high use of herbal medicines among hypertensive patients in Freetown, Sierra Leone. It is essential for healthcare providers to take heed of the findings of this study and routinely ask their patients about their herbal medicine use status. Such practice will provide the opportunity to discuss the benefits and risks of herbal medicine use with the aim of maximizing patient desired therapeutic outcomes. PMID- 29705484 TI - The combined effects of cold therapy and music therapy on pain following chest tube removal among patients with cardiac bypass surgery. AB - BACKGROUND: Chest tube removal is an extremely painful procedure and patients may not respond well to palliative therapies. This study aimed to examine the effect of cold and music therapy individually, as well as a combination of these interventions on reducing pain following chest tube removal. METHODS: A factorial randomized-controlled clinical trial was performed on 180 patients who underwent cardiac surgery. Patients were randomized into four groups of 45. Group A used ice packs for 20 minutes prior to chest tube removal. Group B was assigned to listen to music for a total length of 30 minutes which started 15 minutes prior to chest tube removal. Group C received a combination of both interventions; and Group D received no interventions. Pain intensity was measured in each group every 15 minutes for a total of 3 readings. Analysis of variance, Tukey and Bonferroni post hoc tests, as well as repeated measures ANOVA were employed for data analysis. RESULTS: Cold therapy and combined method intervention effectively reduced the pain caused by chest tube removal (P < 0.001). Additionally, there were no statistically significant difference in pain intensity scores between groups at 15 minutes following chest tube removal (P = 0.07). CONCLUSION: Cold and music therapy can be used by nursing staff in clinical practice as a combined approach to provide effective pain control following chest tube removal. PMID- 29705485 TI - Reflexology: A randomised controlled trial investigating the effects on beta endorphin, cortisol and pregnancy related stress. AB - Reflexology is used for various pregnancy related complaints. A three-armed, pilot randomised controlled trial was conducted to test changes in physiological and biochemical stress parameters. Ninety primiparous volunteers experiencing low back and/or pelvic girdle pain (LBPGP) were recruited to receive either six reflexology or footbath treatments or usual care. Primary outcome data included pain intensity and frequency measured on a visual analog scale (VAS), and salivary beta-endorphin and cortisol levels. 61 (68%) women completed the intervention. A clinically important reduction of 1.63 cm occurred for VAS pain frequency following reflexology. Beta-endorphin levels increased by 8.8% and 10.10% in the footbath and usual care groups respectively and decreased by 15.18% for the reflexology group. Cortisol increased by 31.78% for footbath participants, 31.42% in usual care and 18.82% in the reflexology group. Reflexology during pregnancy may help reduce LBPGP, and associated stress. However, antenatal reflexology is under researched and requires further investigation. PMID- 29705486 TI - Correlation of PROMIS CAT instruments with Oswestry Disability Index in chiropractic patients. AB - BACKGROUND: The inefficiency associated with collecting standard validated instruments has been a barrier to routine use. We utilized computer adaptive testing (CAT) instruments available through Patient-Reported Outcomes Measurement Information System (PROMIS) and correlated these with the Oswestry Disability Index (ODI). METHODS: All measurements were collected at a routine chiropractic visit. The ODI assessment was used for comparison as a widely used patient reported outcomes instrument. RESULTS: The average time to complete all questions during an office visit was 170 +/- 67 s (average +/- Stdev) to answer 25 +/- 6 questions. Regression analysis revealed a good linear fit between ODI and both PROMIS pain behavior and physical function with R2 values of 0.5219 and 0.6754 respectively, and a good linear fit between anxiety and depression with R2 values of 0.5236. CONCLUSIONS: PROMIS CAT instruments can be efficiently administered during routine clinical visits and correlations values found validate the utility when compared to ODI. PMID- 29705487 TI - A preliminary investigation of the effects of one yoga session for service recipients in a behavioral health intensive outpatient program. AB - This was an investigation of the feasibility and effectiveness of a brief yoga intervention (one session) within an intensive outpatient program (IOP) for service recipients diagnosed with various psychiatric disorders. Participants (N = 26) completed the Toronto Mindfulness Scale (TMS) and the Positive and Negative Affect Schedule (PANAS). Data was collected before and after one yoga session and follow-up data was collected via mail after discharge from the IOP. Scores indicated that negative affect significantly decreased and positive affect significantly increased from pre to post yoga session. Mindfulness scores significantly increased from pre to post yoga session. Though the results of this study supported that a yoga intervention is both feasible and effective within an IOP, collection of follow-up data after discharge via mail was not as feasible. The results of this preliminary investigation support a larger and longitudinal study to further examine yoga as a treatment modality with this clinical population. PMID- 29705488 TI - Nurses as boundary actors: Promoting integrative medicine in hospital wards. AB - OBJECTIVE: The objective of the research was to explore attitudes of hospital nurses toward integrative medicine (IM). DESIGN: A special training program was developed in the Bnai-Zion medical center, a public hospital in Israel, where an innovative IM program was launched. METHODS: 65 nurses from 22 wards were asked at the beginning and the end of the program to complete an open-ended questionnaire concerning three major aspects: 1) their attitudes toward complementary medicine and its integration, 2) the importance and impact of the training program and 3) how they perceive their potential role in promoting IM in the wards. RESULTS: Nurses perceive themselves as boundary actors, who can play an important role in promoting IM within the wards. IM training programs for hospital nurses are recommended. This empowers nurses while restoring to clinical practice the essence of nursing as an integrative healing discipline. PMID- 29705490 TI - A mathematical model for pressure-based organs behaving as biological pressure vessels. AB - We introduce a mathematical model that describes the allometry of physical characteristics of hollow organs behaving as pressure vessels based on the physics of ideal pressure vessels. The model was validated by studying parameters such as body and organ mass, systolic and diastolic pressures, internal and external dimensions, pressurization energy and organ energy output measurements of pressure-based organs in a wide range of mammals and birds. Seven rules were derived that govern amongst others, lack of size efficiency on scaling to larger organ sizes, matching organ size in the same species, equal relative efficiency in pressurization energy across species and direct size matching between organ mass and mass of contents. The lung, heart and bladder follow these predicted theoretical relationships with a similar relative efficiency across various mammalian and avian species; an exception is cardiac output in mammals with a mass exceeding 10 kg. This may limit massive body size in mammals, breaking Cope's rule that populations evolve to increase in body size over time. Such a limit was not found in large flightless birds exceeding 100 kg, leading to speculation about unlimited dinosaur size should dinosaurs carry avian-like cardiac characteristics. PMID- 29705489 TI - Rest-activity rhythm profiles associated with manic-hypomanic and depressive symptoms. AB - Rest-activity rhythm (RAR) disturbances are associated with mood disorders. But there remains a need to identify the particular RAR profiles associated with psychiatric symptom dimensions. Establishing such profiles would support the development of tools that track the 24-h sleep-wake phenotypes signaling clinical heterogeneity. We used data-driven clustering to identify RAR profiles in 145 adults aged 36-82 years (mean = 60, standard deviation = 9). Then we evaluated psychiatric symptom dimensions (including positive and negative affect, depressive, manic-hypomanic, panic-agoraphobic, and substance use symptoms) associated with these empirically-derived RAR profiles. Clustering identified three sub-groups characterized, on average, by: (1) earlier and more robust RARs ("earlier/robust," n = 55, 38%); (2) later and irregular RARs ("later/irregular," n = 31, 21%); and (3) later RARs and a narrower active period ("later/narrower," n = 59, 41%). Compared with the "earlier/robust" group: the "later/irregular" group had higher levels of lifetime manic-hypomanic symptoms (beta (standard error) = 0.80 (0.22) higher standardized symptom units, p = 0.0004) and lifetime depression symptoms (beta (standard error) = 0.73 (0.21) higher standardized symptom units, p = 0.0009); the "later/narrower" group had more lifetime depression symptoms (beta (standard error) = 0.48 (0.18) higher standardized symptom units, p = 0.0076). These associations persisted after adjustments for sleep continuity and duration, suggesting that RARs are distinct behavioral correlates of clinical heterogeneity. Longitudinal studies are needed to confirm whether RAR characteristics contribute to the risk of manic and/or depressive episodes, and whether they reflect the consequences of psychiatric disturbance (e.g., on quality of life or disability). Opportunities to monitor or intervene on objectively-assessed RARs could facilitate better mental health related outcomes. PMID- 29705491 TI - Structural discordance in HIV-1 Vpu from brain isolate alarms amyloid fibril forming behavior- a computational perspective. AB - HIV-1 being the most widespread type worldwide, its accounts for almost 95% of all infections including HIV associated dementia (HAD) that triggers neurological dysfunction and neurodegeneration in patients. The common features associated with HAD and other neurodegenerative diseases are accumulation of amyloid plaques, neuronal loss and deterioration of cognitive abilities, amongst which amyloid fibrillation is considered to be a hallmark. The success of effective therapeutics lies in the understanding of mechanisms leading to neurotoxicity. Few viral proteins like gp-120 are known to be involved in aggregation and enhancement of viral infectivity while comprehending the neurotoxic role of some other proteins is still underway. In the current study, amyloidogenic potential of HIV-1 Vpu protein from brain isolate is investigated through computational approaches. The aggregation propensity of brain derived HIV-1 Vpu was assessed by several amyloid prediction servers that projected the region 4-35 to be amyloidogenic. The protein structure was modeled and subjected to 70 ns molecular dynamics (MD) simulation to investigate the transformation of alpha-helical conformation of the predicted aggregate region into beta-sheet, proposing the protein's ability to initiate fibril formation that is central to amyloidogenic proteins. The structural features of brain derived HIV-1 Vpu were consistent with the in silico amyloid prediction results that depicts the conformational change in the region 8-28 of which residues Ala8, Ile9, Val10, Ala19, Ile20 and Val21 constitutes beta-sheet formation. The alpha-helix/beta-sheet discordance of the predicted region was reflected in the simulation study highlighting the possible structural transition associated with HIV-1 Vpu protein of brain isolate. PMID- 29705492 TI - Transient alleviation of tumor hypoxia during first days of antiangiogenic therapy as a result of therapy-induced alterations in nutrient supply and tumor metabolism - Analysis by mathematical modeling. AB - A number of experiments on mouse tumor models, as well as certain clinical data, have demonstrated, that antiangiogenic therapy can lead to transient improvement in tumor oxygenation, that allows to increase efficiency of following radiotherapy. In the majority of works, this phenomenon has been explained by enhanced tumor perfusion due to normalization of capillaries' structure, that results in elevated oxygen inflow in tumor. However, changes in tumor perfusion often haven't been directly measured in relevant works, moreover, antiangiogenic therapy has been proven to have ambiguous effect on tumor perfusion both in mouse tumor models and in clinics. Herein, we suggest that elevation of blood perfusion may be not the only reason for transient alleviation of tumor hypoxia, and that it may manifest itself even under unchanged tumor blood flow. We propose that it may be as well caused by the decrease in tumor oxygen consumption rate (OCR) due to the reduction of tumor proliferation level, caused by nutrient shortage in result of antiangiogenic treatment. We provide detailed explanation of this hypothesis and visualize it using a specially developed mathematical model, which takes into account basic features of tumor growth and antiangiogenic therapy. We investigate the influence of the model parameters on oxygen dynamics; demonstrate, that transient alleviation of tumor hypoxia occurs in a fairly wide range of physiologically justified values of parameters; and point out the major factors, that determine oxygen dynamics during antiangiogenic therapy. PMID- 29705493 TI - Analytical symmetry detection in protein assemblies. I. Cyclic symmetries. AB - Symmetry in protein, and, more generally, in macromolecular assemblies is a key point to understand their structure, stability and function. Many symmetrical assemblies are currently present in the Protein Data Bank (PDB) and some of them are among the largest solved structures, thus an efficient computational method is needed for the exhaustive analysis of these. The cyclic symmetry groups represent the most common assemblies in the PDB. These are also the building blocks for higher-order symmetries. This paper presents a mathematical formulation to find the position and the orientation of the symmetry axis in a cyclic symmetrical protein assembly, and also to assess the quality of this symmetry. Our method can also detect symmetries in partial assemblies. We provide an efficient C++ implementation of the method and demonstrate its efficiency on several examples including partial assemblies and pseudo symmetries. We also compare the method with two other published techniques and show that it is significantly faster on all the tested examples. Our method produces results with a machine precision, its cost function is solely based on 3D Euclidean geometry, and most of the operations are performed analytically. The method is available athttp://team.inria.fr/nano-d/software/ananas. The graphical user interface of the method built for the SAMSON platform is available athttp://samson connect.net. PMID- 29705494 TI - Association Between Early Menarche and School Bullying. AB - PURPOSE: Early pubertal onset may relate to more involvement in bullying in adolescent girls, both as a target and as a perpetrator. However, the few studies of the association between early menarche and school bullying have shown mixed findings. The present study examined whether early menarche is associated with bullying victimization and perpetration. METHODS: We obtained survey data on adolescent girls from the 2001-2002, 2005-2006, and 2009-2010 cycles of the Health Behaviour in School-aged Children study in 35 European and North American countries. We identified school bullying in the past 2 months using the Revised Olweus Bully/Victim Questionnaire. We defined early menarche as a reported onset of menarche before 11 years and tested the associations between early menarche and bullying victimization and perpetration using three-level logistic regression models. RESULTS: The sample included 227,443 adolescent girls with a mean age of 13.64 (standard deviation [SD] 1.63) years, of which 10,172 (4.47%) were early matured; 62,528 (28.33%) and 56,582 (25.67%) were occasional victims and perpetrators, respectively; and 21,985 (9.96%) and 14,115 (6.40%) were frequent victims and perpetrators, respectively. Early menarche related to occasional victimization (adjusted odds ratio [OR] [95% confidence interval [CI] = 1.21 [1.12-1.31]) and perpetration (aOR [95% CI] = 1.19 [1.11-1.27]) and to frequent victimization (aOR [95% CI] = 1.35 [1.22-1.50]) and perpetration (aOR [95% CI] = 1.46 [1.31-1.63]). CONCLUSIONS: Early menarche in European and North American adolescent girls positively relates to bullying victimization and perpetration. Early-maturing girls should not be neglected in antibullying programs. PMID- 29705495 TI - Weight Labeling and Disordered Eating Among Adolescent Girls: Longitudinal Evidence From the National Heart, Lung, and Blood Institute Growth and Health Study. AB - PURPOSE: Weight stigma is implicated in disordered eating, but much of this research focuses on forms of stigma such as weight-based teasing. METHODS: In a large cohort of adolescent girls (N = 2,036), we tested the hypothesis that being labeled as "too fat" by others predicts subsequent greater disordered eating cognitions and behaviors. RESULTS: Compared with girls who did not report weight labeling, girls who were labeled at age 14 showed an increase in unhealthy weight control behaviors and disordered eating cognitions over the subsequent 5 years. These effects were independent of objective body mass index, race, parental income and education, and initial levels of disordered eating. CONCLUSIONS: Exploratory analyses suggest that weight labeling from family members is more strongly associated with disordered eating than labeling from nonfamily members. This study highlights how the long-term consequences of weight stigma can potentially begin when one is labeled as "too fat." PMID- 29705496 TI - Variability of estimates of muscle fiber conduction velocity and surface EMG amplitude across subjects and processing intervals. AB - The force developed by the human neuromuscular system can change very rapidly (15 50 ms). When processing EMG signals for inferring neural control strategies, it is therefore necessary to extract estimates from short time intervals. In this study, we investigate the relation between joint torque and estimates of average muscle fibre conduction velocity (MFCV) and amplitude (RMS) from surface EMG signals, when varying the duration of the processing interval. Moreover, we assessed the inter-subject variability in RMS and MFCV estimates. Ten healthy subjects performed isometric linearly increasing ankle dorsiflexion contractions up to 70% MVC at a rate of 5%MVCs-1. High-density EMG signals were recorded from the tibialis anterior muscle and MFCV and RMS were estimated in eight time intervals ranging from 15 to 2000 ms. MFCV and RMS were significantly correlated with force in all subjects and when using all time-intervals (MFCV = 0.77 +/- 0.07, RMS = 0.79 +/- 0.06 (R2), Pearson-P < 0.01). The variability around the regression line for both MFCV and RMS estimates significantly increased when using intervals <100 ms (P < 0.001). However, the slope of the regression between EMG variables and force did not change with the duration of the interval (P < 0.001). Moreover, MFCV showed a substantially smaller variability across subjects in its relation to force than RMS [average coefficient of variation of regression slopes across all time intervals, 24.48 +/- 1.51 (%), whilst for the RMS it was 56.65 +/- 0.69 (%)]. These results indicate that estimates of MFCV and RMS as a function of joint torque are unbiased with respect to processing interval duration. Moreover, they reveal that estimates of MFCV are more consistent across subjects than EMG amplitude. PMID- 29705497 TI - Presynaptic inhibition mechanisms may subserve the spinal excitability modulation induced by neuromuscular electrical stimulation. AB - This study aimed at deciphering the origins of spinal excitability modulation that follows neuromuscular electrical stimulation (NMES). Ten participants (age: 24.6 +/- 4.2 years) performed 2 randomized NMES sessions on plantar flexors with frequencies of stimulations of 20 or 100 Hz (pulse width: 1 ms) at 20% of maximal voluntary contraction (MVC). Before and after each session, the posterior tibial nerve was stimulated to record H-reflex of soleus (SOL), gastrocnemius medialis (GM) and gastrocnemius lateralis (GL). D1 presynaptic inhibition was assessed by conditioning H reflex with prior common peroneal nerve stimulation. Resting H reflex of SOL decreased after both protocols, but in a greater extent following the 100 Hz session (100 Hz: -34.6 +/- 7.3%, 20 Hz: -17.1 +/- 3.8%; P = 0.002), accompanied by an increase of presynaptic inhibition (+22 +/- 5.8% at 100 Hz vs. +8 +/- 3.7% at 20 Hz, P < 0.001). GM and GL spinal excitability and presynaptic inhibition were also altered after NMES, but in a similarly extent after 20 Hz and 100 Hz protocols. Neuromuscular fatigue following a single session of NMES involves spinal presynaptic circuitry, even at low stimulation frequency. The spinal sensitivity to NMES seems also muscle dependent. PMID- 29705499 TI - High salt intake increases plasma trimethylamine N-oxide (TMAO) concentration and produces gut dysbiosis in rats. AB - OBJECTIVE: A high-salt diet is considered a cardiovascular risk factor; however, the mechanisms are not clear. Research suggests that gut bacteria-derived metabolites such as trimethylamine N-oxide (TMAO) are markers of cardiovascular diseases. We evaluated the effect of high salt intake on gut bacteria and their metabolites plasma level. METHODS: Sprague Dawley rats ages 12-14 wk were maintained on either water (controls) or 0.9% or 2% sodium chloride (NaCl) water solution (isotonic and hypertonic groups, respectively) for 2 wk. Blood plasma, urine, and stool samples were analyzed for concentrations of trimethylamine (TMA; a TMAO precursor), TMAO, and indoxyl sulfate (indole metabolite). The gut-blood barrier permeability to TMA and TMA liver clearance were assessed at baseline and after TMA intracolonic challenge test. Gut bacterial flora was analyzed with a 16S ribosomal ribonucleic acid (rRNA) gene sequence analysis. RESULTS: The isotonic and hypertonic groups showed a significantly higher plasma TMAO and significantly lower 24-hr TMAO urine excretion than the controls. However, the TMA stool level was similar between the groups. There was no significant difference between the groups in gut-blood barrier permeability and TMA liver clearance. Plasma indoxyl concentration and 24-hr urine indoxyl excretion were similar between the groups. There was a significant difference between the groups in gut bacteria composition. CONCLUSIONS: High salt intake increases plasma TMAO concentration, which is associated with decreased TMAO urine excretion. Furthermore, high salt intake alters gut bacteria composition. These findings suggest that salt intake affects an interplay between gut bacteria and their host homeostasis. PMID- 29705498 TI - Whole exome sequencing in an Italian family with isolated maxillary canine agenesis and canine eruption anomalies. AB - OBJECTIVE: The aim of this study was the clinical and molecular characterization of a family segregating a trait consisting of a phenotype specifically involving the maxillary canines, including agenesis, impaction and ectopic eruption, characterized by incomplete penetrance and variable expressivity. DESIGN: Clinical standardized assessment of 14 family members and a whole-exome sequencing (WES) of three affected subjects were performed. WES data analyses (sequence alignment, variant calling, annotation and prioritization) were carried out using an in-house implemented pipeline. Variant filtering retained coding and splice-site high quality private and rare variants. Variant prioritization was performed taking into account both the disruptive impact and the biological relevance of individual variants and genes. Sanger sequencing was performed to validate the variants of interest and to carry out segregation analysis. RESULTS: Prioritization of variants "by function" allowed the identification of multiple variants contributing to the trait, including two concomitant heterozygous variants in EDARADD (c.308C>T, p.Ser103Phe) and COL5A1 (c.1588G>A, p.Gly530Ser), specifically associated with a more severe phenotype (i.e. canine agenesis). Differently, heterozygous variants in genes encoding proteins with a role in the WNT pathway were shared by subjects showing a phenotype of impacted/ectopic erupted canines. CONCLUSIONS: This study characterized the genetic contribution underlying a complex trait consisting of isolated canine anomalies in a medium sized family, highlighting the role of WNT and EDA cell signaling pathways in tooth development. PMID- 29705500 TI - Lactobacillus paracasei HII01, xylooligosaccharides, and synbiotics reduce gut disturbance in obese rats. AB - OBJECTIVES: The beneficial effects of pro-, pre-, and synbiotics on obesity with insulin resistance have been reported previously. However, the strain-specific effect of probiotics and the combination with various types of prebiotic fiber yield controversial outcomes and limit clinical applications. Our previous study demonstrated that the probiotic Lactobacillus paracasei (L. paracasei) HII01, prebiotic xylooligosaccharide (XOS), and synbiotics share similar efficacy in attenuating cardiac mitochondrial dysfunction in obese-insulin resistant rats. Nonetheless, the roles of HII01 and XOS on gut dysbiosis and gut inflammation under obese-insulin resistant conditions have not yet, to our knowledge, been investigated. Our hypothesis was that pro-, pre-, and synbiotics improve the metabolic parameters in obese-insulin resistant rats by reducing gut dysbiosis and gut inflammation. METHODS: Male Wistar rats were fed with either a normal or high-fat diet that contained 19.77% and 59.28% energy from fat, respectively, for 12 wk. Then, the high-fat diet rats were fed daily with a 108 colony forming unit of the probiotic HII01, 10% prebiotic XOS, and synbiotics for 12 wk. The metabolic parameters, serum lipopolysaccharide levels, fecal Firmicutes/Bacteroidetes ratios, levels of Enterobacteriaceae, Bifidobacteria, and gut proinflammatory cytokine gene expression were quantified. RESULTS: The consumption of probiotic L. paracasei HII01, prebiotic XOS, and synbiotics for 12 wk led to a decrease in metabolic endotoxemia, gut dysbiosis (a reduction in the Firmicutes/Bacteroidetes ratio and Enterobacteriaceae), and gut inflammation in obese-insulin resistant rats. CONCLUSIONS: Pro-, pre-, and synbiotics reduced gut dysbiosis and gut inflammation, which lead to improvements in metabolic dysfunction in obese-insulin resistant rats. PMID- 29705501 TI - Quality of radiotherapy services in post-Soviet countries: An IAEA survey. AB - BACKGROUND: The quality of radiotherapy services in post-Soviet countries has not yet been studied following a formal methodology. The IAEA conducted a survey using two sets of validated radiation oncology quality indicators (ROIs). METHODS: Eleven post-Soviet countries were assessed. A coordinator was designated for each country and acted as the liaison between the country and the IAEA. The methodology was a one-time cross-sectional survey using a 58-question tool in Russian. The questionnaire was based on two validated sets of ROIs: for radiotherapy centres, the indicators proposed by Cionini et al., and for data at the country level, the Australasian ROIs. RESULTS: The overall response ratio was 66.3%, but for the Russian Federation, it was 24%. Data were updated on radiotherapy infrastructure and equipment. 256 radiotherapy centres are operating 275 linear accelerators and 337 Cobalt-60 units. 61% of teletherapy machines are older than ten years. Analysis of ROIs revealed significant differences between these countries and radiotherapy practices in the West. Naming, task profile and education programmes of radiotherapy professionals are different than in the West. CONCLUSIONS: Most countries need modernization of their radiotherapy infrastructure coupled with adequate staffing numbers and updated education programmes focusing on evidence-based medicine, quality, and safety. PMID- 29705503 TI - De novo transcriptome assembly and identification of salt-responsive genes in sugar beet M14. AB - Sugar beet (Beta vulgaris) is an important crop of sugar production in the world. Previous studies reported that sugar beet monosomic addition line M14 obtained from the intercross between Beta vulgaris L. (cultivated species) and B. corolliflora Zoss (wild species) exhibited tolerance to salt (up to 0.5 M NaCl) stress. To estimate a broad spectrum of genes involved in the M14 salt tolerance will help elucidate the molecular mechanisms underlying salt stress. Comparative transcriptomics was performed to monitor genes differentially expressed in the leaf and root samples of the sugar beet M14 seedlings treated with 0, 200 and 400 mM NaCl, respectively. Digital gene expression revealed that 3856 unigenes in leaves and 7157 unigenes in roots were differentially expressed under salt stress. Enrichment analysis of the differentially expressed genes based on GO and KEGG databases showed that in both leaves and roots genes related to regulation of redox balance, signal transduction, and protein phosphorylation were differentially expressed. Comparison of gene expression in the leaf and root samples treated with 200 and 400 mM NaCl revealed different mechanisms for coping with salt stress. In addition, the expression levels of nine unigenes in the reactive oxygen species (ROS) scavenging system exhibited significant differences in the leaves and roots. Our transcriptomics results have provided new insights into the salt-stress responses in the leaves and roots of sugar beet. PMID- 29705502 TI - Social group dynamics predict stress variability among children in a New Zealand classroom. AB - Previous research proposes stress as a mechanism for linking social environments and biological bodies. In particular, non-human primate studies investigate relationships between cortisol as a measure of stress response and social hierarchies. Because human social structures often include hierarchies of dominance and social status, humans may exhibit similar patterns. Studies of non human primates, however, have not reached consistent conclusions with respect to relationships between social position and levels of cortisol. While human studies report associations between cortisol and various aspects of social environments, studies that consider social status as a predictor of stress response also report mixed results. Others have argued that perceptions of social status may have different implications for stress response depending upon social context. We propose here that characteristics of children's social networks may be a better predictor of central tendencies and variability of stress response than their perceptions of social status. This is evaluated among 24 children from 9.4 to 11.3 years of age in one upper middle-class New Zealand primary school classroom, assessed through observation within the classroom, self-reports during semi structured interviews and 221 serial saliva samples provided daily over 10 consecutive school days. A synthetic assessment of the children's networks and peer-relationships was developed prior to saliva-cortisol analysis. We found that greater stability of peer-relationships within groups significantly predicts lower within-group variation in mid-morning cortisol over the two-week period, but not overall within-group differences in mean cortisol. PMID- 29705504 TI - E-learning and nursing assessment skills and knowledge - An integrative review. AB - OBJECTIVES: This review examines the current evidence on the effectiveness of digital technologies or e-based learning for enhancing the skills and knowledge of nursing students in nursing assessment. DESIGN & BACKGROUND: This integrative review identifies themes emerging from e-learning and 'nursing assessment' literature. Literature reviews have been undertaken in relation to digital learning and nursing education, including clinical skills, clinical case studies and the nurse-educator role. Whilst perceptions of digital learning are well covered, a gap in knowledge persists for understanding the effectiveness of e learning on nursing assessment skills and knowledge. This is important as comprehensive assessment skills and knowledge are a key competency for newly qualified nurses. DATA-SOURCES: The MEDLINE, CINAHL, Cochrane Library and ProQuest Nursing and Allied Health Source electronic databases were searched for the period 2006 to 2016. Hand searching in bibliographies was also undertaken. REVIEW METHODS: Selection criteria for this review included: FINDINGS: Twenty articles met the selection criteria for this review, and five major themes for e based learning were identified (a) students become self-evaluators; (b) blend and scaffold learning; (c) measurement of clinical reasoning; (d) mobile technology and Facebook are effective; and (e) training and preparation is vital. CONCLUSIONS: Although e-based learning programs provide a flexible teaching method, evidence suggests e-based learning alone does not exceed face-to-face patient simulation. This is particularly the case where nursing assessment learning is not scaffolded. This review demonstrates that e-based learning and traditional teaching methods used in conjunction with each other create a superior learning style. PMID- 29705505 TI - Development of biosynthesized silver nanoparticles based formulation for treating wounds during nursing care in hospitals. AB - Silver nanoparticles (AgNPs) have been emerged as significant wound healing agents because of their improved mechanical properties. However, the green synthesized silver nanoparticleshave reported significant wound healing action in Albino rats which was validated by the measurement of wound closure rate. Silver nanoparticles were efficiently synthesized using Euphorbia milii leaf extract. The UV-visible spectra recorded the effect of the reaction time on AgNPs synthesis and was indentified that the peak became shaper with an increase in time, which corresponds to increase in the number of nanoparticles formed from the reduction of silver ions present in the aqueous solution. X-ray diffraction technique and corresponding XRD patterns confirmed the biphasic nature of the biosynthesized silver nanoparticles. However, low magnification TEM images presented monodispersed AgNPs with their size ranging from 20 to 30 nm while SAED diffraction pattern disclosed their crystalline nature. Furthermore, the wound healing activity of AgNPs was examined through the excision wound model by measuring the rate of wound closure and Group II (treated with 10% Ointment base with biosynthesized AgNPs) revealed significant wound healing activity over Control group and Group I (treated with Standard Nitrofurazone ointment) in Albino rats. PMID- 29705506 TI - Biosynthesis of polyphenols functionalized ZnO nanoparticles: Characterization and their effect on human pancreatic cancer cell line. AB - The present work investigate the green synthesis of zinc oxide nanoparticles (ZnO NPs) using Anacardium occidentale leaf extract by an eco-friendly method. ZnO NPs were synthesized by boiling the mixture of 10 ml of Anacardium occidentale leaf extract and 30 ml 0.1 M zinc nitrate (ZnNO3) at 60 degrees C for 3 h. The obtained nanoparticles were studied using spectroscopic and microscopic techniques such as Fourier transform-infrared spectroscopy (FT-IR), transmission electron microscopy (TEM), X-ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDS) and ultraviolet-visible spectroscopy (UV-Vis).X-ray diffraction results showed the hexagonal structure of the ZnO NPs. TEM results confirmed the hexagonal NPs with average particle size of 33 nm. Further the prepared nanoparticles were studied for their cytotoxicity against human pancreatic cancer cells. The cytotoxicity results have confirmed that the fabricated ZnO NPs exhibited the concentration-dependent cytotoxicity against pancreatic cancer cell lines. PMID- 29705507 TI - Target challenging-cancer drug delivery to gastric cancer tissues with a fucose graft epigallocatechin-3-gallate-gold particles nanocomposite approach. AB - Inhibiting component of therapy with (-)-epigallocatechin-3-gallate (EGCG) is low bioavailability of fresh tea polyphenols that outcome from insecurity under stomach related circumstances, insufficient transcellular transport. As needs are, fucose- carboxymethyl chitosan (FU-CMC) graft EGCG with gold nanoparticles (GNPs) (FU-CMC-EGCG-GNPs) nanocomposites were prepared and managed peritumorally to assess their anticancer action. The physicochemical properties of as-prepared nanocomposite were evaluated by FTIR spectroscopy, UV-visible absorption spectra, XRD, FESEM-EDX and HRTEM-SAD. Additionally, the viability and cell uptake assays revealed that the as-prepared nanocomposite successfully repressed the propagation of gastric tumor cells. In vivo anticancer treatment of FU-CMC-EGCG GNPs nanocomposites showed more anticancer action contrasted with pure EGCG. Immuno-histological investigations established a superior numeral of apoptotic tissues in the as-prepared FU-CMC-EGCG-GNPs nanocomposites contrasted with pure EGCG. Overall, the as-prepared FU-CMC-EGCG-GNPs nanocomposite affords a proficient medicine delivery stage for chemotherapy. PMID- 29705508 TI - Biosynthesis of iron nanoparticles using Trigonella foenum-graecum seed extract for photocatalytic methyl orange dye degradation and antibacterial applications. AB - Trigonella foenum-graecum is the source of various biological and chemical constituents with a wide area of applications, especially in the treatment/prevention of diabetes and other chronic diseases such as cancer. Multiple biological and organic moieties in the aqueous or the organic phase of Trigonella foenum-graecum carry soft reduction properties to reduce the metal cations to nanoparticles. In this investigation, the Trigonella foenum-graecum was found in the seed extract for the first time in an aqueous medium. We successfully synthesized zero-valent iron nanoparticles (Fe0) (ZV-Fe NPs) and stabilized these nanoparticles in an aqueous medium. The stabilization mechanism of Fe NPs by Trigonella foenum-graecum in an aqueous extract was investigated. Further, Fe NPs were characterized by UV-visible spectrometry, X-ray diffraction (XRD), thermogravimetric analysis - derivative thermo-gravimetric (TGA/DTG), magnetization, Fourier transform infrared (FTIR) spectroscopy and transmission electron microscopy (TEM) images. The size of the nanoparticles, calculated using the Debye-Scherer equation and TEM, was found to be approximately 11 nm with the highest particle distribution number. Fe NPs are very effective for methyl orange dye degradation under UV light following pseudo first-order kinetics, and the rate constant kapp was found to be 0.025 min-1. Furthermore, Fe NPs were applied to check the antibacterial activities with microorganisms such as gram-negative E. coli and gram-positive S. aureus. The Minimum Inhibitory Concentration (MIC) of Fe NPs for E. coli and S. aureus was calculated as 32 MUg/mL and 64 MUg/mL, respectively. PMID- 29705510 TI - Validity and Reliability of a Nutrition Knowledge Questionnaire in an Adult Student Population. AB - OBJECTIVE: To assess the validity and reliability of the Kuwait Adult Nutrition Knowledge Questionnaire (KANKQ) in adult students as an initial step to validation in the general adult population. METHODS: Participants (n = 253; aged >=21 years) were categorized based on academic background and designated into groups known to differ in nutrition knowledge. Participants completed the questionnaire twice. Independent-samples t test, Pearson correlation coefficients, and Cronbach alpha were used to assess reliability and validity (P < .05). RESULTS: Participants with health-related (n = 144) and nutrition training backgrounds (n = 58) scored significantly higher than did those without them (n = 109 and 178, respectively; P < .001), indicating good construct validity of the KANKQ. Test-retest reliability (r = .67; P < .001) and internal consistency (alpha = .81) of the questionnaire were moderate to high. CONCLUSIONS AND IMPLICATIONS: Further testing of the KANKQ in workplaces and public areas is required for validation in the general adult population. Applicability to neighboring countries of similar background is warranted. PMID- 29705509 TI - Protection against gamma-radiation injury by protein tyrosine phosphatase 1B. AB - Protein tyrosine phosphatase 1B (PTP1B) is widely expressed in mammalian tissues, in particular in immune cells, and plays a pleiotropic role in dephosphorylating many substrates. Moreover, PTP1B expression is enhanced in response to pro inflammatory stimuli and to different cell stressors. Taking advantage of the use of mice deficient in PTP1B we have investigated the effect of gamma-radiation in these animals and found enhanced lethality and decreased respiratory exchange ratio vs. the corresponding wild type animals. Using bone-marrow derived macrophages and mouse embryonic fibroblasts (MEFs) from wild-type and PTP1B deficient mice, we observed a differential response to various cell stressors. PTP1B-deficient macrophages exhibited an enhanced response to gamma-radiation, UV light, LPS and S-nitroso-glutathione. Macrophages exposed to gamma-radiation show DNA damage and fragmentation, increased ROS production, a lack in GSH elevation and enhanced acidic beta-galactosidase activity. Interestingly, these differences were not observed in MEFs. Differential gene expression analysis of WT and KO macrophages revealed that the main pathways affected after irradiation were an up regulation of protein secretion, TGF-beta signaling and angiogenesis among other, and downregulation of Myc targets and Hedgehog signaling. These results demonstrate a key role for PTP1B in the protection against the cytotoxicity of irradiation in intact animal and in macrophages, which might be therapeutically relevant. PMID- 29705511 TI - Checkpoint blockade after kidney transplantation. PMID- 29705512 TI - Internal concentrations of perfluorobutane sulfonate (PFBS) comparable to those of perfluorooctane sulfonate (PFOS) induce reproductive toxicity in Caenorhabditis elegans. AB - Perfluorobutane sulfonate (PFBS) is considered a less-toxic replacement for perfluorooctane sulfonate (PFOS), with multiple applications in industrial and consumer products. Previous studies comparing their toxicity generally used similar exposure levels, without taking internal concentrations into account. The current study compared the reproductive toxicity of PFOS and PFBS, at similar internal concentrations, to Caenorhabditis elegans (C. elegans). PFBS was much less bioaccumulative than PFOS. The 48-h median lethal concentrations (LC50) for PFOS and PFBS were 1.4 MUM (95% confidence interval [CI]: 1.1-1.6) and 794 MUM (95% CI: 624-1009), respectively. Egg production and brood number of C. elegans decreased markedly following exposure to 0.1 MUM PFOS or 1000 or 1500 MUM PFBS. Germ-cell apoptosis and production of reactive oxygen species increased significantly following exposure to 2 MUM PFOS or 500 or 1000 MUM PFBS. Expression of the antioxidant genes sod-3, ctl-2, and gst-4 and the pro-apoptotic genes egl-1 and ced-13 was altered significantly following PFOS and PFBS exposure. These findings indicate that both chemicals exert reproductive toxicity in C. elegans, probably owing to germ-cell apoptosis resulting from elevated levels of reactive oxygen species. The vastly different exposure concentrations of PFBS and PFOS used in this study produced similar internal concentrations, leading to the reproductive toxicities observed. PMID- 29705513 TI - Iatrogenic lesions-Preface. PMID- 29705514 TI - Spinal injection of newly identified cerebellin-1 and cerebellin-2 peptides induce mechanical hypersensitivity in mice. AB - By screening for neuropeptides in the mouse spinal cord using mass spectrometry (MS), we have previously demonstrated that one of the 78 peptides that is expressed predominantly (> 6-fold) in the dorsal horn compared to the ventral spinal cord is the atypical peptide desCER [des-Ser1]-cerebellin, which originates from the precursor protein cerebellin 1 (CBLN1). Furthermore, we found that intrathecal injection of desCER induces mechanical hypersensitivity in a dose dependent manner. The current study was designed to further investigate the relative expression of other CBLN derived peptides in the spinal cord and to examine whether they share similar nociceptive properties. In addition to the peptides cerebellin (CER) and desCER we identified and relatively quantified nine novel peptides originating from cerebellin precursor proteins CBLN1 (two peptides), CBLN2 (three peptides) and CBLN4 (four peptides). Ten out of eleven peptides displayed statistically significantly (p < 0.05) higher expression levels (200-350%) in the dorsal horn compared to the ventral horn. Intrathecal injection of three of the four CBLN1 and two of the three CBLN2 derived peptides induced mechanical hypersensitivity in response to von Frey filament testing in mice during the first 6 h post-injection compared to saline injected mice, while none of the four CBLN4 derived peptides altered withdrawal thresholds. This study demonstrates that high performance MS is an effective tool for detecting novel neuropeptides in CNS tissues. We show the presence of nine novel atypical peptides originating from CBLN1, CBLN2 and CBLN4 precursor proteins in the mouse dorsal horn, whereof five peptides induce pain-like behavior upon intrathecal injection. Further studies are required to investigate the mechanisms by which CBLN1 and CBLN2 derived peptides facilitate nociceptive signal transmission. PMID- 29705515 TI - Effects of water extract from epimedium on neuropeptide signaling in an ovariectomized osteoporosis rat model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: For the past millennium, water extract from Epimedium (dried leaves of Epimedium brevicornu Maxim.) has been widely used for bone disease therapy in traditional Chinese medicine and has been reported to exhibit salutary effects on osteoporosis in clinical trials. The therapeutic effect of Epimedium is associated with the function of the brain in traditional Chinese medicine theory. STUDY AIM: To determine the potential relationship between treating osteoporosis with Epimedium and neuropeptide regulation. MATERIALS AND METHODS: Water extract from Epimedium was qualitatively and quantitatively analyzed with HPLC-TOF-MS. Ovariectomized rats were used as an osteoporosis model and were treated orally with water extract from Epimedium 16 weeks after surgery to mimic clinical therapy. After treatment, gene expression and protein levels of four neuropeptides, as well as their main receptors or receptor precursors including; neuropeptide Y (NPY) and its receptors NPY 1 (NPYR1) and 2; calcitonin gene-related peptide and its receptor precursor calcitonin receptor-like receptor (CRLR); vasoactive intestinal peptide (VIP) and its receptor VIP 1 (VIP1R) and 2; and substance P (SP) and its receptor neurokinin 1 receptor (NK1R) were detected in samples taken from bone, brain and spinal cord. RESULTS: Treatment with water extract from Epimedium prevented bone mineral loss and reduced femoral bone strength decline associated with osteoporosis. Detection of neuropeptides showed that treatment also affected neuropeptide in the brain/spinal cord/bone axis; specifically, treatment increased brain NPY, bone NPY1R, bone CRLR, bone and spinal cord VIP and VIP2R, bone SP, and brain and spinal cord NK1R. CONCLUSION: The effects of osteoporosis can largely be reduced by treatment with Epimedium most likely through a mechanism associated with several neuropeptides involved in regulation of the brain/spinal cord/bone axis. These novel results contribute to existing literature regarding the possible mechanisms of habitual use of Epimedium in the treatment of osteoporosis. PMID- 29705516 TI - Icones Plantarum Malabaricarum: Early 18th century botanical drawings of medicinal plants from colonial Ceylon. AB - ETHNOPHARMACOLOGICAL RELEVANCE: From 1640-1796, the Dutch East India Company (VOC) occupied the island of Ceylon (now Sri Lanka). Several VOC officers had a keen interest in the medicinal application of the local flora. The Leiden University Library holds a two-piece codex entitled: Icones Plantarum Malabaricarum, adscriptis nominibus et viribus, Vol. I. & II. (Illustrations of Plants from the Malabar, assigned names and strength). This manuscript contains 262 watercolour drawings of medicinal plants from Sri Lanka, with handwritten descriptions of local names, habitus, medicinal properties and therapeutic applications. This anonymous document had never been studied previously. AIM OF THE STUDY: To identify all depicted plant specimens, decipher the text, trace the author, and analyse the scientific relevance of this manuscript as well as its importance for Sri Lankan ethnobotany. MATERIALS AND METHODS: We digitised the entire manuscript, transcribed and translated the handwritten Dutch texts and identified the depicted species using historic and modern literature, herbarium vouchers, online databases on Sri Lankan herbal medicine and 41 botanical drawings by the same artist in the Artis library, Amsterdam. We traced the origin of the manuscript by means of watermark analysis and historical literature. We compared the historic Sinhalese and Tamil names in the manuscript to recent plant names in ethnobotanical references from Sri Lanka and southern India. We published the entire manuscript online with translations and identifications. RESULTS: The watermarks indicate that the paper was made between 1694 and 1718. The handwriting is of a VOC scribe. In total, ca. 252 taxa are depicted, of which we could identify 221 to species level. The drawings represent mainly native species, including Sri Lankan endemics, but also introduced medicinal and ornamental plants. Lamiaceae, Zingiberaceae and Leguminosae were the best represented families. Frequently mentioned applications were to purify the blood and to treat gastro-intestinal problems, fever and snakebites. Many plants are characterised by their humoral properties, of which 'warming' is the most prevalent. Plant species were mostly used for their roots (28%), bark (16%) or leaves (11%). More Tamil names (260) were documented than Sinhalese (208). More than half of the Tamil names and 36% of the Sinhalese names are still used today. The author was probably a VOC surgeon based in northern Sri Lanka, who travelled around the island to document medicinal plant use. Less than half of the species were previously documented from Ceylon by the famous VOC doctor and botanist Paul Hermann in the 1670s. Further archival research is needed to identify the maker of this manuscript. CONCLUSIONS: Although the maker of this early 18th century manuscript remains unknown, the detailed, 300-year-old information on medicinal plant use in the Icones Plantarum Malabaricarum represents an important ethnobotanical treasure for Sri Lanka, which offers ample opportunities to study changes and continuation of medicinal plant names and practices over time. PMID- 29705517 TI - Crossing the roof of the world: Trade in medicinal plants from Nepal to China. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Trade in medicinal and aromatic plants (MAPs) between Nepal and China has taken place for centuries along the Tibetan border. While there is anecdotal evidence that economic development in China over the past decades, coupled with regional infrastructure development and increasing market integration, has substantially changed this trade, there are no current published studies investigating this, e.g. in terms of species and market structure. This knowledge gap impedes the development of public interventions, e.g. in support of sustainable trade. AIM OF THIS STUDY: The primary objective of this study is to provide the first informative insights into the Nepal-China trade in MAPs, with particular emphasis on the value chain in Tibet. METHODS AND MATERIALS: Data was collected from December 2015 to August 2016 in Nepal and Tibet. The data collection included standardized questionnaires to understand and map the value chain of MAPs, including the actors involved and key governance issues. Data was collected from Katmandu-based MAPs wholesalers exporting from Nepal to China, (n = 6) and with regional wholesalers (n = 40) based in Tibet. The questionnaires contained quantitative and qualitative components focusing on key elements of the MAPs value chain, e.g. the traded species and their values. This was augmented with qualitative interviews with Lhasa-based processors (n = 4) and government officials (n = 12) working in border controls, customs, and/or drug administration. We also collected official statistics on the Nepal-China MAPs trade and conducted a workshop in Lhasa with traders and government officials to discuss the nature of the Nepal-China MAPs trade. RESULTS: The Nepal China MAPs trade boomed after 2011 when the value of traded plants increased more than nine-fold. This rapid increase reflected both a broader species composition and higher unit prices in response to increasing demand from China. The trade expansion was also driven by increasing demand in China and facilitated by improved infrastructure in Nepal and Tibet, including direct flight connections for the transport of high-value products. Official records on both sides of the border under-document both the value and the volume of the trade, implying that much of it is extra-legal. The value chain is thus governed by both legal and extra-legal mechanisms. CONCLUSION: This study provides the first structured overview of the current trade in commercial MAPs from Nepal to China. While the trade is thriving, growing in both volume and value to the benefit of producers in Nepal and consumers in China, there is little empirical data or research to support policy formulation on sustainable trading. This study provides informative insights into the value chain and makes public policy recommendations to increase the transparency and sustainability of trade by improving traditional border markets and removing market barriers. PMID- 29705518 TI - A cautionary note on the mutation frequency in microbial research. AB - The mutation frequency, also known as the mutant frequency, is an unnormalized quantity, and its normalized counterpart is the mutation rate. Due to historical reasons, the mutation frequency has been a predominant yardstick of microbial mutability in the field of mutator identification. While the mean mutation frequency is infamously erratic, replacing it with the median mutation frequency is not an effective remedy. By encouraging investigators to substitute mutation rates for mutation frequencies in microbial research, this paper directs attention to substantial open problems such as false positive control and massive nonmutant cell death. PMID- 29705520 TI - Developmental changes in spatial margin of stability in typically developing children relate to the mechanics of gait. AB - BACKGROUND: Immature balance control is considered an important rate limiter for maturation of gait. The spatial margin of stability (MoS) is a biomechanical measure of dynamic balance control that might provide insights into balance control strategies used by children during the developmental course of gait. RESEARCH HYPOTHESIS: We hypothesize there will be an age-dependent decrease in MoS in children with typical development. To understand the mechanics, relations between MoS and spatio-temporal parameters of gait are investigated. METHODS: Total body gait analysis of typically developing children (age 1-10, n = 84) were retrospectively selected from available databases. MoS is defined as the minimum distance between the center of pressure and the extrapolated center of mass along the mediolateral axis during the single support phases. RESULTS: MoS shows a moderate negative correlation with stride length (rho = -0.510), leg length (rho = -0.440), age (rho = -0.368) and swing duration (rho = -0.350). A weak correlation was observed between MoS and walking speed (rho = -0.243) and step width (rho = 0.285). A stepwise linear regression model showed only one predictor, swing duration, explaining 18% of the variance in MoS. MoS decreases with increasing duration of swing (beta = -0.422). This relation is independent of age. SIGNIFICANCE: A larger MoS induces a larger lateral divergence of the CoM that could be compensated by a quicker step. Future research should compare the observed strategies in children to those used in adults and in children with altered balance control related to pathology. PMID- 29705519 TI - The role of IL-1 in postprandial fatigue. AB - OBJECTIVES: Cytokines such as IL-1 seems to play a role in the pathogenesis of fatigue associated with some chronic diseases and anti-inflammatory treatment has been shown to reduce these symptoms. Ingestion of a calorie rich meal leads to postprandial fatigue, and is associated with increased systemic concentrations of cytokines, which is more pronounced in obese than lean subjects. We investigated whether postprandial fatigue is regulated by IL-1, and therefore reduced by IL-1 antagonism, in lean and obese subjects. METHODS: In a double-blind, crossover study in 8 lean and 8 obese male subjects, randomized to receive either saline (placebo) or the IL-1 receptor antagonist anakinra, we investigated whether postprandial fatigue was regulated by IL-1. To promote postprandial fatigue, subjects ran 30 min prior to a high-fat, high-carbohydrate meal. Fatigue was determined using the Stanford Sleepiness Scale and blood samples were drawn at baseline and after the intervention. RESULTS: IL-1 antagonism led to a reduction in postprandial fatigue and this effect was more pronounced in obese than lean individuals. CONCLUSIONS: We conclude that IL-1 is involved in the regulation of postprandial fatigue under physiologic conditions in lean and obese individuals. It remains to be shown whether this effect translates into clinical relevant effects. PMID- 29705521 TI - Vertical stiffness and balance control of two-legged hopping in-place in children with and without Down syndrome. AB - BACKGROUND: Children with Down syndrome (DS) are known for their reduced balance control, and typically take longer to develop motor skills and display less coordinated movement patterns. Hopping in-place is a gross motor skill requiring whole-body vertical stiffness and horizontal movement control, particularly when attempting to modify hopping frequency. However, there is a lack of knowledge of the hopping capacity of children with DS. RESEARCH QUESTION: The purpose of this study was to assess the ability of children with DS aged 5-11 years old to continuously hop in-place on two legs and compare their biomechanical patterns to those of typically developing (TD) children. METHODS: This observational study included 14 children with DS and 16 TD children. Subjects were asked to complete 20 s trials of two-legged hopping in-place at a self-selected frequency, and four metronome guided conditions: preferred (self-selected frequency), moderate (20% increase), fast (40% increase) and slow (20% decrease). Two sample independent t tests were conducted on whole-body vertical stiffness, horizontal center-of-mass movement, and toe displacement between hops for the self-selected hopping condition and two-way ANOVAs were used for the metronome conditions. RESULTS AND SIGNIFICANCE: Our findings suggest that children with DS might not be able to continuously hop in-place until the age of 7 years old, and were unable to hop for as long in duration as their TD peers. Children with DS self-selected a faster hopping frequency, and demonstrated an increased medial-lateral center-of mass movement during the stance phase of hopping, suggesting reduced balance control. Moreover, children with DS were unable to correctly modify their hopping frequency when cued by a metronome and exhibited an inability to modulate whole body vertical stiffness and constrain horizontal or vertical movement. These results demonstrate the utility of a future hopping intervention to improve whole body vertical stiffness and balance control in children with DS. PMID- 29705522 TI - Monodisperse Versus Polydisperse Ultrasound Contrast Agents: Non-Linear Response, Sensitivity, and Deep Tissue Imaging Potential. AB - It has been proposed that monodisperse microbubble ultrasound contrast agents further increase the signal-to-noise ratio of contrast-enhanced ultrasound imaging. Here, the sensitivity of a polydisperse pre-clinical agent was compared experimentally with that of its size- and acoustically sorted derivatives by using narrowband pressure- and frequency-dependent scattering and attenuation measurements. The sorted monodisperse agents had up to a two-orders-of-magnitude increase in sensitivity, that is, in the average scattering cross section per bubble. Moreover, we found, for the first time, that the highly non-linear response of acoustically sorted microbubbles can be exploited to confine scattering and attenuation to the focal region of ultrasound fields used in clinical imaging. This property is a result of minimal pre-focal scattering and attenuation and can be used to minimize shadowing effects in deep tissue imaging. Moreover, it potentially allows for more localized therapy using microbubbles through the spatial control of resonant microbubble oscillations. PMID- 29705523 TI - Linguistic entrenchment: Prior knowledge impacts statistical learning performance. AB - Statistical Learning (SL) is typically considered to be a domain-general mechanism by which cognitive systems discover the underlying statistical regularities in the input. Recent findings, however, show clear differences in processing regularities across modalities and stimuli as well as low correlations between performance on visual and auditory tasks. Why does a presumably domain general mechanism show distinct patterns of modality and stimulus specificity? Here we claim that the key to this puzzle lies in the prior knowledge brought upon by learners to the learning task. Specifically, we argue that learners' already entrenched expectations about speech co-occurrences from their native language impacts what they learn from novel auditory verbal input. In contrast, learners are free of such entrenchment when processing sequences of visual material such as abstract shapes. We present evidence from three experiments supporting this hypothesis by showing that auditory-verbal tasks display distinct item-specific effects resulting in low correlations between test items. In contrast, non-verbal tasks - visual and auditory - show high correlations between items. Importantly, we also show that individual performance in visual and auditory SL tasks that do not implicate prior knowledge regarding co-occurrence of elements, is highly correlated. In a fourth experiment, we present further support for the entrenchment hypothesis by showing that the variance in performance between different stimuli in auditory-verbal statistical learning tasks can be traced back to their resemblance to participants' native language. We discuss the methodological and theoretical implications of these findings, focusing on models of domain generality/specificity of SL. PMID- 29705524 TI - Factors related to gastric neuroendocrine tumors. AB - INTRODUCTION AND AIMS: An association between long-term use of proton pump inhibitors and the development of gastric neuroendocrine tumors has been reported, but it is still a subject of debate. The aims of the present study were to determine the presence of this association in a Mexican population and to identify the risk factors for developing gastric neuroendocrine tumors. MATERIALS AND METHODS: A case-control study was conducted, in which the cases were patients with a histopathologic diagnosis of gastric neuroendocrine tumor and the controls were patients evaluated through upper endoscopy. The controls were paired by age, sex, and endoscopic examination indication. Proton pump inhibitor use was considered prolonged when consumption was longer than 5 years. RESULTS: Thirty three patients with gastric neuroendocrine tumor and 66 controls were included in the study. Eighteen (54.5%) patients in the case group were women, as were 39 (59%) of the patients in the control group. The median age of the patients in the case group was 55 years (minimum-maximum range: 24-82) and it was 54 years (minimum-maximum range:18-85) in the control group. A greater number of patients in the gastric neuroendocrine tumor group presented with gastric atrophy (p<0.0001) and autoimmune atrophic gastritis (p=0.0002), compared with the control group. No association between gastric neuroendocrine tumor and prolonged proton pump inhibitor use, sex, smoking, gastroesophageal reflux disease, Helicobacter pylori infection, diabetes mellitus, or autoimmune diseases was found in the univariate analysis. CONCLUSIONS: The results of our study showed no association between proton pump inhibitor use for more than 5 years and the development of gastric neuroendocrine tumor. The presence of gastric atrophy and autoimmune atrophic gastritis was associated with gastric neuroendocrine tumor development. PMID- 29705525 TI - Corrigendum to '212Pb-labeled B7-H3-targeting antibody for pancreatic cancer therapy in mouse models' [Nucl Med Biol 58 (2018) 67-73]. PMID- 29705526 TI - Determination of denudation rates by the measurement of meteoric 10Be in Guadiana river sediment samples (Spain) by low-energy AMS. AB - The concentration of meteoric 10Be in estuarine sediment samples has been measured by Spanish Accelerator for Radionuclides Analysis (SARA) at CNA and subsequently used to assess the denudation rate in Guadiana river basin together with the sediment budget method, on both sides of the frontier between Spain and Portugal. The two methods yielded coincident results. The estimation by the 10Be method gave the denudation rate of (0.76 +/- 0.10) * 10-2 cm/y. After correcting for an approximate 80% attenuation of the sediment discharge into the ocean, caused by the river dams, the sediment budget method yielded the rate of (0.77 +/ 0.17) * 10-2 cm/y. PMID- 29705527 TI - Efficiencies of Tritium (3H) bubbling systems. AB - Bubbling systems are among the devices most used by nuclear operators to measure atmospheric tritium activity in their facilities or the neighbouring environment. However, information about trapping efficiency and bubbling system oxidation is not accessible and/or, at best, only minimally supported by demonstrations in actual operating conditions. In order to evaluate easily these parameters and thereby meet actual normative and regulatory requirements, a statistical study was carried out over 2000 monitoring records from the CEA Valduc site. From this data collection obtained over recent years of monitoring the CEA Valduc facilities and environment, a direct relation was highlighted between the 3H samplers trapping efficiency of tritium as tritiated water and the sampling time and conditions of use: temperature and atmospheric moisture. It was thus demonstrated that this efficiency originated from two sources. The first one is intrinsic to the bubbling system operating parameters and the sampling time. That part applies equally to all four bubblers. The second part, however, is specific to the first bubbler. In essence, it depends on the sampling time and the sampled air characteristics. It was also highlighted that the water volume variation in the first bubbler, between the beginning and the end of the sampling process, is directly related to the average water concentration of the sampled air. In this way, it was possible to model the variations in trapping efficiency of the 3H samplers relative to the sampling time and the water volume variation in the first bubbler. This model makes it possible to obtain the quantities required to comply with the current standards governing the monitoring of radionuclides in the environment and to associate an uncertainty concerning the measurements as well as the sampling parameters. PMID- 29705528 TI - Influence of ageing on glass and resin bonding of dental glass-ceramic veneer adhesion to zirconia: A fracture mechanics analysis and interpretation. AB - : Adhesion plays a major role in the bonding of dental materials. In this study the adhesion of two glass-ceramic systems (IPS e.max and VITABLOCS) to a zirconia sintered substrate using a glass (for IPS e.max) and resin (VITABLOCS) before and after exposure to ageing for 14 days in distilled water at 37 degrees C are compared using two interfacial fracture mechanics tests, the 3 point bend Schwickerath (Kosyfaki and Swain, 2014; Schneider and Swain, 2015) and 4 point bend (Charalambides et al., 1989) approaches. Both tests result in stable crack extension from which the strain energy release rate (G, N/m or J/m2) can be determined. In the case of the 3 PB test the Work of Fracture was also determined. In addition, the Schwickerath test enables determination of the critical stress for the onset of cracking to occur, which forms the basis of the ISO (ISO9693-2:2016) adhesion test for porcelain ceramic adhesion to zirconia. For the aged samples there was a significant reduction in the resin-bonded strengths (Schwickerath) and strain energy release rate (both 3 and 4 PB tests), which was not evident for the glass bonded specimens. Critical examination of the force-displacement curves showed that ageing of the resin resulted in a major change in the form of the curves, which may be interpreted in terms of a reduction in the critical stress to initiate cracking and also in the development of an R-curve. The extent of the reduction in strain energy release rate following ageing was greater for the Schwickerath test than the Charalambides test. The results are discussed in terms of; the basic mechanics of these two tests, the deterioration of the resin bonding following moisture exposure and the different dimensions of the specimens. These in-vitro results raise concerns regarding resin bonding to zirconia. STATEMENT OF SIGNIFICANCE: The present study uses a novel approach to investigate the role of ageing or environmental degradation on the adhesive bonding of two dental ceramics to zirconia. This continues to be a major clinical problem but current approaches, till now, have relied upon a myriad of strength based tests to quantify the extent of environmental degradation with time. In this paper we use two fracture mechanics approaches, based upon simple 3 and 4 point bend testing procedures that enable stable debonding crack extension to occur. The paper provides a more critical approach to evaluate the role of environmental degradation of adhesion for dental materials. PMID- 29705529 TI - Long-Term Outcomes of Patients With HCV-Associated Cryoglobulinemic Vasculitis After Virologic Cure. AB - Patients with hepatitis C virus-associated cryoglobulinemic vasculitis (HCV-CV) have high rates of clinical remission after treatment with direct-acting antivirals (DAAs), but circulating cryoglobulins persist, and vascular disorders reappear in some patients shortly after DAA treatment ends. We performed a prospective study to assess the long-term clinical and immune system effects of HCV eradication with DAAs in 46 patients with HCV-CV and 42 asymptomatic patients with circulating cryoglobulins. A median of 24 months after DAA treatment (range, 17-41 months), 66% of patients with HCV-CV and 70% of asymptomatic patients with circulating cryoglobulins had an immunologic response, with comparable reductions in cryocrit from 2.6% to 0% (P < .05). However, 20% of patients still had positive test results for cryoglobulins after DAA therapy. Among patients with HCV-CV, 42 (91%) had a clinical response, in that their Birmingham Vasculitis Activity Score (version 3) decreased from 7 to 0 (P < .01). Nevertheless, within 2 years after a sustained viral response to DAA therapy, 5 patients with HCV-CV (11%, 4 with cirrhosis) had relapses of vasculitis that included severe organ damage and death. PMID- 29705530 TI - Prevalence of beliefs about actual and mythical causes of cancer and their association with socio-demographic and health-related characteristics: Findings from a cross-sectional survey in England. AB - BACKGROUND: Literature on population awareness about actual causes of cancer is growing but comparatively little is known about the prevalence of people's belief concerning mythical causes of cancer. This study aimed to estimate the prevalence of these beliefs and their association with socio-demographic characteristics and health behaviours. METHODS: A survey containing validated measures of beliefs about actual and mythical cancer causes and health behaviours (smoking, alcohol consumption, physical activity, fruit and vegetable consumption, overweight) was administered to a representative English population sample (N = 1330). RESULTS: Awareness of actual causes of cancer (52% accurately identified; 95% confidence interval [CI] 51-54) was greater than awareness of mythical cancer causes (36% accurately identified; 95% CI 34-37; P < 0.01). The most commonly endorsed mythical cancer causes were exposure to stress (43%; 95% CI 40-45), food additives (42%; 95% CI 39-44) and non-ionizing electromagnetic frequencies (35%; 95% CI 33-38). In adjusted analysis, greater awareness of actual and mythical cancer causes was independently associated with younger age, higher social grade, being white and having post-16 qualifications. Awareness of actual but not mythical cancer causes was associated with not smoking and eating sufficient fruit and vegetables. CONCLUSIONS: Awareness of actual and mythical cancer causes is poor in the general population. Only knowledge of established risk factors is associated with adherence to behavioural recommendations for reducing cancer risk. PMID- 29705531 TI - Copper and arsenic-induced oxidative stress and immune imbalance are associated with activation of heat shock proteins in chicken intestines. AB - Arsenic and copper, two ubiquitous pollutants, can be oxidative stress inducers when organisms are heavy or chronically exposed, causing adverse effects on digestion and absorption function, resulting in potential losses to poultry husbandry. The present study examined the effects of arsenic trioxide (30 mg/kg)- and copper sulfate (300 mg/kg)-mixed foods, administered alone or in combination for 12 weeks, on various biochemical indices of oxidative stress and immunity in the small intestines of Hy-line chickens. The results showed that for the first four weeks of exposure, both the redox and immune systems were unaffected. Subsequently, exposure to arsenic or copper significantly increased the level of lipid peroxidation (malondialdehyde and ability of anti-hydroxy radical) concomitant with a collapse of the antioxidant system (catalase and glutathione peroxidase), in a time-dependent manner. An increase in the mRNA and protein levels of pro-inflammatory indicators (nuclear factor kappa B, cyclooxygenases-2, tumor necrosis factor-alpha and prostaglandin E2 synthases) with a definite tendency toward Th1 (Th, helper T cell) cytokines was observed in both arsenic and copper treated chickens. Histologically, the destruction of the biofilm structure and inflammatory infiltrates was observed. Thus, in the intestine, heat shock proteins play protective roles against tissue damage. In some cases, we observed that the tissues of the small intestine were more sensitive to arsenic than to copper. Moreover, co-exposure induced more serious intestinal toxicity than single treatment group, and this mechanism needs further exploration. PMID- 29705532 TI - Paeoniflorin augments systemic Candida albicans infection through inhibiting Th1 and Th17 cell expression in a mouse model. AB - Paeoniflorin (PF), a Chinese herbal medicine, has been widely used in clinical practice in China because of its dual immunoregulatory effects. A previous study found that PF inhibited the biofilm formation of Candida albicans (C. albicans) in vitro; however, whether PF plays an antifungal role in vivo is still unexplored. In this study, we sought to examine the effect of PF alone or in combination with an antifungal agent, fluconazole (FCZ), using a mouse model of systemic candidiasis. The results showed that the survival time of mice treated with PF alone or PF + FCZ decreased compared with the Infected alone and FCZ treated groups, respectively (8.20 +/- 1.75 vs 10.40 +/- 2.50 days, P < 0.05; 24.60 +/- 6.55 vs 29.00 +/- 3.16 days, P < 0.05). The fungal burden in the kidney of mice increased in the PF alone and PF + FCZ treated groups compared with the Infected alone or FCZ treated group. Furthermore, it was found that the PF and PF + FCZ treated groups showed significantly decreased levels of serum interferon gamma (IFN-gamma), interleukin (IL)-17, and IL-22, and an increased level of serum IL-4; PF had no effect on the production of tumor necrosis factor alpha (TNF-alpha). PF alone or in combination with FCZ decreased the proliferation of Th1 (IFN-gamma+CD4+) and Th17 cells (IL-17+CD4+) and increased the expression of Th2 cells (IL-4+CD4+). These results suggested that PF treatment could be detrimental to the host response to systemic C. albicans infection in mice. Thus, caution might be required for clinical use of PF in patients with fungal infection. PMID- 29705533 TI - Association between enterovirus infection and speech and language impairments: A nationwide population-based study. AB - BACKGROUND AND AIMS: Delay and impairment in Speech and language are common developmental problems in younger populations. Hitherto, there has been minimal study of the association between common childhood infections (e.g. enterovirus [EV]) and speech and language. The impetus for evaluating this association is provided by evidence linking inflammation to neurodevelopmental disorders. Herein we sought to determine whether an association exists between EV infection and subsequent diagnoses of speech and language impairments in a nationwide population-based sample in Taiwan. METHODS: Our study acquired data from the Taiwan National Health Insurance Research Database. The sample was comprised of individuals under 18 years of age with newly diagnosed EV infection during the period from January 1998 to December 2011. 39669 eligible cases were compared to matched controls and assessed during the study period for incident cases of speech and language impairments. Cox regression analyses were applied, adjusting for sex, age and other physical and mental problems. RESULTS: In the fully adjusted Cox regression model for hazard ratios, EV infection as positively associated with speech and language impairments (HR = 1.14, 95% CI: 1.06-1.22) after adjusting for age, sex and other confounds. Compared to the control group, the hazard ratio for speech and language impairments was 1.12 (95% CI: 1.03-1.21) amongst the group of EV infection without hospitalization, and 1.26 (95% CI: 1.10 1.45) amongst the group of EV infection with hospitalization. CONCLUSIONS: EV infection is temporally associated with incident speech and language impairments. Our findings herein provide rationale for educating families that EV infection may be associated with subsequent speech and language problems in susceptible individuals and that monitoring for such a presentation would be warranted. WHAT THIS PAPER ADDS?: Speech and language impairments associated with central nervous system infections have been reported in the literature. EV are medically important human pathogens and associated with select neuropsychiatric diseases. Notwithstanding, relatively few reports have mentioned the effects of EV infection on speech and language problems. Our study used a nationwide longitudinal dataset and identified that children with EV infection have a greater risk for speech and language impairments as compared with control group. Infected children combined other comorbidities or risk factors might have greater possibility to develop speech problems. Clinicians should be vigilant for the onset of language developmental abnormalities of preschool children with EV infection. PMID- 29705534 TI - Increasing kynurenine brain levels reduces ethanol consumption in mice by inhibiting dopamine release in nucleus accumbens. AB - Recent research suggests that ethanol (EtOH) consumption behaviour can be regulated by modifying the kynurenine (KYN) pathway, although the mechanisms involved have not yet been well elucidated. To further explore the implication of the kynurenine pathway in EtOH consumption we inhibited kynurenine 3 monooxygenase (KMO) activity with Ro 61-8048 (100 mg/kg, i.p.), which shifts the KYN metabolic pathway towards kynurenic acid (KYNA) production. KMO inhibition decreases voluntary binge EtOH consumption and EtOH preference in mice subjected to "drinking in the dark" (DID) and "two-bottle choice" paradigms, respectively. This effect seems to be a consequence of increased KYN concentration, since systemic KYN administration (100 mg/kg, i.p.) similarly deters binge EtOH consumption in the DID model. Despite KYN and KYNA being well-established ligands of the aryl hydrocarbon receptor (AhR), administration of AhR antagonists (TMF 5 mg/kg and CH-223191 20 mg/kg, i.p.) and of an agonist (TCDD 50 MUg/kg, intragastric) demonstrates that signalling through this receptor is not involved in EtOH consumption behaviour. Ro 61-8048 did not alter plasma acetaldehyde concentration, but prevented EtOH-induced dopamine release in the nucleus accumbens shell. These results point to a critical involvement of the reward circuitry in the reduction of EtOH consumption induced by KYN and KYNA increments. PNU-120596 (3 mg/kg, i.p.), a positive allosteric modulator of alpha7 nicotinic acetylcholine receptors, partially prevented the Ro 61-8048-induced decrease in EtOH consumption. Overall, our results highlight the usefulness of manipulating the KYN pathway as a pharmacological tool for modifying EtOH consumption and point to a possible modulator of alcohol drinking behaviour. PMID- 29705535 TI - Associations of myeloid hematological diseases of the elderly with osteoporosis: A longitudinal analysis of routine health care data. AB - BACKGROUND: Myelodysplastic Syndromes (MDS) and Acute Myeloid Leukemia (AML) are hematological stem cell diseases mainly of the elderly. Studies indicate a close relationship between bone metabolism and hematopoietic stem cells within the osteo-hematopoietic niche. However, it remains unclear how the disturbed interaction within the osteo-hematopoietic niche affects bone homeostasis in MDS and AML patients. METHODS: We utilized data of a large German statutory health insurance of approximately 2 million persons living in the German federal state of Saxony. Applying case definitions based on diagnosis, procedures and prescriptions we identified prevalent and incident cases with MDS, AML and osteoporosis (OSP) in persons aged >=60 years. We applied time-to-event analyses to determine the relationship of MDS and AML with OSP with a specific focus on temporality. RESULTS: Among all individuals aged >=60 years (n = 891,095), 2.62% (n = 23,326), 0.14% (n = 1219) and 0.10% (n = 893) were identified with incident OSP, MDS and AML, respectively. The risk of incident OSP was significantly increased in patients with prevalent MDS (sex and age-adjusted model: HR = 1.87, 95%CI: 1.51-2.23). Conversely, patients with prevalent OSP had an increased risk to be diagnosed with incident MDS in the adjusted model (HR = 1.42, 1.19-1.65). For AML no significant associations were observed (adjusted models: inc. OSP with pre. AML; HR = 1.06, 0.65-1.47; inc. AML with pre. OSP; HR = 0.82, 0.41-1.23). DISCUSSION: Our results could indicate a clinically relevant relationship between MDS and OSP in elderly patients, most likely resulting from a disturbed microenvironment within the osteo-hematopoietic niche. An alternative, non-causal explanation that MDS is caused by the medication prescribed for OSP can be partially ruled out, as the association between the two diseases remains if incident OSP cases are considered in patients with pre-existing MDS. These results need to be confirmed within other prospective studies and may allow then for comprehensive strategies for the prevention, early detection and clinical care of patients with MDS and OSP. PMID- 29705536 TI - High dose daunorubicin: New standard of care for FLT3 ITD mutant AML. PMID- 29705537 TI - Monitoring of clonal evolution of double C-KIT exon 17 mutations by Droplet Digital PCR in patients with core-binding factor acute myeloid leukemia. AB - C-KIT gene mutations result in the constitutive activation of tyrosine kinase activity, and greatly affect the pathogenesis and prognosis of core-binding factor acute myeloid leukemia (CBF-AML). C-KIT mutations are often found as single point mutations. However, the rate of double mutations has recently increased in AML patients. In this study, we detected six cases (18.8%) harboring double C-KIT exon17 mutations in 75 patients with CBF-AML. The clone composition and dynamic evolution were analyzed by sequencing and droplet digital PCR (ddPCR). Results revealed that these double mutations can be occurred in either the same or different clones. Different clones of double mutations may result in different sensitivity to the treatment of CBF-AML. The clones with N822 mutation responded better to treatment as compared to those with D816 mutation. Moreover, D816 clone was readily transformed into a predominant clone at relapse. Meanwhile, the predominant clones in the same patient may change during the progression of disease. The emerging mutation can originate from a small quantity of clones at diagnosis or newly acquired during the course of disease. Furthermore, patients with double mutations had better overall survival (OS) and event-free survival (EFS) than those with single mutation, but the differences did not reach statistical significance (P > 0.05). The ddPCR is an effective method for monitoring clonal evolution in patients with CBF-AML. PMID- 29705538 TI - Peripheral ionotropic glutamate receptors contribute to Fos expression increase in the spinal cord through antidromic electrical stimulation of sensory nerves. AB - Previous studies have shown that peripheral ionotropic glutamate receptors are involved in the increase in sensitivity of a cutaneous branch of spinal dorsal ramus (CBDR) through antidromic electrical stimulation (ADES) of another CBDR in the adjacent segment. CBDR in the thoracic segments run parallel to each other and no synaptic contact at the periphery is reported. The present study investigated whether the increased sensitivity of peripheral sensory nerves via ADES of a CBDR induced Fos expression changes in the adjacent segments of the spinal cord. Fos expression increased in the T8 - T12 segments of the spinal cord evoked by ADES of the T10 CBDR in rats. The increased Fos expression in the T11 and T12, but not T8 - T10 spinal cord segments, was significantly blocked by local application of either N-methyl-D-aspartate (NMDA) receptor antagonist dizocilpine maleate (MK-801) or non-NMDA receptor antagonist 6,7 dinitroquinoxaline-2,3-dione (DNQX) into the receptive field of T11 CBDR. The results suggest that endogenous glutamate released by ADES of sensory nerve may bind to peripheral ionotropic glutamate receptors and activate adjacent sensory nerve endings to increase the sensitivity of the spinal cord. These data reveal the potential mechanisms of neuron activation in the spinal cord evoked by peripheral sensitization. PMID- 29705539 TI - Kir 4.1 inward rectifier potassium channel is upregulated in astrocytes in a murine multiple sclerosis model. AB - Multiple sclerosis (MS) is a high prevalence degenerative disease characterized at the cellular level by glial and neuronal cell death. The causes of cell death during the disease course are not fully understood. In this work we demonstrate that in a MS model induced by Theiler's murine encephalomyelitis virus (TMEV) infection, the inward rectifier (Kir) 4.1 potassium channel subunit is overexpressed in astrocytes. In voltage clamp experiments the inward current density from TMEV-infected astrocytes was significantly larger than in mock infected ones. The cRNA hybridization analysis from mock- and TMEV-infected cells showed an upregulation of a potassium transport channel coding sequence. We validated this mRNA increase by RT-PCR and quantitative PCR using Kir 4.1 specific primers. Western blotting experiments confirmed the upregulation of Kir 4.1, and alignment between sequences provided the demonstration that the over expressed gene encodes for a Kir family member. Flow cytometry showed that the Kir 4.1 protein is located mainly in the cell membrane in mock and TMEV-infected astrocytes. Our results demonstrate an increase in K+ inward current in TMEV infected glial cells, this increment may reduce the neuronal depolarization, contributing to cell resilience mechanisms. PMID- 29705540 TI - Sutureless repair and postoperative residual stenosis: "Never leave with a lesion". PMID- 29705541 TI - Subaortic stenosis by accessory mitral tissue: Failure of embryonic positioning? PMID- 29705542 TI - The fenestrated frozen elephant trunk technique for acute type A aortic dissection. PMID- 29705543 TI - Inspiratory muscle training is associated with decreased postoperative pulmonary complications: Evidence from randomized trials. AB - OBJECTIVE: To determine whether preoperative inspiratory muscle training was associated with a significant difference in the rate of postoperative pulmonary adverse outcomes in patients undergoing cardiothoracic or upper abdominal surgery using trial sequential analysis to correct for the risk of random errors. METHODS: We systematically reviewed the Excerpta Medica database, PubMed, Web of Science, Cumulative Index to Nursing and Allied Health Literature, and Cochrane Central Register of Controlled Trials for randomized controlled trials evaluating inspiratory muscle training before cardiothoracic or upper abdominal surgery. Outcome measures included postoperative pulmonary complications, length of hospital stay, maximum inspiratory pressure, and quality of life. A random effects model was used to estimate relative risks with 95% confidence intervals (CIs). We used trial sequential analysis to calculate a diversity-adjusted required information size for meta-analysis. RESULTS: Thirteen randomized controlled trials were included in the meta-analysis for a total of 784 patients. Compared with the standard care group, the inspiratory muscle training group exhibited significantly decreased postoperative pulmonary complications (risk ratio, 0.59; 95% CI, 0.47-0.74). Trial sequential analysis indicated that the cumulative Z curve crossed both the conventional boundary and the trial sequential monitoring boundary for benefit. The length of hospital stay was reduced in the inspiratory muscle training group (mean difference, -1.15 days; 95% CI, -2.10 to 0.20), and the maximum inspiratory pressure was significantly improved at the end of the preoperative training (mean difference, 13.66; 95% CI, 3.88-23.44). The quality of life outcome was unavailable in most of the studies. CONCLUSIONS: Preoperative inspiratory muscle training resulted in significantly improved maximum inspiratory pressure and was associated with decreased postoperative pulmonary complications. PMID- 29705544 TI - Prophylactic appendectomy in the heart? PMID- 29705545 TI - Course of remission from and relapse to heavy drinking following outpatient treatment of alcohol use disorder. AB - BACKGROUND: We sought to understand alcohol behavior change as a process over time by identifying patterns of relapse and remission after outpatient treatment and evaluating how these patterns predict longer-term clinical outcomes. METHOD: We conducted latent profile analyses using data from the outpatient arm in Project MATCH. Relapse and remission episodes were defined by the number of consecutive 14-day periods that included any heavy drinking days and no heavy drinking days. Indicators of each profile were: initial 2-week post-treatment remission/relapse status, number of remission/relapse transitions in the first year after treatment, duration of remission episodes, and duration of relapse episodes. RESULTS: We identified 6 profiles: 1) "remission," 2) "transition to remission", 3) "few long transitions," 4) "many short transitions," 5) "transition to relapse," and 6) "relapse." Profile 1 had the best long-term outcomes. Long-term outcomes were not uniform among individuals with at least some heavy drinking (profiles 2 through 6; ~75% of the sample). Individuals who transitioned back to and sustained periods of remission (profiles 2-4) had better long-term outcomes than those who failed to transition out of relapse (profiles 5 6) following treatment. CONCLUSIONS: Post-treatment change in alcohol use is a process in which individuals variably transition in and out of "relapse" and "remission" statuses. "Any heavy drinking" following treatment is not necessarily a sign of treatment failure. A more nuanced look at the process of AUD change by considering whether individuals are able to transition to and sustain periods of remission seems warranted. PMID- 29705546 TI - Chronic restraint stress during withdrawal increases vulnerability to drug priming-induced cocaine seeking via a dopamine D1-like receptor-mediated mechanism. AB - BACKGROUND: A major obstacle in the treatment of individuals with cocaine addiction is their high propensity for relapse. Although the clinical scenario of acute stress-induced relapse has been well studied in animal models, few pre clinical studies have investigated the role of chronic stress in relapse or the interaction between chronic stress and other relapse triggers. METHODS: We tested the effect of chronic restraint stress on cocaine seeking in rats using both extinction- and abstinence-based animal relapse models. Rats were trained to press a lever for I.V. cocaine infusions (0.50 mg/kg/infusion) paired with a discrete tone + light cue in daily 3-h sessions. Following self-administration, rats were exposed to a chronic restraint stress procedure (3 h/day) or control procedure (unstressed) during the first seven days of a 13-day extinction period during which lever presses had no programmed consequences. This was followed by cue- and cocaine priming-induced drug seeking tests. In a separate group of rats, cocaine seeking was assessed during forced abstinence both before and after the same chronic stress procedure. RESULTS: A history of chronic restraint stress was associated with increased cocaine priming-induced drug seeking, an effect attenuated by co-administration of SCH-23390 (10.0 MUg/kg; i.p.), a dopamine D1 like receptor antagonist, with daily restraint. Repeated SCH-23390 administration but not stress during extinction increased cue-induced reinstatement. CONCLUSIONS: Exposure to chronic stress during early withdrawal may confer lasting vulnerability to some types of relapse, and dopamine D1-like receptors appear to mediate both chronic stress effects on cocaine seeking and extinction of cocaine seeking. PMID- 29705548 TI - Chemical-by-chemical and cumulative risk assessment of residential indoor exposure to semivolatile organic compounds in France. AB - BACKGROUND: The toxic effects of environmental exposure to chemicals are increasingly being studied and confirmed, notably for semivolatile organic compounds (SVOCs). These are found in many products and housing materials, from which they are emitted to indoor air, settled dust and other surfaces. OBJECTIVES: The objective of this work is to assess the human health risk posed by residential indoor exposure to 32 SVOCs, assessed in previous nationwide studies. METHODS: A chemical-by-chemical risk assessment, using a hazard quotient (HQ) or excess risk (ER) method, was supplemented by a cumulative risk assessment (CRA). For CRA, a hazard index (HI) method, as well as higher tier approaches using relative potency factors (RPFs) or toxic equivalency factors (TEFs) were used for the following endpoints: neurotoxicity, reproductive toxicity, genotoxicity and immunotoxicity. RESULTS: HQs were above 1 for 50% of French children from birth to 2 years for BDE 47, and for 5% of children for lindane and dibutyl phthalate (DBP). Corresponding hazards are reprotoxic for BDE 47 and DBP, and immunotoxic for lindane. The CRA approach provided additional information of reprotoxic risks (HI > 1) that may occur for 95% of children and for 5% of the offspring for pregnant women's exposure. The SVOCs contributing most to these risks were PCB 101 and 118, BDE 47, and DBP. The higher tier CRA approaches showed that exposure to dwellings' SVOC mixtures were of concern for 95% of children for neurotoxic compounds having effects linked with neuronal death. To a lesser extent, effects mediated by the aryl hydrocarbon receptor (AhR) or by a decrease in testosterone levels may concern 5% of children and adults. Lastly, unacceptable immunotoxic risk related to exposure to 8 indoor PCBs was also observed for 5% of children. CONCLUSIONS: In view of uncertainties related to compounds' toxicity for humans, these results justify the implementation of preventive measures, as well as the production of more standardized and comprehensive toxicological data for some compounds. PMID- 29705547 TI - Nociceptin/orphanin FQ receptors modulate the discriminative stimulus effects of oxycodone in C57BL/6 mice. AB - BACKGROUND: Nociceptin/orphanin FQ (NOP) receptor ligands have shown efficacy as putative analgesics and can modulate the abuse-related effects of opioids, suggesting therapeutic applications. The discriminative stimulus effects of a drug are related to their subjective effects, a predictor of abuse potential. To determine whether activation of NOP receptors could alter the subjective effects of an abused opioid analgesic, a novel oxycodone discrimination was established in mice, characterized with positive and negative controls, and its expression evaluated with a NOP receptor agonist. METHODS: Adult male C57BL/6 mice were trained to discriminate 1.3 mg/kg oxycodone from vehicle in a two-lever operant procedure. The discrimination was characterized with naloxone challenge, and generalization tests with the MU-opioid receptor agonists, heroin and morphine, and the kappa-opioid receptor selective agonist, U50488. Subsequently, effects of the NOP agonist Ro64-6198 were evaluated with and without oxycodone. RESULTS: Oxycodone generalization occurred in a dose-dependent manner and was reversed by naloxone pretreatment. Heroin and morphine, but not U50488, substituted for oxycodone. Co-treatment of 1 mg/kg Ro64-6198 with the oxycodone training dose reduced % oxycodone lever responding (%OLR) and restored response rates to vehicle control levels. J-113397, a NOP antagonist, reversed these effects. Co administration of 1 mg/kg Ro64-6198 with a range of oxycodone doses resulted in rightward dose-effect curve shifts in %OLR and response rates compared to oxycodone alone. CONCLUSIONS: These results provide additional evidence that NOP receptor activation can modulate the subjective effects of opioid analgesics and represent the first characterization of oxycodone's discriminative stimulus effects in mice. PMID- 29705549 TI - Memory circuits: CA2. AB - The hippocampus is a central region in the coding of spatial, temporal and episodic memory. Recent discoveries have revealed surprising and complex roles of the small area CA2 in hippocampal function. Lesion studies have revealed that this region is required for social memory formation. Area CA2 is targeted by extra-hippocampal paraventricular inputs that release vasopressin and can act to enhance social memory performance. In vivo recordings have revealed nonconventional activity by neurons in this region that act to both initiate hippocampal sharp-wave ripple events as well as encode spatial information during immobility. Silencing of CA2 pyramidal neurons has revealed that this area also acts to control hippocampal network excitability during encoding, and this balance of excitation and inhibition is disrupted in disease. This review summarizes recent findings and attempts to integrate these results into pre existing models. PMID- 29705550 TI - Neuronal coding mechanisms mediating fear behavior. AB - The behavioral repertoire of an organism can be highly diverse, spanning from social to defensive. How an animal efficiently switches between distinct behaviors is a fundamental question whose inquiry will provide insights into the mechanisms that are necessary for an organism's survival. Previous work aimed at identifying the neural systems responsible for defensive behaviors, such as freezing, has demonstrated critical interactions between the prefrontal cortex and amygdala. Indeed, this foundational research has provided an indispensable anatomical framework that investigators are now using to understand the physiological mechanisms of defined neural circuits within the prefrontal cortex that code for the rapid and flexible expression of defensive behaviors. Here we review recent findings demonstrating temporal and rate coding mechanisms of freezing behavior in the prefrontal cortex. We hypothesize that anatomical features, such as target structure and cortical layer, as well as the nature of the information to be coded, may be critical factors determining the coding scheme. Furthermore, detailed behavioral analyses may reveal subtypes of defensive behaviors that represent the principle factor governing coding selection. PMID- 29705551 TI - An intelligent algorithm for identification of optimum mix of demographic features for trust in medical centers in Iran. AB - Healthcare quality is affected by various factors including trust. Patients' trust to healthcare providers is one of the most important factors for treatment outcomes. The presented study identifies optimum mixture of patient demographic features with respect to trust in three large and busy medical centers in Tehran, Iran. The presented algorithm is composed of adaptive neuro-fuzzy inference system and statistical methods. It is used to deal with data and environmental uncertainty. The required data are collected from three large hospitals using standard questionnaires. The reliability and validity of the collected data is evaluated using Cronbach's Alpha, factor analysis and statistical tests. The results of this study indicate that middle age patients with low level of education and moderate illness severity and young patients with high level of education, moderate illness severity and moderate to weak financial status have the highest trust to the considered medical centers. To the best of our knowledge this the first study that investigates patient demographic features using adaptive neuro-fuzzy inference system in healthcare sector. Second, it is a practical approach for continuous improvement of trust features in medical centers. Third, it deals with the existing uncertainty through the unique neuro fuzzy approach. PMID- 29705552 TI - MuDeRN: Multi-category classification of breast histopathological image using deep residual networks. AB - MOTIVATION: Identifying carcinoma subtype can help to select appropriate treatment options and determining the subtype of benign lesions can be beneficial to estimate the patients' risk of developing cancer in the future. Pathologists' assessment of lesion subtypes is considered as the gold standard, however, sometimes strong disagreements among pathologists for distinction among lesion subtypes have been previously reported in the literature. OBJECTIVE: To propose a framework for classifying hematoxylin-eosin stained breast digital slides either as benign or cancer, and then categorizing cancer and benign cases into four different subtypes each. MATERIALS AND METHODS: We used data from a publicly available database (BreakHis) of 81 patients where each patient had images at four magnification factors (*40, *100, *200, and *400) available, for a total of 7786 images. The proposed framework, called MuDeRN (MUlti-category classification of breast histopathological image using DEep Residual Networks) consisted of two stages. In the first stage, for each magnification factor, a deep residual network (ResNet) with 152 layers has been trained for classifying patches from the images as benign or malignant. In the next stage, the images classified as malignant were subdivided into four cancer subcategories and those categorized as benign were classified into four subtypes. Finally, the diagnosis for each patient was made by combining outputs of ResNets' processed images in different magnification factors using a meta-decision tree. RESULTS: For the malignant/benign classification of images, MuDeRN's first stage achieved correct classification rates (CCR) of 98.52%, 97.90%, 98.33%, and 97.66% in *40, *100, *200, and *400 magnification factors respectively. For eight-class categorization of images based on the output of MuDeRN's both stages, CCRs in four magnification factors were 95.40%, 94.90%, 95.70%, and 94.60%. Finally, for making patient level diagnosis, MuDeRN achieved a CCR of 96.25% for eight-class categorization. CONCLUSIONS: MuDeRN can be helpful in the categorization of breast lesions. PMID- 29705553 TI - Dictionary-based monitoring of premature ventricular contractions: An ultra-low cost point-of-care service. AB - While cardiovascular diseases (CVDs) are prevalent across economic strata, the economically disadvantaged population is disproportionately affected due to the high cost of traditional CVD management, involving consultations, testing and monitoring at medical facilities. Accordingly, developing an ultra-low-cost alternative, affordable even to groups at the bottom of the economic pyramid, has emerged as a societal imperative. Against this backdrop, we propose an inexpensive yet accurate home-based electrocardiogram (ECG) monitoring service. Specifically, we seek to provide point-of-care monitoring of premature ventricular contractions (PVCs), high frequency of which could indicate the onset of potentially fatal arrhythmia. Note that the first-generation telecardiology system acquires the ECG, transmits it to a professional diagnostic center without processing, and nearly achieves the diagnostic accuracy of a bedside setup. In the process, such a system incurs high bandwidth cost and requires the physicians to process the entire record for diagnosis. To reduce cost, current telecardiology systems compress data before transmitting. However, the burden on physicians remains undiminished. In this context, we develop a dictionary-based algorithm that reduces not only the overall bandwidth requirement, but also the physicians workload by localizing anomalous beats. Specifically, we detect anomalous beats with high sensitivity and only those beats are then transmitted. In fact, we further compress those beats using class-specific dictionaries subject to suitable reconstruction/diagnostic fidelity. Finally, using Monte Carlo cross validation on MIT/BIH arrhythmia database, we evaluate the performance of the proposed system. In particular, with a sensitivity target of at most one undetected PVC in one hundred beats, and a percentage root mean squared difference less than 9% (a clinically acceptable level of fidelity), we achieved about 99.15% reduction in bandwidth cost, equivalent to 118-fold savings over first-generation telecardiology. In the process, the professional workload is reduced by at least 85.9% for noncritical cases. Our algorithm also outperforms known algorithms under certain measures in the telecardiological context. PMID- 29705554 TI - Glycoprotein 340 in mucosal immunity and ocular surface. AB - Glycoprotein 340 (Gp340) is an innate immune receptor with well-defined roles in mucosal tissues. It is a normal component of mucosal fluids such as tears, breast milk, and saliva, and it is expressed in tissues such as the vagina, gastrointestinal tract, oral cavity, lung alveoli, and pancreas. In the eye, it is expressed in the lacrimal gland, cornea, conjunctiva, and retina. Investigations of the protein in wet-surfaced epithelia of the body show that the effects of Gp340 can be beneficial or harmful depending on the conformation in which it exists. In a fluid phase, Gp340 appears to be protective against mucosal infection, while in a surface-associated form it appears to promote infection. On the ocular surface, it is dysregulated in dry eye disease and inhibits twitching motility of P. aeruginosa in tears. This review discusses what is known about Gp340 in wet-surfaced mucosal epithelia and highlights the potential roles of the protein in ocular surface immunity, inflammation, and infections. PMID- 29705555 TI - DA-9701 on gastric motility in patients with Parkinson's disease: A randomized controlled trial. AB - INTRODUCTION: To evaluate the effect of DA-9701, a novel prokinetic drug, on gastric motility evaluated by magnetic resonance imaging in patients with Parkinson's disease (PD). METHODS: Forty PD patients were randomly allocated to receive either domperidone or DA-9701. Their gastric functions were evaluated using magnetic resonance imaging before and after 4-week treatment period. Information on levodopa daily dose, disease duration, and Unified PD Rating Scale scores was collected. In 18 patients (domperidone: 9, DA-9701: 9), plasma levodopa concentrations were determined. Primary outcome was assessed by a one sided 95% confidence interval to show non-inferiority of DA-9701 vs. domperidone with a pre-determined non-inferiority margin of -10%. RESULTS: Thirty-eight participants (19 men and 19 women; mean age, 67.1 years) completed the study protocol (domperidone: DA-9701 = 19:19). Gastric emptying rate at 120 min (2-hr GER) was comparable between the 2 groups; it was not correlated with levodopa daily dose or disease duration or Unified PD Rating Scale scores (all p > 0.05). DA-9701 was not inferior to domperidone in changes of 2-hr GERs before and after the treatment (absolute difference, 4.0 %; one-sided 95% confidence interval, - 3.7 to infinity). However, a significant increase in 2-hr GER was observed only in DA-9701 group (54.5% and 61.8%, before and after treatment, respectively, p < 0.05). Plasma levodopa concentration showed an insignificant but increasing trend in DA-9701 group. There were neither adverse reactions nor deteriorations of parkinsonian symptoms observed in the study participants. CONCLUSION: DA-9701 can be used for the patients with PD to enhance gastric motility without aggravating PD symptoms (ClinicalTrials.gov number: NCT03022201). PMID- 29705556 TI - Deep brain stimulation parameters for dystonia: A systematic review. AB - INTRODUCTION: Programming of globus pallidus pars interna (GPi) deep brain stimulation (DBS) systems for dystonia is complex because clinical benefits are often gradual. Some groups have advocated starting DBS with higher electrical parameters, whereas others have suggested the opposite. This variability in programming, even within each dystonia subtype, makes it challenging to compare outcomes and program the generators. To determine how variable DBS for dystonia stimulation parameters are, we performed a systematic literature review. METHODS: A comprehensive systematic literature search for GPi DBS stimulation parameters used in dystonia was performed in PubMed/Medline, Embase and Cochrane databases. RESULTS: Of 813 publications retrieved from individual search engines, 593 were eligible for review and 401 publications were excluded. Data were extracted from 192 publications representing 1505 patients and 2964 electrodes. Stimulation amplitude averaged 3.3 V +/- 0.6 V and frequency 131 Hz +/- 5 Hz. Three different common pulse widths were identified at 112 +/- 31 MUs, 203 +/- 22 MUs, and 446 +/ 8 MUs. CONCLUSIONS: Despite anecdotal reports using low frequencies or pulse widths and variability in DBS stimulation parameters required to treat dystonia, there is consistency in amplitude and frequencies utilized. Some dystonia subtypes may improve with specific pulse widths. This review emphasizes the importance of complete data reporting in the literature and suggests that large prospective controlled blinded studies and international registries are needed to understand and optimize DBS settings for dystonia. PMID- 29705557 TI - Alterations in the metabolic and cardiorespiratory response to exercise in Huntington's Disease. AB - BACKGROUND: Limited data suggests that an altered metabolic and cardiorespiratory exercise response may affect exercise performance in individuals with Huntington's disease (HD). There is no clear exploration of the response in individuals at different stages of the disease or in relation to genetic markers. This study aimed to examine the exercise response and recovery of HD participants, and the relationship to genetic and clinical markers. METHOD: HD gene-positive participants (n = 31; 9 pre-manifest; 22 manifest HD) and a healthy control group (n = 29) performed an incremental exercise test until exhaustion. Performance, cardiorespiratory, metabolic and perceptual responses to exercise were determined from a maximal cycle ergometer test throughout the exercise test and during a recovery period. RESULTS: During sub-maximal exercise, metabolic (lactate levels, oxygen uptake) and cardiorespiratory markers (heart rate) were elevated in HD participants compared to controls. Lactate elevation was specific to pre-manifest HD participants. Work capacity was reduced in both pre-manifest and manifest HD participants with tests terminated with no difference in metabolic, perceptual or cardiorespiratory markers. Submaximal oxygen uptake was correlated with motor score, whilst peak measures were unrelated to genetic or clinical markers. Heart rate recovery was attenuated in pre-manifest and manifest HD participants. CONCLUSIONS: Our findings confirm metabolic and cardiorespiratory deficits reduce exercise performance and affect recovery from an early stage in HD, with submaximal deficits related to phenotypic expression. Exercise capacity appears to be limited by an altered movement economy, thus clinicians should consider an altered exercise response and recovery may affect prescription in HD. PMID- 29705558 TI - Decision-support models for empiric antibiotic selection in Gram-negative bloodstream infections. AB - OBJECTIVES: Early empiric antibiotic therapy in patients can improve clinical outcomes in Gram-negative bacteraemia. However, the widespread prevalence of antibiotic-resistant pathogens compromises our ability to provide adequate therapy while minimizing use of broad antibiotics. We sought to determine whether readily available electronic medical record data could be used to develop predictive models for decision support in Gram-negative bacteraemia. METHODS: We performed a multi-centre cohort study, in Canada and the USA, of hospitalized patients with Gram-negative bloodstream infection from April 2010 to March 2015. We analysed multivariable models for prediction of antibiotic susceptibility at two empiric windows: Gram-stain-guided and pathogen-guided treatment. Decision support models for empiric antibiotic selection were developed based on three clinical decision thresholds of acceptable adequate coverage (80%, 90% and 95%). RESULTS: A total of 1832 patients with Gram-negative bacteraemia were evaluated. Multivariable models showed good discrimination across countries and at both Gram stain-guided (12 models, areas under the curve (AUCs) 0.68-0.89, optimism corrected AUCs 0.63-0.85) and pathogen-guided (12 models, AUCs 0.75-0.98, optimism-corrected AUCs 0.64-0.95) windows. Compared to antibiogram-guided therapy, decision-support models of antibiotic selection incorporating individual patient characteristics and prior culture results have the potential to increase use of narrower-spectrum antibiotics (in up to 78% of patients) while reducing inadequate therapy. CONCLUSIONS: Multivariable models using readily available epidemiologic factors can be used to predict antimicrobial susceptibility in infecting pathogens with reasonable discriminatory ability. Implementation of sequential predictive models for real-time individualized empiric antibiotic decision-making has the potential to both optimize adequate coverage for patients while minimizing overuse of broad-spectrum antibiotics, and therefore requires further prospective evaluation. SUMMARY: Readily available epidemiologic risk factors can be used to predict susceptibility of Gram-negative organisms among patients with bacteraemia, using automated decision-making models. PMID- 29705559 TI - Editor's Choice - Open Thoracic and Thoraco-abdominal Aortic Repair After Prior Endovascular Therapy. AB - OBJECTIVE: The aim was to present current results of open thoracic and thoraco abdominal aortic repair as secondary procedure after prior endovascular therapy. METHODS: This was a retrospective cross border single centre study. From 2006 to July 2017 45 open thoracic aortic (TAA) or thoraco-abdominal aortic aneurysm (TAAA) operations were performed on 44 patients (median age 58 [15-80] years) as secondary surgery after previous endovascular therapy comprising TEVAR (n = 38; 86%), EVAR (n = 3; 7%), fenestrated EVAR (n = 1; 2%) and TEVAR plus EVAR (n = 1; 2%). Eleven patients (25%) had had previous open aortic surgery at the secondary surgery site. Indications for TAA(A) repair were Type I endoleak (n = 10; 23%), post-dissection aneurysm progression due to persisting false lumen perfusion (n = 8; 18%), proximal/distal disease progression (n = 16; 36%), device fracture/dislocation (n = 4; 9%), infection (n = 5; 11%), and initial endograft misplacement (n = 1; 2%). The operations included descending thoracic aortic repair (n = 13, 29%), TAAA Type I (n = 4; 9%), Type II (n = 5; 11%), Type III (n = 13; 29%), Type IV (n = 7; 16%), and Type V repair (n = 3; 7%) with simultaneous arch repair in 18% (n = 8). The median time to secondary surgery was 36 (2-168) months. The median follow up was 39 (3-118) months. RESULTS: In hospital mortality was 20% (n = 9) due to intra-operative aneurysm rupture, pneumonia induced sepsis, hemorrhagic cerebellar infarction, mesenteric ischaemia, broncho esophageal fistula, and multiorgan failure (1/9) as well as haemorrhage (3/9). Estimated survival was 73% at 1 year and 71% overall. The most frequent complications were pneumonia (n = 19; 43%), bleeding requiring revision (n = 11; 25%) and sepsis (n = 14; 32%). Transient dialysis was required in 32% (n = 14), permanent dialysis in 6% (n = 2). Permanent spinal cord deficit (paraparesis) occurred in 6% (n = 2). Estimated freedom from aortic re-intervention was 86%. CONCLUSION: Open TAA(A) repair as a secondary procedure after previous endovascular aortic therapy is an important treatment option even in the endovascular era. It represents a durable treatment that can produce respectable outcomes. Yet the peri-operative morbidity and mortality are relevant and a specialised team and infrastructure are mandatory for these complex procedures. Therefore, centralisation is required. PMID- 29705560 TI - Comparative subtractive proteomics based ranking for antibiotic targets against the dirtiest superbug: Acinetobacter baumannii. AB - Multidrug-resistant Acinetobacter baumannii is indeed to be the most successful nosocomial pathogen responsible for myriad infections in modern health care system. Computational methodologies based on genomics and proteomics proved to be powerful tools for providing substantial information about different aspects of A. baumannii biology that made it possible to design new approaches for treating multi, extensive and total drug resistant isolates of A. baumannii. In this current approach, 35 completely annotated proteomes of A. bauamnnii were filtered through a comprehensive subtractive proteomics pipeline for broad-spectrum drug candidates. In total, 10 proteins (KdsA, KdsB, LpxA, LpxC, LpxD, GpsE, PhoB, UvrY, KdpE and OmpR) could serve as ideal candidates for designing novel antibiotics. The work was extended with KdsA enzyme for structure information, prediction of intrinsic disorders, active site details, and structure based virtual screening of library containing natural product-like scaffolds. Most of the enzyme structure has fixed three-dimensional conformation. The selection of inhibitor for KdsA enzyme was based on druglikeness, pharmacokinetics and docking scores. Compound-4636 (5-((3-chloro-5-methyl-2-phenyl-2,3-dihydro-1H-pyrazol-4 yl)methoxy)-2-(((1-hydroxy-4-methylpentan-2-yl)amino)methyl)phenol) was revealed as the most potent inhibitor against A. baumannii KdsA enzyme having Gold fitness score of 77.68 and Autodock binding energy of -6.2 kcal/mol. The inhibitor completely follows Lipinski rule of five, Ghose rule, and Egan rule. Molecular dynamics simulation for KdsA and KdsA-4636 complex was performed for 100 ns to unveil what conformational changes the enzyme underwent in the absence and presence of the inhibitor, respectively. The average root means square deviation (RMSD) for both systems was found 3.5 A, which signifies stable structure of the enzyme in both bounded and unbounded states. Absolute binding energy using Molecular Mechanics-Generalized Born Surface Area (MM-GBSA) reflected high affinity and vigorous interactions of the inhibitor with enzyme active residues. Findings of the current study could open up new avenues for experimentalists to design new potent antibiotics by targeting the targets screened in this study. PMID- 29705561 TI - Hsp83 regulates the fate of germline stem cells in Drosophila ovary. PMID- 29705562 TI - Body fat mass and distribution as predictors of metabolic outcome and weight loss after Roux-en-Y gastric bypass. AB - BACKGROUND: Bariatric surgery such as Roux-en-Y gastric bypass (RYGB) remains the most effective treatment of obesity and associated co-morbidities. Body fat distribution associates with metabolic function. OBJECTIVE: To investigate if preoperative body fat mass and distribution measured by dual-energy x-ray absorptiometry (DXA) predict weight loss and metabolic outcome after RYGB, and to compare predictive value of DXA with simple anthropometric measures. SETTING: Four Swedish hospitals within the Stockholm area. METHODS: Two hundred fifteen women scheduled for RYGB were included. Evaluations before and 2 years after RYGB included determination of insulin sensitivity by the homeostatic model assessment of insulin resistance, blood pressure, plasma lipids, and anthropometric measures, such as waist-to-hip-ratio and fat percentage estimated by formula. Body fat mass and distribution were determined by DXA. RESULTS: Follow-up rate was 77.2% (n = 166). All clinical, anthropometric, and DXA measures were improved/reduced postsurgery (all P<.0001). Android/gynoid fat mass ratio and waist-to-hip-ratio predicted improved homeostatic model assessment of insulin resistance (P = .0028 and .0014), independently of body mass index and age. Body fat percentage, measured by DXA or estimated by formula, predicted percent weight loss (P<.0001 and .0083). Body mass index predicted percent weight loss and percent excess body mass index lost (P = .0022 and<.0001). DXA and anthropometric measures performed equally as predictors, except for DXA measured fat percentage that was slightly better than formula estimated. CONCLUSION: DXA provided predictive values similar to those by basic anthropometric measures, suggesting a limited additional value of preoperative DXA to predict metabolic improvement and weight loss after RYGB in women. PMID- 29705563 TI - Pseudokidney sign showing retrograde Intussusception status post gastric bypass. PMID- 29705564 TI - Management of malabsorptive bariatric surgery after cancer surgery for malignancies of the digestive apparatus. AB - BACKGROUND: Data regarding management of former bariatric operations after onset of a malignancy are still lacking and there is no consensus whether bariatric surgery negatively influences the oncologic management of patients. OBJECTIVES: To investigate the strategy by which patients previously submitted to bariatric surgery were managed after diagnosis of malignancy of the digestive apparatus, whether a revision was performed or not, to assess the incidence of nutritional complications, and the effect of revision versus no revision of bariatric surgery on the outcome of cancer treatment. SETTING: University Hospital, Italy. METHODS: Occurrence of a malignancy of the digestive apparatus in patients submitted to biliopancreatic diversion was investigated retrospectively. Patients' data were collected preoperatively, at 2 and 3 years after the operation, at oncologic diagnosis, and at the longest available postoncologic follow-up. RESULTS: From May 1976 to January 2017, 3341 morbidly obese patients were submitted to biliopancreatic diversion. Sixteen patients were diagnosed with a malignancy involving the digestive apparatus 5 to 28 years after bariatric surgery. Of 10 patients diagnosed with colorectal cancer, 6 were revised. At 2 years after biliopancreatic diversion, body mass index, hemoglobin, and iron levels were significantly lower than preoperatively. Serum transferrin and total protein were unchanged. There was no difference between body mass index, hemoglobin, transferrin, and total protein levels at 2 years and at oncologic diagnosis, or between revised and unrevised patients. CONCLUSION: Revision of a preexisting bariatric operation after digestive cancer surgery is common, although selected, unrevised cases do not seem to be associated with worse outcome. PMID- 29705565 TI - Role of endocytotic uptake routes in impacting the ROS-related toxicity of silver nanoparticles to Mytilus galloprovincialis: A redox proteomic investigation. AB - Oxidative stress is often implicated in nanoparticle toxicity. Several studies have highlighted the role of internalization routes in determining nanotoxicity. Here, we investigate how two endocytotic mechanisms (clathrin- and caveolae mediated) impact on redox balance in gill and digestive gland of the mussel, Mytilus galloprovincialis. Animals were exposed (for 3, 6 and 12 h) to two sizes of silver nanoparticles (AgNP: <50 nm and <100 nm) prior to and after blockade of two endocytic pathways (amantadine blocks clathrin-mediated endocytosis while nystatin blocks caveolae-mediated endocytosis). Redox-proteomic tools were used to determine effects. Our results demonstrate the ability of both sizes of AgNP (<50 and <100 nm) to cause protein thiol oxidation and/or protein carbonylation. However, blockade of endocytotic routes mitigated AgNP toxicity. Differential ROS related toxicity of AgNP to mussel tissues seemed to be linked to tissue-specific mode of action requirements. Cell uptake mechanism strongly influences toxicity of AgNPs in this filter-feeder. PMID- 29705566 TI - Vinorelbine-Cyclophosphamide compared to cyclophosphamide in peripheral blood stem cell mobilization for multiple myeloma. AB - BACKGROUND: High dose Cyclophosphamide (Cy) and Vinorelbine Cyclophosphamide (Vino-Cy) are stem cell (SC) mobilisation options for patients with multiple myeloma (MM). We present a comparison of mobilisation outcomes using these regimens. PATIENTS AND METHODS: Vino-Cy patients received Vinorelbine 25 mg/m2 on day 1, cyclophosphamide 1500 mg/m2 on day 2, and pegylated GCSF on day 4 or GCSF 10 mcg/kg/day from day 4 onwards. Cy patients were given cyclophosphamide 4000 mg/m2 on day 1 and GCSF10 mcg/kg/day from day 5 onwards. The target CD34 + SC collection was 5 * 106 per kg/BW. RESULTS: 149 patients were included. SC collection was lower in the Vino-Cy group (8.20 * 106/Kg BW) compared to the Cy group (11.43 * 106/Kg BW), with adjusted geometric mean ratio of 0.59 (95% CI 0.41 to 0.86, p = 0.006). Time taken to achieve an adequate PB SC count was shorter for Vino-Cy (9 +/- 1 day compared to 12 +/- 2 days for Cy, adjusted absolute mean difference -3.95, 95% CI -4.85 to -3.06, P < .001). Mobilisation related toxicities (in particular, neutropaenic fever) were greater for Cy. CONCLUSION: Vino-Cy is a potential alternative to Cy given the need for effective mobilisation protocols with acceptable toxicity. PMID- 29705567 TI - Intravenous compared to oral busulfan with cyclophosphamide for autologous hematopoietic cell transplant conditioning for plasma cell myeloma. PMID- 29705568 TI - Postharvest responses of sweet cherry fruit and stem tissues revealed by metabolomic profiling. AB - Sweet cherry, a non-climacteric and highly perishable fruit, is usually cold stored during post-harvest period to prevent senescence; therefore, metabolic profiling in response to cold storage in sweet cherry is of economic and scientific interest. In the present work, metabolic analysis was performed in fruit and stem tissues to determine the metabolic dynamics associated with cold storage in response to 1-methylcyclopropene (1-MCP), an ethylene-action inhibitor, and modified atmosphere packaging (MAP). Fruit (cv. Regina) following harvest were treated with 1-MCP and then cold-stored (0 degrees C, relative humidity 95%) for 1 month in the presence or in the absence of MAP and subsequently maintained at 20 degrees C for up to 2 days. Physiological analysis suggested that cold storage stimulated anthocyanin production, respiration rate and stem browning. Cherry stem exposed to 1-MCP displayed senescence symptoms as demonstrated by the higher stem browning and the lower stem traction force while MAP treatment considerably altered these features. The metabolic profile of fruits and stems just following cold storage was distinctly different from those analyzed at harvest. Marked tissue-specific differences were also detected among sweet cherries exposed to individual and to combined 1-MCP and MAP treatments, notably for amino acid biosynthesis. The significance of some of these metabolites as cold storage hallmarks is discussed in the context of the limited knowledge on the 1-MCP and MAP response mechanisms at the level of cherry fruit and stem tissues. Overall, this study provides the first steps toward understanding tissue-specific postharvest behavior in sweet cherry under various conditions. PMID- 29705569 TI - Effects of nitrogen combined with zinc application on glutamate, glutamine, aspartate and asparagine accumulation in two winter wheat cultivars. AB - Zinc (Zn) deficiency remarkably depresses the protein concentration in the grain of winter wheat. Cultivar 'Pingan 8' showed lower Zn concentrations in the grain than did cultivar 'Yangao 006' after nitrogen (N) combined with Zn application. However, little is known about how amino acids are influenced by Zn combined with N application or about the differences in amino acid accumulation between the two winter wheat cultivars. A pot experiment was conducted to characterize amino acid accumulation in the low Zn-accumulating cultivar 'Pingan 8' and the high Zn accumulating cultivar 'Yangao 006' at various growth stages (seedling, jointing, grain filling and maturity) as influenced by N and Zn supply. The N (N0.2) combined with Zn (Zn10) application significantly increased grain yields and the concentrations of N, Zn and crude protein in the grain of both wheat cultivars. N combined with Zn application significantly increased the concentrations of glutamate (Glu) and asparagine (Asn) but decreased the concentrations of glutamine (Gln) and aspartate (Asp) in cultivar 'Yangao 006'; the N combined with Zn application decreased the concentrations of Glu and Gln but increased the concentrations of Asp and Asn in cultivar 'Pingan 8' at the jointing, grain filling and mature stages. Correlation analysis results showed that there were significant relationships between grain yields, spike number, grain number and Zn, N, crude protein, Glu, Gln, Asp and Asn concentrations in the shoots and grain of winter wheat at different growth stages. These results demonstrate that N combined with Zn application enhanced protein synthesis by altering amino acid accumulation in both winter wheat cultivars. Cultivar 'Pingan 8' had lower Gln, Asp and Asn concentrations and higher Glu concentrations than did cultivar 'Yangao 006' after the N0.05 treatment but had higher Glu, Gln, Asp, and Asn concentrations and lower Glu concentrations than did cultivar 'Yangao 006' after the N0.2 treatment. These results revealed that the difference in amino acid concentrations between the two cultivars was related to the N application level. PMID- 29705570 TI - Three members of Medicago truncatula ST family (MtST4, MtST5 and MtST6) are specifically induced by hormones involved in biotic interactions. AB - In this work, we study the function of the Medicago truncatula ST4, ST5 and ST6 proteins that belong to a protein family of unknown function characterized by the DUF2775 domain. Thus, we analyse their promoter sequence and activity, their transcript accumulation, and their subcellular location. The analysis of the three promoters showed different combination of cis-acting regulatory elements and they presented different activity pattern. Throughout development only ST6 mRNAs have been detected in most of the stages analysed, while ST4 was faintly detected in the roots and in the flowers and ST5 was always absent. The addition of MeJA, ET and SA revealed specific responses of the STs, the ST4 transcript accumulation increased by MeJA; the ST5 by MeJA and ET when applied together; and the ST6 by ET and by SA. Finally, the ST4 and ST5 proteins were in the cell wall whereas the ST6 had a dual location. From these results, we can conclude that the ST4, ST5 and ST6 RNAs are specifically and differentially up-regulated by MeJA, ET and SA, plant regulators also involved in the plant defence, pointing that ST4, ST5 and ST6 proteins might be involved in specific biotic interactions through different signalling pathways. PMID- 29705571 TI - Association of a cholesteryl ester transfer protein variant (rs1800777) with fat mass, HDL cholesterol levels, and metabolic syndrome. AB - BACKGROUND: There is little evidence of the association between CETP SNPs and obesity and/or related metabolic parameters. OBJECTIVE: To analyze the association of the polymorphism rs1800777 of the CETP gene with anthropometric parameters, lipid profile, metabolic syndrome and its components, and adipokine levels in obese subjects without type 2 diabetes mellitus or hypertension. DESIGN: A population of 1005 obese subjects was analyzed. Electrical bioimpedance was performed, and blood pressure, presence of metabolic syndrome, dietary intake, physical activity, and biochemical tests were recorded. RESULTS: Nine hundred and sixty eight patients (96.3%) had the GG genotype, 37 patients the GA genotype (3.7%) (no AA genotype was detected). Fat mass (delta: 4.4+/-1.1kg; p=0.04), waist circumference (delta: 5.6+/-2.1cm; p=0.02), and waist to hip ratio (delta: 0.04+/-0.01cm; p=0.01) were higher in A allele carriers than in non-A allele carriers. HDL cholesterol levels were lower in A allele carriers than in non-A allele carriers (delta: 4.2+/-1.0mg/dL; p=0.04). In the logistic regression analysis, the GA genotype was associated to an increased risk of central obesity (OR 7.55, 95% CI 1.10-55.70, p=0.02) and low HDL cholesterol levels (OR 2.46, 95% CI 1.23-4.91, p=0.014). CONCLUSION: The CETP variant at position +82 is associated to lower HDL cholesterol levels, increased fat mass, and central obesity in obese subjects. These results may suggest a potential role of this variant gene in pathophysiology of adipose tissue. PMID- 29705572 TI - Maternal oxytocin predicts relationship survival during the perinatal transition period: Preliminary evidence. AB - It is well-known that the neuropeptide oxytocin plays a critical role regulating the formation of adult-adult pairbonds in non-human animals, and recent work suggests oxytocin may similarly play an important role in romantic bonding in humans. Specifically, endogenous oxytocin is predictive of a host of relationship enhancing behaviors, relationship quality, and even relationship survival amongst newly dating couples. This work suggests that oxytocin can buffer romantic relationships, possibly during especially difficult transition periods. One challenge that many couples face is the birth of a child: a joyous event, but one that is recognized as a major life stressor nonetheless. We aimed to investigate whether maternal oxytocin buffers the parent-partner relationship during the perinatal transition period. To test this, we analyzed data from a longitudinal study of child-bearing women (N = 269) in which endogenous oxytocin was measured in blood plasma during the 1st and 3rd trimesters and at 7-9 weeks postpartum; relationship status was assessed at the outset and 2.5 years postpartum. As predicted, lower maternal oxytocin was associated with greater risk for relationship dissolution by the time the child was a toddler (p < .05). These findings directly replicate research showing that endogenous oxytocin predicts relationship survival in dating couples, but in a novel interpersonal context. That said, only a very small number (N = 7) of couples separated; this, of course, is unsurprising given that the perinatal transition period is not a time when couples typically choose to terminate their relationship. Nonetheless, these findings must be considered preliminary until replicated in future research. PMID- 29705573 TI - The long-term outcomes of sport-related concussion in pediatric populations. AB - Although the field of concussion research is rapidly growing, the majority of research has focused on injured adults, with children being an often-neglected population. Traumatic brain injury is a leading cause of death and disability in children, with over 1.5 million cases being treated in North America annually. Approximately 75% of these injuries are classified as a concussion. Further, children are disproportionately affected by sports-related injuries, with 65% of all pediatric concussions occurring during sport and recreation. Therefore, understanding the outcomes of pediatric sportrelated concussion is of great importance, particularly given the vulnerability of the developing brain. The purpose of this review is to provide an up-to-date understanding of the outcomes of pediatric sport-related concussion from a data-driven perspective, focusing heavily on experimental studies. PMID- 29705574 TI - Automatic recognition of holistic functional brain networks using iteratively optimized convolutional neural networks (IO-CNN) with weak label initialization. AB - fMRI data decomposition techniques have advanced significantly from shallow models such as Independent Component Analysis (ICA) and Sparse Coding and Dictionary Learning (SCDL) to deep learning models such Deep Belief Networks (DBN) and Convolutional Autoencoder (DCAE). However, interpretations of those decomposed networks are still open questions due to the lack of functional brain atlases, no correspondence across decomposed or reconstructed networks across different subjects, and significant individual variabilities. Recent studies showed that deep learning, especially deep convolutional neural networks (CNN), has extraordinary ability of accommodating spatial object patterns, e.g., our recent works using 3D CNN for fMRI-derived network classifications achieved high accuracy with a remarkable tolerance for mistakenly labelled training brain networks. However, the training data preparation is one of the biggest obstacles in these supervised deep learning models for functional brain network map recognitions, since manual labelling requires tedious and time-consuming labours which will sometimes even introduce label mistakes. Especially for mapping functional networks in large scale datasets such as hundreds of thousands of brain networks used in this paper, the manual labelling method will become almost infeasible. In response, in this work, we tackled both the network recognition and training data labelling tasks by proposing a new iteratively optimized deep learning CNN (IO-CNN) framework with an automatic weak label initialization, which enables the functional brain networks recognition task to a fully automatic large-scale classification procedure. Our extensive experiments based on ABIDE-II 1099 brains' fMRI data showed the great promise of our IO-CNN framework. PMID- 29705575 TI - Putting a finger on the problem: Finger stick blood draw and immunization at the well-child exam elicit a cortisol response to stress among one-year-old children. AB - Research examining stress reactivity of the hypothalamic-pituitary-adrenocortical (HPA) axis in young children has historically been hampered by a lack of reliable methods to invoke a cortisol stress response. This report details an effective method of eliciting a cortisol rise in one-year-old children (N = 83) by modifying and combining two naturalistic stressors previously used with infants and children. Salivary cortisol levels were collected from children before and after a finger stick blood draw and immunizations performed during their one year well-child checkup at their pediatrician's office. Results indicated that the stressor was successful at eliciting a significant cortisol response. An extensive set of potential demographic and clinical confounds were also assessed in order to identify methodological considerations important in studies of infant cortisol. The stress paradigm presented here provides a promising alternative for studies of infant HPA activity to enable investigators to more effectively evaluate early functioning of the biological stress system during this developmentally important life stage. PMID- 29705576 TI - Estradiol moderates the relationship between state-trait anxiety and attentional bias to threat in women. AB - Anxiety disorders are characterized by impaired fear extinction and heightened attentional allocation to threatening stimuli. The sex hormones estradiol and progesterone modulate fear extinction in female rats and women; whether these hormones are similarly related to attentional biases to threat has not been examined. In the present study 74 women (53 cycling, 21 using hormonal contraception), and a comparison group of 30 men, completed standard assessments of state-trait anxiety, as well symptoms of depression, anxiety and stress, followed by a computerized assessment of attentional bias, the dot-probe task. Women's endogenous estradiol and progesterone levels were ascertained by a blood sample. No differences in attentional bias were found dependent on sex or hormonal contraceptive use. Estradiol was the only variable measured that was independently positively correlated with attentional bias to threat. Regression analyses revealed a bi-directional relationship between state-trait anxiety, symptoms of anxiety and stress, and attentional bias that was moderated by estradiol, such that a positive relationship was observed amongst women with higher estradiol, and a negative relationship was observed amongst women with lower estradiol. Together, these results indicate that under conditions of anxiety and stress, women may attend to threat differently depending on endogenous estradiol levels, being avoidant when estradiol is lower, and vigilant when estradiol is higher. A more nuanced understanding of the role for attention in anxiety disorders amongst women may be developed by taking hormonal status into consideration. PMID- 29705577 TI - The role of mating context and fecundability in women's preferences for men's facial masculinity and beardedness. AB - The ovulatory shift hypothesis proposes that women's preferences for masculine physical and behavioral traits are greater at the peri-ovulatory period than at other points of the menstrual cycle. However, many previous studies used self reported menstrual cycle data to estimate fecundability rather than confirming the peri-ovulatory phase hormonally. Here we report two studies and three analyses revisiting the ovulatory shift hypothesis with respect to both facial masculinity and beardedness. In Study 1, a large sample of female participants (N = 2,161) self-reported their cycle phase and provided ratings for faces varying in beardedness (clean-shaven, light stubble, heavy stubble, full beards) and masculinity (-50%, -25%, natural, +25% and +50%) in a between-subjects design. In Study 2, 68 women provided the same ratings data, in a within-subjects design in which fertility was confirmed via luteinising hormone (LH) tests and analysed categorically. In Study 2, we also measured salivary estradiol (E) and progesterone (P) at the low and high fertility phases of the menstrual cycle among 36 of these women and tested whether shifts in E, P or E:P ratios predicted face preferences. Preferences for facial masculinity and beardedness did not vary as predicted with fecundability in Study 1, or with respect to fertility as confirmed via LH in Study 2. However, consistent with the ovulatory shift hypothesis, increasing E (associated with cyclical increases in fecundability) predicted increases in preferences for relatively more masculine faces; while high P (associated with cyclical decreases in fecundability) predicted increases in preferences for relatively more feminine faces. We also found an interaction between E and preferences for facial masculinity and beardedness, such that stubble was more attractive on un-manipulated than more masculine faces among women with high E. We consider discrepancies between our findings and those of other recent studies and suggest that closer scrutiny of the stimuli used to measure masculinity preferences across studies may help account for the many conflicting findings that have recently appeared regarding cycle phase preference shifts for facial masculinity. PMID- 29705578 TI - Frequent Penile Erection in a Boy With Autism-spectrum Disorder: Case Report. AB - Risperidone is commonly prescribed by pediatricians for a variety of behavioral and psychological disorders. We report a boy with autism-spectrum disorder, who developed frequent penile erections after an increase in risperidone dosage for a month. The patient fully recovered 2 days after risperidone discontinuation. This report concerns the youngest case of psychotropic medication-induced sexual disorders, which illustrates the differences in presentation between children and adults. Moreover, this case can serve as evidence that discontinuation should be recommended for the management of drug-induced sexual disorders. PMID- 29705579 TI - Melarsoprol Resistance in African Trypanosomiasis. AB - Arsenicals were introduced as monotherapies for the treatment of human African trypanosomiasis, or sleeping sickness, over 100 years ago. Toxicity has always been an issue but these drugs have proven to be both effective and quite durable. Unfortunately, melarsoprol-resistant parasites emerged as early as the 1970s and were widespread by the late 1990s. Resistance was due to mutations affecting an aquaglyceroporin (AQP2), a parasite solute and drug transporter. This is the only example of widespread drug resistance in trypanosomiasis patients for which the genetic basis is known. This link between melarsoprol and AQP2 illustrates how a drug transporter can improve drug selectivity but, at the same time, highlights the risk of resistance when the drug uptake mechanism is dispensable for parasite viability and virulence. PMID- 29705580 TI - Impaired function of cerebral parenchymal arterioles in experimental preeclampsia. AB - Preeclampsia (PE), a dangerous hypertensive complication of pregnancy, is associated with widespread maternal vascular dysfunction. However, the effect of PE on the cerebral vasculature that can lead to stroke and cognitive decline is not well understood. We hypothesized that function of cortical parenchymal arterioles (PAs) would be impaired during PE. Using a high cholesterol diet to induce experimental PE in rats (ePE), we studied the function and structure of isolated and pressurized PAs supplying frontoparietal white matter (WM) tracts and cortex and compared to normal pregnant (Preg) and nonpregnant (Nonpreg) Sprague Dawley rats (n = 8/group). Myogenic reactivity and tone were similar between groups; however, constriction to intermediate-conductance calcium activated potassium (IK) channel inhibition was diminished and dilation to inward rectifying K+ (KIR) channel activation was impaired in PAs from ePE rats, suggesting altered ion channel function. Conducted vasodilation was significantly delayed in response to 12 mM KCl, but not 10 MUM adenosine, in PAs from ePE rats versus Preg and Nonpreg rats (940 +/- 300 ms vs. 70 +/- 50 ms and 370 +/- 90 ms; p < 0.05). Overall, dysfunction of PAs supplying frontoparietal WM and gray matter was present in ePE. If persistent these changes could potentiate neuronal injury that over time could contribute to WM lesions and early-onset cognitive decline. PMID- 29705581 TI - Idleness versus busyness. AB - The elapse of time disregards the human will. Yet different uses of time result in distinct perceptions of time and psychological consequences. In this article, we synthesize the growing research in psychology on the actual and perceived consumption of time, with a focus on idleness and busyness. We propose that the desire to avoid an unproductive use of time and the ceaseless pursuit of meaning in life may underlie many human activities. In particular, while it has been long presumed that people engage in activities in order to pursue goals, we posit a reverse causality: people pursue goals in order to engage in activities. PMID- 29705582 TI - Resolving evolutionary changes in parasite life cycle complexity: Molecular phylogeny of the trematode genus Alloglossidium indicates more than one origin of precociousness. AB - The evolutionary causes and consequences of changes in complex life cycles are of central importance in parasitology. However, data remain limited because in part, knowledge on phylogenetic relationships among species that differ in life cycle patterns remains scarce. We present a molecular phylogeny of the trematode genus Alloglossidium, which contains several species that display precocious (a.k.a., progenetic) life cycles (i.e., maturation in what is typically regarded as an intermediate host). The molecular phylogeny contrasts with previous morphological and life-history based phylogenetic hypotheses. In particular, a precocious life cycle wherein leeches are used as final hosts evolved early in the history of the genus. Among the remaining species, which are a separate clade, a three-host life cycle using ictalurid catfishes is ancestral. Furthermore, there are at least two additional independent evolutionary events that lead to a precocious life cycle where a catfish host is lost and a crustacean is used as a final host. We conclude with a discussion on how existing hypotheses on the evolution of precociousness, and parasite life cycle complexity in general, may or may not relate to the patterns observed in genus Alloglossidium. PMID- 29705583 TI - The international development of forensic science standards - A review. AB - Standards establish specifications and procedures designed to ensure products, services and systems are safe, reliable and consistently perform as intended. Standards can be used in the accreditation of forensic laboratories or facilities and in the certification of products and services. In recent years there have been various international activities aiming at developing forensic science standards and guidelines. The most significant initiative currently underway within the global forensic community is the development of International Organization for Standardization (ISO) standards. This paper reviews the main bodies working on standards for forensic science, the processes used and the implications for accreditation. This paper specifically discusses the work of ISO Technical Committee TC272, the future TC272 work program for the development of forensic science standards and associated timelines. Also discussed, are the lessons learnt to date in navigating the complex environment of multi-country stakeholder deliberations in standards development. PMID- 29705584 TI - Time since intercourse (TSI) data from a large-scale casework study of penile vaginal penetration allegations using Sperm ElutionTM. AB - Time since intercourse (TSI) expectations are dependent on the method used to recover spermatozoa from vaginal swabs. TSI data following Sperm ElutionTM is presented from a large scale study of 2269 cases of penile-vaginal penetration sexual assault allegations analysed by Cellmark Forensic Services and is compared to published TSI data generated using two different water-based elution methods Sperm Elution recovered spermatozoa in 32% of cases analysed where the alleged offence had occurred 3-4 days previously, significantly above the level detected using other elution methods. The improvements afforded by Sperm Elution in the ability to generate clearly distinguishable male DNA profiles from samples containing low levels of spermatozoa, and the recovery of further spermatozoa from swabs previously subjected to water-based elution methods are also discussed. PMID- 29705585 TI - Estimating the uncertainty from sampling in pollution crime investigation: The importance of metrology in the forensic interpretation of environmental data. AB - The forensic interpretation of environmental analytical data is usually challenging due to the high geospatial variability of these data. The measurements' uncertainty includes contributions from the sampling and from the sample handling and preparation processes. These contributions are often disregarded in analytical techniques results' quality assurance. A pollution crime investigation case was used to carry out a methodology able to address these uncertainties in two different environmental compartments, freshwater sediments and landfill leachate. The methodology used to estimate the uncertainty was the duplicate method (that replicates predefined steps of the measurement procedure in order to assess its precision) and the parameters used to investigate the pollution were metals (Cr, Cu, Ni, and Zn) in the leachate, the suspect source, and in the sediment, the possible sink. The metal analysis results were compared to statutory limits and it was demonstrated that Cr and Ni concentrations in sediment samples exceeded the threshold levels at all sites downstream the pollution sources, considering the expanded uncertainty U of the measurements and a probability of contamination >0.975, at most sites. Cu and Zn concentrations were above the statutory limits at two sites, but the classification was inconclusive considering the uncertainties of the measurements. Metal analyses in leachate revealed that Cr concentrations were above the statutory limits with a probability of contamination >0.975 in all leachate ponds while the Cu, Ni and Zn probability of contamination was below 0.025. The results demonstrated that the estimation of the sampling uncertainty, which was the dominant component of the combined uncertainty, is required for a comprehensive interpretation of the environmental analyses results, particularly in forensic cases. PMID- 29705586 TI - Micro-segmental hair analysis for proving drug-facilitated crimes: Evidence that a victim ingested a sleeping aid, diphenhydramine, on a specific day. AB - Sleeping aids are often abused in the commission of drug-facilitated crimes. Generally, there is little evidence that a victim ingested a spiked drink unknowingly because the unconscious victim cannot report the situation to the police immediately after the crime occurred. Although conventional segmental hair analysis can estimate the number of months since a targeted drug was ingested, this analysis cannot determine the specific day of ingestion. We recently developed a method of micro-segmental hair analysis using internal temporal markers (ITMs) to estimate the day of drug ingestion. This method was based on volunteer ingestion of ITMs to determine a timescale within individual hair strands, by segmenting a single hair strand at 0.4-mm intervals, corresponding to daily hair growth. This study assessed the ability of this method to estimate the day of ingestion of an over-the-counter sleeping aid, diphenhydramine, which can be easily abused. To model ingestion of a diphenhydramine-spiked drink unknowingly, each subject ingested a dose of diphenhydramine, followed by ingestion of two doses of the ITM, chlorpheniramine, 14days apart. Several hair strands were collected from each subject's scalp several weeks after the second ITM ingestion. Diphenhydramine and ITM were detected at specific regions within individual hair strands. The day of diphenhydramine ingestion was estimated from the distances between the regions and the days of ITM ingestion. The error between estimated and actual ingestion day ranged from -0.1 to 1.9days regardless of subjects and hair collection times. The total time required for micro segmental analysis of 96 hair segments (hair length: 3.84cm) was approximately 2days and the cost was almost the same as in general drug analysis. This procedure may be applicable to the investigation of crimes facilitated by various drugs. PMID- 29705587 TI - Probability intervals of speed estimations from video images: The Markov Chain Monte Carlo approach. AB - Closed Circuit TV (CCTV) systems often record vehicle motion prior to incidents. From the footage an estimate of the average speed of the vehicle between two frames can be calculated. In a forensic investigation not only an estimate of the average speed is needed but also an estimation of the measurement error. In earlier papers an approach was explained how to estimate the average speed and the corresponding uncertainty in terms of a confidence interval. In practice confidence intervals are often wrongly interpreted as being probability intervals. In this paper we show how to use the Markov Chain Monte Carlo approach to derive probability intervals instead of confidence intervals. We show the robustness of the Markov Chain Monte Carlo approach and the numerical differences between both approaches. In casework the difference between confidence intervals and probability intervals turns out to be very limited. As a consequence the impact of confusion between confidence and probability intervals can also be expected to be limited. PMID- 29705588 TI - Pitx2 and nodal as conserved early markers of the anterior-posterior axis in the rabbit embryo. AB - Attaining molecular and morphological axial polarity during gastrulation is a fundamental early requirement for normal development of the embryo. In mammals, the first morphological sign of the anterior-posterior axis appears anteriorly in the form of the anterior marginal crescent (or anterior visceral endoderm) while in the avian the first such sign is the Koller's sickle at the posterior pole of the embryonic disc. Despite this inverse mode of axis formation many genes and molecular pathways involved in various steps of this process seem to be evolutionarily conserved amongst amniotes, the nodal gene being a well-known example with its functional involvement prior and during gastrulation. The pitx2 gene, however, is a new candidate described in the chick as an early marker for anterior-posterior polarity and as a regulator of axis formation including twinning. To find out whether pitx2 has retained its inductive and early marker function during the evolution of mammals this study analyses pitx2 and nodal expression at parallel stages during formation of the anterior-posterior polarity in the early rabbit embryo using whole-mount in situ hybridization and serial light-microscopical sections. At a late pre-gastrulation stage a localized reduction of nodal expression presages the position of the anterior pole of the embryonic disc and thus serves as the earliest molecular marker of anterior posterior polarity known so far. Pitx2 is expressed in a polarized manner in the anterior marginal crescent and in the posterior half of the embryonic disc during further development. In the anterior segment of the posterior pitx2 expression domain, the anterior streak domain (ASD) is defined by nodal expression as a hypothetical progenitor region of the anterior half of the primitive streak. The expression patterns of both genes thus serve as signs of a conserved involvement in early axis formation in amniotes and, possibly, in twinning in mammals as well. PMID- 29705589 TI - Prevalence and correlates of neurological soft signs in healthy controls without family history of any mental disorder: A neurodevelopmental variation rather than a specific risk factor? AB - OBJECTIVE: Neurological soft signs (NSS) are a group of minor non-localizable neurological abnormalities found more often in patients with schizophrenia and other mental disorders. The aim of the current study was to investigate their prevalence and correlates in healthy controls without family history of any mental disorder. MATERIAL AND METHODS: The study sample included 122 normal subjects (66 males and 56 females; aged 32.89 +/- 9.91 years old). The assessment included the Neurological Evaluation Scale (NES), and a number of scales assessing the subthreshold symptoms (MADRS, STAI) and functioning (GAF). Data on a number of socio-demographic variables were also gathered. The statistical analysis included the development of basic statistics tables and the calculation of Pearson correlation coefficients. RESULTS: The results of the current study suggest that more than half of the study sample manifested at least one NSS and approximately 5% more than four. Still, the reported prevalence and NES scores are lower form those reported in the literature probably because of the carefully selected study sample. There were no significant correlations between NSS and any socio-demographic or clinical variable. DISCUSSION: The current study is the first to study NSS in subjects without family history of any mental disorder and reports the presence of frequent silent neurodevelopmental events in the general population, probably in the form of a neurodevelopmental variation and possibly a weak generic rather than specific risk factor. PMID- 29705590 TI - People who inject drugs and HIV crisis in Pence's Indiana: A media analysis using two policymaking theories. AB - BACKGROUND: In 2015, Scott County, Indiana was the center of an HIV outbreak related to injection drug use. Critiques of the government response exist; however, none examine the response through policymaking theories. This paper examines policy changes affecting people who use drugs (PWID) in Indiana through two theories: the social construction of target populations and punctuated equilibrium. METHODS: A media analysis was performed to examine the prevailing image of PWID in Indiana ten years prior to the outbreak and two years after the crisis emerged. Article tone was assessed to examine the social construction of PWID, and how this construction related to incremental, then punctuated policy making. RESULTS: A total of 372 news articles were examined. Media tone towards PWID was significantly more negative in the 10 years before the outbreak. Most articles regarding PWID pre-outbreak were crime-related, while during crisis, articles types varied and reframed PWID. CONCLUSION: News article tone changed significantly, allowing new approaches to health related to PWID to be considered. This paper demonstrates the utility of these policy frameworks and analysis of target populations through media depictions. Implications for public health practitioners are discussed. PMID- 29705591 TI - Post-transcriptional control of virulence gene expression in Staphylococcus aureus. AB - Opportunistic pathogens have to be ready to change life-style whenever the occasion arises, and therefore need to keep tight control over the expression of their virulence factors. Doubly so for commensal bacteria, such as Staphylococcus aureus, which should avoid harming their hosts when they are in a state of peaceful co-existence. S. aureus carries very few sigma factors to help define the transcriptional programs, but instead uses a plethora of small RNA molecules and RNA-RNA interactions to regulate gene expression post-transcriptionally. The endoribonucleases RNase III and RNase Y contribute to this regulatory diversity, and provide a link to RNA-decay and intra-cellular spatiotemporal control of expression. In this review we describe some of these post-transcriptional mechanisms as well as some of the novel transcriptomic approaches that have been used to find and to study them. PMID- 29705592 TI - Design of eco-friendly fabric softeners: Structure, rheology and interaction with cellulose nanocrystals. AB - HYPOTHESIS: Concentrated fabric softeners are water-based formulations containing around 10-15 wt% of double tailed esterquat surfactants primarily synthesized from palm oil. In recent patents, it was shown that a significant part of the surfactant contained in today's formulations can be reduced by circa 50% and replaced by natural guar polymers without detrimental effects on the deposition and softening performances. We presently study the structure and rheology of these softener formulations and identify the mechanisms at the origin of these effects. EXPERIMENTS: The polymer additives used are guar gum polysaccharides, one cationic and one modified through addition of hydroxypropyl groups. Formulations with and without guar polymers are investigated using optical and cryo-transmission electron microscopy, small-angle light and X-ray scattering and finally rheology. Similar techniques are applied to study the phase behavior of softener and cellulose nanocrystals considered here as a model for cotton. FINDINGS: The esterquat surfactants are shown to assemble into micron-sized vesicles in the dilute and concentrated regimes. In the former, guar addition in small amounts does not impair the vesicular structure and stability. In the concentrated regime, cationic guars induce a local crowding associated to depletion interactions and leads to the formation of a local lamellar order. In rheology, adjusting the polymer concentration at 1/10th that of the surfactant is sufficient to offset the decrease of the elastic property associated with the surfactant reduction. In conclusion, we have shown that through an appropriate choice of natural additives it is possible to lower the concentration of surfactants in fabric conditioners by about half, a result that could represent a significant breakthrough in current home care formulations. PMID- 29705593 TI - Understanding how surface chemistry and topography enhance fog harvesting based on the superwetting surface with patterned hemispherical bulges. AB - The Namib Desert beetle-Stenocara can adapt to the arid environment by its fog harvesting ability. A series of samples with different topography and wettability that mimicked the elytra of the beetle were fabricated to study the effect of these factors on fog harvesting. The superhydrophobic bulgy sample harvested 1.5 times the amount of water than the sample with combinational pattern of hydrophilic bulgy/superhydrophobic surrounding and 2.83 times than the superhydrophobic surface without bulge. These bulges focused the droplets around them which endowed droplets with higher velocity and induced the highest dynamic pressure atop them. Superhydrophobicity was beneficial for the departure of harvested water on the surface of sample. The bulgy topography, together with surface wettability, dominated the process of water supply and water removal. PMID- 29705594 TI - Wetting dynamics of polydimethylsiloxane mixtures on a poly(ethylene terephthalate) fiber. AB - HYPOTHESIS: The wetting dynamics of liquids with identical surface tensions are mostly controlled by their viscosities. We therefore hypothesized that the wetting dynamics of one- (pure liquid) and two-component (mixture) polydimethylsiloxane (PDMS) on a poly(ethylene terephthalate) (PET) fiber with similar surface tensions and viscosities should be controlled by the same underlying physical mechanisms. EXPERIMENTS: We studied the capillary rise of PDMS liquids on a PET fiber. We compared the different contact angle relaxations and characterized the transitions between the molecular-kinetic theory (MKT) and hydrodynamic approach (HD) for the PDMS mixtures and the pure liquids as a function of their viscosities. FINDINGS: Compared to the pure PDMS liquid with a viscosity of 20 mm2/s that presents a contact angle relaxation following a t-1/2 scale law in agreement with HD, the PDMS mixture with a higher viscosity (27.4 mm2/s) shows a t-1 behavior predicted by the MKT. Moreover, the transition between MKT and HD appears in a regime with higher viscosities for PDMS mixtures than for pure liquids. Surface segregation of shorter PDMS chains or precursor film may be responsible for this shift. PMID- 29705595 TI - Investigation of an eco-friendly aerogel as a substrate for the immobilization of MoS2 nanoflowers for removal of mercury species from aqueous solutions. AB - An adsorbent that exhibits high affinity for inorganic mercury (Hg2+) with a high removal efficiency of methylmercury (MeHg+) has been developed. The adsorbent demonstrates a symbiotic relationship between its two components, molybdenum disulphide nanoflowers (MoS2NFs) and a poly (vinyl alcohol) (PVA) aerogel. Furthermore, we modified the distribution and loading of the MoS2NFs, which was possible due to the stable porous support, and investigated the biocompatibility of the aerogel-support adsorbent. The performance of the optimized material exhibited a distribution coefficient of 9.71 * 107 mL g-1. In addition, the adsorbent was effective over a wide pH range and could efficiently purify both contaminated lake and sea water. The key motivation for using an aerogel support was to stabilise the MoS2NFs during purification of the water (resulting in improved performance compared to using freestanding MoS2NFs) and the ability to regenerate the used adsorbent. In addition, animal tests confirmed an extremely low toxicity of the adsorbent to fish, along with the excellent purification results. PMID- 29705596 TI - When gushing leads to blushing: Inflated praise leads socially anxious children to blush. AB - Blushing is an involuntary reddening of the face that typically occurs when people are concerned about making negative impressions on others. Although people typically blush for their mishaps or misdeeds, Darwin observed that some people, and especially children, also blush when they are lavished with praise. We theorize that socially anxious children blush when praised in inflated ways because they believe they do not match the inflated image others hold of them. Such praise-induced blushing might be particularly common in late childhood, when children's worries about their social image escalate. In this randomized experiment, 105 children (ages 8-12, 85% Caucasian) sang in front of an audience. Afterwards, children received inflated praise ("You sang incredibly well!"), noninflated praise ("You sang well!"), or no praise. Children's physiological blushing was assessed through photoplethysmography and a temperature sensor. As predicted, inflated praise-but not non-inflated praise-increased blushing in socially anxious children. This emerged for blood pulse amplitude changes (AC reactivity) and self-reported blushing, not for blood volume (DC reactivity) and temperature changes. Socially anxious children may blush to "apologize" in advance for not being as incredible as others think they are. Thus, blushing may be elicited in situations that seem benign but actually evoke the fear of being evaluated negatively. PMID- 29705597 TI - Transposable elements: all mobile, all different, some stress responsive, some adaptive? AB - Transposable elements (TEs) were first identified through the polymorphisms they induced in plants and animals. Genomic studies have later revealed that TEs were highly abundant in eukaryotic genomes. Recently, more precise single individual genomic analyses have unravelled the huge diversity of TE insertions in many plant and animal species. In most cases the stress conditions behind this diversity are not known and neither is the adaptive capacity of these natural TE induced variants. Here, we review some of the most recent examples of TE-related impacts on gene expression at the locus or the genome level and discuss the rich diversity of the TE repertoire and its potential role in adaptive evolution. PMID- 29705599 TI - The impact of institution use on the wellbeing of Alzheimer's disease patients and their caregivers. AB - In France, temporary institutionalization solutions for dependent elders have been encouraged since the early 2000s. They are targeting patients who are maintained at home, but may need temporary solutions to adjust the constraints of caregivers, e.g. to facilitate transitions between several informal care providers or to allow informal caregivers to leave for holidays. However, the influence of these solutions on dependent elders and their caregivers has not been explored yet. We use French longitudinal data (REAL.FR, 686 elders and their primary caregivers followed between 2000 and 2006) to explore the impact of institution placement on the wellbeing of both Alzheimer's disease patients and their primary informal caregivers. The data distinguishes permanent placements in institution from temporary stays. Using fixed-effect models, we quantify the change in patients' quality of life and caregivers' burden of care following the placement of patients. We find that permanent and temporary stays are associated with a decrease in informal caregivers' burden. However, only permanent stays lead to an improvement of patients' quality of life. Hence, taken together, the results suggest that while long-run placements may maximize the wellbeing of all the members of a household (patient and caregiver), this is not necessarily the case of short-term placements. PMID- 29705598 TI - The Retrotransposon storm and the dangers of a Collyer's genome. AB - Like the famous Collyer's mansion in NY, our genomes have accumulated vast quantities of sequences that have been referred to as 'junk DNA,' much of which consists of retrotransposons (RTEs). A recent literature establishes the phenomenology that many RTEs become expressed at progressively higher levels during the course of normal aging. This seems to reflect gradual loss of heterochromatin in old age. In addition, RTEs appear to be precociously expressed in brains of younger animals that are experiencing neurodegenerative decline. Although it is difficult to distinguish cause from consequence, several recent studies support the contention that RTE expression, and even perhaps transposition, causally contribute to both the normal deterioration seen with age and to the precipitous decline in some neurodegenerative disorders. This may reflect a two hit model in which normal age-dependent loss of heterochromatin synergizes with a disruption to posttranscriptional silencing of RTEs caused by genetic and environmental stress. PMID- 29705600 TI - Engaging police to identify challenging school crossings and potential improvements. AB - This paper discusses the value of police officers as vital sources of information regarding pedestrian safety in their communities by presenting results from a survey of traffic safety police officers. The survey requested information on school crossings that the officers considered most challenging for pedestrians. Officers specified the intersections or mid-block locations with school crossings, and answered questions about elements of the locations, such as what makes the locations challenging, and what might be done to improve conditions at these locations. A key finding from the survey is the police officers' identification of challenging intersections or other crossing locations by criteria other than the occurrence of crashes, including reported pedestrian vehicle near-miss incidents. A broad literature review of pedestrian safety studies provides context for the use of near-miss data in discussions of improvements to pedestrian crossings. Although not typically considered a primary resource for pedestrian safety information, police officers are most often very familiar with their communities, work in locations where pedestrian and motor vehicle traffic can be experienced and observed, and receive information from their staff and members of the public who use pedestrian crossings. The survey findings demonstrate that police officer insights and near-miss data may serve as important supplementary sources of information in the effort to identify locations in need of interventions before crash occurrence. PMID- 29705601 TI - Bayesian Poisson hierarchical models for crash data analysis: Investigating the impact of model choice on site-specific predictions. AB - The Poisson-gamma (PG) and Poisson-lognormal (PLN) regression models are among the most popular means for motor vehicle crash data analysis. Both models belong to the Poisson-hierarchical family of models. While numerous studies have compared the overall performance of alternative Bayesian Poisson-hierarchical models, little research has addressed the impact of model choice on the expected crash frequency prediction at individual sites. This paper sought to examine whether there are any trends among candidate models predictions e.g., that an alternative model's prediction for sites with certain conditions tends to be higher (or lower) than that from another model. In addition to the PG and PLN models, this research formulated a new member of the Poisson-hierarchical family of models: the Poisson-inverse gamma (PIGam). Three field datasets (from Texas, Michigan and Indiana) covering a wide range of over-dispersion characteristics were selected for analysis. This study demonstrated that the model choice can be critical when the calibrated models are used for prediction at new sites, especially when the data are highly over-dispersed. For all three datasets, the PIGam model would predict higher expected crash frequencies than would the PLN and PG models, in order, indicating a clear link between the models predictions and the shape of their mixing distributions (i.e., gamma, lognormal, and inverse gamma, respectively). The thicker tail of the PIGam and PLN models (in order) may provide an advantage when the data are highly over-dispersed. The analysis results also illustrated a major deficiency of the Deviance Information Criterion (DIC) in comparing the goodness-of-fit of hierarchical models; models with drastically different set of coefficients (and thus predictions for new sites) may yield similar DIC values, because the DIC only accounts for the parameters in the lowest (observation) level of the hierarchy and ignores the higher levels (regression coefficients). PMID- 29705602 TI - Liraglutide attenuates the depressive- and anxiety-like behaviour in the corticosterone induced depression model via improving hippocampal neural plasticity. AB - Recent studies indicate that metabolic disorders such as diabetes and obesity are a major risk factor of psychiatric diseases. This relationship opens the opportunity to develop new antidepressant drugs by repurposing antidiabetic drugs. Previous research has demonstrated that GLP-1 analogs are neuroprotective in several neurological disease models including Alzheimer's disease (AD), Parkinson's disease (PD), and stroke. In addition, the GLP-1 analog liraglutide has been shown to promote neurogenesis, which is seen to play important roles in memory formation and cognitive and emotional processing. However, whether liraglutide is an effective antidepressant remains unknown. Therefore, we tested this hypothesis in the depression model of chronic administration of corticosterone (CORT) in mice and treated the animals daily with liraglutide (5 or 20 nmol/kg ip.) to assess its therapeutic potential as an antidepressant. Behavioral studies showed that liraglutide administration attenuated depressive- and anxiety- like behaviors in this depression mouse model, and attenuated the hyperactivity induced by the stress hormone. Additionally, liraglutide treatment protected synaptic plasticity and reversed the suppression of hippocampal long term potentiation induced by CORT administration, demonstrating synaptic protective effects of liraglutide. We also found that liraglutide treatment increased the cell density of immature neurons in the subgranular dentate gyrus region of the hippocampus. In addition, liraglutide prevented the CORT induced impairments and simultaneously increased the level of phosphorylated GSK3beta in the hippocampus, which may be instrumental in the anti-depressant activity of liraglutide treatment. Taken together, liraglutide has the potential to act as a therapeutic treatment of depression. PMID- 29705603 TI - Hypobaric hypoxia impairs cued and contextual fear memory in rats. AB - Fear memory is essential for survival, and its dysregulation leads to disorders. High altitude hypobaric hypoxia (HH) is known to induce cognitive decline. However, its effect on fear memory is still an enigma. We aimed to investigate the temporal effect of HH on fear conditioning and the underlying mechanism. Adult male Sprague-Dawley rats were trained for fear conditioning and exposed to simulated HH equivalent to 25,000 ft for different durations (1, 3, 7, 14 and 21 days). Subsequently, rats were tested for cued and contextual fear conditioning. Neuronal morphology, apoptosis and DNA fragmentation were studied in the medial prefrontal cortex (mPFC), hippocampus and basolateral amygdala (BLA). We observed significant deficit in cued and contextual fear acquisition (at 1, 3 and 7 days) and consolidation (cued at 1 and 3 days and contextual fear at 1, 3 and 7 days) under HH. HH exposure with retraining showed the earlier restoration of contextual fear memory. Further, we found a gradual increase in the number of pyknotic and apoptotic neurons together with the increase in DNA fragmentation in mPFC, hippocampus, and BLA up to 7 days of HH exposure. The present study concludes that HH exposure equivalent to 25,000 ft induced cued and contextual fear memory deficit (acquisition and consolidation) which is found to be correlated with the neurodegenerative changes in the limbic brain regions. PMID- 29705604 TI - Bone marrow mesenchymal stem cells conditioned medium protects VSC4.1 cells against 2,5-hexanedione-induced autophagy via NGF-PI3K/Akt/mTOR signaling pathway. AB - We aimed to investigate the effects of bone marrow mesenchymal stem cell conditioned medium (BMSC-CM) in preventing 2,5-hexanedione (HD)-induced damage to motoneurons, and examined the molecular mechanisms that mediate these effects. VSC4.1 cells were exposed to 25 mM HD for 24 h followed by incubation with DMEM for 24 h. HD-treated cells were incubated with BMSC-CM at varied concentrations. Incubation with BMSC-CM ameliorated the decreased cell viability and reduced LDH release from cells exposed to HD. BMSC-CM suppressed the elevated number of autophagic vacuoles, cells with LC3 puncta, increased LC3-II/LC3-I ratio, and decreased p62 caused by HD exposure. BMSC-CM elevated NGF and p-TrkA expressions in HD-treated cells. Administration of NGF inhibited autophagy, an effect that was similar to that observed after BMSC-CM treatment; this effect was abolished by the addition of NGF-neutralizing antibodies. BMSC-CM or NGF elevated p-protein kinase B (Akt) and p-mammalian target of rapamycin (mTOR) in HD-exposed cells, which was interrupted by TrkA inhibitor, K252a and mTOR inhibitor, rapamycin. BMSC-CM prevented HD-induced autophagic cell damage in VSC4.1 cells. The neuroprotective effect of BMSC-CM appeared to be at least partly associated with its ability to trigger the NGF-phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR signaling pathway. PMID- 29705606 TI - Neuroprotective effects of protein tyrosine phosphatase 1B inhibitor on cerebral ischemia/reperfusion in mice. AB - Akt (Protein kinase B, PKB), a serine/threonine kinase, plays a critical role in cell development, growth, and survival. Akt phosphorylation mediates a neuroprotective effect against ischemic injury. Recently, a protein-tyrosine phosphatase-1B (PTP1B) inhibitor (KY-226) was developed to elicit anti-diabetic and anti-obesity effects via enhancement of insulin signaling. Previously, we reported that the nonselective PTP1B inhibitor, sodium orthovanadate, rescued neurons from delayed neuronal death during brain ischemia. In this study, we confirmed the ameliorative effects of KY-226 on ischemia/reperfusion (I/R) injury using a murine model of middle cerebral artery occlusion (MCAO). ICR mice were subjected to MCAO for 2 h followed by reperfusion. Although KY-226 permeability was poor through the blood-brain barrier (BBB) of normal mice, it could penetrate through the BBB of mice after I/R insult. Intraperitoneal KY-226 administration elicited dose-dependent reductions in infarcted brain areas and improved neurological deficits. The neuroprotective effects of KY-266 were obtained when administered within 0.5 h after reperfusion. KY-226 (10 mg/kg) also restored reduced Akt phosphorylation and eNOS phosphorylation (Ser-1177) levels following I/R insult. Moreover, 10 mg/kg of KY-226 improved I/R-induced decreased extracellular signal-regulated kinase (ERK) phosphorylation. Furthermore, KY-226 attenuated the generation of reactive oxygen species (ROS) in mouse cortex. These results suggest that KY-226 may act as a novel therapeutic candidate for ischemic stroke. Activation of Akt and ERK possibly underlie the neuroprotective mechanism of KY-226. PMID- 29705607 TI - Impulsivity traits in patients with multiple sclerosis. AB - BACKGROUND: Multiple sclerosis (MS) is a demyelinating disease with a lifetime prevalence of 4.41/100000 in Bogota, Colombia. It is known that it can be related with neuropsychiatric disorders, increasing by a factor of three the prevalence of depression in MS patients compared to general population. However, less attention has been given to the association between MS and impulsive behavior. METHODS: This cross-sectional study compared the levels of impulsivity controlling for the presence of MS. 60 patients with MS and 60 sex- and age matched subjects without MS were included. In order to assess depression and impulsivity, participants completed the 13-item short form of the Beck Depression Inventory (BDI-SF), the self-report Barratt Impulsiveness Scale version 11 (BIS 11) and the Immediate and Delayed Memory Tasks (IMT-DMT) as an objective measure of impulsive behavior. RESULTS: Total scores, motor and cognitive subscales on the BIS-11 were significantly higher in the MS group. However, median BDI-SF score was also higher in MS patients than in subjects without MS (p < 0.001). To rule out depression as a confounding factor, stratification was performed using the BDI-SF score. In the subgroup of individuals with a BDI-SF< 8, the BIS-11 cognitive subscale scores were significantly higher in patients with MS than in subjects without MS (p = 0.041). In the IMT/DMT test, subjects with MS had a fewer number of correct detections than did subjects without MS, after controlling for BDI-SF score (p = 0.0001/p = 0.003). The ratio of commission errors to correct detections in the IMT was significantly higher in the MS group (p = 0.011). CONCLUSION: Patients with MS showed higher levels of cognitive impulsivity than subjects without MS. Objective measures for impulsiveness further support this finding. Impulsiveness scales scores might be biased by depression, which should be considered when assessing impulsivity in MS. PMID- 29705608 TI - Improved process performance of the acidification phase in a two-stage anaerobic digestion of complex organic waste: Effects of an iron oxide-zeolite additive. AB - Improvement of the acidification phase is an attractive alternative to break through the rate-limiting step in the two-phase anaerobic digestion of complex organic wastes. An additive named iron oxide-zeolite was introduced into the acidification phase at mesophilic and room temperature. By virtue of the additive supplemented, significantly improved hydrolysis/fermentation in regard to higher soluble chemical oxygen demand (sCOD) concentration (21.53-27.30%) and better lignocellulosic degradation at both temperatures has been obtained. Furthermore, an optimized volatile fatty acid formation type (more favorable acetate and less undesired propionate) has been achieved. The favorable environment of the acidogenic effluent facilitated the subsequent methanogenesis. The increased microbial community abundances of some hydrolytic, acetogenic and cellulolytic bacteria may provide the explanation on the promoted hydrolysis/acidogenesis. The results in this study suggested that supplementation of the iron oxide-zeolite into the acidification phase is a valuable alternative to improve hydrolysis/acidogenesis of the complex substrates. PMID- 29705609 TI - Improved synthesis of 2,5-bis(hydroxymethyl)furan from 5-hydroxymethylfurfural using acclimatized whole cells entrapped in calcium alginate. AB - Upgrading of biomass-derived 5-hydroxymethylfurfural (HMF) has attracted considerable interest recently. In this work, efficient synthesis of 2,5 bis(hydroxymethyl)furan (BHMF) from HMF was reported with the acclimatized Meyerozyma guilliermondii SC1103 cells entrapped in calcium alginate beads. Catalytic activities of the cells as well as their HMF-tolerant level increased significantly upon acclimatization and immobilization. BHMF was obtained within 7 24 h with good yields (82-85%) and excellent selectivities (99%) when the substrate concentrations were 200-300 mM. In scale-up synthesis, BHMF of up to 181 mM was produced within 7 h, and its productivity was approximately 3.3 g/L h. In addition, the immobilized biocatalyst showed satisfactory operational stability; the cell viability of 70% was retained after reuse 4 times. With rice straw hydrolysate as co-substrate, both the reaction rate and selectivity decreased, likely due to the deleterious influence of xylose in the hydrolysate. PMID- 29705610 TI - Organic loading rate and hydraulic retention time shape distinct ecological networks of anaerobic digestion related microbiome. AB - Understanding of how anaerobic digestion (AD)-related microbiomes are constructed by operational parameters or their interactions within the biochemical process is limited. Using high-throughput sequencing and molecular ecological network analysis, this study shows the succession of AD-related microbiome hosting diverse members of the phylum Actinobacteria, Bacteroidetes, Euryarchaeota, and Firmicutes, which were affected by organic loading rate (OLR) and hydraulic retention time (HRT). OLR formed finer microbial network modules than HRT (12 vs. 6), suggesting the further subdivision of functional components. Biomarkers were also identified in OLR or HRT groups (e.g. the family Actinomycetaceae, Methanosaetaceae and Aminiphilaceae). The most pair-wise link between Firmicutes and biogas production indicates the keystone members based on network features can be considered as markers in the regulation of AD. A set of 40% species ("core microbiome") were similar across different digesters. Such noteworthy overlap of microbiomes indicates they are generalists in maintaining the ecological stability of digesters. PMID- 29705611 TI - Anaerobic digestion of high-yielding tropical energy crops for biomethane production: Effects of crop types, locations and plant parts. AB - This study examined the composition and anaerobic digestibility of the different plant parts of two high-yielding tropical energy crops, Energycane and Napier grass, collected across three locations and two seasons. Both biomass composition and biomethane yields varied significantly with crop types, plant parts and harvest seasons. In Energycane, specific methane yield (SMY) (Nm3 (kg VSadded)-1) was higher from stems (0.232 +/- 0.003) than leaves (0.224 +/- 0.003), while in Napier grass, SMY was higher from leaves (0.243 +/- 0.002) than stems (0.168 +/- 0.002). Energycane had higher specific and total (Nm3 ha-1 year-1) methane yields (0.230 +/- 0.002 and 8749 +/- 494, respectively) than Napier grass (0.192 +/- 0.002 and 5575 +/- 494, respectively). The SMYs from biomass correlated negatively with acid detergent fiber, cellulose and lignin content in the biomass. Energycane and Napier grass had lower specific but comparable total methane yields (TMYs) with maize. The ecological, economic and environmental merits associated with perennial crops suggest they could outperform maize as a substrate for bioenergy production. PMID- 29705612 TI - Environmental performances of coproducts. Application of Claiming-Based Allocation models to straw and vetiver biorefineries in an Indian context. AB - Among the renewables, non-food and wastelands based biofuels are essential for the transport sector to achieve country's climate mitigation targets. With the growing interest in biorefineries, setting policy requirements for other coproducts along with biofuels is necessary to improve the products portfolio of biorefinery, increase the bioproducts perception by the consumers and push the technology forward. Towards this context, Claiming-Based allocation models were used in comparative life cycle assessment of multiple products from wheat straw biorefinery and vetiver biorefinery. Vetiver biorefinery shows promising Greenhouse gas emission savings (181-213%) compared to the common crop based lignocellulose (wheat straw) biorefinery. Assistance of Claiming-Based Allocation models favors to find out the affordable allocation limit (0-80%) among the coproducts in order to achieve the individual prospective policy targets. Such models show promising application in multiproduct life cycle assessment studies where appropriate allocation is challenging to achieve the individual products emission subject to policy targets. PMID- 29705613 TI - False human cytomegalovirus IgG-positivity at prenatal screening. AB - BACKGROUND: An incorrect definition of immune status to human cytomegalovirus (HCMV) can lead to incorrect management of pregnant women. OBJECTIVES: Aims of the study were: i) to describe 10 cases of unconfirmed HCMV IgG-seroconversion in pregnancy; ii) to develop a panel of confirmatory tests to define HCMV serostatus; iii) to investigate the frequency of false IgG-positive results in pregnant women screened with the LIAISON(r)CMVIgGII automated assay. STUDY DESIGN: Blood samples from 10 pregnant women referred for HCMV IgG-seroconversion were examined to confirm/exclude a primary infection. In addition, samples were tested for HCMV IgG by immunoblotting, neutralization assay, and ELISA against gB, gH/gL/pUL128L and gH/gL/gO recombinant glycoproteins. LIAISON(r)CMVIgGII results obtained on 1158 pregnant women were reviewed and samples with low IgG titers were further investigated. RESULTS: A primary infection was excluded in the 10 women referred for HCMV IgG seroconversion. None of them was confirmed to be IgG-seropositive. Of the 1158 women prenatally screened by LIAISON(r)CMVIgGII, 678 (59%) were IgG-positive and, of these, 40 (5.9%) showed low levels of IgG (14 50 U/mL). Thirty-three women with low IgG-positivity were further tested by confirmatory tests and 11 (33.3%) were found to be non reactive to HCMV. CONCLUSIONS: At least 1.6% (11/678) women who tested positive with LIAISON(r)CMVIgGII were found to be seronegative when tested with confirmatory tests. These women should be informed to reduce the risk of a primary HCMV infection. Furthermore, should a congenital infection occur in any of these women, a maternal non-primary infection could be erroneously diagnosed. PMID- 29705605 TI - The role of catecholamines in HIV neuropathogenesis. AB - The success of anti-retroviral therapy has improved the quality of life and lifespan of HIV + individuals, transforming HIV infection into a chronic condition. These improvements have come with a cost, as chronic HIV infection and long-term therapy have resulted in the emergence of a number of new pathologies. This includes a variety of the neuropathological and neurocognitive effects collectively known as HIVassociated neurocognitive disorders (HAND) or NeuroHIV. These effects persist even in the absence of viral replication, suggesting that they are mediated the long-term changes in the CNS induced by HIV infection rather than by active replication. Among these effects are significant changes in catecholaminergic neurotransmission, especially in dopaminergic brain regions. In HIV-infected individuals not treated with ARV show prominent neuropathology is common in dopamine-rich brain regions and altered autonomic nervous system activity. Even infected individuals on therapy, there is significant dopaminergic neuropathology, and elevated stress and norepinephrine levels correlate with a decreased effectiveness of antiretroviral drugs. As catecholamines function as immunomodulatory factors, the resultant dysregulation of catecholaminergic tone could substantially alter the development of HIVassociated neuroinflammation and neuropathology. In this review, we discuss the role of catecholamines in the etiology of HIV neuropathogenesis. Providing a comprehensive examination of what is known about these molecules in the context of HIV-associated disease demonstrates the importance of further studies in this area, and may open the door to new therapeutic strategies that specifically ameliorate the effects of catecholaminergic dysregulation on NeuroHIV. PMID- 29705614 TI - Proteomic effects of repeated-dose oral exposure to 2-monochloropropanediol and its dipalmitate in rat testes. AB - 2- and 3-monochloropropanediol (2-MCPD) and their fatty acid esters are food contaminants which are concomitantly formed upon thermal treatment of foodstuff containing fats and salt. Exposure to 2- or 3-MCPD thus results, for example, from refined vegetable oils, in instant meals or infant formula, as well as in cereals or pastries. The molecular mechanisms of 2-MCPD toxicity are poorly understood. Here, we performed a comprehensive proteomic analysis of 2-MCDP induced alterations in the testes from rats following oral administration of 10 mg/kg body weight per day 2-MCPD, or an equimolar dose of 2-MCPD dipalmitate as a representative 2-MCPD fatty acid ester. In the absence of overt histopathologically detectable toxicity, moderate alterations in cellular proteomic signatures were recorded. The observations are in line with the assumption that the molecular mechanisms of 2-MCPD and 3-MCPD toxicity differ. Observed proteomic alterations point towards effects of 2-MCPD on mitogen dependent signaling and mitochondrial energy utilization. Presented data for the first time provide insight into proteomic effects of 2-MCPD in testicular tissue. PMID- 29705616 TI - A graphene oxide-based label-free electrochemical aptasensor for the detection of alpha-fetoprotein. AB - A label-free method for the determination of alpha-fetoprotein (AFP) was successfully developed by graphene oxide (GO)-based electrochemical aptasensor. This aptasensor was constructed by covalently immobilizing NH2-functionalized AFP specific aptamer on GO with plenty of carboxylic groups. Cyclic voltammetry (CV) and electrochemical impedance spectra (EIS) analysis were carried out to investigate the practicability of the fabrication procedures. Fourier transform infrared spectra (FTIR), Raman, atomic force microscopy (AFM) and scanning electron microscope (SEM) were performed to indicate the changes of the sensing interface. CV was used to detect the signal change of the aptasensor. Peak current of CVs changed before and after incubating the aptasensor with different concentration of AFP solution. The changes of peak current were proportional to the AFP concentration, with a wide linear range of 0.01-100 ng mL-1, a low detection limit of 3 pg mL-1 and good specificity. The proposed simple and cost effective label-free strategy is promising for the determination of clinical biomarkers such as AFP. PMID- 29705617 TI - A photoelectrochemical aptasensor based on a 3D flower-like TiO2-MoS2-gold nanoparticle heterostructure for detection of kanamycin. AB - In this work, a sensitive photoelectrochemical aptasensor was developed for kanamycin detection using an enhanced photocurrent response strategy, which is based on the surface plasmon resonance effect of gold nanoparticles deposited on a 3D TiO2-MoS2 flower-like heterostructure. A significant aspect of this development lies in the photoelectrochemical and morphological features of the unique ternary composite, which have contributed to the excellent performance of the sensor. To develop an aptasensor, mercapto-group modified aptamers were immobilised on the photoactive composite as a recognition unit for kanamycin. The TiO2-MoS2-AuNP composite was demonstrated to accelerate the electron transfer, increase the loading of aptamers and improve the visible light excitation of the sensor. Under optimal conditions, the aptasensor exhibited a dynamic range from 0.2 nM to 450 nM of kanamycin with a detection limit of 0.05 nM. Overall, we have successfully synergised both the electrical and the optical merits from individual components to form a ternary composite, which was then demonstrated as an effective scaffold for the development of PEC biosensors. PMID- 29705618 TI - Change in drawing placement: A measure of change in mood state reflective of hemispheric lateralization of emotion. AB - The Valence Hypothesis of cerebral lateralization of emotion suggests greater right hemisphere activation during negative mood and greater left hemisphere activation during positive mood. This can manifest as visual field attentional bias. Here, study participants completed an assessment of current mood state (PANAS) and made a drawing (Drawing 1). To induce positive or negative mood, participants played a game; then, the winner read a script depicting a positive interpersonal interaction and the loser read a script depicting a negative interpersonal interaction. Participants then drew a second picture (Drawing 2) and completed the PANAS. We hypothesized that the game outcome would change current mood state and hemispheric activation, which would be reflected in drawing placement. The placement of Drawing 2 moved right for winners and left for losers. Winners experienced a greater increase in positive affect from Time 1 to Time 2 than losers and had decreased negative affect from Time 1. Losers had decreased positive affect from Time 1 and had a greater increase in negative affect from Time 1 to Time 2 than winners. Our results suggest that change in current mood state may be objectively observed by evaluating hemispatial bias reflective of brain hemispheric activation with drawings. PMID- 29705619 TI - The fate of polar trace organic compounds in the hyporheic zone. AB - The hyporheic zone (HZ) is often considered to efficiently remove polar trace organic compounds (TrOCs) from lotic systems, mitigating potential adverse effects of TrOCs on ecosystem functioning and drinking water production. Predicting the fate of TrOCs in the hyporheic zone (HZ) is difficult as the in situ removal rate constants are not known and the biogeochemical factors as well as hydrological conditions controlling the removal efficiency are not fully understood. To determine the in-situ removal efficiency of the HZ for a variety of TrOCs as a function of the biogeochemical milieu, we conducted a field study in an urban river near Berlin, Germany. Subsurface flow was studied by time series of temperature depth profiles and the biogeochemical milieu of the HZ by concentration depth profiles. These results, in conjunction with a 1D advection dispersion transport model, were used to calculate first-order removal rate constants of several polar TrOCs in the HZ. For the majority of TrOCs investigated, removal rate constants were strongly dependent on redox conditions, with significantly higher removal rates observed under predominantly suboxic (i.e. denitrifying) compared to anoxic (i.e. Fe and Mn reducing) conditions. Compared to previous studies on the fate of TrOCs in saturated sediments, half lives within oxic/suboxic sections of the HZ were relatively low, attributable to the site-specific characteristics of the HZ in a stream dominated by wastewater treatment plant effluent. For nine out of thirteen investigated TrOCs, concentrations decreased significantly in the HZ with relative removal percentages ranging from 32% for primidone to 77% for gabapentin. For many TrOCs, removal efficiency decreased drastically as redox conditions became anoxic. For the majority of compounds investigated here, the HZ indeed acts as an efficient bioreactor that is capable of removing TrOCs along relatively short flow paths. Depending on the TrOC, removal capacity may be enhanced by either increasing the magnitude of groundwater-surface exchange fluxes, by increasing the total residence time in the HZ or the exposure time to suboxic zones, respectively. PMID- 29705620 TI - Impact of doxofylline in COPD: A pairwise meta-analysis. AB - Doxofylline is an effective bronchodilator for relieving airway obstruction in patients with asthma or chronic obstructive pulmonary disease (COPD), and displays a better safety profile with respect to theophylline. Herein, we performed a pairwise meta-analysis of the currently available data to provide consistent and homogeneous findings on the impact of this xanthine in COPD patients. Results obtained from 820 patients were selected from 20 clinical trials. Meta-regression was performed to examine the source of heterogeneity between-studies and identify potential confounder covariates. The quality of the evidence was assessed by the GRADE system. Doxofylline induced a significant (P < 0.001) increase in forced expiratory volume in 1 s (FEV1) of 8.20% (95%CI 4.00 12.41; I2 93%) and 317 ml (95%CI 19-439; I2 87%) compared with baseline. The total administered dose of doxofylline significantly (P < 0.001) interacted with the size of the effect estimates detected for FEV1. Doxofylline induced a significant (P < 0.001), although moderate, increase in adverse events (AEs) frequency (proportion 0.03, 95%CI 0.02-0.04; I2 88%), but only epigastralgia, nausea, dyspepsia and headache were statistically significant (P < 0.05). The GRADE analysis indicated high quality of evidence (++++) for the impact of doxofylline on FEV1, and moderate quality of evidence (+++) for the safety profile in COPD patients. Doxofylline is an effective and safe medicine when administered to patients with COPD and can be considered as an alternative to theophylline. PMID- 29705621 TI - National and subnational mortality and disability-adjusted life years (DALYs) attributable to 17 occupational risk factors in Iran, 1990-2015. AB - We estimated age-sex specific and cause-specific mortality, years of life lost due to premature mortality (YLLs), years lived with disability (YLDs) and disability-adjusted life years (DALYs) attributable to 17 individual occupational risks in Iran at the national and subnational levels in 1990-2015 based on the Global Burden of Disease Study 2015 (GBD 2015). The burden of disease attributable to occupational risk factors was calculated using the comparative risk assessment methodology based on 10 outcomes and 21 risk-outcome pairs. The temporal changes in the attributable burden of disease were decomposed into the contribution of population growth, population ageing, risk-deleted DALY rate, and risk exposure. National DALYs attributable to occupational risks at the national level in 1990, 2005, and 2015 were 138,210 (95% uncertainty interval 64,429 223,028), 193,243 (91,645-310,281), and 228,310 (106,782-371,709), respectively indicating a total increase of 65% (65-67) during the study period. Between 1990 and 2015, the share of the attributable DALYs for women rose by 55% (51-58) from 13% (12-14) to 20% (19-21). The proportion of YLLs in national DALYs attributable to occupational risks during the study period slightly decreased from 24% in 1990 to 23% in 2015. The five occupational risks with the highest contributions in the national attributable DALYs in 2015 were ergonomic factors (107,490), noise (52,122), exposure to particulate matter, gases, and fumes (26,847), asthmagens (19,347), and exposure to asbestos (7842). From 1990 to 2015, the increase in total DALYs attributable to occupational carcinogens (112%) was higher than that for other occupational risks. During the study period, changes in risk deleted DALY rate and risk exposure led to decreases in total DALYs attributable to occupational risks by 14% and 30%, respectively. Based on the Gini coefficient, spatial inequality in DALY rate attributable to occupational risks at the provincial level decreased during 1990-2015. A comprehensive plan for management of exposure to occupational risks, especially occupational carcinogens can cause an important effect for control of the increasing trend of occupational health losses. PMID- 29705622 TI - Impact of resective epilepsy surgery on health-related quality of life in children with and without low intellectual ability. AB - OBJECTIVE: The current study examined pre- and postoperative health-related quality of life (HRQL) across children with and without low intellectual ability. We also aimed to clarify the literature on postsurgical change by assessing domain-specific HRQL pre- and postoperatively in children with drug-resistant epilepsy. METHOD: All patients (n=111) underwent resective epilepsy surgery between 1996 and 2016 at the Hospital for Sick Children in Toronto, comparing baseline and 1-year follow-up HRQL with the Quality of Life in Childhood Epilepsy Questionnaire (QOLCE-76). At the group-level, postsurgical change in HRQL was examined through linear mixed-effects modeling. Clinically important change in HRQL at the individual level was quantified using a standard error of measurement (SEM)-based criterion, and estimates were stratified by intellectual ability. RESULTS: Children with epilepsy and low intellectual ability had lower overall HRQL compared with those with normal intelligence (b=-10.45, SE=4.89, p=.035). No differences in change in HRQL related to intellectual level were found. In the broader sample, significant postoperative improvements were found for HRQL related to physical activity (b=8.28, SE=1.79, p<.001), social activity (b=15.81, SE=2.76, p<.001), and behavior (b=4.34, SE=1.35, p=.001). Postoperative improvements in physical and social HRQL were associated with better seizure control (p=.011). Conversely, cognitive and emotional domains of HRQL did not improve one year postoperatively, even in the presence of improved seizure control. SIGNIFICANCE: Results suggest that children with low intellectual ability can expect to achieve similar improvements in HRQL after epilepsy surgery compared with those with normal intelligence. Further, while overall HRQL is shown to improve in children following epilepsy surgery, domain-specific change is nuanced and has important implications for health practitioners aiming to monitor treatment progress of patients. PMID- 29705623 TI - Pediatric epilepsies misdiagnosed as gastrointestinal disorders. AB - In the last years, several cases of pediatric epilepsies misdiagnosed and treated as gastrointestinal (GI) disorders have been reported. The aim of this study was to evaluate both frequency and characteristics of these erroneous diagnoses. We identified children who had received a previous misdiagnosis of GI disorder out of 858 consecutive patients with a diagnosis of epilepsy at our hospital from 2010 to 2015. Misdiagnosis was observed in 21 patients (2.4%): 7 children with West syndrome, 10 with temporal lobe epilepsy, and 4 with Panayiotopoulos syndrome. The majority of children with a misdiagnosis (12/21) were younger than 1year at epilepsy onset, and median diagnostic delay was 15.5months. The most frequently diagnosed GI disorder was gastroesophageal reflux disease, especially in younger children. The study confirms that epilepsy in a significant percentage of children is wrongly identified and treated as GI disorders. In particular, epilepsy should be considered in the differential diagnosis of "atypical" gastroesophageal reflux in younger children in order to avoid serious prognostic consequences. PMID- 29705624 TI - EQ-5D-based utilities and healthcare utilization in Thai adults with chronic epilepsy. AB - Quality of life and resource use are key parameters that justify economic values in treatments for epilepsy. Health profiles and service utilization were assessed in 224 adults with 15.7years of epilepsy in two super-tertiary care facilities in Thailand. The European Quality of Life, 5-Dimension (EQ-5D)-based utilities and subsequent outpatient (OP) visits and hospitalizations were determined with respect to seizure control outcomes that were assessed by neurologists. Mean utility and visual analogue scale (VAS) scores were respectively higher in 67 patients who are seizure-free (0.82 and 78.9) than in 157 patients who had uncontrolled or persistent seizures, which were divided into seizure reduction (0.79 and 75.5) and no improvement in seizure frequency (0.72 and 73.5). Controlling for patient characteristics, those who are seizure-free had significantly higher utility and VAS scores than those with no improvement by 0.10 (95% confidence interval (CI): 0.03-0.17) and 6.25 (95% CI: 0.09-12.41), respectively. Seizure-free patients were less likely to report pain or discomfort, as compared with patients with seizure reduction (odds ratio (OR): 0.41, 95% CI: 0.19-0.90) and patients with no improvement (OR: 0.32, 95% CI: 0.13 0.75). Over a six-month period, mean OP visits were significantly lower in seizure-free patients (2.27 times) than in those with seizure reduction (3.00 times) and those with no improvement (4.08 times). Mean hospitalizations over 12months among the three groups were 0.03, 0.24, and 0.14 times, respectively. For persistent seizures, 50% received only conventional antiepileptic drugs (AEDs). When epilepsy treatments are considered for their costs and effectiveness, utilities and healthcare use, conditional on seizure control status, can be applied for further analyses. PMID- 29705625 TI - Survey of physician attitudes towards psychogenic nonepileptic seizures and driving. AB - BACKGROUND: Physicians from various disciplines encounter patients presenting with psychogenic nonepileptic seizures (PNES) as part of their routine clinical practice. Recommendations towards assessing fitness to drive and reporting are clearer for conditions such as neurocognitive disorders and epilepsy, but such guidelines do not exist for patients with PNES. Here, we assess physicians' attitudes towards driving for patients diagnosed with PNES. METHODS: Electronic questionnaires were sent to Neurology and Family Medicine physicians practicing at Creighton University Medical Center and Psychiatry physicians practicing at Creighton-Nebraska Psychiatry Residency Program to assess their opinion regarding driving risk when encountering PNES. RESULTS: The survey request was sent to 125 physicians, of which close to 60% completed the survey. Eighty-eight percent of participants encountered PNES in their clinical practice, and 69.1% agreed it was a difficult problem to assess, with only 8.3% endorsing a belief that these patients should drive without restrictions. Ninety-three percent felt having guidelines would help them assess the driving risk in this population. CONCLUSION: Psychogenic nonepileptic seizures are common across neurology, psychiatry, and primary care, and most physicians find assessing driving risk in such individuals highly warranted yet difficult. Developing such assessment guidelines and recommendations is of great need for clinicians. PMID- 29705626 TI - The Montreal procedure: The legacy of the great Wilder Penfield. AB - Wilder Penfield pioneered the early practice of brain surgery. In binding together the disciplines of neurosurgery, neurology, neuropathology, psychology, and related basic sciences, Penfield transformed our understanding of the field of neuroscience. He brought to the operating room the meticulous techniques of Sherrington, combined with methods of stimulation described by Foerster, which he complemented with expert knowledge of the neurocytology of nervous tissue. While developing surgical treatments for epilepsy, Penfield began to map the brain. He established the "Montreal procedure" for the surgical treatment of epilepsy. His scientific contributions on neurostimulation were transformative in their time and continue to resonate today. This article reviews the life of Wilder Penfield and summarizes key scientific contributions. Specifically, we detail the Montreal procedure. We additionally present a painting by Canadian artist Iris Hauser, which purports to display the hidden treasures of the human mind. PMID- 29705627 TI - Research on dissociative seizures: A bibliometric analysis and visualization of the scientific landscape. AB - Dissociative seizures are a common and often elusive differential diagnosis in epilepsy centers. Considering their high prevalence, long diagnostic delays, and disappointing rates of treatment response, scientific research dedicated to dissociative seizures is surprisingly scarce. In order to chart the scientific landscape of dissociative seizures and to visualize thematic clusters and trends in research, a comprehensive bibliometric analysis was performed. The Web of Science database was examined to identify relevant English language documents from the last half-century. A total of 1751 documents with titles referring to dissociative seizures were identified. Automated textual analysis of all titles and abstracts revealed that research clusters around three major topics: differential diagnosis in epilepsy centers, management and treatment, and psychopathology. Time analysis of term networks revealed that the focus of clinical research has moved from diagnostic procedures to treatment approaches. Furthermore, interest within etiological research is shifting from an emphasis on early life trauma and personality traits to the role of anxiety and emotion regulation. With respect to individual contributing authors, a relatively small network of prolific scientists with a remarkable degree of collaboration emerges. By mapping relevant publications, it becomes evident that dissociative seizures still represent a subject mostly within the realm of neurology and epileptology, with a tendency to settle in the latter domain. This analysis sheds light on an important niche subject and highlights trends in research focus and output. PMID- 29705628 TI - Gastrointestinal cancer incidence in type 2 diabetes mellitus; results from a large population-based cohort study in the UK. AB - BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) have been shown to have higher incidences of liver, pancreatic, and colorectal cancer compared to non diabetic individuals. Current evidence is conflicting for other gastrointestinal (GI) cancers. Therefore, we aimed to determine incidence rates (IRs) of all GI cancers in patients with and without T2DM. METHODS: A cohort study was performed using the UK Clinical Practice Research Datalink (1988-2012). A cohort of antidiabetic drug users was matched at baseline to a non-diabetic cohort, by age, sex, and practice. Crude IRs and 95% confidence intervals (95% CI) of GI cancers per 100,000 person-years were calculated stratified by age, sex, and calendar year. RESULTS: 333,438 T2DM and 333,438 non-diabetic individuals were analyzed. IRs of liver (IR 26, 95% CI 24-28 vs. 8.9, 95% CI 7.7-10), pancreatic (IR 65, 95% CI 62-69 vs. 31, 95% CI 28-34), and colon cancer (IR 119, 95% CI 114-124 vs. 109, 95% CI 104-114) were significantly higher in the diabetic compared to the non diabetic cohort, whereas the IR of oesophageal cancer was significantly lower (IR 41, 95% CI 39-44 vs. 47, 95% CI 44-51). Sex-specific IRs of colon cancer remained significantly higher in men with T2DM, and IRs of esophageal cancer remained significantly lower in women with T2DM. CONCLUSION: In this study, T2DM patients were shown to have higher crude IRs of liver, pancreatic and colon cancer, but not of gastric, biliary, and rectal cancer. Moreover, the lower observed IRs of oesophageal cancer in diabetic patients warrants further investigation. PMID- 29705629 TI - Method Optimization for Extracting High-Quality RNA From the Human Pancreas Tissue. AB - Nucleic acid sequencing is frequently used to determine the molecular basis of diseases. Therefore, proper storage of biological specimens is essential to inhibit nucleic acid degradation. RNA isolated from the human pancreas is generally of poor quality because of its high concentration of endogenous RNase. In this study, we optimized the method for extracting high quality RNA from paired tumor and normal pancreatic tissues obtained from eight pancreatic cancer patients post-surgery. RNA integrity number (RIN) was checked to evaluate the integrity of RNA, we tried to extract the RNA with an RIN value of 8 or higher that allows for the latest genetic analysis. The effect of several parameters, including the method used for tissue lysis, RNAlater treatment, tissue weight at storage, and the time to storage after surgical resection, on the quantity and quality of RNA extracted was examined. Data showed that the highest quantity of RNA was isolated using a combination of manual and mechanical methods of tissue lysis. Additionally, sectioning the tissues into small pieces (<100 mg) and treating them with RNAlater solution prior to storage increased RNA stability. Following these guidelines, high quality RNA was obtained from 100% (8/8) of tumor tissues and 75% (6/8) of normal tissues. High-quality RNA was still stable under repeated freezing and thawing. The application of these results during sample handling and storage in clinical settings will facilitate the genetic diagnosis of diseases and their subsequent treatment. PMID- 29705630 TI - Impact of change in neighborhood racial/ethnic segregation on cardiovascular health in minority youth attending a park-based afterschool program. AB - Research on the mechanistic factors associating racial/ethnic residential segregation with health is needed to identify effective points of intervention to ultimately reduce health disparities in youth. We examined the association of changes in racial/ethnic segregation and cardiovascular health outcomes including body mass index percentile, sum of skinfold thicknesses, systolic and diastolic blood pressure percentile, and 400 m run time in non-Hispanic Black (NHB) and Hispanic youth (n = 2,250, mean age 9.1 years, 54% male; 51% Hispanic, 49% NHB; 49% high area poverty; 25% obese) attending Fit2PlayTM, a multisite park-based afterschool program in Miami, Florida, USA. A series of crude and adjusted two level longitudinal generalized linear mixed models with random intercepts for park effects were fit to assess the association of change in segregation between home and program/park site and cardiovascular health outcomes for youth who participated for up to two school years in Fit2PlayTM. After adjusting for individual-level factors (sex, age, time, and park-area poverty) models showed significantly greater improvements in cardiovascular health if youth attended Fit2PlayTM in an area less segregated than their home area (p < 0.05 for all outcomes) except 400 m run time and diastolic blood pressure percentile in Hispanics (p<.001 and p = 0.11, respectively). Area poverty was not found to confound or significantly modify this association. These findings have implications for youth programming focused on reducing health disparities and improving cardiovascular outcomes in NHB and Hispanic youth, particularly in light of a continually expanding obesity epidemic in these groups. Parks and Recreation Departments have potential to expand geographic mobility for minorities, therein supporting the national effort to reduce health inequalities. PMID- 29705632 TI - Bursting onto the scene? Exploring stochastic mRNA production in bacteria. AB - Recent large-scale measurements of gene expression variability (or noise) in E. coli have led to the unexpected conclusion that the variability is in large part dictated by and increasing with the mean level of expression. Here we review the evidence for this apparent universal trend in variability, as well as for the related idea that transcription is fundamentally bursty. We examine recently proposed mechanisms for burstiness and universality and argue that they do not explain important features of observed data. Finally, we discuss potential limitations and pitfalls in the interpretation of experimental measurements of cell-to-cell variability. PMID- 29705631 TI - Metabolic switching in the hypoglycemic and antitumor effects of metformin on high glucose induced HepG2 cells. AB - Metformin, a widely prescribed drug for the management of type 2 diabetes mellitus, has potential anticancer effect. Diabetes patients regularly taking metformin have been reported with decreased cancer risk and improved cancer prognosis in recent years. A cell model of high glucose induced HepG2 cells was conducted to mimic insulin resistance, and a 1H NMR-based metabolomics approach in conjunction with molecular biology was performed to investigate the metabolic changes of high glucose induced HepG2 cells in response to different doses of metformin treatment and to study the differences and links between hypoglycemic and antitumor effects of metformin. Metformin with hypoglycemic effect rectified glucose metabolic imbalance and regulated oxidative stress, energy and amino acid metabolism. Metformin inhibited tumor cell proliferation and induced apoptosis through activation of AMPK/mTOR pathway and further influencing energy metabolism, phospholipid metabolism and glucose catabolism. The integrated metabolomics approach showed its potential in clarifying the different action on metformin treatment and understanding the pleiotropic effect of metformin. PMID- 29705633 TI - Spatial distribution, risk and potential sources of lead in soils in the vicinity of a historic industrial site. AB - Because of measures taken by local and national government agencies to control releases of metals, former industrial sites in China that are contaminated with lead (Pb) in soils have been abandoned. Compared with historic sites themselves, little attention has been paid to contamination with Pb in areas surrounding these sites. In this study, a method by integrating sequential extraction and isotopic fingerprinting was proposed to reveal the key fractions of Pb contaminants in soils, trace their sources and determine the subject of liability for remediation. Topsoils from near a historic site, where lead oxide was produced, were found to be contaminated. Concentrations of Pb in soils were inversely proportional to distances from the industrial site and depth in soils. The predominant form of Pb was the Fe/Mn-oxide-bound fraction (FM3), which accounted for from 53.39% to 82.07% of total concentrations of Pb. Concentrations of Pb in vegetables produced on contaminated soils exceeded those allowed in food for consumption by humans. An assessment of hazards and risks posed by consumption of vegetables grown on these soils indicated relatively high potential for adverse effects on local residents around the closed plant. By use of isotopic finger printing for Pb, the abandoned factory was determined to be the most likely source of Pb in topsoils, especially fraction FM3. To mitigate exposures of people to Pb via consumption of locally produced food, recommended strategies should target legacy sources of Pb to soils in the vicinity of this historic industrial site. PMID- 29705634 TI - Electrodegradation of naphthalenic amines: Influence of the relative position of the substituent groups, anode material and electrolyte on the degradation products and kinetics. AB - The electrodegradation of the 4-aminonaphthalene-1-sulfonic acid (4AN1S), 5 aminonaphthalene-2-sulfonic acid (5AN2S) and 8-aminonaphthalene-2-sulfonic acid (8AN2S) was studied, using two electrode materials as anode, BDD and Ti/Pt/PbO2, and two different electrolytes, sodium sulfate and sodium chloride. The highest COD removal rates were obtained at BDD: for 5AN2S and 8AN2S results were similar in both electrolytes; for 4AN1S, results were better in sodium chloride. The lowest COD removal rates were obtained at the system Ti/Pt/PbO2-sodium sulfate, for all the studied amines. The dissolved organic carbon (DOC) removal was much higher at BDD for all the amines, in sulfate for 5AN2S and 8AN2S and in chloride for 4AN1S. Nitrogen removal was always almost irrelevant in sulfate medium but higher than 60%, after 6-h assays, in chloride. The highest combustion efficiencies were attained at the system BDD-sodium sulfate and were: 4AN1S-75%; 5AN2S-84%; 8AN2S-74%. HPLC results show that total degradation of the studied aminonaphthalene sulfonates is attained at both anode materials, utilizing any of the electrolytes, with a first order kinetics. However, kinetic constants obtained with the variation of the amines concentration in time are 10-40 times higher in chloride, being slightly higher at Ti/Pt/PbO2 than at BDD. Regarding the presence of carboxylic acids during the degradation assays, it was observed that the electrolysis of the amines 5AN2S and 8AN2S always lead to higher amounts of oxalic acid and lower quantities of acetic acid than the electrolysis of the amine 4AN1S. PMID- 29705635 TI - An in vitro analysis of the rat C6 glioma cells to elucidate the linear alkylbenzene sulfonate induced oxidative stress and consequent G2/M phase cell cycle arrest and cellular apoptosis. AB - Linear alkylbenzene Sulphonate (LAS) is the anionic surfactant component of globally consumed detergents. Exposure of sub-inhibitory fractions viz., 1/10th (T1), 1/5th (T2), and 1/2.5th (T3) of IC50 for 48 h, of LAS (5 MUM, 10 MUM, and 20 MUM, respectively) to viable C6 glioma cells of rat, besides imparting morphological alterations leads to gross cytotoxicity. Expression of the damaged DNA coupled with cleaved PARP (p < 0.05; p < 0.01 and p < 0.001) were recorded for T1, T2 and T3, respectively. Subsequently, the cell cycle at G2/M check point was significantly arrested (p < 0.05 for T1 and T2; p < 0.01 for T3). The flow cytometric analysis reveals the initiation of apoptosis in C6 cells as is evident by a significant increase (p < 0.01 for T1, p < 0.001 for T2, and T3) in the intake of annexin-V, the calcium dependent apoptotic phospholipid binding protein. Moreover, significantly increased reactive oxygen species (ROS) (p < 0.05; p < 0.01 and p < 0.001) after 6 h of exposure for all the three sets, registered a declining trend (P < 0.001) when T3 cells were co-treated with N acetyl cysteine (NAC). Furthermore, the significant attenuation (p < 0.01) of expression of the cleaved PARP and a consequent decrease (p < 0.05) in the cell cycle arrest at G2/M phase after scavenging ROS induced oxidative stress by treating C6 cells with NAC clearly evinces that LAS induced apoptosis is mediated by intracellular ROS. Thus, these findings provide a tangible basis for further investigations including in vivo studies, to unravel the molecular mechanism involved in ROS mediated and LAS induced cytotoxic manifestations. PMID- 29705636 TI - Seasonal, spatial variations and risk assessment of heavy elements in street dust from Novi Sad, Serbia. AB - This is the first study carried out to determine the levels, spatial and temporal variations and risk indices of street dust in Serbia. Sixty street dust samples representing four functional areas: school, recreational, residential and industrial were collected from Novi Sad during summer and winter. The purpose was to obtain the concentration of seven heavy elements, evaluate the possible sources and degree of environmental pollution and human health risks. The average concentration of As, Cd, Co, Cr, Cu, Ni and Pb (mg/kg) during winter was: 7.96, 0.40, 7.73, 12.1, 57.6, 14.0 and 70.6, while in summer it was: 1.88, 0.54, 4.31, 60.1, 42.7, 28.1, and 62.5, respectively. Interpolation method together with the correlation matrix and the results of multivariate statistics supported anthropogenic origin of Pb, Cr and Cu, natural origin of Ni, Cd and As and mix origin of Co. Pollution indices such as geoaccumulation index (Igeo) indicated existence of unpolluted to extreme risk regarding to environmental pollution. Moreover, the potential pollution index (Er) showed low (Pb) to moderate (Ni) risk while potential risk index (RI) and modified potential risk index (mRI) indicated considerable and very high risks. Health risk assessment showed no non carcinogenic risk of heavy elements for adults and children. PMID- 29705637 TI - Hierarchical magnetic petal-like Fe3O4-ZnO@g-C3N4 for removal of sulfamethoxazole, suppression of photocorrosion, by-products identification and toxicity assessment. AB - Herein, a petal-like photocatalyst, Fe3O4-ZnO@g-C3N4 (FZG) with different g-C3N4 to ZnO ratios was synthesized with hierarchical structure. The FZG1 photocatalyst, having the weight ratio of 1:1 for the initial urea and Fe3O4-ZnO (Fe-ZnO), presented the highest sulfamethoxazole (SMX) degradation rate of 0.0351 (min-1), which was 2.6 times higher than that of pristine ZnO. Besides the facile separation, the performance of photocatalyst was improved due to the function of iron oxide as an electron acceptor that reduced the electron/hole recombination rate. The coating of g-C3N4 on the Fe-ZnO surface not only acted as a protective layer for ZnO against photocorrosion, but it also enhanced the photocatalytic activity of the catalyst for SMX degradation through the heterojunction mechanism. By using the FZG1 photocatalyst, 95% SMX removal was obtained after 90 min reaction, while 47% COD and 30% TOC removal were achieved after 60 min treatment under a low energy-consuming UV lamp (10 W). Moreover, a substantial reduction in the solution toxicity was shown after the treatment, as compared with the SMX solution before treatment. The LC-HR-MS/MS analysis results showed that the concentration of most detected by-products produced after 90 min reaction by FZG1 was considerably lower than those obtained using other synthesized photocatalysts. By performing radical scavenging experiments, OH degrees radical was found to be the major reactive species. The FZG1 photocatalyst also displayed excellent reusability in five cycles and the leaching of zinc and iron ions was reduced by 54% and ~100%, respectively, after coating Fe-ZnO with g-C3N4. PMID- 29705638 TI - Bio-reduction of free and laden perchlorate by the pure and mixed perchlorate reducing bacteria: Considering the pH and coexisting nitrate. AB - Pure bacteria cell (Azospira sp. KJ) and mixed perchlorate reducing bacteria (MPRB) were employed for decomposing the free perchlorate in water as well as the laden perchlorate on surface of quaternary ammonium wheat residuals (QAWR). Results indicated that perchlorate was decomposed by the Azospira sp. KJ prior to nitrate while MPRB was just the reverse. Bio-reduction of laden perchlorate by Azospira sp. KJ was optimal at pH 8.0. In contrast, bio-reduction of laden perchlorate by MPRB was optimal at pH 7.0. Generally, the rate of perchlorate reduction was controlled by the enzyme activity of PRB. In addition, perchlorate recovery (26.0 mg/g) onto bio-regenerated QAWR by MPRB was observed with a small decrease as compared with that (31.1 mg/g) by Azospira sp. KJ at first 48 h. Basically, this study is expected to offer some different ideas on bio regeneration of perchlorate-saturated adsorbents using biological process, which may provide the economically alternative to conventional methods. PMID- 29705639 TI - Free ammonia-based sludge treatment reduces sludge production in the wastewater treatment process. AB - Excessive sludge production is one of the major challenges for biological wastewater treatment plants. This paper reports a new strategy to enhance sludge reduction from the wastewater treatment process. In this strategy, 1/5 of the sludge is withdrawn from the mainstream reactor into a side-stream unit for sludge treatment with 16 mg/L free ammonia (FA) for 24-40 h. The FA-treated sludge mixture is then returned to the mainstream reactor. To demonstrate this concept, two reactors treating synthetic domestic wastewater were operated, with one serving as the experimental reactor and the other as the control. Experimental results showed that the experimental reactor exhibited 20% lower in sludge production than the control. FA treatment effectively disintegrated a portion of extracellular or intracellular substances of sludge cells in the FA treatment unit and lowered the observed sludge yields in the mainstream reactor, which were the main reasons for the sludge reduction. Although FA treatment decreased the activities of nitrifiers, denitrifiers, and polyphosphate accumulating organisms in the FA treatment unit, this strategy did not negatively affect the reactor performance and sludge properties of the experimental reactor such as sludge settleability, organic removal, nitrogen removal and phosphorus removal. Further investigation showed that the organics released from the FA treatment process could be used by PAOs and denitrifiers for carbon sources. PMID- 29705640 TI - Geochemical signatures and isotopic systematics constraining dynamics of fluoride contamination in groundwater across Jamui district, Indo-Gangetic alluvial plains, India. AB - A data set of 76 water samples are obtained from surface and sub-surface water bodies to investigate chemical parameters and stable isotopic signatures in order to drive factors leading to fluoride (F-) contamination in groundwater of parts of Jamui district, India. Hydrochemical facies reveals that F- concentration is lower in Ca2+-HCO3- facies representative of recharge area, while discharge area has a tendency towards Na+-HCO3- facies with elevated F- concentration. The ionic ratios Na+/Ca2+>1, Na+/Cl->1, (Ca2++Mg2+)/HCO3-<1, Na++K+ = 0.5TZ+ and Ca2++Mg2+ = TZ+ witness silicate weathering by water-rock interaction coupled with ion exchange and prolonged residence time, are the principle factors for fluoride contamination (3.6 mg/L to 5.8 mg/L) in 67% of deeper bore wells. Geochemical modelling testifies excess of alkalinity due to the dominance of bicarbonate ion leading to calcite precipitation and dissolution of fluoride in solution contributing to fluoride contamination. The chemometric analysis reveals that the water chemistry of the study area is controlled by both anthropogenic and natural sources, and enrichment of fluoride in groundwater is possibly from geogenic source (fractured granite gneiss). The stable isotope plot shows that most of the samples fall along local meteoric water line indicating that the groundwater is originated from local precipitation with a possibility of evaporative enrichment. Groundwater enriched in delta18O is positively correlated with F- suggesting evaporation and longer residence time of water. Spatially elevated F- prevails in the eastern bank of Kiul River and along the groundwater flow direction, which is attributed to control of dynamics of hydrogeological conditions. PMID- 29705641 TI - The in vivo action of chronic bisphenol F showing potential immune disturbance in juvenile common carp (Cyprinus carpio). AB - Bisphenol F (BPF) has been increasingly introduced into industrial applications as a replacement for bisphenol A (BPA), and has emerged as a ubiquitous environmental contaminant worldwide. Few studies have assessed the in vivo toxicities of BPF, particularly long-term exposure toxicities. In the present study, we examined whether long-term BPF exposure in vivo would evoke oxidative stress in the immune system of juvenile common carp. The results suggested that BPF exposure increased ROS content, oxidative stress indices, complement component 3, and immunoglobulin M contents, as well as the expression of inflammatory cytokine genes. Moreover, higher levels of nf-kappab p65 gene expression were correlated with the induced ROS content and NF-kappaB pathway associated genes, a strong indication that the mode of action of BPF is related to the NF-kappaB signaling pathway. We also provide evidence that the effects of BPF are comparable to those of BPA with regards to regulation of the immune response in teleosts, and therefore suggest that such chemical analogs should be thoroughly evaluated for their potential toxicity before they can be considered as "safer" replacements. PMID- 29705642 TI - Rare earth elements in German soils - A review. AB - Rare earth elements (REEs) are increasingly used in high-tech industry, agriculture, and healthcare technologies what leads to their release into soils and waters, and to the transfer into plants what may have negative impacts on human health and the environment. The toxicity and potential mobilization of REEs in soils can be assessed by their content and geochemical behavior along with soil properties. However, those interactions are so far not reviewed in German soils although such a review is important for a better understanding and prediction of the potential mobilization and toxicity. Therefore, this review summarizes the recent knowledge about REE contents and potential mobilization in different soil profiles in Germany. We found that the REE content tends to decrease in dependence on the parent material in the following order: Carbonatite > basalt > orthogneiss > clay slate > loess > sandstone > Pleistocene and Holocene sediments > organic material. Also, we used data of earlier studies, summarized and newly evaluated those data aiming to quantify the factors influencing the total REE content in German soil profiles. The contents of REEs in soil profiles of different parent material showed significant relations with content of clay, carbonate, organic matter, aluminium, iron, and manganese. Geochemical fractionation results suggest that the bioavailability of REEs is relatively low while the residual fraction is relatively high in German soils. In soils, where water fluctuations are important, the redox potential is a key factor controlling the mobilization of REEs also via related changes of pH. PMID- 29705643 TI - Exemplar-based inpainting as a solution to the missing wedge problem in electron tomography. AB - A new method for dealing with incomplete projection sets in electron tomography is proposed. The approach is inspired by exemplar-based inpainting techniques in image processing and heuristically generates data for missing projection directions. The method has been extended to work on three dimensional data. In general, electron tomography reconstructions suffer from elongation artifacts along the beam direction. These artifacts can be seen in the corresponding Fourier domain as a missing wedge. The new method synthetically generates projections for these missing directions with the help of a dictionary based approach that is able to convey both structure and texture at the same time. It constitutes a preprocessing step that can be combined with any tomographic reconstruction algorithm. The new algorithm was applied to phantom data, to a real electron tomography data set taken from a catalyst, as well as to a real dataset containing solely colloidal gold particles. Visually, the synthetic projections, reconstructions, and corresponding Fourier power spectra showed a decrease of the typical missing wedge artifacts. Quantitatively, the inpainting method is capable to reduce missing wedge artifacts and improves tomogram quality with respect to full width half maximum measurements. PMID- 29705644 TI - Japaneseplex: A forensic SNP assay for identification of Japanese people using Japanese-specific alleles. AB - It is sometimes necessary to determine whether a forensic biological sample came from a Japanese person. In this study, we developed a 60-locus SNP assay designed for the differentiation of Japanese people from other East Asians using entirely and nearly Japanese-specific alleles. This multiplex assay consisted of 6 independent PCR reactions followed by single nucleotide extension. The average number and standard deviation of Japanese-specific alleles possessed by an individual were 0.81 +/- 0.93 in 108 Koreans from Seoul, 8.87 +/- 2.89 in 103 Japanese from Tottori, 17.20 +/- 3.80 in 88 Japanese from Okinawa, and 0 in 220 Han Chinese from Wuxi and Changsha. The Koreans had 0-4 Japanese-specific alleles per individual, whereas the Japanese had 4-26 Japanese-specific alleles. Almost all Japanese were distinguished from the Koreans and other people by the factorial correspondence and principal component analyses. The Snipper program was also useful to estimate the degree of Japaneseness. The method described here was successfully applied to the differentiation of Japanese from non-Japanese people in forensic cases. This Japanese-specific SNP assay was named Japaneseplex. PMID- 29705645 TI - Recent Pricing Negotiations on Innovative Medicines Pilot in China: Experiences, Implications, and Suggestions. AB - The China National Formulary (CNF) for reimbursable drug use, also known as the National Reimbursement Drug List (NRDL), was formally established in 2000, revised in 2004 and 2009, and covers 52% of China's population under the government urban health insurance programs. A third major and long-awaited update to the formulary was completed in February 2017 based on intensive reviews by a group of experts in medicine, pharmacology, health economics, and health policy. Shortly after this major update, a pilot project at the central government level was implemented for negotiations mainly on innovative but expensive medicines that were still outside the National Formulary. The pilot, conducted between March and July 2017, eventually reached an overall agreement rate of 81.8% regarding approved indications and drug prices between China's government and the pharmaceutical companies. This pilot showcased numerous leading edge features including a working definition of innovative medicines and opportunities to submit dossiers on drug clinical and economic information. This pilot covered 44 medications for negotiations in a breakthrough attempt to increase the appropriate access to innovative but expensive medicines. The implications to the future of the CNF go beyond the drugs included in the pilot. This paper describes the background of the CNF and the negotiation pilot. In addition, authors of this paper make six recommendations critical to CNF future developments, including enhancing criteria and process for evaluations, standardizing the dossier format, specifying data requirements, refining pricing calculation, and cultivating evaluation professional development. PMID- 29705646 TI - Sol-gel based biogenic silica composite as green nanosorbent for chemometric optimization of micro-solid-phase extraction of beta blockers. AB - An environmentally friendly micro-solid phase extraction (MU-SPE) method utilizing a plant based nanocomposite as a sorbent for determination of trace level beta blockers (beta-blockers) in hospital wastewater prior to Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis. MU-SPE extraction conditions were evaluated using a multivariate chemometric approach. Rice husk silica-carbon nanocomposite (5-20Wt.% Fe) in glycerol were synthesized via hydrolytic sol-gel method. The nanosorbent were fully characterized and then evaluated for MU-SPE of trace level beta-blockers in hospital wastewater. To establish the best extraction conditions at minimal experimental cost, multivariate techniques based on fractional factorial (FFD) and central composite designs (CCD) with desirability function (DF) were used to optimize the extraction conditions. Experimental results showed good agreement with predicted values and logical DF was realized at relatively low extraction time. Under optimized conditions, good linearity ranges (0.02-5.0MUgL-1) with correlation of determinations higher than 0.9954 were obtained. The limits of detection and quantitation for the five beta-blockers (atenolol, alprenolol, pindolol, acebutolol and propranolol) ranged from 4.0-6.4 and 13.0-19.0ngL-1, respectively. Inter-day and intra-day precision (percent relative standard deviations, n=5) were lower than 8.3% while relative recoveries for hospital wastewater samples (80.6-105.1%) were in satisfactory ranges. This experimental approach therefore, demonstrated simplicity, reduction in the experimental runs, effectively increased sensitivity of LC-MS/MS and was hence suitable for complex matrix sample analysis. PMID- 29705647 TI - Sample preparation procedure using extraction and derivatization of carboxylic acids from aqueous samples by means of deep eutectic solvents for gas chromatographic-mass spectrometric analysis. AB - The paper presents a new procedure for the determination of organic acids in a complex aqueous matrix using ultrasound-assisted dispersive liquid-liquid microextraction followed by injection port derivatization and GC-MS analysis. A deep eutectic solvent (choline chloride: 4-methylphenol in a 1:2 mol ratio) was used both as an extracting solvent and as a derivatizing agent to yield ion pairs which were next converted to methyl esters of organic acids in a hot GC injection port. The procedure was optimized in terms of selection of a deep eutectic solvent, disperser solvent, and the ratio of their volumes, pH, salting out effect, extraction time, injection port temperature and time of opening the split valve. The developed procedure is characterized by low LOD (1.7-8.3 MUg/L) and LOQ (5.1-25 MUg/L) values, good repeatability (RSD ranging from 4.0 to 6.7%), good recoveries for most of the studied analyte (81,5-106%) and a wide linear range. The procedure was used for the determination of carboxylic acids in real effluents from the production of petroleum bitumens. A total of ten analytes at concentrations ranging from 0.33 to 43.3 MUg/mL were identified and determined in the effluents before and after chemical treatment. The study revealed that in effluents treated by hydrodynamic cavitation an increase in concentration of benzoic acid and related compounds was observed. PMID- 29705648 TI - Chromatographic separation of phenyllactic acid from crude broth using cryogels with dual functional groups. AB - Phenyllactic acid (PLA) is an important organic acid with wide antimicrobial activities against gram-positive and gram-negative bacteria and some fungi. This interesting compound can be synthesized by the microbial fermentation or the bioconversion using phenylpyruvic acid (PPA) as the key substrate and microorganisms as the whole-cell biocatalysts. However, the isolation of high purity PLA with a high recovery from the crude fermentation or conversion broth is a challenging task. In this work, the separation of PLA from the crude conversion broth prepared by employing Lactobacillus buchneri cells as the whole cell catalysts was achieved by the chromatography using the poly(hydroxyethyl methacrylate) (pHEMA)-based cryogel with a combination of anion-exchange and hydrophobic benzyl groups. The static adsorption behaviors of PLA under different salt concentrations and the adsorption capacities of PLA on the cryogel were measured experimentally. The chromatographic performance of PLA from the crude conversion broth was compared with that from the clarified broth. The results showed that the pHEMA-based cryogel has a high capacity of PLA, i.e., 14.64 mg mL 1 cryogel, and the adsorption of PLA was influenced by the salt concentration. By using deionized water as running buffer, PLA with a high purity of 97.6% was obtained with one step elution using 0.3 M NaCl as the elution solution with the recovery at the range of 80.2-90.8% from crude feedstock without any pretreatment at various flow velocities. These values were close to those obtained for the clarified broth, i.e., the purity of 98.4% and the recovery of 92.3% under the same chromatography conditions at 1 cm min-1. The cryogel was then applied to separate PLA from clarified feedstock, high purity (>96.7%) and recovery (>91.4%) of PLA were found with 20 cycles, which verified the selectivity and robustness of prepared pHEMA-VBTAC cryogel. Therefore, the chromatography using pHEMA-based cryogel with the dual functional groups is an effective approach for the isolation of PLA directly from the crude bioconversion broth and thus could be interesting in the separation and production of high-purity PLA in industry. PMID- 29705649 TI - Lab-In-Syringe automation of stirring-assisted room-temperature headspace extraction coupled online to gas chromatography with flame ionization detection for determination of benzene, toluene, ethylbenzene, and xylenes in surface waters. AB - Online coupling of Lab-In-Syringe automated headspace extraction to gas chromatography has been studied. The developed methodology was successfully applied to surface water analysis using benzene, toluene, ethylbenzene, and xylenes as model analytes. The extraction system consisted of an automatic syringe pump with a 5 mL syringe into which all solutions and air for headspace formation were aspirated. The syringe piston featured a longitudinal channel, which allowed connecting the syringe void directly to a gas chromatograph with flame ionization detector via a transfer capillary. Gas injection was achieved via opening a computer-controlled pinch valve and compressing the headspace, upon which separation was initialized. Extractions were performed at room temperature; yet sensitivity comparable to previous work was obtained by high headspace to sample ratio VHS/VSample of 1.6:1 and injection of about 77% of the headspace. Assistance by in-syringe magnetic stirring yielded an about threefold increase in extraction efficiency. Interferences were compensated by using chlorobenzene as an internal standard. Syringe cleaning and extraction lasting over 10 min was carried out in parallel to the chromatographic run enabling a time of analysis of <19 min. Excellent peak area repeatabilities with RSD of <4% when omitting and <2% RSD when using internal standard corrections on 100 MUg L-1 level were achieved. An average recovery of 97.7% and limit of detection of 1-2 MUg L-1 were obtained in analyses of surface water. PMID- 29705650 TI - Baroreflex activation therapy for the treatment of heart failure with reduced ejection fraction in patients with and without coronary artery disease. AB - BACKGROUND: In a randomized trial, baroreflex activation therapy (BAT) improved exercise capacity, quality of life and NT-proBNP in patients with heart failure with reduced ejection fraction (HFrEF). In view of different mechanisms underlying HFrEF, we performed a post-hoc subgroup analysis of efficacy and safety of BAT in patients with and without coronary artery disease (CAD). METHODS AND RESULTS: Patients with left ventricular ejection fraction <35% and NYHA Class III were randomized 1:1 to guideline-directed medical and device therapy alone or plus BAT. Patients with a history of CAD, prior myocardial infarction or coronary artery bypass graft were assigned to the CAD group with all others assigned to the no-CAD group. Of 71 BAT treated patients, 52 had CAD and 19 had no CAD. In the control group, 49 of 69 patients had CAD and 20 had no CAD. The system- or procedure-related major adverse neurological or cardiovascular event rate was 3.8% in the CAD group vs. 0% in the no-CAD group (p = 1.0). In the whole cohort, NYHA Class, Minnesota Living with Heart Failure score, 6-minute hall walk distance and NTproBNP were improved in BAT treated patients compared with controls. Statistical analyses revealed no interaction between the presence of CAD and effect of BAT (all p > 0.05). CONCLUSION: No major differences were found in BAT efficacy or safety between patients with and without CAD, indicating that BAT improves exercise capacity, quality of life and NTproBNP in patients with ischemic and non-ischemic cardiomyopathy. CLINICALTRIALS. GOV IDENTIFIER: NCT01471860 and NCT01720160. PMID- 29705651 TI - Risk stratification of acute pulmonary embolism based on clinical parameters, H FABP and multidetector CT. PMID- 29705652 TI - Nonoperative management of C-2 dens fractures: Single center experience and review of the literature. AB - OBJECTIVE: The demographic change in the population leads to a rising number of patients presenting with fractures of the cervical spine, especially C-2, due to falls. With an increase of co-morbidities in these elder patients, the risk for intra- and postoperative complications is increased likewise. Thus, an alternative strategy instead of operative management of these fractures should be taken into account whenever possible. Conservative management of dens fractures in the elderly is still a subject of great controversy despite numerous studies on this topic. The aim of this study was to analyze the rate of successful osseous consolidation of C-2 fractures with conservative treatment by wearing a semi-rigid collar or halo thoracic vest without further surgical intervention. PATIENTS AND METHODS: We analyzed the medical records and CT-scan of the cervical spine of 254 patients with C-2 fractures retrospectively, who were admitted to our department between January 1990 and September 2015. Fractures were diagnosed by CT-scan of the cervical spine and classified according to the Anderson - D'Alonzo classification. 183 patients were submitted to surgery as treatment of choice. In 71 patients a conservative management with external immobilization was chosen. The latter group was subjected to study analysis. RESULTS: 71 patients (mean age 74.08 years +/- 16.06 years) were diagnosed with C-2 fractures (Typ I: 4; Typ II 36; Typ III: 31) and treated conservatively using a Philadelphia collar (n = 57), or a halo-thoracic vest (n = 14), respectively. 12 patients were lost to follow up and excluded from further analysis. Conservative treatment of the fractures was deemed successful when a bony consolidation of the fracture in follow-up CT scans was seen (45 of 59 patients; 76.3%). 20 patients with a Type II fracture (20/28, 71.4%) showed a successful ossification. In 14 patients (overall 23.7%; Typ I: 1 (7.14%), Typ II: 8 (57.14%), Typ III: 5 (35.71%)) external immobilization failed to achieve primary stability. These patients were submitted to consecutive surgery. CONCLUSION: From our data it can be concluded that elderly patients, presenting with non-dislocated Type II fractures of the axis without accompaining neurological deficits, will have a more than 70% chance for a bony consolidation by conservative management. Consolidation rates may be estimated even higher in Type I and III fractures. Therefore, we suggest that external immobilization might be a valuable option to treat elderly patients with these fractures under certain circumstances. PMID- 29705653 TI - LRRK2-associated Parkinson's disease patients have better stereopsis than idiopathic Parkinson disease. AB - OBJECTIVES: Visual dysfunctions are frequent and have several manifestations in idiopathic Parkinson's disease (PD). However, the characteristics of these complications in LRRK2 (leucine-rich kinase 2)-associated PD patients still lack systematic research. The purpose of this study is to assess visual functions of LRRK2-associated PD patients. PATIENTS AND METHODS: Twenty-five (25) PD patients with LRRK2 R1628P and G2385R variants were included in the study and compared to 28 PD patients without these variants and 28 age-matched healthy controls. The genotypes of PD patients were kept double-blinded. Information on age, sex, disease duration, the movement disorder society-unified Parkinson's disease rating scale (MDS-UPDRS), Hoehn and Yahr staging scale (H&Y), Mini-Mental Examination (MMSE) and Montreal Cognitive Assessment (MoCA) were included. Visual functions assessment included color perception, contrast sensitivity and stereopsis. RESULTS: PD patients with or without LRRK2 R1628P and G2385R variants have declined contrast sensitivity, diminished color discrimination and damaged stereopsis. There was no significant difference in retinal level visual deficiency (color discrimination and contrast sensitivity) between PD with LRRK2 variants and those without, but cortex level visual function, i.e. stereopsis is better in PD with LRRK2 variants than non-carrier PD patients. The associated factors of stereopsis are different. The stereopsis is associated with MoCA scores independently in non-carrier PD patients, but with UPDRSIII scores in LRRK2-associated PD patients. CONCLUSIONS: Visual functions are similarly affected in PD patients with and without LRRK2 R1628P and G2385R variants, but LRRK2-associated PD patients have better stereopsis than idiopathic PD patients. PMID- 29705654 TI - The seizure precipitating effect of alcohol: A prospective observational cross over study. AB - PURPOSE: The aim of this study was to investigate the association between alcohol use and seizures in acutely hospitalized patients. We wished to study the extent of the problem as well as the clinical characteristics of people with various forms of alcohol-related seizures, including their drinking pattern. METHOD: After admission, a semi-structured interview took place with 134 consecutive patients (epilepsy 92, single seizures 42). Alcohol use was assessed by the Alcohol Use Disorders Identification Test (AUDIT) and by the number of alcohol units consumed during 6 days prior to the seizure. Sleep time was recorded during the previous 3 days and nights. A follow-up telephone interview covering the same weekdays was performed on a seizure-free day at least 4 weeks later. RESULTS: 28% of patients had AUDIT scores >=8 (hazardous drinking); 22% in epilepsy, 43% in single seizures (p = .012). Non-focal seizures were increased in single seizures, suggesting a withdrawal mechanism. In the 58 epilepsy patients with social drinking (excluded hazardous drinking or excessive binging), the alcohol intake was not different prior to seizure compared to follow-up, downgrading the role of modest alcohol intake as a seizure precipitant in epilepsy. On the other hand, a high percentage of binge drinkers had epilepsy (57%), and in the subgroup of Idiopathic Generalized Epilepsy (IGE) even social drinking was associated with seizures. Seizures peaked on Sundays and Mondays. Less sleep prior to the seizure was associated with hazardous drinking. CONCLUSION: Alcohol is a major seizure precipitant in the context of hazardous drinking and withdrawal. In people with epilepsy, occasional binge drinking is associated with loss of seizure control. Social drinking is an uncommon cause of seizure breakthrough in predominantly focal epilepsy, but caution is warranted in IGE. Alcohol intake prior to a seizure is often accompanied by other triggers, such as sleep loss. Alcohol alone should not always be blamed. PMID- 29705655 TI - Spatially confined induction of endochondral ossification by functionalized hydrogels for ectopic engineering of osteochondral tissues. AB - Despite the various reported approaches to generate osteochondral composites by combination of different cell types and materials, engineering of templates with the capacity to autonomously and orderly develop into cartilage-bone bi-layered structures remains an open challenge. Here, we hypothesized that the embedding of cells inducible to endochondral ossification (i.e. bone marrow derived mesenchymal stromal cells, BMSCs) and of cells capable of robust and stable chondrogenesis (i.e. nasal chondrocytes, NCs) adjacent to each other in bi layered hydrogels would develop directly in vivo into osteochondral tissues. Poly(ethylene glycol) (PEG) hydrogels were functionalized with TGFbeta3 or BMP-2, enzymatically polymerized encapsulating human BMSCs, combined with a hydrogel layer containing human NCs and ectopically implanted in nude mice without pre culture. The BMSC-loaded layers reproducibly underwent endochondral ossification and generated ossicles containing bone and marrow. The NC-loaded layers formed cartilage tissues, which (under the influence of BMP-2 but not of TGFbeta3 from the neighbouring layer) remained phenotypically stable. The proposed strategy, resulting in orderly connected osteochondral composites, should be further assessed for the repair of osteoarticular defects and will be useful to model developmental processes leading to cartilage-bone interfaces. PMID- 29705656 TI - Humanization of bone and bone marrow in an orthotopic site reveals new potential therapeutic targets in osteosarcoma. AB - BACKGROUND: Existing preclinical murine models often fail to predict effects of anti-cancer drugs. In order to minimize interspecies-differences between murine hosts and human bone tumors of in vivo xenograft platforms, we tissue-engineered a novel orthotopic humanized bone model. METHODS: Orthotopic humanized tissue engineered bone constructs (ohTEBC) were fabricated by 3D printing of medical grade polycaprolactone scaffolds, which were seeded with human osteoblasts and embedded within polyethylene glycol-based hydrogels containing human umbilical vein endothelial cells (HUVECs). Constructs were then implanted at the femur of NOD-scid and NSG mice. NSG mice were then bone marrow transplanted with human CD34 + cells. Human osteosarcoma (OS) growth was induced within the ohTEBCs by direct injection of Luc-SAOS-2 cells. Tissues were harvested for bone matrix and marrow morphology analysis as well as tumor biology investigations. Tumor marker expression was analyzed in the humanized OS and correlated with the expression in 68 OS patients utilizing tissue micro arrays (TMA). RESULTS: After harvesting the femurs micro computed tomography and immunohistochemical staining showed an organ, which had all features of human bone. Around the original mouse femur new bone trabeculae have formed surrounded by a bone cortex. Staining for human specific (hs) collagen type-I (hs Col-I) showed human extracellular bone matrix production. The presence of nuclei staining positive for human nuclear mitotic apparatus protein 1 (hs NuMa) proved the osteocytes residing within the bone matrix were of human origin. Flow cytometry verified the presence of human hematopoietic cells. After injection of Luc-SAOS-2 cells a primary tumor and lung metastasis developed. After euthanization histological analysis showed pathognomic features of osteoblastic OS. Furthermore, the tumor utilized the previously implanted HUVECS for angiogenesis. Tumor marker expression was similar to human patients. Moreover, the recently discovered musculoskeletal gene C12orf29 was expressed in the most common subtypes of OS patient samples. CONCLUSION: OhTEBCs represent a suitable orthotopic microenvironment for humanized OS growth and offers a new translational direction, as the femur is the most common location of OS. The newly developed and validated preclinical model allows controlled and predictive marker studies of primary bone tumors and other bone malignancies. PMID- 29705657 TI - Acute phase proteins and antioxidant responses in queens with pyometra. AB - Acute phase proteins (APP) and biomarkers of oxidative status have proved to be clinically useful biomarkers of pyometra in different species. Despite pyometra is considered one of the most important feline reproductive diseases, information about the APP response and the oxidative status in queens with pyometra is lacking. This study aimed to evaluate the APP and the antioxidant responses at diagnosis and in the post-operative period in feline pyometra. Serum concentrations of serum amyloid A (SAA), haptoglobin (Hp), albumin, total serum thiols (Thiol) and total antioxidant capacity determined by different assays, including trolox equivalent antioxidant capacity (TEAC) assessed by two different methodologies (TEAC1 and TEAC2), ferric reducing ability of plasma (FRAP), and cupric reducing antioxidant capacity (CUPRAC), were determined in 23 queens with pyometra at diagnosis and in 13 healthy control queens submitted to elective ovariohysterectomy. The APP and antioxidants were also evaluated in 11 queens of the pyometra group at days two and 10 after surgery. At diagnosis, queens with pyometra had serum concentrations of SAA, Hp, and FRAP significantly higher (P < 0.001, P < 0.001 and P < 0.05, respectively), and of albumin, Thiol, CUPRAC and TEAC2 significantly lower (P < 0.001, P < 0.001, P < 0.001 and P < 0.01, respectively) than controls. Moreover, concentrations of APP and antioxidants were significantly different (with a tendency to return to physiologic levels) at day 10 after surgery than before surgery. Significant associations were found between APP and antioxidants. According to these results, an APP response and the development of oxidative stress were detected in queens with pyometra. In addition, APP and antioxidants tended to return to physiologic values after surgery in the queens that recovered from the disease. Therefore, our results suggest that APP and selected antioxidants, such as Thiol and CUPRAC, could be potentially useful biomarkers in diagnosis and assessment of the post-operative period in feline pyometra. PMID- 29705658 TI - Laminarin improves developmental competence of porcine early stage embryos by inhibiting oxidative stress. AB - Laminarin (LMA), a beta-glucan mixture with good biocompatibility, improves the growth performance and immune response when used as food additives and nutraceuticals. The aim of the present research was to explore the effects of LMA on porcine early stage embryo development, as well as the underlying mechanisms. The results showed that the developmental competence of porcine early stage embryos was dramatically improved after LMA supplementation during the in vitro culture period. The presence of 20 MUg/mL LMA during the in vitro culture period significantly improved cleavage rate, blastocyst formation rates, hatching rate, and total cell number in the blastocyst compared to that in the control group. Notably, LMA attenuated the intracellular reactive oxygen species generation induced by H2O2. Furthermore, LMA not only increased intracellular glutathione levels, but also ameliorated mitochondrial membrane potential. In addition, the expression of a zygotic genome activation related gene (YAP1), pluripotency related genes (OCT4, NANOG, and SOX2), and hatching-related genes (COX2, GATA4, and ITGA5) were up-regulated following LMA supplementation during porcine early stage embryo development. These results demonstrate that LMA has beneficial effects on the development of porcine early stage embryos via regulation of oxidative stress. This evidence provides a novel method for embryo development improvement associated with exposure to LMA. PMID- 29705659 TI - Effect of hCG and OvaprimTM on reproductive characteristics of male Levantine scraper, Capoeta damascina (Valenciennes, 1842). AB - Species richness and abundance within the genus Capoeta has been depleted. As such, there is great need for developing assisted reproductive technologies for controlling reproduction in captivity. Here, we conducted in vivo studies with single administrations of human chorionic gonadotropin (hCG) and OvaprimTM [(D Arg6, Pro9NEt)-sGnRH + domperidone] in wild-caught Levantine scraper, Capoeta damascina and then evaluated milt characteristics, fertilization success, serum sex steroids, and spermatogenesis via histological testicular development. Spermiation responses were significantly stronger for Ovaprim injected fish than those injected with hCG or saline. hCG had a negative effect on milt quality by reducing the percentage of motile sperm and fertilization success at 12-48 h post injection (hpi), which was not observed after treatment with Ovaprim or the saline injection. Hormonal therapy resulted in higher sperm densities and spermatocrit, although sperm longevity was not impacted. Sex steroids were not impacted by hCG or saline injection, but Ovaprim effectively induced androgen and progestin release, as evident by higher serum levels of testosterone, and 17alpha,20beta-dihydroxy-4-pregnen-3-one. Consequently, their levels peaked at 12 hpi, which coincided with maximal milt production. Histological analysis of the testes and quantification of germ cell types revealed that Ovaprim significantly stimulated spermiogenesis, as a higher number of accumulated spermatozoa were observed at 12 h and 24 hpi. Testes from saline and hCG-injected fish remained unchanged through the experiment, and contained all stages of germ cells, predominantly spermatocytes with few spermatozoa. In conclusion, Ovaprim treatment successfully induced steroidogenesis and maturation of spermatogenic germ cells, leading to spermiation and milt production without having any negative impacts on sperm quality and fertility in wild-caught C. damascina. PMID- 29705660 TI - In situ preparation of highly stable polyaniline/W18O49 hybrid nanocomposite as efficient visible light photocatalyst for aqueous Cr(VI) reduction. AB - In the present study, we prepared novel polyaniline supported W18O49 (PANI/W18O49) nanocomposite by in situ oxidative polymerisation method. We herein focused on enhancing the stability and the photocatalytic performance of W18O49. The prepared PANI/W18O49 was thoroughly characterized by FTIR, TEM, XRD, BET, UV vis DRS and PL. The PANI support presented a great effect on the light harvesting and photo-charge transfer of the W18O49, and the optimum percentage of was found to be 10 wt%. As for treating Cr(VI), the effect of important water quality parameters (such as pH, ions, NOM, DO, temperature and SOAs) on photocatalytic performance was investigated under the visible light irradiation (lambda > 420 nm). SOAs were shown to exert a dramatic accelerating influence on Cr(VI) reduction in the system. The obtained 10%-PANI/W18O49 can completely catalytically reduce 1 mM Cr(VI) in the presence of tartaric acid (1:3) within 50 min. Meanwhile, it can be recycled at ten times without any loss of photocatalytic efficiency, indicating the high stability of the as-prepared photocatalyst. The results of the study demonstrate the potential of the new obtained photocatalyst in efficient utilization of solar energy for treating aqueous Cr(VI). PMID- 29705661 TI - A suggestion to radiological hazards characterization of 226Ra, 232Th, 40K and 137Cs: spatial distribution modelling. AB - Spatial distribution modelling has been proposed to characterize the radiological hazards associated with concentration of natural 226Ra, 232Th, 40K and artificial 137Cs radionuclides in the nature. These elements have been determined for the sediment samples of the Bafa Lake with the aim of radiation hazard evaluation via a high purity germanium detector gamma spectrometry. Their activity concentrations in sediments are in the ranges of 29.87 +/- 2.2-72.56 +/- 11 Bq kg 1 dry weight (dw), 31.57 +/- 3.5-66.48 +/- 8.3 Bq kg- 1 (dw), 332.01 +/- 12 1092.37 +/- 21 and 0.65 +/- 0.04-3.96 +/- 0.78 Bq kg- 1 (dw), respectively. In order to determine the radiological hazard associated with the radioactivity in the samples, the external terrestrial gamma dose rate in air, annual effective dose rate, the radium equivalent activity and the external hazard index are calculated and compared with the data from literature. Moreover, the spatial modelling distributions are obtained visually for radiological hazards characterization of these elements, which are very dangerous in terms of radiological and environmental pollution in the nature. These visual distributions give meaningful information for future researches on the migration of radionuclides in the environment. PMID- 29705662 TI - Combination of bioaugmentation and biostimulation for remediation of paddy soil contaminated with 2,4-dichlorophenoxyacetic acid. AB - The batch and fed-batch tests were performed to evaluate the efficiency of bioaugmentation in combination with biostimulation for remediation of paddy soil contaminated with 2,4-dichlorophenoxyacetic acid (2,4-D). 2,4-D degrading enrichments were used for bioaugmentation, and effluents prepared through biological hydrogen production process were used as substrate for biostimulation. The batch tests indicated that 2,4-D degradation depended on the enrichment/substrate ratio (E/S), where E/S of 0.03 showed an excellent performance. The fed-batch tests showed that biostimulation only led to an improvement in 2,4-D degradation, while the pattern of repeated augmentation of enrichments (FRA) together with biostimulation obviously improved degradation of 2,4-D, 2-chlorophenol (2-CP) and phenol. DNA-sequencing approach showed that the FRA pattern altered the bacterial community composition, and high removal of 2,4 D, 2-CP and phenol may be attributed to the acclimation and persistence of Thauera. The findings demonstrated the importance of the FRA pattern on remediation of paddy soil contaminated with 2,4-D. PMID- 29705663 TI - Dual-template docking oriented ionic imprinted bilayer mesoporous films with efficient recovery of neodymium and dysprosium. AB - Rare earth elements (REEs) are critical materials to many cutting-edge technologies but are difficult to separate from one another because of their chemical similarity. We present ionic imprinted mesoporous bilayer films (IIBFs) as an ideal adsorbent for selective separation of neodymium (Nd) and dysprosium (Dy) from sintered neodymium magnets. IIBFs were prepared according to dual template docking oriented ionic imprinting (DTD-OII). Due to different imprinted compositions of bilayer films, IIBFs exhibited high specific surface area, fast binding equilibrium, and Janus properties for simultaneous selective adsorption of different rare earth ions, which made our imprinted bilayer mesoporous films a specialized adsorbent for adsorption of Nd(III) and Dy(III) at the same time. The adsorption capacities of optimized IIBFs were 17.50 mg g-1 for Dy(III) and 12.15 mg g-1 for Nd(III) at pH = 4.0. Moreover, we grafted thermo-responsive polymer on the one surface of IIBFs to realize controlled release of Nd(III) and Dy(III) by temperature. IIBFs demonstrate a high degree of reusability by cycling experiments by DTD-OII, which develop their promising applications for the REE recycling and separation industry. PMID- 29705664 TI - Kinetics of human serum albumin adsorption at silica sensor: Unveiling dynamic hydration function. AB - Adsorption kinetics of human serum albumin (HSA) at a silica substrate was studied using the QCM-D and AFM methods. Measurements were performed at pH 3.5 for various bulk suspension concentrations and ionic strengths. The QCM experimental data were compared with the dry coverage of HSA derived from AFM and from the solution of the mass transfer equation. In this way, the dynamic hydration functions and water factors of HSA monolayers were quantitatively evaluated as a function of dry coverage for various ionic strengths. Using the hydration functions, the HSA adsorption runs derived from QCM-D measurements were converted to the dry coverage vs. the time relationships. In this way, the maximum coverage of irreversibly bound HSA molecules was determined. It was equal to 0.35 and 1.4 mg m-2 for NaCl concentration of 0.001 and 0.15 M, respectively. These results agree with previous experimental data derived by streaming potential measurements for mica and with theoretical modeling. Therefore, the side-on mechanism of HSA adsorption at silica sensor at pH 3.5 was confirmed. Also, a quantitative analysis of the desorption runs allowed one to calculate the binding energy of the reversibly bound HSA fraction. Beside significance to basic science, these results enable to develop a robust technique of preparing HSA monolayers at silica sensor of well-controlled coverage and molecule orientation. PMID- 29705665 TI - Magnetic nanoparticle decorated graphene based electrochemical nanobiosensor for H2O2 sensing using HRP. AB - To utilize synergetic effect of graphene's higher conductivity and magnetic nanoparticles biocompatibility, an electrochemical nanobiosensor is constructed based on magnetic nanoparticle decorated graphene (MRGO) using Horseradish peroxidase (HRP) for H2O2 sensing. Sensors based on magnetic nanoparticles (MNP) and reduced graphene oxide (RGO) are studied for comparison. MNP, RGO and MRGO were characterized by X-ray diffraction (XRD), Transmission electron microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR). XRD studies have confirmed successful synthesis of Fe3O4 MNPs, RGO and MRGO. TEM micrographs revealed uniform decoration of MNPs on graphene. FTIR confirmed the immobilization of HRP on MNP, RGO and MRGO. The MRGO based sensor exhibited higher sensitivity (48.08 MUA MUM-1 cm-2) compared to MNP (39.08 MUA MUM-1 cm-2) and RGO (41.08 MUA MUM-1 cm-2) based biosensors. PMID- 29705666 TI - The "pre-assembled state" of magainin 2 lysine-linked dimer determines its enhanced antimicrobial activity. AB - Antimicrobial peptides (AMPs) are alternatives to conventional antibiotics against multi-drug resistant bacteria with low potential for developing microbial resistance. The design of such molecules requires understanding of the mechanisms of action, particularly the interaction with bacteria cell membranes. In this work, we determine the mechanism responsible for the higher activity against Escherichia coli of the C-terminal lysine dimer of magainin 2, (MG2)2K, in comparison to the monomeric peptide magainin 2 (MG2). Langmuir monolayers and vesicles made with the E. coli lipid extract were used to address the two possible states for the peptide-membrane interaction, namely the "binding state" and "pore state", respectively. The incorporation of MG2 and (MG2)2K in lipid monolayers at the air-water interface caused slight differences in surface pressure isotherms and polarization-modulated infrared reflection absorption (PM IRRAS) spectra, and therefore the difference in activity is not associated with the binding state. In contrast, large differences were observed in the leakage experiments where (MG2)2K was shown to disrupt the large unilamellar vesicles to a much higher extent owing to efficient pore formation. The binding and penetration of MG2 and (MG2)2K were also probed with molecular dynamics (MD) simulations for bilayers made with 1-palmitoyl-2-oleoyl-sn-glycero-3 phosphoethanolamine:1-palmitoyl-2-oleoyl-sn-glycero-3-phosphoglycerol (POPE:POPG). (MG2)2K forms disordered toroidal pores at a significant lower concentration than for MG2. In summary, the combination of experimental and computational simulation results indicated that the "pre-assembling state" of (MG2)2K dimer leads to a reduced number of molecules and shorter time being required to kill E. coli. PMID- 29705667 TI - Development and evaluation of the Communication over Language Barriers questionnaire (CoLB-q) in paediatric healthcare. AB - OBJECTIVE: To develop a valid and reliable questionnaire addressing the experiences of healthcare personnel of communicating over language barriers and using interpreters in paediatric healthcare. METHODS: A multiple- methods approach to develop and evaluate the questionnaire, including focus groups, cognitive interviews, a pilot test and test-retest. The methods were chosen in accordance with questionnaire development methodology to ensure validity and reliability. RESULTS: The development procedure showed that the issues identified were highly relevant to paediatric healthcare personnel and resulted in a valid and reliable Communication over Language Barriers questionnaire (CoLB-q) with 27 questions. CONCLUSION: The CoLB-q is perceived as relevant, important and easy to respond to by respondents and has satisfactory validity and reliability. PRACTICE IMPLICATIONS: The CoLB-q can be used to map how healthcare personnel overcome language barriers through communication tools and to identify problems encountered in paediatric healthcare. Furthermore, the transparently described process could be used as a guide for developing similar questionnaires. PMID- 29705668 TI - A frequency-domain approach to improve ANNs generalization quality via proper initialization. AB - The ability to train a network without memorizing the input/output data, thereby allowing a good predictive performance when applied to unseen data, is paramount in ANN applications. In this paper, we propose a frequency-domain approach to evaluate the network initialization in terms of quality of training, i.e., generalization capabilities. As an alternative to the conventional time-domain methods, the proposed approach eliminates the approximate nature of network validation using an excess of unseen data. The benefits of the proposed approach are demonstrated using two numerical examples, where two trained networks performed similarly on the training and the validation data sets, yet they revealed a significant difference in prediction accuracy when tested using a different data set. This observation is of utmost importance in modeling applications requiring a high degree of accuracy. The efficiency of the proposed approach is further demonstrated on a real-world problem, where unlike other initialization methods, a more conclusive assessment of generalization is achieved. On the practical front, subtle methodological and implementational facets are addressed to ensure reproducibility and pinpoint the limitations of the proposed approach. PMID- 29705669 TI - Using a model of human visual perception to improve deep learning. AB - Deep learning algorithms achieve human-level (or better) performance on many tasks, but there still remain situations where humans learn better or faster. With regard to classification of images, we argue that some of those situations are because the human visual system represents information in a format that promotes good training and classification. To demonstrate this idea, we show how occluding objects can impair performance of a deep learning system that is trained to classify digits in the MNIST database. We describe a human inspired segmentation and interpolation algorithm that attempts to reconstruct occluded parts of an image, and we show that using this reconstruction algorithm to pre process occluded images promotes training and classification performance. PMID- 29705670 TI - Effect of dilution in asymmetric recurrent neural networks. AB - We study with numerical simulation the possible limit behaviors of synchronous discrete-time deterministic recurrent neural networks composed of N binary neurons as a function of a network's level of dilution and asymmetry. The network dilution measures the fraction of neuron couples that are connected, and the network asymmetry measures to what extent the underlying connectivity matrix is asymmetric. For each given neural network, we study the dynamical evolution of all the different initial conditions, thus characterizing the full dynamical landscape without imposing any learning rule. Because of the deterministic dynamics, each trajectory converges to an attractor, that can be either a fixed point or a limit cycle. These attractors form the set of all the possible limit behaviors of the neural network. For each network we then determine the convergence times, the limit cycles' length, the number of attractors, and the sizes of the attractors' basin. We show that there are two network structures that maximize the number of possible limit behaviors. The first optimal network structure is fully-connected and symmetric. On the contrary, the second optimal network structure is highly sparse and asymmetric. The latter optimal is similar to what observed in different biological neuronal circuits. These observations lead us to hypothesize that independently from any given learning model, an efficient and effective biologic network that stores a number of limit behaviors close to its maximum capacity tends to develop a connectivity structure similar to one of the optimal networks we found. PMID- 29705671 TI - Dosimetric properties of KMgF3:Tb + PTFE. AB - This work presents the results obtained from the dosimetric properties of the new radiation detectors of KMgF3:Tb + PTFE. The thermoluminescent material was obtained by microwave technique. The polycrystalline powder obtained was mixed with polytetrafluoroethylene resin powder in the ratio 2:3 to make dosimeters in pellet form. The thermoluminescent response of these new detectors presented a linear behavior, in the dose range between 1 and 1000 Gy 60Co gamma radiation, the repeatability test in the measurements, during ten cycles of heat treatment, irradiation and readouts, showed +/- 3.7% DS, the stability test of thermoluminescent signal, during two months showed that the fading is practically null. For the results obtained, this new detector could be very useful for radiation dosimetry, in clinical applications. PMID- 29705672 TI - Mechanical properties of cobalt-chromium 3-unit fixed dental prostheses fabricated by casting, milling, and additive manufacturing. AB - STATEMENT OF PROBLEM: New additive manufacturing techniques for nonprecious alloys have made the fabrication of metal-ceramic fixed partial dentures (FPDs) less expensive and less time-consuming. However, whether the mechanical properties produced by these techniques are comparable is unclear. PURPOSE: The purpose of this in vitro study was to evaluate the mechanical properties of cobalt-chromium frameworks for FPDs fabricated by 3 different techniques. MATERIAL AND METHODS: Thirty frameworks for 3-unit FPDs were fabricated by traditional casting, computer-aided design and computer-aided manufacturing (CAD CAM) milling, and selective laser melting (SLM), with n=10 in each group. The frameworks were weighed, and distal and mesial connector areas measured. The frameworks were cemented and loaded centrally (0.5 mm/s) until deformation above 1 mm occurred. Stiffness was measured as the slope of the axis between 500 and 2000 N. Microhardness was measured on sectioned specimens by Vickers indentation. The microstructure was also analyzed by scanning electron microscopy. One-way ANOVA with Tukey post hoc analysis was used to compare the groups (alpha=.05). RESULTS: The framework design differed among the groups, making a comparison of strength impossible. The milled frameworks appeared bulky, while the cast and SLM frameworks were more slender. Statistically significant differences were found in microhardness, stiffness, wall thickness, weight, and connector size (P<.05), and a significant correlation was found between hardness and stiffness (-0.4, P<.005). CONCLUSIONS: Fabrication method affects the design, stiffness, microhardness, and microstructure of cobalt-chromium FPD frameworks. The SLM frameworks were stiffer and harder than the cast and milled specimens. PMID- 29705673 TI - ACE, APOA5, and MTP Gene Polymorphisms Analysis in Relation to Triglyceride and Insulin Levels in Pediatric Patients. AB - BACKGROUND AND AIMS: Obesity is a complex, chronic, and multifactorial disease that has become a major, and worldwide, public health problem contributing to an increased number of pathologies, including type 2 diabetes, cardiovascular disease, hyperlipidemia, and metabolic syndrome, thus suggesting a commolon origin. A diet high in sugar and fats coupled with a sedentary lifestyle has a major role in the development of obesity. However, the genetic background has also been associated with body fat accumulation. The aim of this study was to assess the effect ofACE-rs4646994, APOA5-rs662799, and MTP-rs1800591 gene polymorphisms on clinical and biochemical parameters and to evaluate the association with body phenotypes in children and adolescent population of Saltillo, Coahuila, Mexico. METHODS: Anthropometric, clinical, biochemical parameters and BMI were obtained from 405 children and adolescents. The BMI was used to determine the body phenotype. The rs4646994 gene polymorphism was determined by PCR, whereas rs662799 and rs1800591 were determined by PCR-RFLP. The obtained results were analyzed to determine their association of these single nucleotide polymorphisms with body phenotype and biochemical parameters. RESULTS: TT genotype for APOA5-rs662799 was associated with increased levels of HDL-C in the analyzed population (p <0.05). The ACErs4646994gene polymorphism is associated with high Insulin levels, HOMAIR index, and triglyceride levels, mainly when presenting a I/I genotype (p <0.05). CONCLUSION: The polymorphic allele of the ACE gene is capable of modulating triglyceride levels, insulin levels and HOMA-IR index in the evaluated population; it must be highlighted that this has not been reported in other studied populations elsewhere. PMID- 29705674 TI - The effect of structured personal care on diabetes symptoms and self-rated health over 14 years after diabetes diagnosis. AB - AIMS: To explore the effect of structured personal care on diabetes symptoms and self-rated health over 14 years after diabetes diagnosis while patients are gradually diagnosed with other chronic conditions (multimorbidity). METHODS: Post hoc analysis of the Danish randomized controlled trial Diabetes Care in General Practice including 1381 patients newly diagnosed with type 2 diabetes. The effect of structured personal care compared with routine care on diabetes symptoms and self-rated health was analysed 6 and 14 years after diagnosis with a generalized multilevel Rasch model. RESULTS: Structured personal care reduced the overall likelihood of reporting diabetes symptoms at the end of the intervention (OR 0.79; 95% CI: 0.64-0.97), but this effect was not explained by glycaemic control or multimorbidity. There was no effect of the intervention on diabetes symptoms after 14 years or on self-rated health after 6 years or 14 years. CONCLUSIONS: Structured personal care had a beneficial effect on diabetes symptoms 6 years after diagnosis, but not on self-rated health at either follow up point. To optimally manage patients over time it is important to supplement clinical information by information provided by the patients. PMID- 29705675 TI - Ovarian metastases from right colon cancer treated with systemic cancer chemotherapy, a case report. AB - BACKGROUND: The progression of cancer from its primary site has been the focus of study of surgeons and oncologists for many decades. Why the primary disease goes on to take the life of some patients while others live out their normal lives after a surgical procedure is only partially understood. METHODS: In a patient with caecal cancer metastatic to the right ovary the clinical, radiologic, surgical and histopathologic findings are presented. Efforts were made to confirm that the disease process was from a single primary site (colon cancer) and not two primary sites (colon cancer and ovarian cancer). RESULTS: In this patient there was progression of ovarian metastases from a right colon cancer simultaneous with near complete disappearance of the primary malignancy. The marked difference in control of the metastatic disease as compared to the primary cancer occurred as multiple treatments of systemic chemotherapy were administered over one year. The specimens of disease removed by surgery showed profound histologic differences at the two sites of cancer. CONCLUSIONS: The primary colon cancer regressed to a small nodule while the ovarian metastases progressed. Efforts to understand and interpret the pathobiology of these observations were made. PMID- 29705676 TI - A case of retroperitoneal desmoid-type fibromatosis that involved the unilateral ureter after gynaecologic surgery. AB - INTRODUCTION: Desmoid-type fibromatosis represents a rare, benign, soft tissue tumour that is locally invasive with high recurrence potential. PRESENTATION OF CASE: We encountered a case of retroperitoneal desmoid-type fibromatosis in a 45 year-old woman who presented with chief complaints of stomach ache and vomiting. She underwent total abdominal hysterectomy and left salpingo-oophorectomy due to uterine myoma and a paroophoritic cyst at 42 years of age. Abdominal computed tomography showed a 5-cm left retroperitoneal tumour and severe hydronephrosis of the left kidney. Multiple imaging studies failed to provide a definitive diagnosis. Therefore, we performed tumour resection, right salpingo-oophorectomy, ureterectomy, and ureterocystostomy. The tumour surrounded the left ureter and adhered to the left internal/external iliac artery, rectum, bladder, and the edge of the vagina. Histopathologic examination yielded a diagnosis of retroperitoneal desmoid-type fibromatosis. One month after the operation, transvaginal sonography showed a 2-cm mass in the pelvis. We suspected tumour recurrence and commenced pharmacotherapy with tranilast (300mg/day, three times per day). Four months after the operation, the mass disappeared. DISCUSSION: There are minimal reports of postoperative intra-abdominal desmoid-type fibromatosis and preoperative diagnosis is difficult. To the best of our knowledge, there are no reported cases of desmoid-type fibromatosis that involved the ureter with severe hydronephrosis following a gynaecologic operation. CONCLUSION: We experienced a case of retroperitoneal desmoid-type fibromatosis that involved a unilateral ureter after gynaecologic surgery. PMID- 29705677 TI - Primary breast leiomyosarcoma with metastases to the lung in a young adult: Case report and literature review. AB - INTRODUCTION: Primary leiomyosarcomas of the breast are extremely rare. Because of this rarity, only a small number of studies have been published about the disease; diagnosis, treatment, and prognosis are not well-described. Our work has been reported in line with the SCARE criteria. PRESENTATION OF CASE: We present a 20-year-old female with primary breast leiomyosarcoma who despite mastectomy, developed lung metastases three years later. DISCUSSION: We discuss the rarity of breast leiomyosarcoma and risk of metastatic disease even with treatment. We review the literature and provide an outline of available data to shed light on the best strategies to manage this aggressive disease. CONCLUSION: Physicians and surgeons treating breast leiomyosarcoma must be vigilant of potential lung metastases in order to optimize short- and long-term oncologic outcomes. PMID- 29705678 TI - An interesting case of inflammatory myofibroblastic tumor presenting as cholangiocarcinoma. AB - INTRODUCTION: Inflammatory myofibroblastic tumor (IMT) is a reactive or inflammatory state mostly affecting the pulmonary system and commonly occurs in children and young adults. IMT presentation in the hepatic duct bifurcation is very rare and has sporadically been reported before. PRESENTATION OF CASE: A 12 year-old girl presented with jaundice, pruritus which had begun 5 weeks previously. Ultrasound revealed intrahepatic biliary ductal dilation and an isoechoic 25*30mm lesion at or near the confluence of the right and left hepatic ducts that were suggestive of a hilar cholangiocarcinoma. Limited resection was decided intraoperatively because the intraoperative frozen section assessment of the CBD, right and left hepatic duct wall samples and porta hepatis lymph nodes was normal. Histologically the tumor proved an inflammatory myofibroblastic tumor (IMT). DISCUSSION: Almost all patients with resectable IMT should be managed with radical surgical resection or single nonsteroidal anti-inflammatory drugs. In addition, conservative treatments with NSAIDs, corticosteroids or chemotherapeutic agents could not be started in many cases due to the lack of definitive diagnosis of the mass preoperatively. Thus, surgical removal is frequently unavoidable. CONCLUSION: Biliary IBT is extremely rare and should be considered by all hepatobiliary surgeons dealing with the teens with cholangiocarcinoma, to avoid unnecessary major surgical resections. PMID- 29705679 TI - Preoperative Smoking and Narcotic, Benzodiazepine, and Tramadol Use are Risk Factors for Narcotic Use After Hip and Knee Arthroplasty. AB - BACKGROUND: The use of narcotics has been found to be a modifiable risk factor for success of arthroplasty. We sought to determine the risk factors leading to increased narcotic use after total hip arthroplasty and total knee arthroplasty. METHODS: A retrospective chart review was performed on new patients presenting to an orthopedic reconstructive-service clinic. New patients aged 18 years or older with osteoarthritis of the hip or knee who presented over a 1-year period and underwent total knee arthroplasty or total hip arthroplasty were included. The Arkansas prescription monitoring program was then used to determine recent narcotic and benzodiazepine prescriptions filled within 3 months of surgery, and this was converted into morphine milligram equivalents (MME). RESULTS: One hundred seventy-nine patients met the inclusion criteria. When compared with patients who did not take any preoperative opioids, narcotic- and tramadol-only users filled an average of 86% and 38% more MME, respectively. Benzodiazepine users required an average of 81% more MME postoperative than nonusers, and smokers required an average of 90% more MME postoperative than nonsmokers. Subjects with body mass index >40 kg/m2 had 82% higher average postoperative MME than subjects with body mass index <25 kg/m2. Age and sex had no significant correlation with postoperative narcotic use. CONCLUSION: This study suggests that a patient's preoperative narcotic, tramadol, benzodiazepine, and tobacco use are correlated to the amount of postoperative narcotic prescriptions filled in the 3 months following surgery. Predisposition to substance abuse may be a characteristic which leads to increased postoperative narcotic use. PMID- 29705680 TI - Medial Mobile-Bearing Unicompartmental Knee Arthroplasty in Young Patients Aged Less Than or Equal to 50 Years. AB - BACKGROUND: Contemporary research has shown medial mobile-bearing unicompartmental knee arthroplasty to be an effective treatment in patients younger than 60 years; however, only one other study has specifically investigated unicompartmental arthroplasty outcomes in patients 50 years or younger. The purpose of this study was to determine the clinical outcomes and survivorship of medial mobile-bearing unicompartmental arthroplasty in this younger patient population. METHODS: A retrospective review of patients undergoing primary unicompartmental knee arthroplasty using the Oxford partial knee from 2003 to 2014 in a single practice database was performed. Patients were included in the study if they were 50 years of age or younger with a primary diagnosis of anteromedial osteoarthritis and minimum clinical follow-up of 2 years. Patient clinical outcomes, function, and need for revision surgery were assessed. RESULTS: The study included 340 knees. Average patient age was 46.5 years, and the mean follow-up was 6.1 years. Patients demonstrated significant improvements (P < .05) in range of motion (114.5 v 116.9), University of California Los Angeles activity score (4.4 vs 5.6), Knee Society clinical (37.3 vs 86.5) and functional scores (58.8 v 79.8). Overall, 20 patients required reoperation, and the predicted survival rate was 96% at 6 years and 86% at 10 years. Aseptic loosening occurred in 7 patients at an average of 5.6 years postoperatively, while 4 patients required conversion to total knee arthroplasty because of arthritic progression at a mean time of 6.6 years. There were no revision procedures required due to polyethylene liner wear or breakage. CONCLUSION: Medial mobile-bearing unicompartmental arthroplasty should be considered as a treatment option in patients younger than 50 years of age suffering from anteromedial osteoarthritis of the knee. PMID- 29705681 TI - Midlevel Constraint Without Stem Extensions in Primary Total Knee Arthroplasty Provides Stability Without Compromising Fixation. AB - BACKGROUND: Many total knee arthroplasty (TKA) systems allow for so-called midlevel constraint (MLC) articular bearings that can be used with primary implants. The purpose of this study is to report the early outcomes with MLC bearings in primary TKA. MATERIALS/METHODS: From December 2005 to June 2015, minimum 2-year follow-up was available on 96 patients (103 TKA) who underwent primary TKA with an MLC bearing using the Vanguard Total Knee System. Outcomes included pain, Knee Society clinical and functional score, range of motion, and need for revision. RESULTS: Mean follow-up was 5 years (range, 2-11 years). Range of motion improved from 103 to 113. Knee Society clinical and function scores improved from 28 and 43 to 88 and 62, respectively. There were 10 manipulations (9.9%). There were no failures for aseptic loosening of any components; however, 10% of patients were lost to follow-up. There were 3 revisions (3%): 1 patellar tendon rupture, 1 open lysis of adhesions for stiffness, and 1 2-stage treatment of infection. CONCLUSION: In cases of intraoperative medial collateral ligament incompetence, severe deformity, or valgus deformity requiring release of the lateral collateral ligament, the use of MLC showed good survivorship with no cases of aseptic loosening or instability. PMID- 29705682 TI - High Rate of Failure After Revision of a Constrained Liner. AB - BACKGROUND: The purpose of this study was to examine the outcomes of repeat revision after failure of a constrained liner. METHODS: We reviewed 1212 consecutive revisions and identified 74 (6%) revisions of a failed constrained liner in 46 patients with a mean age of 65 years. The most common reasons for revision of a constrained liner were recurrent instability (64.9%) and infection (25.7%). RESULTS: At a mean of 35 months, 42 of the 74 hips (57%) required repeat revision. Kaplan-Meier revision-free survival was 24% at 10 years. Thirty-two of the 74 revisions (43%) had a dislocation event after the index revision. Kaplan Meier dislocation-free survival was 43% at 10 years. There was a higher failure rate among the 34 patients with abductor deficiency (hazard ratio 1.90, 95% confidence interval, 1.06-3.43; P = .032). CONCLUSION: Patients undergoing revision of a failed constrained liner have a high likelihood of recurrent dislocation and repeat revision surgery. LEVEL OF EVIDENCE: Level IV. PMID- 29705683 TI - Lower Extremity Geometry in Morbid Obesity-Considerations for Total Knee Arthroplasty. AB - BACKGROUND: Obesity has been associated with varying adverse outcomes related to total knee arthroplasty (TKA) and has long been associated with various mechanical complications. Computational modeling holds promise for investigating biomechanical aberrations related to TKA in obese patients. However, basic anthropometric information regarding the shape of the lower extremity in obese patients is lacking. We, therefore, developed a method to determine lower extremity shape both generally and subject specific as a function of body mass index (BMI) and sex. METHODS: A unique set of 4 radiographs (knee anteroposterior/lateral; EOS long-leg alignment anteroposterior/lateral) were reviewed for patients with BMI exceeding 30 kg/m2 before undergoing TKA. Soft tissue thickness in both the coronal and sagittal planes, including anterior adipose tissue thickness overlying the tibial tubercle and patella, was measured. Elliptical parameters were then determined for any distance along the lower extremity. Additional measurements were obtained, including prepatellar thickness and pretubercular thickness and anteroposterior and mediolateral dimensions of the proximal tibia. A total of 232 obese subjects were analyzed. RESULTS: Girth increased as a function of BMI. Anterior prepatellar and pretubercular subcutaneous fat thickness in females exceeded that in males for all values of BMI. Wide variation was seen with regard to overall patterns of adiposity among same-sex subjects with similar BMI. Proximal tibial osseous dimensions did not demonstrate an association with BMI; however, males were found to have deeper and wider tibias compared with females. CONCLUSIONS: BMI and sex influence lower extremity shape. The prediction algorithms developed here holds implications for future biomechanical studies of TKA in obese patients. PMID- 29705684 TI - What Factors Drive Taper Corrosion? AB - Adverse local tissue reactions to corrosion products can lead to total hip arthroplasty failure. Although this problem has been well known for more than 25 years, it has seemingly increased in frequency over the recent years. The occurrence of corrosion is multifactorial-depending on implant, patient, and surgeon factors. As of now, there is no "one-size-fits-all" solution to prevent corrosion in total hip arthroplasty devices. Thus, it is imperative to fully understand the exact mechanisms of modular junction corrosion to prevent premature implant failure. This review highlights a few key concepts that need to be explored to minimize the impact of corrosion. The key concepts include (1) the prevention of micromotion, (2) the role of implant alloy metallurgy in the corrosion process, (3) the in vivo generation of a corrosive environment, and (4) potential unanticipated problems. PMID- 29705685 TI - Translational genomics in pancreatic ductal adenocarcinoma: A review with re analysis of TCGA dataset. AB - Malignancy of the pancreas is a leading cause of cancer-related mortality, with the highest case-fatality of all cancers. Nevertheless, the lack of sensitive biomarkers and presence of biological heterogeneity precludes its early detection and effective treatment. The recent introduction of next-generation sequencing allows characterization of multiple driver mutations at genome- and exome-wide levels. Sequencing of DNA and RNA from circulating tumour cells has also opened an exciting era of non-invasive procedures for tumour detection and prognostication. This massively-parallel sequencing technology has uncovered the previously obscure molecular mechanisms, providing clues for better stratification of patients and identification of druggable targets for the disease. Identification of active oncogenic pathways and gene-gene interactions may reveal oncogene addiction and synthetic lethality. Relevant findings can be extrapolated to develop targeted and personalized therapeutic interventions. In addition to known mutational events, the role of chromosomal rearrangements in pancreatic neoplasms is gradually uncovered. Coupled with bioinformatics pipelines and epidemiological analyses, a better framework for risk stratification and prognostication of pancreatic cancer will be possible in the near future. In this review, we discuss how translational genomic studies facilitate our understanding of pathobiology, and development of novel diagnostics and therapeutics for pancreatic ductal adenocarcinoma with emphases on whole genome sequencing, whole exome sequencing, and liquid biopsies. We have also re-analyzed The Cancer Genome Atlas (TCGA) dataset to look for genetic features associated with altered survival in patients with pancreatic ductal adenocarcinoma. PMID- 29705686 TI - Addiction vulnerability trait impacts complex movement control: Evidence from sign-trackers. AB - Cognitive-motivational vulnerability traits are associated with increased risk for substance addiction and relapse. Sign-tracking (ST) behavior in rats is associated with poor attentional control, mediated by an unresponsive basal forebrain cholinergic system, and an increased risk for substance addiction/relapse. A separate literature links poor attentional control and cholinergic losses to increased fall risk in Parkinson's disease. Here we tested the hypothesis that the relatively inferior attentional control of STs extends to complex movement control and a propensity for falls. STs were found to fall more often than goal-trackers (GTs) while traversing a straight rotating rod and, similar to human fallers, when taxed by a secondary task. Furthermore, STs fell more often while traversing a rotating zig-zag rod. GTs exhibited fewer falls from this rod by avoiding entry to the rotating zig-zag sections when in, or rotating toward, a difficult traversal state. Goal-tracking rats approached risky movement situations using strategies indicative of superior top-down control. These results suggest that the impact of opponent cognitive-cholinergic traits extends to complex movement control, and that impairments in the cognitive-motor interface are likely to be comorbid with addiction vulnerability. Sign-tracking indexes an endophenotype that may increase the risk for a wide range of neurobehavioral disorders. PMID- 29705687 TI - Pharmacokinetics and pharmacodynamic effects in koi carp (Cyprinus carpio) following immersion in propofol. AB - OBJECTIVE: To test the hypothesis that plasma propofol concentration (PPC) is associated with anesthetic effect in koi carp administered propofol by immersion. STUDY DESIGN: Prospective study. ANIMALS: Twenty mature koi carp (mean +/- standard deviation, 409.4 +/- 83.7 g). METHODS: Fish were immersed in propofol (5 mg L-1). Physiological variables and induction and recovery times were recorded. In phase I, blood was sampled for PPC immediately following induction and at recovery. In phase II, following induction, fish were maintained with propofol (4 mg L-1) via a recirculating system for 20 minutes. Following established induction, blood was sampled at 1, 10 and 20 minutes. In phase III (n = 19), fish were anesthetized as in phase II with blood sampled nine times in a sparse sampling strategy. Simultaneously, a pharmacodynamics rubric was used to evaluate anesthetic depth. PPC was determined using high performance liquid chromatography with fluorescence detection. Following evaluation of normality, data were analyzed using paired t test or Spearman correlation test (significance was set at p < 0.05). RESULTS: In phase I, mean PPCs at induction (20.12 MUg mL-1) and recovery (11.62 MUg mL-1) were different (p < 0.001). In phase II, only mean PPCs at induction (17.92 MUg mL-1) and 10 minutes (21.50 MUg mL-1) were different (p = 0.013). In phase III, a correlation between PPCs and the pharmacodynamic rubric scores was found (p < 0.001, r = -0.93). There was no correlation between PPCs and recovery time (p = 0.057, r = 0.433). A two-compartment open model was chosen for the pharmacokinetic model. Absorption rate constant, elimination rate constant and intercompartmental rate constant were 0.48, 0.006 and 0.02 minute-1, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Measurable PPCs were achieved in koi carp anesthetized with propofol by immersion. Anesthetic depth of fish was negatively correlated with PPCs, but recovery time was not. PMID- 29705688 TI - Survey of how different groups of veterinarians manage the use of neuromuscular blocking agents in anesthetized dogs. AB - OBJECTIVE: To analyze practice habits associated with the use, reversal and monitoring of nondepolarizing neuromuscular blocking agents (NMBAs) in dogs by different groups of veterinarians. STUDY DESIGN: Online anonymous survey to veterinarians. POPULATION: Data from 390 answered surveys. METHODS: A questionnaire was sent to e-mail list servers of the American College of Veterinary Anesthesia and Analgesia (ACVAA-list), Sociedad Espanola de Anestesia y Analgesia Veterinaria (SEEAV-list), Colegio Brasileiro de Anestesiologia Veterinaria (Brazilian College of Veterinary Anesthesiology; CBAV-list) and American College of Veterinary Ophthalmologists (ACVO-list) to elicit information regarding use of NMBAs and reversal agents, monitoring techniques, criteria for redosing, reversing and assessing adequacy of recovery of neuromuscular function. Binomial logistic regression was used to test for association between responses and group of veterinarians in selected questions. RESULTS: Veterinarians of the ACVO-list use NMBAs on a higher fraction of their caseload than other groups (all p < 0.0001). Subjective assessment (observation) of spontaneous movement, including spontaneous breathing, is the most common method for assessing neuromuscular function (43% of pooled responses); 18% of participants always reverse NMBAs, whereas 16% never reverse them. Restoration of neuromuscular function is assessed subjectively by 35% of respondents. Residual neuromuscular block is the most common concern regarding the use of NMBAs for all groups of veterinarians. Side effects of reversal agents (anticholinesterases) were of least concern for all groups. CONCLUSIONS AND CLINICAL RELEVANCE: While most veterinarians are concerned about residual neuromuscular block, relatively few steps are implemented to reduce the risks of this complication, such as routine use of quantitative neuromuscular monitoring or routine reversal of NMBAs. These results suggest a limitation in transferring information among groups of veterinarians, or in implementing techniques suggested by scientific research. PMID- 29705689 TI - Polymorphisms that affect GABA neurotransmission predict processing of aversive prediction errors in humans. AB - Learning is one of our most adaptive abilities, allowing us to adjust our expectations about future events. Aberrant learning processes may underlie disorders such as anxiety, motivating the search for the neural mechanisms that underpin learning. Animal studies have shown that the neurotransmitter GABA is required for the computation of prediction errors, the mismatches between anticipated and experienced outcomes, which drive new learning. Given that evidence from human studies is lacking, we sought to determine whether these findings extend to humans. Here, in two samples of Caucasian individuals, we investigated whether genetically determined individual differences in GABA neurotransmission predict the P3 event-related potential, an EEG component known to reflect prediction error processing. Consistent with the results of animal studies, we show that a weighted genetic risk score computed from the number of GABRB2 rs1816072 A alleles (associated with increased expression of the GABAA receptor beta2 subunit gene) and the number of ErbB4 rs7598440 T alleles (associated with increased GABA concentration) predicts optimal prediction error processing during aversive classical conditioning with both visual (Experiment 1, N = 90; p = .010) and auditory (Experiment 2; N = 92; p = .031) unconditioned stimuli. Our finding that optimal processing of aversive prediction errors is reduced in individuals genetically predisposed towards decreased GABA neurotransmission suggests a potential mechanism linking GABA and anxiety. Specifically, reduced GABA signalling via GABAA receptors could result in aberrant learning from aversive experiences and vulnerability to anxiety disorders. PMID- 29705690 TI - Transferring and generalizing deep-learning-based neural encoding models across subjects. AB - Recent studies have shown the value of using deep learning models for mapping and characterizing how the brain represents and organizes information for natural vision. However, modeling the relationship between deep learning models and the brain (or encoding models), requires measuring cortical responses to large and diverse sets of natural visual stimuli from single subjects. This requirement limits prior studies to few subjects, making it difficult to generalize findings across subjects or for a population. In this study, we developed new methods to transfer and generalize encoding models across subjects. To train encoding models specific to a target subject, the models trained for other subjects were used as the prior models and were refined efficiently using Bayesian inference with a limited amount of data from the target subject. To train encoding models for a population, the models were progressively trained and updated with incremental data from different subjects. For the proof of principle, we applied these methods to functional magnetic resonance imaging (fMRI) data from three subjects watching tens of hours of naturalistic videos, while a deep residual neural network driven by image recognition was used to model visual cortical processing. Results demonstrate that the methods developed herein provide an efficient and effective strategy to establish both subject-specific and population-wide predictive models of cortical representations of high-dimensional and hierarchical visual features. PMID- 29705691 TI - CXCL13 concentrations in cerebrospinal fluid of patients with Lyme neuroborreliosis and other neurological disorders determined by Luminex and ELISA. AB - The aims of the study were to determine and compare the concentration of CXCL13 in cerebrospinal fluid (CSF) of patients with Lyme neuroborreliosis (LNB) and various other neurological disorders applying a Luminex based assay and ELISA, and to find factors associated with CXCL13 concentration. CSF samples obtained from four clinically well-defined groups of patients (proven LNB, suspected LNB, tick-borne encephalitis (TBE), and aseptic meningitis/meningoencephalitis other than TBE) - 25 samples per group - were analyzed. The performance of the Luminex recomBead CXCL13 assay (Microgen, Neuried, Germany) and ELISA (Euroimmun, Lubeck, Germany) was assessed by receiver operating characteristics. CXCL13 cut-off values were presented as functions of CSF lymphocyte/monocyte counts. Demographic variables, CSF findings, and history of erythema migrans were assessed as possible predictors for CXCL13 CSF concentrations by a general linear model. The calculated cut-off values determined by the maximum of the Youden index were >131 pg/mL for recomBead and >259 pg/mL for the ELISA. RecomBead showed a sensitivity of 88% (68.8-97.5%) and a specificity of 94% (83.5-98.7%). For the ELISA the corresponding values were 84% (63.9-95.5%) and 98% (89.4-99.9%). The CXCL13 concentration positively correlated with CSF lymphocyte/monocyte count and Borrelia-specific intrathecal antibody index (p < 0.05). High CXCL13 concentrations were only found in the group with proven LNB. CXCL13 levels above cut-off value were established in some patients with viral meningitis/meningoencephalitis but were not detected in patients with suspected LNB without pleocytosis. Applying a linearized cut-off of the CXCL13 concentration in the CSF which is dependent on the CSF cell count is a novel approach in the laboratory diagnosis of LNB. PMID- 29705693 TI - Thiolated arsenic in natural systems: What is current, what is new and what needs to be known. AB - Thiolated arsenic compounds are the sulfur analogous substructures of oxo arsenicals as the arsinoyl (As = O) is substituted by an arsinothioyl (As = S) group. Relatively brief history of thioarsenic research, mostly in the current decade has endeavored to understand their consequences in the natural environment. However, thioarsenic related aspects have by far not attached much research concern on global scale compared to other arsenic species. This review attempts to provide a critical overview for the first time on formation mechanisms of thioarsenicals, their chemistry, speciation and analytical methodologies in order to provide a rational assessment of what is new, what is current, what needs to be known or what should be done in future research. Thioarsenic compounds play a vital role in determining the biogeochemistry of arsenic in sulfidic environments under reducing conditions. Thioarsenic species are widely immobilized by naturally occurring processes such as the adsorption on iron (oxyhydr)oxides and precipitation on iron sulfide minerals. Accurate measurement of thioarsenic species is a challenging task due to their instability upon pH, temperature, redox potential, and concentrations of oxygen, sulfur and iron. Assessment of direct and indirect effects of toxic thioarsenic species on global population those who frequently get exposed to high levels of arsenic is an urgent necessity. Dimethylmonothioarsinic acid (DMMTAV) is the most cytotoxic arsenic metabolite having similar toxicological effects as dimethylarsinous acid (DMAIII) in human and animal tissues. The formation and chemical analysis of thioarsenicals in soil and sediments are highly unknown. Therefore, future research needs to be more inclined towards in determining the molecular structure of unknown thioarsenic complexes in various environmental suites. Contemporary approaches hyphenated to existing technologies would pave the way to overcome critical challenges of thioarsenic speciation such as standards synthesis, structural determination, quantification and sample preservation in future research. PMID- 29705692 TI - Prenatal and childhood exposure to per- and polyfluoroalkyl substances (PFASs) and child cognition. AB - BACKGROUND: Per- and polyfluoroalkyl substances (PFASs) are suspected developmental toxicants, but epidemiological evidence on neurodevelopmental effects of PFAS exposure is inconsistent. We examined associations of prenatal and childhood PFAS exposure with performance on assessments of cognition in children. METHODS: We included mother-child pairs from Project Viva, a longitudinal Boston-area birth cohort enrolled during 1999-2002. We quantified concentrations of eight PFASs, including perfluorooctane sulfonate (PFOS), perfluorooctanoate (PFOA), and perfluorohexane sulfonate (PFHxS), in plasma collected from women during pregnancy (median 9.7 weeks gestation) and from children at a visit in mid-childhood (median age 7.7 years). In early childhood (median age 3.2 years) we administered standardized assessments of visual motor skills and vocabulary comprehension, and in mid-childhood we assessed visual motor skills, visual memory, and verbal and non-verbal intelligence. Using multivariable regression, we estimated associations of prenatal and childhood PFAS plasma concentrations with children's cognitive assessment scores, adjusted for relevant covariates including breastfeeding, maternal intelligence, parental education, and household income. Samples sizes ranged from 631 to 971, depending on analysis. RESULTS: Prenatal PFAS concentrations were associated with both better and worse cognitive performance; children with top quartile prenatal concentrations of some PFASs had better visual motor abilities in early childhood and non-verbal IQ and visual memory in mid-childhood, while children with upper quartile prenatal PFOA and PFOS had lower mid-childhood visual-motor scores. In cross-sectional analyses of mid-childhood PFAS concentrations and cognitive assessments, visual-motor scores on the Wide Range Assessment of Visual Motor Abilities (WRAVMA) (standardized mean = 100, standard deviation = 15) were lower among children with higher PFHxS (fourth quartile (Q4) vs. Q1: -5.0, 95% confidence interval (CI): -9.1, -0.8). Upper quartiles of childhood PFOA and PFOS were also associated with somewhat lower childhood WRAVMA scores, but childhood PFASs were not associated with verbal or non-verbal IQ or visual memory. CONCLUSIONS: We present evidence suggesting associations of prenatal and childhood PFAS exposure with lower childhood visual motor abilities. Other results were inconsistent, with higher prenatal PFASs associated in some cases with better cognitive outcomes. PMID- 29705694 TI - The level and pattern of physical activity among fifth-grade students in Ho Chi Minh City, Vietnam. AB - OBJECTIVES: Despite the benefits of physical activity (PA), a significant proportion of children do not meet physical activity guidelines (PAGs). However, most studies were among secondary-school-aged youth and relied on PA self-report. In addition, information regarding children's PA behaviors during specific segments of day/week is not usually collected. This study, therefore, investigated the level and pattern of PA among fifth-grade students in Ho Chi Minh City (HCMC), Vietnam. STUDY DESIGN: A complex cross-sectional survey was conducted on a representative sample of 619 fifth-grade students in eight public schools in urban areas of HCMC in 2016. METHODS: Demographic/anthropometric characteristics were measured using standard protocols. PA was measured using pedometers. After-school activities were measured using the Previous Day Physical Activity Recall questionnaire. Survey procedures with sampling weights were used for analyses. RESULTS: Approximately 18% of children met the PAG; 52.7% were overweight (OW)/obese (OB). On average, students recorded about 8800 steps/day. Boys were more active than girls at school and on weekdays. Students were more active at school on physical education (PE) days vs non-PE days and weekdays vs weekends. OW/OB students were more active at school on PE days. After-school PAs differed between boys and girls, whereas sedentary activities were popular among both the genders. CONCLUSIONS: Most fifth-grade students had insufficient PA levels. Patterns of PA are different at various times during the day and week. The finding emphasized an urgent need for interventions to improve children's PA and obesity in this area. PMID- 29705695 TI - Circular RNA expression profiles in hippocampus from mice with perinatal glyphosate exposure. AB - Glyphosate is the active ingredient in numerous herbicide formulations. The roles of glyphosate in embryo-toxicity and neurotoxicity have been reported in human and animal models. Recently, several studies have reported evidence linking neurodevelopmental disorders (NDDs) with gestational glyphosate exposure. However, the role of glyphosate in neuronal development is still not fully understood. Our previous study found that perinatal glyphosate exposure resulted in differential microRNA expression in the prefrontal cortex of mouse offspring. However, the mechanism of glyphosate-induced neurotoxicity in the developing brain is still not fully understood. Considering the pivotal role of Circular RNAs (circRNAs) in the regulation of gene expression, a circRNA microarray method was used in this study to investigate circRNA expression changes in the hippocampus of mice with perinatal glyphosate exposure. The circRNA microarrays revealed that 663 circRNAs were significantly altered in the perinatal glyphosate exposure group compared with the control group. Among them, 330 were significantly upregulated, and the other 333 were downregulated. Furthermore, the relative expression levels of mmu-circRNA-014015, mmu-circRNA-28128 and mmu circRNA-29837 were verified using quantitative real-time polymerase chain reaction (qRT-PCR). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses demonstrated that stress-associated steroid metabolism pathways, such as aldosterone synthesis and secretion pathways, may be involved in the neurotoxicity of glyphosate. These results showed that circRNAs are aberrantly expressed in the hippocampus of mice with perinatal glyphosate exposure and play potential roles in glyphosate-induced neurotoxicity. PMID- 29705696 TI - MicroRNA-139-5p suppresses myosin heavy chain I and IIa expression via inhibition of the calcineurin/NFAT signaling pathway. AB - MicroRNAs (miRNAs) are a class of small non-coding RNAs that are widely involved in a variety of biological processes. Different skeletal muscle fiber type composition exhibits characteristic differences in functional properties and energy metabolism of skeletal muscle. However, the molecular mechanism by which miRNAs control the different type of muscle fiber formation is still not fully understood. In the present study, we characterized the role of microRNA-139-5p (miR-139-5p) in the regulation of myosin heavy chain (MyHC) isoform expression and its underlying mechanisms. Here we found that the expression of miR-139-5p was significantly higher in mouse slow-twitch muscle than in fast-twitch muscle. Overexpression of miR-139-5p downregulated the expression of MyHC I and MyHC IIa, whereas inhibition of miR-139-5p upregulated them. We also found that the levels of calcineurin (CaN), NFATc1, MEF2C and MCIP1.4, which are the components of CaN/NFAT signaling pathway that has shown to positively regulate slow fiber selective gene expression, were notably inhibited by miR-139-5p overexpression. Furthermore, treatment of phenylephrine (PE), a alpha1-adrenoceptor agonist, abolished the inhibitory effect of miR-139-5p on MyHC I and MyHC IIa expression. Together, our findings indicated that the role of miR-139-5p in regulating the MyHC isoforms, especially MyHC I and MyHC IIa, may be achieved through inhibiting CaN/NFAT signaling pathway. PMID- 29705697 TI - A monolayer microfluidic device supporting mouse spermatogenesis with improved visibility. AB - In our previous study, we produced a microfluidic device (MFD) which successfully maintained spermatogenesis for over 6 months in mouse testis tissues loaded in the device. In the present study, we developed a new MFD, a monolayer device (ML D) with a barrier structure consisting of pillars and slits, which is simpler in design and easier to make. This ML-D was also effective for inducing mouse spermatogenesis and maintained it for a longer period than the conventional culture method. In addition, we devised a way of introducing sample tissue into the device during its production, just before bonding the upper layer of polydimethylsiloxane (PDMS) and bottom glass slide. The tissue can obtain nutrients horizontally from the medium running beside it and oxygen vertically from above through PDMS. In addition, the glass slide set at the bottom improved the visibility of the sample tissue with an inverted microscope. When we took photos of cultured tissue of the Acr-Gfp transgenic mouse testis in ML-D sequentially every day, morphological changes of the acrosome during spermiogenesis were successfully recorded. The ML-D is simple in design and useful for culturing testis tissue for inducing and maintaining spermatogenesis with clearer visibility. Due to the new method of sample loading, tissues other than testis should also be applicable. PMID- 29705698 TI - Red alga polysaccharides attenuate angiotensin II-induced inflammation in coronary endothelial cells. AB - The pro-inflammatory vasoconstrictor Angiotensin II can cause endothelial dysfunction and is considered to be one of the mediators of atherosclerosis. Our former results demonstrated that polysaccharides derived from the red alga Porphyridium sp. attenuate inflammatory processes by interfering with tumor necrosis factor-alpha-induced inflammation, in human coronary artery endothelial cells. However, the anti-inflammatory effect of these polysaccharides on inflammation processes occurring under Angiotensin II stimulation is yet unknown. Herein, we studied the polysaccharide's anti-inflammatory effect by quantification of inflammatory markers in Angiotensin II- stimulated Human Coronary Artery Endothelial Cells following pre-treatment with polysaccharides. Inflammatory atherosclerotic pathways up-regulated by Angiotensin II, including adhesion molecule expression and nuclear factor kappa-light-chain-enhancer of activated B cells translocation, were significantly attenuated or diminished in cells pre-treated with the polysaccharides. In addition, the polysaccharides increased the antioxidant response elements activity through the nuclear factor E2-related factor 2- antioxidant protection system. These polysaccharide's promising abilities may be considered as a basis for future use as a therapeutic agent aimed at improving vascular health by attenuation of the inflammatory atherosclerotic process. PMID- 29705699 TI - Transplantation of periaortic adipose tissue inhibits atherosclerosis in apoE-/- mice by evoking TGF-beta1-mediated anti-inflammatory response in transplanted graft. AB - Perivascular adipose tissue (PAT) is associated with vascular homeostasis; however, its causal effect on atherosclerosis currently remains undefined. Here, we investigated the effect of experimental PAT transplantation on atherosclerosis. The thoracic periaortic adipose tissue (tPAT) was dissected from 16-week-old wild-type mice and transplanted over the infrarenal aorta of 20-week old apoE deficient (apoE-/-) mice fed high-cholesterol diet for 3 months. Oil-red O staining after 4 weeks showed a significant 20% decrease in the atherosclerotic lesion of suprarenal aorta compared with that of sham control mice, while that of infrarenal aorta showed no difference between the two groups. TGF-beta1 mRNA expression was significantly higher in grafted tPAT than donor tPAT, accompanied by a significant increase in serum TGF-beta1 concentration, which was inversely correlated with the suprarenal lesion area (r = -0.63, P = 0.012). Treatment with neutralizing TGF-beta antibody abrogated the anti-atherogenic effect of tPAT transplantation. Immunofluorescent analysis of grafted tPAT showed that TGF-beta positive cells were co-localized with Mac-2-positive cells and this number was significantly increased compared with donor tPAT. There was also marked increase in mRNA expression of alternatively activated macrophages-related genes. Furthermore, the percentage of eosinophils in stromal vascular fraction of donor tPAT was much higher than that in epididymal white adipose tissue, concomitant with the significantly higher protein level of IL-4. IL-4 mRNA expression levels in grafted tPAT were increased in a time-dependent manner after tPAT transplantation. Our findings show that tPAT transplantation inhibits atherosclerosis development by exerting TGF-beta1-mediated anti-inflammatory response, which may involve alternatively activated macrophages. PMID- 29705700 TI - Anticancer activity of arborinine from Glycosmis parva leaf extract in human cervical cancer cells. AB - Glycosmis parva is a small shrub found in Thailand. Ethyl acetate (EtOAc) extract from its leaves has been shown to exert anticancer effects in vitro; however, the compound responsible for this activity has not been isolated and characterized. In this study, we demonstrate that arborinine, a major acridone alkaloid in the EtOAc fraction, decreased proliferation and was strongly cytotoxic to HeLa cervical cancer cells without significantly affecting normal cells. The compound also inhibited tumor spheroid growth much more potently than chemotherapeutic drugs bleomycin, gemcitabine, and cisplatin. In addition, unlike cisplatin, arborinine activated caspase-dependent apoptosis without inducing DNA damage response. We further show that arborinine strongly suppressed cancer cell migration by downregulating expression of key regulators of epithelial mesenchymal transition. Taken together, our data provide important insights into the molecular mechanism of arborinine's anticancer activity, supporting its potential use for treating cervical cancer. PMID- 29705701 TI - Protective role of AgRP neuron's PDK1 against salt-induced hypertension. AB - In the hypothalamic arcuate nucleus (ARC), orexigenic agouti-related peptide (AgRP) neurons regulate feeding behavior and energy homeostasis. The 3 phosphoinositide-dependent protein kinase-1 (PDK1) in AgRP neurons serves as a major signaling molecule for leptin and insulin, the hormones regulating feeding behavior, energy homeostasis and circulation. However, it is unclear whether PDK1 in AGRP neurons is also involved in regulation of blood pressure. This study explored it by generating and analyzing AgRP neuron-specific PDK1 knockout (Agrp Pdk1flox/flox) mice and effect of high salt diet on blood pressure in KO and WT mice was analyzed. Under high salt diet feeding, systolic blood pressure (SBP) of Agrp-Pdk1flox/flox mice was significantly elevated compared to Agrp-Cre mice. When the high salt diet was switched to control low salt diet, SBP of Agrp Pdk1flox/flox mice returned to the basal level observed in Agrp-Cre mice within 1 week. In Agrp-Pdk1flox/flox mice, urinary noradrenalin excretion and NUCB2 mRNA expression in hypothalamic paraventricular nucleus (PVN) were markedly upregulated. Moreover, silencing of NUCB2 in the PVN counteracted the rises in urinary noradrenalin excretions and SBP. These results demonstrate a novel role of PDK1 in AgRP neurons to counteract the high salt diet-induced hypertension by preventing hyperactivation of PVN nesfatin-1 neurons. PMID- 29705702 TI - PKC delta activation increases neonatal rat retinal cells survival in vitro: Involvement of neurotrophins and M1 muscarinic receptors. AB - Protein kinase C (PKC) is a family of serine/threonine kinases related to several phenomena as cell proliferation, differentiation and survival. Our previous data demonstrated that treatment of axotomized neonatal rat retinal cell cultures for 48 h with phorbol 12-myristate 13-acetate (PMA), a PKC activator, increases retinal ganglion cells (RGCs) survival. Moreover, this treatment decreases M1 receptors (M1R) and modulates BDNF levels. The aim of this work was to assess the possible involvement of neurotrophins BDNF and NGF in the modulation of M1R levels induced by PKC activation, and its involvement on RGCs survival. Our results show that PMA (50 ng/mL) treatment, via PKC delta activation, modulates NGF, BDNF and M1R levels. BDNF and NGF mediate the decrease of M1R levels induced by PMA treatment. M1R activation is essential to PMA neuroprotective effect on RGCs as telenzepine (M1R selective antagonist) abolished it. Based on our results we suggest that PKC delta activation modulates neurotrophins levels by a signaling pathway that involves M1R activation and ultimately leading to an increase in RGCs survival in vitro. PMID- 29705703 TI - Esculetin inhibits oxidative stress and apoptosis in H9c2 cardiomyocytes following hypoxia/reoxygenation injury. AB - Esculetin (6,7-dihydroxycoumarin), a natural coumarin compound extracted from natural plants, was reported to be involved in ischemia/reperfusion (I/R) injury. However, the role of esculetin in myocardial I/R injury remains unclear. This study was designed to investigate the protective effects of esculetin on cardiomyocytes induced by hypoxia/reoxygenation (H/R), and explore the underlying mechanisms. Our results showed that esculetin improved the cell viability and decreased lactate dehydrogenase (LDH) release in H/R-stimulated H9c2 cells. In addition, esculetin significantly suppressed oxidative stress and apoptosis in H9c2 cells exposed to H/R treatment. Exploration of the underlying mechanisms of its action indicated that esculetin enhanced the activation of JAK2/STAT3 pathway in H/R-stimulated H9c2 cells. Taken together, these findings indicated that esculetin inhibits oxidative stress and apoptosis in H9c2 cardiomyocytes following H/R injury through the activation of JAK2/STAT3 pathway. PMID- 29705704 TI - FOXM1 promotes proliferation in human hepatocellular carcinoma cells by transcriptional activation of CCNB1. AB - The transcription factor Forkhead box protein M1 (FOXM1) plays critical roles in cancer development and progression, including human hepatocellular carcinoma (HCC). However, the regulatory role and underlying mechanisms of FOXM1 is still limited. Here, we found that the high level expression of FOXM1 and CCNB1 is closely associated with poor prognosis in HCC patients. And FOXM1 and CCNB1 were overexpressed concomitantly in liver tumor tissues. Knockdown of FOXM1 significantly inhibited the expression levels of CCNB1 in HCC cell lines at both the mRNA and protein levels. Mechanistic studies revealed that FOXM1 binds directly to the promoter region of CCNB1 and regulates the expression levels of the CCNB1 gene in the transcriptional level. Furthermore, the loss of functional and rescue experiments showed that CCNB1 is essential for FOXM1-driven proliferation in HCC cells. In the present study, our results partially explained the dysregulated expression of FOXM1 play an important role in proliferation of human hepatocellular carcinoma cells via transcriptional activation of CCNB1 expression. And it also highlights a FOXM1/CCNB1 axis could be a potential target for the treatment of HCCs. PMID- 29705705 TI - Modulation by orexin A of spontaneous excitatory and inhibitory transmission in adult rat spinal substantia gelatinosa neurons. AB - Hypothalamic neuropeptides, orexins A and B, differently inhibit nociceptive behavior. This difference is possibly due to a distinction between orexins A and B in modulating synaptic transmission in spinal substantia gelatinosa (SG) neurons that play a pivotal role in regulating nociceptive transmission. Although we previously reported a modulatory action of orexin B on synaptic transmission in adult rat SG neurons, it has not been fully examined how the transmission is affected by orexin A. The present study examined the effects of orexin A on spontaneous excitatory and inhibitory transmission in SG neurons of adult rat spinal cord slices by using the whole-cell patch-clamp technique. Like orexin B, orexin A produced an inward current at -70 mV and/or increased the frequency of spontaneous excitatory postsynaptic current without changing its amplitude. Half maximal effective concentration values for their effects were 0.0045 and 0.030 MUM, respectively; the former value was four-fold smaller than that of orexin B while the latter value was comparable to that of orexin B. Orexin A enhanced not only glycinergic but also GABAergic transmission, although only glycinergic transmission was facilitated by orexin B in the majority of neurons tested. Orexin A activities were inhibited by an orexin-1 receptor antagonist (SB334867) but not an orexin-2 receptor antagonist (JNJ10397049), as different from orexin B whose activation was depressed by JNJ10397049 but not SB334867. These results indicate that orexin A has a different action from orexin B in SG neurons in efficacy for inward current production and in GABAergic transmission enhancement, possibly owing to orexin-1 but not orexin-2 receptor activation. This difference could contribute to at least a part of the distinction between orexins A and B in antinociceptive effects. PMID- 29705706 TI - Respective roles of the mitogen-activated protein kinase (MAPK) family members in pancreatic stellate cell activation induced by transforming growth factor-beta1 (TGF-beta1). AB - Activated pancreatic stellate cells (PSCs) play a crucial role in the progression of pancreatic fibrosis. Transforming growth factor-beta (TGF-beta) is one of the strongest stimulator inducing fibrosis. The mitogen-activated protein kinase (MAPK) proteins (including ERK, JNK and p38 MAPK) are known to contribute to PSC activation and pancreatic fibrosis. Previous studies have identified PSC activation induced by TGF-beta1 is related to MAPK pathway, but the respective role of MAPK family members in PSC activation still unclear, and which family member may be the key mediator in mice PSC activation still controversial. In this study, we investigated the influence of different MAPK family member (JNK, ERK, and p38 MAPK) on mice PSC activation using an in vivo and in vitro model. The results showed p-JNK, p-ERK and p-p38 MAPK were all over-expressed in CP group, and p-JNK, p-ERK, and p-p38 MAPK were co-expressed with activated PSC. In vitro, TGF-beta1 induced JNK and ERK over-expression in PSCs. In contrast, p38 MAPK expression in PSC showed only a very weak increase. JNK- and ERK-specific inhibitors inhibited FN and alpha-SMA mRNA expression in PSCs, and a p38 MAPK inhibitor had no effect on PSC activation. These findings indicate that JNK and ERK were directly involved in the PSCs activation induced by TGF-beta1 and the development of pancreatic fibrosis. p38 MAPK participate in the progression of CP, but it does not respond to TGF-beta1 directly and may not be regarded as the target of TGF-beta1 induced PSC activation. PMID- 29705707 TI - Alcohol affects the P3 component of an adaptive stop signal task ERP. AB - BACKGROUND: The P3 component of the event-related potential (ERP) has been particularly useful in alcohol research for identifying endophenotypes of alcohol use disorder (AUD) risk in sober subjects. However, practice and/or fatigue reduce P3 amplitude, limiting the ability to ascertain acute and adaptive effects of alcohol exposure. Here, we report acute alcohol effects on P3 amplitude and latency using an adaptive stop signal task (aSST). METHODS: One hundred forty eight non-dependent moderate to heavy social drinkers, ages 21 to 27, participated in two single-blind, alcohol or placebo, counterbalanced sessions approximately 1 week apart. During each session, subjects performed an adaptive stop signal task (aSST) at 1) baseline, 2) upon reaching the target 60 mg/dL breath alcohol concentration or at the equivalent time during the placebo session, and 3) approximately 135 min later while the breath alcohol concentration was clamped. Here, we report on differences between baseline and first subsequent measurements across the experimental sessions. During each aSST run, the stop signal delay (SSD, the time between stop and go signals) adjusted trial-by-trial, based on the subject's performance. RESULTS: The aSST reliably generated a STOP P3 component that did not change significantly with repeated task performance. The pre-infusion SSD distribution was bimodal, with mean values several hundred msec apart (FAST: 153 msec and SLOW: 390 msec). This suggested different response strategies: FAST SSD favoring "going" over "stopping", and SLOW SSD favoring "stopping" over "going". Exposure to alcohol at 60 mg/dL differentially affected the amplitude and latency of the STOP P3 according to SSD group. Alcohol significantly reduced P3 amplitude in the SLOW SSD compared to the FAST SSD group, but significantly increased P3 latency in the FAST SSD compared to the SLOW SSD group. CONCLUSIONS: The aSST is a robust and sensitive task for detecting alcohol-induced changes in inhibition behavior as measured by the P3 component in a within-subject design. Alcohol was associated with P3 component changes, which varied by SSD group, suggesting a differential effect as a function of task strategy. Overall, the data support the potential utility of the aSST in the detection of alcohol response-related AUD risk. PMID- 29705708 TI - Design, synthesis, structure-activity relationships and X-ray structural studies of novel 1-oxopyrimido[4,5-c]quinoline-2-acetic acid derivatives as selective and potent inhibitors of human aldose reductase. AB - Human aldose reductase (AKR1B1, AR) is a key enzyme of the polyol pathway, catalyzing the reduction of glucose to sorbitol at high glucose concentrations, as those found in diabetic condition. Indeed, AKR1B1 overexpression is related to diabetes secondary complications and, in some cases, with cancer. For many years, research has been focused on finding new AKR1B1 inhibitors (ARIs) to overcome these diseases. Despite the efforts, most of the new drug candidates failed because of their poor pharmacokinetic properties and/or unacceptable side effects. Here we report the synthesis of a series of 1-oxopyrimido[4,5 c]quinoline-2-acetic acid derivatives as novel ARIs. IC50 assays and X-ray crystallographic studies proved that these compounds are promising hits for further drug development, with high potency and selectivity against AKR1B1. Based on the determined X-ray structures with hit-to-lead compounds, we designed and synthesized a second series that yielded lead compound 68 (Kiappvs. AKR1B1 = 73 nM). These compounds are related to the previously reported 2-aminopyrimido[4,5 c]quinolin-1(2H)-ones, which exhibit antimitotic activity. Regardless of their similarity, the 2-amino compounds are unable to inhibit AKR1B1 while the 2-acetic acid derivatives are not cytotoxic against fibrosarcoma HT-1080 cells. Thus, the replacement of the amino group by an acetic acid moiety changes their biological activity, improving their potency as ARIs. PMID- 29705709 TI - Design, synthesis and structure-activity relationship studies of GPR40 agonists containing amide linker. AB - Free fatty acid receptor 1 (FFAR1/GPR40) attracted significant attention as a potential target for developing novel antidiabetic drugs because of its unique mechanism in glucose homeostasis. Several reports have expressed concerns about central nervous system (CNS) penetration of GPR40 agonists, which is possibly attributed to their high lipophilicity and low total polar surface area. Herein, we report our efforts to improve the physicochemical properties and pharmacokinetic profiles of LY2881835, a GPR40 agonist that had undergone Phase I clinical trial, through a series of structural optimizations. We identified an orally efficacious compound, 15k, which possessed increased plasma exposure, prolonged half-life and reduced CNS exposure and liver to plasma distribution ratio compared with LY2881835. 15k is a potentially valuable lead compound in the development of safe and efficacious GPR40-targeted drugs to treat type 2 diabetes mellitus. PMID- 29705710 TI - Synthesis, cytotoxicity and structure-activity relationship of indolizinoquinolinedione derivatives as DNA topoisomerase IB catalytic inhibitors. AB - Our previous studies reveal that indolizinoquinolinedione scaffold is a base to develop novel DNA topoisomerase IB (TOP1) catalytic inhibitors. In this work, twenty-three novel indolizinoquinolinedione derivatives were synthesized. TOP1 mediated relaxation, nicking and unwinding assays revealed that three fluorinated derivatives 26, 28 and 29, and one N,N-trans derivative 46 act as TOP1 catalytic inhibitors with higher TOP1 inhibition (++++) than camptothecin (+++) and without TOP1-mediated unwinding effect. MTT assay against five human cancer cell lines indicated that the highest cytotoxicity is 20 for CCRF-CEM cells, 25 for A549 and DU-145 cells, 26 for HCT116 cells, and 33 for Huh7 cells with GI50 values at nanomolar range. The drug-resistant cell assay indicated that compound 26 may mainly act to TOP1 in cells and are less of Pgp substrates. Flow cytometric analysis showed that compounds 26, 28 and 29 can obviously induce apoptosis of HCT116 cells. Moreover, the structure-activity relationship (SAR) of indolizinoquinolinedione derivatives was analyzed. PMID- 29705711 TI - Alcohol, microbiome, and their effect on psychiatric disorders. AB - There is accumulating evidence that alcohol consumption and especially alcohol withdrawal increase brain levels of known innate immune signaling molecules and cause neuroinflammation. It has been shown that microbiota play a pivotal role in this process and affect central neurochemistry and behavior. Disruption of or alterations in the intimate cross-talk between microbiome and brain may be a significant factor in many psychiatric disorders. Alterations in the composition of the microbiome, so called dysbiosis, may result in detrimental distortion of microbe-host homeostasis modulating the hypothalamic-pituitary-adrenal axis. A variety of pathologies are associated with changes in the community structure and function of the gut microbiota, suggesting a link between dysbiosis and disease etiology, including irritable bowel syndrome depression, anxiety disorders, schizophrenia, and alcoholism. Despite a paucity of clinical studies in alcohol dependent humans, emerging data suggests that alcohol induced alterations of the microbiome may explain reward-seeking behaviors as well as anxiety, depression, and craving in withdrawal and increase the risk of developing psychiatric disorders. PMID- 29705712 TI - Abnormal auditory-evoked gamma band oscillations in first-episode schizophrenia during both eye open and eye close states. AB - Abnormal auditory steady state response (ASSR) is a typical finding among schizophrenia patients, which is thought to directly reflect deficient gamma band oscillations in the brain. However, whether these ASSR alterations are state dependent, e.g. during eye-open or eye-closed conditions, has not yet been carefully elucidated in schizophrenia. Our study aimed to explore whether the abnormality of ASSR in patients with first-episode schizophrenia (FEP) is altered under eye-open (EO) and eye-closed (EC) states. ASSR was elicited using 40 Hz click trains under EO and EC states. Twenty-eight healthy control subjects (HC) and thirty-three FEP individuals, 17 of whom were medication-naive, were recruited. The event-related spectrum perturbation (ERSP) and intertrial coherence (ITC) in response to 40 Hz click sounds were quantified. Compared to HC group, FEP group showed a lower ITC and ERSP during EO state, as well as a decreased ITC during EC state. Our results suggest that abnormalities in gamma band oscillations among first-episode schizophrenia patients are present under both eye open and eye close states. Although differences in gamma band oscillations between EO and EC states within the FEP group were not observed, exploratory results suggest that state-sensitivity may be contingent on medication use. PMID- 29705713 TI - The neural markers of MRI to differentiate depression and panic disorder. AB - Depression and panic disorder (PD) share the common pathophysiology from the perspectives of neurotransmitters. The relatively high comorbidity between depression and PD contributes to the substantial obstacles to differentiate from depression and PD, especially for the brain pathophysiology. There are significant differences in the diagnostic criteria between depression and PD. However, the paradox of similar pathophysiology and different diagnostic criteria in these two disorders were still the issues needing to be addressed. Therefore the clarification of potential difference in the field of neuroscience and pathophysiology between depression and PD can help the clinicians and scientists to understand more comprehensively about significant differences between depression and PD. The researchers should be curious about the underlying difference of pathophysiology beneath the significant distinction of clinical symptoms. In this review article, I tried to find some evidences for the differences between depression and PD, especially for neural markers revealed by magnetic resonance imaging (MRI). The distinctions of structural and functional alterations in depression and PD are reviewed. From the structural perspectives, PD seems to have less severe gray matter alterations in frontal and temporal lobes than depression. The study of white matter microintegrity reveals more widespread alterations in fronto-limbic circuit of depression patients than PD patients, such as the uncinate fasciculus and anterior thalamic radiation. PD might have a more restrictive pattern of structural alterations when compared to depression. For the functional perspectives, the core site of depression pathophysiology is the anterior subnetwork of resting-state network, such as anterior cingulate cortex, which is not significantly altered in PD. A possibly emerging pattern of fronto-limbic distinction between depression and PD has been revealed by these explorative reports. The future trend for machine learning and pattern recognition might confirm the differentiation pattern between depression and PD based on the explorative results. PMID- 29705714 TI - Multifocal occurrence of extra-abdominal desmoid type fibromatosis - A rare manifestation. A clinicopathological study of 6 sporadic cases and 1 hereditary case. AB - Desmoid-type fibromatosis, also called desmoid tumor, is a locally aggressive myofibroblastic neoplasm that usually arises in deep soft tissue with significant potential for local recurrence. It displays an unpredictable clinical course. beta-Catenin, the genetic key player of desmoid tumors shows nuclear accumulation due to mutations that prevent its degradation leading to activation of Wnt signaling and myofibroblastic cell proliferation. The corresponding hot spot mutations are located in exon 3 of the CTNNB1 gene or alternatively, in the APC tumor suppressor gene, most often as a germline mutation. Multifocal desmoid tumors are very rare and clinical characteristics are poorly understood. Here we present six sporadic and one familial case of multifocal desmoid tumors. Four female and three male patients, aged between 7 and 30 years (mean 18.4 years) were identified in a cohort of 1392 cases. Tumors were located in (distal) extremities, thorax, breast, abdominal wall, shoulder, and neck. Four cases showed a CTNNB1 mutation and one an APC germline mutation. In two sporadic cases no CTNNB1 mutation was identified. Four patients showed (multiple) recurrences and one patient was lost to follow-up. In conclusion, multifocal desmoid tumors are a very rare disease and may occur in sporadic cases that are characterized by recurrent CTNNB1 mutations. However, the underlying pathogenesis of multifocal desmoid tumors remains poorly understood with often aggressive clinical behavior and challenging therapeutical management. PMID- 29705715 TI - Solid pseudopapillary neoplasm (SPN) of the testis: Comprehensive mutational analysis of 6 testicular and 8 pancreatic SPNs. AB - BACKGROUND: Recently, we came with the theory of a possible relationship between a group of testicular and pancreatic tumors. We used one case of a pancreatic analogue solid pseudopapillary neoplasm of the testis composed partially of areas reminiscent of solid pseudopapillary neoplasm (SPN) of the pancreas and partially of structures identical to primary signet ring stromal tumor of the testis (PSRSTT) as a connecting link between these two entities. After demonstrating that PSRSTT and pancreatic analogue SPN of the testis share the same immunoprofile and genetic features characteristic for pancreatic SPN, we came to the conclusion that pancreatic analogue SPN of the testis and PSRSTT represent a morphological spectrum of a single entity and that both are related to the pancreatic SPN. DESIGN: The aim of this study is to present a series of 6 cases of testicular tumors, which lacked the signet ring cell component and were thus morphologically very similar to the SPN of the pancreas. The goal of this study is to compare the genetic background of these testicular tumors that are obviously related to the PSRSTT/pancreatic analogue SPN of the testis with the series of 8 pancreatic SPN. RESULTS: The mutational analysis revealed an oncogenic somatic mutation in the exon 3 of the CTNNB1 (beta-catenin) gene in all analyzable (5/6) testicular and all pancreatic (8/8) tumors. The immunoprofile (positivity with beta-catenin, CD10, vimentin, NSE, CD56, and negativity with inhibin, calretinin, chromogranin) was identical in all testicular and pancreatic tumors. CONCLUSION: This study expanded the morphological spectrum of the PSRSTT/pancreatic analogue SPN of the testis by adding 6 cases without the signet ring cell component. Considering the obvious analogy of PSRSTT/pancreatic analogue SPN of the testis/SPN of the testis and their relationship to the pancreatic SPN we propose the collective term "solid pseudopapillary neoplasm of the testis" for these tumors. The mutational profile of the SPN of the testis and pancreas was the same in both groups of tumors which we consider as a final proof that SPN of the testis is identical to the SPN of the pancreas. PMID- 29705716 TI - Methods to investigate structure and activation dynamics of GC-1/GC-2. AB - Soluble guanylyl cyclase (sGC) is a heterodimeric enzyme consisting of one alpha and one beta subunit. The alpha1beta1 (GC-1) and alpha2beta1 (GC-2) heterodimers are important for NO signaling in humans and catalyse the conversion from GTP to cGMP. Each sGC subunit consists of four domains. Several crystal structures of the isolated domains are available. However, crystals of full-length sGC have failed to materialise. In consequence, the detailed three dimensional structure of sGC remains unknown to date. Different techniques including stopped-flow spectroscopy, Forster-resonance energy transfer, direct fluorescence, analytical ultracentrifugation, chemical cross-linking, small-angle X-ray scattering, electron microscopy, hydrogen-deuterium exchange and protein thermal shift assays, were used to collect indirect information. Taken together, this circumstantial evidence from different groups brings forth a plausible model of sGC domain arrangement, spatial orientation and dynamic rearrangement upon activation. For analysis of the active conformation the stable binding mode of sGC activators has a significant methodological advantage over the transient, elusive, complex and highly concentration dependent effects of NO in many applications. The methods used and the results obtained are reviewed and discussed in this article. PMID- 29705717 TI - Mixed method approach to assess atmospheric nitrogen deposition in arid and semi arid ecosystems. AB - Arid and semi-arid ecosystems (aridlands) cover a third of Earth's terrestrial surface and contain organisms that are sensitive to low level atmospheric pollutants. Atmospheric nitrogen (N) inputs to aridlands are likely to cause changes in plant community composition, fire frequency, and carbon cycling and storage. However, few studies have documented long-term rates of atmospheric N inputs in aridlands because dry deposition is technically difficult to quantify, and extensive sampling is needed to capture fluxes with spatially and temporally heterogeneous rainfall patterns. Here, we quantified long-term spatial and temporal patterns of inorganic N deposition in protected aridland ecosystems across an extensive urban-rural gradient using multiple sampling methods. We compared long-term rates of N deposition from ion-exchange resin (IER) collectors (bulk and throughfall, 2006-2015), wet-dry bucket collectors (2006-2015), and dry deposition from the inferential method using passive samplers (2010-2012). From mixed approaches with IER collectors and inferential methods, we determined that 7.2 +/- 0.4 kgNha-1y-1 is deposited to protected Sonoran Desert within metropolitan Phoenix, Arizona and 6.1 +/- 0.3 kgNha-1y-1 in nearby desert ecosystems. Regional scale models overestimated deposition rates for our sampling period by 60% and misidentified hot spots of deposition across the airshed. By contrast, the easy-deployment IER throughfall collectors showed minimal spatial variation across the urban-rural gradient and underestimated deposition fluxes by 54%, largely because of underestimated dry deposition in throughfall. However, seasonal sampling of the IER collectors over 10 years allowed us to capture significant seasonal variation in N deposition and the importance of precipitation timing. These results, derived from the longest, spatially and temporally explicit dataset in drylands, highlight the need for long-term, mixed methods to estimate atmospheric nutrient enrichment to aridlands in a rapidly changing world. PMID- 29705719 TI - Calcium- and ATP-dependent regulation of Na/Ca exchange function in BHK cells: Comparison of NCX1 and NCX3 exchangers. AB - Na+/Ca2+ exchangers (NCX) mediate bidirectional Ca2+ fluxes across cell membranes and contribute to Ca2+ homeostasis in many cell types. Exchangers are regulated by gating reactions that depend on Na+ and Ca2+ binding to transport and regulatory sites. A Na+i-dependent inactivation is prominent in all isoforms, whereas Ca2+i-dependent regulation varies among isoforms. Here we characterize new details of NCX operation and describe differences and similarities between NCX3 and NCX1 regulation by intracellular Ca2+ and ATP. To compare isoforms, we employed BHK cells expressing NCX3 or NCX1 constitutively and exchange activity was analysed in whole-cell and excised patch recordings under "zero-trans" conditions (i.e., with only one transported ion species on each side). Using BHK cells with low cytoplasmic Ca2+ buffering, outward (reverse) currents, reflecting Ca2+ influx, are activated by applying extracellular Ca2+ (Cao) in the presence of Na+ on the cytoplasmic side. When firstly activated, peak outward NCX3 currents rapidly decay over seconds and then typically develop a secondary transient peak with slower kinetics, until Cao removal abolishes all outward current. The delayed rise of outward current is the signature of an activating process since peak outward NCX3 currents elicited at subsequent Cao bouts remain stimulated for minutes and slower decline towards a non-zero level during continued Cao application. Secondary transient peaks and current stimulation are suppressed by increasing the intracellular Ca2+ buffer capacity or by replacing cytoplasmic ATP with the analogues AMP-PNP or ATPgammaS. In BHK cells expressing NCX1, outward currents activated under identical settings decay to a steady-state level during single Cao application and are significantly larger, causing strong and long-lived run down of subsequent outward currents. NCX1 current run down is not prevented by increasing cytoplasmic Ca2+ buffering but secondary transient peaks in the outward current profile can be resolved in the presence of ATP. Finally, inward currents recorded in patches excised from NCX3-expressing cells reveal a proteolysis-sensitive, Ca-dependent inactivation process that is unusual for NCX1 forward activity. Together, our results suggest that NCX function is regulated more richly than appreciated heretofore, possibly including processes that are lost in excised membrane patches. PMID- 29705720 TI - O-(2-(18F)fluoroethyl)-L-tyrosine PET for the differentiation of tumour recurrence from late pseudoprogression in glioblastoma. PMID- 29705718 TI - Neural networks supporting audiovisual integration for speech: A large-scale lesion study. AB - Auditory and visual speech information are often strongly integrated resulting in perceptual enhancements for audiovisual (AV) speech over audio alone and sometimes yielding compelling illusory fusion percepts when AV cues are mismatched, the McGurk-MacDonald effect. Previous research has identified three candidate regions thought to be critical for AV speech integration: the posterior superior temporal sulcus (STS), early auditory cortex, and the posterior inferior frontal gyrus. We assess the causal involvement of these regions (and others) in the first large-scale (N = 100) lesion-based study of AV speech integration. Two primary findings emerged. First, behavioral performance and lesion maps for AV enhancement and illusory fusion measures indicate that classic metrics of AV speech integration are not necessarily measuring the same process. Second, lesions involving superior temporal auditory, lateral occipital visual, and multisensory zones in the STS are the most disruptive to AV speech integration. Further, when AV speech integration fails, the nature of the failure-auditory vs visual capture-can be predicted from the location of the lesions. These findings show that AV speech processing is supported by unimodal auditory and visual cortices as well as multimodal regions such as the STS at their boundary. Motor related frontal regions do not appear to play a role in AV speech integration. PMID- 29705721 TI - Medication errors may be reduced by double-checking method. PMID- 29705722 TI - Insufficient evidence to support ultrasonography as a method to rule out an improperly positioned nasogastric tube. PMID- 29705723 TI - Why do babies cry? AB - Persistent, inconsolable crying in young infants is common, distressing but usually benign. This selective review examines perceptions and perceived origins of this phenomenon in babies where serious pathology has been excluded. Adult brains have evolved to become hypersensitive to infant cries. Babies respond to parental stress by crying more, thus setting up a vicious cycle. Most treatments appear to work largely through a placebo effect. The imperative for healthcare professionals is to reduce parental anxiety by offering reassurance and support. PMID- 29705724 TI - Winter 2017 Children's Cancer and Leukaemia Group febrile neutropenia audit. PMID- 29705725 TI - Do cash transfer programmes yield better health in the first year of life? A systematic review linking low-income/middle-income and high-income contexts. AB - INTRODUCTION: Decades of research unequivocally demonstrates that no matter the society, socioeconomic resources are perhaps the most fundamental determinants of health throughout the life course, including during its very earliest stages. As a result, societies have implemented 'cash transfer' programmes, whichprovide income supplementation to reduce socioeconomic disadvantage among the poorest families with young children. Despite this being a common approach of societies around the world, research on effects of these programmes in low-income/middle income countries, and those in high-income countries has been conducted as if they are entirely distinct phenomena. In this paper, we systematically review the international literature on the association between cash transfer programmes and health outcomes during the first year of life. METHODS: We conducted a systematic review based on Preferred Reporting Items for Systematic Reviews and Meta Analyses protocol. Using a variety of relevant keywords, we searched MEDLINE, EMBASE, CINAHL, Cochrane Reviews, EconLit and Social Sciences Citations Index. RESULTS: Our review yielded 14 relevant studies. These studies suggested cash transfer programmes that were not attached to conditions tended to yield positive effects on outcomes such as birth weight and infant mortality. Programmes that were conditional on use of health services also carried positive effects, while those that carried labour-force participation conditionalities tended to yield no positive effects. DISCUSSION: Given several dynamics involved in determining whether children are healthy or not, which are common worldwide, viewing the literature from a global perspective produces novel insights regarding the tendency of policies and programmes to reduce or, to exacerbate, the effects of socioeconomic disadvantage on child health. PMID- 29705726 TI - Trends in epilepsy admissions in children, 1981-2013: population-based observational study using the Scottish national hospital discharge database. AB - OBJECTIVE: To examine trends in epilepsy admissions in children from 1981 to 2013. DESIGN: Repeated cross-sectional, population-based study. SETTING: Scotland. PATIENTS: We identified admissions among children between 1981 and 2013 inclusive. Epilepsy admissions were identified from the Scottish national hospital discharge database by using relevant diagnostic codes. Primary epilepsy admissions (PEAs) were those with epilepsy as the primary discharge diagnosis, or convulsions as the primary diagnosis but with epilepsy as secondary diagnosis. All other epilepsy admissions were secondary epilepsy admissions (SEAs). MAIN OUTCOME MEASURES: Trends in annual epilepsy and non-epilepsy admission rates, as well as sociodemographic, clinical characteristics, length of stay and readmissions of epilepsy admissions. RESULTS: 57 031 epilepsy and 3 863 809 non epilepsy admissions were available for analysis. Overall, epilepsy and non epilepsy admissions increased, with a greater increase in epilepsy admissions (interaction Chi2 test statistic 252, p<0.00001). Elective epilepsy admissions, unlike elective non-epilepsy admissions, continually increased, but emergency epilepsy admissions increased until 2000 and showed only minor fluctuations thereafter. Increase in SEAs was more marked than PEAs (interaction Chi2 test statistic 627, p<0.0001). 48% of epilepsy admissions were to children's hospitals. No substantial trends were apparent in age, gender or deprivation distribution of epilepsy admissions. There was a clear trend towards shorter length of stay. CONCLUSIONS: Childhood epilepsy admissions are increasing, at a faster rate than non-epilepsy admissions, and have changed towards shorter, more elective admissions. Many will not be to children's hospitals, and the primary reason will often not be because of epilepsy/convulsions. More, not less, epilepsy resources are needed. PMID- 29705727 TI - Does screening for congenital cytomegalovirus at birth improve longer term hearing outcomes? AB - Currently, the diagnosis of congenital cytomegalovirus (cCMV) infection in most highly resourced countries is based on clinical suspicion alone. This means only a small proportion of cCMV infections are diagnosed. Identification, through either universal or targeted screening of asymptomatic newborns with cCMV, who would previously have gone undiagnosed, would allow for potential early treatment with antiviral therapy, ongoing audiological surveillance and early intervention if sensorineural hearing loss (SNHL) is identified. This paper systematically reviews published papers examining the potential benefits of targeted and universal screening for newborn infants with cCMV. We found that the treatment of these infants with antiviral therapy remains controversial, and clinical trials are currently underway to provide further answers. The potential benefit of earlier identification and intervention (eg, amplification and speech therapy) of children at risk of later-onset SNHL identified through universal screening is, however, clearer. PMID- 29705729 TI - Man with hand pain. AB - CLINICAL INTRODUCTION: A right-hand dominant man was transferred to our institution for evaluation by the hand surgery service. He reported that the day prior he had been sliding a sheet of plywood across the ground when he lost his grip, causing the board to slide across his left hand. He presented to an outside hospital where local exploration of the wound did not reveal any foreign body. On arrival, he complained only of mild pain in his hand. Physical examination revealed erythema and swelling over the thenar eminence and a small open area without any drainage. Radiographs (figure 1) and ultrasonography (figures 2 and 3, online supplementary video 1 and 2) were performed.DC1SP110.1136/emermed-2018 207679.supp1Supplementary dataemermed;35/12/731/F1F1F1Figure 1Radiograph of the hand.emermed;35/12/731/F2F2F2Figure 2Long-axis ultrasonography of the hand.emermed;35/12/731/F3F3F3Figure 3Short-axis ultrasonography of the hand. QUESTION: What is you diagnosis?Fracture of the metacarpal of the thumb.Cellulitis of the thenar eminence.Abscess of the thenar eminence.Retained foreign body. PMID- 29705728 TI - Understanding the gut-kidney axis in nephrolithiasis: an analysis of the gut microbiota composition and functionality of stone formers. AB - OBJECTIVES: The involvement of the gut microbiota in the pathogenesis of calcium nephrolithiasis has been hypothesised since the discovery of the oxalate degrading activity of Oxalobacter formigenes, but never comprehensively studied with metagenomics. The aim of this case-control study was to compare the faecal microbiota composition and functionality between recurrent idiopathic calcium stone formers (SFs) and controls. DESIGN: Faecal samples were collected from 52 SFs and 48 controls (mean age 48+/-11). The microbiota composition was analysed through 16S rRNA microbial profiling approach. Ten samples (five SFs, five controls) were also analysed with deep shotgun metagenomics sequencing, with focus on oxalate-degrading microbial metabolic pathways. Dietary habits, assessed through a food-frequency questionnaire, and 24-hour urinary excretion of prolithogenic and antilithogenic factors, including calcium and oxalate, were compared between SFs and controls, and considered as covariates in the comparison of microbiota profiles. RESULTS: SFs exhibited lower faecal microbial diversity than controls (Chao1 index 1460+/-363vs 1658+/-297, fully adjusted p=0.02 with stepwise backward regression analysis). At multivariate analyses, three taxa (Faecalibacterium, Enterobacter, Dorea) were significantly less represented in faecal samples of SFs. The Oxalobacter abundance was not different between groups. Faecal samples from SFs exhibited a significantly lower bacterial representation of genes involved in oxalate degradation, with inverse correlation with 24-hour oxalate excretion (r=-0.87, p=0.002). The oxalate-degrading genes were represented in several bacterial species, whose cumulative abundance was inversely correlated with oxaluria (r=-0.85, p=0.02). CONCLUSIONS: Idiopathic calcium SFs exhibited altered gut microbiota composition and functionality that could contribute to nephrolithiasis physiopathology. PMID- 29705730 TI - Paediatric traumatic cardiac arrest: a Delphi study to establish consensus on definition and management. AB - AIMS: Paediatric traumatic cardiac arrest (TCA) is associated with low survival and poor outcomes. The mechanisms that underlie TCA are different from medical cardiac arrest; the approach to treatment of TCA may therefore also need to differ to optimise outcomes. The aim of this study was to explore the opinion of subject matter experts regarding the diagnosis and treatment of paediatric TCA, and to reach consensus on how best to manage this group of patients. METHODS: An online Delphi study was conducted over three rounds, with the aim of achieving consensus (defined as 70% agreement) on statements related to the diagnosis and management of paediatric TCA. Participants were invited from paediatric and adult emergency medicine, paediatric anaesthetics, paediatric ICU and paediatric surgery, as well as Paediatric Major Trauma Centre leads and representatives from the Resuscitation Council UK. Statements were informed by literature reviews and were based on elements of APLS resuscitation algorithms as well as some concepts used in the management of adult TCA; they ranged from confirmation of cardiac arrest to the indications for thoracotomy. RESULTS: 73 experts completed all three rounds between June and November 2016. Consensus was reached on 14 statements regarding the diagnosis and management of paediatric TCA; oxygenation and ventilatory support, along with rapid volume replacement with warmed blood, improve survival. The duration of cardiac arrest and the lack of a response to intervention, along with cardiac standstill on ultrasound, help to guide the decision to terminate resuscitation. CONCLUSION: This study has given a consensus based framework to guide protocol development in the management of paediatric TCA, though further work is required in other key areas including its acceptability to clinicians. PMID- 29705731 TI - Correction: Unilateral retinitis pigmentosa occurring in an individual with a mutation in the CLRN1 gene. PMID- 29705732 TI - Treatment and reconstruction of a complicated infected scalp squamous cell carcinoma with CNS invasion. AB - A 60-year-old male patient with a large infected cranial apex lesion was admitted with lethargy and mental status changes. The patient underwent evaluation with imaging studies, a skin biopsy, cultures with microscopy and a diagnostic burr hole. MRI and positron emission tomography/CT scan revealed a squamous cell carcinoma with ingrowth in the midline of the brain and subdural empyema infected with Streptococcus anginosus and Staphylococcus aureusHigh dose intravenous antibiotic treatment was initiated and the patient subsequently underwent a surgical resection of the carcinoma with a 1 cm margin of surrounding skin and skull. The defect was reconstructed using a titanium plate and a free microvascular lattisimus dorsi muscle flap then covered with a split skin graft.The patient received 37 radiation therapy sessions (66 GY) as adjuvant therapy.Intensive neurorehabilitation slowly improved an initial paraparesis. The 7-month follow-up revealed a satisfactory cosmetic result and residual gait impairment secondary to central nervous system invasion. PMID- 29705733 TI - Novel management of vaginal chronic graft-versus-host disease causing haematometra and haematocolpos. AB - Genital chronic graft-versus-host disease (GVHD) in women posthaematopoietic cell transplantation may cause vaginal mucosal sclerosis. Human papillomavirus (HPV) reactivation, also common post-transplantation, limits local immunosuppressive, but not oestrogen treatment. A 36-year-old nulliparous woman developed coincidental genital chronic GVHD and HPV 22 months after transplant for aplastic anaemia. Topical immunosuppression for GVHD led to an eruption of warts successfully treated with laser surgery and cone biopsy. She maintained normal ovarian function and used extended cycle combined hormonal contraception. A vaginal oestrogen ring used continuously limited most scarring for 8 years. Progressive apical vaginal scarring obstructed menstrual flow leading to haematocolpos and haematometra. Normal anatomy was restored with a cruciate incision in the cervicovaginal scar performed during menses. When HPV disease limits use of topical immunosuppression in women with vaginal GVHD, the local scar-reducing effect of a vaginal oestrogen ring is limited, and surgery may be needed and can be successful in treating haematocolpos.This study was registered in ClinicalTrials.gov with trial registration number of NCT00003838. PMID- 29705735 TI - Lemierre's syndrome: a rare cause of sepsis presenting with an absence of throat symptoms. AB - A 16-year-old boy presented to hospital with a 6-day history of diarrhoea, vomiting and abdominal pain. During his admission he was found to be hypotensive, tachycardic and persistently feverish. Blood cultures taken on admission isolated Fusobacterium necrophorum CT scanning of his neck showed a non-occlusive thrombus of the right internal jugular vein and a small right parapharyngeal abscess. CT scans of the chest and abdomen revealed multiple pulmonary abscesses, bilateral pleural effusions and splenomegaly. Treatment consisted of an unfractionated heparin infusion and intravenous antibiotics. A right-sided intercostal drain was inserted for a complex right-sided empyema. He subsequently developed a left sided pleural effusion which was treated with a video-assisted thoracoscopic surgery (VATS) pleurodesis procedure. His fever resolved after his VATS pleurodesis procedure 3 weeks after initial presentation. Clinically he made a slow recovery but now is improved after 6 weeks of intravenous antibiotics and was discharged home. PMID- 29705736 TI - One man's wars. PMID- 29705734 TI - Treatment of end-stage renal disease with continuous ambulatory peritoneal dialysis in rural Guatemala. AB - A 42-year-old indigenous Maya man presented to a non-profit clinic in rural Guatemala with signs, symptoms and laboratory values consistent with uncontrolled diabetes. Despite appropriate treatment, approximately 18 months after presentation, he was found to have irreversible end-stage renal disease (ESRD) of uncertain aetiology. He was referred to the national public nephrology clinic and subsequently initiated home-based continuous ambulatory peritoneal dialysis. With primary care provided by the non-profit clinic, his clinical status improved on dialysis, but socioeconomic and psychological challenges persisted for the patient and his family. This case shows how care for people with ESRD in low- and middle-income countries requires scaling up renal replacement therapy and ensuring access to primary care, mental healthcare and social work services. PMID- 29705737 TI - Chairing an academic pathology department: challenges and opportunities. AB - Understanding the heterogeneity of departmental structure, service model and job descriptions for different pathology chairs, this review highlights some common challenges and opportunities facing most pathology chairs in academic institutions. The review is divided into three sections: clinical service, academic development and administration. The views and insights from this review may provide guidance to new chairs and emerging leaders in pathology and other relevant specialties. PMID- 29705739 TI - Veterinary experiences of a Johne's disease control programme in Ireland. PMID- 29705740 TI - Clinical use of organic near-infrared fluorescent contrast agents in image-guided oncologic procedures and its potential in veterinary oncology. AB - One of the major challenges in surgical oncology is the intraoperative discrimination of tumoural versus healthy tissue. Until today, surgeons rely on visual inspection and palpation to define the tumoural margins during surgery and, unfortunately, for various cancer types, the local recurrence rate thus remains unacceptably high. Near-infrared (NIR) fluorescence imaging is an optical imaging technique that can provide real-time preoperative and intraoperative information after administration of a fluorescent probe that emits NIR light once exposed to a NIR light source. This technique is safe, cost-effective and technically easy. Several NIR fluorescent probes are currently studied for their ability to highlight neoplastic cells. In addition, NIR fluorescence imaging holds great promise for sentinel lymph node mapping. The aim of this manuscript is to provide a literature review of the current organic NIR fluorescent probes tested in the light of human oncology and to introduce fluorescence imaging as a valuable asset in veterinary oncology. PMID- 29705742 TI - Response to: 'Unending story of the indirect immunofluorescence assay on HEp-2 cells: old problems and new solutions?' by Meroni et al. PMID- 29705741 TI - Imputation-based analysis of MICA alleles in the susceptibility to ankylosing spondylitis. PMID- 29705743 TI - In vivo visualisation of different modes of action of biological DMARDs inhibiting osteoclastic bone resorption. AB - OBJECTIVES: Osteoclasts play critical roles in inflammatory bone destruction. Precursor cell migration, cell differentiation, and functional cell activation are all in play. Biological disease-modifying antirheumatic drugs (DMARDs) have been shown to significantly inhibit both bone erosion as well as synovitis, although how such agents reduce osteoclastic bone destructionin vivo has not been fully explained. Here, we used an intravital time-lapse imaging technique to directly visualise mature osteoclasts and their precursors, and explored how different biological DMARDs acted in vivo. METHODS: Lipopolysaccharide (LPS) was injected into the calvarial periosteum of fluorescent reporter mice to induce inflammatory bone destruction. Time-lapse imaging was performed via intravital multiphoton microscopy 5 days after LPS injection. Biological DMARDs, including monoclonal antibodies (mAbs) against the interleukin (IL) 6 receptor (IL-6R) and tumour necrosis factor alpha (TNFalpha), or cytotoxic T-lymphocyte-associated protein 4 (CTLA4)-Ig, were intraperitoneally administered at the time of LPS injection. We determined CD80/86 expression levels in mature osteoclasts and their precursors by flow cytometry, quantitative PCR and immunohistochemistry. RESULTS: Of the biologicals tested, anti-IL-6R and anti-TNFalpha mAbs affected mature osteoclasts and switched bone-resorbing osteoclasts to non-resorbing cells. CTLA4-Ig had no action on mature osteoclasts but mobilised osteoclast precursors, eliminating their firm attachment to bone surfaces. In agreement with these results, CD80/86 (the target molecules of CTLA4-Ig) were prominently expressed only in osteoclast precursor cells, being suppressed during osteoclast maturation. CONCLUSIONS: Intravital imaging revealed that various biological DMARDs acted at specific therapeutic time points during osteoclastic bone destruction, with different efficacies. These results enable us to grasp the real modes of action of drugs, optimising the usage of drug regimens. PMID- 29705744 TI - Missing pebble in the mosaic of rheumatic diseases and mental health: younger does not always mean happier. PMID- 29705746 TI - Correction: Prevalence and general health status of people with intellectual disabilities in Scotland: a total population study. PMID- 29705747 TI - Making a difference: the AMSSM Foundation and humanitarian service. PMID- 29705745 TI - Availability, price and promotions for cigarettes and non-cigarette tobacco products: an observational comparison of US Air Force bases with nearby tobacco retailers, 2016. AB - INTRODUCTION: Active duty military personnel have higher cigarette and smokeless tobacco use rates than civilian populations. Although US Airmen (called Airmen regardless of gender or rank) are required to be tobacco-free during initial training, many resume use once this period ends, perhaps as a result of easy access to cheap tobacco products. METHODS: Between July and September 2016, we collected tobacco product, price and promotion information by visiting on-base (n=28) and off-base (n=80) tobacco retailers near the eight technical training bases where approximately 99% of Airmen attend training. We conducted mixed linear effects models to examine on-base versus off-base differences. RESULTS: Cigarette packs were 11%-12% cheaper at on-base retailers compared with off-base retailers. Newport Menthol and Marlboro Red cigarette packs were $0.87 and $0.80 lower on-base (p<0.001) while the cheapest pack available was $0.54 lower on-base (p<0.01). Copenhagen smokeless tobacco was also significantly cheaper on-base (B= 0.65, p<0.01). Interior price promotions were more common on-base. CONCLUSIONS: Retail stores located on Air Force bases sell cigarettes and smokeless tobacco products at prices well below those in nearby off-base retailers: the vast majority of these retailers feature interior price promotions for these products. Federal policies regulating prices of on-base tobacco sales, if implemented more effectively, have the potential to protect the health of Airmen by helping them remain tobacco-free after technical training. PMID- 29705748 TI - Additional perspectives on 'ACL rupture is a single leg injury but a double leg problem...'. PMID- 29705749 TI - Quadriceps tendon autograft for arthroscopic knee ligament reconstruction: use it now, use it often. AB - Traditional bone-patellar tendon-bone and hamstring tendon ACL grafts are not without limitations. A growing body of anatomic, biomechanical and clinical data has demonstrated the utility of quadriceps tendon autograft in arthroscopic knee ligament reconstruction. The quadriceps tendon autograft provides a robust volume of tissue that can be reliably harvested, mitigating the likelihood of variably sized grafts and obviating the necessity of allograft augmentation. Modern, minimally invasive harvest techniques offer the advantages of low rates of donor site morbidity and residual extensor mechanism strength deficits. New data suggest that quadriceps tendon autograft may possess superior biomechanical characteristics when compared with bone-patella tendon-bone (BPTB) autograft. However, there have been very few direct, prospective comparisons between the clinical outcomes associated with quadriceps tendon autograft and other autograft options (eg, hamstring tendon and bone-patellar tendon-bone). Nevertheless, quadriceps tendon autograft should be one of the primary options in any knee surgeon's armamentarium. PMID- 29705750 TI - Development of a screening tool to predict the risk of chronic pain and disability following musculoskeletal trauma: protocol for a prospective observational study in the United Kingdom. AB - INTRODUCTION: Pain is an expected and appropriate experience following traumatic musculoskeletal injury. By contrast, chronic pain and disability are unhelpful yet common sequelae of trauma-related injuries. Presently, the mechanisms that underlie the transition from acute to chronic disabling post-traumatic pain are not fully understood. Such knowledge would facilitate the development and implementation of precision rehabilitation approaches that match interventions to projected risk of recovery, with the aim of preventing poor long-term outcomes. The aim of this study is to identify a set of predictive factors to identify patients at risk of developing ongoing post-traumatic pain and disability following acute musculoskeletal trauma. To achieve this, we will use a unique and comprehensive combination of patient-reported outcome measures, psychophysical testing and biomarkers. METHODS AND ANALYSIS: A prospective observational study will recruit two temporally staggered cohorts (n=250 each cohort; at least 10 cases per candidate predictor) of consecutive patients with acute musculoskeletal trauma aged >=16 years, who are emergency admissions into a Major Trauma Centre in the United Kingdom, with an episode inception defined as the traumatic event. The first cohort will identify candidate predictors to develop a screening tool to predict development of chronic and disabling pain, and the second will allow evaluation of the predictive performance of the tool (validation). The outcome being predicted is an individual's absolute risk of poor outcome measured at a 6 month follow-up using the Chronic Pain Grade Scale (poor outcome >=grade II). Candidate predictors encompass the four primary mechanisms of pain: nociceptive (eg, injury location), neuropathic (eg, painDETECT), inflammatory (biomarkers) and nociplastic (eg, quantitative sensory testing). Concurrently, patient reported outcome measures will assess general health and psychosocial factors (eg, pain self-efficacy). Risk of poor outcome will be calculated using multiple variable regression analysis. ETHICS AND DISSEMINATION: Approved by the NHS Research Ethics Committee (17/WA/0421). PMID- 29705751 TI - Economic analysis of oral dexamethasone for symptom relief of sore throat: the UK TOAST study. AB - OBJECTIVES: To undertake an economic analysis assessing the cost-effectiveness of a single dose of oral dexamethasone compared with placebo for the relief of sore throat. DESIGN: A UK-based, multicentre, two arm, individually randomised, double blind trial. SETTING AND POPULATION: Adults (>=18 years) with acute sore throat and painful swallowing judged to be infective in origin, recruited and randomised in primary care. INTERVENTION: a single dose of 10 mg oral dexamethasone compared with placebo given at primary care visit. MAIN OUTCOME: Incremental cost effectiveness ratios (ICERs), cost per quality-adjusted symptom resolution using the EuroQol-five dimensions-five levels instrument, were estimated as part of a cost-utility analysis performed on an intention-to-treat cohort adopting a health payers perspective. RESULTS: Differences in health-related quality of life (HRQoL) over 7 days from baseline and at 24 hours in the dexamethasone compared with the placebo group (2.9% and 2.5% higher, respectively) were observed. After controlling for the baseline HRQoL imbalances, the economic impact of the intervention was not statistically significant: the quality-adjusted life year difference was -0.00005 (95% CI -0.0002 to 0.00011) equivalent to a loss in HRQoL of a half hour in the dexamethasone group. The average cost per patient associated in the dexamethasone and placebo groups in the basecase analysis was L73 and L69, respectively. In the basecase probabilistic analysis, the mean ICER was -L6440 (95% CI -L132 151 to L126 335) and the median ICER was -L304 (IQR L5816 to L3877); suggesting considerable uncertainty. CONCLUSIONS AND RELEVANCE: The economic burden associated with sore throat is substantial and was estimated at L2.35 billion to the healthcare services payer based on reported resource use and 2015 UK unit costs. There is considerable uncertainty regarding the cost effectiveness of a single dose of oral dexamethasone as a treatment strategy and therefore insufficient evidence to support its use in clinical practice. TRIAL REGISTRATION NUMBER: ISRCTN17435450; Post-results. PMID- 29705752 TI - Systematic review of prediction models for delirium in the older adult inpatient. AB - OBJECTIVE: To identify existing prognostic delirium prediction models and evaluate their validity and statistical methodology in the older adult (>=60 years) acute hospital population. DESIGN: Systematic review. DATA SOURCES AND METHODS: PubMed, CINAHL, PsychINFO, SocINFO, Cochrane, Web of Science and Embase were searched from 1 January 1990 to 31 December 2016. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses and CHARMS Statement guided protocol development. INCLUSION CRITERIA: age >60 years, inpatient, developed/validated a prognostic delirium prediction model. EXCLUSION CRITERIA: alcohol-related delirium, sample size <=50. The primary performance measures were calibration and discrimination statistics. Two authors independently conducted search and extracted data. The synthesis of data was done by the first author. Disagreement was resolved by the mentoring author. RESULTS: The initial search resulted in 7,502 studies. Following full-text review of 192 studies, 33 were excluded based on age criteria (<60 years) and 27 met the defined criteria. Twenty-three delirium prediction models were identified, 14 were externally validated and 3 were internally validated. The following populations were represented: 11 medical, 3 medical/surgical and 13 surgical. The assessment of delirium was often non-systematic, resulting in varied incidence. Fourteen models were externally validated with an area under the receiver operating curve range from 0.52 to 0.94. Limitations in design, data collection methods and model metric reporting statistics were identified. CONCLUSIONS: Delirium prediction models for older adults show variable and typically inadequate predictive capabilities. Our review highlights the need for development of robust models to predict delirium in older inpatients. We provide recommendations for the development of such models. PMID- 29705754 TI - Novel augmented reality solution for improving health literacy around antihypertensives in people living with type 2 diabetes mellitus: protocol of a technology evaluation study. AB - INTRODUCTION: Low health literacy is common in people with type 2 diabetes mellitus (T2DM) (up to 40%), associated with decreased self-efficacy in managing T2DM and its important complications, mainly hypertension. This study introduces, for the first time, an easy-to-use solution based on augmented reality (AR) on smartphones, to enhance health literacy around antihypertensive medicines. It assesses the feasibility of the solution for improving health literacy, oriented specifically to angiotensin II receptor blockers; embedding the health literacy improvement into the use cycle of angiotensin II receptor blockers and providing continuous access to information as a form of patient engagement. METHODS AND ANALYSIS: This is a technology evaluation study with one technology group (AR plus usual care) and one non-technology group (usual care). Both groups receive face-to-face communications with community pharmacists regarding angiotensin II receptor blockers; the technology group receive additional AR-enhanced digital consumer medicine information throughout the use of their medications. The primary outcome is the change in health literacy and the hypothesis is that the proportions of people who show high health literacy will be larger in the technology group. Mixed effects models will be used to analyse solution effectiveness on outcomes. Multiple regression models will be used to find additional variables that might affect the relationship between health literacy and the AR solution. ETHICS AND DISSEMINATION: Queensland University of Technology (QUT) Human Research Ethics Committee has approved the study as a low risk technology evaluation study (approval number: 1700000275). Findings will be disseminated via attending scientific conferences and publishing in peer-reviewed journals. Facilitated by QUT, two press releases have been published in public media and two presentations have been made in university classrooms. PMID- 29705753 TI - High-intensity interval training or continuous training, combined or not with fasting, in obese or overweight women with cardiometabolic risk factors: study protocol for a randomised clinical trial. AB - INTRODUCTION: Physical inactivity and increased caloric intake play important roles in the pathophysiology of obesity. Increasing physical activity and modifying eating behaviours are first-line interventions, frequently hampered by lack of time to exercise and difficulties in coping with different diets. High intensity interval training (HIIT) may be a time-efficient method compared with moderate-intensity continuous training (CT). Conversely, diets with a fasting component may be more effective than other complex and restrictive diets, as it essentially limits caloric intake to a specified period without major diet composition changes. Therefore, the combination of HIIT and fasting may provide incremental benefits in terms of effectiveness and time efficiency in obese and sedentary populations. The aim of this study is to determine the effect of HIIT versus CT, combined or not with fasting, on microcirculatory function, cardiometabolic parameters, anthropometric indices, cardiorespiratory fitness and quality of life in a population of sedentary overweight or obese women with cardiometabolic risk factors. METHODS AND ANALYSIS: Sedentary women aged 30-50 years, with a body mass index >=25 kg/m2 and cardiometabolic risk factors, will be randomised to HIIT performed in the fasting state, HIIT performed in the fed state, CT in the fasting state or CT in the fed state. Cardiometabolic parameters, anthropometric indices, cardiorespiratory fitness, quality of life and microvascular function (cutaneous capillary density and microvascular reactivity evaluated by laser speckle contrast imaging) will be evaluated before initiation of the interventions and 16 weeks thereafter. ETHICS AND DISSEMINATION: The trial complies with the Declaration of Helsinki and has been approved by the local ethics committee (Instituto Nacional de Cardiologia, Rio de Janeiro, Brazil). All patients provide written informed consent before enrolment and randomisation. The study's results will be disseminated to the healthcare community by publications and presentations at scientific meetings. TRIAL REGISTRATION NUMBER: NCT03236285. PMID- 29705755 TI - Chemical peels for acne vulgaris: a systematic review of randomised controlled trials. AB - OBJECTIVE: We evaluated current evidence from randomised controlled trials (RCTs) regarding the effectiveness of chemical peeling for treating acne vulgaris. METHODS: Standard Cochrane methodological procedures were used. We searched MEDLINE, Cochrane Central Register of Controlled Trials and EMBASE via OvidSP through April 2017. Reviewers independently assessed eligibility, risk of bias and extracted data. RESULTS: Twelve RCTs (387 participants) were included. Effectiveness was not significantly different: trichloroacetic acid versus salicylic acid (SA) (percentage of total improvement: risk ratio (RR) 0.89; 95% CI 0.73 to 1.10), glycolic acid (GA) versus amino fruit acid (the reduction of inflammatory lesions: mean difference (MD), 0.20; 95% CI -3.03 to 3.43), SA versus pyruvic acid (excellent or good improvement: RR 1.11; 95% CI 0.73 to 1.69), GA versus SA (good or fair improvement: RR 1.00; 95% CI 0.85 to 1.18), GA versus Jessner's solution (JS) (self-reported improvements: RR 1.00; 95% CI 0.44 to 2.26), and lipohydroxy acid versus SA (reduction of non-inflammatory lesions: 55.6%vs48.5%, p=0.878). Combined SA and mandelic acid peeling was superior to GA peeling (percentage of improvement in total acne score: 85.3%vs68.5%, p<0.001). GA peeling was superior to placebo (excellent or good improvement: RR 2.30; 95% CI 1.40 to 3.77). SA peeling may be superior to JS peeling for comedones (reduction of comedones: 53.4%vs26.3%, p=0.001) but less effective than phototherapy for pustules (number of pustules: MD -7.00; 95% CI -10.84 to -3.16). LIMITATIONS: The methodological quality of the included RCTs was very low to moderate. Meta-analysis was not possible due to the significant clinical heterogeneity across studies. CONCLUSION: Commonly used chemical peels appear to be similarly effective for mild-to-moderate acne vulgaris and well tolerated. However, based on current limited evidence, a robust conclusion cannot be drawn regarding any definitive superiority or equality among the currently used chemical peels. Well-designed RCTs are needed to identify optimal regimens. PMID- 29705756 TI - Cohort profile: China respiratory illness surveillance among pregnant women (CRISP), 2015-2018. AB - PURPOSE: We established the China Respiratory Illness Surveillance among Pregnant women (CRISP) to conduct active surveillance for influenza-associated respiratory illness during pregnancy in China from 2015 to 2018. Among annual cohorts of pregnant women, we assess the incidence of acute respiratory illness (ARI), influenza-like illness (ILI), laboratory-confirmed influenza virus infection and the seroconversion proportion during the winter influenza season. We also plan to examine the effect of influenza virus infection on adverse pregnancy, delivery and infant health outcomes with cumulative data from the three annual cohorts. PARTICIPANTS: Cohort nurses enrol pregnant women in different trimesters of pregnancy from prenatal care facilities in Suzhou, Jiangsu Province, eastern China. Pregnant women who plan to deliver in the study facilities are eligible. Pregnant women who are seeking care for anything other than routine prenatal care, such as confirmation of low progesterone and threatened miscarriage, are excluded. At enrolment, study nurses collect baseline information on demographics, education-level attained, underlying medical conditions, seasonal influenza vaccination receipt, risk factors for influenza infection, gravidity and parity and contact information. For each participant, cohort nurses conduct twice weekly follow-up contacts, one phone call and one WeChat message (free instant messaging), from the time of enrolment until delivery or termination of pregnancy. During follow-up, study nurses ask about symptoms, timing and characteristics of ARI, healthcare-seeking behaviour and medications taken for participants reporting respiratory illness since the last contact. In addition, we collect combined nasal and throat swabs for identified ARI to test for influenza viruses. We collect paired sera before and after the influenza season. Active respiratory illness surveillance and seroinfection data during pregnancy of participants are linked to their medical record and the Suzhou Maternal Child Information System for detailed information on clinical treatment for respiratory illness, pregnancy, delivery and infant health outcomes. FINDINGS TO DATE: In 2015-2016, of 4915 pregnant women approached, 192 (4%) refused to participate, 91 (2%) were ineligible because they did not plan to deliver in one of the study hospitals or because their visit was for anything other than routine prenatal care and 4632 (94%) were enrolled, 46% during their first trimester of pregnancy (range 5-12 weeks), 48% during the second trimester (range 13-27 weeks) and 6% during the third trimester (range 28-37 weeks). The median age of the enrollees was 27 years (range 16-45) and two (0.04%, 95% CI 0.01% to 0.17%) reported influenza vaccination in the previous 12 months before pregnancy, while zero reported influenza vaccination in the previous 12 months during pregnancy. During the observation time of 648 518 person-days, 1355 ARI episodes were identified. Among 1127 swabs collected (for 83% of all ARIs), 68 (6%) tested positive for influenza virus, for a laboratory-confirmed influenza incidence of 0.31 (95% CI 0.25 to 0.40) per 100 person-months during pregnancy in the study cohort. FUTURE PLANS: Results will be used to describe influenza disease burden in this population to model potential numbers of influenza illnesses averted if influenza vaccination coverage were increased and to support enhanced influenza prevention and control strategies among pregnant women in China. We also plan to enrol and follow three cohorts of pregnant women over three influenza seasons during 2015 2018 which will allow an analysis of the effect of influenza virus infection during pregnancy on adverse pregnancy, delivery and infant outcomes. PMID- 29705757 TI - Identification and initial response to children's exposure to intimate partner violence: a qualitative synthesis of the perspectives of children, mothers and professionals. AB - OBJECTIVES: To synthesise evidence on the acceptable identification and initial response to children's exposure to intimate partner violence (IPV) from the perspectives of providers and recipients of healthcare and social services. DESIGN: We conducted a thematic synthesis of qualitative research, appraised the included studies with the modified Critical Appraisal Skills Programme checklist and undertook a sensitivity analysis of the studies scored above 15. DATA SOURCES: We searched eight electronic databases, checked references and citations and contacted authors of the included studies. ELIGIBILITY CRITERIA: We included qualitative studies with children, parents and providers of healthcare or social services about their experiences of identification or initial responses to children's exposure to IPV. Papers that have not been peer-reviewed were excluded as well as non-English papers. RESULTS: Searches identified 2039 records; 11 studies met inclusion criteria. Integrated perspectives of 42 children, 212 mothers and 251 professionals showed that sufficient training and support for professionals, good patient-professional relationship and supportive environment for patient/clients need to be in place before enquiry/disclosure of children's exposure to IPV should occur. Providers and recipients of care favour a phased enquiry about IPV initiated by healthcare professionals, which focuses on 'safety at home' and is integrated into the context of the consultation or visit. Participants agreed that an acceptable initial response prioritises child safety and includes emotional support, education about IPV and signposting to IPV services. Participants had conflicting perspectives on what constitutes acceptable engagement with children and management of safety. Sensitivity analysis produced similar results. CONCLUSIONS: Healthcare and social service professionals should receive sufficient training and ongoing individual and system-level support to provide acceptable identification of and initial response to children's exposure to IPV. Ideal identification and responses should use a phased approach to enquiry and the WHO Listen, Inquire about needs and concerns, Validate, Enhance safety and Support principles integrated into a trauma-informed and violence-informed model of care. PMID- 29705758 TI - Vietnamese medical students and binge drinking: a qualitative study of perceptions, attitudes, beliefs and experience. AB - OBJECTIVES: To explore the perceptions, attitudes, beliefs, and experiences related to Vietnamese medical students' binge drinking. DESIGN: A qualitative study comprising semi-structured focus groups/interviews with medical students and semi-structured interviews with key informants. Thematic analysis of data. SETTING: Participants were a convenience sample of usual volunteers from a medical university in Viet Nam. PARTICIPANTS: 19 medical students from year 1 to 6 and 4 key informants agreed to participate in the study. RESULTS: The study found participants believe medical students drink less than other students and are not binge drinkers yet they experience and/or witness many binge drinking occasions among medical students. Participants consider alcohol use as culturally acceptable in Vietnamese society and a way for medical students to create and improve relationships with their friends, teachers, or work colleagues. Group affiliation and peer pressure to drink excessive alcohol are identified among medical students, especially male students. CONCLUSION: The culture of drinking behaviour was explored among medical students in Viet Nam. This study reveals a dichotomy between the belief of not being binge drinkers and the experience of many binge drinking occasions among medical students. This tension suggests future research about binge drinking behaviour of Vietnamese medical students is required. PMID- 29705759 TI - Education, job position, income or multidimensional indices? Associations between different socioeconomic status indicators and chronic low back pain in a German sample: a longitudinal field study. AB - OBJECTIVE: To investigate associations between socioeconomic status (SES) indicators (education, job position, income, multidimensional index) and the genesis of chronic low back pain (CLBP). DESIGN: Longitudinal field study (baseline and 6-month follow-up). SETTING: Four medical clinics across Germany. PARTICIPANTS: 352 people were included according to the following criteria: (1) between 18 and 65 years of age, (2) intermittent pain and (3) an understanding of the study and the ability to answer a questionnaire without help. Exclusion criteria were: (1) pregnancy, (2) inability to stand upright, (3) inability to give sick leave information, (4) signs of serious spinal pathology, (5) acute pain in the past 7 days or (6) an incomplete SES indicators questionnaire. OUTCOME MEASURES: Subjective intensity and disability of CLBP. RESULTS: Analysis showed that job position was the best single predictor of CLBP intensity, followed by a multidimensional index. Education and income had no significant association with intensity. Subjective disability was best predicted by job position, succeeded by the multidimensional index and education, while income again had no significant association. CONCLUSION: The results showed that SES indicators have different strong associations with the genesis of CLBP and should therefore not be used interchangeably. Job position was found to be the single most important indicator. These results could be helpful in the planning of back pain care programmes, but in general, more research on the relationship between SES and health outcomes is needed. PMID- 29705760 TI - Quality of evidence considered by Health Canada in granting full market authorisation to new drugs with a conditional approval: a retrospective cohort study. AB - OBJECTIVES: This study examines the characteristics of studies that Health Canada uses to grant full marketing authorisation for products given a conditional approval between 1 January 1998 and 30 June 2017. DESIGN: Cohort study. DATA SOURCES: Journal articles listing drugs that fulfilled their conditions and received full marketing authorisation, Notice of Compliance database, Notice of Compliance with conditions website, Qualifying Notices listing required confirmatory studies, clinicaltrials.gov, PubMed, Embase, companies making products being analysed, journal articles resulting from confirmatory studies. INTERVENTIONS: None. PRIMARY AND SECONDARY OUTCOME MEASURES: Characteristics of studies-study design (randomised controlled trials, observational), primary outcome used (clinical, surrogate), blinding, number of patients in studies, patient median age, number of men and women. RESULTS: Eleven companies confirmed 36 publications for 19 products (21 indications). Twenty-nine out of the 36 studies were randomised controlled trials (RCTs) but only 10 stated if they were blinded. Twenty used surrogate outcomes. The median age of patients was 56 (IQR 44-61). The median number of men per study/trial was 184 (IQR 58-514) versus women 141 (IQR 46-263). CONCLUSIONS: Postmarket studies required by Health Canada had more rigorous methodology than those required by either the Food and Drug Administration or the European Medicines Agency. There were still deficiencies in these studies. The absence of blinding in the majority of RCTs may introduce bias in their results. The use of surrogate outcomes especially in oncology trials means that improvements in survival are not available. The relatively young age of patients, even for products for cancer, means that predicting how the elderly will respond is often unknown. The almost universal finding that men outnumbered women may make it hard to differentiate responses by sex. These results raise potential concerns about the quality of evidence that Health Canada accepts. PMID- 29705761 TI - Should surgery be delayed in patients taking direct oral anticoagulants who suffer a hip fracture? A retrospective, case-controlled observational study at a UK major trauma centre. AB - OBJECTIVE: To determine whether not waiting for the elimination of direct oral anticoagulants (DOACs) has an effect on the amount of perioperative bleeding in patients who undergo operative treatment of a hip fracture. DESIGN: Observation, retrospective case-control study. SETTING: A single UK major trauma centre. PARTICIPANTS: Patients who sustained a hip fracture were identified using the National Hip Fracture Database (NHFD). All those found to be taking a DOAC at the time of fracture were identified (n=63). A matched group not taking a DOAC was also identified from the NHFD (n=62). MAIN OUTCOME: Perioperative drop in haemoglobin concentration. RESULTS: There was no relationship between admission to operation interval and perioperative change in haemoglobin concentration in patients taking DOACs (regression coefficient=-0.06 g/L/hour; 95% CI -0.32-0.20; p=0.64). No relationship was found between the time from admission to operation interval and the probability of transfusion (OR=0.94; 95% CI 0.85 to 1.90; p=0.16) or reoperation (OR=1.04; 95% CI 0.93 to 1.16; p=0.49). One mortality was recorded in the DOAC group within 30 days of admission, and this compared with five in the matched group of patients (p=0.2). CONCLUSIONS: Delaying surgery in patients who sustain a hip fracture who are taking a DOAC drug has not been shown to reduce perioperative bleeding or affect their mortality in this study. PMID- 29705762 TI - Does practice analysis agree with the ambulatory care sensitive conditions' list of avoidable unplanned admissions?: a cross-sectional study in the East of England. AB - OBJECTIVES: To use significant event audits (SEAs) in primary care to determine which of a sample of emergency (unplanned) admissions were potentially avoidable; and compare with the National Health Service (NHS) list of ambulatory care sensitive conditions (ACSCs). DESIGN: Analysis of unplanned medical admissions randomly identified in secondary care. SETTING: Primary care in the East of England. PARTICIPANTS: 20 general practice teams trained to use SEA on unplanned admissions to identify potentially preventable factors. INTERVENTIONS: SEA of admissions. MAIN OUTCOME MEASURES: Level of agreement between those admissions identified as potentially preventable by SEA and the NHS ACSC list. RESULTS: 132 (26%) of randomly selected patients with unplanned admissions gave consent and an SEA was performed by their primary practice team. 130 SEA reports had sufficient data for our analysis. Practices concluded that 17 (13%) admissions were potentially preventable. The NHS ACSC list identified 36 admissions (28%) as potentially preventable. There was a low level of agreement between the practices and the NHS list as to which admissions were preventable (kappa=0.253). The ACSC list consisted mainly of respiratory admissions whereas the practice list identified a wider range of cases and identified context-specific factors as important. CONCLUSIONS: There was disagreement between the NHS list and practice conclusions of potentially avoidable admissions. The SEAs suggest that the pathway into unplanned admission may be less dependent on the condition than on context-specific factors, and the assumption that unplanned admissions for ACSCs are reasonable indicators of performance for primary care may not be valid. PMID- 29705763 TI - Development of prediction models of stress and long-term disability among claimants to injury compensation systems: a cohort study. AB - OBJECTIVES: We sought to develop prognostic risk scores for compensation-related stress and long-term disability using markers collected within 3 months of a serious injury. DESIGN: Cohort study. Predictors were collected at baseline and at 3 months postinjury. Outcome data were collected at 72 months postinjury. SETTING: Hospitalised patients with serious injuries recruited from four major trauma hospitals in Australia. PARTICIPANTS: 332 participants who made claims for compensation for their injuries to a transport accident scheme or a workers' compensation scheme. PRIMARY OUTCOME MEASURES: 12-item WHO Disability Assessment Schedule and 6 items from the Claims Experience Survey. RESULTS: Our model for long-term disability had four predictors (unemployed at the time of injury, history of a psychiatric disorder at time of injury, post-traumatic stress disorder symptom severity at 3 months and disability at 3 months). This model had good discrimination (R2=0.37) and calibration. The disability risk score had a score range of 0-180, and at a threshold of 80 had sensitivity of 56% and specificity of 86%. Our model for compensation-related stress had five predictors (intensive care unit admission, discharged to home, number of traumatic events prior to injury, depression at 3 months and not working at 3 months). This model also had good discrimination (area under the curve=0.83) and calibration. The compensation-related stress risk score had score range of 0-220 and at a threshold of 100 had sensitivity of 74% and specificity of 75%. By combining these two scoring systems, we were able to identify the subgroup of claimants at highest risk of experiencing both outcomes. CONCLUSIONS: The ability to identify at an early stage claimants at high risk of compensation-related stress and poor recovery is potentially valuable for claimants and the compensation agencies that serve them. The scoring systems we developed could be incorporated into the claims-handling processes to guide prevention-oriented interventions. PMID- 29705764 TI - Sonic and ultrasonic oscillating devices for the management of pain and dental fear in children or adolescents that require caries removal: a systematic review. AB - OBJECTIVES: To evaluate the effectiveness and degree of acceptance by children and adolescents of the use of oscillating tips compared with rotating drills. DESIGN: Systematic review. DATA SOURCES: PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL), the Cochrane Library and Web of Science (October 2017). ELIGIBILITY CRITERIA: Controlled randomised or non-randomised trials that evaluated sonic and ultrasonic oscillating devices versus rotating drill. DATA EXTRACTION: Eligible studies were selected and data extracted independently by two reviewers. Risk of bias was assessed using the Cochrane Method. RESULTS: Two controlled clinical trials comprising 123 children aged 2-12 years old were identified. Both trials were at high risk of selection bias and unclear risk of detection bias. In one trial, pain due to the use of oscillating drill resulted lower than employing rotating drill (Verbal Hochman Scale: RR 0.64 (95% CI 0.41 to 1.00); Visual Facial Expression Scale: RR 0.64 (95% CI 0.44 to 0.94)). In another study, compared with traditional drill ultrasonic tip was associated with a lower level of patient's discomfort (RR 0.40 (95% CI 0.20 to 0.79)) but not with dental anxiety (RR 1.29 (95% CI 0.97 to 1.71)). The effectiveness of the removal of caries as well as fillings durability were only considered in one study, but no statistically significant differences were found between the two interventions. CONCLUSIONS: The evidence based on two low-quality studies was insufficient to conclude that the use of oscillating tips for the management of pain and dental fear in children or adolescents compared with rotating drills was more effective. PMID- 29705766 TI - Educational differences in psychological distress? Results from a population based sample of men and women in Sweden in 2012. AB - BACKGROUND: Mental health problems are more frequent in socially disadvantaged groups, but the results vary between different studies, different populations and different measures of mental health. This paper investigated the association between educational level, economic difficulties and psychological distress in men and women in Sweden. METHODS: The study population included 24 510 respondents aged 25-74 years who responded to a survey questionnaire in Mid Sweden in 2012 (response rate 53%). Psychological distress was measured with the 12-item version of the General Health Questionnaire, and multivariate logistic regression models were used in statistical analyses, adjusting for age, employment status and social support. RESULTS: The prevalence of psychological distress was higher in women (16.4%) than in men (11.3%; p<0.001). Persons with low and medium educational level had a lower risk of psychological distress than persons with high educational level after adjustment for confounders. Economic difficulties had a strong association with psychological distress (OR 2.80 (95% CI 2.39 to 3.27) and OR 2.40 (95% CI 2.12 to 3.71) in men and women, respectively) after adjustment for confounders. CONCLUSION: We found a strong association between economic difficulties and psychological distress in this study, but no inverse association between educational level and psychological distress. On the contrary, persons with high education had more psychological distress than persons with low and medium education when age, employment status and social support were taken into account. The findings were similar in men and women. PMID- 29705767 TI - Shared research priorities for pessary use in women with prolapse: results from a James Lind Alliance Priority Setting Partnership. AB - OBJECTIVES: To identify the shared priorities for future research of women affected by and clinicians involved with pessary use for the management of prolapse. DESIGN: A priority setting project using a consensus method. SETTING: A James Lind Alliance Pessary use for prolapse Priority Setting Partnership (JLA Pessary PSP) conducted from May 2016 to September 2017 in the UK. PARTICIPANTS: The PSP was run by a Steering Group of three women with experience of pessary use, three experienced clinicians involved with management of prolapse, two researchers with relevant experience, a JLA adviser and a PSP leader. Two surveys were conducted in 2016 and 2017. The first gathered questions about pessaries, and the second asked respondents to prioritise a list of questions. A final workshop was held on 8 September 2017 involving 10 women and 13 clinician representatives with prolapse and pessary experience. RESULTS: A top 10 list of priorities for future research in pessary use for prolapse was agreed by consensus. CONCLUSIONS: Women with experience of pessary use and clinicians involved with prolapse management have worked together to determine shared priorities for future research. Aligning the top 10 results with existing research findings will highlight the gaps in current evidence and signpost future research to areas of priority. Effective dissemination of the results will enable research funding bodies to focus on gathering the evidence to answer the questions that matter most to those who will be affected. PMID- 29705765 TI - PRactice of VENTilation in Middle-Income Countries (PRoVENT-iMIC): rationale and protocol for a prospective international multicentre observational study in intensive care units in Asia. AB - INTRODUCTION: Current evidence on epidemiology and outcomes of invasively mechanically ventilated intensive care unit (ICU) patients is predominantly gathered in resource-rich settings. Patient casemix and patterns of critical illnesses, and probably also ventilation practices are likely to be different in resource-limited settings. We aim to investigate the epidemiological characteristics, ventilation practices and clinical outcomes of patients receiving mechanical ventilation in ICUs in Asia. METHODS AND ANALYSIS: PRoVENT iMIC (study of PRactice of VENTilation in Middle-Income Countries) is an international multicentre observational study to be undertaken in approximately 60 ICUs in 11 Asian countries. Consecutive patients aged 18 years or older who are receiving invasive ventilation in participating ICUs during a predefined 28 day period are to be enrolled, with a daily follow-up of 7 days. The primary outcome is ventilatory management (including tidal volume expressed as mL/kg predicted body weight and positive end-expiratory pressure expressed as cm H2O) during the first 3 days of mechanical ventilation-compared between patients at no risk for acute respiratory distress syndrome (ARDS), patients at risk for ARDS and in patients with ARDS (in case the diagnosis of ARDS can be made on admission). Secondary outcomes include occurrence of pulmonary complications and all-cause ICU mortality. ETHICS AND DISSEMINATION: PRoVENT-iMIC will be the first international study that prospectively assesses ventilation practices, outcomes and epidemiology of invasively ventilated patients in ICUs in Asia. The results of this large study, to be disseminated through conference presentations and publications in international peer-reviewed journals, are of ultimate importance when designing trials of invasive ventilation in resource-limited ICUs. Access to source data will be made available through national or international anonymised datasets on request and after agreement of the PRoVENT-iMIC steering committee. TRIAL REGISTRATION NUMBER: NCT03188770; Pre-results. PMID- 29705768 TI - Soil-transmitted helminth infections and nutritional status in Ecuador: findings from a national survey and implications for control strategies. AB - OBJECTIVE: The estimation of prevalence and intensity of soil-transmitted helminth (STH) infections at a country-level is an essential prerequisite for the implementation of a rational control programme. The aim of this present study was to estimate the prevalence and distribution of STH infections and malnutrition in school-age children in rural areas of Ecuador. DESIGN: Cross-sectional study from October 2011 to May 2012. SETTING: Eighteen rural schools were randomly selected from the three ecological regions of Ecuador (coastal, highlands and Amazon basin). PARTICIPANTS: 920 children aged 6-16 years. MAIN OUTCOME MEASURES: Prevalence and intensity of STH infections associated with malnutrition (thinness/wasting or stunting). RESULTS: The results showed that 257 (27.9%) children were infected with at least one STH parasite. The prevalence of Trichuris trichiura, Ascaris lumbricoides and hookworm was 19.3%, 18.5% and 5.0%, respectively. Malnutrition was present in 14.2% of children and most common was stunting (12.3%). Compared with other regions, schoolchildren in the Amazon region had the highest STH prevalence (58.9%) of which a greater proportion of infections were moderate/heavy intensity (45.6%) and had the highest prevalence of malnutrition (20.4%). A positive association was observed between moderate to heavy infections with A. lumbricoides and malnutrition (adjusted OR 1.85, 95% CI 1.04 to 3.31, p=0.037). CONCLUSIONS: Our estimate of the prevalence of STH infections of 27.9% at a national level in Ecuador is lower than suggested by previous studies. Our data indicate that schoolchildren living in the Amazon region have a greater risk of STH infection and stunting compared with children from other regions. The implementation of school-based preventive chemotherapy and nutritional supplement programmes within the Amazon region should be prioritised. Long-term control strategies require improvements in water, sanitation and hygiene. PMID- 29705769 TI - Ongoing training of community health workers in low-income andmiddle-income countries: a systematic scoping review of the literature. AB - OBJECTIVES: Understanding the current landscape of ongoing training for community health workers (CHWs) in low-income and middle-income countries (LMICs) is important both for organisations responsible for their training, as well as researchers and policy makers. This scoping review explores this under-researched area by mapping the current delivery implementation and evaluation of ongoing training provision for CHWs in LMICs. DESIGN: Systematic scoping review. DATA SOURCES: MEDLINE, Embase, AMED, Global Health, Web of Science, Scopus, ASSIA, LILACS, BEI and ERIC. STUDY SELECTION: Original studies focusing on the provision of ongoing training for CHWs working in a country defined as low income and middle income according to World Bank Group 2012 classification of economies. RESULTS: The scoping review found 35 original studies that met the inclusion criteria. Ongoing training activities for CHWs were described as supervision (n=19), inservice or refresher training (n=13) or a mixture of both (n=3). Although the majority of studies emphasised the importance of providing ongoing training, several studies reported no impact of ongoing training on performance indicators. The majority of ongoing training was delivered inperson; however, four studies reported the use of mobile technologies to support training delivery. The outcomes from ongoing training activities were measured and reported in different ways, including changes in behaviour, attitudes and practice measured in a quantitative manner (n=16), knowledge and skills (n=6), qualitative assessments (n=5) or a mixed methods approach combining one of the aforementioned modalities (n=8). CONCLUSIONS: This scoping review highlights the diverse range of ongoing training for CHWs in LMICs. Given the expansion of CHW programmes globally, more attention should be given to the design, delivery, monitoring and sustainability of ongoing training from a health systems strengthening perspective. PMID- 29705770 TI - Post-treatment surveillance testing of patients with colorectal cancer and the association with survival: protocol for a retrospective cohort study of the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. AB - INTRODUCTION: Although the colorectal cancer (CRC) mortality rate has significantly improved over the past several decades, many patients will have a recurrence following curative treatment. Despite this high risk of recurrence, adherence to CRC surveillance testing guidelines is poor which increases cancer related morbidity and potentially, mortality. Several randomised controlled trials (RCTs) with varying surveillance strategies have yielded conflicting evidence regarding the survival benefit associated with surveillance testing. However, due to differences in study protocols and limitations of sample size and length of follow-up, the RCT may not be the best study design to evaluate this relationship. An observational comparative effectiveness research study can overcome the sample size/follow-up limitations of RCT designs while assessing real-world variability in receipt of surveillance testing to provide much needed evidence on this important clinical issue. The gap in knowledge that this study will address concerns whether adherence to National Comprehensive Cancer Network CRC surveillance guidelines improves survival. METHODS AND ANALYSIS: Patients with colon and rectal cancer aged 66-84 years, who have been diagnosed between 2002 and 2008 and have been included in the Surveillance, Epidemiology, and End Results-Medicare database, are eligible for this retrospective cohort study. To minimise bias, patients had to survive at least 12 months following the completion of treatment. Adherence to surveillance testing up to 5 years post treatment will be assessed in each year of follow-up and overall. Binomial regression will be used to assess the association between patients' characteristics and adherence. Survival analysis will be conducted to assess the association between adherence and 5-year survival. ETHICS AND DISSEMINATION: This study was approved by the National Cancer Institute and the Institutional Review Board of the University of Central Florida. The results of this study will be disseminated by publishing in the peer-reviewed scientific literature, presentation at national/international scientific conferences and posting through social media. PMID- 29705771 TI - Spatial and temporal variation in the community prevalence of antibiotic resistance in Bangladesh: an integrated surveillance study protocol. AB - INTRODUCTION: Increasing antibiotic resistance (ABR) in low-income and middle income countries such as Bangladesh presents a major health threat. However, assessing the scale of the health risk is problematic in the absence of reliable data on the community prevalence of antibiotic-resistant bacteria. We describe the protocol for a small-scale integrated surveillance programme that aims to quantify the prevalence of colonisation with antibiotic-resistant bacteria and concentrations of antibiotic-resistant genes from a 'One Health' perspective. The holistic assessment of ABR in humans, animals and within the environment in urban and rural Bangladesh will generate comprehensive data to inform human health risk. METHODS AND ANALYSIS: The study design focuses on three exposure-relevant sites where there is enhanced potential for transmission of ABR between humans, animals and the environment: (1) rural poultry-owning households, (2) commercial poultry farms and (3) urban live-bird markets. The comparison of ABR prevalence in human groups with high and low exposure to farming and poultry will enable us to test the hypothesis that ABR bacteria and genes from the environment and food producing animals are potential sources of transmission to humans. Escherichia coli is used as an ABR indicator organism due to its widespread environmental presence and colonisation in both the human and animal gastrointestinal tract. ETHICS AND DISSEMINATION: The study has been approved by the Institutional Review Board of the International Centre for Diarrhoeal Disease Research, Bangladesh, and Loughborough University Ethics Committee. Data for the project will be stored on the open access repository of the Centre for Ecology and Hydrology, Natural Environment Research Council. The results of this study will be published in peer reviewed journals and presented at national and international conferences. PMID- 29705772 TI - Burden of lung cancer attributable to occupational diesel engine exhaust exposure in Canada. AB - OBJECTIVE: To estimate the population attributable fraction (PAF) and number of incident and fatal lung cancers in Canada from occupational exposure to diesel engine exhaust (DEE). METHODS: DEE exposure prevalence and level estimates were used with Canadian Census and Labour Force Survey data to model the exposed population across the risk exposure period (REP, 1961-2001). Relative risks of lung cancer were calculated based on a meta-regression selected from the literature. PAFs were calculated using Levin's equation and applied to the 2011 lung cancer statistics obtained from the Canadian Cancer Registry. RESULTS: We estimated that 2.4% (95% CI 1.6% to 6.6%) of lung cancers in Canada are attributable to occupational DEE exposure, corresponding to approximately 560 (95% CI 380 to 1570) incident and 460 (95% CI 310 to 1270) fatal lung cancers in 2011. Overall, 1.6 million individuals alive in 2011 were occupationally exposed to DEE during the REP, 97% of whom were male. Occupations with the highest burden were underground miners, truck drivers and mechanics. Half of the attributable lung cancers occurred among workers with low exposure. CONCLUSIONS: This is the first study to quantify the burden of lung cancer attributable to occupational DEE exposure in Canada. Our results underscore a large potential for prevention, and a large public health impact from occupational exposure to low levels of DEE. PMID- 29705773 TI - Direct mechanical thrombectomy in tPA-ineligible and -eligible patients versus the bridging approach: a meta-analysis. AB - BACKGROUND: Whether pretreatment with intravenous thrombolysis prior to mechanical thrombectomy (IVT+MTE) adds additional benefit over direct mechanical thrombectomy (dMTE) in patients with large vessel occlusions (LVO) is a matter of debate. METHODS: This study-level meta-analysis was presented in accord with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Pooled effect sizes were calculated using the inverse variance heterogeneity model and displayed as summary Odds Ratio (sOR) and corresponding 95% confidence interval (95% CI). Sensitivity analysis was performed by distinguishing between studies including dMTE patients eligible for IVT (IVT-E) or ineligible for IVT (IVT-IN). Primary outcome measures were functional independence (modified Rankin Scale<=2) and mortality at day 90, successful reperfusion, and symptomatic intracerebral hemorrhage. RESULTS: Twenty studies, incorporating 5279 patients, were included. There was no evidence that rates of successful reperfusion differed in dMTE and IVT+MTE patients (sOR 0.93, 95% CI 0.68 to 1.28). In studies including IVT-IN dMTE patients, patients undergoing dMTE tended to have lower rates of functional independence and had higher odds for a fatal outcome as compared with IVT+MTE patients (sOR 0.78, 95% CI 0.61 to 1.01 and sOR 1.45, 95% CI 1.22 to 1.73). However, no such treatment group effect was found when analyses were confined to cohorts with a lower risk of selection bias (including IVT-E dMTE patients). CONCLUSION: The quality of evidence regarding the relative merits of IVT+MTE versus dMTE is low. When considering studies with lower selection bias, the data suggest that dMTE may offer comparable safety and efficacy as compared with IVT+MTE. The conduct of randomized-controlled clinical trials seems justified. PMID- 29705775 TI - The Effect of Age and Body Mass Index on the Surgical Anatomy of Supraumbilical Port Insertion: Implications for Laparoscopic and Robotic Surgery. AB - BACKGROUND: Minimally invasive surgery is the preferred approach for performing many gynecologic procedures. Occasionally, supraumbilical port placement may be preferable to optimize visibility and maneuverability although the risks of complications are less well characterized compared to umbilical entry. METHODS: We conducted a retrospective review of computed tomograms from 92 patients to evaluate the anatomic considerations for umbilical and supraumbilical port entry based on patient age, body mass index (BMI), parity, abdominal wall thickness, and distance to the great vessels. RESULTS: Supraumbilical entry was not associated with differences in distance to the great vessels compared to the umbilicus. However, supraumbilical location and BMI were associated with greater abdominal wall thickness. Age and BMI were associated with greater distance to the great vessels, while age was associated with thinner abdominal wall. Multiple linear regression confirmed independent effects of age and BMI. No association between parity and distance to retroperitoneal vessels was observed. CONCLUSION: Younger patients may be at increased risk for great vessel injury and pre peritoneal insufflation. Obese patients may be at risk for pre-peritoneal insufflation, while patients with BMI < 30, particularly with a skin-to-aorta distance < 7 cm, may be at an increased risk for great vessel injury. Surgeons should consider these factors when considering supraumbilical port entry. PMID- 29705774 TI - Exploring the thesis experience of Master of Health professions education graduates: a qualitative study. AB - Objectives: To explore the thesis experience of recent Master of Health Professions Education (MHPE) graduates in the University of Illinois at Chicago (UIC) program. Methods: This is a qualitative case study exploring the experience of MHPE graduates between 2014 and 2016 (n=31). Using convenience sampling, all graduates with an email address (n=30) were invited to participate in an online survey and semi-structured interviews. Interviews were completed in-person or via telephone or video conference; interviewers collected detailed notes and audio recordings. Two authors independently analyzed the data iteratively using thematic analysis and discrepancies were discussed and resolved. Results: Survey results (n=20, 67%) revealed an average graduation of 5.1 years; 10 graduates (33%) were interviewed. Three themes related to the thesis experience were identified: success factors, challenges, and outcomes. Success factors, when present, promoted completion of a thesis; these included: a supportive program environment, time management, available resources, MHPE foundational coursework, aligning theses with career goals, and identifying a project with limited scope. Challenges made thesis completion more difficult for graduates; these included: institutional factors, personal or professional responsibilities, burnout, externally-imposed deadlines, and barriers in the research process. Despite these challenges, completing the thesis resulted in many professional or personal benefits (outcomes). Conclusions: Multiple success factors and challenges were identified in the master's thesis process among MHPE graduates at UIC. These findings can help students conducting education-based scholarship through the master's thesis process. This study also informs program evaluation and improvements and outlines personal and professional outcomes of completing a master's thesis. PMID- 29705776 TI - C-Met-Activated Mesenchymal Stem Cells Rescue Ischemic Damage via Interaction with Cellular Prion Protein. AB - BACKGROUND/AIMS: Stem cell transplantation has emerged as a promising therapeutic strategy, but the exact mechanisms by which stem cells exposed to hypoxic conditions increase the survival rate and rescue ischemic injury at the graft site are not well known. In this study, we aimed to determine if c-Met-activated mesenchymal stem cells (MSCs) pre-exposed to hypoxia promote therapeutic efficacy when transplanted to ischemic models, and whether c-Met interacts with cellular prion protein (PrPC) present in the ischemic tissue. METHODS: Western blot analysis was performed to determine the expression levels of PrPC, C-caspase-3, and C-PARP-1, as well as the phosphorylation of Akt, p38, JNK, and BAX. A co immunoprecipitation assay was performed to show that PrPC binds with c-Met in vitro. An adhesion assay was performed to explore the alterations in MSCs attached to myoblasts (in vitro), and an invasion assay was performed to determine the effect on MSC invasion capacity upon interaction with myoblast induced c-Met and PrPC. CD31-positive capillaries and alphaSMA-positive arterioles in in vivo hindlimb ischemic tissue were quantified by immunofluorescence staining. The level of apoptosis in the tissue of each group was assessed by quantifying the number of C-caspase-3-positive cells. Finally, laser Doppler technology was utilized to detect the enhanced angiogenic effects in vivo. RESULTS: We showed that hypoxic conditions increased PrPC levels in vivo (hindlimb ischemic tissue) and in vitro (myoblasts) and increased c-Met levels in MSCs. To identify the relationship between c-Met from MSCs and PrPC from myoblasts, we used a co-culturing system with myoblasts and MSCs pre-exposed to hypoxia. Hypoxia increased the phosphorylation of mitogen-activated protein kinases. Transplantation of hypoxia-pre-exposed MSCs to the ischemic site increased anti-apoptosis and enhanced the survival and proliferation of transplanted MSCs in a murine hindlimb model, resulting in improved functional recovery of the ischemic tissue. All the aforementioned effects were inhibited by the pretreatment of MSCs with the c-Met-neutralizing antibody Conclusion: c-Met activated MSCs pre-exposed to hypoxia interact with PrPC at the site of ischemic injury to increase the efficiency of MSC transplantation. Hence, our study demonstrated that c-Met is a potential target for MSC-based therapies. PMID- 29705777 TI - Delayed Ischemic Preconditioning Attenuated Renal Ischemia-Reperfusion Injury by Inhibiting Dendritic Cell Maturation. AB - BACKGROUND/AIMS: Even though delayed ischemic preconditioning (DIPC) has been reported to produce renal protection, the underlying mechanism remains poorly understood. We reported that a 15-minute renal ischemic preconditioning (IPC) 4 days before subsequent ischemia-reperfusion attenuated renal injury Kidney dendritic cells (DCs) are abundant in the renal tubulointerstitium and, depending on their status, can induce immune activation or tolerance. The aim of the present study was to investigate the role of DCs in IPC of the kidney. METHODS: Mouse kidneys were challenged by transient brief episodes of sublethal ischemia followed by subsequent prolonged ischemia. DC abundance and maturation in the spleen and kidney were measured by flow cytometry and immunohistochemical staining. To confirm the function of mature DCs in the renoprotective effect of IPC on renal ischemia-reperfusion injury the A2 adenosine receptor (A2AR) antagonist SCH58261 was administered to stimulate DC maturation prior to assessment of renal functional and histological injury and the inflammatory reaction. RESULTS: Compared with sham-operated animals, preconditioned mice had a reduced injury with less CD11c+ cells, lower levels of the pro-inflammatory cytokine IL-17 and reduced expression of the mature DC marker CCR7. Preconditioned mice also produced more of the anti-inflammatory cytokine IL-10. Both renal cells and splenocytes from these mice had more DCs (CD45+/CD11c+/F4/80 ), but fewer of these DCs were mature (CD45+/CD11c+/ F4/80-/MHC-II+/CD80+) compared with those from sham-treated animals, suggesting that the immunomodulatory effect of renal ischemic preconditioning is both local and systemic. Additionally, injection of the A2AR antagonist SCH58261 reversed IPC induced inhibition of DC maturation and mitigated the protective effect of preconditioning, suggesting that DC maturation contributes to immune cell mediated ischemic preconditioning. CONCLUSION: Our results show that DIPC of the kidney provides local and systemic immunosuppression by inhibiting DC maturation and hence mediates a renal protective effect. PMID- 29705778 TI - Indacaterol/Glycopyrronium in Clinical Practice: The Italian Experience. PMID- 29705779 TI - When Two Drugs Are Better than Three: Re-Modulating the Therapeutic Plan of a Chronic Obstructive Pulmonary Disease Patient. AB - We present the case of a 77-year-old man diagnosed with chronic obstructive pulmonary disease (COPD) stage D with emphysema phenotype and treated with triple therapy (salmeterol, fluticasone propionate, and tiotropium) for 1 year without relevant improvements in exertional dyspnea and disease impact. After switching to combination therapy with a long-acting beta2-agonist (LABA) and a long-acting muscarinic antagonist (LAMA) (indacaterol/glycopyrronium), we observed, in a 3 month period, a substantial reduction of the modified Medical Research Council (mMRC) dyspnea scale and COPD Assessment Test (CAT) scores. Moreover, the patient reported a reduction of dynamic hyperinflation and an improvement of ventilatory response to exercise. PMID- 29705780 TI - A Case of Ventricular Fibrillation in a Frail Patient with Chronic Obstructive Pulmonary Disease, Obstructive Sleep Apnea Syndrome, and Electrolytic Disorder. AB - Chronic obstructive pulmonary disease (COPD) is associated with an increased cardiovascular risk, although the pathophysiological mechanisms responsible for this interdependence are not completely known. For instance, the increased sympathetic activity may be implied. The severity of COPD correlates with various arrhythmic manifestations such as atrial fibrillation, atrial flutter, and either sustained or nonsustained ventricular tachycardia. COPD and obstructive sleep apnea syndrome may increase the overall cardiovascular risk, especially in elderly patients. Additionally, electrolytic disorders may precipitate cardiac rhythm disturbances and thus cause important arrhythmic consequences such as ventricular fibrillation, as reported in our clinical case. We discuss here the possible treatment of this association of pathological conditions on the basis of a single case we have successfully treated, and provide a brief review of the available literature regarding cardiovascular comorbidities in COPD patients. PMID- 29705781 TI - The Respiratory "Overlap Syndrome": Efficacy and Usefulness of the Combined Double Bronchodilation. AB - The coexistence of chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea syndrome in a single patient is known as "overlap syndrome," and worsens the prognosis of the affected subjects. A marked bronchodilation may be useful for the treatment of this condition. In fact, as stated in the GOLD 2017 guidelines, the combination of indacaterol/glycopyrronium may exert positive synergistic effects on smooth muscle cell and airway resistance, with a more pronounced efficiency in reducing lung hyperinflation. Noteworthy, inhaled bronchodilators favorably alter the dynamically determined components of resting lung hyperinflation and help deflate the overinflated lungs. This is particularly important in order to improve dyspnea, exercise performance, and night saturation, especially when combined with continuous positive airway pressure ventilation, as reported in our case series. We report 3 cases of patients with COPD in a stable clinical condition, referred to the Department of Respiratory Pathophysiology at the "Mariano Santo" Hospital in Cosenza, due to possible symptoms suggestive of obstructive sleep apnea, and who were successfully treated with indacaterol/glycopyrronium at a fixed dose. PMID- 29705782 TI - Indacaterol/Glycopyrronium in the Treatment of Severe Respiratory Failure: Marked Improvement of Respiratory Failure in a Few Weeks - A Case Report. AB - Chronic obstructive pulmonary disease is a highly prevalent disease, especially in the aging population, associated with several functional disabilities and a high economic burden. Dual bronchodilation with prefixed associations of long acting beta2-agonists and long-acting muscarinic antagonist have a significant role in the management of this condition. The newer combination, indacaterol/glycopyrronium, is useful as a once-a-day therapy and has proven superior to other treatment strategies including inhaled corticosteroids for improving symptoms and clinical condition with a very rapid effect. We report our experience with a patient suffering from severe respiratory failure who improved significantly when the indacaterol/glycopyrronium combination was added to his therapy. PMID- 29705783 TI - Combination Therapy of Inhaled Indacaterol/Glycopyrronium for Chronic Obstructive Pulmonary Disease in the Very Elderly: Is It Safe? An Electrocardiographic Evaluation. AB - Cardiovascular (CV) comorbidities in patients with chronic obstructive pulmonary disease (COPD) are associated with increased morbidity and mortality, especially in old and very old subjects. The question if long-acting beta-agonist and long acting muscarinic antagonist could be associated with the increased prevalence of CV-related adverse effects has puzzled, particularly in the past, specialists involved in the management of respiratory diseases. The safety of these compounds has scarcely been tested in patients aged >= 65 years with CV comorbidities, since randomized controlled trials rarely include this subpopulation. However, the fixed combination indacaterol/glycopyrronium has shown a favorable CV safety profile in both healthy volunteers and COPD patients. Thus, we aimed to assess the CV safety pro-- file of the fixed combination indacaterol/glycopyrronium 110/50 MUg in a series of COPD patients aged >= 80 years with several comorbidities. Our results indicate that this combination is safe in the comorbid elderly, since no significant electrocardiographic abnormalities were recorded after the administration of the inhaled therapy. Only rare and nonclinically significant changes in heart rate and corrected QT interval duration were evident, mainly in females and in patients with concomitant impaired kidney function. PMID- 29705784 TI - Coexisting Heart Failure and Chronic Obstructive Pulmonary Disease: Report of Two Cases Treated with Indacaterol/Glycopyrronium. AB - Chronic obstructive pulmonary disease (COPD) is a major cause of morbidity and mortality worldwide, and it is associated with a high economic burden. Heart failure shares some general symptoms with COPD; thus, diagnosing COPD is difficult in subjects with a history of heart failure, and spi-rometry is mandatory for confirmation. Moreover, COPD is a highly prevalent comorbidity negatively impacting the outcome of heart failure patients. We document here the treatment with indacaterol/glycopyrronium in 2 patients with concomitant COPD and heart failure. Overall, the combination of indacaterol and glycopyrronium resulted in a reciprocal potentiation with a maximal bronchodilatory effect. PMID- 29705785 TI - Immunotherapy in Gastrointestinal Carcinoma - How to Separate Hope from Hype. PMID- 29705786 TI - Immunotherapy of Esophageal Cancer: Current Status, Many Trials and Innovative Strategies. AB - The majority of patients with esophageal cancer present with advanced disease and chemotherapy is the mainstay of palliation. However, efficacy is limited by the development of chemotherapy resistance and treatment options beyond first- and second-line treatment are scarce. Immunotherapy is a novel treatment option that has shown encouraging efficacy in several types of cancer, also in esophageal cancer. In esophageal squamous cell cancer (ESCC), early phase evaluation of immune checkpoint inhibitors has yielded promising results, however, results from phase 3 trials are currently still lacking. Besides checkpoint inhibitors, other immunogenic approaches e.g. peptide vaccines, adoptive T-cell therapy and oncolytic viruses are under development. This review describes the biological rational for immunotherapy and provides first accumulating data on its use in advanced esophageal cancer, with a focus on ESCC. PMID- 29705787 TI - Immune Checkpoint Inhibition in Gastro-Oesophageal Cancer. AB - Recently some progress has been made in the palliative treatment of gastric cancer. It was shown that second-line chemotherapy and VEGF-R2-directed treatment can prolong survival. Despite these advances most patients with metastatic gastric cancer live for less than 2 years. Immune-checkpoint blockade with anti CTLA4, anti-PD-1 and anti-PD-L1 antibodies has revolutionised the treatment of many cancers. Significant benefit was also proven in gastric adenocarcinomas. Nivolumab improves overall survival as third-line treatment in Asian gastric cancer patients and is already registered in Japan. Pembrolizumab shows significant efficacy, especially in PD-L1-positive patients as third-line treatment and is FDA approved for this indication. Trials with avelumab are promising and studies with atezolizumab and durvalumab are also on the way. To extend the subgroup of benefitting patients combinations of PD-1/PD-L1 antibodies with CTLA4, or VEGF-R2 antibodies or combination with chemotherapy are investigated and show promising results. In this article, the existing evidence of PD1 and PD-L1 blockade as monotherapy or in combination with anti-CTLA4, anti VEGF-R2 and chemotherapy in gastro-oesophageal adenocarcinoma is reviewed and put into perspective. PMID- 29705788 TI - Immunotherapy of Colon Cancer. AB - In contrast to other tumour types inhibitors of PD-1/-L1 or CTLA 4 have not yet shown relevant efficacy in unselected colorectal cancer. Based on the high mutational burden, deficient mismatch repair (dMMR) or microsatellite instable (MSI-H) tumours are yet the only subgroup, which is amenable to checkpoint inhibition. These tumours show relevant and durable responses in the refractory setting by PD-1/-L1 +/- CTLA 4 inhibition. Thus, ongoing phase 3 trials in this subgroup evaluate immunotherapy in the adjuvant setting as well as in the first line metastatic setting with or without chemotherapy. For the by far larger subgroup of non-dMMR/MSI-H patients (95% in the metastatic setting) combination regimen are urgently required, either with chemotherapy and/or molecular targeting drugs, local ablative treatments or other immunotherapeutic agents (e.g. CEA-TCB). PMID- 29705789 TI - Immunotherapy and Combination Strategies in Pancreatic Cancer: Current Status and Emerging Trends. AB - Pancreatic cancer is among the most aggressive malignancies with no effective therapeutic options thus far. Immunotherapy has recently emerged as a promising alternative for the treatment of various solid tumors. In particular, promising results in clinical trials were observed for therapies targeting immune checkpoint molecules. Efforts have been put into investigating the potential of immunotherapy in treating pancreatic cancer. While most of the clinical trial results are still being awaited, several intrinsic features of pancreatic cancer such as low mutational load and the presence of highly immunosuppressive desmoplasia significantly hamper the efficacy of immunotherapy in this disease. These unique features of pancreatic cancer, however, have advanced our understanding of tumor immunology and might help to tailor the future direction of immunotherapy. In this review, we summarize the current immunotherapeutic strategies and clinical trials targeting checkpoint molecules in pancreatic cancer. Emerging trends towards various combinations with therapies targeting immunosuppressive myeloid cells are also discussed. PMID- 29705790 TI - Immunotherapy of Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most deadly and rapidly evolving cancers worldwide. The current systemic treatment strategies in advanced tumor stages remain limited despite promising preclinical and early-phase clinical results for some compounds, highlighting an unmet clinical need. Since the majority of HCCs evolve in the background of a chronic inflammatory liver damage, HCCs can be considered a paradigm for inflammation-induced cancers, which renders immunotherapeutic strategies particularly promising for this tumor entity. Consequently, an improved understanding of key oncogenic and immune response signaling pathways as well as increasing appreciation of the diseased microenvironment for HCC initiation and progression has led to the development of a diverse range of immune-oncological interventions during the last decade. Besides oncolytic viruses, vaccines, or immune cell infusions, first results from early-phase clinical trials particularly encourage the use of immune checkpoint inhibitors against PD-1/PD-L1 and CTLA-4 for HCC. In this review, we delineate the current clinical and preclinical landscape of immunotherapies in HCC, critically discuss recent findings from clinical trials and outline future perspectives in the field of liver cancer. PMID- 29705791 TI - Biliary Tract Cancer: Implicated Immune-Mediated Pathways and Their Associated Potential Targets. AB - There is a well-established link between biliary tract cancers (BTC) and chronic inflammatory conditions such as primary sclerosing cholangitis, chronic cholecystitis, chronic cholelithiasis, liver fluke-associated infestations, and chronic viral hepatic infections. These associated risk factors highlight the potential for development of immune-modulatory agents in this poor-prognostic disease group with limited treatment options. Clinical trials have evaluated the role of immune cells, inflammatory biomarkers, vaccines, cytokines, adoptive cell therapy, and immune checkpoint inhibitors in patients with BTC. Although these have demonstrated the importance of the immune environment in BTC, currently none of the immune-based therapies have been approved for use in this disease group. The role of immunomodulatory agents is a developing field and has yet to find its way 'from bench to bedside' in BTC. PMID- 29705792 TI - Outlook: Immunotherapy in Gastrointestinal Carcinoma - Innovative Strategies. AB - Immune checkpoint inhibitors are emerging as a therapeutic approach for patients with advanced or metastatic gastrointestinal malignancies following the recent Food and Drug Administration and Asian approvals for colorectal, gastric, and hepatocellular carcinoma. As discussed in earlier articles, phase I-II trials demonstrate quite positive clinical activity, particularly in patients with immunogenic cancer subtypes. This outreach paper discusses some of the next innovative immunotherapy strategies under development. Here, tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells are increasingly coming into focus as new targets. Besides the well described use of checkpoint inhibitors, blockade of 'Wnt' or Csf1R signaling pathways as well as combinatorial treatment strategies offer promising examples for overcoming immune silencing within the resistant tumor microenvironment. PMID- 29705793 TI - Society Bulletins. PMID- 29705794 TI - Meetings and Conferences. PMID- 29705795 TI - Leucine-Rich Repeat Kinase 2 in Parkinson's Disease: Updated from Pathogenesis to Potential Therapeutic Target. AB - BACKGROUND: Parkinson's disease (PD) is characterized by the selective loss of dopaminergic neurons in the midbrain. The pathogenesis of PD is not fully understood but is likely caused by a combination of genetic and environmental factors. Several genes are associated with the onset and progression of familial PD. There is increasing evidence that leucine-rich repeat kinase 2 (LRRK2) plays a significant role in PD pathophysiology. SUMMARY: Many studies have been conducted to elucidate the functions of LRRK2 and identify effective LRRK2 inhibitors for PD treatment. In this review, we discuss the role of LRRK2 in PD and recent progress in the use of LRRK2 inhibitors as therapeutic agents. Key Messages: LRRK2 plays a significant role in the pathophysiology of PD, and pharmacological inhibition of LRRK2 has become one of the most promising potential therapies for PD. Further research is warranted to determine the functions of LRRK2 and expand the applications of LRRK2 inhibitors in PD treatment. PMID- 29705796 TI - Clostridium Tyrobutyricum Protect Intestinal Barrier Function from LPS-Induced Apoptosis via P38/JNK Signaling Pathway in IPEC-J2 Cells. AB - BACKGROUND/AIMS: The intestinal mucosa forms a physical and metabolic barrier against the diffusion of pathogens, toxins, and allergens from the lumen into the circulatory system. Early weaning, a critical phase in swine production, can compromise intestinal barrier function through mucosal damage and alteration of tight junction integrity Maintenance of intestinal barrier function plays a pivotal role in optimum gastrointestinal health. In this study, we investigated the effects of Clostridium tyrobutyricum (C.t) on intestinal barrier dysfunction induced by lipopolysaccharide (LPS) and the underlying mechanisms involved in intestinal barrier protection. METHODS: A Transwell model of IPEC-J2 cells was used to imitate the intestinal barrier. Fluorescence microscopy and flow cytometry were used to evaluate apoptosis. Real-time PCR was used to detect apoptosis-related genes and the downstream genes of the p38/c-Jun N-terminal kinase (JNK) signaling pathways. Western blotting was used to measure the expressions of tight junction proteins and mitogen-activated protein kinases. RESULTS: C.t efficiently maintained trans-epithelium electrical resistance values and intestinal permeability after LPS-induced intestinal barrier disruption. The expressions of tight junction proteins (ZO-1, claudin-1, and occludin) were promoted when IPEC-J2 cells were treated with C.t. Fluorescence imaging and flow cytometry revealed that C.t qualitatively and quantitatively inhibited LPS induced cell apoptosis. C.t also increased the relative expression of the anti apoptotic gene Bcl-2 and decreased that of the apoptotic genes Bax and caspase-3/ 8. Moreover, the protective effect of C.t on damaged intestinal cell models was associated with suppression of p38 and JNK phosphorylation, negative regulation of the relative expressions of downstream genes including AP-1, ATF-2, ELK-1, and p53, and activation of Stat3 expression. CONCLUSIONS: These findings indicate that C.t may promote intestinal integrity, suggesting a novel probiotic effect on intestinal barrier function. PMID- 29705797 TI - Actionable Locoregional Relapses after Therapy of Localized Esophageal Cancer: Insights from a Large Cohort. AB - OBJECTIVE: The goal of surveillance after therapy of localized esophageal cancer (LEC) is to identify actionable relapses amenable to salvage; however, the current surveillance algorithms are not optimized. We report on a large cohort of LEC patients with actionable locoregional relapses (LRRs). METHODS: Between 2000 and 2013, 127 (denominator = 752) patients with actionable LRR were identified. Histologic/cytologic confirmation was the gold standard. All surveillance tools (imaging, endoscopy, fine needle aspiration) were assessed. RESULTS: Most patients were men (89%), had adenocarcinoma (79%), and had no new symptoms (72%) when diagnosed with LRR. In trimodality patients, endoscopic confirmation of positron emission tomography-computed tomography-suspected LRR occurred in only 44%, and 56% required additional tools (e.g., fine needle aspiration). Alternatively, in bimodality patients, endoscopy confirmed LRRs in 81%. Trimodality patients had a higher risk of subsequent LRR/distant metastases after the first LRR than the bimodality patients (p = 0.03). In all patients, 78% of the subsequent relapses were distant. For patients who were salvaged, survival was significantly prolonged (50.6 vs. 25.1 months, p < 0.01). CONCLUSIONS: Patients live longer after successful salvage of the LRR than if salvage is not possible. After LRR, patients have a high risk of subsequent distant metastasis and whether the second relapse is local or distant, survival is uniformly poor. PMID- 29705798 TI - Disorders of Lipid Metabolism in Chronic Kidney Disease. AB - Cardiovascular disease (CVD) is the leading cause of death in chronic kidney disease (CKD). One of the most important pathophysiological mechanisms for CVD in patients with CKD is the widespread and possibly accelerated formation of atherosclerotic plaques due to hyperlipidemia, uremic toxins, inflammation, oxidative stress, and endothelial dysfunction. Recent studies showed that the level of oxidized low-density lipoprotein cholesterol increases, and that high- density lipoprotein cholesterol dysfunction occurs as kidney function declines and inflammation becomes more prevalent. In this review, we aimed to discuss the effect of kidney dysfunction, oxidative stress, and inflammation on lipid profile. PMID- 29705799 TI - Modeling Statin-Induced Reductions of Cardiovascular Events in Primary Prevention: A VOYAGER Meta-Analysis. AB - OBJECTIVE: We used individual patient data from the VOYAGER database to estimate cardiovascular (CV) risk reduction with commonly used high-intensity statins. METHODS: In patients with known atherosclerotic CV disease (ASCVD) treated with high-intensity statin therapy (n = 6,735), the predicted risk reduction was estimated using the Cholesterol Treatment Trialists' Collaboration meta-analysis, which determined risk reduction per 38.7 mg/dL statin-mediated reduction in low density lipoprotein cholesterol. RESULTS: The greatest reductions in risk were seen in major vascular events (estimated rate ratios ranged from 0.55 with rosuvastatin [RSV] 40 mg to 0.60 with atorvastatin [ATV] 40 mg) and coronary heart disease death (estimated rate ratios ranged from 0.58 with RSV 40 mg to 0.64 with ATV 40 mg). CONCLUSIONS: Our results show that, in individuals without clinical ASCVD, statin therapy has the potential to reduce the frequency of CV events. PMID- 29705800 TI - Histone Deacetylases Promote ER Stress Induced Epithelial Mesenchymal Transition in Human Lung Epithelial Cells. AB - BACKGROUND/AIMS: Epithelial to mesenchymal transition (EMT) is a crucial process involved in pulmonary fibrosis. This study aimed to explore the role of histone deacetylases (HDACs) and endoplasmic reticulum (ER) stress in EMT in human lung epithelial cells. METHODS: Human lung adenocarcinoma A549 cells were treated with bleomycin and tunicamycin to induce EMT. The proliferation of A549 cells was detected by MTT assay. The expression of HDACs and EMT markers was detected by PCR and Western blot analysis. The secretion of TGF-beta1 and collagen I was examined by ELISA. RESULTS: A549 cells switched from a cobblestone-like appearance to an elongated fibroblast like appearance after exposure to tunicamycin or bleomycin, accompanied by increased expression of N-cadherin, alpha-SMA and Collagen I. Meanwhile, GRP78 was upregulated in A549 cells exposed to tunicamycin or bleomycin. These changes induced by tunicamycin or bleomycin could be abrogated by 4-PBA. Moreover, tunicamycin and bleomycin promoted the expression of HDAC2 and HDAC6, and HDACs inhibitor SAHA abrogated the morphological and biochemical changes in A549 cells. 4-PBA and SAHA inhibited the upregulation of pulmonary fibrosis factors TGF-beta1 and IL-32 and the activation of Smad pathway induced by tunicamycin or bleomycin. CONCLUSIONS: We provide the first evidence that tunicamycin and bleomycin induce ER stress and EMT in lung epithelial cells via the upregulation of HDACs. HDACs inhibitor could inhibit ER stress induced upregulation of pulmonary fibrosis factors and the activation of Smad pathway. HDACs inhibitors are promising agents for the therapy of pulmonary fibrosis. PMID- 29705801 TI - Assessment of Embryo-Induced Transcriptomic Changes in Hamster Uterus Using RNA Seq. AB - BACKGROUND/AIMS: The mouse is widely used as an animal model for studying human embryo implantation. However, the mouse is unique in that both ovarian progesterone and estrogen are critical to implantation, whereas in the majority of species (e.g. human and hamster) implantation can occur in the presence of progesterone alone. METHODS: In this study, we analyzed embryo-induced transcriptomic changes in the hamster uterus during embryo implantation by using RNA-seq. Differentially expressed genes were characterized by bioinformatic analysis. RESULTS: We identified a total of 781 differentially expressed genes, of which 367 genes were up-regulated and 414 genes were down-regulated at the implantation site compared to the inter-implantation site. Functional clustering and gene network analysis highlighted the cell cycle process in uterus upon embryo implantation. By examining of the promoter regions of differentially expressed genes, we identified 7 causal transcription factors. Additionally, through connectivity map (CMap) analysis, multiple compounds were identified to have potential anti-implantation effects due to their ability to reverse embryo induced transcriptomic changes. CONCLUSION: Our study provides a valuable resource for in-depth understanding of the mechanism underlying embryo implantation. PMID- 29705802 TI - Salidroside Protection Against Oxidative Stress Injury Through the Wnt/beta Catenin Signaling Pathway in Rats with Parkinson's Disease. AB - BACKGROUND/AIMS: Parkinson's disease (PD) is the second most common neurodegenerative disease after Alzheimer's disease, and recent studies suggested that oxidative stress (OS) contributes to the cascade that leads to dopamine cell degeneration in PD. In this study, we hypothesized that salidroside (SDS) offers protection against OS injury in 6-hydroxydopamine (6-OHDA) unilaterally lesioned rats as well as the underlying mechanism. METHODS: SDS and LiCl (activators of the Wnt/beta-catenin signaling pathway) administration alone and in combination with 6-OHDA injection in rats was performed 3 days before modeling for 17 consecutive days to verify the regulatory mechanism by which SDS affects the Wnt/beta-catenin signaling pathway as well as to evaluate the protective effect of SDS on PD in relation to OS in vivo. In addition, pheochromocytoma 12 (PC12) cells were incubated with 10 umol/L SDS or LiCl alone or with both in combination for 1 h followed by a 24-h incubation with 100 umol/L 6-OHDA to obtain in vitro data. RESULTS: In vivo the administration of LiCl was found to ameliorate behavioral deficits and dopaminergic neuron loss; increase superoxide dismutase (SOA) activity, glutathione peroxidase (GSH-Px) levels, and glycogen synthase kinase 3beta phosphorylation (GSK-3beta-Ser9); reduce malondialdehyde (MDA) accumulation in the striatum and the GSK-3beta mRNA level; as well as elevate beta-catenin and cyclinD1 mRNA and protein levels in 6-OHDA-injected rats. This SDS treatment regimen was found to strengthen the beneficial effect of LiCl on 6 OHDA-injected rats. In vitro LiCl treatment decreased the toxicity of 6-OHDA on PC12 cells and prevented apoptosis. Additionally, LiCl treatment increased SOA activity, GSH-Px levels, and GSK-3beta-Ser9 phosphorylation; decreased MDA accumulation in the striatum and GSK-3beta mRNA levels; as well as increased beta catenin and cyclinD1 mRNA and protein levels in 6-OHDA-treated PC12 cells. Additionally, SDS treatment increased the protective effect of LiCl on 6-OHDA treated PC12 cells. CONCLUSION: Evidence from experimental models suggested that SDS may confer neuroprotection against the neurotoxicity of 6-OHDA in response to OS injury and showed that these beneficial effects may be related to regulation of the Wnt/beta-catenin signaling pathway. Therefore, SDS might be a potential therapeutic agent for treating PD. PMID- 29705804 TI - Removal of Procalcitonin and Selected Cytokines during Continuous Veno-Venous Hemodialysis Using High Cutoff Hemofilters in Patients with Sepsis and Acute Kidney Injury. AB - INTRODUCTION: The purpose of this study was to evaluate the impact of continuous veno-venous hemodialysis (CVVHD) using high cutoff (HCO) hemofilters on the removal of procalcitonin (PCT), and other inflammatory markers in the treatment of patients during septic shock with acute kidney injury (AKI). MATERIALS AND METHODS: Thirty-six patients with septic shock and AKI were included in the study. Before and after the 24-h HCO-CVVHD, PCT, native C-reactive protein (CRP) and cytokines (interleukin-1beta, interleukin-6, interleukin-12, interleukin-17, tumor necrosis factor-alpha) in serum and effluent were assessed. RESULTS: After the HCO-CVVHD serum concentrations of PCT, CRP and selected cytokines were significantly lower. The decrease in PCT was bigger than in CRP (p = 0.007). The change in PCT concentration was significantly influenced by PCT and IL-17 clearances (R2 = 0.525; p < 0.001). CONCLUSION: In contrast to the native CRP, monitoring of PCT during HCO-CVVHD is less useful because it reflects the clearance of this marker and anti-inflammatory effectiveness of the method. PMID- 29705803 TI - Lipid-Lowering Pretreatment and Outcome Following Intravenous Thrombolysis for Acute Ischaemic Stroke: A Post Hoc Analysis of the Enhanced Control of Hypertension and Thrombolysis Stroke Study Trial. AB - BACKGROUND: Debate exists as to whether statin pretreatment confers an increased risk of 90-day mortality and symptomatic intracranial haemorrhage (sICH) in acute ischaemic stroke (AIS) patients treated with intravenous thrombolysis. We assessed the effects of undifferentiated lipid-lowering pretreatment on outcomes and interaction with low-dose versus standard-dose alteplase in a post hoc subgroup -analysis of the Enhanced Control of Hypertension and Thrombolysis Stroke Study. METHODS: In all, 3,284 thrombolysis-eligible AIS patients (mean age 66.6 years; 38% women), with information on lipid-lowering pretreatment, were randomly assigned to low-dose (0.6 mg/kg) or standard-dose (0.9 mg/kg) intravenous alteplase within 4.5 h of symptom onset. Of the total number of patients, 615 (19%) received statin or other lipid-lowering pretreatment. The primary clinical outcome was combined endpoint of death or disability (modified Rankin Scale scores 2-6) at 90 days. RESULTS: Compared with patients with no lipid-lowering pretreatment, those with lipid-lowering pretreatment were significantly older, more likely to be non-Asian and more likely to have a medical history including vascular co-morbidity. After propensity analysis assessment and adjustment for important baseline variables at the time of randomisation, as well as imbalances in management during the first 7 days of hospital admission, there were no significant differences in mortality (OR 0.85; 95% CI 0.58-1.25, p = 0.42), or in overall -90-day death and disability (OR 0.85, 95% CI 0.67-1.09, p = 0.19), despite a significant decrease in sICH among those with -lipid-lowering pretreatment according to the European Co-operative Acute Stroke Study 2 definition (OR 0.49, 95% CI 0.28-0.83, p = 0.009). No differences in key efficacy or safety outcomes were seen in patients with and without lipid lowering pretreatment between low- and standard-dose alteplase arms. CONCLUSIONS: Lipid-lowering pretreatment is not associated with adverse outcome in AIS patients treated with intravenous alteplase, whether assessed by 90-day death and disability or death alone. PMID- 29705805 TI - Genome-Wide Association Study and Transcriptome Analysis Provide New Insights into the White/Red Earlobe Color Formation in Chicken. AB - BACKGROUND/AIMS: Earlobe color is a typical external trait in chicken. There are some previous studies showing that the chicken white/red earlobe color is a polygenic and sex-linked trait in some breeds, but its molecular genetic and histological mechanisms still remain unclear. METHODS: We herein utilized histological section, genome-wide association study (GWAS) and RNA-seq, further to investigate the potential histological and molecular genetic mechanisms of white/red earlobe formation in Qiangyuan Partridge chicken (QYP). RESULTS: through histological section analysis, we found the dermal papillary layer of red earlobes had many more blood vessels than that of white earlobes. And we identified a total of 44 SNPs from Chromosome 1, 2, 3, 4, 9, 10, 11, 13, 19, 20, 23 and Z, that was significantly associated with the chicken white/red earlobe color from GWAS, along with 73 significantly associated genes obtained (e.g., PIK3CB, B4GALT1 and TP63), supporting the fact that the white/red earlobe color was also polygenic and sex-linked in QYP. Importantly, PIK3CB and B4GALT1 are both involved in the biological process of angiogenesis, which may directly give rise to the chicken white earlobe formation through regulating blood vessel density in chicken earlobe. Additionally, through contrast of RNA-seq profiles between white earlobe skins and red earlobe skins, we further identified TP63 and CDH1 differentially expressed. Combined with the existing knowledge of TP63 in epithelial development and tumor angiogenesis, we propose that down-regulated TP63 in white earlobes may play roles in thickening the skin and decreasing the vessel numbers in dermal papillary layer, thereby contributing to the white earlobe formation via paling the redness of the skin in QYP, but the specific mechanism remains to be further clarified. CONCLUSION: our findings advance the existing understanding of the white earlobe formation, as well as provide new clues to understand the molecular mechanism of chicken white/red earlobe color formation. PMID- 29705806 TI - Vancomycin-Associated Acute Kidney Injury with a Steep Rise in Serum Creatinine. AB - BACKGROUND: Vancomycin-associated (VA) acute kidney injury (AKI) is being increasingly recognized. A distinct pattern of rapid rise in serum creatinine (sCr) during VA-AKI has occasionally been observed. However, such scenarios remain underreported. METHODS: We conducted an online survey at the American Society of Nephrology Communities forum and reviewed publications of VA-AKI via PubMed or Google searching for cases of precipitous AKI (those with rise in sCr >=1.5 mg/dL/day) attributable to vancomycin. RESULTS: We identified 12 original cases compiled from 6 different hospitals and 4 published cases (n = 16; 38% women, age 43.5 +/- 16 years, weight 108 +/- 23 kg, body mass index 35 +/- 7 kg/m2) of precipitous AKI observed shortly after large cumulative doses of VA (8.8 +/- 5 g). The median steepest 24-h rise in sCr was 2.6 mg/dL (range 1.5-3.5 mg/dL) and the slope of the initial 48-h sCr rise was greater than that of a control AKI (non-VA, n = 48) group (2.03 +/- 0.1 vs. 0.62 +/- 0.0 mg/dL/day; p < 0.0001). The steep rise in sCr in the VA-AKI was not accompanied by anuria. Overt rhabdomyolysis was absent in all cases. Further, in 3 precipitous VA-AKI cases, simultaneous serum cystatin C values did not rise precipitously, suggesting that the reductions in glomerular filtration rate were overestimated by the sCr increase. CONCLUSIONS: VA-AKI can manifest with a precipitous rise in sCr shortly after a high cumulative dose of vancomycin. True toxic tubular injury overrepresented by the sCr rise is postulated. PMID- 29705807 TI - Rapamycin Protects Skin Fibroblasts from Ultraviolet B-Induced Photoaging by Suppressing the Production of Reactive Oxygen Species. AB - BACKGROUND/AIMS: Ultraviolet B (UVB) irradiation alters multiple molecular pathways in the skin, thereby inducing skin photoaging. Murine dermal fibroblasts (MDFs) were subjected to a series of 4 sub-cytotoxic UVB doses (120 mJ/cm2), resulting in changes in cell shape, DNA damage, cell cycle arrest, extracellular matrix variations, reactive oxygen species (ROS) generation, and alterations in major intracellular antioxidant and cellular autophagy levels. Rapamycin (RAPA) is a new macrolide immunosuppressive agent that is primarily used in oncology, cardiology, and transplantation medicine and has been found to extend the lifespan of genetically heterogeneous mice. Several studies have shown that RAPA may have anti-aging effects in cells and organisms. Thus, in this study, we explored the effects and mechanisms of RAPA against the photoaging process using a well-established cellular photoaging model. METHODS: We developed a stress induced premature senescence (SIPS) model through repeated exposure of MDFs to ultraviolet B (UVB) irradiation. The cells were cultured in the absence or presence of RAPA for 48 h. Senescent phenotypes were assessed by examining cell viability, cell morphology, senescence-associated beta-galactosidase (SA-beta gal) expression, cell cycle progression, intracellular ROS production, matrix metalloproteinase (MMP) synthesis and degradation, extracellular matrix (ECM) component protein expression, alterations in major intracellular antioxidant levels, and the cellular autophagy level. RESULTS: Compared with the UVB group, pretreatment with RAPA (5 uM) significantly decreased the staining intensity and percentage of SA-beta-gal-positive cells and preserved the elongated cell shape. Moreover, cells pretreated with RAPA showed inhibition of the reduction in the type I collagen content by blocking the UVB-induced upregulation of MMP expression. RAPA also decreased photoaging cell cycle arrest and downregulated p53 and p21 expression. RAPA application significantly attenuated irradiation induced ROS release by modulating intracellular antioxidants and increasing the autophagy level. CONCLUSIONS: Our study demonstrated that RAPA elicited oxidative damage in vitro by reducing ROS accumulation in photoaged fibroblasts. The anti aging effect can be attributed to the maintenance of normal antioxidant and cellular autophagy levels. However, determination of the definitive mechanism requires further study. PMID- 29705808 TI - Sumoylation Negatively Regulates CSR1-Dependent Prostate Cancer Cell Death. AB - BACKGROUND/AIMS: SUMOylation is a dynamic process and reversed by the activity of SUMO-specific proteases (SENPs) family. SENP1, a member of this family, is highly expressed and plays oncogenic roles in diverse cancers including prostate cancer. However, the SENP1-transgenic mice exhibit aberrant transformation of the mouse prostate gland but do not develop cancer. Cellular Stress Response 1 (CSR1) is a tumor suppressor gene and frequently deleted in prostate cancers. Overexpression of CSR1 in prostate cancer cells inhibits colony formation, anchorage-independent growth and induces cell death. METHODS: The relationship between CSR1 and SENP1 were determined by immunoprecipitation-based proteomics screen and verified by GST-pull down assay. In vivo SUMOylation assay was used to detect the direct effect of SENP1 in the regulation of CSR1. Clustered regularly interspaced short palindromic repeats (CRISPR)-based gene editing was used to generate Senp1-/- and CSR1-/- PC3 cells. FACS assay was used to determine the apoptosis ratio of cells after transfection. RESULTS: CSR1 is SUMOylated at K582 and rapid ubiquitinated and degradated in prostate cancer cells. SENP1 interacts with and deSUMOylates CSR1 to prevent its degradation and enhances CSR1-dependent prostate cancer cell death. CONCLUSION: Thus, our data indicates that CSR1 is a critical SUMOylated substrate of SENP1 that might partially explain the controversial roles of SENP1 in prostate cancer development. PMID- 29705810 TI - The Timing of Initiating Complementary Feeding in Preterm Infants and Its Effect on Overweight: A Systematic Review. AB - BACKGROUND: What is the appropriate time to start complementary feeding for preterm infants? The answer to this question is yet under debate. The timing of initiating complementary feeding may be associated with overweight in term infants. This systematic review aimed to study the effect of the timing of initiating complementary feeding on overweight in preterm infants. Predefined search items included preterm infants, complementary feeding, overweight, and their synonyms. SUMMARY: The search identified 15,749 articles, of which 5 articles were included. Three studies presented data of randomized controlled trials and 2 studies were cohort studies. Two randomized controlled trials found no significant difference in body mass index (BMI) Z-score between the intervention groups at 12 months of age. One randomized controlled trial presented a significant greater mean rate of growth in length per week until 12 months in the preterm weaning strategy-group compared with the current best practices. One observational study concluded that each month the infants received complementary food later, the Z-score for length and weight was reduced by 0.1. Key Messages: No clear conclusion could be drawn from the included studies. This review illustrates the need for further research to access the effect of the timing of initiating complementary feeding on overweight in preterm infants. PMID- 29705809 TI - High Glucose-Induced Reactive Oxygen Species Stimulates Human Mesenchymal Stem Cell Migration Through Snail and EZH2-Dependent E-Cadherin Repression. AB - BACKGROUND/AIMS: Glucose plays an important role in stem cell fate determination and behaviors. However, it is still not known how glucose contributes to the precise molecular mechanisms responsible for stem cell migration. Thus, we investigate the effect of glucose on the regulation of the human umbilical cord blood-derived mesenchymal stem cell (hUCB-MSC) migration, and analyze the mechanism accompanied by this effect. METHODS: Western blot analysis, wound healing migration assays, immunoprecipitation, and chromatin immunoprecipitation assay were performed to investigate the effect of high glucose on hUCB-MSC migration. Additionally, hUCB-MSC transplantation was performed in the mouse excisional wound splinting model. RESULTS: High concentration glucose (25 mM) elicits hUCB-MSC migration compared to normal glucose and high glucose-pretreated hUCB-MSC transplantation into the wound sites in mice also accelerates skin wound repair. We therefore elucidated the detailed mechanisms how high glucose induces hUCB-MSC migration. We showed that high glucose regulates E-cadherin repression through increased Snail and EZH2 expressions. And, we found high glucose-induced reactive oxygen species (ROS) promotes two signaling; JNK which regulates gamma secretase leading to the cleavage of Notch proteins and PI3K/Akt signaling which enhances GSK-3beta phosphorylation. High glucose-mediated JNK/Notch pathway regulates the expression of EZH2, and PI3K/Akt/GSK-3beta pathway stimulates Snail stabilization, respectively. High glucose enhances the formation of EZH2/Snail/HDAC1 complex in the nucleus, which in turn causes E-cadherin repression. CONCLUSION: This study reveals that high glucose-induced ROS stimulates the migration of hUCB-MSC through E-cadherin repression via Snail and EZH2 signaling pathways. PMID- 29705811 TI - Influence of the Histopathological Features of the Lesion on the Diagnostic Yield of Fine-Needle Aspiration Cytology of Pancreatic Solid Lesions. AB - OBJECTIVE: The rate of pancreatic lesions has increased in recent decades due to the widespread use of advanced imaging techniques. Nowadays, a significant proportion of cases are incidentally discovered in asymptomatic patients and cytology is an important tool for the diagnosis and multidisciplinary management of these cases. STUDY DESIGN: In this study we retrospectively review the experience with pancreatic fine-needle aspiration cytology in the last 17 years at a single large tertiary hospital in Madrid, Spain. RESULTS: Our results indicate that more than 60% of pancreatic malignant lesions are cytologically confirmed before surgery and 30% of the patients are asymptomatic. Despite this, we have noted that the total number of malignant lesions surgically resected in our hospital has basically remained unchanged over the years, because incidental diagnosis is not always synonymous with resectability and a substantial number of patients are already metastatic at the time of diagnosis. Our series also shows an increase in the number of neuroendocrine tumors, which now represent almost 20% of all cytological diagnoses at our hospital. The sensitivity in our series is 70% and the false negative rate remains 30%, despite sample quality control by experienced cytologists and standardized technical conditions. Fibrosis and necrosis are the 2 features of the primary tumor that significantly and negatively influence the accuracy of cytologic diagnosis. CONCLUSION: We herein report our experience with cytologic diagnosis of pancreatic lesions in a single tertiary hospital. Our results confirm that cytology is a safe, reliable, and important tool for pancreatic lesion diagnosis and management. PMID- 29705812 TI - Imaging-Assisted Diagnosis and Characteristics of Suspected Spinal Brucellosis: A Retrospective Study of 72 Cases. AB - BACKGROUND We clarified the imaging features of Brucella spondylitis to enhance our understanding of the disease and to minimize misdiagnosis. MATERIAL AND METHODS Imaging data (X-ray, computed tomography [CT], and magnetic resonance imaging [MRI] data) of 72 Brucella spondylitis patients treated from 2010 to 2017 were retrospectively analyzed; diagnoses was made by evaluating laboratory and pathological data. RESULTS X-ray films revealed changes in intervertebral space heights, the number of lateral osteophytes, and bone destruction, which were more severe in the following order: lumbosacral vertebrae (56 cases, 77.8%), cervical spine (6 cases, 8.3%), thoracic spine (5 cases, 6.9%), and multi-segmental mixed vertebrae (5 cases, 6.9%). CT revealed osteolytic destruction attributable to early-stage Brucella spondylitis (endplate and vertebral lamellar osteolysis), usually associated with multiple vertebral involvement, with the middle and late disease stages being characterized by osteophytes in the vertebral margins and bony bridges, endplate sclerosis, and vertebral osteosynthesis. We encountered 54 cases (75%) with endplate lamellar osteolysis, 37 (51.4%) with vertebral lamellar osteolysis, 59 (81.9%) with marginal osteophytes, 10 (13.9%) with bony bridges, 25 (34.7%) with vertebral laminar sclerosis, and 17 (23.6%) with vertebral osteosynthesis. MRI revealed early, low-intensity, differential T1WI vertebral and intervertebral signals, with occasional iso-signals, T2WI iso-signals or high intensity signals; and T2WI-FS vertebral and intervertebral high-intensity signals, commonly from vertebral soft tissues and rarely from paravertebral abscesses. CONCLUSIONS A better understanding of the X-ray, CT, and MRI features of Brucella spondylitis could aid in diagnosis when combined with epidemiological and laboratory data, thus minimizing misdiagnosis. PMID- 29705813 TI - Metabolic Status in Patients with Operable vs. Inoperable Left-to-Right Shunts. AB - BACKGROUND Previous studies have shown the prognostic value of insulin resistance, hyperuricemia, and dyslipidemia in clinical outcome of pulmonary arterial hypertension. Whether these metabolic derangements are different between operable and inoperable left-to-right shunts is unknown. MATERIAL AND METHODS Our study included 116 patients with left-to-right shunts (76 with atrial septal defect and 40 with ventricular septal defect) with or without pulmonary arterial hypertension. Operability of defect closure were assessed by cardiac catheterization and patients were subdivided into an operable group or an inoperable group. The metabolic status, including prediabetes, hyperuricemia, dyslipidemia, hypertension and obesity, were compared between groups. RESULTS Patients receiving defect correction had a lower HbA1c (B: 5.52+/-0.49 vs. 5.71+/ 0.41, p=0.042) and uric acid (C: 358+/-105 vs. 406+/-126, p=0.029) but a higher HDLC (D: 1.21+/-0.33 vs. 1.08+/-0.22, p=0.017) and BMI (A: 20.4+/-3.9 vs. 18.8+/ 3.1, p=0.023). Patients in the inoperable group had a higher prevalence of prediabetes (58% vs. 41%, p=0.076), hyperuricemia (37.2% vs. 21.9, p=0.106), dyslipidemia (74% vs. 56%, p=0.049) but a lower prevalence of hypertension (13.9% vs. 30.1%, p=0.049) and obesity (4.6% vs. 12.3%, p=0.301). According to logistic regression, only HbA1c (1.76 (0.53, 2.99), HR (95% CI), p=0.005) remained significant for pulmonary vascular resistance. CONCLUSIONS Although prediabetes, hyperuricemia, and dyslipidemia were all more prevalent in patients with inoperable left-to-right shunts, only prediabetes was found to be significantly associated with higher pulmonary vascular resistance. PMID- 29705814 TI - Serum Cytokine and Growth Factor Levels in Children with Autism Spectrum Disorder. AB - BACKGROUND The immune system may have a role in the pathogenesis of autism spectrum disorder (ASD), including typical and atypical autism. The aim of this study was to determine whether a cytokine and growth factor panel could be identified for the diagnosis and prognosis in children with ASD, including typical and atypical autism. MATERIAL AND METHODS This study included 26 children with ASD (typical or atypical) and 11 of their siblings who did not have ASD. A panel of ten serum cytokines and growth factors were investigated using addressable laser bead assay (ALBIA) and enzyme-linked immunosorbent assay (ELISA) kits. Results were correlated with scores using the Childhood Autism Rating Scale (CARS) and Autism Diagnostic Observation Schedule (ADOS) for the children with ASD and compared with the findings from their siblings without ASD. RESULTS There were no statistically significant differences in serum cytokine and growth factor levels between children with ASD and their siblings. The scores using CARS and ADOS were significantly greater in children with typical autism compared with children with atypical autism as part of the ASD spectrum. Serum levels of cytokines and growth factors showed a positive correlation with CARS and ADOS scores but differed between children with typical and atypical autism and their siblings. CONCLUSIONS The findings of this study showed that serum measurement of appropriately selected panels of cytokines and growth factors might have a role in the diagnosis of ASD. PMID- 29705815 TI - Pancreatic beta cells overexpressing hIAPP impaired mitophagy and unbalanced mitochondrial dynamics. AB - Human islet amyloid polypeptide (hIAPP), or amylin, has the tendency to aggregate into insoluble amyloid fibrils, a typical feature of islets from type 2 diabetes individuals. Thus, we investigated comparatively the impact of hIAPP on key pathways involved in pancreatic beta survival. INS1E-hIAPP cells present a hyperactivation of MTORC1 and an inhibition of autophagy signaling, those cells showing an increase in cell size. Resveratrol, a MTORC1 inhibitor, can reverse TSC2 degradation that occurs in INS1E-hIAPP cells and diminished MTORC1 hyperactivation with concomitant autophagy stimulation. At the same time, a blockade in mitophagy was found in INS1E-hIAPP cells, as compared with control or INS1E-rIAPP cells. Consistently, human amylin overexpression generates a basal induction of nitrotyrosine levels and polyubiquitinated aggregates. Failure of the protein degradation machinery finally results in an accumulation of damaged and fissioned mitochondria, ROS production, and increased susceptibility to endoplasmic reticulum (ER)-stress-induced apoptosis. Overall, hIAPP overexpression in INS1E cells induced MTORC1 activation and mitophagy inhibition, favoring a pro-fission scenario of damaged mitochondria, these cells turn out to be more susceptible to the ER-stress-induced apoptosis and malfunction. PMID- 29705816 TI - Brain perfusion defects by SPET/CT and neurostat semi-quantitative analysis in two patients with congenital erythropoietic porphyria. AB - BACKGROUND: Congenital erythropoietic porphyria (CEP) is a rare autosomal recessively inherited disorder with chronic and relatively stable presentation. Till now brain blood flow derangements have been described only in acute hepatic porphyrias. We describe the first findings of brain perfusion defects, studied by single photon emission tomography/computed tomography (SPET/CT), in two patients affected by CEP, by using a semi-quantification anatomic-standardized voxel-based program compared with magnetic resonance imaging (MRI) results. SUBJECTS AND METHODS: Two Pakistanis brothers were investigated for CEP confirmed by a genetic test. The disease was severe with: skin burning, mood depression and haemolytic anemia. Considering depression, patients underwent brain SPET/CT and MRI. Single photon emission tomography/CT images were processed by neurostat semi quantitative software. Data obtained were compared to a normal database and z score images were generated. RESULTS: In both patients we found several perfusion defects evident in transaxial slices and in z-score images obtained by neurostat processing. Magnetic resonance imaging was negative in both patients. Biochemical mechanisms inducing localized brain hypoperfusion are uncertain. However, mismatch between SPET/CT data and MRI was probably due to absence of necrosis. CONCLUSION: In our opinion, SPET/CT could have a key role in this setting of patients due to its high sensitivity and reliability in mild-to-moderate brain perfusion defects detection. Moreover, the quantitative analysis by using neurostat may allow to recognize even mild brain perfusion alterations, difficult to detect only visually. PMID- 29705817 TI - Application of the alteration uptake ratio of 99mTc-MIBI scintigraphy for evaluating the efficacy of neoadjuvant chemotherapy in osteosarcoma patients. AB - BACKGROUND: We aimed to semi-quantitatively evaluate using technetium-99m methoxyisobutylisonitrile (99mTc-MIBI) scintigraphy the efficacy of neoadjuvant chemotherapy in osteosarcoma (OS) patients. SUBJECTS AND METHODS: A hundred and two patients with OS were retrospectively included in this study. All of them underwent 99mTc-MIBI scintigraphy before and after neoadjuvant chemotherapy. Semi quantitative parameters including the uptake ratio (UR) and alteration of uptake ratio (AUR) were calculated for each patient. According to tumor necrosis rate (TNR), patients were classified into three group: a) Poor response group (grade I, TNR: less than 50%), b) Partial response group (grade II, TNR: 50%-89%) and c) Good response group (grade III, TNR: greater than 90%). The linear regression analysis of the AUR versus TNR was carried out. RESULTS: Poor response, partial response and good response were found in 30, 52 and 20 patients, respectively. In the poor-response group the URpre and URpost were 1.68+/-0.44 and 1.83+/-0.71, respectively and the AUR was -0.02+/-0.33. In the partial-response group the URpre and URpost were 2.42+/-1.42 and 1.59+/-0.71, respectively and the AUR was 0.28+/-0.18. In the good-response group the URpre and URpost were 2.58+/-0.61 and 1.21+/-0.16, respectively and the AUR was 0.46+/-0.10. There was a statistically significant difference of the AUR between poor-response and partial-response groups (P<0.01) and also between the poor-response and good-response groups (P<0.01). The linear regression analysis of the AUR versus TNR which showed a significantly positive correlation (r=0.76). CONCLUSION: The AUR was significant after neoadjuvant chemotherapy in the partial-response group and in the good response group. Furthermore, it exhibited a positive correlation with TNR. All results indicated that 99mTc-MIBI scintigraphy can be used to evaluate neoadjuvant chemotherapy for OS patients. PMID- 29705818 TI - What is behind "centromere repositioning"? AB - An increasing number of observations suggest an evolutionary switch of centromere position on monocentric eukaryotic chromosomes which otherwise display a conserved sequence of genes and markers. Such observations are particularly frequent for primates and equidae (for review see Heredity 108:59-67, 2012) but occur also in marsupials (J Hered 96:217-224, 2005) and in plants (Chromosome Res 25:299-311, 2017 and references therein). The actual mechanism(s) behind remained unclear in many cases (Proc Natl Acad Sci USA 101:6542-6547, 2004; Trends Genet 30:66-74, 2014). The same is true for de novo centromere formation on chromosomes lacking an active centromere. This article focuses on recent reports on centromere repositioning and possible mechanisms behind and addresses open questions. PMID- 29705819 TI - Paradoxical pustular psoriasis induced by ustekinumab in a patient with Crohn's disease-associated spondyloarthropathy. AB - Palmoplantar pustular psoriasis (PPP) is a clinical form of psoriasis, for which tumor necrosis factor alpha inhibitors (TNFi) or interleukins 12/23 inhibitor (ustekinumab) can be a therapeutic option. Paradoxical psoriatic reactions induced by TNFi are now well known. We present the exceptional case of a paradoxical PPP appeared under ustekinumab in a patient with Crohn's disease associated spondyloarthropathy. A 58-year-old woman presented with recent peripheral inflammatory arthralgias appeared in the context of a Crohn's disease diagnosed in 2008. Three weeks after the first injection of ustekinumab 390 mg for a refractory Crohn's disease, a slight pruritic erythematous and pustular dermatosis appeared on the right hand palm. The clinical aspect was strongly in favor of a PPP. Ustekinumab was discontinued and replaced by golimumab, leading to a complete healing of PPP after 15 days of discontinuation. Causality assessment calculated using the French method was plausible for ustekinumab in the induction of PPP. It was based on a compatible chronology according to time to onset associated with complete recovery 2 weeks after cessation of treatment, and on the negative assessment of an alternative etiology (nor bacterial or viral infection, nor other treatment taken by the patient, nor previous history of psoriasis). The worsening of underlying psoriasis under ustekinumab through the appearance of generalized or palmoplantar pustules has already been reported in five cases. We describe to our knowledge the first case of paradoxical PPP under ustekinumab in a patient with no known underlying psoriasis. PMID- 29705820 TI - Eco-epidemiology of Novel Bartonella Genotypes from Parasitic Flies of Insectivorous Bats. AB - Bats are important zoonotic reservoirs for many pathogens worldwide. Although their highly specialized ectoparasites, bat flies (Diptera: Hippoboscoidea), can transmit Bartonella bacteria including human pathogens, their eco-epidemiology is unexplored. Here, we analyzed the prevalence and diversity of Bartonella strains sampled from 10 bat fly species from 14 European bat species. We found high prevalence of Bartonella spp. in most bat fly species with wide geographical distribution. Bat species explained most of the variance in Bartonella distribution with the highest prevalence of infected flies recorded in species living in dense groups exclusively in caves. Bat gender but not bat fly gender was also an important factor with the more mobile male bats giving more opportunity for the ectoparasites to access several host individuals. We detected high diversity of Bartonella strains (18 sequences, 7 genotypes, in 9 bat fly species) comparable with tropical assemblages of bat-bat fly association. Most genotypes are novel (15 out of 18 recorded strains have a similarity of 92-99%, with three sequences having 100% similarity to Bartonella spp. sequences deposited in GenBank) with currently unknown pathogenicity; however, 4 of these sequences are similar (up to 92% sequence similarity) to Bartonella spp. with known zoonotic potential. The high prevalence and diversity of Bartonella spp. suggests a long shared evolution of these bacteria with bat flies and bats providing excellent study targets for the eco-epidemiology of host-vector pathogen cycles. PMID- 29705821 TI - Higher than standard meropenem and linezolid dosages needed for appropriate treatment of an intracerebral hemorrhage patient with augmented renal clearance. PMID- 29705822 TI - Background biomonitoring of residue levels of 137 pesticides in the blood plasma of the general population in Beijing. AB - Due to the widespread use of pesticides, human exposure to pesticides is possible and can potentially cause adverse impacts on public health. We measured 137 pesticides including organophosphorus, organochlorine, pyrethroid and carbamate pesticides together with various herbicides in 100 human blood samples collected from the general population in Beijing. The samples were analysed by triple quadrupole tandem gas chromatography-mass spectrometry. In total, 24 organochlorine pesticides, 5 pyrethroid pesticides and 6 organophosphorus pesticides were detected. The detection rates of HCB, alpha-HCH, beta-HCH, gamma HCH, p,p'-DDE and quintozene were 99, 96, 74, 72, 96 and 95%, respectively. No statistically significant gender difference in the blood concentrations of the pesticides was found. Consistent with the trend of the increasing beta-HCH, p,p' DDE and quintozene concentrations with age, a strong positive correlation between the age and concentrations of beta-BHC, p,p'-DDE and quintozene was observed. PMID- 29705823 TI - Predictive factors for the development of irinotecan-related cholinergic syndrome using ordered logistic regression analysis. AB - Cholinergic syndrome is an acute adverse reaction associated with irinotecan. Development of cholinergic syndrome can be ameliorated or prevented by administering various anticholinergics, including atropine sulfate or scopolamine butylbromide. Although many of the side effects are transient and non-life threatening, their onset is painful and can lower a patient's quality of life (QoL). This retrospective study was performed to identify predictive factors of the development of irinotecan-related cholinergic syndrome in order to develop future strategies for improving the QoL of patients undergoing chemotherapy. We enrolled 150 cancer patients who underwent chemotherapy, which included irinotecan, in our outpatient chemotherapy center between October 2014 and January 2017. For regression analysis, variables related to the development of irinotecan-related cholinergic syndrome were extracted from the patient's clinical records. The degree of cholinergic syndrome was classified as follows: grade 0 = not developed; grade 1 = developed but did not require anticholinergic drugs; and grade 2 = developed and required anticholinergic drugs or stopping the chemotherapy due to cholinergic syndrome. Multivariate ordered logistic regression analysis was performed to identify predictive factors for the development of irinotecan-related cholinergic syndrome. Threshold measurements were determined using a receiver operating characteristic analysis (ROC) curve. Significant factors identified for the development of cholinergic syndrome included female sex [odds ratio (OR) 2.183, 95% confidence interval (CI) 1.010 4.717; P = 0.0471] and irinotecan dose (OR 1.014, 95% Cl 1.007-1.021; P = 0.0001). ROC curve analysis of the group likely to develop cholinergic syndrome indicated that the threshold for the irinotecan dose was 175 mg or above (area under the curve = 0.69). In conclusion, female sex and irinotecan dose were identified as significant predictors of the development of cholinergic syndrome. PMID- 29705824 TI - Assessment of temporal and spatial water quality in international Gomishan Lagoon, Iran, using multivariate analysis. AB - Coastal lagoon ecosystems are vulnerable to eutrophication, which leads to the accumulation of nutrients from the surrounding watershed over the long term. However, there is a lack of information about methods that could accurate quantify this problem in rapidly developed countries. Therefore, various statistical methods such as cluster analysis (CA), principal component analysis (PCA), partial least square (PLS), principal component regression (PCR), and ordinary least squares regression (OLS) were used in this study to estimate total organic matter content in sediments (TOM) using other parameters such as temperature, dissolved oxygen (DO), pH, electrical conductivity (EC), nitrite (NO2), nitrate (NO3), biological oxygen demand (BOD), phosphate (PO4), total phosphorus (TP), salinity, and water depth along a 3-km transect in the Gomishan Lagoon (Iran). Results indicated that nutrient concentration and the dissolved oxygen gradient were the most significant parameters in the lagoon water quality heterogeneity. Additionally, anoxia at the bottom of the lagoon in sediments and re-suspension of the sediments were the main factors affecting internal nutrient loading. To validate the models, R2, RMSECV, and RPDCV were used. The PLS model was stronger than the other models. Also, classification analysis of the Gomishan Lagoon identified two hydrological zones: (i) a North Zone characterized by higher water exchange, higher dissolved oxygen and lower salinity and nutrients, and (ii) a Central and South Zone with high residence time, higher nutrient concentrations, lower dissolved oxygen, and higher salinity. A recommendation for the management of coastal lagoons, specifically the Gomishan Lagoon, to decrease or eliminate nutrient loadings is discussed and should be transferred to policy makers, the scientific community, and local inhabitants. PMID- 29705825 TI - Zero fluid balance and normotension prevents complications, not the amount of fluid per se. PMID- 29705827 TI - Religious Discrimination Scale: Development and Initial Psychometric Evaluation. AB - This study presents the development and initial psychometric evaluation of the Religious Discrimination Scale (RDS). This 11-item instrument identified three dimensions based on perceived discrimination experiences of members of The Church of Jesus Christ of Latter-day Saints (LDS): Perceived Prejudice, Closet Symptoms, and Negative Labels. The psychometric evaluations of the RDS indicated a strong and clear factor structure as well as good internal consistency reliability. The test of measurement and structural invariance across gender also suggested that the RDS scale is equally appropriate to be used with both men and women. Implications for practice and research as well as future directions are discussed. PMID- 29705826 TI - Laparoscopic training using a quantitative assessment and instructional system. AB - PURPOSE: Laparoscopic surgery requires complex surgical skills; hence, surgeons require regular training to improve their surgical techniques. The quantitative assessment of a surgeon's skills and the provision of feedback are important processes for conducting effective training. The aim of this study was to develop an inexpensive training system that provides automatic technique evaluation and feedback. METHODS: We detected the instrument using image processing of commercial web camera images and calculated the motion analysis parameters (MAPs) of the instrument to quantify performance features. Upon receiving the results, we developed a method of evaluating the surgeon's skill level. The feedback system was developed using MAPs-based radar charts and scores for determining the skill level. These methods were evaluated using the videos of 38 surgeons performing a suturing task. RESULTS: There were significant differences in MAPs among surgeons; therefore, MAPs can be effectively used to quantify a surgeon's performance features. The results of skill evaluation and feedback differed greatly between skilled and unskilled surgeons, and it was possible to indicate points of improvement for the procedure performed in this study. Furthermore, the results obtained for certain novice surgeons were similar to those obtained for skilled surgeons. CONCLUSION: This system can be used to assess the skill level of surgeons, independent of the years of experience, and provide an understanding of the individual's current surgical skill level effectively. We conclude that our system is useful as an inexpensive laparoscopic training system that might aid in skill improvement. PMID- 29705828 TI - Changes and Predictors of the Sense of Meaning in Life in Polish University Students Participating in Psychological Workshops Communication-Forgiveness-Love. AB - The aim of this study was to determine changes in the sense of meaning in life of university students who participated in psychological workshops "Communication Forgiveness-Love". The study evaluated 33 university students from first-cycle and second-cycle studies in physical education in the Jozef Pilsudski University of Physical Education in Warsaw. The Reker's Life Attitude Profile-Revised Questionnaire, Social Competencies Questionnaire (KKS) by Matczak, Emotional Intelligence Questionnaire (INTE) by Schutte et al. and the Goldberg's General Health Questionnaire GHQ-28 were used. The study found that psychological workshops can be effective in instilling the sense of meaning in life in university students, especially those from first-cycle studies. The workshops can produce more benefits to students with worse mental status and with lower social competencies. PMID- 29705829 TI - Psychological Resources, Personality Traits and Buddhism: A Study of Italian Young Adults. AB - We aimed to examine whether young adults practicing Buddhism have elevated levels of psychological resources and specific personality traits compared to Catholics and Atheists. We recruited 184 participants: Soka Gakkai Buddhists (n = 60); non practicing Roman Catholic Church believers (n = 62); Atheists (n = 62). We found that the Buddhists have higher optimism than both Catholics and Atheists. They also have higher self-efficacy and self-esteem than Catholics and higher perceived social support than Atheists. Concerning global personality factors, they are more extraverted than the other groups, and they are less tough-minded than Catholics. Differences also emerged relating some primary personality factors. Since we did not find differences between Catholics and Atheists about psychological resources, we speculate that religion alone does not provide an efficacious source of psychological resources; it could be that religious practice is determinant. PMID- 29705831 TI - Deprescribing Benzodiazepines in Older Patients: Impact of Interventions Targeting Physicians, Pharmacists, and Patients. AB - Benzodiazepines (BZDs; including the related Z-drugs) are frequently targets for deprescribing; long-term use in older people is harmful and often not beneficial. BZDs can result in significant harms, including falls, fractures, cognitive impairment, car crashes and a significant financial and legal burden to society. Deprescribing BZDs is problematic due to a complex interaction of drug, patient, physician and systematic barriers, including concern about a potentially distressing but rarely fatal withdrawal syndrome. Multiple studies have trialled interventions to deprescribe BZDs in older people and are discussed in this narrative review. Reported success rates of deprescribing BZD interventions range between 27 and 80%, and this variability can be attributed to heterogeneity of methodological approaches and limited generalisability to cognitively impaired patients. Interventions targeting the patient and/or carer include raising awareness (direct-to-consumer education, minimal interventions, and 'one-off' geriatrician counselling) and resourcing the patient (gradual dose reduction [GDR] with or without cognitive behavioural therapy, teaching relaxation techniques, and sleep hygiene). These are effective if the patient is motivated to cease and is not significantly cognitively impaired. Interventions targeted to physicians include prescribing interventions by audit, algorithm or medication review, and providing supervised GDR in combination with medication substitution. Pharmacists have less frequently been the targets for studies, but have key roles in several multifaceted interventions. Interventions are evaluated according to the Behaviour Change Wheel. Research supports trialling a stepwise approach in the cognitively intact older person, but having a low threshold to use less consultative methods in patients with dementia. Several resources are available to support deprescribing of BZDs in clinical practice, including online protocols. PMID- 29705832 TI - Green Light photoselective vaporization of the prostate: a safe and effective treatment for elderly high-risk benign prostate hyperplasia patients with gland over 80 ml. AB - To analyze the efficacy of Green Light photoselective vaporization of the prostate (PVP) in elderly high-risk benign prostatic hyperplasia (BPH) patients with glands over 80 ml. From December 2013 to February 2016, we allocated 84 elderly (age 71-97) high-risk patients who underwent preoperative transrectal ultrasound (TRUS) examination with glands over 80 ml and divided them into two groups to receive 120 W (n = 40) and 180 W (n = 44) PVP. All the patients have been observed at least one intraoperative comorbidity: hypertension, diabetes mellitus, NYHA II, or combined. They were followed up for 12 months. All the conventional parameters were compared in this study. All the patients received successful operations without severe complications, and no patient needed blood transfusion. The operation time and catheterization time of the 180 W patients were significantly shorter than that of the 120 W patients (p < 0.05). The International Prostate Symptom Scores (IPSS), quality of life (QoL) scores, maximum flow rate (Qmax), and residual urine volume (RUV) in both groups have been significantly improved. PVP is safe and effective for high-risk aging patients with gland over 80 ml. In addition, 180 W XPS system has a short operation time and catheterization time and less inflammatory response. PMID- 29705830 TI - The Mammary Microenvironment in Mastitis in Humans, Dairy Ruminants, Rabbits and Rodents: A One Health Focus. AB - The One Health concept promotes integrated evaluation of human, animal, and environmental health questions to expedite advances benefiting all species. A recognition of the multi-species impact of mastitis as a painful condition with welfare implications leads us to suggest that mastitis is an ideal target for a One Health approach. In this review, we will evaluate the role of the mammary microenvironment in mastitis in humans, ruminants and rabbits, where appropriate also drawing on studies utilising laboratory animal models. We will examine subclinical mastitis, clinical lactational mastitis, and involution-associated, or dry period, mastitis, highlighting important anatomical and immunological species differences. We will synthesise knowledge gained across different species, comparing and contrasting disease presentation. Subclinical mastitis (SCM) is characterised by elevated Na/K ratio, and increased milk IL-8 concentrations. SCM affecting the breastfeeding mother may result in modulation of infant mucosal immune system development, whilst in ruminants notable milk production losses may ensue. In the case of clinical lactational mastitis, we will focus on mastitis caused by Staphylococcus aureus and Escherichia coli. Understanding of the pathogenesis of involution-associated mastitis requires characterization of the structural and molecular changes occurring during involution and we will review these changes across species. We speculate that milk accumulation may act as a nidus for infection, and that the involution 'wound healing phenotype' may render the tissue susceptible to bacterial infection. We will discuss the impact of concurrent pregnancy and a 'parallel pregnancy and involution signature' during bovine mammary involution. PMID- 29705834 TI - Improved Magnesium Levels in Morbidly Obese Diabetic and Non-diabetic Patients After Modest Weight Loss. AB - Serum magnesium (Mg) is reported to be reduced in individuals with obesity, hypertension, and diabetes mellitus and has been suggested as a marker for metabolic syndrome. We have studied changes in serum Mg concentrations in a group of obese patients (n = 92) with and without diabetes mellitus after weight loss induced by dieting and bariatric surgery. At inclusion, 11% (10/92) of the population had severe Mg deficiency (< 0.75 mmol/L) and median serum Mg was lower in diabetic (n = 20) compared to non-diabetic (n = 72) patients (p = 0.002). A weight loss of 10 kg after 8 weeks of lifestyle interventions was accompanied by increased serum Mg of about 5% in both diabetic and non-diabetic patients. Serum Mg remained stable thereafter in the non-diabetic patients, while it continued to increase in the diabetic patients after bariatric surgery. Six months after bariatric surgery, there was no significant difference in serum Mg concentration between the groups (p = 0.08). The optimal range of circulating Mg concentration is not known, but as even small increments in serum Mg are reported to lower the risk of cardiovascular and ischemic heart disease, our results are interesting in a public health perspective. PMID- 29705833 TI - Robotic-assisted thymectomy for early-stage thymoma: a propensity-score matched analysis. AB - The aim of this study was to analyse the feasibility and safety of robotic assisted thymectomy (RoT) in patients with clinically early stage thymoma, investigating clinical and early oncological results. Between 1998 and 2017, we retrospectively reviewed 76 (42.2%) patients who underwent radical thymectomy for clinically early stage thymoma (Masaoka-Koga I and II), identifying all patients who underwent RoT (n = 28) or open thymectomy (OT) with eligibility criteria for robotic surgery (n = 48). Using a propensity-score matched for tumor size (3.9 +/ 1.8 cm) and stage (35% stage I, 42% stage IIA, 23% stage IIB), we paired 24 patients who had RoT with 24 patients undergoing OT. RoT was left-sided in 19 (79.2%) patients. None of the patients required conversion to open surgery. OT was via sternotomy in 21 (87.5%) patients and thoracotomy in 3 (12.5%). Mean operating time was shorter in the RoT group (117 +/- 40 min) than in the OT (141 +/- 46 min) (p = 0.06), even if not statistically significant. Length of stay was significantly shorter in the RoT group (mean 4.0 +/- 1.9 days) than in the OT (mean 5.9 +/- 1.7 days) (p = 0.0009). No significant difference between the two groups regarding post-operative complications. Five patients died in the OT group after a median follow-up of 6.1 years (only one for recurrence). After a median follow-up of 1.3 years, all patients in the RoT group were alive without disease. RoT is feasible and safe for early stage thymoma with clear advantage compared to OT in term of short term outcomes. A longer follow-up is needed to better evaluate the oncological results. PMID- 29705835 TI - Liver Proteome of Mice with Distinct Genetic Susceptibilities to Fluorosis Treated with Different Concentrations of F in the Drinking Water. AB - Appropriate doses of fluoride (F) have therapeutic action against dental caries, but higher levels can cause disturbances in soft and mineralized tissues. Interestingly, the susceptibility to the toxic effects of F is genetically determined. This study evaluated the effects of F on the liver proteome of mice susceptible (A/J) or resistant (129P3/J) to the effects of F. Weanling male A/J (n = 12) and 129P3/J (n = 12) mice were housed in pairs and assigned to two groups given low-F food and drinking water containing 15 or 50 ppm F for 6 weeks. Liver proteome profiles were examined using nano-LC-ESI-MS/MS. Difference in expression among the groups was determined using the PLGS software. Treatment with the lower F concentration provoked more pronounced alterations in fold change in liver proteins in comparison to the treatment with the higher F concentration. Interestingly, most of the proteins with fold change upon treatment with 15 ppm F were increased in the A/J mice compared with their 129P3/J counterparts, suggesting an attempt of the former to fight the deleterious effects of F. However, upon treatment with 50 ppm F, most proteins with fold change were decreased in the A/J mice compared with their 129P3/J counterparts, especially proteins related to oxidative stress and protein folding, which might be related to the higher susceptibility of the A/J animals to the deleterious effects of F. Our findings add light into the mechanisms underlying genetic susceptibility to fluorosis. PMID- 29705836 TI - Commentary on: A cost-effectiveness analysis of onabotulinumtoxin A as first-line treatment for overactive bladder. PMID- 29705837 TI - Outcome of optical iridectomy in Peters anomaly. AB - PURPOSE: Optical iridectomy creates a defect in the iris to allow an alternative clear visual axis in cases of central corneal opacities occluding the pupillary axis. The purpose of this study is to evaluate the outcomes of optical sector iridectomy in children with Peters anomaly. METHODS: Retrospective case series. The medical records of all patients diagnosed with Peters anomaly who underwent optical iridectomy during the years 2002-2014 were reviewed. Data collection included surgical and visual acuity outcomes. RESULTS: Twenty-nine eyes (22 patients) were included in the study. Mean age at the time of surgery was 15.6 +/ 26.3 months. Eighteen (81.8%) patients had bilateral disease. No intraoperative complications occurred. A red reflex was obtained in 28 (96.6%) eyes after surgery. Mean visual acuity improved from 2.5 +/- 0.3 to 1.8 +/- 0.6 in logMAR (p < 0.001). Vision improved in 21 (72.4%) eyes, remained stable in 5 (17.2%) eyes, and deteriorated in 3 (10.3%) eyes. Postoperatively visual acuity improved significantly in the patients with the bilateral disease (p < 0.05), but not in the unilateral group (p = 0.056). Mean follow-up time was 41.6 +/- 43.8 months. During the follow-up period, five (17.2%) eyes were diagnosed with glaucoma, two (6.9%) eyes underwent PK, one (3.4%) eye underwent an additional sector iridectomy, and one (3.4%) eye underwent keratoprosthesis. CONCLUSIONS: In this largest series published of optical iridectomy for Peters anomaly, it was found to be a safe procedure. Improvement in visual acuity is expected, particularly in bilateral cases. The utility of optical iridectomy in unilateral cases necessitates further studies. PMID- 29705839 TI - Stress and Systemic Inflammation: Yin-Yang Dynamics in Health and Diseases. AB - Studies in psychoneuroimmunology (PNI) would provide better insights into the "whole mind-body system." Systems biology models of the complex adaptive systems (CASs), such as a conceptual framework of "Yin-Yang dynamics," may be helpful for identifying systems-based biomarkers and targets for more effective prevention and treatment. The disturbances in the Yin-Yang dynamical balance may result in stress, inflammation, and various disorders including insomnia, Alzheimer's disease, obesity, diabetes, cardiovascular diseases, skin disorders, and cancer. At the molecular and cellular levels, the imbalances in the cytokine pathways, mitochondria networks, redox systems, and various signaling pathways may contribute to systemic inflammation. In the nervous system, Yin and Yang may represent the dynamical associations between the progressive and regressive processes in aging and neurodegenerative diseases. In response to the damages to the heart, the Yin-Yang dynamical balance between proinflammatory and anti inflammatory cytokine networks is crucial. The studies of cancer have revealed the importance of the Yin-Yang dynamics in the tumoricidal and tumorigenic activities of the immune system. Stress-induced neuroimmune imbalances are also essential in chronic skin disorders including atopic dermatitis and psoriasis. With the integrative framework, the restoration of the Yin-Yang dynamics can become the objective of dynamical systems medicine. PMID- 29705838 TI - Potential predictors for frequent relapse in human leukocyte antigen-B27 associated uveitis. AB - PURPOSE: To identify potential predictors for frequent relapse in a cohort of patients with human leukocyte antigen (HLA)-B27-associated uveitis in a tertiary referral center at the initial visit. METHODS: This retrospective cohort study comprised 130 patients diagnosed with HLA-B27-associated uveitis. Subjects were divided into two groups according to the frequency of uveitis attacks (number/year): frequent relapse (FR) (who relapsed more than twice a year, 38) and infrequent relapse (IR) group (who relapsed twice or less than twice a year, 92). RESULTS: The FR group presented more often with hypopyon or posterior synechiae at the initial presentation. Interestingly, posterior segment involvements including vitritis, vasculitis, or cystoid macular edema were not significantly different between the groups. In terms of laboratory findings, the erythrocyte sedimentation rate (ESR) was higher in the FR group. Multivariate Cox hazards analysis showed male sex, the presence of hypopyon, and ESR to be potential predictive factors for frequent relapse. CONCLUSION: We found that male sex, hypopyon at presentation, and high ESR are potential predictors for frequent relapse in HLA-B27-associated uveitis. Identifying patients at higher risk of relapse could provide important information for patients, allowing patients to understand their condition and increase their acceptance of strict management. PMID- 29705840 TI - Intersections Between Neuroimmune and Microbiota. AB - Multidiscipline-based research holds promise toward revealing complex mechanisms that determine health and disease. For decades, scientists have conducted studies defining the relationships between neuroendocrine and immune function culminating into the discipline of psychoneuroimmunology (PNI). In addition, the discipline of microbial endocrinology has similarly enhanced our understanding of disease processes. With an increase in genetic-based sequencing technologies, the convergence of neuroendocrine-immunological-microbial research is expected to significantly further such knowledge needed for medical discoveries. In this chapter, we provide a review of the current findings that support the conceptual framework linking microbiota, immunity, and neuroendocrine disciplines. PMID- 29705841 TI - Psychoneuroimmunology: The Experiential Dimension. AB - Accumulating evidence has made clear that experience-the knowledge an individual acquires during a lifetime of sensing and acting-is of fundamental biological relevance. Experience makes an impact on all adaptive systems, including the endocrine, immune, and nerve systems, and is of the essence, not only for the unfolding of an organisms' healthy status, but also for the development of malfunctional traits. Nevertheless, experience is often excluded from empirical approaches. A variety of complex interactions that influence life histories are thereby neglected. Such ignorance is especially detrimental for psychoneuroimmunology, the science that seeks to understand how the exquisite and dynamic interplay between mind, body, and environment relates to behavioral characteristics. This chapter reviews claims for incorporating experience as a member of good explanatory standing in biology and medicine, and more specifically claims that experiential knowledge is required to enable meaningful and relevant explanations and predictions in the psychoneuroimmunological realm. PMID- 29705842 TI - Ecological Context and Human Variation: Applying the Principles of Biological Anthropology to Psychoneuroimmunology. AB - There is considerable research interest overlap between biological anthropology and psychoneuroimmunology (PNI), particularly given recent anthropological interest in endocrine and immune system functioning over the life span and in different environmental contexts. In this chapter, I argue that conducting research on non-WEIRD populations and applying an anthropological, evolutionary approach to PNI can greatly strengthen our understanding of immune-endocrine behavior connections. This chapter reviews population-level variation in the human immune and endocrine systems, as well as genetic and environmental contributions to this variation. The effects of culture on shaping health outcomes and stress responses are also considered. Finally, this chapter discusses some noninvasive sampling methodologies appropriate to field research and alternatives to laboratory-based research designs. By confronting variable social and environmental contexts, PNI can greatly expand on its existing contributions to the treatment and understanding of depression, mood disorders, stress, and other aspects of health and well-being. PMID- 29705843 TI - Neuroimmune Imbalances and Yin-Yang Dynamics in Stress, Anxiety, and Depression. AB - Evidences from psychoneuroimmunology (PNI) and systems biology studies support a conceptual framework of "Yin-Yang dynamics" for understanding the "whole mind body system." The Yin-Yang dynamical balances in the stress response networks may be critical for health and diseases, especially mental health and psychiatric disorders. Specifically, the neuroimmune imbalances have been found as the important features and potential biomarkers of stress, anxiety, depression, and systemic inflammation. At the system levels, factors such as psychosocial stress and obesity, especially a leaky gut, may result in the imbalance between regulatory and proinflammatory T cells. At the molecular and cellular levels, the imbalances in multiple networks including the cytokine and redox pathways, immune kynurenine networks, HPA axis, and synaptic plasticity in the hypothalamus are the key factors in depression. The recognition of the neuroimmune imbalances and the restoration of the Yin-Yang dynamical balances need to become a high priority toward the development of dynamical systems medicine for psychiatric diseases including depression and schizophrenia. PMID- 29705844 TI - Increasing Resilience to Traumatic Stress: Understanding the Protective Role of Well-Being. AB - The brain maintains homeostasis in part through a network of feedback and feed forward mechanisms, where neurochemicals and immune markers act as mediators. Using a previously constructed model of biobehavioral feedback, we found that in addition to healthy equilibrium another stable regulatory program supported chronic depression and anxiety. Exploring mechanisms that might underlie the contributions of subjective well-being to improved therapeutic outcomes in depression, we iteratively screened 288 candidate feedback patterns linking well being to molecular signaling networks for those that maintained the original homeostatic regimes. Simulating stressful trigger events on each candidate network while maintaining high levels of subjective well-being isolated a specific feedback network where well-being was promoted by dopamine and acetylcholine, and itself promoted norepinephrine while inhibiting cortisol expression. This biobehavioral feedback mechanism was especially effective in reproducing well-being's clinically documented ability to promote resilience and protect against onset of depression and anxiety. PMID- 29705845 TI - Exploring the Diagnostic Potential of Immune Biomarker Co-expression in Gulf War Illness. AB - Complex disorders like Gulf War illness (GWI) often defy diagnosis on the basis of a single biomarker and may only be distinguishable by considering the co expression of multiple markers measured in response to a challenge. We demonstrate the practical application of such an approach using an example where blood was collected from 26 GWI, 13 healthy control subjects, and 9 unhealthy controls with chronic fatigue at three points during a graded exercise challenge. A 3-way multivariate projection model based on 12 markers of endocrine and immune function was constructed using a training set of n = 10 GWI and n = 11 healthy controls. These groups were separated almost completely on the basis of two co expression patterns. In a separate test set these same features allowed for discrimination of new GWI subjects (n = 16) from unhealthy (n = 9) and healthy control subjects with a sensitivity of 70% and a specificity of 90%. PMID- 29705846 TI - Breaking Away: The Role of Homeostatic Drive in Perpetuating Depression. AB - We propose that the complexity of regulatory interactions modulating brain neurochemistry and behavior is such that multiple stable responses may be supported, and that some of these alternate regulatory programs may play a role in perpetuating persistent psychological dysfunction. To explore this, we constructed a model network representing major neurotransmission and behavioral mechanisms reported in literature as discrete logic circuits. Connectivity and information flow through this biobehavioral circuitry supported two distinct and stable regulatory programs. One such program perpetuated a depressive state with a characteristic neurochemical signature including low serotonin. Further analysis suggested that small irregularities in glutamate levels may render this pathology more directly accessible. Computer simulations mimicking selective serotonin reuptake inhibitor (SSRI) therapy in the presence of everyday stressors predicted recidivism rates similar to those reported clinically and highlighted the potentially significant benefit of concurrent behavioral stress management therapy. PMID- 29705847 TI - Neuroimmune Mechanisms of Depression in Adults with Heart Failure. AB - Heart failure (HF) is a major and costly public health concern, and its prognosis is grim-with high hospitalization and mortality rates. HF affects millions of individuals across the world, and this condition is expected to become "the epidemic" of the twenty-first century (Jessup et al., 2016). It is well documented that individuals with HF experience disproportionately high rates of depression and that those who are depressed have worse clinical outcomes than their nondepressed counterparts. The purpose of this chapter is to introduce the reader to the study of depression in HF, and how psychoneuroimmunologic principles have been applied to further elucidate mechanisms (i.e., neurohormonal and cytokine activation) linking these comorbid disorders. PMID- 29705848 TI - How to Monitor the Neuroimmune Biological Response in Patients Affected by Immune Alteration-Related Systemic Diseases. AB - The clinical management of patients affected by systemic diseases, including cancer and autoimmune diseases, is generally founded on the evaluation of the only markers related to the single disease rather than the biological immuno inflammatory response of patients, despite the fundamental role of cytokine network in the pathogenesis of cancer and autoimmunity is well known. Cancer progression has appeared to be associated with a progressive decline in the blood levels of the main antitumor cytokines, including IL-2 and IL-12, in association with an increase in those of inflammatory cytokines, including IL-6, TNF-alpha, and IL-1-beta, and immunosuppressive cytokines, namely TGF-beta and IL-10. On the other hand, the severity of the autoimmune diseases has been proven to be greater in the presence of high blood levels of IL-17, TNF-alpha, IL-6, IL-1-beta, IFN gamma, and IL-18, in association with low levels of TGF-beta and IL-10. However, because of excessive cost and complexity of analyzing the data regarding the secretion of the single cytokines, the relation between lymphocyte-induced immune activation and monocyte-macrophage-mediated immunosuppression has been recently proven to be expressed by the simple lymphocyte-to-monocyte ratio (LMR). The evidence of low LMR values has appeared to correlate with a poor prognosis in cancer and with a disease control in the autoimmune diseases. Moreover, since the in vivo immunoinflammatory response is physiologically under a neuroendocrine modulation, for the evaluation of patient biological response it would be necessary to investigate the function of at least the two main neuroendocrine structures involved in the neuroendocrine modulation of the immune responses, consisting of the hypothalamic-pituitary-adrenal axis and the pineal gland, since the lack of physiological circadian rhythm of cortisol and pineal hormone melatonin has appeared to be associated with a worse prognosis in the human systemic diseases. PMID- 29705849 TI - Application of Chemogenetics and Optogenetics to Dissect Brain-Immune Interactions. AB - For many years, the complexity and multifactorial nature of brain-immune interactions limited our ability to dissect their underlying mechanisms. An especially challenging question was how the brain controls immunity, since the repertoire of techniques to control the brain's activity was extremely limited. New tools, such as optogenetics and chemogenetics (e.g., DREADDs), developed over the last decade, opened new frontiers in neuroscience with major implications for neuroimmunology. These tools enable mapping the causal effects of activating/attenuating defined neurons in the brain, on the immune system. Here, we present a detailed experimental protocol for the analysis of brain-immune interactions, based on chemogenetic or optogenetic manipulation of defined neuronal populations in the brain, and the subsequent analysis of immune cells. Such detailed and systematic dissection of brain-immune interactions has the potential to revolutionize our understanding of how mental and neurological states affect health and disease. PMID- 29705850 TI - Psychoneuroimmunology and Natural Killer Cells: The Chromium-Release Whole-Blood Assay. AB - Natural killer (NK) cells are an essential component of innate immunity. These lymphocytes are also sensitive barometers of the effects of endogenous and exogenous stressors on the immune system. This chapter describes a chromium (51Cr)-release bioassay designed to measure to the target cell killing capacity of NK cells (NKCC). Key features of the cytotoxicity assay are that it is done with whole blood and that numbers of effector cells are determined for each sample by flow cytometry and lymphocyte count. Effector cells are defined as CD3 CD56+ lymphocytes. Target cells are the K562 erythroleukemia cell line. Killing capacity is defined as number of target cells killed per effector cell, at an effector cell/target cell ratio of 1:1 during a 4-h in vitro assay. PMID- 29705851 TI - Mouse Testing Methods in Psychoneuroimmunology 2.0: Measuring Behavioral Responses. AB - The field of psychoneuroimmunology (PNI) aims to uncover the processes and consequences of nervous, immune, and endocrine system relationships. Behavior is a consequence of such interactions and manifests from a complex interweave of factors including immune-to-neural and neural-to-immune communication. Often the signaling molecules involved during a particular episode of neuroimmune activation are not known but behavioral response provides evidence that bioactives such as neurotransmitters and cytokines are perturbed. Immunobehavioral phenotyping is a first-line approach when examining the neuroimmune system and its reaction to immune stimulation or suppression. Behavioral response is significantly more sensitive than direct measurement of a single specific bioactive and can quickly and efficiently rule in or out relevance of a particular immune challenge or therapeutic to neuroimmunity. Classically, immunobehavioral research was focused on sickness symptoms related to bacterial infection but neuroimmune activation is now a recognized complication of diseases and disorders ranging from cancer to diabesity to Alzheimer's. Immunobehaviors include lethargy, loss of appetite, and disinterest in social activity/surrounding environment. In addition, neuroimmune activation can diminish physical activity, precipitate feelings of depression and anxiety, and impair cognitive and executive function. Provided is a detailed overview of behavioral tests frequently used to examine neuroimmune activation in mice with a special emphasis on pre-experimental conditions that can confound or prevent successful immunobehavioral experimentation. PMID- 29705852 TI - The MRL Model: A Valuable Tool in Studies of Autoimmunity-Brain Interactions. AB - The link between systemic autoimmunity, brain pathology, and aberrant behavior is still a largely unexplored field of biomedical science. Accumulating evidence points to causal relationships between immune factors, neurodegeneration, and neuropsychiatric manifestations. By documenting autoimmunity-associated neuronal degeneration and cytotoxicity of the cerebrospinal fluid from disease-affected subjects, the murine MRL model had shown high validity in revealing principal pathogenic circuits. In addition, unlike any other autoimmune strain, MRL mice produce antibodies commonly found in patients suffering from lupus and other autoimmune disorders. This review highlights importance of the MRL model as a useful preparation in understanding the links between immune system and brain function. PMID- 29705853 TI - PET Imaging in Psychoneuroimmunology Research. AB - Positron-emission tomography (PET) imaging is a valuable research tool that enables in vivo quantification of molecular targets in the brain or of a physiologic process. PET imaging can be combined with various experimental and clinical model systems that are commonly used in psychoneuroimmunology research. As PET imaging can be used in animals and humans, promising results can therefore often be translated from an animal model to human disease. PMID- 29705854 TI - The Vaccination Model in Psychoneuroimmunology Research: A Review. AB - This chapter explores the reasoning behind using the vaccination model to examine the influence of psychosocial factors on immunity. It then briefly discusses the mechanics of the vaccination response and the protocols used in psychoneuroimmunology vaccine research, before giving examples from the research literature of the studies examining relationships such as the association between stress and vaccination response. It also explores the ways the vaccination model can be used to answer key questions in psychoneuroimmunology, such as the following: "Does it matter when stressful life events occur relative to when the vaccine is received?" "What are the effects of prior exposure to the antigen?" "Do other psychosocial factors influence vaccine response besides stress?" Finally, it briefly considers the mechanisms underlying psychosocial factors and vaccination response associations and the future research needed to understand these better, and indeed to use current and future knowledge to improve and enhance vaccine responses in key at-risk populations. PMID- 29705855 TI - Measuring Vaccine Responses in the Multiplex Era. AB - Vaccine studies in psychoneuroimmunology (PNI) provide an insight into biopsychosocial interactions and their role in infectious diseases. How to measure vaccine responses is therefore of critical importance for PNI researchers. In this chapter, traditional and modern immunoassays for the assessment of vaccine responses are discussed, highlighting how modern multiplex techniques provide researchers with greater capacity and opportunity for novel research relating to vaccine outcomes. PMID- 29705856 TI - Sculpting the Sculptors: Methods for Studying the Fetal Cholinergic Signaling on Systems and Cellular Scales. AB - The non-neuronal, immunological effects of the cholinergic signaling are exerted on the system's scale of observation via the vagus nerve and on the cellular scale via alpha7 nicotinic acetylcholine receptor (nAChR) signaling in myeloid cells of the periphery or brain's microglia and astrocytes. The developmental effects of such multi-scale signaling can be conceived of as an example of psychoneuroimmunological (PNI) homeokinesis and, while reported in the literature, are not yet systematically well studied. To be better understood, the intricacy of the multi-scale interactions requires relevant preclinical animal models. Chronically instrumented non-anesthetized fetal sheep model comes with a strong track record of bench-to-bed translation and a large body of evidence for its strong resemblance to and relevance for human physiology on various scales of organization. Recently, there has been growing interest in pleiotropic effects of vagus nerve stimulation (VNS) on various organ systems such as innate immunity, metabolism, and emotion with implications for programming of PNI phenotype. Here we describe the procedures required to record and manipulate the vagus nerve activity in this large pregnant mammalian organism. Extending this in vivo model to in vitro, on the cellular scale, we present the method to manipulate the cholinergic signaling in ovine fetal microglia and astrocytes and analyze their responses on protein and RNA levels. Together these models can provide multi scale-level mechanistic insights into the effects of cholinergic signaling on PNI phenotype. PMID- 29705857 TI - Perinatal Psychoneuroimmunology: Protocols for the Study of Prenatal Stress and Its Effects on Fetal and Postnatal Brain Development. AB - Prenatal stress (PS) impacts early behavioral, neuroimmune, and cognitive development. Pregnant rat models have been very valuable in examining the mechanisms of such fetal programming. A newer pregnant sheep model of maternal stress offers the unique advantages of chronic in utero monitoring and manipulation. This chapter presents the techniques used to model single and multigenerational stress exposures and their pleiotropic effects on the offspring. PMID- 29705858 TI - Fluorometric aptasensing of the neonicotinoid insecticide acetamiprid by using multiple complementary strands and gold nanoparticles. AB - A fluorometric aptamer-based assay was developed for ultrasensitive and selective determination of the neonicotinoid insecticide acetamiprid. The method is based on the use of an aptamer against acetamiprid, multiple complementary strands (CSs), and gold nanoparticles (AuNPs). It is found that by using different CSs, the sensitivity and selectivity of the method is enhanced. On addition of acetamiprid to the aptamer, they will bind to each other and CS1-fluorescein (FAM)-labeled CS2 (as a dsDNA) will be formed. The FAM-labeled dsDNA does not bind to the AuNPs (as a strong quencher) and remains free in the environment, resulting in a strong fluorescence intensity. Without the introduction of acetamiprid, FAM-labeled CS2 binds to AuNPs directly and indirectly through hybridization with CS3 immobilized on the surface of the AuNPs. So, the fluorescence intensity of FAM-labeled CS2 is significantly quenched by AuNPs. The method can detect acetamiprid in the 5 to 50 nM concentration range with a 2.8 nM detection limit. The assay was applied to the determination of acetamiprid in spiked tap water where is gave recoveries that ranged between 95.4% and 94.4%. Graphical abstract (a) In the presence of acetamiprid, aptamer interacts with acetamiprid. The formation of aptamer/acetamiprid causes pairing of complementary strand 1 with FAM-labeled complementary strand, leading to a strong fluorescence intensity. (b) In the absence of acetamiprid, aptamer is hybridized with complementary strand 1. Thus, a very weak fluorescence signal is detected. PMID- 29705859 TI - The True Incidence of Gastric GIST: an Update. PMID- 29705862 TI - Cardiovascular Risk in Cancer Survivors. AB - PURPOSE OF REVIEW: As the number of cancer survivors continues to rise with improved early-detection methods and advancing therapies, along with it, there come adverse health outcomes as a result of physiological and psychological effects of cancer, as well as adverse effects of cancer treatment itself. This paper reviews the risk of cardiovascular disease in cancer survivors. RECENT FINDINGS: Cancer survivors are at higher risk of having modifiable cardiovascular (CV) risk factors, such as hypertension, diabetes mellitus, obesity, tobacco smoking, and physical inactivity. Cardiotoxicity is a well-established adverse effect of various anticancer regimens, which further elevates the cardiovascular risk in cancer patients. The increased risk of CVD and CVD-related death in cancer survivors is likely to be multifactorial, involving cardiotoxic effects of cancer treatments as well as comorbidities and harmful lifestyle habits. Targeting and managing known cardiac risk factors should be a main target in CVD prevention in cancer survivors. PMID- 29705861 TI - The prognostic role of E2A-PBX1 expression detected by real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) in B cell acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation. AB - The E2A-PBX1 rearrangement is common in B cell acute lymphoblastic leukemia (B ALL). However, whether this fusion gene can be used as a reliable marker for minimal residual disease (MRD) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains unknown. In this study, clinical data were collected from 28 consecutive B-ALL patients who received allo-HSCT. Their MRD was evaluated by E2A-PBX1 and leukemia-associated immunophenotype (LAIP). The median follow-up was 374 days (55-2342 days). Of the enrolled patients, seven (25%) patients died of leukemia relapse. A total of nine (32.1%) patients experienced relapse at a median of 164 days (75-559 days) after transplantation. The median expression level in the first positive sample was 0.14% (0.0071 902.4%). The duration from E2A-PBX1-positive results to hematological relapse was 74 days (30-469 days). E2A-PBX1 expression generally became positive prior to flow cytometry. Patients with positive E2A-PBX1 gene expression pre transplantation were more likely to have positive E2A-PBX1 expression after transplantation. Taken all together, E2A-PBX1 expression determined by real-time quantitative reverse transcriptase polymerase chain reaction (RQ-PCR) could be used to evaluate MRD status after allo-HSCT. Patients with positive E2A-PBX1 expression after transplant will have a poor prognosis. PMID- 29705860 TI - Bloodstream infections in haematological cancer patients colonized by multidrug resistant bacteria. AB - Infections by multidrug-resistant (MDR) bacteria are a worrisome phenomenon in hematological patients. Data on the incidence of MDR colonization and related bloodstream infections (BSIs) in haematological patients are scarce. A multicentric prospective observational study was planned in 18 haematological institutions during a 6-month period. All patients showing MDR rectal colonization as well as occurrence of BSI at admission were recorded. One-hundred forty-four patients with MDR colonization were observed (6.5% of 2226 admissions). Extended spectrum beta-lactamase (ESBL)-producing (ESBL-P) enterobacteria were observed in 64/144 patients, carbapenem-resistant (CR) Gram negative bacteria in 85/144 and vancomycin-resistant enterococci (VREs) in 9/144. Overall, 37 MDR-colonized patients (25.7%) developed at least one BSI; 23 of them (62.2%, 16% of the whole series) developed BSI by the same pathogen (MDRrel BSI), with a rate of 15.6% (10/64) for ESBL-P enterobacteria, 14.1% (12/85) for CR Gram negative bacteria and 11.1% (1/9) for VRE. In 20/23 cases, MDRrel BSI occurred during neutropenia. After a median follow-up of 80 days, 18 patients died (12.5%). The 3-month overall survival was significantly lower for patients colonized with CR Gram-negative bacteria (83.6%) and VRE (77.8%) in comparison with those colonized with ESBL-P enterobacteria (96.8%). CR-rel BSI and the presence of a urinary catheter were independent predictors of mortality. MDR rectal colonization occurs in 6.5% of haematological inpatients and predicts a 16% probability of MDRrel BSI, particularly during neutropenia, as well as a higher probability of unfavourable outcomes in CR-rel BSIs. Tailored empiric antibiotic treatment should be decided on the basis of colonization. PMID- 29705863 TI - A Sperm Spawn-Inducing Pheromone in the Silver Lip Pearl Oyster (Pinctada maxima). AB - Pheromones are considered to play an important role in broadcast spawning in aquatic animals, facilitating synchronous release of gametes. In oysters, the sperm has been implicated as a carrier for the spawn-inducing pheromone (SIP). In hatchery conditions, male pearl oysters (Pinctata maxima) can be stimulated to spawn through a variety of approaches (e.g. rapid temperature change), while females can only be induced to spawn through exposure to conspecific sperm, thus limiting development of targeted pairing, required for genetic research and management. The capacity for commercial production and improvement of genetic lines of pearl oysters could be greatly improved with access to a SIP. In this study, we prepared and sequenced crude and semi-purified P. maxima sperm extracts that were used in bioassays to localise the female SIP. We report that the P. maxima SIP is proteinaceous and extrinsically associated with the sperm membrane. Bioactivity from pooled RP-HPLC fractions, but not individual fractions, suggests that the SIP is multi-component. We conclude that crude sperm preparations, as described in this study, can be used as a sperm-free inducer of female P. maxima spawning, which enables for a more efficient approach to genetic breeding. PMID- 29705865 TI - Real-time, spectral analysis of the arterial pressure waveform using a wirelessly connected, tablet computer: a pilot study. AB - Spectral analysis of the arterial pressure waveform, using specialized hardware, has been used for the retrospective calculation of the 'Spectral Peak Ratio' (SPeR) of the respiratory and cardiac arterial spectral peaks. The metric can quantify the cardiovascular response to volume loading by analysing the effect of changing tidal volume (indexed to body weight) (VTI) on pulse pressure variability. In this pilot study, the feasibility of real-time SPeR calculation, using a mobile computer which was wirelessly connected to the patient monitor, was evaluated by examining the determinants of SPeR in 60 cardiac-surgical patients. In 30 patients undergoing aortic valve replacement (AVR), graded cyclical changes in ventricular loading were induced by increasing VTI over 2 min, while performing spectral analysis at 1 Hz, before and after AVR. A strong, linear correlation between SPeR and VTI was found and the slope of the regression line (beta) changed significantly after AVR. The change in beta correlated with the width of the preoperative vena contracta. In another 30 patients, SPeR at constant VTI was calculated at 1 Hz during passive leg raising. beta fell significantly on leg raising. The mean arterial pressure change during the manoeuvre was linearly related to the change in beta. Real-time spectral analysis of the arterial waveform was easily accomplished. The regression of SPeR on VTI was linear. beta appeared to represent the slope of the cardiac response curve at the venous return curve equilibrium point. Measurements were possible at a significantly lower VTI than the equivalent time domain metrics. PMID- 29705864 TI - Protection of Coral Larvae from Thermally Induced Oxidative Stress by Redox Nanoparticles. AB - Coral reefs are one of the most biologically diverse and economically important ecosystems on earth. However, the destruction of coral reefs has been reported worldwide owing to rising seawater temperature associated with global warming. In this study, we investigated the potential of a redox nanoparticle (RNPO) to scavenge reactive oxygen species (ROS), which are overproduced under heat stress and play a crucial role in causing coral mortality. When reef-building coral (Acropora tenuis) larvae, without algal symbionts, were exposed to thermal stress at 33 degrees C, RNPO treatment significantly increased the survival rate. Proteome analysis of coral larvae was performed using nano-liquid chromatography tandem mass spectrometry for the first time. The results revealed that several proteins related to ROS-induced oxidative stress were specifically identified in A. tenuis larvae without RNPO treatment, whereas these proteins were absent in RNPO-treated larvae, which suggested that RNPO effectively scavenged ROS from A. tenuis larvae. Results from this study indicate that RNPO treatment can reduce ROS in aposymbiotic coral larvae and would be a promising approach for protecting corals from thermal stress. PMID- 29705867 TI - Erratum to: Animal Cell Expression Systems. PMID- 29705866 TI - Outcomes with a latest generation self-expandable, intra-annular, re-sheathable transcatheter heart valve system: analysis of patients with impaired left ventricular function and determinants for pacemaker implantation. AB - OBJECTIVES: We herein report a single-center experience with the Portico TAVI system. Main focus was set on outcomes in patients with impaired left ventricular (LV) function and predictors for permanent pacemaker (PPM) implantation. METHODS: Between 05/2014 and 10/2017, 106 consecutive patients received TAVI using the Portico device. For comparison of patients with/without impaired LV function, and determination of multi-slice computed tomography and electrocardiogram correlates for PPM implantation subgroups were built (Subgroup I: LVEF >= 50%, n = 69, Subgroup II: LVEF < 50%, n = 37; Subgroup A: no PPM implantation, n = 89; Subgroup B: PPM implantation, n = 17). Data were retrospectively analyzed. RESULTS: Device success was 95.3% (101/106) with resulting transvalvular peak/mean pressure gradients of 10.6 +/- 5.6/5.4 +/- 3.1 and PVL >= moderate in 5/106 patients (4.7%). 30-day mortality was 4.7% (5/106; subgroup I 3/69, 4.3%; subgroup II 2/37, 5.4%; p = 1.0). Regarding VARC-2 adjudicated clinical endpoints stroke (3/106, 2.8%; subgroups I/II: 2/69 vs. 1/37, p = 1.0) and acute kidney injury (9/106, 8.5%; subgroups I/II: 6/69 vs. 3/37, p = 1.0), no significant differences were found. Postprocedural PPM implantation occurred in 17.9% (19/106) of the patients. Logistic regression for PPM implantation demonstrated predictive character of left coronary cusp (LCC) calcium load in zone 1 (annular plane to coronary ostia) (p = 0.05, threshold 193 mm3) and total calcium load of zone 1 (p = 0.05, threshold 751.2 mm3). CONCLUSIONS: The Portico valve demonstrates a satisfying safety outcome, especially for patients with impaired LV function. Results of the CE-mark trial were confirmed, except for higher PPM rates. PPM rates are in accordance with other reports on this TAVI platform. PMID- 29705868 TI - New Hope for Treatment of Duchene Dystrophy by Employing Dystrophin Expressing Chimeric Cells - Studies Published in Stem Cell Reviews and Reports. PMID- 29705869 TI - Safety, Tolerability, and Pharmacokinetics of Suvorexant: A Randomized Rising Dose Trial in Healthy Men. AB - BACKGROUND AND OBJECTIVES: Suvorexant (MK-4305) is an orexin receptor antagonist approved for the treatment of insomnia in the USA and other regions. This randomized, double-blind, placebo-controlled, sequential-panel, Phase 1 trial assessed the safety, tolerability, and pharmacokinetic data following single and multiple dosing of suvorexant in healthy men (aged 18-45 years). METHODS: Within allocated panels, subjects (n = 8) were randomized to receive nightly doses of suvorexant (10, 20, 40, 80, and 100 mg) administered orally for 14 days, or placebo. Safety assessments included daily adverse event (AE) monitoring; pharmacokinetic data were obtained through periodic sampling. RESULTS: Of 40 subjects randomized, 39 completed the trial. The incidence of any AEs in the 10 and 20 mg groups was 67 and 83%, respectively, while 100% of subjects reported AEs in the dose groups of 40, 80, and 100 mg and the placebo group. The most frequently reported AEs were somnolence (n = 19 subjects), fatigue (n = 17), and headache (n = 15). Following single and multiple dosing, median time to reach maximum observed concentration ranged from 1.5 to 4.0 h and the apparent terminal half-life ranged from 7.7 to 14.5 h. Across the investigated doses, accumulation ratios for the area under the concentration-time curve and the maximum observed concentration were independent of dose and ranged from 1.21 to 1.60 and 1.00 to 1.46, respectively. CONCLUSIONS: Suvorexant was generally well tolerated after single and multiple dosing for 14 days. The findings support the once-nightly dosing regimen. PMID- 29705870 TI - Animal models of steroid-induced osteonecrosis of the femoral head-a comprehensive research review up to 2018. AB - Osteonecrosis of the femoral head (ONFH) is a significant cause of both pain and disability that often affects young adults during what ought to be their most productive age. Two broad categories of ONFH exist: traumatic and non-traumatic. Traumatic ONFH results from acute mechanical disruption of the femoral head's blood supply. Many factors that increase the risk of non-traumatic osteonecrosis have been identified. Steroid-induced osteonecrosis of the femoral head (SONFH) is the most common form of non-traumatic ONFH. Many hypotheses as to the pathogenesis of SONFH have been proposed, including intravascular thrombosis, abnormal fat metabolism, intramedullary adipocyte hypertrophy, and osteoporosis; however, the exact mechanism of SONFH is still not clearly understood. Animal models using rats, mice, rabbits, chickens, pigs, and emus have been used to study SONFH. Unfortunately, these models each have limitations. Therefore, it is necessary to establish a reproducible model that better simulates human disease. The present review is intended to summarize the currently available models, evaluative indicators, and application of current understanding to both the prevention and treatment of SONFH. PMID- 29705871 TI - Mid-term results of concentrated autologous bone marrow aspirate transplantation for corticosteroid-associated osteonecrosis of the femoral head in systemic lupus erythematosus. AB - PURPOSE: We had previously established concentrated autologous bone marrow aspirate transplantation (CABMAT), a one-step, low-invasive, joint-preserving surgical technique for treating osteonecrosis of the femoral head (ONFH). This study aimed to evaluate the effects of CABMAT as a hip-preserving surgical approach, preventing conversion to total hip arthroplasty (THA) and femoral head collapse in patients with systemic lupus erythematosus (SLE). METHODS: Since 2003, 52 SLE patients (8 male, 44 female, 92 hips, mean age 35.3 (16-77) (years) were treated with CABMAT. The mean follow-up period was 5.5 (0.7-14) years. Conversion rate to THA and its predicting factors were analyzed. RESULTS: The overall conversion rate to THA was 29% (27/92). Conversion rate to THA was 0% (0/3), 0% (0/4), 22% (9/41), and 41% (18/44) in types A, B, C1, and C2, respectively. Conversion rate to THA was 26% (5/19), 26% (6/23), 28% (11/39), 44% (4/9), and 50% (1/2) in stages 1, 2, 3A, 3B, and 4, respectively. In multivariate logistic regression analysis, sex, body mass index (BMI), pre-operative type, and pre-operative stage were significantly correlated with conversion to THA. CONCLUSION: The conversion rate to THA was lower than that in the natural course and core decompression, but was higher than that seen in other bone marrow transplantation and osteotomy. Since sex, pre-operative type, and pre-operative stage were significantly correlated with conversion to THA, it is suggested that the higher proportion of women, advanced stage (stage 3A or above), and advanced type (type C or above) in this study affected the THA conversion rate. PMID- 29705873 TI - Association of TRIMCyp and TRIM5alpha from assam macaques leads to a functional trade-off between HIV-1 and N-MLV inhibition. AB - TRIM5alpha restricts retroviruses in a species-specific manner. Cyclophilin A was independently retrotransposed into the TRIM5 loci in different species, leading to the generation of antiviral TRIM5-cyclophilin A (TRIMCyp) proteins. Previously, we found that assam macaques express a TRIMCyp chimera (amTRIMCyp), along with a TRIM5alpha allelic protein (amTRIM5alpha). Herein, we investigated the antiviral activity of amTRIMCyp and amTRIM5alpha individually, as well as their interaction and joint effects. amTRIMCyp showed a divergent restriction pattern from amTRIM5alpha. Although both proteins potently restricted the replication of HIV-1, only amTRIM5alpha inhibited N-MLV. Remarkably, cellular anti-HIV-1 activity increased when amTRIMCyp and amTRIM5alpha were coexpressed, indicating a synergistic block of HIV-1 replication. Consistently, PMBCs from heterozygous amTRIM5alpha/TRIMCyp showed stronger resistance to HIV-1 infection than those from amTRIM5alpha/TRIM5alpha homozygotes. The anti-HIV-1 synergistic effect was dependent on the amTRIMCyp-amTRIM5alpha interaction. In contrast, amTRIMCyp completely abrogated the anti-N-MLV activity mediated by amTRIM5alpha, showing a dominant-negative effect, indicating that the generation of amTRIMCyp was involved in the trade-off between divergent restriction activities. Our results provide a new paradigm to study functional trade-offs mediated by allelic proteins, a theoretical basis for utilizing animal models with various TRIM5 alleles, as well as novel HIV-1 gene therapy strategies. PMID- 29705872 TI - Factors associated with falls in older adults with cancer: a validated model from the Cancer and Aging Research Group. AB - BACKGROUND: Falls in older adults with cancer are common, yet factors associated with fall-risk are not well-defined and may differ from the general geriatric population. This study aims to develop and validate a model of factors associated with prior falls among older adults with cancer. METHODS: In this cross-sectional secondary analysis, two cohorts of patients aged >= 65 with cancer were examined to develop and validate a model of factors associated with falls in the prior 6 months. Potential independent variables, including demographic and laboratory data and a geriatric assessment (encompassing comorbidities, functional status, physical performance, medications, and psychosocial status), were identified. A multivariate model was developed in the derivation cohort using an exhaustive modeling approach. The model selected for validation offered a low Akaike Information Criteria value and included dichotomized variables for ease of clinical use. This model was then applied in the validation cohort. RESULTS: The development cohort (N = 498) had a mean age of 73 (range 65-91). Nearly one-fifth (18.2%) reported a fall in the prior 6 months. The selected model comprised nine variables involving functional status, objective physical performance, depression, medications, and renal function. The AUC of the model was 0.72 (95% confidence intervals 0.65-0.78). In the validation cohort (N = 250), the prevalence of prior falls was 23.6%. The AUC of the model in the validation cohort was 0.62 (95% confidence intervals 0.51-0.71). CONCLUSION: In this study, we developed and validated a model of factors associated with prior falls in older adults with cancer. Future study is needed to examine the utility of such a model in prospectively predicting incident falls. PMID- 29705874 TI - Harnessing medical student power in global surgery research. PMID- 29705875 TI - Association between metabolic syndrome and osteoporosis in Taiwanese middle-aged and elderly participants. AB - : This study examined the association between metabolic syndrome and osteoporosis among middle-aged and elderly Taiwanese participants. After controlling for body mass index, age, liver and renal functions, and nutrition and exercise statuses, we found no significant association between MS and osteoporosis in either gender. PURPOSE: The term metabolic syndrome (MS) encompasses different abnormalities with independent effects on bone metabolism, which has led to inconsistencies in the association between MS and osteoporosis. This study evaluated this association among middle-aged and elderly Taiwanese participants by adjusting relevant covariates. METHODS: We enrolled 2007 participants (1045 men and 962 women) older than 50 years, who underwent a health examination at a preventive examination agency in urban Taiwan. We studied age, gender, diabetes mellitus and hypertension histories, smoking and exercise statuses, metabolic and nutrition indices, and liver and renal function profiles. We conducted multiple logistic regression analyses to examine the association between MS and osteoporosis by categorizing participants in terms of gender and body mass index (BMI). RESULTS: Overall, men with osteoporosis were less likely to have MS, and displayed fewer MS components than men without osteoporosis; but we found no significant associations between MS, or its components, and osteoporosis in women. After forming two groups according to BMI and adjusting for covariates, we found no association between MS and osteoporosis in any group. Multiple logistic regression analysis revealed that regular exercise had a negative association with osteoporosis in the low BMI group for men (OR, 0.365; p = 0.008). CONCLUSIONS: After BMI stratification and adjustments for age, nutrition status, liver and renal functions, and exercise status, we found no significant association between MS and osteoporosis in either gender. Regular exercise may prevent osteoporosis, particularly in men with a lean body mass. PMID- 29705876 TI - Comparative study of pulsed-continuous arterial spin labeling and dynamic susceptibility contrast imaging by histogram analysis in evaluation of glial tumors. AB - PURPOSE: Arterial spin labeling (ASL) is a non-invasive perfusion technique that may be an alternative to dynamic susceptibility contrast magnetic resonance imaging (DSC-MRI) for assessment of brain tumors. To our knowledge, there have been no reports on histogram analysis of ASL. The purpose of this study was to determine whether ASL is comparable with DSC-MRI in terms of differentiating high grade and low-grade gliomas by evaluating the histogram analysis of cerebral blood flow (CBF) in the entire tumor. METHODS: Thirty-four patients with pathologically proven glioma underwent ASL and DSC-MRI. High-signal areas on contrast-enhanced T1-weighted images or high-intensity areas on fluid-attenuated inversion recovery images were designated as the volumes of interest (VOIs). ASL CBF, DSC-CBF, and DSC-cerebral blood volume maps were constructed and co registered to the VOI. Perfusion histogram analyses of the whole VOI and statistical analyses were performed to compare the ASL and DSC images. RESULTS: There was no significant difference in the mean values for any of the histogram metrics in both of the low-grade gliomas (n = 15) and the high-grade gliomas (n = 19). Strong correlations were seen in the 75th percentile, mean, median, and standard deviation values between the ASL and DSC images. The area under the curve values tended to be greater for the DSC images than for the ASL images. CONCLUSIONS: DSC-MRI is superior to ASL for distinguishing high-grade from low grade glioma. ASL could be an alternative evaluation method when DSC-MRI cannot be used, e.g., in patients with renal failure, those in whom repeated examination is required, and in children. PMID- 29705877 TI - Experimental evaluation of infection, dissemination, and transmission rates for two West Nile virus strains in European Aedes japonicus under a fluctuating temperature regime. AB - West Nile virus (WNV) is continuously spreading in Eastern and Southern Europe. However, the extent of vector competence of Aedes japonicus (Theobald, 1901) is controversial. In this work, we elucidated the dynamics of virus growth in this invasive mosquito species. Females of Ae. japonicus were reared from eggs collected in the field in Switzerland and fed on bovine blood spiked with two WNV lineage 1 strains (FIN, Italy; NY99, USA). Fully engorged females were incubated for 14 days under a fluctuating temperature regime of 24 +/- 7 degrees C (average 24 degrees C), 45-90% relative humidity, which is realistic for a Central European mid-summer day. Infection, dissemination, and transmission rates were assessed from individual mosquitoes by analyzing the abdomen, legs and wings, and saliva for the presence of viral RNA. Saliva was also investigated for the presence of infectious virus particles. Overall, 302 females were exposed to WNV strain FIN and 293 to strain NY99. A higher infection rate was observed for NY99 (57.4%) compared to FIN (30.4%) (p = 0.003). There was no statistical evidence that the dissemination rate (viral RNA in legs and wings) was different between females infected with FIN (57.1%) compared to NY99 (35.5%) (p = 0.16). Viral RNA load of FIN compared to NY99 was significantly higher in the hemocoel (p = 0.031) of exposed females but not at other sites (legs and wings, saliva). This is the first study describing the vector competence parameters for two WNV strains in a European population of Ae. japonicus. The high dissemination and transmission rates for WNV under a realistic temperature regime in Ae. japonicus together with recent findings on its opportunistic feeding behavior (mammals and birds) indicate its potential role in WNV transmission in Central Europe where it is highly abundant. PMID- 29705878 TI - Comparative validation of amperometric and optical analyzers of dissolved oxygen: a case study. AB - A comprehensive comparative validation for two different types of dissolved oxygen (DO) analyzers, amperometric and optical, is presented on two representative commercial DO analyzers. A number of performance characteristics were evaluated including drift, intermediate precision, accuracy of temperature compensation, accuracy of reading (under different measurement conditions), linearity, flow dependence of the reading, repeatability (reading stability), and matrix effects of dissolved salts. The matrix effects on readings in real samples were evaluated by analyzing the dependence of the reading on salt concentration (at saturation concentration of DO). The analyzers were also assessed in DO measurements of a number of natural waters. The uncertainty contributions of the main influencing parameters were estimated under different experimental conditions. It was found that the uncertainties of results for both analyzers are quite similar but the contributions of the uncertainty sources are different. Our results imply that the optical analyzer might not be as robust as is commonly assumed; however, it has better reading stability, lower stirring speed dependence, and typically requires less maintenance. On the other hand, the amperometric analyzer has a faster response and wider linear range. Both analyzers seem to have issues with the accuracy of temperature compensation. The approach described in this work will be useful to practitioners carrying out DO measurements for ensuring reliability of their measurements. PMID- 29705879 TI - Tumor fragmentation estimated by volume surface ratio of tumors measured on 18F FDG PET/CT is an independent prognostic factor of diffuse large B-cell lymphoma. AB - INTRODUCTION: Our aim was to study the prognostic value of two new 18F-FDG PET biomarkers in diffuse large B-cell lymphoma (DLBCL). We examined the total tumor surface (TTS), describing the tumor-host interface, and the tumor volume surface ratio (TVSR), corresponding to the ratio between the total metabolic tumor volume (TMTV) and TTS, describing the tumor fragmentation. METHODS: We retrospectively included 215 patients with DLBCL. Patients underwent initial 18F-FDG PET/CT before R-CHOP (73%) or intensified R-CHOP (R-ACVBP) regimens (27%). The TMTV was measured using a fixed threshold value of 41% of SUVmax. To calculate TTS and TVSR, the surface was measured using an in-house software based on the marching cube algorithm. Spearman's rank correlation coefficient (rho) was computed between TMTV, TTS, and TVSR, and ROC analysis was performed. Survival functions at 5 years were studied using a Kaplan-Meier method and uni/multivariate Cox analysis. RESULTS: TVSR was poorly correlated with TMTV (rho = 0.5) and TTS (rho = 0.26), while TTS was highly correlated with TMTV (rho = 0.94) and was, therefore, excluded from the analysis. TMTV had the highest area under the ROC curve (0.711) and the best sensitivity (0.797), while TVSR had the best specificity (0.745). The optimal cut-off values to predict 5-year OS were 222 cm3 for TMTV and 6.0 mm for TVSR. Patients with high TMTV and TVSR had significantly worse prognosis in Kaplan-Meier and Cox univariate analysis. In a multivariate Cox analysis combining the International Prognostic Index (IPI), the type of chemotherapy, TMTV, and TVSR, all parameters were independent and significant prognostic factors (HR [95%CI]: IPI 1.4 [1.1-1.8], type of chemotherapy 4.5 [2.0 10.5], TMTV 2.8 [1.4-5.5], TVSR 2.1 [1.3-3.4]). A synergistic effect between TMTV and TVSR was observed in a Kaplan-Meier analysis combining the two parameters. CONCLUSIONS: TVSR measured on the initial 18F-FDG PET is an independent prognostic factor in DLBCL and has an additional prognostic value when combined with TMTV, IPI score and chemotherapy. PMID- 29705880 TI - The Effect of Psychosocial Interventions on Outcomes for Caregivers of Hematopoietic Cell Transplant Patients. AB - PURPOSE OF REVIEW: Hematopoietic cell transplant (HCT) patients are required to have a caregiver present for up to 100 days post-transplant. Caregivers provide essential support during HCT but experience immense stress and burden. Increasing research has developed interventions for HCT caregivers. This review systematically evaluates psychosocial interventions for caregivers of HCT patients. RECENT FINDINGS: The search yielded 12 studies (7 efficacy and 5 feasibility studies) enrolling 931 caregivers. Interventions were feasible and acceptable as evidenced by high rates of completion (70-100%) with attrition due to patient morbidity or mortality. Feasibility was augmented by flexible delivery (in-person, teleconference, smartphones, or Web-based platforms). Acceptability was demonstrated by objective measures of satisfaction. Effectiveness was found for fatigue and mental health service use, but not for burden, sleep-quality, and inconsistently for caregiver depression, anxiety, coping, and quality of life. Psychosocial interventions are feasible, acceptable, and show mixed effects on HCT caregiver outcomes. PMID- 29705881 TI - Age and gender differences in the prevalence and correlates of vitamin D deficiency. AB - : Younger adults and males had a higher prevalence of vitamin D deficiency compared to older participants and females. Low intake of milk, central obesity, and lack of use of vitamin D supplements were associated with vitamin D deficiency, highlighting potentially important avenues for preventive intervention. BACKGROUND: Vitamin D deficiency is a public health concern. This study's objective was to measure the prevalence of vitamin D deficiency and determine its correlates among Saudi adults in Riyadh, Saudi Arabia. METHODS: A cross-sectional study was conducted with 2835 Saudi males and females aged 30-75 years in 18 different primary health care centers (PHCC) in Riyadh. Detailed interviews on sociodemographic and lifestyle factors and anthropometric measurements were conducted. Serum calcium, phosphorus, parathyroid, alkaline phosphatase, and 25(OH) vitamin D were measured. Multiple logistic regression analyses were conducted. RESULTS: The mean age (SD) of male and female participants was 43.0 (+/- 11.7) and 42.8 (+/- 10.3) years, respectively. Serum 25(OH) vitamin D assays for participants revealed that 72.0% (n = 695) of males and 64.0% (n = 1191) of females had levels < 50 nmol/L (deficiency), whereas 17.3% (n = 166) and 19.4% (n = 362), respectively, had levels of 50-75 nmol/L (insufficiency). Multivariate analyses for males revealed that lack of use of vitamin D supplements [adjusted odds ratio (aOR) = 4.0, 95% CI 1.7, 9.4], younger age [30-40 years aOR = 3.6, 95% CI 1.7, 7.3 and 41-50 years aOR = 4.2, 95% CI 2.0, 8.8], low milk intake [aOR = 1.7, 95% CI 1.0, 2.8], consumption of cola drinks [aOR = 2.0, 95% CI 1.1, 3.9], and central obesity [aOR = 1.8, 95% CI 1.0, 3.4] were associated with low vitamin D. In females, lack of use of vitamin D supplements [aOR = 3.7, 95% CI 2.8, 4.9], younger age [30-40 years aOR = 3.4, 95% CI 2.0, 5.8 and 41-50 years aOR = 2.8, 95% CI 1.6, 4.7], central obesity [aOR = 1.4, 95% CI 1.0, 2.2], and seasonal variation [aOR = 1.6, 95% CI 1.3, 2.1] had higher odds for vitamin D deficiency. Significantly lower levels were observed for men than women for mean serum 25(OH) vitamin D [42.6 (+/- 24.1) vs. 46.8 (+/- 30.5)], parathyroid hormone [5.3 (+/- 2.9) vs. 5.9 (+/- 2.7)], and phosphorus [1.1 (+/- 0.2) vs. 1.2 (+/- 0.2)], respectively; alkaline phosphatase levels [106 (+/- 32.8) vs. 99 (+/- 27.8)] [p < 0.01] were significantly higher in males than females. CONCLUSION: Vitamin D deficiency was highly prevalent, particularly among young adults and those with central obesity. Proper fortification policy, health education, and regular screening PHCCs may help prevent and treat vitamin D deficiency. PMID- 29705882 TI - Severe peritoneal sclerosis after repeated pressurized intraperitoneal aerosol chemotherapy with oxaliplatin (PIPAC OX): report of two cases and literature survey. AB - Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is a new laparoscopic administration of chemotherapy for peritoneal metastasis (PM). PIPAC is repeated every 5th week, and seems to stabilize or improve quality of life, and might improve survival. So far, PIPAC has been well tolerated. With this paper, we aim to highlight a potential severe adverse reaction, as we describe the first cases of severe peritoneal sclerosis (SPS) caused by PIPAC. Patients with isolated PM were included in a prospective PIPAC protocol. Following insufflation of normothermic CO2, laparoscopy was performed at an intraabdominal pressure of 12 mmHg. After peritoneal lavage and quadrant biopsies of the PM, the patients were treated with oxaliplatin 92 mg/m2 (flowrate 0.5 ml/s, maximum pressure of 200 per square inch). Treatment related toxicity was evaluated after 2 weeks. Response was evaluated histologically by the Peritoneal Regression Grading Score (PRGS) and cytologically by analysis of the lavage fluid. In a series of 24 PIPAC patients treated with oxaliplatin, two patients developed SPS. Patient one had a mucinous adenocarcinoma of the appendix with PM, the mean PRGS was reduced from 2.75 to 1.75 during the course of therapy. Patient two had an appendiceal goblet cell carcinoid with a dominating mucinous adenocarcinoma component with PM, the mean PRGS was reduced from 2.00 to 1.67. Repeated applications of PIPAC with oxaliplatin can lead to SPS. PMID- 29705883 TI - Systematic Review of Physical Education-Based Physical Activity Interventions Among Elementary School Children. AB - Physical education (PE)-based interventions are a popular method to target children's physical activity (PA) and fitness; however, little is known about their effectiveness or what factors lead to successful interventions. This paper: (1) systematically reviews studies examining PE interventions designed to impact PA, fitness, and/or body composition; and (2) makes recommendations for new research directions based upon these findings. Our systematic review was limited to experimental and quasi-experimental studies conducted in elementary schools. We conducted literature searches using predetermined keywords in 3 databases, identified a total of 4964 potentially relevant studies, and screened their abstracts and full texts for eligibility. This resulted in 12 relevant studies. We used criteria established by Downs and Black (1998) to assess each study's methodological quality. PE interventions consistently showed increases in moderate-to-vigorous PA or vigorous PA during PE class but were less consistent in impacting leisure-time PA. PE interventions affected body composition differentially, depending on the assessment used (i.e., body mass index or skinfold thickness). Half of the studies assessing fitness did not show a significant impact; however, those that did were designed to influence fitness outcomes. Few studies assessed psychosocial determinants regarding PA, and no study demonstrated significant impacts on constructs other than knowledge. Interventions often contained multiple components (e.g., diet, family) implemented alongside PE interventions. Identifying effective intervention components was difficult due to lack of process evaluation. We identify the need for future research to use more objective and accurate PA measurements and adiposity, incorporate measurement of psychological constructs, expand interventions' theoretical basis, and include strong process evaluation. PMID- 29705884 TI - Building predictive in vitro pulmonary toxicity assays using high-throughput imaging and artificial intelligence. AB - Human lungs are susceptible to the toxicity induced by soluble xenobiotics. However, the direct cellular effects of many pulmonotoxic chemicals are not always clear, and thus, a general in vitro assay for testing pulmonotoxicity applicable to a wide variety of chemicals is not currently available. Here, we report a study that uses high-throughput imaging and artificial intelligence to build an in vitro pulmonotoxicity assay by automatically comparing and selecting human lung-cell lines and their associated quantitative phenotypic features most predictive of in vivo pulmonotoxicity. This approach is called "High-throughput In vitro Phenotypic Profiling for Toxicity Prediction" (HIPPTox). We found that the resulting assay based on two phenotypic features of a human bronchial epithelial cell line, BEAS-2B, can accurately classify 33 reference chemicals with human pulmonotoxicity information (88.8% balance accuracy, 84.6% sensitivity, and 93.0% specificity). In comparison, the predictivity of a standard cell-viability assay on the same set of chemicals is much lower (77.1% balanced accuracy, 84.6% sensitivity, and 69.5% specificity). We also used the assay to evaluate 17 additional test chemicals with unknown/unclear human pulmonotoxicity, and experimentally confirmed that many of the pulmonotoxic reference and predicted-positive test chemicals induce DNA strand breaks and/or activation of the DNA-damage response (DDR) pathway. Therefore, HIPPTox helps us to uncover these common modes-of-action of pulmonotoxic chemicals. HIPPTox may also be applied to other cell types or models, and accelerate the development of predictive in vitro assays for other cell-type- or organ-specific toxicities. PMID- 29705885 TI - Round atelectasis: PET/CT findings. PMID- 29705886 TI - Media messaging in diagnosis of acute CXR pathology: an interobserver study among residents. AB - The objectives of the study were to determine whether diagnostic accuracy and reliability by on-call teams is affected by communicating chest radiograph (CXR) images via instant messaging on smartphones in comparison to viewing on a workstation. 12 residents viewed 100 CXR images each with a 24% positive rate for significant or acute findings sent to their phones via a popular instant messaging application and reported their findings if any. After an interval of 42 days they viewed the original DICOM images on personal computers and again reported their findings. There were no statistically significant differences in accuracy, agreement, sensitivity, specificity, positive predictive value or negative predictive value between desktop workstation viewed images and images sent via the mobile application. Media messaging is a useful adjunct for quick second opinions on radiological images, without significant decay in diagnostic accuracy. If technical, ethical and legal issues are addressed, it could be incorporated into practice as a useful adjunct. PMID- 29705887 TI - Analysis of the high incidence of acute kidney injury associated with acute-on chronic liver failure. AB - BACKGROUND: To investigate the incidence, risk, and prognostic factors of acute kidney injury (AKI) in acute-on-chronic liver failure (ACLF) patients. METHODS: A total of 188 patients were prospectively included and divided into AKI and non AKI groups. Patients were followed at 1, 3, 7, 14, 28, 60, and 90 days after the onset of AKI. Significant risk factors were screened by univariate and Cox multivariate survival analyses to confirm the independent risk factors for 30- or 90-day mortality and the 90-day renal function recovery rate. RESULTS: A total of 98 AKI cases (52.1%, [95% CI 44.9-59.3%]) occurred and the risk factors for AKI development in ACLF patients were age > 50 years (p = 0.009) and albumin (Alb) levels < 32 g/L (p = 0.007). The 30- and 90-day mortalities were significantly higher in the AKI than in the non-AKI group (79.6 vs 41.1%, 82.7 vs 56.7%, p < 0.05). AKI highest staging occurring within < 4 days of its onset and spontaneous peritonitis as well as MELD scores > 27 were independent risk factors for 30- and 90-day mortalities of ACLF AKI patients. AKI stage 3 and age > 52 years were independent risk factors for non-renal function recovery in ACLF patients with AKI. CONCLUSIONS: ACLF patients had a high incidence of AKI, which correlated with 30- and 90-day mortalities. PMID- 29705888 TI - A physical exercise program using music-supported video-based training in older adults in nursing homes suffering from dementia: a feasibility study. AB - BACKGROUND: Motivation towards an exercise program is higher in a small group setting in comparison to individual therapy. Due to attentional problems, group exercises are difficult for people with Alzheimer disease (AD). This study evaluates the feasibility of a music-supported video-based group exercise program in older adults suffering from AD. METHODS: Five participants with moderate AD were recruited from a nursing home. A progressive physical exercise program using a video-based training with musical accompaniment was performed and digitally recorded to investigate the adherence and performed accuracy of the exercises. RESULTS: The overall participation during the exercises was 84.1%. The quality of the performance was for all exercises above the cut-off scores. CONCLUSION: A music-supported video-based group exercise program is feasible in persons with AD. The participants were motivated and the expectations towards the program increased over time. Music seemed an important factor for attention in participants with AD. PMID- 29705889 TI - Ultrasensitive colorimetric determination of silver(I) based on the peroxidase mimicking activity of a hybrid material composed of graphitic carbon nitride and platinum nanoparticles. AB - A hybrid material composed of graphitic carbon nitride (g-C3N4) and platinum nanoparticles (PtNPs) with peroxidase mimicking activity was used to design a rapid, sensitive and low-cost colorimetric method for the determination of Ag(I). The g-C3N4-PtNPs hybrid was synthesized by reduction of chloroplatinic acid using sodium borohydride under ultrasonication and in the presence of g-C3N4. The hybrid can catalyze the oxidation 3,3',5,5'-tetramethylbenzidine (TMB) to produce a blue-colored product with an absorption maximum at 652 nm. On addition of Ag(I) and in the presence of citric acid, it will be reduced to form Ag(0) under the catalytic action of PtNPs. Ag(0) is then adsorbed on the surface of the g-C3N4 PtNPs. This results in the inhibition of the enzyme mimetic activity of the hybrid. Hence, less blue product will be formed from TMB. Under optimum conditions, Ag(I) can be quantified in the 0.05-5.0 nM concentration range with a 22 pM detection limit. This assay is rapid and reliable and was applied to the determination of Ag(I) in spiked real water samples. Graphical abstract A hybrid nanomaterial consisting of graphitic carbon nitride and platinum nanoparticles (g C3N4-PtNPs) can catalyze the oxidation of tetramethylbenzidine (TMB) to produce a blue-colored product (TMBox). The enzyme mimetic activity of the hybrid is inhibited by Ag+, thereby decreasing the generation of blue product from TMB. PMID- 29705890 TI - Selective Formation of Ser-His Dipeptide via Phosphorus Activation. AB - The Ser-His dipeptide is the shortest active peptide. This dipeptide not only hydrolyzes proteins and DNA but also catalyzes the formation of peptides and phosphodiester bonds. As a potential candidate for the prototype of modern hydrolase, Ser-His has attracted increasing attention. To explore if Ser-His could be obtained efficiently in the prebiotic condition, we investigated the reactions of N-DIPP-Ser with His or other amino acids in an aqueous system. We observed that N-DIPP-Ser incubated with His can form Ser-His more efficiently than with other amino acids. A synergistic effect involving the two side chains of Ser and His is presumed to be the critical factor for the selectivity of this specific peptide formation. PMID- 29705891 TI - Keratomycosis due to Tintelnotia destructans refractory to common therapy treated successfully with systemic and local terbinafine in combination with polyhexamethylene biguanide. AB - PURPOSE: To report on a wearer of rigid gas-permeable contact lenses with a keratomycosis due to Tintelnotia-a new genus of Phaeosphaeriaceae-treated with terbinafine and polyhexamethylene biguanide. METHODS: Chart review of a patient with fungal keratitis treated additionally with systemic and topical terbinafine 0.25% after symptoms increased under conventional antimycotic therapy with voriconazole. Antifungal susceptibility had been tested in vitro. RESULTS: After starting an additional treatment with systemic and topical terbinafine, the severe corneal infection was sufficiently resolved. The drug was well tolerated without any neurological, dermatological or gastroenterological problems. Terbinafine revealed a marked in vitro antifungal activity of 0.12 ug/ml. The fungus was identified as Tintelnotia destructans. CONCLUSIONS: Terbinafine might be considered as a therapeutic option in severe cases of fungal keratitis refractory to common antifungal therapy. PMID- 29705892 TI - The ophthalmic diagnosis and management of four siblings with Werner syndrome. AB - INTRODUCTION: Werner syndrome is a rare autosomal recessive disorder caused by mutations in the Werner syndrome WRN gene, on chromosome 8. Those affected manifest early the features of ageing. DISCUSSION: Cataract surgery is prone to post-operative complications in those with Werner syndrome. The development of cystoid macular oedema (CMO) is likely multifactorial. Patients with WS have diabetes mellitus type 2 which can contribute to macular oedema. There is a deposition of abnormal WRN proteins in the macula which also predisposes to macular oedema. The trauma of cataract surgery appears to be the main stimulus for the development of CMO. CMO may, as a result, be difficult to manage in Werner syndrome patients. CONCLUSION: Further study is needed to elucidate the precise role of retinal WRN protein expression in the development of CMO in those with Werner syndrome. A tailored and more successful approach to the treatment of CMO in such patients may result. PMID- 29705893 TI - A study of changes in levator muscle in congenital ptosis. AB - PURPOSE: To study microscopic and ultrastructural changes of levator palpebrae superioris (LPS) muscle in congenital ptosis. METHODS: In this prospective observational study, LPS muscle was studied in 77 eyelids with congenital ptosis; 35-simple congenital ptosis (SCP), 12-Marcus Gunn jaw winking phenomenon (MGJWP), and 30-blepharophimosis epicanthus inversus syndrome (BPES). Light microscopy, enzyme histochemistry, immunohistochemistry and electron microscopy were performed, and results were analyzed. RESULTS: Muscle fibers were detected in 83.33% of MGJWP, 22.86% of SCP and 16.67% of BPES eyelids. Fibers were detected significantly more in individuals with moderate ptosis, LPS action > 4 mm, present eyelid crease and eyelid fold. Severe endomysial and perimysial fibrosis was seen significantly more in individuals with MGJWP. Fat infiltration and nuclei internalization were seen in all three groups. The absence of degenerating or regenerating fibers and inflammatory cells, normal staining pattern on immunohistochemistry and absence of accumulation of any abnormal substance were found in all three groups. Abnormal mitochondrial staining pattern was seen occasionally in three groups. On electron microscopy, muscle was detected in 1 SCP eyelid and 8 MGJWP eyelids out of which 4 had myofibrillary disruption. All other eyelids where muscle fibers were not detected had only fibrocollagenous tissue. CONCLUSION: Fibrocollagenous tissue predominated in all the cases, and muscle fibers detected correlated inversely with the severity of ptosis. The absence of degenerating, regenerating fibers and inflammatory cells supported the theory of dysgenesis of muscle. However, internalization of nucleus seen in all the subtypes is a feature favoring dystrophy. PMID- 29705895 TI - Correction to: Assessment of Lemna minor (duckweed) and Corbicula fluminea (freshwater clam) as potential indicators of contaminated aquatic ecosystems: responses to presence of psychoactive drug mixtures. AB - The correct presentation of the Author names are shown in this paper. PMID- 29705894 TI - Quality of Life in Patients with Non-melanoma Skin Cancer: Implications for Healthcare Education Services and Supports. AB - Non-melanoma skin cancer (NMSC) is the most prevalent type of cancer among Caucasian populations worldwide. The purpose of this work was to measure quality of life (QOL) of the patients with diagnosis of basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) who were referred to our cancer clinic. During 1 year, 95 patients were selected and asked to complete Dermatology Life Quality Index (DLQI) questionnaires. Ninety-five patients with NMSC (74 men and 21 women) with mean age of 64.6 +/- 12.5 participated in this cross-sectional study. From 95 patients, 75 had BCC, 15 had SCC, and 5 patients had both SCC and BCC. The total DLQI scores of the all participants were between 0 and 16; the mean was 4.1 +/- 4.25 and median was 2. Variables which were associated with impaired QOL were marital status (P = 0.03) and tumor location (P = 0.02). By using general dermatology QOL questionnaire, it had been demonstrated that patients with NMSC faced with minimal QOL impairment; also, this handicap was more pronounced in younger patients and singles and patients with tumors located in exposed areas. Our findings demonstrated a need to educate our patients to improve patients' knowledge about different aspects of disease. PMID- 29705896 TI - Degradation of polycyclic aromatic hydrocarbons (PAHs) during Sphagnum litters decay. AB - The dynamics of polycyclic aromatic hydrocarbon (PAH) degradation in Sphagnum litters and the decomposition of the litters were investigated. PAH concentration decreased to approximately half of the initial concentration as Sphagnum litters decayed. The initial PAH concentration was 489.2 +/- 72.2 ng g-1, and the concentration after 120 days of incubation was 233.0 +/- 5.8 ng g-1. The different PAH compositions changed concentrations at different times. The low molecular-weight (LMW) and high-molecular-weight (HMW) PAHs started to be degraded after incubation and after 40 days of incubation, respectively. PAH concentrations in the Sphagnum litters correlated with the total organic carbon (TOC) content (p < 0.05), indicating that PAHs were associated with the TOC of the Sphagnum litters and were degraded as organic matter decayed. The positive relationship between LMW PAH concentration and the soluble carbohydrate content (p < 0.05) indicated that LMW PAHs and the readily decomposed organic carbon fractions were cometabolized, or that LMW PAHs were mainly absorbed by soluble carbohydrate. The weak negative correlation between fulvic acid (FA) and PAH concentrations (p < 0.1) indicated that FA may enhance PAH degradation. Redundancy analysis suggested that the contents of both soluble carbohydrate and cellulose significantly affected the changes in PAH concentrations (p < 0.05), and that FA content and C/N ratios may also contribute to the changes in PAH concentrations (p < 0.1). However, the polyphenol that was related to microbial activities was not associated with changes in PAH concentrations. These results suggested that litter quality is more important than microbial activities in PAH degradation in Sphagnum litters. PMID- 29705897 TI - The nexus between energy consumption and financial development: estimating the role of globalization in Next-11 countries. AB - In the modern era of globalization, the economic activities expand with the passage of time. This expansion may increase demand for energy both in developing and developed countries. Therefore, this study assesses the impact of financial development on energy consumption incorporating the role of globalization in Next 11 countries. A group of panel estimation techniques is used to analyze the panel data and time series data for the time 1990-2014. The empirical results of the study suggest that financial development stimulates energy consumption. Also, globalization increases demand for energy consumption, although the single country analysis suggests that the effect of globalization on energy demand is heterogeneous among N-11 countries. Furthermore, feedback hypothesis is confirmed between financial development and energy consumption. Also, bidirectional causality is found between economic growth and energy consumption. The findings urge for the attention of policymaker in emerging countries to develop a strategy to reduce the consequences of energy consumption by controlling resource transfer through globalization to the host country and by adopting energy conversation policies. PMID- 29705898 TI - Ammonia production in poultry houses can affect health of humans, birds, and the environment-techniques for its reduction during poultry production. AB - Due to greater consumption of poultry products and an increase in exports, more poultry houses will be needed. Therefore, it is important to investigate ways that poultry facilities can coexist in close proximity to residential areas without odors and environmental challenges. Ammonia (NH3) is the greatest concern for environmental pollution from poultry production. When birds consume protein, they produce uric acid, ultimately converted to NH3 under favorable conditions. Factors that increase production include pH, temperature, moisture content, litter type, bird age, manure age, relative humidity, and ventilation rate (VR). NH3 concentration and emissions in poultry houses depend on VR; seasons also have effects on NH3 production. Modern ventilation systems can minimize NH3 in enclosed production spaces quickly but increase its emissions to the environment. NH3 adversely affects the ecosystem, environment, and health of birds and people. Less than 10 ppm is the ideal limit for exposure, but up to 25 ppm is also not harmful. NH3 can be minimized by housing type, aerobic and anaerobic conditions, manure handling practices, litter amendment, and diet manipulation without affecting performance and production. Antibiotics can minimize NH3, but consumers have concerns about health effects. Administration of probiotics seems to be a useful replacement for antibiotics. More studies have been conducted on broilers, necessitating the need to evaluate the effect of probiotics on NH3 production in conjunction with laying hen performance and egg quality. This comprehensive review focuses on research from 1950 to 2018. PMID- 29705900 TI - Heavy metal availability, bioaccessibility, and leachability in contaminated soil: effects of pig manure and earthworms. AB - A pot experiment and a leaching experiment were conducted to investigate the effects of earthworms and pig manure on heavy metals (Cd, Pb, and Zn) immobility, in vitro bioaccessibility and leachability under simulated acid rain (SAR). Results showed manure significantly increased soil organic carbon (SOC), dissolved organic carbon (DOC), available phosphorus (AP), total N, total P and pH, and decreased CaCl2-extractable metals and total heavy metals in water and SAR leachate. The addition of earthworms significantly increased AP (from 0.38 to 1.7 mg kg-1), and a downward trend in CaCl2-extractable and total leaching loss of heavy metals were observed. The combined earthworm and manure treatment decreased CaCl2-extractable Zn, Cd, and Pb. For Na4P2O7-extractable metals, Cd and Pb were decreased with increasing manure application rate. Application of earthworm alone did not contribute to the remediation of heavy metal polluted soils. Considering the effects on heavy metal immobilization and cost, the application of 6% manure was an alternative approach for treating contaminated soils. These findings provide valuable information for risk management during immobilization of heavy metals in contaminated soils. PMID- 29705901 TI - An approach for phycoremediation of different wastewaters and biodiesel production using microalgae. AB - Four microalgal strains, namely, Tetraselmis indica (T. indica), Scenedesmus abundans (S. abundans), Spirulina sp., and Nostoc muscorum (N. muscorum) were cultivated on four different wastewaters in 1000 ml photobioreactors with 750 ml working volume under 94.5 MUmol m-2 s-1 light intensity for 14 days for phycoremediation of wastewaters and sustainable biodiesel production. These microalgal strains attained maximum biomass growth in the secondary treated sewage (STS). Maximum biomass yield (0.6533 g L-1) and lipid productivity (25.44 mg L-1 d-1) for T. indica were achieved in STS. T. indica removed (63.6-78.24%) of nitrate, (60.90-65.97%) of phosphate, (61.01-80.01%) of ammonical nitrogen, and (71.16-85.70%) of total organic carbon (TOC) in all four wastewaters. The fatty acid methyl ester (FAME) profile of T. indica shows the presence of myristic acid (1.2%) pentadecylic acid (0.28%), palmitic acid (10.32%), oleic acid (34.59%), linoleic acid (12.38%), and eicosanoic acid (14.88%) in STS. This study demonstrates that T. indica is the most suitable microalgal species among the four microalgal strains selected for phycoremediation of wastewaters and higher biomass production for sustainable biodiesel production. PMID- 29705899 TI - Interplay between elemental imbalance-related PI3K/Akt/mTOR-regulated apoptosis and autophagy in arsenic (III)-induced jejunum toxicity of chicken. AB - Arsenic trioxide (As2O3), the most toxic form of arsenic found in foodstuffs, is considered a carcinogen for human and animal. But many of the events that occur during its passage through the gastrointestinal tract are uncharted in birds. This study assesses the toxic effect on the jejunum of chicken which subchronically exposed to diets that contain As2O3 (0, 0.625, 1.25, 2.5 mg/kg body weight) for 90 days. Electron microscopy, TdT-mediated dUTP nick-end labeling (TUNEL), qPCR, and Western blot were performed. The results showed that mitochondrial fusion and apoptosis inhibiting genes had degressive trends, whereas mitochondrial fission and apoptosis activating genes presented heightened expressions in the treatment group compared with the control (P < 0.05). Subsequently, significant inhibition in PI3K/AKT/mTOR signaling was observed. Moreover, the expression of autophagy markers (LC3-II/LC3-I, Beclin-1) increased time and dose-dependently. Additionally, metabolic disorders of trace elements were detected evidenced by their significant decreases (aluminum, silicon, calcium, manganese, strontium, titanium, lithium, boron, cobalt, mercury, chromium) and increases (arsenic, cadmium, selenium, lead, nickel) on 90 days using inductively coupled plasma mass spectrometer (ICP-MS). It is possible that the changes of trace elements have a hand in the come on and development of arsenism. Taken together, we conjectured that, in chicken jejunum, arsenic led to redistribution of trace elements, promoting apoptosis via regulating mitochondrial dynamics, leading to autophagy through PI3K/AKT/mTOR signal pathways. PMID- 29705902 TI - Source characterization and risk of exposure to atmospheric polychlorinated biphenyls (PCBs) in Ghana. AB - With recent evidence that persistent organic pollutants (POPs) such as polychlorinated biphenyls (PCBs) are emerging in environmental media in some developing countries that otherwise have sparing production and usage history, it has become important to identify such contemporary source factors of PCBs and the risks this may pose, in line with the global consensus on POP management and elimination. The present study investigated contaminations from atmospheric PCBs in Ghana, deciphered source factors, and accessed risk of exposure to dioxin-like PCBs (DL-PCBs). Atmospheric PCBs were monitored by deployment of PUF-disk passive air samplers (PAS) at several sites across Ghana for 56 days. Atmospheric ?190PCB concentration in Ghana ranged from 0.28 ng/m3 in Kumasi to 4.64 ng/m3 at Agbogbloshie, a suburb in Accra noted for informal electronic waste (e-waste) recycling activities. As high as 11.10 ng/m3 of PCB concentration was measured in plumes from uncontrolled open burning of e-wastes at Agbogbloshie. Applying statistical source characterization tools, it emerged that e-wastes were a major contributor to the environmental burden of atmospheric PCBs in Ghana. The risk of DL-PCB toxicity via inhalation in the Agbogbloshie area was 4.2 pg TEQ/day, within similar order of magnitude of an estimated risk of 3.85 pg TEQ/day faced by e-waste workers working averagely for 8 h per day. It is suggested that elimination of e-waste sites would help to significantly reduce PCB-related toxicity issues in Ghana. Graphical abstract ?. PMID- 29705903 TI - Cadmium bioaccumulation and antioxidant enzyme activity in hepatopancreas, kidney, and stomach of invasive apple snail Pomacea canaliculata. AB - The acute toxicity of Cd was tested, and metal bioaccumulation in tissue was determined for the alien invasive species Pomacea canaliculata and its native competitor Sinotaia quadrata under experimental conditions. The invasive species was more tolerant to Cd toxicity than native species, for which the LC50 values were 4.26, 2.24, and 1.98 mg/L at exposure times of 48, 72, and 96 h, respectively, approximately three times higher than those of the native snails. The viscera accumulated the highest Cd concentration, followed by the foot and shell in both species. Metal concentrations in the above three tissues of P. canaliculata were much higher than those of S. quadrata, irrespective of Cd dose and exposure time. For P. canaliculata, the highest concentration of metal was further observed in the hepatopancreas (0.64-3.98 mg/g) followed by the kidney (0.067-3.78 mg/g), with lowest levels in the stomach (0.062-1.53 mg/g). Among the five antioxidant enzymes, the most responsive enzymes were CAT, ALP, and GST in the hepatopancreas; CAT, POD, and GST in the kidney; and POD in the stomach of exposed animals. These results, demonstrating a high Cd tolerance, may partly explain the ability of P. canaliculata to displace S. quadrata in Cd-contaminated habitat. The Cd was accumulated mainly in the hepatopancreas and kidney of invasive species, which changed the activity of antioxidant enzymes allowing the animals to cope with the toxicity. Graphical abstract Cadmium bioaccumulation and antioxidant enzyme activity in the invasive Pomacea canaliculata. PMID- 29705905 TI - Concentration-dependent responses of soil bacterial, fungal and nitrifying communities to silver nano and micron particles. AB - The growing use of silver nanoparticles (AgNPs) is likely to result in increased environmental contamination. Although AgNPs have been reported to affect microbial communities in a range of ecosystems, there is still a lack of information concerning the effect of low concentrations of AgNPs on soil microbial community structures and functional groups involved in biogeochemical cycling. In this study, the concentration-dependent effects of AgNPs and silver micron particles (AgMPs) on bacterial and fungal community structures in an agricultural pastureland soil were examined in a microcosm-based experiment using enzyme analysis, molecular fingerprinting, qPCR and amplicon sequencing. Soil enzyme processes were impacted by Ag contamination, with soil dehydrogenase activity reduced by 1 mg kg-1 of AgNPs and AgMPs. Soil urease activity was less susceptible, but was inhibited by >= 10 mg kg-1 AgNPs. The significant (P <= 0.001) decrease in copy numbers of the amoA gene by 10 mg kg-1 AgNPs indicated that archaea ammonia oxidisers may be more sensitive to AgNP contamination than bacteria. Amplicon sequencing revealed the bacterial phyla Acidobacteria and Verrucomicrobia to be highly sensitive to AgNP contamination. A broad reduction in the relative abundance of Acidobacterial genera was observed, with the exception of the genus Geothrix which increased in response to AgNP and AgMP amendment. Broad tolerance to Ag was observed among the Bacteriodetes, with higher relative abundance of most genera observed in the presence of AgNPs and AgMPs. The proteobacterial genus Dyella was highly tolerant to AgNPs and AgMPs and relative abundance of this genus increased with Ag concentration. Soil fungal community structure responded to both AgNPs and AgMPs, but the nanoparticle had an impact at a lower concentration. This study demonstrates that pastureland soil microbial communities are highly sensitive to AgNP amendment and key functional processes may be disrupted by relatively low levels of contamination. PMID- 29705904 TI - Ionizing radiation exposure: hazards, prevention, and biomarker screening. AB - Radiation is a form of energy derived from a source that is propagated through material in space. It consists of ionizing radiation or nonionizing radiation. Ionizing radiation is a feature of the environment and an important tool in medical treatment, but it can cause serious damage to organisms. A number of protective measures and standards of protection have been proposed to protect against radiation. There is also a need for biomarkers to rapidly assess individual doses of radiation, which can not only estimate the dose of radiation but also determine its effects on health. Proteomics, genomics, metabolomics, and lipidomics have been widely used in the search for such biomarkers. These topics are discussed in depth in this review. PMID- 29705906 TI - Facile synthesis of highly porous "carbon sponge" with adsorption and co adsorption behavior of lead ions and atrazine. AB - The rapid industrialization and modern agriculture, increasing emission of heavy metals, and abusing application of pesticide have changed biochemical features of the soil system and water system. Additionally, heavy metals and pesticide compounds may occur together in environments, giving rise to more serious damage to the environment because of their combined toxicity and carcinogenic properties. Therefore, there is a growing need for the development of low-cost adsorbents for their removal. Porous carbon materials have been considered as highly effective materials for pollutant ion control. In this thesis, a novel porous "carbon sponge" is produced using sucrose (S-PCS) with gas-producing molten salt KHCO3 as the activator at different pyrolysis temperatures under a limited-oxygen condition. Results from these characterizations have indicated that the as-prepared carbon sponges share high surface area (up to 457.6434 m2 g 1) and abundant oxygen-containing functional groups existed on the surface. The essential factors of contact time, initial concentrations, and cyclic availability on adsorption of lead ions and atrazine onto the as-prepared porous samples are also discussed. The typical kinetic and thermodynamic models are carried out to interpret the adsorption behaviors of lead ions and atrazine. The interactive effects and mechanism of lead ions and atrazine adsorption onto S-PCS samples are examined by simultaneous adsorption and preloading adsorption procedures. Combined with the economic and environmental merits of the raw materials, the porous carbon sponges of sucrose by KHCO3 activated are promising materials for potential practical applications. Graphical abstract The schematic diagram on the preparation of porous carbon sponse from sucrose. PMID- 29705907 TI - Impact of selected drugs and their binary mixtures on the germination of Sorghum bicolor (sorgo) seeds. AB - The aim of this study was to assess the toxicological potential of binary drug mixtures and individual drugs under different pH conditions with different inorganic ion additions on the germination of Sorghum bicolor (sorgo) seeds. To assess whether the given drug mixtures were more phytotoxic than the individual compounds, concentration addition (CA) and independent action (IA) approaches were applied to estimate the predicted phytotoxicity values, followed by calculations of the MDR (model deviation factor) to determine the deviation from the predicted values. Binary mixtures of chloramphenicol with ketoprofen, diclofenac sodium, and oxytetracycline hydrochloride proved to be synergistic. The pH changes had the largest impact on the phytotoxicity of the diclofenac sodium and ketoprofen solutions, elevating their toxicity toward S. bicolor, and the co-presence of inorganic ions was shown to have an impact on ketoprofen, chloramphenicol, and oxytetracycline hydrochloride. Most of the interactions between sorgo plants and pharmaceuticals with added ions were antagonistic in nature, particularly those calculated using the IA model, with a few cases (one case for ketoprofen and chloramphenicol, two cases for oxytetracycline hydrochloride, and four cases for diclofenac sodium) of overestimation. PMID- 29705909 TI - Prompt admission to the ICU: an instrument to improve mortality for deteriorating ward patients. PMID- 29705910 TI - A Health Profile and Overview of Healthcare Experiences of Cambodian American Refugees and Immigrants Residing in Southern California. AB - Asian Americans are understudied in health research and often aggregated into one homogenous group, thereby disguising disparities across subgroups. Cambodian Americans, one of the largest refugee communities in the United States, may be at high risk for adverse health outcomes. This study compares the health status and healthcare experiences of Cambodian American refugees and immigrants. Data were collected via questionnaires and medical records from two community clinics in Southern California (n = 308). Chi square and t-tests examined the socio demographic differences between immigrants and refugees, and ANCOVA models compared the mean differences in responses for each outcome, adjusting for age at immigration, education level, and clinic site. Cambodian American refugees reported overall lower levels of health-related quality of life (all p's < 0.05 in unadjusted models) and self-rated health [unadjusted means (SD) = 18.2 (16.8) vs. 21.7 (13.7), p < 0.05], but either similar or more positive healthcare experiences than Cambodian American immigrants. In adjusted analyses, refugees had higher rates of diabetes and cardiovascular disease risk (e.g. heart condition and hypertension; p's < 0.05) compared to Cambodian American immigrants. There were minimal differences in self-reported health behaviors between the two groups. There is a need for more health promotion efforts among Cambodian American refugees and immigrants to improve their health outcomes and perceived wellbeing. PMID- 29705908 TI - Somatic mutations in neurons during aging and neurodegeneration. AB - The nervous system is composed of a large variety of neurons with a diverse array of morphological and functional properties. This heterogeneity is essential for the construction and maintenance of a distinct set of neural networks with unique characteristics. Accumulating evidence now indicates that neurons do not only differ at a functional level, but also at the genomic level. These genomic discrepancies seem to be the result of somatic mutations that emerge in nervous tissue during development and aging. Ultimately, these mutations bring about a genetically heterogeneous population of neurons, a phenomenon that is commonly referred to as "somatic brain mosaicism". Improved understanding of the development and consequences of somatic brain mosaicism is crucial to understand the impact of somatic mutations on neuronal function in human aging and disease. Here, we highlight a number of topics related to somatic brain mosaicism, including some early experimental evidence for somatic mutations in post-mitotic neurons of the hypothalamo-neurohypophyseal system. We propose that age-related somatic mutations are particularly interesting, because aging is a major risk factor for a variety of neuronal diseases, including Alzheimer's disease. We highlight potential links between somatic mutations and the development of these diseases and argue that recent advances in single-cell genomics and in vivo physiology have now finally made it possible to dissect the origins and consequences of neuronal mutations in unprecedented detail. PMID- 29705911 TI - Drilling through anteromedial portal with a femoral aiming device ensures a sufficient length and a proper graft position, and prevents posterior wall breakage during anterior cruciate ligament reconstruction. AB - OBJECTIVE: The aim of this study was to evaluate the characteristics of the femoral tunnel (FT) which was drilled through the AM portal by using a femoral aimer device and AP stability of the knee. METHODS: Thirty-eight patients, with the mean age 29.6 (range: 20-43) years, were evaluated after ACL reconstruction. The mean follow-up time was 31.9 (range: 16-57) months. The FT was drilled using a femoral aimer with different offset according to the graft size measured, through the AM portal. The semitendinous and gracilis tendon autograft was used for reconstruction. The angles of FT and the exit point on the lateral condyle were measured on AP views of the knee. AP stability of the knee was measured with the KT-2000. RESULTS: The mean angle of FT was 46.5 degrees (+/- 8.4 degrees ), on the AP view. The mean distance between the exit point of FT and the most distal end of the femoral condyles was 46.7 (+/- 4.9) mm. The mean FT length was 36.1 (+/- 3.1) mm. The mean difference of anterior translation compared to the intact knee was 1.9 (+/- 1.6) mm. Except the three patients, with "one positive" pivot shift test, in the remaining 35 knees stability was equal to the healthy knee. CONCLUSIONS: Femoral drilling by using a femoral aimer device through AM portal provided long enough FT for safe graft fixation and appropriate coronal plan obliquity. The exit point was far proximal from the insertion site of the popliteus tendon and lateral collateral ligament. Furthermore, the AM portal technique significantly improved AP stability of the knee. PMID- 29705912 TI - Acute myelitis as presentation of a reemerging disease: measles. PMID- 29705913 TI - BK-virus progressive multifocal leukoencephalitis in a patient with systemic lupus erythematosus. PMID- 29705914 TI - A longitudinal study of painless and painful intercostobrachial neuropathy after breast cancer surgery. AB - Intercostobrachial neuropathy, often resulting in neuropathic pain, is a common complication of breast cancer surgery. In this 1-year longitudinal study, we aimed at seeking information on the frequency, clinical features, and course of painless and painful intercostobrachial neuropathy. We enrolled 40 women previously undergoing breast cancer surgery. In these patients, we collected, at 3, 6 and 12 months after surgery, clinical and quantitative sensory testing (QST) variables to diagnose intercostobrachial neuropathy, DN4 questionnaire to identify neuropathic pain, Neuropathic Pain Symptom Inventory to assess the different neuropathic pain symptoms, the Beck Depression Inventory to assess depressive symptoms, and SF36 to assess quality of life and Patient Global Impression of Change. Clinical and QST examination showed an intercostobrachial neuropathy in 23 patients (57.5%). Out of the 23 patients, five experienced neuropathic pain, as assessed with clinical examination and DN4. Axillary surgery clearance was associated with an increased risk of intercostobrachial neuropathy. Whereas sensory disturbances improved during the 1-year observation, neuropathic pain did not. Nevertheless, Beck Depression Inventory, SF36, and the Patient Global Impression of Change scores significantly improved over time. Our study shows that although intercostobrachial neuropathy is a common complication of breast cancer surgery, neuropathic pain affects only a minor proportion of patients. After 1 year, sensory disturbances partially improve and have only a mild impact on mood and quality of life. PMID- 29705915 TI - Molecular mapping and inheritance of restoration of fertility (Rf) in A4 hybrid system in pigeonpea (Cajanus cajan (L.) Millsp.). AB - KEY MESSAGE: We report molecular mapping and inheritance of restoration of fertility (Rf) in A4 hybrid system in pigeonpea. We have also developed PCR-based markers amenable to low-cost genotyping to identify fertility restorer lines. Commercial hybrids in pigeonpea are based on A4 cytoplasmic male sterility (CMS) system, and their fertility restoration is one of the key prerequisites for breeding. In this context, an effort has been made to understand the genetics and identify quantitative trait loci (QTL) associated with restoration of fertility (Rf). One F2 population was developed by crossing CMS line (ICPA 2039) with fertility restorer line (ICPL 87119). Genetic analysis has shown involvement of two dominant genes in regulation of restoration of fertility. In parallel, the genotyping-by-sequencing (GBS) approach has generated ~ 33 Gb data on the F2 population. GBS data have provided 2457 single nucleotide polymorphism (SNPs) segregating across the mapping population. Based on these genotyping data, a genetic map has been developed with 306 SNPs covering a total length 981.9 cM. Further QTL analysis has provided the region flanked by S8_7664779 and S8_6474381 on CcLG08 harboured major QTL explained up to 28.5% phenotypic variation. Subsequently, sequence information within the major QTLs was compared between the maintainer and the restorer lines. From this sequence information, we have developed two PCR-based markers for identification of restorer lines from non restorer lines and validated them on parental lines of hybrids as well as on another F2 mapping population. The results obtained in this study are expected to enhance the efficiency of selection for the identification of restorer lines in hybrid breeding and may reduce traditional time-consuming phenotyping activities. PMID- 29705916 TI - A population of wheat multiple synthetic derivatives: an effective platform to explore, harness and utilize genetic diversity of Aegilops tauschii for wheat improvement. AB - KEY MESSAGE: The multiple synthetic derivatives platform described in this study will provide an opportunity for effective utilization of Aegilops tauschii traits and genes for wheat breeding. Introducing genes from wild relatives is the best option to increase genetic diversity and discover new alleles necessary for wheat improvement. A population harboring genomic fragments from the diploid wheat progenitor Aegilops tauschii Coss. in the background of bread wheat (Triticum aestivum L.) was developed by crossing and backcrossing 43 synthetic wheat lines with the common wheat cultivar Norin 61. We named this population multiple synthetic derivatives (MSD). To validate the suitability of this population for wheat breeding and genetic studies, we randomly selected 400 MSD lines and genotyped them by using Diversity Array Technology sequencing markers. We scored black glume as a qualitative trait and heading time in two environments in Sudan as a quantitative trait. Our results showed high genetic diversity and less recombination which is expected from the nature of the population. Genome-wide association (GWA) analysis showed one QTL at the short arm of chromosome 1D different from those alleles reported previously indicating that black glume in the MSD population is controlled by new allele at the same locus. For heading time, from the two environments, GWA analysis revealed three QTLs on the short arms of chromosomes 2A, 2B and 2D and two on the long arms of chromosomes 5A and 5D. Using the MSD population, which represents the diversity of 43 Ae. tauschii accessions representing most of its natural habitat, QTLs or genes and desired phenotypes (such as drought, heat and salinity tolerance) could be identified and selected for utilization in wheat breeding. PMID- 29705917 TI - Management of Hepatic Encephalopathy Not Responsive to First-Line Treatments. AB - PURPOSE OF REVIEW: Hepatic encephalopathy (HE) is a neuropsychiatric syndrome that occurs in up to 30% of patients with cirrhosis. HE may be a consequence of pure liver failure, as in patients with fulminant hepatitis, or of the combination of liver failure and portal-systemic shunting, as in patients with liver cirrhosis. Episodes of HE are usually related to precipitating events, such as infections or gastrointestinal bleeding; a minority of cirrhotic patients experienced a chronic HE, refractory to standard medical treatment. The prevention of HE recurrence, after the first episode of HE, could be obtained by the administration of prophylactic therapy with lactulose, rifaximin or a combination of both. The aim of this review is to clarify some key points in the management of cirrhotic patients with HE, not responsive to first line treatment. RECENT FINDINGS: Recent studies investigated the role of fecal microbiota transplantation in the treatment of HE with promising results, but further investigations are needed. In a cirrhotic patient with acute cognitive impairment, the correct diagnosis of HE, after excluding other causes of neurological diseases, is mandatory for the correct management of the precipitating factors and for the treatment. In patients not responsive to standard treatment, the probable precipitating factors have not been correctly identified, multiple precipitating events are coexisting or a new precipitating event is superimposed. In some patients with recurrent HE, characterized by persistent alterations in neurological symptoms, without specific precipitants events, the presence of spontaneous or iatrogenic shunts should be investigated. PMID- 29705918 TI - Expert's comment concerning Grand Rounds case entitled "Low energy chronic traumatic spondylolisthesis of the axis" by C. J. Dunn, S. Mease, K. Issa, K. Sinha, A. Emami (Eur Spine J; 2017: DOI 10.1007/s00586-017-5206-4). PMID- 29705919 TI - Retraction Note to: Combination Antiemetic Regimens for Prevention of Postoperative Nausea and Vomiting : Focus on High-Risk Patients. AB - The Editor-in-Chief has retracted the original article [1] because a number of studies [2-15] included in this review (cited as references 25-29, 31, 32, 47, 48, 50-54) have been retracted, specifically those included in table III, table IV, section 3 and section 4.2. This has rendered the content of the review scientifically unreliable. PMID- 29705920 TI - Retraction Note to: Efficacy of Menatetrenone (Vitamin K2) against Non-Vertebral and Hip Fractures in Patients with Neurological Diseases : Meta-Analysis of Three Randomized, Controlled Trials. AB - The Editor-in-Chief has retracted this article because two of the three studies [1, 2] included in the meta-analysis (cited as references 11 and 12) have been retracted due to fabrication of the data, which has rendered the results of this meta-analysis invalid. PMID- 29705921 TI - Comparison of DSM-IV-TR and DSM-5 Criteria in Diagnosing Autism Spectrum Disorders in Singapore. AB - Our study examines the Diagnostic and Statistical Manual-Fifth Edition (DSM-5) and Diagnostic and Statistical Manual-Fourth Edition, Text Revision (DSM-IV-TR) when applied concurrently against the best estimate clinical diagnoses for 110 children (5.1-19.6 years old) referred for diagnostic assessments of Autism Spectrum Disorder (ASD) in a Singaporean outpatient speciality clinic. DSM-IV-TR performed slightly better, yielding sensitivity of 0.946 and specificity of 0.889, compared to DSM-5 (sensitivity = 0.837; specificity = 0.833). When considering the ASD sub-categories, sensitivity ranged from 0.667 to 0.933, and specificity ranged from 0.900 to 0.975. More participants with a PDD-NOS best estimate clinical diagnosis (40%) were misclassified on DSM-5. Merits and weaknesses to both classification systems, and implications for access to services and policy changes are discussed. PMID- 29705922 TI - Gender Identity in Autism: Sex Differences in Social Affiliation with Gender Groups. AB - High rates of gender variance have been reported in autistic people, with higher variance in autistic females than males. The social component of gender identity may be affected, with autistic females experiencing lower identification with and feeling less positively about their gender groups than controls. We measured gender identification, gender self-esteem, and aspects of gender expression (masculinity and femininity) in autistic natal males and females, and controls (N = 486). We found that autistic people had lower gender identification and gender self-esteem than controls, and autistic natal females had lower gender identification than autistic natal males and natal female controls. In conclusion, autistic people, particularly natal females, had lower social identification with and more negative feelings about a gender group. PMID- 29705923 TI - Patterns and Predictors of Language Development from 4 to 7 Years in Verbal Children With and Without Autism Spectrum Disorder. AB - This study used a prospective community-based sample to describe patterns and predictors of language development from 4 to 7 years in verbal children (IQ >= 70) with autism spectrum disorder (ASD; n = 26-27). Children with typical language (TD; n = 858-861) and language impairment (LI; n = 119) were used for comparison. Children with ASD and LI had similar mean language scores that were lower on average than children with TD. Similar proportions across all groups had declining, increasing and stable patterns. Language progressed at a similar rate for all groups, with progress influenced by IQ and language ability at 4 years rather than social communication skills or diagnosis of ASD. These findings inform advice for parents about language prognosis in ASD. PMID- 29705925 TI - KNEES-ACL has superior responsiveness compared to the most commonly used patient reported outcome measures for anterior cruciate ligament injury. AB - PURPOSE: For clinical trials, it is essential that measures are sensitive to change. The aim of this study was to conduct a head-to-head comparison of responsiveness of four PROMs used to measure outcome after anterior cruciate ligament (ACL) reconstruction. The PROMs compared were the knee injury osteoarthritis outcome score (KOOS), the international knee documentation committee subjective form (IKDC), the Lysholm score, and the knee numeric-entity evaluation score (KNEES-ACL). We hypothesized that KNEES-ACL would be more responsive than the other PROMs, as KNEES-ACL was created based on patient interviews and validated using Rasch analysis. METHODS: One-hundred and sixty-six consecutive adults completed the four PROMs before and 3, 6, and 12 months after ACL-reconstructive surgery. Responsiveness was calculated as Cohen's Effect Size and Standardized Response Means. Bootstrapping was used to generate 95% confidence intervals for comparisons of responsiveness across PROMs. Repeated measures ANOVA was also computed for each PROM. RESULTS: The largest effect sizes at 12 months were seen for KNEES-ACLSports-Behaviour (1.35, p < 0.001) and KNEES ACLSports-Physical (1.19, p < 0.001), the smallest for KOOSADL (0.35, p < 0.001) and KOOSSymptoms (0.39, p < 0.001). IKDC and Lysholm lay between these with IKDC slightly more responsive. Head-to-head comparisons of similar subscales of KOOS and KNEES-ACL showed substantial differences in effect size in the domains of symptoms (0.69, p < 0.001), daily activities (0.31, p = 0.005), and Sports activity (0.63, p = 0.013) all in favour of KNEES-ACL. CONCLUSION: These results demonstrate superior responsiveness for KNEES-ACL, which is the only PROM that has been constructed through exhaustive patient feedback and validated for patients with ACL deficiency using the most stringent psychometric methods (Rasch analysis). KNEES-ACL is the most precise and accurate PROM for patients with ACL injury and the most trustworthy instrument for clinicians and clinical researchers. LEVEL OF EVIDENCE: Prospective cohort study, Level II. PMID- 29705926 TI - Executive Functioning Heterogeneity in Pediatric ADHD. AB - Neurocognitive heterogeneity is increasingly recognized as a valid phenomenon in ADHD, with most estimates suggesting that executive dysfunction is present in only about 33%-50% of these children. However, recent critiques question the veracity of these estimates because our understanding of executive functioning in ADHD is based, in large part, on data from single tasks developed to detect gross neurological impairment rather than the specific executive processes hypothesized to underlie the ADHD phenotype. The current study is the first to comprehensively assess heterogeneity in all three primary executive functions in ADHD using a criterion battery that includes multiple tests per construct (working memory, inhibitory control, set shifting). Children ages 8-13 (M = 10.37, SD = 1.39) with and without ADHD (N = 136; 64 girls; 62% Caucasian/Non-Hispanic) completed a counterbalanced series of executive function tests. Accounting for task unreliability, results indicated significantly improved sensitivity and specificity relative to prior estimates, with 89% of children with ADHD demonstrating objectively-defined impairment on at least one executive function (62% impaired working memory, 27% impaired inhibitory control, 38% impaired set shifting; 54% impaired on one executive function, 35% impaired on two or all three executive functions). Children with working memory deficits showed higher parent- and teacher-reported ADHD inattentive and hyperactive/impulsive symptoms (BF10 = 5.23 * 104), and were slightly younger (BF10 = 11.35) than children without working memory deficits. Children with vs. without set shifting or inhibitory control deficits did not differ on ADHD symptoms, age, gender, IQ, SES, or medication status. Taken together, these findings confirm that ADHD is characterized by neurocognitive heterogeneity, while suggesting that contemporary, cognitively-informed criteria may provide improved precision for identifying a smaller number of neuropsychologically-impaired subtypes than previously described. PMID- 29705927 TI - Single nucleotide polymorphism rs11614913 associated with CC genotype in miR 196a2 is overrepresented in laryngeal squamous cell carcinoma, but not salivary gland tumors in Polish population. AB - The miRNA-196a2 has shown significance in the development of various neoplasms, including head and neck squamous cell carcinoma (HNSCC). The oncogenic functionality of this miRNA is mediated via its potential to target annexin A1 mRNA, a tumor suppressor gene involved in inhibition of the NF-kappaB pathway. Interestingly, recent data indicate a susceptibility for aforementioned neoplasms in patients with the CC genotype vs the CT and TT genotypes of the rs11614913 SNP located within the DNA sequence of the miR-196a2 that results in elevated expression of the gene. To further investigate this phenomenon, we genotyped this SNP in 40 patients with laryngeal squamous cell carcinoma (LSCC), the most common tumor of the head and neck region and 60 patients with salivary gland tumors (SGT) that show a yet unexplained incidence increase in the last two decades. In agreement with previous reports, we have identified a statistically significant (p < 0.05) overrepresentation of the CC genotype in LSCC patients and demonstrated in LSCC cell lines that it results in elevated expression of miR 196a2 as compared to cell lines with the TT genotype of the respective SNP. Importantly, none of these correlations was found in patients with SGT. These findings underline the importance of the SNP rs11614913 for LSCC development in the Polish population and moreover highlight the different genetic background of the two studied neoplasms of the head and neck region. PMID- 29705928 TI - Prokaryotic and eukaryotic community structure affected by the presence of an acid mine drainage from an abandoned gold mine. AB - The acid mine drainage that originates in the abandoned gold mine in San Luis, Argentina, is released into La Carolina stream. The aim of this study was to determine the influence of this mine drainage on the physicochemical parameters of the area studied and on both prokaryotic and eukaryotic community structure. In addition, specific relationships between microbial taxonomic groups and physicochemical parameters were established. The drainage that flows into La Carolina stream acidifies the stream and increases its sulfate, Zn, Cd and Te concentrations. Microbial analysis showed that prokaryotic community structure is mainly affected by pH values. Actinobacteria and Gammaproteobacteria were abundant in samples characterized by low pH values, while Nitrospirae, Chloroflexi, Deltaproteobacteria, Thaumarchaeota and Euryarchaeota were associated with high concentrations of heavy metals. Otherwise, Alphaproteobacteria was present in samples taken in sunlit areas. Regarding eukaryotic community structure, the sunlight had the greatest impact. Inside the mine, in the absence of light, fungi and protists members were the most abundant microorganisms, while those samples taken in the presence of light displayed algae (green algae and diatoms) as the most abundant ones. After receiving the mine drainage, the stream showed a decrease in the diatom abundance and green algae predominated. PMID- 29705930 TI - United States National Trends in Mortality, Length of Stay (LOS) and Associated Costs of Cognitive Impairment in HIV Population from 2005 to 2014. AB - We evaluated national trends of in-hospital discharge rates, mortality outcomes, health care costs, length of stay in HIV patients with cognitive disorders. Neurological involvement in HIV is commonly associated with cognitive impairment termed as HIV-associated neurocognitive disorder (HAND) which includes a spectrum of neurocognitive dysfunction associated with HIV infection. Although severe and progressive neurocognitive impairment has become rare in HIV patients in the era of potent antiretroviral therapy, a majority of HIV patients have mild to moderate degree of neurocognitive impairment. Study population for this analysis was derived from the Nationwide Inpatient Sample from 2005 to 2014. Patients with ICD-9 code of HIV (042) with discharge diagnosis (Dx) listed top 1 through 5 were included in the analysis. Within this population, we identified patients with cognitive impairment using ICD-9 codes of 294 (persistent mental disorders; organic psychotic brain syndromes (chronic), 323.9 (encephalitis, myelitis, and encephalomyelitis), 331.83 (mild cognitive impairment) with Dx listed from 1 to 25. Patient variables obtained included: age, race, gender, length of stay, in hospital mortality and insurance status. Hospital level variables included teaching status, location and region of country. SAS 9.4 software was used for data analysis. Comparisons of variables between hospitalized HIV patients with and without HAND showed significant increase in cost per hospital admissions, longer hospital stay and higher risk of mortality in patients with HAND. PMID- 29705929 TI - Pharmacomicrobiomics: a novel route towards personalized medicine? AB - Inter-individual heterogeneity in drug response is a serious problem that affects the patient's wellbeing and poses enormous clinical and financial burdens on a societal level. Pharmacogenomics has been at the forefront of research into the impact of individual genetic background on drug response variability or drug toxicity, and recently the gut microbiome, which has also been called the second genome, has been recognized as an important player in this respect. Moreover, the microbiome is a very attractive target for improving drug efficacy and safety due to the opportunities to manipulate its composition. Pharmacomicrobiomics is an emerging field that investigates the interplay of microbiome variation and drugs response and disposition (absorption, distribution, metabolism and excretion). In this review, we provide a historical overview and examine current state-of-the art knowledge on the complex interactions between gut microbiome, host and drugs. We argue that combining pharmacogenomics and pharmacomicrobiomics will provide an important foundation for making major advances in personalized medicine. PMID- 29705931 TI - Structural Network Position and Performance of Health Leaders Within an HIV Prevention Trial. AB - The effectiveness of peer leaders in promoting health may depend on the position they occupy within their social networks. Using sociocentric (whole network) and behavioral data from the intervention arm of a cluster-randomized HIV prevention trial in Dar es Salaam, Tanzania, we used generalized linear models with standardized predictors to examine the association between heath leaders' baseline structural network position (i.e., in-degree and betweenness centrality) and their 12-month self-reported (1) confidence in educating network members about HIV and gender-based violence (GBV) and (2) number of past-week conversations about HIV and GBV. As in-degree centrality increased, leaders reported fewer HIV-related conversations. As betweenness centrality increased, leaders reported greater number of conversations about GBV. Network position was not significantly associated with confidence in discussing either topic. Our results suggest that peer leaders who occupy spaces between sub-groups of network members may be more effective in engaging their peers in sensitive or controversial topics like GBV than more popular peer leaders. PMID- 29705932 TI - Neonatal thrombocytopenia-causes and outcomes following platelet transfusions. AB - : We evaluated the causes for neonatal thrombocytopenia (NT), the duration of NT, and the indications of platelet transfusions (PT) by means of a retrospective cohort study over a 23-year period. Neonates with NT were identified via ICD-10 code D69.6. Of 371 neonates (1.8/1000 live births) with NT, the majority (312; 84.1%) had early onset thrombocytopenia, and 282 (76%) were preterm born. The most frequent causes for NT were early and late onset sepsis and asphyxia. The mean duration of thrombocytopenia was 10.2 days and was negatively correlated (KK = - 0.35) with the number of PT. PT were given to 78 (21%) neonates, 38 (49%) of whom had very severe NT. The duration of NT was positively related to the severity of NT and the number of subsequent PT. A mortality rate of 10.8% was significantly associated with bleeding signs (p < 0.05) and correlated with increasing number of PT (p < 0.05) but not with the severity of NT (p = 0.4). In the case of relevant hemorrhage, PT did not influence the mortality rate (p = 0.09). All deaths followed neonatal sepsis. CONCLUSIONS: Prematurity and diagnoses including early and late onset sepsis and asphyxia were the most common causes of NT. Mortality was not associated with the severity of NT but increased with the number of PT. What is Known: * The causes for neonatal thrombocytopenia (NT) are well known. * The effects of platelet transfusions (PT) and its indications are still a matter of debate and recommendations differ widely. What is New: * The duration of NT is positively related to the severity of NT and the number of subsequent PT. * The mortality rate is not associated with the severity of NT but increases with increasing numbers of PT and in the case of relevant intraventricular hemorrhage (>= grade II), PT does not influence the mortality rate. PMID- 29705933 TI - Mesenchymal Stem Cells Form 3D Clusters Following Intraventricular Transplantation. AB - Mesenchymal stem cells (MSCs) are regarded as an immune privileged cell type with numerous regeneration-promoting effects. The in vivo behavior of MSC and underlying mechanisms leading to their regenerative effects are largely unknown. The aims of this study were to comparatively investigate the in vivo behavior of canine (cMSC), human (hMSC), and murine MSC (mMSC) following intra cerebroventricular transplantation. At 7 days post transplantation (dpt), clusters of cMSC, hMSC, and mMSC were detected within the ventricular system. At 49 dpt, cMSC-transplanted mice showed clusters mostly consisting of extracellular matrix lacking transplanted MSC. Similarly, hMSC-transplanted mice lacked MSC clusters at 49 dpt. Xenogeneic MSC transplantation was associated with a local T lymphocyte-dominated immune reaction at both time points. Interestingly, no associated inflammation was observed following syngeneic mMSC transplantation. In conclusion, transplanted MSC formed intraventricular cell clusters and exhibited a short life span in vivo. Xenogeneically in contrast to syngeneically transplanted MSC triggered a T cell-mediated graft rejection indicating that MSCs are not as immune privileged as previously assumed. However, MSC may mediate their effects by a "hit and run" mechanism and future studies will show whether syngeneically or xenogeneically transplanted MSCs exert better therapeutic effects in animals with CNS disease. PMID- 29705935 TI - Project SHINE: effects of a randomized family-based health promotion program on the physical activity of African American parents. AB - This study examined the effects of a family-based health promotion intervention on the moderate-to-vigorous physical activity (MVPA), light physical activity, sedentary behavior, and fruit and vegetable intake of African American parents. Eighty-nine African American parents (41.5 +/- 8.5 years; 92% females; 74% obese; 64% < $40 K income) and adolescents (12.5 +/- 1.4 years; 61% girls; 48% obese) were randomized to a 6-week behavioral skills plus positive parenting and peer monitoring intervention grounded in social cognitive, self-determination, and family systems theories or a general health comparison program. Parents wore accelerometers for 7 days and completed three 24-h dietary recalls at baseline and post-intervention. Multilevel regression models (controlling for baseline variables) demonstrated a significantly greater increase in parent MVPA for those in the intervention versus comparison condition (b = 9.44, SE = 4.26, p < 0.05). There were no other significant effects. Family-based approaches that include African American parents and youth may increase parent MVPA and hold promise for preventing chronic diseases. PMID- 29705934 TI - Exosomes Secreted by Adipose-Derived Stem Cells Contribute to Angiogenesis of Brain Microvascular Endothelial Cells Following Oxygen-Glucose Deprivation In Vitro Through MicroRNA-181b/TRPM7 Axis. AB - Adipose-derived stem cells (ADSCs) have been demonstrated to promote cerebral vascular remodeling processes after stroke. However, the exact molecular mechanism by which ADSCs exert protective roles in ischemic stroke is still poorly understood. In this study, we identified the role of exosomal microRNA 181b-5p (181b-Exos) in regulating post-stroke angiogenesis. The results of migration assay and capillary network formation assay showed that exosomes secreted by ADSCs (ADSCs-Exos) promoted the mobility and angiogenesis of brain microvascular endothelial cells (BMECs) after oxygen-glucose deprivation (OGD). Quantitative real-time polymerase chain reaction (qRT-PCR) showed that microRNA 212-5p (miR-212-5p) and miR-181b-5p were upregulated in BMECs subjected to the brain extract of the middle cerebral artery occlusion rats. The migration distance and tube length were increased in BMECs cultured with 181b-Exos. Furthermore, we identified that transient receptor potential melastatin 7 (TRPM7) was a direct target of miR-181b-5p. TRPM7 mRNA and protein levels were declined in BMECs cultured with 181b-Exos, but not in BMECs cultured with 212-Exos. Overexpression of TRPM7 reversed the effects of 181b-Exos on migration and tube formation of BMECs. In addition, 181b-Exos upregulated the protein expression of hypoxia-inducible factor 1alpha and vascular endothelial cell growth factor, and downregulated the protein expression of tissue inhibitor of metalloproteinase 3. The regulatory effect of 181b-Exos was attenuated by overexpressing TRPM7. Altogether, ADSCs-Exos promote the angiogenesis of BMECs after OGD via miR-181b 5p/TRPM7 axis, suggesting that ADSCs-Exos may represent a novel therapeutic approach for stroke recovery. PMID- 29705937 TI - Isolated oculomotor palsy due to acute ischemic midbrain stroke. PMID- 29705936 TI - Microsatellite analysis and marker development in garlic: distribution in EST sequence, genetic diversity analysis, and marker transferability across Alliaceae. AB - Allium vegetables, such as garlic and onion, have understudied genomes and limited molecular resources, hindering advances in genetic research and breeding of these species. In this study, we characterized and compared the simple sequence repeats (SSR) landscape in the transcriptomes of garlic and related Allium (A. cepa, A. fistulosum, and A. tuberosum) and non-Allium monocot species. In addition, 110 SSR markers were developed from garlic ESTs, and they were characterized-along with 112 previously developed SSRs-at various levels, including transferability across Alliaceae species, and their usefulness for genetic diversity analysis. Among the Allium species analyzed, garlic ESTs had the highest overall SSR density, the lowest frequency of trinucleotides, and the highest of di- and tetranucleotides. When compared to more distantly related monocots, outside the Asparagales order, it was evident that ESTs of Allium species shared major commonalities with regards to SSR density, frequency distribution, sequence motifs, and GC content. A significant fraction of the SSR markers were successfully transferred across Allium species, including crops for which no SSR markers have been developed yet, such as leek, shallot, chives, and elephant garlic. Diversity analysis of garlic cultivars with selected SSRs revealed 36 alleles, with 2-5 alleles/locus, and PIC = 0.38. Cluster analysis grouped the accessions according to their flowering behavior, botanical variety, and ecophysiological characteristics. Results from this study contribute to the characterization of Allium transcriptomes. The new SSR markers developed, along with the data from the polymorphism and transferability analyses, will aid in assisting genetic research and breeding in garlic and other Allium. PMID- 29705938 TI - Pyridoxine-induced sensory ataxic ganglionopathy: a case report and literature review. PMID- 29705939 TI - Macroscopic serosal invasion and small tumor size as independent prognostic factors in stage IIA colon cancer. AB - BACKGROUND: This study aimed to investigate the prognostic factors of patients with stage IIA (T3N0M0) colon cancer in terms of macroscopic serosal invasion and small tumor size. METHODS: We enrolled 375 stage IIA colon cancer patients who underwent curative resection between January 2004 and December 2011. Macroscopic serosal invasion was defined as tumor nodules or colloid changes protruding the surface of the serosa. The clinicopathologic characteristics were analyzed to identify independent prognostic factors. RESULTS: The median follow-up was 47 months (range, 1-90 months). On multivariate survival analysis, macroscopic serosal invasion (adjusted hazard ratio [HR] = 4.750; p = 0.013), tumor size < 5 cm (adjusted HR = 3.112, p = 0.009), perineural invasion (adjusted HR = 3.528; p = 0.002), < 12 retrieved lymph nodes (adjusted HR = 4.257; p = 0.002), and localized perforation (adjusted HR = 7.666; p = 0.008) were independent risk factors for recurrence. CONCLUSION: We found novel prognostic factors of stage IIA colon cancer, including macroscopic serosal invasion and small tumor size (< 5 cm). Further studies are needed to evaluate the benefit of adjuvant chemotherapy in patients with these prognostic factors. PMID- 29705940 TI - Subtypes and symptoms of fecal incontinence in the Dutch population: a cross sectional study. AB - PURPOSE: To study the distribution of subtypes and symptoms of fecal incontinence in the general Dutch population. METHODS: We performed a cross-sectional study in a representative sample of the general Dutch population. All respondents (N = 1259) completed the Groningen Defecation and Fecal Continence questionnaire. We assigned the respondents to a so-called healthy subgroup (n = 1008) and a comorbidity subgroup (n = 251). The latter subgroup comprised the respondents who reportedly suffered from chronic diseases and who had undergone surgery known to influence fecal continence. We defined fecal incontinence according to the Rome IV criteria. RESULTS: The combination of urge fecal incontinence and soiling was the most frequent form of fecal incontinence in the total study group, the "healthy" subgroup, and the comorbidity subgroup (49.0, 47.3, and 51.5%). Passive fecal incontinence was the least frequent form of fecal incontinence in all three groups (4.0, 5.4, and 2.2%). The prevalence and severity of fecal incontinence was significantly higher in the comorbidity subgroup than in the "healthy" subgroup. Only in the comorbidity subgroup did the fecally incontinent respondents feel urge sensation significantly less often before defecating than their fecally continent counterparts (16.5 versus 48.8%, P < 0.001). CONCLUSION: Urge fecal incontinence combined with soiling is commonest in the general Dutch population. Chronic diseases and bowel and pelvic surgery both increase and aggravate fecal incontinence. PMID- 29705941 TI - Hemorrhoidal disease: is it time for a new classification? PMID- 29705943 TI - Critical contribution of RIPK1 mediated mitochondrial dysfunction and oxidative stress to compression-induced rat nucleus pulposus cells necroptosis and apoptosis. AB - The aim of this study was to investigate whether RIPK1 mediated mitochondrial dysfunction and oxidative stress contributed to compression-induced nucleus pulposus (NP) cells necroptosis and apoptosis, together with the interplay relationship between necroptosis and apoptosis in vitro. Rat NP cells underwent various periods of 1.0 MPa compression. To determine whether compression affected mitochondrial function, we evaluated the mitochondrial membrane potential, mitochondrial permeability transition pore (mPTP), mitochondrial ultrastructure and ATP content. Oxidative stress-related indicators reactive oxygen species, superoxide dismutase and malondialdehyde were also assessed. To verify the relevance between oxidative stress and necroptosis together with apoptosis, RIPK1 inhibitor necrostatin-1(Nec-1), mPTP inhibitor cyclosporine A (CsA), antioxidants and small interfering RNA technology were utilized. The results established that compression elicited a time-dependent mitochondrial dysfunction and elevated oxidative stress. Nec-1 and CsA restored mitochondrial function and reduced oxidative stress, which corresponded to decreased necroptosis and apoptosis. CsA down-regulated mitochondrial cyclophilin D expression, but had little effects on RIPK1 expression and pRIPK1 activation. Additionally, we found that Nec-1 largely blocked apoptosis; whereas, the apoptosis inhibitor Z-VAD-FMK increased RIPK1 expression and pRIPK1 activation, and coordinated regulation of necroptosis and apoptosis enabled NP cells survival more efficiently. In contrast to Nec-1, SiRIPK1 exacerbated mitochondrial dysfunction and oxidative stress. In summary, RIPK1-mediated mitochondrial dysfunction and oxidative stress play a crucial role in NP cells necroptosis and apoptosis during compression injury. The synergistic regulation of necroptosis and apoptosis may exert more beneficial effects on NP cells survival, and ultimately delaying or even retarding intervertebral disc degeneration. PMID- 29705942 TI - Inflammatory cell ratios predict major septic complications following rectal cancer surgery. AB - INTRODUCTION: The inflammatory response is known to have an important role in tumourigenesis and the response to treatment. Previous studies have demonstrated that inflammatory cell ratios such as the neutrophil-to-lymphocyte ratio (NLR) can predict survival and recurrence following surgery for various cancers. The objective of this study was to demonstrate if pre-operative NLR has a role in predicting post-operative septic complications in patients undergoing rectal cancer surgery. METHODOLOGY: Consecutive patients undergoing scheduled resection for rectal cancer in a tertiary centre from July 2007 to Dec 2015 were included. Data was gathered from a prospectively held database of rectal cancer. Normally distributed data were compared with paired t tests (mean +/- standard error in the mean (SEM)), and proportions were compared with Fisher's exact test. A p value of < 0.05 was considered statistically significant. RESULTS: Three hundred fourteen patients were identified in this study. Sixty nine (22.0%) patients had a major septic complication following surgery for rectal cancer, which was associated with a poor survival outcome (p < 0.01) Both pre and post-operative NLR and PLR (platelet lymphocyte ratio) were associated with post-operative septic complications (both p < 0.01). A pre-operative NLR threshold level of 4 was chosen from ROC analysis, and this provided a relatively specific test to predict post-operative septic complications in these patients (specificity = 83.7%, negative predictive value (NPV) = 74.8%). DISCUSSION: In this study, the pre-operative NLR and PLR were both predictive of major post-operative septic complications. A pre-operative NLR of less than 4 was strongly negative predictor of post-operative complications in rectal cancer surgery. It can be regarded as a predictive and prognostic factor for these patients. PMID- 29705944 TI - Incorporation of musculoskeletal ultrasound training into the radiology core curriculum. PMID- 29705945 TI - Could Alzheimer's Disease Originate in the Periphery and If So How So? AB - The classical amyloid cascade model for Alzheimer's disease (AD) has been challenged by several findings. Here, an alternative molecular neurobiological model is proposed. It is shown that the presence of the APOE epsilon4 allele, altered miRNA expression and epigenetic dysregulation in the promoter region and exon 1 of TREM2, as well as ANK1 hypermethylation and altered levels of histone post-translational methylation leading to increased transcription of TNFA, could variously explain increased levels of peripheral and central inflammation found in AD. In particular, as a result of increased activity of triggering receptor expressed on myeloid cells 2 (TREM-2), the presence of the apolipoprotein E4 (ApoE4) isoform, and changes in ANK1 expression, with subsequent changes in miR 486 leading to altered levels of protein kinase B (Akt), mechanistic (previously mammalian) target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3), all of which play major roles in microglial activation, proliferation and survival, there is activation of microglia, leading to the subsequent (further) production of cytokines, chemokines, nitric oxide, prostaglandins, reactive oxygen species, inducible nitric oxide synthase and cyclooxygenase-2, and other mediators of inflammation and neurotoxicity. These changes are associated with the development of amyloid and tau pathology, mitochondrial dysfunction (including impaired activity of the electron transport chain, depleted basal mitochondrial potential and oxidative damage to key tricarboxylic acid enzymes), synaptic dysfunction, altered glycogen synthase kinase-3 (GSK-3) activity, mTOR activation, impairment of autophagy, compromised ubiquitin-proteasome system, iron dyshomeostasis, changes in APP translation, amyloid plaque formation, tau hyperphosphorylation and neurofibrillary tangle formation. PMID- 29705946 TI - Extracellular Zn2+ Influx into Nigral Dopaminergic Neurons Plays a Key Role for Pathogenesis of 6-Hydroxydopamine-Induced Parkinson's Disease in Rats. AB - Parkinson's disease (PD) is a progressive neurological disease characterized by a selective loss of nigrostriatal dopaminergic neurons. The exact cause of the neuronal loss remains unclear. Here, we report a unique mechanism of nigrostriatal dopaminergic neurodegeneration, in which extracellular Zn2+ influx plays a key role for PD pathogenesis induced with 6-hydroxydopamine (6-OHDA) in rats. 6-OHDA rapidly increased intracellular Zn2+ only in the substantia nigra pars compacta (SNpc) of brain slices and this increase was blocked in the presence of CaEDTA, an extracellular Zn2+ chelator, and 6-cyano-7 nitroquinoxaline-2,3-dione (CNQX), an alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionate (AMPA) receptor antagonist, indicating that 6-OHDA rapidly increases extracellular Zn2+ influx via AMPA receptor activation in the SNpc. Extracellular Zn2+ concentration was decreased under in vivo SNpc perfusion with 6-OHDA and this decrease was blocked by co-perfusion with CNQX, supporting 6-OHDA induced Zn2+ influx via AMPA receptor activation in the SNpc. Interestingly, both 6-OHDA-induced loss of nigrostriatal dopaminergic neurons and turning behavior to apomorphine were ameliorated by co-injection of intracellular Zn2+ chelators, i.e., ZnAF-2DA and N,N,N',N'-Tetrakis(2-pyridylmethyl)ethylenediamine (TPEN). Co injection of TPEN into the SNpc blocked 6-OHDA-induced increase in intracellular Zn2+ but not in intracellular Ca2+. These results suggest that the rapid influx of extracellular Zn2+ into dopaminergic neurons via AMPA receptor activation in the SNpc induces nigrostriatal dopaminergic neurodegeneration, resulting in 6 OHDA-induced PD in rats. PMID- 29705947 TI - Provably Secure Heterogeneous Access Control Scheme for Wireless Body Area Network. AB - Wireless body area network (WBAN) provides a medium through which physiological information could be harvested and transmitted to application provider (AP) in real time. Integrating WBAN in a heterogeneous Internet of Things (IoT) ecosystem would enable an AP to monitor patients from anywhere and at anytime. However, the IoT roadmap of interconnected 'Things' is still faced with many challenges. One of the challenges in healthcare is security and privacy of streamed medical data from heterogeneously networked devices. In this paper, we first propose a heterogeneous signcryption scheme where a sender is in a certificateless cryptographic (CLC) environment while a receiver is in identity-based cryptographic (IBC) environment. We then use this scheme to design a heterogeneous access control protocol. Formal security proof for indistinguishability against adaptive chosen ciphertext attack and unforgeability against adaptive chosen message attack in random oracle model is presented. In comparison with some of the existing access control schemes, our scheme has lower computation and communication cost. PMID- 29705948 TI - Variations in biochemical values for common laboratory tests: a comparison among multi-ethnic Israeli women cohort. AB - BACKGROUND: Biochemical laboratory values are an essential tool in medical diagnosis, treatment, and follow-up; however, they are known to vary between populations. Establishment of ethnicity-adjusted reference values is recommended by health organizations. AIM: To investigate the ethnicity element in biochemical lab values studying women of different ethnic groups. METHODS: Biochemical lab values (n = 27) of 503 adult Israeli women of three ethnicities (Jewish Ashkenazi, Jewish Sephardic, and Bedouin Arab) attending a single medical center were analyzed. Biochemical data were extracted from medical center records. Ethnic differences of laboratory biochemicals were studied using ANCOVA to analyze the center of the distribution as well as quartile regression analysis to analyze the upper and lower limits, both done with an adjustment for age. RESULTS: Significant ethnic differences were found in almost half (n = 12) of the biochemical laboratory tests. Ashkenazi Jews exhibited significantly higher mean values compared to Bedouins in most of the biochemical tests, including albumin, alkaline phosphatase, calcium, cholesterol, cholesterol LDL and HDL, cholesterol LDL calc., folic acid, globulin, and iron saturation, while the Bedouins exhibited the highest mean values in the creatinine and triglycerides. For most of these tests, Sephardic Jews exhibited biochemical mean levels in between the two other groups. Compared to Ashkenazi Jews, Sephardic Jews had a significant shift to lower values in cholesterol LDL. CONCLUSIONS: Ethnic subpopulations have distinct distributions in biochemical laboratory test values, which should be taken into consideration in medical practice enabling precision medicine. PMID- 29705949 TI - A network map of IL-33 signaling pathway. AB - Interleukin-33 (IL-33) is a member of the IL-1 family of cytokines that play a central role in the regulation of immune responses. Its release from epithelial and endothelial cells is mediated by pro-inflammatory cytokines, cell damage and by recognition of pathogen-associated molecular patterns (PAMPs). The activity of IL-33 is mediated by binding to the IL-33 receptor complex (IL-33R) and activation of NF-kappaB signaling via the classical MyD88/IRAK/TRAF6 module. IL 33 also induces the phosphorylation and activation of ERK1/2, JNK, p38 and PI3K/AKT signaling modules resulting in the production and release of pro inflammatory cytokines. Aberrant signaling by IL-33 has been implicated in the pathogenesis of several acute and chronic inflammatory diseases, including asthma, atopic dermatitis, rheumatoid arthritis and ulcerative colitis among others. Considering the biomedical importance of IL-33, we developed a pathway resource of signaling events mediated by IL-33/IL-33R in this study. Using data mined from the published literature, we describe an integrated pathway reaction map of IL-33/IL-33R consisting of 681 proteins and 765 reactions. These include information pertaining to 19 physical interaction events, 740 enzyme catalysis events, 6 protein translocation events, 4 activation/inhibition events, 9 transcriptional regulators and 2492 gene regulation events. The pathway map is publicly available through NetPath ( http://www.netpath.org /), a resource of human signaling pathways developed previously by our group. This resource will provide a platform to the scientific community in facilitating identification of novel therapeutic targets for diseases associated with dysregulated IL-33 signaling. Database URL: http://www.netpath.org/pathways?path_id=NetPath_120 . PMID- 29705950 TI - The Study of Language in the Amyotrophic Lateral Sclerosis - Frontotemporal Spectrum Disorder: a Systematic Review of Findings and New Perspectives. AB - Amyotrophic Lateral Sclerosis is a neurodegenerative disorder characterized primarily by motor network disruption. Extra-motor manifestations including executive functions, social cognition, and behavioral changes are now well recognized as important features of ALS, and are associated with frontotemporal and frontostriatal network disruption. However, the presence and characterization of language changes has received less attention. This systematic review characterizes the profile of reported language dysfunction in ALS. PRISMA guidelines were implemented to carry out and report the review. Current evidence suggests that areas of neuroanatomical disruption in ALS spread to language centers such as posterior, inferior frontal and superior temporal areas leading to deficits in word retrieval, syntactic and grammatical processing, and spelling. However, the majority of studies of language in ALS have been limited by the recruitment of small clinic-based prevalent samples and important questions remain regarding the incidence and progression of language impairment in ALS. Further studies from population-based incident cohorts will help to determine the range of language deficits in ALS, and how these relate to previously defined executive and behavioral sub-phenotypes. PMID- 29705951 TI - Fibroblast growth factor receptor 1 signaling transcriptionally regulates the axon guidance cue slit1. AB - Axons sense molecular cues in their environment to arrive at their post-synaptic targets. While many of the molecular cues have been identified, the mechanisms that regulate their spatiotemporal expression remain elusive. We examined here the transcriptional regulation of the guidance gene slit1 both in vitro and in vivo by specific fibroblast growth factor receptors (Fgfrs). We identified an Fgf responsive 2.3 kb slit1 promoter sequence that recapitulates spatiotemporal endogenous expression in the neural tube and eye of Xenopus embryos. We found that signaling through Fgfr1 is the main regulator of slit1 expression both in vitro in A6 kidney epithelial cells, and in the Xenopus forebrain, even when other Fgfr subtypes are present in cells. These data argue that a specific signaling pathway downstream of Fgfr1 controls in a cell-autonomous manner slit1 forebrain expression and are novel in identifying a specific growth factor receptor for in vivo control of the expression of a key embryonic axon guidance cue. PMID- 29705953 TI - Microbial ecological succession during municipal solid waste decomposition. AB - The decomposition of landfilled refuse proceeds through distinct phases, each defined by varying environmental factors such as volatile fatty acid concentration, pH, and substrate quality. The succession of microbial communities in response to these changing conditions was monitored in a laboratory-scale simulated landfill to minimize measurement difficulties experienced at field scale. 16S rRNA gene sequences retrieved at separate stages of decomposition showed significant succession in both Bacteria and methanogenic Archaea. A majority of Bacteria sequences in landfilled refuse belong to members of the phylum Firmicutes, while Proteobacteria levels fluctuated and Bacteroidetes levels increased as decomposition proceeded. Roughly 44% of archaeal sequences retrieved under conditions of low pH and high acetate were strictly hydrogenotrophic (Methanomicrobiales, Methanobacteriales). Methanosarcina was present at all stages of decomposition. Correspondence analysis showed bacterial population shifts were attributed to carboxylic acid concentration and solids hydrolysis, while archaeal populations were affected to a higher degree by pH. T RFLP analysis showed specific taxonomic groups responded differently and exhibited unique responses during decomposition, suggesting that species composition and abundance within Bacteria and Archaea are highly dynamic. This study shows landfill microbial demographics are highly variable across both spatial and temporal transects. PMID- 29705952 TI - Phosphatidylinositol-3,5-bisphosphate lipid-binding-induced activation of the human two-pore channel 2. AB - Mammalian two-pore channels (TPCs) are activated by the low-abundance membrane lipid phosphatidyl-(3,5)-bisphosphate (PI(3,5)P2) present in the endo-lysosomal system. Malfunction of human TPC1 or TPC2 (hTPC) results in severe organellar storage diseases and membrane trafficking defects. Here, we compared the lipid binding characteristics of hTPC2 and of the PI(3,5)P2-insensitive TPC1 from the model plant Arabidopsis thaliana. Combination of simulations with functional analysis of channel mutants revealed the presence of an hTPC2-specific lipid binding pocket mutually formed by two channel regions exposed to the cytosolic side of the membrane. We showed that PI(3,5)P2 is simultaneously stabilized by positively charged amino acids (K203, K204, and K207) in the linker between transmembrane helices S4 and S5 and by S322 in the cytosolic extension of S6. We suggest that PI(3,5)P2 cross links two parts of the channel, enabling their coordinated movement during channel gating. PMID- 29705954 TI - Rhodococcus strains as source for ene-reductase activity. AB - Rhodococcus strains are ubiquitous in nature and known to metabolise a wide variety of compounds. At the same time, asymmetric reduction of C=C bonds is important in the production of high-valued chiral building blocks. In order to evaluate if Rhodococci can be used for this task, we have probed several Rhodococcus rhodochrous and R. erythropolis strains for ene-reductase activity. A series of substrates including activated ketones, an aldehyde, an imide and nitro compound were screened using whole cells of seven Rhodococcus strains. This revealed that whole cells of all Rhodococcus strains showed apparent (S) selectivity towards ketoisophorone, while most other organisms show (R) selectivity for this compound. Three putative ene-reductases from R. rhodochrous ATCC 17895 were heterologously expressed in Escherichia coli. One protein was purified and its biocatalytic and biochemical properties were characterised, showing typical (enantioselective) properties for class 3 ene-reductases of the old yellow enzyme family. PMID- 29705955 TI - Identification and characterization from Candida glycerinogenes of hexose transporters having high efficiency at high glucose concentrations. AB - During high gravity fermentation, a set of hexose transporters in yeasts plays an important role in efficient sugar transport. However, hexose transporters have been studied mainly in the Saccharomyces cerevisiae model and at low or moderate sugar concentrations. The hexose transporters are still poorly understood in the industrial glycerol producer Candida glycerinogenes, which assimilates sugar efficiently at high glucose concentration. To explore these hexose transporters, 14 candidates were identified using a hidden Markov model and characterized. Five of these functioned as hexose transporters when expressed in S. cerevisiae. In particular, CgHxt4 showed the highest efficiency of glucose transport at elevated glucose concentration among a group of transporters including Hxt1 and Hxt7 from S. cerevisiae. qRT-PCR in C. glycerinogenes revealed that transcription of CgHXT4 was induced by high glucose concentrations while fluorescence localization analysis indicated that CgHxt4 remained relatively stable on the membrane under these conditions. In addition, site-directed mutagenesis revealed that the asparagine 329 from CgHxt4, located in the YYX(T/P) conserved motif of hexose transporters, promoted an increased glucose transport. Overexpressing CgHXT4 in S. cerevisiae enhanced glucose consumption and ethanol production more effectively at high glucose concentrations than ScHXT1, the most significant native transporter from S. cerevisiae. These results indicate that CgHxt4 plays an important role in the fermentation process as a hexose transporter with strong transport activity and efficient expression regulation at high glucose concentrations. PMID- 29705956 TI - Production of methoxylated flavonoids in yeast using ring A hydroxylases and flavonoid O-methyltransferases from sweet basil. AB - Numerous methoxylated flavonoids exhibit pronounced bioactivities. Their biotechnological production and diversification are therefore of interest to pharmaceutical and nutraceutical industries. We used a set of enzymes from sweet basil (Ocimum basilicum) to construct five strains of Saccharomyces cerevisiae producing 8- and/or 6-substituted, methoxylated flavones from their natural precursor apigenin. After identifying several growth parameters affecting the overall yields and flux, we applied optimized conditions and explored the ability of the generated strains to utilize alternative substrates. The yeast cells produced substantial amounts of 6-hydroxylated, methylated derivatives of naringenin and luteolin while the corresponding derivatives of flavonol kaempferol were only detected in trace amounts. Analysis of the intermediates and by-products of the different bioconversions suggested that the substrate specificity of both the hydroxylases and the flavonoid O-methyltransferases is imposing barriers on yields obtained with alternative substrates and highlighted steps that appear to represent bottlenecks en route to increasing the strains' efficiencies. Additionally, analysis of flavonoid localization during fermentation revealed unequal distribution with strong intracellular accumulation of a number of methylated flavonoids and extracellular enrichment of several pathway intermediates. This work establishes a platform for the production of complex methoxylated flavonoids and discusses strategies for its improvement. PMID- 29705958 TI - Effects of transcriptional mode on promoter substitution and tandem engineering for the production of epothilones in Myxococcus xanthus. AB - Promoter optimization is an economical and effective approach to overexpress heterologous genes and improve the biosynthesis of valuable products. In this study, we swapped the original promoter of the epothilone biosynthetic gene cluster in Myxococcus xanthus with two endogenous strong promoters P pilA and P groEL1 , respectively, which, however, decreased the epothilone production ability. The transcriptional abilities by the two promoters were found to be bloomed in the growth stage but markedly decreased after the growth, whereas the original promoter P epo functioned majorly after the exponential growth stage. Tandem repeat engineering on the original promoter P epo remarkably increased epothilone production. The tandem promoter exerted similar expressional pattern as P epo did in M. xanthus. We demonstrated that differential transcriptional modes markedly affected the efficiency of promoters in controlling the gene expressions for the production of the secondary metabolite epothilones. Our study provides an insight into exploiting powerful promoters to produce valuable secondary metabolites, especially in host with limited known promoters. PMID- 29705959 TI - Molecular cloning, codon-optimized gene expression, and bioactivity assessment of two novel fungal immunomodulatory proteins from Ganoderma applanatum in Pichia. AB - Fungal immunomodulatory proteins (FIPs) have been identified from a series of fungi, especially in Ganoderma species. However, little is known about the FIPs from G. applanatum. In this study, two novel FIP genes, termed as FIP-gap1 and FIP-gap2, were cloned from G. applanatum, characterized and functionally expressed after codon optimization in Pichia pastoris GS115. Results showed that FIP-gap1 and FIP-gap2 comprised 342-bp encoding peptides of 113 amino acids, which shared a high homology with other Ganoderma FIPs. The yield of recombinant FIP-gap1 and FIP-gap2 increased significantly after codon optimization and reached 247.4 and 197.5 mg/L, respectively. Bioactivity assay in vitro revealed that both rFIP-gap1 and rFIP-gap2 could agglutinate mouse, sheep, and human red blood cells. Besides, rFIP-gap1 and rFIP-gap2 obviously stimulated the proliferation of mouse splenocytes and enhanced IL-2 and IFN-gamma release. Cytotoxicity detection indicated that IC50 of rFIP-gap1 towards A549 and HeLa cancer cells were 29.89 and 8.34 MUg/mL, respectively, whereas IC50 of rFIP-gap2 to the same cancer cells were 60.92 and 41.05 MUg/mL, respectively. Taken together, novel FIP gaps were cloned and functionally expressed in P. pastoris, which can serve as feasible and stable resources of rFIP gaps for further studies and potential applications. PMID- 29705957 TI - The mechanisms of granulation of activated sludge in wastewater treatment, its optimization, and impact on effluent quality. AB - Granular activated sludge has gained increasing interest due to its potential in treating wastewater in a compact and efficient way. It is well-established that activated sludge can form granules under certain environmental conditions such as batch-wise operation with feast-famine feeding, high hydrodynamic shear forces, and short settling time which select for dense microbial aggregates. Aerobic granules with stable structure and functionality have been obtained with a range of different wastewaters seeded with different sources of sludge at different operational conditions, but the microbial communities developed differed substantially. In spite of this, granule instability occurs. In this review, the available literature on the mechanisms involved in granulation and how it affects the effluent quality is assessed with special attention given to the microbial interactions involved. To be able to optimize the process further, more knowledge is needed regarding the influence of microbial communities and their metabolism on granule stability and functionality. Studies performed at conditions similar to full-scale such as fluctuation in organic loading rate, hydrodynamic conditions, temperature, incoming particles, and feed water microorganisms need further investigations. PMID- 29705960 TI - Solvent production by engineered Ralstonia eutropha: channeling carbon to biofuel. AB - Microbial production of solvents like acetone and butanol was a couple of the first industrial fermentation processes to gain global importance. These solvents are important feedstocks for the chemical and biofuel industry. Ralstonia eutropha is a facultatively chemolithoautotrophic bacterium able to grow with organic substrates or H2 and CO2 under aerobic conditions. This bacterium is a natural producer of polyhydroxyalkanoate biopolymers. Recently, with the advances in the development of genetic engineering tools, the range of metabolites R. eutropha can produce has enlarged. Its ability to utilize various carbon sources renders it an interesting candidate host for synthesis of renewable biofuel and solvent production. This review focuses on progress in metabolic engineering of R. eutropha for the production of alcohols, terpenes, methyl ketones, and alka(e)nes using various resources. Biological synthesis of solvents still presents the challenge of high production costs and competition from chemical synthesis. Better understanding of R. eutropha biology will support efforts to engineer and develop superior microbial strains for solvent production. Continued research on multiple fronts is required to engineer R. eutropha for truly sustainable and economical solvent production. PMID- 29705961 TI - Development of a versatile high-temperature short-time (HTST) pasteurization device for small-scale processing of cell culture medium formulations. AB - The compatibility of CHO cell culture medium formulations with all stages of the bioprocess must be evaluated through small-scale studies prior to scale-up for commercial manufacturing operations. Here, we describe the development of a bespoke small-scale device for assessing the compatibility of culture media with a widely implemented upstream viral clearance strategy, high-temperature short time (HTST) treatment. The thermal stability of undefined medium formulations supplemented with soy hydrolysates was evaluated upon variations in critical HTST processing parameters, namely, holding times and temperatures. Prolonged holding times of 43 s at temperatures of 110 degrees C did not adversely impact medium quality while significant degradation was observed upon treatment at elevated temperatures (200 degrees C) for shorter time periods (11 s). The performance of the device was benchmarked against a commercially available mini-pilot HTST system upon treatment of identical formulations on both platforms. Processed medium samples were analyzed by untargeted LC-MS/MS for compositional profiling followed by chemometric evaluation, which confirmed the observed degradation effects caused by elevated holding temperatures but revealed comparable performance of our developed device with the commercial mini-pilot setup. The developed device can assist medium optimization activities by reducing volume requirements relative to commercially available mini-pilot instrumentation and by facilitating fast throughput evaluation of heat-induced effects on multiple medium lots. PMID- 29705962 TI - Recent advances in glyphosate biodegradation. AB - Glyphosate has emerged as the most widespread herbicide to control annual and perennial weeds. Massive use of glyphosate for decades has resulted in its ubiquitous presence in the environment, and poses a threat to humans and ecosystem. Different approaches such as adsorption, photocatalytic degradation, and microbial degradation have been studied to break down glyphosate in the environment. Among these, microbial degradation is the most effective and eco friendly method. During its degradation, various microorganisms can use glyphosate as a sole source of phosphorus, carbon, and nitrogen. Major glyphosate degradation pathways and its metabolites have been frequently investigated, but the related enzymes and genes have been rarely studied. There are many reviews about the toxicity and fate of glyphosate and its major metabolite, aminomethylphosphonic acid. However, there is lack of reviews on biodegradation and bioremediation of glyphosate. The aims of this review are to summarize the microbial degradation of glyphosate and discuss the potential of glyphosate degrading microorganisms to bioremediate glyphosate-contaminated environments. This review will provide an instructive direction to apply glyphosate-degrading microorganisms in the environment for bioremediation. PMID- 29705963 TI - Metabolite diagnosis of primary hyperoxaluria type 3. AB - BACKGROUND: Primary hyperoxaluria type 3 (PH3) is a recently described cause of childhood renal calculi. It results from mutations in the HOGA1 gene and most cases have been diagnosed after clinical ascertainment, exclusion of other genetic hyperoxalurias and mutation testing. Metabolite testing has not been widely applied but holds promise for the rapid screening and diagnosis of patients who are not specifically suspected to have PH3. CASE DIAGNOSIS/TREATMENT: Two cases presented with renal calculi. Urine metabolite testing by tandem mass spectrometry was performed as part of the routine diagnostic work-up for this condition. Both had significantly increased levels of the PH3 urine marker 4-hydroxyglutamate and related metabolites. The diagnosis of PH3 was confirmed by the finding of bi-allelic damaging HOGA1 mutations. CONCLUSIONS: Urine screening by tandem mass spectrometry is a rapid, high throughput test that can detect PH3 cases that may otherwise not be diagnosed. PMID- 29705964 TI - Morphological deformities of benthic foraminifera in response to nearshore pollution of the Red Sea, Egypt. AB - The Red Sea encompasses a wide range of tropical marine habitats that are stressed due to anthropogenic activities. The main anthropogenic activities are hydrocarbon exploration and important trading harbors. This work aims to assess the influence of the Red Sea coastal heavy metal contamination on the marine meiofauna along three sites (Ras Gharib, Safaga, and Quseir). Eight heavy metal (Cu, Cd, Zn, Pb, Cr, Co, Ni, and Mn) contents are considered in four benthic foraminiferal species (Elphidium striatopunctatum, Amphistegina lobifera, Amphisorus hemprichii, and Ammonia beccarii). Quseir Harbor showed the highest level of pollution followed by Safaga and Ras Gharib sites. The analyzed benthic foraminiferal tests displayed noteworthy high concentrations of Cd, Zn, and Pb in Quseir Harbor which could be attributed to the anthropogenic activities in the nearshore areas. Some foraminiferal tests exhibited abnormalities in their apertures, coiling, and shape of chambers. A comparison between normal and deformed foraminiferal tests revealed that the deformed ones are highly contaminated with elevated heavy metal contents such as Fe, Mn, Ni, and Cd. Statistics in addition to geo-accumulation and pollution load indices reveal a whistling alarm for the Quseir harbor. The present data are necessary to improve conservation and management of the Red Sea ecosystem in the near future. PMID- 29705965 TI - Evaluation of implant screw loosening by resonance frequency analysis with triaxial piezoelectric pick-up: in vitro model and in vivo animal study. AB - OBJECTIVE: The aim of this study was to evaluate implant screw loosening using resonance frequency (RF) analysis with triaxial piezoelectric pick-up in vitro and in vivo. METHODS: For the in vitro experiment, a titanium implant was inserted into a mandibular model. The abutment screws were tightened to 10 N torque and loosened from 0 to 90 degrees for RF measurement using 13 different screw conditions. In the in vivo experiment, three titanium implants were installed in each tibia of a New Zealand white rabbit, and the RF values were recorded after 8 weeks. For the RF analyses, a small 3D accelerometer was mounted rigidly onto the implant abutment, and impulsive vibration was directly applied to the abutment to vibrate the implant in a direction perpendicular to the tibia and implant (x-axis). The y-axis was defined as parallel to the tibia. The RF values of the x- and y-axis directions (RF-X and RF-Y) were used for evaluation. RESULTS: The RF values significantly decreased according to the degree of screw loosening (p < 0.05, ANOVA). In the in vitro model, RF-Y with x- and y-axis vibrations (RF-Yx and RF-Yy) significantly differed from the initial value at 10 and 15 degrees , respectively (p < 0.05, Dunnett's test). In the in vivo experiment, the RF-Yy significantly differed from the initial value between 5 and 20 degrees (p < 0.05). CONCLUSION: The results suggest that RF analysis with triaxial piezoelectric pick-up can be used to detect implant screw loosening. CLINICAL RELEVANCE: RF analysis with the triaxial piezoelectric pick-up can be used to detect screw loosening after mounting the superstructure. PMID- 29705966 TI - Molecular cloning of adipose triglyceride lipase (ATGL) gene from blunt snout bream and its expression after LPS-induced TNF-alpha factor. AB - The aims of the present study were to clone the full-length cDNA of adipose triglyceridelipase (ATGL) and to analyze its expression after lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha). The cDNA obtained covered 1801 bp with an open reading frame of 1500 bp encoding 499 amino acids. Sequence alignment and phylogenetic analysis show the best identity with Cyprinus carpio (86%). The ATGL protein shared a highly conserved 169-amino acid patatin domain, containing a glycine-rich motif, an active serine hydrolase motif, and an aspartic active site. The highest ATGL expression was observed in the liver followed by muscle, whereas relatively low values were detected in the brain and adipose. TNF-alpha is regarded as an important factor in regulating fat metabolism. Here, LPS was used to induce TNF-alpha in vivo to verify whether TNF alpha can affect ATGL expression. TNF-alpha expression in liver and muscle is increased and remains unchanged in adipose tissue and brain. The variation of ATGL activity is consistent with that of TNF-alpha gene expression. Next, we explored the mechanism by which LPS-induced TNF-alpha mediates the mRNA expression of ATGL in the liver and muscle. For liver, the mRNA levels of c-Jun N terminal kinase (JNK), nuclear factor kappa B (NF-kappaB), Sirtuin 1 (SIRT1), and AMP-activated protein kinase (AMPK) were increased by LPS-induced TNF-alpha. Differencing from the situation in the liver, there was a near-significant decrease trend in the expression of SIRT1 in muscle. Those results indicated that the ATGL gene of blunt snout bream shared a high similarity with the other vertebrates. The expression level of ATGL in tissues with high-fat content was intended to be high. LPS can induce ATGL expression perhaps related to TNF-alpha. PMID- 29705967 TI - Diminutive intramucosal invasive (Tis) sigmoid colon carcinoma. AB - A 60-year-old woman underwent colonoscopy, which revealed a red, 5-mm protruded lesion in the sigmoid colon, surrounded by white spots in white-light imaging. Indigo carmine spray indicated endoscopic morphological type Is + IIc. The vessel pattern was diagnosed as JNET-type 2B in magnifying narrow-band imaging, and magnified crystal violet-stained images revealed a VI low-grade pit pattern. We endoscopically diagnosed this lesion as an intramucosal or slightly invasive submucosal carcinoma with low confidence, and performed endoscopic mucosal resection to obtain a total biopsy. Hematoxylin and eosin staining of the resected specimen showed that the surface of the lesion was well-differentiated adenocarcinoma. The muscularis mucosae was identified by desmin immunostaining. There was no lymphovascular infiltration. Structural atypia was notable in the invasive front, indicating well-to-moderately differentiated adenocarcinoma, which invaded the lamina muscularis mucosae. In addition, desmoplastic reaction was recognized to be present. The lesion was, therefore, diagnosed as an intramucosal invasive (Tis) carcinoma, rather than high-grade dysplasia, according to the World Health Organization definition. PMID- 29705968 TI - Performance validation of an amplicon-based targeted next-generation sequencing assay and mutation profiling of 648 Chinese colorectal cancer patients. AB - Next-generation sequencing (NGS) has become a promising approach for tumor somatic mutation detection. However, stringent validation is required for its application on clinical specimens, especially for low-quality formalin-fixed paraffin-embedded (FFPE) tissues. Here, we validated the performance of an amplicon-based targeted NGS assay, OncoAimTM DNA panel, on both commercial reference FFPE samples and clinical FFPE samples of Chinese colorectal cancer (CRC) patients. Then we profiled the mutation spectrum of 648 Chinese CRC patients in a multicenter study to explore its clinical utility. This NGS assay achieved 100% test specificity and 95-100% test sensitivity for variants with mutant allele frequency (MAF) >= 5% when median read depth >= 500*. The orthogonal methods including amplification refractory mutation system (ARMS)-PCR and Sanger sequencing validated that NGS generated three false negatives (FNs) but no false positives (FPs) among 516 clinical samples for KRAS aberration detection. Genomic profiling of Chinese CRC patients with this assay revealed that 63.3% of the tumors harbored clinically actionable alterations. Besides the commonly mutated genes including TP53 (52.82%), KRAS (46.68%), APC (24.09%), PIK3CA (18.94%), SMAD4 (9.47%), BRAF (6.15%), FBXW7 (5.32%), and NRAS (4.15%), other less frequently mutated genes were also identified. Statistically significant association of specific mutated genes with certain clinicopathological features was detected, e.g., both BRAF and PIK3CA were more prevalent in right-side CRC (p < 0.001 and p = 0.002, respectively). We concluded this targeted NGS assay is qualified for clinical practice, and our findings could help the diagnosis and prognosis of Chinese CRC patients. PMID- 29705970 TI - "I would rather have it done by a doctor"-laypeople's perceptions of direct-to consumer genetic testing (DTC GT) and its ethical implications. AB - Direct-to-consumer genetic testing (DTC GT) has been available for several years now, with varying degrees of regulation across different countries. Despite a restrictive legal framework it is possible for consumers to order genetic tests from companies located in other countries. However, German laypeople's awareness and perceptions of DTC GT services is still unexplored. We conducted seven focus groups (participants n = 43) with German laypeople to explore their perceptions of and attitudes towards commercial genetic testing and its ethical implications. Participants were critical towards DTC GT. Criticism was directed at health related, predictive testing, while lifestyle tests were accepted and even welcomed to some extent. Participants expressed strong reservations regarding commercial provision of genetic diagnostics and expressed a lack of trust in respective companies. They preferred non-commercial distribution within the public healthcare system. Participants also expressed high expectations of physicians' abilities to interpret information obtained via DTC GT companies and provide counseling. Legal restrictions on commercial distribution of genetic tests were opposed, with participants arguing that it should be available to consumers. DTC GT companies are not perceived as trustworthy when compared to the public healthcare system and its professional ethical standards and practices. Laypeople rated general consumer autonomy higher than their own concerns, thus recommending against strong legal regulation. We conclude that medicine's trustworthiness may be negatively affected if commercial provision is not visibly opposed by the medical professions, while DTC GT companies may gain in trustworthiness if they adapt to standards and practices upheld in medicine. PMID- 29705969 TI - The impact of complete embedding of remaining tissue in gynecological lymph node dissection specimen in surgical pathology on lymph node yield: is it clinically relevant? AB - The assessment of nodal metastases in gynecological surgical specimen is an important staging parameter, directing further therapeutic procedures. Since the number of lymph nodes (LNs) removed is seen as an indicator of surgical and pathological quality, the demand for higher lymph node (LN) counts is raising. The goal of this prospective study was the comparison between lymph node counts of macroscopically detectable LNs and the LN yield by complete embedding and proceeding of all submitted LN-containing tissue in the pathology laboratory. One hundred six cases of cervical, uterine, or ovarian cancer, treated in three different hospitals within 3 years, were analyzed. All tissue submitted to the pathology from the surgically performed LN dissections was completely dissected and embedded in the institute of pathology. Subsequently, the amount of LN of all macroscopically detectable nodes was compared to the final histologically reached numbers of LN. Furthermore the histologically visible area of the LNs and their metastases was analyzed to assess the relation of LN numbers to the whole examined LN area. Complete embedding raises the average number of LN counted by 3 to 7 but did only minimally increase the LN area for microscopical examination by about 5% due to the small area of the additional LNs in the remaining fat tissue. The staging was in no case altered by complete embedding, even when additional nodal metastases were detected in the remaining fat tissue, since this was only seen in cases which had already metastatic nodes. Complete embedding of LN containing tissue did not provide relevant additional staging information and seems therefore unnecessarily laborious, careful pathological work-up assumed. PMID- 29705971 TI - Roles of catechol neurochemistry in autonomic function testing. AB - Catechols are a class of compounds that contain adjacent hydroxyl groups on a benzene ring. Endogenous catechols in human plasma include the catecholamines norepinephrine, epinephrine (adrenaline), and dopamine; the catecholamine precursor DOPA, 3,4-dihydroxyphenylglycol (DHPG), which is the main neuronal metabolite of norepinephrine; and 3,4-dihydroxyphenylacetic acid (DOPAC), which is the main neuronal metabolite of dopamine. In the diagnostic evaluation of patients with known or suspected dysautonomias, measurement of plasma catechols is rarely diagnostic but often is informative. This review summarizes the roles of clinical catechol neurochemistry in autonomic function testing. PMID- 29705972 TI - P-Tau and Subunit c Mitochondrial ATP Synthase Accumulation in the Central Nervous System of a Woman with Hurler-Scheie Syndrome Treated with Enzyme Replacement Therapy for 12 Years. AB - We report an autopsy case of a woman with mucopolysaccharidosis type I (MPS I) Hurler-Scheie syndrome who was treated with enzyme replacement therapy (ERT) for 12 years. This was the first case of MPS I treated with ERT in Japan. Pathological analysis showed no glycosaminoglycan accumulation in the liver and spleen as a result of long-term ERT, although severe aortic stenosis, diffuse intimal hyperplasia of the coronary artery, and fibrous hypertrophy of the endocardium were observed. Additionally, we detected subunit c mitochondrial ATP synthase (SCMAS) accumulation and mild tauopathy (hyperphosphorylated tau or p tau, both 3-repeat and 4-repeat tau accumulation) in the same area of the cerebral limbic system and central gray matter of the mid brain and pons. Tauopathy is an important pathological finding in Alzheimer's disease and other neurodegenerative disorders; however, in MPS I, it is unclear whether tauopathy is a primary or secondary phenomenon. Thus, in this report, we describe pathological accumulation of p-tau and SCMAS in the context of MPS I and discuss the mechanisms and importance of these findings in the pathogenesis of MPS I. PMID- 29705973 TI - Review of autopsy reports of deaths relating to fire in South Australia 2000 2015. AB - It has been noted there are gaps and inconsistencies in data pertaining to fire related deaths in Australia, which poses difficulties for analysis of national statistics. A search of post-mortem examination reports at Forensic Science SA from 2000 to 2015 revealed 275 cases regarded as fire related in which the body had been involved in a fire. The autopsy reports were evaluated to determine parameters including the location of the fire event, age and sex of victim, as well as the presence of soot in the airways and cherry-red coloration to the blood and/or organs, in addtion to toxicological levels of carboxyhemoglobin and alcohol. Fire events were clasified as structural, transportation or open air in type. Males were more commonly victims than females, especially in transportation fires, where males aged below 50 years were most at risk of death. Carboxyhemoglobin levels tended to be lower in victims of transportation fires. This study has confirmed that presence of soot in the respiratory tract and cherry-red coloration of a body retrieved from a fire are both linked to an increased level of blood carboxyhemoglobin. These findings significantly contribute to the documentation of fire deaths in Australia. PMID- 29705974 TI - Extreme hypercalcemia in a kidney transplant recipient. AB - Post-transplant hypercalcemia is a major problem in renal transplant recipients, which may negatively affect both graft and patient survival. In this paper, we present a 66-year-old male kidney transplant recipient, who was admitted to our clinic with symptoms of fever, nausea, vomiting and lethargy. Laboratory data showed good renal function; however, a serum calcium level of 22.1 mg/dL. The patient was treated by isotonic saline together with furosemide and methylprednisolone. Because of treatment resistance, subcutaneous calcitonin and ibandronate were added to the treatment protocol as well. Since all these medications were not effective, hemodialysis with low-calcium (1.25 mmol/L) dialysate was applied for three consecutive days, which resulted in normalization of serum calcium. Several investigations were carried out for diagnosing the underlying etiology. Positron-emission tomography (PET)/CT revealed a strong diffuse uptake of FDG in the bones and spleen. A bone marrow biopsy showed diffuse interstitial infiltration of CD20 + neoplastic B cells and, thus, post transplant lymphoproliferative disease (PTLD) was diagnosed. Tacrolimus was switched to everolimus, mycophenolate mofetil was stopped, while treatment with R CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) was initiated. Despite all therapeutic interventions, the patient died of septic shock in the intensive care unit on the 10th day of emergency service admission. Importance of hemodialysis as an emergent treatment modality in extreme hypercalcemia, and unfavorable course of PTLD were underlined. PMID- 29705975 TI - Patterns of microcracking in apple fruit skin reflect those of the cuticular ridges and of the epidermal cell walls. AB - MAIN CONCLUSION: Microcracks in the cuticle of developing apples are aligned with ridges on the inner cuticle surface and are indicative of stress-strain concentrations above the anticlinal cell walls. Microcracks occur in cuticles of most fruits. Growth strains are considered causal. In apples (Malus * domestica), microcracks usually form a mesh pattern similar to that formed by cuticular ridges. Ridge patterns are similar to those of the epidermal cells' anticlinal walls. Our aim was to identify the mechanistic bases for these pattern similarities. By quantifying ridge depth, ridge width, and the areas enclosed by ridges, we reveal the presence of major and minor ridges. Major ridges enclose two-to-four epidermal cells, minor ridges only one cell. There are similar and overlying patterns of microcracking on the cuticle's outer surface and of ridges on its inner surface-microcracks generally follow the outlines of the major ridges. In biaxial tensile tests at 20 kPa, strains were low and microcracks shallow, but at > 40 kPa, strains were higher and microcracks deeper. Microcracks traversing the cuticle are usually aligned with the anticlinal walls of the underlying epidermal cells. In general, increased skin strain is associated with increased skin transpiration. Transpiration increases are reversible for low strains but irreversible for high strains. The alignment of cuticular microcracks with the major ridges, and these with the anticlinal cell walls, indicates associated stress/strain concentrations. PMID- 29705977 TI - New Features for Neuron Classification. AB - This paper addresses the problem of obtaining new neuron features capable of improving results of neuron classification. Most studies on neuron classification using morphological features have been based on Euclidean geometry. Here three one-dimensional (1D) time series are derived from the three-dimensional (3D) structure of neuron instead, and afterwards a spatial time series is finally constructed from which the features are calculated. Digitally reconstructed neurons were separated into control and pathological sets, which are related to three categories of alterations caused by epilepsy, Alzheimer's disease (long and local projections), and ischemia. These neuron sets were then subjected to supervised classification and the results were compared considering three sets of features: morphological, features obtained from the time series and a combination of both. The best results were obtained using features from the time series, which outperformed the classification using only morphological features, showing higher correct classification rates with differences of 5.15, 3.75, 5.33% for epilepsy and Alzheimer's disease (long and local projections) respectively. The morphological features were better for the ischemia set with a difference of 3.05%. Features like variance, Spearman auto-correlation, partial auto correlation, mutual information, local minima and maxima, all related to the time series, exhibited the best performance. Also we compared different evaluators, among which ReliefF was the best ranked. PMID- 29705976 TI - Feasibility study of postoperative adjuvant chemotherapy with S-1 in patients with biliary tract cancer. AB - BACKGROUND: The role of adjuvant chemotherapy has not yet been established for patients with resected biliary tract cancer. S-1 has been shown to exert activity against advanced biliary tract cancer. Therefore, we evaluated the feasibility of adjuvant chemotherapy with S-1 in patients with resected biliary tract cancer. METHODS: Patients with complete macroscopic resection of intrahepatic/extrahepatic bile duct, gall bladder, or ampullary cancer were eligible. S-1 was administered orally twice daily for 4 weeks every 6 weeks, up to 4 cycles. The treatment was continued up to 24 weeks or until recurrence/appearance of unacceptable toxicity. The primary endpoint was the treatment completion rate, which was defined as the percentage of patients who received a relative dose intensity of >= 75%. This trial was registered as UMIN000004051. RESULTS: Thirty-three patients were enrolled between June 2010 and March 2011. The relative dose intensity was >= 75% in 27 patients representing a treatment completion rate of 81.8%. The most common grade 3/4 adverse event was neutropenia (18%). Grade 2 nausea or diarrhea was observed in 12%. The 3-year relapse-free survival rate was 39.4%. The 3-year survival rate was 54.5%. CONCLUSION: Adjuvant chemotherapy with S-1 is feasible treatment in patients with resected biliary tract cancer. It is necessary to conduct a phase III study to confirm the efficacy of adjuvant therapy of S-1 in patients with resected BTC. PMID- 29705979 TI - Achieving Service Change Through the Implementation of a Trauma-Informed Care Training Program Within a Mental Health Service. AB - As evidence continues to accumulate for the association between childhood trauma and long-term adverse outcomes, Trauma-Informed Care (TIC) approaches are emerging as fundamental to contemporary mental health services. To evaluate a workshop designed to influence mental health practitioners in TIC principles and practices. Nursing, medical and allied health professionals completed pre and post measures of confidence, awareness and attitudes towards TIC practice. The workshop was rated as highly relevant and useful to clinician's practice. Participants' self-reported confidence, awareness and attitudes towards TIC significantly increased (p < .001) and the perceived number of barriers to working within a TIC framework significantly decreased (p < .05). Child and Adolescent Mental Health clinicians routinely screened for trauma and 80% had received training in a trauma specific intervention at follow-up. This brief training provides an important foundation for the development of trauma-informed, evidence-based mental health services. PMID- 29705978 TI - High-depth whole genome sequencing of an Ashkenazi Jewish reference panel: enhancing sensitivity, accuracy, and imputation. AB - While increasingly large reference panels for genome-wide imputation have been recently made available, the degree to which imputation accuracy can be enhanced by population-specific reference panels remains an open question. Here, we sequenced at full-depth (>= 30*), across two platforms (Illumina X Ten and Complete Genomics, Inc.), a moderately large (n = 738) cohort of samples drawn from the Ashkenazi Jewish population. We developed a series of quality control steps to optimize sensitivity, specificity, and comprehensiveness of variant calls in the reference panel, and then tested the accuracy of imputation against target cohorts drawn from the same population. Quality control (QC) thresholds for the Illumina X Ten platform were identified that permitted highly accurate calling of single nucleotide variants across 94% of the genome. QC procedures also identified numerous regions that are poorly mapped using current reference or alternate assemblies. After stringent QC, the population-specific reference panel produced more accurate and comprehensive imputation results relative to publicly available, large cosmopolitan reference panels, especially in the range of rare variants that may be most critical to further progress in mapping of complex phenotypes. The population-specific reference panel also permitted enhanced filtering of clinically irrelevant variants from personal genomes. PMID- 29705981 TI - Reconstructive Microsurgery: From a Set of Skills to a Stand-Alone Specialty of Elite Surgeons. PMID- 29705980 TI - Blastic plasmacytoid dendritic cell neoplasm arising from clonal hematopoiesis. AB - Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare subtype of myeloid neoplasm. Clonal evolution in the development of BPDCN remains to be elucidated. In the present study, we examined clonal evolution in a case of BPDCN by analyzing the distribution of gene mutations in tumor cells and non-tumor blood cells. The p.D1129fs and p.K1005fs TET2 mutations, p.P95H SRSF2 mutation, and p.L287fs NPM1 mutation were identified in a skin tumor at diagnosis and peripheral blood mononuclear cells at relapse. Notably, the p.D1129fs TET2 and p.L287fs NPM1 mutations were observed only in tumor cells, while the p.K1005fs TET2 and p.P95H SRSF2 mutations were found in both tumor cells and non-tumor blood cells. Recent genetic studies have suggested that some blood cancers may originate from clonal hematopoiesis, harboring somatic mutations. In the present case, the data suggest that BPDCN originated from clonal hematopoiesis with the p.K1005fs TET2 and p.P95H SRSF2 mutations via acquisition of the additional p.D1129fs TET2 and p.L287fs NPM1 mutations. PMID- 29705982 TI - Urinary and Fecal Diversion Following Pelvic Exenteration: Comparison of Double Barrelled and Plain Wet Colostomy. AB - PURPOSE: To assess early and late-term outcomes of patients who had undergone pelvic exenteration and simultaneous fecal and urinary diversion with plain wet colostomy (PWC) or double-barrelled wet colostomy (DBWC). MATERIALS AND METHODS: The medical records of all patients who had undergone pelvic exenteration and urinary diversion between 2006 and 2017 at our hospital were reviewed retrospectively. RESULTS: In total, 15 patients with a mean age of 56 +/- 13 years were included in the study. Simultaneous urinary and fecal diversions were carried out as PWC (n = 8), or DBWC (n = 7). No significant differences were found between PWC and DBWC groups in terms of operation time (373.7 +/- 66.5 versus 394.2 +/- 133.2 min, P = .955), estimated blood loss (862.8 +/- 462.4 versus 726.2 +/- 489.4 mL, P = .613), length of hospital stay (13.2 +/- 9.1 versus 14.1 +/-6.9 days), early complications (25% versus 28.6%, P = 1.0) and late term complications (37.5% versus 42.9%, P = 1.0). The rate of recurrent pyelonephritis in PWC group was higher than DBWC group but not statistically significant (37.5% versus 14.3%, P = .569). Overall survival (OS) of the patients was 385 +/- 91 days. There was no difference between OS of patients with PWC and DBWC (414 +/- 165 versus 352 +/- 70 days, P = .618). CONCLUSION: PWC and DBWC are valid options for creating simultaneous urinary and fecal diversion after extensive pelvic surgery in patients with short life expectancy. DBWC might be superior to PWC in terms of decreased risk of recurrent pyelonephritis. PMID- 29705983 TI - Current practices for the prophylaxis against bone mineral density loss in patients with autoimmune blistering disease treated with corticosteroids: an expert survey. PMID- 29705984 TI - Drivers of leaf carbon exchange capacity across biomes at the continental scale. AB - Realistic representations of plant carbon exchange processes are necessary to reliably simulate biosphere-atmosphere feedbacks. These processes are known to vary over time and space, though the drivers of the underlying rates are still widely debated in the literature. Here, we measured leaf carbon exchange in >500 individuals of 98 species from the Neotropics to high boreal biomes to determine the drivers of photosynthetic and dark respiration capacity. Covariate abiotic (long- and short-term climate) and biotic (plant type, plant size, ontogeny, water status) data were used to explore significant drivers of temperature standardized leaf carbon exchange rates. Using model selection, we found the previous week's temperature and soil moisture at the time of measurement to be a better predictor of photosynthetic capacity than long-term climate, with the combination of high recent temperatures and low soil moisture tending to decrease photosynthetic capacity. Non-trees (annual and perennials) tended to have greater photosynthetic capacity than trees, and, within trees, adults tended to have greater photosynthetic capacity than juveniles, possibly as a result of differences in light availability. Dark respiration capacity was less responsive to the assessed drivers than photosynthetic capacity, with rates best predicted by multi-year average site temperature alone. Our results suggest that, across large spatial scales, photosynthetic capacity quickly adjusts to changing environmental conditions, namely light, temperature, and soil moisture. Respiratory capacity is more conservative and most responsive to longer-term conditions. Our results provide a framework for incorporating these processes into large-scale models and a data set to benchmark such models. PMID- 29705985 TI - Systematic review of pelvic floor interventions during pregnancy. AB - BACKGROUND: Pelvic floor interventions during pregnancy could reduce the impact of pregnancy and delivery on the pelvic floor. OBJECTIVE: To determine the effects of pelvic floor interventions during pregnancy on childbirth-related and pelvic floor parameters. SEARCH STRATEGY: PubMed, Embase, and LILACS were searched for reports published during between 1990 and 2016 in English, Spanish, or Portuguese. The search terms were "pregnancy," "pelvic floor muscle training," and related terms. SELECTION CRITERIA: Randomized controlled trials with healthy pregnant women were included. DATA COLLECTION AND ANALYSIS: Baseline and outcome data (childbirth-related parameters, pelvic floor symptoms) were compared for three interventions: EPI-NO (Tecsana, Munich, Germany) perineal dilator, pelvic floor muscle training, and perineal massage. MAIN RESULTS: A total of 22 trials were included. Two of three papers assessing EPI-NO showed no benefit. The largest study investigating pelvic floor muscle training reported a significant reduction in the duration of the second stage of labor (P<0.01), and this intervention also reduced the incidence of urinary incontinence (evaluated in 10 trials). Two of six trials investigating perineal massage reported that a lower rate of perineal pain was associated with this intervention. CONCLUSION: Pelvic floor muscle training and perineal massage improved childbirth-related parameters and pelvic floor symptoms, whereas EPI-NO showed no benefit. PMID- 29705986 TI - Psoriasis and multiple sclerosis: two diseases, one treatment. PMID- 29705987 TI - Habitat availability and ontogenetic shifts alter bottlenecks in size-structured fish populations. AB - For species that utilize different habitats throughout their life cycle, the habitat limitation at a given stage can act as a bottleneck on population abundance, impacting density-dependent processes such as individual growth and survival. We explore the influence of habitat limitation on population dynamics by developing a multi-stage population model based on lake-dwelling rainbow trout (Oncorhynchus mykiss) populations where adults occupy the lake habitat but use tributaries for spawning and juvenile rearing. The model details density dependent ecological processes and ontogenetic habitat shifts, harvest mortality, and the impact of climate on growth. We ran model simulations using a range of early life stage habitat availabilities and climatic conditions representative of the native range of rainbow trout in Canada and compared the results to empirical data. The results suggest that (1) increases in early life stage habitat leads to increases in population abundance but, due to density-dependent processes, also results in slower growing stunted populations; (2) population bottlenecks can occur at any life stage, even at the adult stage if spawning and rearing habitats are abundant; (3) when the level of competition for early life stages is increased, inter-cohort competition can lead to population cycles. The model's conclusions are further reinforced by empirical data showing a similar trend in the relationship between fish density and maximum size and providing evidence that limited early life stage habitat leads to lower fish densities and larger fish size. We provide a model that links environmental conditions to population dynamics and is useful for fisheries management and habitat conservation decisions. PMID- 29705988 TI - How home ventilation rates affect health: A literature review. AB - This paper reviews studies of the relationships between ventilation rates (VRs) in homes and occupant health, primarily respiratory health. Five cross-sectional studies, seven case-control studies, and eight intervention studies met inclusion criteria. Nearly all studies controlled for a range of potential confounders and most intervention studies included placebo conditions. Just over half of studies reported one or more statistically significant (SS) health benefits of increased VRs. Wheeze was most clearly associated with VR. No health outcomes had SS associations with VRs in the majority of statistical tests. Most studies that reported SS health benefits from increased VRs also had additional health outcomes that did not improve with increased VRs. Overall, the number of SS improvements in health with increased VRs exceeded the anticipated chance improvements by approximately a factor of seven. The magnitude of the improvements in health outcomes with increased VRs ranged from 20% to several fold improvements. In summary, the available research indicates a tendency for improvements in respiratory health with increased home VRs; however, health benefits do not occur consistently and other exposure control measures should be used together with ventilation. The research did not enable identification of a threshold VR below which adverse health effects occur. PMID- 29705989 TI - Panzi score as a parsimonious indicator of urogenital fistula severity derived from Goh and Waaldijk classifications. AB - OBJECTIVE: To derive a comprehensive system that allows a single score to define relative fistula severity. METHODS: The present observational study included women with urogenital fistula treated at the Panzi Hospital, Democratic Republic of Congo, or its outreach clinics across the Democratic Republic of Congo between September 1, 2013, and December 31, 2014. Fistula severity was assessed by Goh and Waaldijk classifications and surgical success was ascertained. Logistic regression was used to select fistula characteristics predictive of surgical failure, and to preliminarily verify the newly derived Panzi score. RESULTS: Overall, 837 women were included in the analysis. Goh or Waaldijk fistula descriptors associated with a higher probability of poor surgical outcomes in the unadjusted bivariate analysis were circumferential defect (P=0.007), proximity to the external urethral orifice (P=0.001), and size (P=0.001). These fistula characteristics were used to construct the Panzi score, which varied from 3 (most severe) to 0 (minor fistula). For each increase above 0, the odds of surgical failure increase by a factor of 1.65 (P<0.001). CONCLUSION: The Panzi score of urogenital fistula provided a data-driven, simple, comprehensive, and parsimonious score. It could be used to report group data, to provide continuous level data for use in higher order statistics, and to resolve issues such as the cut-off point for referring women to hospital in accordance with fistula complexity. PMID- 29705990 TI - A gentle floriphilic katydid Phaneroptera brevis can help with the pollination of Bidens pilosa. PMID- 29705991 TI - The therapeutic potential of TNF-alpha antagonists in toxic epidermal necrosis: insights from two cases and adverse event reports. PMID- 29705992 TI - Outpatients with acute osteoarticular infections had favourable outcomes when they received just oral antibiotics without intravenous antibiotics. AB - AIM: The traditional approach for acute paediatric osteoarticular infections (OAI) has comprised initial intravenous antibiotics followed by prompt oral antibiotics. We assessed how providing just oral antibiotics compared to the traditional two-step approach. METHODS: This prospective study was performed at the Hospital La Paz, Madrid, Spain, from September 2015 to September 2016. We compared 25 outpatients, with good general health and a mean age of 25 months who received just oral antibiotics, with 228 hospitalised children of a similar age who received intravenous and oral antibiotics from other hospitals in the Spanish Network of Osteoarticular Infections. RESULTS: The groups were comparable in terms of age, sex, fever, erythrocyte sedimentation rate value, C-reactive protein and diagnosis. The oral group comprised 15 with osteomyelitis, seven with septic arthritis, two with osteoarthritis and one with spondylodiscitis. This group had a lower percentage of Staphylococcus aureus (8% vs 26%, p = 0.06) and higher proportion of Kingella kingae (24% vs 9%, p = 0.017) than the intravenous group. There were complications (24%) and follow-up sequelae (6%) in the intravenous group, but none in the oral group. CONCLUSION: Outpatients with OAI who were in good general health had favourable outcomes when they received oral antibiotics without intravenous antibiotics. PMID- 29705993 TI - Directing adipose-derived stem cells into keratinocyte-like cells: impact of medium composition and culture condition. AB - BACKGROUND: Adipose-derived stem cells (ASC) are known to transdifferentiate into a wide range of different cell species in vitro including along the epidermal lineage. This property makes them a promising tool for regenerative medicine to restore the epidermal barrier. OBJECTIVE: This study is dedicated to identify in vitro conditions enabling transdifferentiation to a keratinocyte-like phenotype. In particular, the impact of different culture conditions (media compositions, 2D, 3D cultures) and extracellular matrix (ECM) molecules was evaluated. METHODS: Adipose-derived stem cells derived from subcutaneous abdominal fat were characterized by stemness-associated markers and subjected to different media. Epithelial differentiation in 2D cultures was monitored by pan-cytokeratin expression using flow cytometry and immunocytochemistry. To evaluate the impact of different ECM molecules on epidermal stratification, 3D cultures were produced, lifted to the air-liquid interface (ALI) and examined by histological analysis and quantitative real-time RT-PCR. RESULTS: We identified a medium composition containing retinoic acid, hydrocortisone, ascorbic acid and BMP-4 enabling maximum pan-cytokeratin expression in 2D cultures. Moreover, adhesion to type IV collagen further promotes the pan-cytokeratin expression. When cultures were lifted to the ALI, significant stratification was observed, particularly in supports coated with type IV collagen or fibronectin. Moreover, epidermal differentiation markers (involucrin, cytokeratin 1 and 14) become induced. CONCLUSION: Conditions with hampered wound healing such as non-healing ulcers demand new treatment regimes. The here introduced optimized protocols for transdifferentiation of ASC into keratinocyte-like cells may help to establish more effective treatment procedures. PMID- 29705994 TI - Weak interspecific interactions in a sagebrush steppe? Conflicting evidence from observations and experiments. AB - Stable coexistence requires intraspecific limitations to be stronger than interspecific limitations. The greater the difference between intra- and interspecific limitations, the more stable the coexistence, and the weaker the competitive release any species should experience following removal of competitors. We conducted a removal experiment to test whether a previously estimated model, showing surprisingly weak interspecific competition for four dominant species in a sagebrush steppe, accurately predicts competitive release. Our treatments were (1) removal of all perennial grasses and (2) removal of the dominant shrub, Artemisia tripartita. We regressed survival, growth, and recruitment on the locations, sizes, and species identities of neighboring plants, along with an indicator variable for removal treatment. If our "baseline" regression model, which accounts for local plant-plant interactions, accurately explains the observed responses to removals, then the removal coefficient should be non-significant. For survival, the removal coefficients were never significantly different from zero, and only A. tripartita showed a (negative) response to removals at the recruitment stage. For growth, the removal treatment effect was significant and positive for two species, Poa secunda and Pseudoroegneria spicata, indicating that the baseline model underestimated interspecific competition. For all three grass species, population models based on the vital rate regressions that included removal effects projected 1.4- to 3 fold increases in equilibrium population size relative to the baseline model (no removal effects). However, we found no evidence of higher response to removal in quadrats with higher pretreatment cover of A. tripartita, or by plants experiencing higher pre-treatment crowding by A. tripartita, raising questions about the mechanisms driving the positive response to removal. While our results show the value of combining observations with a simple removal experiment, more tightly controlled experiments focused on underlying mechanisms may be required to conclusively validate or reject predictions from phenomenological models. PMID- 29705995 TI - Using 'collective omics data' for biomedical research training. AB - Systems-scale molecular profiling data accumulating in public repositories may constitute a useful resource for immunologists. It is for instance likely that information relevant to their chosen line of research be found among the more than 90,000 data series available in the NCBI Gene Expression Omnibus. Such 'collective omics data' may also be employed as source material for training purposes. This is the case when training curricula aim at the development of bioinformatics skills necessary for the analysis, interpretation or visualization of data generated on global scales. But 'collective omics data' may also be reused for training purposes to foster the development of the skills and 'mental habits' underpinning traditional reductionist science approaches. This review describes a small-scale initiative involving investigators, for the most part immunologists, having engaged in a range of training activities relying on 'collective omics data'. PMID- 29705997 TI - Longitudinal subungual acanthoma: one denomination for various clinical presentations. AB - BACKGROUND: Benign subungual proliferation of the distal nail matrix and bed such as longitudinal keratosis, seborrhoeic keratosis or onychocytic matricoma should belong to a single spectrum of diseases. OBJECTIVE: This article intends to demonstrate clinically and histologically the different facets of Nail unit longitudinal acanthoma. METHODS: We report three new cases that present as a longitudinal melanonychia with thickening of the nail plate in two of them and as leukoxanthonychia in the third one. We compared them with the two original cases we described in 1999, reminiscent of seborrhoeic keratosis and all the new cases published since then. RESULTS: We therefore consider that all these tumours belong to a single spectrum of diseases, we have called 'nail unit longitudinal acanthoma' which describes a histopathological process. The distinct clinical features of these tumours, melanonychia or leukoxanthonychia may be linked to their variable anatomic locations in different zones of the nail unit. PMID- 29705998 TI - Photoacoustic imaging system visualizes restoration of peripheral oxygenation in psoriatic lesions. PMID- 29705996 TI - Long-term real-life safety profile and effectiveness of fumaric acid esters in psoriasis patients: a single-centre, retrospective, observational study. AB - BACKGROUND: Fumaric acid esters (FAEs) are an established systemic treatment for moderate-to-severe psoriasis. However, the long-term clinical safety and effectiveness of continuous FAE monotherapy and combination therapy have not been established. OBJECTIVE: To examine the long-term safety and effectiveness of FAEs as monotherapy and in combination with phototherapy or methotrexate in patients with psoriasis treated at a single centre in Germany. METHODS: This monocentric, retrospective observational study, with a follow-up period of up to 32.5 years, included 859 patients: 626 received FAE monotherapy, 123 received FAEs with concomitant phototherapy and 110 received FAEs with methotrexate. RESULTS: Approximately half of patients (49.0%) reported adverse events (566 total events), most of which involved the gastrointestinal tract. Serious adverse events were reported in 2.3% of patients, but none were deemed to have a causal relationship with any of the treatment regimens. Adverse events leading to treatment discontinuation were observed in 12.9% of patients. A median duration of 1 year was observed in all three treatment subcohorts (P = 0.70) from initiation of FAE treatment to a 50% response rate, where response was defined as achieving a cumulative static Physician's Global Assessment (PGA) score of 'light' and at least a 2-point reduction in baseline PGA. A 50% response rate for the cumulative Psoriasis Area and Severity Index 75 was achieved in the FAE monotherapy subcohort after a median of 3 years of treatment, in the FAEs + phototherapy subcohort after 6.7 years and in the FAEs + methotrexate subcohort after 8.1 years (P = 0.001). CONCLUSION: According to our data, FAEs as monotherapy or in combination with phototherapy or methotrexate are safe and beneficial for long-term clinical use. However, multicentre, randomized controlled trials are required to establish the clinical value of monotherapy versus combination therapy and the optimal treatment duration. PMID- 29706000 TI - Ipilimumab more and more discussed: urgent need for predictive markers of response. PMID- 29705999 TI - Mild Hailey-Hailey disease cases with aberrant splicing variants of ATP2C1 successfully controlled with excimer light. PMID- 29706001 TI - The dual delivery of KGF and bFGF by collagen membrane to promote skin wound healing. AB - The major challenges associated with skin regeneration can include hindered vascularization and an insufficient degree of epithelization. In view of the complexity of these processes and the control signals on which they depend, one possible solution to these limitations could be simulating normal skin development and wound repair via the exogenous delivery of multiple cytokines. Here, we report the use of keratinocyte growth factor (KGF or FGF-7) and basic fibroblast growth factor (bFGF or FGF-2) released chemically modified collagen membranes to facilitate skin wound healing. The results from in vitro studies confirmed that this system resulted in higher cellular proliferation and faster cell migration. After transplanting the biomaterial onto an excisional wound healing model, the dual growth factor group, compared with the single growth factor groups and empty control group, showed more highly developed vascular networks and organized epidermal regeneration in the wounds. As a consequence, this experimental group showed mature epidermal coverage. Overall, this novel approach of releasing growth factors from a collagen membrane opens new avenues for fulfilling unmet clinical needs for wound care. PMID- 29706002 TI - Subclinical enthesopathy of extensor digitorum tendon is highly prevalent and associated with clinical and ultrasound alterations of the adjacent fingernails in patients with psoriatic disease. AB - BACKGROUND: Nail psoriasis disease is associated with an increased probability of psoriatic arthritis, and its clinical signs may have different correlates with the pathogenesis of adjacent bone destruction and have different prognostic value. Recent publications about psoriasis and nail psoriatic disease describe different ultrasonographic findings but the relationship between these ungueal alterations measured by ultrasonography and the presence of enthesopathy of the extensor digitorum has yet to be discovered. OBJECTIVE: To describe which ultrasonographic characteristics of nail psoriasis are associated with the presence of subclinical enthesopathy in patients with PsO and asymptomatic PsA. METHODS: Patients with psoriasis and asymptomatic psoriatic arthritis were included in the prospective study. Demographic, clinical data and PASI and NAPSI indexes were recorded of all the patients in the assessment visit. The US assessment included Achilles tendon, extensor digitorum tendon and US scan of the nail plate, nail matrix, nail bed and adjacent skin over nail matrix of the five nails of each hand. RESULTS: Forty-eight patients were included in the study; 33 of them presented ultrasound evidence of extensor digitorum tendon enthesopathy. Nails of the patients with subclinical enthesopathy had a higher NAPSI and skin thickness than the nails of the patients without subclinical enthesopathy (P = 0.047). Patients with asymptomatic enthesopathy had significantly thicker proximal nail folds (1.44 +/- 0.312 vs. 1.23 +/- 0.27, P = 0.023). Nail beds and matrices were also thicker but the differences were not statistically significant (1.77 +/- 0.27 vs. 1.74 +/- 0.21, P = 0.66, and 1.79 +/- 0.28 vs. 1.67 +/- 0.19, P = 0.10, respectively). No statistically significant differences in the trilaminar structure were found between both groups. Patients with and without asymptomatic enthesopathy of extensor digitorum tendons did not statistically differ as regards ultrasonographic alterations of the Achilles tendons (60.6% vs. 46.4%, P 0.368). CONCLUSION: Enthesopathy abnormalities can be detected by US in patients with psoriasis without musculoskeletal complaints frequently. There is a close relationship between subclinical enthesopathy of the extensor digitorum tendon and the presence of nail alterations. Further studies are required to research what implications have the presence of these ungual alterations measured by US, and how it affects later development of a PsA. PMID- 29706003 TI - Risk factors including the presence of inflammation at the resection margins for colorectal anastomotic stenosis following surgery for diverticular disease. AB - AIM: The aim of this study was to investigate risk factors for anastomotic stenosis in patients operated on for diverticular disease. Histological inflammation and diverticula at the resection margins were also considered. METHOD: Patients' characteristics, the surgical technique and postoperative complications were collected from the medical records. Anastomotic stenoses were evaluated prospectively by rigid sigmoidoscopy during follow-up examination. Histological specimens were examined by a single pathologist who investigated inflammation and diverticula at the resection margins. Twenty patients with anastomotic colorectal stenosis from a single tertiary centre were compared with 24 consecutive patients without stenosis. They were all operated on for diverticular disease over a specified time period. RESULTS: Histological inflammation and diverticula were found in 25% and 30% of the resection margins respectively. Univariate analysis showed that age > 71 years (P = 0.0002), female gender (P = 0.0069) and anastomoses located below 12 cm from the anal verge (P = 0.020) were risk factors for stenosis. No correlation was found between anastomotic stenosis and the presence of histological inflammation or diverticula at the resection margins. By multivariate analysis, only age > 71 years was found to be a statistically significant risk factor for stenosis (P = 0.0003, OR = 60.8, 95% CI: 6.4-575.5). CONCLUSION: Anastomotic stenosis is a frequent, long term complication following surgery for diverticular disease. An analysis demonstrated that age is a risk factor for colorectal stenosis and that histological inflammation and the presence of diverticula near/at the resection margins have no effect on the incidence of stenosis. PMID- 29706004 TI - Indian irrational skin creams and steroid-modified dermatophytosis - an unholy nexus and alarming situation. PMID- 29706005 TI - Cutaneous melanoma in France in 2015 attributable to solar ultraviolet radiation and the use of sunbeds. AB - BACKGROUND: Exposure to solar ultraviolet radiation (UVR) and the use of UV emitting tanning devices are associated with cutaneous malignant melanoma occurrence. OBJECTIVE: The aim of this study was to quantify the proportion and number of melanoma cases attributable to solar UVR exposure and sunbed use in France in 2015. METHODS: Population attributable fractions (PAFs) and numbers of melanoma cases attributable to solar UVR exposure were estimated by age and sex using the incidence rates of a 1903 birth cohort as the primary reference. Further analyses were performed using the following: (i) contemporary melanoma incidence rates in low-incidence regions within France and (ii) national melanoma incidence rates for the year 1980, as additional references. Assuming a 15-year lag period, PAF and melanoma cases attributable to sunbed use were calculated using prevalence estimates from a cross-sectional population survey and published relative risk estimates. RESULTS: In 2015, an estimated 10 340 melanoma cases diagnosed in French adults were attributable to solar UVR exposure, corresponding to 83% of all melanomas and 3% of all cancer cases in that year. PAFs for melanoma were highest in the youngest age group (30-49 years) and higher in men than in women (89% vs. 79%). A total of 382 melanoma cases occurring in French adults in 2015 were attributed to the use of sunbeds, equivalent to 1.5% and 4.6% of all melanoma cases in men and women, respectively. CONCLUSIONS: A considerable proportion of melanoma cases in France in 2015 were attributable to solar UVR exposure, suggesting that targeted prevention strategies need to be implemented. PMID- 29706007 TI - mRNA-miRNA crosstalk in basal cell carcinoma. PMID- 29706006 TI - It is time to revise the kidney allocation system to restore the pediatric advantage. PMID- 29706008 TI - Anxiety and depression in patients with moderate-to-severe psoriasis and comparison of change from baseline after treatment with guselkumab vs. adalimumab: results from the Phase 3 VOYAGE 2 study. AB - BACKGROUND: Anxiety and depression are clinically significant comorbidities associated with psoriasis. Improvements in psoriasis are known to decrease anxiety and depression. Guselkumab, an anti-interleukin-23 monoclonal antibody, has demonstrated efficacy and safety for the treatment of moderate-to-severe psoriasis. OBJECTIVE: Assess improvements in anxiety and depression with guselkumab vs. placebo and adalimumab using the Hospital Anxiety and Depression Scale (HADS). METHODS: In VOYAGE 2, a Phase 3, randomized, double-blind, placebo- and adalimumab-controlled study, patients received placebo (through week 16 followed by crossover to guselkumab), guselkumab, or adalimumab through week 24. HADS consists of two subscales measuring anxiety (HADS-A) and depression (HADS D), with scores ranging from 0 to 21 and higher scores indicating more severe symptoms. Scores >=8 indicate instrument-defined anxiety or depression. Severity of psoriasis was assessed using the Psoriasis Area and Severity Index (PASI). RESULTS: Among 989 patients randomized (with baseline HADS measurements), mean HADS-A and HADS-D scores were 6.8 +/- 4.2 and 5.3 +/- 4.2, respectively; 38.6% of patients reported HADS-A >=8 and 27.7% HADS-D >=8 at baseline. At week 16, a significantly greater proportion of guselkumab patients with baseline HADS-A or HADS-D >=8 reported HADS-A <8 (51.4% vs. 25.9%; P < 0.001) or HADS-D <8 (59.2% vs. 27.0%; P < 0.001) vs. placebo patients. At week 24, a greater proportion of guselkumab patients with baseline HADS-A or HADS-D >=8 reported HADS-A <8 (58.4% vs. 42.9%; P = 0.028) or HADS-D <8 (59.8% vs. 46.4%; P = 0.079) vs. adalimumab patients. PASI improvements correlated with improvement in anxiety (r = 0.27; P < 0.0001) and depression (r = 0.25; P < 0.0001) scores in patients with baseline HADS-A or HADS-D >=8. Greater improvements in HADS were also observed at week 16 in guselkumab-treated patients vs. placebo using a more stringent cut-off of HADS >=11. CONCLUSION: Guselkumab treatment was associated with greater improvements in symptoms of anxiety and depression scores in patients with psoriasis compared with placebo and adalimumab. PMID- 29706009 TI - Relations between a standardized experimental stressor and cutaneous sensory function in patients with chronic pruritus and healthy controls: an experimental case-control study. AB - BACKGROUND: While chronic pruritus (CP) is a frequent symptom, many aspects of its underlying pathophysiological mechanisms still need elucidation. Research on sensory cutaneous function and on the influence of stress has been conducted mainly in patients with atopic dermatitis but is lacking for patients with CP. OBJECTIVE: To assess whether a standardized social stressor influences cutaneous sensory function in patients with CP in comparison with healthy controls (HC). METHODS: Case-control study; 33 CP and 30 HC were submitted to the standardized quantitative sensory testing protocol before and after the Trier Social Stress Test and 1 h later. Intraepidermal nerve fibre density (IENFD) was determined. RESULTS: Mechanical pain sensitivity and mechanical detection thresholds were significantly higher in CP than in HC, and mechanical detection thresholds increased more in CP than in HC over the three measurements. In both groups, cold pain threshold increased and heat pain threshold decreased from before to after the stress test and remained constant 1 h later. Only in CP, almost all QST tests induced at least a small amount of pruritus, which was not significantly altered by the stress test. IENFD in pruritic skin was significantly reduced in CP when compared to healthy controls. CONCLUSION: Peripheral thermal sensory function was not altered in CP despite reduced IENFD in lesional skin, but we could demonstrate central sensitization processes specifically in CP and influences of an acute stressor inducing more sensitivity to thermal pain in both groups. PMID- 29706010 TI - Long-term study showed that vaccination protected paediatric renal transplant recipients from life-threatening varicella zoster virus. AB - AIM: Renal transplant patients are particularly susceptible to highly contagious diseases due to their reduced immunity. We studied transplant recipients to gauge their varicella zoster virus (VZV) serology status over time and the outcome of any VZV infections. METHOD: This retrospective study comprised 85 children who underwent renal transplants in Gothenburg, Sweden, from 1986 to 2014, at a mean age of eight (1-18) years. The children's medical records were reviewed and 47 had the VZV infection pre-transplant and 38 had been vaccinated pre-transplant. Clinical outcomes were available for 85 children and serology results for 72. RESULTS: At transplantation, the VZV seropositivity rate was 50% in the vaccination group and 94% in the infection group and the antibody titres were significantly lower in the vaccination group (p = 0.031). During the median follow-up period of five years post-transplant, 28% of the vaccinated children and 97% of the infection group remained seropositive and the varicella infection affected eight children: one in the infection group and seven in the vaccination group. The herpes zoster was observed in two children in the infection group. CONCLUSION: This study demonstrated that VZV vaccination protected from symptomatic infections to a lesser extent than natural infection, but provided effective protection from life-threatening disease. PMID- 29706011 TI - Clinical usefulness of the faecal calprotectin test in suspected paediatric inflammatory bowel disease. AB - AIM: The faecal calprotectin (FC) test is increasingly being used in clinical practice to help select children with gastrointestinal symptoms who might have inflammatory bowel disease (IBD) and benefit from endoscopies. We provide an overview of the advantages and limitations of the FC test. METHODS: PubMed was searched for meta-analyses that had investigated the diagnostic accuracy of the FC test and the pooled sensitivity and specificity for distinguishing IBD from non-IBD patients were used to calculate likelihood ratios (LR). These were applied to practical examples to explain how easily clinicians can use the results to modify pre-test probabilities of IBD and generate post-test probabilities for IBD. RESULTS: The positive LR and negative LR of the FC test were 2.8 and 0.015, respectively. The usefulness of the FC test depended on the pre-test probability of IBD. When the pre-test probability of IBD was low, a positive FC test did not necessarily indicate IBD. However, because of the very small negative LR, a negative FC result virtually ruled out IBD in most cases. CONCLUSION: The FC test should not be used indiscriminately in children with gastrointestinal symptoms but should be targeted at those who are likely to have IBD. PMID- 29706012 TI - Characteristics and Antioxidant Activity of Lignans in Schisandra chinensis and Schisandra sphenanthera from Different Locations. AB - Twenty Schisandra samples were collected from different locations. Contents of 7 lignans in the samples were determined and analyzed by HPLC method coupled with hierarchical clustering analysis (HCA) and principal component analysis (PCA), and the antioxidant capacity of Schisandra from the different locations was evaluated by reducing power, ferric thiocyanate (FTC) and 2,2'-diphenyl-1 picrylhydrazyl (DPPH) assay. The results showed that there was a significant difference in the content of lignans between Schisandra chinensis and Schisandra sphenanthera. The Schisandra sphenanthera samples in the southwest of China were significantly different from those from the other locations. The antioxidant capacity of Schisandra chinensis was significantly superior to that of Schisandra sphenanthera, and the main antioxidant components were schisandrol A, schisandrol B and schisandrin B based on the result of discrimination analyses. The differences in the chemical composition and antioxidant activity of lignans in Schisandra chinensis and Schisandra sphenanthera from the different locations were investigated in this study, which may provide an experimental basis for the quality control of Schisandra. PMID- 29706013 TI - Re: The Pursuit of Happiness. The thin line between rights and duties. PMID- 29706014 TI - Germline V repertoires: Origin, maintenance, diversification. AB - In our view, Melvin Cohn (Scand J Immunol. 2018;87:e12640) has set out the logical guidelines towards a resolution of the very real enigma of the selectability of vertebrate germline Ig V repertoires under the current evolutionary paradigm..." A somatically derived repertoire scrambles this (germline VL + VH) substrate so that its specificities are lost, making it un selectable in the germline. Consequently, evolution faced an incompatibility." It is argued here in Reply that a reverse transcriptase-based soma-to-germline process (S->G) targeting germline V segment arrays goes some considerable way to resolving fundamental contradictions on the origin, maintenance and then real time adaptive diversification of these limited sets of V segments encoded within various V repertoire arrays. PMID- 29706015 TI - Children with a very low birthweight showed poorer reading skills at eight years of age but caught up in most areas by the age of 10. AB - AIM: We evaluated the development of reading skills in very low birthweight (VLBW) children and controls at 8-10 years of age. METHODS: This study was part of a longitudinal study of VLBW infants born between January 1998 and December 1999 in Sweden. We recruited 49 VLBW children and 44 sex and age-matched full term controls when they started school at the age of seven and tested them using identical methods for decoding, rapid naming ability, reading comprehension, and spelling and cognitive skills at about eight and 10 years of age. Univariate analysis of variance was performed to assess the effects of VLBW on reading performance at each age and to evaluate the differences between the groups and ages. RESULTS: Very low birthweight children scored significantly lower in all domains of reading at 7.8 +/- 0.3 years, but the performance gap had narrowed by 9.8 +/- 0.3 years. Significant catch-up gains were found in phonological awareness, rapid naming ability and reading comprehension. The differences between the groups were minor at 10 years, when controlled for non-verbal cognition. CONCLUSION: Very low birthweight children demonstrated worse reading performance at eight years of age than term-born controls. The gap in reading skills between the groups had largely narrowed two years later. PMID- 29706016 TI - Role of local anaesthetic nerve block in endoscopic sinus surgery: A systematic review and meta-analysis. AB - OBJECTIVE: The aim of the study was to perform a systematic review of existing evidence on the role of local anaesthetic nerve block (LAB) in patients undergoing endoscopic sinus surgery (ESS). DESIGN: The databases searched were the Cochrane Register of Controlled Trials, MEDLINE and Embase using the Ovid portal (1946-2017). RESULTS: Seven randomised controlled trials were included. Due to considerable heterogeneity of data, only two studies were pooled into meta analysis which demonstrated a statistically significantly better surgical field quality during ESS in the LAB group compared with the control group (MD -0.86; 95% CI -2.24, 0.51; P = .009). No adverse events related to LAB toxicity were reported. CONCLUSIONS: Sphenopalatine ganglion LAB with adrenaline carries relatively low risk of morbidity, but may improve the quality of the surgical field in terms of bleeding. However, there are limitations of the study due to heterogeneity of methods, quality and size of the studies. Well-conducted large RCTs are needed using standardised inclusion criteria, balanced baseline characteristics of cohorts, and validated subjective and objective outcome measures. PMID- 29706017 TI - Distribution of exogenous complement factor H in mice in vivo. AB - Factor H is an important regulator of complement activation in plasma and on cell surfaces in both humans and mice. If FH function is compromised, inappropriate complement activation on self-surfaces can have disastrous effects as seen in the kidney diseases atypical haemolytic uremic syndrome (aHUS) and C3 glomerulopathy. As FH constructs have been proposed to be used in treatment for these diseases, we studied the distribution of exogenous FH fragments in mice. Full-length mFH, mFH1-5 and mFH18-20 fragments were radiolabelled, and their distribution was examined in WT, FH-/- and FH-/- C3-/- mice in vivo. Whole body scintigraphy revealed accumulation of radioactivity in the abdominal part of the mice, but also to the thyroid gland and urinary bladder. At organ level in WT mice, some full-length FH accumulated in internal organs, but most of it remained in the circulation. Both of the mFH fragments accumulated in the kidneys and were excreted in urine. For mFH1-5, urinary secretion is the likely cause for the accumulation. Concentration of mFH18-20 to kidneys was slower, and at tissue level, mFH18-20 was localized at the proximal tubuli in WT and FH-/- C3-/- mice. No C3-independent binding to glomeruli was detected. In conclusion, these results show that glomerular glycosaminoglycans and sialic acids alone do not collect FH in kidneys. Deposition of C3 fragments is also needed, which implies that in aHUS, the problem is in simultaneous recognition of C3 fragments and glycosaminoglycans or sialic acids by FH, not just the inability of FH to recognize glomerular endothelium as such. PMID- 29706018 TI - Human papillomavirus prevalence in a Mid-European oral squamous cell cancer population: A cohort study. AB - OBJECTIVES: Human papillomavirus infection has been investigated intensively regarding oropharyngeal carcinoma. However, there is still lack of knowledge about the impact of oral HPV infections concerning oral squamous cell carcinoma. This study investigates the prevalence of oral HPV infection in such patients, identifying possible differences between HPV+ and HPV- patients. SUBJECTS AND METHODS: One hundred and six consequent patients were investigated. After completion of a study questionnaire regarding risk factors, a brush smear sample was taken in each subject to identify the individual oral HPV status (overall/low risk/high risk). RESULTS: About 35.8% of the patients were tested positive for HPV in the oral cavity (14% low risk, 28.3% high risk). Patients with oral HPV infection and high-risk HPV infection were significantly younger (p < 0.001) and had a higher alcohol consumption (p = 0.0075 resp. p = 0.0022). A high number of different sexual partners were significantly correlated with any type of HPV infection. At last, patients with high-risk oral HPV infection had experienced more tooth extractions during their lifetime. CONCLUSION: Oral HPV infections may influence the course of disease of oral squamous cell carcinoma as HPV+ patients are about 10 years younger. It seems that high alcohol consumption facilitates high-risk HPV infection. It may be presumed that both alcohol consumption and high-risk oral HPV infection act synergistically, explaining earlier cancer onset. PMID- 29706019 TI - Factors predicting early postpartum glucose intolerance in Japanese women with gestational diabetes mellitus: decision-curve analysis. AB - AIMS: To identify factors predicting early postpartum glucose intolerance in Japanese women with gestational diabetes mellitus, using decision-curve analysis. METHODS: A retrospective cohort study was performed. The participants were 123 Japanese women with gestational diabetes who underwent 75-g oral glucose tolerance tests at 8-12 weeks after delivery. They were divided into a glucose intolerance and a normal glucose tolerance group based on postpartum oral glucose tolerance test results. Analysis of the pregnancy oral glucose tolerance test results showed predictive factors for postpartum glucose intolerance. We also evaluated the clinical usefulness of the prediction model based on decision-curve analysis. RESULTS: Of 123 women, 78 (63.4%) had normoglycaemia and 45 (36.6%) had glucose intolerance. Multivariable logistic regression analysis showed insulinogenic index/fasting immunoreactive insulin and summation of glucose levels, assessed during pregnancy oral glucose tolerance tests (total glucose), to be independent risk factors for postpartum glucose intolerance. Evaluating the regression models, the best discrimination (area under the curve 0.725) was obtained using the basic model (i.e. age, family history of diabetes, BMI >=25 kg/m2 and use of insulin during pregnancy) plus insulinogenic index/fasting immunoreactive insulin <1.1. Decision-curve analysis showed that combining insulinogenic index/fasting immunoreactive insulin <1.1 with basic clinical information resulted in superior net benefits for prediction of postpartum glucose intolerance. CONCLUSIONS: Insulinogenic index/fasting immunoreactive insulin calculated using oral glucose tolerance test results during pregnancy is potentially useful for predicting early postpartum glucose intolerance in Japanese women with gestational diabetes. PMID- 29706020 TI - The effects of season and weather on healthcare utilization among patients with atopic dermatitis. AB - BACKGROUND: Patient-reported triggers for atopic dermatitis (AD) flares include changes in ultraviolet irradiation, humidity and temperature. OBJECTIVES: To identify the relationships between weather data and healthcare utilization in AD patients. METHODS: Using nationwide healthcare registries, clinic (1994-2012) and hospital visits (1977-2012) for AD treatment were calculated as well as monthly totals of topical corticosteroid (TCS) (1996-2012) and calcineurin inhibitor (TCI) prescriptions (2003-20012) filled by AD patients. We calculated monthly averages of temperature, atmospheric pressure, cloud cover and hours of bright sunlight and compared these variables to healthcare utilization endpoints, for the years 2000-2012 (n = 156 months), using linear regression models. RESULTS: In Denmark, between the year 2000 and 2012, mean monthly totals of AD emergency room visits were 6, AD hospitalizations 32, AD outpatient visits 170, TCS prescriptions filled by AD patients 3811 and TCI prescriptions 2552. Healthcare utilization among AD patients was highest in winter/spring. Temperature was the environmental variable that had the strongest association with healthcare utilization: per 1 degrees C lower monthly temperature, 2 more (95% confidence interval [CI] 1-4) AD clinic/hospital visits hospitalizations were observed, 18 (95% CI 9-26) more TCS prescriptions and 53 (95% CI 36-70) more TCI prescriptions were filled by patients with AD. Environmental variables were highly correlated. Associations between AD healthcare utilization and hours of cloud cover were generally positive, while those with hours of bright sunlight were generally inverse. CONCLUSIONS: AD healthcare utilization markers changed significantly with season. A decline in temperature correlated well with AD patients' healthcare utilization, but a causative role could not be determined with certainty. PMID- 29706021 TI - Effect of pathologist's dedication on lymph node detection rate and postoperative survival in colorectal cancer. AB - AIM: As adjuvant chemotherapy in colorectal cancer relies on the identification of lymph node metastases, the pathologist's dedication may have a considerable influence on postoperative survival. METHOD: The aim of this retrospective study was to assess the impact of the pathologist's dedication on lymph node detection rate and postoperative survival in patients operated on by a single experienced colorectal surgeon within a 5-year period. We assessed 229 patients undergoing total mesorectal excision or complete mesocolic excision by the senior author between 1 January 2009 and 31 December 2013. Pathologists were grouped as 'general pathologist' or 'dedicated pathologist' depending on their dedication/specialization. RESULTS: Dedicated pathologists found statistically significantly more lymph nodes in colorectal specimens than general pathologists [23 (interquartile range 24) vs 14 (interquartile range 11), respectively; P < 0.001]. The detection rate of >= 12 lymph nodes per specimen was significantly higher in the dedicated pathologist group [65/74 (87.8%) vs 105/155 (67.7%); P = 0.016]. However, postoperative survival did not differ in the respective subgroups. In the multivariable analysis by Cox proportional hazard model, International Union against Cancer Stage IV was the only factor associated with decreased disease-specific survival (hazard ratio 28.257; 95% CI 3.850-207.386; P = 0.001). CONCLUSION: In our centre, the pathologist's dedication has an impact on lymph node detection rate but does not influence postoperative disease specific survival. PMID- 29706022 TI - Terra firma-forme dermatosis is underestimated in children and is associated with atopic dermatitis. PMID- 29706023 TI - Plasma markers of oxidative status were associated with increasing continuous cardiometabolic risk scores in healthy students aged 16-20 years without central obesity. AB - AIM: We studied the association between increased cardiometabolic risk and markers of oxidative status and glycation in apparently healthy subjects who did not present with central obesity. METHODS: From 2011 to 2012, we recruited 2064 students (53% girls) aged 16-20 years from Western Slovakia. Their continuous metabolic syndrome scores (MSS) were calculated as a mean of the sum of the z scores of waist-to-height ratio, mean arterial pressure, triacylglycerols, high density lipoprotein-cholesterol and quantitative insulin sensitivity check index. Plasma markers of protein glycation and oxidation, lipid peroxidation and total antioxidant status were analysed. RESULTS: In both genders, advanced oxidation protein products (AOPPs) increased across the MSS quintiles (p < 0.001). AOPPs and fructosamines were significant predictors of the MSS in both genders. Moreover, high-sensitivity C-reactive protein, leukocyte counts and advanced glycation end-products (AGEs) contributed significantly in girls. Triacylglycerols, fructosamines, AGEs and total antioxidant capacity correlated significantly with AOPPs in both genders. CONCLUSION: Advanced oxidation protein products may act as inflammatory mediators that contribute to the development of cardiometabolic afflictions. Determining these may provide information related to cardiometabolic risk and represent potential target to reduce or prevent irreversible oxidative stress-induced cellular damage. PMID- 29706024 TI - Overexpression of CYB5R3 and NQO1, two NAD+ -producing enzymes, mimics aspects of caloric restriction. AB - Calorie restriction (CR) is one of the most robust means to improve health and survival in model organisms. CR imposes a metabolic program that leads to increased stress resistance and delayed onset of chronic diseases, including cancer. In rodents, CR induces the upregulation of two NADH-dehydrogenases, namely NAD(P)H:quinone oxidoreductase 1 (Nqo1) and cytochrome b5 reductase 3 (Cyb5r3), which provide electrons for energy metabolism. It has been proposed that this upregulation may be responsible for some of the beneficial effects of CR, and defects in their activity are linked to aging and several age-associated diseases. However, it is unclear whether changes in metabolic homeostasis solely through upregulation of these NADH-dehydrogenases have a positive impact on health and survival. We generated a mouse that overexpresses both metabolic enzymes leading to phenotypes that resemble aspects of CR including a modest increase in lifespan, greater physical performance, a decrease in chronic inflammation, and, importantly, protection against carcinogenesis, one of the main hallmarks of CR. Furthermore, these animals showed an enhancement of metabolic flexibility and a significant upregulation of the NAD+ /sirtuin pathway. The results highlight the importance of these NAD+ producers for the promotion of health and extended lifespan. PMID- 29706025 TI - Disseminated filiform hyperkeratosis - a variant of porokeratosis? PMID- 29706026 TI - Tripartite motif-containing proteins precisely and positively affect host antiviral immune response. AB - The tripartite motif-containing proteins (TRIMs) comprise a large family of proteins with over 70 members in humans. Recent studies have shown that TRIMs play unexpected roles in the antiviral immune responses to infections by HIV, MLV, EMCV, AIV and other viruses. There are two mechanisms used by TRIMs in the inhibition of virus infections: (1) TRIMs target the produced viruses for ubiquitination, which induces proteasome-dependent degradation, or they interact with host proteins to inhibit viral infection in various periods of the viral life cycle. (2) TRIMs activate innate immune signalling pathways, such as RLR and TLR, which induce IFN production. In this study, we will review recent studies regarding the means by which TRIMs function as inhibitors in viral infection through the mechanisms described above. PMID- 29706027 TI - Monitoring and interventions are needed to reduce the very high Caesarean section rates in Vietnam. AB - AIM: The aim of this study was to estimate the prevalence of Caesarean sections in the third largest city in Vietnam and identify the associated risk factors. METHODS: This descriptive study was conducted in Da Nang from April 2015 to March 2016 and the hospital-based sample comprised 20 535 women who delivered during this period. Caesarean section cases were categorised into private and public hospitals and groups of primiparous and multiparous women. RESULTS: We recruited 10 of the 12 hospitals in the City and they covered 90% of births during the study period. The overall Caesarean section rate was 58.6%: 57.9% in public hospitals and 70.6% in private hospitals. The three main indications for Caesarean sections were previous Caesarean sections, cephalopelvic disproportion and foetal distress. The factors that increased the likelihood of Caesarean sections were the mother being over 30, having an office job, a history of abortions, having a male infant and a higher neonatal birth weight. CONCLUSION: Our study demonstrated an extremely high rate of Caesarean section and associated factors in public and private hospitals in one of the biggest cities in Vietnam. The findings highlight the need for monitoring and interventions to reduce the Caesarean section rates. PMID- 29706028 TI - Emerging concepts on the role of epigenetics in the relationships between nutrition and health. AB - Understanding the physiological and metabolic underpinnings that confer individual differences in responses to diet and diet-related chronic disease is essential to advance the field of nutrition. This includes elucidating the differences in gene expression that are mediated through programming of the genome through epigenetic chromatin modifications. Epigenetic landscapes are influenced by age, genetics, toxins and other environmental factors, including dietary exposures and nutritional status. Epigenetic modifications influence transcription and genome stability are established during development with life long consequences. They can be inherited from one generation to the next. The covalent modifications of chromatin, which include methylation and acetylation, on DNA nucleotide bases, histone proteins and RNA are derived from intermediates of one-carbon metabolism and central metabolism. They influence key physiological processes throughout life, and together with inherited DNA primary sequence, contribute to responsiveness to environmental stresses, diet and risk for age related chronic disease. Revealing diet-epigenetic relationships has the potential to transform nutrition science by increasing our fundamental understanding of: (i) the role of nutrients in biological systems, (ii) the resilience of living organisms in responding to environmental perturbations, and (iii) the development of dietary patterns that programme physiology for life-long health. Epigenetics may also enable the classification of individuals with chronic disease for specific dietary management and/or for efficacious diet pharmaceutical combination therapies. These new emerging concepts at the interface of nutrition and epigenetics were discussed, and future research needs identified by leading experts at the 26th Marabou Symposium entitled 'Nutrition, Epigenetics, Genetics: Impact on Health and Disease'. For a compilation of the general discussion at the marabou symposium, click here http://www.marabousymposium.org/. PMID- 29706029 TI - Oncologist provision of smoking cessation support: A national survey of Australian medical and radiation oncologists. AB - AIM: Continued smoking in patients diagnosed with cancer affects treatment outcomes and overall survival. With national surveys of Australian medical oncologists (MO) and radiation oncologists (RO) we sought to determine current clinical practices, preferences and barriers in providing patient smoking cessation support. METHODS: Oncologist members of the Medical Oncology Group of Australia (n = 452) and Trans-Tasman Radiation Oncology Group (n = 230) were invited to participate in a multiple choice survey exploring smoking cessation practices and beliefs. RESULTS: The survey response rate was 43%. At first consultations more than 90% of MO and RO regularly asked patients if they smoke or use tobacco products, closely followed by documentation of duration of smoking history and current level of consumption. Less common was asking the patient if they intended to quit (MO 63%, RO 53%) and advising cessation (MO 70%, RO 72%). Less than 50% of oncologists regularly asked about current smoking in follow-up consultations. Although a range of referral options for smoking cessation care were used by oncologists, only 2% of MO and 3% of RO actively managed the patients' smoking cessation themselves and this was the least preferred option. The majority believed they require more training in cessation interventions (67% MO, 57% RO) and cited multiple additional barriers to providing cessation care. CONCLUSIONS: Oncologists strongly prefer smoking cessation interventions to be managed by other health workers. A collaborative approach with other health professionals is needed to aid the provision of comprehensive smoking cessation care tailored to patients with cancer. PMID- 29706030 TI - Preconception management of thyroid dysfunction. AB - Uncorrected thyroid dysfunction in pregnancy has well-recognized deleterious effects on foetal and maternal health. The early gestation period is one of the critical foetal vulnerability during which maternal thyroid dysfunction may have lasting repercussions. Accordingly, a pragmatic preconception strategy is key for ensuring optimal thyroid disease outcomes in pregnancy. Preconception planning in women with hypothyroidism should pre-empt and mirror the adaptive changes in the thyroid gland by careful levothyroxine dose adjustments to ensure adequate foetal thyroid hormone delivery in pregnancy. In hyperthyroidism, the goal of preconception therapy is to control hyperthyroidism while curtailing the unwanted side effects of foetal and maternal exposure to antithyroid drugs. Thus, pregnancy should be deferred until a stable euthyroid state is achieved, and definitive therapy with radioiodine or surgery should be considered in women with Graves' disease planning future pregnancy. Women with active disease who are imminently trying to conceive should be switched to propylthiouracil either preconception or at conception in order to minimize the risk of birth defects from carbimazole or methimazole exposure. Optimal strategies for women with borderline states of thyroid dysfunction namely subclinical hypothyroidism, isolated hypothyroxinaemia and thyroid autoimmunity remain uncertain due to the dearth of controlled interventional trials. Future trial designs should aspire to recruit and initiate therapy before conception or as early as possible in pregnancy. PMID- 29706031 TI - Mohs micrographic surgery for nail unit tumours: an update and a critical review of the literature. AB - Mohs micrographic surgery (MMS) is a good treatment option for epithelial neoplasms, especially when localized in areas where tissue conservation is crucial, such as the nail unit (NU). MMS is a method of radical excision offering high cure rates due to the margin control and functional preservation. Our aim is to provide a review on the use of MMS for the treatment of the most common nail tumours. We revised the current literature on the use of MMS to treat malignant neoplasms (Bowen's disease, squamous cell carcinoma, melanoma, basal cell carcinoma, keratoacanthoma, carcinoma cuniculatum) and benign neoplasms (onychomatricoma and glomus tumour). MMS represents a successful surgical option for nail tumours, firstly in terms of tissue conservation: the NU anatomy is complex and the preservation of the component structures is imperative for its functionality. Secondly, due to the surgical radicality, which is essential not only for the clearing of malignant tumours, but also for benign cases, in order to reduce recurrences. Although a conservative treatment of NU melanoma with MMS has been proposed, in our experience, the conservative approach with functional surgery is a good option for the treatment of non-invasive melanoma (in situ and Ia). PMID- 29706032 TI - Sustaining quality in the community: trends in the performance of a structured diabetes care programme in primary care over 16 years. AB - AIM: To examine the quality of care delivered by a structured primary care-led programme for people with Type 2 diabetes mellitus in 1999-2016. METHODS: The Midland Diabetes Structured Care Programme provides structured primary care-led management. Trends over time in care processes were examined (using a chi-squared trend test and age- and gender-adjusted logistic regression). Screening and annual review attendance were reviewed. A composite of eight National Institute for Health and Care Excellence-recommended processes was used as a quality indicator. Participants who were referred to diabetes nurse specialists were compared with those not referred (Student's t-test, Pearson's chi-squared test, Wilcoxon-Mann-Whitney test). Proportions achieving outcome targets [HbA1c <=58 mmol/mol (7.5%), blood pressure <=140/80 mmHg, cholesterol <5.0 mmol/l] were calculated. RESULTS: Data were available for people with diabetes aged >=18 years: 1998/1999 (n=336); 2003 (n=843); 2008 (n=988); and 2016 (n=1029). Recording of some processes improved significantly over time (HbA1c , cholesterol, blood pressure, creatinine), and in 2016 exceeded 97%. Foot assessment and annual review attendance declined. In 2016, only 29% of participants had all eight National Institute for Health and Care Excellence processes recorded. A higher proportion of people with diabetes who were referred to a diabetes nurse specialist had poor glycaemic control compared with those not referred. The proportions meeting blood pressure and lipid targets increased over time. CONCLUSIONS: Structured primary care led to improvements in the quality of care over time. Poorer recording of some processes, a decline in annual review attendance, and participants remaining at high risk suggest limits to what structured care alone can achieve. Engagement in continuous quality improvement to target other factors, including attendance and self-management, may deliver further improvements. PMID- 29706033 TI - Breast and reproductive cancers in the transgender population: a systematic review. AB - BACKGROUND: The medical transition undergone by a transgender person may influence their risk of breast or reproductive cancer. OBJECTIVES: To assess breast and reproductive cancer prevalence in the transgender population. To elucidate any associations between gender-affirming hormones and risk of these cancers. SEARCH STRATEGY: Following registration of review protocol with PROSPERO, five databases were searched. SELECTION CRITERIA: Included studies investigated breast, ovarian, uterine, cervical, vaginal, neovaginal, testicular and prostate cancer in the transgender population. Secondary studies, opinions, editorials and conference abstracts were excluded. No date, language or setting restrictions were applied. DATA COLLECTION AND ANALYSIS: Two reviewers conducted literature searches and applied inclusion and exclusion criteria to the results. Studies were categorised, aggregated and analysed by study population (transmen/transwomen) and type of cancer. MAIN RESULTS: The literature search produced 228 articles; 43 were included. The overall evidence quality was very low to low. In transgender women, 20 breast cancer cases, two neovaginal cancer cases, one testicular cancer case and eight prostate cancer cases were reported. In transgender men, 18 breast cancer cases, five ovarian cancer cases, four uterine/cervical cancer cases and one vaginal cancer case were reported. CONCLUSIONS: There is insufficient evidence to estimate breast or reproductive cancer prevalence in the transgender population. Gender-affirming hormones have not been shown to affect cancer risk, but there is a clear need for well designed, robust studies to confirm or refute this. FUNDING: This study was undertaken as an education dissertation. No funding was received. TWEETABLE ABSTRACT: Little is known about the impact of gender-affirming hormones on breast or reproductive cancers in trans people. PMID- 29706034 TI - Emerging Evidences in the Long Standing Controversy Regarding Testosterone Replacement Therapy and Cardiovascular Events. AB - The increasing rate of late-onset hypogonadism has led to an exceptional growth in the use of testosterone therapy (TTh). Even though TTh has been used for more than 70 years, there has been an emerging controversy in the past several years regarding its safety due to a suggested increased risk of cardiovascular (CV) disease among its users. Given the growing prevalence of testosterone deficiency in our population and the increased use of TTh, the goal of this review is to present the history and emerging evidence in regards to this controversy. CV safety concerns are mostly based on a few studies and trials that have been noted to have multiple flaws and limitations. However, the most recent data has found no association between TTh and the development of CV disease. Nevertheless, until this controversy is clarified with larger clinical trials, health-care professionals should continue to inform their patients about the possible CV risk when prescribing TTh products to patients. PMID- 29706036 TI - Breast tumor hemodynamic response during a breath-hold as a biomarker to predict chemotherapeutic efficacy: preclinical study. AB - Continuous wave diffuse optical tomographic/spectroscopic system does not provide absolute concentrations of chromophores in tissue and monitor only the changes of chromophore concentration. Therefore, it requires a perturbation of physiological signals, such as blood flow and oxygenation. In that sense, a few groups reported that monitoring a relative hemodynamic change during a breast tissue compression or a breath-hold to a patient can provide good contrast between tumor and nontumor. However, no longitudinal study reports the utilization of a breath-hold to predict tumor response during chemotherapy. A continuous wave near-infrared spectroscopy was employed to monitor hemodynamics in rat breast tumor during a hyperoxic to normoxic inhalational gas intervention to mimic a breath-hold during tumor growth and chemotherapy. The reduced oxyhemoglobin concentration during inhalational gas intervention correlated well with tumor growth, and it responded one day earlier than the change of tumor volume after chemotherapy. In conclusion, monitoring tumor hemodynamics during a breath-hold may serve as a biomarker to predict chemotherapeutic efficacy of tumor. PMID- 29706035 TI - Silencing Histone Deacetylase 7 Alleviates Transforming Growth Factor-beta1 Induced Profibrotic Responses in Fibroblasts Derived from Peyronie's Plaque. AB - PURPOSE: Epigenetic modifications, such as histone acetylation/deacetylation and DNA methylation, play a crucial role in the pathogenesis of inflammatory disorders and fibrotic diseases. The aim of this study was to study the differential gene expression of histone deacetylases (HDACs) in fibroblasts isolated from plaque tissue of Peyronie's disease (PD) or normal tunica albuginea (TA) and to examine the anti-fibrotic effect of small interfering RNA (siRNA) mediated silencing of HDAC7 in fibroblasts derived from human PD plaque. MATERIALS AND METHODS: For differential gene expression study, we performed reverse-transcriptase polymerase chain reaction for HDAC isoforms (1-11) in fibroblasts isolated from PD plaque or normal TA. Fibroblasts isolated from PD plaque were pretreated with HDAC7 siRNA (100 pmol) and then stimulated with transforming growth factor-beta1 (TGF-beta1, 10 ng/mL). Protein was extracted from treated fibroblasts for Western blotting. We also performed immunocytochemistry to detect the expression of extracellular matrix proteins and to examine the effect of HDAC2 siRNA on the TGF-beta1-induced nuclear translocation of Smad2/3 and myofibroblastic differentiation. RESULTS: The mRNA expression of HDAC2, 3, 4, 5, 7, 8, 10, and 11 was higher in fibroblasts isolated from PD plaque than in fibroblasts isolated from normal TA tissue. Knockdown of HDAC7 in PD fibroblasts inhibited TGF-beta1-induced nuclear shuttle of Smad2 and Smad3, transdifferentiation of fibroblasts into myofibroblasts, and abrogated TGF beta1-induced production of extracellular matrix protein. CONCLUSIONS: These findings suggest that specific inhibition of HDAC7 with RNA interference may represent a promising epigenetic therapy for PD. PMID- 29706037 TI - [PI3K/p110beta-specific inhibitors in castration-resistant prostate cancer]. AB - Advanced prostate cancer, especially at the castration-resistant stage, remains incurable clinically and, therefore, urgently requires new therapeutics for the patients. PI3K is a family of critical cell signal transduction molecules and their over-activation is an important factor in cancer development and progression. It has been demonstrated that class IA PI3K p110 is drastically overexpressed in prostate cancer and involved in androgen receptor-mediated gene expression and castration-resistant progression and regarded as a potential therapeutic target for prostate cancer. Several p110-specific inhibitors have been reported recently and two of them, GSK2636771 and AZD8186, are being tested in clinical trials. PMID- 29706038 TI - [Expression characteristics of the 1700008O03Rik gene in the mouse testis during spermatogenesis and results of bioinformatic analysis]. AB - Objective: To investigate the characteristics of the expression of the RIKEN cDNA 1700008O03 (1700008O03Rik) gene in the testis of the mouse from birth to sexual maturity and its potential role in regulating spermatogenesis. METHODS: Using mouse gene expression profile microarray, we screened the testis-specific gene 1700008O03Rik from the mouse. We studied the expression characteristics of the gene in the development of the mouse testis by reverse transcription PCR, quantitative real-time PCR, Western-blot, immunohistochemistry and immunofluorescence, and analyzed the structure of the 1700008O03Rik protein and its homology with other species using the bioinformatic software. RESULTS: 1700008O03Rik gene was highly expressed in the testis of the mouse, increasing in an age-dependent manner, and mainly in the endochylema of oblong spermatozoa. Bioinformatic analysis revealed a high homology of the 1700008O03Rik protein between human and mice, and phylogenetic tree analysis showed it to be highly conserved in mammalian evolution. CONCLUSIONS: 1700008O03Rik is a highly expressed gene in the mouse testis, mainly in the endochylema of oblong spermatozoa, which may be involved in the regulation of spermatogenesis in mice. PMID- 29706039 TI - [Protective effect of astaxanthin against epididymal oxidative damagein rats with ornidazole-induced oligoasthenozoospermia]. AB - Objective: To investigate the improving effect of astaxanthin (AST) on the sperm quality of rats with ornidazole (ORN)-induced oligoasthenozoospermiaand its action mechanism. METHODS: Forty adult male SD rats were equally randomized into groups A (solvent control), B (low-dose ORN [400 mg/(kg.d)]), C (high-dose ORN [800 mg/(kg.d)]), D (low-dose ORN [400 mg/(kg.d)] + AST [20 mg/(kg.d)]), and E (high-dose ORN [800 mg/(kg.d)] + AST [20 mg/(kg.d)]), all treated intragastrically for3 weeks.After treatment, the epididymal tails ononeside was taken for determination of sperm concentration and activity, and the epididymideson the other side harvested for measurement of the activities of GSH Px, GR, CAT and SOD and the MDA contentin the homogenate. RESULTS: Compared with group A, sperm motilityin the epididymal tail andGSH-Px and SOD activities in theepididymiswere markedly decreased while the MDAcontent significantlyincreased in group B (P<0.05), spermmotility and concentrationin the epididymal tail, testisindex, and the activities of GSH-Px, GR, CAT and SOD in the epididymis were remarkably reduced while theMDA contentsignificantly increased in group C(P<0.05). In comparison with group B, group D showed markedly increased sperm motility ([45.3+/-8.7]% vs [66.3+/-8.9]%, P<0.05) in the epididymal tail and SOD activity in the epididymis ([116.7+/-25.3] U/mg prot vs [146.1+/-23.8] U/mg prot, P<0.05), decreased MDA content([1.68+/-0.45] nmol/mg prot vs [1.19+/-0.42] nmol/mg prot, P<0.05).Compared with group C, group Eexhibited significant increases in the weight gained ([89.0+/-9.5] vs [99.9+/-4.1] %, P<0.05) and sperm motility ([17.9+/-3.5]% vs [27.3+/-5.3] %, P<0.05) but a decrease in the content of MDA ([2.03+/-0.30] nmol/mg prot vs [1.52+/-0.41] nmol/mg prot, P<0.05). CONCLUSIONS: AST can improve spermquality in rats with ORN inducedoligoasthenozoospermia, which may be associated with its enhancing effect on the antioxidant capacity of the epididymis. PMID- 29706040 TI - [Low serum testosterone level does not predict bone metastasis of prostate cancer]. AB - Objective: To evaluate the role of the serum testosterone level as an independent predictor of bone metastasis of prostate cancer. METHODS: This study included 165 male patients with prostate cancer confirmed by biopsy. The patients were aged 58 78 (66.6+/-5.3) years and none had received androgen-deprivation therapy, chemotherapy or radiotherapy previously. We obtained the baseline clinical data from the patients, including prostate biopsy Gleason scores and the levels of serum prostate-specific antigen (PSA), total testosterone (TT), luteinizing hormone (LH), follicle-stimulating hormone (FSH), estradiol (E2), alkaline phosphatase (ALP) and prolactin. According to the results of bone scanning, we divided the patients into a bone metastasis and a non-bone metastasis group and screened out the differential factors by univariate analysis and the independent predictor of bone metastasis using the multivariate non-conditional logistic regression model. RESULTS: Univariate analysis showed no statistically significant differences between the bone metastasis and non-bone metastasis groups in age (P = 0.126) or the levels of serum LH (P = 0.930), FSH (P = 0.763) and E2 (P = 0.256), but that the former had remarkably higher Gleason scores (P < 0.01), total PSA (P <0.01) and ALP (P <0.01) but a lower TT level than the latter (P = 0.013). According to the results of multivariate logistic regression analysis, serum ALP (P <0.01, OR = 1.018 [1.011-1.026]) and total PSA (P <0.01, OR = 1.029 [1.015-1.044]) could be regarded as independent predictors of bone metastasis of prostate cancer but not low serum TT (P = 0.531, OR = 0.999 [0.996 1.002]) or biopsy Gleason score (P = 0.898, OR = 0.787 [0.412-1.9559]). CONCLUSIONS: The low level of serum testosterone is closely associated with but not an independent predictor of bone metastasis of prostate cancer. PMID- 29706041 TI - [Transurethral diode laser enucleation versus transurethral electrovaporization resection of the prostate for benign prostatic hyperplasia with different prostate volumes]. AB - Objective: To compare the clinical effect of diode laser enucleation of the prostate (DIOD) with that of transurethral resection of the prostate (TURP) on benign prostate hyperplasia (BPH) with different prostate volumes. METHODS: This retrospective study included 256 BPH patients treated by DIOD (n = 141) or TURP (n = 115) from March 2012 to August 2015. According to the prostate volume, we divided the patients into three groups: <60 ml (42 for DIOD and 31 for TURP), 60 80 ml (51 for DIOD and 45 for TURP), and >80 ml (48 for DIOD and 39 for TURP). We obtained the relevant data from the patients before, during and at 6 months after surgery, and compared the two surgical strategies in operation time, perioperative levels of hemoglobin and sodium ion, post-operative urethral catheterization time and bladder irrigation time, pre- and post-operative serum PSA levels, International Prostate Symptoms Score (IPSS), post-void residual urine (PVR) volume and maximum urinary flow rate (Qmax), and incidence of post operative complications among different groups. RESULTS: In the <60 ml group, there were no remarkable differences in the peri- and post-operative parameters between the two surgical strategies. In the 60-80 ml group, DIOD exhibited a significant superiority over TURP in the perioperative levels of hemoglobin ([3.25 +/- 1.53] g/L vs [4.77 +/- 1.67] g/L, P <0.05) and Na+ ([3.58 +/- 1.27]mmol/L vs [9.67 +/- 2.67] mmol/L, P <0.01), bladder irrigation time ([30.06 +/- 6.22]h vs [58.32 +/- 10.25] h, P <0.01), and urethral catheterization time ([47.61 +/- 13.55] h vs [68.01 +/- 9.69] h, P <0.01), but a more significant decline than the latter in the postoperative PSA level ([2.34 +/- 1.29] ng/ml vs [1.09 +/- 0.72] ng/ml, P <0.05), and similar decline was also seen in the >80 ml group ([3.35 +/- 1.39] ng/ml vs [1.76 +/- 0.91] ng/ml, P <0.05). No blood transfusion was necessitated and nor postoperative transurethral resection syndrome or urethral stricture observed in DIOD. However, the incidence rate of postoperative pseudo-urinary incontinence was significantly higher in the DIOD (22.7%, 32/141) than in the TURP group (7.83%, 9/115) (P <0.05). CONCLUSIONS: DIOD, with its obvious advantages of less blood loss, higher safety, faster recovery, and more definite short-term effectiveness, is better than TURP in the treatment of BPH with medium or large prostate volume and similar to the latter with small prostate volume. PMID- 29706042 TI - [Persistent chlamydial genital infection in Tianjin area: An epidemiological study]. AB - Objective: To investigate the epidemic features of persistent genital chlamydial infection (GCI) in Tianjin area. METHODS: We statistically analyzed the clinical data about the persistent GCI patients received at the Venereal Disease Clinic of Tianjin Medical University General Hospital from 2009 to 2011. RESULTS: A total of 158 patients with persistent GCI were received from Tianjin area. The patients ranged in age from 19 to 67 years, 39.24% from 20 to 29 and 34.81% from 30 to 39 years, 36.71% with commercial occupation, and 55.06% with college education or above. The sex partners of the patients included their spouses (32.91%) and waitresses (41.77%). The incidence probability of persistent GCI was higher in the females (59.49%) than in the males. Many of the patients were complicated with infections of mycoplasma, syphilis, candida albicans, or condyloma acuminatum. CONCLUSIONS: The epidemic trend of persistent GCI is rather grim in Tianjin area. New measures have to be developed targeting the epidemiological features of persistent GCI for better prevention and control of the disease. PMID- 29706043 TI - [Therapeutic effect of Jinghuosu on oligospermia and asthenospermia.] AB - Objective: To investigate the effects of the compound preparation Jinghuosu on oligospermia and asthenospermia. METHODS: This multi-centered clinical study included 120 cases of mild to moderate idiopathic oligospermia or asthenospermia, all treated with oral Jinghuosu once a bag, bid, for 3 successive months. Before and at 1, 2 and 3 months after treatment, we detected sperm concentration, total sperm motility, progressive sperm motility and normal sperm morphology of each ejaculate, and recorded whether the patients had any adverse reactions. RESULTS: After 3 months of treatment, all the patients showed obvious improvement in semen parameters, most significantly in sperm concentration, total sperm motility, and the percentages of progressive motile sperm and morphologically normal sperm (P <0.05). No significant adverse reactions were observed during the 3 months of medication. CONCLUSIONS: Jinghuosu has a significant efficacy and no obvious adverse effect in the treatment of mild to moderate oligospermia and asthenospermia. PMID- 29706044 TI - [In vitro culture medium for sparse spermatozoa improves human sperm motility]. AB - Objective: To investigate whether in vitro culture medium (IVCM) for sparse spermatozoa can improve human sperm motility for the purpose of helping clinicians, laboratorians and patients choose a better strategy of assisted reproduction. METHODS: Semen samples were obtained from 178 males for routine semen examination from March to August 2016, including 151 cases of asthenozoospermia and 27 cases of normal sperm motility. A total of 200 MUl was collected from each sample and divided into two equal portions and equal volumes of IVCM (experimental group) and F10 (1*) (control group) were added to the two portions, respectively, followed by 30-minute incubation at 37C in an incubator with 5% CO2. Sperm concentration, motility and viability and the percentages of progressively motile, non-progressively motile and immotile sperm were recorded before and after incubation. RESULTS: After activated with IVCM, neither the samples with asthenozoospermia nor those with normal sperm motility showed any statistically significant difference in sperm viability from the baseline or the control group (P>0.05). The rates of progressively and non-progressively motile sperm from the asthenozoospermia males were increased by 14.02% and 4.86% respectively, while that of immotile sperm decreased by 19.01% in the experimental group (P >0.01), and similar results were observed in the semen samples from the men with normal sperm motility. The percentage of reduced immotile viable sperm was positively correlated with that of immotile viable sperm in both the asthenozoospermia patients (r = 0.260, P <0.01) and the men with normal sperm motility (r = 0.679, P <0.01). CONCLUSIONS: IVCM can increase sperm motility without affecting sperm viability in men with either asthenozoospermia or normal sperm motility. The larger the proportion of immotile viable sperm, the higher the percentages of progressively and non-progressively motile sperm in the semen after IVCM activation, and this correlation is more significant in men with normal sperm motility than in asthenozoospermia patients. PMID- 29706045 TI - [Vacuum sealing drainage as an adjuvant treatment of penile and scrotal gangrene: Clinical analysis of 4 cases]. AB - Objective: To search for an optimal strategy for the treatment of penile and scrotal gangrene by analyzing the clinical effect of vacuum sealing drainage (VSD) as an adjuvant treatment on this disease. METHODS: We retrospectively analyzed the clinical data about 4 cases of penile and scrotal gangrene treated by VSD as an adjuvant treatment from January 2015 to June 2016. The 4 patients all underwent early extensive and radical debridement of gangrene of the scrotum and penis and received intravenous injection of two broad-spectrum antibiotics, followed by VSD for wound drainage and irrigation. RESULTS: Adequate wound drainage was achieved in all the 4 cases, the gangrene range rapidly localized and testicular necrosis avoided. The wound surface healed satisfactorily after cleansing and suturing. The patients were followed up for 3 months after discharged from the hospital and none experienced recurrence. CONCLUSIONS: VSD combined with early adequate debridement can effectively localize the gangrene range, significantly reduce the frequency of changing dressings and shorten the hospitalization time of the patient, and therefore is a very effective adjuvant treatment of penile and scrotal gangrene. PMID- 29706046 TI - [Effect of Shirexiao waist hot-compress on the expressions of Th17/Treg-specific factors in the mouse model of experimental autoimmune prostatitis with damp heat syndrome]. AB - Objective: To investigate the effect of waist hot-compress with the Shirexiao (SRX) pad on the expressions of Th17/Treg-specific factors in the prostatic tissue of the mouse model of experimental autoimmune prostatitis (EAP) with damp heat syndrome, and explore its possible action mechanisms. METHODS: Twenty healthy male mice were included as normal controls and another 100 chosen for establishing the model of EAP with damp heat syndrome by subcutaneous injection of purified prostate protein solution from the Wistar rat and Freund's complete adjuvant using the TCM method. The model mice were randomly divided into five groups: model control, matrix, and low-, medium- and high-dose SRX. After chemical removal of the hair at lumbar vertebrae 1-3, the animals of the low-, medium- and high-dose SRX groups were treated with the SRX pad heated to 45C and externally applied to the non-hair area, qd, bid, and tid, respectively, 10 minutes each time, those of the matrix group with the vaseline pad, and those of the normal and model control groups with the saline pad. After 4 weeks of continuous treatment, all the mice were sacrificed for determination of the protein and mRNA expressions of RORgammat and Foxp3 in the prostate tissue by Western blot and quantitative real-time PCR. RESULTS: The symptoms, signs and pathological changes of the EAP model mice were similar to the manifestations of chronic prostatitis. After intervention, the protein and mRNA expressions of Foxp3 were significantly down-regulated while those of RORgammat markedly up regulated in the EAP model group as compared with the normal control (P <0.05). In comparison with the model controls, the protein and mRNA expressions of RORgammat were remarkably decreased in the medium- and high-dose SRX groups (P <0.05), that of the Foxp3 protein was markedly increased in the high-dose group (P <0.05), while that of Foxp3 mRNA exhibited no statistically significant difference in the low-, medium- or high-dose groups (P >0.05). CONCLUSIONS: The Shirexiao waist hot-compress therapy plays a positive role in the treatment of autoimmune prostatitis with damp heat syndrome by reducing the expression of RORgammat, inhibiting the differentiation of Th17 and thus checking the differentiation imbalance of Th17/Treg. PMID- 29706047 TI - [Qilin Pills for idiopathic oligoasthenospermia: A multi-centered randomized double-blind controlled clinical trial]. AB - Objective: To evaluate the clinical efficacy and safety of Qilin Pills in the treatment of oligoasthenospermia in infertile men. METHODS: This multi-centered randomized double-blind controlled clinical trial included 216 infertile males with oligoasthenospermia, 108 in the trial group and the other 108 in the control, the former treated with Qilin Pills at the dose of 6 g tid while the latter with Wuziyanzong Pills at 6 g bid, both for 12 weeks. We examined the total sperm count, sperm motility and the count of progressively motile sperm of the patients before and at 4, 8 and 12 weeks after medication and evaluated the safety of the drug based on the adverse events and the laboratory results of blood and urine routine examinations and liver and kidney function tests. RESULTS: Compared with the baseline, the patients in the trial group showed a significant time-dependent improvement after 4, 8 and 12 weeks of medication in sperm motility (21.75% vs 27.54%, 29.04% and 32.95%, P <0.05), total sperm count (156.27 *106 vs 177.33, 188.18 and 205.44 *106, P <0.05), and the count of progressively motile sperm (32.08 *106/ml vs 46.33, 50.98 and 61.10 *106/ml, P <0.05). The three parameters above were also improved in the controls, but more significantly in the trial group (P <0.05). CONCLUSIONS: Qilin Pills can evidently improve the semen quality of oligoasthenospermia patients with no obvious adverse events. PMID- 29706048 TI - [Correlation of psoriasis with erectile dysfunction: A meta-analysis]. AB - Objective: To systematically analyze the correlation between psoriasis and erectile dysfunction (ED). METHODS: We searched the Cochrane Library, EMbase, PubMed, OVID, Medline, VIP, WanFang, China National Knowledge Infrastructure (CNKI), and Chinese Biomedical Literature Database (CBM via SinoMed) for the published literature about the relationship between psoriasis and ED up to June 2016. According to inclusion and exclusion criteria, two researchers respectively extracted the relevant data and made a meta-analysis on the correlation of psoriasis with ED and IIEF-5 scores using the Review Manager 5.3 software. RESULTS: A total of 6 studies were included in this analysis. The analysis with the fixed-effects model revealed a significant correlation between psoriasis and ED (OR = 1.92, 95% CI: 1.53-2.40, P <0.01), and that on 3 of the studies with the random-effects model showed that the IIEF-5 scores were significantly lower in psoriasis patients than in non-psoriasis males (MD = -3.11, 95% CI: -4.85--1.37, P <0.01). CONCLUSIONS: There is a certain correlation between psoriasis and ED. Psoriasis patients may have a higher incidence of ED though it is to be further confirmed by more higher-quality studies. PMID- 29706049 TI - [Fertility preservation for male adolescent cancer patients]. AB - Fertility preservation is a hotspot of research in reproductive medicine, and that of male adolescent cancer patients is drawing even more attention from reproductive and oncologic clinicians. Both cancer and its treatment can decrease semen quality and even induce irreversible damage to fertility. Sperm cryopreservation is an effective method for fertility preservation. In the past few years, marked advances have been made in the cryopreservation, transplantation, and in vitro culture of testis tissue and stem spermatogonial cells. Although still experimental, these approaches may offer some options to those with no mature sperm in the testis. Unfortunately, very few people know and participate in the studies of fertility preservation and the utilization rate of cryopreserved sperm remains low. Therefor reproductive physicians and oncologists are required to make more efforts to search for effective fertility preservation methods for male adolescent cancer patients. PMID- 29706050 TI - [Correlation of connexin 43 with testicular tumors]. AB - Gap junctions (GJ), as a special membrane structure between adjacent cells, are composed of connexins (Cx) and regulate the proliferation and differentiation of cells. Studies show that gap junctional intercellular communication is weakened or lost in most tumor cells and this abnormality is often accompanied by changed expression of Cxs. Cx43 is a major connexin in the testis tissue. This review focuses on the latest progress in the studies of Cx43 in testicular tumors. PMID- 29706051 TI - [Risk and protection of fertility in male cancer patients]. AB - Gonad damage is one of the major complications of chemotherapy, radiotherapy or surgery in male cancer patients. For those who wish for childbearing after treatment, it is of great significance how to protect the reproductive function of the cancer patients. The main strategy for fertility protection is to optimize the treatment protocol, hormone therapy, antioxidant therapy, and the preservation of sperm and testicular tissue. This article presents an overview on the pathogenesis of gonadal damage induced by different treatments and protection of the reproductive function of the patient. PMID- 29706053 TI - Night shift preparation, performance, and perception: are there differences between emergency medicine nurses, residents, and faculty? AB - Objective: Determine differences between faculty, residents, and nurses regarding night shift preparation, performance, recovery, and perception of emotional and physical health effects. Methods: Survey study performed at an urban university medical center emergency department with an accredited residency program in emergency medicine. Results: Forty-seven faculty, 37 residents, and 90 nurses completed the survey. There was no difference in use of physical sleep aids between groups, except nurses utilized blackout curtains more (69%) than residents (60%) and faculty (45%). Bedroom temperature preference was similar. The routine use of pharmacologic sleep aids differed: nurses and residents (both 38%) compared to faculty (13%). Residents routinely used melatonin more (79%) than did faculty (33%) and nurses (38%). Faculty preferred not to eat (45%), whereas residents (24%) preferred a full meal. The majority (>72%) in all groups drank coffee before their night shift and reported feeling tired despite their routine, with 4:00 a.m. as median nadir. Faculty reported a higher rate (41%) of falling asleep while driving compared to residents (14%) and nurses (32%), but the accident rate (3% to 6%) did not differ significantly. All had similar opinions regarding night shift-associated health effects. However, faculty reported lower level of satisfaction working night shifts, whereas nurses agreed less than the other groups regarding increased risk of drug and alcohol dependence. Conclusion: Faculty, residents, and nurses shared many characteristics. Faculty tended to not use pharmacologic sleep aids, not eat before their shift, fall asleep at a higher rate while driving home, and enjoy night shift work less. PMID- 29706052 TI - [Anatomic application of the genitofemoral nerve in uroandrological surgery]. AB - The genitofemoral nerve (GFN) has its unique anatomic characteristics of location, run and function in the male urinary system and its relationship with the ureter, deferens and inguinal region is apt to be ignored in clinical anatomic application. Clinical studies show that GFN is closely correlated with postoperative ureteral complications and pain in the inguinal region after spermatic cord or hernia repair. GFN transplantation can be used in the management of erectile dysfunction caused by cavernous nerve injury. Therefore, GFN played an important role in the clinical application of uroandrology. This review summarizes the advances in the studies of GFN in relation to different diseases in uroandrology. PMID- 29706054 TI - Heparin-free extracorporeal membrane oxygenation in a patient with severe pulmonary contusions and bronchial disruption. AB - Pulmonary contusion complicated with endobronchial hemorrhage is potentially life threatening, particularly in patients with tracheobronchial tree disruption and severe airway bleeding after blunt trauma, and pose a high mortality risk. In such cases, extracorporeal membrane oxygenation (ECMO) can be used as a salvage treatment modality. However, the use of ECMO for moribund trauma patients with respiratory failure may be limited for several reasons, such as intractable bleeding. In this case report, we describe a patient with severe bilateral pulmonary contusions with tracheobronchial tree disruption that was successfully treated using heparin-free venovenous ECMO. PMID- 29706055 TI - Hemoglobin concentration is associated with neurologic outcome after cardiac arrest in patients treated with targeted temperature management. AB - OBJECTIVE: The objective of this study was to test the hypothesis that hemoglobin concentration after return of spontaneous circulation (ROSC) is associated with neurologic outcome after cardiac arrest in patients treated with targeted temperature management. METHODS: We studied consecutive adult patients with out of-hospital cardiac arrest treated with targeted temperature management between January 2009 and December 2015. We quantified the association between post ROSC hemoglobin concentrations and good neurologic outcome (defined as Cerebral Performance Category of 1 and 2) at hospital discharge using multivariate logistic regression analysis. RESULTS: A total of 246 subjects were ultimately included in this study. The mean age was 54 years (standard deviation, 17); 168 (68%) subjects were male. Eighty-seven (35%) subjects had a good neurologic outcome at hospital discharge. Hemoglobin concentrations were higher in the good outcome group than in the poor outcome group (14.4+/-2.0 vs. 12.8+/-2.5 g/dL, P<0.001). Multivariate logistic regression analysis showed that hemoglobin concentrations were associated with good neurologic outcome at hospital discharge after adjusting for other confounding factors (adjusted odds ratio, 1.186; 95% confidence interval, 1.008 to 1.395). CONCLUSION: These results show that hemoglobin concentrations after ROSC are associated with neurologic outcome at hospital discharge. Future research to examine the association between hemoglobin levels and neurologic outcome after cardiac arrest is warranted. PMID- 29706056 TI - Changes in medical care due to the absence of internal medicine physicians in emergency departments. AB - Objective: Especially in emergency departments (EDs), a lack of internal medicine (IM) residents in charge causes difficulties in medical care and ED overcrowding. Thus, protocols without IM residents in EDs is needed. This study aimed to investigate changes in medical care when emergency medicine residents replaced the roles of IM residents. Methods: This study was conducted at a single-site ED of a university medical center. The study group contained patients admitted to the IM department between September and December 2015, during which IM residents were absent in the ED. The control group contained patients admitted to the IM department between September and December 2014, during which IM residents were present in the ED. Changes in medical care between the presence and absence of IM residents in the ED were studied by comparing admission rates from the ED, length of ED stay, duration of hospitalization, and concordance of diagnoses between admission and discharge by the IM department. Results: The study group contained 2,341 patients; the control group contained 2,215 patients. Admission rates from the ED increased by 53.4% (95% confidence interval [CI], P<0.001); lengths of stay decreased by 15.1% (95% CI, P<0.001); and durations of hospitalization in the pulmonology department decreased by 38.4% (95% CI, P=0.001). Concordance of diagnoses between admission and discharge decreased by 14.2% in the cardiology department (95% CI, P=0.021). Conclusion: Lengths of stay were reduced without critical declines in diagnostic concordance rates when emergency medicine physicians, instead of IM residents in the ED, decided upon admissions of IM patients. PMID- 29706057 TI - Monomorphic ventricular tachycardia due to protease inhibitor intoxication by atazanavir. AB - Atazanavir is a protease inhibitor approved for use in combination with other antiretroviral drugs for the treatment of human immunodeficiency virus infection. Atazanavir and other protease inhibitors can sometimes induce corrected QT prolongation and ventricular arrhythmia. A 40-year-old man with no comorbidities, except human immunodeficiency virus 1 infection, presented with palpitations 3 days after an overdose of 150 caps of atazanavir, with suicidal intent. His initial electrocardiogram showed monomorphic ventricular tachycardia, and hyperbilirubinemia was observed in his initial blood test. Immediately after magnesium sulfate infusion, his ventricular tachycardia was converted into junctional bradycardia with prolonged corrected QT. After 3 days of close observation in the intensive care unit, the corrected QT prolongation and hyperbilirubinemia were normalized. PMID- 29706058 TI - Clinical usefulness of psoas muscle thickness for the diagnosis of sarcopenia in patients with liver cirrhosis. AB - BACKGROUND/AIMS: The most widely used method for diagnosing sarcopenia is the skeletal muscle index (SMI). Several studies have suggested that psoas muscle thickness per height (PMTH) is also effective for detecting sarcopenia and predicting prognosis in patients with cirrhosis. The aim of this study was to evaluate the optimal cutoff values of PMTH for detecting sarcopenia in cirrhotic patients. METHODS: All cirrhotic patients who underwent abdominal computed tomography (CT) scan including L3 and umbilical levels for measuring SMI and transverse psoas muscle thickness, respectively, were included. Two definitions of sarcopenia were used: (1) sex-specific cutoffs of SMI (<=52.4 cm2 /m2 in men and <=38.5 cm2 /m2 in women) for SMI-sarcopenia and (2) cutoff of PMTH (<16.8 mm/m) for PMTH-sarcopenia. RESULTS: Six hundred fifty-three patients were included. The average age was 53.6 +/- 10.2 years, and 499 patients (76.4%) were men. PMTH correlated well with SMI in both men and women (P<0.001). Two hundred forty-one (36.9%) patients met the criteria for SMI-sarcopenia. The best PMTH cutoff values for predicting SMI-sarcopenia were 17.3 mm/m in men and 10.4 mm/m in women, and these were defined as sex-specific cutoffs of PMTH (SsPMTH). The previously published cutoff of PMTH was defined as sex-nonspecific cutoff of PMTH (SnPMTH). Two hundred thirty (35.2%) patients were diagnosed with SsPMTH sarcopenia, and 280 (44.4%) patients were diagnosed with SnPMTH-sarcopenia. On a multivariate Cox regression analysis, SsPMTH-sarcopenia (hazard ratio [HR], 1.944; 95% confidence interval [CI], 1.144-3.304; P=0.014) was significantly associated with mortality, while SnPMTH-sarcopenia was not (HR, 1.446; 95% CI, 0.861-2.431; P=0.164). CONCLUSION: PMTH was well correlated with SMI in cirrhotic patients. SsPMTH-sarcopenia was an independent predictor of mortality in these patients and more accurately predicted mortality compared to SnPMTH-sarcopenia. PMID- 29706059 TI - Identification of Smoking-Associated Differentially Methylated Regions Using Reduced Representation Bisulfite Sequencing and Cell type-Specific Enhancer Activation and Gene Expression. AB - BACKGROUND: Cigarette smoke is a causal factor in cancers and cardiovascular disease. Smoking-associated differentially methylated regions (SM-DMRs) have been observed in disease studies, but the causal link between altered DNA methylation and transcriptional change is obscure. OBJECTIVE: Our objectives were to finely resolve SM-DMRs and to interrogate the mechanistic link between SM-DMRs and altered transcription of enhancer noncoding RNA (eRNA) and mRNA in human circulating monocytes. METHOD: We integrated SM-DMRs identified by reduced representation bisulfite sequencing (RRBS) of circulating CD14+ monocyte DNA collected from two independent human studies [n=38 from Clinical Research Unit (CRU) and n=55 from the Multi-Ethnic Study of Atherosclerosis (MESA), about half of whom were active smokers] with gene expression for protein-coding genes and noncoding RNAs measured by RT-PCR or RNA sequencing. Candidate SM-DMRs were compared with RRBS of purified CD4+ T cells, CD8+ T cells, CD15+ granulocytes, CD19+ B cells, and CD56+ NK cells (n=19 females, CRU). DMRs were validated using pyrosequencing or bisulfite amplicon sequencing in up to 85 CRU volunteers, who also provided saliva DNA. RESULTS: RRBS identified monocyte SM-DMRs frequently located in putative gene regulatory regions. The most significant monocyte DMR occurred at a poised enhancer in the aryl-hydrocarbon receptor repressor gene (AHRR) and it was also detected in both granulocytes and saliva DNA. To our knowledge, we identify for the first time that SM-DMRs in or near AHRR, C5orf55 EXOC-AS, and SASH1 were associated with increased noncoding eRNA as well as mRNA in monocytes. Functionally, the AHRR SM-DMR appeared to up-regulate AHRR mRNA through activating the AHRR enhancer, as suggested by increased eRNA in the monocytes, but not granulocytes, from smokers compared with nonsmokers. CONCLUSIONS: Our findings suggest that AHRR SM-DMR up-regulates AHRR mRNA in a monocyte-specific manner by activating the AHRR enhancer. Cell type-specific activation of enhancers at SM-DMRs may represent a mechanism driving smoking related disease. https://doi.org/10.1289/EHP2395. PMID- 29706060 TI - Variability of extracorporeal cardiopulmonary resuscitation utilization for refractory adult out-of-hospital cardiac arrest: an international survey study. AB - Objective: A growing interest in extracorporeal cardiopulmonary resuscitation (ECPR) as a rescue strategy for refractory adult out-of-hospital cardiac arrest (OHCA) currently exists. This study aims to determine current standards of care and practice variation for ECPR patients in the USA and Korea. Methods: In December 2015, we surveyed centers from the Korean Hypothermia Network (KORHN) Investigators and the US National Post-Arrest Research Consortium (NPARC) on current targeted temperature management and ECPR practices. This project analyzes the subsection of questions addressing ECPR practices. We summarized survey. Results: using descriptive statistics. Results: Overall, 9 KORHN and 4 NPARC centers reported having ECPR programs and had complete survey data available. Two KORHN centers utilized extracorporeal membrane oxygenation only for postarrest circulatory support in patients with refractory shock and were excluded from further analysis. Centers with available ECPR generally saw a high volume of OHCA patients (10/11 centers care for >75 OHCA a year). Location of, and providers trained for cannulation varied across centers. All centers in both countries (KORHN 7/7, NPARC 4/4) treated comatose ECPR patients with targeted temperature management. All NPARC centers and four of seven KORHN centers reported having a standardized hospital protocol for ECPR. Upper age cutoff for eligibility ranged from 60 to 75 years. No absolute contraindications were unanimous among centers. Conclusion: A wide variability in practice patterns exist between centers performing ECPR for refractory OHCA in the US and Korea. Standardized protocols and shared research databases might inform best practices, improve outcomes, and provide a foundation for prospective studies. PMID- 29706061 TI - Molecular Signaling in Tumorigenesis of Gastric Cancer AB - Gastric cancer (GC) is regarded as the fifth most common cancer and the third cause of cancer-related deaths worldwide. Mechanism of GC pathogenesis is still unclear and relies on multiple factors, including environmental and genetic characteristics. One of the most important environmental factors of GC occurrence is infection with Helicobacter pylori that is classified as class one carcinogens. Dysregulation of several genes and pathways play an essential role during gastric carcinogenesis. Dysregulation of developmental pathways such as Wnt/beta-catenin signaling, Hedgehog signaling, Hippo pathway, Notch signaling, nuclear factor-kB, and epidermal growth factor receptor have been found in GC. Epithelial-mesenchymal transition, as an important process during embryogenesis and tumorigenesis, is supposed to play a role in initiation, invasion, metastasis, and progression of GC. Although surgery is the main therapeutic modality of the disease, the understanding of biological processes of cell signaling pathways may help to develop new therapeutic targets for GC. PMID- 29706062 TI - Chemometric Approach to the Calibration of Light Emitting Diode Based Optical Gas Sensors Using High-Resolution Transmission Molecular Absorption Data. AB - Modeling the propagation of light from LED sources is problematic since the emission covers a broad range of wavelengths and thus cannot be considered as monochromatic. Furthermore, the lack of directivity of such sources is also problematic. Both attributes are characteristic of LEDs. Here we propose a HITRAN ( high-resolution transmission molecular absorption database) based chemometric approach that incorporates not-perfect-monochromaticity and spatial directivity of near-infrared (NIR) LED for absorbance calculations in 1-6% methane (CH4) in air, considering CH4 as a model absorbing gas. We employed the absorbance thus calculated using HITRAN to validate the experimentally measured absorbance of CH4. The maximum error between the measured and calculated absorbance values were within 1%. The approach can be generalized as a chemometric calibration technique for measuring gases and gas mixtures that absorb emissions from polychromatic or not-perfect-monochromatic sources, provided the gas concentration, optical path length, as well as blank and attenuated emission spectra of the light source are incorporated into the proposed chemometric approach. PMID- 29706063 TI - Feasibility of Rare Earth Element Determination in Low Concentration in Crude Oil: Direct Sampling Electrothermal Vaporization-Inductively Coupled Plasma Mass Spectrometry. AB - A comprehensive study was developed showing the feasibility of determination of rare earth elements (REE) in low concentration in crude oil by using direct sampling electrothermal vaporization system coupled to inductively coupled plasma mass spectrometry (ETV-ICP-MS). The effect of organic modifier on the REE signal was evaluated and the use of 6 mg of citric acid allowed calibration using aqueous reference solutions (selected pyrolysis and vaporization temperatures were 700 and 2200 degrees C, respectively). Because of the facility of REE in forming refractory compounds inside the graphite furnace during the heating step, the use of a modifier gas (Freon R-12, 3.0 mL min-1) was necessary to allow quantitative vaporization of these elements. A flow rate of 0.40 L min-1 was selected for both bypass and carrier gases. Under optimized conditions, the influence of sample mass was evaluated, and even using a relatively high mass of crude oil (up to 18 mg), accurate results were obtained. The accuracy was evaluated by the comparison of results by ETV-ICP-MS with those obtained by ICP MS with ultrasonic nebulizer (USN) after high-pressure microwave-assisted wet digestion (MAWD) and microwave-induced combustion (MIC) and no statistical difference was observed between the results. The limits of quantification for REE by ETV-ICP-MS were lower (0.02-0.8 ng g-1) than those obtained by USN-ICP-MS after MAWD and MIC (0.6-5.1 ng g-1). Negligible blank values and relative standard deviations lower than 12% show the feasibility of the proposed ETV-ICP MS method for routine analysis of crude oil. PMID- 29706064 TI - Electron Attachment to Microhydrated Deoxycytidine Monophosphate. AB - DNA constituents are effectively decomposed via dissociative electron attachment (DEA). However, the DEA contribution to radiation damage in living tissues is a subject of ongoing discussion. We address an essential question, how aqueous environment influences the DEA to DNA. In particular, we report experimental fragmentation patterns for DEA to microhydrated 2-deoxycytidine 5-monophosphate (dCMP). Isolated dCMP was previously set as a model to describe mechanisms of DNA strand breaks induced by secondary electrons and decomposes primarily by dissociation of the C-O phosphoester bond. We show that hydrated molecules decompose via dissociation of the C-N glycosidic bond followed by dissociation of the P-O bond. This significant change of the proposed mechanism can be interpreted by a reactive role of water in the postattachment dynamics. Comparison of the fragmentation with previous macroscopic irradiation studies suggests that the actual contribution of DEA to DNA radiation damage in living tissue is rather small. PMID- 29706065 TI - Anomalous Nanoscale Optoacoustic Phonon Mixing in Nematic Mesogens. AB - Recent inelastic X-ray scattering (IXS) experiments on mesogens have revealed entirely new capabilities with regards to their nanoscale phonon-assisted heat management. Mesogens such as nematic liquid crystals (LCs) are appealing systems for study because their structure and morphology can easily be tuned. We report on Q-resolved ultra-high-resolution IXS, X-ray diffraction, and THz time-domain spectroscopy experiments combined with large-scale all-atom molecular dynamics simulations on the dynamic properties of 5CB LCs. For the first time, we observe a strong mixing of phonon excitations originating from independent in-phase and out-of-phase van-der-Waals-mediated displacement patterns. The coexistence of transverse acoustic and optical modes of 5CB LCs at near room temperature is revealed through the emergent transverse phonon gap and THz light-phonon coupling taking place within the same energy range. Furthermore, our experimental observations are supported by analysis showing correlations of spontaneous fluctuations of LCs on picosecond time scales. These findings are significant for the design of a new generation of soft molecular vibration-sensitive nanoacoustic and optomechanical applications. PMID- 29706066 TI - Interface Engineering of Monolayer MoS2/GaN Hybrid Heterostructure: Modified Band Alignment for Photocatalytic Water Splitting Application by Nitridation Treatment. AB - Interface engineering is a key strategy to deal with the two-dimensional (2D)/three-dimensional (3D) hybrid heterostructure, since the properties of this atomic-layer-thick 2D material can easily be impacted by the substrate environment. In this work, the structural, electronic, and optical properties of the 2D/3D heterostructure of monolayer MoS2 on wurtzite GaN surface without and with nitridation interfacial layer are systematically investigated by first principles calculation and experimental analysis. The nitridation interfacial layer can be introduced into the 2D/3D heterostructure by remote N2 plasma treatment to GaN sample surface prior to stacking monolayer MoS2 on top. The calculation results reveal that the 2D/3D integrated heterostructure is energetically favorable with a negative formation energy. Both interfaces demonstrate indirect band gap, which is a benefit for longer lifetime of the photoexcited carriers. Meanwhile, the conduction band edge and valence band edge of the MoS2 side increases after nitridation treatment. The modification to band alignment is then verified by X-ray photoelectron spectroscopy measurement on MoS2/GaN heterostructures constructed by a modified wet-transfer technique, which indicates that the MoS2/GaN heterostructure without nitridation shows a type-II alignment with a conduction band offset (CBO) of only 0.07 eV. However, by the deployment of interface nitridation, the band edges of MoS2 move upward for ~0.5 eV as a result of the nitridized substrate property. The significantly increased CBO could lead to better electron accumulation capability at the GaN side. The nitridized 2D/3D heterostructure with effective interface treatment exhibits a clean band gap and substantial optical absorption ability and could be potentially used as practical photocatalyst for hydrogen generation by water splitting using solar energy. PMID- 29706067 TI - Sorption of Perfluoroalkyl Acids to Fresh and Aged Nanoscale Zerovalent Iron Particles. AB - The sorption of perfluoroalkyl acids (PFAAs), particularly perfluorooctanesulfonic acid (PFOS), to freshly synthesized nanoscale zerovalent iron (nZVI) and aged (oxidized) and sulfidated nZVI, was investigated under anaerobic conditions. The sorption of PFAAs to nZVI was 2-4 orders of magnitude higher than what has been reported for sediments, soils, and iron oxides. The hydrophobicity of the perfluorocarbon chain dominated the sorption, although FTIR spectra indicated specific interactions between sulfonate and carboxylate head groups and nZVI. The contributions from electrostatic interactions depended on the surface charge and pH. Humic acids influenced sorption only at concentrations above 50 mg/L. nZVI aged in deoxygenated water up to 95 days showed similar sorption isotherms for PFOS to fresh nZVI, because Fe(OH)2 was the predominant phase on the nZVI surface independent of aging time. Sulfidation of nZVI reduced sorption of PFOS by 1 log unit owing to the FeS deposited, but the sorption affinity was restored after aging because of formation of Fe(OH)2. Oxidation of nZVI by water and dissolved oxygen also resulted in similar sorption of PFOS as fresh nZVI at environmentally relevant concentrations. The results suggest that injection of nZVI could reduce PFAA concentrations in groundwater despite changes to its surface chemistry with aging. PMID- 29706068 TI - Beef Protein-Derived Peptides as Bitter Taste Receptor T2R4 Blockers. AB - The aim of this work was to determine the T2R4 bitter taste receptor-blocking ability of enzymatic beef protein hydrolysates and identified peptide sequences. Beef protein was hydrolyzed with each of six commercial enzymes (alcalase, chymotrypsin, trypsin, pepsin, flavourzyme, and thermoase). Electronic tongue measurements showed that the hydrolysates had significantly ( p < 0.05) lower bitter scores than quinine. Addition of the hydrolysates to quinine led to reduced bitterness intensity of quinine with trypsin and pepsin hydrolysates being the most effective. Addition of the hydrolysates to HEK293T cells that heterologously express one of the bitter taste receptors (T2R4) showed alcalase, thermoase, pepsin, and trypsin hydrolysates as the most effective in reducing calcium mobilization. Eight peptides that were identified from the alcalase and chymotrypsin hydrolysates also suppressed quinine-dependent calcium release from T2R4 with AGDDAPRAVF and ETSARHL being the most effective. We conclude that short peptide lengths or the presence of multiple serine residues may not be desirable structural requirements for blocking quinine-dependent T2R4 activation. PMID- 29706069 TI - Biotransformation of Sulfonamide Antibiotics in Activated Sludge: The Formation of Pterin-Conjugates Leads to Sustained Risk. AB - The presence of antibiotics in treated wastewater and consequently in surface and groundwater resources raises concerns about the formation and spread of antibiotic resistance. Improving the removal of antibiotics during wastewater treatment therefore is a prime objective of environmental engineering. Here we obtained a detailed picture of the fate of sulfonamide antibiotics during activated sludge treatment using a combination of analytical methods. We show that pterin-sulfonamide conjugates, which are formed when sulfonamides interact with their target enzyme to inhibit folic acid synthesis, represent a major biotransformation route for sulfonamides in laboratory batch experiments with activated sludge. The same major conjugates were also present in the effluents of nine Swiss wastewater treatment plants. The demonstration of this biotransformation route, which is related to bacterial growth, helps explain seemingly contradictory views on optimal conditions for sulfonamide removal. More importantly, since pterin-sulfonamide conjugates show retained antibiotic activity, our findings suggest that risk from exposure to sulfonamide antibiotics may be less reduced during wastewater treatment than previously assumed. Our results thus further emphasize the inadequacy of focusing on parent compound removal and the importance of investigating biotransformation pathways and removal of bioactivity to properly assess contaminant removal in both engineered and natural systems. PMID- 29706070 TI - Vertically Aligned High-Quality Graphene Foams for Anisotropically Conductive Polymer Composites with Ultrahigh Through-Plane Thermal Conductivities. AB - Although graphene-based thermal interface materials (TIMs) have great potentials in removing excess heat generated during highly efficient running of electronic devices, their practical applications are usually limited by their unsatisfactory thermal conductions, which are mainly caused by unsatisfactory dispersion and distribution, low loading, and low quality of graphene sheets, as well as the thermal interfacial resistance between graphene sheets and polymer matrix. Herein, we develop vertically aligned graphene hybrid foams (GHFs) with high densities by hydrothermal reduction of graphene oxide in the presence of high quality graphene nanoplatelets (GNPs) followed by air-drying. The reduced graphene oxide sheets play an important role in constructing a vertically aligned interconnection network for accommodating GNPs during the hydrothermal reduction process, while the incorporated GNPs not only make the thermal conductance network denser but also prevent excessive shrinkage of the foams during air drying. More critically, graphitization of GHF at 2800 degrees C removes the residual oxygen-containing groups and heals the defects of their reduced graphene oxide component, leading to high-quality graphene foams. The resultant vertically aligned high-quality graphene porous architecture with high density as an ideal thermal conductance network of TIMs is highly efficient in improving the thermal conductivity of its epoxy composite, which exhibits an ultrahigh through-plane thermal conductivity of 35.5 W m-1 K-1 at a graphene loading of 19.0 vol %. The excellent thermally conductive performance makes the annealed GHF/epoxy composites suitable for the thermal management. PMID- 29706071 TI - Ultrahigh Sensitive and Flexible Magnetoelectronics with Magnetic Nanocomposites: Toward an Additional Perception of Artificial Intelligence. AB - In recent years, flexible magnetoelectronics has attracted a great attention for its intriguing functionalities and potential applications, such as healthcare, memory, soft robots, navigation, and touchless human-machine interaction systems. Here, we provide the first attempt to demonstrate a new type of magneto piezoresistance device, which possesses an ultrahigh sensitivity with several orders of resistance change under an external magnetic field (100 mT). In our device, Fe-Ni alloy powders are embedded in the silver nanowire-coated micropyramid polydimethylsiloxane films. Our devices can not only serve as an on/off switch but also act as a sensor that can detect different magnetic fields because of its ultrahigh sensitivity, which is very useful for the application in analog signal communication. Moreover, our devices contain several key features, including large-area and easy fabrication processes, fast response time, low working voltage, low power consumption, excellent flexibility, and admirable compatibility onto a freeform surface, which are the critical criteria for the future development of touchless human-machine interaction systems. On the basis of all of these unique characteristics, we have demonstrated a nontouch piano keyboard, instantaneous magnetic field visualization, and autonomous power system, making our new devices be integrable with magnetic field and enable to be implemented into our daily life applications with unfamiliar human senses. Our approach therefore paves a useful route for the development of wearable electronics and intelligent systems. PMID- 29706073 TI - Crystal Facet Effects on Nanomagnetism of Co3O4. AB - The magnetic performance of nanomaterials depends on size, shape, and surface of the nanocrystals. Here, the exposed crystal planes of Co3O4 nanocrystals were analyzed to research the dependence of magnetic properties on the configuration environment of the ions exposed on different surfaces. The Co3O4 nanocrystals with exposed (1 0 0), (1 1 0), (1 1 1), and (1 1 2) planes were synthesized using a hydrothermal method in the shapes of nanocube, nanorod, hexagonal nanoplatelet, and nanolaminar, respectively. Ferromagnetic performance was detected in the (1 0 0) and (1 1 1) plane-exposed samples. First-principles calculation results indicate that unlike the nonmagnetic nature in the bulk, the Co3+ ions exposed on or close to the surface possess sizable magnetic moments because of the variation of coordination numbers and lattice distortion, which is responsible for the ferromagnetic-like behavior. The (1 1 0)-exposed sample keeps the natural antiferromagnetic behavior of bulk Co3O4 because either the surface Co3+ ions have no magnetic moments or their moments are in antiferromagnetic coupling. The (1 1 2)-exposed sample also displays antiferromagnetism because the interaction distances between the magnetized Co3+ ions are too long to form effective ferromagnetic coupling. PMID- 29706072 TI - Proteomic and Phosphoproteomic Changes Induced by Prolonged Activation of Human Eosinophils with IL-3. AB - Purified human eosinophils treated for 18-24 h with IL-3 adopt a unique activated phenotype marked by increased reactivity to aggregated immunoglobulin-G (IgG). To characterize this phenotype, we quantified protein abundance and phosphorylation by multiplexed isobaric labeling combined with high-resolution mass spectrometry. Purified blood eosinophils of five individuals were treated with IL-3 or no cytokine for 20 h, and comparative data were obtained on abundance of 5385 proteins and phosphorylation at 7330 sites. The 1150 proteins that were significantly up-regulated ( q < 0.05, pairwise t test with Benjamini-Hochberg correction) by IL-3 included the IL3RA and CSF2RB subunits of the IL-3 receptor, the low-affinity receptor for IgG (FCGR2B), 96 proteins involved in protein translation, and 55 proteins involved in cytoskeleton organization. Among the 703 proteins that decreased were 78 mitochondrial proteins. Dynamic regulation of protein phosphorylation was detected at 4218 sites. These included multiple serines in CSF2RB; Y694 of STAT5, a key site of activating phosphorylation downstream of IL3RA/CSF2RB; and multiple sites in RPS6KA1, RPS6, and EIF4B, which are responsible for translational initiation. We conclude that IL-3 up-regulates overall protein synthesis and targets specific proteins for up-regulation, including its own receptor. PMID- 29706074 TI - Oxidized Buckypaper for Stir-Disc Solid Phase Extraction: Evaluation of Several Classes of Environmental Pollutants Recovered from Surface Water Samples. AB - This paper describes, for the first time, the use of oxidized buckypaper (BP) as a sorbent membrane of a stir-disc solid phase extraction module. The original device, consisting of a BP disc ( d = 34 mm) enveloped in a polypropylene mesh pouch, was designed to extract organic micropollutants (OMPs) from environmental water samples in dynamic mode. High-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) was used to analyze the extracts. Several classes of pesticides and pharmaceuticals were chosen as model compounds to evaluate key parameters affecting the recovery rates. To this end, the effects of adsorption time, desorption time, stirring speed, type and volume of solvent, and sample volume were thoroughly examined. After optimization, a novel and in-depth study was conducted to find a correlation between physicochemical properties of the analytes and extraction yields. Recoveries were mainly governed by a combination of log P and p Ka values. As indicated, hydrophilic compounds with log P < 1 showed poor affinity for the oxidized BP, compounds having log P > 1 exhibited recoveries ranging between 50% and 100% depending on their p Ka, while compounds with p Ka between 6 and 7.5 gave low yields irrespective of their log P. The analytical method was also validated and tested as large scale screening method of OMPs in surface waters. The analysis of real samples revealed the presence of some nonsteroidal anti-inflammatory drugs, sulfonamides, and pesticides at low ng L-1 concentration levels with relative standard deviations lower than 8%. PMID- 29706075 TI - Rhodium(III)-Catalyzed Oxidative Coupling of N-Phenylindole-3-carboxylic Acids with Alkenes and Alkynes via C4-H and C2-H/C2'-H Bond Cleavage. AB - The rhodium(III)-catalyzed direct alkenylation of N-phenylindole-3-carboxylic acids with alkenes including acrylate ester, acrylamide, and acrylonitrile proceeds smoothly at the C4-position through regioselective C-H bond cleavage directed by the carboxyl group. In marked contrast, the indole substrates react with diarylacetylenes accompanied by cleavage of the C2-H and C2'-H bonds and decarboxylation to produce 5,6-diarylindolo[1,2- a]quinolone derivatives. DFT calculations have suggested that the smooth insertion of an alkene to a C4 rhodated six-membered metallacycle intermediate leads to the C4 alkenylated products, while the latter annulation at the C2- and C2'-positions is attributable to facile reductive elimination in the corresponding seven-membered metallacycles formed by the double C-H bond cleavage and alkyne insertion. PMID- 29706076 TI - High Temperature Quadruple-Detector Size Exclusion Chromatography for Topological Characterization of Polyethylene. AB - Modifying material properties in simple macromolecules such as polyethylene (PE) is achieved by different connection modes of ethylene monomers resulting in a plurality of possible topologies-from highly linear to dendritic species. However, the challenge still lies within the experimental identification of the topology and conformation of the isolated macromolecules because of their low solubility, which demands methods with specific solvents and high operating temperatures. Additionally, a separation technique has to be coupled to different detection methods to meet the specific demands of the respective characterization goal. In this work, we report a quadruple-detector high temperature size exclusion chromatography (HT-SEC) system which contains online multiangle laser light scattering, dynamic light scattering, differential viscometry, and differential refractometry detectors. Quadruple-detector HT-SEC was successfully applied to explore the full range of physical parameters of various PE samples with different branching topologies ranging from highly linear macromolecules, polymers with moderate level of branching, to highly branched PEs with hyperbranched structure. This method is a useful tool not only to investigate molecular weight, mass distribution, and size but also to enable access to important factors which describe the conformation in dilute solution and branching density. PMID- 29706077 TI - Nonwettable Hierarchical Structure Effect on Droplet Impact and Spreading Dynamics. AB - In this study, the nano/micro hierarchical structure effect of a nonwettable surface on droplet impact was investigated by high-speed visualization. A dual scale structure of a superhydrophobic surface was designed for manipulating a wide range of capillary pressures (103-106 Pa), and it was supposed to trigger a hierarchical effect on the droplet dynamics. Distilled water droplets of various sizes and initial velocity were subjected to the prepared samples, and the impact behavior, the spreading diameter, and contacted time, were quantitatively measured. The apparent maximum spreading and contact time of the low Weber number ( We#) condition was less dependent on the microscaled design factor of the multiscale-fabricated surface. However, in the high We# condition, the wavy formation shape and the fragmented criteria of the droplet impact were affected by the configuration of the surface morphology. The hierarchical effect from the dual-scale structure on droplet spreading dynamics has been discussed through a balance between capillary pressure induced by the structure and the dynamic pressure of droplet impact. PMID- 29706078 TI - Intense Femtosecond Laser-Mediated Electrical Discharge Enables Preparation of Amorphous Nickel Phosphide Nanoparticles. AB - Reported here is a high-efficiency preparation method of amorphous nickel phosphide (Ni-P) nanoparticles by intense femtosecond laser irradiation of nickel sulfate and sodium hypophosphite aqueous solution. The underlying mechanism of the laser-assisted preparation was discussed in terms of the breaking of chemical bond in reactants via highly intense electric field discharge generated by the intense femtosecond laser. The morphology and size of the nanoparticles can be tuned by varying the reaction parameters such as ion concentration, ion molar ratio, laser power, and irradiation time. X-ray diffraction and transmission electron microscopy results demonstrated that the nanoparticles were amorphous. Finally, the thermogravimetric-differential thermal analysis experiment verified that the as-synthesized noncrystalline Ni-P nanoparticles had an excellent catalytic capability toward thermal decomposition of ammonium perchlorate. This strategy of laser-mediated electrical discharge under such an extremely intense field may create new opportunities for the decomposition of molecules or chemical bonds that could further facilitate the recombination of new atoms or chemical groups, thus bringing about new possibilities for chemical reaction initiation and nanomaterial synthesis that may not be realized under normal conditions. PMID- 29706079 TI - Amelioration of Alcoholic Liver Steatosis by Dihydroquercetin through the Modulation of AMPK-Dependent Lipogenesis Mediated by P2X7R-NLRP3-Inflammasome Activation. AB - Dihydroquercetin (TAX) is the most abundant dihydroflavone found in onions, milk thistle, and Douglas fir bark. We investigated whether TAX could inhibit lipid accumulation in alcoholic liver steatosis in vivo and in vitro. An in vivo model was established by intragastrically treating mice with ethanol, and an in vitro model was created by treating HepG2 cells with ethanol. TAX regulated SREBP1 and ACC expression by elevating LKB1 and AMPK phosphorylation. Also, TAX upregulated SIRT1 expression, which was suppressed by ethanol intake. Decreased expression of P2X7R and NLRP3 and suppressed cleavage of caspase-1 by TAX resulted in the inhibition of IL-1beta production and release. Additionally, TAX reduced lipogenesis and promoted lipid oxidation via the regulation of AMPK and ACC in ethanol-treated steatotic HepG2 cells. TAX downregulated IL-1beta cleavage responses to LPS and ATP stimulation in HepG2 cells. P2X7R deficiency attenuated lipid accumulation, characterized by increased AMPK activity and decreased SREBP1 expression in ethanol-treated HepG2 cells. Our data showed that TAX exhibited the ability to inhibit lipogenesis and a hepatoprotective capacity, indicating that TAX has therapeutic potential for preventing alcoholic liver steatosis. PMID- 29706080 TI - Bioactive Compounds of Kimchi Inhibit Apoptosis by Attenuating Endoplasmic Reticulum Stress in the Brain of Amyloid beta-Injected Mice. AB - This study investigated the inhibitory effects of kimchi bioactive compounds against endoplasmic reticulum (ER) stress-induced apoptosis in amyloid beta (Abeta)-injected mice. Mice received a single intracerebroventricular injection of Abeta25-35, except for the normal group. Mice were subjected to oral administration of 10 mg of capsaicin, 50 mg of 3-(4'-hydroxyl-3',5' dimethoxyphenyl)propionic acid (HDMPPA), 50 mg of quercetin, 50 mg of ascorbic acid, or 200 mg of kimchi methanol extract (KME) per kilogram of body weight for 2 weeks ( n = 7 per group). In the in vitro blood-brain barrier (BBB) permeability test, all bioactive compounds penetrated the BBB except ascorbic acid. The protein expression level of APP, BACE, and p-Tau elevated by Abeta injection was decreased by kimchi bioactive compounds ( P < 0.05). Quercetin, HDMPPA, and KME decreased oxidative stress, as indicated by ROS and TBARS levels ( P < 0.05). The protein expression level of ER stress markers GRP78, p-PERK, p eIF2alpha, XBP1, and CHOP and the proapoptotic molecules Bax, p-JNK, and cleaved caspases-3 and -9 decreased ( P < 0.05). In contrast, the protein expression level of antiapoptotic molecules Bcl2 and cIAP increased ( P < 0.05). These results were supported by histological analysis. PMID- 29706081 TI - Mechanochemical Association Reaction of Interfacial Molecules Driven by Shear. AB - Shear-driven chemical reaction mechanisms are poorly understood because the relevant reactions are often hidden between two solid surfaces moving in relative motion. Here, this phenomenon is explored by characterizing shear-induced polymerization reactions that occur during vapor phase lubrication of alpha pinene between sliding hydroxylated and dehydroxylated silica surfaces, complemented by reactive molecular dynamics simulations. The results suggest that oxidative chemisorption of the alpha-pinene molecules at reactive surface sites, which transfers oxygen atoms from the surface to the adsorbate molecule, is the critical activation step. Such activation takes place more readily on the dehydroxylated surface. During this activation, the most strained part of the alpha-pinene molecules undergoes a partial distortion from its equilibrium geometry, which appears to be related to the critical activation volume for mechanical activation. Once alpha-pinene molecules are activated, association reactions occur between the newly attached oxygen and one of the carbon atoms in another molecule, forming ether bonds. These findings have general implications for mechanochemistry because they reveal that shear-driven reactions may occur through reaction pathways very different from their thermally induced counterparts and specifically the critical role of molecular distortion in such reactions. PMID- 29706082 TI - Alkali Potassium Induced HCl/CO2 Selectivity Enhancement and Chlorination Reaction Inhibition for Catalytic Oxidation of Chloroaromatics. AB - Industrial combustion of chloroaromatics is likely to generate unintentional biphenyls (PCBs), polychlorinated dibenzo- p-dioxins (PCDDs), and polychlorinated dibenzofurans (PCDFs). This process involves a surface-mediated reaction and can be accelerated in the presence of a catalyst. In the past decade, the effect of surface nature of applied catalysts on the conversion of chloroaromatics to PCBs/PCDD/PCDF has been well explored. However, studies on how the flue gas interferent components affect such a conversion process remain insufficient. In this article, a critical flue gas interferent component, alkali potassium, was investigated to reveal its effect on the chloroaromatics oxidation at a typical solid acid-base catalyst, Mn xCe1- xO2/HZSM-5. The loading of alkali potassium was found to improve the Lewis acidity of the catalyst (by increasing the amounts of surface Mn4+ after calcination), which thus promoted the CO2 selectivity for catalytic chlorobenzene (CB) oxidation. The KOH with a high hydrophilicity has favored the adsorption/activation of H2O molecules that provided sufficient hydroxyl groups and possibly induced a hydrolysis process to promote the formation of HCl. The K ion also served as a potential sink for chorine ions immobilization (via forming KCl). Both of these inhibited the formation of phenyl polychloride byproducts, thereby blocking the conversion of CB to chlorophenol and then PCDDs/PCDFs, and potentially ensuring a durable operation and less secondary pollution for the catalytic chloroaromatics combustion in industry. PMID- 29706083 TI - Urban-suburban differences in GP requests for lumbosacral spine radiographs in a primary healthcare centre in Malta. AB - INTRODUCTION: Due to demographic changes, growing demands, technological developments and rising healthcare costs, analysis of resources in rural and urban primary care clinics is crucial. However, data on primary care provision in rural and suburban areas are lacking. Moreover, health inequities in small island communities tend to be reduced by social homogeneity and an almost indiscernible urban-rural difference. The aim of the study was to examine the urban-suburban differences in the indications for lumbosacral spine radiographs in a public primary healthcare centre in Malta. METHODS: A list of all patients who underwent lumbosacral spine radiography in a public primary healthcare centre between January and June 2014 was obtained. The indications for lumbosacral spine radiographs were compared against the evidence-based indications posited by the America College of Radiology, the American Society of Spine Radiology, the Society for Pediatric Radiology and the Society of Skeletal Radiology in 2014. Differences between suburban and urban areas were analysed using the χ² test. Direct logistic regression was used to estimate the influences of different patients' characteristics and imaging indications in urban and suburban areas. RESULTS: The logistic regression model predicting the likelihood of different factors occurring with suburban patients as opposed to those residing in urban areas contained four independent variables (private/public sector, examination findings, osteoporosis, infection). The full model containing all predictors was statistically significant, c2 (4, N=1112) = 26.57, p≤0.001, indicating that the model was able to distinguish between patients residing in rural and urban areas. All four of the independent variables made a unique, statistically significant contribution to the model. The model as a whole explained between 2.4% (Cox and Snell R2) and 3.6% (Nagelkerke R2) of the variance in suburban/urban areas, and correctly classified 78.5% of cases. All four of the independent variables made a unique statistically significant contribution to the model. General practitioner (GP) requests for patients residing in suburban areas were more likely to be submitted from the private sector whereas urban GPs tended to include more examination findings. Requests by GPs for lumbosacral spine radiographs due to osteoporosis and infection tended to be more prevalent for urban patients. CONCLUSIONS: Such findings provide information for policymakers to improve equity in health care and resource allocations within the settings of urbanity and rurality. PMID- 29706084 TI - Increased Peripheral Blood Visfatin Concentrations May Be a Risk Marker of Coronary Artery Disease: A Meta-Analysis of Observational Studies. AB - A comprehensive quantitative evaluation of the relationship between peripheral blood visfatin concentrations and coronary artery disease (CAD) is lacking. This study is the first attempt to quantify this relationship via a meta-analysis of published observational studies in terms of weighted mean difference (WMD). Literature retrieval, article selection, and data extraction were conducted. Heterogeneity was inspected using both subgroup and meta-regression analyses. In total, 15 articles involving 1053 CAD cases and 714 controls were included. Overall, peripheral blood visfatin concentrations were significantly higher in CAD cases than in controls (WMD: 4.72 ng/mL; 95% confidence interval [CI]: 2.97 6.47; P < .001), with significant heterogeneity and publication bias. Six studies were theoretically missing based on filled funnel plot, and considering the impact of these missing studies still detected a significant overall mean difference in visfatin (WMD: 2.82 ng/mL; 95% CI: 2.22-3.58; P < .001; number of studies: 21). Subgroup and meta-regression analyses indicated age, body mass index, race, diabetes, systolic blood pressure, triglycerides, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were identified as possible causes of heterogeneity. In conclusion, our findings suggest that increased peripheral blood visfatin concentrations may be a risk marker of CAD. PMID- 29706085 TI - PCI Versus CABG in Left Main and Multivessel Disease: Do We Still Have the Gordian Knot? PMID- 29706086 TI - Management of extranodal lymphoma of the spine: a study of 30 patients. AB - Extranodal lymphoma of the spine is often a late manifestation of systemic disease, and may result in symptoms of pain, neurologic compromise or spinal instability. Symptomatic relief is generally achieved by radiotherapy alone, but is not sufficient in addressing spinal instability. The indications for surgery remain controversial, but may be required for spinal stabilization, or refractory disease. Currently, there is a lack of studies that compare the indications and clinical outcomes of patients receiving surgical and nonsurgical management of spinal extranodal lymphoma. Medical records of 30 patients seen from March 2006 to August 2015, with histologically confirmed spinal lymphoma, were retrospectively reviewed. Demographic information, clinical factors, imaging, treatment and clinical outcomes were recorded. 19 patients were treated surgically and 11 nonsurgically (i.e., chemotherapy, radiation or combination). Surgery was performed for emergent neurological deterioration, mechanical stabilization, refractoriness to medical management or to perform an open biopsy for pathological diagnosis. Among those treated surgically, significantly fewer patients could carry on normal activities (KPS <70) at baseline, compared with those treated nonsurgically. However, there were no significant differences regarding pain medication use, functional status at 1 year, or mean survival (87.6 months) between groups. Surgery for extranodal lymphoma may be required in specific cases, resulting in favorable and similar outcomes compared with nonsurgical management. PMID- 29706087 TI - Association of aflatoxin exposure and height-for-age among young children in Guatemala. AB - Aflatoxin exposure has been proposed to affect child height-for-age. The following hypothesized associations were tested in Guatemala: (1) aflatoxin (B1, B2, G1, G2) exposure and environmental enteric dysfunction (EED) and child height for-age z-score; and (2) aflatoxin exposures and subsequent symptoms of aflatoxins. Maize consumption data, health data, and samples of maize from households were collected from mothers and their children - under five - in October 2016 (n = 320) and February 2017 (n = 120). Maize samples were tested for aflatoxin levels and maize consumption data were used to compute an aflatoxin exposure level. Results suggest that there was a significant negative correlation between the putative aflatoxin exposure level and child height-for-age z-score ( 0.073, p = 0.030), but not for EED. Furthermore, aflatoxin exposure was significantly correlated with aflatoxin symptoms only at the same time point (0.123, p = 0.026). These results support the potential need for engineered solutions to household aflatoxin transmission problems in rural communities of Guatemala. PMID- 29706088 TI - Mechanisms and Measurement of Changes in Gene Expression. AB - Research on gene expression (GE) provides insights into the physiology of a cell or group of cells at a given point in time. Studies of changes in GE can be used to identify patients at higher risk for various medical conditions, a higher symptom burden, and/or the adverse consequences associated with various treatments. The aims of this article are as follows: (1) to describe the different types of RNA transcripts, (2) to describe the processes involved in GE (i.e., RNA transcription, epigenetics, and posttranscriptional modifications), (3) to describe common sources of variation in GE, (4) to describe the most common methods used to measure GE, and (5) to discuss factors to consider when choosing tissue for a GE study. This article begins with an overview of the mechanisms involved in GE. Then, the factors that can influence the findings from GE experiments (e.g., tissue specificity, host age, host gender, and time of sample collection) are described and potential solutions are presented. This article concludes with a discussion of how the types of tissue used in GE studies can affect study findings. Given that the costs associated with the measurement of changes in GE are decreasing and the methods to analyze GE data are becoming easier to use, nurse scientists need to understand the basic principles that underlie any GE study. PMID- 29706090 TI - News & Views. PMID- 29706089 TI - Mortality in Advanced Chronic Obstructive Pulmonary Disease and Heart Failure Following Cardiopulmonary Rehabilitation. AB - : Cardiopulmonary rehabilitation (CR) improves physical function and quality of life (QoL) in chronic obstructive pulmonary disease (COPD) and heart failure (HF), but it is unknown if CR improves outcomes in very severe disease. This study's purpose was to describe functional capacity (6-min walk distance [6MWD], steps/day), symptoms (dyspnea, depression), QoL (Short-Form Health Survey Veterans [SF-36 V]) and cardiopulmonary function ( N-terminal pro-brain natriuretic peptide [NT-proBNP], forced expiratory volume in 1 s [FEV1]), and derive predictors of mortality among patients with severe COPD and HF who participated in CR. METHODS AND RESULTS: In this secondary analysis of a randomized controlled trial comparing two CR methods in severe COPD and HF, 90 (COPD = 63, HF = 27) male veterans, mean age 66 +/- 9.24 years, 79% Caucasian, and body mass index 31 kg/m2, were followed for 12 months after CR. The COPD group had greater functional decline than the HF group (6MWD, p = .006). Dyspnea was lower ( p = .001) and QoL higher ( p = .006) in the HF group. Mean NT-proBNP was higher in the HF group at all time points. FEV1 improved over 12 months in both groups ( p = .01). Mortality was 8.9%, 16.7%, and 37.8% at 12, 24, and 60 months, respectively. One-year predictors of mortality were baseline total steps (<3,000/day), 6MWD (<229 meters), and NT-proBNP level (>2,000 mg/pg). CONCLUSIONS: In very severe COPD and HF, risks of mortality over 12 months can predict patients unlikely to benefit from CR and should be considered at initial referral. PMID- 29706091 TI - Behavioral awareness in the feline consultation: Understanding physical and emotional health. AB - : Practical relevance: Awareness of the strong connection between observed behavior and physical and emotional health is essential for patient welfare. It is often a change in the individual's normal behavior that informs owners and veterinarians of the possibility of illness, pain and stress/distress. There is ample evidence in the feline literature that medical and behavioral health go hand in hand. In most feline cases, medical and behavioral conditions contribute concurrently to clinical signs. Clinical challenges: Our domestic cats do not express change in physiological and emotional states in a way that is easily recognized. Therefore, it can be difficult to diagnose medical and behavioral illnesses and ascertain contributions from each one to the final diagnosis. When various levels of stress are present, especially distress, this compromises behavioral and physical health, and influences treatment outcomes. AIMS: This review is intended to help veterinarians recognize physical and behavioral changes associated with acute stress through to chronic distress, including stress-associated diseases. An emphasis on thorough history-taking will allow the clinician to ascertain which signs are behavioral and which are medical, with the understanding that they are not mutually exclusive. Equally important is the contribution of pain, chronic disease and poor environmental situations to behavioral changes and the expression of medical disorders. Evidence base: There is an increasing amount of evidence that stress and distress have profound effects on feline health, behavior and welfare. The authors have drawn on a substantial body of published veterinary research in producing this review. PMID- 29706093 TI - Behaviour ... by popular request. PMID- 29706092 TI - Normal feline behaviour: ... and why problem behaviours develop. AB - Practical relevance: Cats are descended from a solitary, territorial ancestor, and while domestication has reduced their inherited tendency to be antagonistic towards all animals larger than their typical prey, they still place more reliance on the security of their territory than on psychological attachments to people or other cats, the exact opposite to dogs. Many feline problem behaviours stem from perceived threats to this security, often due to conflicts with other cats. Others are more developmental in origin, often caused by inadequate exposure to crucial stimuli, especially people, during the socialisation period. Strongly aversive events experienced at any age can also contribute. A third category comprises normal behaviour that owners deem unacceptable, such as scratching of furniture. Evidence base: This review identifies three areas in which basic research is inadequate to support widely employed concepts and practices in feline behavioural medicine. First, classification of cats' problem behaviours relies heavily on approaches derived from studies of their behavioural ecology and, to some extent, extrapolation from canine studies. Few studies have focused on cats in the home, the environment in which most behavioural disorders are expressed. Secondly, cats' chemical senses (olfactory and vomeronasal) are far more sensitive than our own, making it difficult for owners or clinicians to fully comprehend the sensory information upon which they base their behaviour. Thirdly, although the concept of psychological distress is widely invoked as an intervening variable in behavioural disorders, there are still no reliable measures of distress for pet cats in the home. Global importance: Psychological distress of some kind is the primary cause of many of the behavioural problems presented to clinicians, but surveys indicate that many more cats display the same clinical signs without their owners ever seeking help. The welfare of this 'invisible' group could be improved by veterinarians taking a more proactive approach to educating their clients about the behavioural needs of pet cats. PMID- 29706094 TI - Recognising and assessing feline emotions during the consultation: History, body language and behaviour. AB - Practical relevance: Crucial to successful treatment of problem behaviour and optimising the welfare of the individual cat is determining which underpinning emotion(s) are involved in the presentation of the behaviour. Feline emotions are not feelings per se, but motivational-emotional systems that are responsible for instinctual emotional arousal. Often different interventions are required to alleviate different negative emotional motivations. Clinical challenges: Identifying different emotional motivations and the arousal level associated with them solely from observations of behaviour and body language is a difficult task because, as with any species, the behavioural repertoire of the domestic cat is finite and the same behaviour may occur with the activation of different emotional systems. In addition, cats, like people, may experience more than one emotion at the same time or switch quickly between emotional motivations, and this further complicates identification. The behavioural assessment of pain is also notoriously difficult in cats. Evidence base: This review draws on the published literature where available and, where there is a paucity of research, on hypotheses derived from observations of professionals in the field. Global importance: Being able to recognise and assess feline emotional motivations in order to address problem behaviours and improve welfare is important for all veterinarians who see cats. PMID- 29706095 TI - Understanding feline emotions: ... and their role in problem behaviours. AB - Practical relevance: Despite its importance, emotional health is a subject that is sadly neglected in the context of companion animals. Understanding emotions is at the heart of veterinary behavioural medicine and is key to preventing, managing and treating reported behavioural problems in domestic cats. Clinical challenges: On a daily basis, veterinary practices are presented with the physical health impact of emotional health and with emotionally motivated behaviours that are undesirable to owners and/or detrimental to the cat. Emotional health is of equal importance to physical health and lies at the very core of veterinary medicine. Clinically, the emotional motivation for a behaviour must be identified before an assessment is made of whether the motivation is contextually appropriate and whether the cat's response is justified and normal, or abnormal in the circumstances. Evidence base: The majority of referenced evidence for our understanding of emotional motivations in mammals has come from the human field, but recently there has been increasing interest in the emotional health of non-human animals and a resulting growth in research. This review draws on the published literature and the author's personal experience to explore how emotions can influence feline behaviours. Global importance: Understanding the importance of emotional health is a major factor in ensuring positive welfare for cats, wherever they are kept as companion animals. It impacts on their physical health and their quality of life, and also on the relationship between cat and owner. PMID- 29706098 TI - Effects of Dicloxacillin on Warfarin Dose in Patients With a Left Ventricular Assist Device. AB - Patients with a durable, continuous flow left ventricular assist device (CF-LVAD) require anticoagulation with warfarin to prevent thromboembolic events. Driveline infections (DLIs) are a common CF-LVAD complication. A common pathogen implicated in DLI is oxacillin-sensitive Staphylococcus aureus (OSSA), which is effectively treated by oral dicloxacillin. Previous published experiences have observed a significant drug interaction between dicloxacillin and warfarin resulting in decreased international normalized ratio (INR) and increased warfarin dosing requirements. We sought to analyze the effect of dicloxacillin on INR and warfarin dose when used for DLI in our CF-LVAD program. Five of 106 patients having received an CF-LVAD at our institution met the inclusion criteria for this case series. These patients required a mean 51.8% (standard deviation of 29.8%) weekly warfarin dose increase to restore INR to the therapeutic range after the addition of dicloxacillin. Three of the five patients subsequently had their dicloxacillin discontinued, with a mean decrease in weekly warfarin dose of 30.6% (standard deviation of 19.1%). In our experience, when coalesced with prior published reports, an empiric warfarin dose increase of 25% to 33% is reasonable upon initiation of dicloxacillin and an empiric warfarin dose reduction of 10% to 15% is recommended upon discontinuation of dicloxacillin. Close INR follow-up is warranted during and after dicloxacillin treatment. PMID- 29706097 TI - Fluoroenesulphonamides: N-sulphonylurea isosteres showing nanomolar selective cancer-related transmembrane human carbonic anhydrase inhibition. AB - After hydrofluorination of ynesulphonamides in superacid or in the presence of hydrofluoric acid/base reagents, a series of alpha-fluoroenamides has been synthesised and tested for the inhibition of carbonic anhydrase (CA, EC 4.2.1.1) isoforms. This study reveals a new, highly selective family of cancer-related transmembrane human (h) CA IX/XII inhibitors. These original fluorinated ureido isosters do not inhibit the widespread cytosolic isoforms hCA I and II and selectively inhibit the transmembrane cancer-related hCA IX and XII, offering interesting new leads for future studies. PMID- 29706099 TI - Economic evaluation of human urinary kallindinogenase for patients with acute ischemic stroke in China. AB - OBJECTIVES: In China, both human urinary kallindinogenase (HUK) and 3-n butylphthalide (NBP) are recommended for clinical use to improve cerebral blood circulation during an acute ischemic stroke (AIS). The objective was to evaluate the economic value of HUK vs NBP for patients with AIS from a Chinese payer's perspective. METHODS: An economic evaluation based on data of patients who have been treated with either HUK (n = 488) or NBP (n = 885) from a prospective, phase IV, multi-center, clinical registry study (Chinese Acute Ischemic Stroke Treatment Outcome Registry, CASTOR) was conducted to analyze the cost and effectiveness of HUK vs NBP for AIS in China. Before the analysis, the patients were matched using propensity score. Both a cost-minimization analysis and a cost effectiveness analysis were conducted to compare the matched pairs. A bootstrapping exercise was conducted for the matched arms to demonstrate the probability of one intervention being cost-effective over another for a given willingness-to-pay for an extra quality-adjusted life-year (QALY). RESULTS: After propensity score matching, 463 pairs were matched. The overall medical cost in the HUK arm is USD 2,701.20, while the NBP arm is USD 3,436.83, indicating HUK is preferred with cost-minimization analysis. Although the QALY gained in the HUK arm (0.77176) compared with the NBP arm (0.76831) is statistically insignificant (p = .4862), the cost-effectiveness analysis as exploratory analysis found that, compared with NBP, HUK is a cost-saving strategy with the lower costs of USD 735.63 and greater QALYs gained of 0.00345. Among the 5,000 bootstrapping replications, 100% indicates that HUK is cost-effective compared with NBP under a 1-time-GDP threshold; and 97.12% indicates the same under a 3-time-GDP threshold. CONCLUSION: This economic evaluation study indicates that administrating HUK is a cost-saving therapy compared with NBP for managing blood flow during AIS in the Chinese setting. PMID- 29706100 TI - Correction to: Li et al., Fitting the right non-vitamin K antagonist oral anticoagulant to the right patient with non-valvular atrial fibrillation: an evidence-based choice. PMID- 29706101 TI - A systematic review of predictors, moderators, and mediators of augmentative and alternative communication (AAC) outcomes for children with autism spectrum disorder. AB - Documented variability in augmentative and alternative communication (AAC) intervention outcomes makes it difficult for clinicians to select systems most likely to be effective for individual children with autism spectrum disorder (ASD). The aim of this study was to identify child-related factors associated with AAC intervention outcomes through a systematic review of the research literature. A search was conducted of peer-reviewed research articles in which AAC intervention outcomes and associated factors were reported for children with ASD. The search yielded 965 titles and abstracts, of which seven articles relating to six studies met criteria for inclusion. In total, 18 factors were examined, of which nine were assessed as predictors (e.g., cognition, ASD severity, language use), three as moderators (e.g., joint attention, object exploration), and six as mediators (e.g., frequency of therapy, communication partner knowledge). Child characteristics associated with communication outcomes were pre-intervention cognition, severity of ASD, verbal imitation, vocabulary comprehension, object use, joint attention, language use, and two multi dimensional measures of communication competence. This study suggests emerging evidence for predictors, but less is known about what factors moderate and mediate response to AAC interventions. PMID- 29706102 TI - A narrative review of mental health support for people during transition from incarceration to community: the grass can be greener on the other side of the fence. AB - BACKGROUND: Despite significant need for mental health services targeting the requirements of inmates transitioning into the community there is little research about successful recovery-oriented or person-centred transition programs. AIMS: This systematic narrative review brings together existing evidence to inform policymakers and practitioners about current practice in transition support, and barriers and facilitators of effective practice. METHOD: We carried out a systematic narrative review of recovery-oriented or person-centred mental health support programs supporting transition from incarceration to the community. Results were obtained from a systematic search of Medline, PubMed and Scopus databases. RESULTS: We found 23 papers which met the paper inclusion criteria along with four other papers which were identified incidentally. CONCLUSIONS: Identified barriers to the implementation of effective transition support programs are: administrative problems leading to ineffective in-reach into correctional facilities or untimely support, lack of support for immediate needs meaning that inmates deprioritise their mental health needs, a lack of ongoing program resources and poor communication between correctional facilities and mental health services. Enablers for transition reflect the inverse of these barriers, alongside other successful strategies including medical home models, regionalised programs, programs which target connections with primary care, nurse led patient-centred health programs and peer support initiatives. PMID- 29706103 TI - Topical treatment utilization for patients with atopic dermatitis in the United States, and budget impact analysis of crisaborole ointment, 2. AB - BACKGROUND: Atopic dermatitis (AD), a chronic inflammatory skin disease, is often treated with topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI). Crisaborole ointment is a non-steroidal, phosphodiesterase 4 inhibitor for the treatment of mild-to-moderate AD. In December 2016, crisaborole was approved in the US for mild-to-moderate AD in patients >=2 years of age. AIMS: To evaluate real-world utilization and cost of TCS and TCI in the US and estimate the budget impact of crisaborole over 2 years from a third-party payer perspective. METHODS: TCS and TCI prescriptions in 2015 for patients >=2 years of age with >=1 AD diagnosis in the Truven Health Analytics MarketScan Commercial and Medicare Supplemental Research Databases were analyzed for patients receiving TCI or TCS alone or in combination (TCS/TCI population) and patients receiving TCI alone or in combination with TCS (TCI population). A budget impact model used TCS and TCI market shares, annual use, and cost per prescription. Crisaborole uptake rates of 4.7% (TCS) and 20.2% (TCI), with an annual increase of 1% in year 2, were assumed. Budget impact was calculated as total and per-member-per-month (PMPM) cost over 2 years for a health plan of 1 million members. RESULTS: Annual prescriptions/patient ranged from 1.36-6.41; annual cost/patient was $53-$1,465. The budget impact of crisaborole over 2 years in the TCS/TCI population was $350,946 (PMPM, $0.015), with increases of $162,106 in year 1 (PMPM, $0.014) and $188,841 in year 2 (PMPM, $0.016). The budget impact in the TCI population was $22,871, with decreases of $11,160 in year 1 and $11,712 in year 2 (each PMPM, $0.001). For both populations, one-way sensitivity analyses showed that budget impact was most sensitive to changes in crisaborole cost and annual use. CONCLUSIONS: From US payer perspectives, adoption of crisaborole results in modest pharmacy budget impact/savings. PMID- 29706104 TI - Perception of the tactile texture of raised-dot patterns: further evidence of an opponent process in the sense of touch. AB - Observers judged the tactile dissimilarities of raised-dot surfaces presented in pairs. The role of the SA I channel in determining these tactile dissimilarities was investigated by examining the dissimilarity judgments when this channel was adapted and when it was not. In an earlier study, the role of the PC channel in determining tactile dissimilarity was examined using the same stimulus materials when the PC channel was adapted and when it was not. Three orthogonal perceptual dimensions identified as blur, pattern roughness, and clarity were found using ALSCAL multidimensional analysis to account for the judged dissimilarities. The same three dimensions were found again in the present study. The dimensions of blur and pattern roughness were unaffected by adaptation of either the SA I or the PC channel. The finding of no effect of adaptation of the SA I channel on either of these two dimensions suggests that the roughness of the macrostructure of a textured surface is coded by the relative rather than by the absolute spatial variation in the firing rates of SA I nerve fibers. The dimension of dot clarity was strongly affected by adaptation of both the SA I channel and the PC channel. Adaptation of the PC channel increased dot clarity but adaptation of the SA I channel decreased it. This finding suggests that the perceived roughness of the microstructure of a textured surface is enhanced by the activity of the PC channel but decreased by the activity of the SA I channel. PMID- 29706105 TI - Quality of life and depression in haemodialysis patients. AB - Chronic kidney disease is associated with a high prevalence of depression, which increases inversely with the glomerular filtration rate. This paper aims to evaluate the factors associated with a low quality of life and depression in patients on haemodialysis. Two hundred patients undergoing haemodialysis answered the Medical Outcomes Study 36 - Item Short - Form Health Survey (SF-36) and Beck Depression Inventory (BDI). Clinical and laboratory variables were analysed and correlated with these two tools. The prevalence of depression was 29%. Anaemia and hypoalbuminemia were independent risk factors for depression. All SF-36 domains showed worse results in patients with depression, and the pain domain presented the highest correlation. Our findings provide evidence that patients on haemodialysis have a low quality of life and a high prevalence of depression. A greater number of comorbidities, an excessive number of medications, diabetes mellitus, anaemia and hypoalbuminemia were associated with a reduced quality of life. PMID- 29706107 TI - Adaptive radiotherapy in head and neck cancer is required to avoid tumor underdose. PMID- 29706108 TI - The use of a simultaneous integrated boost in spinal stereotactic body radiotherapy to reduce the risk of vertebral compression fractures: a treatment planning study. PMID- 29706106 TI - The Impact of Pazopanib on the Cardiovascular System. AB - Pazopanib is an approved treatment for renal cell carcinoma and a second-line treatment for nonadipocytic soft-tissue sarcoma. However, its clinical efficacy is limited by its cardiovascular side effects. Pazopanib and other vascular endothelial growth factor receptor tyrosine kinase inhibitors have been associated with the development of hypertension, QT interval prolongation, and other cardiovascular events; however, these mechanisms are largely unknown. Gaining a deeper understanding of these mechanisms is essential for the development of appropriate surveillance strategies and possible diagnostic biomarkers to allow us to monitor patients and modulate therapy prior to significant cardiac insult. This approach will be vital in keeping patients on these life-saving therapies and may be applicable to other tyrosine kinase inhibitors as well. In this review, we provide a comprehensive overview of the preclinical and clinical side effects of pazopanib with a focus on the mechanisms responsible for its toxicity to the cardiovascular system. PMID- 29706109 TI - Factors influencing access to palliative radiotherapy: a Norwegian population based study. AB - BACKGROUND: Palliative radiotherapy (PRT) comprises half of all radiotherapy use and is an effective and important treatment modality for improving quality of life in incurable cancer patients. We have described the use of PRT in Norway and aimed to identify and quantify the impact of factors associated with PRT utilization. MATERIAL AND METHODS: Population-based data from the Cancer Registry of Norway identified 25,281 patients who died of cancer, 1 July 2009-31 December 2011. Additionally, individual-level data on socioeconomic status and community level data on travel distance were collected. The proportion of patients who received PRT in the last two years of life (PRT2Y) was calculated, and multivariable logistic regression was used to determine factors that influenced the PRT2Y. Analyses of geographic variation in PRT use were also performed for the time period 2012-2016. RESULTS: PRT2Y for all cancer sites combined was 29.6% with wide geographic variations (standardized inter-county range; 21.8-36.6%). Female gender, increasing age at death, certain cancer sites, short survival time, and previous receipt of curative radiotherapy were associated with decreased odds of receiving PRT. Patients with low education, those living in certain counties, or with travel distances 100-499 km, were also less likely to receive PRT. Patients with low household income (adjusted odds ratio (OR) = 0.63; 95% confidence interval (CI) = 0.56-0.72) and those diagnosed in hospitals without radiotherapy facility (OR = 0.70; 95% CI = 0.64-0.77) had especially low likelihood of receiving PRT. Significant inter-county variation in use of PRT remained during the time period 2012-2016. CONCLUSIONS: Despite a publicly funded, universal healthcare system with equity as a stated health policy aim, utilization of PRT in Norway is significantly associated with factors such as household income and availability of radiotherapy facility at the diagnosing hospital. Even after adjustments for relevant factors, unexplained geographic variations in PRT utilization exist. PMID- 29706110 TI - The Relationship Between Physical Activity Level of Parents and That of Their Adolescent Children. AB - BACKGROUND: Intergenerational transmission, which refers to the similarity between parent and their children, is a possible explanation of adolescent physical activity (PA). However, only a few existing studies explore the relationship of parent-adolescent PA in East Asian countries. Therefore, this study aimed to investigate the association of parent-adolescent PA using a nationally representative data in Korea with a large sample size. METHODS: Data were collected from the Korean National Health and Nutrition Examination Survey conducted from 2010 to 2014. The authors performed a linear mixed effects regression analysis with 1342 cases after using log conversion of parent and adolescent moderate- to vigorous-intensity physical activity (MVPA) levels. RESULTS: In the study, the median MVPA of adolescents was 150 (interquartile range: 360) minutes per week. Adolescent MVPA levels were significantly correlated with their mother's MVPA (beta = 0.055, P = .02). Similar findings of greater association in girls and younger adolescents (age: 13-15 y) were found in subgroup analysis (girls: beta = 0.073, P = .05; younger adolescents: beta = 0.103, P = .001). CONCLUSION: Increasing maternal PA levels could stimulate their adolescent's PA levels. Therefore, intervention at the family level may lead to an increase in adolescent PA levels. PMID- 29706111 TI - Changes in the microbial flora in patients of a Greek intensive care unit over two decades. PMID- 29706113 TI - Neck haematoma after carotid endarterectomy: risks, rescue, and prevention. AB - OBJECTIVE: This study was performed to identify risk factors for neck haematoma requiring re-exploration after carotid endarterectomy. Neck haematoma is a well known complication after carotid endarterectomy, but there has been little discussion about intraoperative techniques for its prevention. We also investigated an intraoperative neck flexion technique for prevention of neck haematoma. METHODS: A retrospective study reviewed 384 carotid endarterectomies performed at our institution from 2003 to 2016. The endpoint was neck haematomas requiring re-exploration after carotid endarterectomy. Endpoint predictors (general factors, preoperative medication, and intraoperative factors) were identified by univariate analysis. Our intraoperative neck flexion technique involved changing the neck and head position from extension to flexion during carotid endarterectomy. In patients with neck haematoma, we assessed the interval from carotid endarterectomy to re-exploration, the source of bleeding, and the method of airway rescue. RESULTS: There was one major and three minor perioperative strokes (1.1%). Neck haematoma occurred in 9 patients (2.4%). Univariate analysis (odds ratio [95% confidence interval]) identified preoperative clopidogrel therapy (4.19 [1.03-17.06], P = .04) and not using protamine sulfate after heparin (4.13 [1.02-25.06], P = .04) as risk factors for haematoma. We used the intraoperative neck flexion technique in 87 patients and no neck haematomas occurred. There was no additional morbidity and no mortality in the patients who required re-exploration. The interval between carotid endarterectomy and re-exploration ranged from 0 to 30 hours. Intubation before re exploration was often difficult. We recommend using a laryngeal mask and performing minor wound re-exploration under local anesthesia before tracheal intubation for general anesthesia. Haematomas were mainly caused by venous bleeding or capillary oozing. CONCLUSIONS: This study showed that neck haematoma is uncommon after carotid endarterectomy, but requires emergency airway rescue and re-exploration. PMID- 29706112 TI - Ventriculoperitoneal shunt infections and re-infections in children: a multicentre retrospective study. AB - PURPOSE: Ventriculoperitoneal shunt (VPS) is the most common treatment modality for hydrocephalus. However, VPS infection is a common and serious complication with high rates of mortality and morbidity. The objective of this study was to investigate causative agents and the management of VPS infections and to identify risk factors for re-infection in children. MATERIALS AND METHODS: Retrospective, multicentre study on patients with VPS infection at paediatric and neurosurgery departments in four tertiary medical centres in Turkey between January 2011 and September 2014. RESULTS: A total of 290 patients with VPS infections were identified during the study period. The aetiology of hydrocephalus was congenital malformations in 190 patients (65.5%). The most common symptom of shunt infection was fever in 108 (37.2%) cases. At least one pathogen was identified in 148 VPS infections (51%). The most commonly isolated pathogen was coagulase-negative staphylococci, which grew in 63 cases (42.5%), followed by Pseudomonas aeruginosa in 22 cases (14.9%), Klebsiella pneumoniae in 15 cases (10.1%), and Staphylococcus aureus in 15 cases (10.1). The median duration of VPS infection was 2 months (range, 15 days to 60 months) after insertion of the shunt, with half (49.8%) occurring during the first month. VPS infection was treated by antibiotics and shunt removal in 211 cases (76.4%) and antibiotics alone without shunt removal in 65 patients (23.5%). Among the risk factors, CSF protein level greater than 100 mg/dL prior to VPS insertion was associated with a potential risk of re-infection (OR, 1.65; p =.01). CONCLUSION: High protein levels (>100 mg/dL) before the re-insertion of a VPS may be a risk factor for VPS re infection. PMID- 29706114 TI - Service delivery innovation for hospital emergency management using rich organizational modelling. AB - The purpose of this article is to identify and assess service delivery issues within a hospital emergency department and propose an improved model to address them. Possible solutions and options to these issues are explored to determine the one that best fits the context. In this article, we have analysed the emergency department's organizational models through i* strategic dependency and rational modelling technique before proposing updated models that could potentially drive business process efficiencies. The results produced by the models, framework and improved patient journey in the emergency department were evaluated against the statistical data revealed from a reputed government organization related to health, to ensure that the key elements of the issues such as wait time, stay time/throughput, workload and human resource are resolved. The result of the evaluation was taken as a basis to determine the success of the project. Based on these results, the article recommends implementing the concept on actual scenario, where a positive result is achievable. PMID- 29706115 TI - In Vivo Potency Assay for Adeno-Associated Virus-Based Gene Therapy Vectors Using AAVrh.10 as an Example. AB - The development of a drug product requires rigorous methods of characterization and quality control to assure drug potency. Gene therapy products, a relatively new strategy for drug design with very few licensed examples, represent a unique challenge for the measure of potency. Unlike traditional drugs, potency for a gene therapeutic is a tally of the measures of multiple steps, including infectivity, transcription, translation, protein modifications, proper localization of the protein product, and protein function. This is particularly challenging for products based on the adeno-associated virus (AAV) platform, which has poor in vitro infectivity, limiting the sensitivity and thus the usefulness of cell-based assays. A rigorous in vivo assay has been established that separately evaluates infection, transcription, and resulting protein levels with specifications for each based on real time polymerase chain reaction (DNA and RNA) and standard protein assays. For an acceptance criterion, an administered vector must have vector DNA, transgene mRNA, and transgene expressed protein each concurrently meet individual specifications or the production lot fails. Using the AAVrh.10 serotype as a model vector and three different transgenes as examples, the assay is based on intravenous administration of the vector to male mice. At 2 weeks, the harvested liver is homogenized and assessed for vector genome levels (to assess for vector delivery), mRNA (to assess vector infectivity and transcription), and protein in the liver or serum (to assess protein expression). For all AAV vectors, the assay is robust and reproducible: vector DNA (linearity 102-109 copies, coefficient of variation) intra-assay <0.8%, inter-assay <0.5%; mRNA intra-assay <3.3%, inter-assay <3.4%. The reproducibility of the assay for transgene expressed protein is product specific. This in vivo potency assay is a strategy for characterization and a quantitative lot release test, providing a path forward to meet regulatory drug requirements for any AAV gene therapy vectors. PMID- 29706116 TI - Approved and Off-Label Use of Prescribed Psychotropic Medications among Federal Canadian Inmates. AB - OBJECTIVE: To examine psychotropic medication prescription practices in federal Canadian penitentiaries. METHOD: 468 files were drawn from a purposive sample of thirteen Canadian federal institutions representing the five regions, different security levels, and male and female designated facilities. Information on the names of all psychotropic medications prescribed, indications for use, dosage, frequency, and route of administration was retrieved. Designation of approved or off-label use of medications was determined by consulting: (1) the Health Canada (2016) Drug Product Database, (2) the Canadian Compendium of Pharmaceuticals and Specialties 2016, and (3) the American Hospital Formulary Service Drug Information 2016. Prescription rates were examined by gender, Indigenous ancestry, drug class, institutional infractions, and current offence. RESULTS: 36.2% of prescriptions for psychotropic medication were coded as 'off-label'. Anxiolytic/hypnotics drugs were the psychotropic drugs most commonly used for off label purposes. There were no differences in the prevalence of approved versus off-label prescriptions based on Indigenous ancestry or gender, and no pattern of elevated off-label prescription practices for offenders involved in institutional misconducts or those sentenced for the most serious crimes. CONCLUSIONS: The rates of prescribing 'off-label' psychotropic medication are not elevated relative to other correctional settings or to rates cited in Canadian surveys conducted in the community. PMID- 29706117 TI - Physical Education and Leisure-Time Physical Activity in Youth Are Both Important for Adulthood Activity, Physical Performance, and Health. AB - BACKGROUND: The importance of youth physical activity (PA) for adulthood PA, performance, and health was retrospectively evaluated. METHODS: A total of 258,146 participants (49% women), aged 19-70, with a first-time health-profile assessment between 1982 and 2015, provided self-reported data on current perceived health, PA, lifestyle, and physical education class participation, and PA outside school hours before age 20. Data on anthropometrics, blood pressure, and estimated maximal oxygen consumption (VO2max) were obtained. RESULTS: Women participating in physical education class, compared with those who did not, had significantly lower OR (range: 0.81-0.87) for perceiving poor overall health, general obesity, and high diastolic blood pressure after adjustment for potential confounders, and increased OR (range: 1.17-1.23) for exercising regularly and a normal/high VO2max in adulthood. For men, the ORs were significantly lower (range: 0.66-0.86) for poor perceived overall health, general, and abdominal obesity. These associations were seen for participants up to 70 years. Increased PA outside school hours revealed even stronger beneficial associations. In joint analyses, both youth and current PA were important for lower OR of poor health and being obese in adulthood. CONCLUSIONS: Physical education class participation and additional PA after school hours were both important for perceived health, PA, VO2max, and metabolic health in adulthood up to 70 years. PMID- 29706118 TI - Examining Individual Characteristics and Program Performance to Understand Two Year Recidivism Rates Among Drug Court Participants: Comparing Graduates and Terminators. AB - Drug courts strive to break the cycle of substance use and crime by providing community-based treatment and rehabilitation. The purpose of the present study was to (a) identify significantly different factors between program participants (i.e., graduates/terminators) that may affect recidivism and (b) examine these significant individual and program performance factors associated with two-year recidivism. Secondary data were examined for a stratified random sample of drug court participants ( N = 534). Examining any two-year post-program recidivism (defined as an arrest, conviction, or incarceration), over one third (37.6%) of graduates and almost all program terminators (95.3%) had two-year post-program recidivism ( p < .001). For the overall sample, age, outpatient treatment, marital status, number of times treated for a psychiatric problem in a hospital, substance use (i.e., past-30-day cocaine use and intravenous opiate use), number of positive drug tests, and receiving any sanction/therapeutic response were associated with two-year post-program recidivism. Further analyses suggested age and outpatient treatment were particularly important for program graduates. Findings provide information for early targeting of resources to drug court participants most at risk of poorer post-program outcomes by identifying factors known at program entry and indicators during program participation. PMID- 29706119 TI - Nucleofection with Plasmid DNA for CRISPR/Cas9-Mediated Inactivation of Programmed Cell Death Protein 1 in CD133-Specific CAR T Cells. AB - CRISPR/Cas9-mediated programmed cell death protein 1 (PD-1) disruption in chimeric antigen receptor (CAR) T cells could be an appealing choice to improve the therapeutic efficacy of CAR T cells in an immunosuppressive tumor microenvironment. In most of the reported cases, Cas9 was delivered into T cells by way of electroporation with RNA or protein. However, transient expression of Cas9 by transfection with a plasmid encoding its gene is apparently simpler, as it avoids the steps of in vitro transcription of DNA or protein production. This study tried nucleofection into human primary T cells of plasmids encoding both CRISPR/Cas9 for disrupting the PD-1 gene and the piggyBac transposon system for expressing CD133-specific CAR in one reaction. Based on drug selection, CD133 specific CAR T cells were obtained in which, on average, 91.5% of the PD-1 gene sites were disrupted, but almost no Cas9 gene expression was found in the final engineered CAR T cells. The PD-1-deficient CD133-specific CAR T cells showed similar levels of cytokine secretion and improved proliferation and cytotoxicity in vitro, and enhanced inhibition of tumor growth in an orthotopic mouse model of glioma, compared to conventional CD133-CAR T cells. The described method could be useful for the production of PD-1-deficient CAR T cells for cancer immunotherapy. PMID- 29706120 TI - Is jellyfish more of a fish in English than in Dutch? The effect of informative labels. AB - Some words are lexically suggestive about the taxonomic position of their referent (e.g., jellyfish in English), and this information can vary across languages (e.g., in Dutch the equivalent of jellyfish holds no taxonomic information: kwal). To evaluate the role of such lexical suggestions, we conducted a cross-linguistic study in which similarity judgements from two language groups (Dutch and English speakers) were compared. We paired asymmetrically informative items with items that are considered to be typical members of the referenced category (e.g., jellyfish-salmon). Our analyses revealed that items were deemed more similar by speakers of a language in which the lexical information was present (e.g., English speakers tended to give relatively higher ratings for jellyfish-salmon than Dutch participants did for the non-informative equivalent kwal-zalm). Results are discussed in light of theories of concept representation and compound processing. PMID- 29706121 TI - Facing the facts: Naive participants have only moderate insight into their face recognition and face perception abilities. AB - A reliable self-report measure to assess the broad spectrum of face recognition ability (FRA) from developmental prosopagnosia (DP) to super-recognition would make a valuable contribution to initial screening of large populations. We examined the performance of 96 naive participants and seven super-recognisers (SRs) using a range of face and object processing tasks and a newly developed 20 item questionnaire, the Stirling Face Recognition Scale (SFRS). Overall, our findings suggest that young adults have only moderate insight into their FRA, but those who have been previously informed of their (exceptional) performance, the SRs, estimate their FRA accurately. Principal component analysis of SFRS yielded two components. One loads on questions about low ability and correlates with perceptual tasks, and one loads on questions about high FRA and correlates with memory for faces. We recommend that self-report measures of FRA should be used in addition to behavioural testing, to allow for cross-study comparisons, until new, more reliable instruments of self-report are developed. However, self-report measures should not be solely relied upon to identify highly skilled individuals. Implications of these results for theory and applied practice are discussed. PMID- 29706122 TI - A Qualitative Analysis of South African Health Professionals' Discussion on Distrust and Unwillingness to Refer Organ Donors. AB - INTRODUCTION: South Africa is faced with very low deceased organ donor numbers. Often, sociocultural practices, which are thought to be fundamentally opposed to deceased organ donation, are hailed as the cause. However, other factors such as context, social perceptions, and clinical environment may play a role. AIM: The aim of this article is to present research that explored communication in organ transplant and identified barriers to organ donation decisions in a province of South Africa. METHODS: Qualitative methods were used. Thirty semistructured interviews with transplant professionals and 2 focus groups with transplant coordinators took place across 6 health institutions in Gauteng Province. RESULTS: Barriers that may prevent transplant professionals from referring potential donors were identified: The wider public and transplant professionals may be suspicious of biomedicine and have a perception that people could be killed for their organs. Organ donation was sometimes framed as "murder," "killing," or a "bunch of vultures." Doctors may be unwilling to refer brain-dead patients, as this was seen as failing in one's professional duty to cure the patient. The role of sociocultural practices was inconclusive, with the sample divided based on the extent of their influence. CONCLUSION: Low donor numbers may be a manifestation of barriers to referral in the clinical setting. These barriers interplay in a context of suspicion and are framed by a clinical transplant discourse that is sometimes loaded with negative connotation. Sociocultural practices are influential, but they may not be the overriding cause of low donor numbers. PMID- 29706123 TI - Pharmacogenomics of blood lipid regulation. AB - Blood lipids are important modifiable risk factors for coronary heart disease and various drugs have been developed to target lipid fractions. Considerable efforts have been made to identify genetic variants that modulate responses to drugs in the hope of optimizing their use. Pharmacogenomics and new biotechnologies now allow for meaningful integration of human genetic findings and therapeutic development for increased efficiency and precision of lipid-lowering drugs. Polygenic predictors of disease risk are also changing how patient populations can be stratified, enabling targeted therapeutic interventions to patients more likely to derive the highest benefit, marking a shift from single variant to genomic approaches in pharmacogenomics. PMID- 29706124 TI - Sensorimotor Activity Partially Ameliorates Pain and Reduces Nociceptive Fiber Density in the Chronically Injured Spinal Cord. AB - A large proportion of patients suffering from spinal cord injury (SCI) develop chronic central neuropathic pain. Previously, we and others have shown that sensorimotor training early after SCI can prevent the development of mechanical allodynia. To determine whether training initiated in the subchronic/chronic phase remains effective, correlates of below-level neuropathic pain were analyzed in the hindpaws 5-10 weeks after a moderate T11 contusion SCI (50 kDyn) in adult female C57BL/6 mice. In a comparison of SCI and sham mice 5 weeks post-injury, about 80% of injured animals developed mechanical hypersensitivity to light mechanical stimuli, whereas testing of noxious stimuli revealed hypo responsiveness. Thermal sensitivity testing showed a decreased response latency after injury. Without intervention, mechanical and thermal hyper-responsiveness were evident until the end of the experiment (10 weeks). In contrast, treadmill training (2 * 15 min/day; 5 * /week) initiated 6 weeks post-injury resulted in partial amelioration of pain behavior and this effect remained stable. Analysis of calcitonin gene-related peptide (CGRP)-labeled fibers in lamina III-IV of the lumbar dorsal horn revealed an increase in labeling density after SCI. This was not due to changes in the number or size distribution of CGRP-labeled lumbar dorsal root ganglion neurons. Treadmill training reduced the CGRP-labeling density in the spinal cord of injured mice, whereas the density of non peptidergic isolectin-B4 (IB4)+ fibers showed no changes in lamina IIi and a slight reduction of sparse IB4 labeling in laminae III-IV. Thus, sensorimotor activity initiated in the subchronic/chronic phase of SCI remains effective in ameliorating pain behavior and influencing structural changes of the nociceptive system. PMID- 29706125 TI - Uterine Paramesonephric Cysts in Sprague-Dawley Rats from National Toxicology Program Studies. AB - Congenital uterine wall cysts arising from paramesonephric (Mullerian) and mesonephric (Wolffian) ducts are typically incidental findings in most species. We used immunohistochemistry to characterize and determine the origin of uterine cysts in Sprague-Dawley (SD) rats from multigeneration studies conducted by the National Toxicology Program. Subserosal uterine cysts were observed in 20 of the 2,400 SD rats evaluated in five studies, and 10 cysts were characterized for this study. Single cysts were unilocular, fluid-filled, and occurred throughout the uterus. Microscopically, all cysts had a well-developed smooth muscle wall, lined by flattened to cuboidal, sometimes ciliated, epithelium that stained intensely positive for cytokeratin 18 and paired box protein 8 (PAX8). Most cyst epithelia displayed weak to moderate positivity for progesterone receptor (PR) and/or estrogen receptor alpha (ER-alpha), as well as were negative for GATA binding protein 3 (GATA3). Cyst lumens contained basophilic flocculent material. The cysts appeared to be developmental anomalies arising from paramesonephric tissue based on positive PAX8 and ER-alpha and/or PR staining. Additionally, 70% of the cysts lacked GATA3 expression. Taken together, the subserosal uterine cysts observed in adult rats in these studies most likely arose from the paramesonephric duct. PMID- 29706126 TI - Regional Anesthesia for Arteriovenous Fistula Surgery May Reduce Hospital Length of Stay and Reoperation Rates. AB - BACKGROUND AND OBJECTIVES: Regional anesthesia has been proposed as the preferred mode of anesthesia for arteriovenous fistula surgery due to its associated vasodilatory effects and fistula patency rates. We analyzed patient outcomes after arteriovenous fistula surgery for their association with the type of anesthesia received. METHODS: The National Surgical Quality Improvement Project database was accessed to identify a cohort of 3199 patients undergoing arteriovenous fistula surgery from 2007 to 2015. Multiple regression models were used to examine the association of anesthesia with 12 postoperative outcomes. Additional multivariate logistic regression was performed to assess significant independent variables predictive of anesthesia choice. RESULTS: Patients who received regional anesthesia had the shortest postoperative length of stay (0.67 [standard deviation: 2.0] days) compared to monitored anesthesia care/intravenous (IV) sedation (0.77 [1.8] days) and general anesthesia (1.44 [2.8] days). Administration of regional anesthesia was associated with a shorter length of stay compared to general anesthesia (odds ratio [OR]: 0.55, P = .001). Patients who received monitored anesthesia care/IV sedation had a lower risk of reoperation compared to general anesthesia (OR: 0.65, P = .012) but not compared to regional anesthesia (OR: 0.89, P = .759). Anesthesia type had no significant effects on other measured postoperative complications. Predictors of the type of anesthesia were age and surgical procedure as defined by Current Procedural Terminology code ( P < .001). CONCLUSIONS: Use of regional anesthesia is associated with a shorter postoperative length of stay after arteriovenous fistula surgery and lower risk of reoperation compared to general anesthesia or monitored anesthesia care/IV sedation. Regional anesthesia may be an excellent choice for arteriovenous fistula surgery to reduce postoperative length of stay and risk of reoperation. PMID- 29706127 TI - Utility of the 18F-Florbetapir positron emission tomography in systemic amyloidosis. AB - Amyloidosis comprises a group of heterogeneous conditions. To ascertain the burden of disease is important because it can determine the treatment as well as the evolution of the disease. Recent reports have shown good results in diagnosing cardiac amyloidosis using 18F-florbetapir. We hypothesize that combining whole body PET/CT with 18F-Florbetapir can be useful to characterize the burden of the disease. We included 25 patients, 13 of them with different types of amyloidosis, and 12 with Alzheimer's disease as controls. Target-to background ratio was computed for multiple organ using maximum standardized uptake values. Organ involvement was described (standardized techniques versus PET) according to different kinds of amyloidosis showing promising results in AA and AL types. Heart involvement showed poorer results when compared to tongue, lung or thyroid gland. Multiple organ involvement in patients previously labelled as having negative organ affectation could be identified. This is the first study to evaluate the utility of 18F-florbetapir in the assessment of the global extension of disease. Our results show that this technique is useful for its diagnosis. PMID- 29706128 TI - Evolution of the Proximal Sealing Rings of the Anaconda Stent-Graft After Endovascular Aneurysm Repair. AB - PURPOSE: To provide insight into the evolution of the saddle-shaped proximal sealing rings of the Anaconda stent-graft after endovascular aneurysm repair (EVAR). METHODS: Eighteen abdominal aortic aneurysm patients were consecutively enrolled in a single-center, prospective, observational cohort study (LSPEAS; Trialregister.nl identifier NTR4276). The patients were treated electively using an Anaconda stent-graft with a mean 31% oversizing (range 17-47). According to protocol, participants were to be followed for 2 years, during which 5 noncontrast electrocardiogram-gated computed tomography scans would be conducted. Three patients were eliminated within 30 days (1 withdrew, 1 died, and a third was converted before stent-graft deployment), leaving 15 patients (mean age 72.8+/-3.7 years; 14 men) for this analysis. Evolution in size and shape (symmetry) of both proximal infrarenal sealing rings were assessed from discharge to 24 months using dedicated postprocessing algorithms. RESULTS: At 24 months, the mean diameters of the first and second ring stents had increased significantly (first ring: 2.2+/-1.0 mm, p<0.001; second ring: 2.7+/-1.1 mm, p<0.001). At 6 months, the first and second rings had expanded to a mean 96.6%+/ 2.1% and 94.8%+/-2.7%, respectively, of their nominal diameter, after which the rings expanded slowly; ring diameters stabilized to near nominal size (first ring, 98.3%+/-1.1%; second ring, 97.2%+/-1.4%) at 24 months irrespective of initial oversizing. No type I or III endoleaks or aneurysm-, device-, or procedure-related adverse events were noted in follow-up. The difference in the diametric distances between the peaks and valleys of the saddle-shaped rings was marked at discharge but became smaller after 24 months for both rings (first ring: median 2.0 vs 1.2 mm, p=0.191; second ring: median 2.8 vs 0.8 mm; p=0.013). CONCLUSION: Irrespective of initial oversizing, the Anaconda proximal sealing rings radially expanded to near nominal size within 6 months after EVAR. Initial oval-shaped rings conformed symmetrically and became nearly circular through 24 months. These findings should be taken into account in planning and follow-up. PMID- 29706129 TI - Sustained Effectiveness of Cilostazol After Endovascular Treatment of Femoropopliteal Lesions: Midterm Follow-up From the Sufficient Treatment of Peripheral Intervention by Cilostazol (STOP-IC) Study. AB - PURPOSE: To investigate the midterm safety and effectiveness of cilostazol treatment in claudicant patients undergoing endovascular therapy. METHODS: The Sufficient Treatment of Peripheral Intervention by Cilostazol (STOP-IC) study ( ClinicalTrials.gov identifier NCT00912756; University Hospital Medical Information Network identifier UMIN000002091) enrolled 200 patients (mean age 73 years; 131 men) treated for femoropopliteal disease from March 2009 to April 2011 at 13 cardiovascular centers in Japan. The participants were randomized 1:1 to receive oral aspirin with or without cilostazol. Of the 100 patients assigned to the 2 treatment groups, 7 patients in the cilostazol group and 2 patients in the no-cilostazol group were withdrawn from the study without undergoing endovascular treatment, leaving 93 patients in the cilostazol group and 98 patients in the no cilostazol group for follow-up analysis. The primary outcome measure was primary patency; secondary outcome measures were freedom from clinically-driven target lesion revascularization (CD-TLR) and overall survival. Outcomes were analyzed on an intention-to-treat basis using the Kaplan-Meier method; estimates were compared with the log-rank test. RESULTS: The median follow-up was 38.1 months (interquartile range 25.1, 47.7). Among the 93 subjects in the cilostazol group, 7 died and 26 withdrew from administration 1 year after the endovascular procedure. Discontinuation of cilostazol was not a significant factor for restenosis. Primary patency was significantly higher in the cilostazol group than in the no-cilostazol group (69% vs 54%, p=0.026) at 3 years. The cilostazol group also had better 3-year freedom from CD-TLR (78% vs 63%, p=0.014), although overall survival estimates did not differ significantly (p=0.95). CONCLUSION: These results suggest that the safety and effectiveness of cilostazol treatment were sustained in patients with femoropopliteal disease undergoing endovascular treatment. PMID- 29706130 TI - Migration and tuberculosis transmission in a middle-income country: a cross sectional study in a central area of Sao Paulo, Brazil. AB - BACKGROUND: Little is known about the impact of growing migration on the pattern of tuberculosis (TB) transmission in middle-income countries. We estimated TB recent transmission and its associated factors and investigated the presence of cross-transmission between South American migrants and Brazilians. METHODS: We studied a convenient sample of cases of people with pulmonary TB in a central area of Sao Paulo, Brazil, diagnosed between 2013 and 2014. Cases with similar restriction fragment length polymorphism (IS6110-RFLP) patterns of their Mycobacterium tuberculosis complex isolates were grouped in clusters (recent transmission). Clusters with both Brazilian and South American migrants were considered mixed (cross-transmission). Risk factors for recent transmission were studied using logistic regression. RESULTS: Isolates from 347 cases were included, 76.7% from Brazilians and 23.3% from South American migrants. Fifty clusters were identified, which included 43% South American migrants and 60.2% Brazilians (odds ratio = 0.50, 95% confidence interval = 0.30-0.83). Twelve cross transmission clusters were identified, involving 24.6% of all clustered cases and 13.8% of all genotyped cases, with migrants accounting for either an equal part or fewer cases in 11/12 mixed clusters. CONCLUSIONS: Our results suggest that TB disease following recent transmission is more common among Brazilians, especially among those belonging to high-risk groups, such as drug users. Cross-transmission between migrants and Brazilians was present, but we found limited contributions from migrants to Brazilians in central areas of Sao Paulo and vice versa. PMID- 29706131 TI - Schistosomiasis in Zambia: a systematic review of past and present experiences. AB - BACKGROUND: The speedy rate of change in the environmental and socio-economics factors may increase the incidence, prevalence and risk of schistosomiasis infections in Zambia. However, available information does not provide a comprehensive understanding of the biogeography and distribution of the disease, ecology and population dynamics of intermediate host snails. The current study used an information-theoretical approach to understand the biogeography and prevalence schistosomiasis and identified knowledge gaps that would be useful to improve policy towards surveillance and eradication of intermediate hosts snails in Zambia. METHODS: To summarise the existing knowledge and build on past and present experiences of schistosomiasis epidemiology for effective disease control in Zambia, a systematic search of literature for the period 2000-2017 was done on PubMed, Google Scholar and EBSCOhost. Using the key words: 'Schistosomiasis', 'Biomphalaria', 'Bulinus', 'Schistosoma mansoni', 'Schistosoma haematobium', and 'Zambia', in combination with Booleans terms 'AND' and 'OR', published reports/papers were obtained and reviewed independently for inclusion. RESULTS: Thirteen papers published in English that fulfilled the inclusion criteria were selected for the final review. The papers suggest that the risk of infection has increased over the years and this has been attributed to environmental, socio economic and demographic factors. Furthermore, schistosomiasis is endemic in many parts of the country with infection due to Schistosoma haematobium being more prevalent than that due to S. mansoni. This review also found that S. haematobium was linked to genital lesions, thus increasing risks of contracting other diseases such as HIV and cervical cancer. CONCLUSIONS: For both S. haematobium and S. mansoni, environmental, socio-economic, and demographic factors were influential in the transmission and prevalence of the disease and highlight the need for detailed knowledge on ecological modelling and mapping the distribution of the disease and intermediate host snails for effective implementation of control strategies. PMID- 29706133 TI - Intestinal paracoccidioidomycosis resembling Crohn's disease in a teenager: a case report. AB - BACKGROUND: Differential diagnosis of inflammatory bowel disease is often very challenging. Paracoccidioidomycosis is a fungal disease that can mimic manifestations of Crohn's disease. CASE PRESENTATION: We report a case of a 13 year-old Caucasian boy with abdominal pain for 1.5 years associated with nausea, diarrhea, and weight loss of 10 kg. He presented increased C-reactive protein and an increased erythrocyte sedimentation rate. A colonoscopy showed deep serpiginous ulcers throughout his entire colon and rectum, which suggested Crohn's disease. He received one dose of infliximab, which is an anti-tumor necrosis factor-alpha, and showed no improvement. After the second dose, he got worse and started to have bloody diarrhea. A new colonoscopy was performed and pathological examination revealed ulcerative chronic inflammation with non caseating granulomas and fungal structures (budding forms) compatible with Paracoccidioides brasiliensis. He underwent intravenously administered and then orally administered trimethoprim-sulfamethoxazole treatment. Due to drug intolerance, he was treated with amphotericin B and itraconazole, then he showed clinical improvement and mucosal healing with good outcome. CONCLUSION: Paracoccidioidomycosis must be part of the differential diagnosis of inflammatory bowel diseases in endemic areas and must be excluded before starting immunosuppressive therapy. PMID- 29706134 TI - Additive value of 3T cardiovascular magnetic resonance coronary angiography for detecting coronary artery disease. AB - BACKGROUND: The purpose of the work was to evaluate the incremental diagnostic value of free-breathing, contrast-enhanced, whole-heart, 3 T cardiovascular magnetic resonance coronary angiography (CE-MRCA) to stress/rest myocardial perfusion imaging (MPI) and late gadolinium enhancement (LGE) imaging for detecting coronary artery disease (CAD). METHODS: Fifty-one patients with suspected CAD underwent a comprehensive cardiovascular magnetic resonance (CMR) examination (CE-MRCA, MPI, and LGE). The additive diagnostic value of MRCA to MPI and LGE was evaluated using invasive x-ray coronary angiography (XA) as the standard for defining functionally significant CAD (>= 50% stenosis in vessels > 2 mm in diameter). RESULTS: 90.2% (46/51) patients (54.0 +/- 11.5 years; 71.7% men) completed CE-MRCA successfully. On per-patient basis, compared to MPI/LGE alone or MPI alone, the addition of MRCA resulted in higher sensitivity (100% vs. 76.5%, p < 0.01), no change in specificity (58.3% vs. 66.7%, p = 0.6), and higher accuracy (89.1% vs 73.9%, p < 0.01) for CAD detection (prevalence = 73.9%). Compared to LGE alone, the addition of CE-MRCA resulted in higher sensitivity (97.1% vs. 41.2%, p < 0.01), inferior specificity (83.3% vs. 91.7%, p = 0.02), and higher diagnostic accuracy (93.5% vs. 54.3%, p < 0.01). CONCLUSION: The inclusion of successful free-breathing, whole-heart, 3 T CE-MRCA significantly improved the sensitivity and diagnostic accuracy as compared to MPI and LGE alone for CAD detection. PMID- 29706132 TI - When complexity science meets implementation science: a theoretical and empirical analysis of systems change. AB - BACKGROUND: Implementation science has a core aim - to get evidence into practice. Early in the evidence-based medicine movement, this task was construed in linear terms, wherein the knowledge pipeline moved from evidence created in the laboratory through to clinical trials and, finally, via new tests, drugs, equipment, or procedures, into clinical practice. We now know that this straight line thinking was naive at best, and little more than an idealization, with multiple fractures appearing in the pipeline. DISCUSSION: The knowledge pipeline derives from a mechanistic and linear approach to science, which, while delivering huge advances in medicine over the last two centuries, is limited in its application to complex social systems such as healthcare. Instead, complexity science, a theoretical approach to understanding interconnections among agents and how they give rise to emergent, dynamic, systems-level behaviors, represents an increasingly useful conceptual framework for change. Herein, we discuss what implementation science can learn from complexity science, and tease out some of the properties of healthcare systems that enable or constrain the goals we have for better, more effective, more evidence-based care. Two Australian examples, one largely top-down, predicated on applying new standards across the country, and the other largely bottom-up, adopting medical emergency teams in over 200 hospitals, provide empirical support for a complexity-informed approach to implementation. The key lessons are that change can be stimulated in many ways, but a triggering mechanism is needed, such as legislation or widespread stakeholder agreement; that feedback loops are crucial to continue change momentum; that extended sweeps of time are involved, typically much longer than believed at the outset; and that taking a systems-informed, complexity approach, having regard for existing networks and socio-technical characteristics, is beneficial. CONCLUSION: Construing healthcare as a complex adaptive system implies that getting evidence into routine practice through a step-by-step model is not feasible. Complexity science forces us to consider the dynamic properties of systems and the varying characteristics that are deeply enmeshed in social practices, whilst indicating that multiple forces, variables, and influences must be factored into any change process, and that unpredictability and uncertainty are normal properties of multi-part, intricate systems. PMID- 29706135 TI - De novo subgaleal abscess - a rare presentation of melioidosis: a case report. AB - BACKGROUND: Melioidosis is an emerging infection in the tropics caused by the bacterium Burkholderia pseudomallei. Poorly controlled diabetes is a known risk factor. Melioidosis has a broad spectrum of clinical manifestations ranging from a localized abscess to pneumonia to disseminated sepsis with multiorgan failure. Pyrexia of unknown origin is a common presentation. Abscesses in unusual anatomical locations are well known to be associated with melioidosis. CASE PRESENTATION: We report a case of a 64-year-old Sri Lankan Sinhalese man with prolonged fever and constitutional symptoms with a neglected swelling over the back of the scalp who was found to have an abscess in the subgaleal space of the scalp during surgical drainage. Burkholderia pseudomallei was isolated in pus culture, and melioidosis serology was highly positive. The patient was treated with ceftazidime for 2 weeks, followed by co-trimoxazole for another 3 months. He made a complete clinical recovery with normalization of inflammatory markers. To the best of our knowledge, this is the first case of subgaleal abscess following melioidosis infection reported in the literature. CONCLUSIONS: Abscesses in anatomically unusual locations should raise suspicion for melioidosis infection, particularly among patients with risk factors such as diabetes mellitus. PMID- 29706138 TI - Allergic rhinitis and arterial blood pressure: a population-based study. AB - OBJECTIVES: To investigate the likelihood of allergic rhinitis and potential co morbidities, and to assess whether allergic rhinitis is associated with arterial blood pressure and hypertension. METHODS: In this population-based study, 369 adults with allergic rhinitis and asthma were assessed via a questionnaire and immunoglobulin E levels. There were four groups: control (n = 90), allergic rhinitis (n = 99), asthma (n = 87) and hypertension (n = 93). Arterial blood pressure was measured in all groups. RESULTS: There were no significant differences in systolic or diastolic blood pressure between males and females in any group. Pairwise comparisons revealed no significant differences between: the control and allergic rhinitis groups, the control and asthma groups, or the allergic rhinitis and asthma groups. The systolic and diastolic blood pressure values of males and females were significantly higher in the hypertension group than the allergic rhinitis group. There were no significant differences in systolic blood pressure or diastolic blood pressure for seasonal and perennial allergic rhinitis patients. CONCLUSION: Rhinitis was not associated with increased blood pressure. Allergic rhinitis can coincide with asthma and hypertension. The findings do not support the need for blood pressure follow up in allergic rhinitis patients. PMID- 29706139 TI - Enduring effects of psychological treatments for anxiety disorders: meta-analysis of follow-up studies. AB - BACKGROUND: It is a widespread opinion that after treatment with psychotherapy, patients with anxiety disorders maintain their gains beyond the active treatment period, whereas patients treated with medication soon experience a relapse after treatment termination.AimsWe aimed to provide evidence on whether enduring effects of psychotherapy differ from control groups. METHOD: We searched 93 randomised controlled studies with 152 study arms of psychological treatment (cognitive-behavioural therapy or other psychotherapies) for panic disorder, generalised anxiety disorder and social anxiety disorder that included follow-up assessments. In a meta-analysis, pre-post effect sizes for end-point and all follow-up periods were calculated and compared with control groups (medication: n = 16 study arms; pill and psychological placebo groups: n = 17 study arms). RESULTS: Gains with psychotherapy were maintained for up to 24 months. For cognitive-behavioural therapy, we observed a significant improvement over time. However, patients in the medication group remained stable during the treatment free period, with no significant difference when compared with psychotherapy. Patients in the placebo group did not deteriorate during follow-up, but showed significantly worse outcomes than patients in cognitive-behavioural therapy. CONCLUSIONS: Not only psychotherapy, but also medications and, to a lesser extent, placebo conditions have enduring effects. Long-lasting treatment effects observed in the follow-up period may be superimposed by effects of spontaneous remission or regression to the mean.Declaration of interestIn the past 12 months and in the near future, Dr Bandelow has been/will be on the speakers/advisory board for Hexal, Mundipharma, Lilly, Lundbeck, Pfizer and Servier. Dr Wedekind was on the speakers' board of AstraZeneca, Essex Pharma, Lundbeck and Servier. All other authors have nothing to declare. PMID- 29706137 TI - Position-specific intron retention is mediated by the histone methyltransferase SDG725. AB - BACKGROUND: Intron retention (IR), the most prevalent alternative splicing form in plants, plays a critical role in gene expression during plant development and stress response. However, the molecular mechanisms underlying IR regulation remain largely unknown. RESULTS: Knockdown of SDG725, a histone H3 lysine 36 (H3K36)-specific methyltransferase in rice, leads to alterations of IR in more than 4700 genes. Surprisingly, IR events are globally increased at the 5' region but decreased at the 3' region of the gene body in the SDG725-knockdown mutant. Chromatin immunoprecipitation sequencing analyses reveal that SDG725 depletion results in a genome-wide increase of the H3K36 mono-methylation (H3K36me1) but, unexpectedly, promoter-proximal shifts of H3K36 di- and tri-methylation (H3K36me2 and H3K36me3). Consistent with the results in animals, the levels of H3K36me1/me2/me3 in rice positively correlate with gene expression levels, whereas shifts of H3K36me2/me3 coincide with position-specific alterations of IR. We find that either H3K36me2 or H3K36me3 alone contributes to the positional change of IR caused by SDG725 knockdown, although IR shift is more significant when both H3K36me2 and H3K36me3 modifications are simultaneously shifted. CONCLUSIONS: Our results revealed that SDG725 modulates IR in a position-specific manner, indicating that H3K36 methylation plays a role in RNA splicing, probably by marking the retained introns in plants. PMID- 29706136 TI - Human antibodies activate complement against Plasmodium falciparum sporozoites, and are associated with protection against malaria in children. AB - BACKGROUND: Antibodies targeting Plasmodium falciparum sporozoites play a key role in human immunity to malaria. However, antibody mechanisms that neutralize sporozoites are poorly understood. This has been a major constraint in developing highly efficacious vaccines, as we lack strong correlates of protective immunity. METHODS: We quantified the ability of human antibodies from malaria-exposed populations to interact with human complement, examined the functional effects of complement activity against P. falciparum sporozoites in vitro, and identified targets of functional antibodies. In children and adults from malaria-endemic regions, we determined the acquisition of complement-fixing antibodies to sporozoites and their relationship with antibody isotypes and subclasses. We also investigated associations with protective immunity in a longitudinal cohort of children (n = 206) residing in a malaria-endemic region. RESULTS: We found that antibodies to the major sporozoite surface antigen, circumsporozoite protein (CSP), were predominately IgG1, IgG3, and IgM, and could interact with complement through recruitment of C1q and activation of the classical pathway. The central repeat region of CSP, included in leading vaccines, was a key target of complement-fixing antibodies. We show that antibodies activate human complement on P. falciparum sporozoites, which consequently inhibited hepatocyte cell traversal that is essential for establishing liver-stage infection, and led to sporozoite death in vitro. The natural acquisition of complement-fixing antibodies in malaria-exposed populations was age-dependent, and was acquired more slowly to sporozoite antigens than to merozoite antigens. In a longitudinal cohort of children, high levels of complement-fixing antibodies were significantly associated with protection against clinical malaria. CONCLUSIONS: These novel findings point to complement activation by antibodies as an important mechanism of anti-sporozoite human immunity, thereby enabling new strategies for developing highly efficacious malaria vaccines. We also present evidence that complement-fixing antibodies may be a valuable correlate of protective immunity in humans. PMID- 29706140 TI - Health Care Providers in War and Armed Conflict: Operational and Educational Challenges in International Humanitarian Law and the Geneva Conventions, Part I. Historical Perspective. AB - Since 1945, the reason for humanitarian crises and the way in which the world responds to them has dramatically changed every 10 to 15 years or less. Planning, response, and recovery for these tragic events have often been ad hoc, inconsistent, and insufficient, largely because of the complexity of global humanitarian demands and their corresponding response system capabilities. This historical perspective chronicles the transformation of war and armed conflicts from the Cold War to today, emphasizing the impact these events have had on humanitarian professionals and their struggle to adapt to increasing humanitarian, operational, and political challenges. An unprecedented independent United Nations-World Health Organization decision in the Battle for Mosul in Iraq to deploy to combat zones emergency medical teams unprepared in the skills of decades-tested war and armed conflict preparation and response afforded to health care providers and dictated by International Humanitarian Law and Geneva Convention protections has abruptly challenged future decision-making and deployments. (Disaster Med Public Health Preparedness. 2018;page 1 of 7). PMID- 29706141 TI - Effects of sire genotype on lamb performance at weaning in extensive sheep systems. AB - A low finishing weight and poor carcass characteristics are major causes of lower incomes in extensive sheep flocks; however, the use of terminal sire crossbreeding would improve lamb performance and carcass traits under these conditions. The aim of this study was to evaluate sire breed effects on the performance of lambs born to Corriedale ewes in extensive sheep systems in Western Patagonia. A total of 10 Corriedale, 10 Dorset, nine Suffolk and seven Texel sires, 16 of which were under a genetic recorded scheme and 20 selected from flocks not participating in genetic improvement programmes, were used across six commercial farms for 2 successive years. Data were collected from 685 lambs of the four resulting genotypes. Overall, Corriedale lambs were 0.47 kg lighter at birth than crossbred lambs (P0.05). Carcass conformation was higher in Texel sired lambs compared with Corriedale lambs (P<0.05), with Dorset and Suffolk sired lambs being intermediate. Crossbred lambs showed a greater (P<0.001) eye muscle than Corriedale. Commercial cuts were affected by sire breed, as a result of the Corriedale lambs being smaller and having lighter carcass than crossbred lambs. Significant improvement in lamb weights at weaning and carcass traits could be expected when using a terminal sire on Corriedale ewes in Western Patagonia. However, no advantages were detected with the use of recorded sires under these production systems. PMID- 29706142 TI - Prenatal lead exposure in relation to age at menarche: results from a longitudinal study in Mexico City. AB - Animal and cross-sectional epidemiological studies suggest that prenatal lead exposure is related to delayed menarche, but this has not been confirmed in longitudinal studies. We analyzed this association among 200 girls from Mexico City who were followed since the first trimester of gestation. Maternal blood lead levels were analyzed once during each trimester of pregnancy, and daughters were asked about their first menstrual cycle at a visit between the ages of 9.8 and 18.1 years. We estimated hazard ratios (HRs) and 95% confidence intervals (CI) for probability of menarche over the follow-up period using interval censored Cox models, comparing those with prenatal blood lead level ?5 ug/dl to those with prenatal blood lead <5 ug/dl. We also estimated HRs and 95% CI with conventional Cox regression models, which utilized the self-reported age at menarche. In adjusted analyses, we accounted for maternal age, maternal parity, maternal education, and prenatal calcium treatment status. Across trimesters, 36 47% of mothers had blood lead levels ?5 ug/dl. Using interval-censored models, we found that during the second trimester only, girls with ?5 ug/dl prenatal blood lead had a later age at menarche compared with girls with prenatal blood lead levels <5 ug/dl (confounder-adjusted HR=0.59, 95% CI 0.28-0.90; P=0.05). Associations were in a similar direction, although not statistically significant, in the conventional Cox regression models, potentially indicating measurement error in the self-recalled age at menarche. In summary, higher prenatal lead exposure during the second trimester could be related to later onset of sexual maturation. PMID- 29706143 TI - Genome-wide association studies for seven production traits highlight genomic regions useful to dissect dry-cured ham quality and production traits in Duroc heavy pigs. AB - Protected designation of origin dry-cured hams are obtained from heavy pigs (slaughtered at about 160 kg of live weight). A specific breeding program designed to improve meat quality for this production has included as key traits the level of intermuscular fat between the leg muscles and ham weight loss during the seasoning period together with a balance between fat and lean cuts. In this study we carried out genome-wide association studies for seven traits used in the genetic merit of Italian Duroc heavy pigs, five related to meat and carcass quality traits (visible intermuscular fat, ham weight loss at first salting, backfat thickness, ham weight and lean cuts), and two related to performance and efficiency traits (average daily gain and feed : gain ratio). A total of 573 performance-tested pigs were genotyped with the Illumina PorcineSNP60 BeadChip and genome-wide association analyses were carried out using the Bayes B approach with the 1 Mb window option of GenSel and random residuals for each of the seven traits. Detected windows were supported by independent single nucleotide polymorphism analyses with a linear mixed model (LMM) approach on the same animals for the same traits. A total of 30 windows identifying different quantitative trait loci (QTL) were detected and among those, 27 were confirmed by LMM in one of these traits. Among the confirmed windows, three QTL were reported for visible intermuscular fat, seven for ham weight loss at first salting and five and four for backfat thickness and lean cut, respectively. A total of eight QTL were detected for the other production traits. No overlapping QTL were reported except for one window on porcine chromosome 10 between lean cuts and ham weight that contained the CACNB2 gene that has been already associated with loin marbling score in other Duroc pigs. Several regions contained genes that have been already associated with production traits in other pig breeds, including Duroc lines, related to fat deposition or muscle structure. This work reports, for the first time, genome-wide association study results for several traits in Italian Duroc heavy pigs. These results will be useful to dissect the genetic basis for dry-cured ham production traits that determine the total genetic merit index of Italian Duroc pigs. PMID- 29706144 TI - Genotype imputation from various low-density SNP panels and its impact on accuracy of genomic breeding values in pigs. AB - The uptake of genomic selection (GS) by the swine industry is still limited by the costs of genotyping. A feasible alternative to overcome this challenge is to genotype animals using an affordable low-density (LD) single nucleotide polymorphism (SNP) chip panel followed by accurate imputation to a high-density panel. Therefore, the main objective of this study was to screen incremental densities of LD panels in order to systematically identify one that balances the tradeoffs among imputation accuracy, prediction accuracy of genomic estimated breeding values (GEBVs), and genotype density (directly associated with genotyping costs). Genotypes using the Illumina Porcine60K BeadChip were available for 1378 Duroc (DU), 2361 Landrace (LA) and 3192 Yorkshire (YO) pigs. In addition, pseudo-phenotypes (de-regressed estimated breeding values) for five economically important traits were provided for the analysis. The reference population for genotyping imputation consisted of 931 DU, 1631 LA and 2103 YO animals and the remainder individuals were included in the validation population of each breed. A LD panel of 3000 evenly spaced SNPs (LD3K) yielded high imputation accuracy rates: 93.78% (DU), 97.07% (LA) and 97.00% (YO) and high correlations (>0.97) between the predicted GEBVs using the actual 60 K SNP genotypes and the imputed 60 K SNP genotypes for all traits and breeds. The imputation accuracy was influenced by the reference population size as well as the amount of parental genotype information available in the reference population. However, parental genotype information became less important when the LD panel had at least 3000 SNPs. The correlation of the GEBVs directly increased with an increase in imputation accuracy. When genotype information for both parents was available, a panel of 300 SNPs (imputed to 60 K) yielded GEBV predictions highly correlated (?0.90) with genomic predictions obtained based on the true 60 K panel, for all traits and breeds. For a small reference population size with no parents on reference population, it is recommended the use of a panel at least as dense as the LD3K and, when there are two parents in the reference population, a panel as small as the LD300 might be a feasible option. These findings are of great importance for the development of LD panels for swine in order to reduce genotyping costs, increase the uptake of GS and, therefore, optimize the profitability of the swine industry. PMID- 29706145 TI - Poisoning from the Kambo ritual. PMID- 29706147 TI - Risky business: is pubic hair removal by women associated with body image and sexual health? AB - : Background Body hair removal is a behaviour that has become normative among women in Westernised cultures, and is presented by the media as the feminine ideal, despite being painful and a potential cause of infection. Of concern, removal may be part of a more global pattern of appearance dissatisfaction and risky sexual behaviour. The aim of the present study was to examine the relationships among pubic hair removal, body image and sexual health indicators. METHODS: Women (n=264; Mage=33.82, s.d.=11.13, range=18-66) completed self-report questionnaires assessing these constructs, including an assessment of body hair removal practices. RESULTS: Greater appearance concerns (as measured by thin ideal internalisation, appearance investment and self-objectification) and sexual health indicators (i.e. less condom use self-efficacy when a partner disapproves of condom use) all predicted greater importance of reasons for pubic hair removal (R2=0.315, F(8184)=9.97, P<0.001), controlling for age groups. Additionally, women who removed a greater amount of hair reported more thin-ideal internalisation and appearance investment than those who removed less hair. CONCLUSIONS: Women who express stronger reasoning for pubic hair removal, and remove a larger amount of it, may endorse problematic beliefs and behaviours particularly related to appearance concerns. It is important for practitioners to consider this practice as distinct from grooming and to be aware of its association with a broader array of risky beliefs and behaviours that can compromise women's well-being. PMID- 29706146 TI - Neuropsychological Profiles and Trajectories in Preclinical Alzheimer's Disease. AB - OBJECTIVES: The present study investigated the independent and synergistic effects of amyloid beta (Abeta1-42) and phosphorylated tau (Ptau) pathologies on neuropsychological profiles and trajectories in cognitively normal older adults. METHODS: Alzheimer's Disease Neuroimaging Initiative participants identified as cognitively normal at baseline underwent longitudinal assessment (N=518; 0, 12, 24, 36 months), baseline lumbar puncture and follow-up cognitive exams. Cerebral spinal fluid (CSF) biomarker profiles (Abeta-Ptau-, Abeta+Ptau-, Abeta-Ptau+, Abeta+Ptau+) were compared on baseline profiles and trajectories for memory (Rey Auditory Verbal Learning Test), attention/executive function (Trail Making Test, A and B), language (Animal Fluency, Vegetable Fluency, Boston Naming Test) and processing speed (Digit Symbol) using multilevel models. RESULTS: The Abeta+Ptau+ group exhibited significantly worse baseline performance on tests of memory and executive function relative to the Abeta-Ptau+ and Abeta-Ptau- groups. The Abeta+Ptau- group fell between the Abeta+Ptau+ participants and the Abeta-Ptau- and Abeta-Ptau+ groups on all three cognitive domains and exhibited worse baseline executive function. The Abeta-Ptau+ group performed worse than Abeta Ptau- participants on processing speed. Over 36-month follow-up, the Abeta+Ptau+ group exhibited the greatest declines in memory and semantic fluency compared to all other groups. CONCLUSIONS: Cognitively normal older adults with both Abeta and Ptau pathology exhibited the weakest profile, marked by the worst memory decline compared to the other groups. Other subtle changes in this group included declines in executive function and semantic fluency. Those with Ptau pathology alone showed slowed processing speed, and those with Abeta pathology alone showed worse attention and executive function compared to biomarker negative participants. (JINS, 2018, 24, 693-702). PMID- 29706148 TI - Fluoxetine treatment of prepubertal male rats uniformly diminishes sex hormone levels and, in a subpopulation of animals, negatively affects sperm quality. AB - Fluoxetine (Flx) is a selective serotonin reuptake inhibitor that alters the male reproductive system when administered at the adult stage or after maternal exposure. In the present study we evaluated the effects of Flx administration on reproductive parameters during juvenile-peripubertal development when treated male rats reached adulthood. Groups of rats were treated daily with Flx (5mgkg-1, i.p.) or saline (0.9% NaCl), or were left untreated. Rats were treated between 30 and 53 days of age and were killed at 65 days of age. Serotonin concentrations were determined in the hypothalamus, hypophysis and testis. Gonadotrophins, sex steroids and sperm quality (membrane integrity, sperm with functional mitochondria, sperm density, sperm motility and morphological abnormalities) were also evaluated. Flx did not affect bodyweight, but significantly diminished LH, FSH, progesterone and testosterone serum concentrations. After graphical analysis, a subgroup of rats was identified whose sperm quality parameters were greatly affected by Flx. In the present study we show that Flx administered to juvenile rats disrupts the hypothalamic-hypophyseal-testicular axis and its effects on sperm quality are not homogeneous in adults. In contrast, Flx altered concentrations of gonadotrophins and sexual steroids in all treated rats. These results suggest caution should be exercised in the prescription of Flx to prepubertal males. PMID- 29706149 TI - Management of sexually transmissible infections in the era of multiplexed molecular diagnostics: a primary care survey. AB - Background: Data regarding sexually transmissible infections (STI) often originate from STI clinics, screening programs or laboratory-based studies, thus are biased for specific risk groups or lack clinical details. This real-life observational study presents sample data of most young adult Israeli population by exploiting the centralised diagnostic and documentation platforms resulting from a mandatory military service at the age of 18 years for both genders. Methods: All STI diagnoses of Israeli Defence Forces soldiers during a 6-month period were reviewed. Patients with Chlamydia trachomatis (CT), Mycoplasma genitalium (MG), Neisseria gonorrhoeae (NG) and Trichomonas vaginalis (TV) (major STI) and Ureaplasma urealyticum (UU), Ureaplasma parvum (UP) and Mycoplasma hominis (MH) (equivocal STI) were compared with STI-negative controls. Results: Sexually transmissible infection positivity rates (n=2816) were as follows: CT 6.6%; MG 1.9%; NG 0.7%; TV 0.5%; UU 15.7%; UP 28.2%; and MH 6.2%. The CT+MG coinfection rate was 4.1%, yet CT+NG coinfections were rare (~0.5%). More than half of the patients with ureaplasmas and/or MH were treated; 40% of them were recommended partner treatment. Most antibiotics were prescribed to patients with equivocal infections. Classic STI symptoms in males were linked to major-STI and UU, while females were asymptomatic or presented non-specific symptoms. Conclusions: The judicious use of antibiotics in the era of antimicrobial resistance necessitates re-evaluating the significance of equivocal pathogen detection and reporting (MH, UU, UP). Likewise, universal empiric treatment for NG should be reconsidered in light of its low rates in non-high-risk groups. Conversely, a high MG rate, a pathogen with potential resistance to common STI protocols, requires evaluation of guidelines adequacy. PMID- 29706151 TI - Newly revised guide to clinically important microbes-available in print and digital formats. PMID- 29706150 TI - Neurosyphilis: mighty imitator forays with benign presentation and unique neuroimaging findings. AB - Background: Common causes of temporal lobe hyper intensities are central nervous system infections like herpes simplex encephalitis, Lyme disease, limbic encephalitis and vascular pathology like Cerebral Autosomal Dominant Arteriopathy with Subcortical infarcts and Leukoencephalopathy. Methods: Personal assessment, laboratory data analysis and neuroimaging for the patient who was admitted to a central Pennsylvania tertiary care referral centre were conducted. Results: A 52 year-old male presented with a 1-year history of diffuse dysesthesia in upper and lower extremities with associated intermittent headaches and neck stiffness. Evaluation with lumbar puncture revealed increased nucleated cells (50ul) with lymphocytic predominance (96%) and an elevated protein level of 109mg/dl. Magnetic resonance imaging (MRI) of the brain showed T2/FLAIR hyper intensity in bilateral subcortical temporal white matter, left-greater-than-right and associated volume loss in cerebral parenchyma. Additional abnormal work up included reactive serum reactive plasma regain and Treponema pallidum antibody particle agglutination. Diagnosis of neurosyphilis was made and the patient was treated with intramuscular (IM) penicillin for 3 weeks. At the time of discharge, his headache and neck stiffness resolved and dysesthesias were decreased in intensity. Conclusions: The diagnosis of neurosyphilis is intricate, and no reference standard exists. Neuroimaging findings of neurosyphilis commonly are cerebral infarctions, leptomeningeal enhancement or non-specific white matter lesions. Less common features on fluid-attenuated inversion recovery (FLAIR) sequences are cortical atrophy and mesial temporal parenchymal signal changes. It is prudent to keep neurosyphilis in differential of mesial temporal lobe white matter changes, as early diagnosis and treatment results in better prognosis. PMID- 29706153 TI - Erratum. PMID- 29706152 TI - Health care system leaders' perspectives on infection preventionist and registered nurse engagement in antibiotic stewardship. AB - BACKGROUND: Infection preventionists (IPs) and registered nurses (RNs) have an important role to play in antibiotic stewardship programs (ASPs). Recent articles highlight their potential roles in practice, research, education, and policy; however, little is known about their actual ASP engagement. Leaders often have early knowledge of emerging trends and evolving health care worker roles. METHODS: A survey was developed using the Centers for Disease Control and Prevention's Core Elements of Hospital Antibiotic Stewardship Programs to assess health care system infection prevention and control leaders' perceptions of IP and RN engagement in hospital ASPs. RESULTS: Thirty-five leaders representing all regions of the United States completed the survey. Their organizations tended to have significant ASP leadership support, but lacked ASP policies indicating IP and RN roles and responsibilities. IPs were more likely than RNs to be members of the ASP team and have greater ASP knowledge. Neither discipline was conducting patient education related to proper use of antibiotics, but this was identified as a future ASP role. The 2017 Joint Commission Antimicrobial Stewardship Standard was accelerating ASP implementation. CONCLUSIONS: IPs and RNs are well positioned to assume greater roles in ASPs, especially in educating patients about the safe and proper use of antibiotics. However, their roles must be clearly identified, defined, and quantified. In so doing, knowledge and skill gaps can be identified and specific educational programs developed to advance their successful engagement in ASPs. PMID- 29706154 TI - The Journal and the Academy. AB - Every issue of the Journal includes 2 pages between the front cover and the table of contents-1 that lists the editorial team, or masthead, who assess submissions and select content and another that lists the officers of the American Academy of Child and Adolescent Psychiatry, the Journal's sponsoring society and owner. As noted in the policies of the World Association of Medical Editors. PMID- 29706155 TI - The Workforce Shortage of Child and Adolescent Psychiatrists: Is It Time for a Different Approach? AB - Psychiatric disorders affect a large number of children around the world. Recent data have reported that approximately 10% to 13% of children have a serious emotional disturbance with significant functional impairment, suggesting that at least 1 in 10 children require mental health services.1,2 Approximately half the adults with mental illness received their diagnosis before 15 years of age3 and close to three fourths of mental health disorders start by the mid-20s.4 Mental illnesses are associated with a large disease burden because these conditions lead to increases in morbidity, mortality, and financial costs. For example, in high-income countries such as the United States, 3 of the leading illnesses associated with pediatric disease burden are psychiatric (depression, bipolar disorder, and schizophrenia) and psychiatric illness in children and adolescents is a key risk factor for completed suicide.5 In the United States, suicide is the second leading cause of death in people 15 to 24 years of age,6 with rural areas having particularly high suicide rates.7 What is even more disconcerting is the fact that most youngsters who might benefit from psychiatric or behavioral health treatment do not receive it. For example, only 45% of adolescents with mental illness received psychiatric services in 2013. This number is even smaller for children and adolescents with internalizing disorders and for minorities.8. PMID- 29706156 TI - Recognizing the Problem of Suicidality in Autism Spectrum Disorder. AB - Until recently, suicidality in autism spectrum disorder (ASD) was rarely discussed. A cluster of recent articles, including an article by Culpin et al.1 in this issue, has highlighted not only that suicidal thoughts and suicide attempts can occur in adolescents and young adults with ASD, but also that suicidality is likely more common in ASD than in the general population. Retrospectively, the lack of focus on suicidality in ASD seems surprising when self-injurious behavior has long been a focus of attention in ASD.2 The emerging studies indicate that the increased risk of self-injurious behavior in younger and less cognitively able children with ASD3,4 is matched by an increased risk of suicidality in those at a more advanced developmental level. PMID- 29706157 TI - What Happens to Disinhibited Social Engagement Disorder Over Time? AB - Disinhibited social engagement disorder (DSED) is one of the most intriguing syndromes in child and adolescent psychiatry but also one of the least understood. We know little about its developmental course in different groups of children, so I was delighted to see the incisive longitudinal work from the Bucharest Early Intervention Study by Guyon-Harris and colleagues.1 My own interest in DSED was sparked back in the early 1990s, when a travel bug had taken me to Guatemala and I had found a job in an orphanage. I was also the family doctor to the surrounding villages, in which children were considerably more materially deprived than their peers in the orphanage who had three meals a day, chlorinated running water, and a reliable school. What the orphanage children did not have was family care-instead they experienced rotating shifts of carers, many of whom were travelers like me, some only there for one or two weeks. Prior to my trip, a senior child psychiatrist had armed me with Bowlby's Attachment and Loss2 and a photocopy of the ICD-10 classification of "disinhibited attachment disorder." My dual role in the orphanage soon made it obvious that the social behavior of many of the institutionalized children was grossly different from that of their family-reared peers. Strangers could not walk into the orphanage until they had peeled off the hands of the small children who had crowded them. In contrast, children in local family homes peeked out from behind their mother's skirts-just as John Bowlby had said they would. Indiscriminate behavior was adaptive in the orphanage setting, because otherwise emotionally neglected children received bursts of attunement from whichever carer was available. The same indiscriminate behavior was, however, highly maladaptive outside the orphanage setting, as children would wander off without checking back and put themselves in danger. PMID- 29706158 TI - Time Trends in the Global Prevalence of Mental Disorders in Children and Adolescents: Gap in Data on U.S. Youth. AB - There have been numerous reports in the media of alarming increases in the rates of childhood mental health symptoms and conditions in U.S. youth, including severe anxiety.1-3 Calling attention to striking increases in the rates of mental health problems is not required to raise public awareness of their significant impact on childrens' lives. In fact, the evidence base for increasing prevalence of mental disorders, or of any of these conditions in the United States or elsewhere, is quite weak. PMID- 29706159 TI - Psychosis in Children and Adolescents. AB - Psychosis is characterized by overt disruptions in thought, perceptions, and behavior. Complex syndromes presenting with psychosis, including schizophrenia spectrum disorders, mood disorders, and medical illnesses, are differentiated by characteristic patterns of symptom presentation and course of illness. Accurate diagnosis is important to guide treatment and to avoid inaccurate labeling, because most youth reporting psychotic-like experiences do not have a true psychotic disorder. PMID- 29706160 TI - Autistic Traits and Suicidal Thoughts, Plans, and Self-Harm in Late Adolescence: Population-Based Cohort Study. AB - OBJECTIVE: To examine the hypothesis that autism spectrum disorders (ASD) diagnosis and traits in childhood are associated with suicidal thoughts, plans and self-harm at 16 years, and that any observed associations are explained by depression at 12 years. METHOD: We examined associations between ASD diagnosis and 4 dichotomized ASD traits (social communication, pragmatic language, repetitive behavior, and sociability) with suicidal and nonsuicidal self-harm, suicidal thoughts, and suicidal plans at age 16 years in 5,031 members of the United Kingdom-based birth cohort study the Avon Longitudinal Study of Parents and Children. We assessed whether any associations were explained by depressive symptoms in early adolescence measured by the Short Moods and Feelings Questionnaire at 12 years. RESULTS: Children with impaired social communication had a higher risk of self-harm with suicidal intent (relative risk [RR] = 2.14, 95% CI = 1.28-3.58), suicidal thoughts (RR = 1.42, 95% CI = 1.06-1.91), and suicidal plans (RR = 1.95, 95% CI = 1.09-3.47) by age 16 years as compared to those without. There was no evidence for an association between ASD diagnosis and outcomes, although these analyses were imprecise because of small numbers. There was also no evidence of an association between other autism traits and the outcomes. Approximately 32% of the total estimated association between social communication impairment and self-harm was explained by depressive symptoms at 12 years. CONCLUSION: Social communication impairments are an important autistic trait in relation to suicidality. Early identification and management of depression may be a preventative mechanism, and future research identifying other potentially modifiable mechanisms may lead to interventions against suicidal behavior in this high-risk group. PMID- 29706161 TI - The Epigenetic Clock at Birth: Associations With Maternal Antenatal Depression and Child Psychiatric Problems. AB - OBJECTIVE: Maternal antenatal depression may compromise the fetal developmental milieu and contribute to individual differences in aging and disease trajectories in later life. We evaluated the association between maternal antenatal depression and a novel biomarker of aging at birth, namely epigenetic gestational age (GA) based on fetal cord blood methylation data. We also examined whether this biomarker prospectively predicts and mediates maternal effects on early childhood psychiatric problems. METHOD: A total of 694 mothers from the Prediction and Prevention of Preeclampsia and Intrauterine Growth Restriction (PREDO) Study provided information on history of depression diagnosed before pregnancy; 581 completed the Center for Epidemiological Studies Depression Scale throughout pregnancy, and 407 completed the Child Behavior Checklist at child's age 3.7 years (SD = 0.75 year). DNA methylation (DNAm) GA of fetal cord blood DNA was based on the methylation profile of 148 selected cytosine linked to guanine by phosphate (CpG) sites. Epigenetic GA was calculated as the arithmetic difference between DNAm GA and chronological GA and adjusted for chronological GA. RESULTS: Maternal history of depression diagnosed before pregnancy (mean difference = 0.25 SD units, 95% CI = -0.46 to -0.03) and greater antenatal depressive symptoms (-0.08 SD unit per 1-SD unit increase, 95% CI = -0.16 to -0.004) were associated with child's lower epigenetic GA. Child's lower epigenetic GA, in turn, prospectively predicted total and internalizing problems and partially mediated the effects of maternal antenatal depression on internalizing problems in boys. CONCLUSION: Maternal antenatal depression is associated with lower epigenetic GA in offspring. This lower epigenetic GA seems to be associated with a developmental disadvantage for boys, who, in early childhood, show greater psychiatric problems. PMID- 29706162 TI - Course of Disinhibited Social Engagement Disorder From Early Childhood to Early Adolescence. AB - OBJECTIVE: Disinhibited social engagement disorder (DSED) is poorly understood beyond early childhood. The course of DSED signs in a sample of children who experienced severe, early deprivation from early childhood to early adolescence was examined using variable-centered (linear mixed modeling) and person-centered (growth mixture modeling) approaches. METHOD: The study included 124 children with a history of institutional care from a randomized controlled trial of foster care as an alternative to institutional care and 69 community comparison children matched by age and sex. DSED signs were assessed at baseline (mean age 22 months), 30, 42, and 54 months of age, and 8 and 12 years of age using a validated caregiver report of disturbed attachment behavior. RESULTS: Variable centered analyses based on intent-to-treat groups indicated that signs of DSED decreased sharply for children randomized to foster care and decreased slightly but remained high for children randomized to care as usual. Person-centered analyses showed 4 profiles (i.e., elevated, persistent modest, early decreasing, and minimal). Elevated and persistent modest courses were associated with greater placement disruptions (F3,99 = 4.29, p = .007, partial eta-squared [eta2] = 0.12), older age at placement into foster care (F3,56 = 3.41, p < .05, partial eta2 = 0.16), and more time in institutional care (F3,115 = 11.91, p < .001, partial eta2 = 0.24) compared with decreasing and minimal courses. CONCLUSION: Early and sustained placement into families after deprivation is associated with minimal or decreasing signs of DSED across development. Shortening the amount of time children spend in institutions and preserving placements could help decrease signs of DSED into early adolescence in previously institutionalized children. PMID- 29706164 TI - Has the Prevalence of Child and Adolescent Mental Disorders in Australia Changed Between 1998 and 2013 to 2014? AB - OBJECTIVE: This study examined whether the 12-month prevalence of major depressive disorder (MDD), attention-deficit/hyperactivity disorder (ADHD), and conduct disorder (CD) among 6- to 17-year-olds in Australia changed between 1998 and 2013 to 2014. It also investigated whether changes in the prevalence of disorders over this time varied for children living in families containing 2 parents versus single parents, and families with high versus low income. METHOD: The study used data from national surveys conducted in Australia in 1998 (N = 3,597) and 2013 to 2014 (N = 5,359). In both surveys, the participating individuals were randomly selected from all 6- to 17-year-olds in Australia, and mental disorders were assessed using the Diagnostic Interview Schedule for Children Version IV (DISC-IV), completed by parents. RESULTS: There was little change in the overall prevalence of mental disorders between 1998 (12.5%, 95% CI = 11.4-13.7) and 2013 to 2014 (11.1%, 95% CI = 10.1-12.2). Although there were some differences in the changes for children with different disorders, most were small in magnitude. Specifically, MDD prevalence increased from 2.1% (95% CI = 1.7-2.7) to 3.2% (95% CI = 2.7-3.8), ADHD prevalence declined from 9.9% (95% CI = 8.9-10.9) to 7.8% (95% CI = 6.9-8.7), and CD prevalence declined from 2.7% (95% CI = 2.2-3.3) to 2.1% (95% CI = 1.7-2.7). There was a persisting pattern of higher prevalence among children living in single-parent and low-income households. CONCLUSION: Lack of change at a population level in the prevalence of child mental disorders suggests that new innovations in research, policy, and practice are needed to successfully address the major public health problem posed by child and adolescent mental disorders in the community. PMID- 29706163 TI - Irritability Trajectories, Cortical Thickness, and Clinical Outcomes in a Sample Enriched for Preschool Depression. AB - OBJECTIVE: Cross-sectional, longitudinal, and genetic associations exist between irritability and depression. Prior studies have examined developmental trajectories of irritability, clinical outcomes, and associations with child and familial depression. However, studies have not integrated neurobiological measures. The present study examined developmental trajectories of irritability, clinical outcomes, and cortical structure among preschoolers oversampled for depressive symptoms. METHOD: Beginning at 3 to 5 years old, a sample of 271 children enriched for early depressive symptoms were assessed longitudinally by clinical interview. Latent class mixture models identified trajectories of irritability severity. Risk factors, clinical outcomes, and cortical thickness were compared across trajectory classes. Cortical thickness measures were extracted from 3 waves of magnetic resonance imaging at 7 to 12 years of age. RESULTS: Three trajectory classes were identified among these youth: 53.50% of children exhibited elevated irritability during preschool that decreased longitudinally, 30.26% exhibited consistently low irritability, and 16.24% exhibited consistently elevated irritability. Compared with other classes, the elevated irritability class exhibited higher rates of maternal depression, early life adversity, later psychiatric diagnoses, and functional impairment. Further, elevated baseline irritability predicted later depression beyond adversity and personal and maternal depression history. The elevated irritability class exhibited a thicker cortex in the left superior frontal and temporal gyri and the right inferior parietal lobule. CONCLUSION: Irritability manifested with specific developmental trajectories in this sample enriched for early depression. Persistently elevated irritability predicted poor psychiatric outcomes, higher risk for later depression, and decreased overall function later in development. Greater frontal, temporal, and parietal cortical thickness also was found, providing neural correlates of this risk trajectory. PMID- 29706165 TI - What Happens to Children Whose Parents Commit Suicide? AB - Suicide remains one of the leading causes of death among 25- to 49-year-olds in the United States, and each year roughly 30,000 children are victims of parental suicide in the United States (Center for Disease Control and Prevention, 2005).1 We report a case of a young child who lost both of his parents to suicide. PMID- 29706166 TI - Clinical Relevance Versus Statistical Significance: Aman and Colleagues Respond to Editorial. AB - We would like to respond to the thought-provoking editorial by Dr. Jon McClellan1 regarding our article "Clinical Implications from the Treatment of Severe Childhood Aggression (TOSCA) Study: A Re-Analysis and Integration of Findings," published in the December 2017 issue of JAACAP.2 We address some issues on which we partially disagree, and comment on convergence of opinion. PMID- 29706167 TI - Clinical Relevance Versus Statistical Significance: DelBello and Colleagues Respond to Editorial. AB - We would like to respond to some concerns raised by Dr. McClellan in his editorial comment1 on our article that reported the results of a placebo controlled study of lurasidone for the treatment of children and adolescents with bipolar I depression.2. PMID- 29706168 TI - March, April, Maybe a Video Game or Two? PMID- 29706169 TI - A pilot trial of text-delivered peer network counseling to treat young adults with cannabis use disorder. AB - Approximately 1.8 million young adults aged 18 to 25 had a Cannabis Use Disorder (CUD) in the past year. Unfortunately, engaging young adults in treatment is very challenging. Creative approaches to treat cannabis disorders such as integrating mobile technology with evidence-based treatments are warranted. In light of these challenges, we developed a text message-delivered version of Peer Network Counseling (PNC-txt), which is a substance use intervention that focuses on peer relations. PNC-txt engages participants in 16 automated, personalized text interactions over 4weeks. We conducted a randomized controlled trial to test the efficacy of PNC-txt against a waitlist control group with 30 treatment seeking young adults (ages 18-25) who met DSM-5 criteria for CUD. Self-report and urine analyses were used to test outcomes at the three-month follow-up. The PNC-txt group significantly reduced their cannabis use related problems as well as cannabis cravings, compared to the control group. PNC-txt participants also had a significantly greater percentage with urines negative for cannabis metabolites compared to controls. Moderation analysis showed that CUD severity level moderated treatment, suggesting that PNC-txt is more effective for participants with medium and high levels of CUD severity. All effect sizes ranged from medium to large. Results from this pilot trial are promising and warrant further research on PNC-txt for addressing cannabis use disorder. PMID- 29706170 TI - A randomized clinical trial of motivational enhancement therapy for alcohol problems in partner violent men. AB - This study examined the efficacy of brief alcohol intervention in the context of community-based treatment for partner violence. In a randomized clinical trial, 228 partner-violent men with hazardous or problem drinking were recruited at three Intimate Partner Violence (IPV) treatment agencies and randomly assigned to receive one of two 4-session alcohol interventions: Motivational Enhancement Therapy (MET: N = 110) or Alcohol Education (AE: N = 118). After completing alcohol intervention, participants received standard agency counseling services for IPV. Participants completed assessments of alcohol use, drug use, and IPV at pre-treatment, post-alcohol intervention, and quarterly follow-ups for 12 months. At the end of the 4-session alcohol intervention, MET participants displayed greater acknowledgment of problems with alcohol than AE participants (Partial eta2 = 0.039, p = 0.006). Significant changes from baseline across treatment conditions (at p < 0.001) were observed for percent days of alcohol abstinence [95% empirical CI for Partial eta2 =0.226, 0.296], heavy drinking [0.292, 0.349], illicit drug use [0.096, 0.156] and partner violence [0.282, 0.334]. No significant condition differences (treatment by time interactions) were found for alcohol abstinence [95% empirical CI for Partial eta2 = 0.007, 0.036], heavy drinking [0.016, 0.055], illicit drug use [0.005, 0.035] or partner violence [0.001, 0.004]. Results encourage continued use of brief alcohol interventions in community IPV services, but do not provide evidence of a unique benefit of MET in reducing alcohol use in this population. PMID- 29706171 TI - Who attends recovery high schools after substance use treatment? A descriptive analysis of school aged youth. AB - Recovery high schools (RHSs) are an alternative high school option for adolescents with substance use disorders (SUDs), designed to provide a recovery focused learning environment. The aims of this study were to examine the characteristics of youth who choose to attend RHSs, and to compare them with local and national comparison samples of youth in recovery from SUDs who were not enrolled in RHSs. We conducted secondary analysis of existing data to compare characteristics of youth in three samples: (1) adolescents with SUDs who enrolled in RHSs in Minnesota, Texas, and Wisconsin after discharge from treatment (RHSs; n = 171, 51% male, 86% White, 4% African American, 5% Hispanic); (2) a contemporaneously recruited local comparison sample of students with SUDs who did not enroll in RHSs (n = 123, 60% male, 77% White, 5% African American, 12% Hispanic); and (3) a national comparison sample of U.S. adolescents receiving SUD treatment (n = 12,967, 73% male, 37% White, 15% African American, 30% Hispanic). Students enrolled in RHSs had elevated levels of risk factors for substance use and relapse relative to both the local and national comparison samples. For instance, RHS students reported higher rates of pre-treatment drug use, past mental health treatment, and higher rates of post-treatment physical health problems than adolescents in the national comparison sample. We conclude that RHSs serve a population with greater co-occurring problem severity than the typical adolescent in SUD treatment; programming offered at RHSs should attend to these complex patterns of risk factors. SUD service delivery policy should consider RHSs as an intensive recovery support model for the most high-risk students with SUDs. PMID- 29706172 TI - Effects of medication assisted treatment (MAT) for opioid use disorder on functional outcomes: A systematic review. AB - This systematic review synthesizes evidence on the effects of Medication-Assisted Treatment (MAT) for opioid use disorder (OUD) on functional outcomes, including cognitive (e.g., memory), physical (e.g., fatigue), occupational (e.g., return to work), social/behavioral (e.g., criminal activity), and neurological (e.g., balance) function. Five databases were searched from inception to July 2017 to identify English-language controlled trials, case control studies, and cohort comparisons of one or more groups; cross-sectional studies were excluded. Two independent reviewers screened identified literature, abstracted study-level information, and assessed the quality of included studies. Meta-analyses used the Hartung-Knapp method for random-effects models. The quality of evidence was assessed using the GRADE approach. A comprehensive search followed by 1411 full text publication screenings yielded 30 randomized controlled trials (RCTs) and 10 observational studies meeting inclusion criteria. The studies reported highly diverse functional outcome measures. Only one RCT was rated as high quality, but several methodologically sound observational studies were identified. The statistical power to detect differences in functional outcomes was unclear in most studies. When compared with matched "healthy" controls with no history of substance use disorder (SUD), in two studies MAT patients had significantly poorer working memory and cognitive speed. One study found MAT patients scored worse in aggressive responding than did "healthy" controls. A large observational study found that MAT users had twice the odds of involvement in an injurious traffic accident as non-users. When compared with persons with OUD not on MAT, one cohort study found lower fatigue rates among buprenorphine-treated OUD patients. No differences were reported for occupational outcomes and results for criminal activity and other social/behavioral areas were mixed. There were few differences among MAT drug types. A pooled analysis of three RCTs found a significantly lower prevalence of fatigue with buprenorphine compared to methadone, while a meta-analysis of the same RCTs found no statistical difference in insomnia prevalence. Three RCTs that focused on cognitive function compared the effects of buprenorphine to methadone; no statistically significant differences in memory, cognitive speed and flexibility, attention, or vision were reported. The quality of evidence for most functional outcomes was rated low or very low. In sum, weaknesses in the body of evidence prevent strong conclusions about the effects of MAT for opioid use disorder on functional outcomes. Rigorous studies of functional effects would strengthen the body of literature. PMID- 29706174 TI - The long-term impact of post traumatic stress disorder on recovery from heroin dependence. AB - The high prevalence of post traumatic stress disorder (PTSD) among people with heroin dependence and its impact on short term outcomes has been well established. The impact of PTSD on long-term recovery is, however, unknown. This paper examines the impact of current and lifetime PTSD on long-term recovery from heroin dependence among participants who took part in the 11-year follow-up of the Australian Treatment Outcome Study (ATOS), a prospective naturalistic longitudinal study of 615 people with heroin dependence recruited from Sydney, Australia, in 2001-2002. Seventy-one percent of the cohort (n = 431) were re interviewed 11-years post study entry. Outcomes examined included heroin and other drug use, dependence, general physical and mental health, depression, PTSD, employment, and the incidence of trauma exposure, overdose, imprisonment, and attempted suicide over the 11- year follow-up. Despite having a poorer profile at baseline, individuals with current PTSD or a history of PTSD at baseline demonstrated similar levels of improvement to those without a history of PTSD in all outcome domains across the 11-year follow-up, PTSD was associated with consistently higher levels of major depression, and attempted suicide, subsequent trauma exposure, and poorer occupational functioning across the 11-year follow up. These findings highlight the importance of interventions aimed at occupational rehabilitation, reducing the likelihood of retraumatisation, and addressing PTSD and associated comorbidities among people with heroin dependence. PMID- 29706173 TI - Parenting outcomes of parenting interventions in integrated substance-use treatment programs: A systematic review. AB - The high prevalence of women in substance use treatment programs with children, and the co-occurring negative physical and mental health outcomes associated with substance use, led to the development of integrated substance use treatment programs that target a range of women-specific issues. Integrated programs typically offer some type of parenting component, although the level of parenting services varies widely. Existing reviews have found positive child and parent outcomes following integrated treatment programs in general, although studies were not selected on the basis of whether they included parenting interventions. Due to the large percentage of substance using parents and research that parenting interventions contribute to decreased maternal substance use, this critical review examines parental outcomes of published studies on integrated programs that specifically include a parenting intervention component, as well as moderators of parenting and parental substance use/relapse. Across the 15 studies identified, this systematic review primarily focused on 8 parenting outcomes, including program retention, substance use, parenting stress, psychosocial adjustment, depression, child abuse potential, parenting behaviors, and parent child interaction; as well as 5 additional secondary outcomes. The review discusses results on each of these outcomes, as well as retention rates across the parenting interventions. PMID- 29706175 TI - Trends and disparities in receipt of pharmacotherapy among pregnant women in publically funded treatment programs for opioid use disorder in the United States. AB - OBJECTIVE: To describe differences in geographic, demographic, treatment, and substance use characteristics by pharmacotherapy receipt among pregnant women entering publically funded treatment for opioid use disorder (OUD) in the United States. METHODS: 1996 to 2014 Treatment Episode Data Set-Admissions data from pregnant admissions with OUD, defined as reporting opioids as the primary substance of use leading to the treatment episode, were analyzed for this cross sectional study. The proportion of all pregnant admissions with OUD who received pharmacotherapy was calculated by year and U.S. census region. Trends across time were assessed using the Cochrane-Armitage Trend test. Associations between demographic, substance use, and treatment characteristics and pharmacotherapy receipt were assessed using Chi-square tests and multivariable logistic regression. RESULTS: The proportion of pregnant admissions where opioids were the primary substance of use increased from 16.9% to 41.6% during the study period, while the proportion of pregnant admissions with OUD who received pharmacotherapy remained relatively unchanged at around 50%. Overall, pharmacotherapy recipients were generally older and white, more likely to receive treatment in an outpatient setting, be self-referred, and report heroin as the primary substance, daily substance use, and intravenous drug use, and less likely to have a co-occurring psychiatric problem compared to those who did not receive pharmacotherapy. Regional differences in pharmacotherapy utilization exist; the South consistently had the fewest pregnant admissions with OUD receiving pharmacotherapy. CONCLUSION: Although the proportion of pregnant admissions to substance use treatment centers with OUD has increased since the mid-1990s, the proportion receiving pharmacotherapy has not changed. Significant variations in pharmacotherapy utilization exist by geography and demographic, substance use and treatment characteristics. Utilization of pharmacotherapy at publically funded treatment centers providing care for pregnant women with OUD should be expanded. PMID- 29706177 TI - It's raining MEN: Putting order to multiple endocrine neoplasms. PMID- 29706176 TI - State variations in Medicaid enrollment and utilization of substance use services: Results from a National Longitudinal Study. AB - Medicaid enrollment varies considerably among states. This study examined the association of Medicaid enrollment with the use of substance health services in the longitudinal National Epidemiologic Survey on Alcohol and Related Conditions of 2001-2005. Instrumental variable methods were used to assess endogeneity of individual-level Medicaid enrollment using state-level data as instruments. Compared to the uninsured, Medicaid covered adults were more likely to use substance use disorder treatment services over the next three years. States that have opted to expand Medicaid enrollment under the Affordable Care Act will likely experience further increases in the use of these service over the coming years. PMID- 29706178 TI - Antipsychotic Polypharmacy: State of the Science and Guidelines for Practice. It's difficult to stop once you start. PMID- 29706179 TI - How Can You Have a Myocardial Infarction Without Significant Coronary Artery Disease? PMID- 29706180 TI - Atrial Fibrillation, an Under-Appreciated Reversible Cause of Cardiomyopathy: Implications for Clinical Practice From the CAMERA-MRI Study. PMID- 29706181 TI - Veno-Arterial ECMO in the Setting of Post-Infarct Ventricular Septal Defect: A Bridge to Surgical Repair. PMID- 29706182 TI - Prognostic Impact of Calcium Score after Transcatheter Aortic Valve Implantation Performed With New Generation Prosthesis. AB - Calcium score (CS) is a well-known prognostic factor after transcatheter aortic valve implantation (TAVI) performed with first generation prosthesis but few data are available concerning new generation valves. The aim of this study was to evaluate if CS remains a prognostic factor after Sapien 3 and Evolut R valves implantation. Agatston CS was evaluated on multislice computed tomography before TAVI in 346 patients implanted with Sapien XT (n = 61), CoreValve (n = 57) devices, (group 1, n = 118), and with new generation Sapien 3 (n = 147), Evolut R (n = 81) prosthesis, (group 2, n = 228). Major adverse cardiovascular events and aortic regurgitation (AR) were evaluated at 1 month. The 2 groups were similar at baseline except for logistic Euroscore (20.1% in group 1 vs 15.0 % in group 2; p = 0.001), chronic renal failure (44.1% vs 37.2% respectively, p = 0.007) and preprocedural CS (4,092 +/- 2,176 vs 3,682 +/- 2,109 respectively, p = 0.022). In group 1, 28 patients (23.7%) had adverse clinical events vs 21 (9.2%) in group 2 (p <0.01). In multivariate analysis, a higher CS was predictive of adverse events in group 1 (5,785 +/- 3,285 vs 3,565 +/- 1,331 p <0.0001) but not in group 2 (p = 0.28). A higher CS was associated with AR in group 1 (6,234 +/- 2711 vs 3,429 +/- 1,505; p <0.001) and in patients implanted with an Evolut R device from group 2 (4,085 +/- 3,645 vs 2,551 +/- 1,356; p = 0.01). In conclusion, CS appears as an important prognostic factor of major events after TAVI with first generation valves but not with new generation devices. CS remains associated with AR only with new generation self-expandable Evolut R devices. PMID- 29706183 TI - Beneficial effects of anti-EGFR agents, Cetuximab or Nimotuzumab, in combination with concurrent chemoradiotherapy in advanced nasopharyngeal carcinoma. AB - OBJECTIVE: This study aimed to evaluate the efficacy and safety in locoregionally advanced nasopharyngeal carcinoma (NPC) patients receiving concurrent chemoradiotherapy (CCRT) plus Cetuximab (CTX) or Nimotuzumab (NTZ) compared to those receiving induction chemotherapy (IC) plus CCRT. MATERIALS AND METHODS: From January 2008 to December 2013, 715 eligible patients were enrolled in the study. Using propensity scores to adjust for gender, age, Karnofsky performance status (KPS), tumor stage, node stage, and clinical stage, a well-balanced cohort was created by matching each patient who received CTX/NTZ plus CCRT (137 patients) with two patients who underwent IC plus CCRT (274 patients). The primary endpoint was overall survival (OS), and other outcome variables included disease-free survival (DFS), distant metastasis-free survival (DMFS) and loco regional relapse-free survival (LRRFS). RESULTS AND CONCLUSION: The median follow up was 57.0 months and 55.0 months for the CTX/NTZ plus CCRT group and IC plus CCRT group, respectively. No significant differences were found between the CTX/NTZ plus CCRT group and the IC plus CCRT group in 3-year OS (95.5% vs. 94.7%, P = 0.083), 3-year DFS (93.3% vs. 86.1%, P = 0.104), 3-year DMFS (96.2% vs. 92.5%, P = 0.243) and 3-year LRRFS (97.0% vs. 95.1%, P = 0.297). Patients undergoing IC plus CCRT suffered from severe hematologic toxicity and diarrhea compared with those treated with CTX/NTZ plus CCRT. The combination of CTX/NTZ with CCRT is comparable to IC plus CCRT treatment in survival outcomes for locoregionally advanced NPC patients but has a better safety profile than IC plus CCRT treatment. PMID- 29706184 TI - Definitive chemoradiation for locally-advanced oral cavity cancer: A 20-year experience. AB - OBJECTIVES: Definitive chemoradiation (CRT) for oral cavity squamous cell carcinoma (OC-SCC) is often criticized for poor efficacy or toxicity. We describe a favorable 20-year experience of primary CRT for locally-advanced OC-SCC. MATERIALS AND METHODS: Patients with locally-advanced, stage III/IV OC-SCC receiving primary concomitant CRT on protocols from 1994 to 2014 were analyzed. Chemotherapy included fluorouracil and hydroxyurea with other third agents. Radiotherapy (RT) was delivered once or twice daily to a maximum dose of 70-75 Gy. Intensity-modulated RT (IMRT) was exclusively used after 2004. Progression free survival (PFS), overall survival (OS), locoregional control (LRC), and distant control (DC) were calculated by the Kaplan-Meier method and compared across treatment decades using the log-rank test. Rates of osteoradionecrosis (ORN) requiring surgery were compared across treatment decades using the Chi square test. RESULTS: 140 patients with locally-advanced OC-SCC were treated with definitive CRT. Of these, 75.7% had T3/T4 disease, 68.6% had >=N2 nodal disease, and 91.4% had stage IV disease. Most common primary sites were oral tongue (47.9%) and floor of mouth (24.3%). Median follow-up was 5.7 years. Five-year OS, PFS, LRC, and DC were 63.2%, 58.7%, 78.6%, and 87.2%, respectively. Rates of ORN and long-term feeding tube dependence were 20.7% and 10.0%, respectively. Differences in LRC (P = 0.90), DC (P = 0.24), PFS (P = 0.38), OS (P = 0.10), or ORN (P = 0.38) were not significant across treatment decades. CONCLUSION: Definitive CRT is a viable and feasible strategy for organ preservation for patients with locally-advanced OC-SCC. PMID- 29706185 TI - Hypoxia induced EMT: A review on the mechanism of tumor progression and metastasis in OSCC. AB - Hypoxia, a condition of low oxygen tension in tissues, has emerged as a crucial factor in tumor pathophysiology. Hypoxic microenvironment gives rise to altered cellular metabolism and triggers varied molecular responses. These responses promote tumor progression and confer radiation resistance and chemo resistance to tumors. The predominant molecules that are associated with hypoxia research are the hypoxia inducible factors (HIFs). HIFs are known to regulate a large group of genes that are involved in cell survival, proliferation, motility, metabolism, pH regulation, extracellular matrix function, inflammatory cell recruitment and angiogenesis by inducing the expression of their downstream target genes. The process of epithelial to mesenchymal transition (EMT) has been associated with metastasis in cancer. Reports also suggest that hypoxia triggers EMT in several types of cancer including breast cancer, prostate cancer and oral cancer. Oral cancer is a predominant cancer in Central and South East Asia. However, in the recent times, the incidence rates of oral cancer have been increasing in Northern and Eastern Europe as well. This review articulates the role of hypoxia and the associated factors like HIFs in inducing EMT in oral cancer (OSCC). PMID- 29706186 TI - Data-Driven prioritisation of antibody-drug conjugate targets in head and neck squamous cell carcinoma. AB - BACKGROUND: For patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) palliative treatment options that improve overall survival are limited. The prognosis in this group remains poor and there is an unmet need for new therapeutic options. An emerging class of therapeutics, targeting tumor specific antigens, are antibodies bound to a cytotoxic agent, known as antibody drug conjugates (ADCs). The aim of this study was to prioritize ADC targets in HNSCC. METHODS: With a systematic search, we identified 55 different ADC targets currently targeted by registered ADCs and ADCs under clinical evaluation. For these 55 ADC targets, protein overexpression was predicted in a dataset containing 344 HNSCC mRNA expression profiles by using a method called functional genomic mRNA profiling. The ADC target with the highest predicted overexpression was validated by performing immunohistochemistry (IHC) on an independent tissue microarray containing 414 HNSCC tumors. RESULTS: The predicted top 5 overexpressed ADC targets in HNSCC were: glycoprotein nmb (GPNMB), SLIT and NTRK like family member 6, epidermal growth factor receptor, CD74 and CD44. IHC validation showed combined cytoplasmic and membranous GPNMB protein expression in 92.0% of the cases. Strong expression was seen in 65.9% of the cases. In addition, 86.5% and 67.7% of cases showed >=5% and >25% GPNMB positive tumor cells, respectively. CONCLUSIONS: This study provides a data-driven prioritization of ADCs targets that will facilitate clinicians and drug developers in deciding which ADC should be taken for further clinical evaluation in HNSCC. This might help to improve disease outcome of HNSCC patients. PMID- 29706187 TI - Locally advanced squamous cell carcinoma of the head and neck: A systematic review and Bayesian network meta-analysis of the currently available treatment options. AB - BACKGROUND: There are still many unresolved questions in the management of locally advanced Head and Neck Cancer (HNC). Many chemotherapeutic drugs and radiotherapy fractionation schemes are available and not all have been evaluated in head-to-head clinical trials. This systematic review and Bayesian network meta analysis aims to compare the available treatment strategies and chemotherapeutic options for locally advanced HNC. METHODS: We performed a search on bibliography databases, trials registries and meetings proceedings for published and unpublished randomized trials from January 1st 2000 to December 1st 2017. Trials had to compare systemic interventions and radiotherapy (RT) approaches for locally advanced, non-metastatic HNC. Trials recruiting patients whose surgery was the first treatment option, sample size less than 20 per arm or that did not use randomization for treatment allocation were excluded from the analysis. Summary estimates on Overall survival (OS), Progression-free survival (PFS) and toxicity outcomes (grade 3-4 mucositis and neutropenia) were extracted from the included studies on a predefined database sheet. Bias was assessed through the Chocrane risk of bias assessment tool. We performed a set of pair-wise meta analyses using a random effect model. We also performed a random effect network meta-analysis under a Bayesian framework. FINDINGS: From the 57 included trials, including 15,723 patients, was possible to conduct analysis on 26 treatments for OS, 22 treatments for PFS and 10 treatments for toxicity. In terms of OS Concurrent chemoradiotherapy (CCRT) with cisplatin (HR 0.70, 95% CrI [credible interval] 0.62-0.78) and cetuximab on top of CCRT (HR 0.7, 95% CrI 0.5-0.97) are clearly superior to conventional RT alone. Induction chemotherapy (IC) with cisplatin and fluorouracil (HR 0.74, 95% CrI 0.52-0.95), IC with docetaxel, cisplatin, fluorouracil (HR 0.55, 95% CrI 0.54-0.89) and IC with paclitaxel, cisplatin, fluorouracil (HR 0.55, 95% CrI 0.34-0.89) before CCRT are all superior to conventional RT. CCRT with cisplatin is also superior to altered fractionation RT (HR 0.74, 95% CrI 0.64-0.84). Altered fractionation RT is not superior to conventional RT (HR 0.95, 95% CrI 0.85-1.06). Regarding PFS, CCRT with cisplatin (HR 0.72, 95% CrI 0.63-0.83), cisplatin and fluorouracil (HR 0.67, 95% CrI 0.5 0.88), carboplatin (HR 0.63, 95% CrI 0.46-0.87), carboplatin and fluorouracil (HR 0.75, 95% CrI 0.56-1), IC with cisplatin and fluorouracil (HR 0.59, 95% CrI 0.45 0.78), IC with docetaxel, cisplatin and fluorouracil (HR 0.53, 95% CrI 0.41-0.68) and IC with paclitaxel, cisplatin and fluorouracil (HR 0.59, 95% CrI 0.35-0.99) are superior to conventional RT and altered fractionation RT. IC with docetaxel, cisplatin and fluorouracil shows a significant superiority against CCRT with cisplatin (HR 0.73 95% CrI 0.58-0.92). Altered fractionation RT is not superior to conventional RT (HR 0.91, 95% CrI 0.81-1.02). Altered fractionation increases the risk of developing grade 3-4 mucositis compared to conventional RT (OR 3.74 95% 1.64-8.67) INTERPRETATION: CCRT with cisplatin remains the gold standard of treatment. Taxane based IC regimens may have a impact on locally advanced disease. Altered fractionation RT is inferior to CCRT and also does not seem to be meaningfully better than conventionally fractionated RT alone. Its role in locally advanced disease should be reevaluated. PMID- 29706188 TI - Patients with integrated HPV16 in head and neck cancer show poor survival. AB - OBJECTIVES: We previously reported identifying three categories of HPV16-positive head and neck tumors based on The Cancer Genome Atlas (TCGA) RNA and DNA sequence data. Category 1 had truly integrated HPV16 genomes, category 2 had simple episomal genomes, and category 3 had novel episomes that were a hybrid between viral and human DNA. Using our categorization, we investigated in this study survival of patients with integrated HPV16 tumors versus patients with episomal HPV16 tumors. MATERIALS AND METHODS: The TCGA RNA-Seq sequence reads were used to quantify HPV E2 and E7 gene expression, which was used as a marker for HPV integration. RESULTS: The results demonstrate that integration is associated with poor survival; those patients with integrated HPV tumors fared no better than non HPV tumors in their five-year survival. Integrated HPV in tumors was found strikingly to be prevalent in patients born earlier while episomal HPV was prevalent in patients born later. We also observed a fairly constant incidence of all HPV forms among head and neck cancer patients over the last eight years of this study (2006-2013). CONCLUSION: We propose our characterization of HPV integrated and episomal state is more accurate than previous studies that may have mischaracterized the hybrid HPV-human DNA episomes as integrated. The state of integrated HPV is associated with a poor clinical outcome. Results suggest that the incidence of integrated HPV among all HPV forms peaked and is decreasing. We discuss the importance of our findings for the management of HPV positive head and neck cancer. PMID- 29706189 TI - Risk factors for salivary gland cancers in France: Results from a case-control study, the ICARE study. AB - OBJECTIVES: Epidemiological studies on the risk factors for salivary gland cancers (SGC) are rare, concern a small sample size, and show inconsistent results. The aim of the present work was to analyze several risk factors for SGC, using the data from the ICARE study, a multicenter, population-based case-control study. MATERIALS AND METHODS: Data from 73 SGC cases and 3555 controls were collected using a standardized questionnaire on lifestyle habits, personal and family medical history, and lifetime occupational history. Odds ratios (OR) and 95% confidence intervals (CI) were estimated using unconditional logistic regressions. RESULTS: Tobacco use and alcohol consumption were not associated with the risk of SGC. A history of head and neck cancer or that of cervicofacial radiotherapy was associated with a higher risk of SGC (OR = 17.06, 95% CI: 4.34 67.05, and OR = 31.74, 2.48-405.25, respectively). Significantly increased risks were observed for some occupations: waiter (OR = 2.94, 1.11-7.78), charworker (OR = 3.02, 1.38-6.60), electrical and electronic equipment assembler (OR = 7.16, 2.02-25.38), plumber (OR = 3.95, 1.33-11.67), electric arc welder (OR = 6.15, 1.76-21.48), sheet-metal worker (OR = 2.89, 1.01-8.32), building painter (OR = 3.42, 1.01-11.49), and material handling equipment operator (OR = 5.05, 1.71 14.84). Results for industries were consistent with those observed for occupations. CONCLUSION: Our results showed that a history of head and neck cancer, cervicofacial radiotherapy, and several occupations and industries, were associated with an increased risk of SGC. Further studies with larger sample sizes are indicated to confirm our results. PMID- 29706190 TI - Hypoxia modulates CCR7 expression in head and neck cancers. AB - BACKGROUND: The chemokine receptor CCR7 is expressed on lymphocytes and dendritic cells and is responsible for trafficking of these cells in and out of secondary lymphoid organs. It has recently been shown that CCR7 expression is elevated in a number of cancers, including head and neck cancers, and that its expression correlates to lymph node (LN) metastasis. However, little is known about the factors that can induce CCR7 expression in head and neck cancers. METHOD: We compared the protein expression and functional responses of CCR7 under normoxia and hypoxia in head and neck cancer cell lines OSC-19, FaDu, SCC-4, A-253 and Detroit-562 cultured as monolayers, spheroids, and grown in vivo as xenografts in balb/c mice. In addition, we analysed the correlation between hypoxia marker HIF 1alpha and CCR7 expression in a tissue microarray comprising 80 clinical samples with various stages and grades of malignant tumour and normal tissue. RESULTS: Under hypoxia, the expression of CCR7 is elevated in both in vitro and in vivo models. Furthermore, in malignant tissue, a correlation is observed between hypoxia marker HIF-1alpha and CCR7 across all clinical stages. This correlation is also strong in early histological grade of tumours. CONCLUSION: Hypoxia plays a role in the regulation of the expression of CCR7 and it may contribute to the development of a metastatic phenotype in head and neck cancers through this axis. PMID- 29706191 TI - Multi-criteria optimization achieves superior normal tissue sparing in intensity modulated radiation therapy for oropharyngeal cancer patients. AB - OBJECTIVES: To evaluate the benefit of intensity-modulated radiation therapy (IMRT) with multi-criteria optimization (MCO) in patients with oropharyngeal cancer (OPC) and compare the dose difference between the MCO plans navigated by physicians and dosimetrists. MATERIALS AND METHODS: The conventional IMRT plans (nonMCO) and MCO IMRT plans navigated by physicians and dosimetrists (MCOp and MCOd) were created for 30patients with OPC. All the plans were reviewed, and the planning time and dose-volume parameters were compared. RESULTS: The difference of D95 among three kinds of plans was not significant (p > 0.05). The maximum dose and D2 of spinal cord, brain stem, the mean dose of bilateral parotids, cochlea, oral cavity and glottic larynx were lower in MCO plans than those in nonMCO plans (p < 0.017). Furthermore, MCOp showed better bilateral parotids, oral cavity and glottic larynx sparing compared to MCOd (p < 0.017), in which the magnitude was related to the overlapping volume of the corresponding organ at risk (OAR) and targets. The active planning time was reduced by a median of 94.3 min (MCOd vs. nonMCO) or 91.6 min (MCOp vs. nonMCO). CONCLUSION: MCO IMRT plans significantly reduced the dose of OARs and the active planning time, without compromising the target coverage in OPC patients; navigations by physicians could be beneficial to the dose sparing of the OARs with high complication rate and those overlapping with targets; the constraints could be the predominant factor affecting the results of optimization in the MCO IMRT planning. PMID- 29706193 TI - Utility of PET-CT in detecting nodal metastasis in cN0 early stage oral cavity squamous cell carcinoma. AB - BACKGROUND: Management of the clinically node-negative neck (cN0) in patients with early stage oral cavity squamous cell carcinoma (OCSCC) is challenging. Accurate imaging alternatives to elective neck dissections would help reduce surgical morbidity. While pooled studies suggest that imaging modalities have similar accuracy in predicting occult nodal disease, no study has examined the utility of PET-CT in this specific population of low-volume, clinically T1 and T2 OCSCC patients. METHODS: A retrospective review of patients in the Alberta Cancer Registry who were diagnosed with cT1 or T2N0M0 OCSCC who underwent elective unilateral or bilateral neck dissections was performed. Pre-operative PET-CT and CT necks were reviewed for number of radiographically suspicious lymph nodes. Surgical pathology reports were reviewed to obtain the total number of nodes sampled and number of malignant nodes. RESULTS: Between 2009 and 2013, 148 patients were diagnosed with cT1 or T2N0M0 OCSCC. Of these, 96 patients underwent elective neck dissections. All patients underwent preoperative CT of the neck with 32 patients having undergone additional preoperative PET-CT. Based on finally surgical pathology, the overall rate of occult metastasis was 13.5% (13/96). The overall sensitivity and specificity of PET-CT in this cohort was 21.4% and 98.4%, respectively with a negative predictive value of 99.1%. Although sensitivity improved in patients with tumors >=2 cm and depth >=4 mm, specificity remained unchanged. CONCLUSION: In patients with cT1 and T2N0 OCSCC, PET-CT has high negative predictive value. These patients can be considered for treatment with single modality surgical resection and elective neck dissection. PMID- 29706192 TI - A predictive model for recurrence in patients with glottic cancer implemented in a mobile application for Android. AB - OBJECTIVES: The existing predictive models of laryngeal cancer recurrence present limitations for clinical practice. Therefore, we constructed, internally validated and implemented in a mobile application (Android) a new model based on a points system taking into account the internationally recommended statistical methodology. MATERIALS AND METHODS: This longitudinal prospective study included 189 patients with glottic cancer in 2004-2016 in a Spanish region. The main variable was time-to-recurrence, and its potential predictors were: age, gender, TNM classification, stage, smoking, alcohol consumption, and histology. A points system was developed to predict five-year risk of recurrence based on a Cox model. This was validated internally by bootstrapping, determining discrimination (C-statistics) and calibration (smooth curves). RESULTS: A total of 77 patients presented recurrence (40.7%) in a mean follow-up period of 3.4 +/- 3.0 years. The factors in the model were: age, lymph node stage, alcohol consumption and stage. Discrimination and calibration were satisfactory. CONCLUSION: A points system was developed to obtain the probability of recurrence of laryngeal glottic cancer in five years, using five clinical variables. Our system should be validated externally in other geographical areas. PMID- 29706194 TI - The risk of carotid stenosis in head and neck cancer patients after radiation therapy. AB - OBJECTIVES: Head and neck radiotherapy (RT) is a risk factor for cerebrovascular disease. We performed a retrospective cohort study to evaluate carotid artery stenosis (CAS) incidence in head and neck cancer (HNC) patients undergoing RT, characterizing associated risk factors. MATERIALS AND METHODS: Records were retrospectively reviewed for HNC patients undergoing carotid ultrasound screening after definitive or adjuvant RT between January 2000 and May 2016. CAS was defined as >=50% stenosis on imaging, stroke, or transient ischemic attack. Actuarial CAS rates were calculated by Kaplan-Meier method. Univariate and multivariate analyses predicted CAS risk based on carotid dosimetric and clinical parameters. RESULTS: 366 patients met inclusion criteria. Median time from RT completion to last follow-up was 4.1 yr. Actuarial risk for CAS was 29% (95% CI 22-36%) at 8 years. Univariate analysis showed that smoking (HR 1.7; 95% CI 1.1 2.7), hyperlipidemia (HR 1.6; 95% CI 1.03-2.6), diabetes (HR 2.8; 95% CI 1.6 4.8), coronary artery disease (HR 2.4; 95% CI 1.4-4.2), and peripheral artery disease (HR 3.6; 95% CI 1.1-11.6) were significantly associated with increased CAS. In multivariate analysis, diabetes was predictive of time to CAS (HR 1.9; 95% CI 1.1-3.4). Carotid dose parameters were not significantly associated with CAS. CONCLUSIONS: CAS incidence is high after head and neck radiotherapy, gradually rising over time. No clear dose-response effect between carotid dose and CAS was identified for HNC patients. Carotid artery screening and preventative strategies should be employed in this high-risk patient population. PMID- 29706195 TI - Listening, then managing: The role of the team in addressing pain in the upper limb. PMID- 29706196 TI - Peripheral nerve injuries, pain, and neuroplasticity. AB - INTRODUCTION: Peripheral nerve injuries (PNIs) cause both structural and functional brain changes that may be associated with significant sensorimotor abnormalities and pain. PURPOSE OF THE STUDY: The aim of this narrative review is to provide hand therapists an overview of PNI-induced neuroplasticity and to explain how the brain changes following PNI, repair, and during rehabilitation. METHODS: Toward this goal, we review key aspects of neuroplasticity and neuroimaging and discuss sensory testing techniques used to study neuroplasticity in PNI patients. RESULTS: We describe the specific brain changes that occur during the repair and recovery process of both traumatic (eg, transection) and nontraumatic (eg, compression) nerve injuries. We also explain how these changes contribute to common symptoms including hypoesthesia, hyperalgesia, cold sensitivity, and chronic neurogenic pain. In addition, we describe how maladaptive neuroplasticity as well as psychological and personality characteristics impacts treatment outcome. DISCUSSION AND CONCLUSION: Greater understanding of the brain's contribution to symptoms in recovering PNI patients could help guide rehabilitation strategies and inform the development of novel techniques to counteract these maladaptive brain changes and ultimately improve outcomes. PMID- 29706197 TI - Complex regional pain syndrome in distal radius fractures: How to implement changes to reduce incidence and facilitate early management. AB - STUDY DESIGN: Implementation paper. INTRODUCTION: Complex regional pain syndrome (CRPS) is relatively a common condition in the distal radius fracture (DRF) population with the effects resulting in many sufferers experiencing persistent pain and impairment 2 to 6 years after onset. Prevention is desirable as there is no known proven cure. PURPOSE OF THE STUDY: This study demonstrates how knowledge about CRPS and its prevention generated through iterative studies can be translated into practice in the workplace and how an interdisciplinary community of practice with therapists at the core can effect change. METHODS: A series of practice changes were introduced including a patient information leaflet, a local gold standard for care of DRF, education for staff regarding risk factors and early warning signs of CRPS, and simple patient and staff visual aids. RESULTS: The incidence of CRPS was reduced from 25% to 1% in the DRF population at the study site, and collaborative care pathways were ingrained onto the working culture. DISCUSSION: The process of learning together fostered the development of an interdisciplinary team with therapists acting as CRPS champions. Interdisciplinary team reflective practice facilitated simple but effective interventions, which reduced the incidence of CRPS in DRF population locally. It is not yet known whether this is transferable. CONCLUSIONS: Simple interventions can have a significant impact on the incidence of CRPS in a community of practice where a culture of team reflection and shared learning occurs. PMID- 29706198 TI - Evaluation of pain in pediatric upper extremity conditions. AB - STUDY DESIGN: Narrative Review. INTRODUCTION: Hand surgeons and therapists play an important role in the early identification of children at risk of developing chronic or recurrent pain after an upper extremity injury. Early identification of children at risk of developing a pain syndrome is critical because their physical, psychological, and/or social functioning may decline quickly without proper management due to the multidimensional nature of pain. PURPOSE OF THE STUDY: This article outlines one approach to evaluating upper extremity pain in children to help identify those with, or at risk of, chronic pain. METHODS: An assessment framework that recognizes the biological, sensory, emotional, and psychosocial components of pain is described. RESULTS: The key components of a screening evaluation include obtaining a detailed history and a thorough physical examination that involves: systematic upper extremity mapping of sensory thresholds, mapping of sensory disturbances, and screening of self-reported pain intensity, location, descriptors, and interference. DISCUSSION AND CONCLUSION: The evaluation approach described will enable hand therapists to identify children with upper extremity pain that are at risk of developing a chronic pain and make an early referral to a multidisciplinary pain team that provides education, pharmacological pain management, physical rehabilitation, and psychological treatments. PMID- 29706199 TI - Management of long-term complex regional pain syndrome with allodynia: A case report. AB - STUDY DESIGN: Case report. INTRODUCTION: Conventional rehabilitation alone may not be effective in reducing symptoms in some patients with complex regional pain syndrome. PURPOSE OF THE STUDY: This case report portrays the benefits of a new tailored rehabilitation program for a 39-year-old patient suffering from upper limb complex regional pain syndrome with severe touch-evoked pain (static mechanical allodynia). METHODS: This patient had previously received conventional rehabilitation for a year and a half including physical and nonsurgical medical interventions that did not improve symptoms or function. In the search for an alternative, this patient was referred to occupational therapy to try a tailored rehabilitation program, drawing on multiple strategies used sequentially according to the patient's tolerance and symptom evolution. During this 22-month program, the following methods were added (listed chronologically): somatosensory rehabilitation of pain method, graded motor imagery, pain management modalities, active mobilizations, strengthening exercises, and task simulation. The patient successively showed resolution of mechanical allodynia, decreased pain, reduction of tactile hypesthesia and improvement in active range of motion, strength, and function. These improvements allowed him to return to work. DISCUSSION: This suggests that a tailored rehabilitation program combining somatosensory rehabilitation of pain method, graded motor imagery and more conventional approaches could improve symptoms and functional status in patients with upper limb complex regional pain syndrome, even with persistent refractory symptoms. CONCLUSION: The addition of the somatosensory rehabilitation of pain method and the graded motor imagery approach to conventional therapy could be considered in cases of complex regional pain syndrome that do not respond to conventional rehabilitation alone. PMID- 29706200 TI - A client-centered approach for thumb carpometacarpal joint osteoarthritis pain: Two case studies. AB - DESIGN: Case study. INTRODUCTION: Hand therapists are often called upon to provide treatment for thumb carpometacarpal joint osteoarthritis. PURPOSE: These 2 case studies present a client-centered approach in the selection of orthoses and joint protection strategies for patients with thumb carpometacarpal joint osteoarthritis. At baseline, the participants presented with pain, decreased active range of motion, decreased pinch strength, and limitations in activity and participation. METHODS: The outcome measures utilized at study entry and 6 weeks included the pain Visual Analog Scale, the Australian Canadian Osteoarthritis Hand Index, the Disabilities of the Arm, Shoulder and Hand questionnaire, the Canadian Occupational Performance Measure, active range of motion measured with goniometry, and pinch strength measured with a pinch gauge. The Canadian Occupational Performance Measure facilitated the client-centered approach by identifying occupational performance issues and rating the participant's performance and satisfaction for each. Each participant was prescribed a different orthotic design, received client-centered joint protection instruction, and evidence-based exercises. RESULTS: After 6 weeks, both clients had decreased pain and improvement in their activities, participation, and satisfaction. DISCUSSION: Using a client-centered approach can help therapists to carefully consider a patient's occupational needs when designing and fabricating orthoses and customizing their joint protection education for carpometacarpal joint osteoarthritis. CONCLUSION: Focusing rehabilitation strategies on that which is most important to the client should be considered to optimize their occupational performance. PMID- 29706201 TI - Emotional see-saw affects rationality of decision-making: Evidence for metacognitive impairments. AB - This research investigated the cognitive mechanisms that underlie impairments in human reasoning triggered by the emotional see-saw technique. It has previously been stated that such manipulation is effective as it presumably induces a mindless state and cognitive deficits in compliant individuals. Based on the dual system architecture of reasoning (system 2) and affective decision-making (system 1), we challenged the previous theoretical account by indicating that the main source of compliance is impairment of the meta-reasoning system when rapid affective changes occur. To examine this hypothesis, we manipulated affective feelings (system 1 processing) by violating participants' expectations regarding reward and performance in a go/no-go task in which individuals were to inhibit their responses to earn money. Aside from the go/no-go performance, we measured rationality (meta-reasoning system 2) in decision-making by asking participants to comply with a nonsensical request. We found that participants who were exposed to meta-reasoning impairments due to the emotional see-saw phenomenon exhibited mindless behavior. PMID- 29706202 TI - Atrial Fibrillation Manifestations Risk Factors and Sex Differences in a Population-Based Cohort (From the Gutenberg Health Study). AB - Sex differences in cardiovascular risk factors, cardiac structure and function, and disease and symptom burden in the common arrhythmia atrial fibrillation (AF) have not been investigated systematically at the population level. Cross sectional data of 14,796 subjects (age range 35 to 74 years, 50.5% men) from the population-based Gutenberg Health Study were examined to show the distribution of cardiovascular risk factors by AF status and sex, and to determine sex-specific predictors for AF. The prevalence of AF was higher in men (4.3%) than in women (1.9%). Men had a worse cardiovascular risk factor profile, a higher prevalence of cardiovascular disease, but fewer symptoms than women. Age-adjusted Cox regressions showed sex interactions in the association of high-density lipoprotein-cholesterol, triglycerides, diabetes mellitus, coronary artery disease, myocardial infarction, generalized anxiety disorder, and heart rate with AF. After multivariable adjustment, sex interactions were seen for thickness of interventricular end-diastolic septum, odds ratio (OR) per standard deviation (SD), 95% confidence interval women: 0.9 (0.8, 1.1), men: 1.2 (1.1, 1.4), interaction p value = 0.02; left atrial diameter index, OR per SD women: 1.5 (1.3, 1.8), men: 1.9 (1.7, 2.1), interaction p value = 0.03; and myocardial infarction, OR women: 2.7 (1.3, 5.6), men: 0.7 (0.5, 1.1), interaction p value = 0.002. In conclusion, in our large cohort, we observed substantial sex differences in AF distribution and clinical characteristics including comorbidities, symptom burden, and structural cardiac changes. PMID- 29706203 TI - Complications of Radiofrequency Ablation for Supraventricular Tachycardia in the Wolff-Parkinson-White Syndrome Associated With Noncompaction Cardiomyopathy. AB - Described herein is a 52-year-old man with Wolff-Parkinson-White syndrome and noncompaction cardiomyopathy who underwent 4 sternotomies to correct complications of 3 ablation procedures (2 open) for recurring supraventricular tachycardia, mitral valve repair for a damaged mitral valve during the third radiofrequency ablation procedure, and finally orthotopic heart transplantation. PMID- 29706204 TI - Markers of Reperfusion and Long-Term (8-Year) Prognosis after Primary Percutaneous Coronary Intervention. AB - Thrombolysis in Myocardial Infarction (TIMI) flow, myocardial perfusion grade (MPG), and infarct size are established markers of reperfusion in patients with ST-segment elevation myocardial infarction. Whether these markers provide long term prognostic information remains unknown. This study included 1,406 patients with ST-segment elevation myocardial infarction who underwent primary percutaneous coronary intervention. Postreperfusion TIMI flow, MPG, and infarct size (evaluated by scintigraphy at 7 to 14 days) were measured. The primary outcome was 8-year mortality. Overall there were 190 deaths. The Kaplan-Meier estimates of mortality were 22.6% (37 deaths) and 16.8% (153 deaths) according to TIMI flow <=2 and TIMI flow 3 (adjusted hazard ratio [HR] 0.82, 95% confidence interval [CI] 0.66 to 1.00, p = 0.058 for 1 grade increment), 21.6% (106 deaths) and 14.5% (84 deaths) according to MPG <=2 and MPG 3 (adjusted HR 0.87 [0.77 to 0.98], p = 0.020 for 1 grade increment) and 21.7% (115 deaths) and 13.7% (75 deaths) according to infarct size >10% (median value) and infarct size <=10% of the left ventricle (adjusted HR 1.08 [1.03 to 1.13], p = 0.001, for 5% of left ventricle increment in infarct size). The C statistic of the model for all-cause mortality was 0.810 (0.781 to 0.839) with baseline variables, 0.812 (0.783 to 0.841) after incorporation of TIMI flow (P for significance compared to the model with baseline variables = 0.140), 0.813 (0.784 to 0.841) after incorporation of MPG (p = 0.345) and 0.815 (0.786 to 0.842) after incorporation of infarct size (p = 0.08). In conclusion, markers of reperfusion independently predict long-term mortality after primary percutaneous coronary intervention but offer limited incremental prognostic value to that provided by evaluation of baseline cardiovascular risk factors and clinical data. PMID- 29706205 TI - Principles of ethical practice. PMID- 29706206 TI - Authors' response. PMID- 29706207 TI - Prevalence of gingival recession after orthodontic tooth movements. PMID- 29706209 TI - On being human. PMID- 29706210 TI - Influence of antibiotic prophylaxis on the stability of orthodontic microimplants: A pilot randomized controlled trial. AB - INTRODUCTION: The aims of this 2-arm parallel pilot randomized controlled trial were to investigate the influence of antibiotic prophylaxis on the stability of orthodontic microimplants and to evaluate the efficacy of systemic inflammatory marker measurements in detecting infections in tissues surrounding microscrews. METHODS: Orthodontic patients requiring en-masse distalization in the maxilla received antibiotics or a placebo before microimplant placement. Eligibility criteria included 13 years of age, and good general and oral health. Exclusion criteria comprised allergy to antibiotics, severe systemic allergy, heart and kidney diseases, and recent antibiotic treatment. Stability of the microimplants was the primary outcome; inflammation of the tissues surrounding the microscrews, pain related to the microimplantation, and serum levels of inflammatory markers were the secondary outcomes. Randomization in a 1:1 ratio was performed by auxilliary staff via a flip of a coin between 2 participants of the same sex and developmental stage, and the "winner" was allocated to the intervention group. Pharmaceutically prepared identical capsules with either amoxicillin (intervention) or glucose (control) given 1 hour before microimplant placement according to the allocation provided blinding of the participants. Subsequently, 1 clinician unaware of the allocation inserted the microimplants and assessed the outcomes, which simultaneously blinded the operator-assessor. Blood samples for laboratory analysis of inflammatory markers were collected a day before and 1, 3, and 7 days postoperatively. RESULTS: Out of 80 participants initially assessed for eligibility, 41 received the randomized allocation. Three patients were lost to follow-up. Eventually, data of 18 and 20 participants (mean age, 20.4 +/- 5.9 years) were available for analysis in the intervention and control groups, in which 1 and 2 patients lost a microimplant, respectively, resulting in odds ratio of 0.53 (95% confidence interval [CI], 0.0084-11.23; P = 1.0). The odds ratio for inflammation development was 1.22 (95% CI, 0.34-4.38), and the odds ratio for feeling milder pain was 1.174 (95% CI, 0.350-3.941) in the intervention compared with the control group, but the result was not statistically significant (P = 0.758; P = 0.795, respectively). The inflammatory marker levels did not increase due to either microimplantation (procalcitonin, P = 0.445; C-reactive protein, P = 0.4) or peri-implantitis. Antibiotic prophylaxis slightly decreased the levels of the biomarkers in the intervention group; however, the results were not statistically significant (P = 0.68; P = 0.908, respectively). No harms caused by the microimplantation procedure or drug intake were noted. CONCLUSIONS: Antibiotics provided no benefit in terms of microimplant stability, inflammation of soft tissues, or postoperative pain in our pilot sample. Measurements of serum levels of inflammatory markers were inefficient in detecting soft tissue inflammations. These initial results should be interpreted with caution until validated by a large multicenter definitive trial. REGISTRATION: This trial was not registered. PROTOCOL: The protocol was not published before trial commencement. FUNDING: The trial was funded by Wroclaw Medical University; grant number pbmn91 and supported by Diagnostyka. PMID- 29706211 TI - Age-dependent biologic response to orthodontic forces. AB - INTRODUCTION: Orthodontic tooth movement results from increased inflammation and osteoclast activation. Since patients of all ages now routinely seek orthodontics treatment, we investigated whether age-dependent biologic responses to orthodontic force correlate with the rate of tooth movement. METHODS: We studied 18 healthy subjects, adolescents (11-14 years) and adults (21-45 years), with Class II Division 1 malocclusion requiring 4 first premolar extractions. Canines were retracted with a constant force of 50 cN. Gingival crevicular fluid was collected before orthodontic treatment and at days 1, 7, 14, and 28 after the canine retraction. Cytokine (IL-1beta, CCL2, TNF-alpha) and osteoclast markers (RANKL and MMP-9) were measured using antibody-based protein assays. Pain and discomfort were monitored with a numeric rating scale. The canine retraction rate was measured from study models taken at days 28 and 56. RESULTS: Although the cytokine and osteoclast markers increased significantly in both age groups at days 1, 7, and 14, the increases were greater in adults than in adolescents. Interestingly, the rate of tooth movement in adults was significantly slower than in adolescents over the 56-day study period. Adults also reported significantly more discomfort and pain. CONCLUSIONS: Age is a significant variable contributing to the biologic response to orthodontic tooth movement. Adults exhibited a significantly higher level of cytokine and osteoclasts activity but, counterintuitively, had a significantly slower rate of tooth movement. PMID- 29706212 TI - Gingival recession in orthodontic patients 10 to 15 years posttreatment: A retrospective cohort study. AB - INTRODUCTION: The aims of this study were to retrospectively investigate the long term development of gingival recession in a cohort of orthodontic patients and to compare the prevalence of gingival recession in orthodontically treated patients 10 to 15 years posttreatment to that of untreated subjects with malocclusion. METHODS: The sample included 88 patients with mean ages of 12.1 years (SD, 2.4 years) at pretreatment, 15.1 years (SD, 2.4 years) at posttreatment, and 27.9 years (SD, 2.5 years) 10 to 15 years posttreatment. The control group comprised 102 untreated patients seeking orthodontic treatment with a mean age of 28.7 years (SD, 3.1 years). Gingival recession was evaluated on study models. RESULTS: The prevalence of both labial/buccal and lingual/palatal gingival recession increased during orthodontic treatment with further increases during the long term posttreatment period; 98.9% of the orthodontically treated participants had at least 1 labial/buccal recession, and 85.2% of the patients had at least 1 lingual/palatal recession 10 to 15 years posttreatment. In addition, the proportion of patients with multiple labial/buccal or lingual/palatal recession sites increased considerably in the same time period. The prevalences of labial/buccal gingival recession were similar in the orthodontically treated patients 10 to 15 years posttreatment and the untreated controls. Study group patients with a crossbite before treatment showed 2.73 more recessions (95% CI, 0.28-5.17; P = 0.029) than did those without a transverse discrepancy. Untreated subjects with crowding greater than 3 mm per arch had 3.29 more recessions (95% CI, 0.73-5.68; P = 0.012) to 4.92 more recession sites (95% CI, 1.70-8.15; P = 0.003) than did those with mild or no crowding. CONCLUSIONS: Within the limitations of this study, it seems that, in regard to the prevalence of gingival recession, orthodontically treated patients are not compromised in the long term compared with those with malocclusion that was untreated for many years. PMID- 29706213 TI - Influence of orthodontic mini-implant penetration of the maxillary sinus in the infrazygomatic crest region. AB - INTRODUCTION: Mini-implants are widely used for predictable tooth movements, but insertion is often restricted by anatomic structures. The aims of this study were to investigate the incidence of penetration of mini-implants into the sinus and the relationship between penetration depth and sinus tissue. METHODS: Data from 32 patients who received mini-implants in the infrazygomatic crest were collected from a data base. The success rate of mini-implants was determined by clinical retrospective analysis. The incidence of penetration, penetration depth, and sinus configuration were investigated and compared between cone-beam computed tomography scans obtained immediately after insertion and before mini-implant removal. RESULTS: The overall success rate of mini-implants in the infrazygomatic crest was 96.7%, and 78.3% penetrated into the sinus. In the group in which penetration exceeded 1 mm, the incidence of membrane thickening was 88.2%, and the mean value of thickening was 1.0 mm; however, the variable values of penetration in the 1-mm group were only 37.5% and 0.2 mm, respectively (P <0.05). CONCLUSIONS: The incidence of penetration of infrazygomatic crest mini-implants into the sinus may be high. Penetration through double cortical bone plates with limitation of the penetration depth within 1 mm is recommended for infrazygomatic crest mini-implant anchorage. PMID- 29706214 TI - Evaluation of facial asymmetry in patients with juvenile idiopathic arthritis: Correlation between hard tissue and soft tissue landmarks. AB - INTRODUCTION: The aims of this study were to assess the correlation between facial hard and soft tissue asymmetry in patients with juvenile idiopathic arthritis, to identify valid soft tissue points for clinical examination, and to assess the smallest clinically detectable level of dentofacial asymmetry. METHODS: Full-face cone-beam computed tomography scans and 3-dimensional photographs were used to assess facial hard and soft tissue asymmetry in 21 patients with juvenile idiopathic arthritis. A survey was conducted to assess how asymmetry is perceived observationally based on cone-beam computed tomography scans and 3-dimensional photographs. RESULTS: Significant linear correlations were seen between the hard and soft tissue landmark deviations at both the transverse and vertical positions. Among medial soft tissue points, glabella had the smallest deviation and pogonion the largest deviation from the midsagittal plane. Professionals could identify facial asymmetry based on images beyond a cutoff threshold of 2 mm for both pogonion and gonion. CONCLUSIONS: Soft tissue pogonion and gonion were identified as the most appropriate landmarks to clinically predict hard tissue facial asymmetry. Facial asymmetries are most pronounced in the lower facial third in patients with juvenile idiopathic arthritis. Professionals can accurately identify asymmetry exceeding 2 mm. PMID- 29706215 TI - Longitudinal eruptive and posteruptive tooth movements, studied on oblique and lateral cephalograms with implants. AB - INTRODUCTION: The purpose of this study was to investigate the eruptive and posteruptive tooth displacements of untreated growing subjects longitudinally and the potential connections between posteruptive displacement of the maxillary and mandibular first molars and skeletal facial growth. METHODS: The sample comprised 11 series of right 45 degrees oblique cephalograms and lateral cephalograms of untreated children with metallic implants of the Bjork type obtained from the archives of a growth study. Cephalograms generated at approximately 2-year intervals between the ages of 8.5 and 16 years were selected and traced. Superimpositions of serial tracings of oblique cephalograms on stable intraosseous implants were made to determine the displacements of buccal segment teeth in both arches, and superimpositions of serial tracings of lateral cephalograms were used to evaluate growth of the jaws. RESULTS: Continuous mesial tipping of the maxillary molars was observed from 8.5 to 16 years of age, averaging 8.2 degrees +/- 5.5 degrees for the first molars and 18.3 degrees +/- 8.5 degrees for the second molars. Compared with the maxillary molars, the mandibular first molars showed less change in angulation except in the later mixed dentition when more than half of the subjects had accelerated forward tipping of the first molar in the late mixed dentition associated with migration into the leeway space. Average amounts of cumulative eruption from 8.5 to 16 years of age were 12.1 +/- 2.1 mm downward and 3.8 +/- 1.7 mm forward for the maxillary first molar. The mandibular first molar showed 8.6 +/- 2.3 mm of eruption and 4.4 +/- 1.9 mm of mesial migration. Peak velocity of vertical eruption of the maxillary and mandibular first molars corresponded to the skeletal vertical growth spurt. The maxillary canines and first premolars showed remarkable and continuous uprighting migration during eruption, averaging 9.5 degrees +/- 5.0 degrees and 10.5 degrees +/- 6.7 degrees , respectively. However, when they erupted into the occlusion, their changes in angulation reverted to forward tipping. The same tendency was also found in the mandibular canines and first premolars. CONCLUSIONS: Remarkable eruption and migration occur to the teeth of both arches during childhood and adolescence. Rates of first molar eruption during adolescence follow the general pattern of somatic growth. We infer that maintaining the original distal crown angulation of the maxillary molars may be an effective protocol for preservation of anchorage. PMID- 29706216 TI - Three-dimensional computed tomography analysis of mandibular morphology in patients with facial asymmetry and mandibular retrognathism. AB - INTRODUCTION: The purpose of this study was to analyze the morphologic features of skeletal units in the mandibles of patients with facial asymmetry and mandibular retrognathism using cone-beam computed tomography. METHODS: The subjects consisted of 50 adults with facial asymmetry and mandibular retrognathism, divided into the symmetry group (n = 25) and the asymmetry group (n = 25) according to the degree of menton deviation. Three-dimensional computed tomography scans were obtained with cone beam computed tomography. Landmarks were designated on the reconstructed 3-dimensional images. Linear and volumetric measurements were made on the mandibles. RESULTS: In the asymmetry group, the lengths of condylar, body, and coronoid units were shorter, and condylar width was narrower on the deviated side than on the nondeviated side (P <0.01). The lengths of angular and chin units were not significantly different between the deviated and nondeviated sides (P >0.05). Hemimandibular, ramal, and body volumes were less on the deviated side than on the nondeviated side (P <0.01). CONCLUSIONS: Condylar, body, and coronoid units contribute to mandibular asymmetry in patients with facial asymmetry and mandibular retrognathism. PMID- 29706217 TI - Three-dimensional evaluation of dentofacial transverse widths of adults with various vertical facial patterns. AB - INTRODUCTION: The purpose of this study was to investigate maxillomandibular transverse widths and molar inclinations of adults with hypodivergent, normodivergent, and hyperdivergent facial patterns using cone-beam computed tomography. METHODS: We evaluated Class I subjects (55 men, 66 women) who were divided into hypodivergent (<27 degrees ), normodivergent (28 degrees -37 degrees ), and hyperdivergent (>38 degrees ) groups by their mandibular plane angles. Frontal and coronal views of the images were analyzed. Sex differences, vertical facial pattern differences, and related factors were assessed with independent 2 sample t tests, 1-way analysis of variance followed by post hoc Tukey tests, and Pearson correlation analysis. RESULTS: The hypodivergent group had greater maxillary alveolar widths 7 mm apically from the alveolar crest. The intermolar widths and molar inclinations showed no significant differences among the groups. As the mandibular plane angles increased, interjugular widths, transverse mandibular widths, and buccolingual maxillary alveolar widths at the midroot level decreased, whereas the maxillomandibular width differences and palatal heights increased im both sexes. CONCLUSIONS: An increase in the mandibular plane angle is associated with tendencies of narrow mandibular arches, thinner maxillary alveolar bones at the midroot level, and higher palatal arches in both sexes. Intermolar widths and molar inclinations were not significantly affected by vertical facial patterns. PMID- 29706218 TI - Prediction of the occurrence and severity of mandibular incisor crowding in the early mixed dentition using craniofacial parameters. AB - INTRODUCTION: With the recent interest in esthetics at an early age, prediction of mandibular incisor crowding is of significant importance. Since dental arch development is related to craniofacial growth, we conducted a cohort study to find a regression model for mandibular incisor crowding based on various craniofacial parameters in children. METHODS: A total of 250 children, all in the early mixed dentition, were selected randomly by cluster sampling from primary schools. Craniofacial parameters were measured by a caliper bow, and intercanine widths were measured on dental casts. After a 12-month follow-up period, mandibular incisor crowding and intercanine width were assessed on each subject's dental cast. Discriminant and multiple regression analyses were performed separately for boys and girls. RESULTS: Of 250 children, 148 returned for the 1 year follow-up and met the inclusion criteria. Regression analyses of patients with normal occlusion showed a statistically significant correlation between anterior dental crowding and facial height and bigonial width in both sexes. A significant inverse correlation was found between initial intercanine width and incisor crowding in girls. Furthermore, using the aforementioned parameters, the occurrence of mandibular incisor crowding could be predicted with an accuracy of 92.6%. CONCLUSIONS: We found that the occurrence and severity of mandibular incisor crowding in the early mixed dentition can be predicted accurately based on certain craniofacial parameters. PMID- 29706219 TI - Factors affecting treatment duration of labial inversely impacted maxillary central incisors. AB - INTRODUCTION: A labial inversely impacted maxillary central incisor is a relatively rare occurrence. The crown of the tooth is directed upward, and its palatal aspect is facing labially. This typical orientation can be the result of trauma to the deciduous incisor transmitted to the palatal side of the crown of the permanent incisor. Labial inversely impacted maxillary central incisors are most commonly combined with labial-lingual root dilacerations. The aim of this study was to examine factors that affect the surgical-orthodontic treatment duration of labial inversely impacted maxillary central incisors. METHOD: The records of 35 consecutively treated patients were retrospectively evaluated. Cone beam computed tomography images were taken before treatment, and factors affecting treatment time, including age, length, crown-root angle, crown height and depth, angle of inversion, rotation to axial plane, and distance and angle to midline, were measured using Dolphin Imaging software (version 11.8; Patterson Supply, St Paul, Minn). Treatment duration was evaluated for each patient, and logistic regression analyses were applied. RESULTS: The 15 boys and 20 girls had a mean age 8.36 +/- 1.36 years. The mean orthodontic traction duration was 11.28 +/- 3.08 months. Multiple regression analyses indicated that factors resulting in a longer duration were age (beta = 0.779; P = 0.043), crown height (beta = 0.344; P = 0.007), crown-root angle (beta = -0.037; P = 0.018), and tooth length (beta = -0.623; P = 0.038). CONCLUSIONS: Surgical-orthodontic correction of labial inversely impacted maxillary incisors requires an average of 1 year. Assessments of age, crown height, root dilaceration, and length of incisor can help the orthodontist to better predict treatment duration during consultations with patients and parents. PMID- 29706220 TI - Asymmetric extractions in a patient with a hopeless maxillary central incisor, followed by treatment with mini-implant anchorage. AB - Premolar extraction is 1 option for treatment of patients with malocclusion and severe crowding or protrusion. When the patient has missing or hopeless teeth other than premolars, it is possible to consider removal of those teeth to use the space to decrease crowding. A 15-year-old girl sought treatment for severe crowding. She had already lost her maxillary right first premolar as a result of caries 1 year previously and had a hopeless maxillary right central incisor. Her mandibular left first molar still caused discomfort even after endodontic treatment. Extractions of the maxillary right central incisor and mandibular right first premolar and left first molar were chosen to resolve the occlusion problems. Orthodontic mini-implants were placed to translocate the maxillary left central incisor across the midpalatal suture to use the space in the maxillary right quadrant to relieve the crowding. Although a different extraction option was used in each quadrant, the final occlusion was acceptable. After debonding, porcelain crowns were placed on the anterior teeth to improve esthetics. The treatment result remained stable after 2 years of retention. PMID- 29706221 TI - Orthodontic treatment of a patient with maxillary lateral incisors with dens invaginatus: 6-year follow-up. AB - INTRODUCTION: Dens invaginatus is an anomaly of dental development in which calcified tissues, such as enamel and dentin, are invaginated into the pulp cavity. This morphologic alteration is more frequent in maxillary permanent lateral incisors and makes them more susceptible to carious lesions and pulp alterations. METHODS: This case report describes a patient with maxillary lateral incisors affected by dens invaginatus. The maxillary right lateral incisor had already undergone endodontic treatment, and the maxillary left one had a periapical lesion. Additionally, the patient had a Class II Division 1 malocclusion, with anterior open bite, posterior crossbite, and an impacted mandibular left second molar. RESULTS: The orthodontic treatment involved extraction of the maxillary lateral incisors and 2 mandibular premolars, resulting in proper overjet and overbite with good arch coordination and occlusal stability. CONCLUSIONS: Treatment results were stable, as evaluated in a 6-year posttreatment follow-up. PMID- 29706222 TI - Using a single cone-beam computed tomography scan to obtain full occlusal details, with the mandible in centric relation and maximum intercuspation. AB - INTRODUCTION: One obstacle with the implementation of digital technology in orthodontics is the acquisition of occlusal details while maintaining the mandible in the full interdigitation position. With 1 cone-beam computed tomography (CBCT) scan of the patient and 1 digital scan of the patient's dental models in occlusion, it might be possible to obtain full occlusal details and generate 2 volumes, with the mandible in centric relation and maximum intercuspation positions. The purpose of this article was to describe the technique. METHODS: Orthodontic models of enrolled subjects were digitized in maximum intercuspation. They wore splints that were initially 2 mm thick before CBCT imaging. On the CBCT volume, the mandible is separated from the rest of the skull, and the digitized dental model in maximum intercuspation is registered on the skull volume. The separated mandibular volume is then registered on the mandibular dentition using the tooth surfaces as a guide. RESULTS: Two CBCT volumes are rendered: original scan with teeth in minimal disclusion and the constructed one with teeth in maximum interdigitation. CONCLUSIONS: Mobilizing digital technology in orthodontics allows the acquisition of crucial occlusal details while sparing patients an extra radiation dose from the CBCT. PMID- 29706223 TI - Three-dimensional mandibular regional superimposition in growing patients. AB - INTRODUCTION: The aims of this study were to identify stable mandibular structures in 3 dimensions in growing patients using a regional implant technique and to test the reproducibility of mandibular regional superimposition in 3 dimensions using the regions identified. METHODS: Three-dimensional voxel-based regional mandibular registrations were performed on bone plates, and screws were placed in the anterior chin and symphysis regions of 20 growing patients (mean age, 12.1 +/- 1.3 years). Three-dimensional models of the resulting superimpositions were built for the chin, symphysis, and third molar crypts. Absolute mean errors were calculated for each region to evaluate stability. Longitudinal cone-beam computed tomography scans were obtained of 25 patients (mean age, 12.7 +/- 1.4 years) with different skeletal malocclusions (20 Class II, 5 Class III). To evaluate reliability of mandibular registrations using the chin and symphysis regions, voxel-based superimpositions were performed independently by 2 observers. The resulting superimpositions between the 2 examiners were overlaid, and the mean difference along the entire surface of the mandible was calculated. RESULTS: The chin and symphysis regions showed high levels of precision (chin absolute mean error, 0.37 +/- 0.16 mm; symphysis absolute mean error, 0.4 +/- 0.15 mm). The third molar region had a high registration error (absolute mean error, 1.94 +/- 0.06 mm). The voxel-based registrations using the chin and symphysis were reliable and reproducible between examiners (absolute mean error, 0.12 +/- 1.1 mm). Intraclass correlation coefficient results showed a high degree of agreement between examiners. CONCLUSIONS: The chin and symphysis regions are stable areas for 3-dimensional mandibular regional superimpositions. PMID- 29706224 TI - Poaching employees. PMID- 29706226 TI - School start times and teenage driver motor vehicle crashes. AB - INTRODUCTION: Shifting school start times to 8:30 am or later has been found to improve academic performance and reduce behavior problems. Limited research suggests this may also reduce adolescent driver motor vehicle crashes. A change in the school start time from 7:30 am to 8:45 am for all public high schools in one North Carolina county presented the opportunity to address this question with greater methodologic rigor. METHOD: We conducted ARIMA interrupted time-series analyses to examine motor vehicle crash rates of high school age drivers in the intervention county and 3 similar comparison counties with comparable urban-rural population distribution. To focus on crashes most likely to be affected, we limited analysis to crashes involving 16- & 17-year-old drivers occurring on days when school was in session. RESULTS: In the intervention county, there was a 14% downward shift in the time-series following the 75 min delay in school start times (p = .076). There was no change approaching statistical significance in any of the other three counties. Further analysis indicated marked, statistically significant shifts in hourly crash rates in the intervention county, reflecting effects of the change in school start time on young driver exposure. Crashes from 7 to 7:59 am decreased sharply (-25%, p = .008), but increased similarly from 8 to 8:59 am (21%, p = .004). Crashes from 2 to 2:59 pm declined dramatically ( 48%, p = .000), then increased to a lesser degree from 3 to 3:59 pm (32%, p = .024) and non-significantly from 4 to 4:59 (19%, p = .102). There was no meaningful change in early morning or nighttime crashes, when drowsiness-induced crashes might have been expected to be most common. DISCUSSION: The small decrease in crashes among high school age drivers following the shift in school start time is consistent with the findings of other studies of teen driver crashes and school start times. All these studies, including the present one, have limitations, but the similar findings suggest that crashes and school start times are indeed related, with earlier start times equating to more crashes. CONCLUSION: Later high school start times (>8:30 am) appear to be associated with lower adolescent driver crash rates, but additional research is needed to confirm this and to identify the mechanism by which this occurs (reduced drowsiness or reduced exposure). PMID- 29706225 TI - Photophysical Behavior of mNeonGreen, an Evolutionarily Distant Green Fluorescent Protein. AB - Fluorescent proteins (FPs) feature complex photophysical behavior that must be considered when studying the dynamics of fusion proteins in model systems and live cells. In this work, we characterize mNeonGreen (mNG), a recently introduced FP from the bilaterian Branchiostoma lanceolatum, in comparison to the well-known hydrozoan variants enhanced green fluorescent protein (EGFP) and Aequorea coerulescens GFP by steady-state spectroscopy and fluorescence correlation spectroscopy in solutions of different pH. Blind spectral unmixing of sets of absorption spectra reveals three interconverting electronic states of mNG: a nonfluorescent protonated state, a bright state showing bell-shaped pH dependence, and a similarly bright state dominating at high pH. The gradual population of the acidic form by external protonation is reflected by increased flickering at low pH in fluorescence correlation spectroscopy measurements, albeit with much slower flicker rates and lower amplitudes as compared to Aequorea GFPs. In addition, increased flickering of mNG indicates a second deprotonation step above pH 10 leading to a slight decrease in fluorescence. Thus, mNG is distinguished from Aequorea GFPs by a two-step protonation response with opposite effects that reflects a chemically distinct chromophore environment. Despite the more complex pH dependence, mNG represents a superior FP under a broad range of conditions. PMID- 29706227 TI - Client and provider experiences with self-administration of subcutaneous depot medroxyprogesterone acetate (DMPA-SC) in Malawi. AB - OBJECTIVE: As low- and middle-income countries (LMICs) consider adding self administration of subcutaneous depot medroxyprogesterone acetate (DMPA-SC) to their contraceptive method mix, learning about family planning clients' and providers' experiences with self-injectable DMPA-SC during trials will inform introduction and scale-up efforts. STUDY DESIGN: We conducted semistructured interviews with 30 randomly selected adult women enrolled in the self administration group of a 12-month randomized controlled trial studying DMPA-SC continuation rates in rural Malawi. We asked about their experiences learning to self-inject, self-injecting, remembering when to reinject, and storing and disposing of DMPA-SC. We also interviewed 12 providers - clinic-based providers (CBPs) and community-based health surveillance assistants (HSAs) - who trained clients to self-inject DMPA-SC during the trial. We asked about their experiences training and supporting women to self-inject DMPA-SC during the trial and their recommendations for scale-up of self-administered DMPA-SC. RESULTS: Clients and providers reported positive experiences with DMPA-SC self-injection. Clients felt that DMPA-SC self-injection saved them time and money, and providers felt that it reduced their workload and saved them time. We found that both CBPs and HSAs successfully trained clients to self-inject DMPA-SC and that clients safely and appropriately stored and disposed of DMPA-SC. CONCLUSIONS: Our findings contribute to the growing body of evidence of the feasibility of DMPA-SC self injection in LMIC settings. We recommend that providers plan to train clients for at least 30min, emphasize the activating and injecting steps during training, use up to four practice injections per client trained and give self-injectors calendars to help them remember when to reinject. IMPLICATIONS: DMPA-SC self administration should be made available in LMIC settings, but because it is a new practice, implementation guidance is needed. We offer practical recommendations for introducing and scaling up DMPA-SC self-administration based on clients' and providers' experiences during a trial investigating this practice in Malawi. PMID- 29706228 TI - Does the size matter? Evaluation of effect of incorporation of silver nanoparticles of varying particle size on the antimicrobial activity and properties of irreversible hydrocolloid impression material. AB - OBJECTIVES: The main objective of the present in vitro study is to evaluate the antimicrobial activity and properties of irreversible hydrocolloid impression material incorporated with silver nanoparticles of varying size at different concentrations. METHODS: Silver nanoparticles of 80-100, 50-80, 30-50 and 10-20nm size were added to irreversible hydrocolloid impression material at 0.5, 1.0, 2.0 and 5.0wt%. Antimicrobial activity of the silver nanoparticle incorporated irreversible hydrocolloid was measured using disk diffusion method. The gel strength, flow, gelation time and permanent deformation were measured according to American Dental Association specification #18. Data were analyzed using analysis of variation at a confidence interval of 95% (alpha=0.05). RESULTS: Silver nanoparticles of 80-100nm size have imparted superior antimicrobial activity to the irreversible hydrocolloid in a dose-dependent manner whereas finer nanoparticle size did not exhibit any antimicrobial activity. The addition of silver nanoparticles did not alter the properties of irreversible hydrocolloid at 0.5 and 1.0wt% whereas at higher concentrations significant differences in flow, gelation time and strength were observed. SIGNIFICANCE: The results of the present study indicate that silver nanoparticles of size range 80-100nm are superior in imparting antimicrobial activity to irreversible hydrocolloid compared to finer particle size range. PMID- 29706229 TI - New hominin postcranial remains from locality OMO 323, Shungura Formation, Lower Omo Valley, southwestern Ethiopia. PMID- 29706230 TI - Human-like hip joint loading in Australopithecus africanus and Paranthropus robustus. AB - Adaptations indicative of habitual bipedalism are present in the earliest recognized hominins. However, debate persists about various aspects of bipedal locomotor behavior in fossil hominins, including the nature of gait kinematics, locomotor variability across different species, and the degree to which various australopith species engaged in arboreal behaviors. In this study, we analyze variation in trabecular bone structure of the femoral head using a sample of modern humans, extant non-human hominoids, baboons, and fossil hominins attributed to Australopithecus africanus, Paranthropus robustus, and the genus Homo. We use MUCT data to characterize the fabric anisotropy, material orientation, and bone volume fraction of trabecular bone to reconstruct hip joint loading conditions in these fossil hominins. Femoral head trabecular bone fabric structure in australopiths is more similar to that of modern humans and Pleistocene Homo than extant apes, indicating that these australopith individuals walked with human-like hip kinematics, including a more limited range of habitual hip joint postures (e.g., a more extended hip) during bipedalism. Our results also indicate that australopiths have robust femoral head trabecular bone, suggesting overall increased loading of the musculoskeletal system comparable to that imposed by extant apes. These results provide new evidence of human-like bipedal locomotion in Pliocene hominins, even while other aspects of their musculoskeletal systems retain ape-like characteristics. PMID- 29706231 TI - Reconstruction, endocranial form and taxonomic affinity of the early Homo calvaria KNM-ER 42700. AB - When first described, the small calvaria KNM-ER 42700 from Ileret, Kenya, was considered a late juvenile or young adult and assigned to Homo erectus. However, this species attribution has subsequently been challenged because the specimen's neurocranial shape differs substantially from that of H. erectus adults. Here, (1) we describe the postmortem damage and deformation that could have influenced previous shape analyses, (2) present digital reconstructions based on computed tomographic scans correcting for these taphonomic defects, and (3) analyze the reconstructed endocranial shape and form, considering both static allometry among adults and ontogenetic allometry. To this end, we use geometric morphometrics to analyze the shape of digital endocasts based on landmarks and semilandmarks. Corroborating previous studies of the external surface, we find that the endocranial shape of KNM-ER 42700 falls outside the known adult variation of H. erectus. With an endocranial volume estimate between 721 and 744 ml, size cannot explain its atypical endocranial shape when static allometry within H. erectus is considered. However, the analysis of ontogenetic allometry suggests that it may be a H. erectus individual that is younger than previously thought and had not yet reached adult endocranial shape. Future work should therefore comprehensively review all cranial indicators of its developmental age, including closure of the spheno-occipital synchondrosis. An alternative hypothesis is that KNM-ER 42700 represents an as yet unidentified species of early Homo. Importantly, KNM-ER 42700 should not be included in the adult hypodigm of H. erectus. PMID- 29706232 TI - Technological behaviour in the early Acheulean of EF-HR (Olduvai Gorge, Tanzania). AB - Technological strategies of early humans are discussed in the light of a recently excavated stone tool assemblage from EF-HR, an archaeological site older than 1.33 Ma at Olduvai Gorge, Tanzania. Renewed fieldwork at EF-HR has unearthed a lithic collection containing over 2300 artefacts (including a hundred handaxes in stratigraphic position), which represents one of the largest assemblages for the early Acheulean in eastern Africa. Our technological study shows co-occurrence of two distinctive reduction sequences in the same assemblage, one aimed at obtaining small flakes and the other focused on the production of large, thick, heavy flakes that were then used as blanks for handaxe shaping. Flaking of small cores is expedient and low intensity, and knapping methods are similar to those observed in earlier Oldowan assemblages. Large Cutting Tools (LCTs) show no evidence of planform and biconvex symmetry, and shaping sequences are brief and discontinuous, indicating short use-lives for handaxes. Bifaces are rare and atypical. Recurrent morphotypes are knives, which are poorly-shaped, scraper like, large-sized handaxes. Despite the apparent expediency of EF-HR handaxe production, a closer inspection of the interplay between debitage and faconnage stages reveals remarkably standardized procedural patterns. Large Cutting Tool blanks were produced following fixed knapping rules resulting in flakes with a specific morphology and mass distribution. Adapted to the idiosyncrasies of each blank, shaping was almost invariably imposed over the same areas in all LCTs and sought to produce morphotypes that, technologically, are remarkably identical to each other. This strongly supports the existence of mental templates and technical rules that were systematically practiced in LCT production at EF-HR, and underscore the structured nature of technological behaviour at the onset of the Acheulean in eastern Africa. PMID- 29706233 TI - Effects of Peer Education on Attitudes Toward Organ Donation in Nursing Students. AB - BACKGROUND: Nurses play an effective role in the identification of donors and in the families' decision-making processes related to organ donation. It is recommended that nursing students be offered specific education regarding organ donation and transplantation. The aim of this study was to examine the effects of peer education on attitudes toward organ donation and the rate of attaining a donor card in undergraduate nursing students. METHODS: This study was a quasi experimental trial in a single group conducted between February 2016 and October 2016. Data were collected in 3 stages (pretest, posttest 1, and posttest 2) by using the Organ Donation Attitudes Scale. Data analysis was made with descriptive statistics, repeated measures analysis of variance, and the McNemar test. RESULTS: The mean age of the participants was 21.63 +/- 1.19 years. There was no statistically significant difference in students' attitudes toward organ donation after peer education (P > .05). The difference in the number of students having a donor card after peer education was highly significant (P < .05). CONCLUSIONS: These study results showed that peer training did not positively change nursing students' attitudes toward organ donation but encouraged them to acquire a donor card and increased their knowledge of the organ donation system. PMID- 29706234 TI - Bioinspired supramolecular engineering of self-assembling immunofibers for high affinity binding of immunoglobulin G. AB - Many one-dimensional (1D) nanostructures are constructed by self-assembly of peptides or peptide conjugates containing a short beta-sheet sequence as the core building motif essential for the intermolecular hydrogen bonding that promotes directional, anisotropic growth of the resultant assemblies. While this molecular engineering strategy has led to the successful production of a plethora of bioactive filamentous beta-sheet assemblies for interfacing with biomolecules and cells, concerns associated with effective presentation of alpha-helical epitopes and their function preservation have yet to be resolved. In this context, we report on the direct conjugation of the protein A mimicking peptide Z33, a motif containing two alpha-helices, to linear hydrocarbons to create self-assembling immuno-amphiphiles (IAs). Our results suggest that the resulting amphiphilic peptides can, despite lacking the essential beta-sheet segment, effectively associate under physiological conditions into supramolecular immunofibers (IFs) while preserving their native alpha-helical conformation. Isothermal titration calorimetry (ITC) measurements confirmed that these self-assembling immunofibers can bind to the human immunoglobulin G class 1 (IgG1) with high specificity at pH 7.4, but with significantly weakened binding at pH 2.8. We further demonstrated the accessibility of Z33 ligand in the immunofibers using transmission electron microscopy (TEM) and confocal imaging. We believe these results shed important light into the supramolecular engineering of alpha-helical peptides into filamentous assemblies that may possess an important potential for antibody isolation. PMID- 29706235 TI - COSCA (Core Outcome Set for Cardiac Arrest) in Adults: An Advisory Statement From the International Liaison Committee on Resuscitation. AB - Cardiac arrest effectiveness trials have traditionally reported outcomes that focus on survival. A lack of consistency in outcome reporting between trials limits the opportunities to pool results for meta-analysis. The COSCA initiative (Core Outcome Set for Cardiac Arrest), a partnership between patients, their partners, clinicians, research scientists, and the International Liaison Committee on Resuscitation, sought to develop a consensus core outcome set for cardiac arrest for effectiveness trials. Core outcome sets are primarily intended for large, randomised clinical effectiveness trials (sometimes referred to as pragmatic trials or phase III/IV trials) rather than for pilot or efficacy studies. A systematic review of the literature combined with qualitative interviews among cardiac arrest survivors was used to generate a list of potential outcome domains. This list was prioritised through a Delphi process, which involved clinicians, patients, and their relatives/partners. An international advisory panel narrowed these down to 3 core domains by debate that led to consensus. The writing group refined recommendations for when these outcomes should be measured and further characterised relevant measurement tools. Consensus emerged that a core outcome set for reporting on effectiveness studies of cardiac arrest (COSCA) in adults should include survival, neurological function, and health-related quality of life. This should be reported as survival status and modified Rankin scale score at hospital discharge, at 30 days, or both. Health-related quality of life should be measured with >=1 tools from Health Utilities Index version 3, Short-Form 36-Item Health Survey, and EuroQol 5D-5L at 90 days and at periodic intervals up to 1 year after cardiac arrest, if resources allow. (c) 2018 European Resuscitation Council and American Heart Association, Inc. Published by Elsevier B.V. All rights reserved. PMID- 29706236 TI - ILCOR Scientific Knowledge Gaps and Clinical Research Priorities for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care: A Consensus Statement. AB - Despite significant advances in the field of resuscitation science, important knowledge gaps persist. Current guidelines for resuscitation are based on the International Liaison Committee on Resuscitation 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations, which includes treatment recommendations supported by the available evidence. The writing group developed this consensus statement with the goal of focusing future research by addressing the knowledge gaps identified during and after the 2015 International Liaison Committee on Resuscitation evidence evaluation process. Key publications since the 2015 International Consensus on Cardiopulmonary Resuscitation and Emergency Cardiovascular Care Science With Treatment Recommendations are referenced, along with known ongoing clinical trials that are likely to affect future guidelines. (c) 2018 European Resuscitation Council and American Heart Association, Inc. Published by Elsevier B.V. All rights reserved. PMID- 29706237 TI - [Pathway to diagnosis and real-life experience of patients believing they are affected by "chronic Lyme disease"]. AB - OBJECTIVES: Chronic Lyme disease is a subject of scientific and social controversy in both Europe and the United States. The aim of our study was to analyze the pathway to diagnosis of patients believing they were affected by the disease, and to describe their real-life experience. METHOD: A qualitative study was performed with 13 patients declaring themselves to be affected by chronic Lyme disease. Interviews were analyzed by 2 general medical practice interns, supervised by a general practitioner with a diploma in socio-anthropology and an infectious diseases specialist. RESULTS: Internet and other media played a major role in informing the patients or their doctor about the existence and the characteristics of chronic Lyme disease. The diagnosis was confirmed by features considered objective (chronic infection by Borrelia, tick bite, positive serology, beneficial or worsening effects of antibiotics). The long medical diagnosis and treatment process of those interviewed was marked by a conflicted relationship with the medical profession, caused by a feeling of non-recognition and abandonment. They reported their experience as being very painful, both because of the physical pain and also the psychological consequences of their condition. CONCLUSION: Improving the diagnosis and therapeutic management of patients believing themselves to be affected by chronic Lyme disease appears highly necessary both to limit their search for diagnosis and their experience of pain. It could be based on existing guidelines concerning medically unexplained symptoms to which the chronic Lyme disease issue appears quite similar on several points. PMID- 29706238 TI - [A fatal septic shock due to Capnocytophaga canimorsus and review of literature]. AB - INTRODUCTION: Capnocytophaga canimorsus is a Gram-negative bacterium present in normal dogs and cats mouths. It can be responsible for septic shocks after dog or cat bite, especially in asplenic patients. CASE REPORT: We report here a case of C. canimorsus infection rapidly presenting as a multiple organ dysfonction syndrome in an immunocompetent 54 years old patient, who lives near a dog, without any sign of bite. The evolution was a rapidly fatal fulminant septic shock. CONCLUSION: Among patients with a septic shock of unknown etiology, fatal evolution due to C. canimorsus should be avoided by systematic use of early antibiotherapy with amoxicilline and clavulanic acid, especially in patients who live near a pet, even if they are immunocompetent. PMID- 29706239 TI - The sequential treatment of temporomandibular joint ankylosis with secondary deformities by distraction osteogenesis and arthroplasty or TMJ reconstruction. AB - The purpose of this study was to evaluate the sequential treatment of patients with temporomandibular joint (TMJ) ankylosis and secondary deformities by distraction osteogenesis and subsequent arthroplasty or TMJ reconstruction. This study included 40 patients treated at a stomatological hospital in China; they ranged in age from 9 to 53years (mean age 24.5years). Ten of these patients were diagnosed with unilateral TMJ ankylosis and 30 with bilateral TMJ ankylosis. Twenty-seven patients also presented obstructive sleep apnoea-hypopnoea syndrome (OSAHS). All patients underwent distraction osteogenesis as the initial surgery, followed by arthroplasty or TMJ reconstruction. Some patients underwent orthognathic surgery to improve occlusion and face shape along with or after arthroplasty or TMJ reconstruction. The therapeutic effects were evaluated in terms of the improvements in maximum inter-incisal opening (MIO), appearance, and respiratory function. After the completion of treatment, all patients showed improvements in MIO and appearance, and the symptom of snoring disappeared. The airway space was significantly increased. Patient follow-up ranged from 6 to 85months (mean 28.3months), and four patients experienced relapse. This study suggests that treating TMJ ankylosis with secondary deformities by distraction osteogenesis as the initial surgery and arthroplasty or TMJ reconstruction as the second-stage treatment may achieve favourable outcomes, especially for patients with OSAHS; however, some patients may require orthognathic surgery. PMID- 29706240 TI - Analysis of efficacy and safety of core-needle biopsy versus fine-needle aspiration cytology in patients with cervical lymphadenopathy and salivary gland tumour. AB - In this study, we compared the diagnostic accuracy and safety of fine-needle aspiration cytology and core-needle biopsy in patients with cervical lymphadenopathy or salivary gland tumour, and provided a basis for selecting the appropriate diagnostic method in clinical situations. A total of 278 patients were included in this study. The sensitivities of fine-needle aspiration cytology and core-needle biopsy were 66.7% and 100%, respectively, and negative predictive values were 92.6% and 100%, respectively, for diagnosing malignancy. In diagnosing lymphoma, fine-needle aspiration cytology gave false-negative results in all patients. In diagnosing tuberculous lymphadenopathy, the sensitivities of fine-needle aspiration cytology and core-needle biopsy were 33.3% and 91.15%, respectively, and the negative predictive values were 90.0% and 95.1%, respectively. The sensitivities of fine-needle aspiration cytology and core needle biopsy were 42.9% and 100% in diagnosing malignant salivary gland tumours, and the negative predictive values were 91% and 100%, respectively. The results of this study showed that core-needle biopsy was superior in diagnosing and distinguishing critical diseases such as malignant lymphadenopathy and tuberculosis in patients with cervical lymphadenopathy and salivary gland tumour. PMID- 29706241 TI - The nomenclature of the basic disease elements of gout: A content analysis of contemporary medical journals. AB - OBJECTIVES: There is currently no standardised nomenclature for the basic disease elements of gout. This study aimed to identify these elements and examine how they are labelled in contemporary medical literature. METHODS: We analysed articles from the ten highest ranked general rheumatology journals, and five highest ranked general internal medicine journals (by Impact Factor, according to 2015 Thomson-Reuters Journal Citation Reports), published between 1 January 2012 and 31 January 2017. For each journal, articles relevant to gout and hyperuricaemia were identified by the search terms 'gout' and/or 'urate' and/or 'uric acid' using MEDLINE. Basic disease elements were identified and their labels extracted. Labels designated 'unique' used different words or phrases to describe an element. RESULTS: A total of 549 articles were analysed. Eleven basic disease elements and 343 unique labels were identified. Labelling was imprecise for most elements. 'An episode of acute inflammation triggered by the presence of pathogenic crystals' was represented by a total of 162 unique labels; 33.6% of articles referring to this element used at least four unique labels. For articles referencing 'the circulating form of the final enzymatic product generated by xanthine oxidase in purine metabolism in humans', the labels 'uric acid' and 'urate' were used with similar frequency (63.0% and 62.5%, respectively), and both labels were used in 25.9% of articles. CONCLUSION: Labelling of the basic disease elements of gout is characterised by imprecision, inaccuracy and lack of clarity. Consensus regarding the nomenclature of these elements is required. PMID- 29706242 TI - Diagnostic utility of automated indirect immunofluorescence compared to manual indirect immunofluorescence for anti-nuclear antibodies in patients with systemic rheumatic diseases: A systematic review and meta-analysis. AB - OBJECTIVE: This study aimed to review and compare the analytical and clinical performance of automated indirect immunofluorescence (AIIF) and manual indirect immunofluorescence (MIIF) as anti-nuclear antibody screening assays for patients with systemic rheumatic diseases (SRDs), such as systemic lupus erythematosus (SLE) and systemic sclerosis (SSc). METHODS: A systematic literature search was performed in the Medline, Embase, Cochrane, Web of Science, and Scopus databases for studies published before August 2017. A bivariate random effects model was used to calculate the summary diagnostic values. RESULTS: Twenty-two studies involving 6913 positive and 1818 negative samples of MIIF, as well as 524 combined SRD, 132 SLE, and 104 SSc patients, and 520 controls were available for meta-analysis. The summary positive concordance (PC) of qualitative result between AIIF and MIIF was 93.7%, whereas PCs of total pattern (68.5%; homogeneous, 52.3%; speckled, 56.5%; nucleolar, 52.7%; centromere, 51.4%; nuclear dot, 11.7%) and titer (77.8%) exhibited significantly lower values. The summary clinical sensitivities of AIIF vs. MIIF were 84.7% vs 78.2% for combined SRDs, 95.5% vs. 93.9% for SLE, and 86.5% vs. 83.7% for SSc, respectively. Meanwhile, the summary specificities of AIIF vs. MIIF were 75.6% vs. 79.6% for combined SRDs, 74.2% vs. 83.3% for SLE, and 74.2% vs. 83.3% for SSc, respectively. Although the differences in sensitivity and specificity between AIIF and MIIF were not significant in most subgroups, the summary specificity of SLE and SSc showed statistically significant changes. CONCLUSIONS: Our systematic meta analysis demonstrates that AIIF is comparable to MIIF in distinguishing between the positive and negative results, and screening SRDs based on clinical sensitivities and standardization. However, improvements in the pattern and titer recognition and clinical specificities are necessary. PMID- 29706243 TI - Practical suggestions on intravenous iloprost in Raynaud's phenomenon and digital ulcer secondary to systemic sclerosis: Systematic literature review and expert consensus. AB - BACKGROUND: Systemic sclerosis (SSc) is an autoimmune chronic disease characterized by vascular impairment, immune dysfunction and collagen deposition. Raynaud's phenomenon (RP) and digital ulcers (DU) are prominent features of SSc. Intravenous (IV) iloprost (ILO), according to the recently updated EULAR recommendations, is indicated for RP after failure of oral therapy. Moreover, IV ILO could be useful in DU healing. IV ILO is currently available mainly on the European market approved for RP secondary to SSc with 3-5 days infusion cycle. Unfortunately, data published varies regarding regimen (dosage, duration and frequency). Up to now, ILO has been studied in small cohorts of patients and in few randomized controlled trials. METHODS: A systematic review of studies on IV ILO in patients with SSc complicated by DU and RP was performed. Insufficient data were available to perform a meta-analysis according to the GRADE system. We performed a three-stage internet-based Delphi consensus exercise. RESULTS: Three major indications were identified for IV ILO usage in SSc: RP non-responsive to oral therapy, DU healing, and DU prevention. IV ILO should be administered between 0.5 and 2.0ng/kg/min according to patient tolerability with a frequency depending on the indication. CONCLUSIONS: Although these suggestions are supported by this expert group to be used in clinical setting, it will be necessary to formally validate the present suggestions in future clinical trials. PMID- 29706244 TI - Model-based analyses of the cesium dynamics in the small mesotrophic reservoir Pond 4. II. Development of a rate-based kinetic model. PMID- 29706245 TI - Non-invasive bioluminescence imaging as a standardized assessment measure in mouse models of dermal inflammation. AB - BACKGROUND: Myeloperoxidase is used as a marker and diagnostic tool for inflammatory processes. Hypochlorous acid produced by myeloperoxidase oxidizes luminol to produce light. By injecting luminol into experimental animals, inflammatory processes can be tracked in real-time by bioluminescence imaging (BLI). OBJECTIVE: We aimed to establish BLI as a standardized assessment measure in three mouse models of dermal inflammation. METHODS: Oxazolone-induced delayed type-hypersensitivity (DTH) (acute), a model for dermatitis, imiquimod (IMQ) (sub chronic) model for psoriasis and the (chronic) bleomycin model for scleroderma were used. In the first two models, dexamethasone and clobetasol, respectively, were used as reference compounds. In all cases, classical readouts such as dermal swelling, severity scores and histological analyses were compared with in- vivo bioluminescence. RESULTS: In DTH, bioluminescence peaked earlier than ear swelling, reflecting early cell infiltration. Dexamethasone blocked both ear swelling and bioluminescence. In the IMQ model, bioluminescence closely reflected the psoriasis scores and histology and revealed a relapse-remitting course of the disease. Clobetasol partially decreased the disease severity. After stopping IMQ and clobetasol treatment, BLI adopted a rhythmic pattern during resolution. Bleomycin induced an increase in bioluminescence and in collagen thickness. BLI revealed a time-course of the effects of bleomycin that was not reflected by histology alone. CONCLUSION: For drug discovery and translational purposes, it is important that disease processes be tracked in vivo and possibly over a long period. We conclude that BLI is a valuable and reliable method for in-vivo measurement of dermal inflammation and potentially for inflammation resolution. PMID- 29706246 TI - Cross-Sectional Area Measurement of the Central Tarsometatarsal Articulation: A Review of Computed Tomography Scans. AB - Currently, disagreement exists regarding the superior method for repairing a ligamentous Lisfranc injury regarding whether to use arthrodesis or open reduction internal fixation. The 2 procedures differ in the amount of articular cartilage destroyed. Arthrodesis removes all the articular cartilage, and open reduction internal fixation places transarticular screws, essentially destroying a portion of cartilage. We performed a review of 30 consecutive computed tomography scans that included both foot length and undamaged first, second, and third tarsometatarsal joints to quantify the amount of articular surface area destroyed by placement of standardized 4-mm diameter screws. Measurements were performed using a freeform tool. The calculated surface area of the screws was subtracted from the measured surface area of the joint to yield the amount of surface area occupied by the screws. Our results demonstrated that the average amount of articular surface area destroyed in the first, second, and third tarsometatarsal joints was 4.87%, 4.79%, and 4.86% respectively, with a standard deviation of <1% for each of the joints. Our results have demonstrated that screw placement accounts for only a small percentage of articular surface destroyed. They also showed that the articular surface damage was comparable among the first 3 tarsometatarsal joints. Additionally, our results were similar to the articular surface area calculated from cadaveric specimens in a previous biomechanical study, demonstrating that computed tomography can allow for reliable and accurate assessments of articular surface areas in the foot. PMID- 29706247 TI - Publication Rates for Oral Manuscript and Poster Presentations From the American College of Foot and Ankle Surgeons: 2010 to 2014. AB - The American College of Foot and Ankle Surgeons (ACFAS) annual conference has served as a premiere platform to disseminate the latest innovations and research in the field of foot and ankle surgery. The quality of national society conferences is often assessed indirectly by analyzing the the journal publication rate of the abstracts presented. The purpose of this retrospective study was to assess the journal publication rate for abstracts (oral manuscripts and posters) accepted for presentation at the ACFAS conference from 2010 to 2014. All accepted abstracts from this period were compiled by the ACFAS office. PubMed, Google Scholar, and Scopus searches were performed using abstract titles and author names. Overall, the journal publication rate was 76.9% (83 of 108) for oral manuscripts and 23.2% (258 of 1113) for poster abstracts. The mean time to publication was 9.6 (range 0 to 44) months and 19.8 (range 0 to 66) months for oral and poster abstracts, respectively. The most common journal for abstract publication was The Journal of Foot and Ankle Surgery. Notably, the ACFAS oral manuscript publication rate from 2010 to 2014 (76.9%) exceeded its previously reported rate from 1999 to 2008 (67.5%) and the American Orthopaedic Foot and Ankle Society podium publication rate from 2008 to 2012 (73.7%). To the best of our knowledge, the publication incidence for oral abstracts presented at the ACFAS conference is now the highest reported of any national foot and ankle society conference to date. PMID- 29706248 TI - A new sign allowing diagnosis in the pathologies of the extensor tendons of the hand. AB - INTRODUCTION: The thorough knowledge of the anatomy of the extensor tendon system of the hand is crucial for clinical examination and detection of tendon injuries. The Juncturae between the EDCII and other extensor tendons presents different incidences, shapes ("r" or "y") and morphologies (Type I, II, III). The EIP does not receive connection. These characteristics may result in variable effects on extensor tendons during active finger movements. The purpose of this study is to investigate and describe a new sign helping diagnosis for injuries or pathologies of EIP and EDC index finger (EDC II), based on a cadaveric dissection and clinical observation. MATERIALS AND METHODS: The authors performed a clinical observational study in 520 patients in order to distinctly evaluate by means of inspection and palpation the EIP and EDC II tendons and an anatomical analysis of extensor tendon apparatus of long fingers was then performed in 89 cadaver hands focusing the investigation on the juncturae system. RESULTS: The observational studies showed that during the flexion of the III, IV and V fingers, associated to the active extension of the I and II fingers, the EDC of the III, IV and V fingers moved the EDC II in ulnar direction by means of juncturae action. The EIP remained in its position becoming visible and isolated from the migrated EDC II. CONCLUSIONS: This feature allows the distinct clinical evaluation by observation and palpation of both EDC II and EIP tendons and may be helpful in clinical conditions such as diagnosis of tendon lesions, pre-operative planning of EIP transfer and extensor tendon tenolysis associated to soft tissue scar at the second MPj. PMID- 29706249 TI - Isolated traumatic brain injury results in significant pre-hospital derangement of cardiovascular physiology. AB - INTRODUCTION: Major trauma can result in both life-threatening haemorrhage and traumatic brain injury (TBI). The pre-hospital management of these conditions, particularly in relation to the cardiovascular system, is very different. TBI can result in cardiovascular instability but the exact incidence remains poorly described. This study explores the incidence of cardiovascular instability in patients undergoing pre-hospital anaesthesia for suspected TBI. METHODS: Retrospective case series of all pre-hospital trauma patients attended by Kent, Surrey & Sussex Air Ambulance Trust (United Kingdom) trauma team during the period 1 January 2015-31 December 2016. Patients were included if they showed clinical signs of TBI, underwent pre-hospital anaesthesia and hospital computed tomography scanning subsequently confirmed an isolated TBI. RESULTS: Out of 121 patients with confirmed isolated TBI, 68 were cardiovascularly stable throughout the pre-anaesthesia phase, whilst 53 (44%) showed signs of instability (HR > 100bpm and/or SBP < 100 mmHg pre-anaesthesia). Hypotension (SBP < 100) with or without tachycardia was present in 14 (12%) patients. 10 (8%) patients with isolated TBI received pre-hospital blood product transfusion. CONCLUSION: Increased awareness that traumatic brain injury can cause significant derangement to heart rate and blood pressure, even in the absence of major haemorrhage, would allow the pre-hospital clinician to treat cardiovascular instability with the most appropriate means, such as crystalloid and vasopressors, to limit secondary brain injury. PMID- 29706250 TI - Incidence and severity of malreduction of the tibiofibular syndesmosis following surgical treatement of displaced ankle fractures and impact on the function Clinical study and MRI evaluation. AB - PURPOSE: To compare tibiofibular reduction quality in different types of operatively treated ankle fractures and the impact on clinical and functional outcome at mid-term follow-up. PATIENTS AND METHODS: One hundred patients with an acute ankle fracture who had undergone open reduction and internal fixation were included. Eighty-eight patients who suffered from ligamentous ankle injury with neither fracture nor syndesmotic lesions served as a control group. Tibiofibular alignment was measured on MR images in all 188 patients. In case of tibiofibular malreduction tibiotalar positioning was determined as well. Clinical and functional outcome was assessed using the AOFAS hindfoot score as well as the SF 36. RESULTS: No tibiofibular malreduction was found in type Weber B fractures, irrespective of syndesmotic instability followed by syndesmotic screw placement, as compared to the control group. A significant tibiofibular malreduction was detected in bimalleolar/trimalleolar/dislocated type Weber B fractures and in isolated type Weber C fractures with syndesmotic screw, in comparison to the control group. Tibiotalar displacement could not be detected. Clinical and functional outcome analysis revealed no significant differences between the treatment groups. CONCLUSION: Three-dimensional imaging may improve tibiofibular malreduction visualization in bimalleolar/trimalleolar/dislocated type Weber B fractures and in isolated type Weber C fractures with syndesmotic transfixation. The clinical impact of improving tibiofibular positioning remains highly questionable since there was no correlation between tibiofibular alignment and the clinical outcome at mid-term follow-up. PMID- 29706251 TI - A Brave New World Without Diagnostic Radiologists? Really? PMID- 29706252 TI - Gadolinium-Based Contrast Agents in Kidney Disease: Comprehensive Review and Clinical Practice Guideline Issued by the Canadian Association of Radiologists. AB - Use of gadolinium-based contrast agents (GBCAs) in renal impairment is controversial, with physician and patient apprehension in acute kidney injury (AKI), chronic kidney disease (CKD), and dialysis because of concerns regarding nephrogenic systemic fibrosis (NSF). The position that GBCAs are absolutely contraindicated in AKI, CKD stage 4 or 5 (estimated glomerular filtration rate [eGFR] <30 mL/min/1.73 m2) and dialysis-dependent patients is outdated, and may limit access to clinically necessary contrast-enhanced MRI examinations. Following a comprehensive review of the literature and reported NSF cases to date, a committee of radiologists and nephrologists developed clinical practice guidelines to assist physicians in making decisions regarding GBCA administrations. In patients with mild-to-moderate CKD (eGFR >=30 and <60 mL/min/1.73 m2), administration of standard doses of GBCA is safe and no additional precautions are necessary. In patients with AKI, with severe CKD (eGFR <30 mL/min/1.73 m2), or on dialysis, administration of GBCAs should be considered individually and alternative imaging modalities utilized whenever possible. If GBCAs are necessary, newer GBCAs may be administered with patient consent obtained by a physician (or their delegate), citing an exceedingly low risk (much less than 1%) of developing NSF. Standard GBCA dosing should be used; half or quarter dosing is not recommended and repeat injections should be avoided. Dialysis-dependent patients should receive dialysis; however, initiating dialysis or switching from peritoneal to hemodialysis to reduce the risk of NSF is unproven. Use of a macrocyclic ionic instead of macrocyclic nonionic GBCA or macrocyclic instead of newer linear GBCA to further prevent NSF is unproven. Gadopentetate dimeglumine, gadodiamide, and gadoversetamide remain absolutely contraindicated in patients with AKI, with stage 4 or 5 CKD, or on dialysis. The panel agreed that screening for renal disease is important but less critical when using macrocyclic and newer linear GBCAs. Monitoring for and reporting of potential cases of NSF in patients with AKI or CKD who have received GBCAs is recommended. PMID- 29706253 TI - Endoclip Magnetic Resonance Imaging Screening: A Local Practice Review. AB - PURPOSE: Not all endoscopically placed clips (endoclips) are magnetic resonance imaging (MRI) compatible. At many institutions, endoclip screening is part of the pre-MRI screening process. Our objective is to determine the contribution of each step of this endoclip screening protocol in determining a patient's endoclip status at our institution. METHODS: A retrospective review of patients' endoscopic histories on general MRI screening forms for patients scanned during a 40-day period was performed to assess the percentage of patients that require endoclip screening at our institution. Following this, a prospective evaluation of 614 patients' endoclip screening determined the percentage of these patients ultimately exposed to each step in the protocol (exposure), and the percentage of patients whose endoclip status was determined with reasonable certainty by each step (determination). RESULTS: Exposure and determination values for each step were calculated as follows (exposure, determination): verbal interview (100%, 86%), review of past available imaging (14%, 36%), review of endoscopy report (9%, 57%), and new abdominal radiograph (4%, 96%), or CT (0.2%, 100%) for evaluation of potential endoclips. Only 1 patient did not receive MRI because of screening (in situ gastrointestinal endoclip identified). CONCLUSIONS: Verbal interview is invaluable to endoclip screening, clearing 86% of patients with minimal monetary and time investment. Conversely, the limited availability of endoscopy reports and relevant past imaging somewhat restricts the determination rates of these. New imaging (radiograph or computed tomography) is required <5% of the time, and although costly and associated with patient irradiation, has excellent determination rates (above 96%) when needed. PMID- 29706254 TI - Mammography Clinical Image Quality and the False Positive Rate in a Canadian Breast Cancer Screening Program. AB - PURPOSE: The study sought to determine if mammography quality is associated with the false positive (FP) rate in the Quebec breast cancer screening program in 2004 and 2005. METHODS: Mammography quality of a random sample of screen-film mammograms was evaluated by an expert radiologist following the criteria of the Canadian Association of Radiologists. For each screening examination, scores ranging from 1 (poor quality) to 5 (excellent quality) were attributed for positioning, compression, contrast, exposure level, sharpness, and artifacts. A final overall quality score (lower or higher) was also given. Poisson regression models with robust estimation of variance and adjusted for potential confounding factors were used to assess associations of mammography quality with the FP rate. RESULTS: Among 1,209 women without cancer, there were 104 (8.6%) FPs. Lower overall mammography quality is associated with an increase in the FP rate (risk ratio [RR], 1.4; 95% confidence interval [CI], 1.0-2.1; P = .07) but this increase was not statistically significant. Artifacts were associated with an increase in the FP rate (RR, 2.1; 95% CI, 1.3-3.3; P = .01) whereas lower quality of exposure level was related to a reduction of the FP rate (RR, 0.4; 95% CI, 0.1 1.0; P = .01). Lower quality scores for all other quality attributes were related to a nonstatistically significant increase in the FP rate of 10%-30%. CONCLUSIONS: Artifacts can have a substantial effect on the FP rate. The effect of overall mammography quality on the FP rate may also be substantial and needs to be clarified. PMID- 29706255 TI - Magnetic Resonance Imaging of Cysts, Cystlike Lesions, and Their Mimickers Around the Knee Joint. AB - While interpreting routine magnetic resonance imaging (MRI) of the knee joint, a radiologist may encounter various cystic lesions such as ganglion, synovial, and meniscal cysts, among others. In some cases, MRI may demonstrate cystlike lesions around the knee due to fluid distention of normal bursa and recesses, the diagnosis of which should not be difficult if a radiologist is familiar with their characteristic location and MRI appearance. In addition, there are cyst mimickers such as hematomas, abscesses, vascular lesions, and neoplasms around knee joint that may pose a diagnostic challenge on routine MRI. Due to their atypical location and variable morphology, contrast administration is helpful as the enhancement pattern aids to differentiate them from cysts and cystlike lesions. This pictorial essay aims to classify cysts, cystlike lesions, and cyst mimickers in and around the knee joint based on their anatomic location and highlight their characteristic MRI features. PMID- 29706256 TI - Primary Total Hip Arthroplasty for Charcot Arthropathy is Associated With High Complications but Improved Clinical Outcomes. AB - BACKGROUND: Neuropathic (Charcot) arthropathy of the hip is rare but can lead to joint destruction, bone loss, and dysfunction. While total hip arthroplasty (THA) may be considered a treatment option, only very limited data in the form of case reports are available on the results of THA. The goal of this study was to analyze the outcomes of primary THA for Charcot arthropathy with emphasis on implant survivorship, complications, and clinical outcomes. METHODS: Eleven patients undergoing 12 primary THAs for Charcot arthropathy from 2007 to 2014 were retrospectively reviewed. All patients had a severe underlying neuropathy and clear radiographic evidence of Charcot arthropathy. Mean age was 54 years with 4 patients being female. Mean follow-up was 5 years. RESULTS: Survivorship free of any revision was 75% at both 2 and 5 years. Three THAs (3/12) were revised: 2 for recurrent instability and 1 for femoral component loosening. Survivorship free of any reoperation was 67% at both 2 and 5 years. One additional THA underwent open reduction and internal fixation of a Vancouver B1 periprosthetic fracture. The overall complication rate (including revisions and reoperations) was high at 58% with 3 recurrent dislocations, 2 periprosthetic fractures, 1 femoral component loosening, and 1 delayed wound healing. Harris Hip Scores improved from a mean of 43 preoperatively to 81 postoperatively (P < .001). CONCLUSION: In this study, the largest to date, we found that patients undergoing primary THA for Charcot arthropathy have a significant improvement in clinical outcomes but that there was a high risk of early complications and revisions, mostly related to recurrent instability. Specific precautions to avoid early complications, namely utilization of components that provide robust fixation and strategies that provide enhanced hip stability, should be considered. LEVEL OF EVIDENCE: Level IV. PMID- 29706257 TI - Primary Total Knee Arthroplasty in Patients With Neuropathic (Charcot) Arthropathy: Contemporary Results. AB - BACKGROUND: Total knee arthroplasty (TKA) for neuropathic (Charcot) arthropathy is technically challenging with higher complication rates than primary TKA for osteoarthritis. There is a paucity of data regarding outcomes of TKA in contemporary cohorts with modern implants, techniques, and indications. Our study aimed to determine the (1) survivorship of implants, (2) rates and types of complications, (3) clinical outcomes, and (4) radiographic outcomes in patients treated with primary TKA for Charcot arthropathy. METHODS: Twenty-seven patients undergoing 37 TKAs for Charcot arthropathy from 2000 to 2015 were retrospectively reviewed. Mean patient age and follow-up were 60 years and 6 years, respectively. Eighty-one percent were treated with either a varus-valgus constrained or rotating-hinge device, and 81% had supplemental stem fixation. Metaphyseal cones were utilized in 19% of cases. RESULTS: The 10-year survivorship free of aseptic revision was 88% and free of any revision was 70%. There were 6 revisions (16%): 4 for infection, 1 for tibial component loosening, and 1 for global instability. There were 3 reoperations (8%). Additional complications occurred in 6 patients (16%) including 3 patients with an intraoperative fracture. Mean Knee Society scores improved from 37 preoperatively to 82 postoperatively (P < .001). There was no radiographic evidence of component loosening in any unrevised knee at latest follow-up. CONCLUSIONS: Primary TKA for Charcot arthropathy with selective use of increased constraint and enhanced metaphyseal component fixation led to significant improvement in pain and clinical outcomes when compared with older techniques; however, there was a high perioperative complication rate. While 10 year survivorship free of aseptic revision was 88%, periprosthetic joint infection led to the poorer survivorship free of any revision of 70% at 10 years. LEVEL OF EVIDENCE: Level IV. PMID- 29706258 TI - Proceedings of the 2017 AAHKS Meeting. PMID- 29706259 TI - New Technologies in Knee Arthroplasty. PMID- 29706260 TI - An Experimental Study of Laser in situ Fenestration of Current Aortic Endografts. AB - OBJECTIVE/BACKGROUND: Laser in situ fenestration (LISF) is emerging as an immediately available alternative in the endovascular treatment of complex aortic aneurysm. However, its biomechanical features remain poorly understood. The aim of this study was to experimentally evaluate textile damage secondary to LISF and to compare LISF with mechanical in situ fenestration (MISF). METHODS: An in vitro study evaluated the damage created by LISF on endograft fabrics versus MISF using a needle. Five different models of commercially available aortic endografts were used (32 samples of polyethylene terephthalate and expanded polytetrafluoroethylene fabrics). Tensile strength tests were performed on the fabrics before and after in situ fenestration, to determine the loss of mechanical strength. Integral water permeability tests at the stent-fenestration interface evaluated the watertightness of junctions. Stability of the connection was assessed with a fatigue bench test flexing the branch on the fenestration. In a second step, an in vivo study evaluating LISF in sheep was conducted. RESULTS: Resulting holes had circular and cauterised edges following LISF, whereas fabric filaments were pushed aside after MISF. Tensile tests demonstrated a 34% and a 27% mechanical resistance loss after LISF (p = .004) and MISF (p = .001) compared with non-fenestrated samples. A non-significant global decrease of 7% in mechanical resistance was found following LISF compared with MISF (p = .520). Water permeability tests highlighted that leak rates were higher following LISF than with MISF with regard to multifilament specimens (p < .05). Fatigue tests induced modification of the morphology of fenestrations. The surface area of the fenestration was increased for all samples after 170,000 cycles. Regarding the in vivo study, 14 LISF were performed in 12 sheep with a technical success rate of 88%. CONCLUSION: This study demonstrates that both LISF and MISF create substantial damage to all available endograft fabrics. Until comparisons with reinforced fenestrations are performed, LISF and MISF should not be used outside investigational studies. PMID- 29706261 TI - Garlic and Gaseous Mediators. AB - Garlic (Allium sativum) and allied plant species are rich sources of sulfur compounds. Major roles for garlic and its sulfur constituents include the regulation of vascular homeostasis and the control of metabolic systems linked to nutrient metabolism. Recent studies have indicated that some of these sulfur compounds, such as diallyl trisulfide (DATS), alter the levels of gaseous signalling molecules including nitric oxide (NO), hydrogen sulfide (H2S), and perhaps carbon monoxide (CO) in mammalian tissues. These gases are important in cellular processes associated with the cardiovascular system, inflammation, and neurological functions. Importantly, these studies build on the known biological effects of garlic and associated sulfur constituents. This review highlights our current understanding of the health benefits attributed to edible plants like garlic. PMID- 29706262 TI - The Importance of Sodium Restrictions in Chronic Kidney Disease. PMID- 29706263 TI - Clinical pharmacy academic career transitions: Viewpoints from the field. AB - The six authors of this commentary series, who have recently transitioned into or within an academic career, discuss challenging aspects of an academic career change. This is a three-part commentary series that explores select challenges: 1) feedback, evaluation, and advancement; 2) understanding and balancing of distribution of effort; 3) learning how and when to say yes. Faculty, or those interested in pursuing a career in pharmacy academia, can refer to this commentary series as a reference. Schools of pharmacy may utilize this as a tool for new faculty members during orientation in order to ensure smooth integration into the academic environment. PMID- 29706264 TI - Clinical pharmacy academic career transitions: Viewpoints from the fieldPart 1: Understanding feedback, evaluation, and advancement. AB - The six authors of this commentary series, who have recently transitioned into or within an academic career, discuss challenging aspects of an academic career change. This is a three-part commentary series that explores select challenges: 1) feedback, evaluation and advancement; 2) understanding and balancing of distribution of effort; 3) learning how and when to say yes. Faculty, or those interested in pursuing a career in pharmacy academia, can refer to this commentary series as a reference. Schools of pharmacy may utilize this as a tool for new faculty members during orientation in order to ensure smooth integration into the academic environment. PMID- 29706265 TI - Clinical pharmacy academic career transitions: Viewpoints from the field Part 2: Understanding and balancing the distribution of effort. AB - INTRODUCTION: The six authors of this commentary series, who have recently transitioned into or within an academic career, discuss challenging aspects of an academic career change. The authors represent faculty members teaching within a large, state-funded, research-intensive School of Pharmacy located within a large academic health center. The authors have various backgrounds and represent individuals making transitions at various points in their careers (from residency into academia, from a non-academic environment into academia, and from one academic environment to another). COMMENTARY: This is Part 2 of a three-part commentary series that focuses on understanding and balancing the distribution of effort. Parts 1 and 3 of this commentary series explore feedback, evaluation and advancement; and learning when and how to say yes, respectively. While the entire series is intended to be read in continuity, faculty, or those interested in pursuing a career in pharmacy academia, can refer to Part 2 as a reference to aid in understanding and balancing the different components and the distribution of effort associated with a position in academic pharmacy, specifically. IMPLICATIONS: Schools of Pharmacy may utilize this as a tool for new faculty members during orientation in order to help ensure faculty success. PMID- 29706266 TI - Clinical pharmacy academic career transitions: Viewpoints from the field part 3: Learning when and how to say yes. AB - The six authors of this commentary series, who have recently transitioned into or within an academic career, discuss challenging aspects of an academic career change. This is Part 3 of a three-part commentary series that focuses on when and how to say yes to the multitude of opportunities available to pharmacy practice faculty. Part 1 discusses feedback, evaluation, and advancement. Part 2 explains distribution of effort (DOE) and how to marry the different components of teaching, research, and service. While the entire series is intended to be read in continuity, faculty, or those interested in pursuing a career in pharmacy academia, can refer to Part 3 as a reference on how to screen opportunities within academia to maximize professional and personal growth and minimize career burnout. Schools of pharmacy may utilize this as a tool for new faculty members during orientation to help ensure faculty success. PMID- 29706267 TI - Students' versus residency programs' perceptions of a high-quality PGY1 residency applicant. AB - INTRODUCTION: Securing a pharmacy residency position is highly competitive, and pharmacy students must work throughout pharmacy school to ensure their applications are as competitive as possible. Several surveys asking residency programs to describe the most crucial qualities of a high-quality residency candidate have been conducted. However, no study has investigated whether congruency exists between pharmacy students' and residency programs' perceptions of these sought-after qualities. METHODS: We surveyed pharmacy students to compare their perceptions of important qualities of residency candidates for securing an interview and ultimately being ranked by residency programs. The results were compared to results of an identical previously-published survey of residency program directors. RESULTS: Student and program perceptions of important qualities of residency candidates were mostly in agreement. Students' perceptions of qualities considered for final ranking of candidates are similar among pharmacy students in professional years 1-3 (P1-P3). However, P3 students' perceptions of qualities important for interview invitations are better aligned with residency programs than P1 and P2 students. DISCUSSION: Students' and programs' perceptions of important qualities for residency candidates were well aligned on most items. However, only students perceived a letter of recommendation from the dean and North American Pharmacist Licensure Examination (NAPLEX) scores as an important factor for residency. As the pharmacy curriculum progresses, students' and residency programs' perceptions of the most important qualities used to ultimately rank candidates appear to converge; however, perceptions of important characteristics for an interview invitation were consistent over time. CONCLUSIONS: Overall, perceptions of components of a high quality residency applicant are congruent between residency programs and students. PMID- 29706268 TI - Assessing experiential education factors contributing to a PGY1 residency match: Pharmacy residency program director and comparative student survey. AB - OBJECTIVE: To compare and contrast experiential education perceptions of pharmacy residency program directors (RPDs) and doctor of pharmacy students in their last year of the curriculum for residency application considerations. METHODS: The New England Regional Departments of Experiential Education (NERDEE) consortium developed a 17-question survey to assess residency factors, including those related to experiential education. The survey was dispersed to advanced pharmacy practice experience (APPE) students from six colleges/schools of pharmacy and RPDs nationwide. RESULTS: Students have different values on experiential preferences compared to RPDs. Sample findings include internal medicine and specialty clinical elective experiences prior to American Society of Health System Pharmacists (ASHP) Midyear were extremely important to important for students, while RPDs viewed these experiences as somewhat important at best (p < 0.02). The majority of RPDs (67%) have no APPE schedule preference, while most students (77%) feel that certain APPE schedules may influence acceptance into residency. CONCLUSION: Based on findings, information outlined can be used to dispel and/or validate common beliefs held by students regarding experiential factors that help or hinder a successful postgraduate year 1 (PGY1) residency match. PMID- 29706269 TI - Traditional matriculation vs an early assurance program: Effect on elected student leadership positions and academic performance. AB - INTRODUCTION: The objective of this study was to compare leadership and academic performance among students admitted by traditional pathways vs. a dual acceptance program (DAP). METHODS: A list of students admitted to the Midwestern University Chicago College of Pharmacy (MWUCCP) DAP was cross-checked with students elected to serve in leadership positions and students on the MWUCCP Dean's List for their first professional year from 2010 to 2015. The proportion of students serving in leadership positions and those on the Dean's List were compared to students that matriculated via the traditional route. RESULTS: In total, 1069 students were analyzed (n = 937 traditional; n = 132 DAP). DAP students were more likely to have an elected leadership role (n = 61, 46.2% vs. n = 314, 33.5%, p < 0.01) and achieve Dean's List for their first professional year (n = 64, 48.5% vs. n = 292, 31.2%, p < 0.01) compared to traditional students. DISCUSSION AND CONCLUSIONS: DAP students were more likely to hold an elected leadership position than traditional students. Further study of DAP student motivation is needed to potentially assist in the success of other students. PMID- 29706270 TI - Prevalence and characteristics of pharmacies owned and operated by schools of pharmacy in the United States. AB - INTRODUCTION: To identify schools/colleges of pharmacy that own and operate a pharmacy and to gather key details about such pharmacies. METHODS: Schools of pharmacy (n = 134) in the United States were contacted to determine whether they own and operate a pharmacy. Schools identified as having a pharmacy were subsequently sent an online questionnaire to solicit information about school and pharmacy characteristics. RESULTS: Eighteen (13.4%) schools reported owning and operating at least one pharmacy; of these, 14 (77.8%) responded to the questionnaire. The provision of education was a goal for all pharmacies. Pharmacy services were provided to students, faculty/staff, and community members (85.7%, 78.6%, and 50%, respectively). Student pharmacists were regularly involved in the operations of 13 (92.9%) pharmacies, largely as part of their introductory and advanced pharmacy practice experiences and/or as paid employees. CONCLUSION: Few schools of pharmacy in the United States own and operate a pharmacy. These pharmacies primarily serve as teaching and learning venues and provide services to the campus community and/or the community at large. PMID- 29706271 TI - Preceptor's grading scale preference for student pharmacy practice experience and assessment of the common grading scale among US schools of pharmacy. AB - INTRODUCTION: The objective of this study was to gain an understanding of preceptors' grading scale preferences for introductory and advanced pharmacy practice experiences (IPPE/APPE). Secondarily, assess if there is a common grading scale for IPPE/APPE rotations among US pharmacy programs. METHODS: An online, 22-item survey questionnaire was sent to all preceptors at a fully accredited school of pharmacy. The survey instrument assessed preceptor attitudes toward the effectiveness of the primary grading scales, letter or pass/no pass. Demographic variables were also assessed, including gender, age, practice setting, years as a preceptor, and annual number of students precepted. In addition, a phone survey was conducted with all pharmacy programs in the United States at the time to assess grading scales used for introductory and advanced pharmacy practice experiences (IPPE/APPEs). RESULTS: Three hundred sixty-five preceptors responded to the survey questionnaire. Overall, preceptors had more favorable attitudes toward the letter grade system as opposed to the pass/no pass system, and when asked specifically which they preferred, approximately 70% preferred the letter grading system. The phone survey of different pharmacy programs grading systems revealed most use the letter grading system. Fifty-six of 87 responding schools (64%) reported use of a letter grading system, compared to 26 of 87 (30%) using a pass/no pass system and five using 'other variations' (6%). CONCLUSION: The majority of preceptors preferred the letter grading system over the pass/no pass system. Familiarity with this system was a contributing factor, as a significant number of preceptors preferred the grading scale they had as a pharmacy student - the letter grade system. This trend mimics current pharmacy school's grading system, as approximately 2/3 currently use a letter grading system to evaluate IPPE/APPEs. PMID- 29706272 TI - Using peer teaching to introduce the Pharmaceutical Care Model to incoming pharmacy students. AB - BACKGROUND: The aim of this initiative was to design and evaluate a peer teaching activity where pairs of second-year pharmacy students introduced the Pharmaceutical Care Model and discussed success in the broader first-year pharmacy curriculum with pairs of first year students. EDUCATIONAL ACTIVITY: Second-year pharmacy students individually created concept maps illustrating the main components of pharmaceutical care to be used as teaching tools with first year students. First-year students were given a brief introduction to pharmaceutical care by faculty and prepared questions to ask their second-year colleagues. Two second-year students were then matched with two first-year students for a two-part peer teaching event. Each student completed documentation of the peer experience, which included questions about the effectiveness of the teaching, changes to be made in the future, and the usefulness of the exercise. The documentation was analyzed via content analysis and instructors evaluated the concept maps based on their effectiveness as a teaching tool for novices. A rubric was used to evaluate 166 concept maps of which 145 were rated good, 18 were rated as better, and 3 as best. Themes emerging from the content analysis included: positive impact of teaching and learning pharmaceutical care, value of broader curriculum discussion, and beneficial first- and second-year connections. CRITICAL ANALYSIS OF THE EDUCATIONAL ACTIVITY: A structured peer teaching event outside the traditional classroom setting can create a space for: teaching and learning to occur, student-student connections to be made, and advice on the curriculum to be shared. PMID- 29706273 TI - Assessment of a simulated contraceptive prescribing activity for pharmacy students. AB - BACKGROUND AND PURPOSE: The role of the pharmacist has been shifting rapidly. One example of change is the passage of legislation allowing pharmacists to independently initiate self-administered hormonal contraceptives in several states. There is no evidence of this specific topic being covered in pharmacy school curricula, and many states are requiring additional post-graduate training. This activity was designed to determine the utility of a contraceptive prescribing simulation activity for pharmacy students. EDUCATIONAL ACTIVITY AND SETTING: Pharmacy students enrolled in a women's health elective learned about relevant state legislation and attended a clinical skills center simulation activity where they utilized an available prescribing algorithm. Students completed two scenarios and received grades based on their clinical decision making and patient interaction skills. An electronic survey was distributed post activity to assess student satisfaction and confidence when prescribing contraceptives. Responses and grades on the assignment were analyzed to determine the activity's utility. FINDINGS: Students finished with median scores of 15, 14.8, and 14.5 out of 15 possible points for the three scenarios. Students reported overall satisfaction with the activity, with general agreement that the activity was realistic and made them feel like they were prepared to prescribe contraceptives. SUMMARY: Independently initiating contraceptives is a novel practice area for pharmacists. This activity introduced students to the process of prescribing using realistic forms and scenarios. The utility of the activity was twofold - it introduced students to the changing environment of pharmacy practice and allowed students to apply their knowledge of contraceptives and women's health. Students performed well on the activity and reported high levels of satisfaction. PMID- 29706274 TI - "How do I say that?": Using communication principles to enhance medication therapy management instruction. AB - BACKGROUND AND PURPOSE: Medication therapy management (MTM) is a comprehensive, patient-centered approach to improving medication use, reducing the risk of adverse events and improving medication adherence. Given the service delivery model and required outputs of MTM services, communication skills are of utmost importance. The objectives of this study were to identify and describe communication principles and instructional practices to enhance MTM training. EDUCATIONAL ACTIVITY AND SETTING: Drawing on formative assessment data from interviews of both pharmacy educators and alumni, this article identifies and describes communication principles and instructional practices that pharmacy educators can use to enhance MTM training initiatives to develop student communication strategies. FINDINGS: Analysis revealed five key communication challenges of MTM service delivery, two communication principles that pharmacy teachers and learners can use to address those challenges, and a range of specific strategies, derived from communication principles, that students can use when challenges emerge. Implications of the analysis for pharmacy educators and researchers are described. SUMMARY: Proactive communication training provided during MTM advanced pharmacy practice experiences enabled students to apply the principles and instructional strategies to specific patient interactions during the advanced pharmacy practice experiences and in their post-graduation practice settings. PMID- 29706275 TI - Medical apps used during advanced pharmacy practice experiences. AB - BACKGROUND AND PURPOSE: The purpose of this study was to determine what type of medical applications (apps) are being used by fourth-year students during advanced pharmacy practice experiences (APPEs). EDUCATIONAL ACTIVITY AND SETTING: Recent doctor of pharmacy school graduates were surveyed pertaining to their use of medical apps on APPEs, frequency of use for select apps, willingness to buy apps and at what cost, and their perceived importance on using medical apps in their pharmacy practice. The survey concluded by inquiring if medical apps should be taught in the pharmacy curriculum. FINDINGS: Ninety of 132 recent graduates responded to the survey and over 97% of the students used medical apps on their APPEs. Lexicomp(r), UpToDate(r) and the Atherosclerotic Cardiovascular Disease (ASCVD) Risk calculator were the most frequently used applications during APPEs. Of those surveyed, 83% believe that medical apps should be taught in pharmacy school. DISCUSSION AND SUMMARY: Medical apps are frequently used on APPEs. It may be prudent to teach students how to use and evaluate medical apps before going on experiences so that students and patients can get the most benefit from these tools. PMID- 29706276 TI - Comparison of faculty and student self-assessment scores of aseptic technique skills and the impact of video review on self-awareness for second-year pharmacy students. AB - BACKGROUND AND PURPOSE: Educating students about aseptic technique presents many challenges. Students at Drake University have limited exposure to this skill outside of the classroom setting, and students have previously shown a lack of awareness related to their own aseptic technique skills. One approach to developing self-awareness in this area may be the incorporation of activities involving video viewing and self-reflection. EDUCATIONAL ACTIVITY AND SETTING: Second-year pharmacy students in the Intermediate Pharmacy Skills and Applications 2 course completed four total aseptic technique activities, each of which was assessed by faculty using a standardized assessment tool. Each student was video-recorded during one of these aseptic technique activities. Students were asked to self-reflect on their performance immediately after the activity and again after viewing the video recording of their performance (using the same criteria included in a standardized faculty assessment tool). Student self reflection scores before and after video viewing were then compared to faculty scores. FINDINGS: One-hundred six students participated in the video recording and self-reflection activity. Compared to faculty assessment scores, there was no significant difference between the self-reflections before or after video viewing (p = 0.571). DISCUSSION: Video self-reflection had no significant impact on the ability to accurately self-assess aseptic technique skills, but this study did reveal several other opportunities for future teaching and research. SUMMARY: Future efforts to impact student self-awareness should include additional self reflection instruction, repeated self-reflection activities conducted over the course of a semester, and improved video recording technology. PMID- 29706277 TI - Use of condensed videos in a flipped classroom for pharmaceutical calculations: Student perceptions and academic performance. AB - BACKGROUND AND PURPOSE: The flipped teaching method was implemented through a series of multiple condensed videos for pharmaceutical calculations with student perceptions and academic performance assessed post-intervention. EDUCATIONAL ACTIVITY AND SETTING: Student perceptions from the intervention group were assessed via an online survey. Pharmaceutical exam scores of the intervention group were compared to the control group. The intervention group spent a greater amount of class time on active learning. FINDINGS: The majority of students (68.2%) thought that the flipped teaching method was more effective to learn pharmaceutical calculations than the traditional method. The mean exam scores of the intervention group were not significantly different than the control group (80.5 +/- 15.8% vs 77.8 +/- 16.8%; p = 0.253). DISCUSSION: Previous studies on the flipped teaching method have shown mixed results in regards to student perceptions and exam scores, where either student satisfaction increased or exam scores improved, but rarely both. SUMMARY: The flipped teaching method was rated favorably by a majority of students. The flipped teaching method resulted in similar outcomes in pharmaceutical calculations exam scores, and it appears to be an acceptable and effective option to deliver pharmaceutical calculations in a Doctor of Pharmacy program. PMID- 29706278 TI - Educational outcomes associated with early immersion of second-year student pharmacists into direct patient care roles in health-system practice. AB - BACKGROUND AND PURPOSE: To assess the educational impact of engaging second professional year student pharmacists in active, direct patient care experiences in health system practice. EDUCATIONAL ACTIVITY AND SETTING: Student pharmacists in their second professional year completed a redesigned, skill-based four-week introductory pharmacy practice experience in health system practice. The immersion consisted of experiences in both operational and clinical pharmacy environments. Students were assessed with skill development checklist assessments. Pre-post surveys were also collected. Data were analyzed using a mixed methods approach. FINDINGS: Twenty-eight student pharmacists were included; of those, 26 completed both surveys (92.9% response rate). Survey results revealed significant increases in 81.8% of operational and 100% of clinical self efficacy statements (p<0.05) and positive perceptions of the program overall. Overall, findings suggested that student pharmacists developed skills in health system practice while identifying additional areas for emphasized learning. SUMMARY: Student pharmacists engaged in early, hands-on, direct patient care experiences enhanced their skill development in operational and clinical pharmacy practice. PMID- 29706279 TI - A pilot IPE workshop integrating OT, pharmacy, PT, and PA programs. AB - BACKGROUND AND PURPOSE: This article describes the development, implementation, and evaluation of an interprofessional education (IPE) experience. EDUCATIONAL ACTIVITY AND SETTING: The IPE experience included 53 student learners from occupational therapy, pharmacy, physical therapy, and physician assistant programs at the University of the Sciences (USciences). This experience used an icebreaker activity and a stroke case-based activity as the activities within the workshop. The core faculty utilized the jigsaw technique to increase student confidence with uni-profession and interprofessional discussions of the patient case. Learners were asked to evaluate their perceptions of the IPE learning experience. FINDINGS: Results from a summative quality improvement evaluation indicated that learners had positive perceptions of this curricular innovation. DISCUSSION: This pilot IPE workshop illustrates the possibilities for collaboration among health professional programs at USciences, a private health sciences university without an affiliated medical center. SUMMARY: Discussion of the process to create, implement, and evaluate this pilot IPE activity is imperative due to increased expectations within professional accrediting guidelines in regards to IPE. PMID- 29706280 TI - Students views of an online ethical decision-support tool. AB - BACKGROUND AND PURPOSE: Ethical reasoning is a key skill that must be developed during the undergraduate pharmacy course to prepare students for ethical decision making in future practice as pharmacy professionals. In this initial study, we sought and documented the views of pharmacy students at a United Kingdom (UK) university on the use of Values ExchangeTM (Vx), an online ethical decision support tool. EDUCATIONAL ACTIVITY AND SETTING: Students deliberated on up to three ethical case scenarios every academic year using the tool. A preliminary study using a qualitative methodology was conducted with students nearing the end of their third-year of study to explore their views of the tool. Two focus groups were used to collect the data. Discussions were digitally recorded, anonymised and transcribed verbatim. Data was analysed using the five-stage framework approach. FINDINGS: Four main themes emerged from the data: students felt that Values ExchangeTM enabled them to gain a wider perspective on ethical issues; it promoted reflection; it helped to prepare them for future practice; students liked the online environment. DISCUSSION: Vx prompted students to deliberate on many facets of a case, enabled them to consider and challenge the views of their peers, facilitated reflection and promoted greater honesty in responses and inclusivity, all supporting the development of moral reasoning skills. SUMMARY: Vx supports the process of ethical decision-making, encouraging a deep approach to learning within a safe virtual environment. Students believed Vx to be an effective tool for developing ethical reasoning skills in preparation for practice. PMID- 29706281 TI - Using a course pilot in the development of an online problem-based learning (PBL) therapeutics course in a post-professional PharmD program. AB - BACKGROUND AND PURPOSE: To assess whether the traditional problem-based learning (PBL) process can be replicated in an online environment, and to identify any barriers and facilitators to learning using a course pilot. EDUCATIONAL ACTIVITY AND SETTING: Eight alumni and one experienced tutor participated in a two-week simulated PBL course comprised of two three-hour synchronous online tutorials. Blackboard Collaborate(r) software was used to permit audio and visual interaction. The PBL tutorials were recorded and observed by the researchers. Participants completed satisfaction surveys after the pilot, and were invited to take part in a focus group to debrief about their experience. FINDINGS: Once the steep learning curve with the technology was overcome, the quality of the PBL process was similar in the online course as it was in the face-to-face course. Several key factors for success were identified through analysis of the videotaped sessions, and interviews with the participants in the course pilot. SUMMARY: Conducting a course pilot study demonstrated that an online PBL course is feasible, and identified some considerations to facilitate success. PMID- 29706282 TI - Perceptions and performance using computer-based testing: One institution's experience. AB - BACKGROUND AND PURPOSE: The purpose of this study was to evaluate student and faculty perceptions of the transition to a required computer-based testing format and to identify any impact of this transition on student exam performance. EDUCATIONAL ACTIVITY AND SETTING: Separate questionnaires sent to students and faculty asked about perceptions of and problems with computer-based testing. Exam results from program-required courses for two years prior to and two years following the adoption of computer-based testing were compared to determine if this testing format impacted student performance. FINDINGS: Responses to Likert type questions about perceived ease of use showed no difference between students with one and three semesters experience with computer-based testing. Of 223 student-reported problems, 23% related to faculty training with the testing software. Students most commonly reported improved feedback (46% of responses) and ease of exam-taking (17% of responses) as benefits to computer-based testing. Faculty-reported difficulties were most commonly related to problems with student computers during an exam (38% of responses) while the most commonly identified benefit was collecting assessment data (32% of responses). Neither faculty nor students perceived an impact on exam performance due to computer-based testing. An analysis of exam grades confirmed there was no consistent performance difference between the paper and computer-based formats. DISCUSSION AND SUMMARY: Both faculty and students rapidly adapted to using computer-based testing. There was no evidence that switching to computer-based testing had any impact on student exam performance. PMID- 29706283 TI - A unique degree program for pre-pharmacy education: An undergraduate degree in pharmaceutical sciences. AB - BACKGROUND AND PURPOSE: Within the coming decade, the demand for well-trained pharmacists is expected to only increase, especially with the aging of the United States (US) population. EDUCATIONAL ACTIVITY AND SETTING: To help fill this growing demand, the University of California, Irvine (UCI) aims to offer a unique pre-pharmacy degree program and has developed a Bachelor of Science (BS) degree in Pharmaceutical Sciences to help achieve this goal. In this commentary, we share our experience with our curriculum and highlight its features in an effort to encourage other institutions to enhance the learning experience of their pre pharmacy students. FINDINGS: The efforts of the UCI Department of Pharmaceutical Sciences has resulted in UCI being consistently ranked as one of the top feeder institutions by the Pharmacy College Application Service (PharmCAS) in recent years. DISCUSSION AND SUMMARY: The UCI Pharmaceutical Sciences Bachelor of Science offers a unique pre-pharmacy educational experience in an effort to better prepare undergraduates for the rigors of the doctorate of pharmacy curriculum. PMID- 29706284 TI - Ulipristal acetate for the management of large uterine fibroids associated with heavy bleeding: a review. AB - Ulipristal acetate (UPA), a selective progesterone receptor modulator (SPRM), offers new therapeutic options for the clinical management of large uterine fibroids associated with heavy menstrual bleeding or with other moderate or severe symptoms (bulk symptoms, pelvic pain, decreased quality of life). SPRM are synthetic compounds that exert an agonist or antagonist effect on target tissues by their binding to progesterone receptors. UPA reduces fibroid size, controls bleeding in a high percentage of women and significantly improves quality of life. The present review aims to provide insights into UPA indications and its mechanism of action. PMID- 29706285 TI - Blastocyst vitrification, cryostorage and warming does not affect live birth rate, infant birth weight or timing of delivery. AB - RESEARCH QUESTION: Does vitrification and warming affect live birth rate, infant birth weight and timing of delivery? DESIGN: Retrospective, cohort study comparing outcomes of donor oocyte recipient fresh (n = 25) versus vitrified (n = 86) euploid blastocyst transfers; donor oocyte recipient singleton live births from fresh (n = 100) versus vitrified (n = 102) single embryo transfers (SET); and autologous vitrified euploid SET (n = 1760) (cryostored 21-1671 days). RESULTS: Group 1: fresh and vitrified-warmed blastocysts had similar live birth (OR 1.7; 95% CI 0.5 to 5.9), implantation (OR 0.9; 95% CI 0.2 to 3.9), clinical pregnancy (OR 3.4; 95% CI 0.9 to 13.0) and pregnancy loss (OR 1.2; 95% CI 0.98 to 1.4); group 2: low birth weight (OR 0.44; 95% CI 0.1 to 1.6) and preterm delivery (0.99; 95% CI 0.4 to 2.3) rates were similar in fresh and vitrified-warmed blastocyst transfers; group 3: cryostorage duration did not affect live birth (OR 1.0; 95% CI 1.0 to 1.0), implantation (OR 1.0; 95% CI 0.99 to 1.01), clinical pregnancy (OR 1.0; 95% CI 1.0 to 1.0]), pregnancy loss (OR 0.99; 95% CI 1.0 to 1.0), birth weight (beta = -15.7) or gestational age at delivery (beta = -0.996). CONCLUSIONS: Vitrification and cryostorage (up to 4 years) are safe and effective practices that do not significantly affect clinical outcome after embryo transfer. PMID- 29706286 TI - Practice Standards Developed and Quality Improvement for Use of Coronary CT Angiography in Taiwan. PMID- 29706287 TI - The Pareto Principle. PMID- 29706288 TI - Can cerebrospinal fluid diversion be beneficial in the treatment of chronic fatigue syndrome? PMID- 29706290 TI - Response to "Re. Early versus delayed closure of bladder exstrophy: A National Surgical Quality Improvement Program Pediatric analysis". PMID- 29706289 TI - Urinary antimicrobial peptides: Potential novel biomarkers of obstructive uropathy. AB - INTRODUCTION: Antimicrobial peptides (AMPs) have historically been evaluated for their role in protecting against uropathogens. However, there is mounting evidence to support their expression in noninfectious injury, with unclear meaning as to their function. It is possible that AMPs represent urothelial injury. Urinary tract obstruction is known to alter the urothelium; however, AMPs have not been evaluated for expression in this noninfectious injury. OBJECTIVE: A pilot study to compare urinary AMP expression in children undergoing surgical intervention for ureteropelvic junction obstruction (UPJO) with nonobstructed controls. STUDY DESIGN: Bladder urine was collected from consenting/assenting pediatric patients with UPJO at intervention. Control bladder urines were obtained from age-matched and sex-matched healthy children without known obstruction or infection. Enzyme-linked immunosorbent assays were run for the following AMPs: beta defense 1 (BD-1), neutrophil gelatinase-associated lipocalin (NGAL), cathelicidin (LL-37), hepatocarcinoma-intestine-pancreas/pancreatitis associated protein (HIP/PAP), and human alpha defensin 5 (HD-5); and normalized to urine creatinine. Results were analyzed with Student's t-test or Mann-Whitney U test, when appropriate, and receiver operating characteristic curves. A P-value of <0.05 was considered significant. RESULTS: Thirty bladder urine samples were obtained from children with UPJO at the time of decompressive intervention. Mean patient age was 4.7 years (range 0.3-18.4); 20 (67%) patients were male. Fifteen bladder urine samples were obtained from age-matched and sex-matched controls. Urinary AMP levels were significantly higher in UPJO patients than controls for BD-1 (P = 0.015), NGAL (P < 0.001), LL-37 (P < 0.001), and HIP/PAP (P = 0.046). Optimal threshold values of these AMPs were determined, with each demonstrating significant odds ratios of predicting urinary obstruction. DISCUSSION: Certain urinary AMPs are altered even in noninfectious urinary tract pathology. This represents a novel induction of AMP expression, as the current study is the first to report elevations in BD-1 and HIP/PAP in urinary tract obstruction. This suggests other roles for these AMPs outside of their antimicrobial properties, and likely is a reflection of the urothelial and tubular stress resulting from obstructive uropathy. CONCLUSIONS: Induction of AMPs BD-1, NGAL, LL-37, and HIP/PAP was found to occur in urinary tract obstruction. Further evaluation of AMP expression as a biomarker of uroepithelial injury outside of infection is indicated. PMID- 29706291 TI - Characterization of recombinant yellow fever-dengue vaccine viruses with human monoclonal antibodies targeting key conformational epitopes. AB - The recombinant yellow fever-17D-dengue virus, live, attenuated, tetravalent dengue vaccine (CYD-TDV) is licensed in several dengue-endemic countries. Although the vaccine provides protection against dengue, the level of protection differs by serotype and warrants further investigation. We characterized the antigenic properties of each vaccine virus serotype using highly neutralizing human monoclonal antibodies (hmAbs) that bind quaternary structure-dependent epitopes. Specifically, we monitored the binding of dengue virus-1 (DENV-1; 1F4), DENV-2 (2D22) or DENV-3 (5J7) serotype-specific or DENV-1-4 cross-reactive (1C19) hmAbs to the four chimeric yellow fever-dengue vaccine viruses (CYD-1-4) included in phase III vaccine formulations using a range of biochemical and functional assays (dot blot, ELISA, surface plasmon resonance and plaque reduction neutralization assays). In addition, we used the "classic" live, attenuated DENV 2 vaccine serotype, immature CYD-2 viruses and DENV-2 virus-like particles as control antigens for anti-serotype-2 reactivity. The CYD vaccine serotypes were recognized by each hmAbs with the expected specificity, moreover, surface plasmon resonance indicated a high functional affinity interaction with the CYD serotypes. In addition, the hmAbs provided similar protection against CYD and wild-type dengue viruses in the in vitro neutralization assay. Overall, these findings demonstrate that the four CYD viruses used in clinical trials display key conformational and functional epitopes targeted by serotype-specific and/or cross-reactive neutralizing human antibodies. More specifically, we showed that CYD-2 displays serotype- specific epitopes present only on the mature virus. This indicates that the CYD-TDV has the ability to elicit antibody specificities which are similar to those induced by the wild type DENV. Future investigations will be needed to address the nature of CYD-TDV-induced responses after vaccine administration, and how these laboratory markers relate to vaccine efficacy and safety. PMID- 29706292 TI - A novel adjuvant G3 induces both Th1 and Th2 related immune responses in mice after immunization with a trivalent inactivated split-virion influenza vaccine. AB - A preferred adjuvant should promote both Th1 and Th2 responses. However, most adjuvants in common use are biased towards a Th2-driven response. Therefore, the ability of a novel saponin-based adjuvant G3 to inducing balanced Th1 and Th2 responses in BALB/c mice immunized with a split trivalent seasonal influenza vaccine was evaluated in comparison to that of the adjuvant Al(OH)3. Clear differences in the IgG profiles induced by G3, Al(OH)3 or non-adjuvanted vaccine were recorded. Both adjuvants enhanced high and similar levels of the Th2 associated IgG1 subtype compared to mice given vaccine alone. Only G3 enhanced the IgG2a subclass reflecting a Th1 response, whereas Al(OH)3 even abrogated the IgG2a production. Accordingly, G3 enhanced the production of IL-2 and IFN-gamma and also of IL-2/IFN-gamma double secreting cells, emphasizing the strong Th1 driving effect of G3. Only Al(OH)3 increased splenocyte production of IL-17. Taken together, the results indicate a strong propensity for G3 to induce both Th1 and Th2 driven immune responses. PMID- 29706293 TI - Long-term impact of childhood hepatitis B vaccination programs on prevalence among Aboriginal and non-Aboriginal women giving birth in Western Australia. AB - BACKGROUND/AIMS: To evaluate the long-term effect of infant and childhood hepatitis B (HBV) vaccination programs among birthing women in Western Australia. METHODS: A cohort of Western Australian women born from 1974 to 1995 was created using Birth Registrations and Electoral Roll records. They were linked to a perinatal register and notifiable diseases register to identify women having respectively their first births between 2000 and 2012 and diagnoses of HBV infections. HBV prevalence was estimated in Aboriginal and non-Aboriginal women, and according to maternal birth year cohorts. RESULTS: Of 66,073 women, 155 (0.23%) had a linked non-acute HBV notification. HBV prevalence was five times higher in Aboriginal women compared to their non-Aboriginal counterparts (0.92%, 95%CI 0.65-1.18 versus 0.18%, 0.15-0.21). Among Aboriginal women, after adjusting for year of giving birth and region of residence, those born in the targeted infant and school-based vaccination era (maternal year of birth 1988-1995) had an 89% lower risk (adjusted odds ratio [aOR] 0.11, 0.04-0.33) of HBV than those born in the pre-vaccination era (1974-1981). Prevalence also differed between Aboriginal women residing in rural/remote areas compared to those in major cities (aOR 3.06, 1.36-6.88). Among non-Aboriginal women, no significant difference in HBV prevalence was observed by maternal birth cohort (p = 0.20) nor by residence (p = 0.23), but there were significant differences by ethnicity with a 36-fold higher prevalence (aOR 36.08, 22.66-57.46) in non-Caucasian versus Caucasian women. CONCLUSIONS: A significant decline in HBV prevalence in Aboriginal birthing mothers was observed following the introduction of HBV vaccination programs in Western Australia. There were also considerable disparities in prevalence between women by area of residence and ethnicity. Our findings reflect those observed in women in other Australian jurisdictions. Continued surveillance of HBV prevalence in birthing mothers will provide ongoing estimates of HBV vaccination program impact across Australia and the populations most at risk of chronic HBV. PMID- 29706294 TI - Identifying ways to increase seasonal influenza vaccine uptake among pregnant women in China: A qualitative investigation of pregnant women and their obstetricians. AB - BACKGROUND: Pregnant women are at higher risk for complications from influenza infection. Nevertheless, seasonal influenza vaccination among pregnant women in China is low. A better understanding of perceptions of pregnant women and their physicians, and factors influencing decisions about receiving seasonal influenza vaccine could be used to develop effective strategies for improving seasonal influenza vaccine uptake during pregnancy. METHODS: We recruited pregnant women from 9 hospitals located in 5 cities across China to participate in focus group interviews. Obstetricians from the same hospitals were recruited for one on one in-depth interviews. We collected information about perceptions of barriers and motivating factors for utilizing seasonal influenza vaccine during pregnancy. We systematically analyzed the information using qualitative methods. RESULTS: We conducted 18 focus groups with 108 pregnant women and interviewed 18 obstetricians. Awareness about the use of influenza vaccine during pregnancy was minimal in both subject groups. None of the pregnant women had received influenza vaccine during pregnancy and none of the obstetricians had recommended influenza vaccine for their patients. Both groups noted insufficient knowledge about influenza infection and benefits of the vaccine, concerns about vaccine safety, and lack of local data related to vaccine use in Chinese pregnant women. Obstetricians cited the lack of a national policy as a major barrier to recommending seasonal influenza vaccine to pregnant women. Pregnant women cited not receiving a recommendation for vaccination from healthcare workers as an additional barrier. CONCLUSION: Our findings highlight the immediate need to increase awareness and knowledge about the risks of influenza infection and the benefits and safety of seasonal influenza vaccination among both pregnant women and obstetricians in China. Obstetricians interviewed stated that the development and implementation of a national policy prioritizing pregnant women for seasonal influenza vaccination would facilitate their willingness to recommend seasonal influenza vaccine to pregnant women. PMID- 29706295 TI - Recent advances in the development of vaccines for chronic inflammatory autoimmune diseases. AB - Chronic inflammatory autoimmune diseases leading to target tissue destruction and disability are not only causing increase in patients' suffering but also contribute to huge economic burden for the society. General increase in life expectancy and high prevalence of these diseases both in elderly and younger population emphasize the importance of developing safe and effective vaccines. In this review, at first the possible mechanisms and risk factors associated with chronic inflammatory autoimmune diseases, such as rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE) and type 1 diabetes (T1D) are discussed. Current advances in the development of vaccines for such autoimmune diseases, particularly those based on DNA, altered peptide ligands and peptide loaded MHC II complexes are discussed in detail. Finally, strategies for improving the efficacy of potential vaccines are explored. PMID- 29706296 TI - Stent retriever thrombectomy for acute ischemic stroke: A systematic review and meta-analysis of randomized controlled trials, including THRACE. AB - BACKGROUND AND PURPOSE: Endovascular thrombectomy has become the reference therapy for patients with large vessel occlusion (LVO). However, no meta-analysis including the THRACE Trial has yet been reported. Thus, the present review assessed the outcomes of stent retriever thrombectomy added to medical care compared with medical care alone in LVO patients. MATERIALS AND METHODS: A systematic review was conducted of all randomized controlled trials (RCTs) examining stent retrievers added to medical care vs medical care alone in the MEDLINE, Embase and Web of Science databases. Meta-analyses of 90-day functional outcomes and mortality, and the occurrence of symptomatic intracranial hemorrhage (sICH), with thrombectomy plus medical care vs medical care alone were performed. RESULTS: Six multicenter RCTs involving 1673 patients were included. Successful recanalization (modified thrombolysis in cerebral ischemia grades 2b-3) was seen in 71% of patients (95% CI: 62-79%) after thrombectomy. These patients also had significantly higher rates of 90-day functional independence (mRS scores 0-2) compared with those receiving medical care only (OR: 2.14, 95% CI: 1.72-2.67; P<0.00001), as well as excellent outcomes (mRS scores 0-1, OR: 2.05, 95% CI: 1.58 2.67; P<0.00001). Also, the rate of functional independence was higher (OR: 2.39, 95% CI: 1.88-3.04; P<0.00001) in the subgroup analysis without the THRACE Trial. The effect of endovascular therapy on 90-day mortality was inconclusive (OR: 0.82, 95% CI: 0.62-1.07; P=0.15), and there was no increased occurrence of sICH (OR: 1.11, 95% CI: 0.66-1.88; P=0.70). CONCLUSION: Stent retriever thrombectomy added to medical care improved 90-day functional outcomes compared with medical care alone with no impact on mortality and risk of sICH in LVO patients. PMID- 29706297 TI - Ecological relevance of the Iowa gambling task in patients with Alzheimer's disease and mild cognitive impairment. AB - BACKGROUND: In spite of their extensive use, the ecological relevance of tasks dedicated to assessing real-world decision-making in a laboratory setting remains unclear. OBJECTIVES: Our study aimed to evaluate the relationship between decision-making and behavioral competency and awareness of limitations. METHODS: A total of 20 patients with Alzheimer's disease (AD), 20 with amnestic mild cognitive impairment (aMCI) and 20 healthy controls (HC) were assessed for decision-making using the Iowa Gambling Task (IGT). Behavioral competency was evaluated by the Patient Competency Rating Scale (PCRS), which requires each participant and a relative to answer the same 30 questions on participant's competency and to rate each item, while awareness of limitations was evaluated by subtracting the self-rated score from the relative-rated score. RESULTS: Using the median-split approach, the proportion of disadvantageous decision-makers was higher in both the MCI and AD groups than in HC (P=0.02 and P=0.03, respectively), with no differences between clinical groups. The percentage of participants with poorer behavioral competency was also higher in the MCI and AD than in the HC (self-rated: P=0.025 and P=0.01, respectively; relative-rated: P=0.008 and P=0.008, respectively), again with no differences between MCI and AD. All groups were comparable in awareness. For all participants, disadvantageous decision-making was associated with both reduced behavioral competency and poor awareness of limitations (OR: 3.47, P=0.03 and OR: 5.4, P=0.004, respectively). CONCLUSION: Our findings support the ecological relevance of the IGT. Behavioral competency integrity and awareness of limitations are both associated with advantageous decision-making profiles. PMID- 29706298 TI - Changes in Perceived Supervision Quality After Introduction of Competency-Based Orthopedic Residency Training: A National 6-Year Follow-Up Study. AB - OBJECTIVE: To evaluate the perceived quality of the learning environment, before and after introduction of competency-based postgraduate orthopedic education. DESIGN: From 2009 to 2014, we conducted annual surveys among Dutch orthopedic residents. The validated Dutch Residency Educational Climate Test (D-RECT, 50 items on 11 subscales) was used to assess the quality of the learning environment. Scores range from 1 (poor) to 5 (excellent). SETTING: Dynamic cohort follow-up study. PARTICIPANTS: All Dutch orthopedic residents were surveyed during annual compulsory courses. RESULTS: Over the 6-year period, 641 responses were obtained (response rate 92%). Scores for "supervision" (95% CI for difference 0.06-0.28, p = 0.002) and "coaching and assessment" (95% CI 0.11-0.35, p < 0.001) improved significantly after introduction of competency-based training. There was no significant change in score on the other subscales of the D-RECT. CONCLUSIONS: After the introduction of some of the core components of competency-based postgraduate orthopedic education the perceived quality of "supervision" and "coaching and assessment" improved significantly. PMID- 29706299 TI - Parent and Nurse Satisfaction Using Pacidose(r) Oral Medication Delivery Device in the Pediatric Emergency Department: A Pilot Study. AB - PURPOSE: Administering oral medication to infants is challenging for caregivers, often resulting in incomplete delivery of the intended dose. Pacidose(r) is an oral medication delivery device that consists of a syringe attached to a tunneled pacifier. This study aimed to determine caregiver and nurse satisfaction and success rate of the Pacidose in the administration of acetaminophen to infants in the pediatric emergency department (ED). DESIGN AND METHODS: This was a prospective trial involving a convenience sample of patients who presented to a pediatric ED between November 2015 and August 2016. Patients younger than 24 months with a physician order for acetaminophen were eligible. Each child received a single dose of acetaminophen delivered by the Pacidose. Nurses, parents, and observing investigators were surveyed with a standardized questionnaire regarding the effectiveness, satisfaction and success rate of Pacidose. RESULTS: 61 patients were enrolled. The median age was 10 months and Pacidose was successful in 77% of patients. Those who required an alternative delivery route were older and no longer used pacifiers. Nurses reported that Pacidose helped administer the medication more easily in 66% of infants and 95% of parents preferred the Pacidose over standard delivery devices. CONCLUSIONS: Pacidose was well tolerated by infants, and both parents and nurses were highly satisfied with this method of administering acetaminophen. PRACTICE IMPLICATIONS: Pacidose is an easy to implement device that can help nurses with oral medication administration. It may have the greatest impact in younger children with recent pacifier use. PMID- 29706300 TI - [Concept analysis: Nurse demand management]. AB - Nurse demand management (NDM) is an emerging concept that requires some useful clarification, not only for professionals and users but also for managers. The NDM was born in 2009 after the need to reorganize the flow of demand, but it has become more than this. NDM is understood as a program led by the primary care nurse to take care of people with acute minor illnesses. Nurses, under a consensual protocol and within their competence area, can be autonomous in patient care and in the resolution of acute minor illnesses. Therefore, following Primary Care's philosophy, both the doctor and the nurse are the professionals that will follow up the health-disease process throughout the user's life. This article was written according to the methodology described by Wilson. PMID- 29706303 TI - The rolling stones: An inappropriate surrogate for upper-abdominal image-guided radiation therapy. PMID- 29706301 TI - Inflammatory breast cancer: The pathologists' perspective. AB - Inflammatory breast cancer (IBC) is a clinico-pathological entity, which has specific features of inflammation and pathological evidence of cancer, most often involving dermal lymphatics. This review looks at IBC from the pathologists point of view. The diagnostic criteria and differential diagnosis are summarized first. The staging implications are described next. Despite the overall poor prognosis of IBC, it is heterogeneous in terms of most prognostic and predictive factors (such as histological type, grade, receptor status, intrinsic subtype, inflammatory infiltrate). It seems that some molecular features (genes expressed) are unique to IBC, and this may help to identify them as IBC at the molecular level. The key carcinogenetic pathways activated in IBC, the inflammatory pathways present in the disease as well as the relation of IBC to cancer stem cells are also briefly covered. Due to the relative rarity of IBC, preclinical trials are very important in the study of this entity, and models with stromal and microenvironmental elements are expected to outperform the traditional models without these features, as the microenvironment seems to be a key component of IBC. PMID- 29706302 TI - The role of proton beam therapy in central neurocytoma: A single-institution experience. AB - PURPOSE: Central neurocytomas (CNs) are rare World Health Organization grade II tumors managed with surgery and radiation therapy. We report our experience in managing CN with proton beam therapy (PBT) when radiation therapy was used. METHODS AND MATERIALS: We identified 61 patients with pathologically diagnosed CN treated at our institution between 1996 and 2016, of which 24 met inclusion criteria. Patient, tumor, and treatment characteristics are reported in context of progression-free survival and treatment-related adverse events. RESULTS: Of 24 patients identified, median age at diagnosis was 21 years (range, 14-60). Median maximal tumor diameter was 4.5 cm (range, 1.4-6.8). Eighteen (75%) patients underwent upfront surgery alone. Sixteen (67%) patients received adjuvant or salvage PBT at a median dose of 54 Gy (relative biological effectiveness). Median follow-up was 56 months. Median progression-free survival (PFS) was 61 months. Eleven patients had disease progression with median time to progression of 22 months. Of the 5 patients with gross total resection, 4 experienced local recurrence and had MIB-1 >4% (range, 4.5-30). There was improved PFS with addition of PBT to definitive surgery (log-rank, P = .06); there was no disease progression to date. In patients who experienced disease recurrence/progression, MIB-1 <4% was associated with improved PFS (log-rank, P = .007). All patients tolerated PBT well with toxicities typical for cranial irradiation and with no grade 3+ toxicities. CONCLUSION: In our cohort, CN with elevated MIB-1 index were at increased risk for disease progression. However, adjuvant radiation therapy appears to effectively prevent failure. PBT toxicities appear to be comparable to if not less than published photon experiences. PMID- 29706304 TI - Renal cell carcinoma brain metastasis with pseudoprogression and radiation necrosis on nivolumab after previous treatment with stereotactic radiosurgery: An illustrative case report and review of the literature. PMID- 29706305 TI - Impact of rectal distension on prostate CBCT-based positioning assessed with 6 degrees-of-freedom couch. AB - INTRODUCTION: Prostate requires a daily correction of its 3-dimensional position in relation with rectal distension. In this study, we sought to determine whether rectal distension with respect to the rectal behavior might have an impact on prostate translations and/or rotations during prostate image guided radiation therapy using a 6 degrees-of-freedom (DOF) couch. METHODS AND MATERIALS: We reviewed the data from 39 patients with localized prostate cancer treated with protracted external radiation therapy using a 6 DOF couch. Before each fraction, a kilovoltage cone beam computed tomography (kV-CBCT) scan was performed. The automatic fusion algorithm was set to fuse on soft tissue and allowed correction for translations in 3 dimensions and rotations in the longitudinal axis ("roll") and lateral axis ("pitch"). After contouring the rectum on each kV-CBCT, we determined the cross-sectional area (CSA) and relative CSA (CSArel) by dividing with the CSA of planning CT. The standard deviation of CSArel per patient was used to classify the patients in 2 groups: patients with a stable rectum and patients with an unstable rectum. The CSArel was compared between these 2 groups with a linear mixed model with group as fixed effect and patient as random effect. RESULTS: A total of 616 kV-CBCT were analyzed, and 2 subgroups of patients could be defined a posteriori: 19 patients had a stable rectum, mean CSArel (1.06 +/- 0.08); the other 20 patients had an unstable rectum, mean CSArel (1.43 +/- 0.08). The average pitch in the group with a stable rectum was 0.36 degrees (+/-0.21) versus 0.40 degrees (+/-0.20) (P = .898). The pitch was not correlated with the CSArel (P = -.065, r = 0.119). The average roll in the group with a stable rectum was 0.27 degrees (+/-0.16) versus 0.05 degrees (+/-0.16) (P = .137). The roll was not correlated with the CSA (P = .094, r = 0.068). The average CSArel was higher (P = .0013) and more variable (P = .035) in the unstable group. CONCLUSION: Rectal distension had no impact on the pitch or on the roll, which suggest that a 6 DOF couch has little interest in daily practice for prostate image guided radiation therapy. PMID- 29706306 TI - Psychiatric comedication in patients with epilepsy. AB - Psychiatric disorders are more common in patients with epilepsy than in the general population. The aims of the study were to assess the frequency and type of psychotropic drug usage in patients with epilepsy, to assess the risk factors for their use, and to assess their proconvulsive potential and the risk of interactions with antiepileptic drugs. This 20-month prospective study included patients treated at the university hospital outpatient clinic. Psychotropic drugs have been classified according to the Anatomical Therapeutic Chemical Classification System. Of the 621 patients (with a mean age of 35.4years), 60% were women, and 37.5% were in remission; 54.8% of the patients used antiepileptic drug monotherapy. The most commonly used antiepileptic drugs were valproate, levetiracetam, lamotrigine, and carbamazepine. Eighty-nine (14.3%) patients received psychiatric comedication. Sertraline, perazine, and hydroxyzine were the predominantly used psychotropic drugs. Independent variables associated with psychotropic drug usage in the logistic regression model included age, active epilepsy, combined focal and generalized epilepsy type, use of somatic comedication, and phenobarbital. Over one-third of the patients simultaneously received antiepileptic drugs and psychotropic drugs, between which clinically significant interactions may occur, 10% of patients used psychotropic drugs to lower the seizure threshold. The results of the study indicate the need for closer cooperation between doctors of various specialties when caring for patients with epilepsy. PMID- 29706307 TI - Reducing stroke risk in epilepsy. PMID- 29706308 TI - Evaluation of End Points in Cancer Clinical Trials. PMID- 29706309 TI - Drug survival of biologic therapies for the treatment of psoriasis: Results of Slovenian national registry. AB - The study was designed as observational retrospective analysis of the data from Slovenian Registry of patients with moderate and severe psoriasis treated with adalimumab, etanercept, infliximab or ustekinumab from 2005 to 2015. The survival rates of biologics were compared using survival analysis, and predictors of discontinuation were evaluated using a Cox regression model. All biologics have been prescribed as a first line therapy for moderate or severe psoriasis; 650 (94.9%) adalimumab, 254 (72.0%) ustekinumab, 76 (69.7%) infliximab, 68 (67.3%) etanercept. The overall biologics survival rate was 83.2% in the first line and 79.1% in the second line treatment. Drug survival for the first and second line of therapy was significantly longer for ustekinumab than for anti-TNFalpha agents (p < 0.001 and p = 0.014, respectively). Loss of efficacy accounted for 63% of all treatment discontinuations. Multivariate regression analysis showed that younger patients, being on etanercept, systemic conventional co-therapy, lower BSA and higher DLQI were independent predictors for treatment discontinuation. Our data showed the real-life situation in the treatment of moderate to severe psoriasis with biologics. Since longevity of drug survival is considered as a measure of treatment success, this data represents an important information when selecting a biologic treatment for individual patient. PMID- 29706310 TI - The associated risk factors for underweight and overweight high school students in Cambodia. AB - PURPOSE: Overweight and underweight are one of the leading risk factors for non communicable diseases (NCDs), but little research on this area has been undertaken in Cambodia. Therefore, this study aimed to measure underweight and overweight and their associated risk behaviors among Cambodian high school students. METHODS: 3806 students (mean ag = 15.65 years, SD = 1.80, age range = 11-18 years) from the 2013 Cambodia-Global School-based Student Health Survey were used to yield representative samples of the Cambodian students. Body Mass Index (BMI) was assessed by students' self-reported height and weight. The substance use, depression, eating behaviors, suicidal ideation, and violence were examined as risk factors. The Chi-square and multinomial regressions were performed to assess the relationships between risk factors and BMI. RESULTS: The prevalence of underweight was 47.4% (N = 1805, Male = 23.3%vs.24.1%) and overweight was 2.3% (N = 89, Male = 1.0%vs.1.3%). The BMI was significantly controlled by age, gender, and body height. Both underweight and overweight students were significantly vulnerable to substance use, feeling depressed, and violent behaviors. Of the risk factors, shortest sleep was prevalent for underweight students while feeling lonely and suicide attempts were the critical risks for overweight students. The daily fruit/vegetable consumption and physical activity were good preventive factors of both underweight and overweight epidemics. CONCLUSIONS: The risk behaviors of students appear to be strongly associated with underweight and overweight. Interventions targeting these risk behaviors may have the potential to reduce risks. Meanwhile, the preventive strategies should focus on vulnerable students who have poor academic performance, mental health issues and a history of violent experiences. PMID- 29706311 TI - The association between obesity and migraine in a population of Iranian adults: a case-control study. AB - AIM: To assess the association between obesity and risk of migraine with aura and features of migraine attacks among a population of Iranian adults. METHODS: In this case-control study, 102 confirmed cases of migraine with aura were matched based on age and gender with 102 healthy subjects. Data on demographic characteristics and anthropometric measurements were collected from all cases and controls by the same methods. Overweight and obesity were considered as body mass index >=25-30 kg/m2 and >= 30 kg/m2, respectively. Features of migraine attacks including frequency, duration and headache daily result were determined for patients based on international headache society criteria. RESULTS: Mean age of subjects was 34.5 +/- 7.4 years and 77.9% of them were female. Compared with subjects with normal body mass index, those with obesity had greater odds for having migraine with aura (OR: 3.06, 95% CI: 1.11-8.43). Such finding was also seen even after adjusting for confounding variables; in a way that subjects with obesity were 2.92 times more likely for having migraine with aura compared with those with normal weight (OR: 2.92, 95% CI: 1.03-8.33). Among migraine with aura patients, we found that those with obesity had higher headache daily result compared with subjects with normal weight. However, obesity was not associated with frequency and duration of migraine attacks. CONCLUSIONS: We found that obesity was positively associated with risk of migraine with aura. In addition, subjects with obesity had higher headache daily result compared with those with normal weight. PMID- 29706312 TI - Metabolic syndrome marks early risk for cognitive decline with APOE4 gene variation: A case study. AB - A vast amount of research has been done on the APOE4 genetic marker for Alzheimer's disease (AD), but its connection to metabolic processes associated with peripheral insulin resistance and cerebral glucose metabolism is still relatively unknown. The APOE4 allele is the strongest genetic risk factor for developing late-onset Alzheimer's disease, particularly in individuals who have inherited two copies of the gene (Zhao et al., 2017). In this case study, a 38 year old male with metabolic syndrome (MetS), the APOE4 gene, early stage memory problems and a family history of Alzheimer's Disease (AD) was placed on a ketogenic diet combined with high intensity interval training (HIIT) for 10 weeks. The primary intervention goal was reduce insulin defect, impaired cerebral and peripheral insulin signaling, associated with metabolic syndrome. Recent research demonstrates that insulin defect competes for space with APOE4 in brain cells, thus exacerbating amyloid pathology (Zhao et al., 2017). Primary biomarkers for metabolic syndrome were measured at baseline and after 10 weeks. The MoCA (Montreal Cognitive Assessment) was administered at baseline and after 10 weeks. The results were statistically significant. The HOMA-IR (homeostatic measure of insulin resistance) decreased by 59% from 4.3 to 1.8. The triglyceride/HDL ratio decreased by 77% from 14.7 to 3.4. Fasting triglycerides were reduced from 573 mg/dL to 167 mg/dL (71% reduction); VLDL decreased from 114.6 mg/dL to 33.4 mg/dL (71% decrease); and fasting insulin was reduced by 55% from 15.6 mU/L to 7.1 mU/L. The baseline MoCA score was 22/30; post treatment score was 30/30. If APOEE4 is the strongest genetic risk factor for developing late-onset Alzheimer's Disease, then implementing a ketogenic diet and high intensity exercise could essentially turn "off" the effects of this APOE4 gene earlier in life for prevention of future neurodegeneration. PMID- 29706313 TI - A description of the ABCD organizational structure and communication framework. AB - The Adolescent Brain Cognitive Development (ABCD) study is designed to be the largest study of brain development and child health in the United States, performing comprehensive assessments of 11,500 children repeatedly for 10 years. An endeavor of this magnitude requires an organized framework of governance and communication that promotes collaborative decision-making and dissemination of information. The ABCD consortium structure, built upon the Matrix Management approach of organizational theory, facilitates the integration of input from all institutions, numerous internal workgroups and committees, federal partners, and external advisory groups to make use of a broad range of expertise to ensure the study's success. PMID- 29706314 TI - Dengue haemorrhagic fever: An emerging disease in Nigeria, West Africa. AB - INTRODUCTION: In Nigeria, dengue fever caused by dengue virus, types 1 and 2 has been diagnosed for many years. Although, seroepidemiological surveys have shown that dengue virus activity is, widespread in the country, there is scanty information on dengue, hemorrhagic fever with little attention paid to dengue fever largely, because it presents as classical dengue fever characterized by fever, myalgia, headache, arthralgia, retro-orbital pain, gastro intestinal, symptoms and skin rash. We are updating the current information of dengue, in Nigeria, as well as DHF which is an emerging disease in the west, African country. METHODS: PUBMED, Google scholar, cross-reference databases and individual publications not publicly archived were used. All available literature on, dengue from Nigeria were identified. RESULTS: Dengue virus 3 and 4 have been recently detected in Nigeria, with the emergence of dengue haemorrhagic fever for the first time. Poor, surveillance, underreporting, and misdiagnosis of the disease as malaria, are major problems. CONCLUSION: Priority must be given to increasing surveillance activity to, detect more dengue haemorrhagic fever cases and determine the magnitude, of the dengue problem. It is important to enhance the capacity of, laboratories to diagnose dengue haemorrhagic fever by providing them with, modern equipment, reagents and new infrastructure. PMID- 29706315 TI - Recurrent Streptococcus pneumoniae meningitis and Mondini dysplasia: Association or causation? AB - Mondini dysplasia is a developmental disorder of the inner ear structures and it is a rare cause of recurrent bacterial meningitis in children. A 10-year-old boy presented with acute febrile encephalopathy and right ear pain. In the past, he had suffered from two distinct episodes of pyogenic meningitis. On examination, he had signs of meningeal irritation and right ear sensorineural deafness. Magnetic resonance imaging of the brain and computerized tomography of the temporal bone was suggestive of Mondini dysplasia in the right ear. Our case highlights the need for (a) screening of hearing loss at the bedside by Rinne and Weber test in case of recurrent bacterial meningitis (b) searching for an underlying inner ear malformation if there is a hearing loss. PMID- 29706316 TI - Mutations inside rifampicin-resistance determining region of rpoB gene associated with rifampicin-resistance in Mycobacterium tuberculosis. AB - BACKGROUND: Rifampicin (RIF) plays a pivotal role in the treatment of tuberculosis due to its bactericidal effects. Because the action of RIF is on rpoB gene encoding RNA polymerase beta subunit, 95% of RIF resistant mutations are present in rpoB gene. The majority of the mutations in rpoB gene are found within an 81bp RIF-resistance determining region (RRDR). METHODOLOGY: Literatures on RIF resistant mutations published between 2010 and 2016 were thoroughly reviewed. RESULTS: The most commonly mutated codons in RRDR of rpoB gene are 531, 526 and 516. The possibilities of absence of mutation in RRDR of rpoB gene in MDR TB isolates in few studies was due to existence of other rare rpoB mutations outside RRDR or different mechanism of rifampicin resistance. CONCLUSION: Molecular methods which can identify extensive mutations associated with multiple anti-tuberculous drugs are in urgent need so that the research on drug resistant mutations should be extended. PMID- 29706317 TI - Experience with ceftazidime-avibactam treatment in a tertiary care center in Saudi Arabia. AB - INTRODUCTION: Carbapenem-resistant organisms have become major healthcare associated pathogens and are responsible for significant morbidity and mortality worldwide. CASES AND MANAGEMENTS: This case-series describes our experience with ceftazidime-avibactam in the treatment of six cases with carbapenem-resistant organisms in King Abdulaziz Medical City in Riyadh, Saudi Arabia. After trying various combinations of antibiotic therapies without improvement, cases were treated with ceftazidime-avibactam. OUTCOMES: Five of the six achieved complete cure, both clinically and microbiologically. PMID- 29706318 TI - Premature labor and neonatal sepsis caused by Actinomyces neuii. AB - Actinomycosis is a rare infection in patients younger than 10years of age. It mainly affects the cervicofacial region, but many other sites of infection have been recognized. About 70% of infections are due to either Actinomyces israelii or Actinomyces gerencseriae. Actinomyces neuii was first described in 1985 in two patients with post cataract endophthalmitis, A. neuii represents 17% of clinical Actinomyces isolates. Several reports indicated a well-known association between Actinomyces infections and Intrauterine devices (IUD). We are reporting a case of neonatal sepsis due to A. neuii as a first case reported from Saudi Arabia. It was thought to be the cause of the premature labor and neonatal sepsis. The prevalence of Actinomyces infection is likely underestimated and additional premature labors and abortions could have been caused by Actinomyces infections that were never detected. More studies are needed to confirm the association of maternal Actinomyces infections with preterm labor. PMID- 29706319 TI - Zika virus: Epidemiological study and its association with public health risk. AB - Propagation of Zika virus has become an alarming global public health issue. The infection is spreading rapidly to different countries by several methods, especially by the transmission through traveling. Bangladesh is also at a risk to be affected with such newly viral infections. Though the virus initially appears to cause mild problems, the long term effects are more devastating to the next generation as seen in case of the delivery of the microcephalic babies. Current review discussed the epidemiologic era of the virus; i.e., the administration of Zika virus in the non-human mammals and finally to the human host across the world. Typical sign-symptoms which can often be considered as dengue or chikungunya for their similarities have been stated. The diagnosis of Zika virus, the protective measures taken by mass people as well as the actions that should be endorsed to prevent acquisition of the infection from travelers are discussed. PMID- 29706320 TI - Sex differences in obesity, lipid metabolism, and inflammation-A role for the sex chromosomes? AB - BACKGROUND: Sex differences in obesity and related diseases are well established. Gonadal hormones are a major determinant of these sex differences. However, sex differences in body size and composition are evident prior to exposure to gonadal hormones, providing evidence for gonadal-independent contributions attributable to the XX or XY sex chromosome complement. Large-scale genetic studies have revealed male/female differences in the genetic architecture of adipose tissue amount and anatomical distribution. However, these studies have typically neglected the X and Y chromosomes. SCOPE OF THE REVIEW: Here we discuss how the sex chromosome complement may influence obesity, lipid levels, and inflammation. Human sex chromosome anomalies such as Klinefelter syndrome (XXY), as well as mouse models with engineered alterations in sex chromosome complement, support an important role for sex chromosomes in obesity and metabolism. In particular, the Four Core Genotypes mouse model-consisting of XX mice with either ovaries or testes, and XY mice with either ovaries or testes-has revealed an effect of X chromosome dosage on adiposity, hyperlipidemia, and inflammation irrespective of male or female gonads. Mechanisms may include enhanced expression of genes that escape X chromosome inactivation. MAJOR CONCLUSIONS: Although less well studied than effects of gonadal hormones, sex chromosomes exert independent and interactive effects on adiposity, lipid metabolism, and inflammation. In particular, the presence of two X chromosomes has been associated with increased adiposity and dyslipidemia in mouse models and in XXY men. The enhanced expression of genes that escape X chromosome inactivation may contribute, but more work is required. PMID- 29706321 TI - Resveratrol improves ex vivo mitochondrial function but does not affect insulin sensitivity or brown adipose tissue in first degree relatives of patients with type 2 diabetes. AB - OBJECTIVE: Resveratrol supplementation improves metabolic health in healthy obese men, but not in patients with type 2 diabetes (T2D) when given as add-on therapy. Therefore, we examined whether resveratrol can enhance metabolic health in men at risk of developing T2D. Additionally, we examined if resveratrol can stimulate brown adipose tissue (BAT). METHODS: Thirteen male first degree relatives (FDR) of patients with T2D received resveratrol (150 mg/day) and placebo for 30 days in a randomized, placebo controlled, cross-over trial. RESULTS: Resveratrol significantly improved ex vivo muscle mitochondrial function on a fatty acid derived substrate. However, resveratrol did not improve insulin sensitivity, expressed as the rate of glucose disposal during a two-step hyperinsulinemic euglycemic clamp. Also, intrahepatic and intramyocellular lipid content, substrate utilization, energy metabolism, and cold-stimulated 18F-FDG glucose uptake in BAT (n = 8) remained unaffected by resveratrol. In vitro experiments in adipocytes derived from human BAT confirmed the lack of effect on BAT. CONCLUSIONS: Resveratrol stimulates muscle mitochondrial function in FDR males, which is in concordance with previous results. However, no other metabolic benefits of resveratrol were found in this group. This could be attributed to subject characteristics causing alterations in metabolism of resveratrol and thereby affecting resveratrol's effectiveness. CLINICALTRIALS. GOV ID: NCT02129595. PMID- 29706323 TI - Torulaspora delbrueckii for secondary fermentation in sparkling wine production. AB - In the search for the desired oenological features and flavour complexity of wines, there is growing interest in the potential use of non-Saccharomyces yeast that are naturally present in the winemaking environment. Torulaspora delbrueckii is one such yeast that has seen profitable use in mixed fermentations with Saccharomyces cerevisiae and with different grape varieties. T. delbrueckii can have positive and distinctive impacts on the overall aroma of wines, and has also been used at an industrial level. Here, T. delbrueckii was successfully used in pure and mixed secondary fermentations for sparkling wine. The two selected T. delbrueckii strains used completed the secondary fermentation 'prise de mousse' in these pure and mixed fermentations. The sparkling wines obtained with T. delbrueckii showed different aromatic compositions and sensory profiles to those of S. cerevisiae. T. delbrueckii strain DiSVA 130 showed high esters production and significantly high scores for some of the aromatic descriptors that positively influence the sensory profile of sparkling wine. Thus, the use of T. delbrueckii in pure and mixed fermentations is a suitable strategy to further develop the flavour complexity during secondary fermentation of sparkling wines. PMID- 29706322 TI - Multiplex PCR identification and culture-independent quantification of Bacillus licheniformis by qPCR using specific DNA markers. AB - Probiotics benefits in fish farming have been usually inferred appraising the effects observed on the host and not through the direct assessment of probiotic dynamics in the host gut microbiota. To overcome this gap, quantitative PCR (qPCR) can be a powerful approach to study the bacterial dynamics in fish gut microbiota. The presented work proposes four B. licheniformis-specific DNA markers and details a qPCR method to track putative probiotics B. licheniformis on fish gut. The four B. licheniformis-specific DNA markers - BL5B (hypothetical protein BL00303), BL8A (serA2), BL13C (rfaB) and BL18A (ligD) - were selected and validated by PCR and multiplex-PCR with 20 B. licheniformis isolates and a broad range of non-target bacteria. To assess the dynamics of B. licheniformis in the digesta of farmed fish, a qPCR was validated using markers BL8A and BL18A and calibration curves obtained for both markers with digesta samples spiked with B. licheniformis cells showed a high correlation (R2 > 0.99) over 6 log units (CFU/reaction), and a limit of detection (LOD) as low as 247 CFUs/reaction. Furthermore, the consistent qPCR repeatability and reproducibility underline the specificity and reliability of the qPCR proposed. Ultimately, the possibility to monitor the dynamics of B. licheniformis probiotics in the gut microbiota of farmed fish might be instrumental to optimize best practices in aquaculture. PMID- 29706324 TI - Edible coatings incorporating pomegranate peel extract and biocontrol yeast to reduce Penicillium digitatum postharvest decay of oranges. AB - This study investigated the potential use of two edible coatings, chitosan (CH) and locust bean gum (LBG), which incorporated chemically characterized water pomegranate peel extract (WPPE) or methanol pomegranate peel extract (MPPE) and the biocontrol agent (BCA) Wickerhamomyces anomalus, to control the growth of Penicillium digitatum and to reduce the postharvest decay of oranges. CH and LBG including pomegranate peel extracts (PPEs) at different concentrations were tested in vitro against P. digitatum to determine their antifungal efficacy; at the same time, the tolerance of viable cells of W. anomalus to increasing concentrations of WPPE and MPPE extracts was assessed. The potential application of selected bioactive coatings was evaluated in vivo on oranges, which had been artificially inoculated with P. digitatum, causal agent of green mold decay. CH incorporating MPPE or WPPE at all concentrations was able to inhibit in vitro P. digitatum, while LBG was active only at the highest MPPE or WPPE concentrations. W. anomalus BS91 was slightly inhibited only by MPPE-modified coatings, while no inhibition was observed by WPPE, which was therefore selected for the in vivo trials on oranges artificially inoculated with P. digitatum. The experimental results proved that the addition of 0.361 g dry WPPE/mL, both to CH and LBG coatings, significantly reduced disease incidence (DI) by 49 and 28% respectively, with respect to the relative controls. Besides the combination CH or LBG + WPPE, the addition of W. anomalus cells to coatings strengthened the antifungal effect with respect to the relative controls, as demonstrated by the significant reduction of DI (up to 95 and 75% respectively). The findings of the study contribute to the valorization of a value-added industrial byproduct and provide a significant advancement in the development of new food protectant formulations, which benefit from the synergistic effect between biocontrol agents and natural bioactive compounds. PMID- 29706325 TI - The effect of pectins on survival of probiotic Lactobacillus spp. in gastrointestinal juices is related to their structure and physical properties. AB - Pectins are plant polysaccharides used in food industry as gelling and stabilizing agents. This study investigated the ability of pectins to improve survival of probiotic species Lactobacillus fermentum PCC, L. reuteri RC-14, L. rhamnosus LGG and L. paracasei F-19 in simulated gastric solution in relationship to their structural and physical properties. Electrostatic interactions between pectins and bacteria were evaluated by the Zeta-potential approach. Bacterial survival was assessed by flow cytometry and plate counting. L. fermentum PCC and L. reuteri RC-14 were more resistant to gastric conditions; their survival rate was further improved in the presence of five out of ten tested pectins. Additionally, two of the pectins had a positive effect on viability of the less resistant L. rhamnosus LGG and L. paracasei F-19. The beneficial effect was generally observed for the high-methoxylated pectins, indicating that substituted polygalacturonic acid in the backbone is essential for bacterial protection. Other pectin features associated with improved survival, included less negative Zeta-potential, higher molecular weight, as well as lower values of hydrodynamic sizes, viscosity and degree of branching. The study indicates that pectins have a potential to protect probiotic bacteria through the gastro-intestinal transit and identifies the features linked to their functionality. PMID- 29706326 TI - Advancement in LH-PCR methodology for multiple microbial species detections in fermented foods. AB - The length-heterogeneity PCR is a low throughput molecular biology methods explored to monitor bacteria populations in different environments. It could be more used in food microbiology analysis, not only for fingerprinting analysis, but it has been hampered until now by a limiting factor which relates to the high percentage of secondary peaks. With the aim to overcome this problem, different experiments were performed focusing on changing PCR parameters in order to obtain more specific amplicon patterns and also to reduce the complexity of community patterns. With this purpose, different annealing temperatures were tested on complex fermented food matrices taken from both animal and vegetable origin and also on the bacteria isolated from the same food source. In particular, the optimal annealing temperature identified for the fermented food samples is 59 degrees C and the optimal for bacterial strains varied between 63 degrees C and 65 degrees C. The approach allowed the modification of the LH-PCR protocol increasing the amplification efficiency and therefore the bacteria species discrimination. These temperatures also allowed the implementation of the previous LH-PCR published database. The modification in the level of accuracy of the LH-PCR technique could also allow an improvement in the relative species quantification by the peak area evaluation. PMID- 29706327 TI - Occurrence of Aichi virus in retail shellfish in Italy. AB - AiV-1 is considered an emerging human enteric pathogens and foodborne transmission has been documented as an important source of exposure for humans, chiefly in relation to non-safe, risky food habits. We surveyed the presence of AiV-1 in retail shellfish, including oysters and mussles, identifying the virus in 3/170 (1.8%) of the analysed samples. The AiV-1 positive samples were of different geographic origin. Upon sequence analysis of a portion of the 3CD junction region, two AiV strains identified from harvesting areas in Northern Italy were characterised as genotype B and displayed 99-100% identity at the nucleotide level to other AiV-1 strains detected in sewages in Central Italy in 2012, suggesting that such strains are stably circulating in Italian ecosystems. Interestingly, a strain identified from mussles harvested in Southern Italy could not be characterised firmly, as inferred in the Bayesian analysis and by sequence comparison, indicating that different AiV strains are also circulating in Italy. Viral contamination in retail shellfish challenges the microbiological guidelines for food control and requires the development and optimization of additional diagnostic and prevention strategies. PMID- 29706328 TI - Enhanced control of Bacillus subtilis endospores development by hyperbaric storage at variable/uncontrolled room temperature compared to refrigeration. AB - The effect of hyperbaric storage on Bacillus subtilis endospores, as a new food preservation methodology with potential to replace the conventional refrigeration processes, was assessed and compared to refrigeration. To do so, three different matrices (McIlvaine buffer, carrot juice and brain-heart infusion broth, BHI broth) were inoculated with B. subtilis endospores and stored at 25, 50 and 100 MPa at variable/uncontrolled room temperature (18-23 degrees C), under refrigeration (4 degrees C), and room temperature at atmospheric pressure (0.1 MPa), up to 60 days. Two different quantification procedures were performed to assay both vegetative and endospores (unheated samples) and endospores (heated samples), to assess germination under pressure. The results showed that hyperbaric storage yielded pronounced endospore loads reductions in carrot juice and BHI-broth at 50 and 100 MPa, while in McIlvaine buffer, lower endospore loads reductions were observed. At 25 MPa, the endospores germinated and outgrew in carrot juice. Under refrigeration conditions, both carrot juice and BHI-broth underwent endospore germination and outgrowth after 60 and 9 days of storage, respectively, while in McIlvaine buffer there were no endospore outgrowth. These results suggest that hyperbaric storage at room temperature might not only be a feasible preservation procedure regarding endospores, but also that the food product (matrix characteristics) seems to influence the microbial inactivation that occurs during hyperbaric storage. PMID- 29706329 TI - Study of Lactococcus lactis during advanced ripening stages of model cheeses characterized by GC-MS. AB - Lactococcus lactis, is extensively used as starter culture in dairy products. Nevertheless, it has recently been detected in cheese, as metabolically active cells, in advanced ripening stages. In this study, we assessed the viability of L. lactis subsp. lactis in model cheeses up to 180 days of ripening by both culture-dependent and -independent methods. In addition, we studied the expression of metC and als genes involved in the production of aroma compounds detected by Gas Chromatography-Mass Spectrometry (GC-MS). Three L. lactis subsp. lactis commercial starters were inoculated in pasteurized milk and model cheeses were manufactured and ripened for six months. Samples were analysed at manufacturing and ripening steps, in terms of viability of L. lactis by both traditional plating and direct analysis of RNA by reverse transcription quantitative PCR (RT-qPCR), and in terms of aroma profile by GC-MS. Relatively to RT-qPCR analysis, L. lactis was found viable throughout the whole process of cheesemaking and aging, with final average loads of 3-4 Log CFU/g at 180 days. On the contrary, the microorganism was not detected, in ripened samples, by traditional plating on M17 medium, suggesting its entering in a viable but not cultivable (VBNC) state. The aroma profiles of the cheeses highlighted the presence of volatile compounds related to cheese flavor as acetoin, diacetyl, 2,3 butanediol and dimethyl disulfide, whose presence was partially correlated to metC and als genes expression. These results add new insights on the capability of L. lactis to persist during late cheese ripening and suggest a potential contribution of the microorganism to cheese flavor formation. PMID- 29706330 TI - Scanning electron microscopy of Salmonella biofilms on various food-contact surfaces in catfish mucus. AB - The objective of this study was to determine the growth and survival of Salmonella enterica in the presence of high and low concentrations (375 MUg/ml and 15 MUg/ml) of catfish mucus extract at 10 degrees C and 22 degrees C for 63 days. The second objective of this study was to investigate the biofilm formation of Salmonella enterica serovar Blockley (7175) in catfish mucus extract for 48 h at 22 degrees C on four food-contact surfaces and to observe the biofilm populations using Scanning Electron Microscopy (SEM). The surface properties, surface roughness and surface energies were determined using contact angle measurement and atomic force microscopy. In 375 MUg/ml of catfish mucus extract that was inoculated with 3 log CFU/ml, the growth of Salmonella counts were increased to a maximum of 6-7 log CFU/ml at 10 degrees C and 7-8 log CFU/ml at 22 degrees C in 7-14 d and decreased by 1-2 log CFU/ml from these peak levels at both 10 degrees C and 22 degrees C from 21 to 63 d. In 15 MUg/ml of catfish mucus extract, Salmonella counts were in the range of 4-5 log CFU/ml at 10 degrees C and 5-6 log CFU/ml at 22 degrees C over 7-63 d of storage. By contrast, Salmonella counts were non-detectable in the absence of catfish mucus by 21-28 d of storage at 10 degrees C or 22 degrees C. The biofilm counts of S. Blockley (7175) on a stainless steel surface were 4 log CFU/cm2 and 5.5 log CFU/cm2 in 15 MUg/ml and 375 MUg/ml of catfish mucus extract respectively after 48 h incubation at 22 degrees C. SEM revelead that biofilm formation by S. Blockley (7175) was less in 15 MUg/ml than 375 MUg/ml of catfish mucus extract on stainless steel. In addition, SEM indicated that the visible biofilms were least on buna-N rubber as compared to stainless steel, polyethylene and polyurethane surfaces. Contact angle and atomic force microscopy confirmed that buna-N rubber was highly hydrophobic with low surface energy and low roughness when compared to other three surfaces. These findings indicate that Salmonella can utilize catfish mucus as a nutrient source to survive for longer periods and promote biofilm formation for its persistence on different food-contact surfaces. PMID- 29706331 TI - Differentiation of Saccharomyces cerevisiae populations from vineyards of the Azores Archipelago: Geography vs Ecology. AB - Aiming to elucidate the roles that ecology and geography play in shaping the differentiation of fermentative grape-associated Saccharomyces cerevisiae populations, several locations on six islands of the Azores Archipelago were surveyed. A total of 249 strains were isolated from spontaneous fermentations of grape samples from several varieties of two distinct grapevine species (Vitis vinifera L. and Vitis labrusca L.), in vineyards that are under regular cultivation or in abandoned vineyards. Strains were genetically analyzed using a set of nine microsatellite loci, and also phenotypically characterized using relevant physiological/biotechnological tests. Results showed that genetic divergence among populations of the same island was lower than from populations from different islands. Phenotypic comparison of the populations from each of the islands revealed significant differences between them. Strains isolated from the islands with more intensive viticultural activity - Pico, Terceira and Graciosa - showed higher levels of SO2 tolerance, possibly resulting from selection by human activity. The percentage of strains producing low levels of H2S was higher in S. Jorge (60%). Our findings were supported both by genetic and phenotypic data and provide clear evidence for the prevailing role of the geography over ecology in the differentiation of S. cerevisiae populations in the Azores Archipelago. PMID- 29706332 TI - Public health significance of Campylobacter spp. colonisation of wild game pheasants (Phasianus colchicus) in Scotland. AB - Campylobacter is the most common cause of bacterial food-borne diarrhoeal disease worldwide. Chicken meat is considered the main source of human infection; however, C. jejuni and C. coli have also been reported in a range of livestock and wildlife species, including pheasants. Wild pheasant meat reaches the consumer's table because of hunting but there is a lack of information concerning the risk of Campylobacter infection in humans. This study aimed to determine the prevalence of Campylobacter in wild game pheasants in Scotland, to identify the main sequence types (STs) present and to evaluate their impact on public health. A total of 287 caecal samples from five Scottish regions were collected during the hunting season 2013/2014. Campylobacter was detected and enumerated using standard culture methods. PCR and High Throughput Multi Locus Sequence Typing (HiMLST) were used for species identification and sequence typing. In total, 36.6% of 287 caecal samples (n = 105; 95% CI: 14-59.2) were Campylobacter positive. Using PCR, 62.6% of samples (n = 99) were identified as C. coli and 37.4% as C. jejuni. HiMLST (n = 80) identified 19 different STs. ST-828 (n = 19) was the most common, followed by ST-827 (n = 12) and ST19 (n = 7). Sixteen of the 19 STs isolated are present in humans and eight are C. coli STs that account for 6.96% of human infections, although the overall risk to public health from pheasant meat is still considered to be low. PMID- 29706333 TI - The impact of vegan production on the kimchi microbiome. AB - Despite previous inquiry into the fermentative bacterial community of kimchi, there has been little insight into the impacts of starting ingredients on the establishment and dynamics of the microbial community. Recently some industrial producers have begun to utilize vegan production methods that omit fermented seafood ingredients. The community-level impacts of this change are unknown. In this study, we investigated the differences in the taxonomic composition of the microbial communities of non-vegan kimchi and vegan kimchi prepared through quick fermentation at room temperature. In addition to tracking the community dynamics over the fermentation process, we looked at the impact of the constituent ingredients and the production facility environment on the microbial community of fermenting kimchi. Our results indicate that the bacterial community of the prepared vegan product closely mirrors the progression and final structure of the non-vegan final product. We also found that room temperature-fermented kimchi differs minimally from more traditional cold-fermented kimchi. Finally, we found that the bacterial community of the starting ingredients show a low relative abundance of the lactic acid bacteria in fermented kimchi, whereas the production facility is dominated by these bacteria. PMID- 29706334 TI - Greek functional Feta cheese: Enhancing quality and safety using a Lactobacillus plantarum strain with probiotic potential. AB - The aim of the study was to investigate the performance of Lactobacillus plantarum T571 with probiotic potential as a co-starter culture in Feta cheese production and in its long-term storage. For this reason, Feta cheese was manufactured without (control) or with the probiotic T571 strain (probiotic) and then monitored during storage at 4 and 12 degrees C, respectively. The products were also inoculated with Listeria monocytogenes (3-strain cocktail). The results showed that lactic acid bacteria exceeded 6 log CFU/g during storage in all trials. The probiotic samples displayed higher acidity (~1.5% lactic acid) and lower pH (~4.2). Coliforms and L. monocytogenes, were inactivated in shorter time in probiotic samples, in comparison with the control ones. Pulsed field gel electrophoresis verified the presence of the probiotic strain in the cheese, until the end of storage at both temperatures, whilst the survival and distribution of the pathogenic strains depended on the trial. The sensory evaluation showed that the probiotic cheeses had desirable sensory characteristics similar to the control ones, with scores of ca. 8 on a 10 cm scale. Finally, Fourier transform infrared spectroscopy was applied for the first time during Feta cheese storage with promising results for the rapid estimation of the microbiological counts and sensory status of cheese. Results showed that Lb. plantarum T571 highlighted desirable and robust technological properties and may be used in cheese making as an adjunct culture. PMID- 29706335 TI - Effectiveness of different antimicrobial washes combined with freezing against Escherichia coli O157:H7, Salmonella Typhimurium, and Listeria monocytogenes inoculated on blueberries. AB - To ensure the safety of produce, including blueberries, elimination of potential pathogens is critical. This study evaluated the efficacy of antimicrobial washes when coupled with frozen storage against Escherichia coli O157:H7, Salmonella Typhimurium and Listeria monocytogenes on wild blueberries. Inoculated blueberries were sprayed with antimicrobial solutions at different concentrations for various contact times (chlorine dioxide -2.5, 5, 10, and 15 ppm for 10 s, 1, 5, and 10 min; chlorine -100, 150, and 200 ppm for 10s, 1, 5, and 10 min; lactic acid 1 and 2% for 5, 10 and 20 min) and following treatment, stored at -12 degrees C for 1 week. Compared to antimicrobial washing alone, the additional freezing significantly reduced pathogens (P < 0.05). Concentrations of all three antimicrobials combined with freezing reduced L. monocytogenes to undetectable levels (detection limit < 1 log CFU/g). The greatest reduction of E. coli O157:H7 (4.4 log CFU/g) and Salmonella (5.4 log CFU/g) was achieved by 2% lactic acid or 200 ppm Cl2 followed with frozen storage. These antimicrobials maintained the visual quality of blueberries and did not leave detectable residues. In conclusion, antimicrobial washes, when combined with frozen storage, effectively reduce the risk of pathogen contamination on blueberries. PMID- 29706336 TI - Development and validation of predictive models for the effect of storage temperature and pH on the growth boundaries and kinetics of Alicyclobacillus acidoterrestris ATCC 49025 in fruit drinks. AB - This study was undertaken to provide quantitative tools for predicting the behavior of the spoilage bacterium Alicyclobacillus acidoterrestris ATCC 49025 in fruit drinks. In the first part of the study, a growth/no growth interface model was developed, predicting the probability of growth as a function of temperature and pH. For this purpose, the growth ability of A. acidoterrestris was studied at different combinations of temperature (15-45 degrees C) and pH (2.02-5.05). The minimum pH and temperature where growth was observed was 2.52 (at 35 and 45 degrees C) and 25 degrees C (at pH >= 3.32), respectively. Then a logistic polynomial regression model was fitted to the binary data (0: no growth, 1: growth) and, based on the concordance index (98.8%) and the Hosmer-Lemeshow statistic (6.226, P = 0.622), a satisfactory goodness of fit was demonstrated. In the second part of the study, the effects of temperature (25-55 degrees C) and pH (3.03-5.53) on A. acidoterrestris growth rate were investigated and quantitatively described using the cardinal temperature model with inflection and the cardinal pH model, respectively. The estimated values for the cardinal parameters Tmin, Tmax, Topt and pHmin, pHmax, pHopt were 18.11, 55.68, 48.60 degrees C and 2.93, 5.90, 4.22, respectively. The developed models were validated against growth data of A. acidoterrestris obtained in eight commercial pasteurized fruit drinks. The validation results showed a good performance of both models. In all cases where the growth/no growth interface model predicted a probability lower than 0.5, A. acidoterrestris was, indeed, not able to grow in the tested fruit drinks; similarly, when the model predicted a probability above 0.9, growth was observed in all cases. A good agreement was also observed between growth predicted by the kinetic model and the observed kinetics of A. acidoterrestris in fruit drinks at both static and dynamic temperature conditions. PMID- 29706337 TI - Use of Carnobacterium spp protective culture in MAP packed Ricotta fresca cheese to control Pseudomonas spp. AB - Ricotta fresca is a whey cheese susceptible of secondary contamination, mainly from Pseudomonas spp. The extension of the shelf life of refrigerated ricotta fresca could be obtained using protective cultures inhibiting the growth of this spoilage microorganism. A commercial biopreservative, Lyofast CNBAL, comprising Carnobacterium spp was tested against Pseudomonas spp. The surface of ricotta fresca samples were inoculated either with Pseudomonas spp or Pseudomonas and Carnobacterium spp. Samples were MAP packed, stored at 4 degrees C and analyzed the day of the inoculum and 7, 14 and 21 days after the contamination. Microbiological analyses included total bacterial count, mesophilic lactic acid bacteria, Enterobacteriaceae, Pseudomonas spp, Listeria monocytogenes, moulds and yeasts. Pseudomonas mean initial contamination level was comparable in blank and artificially inoculated samples, respectively with values of 2.15 +/- 0.21 and 2.34 +/- 0.26 log cfu g-1. Carnobacterium spp. significantly reduced the growth of Pseudomonas spp respectively of 1.28 log and 0.83 log after 14 and 21 days of refrigerated storage. Intrinsic properties and physico-chemical composition were also investigated. Limited variation of pH was observed in samples inoculated with the protective cultures, indicating low acidification properties of Carnobacterium spp. Instead, no significant differences were observed for aW, moisture, fat and proteins during storage and between inoculated and control samples. PMID- 29706338 TI - Survival of Mycobacterium avium subspecies paratuberculosis in retail pasteurised milk. AB - A survey of retail purchased semi-skimmed pasteurised milk (n = 368) for Mycobacterium avium subspecies paratuberculosis (MAP) was conducted between May 2014 and June 2015 across the midlands of England using the Phage-PCR assay. Overall, 10.3% of the total samples collected contained viable MAP cells, confirming that pasteurisation is not capable of fully eliminating human exposure to viable MAP through milk. Comparison of the results gained using the Phage-PCR assay with the results of surveys using either culture or direct PCR suggest that the phage-PCR assay is able to detect lower numbers of cells, resulting in an increase in the number of MAP-positive samples detected. Comparison of viable count and levels of MAP detected in bulk milk samples suggest that MAP is not primarily introduced into the milk by faecal contamination but rather are shed directly into the milk within the udder. In addition results detected an asymmetric distribution of MAP exists in the milk matrix prior to somatic cell lysis, indicating that the bacterial cells in naturally contaminated milk are clustered together and may primarily be located within somatic cells. These latter two results lead to the hypothesis that intracellular MAP within the somatic cells may be protected against heat inactivation during pasteurisation, accounting for the presence of low levels of MAP detected in retail milk. PMID- 29706339 TI - The production of aromatic alcohols in non-Saccharomyces wine yeast is modulated by nutrient availability. AB - Aromatic alcohols (tryptophol, phenylethanol, tyrosol) positively contribute to organoleptic characteristics of wines, and are also described as bioactive compounds and quorum sensing molecules. These alcohols are produced by yeast during alcoholic fermentation via the Erhlich pathway, although in non Saccharomyces this production has been poorly studied. We studied how different wine yeast species modulate the synthesis patterns of aromatic alcohol production depending on glucose, nitrogen and aromatic amino acid availability. Nitrogen limitation strongly promoted the production of aromatic alcohols in all strains, whereas low glucose generally inhibited it. Increased aromatic amino acid concentrations stimulated the production of aromatic alcohols in all of the strains and conditions tested. Thus, there was a clear association between the nutrient conditions and production of aromatic alcohols in most of the wine yeast species analysed. Additionally, the synthesis pattern of these alcohols has been evaluated for the first time in Torulaspora delbrueckii, Metschnikowia pulcherrima and Starmellera bacillaris. PMID- 29706340 TI - Predicting the combinatorial effects of water activity, pH and organic acids on Listeria growth in media and complex food matrices. AB - The aim of this study was to develop a model to predict growth of Listeria in complex food matrices as a function of pH, water activity and undissociated acetic and propionic acid concentration i.e. common food hurdles. Experimental growth curves of Listeria in food products and broth media were collected from ComBase, the literature and industry sources from which a bespoke secondary gamma model was constructed. Model performance was evaluated by comparing predictions to measured growth rates in growth media (BHI broth) and two adjusted food matrices (zucchini puree and bearnaise sauce). In general, observed growth rates were higher in broth than in the food matrices which resulted in the model over estimating growth in the adjusted food matrices. In addition, model outputs were more accurate for conditions without acids, indicating that the organic acid component of the model was a source of inaccuracy. In summary, a new predictive growth model for innovating or renovating food products that rely on multi-hurdle technology was created. This study is the first to report on modelling of propionic acid as an inhibitor of Listeria in combination with other hurdles. Our findings provide valuable insights into predictive model design and performance and highlight the importance of experimental validation of models in real food matrices rather than laboratory media alone. PMID- 29706341 TI - Evaluation of short purification cycles in naturally contaminated Mediterranean mussels (Mytilus galloprovincialis) harvested in Sardinia (Italy). AB - The aim of the present study was to investigate the effect of short purification cycles on the safety of naturally contaminated Mytilus galloprovincialis from harvesting areas of the Gulf of Olbia (Sardinia, Italy). Samples from ten batches of mussels were collected before, during and after purification treatment at two purification centres (A-B). All the samples were analysed for Escherichia coli and Salmonella spp according to Council Regulation (EC) 2285/2015. Detection and enumeration of Vibrio spp were performed according to previously published methods. Presumptive identification of Vibrio spp isolates were performed by means of conventional biochemical tests and polymerase chain reaction. The presence of Hepatitis A virus was detected by nested reverse transcriptase polymerase chain reaction. Environmental parameters (water temperature and salinity) were also recorded. The results of Escherichia coli counts showed the overall efficacy of the short purification cycles; a purification cycle of 8 h led to a rapid decline in the concentration. The decrease in Escherichia coli counts does not correlate with the presence of naturally occurring vibrios, the decline of which occurs at an even slower rate. The average contamination levels for Vibrio spp before purification were 8.20 +/- 0.47 and 7.99 +/- 0.62 Log10 CFU/g in samples collected at purification plants A and B, respectively. After purification, the average contamination levels were 8.10 +/- 0.60 Log10 CFU/g at purification plant A and 7.85 +/- 0.57 Log10 CFU/g at purification plant B. The contaminated samples revealed the presence of Vibrio alginolyticus (n=21), Vibrio fluvialis (n=12), Vibrio cholerae (n=4), Vibrio parahaemolyticus (n=2) and Vibrio vulnificus (n=1). The Vibrio parahaemolyticus isolates carried the tdh or the trh genes. None of the isolates was tdh+/trh+. Salmonella spp and Hepatitis A virus were not detected. The adoption of short purification cycles for Mytilus galloprovincialis in the presence of pathogenic vibrios might not be sufficient to guarantee the safety of consumers. PMID- 29706342 TI - Enterococcus faecium as a Salmonella surrogate in the thermal processing of wheat flour: Influence of water activity at high temperatures. AB - This study investigated the influence of temperature-dependent water activity (aw) on thermal resistances of Enterococcus faecium NRRL B-2354 (E. faecium) and Salmonella Enteritidis PT 30 (S. Enteritidis) in wheat flour. The aw for wheat flour samples at 20, 40, and 60 degrees C was determined by a vapor sorption analyzer and at 75, 80 and 85 degrees C using custom-built thermal cells with high temperature humidity sensors. Full-factorial isothermal inactivation studies of both strains in sealed aluminum-test-cells included three temperatures (75, 80, and 85 degrees C) and three aw,25 degrees C levels (0.30, 0.45 and 0.60 within +/-0.02 range, prior to the thermal treatments). Isotherm results of wheat flour demonstrate a significant increase (P < 0.05) of aw as temperature rises (e.g. aw,25 degrees C = 0.45 +/- 0.02 became aw,80 degrees C = 0.71 +/- 0.02 in a closed system). Inactivation kinetics of both microorganisms fitted a log-linear model, the yielded D-values varied from 2.7 +/- 0.2 min (D85 degrees C of S. Enteritidis at aw,25 degrees C 0.60 +/- 0.02) to 65.8 +/- 2.5 min (D75 degrees C of E. faecium at aw,25 degrees C 0.30 +/- 0.02). The zT of E. faecium and S. Enteritidis decreased from 16.4 and 16.9 degrees C, respectively, to 10.2 degrees C with increased moisture content (dry basis) from 10 to 14%. Under all tested conditions, E. faecium exhibited equal or higher (1.0-3.1 times) D- and zT values than those of Salmonella. Overall, E. faecium should be a conservative surrogate for Salmonella in thermal processing of wheat flour for control of Salmonella over a moisture content of 10-14% and treatment temperatures between 75 and 85 degrees C. PMID- 29706343 TI - An Economic Analysis of Stent Grafts for Treatment of Vascular Access Stenosis: Point-of-Care and Medicare Perspectives in the United States. AB - PURPOSE: To conduct an economic analysis on the impact of increased stent graft (SG) use for treatment of arteriovenous graft (AVG) anastomotic stenosis or arteriovenous fistula (AVF)/AVG in-stent restenosis (ISR) from United States point-of-care (POC) and Medicare perspectives. MATERIALS AND METHODS: The analyses compared initial device and reintervention costs over 2 years between current and projected treatment mixes, including percutaneous transluminal angioplasty (PTA), bare metal stents (BMSs), and SGs. In projected scenarios, the absolute increase in SG use was approximately 3%. Costs included procedure reimbursement rates (Medicare) and device list prices (POC) for index procedures and reinterventions. Reintervention rates and types were informed by the RENOVA and RESCUE randomized trials. Reinterventions were primarily PTA only; however, stent use occurred a proportion of the time. BMS reintervention rates were assumed to be identical to PTA based on observational data. A population size of 1,000 patients was assumed. RESULTS: To the POC (n = 1,000), increased SG use was predicted to result in cost savings ranging from $4,106 to $34,420 for AVG anastomotic stenosis. For AVF/AVG ISR, increased SG use was predicted to result in either a cost increase of $17,187 or a cost savings of $13,159. To Medicare (n = 1,000), increased SG use was predicted to save costs for both populations, with savings ranging from $57,401 to $169,544. CONCLUSIONS: The use of SG for treatment of AVG anastomotic stenosis and AVF/AVG ISR appears to be economically favorable for POC providers and Medicare. Further data on reintervention rates are required from other SG trials to validate findings. PMID- 29706344 TI - Endovascular Removal of Fractured Inferior Vena Cava Filter Fragments: 5-Year Registry Data with Prospective Outcomes on Retained Fragments. AB - PURPOSE: To evaluate the safety and efficacy of attempted percutaneous filter fragment removal during retrieval of fractured inferior vena cava (IVC) filters and to report outcomes associated with retained filter fragments. MATERIALS AND METHODS: Over a 5-year period, 82 consecutive patients presenting with a fractured IVC filter were prospectively enrolled into an institutional review board-approved registry. There were 27 men and 55 women (mean, 47 y; range, 19-85 y). After main filter removal, percutaneous removal of fragments was attempted if they were deemed intravascular and accessible on preprocedural computed tomography (CT), cone-beam CT, and/or intravascular ultrasound; distal pulmonary artery (PA) fragments were left alone. A total of 185 fragments were identified (81 IVC, 33 PA, 16 cardiac, 2 hepatic vein, 1 renal vein, 1 aorta, 51 retroperitoneal). Mean filter dwell time was 2,183 days (range, 59-9,936 d). Eighty-seven of 185 fragments (47%) were deemed amenable to attempted removal: 65 IVC, 11 PA, 8 cardiac, 2 hepatic, and 1 aortic. Primary safety outcomes were major procedure-related complications. RESULTS: Fragment removal was successful in 78 of 87 cases (89.7%; 95% confidence interval [CI], 81.3-95.2). There were 6 minor complications with no consequence (6.9%; 95% CI, 2.6-14.4) involving intraprocedural fragment embolization and 1 major complication (1.1%; 95% CI, 0.0 6.2), a cardiac tamponade that was successfully treated. The complication rate from attempted cardiac fragment removal was 12.5% (1 of 8; 95% CI, 0.3-52.7). Among patients with retained cardiopulmonary fragments (n = 19), 81% remained asymptomatic during long-term clinical follow-up of 845 days (range, 386-2,071 d). CONCLUSIONS: Percutaneous removal of filter fragments from the IVC and proximal PAs is safe and effective overall, but attempted intracardiac fragment removal carries a higher risk of complication. Most residual filter fragments not amenable to percutaneous removal remain asymptomatic and may be monitored clinically. PMID- 29706345 TI - Patterns of Genetic Coding Variation in a Native American Population before and after European Contact. AB - The effects of European colonization on the genomes of Native Americans may have produced excesses of potentially deleterious features, mainly due to the severe reductions in population size and corresponding losses of genetic diversity. This assumption, however, neither considers actual genomic patterns that existed before colonization nor does it adequately capture the effects of admixture. In this study, we analyze the whole-exome sequences of modern and ancient individuals from a Northwest Coast First Nation, with a demographic history similar to other indigenous populations from the Americas. We show that in approximately ten generations from initial European contact, the modern individuals exhibit reduced levels of novel and low-frequency variants, a lower proportion of potentially deleterious alleles, and decreased heterozygosity when compared to their ancestors. This pattern can be explained by a dramatic population decline, resulting in the loss of potentially damaging low-frequency variants, and subsequent admixture. We also find evidence that the indigenous population was on a steady decline in effective population size for several thousand years before contact, which emphasizes regional demography over the common conception of a uniform expansion after entry into the Americas. This study examines the genomic consequences of colonialism on an indigenous group and describes the continuing role of gene flow among modern populations. PMID- 29706346 TI - An Osteoporosis Risk SNP at 1p36.12 Acts as an Allele-Specific Enhancer to Modulate LINC00339 Expression via Long-Range Loop Formation. AB - Genome-wide association studies (GWASs) have reproducibly associated variants within intergenic regions of 1p36.12 locus with osteoporosis, but the functional roles underlying these noncoding variants are unknown. Through an integrative functional genomic and epigenomic analyses, we prioritized rs6426749 as a potential causal SNP for osteoporosis at 1p36.12. Dual-luciferase assay and CRISPR/Cas9 experiments demonstrate that rs6426749 acts as a distal allele specific enhancer regulating expression of a lncRNA (LINC00339) (~360 kb) via long-range chromatin loop formation and that this loop is mediated by CTCF occupied near rs6426749 and LINC00339 promoter region. Specifically, rs6426749-G allele can bind transcription factor TFAP2A, which efficiently elevates the enhancer activity and increases LINC00339 expression. Downregulation of LINC00339 significantly increases the expression of CDC42 in osteoblast cells, which is a pivotal regulator involved in bone metabolism. Our study provides mechanistic insight into how a noncoding SNP affects osteoporosis by long-range interaction, a finding that could indicate promising therapeutic targets for osteoporosis. PMID- 29706347 TI - The Effect of ACTN3 Gene Doping on Skeletal Muscle Performance. AB - Loss of expression of ACTN3, due to homozygosity of the common null polymorphism (p.Arg577X), is underrepresented in elite sprint/power athletes and has been associated with reduced muscle mass and strength in humans and mice. To investigate ACTN3 gene dosage in performance and whether expression could enhance muscle force, we performed meta-analysis and expression studies. Our general meta analysis using a Bayesian random effects model in elite sprint/power athlete cohorts demonstrated a consistent homozygous-group effect across studies (per allele OR = 1.4, 95% CI 1.3-1.6) but substantial heterogeneity in heterozygotes. In mouse muscle, rAAV-mediated gene transfer overexpressed and rescued alpha actinin-3 expression. Contrary to expectation, in vivo "doping" of ACTN3 at low to moderate doses demonstrated an absence of any change in function. At high doses, ACTN3 is toxic and detrimental to force generation, to demonstrate gene doping with supposedly performance-enhancing isoforms of sarcomeric proteins can be detrimental for muscle function. Restoration of alpha-actinin-3 did not enhance muscle mass but highlighted the primary role of alpha-actinin-3 in modulating muscle metabolism with altered fatiguability. This is the first study to express a Z-disk protein in healthy skeletal muscle and measure the in vivo effect. The sensitive balance of the sarcomeric proteins and muscle function has relevant implications in areas of gene doping in performance and therapy for neuromuscular disease. PMID- 29706348 TI - Missense Variants in HIF1A and LACC1 Contribute to Leprosy Risk in Han Chinese. AB - Genome-wide association studies (GWASs) and genome-wide linkage studies (GWLSs) have identified numerous risk genes affecting the susceptibility to leprosy. However, most of the reported GWAS hits are noncoding variants and account for only part of the estimated heritability for this disease. In order to identify additional risk genes and map the potentially functional variants within the GWAS loci, we performed a three-stage study combining whole-exome sequencing (WES; discovery stage), targeted next-generation sequencing (NGS; screening stage), and refined validation of risk missense variants in 1,433 individuals with leprosy and 1,625 healthy control individuals from Yunnan Province, Southwest China. We identified and validated a rare damaging variant, rs142179458 (c.1045G>A [p.Asp349Asn]) in HIF1A, as contributing to leprosy risk (p = 4.95 * 10-9, odds ratio [OR] = 2.266). We were able to show that affected individuals harboring the risk allele presented with multibacillary leprosy at an earlier age (p = 0.025). We also confirmed the association between missense variant rs3764147 (c.760A>G [p.Ile254Val]) in the GWAS hit LACC1 (formerly C13orf31) and leprosy (p = 6.11 * 10-18, OR = 1.605). By using the population attributable fraction, we have shown that HIF1A and LACC1 are the major genes with missense variants contributing to leprosy risk in our study groups. Consistently, mRNA expression levels of both HIF1A and LACC1 were upregulated in the skin lesions of individuals with leprosy and in Mycobacterium leprae-stimulated cells, indicating an active role of HIF1A and LACC1 in leprosy pathogenesis. PMID- 29706350 TI - A Saturation Mutagenesis Approach to Understanding PTEN Lipid Phosphatase Activity and Genotype-Phenotype Relationships. AB - Phosphatase and tensin homolog (PTEN) is a tumor suppressor frequently mutated in diverse cancers. Germline PTEN mutations are also associated with a range of clinical outcomes, including PTEN hamartoma tumor syndrome (PHTS) and autism spectrum disorder (ASD). To empower new insights into PTEN function and clinically relevant genotype-phenotype relationships, we systematically evaluated the effect of PTEN mutations on lipid phosphatase activity in vivo. Using a massively parallel approach that leverages an artificial humanized yeast model, we derived high-confidence estimates of functional impact for 7,244 single amino acid PTEN variants (86% of possible). We identified 2,273 mutations with reduced cellular lipid phosphatase activity, which includes 1,789 missense mutations. These data recapitulated known functional findings but also uncovered new insights into PTEN protein structure, biochemistry, and mutation tolerance. Several residues in the catalytic pocket showed surprising mutational tolerance. We identified that the solvent exposure of wild-type residues is a critical determinant of mutational tolerance. Further, we created a comprehensive functional map by leveraging correlations between amino acid substitutions to impute functional scores for all variants, including those not present in the assay. Variant functional scores can reliably discriminate likely pathogenic from benign alleles. Further, 32% of ClinVar unclassified missense variants are phosphatase deficient in our assay, supporting their reclassification. ASD associated mutations generally had less severe fitness scores relative to PHTS associated mutations (p = 7.16 * 10-5) and a higher fraction of hypomorphic mutations, arguing for continued genotype-phenotype studies in larger clinical datasets that can further leverage these rich functional data. PMID- 29706349 TI - Haplotype Sharing Provides Insights into Fine-Scale Population History and Disease in Finland. AB - Finland provides unique opportunities to investigate population and medical genomics because of its adoption of unified national electronic health records, detailed historical and birth records, and serial population bottlenecks. We assembled a comprehensive view of recent population history (<=100 generations), the timespan during which most rare-disease-causing alleles arose, by comparing pairwise haplotype sharing from 43,254 Finns to that of 16,060 Swedes, Estonians, Russians, and Hungarians from geographically and linguistically adjacent countries with different population histories. We find much more extensive sharing in Finns, with at least one >= 5 cM tract on average between pairs of unrelated individuals. By coupling haplotype sharing with fine-scale birth records from more than 25,000 individuals, we find that although haplotype sharing broadly decays with geographical distance, there are pockets of excess haplotype sharing; individuals from northeast Finland typically share several fold more of their genome in identity-by-descent segments than individuals from southwest regions. We estimate recent effective population-size changes through time across regions of Finland, and we find that there was more continuous gene flow as Finns migrated from southwest to northeast between the early- and late settlement regions than was dichotomously described previously. Lastly, we show that haplotype sharing is locally enriched by an order of magnitude among pairs of individuals sharing rare alleles and especially among pairs sharing rare disease-causing variants. Our work provides a general framework for using haplotype sharing to reconstruct an integrative view of recent population history and gain insight into the evolutionary origins of rare variants contributing to disease. PMID- 29706351 TI - Monoallelic Mutations to DNAJB11 Cause Atypical Autosomal-Dominant Polycystic Kidney Disease. AB - Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts, often resulting in end-stage renal disease (ESRD). This disorder is genetically heterogeneous with ~7% of families genetically unresolved. We performed whole-exome sequencing (WES) in two multiplex ADPKD-like pedigrees, and we analyzed a further 591 genetically unresolved, phenotypically similar families by targeted next-generation sequencing of 65 candidate genes. WES identified a DNAJB11 missense variant (p.Pro54Arg) in two family members presenting with non-enlarged polycystic kidneys and a frameshifting change (c.166_167insTT) in a second family with small renal and liver cysts. DNAJB11 is a co-factor of BiP, a key chaperone in the endoplasmic reticulum controlling folding, trafficking, and degradation of secreted and membrane proteins. Five additional multigenerational families carrying DNAJB11 mutations were identified by the targeted analysis. The clinical phenotype was consistent in the 23 affected members, with non-enlarged cystic kidneys that often evolved to kidney atrophy; 7 subjects reached ESRD from 59 to 89 years. The lack of kidney enlargement, histologically evident interstitial fibrosis in non-cystic parenchyma, and recurring episodes of gout (one family) suggested partial phenotypic overlap with autosomal-dominant tubulointerstitial diseases (ADTKD). Characterization of DNAJB11-null cells and kidney samples from affected individuals revealed a pathogenesis associated with maturation and trafficking defects involving the ADPKD protein, PC1, and ADTKD proteins, such as UMOD. DNAJB11-associated disease is a phenotypic hybrid of ADPKD and ADTKD, characterized by normal-sized cystic kidneys and progressive interstitial fibrosis resulting in late-onset ESRD. PMID- 29706352 TI - Whole-Exome Sequencing Reveals Uncaptured Variation and Distinct Ancestry in the Southern African Population of Botswana. AB - Large-scale, population-based genomic studies have provided a context for modern medical genetics. Among such studies, however, African populations have remained relatively underrepresented. The breadth of genetic diversity across the African continent argues for an exploration of local genomic context to facilitate burgeoning disease mapping studies in Africa. We sought to characterize genetic variation and to assess population substructure within a cohort of HIV-positive children from Botswana-a Southern African country that is regionally underrepresented in genomic databases. Using whole-exome sequencing data from 164 Batswana and comparisons with 150 similarly sequenced HIV-positive Ugandan children, we found that 13%-25% of variation observed among Batswana was not captured by public databases. Uncaptured variants were significantly enriched (p = 2.2 * 10-16) for coding variants with minor allele frequencies between 1% and 5% and included predicted-damaging non-synonymous variants. Among variants found in public databases, corresponding allele frequencies varied widely, with Botswana having significantly higher allele frequencies among rare (<1%) pathogenic and damaging variants. Batswana clustered with other Southern African populations, but distinctly from 1000 Genomes African populations, and had limited evidence for admixture with extra-continental ancestries. We also observed a surprising lack of genetic substructure in Botswana, despite multiple tribal ethnicities and language groups, alongside a higher degree of relatedness than purported founder populations from the 1000 Genomes project. Our observations reveal a complex, but distinct, ancestral history and genomic architecture among Batswana and suggest that disease mapping within similar Southern African populations will require a deeper repository of genetic variation and allelic dependencies than presently exists. PMID- 29706354 TI - Pupil Size Variation and Pain-Can the Results be Generalized? PMID- 29706355 TI - Reply to "A New Pupillary Measure to Assess Pain: A Prospective Study". PMID- 29706356 TI - Haploidentical stem cell transplantation: T cell depleted and repleted. AB - Allogeneic hematopoietic stem cell transplantation (AHSCT), is a curative treatment option for many hematological diseases. Donor availability is the major limiting factor in the transplantation setting. More than half of the patients do not have a HLA fully matched related/unrelated donor but almost all patients have an haploidentical donor. Haploidentical transplantion can be performed either as T cell depleted or repleted. Despite the promising results in T cell depletion methods, expensive T cell selection and the necessity for experienced staff seem to be the limiting factors. However, a T cell repleted haploidentical stem cell transplantation strategy is simple, cheap and has been preferred by different transplant centers worldwide. PMID- 29706353 TI - Patient-iPSC-Derived Kidney Organoids Show Functional Validation of a Ciliopathic Renal Phenotype and Reveal Underlying Pathogenetic Mechanisms. AB - Despite the increasing diagnostic rate of genomic sequencing, the genetic basis of more than 50% of heritable kidney disease remains unresolved. Kidney organoids differentiated from induced pluripotent stem cells (iPSCs) of individuals affected by inherited renal disease represent a potential, but unvalidated, platform for the functional validation of novel gene variants and investigation of underlying pathogenetic mechanisms. In this study, trio whole-exome sequencing of a prospectively identified nephronophthisis (NPHP) proband and her parents identified compound-heterozygous variants in IFT140, a gene previously associated with NPHP-related ciliopathies. IFT140 plays a key role in retrograde intraflagellar transport, but the precise downstream cellular mechanisms responsible for disease presentation remain unknown. A one-step reprogramming and gene-editing protocol was used to derive both uncorrected proband iPSCs and isogenic gene-corrected iPSCs, which were differentiated to kidney organoids. Proband organoid tubules demonstrated shortened, club-shaped primary cilia, whereas gene correction rescued this phenotype. Differential expression analysis of epithelial cells isolated from organoids suggested downregulation of genes associated with apicobasal polarity, cell-cell junctions, and dynein motor assembly in proband epithelial cells. Matrigel cyst cultures confirmed a polarization defect in proband versus gene-corrected renal epithelium. As such, this study represents a "proof of concept" for using proband-derived iPSCs to model renal disease and illustrates dysfunctional cellular pathways beyond the primary cilium in the setting of IFT140 mutations, which are established for other NPHP genotypes. PMID- 29706358 TI - The role of cannabinoid signaling in acute and chronic kidney diseases. AB - The endogenous cannabinoids anandamide and 2-arachidonoylglycerol bind to the cannabinoid receptors of type 1 and 2. These receptors are also the binding sites for exogenous, both natural and synthetic, cannabinoids that are used for recreation purposes. Until recently, cannabinoids and cannabinoid receptors have attracted little interest among nephrologists; however, a full endocannabinoid system (ECS) is present in the kidney and it has recently emerged as an important player in the pathogenesis of diabetic nephropathy, drug nephrotoxicity, and progressive chronic kidney disease. This newly established role of the ECS in the kidney might have therapeutic relevance, as pharmacological modulation of the ECS has renoprotective effects in experimental animals, raising hope for future potential applications in humans. In addition, over the last years, there has been a number of reported cases of acute kidney injury (AKI) associated with the use of synthetic cannabinoids that appear to have higher potency and rate of toxicity than natural Cannabis. This poorly recognized cause of renal injury should be considered in the differential diagnosis of AKI, particularly in young people. In this review we provide an overview of preclinical evidence indicating a role of the ECS in renal disease and discuss potential future therapeutic applications. Moreover, we give a critical update of synthetic cannabinoid induced AKI. PMID- 29706359 TI - Considerations in Treating Insomnia During Pregnancy: A Literature Review. AB - BACKGROUND: The prevalence of pregnancy-associated insomnia is high. Although insomnia may flow from normal physiologic features of pregnancy, it may also be an early warning sign of a relapse, or a trigger for a relapse, of a psychiatric illness. Those at risk for psychiatric illnesses may require medications as well as behavioral and psychotherapeutic interventions, to prevent relapse in the perinatal period. Unfortunately, few reviews of psychotropics used to treat pregnancy-related sleep disorders exist. OBJECTIVE: We discuss issues related to sleep and sleep disorders in pregnancy in the context of co-morbid psychiatric illness, and review the literature on the commonly-used medications (e.g., benzodiazepines, sedative-hypnotics, antihistamines, trazodone, and melatonin) for insomnia during pregnancy. PMID- 29706357 TI - [ROS-1 rearranged bronchopulmonary adenocarcinoma revealed by a pulmonary miliary]. PMID- 29706361 TI - Accessory lobe of the liver in a 14-year-old girl. PMID- 29706360 TI - Whole-Exome Sequencing in Age-Related Macular Degeneration Identifies Rare Variants in COL8A1, a Component of Bruch's Membrane. AB - PURPOSE: Genome-wide association studies and targeted sequencing studies of candidate genes have identified common and rare variants that are associated with age-related macular degeneration (AMD). Whole-exome sequencing (WES) studies allow a more comprehensive analysis of rare coding variants across all genes of the genome and will contribute to a better understanding of the underlying disease mechanisms. To date, the number of WES studies in AMD case-control cohorts remains scarce and sample sizes are limited. To scrutinize the role of rare protein-altering variants in AMD cause, we performed the largest WES study in AMD to date in a large European cohort consisting of 1125 AMD patients and 1361 control participants. DESIGN: Genome-wide case-control association study of WES data. PARTICIPANTS: One thousand one hundred twenty-five AMD patients and 1361 control participants. METHODS: A single variant association test of WES data was performed to detect variants that are associated individually with AMD. The cumulative effect of multiple rare variants with 1 gene was analyzed using a gene based CMC burden test. Immunohistochemistry was performed to determine the localization of the Col8a1 protein in mouse eyes. MAIN OUTCOME MEASURES: Genetic variants associated with AMD. RESULTS: We detected significantly more rare protein-altering variants in the COL8A1 gene in patients (22/2250 alleles [1.0%]) than in control participants (11/2722 alleles [0.4%]; P = 7.07*10-5). The association of rare variants in the COL8A1 gene is independent of the common intergenic variant (rs140647181) near the COL8A1 gene previously associated with AMD. We demonstrated that the Col8a1 protein localizes at Bruch's membrane. CONCLUSIONS: This study supported a role for protein-altering variants in the COL8A1 gene in AMD pathogenesis. We demonstrated the presence of Col8a1 in Bruch's membrane, further supporting the role of COL8A1 variants in AMD pathogenesis. Protein-altering variants in COL8A1 may alter the integrity of Bruch's membrane, contributing to the accumulation of drusen and the development of AMD. PMID- 29706362 TI - State-of-the-art acute phase management of Kawasaki disease after 2017 scientific statement from the American Heart Association. AB - Kawasaki disease (KD) has become the most common form of pediatric systemic vasculitis. Although patients with KD received intravenous immunoglobulin (IVIG) therapy, coronary arterial lesions (CALs) still occurred in 5%-10% of these patients during the acute stage. CALs may persist and even progress to stenosis or obstruction. Therefore, CALs following KD are currently the leading cause of acquired heart diseases in children. The etiology of CALs remains unknown despite more than four decades of research. Two unsolved problems are IVIG unresponsiveness and the diagnosis of incomplete KD. The two subgroups of KD patients with these problems have a high risk of CAL. In April 2017, the American Heart Association (AHA) updated the guidelines for the diagnosis, treatment, and long-term management of KD. Compared with the previous KD guidelines published in 2004, the new guidelines provide solutions to the aforementioned two problems and emphasize risk stratification by using coronary artery Z score systems, as well as coronary severity-based management and long-term follow-up. Therefore, in this study, we merged the AHA Scientific Statement in 2017 with recent findings for Taiwanese KD patients to provide potential future care directions for Taiwanese patients with KD. PMID- 29706363 TI - What proportion of older adults in hospital are frail? PMID- 29706364 TI - Development and validation of a Hospital Frailty Risk Score focusing on older people in acute care settings using electronic hospital records: an observational study. AB - BACKGROUND: Older people are increasing users of health care globally. We aimed to establish whether older people with characteristics of frailty and who are at risk of adverse health-care outcomes could be identified using routinely collected data. METHODS: A three-step approach was used to develop and validate a Hospital Frailty Risk Score from International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic codes. First, we carried out a cluster analysis to identify a group of older people (>=75 years) admitted to hospital who had high resource use and diagnoses associated with frailty. Second, we created a Hospital Frailty Risk Score based on ICD-10 codes that characterised this group. Third, in separate cohorts, we tested how well the score predicted adverse outcomes and whether it identified similar groups as other frailty tools. FINDINGS: In the development cohort (n=22 139), older people with frailty diagnoses formed a distinct group and had higher non-elective hospital use (33.6 bed-days over 2 years compared with 23.0 bed-days for the group with the next highest number of bed-days). In the national validation cohort (n=1 013 590), compared with the 429 762 (42.4%) patients with the lowest risk scores, the 202 718 (20.0%) patients with the highest Hospital Frailty Risk Scores had increased odds of 30-day mortality (odds ratio 1.71, 95% CI 1.68-1.75), long hospital stay (6.03, 5.92-6.10), and 30-day readmission (1.48, 1.46-1.50). The c statistics (ie, model discrimination) between individuals for these three outcomes were 0.60, 0.68, and 0.56, respectively. The Hospital Frailty Risk Score showed fair overlap with dichotomised Fried and Rockwood scales (kappa scores 0.22, 95% CI 0.15-0.30 and 0.30, 0.22-0.38, respectively) and moderate agreement with the Rockwood Frailty Index (Pearson's correlation coefficient 0.41, 95% CI 0.38-0.47). INTERPRETATION: The Hospital Frailty Risk Score provides hospitals and health systems with a low-cost, systematic way to screen for frailty and identify a group of patients who are at greater risk of adverse outcomes and for whom a frailty-attuned approach might be useful. FUNDING: National Institute for Health Research. PMID- 29706365 TI - Clinical epidemiology of carbapenem-resistant gram-negative sepsis among hospitalized patients: Shifting burden of disease? AB - BACKGROUND: Infections caused by carbapenem-resistant gram-negative bacilli are an emerging public health threat. However, there is a paucity of data examining comparative incidence rates, risk factors, and outcomes in this population. METHODS: This single-center retrospective cohort study was conducted at an urban tertiary-care academic medical center. We included patients admitted from 2012 to 2015 who met the following criteria: i) age >= 18 years; and ii) culture positive for carbapenem-resistant Enterobacteriaceae (CRE) or carbapenem-resistant non Enterobacteriaceae (CRNE) from any site. Exclusion criteria were: i) < 2 systemic inflammatory response criteria; ii) cystic fibrosis; and iii) no targeted treatment. We evaluated hospital survival by Cox regression and year-by-year differences in the distribution of cases by the Cochran-Armitage test. RESULTS: 448 patients were analyzed (CRE, n = 111 [24.8%]; CRNE, n = 337 [75.2%]). CRE sepsis cases increased significantly over the study period (P <.001), driven primarily by increasing incidence of Enterobacter spp. infection (P = .004). No difference was observed in hospital survival between patients with CRE versus CRNE sepsis (hazard ratio [HR], 1.29; 95% confidence interval [CI], 0.83-2.02; P = .285), even after adjusting for confounding factors (adjusted HR, 1.08; 95% CI, 0.62-1.87; P = .799). CONCLUSIONS: Clinical outcomes did not differ between patients with CRE versus CRNE sepsis. Dramatic increases in CRE, particularly Enterobacter spp., appear to be causing a shift in the burden of clinically significant carbapenem-resistant gram-negative infection. PMID- 29706366 TI - Retention and distribution of methylmercury administered in the food in marine invertebrates: Effect of dietary selenium. AB - Methylmercury is transported along aquatic food chains from the lower trophic levels and selenium modulates the biokinetics of mercury in organisms in complex ways. We investigated the retention of orally administered methylmercury in various marine invertebrates and the effect of selenium hereon. Shrimps (Palaemon adpersus and P. elegans), blue mussels (Mytilus edulis), shore crabs (Carcinus maenas) and sea stars (Asterias rubens) eliminated methylmercury slowly (t1/2 = 1/2 to >1 year) and the copepod (Acartia tonsa) faster (t1/2 ~ 12-24 h). Orally administered selenite augmented elimination of methylmercury in the copepod (in one of two experiments) and blue mussels, but not in shrimps, crabs and sea stars. Selenium generally alters the distribution of the body burden of mercury, leaving more mercury in muscle and less mercury in digestive glands or rest of the body - also in the species where total body retention is not affected. PMID- 29706367 TI - Reduction of herbivorous fish pressure can facilitate focal algal species forestation on artificial structures. AB - Coastal areas have been transformed worldwide by urbanization, so that artificial structures are now widespread. Current coastal development locally depletes many native marine species, while offering limited possibilities for their expansion. Eco-engineering interventions intend to identify ways to facilitate the presence of focal species and their associated functions on artificial habitats. An important but overlooked factor controlling restoration operations is overgrazing by herbivores. The aim of this study was to quantify the effects of different potential feeders on Cystoseira amentacea, a native canopy-forming alga of the Mediterranean infralittoral fringe, and test whether manipulation of grazing pressure can facilitate the human-guided installation of this focal species on coastal structures. Results of laboratory tests and field experiments revealed that Sarpa salpa, the only strictly native herbivorous fish in the Western Mediterranean Sea, can be a very effective grazer of C. amentacea in artificial habitats, up to as far as the infralittoral fringe, which is generally considered less accessible to fishes. S. salpa can limit the success of forestation operations in artificial novel habitats, causing up to 90% of Cystoseira loss after a few days. Other grazers, such as limpets and crabs, had only a moderate impact. Future engineering operations,intended to perform forestation of canopy forming algae on artificial structures, should consider relevant biotic factors, such as fish overgrazing, identifying cost-effective techniques to limit their impact, as is the usual practice in restoration programmes on land. PMID- 29706368 TI - Accumulation of PBDEs in stranded harp (Pagophilus groenlandicus) and hooded seals (Cystophora cristata) from the Northeastern United States. AB - Polybrominated diphenyl ethers (PBDEs) are highly lipophilic components of brominated flame retardants that are environmentally persistent and bioaccumulate. PBDEs are taken up from the gastrointestinal tract and accumulate mainly in fat depots and liver tissues. Seal species inhabiting Arctic and sub Arctic regions can have upwards of 30% of their body mass composed of blubber. When those blubber stores are mobilized for energy, stored toxicants are also released into circulation. Most studies reporting accumulation of PBDEs in seals have focused on harbor and grey seals with few examining harp and hooded seals. In this study, PBDEs concentrations were analyzed in seal blubber from 21 stranded harp and 9 stranded hooded seals sampled along the northeast coast of the U.S. (1999-2010). A PBDE congener profile was determined for each individual. The results show that both species of seals are accumulating PBDEs with BDE-47 being the dominant congener. Mean ?PBDE concentrations in harp seals were 70.55 +/- 33.59 ng/g ww and for hooded seals 94.28 +/- 42.65 ng/g ww. The results of this study are consistent with previous studies reporting a decrease in bioaccumulation with an increase in bromination. For both species, BDE-47 represented the highest percentage of the ?PBDEs, composing over 50% of the ?PBDEs in harp seals. When compared to stranding condition code, animals found alive had overall higher PBDE concentrations than those found in a state of moderate decomposition. This difference could be due to decreased blubber levels in the decomposed animals or potential degradation of the compounds in the blubber. Almost all seals used in this study were yearlings which is the most likely age class to strand. Yearling seals are at a crucial stage of development, especially of their immune system, which can be impacted by high levels of contaminants like PBDEs and increase the susceptibility to disease. PMID- 29706369 TI - Seagrass macrofaunal abundance shows both multifractality and scale-invariant patchiness. AB - Spatial patterns of abundance of the whole macrobenthic assemblage and of its 10 most numerous species were examined across hierarchically nested scales within a 0.85 ha area of intertidal seagrass in subtropical Moreton Bay, Queensland. Multifractality characterised the assemblage and all ten dominant species across those scales (c. 33, 130, 530 & 2115 m2), with patchiness of assemblage numbers and those of at least some dominants exhibiting scale-invariance. The system displayed several abundance peaks, 12% of stations accounting for 88% of total variance, with many individual dominants showing a series of non-overlapping 'hot spots'. Scale invariance and multifractality occurred notwithstanding low levels of species interaction consequent on maintenance at very low density. This suggests that critical self-organisation cannot be responsible for such patterning. Contrary to received wisdom, coefficient beta of Taylor's power-law cannot form an index of aggregation, although it does indicate direction of change in dispersion pattern with changing numbers. PMID- 29706370 TI - Advanced imaging unveils aortic valve secrets: What is next, theoretic biology? PMID- 29706371 TI - An anticoagulation protocol for use after congenital cardiac surgery. AB - BACKGROUND: Patients undergoing surgery for congenital heart disease are at high risk for bleeding as well as thrombosis in the postoperative period. The objective of the study was to describe the design and effects of implementing a standardized unfractionated heparin anticoagulation protocol for children after congenital heart surgery. METHODS: We created a tiered guideline for the postoperative management of bleeding and thrombosis. In patients treated with unfractionated heparin, anti-factor Xa activity level as well as activated partial thromboplastin time were used for dose titration. Clinical outcomes, including bleeding and thrombosis events, were prospectively collected for 5 months before and after protocol implementation and adjudicated as either minor, clinically relevant nonmajor, or major. RESULTS: Among 792 surgical patients followed during the study period, a total of 203 patients (87 preimplementation, 116 postimplementation) were treated with therapeutic unfractionated heparin over a total of 1481 patient days. Of these, 28% were neonates and 35% were infants (29 days to 1 year), with a trend toward fewer neonates and lower Risk Adjustment for Congenital Heart Surgery (RACHS) scores after protocol implementation. Among 1321 time-matched pairs, activated partial thromboplastin time and antifactor Xa activity levels were poorly correlated (r2 = 0.33). Clinically relevant bleeding events, which required increased medical care, including blood transfusion, decreased after protocol implementation (4.14 vs 1.62 bleeding events per 100 patient-days; risk ratio, 0.39 [0.20-0.75]; P = .005), even after correcting for differences in age and RACHS scores (P = .006). This finding was primarily found after RACHS category 1 to 3 procedures (risk ratio, 0.27 [0.10-0.73]; P = .0099) and in noninfants (risk ratio, 0.25 [0.09-0.65]; P = .005). There were no significant differences in the incidences of major bleeding (P = .88) or any thrombosis (P = .55). CONCLUSIONS: The use of a standardized anticoagulation protocol is feasible and might reduce the incidence of bleeding and thrombosis events in postcardiotomy patients. PMID- 29706373 TI - Discussion. PMID- 29706372 TI - Preoperative anemia versus blood transfusion: Which is the culprit for worse outcomes in cardiac surgery? AB - BACKGROUND: Reducing blood product utilization after cardiac surgery has become a focus of perioperative care as studies have suggested improved outcomes. The relative impact of preoperative anemia versus packed red blood cells (PRBC) transfusion on outcomes remains poorly understood, however. In this study, we investigated the relative association between preoperative hematocrit (Hct) level and PRBC transfusion on postoperative outcomes after coronary artery bypass grafting (CABG) surgery. METHODS: Patient records for primary, isolated CABG operations performed between January 2007 and December 2017 at 19 cardiac surgery centers were evaluated. Hierarchical logistic regression modeling was used to estimate the relationship between baseline preoperative Hct level as well as PRBC transfusion and the likelihoods of postoperative mortality and morbidity, adjusted for baseline patient risk. Variable and model performance characteristics were compared to determine the relative strength of association between Hct level and PRBC transfusion and primary outcomes. RESULTS: A total of 33,411 patients (median patient age, 65 years; interquartile range [IQR], 57-72 years; 26% females) were evaluated. The median preoperative Hct value was 39% (IQR, 36%-42%), and the mean Society of Thoracic Surgeons (STS) predicted risk of mortality was 1.8 +/- 3.1%. Complications included PRBC transfusion in 31% of patients, renal failure in 2.8%, stroke in 1.3%, and operative mortality in 2.0%. A strong association was observed between preoperative Hct value and the likelihood of PRBC transfusion (P < .001). After risk adjustment, PRBC transfusion, but not Hct value, demonstrated stronger associations with postoperative mortality (odds ratio [OR], 4.3; P < .0001), renal failure (OR 6.3; P < .0001), and stroke (OR, 2.4; P < .0001). A 1-point increase in preoperative Hct was associated with decreased probabilities of mortality (OR, 0.97; P = .0001) and renal failure (OR, 0.94; P < .0001). The models with PRBC had superior predictive power, with a larger area under the curve, compared with Hct for all outcomes (all P < .01). Preoperative anemia was associated with up to a 4-fold increase in the probability of PRBC transfusion, a 3-fold increase in renal failure, and almost double the mortality. CONCLUSIONS: PRBC transfusion appears to be more closely associated with risk-adjusted morbidity and mortality compared with preoperative Hct level alone, supporting efforts to reduce unnecessary PRBC transfusions. Preoperative anemia independently increases the risk of postoperative morbidity and mortality. These data suggest that preoperative Hct should be included in the STS risk calculators. Finally, efforts to optimize preoperative hematocrit should be investigated as a potentially modifiable risk factor for mortality and morbidity. PMID- 29706374 TI - Risk of gastrointestinal cancers in patients with cystic fibrosis: a systematic review and meta-analysis. AB - BACKGROUND: The management and life expectancy of patients with cystic fibrosis have improved substantially in the past three decades, which has resulted in an increased number of these patients being diagnosed with malignancies. Our aim was to assess the risk of gastrointestinal cancers in patients with cystic fibrosis. METHODS: In this systematic review and meta-analysis, we searched PubMed, MEDLINE, Google Scholar, Scopus, Embase, and Cochrane databases with no language restrictions for studies published from inception of the databases to Aug 1, 2017, assessing the risk of gastrointestinal cancers in patients with cystic fibrosis. We also searched abstracts from scientific meetings and the bibliographies of identified articles for additional references. Studies were included if they reported the standardised incidence ratio (SIR) or incidence ratio per person-years. No exclusion criteria with regard to patient characteristics (age, sex, comorbidities, cystic fibrosis mutation type), study setting (location and time period), or method of reporting cancer diagnoses were applied. The primary outcome was risk of gastrointestinal cancer and site specific gastrointestinal cancers in patients with cystic fibrosis compared with the general population. Pooled summary estimates were calculated using a random effects model, and subgroup analyses were done to establish whether risk of gastrointestinal cancer varied according to patient lung transplant status. The study is registered with PROSPERO, number CRD42017075396. FINDINGS: Our search identified 95 681 records, of which six cohort studies including 99 925 patients (544 695 person-years) were eligible for the meta-analysis. The overall risk of gastrointestinal cancer was significantly higher in patients with cystic fibrosis than in the general population (pooled SIR 8.13, 95% CI 6.48-10.21; p<0.0001; log SIR 2.10, 95% CI 1.87-2.32; p<0.0001, I2=93.93%). Subgroup analyses showed that the risk of gastrointestinal cancer among patients with cystic fibrosis who had a lung transplant was increased compared with that of patients who did not receive a transplant (pooled SIR 21.13, 95% CI 14.82-30.14; p<0.0001; log SIR 3.05, 95% CI 2.70-3.41; p<0.0001, I2=28.52% vs pooled SIR 4.18, 3.10-5.62; p<0.0001; log SIR 1.43, 1.13-1.73; p<0.0001, I2=22.66%). The risk for the following site specific cancers was also significantly increased in patients with cystic fibrosis compared with the general population: small bowel cancer (pooled SIR 18.94, 95% CI 9.37-38.27; p<0.0001; log SIR 2.94, 95% CI 2.24-3.64; p<0.0001, I2=38.61%), colon cancer (10.91, 8.42-14.11; p<0.0001; log SIR 2.39, 2.13-2.65; p<0.0001, I2=88.09%), biliary tract cancer (17.87, 8.55-37.36; p<0.0001; log SIR 2.88, 2.15-3.62; p<0.0001, I2=10.16%), and pancreatic cancer (6.18, 1.31-29.27; p=0.022; log SIR 1.82, 0.27-3.38; p<0.0001, I2=62.57%). INTERPRETATION: Our study suggests that patients with cystic fibrosis had a significantly increased risk of gastrointestinal cancer compared with the general population, including small bowel, colon, biliary tract, and pancreatic cancers. These findings highlight the need to develop individualised screening strategies for site-specific gastrointestinal cancers in patients with cystic fibrosis. FUNDING: None. PMID- 29706375 TI - Balixafortide plus eribulin in HER2-negative metastatic breast cancer: a phase 1, single-arm, dose-escalation trial. AB - BACKGROUND: The C-X-C chemokine receptor type 4 (CXCR4)-stromal cell-derived factor-1alpha (SDF-1alpha) axis regulates function and trafficking of immune cells and the tumour microenvironment. CXCR4 antagonists have been shown to enhance the activity of different anticancer treatments in preclinical models. We assessed the safety, tolerability, pharmacokinetics, and preliminary phase 1 activity of the CXCR4 antagonist, balixafortide, in combination with eribulin chemotherapy in patients with heavily pretreated, relapsed metastatic breast cancer. METHODS: This single-arm, dose-escalation, phase 1 trial enrolled patients at 11 sites in Spain and the USA. Eligible patients were women aged 18 years or older who had histologically confirmed HER2-negative metastatic breast cancer, evidence of tumour cell CXCR4 expression, an Eastern Cooperative Oncology Group performance status of 0 or 1, and who had previously received between one and three chemotherapy regimens for metastatic breast cancer, and at least one endocrine therapy if they had hormone receptor-positive disease, unless they were considered unsuitable for endocrine therapy. A standard 3+3 dose-escalation design was used, followed by an expanded cohort at the established maximum tolerated dose or highest dose if no dose-limiting toxicity was observed for the combination. After a treatment-related fatal adverse event in the first cohort who received 21-day cycles of treatment with eribulin and balixafortide, a protocol amendment modified the study design to be done in two parts. Patients enrolled to part 1 received an initial 28-day run-in cycle, with some cohorts receiving de-escalated doses of eribulin plus balixafortide to assess the safety and pharmacokinetics of the combination. The evaluation of part 1 did not confirm any dose-limiting toxicities or eribulin-balixafortide interactions, and therefore part 2 started enrolling patients to receive eribulin at the originally planned dose of 1.4 mg/m2 on days 2 and 9 of a 21-day cycle and balixafortide from a starting dose of 2 mg/kg with dose increments of 0.5 or 1 mg/kg on days 1 3 and 8-10 of the 21-day cycle. Both drugs were administered as intravenous infusions. All patients were to receive treatment until disease progression or unacceptable toxicity. The primary endpoints were dose-limiting toxicities and adverse events, and the establishment of a maximum tolerated dose or recommended phase 2 dose, and pharmacokinetic parameters. Safety analysis was done in all patients who received at least one dose of study treatment. Analysis of antitumour activity was done in all patients who received at least one full cycle of study treatment. The trial is registered at ClinicalTrials.gov, number NCT01837095, and is closed to accrual. FINDINGS: Between Jan 28, 2014, and Oct 4, 2016, 56 patients were enrolled into the trial. No dose-limiting toxicities were confirmed and the maximum tolerated dose was not reached. The highest dose was established as eribulin 1.4 mg/m2 on days 2 and 9, and balixafortide 5.5 mg/kg on days 1-3 and 8-10 of the 21-day cycle. Objective responses (all partial responses) were observed in 16 (30%; 95% CI 18-44) of 54 patients who were evaluable for antitumour activity. The most common treatment-emergent adverse events of any grade were fatigue (44 [79%] of 56 patients), neutropenia (32 [57%]), infusion-related reactions (27 [48%]), alopecia (26 [46%]), constipation (26 [46%]), and nausea (25 [45%]). Serious adverse events occurred in 21 (38%) of 56 patients, including febrile neutropenia in five (9%) of 56 patients, neutrophil count decrease in two (4%) patients, constipation in two (4%) patients, pneumonia in two (4%) patients, and urinary tract infection in three (5%) patients. Two (4%) of 56 patients died while receiving study treatment; one from septic shock and one from pneumonia. INTERPRETATION: The safety and tolerability of balixafortide plus eribulin seems to be similar to that of eribulin or balixafortide monotherapy, and the preliminary activity of the combination seems promising in patients with HER-negative metastatic breast cancer. The results suggest that balixafortide plus eribulin has potential to provide a new therapeutic option in heavily pretreated patients with metastatic breast cancer and warrants further investigation in randomised trials. FUNDING: Polyphor. PMID- 29706376 TI - New treatment option for Waldenstrom macroglobulinaemia. PMID- 29706377 TI - Late infection-related mortality in asplenic cancer survivors. PMID- 29706378 TI - UK to align with EU clinical trial rules post-Brexit. PMID- 29706379 TI - American Association for Cancer Research Annual Meeting 2018. PMID- 29706380 TI - Outcomes after autoBMT in cancer survivors. PMID- 29706381 TI - Cystic fibrosis: a gastrointestinal cancer syndrome. PMID- 29706382 TI - Consensus statement on an updated core communication curriculum for UK undergraduate medical education. AB - OBJECTIVES: Clinical communication is a core component of undergraduate medical training. A consensus statement on the essential elements of the communication curriculum was co-produced in 2008 by the communication leads of UK medical schools. This paper discusses the relational, contextual and technological changes which have affected clinical communication since then and presents an updated curriculum for communication in undergraduate medicine. METHOD: The consensus was developed through an iterative consultation process with the communication leads who represent their medical schools on the UK Council of Clinical Communication in Undergraduate Medical Education. RESULTS: The updated curriculum defines the underpinning values, core components and skills required within the context of contemporary medical care. It incorporates the evolving relational issues associated with the more prominent role of the patient in the consultation, reflected through legal precedent and changing societal expectations. The impact on clinical communication of the increased focus on patient safety, the professional duty of candour and digital medicine are discussed. CONCLUSION: Changes in the way medicine is practised should lead rapidly to adjustments to the content of curricula. PRACTICE IMPLICATIONS: The updated curriculum provides a model of best practice to help medical schools develop their teaching and argue for resources. PMID- 29706383 TI - Predicting net joint moments during a weightlifting exercise with a neural network model. AB - The purpose of this study was to develop and train a Neural Network (NN) that uses barbell mass and motions to predict hip, knee, and ankle Net Joint Moments (NJM) during a weightlifting exercise. Seven weightlifters performed two cleans at 85% of their competition maximum while ground reaction forces and 3-D motion data were recorded. An inverse dynamics procedure was used to calculate hip, knee, and ankle NJM. Vertical and horizontal barbell motion data were extracted and, along with barbell mass, used as inputs to a NN. The NN was then trained to model the association between the mass and kinematics of the barbell and the calculated NJM for six weightlifters, the data from the remaining weightlifter was then used to test the performance of the NN - this was repeated 7 times with a k-fold cross-validation procedure to assess the NN accuracy. Joint-specific predictions of NJM produced coefficients of determination (r2) that ranged from 0.79 to 0.95, and the percent difference between NN-predicted and inverse dynamics calculated peak NJM ranged between 5% and 16%. The NN was thus able to predict the spatiotemporal patterns and discrete peaks of the three NJM with reasonable accuracy, which suggests that it is feasible to predict lower extremity NJM from the mass and kinematics of the barbell. Future work is needed to determine whether combining a NN model with low cost technology (e.g., digital video and free digitising software) can also be used to predict NJM of weightlifters during field-testing situations, such as practice and competition, with comparable accuracy. PMID- 29706384 TI - The journey continues after the war-zone minefield. PMID- 29706385 TI - Economic disparities in sepsis-New insights with new implications. PMID- 29706386 TI - Paradoxically simple: A new nutritional index for predicting coronary risk. PMID- 29706387 TI - Gender and cardiovascular disease in the workplace - it's not just about pay gaps. PMID- 29706388 TI - Understanding the patient perspective on research access to national health records databases for conduct of randomized registry trials. AB - BACKGROUND: Use of health administrative databases is proposed for screening and monitoring of participants in randomized registry trials. However, access to these databases raises privacy concerns. We assessed patient's preferences regarding use of personal information to link their research records with national health databases, as part of a hypothetical randomized registry trial. METHODS AND RESULTS: Cardiology patients were invited to complete an anonymous self-reported survey that ascertained preferences related to the concept of accessing government health databases for research, the type of personal identifiers to be shared and the type of follow-up preferred as participants in a hypothetical trial. A total of 590 responders completed the survey (90% response rate), the majority of which were Caucasians (90.4%), male (70.0%) with a median age of 65years (interquartile range, 8). The majority responders (80.3%) would grant researchers access to health administrative databases for screening and follow-up. To this end, responders endorsed the recording of their personal identifiers by researchers for future record linkage, including their name (90%), and health insurance number (83.9%), but fewer responders agreed with the recording of their social security number (61.4%, p<0.05 with date of birth as reference). Prior participation in a trial predicted agreement for granting researchers access to the administrative databases (OR: 1.69, 95% confidence interval: 1.03-2.90; p=0.04). CONCLUSION: The majority of Cardiology patients surveyed were supportive of use of their personal identifiers to access administrative health databases and conduct long-term monitoring in the context of a randomized registry trial. PMID- 29706389 TI - What is not to like about large national or international registries and databases? PMID- 29706390 TI - Does Googling lead to statin intolerance? AB - BACKGROUND: The nocebo effect, where patients with expectations of adverse effects are more likely to experience them, may contribute to the high rate of statin intolerance found in observational studies. Information that patients read on the internet may be a precipitant of this effect. The objective of the study was to establish whether the number of websites about statin side effects found using Google is associated with the prevalence of statin intolerance. METHODS: The prevalence of statin intolerance in 13 countries across 5 continents was established in a recent study via a web-based survey of primary care physicians and specialists. Using the Google search engine for each country, the number of websites about statin side effects was determined, and standardized to the number of websites about statins overall. Searches were restricted to pages in the native language, and were conducted after connecting to each country using a virtual private network (VPN). RESULTS: English-speaking countries (Australia, Canada, UK, USA) had the highest prevalence of statin intolerance and also had the largest standardized number of websites about statin side effects. The sample Pearson correlation coefficient between these two variables was 0.868. CONCLUSIONS: Countries where patients using Google are more likely to find websites about statin side effects have greater levels of statin intolerance. The nocebo effect driven by online information may be contributing to statin intolerance. PMID- 29706391 TI - Statins - Good drugs, not so good reputation. PMID- 29706392 TI - Patient delay in women with STEMI: Time to raise awareness. PMID- 29706394 TI - 'Some doors are better left closed': Using LAA occluders as an alternative to warfarin in very high-risk dialysed patients with atrial fibrillation. PMID- 29706393 TI - Implant success and safety of left atrial appendage occlusion in end stage renal disease patients: Peri-procedural outcomes from an Italian dialysis population. AB - AIMS: To estimate the safety and the efficacy of the off label left atrial appendage (LAA) occlusion in chronic dialysis patients with atrial fibrillation (AF). In this preliminary paper, we report the design of the study and the data on peri-procedural complications. METHODS: This is a prospective cohort study. Primary endpoints are i) incidence of peri-procedural complications, ii) cumulative incidence of two-year thromboembolic events iii) cumulative incidence of two-year bleedings iiii) mortality at two years. Adverse events and death within 30 days of the procedure were recorded. RESULTS: Fifty patients who underwent LAA occlusion between May 2014 and September 2017 were recruited. Both the mean age of the sample study and the dialysis duration were high [71.8 (9.6) years and 59.4 (78.2) months, respectively]. Most patients (84%) were hypertensive and 62% suffered a previous major bleeding. About half of them presented cardiovascular diseases. CHA2DS2VASCs and HASBLED scores were 4.0 (1.5) and 4.4 (0.9), respectively. Most patients (88%) showed atrial dilatation and 44% left ventricular hypertrophy; 32% had left ventricular ejection fraction <50%. Fifty five percent of patients had permanent AF and 32% paroxysmal AF. All devices were implanted successfully. No deaths or major adverse events were reported during a 30-day follow-up. Three episodes of peri-procedural access site bleeding were reported, requiring no transfusion. CONCLUSIONS: Our preliminary data suggest the feasibility and safety of LAA occlusion in patients undergoing dialysis. Only the follow-up of these patients over time can provide evidence that LAA occlusion is effective in preventing of thromboembolic events in this very high-risk population. PMID- 29706395 TI - Water is a good electrical conductor! PMID- 29706396 TI - A novel and simply calculated nutritional index serves as a useful prognostic indicator in patients with coronary artery disease. AB - OBJECTIVE: No nutritional index has been firmly established yet in patients with coronary artery disease (CAD). In this study, we propose a simple to calculate nutritional indicator in patients who underwent percutaneous coronary intervention (PCI) by using parameters routinely measured in CAD and evaluated its prognostic implication. METHODS: This study is a retrospective observational analysis of a prospective database. The subjects were consecutive 3567 patients underwent their first PCI between 2000 and 2013 at Juntendo University Hospital in Tokyo. The median of the follow-up period was 6.3 years (range: 0-13.6 years). The novel nutritional index was calculated by the formula; Triglycerides (TG) * Total Cholesterol (TC) * Body Weight (BW) Index (TCBI) = TG * TC * BW / 1000 (TG and TC: mg/dl, and BW: kg). RESULTS: The Spearman non-parametric correlation coefficient between TCBI and the most often used conventional nutritional index, Geriatric Nutritional Risk Index (GNRI), was 0.355, indicating modest correlation. Moreover, Unadjusted Kaplan-Meier analysis showed higher all-cause mortality, cardiovascular mortality, and cancer mortality in patients with low TCBI. Consistently, elevation of TCBI was associated with reduced all-cause (hazard ratio: 0.86, 95%CI: 0.77-0.96, p < 0.001), cardiovascular (0.78, 0.66 0.92, p = 0.003), and cancer mortality (0.76, 0.58-0.99, p = 0.041) in patients after PCI by multivariate Cox proportional hazard analyses. CONCLUSION: TCBI, a novel and easy to calculate nutrition index, is a useful prognostic indicator in patients with CAD. PMID- 29706397 TI - Cardiovascular risk goes up as your mood goes down: Interaction of depression and socioeconomic status in determination of cardiovascular risk in the CONSTANCES cohort. AB - BACKGROUND: Recent evidence suggests that the association of psychological variables with the risk of coronary heart disease (CHD) might depend upon socioeconomic status (SES). However, it is unclear whether the association between depressive symptoms and CHD risk might differ according to three SES indicators (education, occupational status and household monthly income). METHODS: Among 34,836 working participants of the French CONSTANCES cohort (16,221 men, mean age [SD]: 44.0 [10.4] years) without history of cardiovascular disease, depressive symptoms were assessed with the Center of Epidemiologic Studies Depression scale (CES-D). The Framingham risk equation calibrated to the French population estimated the participant's 10-year risk of CHD. Associations between depressive symptoms and CHD risk were estimated using linear regression models in SES strata. RESULTS: The estimated 10-year risk of CHD was 16.9% in men and 1.8% in women. In men, the increased CHD risk in those with (versus without) depressive symptoms was more pronounced as occupational status decreased, being 0.65% (-0.57; 1.88), 1.58% (0.50; 2.66) and 3.19% (1.30; 5.07) higher in individuals of high, medium and low occupational status, respectively (p for interaction: 0.01). In contrast, effect modification by education or household income was less evident, despite similar trends. In women, no effect modification was found whatever the SES indicator. CONCLUSIONS: Depressive symptoms and 10 year estimated CHD risk were more tightly linked in individuals of lower SES, at least in men. Occupational status was the SES indicator that displays the most obvious effect modification on this association. PMID- 29706398 TI - Whole Brain Radiotherapy in Metastatic Non-small Cell Lung Cancer - the Debate should Continue. PMID- 29706399 TI - High performance liquid chromatography column efficiency enhancement by zero dead volume recycling and practical approach using park and recycle arrangement. AB - A new instrumental approach to recycling HPLC is described. The concept is based on fast reintroduction of incremental peak sections back onto the separation column. The re-circulation is performed within a closed loop containing only the column and two synchronized switching valves. By having HPLC pump out of the cycle, the method minimizes peak broadening due to dead volume. As a result the efficiency is dramatically increased allowing for the most demanding analytical applications. In addition, a parking loop is employed for temporary storage of analytes from the middle section of the separated mixture prior to their recycling. PMID- 29706400 TI - A study of column equilibration time in hydrophilic interaction chromatography. AB - The time taken to achieve full column equilibration for isocratic analysis of acidic, basic, and neutral solutes in hydrophilic interaction liquid chromatography (HILIC) was compared using the mobile phase disturbance method, column efficiency measurements and retention time stability. Full equilibration, which could take up to an hour, was best measured by the last procedure and was found to depend on the nature of the stationary phase, the pre-equilibrium (e.g. storage) solvent and the flow rate. While longer equilibration times are a relatively minor inconvenience in isocratic analysis, they are surprisingly not a barrier to the use of gradient elution in HILIC. A repeatable partial equilibration giving retention time stability equivalent to that in isocratic analysis was demonstrated for an equilibration time of only ~5 min, using as few as 2 preliminary conditioning runs on a column that had taken the longest time to achieve full equilibration. Due to selectivity changes that occur dependent on the equilibration time, it is necessary to use identical gradient conditions in a series of analyses, which however appears to be facile on a modern HPLC instrument. PMID- 29706401 TI - Quasi-targeted analysis of halogenated organic pollutants in fly ash, soil, ambient air and flue gas using gas chromatography-high resolution mass spectrometry with isotopologue distribution comparison and predicted retention time alignment. AB - Identifying environmental pollutants, particularly emerging and new pollutants, in various matrices is a prerequisite for further research involving these pollutants. In this study, we developed a quasi-targeted analysis method to identify halogenated organic pollutants (HOPs) by joint application of gas chromatography-double focus magnetic-sector high resolution mass spectrometry (GC DFS-HRMS), isotopologue distribution comparison and predicted retention time (PRT) alignment. Structures of a variety of unreported/scarcely reported HOPs were conceived and sketched, and then, multiple isotopologue ions of individual HOPs were detected by GC-DFS-HRMS in multiple ion detection mode. Comparisons between the detected mass spectra and the theoretically simulated isotopologue distributions were conducted via paired-samples T-test and cosine similarity analysis. PRT alignment was further applied to exclude interferences that presented unreasonable retention times. The method was validated with dozens of commercially available reference standards of conventional HOPs and several unintended byproducts comprising mix-chlorinated/brominated benzenes in some commercial halogenated-benzene standards, showing good reliability and accuracy. Application of the developed method was primarily implemented with fly ash from municipal solid waste incineration plants. In total, 106 molecular formulas corresponding to unknown or little-known HOPs were identified, of which many were mix-halogenated compounds. Six HOPs were structurally elucidated, including three sulfur-containing dioxin-like HOPs, two mix-perhalogenated benzenes, and a pentabrominated anisole. The structures of 18 compounds that individually contained 2-4 theoretical isomers were putatively elucidated according to the PRT alignment. In addition to fly ash, other environmental matrices, including soil, ambient air and flue gas, were screened by the method, and a number of HOPs were also found in these matrices. This method is feasible, reliable, accurate and sensitive for the identification and screening of potential unknown HOPs in the environment and should facilitate further research, such as pollution investigations and eco-environmental risk assessments for these pollutants. PMID- 29706402 TI - Fast and sensitive determination of per- and polyfluoroalkyl substances in seawater. AB - In this work, a novel, fast, and sensitive method was developed for perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS) and PFOS precursor's determination in seawater. The proposed method consists in a vortex assisted liquid-liquid microextraction (VALLME) combined with liquid chromatography (LC) and LTQ-Orbitrap high resolution mass spectrometry (LTQ Orbitrap HRMS) determination. Several parameters affecting both the HPLC-LTQ Orbitrap HRMS determination and the VALLME were studied, with special attention to blank contamination problem. The use of LTQ-Orbitrap-HRMS in full mode, quantifying the target analytes using the exact mass, provides a very powerful detection in terms of sensitivity and specificity maintaining all the information provided by the full mass spectra, allowing, also, the identification of non target substances. The use of matrix-matched calibration, together with labelled surrogate standards, minimize matrix effects and compensate potential recovery losses, resulting in recoveries between 95 and 105%, with excellent sensitivity (quantitation limit between 0.7 and 6 ng L-1) and precision (4-10%). The proposed method requires only 35 mL of sample and 100 MUL of extracting solvent, is fast and avoids the use of other solvents to obtain the dispersive cloudy solution, simplifying the procedure and improving the existing procedures for the determination of per- and polyfluoroalkyl substances (PFASs) in seawater in terms of green analytical chemistry. The method was successfully validated by participating in a proficiency test assay provided by the National Measurement Institute of the Australian Government for the determination of PFOA, total PFOS and linear PFOS in waters. A revision of the state of the art in the last twelve years of methods for the analysis of PFASs in seawater and other types of water was performed, and a critical comparison between the developed method and the previously published was included. Finally, the method was applied to the analysis of samples from Ria de Vigo, a sensitive and semiconfined coastal area located in the northwest of Spain. PFOS, N-methyl perfluorooctanesulfonamide (n MeFOSA) and N-ethyl perfluorooctanesulfonamide (n-EtFOSA) were detected in samples at levels lower than the maximum allowable concentration (MAC) established by Directive 2013/39/EU, but above the annual average (AA) levels. PMID- 29706403 TI - Facile preparation of an alternating copolymer-based high molecular shape selective organic phase for reversed-phase liquid chromatography. AB - The synthesis of a new alternating copolymer-grafted silica phase is described for the separation of shape-constrained isomers of polycyclic aromatic hydrocarbons (PAHs) and tocopherols in reversed-phase high-performance liquid chromatography (RP-HPLC). Telomerization of the monomers (octadecyl acrylate and N-methylmaleimide) was carried out with a silane coupling agent; 3 mercaptopropyltrimethoxysilane (MPS), and the telomer (T) was grafted onto porous silica surface to prepare the alternating copolymer-grafted silica phase (Sil-alt T). The new hybrid material was characterized by elemental analyses, diffuse reflectance infrared Fourier transform (DRIFT) spectroscopy, and solid-state 13C and 29Si cross-polarization magic-angle spinning (CP/MAS) NMR spectroscopy. The results of 13C CP/MAS NMR demonstrated that the alkyl chains of the grafted polymers in Sil-alt-T remained disordered, amorphous, and mobile represented by gauche conformational form. Separation abilities and molecular-shape selectivities of the prepared organic phase were evaluated by the separation of PAHs isomers and Standard Reference Material 869b, Column Selectivity Test Mixture for Liquid Chromatography, respectively and compared with commercially available octadecylsilylated silica (ODS) and C30 columns as well as previously reported alternating copolymer-based column. The effectiveness of this phase is also demonstrated by the separation of tocopherol isomers. Oriented functional groups along the polymer main chains and cavity formations are investigated to be the driving force for better separation with multiple-interactions with the solutes. One of the advantages of the Sil-alt-T phase to that of the previously reported phase is the synthesis of the telomer first and then immobilized onto silica surface. In this case, the telomer was characterized easily with simple spectroscopic techniques and the molecular mass and polydispersity index of the telomer were determined by size exclusion chromatography (SEC) before grafting onto silica surface. Moreover, both of the monomers were commercially available. Therefore, the technique of preparation was very facile and better separation was achieved with the Sil-alt-T phase compared to the ODS, C30 and other previously reported alternating copolymer-based columns. PMID- 29706404 TI - Appropriate doses of non-vitamin K antagonist oral anticoagulants in high-risk subgroups with atrial fibrillation: Systematic review and meta-analysis. AB - BACKGROUND: We evaluated the dose-dependent efficacy, safety, and all-cause mortality of non-vitamin K antagonist oral anticoagulants (NOACs) in "atrial fibrillation (AF) patients who were OAC-naive," or "AF patients with prior-stroke history" with those who were known to be high-risk subgroups under OAC. METHODS: After a systematic database search (Medline, EMBASE, CENTRAL, SCOPUS, and Web of Science), five phase-III randomized trials comparing NOACs and warfarin in "OAC naive/OAC-experienced," or "with/without prior-stroke history" subgroups were included. The outcomes were pooled using a random-effects model to determine the relative risk (RR) for stroke/systemic thromboembolism (SSTE), major bleeding, intracranial hemorrhage, and all-cause mortality. RESULTS: 1. In OAC-naive patients, standard-dose NOACs showed superior efficacy and safety with lower mortality [RR 0.90 (0.84-0.97), p=0.008, I2=0%] compared to warfarin. 2. For OAC experienced patients, low-dose NOACs showed equivalent efficacy but reduced risk of major bleeding [RR 0.61 (0.40-0.91), p=0.02, I2=89%], and had lower all-cause mortality [RR 0.86 (0.75-0.99), p=0.04, I2=38%] compared to warfarin. 3. For patients with prior-stroke history, low-dose NOACs showed equivalent efficacy, but reduced risk of major bleeding [RR 0.58 (0.48-0.70), p<0.001, I2=0%] and all cause mortality [RR 0.76 (0.66-0.88), p<0.001, I2=0%] compared to warfarin. 4. Among patients without prior-stroke history, standard-dose NOAC was superior to warfarin for both SSTE prevention [RR 0.78 (0.66-0.91), p=0.002, I2=43%] and all cause mortality [RR 0.91 (0.85-0.97), p=0.004, I2=0%]. CONCLUSIONS: In conclusion, standard-dose NOAC showed lower all-cause mortality than warfarin in OAC-naive patients with AF, and low-dose NOAC was better than warfarin among the patients with prior-stroke history in terms of all-cause mortality. PMID- 29706405 TI - Detection of white matter lesion regions in MRI using SLIC0 and convolutional neural network. AB - BACKGROUND AND OBJECTIVE: White matter lesions are non-static brain lesions that have a prevalence rate up to 98% in the elderly population. Because they may be associated with several brain diseases, it is important that they are detected as soon as possible. Magnetic Resonance Imaging (MRI) provides three-dimensional data with the possibility to detect and emphasize contrast differences in soft tissues, providing rich information about the human soft tissue anatomy. However, the amount of data provided for these images is far too much for manual analysis/interpretation, representing a difficult and time-consuming task for specialists. This work presents a computational methodology capable of detecting regions of white matter lesions of the brain in MRI of FLAIR modality. The techniques highlighted in this methodology are SLIC0 clustering for candidate segmentation and convolutional neural networks for candidate classification. METHODS: The methodology proposed here consists of four steps: (1) images acquisition, (2) images preprocessing, (3) candidates segmentation and (4) candidates classification. RESULTS: The methodology was applied on 91 magnetic resonance images provided by DASA, and achieved an accuracy of 98.73%, specificity of 98.77% and sensitivity of 78.79% with 0.005 of false positives, without any false positives reduction technique, in detection of white matter lesion regions. CONCLUSIONS: It is demonstrated the feasibility of the analysis of brain MRI using SLIC0 and convolutional neural network techniques to achieve success in detection of white matter lesions regions. PMID- 29706406 TI - Parental overcontrol x OPRM1 genotype interaction predicts school-aged children's sympathetic nervous system activation in response to performance challenge. AB - Parental overcontrol (OC), the excessive regulation of a child's behavior, cognition, and emotion, is associated with the development of child anxiety. While studies have shown that genetic factors may increase sensitivity to stress, genetic vulnerability to parental OC has not been examined in anxiety etiology. A functional polymorphism in the mu opioid receptor OPRM1 (A118G, rs1799971) has been shown to impact stress reactivity. Using a community sample of children (N = 85, 9-12 years old), we examined the main and interactive effects of maternal OC and child OPRM1 genotype in predicting children's sympathetic nervous system reactivity during a performance stressor. Neither OC nor genotype predicted children's electrodermal activity (EDA); however, the interaction between OC and child genotype significantly predicted stress reactivity, as indexed by EDA, during the challenging task. Among children with the minor G-allele, higher maternal OC was associated with higher reactivity. In A homozygotes, maternal OC was not associated with EDA, suggesting a diathesis-stress pattern of gene x environment interaction. We discuss implications for anxiety etiology and intervention. PMID- 29706407 TI - Echocardiographic Analysis of Cardiac Function after Infarction in Mice: Validation of Single-Plane Long-Axis View Measurements and the Bi-Plane Simpson Method. AB - Although echocardiography is commonly used to analyze cardiac function in small animal models of cardiac remodeling after myocardial infarction, the different echocardiographic methods are validated poorly. End-diastolic volume, end systolic volume and ejection fraction were analyzed using either standard single plane analysis from parasternal long-axis B-mode views (PSLAX) or the bi-plane Simpson method (using PSLAX and three short-axis views) and validated using magnetic resonance imaging as standard. Ejection fraction measured by PSLAX was moderately correlated with a coefficient of R2 = 0.49. The standard deviation of residuals was 9.91. Simpson analysis revealed an improved correlation coefficient of R2 = 0.77 and a reduction in standard deviation of residuals by 45% (5.45 vs. 9.92, p = 0.014). Subgroup analysis revealed that the high variation in PSLAX is due to changes in ventricular geometry after myocardial infarction. Our results indicate that the bi-plane Simpson method is advantageous for the assessment of cardiac function after myocardial infarction. PMID- 29706408 TI - Analysis of Transient Shear Wave in Lossy Media. AB - The propagation of shear waves from impulsive forces is an important topic in elastography. Observations of shear wave propagation can be obtained with numerous clinical imaging systems. Parameter estimations of the shear wave speed in tissues, and more generally the viscoelastic parameters of tissues, are based on some underlying models of shear wave propagation. The models typically include specific choices of the spatial and temporal shape of the impulsive force and the elastic or viscoelastic properties of the medium. In this work, we extend the analytical treatment of 2-D shear wave propagation in a biomaterial. The approach applies integral theorems relevant to the solution of the generalized Helmholtz equation, and does not depend on a specific rheological model of the tissue's viscoelastic properties. Estimators of attenuation and shear wave speed are derived from the analytical solutions, and these are applied to an elastic phantom, a viscoelastic phantom and in vivo liver using a clinical ultrasound scanner. In these samples, estimated shear wave group velocities ranged from 1.7 m/s in the liver to 2.5 m/s in the viscoelastic phantom, and these are lower bounded by independent measurements of phase velocity. PMID- 29706409 TI - Dual-Targeted Microbubbles Specific to Integrin alphaVbeta3 and Vascular Endothelial Growth Factor Receptor 2 for Ultrasonography Evaluation of Tumor Angiogenesis. AB - Aggressive tumors are characterized by angiogenesis that promotes the migration and dissemination of tumor cells. Our aim was to develop a dual-targeted microbubble system for non-invasive evaluation of tumor angiogenesis in ultrasound. Avidinylated microbubbles were conjugated with biotinylated arginylglycylaspartic acid and vascular endothelial growth factor receptor 2 (VEGFR2) antibodies. Subcutaneous MHCC-97H liver carcinoma models were established. Non-targeted, alphavbeta3-targeted, VEGFR2-targeted and dual targeted microbubbles was intravenously injected in series while acquiring ultrasound images of the tumor. The microbubbles were destroyed by a high mechanical-index pulse 4 min after the injection. Peak intensity (PI) before and after the destructive pulse was recorded to compare contrast enhancement by different microbubbles. The targeting rates of the integrin-targeted, VEGFR2 targeted and dual-targeted groups were 95.02%, 96.04% and 94.23%, respectively, with no significant differences. Tumors in all groups were significantly enhanced. The time-intensity curve indicated no significant differences in arrival time, PI, area under the curve, amplitude and mean transit time. The difference in ultrasound signal intensity before and after the destructive pulse (?PI) for all targeted microbubble groups was significantly greater than that for the non-targeted microbubble group (all p values < 0.05), and the difference for the dual-targeted microbubble group was significantly greater than those of both mono-targeted groups (p <0.05). PMID- 29706410 TI - Muscle Shear Wave Elastography in Inclusion Body Myositis: Feasibility, Reliability and Relationships with Muscle Impairments. AB - Degenerative muscle changes may be associated with changes in muscle mechanical properties. Shear wave elastography (SWE) allows direct quantification of muscle shear modulus (MSM). The aim of this study was to evaluate the feasibility and reliability of SWE in the severely disordered muscle as observed in inclusion body myositis. To explore the clinical relevance of SWE, potential relationships between MSM values and level muscle impairments (weakness and ultrasound-derived muscle thickness and echo intensity) were investigated. SWE was performed in the biceps brachii at 100 degrees , 90 degrees , 70 degrees and 10 degrees elbow flexion in 34 patients with inclusion body myositis. MSM was assessed before and after five passive stretch-shortening cycles at 4 degrees /s from 70 degrees to 10 degrees elbow angle and after three maximal voluntary contractions to evaluate potential effects of muscle pre-conditioning. Intra-class correlation coefficients and standard errors of measurements were >0.83 and <1.74 kPa and >0.64 and <1.89 kPa for within- and between-day values, respectively. No significant effect of passive loading-unloading and maximal voluntary contractions was found (all p values >0.18). MSM correlated to predicted muscle strength (all Spearman correlation coefficients (rho) > 0.36; all p values < 0.05). A significant correlation was found between muscle echo intensity and muscle shear modulus at 70 degrees only (rho = 0.38, p <0.05). No correlation was found between muscle thickness and MSM (all rho values > 0.23 and all p values > 0.25, respectively). Within- and between-day reliability of muscle SWE was satisfactory and moderate, respectively. SWE shows promise for assessing changes in mechanical properties of the severely disordered muscle. Further investigations are required to clarify these findings and to refine their clinical value. PMID- 29706411 TI - Role of Coronary Flow Velocity in Predicting Adverse Outcome in Clinical Practice. AB - There is a lack of information on the prognostic value of local high velocity in coronary arteries during echocardiography. The aim of the study described here was to define the prognostic value of local velocity >70 cm/s in the left main, anterior or circumflex artery during echocardiography. There were 412 patients in the prospective study. Death, non-fatal myocardial infarction, acute pulmonary edema, acute coronary syndrome and revascularization were defined as major adverse cardiac events (MACEs). Over 10.5 mo, there were 207 patients with MACEs. Seventeen patients died, 10 had non-fatal acute cardiac events and 184 underwent revascularization. Deaths occurred in patients with high local velocity (6.4% vs. 0%, p <0.009). Acute cardiac events occurred in 10% versus 0% (p <0.003). MACEs were observed in 62% versus 0% (p <0.0000001). Only maximal velocity was an independent prognostic predictor of death (odds ratio = 1.02, 95% confidence interval: 1.01-1.03, p <0.02) and MACEs (odds ratio = 1.04, 95% confidence interval: 1.02-1.05, p <0.0001). The success rate of coronary artery visualization for at least one segment was 91%. PMID- 29706412 TI - Handover from operating theatre to the intensive care unit: A quality improvement study. AB - BACKGROUND: Transitioning a patient from the operating theatre (OT) to the intensive care unit (ICU) is a dynamic and complex process. Handover of the critically ill postoperative patient can contribute to procedural and communication errors. Standardised protocols are means for structuring and improving handover content. Both have been shown to be effective in reducing information omission and improve communication during this transition period. OBJECTIVES: The aim of this uncontrolled before and after study was to improve handover processes and communication about the care for critically ill patients transferred from OT to ICU. METHODS: Thirty-two OT to ICU handovers (16 before and 16 after implementation) were observed. Using a structured tool, we documented who was present, participated in, and initiated handover during ICU admission. Where and when handover was performed, information provided, distractions and interruptions, and handover duration were also recorded. Unstructured field notes and diagrams provided information on staff interaction. Following implementation, semistructured interviews with 27 participants were conducted to understand participants' perceptions of intervention acceptability and to determine factors influencing intervention implementation and spread. FINDINGS: Following implementation, a "hands-off" approach was observed with fewer technical tasks completed during handover (43.8% before implementation vs 12.5% after implementation) without an increase in handover time. A single, multidisciplinary handover most often led by the anaesthetist was observed after implementation. Despite these improvements, the use of the physical checklist was not observed in practice, and an situation, background, assessment, recommendation (SBAR) format was not followed. Anaesthetists leading the handover did not view the handover checklist as being beneficial to their practice although some nurses were observed to use the checklist as a prompt for additional information. CONCLUSIONS: A single, multidisciplinary handover demonstrated improvement in handover practice despite low uptake of the protocol checklist. Further information is required to inform targeted strategies to improve uptake and sustainability although broader interdisciplinary engagement and commitment may be helpful. PMID- 29706413 TI - Adaptive twisting sliding mode algorithm for hypersonic reentry vehicle attitude control based on finite-time observer. AB - This paper focuses on the adaptive twisting sliding mode control for the Hypersonic Reentry Vehicles (HRVs) attitude tracking issue. The HRV attitude tracking model is transformed into the error dynamics in matched structure, whereas an unmeasurable state is redefined by lumping the existing unmatched disturbance with the angular rate. Hence, an adaptive finite-time observer is used to estimate the unknown state. Then, an adaptive twisting algorithm is proposed for systems subject to disturbances with unknown bounds. The stability of the proposed observer-based adaptive twisting approach is guaranteed, and the case of noisy measurement is analyzed. Also, the developed control law avoids the aggressive chattering phenomenon of the existing adaptive twisting approaches because the adaptive gains decrease close to the disturbance once the trajectories reach the sliding surface. Finally, numerical simulations on the attitude control of the HRV are conducted to verify the effectiveness and benefit of the proposed approach. PMID- 29706414 TI - [Current insights about recurrence of glomerular diseases after renal transplantation]. AB - Recurrence of glomerular disease after renal transplantation is a frequent cause of graft loss. Incidence, risk factors and outcome of recurrence are widely due to the underlying glomerular disease. Graft biopsy analysis is required to confirm the definitive diagnosis of recurrence and to start an appropriate therapy that, in some cases, remains challenging to prevent graft failure. Increased use of protocol biopsy and recent advances in our understanding of the pathogenesis of some glomerular diseases with the identification of some relevant biomarkers provide a unique opportunity to initiate kidney-protective therapy at early stages of recurrence on the graft. This review summarizes our current knowledge on the management of many recurrent primary and secondary glomerulonephritis after kidney transplantation. PMID- 29706415 TI - The palatal septal cartilage implantation for snoring and obstructive sleep apnea. AB - OBJECTIVE: Patients with snoring and obstructive sleep apnea frequently have nasal and palatal obstruction. The objective of this study was to investigate the safety and feasibility of a palatal septal cartilage implant (SCI) for snoring and obstructive sleep apnea. METHODS: This was a preliminary study of 10 consecutive patients who were enrolled retrospectively from electronic charts. The patients had undergone a single-stage operation including septoturbinoplasty and palatal SCI at a tertiary referral hospital. After nasal surgery, the harvested cartilage was prepared and trimmed into strips for palatal implantation. Key procedures of palatal SCI include vertical tunneling of the midline and paramedian soft palate, insertion of the septal cartilage strips, and fixation suture of the implants. The primary outcome measures were adverse events, including implant extrusion, infection, bleeding, velopharyngeal insufficiency and globus symptoms, assessed by the Glasgow-Edinburgh Throat Scale (GETS) questionnaire (10-item, 8-grade [0-7] Likert scale). Secondary outcomes were subjective snoring loudness (visual analogue scale, VAS), excessive daytime sleepiness (Epworth sleepiness scale, ESS) and objective apnea-hypopnea index. All patients were followed up for at least 1 year. RESULTS: None of the aforementioned adverse events were noted during the one-year follow-up. Among the ten items of the GETS, the median score of nine items was 0, and the median score of the total GETS was 2.0, which was classified as "asymptomatic". The snoring loudness improved significantly from 8.0 points (IQR 8.0-9.0) preoperation to 4.0 points (IQR 2.5-6.0) at 3 months postoperation and 4.5 points (IQR 3.3-6.0) at 1 year postoperation (P=0.002 and P=0.002, respectively). The ESS score improved significantly from 11.5 points (IQR 8.3-18.5) preoperation to 8.0 points (IQR 6.3 10.8) at 3 months postoperation and 8.5 points (IQR 6.3-10.8) at 1 year postoperation (P=0.004 and P=0.004, respectively). The apnea-hypopnea index significantly decreased from 54.7 (IQR 23.4-62.8) to 20.5 (IQR 14.7-45.6) (P=0.047) in patients with a lower tongue position (modified Mallampati class<=II; n=7). CONCLUSION: Palatal SCI is a safe and feasible procedure. The advantages include providing implants of tailor-made length, biocompatible autologous cartilage and no need for extra-payment for the implant material. By using the SCI procedure, both nasal obstruction and sleep-disordered breathing can be managed in a single-stage operation. The long-term effectiveness of SCI deserves further research. PMID- 29706416 TI - Characteristics of tinnitus found in anemia patients and analysis of population based survey. AB - OBJECTIVE: This study analyzed the characteristics of tinnitus identified in anemia patients with cohort- and population-based studies in a single institute and suggests a management algorithm. METHODS: Fifty patients who were treated for anemia and referred for tinnitus treatment were included in a single institute retrospective study. Characteristics of tinnitus were investigated in a correlation analysis with demographic and audiologic parameters. For the population-based study, data from the Korea National Health and Nutrition Examination Survey collected between 2010 and 2011 were analyzed. The study population consisted of 11,402 individuals aged 20-97 years with complete tinnitus-related data. The prevalence of tinnitus in anemia patients was investigated using the questionnaire, and associations between tinnitus and blood/urine parameters were evaluated by binary logistic regression analysis. RESULTS: In a single-institute study, patients with non-pulsatile tinnitus were significantly older and their initial hemoglobin was higher than those with pulsatile tinnitus (p=0.001, 0.008, respectively). In pulsatile tinnitus, age and difference between initial and post-treatment hemoglobin were significantly associated with a subjective improvement in tinnitus (p=0.002, 0.016, respectively). There were no significant audiologic or hematologic parameters associated with the improvement of non-pulsatile tinnitus. In the population based study, there was no significant correlation between anemia and tinnitus (p=0.064). In a multivariate analysis, age was the only parameter associated with tinnitus in participants with anemia. CONCLUSION: The therapeutic strategy and prognosis of tinnitus in anemia patients differ according to the characteristics of tinnitus and the severity of anemia. PMID- 29706417 TI - Influence of x-ray direction on measuring shortening of the fractured clavicle. AB - BACKGROUND: Midshaft clavicle fractures are often associated with a certain degree of shortening. There is great variety in the imaging techniques and methods to quantify this shortening. This study aims to quantify the difference in measurements of shortening and length of fracture elements between 5 views of the fractured clavicle. Furthermore, the interobserver and intraobserver agreement between these views using a standardized method is evaluated. MATERIALS AND METHODS: Digitally reconstructed radiographs were created for 40 computed tomography datasets in the anteroposterior (AP), 15 degrees and 30 degrees craniocaudal, and 15 degrees and 30 degrees caudocranial views. A standardized method for measuring the length of fracture elements and the amount of shortening was used. Interobserver and intraobserver agreement for each of the 5 views was calculated. RESULTS: The interobserver and intraobserver agreement was excellent for all 5 views, with all intraclass correlation coefficient values greater than 0.75. The measured differences in relative and absolute shortening between views were statistically significant between the 30 degrees caudocranial view and all other views. The increase in median shortening measured between the commonly used 30 degrees caudocranial view (2.7 mm) and the AP view (8.5 mm) was 5.8 mm (P < .001). The relative median shortening between these views increased by 3.5% (P < .001). CONCLUSION: The length of fracture elements and the amount of shortening in the fractured clavicle can be reliably measured using a standardized method. The increase in absolute and relative shortening when comparing the caudocranial measurements with the AP and craniocaudal measurements may indicate that the AP and craniocaudal views provide a more accurate representation of the degree of shortening. PMID- 29706418 TI - Seminal plasma differentially alters the resistance of dog, ram and boar spermatozoa to hypotonic stress. AB - During ejaculation and the deposition in the female genital tract, spermatozoa undergo hypo-osmotic stress and need to withstand it for optimal fertility. Resistance to hypo-osmotic stress may be affected by the interaction of the spermatozoa with seminal fluid components. The hypo-osmotic resistance of epididymal and ejaculated spermatozoa from dogs, rams and boars was assessed by flow cytometric measurement of sperm viability after incubation in NaCl solutions with osmolalities ranging from 0 to 300 mmol/kg. The hypotonic resistance of epididymal spermatozoa was greater than those of ejaculated spermatozoa in all three species. Among species comparison revealed that ejaculated spermatozoa from dogs were much more resistant than those from rams and boars as 80.4 +/- 5.3%, 56.7 +/- 4.7 and 9.6 +/- 3.6% of live spermatozoa were observed following exposure to an osmolality of 90 mmol/kg in dogs, rams and boars respectively. This can be explained by the fact that dog, ram and boar differ markedly in composition of the seminal plasma owing to the presence (ram, boar) or absence (dog) of seminal vesicles. Hypotonic resistance of epididymal and ejaculated dog spermatozoa was similar whereas ram and boar spermatozoa showed a marked drop in resistance after ejaculation. The in vitro incubation of boar epididymal spermatozoa with raw seminal plasma or the seminal plasma protein fraction induced a similar loss of resistance, suggesting that seminal proteins are involved in the lack of resistance to hypotonic stress of boar ejaculated spermatozoa. PMID- 29706419 TI - Cardiac abnormalities in Parkinson's disease and Parkinsonism. AB - OBJECTIVES: Though there is increasing evidence for primary cardiac disease in Parkinson's disease (PD) and Parkinsonism (PS), this evidence is hardly included in the general management of these patients. METHODS: Literature review. RESULTS: PD is one of the most common age-related neurodegenerative disorders. Epidemiological studies have shown that PD is accompanied by high rates of premature death compared with the general population. In general, death in PD/PS is usually caused by determinant factors such as pneumonia, cerebrovascular, and cardiovascular disease. There is a significant body of literature demonstrating involvement of the heart in PD/PS. Cardiac involvement in PD/PS includes cardiac autonomic dysfunction, cardiomyopathy, coronary heart disease, arrhythmias, conduction defects, and sudden cardiac death (SCD), and sudden unexpected death in Parkinson's disease (SUDPAR). CONCLUSIONS: Cardiac abnormalities found in PD/PS are manifold but the most prominent is cardiac autonomic dysfunction. The frequency of coronary heart disease in PD is a matter of debate. Only rarely reported in PD/PS are cardiomyopathies, arrhythmias, and sudden cardiac death, and SUDPAR. It is particularly recommended that PD/PS patients are more intensively investigated cardiologically as soon as the diagnosis is established. Early recognition of cardiac involvement is important for preventing SCD and SUDPAR. PMID- 29706420 TI - Spontaneous resolution of a non-traumatic vertebro-vertebral arteriovenous fistula in a paediatric patient. AB - We report the case of a 10 year old male who presented with right sided tinnitus and a pulsatile neck mass. MRI of the neck demonstrated a vertebro-vertebral arteriovenous fistula (VAVF), with supply from the right vertebral artery and drainage into a paraspinal venous plexus at C1/2. Endovascular treatment would have necessitated vertebral artery sacrifice with significant risk of complication, therefore a conservative approach was adopted; the patient was lost to follow up but presented 5 years later with complete resolution. We therefore advocate a role for conservative management when treatment would pose undue risk. PMID- 29706422 TI - Design, synthesis and evaluation of substituted piperidine based KCNQ openers as novel antiepileptic agents. AB - Epilepsy is a kind of disease with complicated pathogenesis. KCNQ (Kv7) is a voltage dependent potassium channel that is mostly associated with epilepsy and thus becomes an important target in the treatment of epilepsy. In this paper, a series of substituted piperidine derivatives targeting KCNQ were designed and synthesized by using scaffold hopping and active substructure hybridization. Compounds were evaluated by fluorescence-based thallium influx assay, Rb+ flow assay and electrophysiological patch-clamp assay. Results showed that some compounds possessed more potent potassium channel opening activity than Retigabine. More significantly, compound 11 was found to have good pharmacokinetic profiles in vivo. PMID- 29706421 TI - Factors associated with uninvestigated dyspepsia in students at 4 Latin American schools of medicine: A multicenter study. AB - INTRODUCTION AND AIMS: Dyspepsia is a multifactorial disease that can involve alcohol, tobacco, or nonsteroidal anti-inflammatory drug use, as well as lifestyle, diet, socioeconomic elements, or psychologic factors. The aim of the present article was to establish the frequency of uninvestigated dyspepsia and determine its associated factors in students at 4 Latin American schools of medicine. MATERIALS AND METHODS: A cross-sectional, analytic study was conducted, in which a survey made up of closed-ended questions was applied at just one point in time. The association between the variables was then analyzed. A new questionnaire for the diagnosis of dyspepsia was one of the tests utilized to diagnose uninvestigated dyspepsia. Generalized linear models were used for the bivariate and multivariate analyses, employing the Poisson model with the log link function, obtaining crude prevalence ratios, adjusted prevalence ratios, and their 95% confidence intervals. RESULTS: Of the 1,241 individuals surveyed, 54% (841) were females and the median age was 21 years (range: 19-23 years). Prevalence of uninvestigated dyspepsia was 46%. The factors that had a direct association with dyspepsia were: depression, difficulty sleeping, and coffee consumption. On the contrary, eating regularly in a boarding house and the male sex had an inverse association. CONCLUSIONS: Uninvestigated dyspepsia frequency was high in students at 4 Latin American schools. Depression, difficulty sleeping, and steady coffee drinking were factors directly associated with dyspepsia, whereas male sex and eating out at regular hours were factors with a reverse association. Therefore, we recommend that universities implement early detection programs for this highly preventable pathology. PMID- 29706424 TI - Patient- and tumor-related predictors of chemotherapy intolerance in older patients with cancer: A systematic review. AB - OBJECTIVE: The aim of this systematic review was to investigate patient-related factors (e.g. depressive symptoms, cognition, mobility, activities of daily living (ADL)) as well as tumor-related factors (e.g. tumor type, chemotherapy regimen) influencing chemotherapy intolerance in cancer patients aged 65 years or older. METHODS: We included observational studies that reported data on possible predictors of chemotherapy intolerance in older patients with cancer. We studied chemotherapy intolerance using the following outcomes: chemotherapy toxicity grade 3 to 5, unplanned hospitalization, chemotherapy discontinuation, chemotherapy dose reduction, functional decline, and chemotherapy mortality. We searched PubMed, Embase, and PsycInfo for articles between January 1995 and July 2016. The quality of the included studies was assessed using the Quality in Prognosis Studies (QUIPS) tool. RESULTS: The search yielded 1774 articles, and 30 articles from 27 studies were included. The patient-related factors associated with chemotherapy intolerance, in terms of the size of the association and the consistency of the results, were more than one fall in the last six months, mobility problems, poor performance status and the presence of severe comorbid conditions. The tumor-related factors that were associated with chemotherapy intolerance in older patients with cancer were certain regimens of chemotherapy and polychemotherapy, as compared to monochemotherapy. The number of studies on unplanned hospitalization and functional decline was small. CONCLUSION: The included studies were heterogeneous with respect to endpoints and included parameters. Nevertheless, the size of the association and the consistency of results suggest that all these factors are relevant for everyday oncological practice. PMID- 29706423 TI - Structure-based design of Trifarotene (CD5789), a potent and selective RARgamma agonist for the treatment of acne. AB - Retinoids have a dominant role in topical acne therapy and to date, only RARbeta and RARgamma dual agonists have reached the market. Given the tissue distribution of RAR isoforms, it was hypothesized that developing RARgamma -selective agonists could yield a new generation of topical acne treatments that would increase safety margins while maintaining the robust efficacy of previous drugs. Structural knowledge derived from the X-ray structure of known gamma-selective CD437, suggested the design of a novel triaryl series of agonists which was optimized and ultimately led to the discovery of Trifarotene/CD5789. PMID- 29706425 TI - Outcome of neoadjuvant chemotherapy in "locally advanced/borderline resectable" gallbladder cancer: the need to define indications. AB - BACKGROUND: Studies evaluating neo-adjuvant chemotherapy (NACT) exclusively in gallbladder cancer (GBC) are few and there are no randomized trials on the subject. Locally advanced GBC and indications for NACT in GBC are not yet clearly defined. METHODS: We analysed 160 consecutive GBC patients who received NACT based on clinico-radiologic criteria suggesting high-risk disease (TMH Criteria) from January 2010 to February 2016. RESULTS: On initial assessment, 140 (87.5%) patients had T3/T4 disease and 105 (65%) patients were node positive. Response rate and clinical benefit rate was 52.5% and 70% respectively. Sixty six (41.2%) patients could undergo curative intent resection. With a median follow-up of 33 months, the median OS and EFS of the entire cohort were 13 and 8 months respectively. Patient undergoing curative surgery had a statistically superior OS (49 vs. 7 months; p = 0.0001) and EFS (25 months vs. 5 months; p = 0.0001) compared to those who did not. CONCLUSION: Locally advanced GBC remains a disease with poor prognosis. Chemotherapy with neoadjuvant intent in locally advanced/borderline resectable GBC showed good response rates. This resulted in curative surgical resection or disease stabilisation in significant proportion of patients. Patients who undergo definitive surgery after favourable response to NACT experience good survival. PMID- 29706426 TI - Cholecystectomy and risk of metabolic syndrome. PMID- 29706427 TI - Effect of acute stressors, adrenocorticotropic hormone administration, and cortisol release on milk yield, the expression of key genes, proliferation, and apoptosis in goat mammary epithelial cells. AB - Cortisol is essential to milk synthesis; however, different acute stressors and the exogenous administration of adrenocorticotropic hormone (ACTH) decrease milk yield. Therefore, the effect of cortisol on milk yield and its influence on the survival of mammary epithelial cells have not been fully elucidated. In this context, the objective of this study was to evaluate the effect of cortisol on the expression of growth hormone receptor (GHR), insulin-like growth factor type 1 (IGF1), insulin-like growth factor type 1 receptor (IGF1R), insulin-like growth factor-binding protein 3 and 5 (IGFBP3 and IGFBP5), BAX, and BCL2 genes on the proliferation and apoptotic rates of mammary epithelial cells, and on milk yield in Saanen goats. In the present study, 3 experiments were conducted: (1) comparing the in vivo effects of first milking, vaccination, vermifugation, preventive hoof trimming, and the administration of ACTH or a placebo on cortisol release in dairy goats; (2) studying the in vivo effects of immediate increases in cortisol on the mammary gland of lactating goats; and (3) studying the in vitro effects of a prolonged increase in cortisol on mammary epithelial cells obtained from lactating goats. Cortisol release by goats increased significantly after ACTH administration compared with that observed after a placebo, and the cortisol profiles after first milking, vaccination, vermifugation, hoof trimming, and ACTH administration were similar. However, there was no effect of the immediate increase in cortisol in vivo on IGF-1 release, milk yield, milk quality, or the apoptosis and proliferation rates, nor was there any effect on the expression of the target genes. Furthermore, no interaction was observed between IGF-1 and cortisol in either the in vivo or in vitro experiments. However, the addition of cortisol in vitro significantly increased the expression of the GHR and IGF1R genes, which stimulate cell proliferation, and the BAX gene, which causes apoptosis. These contrasting results can explain why cortisol did not change the rates of proliferation or apoptosis in epithelial cells. Indeed, cortisol supplementation in vitro did not change the number or apoptotic rate of epithelial cells over the course of 5 d. Finally, further studies must be performed to understand the effect of cortisol on the expression of the GHR, IGF1R, and BAX genes by epithelial cells and the roles of these genes in milk synthesis during early lactation. PMID- 29706428 TI - Functional CT assessment of extravascular contrast distribution volume and myocardial perfusion in acute myocardial infarction. AB - PURPOSE: In a pig model of acute myocardial infarction (AMI), we validated a functional computed tomography (CT) technique for concomitant assessment of myocardial edema and ischemia through extravscualar contrast distribution volume (ECDV) and myocardial perfusion (MP) measurements from a single dynamic imaging session using a single contrast bolus injection. METHODS: In seven pigs, balloon catheter was used to occlude the distal left anterior descending artery for one hour followed by reperfusion. CT and cardiac magnetic resonance (CMR) imaging studies were acquired on 3 days and 12 +/- 3 day post ischemic insult. In each CT study, 0.7 ml/kg of iodinated contrast was intravenously injected at 3-4 ml/s before dynamic contrast-enhanced (DCE) cardiac images were acquired with breath hold using a 64-row CT scanner. DCE cardiac images were analyzed with a model based deconvolution to generate ECDV and MP maps. ECDV as an imaging marker of edema was validated against CMR T2 weighted imaging in normal and infarcted myocardium delineated from ex-vivo histological staining. RESULTS: ECDV in infarcted myocardium was significantly higher (p < 0.05) than that in normal myocardium on both days post AMI and was in agreement with the findings of CMR T2 weighted imaging. MP was significantly lower (p < 0.05) in the infarcted region compared to normal on both days post AMI. CONCLUSION: This imaging technique can rapidly and simultaneously assess myocardial edema and ischemia through ECDV and MP measurements, and may be useful for delineation of salvageable tissue within at-risk myocardium to guide reperfusion therapy. PMID- 29706429 TI - Heart failure subtypes and thromboembolic risk in patients with atrial fibrillation: The PREFER in AF - HF substudy. AB - BACKGROUND AND OBJECTIVES: To assess thromboembolic and bleeding risks in patients with heart failure (HF) and atrial fibrillation (AF) according to HF type. METHODS: We analyzed 6170 AF patients from the Prevention of thromboembolic events - European Registry in Atrial Fibrillation (PREFER in AF), and categorized patients into: HF with reduced left-ventricular ejection fraction (HFrEF; LVEF < 40%); mid-range EF (HFmrEF; LVEF: 40-49%); lower preserved EF (HFLpEF; LVEF: 50 60%), higher preserved EF (HFHpEF; LVEF > 60%), and no HF. Outcomes were ischemic stroke, major adverse cardiovascular and cerebral events (MACCE) and major bleeding occurring within 1-year. RESULTS: The annual incidence of stroke was linearly and inversely related to LVEF, increasing by 0.054% per each 1% of LVEF decrease (95% CI: 0.013%-0.096%; p = 0.031). Patients with HFHpEF had the highest CHA2DS2-VASc score, but significantly lower stroke incidence than other HF groups (0.65%, compared to HFLpEF 1.30%; HFmrEF 1.71%; HFrEF 1.75%; trend p = 0.014). The incidence of MACCE was also lower in HFHpEF (2.0%) compared to other HF groups (range: 3.8-4.4%; p = 0.001). Age, HF type, and NYHA class were independent predictors of thromboembolic events. Conversely, major bleeding did not significantly differ between groups (p = 0.168). CONCLUSION: Our study in predominantly anticoagulated patients with AF shows that, reduction in LVEF is associated with higher thromboembolic, but not higher bleeding risk. HFHpEF is a distinct and puzzling group, featuring the highest CHA2DS2-VASc score but the lowest residual risk of thromboembolic events, which warrants further investigation. PMID- 29706430 TI - Hepatitis B virus and the risk of coronary heart disease: A comprehensive systematic review and meta-analyses of observational studies. AB - BACKGROUND: Several studies have reported that hepatitis B virus (HBV) infection affects the risk of coronary heart disease. However, its association is controversial. Thus, we conducted a systematic review and meta-analysis to better understand it. METHODS: Relevant studies published before October 2017 were identified by searching PubMed, EMBASE, and ISI Web of Science. The relationships between HBV and the risk of coronary heart disease were assessed using Relative risk (RR) values and the corresponding 95% confidence intervals (CIs). We used the random effects model proposed by DerSimonian and Laird to quantify the relationship. RESULTS: Nine articles, including 65,058 HBV-infected patients and 534,998 uninfected controls, were included in the meta-analysis. The present study does not support that HBV infection is associated with the risk of coronary heart disease (RR = 0.99, CI = 0.76-1.22; I2 = 68.9%). Sensitivity analysis and 'trim and fill' method yielded similar results. No evidence of publication bias was observed. CONCLUSIONS: HBV infection does not increase the risk of coronary heart disease. The associations were not significant both in cohort studies and in case-control studies. PMID- 29706431 TI - Atrial remodeling and metabolic dysfunction in idiopathic isolated fibrotic atrial cardiomyopathy. AB - BACKGROUND: Idiopathic isolated fibrotic atrial cardiomyopathy (IIF-ACM) is a novel subtype of cardiomyopathy characterized by atrial fibrosis that does not involve the ventricular myocardium and is associated with significant atrial tachyarrhythmia. The mechanisms underlying its pathogenesis are unknown. METHODS: Atrium samples were obtained from 3 patients with IIF-ACM via surgical intervention. Control samples were consisted of 3 atrium biopsies from patients with congenital heart disease and normal sinus rhythm, matched for gender, age and basic clinical characteristics. Comparative histology, immunofluorescence staining, electron microscopy and proteomics analyses were carried out to explore the unique pathogenesis of IIF-ACM. RESULTS: IIF-ACM atria displayed disordered myofibrils, profound fibrosis and mitochondrial damages compared to the control atria. Proteomics profiling identified metabolic pathways as the most profound changes in IIF-ACM. CONCLUSIONS: Our study suggested that metabolic changes in the atrial myocardium caused mitochondrial oxidative stress and potential cell damage, which further led to atrial fibrosis and myofibril disorganization, the characteristic phenotype of IIF-ACM. PMID- 29706432 TI - Increased risk of ischemic stroke associated with new-onset atrial fibrillation complicating acute coronary syndrome: A systematic review and meta-analysis. AB - BACKGROUND: Atrial fibrillation has been established as a major risk factor of ischemic stroke, however, the influence of new-onset atrial fibrillation (NOAF) complicating acute coronary syndrome (ACS) on ischemic stroke remains controversial. This meta-analysis aimed to validate the association between NOAF complicating ACS and ischemic stroke. METHODS: We identified randomized controlled trials and cohort studies comparing the ischemic stroke risk between patients with NOAF and sinus rhythm after ACS by searching MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials databases. We included studies reporting the number of ischemic stroke events or their risk estimates at the longest follow-up. We pooled risk ratios (RRs) using a random-effects model. This meta-analysis is registered in PROSPERO (CRD42017079858). RESULTS: In the 14 included studies (n = 292,774, 5 randomized controlled trials and 9 cohort studies), NOAF was associated with an increased risk of ischemic stroke (RR: 2.84, 95% confidence interval [CI]: 1.91-4.23; 6 studies), especially for patients with ST-segment elevation myocardial infarction (RR: 4.01, 95% CI: 2.61 6.18; 3 studies). In addition, the detrimental impact persisted in patients with transient NOAF (RR: 3.05, 95% CI: 1.63-5.70; 3 studies). The pooled result from a sensitivity analysis in which all individual components in the CHA2DS2-VASc score (heart failure, hypertension, age, diabetes, previous stroke, vascular disease and female sex) had been adjusted further validated the association between NOAF and ischemic stroke (RR: 2.32, 95% CI: 1.53-3.52; 4 studies). CONCLUSIONS: NOAF is significantly associated with ischemic stroke events in patients with ACS, even after adjustment for several important ischemic stroke risk factors. PMID- 29706433 TI - Cognitive correlates of "pure apathy" in Parkinson's disease. AB - INTRODUCTION: Previous studies exploring the association between apathy and cognitive deficits in Parkinson's disease (PD) employed scales and questionnaires for apathy, which did not control for the possible confounding effect of motor symptoms. Here we investigated the cognitive correlates of "pure apathy" by the Dimensional Apathy Scale, which allows us to assess apathy minimizing the influence of motor symptoms. METHODS: Consecutive PD outpatients referred to our centre were screened. All participants underwent a neuropsychological battery to assess verbal memory, executive functions and visuospatial abilities, apathy and depressive symptoms. RESULTS: We enrolled 56 non-depressed and non-demented PD patients, of whom 28 were apathetic and 28 were not. The two groups did not differ on demographic and clinical aspects; apathetic PD patients performed worse than non-apathetic PD patients on the part A, B and B-A of Trail Making Test and the interference task of Stroop test. No significant differences were found on memory and perceptual visuospatial tasks. CONCLUSIONS: Our results demonstrated that "pure apathy" is associated with more severe executive dysfunctions such as alteration of set-shifting and inhibitory control, which are mediated by prefrontal cortex and subcortical regions (i.e. basal ganglia). Our findings also supported the hypothesis that co-occurrence of apathy and executive deficits may be the epiphenomenon of damage in prefrontal-striatal cortical circuitries connecting dorsolateral prefrontal cortex, anterior cingulate cortex and basal ganglia. PMID- 29706434 TI - Microcosm environment models for studying the stability of adenovirus and murine norovirus in water and sediment. AB - Microcosms are useful tools for understanding the survival and fate of enteric viruses in aquatic environments. This study set out to determine the stability of infectious enteric viruses in an aquatic environment using a laboratory scale microcosm. Sediment and overlaying water were collected from a lagoon and inoculated with known concentrations of recombinant adenovirus (AdV-GFP) and murine norovirus (MNV-1). Infectious particles of these viruses were measured using fluorescence microscopy (AdV-GFP) or the plaque assay method (MNV-1), over 85 days in two different conditions: under natural sunlight and in fully darkened environments. The time required to reach one log reduction in viral titres (T90) of viable viruses in a natural condition microcosm for AdV-GFP and MNV-1 was shorter than in a dark condition microcosm. There was also a negative correlation between the temperature and infectivity of these viruses in both water and sediment samples. Considering that microcosms aim to mimic natural environment conditions and that AdV-GFP and MNV-1 are excellent surrogates for measuring the infectivity of the respective viruses strains, the results presented here have the potential to be applied in future health hazard studies and also would be useful for future climate scenarios. PMID- 29706435 TI - Decreasing urinary organophosphate pesticide metabolites among pregnant women and their offspring in Jerusalem: Impact of regulatory restrictions on agricultural organophosphate pesticides use? AB - INTRODUCTION: Maternal urinary levels of dialkyl phosphate (DAP) metabolites of organophosphate pesticides (OP) during pregnancy are associated with adverse outcomes in the offspring. Between 2012 and 2014, eighteen active OP ingredients were restricted or banned in Israel for agricultural use. AIM: We aimed to study trends of urinary DAP metabolites among pregnant women and their offspring in the era of the new regulations. METHODS: Pregnant women were recruited at 11-18 weeks of gestation and provided spot urine samples (n = 273). Soon after birth, neonatal urine samples were collected (n = 107). All urine specimens analyzed for DAP metabolites. Trends in DAP metabolites were tested using Mann-Kendall trend statistic (M-K S) and linear regression models were constructed to estimate the association between calendar period and DAP levels between September 2012 and March 2016. RESULTS: Over the study period, median maternal ?DAP levels decreased from 248 nmol/L to 148 nmol/L. Time of recruitment was associated with a statistically significant decrease in DAP metabolites, which remained significant after multivariate adjustment. Overall, the results for the analysis of before and after June 2014 showed a significant decrease in ?DAP of -0.198 log10 nmol/L (95%CI: -0.311,-0.084) which corresponds with a decrease of 36.6% in ?DAP. A similar trend was found for DAP metabolites in neonatal urine. Compared to other studies, pregnant women in Jerusalem had higher ?DAP levels, even at the end of the study period. CONCLUSION: We observed significant reductions in maternal and neonatal DAP urinary levels during the period of 2012-2016. Regulations restricting agricultural use of OP seem to be effective in reducing population exposure to OP, in an era when residential use of OP is banned. PMID- 29706436 TI - Effects of long-term exposure to CO and PM2.5 on microalbuminuria in type 2 diabetes. AB - OBJECTIVE: No study has examined the effects of air pollutants on albuminuria in type 2 diabetes. Therefore, the present study investigated this association. METHODS: This follow-up study enrolled 812 patients with type 2 diabetes between 2003 and 2012. The urinary albumin-to-creatinine ratio (ACR) was recorded annually. Exposure to the air pollutants CO, NO2, O3, SO2, and PM2.5 was interpolated from 72 air-quality monitoring stations to residences by using the kriging method. The association between air pollutants and ACR increase was assessed using mixed-effect model with random intercepts for 36 clinics. RESULTS: The study objects (mean age: 55.4 years) were followed for 3 or more years (average period: 5.4 years). ACR increase was found to be positively associated with the male sex, baseline hemoglobin A1c, and exposure to CO and PM2.5, and negatively associated with waist circumference through multiple linear regression. Annually urine albumin/creatinine ratio increase was estimated by the final model, Patients exposed to higher levels of CO (e.g., third quartile, 1025 ppb) and lower levels of CO (e.g., first quartile, 850 ppb) had an annual ACR increase of 3.73 and 3.54 mg/g, respectively. Patients exposed to higher levels of PM2.5 (e.g., third quartile, 38.8 MUg/M3) and lower levels of PM2.5 (e.g., first quartile, 27.7 MUg/M3) had an annual ACR increase of 3.96 and 3.17 mg/g, respectively. CONCLUSIONS: Exposure to high CO and PM2.5 levels increased albuminuria in type 2 diabetes. PMID- 29706437 TI - Burden of climate change on malaria mortality. AB - In 2016, an estimated 445,000 deaths and 216 million cases of malaria occurred worldwide, while 70% of the deaths occurred in children under five years old. Changes in climatic exposures such as temperature and precipitation make malaria one of the most climate sensitive outcomes. Using a global malaria mortality dataset for 105 countries between 1980 and 2010, we find a non-linear relationship between temperature and malaria mortality and estimate that the global optimal temperature threshold beyond which all-age malaria mortality increases is 20.8 degrees C, while in the case of child mortality; a significantly lower optimum temperature of 19.3 degrees is estimated. Our results also suggest that this optimal temperature is 28.4 degrees C and 26.3 degrees C in Africa and Asia, respectively - the continents where malaria is most prevalent. Furthermore, we estimate that child mortality (ages 0-4) is likely to increase by up to 20% in some areas due to climate change by the end of the 21st century. PMID- 29706438 TI - [Current situation of the organisation, resources and activity in paediatric cardiology in Spain]. AB - INTRODUCTION: The results are presented on the "current situation of the organisation, resources and activity in paediatric cardiology in Spain". It was promoted by the Spanish Society of Paediatric Cardiology and Congenital Heart disease. MATERIAL AND METHODS: An analysis was carried out on the results obtained from a specifically designed questionnaire, prepared by the Spanish Society of Paediatric Cardiology and Congenital Heart disease, that was sent to all hospitals around the country that offer the speciality of paediatric cardiology. RESULTS: A total of 86 questionnaires were obtained, including 14 hospitals that perform cardiac surgery on children. A total of 190 paediatric cardiology consultants, 40 cardiac surgeons, and 27 middle grade doctors performing their paediatric residency (MIR program) were identified. All hospitals had adequate equipment to perform an optimal initial evaluation of any child with a possible cardiac abnormality, but only tertiary centres could perform complex diagnostic procedures, interventional cardiology, and cardiac surgery. In almost all units around the country, paediatric cardiology consultants were responsible for outpatient clinics and hospital admissions, whereas foetal cardiology units were still mainly managed by obstetricians. The number of diagnostic and therapeutic procedures was similar to those reported in the first survey, except for a slight decrease in the total number of closed cardiac surgery procedures, and a proportional increase in the number of therapeutic catheterisations. CONCLUSIONS: Paediatric Cardiology in Spain is performed by paediatric cardiology consultants that were trained initially as general paediatricians, and then completed a paediatric cardiology training period. Almost all units have adequate means for diagnosis and treatment. Efforts should be directed to create a national registry that would not only allow a prospective quantification of diagnostic and therapeutic procedures, but also focus on their clinical outcomes. PMID- 29706439 TI - Recognition of Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy (CADASIL) in Two Oligosymptomatic Sisters with Low CADASIL Scale Scores and a Venous Dysplasia: Report of a Novel Greek Family. AB - Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) due to mutations of the NOTCH3 gene is the most common cause of inherited cerebral small-vessel disease and one of the genetic causes of migraine with aura. The so-called CADASIL scale has been proposed as a clinical screening tool, and a score of 15 or higher seems useful in identifying patients with high probability of carrying NOTCH3 mutations. We studied a novel Greek family with clinical features compatible with CADASIL. Genetic analysis of NOTCH3 in the 2 living patients revealed the R182C mutation. Both patients had low scores (12 and 14) in the CADASIL scale, probably due to their relatively young age (38 and 37 years, respectively) at which cognitive decline and external capsule involvement have not developed yet. Another unusual feature in the second patient was a venous dysplasia in the parietal lobe. Observations presented here add to the notion that the CADASIL scale, although useful, probably needs a revision, taking into account the patient's age at which the score is calculated. PMID- 29706440 TI - Recurrent Acute Ischemic Stroke after Infective Endocarditis Caused by Streptococcus Constellatus: First Case Report and Analysis of the Case Series. AB - Acute ischemic stroke (AIS) is highly prevalent in patients with infective endocarditis (IE) and associated with high rates of death and disability. IE presenting as an acute ischemic stroke, especially recurrent concurrence of acute anterior and posterior circulation infarct, has rarely been reported. Herein, we report a case study of a 60-year-old man with a history of aortic valve replacement and was under warfarin, presented with recurrent acute ischemic stroke which was found to have no vegetation secondary to infective endocarditis caused by Streptococcus constellatus as the embolic source. This is the first case report of recurrent ischemic stroke secondary to IE without vegetation caused by Streptococcus constellatus involving concurrence of acute anterior and posterior circulation. We also then systematically analyze the cases with IE initially presenting as AIS reported in the literature to establish possible demographic, clinical, laboratory patterns, and prognostic features of these cases. PMID- 29706441 TI - Retrospective Analysis of Argatroban in 353 Patients with Acute Noncardioembolic Stroke. AB - BACKGROUND: Argatroban is a thrombin inhibitor agent for acute noncardioembolic ischemic stroke in Japan. We studied the prognosis in patients with acute stroke treated by argatroban in comparison with the control group with ozagrel in our hospital. SUBJECTS AND METHODS: A total of 513 patients with acute noncardioembolic ischemic stroke were enrolled retrospectively from our hospital database. Of all patients with stroke, 353 were administered with argatroban. The other 160 control patients were administered with ozagrel. The patients were examined as to their stroke types, the neurological severity according to the National Institutes of Health Stroke Scale (NIHSS), and clinical outcomes on discharge were determined according to the modified Rankin Scale (mRS). RESULTS: A total of 353 patients with acute noncardioembolic stroke, including 138 with lacunar infarction (LIs) and 215 with atherothrombotic infarction (ATI) showed functional recovery by argatroban, but the effectiveness of argatroban was not superior to ozagrel therapy defined by the control group. A total of 255 patients with ATI who were treated with both argatroban and ozagrel showed improvement by 1 point. We could not find any significant difference between argatroban and ozagrel in the 2 stroke subtypes, LI and ATI. We also found that combination therapy of argatroban and edaravone was not superior to argatroban monotherapy in clinical outcome. CONCLUSIONS: Argatroban therapy was not superior to control with ozagrel therapy in acute noncardioembolic ischemic stroke, including LI and ATI, regardless of the use of edaravone. PMID- 29706442 TI - The Effect of Functional Stretching Exercises on Neural and Mechanical Properties of the Spastic Medial Gastrocnemius Muscle in Patients with Chronic Stroke: A Randomized Controlled Trial. AB - BACKGROUND: Following spasticity, neural and mechanical changes of the paretic muscle often occur, which affect the muscle function. The aim of this study was to investigate the effect of functional stretching exercises on neural and mechanical properties of the spastic muscle in patients with stroke. MATERIALS AND METHODS: This study was a single-blinded, randomized control trial. Forty five patients with stroke (experimental group: n = 30; control group: n = 15) participated in this study. Subjects in the experimental group participated in a functional stretching program 3 times a week for 4 weeks. Subjects in both groups were evaluated before the training, at the end of training, and then during a 2 month follow-up. Neural properties, including H-reflex latency and Hmax/Mmax ratio, were acquired. Mechanical properties, including fascicle length, pennation angle, and muscle thickness in the spastic medial gastrocnemius muscle, were evaluated. Repeated measure analysis of variance was used in the analysis. RESULTS: Time by group interaction in the pennation angle (P = .006), and in muscle thickness (P = .030) was significant. The results indicated that the H reflex latency (P = .006), pennation angle (P < .001), and muscle thickness (P = .001) were altered after stretching training program and these changes were at significant level after 2-month follow-up. CONCLUSION: The results indicated that the use of functional stretching exercises can cause significant differences in neural and mechanical properties of spastic medial gastrocnemius muscle in patients with chronic stroke. PMID- 29706443 TI - Tunnelled central venous access devices in small children: A comparison of open vs. ultrasound-guided percutaneous insertion in children weighing ten kilograms or less. AB - PURPOSE: Ultrasound-guided (USG) percutaneous insertion of tunnelled central venous access devices (CVADs) has been shown to be safe and effective in adults. However, there have been concerns over the safety of this technique in small children. This paper analyses the safety of USG percutaneous CVAD insertion in the pediatric population weighing ten kilograms or less. METHOD: All surgically inserted CVADs for children weighing ten kilograms or less, between January 2010 and December 2015 at the Children's Hospital at Westmead were retrospectively reviewed. Open and USG percutaneous techniques were compared with intraoperative complications as the primary outcome variable. Secondary outcome measures included conversion to open technique, postoperative complications, operating time and catheter longevity. RESULTS: 232 cases were identified: 96 (41.4%) open, 136 (58.6%) USG percutaneous. Age ranged <1-48 months; weight 0.7-10 kg. CVADs ranged 2Fr-9Fr in size. Eleven USG percutaneous cases required conversion to open. There was no significant difference in intraoperative complication rate between open (11/96, 11.5%) and USG percutaneous (19/136, 14.0%) groups (p = 0.574). There was no significant difference in overall postoperative complications, operative time or catheter longevity. Mechanical blockage was significantly higher in the open group than the USG percutaneous group (21% vs 10%, p = 0.015). CONCLUSION: USG percutaneous CVAD insertion is safe in children weighing ten kilograms or less. Open catheter insertion may be associated with higher rates of post-operative catheter blockage in small children. LEVEL OF EVIDENCE: Level III. PMID- 29706444 TI - Impaired serum inhibin-B and number of germ cells in boys with cryptorchidism following heavily gestational maternal smoking. AB - PURPOSE: A meta-analysis including 11,900 cases showed that maternal gestational smoking was associated with increased risk of cryptorchidism. The aim of study was to investigate whether a hormone profile of cryptorchid boys and a supplementing histopathological evaluation of testicular biopsies could add detailed knowledge to the impact of maternal gestational smoking on pathogenesis of cryptorchidism. METHODS: 601 cryptorchid boys aged 4 months to 14 years old were included. Because normal hormones have a pronounced age dependency, we compared results from boys whose mothers had smoked heavily (>10 cigarettes/day) during pregnancy with age matched cryptorchid controls of nonsmoking mothers (1:6). We studied: birthweight, germ-cell number/tubular cross section, frequency of germ cells positive for placental-like alkaline phosphatase (PLAP), gonadotropins and inhibin-B. RESULTS: 501 boys were sons of nonsmokers, 72 boys of intermittent smokers and 28 boys of heavy smokers. 39%, 44% and 61% respectively had bilateral cryptorchidism. Compared to age-matched cryptorchid controls of nonsmoking mothers, sons of heavy smokers had lower birthweight (p = 0.006), germ-cell number/tubular cross section (p = 0.009), frequency of germ cells positive for PLAP (p = 0.037) and inhibin-B (p = 0.042). CONCLUSIONS: All findings could be associated with placental dysfunction with altered human chorionic gonadotropin production well described in women smoking during pregnancy. TYPE OF STUDY: Prognosis study (prospective cohort study with >80% follow-up). LEVEL OF EVIDENCE: Level 1. PMID- 29706446 TI - The effect of implementation of an early detection team: A nationwide register based study of characteristics and help-seeking behavior in first-episode schizophrenia in Denmark. AB - BACKGROUND: In an effort to make people with signs of psychosis seek help as early as possible, Region Zealand launched in 2012 an early detection team project as the first and only in Denmark. The project consisted of a combination of easy access and an information campaign targeting the public. This nation-wide study examined characteristics and help-seeking behavior of patients with first episode schizophrenia (FES) in the early detection region in comparison with other Danish regions. METHOD: Data from the Danish National Schizophrenia register on all Danish patients diagnosed with first-episode schizophrenia during 2012 to 2015 were linked to demographic and health care data drawn from official national registers. Binary logistic regression analyses examined the difference between the early detection region and other regions controlling for demographic characteristics and utilization of mental health care services and contacts to general practitioner (GP). RESULTS: Patients in the early detection region were younger (OR = 0.51; CI: 0.42-0.62; p < 0.000) than in regions without early detection teams. Furthermore, they were more likely to be of Danish origin, and less likely to have contact with mental health services and GPs prior to FES. CONCLUSION: The study suggests that implementing an early detection team in combination with an information campaign contributed to detecting patients with first-episode schizophrenia earlier than in regions without the early detection team. The study gives an indication of different pathways among patients in the early detection region. PMID- 29706445 TI - Reoperative complications following pediatric liver transplantation. AB - BACKGROUND: The aim of this study is to describe the incidence and impact of reoperation following pediatric liver transplantation, as well as the indications and risk factors for these complications. METHODS: All primary pediatric liver transplants performed at our institution between January 2012 and September 2016 were reviewed. A reoperative complication was defined as a complication requiring return to the operating room within 30 days or the same hospital admission as the transplant operation, excluding retransplantation. RESULTS: Among the 144 pediatric liver transplants performed during the study period, 9% of the recipients required reoperation. The most common indications for reoperation were bleeding and bowel complications. There was no significant difference in the graft survival of patients with a reoperation and those without a reoperation (p = 0.780), but patients with a reoperation had a significantly longer hospital length of stay (median of 39 days vs. 11 days, p = 0.001). Variant donor arterial anatomy, transplant operative time, intraoperative blood loss, transfusion volume of packed red blood cells or cell saver per weight, and transfusion with fresh frozen plasma, platelets, or cryoprecipitate were significantly associated with reoperation upon univariable logistic regression, but none of these risk factors remained statistically significant upon multivariable regression. CONCLUSION: At our institution, reoperation did not significantly impact graft survival. We identified variant donor arterial anatomy, transplant operative time, intraoperative blood loss, transfusion volume of packed red blood cells or cell saver per weight, and transfusion with fresh frozen plasma, platelets, or cryoprecipitate as risk factors for reoperation, although none of these risk factors demonstrated independent association with reoperation in a multivariable model. TYPE OF STUDY: Prognosis Study. LEVEL OF EVIDENCE: Level III. PMID- 29706448 TI - Decreased peripheral TNF alpha (TNF-alpha) mRNA expression in patients with treatment-resistant schizophrenia. PMID- 29706447 TI - Spared and impaired sleep-dependent memory consolidation in schizophrenia. AB - OBJECTIVE: Cognitive deficits in schizophrenia are the strongest predictor of disability and effective treatment is lacking. This reflects our limited mechanistic understanding and consequent lack of treatment targets. In schizophrenia, impaired sleep-dependent memory consolidation correlates with reduced sleep spindle activity, suggesting sleep spindles as a potentially treatable mechanism. In the present study we investigated whether sleep-dependent memory consolidation deficits in schizophrenia are selective. METHODS: Schizophrenia patients and healthy individuals performed three tasks that have been shown to undergo sleep-dependent consolidation: the Word Pair Task (verbal declarative memory), the Visual Discrimination Task (visuoperceptual procedural memory), and the Tone Task (statistical learning). Memory consolidation was tested 24 h later, after a night of sleep. RESULTS: Compared with controls, schizophrenia patients showed reduced overnight consolidation of word pair learning. In contrast, both groups showed similar significant overnight consolidation of visuoperceptual procedural memory. Neither group showed overnight consolidation of statistical learning. CONCLUSION: The present findings extend the known deficits in sleep-dependent memory consolidation in schizophrenia to verbal declarative memory, a core, disabling cognitive deficit. In contrast, visuoperceptual procedural memory was spared. These findings support the hypothesis that sleep-dependent memory consolidation deficits in schizophrenia are selective, possibly limited to tasks that rely on spindles. These findings reinforce the importance of deficient sleep-dependent memory consolidation among the cognitive deficits of schizophrenia and suggest sleep physiology as a potentially treatable mechanism. PMID- 29706449 TI - Predictors of 'all-cause discontinuation' of initial oral antipsychotic medication in first episode psychosis. AB - INTRODUCTION: Discontinuation of the initial oral antipsychotic prescribed for a first episode of psychosis (FEP) can derail outcome. Our objective was to examine the rate of and time to all-cause discontinuation of the first antipsychotic prescribed and the factors influencing such discontinuation. METHODS: In a sample of 390 FEP patients, we estimated the rate of and time to discontinuation of the initial antipsychotic over a one-year period. The effects of a number of putative predictors of discontinuation were estimated using regression analyses. RESULTS: Rate of discontinuation of the first antipsychotic was 72%, with no difference between the 3 investigated antipsychotics (olanzapine (73%), risperidone (68%) and aripiprazole (75%)), (chi2 (2) = 1.89, p = 0.388). Mean time to discontinuation was 7.2 (4.6) months and was not different among the three antipsychotics (Log-rank chi2 (2) = 0.257, p = 0.879). Binary logistic regression showed that higher positive and negative symptoms remission and baseline functioning were associated with lower rates of discontinuation (Nagelkerke R2 = 0.36, chi2 (10) = 66.9, p < 0.001). Multiple linear regression showed the same predictors, in addition to male gender and less weight gain per month of exposure to the initial antipsychotic, to be associated with longer time to discontinuation (adjusted R2 = 0.336, F (9, 219) = 13.8, p < 0.001). CONCLUSION: Discontinuation of the initial antipsychotic is a major concern in the course of treating FEP. Symptom relief, better functioning and lower side effects appear to be the major factors associated with continuing an antipsychotic medication. PMID- 29706450 TI - A close encounter: Hand injuries in the ED. PMID- 29706451 TI - In search of decoding the syntax of the bioelements in human hair - A critical overview. AB - The principles and practice of assessing the human body nutritional status or its environmental exposure through hair bioelement analysis are presented; herein the term "bioelements" is used as a common denominator for the major elements, trace elements and ultra-trace elements that are found in the human body. The accumulation of bioelements in the hair followed the statistical Power Law and the resulting sigmoid curve can be zoned into five regions in the ascending order of abundance (Low, Marginal, Adequate, High, and Excessive). The Adequate linear region of the bioassay sigmoid curve may be further subdivided into Low adequate, Recommended, and Ample adequate sub regions in a 60:30:10 ratio. Phosphorus was the most invariant bioelement since its hair concentration varies minimally regardless of the geographical place of living, the twenty years' time interval between the analyses, sex, race and instrumentation, i.e., atomic absorption spectrometry (AAS) atomic emission spectrometry (AES), and inductively plasma mass spectrometry (ICP MS). The osteotrophic (bone seeking) bioelements: Ca, Mg, and Sr, were 2.5 times more abundant in the hair of women than men. Two principal electrolytes of the body (Na, K) of the multi-bioelement hair profile were markedly increased in the depressed subjects diagnosed according to the American Psychiatric Association MSD-IV classification criteria. This increase in the hair Na and K of the depressed subjects was also associated with the decrease of vasopressin in the peripheral blood. The factor analysis revealed strong association of depression with sex (women > men in a 2.5:1 ratio), and with the metals from the Nieboer-Richardson series which form strong covalent bonds with proteins. We propose that the biological roots of depression are related to the non-specific impairment of the intracellular osmotic balance and ionic gradient due to the Na+K+ATPase failure from whatever cause acting either separately or in combination. We also put forward the idea of how children's autism may be related to a disproportional growth rate of various organs and tissues if children are fed up to their maximal genetic growth capacity. Finally, we have suggested the hypothesis on how the syntax or integration of the internal metabolic wiring of the bioelements in the body may occur. We have suggested the hypothetical existence of two complex distinct five-bioelement "rotors", the P-rotor and the N rotor, where the P-rotor integrates the mileau interior (Na, K) ions with the perception/excitability (Mg, Ca) ions. Thus, the complex five element interdependence is cross related to P which provides the energy from the phosphorus of the DNA nucleotide backbone. The hair multi-bioelement profile analysis allows us to envisage the more complex structural metabolic features that bioelements are playing in our bodies. PMID- 29706452 TI - Comparative effects of meso-2,3-dimercaptosuccinic acid, monensin and salinomycin on the concentrations of cadmium and some essential elements in skeletal muscles of Cd-exposed mice. AB - Cadmium (Cd) is an environmental pollutant shown to induce multi organ dysfunction. In this study we present novel data about the effects of meso-2,3 dimercaptosuccinic acid (DMSA), monensin and salinomycin on the concentration of Cd in skeletal muscles of mice exposed to Cd (II) acetate treatment for 14 days. The impact of Cd and the chelating agents on the endogenous concentrations of calcium (Ca), copper (Cu), iron (Fe), magnesium (Mg), phosphorous (P), selenium (Se) and zinc (Zn) was also investigated. Subacute exposure of mice to Cd (II) acetate resulted in a significant accumulation of the toxic metal ion in the skeletal muscles compared to the untreated controls. Salinomycin most effectively mobilized Cd from the muscles compared to DMSA and monensin. The Cd exposure and the tested chelating agents did not significantly alter the endogenous concentrations of the selected essential elements in mouse muscles. The presented results confirmed that among the tested chelating agents salinomycin is superior as a potential antidote to Cd poisoning. PMID- 29706453 TI - Calyceal diverticula in children: imaging findings and presentations. AB - A calyceal diverticulum consists of a cystic eventration in the renal parenchyma that is lined with transitional cell epithelium with a narrow infundibular connection with the calyces or pelvis of the renal collector system; thus, the term pyelocalyceal diverticulum would be more accurate. Very rare in pediatric patients, calyceal diverticula can be symptomatic and require treatment. Calyceal diverticula are underdiagnosed because they can be mistaken for simple renal cysts on ultrasonography. To determine the approach to their follow-up and management, the diagnosis must be confirmed by excretory-phase computed tomography (CT) or magnetic resonance imaging (MRI). This article aims to show the different ways that calyceal diverticula can present in pediatric patients; it emphasizes the ultrasonographic findings that enable the lesion to be suspected and the definitive findings that confirm the diagnosis on CT and MRI. It also discusses the differential diagnosis with other cystic kidney lesions and their treatment. PMID- 29706454 TI - A-to-I RNA Editing Contributes to Proteomic Diversity in Cancer. AB - Adenosine (A) to inosine (I) RNA editing introduces many nucleotide changes in cancer transcriptomes. However, due to the complexity of post-transcriptional regulation, the contribution of RNA editing to proteomic diversity in human cancers remains unclear. Here, we performed an integrated analysis of TCGA genomic data and CPTAC proteomic data. Despite limited site diversity, we demonstrate that A-to-I RNA editing contributes to proteomic diversity in breast cancer through changes in amino acid sequences. We validate the presence of editing events at both RNA and protein levels. The edited COPA protein increases proliferation, migration, and invasion of cancer cells in vitro. Our study suggests an important contribution of A-to-I RNA editing to protein diversity in cancer and highlights its translational potential. PMID- 29706455 TI - Extrinsic Phagocyte-Dependent STING Signaling Dictates the Immunogenicity of Dying Cells. AB - The ability of dying cells to activate antigen-presenting cells (APCs) is carefully controlled to avoid unwarranted inflammatory responses. Here, we show that engulfed cells containing cytosolic double-stranded DNA species (viral or synthetic) or cyclic di-nucleotides (CDNs) are able to stimulate APCs via extrinsic STING (stimulator of interferon genes) signaling, to promote antigen cross-presentation. In the absence of STING agonists, dying cells were ineffectual in the stimulation of APCs in trans. Cytosolic STING activators, including CDNs, constitute cellular danger-associated molecular patterns (DAMPs) only generated by viral infection or following DNA damage events that rendered tumor cells highly immunogenic. Our data shed insight into the molecular mechanisms that drive appropriate anti-tumor adaptive immune responses, while averting harmful autoinflammatory disease, and provide a therapeutic strategy for cancer treatment. PMID- 29706457 TI - Morgellons disease treatment with quetiapine. PMID- 29706456 TI - A cost-effectiveness analysis of the up-front use of balloon catheter dilation in the treatment of pediatric chronic rhinosinusitis. AB - BACKGROUND: The treatment of pediatric sinusitis continues to be a controversial topic. It has been recommended to treat pediatric chronic rhinosinusitis (CRS) with adenoidectomy before proceeding to more invasive techniques. There are concerns regarding side effects of endoscopic sinus surgery in pediatric patients. With the advent of balloon catheter dilation (BCD) as a minimally invasive technique, some authors are recommending up front adenoidectomy with BCD in order to maximize disease resolution while minimizing risk. PURPOSE: Our study examines the cost effectiveness of adenoidectomy alone versus adenoidectomy and upfront BCD for the management of pediatric CRS. METHODS: A decision tree analysis was created to determine the cost effectiveness of treating a pediatric patient who has failed medical management, using adenoidectomy versus adenoidectomy with up-front BCD. Three separate decision trees were made. The incremental cost effectiveness ratio (ICER) was calculated for each scenario and a sensitivity analysis was done to determine how different values impacted our results. RESULTS: Adenoidectomy as the sole first procedure was found to be more cost effective in all three decision trees. For tree 1, the adenoidectomy plus BCD arm was 0.03% more effective in the end, but with an $81, 431 incremental cost. CONCLUSIONS: Costs in addition to outcomes must be considered when comparing treatment modalities in our current health care environment. This study found that adenoidectomy as a first intervention before proceeding to more advanced techniques is nearly as effective and is a much more cost-effective algorithm for the treatment of pediatric CRS. However, the physician must advocate the best treatment for his or her own patients. PMID- 29706458 TI - Psychological and functional effect of different primary treatments for prostate cancer: A comparative prospective analysis. AB - OBJECTIVES: The aim of the study was to comparatively evaluate the psychological and functional effect of different primary treatments in patients with prostate cancer. METHODS AND MATERIALS: We conducted a single-center prospective non randomized study in a real-life setting using functional and psychological questionnaires in prostate cancer cases submitted to radical prostatectomy, external radiotherapy, or active surveillance. Totally, 220 cases were evaluated at baseline and during the follow-up at 1-, 3-, 6-, and 12-month interval after therapy. Patients self-completed questionnaires on urinary symptoms and incontinence, erectile and bowel function, psychological distress (PD), anxiety, and depression. RESULTS: Several significant differences among the three groups of treatment were found regarding the total score of the functional questionnaires. Regarding PD, cases submitted to radical prostatectomy showed stable scores during all the 12 months of follow-up whereas cases submitted to radiotherapy showed a rapid significant worsening of scores at 1-month interval and persistent also at 6- and 12-month interval. Cases submitted to active surveillance showed a slight and slow worsening of scores only at 12-month interval. PD and depression resulted to be more associated with urinary symptoms than sexual function worsening whereas anxiety resulted to be associated either with urinary symptoms or sexual function worsening. CONCLUSIONS: The results of our comparative and prospective analysis could be used to better inform treatment decision-making. Patients and their teams might wish to know how functional and psychological aspects may differently be influenced by treatment choice. PMID- 29706459 TI - Detection of urothelial carcinoma, upper tract urothelial carcinoma, bladder carcinoma, and urothelial carcinoma with gross hematuria using selected urine-DNA methylation biomarkers: A prospective, single-center study. AB - INTRODUCTION: Hematuria is the most common symptom of urothelial carcinomas (UC) but is often idiopathic. Cystoscopy is expensive which involves considerable patient discomfort, and conventional urine cytology for noninvasive UC detection and disease monitoring suffers from poor sensitivity. We aim to evaluate the performance of genes selected from a previous study in detecting UC, especially among patients with gross hematuria, as well as upper tract urothelial carcinoma (UTUC) and bladder carcinoma separately, in voided urine samples. METHODS: Using methylation-specific polymerase chain reaction, we examined the promoter methylation status of 10 genes in voided urine samples among 473 patients at our institution, including 217 UC patients and 256 control subjects. RESULTS: The final combination of VIM, CDH1, SALL3, TMEFF2, RASSF1A, BRCA1, GDF15, and ABCC6 identified UC with a sensitivity of 0.83 and a specificity of 0.60. Additionally, a panel of selected genes (CDH1, HSPA2, RASSF1A, TMEFF2, VIM, and GDF15) identified UTUC with a sensitivity of 0.82 and a specificity of 0.68, while a panel of selected genes (VIM, RASSF1A, GDF15, and TMEFF2) identified bladder carcinoma with a sensitivity of 0.82 and a specificity of 0.53. Remarkably, a different panel (CDH1, SALL3, THBS1, TMEFF2, VIM, and GDF15) identified UC in patients with gross hematuria with 0.89 sensitivity and 0.74 specificity, and sensitivity (0.91) and specificity (0.92) could be achieved when cytology was included. CONCLUSIONS: The selected urine-DNA methylation biomarkers are reliable, noninvasive, and cost-effective diagnostic tools for bladder carcinoma and UTUC, especially among patients with gross hematuria. PMID- 29706460 TI - Local control and fracture risk following stereotactic body radiation therapy for non-spine bone metastases. AB - AIMS: To report local control and toxicity rates for patients treated with stereotactic body radiotherapy (SBRT) for non-spine bone metastases. METHODS AND MATERIALS: Eighty-one patients with 106 non-spine bone metastases were treated between 2011 and 2014 and retrospectively reviewed. Indications included: oligometastases (63%), oligoprogression (17.3%), retreatment (2.4%) or other (17.3%). Cumulative incidence function was used to assess local recurrence and fracture probability. Bivariate relationships were investigated based on selected patient, tumour and dose-volume factors. RESULTS: Mean follow-up was 13 months (range, 0.25-45.6) and the median patient age was 66.4 years (range, 36-86). Most patients were male (60.5%) and the predominant histology prostate cancer (32%). Bone metastases were most commonly located in the pelvis (41.5%) and almost half sclerotic. The most common prescriptions were 30 Gy/5 (30.2%) and 35 Gy/5 (42.5%). The cumulative incidence of local recurrence at 6,18 and 24 months respectively was 4.7%, 8.3% and 13.3% with a mean time to local recurrence of 11.8 months (range, 3.9-23.4). A significant association was found between local recurrence and volume of the PTV (p = 0.02), with larger PTVs having a greater risk of local failure. Fracture was observed radiographically in the treatment volume in 9/106 (8.5%) of treated lesions and the mean time to fracture was 8.4 months (range, 0.7-32.5 months). With respect to predictors, a trend was observed for lytic lesions (p = 0.11) and female gender (p = 0.09). CONCLUSIONS: The results of this study confirm that SBRT yields high rates of long-term local control for non-spine bone metastases with a low fracture risk. PMID- 29706461 TI - Abnormal neuronal response to rectal and anal stimuli in patients treated with primary radiotherapy for anal cancer. AB - INTRODUCTION: Sphincter-sparing radiotherapy or chemoradiation (RT/CRT) have become the standard treatments for most patients with anal cancer. Unfortunately, long-term survivors often suffer from severe bowel symptoms indicating sensory dysfunction. The aim of the present study was to characterize the sensory pathways of the brain-gut axis after radiotherapy for anal cancer. METHOD: Cortical evoked potentials (CEPs) were recorded during repeated, rapid balloon distensions of the rectum and anal canal in 13 patients with anal cancer treated with radiotherapy or chemoradiation and in 17 healthy volunteers. Latencies and amplitudes of rectal CEPs were compared between the groups. CEPs from both rectal and anal distensions were examined using single sweep spectral band analysis to determine the relative amplitude of five spectral bands as a proxy of neuronal processing. RESULTS: Groups were comparable by age (62.4 +/- 7.8 vs 58.9 +/- 8.9, p < 0.32) and gender. Patients had a mean Wexner fecal incontinence score of 5.5 (+/-3.8) and median LARS Score of 29 (0-39). Rectal CEP latencies were prolonged in patients (F = 11.7; p < 0.001), whereas amplitudes were similar (F = 0.003; p = 0.96). Spectral analysis of CEPs from rectal distensions showed significant differences between groups in theta (4-8 Hz), alpha (8-12 Hz), beta (12-32 Hz) and gamma (32-70 Hz) bands (all p < 0.001) and CEPs from anal distensions showed significant differences in the alpha, beta and gamma bands (all p <= 0.002). CONCLUSION: Patients treated with RT/CRT for anal cancer have impaired ano-rectal sensory pathways and abnormal cortical processing. This may play a central role for the pathogenesis of late proctopathy. PMID- 29706462 TI - Cost-effectiveness analysis of stereotactic body radiotherapy and surgery for medically operable early stage non small cell lung cancer. AB - BACKGROUND: Projections estimate an increase of 50% of the incidence of lung cancer by 2030. Early-stage non-small cell lung cancer represented 19% of NSCLC cases diagnosed in the US between 2005 and 2011. There is rising evidence in favour of lung cancer screening, which will reduce the occurrence of later-stage lung cancers while raising the incidence of early-stage NSCLC. Current guidelines state that for early-stage NSCLC, surgical resection should be performed, and stereotactic body radiotherapy (SBRT) is an option for patients who are non medically operable. In this study, we compared the cost-effectiveness of SBRT with lobectomy in medically operable patients. METHODS: We developed a Markov model based on the survival results of two randomized studies comparing SBRT and video assisted thoracoscopic surgery (VATS) lobectomy in early-stage NSCLC, to describe survival and treatment related complications of patients treated for early-stage NSCLC. This analysis was conducted from the French payer perspective on a lifetime perspective. Utility values, recurrence risks, and costs were adapted from the literature. Deterministic (DSA) and probabilistic (PSA) sensitivity analyses were performed to assess the influence of the assumptions made. RESULTS: The Markov model developed was consistent with survival data reported in the pool analysis of the randomized studies. SBRT and lobectomy total costs were 9,234.15? and 10,726.98?, respectively, and the quality-adjusted life expectancies were 16.35 and 15.80 QALYs, respectively. The DSA, run on every assumption made, revealed that the incremental cost-effectiveness ratio was mainly sensitive to the decrement of utility caused by treatment related complications and initial cost of both surgery and SBRT. The PSA showed that SBRT had the highest probability of cost-effectiveness compared to lobectomy. CONCLUSIONS: This is the first medico-economic study evaluating SBRT and lobectomy in stage I NSCLC based on randomized studies, and our analyses suggest that SBRT is dominant over lobectomy in operable early-stage NSCLC treatment. Deterministic and probabilistic sensitivity analyses confirmed that this result was robust and that it was not modified by the assumptions made in the Markov model building. PMID- 29706463 TI - Characterizing a novel vGlut3-P2A-iCreER knockin mouse strain in cochlea. AB - Precise mouse genetic studies rely on specific tools that can label specific cell types. In mouse cochlea, previous studies suggest that vesicular glutamate transporter 3 (vGlut3), also known as Slc17a8, is specifically expressed in inner hair cells (IHCs) and loss of vGlut3 causes deafness. To take advantage of its unique expression pattern, here we generate a novel vGlut3-P2A-iCreER knockin mouse strain. The P2A-iCreER cassette is precisely inserted before stop codon of vGlut3, by which the endogenous vGlut3 is intact and paired with iCreER as well. Approximately, 10.7%, 85.6% and 41.8% of IHCs are tdtomato + when tamoxifen is given to vGlut3-P2A-iCreER/+; Rosa26-LSL-tdtomato/+ reporter strain at P2/P3, P10/P11 and P30/P31, respectively. Tdtomato + OHCs are never observed. Interestingly, besides IHCs, glia cells, but not spiral ganglion neurons (SGNs), are tdtomato+, which is further evidenced by the presence of Sox10+/tdtomato+ and tdtomato+/Prox1(Gata3 or Tuj1)-negative cells in SGN region. We further independently validate vGlut3 expression in SGN region by vGlut3 in situ hybridization and antibody staining. Moreover, total number of tdtomato + glia cells decreased gradually when tamoxifen is given from P2/P3 to P30/P31. Taken together, vGlut3-P2A-iCreER is an efficient genetic tool to specifically target IHCs for gene manipulation, which is complimentary to Prestin-CreER strain exclusively labelling cochlear outer hair cells (OHCs). PMID- 29706464 TI - Factors related to masticatory performance in healthy elderly individuals. AB - PURPOSE: Maintenance of natural dentition and/or prosthodontic rehabilitation is necessary for good masticatory function. Although other factors such as physical and oral functions are also important for masticatory performance, only a few studies have evaluated their roles. The aim of the current study was to assess factors associated with masticatory performance among elderly individuals, while maintaining and/or reconstructing all occlusal support areas. METHODS: The present study was designed and implemented as a cross-sectional study, involving a total of 262 participants (mean age: 74.2+/-5.9years) who participated in the Kyoto Elders Physical Fitness Measurement Research Project. Individuals with partial or complete edentulousness who did not use dentures were excluded from the study. The predictor variables included physical status (i.e., age, gender, body-mass index, and grip strength), oral conditions (i.e., number of present teeth, temporomandibular joint noise, and denture wearer), and oral functions (i.e., maximum voluntary occlusal force; occlusal contact area; cheek pressure; oral diadochokinesis test /pa/, /ta/, /ka/; and maximum voluntary tongue pressure). The variable outcome was masticatory performance. These variables among the participants using univariate and multivariate analyses were compared. RESULTS: Grip strength, number of present teeth, maximum voluntary occlusal force, occlusal contact area, oral diadochokinesis /ka/ /ta/, and maximum voluntary tongue pressure were significant factors for masticatory performance. Stepwise regression analysis showed that grip strength, maximum voluntary occlusal force, and diadochokinesis /ta/ significantly affected masticatory performance. CONCLUSIONS: Masticatory performance was closely associated with grip strength, maximum voluntary occlusal force, and diadochokinesis /ta/ among healthy elderly participants. PMID- 29706465 TI - [Do initial experience with an enhanced recovery program after surgery (ERAS) improve postoperative outcomes after cystectomy?] AB - OBJECTIVE: To estimate the feasibility and the impact of an ERAS program after radical cystectomy for bladder cancer. MATERIALS AND METHODS: This was a retrospective study comparing a historical pre ERAS group, including all the patients undergoing cystectomy for bladder cancer from January 2013 to December 2015 with a classic procedure, and an interventional ERAS group after introducing an enhanced recovery protocol before, during and after surgery, from February 2016. The principal outcome was the postoperative length of stay. Secondary outcomes mesures were impact on perioperative complication rate (Clavien classification>=3B), readmission rate, reanimation length of stay, ileus rate and adherence to the ERAS protocol. RESULTS: There were no differences between the 2 groups as far as demographics characteristics are concerned. In total, 97 patients were included, 56 in the control group, and 41 in the ERAS group. The adherence to the protocol was about 65.8%. The ERAS group had statistically significantly shorter median length of stay (D19 versus D14; P: 0.021). The major complications rate (Clavien>=3B) were about 23.2% for the control group and 12.1% for the ERAS group (P: NS). The reinsertion of nasogastric tube were higher in the control group (39.3% vs 21.9%; P: NS) and the readmission rate was about 7.1% in the control group versus 14.6% in the ERAS group (P: NS). CONCLUSION: In conclusion, introduction and application of an enhanced recovery protocol (ERAS) after cystectomy for bladder cancer allowed for better management of postoperative outcomes. It is clearly feasible in cystectomy, and improve significantly the median postoperative length of stay. Moreover, it may be effective in terms of faster return of bowel function and reduction of majors complications. LEVEL OF EVIDENCE: 4. PMID- 29706466 TI - Ventricular assist device in the emergency department: Evaluation and management considerations. AB - Ventricular assist devices (VAD) are being used at increasing rates in patients with severe, end-stage heart failure. Specific indications include VAD placement as a bridge to cardiac function recovery, a bridge to cardiac transplantation, or destination therapy (long-term support for patients ineligible for transplant). The assessment and management of the VAD patient is rather complex, requiring a basic knowledge of device structure and function. This article reviews the basic structure and function, discusses the approach to the VAD patient in the ED, and reviews the more common presentations and complications encountered in these technology-complex patients who are critically ill at baseline. PMID- 29706467 TI - HPV: Molecular pathways and targets. AB - Infection of high-risk human papillomaviruses (HPVs) is a prerequisite for the development of cervical carcinoma. HPV infections are also implicated in the development of other types of carcinomas. Chronic or persistent infection of HPV is essential but HPV alone is inadequate, additional endogenous or exogenous cues are needed along with HPV to induce cervical carcinogenesis. The strategies that high-risk HPVs have developed in differentiating epithelial cells to reach a DNA synthesis competent state leading to tumorigenic transformation are basically due to overexpression of the E6 and E7 oncoproteins and the activation of diverse cellular regulatory or signaling pathways that are targeted by them. Moreover, the Wnt/beta-catenin/Notch and phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathways are deregulated in various cancers, and have also been implicated in HPV-induced cancers. These are basically related to the "cancer hallmarks," and include sustaining proliferative signals, the evasion of growth suppression and immune destruction, replicative immortality, inflammation, invasion, metastasis and angiogenesis, as well as genome instability, resisting cell death, and deregulation of cellular energetics. These information could eventually aid in identifying or developing new diagnostic, prognostic biomarkers, and may contribute to design more effective targeted therapeutics and treatment strategies. Although surgery, chemotherapy and radiotherapy can cure more than 90% of women with early stage cervical cancer, the recurrent and metastatic disease remains a major cause of cancer mortality. Numerous efforts have been made to design new drugs and develop gene therapies to treat cervical cancer. In recent years, research on treatment strategies has proposed several options, including the role of HPV E5, E6, and E7 oncogenes, which are retained and overexpressed in most of the cervical cancers and whose respective oncoproteins are critical to the induction and maintenance of the malignant phenotype. Other efforts have been focused on antitumor immunotherapy strategies. It is known that during the development of cervical cancer, a cascade of abnormal events is induced, including disruption of cell cycle control, perturbation of antitumor immune response, alteration of gene expression, deregulation of microRNA and cancer stem cell and stemness related markers expression could serve as novel molecular targets for reliable diagnosis and treatment of HPV-positive cancers. However, the search for new proposals for disease control and prevention has brought new findings and approaches in the context of molecular biology indicating innovations and perspectives in the early detection and prevention of the disease. Thus, in this article, we discuss molecular signaling pathways activated by HPV and potential targets or biomarkers for early detection or prevention and the treatment of HPV-associated cancers. PMID- 29706468 TI - [Assessing post-hospitalization therapeutic ranges in elderly patients treated for atrial fibrillation with vitamin k antagonists]. AB - BACKGROUND: In France, anticoagulants are among the most recommended treatments for serious accidents, particularly among the elderly. OBJECTIVES: The purpose of this study was to evaluate the impact of practical and validated tools designed to reduce the negative effects of vitamin K antagonist (VKA) treatments by assessing patients before and after the tools were implemented. METHODS: An exhaustive before and after multi-centric cohort study was performed in the Agen territory. The follow-up period corresponded to the six-month period post hospitalization. The principal criterion was the time in the therapeutic range (TTR) at values of 2 to 3 according to the Rosendaal method. RESULTS: The overall time spent in the follow-up period before and after the implementation of the tools in 65- and 74-year-old patients was 58% and 64%, respectively (P=0.584). After the treatments, the TTR in the 85- to 90-year-old patients was 71.1%. An increase was observed in the number of subjects with a TTR>=70% after the implementation of the tools according to age, particularly in the 85- to 90-year old patients (8 vs. 41; [P=0.01]). Prescription help software revealed a tendency of improvement in TTR values from 61% to 68% (P=0.472). In addition, longer therapeutic periods corresponded to longer patient lifespans (r=0.86). CONCLUSION: This study demonstrates the feasibility and advantages of implementing tools to improve the efficacy of VKA treatment in primary care, particularly for patients from 85 to 90 years old. The results should promote the implementation of this type of treatment method at the national level. PMID- 29706469 TI - What drives intentional overdose with non-prescription drugs? A cross-sectional study. AB - BACKGROUND: Use of overdosage of Non-Prescription Drugs (NPD) among university students is a serious public health issue. However, there are no extensive studies that measured the prevalence of taking more than the recommended dose of NPD and/or identified the risk associated with this behavior among university students. OBJECTIVES: This study was undertaken to assess the prevalence and associated risks of self-overdosage with NPDs in university students in United Arab Emirates (UAE). METHODS: A cross-sectional survey-based study was conducted from January to April 2014, among 2875 students in three randomly selected universities. A structured and validated questionnaire was used to collect the responses of the students. SPSS version 20 was used to analyze the data. RESULTS: Out of 2875 students, only 2355 surveys were fully answered, returned back and included in the present study. Of 2355, more than half (1348; 57.2%) the participants reported using Oral NPD (ONPD) in the past 90 days before conducting the study and were asked to complete the survey. Only 290 (22%) of a total 1348 participants reported taking more than the recommended dose of ONPD in the previous three months before conducting the study. Analgesic/antipyretic (223, 16.5%) and anti-allergic (67, 4.9%) drugs were more than other classes of the ONPD, reported to be taken in a dose, more than the recommended dosage. The most common justifications for taking more than the recommended dose of ONPD among respondents were severe symptoms (6%), the belief that the recommended dose would not be sufficient to relieve the symptom (5%), the belief that a stronger dose would relieve the symptoms faster (11%), and previous experience (4%). Our results identified three risk factors for taking more than the recommended dose of NPD. High frequently drug-users of daily use (OR=3.494, 95% CI: 1.677-7.279) (P<0.001), and students from non-medical colleges had higher odds of taking more than the recommended dosage as compared to students from medical colleges (OR=1.486, 95% CI: 1.060-2.085, P-value<0.05). Furthermore?re, participants with a poly-pharmacy behavior had higher odds of taking overdosage of ONPD than single NPD users (OR=1.918, 95% CI: 1.440-2.555) (P<0.001). CONCLUSION: There are a sizable proportion of university students that use overdosage of NPD, but it is more serious issue when it comes to non-medical student. There is a need for educational programs designed to increase awareness among all university students and to motivate them not to use overdosage of NPD. Further studies are also required to investigate additional explanatory variables that could influence the practice of overdosage with NPD. PMID- 29706470 TI - Impact of sex and glucose-lowering treatments on hypoglycaemic symptoms in people with type 2 diabetes and chronic kidney disease. The French Chronic Kidney Disease - Renal Epidemiology and Information Network (CKD-REIN) Study. AB - AIM: To describe current practices of glucose-lowering treatments in people with diabetes and chronic kidney disease (CKD), the associated glucose control and hypoglycaemic symptoms, with an emphasis on sex differences. METHODS: Among the 3033 patients with CKD stages 3-5 recruited into the French CKD-REIN study, 645 men and 288 women had type 2 diabetes and were treated by glucose-lowering drugs. RESULTS: Overall, 31% were treated only with insulin, 28% with combinations of insulin and another drug, 42% with non-insulin glucose-lowering drugs. In CKD stage 3, 40% of patients used metformin, 12% at stages 4&5, similar for men and women; in CKD stage 3, 53% used insulin, similar for men and women, but at stages 4&5, 59% of men and 77% of women used insulin. Patients were reasonably well controlled, with a median HbA1c of 7.1% (54mmol/mol) in men, 7.4% (57mmol/mol) in women (P=0.0003). Hypoglycaemic symptoms were reported by 40% of men and 59% of women; they were not associated with the estimated glomerular filtration rate, nor with albuminuria or with HbA1c in multivariable analyses, but they were more frequent in people treated with insulin, particularly with fast-acting and pre mixed insulins. CONCLUSION: Glucose-lowering treatment, HbA1c and hypoglycaemic symptoms were sex dependent. Metformin use was similar in men and women, but unexpectedly low in CKD stage 3; its use could be encouraged rather than resorting to insulin. Hypoglycaemic symptoms were frequent and need to be more closely monitored, with appropriate patient-education, especially in women. PMID- 29706471 TI - Subcutaneous advanced glycation end-products and lung function according to glucose abnormalities: The ILERVAS Project. PMID- 29706472 TI - May high salt intakes affect offspring sex ratio? PMID- 29706473 TI - Procedural and perioperative results in patients treated with fenestrated endovascular aneurysm repair planned by automated software in a physician sponsored investigational device exemption trial of physician-modified endografts. AB - OBJECTIVE: Fenestrated endovascular aneurysm repair (FEVAR) has been used successfully to treat patients with juxtarenal abdominal aortic aneurysms (JAAAs). Barriers to wide adoption of FEVAR include complexity in planning of fenestration locations on endografts. The purpose of this study was to validate the use of automated planning software to design fenestrated endografts and to treat patients with complex abdominal aortic aneurysms. METHODS: Patients with JAAA who were not candidates for open repair were enrolled into the automated planning arm of an ongoing investigational device exemption clinical trial and treated with FEVAR. Patient-specific fenestration size and location were determined by automated planning software using patient imaging data and algorithms that account for the interaction between the endograft delivery system and angulated aortic anatomy. Standard, off-the-shelf abdominal aortic aneurysm endografts from multiple manufacturers were modified on the back table by the physician according to the automated graft plan in the form of a patient-specific three-dimensional printed cylindrical template. Endografts typically included fenestrations for the superior mesenteric artery and both renal arteries. Procedural, perioperative, and long-term clinical and imaging data were collected per protocol. RESULTS: Thirty nonoperative JAAA candidate patients (American Society of Anesthesiologists class >=3) were consented and treated with fenestrated endografts planned by automated software. The mean age was 74 +/- 7 (61-86) years. The mean aneurysm diameter was 61.3 mm (range, 49-96 mm), and the mean infrarenal neck length was 6.1 mm (range, 2-15 mm). At the index procedure, 100% (30/30) of the patient-specific, surgeon-modified grafts were implanted with preservation of 97% (84/87) of branch vessels and a mean final proximal seal zone length of 41.9 mm (range, 27.3-60.6 mm). Three renal arteries were not cannulated during the index procedure because of complications not related to graft planning. The 30-day mortality rate in these high-risk JAAA patients was 6.7% (2/30), and both deaths were unrelated to the aneurysm. The 30-day major adverse event rate was 16.7% (5/30). There were no type IA or type III endoleaks, ruptures, or conversions to open surgery through 30 days. CONCLUSIONS: This automated FEVAR planning software accurately and efficiently identifies fenestration locations for vital branch arteries, thus simplifying the planning process and facilitating the FEVAR procedure. Validated automated FEVAR planning could help bring this beneficial therapy to most patients harboring JAAAs. PMID- 29706474 TI - A series of 240 odontogenic keratocysts: Should we continue to use the terminology of 'keratocystic odontogenic tumour' for the solid variant of odontogenic keratocyst? AB - Most of the odontogenic keratocysts show an indolent behaviour like non neoplastic lesions. For this reason, the odontogenic keratocyst was reclassified within the odontogenic cysts category in the WHO 2017 classification. Some odontogenic keratocysts may contain satellite cysts or solid squamoid islands within their wall. Recently, a solid form of odontogenic keratocyst has also been described which is composed entirely of multiple epithelial islands and small cysts in a collagenous stroma. The true nature of this variant is unclear yet. In this article, we present a series of 204 odontogenic keratocyst cases. Clinical and histologic findings of the cases in this series were described. These were also categorised according to the presence of satellite lesions. Additionally, the features of two cases of the solid form of odontogenic keratocysts were compared with those of the previous reports and other histologically similar odontogenic lesions. Current evidence suggests that this variant may be neoplastic and it differs from other odontogenic keratocysts, at least histologically. We believe diagnosing a solid lesion as a cyst is counterintuitive and the term "keratocystic odontogenic tumour" better describes this particular variant. PMID- 29706475 TI - Enantiospecific toxicity, distribution and bioaccumulation of chiral antidepressant venlafaxine and its metabolite in loach (Misgurnus anguillicaudatus) co-exposed to microplastic and the drugs. AB - In present study, we investigated the enantioselective behaviors of the chiral antidepressant venlafaxine and its metabolite O-desmethylvenlafaxine in loach Misgurnus anguillicaudatus (M. anguillicaudatus), as well as effects of microplastic on toxicity, distribution and metabolism through a 40-day co exposure. The contents of SOD and MDA in loach liver elevated when the loach was exposed to venlafaxine and O-desmethylvenlafaxine. Moreover, co-exposure with microplastic might lead to more adverse effect against loach. The distribution of venlafaxine and O-desmethylvenlafaxine were both detected in loach tissues and liver subcellular. The concentrations of venlafaxine and O-desmethylvenlafaxine were lower in water in microplastic-present treatment. Whilst, more contaminants were accumulated in liver through the "vehicle" (microplastic). Enantioselective behavior of venlafaxine and O-desmethylvenlafaxine occurred with R-enantiomers being preferentially degraded. With microplastic present, the bioaccumulation factor (BAF) of venlafaxine and O-desmethylvenlafaxine in loach tissue amplified more than 10 times. In liver subcellular structure, microplastic may help to transport more compounds into subtle areas and postpone the contaminants metabolism in organisms. The present study for the first time gained an insight into the potential ecological effects and environmental behaviors of combined pollutions of chiral pharmaceuticals and microplastic, which could supply important information for environment risk assessment of concurrent organic pollutants and microplastic. PMID- 29706476 TI - The evolving approach to the evaluation of low-gradient aortic stenosis. AB - Severe aortic stenosis (AS) is typically identified by a low valve area (<=1.0 cm2) and high mean gradient (>=40 mm Hg). A subset of patients are found to have a less than severe mean gradient (<40 mm Hg) despite a low valve area. These latter types can present as either low ejection fraction with low-gradient AS (stage D2) or normal ejection fraction with low-gradient AS (stage D3). Determining the true severity of disease within these categories has proved difficult. In this review we illustrate both traditional and novel techniques that can be used for further valvular assessment. We also propose a simple algorithm that can be used to evaluate low-gradient AS. PMID- 29706477 TI - Usefulness of the Finet law to guide stent size selection in ostial left main stenting: Comparison with standard angiographic estimation. AB - BACKGROUNDS: Intravascular ultrasound has been suggested to optimize stent diameter and length in Left Main (LM) procedures, but in the real-world ostial LM stenting is often accomplished with angiography only guidance. The Finet law which regulates the fractal geometry of human bifurcation has the potential to increase the accuracy of stent-sizing. To retrospectively evaluating the impact on outcomes of the addition of Finet Law to standard quantitative coronary angiography (QCA) in guiding stent selection of ostial LM stenting compared to standard angiography estimation. METHODS: We retrospectively evaluated the clinical and instrumental records of patients with isolated ostial LM disease and bypass surgery contraindications or refusal as determined by the local Heart Team who received stenting from 1 January 2012 to 1 January 2017 at Rovigo General Hospital. Patients were discrimined on the basis of the addition to QCA angiographic evaluation of the Finet-law. RESULTS: Seventy-three patients (45 males, mean age 69.9 +/- 10.9 years old) ostial LM stenting, 36 patients using QCA and Finet law (QCA-Finet) and 37 using standard QCA angiographic (QCA-angio) evaluation of the vessel diameter. By QCA, vessel size, mean stent diameter at implantation and after post-dilatation were clearly bigger in the QCA+ Finet than QCA-angio (4.4 +/- 0.8 and 3.8 +/- 0.7, p < 0.001). At a mean follow-up of 5.0 +/ 0.4 years, cardiovascular mortality and cardiovascular events incidence were higher in QCA-angio compared to QCA+Finet group of patients. CONCLUSIONS: Our study suggested that adding the Finet law to standard angiography estimation of the LM stent size may improve long-term outcomes. PMID- 29706478 TI - Impact of a multiplex PCR point-of-care test for influenza A/B and respiratory syncytial virus on an acute pediatric hospital ward. AB - Patients with respiratory infections are often managed presumptively until confirmation of infection status. We assessed the impact of introducing the Enigma(r) MiniLabTM FluAB-RSV point-of-care test (POCT) on patients admitted with a suspected respiratory virus driven illness in an acute pediatric ward. This utilized a before and after design (respiratory viral seasons 2013/14 versus 2014/15). Following POCT implementation, oseltamivir prescribing increased in patients with influenza (OR = 12.7, P = 0.05, 95% CI [1.0, 153.8]). A reduction in the average reimbursement charges without a change in the length of stay was observed. Modeling suggested that laboratory test cost savings could be achieved if the POCT cost L30 and was used for screening, followed by the respiratory viral panel for RSV and influenza negative patients. A rapid POCT for influenza A/B and RSV infections in pediatric inpatients may improve oseltamivir prescribing, strengthen antimicrobial stewardship, reduce reimbursement charges and decrease laboratory costs. PMID- 29706479 TI - Scrub typhus diagnosis on acute specimens using serological and molecular assays a 3-year prospective study. AB - Scrub typhus (ST) is an underdiagnosed acute febrile illness in the Asia Pacific region with recent reemergence. Clinical diagnosis is difficult, and laboratory confirmation is largely based on serological and molecular tests. However, Weil Felix test still remains the only test available in much of the rural tropics where a disproportionate number of cases occur. Sensitive and affordable assays are important for broader use and accurate diagnosis. We evaluated the diagnostic capabilities of serological and molecular assays on single acute clinical samples. Out of 1036 cases, 319 were confirmed as ST, and the sensitivities of immunofluorescent assay (IFA), IgM enzyme-linked immunosorbent assay (ELISA), nested polymerase chain reaction (n-PCR) and WFT were 93.4%, 80.3%, 75.2%, and 54.2%, respectively. IgM ELISA + n-PCR combination demonstrated highest degree of agreement (kappa = .911) in the absence of IFA. Additionally, 16 cases were detected by n-PCR only. Our study emphasizes the diagnostic challenges in the developing world, importance of molecular tests, and best alternate assays in ST diagnosis. PMID- 29706480 TI - Recovery of value-added products from cathode and anode material of spent lithium ion batteries. AB - Herein we report a low cost and eco-friendly approach for the recovery of metals from cathode and anode materials of mobile phone spent lithium-ion batteries (LIBs). Li-based metal oxide and graphite were efficiently separated from their respective foils and used for lixiviation. Acetic acid (CH3COOH) and water were used as lixiviants for the recovery of metals from cathode and anode materials respectively. It was found that with 3 M Acetic acid and 7.5 vol% H2O2 as reducing agent 99.9% Li, 98.7% Co, and 99.5% Mn were leached out from cathode material in 40 min at 70 degrees C and a pulp density of 20 g/L. Besides the cathode leaching, Li was also extracted from anodic material graphite using water as a solvent and further recovered as solid Li2CO3 (99.7% Li). The kinetic evaluation of the cathode lixiviate process was studied using three different shrinking-core kinetic Models and established that the reaction follows the product layer diffusion controlled mechanism. From the cathode leach liquor, 99% Co was recovered as metal sulfide by controlled sulfide precipitation with 99.2% purity, and subsequently, MnCO3 and Li2CO3 were obtained with the purity of 98.7% and 99.4%, respectively. The purity of the salts revealed that these products recovered from spent LIBs might be utilized in the electrochemical energy-storage applications. In addition, this recycling process would promote the sustainable development of the battery industry. PMID- 29706481 TI - Estimating solid waste generation by hospitality industry during major festivals: A quantification model based on multiple regression. AB - Major-religious festivals hosted in the city of Kerbala, Iraq, annually generate large quantities of Municipal Solid Waste (MSW) which negatively impacts the environment and human health when poorly managed. The hospitality sector, specifically hotels, is one of the major sources of MSW generated during these festivals. Because it is essential to establish a proper waste management system for such festivals, accurate information regarding MSW generation is required. This study therefore investigated the rate of production of MSW from hotels in Kerbala during major festivals. A field questionnaire survey was conducted with 150 hotels during the Arba'een festival, one of the largest festivals in the world, attended by about 18 million participants, to identify how much MSW is produced and what features of hotels impact on this. Hotel managers responded to questions regarding features of the hotel such as size (Hs), expenditure (Hex), area (Ha) and number of staff (Hst). An on-site audit was also carried out with all participating hotels to estimate the mass of MSW generated from these hotels. The results indicate that MSW produced by hotels varies widely. In general, it was found that each hotel guest produces an estimated 0.89 kg of MSW per day. However, this figure varies according to the hotels' rating. Average rates of MSW production from one and four star hotels were 0.83 and 1.22 kg per guest per day, respectively. Statistically, it was found that the relationship between MSW production and hotel features can be modelled with an R2 of 0.799, where the influence of hotel feature on MSW production followed the order Hs > Hex > Hst. PMID- 29706483 TI - Introduction to the Oral and Maxillofacial Pathology focus issue on "Preneoplastic oral epithelial lesions". PMID- 29706482 TI - Pain in pancreatic ductal adenocarcinoma: A multidisciplinary, International guideline for optimized management. AB - Abdominal pain is an important symptom in most patients with pancreatic ductal adenocarcinoma (PDAC). Adequate control of pain is often unsatisfactory due to limited treatment options and significant variation in local practice, emphasizing the need for a multidisciplinary approach. This review contends that improvement in the management of PDAC pain will result from a synthesis of best practice and evidence around the world in a multidisciplinary way. To improve clinical utility and evaluation, the evidence was rated according to the GRADE guidelines by a group of international experts. An algorithm is presented, which brings together all currently available treatment options. Pain is best treated early on with analgesics with most patients requiring opioids, but neurolytic procedures are often required later in the disease course. Celiac plexus neurolysis offers medium term relief in a substantial number of patients, but other procedures such as splanchnicectomy are also available. Palliative chemotherapy also provides pain relief as a collateral benefit. It is stressed that the assessment of pain must take into account the broader context of other physical and psychological symptoms. Adjunctive treatments for pain, depression and anxiety as well as radiotherapy, endoscopic therapy and neuromodulation may be required in selected patients. There are few comparative studies to help define which combination and order of these treatment options should be applied. New pain therapies are emerging and could for example target neural transmitters. However, until better methods are available, management of pain should be individualized in a multidisciplinary setting to ensure optimal care. PMID- 29706484 TI - Air conditioning analysis among human nasal passages with anterior anatomical variations. AB - A major functional role of the nasal cavity is air conditioning of the inspired environmental air to near alveolar conditions. It is well known that the anatomical disparities among nasal passages can change airflow patterns to a great extent. However, its effect on nasal air conditioning performance remains largely unexplored. This research investigated the nasal air conditioning performance among nasal models with distinct vestibule phenotypes, including subjects with and without vestibule notches. For the mass transfer, we used a two film theory model to determine the species transport. Airflow patterns, heat and mass transfer between the inhaled airflow and the nasal mucosa were analysed and compared. Results showed that the nasal air conditioning performance is closely related to nasal passage structures. The anatomical variations, especially the geometry changes in the anterior vestibule region, can increase both heat and mass transfer rate between nasal mucous and respiratory air at the vicinity of the notched regions, while for other regions such as the anterior superior nasal cavity, the heat transfer is greatly reduced to even zero heat flux due to lack of active airflow passing. PMID- 29706485 TI - Advances in the Molecular Pathophysiology, Genetics, and Treatment of Primary Ovarian Insufficiency. AB - Primary ovarian insufficiency (POI) affects ~1% of women before 40 years of age. The recent leap in genetic knowledge obtained by next generation sequencing (NGS) together with animal models has further elucidated its molecular pathogenesis, identifying novel genes/pathways. Mutations of >60 genes emphasize high genetic heterogeneity. Genome-wide association studies have revealed a shared genetic background between POI and reproductive aging. NGS will provide a genetic diagnosis leading to genetic/therapeutic counseling: first, defects in meiosis or DNA repair genes may predispose to tumors; and second, specific gene defects may predict the risk of rapid loss of a persistent ovarian reserve, an important determinant in fertility preservation. Indeed, a recent innovative treatment of POI by in vitro activation of dormant follicles proved to be successful. PMID- 29706486 TI - Time to repeal and replace response criteria for acute myeloid leukemia? AB - The International Working Group (IWG) response criteria for acute myeloid leukemia, published in 2003, have remained the standard by which the efficacy of new drugs is measured in clinical trials. Over the last decade, concepts related to treatment response have been challenged by several factors; for example, the dissociation between early clinical response and survival outcome in older patients, the recognition that epigenetic and newer differentiating-agent therapies may produce delayed responses and also hematologic improvement/transfusion independence without a morphologic response, and evidence that remissions without minimal (or measurable) residual disease (MRD) may result in outcomes superior to those of morphologic remissions with persistent MRD. The evolving role of MRD status as a potential surrogate for predicting long-term survival has enhanced the clinical need to standardize and incorporate emerging technologies that enable deeper responses beyond those recognized by the IWG, and to pre-emptively identify patients at risk of early relapse. The potential for therapeutic interventions to erase MRD and alter the natural history represents an important and open research question. Reviewed here are some of the implications and challenges associated with establishing and incorporating new treatment response criteria, initially into clinical research, and eventually into real-world practice. PMID- 29706487 TI - Acetylcholinesterase inhibitors and risk of stroke and death in people with dementia. AB - INTRODUCTION: The aim of this study was to investigate the association between acetylcholinesterase inhibitor (AChEI) use and risk of ischemic stroke and death in people with dementia. METHODS: A cohort study of 44,288 people with dementia registered in the Swedish Dementia Registry from 2007 to 2014. Propensity score matched competing risk regression models were used to compute hazard ratios and 95% confidence intervals for the association between time-dependent AChEI use and risk of stroke and death. RESULTS: Compared with matched controls, AChEI users had a lower risk of stroke (hazard ratio: 0.85, 95% confidence interval: 0.75 0.95) and all-cause death (hazard ratio: 0.76, 95% confidence interval: 0.72 0.80). After considering competing risk of death, high doses (>=1.33 defined daily doses) of AChEI remained significantly associated with reduced stroke risk. DISCUSSION: The use of AChEIs in people with dementia may be associated with reduced risk of ischemic stroke and death. These results call for a closer examination of the cardiovascular effects of AChEIs. PMID- 29706488 TI - Corrigendum to "Phylogenetic analysis of a newfound bat-borne hantavirus supports a Laurasiatherian host association for ancestral mammalian hantaviruses" [Infect. Genet. Evol. 41 (2016) 113-119]. PMID- 29706490 TI - Immediate Superficial Venous Thrombophlebitis Associated with Intravenous Administration of Ciprofloxacin. PMID- 29706489 TI - Evaluation of FODMAP Carbohydrates Content in Selected Foods in the United States. AB - We analyzed the fermentable oligosaccharide, disaccharide, monosaccharide, and polyols (FODMAP) content of several foods potentially low in FODMAP which are commonly consumed by children. We determined that several processed foods (eg, gluten-free baked products) had unlabeled FODMAP content. Determining FODMAP content within foods distributed in the US may support educational and dietary interventions. PMID- 29706491 TI - Risk Factors, Geographic Distribution, and Healthcare Burden of Symptomatic Congenital Cytomegalovirus Infection in the United States: Analysis of a Nationally Representative Database, 2000-2012. AB - OBJECTIVE: To assess risk factors, geographic distribution, length of stay, and total charges per case of symptomatic congenital cytomegalovirus infection (cCMV). STUDY DESIGN: We performed retrospective analyses of serial cross sectional data using the Kids' Inpatient Database, a nationally representative sample of US pediatric hospital discharges, from 2000, 2003, 2006, 2009, and 2012. Symptomatic cCMV was identified via use of the International Classification of Diseases, Ninth Revision, Clinical Modification code 771.1 among records with in-hospital birth that were accompanied by 1 or more characteristic symptoms. Demographic characteristics were compared with multivariable logistic regression. Temporal trend was assessed using linear regression. Charges were adjusted for inflation to 2012 US dollars. RESULTS: We identified 1349 cases of symptomatic cCMV (SE 56). Symptomatic cCMV was associated with non-Hispanic black race (OR 1.70; 95% CI 1.37-2.10), government-sponsored insurance (OR 1.95; 95% CI 1.34 2.83), and birth in the American South and West (OR 1.68, 95% CI 1.35-2.09 and OR 1.61, 95% CI 1.23-2.09, respectively). In-hospital mortality and preterm birth rate ranged from 3.2%-6.8% and 50.4%-59.2%, respectively, without temporal changes. The geometric mean of total charges per case doubled from $45 771 (SE $8509) in 2000 to $89 846 (SE $10 358) in 2006 (P = .002) but did not change from 2006 to 2012. Length of stay in days was 15 (IQR 8-22) in 2000, 27 (IQR, 9-51) in 2009, and 18 (IQR, 8-47) in 2012. CONCLUSIONS: Symptomatic cCMV was associated with non-Hispanic black race, low socioeconomic status, and birth in the American South and West and resulted in substantial healthcare burden. PMID- 29706492 TI - Chronic School Absenteeism of Children with Chronic Kidney Disease. AB - We evaluated the frequency of chronic school absenteeism (>=18 missed school days per year) among children with mild-to-moderate chronic kidney disease. Chronic absenteeism was present in 17.3% of children with chronic kidney disease, compared with 2.7% of children in the US National Health and Nutrition Examination Survey. PMID- 29706493 TI - Intravenous Fish Oil Lipid Emulsion Prevents Catheter-Related Thromboses in Pediatric Patients with Intestinal Failure. AB - A central venous catheter is a risk factor for deep vein thrombosis. We compared the incidence of deep vein thrombosis in children with intestinal failure patients receiving soy oil lipid emulsion (n = 35) vs fish oil lipid emulsion (n = 35). Ten deep vein thrombosis occurred in the soy oil lipid emulsion group, and none in the fish oil lipid emulsion group (P < .001). PMID- 29706494 TI - Is There a Role for Genes in Exercise-Induced Atrial Cardiomyopathy? AB - In endurance athletes, prolonged high intensity exercise participation can have deleterious effects on the myocardium with subsequent structural and electrical remodelling. In a subset of athletes, there is a predilection for atrial involvement and the risk of atrial fibrillation (AF) is increased. The mechanisms underpinning exercise-induced atrial cardiomyopathy have yet to be fully elucidated and the contribution of an individual's genetic makeup is unknown. Some athletes may have rare genetic variants that are sufficient to cause AF irrespective of exercise exposure. In AF-causing variant carriers, the additional haemodynamic stress of exercise on atrial structure and function might accelerate or increase the severity of disease. Variants in genes that lack known links to AF may indirectly promote an arrhythmogenic substrate by affecting threshold levels for exercise-induced myocardial damage and remodelling responses, or by effects on AF-associated co-morbidities, sinus node function, and autonomic nervous system tone. Given the exquisite stress-sensitivity of the atria, mechanosensitive ion channels could plausibly have a key role in mediating exercise effects on atrial structure and function. Knowing an athlete's profile of genetic variants may be useful for AF risk stratification and have implications for clinical management. Pre-participation genetic testing may influence sports choices and facilitate AF prevention. PMID- 29706495 TI - Effect of Red Blood Cell Storage Duration on Outcome After Paediatric Cardiac Surgery: A Prospective Observational Study. AB - BACKGROUND: Retrospective reviews have found the use of stored packed red blood cells (PRBCs) in priming to be associated with increased risk of postoperative complications. The purpose of study was to prospectively investigate the influence of duration of storage of PRBCs used in priming the cardiopulmonary bypass (CPB) circuit on the metabolic profile of the patients, and postoperative outcome after paediatric cardiac surgery. METHODS: Between January 2015 and December 2015, 198 consecutive children operated for cardiac surgery using CPB and received blood for priming the circuit were included. Patients were divided into two groups based on the duration of storage of the blood, newer PRBCs group who received blood stored for <=14days and the older PRBCs group who received blood stored for >14 days. RESULTS: Mean duration of blood storage used for priming in newer PRBCs blood group (n=103) was 8.4+/-3.7days while it was 21.9+/ 4.5days in older PRBCs group (n=95). Metabolic parameters of the PRBCs improved to physiological limits in both the groups after initiation of CPB. Postoperative hepatic, pulmonary, haematological complications, sepsis and multi-organ failure were more in the old PRBCs group. However, the difference was not significant. Similarly, there was no significant difference in incidence of prolonged mechanical ventilation, intensive care unit stay and hospital stay and mortality between the two groups. CONCLUSIONS: Metabolic parameters of the stored blood become normal after initiation of CPB irrespective of duration of storage. In paediatric patients without significant co-morbidity, undergoing cardiac surgery, transfusion of washed stored blood up to 28days in CPB priming is safe especially if lesser amount of transfusion is required. PMID- 29706496 TI - Long-term weight loss outcomes after banded Roux-en-Y gastric bypass: a prospective 10-year follow-up study. AB - OBJECTIVE: To evaluate the weight loss outcomes of banded Roux-en-Y gastric bypass (RYGB) during a 10-year follow-up. SETTING: Private health-providing service, Brazil. METHODS: A prospective study was conducted on 928 patients with obesity who underwent banded RYGB. Patients were divided into 2 groups according to their initial body mass index (BMI), morbid obesity (BMI 35-49.9 kg/m2) and super obesity (BMI >=50 kg/m2). The percentages of excess weight loss (%EWL) and total weight loss (%TWL) at 18, 24, 36, 48, 60, 72, 84, 96, 108, and 120 months after surgery were assessed and compared, and the rates of surgical failure were also assessed. RESULTS: There were individuals who were lost to follow-up at each year, including 423 (45.6%) at 18 months, 431 (46.4%) at 24 months, 482 (51.9%) at 36 months, 568 (61.2%) at 48 months, 658 (70.9%) at 60 months, 725 (78.1%) at 72 months, 781 (84.2%) at 84 months, 819 (88.3%) at 96 months, 838 (90.3%) at 108 months, and 819 (88.3%) at 120 months. The maximal %EWL was achieved at 18 months (P<.001). After 10 years, there was no significant change in mean BMI (28.7 +/- 4.1 versus 28.5 +/- 3.6 kg/m2; P = .07) or %EWL (80.4 +/- 19.1 versus 79.7 +/- 23.4; P = .065), but the mean %TWL was significantly lower at 10 years (30.8 +/- 8.5 versus 32.5 +/- 8.1; P = .035) in the morbid obesity group, compared with the values observed over 5 years. In the super obesity group, the %EWL significantly decreased from 77.7 +/- 16.5 kg/m2 at 24 months to 71.3 +/- 18.1 kg/m2 at 72 months (P = .008); at 5 years, mean BMI (33.1 +/- 5.8 kg/m2) did not differ from the one observed at 10 years (36.4 +/- 5 kg/m2; P = .21), as well as the mean %TWL (40.1 +/- 8.5 versus 34.8 +/- 8.9; P = .334). CONCLUSION: Banded RYGB leads to significant and sustained weight loss in a 10-year follow-up. Despite a slight late weight regain evaluated by %TWL, RYGB leads to an optimal weight loss in the majority of the individuals. PMID- 29706497 TI - Effects of gastric bypass followed by a randomized study of physical training on markers of coagulation activation, fibrin clot properties, and fibrinolysis. AB - BACKGROUND: The risk of cardiovascular disease is reduced by bariatric surgery, but it is unknown if exercise after bariatric surgery reduces this risk even further. OBJECTIVE: To investigate if Roux-en-Y-gastric bypass (RYGB) and supervised physical training after RYGB improve cardiovascular disease risk markers within coagulation activation, fibrin clot properties, and fibrinolysis. SETTING: Bariatric center, Hospital of Southwest Jutland, Denmark. METHODS: Sixty obese patients underwent RYGB and 6 months after RYGB were randomized to 26 weeks of physical training or a control group. Biomarkers within coagulation activation, fibrin clot properties, and fibrinolysis were measured presurgery, and 6, 12, and 24 months postsurgery. RESULTS: Six months after RYGB, the endogenous thrombin potential decreased from 1744 (1603-2003) to 1416 (1276-1582) nM * min (P<.001). Alterations in fibrin clot properties resulted in an increased clot lysis from 23.8% (16.1%-38.9%) to 40.3% (28.5%-59.35; P<.0001). Furthermore, fibrinogen was reduced from 12.6 (11.1-14.7) to 11.5 (9.90-13.3) uM (P<.001), and plasminogen activator inhibitor antigen was reduced from 40.5 (28.4-49.4) to 24.4 (15.4-32.7) ng/mL (P<.0001). Physical training after RYGB increased fibrinolytic activity from 58.0 (36.0-75.5) to 88.0 (66.0-132.0) IU/mL compared with 52.5 (30.0-80.0) to 64.0 (49.0-100.0) IU/mL in controls (P<.01) and reduced plasminogen activator inhibitor antigen from 23.5 (16.7-35.4) to 18.1 (14.3-25.4) ng/mL compared with 24.4 (13.9-28.7) to 24.2 (14.1-29.6) ng/mL in controls (P<.05). No effects of physical training were observed on markers of coagulation activation and fibrin clot properties. CONCLUSION: We observed favorable long term reductions in markers of thrombin generation, improved fibrin clot properties, and increases in fibrinolysis after RYGB. Supervised physical training after RYGB further increased fibrinolysis. PMID- 29706498 TI - The STAT3 Target Mettl8 Regulates Mouse ESC Differentiation via Inhibiting the JNK Pathway. AB - The capacity of embryonic stem cells (ESCs) to differentiate into all lineages of mature organism is precisely regulated by cellular signaling factors. STAT3 is a crucial transcription factor that plays a central role in maintaining ESC identity. However, the underlying mechanism by which STAT3 directs differentiation is still not completely understood. Here, we show that STAT3 positively regulates gene expression of methyltransferase-like protein 8 (Mettl8) in mouse ESCs. We found that METTL8 is dispensable for pluripotency but affects ESC differentiation. Subsequently, we discovered that METTL8 interacts with Mapkbp1's mRNA, which is an intermediate factor in c-Jun N-terminal kinase (JNK) signaling, and inhibits the translation of the mRNA. Thereby, METTL8 prohibits the activation of JNK signaling and enhances the differentiation of mouse ESCs. Collectively, our study uncovers a STAT3 target, Mettl8, which regulates mouse ESC differentiation via JNK signaling. PMID- 29706499 TI - INK4a/ARF Expression Impairs Neurogenesis in the Brain of Irradiated Mice. AB - Brain neurogenesis is severely impaired following exposure to ionizing radiation (IR). We and others have shown that the expression of the tumor suppressor gene p16INK4a is increased in tissues exposed to IR and thus hypothesized that its expression could limit neurogenesis in the irradiated brain. Here, we found that exposure to IR leads to persistent DNA damage and the expression of p16INK4a in the hippocampus and subventricular zone regions. This was accompanied by a decline in neurogenesis, as determined by doublecortin expression and bromodeoxyuridine incorporation, an effect partially restored in Ink4a/arf-null mice. Increased neurogenesis in the absence of INK4a/ARF expression was independent of apoptosis and activation of the microglia. Moreover, treatment of irradiated mice with a superoxide dismutase mimetic or clearance of p16INK4a expressing cells using mouse genetics failed to increase neurogenesis. In conclusion, our results suggest that IR-induced p16INK4a expression is a mechanism that limits neurogenesis. PMID- 29706500 TI - Thyroid Hormone Transporters MCT8 and OATP1C1 Control Skeletal Muscle Regeneration. AB - Thyroid hormone (TH) transporters are required for the transmembrane passage of TH in target cells. In humans, inactivating mutations in the TH transporter MCT8 cause the Allan-Herndon-Dudley syndrome, characterized by severe neuromuscular symptoms and an abnormal TH serum profile, which is fully replicated in Mct8 knockout mice and Mct8/Oatp1c1 double-knockout (M/O DKO) mice. Analysis of tissue TH content and expression of TH-regulated genes indicate a thyrotoxic state in Mct8-deficient skeletal muscles. Both TH transporters are upregulated in activated satellite cells (SCs). In M/O DKO mice, we observed a strongly reduced number of differentiated SCs, suggesting an impaired stem cell function. Moreover, M/O DKO mice and mice lacking both transporters exclusively in SCs showed impaired skeletal muscle regeneration. Our data provide solid evidence for a unique gate-keeper function of MCT8 and OATP1C1 in SC activation, underscoring the importance of a finely tuned TH signaling during myogenesis. PMID- 29706501 TI - Inducible Expression of GDNF in Transplanted iPSC-Derived Neural Progenitor Cells. AB - Trophic factor delivery to the brain using stem cell-derived neural progenitors is a powerful way to bypass the blood-brain barrier. Protection of diseased neurons using this technology is a promising therapy for neurodegenerative diseases. Glial cell line-derived neurotrophic factor (GDNF) has provided benefits to Parkinsonian patients and is being used in a clinical trial for amyotrophic lateral sclerosis. However, chronic trophic factor delivery prohibits dose adjustment or cessation if side effects develop. To address this, we engineered a doxycycline-regulated vector, allowing inducible and reversible expression of a therapeutic molecule. Human induced pluripotent stem cell (iPSC) derived neural progenitors were stably transfected with the vector and transplanted into the adult mouse brain. Doxycycline can penetrate the graft, with addition and withdrawal providing inducible and reversible GDNF expression in vivo, over multiple cycles. Our findings provide proof of concept for combining gene and stem cell therapy for effective modulation of ectopic protein expression in transplanted cells. PMID- 29706502 TI - Unraveling the Inconsistencies of Cardiac Differentiation Efficiency Induced by the GSK3beta Inhibitor CHIR99021 in Human Pluripotent Stem Cells. AB - Cardiac differentiation efficiency is hampered by inconsistencies and low reproducibility. We analyzed the differentiation process of multiple human pluripotent stem cell (hPSC) lines in response to dynamic GSK3beta inhibition under varying cell culture conditions. hPSCs showed strong differences in cell cycle profiles with varying culture confluency. hPSCs with a higher percentage of cells in the G1 phase of the cell cycle exhibited cell death and required lower doses of GSK3beta inhibitors to induce cardiac differentiation. GSK3beta inhibition initiated cell-cycle progression via cyclin D1 and modulated both Wnt signaling and the transcription factor (TCF) levels, resulting in accelerated or delayed mesoderm differentiation. The TCF levels were key regulators during hPSC differentiation with CHIR99021. Our results explain how differences in hPSC lines and culture conditions impact cell death and cardiac differentiation. By analyzing the cell cycle, we were able to select for highly cardiogenic hPSC lines and increase the experimental reproducibility by predicting differentiation outcomes. PMID- 29706503 TI - Nomogram to Assess the Survival Benefit of New Salvage Agents for Metastatic Urothelial Carcinoma in the Era of Immunotherapy. AB - INTRODUCTION: Optimal end points in phase 2 trials evaluating salvage therapy for metastatic urothelial carcinoma are necessary to identify promising drugs, particularly immunotherapeutics, where response and progression-free survival may be unreliable. We developed a nomogram using data from phase 2 trials of historical agents to estimate the 12-month overall survival (OS) for patients to which observed survival of nonrandomized data sets receiving immunotherapies could be compared. PATIENTS AND METHODS: Survival and data for major prognostic factors were obtained from phase 2 trials: hemoglobin, performance status, liver metastasis, treatment-free interval, and albumin. A nomogram was developed to estimate 12-month OS. Patients were randomly allotted to discovery:validation data sets in a 2:1 ratio. Calibration plots were constructed in the validation data set and data bootstrapped to assess performance. The nomogram was tested on external nonrandomized cohorts of patients receiving pemetrexed and atezolizumab. RESULTS: Data were available from 340 patients receiving sunitinib, everolimus, docetaxel + vandetanib, docetaxel + placebo, pazopanib, paclitaxel, or docetaxel. Calibration and prognostic ability were acceptable (c index = 0.634; 95% confidence interval [CI], 0.596-0.652). Observed 12-month survival for patients receiving pemetrexed (n = 127, 23.5%; 95% CI, 16.2-31.7) was similar to nomogram predicted survival (19%; 95% CI, 16.5-21.5; P > .05), while observed results with atezolizumab (n = 403, 39.0%; 95% CI, 34.1-43.9) exceeded predicted results (24.6%; 95% CI, 23.4-25.8; P < .001). CONCLUSION: This nomogram may be a useful tool to interpret results of nonrandomized phase 2 trials of salvage therapy for metastatic urothelial carcinoma by assessing the OS contributions of drug intervention independent of prognostic variables. PMID- 29706504 TI - Combined Human Genome-wide RNAi and Metabolite Analyses Identify IMPDH as a Host Directed Target against Chlamydia Infection. AB - Chlamydia trachomatis (Ctr) accounts for >130 million human infections annually. Since chronic Ctr infections are extremely difficult to treat, there is an urgent need for more effective therapeutics. As an obligate intracellular bacterium, Ctr strictly depends on the functional contribution of the host cell. Here, we combined a human genome-wide RNA interference screen with metabolic profiling to obtain detailed understanding of changes in the infected cell and identify druggable pathways essential for Ctr growth. We demonstrate that Ctr shifts the host metabolism toward aerobic glycolysis, consistent with increased biomass requirement. We identify key regulator complexes of glucose and nucleotide metabolism that govern Ctr infection processes. Pharmacological targeting of inosine-5'-monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in guanine nucleotide biosynthesis, efficiently inhibits Ctr growth both in vitro and in vivo. These results highlight the potency of genome-scale functional screening for the discovery of drug targets against bacterial infections. PMID- 29706506 TI - Investigating pneumonia-a neglected tragedy. PMID- 29706507 TI - Does free choice of hospital conflict with equity of access to highly specialized hospitals? A case study from the Danish health care system. AB - Equity of access to health care is a central objective of European health care systems. In this study, we examined whether free choice of hospital, which has been introduced in many systems to strengthen user rights and improve hospital competition, conflicts with equity of access to highly specialized hospitals. We chose to carry out a study on 134,049 women who had uncomplicated pregnancies from 2005 to 2014 in Denmark because of their homogeneity in terms of need, the availability of behavioral data, and their expected engagement in choice of hospital. Multivariate logistic regression was used to link the dependent variable of bypassing the nearest non-highly specialized public hospital in order to "up-specialize", with independent variables related to socioeconomic status, risk attitude, and choice premises, using administrative registries. Overall, 16,426 (12%) women were observed to bypass the nearest hospital to up-specialize. Notably, high education level was significantly associated with up specialization, with an odds ratio of 1.50 (95% CI: 1.40-1.60, p < 0.001) compared to low education group. This confirms our hypothesis that there is a socioeconomic gradient in terms of exercising the right to a free choice of hospital, and so the results indicate that the policy exacerbates inequity of access to health care. PMID- 29706505 TI - Host Nitric Oxide Disrupts Microbial Cell-to-Cell Communication to Inhibit Staphylococcal Virulence. AB - Staphylococcus aureus is a commensal bacterium that can asymptomatically colonize its host but also causes invasive infections. Quorum sensing regulates S. aureus virulence and the transition from a commensal to a pathogenic organism. However, little is known about how host innate immunity affects interbacterial communication. We show that nitric oxide suppresses staphylococcal virulence by targeting the Agr quorum sensing system. Nitric oxide-mediated inhibition occurs through direct modification of cysteine residues C55, C123, and C199 of the AgrA transcription factor. Cysteine modification decreases AgrA promoter occupancy as well as transcription of the agr operon and quorum sensing-activated toxin genes. In a staphylococcal pneumonia model, mice lacking inducible nitric oxide synthase develop more severe disease with heightened mortality and proinflammatory cytokine responses. In addition, staphylococcal alpha-toxin production increases in the absence of nitric oxide or nitric oxide-sensitive AgrA cysteine residues. Our findings demonstrate an anti-virulence mechanism for nitric oxide in innate immunity. PMID- 29706509 TI - Percutaneous Coronary Intervention of Chronic Total Occlusions: Conquering the Final Frontier. PMID- 29706508 TI - The Hybrid Approach to Chronic Total Occlusion Percutaneous Coronary Intervention: Update From the PROGRESS CTO Registry. AB - OBJECTIVES: The aim of this study was to determine the techniques and outcomes of hybrid chronic total occlusion (CTO) percutaneous coronary intervention (PCI) in a diverse group of patients and operators on 2 continents. BACKGROUND: CTO PCI has been evolving with constant improvement of equipment and techniques. METHODS: Contemporary outcomes of CTO PCI were examined by analyzing the clinical, angiographic, and procedural characteristics of 3,122 CTO interventions performed in 3,055 patients at 20 centers in the United States, Europe, and Russia. RESULTS: The mean age was 65 +/- 10 years, and 85% of the patients were men, with high prevalence of diabetes (43%), prior myocardial infarction (46%), prior coronary artery bypass graft surgery (33%), and prior PCI (65%). The CTO target vessels were the right coronary artery (55%), left anterior descending coronary artery (24%), and left circumflex coronary artery (20%). The mean J-CTO (Multicenter Chronic Total Occlusion Registry of Japan) and PROGRESS CTO (Prospective Global Registry for the Study of Chronic Total Occlusion Intervention) scores were 2.4 +/- 1.3 and 1.3 +/- 1.0, respectively. The overall technical and procedural success rate was 87% and 85%, respectively, and the rate of in-hospital major complications was 3.0%. The final successful crossing strategy was antegrade wire escalation in 52.0%, retrograde in 27.1%, and antegrade dissection re-entry in 20.9%; >1 crossing strategy was required in 40.9%. Median contrast volume, air kerma radiation dose, and procedure and fluoroscopy time were 270 ml (interquartile range: 200 to 360 ml), 2.9 Gy (interquartile range: 1.7 to 4.7 Gy), 123 min (interquartile range: 81 to 188 min) and 47 min (interquartile range: 29 to 77 min), respectively. CONCLUSIONS: CTO PCI is currently being performed with high success and acceptable complication rates among various experienced centers in the United States, Europe, and Russia. (Prospective Global Registry for the Study of Chronic Total Occlusion Intervention [PROGRESS CTO]; NCT02061436). PMID- 29706510 TI - Coin Tossing Explains the Activity of Opposing Microtubule Motors on Phagosomes. AB - How the opposing activity of kinesin and dynein motors generates polarized distribution of organelles inside cells is poorly understood and hotly debated [1, 2]. Possible explanations include stochastic mechanical competition [3, 4], coordinated regulation by motor-associated proteins [5-7], mechanical activation of motors [8], and lipid-induced organization [9]. Here, we address this question by using phagocytosed latex beads to generate early phagosomes (EPs) that move bidirectionally along microtubules (MTs) in an in vitro assay [9]. Dynein/kinesin activity on individual EPs is recorded as real-time force generation of the motors against an optical trap. Activity of one class of motors frequently coincides with, or is rapidly followed by opposite motors. This leads to frequent and rapid reversals of EPs in the trap. Remarkably, the choice between dynein and kinesin can be explained by the tossing of a coin. Opposing motors therefore appear to function stochastically and independently of each other, as also confirmed by observing no effect on kinesin function when dynein is inhibited on the EPs. A simple binomial probability calculation based on the geometry of EP microtubule contact explains the observed activity of dynein and kinesin on phagosomes. This understanding of intracellular transport in terms of a hypothetical coin, if it holds true for other cargoes, provides a conceptual framework to explain the polarized localization of organelles inside cells. PMID- 29706511 TI - A Tandem Amino Acid Residue Motif in Guard Cell SLAC1 Anion Channel of Grasses Allows for the Control of Stomatal Aperture by Nitrate. AB - The latest major group of plants to evolve were the grasses. These became important in the mid-Paleogene about 40 million years ago. During evolution, leaf CO2 uptake and transpirational water loss were optimized by the acquisition of grass-specific stomatal complexes. In contrast to the kidney-shaped guard cells (GCs) typical of the dicots such as Arabidopsis, in the grasses and agronomically important cereals, the GCs are dumbbell shaped and are associated with morphologically distinct subsidiary cells (SCs). We studied the molecular basis of GC action in the major cereal crop barley. Upon feeding ABA to xylem sap of an intact barley leaf, stomata closed in a nitrate-dependent manner. This process was initiated by activation of GC SLAC-type anion channel currents. HvSLAC1 expressed in Xenopus oocytes gave rise to S-type anion currents that increased several-fold upon stimulation with >3 mM nitrate. We identified a tandem amino acid residue motif that within the SLAC1 channels differs fundamentally between monocots and dicots. When the motif of nitrate-insensitive dicot Arabidopsis SLAC1 was replaced by the monocot signature, AtSLAC1 converted into a grass-type like nitrate-sensitive channel. Our work reveals a fundamental difference between monocot and dicot GCs and prompts questions into the selective pressures during evolution that resulted in fundamental changes in the regulation of SLAC1 function. PMID- 29706512 TI - Decodability of Reward Learning Signals Predicts Mood Fluctuations. AB - Our mood often fluctuates without warning. Recent accounts propose that these fluctuations might be preceded by changes in how we process reward. According to this view, the degree to which reward improves our mood reflects not only characteristics of the reward itself (e.g., its magnitude) but also how receptive to reward we happen to be. Differences in receptivity to reward have been suggested to play an important role in the emergence of mood episodes in psychiatric disorders [1-16]. However, despite substantial theory, the relationship between reward processing and daily fluctuations of mood has yet to be tested directly. In particular, it is unclear whether the extent to which people respond to reward changes from day to day and whether such changes are followed by corresponding shifts in mood. Here, we use a novel mobile-phone platform with dense data sampling and wearable heart-rate and electroencephalographic sensors to examine mood and reward processing over an extended period of one week. Subjects regularly performed a trial-and-error choice task in which different choices were probabilistically rewarded. Subjects' choices revealed two complementary learning processes, one fast and one slow. Reward prediction errors [17, 18] indicative of these two processes were decodable from subjects' physiological responses. Strikingly, more accurate decodability of prediction-error signals reflective of the fast process predicted improvement in subjects' mood several hours later, whereas more accurate decodability of the slow process' signals predicted better mood a whole day later. We conclude that real-life mood fluctuations follow changes in responsivity to reward at multiple timescales. PMID- 29706513 TI - The Geomagnetic Field Is a Compass Cue in Cataglyphis Ant Navigation. AB - Desert ants (Cataglyphis) are famous insect navigators. During their foraging lives, the ants leave their underground colonies for long distances and return to their starting point with fair accuracy [1, 2]. Their incessantly running path integrator provides them with a continually updated home vector [3-5]. Directional input to their path integrator is provided by a visual compass based on celestial cues [6, 7]. However, as path integration is prone to cumulative errors, the ants additionally employ landmark guidance routines [8-11]. At the start of their foraging lives, they acquire the necessary landmark information by performing well-structured learning walks [12, 13], including turns about their vertical body axes [14]. When Cataglyphis noda performs these pirouettes, it always gazes at the nest entrance during the longest of several short stopping phases [14]. As the small nest entrance is not visible, the ants can adjust their gaze direction only by reading out their path integrator. However, recent experiments have shown that, for adjusting the goal-centered gaze directions during learning walks, skylight cues are not required [15]. A most promising remaining compass cue is the geomagnetic field, which is used for orientation in one way or the other by a variety of animal species [16-25]. Here, we show that the gaze directions during the look-back-to-the-nest behavior change in a predictable way to alterations of the horizontal component of the magnetic field. This is the first demonstration that, in insects, a geomagnetic compass cue is both necessary and sufficient for accomplishing a well-defined navigational task. PMID- 29706514 TI - Coordination of Septate Junctions Assembly and Completion of Cytokinesis in Proliferative Epithelial Tissues. AB - How permeability barrier function is maintained when epithelial cells divide is largely unknown. Here, we have investigated how the bicellular septate junctions (BSJs) and tricellular septate junctions (TSJs) are remodeled throughout completion of cytokinesis in Drosophila epithelia. We report that, following cytokinetic ring constriction, the midbody assembles, matures within SJs, and is displaced basally in two phases. In a first slow phase, the neighboring cells remain connected to the dividing cells by means of SJ-containing membrane protrusions pointing to the maturing midbody. Fluorescence recovery after photobleaching (FRAP) experiments revealed that SJs within the membrane protrusions correspond to the old SJs that were present prior to cytokinesis. In contrast, new SJs are assembled below the adherens junctions and spread basally to build a new belt of SJs in a manner analogous to a conveyor belt. Loss of function of a core BSJ component, the Na+/K+-ATPase pump Nervana 2 subunit, revealed that the apical-to-basal spread of BSJs drives the basal displacement of the midbody. In contrast, loss of the TSJ protein Bark beetle indicated that remodeling of TSJs is rate limiting and slowed down midbody migration. In the second phase, once the belt of SJs is assembled, the basal displacement of the midbody is accelerated and ultimately leads to abscission. This last step is temporally uncoupled from the remodeling of SJs. We propose that cytokinesis in epithelia involves the coordinated polarized assembly and remodeling of SJs both in the dividing cell and its neighbors to ensure the maintenance of permeability barrier integrity in proliferative epithelia. PMID- 29706515 TI - Puncture-and-Pull Biomechanics in the Teeth of Predatory Coelurosaurian Dinosaurs. AB - The teeth of putatively carnivorous dinosaurs are often blade-shaped with well defined serrated cutting edges (Figure 1). These ziphodont teeth are often easily differentiated based on the morphology and density of the denticles [1, 2]. A tearing function has been proposed for theropod denticles in general [3], but the functional significance of denticle phenotypic variation has received less attention. In particular, the unusual hooked denticles found in troodontids suggest a different feeding strategy or diet compared to other small theropods. We used a two-pronged approach to investigate the function of denticle shape variation across theropods with both congruent body shapes and sizes (e.g., dromaeosaurids versus troodontids) and highly disparate body shapes and sizes (e.g., troodontids versus tyrannosaurids), using microwear and finite element analyses (Figure 1). We found that many toothed coelurosaurian theropods employed a puncture-and-pull feeding movement, in which parallel scratches form while biting down into prey and oblique scratches form as the head is pulled backward with the jaws closed. In finite element simulations, theropod teeth had the lowest stresses when bite forces were aligned with the oblique family of microwear scratches. Different denticle morphologies performed differently under a variety of simulated biting angles: Dromaeosaurus and Saurornitholestes were well-adapted for handling struggling prey, whereas troodontid teeth were more likely to fail at non-optimal bite angles. Troodontids may have favored softer, smaller, or immobile prey. PMID- 29706517 TI - Liverwort Mimesis in a Cretaceous Lacewing Larva. AB - Camouflage and mimicry are staples among predator-prey interactions, and evolutionary novelties in behavior, anatomy, and physiology that permit such mimesis are rife throughout the biological world [1, 2]. These specializations allow for prey to better evade capture or permit predators to more easily approach their prey, or in some cases, the mimesis can serve both purposes. Despite the importance of mimesis and camouflage in predator-avoidance or hunting strategies, the long-term history of these traits is often obscured by an insufficient fossil record. Here, we report the discovery of Upper Cretaceous (approximately 100 million years old) green lacewing larvae (Chrysopoidea), preserved in amber from northern Myanmar, anatomically modified to mimic coeval liverworts. Chrysopidae are a diverse lineage of lacewings whose larvae usually camouflage themselves with a uniquely constructed packet of exogenous debris, conveying greater stealth upon them as they hunt prey such as aphids as well as evade their own predators [3, 4]. However, no lacewing larvae today mimic their surroundings. While the anatomy of Phyllochrysa huangi gen. et sp. nov. allowed it to avoid detection, the lack of setae or other anatomical elements for entangling debris as camouflage means its sole defense was its mimicry, and it could have been a stealthy hunter like living and other fossil Chrysopoidea or been an ambush predator aided by its disguise. The present fossils demonstrate a hitherto unknown life-history strategy among these "wolf in sheep's clothing" predators, one that apparently evolved from a camouflaging ancestor but did not persist within the lineage. PMID- 29706516 TI - The Same Hippocampal CA1 Population Simultaneously Codes Temporal Information over Multiple Timescales. AB - It has long been hypothesized that a primary function of the hippocampus is to discover and exploit temporal relationships between events. Previously, it has been reported that sequences of "time cells" in the hippocampus extend for tens of seconds. Other studies have shown that neuronal firing in the hippocampus fluctuates over hours and days. Both of these mechanisms could enable temporal encoding of events over very different timescales. However, thus far, these two classes of phenomena have never been observed simultaneously, which is necessary to ascribe broad-range temporal coding to the hippocampus. Using in vivo calcium imaging in unrestrained mice, we observed sequences of hippocampal neurons that bridged a 10 s delay. Similar sequences were observed over multiple days, but the set of neurons participating in those sequences changed gradually. Thus, the same population of neurons that encodes temporal information over seconds can also be used to distinguish periods of time over much longer timescales. These results unify two previously separate paradigms of temporal processing in the hippocampus that support episodic memory. PMID- 29706518 TI - Fraternal Polyandry and Clannish Spatial Organization in a Flightless Island Bird. AB - Polyandry has been studied in many species, especially birds [1]. Exclusively fraternal polyandry (several full or half-brothers with one unrelated female) is only known in human societies [2, 3], in which it is an important mechanism for limiting reproductive output [3] in association with scarce environmental resources [2]. However, the social organization of the Kagu Rhynochetos jubatus, a bird species endemic to New Caledonia, has the characteristics of this mating system. Kagu are cooperative breeders and evolved in the absence of predators [4, 5]. Breeding birds and their helpers contributes to the care and defense of the chick [6]. Kagu populations occur in both poor and rich habitats [7] and differ substantially in food supply and associated reproduction rates [8]. This enabled us to verify whether fraternal polyandry increased reproductive output in low density situations but limited reproduction in high-density populations. Our 15 year study revealed that, regardless of resource availability, Kagu were organized in facultative fraternal polyandrous families grouped in clans. Within a clan, all breeding females were unrelated, whereas all males were related. There was no extra-clan paternity. An average family size of four to five adults was optimal for breeding success. Males that have long-established families in their own territory regularly visited their parents. We conclude that fraternal polyandry in Kagu increases reproductive output under poor environmental conditions but limits population growth when the population is near carrying capacity because the clannish spatial organization prevents new families from establishing territories. PMID- 29706519 TI - Animals Remember Previous Facial Expressions that Specific Humans Have Exhibited. AB - For humans, facial expressions are important social signals, and how we perceive specific individuals may be influenced by subtle emotional cues that they have given us in past encounters. A wide range of animal species are also capable of discriminating the emotions of others through facial expressions [1-5], and it is clear that remembering emotional experiences with specific individuals could have clear benefits for social bonding and aggression avoidance when these individuals are encountered again. Although there is evidence that non-human animals are capable of remembering the identity of individuals who have directly harmed them [6, 7], it is not known whether animals can form lasting memories of specific individuals simply by observing subtle emotional expressions that they exhibit on their faces. Here we conducted controlled experiments in which domestic horses were presented with a photograph of an angry or happy human face and several hours later saw the person who had given the expression in a neutral state. Short term exposure to the facial expression was enough to generate clear differences in subsequent responses to that individual (but not to a different mismatched person), consistent with the past angry expression having been perceived negatively and the happy expression positively. Both humans were blind to the photograph that the horses had seen. Our results provide clear evidence that some non-human animals can effectively eavesdrop on the emotional state cues that humans reveal on a moment-to-moment basis, using their memory of these to guide future interactions with particular individuals. PMID- 29706520 TI - Phylogenomics, Diversification Dynamics, and Comparative Transcriptomics across the Spider Tree of Life. AB - Dating back to almost 400 mya, spiders are among the most diverse terrestrial predators [1]. However, despite considerable effort [1-9], their phylogenetic relationships and diversification dynamics remain poorly understood. Here, we use a synergistic approach to study spider evolution through phylogenomics, comparative transcriptomics, and lineage diversification analyses. Our analyses, based on ca. 2,500 genes from 159 spider species, reject a single origin of the orb web (the "ancient orb-web hypothesis") and suggest that orb webs evolved multiple times since the late Triassic-Jurassic. We find no significant association between the loss of foraging webs and increases in diversification rates, suggesting that other factors (e.g., habitat heterogeneity or biotic interactions) potentially played a key role in spider diversification. Finally, we report notable genomic differences in the main spider lineages: while araneoids (ecribellate orb-weavers and their allies) reveal an enrichment in genes related to behavior and sensory reception, the retrolateral tibial apophysis (RTA) clade-the most diverse araneomorph spider lineage-shows enrichment in genes related to immune responses and polyphenic determination. This study, one of the largest invertebrate phylogenomic analyses to date, highlights the usefulness of transcriptomic data not only to build a robust backbone for the Spider Tree of Life, but also to address the genetic basis of diversification in the spider evolutionary chronicle. PMID- 29706521 TI - Chromosome Segregation Is Biased by Kinetochore Size. AB - Chromosome missegregation during mitosis or meiosis is a hallmark of cancer and the main cause of prenatal death in humans. The gain or loss of specific chromosomes is thought to be random, with cell viability being essentially determined by selection. Several established pathways including centrosome amplification, sister-chromatid cohesion defects, or a compromised spindle assembly checkpoint can lead to chromosome missegregation. However, how specific intrinsic features of the kinetochore-the critical chromosomal interface with spindle microtubules-impact chromosome segregation remains poorly understood. Here we used the unique cytological attributes of female Indian muntjac, the mammal with the lowest known chromosome number (2n = 6), to characterize and track individual chromosomes with distinct kinetochore size throughout mitosis. We show that centromere and kinetochore functional layers scale proportionally with centromere size. Measurement of intra-kinetochore distances, serial-section electron microscopy, and RNAi against key kinetochore proteins confirmed a standard structural and functional organization of the Indian muntjac kinetochores and revealed that microtubule binding capacity scales with kinetochore size. Surprisingly, we found that chromosome segregation in this species is not random. Chromosomes with larger kinetochores bi-oriented more efficiently and showed a 2-fold bias to congress to the equator in a motor independent manner. Despite robust correction mechanisms during unperturbed mitosis, chromosomes with larger kinetochores were also strongly biased to establish erroneous merotelic attachments and missegregate during anaphase. This bias was impervious to the experimental attenuation of polar ejection forces on chromosome arms by RNAi against the chromokinesin Kif4a. Thus, kinetochore size is an important determinant of chromosome segregation fidelity. PMID- 29706523 TI - Achieving alignment in graduate medical education to train the next generation of healthcare professionals to improve healthcare delivery. AB - Medical training is increasingly focused on the need to improve healthcare delivery. To succeed in this endeavor, teaching hospitals should align their educational and clinical operations. This article discusses recent innovations and emerging strategies in medical training across three key components for achieving alignment: (1) bridging educational and clinical priorities; (2) developing curricula to support alignment; (3) and fostering resident-led programs that lead to systems change. Understanding the current landscape of educational and operational innovations across clinical learning environments can help health system leaders and medical educators work together to implement cohesive programs that achieve all of these key components. PMID- 29706524 TI - Improving detection window of scopolamine. PMID- 29706522 TI - The association between diabetes, comorbidities, body mass index and all-cause and cause-specific mortality among women with endometrial cancer. AB - OBJECTIVE: Although endometrial cancer (EC) is associated with relatively good survival rates overall, women diagnosed with high-risk subtypes have poor outcomes. We examined the relationship between lifestyle factors and subsequent all-cause, cancer-specific and non-cancer related survival. METHODS: In a cohort of 1359 Australian women diagnosed with incident EC between 2005 and 2007 pre diagnostic information was collected by interview at recruitment. Clinical and survival information was abstracted from women's medical records, supplemented by linkage to the Australian National Death Index. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific survival (EC death vs. non-EC death) associated with each exposure, overall and by risk group (low-grade endometrioid vs. high-grade endometrioid and non-endometrioid). RESULTS: After a median follow up of 7.1 years, 179 (13%) women had died, with 123 (69%) deaths from EC. As expected, elevated body mass index (BMI), diabetes and the presence of other co morbidities were associated with a significantly increased risk of all-cause and non-cancer related death. Women with diabetes had higher cancer-specific mortality rates (HR 2.09, 95% CI 1.31-3.35), particularly those who had were not obese (HR 4.13, 95% CI 2.20-7.76). The presence of >=2 other co-morbidities (excluding diabetes) was also associated with increased risk of cancer-specific mortality (HR 3.09, 95% CI 1.21-7.89). The patterns were generally similar for women with low-grade and high-grade endometrioid/non-endometrioid EC. CONCLUSION: Our findings demonstrate the importance of diabetes, other co-morbidities and obesity as negative predictors of mortality among women with EC but that the risks differ for cancer-specific and non-cancer related mortality. PMID- 29706525 TI - Structure-activity relationship of clovamide and its related compounds for the inhibition of amyloid beta aggregation. AB - Alzheimer's disease (AD), a neurodegenerative disorder, is characterized by aggregation of amyloid beta-protein (Abeta). Abeta aggregates through beta-sheet formation and induces cytotoxicity against neuronal cells. Inhibition of Abeta aggregation by naturally occurring compounds is thus a promising strategy for the treatment of AD. We have already reported that caffeoylquinic acids and phenylethanoid glycosides, which possess two or more catechol moieties, strongly inhibited Abeta aggregation. Clovamide (1) containing two catechol moieties, isolated from cacao beans (Theobroma cacao L.), is believed to exhibit preventive effects on Abeta aggregation. To investigate the structure-activity relationship of clovamide (1) for the inhibition of Abeta aggregation, we synthesized 1 and related compounds 2-11 through reaction between l-DOPA, d-DOPA, l-tyrosine, or l phenylalanine and caffeic acid, p-coumaric acid, or cinnamic acid, and compounds 12 and 13 were derived from 1. Among tested compounds 1-13, those containing one or two catechol moieties exhibited potent anti-aggregation activity, whereas the non-catechol-type related compounds showed little or no activity. This suggests that at least one catechol moiety is essential for inhibition of Abeta42 aggregation, and this activity increases depending on the number of catechol moieties. Consequently, clovamide (1) and its related compounds may be a promising therapeutic option for inhibiting Abeta-mediated pathology in AD. PMID- 29706526 TI - Synthesis, antimycobacterial activity and influence on mycobacterial InhA and PknB of 12-membered cyclodepsipeptides. AB - In recent years, several small natural cyclopeptides and cyclodepsipeptides were reported to have antimycobacterial activity. Following this lead, a synthetic pathway was developed for a small series of 12-membered ring compounds with one amide and two ester bonds (cyclotridepsipeptides). Within the series, the ring system proved to be necessary for growth inhibition of Mycobacterium smegmatis and Mycobacterium tuberculosis in the low micromolar range. Open-chain precursors and analogues were inactive. The compounds modulated autophosphorylation of the mycobacterial protein kinase B (PknB). PknB inhibitors were active at uM concentration against mycobacteria while inducers were inactive. PknB regulates the activity of the mycobacterial reductase InhA, the target of isoniazid. The activity of the series against Mycobacterium bovis BCG InhA overexpressing strains was indistinguishable from that of the parental strain suggesting that they do not inhibit InhA. All substances were not cytotoxic (HeLa > 5 ug/ml) and did not show any significant antiproliferative effect (HUVEC > 5 ug/ml; K-562 > 5 ug/ml). Within the scope of this study, the molecular target of this new type of small cyclodepsipeptide was not identified, but the data suggest interaction with PknB or other kinases may partly cause the activity. PMID- 29706527 TI - Screening serine/threonine and tyrosine kinase inhibitors for histidine kinase inhibition. AB - Histidine kinases of bacterial two-component systems are promising antibacterial targets. Despite their varied, numerous roles, enzymes in the histidine kinase superfamily share a catalytic core that may be exploited to inhibit multiple histidine kinases simultaneously. Characterized by the Bergerat fold, the features of the histidine kinase ATP-binding domain are not found in serine/threonine and tyrosine kinases. However, because each kinase family binds the same ATP substrate, we sought to determine if published serine/threonine and tyrosine kinase inhibitors contained scaffolds that would also inhibit histidine kinases. Using select assays, 222 inhibitors from the Roche Published Kinase Set were screened for binding, deactivation, and aggregation of histidine kinases. Not only do the results of our screen support the distinctions between ATP binding domains of different kinase families, but the lead molecule identified also presents inspiration for further histidine kinase inhibitor development. PMID- 29706528 TI - Applications of a novel biodetection system to saliva using protein fingerprints with data processing. AB - A fundamental method has been developed focusing on a facile and rapid examination of periodontal disease. Periodontal disease is an oral disease thought to affect 80% of adults, and early detection with treatment is desirable for the improvement of the quality of life. Unfortunately conventional methods are not consistent as the disease is caused by a number of undefined bacteria and detection relies on the skills of the dentist. Thus an objective detection system is required. We have performed an experiment on saliva using a novel biodetection system, designated PepTenChip(r). A disease model for saliva was prepared using a specimen from a healthy subject and a mixture of hemoglobin (f-Hb) and lactate dehydrogenase (LDH), which is used as a periodontal disease marker protein with healthy saliva. PepTenChip(r) is a peptide microarray in which fluorescent labelled structured peptides are immobilized on a novel amorphous carbon substrate. Since the peptides used as capture molecules are fluorescently labelled, labeling of analytes is not necessary. The fluorescence intensity change before and after application of analytes are detected rather than the ON/OFF detection common to conventional microarrays using a set of antigen antibody. The fluorescence intensity value changes according to the concentration of captured protein allowing the generation of protein fingerprint (PFP) and dendrograms. The present method does not rely on a "one to one" interaction, unlike conventional biodetection, and advantages can be envisaged in the case of an undefined or unknown cause of disease. The statistical analyses, such as multivariate analyses, allow classification of the type of proteins added in saliva as mimetics of disease. PepTenChip(r) system is useful and convenient for examination of periodontal disease in health care. PMID- 29706529 TI - Design, synthesis and cardiovascular evaluation of some aminoisopropanoloxy derivatives of xanthone. AB - A series of aminoisopropanoloxy derivatives of xanthone has been synthesized and their pharmacological properties regarding the cardiovascular system has been evaluated. Radioligand binding and functional studies in isolated organs revealed that title compounds present high affinity and antagonistic potency for alpha1 (compound 2 and 8), beta-(compounds 1, 3, 4, 7), alpha1/beta-(compounds 5 and 6) adrenoceptors. Furthermore, compound 7, the structural analogue of verapamil, possesses calcium entry blocking activity. The title compounds showed hypotensive and antiarrhythmic properties due to their adrenoceptor blocking effect. Moreover, they did not affect QRS and QT intervals, and they did not have proarrhythmic potential at tested doses. In addition they exerted anti aggregation effect. The results of this study suggest that new compounds with multidirectional activity in cardiovascular system might be found in the group of xanthone derivatives. PMID- 29706530 TI - Analysis of Global and Site-Specific Radiation Damage in Cryo-EM. AB - Micro-crystal electron diffraction (MicroED) combines the efficiency of electron scattering with diffraction to allow structure determination from nano-sized crystalline samples in cryoelectron microscopy (cryo-EM). It has been used to solve structures of a diverse set of biomolecules and materials, in some cases to sub-atomic resolution. However, little is known about the damaging effects of the electron beam on samples during such measurements. We assess global and site specific damage from electron radiation on nanocrystals of proteinase K and of a prion hepta-peptide and find that the dynamics of electron-induced damage follow well-established trends observed in X-ray crystallography. Metal ions are perturbed, disulfide bonds are broken, and acidic side chains are decarboxylated while the diffracted intensities decay exponentially with increasing exposure. A better understanding of radiation damage in MicroED improves our assessment and processing of all types of cryo-EM data. PMID- 29706531 TI - Crystal Structure of Ripk4 Reveals Dimerization-Dependent Kinase Activity. AB - Receptor-interacting protein kinase 4 (RIPK4) is a highly conserved regulator of epidermal differentiation. Members of the RIPK family possess a common kinase domain as well as unique accessory domains that likely dictate subcellular localization and substrate preferences. Mutations in human RIPK4 manifest as Bartsocas-Papas syndrome (BPS), a genetic disorder characterized by severe craniofacial and limb abnormalities. We describe the structure of the murine Ripk4 (MmRipk4) kinase domain, in ATP- and inhibitor-bound forms. The crystallographic dimer of MmRipk4 is similar to those of RIPK2 and BRAF, and we show that the intact dimeric entity is required for MmRipk4 catalytic activity through a series of engineered mutations and cell-based assays. We also assess the impact of BPS mutations on protein structure and activity to elucidate the molecular origins of the disease. PMID- 29706533 TI - K-Ras Populates Conformational States Differently from Its Isoform H-Ras and Oncogenic Mutant K-RasG12D. AB - Structures of wild-type K-Ras from crystals obtained in the presence of guanosine triphosphate (GTP) or its analogs have remained elusive. Of the K-Ras mutants, only K-RasG12D and K-RasQ61H are available in the PDB representing the activated form of the GTPase not in complex with other proteins. We present the crystal structure of wild-type K-Ras bound to the GTP analog GppCH2p, with K-Ras in the state 1 conformation. Signatures of conformational states obtained by one dimensional proton NMR confirm that K-Ras has a more substantial population of state 1 in solution than H-Ras, which predominantly favors state 2. The oncogenic mutant K-RasG12D favors state 2, changing the balance of conformational states in favor of interactions with effector proteins. Differences in the population of conformational states between K-Ras and H-Ras, as well as between K-Ras and its mutants, can provide a structural basis for focused targeting of the K-Ras isoform in cancer-specific strategies. PMID- 29706532 TI - The Structure of an Infectious Human Polyomavirus and Its Interactions with Cellular Receptors. AB - BK polyomavirus (BKV) causes polyomavirus-associated nephropathy and hemorrhagic cystitis in immunosuppressed patients. These are diseases for which we currently have limited treatment options, but potential therapies could include pre transplant vaccination with a multivalent BKV vaccine or therapeutics which inhibit capsid assembly or block attachment and entry into target cells. A useful tool in such efforts would be a high-resolution structure of the infectious BKV virion and how this interacts with its full repertoire of cellular receptors. We present the 3.4-A cryoelectron microscopy structure of native, infectious BKV in complex with the receptor fragment of GT1b ganglioside. We also present structural evidence that BKV can utilize glycosaminoglycans as attachment receptors. This work highlights features that underpin capsid stability and provides a platform for rational design and development of urgently needed pharmacological interventions for BKV-associated diseases. PMID- 29706536 TI - Repetitive DNA Reeling by the Cascade-Cas3 Complex in Nucleotide Unwinding Steps. AB - CRISPR-Cas provides RNA-guided adaptive immunity against invading genetic elements. Interference in type I systems relies on the RNA-guided Cascade complex for target DNA recognition and the Cas3 helicase/nuclease protein for target degradation. Even though the biochemistry of CRISPR interference has been largely covered, the biophysics of DNA unwinding and coupling of the helicase and nuclease domains of Cas3 remains elusive. Here, we employed single-molecule Forster resonance energy transfer (FRET) to probe the helicase activity with high spatiotemporal resolution. We show that Cas3 remains tightly associated with the target-bound Cascade complex while reeling the DNA using a spring-loaded mechanism. This spring-loaded reeling occurs in distinct bursts of 3 bp, which underlie three successive 1-nt unwinding events. Reeling is highly repetitive, allowing Cas3 to repeatedly present its inefficient nuclease domain with single strand DNA (ssDNA) substrate. Our study reveals that the discontinuous helicase properties of Cas3 and its tight interaction with Cascade ensure controlled degradation of target DNA only. PMID- 29706535 TI - Redundant and Antagonistic Roles of XTP3B and OS9 in Decoding Glycan and Non glycan Degrons in ER-Associated Degradation. AB - Glycoproteins engaged in unproductive folding in the ER are marked for degradation by a signal generated by progressive demannosylation of substrate N glycans that is decoded by ER lectins, but how the two lectins, OS9 and XTP3B, contribute to non-glycosylated protein triage is unknown. We generated cell lines with homozygous deletions of both lectins individually and in combination. We found that OS9 and XTP3B redundantly promote glycoprotein degradation and stabilize the SEL1L/HRD1 dislocon complex, that XTP3B profoundly inhibits the degradation of non-glycosylated proteins, and that OS9 antagonizes this inhibition. The relative expression of OS9 and XTP3B and the distribution of glycan and non-glycan degrons within the same protein contribute to the fidelity and processivity of glycoprotein triage and, therefore, determine the fates of newly synthesized proteins in the early secretory pathway. PMID- 29706534 TI - Ca2+-Triggered Synaptic Vesicle Fusion Initiated by Release of Inhibition. AB - Recent structural and functional studies of the synaptic vesicle fusion machinery suggest an inhibited tripartite complex consisting of neuronal soluble N ethylmaleimide sensitive factor attachment protein receptors (SNAREs), synaptotagmin, and complexin prior to Ca2+-triggered synaptic vesicle fusion. We speculate that Ca2+-triggered fusion commences with the release of inhibition by Ca2+ binding to synaptotagmin C2 domains. Subsequently, fusion is assisted by SNARE complex zippering and by active membrane remodeling properties of synaptotagmin. This additional, inhibitory role of synaptotagmin may be a general principle since other recent studies suggest that Ca2+ binding to extended synaptotagmin C2 domains enables lipid transport by releasing an inhibited state of the system, and that Munc13 may nominally be in an inhibited state, which is released upon Ca2+ binding to one of its C2 domains. PMID- 29706537 TI - Hsp90 Breaks the Deadlock of the Hsp70 Chaperone System. AB - Protein folding in the cell requires ATP-driven chaperone machines such as the conserved Hsp70 and Hsp90. It is enigmatic how these machines fold proteins. Here, we show that Hsp90 takes a key role in protein folding by breaking an Hsp70 inflicted folding block, empowering protein clients to fold on their own. At physiological concentrations, Hsp70 stalls productive folding by binding hydrophobic, core-forming segments. Hsp90 breaks this deadlock and restarts folding. Remarkably, neither Hsp70 nor Hsp90 alters the folding rate despite ensuring high folding yields. In fact, ATP-dependent chaperoning is restricted to the early folding phase. Thus, the Hsp70-Hsp90 cascade does not fold proteins, but instead prepares them for spontaneous, productive folding. This stop-start mechanism is conserved from bacteria to man, assigning also a general function to bacterial Hsp90, HtpG. We speculate that the decreasing hydrophobicity along the Hsp70-Hsp90 cascade may be crucial for enabling spontaneous folding. PMID- 29706538 TI - HMGB2 Loss upon Senescence Entry Disrupts Genomic Organization and Induces CTCF Clustering across Cell Types. AB - Processes like cellular senescence are characterized by complex events giving rise to heterogeneous cell populations. However, the early molecular events driving this cascade remain elusive. We hypothesized that senescence entry is triggered by an early disruption of the cells' three-dimensional (3D) genome organization. To test this, we combined Hi-C, single-cell and population transcriptomics, imaging, and in silico modeling of three distinct cells types entering senescence. Genes involved in DNA conformation maintenance are suppressed upon senescence entry across all cell types. We show that nuclear depletion of the abundant HMGB2 protein occurs early on the path to senescence and coincides with the dramatic spatial clustering of CTCF. Knocking down HMGB2 suffices for senescence-induced CTCF clustering and for loop reshuffling, while ectopically expressing HMGB2 rescues these effects. Our data suggest that HMGB2 mediated genomic reorganization constitutes a primer for the ensuing senescent program. PMID- 29706539 TI - The Ftx Noncoding Locus Controls X Chromosome Inactivation Independently of Its RNA Products. AB - Accumulation of the Xist long noncoding RNA (lncRNA) on one X chromosome is the trigger for X chromosome inactivation (XCI) in female mammals. Xist expression, which needs to be tightly controlled, involves a cis-acting region, the X inactivation center (Xic), containing many lncRNA genes that evolved concomitantly to Xist from protein-coding ancestors through pseudogeneization and loss of coding potential. Here, we uncover an essential role for the Xic-linked noncoding gene Ftx in the regulation of Xist expression. We show that Ftx is required in cis to promote Xist transcriptional activation and establishment of XCI. Importantly, we demonstrate that this function depends on Ftx transcription and not on the RNA products. Our findings illustrate the multiplicity of layers operating in the establishment of XCI and highlight the diversity in the modus operandi of the noncoding players. PMID- 29706540 TI - Universal Chimeric Antigen Receptors for Multiplexed and Logical Control of T Cell Responses. AB - T cells expressing chimeric antigen receptors (CARs) are promising cancer therapeutic agents, with the prospect of becoming the ultimate smart cancer therapeutics. To expand the capability of CAR T cells, here, we present a split, universal, and programmable (SUPRA) CAR system that simultaneously encompasses multiple critical "upgrades," such as the ability to switch targets without re engineering the T cells, finely tune T cell activation strength, and sense and logically respond to multiple antigens. These features are useful to combat relapse, mitigate over-activation, and enhance specificity. We test our SUPRA system against two different tumor models to demonstrate its broad utility and humanize its components to minimize potential immunogenicity concerns. Furthermore, we extend the orthogonal SUPRA CAR system to regulate different T cell subsets independently, demonstrating a dually inducible CAR system. Together, these SUPRA CARs illustrate that multiple advanced logic and control features can be implemented into a single, integrated system. PMID- 29706541 TI - The Egyptian Rousette Genome Reveals Unexpected Features of Bat Antiviral Immunity. AB - Bats harbor many viruses asymptomatically, including several notorious for causing extreme virulence in humans. To identify differences between antiviral mechanisms in humans and bats, we sequenced, assembled, and analyzed the genome of Rousettus aegyptiacus, a natural reservoir of Marburg virus and the only known reservoir for any filovirus. We found an expanded and diversified KLRC/KLRD family of natural killer cell receptors, MHC class I genes, and type I interferons, which dramatically differ from their functional counterparts in other mammals. Such concerted evolution of key components of bat immunity is strongly suggestive of novel modes of antiviral defense. An evaluation of the theoretical function of these genes suggests that an inhibitory immune state may exist in bats. Based on our findings, we hypothesize that tolerance of viral infection, rather than enhanced potency of antiviral defenses, may be a key mechanism by which bats asymptomatically host viruses that are pathogenic in humans. PMID- 29706542 TI - Cryo-EM Structure of Human Dicer and Its Complexes with a Pre-miRNA Substrate. AB - Human Dicer (hDicer) is a multi-domain protein belonging to the RNase III family. It plays pivotal roles in small RNA biogenesis during the RNA interference (RNAi) pathway by processing a diverse range of double-stranded RNA (dsRNA) precursors to generate ~22 nt microRNA (miRNA) or small interfering RNA (siRNA) products for sequence-directed gene silencing. In this work, we solved the cryoelectron microscopy (cryo-EM) structure of hDicer in complex with its cofactor protein TRBP and revealed the precise spatial arrangement of hDicer's multiple domains. We further solved structures of the hDicer-TRBP complex bound with pre-let-7 RNA in two distinct conformations. In combination with biochemical analysis, these structures reveal a property of the hDicer-TRBP complex to promote the stability of pre-miRNA's stem duplex in a pre-dicing state. These results provide insights into the mechanism of RNA processing by hDicer and illustrate the regulatory role of hDicer's N-terminal helicase domain. PMID- 29706543 TI - Modulation of Protein-Interaction States through the Cell Cycle. AB - Global profiling of protein expression through the cell cycle has revealed subsets of periodically expressed proteins. However, expression levels alone only give a partial view of the biochemical processes determining cellular events. Using a proteome-wide implementation of the cellular thermal shift assay (CETSA) to study specific cell-cycle phases, we uncover changes of interaction states for more than 750 proteins during the cell cycle. Notably, many protein complexes are modulated in specific cell-cycle phases, reflecting their roles in processes such as DNA replication, chromatin remodeling, transcription, translation, and disintegration of the nuclear envelope. Surprisingly, only small differences in the interaction states were seen between the G1 and the G2 phase, suggesting similar hardwiring of biochemical processes in these two phases. The present work reveals novel molecular details of the cell cycle and establishes proteome-wide CETSA as a new strategy to study modulation of protein-interaction states in intact cells. PMID- 29706544 TI - Co-optation of Tandem DNA Repeats for the Maintenance of Mesenchymal Identity. AB - Tandem repeats (TRs) are generated by DNA replication errors and retain a high level of instability, which in principle would make them unsuitable for integration into gene regulatory networks. However, the appearance of DNA sequence motifs recognized by transcription factors may turn TRs into functional cis-regulatory elements, thus favoring their stabilization in genomes. Here, we show that, in human cells, the transcriptional repressor ZEB1, which promotes the maintenance of mesenchymal features largely by suppressing epithelial genes and microRNAs, occupies TRs harboring dozens of copies of its DNA-binding motif within genomic loci relevant for maintenance of epithelial identity. The deletion of one such TR caused quasi-mesenchymal cancer cells to reacquire epithelial features, partially recapitulating the effects of ZEB1 gene deletion. These data demonstrate that the high density of identical motifs in TRs can make them suitable platforms for recruitment of transcriptional repressors, thus promoting their exaptation into pre-existing cis-regulatory networks. PMID- 29706545 TI - Dendritic Integration of Sensory Evidence in Perceptual Decision-Making. AB - Perceptual decisions require the accumulation of sensory information to a response criterion. Most accounts of how the brain performs this process of temporal integration have focused on evolving patterns of spiking activity. We report that subthreshold changes in membrane voltage can represent accumulating evidence before a choice. alphabeta core Kenyon cells (alphabetac KCs) in the mushroom bodies of fruit flies integrate odor-evoked synaptic inputs to action potential threshold at timescales matching the speed of olfactory discrimination. The forkhead box P transcription factor (FoxP) sets neuronal integration and behavioral decision times by controlling the abundance of the voltage-gated potassium channel Shal (KV4) in alphabetac KC dendrites. alphabetac KCs thus tailor, through a particular constellation of biophysical properties, the generic process of synaptic integration to the demands of sequential sampling. PMID- 29706547 TI - Self-Recognition of an Inducible Host lncRNA by RIG-I Feedback Restricts Innate Immune Response. AB - The innate RNA sensor RIG-I is critical in the initiation of antiviral type I interferons (IFNs) production upon recognition of "non-self" viral RNAs. Here, we identify a host-derived, IFN-inducible long noncoding RNA, lnc-Lsm3b, that can compete with viral RNAs in the binding of RIG-I monomers and feedback inactivate the RIG-I innate function at late stage of innate response. Mechanistically, binding of lnc-Lsm3b restricts RIG-I protein's conformational shift and prevents downstream signaling, thereby terminating type I IFNs production. Multivalent structural motifs and long-stem structure are critical features of lnc-Lsm3b for RIG-I binding and inhibition. These data reveal a non-canonical self-recognition mode in the regulation of immune response and demonstrate an important role of an inducible "self" lncRNA acting as a potent molecular decoy actively saturating RIG-I binding sites to restrict the duration of "non-self" RNA-induced innate immune response and maintaining immune homeostasis, with potential utility in inflammatory disease management. PMID- 29706546 TI - Pervasive Protein Thermal Stability Variation during the Cell Cycle. AB - Quantitative mass spectrometry has established proteome-wide regulation of protein abundance and post-translational modifications in various biological processes. Here, we used quantitative mass spectrometry to systematically analyze the thermal stability and solubility of proteins on a proteome-wide scale during the eukaryotic cell cycle. We demonstrate pervasive variation of these biophysical parameters with most changes occurring in mitosis and G1. Various cellular pathways and components vary in thermal stability, such as cell-cycle factors, polymerases, and chromatin remodelers. We demonstrate that protein thermal stability serves as a proxy for enzyme activity, DNA binding, and complex formation in situ. Strikingly, a large cohort of intrinsically disordered and mitotically phosphorylated proteins is stabilized and solubilized in mitosis, suggesting a fundamental remodeling of the biophysical environment of the mitotic cell. Our data represent a rich resource for cell, structural, and systems biologists interested in proteome regulation during biological transitions. PMID- 29706548 TI - The Energetics and Physiological Impact of Cohesin Extrusion. AB - Cohesin extrusion is thought to play a central role in establishing the architecture of mammalian genomes. However, extrusion has not been visualized in vivo, and thus, its functional impact and energetics are unknown. Using ultra deep Hi-C, we show that loop domains form by a process that requires cohesin ATPases. Once formed, however, loops and compartments are maintained for hours without energy input. Strikingly, without ATP, we observe the emergence of hundreds of CTCF-independent loops that link regulatory DNA. We also identify architectural "stripes," where a loop anchor interacts with entire domains at high frequency. Stripes often tether super-enhancers to cognate promoters, and in B cells, they facilitate Igh transcription and recombination. Stripe anchors represent major hotspots for topoisomerase-mediated lesions, which promote chromosomal translocations and cancer. In plasmacytomas, stripes can deregulate Igh-translocated oncogenes. We propose that higher organisms have coopted cohesin extrusion to enhance transcription and recombination, with implications for tumor development. PMID- 29706549 TI - Integrated Single-Cell Analysis Maps the Continuous Regulatory Landscape of Human Hematopoietic Differentiation. AB - Human hematopoiesis involves cellular differentiation of multipotent cells into progressively more lineage-restricted states. While the chromatin accessibility landscape of this process has been explored in defined populations, single-cell regulatory variation has been hidden by ensemble averaging. We collected single cell chromatin accessibility profiles across 10 populations of immunophenotypically defined human hematopoietic cell types and constructed a chromatin accessibility landscape of human hematopoiesis to characterize differentiation trajectories. We find variation consistent with lineage bias toward different developmental branches in multipotent cell types. We observe heterogeneity within common myeloid progenitors (CMPs) and granulocyte-macrophage progenitors (GMPs) and develop a strategy to partition GMPs along their differentiation trajectory. Furthermore, we integrated single-cell RNA sequencing (scRNA-seq) data to associate transcription factors to chromatin accessibility changes and regulatory elements to target genes through correlations of expression and regulatory element accessibility. Overall, this work provides a framework for integrative exploration of complex regulatory dynamics in a primary human tissue at single-cell resolution. PMID- 29706551 TI - Anesthesia for collagenase clostridium histolyticum injection in patients with dupuytren disease: A cohort analysis. AB - Procedural pain is one of the most common adverse effects reported by patients with Dupuytren disease (DD) treated with collagenase clostridium histolyticum (CCH). The aim of this study was to assess the effectiveness of wrist block before CCH injection in reducing procedural pain and to analyze its impact on adverse effects. We performed a prospective, single-center study in which we compared two groups of patients in a consecutive cohort. In the first group (NO BLOCK), wrist block was only performed before finger extension, whereas in the second group (BLOCK), it was performed before CCH injection and finger extension. Pain was assessed on a 10-item numerical rating scale. Our results show that pain scores were clearlylower in the BLOCK group than in the NO-BLOCK group: 4.72 vs. 0.61 for CCH injection and 3.43 vs. 0.82 for finger extension. Patients who rated CCH injection pain with a score of 4 or higher were 11 times more likely to experience pain during extension. There was a weak correlation between the use of wrist block for CCH injection and the occurrence of skin lacerations (Spearman's rho = -0.222, p < 0.01) and the presence of pruritus (Spearman's rho = 0.183, p < 0.07). In conclusion, wrist block before CCH injection is an effective measure of decreasing perceived pain throughout the different stages of CCH treatment in patients with DD. PMID- 29706550 TI - Single-Cell Chromatin Modification Profiling Reveals Increased Epigenetic Variations with Aging. AB - Post-translational modifications of histone proteins and exchanges of histone variants of chromatin are central to the regulation of nearly all DNA-templated biological processes. However, the degree and variability of chromatin modifications in specific human immune cells remain largely unknown. Here, we employ a highly multiplexed mass cytometry analysis to profile the global levels of a broad array of chromatin modifications in primary human immune cells at the single-cell level. Our data reveal markedly different cell-type- and hematopoietic-lineage-specific chromatin modification patterns. Differential analysis between younger and older adults shows that aging is associated with increased heterogeneity between individuals and elevated cell-to-cell variability in chromatin modifications. Analysis of a twin cohort unveils heritability of chromatin modifications and demonstrates that aging-related chromatin alterations are predominantly driven by non-heritable influences. Together, we present a powerful platform for chromatin and immunology research. Our discoveries highlight the profound impacts of aging on chromatin modifications. PMID- 29706552 TI - Flap choice does not affect complication rates or functional outcomes following extremity soft tissue sarcoma reconstruction. AB - BACKGROUND: Flap reconstruction plays an essential role in facilitating limb preservation in patients with extremity soft tissue sarcoma (ESTS). However, the effect of flap choice on the rates of postoperative complications and functional outcomes has not been clearly established. This study directly compares the outcomes of free and pedicled flap reconstructions in patients with ESTS. METHODS: Two hundred sixty-six patients who underwent flap reconstruction following ESTS resection were included. Associations between flap type and complications were determined using logistic regression analyses. Functional outcome was evaluated using the Toronto Extremity Salvage Score (TESS) and the Musculoskeletal Tumor Society Scales (MSTS). RESULTS: There was no significant difference between complication rates in the pedicled and free flap groups (32% vs. 38%, p = 0.38). In the lower limb, pedicled flaps had complication rates similar to those of free flaps on univariate analysis (odds ratio [OR] = 1.12, 95% confidence interval [CI] = 0.56-2.26, p = 0.75). Conversely, in the upper limb, pedicled flaps were associated with fewer complications on univariate analysis (OR = 0.31, 95% CI = 0.11-0.86, p = 0.03), but this was not significant on multivariate analysis (OR = 0.45, 95% CI = 0.13-1.59, p = 0.22). Obesity was a strong predictor of complications in the upper limb group on multivariate analysis (body mass index [BMI] >= 30 kg/m2, OR = 7.01, 95% CI = 1.28-38.51, p = 0.03). There was no significant difference in functional outcomes between both flap groups in either upper or lower limbs. CONCLUSIONS: Postoperative complications and functional outcomes for patients undergoing free and pedicled flaps are similar in ESTS reconstruction. Selecting the most suitable reconstructive option in each individual case is paramount to preserving function while minimizing postoperative morbidity. PMID- 29706553 TI - Keeping the fat on the right spot prevents contour deformity in temporalis muscle transposition. AB - The temporalis muscle transposition is a reliable, one-stage reanimation technique for longstanding facial paralysis. In the variation described by Rubin, the muscle is released from the temporal bone and folded over the zygomatic arch towards the modiolus. This results in unsightly temporal hollowing and zygomatic bulging. We present a modification of this technique, which preserves the temporal fat pad in its anatomical location as well as conceals temporal hollowing and prevents zygomatic bulging. The data of 23 patients treated with this modification were analysed. May classification was used for evaluation of mouth reanimation. Experts and patients scored visibility of the contour deformity on a 100-mm visual analogue scale (VAS) (score 0 = poor/100 = best). 3D images of the face were used to measure temporal hollowing and zygomatic bulging. 3D images were compared to those of controls with a similar gender and age distribution. After a median follow-up of 5.7 years, all patients achieved symmetry at rest. Eleven patients achieved symmetry while smiling with closed lips (May classification "Good"). A median (interquartile range [IQR]) VAS score of 19 (6; 41) was given by experts and 25 (5; 59) by patients themselves. 3D volumes of zygomatic bulging differed from those of control subjects, although all volume differences were small (median <3.3 ml) and temporal hollowing did not differ significantly. On the basis of our results, we conclude that our modified Rubin temporalis transposition technique provides an elegant way to conceal bulging over the zygomatic arch and prevents temporal hollowing, without the need for fascial extensions to reach the modiolus. PMID- 29706554 TI - [Deferred versus immediate stenting in patients with ST - segment elevation myocardial infarction and residual large thrombus burden reclassified in the culprit lesion]. AB - BACKGROUND: Reclassification of a large thrombus burden is an independent predictor of major adverse cardiac events and no-reflow in patients with ST- segment elevation myocardial infarction (STEMI). Patients with a greater residual thrombus burden have worse microvascular dysfunction and greater myocardial damage. METHODS: A retrospective analysis was performed on 833 STEMI patients who underwent primary percutaneous coronary intervention. The final residual thrombus burden was reclassified after the lesion was wired, and a thrombus aspiration or balloon dilatation was performed to restore and stabilise a thrombolysis in myocardial infarction (TIMI) 2-3 flow. Deferred stenting (DEI) was compared with immediate stenting (ISI) group, and the primary outcome was the incidence of no /slow-reflow (TIMI <= 2, or TIMI 3 with myocardial blush grade < 2). RESULTS: Overall, 47 patients (6.8%) had a residual large thrombus burden reclassified. The right coronary artery was the culprit vessel in 34 cases. More patients had coronary ectasia in the DSI group (P=.005). Fewer patients in the DSI had no /slow-reflow (36% vs. 58%), and the myocardial blush grade 3 was more frequent in the DSI group (P=.005). After repeat coronary angiography in the DSI group, stenting was not performed in 56%, and oral anticoagulation was more frequent in the follow-up (P=.031). Major cardiac adverse events were similar between groups. There was a tendency to better left ventricular function in the DSI group (P=.056). CONCLUSIONS: Deferred stenting may be an efficient option in STEMI patients with a residual large thrombus burden reclassified after achieving a stable TIMI 2-3 flow. PMID- 29706555 TI - Trajectories in hypnotic use and approaching death: a register linked case control study. AB - PURPOSE: Whether the association between hypnotic and increased mortality risk is created by causation or confounding, has been long debated. We further examined the possibility of confounding by indication with a comprehensive approach. METHODS: The National FINRISK Study cohorts of 1997, 2002, and 2007 (25,436 participants aged 25-74) were followed up until July 2012. There were 1822 deaths, and at least one gender, baseline age and cohort matched 'control' was found for 1728 'cases' yielding a final analytical sample of 3955 individuals. An index age, equivalent to the age at death of their respective cases' was set for each control. Hypnotic drug purchases were followed from the Finnish nationwide register during a 36-month run-up period before the date of death/index date. The prevalence and incidence of hypnotic purchases were compared between cases and matched controls. Moreover, latent developmental trajectories of purchases were modelled and their relations with specific and all-cause death risks were analysed. RESULTS: An increasing difference between cases and controls was observed as regards the use of hypnotic drugs. During the last 30 months before the date of death/index date, the rate ratio of incident purchases between cases and controls was 2.37 (95% CL, 1.79-3.12) among older and 3.61 (95% CL, 2.37 5.89) among younger individuals. The developmental trajectories of hypnotic drug purchases were differently and by interpretation plausibly associated with specific mortality risks. CONCLUSIONS: In most cases the association between hypnotics and mortality risk is created by symptomatic treatment when death is approaching. PMID- 29706556 TI - Liquid biopsies: DNA methylation analyses in circulating cell-free DNA. AB - Analysis of patient's materials like cells or nucleic acids obtained in a minimally invasive or noninvasive manner through the sampling of blood or other body fluids serves as liquid biopsies, which has huge potential for numerous diagnostic applications. Circulating cell-free DNA (cfDNA) is explored as a prognostic or predictive marker of liquid biopsies with the improvements in genomic and molecular methods. DNA methylation is an important epigenetic marker known to affect gene expression. cfDNA methylation detection is a very promising approach as abnormal distribution of DNA methylation is one of the hallmarks of many cancers and methylation changes occur early during carcinogenesis. This review summarizes the various investigational applications of cfDNA methylation and its oxidized derivatives as biomarkers for cancer diagnosis, prenatal diagnosis and organ transplantation monitoring. The review also provides a brief overview of the technologies for cfDNA methylation analysis based on next generation sequencing. PMID- 29706557 TI - Boundaries Shape Cognitive Representations of Spaces and Events. AB - Efficient navigation from one place to another is facilitated by the ability to use spatial boundaries to segment routes into their component parts. Similarly, memory for individual episodes relies on the ability to use shifts in spatiotemporal contexts to segment the ongoing stream of experience. The segmentation of experiences in spatial and episodic domains may therefore share neural underpinnings, manifesting in similar behavioral phenomena and cognitive biases. Here, we review evidence for such shared mechanisms, focusing on the key role of boundaries in spatial and episodic memory. We propose that a fundamental event boundary detection mechanism enables navigation in both the spatial and episodic domains, and serves to form cohesive representations that can be used to predict and guide future behavior. PMID- 29706559 TI - PALB2 as a familial gastric cancer gene: is the wait over? PMID- 29706558 TI - Germline pathogenic variants in PALB2 and other cancer-predisposing genes in families with hereditary diffuse gastric cancer without CDH1 mutation: a whole exome sequencing study. AB - BACKGROUND: Germline pathogenic variants in the E-cadherin gene (CDH1) are strongly associated with the development of hereditary diffuse gastric cancer. There is a paucity of data to guide risk assessment and management of families with hereditary diffuse gastric cancer that do not carry a CDH1 pathogenic variant, making it difficult to make informed decisions about surveillance and risk-reducing surgery. We aimed to identify new candidate genes associated with predisposition to hereditary diffuse gastric cancer in affected families without pathogenic CDH1 variants. METHODS: We did whole-exome sequencing on DNA extracted from the blood of 39 individuals (28 individuals diagnosed with hereditary diffuse gastric cancer and 11 unaffected first-degree relatives) in 22 families without pathogenic CDH1 variants. Genes with loss-of-function variants were prioritised using gene-interaction analysis to identify clusters of genes that could be involved in predisposition to hereditary diffuse gastric cancer. FINDINGS: Protein-affecting germline variants were identified in probands from six families with hereditary diffuse gastric cancer; variants were found in genes known to predispose to cancer and in lesser-studied DNA repair genes. A frameshift deletion in PALB2 was found in one member of a family with a history of gastric and breast cancer. Two different MSH2 variants were identified in two unrelated affected individuals, including one frameshift insertion and one previously described start-codon loss. One family had a unique combination of variants in the DNA repair genes ATR and NBN. Two variants in the DNA repair gene RECQL5 were identified in two unrelated families: one missense variant and a splice-acceptor variant. INTERPRETATION: The results of this study suggest a role for the known cancer predisposition gene PALB2 in families with hereditary diffuse gastric cancer and no detected pathogenic CDH1 variants. We also identified new candidate genes associated with disease risk in these families. FUNDING: UK Medical Research Council (Sackler programme), European Research Council under the European Union's Seventh Framework Programme (2007-13), National Institute for Health Research Cambridge Biomedical Research Centre, Experimental Cancer Medicine Centres, and Cancer Research UK. PMID- 29706560 TI - Androgen Receptor CAG Repeat Length as a Risk Factor of Late-Onset Hypogonadism in a Korean Male Population. AB - BACKGROUND: Testosterone action is mediated through the androgen receptor (AR), whose sensitivity is influenced by the AR CAG repeat polymorphism. However, the relation between late-onset hypogonadism (LOH) and AR CAG repeat length is unclear and studies of Asian populations are limited. AIM: To investigate the relation between AR CAG repeat length and LOH in Korean men. METHODS: 263 Korean men (mean age = 63.43 +/- 10.9 years) were enrolled from 2014 to 2015. LOH diagnosis was based on a serum testosterone level lower than 3.5 ng/mL and positive androgen deficiency according to the Aging Males' Symptom Scale (AMS). Total testosterone levels and answers to the LOH-related questionnaire were analyzed. OUTCOMES: The relation between AR CAG repeat length and LOH was determined. RESULTS: Mean CAG repeat length was 22.1 +/- 4.6 and mean serum testosterone levels were 2.6 +/- 0.7 and 6.0 +/- 2.0 ng/mL in men with and without LOH, respectively. Men with LOH showed significantly longer AR CAG repeat lengths than men without LOH (26.1 vs 21.6, P < .001). Longer CAG repeat lengths were correlated with higher AMS total scores (r = 0.454, P = .001) and AMS psychotic, somatic, and sexual sub-scores (r = 0.276, 0.246, and 0.571, P = .006, .007, .001, respectively) and significantly lower 5-item International Index of Erectile Function scores (r = -0.261, P = .001). Multivariate analysis showed that patient age and CAG repeat length were independently associated with LOH (odds ratio = 1.05 and 1.29, P = .041 and <.001, respectively). CLINICAL IMPLICATIONS: A longer CAG repeat length is associated with LOH symptoms and LOH. STRENGTHS AND LIMITATIONS: Associations between CAG repeats and LOH were verified in Korean patients. Moreover, a longer CAG repeat length was shown to be an independent risk factor for LOH. Limitations included the small number of LOH patients studied and that other sex hormone-associated factors were not measured. CONCLUSIONS: AR CAG repeat length was associated with LOH prevalence and clinical symptoms in this Korean male population. Thus, it is important to measure CAG repeat length for patients with LOH symptoms with normal testosterone levels. Kim JW, Bae YD, Ahn ST, et al. Androgen Receptor CAG Repeat Length as a Risk Factor of Late-Onset Hypogonadism in a Korean Male Population. Sex Med 2018;6:203-209. PMID- 29706561 TI - Sexual Health During Postgraduate Training-European Survey Across Medical Specialties. AB - BACKGROUND: Sexual health problems are common. Therefore, training in sexual health is relevant for the clinical practice of trainees and early-career specialists in several specialties who deal with patients with sexual health problems. However, little is known about how sexual health training is provided across countries and specialties. AIM: To assess (i) sexual health training during postgraduate training programs in psychiatry, obstetrics and gynecology, urology, and endocrinology across Europe; (ii) the confidence of trainees and early-career specialists in dealing with patients with sexual health problems; and (iii) their need for further training in sexual health during postgraduate training programs. METHODS: The study was based on a collaboration among European societies of trainees in these 4 specialties. An online survey was developed and conducted from January 2015 through June 2016. MAIN OUTCOME MEASURES: Self reported questionnaire. RESULTS: We collected 366 completed surveys from 40 countries. Sexual health training was considered an important or very important part of specialty training by 78.7% of participants. Overall, 62.3% of participants had not received any training in sexual health. Especially in obstetrics and gynecology, the large majority did not have training in sexual health (82.8%), followed by psychiatry (59.8%), urology (58.4%), and endocrinology (56.1%). There were statistically significant differences among specialties in the confidence of participants in managing patients with sexual health problems. In general, trainees and early-career specialists who had received sexual health training felt more confident in dealing with patients with gender dysphoria (P = .011), need for sexual therapy (P = .0004), paraphilic disorders (P = .0003), and sexual dysfunction (P = .0017). CONCLUSIONS: Trainees and early-career specialists found sexual health training important for their future medical practice; however, less than half received it during their postgraduate training. Participants felt more confident in managing patients with sexual health problems when sexual health training was included in the postgraduate training program. Kristufkova A, Pinto Da Costa M, Mintziori G, et al. Sexual Health During Postgraduate Training-European Survey Across Medical Specialties. Sex Med 2018;6:255-262. PMID- 29706562 TI - Implications of WASH Benefits trials for water and sanitation - Authors' reply. PMID- 29706563 TI - Implications of WASH Benefits trials for water and sanitation. PMID- 29706564 TI - Implications of WASH Benefits trials for water and sanitation. PMID- 29706566 TI - FGF21 Prevents Angiotensin II-Induced Hypertension and Vascular Dysfunction by Activation of ACE2/Angiotensin-(1-7) Axis in Mice. AB - Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity. However, the role of FGF21 in hypertension remains elusive. Here we show that FGF21 deficiency significantly exacerbates angiotensin II-induced hypertension and vascular dysfunction, whereas such negative effects are reversed by replenishment of FGF21. Mechanistically, FGF21 acts on adipocytes and renal cells to promote induction of angiotensin-converting enzyme 2 (ACE2), which in turn converts angiotensin II to angiotensin-(1-7), then inhibits hypertension and reverses vascular damage. In addition, ACE2 deficiency strikingly abrogates these beneficial effects of FGF21 in mice, including alleviation of angiotensin II associated hypertension and vascular damage. Otherwise, pharmaceutical inhibition of angiotensin-(1-7) attenuates the protective effect of FGF21 on angiotensin II induced vascular dysfunction, but not on hypertension. Thus, FGF21 protects against angiotensin II-induced hypertension and vascular impairment by activation of the ACE2/angiotensin-(1-7) axis via fine-tuning the multi-organ crosstalk between liver, adipose tissue, kidney, and blood vessels. PMID- 29706565 TI - Aldolase B-Mediated Fructose Metabolism Drives Metabolic Reprogramming of Colon Cancer Liver Metastasis. AB - Cancer metastasis accounts for the majority of cancer-related deaths and remains a clinical challenge. Metastatic cancer cells generally resemble cells of the primary cancer, but they may be influenced by the milieu of the organs they colonize. Here, we show that colorectal cancer cells undergo metabolic reprogramming after they metastasize and colonize the liver, a key metabolic organ. In particular, via GATA6, metastatic cells in the liver upregulate the enzyme aldolase B (ALDOB), which enhances fructose metabolism and provides fuel for major pathways of central carbon metabolism during tumor cell proliferation. Targeting ALDOB or reducing dietary fructose significantly reduces liver metastatic growth but has little effect on the primary tumor. Our findings suggest that metastatic cells can take advantage of reprogrammed metabolism in their new microenvironment, especially in a metabolically active organ such as the liver. Manipulation of involved pathways may affect the course of metastatic growth. PMID- 29706567 TI - DGAT2 Inhibition Alters Aspects of Triglyceride Metabolism in Rodents but Not in Non-human Primates. AB - Diacylglycerol acyltransferase 2 (DGAT2) catalyzes the final step in triglyceride (TG) synthesis and has been shown to play a role in regulating hepatic very-low density lipoprotein (VLDL) production in rodents. To explore the potential of DGAT2 as a therapeutic target for the treatment of dyslipidemia, we tested the effects of small-molecule inhibitors and gene silencing both in vitro and in vivo. Consistent with prior reports, chronic inhibition of DGAT2 in a murine model of obesity led to correction of multiple lipid parameters. In contrast, experiments in primary human, rhesus, and cynomolgus hepatocytes demonstrated that selective inhibition of DGAT2 has only a modest effect. Acute and chronic inhibition of DGAT2 in rhesus primates recapitulated the in vitro data yielding no significant effects on production of plasma TG or VLDL apolipoprotein B. These results call into question whether selective inhibition of DGAT2 is sufficient for remediation of dyslipidemia. PMID- 29706568 TI - Hemopericardium After TAVR: Assessment. PMID- 29706569 TI - Continuous Erector Spinae Plane (ESP) Block: Optimizing the Analgesia Technique. PMID- 29706570 TI - Tetralogy of Fallot: Perioperative Management and Analysis of Outcomes. PMID- 29706571 TI - Anesthetic Considerations in a Patient With Large Anterior Mediastinal Mass. PMID- 29706572 TI - Inhibitory potentials of phenolic-rich extracts from Bridelia ferruginea on two key carbohydrate-metabolizing enzymes and Fe2+-induced pancreatic oxidative stress. AB - OBJECTIVE: The current study was designed to evaluate the various antioxidant potentials and inhibitory effects of phenolic-rich leaf extracts of Bridelia ferruginea (BF) on the in vitro activities of some key enzymes involved in the metabolism of carbohydrates. METHODS: In this study, BF leaf free and bound phenolic-rich extracts were used. We quantified total phenolic and flavonoid contents, and evaluated several antioxidant activities using assays for ferric reducing antioxidant power, total antioxidant activity (phosphomolybdenum reducing ability), 1,1-diphenyl-2-picrylhydrazyl and thiobarbituric acid reactive species. Also, extracts were tested for their ability to inhibit alpha-amylase and alpha-glucosidase activity. RESULTS: The total phenolic and total flavonoid contents in the free phenolic extract of BF were significantly greater than in the bound phenolic extract. Also, all the antioxidant activities considered were significantly greater in the free phenolic extract than in the bound phenolic extract. In the same vein, the free phenolic-rich extract had a significantly higher percentage inhibition against alpha-glucosidase activity (IC50 = 28.5 ug/mL) than the bound phenolic extract (IC50 = 340.0 ug/mL). On the contrary, the free phenolic extract (IC50 = 210.0 ug/mL) had significantly lower inhibition against alpha-amylase than the bound phenolic-rich extract (IC50 = 190.0 ug/mL). CONCLUSION: The phenolic-rich extracts of BF leaves showed antioxidant potentials and inhibited two key carbohydrate-metabolizing enzymes in vitro. PMID- 29706573 TI - Evaluation of phenolic composition, antioxidant, anti-inflammatory and anticancer activities of Polygonatum verticillatum (L.). AB - OBJECTIVE: Polygonatum verticillatum (L.) All. (Ruscaceae), one of the Ashtawarga plants, is widely used for treatment of various ailments. The present study was undertaken to determine the phenolic composition, antioxidant, anti-inflammatory and anticancer activities of several extracts (petroleum ether, dichloromethane, chloroform, ethanol, and aqueous) from the rhizomes of the plant. METHODS: Coarsely powdered dry rhizome was successively extracted with different solvents of increasing polarity (petroleum ether, dichloromethane, chloroform, ethanol and water). The phenolic compositions, in terms of total phenolic content (TPC), total flavonoid content (TFC) and total condensed tannin content (TTC), were evaluated with the Folin-Ciocalteu assay, aluminum chloride colorimetric assay and vanillin spectrophotometric assay, respectively. Total antioxidant capacity, 1,1-diphenyl-2-picrylhydrazyl and 2,2'-azino-bis(3-ethylbenzothiazoline-6 sulfonic acid) assays were used to assess the antioxidant potential of each extract. A protein denaturation model and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay were used to evaluate in vitro anti inflammatory and anticancer activities, respectively. Gas chromatography-mass spectrometry (GC/MS) analysis was carried out to demonstrate various phytoconstituents in each extract. Correlation studies were also performed between phenolic composition (TPC, TFC and TTC) and different biological activities. RESULTS: Ethanol extract showed maximum TPC (0.126 mg/g, gallic acid equivalent in dry sample), TFC (0.094 mg/g, rutin equivalent in dry sample) and TTC (29.32 mg/g, catechin equivalent in dry sample), as well as antioxidant and anti-inflammatory properties. Chloroform extract exhibited the strongest cytotoxicity against the human breast cancer cell line, MCF-7. GC/MS analysis revealed the presence of 90 different phytoconstituents among the extracts. Antioxidant and anti-inflammatory activities had a positive correlation with TPC, TFC and TTC. However, the anticancer activity showed a negative correlation with TPC, TFC and TTC. CONCLUSION: From the present study, it can be concluded that P. verticillatum possessed remarkable antioxidant, anti-inflammatory, and anticancer activities, which could be due to different secondary metabolites of the plant. Phenolic compounds are likely responsible for antioxidant and anti-inflammatory activities. However, flavonoids and other compounds might contribute to the anticancer potential of the plant. PMID- 29706574 TI - Early detection of cardiac allograft vasculopathy using highly automated 3 dimensional optical coherence tomography analysis. AB - BACKGROUND: Optical coherence tomography (OCT)-based studies of cardiac allograft vasculopathy (CAV) published thus far have focused mainly on frame-based qualitative analysis of the vascular wall. Full capabilities of this inherently 3 dimensional (3D) imaging modality to quantify CAV have not been fully exploited. METHODS: Coronary OCT imaging was performed at 1 month and 12 months after heart transplant (HTx) during routine surveillance cardiac catheterization. Both baseline and follow-up OCT examinations were analyzed using proprietary, highly automated 3D graph-based optimal segmentation software. Automatically identified borders were efficiently adjudicated using our "just-enough-interaction" graph based segmentation approach that allows to efficiently correct local and regional segmentation errors without slice-by-slice retracing of borders. RESULTS: A total of 50 patients with paired baseline and follow-up OCT studies were included. After registration of baseline and follow-up pullbacks, a total of 356 +/- 89 frames were analyzed per patient. During the first post-transplant year, significant reduction in the mean luminal area (p = 0.028) and progression in mean intimal thickness (p = 0.001) were observed. Proximal parts of imaged coronary arteries were affected more than distal parts (p < 0.001). High levels of LDL cholesterol (p = 0.02) and total cholesterol (p = 0.031) in the first month after HTx were the main factors associated with early CAV development. CONCLUSIONS: Our novel, highly automated 3D OCT image analysis method for analyzing intimal and medial thickness in HTx recipients provides fast, accurate, and highly detailed quantitative data on early CAV changes, which are characterized by significant luminal reduction and intimal thickness progression as early as within the first 12 months after HTx. PMID- 29706575 TI - First identification of clinical isolate of a Novel "NDM-4" producing Escherichia coli ST405 from urine sample in Pakistan. PMID- 29706576 TI - Antifungal activity of Gallesia integrifolia fruit essential oil. AB - Gallesia integrifolia (Phytolaccaceae) is native to Brazil and has a strong alliaceous odor. The objective of this study was to identify the chemical composition of G. integrifolia fruit essential oil and evaluate fungicidal activity against the main food-borne diseases and food spoilage fungi. The essential oil was extracted by hydrodistillation and identified by GC-MS. From 35 identified compounds, 68% belonged to the organosulfur class. The major compounds were dimethyl trisulfide (15.49%), 2,8-dithianonane (52.63%) and lenthionine (14.69%). The utilized fungi were Aspergillus fumigatus, Aspergillus niger, Aspergillus ochraceus, Aspergillus versicolor, Penicillium funiculosum, Penicillium ochrochloron, Penicillium verrucosum var. cyclopium, and Trichoderma viride. Minimal fungicidal concentration for the essential oil varied from 0.02 to 0.18mg/mL and bifonazole and ketoconazole controls ranged from 0.20 to 3.50mg/mL. The lower concentration of the essential oil was able to control P. ochrochloron, A. fumigatus, A. versicolor, A. ochraceus and T. viride. This study shows a high fungicidal activity of G. integrifolia fruit essential oil and can support future applications by reducing the use of synthetic fungicides. PMID- 29706578 TI - Does Depth Matter? Factors Affecting Choice of Vulvoplasty Over Vaginoplasty as Gender-Affirming Genital Surgery for Transgender Women. AB - BACKGROUND: Gender-affirming vaginoplasty aims to create the external female genitalia (vulva) as well as the internal vaginal canal; however, not all patients desire nor can safely undergo vaginal canal creation. AIM: Our objective is to describe the factors influencing patient choice or surgeon recommendation of vulvoplasty and to assess the patient's satisfaction with this choice. METHODS: Gender-affirming genital surgery consults were reviewed from March 2015 until December 2017, and patients scheduled for or who had completed vulvoplasty were interviewed by telephone. OUTCOMES: We report demographic data and the reasons for choosing vulvoplasty as gender-affirming surgery for patients who either completed or were scheduled for surgery, in addition to patient reports of satisfaction with choice of surgery, satisfaction with the surgery itself, and sexual activity after surgery. RESULTS: In total, 486 patients were seen in consultation for trans-feminine gender-affirming genital surgery: 396 requested vaginoplasty and 39 patients requested vulvoplasty. 30 Patients either completed or are scheduled for vulvoplasty. Vulvoplasty patients were older and had higher body mass index than those seeking vaginoplasty. The majority (63%) of the patients seeking vulvoplasty chose this surgery despite no contra-indications to vaginoplasty. The remaining patients had risk factors leading the surgeon to recommend vulvoplasty. Of those who completed surgery, 93% were satisfied with the surgery and their decision for vulvoplasty. CLINICAL TRANSLATION: Vulvoplasty creates the external appearance of female genitalia without creation of a neovaginal canal; it is associated with high satisfaction and low decision regret. CONCLUSIONS: This is the first study of factors impacting a patient's choice of or a surgeon's recommendation for vulvoplasty over vaginoplasty as gender-affirming genital surgery; it also is the first reported series of patients undergoing vulvoplasty only. Limitations of this study include its retrospective nature, non-validated questions, short-term follow-up, and selection bias in how we offer vulvoplasty. Vulvoplasty is a form of gender affirming feminizing surgery that does not involve creation of a neovagina, and it is associated with high satisfaction and low decision regret. Jiang D, Witten J, Berli J, et al. Does Depth Matter? Factors Affecting Choice of Vulvoplasty Over Vaginoplasty as Gender-Affirming Genital Surgery for Transgender Women. J Sex Med 2018;15:902-906. PMID- 29706577 TI - Spred1 Safeguards Hematopoietic Homeostasis against Diet-Induced Systemic Stress. AB - Stem cell self-renewal is critical for tissue homeostasis, and its dysregulation can lead to organ failure or tumorigenesis. While obesity can induce varied abnormalities in bone marrow components, it is unclear how diet might affect hematopoietic stem cell (HSC) self-renewal. Here, we show that Spred1, a negative regulator of RAS-MAPK signaling, safeguards HSC homeostasis in animals fed a high fat diet (HFD). Under steady-state conditions, Spred1 negatively regulates HSC self-renewal and fitness, in part through Rho kinase activity. Spred1 deficiency mitigates HSC failure induced by infection mimetics and prolongs HSC lifespan, but it does not initiate leukemogenesis due to compensatory upregulation of Spred2. In contrast, HFD induces ERK hyperactivation and aberrant self-renewal in Spred1-deficient HSCs, resulting in functional HSC failure, severe anemia, and myeloproliferative neoplasm-like disease. HFD-induced hematopoietic abnormalities are mediated partly through alterations to the gut microbiota. Together, these findings reveal that diet-induced stress disrupts fine-tuning of Spred1-mediated signals to govern HSC homeostasis. PMID- 29706579 TI - Does Endometriosis Affect Sexual Activity and Satisfaction of the Man Partner? A Comparison of Partners From Women Diagnosed With Endometriosis and Controls. AB - BACKGROUND: Endometriosis-associated pain and dyspareunia influence female sexuality, but little is known about men's experiences in affected couples. AIM: To investigate how men partners experience sexuality in partnership with women with endometriosis. METHODS: A multi-center case-control study was performed between 2010 and 2015 in Switzerland, Germany, and Austria. 236 Partners of endometriosis patients and 236 partners of age-matched control women without endometriosis with a similar ethnic background were asked to answer selected, relevant questions of the Brief Index of Sexual Functioning and the Global Sexual Functioning questionnaire, as well as some investigator-derived questions. OUTCOMES: We sought to evaluate sexual satisfaction of men partners of endometriosis patients, investigate differences in sexual activities between men partners of women with and without endometriosis, and identify options to improve partnership sexuality in couples affected by endometriosis. RESULTS: Many partners of endometriosis patients reported changes in sexuality (75%). A majority of both groups was (very) satisfied with their sexual relationship (73.8% vs 58.1%, P = .002). Nevertheless, more partners of women diagnosed with endometriosis were not satisfied (P = .002) and their sexual problems more strongly interfered with relationship happiness (P = .001) than in partners of control women. Frequencies of sexual intercourse (P < .001) and all other partnered sexual activities (oral sex, petting) were significantly higher in the control group. The wish for an increased frequency of sexual activity (P = .387) and sexual desire (P = .919) did not differ statistically between both groups. CLINICAL TRANSLATION: There is a need to evaluate qualitative factors that influence sexual satisfaction in endometriosis patients. CONCLUSIONS: This is one of the first studies to investigate male sexuality affected by endometriosis. The meticulous verification of diagnosis and disease stage according to operation reports and histology allows for a high reliability of diagnosis. Our men's response rate of almost 50% is higher compared to other studies. Recruiting men through their woman partner may have caused selection bias. The adjustment to the specific situation in endometriosis by selecting questions from the Brief Index of Sexual Functioning and Global Sexual Functioning and adding investigator derived questions likely influenced the validity of the questionnaires. Despite the fact that both partners of endometriosis patients and of control women largely reported high sexual satisfaction, there are challenges for some couples that arise in the context of a sexual relationship when one partner has endometriosis. Challenges such as sexuality-related pain or a reduced frequency of sexual activities should be addressed by health care professionals to ameliorate any current difficulties and to prevent the development or aggravation of sexual dysfunction. Hammerli S, Kohl Schwartz AS, Geraedts K, et al. Does Endometriosis Affect Sexual Activity and Satisfaction of the Man Partner? A Comparison of Partners From Women Diagnosed With Endometriosis and Controls. J Sex Med 2018;15:853-865. PMID- 29706580 TI - Do complications following pancreatic resections impact hospital costs in France: Medico-economic study on 127 patients. AB - OBJECTIVE: To define the cost of pancreatectomies and to identify factors associated with increased hospital costs after pancreatic resection. METHODS: All patients undergoing pancreatic surgery in our department between January 2008 and December 2014 were included. All complications occurring during hospitalization or in the 90-day period after discharge were documented. The hospital costs were analyzed and predictive factors of increased hospital costs were determined. RESULTS: One hundred and twenty seven patients were identified. Most patients underwent pancreatectomy for malignant tumors (70%). Median hospital costs were 21,392 [15,998-29,667] euros. Age (P=0.011) and preoperative jaundice (P<0.001) were associated with higher hospital costs. Intraoperative surgical time and blood loss were correlated with increased costs (P=0.001 and P=0.002, respectively). Pancreatoduodenectomy was associated with statistically significantly higher costs compared to distal pancreatectomy (21,770 vs. 15,422 euros, P=0.001). Severe postoperative complications (Clavien-Dindo grade>=3) (P=0.001), septic complications (P=0.002) and hemorrhage (P=0.001) statistically significantly increased costs. In multivariate analysis, septic (P=0.003) and severe complications (P=0.01) were statistically significantly associated with increased hospital costs. CONCLUSION: Pancreatic surgery is associated with high hospital costs, essentially related to postoperative complications. PMID- 29706581 TI - Cortical Circuit Activity Evokes Rapid Astrocyte Calcium Signals on a Similar Timescale to Neurons. AB - Sensory stimulation evokes intracellular calcium signals in astrocytes; however, the timing of these signals is disputed. Here, we used novel combinations of genetically encoded calcium indicators for concurrent two-photon imaging of cortical astrocytes and neurons in awake mice during whisker deflection. We identified calcium responses in both astrocyte processes and endfeet that rapidly followed neuronal events (~120 ms after). These fast astrocyte responses were largely independent of IP3R2-mediated signaling and known neuromodulator activity (acetylcholine, serotonin, and norepinephrine), suggesting that they are evoked by local synaptic activity. The existence of such rapid signals implies that astrocytes are fast enough to play a role in synaptic modulation and neurovascular coupling. VIDEO ABSTRACT. PMID- 29706582 TI - The GABAA Receptor beta Subunit Is Required for Inhibitory Transmission. AB - While the canonical assembly of a GABAA receptor contains two alpha subunits, two beta subunits, and a fifth subunit, it is unclear which variants of each subunit are necessary for native receptors. We used CRISPR/Cas9 to dissect the role of the GABAA receptor beta subunits in inhibitory transmission onto hippocampal CA1 pyramidal cells and found that deletion of all beta subunits 1, 2, and 3 completely eliminated inhibitory responses. In addition, only knockout of beta3, alone or in combination with another beta subunit, impaired inhibitory synaptic transmission. We found that beta3 knockout impairs inhibitory input from PV but not SOM expressing interneurons. Furthermore, expression of beta3 alone on the background of the beta1-3 subunit knockout was sufficient to restore synaptic and extrasynaptic inhibitory transmission. These findings reveal a crucial role for the beta3 subunit in inhibitory transmission and identify a synapse-specific role of the beta3 subunit in GABAergic synaptic transmission. PMID- 29706583 TI - Serotonergic Signaling Controls Input-Specific Synaptic Plasticity at Striatal Circuits. AB - Monoaminergic modulation of cortical and thalamic inputs to the dorsal striatum (DS) is crucial for reward-based learning and action control. While dopamine has been extensively investigated in this context, the synaptic effects of serotonin (5-HT) have been largely unexplored. Here, we investigated how serotonergic signaling affects associative plasticity at glutamatergic synapses on the striatal projection neurons of the direct pathway (dSPNs). Combining chemogenetic and optogenetic approaches reveals that impeding serotonergic signaling preferentially gates spike-timing-dependent long-term depression (t-LTD) at thalamostriatal synapses. This t-LTD requires dampened activity of the 5-HT4 receptor subtype, which we demonstrate controls dendritic Ca2+ signals by regulating BK channel activity, and which preferentially localizes at the dendritic shaft. The synaptic effects of 5-HT signaling at thalamostriatal inputs provide insights into how changes in serotonergic levels associated with behavioral states or pathology affect striatal-dependent processes. PMID- 29706586 TI - Childhood Adversities and Thriving Skills: Sample Case of Older Swiss Former Indentured Child Laborers. AB - OBJECTIVE: The study of life-long consequences of severe childhood adversities or trauma has recently received much attention. However, little is known about the subjective coping success and development of positively evaluated resources that may originate within these adverse experiences and may be conceptualized as thriving. This study set out to examine the relationship between thriving in response to early adversity and successful aging with a sample of former indentured child laborers in Switzerland (Verdingkinder). METHODS: Participants were screened according to subjective and objective health-related attributes, and those who were evaluated to be "successful agers" were included. Semistructured interviews were conducted with 12 former Verdingkinder (mean age: 71 years) that lasted 60-120 minutes. The interviews were analyzed using the paradigm model of the Grounded Theory. RESULTS: In the interviews adverse experiences and negative consequences were reported. However, where thriving was triggered in response to these experiences, the factors identified as "lightheartedness," "social purpose," and "self-enhancement" were associated with successful aging. Factors including motivation, reflection, personality traits, social support, individual coping strategies, turning points, and processing were reported as central to thriving. CONCLUSION: The identified factors show similarities with established predictors of health and well-being. Thus, under certain circumstances early and prolonged adverse experiences can also provide the opportunity to develop positive resources for successful aging. PMID- 29706585 TI - Odor Perception on the Two Sides of the Brain: Consistency Despite Randomness. AB - Neurons in piriform cortex receive input from a random collection of glomeruli, resulting in odor representations that lack the stereotypic organization of the olfactory bulb. We have performed in vivo optical imaging and mathematical modeling to demonstrate that correlations are retained in the transformation from bulb to piriform cortex, a feature essential for generalization across odors. Random connectivity also implies that the piriform representation of a given odor will differ among different individuals and across brain hemispheres in a single individual. We show that these different representations can nevertheless support consistent agreement about odor quality across a range of odors. Our model also demonstrates that, whereas odor discrimination and categorization require far fewer neurons than reside in piriform cortex, consistent generalization may require the full complement of piriform neurons. PMID- 29706584 TI - Ras and Rap Signal Bidirectional Synaptic Plasticity via Distinct Subcellular Microdomains. AB - How signaling molecules achieve signal diversity and specificity is a long standing cell biology question. Here we report the development of a targeted delivery method that permits specific expression of homologous Ras-family small GTPases (i.e., Ras, Rap2, and Rap1) in different subcellular microdomains, including the endoplasmic reticulum, lipid rafts, bulk membrane, lysosomes, and Golgi complex, in rodent hippocampal CA1 neurons. The microdomain-targeted delivery, combined with multicolor fluorescence protein tagging and high resolution dual-quintuple simultaneous patch-clamp recordings, allows systematic analysis of microdomain-specific signaling. The analysis shows that Ras signals long-term potentiation via endoplasmic reticulum PI3K and lipid raft ERK, whereas Rap2 and Rap1 signal depotentiation and long-term depression via bulk membrane JNK and lysosome p38MAPK, respectively. These results establish an effective subcellular microdomain-specific targeted delivery method and unveil subcellular microdomain-specific signaling as the mechanism for homologous Ras and Rap to achieve signal diversity and specificity to control multiple forms of synaptic plasticity. PMID- 29706587 TI - Frontostriatal Dysfunction During Decision Making in Attention Deficit/Hyperactivity Disorder and Obsessive-Compulsive Disorder. AB - BACKGROUND: The aim of the current paper is to provide the first comparison of computational mechanisms and neurofunctional substrates in adolescents with attention-deficit/hyperactivity disorder (ADHD) and adolescents with obsessive compulsive disorder (OCD) during decision making under ambiguity. METHODS: Sixteen boys with ADHD, 20 boys with OCD, and 20 matched control subjects (12-18 years of age) completed a functional magnetic resonance imaging version of the Iowa Gambling Task. Brain activation was compared between groups using three-way analysis of covariance. Hierarchical Bayesian analysis was used to compare computational modeling parameters between groups. RESULTS: Patient groups shared reduced choice consistency and relied less on reinforcement learning during decision making relative to control subjects, while adolescents with ADHD alone demonstrated increased reward sensitivity. During advantageous choices, both disorders shared underactivation in ventral striatum, while OCD patients showed disorder-specific underactivation in the ventromedial orbitofrontal cortex. During outcome evaluation, shared underactivation to losses in patients relative to control subjects was found in the medial prefrontal cortex and shared underactivation to wins was found in the left putamen/caudate. ADHD boys showed disorder-specific dysfunction in the right putamen/caudate, which was activated more to losses in patients with ADHD but more to wins in control subjects. CONCLUSIONS: The findings suggest shared deficits in using learned reward expectancies to guide decision making, as well as shared dysfunction in medio fronto-striato-limbic brain regions. However, findings of unique dysfunction in the ventromedial orbitofrontal cortex in OCD and in the right putamen in ADHD indicate additional, disorder-specific abnormalities and extend similar findings from inhibitory control tasks in the disorders to the domain of decision making under ambiguity. PMID- 29706588 TI - Going Beyond the Mortality: The Forgotten Quality of Life in the Very Elderly. PMID- 29706589 TI - Update of the 6-Item Brief Geriatric Assessment Screening Tool of Older Inpatients at Risk for Long Length of Hospital Stay: Results From a Prospective and Observational Cohort Study. PMID- 29706590 TI - Dysphagia 27 years after cervical disc arthroplasty. AB - INTRODUCTION: Dysphagia is a frequent postoperative symptom after anterior cervical disc arthroplasty. However, onset of dysphagia and neck pain a long time after surgery should suggest a diagnosis of prosthesis dislocation. CARE REPORT: A 65-year-old man with a history of cervical disc arthroplasty 27 years previously consulted for rapidly progressive dysphagia with no other associated symptoms. Physical examination and CT scan confirmed the diagnosis of anterior dislocation of the prosthesis with no signs of perforation. Surgical extraction via a neck incision allowed resolution of the symptoms. DISCUSSION: Prosthesis dislocation should be considered in a patient with a history of cervical disc arthroplasty presenting with dysphagia and neck pain. The clinical and radiological assessment confirmed the diagnosis and early surgical management allowed resolution of the symptoms and avoided complications such as pharyngo oesophageal perforation. PMID- 29706591 TI - Semilunar conchal cartilage graft in saddle nose reconstruction. AB - INTRODUCTION: The saddle nose deformity is easily recognized by the loss of septal support and nasal dorsal height with adverse functional and aesthetic consequences. TECHNIQUE: We treated a 50-year-old woman and a 54-year old man that presented with a moderate saddle nose deformity following a previous septorhinoplasty (female patient) and a posttraumatic severe saddle nose deformity (male patient). The patients were treated by open approach rhinoplasty under general anesthesia, and the saddle nose deformity was reconstructed with a semilunar conchal cartilage graft. A semilunar part of the conchal cartilage is excised, lending its name to the graft. A smaller leaf shaped cartilage part is excised and sutured upside-down with PDS 5-0 sutures on the opposite of the cartilage, so that the concave surfaces are facing each other. The newly formed graft is then sutured in its place on the nasal dorsum in the supratip saddle area over the triangular cartilages to widen the inner nasal valve angle. The lateral tips of the semilunar graft are placed below the lateral alar crura to improve external nasal valve functionality. DISCUSSION: This modified conchal cartilage graft presents itself as an excellent reconstructive option, especially considering its low morbidity, availability and ability to retrieve an adequate amount of cartilage in the vast majority of patients. These modifications of the conchal cartilage are previously unreported, and provide the needed height and elasticity in saddle nose reconstruction without the need for additional grafting. It is important to stress that when positioned properly, a beneficial effect in peak nasal inspiratory flow may be observed, adding to its usefulness in repairing both function and aesthetics. PMID- 29706592 TI - Mitochondria Export Sulfur Species Required for Cytosolic tRNA Thiolation. AB - In eukaryotes, mitochondria have been hypothesized to generate sulfur species required for tRNA thiolation in the cytosol, although no direct evidence thus far exists. Here we have detected these sulfur species, making use of our observation that isolated yeast cytosol alone is unable to thiolate tRNAs but can do so upon addition of mitochondria. Mitochondria were found to utilize the cysteine desulfurase Nfs1 to produce sulfur-containing species with masses ranging from 700 to 1,100 Da. Mitochondria exported these species via the Atm1 transporter in the inner membrane. Once exported to the cytosol, these sulfur species promoted cytosolic tRNA thiolation with no further requirement of mitochondria. Furthermore, we found that the Isu1/2 scaffolds but not the Ssq1 chaperone of the mitochondrial iron-sulfur cluster machinery were required for cytosolic tRNA thiolation, and thus the sulfur utilization pathway bifurcates at the Isu1/2 site for intra-organellar use in mitochondria or export to the cytosol. PMID- 29706594 TI - Patients' perspectives on how to decrease the burden of treatment: a qualitative study of HIV care in sub-Saharan Africa. AB - OBJECTIVE: Patients living with HIV infection (PLWH) in sub-Saharan Africa face an important burden of treatment related to everything they do to take care of their health: doctor visits, tests, regular refills, travels, and so on. In this study, we involved PLWH in proposing ideas on how to decrease their burden of treatment and assessed to what extent these propositions could be implemented in care. METHODS: Adult PLWH recruited in three HIV care centres in Cote d'Ivoire participated in qualitative interviews starting with 'What do you believe are the most important things to change in your care to improve your burden of treatment?' Two independent investigators conducted a thematic analysis to identify and classify patients' propositions to decrease their burden of treatment. A group of experts involving patients, health professionals, hospital leaders and policymakers evaluated each patient proposition to assess its feasibility. RESULTS: Between February and April 2017, 326 participants shared 748 ideas to decrease their burden of treatment. These ideas were grouped into 59 unique patient propositions to improve their personal care and the organisation of their hospital or clinic and/or the health system. Experts considered that 27 (46%), 19 (32%) and 13 (22%) of patients' propositions were easy, moderate and difficult, respectively, to implement. A total of 118 (36%) participants offered at least one proposition considered easily implementable by our experts. CONCLUSION: Asking PLWH in sub-Saharan Africa about how their care could be improved led to identifying meaningful propositions. According to experts, half of the ideas identified could be implemented easily at low cost for minimally disruptive HIV care. PMID- 29706595 TI - Sex differences in mortality among critically ill children in Pakistan. PMID- 29706593 TI - Repurposing HAMI3379 to Block GPR17 and Promote Rodent and Human Oligodendrocyte Differentiation. AB - Identification of additional uses for existing drugs is a hot topic in drug discovery and a viable alternative to de novo drug development. HAMI3379 is known as an antagonist of the cysteinyl-leukotriene CysLT2 receptor, and was initially developed to treat cardiovascular and inflammatory disorders. In our study we identified HAMI3379 as an antagonist of the orphan G protein-coupled receptor GPR17. HAMI3379 inhibits signaling of recombinant human, rat, and mouse GPR17 across various cellular backgrounds, and of endogenous GPR17 in primary rodent oligodendrocytes. GPR17 blockade by HAMI3379 enhanced maturation of primary rat and mouse oligodendrocytes, but was without effect in oligodendrocytes from GPR17 knockout mice. In human oligodendrocytes prepared from inducible pluripotent stem cells, GPR17 is expressed and its activation impaired oligodendrocyte differentiation. HAMI3379, conversely, efficiently favored human oligodendrocyte differentiation. We propose that HAMI3379 holds promise for pharmacological exploitation of orphan GPR17 to enhance regenerative strategies for the promotion of remyelination in patients. PMID- 29706596 TI - Ivy League-Big Ten Epidemiology of Concussion Study. PMID- 29706598 TI - Cost-effectiveness of unicompartmental compared with total knee replacement: a population-based study using data from the National Joint Registry for England and Wales. AB - OBJECTIVES: To assess the value for money of unicompartmental knee replacement (UKR) compared with total knee replacement (TKR). DESIGN: A lifetime Markov model provided the framework for the analysis. SETTING: Data from the National Joint Registry (NJR) for England and Wales primarily informed the analysis. PARTICIPANTS: Propensity score matched patients in the NJR who received either a UKR or TKR. INTERVENTIONS: UKR is a less invasive alternative to TKR, where only the compartment affected by osteoarthritis is replaced. PRIMARY OUTCOME MEASURES: Incremental quality-adjusted life years (QALYs) and healthcare system costs. RESULTS: The provision of UKR is expected to lead to a gain in QALYs compared with TKR for all age and gender subgroups (male: <60 years: 0.12, 60-75 years: 0.20, 75+ years: 0.19; female: <60 years: 0.10, 60-75 years: 0.28, 75+ years: 0.44) and a reduction in costs (male: <60: L-1223, 60-75 years: L-1355, 75+ years: L-2005; female: <60 years: L-601, 60-75 years: L-935, 75+ years: L-1102 per patient over the lifetime). UKR is expected to lead to a reduction in QALYs compared with TKR when performed by surgeons with low UKR utilisation but an increase among those with high utilisation (<10%, median 6%: -0.04, >=10%, median 27%: 0.26). Regardless of surgeon usage, costs associated with UKR are expected to be lower than those of TKR (<10%: L-127, >=10%: L-758). CONCLUSIONS: UKR can be expected to generate better health outcomes and lower lifetime costs than TKR. Surgeon usage of UKR does, however, have a significant impact on the cost effectiveness of the procedure. To achieve the best results, surgeons need to perform a sufficient proportion of knee replacements as UKR. Low usage surgeons may therefore need to broaden their indications for UKR. PMID- 29706597 TI - Variations in outcomes by residential location for women with breast cancer: a systematic review. AB - OBJECTIVES: To systematically assess the evidence for variations in outcomes at each step along the breast cancer continuum of care for Australian women by residential location. DESIGN: Systematic review. METHODS: Systematic searches of peer-reviewed articles in English published from 1 January 1990 to 24 November 2017 using PubMed, EMBASE, CINAHL and Informit databases. Inclusion criteria were: population was adult female patients with breast cancer; Australian setting; outcome measure was survival, patient or tumour characteristics, screening rates or frequencies, clinical management, patterns of initial care or post-treatment follow-up with analysis by residential location or studies involving non-metropolitan women only. Included studies were critically appraised using a modified Newcastle-Ottawa Scale. RESULTS: Seventy-four quantitative studies met the inclusion criteria. Around 59% were considered high quality, 34% moderate and 7% low. No eligible studies examining treatment choices or post treatment follow-up were identified. Non-metropolitan women consistently had poorer survival, with most of this differential being attributed to more advanced disease at diagnosis, treatment-related factors and socioeconomic disadvantage. Compared with metropolitan women, non-metropolitan women were more likely to live in disadvantaged areas and had differing clinical management and patterns of care. However, findings regarding geographical variations in tumour characteristics or diagnostic outcomes were inconsistent. CONCLUSIONS: A general pattern of poorer survival and variations in clinical management for Australian female patients with breast cancer from non-metropolitan areas was evident. However, the wide variability in data sources, measures, study quality, time periods and geographical classification made direct comparisons across studies challenging. The review highlighted the need to promote standardisation of geographical classifications and increased comparability of data systems. It also identified key gaps in the existing literature including a lack of studies on advanced breast cancer, geographical variations in treatment choices from the perspective of patients and post-treatment follow-up. PMID- 29706599 TI - Mental health challenges and experiences in displaced populations following Hurricane Sandy and Hurricane Harvey: the need for more comprehensive interventions in temporary shelters. AB - Hurricane exposure can have a profound impact on mental health, leading to increased symptoms of stress, anxiety, depression and post-traumatic stress disorder that are still present years after the storm. Those displaced following a hurricane are particularly vulnerable to adverse mental health outcomes, especially if displaced to temporary shelters. The current work highlights the experiences and mental health challenges of displaced populations following Hurricane Sandy and Hurricane Harvey, as well as describing barriers to conducting research in the immediate aftermath of Hurricane Harvey and the need for more comprehensive interventions in these vulnerable populations. PMID- 29706600 TI - Retrospective cohort study exploring whether an association exists between spatial distribution of cystoid spaces in cystoid macular oedema secondary to retinitis pigmentosa and response to treatment with carbonic anhydrase inhibitors. AB - BACKGROUND: Carbonic anhydrase inhibitors (CAIs) are frequently used as an initial step to treat retinitis pigmentosa-associated cystoid macular oedema (RP CMO). Interestingly, it has been postulated that CAIs might reduce outer nuclear layer (ONL) fluid more effectively than inner nuclear layer (INL) fluid due to better access to retinal pigment epithelium basolateral membrane than neurosensory retina. This retrospective cohort study explores if an association between spatial distribution of cystoid spaces in RP-CMO and CAI response exists. METHODS: Two independent graders reviewed pretreatment and post-treatment optical coherence tomography (OCT) images of 25 patients (43 eyes) initiated on topical and/or oral CAIs between January 2013 and December 2014. Documentation included the presence/absence of fluid (and layer(s) involved), external limiting membrane, epiretinal membrane (ERM), vitreomacular adhesion/traction, lamellar/full-thickness macular hole and central macular thickness (CMT)/volume. RESULTS: INL fluid was found in all study eyes. All 13 'responders' (at least 11% reduction of CMT after treatment) demonstrated pretreatment ONL fluid. In seven patients (four responders and three non-responders), complete clearance of ONL fluid was achieved despite persistence of INL fluid. ERM presence was similar in responders and non-responders. CONCLUSION: In this study, INL fluid was found to be the most common spatial distribution of RP-CMO. However, patients who were classed as a 'responder' to CAI treatment all demonstrated coexisting ONL fluid on their pretreatment OCT scans. This may be explained by CAIs having better access to retinal pigment epithelium basolateral membrane than neurosensory retina. Our study also suggests a minimal impact on response to CAIs by ERM. PMID- 29706601 TI - Quantifying vascular density and morphology using different swept-source optical coherence tomography angiographic scan patterns in diabetic retinopathy. AB - AIMS: To evaluate quantitative metrics of the retinal microvasculature in eyes with diabetic retinopathy (DR) using various en face swept-source optical coherence tomography angiography (SS-OCTA) image sizes. METHODS: Non-segmented and segmented images were acquired using an SS-OCTA device (PLEX Elite 9000; Carl Zeiss Meditec, Dublin, California, USA). The scanning protocols included the 3*3 mm, 6*6 mm and 12*12 mm fields of view. Quantitative analysis of the perfusion density (PD), vessel length density (VLD) and fractal dimension (FD) was performed. The area under the receiver operating characteristic curve was estimated to assess the ability of each image size to predict DR. RESULTS: This prospective, cross-sectional study included 60 eyes, (non-DR, 13 eyes; non proliferative DR (NPDR), 24 eyes; proliferative DR (PDR), 23 eyes) of 46 patients with diabetes and 21 eyes of 16 healthy individuals. In the 12*12 mm images, the PD of healthy individuals was significantly greater than that of patients with NPDR or PDR for all layers (NPDR, p<0.05; PDR, p<0.001 0.001; FD, p<0.001) or PDR (VLD, p<0.001; FD, p<0.001 for all layers). The results were similar for the 3*3 mm and 6*6 mm images. Overall, PD, VLD and FD progressively decreased with worsening DR severity in segmented and non-segmented layers for all SS-OCTA scan sizes. For detecting DR, 3*3 mm images best predicted DR for all evaluated quantitative parameters. CONCLUSIONS: Vascular changes in DR can be monitored in detail through quantitative evaluations that combine different SS-OCTA scan sizes and parameters. PMID- 29706602 TI - Association between HLA-B*44:03-HLA-C*07:01 haplotype and cold medicine-related Stevens-Johnson syndrome with severe ocular complications in Thailand. AB - BACKGROUND: Polymorphisms in human leucocyte antigen (HLA) class I genes have been found to be associated with cold medicine (CM)-related Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with severe ocular complications (SOC). Because ethnic differences in genetic predisposition to SJS/TEN among different populations have been proposed, we focused on Thai patients and investigated the association between HLA class I genotypes and CM SJS/TEN with SOC. METHODS: This multicentre case-control study was conducted between September 2014 and August 2017. Seventy-one Thai patients with SJS/TEN with SOC and 159 healthy Thai controls were enrolled. HLA typing was performed. Genetic relationships were analysed using Fisher's exact test. RESULTS: Of 71 patients with SJS/TEN with SOC (28 male, 43 female), 49 (69%) had a history of taking cold medications prior to SJS/TEN onset. The mean age of onset was 26.7+/ 17.1 years (range, 2-77 years). HLA-B*44:03 (OR, 7.2, p=5.5*10-6, pc=1.1*10-4) and HLA-C*07:01 (OR, 6.1, p=7.1*10-6, pc=1.1*10-4) showed significant positive associations with Thai patients with CM-SJS/TEN with SOC. Additionally, 17 of 49 patients with CM-SJS/TEN with SOC (34.7%) significantly harboured the HLA-B*44:03 and HLA-C*07:01 haplotype compared with only 11 of 159 healthy controls (6.9%) (OR=7.1, p=5.5*10-6). CONCLUSIONS: HLA-B*44:03-HLA-C*07:01 haplotype is a potential risk factor for CM-SJS/TEN with SOC in the Thai population. This study supports that HLA-B*44:03 might be a common marker for CM-SJS/TEN with SOC in Eurasia populations, including European, Indian, Japanese and Thai. PMID- 29706603 TI - Impact of drusen and drusenoid retinal pigment epithelium elevation size and structure on the integrity of the retinal pigment epithelium layer. AB - PURPOSE: To evaluate the impact of drusen size and structure on retinal pigment epithelium (RPE) and photoreceptor layers in eyes with early to intermediate age related macular degeneration (AMD) using polarisation-sensitive optical coherence tomography (OCT). DESIGN: Retrospective investigation of an observational cross sectional study. PARTICIPANTS: Patients with early to intermediate AMD. METHODS: Twenty-five eyes of 25 patients with drusen were imaged with polarisation sensitive OCT using macular volume scans. Each scan was manually graded for six distinct drusen characteristics and the integrity of both the overlying RPE and photoreceptor layer. The central scan of each single druse, as well as its diameter and location, were selected for statistical calculations. RESULTS: A total number of 5933 individual drusen including their adjacent RPE and photoreceptor layer were evaluated. 41.3% of all drusen demonstrated an intact overlying RPE; in 28.1% the RPE layer was irregular, but continuous. In 30.6%, the RPE layer signal was discontinuous above the area of drusen. The level of RPE alteration was significantly related to shape (p<0.001), internal reflectivity (p<0.001) and homogeneity (p<0.001) of the drusen and their diameter, with a higher probability for larger drusen to have a discontinuous RPE (OR 3.2, p<0.001). The number of drusen showing overlying foci or an altered photoreceptor layer was too small to be conclusive, but showed a trend towards an altered RPE if present. CONCLUSIONS: Polarisation-sensitive OCT reveals a correlation between specific drusen characteristics and the integrity of the overlying RPE layer. Drusen diameter and configuration were significantly associated with RPE loss. PMID- 29706604 TI - Clinical characteristics and treatment outcomes of natural killer/T-cell lymphoma involving the ocular adnexa. AB - AIMS: To evaluate the clinical characteristics and treatment outcomes of natural killer/T-cell lymphoma (NKTL) involving the ocular adnexa. METHODS: Retrospective, comparative, observational case series. A total of 350 patients with NKTL, including 27 patients with NKTL involving the ocular adnexa from 1999 to 2016. The patients were grouped into two groups: group 1 comprised patients presenting with ophthalmic symptoms, and group 2 comprised patients presenting with symptoms from other organs but subsequently developed ophthalmic involvement. RESULTS: Group 1 comprised 12 patients (44.4%) and group 2 comprised 15 (55.6%). Mean duration of symptoms in group 1 was 1.8+/-1.2 months, while the time from diagnosis of NKTL to development of ophthalmic symptoms in group 2 was 45.3+/-65.6 months. Periorbital swelling was the most common presenting symptom in both groups (83.3% in group 1 and 73.3% in group 2). Symptoms mimicking cellulitis and pseudotumor were present in 50.0% and 16.7% of cases, respectively. The 5-year overall survival rate was 18.5% in group 1 and 26.4% in group 2, while the 5-year progression-free survival rate was 0% and 13.3%, respectively. CONCLUSIONS: Our series is to our knowledge the largest cohort study on NKTL reported to date and demonstrates that ocular adnexal NKTL is a rare but seriously fatal disease. It is characterised by acute inflammatory signs as present in as many as two-thirds of our patients in this series. It should be considered as a differential diagnosis in patients presenting with rapidly progressing proptosis and diagnosed promptly for optimal management. PMID- 29706606 TI - Angioplasty and stenting for symptomatic extracranial non-tandem internal carotid artery occlusion. AB - INTRODUCTION: Symptomatic internal carotid artery occlusion (ICAO) can lead to neurologic decline, recurrent stroke, and mortality. OBJECTIVE: We sought to evaluate the safety and feasibility of endovascular revascularization for ICAO without tandem intracranial large vessel occlusion (LVO). DESIGN, SETTING, AND PARTICIPANTS: This is a retrospective cohort analysis of all patients presenting to a single academic center with ischemic stroke and ipsilateral cervical ICAO from November 2003 through April 2016. Patients were excluded if pre-procedural angiography demonstrated tandem LVO or if patients were known to have chronic ICAO. MAIN OUTCOMES AND MEASURES: Study endpoints included discharge neurologic examination, post-procedural infarct burden, 3-month functional outcomes, and treatment durability. RESULTS: A total of 107 patients with symptomatic angiographically-confirmed cervical ICAO without tandem LVO were identified. Median admission NIH Stroke Scale (NIHSS) score was 8 (IQR 11). Baseline radiographic stroke severity was assessed by ASPECT score (median 9; IQR 2), perfusion mismatch (present in 93%), and clinical imaging mismatch (42%). Median time from symptom onset to treatment was 25 hours (IQR 61). Successful revascularization was achieved in 92% of patients. At discharge, 83% had stable/improved NIHSS score, while at 3 months 65% achieved independence (modified Rankin Scale score <=2). The most common complication was distal embolization (22%) of which 16% required intra-arterial treatment. Rate of significant restenosis (>=70%) was 15% at 1 year. CONCLUSIONS: Stenting in selected patients at risk of neurologic deterioration due to symptomatic ICAO can be performed with high rates of technical success and good clinical outcomes. Because of significant peri-procedural risks and high rates of restenosis, randomized studies are necessary to understand the benefit of this approach. PMID- 29706605 TI - Hypermetabolism in ALS is associated with greater functional decline and shorter survival. AB - OBJECTIVE: To determine the prevalence of hypermetabolism, relative to body composition, in amyotrophic lateral sclerosis (ALS) and its relationship with clinical features of disease and survival. METHODS: Fifty-eight patients with clinically definite or probable ALS as defined by El Escorial criteria, and 58 age and sex-matched control participants underwent assessment of energy expenditure. Our primary outcome was the prevalence of hypermetabolism in cases and controls. Longitudinal changes in clinical parameters between hypermetabolic and normometabolic patients with ALS were determined for up to 12 months following metabolic assessment. Survival was monitored over a 30-month period following metabolic assessment. RESULTS: Hypermetabolism was more prevalent in patients with ALS than controls (41% vs 12%, adjusted OR=5.4; p<0.01). Change in body weight, body mass index and fat mass (%) was similar between normometabolic and hypermetabolic patients with ALS. Mean lower motor neuron score (SD) was greater in hypermetabolic patients when compared with normometabolic patients (4 (0.3) vs 3 (0.7); p=0.04). In the 12 months following metabolic assessment, there was a greater change in Revised ALS Functional Rating Scale score in hypermetabolic patients when compared with normometabolic patients (-0.68 points/month vs -0.39 points/month; p=0.01). Hypermetabolism was inversely associated with survival. Overall, hypermetabolism increased the risk of death during follow-up to 220% (HR 3.2, 95% CI 1.1 to 9.4, p=0.03). CONCLUSIONS AND RELEVANCE: Hypermetabolic patients with ALS have a greater level of lower motor neuron involvement, faster rate of functional decline and shorter survival. The metabolic index could be important for informing prognosis in ALS. PMID- 29706607 TI - Identifying circRNA-associated-ceRNA networks in the hippocampus of Abeta1-42 induced Alzheimer's disease-like rats using microarray analysis. AB - Alzheimer's disease (AD) is the most common form of dementia worldwide. Accumulating evidence indicates that non-coding RNAs are strongly implicated in AD-associated pathophysiology. However, the role of these ncRNAs remains largely unknown. In the present study, we used microarray analysis technology to characterize the expression patterns of circular RNAs (circRNAs), microRNAs (miRNAs), and mRNAs in hippocampal tissue from Abeta1-42-induced AD model rats, to integrate interaction data and thus provide novel insights into the mechanisms underlying AD. A total of 555 circRNAs, 183 miRNAs and 319 mRNAs were identified to be significantly dysregulated (fold-change >= 2.0 and p-value < 0.05) in the hippocampus of AD rats. Quantitative real-time polymerase chain reaction (qRT PCR) was then used to validate the expression of randomly-selected circRNAs, miRNAs and mRNAs. Next, GO and KEGG pathway analyses were performed to further investigate ncRNAs biological functions and potential mechanisms. In addition, we constructed circRNA-miRNA and competitive endogenous RNA (ceRNA) regulatory networks to determine functional interactions between ncRNAs and mRNAs. Our results suggest the involvement of different ncRNA expression patterns in the pathogenesis of AD. Our findings provide a novel perspective for further research into AD pathogenesis and might facilitate the development of novel therapeutics targeting ncRNAs. PMID- 29706608 TI - Age-associated bimodal transcriptional drift reduces intergenic disparities in transcription. AB - This study addressed the question of how well the quantitative transcriptome structure established in early life is maintained and how consistently it appears with increasing age, and if there is age-associated alteration of gene expression (A3GE), how much influence the Huntington's disease (HD) genotype exerts on it. We examined 285 exonic sequences of 175 genes using targeted PCR sequencing in skeletal muscle, brain, and splenic CD4+ T cells of wild-type and HD mice. In contrast to the muscle and brain, T cells exhibited large A3GE, suggesting a strong contribution to functional decline of the organism. This A3GE was markedly intensified in age-matched HD T cells, which exhibited accelerated aging as determined by reduced telomere length. Regression analysis suggested that gene expression levels change at a rate of approximately 3% per month with age. We found a bimodal relationship in A3GE in T cells in that weakly expressed genes in young mice were increasingly transcribed in older animals whereas highly expressed genes in the young were decreasingly expressed with age. This bimodal transcriptional drift in the T cell transcriptome data causes the differences in transcription rate between genes to progressively reduce with age. PMID- 29706609 TI - RAN/RANBP2 polymorphisms and neuroblastoma risk in Chinese children: a three center case-control study. AB - The genetic etiology of sporadic neuroblastoma remains largely obscure. RAN and RANBP2 genes encode Ras-related nuclear protein and Ran-binding protein 2, respectively. These two proteins form Ran-RanBP2 complex that regulate various cellular activities including nuclear transport. Aberrant functions of the two proteins are implicated in carcinogenesis. Given the unknown role of RAN/RANBP2 single nucleotide polymorphisms (SNPs) in neuroblastoma risk, we performed a multi-center case-control study in Chinese children to assess the association of the RAN/RANBP2 SNPs with neuroblastoma risk. We analyzed three potentially functional SNPs in RAN gene (rs56109543 C>T, rs7132224 A>G, rs14035 C>T) and one in RANBP2 (rs2462788 C>T) in 429 cases and 884 controls. Odds ratios (ORs) and 95% confidence intervals (CIs) were used to access the association between these four polymorphisms and neuroblastoma risk. No single variant was found to statistically significantly associate with neuroblastoma risk. However, individuals with 3 protective genotypes were less likely to develop neuroblastoma, in comparison to non-carriers (adjusted OR=0.33; 95% CI=0.12-0.96; P=0.042), as well as those with 0-2 protective genotypes (adjusted OR=0.33; 95% CI=0.11-0.94; P=0.038). Stratified analysis revealed no significant association for any of the four polymorphisms. Further studies are warranted to validate the weak impact of RAN/RANBP2 SNPs on neuroblastoma risk. PMID- 29706610 TI - Age-related neuropathies and tubulin acetylation. PMID- 29706611 TI - Decreased NAD+ in dopaminergic neurons. PMID- 29706612 TI - Phospholipid transfer by ERMES components. PMID- 29706613 TI - Accessory signals in protein translocation. PMID- 29706614 TI - Coherent apoptotic and autophagic activities involved in regression of chicken postovulatory follicles. AB - After ovulation in mammals, rupture of mature follicles is reorganized into the corpus luteum that secrets progesterone (P4) to stimulate endometrial development. The situation in birds differs considerably. Beyond ovulation the ruptured avian follicle forms a postovulatory follicle (POF) that is not considered analogous to mammalian corpus luteum. The function and regression mechanisms of avian POFs remain poorly understood. Here we investigated the changes in apoptotic and autophagic activities that were involved during POF degradation. Results showed that the structure and secretory function of POF3 manifested the most apparent deterioration during whole processes of regression. A TUENL assay revealed that the granulosa layer maintained longer viability than the theca layer. Importantly, mitochondrial apoptosis and endoplasmic reticulum (ER) stress-associated genes and proteins reached their highest levels in the granulosa cells of POF3. Beclin1 was distributed mainly in theca cells and coupled with LC3beta-II accumulation, Sequestosome-1 (p62) degradation and Beclin1 elevation confirmed that autophagic activity had increased dramatically in the theca layer of POFs. These results indicate that the apoptosis of the granulosa cells from POFs occurs by mitochondrial apoptosis and ER stress and that a coherence of Beclin1-induced autophagy and caspase-induced apoptosis results in regression of theca layers of avian POFs. PMID- 29706615 TI - Clinical Benefit from Tyrosine Kinase Inhibitors in Metastatic Merkel Cell Carcinoma: A Case Series of 5 Patients. AB - BACKGROUND Merkel cell carcinoma (MCC) is a rare but aggressive neuroendocrine skin cancer. The estimated 5-year survival of patients with metastatic disease is approximately 14%. Cytotoxic chemotherapy is associated with a modest median progression-free survival (PFS) of only 3 months. In recent studies, immunotherapy with anti-PD-1/anti-PD-L1 antibodies has demonstrated a high response rate in immunocompetent patients (>50% in chemotherapy-naive patients) and responses are typically durable. However, approximately 50% of immunocompetent patients do not respond to immunotherapy. In addition, immunosuppressed patients have limited therapeutic options. Hence, there is a significant unmet need for effective treatments in these subpopulations. CASE REPORT We describe 5 patients (out of 24 total) with metastatic MCC who were treated with a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), either pazopanib (n=4) or cabozantinib (n=1), with clinical benefit. One patient had a complete response to pazopanib after 3 months of therapy. Four patients had stabilization of disease that lasted from 5 months to 3.5 years. In an immunosuppressed patient with psoriatic arthritis, stabilization of MCC was also associated with improvement in his arthritis that allowed cessation of immunosuppression. Patients did not develop any unusual toxicities from VEGFR-TKIs. CONCLUSIONS Treatment with VEGFR-TKIs demonstrated clinical benefit in this selected small group of patients with metastatic MCC. Prospective investigation of VEGFR-TKIs is warranted in this population, especially in patients with disease refractory to immunotherapy. PMID- 29706616 TI - Identification of Potentially Functional CircRNA-miRNA-mRNA Regulatory Network in Hepatocellular Carcinoma by Integrated Microarray Analysis. AB - BACKGROUND Hepatocellular carcinoma (HCC) is the most common malignancy of the liver and recent studies have revealed that circular RNA (circRNA) plays an important role in the pathogenesis of HCC. Some circRNAs may act as a microRNA (miRNA) sponge to affect miRNA activities in the regulation of messenger RNA (mRNA) expression. However, the circRNA-miRNA-mRNA network in HCC remains largely unknown. MATERIAL AND METHODS The circRNA expression profiles (GSE94508 and GSE97332), miRNA and mRNA expression profile (GSE22058) were downloaded from Gene Expression Omnibus microarray data and then a circRNA-miRNA-mRNA regulatory network in HCC was constructed. Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of differentially expressed (DE) genes were performed. The functional circRNA-miRNA-mRNA regulatory modules were constructed using cytoHubba plugin based on Cytoscape and KEGG enrichment analysis. RESULTS The network contained 60 circRNA-miRNA pairs and 4982 miRNA-mRNA pairs, including 29 circRNAs, 16 miRNAs, and 1249 mRNAs. GO and KEGG pathway analysis revealed the network might be involved in the procession of carcinogenesis such as cell proliferation, cell cycle, and p53 signaling pathway. In addition, 3 top ranked circRNAs (hsa_circ_0078279, hsa_circ_0007456, and hsa_circ_0004913) related networks were identified to be highly correlated with the pathogenesis of HCC. Furthermore, the functional circRNA-miRNA-mRNA regulatory modules were constructed based on the 3 top-ranked circRNAs and those DE genes enriched in carcinogenesis related pathways. CONCLUSIONS This study suggests that a specific circRNA-miRNA-mRNA network is associated with the carcinogenesis of HCC, which might aid in the identification of molecular biomarkers and therapeutic targets for HCC. PMID- 29706617 TI - Effect of Hexadecyl Azelaoyl Phosphatidylcholine on Cardiomyocyte Apoptosis in Myocardial Ischemia-Reperfusion Injury: A Hypothesis. AB - Reperfusion after myocardial ischemia can induce cardiomyocyte death, known as myocardial reperfusion injury. The pathophysiology of the process of reperfusion suggests the confluence multiple pathways. Recent studies have focused on the inflammatory response, which is considered to be the main mechanism during the process of myocardial ischemia-reperfusion injury and can cause cardiomyocyte apoptosis. Peroxisome proliferator-activated receptors gamma activated by endogenous ligands and exogenous ligand can decrease the inflammatory response in cardiomyocytes. Thiazolidinediones are synthetic, high-affinity, selective ligands for peroxisome proliferator-activated receptors gamma, and can inhibit the inflammatory response, decrease myocardial infarct size, and protect cardiac function. However, thiazolidinediones, including rosiglitazone and pioglitazone, can also contribute to adverse cardiovascular events such as congestive heart failure. Therefore, there are some limitations to the use of thiazolidinediones. Most endogenous ligands were of low affinity until hexadecyl azelaoyl phosphatidylcholine was identified as a high-affinity ligand and agonist for peroxisome proliferator-activated receptors gamma. Hexadecyl azelaoyl phosphatidylcholine binds recombinant peroxisome proliferator-activated receptors with an affinity (Kd(app) ~40 nM) which is equivalent to rosiglitazone. Therefore, hexadecyl azelaoyl phosphatidylcholine is a specific peroxisome proliferator-activated receptors gamma agonist. Given these findings, we hypothesized that the use of hexadecyl azelaoyl phosphatidylcholine can activate the peroxisome proliferator-activated receptors gamma signal pathways and prevent the inflammatory response process of myocardial ischemia-reperfusion injury, with reduced cardiomyocyte apoptosis and death. PMID- 29706619 TI - Microperimetry and optical coherence tomography imaging in the fellow eye of patients with unilateral focal ischaemic glaucoma. AB - PURPOSE: To determine whether microperimetry or optical coherence tomography (OCT) imaging can detect early disease in the fellow eye of patients with unilateral focal ischaemic glaucoma. METHODS: Thirty-seven consecutive adult patients with unilateral focal ischaemic glaucoma with a unilateral split fixation visual field defect on standard automated perimetry (SAP) with normal SAP in the fellow eye were selected. All patients underwent microperimetry (MAIA, CenterVue, Italy) of the central 10 degrees and OCT imaging (Spectralis, Heidelberg Engineering, Germany) of the retinal nerve fibre layer of both eyes. The main outcome measures were reduced retinal sensitivity on microperimetry and/or retinal nerve fibre layer thinning on OCT imaging of the fellow eye. RESULTS: Thirty fellow eyes had abnormal global thresholds on microperimetry, and 20 had abnormal OCT imaging studies. Kappa agreement between tests in fellow eyes was poor (p = 0.2546). Fixation was significantly poorer in fellow eyes on microperimetry when compared to eyes with glaucoma (p < 0.003). In the fellow eyes that were abnormal, microperimetry identified reduced retinal sensitivity at fixation. CONCLUSION: Microperimetry detects reduced retinal sensitivity close to fixation and OCT detects focal thinning of the retinal nerve fibre layer in the fellow eye of most patients with presumed unilateral focal ischaemic glaucoma. Further studies are required to correlate specific optic disc features on OCT imaging with microperimetry in the fellow eye of this patient group. PMID- 29706618 TI - ECD promotes gastric cancer metastasis by blocking E3 ligase ZFP91-mediated hnRNP F ubiquitination and degradation. AB - The human ortholog of the Drosophila ecdysoneless gene (ECD) is required for embryonic development and cell-cycle progression; however, its role in cancer progression and metastasis remains unclear. Here, we found that ECD is frequently overexpressed in gastric cancer (GC), especially in metastatic GC, and is correlated with poor clinical outcomes in GC patients. Silencing ECD inhibited GC migration and invasion in vitro and metastasis in vivo, while ECD overexpression promoted GC migration and invasion. ECD promoted GC invasion and metastasis by protecting hnRNP F from ubiquitination and degradation. We identified ZFP91 as the E3 ubiquitin ligase that is responsible for hnRNP F ubiquitination at Lys 185 and proteasomal degradation. ECD competitively bound to hnRNP F via the N terminal STG1 domain (13-383aa), preventing hnRNP F from interacting with ZFP91, thus preventing ZFP91-mediated hnRNP F ubiquitination and proteasomal degradation. Collectively, our findings indicate that ECD promotes cancer invasion and metastasis by preventing E3 ligase ZFP91-mediated hnRNP F ubiquitination and degradation, suggesting that ECD may be a marker for poor prognosis and a potential therapeutic target for GC patients. PMID- 29706620 TI - The effect of trabeculectomy surgery on the central visual field in patients with glaucoma using microperimetry and optical coherence tomography. AB - PURPOSE: To determine the functional and structural effects of trabeculectomy surgery on patients with advanced glaucoma and central visual field defects in the early post-operative period. METHODS: Thirty consecutive adult subjects with advanced glaucoma requiring trabeculectomy surgery and an established visual field defect within 10 degrees of fixation underwent microperimetry (MAIA MP-1, CenterVue, Padova, Italy) and optic disc optical coherence tomography (OCT) imaging (Spectralis, Heidelberg Engineering, Germany) pre-operatively, and 1 month and 3 months following trabeculectomy surgery. Main outcome measures were post-trabeculectomy change in mean threshold on microperimetry and nerve fibre layer thickness on OCT. Fellow eyes were used as controls. RESULTS: The mean change in MP average threshold values from pre-operative to post-operative was 0.6 +/- 1.9 dB for treated eyes and 0.1 +/- 1.3 dB for control eyes (p = 0.14) at 1 month and 0.2 +/- 2.3 and -0.3 +/- 1.6 dB at 3 months (p = 0.22). Mean change in global nerve fibre layer thickness was -0.6 and -0.5 um for operated and control eyes, respectively (p = 0.83), at 1 month and 0.8 and -0.4 um at 3 months (p = 0.88). The kappa agreement for structure-function correlation between OCT and MP was 0.735 (confidence interval 0.59-0.88) (p < 0.005). CONCLUSIONS: Central visual function and retinal nerve fibre layer thickness appear to be preserved in glaucoma patients with central visual field defects undergoing trabeculectomy surgery in the early post-operative period. These data may inform glaucoma surgeons considering trabeculectomy surgery in this patient group. PMID- 29706621 TI - Childhood lead biokinetics and associations with age among a group of lead poisoned children in China. AB - Childhood lead exposure has been shown to have a significant effect on neurodevelopment. Many of the biokinetics involved with lead biomarkers in children still remain unknown. Two hundred fifty (157 in the exposed group and 93 controls) children were enrolled in our study and lead exposed children returned for multiple visits for measurement of blood and bone lead and chelation treatment. We demonstrated that the correlation between blood and bone lead increased with subsequent visits. We calculated the blood lead half-life for 50 patients, and found a significant (p-value < 0.001) positive correlation with age. For ages 1-3 years (N = 17), the blood lead half-life was found to be 6.9 +/ 4.0 days and for 3+ years it was found to be (N = 33) 19.3 +/- 14.1 days. In conclusion, the turnover of lead in children is faster than in adults. Our results indicate that blood lead is a more acute biomarker of exposure than previously thought, which will impact studies of children's health using blood lead as a biomarker. PMID- 29706622 TI - Ambient particulate matter air pollution associated with acute respiratory distress syndrome in Guangzhou, China. AB - Limited evidence exists concerning the impact of particulate pollution on acute respiratory distress syndrome (ARDS). We examined the effects of particulate pollution on emergency ambulance dispatches (EAD) for ARDS in Guangzhou, China. Daily air pollution concentrations for PM10, PM2.5, and PM1, as well as PM2.5 chemical compositions, were available from a central air monitoring station. The association between incident ARDS and air pollution on the concurrent and previous 5 days was estimated by an over-dispersed Poisson generalized additive model controlling for meteorological factors, temporal trends, public holidays and day of the week. We identified a total of 17,002 EADs for ARDS during the study period. There were significant associations between concentrations of PM10, PM2.5, PM1, and ARDS; corresponding excess risk (ER) for an interquartile range IQR increase in 1-day lagged concentration was 5.45% [95% confidence interval (CI): 1.70%, 9.33%] for PM10 (45.4 MUg/m3), 4.71% (95% CI: 1.09%, 8.46%) for PM2.5 (31.5 MUg/m3), and 4.45% (95% CI: 0.81%, 8.23%) for PM1 (28.8 MUg/m3), respectively. For PM2.5 chemical compositions, we found that OC, EC, sulfate and ammonium were significantly associated with ARDS. The observed effects remained even after adjusting for potentially confounding factors. This study suggests that PM10, PM2.5, and PM1, as well as chemical constituents from combustion and secondary aerosols might be important triggers of ARDS in Guangzhou. PMID- 29706623 TI - The deubiquitinase USP21 stabilizes MEK2 to promote tumor growth. AB - Deubiquitinases (DUBs) play essential roles in normal cell proliferation and tumor growth. However, the molecular mechanisms of DUBs on hepatocellular carcinoma (HCC) remains largely unknown. In this study, based on analysis of several HCC datasets, we found that the USP21 gene, which encodes a member of the ubiquitin-specific protease family, is highly amplified and overexpressed in HCCs, with the extent of this up-regulation significantly correlating with poor clinical outcomes. Inhibition of USP21 in HCC cell lines decreased cell proliferation, anchorage-independent growth, cell cycle progression, and in vivo tumor growth. Conversely, ectopic expression of USP21 transformed the normal human hepatocyte line HL-7702 and increased the tumorigenicity of the HCC cell line MHCC97L. Mechanistically, USP21 stabilized MEK2 by decreasing its polyubiquitination at Lys48, thereby activating the ERK signaling pathway. Importantly, MEK2 partially mediated the optimal expression of USP21-mediated oncogenic phenotypes. These findings indicate that USP21-mediated deubiquitination and stabilization of MEK2 play a critical role in HCC development. PMID- 29706624 TI - KIF4A facilitates cell proliferation via induction of p21-mediated cell cycle progression and promotes metastasis in colorectal cancer. AB - Kinesin family member 4A (KIF4A) was found to be implicated in the regulation of chromosome condensation and segregation during mitotic cell division, which is essential for eukaryotic cell proliferation. However, little is known about the role of KIF4A in colorectal carcinoma (CRC). This study explored the biological function of KIF4A in CRC progression and investigated the potential molecular mechanisms involved. Here, we found that KIF4A was remarkably upregulated in primary CRC tissues and cell lines compared with paired non-cancerous tissues and normal colorectal epithelium. Elevated expression of KIF4A in CRC tissues was significantly correlated with clinicopathological characteristics in patients as well as with shorter overall and disease-free cumulative survival. Multivariate Cox regression analysis revealed that KIF4A was an independent prognostic factor for poor survival in human CRC patients. Functional assays, including a CCK-8 cell proliferation assay, colony formation analysis, cancer xenografts in nude mice, cell cycle and apoptosis analysis, indicated that KIF4A obviously enhanced cell proliferation by promoting cell cycle progression in vitro and in vivo. Furthermore, gene set enrichment analysis, Luciferase reporter assays, and ChIP assays revealed that KIF4A facilitates cell proliferation via regulating the p21 promoter, whereas KIF4A had no effect on cell apoptosis. In addition, Transwell analysis indicated that KIF4A promotes migration and invasion in CRC. Taken together, these findings not only demonstrate that KIF4A contributes to CRC proliferation via modulation of p21-mediated cell cycle progression but also suggest the potential value of KIF4A as a clinical prognostic marker and target for molecular treatments. PMID- 29706626 TI - Long non-coding RNA Lnc-Tim3 exacerbates CD8 T cell exhaustion via binding to Tim 3 and inducing nuclear translocation of Bat3 in HCC. AB - Although one of the first comprehensive examinations of long non-coding RNA (lncRNA) expression was performed in human CD8 T lymphocytes, little is known about their roles in CD8 T cells functions during the progression of hepatocellular carcinoma (HCC). Here, we show that Lnc-Tim3 is upregulated and negatively correlates with IFN-gamma and IL-2 production in tumor-infiltrating CD8 T cells of HCC patients. Lnc-Tim3 plays a pivotal role in stimulating CD8 T exhaustion and the survival of the exhausted CD8 T cells. Mechanistically, Lnc Tim3 specifically binds to Tim-3 and blocks its interaction with Bat3, thus suppressing downstream Lck/ NFAT1/AP-1 signaling, leading to nuclear localization of Bat3, and enhancing p300-dependent p53 and RelA transcriptional activation of anti-apoptosis genes including MDM2 and Bcl-2. In summary, Lnc-Tim3 promotes T cell exhaustion, a phenotype which is correlated with compromised anti-tumor immunity, suggesting that Lnc-Tim3 and its associated signaling pathways may influence the outcome of cancer therapies aimed at modulating the acquired immune system. PMID- 29706625 TI - Activation of AhR with nuclear IKKalpha regulates cancer stem-like properties in the occurrence of radioresistance. AB - Most cancer patients receive radiotherapy in the course of their disease and the occurrence of radioresistance is associated with poor prognosis. The molecular pathways that drive enhanced tumorigenic potential during the development of radioresistance are poorly understood. Here, we demonstrate that aryl hydrocarbon receptor (AhR) plays a vital role in the maintenance of cancer stem-like properties. AhR promotes the cancer stem-like phenotype and drives metastasis by directly targeting the promoters of 'stemness' genes, such as the ATP-binding cassette sub-family G member 2 (ABCG2) gene. Moreover, the radioresistant sublines display high levels of oncometabolites including alpha-ketoglutarate, and treatment of cancer cells with alpha-ketoglutarate enhances their stem-like properties in an AhR activation-dependent manner. IKKalpha directly activates stemness-related genes through an interaction with AhR as a bone fide chromatin modifier. Thus, AhR is functionally linked with cancer stem-like properties, and it drives tumorigenesis in the occurrence of radioresistance. PMID- 29706627 TI - The Rho GTPase Rnd1 inhibits epithelial-mesenchymal transition in hepatocellular carcinoma and is a favorable anti-metastasis target. AB - Rnd1, a member of Rho GTPases, was found to be downregulated in human malignancies and downregulation of Rnd1 promotes tumor invasion via various mechanisms. However, the role of Rnd1 in hepatocellular carcinoma (HCC) progression remains unclear. In this study, our results demonstrated that Rnd1 was downregulated in HCC cells and in human HCC tissues. Low expression of Rnd1 was associated with aggressive clinic-pathologic characteristics, such as vascular invasion, and poor prognosis in patients who underwent curative surgery for HCC. Overexpression of Rnd1-suppressed cell growth, migration, invasion, and EMT processes in vitro and in vivo. Furthermore, Rnd1 blocked HCC progression by restricting EMT process through inhibition of the Raf/MEK/ERK cascade, and this was correlated with a reduction in RhoA activity. Combination of Rnd1 overexpression with sorafenib, a Raf signaling pathway inhibitor, showed a more potent inhibition on HCC metastasis. Moreover, epigenetic inhibitors (5-Aza and SAHA) increased the expression of Rnd1, and potentiated sorafenib-induced toxicity in HCC cells. In a conclusion, Rnd1-suppressed EMT-mediated metastasis of HCC by reducing the activity of the RhoA/Raf/MEK/ERK signaling pathway, functioning as a favorable anti-metastasis target for HCC patients. Rnd1 overexpression in combination with sorafenib may result in enhanced anti metastasis efficacy in HCC. PMID- 29706628 TI - Modulation of alternative splicing induced by paclitaxel in human lung cancer. AB - Paclitaxel is utilized as the first-line chemotherapeutic regimen for the majority of advanced non-small-cell lung carcinoma. However, whether paclitaxel could suppress cancer progression through modulating RNA alternative splicing remains largely unknown. Here, we demonstrated the effects of paclitaxel on cell proliferation inhibition, cell cycle arrest, and apoptosis. Mechanistically, paclitaxel leads to transcriptional alteration of networks involved in DNA replication and repair, chromosome segregation, chromatin silencing at rDNA, and mitosis at the transcriptional level. Moreover, paclitaxel regulates a number of cancer-associated RNA alternative splicing events, including genes involved in cellular response to DNA damage stimulus, preassembly of GPI anchor in ER membrane, transcription, and DNA repair. In particular, paclitaxel modulates the splicing of ECT2, a key factor involved in the regulation of cytokinesis. Briefly, paclitaxel favors the production of ECT2-S, the short splicing isoforms of ECT2, thereby inhibiting cancer cell proliferation. Our study provides mechanistic insights of paclitaxel on RNA alternative splicing regulation, thus to offer a potential novel route for paclitaxel to inhibit cancer progression. PMID- 29706629 TI - Targeting the miR-665-3p-ATG4B-autophagy axis relieves inflammation and apoptosis in intestinal ischemia/reperfusion. AB - Autophagy is an essential cytoprotective response against pathologic stresses that selectively degrades damaged cellular components. Impaired autophagy contributes to organ injury in multiple diseases, including ischemia/reperfusion (I/R), but the exact mechanism by which impaired autophagy is regulated remains unclear. Several researchers have demonstrated that microRNAs (miRNAs) negatively regulate autophagy by targeting autophagy-related genes (ATGs). Therefore, the effect of ATG-related miRNAs on I/R remains a promising research avenue. In our study, we found that autophagy flux is impaired during intestinal I/R. A miRNA microarray analysis showed that miR-665-3p was highly expressed in the I/R group, which was confirmed by qRT-PCR. Then, we predicted and proved that miR-665-3p negatively regulates ATG4B expression in Caco-2 and IEC-6 cells. In ileum biopsy samples from patients with intestinal infarction, there was an inverse correlation between miR-665-3p and ATG4B expression, which supports the in vitro findings. Moreover, based on miR-665-3p regulation of autophagy in response to hypoxia/reoxygenation in vitro, gain-of-function and loss-of-function approaches were used to investigate the therapeutic potential of miR-665-3p. Additionally, we provide evidence that ATG4B is indispensable for protection upon inhibition of miR-665-3p. Finally, we observed that locked nucleic acid-modified inhibition of miR-665-3p in vivo alleviates I/R-induced systemic inflammation and apoptosis via recovery of autophagic flux. Our study highlights miR-665-3p as a novel small molecule that regulates autophagy by targeting ATG4B, suggesting that miR-665-3p inhibition may be a potential therapeutic approach against inflammation and apoptosis for the clinical treatment of intestinal I/R. PMID- 29706630 TI - lncAKHE enhances cell growth and migration in hepatocellular carcinoma via activation of NOTCH2 signaling. AB - Hepatocellular carcinoma is the sixth most common cancer and gives rise to numerous deaths around the world every year. However, the molecular mechanism that controls hepatocarcinogenesis remains largely unknown. Here we found out an uncharacterized long noncoding RNA named lncAKHE. We found that lncAKHE was highly expressed in hepatocellular carcinoma tissues. lncAKHE depletion remarkably impaired the abilities of cell proliferation, migration, and invasion in hepatocellular carcinoma while promgoogoting cell apoptosis. Moreover, higher expression level of lncAKHE in hepatocellular carcinoma tissues was associated with more clinical severity and lower survival rates. Mechanistically, lncAKHE cooperated with YEATS4 to enhance the activation of NOTCH2 signaling which is usually abnormally upregulated in hepatocellular carcinoma. In conclusions, our study showed that lncAKHE may promote tumor progression in HCC and serve as a novel target for HCC treatment. PMID- 29706631 TI - O-GlcNAc elevation through activation of the hexosamine biosynthetic pathway enhances cancer cell chemoresistance. AB - Chemoresistance has become a major obstacle to the success of cancer therapy, but the mechanisms underlying chemoresistance are not yet fully understood. O GlcNAcylation is a post-translational modification that is regulated by the hexosamine biosynthetic pathway (HBP) and has an important role in a wide range of cellular functions. Here we assessed the role of O-GlcNAcylation in chemoresistance and investigated the underlying cellular mechanisms. The results showed that the HBP has an important role in cancer cell chemoresistance by regulating O-GlcNAcylation. An increase in the levels of O-GlcNAcylation indicates an increased resistance of cancer cells to chemotherapy. Acute treatment with doxorubicin (DOX) or camptothecin (CPT) induced O-GlcNAcylation through HBP activation. In fact, the chemotherapy agents activated the AKT/X-box binding protein 1 (XBP1) axis and then induced the HBP. Furthermore, the observed elevation of cellular O-GlcNAcylation led to activation of survival signalling pathways and chemoresistance in cancer cells. Finally, suppression of O GlcNAcylation reduced the resistance of both established and primary cancer cells to chemotherapy. These results provide significant novel insights regarding the important role of the HBP and O-GlcNAcylation in regulating cancer chemoresistance. Thus, O-GlcNAc inhibition might offer a new strategy for improving the efficacy of chemotherapy. PMID- 29706632 TI - Distress, uncertainty, and positive experiences associated with receiving information on personal genomic risk of melanoma. AB - The aim of this research was to understand how genomics-based personal melanoma risk information impacts psychological and emotional health outcomes in the general population. In a pilot randomized controlled trial, participants (n = 103) completed the Multidimensional Impact of Cancer Risk Assessment (MICRA) questionnaire, 3 months after receiving personal melanoma genomic risk information. Mean scores for MICRA items and subscales were stratified by genomic risk group (low, average, high), gender, education, age, and family history of melanoma. P values were obtained from t-tests and analysis of variance tests. We found that overall, participants (mean age: 53 years, range: 21-69; 52% female) had a total MICRA mean score of 18.6 (standard deviation: 11.1, range: 1-70; possible range: 0-105). The high genomic risk group had higher mean scores for the total (24.2, F2,100 = 6.7, P = 0.0019), distress (3.3, F2,100 = 9.4, P = 0.0002) and uncertainty (8.5, F2,100 = 6.5, P = 0.0021) subscales compared with average (17.6, 1.1, and 4.5, respectively) and low-risk groups (14.1, 0.5, and 2.5, respectively). Positive experiences scores were consistent across risk groups. In conclusion, MICRA scores for the total, distress and uncertainty subscales in our study were relatively low overall, but people who receive a high genomic risk result may benefit from increased support following testing. PMID- 29706633 TI - A pathogenic role for germline PTEN variants which accumulate into the nucleus. AB - The PTEN gene encodes a master regulator protein that exerts essential functions both in the cytoplasm and in the nucleus. PTEN is mutated in the germline of both patients with heterogeneous tumor syndromic diseases, categorized as PTEN hamartoma tumor syndrome (PHTS), and a group affected with autism spectrum disorders (ASD). Previous studies have unveiled the functional heterogeneity of PTEN variants found in both patient cohorts, making functional studies necessary to provide mechanistic insights related to their pathogenicity. Here, we have functionally characterized a PTEN missense variant [c.49C>G; p.(Gln17Glu); Q17E] associated to both PHTS and ASD patients. The PTEN Q17E variant displayed partially reduced PIP3-catalytic activity and normal stability in cells, as shown using S. cerevisiae and mammalian cell experimental models. Remarkably, PTEN Q17E accumulated in the nucleus, in a process involving the PTEN N-terminal nuclear localization sequence. The analysis of additional germline-associated PTEN N terminal variants illustrated the existence of a PTEN N-terminal region whose targeting in disease causes PTEN nuclear accumulation, in parallel with defects in PIP3-catalytic activity in cells. Our findings highlight the frequent occurrence of PTEN gene mutations targeting PTEN N-terminus whose pathogenicity may be related, at least in part, with the retention of PTEN in the nucleus. This could be important for the implementation of precision therapies for patients with alterations in the PTEN pathway. PMID- 29706634 TI - Germline variants in SMARCB1 and other members of the BAF chromatin-remodeling complex across human disease entities: a meta-analysis. AB - Germline variants that affect function are found in seven genes of the BAF chromatin-remodeling complex. They are linked to a broad range of diseases that, according to the gene affected, range from non-syndromic or syndromic neurodevelopmental disorders to low-grade tumors and malignancies. In the current meta-analysis, we evaluate genetic and clinical data from more than 400 families and 577 patients affected by BAF germline alterations. We focus on SMARCB1, including 43 unpublished patients from the EU-RHAB registry and our institution. For this gene, we further demonstrate whole gene as well as exon deletions and truncating variants to be associated with malignancy and early-onset disease. In contrast, non-truncating variants are associated with non-malignant disorders, such as Coffin-Siris syndrome or late-onset tumors like schwannoma or meningioma (p < 0.0001). SMARCB1 germline variants are distributed across the gene with variants in exons 1, 2, 8, and 9 being associated with low-grade entities, and single-nucleotide variants or indels outside of exon 9 that appear in patients with malignancies (p < 0.001). We attribute variants in specific BAF genes to certain disease entities. Finally, single-nucleotide variants and indels are sometimes detected in the healthy relatives of tumor patients, while Coffin-Siris syndrome and Nicolaides-Baraitser syndrome generally seem to appear de novo. Our findings add further information on the genotype-phenotype association of germline variants detected in genes of the BAF complex. Functional studies are urgently needed for a deeper understanding of BAF-related disorders and may take advantage from the comprehensive information gathered in this article. PMID- 29706635 TI - Functional missense and splicing variants in the retinoic acid catabolizing enzyme CYP26C1 in idiopathic short stature. AB - Height is a complex quantitative trait with a high heritability. Short stature is diagnosed when height is significantly below the average of the general population for that person's age and sex. We have recently found that the retinoic acid degrading enzyme CYP26C1 modifies SHOX deficiency phenotypes toward more severe clinical manifestations. Here, we asked whether damaging variants in CYP26C1 alone could lead to short stature. We performed exome and Sanger sequencing to analyze 856 individuals with short stature where SHOX deficiency was previously excluded. Three different damaging missense variants and one splicing variant were identified in six independent individuals; the functional significance of the identified variants was tested in vitro or in vivo using zebrafish as a model. The genetic and functional data reported here indicate that CYP26C1 represents a novel gene underlying growth disorders and that damaging variants in the absence of SHOX variants can lead to short stature. PMID- 29706636 TI - Does ATRX germline variation predispose to osteosarcoma? Three additional cases of osteosarcoma in two ATR-X syndrome patients. AB - Osteosarcoma is the most common malignant bone tumor in adolescents and young adults. Most osteosarcomas are sporadic but the risk of osteosarcoma is also increased by germline variants in TP53, RB1 and RECQL4 genes. ATRX germline variations are responsible for the rare genetic disorder X-linked alpha thalassemia mental retardation (ATR-X) syndrome characterized by severe developmental delay and alpha-thalassemia but no obvious increased risk of cancer. Here we report two children with ATR-X syndrome who developed osteosarcoma. Notably, one of the children developed two osteosarcomas separated by 10 years. Those two cases raise the possibility that ATRX germline variant could be associated with an increased risk of osteosarcoma. PMID- 29706637 TI - Tubulinopathies continued: refining the phenotypic spectrum associated with variants in TUBG1. AB - Tubulinopathies are a heterogeneous group of conditions with a wide spectrum of clinical severity resulting from variants in genes of the tubulin superfamily. Variants in TUBG1 have been described in three patients with posterior predominant pachygyria and microcephaly. We here report eight additional patients with four novel heterozygous variants in TUBG1 identified by next-generation sequencing (NGS) analysis. All had severe motor and cognitive impairment and all except one developed seizures in early life. The core imaging features included a pachygyric cortex with posterior to anterior gradient, enlarged lateral ventricles most pronounced over the posterior horns, and variable degrees of reduced white matter volume. Basal ganglia, corpus callosum, brainstem, and cerebellum were often normal, in contrast to patients with variants in other tubulin genes where these structures are frequently malformed. The imaging phenotype associated with variants in TUBG1 is therefore more in line with the phenotype resulting from variants in LIS1 (a.k.a. PAFAH1B1). This difference may, at least in part, be explained by gamma-tubulin's physiological function in microtubule nucleation, which differs from that of alpha and beta-tubulin. PMID- 29706638 TI - Genome-wide linkage analysis in Spanish melanoma-prone families identifies a new familial melanoma susceptibility locus at 11q. AB - The main genetic factors for familial melanoma remain unknown in >75% of families. CDKN2A is mutated in around 20% of melanoma-prone families. Other high risk melanoma susceptibility genes explain <3% of families studied to date. We performed the first genome-wide linkage analysis in CDKN2A-negative Spanish melanoma-prone families to identify novel melanoma susceptibility loci. We included 68 individuals from 2, 3, and 6 families with 2, 3, and at least 4 melanoma cases. We detected a locus with significant linkage evidence at 11q14.1 q14.3, with a maximum het-TLOD of 3.449 (rs12285365:A>G), using evidence from multiple pedigrees. The genes contained by the subregion with the strongest linkage evidence were: DLG2, PRSS23, FZD4, and TMEM135. We also detected several regions with suggestive linkage evidence (TLOD >1.9) (1q, 6p, 7p, 11q, 12p, 13q) including the region previously detected in melanoma-prone families from Sweden at 3q29. The family-specific analysis revealed three loci with suggestive linkage evidence for family #1: 1q31.1-q32.1 (max. TLOD 2.447), 6p24.3-p22.3 (max. TLOD 2.409), and 11q13.3-q21 (max. TLOD 2.654). Future next-generation sequencing studies of these regions may allow the identification of new melanoma susceptibility genetic factors. PMID- 29706639 TI - Carrier frequency analysis of mutations causing autosomal-recessive-inherited retinal diseases in the Israeli population. AB - Inherited retinal diseases (IRDs) are heterogeneous phenotypes caused by variants in a large number of genes. Disease prevalence and the frequency of carriers in the general population have been estimated in only a few studies, but are largely unknown. To this end, we developed two parallel methods to calculate carrier frequency for mutations causing autosomal-recessive (AR) IRDs in the Israeli population. We created an SQL database containing information on 178 genes from gnomAD (including genotyping of 5706 Ashkenazi Jewish (AJ) individuals) and our cohort of >2000 families with IRDs. Carrier frequency for IRD variants and genes was calculated based on allele frequency values and the Hardy-Weinberg (HW) equation. We identified 399 IRD-causing variants in 111 genes in Israeli patients and AJ controls. For the AJ subpopulation, gnomAD and HW-based regression analysis showed high correlation, therefore allowing one to use HW-based data as a reliable estimate of carrier frequency. Overall, carrier frequency per subpopulation ranges from 1/2.2 to 1/9.6 individuals, with the highest value obtained for the Arab-Muslim subpopulation in Jerusalem reaching an extremely high carrier rate of 44.7%. Carrier frequency per gene ranges from 1/31 to 1/11994 individuals. We estimate the total carrier frequency for AR-IRD mutations in the Israeli population as over 30%, a relatively high carrier frequency with marked variability among subpopulations. Therefore, these data are highly important for more reliable genetic counseling and genetic screening. Our method can be adapted to study other populations, either based on allele frequency data or cohort of patients. PMID- 29706641 TI - Australians' views on personal genomic testing: focus group findings from the Genioz study. AB - Personal genomic testing provides healthy individuals with access to information about their genetic makeup for purposes including ancestry, paternity, sporting ability and health. Such tests are available commercially and globally, with accessibility expected to continue to grow, including in Australia; yet little is known of the views/expectations of Australians. Focus groups were conducted within a multi-stage, cross-disciplinary project (Genioz) to explore this. In mid 2015, 56 members of the public participated in seven focus groups, allocated into three age groups: 18-24, 25-49, and >=50 years. Three researchers coded transcripts independently and generated themes. Awareness of personal genomic testing was low, but most could deduce what "personal genomics" might entail. Very few had heard of the term "direct-to-consumer" testing, which has implications for organisations developing information to support individuals in their decision-making. Participants' understanding of genetics was varied and drawn from several sources. There were diverse perceptions of the relative influence of genetics and environment on health, mental health, behavior, talent, or personality. Views about having a personal genomic test were mixed, with greater interest in health-related tests if they believed there was a reason for doing so. However, many expressed scepticisms about the types of tests available, and how the information might be used; concerns were also raised about privacy and the potential for discrimination. These exploratory findings inform subsequent stages of the Genioz study, thereby contributing to strategies of supporting Australians to understand and make meaningful and well-considered decisions about the benefits, harms, and implications of personal genomic tests. PMID- 29706640 TI - RNA analysis of cancer predisposing genes in formalin-fixed paraffin-embedded tissue determines aberrant splicing. AB - High-throughput sequencing efforts in molecular tumour diagnostics detect increasing numbers of novel variants, including variants predicted to affect splicing. In silico prediction tools can reliably predict the effect of variant disrupting canonical splice sites; however, experimental validation is required to confirm aberrant splicing. Here, we present RNA analysis performed for 13 canonical splice site variants predicted or known to result in splicing in the cancer predisposition genes MLH1, MSH2, MSH6, APC and BRCA1. Total nucleic acid was successfully isolated for 10 variants from eight formalin-fixed paraffin embedded (FFPE) tumour tissues and two B-cell lines. Aberrant splicing was confirmed in all six variants known to result in splicing. Of one known variant in the B-cell line, aberrant splicing could only be detected after formalin fixation, which indicated that formalin fixation could possibly inhibit RNA degradation. Aberrant splicing was concluded in three of four predicted splice variants of uncertain significance, supporting their pathogenic effect. With this assay, somatic splice variants can be easily and rapidly analysed, enabling retrospective analysis to support the pathogenicity of variants predicted to result in splicing when only FFPE material is available. PMID- 29706642 TI - Genes flow by the channels of culture: the genetic imprint of matrilocality in Ngazidja, Comoros Islands. AB - Post-marital residence of spouses is one of the architects of population genetic structure. In the present study, we tested how the place of residence of males and females in Ngazidja, Comoros Islands, has unequally channeled, by dispersal among villages, the male and female genetic diversity. Using sequences of the hypervariable segment I of the mitochondrial DNA (mtDNA HVS-I) and six Y chromosome microsatellites (Y-STRs), we measured the genetic variation and male to-female effective number of migrants ratios based on FST values and revealed a genetic structure mostly driven by male gene flow across villages. This genetic feature illustrates the uxori-matrilocality inherited from the Bantu expansion, though one exception exists in Bandamadji whose historically documented military status implied patrilocality in this locality. PMID- 29706643 TI - Are your covariates under control? How normalization can re-introduce covariate effects. AB - Many statistical tests rely on the assumption that the residuals of a model are normally distributed. Rank-based inverse normal transformation (INT) of the dependent variable is one of the most popular approaches to satisfy the normality assumption. When covariates are included in the analysis, a common approach is to first adjust for the covariates and then normalize the residuals. This study investigated the effect of regressing covariates against the dependent variable and then applying rank-based INT to the residuals. The correlation between the dependent variable and covariates at each stage of processing was assessed. An alternative approach was tested in which rank-based INT was applied to the dependent variable before regressing covariates. Analyses based on both simulated and real data examples demonstrated that applying rank-based INT to the dependent variable residuals after regressing out covariates re-introduces a linear correlation between the dependent variable and covariates, increasing type-I errors and reducing power. On the other hand, when rank-based INT was applied prior to controlling for covariate effects, residuals were normally distributed and linearly uncorrelated with covariates. This latter approach is therefore recommended in situations were normality of the dependent variable is required. PMID- 29706644 TI - Distinct variants affecting differential splicing of TGFBR1 exon 5 cause either Loeys-Dietz syndrome or multiple self-healing squamous epithelioma. AB - Variants in TGFBR1 have been reported to induce two completely distinct diseases, namely Loeys-Dietz syndrome (LDS) and multiple self-healing squamous epithelioma (MSSE). However, detailed mechanisms underlying this effect remain unknown. We report a Japanese familial case of LDS with a novel splice donor site variant in TGFBR1 gene (c.973 + 1 G > A; NG_007461.1). The intronic variant was predicted to mediate in-frame exon 5 skipping within the serine/threonine kinase (STK) domain, which may also be mediated by a similar TGFBR1 variant of a splice acceptor site in intron 4 (c.806-2 A > C), identified in a British familial case of MSSE. Therefore, ex vivo splicing and functional assays were performed in mammalian cells to evaluate the effect of these sequence variants. The MSSE variant activated a cryptic acceptor site at 76 bp downstream of the 3' natural splice acceptor site, which produced an out-of-frame transcript (r.807_882del, p.Asn270Thrfs*8). In contrast, the LDS variant generated two types of in-frame transcription products, r.[806_973del, 965_973 del], and produced two functionally inactivated proteins, p.[Asp269_Gln324del, Thr323_Gly325del], as a result of exon 5 skipping and the activation of a cryptic donor splice site at 9 bp upstream of the 5' natural splice donor site, respectively. Our results support the previously proposed but not yet approved mechanism that dominant negative and truncating variants in STK domain induce LDS and MSSE, respectively. PMID- 29706645 TI - Identification of variants in pleiotropic genes causing "isolated" premature ovarian insufficiency: implications for medical practice. AB - Next-generation sequencing (NGS) is increasingly being used in a clinical setting for the molecular diagnosis of patients with heterogeneous disorders, such as premature ovarian insufficiency (POI). We performed NGS of ~1000 candidate genes in four unrelated patients with POI. We discovered the genetic cause of "isolated" POI in two cases, both of which had causative variants in surprising genes. In the first case, a homozygous nonsense variant in NBN was causative. Recessive function-altering NBN variants typically cause Nijmegen breakage syndrome characterized by microcephaly, cancer predisposition, and immunodeficiency, none of which are evident in the patient. At a cellular level, we found evidence of chromosomal instability. In the second case, compound heterozygous variants in EIF2B2 were causative. Recessive EIF2B2 function altering variants usually cause leukoencephalopathy with episodic decline. Subsequent MRI revealed subclinical neurological abnormalities. These cases demonstrate that variants in NBN and EIF2B2, which usually cause severe syndromes, can cause apparently isolated POI, and that (1) NGS can precede clinical diagnosis and guide patient management, (2) NGS can redefine the phenotypic spectrum of syndromes, and (3) NGS may make unanticipated diagnoses that must be sensitively communicated to patients. Although there is rigorous debate about the handling of secondary/incidental findings using NGS, there is little discussion of the management of causative pleiotropic gene variants that have broader implications than that for which genetic studies were sought. PMID- 29706646 TI - Comprehensive genomic analysis of patients with disorders of cerebral cortical development. AB - Malformations of cortical development (MCDs) manifest with structural brain anomalies that lead to neurologic sequelae, including epilepsy, cerebral palsy, developmental delay, and intellectual disability. To investigate the underlying genetic architecture of patients with disorders of cerebral cortical development, a cohort of 54 patients demonstrating neuroradiologic signs of MCDs was investigated. Individual genomes were interrogated for single-nucleotide variants (SNV) and copy number variants (CNV) with whole-exome sequencing and chromosomal microarray studies. Variation affecting known MCDs-associated genes was found in 16/54 cases, including 11 patients with SNV, 2 patients with CNV, and 3 patients with both CNV and SNV, at distinct loci. Diagnostic pathogenic SNV and potentially damaging variants of unknown significance (VUS) were identified in two groups of seven individuals each. We demonstrated that de novo variants are important among patients with MCDs as they were identified in 10/16 individuals with a molecular diagnosis. Three patients showed changes in known MCDs genes and a clinical phenotype beyond the usual characteristics observed, i.e., phenotypic expansion, for a particular known disease gene clinical entity. We also discovered 2 likely candidate genes, CDH4, and ASTN1, with human and animal studies supporting their roles in brain development, and 5 potential candidate genes. Our findings emphasize genetic heterogeneity of MCDs disorders and postulate potential novel candidate genes involved in cerebral cortical development. PMID- 29706648 TI - Transient PP2A inhibition alleviates normal tissue stem cell susceptibility to cell death during radiotherapy. AB - Unintended outcomes of cancer therapy include ionizing radiation (IR)-induced stem cell depletion, diminished regenerative capacity, and accelerated aging. Stem cells exhibit attenuated DNA damage response (DDR) and are hypersensitive to IR, as compared to differentiated non-stem cells. We performed genomic discovery research to compare stem cells to differentiated cells, which revealed Phosphoprotein phosphatase 2A (PP2A) as a potential contributor to susceptibility in stem cells. PP2A dephosphorylates pATM, gammaH2AX, pAkt etc. and is believed to play dual role in regulating DDR and apoptosis. Although studied widely in cancer cells, the role of PP2A in normal stem cell radiosensitivity is unknown. Here we demonstrate that constitutively high expression and radiation induction of PP2A in stem cells plays a role in promoting susceptibility to irradiation. Transient inhibition of PP2A markedly restores DNA repair, inhibits apoptosis, and enhances survival of stem cells, without affecting differentiated non-stem and cancer cells. PP2Ai-mediated stem cell radioprotection was demonstrated in murine embryonic, adult neural, intestinal, and hematopoietic stem cells. PMID- 29706649 TI - Translational attenuation and retinal degeneration in mice with an active integrated stress response. AB - An integrated stress response (ISR), identified in several different animal models of inherited retinal degeneration (IRD), is activated following various cellular stresses. The ISR results in the phosphorylation of eIF2alpha (p eIF2alpha) and a consequent halt in protein synthesis. Although generally protective, persistent elevations in p-eIF2alpha could lead to cell demise. Therefore, we aimed to determine whether ISR activation is associated with diminished translation rates in mice with IRD. Retinal protein extracts from rd16 mice at different time points were analyzed and the retinal levels of protein synthesis were assessed using the SUnSET method. We found that rd16 mice experience persistent ISR activation: p-eIF2alpha, ATF4, and CHOP were significantly upregulated at P15 and P20. In agreement with ISR activation, we found that rd16 mice experience translational attenuation at P15. Similar to rd16, other IRD models, T17M RHO, and rd10 also demonstrated a decline in protein synthesis, correlating with p-eIF2alpha elevation. We then assessed the role of PERK and eIF2alpha in translational attenuation in rd16 using a PERK inhibitor, GSK2606414. We found that while the treatment significantly reduced p-eIF2alpha, it did not cause a complete recovery in translation. This suggests that eIF2alpha is not the only or even the primary point of translational control in IRD, and a second node of translational regulation comprising AKT and mTOR should be evaluated. Surprisingly, we found that AKT-mTOR signaling was diminished in rd16 and rd10 retinas, suggesting a potential link between AKT-mTOR and translational inhibition. Therefore, for the first time, this study shows translation attenuation in IRD models, and highlights the potential roles of eIF2alpha kinases and AKT-mTOR signaling that could grant valuable insight into the potential treatments for IRD. PMID- 29706647 TI - The microbiome and autoimmunity: a paradigm from the gut-liver axis. AB - Microbial cells significantly outnumber human cells in the body, and the microbial flora at mucosal sites are shaped by environmental factors and, less intuitively, act on host immune responses, as demonstrated by experimental data in germ-free and gnotobiotic studies. Our understanding of this link stems from the established connection between infectious bacteria and immune tolerance breakdown, as observed in rheumatic fever triggered by Streptococci via molecular mimicry, epitope spread and bystander effects. The availability of high throughput techniques has significantly advanced our capacity to sequence the microbiome and demonstrated variable degrees of dysbiosis in numerous autoimmune diseases, including rheumatoid arthritis, type 1 diabetes, multiple sclerosis and autoimmune liver disease. It remains unknown whether the observed differences are related to the disease pathogenesis or follow the therapeutic and inflammatory changes and are thus mere epiphenomena. In fact, there are only limited data on the molecular mechanisms linking the microbiota to autoimmunity, and microbial therapeutics is being investigated to prevent or halt autoimmune diseases. As a putative mechanism, it is of particular interest that the apoptosis of intestinal epithelial cells in response to microbial stimuli enables the presentation of self-antigens, giving rise to the differentiation of autoreactive Th17 cells and other T helper cells. This comprehensive review will illustrate the data demonstrating the crosstalk between intestinal microbiome and host innate and adaptive immunity, with an emphasis on how dysbiosis may influence systemic autoimmunity. In particular, a gut-liver axis involving the intestinal microbiome and hepatic autoimmunity is elucidated as a paradigm, considering its anatomic and physiological connections. PMID- 29706650 TI - Innovative strategies minimize engraftment syndrome in multiple myeloma patients with novel induction therapy following autologous hematopoietic stem cell transplantation. AB - Autologous stem cell transplantation (PBSCT) is standard for young patients in MM and its TRM has decreased after the 2000s. Bortezomib and immunomodulatory agents (IMiDs) in MM have improved the outcome. However, they seem to boost pro inflammatory stage increasing the incidence of engraftment syndrome (ES). Favorable factors in PBSCT such as G-CSF could increase inflammatory stage during transplant. Corticosteroids have shown an excellent response of ES and some authors propose them as prophylaxis for ES. The aim was to analyze the impact of G-CSF avoidance and corticosteroids' prophylaxis in 170 patients diagnosed of MM treated with bortezomib/IMiDs that underwent PBSCT. We established three groups: Group-I [(G-CSF_administration), 60 patients (35%)], group-II [(nonG-CSF), 60 patients (35%)] and group-III [(nonG-CSF plus corticosteroid's prophylaxis), 50 patients (30%)]. A decreased ES incidence among groups was observed: 62, 42, and 22% (P < 0.0001). The incidence of symptoms mimicking a capillary leak syndrome associated with ES dropped: 43, 32, and 0% (P = 0.03). The G-CSF avoidance and corticosteroids had impact over admission 24, 21, and 20 days (P = 0.001). The most important variables related to ES were HCT-CI >2 (p < 0.0001; HR 8.5) and risk groups (p < 0.0001; HR 7.2). Hence, G-CSF avoidance and corticosteroid's prophylaxis decrease morbidity in patients undergoing PBSCT with MM treated with bortezomib/IMiDs. PMID- 29706652 TI - LncRNA PVT1 promotes angiogenesis via activating the STAT3/VEGFA axis in gastric cancer. AB - Angiogenesis can aggravate gastric cancer progression. LncRNAs exert important roles in regulating various cancer behaviors. However, the functions and mechanisms of lncRNAs in angiogenesis remain largely unknown. Here we demonstrated that lncRNA PVT1 was upregulated and significantly associated with high-microvessel density and poor prognosis in gastric cancer. Through gain- and loss-of PVT1 expression, we found PVT1 could obviously induce angiogenesis within tumors, in addition to promoting tumor growth in vitro and in vivo. Mechanistically, PVT1 directly interacted with the signal transducer activator phospho-STAT3 in the nucleus, and increased its protein stability by protecting it from poly-ubiquitination and proteasome-dependent degradation. The binding of PVT1 activated the STAT3 signalling pathway, and successively elevated VEGFA expression to stimulate angiogenesis. The positive correlation of PVT1 and VEGFA expression was also verified in gastric cancer specimens, and high levels of PVT1 and VEGFA in combination frequently predicted shorter survival time. Moreover, we revealed that PVT1 was a STAT3-responsive lncRNA, as STAT3 could occupy the PVT1 promoter to facilitate its transcription. The positive feed-back loop of PVT1 and STAT3 continuously enhanced the oncogenic effects. Collectively, our study first elucidates the mechanism of PVT1-mediated angiogenesis via evoking the STAT3/VEGFA signalling axis, which provides promising target for developing new therapeutic strategy in gastric cancer. PMID- 29706653 TI - Programmed death ligand 1 promotes lymph node metastasis and glucose metabolism in cervical cancer by activating integrin beta4/SNAI1/SIRT3 signaling pathway. AB - Although PD-L1 has been shown to play a well-characterized role in inhibiting antitumor immunity via engagement of its receptor PD-1 in T lymphocytes, little is known about the tumor cell-intrinsic function of PD-L1 and its association with prognosis. Here, we investigate this issue and dissect the molecular mechanisms underlying the role of PD-L1 in glucose metabolism, proliferation, migration, and invasion in human cervical cancer cells. As a result, we found that PD-L1 overexpression in cervical cancer cells increases glucose metabolism and metastasis-related behaviors. Mechanistically, PD-L1 bound directly to integrin beta4 (ITGB4), activating the AKT/GSK3beta signaling pathway and consequently inducing the expression of the transcriptional repressor SNAI1. SNAIL in turn influenced the expression of genes involved in the epithelial-to mesenchymal transition and regulated glucose metabolism by inhibiting SIRT3 promoter activity. High expression of PD-L1 and ITGB4 in human cervical carcinomas was significantly associated with lymph node metastasis and poor prognosis. Finally, 18F-fluorodeoxyglucose microPET/CT and bioluminescence imaging analyses of cervical xenograft tumors in mice revealed that PD-L1 overexpression markedly increases tumor glucose uptake and promotes lymph node metastasis. Together, these results demonstrate that PD-L1 can promote the growth and metastasis of cervical cancer by activating the ITGB4/SNAI1/SIRT3 signaling pathway, and also suggest the possibility of targeting PD-L1 and its downstream effectors as a potential approach for interfering with cervical cancer growth and metastasis. PMID- 29706651 TI - Wild-type p53 upregulates an early onset breast cancer-associated gene GAS7 to suppress metastasis via GAS7-CYFIP1-mediated signaling pathway. AB - The early onset breast cancer patients (age <= 40) often display higher incidence of axillary lymph node metastasis, and poorer five-year survival than the late onset patients. To identify the genes and molecules associated with poor prognosis of early onset breast cancer, we examined gene expression profiles from paired breast normal/tumor tissues, and coupled with Gene Ontology and public data base analysis. Our data showed that the expression of GAS7b gene was lower in the early onset breast cancer patients as compared to the elder patients. We found that GAS7 was associated with CYFIP1 and WAVE2 complex to suppress breast cancer metastasis via blocking CYFIP1 and Rac1 protein interaction, actin polymerization, and beta1-integrin/FAK/Src signaling. We further demonstrated that p53 directly regulated GAS7 gene expression, which was inversely correlated with p53 mutations in breast cancer specimens. Our study uncover a novel regulatory mechanism of p53 in early onset breast cancer progression through GAS7 CYFIP1-mediated signaling pathways. PMID- 29706654 TI - The essential role of WD repeat domain 77 in prostate tumor initiation induced by Pten loss. AB - Prostate cancer is the most commonly diagnosed malignancy among men, but few genetic factors that drive prostate cancer initiation have been identified. The WD repeat domain 77 (Wdr77) protein is essential for cellular proliferation when localizes in the cytoplasm of epithelial cells at the early stage of prostate development. In the adult prostate, it is transported into the nucleus and functions as a co-regulator of the androgen receptor to promote cellular differentiation and prostate function. This developmental process is reversed during prostate tumorigenesis, i.e., Wdr77 is translocated from the nucleus into the cytoplasm to drive proliferation of prostate cancer cells. In this study, we used in vivo genetic studies to further investigate the role of Wdr77 in prostate tumorigenesis. We found that prostate-specific deletion of Wdr77 abolished prostate tumor initiation induced by loss of the tumor suppressor Pten. Mechanistically, Wdr77 ablation inhibited E2F3 activation and enhanced TGFbeta signaling, leading to attenuated cellular proliferation induced by loss of Pten. These findings establish a critical role of Wdr77 for prostate tumor initiation. PMID- 29706655 TI - Novel tumour suppressive protein encoded by circular RNA, circ-SHPRH, in glioblastomas. AB - The previously unchartered gene expression territory governed by circular RNAs is becoming clearer with the onset of deeper sequencing technologies. The translation of circular RNAs remained a controversial theory until earlier this year, when two studies [1, 2] showed endogenous circular RNA translation in vitro and in vivo, and have further provided mechanistical evidence. In this edition of Oncogene, Zhang et al., provide evidence for the first circular RNA translated with relevance to cancer; a novel tumour suppressor protein, SHPRH-146aa, produced by circ-SHPRH driven by IRES elements. The novel tumour suppressor protein produced by the circular RNA was found to work in synergy with the full length protein, behaving as a protective decoy molecule to decrease degradation, and thus increasing the tumour suppressive functionality of the gene. An extended patient survival time was seen in glioblastoma patients with elevated levels of SHPRH-146aa. This study also marks the discovery of the first circular RNA with an overlapping initiation and termination codon, resulting in the translation of the full circRNA, exploring a mechanism not previously found or seen. PMID- 29706656 TI - The constitutive activity of the virally encoded chemokine receptor US28 accelerates glioblastoma growth. AB - Glioblastoma (GBM) is the most aggressive and an incurable type of brain cancer. Human cytomegalovirus (HCMV) DNA and encoded proteins, including the chemokine receptor US28, have been detected in GBM tumors. US28 displays constitutive activity and is able to bind several human chemokines, leading to the activation of various proliferative and inflammatory signaling pathways. Here we show that HCMV, through the expression of US28, significantly enhanced the growth of 3D spheroids of U251- and neurospheres of primary glioblastoma cells. Moreover, US28 expression accelerated the growth of glioblastoma cells in an orthotopic intracranial GBM-model in mice. We developed highly potent and selective US28 targeting nanobodies, which bind to the extracellular domain of US28 and detect US28 in GBM tissue. The nanobodies inhibited chemokine binding and reduced the constitutive US28-mediated signaling with nanomolar potencies and significantly impaired HCMV/US28-mediated tumor growth in vitro and in vivo. This study emphasizes the oncomodulatory role of HCMV-encoded US28 and provides a potential therapeutic approach for HCMV-positive tumors using the nanobody technology. PMID- 29706657 TI - Hypertonicity-enforced BCL-2 addiction unleashes the cytotoxic potential of death receptors. AB - Attempts to exploit the cytotoxic activity of death receptors (DR) for treating cancer have thus far been disappointing. DR activation in most malignant cells fails to trigger cell death and may even promote tumor growth by activating cell death-independent DR-associated signaling pathways. Overcoming apoptosis resistance is consequently a prerequisite for successful clinical exploitation of DR stimulation. Here we show that hyperosmotic stress in the tumor microenvironment unleashes the deadly potential of DRs by enforcing BCL-2 addiction of cancer cells. Hypertonicity robustly enhanced cytotoxicity of tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) and other DR ligands in various cancer entities. Initial events in TRAIL DR signaling remained unaffected, but hypertonic conditions unlocked activation of the mitochondrial death pathway and thus amplified the apoptotic signal. Mechanistically, we demonstrate that hyperosmotic stress imposed a BCL-2-addiction on cancer cells to safeguard the integrity of the outer mitochondrial membrane (OMM), essentially exhausting the protective capacity of BCL-2-like pro-survival proteins. Deprivation of these mitochondrial safeguards licensed DR-generated truncated BH3 interacting domain death agonist (tBID) to activate BCL-2-associated X protein (BAX) and initiated mitochondrial outer membrane permeabilization (MOMP). Our work highlights that hyperosmotic stress in the tumor environment primes mitochondria for death and lowers the threshold for DR-induced apoptosis. Beyond TRAIL-based therapies, our findings could help to strengthen the efficacy of other apoptosis-inducing cancer treatment regimens. PMID- 29706658 TI - ACTN4 regulates the stability of RIPK1 in melanoma. AB - The actin crosslinking protein alpha-actinin-4 (ACTN4) is emerging as an important contributor to the pathogenesis of cancer. This has largely been attributed to its role in regulating cytoskeleton organization and its involvement in transcriptional regulation of gene expression. Here we report a novel function of ACTN4 as a scaffold necessary for stabilization of receptor interacting protein kinase 1 (RIPK1) that we have recently found to be an oncogenic driver in melanoma. ACTN4 bound to RIPK1 and cellular inhibitor of apoptosis protein 1 (cIAP1) with its actin-binding domain at the N-terminus and the CaM-like domain at the C-terminus, respectively. This facilitated the physical association between RIPK1 and cIAP1 and was critical for stabilization of RIPK1 that in turn activated NF-kappaB. Functional investigations showed that silencing of ACTN4 suppressed melanoma cell proliferation and retarded melanoma xenograft growth. In contrast, overexpression of ACTN4 promoted melanocyte and melanoma cell proliferation and moreover, prompted melanocyte anchorage independent growth. Of note, the expression of ACTN4 was transcriptionally activated by NF-kappaB. Taken together, our findings identify ACTN4 as an oncogenic regulator through driving a feedforward signaling axis of ACTN4-RIPK1 NF-kappaB, with potential implications for targeting ACTN4 in the treatment of melanoma. PMID- 29706659 TI - Nonspherical particles in a pseudo-2D fluidized bed: Experimental study. AB - Fluidization is widely used in industries and has been extensively studied, both experimentally and theoretically, in the past. However, most of these studies focus on spherical particles while in practice granules are rarely spherical. Particle shape can have a significant effect on fluidization characteristics. It is therefore important to study the effect of particle shape on fluidization behavior in detail. In this study, experiments in pseudo-2D fluidized beds are used to characterize the fluidization of spherocylindrical (rod-like) Geldart D particles of aspect ratio 4. Pressure drop and optical measurement methods (Digital Image Analysis, Particle Image Velocimetry, Particle Tracking Velocimetry) are employed to measure bed height, particle orientation, particle circulation, stacking, and coordination number. The commonly used correlations to determine the pressure drop across a bed of nonspherical particles are compared to experiments. Experimental observations and measurements have shown that rod like particles are prone to interlocking and channeling behavior. Well above the minimum fluidization velocity, vigorous bubbling fluidization is observed, with groups of interlocked particles moving upwards, breaking up, being thrown high in the freeboard region and slowly raining down as dispersed phase. At high flowrates, a circulation pattern develops with particles moving up through the center and down at the walls. Particles tend to orient themselves along the flow direction. PMID- 29706660 TI - Health behaviours of young mothers: Implications for health promotion and cancer prevention. AB - Objective: Evidence suggests that younger mothers engage in poorer health behaviours, resulting in increased cancer risk. We aimed to better understand the health behaviours of younger mothers and the factors that influence their lifestyle choices, in order to improve cancer prevention within this population. Methods: A multiple focus group, photo-elicitation-aided approach was used, in which young mothers (n = 27; aged 16-24 years) were provided with cameras and asked to capture 'a week in your life'. Photographs were developed and participants invited to an initial focus group where photographs were used to elicit discussion, exploring participants' health behaviours. Data were thematically analysed particularly identifying themes relating to barriers and facilitators of positive health behaviours. Participants were later invited to participate in a second focus group, to explore and validate identified themes further. Results: Themes emerged from the data relating to (1) the mothers' personal perceptions of health, (2) health-related behaviours and (3) beliefs about cancer and its causes. Barriers to positive health behaviours included a lack of money, childcare and cookery skills; facilitators included the social media, commercial weight loss programmes and local community organisations. Conclusion: Study findings provide insight into the health behaviours and life choices of young mothers. They help illustrate health perceptions in relation to cancer risk, providing an understanding of how their daily routine and circumstance influence young women's decisions and lifestyle behaviour choices and highlighting barriers to, and facilitators of, positive health behaviours. Data hold potential to inform future health-related research among young mothers, particularly relating to cancer prevention intervention. PMID- 29706661 TI - DANUBE: Data-driven meta-ANalysis using UnBiased Empirical distributions-applied to biological pathway analysis. AB - Identifying the pathways and mechanisms that are significantly impacted in a given phenotype is challenging. Issues include patient heterogeneity and noise. Many experiments do not have a large enough sample size to achieve the statistical power necessary to identify significantly impacted pathways. Meta analysis based on combining p-values from individual experiments has been used to improve power. However, all classical meta-analysis approaches work under the assumption that the p-values produced by experiment-level statistical tests follow a uniform distribution under the null hypothesis. Here we show that this assumption does not hold for three mainstream pathway analysis methods, and significant bias is likely to affect many, if not all such meta-analysis studies. We introduce DANUBE, a novel and unbiased approach to combine statistics computed from individual studies. Our framework uses control samples to construct empirical null distributions, from which empirical p-values of individual studies are calculated and combined using either a Central Limit Theorem approach or the additive method. We assess the performance of DANUBE using four different pathway analysis methods. DANUBE is compared with five meta-analysis approaches, as well as with a pathway analysis approach that employs multiple datasets (MetaPath). The 25 approaches have been tested on 16 different datasets related to two human diseases, Alzheimer's disease (7 datasets) and acute myeloid leukemia (9 datasets). We demonstrate that DANUBE overcomes bias in order to consistently identify relevant pathways. We also show how the framework improves results in more general cases, compared to classical meta-analysis performed with common experiment-level statistical tests such as Wilcoxon and t-test. PMID- 29706662 TI - Colony size and brood investment of Myrmica rubra ant colonies in habitats invaded by goldenrods. AB - Ant richness and abundance are negatively affected by the invasion of alien goldenrods (Solidago sp.). However, little is known about the mechanisms standing behind the impact of the invaders on ant life history, such as colony investments in growth and reproduction. We examined this problem of the investments of Myrmica rubra ant colonies living in different grasslands invaded and non-invaded by goldenrods. Altogether, 47 colonies were analysed; and for each colony, we calculated the number of queens, workers and the production of young workers, gynes, and males. We found that colonies from invaded meadows are smaller in size, but have a similar number of adult queens compared to colonies from non invaded sites. We also found different brood investments among colonies from invaded and non-invaded meadows-colonies from non-invaded meadows produce more young workers and invest more in growth, whereas colonies from invaded meadows invest more in reproduction through higher gyne production. Male production was at a similar level in colonies from both habitat types. The observed patterns may be explained by the effect of various environmental factors occurring in both grassland types, such as stress in changed habitats, higher competition among gynes in non-invaded grasslands, or finally, by the adaptive colony-level response of ants to stress. The higher production of gynes observed in the invaded grasslands may support dispersal and enhance the probability of establishing a colony in a more favourable location. PMID- 29706663 TI - Religious Pathways from Adolescence to Adulthood. AB - Prior research suggests the significance of religion for development and wellbeing in adolescence and beyond. Further, new developments and applications of statistical methods have led to ways of better accounting for the multidimensional nature of religiosity (e.g. latent class analysis), as well as the dynamic aspects of religiosity (e.g. latent growth curve models). Yet, rarely if ever are both features of religiosity incorporated and examined together. Therefore, we propose and conduct a latent class analysis using data from the National Longitudinal Study of Adolescent to Adult Health (Add Health) to identify seven distinct pathways of religiosity that involve independently changing levels of religious affiliation, religious service attendance, personal importance of religion, and prayer from adolescence to adulthood. We also show how individuals' religious pathways are related to gender, race, parents' education, their own education, and family formation experiences in the transition to adulthood. Our findings inform the study of how multiple dimensions of religiosity take shape across adolescence and the transition to adulthood, and suggest a new way for measuring the dynamics of religiosity in studies of the impact of religion across the life course. PMID- 29706665 TI - Electrostatic Control of Polymer Translocation Speed through alpha-Hemolysin Protein Pore. AB - The electrostatic origins behind the speed of translocation of a uniformly charged flexible macromolecule through alpha-hemolysin (alphaHL) protein pores under a voltage are investigated using variations in pH and electrolyte concentration. We have measured durations of successful threading of poly(styrenesulfonate) through alphaHL at two different pH conditions, pH 4.5 and pH 7.5, under various salt concentration conditions. Salt concentrations in the donor (cis) and the recipient (trans) compartments influence the polymer translocation dynamics differently, depending on pH. At both pH 4.5 and pH 7.5, decreasing the cis salt concentration, cs,cis , results in faster polymer translocations. On the other hand, a decrease in trans salt concentration, cs,trans , retards the polymer transport process at pH 4.5, while at pH 7.5 the translocation time is observed to be independent of cs,trans . We present a theoretical model to calculate the translocation times from the free energy of the polymer along the translocation process to describe our experimental results. We show that the charge density of the polymer inside the nanopore is significantly affected by cs,cis , explaining the cis salt effect on the speed of polymer translocation. The trans salt effects are attributed to the electrostatic interaction between the polymer and the exit portion of the alphaHL pore, which is determined by the pH of the trans compartment. At low pH where the net charge of the end of the alphaHL is positive, the attractive electrostatic interaction in trans becomes stronger, as cs,trans decreases, resulting in delays in translocation process. PMID- 29706664 TI - Implications of Debunking the "Critical Positivity Ratio" for Humanistic Psychology: Introduction to Special Issue. AB - An extraordinary claim was made by one of the leading researchers within positive psychology, namely, there is a universal-invariant ratio between positive to negative emotions that serves as a unique tipping point between flourishing and languishing in individuals, marriages, organizations, and other human systems across all cultures and times. Known as the "critical positivity ratio," this finding was supposedly derived from the famous Lorenz equation in physics by using the mathematics of nonlinear dynamic systems, and was defined precisely as "2.9013." This exact number was widely touted as a great discovery by many leaders of positive psychology, had tremendous impact in various applied areas of psychology, and, more broadly, and was extensively cited in both the scientific literature and in the global popular media. However, this finding has been demonstrated to be bogus. Since its advent as a relatively new subdiscipline, positive psychology has claimed superiority to its precursor, the subdiscipline of humanistic psychology, in terms of supposedly both using more rigorous science and avoiding popularizing nonsense. The debunking of the critical positivity ratio demonstrates that positive psychology did not live up to these claims, and this has important implications, which are discussed in terms of "romantic scientism" and "voodoo science." In addition, articles in the special issue on the "Implications of Debunking the 'Critical Positivity Ratio' for Humanistic Psychology" are introduced, as they also delve into these concerns. PMID- 29706666 TI - Characterizing the Interface Scaling of High chi Block Copolymers near the Order Disorder Transition. AB - Advancements in the directed self-assembly of block copolymers (BCPs) have prompted the development of new materials with larger effective interaction parameters (chie). This enables BCP systems with phase separation at increasingly small degrees of polymerization (N). Very often these systems reside near the order-disorder transition and fit between the weak and strong segregation limits where the behavior of BCP systems is not as thoroughly understood. Utilizing resonant soft X-ray reflectivity (RSoXR) enables both the BCP pitch (L0) and interface width (wM) to be determined simultaneously, through a direct characterization of the composition profile of BCP lamellae oriented parallel to a substrate. A series of high chie BCPs with chie ranging from ~0.04 to 0.25 and chieN from 19 to 70 have been investigated. The L0/wm ratio serves as an important metric for the feasibility of a material for nanopatterning applications; the results of the RSoXR measurement are used to establish a relationship between chie and L0/wm. The results of this analysis are correlated with experimentally established limits for the functionality of BCPs in nanopatterning applications. These results also provide guidance for the magnitude of chie needed to achieve small interface width for samples with sub-10 nm L0. PMID- 29706667 TI - Limited impact of an invasive oyster on intertidal assemblage structure and biodiversity: the importance of environmental context and functional equivalency with native species. AB - Impacts of invasive species are context dependent and linked to the ecosystem they occur within. To broaden the understanding of the impact of a globally widespread invasive oyster, Crassostrea (Magallana) gigas, intertidal surveys were carried out at 15 different sites in Europe. The impact of C. gigas on macro (taxa surrounding oyster > 1 cm) and epifaunal (taxa on oyster < 1 cm) benthic communities and alpha and beta-diversity was assessed and compared to those associated with native ecosystem engineers, including the flat oyster Ostrea edulis. Whilst the effect of C. gigas on benthic community structures was dependent on habitat type, epifaunal communities associated with low densities of O. edulis and C. gigas did not differ and changes in benthic assemblage structure owing to the abundance of C. gigas were therefore attributed to the presence of oyster shells. Macrofaunal alpha-diversity increased with C. gigas cover in muddy habitats, while epifaunal alpha-diversity decreased at greater oyster densities. Macrofaunal beta-diversity was greatest at low densities of C. gigas; however, it did not differ between samples without and increased densities of oysters. In contrast, epifaunal beta-diversity decreased with increasing oyster cover. Different environmental contexts enabled more independent predictions of the effect of C. gigas on native communities. These were found to be low and more importantly not differing from O. edulis. This indicates that, at low densities, C. gigas may be functionally equivalent to the declining native oyster in terms of biodiversity facilitation and aid in re-establishing benthic communities on shores where O. edulis has become extinct. PMID- 29706669 TI - Bodies, Sport and Science in the Nineteenth Century. PMID- 29706668 TI - Food Consumption Patterns and Micronutrient Density of Complementary Foods Consumed by Infants Fed Commercially Prepared Baby Foods. AB - Nutrition is critically important in the first 1000 days, and while most American babies are fed commercial baby foods, there is little or no evidence from nationally representative data to understand the implications of such consumption. We used 24-hour dietary recall data for 505 infants from The Feeding Infants and Toddlers Study to describe food consumption patterns and micronutrient density of complementary foods consumed by infants fed commercially prepared baby food fruit, vegetables, and dinners and compared with those eaten by nonconsumers of these products. Results show that consumers were significantly more likely to report eating all vegetables (excluding white potatoes, 71% vs 51%), deep yellow vegetables (42% vs 18%), and fruits (79% vs 65%) and were less likely to report eating white potatoes (10% vs 24%), dark green vegetables (4% vs 20%), and sweets (23% vs 47%) than were nonconsumers. Nutrient density of the complementary foods of consumers was greater for fiber, potassium, vitamin A, vitamin C, vitamin E, and magnesium, but lower in sodium and vitamin D. We conclude that infants fed commercially prepared baby foods were more likely to eat vegetables and fruits, and their diets were higher in several micronutrients. These findings provide important insights on complementary feeding and are useful to support the development of evidence-based infant-feeding guidelines. PMID- 29706671 TI - Review of Methods in Enzymology Volumes 551 and 552 Circadian Rhythms and Biological Clocks, Part A and B Edited by Amita Sehgal. PMID- 29706672 TI - Professor Maria Plachecka-Gutowska. PMID- 29706670 TI - In situ observation of localized, sub-mm scale changes of phosphorus biogeochemistry in the rhizosphere. AB - Aims: We imaged the sub-mm distribution of labile P and pH in the rhizosphere of three plant species to localize zones and hot spots of P depletion and accumulation along individual root axes and to relate our findings to nutrient acquisition / root exudation strategies in P-limited conditions at different soil pH, and to mobilization pattern of other elements (Al, Fe, Ca, Mg, Mn) in the rhizosphere. Methods: Sub-mm distributions of labile elemental patterns were sampled using diffusive gradients in thin films and analysed using laser ablation inductively coupled plasma mass spectrometry. pH images were taken using planar optodes. Results: We found distinct patterns of highly localized labile P depletion and accumulation reflecting the complex interaction of plant P acquisition strategies with soil pH, fertilizer treatment, root age, and elements (Al, Fe, Ca) that are involved in P biogeochemistry in soil. We show that the plants respond to P deficiency either by acidification or alkalization, depending on initial bulk soil pH and other factors of P solubility. Conclusions: P solubilization activities of roots are highly localized, typically around root apices, but may also extend towards the extension / root hair zone. PMID- 29706673 TI - Custodial Parole Sanctions and Earnings after Release from Prison. AB - Although the labor market consequences of incarceration in prison have been central to the literature on mass incarceration, punishment, and inequality, other components of the growing criminal justice system have received less attention from sociologists. In particular, the rise of mass incarceration was accompanied by an even larger increase in community supervision. In this paper, we examine the labor market effects of one frequently experienced aspect of post prison parole, short-term custody for parole violations. Although such sanctions are viewed as an alternative to returning parole violators to prison, they have the potential to affect labor market outcomes in ways similar to imprisonment, including both adverse and positive effects on earnings. We estimate that parolees lost approximately 37 percent of their earnings in quarters during which they were in short-term custody. Although their earnings tended to increase in the quarter immediately following short-term custody-consistent with the stated intentions of such sanctions-parolees experienced further earnings loss over the longer term after such sanctions. In the third quarter following a short-term custody sanction, earnings are lowered by about 13 percent. These associations are larger for those who were employed in the formal labor market before their initial incarceration. PMID- 29706675 TI - A practical microwave method for the synthesis of fluoromethy 4 methylbenzenesulfonate in tert-amyl alcohol. AB - Fluorine substitution is an established tool in medicinal chemistry to favourably alter the molecular properties of a lead compound of interest. However, gaps still exist in the library of synthetic methods for accessing certain fluorine substituted motifs. One such area is the fluoromethyl group, particularly when required in a fluoroalkylating capacity. The cold fluorination of methylene ditosylate is under evaluated in the literature, often proceeding with low yields or harsh conditions. This report describes a novel microwave method for the rapid nucleophilic fluorination of methylene ditosylate using inexpensive reagents in good isolated yield (65%). PMID- 29706676 TI - Water Resource Planning Under Future Climate and Socioeconomic Uncertainty in the Cauvery River Basin in Karnataka, India. AB - Decision-Making Under Uncertainty (DMUU) approaches have been less utilized in developing countries than developed countries for water resources contexts. High climate vulnerability and rapid socioeconomic change often characterize developing country contexts, making DMUU approaches relevant. We develop an iterative multi-method DMUU approach, including scenario generation, coproduction with stakeholders and water resources modeling. We apply this approach to explore the robustness of adaptation options and pathways against future climate and socioeconomic uncertainties in the Cauvery River Basin in Karnataka, India. A water resources model is calibrated and validated satisfactorily using observed streamflow. Plausible future changes in Indian Summer Monsoon (ISM) precipitation and water demand are used to drive simulations of water resources from 2021 to 2055. Two stakeholder-identified decision-critical metrics are examined: a basin wide metric comprising legal instream flow requirements for the downstream state of Tamil Nadu, and a local metric comprising water supply reliability to Bangalore city. In model simulations, the ability to satisfy these performance metrics without adaptation is reduced under almost all scenarios. Implementing adaptation options can partially offset the negative impacts of change. Sequencing of options according to stakeholder priorities into Adaptation Pathways affects metric satisfaction. Early focus on agricultural demand management improves the robustness of pathways but trade-offs emerge between intrabasin and basin-wide water availability. We demonstrate that the fine balance between water availability and demand is vulnerable to future changes and uncertainty. Despite current and long-term planning challenges, stakeholders in developing countries may engage meaningfully in coproduction approaches for adaptation decision-making under deep uncertainty. PMID- 29706674 TI - Is biochar-manure co-compost a better solution for soil health improvement and N2O emissions mitigation? AB - Land application of compost has been a promising remediation strategy for soil health and environmental quality, but substantial emissions of greenhouse gases, especially N2O, need to be controlled during making and using compost of high N load wastes, such as chicken manure. Biochar as a bulking agent for composting has been proposed as a novel approach to solve this issue, due to large surface area and porosity, and thus high ion exchange and adsorption capacity. Here, we compared the impacts of biochar-chicken manure co-compost (BM) and chicken manure compost (M) on soil biological properties and processes in a 120-d microcosm experiment at the soil moisture of 60% water-filled pore space. Our results showed that BM and M addition significantly enhanced soil total C and N, inorganic and KCl-extractable organic N, microbial biomass C and N, cellulase enzyme activity, abundance of N2O-producing bacteria and fungi, and gas emissions of N2O and CO2. However, compared to the M treatment, BM significantly reduced soil CO2 and N2O emissions by 35% and 27%, respectively, over the experimental period. The 15N-N2O site preference, i.e., difference between 15N-N2O in the center position (delta15Nalpha) and the end position (delta15Nbeta), was ~170/00 for M and ~260/00 for BM during the first week of incubation, suggesting that BM suppressed N2O from bacterial denitrification and/or nitrifier denitrification. This inference was well aligned with the observation that soil glucosaminidase activity and nirK gene abundance were lower in BM than M treatment. Further, soil peroxidase activity was greater in BM than M treatment, implying soil organic C was more stable in BM treatment. Our data demonstrated that the biochar-chicken manure co-compost could substantially reduce soil N2O emissions compared to chicken manure compost, via controls on soil organic C stabilization and the activities of microbial functional groups, especially bacterial denitrifiers. PMID- 29706677 TI - Using Spatial, Economic, and Ecological Opinion Data to Inform Gray Wolf Conservation. AB - Public opinion can be an influential factor in wildlife management decisions. Evaluating public opinions can help legitimize, or delegitimize, management and facilitate long-term conservation goals. This is especially true for the controversial issues surrounding the management of predators. We surveyed Montana, USA, residents during summer of 2013 to measure public opinion regarding economic and ecological impacts of the gray wolf (Canis lupus), and current management of this species. Although opinions were polarized in some areas, a greater percentage of Montanans think that wolves negatively affect the economy, but impact tourism (which contributes to the economy) positively. These differences may reflect the belief that rancher economic losses from wolf predation of cattle is greater than overall tourism gains related to wolves (e.g., wolf-watching), in addition to the perception of wolves negatively affecting big game (e.g., elk [Cervus canadensis]). Results also show that a slightly greater percentage of Montanans feel that wolves positively rather than negatively affect the ecosystem. Regarding specific practices, more Montanans than not have a positive opinion of maintaining wolves on the landscape and also support hunting of wolves. More Montanans hold negative rather than positive opinions, however, regarding wolf trapping. This result was most evident in western Montana as assessed by a spatial distribution of opinions by county and has implications for current wolf management and nontarget species. Results of ordinal regression analyses revealed that big game hunters, males, and those who held negative opinions of the effect of wolves on the Montana ecosystem and economy were significantly more likely to support both hunting and trapping practices. Living in western Montana predicted positive opinions of hunting, but alternatively, negative opinions of trapping. These results provide an understanding of public opinion of wolf management by county as well as statistical inferences that can be useful for informing more regionally oriented management practices. PMID- 29706678 TI - Joint inversion of satellite-detected tidal and magnetospheric signals constrains electrical conductivity and water content of the upper mantle and transition zone. AB - We present a new global electrical conductivity model of Earth's mantle. The model was derived by using a novel methodology, which is based on inverting satellite magnetic field measurements from different sources simultaneously. Specifically, we estimated responses of magnetospheric origin and ocean tidal magnetic signals from the most recent Swarm and CHAMP data. The challenging task of properly accounting for the ocean effect in the data was addressed through full three-dimensional solution of Maxwell's equations. We show that simultaneous inversion of magnetospheric and tidal magnetic signals results in a model with much improved resolution. Comparison with laboratory-based conductivity profiles shows that obtained models are compatible with a pyrolytic composition and a water content of 0.01 wt% and 0.1 wt% in the upper mantle and transition zone, respectively. PMID- 29706679 TI - Stakeholders' Voices: Defining Needs of Students with Emotional and Behavioral Disorders Transitioning between School Settings. AB - Students with emotional and behavioral disorders (EBD) too often do not receive adequate services or care in their school settings, particularly during transitions in educational placements. In addition, school support teams often struggle with creating transition plans that honor the needs of students with input from key stakeholders responsible for supporting student success. This article presents findings from the information-gathering phase of an iterative project that aims to develop a support program for students with EBD transitioning from day-treatment schools to district schools. We conducted 5 semistructured, qualitative focus groups with parents and teachers to explore needs during students' transitions between school settings. Five themes emerged from the focus groups: (a) consistent, behavior-specific feedback and positive reinforcement are vital to sustaining learned prosocial skills; (b) students benefit from regular opportunities to learn and practice social skills; (c) transition programming should emphasize communication between school and home; (d) routines at home and school should be coordinated; and (e) parents need support at school meetings. We will use findings from this study to develop a multifaceted intervention that aims to support students, their caregivers, and their teachers during transitions between the aforementioned types of schools. PMID- 29706680 TI - Novel diffuse optics system for continuous tissue viability monitoring - extended recovery in vivo testing in a porcine flap model. AB - In reconstructive surgery, tissue perfusion/vessel patency is critical to the success of microvascular free tissue flaps. Early detection of flap failure secondary to compromise of vascular perfusion would significantly increase the chances of flap salvage. We have developed a compact, clinically-compatible monitoring system to enable automated, minimally-invasive, continuous, and quantitative assessment of flap viability/perfusion. We tested the system's continuous monitoring capability during extended non-recovery surgery using an in vivo porcine free flap model. Initial results indicated that the system could assess flap viability/perfusion in a quantitative and continuous manner. With proven performance, the compact form constructed with cost-effective components would make this system suitable for clinical translation. PMID- 29706681 TI - A capillary-mimicking optical tissue phantom for diffuse correlation spectroscopy. AB - Optical tissue phantoms are necessary for instrument benchmarking and providing a consistent baseline for experiments in various fields of tissue spectroscopy, including diffuse correlation spectroscopy (DCS). To provide the most useful comparisons, a phantom would ideally mimic tissue as closely as possible, including the geometry of static and dynamic scatterers. A branching design that keeps the capillary cross section constant ensures that the same flow velocity is found throughout the phantom while allowing for single input and output fittings to feed all of the capillaries simultaneously. The direction of each capillary is randomized every few millimeters by randomly allocating 2 by 2 "twisting" squares within each layer. These squares swap the locations of four adjacent artificial capillaries either clockwise or counterclockwise. Numerical simulations were used to verify the random walk-like behavior of the capillary paths resulting from this pattern. This is a step toward replicating the randomly varying directionality of actual capillaries. This design was verified by taking DCS measurements at different flow rates of Intralipid through the phantom, demonstrating the effect of the flow rate on the characteristic decay time of the autocorrelation. PMID- 29706682 TI - Fast axial scanning for 2-photon microscopy using liquid lens technology. AB - Scanning microscopy methods require movement of the focus in Z coordinates to produce an image of a 3-dimensional volume. In a typical imaging system, the optical setup is kept fixed and either the sample or the objective is translated with a mechanical stage driven by a stepper motor or a piezoelectric element. Mechanical Z scanning is precise, but its slow response and vulnerability to mechanical vibrations and stress make it disadvantageous to image dynamic, time varying samples such as live cell structures. An alternative method less susceptible to these problems is to change the focal plane using conjugate optics. Deformable mirrors, acoustooptics, and electrically tunable lenses have been experimented with to achieve this goal and have attained very fast and precise Z-scanning without physically moving the sample. Here, we present the use of a liquid lens for fast axial scanning. Liquid lenses have a long functional life, high degree of phase shift, and low sensitivity to mechanical stress. They work on the principle of refraction at a liquid-liquid interface. At the boundary of a polar and an apolar liquid a spherical surface is formed whose curvature can be controlled by adjusting its relative wettability using electrowetting. We characterize the effects of the lens on attainable Z displacement, beam spectral characteristics, and pulse duration as compared with mechanical scanning. PMID- 29706684 TI - Strain Map of the Tongue in Normal and ALS Speech Patterns from Tagged and Diffusion MRI. AB - Amyotrophic Lateral Sclerosis (ALS) is a neurological disease that causes death of neurons controlling muscle movements. Loss of speech and swallowing functions is a major impact due to degeneration of the tongue muscles. In speech studies using magnetic resonance (MR) techniques, diffusion tensor imaging (DTI) is used to capture internal tongue muscle fiber structures in three-dimensions (3D) in a non-invasive manner. Tagged magnetic resonance images (tMRI) are used to record tongue motion during speech. In this work, we aim to combine information obtained with both MR imaging techniques to compare the functionality characteristics of the tongue between normal and ALS subjects. We first extracted 3D motion of the tongue using tMRI from fourteen normal subjects in speech. The estimated motion sequences were then warped using diffeomorphic registration into the b0 spaces of the DTI data of two normal subjects and an ALS patient. We then constructed motion atlases by averaging all warped motion fields in each b0 space, and computed strain in the line of action along the muscle fiber directions provided by tractography. Strain in line with the fiber directions provides a quantitative map of the potential active region of the tongue during speech. Comparison between normal and ALS subjects explores the changing volume of compressing tongue tissues in speech facing the situation of muscle degradation. The proposed framework provides for the first time a dynamic map of contracting fibers in ALS speech patterns, and has the potential to provide more insight into the detrimental effects of ALS on speech. PMID- 29706683 TI - In vivo preclinical verification of a multimodal diffuse reflectance and correlation spectroscopy system for sensing tissue perfusion. AB - In reconstructive surgery, impeded blood flow in microvascular free flaps due to a compromise in arterial or venous patency secondary to blood clots or vessel spasms can rapidly result in flap failures. Thus, the ability to detect changes in microvascular free flaps is critical. In this paper, we report progress on in vivo pre-clinical testing of a compact, multimodal, fiber-based diffuse correlation and reflectance spectroscopy system designed to quantitatively monitor tissue perfusion in a porcine model's surgically-grafted free flap. We also describe the device's sensitivity to incremental blood flow changes and discuss the prospects for continuous perfusion monitoring in future clinical translational studies. PMID- 29706685 TI - Quantifying predictive capability of electronic health records for the most harmful breast cancer. AB - Improved prediction of the "most harmful" breast cancers that cause the most substantive morbidity and mortality would enable physicians to target more intense screening and preventive measures at those women who have the highest risk; however, such prediction models for the "most harmful" breast cancers have rarely been developed. Electronic health records (EHRs) represent an underused data source that has great research and clinical potential. Our goal was to quantify the value of EHR variables in the "most harmful" breast cancer risk prediction. We identified 794 subjects who had breast cancer with primary non benign tumors with their earliest diagnosis on or after 1/1/2004 from an existing personalized medicine data repository, including 395 "most harmful" breast cancer cases and 399 "least harmful" breast cancer cases. For these subjects, we collected EHR data comprised of 6 components: demographics, diagnoses, symptoms, procedures, medications, and laboratory results. We developed two regularized prediction models, Ridge Logistic Regression (Ridge-LR) and Lasso Logistic Regression (Lasso-LR), to predict the "most harmful" breast cancer one year in advance. The area under the ROC curve (AUC) was used to assess model performance. We observed that the AUCs of Ridge-LR and Lasso-LR models were 0.818 and 0.839 respectively. For both the Ridge-LR and Lasso-LR models, the predictive performance of the whole EHR variables was significantly higher than that of each individual component (p<0.001). In conclusion, EHR variables can be used to predict the "most harmful" breast cancer, providing the possibility to personalize care for those women at the highest risk in clinical practice. PMID- 29706686 TI - A compact instrument to measure perfusion of vasculature in transplanted maxillofacial free flaps. AB - The vascularization and resulting perfusion of transferred tissues are critical to the success of grafts in buried free flap transplantations. To enable long term clinical monitoring of grafted tissue perfusion during neovascularization and endothelialization, we are developing an implantable instrument for the continuous monitoring of perfusion using diffuse correlation spectroscopy (DCS), and augmented with diffuse reflectance spectroscopy (DRS). This work discusses instrument construction, integration, and preliminary results using a porcine graft model. PMID- 29706687 TI - The Competition-Violence Hypothesis: Sex, Marriage, and Male Aggression. AB - Sexually active men, who are not in a monogamous relationship, may be at a greater risk for violence than men who are sexually active within monogamous relationships and men who are not sexually active. The current study examines changes in sexual behavior and violence in adolescence to early adulthood. Data on male (n = 4,597) and female (n = 5,523) respondents were drawn from four waves of the National Longitudinal Study of Adolescent and Adult Health (Add Health). HLM regression models indicate that men who transition to a monogamous, or less competitive, mode of sexual behavior (fewer partners since last wave), reduce their risk for violence. The same results were not replicated for females. Further, results were not accounted for by marital status or other more readily accepted explanations of violence. Findings suggest that competition for sex be further examined as a potential cause of male violence. PMID- 29706688 TI - Comprehensive Assessment of Composition and Thermochemical Variability by High Resolution GC/QToF-MS and the Advanced Distillation-Curve Method as a Basis of Comparison for Reference Fuel Development. AB - Commercial and military aviation is faced with challenges that include high fuel costs, undesirable emissions, and supply chain insecurity that result from the reliance on petroleum-based feedstocks. The development of alternative gas turbine fuels from renewable resources will likely be part of addressing these issues. The United States has established a target for one billion gallons of renewable fuels to enter the supply chain by 2018. These alternative fuels will have to be very similar in properties, chemistry, and composition to existing fuels. To further this goal, the National Jet Fuel Combustion Program (a collaboration of multiple U.S. agencies under the auspices of the Federal Aviation Administration, FAA) is coordinating measurements on three reference gas turbine fuels to be used as a basis of comparison. These fuels are reference fuels with certain properties that are at the limits of experience. These fuels include a low viscosity, low flash point, high hydrogen content "best case" JP-8 (POSF 10264) fuel, a relatively high viscosity, high flash point, low hydrogen content "worst case" JP-5 (POSF 10259) fuel, and a Jet-A (POSF 10325) fuel with relatively average properties. A comprehensive speciation of these fuels is provided in this paper by use of high resolution gas chromatography/quadrupole time-of-flight - mass spectrometry (GC/QToF-MS), which affords unprecedented resolution and exact molecular formula capabilities. The volatility information as derived from the measurement of the advanced distillation curve temperatures, Tk and Th, provides an approximation of the vapor liquid equilibrium and examination of the composition channels provides detailed insight into thermochemical data. A comprehensive understanding of the compositional and thermophysical data of gas turbine fuels is required not only for comparison but also for modeling of such complex mixtures, which will, in turn, aid in the development of new fuels with the goals of diversified feedstocks, decreased pollution, and increased efficiency. PMID- 29706689 TI - GENDER AND THE MBA: Differences in Career Trajectories, Institutional Support, and Outcomes. AB - This study asks how men's and women's careers diverge following MBA graduation from an elite university, using qualitative interview data from 74 respondents. We discover men and women follow three career pathways post-graduation: lockstep (stable employment), transitory (3 or more employers), and exit (left workforce). While similar proportions of men and women followed the lockstep pathways and launched accelerated careers, sizable gender differences emerged on the transitory pathway; men's careers soared as women's faltered on this path-the modal category for both. On the transitory path, men fared much better than women when moving to new organizations, suggesting that gender may become more salient when people have a shorter work history with a company. Our findings suggest that clear building blocks to promotions reduce gender bias and ambiguity in the promotion process, but multiple external moves hamper women, putting them at a clear disadvantage to men whose forward progress is less likely to be stalled by such moves. PMID- 29706690 TI - Effects of McGill stabilization exercises and conventional physiotherapy on pain, functional disability and active back range of motion in patients with chronic non-specific low back pain. AB - [Purpose] The aim of this study was to compare the effects of "McGill stabilization exercises" and "conventional physiotherapy" on pain, functional disability and active back flexion and extension range of motion in patients with chronic non-specific low back pain. [Subjects and Methods] Thirty four patients with chronic non-specific low back pain were randomly assigned to McGill stabilization exercises group (n=17) and conventional physiotherapy group (n=17). In both groups, patients performed the corresponding exercises for six weeks. The visual analog scale (VAS), Quebec Low Back Pain Disability Scale Questionnaire and inclinometer were used to measure pain, functional disability, and active back flexion and extension range of motion, respectively. [Results] Statistically significant improvements were observed in pain, functional disability, and active back extension range of motion in McGill stabilization exercises group. However, active back flexion range of motion was the only clinical symptom that statistically increased in patients who performed conventional physiotherapy. There was no significant difference between the clinical characteristics while compared these two groups of patients. [Conclusion] The results of this study indicated that McGill stabilization exercises and conventional physiotherapy provided approximately similar improvement in pain, functional disability, and active back range of motion in patients with chronic non-specific low back pain. However, it appears that McGill stabilization exercises provide an additional benefit to patients with chronic non-specific low back, especially in pain and functional disability improvement. PMID- 29706691 TI - The effect of short-term upper thoracic self-mobilization using a Kaltenborn wedge on pain and cervical dysfunction in patients with neck pain. AB - [Purpose] The aim of this study was to determine the effect of short-term self joint mobilization of the upper spine using a Kaltenborn wedge on the pain and cervical dysfunction of patients with neck pain. [Subjects and Methods] Twenty seven patients with neck pain were divided into two groups; the self-mobilization group (SMG, n=13) and the self-stretching group (SSG, n=14). The SMG performed upper thoracic self-mobilization and the SSG performed self-stretching exercises as a short-term intervention for a week. To assess the degree of neck pain, the visual analog scale (VAS) was utilized, and to measure the joint range of motion at the flexion-extension, it was compared and analyzed by using the goniometer. [Results] Both SMG and SSG show a significant decrease in the visual analog scale and a significant increase in joint range of motion within the group. In the comparison of groups, there was no significant difference, but it indicated effects on improving the range of motion of extension in SMG. [Conclusion] Self mobilization of the upper spine, using a Kaltenborn wedge, was useful in alleviating pain in and dysfunction of the cervical spine, and in particular, in improving cervical spine extension in this study. PMID- 29706692 TI - Relationship between isometric shoulder strength and arms-only swimming power among male collegiate swimmers: study of valid clinical assessment methods. AB - [Purpose] The purpose of the present study was to confirm the relationships between shoulder strength (extensor strength and internal rotator strength) of the abducted position and swimming power during arm-only swimming. [Subjects and Methods] Fourteen healthy male collegiate swimmers participated in the study. Main measures were shoulder strength (strength using torque that was calculated from the upper extremity length and the isometric force of the abducted position) and swimming power. [Results] Internal rotation torque of the dominant side in the abducted external rotated position (r=0.85) was significantly correlated with maximum swimming power. The rate of bilateral difference in extension torque in the maximum abducted position (r=-0.728) was significantly correlated with the swimming velocity-to-swimming power ratio. [Conclusion] The results of this study suggest that internal rotator strength measurement in the abducted external rotated position and extensor strength measurement in the maximum abducted position are valid assessment methods for swimmers. PMID- 29706693 TI - Effects of regular Taekwondo exercise on mood changes in children from multicultural families in South Korea: a pilot study. AB - [Purpose] The purpose of this study was to investigate the effects of regular Taekwondo training on mood state in children from multicultural families. [Subjects and Methods] Twenty-four children participated in the study. Eight children from non-multicultural families were assigned to the non-multicultural family children group. The remaining 16 children from multicultural families were randomly assigned to the multicultural family children (control, n=8) or multicultural family children trained in Taekwondo (Taekwondo training, n=8) group. Mood state was measured using the Profile of Mood States (Tension-Anxiety, Depression-Dejection, Anger-Hostility, Vigor-Activity, Fatigue-Inertia, and Confusion-Bewilderment). [Results] Vigor-Activity scores increased significantly, whereas Tension-Anxiety and Anger-Hostility scores decreased significantly after intervention when compared with the pre-intervention scores in the multicultural family children trained in Taekwondo group. [Conclusion] It is suggested that regular Taekwondo training may be effective in improving the mood states of children from multicultural families living in Korea. PMID- 29706694 TI - Difference in contributions to the team's score in female wheelchair basketball at the 2016 Rio Paralympics by physical capability classification. AB - [Purpose] This study clarified differences in players' contributions to the team's score in female wheelchair basketball at the 2016 Rio Paralympics by physical capacity classification, and examined the roles required in the team. [Subjects and Methods] This study used stats (record of play contents) for players who played for more than 20 minutes from the official box scores of all 31 games at the 2016 Paralympics. Players were divided into three groups by physical capacity classification: low, middle, and high. The average stats for each group were compared and the covariance structure was analyzed to determine the role of each group during the game. [Results] Comparisons showed that the higher the class, the higher the value of many stats items. Important elements were defensive rebound, steal, and turnover in the low group; and score, offensive rebound, and turnover in the high group. [Conclusion] Players in the high group have more plays related to the ball. Those in the low group should increase the numbers of steals and defensive rebounds and reduce turnover. High group players are required to have scoring ability, acquire offensive rebound, and reduce turnover. PMID- 29706695 TI - Effects of deep breathing on internal oblique and multifidus muscle activity in three sitting postures. AB - [Purpose] This study was to investigate differences in the level of activity of the external oblique (EO), internal oblique (IO), and multifidus (MF) muscles with deep breathing in three sitting postures. [Subjects and Methods] Sixteen healthy women were recruited. The muscle activity (EO, IO, MF) of all subjects was measured in three sitting postures (slumped, thoracic upright, and lumbo pelvic upright sitting postures) using surface electromyography. The activity of the same muscles was then remeasured in the three sitting postures during deep breathing. [Results] Deep breathing significantly increased activity in the EO, IO, and MF compared with normal breathing. Comparing postures, the activity of the MF and IO muscles was highest in the lumbo-pelvic upright sitting posture. [Conclusion] An lumbo-pelvic upright sitting posture with deep breathing could increase IO and MF muscle activity, thus improving lumbo-pelvic region stability. PMID- 29706696 TI - The known-groups validity of intensity-based physical activity measurement using an accelerometer in people with subacute stroke. AB - [Purpose] This study aimed to assess the known-groups validity of the estimated metabolic equivalents during physical activities using accelerometer, Active Style Pro HJA 350-IT, in people with subacute stroke. [Subjects and Methods] Ten participants with subacute stroke and ten healthy people performed six activities (lying, sitting, standing, sitting with reaching task, standing with reaching task, and walking) and metabolic equivalents were estimated using the accelerometer during each activity. These estimated metabolic equivalents were compared with reported metabolic equivalents through compendiums or previous studies. Additionally, the estimated metabolic equivalents were compared between subacute stroke and healthy control participants. [Results] The estimated metabolic equivalents of both groups during maintaining posture showed significantly lower values in comparison with previous studies. There were no significant differences between the estimated metabolic equivalents during sitting with reaching tasks or standing with reaching tasks when compared with compendium metabolic equivalents across both groups. The estimated metabolic equivalents during walking were inevitable values significantly differed from previous study which conducted with stroke patients with lower gait abilities in both groups. [Conclusion] The estimated metabolic equivalents using accelerometer may be suitable to assess movement activity rather than motionless activity, and accelerometer demonstrated acceptable validity in people with subacute stroke. PMID- 29706698 TI - The prevalence of the flat foot condition and insole prescription in people with Down's syndrome: a retrospective population-based study. AB - [Purpose] The general approach for flat foot (FF) treatment in people with Down's syndrome (DS) is the use of insoles. However, the appropriate timing of the first insole prescription remains unclear. An aim of this present research was to investigate the status of prevalence of FF and orthosis prescription in the DS population. [Subjects and Methods] Two hundred fifteen subjects with DS who were seen at our hospital were retrospectively investigated. Investigated parameters were: prevalence of FF and other foot diseases, ratio and timing of orthopaedic consultation, ratio and timing of orthoses prescription, and mean age at the time of orthosis prescription. [Results] The prevalence of FF was 27.0% (58 subjects), and 50 subjects (23.3%) consulted an orthopaedic surgeon. An orthosis was prescribed for 54 subjects; 88.9% of these orthoses were insoles. Foot and leg orthoses other than insoles were prescribed significantly more frequently for females than males. The mean ages at the time of the first prescription of all types of orthoses and an insole were 7.3 years and 6.4 years, respectively. [Conclusion] The prevalence of FF was low, and the age at which subjects with DS were prescribed an orthosis was relatively high at our institution compared to previous reports. Since physical therapists see patients who could potentially have FF, those with suspected FF should then be referred to an orthopaedic doctor, which would enable the earlier orthosis prescription. PMID- 29706697 TI - Prediction of falling risk after discharge in ambulatory stroke or history of fracture patients using Balance Evaluation Systems Test (BESTest). AB - [Purpose] The purpose of this study was to clarify the relationships between falls and sections of the Balance Evaluation Systems Test (BESTest) in patients with stroke or those with a history of fracture. [Subjects and Methods] This longitudinal study included 51 self-ambulatory inpatients. Balance was assessed 1 week prior to discharge using the BESTest, and the incidence of falls within 6 months after discharge was investigated. Relationships between falling and balance components were analyzed using the t-test or the Mann-Whitney U test and receiver operating characteristic (ROC) curve analysis. [Results] Five subjects were dropped out before follow-up at 6 months. Falls were reported by 10 of the remaining 46 participants. Scores for two sections (Anticipatory Postural Adjustments and Sensory Orientation) were significantly lower in fallers than in non-fallers with stroke. Four of the six sections (Biomechanical Constraints, Anticipatory Postural Adjustments, Sensory Orientation, and Stability in Gait) showed areas under the ROC curves >0.8 (0.82, 0.83, 0.84, and 0.81, respectively). In patients with a history of fractures, all sections were not significantly different between fallers and non-fallers. [Conclusion] Anticipatory Postural Adjustments and Sensory Orientation sections of the BESTest were related to future occurrence of fall after discharge in self-ambulatory stroke patients. PMID- 29706699 TI - Evaluation of left-right difference of impulse in impact forces at stance phase: comparison of measurements on flat land and stairs. AB - [Purpose] The purpose of this study was to investigate the measurement method and parameters to simply evaluate the condition of the knee that are necessary for preventing locomotive syndrome as advocated by the Japan Orthopedic Association. [Subjects and Methods] The subjects installed acceleration sensors in lateral condyles of the tibia and measured acceleration and load under the conditions of walking on a flat ground and walking using stairs; the difference between the impulse of impact forces (acceleration * load) of the two knees was defined as a simple evaluation parameter. [Results] Simple evaluation parameters were not correlated with age during walking on a flat ground, but during walking using stairs, it was almost flat up to the age of 20-40 years, and after the age of 49 years, based on the quadratic curve approximation (R2=0.99), a correlation of simple evaluation parameters with age could be confirmed. [Conclusion] The simple evaluation parameter during walking using stairs was highly correlated with age, suggesting a contribution to preventing locomotive syndrome by improving reliability. In the future, we plan to improve reliability by increasing the data, and establish it as a simple evaluation parameter that can be used for preventing locomotive syndrome in elderly people and those with KL classification grades 0-1. PMID- 29706700 TI - Relationship between the thoracolumbar flexion angle and pelvic posterior movement during trunk flexion. AB - [Purpose] The purpose of this study was to investigate the linear relationship between the thoracolumbar flexion angle and hip posterior displacement. [Subjects and Methods] This study was performed on 15 subjects. The subjects performed three trials of a lumbar flexion-extension task. To quantify the statistical linear relationship between the thoracolumbar flexion angle and hip posterior displacement, Spearman's rank correlation coefficient was used. [Results] The thoracolumbar flexion angle was significantly correlated with the degree of hip posterior displacement. [Conclusion] According to the results of this study, movement of the thoracolumbar joint and posterior movement of the pelvis must be considered for accurate analysis of the lumbopelvic rhythm. PMID- 29706701 TI - The effects of flexion-distraction and drop techniques on disorders and Ferguson's angle in female patients with lumbar intervertebral disc herniation. AB - [Purpose] This study examines the effects of the flexion-distraction technique and the drop technique on disorders and on Ferguson's angle in female patients with lumbar intervertebral disc herniation. [Subjects and Methods] Thirty female patients with lumbar intervertebral disc herniation were divided into an experimental group (n=15) treated with flexion-distraction and drop techniques and a control group (n=15) treated with spinal decompression therapy. Both groups were treated three times a week over an eight-week period. [Results] In the comparison of changes within each group after treatment, both groups showed statistically significant decreases in disorders and in Ferguson's angle. [Conclusion] Flexion-distraction and drop techniques may be an effective intervention to improve disorders and Ferguson's angle in female patients with lumbar intervertebral disc herniation. PMID- 29706702 TI - Does the relative muscle activation of the vastus medialis, rectus femoris, and vastus lateralis, during the various activities, change in relation to the quadriceps angle? AB - [Purpose] The purpose of this study was to examine the correlation between the quadriceps angle and muscle-activation ratios for the vastus medialis, rectus femoris, and vastus lateralis during various activities. [Subjects and Methods] Seventeen heathy females were recruited. The quadriceps angles were measured with long-arm goniometers. The muscle activity of the vastus medialis, rectus femoris, and vastus lateralis were measured using electromyography under four different activity settings: walking, squatting, step-up, and sit-to-stand. The muscle activation ratios were calculated and their correlations with the quadriceps angles were analyzed. [Results] The activation ratio of the rectus femoris to the vastus medialis (and, although less significant, of the vastus lateralis to the vastus medialis) was positively correlated with the quadriceps angle during the step-up and sit-to-stand. A similar tendency was also seen during squatting. The activation ratio of the vastus lateralis to the rectus femoris was negatively correlated with the quadriceps angle during walking. [Conclusion] The relative muscle activity among the muscles composing the quadriceps was correlated with the quadriceps angle. During activities involving deeper knee flexion like the step-up, sit-to-stand, and squatting, the relative activity of the lateral muscles tended to increase as the quadriceps angle increased. Meanwhile, during walking the activity of the medial muscles seemed to increase with a larger quadriceps angle. PMID- 29706703 TI - Influence of adequate pelvic floor muscle contraction on the movement of the coccyx during pelvic floor muscle training. AB - [Purpose] Pelvic floor muscle training is a first-line therapy for female stress urinary incontinence. Previous studies have suggested that the coccyx tip moves ventrally and cranially during pelvic floor muscle contraction. The study aimed to elucidate the influence of adequate pelvic floor muscle contraction on coccyx movement. [Subjects and Methods] Sixty-three females (57 patients with stress urinary incontinence and additional 6 healthy volunteers) were enrolled. Using magnetic resonance imaging, coccyx movement was evaluated during pelvic floor muscle contraction and strain. An adequate contraction was defined as a contraction with good Oxford grading scale [>=3] and without inadequate muscle substitution patterns. [Results] Inadequate muscle substitution patterns were observed in 33 participants (52.4%). No significant difference was observed in the movement of the coccyx tip in the ventrodorsal direction between females with and without inadequate muscle substitution patterns. However, a significant increase in the movement of the coccyx tip in the cranial direction was detected in the group without inadequate muscle substitution patterns. Compared to participants with inadequate pelvic floor muscle contraction, those who had adequate pelvic floor muscle contraction exhibited significantly increased cranial movement of the coccyx. [Conclusion] Adequate pelvic floor muscle contraction can produce cranial movement of the coccyx tip. PMID- 29706704 TI - Effects of a 12-week marching in place and chair rise daily exercise intervention on ADL and functional mobility in frail older adults. AB - [Purpose] To determine the effects of a 12-week intervention consisting of marching in place and chair rising daily exercise on activities of daily living and functional mobility (ability to quickly rise from a chair and walk) in frail older adults. [Subjects and Methods] Thirty-one participants were divided into exercise (n=18, age=77.6 +/- 7.2 years; 11 males, 7 females) and non-exercise (n=13, age=79.6 +/- 7.7 years; 7 males, 6 females) groups. The exercise group performed 12 weeks of training, 7 days per week, and 20 minutes per session. The exercise program consisted of low to moderate intensity marching in place and chair rising movements. The speed of movements was gradually increased over time. The Barthel index, mean power during chair stand, and time to complete a 10-m walk were assessed before and after the intervention. [Results] Significant improvements were noted in the exercise group compared to the non-exercise group for the Barthel Index (11.6%), mean power (33%), and 10-M walk (14.6%) with a medium effect size, and relative mean power (power/body mass) (32.9%) with a large effect size. [Conclusion] The progressive marching in place and chair rising exercise intervention appears to be effective in improving activities of daily living and functional mobility among frail older adults. PMID- 29706705 TI - The feasibility of using exergames as a rehabilitation tool: the attitudes, awareness, opinions and experiences of physiotherapists, and older people towards exergames. AB - [Purpose] The aim of this study was to investigate the feasibility of using exergames as a rehabilitation tool by determining the attitudes, awareness, opinions and experiences of physiotherapists, and older people towards exergames. [Subjects and Methods] A cross-sectional study was conducted and two short self developed questionnaires (for physiotherapists and older people) were distributed in three hospitals in Cork (Ireland) to assess the attitudes towards and familiarity with exergames among physiotherapists and older people. The data were analysed using Microsoft Excel version 2013. [Results] The results show that a lot of older people have seen exergames devices but have not attempted to play them. This may indicate a lack of interest in or information about these devices and how to use them. With regard to the second group, physiotherapists underestimate older people's knowledge about exergames. [Conclusion] Older people were not very familiar with exergames but they were willing to try them. In addition, despite physiotherapists being familiar with exergames, they see them as an additional tool that will not replace or change any traditional exercise methods. PMID- 29706706 TI - Factors affecting physical therapists' job satisfaction: questionnaire survey targeting first-year physical therapists. AB - [Purpose] The survey aimed to clarify the factors that affect physiotherapists' job satisfaction. [Subjects and Methods] To examine factors affecting physical therapists' job satisfaction using a cross-sectional study with a questionnaire survey. Subjects were 193 first-year physical therapists who participated in a newcomer orientation at Hiroshima Prefectural Physical Therapy Association. The questionnaire comprised items concerning physical therapists' satisfaction with their work, motives for becoming physical therapists, education in school, internships, the workplace, and comfort in the workplace. [Results] Subjects were divided into two groups according to their satisfaction with their occupation. The "high satisfaction" group included 157 subjects, and the group "low satisfaction" group included 36 subjects. Using logistic regression analysis, items concerning comfort in the workplace, motives for becoming physical therapists, and learning in school were analysed. [Conclusion] Factors affecting physical therapists' job satisfaction were primarily influenced by previous experience and working conditions. PMID- 29706707 TI - Effect of trunk stabilization exercises on trunk muscle activation using different respiratory conditions. AB - [Purpose] The purpose of this study is to evaluate differences in trunk muscle activity after 4 weeks of trunk stabilization exercises performed under expiration and inspiration conditions. [Subjects and Methods] Thirty subjects were assigned randomly to an expiration group (n=15) or an inspiration group (n=15). The outcomes measured were magnitude of muscle activation (rectus abdominis, multifidus, internal oblique and external oblique) in the bridge position and performance on a trunk muscle endurance test. Paired t-tests were used to assess the statistical significance of the effects of the trunk stabilization exercise program within each group. [Results] Comparison of the electromyography activity of the trunk muscles revealed a significant increase in internal oblique activation in the inspiration group, and a significant increase in multifidus activation in the expiration group. Assessment of the endurance of the trunk muscles revealed a significant increase in both groups. [Conclusion] Our results showed that expiration during trunk stabilization exercises increased the activity of the multifidus muscle, while inspiration enhanced the activity of the internal oblique muscle. Different types of respiration seem to differentially affect trunk muscles during trunk stabilization exercises. PMID- 29706709 TI - The effect of wearing night splints for one year on the standing motor function of patients with Duchenne muscular dystrophy. AB - [Purpose] To investigate the effect of night splints on the standing motor function and ankle dorsiflexion angles of patients with Duchenne muscular dystrophy (DMD). [Subjects and Methods] Nine boys (age <11 years) with DMD were divided into the sufficiently-wearing group and the insufficiently-wearing group, according to how often they wore their splint for one year. We evaluated the changes between the pre-implementation and the one-year-after assessments of both the sufficiently-wearing group and the insufficiently-wearing group for the ankle dorsiflexion angle, North Star Ambulatory Assessment, 10-m running time, and time to stand from the floor. [Results] Only the left dorsiflexion angle of the ankle showed significantly difference for the sufficiently-wearing group. For other indicators, there were tendency toward improvement and maintenance in the sufficiently-wearing group. [Conclusion] The standing motor function improved significantly in some patients in the sufficiently-wearing group, suggesting that wearing night splints may promote the improvement and/or maintain of standing motor function in patients with DMD. PMID- 29706708 TI - Effect of pulsed high intensity laser therapy on delayed caesarean section healing in diabetic women. AB - [Purpose] The objective of this study was to determine the effect of pulsed high intensity laser therapy on delayed caesarean section healing in diabetic women. [Subjects and Methods] This study was conducted on forty diabetic women with delayed caesarean wound healing, ranging in age from 28 to 38 years. They were randomly assigned into two groups; the group I (n=20) received pulsed high intensity laser therapy for 6-weeks, 3 times per week plus standard medical treatment for treatment of diabetes and caesarean wound patients, the group II (n=20) received sham laser treatment for 6 weeks, 3 times per week plus standard medical treatment for treatment of diabetes and caesarean wound patients. The wound size and appearance in all participants were measured by the tracing method and pressure sore status tool before and after the 6-week treatment. [Results] Pulsed high intensity laser therapy produced a significant difference in wound size and appearance in comparison to the sham laser treatment in diabetic women with delayed caesarean wound healing. [Conclusion] Pulsed high intensity laser therapy is effective in the treatment of delayed caesarean section healing in diabetic women. PMID- 29706710 TI - Upper limb robotic rehabilitation for chronic stroke survivors: a single-group preliminary study. AB - [Purpose] This study aimed to assess whether robotic rehabilitation can improve upper limb function, activities of daily living performance, and kinematic performance of chronic stroke survivors. [Subjects and Methods] Participants were 21 chronic stroke survivors (19 men; 60.8 years; Mini-Mental State Examination score: 28; onset duration: 10.2 years). Training exercises were performed with a Whole Arm Manipulator and a 120-inch projective display to provide visual and auditory feedback. Once the training began, red and grey balls appeared on the projective display, and participants performed reaching movements, in the assist as-needed mode, toward 6 directional targets in a 3-dimensional space. All participants received training for 40 minutes per day, thrice per week, for 6 weeks. Main outcome measures were upper limb function (Fugl-Meyer Assessment, Action Research Arm Test, and Box and Blocks Test scores), activities of daily living performance (Modified Barthel Index), and kinematic performance (movement velocity) in 6 directions. [Results] After 6 weeks, significant improvement was observed in upper limb function, activities of daily living performance, and kinematic performance. [Conclusion] This study demonstrated the positive effects of robotic rehabilitation on upper limb function, activities of daily living performance, and kinematic performance in chronic stroke survivors. PMID- 29706711 TI - Comparison of the effects of pectoralis muscles stretching exercise and scapular retraction strengthening exercise on forward shoulder. AB - [Purpose] The purpose of this study was to compare effect in a group of stretching and a group of muscle strengthening exercise for patients with forward scapular posture. [Subjects and Methods] This study was performed in 20 subjects who defined to the forward shoulder posture. The subjects were divided into a group of pectoralis muscles stretching and a group of muscle strength exercise for scapular retraction. [Results] The forward shoulder posture of the group of the scapular retraction exercise was significantly decreased when compared to that of the group of the pectoralis muscles stretching. [Conclusion] It is expected that therapeutic effect can be improved and the period can be shortened when strength exercise for forward shoulder posture is applied as a therapeutic intervention. PMID- 29706712 TI - The best body spot to detect the vital capacity from the respiratory movement data obtained by the wearable strain sensor. AB - [Purpose] The purpose of this study is to find the best body spots on the chest and abdomen wall to obtain the correlated indicators to the vital capacity. [Subjects and Methods] Thirty healthy male staff of the center served as the participants were advised to conduct a breathing movement using spirometer and a wearable strain sensor (WSS) respectively, which was the measured at four spots on chest and abdomen wall from maximal end of inspiration to maximal end of expiration. The Pearson's correlation analysis was conducted to find the correlation of the data obtained respectively by the WSS and spirometer. [Results] The correlation of the mobility data at the four body spots to the vital capacity data were calculated for each level by means of Pearson's correlation coefficient, which showed that the values at each body spot were positive significant correlations and the highest value was at the 10th rib. [Conclusion] There was a correlation between the mobility data of the chest and abdomen obtained by the WSS and the vital capacity data obtained by the spirometer, for which, the 10th rib is the best body spot to detect the positive significant correlation. PMID- 29706713 TI - Effects of eccentric control exercise for wrist extensor and shoulder stabilization exercise on the pain and functions of tennis elbow. AB - [Purpose] This study aimed to conduct experiments to examine the effects of wrist eccentric control exercise or shoulder stabilization exercises after a basic direct treatment of the elbow in the treatment of tennis elbow patients in terms of pain and grip strength. [Subjects and Methods] The subjects were divided into two groups: one group conducted wrist eccentric control exercise and was comprised of 5 male and 4 female subjects, and the other group received shoulder stabilization exercise and was comprised of 5 male and 4 female subjects. [Results] In the intragroup comparison, both groups showed a significant decrease in pain level and a significant increase in the measurement of the tenderness thresholds of the upper trapezius muscle, lateral epicondyle, and grip strength. In the intergroup comparison, the shoulder stabilization exercise group showed a significantly greater increase in the measurement of the tenderness thresholds of the upper trapezius muscle and grip strength, and the differences were not significant in the pain level and tenderness threshold of the lateral epicondyle. [Conclusion] Wrist eccentric control exercise and shoulder stabilization exercises can be useful as intervention methods for relief from pain due to lateral epicondylitis and for the improvement of functions impaired by tennis elbow. PMID- 29706714 TI - Effects of smoking and aerobic exercise on male college students' metabolic syndrome risk factors. AB - [Purpose] The aim was to investigate the effects of university students' smoking and aerobic exercise on metabolic syndrome risk factors. [Subjects and Methods] Twenty-three male students were randomly assigned to the following groups: exercise smoker (n=6), non-exercise smoker (n=6), exercise non-smoker (n=6), and non-exercise non-smoker (n=5). A basketball exercise program was conducted three times per week (70 minutes per session) for 8 weeks with exercise intensity set at 50-80% of heart rate reserve. After 8 weeks, the variables of risk factors for metabolic syndrome were obtained. [Results] Systolic blood pressure and diastolic blood pressure were significantly decreased in the exercise non-smoker group and significantly increased in the non-exercise smoker group. Waist circumference was significantly reduced in both exercise groups regardless of smoking and significantly increased in the non-exercise smoker group. Triglyceride, high density lipoprotein-cholesterol, and fasting plasma glucose showed no differences between the groups. [Conclusion] Obesity and smoking management should be conducted together for students as well as for those with metabolic syndrome risk factors. It is recommended that more students participate in such programs, and exercise programs should be further developed and diversified to prevent metabolic syndrome and cardiovascular diseases. PMID- 29706715 TI - Effects of visual cue and cognitive motor tasks on standing postural control following a chronic stroke. AB - [Purpose] The objective of the study was to examine the effects of visual cue and cognitive motor tasks on quiet standing posture center of pressure (COP) and the weight loads to the paretic and non-paretic legs in chronic stroke patients. [Subjects and Methods] Twenty chronic stroke patients were included in the study. COP total distance, sway velocity, and the weight loads to the paretic and non paretic legs of the participants were measured while they performed a visual cue task, cognitive motor task, and dual task. The parameters were compared using a repeated three-way analysis of variance. [Results] When the visual cue was provided, the COP total distance and sway velocity were significantly reduced compared with when no visual cue was given. When the cognitive motor task was performed, the COP total distance and sway velocity decreased significantly compared to when the task was not performed. [Conclusion] These findings suggest that visual cue and cognitive motor tasks could be used as parts of a rehabilitative training program to improve the control of standing in chronic stroke patients. In addition, visual cues can be used as an intervention to train the paretic leg of stroke patients. PMID- 29706716 TI - The relationship between physical fitness and academic achievement among adolescent in South Korea. AB - [Purpose] The purpose of this study was to identify the relationship between physical fitness level and academic achievement in middle school students. [Subjects and Methods] A total of 236 students aged 13-15 from three middle schools in D city, South Korea, were selected using a random sampling method. Academic achievement was measured by students' 2014 fall-semester final exam scores and the level of physical fitness was determined according to the PAPS (Physical Activity Promotion System) score administrated by the Korean Ministry of Education. A Pearson correlation test with SPSS 20.0 was employed. [Results] The Pearson correlation test revealed a significant correlation between physical fitness and academic achievement. Specifically, students with higher levels of physical fitness tend to have higher academic performance. In addition, final exam scores of core subjects (e.g., English, mathematics, and science) were significantly related to the PAPS score. [Conclusion] Results of this study can be used to develop more effective physical education curricula. In addition, the data can also be applied to recreation and sport programs for other populations (e.g., children and adult) as well as existing national physical fitness data in various countries. PMID- 29706717 TI - Effects of acute exercise in the sitting position on executive function evaluated by the Stroop task in healthy older adults. AB - [Purpose] Exercise effects on executive functioning depend on exercise mode. We tested the effects of three acute exercises in the sitting position-stepping, stretching, and finger movement-on older adults' executive functioning in comparison to a resting state (i.e., control condition). [Subjects and Methods] Participants were 26 healthy older adults (mean age, 71.8 +/- 4.7 years). All participants performed the three sitting exercises for 10 minutes; resting for an equal amount of time was used as a control condition. These four conditions were presented in random order. The color-word matching Stroop task was used to evaluate executive function before and after the sitting exercises and control condition. [Results] All three sitting exercises significantly reduced Stroop interference scores, while the control condition did not. There was a significant difference between the finger movement exercise and the control condition in pre to-post-intervention changes in Stroop interference scores. [Conclusion] The acute finger movement exercise was especially beneficial for executive function as evaluated by the color-word matching Stroop task. PMID- 29706719 TI - Effects of pelvic range of motion and lower limb muscle activation pattern on over-ground and treadmill walking at the identical speed in healthy adults. AB - [Purpose] Many studies have compared over-ground and treadmill walking, but the biomechanical relationship between the two gait modes is unclear. The aim of this study was to analyze differences in pelvic range of motion and lower limb muscles activity during over-ground and treadmill walking in healthy adults. Moreover, we aimed to analyze differences according to gender. [Subjects and Methods] Twenty three healthy adults (9 men, 14 women) between 25 and 35 years of age walked at the identical speed for 30 seconds each in two difference gait modes. The pelvic range of motion were obtained by using three-axis accelerometer and lower limb muscle activation data were obtained by using wireless surface EMG. [Results] The results showed that pelvic obliquity showed a greater angular range of women than men, and the pelvic rotation decreased more in treadmill walking than over-ground walking. In the muscles activity, vastus lateralis and tibialis anterior increased, and gastrocnemius medialis decreased in treadmill walking than over ground walking. [Conclusion] We conclude that treadmill walking reduces the range of motion of the pelvic and increases lower limb muscles activity therefore, when using treadmill for the purpose of rehabilitation at the clinic, consider this difference. PMID- 29706718 TI - Comparison of two instructions for deep breathing exercise: non-specific and diaphragmatic breathing. AB - [Purpose] Breathing exercises are frequently prescribed to reduce pulmonary complications after abdominal and thoracic surgery. Appropriate instructions ensuring the integrity of the self-exercise are important. This study compared the effects of two instructions, focusing on non-specific breathing (NB) and diaphragmatic breathing (DB) patterns, respectively, on the ventilatory efficiency and work of breathing. [Subjects and Methods] The participants were healthy men (n=15) and women (n=15). Ventilatory parameters, heart rate, and autonomic nervous system activity were measured during natural and deep breathing phases performed under the two instructions (NB and DB), with the deep breathing phase following the natural breathing phase. [Results] For both men and women, ventilatory efficiency was increased during deep breathing relative to natural breathing, regardless of the instructions. In women, the increment in ventilatory efficiency during deep breathing was greater under NB compared to that under DB. The work of breathing decreased during deep breathing in women under both instructions, but did not change in men under DB. [Conclusion] Under NB instruction, deep breathing elicits similar or greater effects on ventilatory efficiency compared to that under DB instruction. PMID- 29706720 TI - The effects of gum chewing while walking on physical and physiological functions. AB - [Purpose] This study examined the effects of gum chewing while walking on physical and physiological functions. [Subjects and Methods] This study enrolled 46 male and female participants aged 21-69 years. In the experimental trial, participants walked at natural paces for 15 minutes while chewing two gum pellets after a 1-hour rest period. In the control trial, participants walked at natural paces for 15 minutes after ingesting powder containing the same ingredient, except the gum base, as the chewing gum. Heart rates, walking distances, walking speeds, steps, and energy expenditure were measured. [Results] Heart rates during walking and heart rate changes (i.e., from at rest to during walking) significantly increased during the gum trial compared with the control trial. Walking distance, walking speed, walking heart rate, and heart rate changes in male participants and walking heart rate and heart rate changes in female participants were significantly higher during the gum trial than the control trial. In middle-aged and elderly male participants aged >=40 years, walking distance, walking speed, steps, and energy expenditure significantly increased during the gum trial than the control trial. [Conclusion] Gum chewing while walking measurably affects physical and physiological functions. PMID- 29706721 TI - Relationship between transverse arch height and foot muscles evaluated by ultrasound imaging device. AB - [Purpose] Few studies on the transverse arch (TA) in the forefoot have been conducted. The forefoot is where pains occur most frequently and is related to walking and balance; hence, paying attention to TA is vital. However, the relationship between TA and foot muscles has not been investigated. Therefore, this study aims to investigate muscles related to TA. [Subjects and Methods] Nineteen healthy young males were included. Measurements of their feet, excluding one foot with recent foot pain (n=37), were obtained. The height of TA (TAH) was measured in two ways: during 10% and 90% loading of body weight. The cross sectional area and thickness of five muscles were measured: flexor digitorum longus, peroneus longus and brevis, flexor hallucis brevis, flexor digitorum brevis (FDB) and abductor hallucis (ABH). All measurements were performed with an ultrasound device. [Results] FDB and ABH were correlated with TAH during 10% and 90% loading after removing the effect of body mass index and age. The greater FDB and ABH, the higher TAH. [Conclusion] As FDB becomes larger, the second, third and fourth metatarsal heads are raised more. Furthermore, the height of the first metatarsal head is lowered by a larger ABH. These mechanisms may increase TAH. PMID- 29706722 TI - The JFK BIG study: the impact of LSVT BIG(r) on dual task walking and mobility in persons with Parkinson's disease. AB - [Purpose] The aim of this study was to test the hypothesis that Lee Silverman Voice Treatment-BIG decreases the negative impact of hypokinesia on dual task performance in persons with Parkinson's disease. [Subjects and Methods] The records of 114 patients with Parkinson's admitted to outpatient rehabilitation at a suburban hospital were reviewed. Demographics and data for 8 outcome measures were extracted for subjects that completed 14 of 16 sessions of BIG. 93 of these subjects had records of pre and post-test Timed Up and Go, Timed Up and Go Motor, and Timed Up and Go Cognitive scores. Average age was 68.4 years (SD=10.6) and average disease duration was 4.9 years (SD=5.3). [Results] Subjects demonstrated statistically significant improvements for Timed Up and Go (3.3 SD=4.5), Timed Up and Go Motor (4.4 SD=5.8) and Timed Up and Go Cognitive (4.7 SD=5.4). Concurrent motor and cognitive performance remained stable. Dual task cost decreased at a statistically significant level for Timed Up and Go Cognitive (7% SD=31%) but not Motor (4% SD=32%). [Conclusion] These findings suggest that cueing strategies associated with LSVT BIG become internalized and decrease the negative impact of hypokinesia on mobility and cognitive performance while performing two tasks simultaneously in persons with Parkinson's. PMID- 29706723 TI - Electromyographic activity of selected trunk, core, and thigh muscles in commonly used exercises for ACL rehabilitation. AB - [Purpose] Most of rehabilitation programmes for Anterior Cruciate Ligament (ACL) injury focus on quadriceps-hamstrings activation imbalances and less is known about kinetically linked muscles. This study investigated electromyographic activity of selected trunk, core, and thigh muscles during common rehabilitation exercises for ACL injury. [Subjects and Methods] Twelve active female volunteers participated in this cross-sectional laboratory study. Surface EMG was used to compare activation of eight trunk, hip/core, and lower limb muscles: Erector Spinae (ES), Rectus Abdominis (RA), Gluteus Maximus (GM), Vastus Lateralis (VL), Rectus Femoris (RF), Vastus Medialis (VM), Biceps Femoris (BF), and Semitendinosus (ST) during Forward Lunge, Double Leg Raise, Glute Bridge, Sit-Up, and Squat. [Results] Forward lunge produced significantly higher activation in the VM (61.1 +/- 19.4), VL (59.2 +/- 12.9), and RF (32.0 +/- 2.6). Double leg raise generated highest activity in the RF (26.6 +/- 2.8) and RA (43.3 +/- 4.4); and Glute Bridge in the GM (44.5 +/- 19.0) and BF (22.4 +/- 4.3). Sit-up produced the highest activation in the RF (36.6 +/- 4.7) followed by RA (18.9 +/- 3.8). Squat produced a higher activation in VL (55.0 +/- 12.9), VM (51.5 +/- 18.2), and ES (40.4 +/- 18.3). [Conclusion] This study provide further evidence for developing training programmes for ACL injury prevention and rehabilitation. A combination of exercises to reinstate quadriceps-hamstrings activation balance and enhance core stability is recommended. PMID- 29706724 TI - Outcome measures for adherence to home exercises among patients with chronic low back pain: a systematic review. AB - [Purpose] The aim of this study was to investigate what outcome measures are reliable in the evaluation of adherence to home exercises among patients with chronic low back pain. [Methods] A systematic review on articles related to adherence to home exercises for patients with chronic low back pain was conducted, and outcome measures and psychometric properties were extracted and evaluated in terms of validity and reliability. [Results] A total of 4,583 articles were identified, and eight articles were finally included after screening. The identified outcome measures were self-reported frequency, duration and intensity of home exercises and Treatment Self-Regulation Questionnaire results. Although the internal consistency and criterion validity of the Treatment Self-Regulation Questionnaire results have been proven in the literature, none of the included articles validated the self-reported frequency, duration, and intensity of the home exercises. [Conclusion] Only the Treatment Self-Regulation Questionnaire results were found to be a reliable measure, and further research to validate self-reported outcome measures is required. PMID- 29706725 TI - Alleviation of neck pain by the non-surgical rehabilitation of a pathologic cervical kyphosis to a normal lordosis: a CBP(r) case report. AB - [Purpose] To present a case of the therapeutic reversal of a cervical kyphosis into a lordosis in a patient who presented with neck pain and headaches. [Subject and Methods] A 24-year-old male irritated his neck while dancing. Upon examination it was revealed he had an excessive, 45 mm forward head translation and a 15 degrees cervical kyphosis from C3-C6. The patient was treated with Chiropractic BioPhysics(r) methods aimed at restoring the cervical lordosis by mirror image(r), neck extension exercises, cervical extension traction, and spinal manipulative therapy. [Results] After two weeks of treatments the patient reported a complete resolution of neck pain. After 24 treatments over 10-weeks, a lateral radiograph demonstrated the restoration of a cervical lordosis and a complete reduction of forward head translation. [Conclusion] This case demonstrates that a cervical kyphosis may be reversed into a lordosis in as little as 10-weeks by specific care incorporating cervical extension protocols. This case also supports the biomechanical literature that suggests those with cervical kyphosis may be predisposed to spinal injury. We suggest that correcting even asymptomatic patients with obvious cervical spine deformity should be accomplished prior to future injury and/or degenerative changes. PMID- 29706726 TI - Neuroforecasting Aggregate Choice. AB - Advances in brain-imaging design and analysis have allowed investigators to use neural activity to predict individual choice, while emerging Internet markets have opened up new opportunities for forecasting aggregate choice. Here, we review emerging research that bridges these levels of analysis by attempting to use group neural activity to forecast aggregate choice. A survey of initial findings suggests that components of group neural activity might forecast aggregate choice, in some cases even beyond traditional behavioral measures. In addition to demonstrating the plausibility of neuroforecasting, these findings raise the possibility that not all neural processes that predict individual choice forecast aggregate choice to the same degree. We propose that although integrative choice components may confer more consistency within individuals, affective choice components may generalize more broadly across individuals to forecast aggregate choice. PMID- 29706728 TI - Acute Arthrodesis of Interphalangeal Joints of the Hand in Traumatic Injuries. AB - Background: Trauma resulting in severe comminution, bone loss, and articular involvement of the fingers is a challenging injury. Osteosynthesis of the digits is nonviable when there is an inability to restore a stable articular surface adequately. Acute arthrodesis of the proximal and distal interphalangeal joints may be an option in such scenarios. The aim of this study is to evaluate the role of finger joint arthrodesis in the setting of trauma, in terms of fusion rates and clinical outcomes. Materials and Methods: Patients with injuries treated via acute finger arthrodesis between 2010 and 2012 at a single institution were retrospectively reviewed. Complete finger amputations requiring replantation were excluded. Finger arthrodesis was performed acutely via intraosseous cerclage wires, Kirschner wires, or tension band wiring. Fusion rates were determined by plain radiography, and clinical outcomes were assessed with the Disabilities of the Arm, Shoulder and Hand (DASH) score. Results: A total of 11 patients were recruited. All patients were males with an average age of 35.3 years (range: 21 63 years). None of the cases involved the thumb, and there was an equal distribution of injury amongst the fingers. Nine of the 11 patients involved the distal interphalangeal joint with the remaining involving the proximal interphalangeal joint. Radiologic union was achieved in 9 out of 11 patients, and the average time to fusion was 75.5 days. The average DASH score for the patients was 16.5 (10.8-22.5). All patients were able to return to their premorbid occupation, with average time to return to work of 104.3 days (59-168 days). There were no cases of infection or reoperation. Conclusion: We propose that posttraumatic acute arthrodesis of the finger joints is a viable treatment in situations in which there is difficulty in restoring the articular congruity, with early return to work and good function. PMID- 29706727 TI - a-Factor: a chemical biology tool for the study of protein prenylation. AB - The mating pheromone a-factor is a lipidated dodecapeptide found in the budding yeast S. cerevisiae. The biosynthesis of this peptide encompasses the same three step processing pathway (farnesylation of C-terminal cysteine, C-terminal proteolysis and C-terminal methyl esterification) as Ras proteins, mutated forms of which have been found in ~30% of human cancers. For the mating of two haploid yeast cells into a diploid cell to happen, the a-factor pheromone travels to the cell surface of the opposite mating cell, where it binds and activates a G protein coupled receptor. This lipidated-peptide/protein interaction has caught the attention of researchers studying protein prenylation, and studies have shown that this peptide can be used as a model system to understand the role of prenyl groups in protein-protein interactions. Here, we review the different methods used for the synthesis of a-factor and a-factor analogs containing C-terminal cysteine esters and the assays developed for detecting pheromone bioactivity and quantitation of pheromone efficiency. Also, we review crucial peptide modifications that have been used to investigate relationships between the structure and activity of this lipopeptide with its receptor Ste3p. Finally, we aim to discuss recent and future applications of a-factor as a chemical biology tool to study protein prenylation. These include the use of photo crosslinking reactions to map peptide/receptor interactions, the addition of fluorophore tags to visualize the peptide binding, and the use of bio-orthogonal reactions for protein labeling and protein purification. PMID- 29706729 TI - Use of a Multivector Mandibular Distractor for Treatment of Pediatric Proximal Interphalangeal Joint Pilon Fractures: A Case-Based Review. AB - Background: The difficulties in surgical treatment of pilon fractures of the finger include fragment reconstitution and posthealing stiffness. In adults, external fixation with traction and early active range of motion (AROM)/passive range of motion (PROM) during healing is considered necessary for avoiding joint stiffness and attaining realignment. The authors present a unique approach to pediatric pilon fractures that uses open reduction and multivector external fixation with delayed AROM/PROM. Initial immobilization and significant traction allowed for joint realignment and prevented noncompliance with staged distraction. The authors believe this immobilization leads to a superior outcome because, unlike adults, children tend to avoid stiffness and a larger distraction force allowed for sufficient joint realignment to regain range of motion (ROM). Methods: A right-handed 13-year-old boy sustained a right ring finger fracture and presented 12 days later. Radiographs revealed a comminuted Salter-Harris 4 fracture of the middle phalanx. The patient underwent open reduction and placement of multivector external fixation using a pediatric mandibular distractor/fixator. Significant traction was applied to distract the finger to length. Results: Hardware was removed 6 weeks postoperatively and AROM was initiated after splinting. The patient started PROM 8 weeks postoperatively. Strengthening was initiated 2 weeks later. ROM improved and rehabilitation was continued. The patient exhibited nearly equal grip strength 12 weeks postoperatively. At 14 months follow-up, radiographs showed complete healing and joint realignment. There was no deformity or pain and finger length was restored. Conclusion: Management of pediatric pilon fractures is rarely described and presents unique considerations. Early-stage traction and immobilization using a multivector mandibular fixator/distractor is suitable in a child because noncompliance is avoided and there is a decreased risk for stiffness. Combining early immobilization with subsequent-staged AROM, PROM, and strengthening resulted in no loss of ROM and maintained articular symmetry. PMID- 29706731 TI - Percutaneous Intramedullary Headless Screw Fixation and Wide-Awake Anesthesia to Treat Metacarpal Fractures: Early Results in 25 Patients. AB - Metacarpal fractures constitute 7.8% of the upper extremity fractures. The common treatments remain nonsurgical procedure, but high-demanding patients or unstable fractures require fixation with Kirschner wire (K-wires), plate, and screws. However, these approaches may cause scarring and adhesion with poor functional results. From 2014 to 2015, the authors used an intramedullary headless screw to treat 25 patients (24 men, 1 woman) with metacarpal bones fractures (20 V, 3 IV, 1 III, and 1 II). The fractures patterns were 23 fractures of distal third of metacarpal bone (16 oblique, 5 comminute configurations, and 2 transverse), 1 fracture of the base of the II metacarpal bone. One case presented a multiple metacarpal and phalangeal facture associated. The authors used wide-awake anesthesia (bupivacaine-epinephrine 1:100,000) and intramedullary titanium headless screw fixation percutaneously inserted (CCS Medartis and HCS Synthes 3 mm of diameter). No open reduction was needed. Early active mobilization started with a buddy strapping soon after surgery (0-3 days). The authors followed all patients until satisfactory function was achieved (4-6 weeks) and recorded the time till return to work. All fracture healed with less than 5 degrees of rotational or axial deformities. All patients return to work within 2.38 weeks after surgery (0.5-6 weeks). No cases of complex regional pain syndrome (CRPS), tendon lesions, nerve injuries, infection, hardware protruding, or mobilization were reported. Intramedullary screw fixation with wide-awake anesthesia for transverse, oblique, and select comminuted fractures treatment metacarpal fractures represent a reliable option to early active mobilization recovery and a quick return to the work and ordinary activities. PMID- 29706730 TI - Relationship between Smoking and Outcomes after Cubital Tunnel Release. AB - Purpose: Several studies have drawn a connection between cigarette smoking and cubital tunnel syndrome. One comparison article demonstrated worse outcomes in smokers treated with transmuscular transposition of the ulnar nerve. However, very little is known about the effect that smoking might have on patients who undergo ulnar nerve decompression at the elbow. The purpose of this study is to evaluate the effect of smoking preoperatively on outcomes in patients treated with ulnar nerve decompression. Materials and Methods: This study used a survey developed from the comparison article with additional questions based on outcome measures from supportive literature. Postoperative improvement was probed, including sensation, strength, and pain scores. A thorough smoking history was obtained. The study spanned a 10-year period. Results: A total of 1,366 surveys were mailed to former patients, and 247 surveys with adequate information were returned. No significant difference was seen in demographics or comorbidities. Patients who smoked preoperatively were found to more likely relate symptoms of pain. Postoperatively, nonsmoking patients generally reported more favorable improvement, though these findings were not statistically significant. Conclusion: This study finds no statistically significant effect of smoking on outcomes after ulnar nerve decompression. Finally, among smokers, there were no differences in outcomes between simple decompression and transposition. PMID- 29706732 TI - Reliability of Metacarpal Subsidence Measurements after Thumb Carpometacarpal Joint Arthroplasty. AB - Background: Thumb metacarpal subsidence after trapeziectomy can affect clinical function over time. Methods for measuring subsidence after trapeziectomy have been described, and they rely on an intact thumb metacarpal or proximal phalanx for measurement. The authors evaluated the reliability and reproducibility of measuring the trapezial space ratio, using previously described methods. In addition, the authors evaluated a new method that measures trapezial space on a posteroanterior (PA) hand/wrist radiograph that does not rely on an intact thumb metacarpal or proximal phalanx for measurement, which can often be altered by degenerative changes or in cases in which metacarpophalangeal arthrodesis is performed during carpometacarpal (CMC) joint arthroplasty to correct excessive hyperextension. The authors hypothesized that a new method of calculating trapezial space would have comparable reliability and reproducibility to previously proposed methods. Methods: Thirty-seven PA hand/wrist radiographs from patients who had trapeziectomy with ligament reconstruction and tendon interposition were evaluated. Trapezial space was measured using PACS (Picture Archiving and Communication System) digital tools as the distance perpendicular to the tangents of the scaphoid and first metacarpal joint surfaces. All X-rays were evaluated individually by five fellowship-trained hand surgeons, twice, 4 weeks apart. The reviewers calculated trapezial space ratios, using three different methods, two previously described and a novel one: (1) trapezial space relative to first metacarpal length (classic 1); (2) trapezial space relative to proximal phalanx length (classic 2); and (3) trapezial space relative to capitate height (novel). Inter- and intraobserver reliabilities were measured using intraclass correlation coefficients (ICC) and limits of agreement for each method. Results: The authors identified excellent agreement between the classic 1, classic 2, and novel methods with an ICC greater than 0.8, indicating excellent agreement. The average trapezial space ratios for the thumb proximal phalanx, thumb metacarpal, and capitate methods were measured as 0.19, 0.12, and 0.24, respectively. The upper and lower limits of the 95% confidence intervals for both the inter- and intraobserver agreements of the aforementioned trapezial space ratios were (0.17-0.26), (0.11-0.17), and (0.21-0.34) for the interobserver rates and (0.11-0.25), (0.06-0.16), and (0.12-0.33) for the intraobserver rates, respectively. Conclusion: Measuring trapezial space is an important diagnostic tool to assess postoperative changes in thumb length. The trapezial space indexed to the capitate height method (novel) provides a simple and similarly reliable method for calculating the trapezial space ratio on a PA radiograph of the hand/wrist when other measurement techniques are unavailable and when the thumb metacarpal or proximal phalanx is not intact. The authors found a high degree of reproducibility and inter- and intraobserver reliability as measured by the ICC and the 95% limits of agreement that compare with previous agreements in the literature. PMID- 29706733 TI - Decreased Rate of Complications in Carpal Tunnel Release with Hand Fellowship Training. AB - Purpose: In many procedures, both high case volumes and fellowship training have been shown to improve outcomes. One of the most common procedures performed by hand surgeons, the carpal tunnel release (CTR) is also performed by several other specialties without specialty training in a hand fellowship. This study analyzed the effect that hand fellowship training has on outcomes of CTRs. Materials and Methods: Using the American Board of Orthopedic Surgeons (ABOS) Part II candidates' case list submissions, a database was created for all open and endoscopic CTRs. Surgeon training, demographics, technique, and complications were recorded. Complications were then categorized and broken down by technique. Results were then analyzed for statistical significance. Results: A total of 29,916 cases were identified. Hand fellowship-trained surgeons performed six times more CTRs at 31 cases per surgeon compared with five for non-hand fellowship-trained surgeons. They also improved outcomes in rates of infection, wound dehiscence, and overall complications. Rates of nerve injury or recurrence showed no statistical difference. This held true for the open release subset. Endoscopically, fellowship-trained surgeons had only improved rates of overall complications. Conclusion: Surgeons undergoing additional hand fellowship training may show improved outcomes in the surgical treatment of carpal tunnel syndrome. However, no effect was seen on nerve injury or recurrence of symptoms. PMID- 29706734 TI - Thoracoumbilical Flap: Anatomy, Technique, and Clinical Applications in Upper Limb Reconstruction in the Era of Microvascular Surgery. AB - Purpose: Microvascular reconstruction is the standard of care for salvage of soft tissue defects in complex upper extremity due to their distinct advantages over the pedicled flaps. However, in the era of microsurgery, pedicled flaps have an acceptable significant role for reconstruction of complex soft tissue defects. The authors aim to demonstrate the versatility of pedicled thoracoumbilical flap (TUF) in selected clinical scenarios. Patients and Methods: Retrospective analysis of patients who underwent TUF for upper limb posttraumatic reconstruction was performed between January 2016 and October 2017. The demographic details, etiology, wound parameters, clinical circumstances, and complications were recorded. Results: Ten patients were included in the retrospective case series. Out of them, nine of the patients had critical issues, which justified a pedicled TUF over free flap. The critical issues were severe comorbid illnesses ( n = 3), the paucity of recipient vessels ( n = 1), salvage of hand replant and revascularization ( n = 2), circumferential degloving injury to the multiple fingers and palm ( n = 1), coverage for metacarpal hand ( n = 1), and extensive scarring at the surgical site ( n = 1). Mean age was 34.4 years (range: 11-70 years), six of them were males, and four were females. Two patients had infections resulting in wound gaping. One of the patients had flap tip necrosis. Conclusion: Pedicled flaps have a significant acceptable role in this era of microsurgery, and a pedicled TUF is a versatile option for coverage of complex soft tissue defects of the forearm, wrist, hand, and fingers. Level of Evidence: This is a level IV, therapeutic, and retrospective study. PMID- 29706735 TI - Traumatic Dislocation of the Pisiform Bone. AB - Pisiform dislocation is a rare wrist injury. The limited literature available describes this pathology in the form of case reports. An immediate closed reduction and immobilization is indicated for acute injury while there is a debate in the management of cases with delayed diagnosis or failed closed reduction. In this case, a 32-year-old, right-handed man visited the emergency department with pain at the ulnar side of his left wrist after a fall. The initial management involved immobilization, and the patient was referred to the authors' specialized clinic 10 days later because of persistence of important ulnar wrist pain. The choice of treatment was pisiform excision without ligament reconstruction with excellent functional results. PMID- 29706736 TI - Deep Invasive Fungal Infection of the Hand in a Child Mimicking a Local Gigantism. AB - Subcutaneous and deep fungal infections in the hand are rare among children. These are usually found in immunocompromised adults or in persons engaged in soil handling activities, due to direct exposure, especially in the tropics. Delay in diagnosis is usual because pyogenic and other granulomatous infections are considered first. The authors present the case of a healthy, immunocompetent 21/2 year-old child who presented with progressive swelling of the right hand mimicking a localized gigantism of the entire hand. Multiple operative drainage procedures done previously had failed to resolve the condition. A biopsy established the presence of fungal hyphae, thus confirming the diagnosis of deep fungal infection of the hand and guided proper therapeutic intervention. A strong index of suspicion needs to be maintained in cases not responding to conventional antibacterial therapy, and both microbiologic and histopathologic samples need to be obtained to establish the diagnosis. PMID- 29706737 TI - A Rare Case of Triceps Brachii Injury after Electrocution. AB - Injuries of the triceps brachii muscle are a rare entity and mostly concern its distal tendon. These represent the least common of all muscle and tendons injuries. The most common reported causes are repeated strong physical efforts, a fall on an outstretched forearm when a sudden deceleration is put on contract triceps, or a direct trauma. High-dosed and prolonged corticosteroid therapies, repeated local steroid injections, chronic renal failure, diabetes, rheumatoid arthritis, hyperparathyroidism, and osteogenesis imperfecta are reported as systemic causes. Even rarer are lesions of muscle fibers and avulsions or rupture at its musculotendinous junction, and these can be caused by direct trauma or by forced elbow flexion during triceps contraction. To the best of our knowledge, there is no article in the literature describing this type of injury that occurred after electrocution. In this article, we report an uncommon case of intramuscular tear associated with insertional distal tendon injury occurred in a man survived to high-voltage electric discharge. PMID- 29706738 TI - Double-Layer Reconstruction of the Achilles' Tendon Using a Modified Lindholm's Technique and Vascularized Fascia Lata. AB - Loss of the Achilles' tendon with overlying soft tissue and skin defects remains a complex reconstructive challenge. Herein we present our experience using a free composite anterolateral thigh (ALT) flap with vascularized fascia lata and a modified Lindholm's technique to repair the Achilles' tendon. A 37-year-old man suffered from tertiary Achilles' tendon rupture. For reconstruction, the free composite ALT flap with vascularized fascia lata was used to wrap Achilles' tendon. A modified Lindholm's technique was used to cover overlying soft tissue defects. The patient was followed up for 12 months. No wound healing problems were reported, and the patient was able to walk and return to his daily ambulating activities without any support after 5 months postoperatively. This technique may be useful to achieve satisfactory outcomes in patients with ruptured Achilles' tendons following tertiary repair. PMID- 29706739 TI - The Palmar Cutaneous Branch Mimicking the Recurrent Motor Branch of the Median Nerve. AB - We report an unusual anatomical variant of the palmar cutaneous branch (PCB) of the median nerve in a 46-year-old man presenting with recurrent carpal tunnel syndrome. At surgery, after neurolysis, the PCB was visualized arising at the level of the proximal margin of the transverse carpal ligament, mimicking the appearance of the recurrent motor branch. To date, there has been no description of this branch arising at this level. We aim to remind surgeons of this variation and highlight the importance of maintaining vigilance to avoid iatrogenic nerve injury. PMID- 29706740 TI - "The Serpentine Zone": A Surgeon's Guide to the Surface Anatomy of the Digital Neurovascular Spiral in Dupuytren's Contracture. AB - The anatomy of the cords that form in Dupuytren's disease is complicated and a spiral cord is the most challenging variant to address. It displaces the neurovascular bundle toward or beyond the midline and closer to the skin. This article illustrates the surface anatomy of the neurovascular spiral to help surgeons identify this zone of danger that the authors term "the serpentine zone." Careful dissection in this zone will help avoid iatrogenic digital neurovascular injury. PMID- 29706741 TI - Surgical Treatment of a Catfish Spine Puncture Wound in the Hand. PMID- 29706742 TI - An Uncommon Fracture of the Thumb: Two Cases of Sesamoid Fracture. PMID- 29706743 TI - Some characterizations of disjoint topological transitivity on Orlicz spaces. AB - In this paper, we study the disjointness of topological transitivity on Orlicz spaces endowed with the Orlicz norm. We first give the characterization for weighted translations to be topologically transitive. Based on this, a sufficient condition and a necessary condition for powers of weighted translations to be disjoint topologically transitive are obtained as well. PMID- 29706744 TI - Approximation of certain bivariate functions by almost Euler means of double Fourier series. AB - In this paper, we study the degree of approximation of 2pi-periodic functions of two variables, defined on [Formula: see text] and belonging to certain Lipschitz classes, by means of almost Euler summability of their Fourier series. The degree of approximation obtained in this way depends on the modulus of continuity associated with the functions. We also derive some corollaries from our theorems. PMID- 29706745 TI - Pointwise approximation of modified conjugate functions by matrix operators of conjugate Fourier series of [Formula: see text]-periodic functions. AB - We extend the results of Xh. Z. Krasniqi (Acta Comment. Univ. Tartu Math. 17:89 101, 2013) and the authors (Acta Comment. Univ. Tartu Math. 13:11-24, 2009; Proc. Est. Acad. Sci. 67:50-60, 2018) to the case when considered function is [Formula: see text]-periodic and the measure of approximation depends on r-differences of the entries of the considered matrices. PMID- 29706746 TI - Variation and oscillation for the multilinear singular integrals satisfying Hormander type conditions. AB - Suppose that the kernel K satisfies a certain Hormander type condition. Let b be a function satisfying [Formula: see text] for [Formula: see text], and let [Formula: see text] be a family of multilinear singular integral operators, i.e., [Formula: see text] The main purpose of this paper is to establish the weighted [Formula: see text]-boundedness of the variation operator and the oscillation operator for [Formula: see text]. PMID- 29706747 TI - On frame's inequalities. AB - In this paper, the errors of the two inequalities in Theorem 3.4.20 in the classic "Analytic Inequalities" by Mitrinovic are corrected, and the corresponding inequalities for circular functions and hyperbolic functions are rebuilt. PMID- 29706748 TI - Existence and uniqueness result for a class of mixed variational problems. AB - Our aim in this paper is to investigate the existence and uniqueness result for a class of mixed variational problems. They are governed by two variational inequalities. By applying the saddle-point theory, we obtain the existence of solutions to mixed variational problems. Finally, some frictional contact problems are given to illustrate our main results. PMID- 29706749 TI - Scattering and Gradient Forces from the Electromagnetic Stress Tensor Acting on a Dielectric Sphere. AB - The derivation of the scattering force and the gradient force on a spherical particle due to an electromagnetic wave often invokes the Clausius-Mossotti factor, based on an ad hoc physical model. In this article, we derive the expressions including the Clausius-Mossotti factor directly from the fundamental equations of classical electromagnetism. Starting from an analytic expression for the force on a spherical particle in a vacuum using the Maxwell stress tensor, as well as the Mie solution for the response of dielectric particles to an electromagnetic plane wave, we derive the scattering and gradient forces. In both cases, the Clausius-Mossotti factor arises rigorously from the derivation without any physical argumentation. The limits agree with expressions in the literature. PMID- 29706750 TI - Synthesis and anticancer activity of multisubstituted purines and xanthines with one or two propynylthio and aminobutynylthio groups. AB - A synthesis of new 2,6-disubstituted and 2,6,8-trisubstituted 7-methylpurines as well as 8-substituted 3,7-dimethylxanthines containing a triple bond chain have been worked out. Purinethiones and xanthinethiones were converted into propynylthio derivatives, which were then further transformed via a Mannich reaction into aminobutynylthio derivatives (amine = pyrrolidine, piperidine, morpholine, and diethylamine). The products thus obtained represent various types of the purine and xanthine structure: 8-mono-, 2,6- and 6,8-dipropynylthio, 6- and 8-monoaminobutynylthio, 2,6- and 6,8-diaminobutynylthio derivatives. All of these compounds were tested for their anticancer activity against human glioblastoma SNB-19, human adenocarcinoma MDA-MB-231, and melanoma C-32 cell lines. The anticancer activity depends on the nature of the substituent and its localization in the purine and xanthine framework. Generally, compounds possessing two alkynylthio groups (propynylthio or aminobutynylthio) were more active than those possessing only one group. Some compounds exhibited stronger or similar anticancer activity to cisplatin. All compounds were also tested for their cytotoxic activity against normal human fibroblasts (HFF-1). The most promising anticancer compounds were found to be 2,6-dipropynylthio-7-methylpurine 4, 2-chloro-6,8-dipropynylthio-7-methylpurine 14, and 2-chloro-6,8-di(N morpholinylbutynylthio)-7-methylpurine 15c acting selectively on glioblastoma SNB 19, melanoma C-32, and adenocarcinoma MDA-MB-231 with the IC50 = 0.07-4.08 MUg/mL. PMID- 29706751 TI - EXPLORATION AND DATA REFINEMENT VIA MULTIPLE MOBILE SENSORS BASED ON GAUSSIAN PROCESSES. AB - We consider configuration of multiple mobile sensors to explore and refine knowledge in an unknown field. After some initial discovery, it is desired to collect data from the regions that are far away from the current sensor trajectories in order to favor the exploration purposes, while simultaneously, exploring the vicinity of known interesting phenomena to refine the measurements. Since the collected data only provide us with local information, there is no optimal solution to be sought for the next trajectory of sensors. Using Gaussian process regression, we provide a simple framework that accounts for both the conflicting data refinement and exploration goals, and to make reasonable decisions for the trajectories of mobile sensors. PMID- 29706752 TI - Estimating Individual Treatment Effect in Observational Data Using Random Forest Methods. AB - Estimation of individual treatment effect in observational data is complicated due to the challenges of confounding and selection bias. A useful inferential framework to address this is the counterfactual (potential outcomes) model, which takes the hypothetical stance of asking what if an individual had received both treatments. Making use of random forests (RF) within the counterfactual framework we estimate individual treatment effects by directly modeling the response. We find that accurate estimation of individual treatment effects is possible even in complex heterogenous settings but that the type of RF approach plays an important role in accuracy. Methods designed to be adaptive to confounding, when used in parallel with out-of-sample estimation, do best. One method found to be especially promising is counterfactual synthetic forests. We illustrate this new methodology by applying it to a large comparative effectiveness trial, Project Aware, to explore the role drug use plays in sexual risk. The analysis reveals important connections between risky behavior, drug usage, and sexual risk. PMID- 29706753 TI - Current approaches to measuring functional status among older adults in VA primary care clinics. PMID- 29706754 TI - Understanding and Preventing Loss to Follow-up: Experiences From the Spinal Cord Injury Model Systems. AB - Background: One of the most critical threats to the validity of any longitudinal research is the bias caused by study attrition. Prevention efforts should be focused on those individuals at high risk of non-participation to improve the generalizability of study findings. Objective: To identify demographic and clinical factors associated with loss to follow-up (FU) at post-injury years 1 to 35 among 25,871 people with spinal cord injury (SCI) enrolled in the National Spinal Cord Injury Database. Methods: Loss to FU was defined as no research information obtained from participants who were eligible for the planned data collection. Generalized linear mixed models were used for analysis of factors at each post-injury year. Results: The loss to FU rates were 23.1% and 32.9% for post-injury years 1 and 5, respectively, and remained >40% between post-injury years 20 and 35. The FU rate varied by study sites and was improved in recent injury cohorts. People who were more seriously injured and those who attained higher levels of education were more likely to return for FU than their counterparts. People who were at risk of being marginalized in society (non whites, those with less education, the unemployed, victims of violence, and those with no health insurance) had the highest odds of being lost to FU across all post-injury years. Conclusion: These findings can be used to identify individuals who are less likely to participate in follow-up, which may allow targeted attention to improve their response rate. PMID- 29706755 TI - Racial Differences in Data Quality and Completeness: Spinal Cord Injury Model Systems' Experiences. AB - Background: Among people with spinal cord injury (SCI), minorities experience a disproportionately higher burden of diseases. Knowledge of data quality by race/ethnicity will help better design racial health disparity research and understand potential errors/biases. Objective: To investigate racial/ethnic differences in response completeness in a longitudinal SCI database. Methods: This study included 7,507 participants (5,483 non-Hispanic whites, 1,414 non Hispanic blacks, and 610 Hispanics) enrolled in the National SCI Database who returned for follow-up between 2001 and 2006 and were aged >=18 years at follow up. Missing data were defined as any missing, unknown, or refusal response to interview items. Results: The overall missing rate was 29.7%, 9.5%, 9.7%, 10.7%, 12.0%, and 9.8% for the Craig Handicap Assessment and Reporting Technique-Short Form (CHART) economic self-sufficiency subscale, CAGE questionnaire, drug use, Diener's Satisfaction with Life Scale, Patient Health Questionnaire, and pain severity, respectively. The missing rate for the CHART measure was significantly higher among non-Hispanic blacks and Hispanics than among non-Hispanic whites, after controlling for demographics, injury factors, mode of data collection, and study sites. The missing data in the other outcome measures examined were also significantly higher among non-Hispanic blacks than among non-Hispanic whites but were not significantly different between Hispanics and non-Hispanic whites. Conclusion: Our study highlights the importance of research methodology designed to improve non-response or response incompleteness, particularly in non-Hispanic blacks, as we move to reduce racial/ethnic disparities and strive to explain how and why disparities occur in the SCI population. PMID- 29706756 TI - Comparing Blunt and Penetrating Trauma in Spinal Cord Injury: Analysis of Long Term Functional and Neurological Outcomes. AB - Background: Comparisons between patients with penetrating spinal cord injury (PSCI) and blunt spinal cord injury (BSCI) are scarce. Purpose: To describe baseline characteristics and neurological and functional outcomes for patients with BSCI and PSCI. Methods: Participants with BSCI (n = 5,316) and PSCI (n = 1,062) were extracted from the Spinal Cord Injury Model Systems database from January 1994 to January 2015. Participant injury and demographic characteristics were recorded. Outcomes were measured using the International Standards for Neurological Classification of Spinal Cord Injury and FIM motor scores. Outcomes for patients with American Spinal Injury Association Impairment Scale (AIS) complete injuries were analyzed separately from incomplete injuries at three time points: acute hospitalization, SCI rehabilitation, and 1-year follow-up. Results: Patients with PSCI compared to those with BSCI were more likely to present with complete injuries (56.8% vs 35.9%; p < .001) and were less likely to undergo spine surgery (19.6% vs 80.6%; p < .001). For incomplete injuries, no significant differences were observed between groups in FIM scores or AIS grade improvement at 1 year. For complete injuries, patients with BSCI showed an increased one grade (15.7% vs 9.1%; p < .001) and three-grade (5.4% vs 1.9%; p = .014) AIS improvement at 1 year. Multivariate regression analysis demonstrated an independent effect for BSCI on AIS improvement at 1 year (odds ratio [OR], 1.74; 95% CI, 1.13-2.70; C-stat = 0.66). Conclusion: Patient with PSCI had more complete injuries and lower surgery rates. Patients with complete BSCI show greater AIS improvement at 1 year, and incomplete injuries show no difference in neurological improvement between groups. Overall, patients with PSCI demonstrated worse functional outcomes at 1 year. PMID- 29706757 TI - Implementation of a Standardized Dataset for Collecting Information on Patients With Spinal Cord Injury. AB - Background: Over the last decade, the International Spinal Cord Injury Data Sets project developed a number of International Spinal Cord Injury Data Sets (ISCIDS) that can be used to collect standardized information on patients with SCI. Objective and Methods: The aim of this article is to describe the process of translating the ISCIDS into Dutch and reaching consensus on a Dutch National SCI Data Set (NDD). The interrater reliability of the NDD and implementation of the NDD at eight rehabilitation centers with a specialty in rehabilitation after SCI in the Netherlands are described. Results: NDD was implemented successfully at all eight centers. Some adaptations were made to the ISCIDS, especially to the core data set. The reliability coefficients of the NDD items were at least sufficient (mean kappa per data set ranged between .68 and .91), and mean agreement per data set ranged from 66% to 97%. Experiences from the participating centers were mainly positive as well. The main obstacle for use was thought to be the absence of a link between the local patient files and the national database, which necessitates double data entry. Conclusion: Although the results on interrater reliability are based on a small sample size and the assessment situation is different from the normal clinical situation, this study showed the NDD to be a useful instrument to collect standardized information on patients with SCI in the Netherlands. In the future, a connection between systems or another way to centrally collect the data is recommended to prevent double data entry and to guarantee continuation of administration of the NDD. PMID- 29706758 TI - Progress of the Dutch Spinal Cord Injury Database: Completeness of Database and Profile of Patients Admitted for Inpatient Rehabilitation in 2015. AB - Background: In the Dutch International Spinal Cord Injury (SCI) Data Sets project, we translated all International SCI Data Sets available in 2012 and created a Dutch SCI Database (NDD). Objective: To describe the number of included patients and completeness of the NDD, and to use the NDD to provide a profile of people with traumatic SCI (T-SCI) and non-traumatic SCI (NT-SCI) in the Netherlands. Methods: The NDD includes patients admitted for their first inpatient rehabilitation after onset of SCI to 1 of the 8 rehabilitation centers with a specialty in SCI rehabilitation in the Netherlands. Data of patients admitted in 2015 were analyzed. Results: Data for 424 patients were available at admission; for 310 of these patients (73.1%), discharge data were available. No significant differences were found between patients with and without data at discharge. Data were nearly complete (>90%) for lower urinary tract, bowel, pain, and skin. Data on sexual function has the lowest completion rate. Complete neurological and functional data were available for 41.7% and 38%, respectively. Most patients were male (63.4%), had NT-SCI (65.5%), and had incomplete SCI (58.4% D). Patients with T-SCI differed from patients with NT-SCI on most characteristics, and they stayed considerably longer in the rehabilitation center (112 days vs 65 days, p < .001). Place of discharge was not different between both groups. Conclusion: With the NDD, we collect important data on the majority of Dutch SCI patients, although much work needs to be done to improve the completeness of the data collection. PMID- 29706759 TI - Prediction Model for the Presence of Complications at Admission to Rehabilitation After Traumatic Spinal Cord Injury. AB - Background: Complications frequently occur in patients with spinal cord injury (SCI) during acute care or rehabilitation and have an impact on rehabilitation outcomes. Purpose: The aim of this study was to determine the occurrence and risk factors for complications in recently injured SCI patients. Methods: Two hundred fifty patients with traumatic injuries with and without complications were counted for the following dichotomous parameters: gender (male/female), associated lesions (presence/absence), surgery (yes/no), American Spinal Injury Association Impairment Scale (AIS) grade (A/other categories), lesion level (lumbar/other levels), and lesion-to-admission time (less than/longer than 1 month). The odds ratio (OR) and 95% confidence interval were computed for all the parameters that influenced the presence of complications at admission. These factors have been included in a binary logistic regression analysis (forward stepwise). Results: Complications at admission were observed in 104 patients (41.6%), especially for males, lesion-to-admission time longer than 1 month, presence of associated lesions, AIS grade A, and motor completeness, whereas lumbar lesions were associated with a reduced presence of complications at admission. In the regression analysis, 4 factors entered into the model: motor completeness, lesion-to-admission time, associated lesions, and gender. The final model explained 74% of the variance of data. Conclusions: Despite advances in the acute management of patients with SCI, the study unveiled a high percentage of patients with complications at admission to rehabilitation. The risk factors identified in the study allow determination of the population of subjects who are at higher risk of developing complications and need special management. PMID- 29706760 TI - Brain Motor Control Assessment Post Early Intensive Hand Rehabilitation After Spinal Cord Injury. AB - Background: The Brain Motor Control Assessment (BMCA) is a surface electromyography (sEMG)-based measure of motor output from the central nervous system during a variety of reflex and voluntary motor tasks. Objective: The aim of this study was to assess the pattern of voluntary movements in patients with spinal cord injury (SCI) to investigate whether BMCA could add more resolution to clinical assessments and the recovery path of these patients. Method: Ten participants were recruited from the Royal Talbot Rehabilitation Centre as part of a multicenter randomized controlled trial. Four participants received usual care while the other 3 participants received usual care plus an intensive task specific hand training program in conjunction with functional electrical stimulation for 8 weeks. BMCA assessments were completed for 7 participants at this center 4 times over a period of 1 year. Results: Generalized linear model analysis showed a significant main effect of task (p < .001) and assessment time (p = .003) on the Similarity Index. However, there were no significant interactions among the factors (p > .05). Based on ARAT or summed upper limb strength scores, some participants showed significant improvement after 8 weeks of rehabilitation, however this improvement was not reflected in the pattern of muscle activation that was captured by BMCA. Conclusion: The quantifiable features of BMCA through surface EMG may increase the resolution of SCI characterization by adding subclinical details to the clinical picture of lesion severity and progression during rehabilitation. PMID- 29706761 TI - Effects of Spinal Cord Injury in Heart Rate Variability After Acute and Chronic Exercise: A Systematic Review. AB - Background: Spinal cord injury (SCI) above T6 is followed by a loss of sympathetic supraspinal control of the heart, disturbing the autonomic balance and increasing cardiovascular risk. Heart rate variability (HRV) is a widely used tool for assessing the cardiac autonomic nervous system and positive adaptations after regular exercise in able-bodied subjects. However, adaptations in SCI subjects are not well known. Objectives: To compare HRV between able-bodied and SCI subjects and analyze the effects of chronic and acute exercise on HRV in the SCI group. Methods: We searched MEDLINE, Embase, Web of Science, SciELO, and Google Scholar databases to July 2016. We selected English and Spanish observational or experimental studies reporting HRV after training or acute exercise in SCI patients. We also included studies comparing HRV in SCI individuals with able-bodied subjects. Animal studies and nontraumatic SCI studies were excluded. We screened 279 articles by title and abstract; of these, we fully reviewed 29 articles. Eighteen articles fulfilled criteria for inclusion in this study. Results: SCI individuals showed lower HRV values in the low frequency band compared to able-bodied subjects. Regular exercise improved HRV in SCI subjects, however time and intensity data were lacking. HRV decreases after an acute bout of exercise on SCI subjects, but recovery kinetics are unknown. Conclusion: HRV is affected following SCI. Able-bodied subjects and SCI individuals have different values of HRV. Acute bouts of exercise change HRV temporarily, and chronic exercise might improve autonomic balance in SCI. PMID- 29706762 TI - Clinical Instruments for Measuring Unsupported Sitting Balance in Subjects with Spinal Cord Injury: A Systematic Review. AB - Background: Evidence of intervention effectiveness depends on, among other things, the use of a common set of valid and reliable measures that are responsive to change and reflect clinically important outcomes. Objective: To identify clinical assessment instruments with properties for measuring unsupported sitting balance in subjects with spinal cord injury (SCI). Methods: Bibliographic databases (PubMed, Science Direct, CINAHL, and Central) were searched for articles with the key words "spinal cord injury," "unsupported sitting," and "outcome assessment" in combination with a specific methodological search filter for each database. Studies describing the application of any assessment instrument for measuring unsupported sitting balance in subjects with SCI, which had the evaluation of any measurement property, were included in the review. Publication details, measure's name, setting, summary statistics, measurement properties (reliability, validity, responsiveness), and statistical significance (p values) were extracted. Results: Eight hundred forty publications were identified; 8 articles were included in the systematic review. Twelve instruments were identified and analyzed, showing limited and incomplete measurement properties. Among them, 10 addressed activity, 1 addressed structures/body functions, and 1 addressed both activity and structures/body functions domains of the International Classification of Functioning, Disability and Health (ICF). Conclusion: Based mainly on the measurement properties and the development of the instruments analyzed in this review, the Sitting Balance Measure, the Trunk Control Test, and the Set of Assessment Tools for Measuring Unsupported Sitting seem to be the most appropriate and recommended measures to assess unsupported sitting in subjects with SCI. PMID- 29706764 TI - The Dilemma of Service Productivity and Service Innovation: An Empirical Exploration in Financial Services. AB - We conduct a systematic exploratory investigation of the effects of firms' existing service productivity on the success of their new service innovations. Although previous research extensively addresses service productivity and service innovation, this is the first empirical study that bridges the gap between these two research streams and examines the links between the two concepts. Based on a comprehensive data set of new service introductions in a financial services market over a 14-year period, we empirically explore the relationship between a firm's existing service productivity and the firm's success in introducing new services to the market. The results unveil a fundamental service productivity service innovation dilemma: Being productive in existing services increases a firm's willingness to innovate new services proactively but decreases the firm's capabilities of bringing these services to the market successfully. We provide specific insights into the mechanism underlying the complex relationship between a firm's productivity in existing services, its innovation proactivity, and its service innovation success. For managers, we not only unpack and elucidate this dilemma but also demonstrate that a focused customer scope and growth market conditions may enable firms to mitigate the dilemma and successfully pursue service productivity and service innovation simultaneously. PMID- 29706763 TI - alphaA-crystallin-derived minichaperone stabilizes alphaAG98R-crystallin by affecting its zeta potential. AB - Purpose: The G98R mutant of alphaA-crystallin is associated with the development of presenile cataracts. In vitro, the recombinant mutant protein exhibits altered structural and functional characteristics, along with the propensity to aggregate by itself and precipitate. Previously, we have reported that the N-terminal aspartate substituted form of the antiaggregation peptide, D71FVIFLDVKHFSPEDLTVK88 (alphaA-minichaperone or mini-alphaA) prevented aggregation of alphaAG98R. However, the mechanism of stabilization of alphaAG98R from aggregation is not fully understood. The purpose of this study was to determine whether the surface charge (zeta (zeta) potential) of alphaAG98R in the presence of the peptide chaperone contributed to the stabilization of mutant protein, and to identify the sites of interaction between alphaAG98R and the peptide chaperone. Methods: Wild-type alphaA-crystallin (alphaAWT) and recombinant mutant alphaAG98R were purified from Escherichia coli BL21(DE3)pLysS cells. The zeta potential values of alphaA-crystallins in the presence or absence of alphaA-minichaperone and purified protein-peptide complexes were estimated in a zeta potential analyzer. Potential regions within alphaAG98R that bind the alphaA-minichaperone were investigated by incubating the protein with a photoactivable minichaperone variant, followed by mass spectrometric analysis. Results: Binding of the alphaA-minichaperone to aggregation-prone alphaAG98R was accompanied by an increase in the zeta potential from -15.19+/-0.870 mV corresponding to alphaAG98R alone to -28.64+/-1.640 mV for the purified complex. Mass spectrometric analysis identified 1MDVTIQHPWFK11, 13TLGPFYPSR21, 55TVLDSGISEVR65, and 113EFHRR117 as the alphaA-minichaperone-binding regions in alphaAG98R. The results suggest the involvement of the N-terminal region and the alpha-crystallin domain in the peptide-mediated stabilization of alphaAG98R. Conclusions: The alphaA-crystallin-derived minichaperone stabilizes alphaAG98R by compensating its lost surface charge. Methods for increasing the zeta potential of aggregating proteins can be a potential approach for therapy to protein aggregation diseases. PMID- 29706765 TI - Correlation Between Mammographic Breast Density, Breast Tissue Type in Ultrasonography, Fibroglandular Tissue, and Background Parenchymal Enhancement in Magnetic Resonance Imaging. AB - Objective: Breast cancer is the most common malignancy in the female population, and imaging studies play a critical role for its early detection. Mammographic breast density (MBD) is one of the markers used to predict the risk stratification of breast cancer in patients. We aimed to assess the correlations among MBD, ultrasound breast composition (USBC), fibroglandular tissue (FGT), and the amount of background parenchymal enhancement (BPE) in magnetic resonance imaging, after considering the subjects' menopausal status. Methods: In this retrospective cross-sectional study, the medical records' archives in a tertiary referral hospital were reviewed. Data including age, menopausal status, their mammograms, and ultrasound assessments were extracted from their records. All of their imaging studies were reviewed, and MBD, USBC, FGT, and BPE were determined, recorded, and entered into SPSS software for analysis. Results: A total of 121 women (mean age = 42.7 +/- 11.0 years) were included, of which 35 out of 115 (30.4%) had reached menopause. Using the Jonckheere-Terpstra test for evaluating the trends among above mentioned 4 radiologic characteristics in the total sample population, a significant positive relation was found between each of these paired variables: (1) USBC-MBD (P = .006), (2) FGT-MBD (P = .001), (3) USBC-BPE (P = .046), (4) USBC-FGT (P = .036), and (5) BPE-FGT (P < .001). These trends were not found to be significant among premenopausal subjects. Conclusions: Considering the trends between different measures of breast density in the 3 radiologic modalities, these factors can be used interchangeably in certain settings. PMID- 29706766 TI - Test for Non-Synergistic Interactions in Phytomedicine, Just as You Do for Isolated Compounds. AB - Phytomedicine has often been used as "alternative therapy," which in our opinion is unfortunate as it prevents its main actions being systematically studied, side effects explored, and toxicity tested, like all single-compound-based medicine. Our group is interested in finding which traditional or modern phytomedicines actually work and which are simply "working" through placebo, standardizing phytomedicine preparations, studying their toxicity, and finding active molecules in plants for modification and chemical synthesis as single compounds. Although fluctuation in efficacy due to seasonal and geographical variations in phytomedicine remains a concern, if well regulated, even plant extracts without isolated compounds can serve medicinal needs where single-compound options are currently not great. A potential concern with such phytomedicine is frequent mixing of ingredients in commercial formulations without test of synergism. Our study on the use of 2 traditional plants for Parkinson disease shows a clear lack of synergism, and to study nonsynergism better, we developed a new visualization approach. In this commentary, using our study on Parkinson disease as an example, we make a case for better evaluation of phytomedicines, especially testing for synergistic interactions. We also critique our own exploration of oxidative stress and few behavioral parameters alone to lay grounds for what we and hopefully others can do in future to extract more information from their phytomedicine studies. We hope this commentary acts as a good warning for anyone mixing 2 phytomedicines without testing. PMID- 29706767 TI - M-mode Diagnosis of Tachyarrhythmia Can be Erroneous Owing to "Pseudo 1:1 Atrioventricular Movement" of the Atrial Wall Adjacent to the Atrioventricular Valve Possibly due to Atrioventricular Constraint: A Case of Neonatal Atrial Flutter With 2:1 Atrioventricular Conduction. AB - M-mode echocardiography has been playing an important role in the diagnosis of fetal tachyarrhythmia. We recently encountered a neonatal case of atrial flutter with 2:1 atrioventricular conduction. However, M-mode erroneously indicated 1:1 atrioventricular movement. While the movement of the atrial wall far from the atrioventricular valve was much faster than that of the ventricular wall, the atrial wall adjacent to the atrioventricular valve fully synchronized to that of the ventricular wall. Thus, to avoid this novel pitfall, it would be important to add an additional assessment focusing on the movement of the atrial wall far from the ventricle. PMID- 29706768 TI - Small Fiber Neuropathy: Disease Classification Beyond Pain and Burning. AB - Small fiber neuropathy (SFN) has a poorly understood pathology, but patients would benefit from determination of clinical phenotypes that allows for better diagnosis and treatment planning. I propose that patients should be classified dependent on whether there is sodium channel dysfunction, classic neurologic symptoms only, widespread neuropathic pain, or autonomic symptoms. Patients with SFN can then be considered in light of their clinical phenotype, allowing for focus on subsets of patients who might have diagnosable conditions or be more prone to responding to a particular type of therapy that may not be efficacious in the broader patient population with SFN. There are several therapies currently available that can address the symptoms of SFN; however, to develop novel therapeutic strategies, it will be imperative to classify patients to understand and target the underlying pathology. PMID- 29706769 TI - Proceedings of the 17th International Congress of Myriapodology, Krabi, Thailand. PMID- 29706770 TI - Distribution, diversity patterns and faunogenesis of the millipedes (Diplopoda) of the Himalayas. AB - The Himalayas support a highly rich, diverse, multi-layered, mostly endemic diplopod fauna which presently contains >270 species, 53 genera, 23 families and 13 orders. This is the result of mixing the ancient, apparently Tertiary and younger, Plio-Pleistocene elements of various origins, as well as the most recent anthropochore (= man-mediated) introductions. At the species and, partly, generic levels, the fauna is largely autochthonous and sylvicolous, formed through abounding in situ radiation and vicariance events. In general, the species from large genera and families tend to occupy a wide range of altitudes, but nearly each of the constituent species shows a distribution highly localized both horizontally and altitudinally, yet quite often with sympatry or even syntopy involved. The bulk of the fauna is Indo-Malayan in origin, with individual genera or families shared with those of SE Asia (mostly) and/or S India (few). Sino Himalayan and, especially, Palaearctic components are subordinate, but also clearly distinguishable. PMID- 29706771 TI - A checklist of the millipedes of Georgia, Caucasus (Diplopoda). AB - The diplopod fauna of Georgia, Transcaucasia, is very rich given the country's relatively small territory, presently comprising 95 species from 42 genera, 12 families, and seven orders. Most of the Diplopoda known from Georgia are subendemics (39 species, or 38%), shared with one or more neighbouring countries, but another 33 species (33%) are strict endemics, nearly all highly localized, including 12 presumed troglobites. Several genera are likewise endemic to Georgia, including a few troglobionts. Within Georgia, the fauna of the western part (= Colchis) is particularly rich and diverse, the faunas of the central and eastern parts of the country growing increasingly depauperate inland and apparently following a rather gradual climatic aridisation gradient from west (the Black Sea coast) to east (Armenia and Azerbaijan). Much more work to include alpine and cave environments is required in order to reveal and refine the real diversity of Georgia's Diplopoda. PMID- 29706772 TI - The peristomatic structures as a source of systematic characters in the genus Lithobius Leach, 1814 (Myriapoda, Chilopoda). AB - Morphological characters have been widely used in centipede systematics. Here, we aim to obtain morphological information from the preoral chamber and peristomatic structures of lithobiomorph centipedes, with taxonomic sampling focused on the species-rich genus Lithobius Leach, 1814. Towards this goal, we (i) examined the epipharynx and hypopharynx of 32 species belonging to four subgenera of the genus Lithobius, viz. Lithobius Leach, 1814, Monotarsobius Verhoeff, 1905, Sigibius Chamberlin, 1913 and Ezembius Chamberlin, 1919 using light and scanning electron microscopy, (ii) searched for phylogenetically informative characters and (iii) described interspecific variation. Three species of the lithobiid genera Eupolybothrus Verhoeff, 1907, Disphaerobius Attems, 1926 and Neolithobius Stuxberg, 1875 were additionally examined and considered as likely outgroups. New characters and character states are proposed as additions to current phylogenetic datasets. Similarities in the peristomatic structures ally Disphaerobius with Lithobius (Ezembius), suggesting that the subfamily Pterygoterginae is nested within Lithobiinae and Lithobius. PMID- 29706774 TI - Two new Lophoturus species (Diplopoda, Polyxenida, Lophoproctidae) from Queensland, Australia. AB - Lophoturus queenslandicus Verhoeff, 1924 was the first penicillate millipede in the family Lophoproctidae collected from Cairns, a tropical region in Queensland, Australia, to be formally described. Specimens collected from this region in a recent study had the morphological characters known to define this genus. However, their body form and length, as well as dorsal colouration proved to be different, suggesting the possibility of more than one Lophoturus species. This assertion was supported by the results of a phylogenetic analysis of DNA extracted and sequenced using 18S and COI regions from L. queenslandicus and two undescribed species from this genus. Specimens preserved in ethanol can prove difficult to confidently identify to species level because their colour gradually fades. Examination of live specimens with their body colour visible, together with morphological characters and DNA analysis is the most reliable way of correctly distinguishing between these three species. Two new species, L. boondallussp. n. and L. molloyensissp. n. collected in Queensland, Australia are described. PMID- 29706773 TI - An apparently non-swinging tentorium in the Diplopoda (Myriapoda): comparative morphology of the tentorial complex in giant pill-millipedes (Sphaerotheriida). AB - The presence of a swinging tentorium is a key apomorphy of Myriapoda, but this character has been studied in detail in only few species. Here the tentorium, i.e., the peristomatic skeleton of the preoral chamber, is comparatively studied in three species of the millipede order Sphaerotheriida Brandt, 1833. Since dissections of the fragile tentorial components proved to be difficult, despite the large head size, they were analysed mainly in situ via micro-computed tomography. Our results confirm previous observations of large differences in the tentorial construction in the giant pill-millipedes compared to chilognathan diplopods. The tentorium of Sphaerotheriida consists of a curved, plate-like epipharyngeal bar with distal projections, an elongate and thin hypopharyngeal bar, and a plate-like triangular posterior process; a transverse bar is absent. Only seven muscles attach at the tentorium in giant pill-millipedes, including two antennal muscles and two muscles of the gnathochilarium. Within the order Sphaerotheriida, the composition of the tentorium and its muscular equipment seems to be conserved, except for some variability in the shape of the epipharyngeal bar. As the transverse bar has been considered essential for the mobility of the tentorium in myriapods, its absence in Sphaerotheriida may indicate that their tentorium is not capable of performing a swing. Loss of tentorial mobility may also pertain to the order Glomerida Brandt, 1833, inferred here from the absence of a posterior process. An apparently immobile tentorium in Glomerida and Sphaerotheriida can straightforwardly be correlated with transformations of the head related to their ability of volvation. The different transformations of the tentorium, here hypothesised to cause immobility, may support current assumptions that the ability of volvation evolved convergently in Glomerida and Sphaerotheriida. This conclusion, however, still requires more detailed studies of the head anatomy in Glomerida and Glomeridesmida Cook, 1895. PMID- 29706775 TI - Four new species of the Glyphiulus javanicus group from southern China (Diplopoda, Spirostreptida, Cambalopsidae). AB - Hitherto, 24 species of the Glyphiulus javanicus group have been recorded, all endemic to Southeast Asia, including 14 in China. Nevertheless, this species group needs further exploration. In this context, four new species of this group are described, all collected from limestone caves in Southern China: G. calceussp. n., G. foetidussp. n., G. guangnanensissp. n., and G. impletussp. n. They can be separated easily from each other and other congeners by their carinotaxic formulae, the structures of male legs I, and the gonopods. Due to the absence of any troglomorphic traits in our specimens, they may be troglophilic only. PMID- 29706777 TI - Lithobius (Ezembius) tetraspinus, a new species of centipede from northwest China (Lithobiomorpha, Lithobiidae). AB - Lithobius (Ezembius) tetraspinus sp. n. (Lithobiomorpha: Lithobiidae), recently discovered from Hami City, Xinjiang Autonomous Region, NW China, is described. Morphologically this species resembles L. (E.) sibiricus, Gersfeldt, 1858, but is distinguishable by a different coxal pore formula, absence of accessory spurs on leg 15, morphology of the second article of the female gonopod, and legs 14 plectrotaxy. A table of the main morphological characters of Chinese Lithobius (Ezembius) species is presented. PMID- 29706776 TI - Hessebius luculentus, a new species of the genus Hessebius Verhoeff, 1941 from China (Lithobiomorpha, Lithobiidae). AB - Hessebius luculentussp. n. (Lithobiomorpha: Lithobiidae), recently discovered from Shandan County, Zhangye City, Province Gansu, Qinghai-Tibet Plateau, China, is described. Morphologically it resembles H. jangtseanus (Verhoeff, 1942), but can be easily distinguished from the latter by size of Tomosvary's organ's, the morphological characters of a protuberance on the dorsal end of the second article of the female gonopods; and obvious differences in the dorsal plectrotaxy of both the 14th and 15th legs. The main morphological characters and a key to the known Chinese species of genus Hessebius based on adult specimens are presented. PMID- 29706778 TI - Millipede and centipede assemblages on the northern and southern slopes of the lowland Altais, southwestern Siberia, Russia (Diplopoda, Chilopoda). AB - The total species richness in the myriapod assemblages of the lowland Altais near Charyshskoe Village, Altai Province, southwestern Siberia, Russia is estimated to be at least 19 species from ten genera, eight families, five orders, and two classes. The following species are new to SW Siberia: Lithobius (Ezembius) ostiacorum Stuxberg, 1876, L. vagabundus Stuxberg, 1876, and L. (Monotarsobius) nordenskioeldii Stuxberg, 1876, while L. (E.) proximus Sseliwanoff, 1880 and L. (M.) insolens Danyi & Tuf, 2012 are recorded for the first time from the Altai Province of Russia. A species of Strigamia which is morphologically similar to Strigamia cf. transsilvanica (Verhoeff, 1928) has been found in the study area but its true specific identity is yet to be determined. The seasonal dynamics of myriapod assemblages in terms of the species diversity, density, sex-age structure, and vertical distribution along the soil profile have been studied with regard to the different slope exposures. PMID- 29706779 TI - Why be red listed? Threatened Myriapoda species in Brazil with implications for their conservation. AB - The biodiversity crisis we live in, marked by high extinction rates, requires well-planned conservation efforts. To overcome this issue, red lists of threatened species are recognized as the main objective approach for evaluating the conservation status of species and therefore guiding conservation priorities. This work focuses on the Myriapoda (Chilopoda and Diplopoda) species listed in the Brazilian red list of fauna to enable discussion of the practical implications of red lists for conservation. Almost all myriapods assessed are endemic to Brazil (99 %) and 73 % are known from subterranean habitats only. Despite of 33 % being recorded from protected areas (PAs), downgrading, degazettement or downsizing of PAs and intense and unregulated ecotourism represent great threats. The PAs network in Brazil tends to fail in conserving myriapod species. The number of data deficient species (42 %) states the need of investing in ecological and taxonomic studies about the group, in order to fill in important knowledge gaps in species assessments nationally and globally. In this work we show that there is a lack of communication between national and global agencies concerning red lists, which results in a significant loss for science and for conservation. Despite investing in national and state red lists, individual countries must take the final step of submitting its data to IUCN global database, as significant international funding is available for IUCN red listed species conservation. Being one of the most diverse countries in the world, and facing the biggest cuts ever on national science funding, losing these important funding opportunities is a huge loss for Brazilian biodiversity conservation and for science. This study raises awareness on subterranean habitats conservation, due to its high endemism and fragility. Since the first edition of the Brazilian Red List in 1968, centipedes are now included for the first time, and millipedes for the second time. The presence of these myriapods in the list brings attention to the group, which usually receives little or no attention in conservation programs and environmental impact assessments. Rather than a specific case for Myriapoda and for Brazil, the points discussed here can be related to arthropods and the tropics, as the most biodiverse countries are emerging economies facing similar challenges in PAs network management, species extinction risks and science funding. PMID- 29706780 TI - VIRMISCO - The Virtual Microscope Slide Collection. AB - Digitisation allows scientists rapid access to research objects. For transparent to semi-transparent three-dimensional microscopic objects, such as microinvertebrates or small body parts of organisms, available databases are scarce. Most mounting media used for permanent microscope slides deteriorate after some years or decades, eventually leading to total damage and loss of the object. However, restoration is labour-intensive, and often the composition of the mounting media is not known. A digital preservation of important material, especially types, is important and an urgent need. The Virtual Microscope Slide Collection - VIRMISCO project has developed recommendations for taking microscopic image stacks of three-dimensional objects, depositing and presenting such series of digital image files or z-stacks as an online platform. The core of VIRMISCO is an online viewer, which enables the user to virtually focus through an object online as if using a real microscope. Additionally, VIRMISCO offers features such as search, rotating, zooming, measuring, changing brightness or contrast, taking snapshots, leaving feedback as well as downloading complete z stacks as jpeg files or video file. The open source system can be installed by any institution and can be linked to common database or images can be sent to the Senckenberg Museum of Natural History Gorlitz. The benefits of VIRMISCO are the preservation of important or fragile material, to avoid loan, to act as a digital archive for image files and to allow determination by experts from the distance, as well as providing reference libraries for taxonomic research or education and providing image series as online supplementary material for publications or digital vouchers of specimens of molecular investigations are relevant applications for VIRMISCO. PMID- 29706781 TI - A new species of Neopanorpa with an extremely long notal organ from Sichuan, China (Mecoptera, Panorpidae). AB - Neopanorpa setigerasp. n. is described and illustrated from Sichuan, China. It is characterized by an extremely long notal process, a well-developed postnotal organ, and a pair of setiferous gonostyli. This is the second species of Neopanorpa van der Weele with an extremely long notal organ in Sichuan. A key to Sichuan species of Neopanorpa is provided. PMID- 29706782 TI - Two new species of the genus Xanthochlorus from China (Diptera, Dolichopodidae, Xanthochlorinae). AB - The subfamily Xanthochlorinae comprises a single genus Xanthochlorus, and is rare in collections. Previously, there were four known species in the genus Xanthochlorus from China. In this paper, the species of the Xanthochlorus from China are reviewed. The following two species from Gansu Province of China are described as new to science: Xanthochlorus gansuensissp. n. and Xanthochlorus tewoensissp. n. A key to species of the Xanthochlorus from China is provided. PMID- 29706783 TI - Colobopsis explodens sp. n., model species for studies on "exploding ants" (Hymenoptera, Formicidae), with biological notes and first illustrations of males of the Colobopsis cylindrica group. AB - A taxonomic description of all castes of Colobopsis explodens Laciny & Zettel, sp. n. from Borneo, Thailand, and Malaysia is provided, which serves as a model species for biological studies on "exploding ants" in Southeast Asia. The new species is a member of the Colobopsis cylindrica (COCY) group and falls into a species complex that has been repeatedly summarized under the name Colobopsis saundersi (Emery, 1889) (formerly Camponotus saundersi). The COCY species group is known under its vernacular name "exploding ants" for a unique behaviour: during territorial combat, workers of some species sacrifice themselves by rupturing their gaster and releasing sticky and irritant contents of their hypertrophied mandibular gland reservoirs to kill or repel rivals. This study includes first illustrations and morphometric characterizations of males of the COCY group: Colobopsis explodens Laciny & Zettel, sp. n. and Colobopsis badia (Smith, 1857). Characters of male genitalia and external morphology are compared with other selected taxa of Camponotini. Preliminary notes on the biology of C. explodens Laciny & Zettel, sp. n. are provided. To fix the species identity of the closely related C. badia, a lectotype from Singapore is designated. The following taxonomic changes within the C. saundersi complex are proposed: Colobopsis solenobia (Menozzi, 1926), syn. n. and Colobopsis trieterica (Menozzi, 1926), syn. n. are synonymized with Colobopsis corallina Roger, 1863, a common endemic species of the Philippines. Colobopsis saginata Stitz, 1925, stat. n., hitherto a subspecies of C. badia, is raised to species level. PMID- 29706784 TI - Madicolous Chironomidae from the Brazilian Atlantic Forest: a checklist with notes on altitudinal distributions (Diptera, Insecta). AB - Thin layers of water running over rocky surfaces are characteristic of madicolous habitats, which harbor a peculiar Chironomidae community. However, information on the identity, distribution, and ecology of madicolous chironomids in the Neotropical region are still sparse. The main purpose of this research is to reveal and contribute to the ecology of madicolous Chironomidae species, especially regarding their altitudinal distribution in the Atlantic Forest. Sampling was performed using our own designed emergence traps deployed from 0 to 2700 m a.s.l. in 70 sites in three mountains in southeastern Brazil. Sixty taxa of chironomids were collected and identified, of which only 22 are known to science. Most of the species showed a wider distribution than previously known, both in terms of geographic and altitudinal ranges, while others showed significant association with particular altitudinal bands (as evidenced by the indicator species analysis). Atlantic Forest mountainous regions are known to harbor one of the richest fauna in the world and have been suffering from several types of environmental impacts, including climate change, which will especially affect taxa living in specialized habitats. The narrow range of tolerance to environmental conditions verified for mountain species, and the fact that many of them are rare and endemic, make the conservation efforts in these areas indispensable. PMID- 29706785 TI - New species of the genus Mesocletodes Sars, 1909 from the deep Gulf of California (Copepoda, Harpacticoida). AB - Investigations on the effects of the oxygen minimum zone on the distribution, abundance, and diversity of deep-sea benthic and pelagic fauna of the Gulf of California and Eastern Tropical Pacific has received attention recently. However, very little is known about the diversity of deep-sea benthic harpacticoids from this region, and only three species, Ancorabolus hendrickxi Gomez & Conroy Dalton, 2002, Ceratonotus elongatus Gomez & Diaz, 2017 and Dendropsyllus californiensis Gomez & Diaz, 2017, have been described so far. The genus Mesocletodes Sars, 1909 is one of the most common and abundant genera of deep-sea harpacticoids. This genus has been traditionally subdivided into two species groups, the abyssicola and the inermis groups, based on the presence/absence of a dorsal cuticular process on the cephalothorax and anal somite, but some species have been reported to deviate from this scheme. As a result of their investigations, other researchers proposed the monophyly of the abyssicola group, and suggested the probable monophyly of two other species-groups. In this paper, the descriptions of three new species of the genus Mesocletodes from the deep sea of the Gulf of California are presented with some notes on their relationships with other species. Some comments on the monophyly of the genus are given. PMID- 29706786 TI - The hidden Heuchera: How science Twitter uncovered a globally imperiled species in Pennsylvania, USA. AB - The genus Heuchera is recognized as one of the most diverse endemic radiations of Saxifragaceae in North America, yet species delimitation and geographic distribution within the group remain controversial. Many species remain difficult to identify, including Heuchera alba, a narrow Appalachian endemic and globally imperiled (G2) taxon recorded only from West Virginia and Virginia that occurs in sympatry with H. pubescens and H. americana. A recent survey of the cliffside flora of the Shikellamy Bluffs, PA recorded dozens of Heuchera individuals that, through the use of social media, were positively identified as H. alba. Aided by examination of historical herbarium records, subsequent searches of similar habitats in Pennsylvania led to the discovery of seven more populations and established a significant range expansion for this rare species. The uncovering of H. alba in Pennsylvania is an exciting conservation outcome and an example of what can happen when botanists embrace a combination of modern and classical approaches to discovery and collaboration. PMID- 29706787 TI - Two new Phlegmariurus species (Lycopodiaceae) and one new combination from Peninsular Malaysia. AB - Two new species, Phlegmariurus iminii Kiew (Lycopodiaceae) from limestone karst and P. monticola Kiew from montane habitats, are described from Peninsular Malaysia and a new combination is made for Phlegmariurus pinifolius (Trevis.) Kiew. Phlegmariurus iminii, known from a single hill threatened by quarrying, is Critically Endangered; while P. monticola and P. pinifolius that are relatively widespread are of Least Concern. PMID- 29706788 TI - Staying cool: preadaptation to temperate climates required for colonising tropical alpine-like environments. AB - Plant species tend to retain their ancestral ecology, responding to temporal, geographic and climatic changes by tracking suitable habitats rather than adapting to novel conditions. Nevertheless, transitions into different environments or biomes still seem to be common. Especially intriguing are the tropical alpine-like areas found on only the highest mountainous regions surrounded by tropical environments. Tropical mountains are hotspots of biodiversity, often with striking degrees of endemism at higher elevations. On these mountains, steep environmental gradients and high habitat heterogeneity within small spaces coincide with astounding species diversity of great conservation value. The analysis presented here shows that the importance of in situ speciation in tropical alpine-like areas has been underestimated. Additionally and contrary to widely held opinion, the impact of dispersal from other regions with alpine-like environments is relatively minor compared to that of immigration from other biomes with a temperate (but not alpine-like) climate. This suggests that establishment in tropical alpine-like regions is favoured by preadaptation to a temperate, especially aseasonal, freezing regime such as the cool temperate climate regions in the Tropics. Furthermore, emigration out of an alpine-like environment is generally rare, suggesting that alpine-like environments - at least tropical ones - are species sinks. PMID- 29706789 TI - Species conservation profile of moths (Insecta, Lepidoptera) from Azores, Portugal. AB - Background: The few remnants of Azorean native forests harbour a unique set of endemic moths (Insecta, Lepidoptera), some of them under severe long term threats due to small sized habitats or climatic changes. In this contribution, we present the IUCN Red List profiles of 34 endemic moths to the Azorean archipelago, including species belonging to two diverse families: Noctuidae (11 species) and Crambidae (eight species). The objective of this paper is to assess all endemic Azorean moth species and advise on possible future research and conservation actions critical for the long-trem survival of the most endangered species. New information: Most species have a large distribution (i.e. 58% occur in at least four islands), very large extent of occurrence (EOO) and a relatively large area of occupancy (AOO). Only nine species are single-island endemics, three of them from Flores, three from Sao Miguel and one from Pico, Sao Jorge and Faial. Most of the species also experience continuing decline in habitat quality, number of locations and subpopulations caused by the ongoing threat from pasture intensification, forestry, invasive plant species and future climatic changes. The lack of new records may indicate that one of the species previously named is extinct (Eupithecia ogilviata). Therefore, we suggest as future conservation actions: (1) a long-term species monitoring plan and (2) control of invasive species. PMID- 29706790 TI - Ceraphron krogmanni (Hymenoptera: Ceraphronidae), a new species from Lower Saxony with unusual male genitalia. AB - Background: Male genitalia phenotypes of Ceraphron (Jurine, 1807) are informative for species delimitation, but due to their minute size, these characters have not been used extensively. Recent developments in visualisation techniques, e.g. confocal laser scanning microscopy and high resolution bright field imaging, allow for more thorough examination of these minute anatomical structures and the development of a robust, male genitalia-based taxonomic system. We also establish a character set, a template, that will facilitate future revisions of these wasps. New information: Ceraphron krogmanni sp. nov. is described with outsized male genitalia and multiple diagnostic traits that are unique amongst Ceraphron species. PMID- 29706791 TI - The lichens of the Alps - an annotated checklist. AB - This is the first attempt to provide an overview of the lichen diversity of the Alps, one of the biogegraphically most important and emblematic mountain systems worldwide. The checklist includes all lichenised species, plus a set of non- or doubtfully lichenised taxa frequently treated by lichenologists, excluding non lichenised lichenicolous fungi. Largely based on recent national or regional checklists, it provides a list of all infrageneric taxa (with synonyms) hitherto reported from the Alps, with data on their distribution in eight countries (Austria, France, Germany, Liechtenstein, Monaco, Italy, Slovenia, Switzerland) and in 42 Operational Geographic Units, mostly corresponding to administrative subdivisions within the countries. Data on the main substrates and on the altitudinal distribution are also provided. A short note points to the main ecological requirements of each taxon and/or to open taxonomic problems. Particularly poorly known taxa are flagged and often provided with a short description, to attract the attention of specialists. The total number of infrageneric taxa is 3,163, including 117 non- or doubtfully lichenised taxa. The richness of the lichen biota fairly well corresponds with the percent of the Alpine area occupied by each country: Austria (2,337 taxa), Italy (2,169), France (2,028), Switzerland (1,835), Germany (1,168), Slovenia (890) and Lichtenstein (152), no lichen having ever been reported from Monaco. The number of poorly known taxa is quite high (604, 19.1% of the total), which indicates that, in spite of the Alps being one of the lichenologically most studied mountain systems worldwide, much work is still needed to reach a satisfactory picture of their real lichen diversity. Thirteen new combinations are proposed in the genera Agonimia, Aspicilia, Bagliettoa, Bellemerea, Carbonea, Lepra, Miriquidica, Polysporina, Protothelenella, Pseudosagedia and Thelidium. PMID- 29706792 TI - Distribution and depth of bottom-simulating reflectors in the Nankai subduction margin. AB - Surface heat flow has been observed to be highly variable in the Nankai subduction margin. This study presents an investigation of local anomalies in surface heat flows on the undulating seafloor in the Nankai subduction margin. We estimate the heat flows from bottom-simulating reflectors (BSRs) marking the lower boundaries of the methane hydrate stability zone and evaluate topographic effects on heat flow via two-dimensional thermal modeling. BSRs have been used to estimate heat flows based on the known stability characteristics of methane hydrates under low-temperature and high-pressure conditions. First, we generate an extensive map of the distribution and subseafloor depths of the BSRs in the Nankai subduction margin. We confirm that BSRs exist at the toe of the accretionary prism and the trough floor of the offshore Tokai region, where BSRs had previously been thought to be absent. Second, we calculate the BSR-derived heat flow and evaluate the associated errors. We conclude that the total uncertainty of the BSR-derived heat flow should be within 25%, considering allowable ranges in the P-wave velocity, which influences the time-to-depth conversion of the BSR position in seismic images, the resultant geothermal gradient, and thermal resistance. Finally, we model a two-dimensional thermal structure by comparing the temperatures at the observed BSR depths with the calculated temperatures at the same depths. The thermal modeling reveals that most local variations in BSR depth over the undulating seafloor can be explained by topographic effects. Those areas that cannot be explained by topographic effects can be mainly attributed to advective fluid flow, regional rapid sedimentation, or erosion. Our spatial distribution of heat flow data provides indispensable basic data for numerical studies of subduction zone modeling to evaluate margin parallel age dependencies of subducting plates. PMID- 29706793 TI - An algorithm to correct saturated mass spectrometry ion abundances for enhanced quantitation and mass accuracy in omic studies. AB - The mass accuracy and peak intensity of ions detected by mass spectrometry (MS) measurements are essential to facilitate compound identification and quantitation. However, high concentration species can yield erroneous results if their ion intensities reach beyond the limits of the detection system, leading to distorted and non-ideal detector response (e.g. saturation), and largely precluding the calculation of accurate m/z and intensity values. Here we present an open source computational method to correct peaks above a defined intensity (saturated) threshold determined by the MS instrumentation such as the analog-to digital converters or time-to-digital converters used in conjunction with time-of flight MS. In this method, the isotopic envelope for each observed ion above the saturation threshold is compared to its expected theoretical isotopic distribution. The most intense isotopic peak for which saturation does not occur is then utilized to re-calculate the precursor m/z and correct the intensity, resulting in both higher mass accuracy and greater dynamic range. The benefits of this approach were evaluated with proteomic and lipidomic datasets of varying complexities. After correcting the high concentration species, reduced mass errors and enhanced dynamic range were observed for both simple and complex omic samples. Specifically, the mass error dropped by more than 50% in most cases for highly saturated species and dynamic range increased by 1-2 orders of magnitude for peptides in a blood serum sample. PMID- 29706794 TI - Local-duality QCD sum rules for strong isospin breaking in the decay constants of heavy-light mesons. AB - We discuss the leptonic decay constants of heavy-light mesons by means of Borel QCD sum rules in the local-duality (LD) limit of infinitely large Borel mass parameter. In this limit, for an appropriate choice of the invariant structures in the QCD correlation functions, all vacuum-condensate contributions vanish and all nonperturbative effects are contained in only one quantity, the effective threshold. We study properties of the LD effective thresholds in the limits of large heavy-quark mass [Formula: see text] and small light-quark mass [Formula: see text]. In the heavy-quark limit, we clarify the role played by the radiative corrections in the effective threshold for reproducing the pQCD expansion of the decay constants of pseudoscalar and vector mesons. We show that the dependence of the meson decay constants on [Formula: see text] arises predominantly (at the level of 70-80%) from the calculable [Formula: see text]-dependence of the perturbative spectral densities. Making use of the lattice QCD results for the decay constants of nonstrange and strange pseudoscalar and vector heavy mesons, we obtain solid predictions for the decay constants of heavy-light mesons as functions of [Formula: see text] in the range from a few to 100 MeV and evaluate the corresponding strong isospin-breaking effects: [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text]. PMID- 29706795 TI - Experimental search for the violation of Pauli exclusion principle: VIP-2 Collaboration. AB - The VIolation of Pauli exclusion principle -2 experiment, or VIP-2 experiment, at the Laboratori Nazionali del Gran Sasso searches for X-rays from copper atomic transitions that are prohibited by the Pauli exclusion principle. Candidate direct violation events come from the transition of a 2p electron to the ground state that is already occupied by two electrons. From the first data taking campaign in 2016 of VIP-2 experiment, we determined a best upper limit of [Formula: see text] for the probability that such a violation exists. Significant improvement in the control of the experimental systematics was also achieved, although not explicitly reflected in the improved upper limit. By introducing a simultaneous spectral fit of the signal and background data in the analysis, we succeeded in taking into account systematic errors that could not be evaluated previously in this type of measurements. PMID- 29706796 TI - Measuring extended families over time in informal settlements in Nairobi, Kenya: Retention and data consistency in a two-round survey. AB - BACKGROUND: Researchers have increasingly turned to longitudinal data to understand how the family environment of children changes over time and how this change affects their well-being. While the value of such efforts is clear, the inherent challenges of collecting robust data over time may limit or bias our understanding of family complexity. OBJECTIVE: Drawing on data from an exploratory study on kinship structure and support for low income single mothers and their young children in Nairobi, Kenya, this paper aims to (1) assess the strengths and weaknesses of our approach in reflecting the complexities of kinship dynamics and (2) analyze how methodological issues such as selection and reporting inconsistency can influence our understanding of the role of kin in children's lives. METHODS: The analysis used data from two waves of the Kinship Support Tree (KST) project. The starting sample consisted of 462 single mothers with at least one child under the age of 7, with data collected on approximately 5,000 resident and nonresident kin. Descriptive statistics and conventional tests of significance were used to analyze selection factors and inconsistencies in reporting across waves. RESULTS: The study yielded a 91% retention rate after six months and the analysis provides some assurance that selectivity from attrition and reporting inconsistency are not entirely driven by shifts in support provision by kin. However, the selectivity of the sample underscores caution in generalizing the results. CONCLUSIONS: While the challenges of conducting follow up surveys such as the KST are serious, these findings suggest that it is possible to collect consistent data on kinship structure and support from the perspective of children in a mobile population. Tracking kinship structure over time using the KST is not only feasible but more importantly is unlikely to lead to incomplete or biased understanding of kinship. CONTRIBUTION: After further testing with a wider range of women, we hope to disseminate our results for use in a wide range of contexts both in and out of Africa. We believe this data is vital to designing appropriate interventions to improve the well-being of children growing up in these communities. PMID- 29706797 TI - Hosting Non-University Guests and Party-Related Drinking Behaviors of College Students. AB - Background: Hosting non-university guests is common among college students, especially during sports and traditional party weekends. However, the effect of non-university guests - a common social reference group - on host-students' drinking behaviors is not well understood. Method: Data was drawn from a cross sectional survey conducted at a public Midwestern university (N=2,951; Mage=20 years) from 2005-2007. Results: Participants who hosted non-university guests tended to be younger in age, male, of white racial background, members of athletic teams, had younger ages of drinking onset, and were more likely to reside off-campus as compared to non-hosts. Host-students also had significantly elevated risk for engaging in heavy party-related drinking while hosting non university guests, and were more likely to report similar risky drinking behaviors among other party-attendees. Conclusions: Preliminary evidence from this study suggests that college-based prevention efforts would benefit from specifically targeting students who are more likely to host non-university guests. PMID- 29706798 TI - Rooming-in Reduces Salivary Cortisol Level of Newborn. AB - Background: Rooming-in practice improves breastfeeding and reduces newborn stress reactivity. When this modality is not available, partial rooming-in after birth can be considered. Salivary cortisol levels (SCLs) are considered reliable biomarkers to indicate stress. Objective: To test the hypothesis that rooming-in duration impacts neonatal stress response in hospitalized newborns. Design/methods: Forty term newborns, enrolled in the Neonatology and Obstetrics Nursing, C.G. Ruesch, Naples, Italy, were divided, according to the mother's choice, into the study (SG; n = 20) and control (CG; n = 20) groups if they received full (24 hs) or partial (14 hs) rooming-in care, respectively. Saliva samples were collected from all babies between 7:00 a.m. and 8:00 a.m. of the 3rd day of life by using oral swab. Salivary cortisol levels were measured using an enzyme immunoassay kit (Salimetrics LLC, PA, USA). Results: A statistically significant difference in the SCLs between SG and CG was found (median: 258 ng/dl versus 488.5 ng/dl; p = 0.048). Conclusions: Data support the practice of full rooming-in care compared with partial rooming-in. The rooming-in duration clearly reduces SCLs and likely neonatal stress. These lower SCLs may have long-term positive effects reducing the risk of metabolic syndrome, high blood pressure, and cognitive and behavioural changes. PMID- 29706799 TI - Recent Advances in the Molecular Mechanisms Underlying Pyroptosis in Sepsis. AB - Sepsis is recognized as a life-threatening organ dysfunctional disease that is caused by dysregulated host responses to infection. Up to now, sepsis still remains a dominant cause of multiple organ dysfunction syndrome (MODS) and death among severe condition patients. Pyroptosis, originally named after the Greek words "pyro" and "ptosis" in 2001, has been defined as a specific programmed cell death characterized by release of inflammatory cytokines. During sepsis, pyroptosis is required for defense against bacterial infection because appropriate pyroptosis can minimize tissue damage. Even so, pyroptosis when overactivated can result in septic shock, MODS, or increased risk of secondary infection. Proteolytic cleavage of gasdermin D (GSDMD) by caspase-1, caspase-4, caspase-5, and caspase-11 is an essential step for the execution of pyroptosis in activated innate immune cells and endothelial cells stimulated by cytosolic lipopolysaccharide (LPS). Cleaved GSDMD also triggers NACHT, LRR, and PYD domain containing protein (NLRP) 3-mediated activation of caspase-1 via an intrinsic pathway, while the precise mechanism underlying GSDMD-induced NLRP 3 activation remains unclear. Hence, this study provides an overview of the recent advances in the molecular mechanisms underlying pyroptosis in sepsis. PMID- 29706801 TI - Lactate as a Potential Biomarker of Sepsis in a Rat Cecal Ligation and Puncture Model. AB - We attempted to investigate whether blood lactate is a useful biomarker for sepsis in a rat cecal ligation and puncture (CLP) model. Male Sprague-Dawley rats underwent approximately 75% cecum ligation and two punctures to induce high-grade sepsis. A lactate of 1.64 mmol/L (Youden score of 0.722) was selected as the best cutoff value to predict the onset of sepsis after CLP exposure; 46 of 50 rats who survived 24 hours after the CLP were divided into the L group (lactate < 1.64 mmol/L) and M group (lactate >= 1.64 mmol/L). In the M group, the animals had significantly higher murine sepsis scores and none survived 5 days post-CLP, and the rate of validated septic animals, serum procalcitonin, high mobility group box 1, blood urea nitrogen, alanine transaminase, cardiac troponin I, and the wet to-dry weight ratio were significantly higher compared to the L group. Worsen PaO2/FiO2, microcirculations, and mean arterial pressure were observed in the M group. More severe damage in major organs was confirmed by histopathological scores in the M group compared with the L group. In conclusion, lactate >= 1.64 mmol/L might serve as a potential biomarker to identify the onset of sepsis in a rat CLP model. PMID- 29706800 TI - The Role of Immunosenescence in Neurodegenerative Diseases. AB - Aging is characterized by the progressive decline of physiological function and tissue homeostasis leading to increased vulnerability, degeneration, and death. Aging-related changes of the innate and adaptive immune system include decline in the preservation and enhancement of many immune functions, such as changes in the number of circulating monocytic and dendritic cells, thymic involution, T cell polyfunctionality, or production of proinflammatory cytokines, and are defined as immunosenescence. Inflammatory functions are increased with age, causing the chronic low-grade inflammation, referred to as inflamm-aging, that contribute, together with immunosenescence, to neurodegenerative diseases. In this review, we discuss the link between the immune and nervous systems and how the immunosenescence and inflamm-aging can contribute to neurodegenerative diseases. PMID- 29706802 TI - The Trans Pacific Partnership Agreement, intellectual property and medicines: Differential outcomes for developed and developing countries. AB - The final text of the Trans Pacific Partnership Agreement (TPP), agreed between the 12 negotiating countries in 2016, included a suite of intellectual property provisions intended to expand and extend pharmaceutical company exclusivities on medicines. It drew wide criticism for including such provisions in an agreement that involved developing countries (Vietnam, Peru, Malaysia, Mexico, Chile and Brunei Darussalam) because of the effect on delaying the introduction of low-cost generics. While developing nations negotiated transition periods for implementing some obligations, all parties would have eventually been expected to meet the same standards had the TPP come into force. While the TPP has stalled following US withdrawal, there are moves by some of the remaining countries to reinvigorate the agreement without the United States. The proponents may seek to retain as much as possible of the original text in the hope that the United States will re join the accord in future. This article presents a comparative analysis of the impact the final 2016 TPP intellectual property chapter could be expected to have (if implemented in its current form) on the intellectual property laws and regulatory regimes for medicines in the TPP countries. Drawing on the published literature, it traces the likely impact on access to medicines. It focuses particularly on the differential impact on regulatory frameworks for developed and developing nations (in terms of whether or not legislative action would have been required to implement the agreement). The article also explores the political and economic dynamics that contributed to these differential outcomes. PMID- 29706803 TI - Why are social sciences and humanities needed in the works of IPBES? A systematic review of the literature. AB - Despite the increased attention, which has been given to the issue of involving knowledge and experts from the social sciences and humanities (SSH) into the products and works of the Intergovernmental Science-Policy Platform on Biodiversity and Ecosystem Services (IPBES), little is known on what the expectations towards the involvement of SSH in IPBES actually are. The aim of this paper is to close this gap by identifying the range of possible SSH contributions to IPBES that are expected in the literature, and discuss the inherent challenges of and concrete ways to realize these contributions in the particular institutional setting of IPBES. We address these two points by: firstly, assessing the literature dealing with IPBES and building a typology describing the main ways in which contributions from SSH to IPBES have been conceived between 2006 and 2017. We discuss these expected contributions in light of broader debates on the role of SSH in nature conservation and analyse some of the blind spots and selectivities in the perception of how SSH could substantially contribute to the works of IPBES. Then, secondly, by looking at one particular example, economics and its use in the first thematic assessment on pollinators, pollination and food production, we will concretely illustrate how works in a given discipline could contribute in many different and unprecedented ways to the works of IPBES and help identify paths for enhancing the conservation of biodiversity. Finally, we propose a range of practical recommendations as to how to increase the contribution of SSH in the works of IPBES. PMID- 29706804 TI - Building a potential wetland restoration indicator for the contiguous United States. AB - Wetlands provide key functions in the landscape from improving water quality, to regulating flows, to providing wildlife habitat. Over half of the wetlands in the contiguous United States (CONUS) have been converted to agricultural and urban land uses. However, over the last several decades, research has shown the benefits of wetlands to hydrologic, chemical, biological processes, spurring the creation of government programs and private initiatives to restore wetlands. Initiatives tend to focus on individual wetland creation, yet the greatest benefits are achieved when strategic restoration planning occurs across a watershed or multiple watersheds. For watershed-level wetland restoration planning to occur, informative data layers on potential wetland areas are needed. We created an indicator of potential wetland areas (PWA), using nationally available datasets to identify characteristics that could support wetland ecosystems, including: poorly drained soils and low-relief landscape positions as indicated by a derived topographic data layer. We compared our PWA with the National Wetlands Inventory (NWI) from 11 states throughout the CONUS to evaluate their alignment. The state-level percentage of NWI-designated wetlands directly overlapping the PWA ranged from 39 to 95%. When we included NWI that was immediately adjacent to the overlapping NWI, our range of correspondence to NWI ranged from 60 to 99%. Wetland restoration is more likely on certain landscapes (e.g., agriculture) than others due to the lack of substantive infrastructure and the potential for the restoration of hydrology; therefore, we combined the National Land Cover Dataset (NLCD) with the PWA to identify potentially restorable wetlands on agricultural land (PRW-Ag). The PRW-Ag identified a total of over 46 million ha with the potential to support wetlands. The largest concentrations of PRW-Ag occurred in the glaciated corn belt of the upper Mississippi River from Ohio to the Dakotas and in the Mississippi Alluvial Valley. The PRW-Ag layer could assist land managers in identifying sites that may qualify for enrollment in conservation programs, where planners can coordinate restoration efforts, or where decision makers can target resources to optimize the services provided across a watershed or multiple watersheds. PMID- 29706805 TI - Comparison of outcomes in patients with intracranial hemorrhage on factor Xa inhibitors versus vitamin K antagonists treated with 4-factor prothrombin complex concentrate. AB - The relative clinical efficacy of 4-factor prothrombin complex concentrate (4F PCC) in oral anticoagulant-associated intracranial hemorrhage is unknown, especially for factor Xa-inhibiting anticoagulants. We report short-term outcomes of patients with oral anticoagulant-associated intracranial hemorrhage on vitamin K antagonists and factor Xa inhibitors who were treated with 4F-PCC. This multicenter, observational study involved patients presenting to the emergency department in nine hospitals in an integrated health care delivery system in Texas between July 2013 and December 2015. Forty-two patients diagnosed with oral anticoagulant-associated intracranial hemorrhage-24 taking a vitamin K antagonist and 14 taking a factor Xa inhibitor-were treated with 4F-PCC as part of usual care. Study patients had similar baseline demographics, with the exception of suspected etiology of hemorrhage. Outcomes of the vitamin K antagonist group were similar to those of the factor Xa inhibitor group, with no significant differences in overall in-hospital mortality (32.1% vs 14.2%, respectively), length of stay, or rates of hemorrhagic expansion, thromboembolism, or discharge to home. In conclusion, this small sample of patients with oral factor Xa inhibitor and vitamin K antagonist-associated intracranial hemorrhage treated with 4F-PCC had similar mortality and neurological outcomes, with no venous thromboembolic events. PMID- 29706806 TI - Factors associated with emergency room visits within 30 days of outpatient foot and ankle surgeries. AB - The number of emergency department (ED) visits within 30 days after elective surgery has been utilized as a quality measure by many institutions. The significance of the measure as a postoperative complication in foot and ankle surgery, and risk factors for it, are unknown. We conducted a retrospective cohort study involving 386 patients to determine risk factors associated with ED visits after outpatient foot and ankle surgeries. After adjusting for clinically relevant covariates, we found that previous ED visits within 6 months of surgery, and nonelective surgeries were associated with the postoperative ED visit. Having private insurance was protective against postoperative ED visits. Though these risk factors may not be easily modifiable by surgeons, understanding them may improve patient education and transitional care to prevent overcrowding of the ED. PMID- 29706807 TI - Frequency of psychological distress in gynecologic cancer patients seen in a large urban medical center. AB - Psychological distress in cancer is a well-documented phenomenon, but additional information is needed about demographic and disease correlates in diverse populations with different forms of cancer. This study focused on gynecologic cancers. Using the Distress Thermometer and the Hospital Anxiety and Depression Scale, this study examined distress levels in 94 women with gynecologic cancer who were being treated as outpatients at a large urban medical center. The distress levels in this sample were lower than in comparable studies, raising questions about openness to reporting distress. Those who reported higher levels of distress were more likely to also report a mental health diagnosis or psychiatric medication. This suggests that an alternate form for distress screening may involve inquiring about mental health treatment. In this sample, younger women and those with higher educational achievement or private health insurance had higher levels of distress. Conversely, there were no relations between distress levels and disease characteristics, indicating that, for example, women with early stage disease have just as much risk of distress as those with later-stage disease. PMID- 29706808 TI - Time trends for bacterial species and resistance patterns in semen in patients undergoing evaluation for male infertility. AB - Semen from asymptomatic men who are being evaluated as male partners in interfile couples have been reported to contain a variety of bacteria. Longitudinal studies of the variation of these bacteria over time and their resistance patterns have not been commonly reported. At our institution, residues from semen samples are routinely evaluated for bacteria, including antibiotic sensitivity profiles. We set out to profile the changes in semen bacteria and antibiotic resistance at our institution over time. A total of 72 semen isolates were examined for type of bacteria and sensitivity to a panel of antibiotics. The results were divided into two separate 5-year intervals (the first beginning in 2006, the second in 2011) and compared. The majority of bacteria were skin flora, with Streptococcus and Staphylococcus being the most prevalent. The resistance data for these two pathogens showed minimal statistically significant difference between the two time periods, although the Staphylococcus species did show a trend toward increasing resistance, suggesting that antibiotics currently used in sperm cell preparations may need to be varied. PMID- 29706809 TI - Effect of intravenous infusion dead space on time to drug delivery in infants. AB - Infusion dead space is the internal volume of a catheter and tubing through which a fluid must pass before reaching a patient's intravenous space. It is a factor in time to delivery for intravenous administration and can be significant, depending on the volume and rate of infusion. A 10-kg infant was simulated, receiving an epinephrine infusion with a concentration of 20 mcg/mL at a rate of 0.1 mcg/kg/min, which equals 3 mL/h. Commonly used pediatric intravenous equipment was selected. The tubing was flushed with a dyed solution. The setup was connected to 24- and 22-gauge catheters, with and without extension tubing. Each configuration was tested by allowing the intravenous solution to drip onto chromatography paper until color could be seen. The time from the start of the infusion to the visualization of dye was recorded 10 times for each configuration. The average time was 88 seconds for a 24-gauge catheter and 439 seconds with extension tubing added. For the 22-gauge catheter, the average time was 98 seconds and 431 seconds with extension tubing. Though often considered inconsequential, infusion dead space can cause significant delays in drug administration, especially in small patients and with slow, concentrated infusions. When appropriate, clinicians should consider bolus administration of critical medication before starting an infusion. PMID- 29706810 TI - Novel renal biomarker evaluation for early detection of acute kidney injury after transcatheter aortic valve implantation. AB - Acute kidney injury (AKI) following transcatheter aortic valve implantation (TAVI) is associated with increased morbidity and mortality. The biomarkers neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM 1), and interleukin-18 (IL-18) are predictive of AKI after cardiac surgery, but there is little data regarding these biomarkers after TAVI. We evaluated the associations between NGAL, KIM-1, and IL-18 levels and the incidence and severity of AKI and changes in serum creatinine after TAVI. This was a prospective pilot study of 66 TAVI cases. Urinary biomarkers were measured at baseline and at 2, 4, and 12 hours after TAVI. Demographics, procedural features, and renal function until discharge were compared between patients with and without subsequent AKI. Seventeen patients (25.8%) developed AKI postoperatively (stage 1, n = 14; stage 2, n = 1; stage 3, n = 2). There were no significant differences in unadjusted mean NGAL, KIM-1, and IL-18 levels between patients with and without AKI at 2, 4, and 12 hours following surgery. After adjusting for the Society of Thoracic Surgeons risk of mortality, this study of three urinary biomarkers showed no association with AKI or creatinine after TAVI. Ongoing efforts to predict and modify the risk of AKI after TAVI remain challenging. PMID- 29706811 TI - Use of neuromuscular blocking agents in acute respiratory distress syndrome. AB - Acute respiratory distress syndrome is the result of an acute inflammatory response of the lungs, causing severe hypoxemia. A variety of therapeutic modalities have been extensively studied, with only a few demonstrating improvement in survival. Specifically, mechanical ventilation with use of low tidal volumes, prone positioning, and treatment with neuromuscular blocking agents have proven beneficial. This article focuses on the utilization of neuromuscular blocking agents in this entity. In particular, we briefly review the mechanism of action of neuromuscular blockades, the latest published evidence supporting their use in acute respiratory distress syndrome, and current recommendations for their utilization in clinical practice. PMID- 29706812 TI - Usefulness of alirocumab and evolocumab for the treatment of patients with diabetic dyslipidemia. AB - In 2015, the US Food and Drug Administration (FDA) approved the anti-proprotein convertase subtilsin/kexin type 9 (PCSK9) monoclonal antibodies, alirocumab and evolocumab, to treat patients with hypercholesterolemia and mixed dyslipidemia. Since then, considerable attention has been paid to the use of these monoclonal antibodies for the treatment of diabetic dyslipidemia with a goal of reducing the risk for cardiovascular disease. Recently, consensus statements on the clinical use of PCSK9 inhibitors in patients with type 2 diabetes mellitus, who are unable to achieve the goal of low-density lipoprotein cholesterol (<70 mg/dL or <1.8 mmol/L), have been published by panels of experts in Greece, Europe (European Society of Cardiology and European Atherosclerosis Society Task Force), and the United States (American College of Cardiology Consensus Committee). On December 1, 2017, the FDA approved evolocumab to prevent heart attack, stroke, and coronary revascularization. In this article, we review recent advances concerning the pathophysiology of diabetic dyslipidemia, the physiology of PCSK9, the mechanisms of action of PCSK9 inhibitors, clinical trials examining PCSK9 inhibitors in type 2 diabetes, and perspectives of nonstatin therapy in the treatment of diabetic dyslipidemia. PMID- 29706813 TI - Dramatic change in cerebral oximetry during liver transplantation. AB - We report dramatic changes in bilateral cerebral tissue oxygenation in a patient undergoing an orthotopic liver transplant coincident with clamping and subsequent restoration of flow through the inferior vena cava. Although hemodynamic stability was maintained with low-dose vasopressor support, cardiac output was decreased, suggesting preload dependence of the measured cerebral oxygenation. Further investigation is warranted in patients with end-stage liver disease and interruption of venous return. PMID- 29706814 TI - Proliferative glomerulonephritis with monoclonal immunoglobulin deposits of lambda chains. AB - Increasingly, monoclonal gammopathies of renal significance (MGRS) are being described as unique, distinct disease states. We describe a type of MGRS with proliferative glomerular lesions with monoclonal immunoglobulin deposits of rarely reported IgG2 lambda chains. PMID- 29706815 TI - Acute pancreatitis secondary to hypertriglyceridemia precipitated by diabetic ketoacidosis in a previously undiagnosed ketosis-prone patient with diabetes mellitus. AB - Diabetic ketoacidosis is a potentially fatal complication of diabetes mellitus that may result in hypertriglyceridemia. Rarely, the resulting hypertriglyceridemia may precipitate acute pancreatitis. We report a case of acute pancreatitis secondary to hypertriglyceridemia precipitated by diabetic ketoacidosis and postulate that this unusual presentation is due to the patient being prone to ketosis. PMID- 29706816 TI - Thoracoscopic management of a mediastinal abscess caused by extra-esophageal migration of a metal brush bristle. AB - Foreign body perforations of the esophagus are infrequent events yet have the potential to cause significant morbidity and mortality. The clinical consequences of esophageal perforation by a foreign body are dependent upon the severity of infectious sequelae and damage to surrounding structures by the foreign object itself, as detailed in previous published reports. We describe the thoracoscopic management of a mediastinal abscess caused by a foreign body perforation in a patient with an intact esophagus. PMID- 29706817 TI - The PHACES syndrome: Multiple episodes of reproliferation of subglottic hemangioma. AB - Subglottic hemangioma is a potentially life-threatening manifestation of the PHACES syndrome. The disease process has been treated with corticosteroids, oral chemotherapeutic agents, endoscopic airway interventions, tracheostomy, and even laryngotracheal reconstruction. Oral propranolol has emerged as an effective therapy and in many cases has led to complete regression of hemangioma during the proliferative phase. There have been several reports of patients showing signs of reproliferation after discontinuing propranolol therapy. This article illustrates a patient who has had multiple episodes of reproliferation of subglottic hemangioma after weaning from propranolol therapy. PMID- 29706818 TI - Multiple admissions to the coronary care unit due to falsely elevated cardiac troponin. AB - The measurement of cardiac troponin, released from injured cardiomyocytes, is of paramount importance in the diagnosis of acute myocardial infarction. Elevated troponin can be encountered, however, in patients with cardiomyopathy, significant cardiac arrhythmias, vasculitis, right-sided heart strain, critical systemic illnesses, stroke, drug toxicity (such as Adriamycin), poisons (such as snake venoms), renal failure, seizure, and rhabdomyolysis. If the clinical picture is not consistent with any of these causes, a false-positive result should be considered. We herein describe a 94-year-old man with a prior history of coronary artery disease who presented with altered mental status and was found to have a persistently high troponin level resulting in three admissions to the coronary care unit for various noncardiac complaints. Because of discordance between clinical and laboratory data, immunological interference due to heterophile antibodies in the locally used assay (AccuTnI+3, Beckman Coulter) was suspected. The same serum sample tested on a different assay (Elecsys Troponin I Assay, Roche) resulted in an undetectable cardiac troponin I level, thus confirming the diagnosis. PMID- 29706819 TI - Acute myocardial infarction triggered by use of synthetic cannabis. AB - A young woman presented with an anterior ST elevation myocardial infarction shortly after synthetic cannabis use. This report highlights the cardiovascular risks of these drugs. PMID- 29706820 TI - Systolic anterior motion of the mitral valve after aortic valve replacement. AB - We present a case of severe systolic anterior motion developing intraoperatively after aortic valve replacement for aortic valve stenosis. PMID- 29706821 TI - Late rhythm changes after operative closure of a ventricular septal defect. PMID- 29706822 TI - High-intensity, sport-specific cardiac rehabilitation training of a 22-year-old competitive cyclist after spontaneous coronary artery dissection. AB - A 22-year-old man with spontaneous coronary artery dissection wanted to assess the feasibility of returning to competitive cycling. He was referred to the cardiac rehabilitation (CR) program at Baylor Hamilton Heart and Vascular Hospital where staff designed a high-intensity, sport-specific training program that simulated the movements and forces associated with his goal activity. The program was symptom limited and enabled the patient to train earlier and at a higher intensity than is typically allowed in conventional CR programs. Daily exercise training was customized to match the physical demands of competitive cycling by using a road bike, an indoor bike power trainer, and an interactive indoor-cycling software program. This case illustrates how specialized CR training, tailored to a patient's specific goals, can aid in the return to vigorous physical activity. He completed the high-intensity exercise training program without adverse signs or symptoms. PMID- 29706823 TI - Locally advanced carcinosarcoma of the pancreas. AB - Carcinosarcoma is a rare subtype of pancreatic neoplasm including both carcinomatous and sarcomatous components. Fewer than 30 cases have been reported to the Surveillance, Epidemiology, and End Results Program database. Given such rarity, definitive treatment guidelines are not well defined. We report a case of pancreatic carcinosarcoma diagnosed in our institution, review tumor clinicopathological characteristics, and describe our medical and surgical management strategy. PMID- 29706824 TI - Late breast cancer recurrence with bone marrow metastases and acute pulmonary hypertension. AB - Bone marrow is one of the most common sites of metastasis from breast cancer. Micrometastases to the bone marrow usually evade the systemic therapies used for the treatment of cancer and eventually lead to relapse later in the course of the illness. We report here a unique case of parallel progression of these bone marrow metastases in a patient with breast cancer who had a relapse a few years after treatment of her primary breast cancer, and she presented with diffuse marrow involvement and pulmonary hypertension without any definitive metastases elsewhere. PMID- 29706825 TI - Medulloblastoma in a toddler with Gorlin syndrome. AB - Gorlin syndrome (GS) is a rare hereditary multisystem disorder caused by mutations in PTCH1, PTCH2, or SUFU. It is characterized by multiple anomalies and an increased risk of developing various tumors. Basal cell carcinoma is most common, and medulloblastoma (MB) is especially frequent in patients with SUFU mutations. MB treatment often includes radiation therapy in patients older than 3 years; however, such treatment is very toxic to patients with GS. Most reported cases of MB in patients with GS present after GS is diagnosed. We report a male toddler with multicentric posterior fossa tumor and calcifications along the falx cerebri, suggesting MB and GS. Pathology revealed nodular MB. His testing confirmed a germline SUFU mutation. His tumor resolved with three induction cycles of chemotherapy, but he died of respiratory failure due to infection at 20 months of age. Overlooking calcifications along the falx cerebri in children with MB can induce significant morbidity. PMID- 29706826 TI - Rectal cancer presenting with synchronous intraperitoneal spread of disease. AB - There are differing definitions regarding what portion of the large intestine should be considered "rectum" as opposed to "colon." The transition from intra- to extraperitoneal rectum results in potentially disparate patterns of spread for rectal cancer dependent on tumor location relative to the peritoneal reflection. Here we report the case of a 50-year-old woman with a mid to upper rectal adenocarcinoma who presented with a synchronous biopsy-proven tumor implant in the peritoneal cavity. Her case highlights issues of varying definitions of organ anatomy within the literature, the role of primary tumor localization within different compartments of the abdominopelvic cavity for predicting potential routes of tumor spread, and the implications for adjuvant therapies. PMID- 29706827 TI - Hepatocellular carcinoma disguised as liver abscesses. AB - The incidence of hepatocellular carcinoma (HCC) is growing rapidly in the United States. Nonalcoholic fatty liver disease and nonalcoholic steatohepatitis are being increasingly recognized as known risk factors for the development of HCC. However, this risk seems to be associated with their progression to cirrhosis. This case demonstrates an unusual initial presentation of HCC masquerading as liver abscesses in a previously healthy woman with nonalcoholic fatty liver disease without cirrhosis. Our patient's clinical presentation was suspicious for an infectious etiology due to her ongoing fever in the setting of possible zoonotic transmission, because she had just acquired two unvaccinated kittens. Abscess-like clinical presentation can be seen in HCC and is due to neoplasm associated granulocytosis. Fever is due to pyrogen production by malignant tumor cells or by macrophages. Therefore, HCC can be difficult to differentiate from a hepatic abscess, and aspiration of malignant cells may be needed for an accurate diagnosis. Although the incidence of HCC in nonalcoholic fatty liver disease without cirrhosis is low or unknown, surveillance for HCC should be considered due to the higher prevalence of nonalcoholic fatty liver disease in the developed world and its potential risk for HCC. PMID- 29706828 TI - Symptomatic hypercalcemia and scarring alopecia as presenting features of sarcoidosis. AB - Sarcoidosis is a multisystem granulomatous disease most frequently affecting the lungs, lymph nodes, and eyes. Skin involvement occurs in approximately 25% to 35% of cases, with the scalp uncommonly affected. Abnormal calcium metabolism is associated with sarcoidosis and other granulomatous disorders and most commonly presents as hypercalciuria (40%-60%) and, less frequently, hypercalcemia (10% 20%). Symptomatic hypercalcemia is unusual, presenting in <5% of sarcoidosis patients, and rarely results in kidney damage. We report here a case of sarcoidosis presenting with severe symptomatic hypercalcemia (>14 mg/dL, 3.5 mmol/L), scarring alopecia, and acute-on-chronic kidney failure. PMID- 29706829 TI - Scurvy in 2017 in the USA. AB - Vitamin C deficiency may be common in third-world countries due to malnutrition, but it is currently rare in the USA. Initially, nonspecific symptoms like exhaustion and depression may make this disease difficult to diagnose until classical dermatological manifestations appear. Diagnosis mainly relies on clinical presentation, dietary history to identify risk factors, and dramatic recession of symptoms and signs following vitamin C therapy. Human beings cannot synthesize vitamin C and hence need 90% of vitamin C intake from fruits and vegetables. As a processed carbohydrate-rich diet becomes the staple food, scurvy must be recognized before it becomes potentially fatal. We describe a 65-year-old man with dyspnea, fatigue, anemia, and bleeding diathesis from scurvy and emphasize the importance of dietary history and the critical role of vitamin C in diagnosis and management of this forgotten entity. PMID- 29706830 TI - Christiaan Barnard's views on euthanasia. PMID- 29706831 TI - Vulnus sclopetarium (gunshot wound). AB - Fading from the vernacular, the Latin phrase vulnus sclopetarium is a quaint, mystifying, and fascinating term that is translated as gunshot wound. There is a fulminating paucity of published information regarding the meaning of this term and the etymology. Trauma surgeons, military surgeons, and scholars of the medical aspects of the civil war may be familiar with the term. Vulnus is easily deciphered from ancient Latin as wound, whereas the origin of sclopetarium proves more difficult to discern. No guns were present in ancient Rome because guns were not invented until around the 13th century; hence, no Latin word for them existed. Thus, sclopetarium is classified as neo-Latin, and deconstruction of the word reveals that sclopeta means gun, but that destination was arrived at via a convoluted path. The suffix -arium implies a place. Remarriage of the two parts suggests that the gun is an instrument of injury, which is typically incurred on a battlefield. An alternative explanation may be that -arium may also refer to the anatomical location of the wound. PMID- 29706832 TI - How I met some pioneers of cardiology. PMID- 29706833 TI - The trouble with troponin. PMID- 29706834 TI - Relation of behavioral health to quality health care. AB - Primary health care provided by an integrated treatment team (e.g., physician, nurse, behavioral health specialist) is becoming increasingly common. This article provides background on integrated care, offers a description of the breadth of behavioral health, and notes institutions such as the Veterans Health Administration in which behavioral health is utilized. We also propose that behavioral health contributes to quality health care and is part of best practices, even as it is provided in a practical and cost-effective way within a medical center primary care setting. PMID- 29706835 TI - The undead in culture and science. AB - The undead have a significant role in mythology, religion, folklore, and literature. In the 1800s, the word zombie was used to describe reanimated corpses in the Caribbean who often worked on plantations doing long, arduous field work. The movie White Zombie was released in 1932 and exploited this folklore, but it ignored the fact that zombies represent one outcome in Vodou religious beliefs regarding death and the migration of spirits following death. The interest in zombies eventually led to sociological and medical investigations into zombification. Wade Davis reported that powders used by malevolent priests (bokors) contained tetrodotoxin, which could cause the neurologic changes underlying the zombie phenotype. Recent clinical studies have indicated that synthetic cannabinoids and synthetic cathinones can cause bizarre zombie-like behavior. According to Haitian folklore, zombies can develop when bokors reanimate someone who suddenly died from an acute illness or who was purposely poisoned. Recent studies in molecular biology suggest that the sequence of programmed cell death can be reversed when the stressor is removed and that cells, tissues, and bodies (at least in Drosophila flies) can recover. These scientific studies would support the remote possibility that the near dead might recover under certain circumstances but have residual neuropsychological dysfunction. Alternatively, the bokors could maintain control of their victims using drugs with properties similar to those of synthetic cannabinoids. The concept of zombification needs to be considered in the context of culture, religion, and science. PMID- 29706836 TI - Mindfulness in the social media age. PMID- 29706837 TI - Nuclear Whole-Body Bone Scanning for Leprosy. PMID- 29706839 TI - Baylor Scott & White Health news. PMID- 29706838 TI - Some Comments on President Trump's Medical Examination in January 2018. PMID- 29706840 TI - Facts and ideas from anywhere. PMID- 29706841 TI - Comparing the established competency categories of the biosafety and infection prevention professions: a possible roadmap for addressing professional development training needs for a new era. PMID- 29706842 TI - Alibis for Adult Play: A Goffmanian Account of Escaping Embarrassment in Adult Play. AB - The social meanings of play sit at odds with norms of responsible and productive adult conduct. To be "caught" playing as an adult therefore risks embarrassment. Still, many designers want to create enjoyable, nonembarrassing play experiences for adults. To address this need, this article reads instances of spontaneous adult play through the lens of Erving Goffman's theory of the interaction order to unpack conditions and strategies for nonembarrassing adult play. It identifies established frames, segregated audiences, scripts supporting smooth performance, managing audience awareness, role distancing, and, particularly, alibis for play: Adults routinely provide alternative, adult-appropriate motives to account for their play, such as child care, professional duties, creative expression, or health. Once legitimized, the norms and rules of play themselves then provide an alibi for behavior that would risk being embarrassing outside play. PMID- 29706843 TI - NIRF Optical/PET Dual-Modal Imaging of Hepatocellular Carcinoma Using Heptamethine Carbocyanine Dye. AB - Combining near-infrared fluorescence (NIRF) and nuclear imaging techniques provides a novel approach for hepatocellular carcinoma (HCC) diagnosis. Here, we report the synthesis and characteristics of a dual-modality NIRF optical/positron emission tomography (PET) imaging probe using heptamethine carbocyanine dye and verify its feasibility in both nude mice and rabbits with orthotopic xenograft liver cancer. This dye, MHI-148, is an effective cancer-specific NIRF imaging agent and shows preferential uptake and retention in liver cancer. The corresponding NIRF imaging intensity reaches 109/cm2 tumor area at 24 h after injection in mice with HCC subcutaneous tumors. The dye can be further conjugated with radionuclide 68Ga (68Ga-MHI-148) for PET tracing. We applied the dual modality methodology toward the detection of HCC in both patient-derived orthotopic xenograft (PDX) models and rabbit orthotopic transplantation models. NIRF/PET images showed clear tumor delineation after probe injection (MHI-148 and 68Ga-MHI-148). The tumor-to-muscle (T/M) standardized uptake value (SUV) ratios were obtained from PET at 1 h after injection of 68Ga-MHI-148, which was helpful for effectively capturing small tumors in mice (0.5 cm * 0.3 cm) and rabbits (1.2 cm * 1.8 cm). This cancer-targeting NIRF/PET dual-modality imaging probe provides a proof of principle for noninvasive detection of deep-tissue tumors in mouse and rabbit and is a promising technique for more accurate and early detection of HCC. PMID- 29706844 TI - Thyroid Cancer Detection by Ultrasound Molecular Imaging with SHP2-Targeted Perfluorocarbon Nanoparticles. AB - Background: Contrast-enhanced ultrasound imaging has been widely used in the ultrasound diagnosis of a variety of tumours with high diagnostic accuracy, especially in patients with hepatic carcinoma, while its application is rarely reported in thyroid cancer. The currently used ultrasound contrast agents, microbubbles, cannot be targeted to molecular markers expressed in tumour cells due to their big size, leading to a big challenge for ultrasound molecular imaging. Phase-changeable perfluorocarbon nanoparticles may resolve the penetrability limitation of microbubbles and serve as a promising probe for ultrasound molecular imaging. Methods: 65 thyroid tumour samples and 40 normal samples adjacent to thyroid cancers were determined for SHP2 expression by IHC. SHP2-targeted PLGA nanoparticles (NPs-SHP2) encapsulating perfluoropentane (PFP) were prepared with PLGA-PEG as a shell material, and their specific target binding ability was assessed in vitro and in vivo, and the effect on the enhancement of ultrasonic imaging induced by LIFU was studied in vivo. Results: In the present study, we verified that tumour overexpression of SHP2 and other protein tyrosine phosphatases regulated several cellular processes and contributed to tumorigenesis, which could be introduced to ultrasound molecular imaging for differentiating normal from malignant thyroid diagnostic nodes. The IHC test showed remarkably high expression of SHP2 in human thyroid carcinoma specimens. In thyroid tumour xenografts in mice, the imaging signal was significantly enhanced by SHP2-targeted nanoparticles after LIFU induction. Conclusion: This study provides a basis for preclinical exploration of ultrasound molecular imaging with NPs-SHP2 for clinical thyroid nodule detection to enhance diagnostic accuracy. PMID- 29706846 TI - Synthesis and characterization of semiaromatic copolyamide 10T/1014 with high performance and flexibility. AB - Poly (decamethylene terephthalamide) (PA10T) is a kind of engineering plastics with high strength and high modulus, but one of its disadvantages is its low elongation at break. In order to improve the flexibility of PA10T, one aliphatic comonomer with a long alkyl chain is introduced to the molecular chain of PA10T. Then long chain semiaromatic copolyamides 10T/1014 were synthesized with different contents of 1014 units by polycondensation reaction of 1,10 diaminodecane, terephthalic acid and 1,12-dodecanedicarboxylic acid in deionized water. The intrinsic viscosities of the resultant polyamides ranged from 0.90 to 1.03 dL/g were obtained. The chemical and crystal structures of the copolymers were characterized by FTIR, 1H-NMR and WAXD. These copolyamides exhibited outstanding thermal properties with melting points range of 306-295 degrees C and degradation temperatures range of 479-472 degrees C at maximum degradation rate, and also have a wider processing window than PA10T. The tensile strength of PA10T/1014 copolymers decreased gradually from 80.02 to 72.95 MPa as the content of 1014 units increasing from 5 to 20 mol %, while the elongation at break increased significantly from 57 to 150%. The moisture content of 10T/1014 copolyamides decreased with increasing the 1014 unit contents. It suggests that 10T/1014 copolyamides could be a kind of promising heat-resistant engineering thermoplastic in the future applications. PMID- 29706845 TI - Reduced Lung Cancer Mortality With Lower Atmospheric Pressure. AB - Background: Research has shown that higher altitude is associated with lower risk of lung cancer and improved survival among patients. The current study assessed the influence of county-level atmospheric pressure (a measure reflecting both altitude and temperature) on age-adjusted lung cancer mortality rates in the contiguous United States, with 2 forms of spatial regression. Methods: Ordinary least squares regression and geographically weighted regression models were used to evaluate the impact of climate and other selected variables on lung cancer mortality, based on 2974 counties. Results: Atmospheric pressure was significantly positively associated with lung cancer mortality, after controlling for sunlight, precipitation, PM2.5 (ug/m3), current smoker, and other selected variables. Positive county-level beta coefficient estimates (P < .05) for atmospheric pressure were observed throughout the United States, higher in the eastern half of the country. Conclusion: The spatial regression models showed that atmospheric pressure is positively associated with age-adjusted lung cancer mortality rates, after controlling for other selected variables. PMID- 29706847 TI - Design and synthesis study of the thermo-sensitive poly (N-vinylpyrrolidone-b- N, N-diethylacrylamide). AB - The reversible addition fragmentation chain transfer (RAFT) polymerization method was adopted here to prepare a series of thermo-sensitive copolymers, poly (N,N diethyl- acrylamide-b-N-vinylpyrrolidone). Their structures, molecular weight distribution and temperature sensitivity performances were characterized by the nuclear magnetic resonance (1HNMR), the gel permeation chromatography (GPC) and the fluorescence spectrophotometer, respectively. It has been identified that the synthesis reaction of the block copolymer was living polymerization. The thermo sensitivity study suggested that N-vinylpyrrolidone (NVP), played a key role on the lower critical solution temperature (LCST) performance. PMID- 29706848 TI - Synthesis and properties of shape memory polyurethanes generated from schiff-base chain extender containing benzoyl and pyridyl rings. AB - In this study, 4,4'-diphenylmethane diisocyanate and polytetramethylene glycol were used to prepare a prepolymer; N,N'-bis(4-hydroxybenzylidene)-2,6 diaminopyridine (BHBP) was used as a chain extender; and these elements were combined to prepare a novel polyurethane, BHBP/PU. Gel permeation chromatography revealed that the molecular weight of the BHBP/PU samples increased as the BHBP content was increased. Fourier transform infrared spectroscopy demonstrated that high BHBP content facilitated strong hydrogen bonding in the samples. Differential thermogravimetry indicated that the initial decomposition temperature of BHBP/PU-3 was approximately 10 degrees C higher than that of BHBP/PU-1. Differential scanning calorimetry and dynamic mechanical analysis revealed that increasing the BHBP content substantially increased both the glass transition and dynamic glass transition temperatures of the BHBP/PU samples. The tensile strengths of BHBP/PU-1, BHBP/PU-2, and BHBP/PU-3 were 7.7, 10.9, and 21.6 MPa, respectively, with corresponding Young's moduli of 0.7, 1.9, and 3.3 MPa. These results demonstrated that both the tensile strength and Young's modulus of the BHBP/PU samples increased as the BHBP content was increased. Moreover, the BHBP/PU samples exhibited excellent shape recovery of >90%. PMID- 29706849 TI - An untargeted metabolomics method for archived newborn dried blood spots in epidemiologic studies. AB - Introduction: For pediatric diseases like childhood leukemia, a short latency period points to in-utero exposures as potentially important risk factors. Untargeted metabolomics of small molecules in archived newborn dried blood spots (DBS) offers an avenue for discovering early-life exposures that contribute to disease risks. Objectives: The purpose of this study was to develop a quantitative method for untargeted analysis of archived newborn DBS for use in an epidemiological study (California Childhood Leukemia Study, CCLS). Methods: Using experimental DBS from the blood of an adult volunteer, we optimized extraction of small molecules and integrated measurement of potassium as a proxy for blood hematocrit. We then applied this extraction method to 4.7-mm punches from 106 control DBS samples from the CCLS. Sample extracts were analyzed with liquid chromatography high resolution mass spectrometry (LC-HRMS) and an untargeted workflow was used to screen for metabolites that discriminate population characteristics such as sex, ethnicity, and birth weight. Results: Thousands of small molecules were measured in extracts of archived DBS. Normalizing for potassium levels removed variability related to varying hematocrit across DBS punches. Of the roughly 1,000 prevalent small molecules that were tested, multivariate linear regression detected significant associations with ethnicity (3 metabolites) and birth weight (15 metabolites) after adjusting for multiple testing. Conclusions: This untargeted workflow can be used for analysis of small molecules in archived DBS to discover novel biomarkers, to provide insights into the initiation and progression of diseases, and to provide guidance for disease prevention. PMID- 29706850 TI - Serum metabolomics using ultra performance liquid chromatography coupled to mass spectrometry in lactating dairy cows following a single dose of sporidesmin. AB - Introduction: Photosensitization is a common clinical sign in cows suffering from liver damage caused by the mycotoxin sporidesmin. This disease, called facial eczema (FE), is of major importance in New Zealand. Current techniques for diagnosing animals with subclinical sporidesmin-induced liver damage (i.e. without photosensitization) are nonspecific. In addition, little is known of the mechanisms involved in sporidesmin resistance, nor the early effects seen following low-dose sporidesmin intoxication. Objective: The objective of this study was to identify individual metabolites or metabolic profiles that could be used as serum markers for early stage FE in lactating cows. Methods: Results are presented from a 59-day sporidesmin challenge in Friesian-cross dairy cows. Serum metabolite profiles were obtained using reversed phase ultra-performance liquid chromatography (UPLC) electrospray ionization mass spectrometry (MS) and UPLC tandem MS. Multivariate and time series analyses were used to assess the data. Results: Statistical analysis, both with and without the temporal component, could distinguish the profiles of animals with clinical signs from the others, but not those affected subclinically. An increase in the concentrations of a combination of taurine- and glycine-conjugated secondary bile acids (BAs) was the most likely cause of the separation. This is the first time that MS methods have been applied to FE and that bile acids changes have been detected in cattle exposed to sporidesmin. Conclusions: It is well known that BA concentrations increase during cholestasis due to damage to bile ducts and leakage of the bile. This is the first study to investigate metabolomic changes in serum following a sporidesmin challenge. Further work to establish the significance of the elevation of individual BAs concentrations in the serum of early-stage sporidesmin-poisoned cows is necessary. PMID- 29706851 TI - A Python library for FAIRer access and deposition to the Metabolomics Workbench Data Repository. AB - Introduction: The Metabolomics Workbench Data Repository is a public repository of mass spectrometry and nuclear magnetic resonance data and metadata derived from a wide variety of metabolomics studies. The data and metadata for each study is deposited, stored, and accessed via files in the domain-specific 'mwTab' flat file format. Objectives: In order to improve the accessibility, reusability, and interoperability of the data and metadata stored in 'mwTab' formatted files, we implemented a Python library and package. This Python package, named 'mwtab', is a parser for the domain-specific 'mwTab' flat file format, which provides facilities for reading, accessing, and writing 'mwTab' formatted files. Furthermore, the package provides facilities to validate both the format and required metadata elements of a given 'mwTab' formatted file. Methods: In order to develop the 'mwtab' package we used the official 'mwTab' format specification. We used Git version control along with Python unit-testing framework as well as continuous integration service to run those tests on multiple versions of Python. Package documentation was developed using sphinx documentation generator. Results: The 'mwtab' package provides both Python programmatic library interfaces and command-line interfaces for reading, writing, and validating 'mwTab' formatted files. Data and associated metadata are stored within Python dictionary and list-based data structures, enabling straightforward, 'pythonic' access and manipulation of data and metadata. Also, the package provides facilities to convert 'mwTab' files into a JSON formatted equivalent, enabling easy reusability of the data by all modern programming languages that implement JSON parsers. The 'mwtab' package implements its metadata validation functionality based on a pre defined JSON schema that can be easily specialized for specific types of metabolomics studies. The library also provides a command-line interface for interconversion between 'mwTab' and JSONized formats in raw text and a variety of compressed binary file formats. Conclusions: The 'mwtab' package is an easy-to use Python package that provides FAIRer utilization of the Metabolomics Workbench Data Repository. The source code is freely available on GitHub and via the Python Package Index. Documentation includes a 'User Guide', 'Tutorial', and 'API Reference'. The GitHub repository also provides 'mwtab' package unit-tests via a continuous integration service. PMID- 29706852 TI - Associations of branched-chain amino acids with parameters of energy balance and survival in colorectal cancer patients: Results from the ColoCare Study. AB - Background: Branched-chain amino acids (BCAA) have been previously linked to survival in colorectal cancer (CRC) patients. It is unclear whether BCAAs are prognostic biomarkers or surrogate markers for energy balance. Objectives: We aimed to determine correlations of BCAAs with markers of energy balance over time and to investigate prognostic significance of BCAAs in CRC. Methods: We used urinary samples from newly diagnosed CRC patients [n=163; (stage I - IV)] from the ColoCare study in Heidelberg, Germany, collected at surgery (n=163), 6 (n=83) and 12 months follow-up (n=54). Isoleucine, leucine, valine, (2Z)-3 methylglutaconic acid (3HM), 2-ethylhydracrylic acid (2EA), 2-methyl-3 hydroxybutyrate (2M3H) were detected using gas-chromatography mass-spectrometry and proton-nuclear-magnetic-resonance spectroscopy. Partial correlation coefficients between BCAAs with body mass index (BMI), physical activity (metabolic equivalent [MET]) and muscle area were computed and adjusted for sex and age at diagnosis. We used Cox proportional hazard models to investigate overall survival (OS) after 24 months of follow-up. Results: We did not observe significant correlations between BCAAs and parameters of energy balance at all time points (correlation ranges: BMI: r= -0.13 to -0.01; METs: r=-0.14 to 0.02; dorsal muscle: r=-0.03 to 0.10). BCAAs were not associated with risk of death in stage I-III (e.g., valine: HRlog2=1.62, p=0.25) or in stage IV tumors. Elevated concentrations of 2EA and 2M3H were significantly associated with OS, independent of stage (2EA: stage I-III: HRlog2=0.42, p=0.04; stage IV: HRlog2=0.51, p=0.01). Conclusion: Our study suggests that BCAAs in colorectal cancer patients do not reflect parameters of energy balance and may be independently associated with overall survival. PMID- 29706853 TI - Direct Reductive Amination of Carbonyl Compounds Catalyzed by a Moisture Tolerant Tin(IV) Lewis Acid. AB - Despite the ever-broadening applications of main-group 'frustrated Lewis pair' (FLP) chemistry to both new and established reactions, their typical intolerance of water, especially at elevated temperatures (>100 degrees C), represents a key barrier to their mainstream adoption. Herein we report that FLPs based on the Lewis acid iPr3SnOTf are moisture tolerant in the presence of moderately strong nitrogenous bases, even under high temperature regimes, allowing them to operate as simple and effective catalysts for the reductive amination of organic carbonyls, including for challenging bulky amine and carbonyl substrate partners. PMID- 29706854 TI - Sustained-release synthetic biomarkers for monitoring thrombosis and inflammation using point-of-care compatible readouts. AB - Postoperative infection and thromboembolism represent significant sources of morbidity and mortality but cannot be easily tracked after hospital discharge. Therefore, a molecular test that could be performed at home would significantly impact disease management. Our lab has previously developed intravenously delivered 'synthetic biomarkers' that respond to dysregulated proteases to produce a urinary signal. These assays, however, have been limited to chronic diseases or acute diseases initiated at the time of diagnostic administration. Here, we formulate a subcutaneously administered sustained release system by using small PEG scaffolds (<10 nm) to promote diffusion into the bloodstream over a day. We demonstrate the utility of a thrombin sensor to identify thrombosis and an MMP sensor to measure inflammation. Finally, we developed a companion paper ELISA using printed wax barriers with nanomolar sensitivity for urinary reporters for point-of-care detection. Our approach for subcutaneous delivery of nanosensors combined with urinary paper analysis may enable facile monitoring of at-risk patients. PMID- 29706855 TI - Actively Targeted Deep Tissue Imaging and Photothermal-Chemo Therapy of Breast Cancer by Antibody-Functionalized Drug-Loaded X-Ray-Responsive Bismuth Sulfide@Mesoporous Silica Core-Shell Nanoparticles. AB - A theranostic platform combining synergistic therapy and real-time imaging attracts enormous attention but still faces great challenges, such as tedious modifications and lack of efficient accumulation in tumor. Here, a novel type of theranostic agent, bismuth sulfide@mesoporous silica (Bi2S3@ mPS) core-shell nanoparticles (NPs), for targeted image-guided therapy of human epidermal growth factor receptor-2 (HER-2) positive breast cancer is developed. To generate such NPs, polyvinylpyrrolidone decorated rod-like Bi2S3 NPs are chemically encapsulated with a mesoporous silica (mPS) layer and loaded with an anticancer drug, doxorubicin. The resultant NPs are then chemically conjugated with trastuzumab (Tam, a monoclonal antibody targeting HER-2 overexpressed breast cancer cells) to form Tam-Bi2S3@mPS NPs. By in vitro and in vivo studies, it is demonstrated that the Tam-Bi2S3@mPS bear multiple desired features for cancer theranostics, including good biocompatibility and drug loading ability as well as precise and active tumor targeting and accumulation (with a bismuth content in tumor being ~16 times that of nontargeted group). They can simultaneously serve both as an excellent contrast enhancement probe (due to the presence of strong X ray-attenuating bismuth element) for computed tomography deep tissue tumor imaging and as a therapeutic agent to destruct tumors and prevent metastasis by synergistic photothermalchemo therapy. PMID- 29706856 TI - CD58; leucocyte function adhesion-3 (LFA-3) could be used as a differentiating marker between immune and non-immune thyroid disorders. AB - The link between Graves' disease (GD) and Hashimoto's thyroiditis (HT) has been debated for decades due to the shared pathological and immunological components. Immune intolerance and inappropriate immune reaction against self-thyroid cells are distinctive features of both diseases, but definitive data for the clinical presentation of autoimmune thyroid disease remains unclear. To analyse the expression of T-regulatory cells, CD58, the CD4/CD8 ratio and the neutrophil/lymphocyte ratio and to determine if these parameters could be used as differentiating markers between auto- and non-immune thyroid diseases, 75 patients were enrolled in this study-40 with autoimmune thyroid disease (HT and GD ), 15 with non-immune thyroid disease, and 20 healthy controls. Multicolour flow cytometry was used to analyse CD58, T-regulatory cells (Treg) expressing CD4, CD25, HLA-DR and CD8 using different stained fluorescent labelled monoclonal antibodies. The neutrophils and lymphocyte ratio was also measured. Lower expression of Treg with higher expression of CD58 (LFA-3) was found in the autoimmune diseases when compared with the non-immune and control groups. ROC analysis showed that CD58 with sensitivity 88% and specificity 100% with cut-off value more than or equal to 29.9 indicates Hashimoto's disease, while lower value indicates colloid goitre, and higher or equal to 29.84 indicates Graves' disease and lower indicates colloid goitre with 100% sensitivity and specificity. CD58 could be used as differentiating marker between immune and non-immune thyroid disorders. PMID- 29706858 TI - Matching events and activities by integrating behavioral aspects and label analysis. AB - Nowadays, business processes are increasingly supported by IT services that produce massive amounts of event data during the execution of a process. These event data can be used to analyze the process using process mining techniques to discover the real process, measure conformance to a given process model, or to enhance existing models with performance information. Mapping the produced events to activities of a given process model is essential for conformance checking, annotation and understanding of process mining results. In order to accomplish this mapping with low manual effort, we developed a semi-automatic approach that maps events to activities using insights from behavioral analysis and label analysis. The approach extracts Declare constraints from both the log and the model to build matching constraints to efficiently reduce the number of possible mappings. These mappings are further reduced using techniques from natural language processing, which allow for a matching based on labels and external knowledge sources. The evaluation with synthetic and real-life data demonstrates the effectiveness of the approach and its robustness toward non-conforming execution logs. PMID- 29706857 TI - WESSBAS: extraction of probabilistic workload specifications for load testing and performance prediction-a model-driven approach for session-based application systems. AB - The specification of workloads is required in order to evaluate performance characteristics of application systems using load testing and model-based performance prediction. Defining workload specifications that represent the real workload as accurately as possible is one of the biggest challenges in both areas. To overcome this challenge, this paper presents an approach that aims to automate the extraction and transformation of workload specifications for load testing and model-based performance prediction of session-based application systems. The approach (WESSBAS) comprises three main components. First, a system- and tool-agnostic domain-specific language (DSL) allows the layered modeling of workload specifications of session-based systems. Second, instances of this DSL are automatically extracted from recorded session logs of production systems. Third, these instances are transformed into executable workload specifications of load generation tools and model-based performance evaluation tools. We present transformations to the common load testing tool Apache JMeter and to the Palladio Component Model. Our approach is evaluated using the industry-standard benchmark SPECjEnterprise2010 and the World Cup 1998 access logs. Workload-specific characteristics (e.g., session lengths and arrival rates) and performance characteristics (e.g., response times and CPU utilizations) show that the extracted workloads match the measured workloads with high accuracy. PMID- 29706859 TI - Scalable process discovery and conformance checking. AB - Considerable amounts of data, including process events, are collected and stored by organisations nowadays. Discovering a process model from such event data and verification of the quality of discovered models are important steps in process mining. Many discovery techniques have been proposed, but none of them combines scalability with strong quality guarantees. We would like such techniques to handle billions of events or thousands of activities, to produce sound models (without deadlocks and other anomalies), and to guarantee that the underlying process can be rediscovered when sufficient information is available. In this paper, we introduce a framework for process discovery that ensures these properties while passing over the log only once and introduce three algorithms using the framework. To measure the quality of discovered models for such large logs, we introduce a model-model and model-log comparison framework that applies a divide-and-conquer strategy to measure recall, fitness, and precision. We experimentally show that these discovery and measuring techniques sacrifice little compared to other algorithms, while gaining the ability to cope with event logs of 100,000,000 traces and processes of 10,000 activities on a standard computer. PMID- 29706860 TI - Detection and quantification of flow consistency in business process models. AB - Business process models abstract complex business processes by representing them as graphical models. Their layout, as determined by the modeler, may have an effect when these models are used. However, this effect is currently not fully understood. In order to systematically study this effect, a basic set of measurable key visual features is proposed, depicting the layout properties that are meaningful to the human user. The aim of this research is thus twofold: first, to empirically identify key visual features of business process models which are perceived as meaningful to the user and second, to show how such features can be quantified into computational metrics, which are applicable to business process models. We focus on one particular feature, consistency of flow direction, and show the challenges that arise when transforming it into a precise metric. We propose three different metrics addressing these challenges, each following a different view of flow consistency. We then report the results of an empirical evaluation, which indicates which metric is more effective in predicting the human perception of this feature. Moreover, two other automatic evaluations describing the performance and the computational capabilities of our metrics are reported as well. PMID- 29706861 TI - How do humans inspect BPMN models: an exploratory study. AB - Even though considerable progress regarding the technical perspective on modeling and supporting business processes has been achieved, it appears that the human perspective is still often left aside. In particular, we do not have an in-depth understanding of how process models are inspected by humans, what strategies are taken, what challenges arise, and what cognitive processes are involved. This paper contributes toward such an understanding and reports an exploratory study investigating how humans identify and classify quality issues in BPMN process models. Providing preliminary answers to initial research questions, we also indicate other research questions that can be investigated using this approach. Our qualitative analysis shows that humans adapt different strategies on how to identify quality issues. In addition, we observed several challenges appearing when humans inspect process models. Finally, we present different manners in which classification of quality issues was addressed. PMID- 29706862 TI - A Miniaturized, Programmable Deep-Brain Stimulator for Group-Housing and Water Maze Use. AB - Pre-clinical deep-brain stimulation (DBS) research has observed a growing interest in the use of portable stimulation devices that can be carried by animals. Not only can such devices overcome many issues inherent with a cable tether, such as twisting or snagging, they can also be utilized in a greater variety of arenas, including enclosed or large mazes. However, these devices are not inherently designed for water-maze environments, and their use has been restricted to individually-housed rats in order to avoid damage from various social activities such as grooming, playing, or fighting. By taking advantage of 3D-printing techniques, this study demonstrates an ultra-small portable stimulator with an environmentally-protective device housing, that is suitable for both social-housing and water-maze environments. The miniature device offers 2 channels of charge-balanced biphasic pulses with a high compliance voltage (12 V), a magnetic switch, and a diverse range of programmable stimulus parameters and pulse modes. The device's capabilities have been verified in both chronic pair-housing and water-maze experiments that asses the effects of nucleus reuniens DBS. Theta-burst stimulation delivered during a reference-memory water maze task (but not before) had induced performance deficits during both the acquisition and probe trials of a reference memory task. The results highlight a successful application of 3D-printing for expanding on the range of measurement modalities capable in DBS research. PMID- 29706863 TI - Is There Evidence for a Rostral-Caudal Gradient in Fronto-Striatal Loops and What Role Does Dopamine Play? AB - Research has shown that the lateral prefrontal cortex (LPFC) may be hierarchically organized along a rostral-caudal functional gradient such that control processing becomes progressively more abstract from caudal to rostral frontal regions. Here, we briefly review the most recent functional MRI, neuropsychological, and electrophysiological evidence in support of a hierarchical LPFC organization. We extend these observations by discussing how such a rostral-caudal gradient may also exist in the striatum and how the dopaminergic system may play an important role in the hierarchical organization of fronto-striatal loops. There is evidence indicating that a rostral-caudal gradient of dopamine receptor density may exist in both frontal and striatal regions. Here we formulate the hypothesis that dopamine may be an important neuromodulator in hierarchical processing, whereby frontal and striatal regions that have higher dopamine receptor density may have a larger influence over regions that exhibit lower dopamine receptor density. We conclude by highlighting directions for future research that will help elucidating the role dopamine might play in hierarchical frontal-striatal interactions. PMID- 29706864 TI - Ethanol-Induced Changes in PKCepsilon: From Cell to Behavior. AB - The long-term binge intake of ethanol causes neuroadaptive changes that lead to drinkers requiring higher amounts of ethanol to experience its effects. This neuroadaptation can be partly attributed to the modulation of numerous neurotransmitter receptors by the various protein kinases C (PKCs). PKCs are enzymes that control cellular activities by regulating other proteins via phosphorylation. Among the various isoforms of PKC, PKCepsilon is the most implicated in ethanol-induced biochemical and behavioral changes. Ethanol exposure causes changes to PKCepsilon expression and localization in various brain regions that mediate addiction-favoring plasticity. Ethanol works in conjunction with numerous upstream kinases and second messenger activators to affect cellular PKCepsilon expression. Chauffeur proteins, such as receptors for activated C kinase (RACKs), cause the translocation of PKCepsilon to aberrant sites and mediate ethanol-induced changes. In this article, we aim to review the following: the general structure and function of PKCepsilon, ethanol-induced changes in PKCepsilon expression, the regulation of ethanol-induced PKCepsilon activities in DAG-dependent and DAG-independent environments, the mechanisms underlying PKCepsilon-RACKepsilon translocation in the presence of ethanol, and the existing literature on the role of PKCepsilon in ethanol-induced neurobehavioral changes, with the goal of creating a working model upon which further research can build. PMID- 29706865 TI - Mental Illnesses-Associated Fxr1 and Its Negative Regulator Gsk3beta Are Modulators of Anxiety and Glutamatergic Neurotransmission. AB - Genetic variants of the fragile X mental retardation syndrome-related protein 1 (FXR1) have been associated to mood regulation, schizophrenia, and bipolar disorders. Nonetheless, genetic association does not indicate a functional link of a given gene to neuronal activity and associated behaviors. In addition, interaction between multiple genes is often needed to sculpt complex traits such as behavior. Thus, modulation of neuronal functions by a given gene product, such as Fxr1, has to be thoroughly studied in the context of its interactions with other gene products. Glycogen synthase kinase-3 beta (GSK3beta) is a shared target of several psychoactive drugs. In addition, interaction between functional polymorphisms of GSK3b and FXR1 has been implicated in mood regulation in healthy subjects and bipolar patients. However, the mechanistic underpinnings of this interaction remain unknown. We used somatic CRISPR/Cas9 mediated knockout and overexpression to investigate the impact of Fxr1 and its regulator Gsk3beta on neuronal functions directly in the adult mouse brain. Suppression of Gsk3beta or increase of Fxr1 expression in medial prefrontal cortex neurons leads to anxiolytic-like responses associated with a decrease in AMPA mediated excitatory postsynaptic currents. Furthermore, Fxr1 and Gsk3beta modulate glutamatergic neurotransmission via regulation of AMPA receptor subunits GluA1 and GluA2 as well as vesicular glutamate transporter VGlut1. These results underscore a potential mechanism underlying the action of Fxr1 on neuronal activity and behaviors. Association between the Gsk3beta-Fxr1 pathway and glutamatergic signaling also suggests how it may contribute to emotional regulation in response to mood stabilizers, or in illnesses like mood disorders and schizophrenia. PMID- 29706866 TI - Drosophila RSK Influences the Pace of the Circadian Clock by Negative Regulation of Protein Kinase Shaggy Activity. AB - Endogenous molecular circadian clocks drive daily rhythmic changes at the cellular, physiological, and behavioral level for adaptation to and anticipation of environmental signals. The core molecular system consists of autoregulatory feedback loops, where clock proteins inhibit their own transcription. A complex and not fully understood interplay of regulatory proteins influences activity, localization and stability of clock proteins to set the pace of the clock. This study focuses on the molecular function of Ribosomal S6 Kinase (RSK) in the Drosophila melanogaster circadian clock. Mutations in the human rsk2 gene cause Coffin-Lowry syndrome, which is associated with severe mental disabilities. Knock out studies with Drosophila ortholog rsk uncovered functions in synaptic processes, axonal transport and adult behavior including associative learning and circadian activity. However, the molecular targets of RSK remain elusive. Our experiments provide evidence that RSK acts in the key pace maker neurons as a negative regulator of Shaggy (SGG) kinase activity, which in turn determines timely nuclear entry of the clock proteins Period and Timeless to close the negative feedback loop. Phosphorylation of serine 9 in SGG is mediated by the C terminal kinase domain of RSK, which is in agreement with previous genetic studies of RSK in the circadian clock but argues against the prevailing view that only the N-terminal kinase domain of RSK proteins carries the effector function. Our data provide a mechanistic explanation how RSK influences the molecular clock and imply SGG S9 phosphorylation by RSK and other kinases as a convergence point for diverse cellular and external stimuli. PMID- 29706867 TI - RNA-Sequencing Reveals Unique Transcriptional Signatures of Running and Running Independent Environmental Enrichment in the Adult Mouse Dentate Gyrus. AB - Environmental enrichment (EE) is a powerful stimulus of brain plasticity and is among the most accessible treatment options for brain disease. In rodents, EE is modeled using multi-factorial environments that include running, social interactions, and/or complex surroundings. Here, we show that running and running independent EE differentially affect the hippocampal dentate gyrus (DG), a brain region critical for learning and memory. Outbred male CD1 mice housed individually with a voluntary running disk showed improved spatial memory in the radial arm maze compared to individually- or socially-housed mice with a locked disk. We therefore used RNA sequencing to perform an unbiased interrogation of DG gene expression in mice exposed to either a voluntary running disk (RUN), a locked disk (LD), or a locked disk plus social enrichment and tunnels [i.e., a running-independent complex environment (CE)]. RNA sequencing revealed that RUN and CE mice showed distinct, non-overlapping patterns of transcriptomic changes versus the LD control. Bio-informatics uncovered that the RUN and CE environments modulate separate transcriptional networks, biological processes, cellular compartments and molecular pathways, with RUN preferentially regulating synaptic and growth-related pathways and CE altering extracellular matrix-related functions. Within the RUN group, high-distance runners also showed selective stress pathway alterations that correlated with a drastic decline in overall transcriptional changes, suggesting that excess running causes a stress-induced suppression of running's genetic effects. Our findings reveal stimulus-dependent transcriptional signatures of EE on the DG, and provide a resource for generating unbiased, data-driven hypotheses for novel mediators of EE-induced cognitive changes. PMID- 29706869 TI - Fibronectin Promotes the Malignancy of Glioma Stem-Like Cells Via Modulation of Cell Adhesion, Differentiation, Proliferation and Chemoresistance. AB - Glioma stem-like cells (GSCs) are regarded as the sources of oncogenesis, recurrence, invasion and chemoresistance in malignant gliomas. Growing evidence suggests that the microenvironment surrounding GSCs interacts with tumor cells to influence biological behavior; however, the functional mechanisms involved are still unclear. In the present study, we investigated the modulation of GSCs triggered by fibronectin (FN), a main component of the extracellular matrix (ECM), in terms of cell adhesion, differentiation, proliferation and chemoresistance. We demonstrated that pre-coated FN prompted increased adherence by GSCs, with increased matrix metallopeptidases (MMPs)-2 and -9 expression, in a concentration-dependent manner. Decreases in sox-2 and nestin levels, and increased levels of glial fibrillary acidic protein (GFAP) and beta-tubulin were also found in GSCs, indicating cell differentiation driven by FN. Further investigation revealed that FN promoted cell growth, as demonstrated by the elevation of Ki-67, with the activation of p-ERK1/2 and cyclin D1 also evident. In addition, FN suppressed p53-mediated apoptosis and upregulated P-glycoprotein expression, making GSCs more chemoresistant to alkylating agents such as carmustine. In contrast, this effect was reversed by an integrin inhibitor, cilengitide. Activation of the focal adhesion kinase/paxillin/AKT signaling pathway was involved in the modulation of GSCs by FN. Focusing on the interactions between tumor cells and the ECM may be an encouraging aspect of research on novel chemotherapeutic therapies in future. PMID- 29706870 TI - Studying Axon-Astrocyte Functional Interactions by 3D Two-Photon Ca2+ Imaging: A Practical Guide to Experiments and "Big Data" Analysis. AB - Recent advances in fast volumetric imaging have enabled rapid generation of large amounts of multi-dimensional functional data. While many computer frameworks exist for data storage and analysis of the multi-gigabyte Ca2+ imaging experiments in neurons, they are less useful for analyzing Ca2+ dynamics in astrocytes, where transients do not follow a predictable spatio-temporal distribution pattern. In this manuscript, we provide a detailed protocol and commentary for recording and analyzing three-dimensional (3D) Ca2+ transients through time in GCaMP6f-expressing astrocytes of adult brain slices in response to axonal stimulation, using our recently developed tools to perform interactive exploration, filtering, and time-correlation analysis of the transients. In addition to the protocol, we release our in-house software tools and discuss parameters pertinent to conducting axonal stimulation/response experiments across various brain regions and conditions. Our software tools are available from the Volterra Lab webpage at https://wwwfbm.unil.ch/dnf/group/glia-an-active-synaptic partner/member/volterra-andrea-volterra in the form of software plugins for Image J (NIH)-a de facto standard in scientific image analysis. Three programs are available: MultiROI_TZ_profiler for interactive graphing of several movable ROIs simultaneously, Gaussian_Filter5D for Gaussian filtering in several dimensions, and Correlation_Calculator for computing various cross-correlation parameters on voxel collections through time. PMID- 29706868 TI - The Blood-Brain Barrier and the EphR/Ephrin System: Perspectives on a Link Between Neurovascular and Neuropsychiatric Disorders. AB - Interactions among endothelial cells (EC) forming blood vessels and their surrounding cell types are essential to establish the blood-brain barrier (BBB), an integral part of the neurovascular unit (NVU). Research on the NVU has recently seen a renaissance to especially understand the neurobiology of vascular and brain pathologies and their frequently occurring comorbidities. Diverse signaling molecules activated in the near proximity of blood vessels trigger paracellular pathways which regulate the formation and stabilization of tight junctions (TJ) between EC and thereby influence BBB permeability. Among regulatory molecules, the erythropoietin-producing-hepatocellular carcinoma receptors (EphR) and their Eph receptor-interacting signals (ephrins) play a pivotal role in EC differentiation, angiogenesis and BBB integrity. Multiple EphR ligand interactions between EC and other cell types influence different aspects of angiogenesis and BBB formation. Such interactions additionally control BBB sealing properties and thus the penetration of substances into the brain parenchyma. Thus, they play critical roles in the healthy brain and during the pathogenesis of brain disorders. In this mini-review article, we aim at integrating the constantly growing literature about the functional roles of the EphR/ephrin system for the development of the vascular system and the BBB and in the pathogenesis of neurovascular and neuropsychiatric disorders. We suggest the hypothesis that a disrupted EphR/ephrin signaling at the BBB might represent an underappreciated molecular hub of disease comorbidity. Finally, we propose the possibility that the EphR/ephrin system bears the potential of becoming a novel target for the development of alternative therapeutic treatments, focusing on such comorbidities. PMID- 29706872 TI - Thalamocortical Projection Neuron and Interneuron Numbers in the Visual Thalamic Nuclei of the Adult C57BL/6 Mouse. AB - A key parameter to constrain predictive, bottom-up circuit models of a given brain domain is the number and position of the neuronal populations involved. These include not only the neurons whose bodies reside within the domain, but also the neurons in distant regions that innervate the domain. The mouse visual cortex receives its main subcortical input from the dorsal lateral geniculate nucleus (dLGN) and the lateral posterior (LP) complex of the thalamus. The latter consists of three different nuclei: lateral posterior lateral (LPL), lateral posterior medial rostral (LPMR), and lateral posterior medial caudal (LPMC), each exhibiting specific patterns of connections with the various visual cortical areas. Here, we have determined the number of thalamocortical projection neurons and interneurons in the LP complex and dLGN of the adult C57BL/6 male mouse. We combined Nissl staining and histochemical and immunolabeling methods for consistently delineating nuclei borders, and applied unbiased stereological cell counting methods. Thalamic interneurons were identified using GABA immunolabeling. The C57BL/6 dLGN contains ~21,200 neurons, while LP complex contains ~31,000 total neurons. The dLGN and LP are the only nuclei of the mouse dorsal thalamus containing substantial numbers GABA-immunoreactive interneurons. These interneurons, however, are scarcer than previously estimated; they are 5.6% of dLGN neurons and just 1.9% of the LP neurons. It can be thus inferred that the dLGN contains ~20,000 and the LP complex ~30,400 thalamocortical projection neurons (~12,000 in LPL, 15,200 in LPMR, and 4,200 in LPMC). The present dataset is relevant for constraining models of mouse visual thalamocortical circuits, as well as for quantitative comparisons between genetically modified mouse strains, or across species. PMID- 29706871 TI - Plasticity in One Hemisphere, Control From Two: Adaptation in Descending Motor Pathways After Unilateral Corticospinal Injury in Neonatal Rats. AB - After injury to the corticospinal tract (CST) in early development there is large scale adaptation of descending motor pathways. Some studies suggest the uninjured hemisphere controls the impaired forelimb, while others suggest that the injured hemisphere does; these pathways have never been compared directly. We tested the contribution of each motor cortex to the recovery forelimb function after neonatal injury of the CST. We cut the left pyramid (pyramidotomy) of postnatal day 7 rats, which caused a measurable impairment of the right forelimb. We used pharmacological inactivation of each motor cortex to test its contribution to a skilled reach and supination task. Rats with neonatal pyramidotomy were further impaired by inactivation of motor cortex in both the injured and the uninjured hemispheres, while the forelimb of uninjured rats was impaired only from the contralateral motor cortex. Thus, inactivation demonstrated motor control from each motor cortex. In contrast, physiological and anatomical interrogation of these pathways support adaptations only in the uninjured hemisphere. Intracortical microstimulation of motor cortex in the uninjured hemisphere of rats with neonatal pyramidotomy produced responses from both forelimbs, while stimulation of the injured hemisphere did not elicit responses from either forelimb. Both anterograde and retrograde tracers were used to label corticofugal pathways. There was no increased plasticity from the injured hemisphere, either from cortex to the red nucleus or the red nucleus to the spinal cord. In contrast, there were very strong CST connections to both halves of the spinal cord from the uninjured motor cortex. Retrograde tracing produced maps of each forelimb within the uninjured hemisphere, and these were partly segregated. This suggests that the uninjured hemisphere may encode separate control of the unimpaired and the impaired forelimbs of rats with neonatal pyramidotomy. PMID- 29706874 TI - Sensorimotor and Neurocognitive Dysfunctions Parallel Early Telencephalic Neuropathology in Fucosidosis Mice. AB - Fucosidosis is a lysosomal storage disorder (LSD) caused by lysosomal alpha-L fucosidase deficiency. Insufficient alpha-L-fucosidase activity triggers accumulation of undegraded, fucosylated glycoproteins and glycolipids in various tissues. The human phenotype is heterogeneous, but progressive motor and cognitive impairments represent the most characteristic symptoms. Recently, Fuca1 deficient mice were generated by gene targeting techniques, constituting a novel animal model for human fucosidosis. These mice display widespread LSD pathology, accumulation of secondary storage material and neuroinflammation throughout the brain, as well as progressive loss of Purkinje cells. Fuca1-deficient mice and control littermates were subjected to a battery of tests detailing different aspects of motor, emotional and cognitive function. At an early stage of disease, we observed reduced exploratory activity, sensorimotor disintegration as well as impaired spatial learning and fear memory. These early markers of neurological deterioration were related to the respective stage of neuropathology using molecular genetic and immunochemical procedures. Increased expression of the lysosomal marker Lamp1 and neuroinflammation markers was observed throughout the brain, but appeared more prominent in cerebral areas in comparison to cerebellum of Fuca1-deficient mice. This is consistent with impaired behaviors putatively related to early disruptions of motor and cognitive circuits particularly involving cerebral cortex, basal ganglia, and hippocampus. Thus, Fuca1-deficient mice represent a practical and promising fucosidosis model, which can be utilized for pathogenetic and therapeutic studies. PMID- 29706873 TI - Inflammation and Tissue Remodeling in the Bladder and Urethra in Feline Interstitial Cystitis. AB - Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating chronic disease of unknown etiology. A naturally occurring disease termed feline interstitial cystitis (FIC) reproduces many features of IC/BPS patients. To gain insights into mechanisms underlying IC/BPS, we investigated pathological changes in the lamina propria (LP) of the bladder and proximal urethra in cats with FIC, using histological and molecular methods. Compared to control cat tissue, we found an increased number of de-granulated mast cells, accumulation of leukocytes, increased cyclooxygenase (COX)-1 expression in the bladder LP, and increased COX-2 expression in the urethra LP from cats with FIC. We also found increased suburothelial proliferation, evidenced by mucosal von Brunn's nests, neovascularization and alterations in elastin content. Scanning electron microscopy revealed normal appearance of the superficial urethral epithelium, including the neuroendocrine cells (termed paraneurons), in FIC urethrae. Together, these histological findings suggest the presence of chronic inflammation of unknown origin leading to tissue remodeling. Since the mucosa functions as part of a "sensory network" and urothelial cells, nerves and other cells in the LP are influenced by the composition of the underlying tissues including the vasculature, the changes observed in the present study may alter the communication of sensory information between different cellular components. This type of mucosal signaling can also extend to the urethra, where recent evidence has revealed that the urethral epithelium is likely to be part of a signaling system involving paraneurons and sensory nerves. Taken together, our data suggest a more prominent role for chronic inflammation and tissue remodeling than previously thought, which may result in alterations in mucosal signaling within the urinary bladder and proximal urethra that may contribute to altered sensations and pain in cats and humans with this syndrome. PMID- 29706875 TI - Right Fronto-Subcortical White Matter Microstructure Predicts Cognitive Control Ability on the Go/No-go Task in a Community Sample. AB - Go/no-go tasks are widely used to index cognitive control. This construct has been linked to white matter microstructure in a circuit connecting the right inferior frontal gyrus (IFG), subthalamic nucleus (STN), and pre-supplementary motor area. However, the specificity of this association has not been tested. A general factor of white matter has been identified that is related to processing speed. Given the strong processing speed component in successful performance on the go/no-go task, this general factor could contribute to task performance, but the general factor has often not been accounted for in past studies of cognitive control. Further, studies on cognitive control have generally employed small unrepresentative case-control designs. The present study examined the relationship between go/no-go performance and white matter microstructure in a large community sample of 378 subjects that included participants with a range of both clinical and subclinical nonpsychotic psychopathology. We found that white matter microstructure properties in the right IFG-STN tract significantly predicted task performance, and remained significant after controlling for dimensional psychopathology. The general factor of white matter only reached statistical significance when controlling for dimensional psychopathology. Although the IFG-STN and general factor tracts were highly correlated, when both were included in the model, only the IFG-STN remained a significant predictor of performance. Overall, these findings suggest that while a general factor of white matter can be identified in a young community sample, white matter microstructure properties in the right IFG-STN tract show a specific relationship to cognitive control. The findings highlight the importance of examining both specific and general correlates of cognition, especially in tasks with a speeded component. PMID- 29706877 TI - Perceived Simultaneity and Temporal Order of Audiovisual Events Following Concussion. AB - The central nervous system allows for a limited time span referred to as the temporal binding window (TBW) in order to rapidly determine whether multisensory events correspond with the same event. Failure to correctly identify whether multisensory events occur simultaneously and their sequential order can lead to inaccurate representations of the physical world, poor decision-making and dangerous behavior. Damage to the neural systems that coordinate the relative timing of sensory events may explain some of the long-term consequences associated with concussion. The aim of this study was to investigate whether the perception of simultaneity and the discrimination of temporal order of audiovisual stimuli are impaired in those with a history of concussion. Fifty participants (17 with concussion history) were recruited to complete audiovisual simultaneity judgment (SJ) and temporal order judgment (TOJ) tasks. From these tasks, the TBW and point of subjective simultaneity (PSS) were extracted to assess whether the precision and or the accuracy of temporal perception changes with concussion, respectively. Results demonstrated that those with concussion history have a significantly wider TBW (less precise), with no significant change in the PSS (no change in accuracy), particularly for the TOJ task but no significant differences were found between the SJ and TOJ tasks. Importantly, a negative correlation between the time elapsed since last concussion and TBW width in the TOJ task suggests that precision in temporal perception does improve over time. These findings suggest that those with concussion history display an impairment in the perceived timing of sensory events and that monitoring performance in the SJ and TOJ tasks may be a useful additional assessment tool when making decisions about returning to regular work and play following concussion. PMID- 29706879 TI - Experimental Directory Structure (Exdir): An Alternative to HDF5 Without Introducing a New File Format. AB - Natural sciences generate an increasing amount of data in a wide range of formats developed by different research groups and commercial companies. At the same time there is a growing desire to share data along with publications in order to enable reproducible research. Open formats have publicly available specifications which facilitate data sharing and reproducible research. Hierarchical Data Format 5 (HDF5) is a popular open format widely used in neuroscience, often as a foundation for other, more specialized formats. However, drawbacks related to HDF5's complex specification have initiated a discussion for an improved replacement. We propose a novel alternative, the Experimental Directory Structure (Exdir), an open specification for data storage in experimental pipelines which amends drawbacks associated with HDF5 while retaining its advantages. HDF5 stores data and metadata in a hierarchy within a complex binary file which, among other things, is not human-readable, not optimal for version control systems, and lacks support for easy access to raw data from external applications. Exdir, on the other hand, uses file system directories to represent the hierarchy, with metadata stored in human-readable YAML files, datasets stored in binary NumPy files, and raw data stored directly in subdirectories. Furthermore, storing data in multiple files makes it easier to track for version control systems. Exdir is not a file format in itself, but a specification for organizing files in a directory structure. Exdir uses the same abstractions as HDF5 and is compatible with the HDF5 Abstract Data Model. Several research groups are already using data stored in a directory hierarchy as an alternative to HDF5, but no common standard exists. This complicates and limits the opportunity for data sharing and development of common tools for reading, writing, and analyzing data. Exdir facilitates improved data storage, data sharing, reproducible research, and novel insight from interdisciplinary collaboration. With the publication of Exdir, we invite the scientific community to join the development to create an open specification that will serve as many needs as possible and as a foundation for open access to and exchange of data. PMID- 29706876 TI - Changing Brain Networks Through Non-invasive Neuromodulation. AB - Background/Objective: Non-invasive neuromodulation techniques, such as repetitive Transcranial Magnetic Stimulation (rTMS) and transcranial Direct Current Stimulation (tDCS), have increasingly been investigated for their potential as treatments for neurological and psychiatric disorders. Despite widespread dissemination of these techniques, the underlying therapeutic mechanisms and the ideal stimulation site for a given disorder remain unknown. Increasing evidence support the possibility of non-invasive neuromodulation affecting a brain network rather than just the local stimulation target. In this article, we present evidence in a clinical setting to support the idea that non-invasive neuromodulation changes brain networks. Method: This article addresses the idea that non-invasive neuromodulation modulates brain networks, rather than just the local stimulation target, using neuromodulation studies in tinnitus and major depression as examples. We present studies that support this hypothesis from different perspectives. Main Results/Conclusion: Studies stimulating the same brain region, such as the dorsolateral prefrontal cortex (DLPFC), have shown to be effective for several disorders and studies using different stimulation sites for the same disorder have shown similar results. These findings, as well as results from studies investigating brain network connectivity on both macro and micro levels, suggest that non-invasive neuromodulation affects a brain network rather than just the local stimulation site targeted. We propose that non invasive neuromodulation should be approached from a network perspective and emphasize the therapeutic potential of this approach through the modulation of targeted brain networks. PMID- 29706878 TI - Mirror-Image Equivalence and Interhemispheric Mirror-Image Reversal. AB - Mirror-image confusions are common, especially in children and in some cases of neurological impairment. They can be a special impediment in activities such as reading and writing directional scripts, where mirror-image patterns (such as b and d) must be distinguished. Treating mirror images as equivalent, though, can also be adaptive in the natural world, which carries no systematic left-right bias and where the same object or event can appear in opposite viewpoints. Mirror image equivalence and confusion are natural consequences of a bilaterally symmetrical brain. In the course of learning, mirror-image equivalence may be established through a process of symmetrization, achieved through homotopic interhemispheric exchange in the formation of memory circuits. Such circuits would not distinguish between mirror images. Learning to discriminate mirror image discriminations may depend either on existing brain asymmetries, or on extensive learning overriding the symmetrization process. The balance between mirror-image equivalence and mirror-image discrimination may nevertheless be precarious, with spontaneous confusions or reversals, such as mirror writing, sometimes appearing naturally or as a manifestation of conditions like dyslexia. PMID- 29706880 TI - A Dictionary Learning Approach for Signal Sampling in Task-Based fMRI for Reduction of Big Data. AB - The exponential growth of fMRI big data offers researchers an unprecedented opportunity to explore functional brain networks. However, this opportunity has not been fully explored yet due to the lack of effective and efficient tools for handling such fMRI big data. One major challenge is that computing capabilities still lag behind the growth of large-scale fMRI databases, e.g., it takes many days to perform dictionary learning and sparse coding of whole-brain fMRI data for an fMRI database of average size. Therefore, how to reduce the data size but without losing important information becomes a more and more pressing issue. To address this problem, we propose a signal sampling approach for significant fMRI data reduction before performing structurally-guided dictionary learning and sparse coding of whole brain's fMRI data. We compared the proposed structurally guided sampling method with no sampling, random sampling and uniform sampling schemes, and experiments on the Human Connectome Project (HCP) task fMRI data demonstrated that the proposed method can achieve more than 15 times speed-up without sacrificing the accuracy in identifying task-evoked functional brain networks. PMID- 29706881 TI - A Real-Time Lift Detection Strategy for a Hip Exoskeleton. AB - Repetitive lifting of heavy loads increases the risk of back pain and even lumbar vertebral injuries to workers. Active exoskeletons can help workers lift loads by providing power assistance, and therefore reduce the moment and force applied on L5/S1 joint of human body when performing lifting tasks. However, most existing active exoskeletons for lifting assistance are unable to automatically detect user's lift movement, which limits the wide application of active exoskeletons in factories. In this paper, we propose a simple but effective lift detection strategy for exoskeleton control. This strategy uses only exoskeleton integrated sensors, without any extra sensors to capture human motion intentions. This makes the lift detection system more practical for applications in manufacturing environments. Seven healthy subjects participated in this research. Three different sessions were carried out, two for training and one for testing the algorithm. In the two training sessions, subjects were asked to wear a hip exoskeleton, controlled in transparent mode, and perform repetitive lifting and a locomotion circuit; lifting was executed with different techniques. The collected data were used to train the lift detection model. In the testing session, the exoskeleton was controlled in order to deliver torque to assist the lifting action, based on the lift detection made by the trained algorithm. The across subject average accuracy of lift detection during online test was 97.97 +/- 1.39% with subject-dependent model. Offline, the algorithm was trained with data acquired from all subjects to verify its performance for subject-independent detection, and an accuracy of 97.48 +/- 1.53% was achieved. In addition, timeliness of the algorithm was quantitatively evaluated and the time delay was <160 ms across different lifting speeds. Surface electromyography was also measured to assess the efficacy of the exoskeleton in assisting subjects in performing load lifting tasks. These results validate the promise of applying the proposed lift detection strategy for exoskeleton control aiming at lift assistance. PMID- 29706882 TI - Cognitive Function and Brain Atrophy Predict Non-pharmacological Efficacy in Dementia: The Mihama-Kiho Scan Project2. AB - We aimed to determine whether neuropsychological deficits and brain atrophy could predict the efficacy of non-pharmacological interventions. Forty-six participants with mild-to-moderate dementia were monitored for 6 months; 25 underwent an intervention involving physical exercise with music, and 21 performed cognitive stimulation tasks. Participants were categorized into improvement (IMP) and no IMP subgroups. In the exercise-with-music group, the no-IMP subgroup performed worse than the IMP subgroup on the Rivermead Behavioural Memory Test at baseline. In the cognitive-stimulation group, the no-IMP subgroup performed worse than the IMP subgroup on Raven's Colored Progressive Matrices and the cognitive functional independence measure at baseline. In the no-IMP subgroup, voxel-based morphometric analysis at baseline revealed more extensive gray matter loss in the anterior cingulate gyrus and left middle frontal gyrus in the exercise-with-music and cognitive-stimulation groups, respectively. Participants with mild-to moderate dementia with cognitive decline and extensive cortical atrophy are less likely to show improved cognitive function after non-pharmaceutical therapy. PMID- 29706883 TI - Resting-State Functional Connectivity Predicts Cognitive Impairment Related to Alzheimer's Disease. AB - Resting-state functional connectivity (rs-FC) is a promising neuromarker for cognitive decline in aging population, based on its ability to reveal functional differences associated with cognitive impairment across individuals, and because rs-fMRI may be less taxing for participants than task-based fMRI or neuropsychological tests. Here, we employ an approach that uses rs-FC to predict the Alzheimer's Disease Assessment Scale (11 items; ADAS11) scores, which measure overall cognitive functioning, in novel individuals. We applied this technique, connectome-based predictive modeling, to a heterogeneous sample of 59 subjects from the Alzheimer's Disease Neuroimaging Initiative, including normal aging, mild cognitive impairment, and AD subjects. First, we built linear regression models to predict ADAS11 scores from rs-FC measured with Pearson's r correlation. The positive network model tested with leave-one-out cross validation (LOOCV) significantly predicted individual differences in cognitive function from rs-FC. In a second analysis, we considered other functional connectivity features, accordance and discordance, which disentangle the correlation and anticorrelation components of activity timecourses between brain areas. Using partial least square regression and LOOCV, we again built models to successfully predict ADAS11 scores in novel individuals. Our study provides promising evidence that rs-FC can reveal cognitive impairment in an aging population, although more development is needed for clinical application. PMID- 29706885 TI - Brain Transcriptomic Analysis of Hereditary Cerebral Hemorrhage With Amyloidosis Dutch Type. AB - Hereditary cerebral hemorrhage with amyloidosis-Dutch type (HCHWA-D) is an early onset hereditary form of cerebral amyloid angiopathy (CAA) caused by a point mutation resulting in an amino acid change (NP_000475.1:p.Glu693Gln) in the amyloid precursor protein (APP). Post-mortem frontal and occipital cortical brain tissue from nine patients and nine age-related controls was used for RNA sequencing to identify biological pathways affected in HCHWA-D. Although previous studies indicated that pathology is more severe in the occipital lobe in HCHWA-D compared to the frontal lobe, the current study showed similar changes in gene expression in frontal and occipital cortex and the two brain regions were pooled for further analysis. Significantly altered pathways were analyzed using gene set enrichment analysis (GSEA) on 2036 significantly differentially expressed genes. Main pathways over-represented by down-regulated genes were related to cellular aerobic respiration (including ATP synthesis and carbon metabolism) indicating a mitochondrial dysfunction. Principal up-regulated pathways were extracellular matrix (ECM)-receptor interaction and ECM proteoglycans in relation with an increase in the transforming growth factor beta (TGFbeta) signaling pathway. Comparison with the publicly available dataset from pre-symptomatic APP-E693Q transgenic mice identified overlap for the ECM-receptor interaction pathway, indicating that ECM modification is an early disease specific pathomechanism. PMID- 29706886 TI - Lower Choline and Myo-Inositol in Temporo-Parietal Cortex Is Associated With Apathy in Amnestic MCI. AB - Apathy is a common symptom in patients with amnestic mild cognitive impairment (aMCI) and is associated with an increased risk of progression to Alzheimer's disease (AD). The neural substrates underlying apathy in aMCI may involve multiple brain regions, including the anterior cingulate cortex and the temporo parietal region. Here we investigated neurometabolites in brain regions that may underlie apathy in aMCI patients using proton magnetic resonance spectroscopy (1H MRS). Twenty-eight aMCI patients with varying degrees of apathy and 20 matched controls underwent 1H-MRS. Spectra were acquired from single voxels in the posterior cingulate cortex (PCC), dorsal anterior cingulate cortex (DACC), right dorsolateral prefrontal cortex (DLPFC), and right temporo-parietal cortex (TPC). Apathy was measured with the Apathy Evaluation Scale (AES). Spearman partial correlations between metabolite concentrations in each region and severity of apathy were determined. Additionally, analyses of covariance (ANCOVA) were performed to determine whether metabolite changes differed between patients with or without clinically-diagnosed apathy. The degree of apathy was found to be negatively correlated with choline and myo-inositol (mI) in the TPC. Additional exploratory analyses suggested that N-acetylaspartate (NAA)/mI ratio was reduced in aMCI without clinical apathy but not in aMCI with clinical apathy. In the DACC, glutamate and glutamine (Glx) levels tended to be higher in the aMCI with apathy group compared to controls and reduced in association with depression scores. In conclusion, apathy in aMCI patients was associated with neurometabolite changes indicative of altered membranal integrity and glial function in the right TPC. Findings also indicated that in a clinically-diagnosed aMCI cohort, apathy symptoms may be suggestive of neural changes that are distinct from aMCI without apathy. PMID- 29706884 TI - Mechanisms of Risk Reduction in the Clinical Practice of Alzheimer's Disease Prevention. AB - Alzheimer's disease (AD) is a neurodegenerative dementia that affects nearly 50 million people worldwide and is a major source of morbidity, mortality, and healthcare expenditure. While there have been many attempts to develop disease modifying therapies for late-onset AD, none have so far shown efficacy in humans. However, the long latency between the initial neuronal changes and onset of symptoms, the ability to identify patients at risk based on family history and genetic markers, and the emergence of AD biomarkers for preclinical disease suggests that early risk-reducing interventions may be able to decrease the incidence of, delay or prevent AD. In this review, we discuss six mechanisms dysregulation of glucose metabolism, inflammation, oxidative stress, trophic factor release, amyloid burden, and calcium toxicity-involved in AD pathogenesis that offer promising targets for risk-reducing interventions. In addition, we offer a blueprint for a multi-modality AD risk reduction program that can be clinically implemented with the current state of knowledge. Focused risk reduction aimed at particular pathological factors may transform AD to a preventable disorder in select cases. PMID- 29706887 TI - The rs696880 Polymorphism in the Nogo-A Receptor Gene (RTN4R) Is Associated With Susceptibility to Sporadic Amyotrophic Lateral Sclerosis in the Chinese Population. AB - Single-nucleotide polymorphisms (SNPs) in the Nogo-A receptor gene (RTN4R) have been associated with increased risk for sporadic amyotrophic lateral sclerosis (SALS) in the French population. In the present study, we investigated the associations between RTN4R tag SNPs and SALS in a large Chinese population. Four tag SNPs (rs854971, rs887765, rs696880 and rs1567871) in the RTN4R gene with an r2 threshold of 0.8 and a minor allele frequency (MAF) greater than 0.2% were selected based on Chinese population data from HapMap. A total of 499 SALS patients and 503 healthy controls were genotyped for the SNPs by SNaPshot technology. Haplotype analysis of the four SNPs was performed using the SHEsis software platform. The results showed a significant association between the rs696880 risk allele (A) and SALS in the Han Chinese population (P = 0.009, odds ratio (OR) = 1.266 [1.06-1.51]). The allele and genotype frequencies of rs854971, rs887765 and rs1567871 were not associated with SALS. The distribution of the GAAT haplotype was different between the case and control groups (P = 0.008, OR = 1.289 [1.066-1.558]). In conclusion, our study showed an association between the RTN4R SNP rs696880 and the risk of SALS in the Han Chinese population, with the A allele increasing risk. PMID- 29706888 TI - Antinociceptive and Anxiolytic and Sedative Effects of Methanol Extract of Anisomeles indica: An Experimental Assessment in Mice and Computer Aided Models. AB - Anisomeles indica (L.) kuntze is widely used in folk medicine against various disorders including allergy, sores, inflammation, and fever. This research investigated the antinociceptive, anxiolytic and sedative effects of A. indica methanol extract. The antinociceptive activity was assessed with the acetic acid induced writhing test and formalin-induced flicking test while sedative effects with open field and hole cross tests and anxiolytic effects with elevated plus maze (EPM) and thiopental-induced sleeping time tests were assayed. Computer aided (pass prediction, docking) analyses were undertaken to find out the best fit phytoconstituent of total 14 isolated compounds of this plant for aforesaid effects. Acetic acid treated mice taking different concentrations of extract (50, 100, and 200 mg/kg, intraperitoneal) displayed reduced the writhing number. In the formalin-induced test, extract minimized the paw licking time of mice during the first phase and the second phase significantly. The open field and hole-cross tests were noticed with a dose-dependent reduction of locomotor activity. The EPM test demonstrated an increase of time spent percentage in open arms. Methanol extract potentiated the effect of thiopental-induced hypnosis in lesser extent comparing with Diazepam. The results may account for the use of A. indica as an alternative treatment of antinociception and neuropharmacological abnormalities with further intensive studies. The compound, 3,4-dihydroxybenzoic acid was found to be most effective in computer aided models. PMID- 29706889 TI - Variation in Antiosteoporotic Drug Prescribing and Spending Across Spain. A Population-Based Ecological Cross-Sectional Study. AB - Introduction: Evidence has shown that utilization of antiosteoporotic medications does not correspond with risk, and studies on other therapies have shown that adequacy of pharmaceutical prescribing might vary between regions. Nevertheless, very few studies have addressed the variability in osteoporotic drug consumption. We aimed to describe variations in pharmaceutical utilization and spending on osteoporotic drugs between Health Areas (HA) in Spain. Methods: Population-based cross-sectional ecological study of expenditure and utilization of the five therapeutic groups marketed for osteoporosis treatment in Spain in 2009. Small area variation analysis (SAVA) methods were used. The units of analysis were the 168 HA of 13 Spanish regions, including 7.2 million women aged 50 years and older. The main outcomes were the defined daily dose (DDD) per 1000 inhabitants and day (DDD/1000/Day) dispensed according to the pharmaceutical claims reimbursed, and the expenditure on antiosteoporotics at retail price per woman >=50 years old and per year. Results: The average osteoporosis drug consumption was 116.8 DDD/1000W/Day, ranging from 78.5 to 158.7 DDD/1000W/Day between the HAs in the 5th and 95th percentiles. Seventy-five percent of the antiosteoporotics consumed was bisphosphonates, followed by raloxifene, strontium ranelate, calcitonins, and parathyroid hormones including teriparatide. Regarding variability by therapeutic groups, biphosphonates showed the lowest variation, while calcitonins and parathyroid hormones showed the highest variation. The annual expenditure on antiosteoporotics was ?426.5 million, translating into an expenditure of ?59.2 for each woman >=50 years old and varying between ?38.1 and ?83.3 between HAs in the 5th and 95th percentiles. Biphosphonates, despite accounting for 79% of utilization, only represented 63% of total expenditure, while parathyroid hormones with only 1.6% of utilization accounted for 15% of the pharmaceutical spending. Conclusion: This study highlights a marked geographical variation in the prescription of antiosteoporotics, being more pronounced in the case of costly drugs such as parathyroid hormones. The differences in rates of prescribing explained almost all of the variance in drug spending, suggesting that the difference in prescription volume between territories, and not the price of the drugs, is the main source of variation in this setting. Data on geographical variation of prescription can help guide policy proposals for targeting areas with inadequate antiosteoporotic drug use. PMID- 29706890 TI - Simvastatin Enhances Activity and Trafficking of alpha7 Nicotinic Acetylcholine Receptor in Hippocampal Neurons Through PKC and CaMKII Signaling Pathways. AB - Simvastatin (SV) enhances glutamate release and synaptic plasticity in hippocampal CA1 region upon activation of alpha7 nicotinic acetylcholine receptor (alpha7nAChR). In this study, we examined the effects of SV on the functional activity of alpha7nAChR on CA1 pyramidal cells using patch-clamp recording and explored the underlying mechanisms. We found that the treatment of hippocampal slices with SV for 2 h induced a dose-dependent increase in the amplitude of ACh evoked inward currents (IACh) and the level of alpha7nAChR protein on the cell membrane without change in the level of alpha7nAChR phosphorylation. These SV induced phenotypes were suppressed by addition of farnesol (FOH) that converts farnesyl pyrophosphate, but not geranylgeraniol. Similarly, the farnesyl transferase inhibitor FTI277 was able to increase the amplitude of IACh and enhance the trafficking of alpha7nAChR. The treatment with SV enhanced phosphorylation of CaMKII and PKC. The SV-enhanced phosphorylation of CaMKII rather than PKC was blocked by FOH, Src inhibitor PP2 or NMDA receptor antagonist MK801 and mimicked by FTI. The SV-enhanced phosphorylation of PKC was sensitive to the IP3R antagonist 2-APB. The SV-increased amplitude of IACh was suppressed by PKC inhibitor GF109203X and Go6983, or CaMKII inhibitor KN93. The SV- and FTI enhanced trafficking of alpha7nAChR was sensitive to KN93, but not GF109203X or Go6983. The PKC activator PMA increased alpha7nAChR activity, but had no effect on trafficking of alpha7nAChR. Collectively, these results indicate that acute treatment with SV enhances the activity and trafficking of alpha7nAChR by increasing PKC phosphorylation and reducing farnesyl-pyrophosphate to trigger NMDA receptor-mediated CaMKII activation. PMID- 29706892 TI - Association of STAT-3 rs1053004 and VDR rs11574077 With FOLFIRI-Related Gastrointestinal Toxicity in Metastatic Colorectal Cancer Patients. AB - Pharmacogenomics has largely been applied to the personalization of irinotecan based treatment, focusing mainly on the study of genetic variants in adsorption, distribution, metabolism, and excretion (ADME) genes. The transcriptional control of ADME gene expression is mediated by a set of nuclear factors responding to cancer-related inflammation, which could have pharmacological implications. The aim of the present study was to uncover novel genetic predictors of neutropenia and gastrointestinal toxicity risk among 246 haplotype-tagging polymorphisms in 22 genes encoding inflammation-related cytokines and transcriptional regulators of ADME genes. The study comprised overall more than 400 metastatic colorectal cancer (mCRC) patients treated with first-line FOLFIRI, grouped in a discovery and a replication cohorts. A concordant protective effect of STAT-3 rs1053004 polymorphism against the risk of grade 3-4 gastrointestinal toxicity was observed in both the cohorts of patients (OR = 0.51, p = 0.045, q = 0.521 and OR = 0.39, p = 0.043, respectively). VDR rs11574077 polymorphism was demonstrated to affect both irinotecan biliary index (BI) and glucuronidation ratio (GR) by a pharmacokinetic analysis. This effect was consistent with an increased risk of grade 3-4 gastrointestinal toxicity in the discovery cohort (OR = 4.46, p = 0.010, q = 0.305). The association was not significant in the replication cohort (OR = 1.44, p = 0.601). These findings suggest an effect of STAT-3 and VDR polymorphisms on FOLFIRI-related gastrointestinal toxicity. If prospectively validated as predictive markers, they could be used to improve the clinical management of mCRC. PMID- 29706893 TI - Determinants of Isoform-Specific Gating Kinetics of hERG1 Channel: Combined Experimental and Simulation Study. AB - IKr is the rapidly activating component of the delayed rectifier potassium current, the ion current largely responsible for the repolarization of the cardiac action potential. Inherited forms of long QT syndrome (LQTS) (Lees-Miller et al., 1997) in humans are linked to functional modifications in the Kv11.1 (hERG) ion channel and potentially life threatening arrhythmias. There is little doubt now that hERG-related component of IKr in the heart depends on the tetrameric (homo- or hetero-) channels formed by two alternatively processed isoforms of hERG, termed hERG1a and hERG1b. Isoform composition (hERG1a- vs. the b-isoform) has recently been reported to alter pharmacologic responses to some hERG blockers and was proposed to be an essential factor pre-disposing patients for drug-induced QT prolongation. Very little is known about the gating and pharmacological properties of two isoforms in heart membranes. For example, how gating mechanisms of the hERG1a channels differ from that of hERG1b is still unknown. The mechanisms by which hERG 1a/1b hetero-tetramers contribute to function in the heart, or what role hERG1b might play in disease are all questions to be answered. Structurally, the two isoforms differ only in the N terminal region located in the cytoplasm: hERG1b is 340 residues shorter than hERG1a and the initial 36 residues of hERG1b are unique to this isoform. In this study, we combined electrophysiological measurements for HEK cells, kinetics and structural modeling to tease out the individual contributions of each isoform to Action Potential formation and then make predictions about the effects of having various mixture ratios of the two isoforms. By coupling electrophysiological data with computational kinetic modeling, two proposed mechanisms of hERG gating in two homo-tetramers were examined. Sets of data from various experimental stimulation protocols (HEK cells) were analyzed simultaneously and fitted to Markov-chain models (M-models). The minimization procedure presented here, allowed assessment of suitability of different Markov model topologies and the corresponding parameters that describe the channel kinetics. The kinetics modeling pointed to key differences in the gating kinetics that were linked to the full channel structure. Interactions between soluble domains and the transmembrane part of the channel appeared to be critical determinants of the gating kinetics. The structures of the full channel in the open and closed states were compared for the first time using the recent Cryo-EM resolved structure for full open hERG channel and an homology model for the closed state, based on the highly homolog EAG1 channel. Key potential interactions which emphasize the importance of electrostatic interactions between N-PAS cap, S4-S5, and C-linker are suggested based on the structural analysis. The derived kinetic parameters were later used in higher order models of cells and tissue to track down the effect of varying the ratios of hERG1a and hERG1b on cardiac action potentials and computed electrocardiograms. Simulations suggest that the recovery from inactivation of hERG1b may contribute to its physiologic role of this isoform in the action potential. Finally, the results presented here contribute to the growing body of evidence that hERG1b significantly affects the generation of the cardiac Ikr and plays an important role in cardiac electrophysiology. We highlight the importance of carefully revisiting the Markov models previously proposed in order to properly account for the relative abundance of the hERG1 a- and b- isoforms. PMID- 29706894 TI - High-Performance Agent-Based Modeling Applied to Vocal Fold Inflammation and Repair. AB - Fast and accurate computational biology models offer the prospect of accelerating the development of personalized medicine. A tool capable of estimating treatment success can help prevent unnecessary and costly treatments and potential harmful side effects. A novel high-performance Agent-Based Model (ABM) was adopted to simulate and visualize multi-scale complex biological processes arising in vocal fold inflammation and repair. The computational scheme was designed to organize the 3D ABM sub-tasks to fully utilize the resources available on current heterogeneous platforms consisting of multi-core CPUs and many-core GPUs. Subtasks are further parallelized and convolution-based diffusion is used to enhance the performance of the ABM simulation. The scheme was implemented using a client-server protocol allowing the results of each iteration to be analyzed and visualized on the server (i.e., in-situ) while the simulation is running on the same server. The resulting simulation and visualization software enables users to interact with and steer the course of the simulation in real-time as needed. This high-resolution 3D ABM framework was used for a case study of surgical vocal fold injury and repair. The new framework is capable of completing the simulation, visualization and remote result delivery in under 7 s per iteration, where each iteration of the simulation represents 30 min in the real world. The case study model was simulated at the physiological scale of a human vocal fold. This simulation tracks 17 million biological cells as well as a total of 1.7 billion signaling chemical and structural protein data points. The visualization component processes and renders all simulated biological cells and 154 million signaling chemical data points. The proposed high-performance 3D ABM was verified through comparisons with empirical vocal fold data. Representative trends of biomarker predictions in surgically injured vocal folds were observed. PMID- 29706891 TI - Targeting DNA Methyltranferases in Urological Tumors. AB - Urological cancers are a heterogeneous group of malignancies accounting for a considerable proportion of cancer-related morbidity and mortality worldwide. Aberrant epigenetic traits, especially altered DNA methylation patterns constitute a hallmark of these tumors. Nonetheless, these alterations are reversible, and several efforts have been carried out to design and test several epigenetic compounds that might reprogram tumor cell phenotype back to a normal state. Indeed, several DNMT inhibitors are currently under evaluation for therapeutic efficacy in clinical trials. This review highlights the critical role of DNA methylation in urological cancers and summarizes the available data on pre clinical assays and clinical trials with DNMT inhibitors in bladder, kidney, prostate, and testicular germ cell cancers. PMID- 29706895 TI - LiverSex Computational Model: Sexual Aspects in Hepatic Metabolism and Abnormalities. AB - The liver is to date the best example of a sexually dimorphic non-reproductive organ. Over 1,000 genes are differentially expressed between sexes indicating that female and male livers are two metabolically distinct organs. The spectrum of liver diseases is broad and is usually prevalent in one or the other sex, with different contributing genetic and environmental factors. It is thus difficult to predict individual's disease outcomes and treatment options. Systems approaches including mathematical modeling can aid importantly in understanding the multifactorial liver disease etiology leading toward tailored diagnostics, prognostics and therapy. The currently established computational models of hepatic metabolism that have proven to be essential for understanding of non alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC) are limited to the description of gender-independent response or reflect solely the response of the males. Herein we present LiverSex, the first sex-based multi tissue and multi-level liver metabolic computational model. The model was constructed based on in silico liver model SteatoNet and the object-oriented modeling. The crucial factor in adaptation of liver metabolism to the sex is the inclusion of estrogen and androgen receptor responses to respective hormones and the link to sex-differences in growth hormone release. The model was extensively validated on literature data and experimental data obtained from wild type C57BL/6 mice fed with regular chow and western diet. These experimental results show extensive sex-dependent changes and could not be reproduced in silico with the uniform model SteatoNet. LiverSex represents the first large-scale liver metabolic model, which allows a detailed insight into the sex-dependent complex liver pathologies, and how the genetic and environmental factors interact with the sex in disease appearance and progression. We used the model to identify the most important sex-dependent metabolic pathways, which are involved in accumulation of triglycerides representing initial steps of NAFLD. We identified PGC1A, PPARalpha, FXR, and LXR as regulatory factors that could become important in sex-dependent personalized treatment of NAFLD. PMID- 29706896 TI - Modulation of Connexin-36 Gap Junction Channels by Intracellular pH and Magnesium Ions. AB - Connexin-36 (Cx36) protein forms gap junction (GJ) channels in pancreatic beta cells and is also the main Cx isoform forming electrical synapses in the adult mammalian brain. Cx36 GJs can be regulated by intracellular pH (pHi) and cytosolic magnesium ion concentration ([Mg2+]i), which can vary significantly under various physiological and pathological conditions. However, the combined effect and relationship of these two factors over Cx36-dependent coupling have not been previously studied in detail. Our experimental results in HeLa cells expressing Cx36 show that changes in both pHi and [Mg2+]i affect junctional conductance (gj) in an interdependent manner; in other words, intracellular acidification cause increase or decay in gj depending on whether [Mg2+]i is high or low, respectively, and intracellular alkalization cause reduction in gj independently of [Mg2+]i. Our experimental and modelling data support the hypothesis that Cx36 GJ channels contain two separate gating mechanisms, and both are differentially sensitive to changes in pHi and [Mg2+]i. Using recombinant Cx36 we found that two glutamate residues in the N-terminus could be partly responsible for the observed interrelated effect of pHi and [Mg2+]i. Mutation of glutamate at position 8 attenuated the stimulatory effect of intracellular acidification at high [Mg2+]i, while mutation at position 12 and double mutation at both positions reversed stimulatory effect to inhibition. Moreover, Cx36*E8Q lost the initial increase of gj at low [Mg2+]i and double mutation lost the sensitivity to high [Mg2+]i. These results suggest that E8 and E12 are involved in regulation of Cx36 GJ channels by Mg2+ and H+ ions. PMID- 29706898 TI - Injection-Less Conductance Method for Vascular Sizing. AB - Lumen vessel sizing is important for optimization of interventional outcomes for treatment of vascular disease. The objective of this study is to develop an injection-less method to determine the lumen diameter, using multiple frequencies that eliminates the need for saline injections. We utilize the same electrical conductance devices developed for the two-injection method. A mathematical electrical model was devised to estimate the lumen area and diameter of the arteries. In vitro experiments were used to validate the method for various lumen diameters with both 5-5-5 (peripheral) and 2-2-2 (coronary) spacing conductance guidewires. The majority of 11 vessel data fall within one standard deviation and all the data fall within two standard deviations. The results indicate that the two-frequency model can reasonably predict the lumen diameter in an in-vitro test set-up. Our findings show that this approach can potentially translate to in vivo which would enable pull-back to reconstruct the lumen area profile of the vessel. PMID- 29706897 TI - Hypoxia Tolerance in Teleosts: Implications of Cardiac Nitrosative Signals. AB - Changes in environmental oxygen (O2) are naturally occurring phenomena which ectotherms have to face on. Many species exhibit a striking capacity to survive and remain active for long periods under hypoxia, even tolerating anoxia. Some fundamental adaptations contribute to this capacity: metabolic suppression, tolerance of pH and ionic unbalance, avoidance and/or repair of free-radical induced cell injury during reoxygenation. A remarkable feature of these species is their ability to preserve a normal cardiovascular performance during hypoxia/anoxia to match peripheral (tissue pO2) requirements. In this review, we will refer to paradigms of hypoxia- and anoxia-tolerant teleost fish to illustrate cardiac physiological strategies that, by involving nitric oxide and its metabolites, play a critical role in the adaptive responses to O2 limitation. The information here reported may contribute to clarify the molecular and cellular mechanisms underlying heart vulnerability vs. resistance in relation to O2 availability. PMID- 29706899 TI - Development of the Human Placenta and Fetal Heart: Synergic or Independent? AB - The placenta is the largest fetal organ, and toward the end of pregnancy the umbilical circulation receives at least 40% of the biventricular cardiac output. It is not surprising, therefore, that there are likely to be close haemodynamic links between the development of the placenta and the fetal heart. Development of the placenta is precocious, and in advance of that of the fetus. The placenta undergoes considerable remodeling at the end of the first trimester of pregnancy, and its vasculature is capable of adapting to environmental conditions and to variations in the blood supply received from the mother. There are two components to the placental membranes to consider, the secondary yolk sac and the chorioallantoic placenta. The yolk sac is the first of the extraembryonic membranes to be vascularized, and condensations in the mesenchyme at ~17 days post-conception (p.c.) give rise to endothelial and erythroid precursors. A network of blood vessels is established ~24 days p.c., with the vitelline vein draining through the region of the developing liver into the sinus venosus. Gestational sacs of early pregnancy failures often display aberrant development of the yolk sac, which is likely to be secondary to abnormal fetal development. Vasculogenesis occurs in the villous mesenchyme of the chorioallantoic placenta at a similarly early stage. Nucleated erythrocytes occupy the lumens of the placental capillaries and end-diastolic flow is absent in the umbilical arterial circulation throughout most of the first trimester, indicating a high resistance to blood flow. Resistance begins to fall in the umbilico-placental circulation around 12-14 weeks. During normal early pregnancy the placental capillary network is plastic, and considerable remodeling occurs in response to the local oxygen concentration, and in particular to oxidative stress. In pregnancies complicated by preeclampsia and/or fetal growth restriction, utero-placental malperfusion induces smooth muscle cells surrounding the placental arteries to dedifferentiate and adopt a proliferative phenotype. This change is associated with increased umbilical resistance measured by Doppler ultrasound, and is likely to exert a major effect on the developing heart through the afterload. Thus, both the umbilical and maternal placental circulations may impact on development of the heart. PMID- 29706900 TI - Short-Term Dosage Regimen for Stimulation-Induced Long-Lasting Desynchronization. AB - In this paper, we computationally generate hypotheses for dose-finding studies in the context of desynchronizing neuromodulation techniques. Abnormally strong neuronal synchronization is a hallmark of several brain disorders. Coordinated Reset (CR) stimulation is a spatio-temporally patterned stimulation technique that specifically aims at disrupting abnormal neuronal synchrony. In networks with spike-timing-dependent plasticity CR stimulation may ultimately cause an anti-kindling, i.e., an unlearning of abnormal synaptic connectivity and neuronal synchrony. This long-lasting desynchronization was theoretically predicted and verified in several pre-clinical and clinical studies. We have shown that CR stimulation with rapidly varying sequences (RVS) robustly induces an anti kindling at low intensities e.g., if the CR stimulation frequency (i.e., stimulus pattern repetition rate) is in the range of the frequency of the neuronal oscillation. In contrast, CR stimulation with slowly varying sequences (SVS) turned out to induce an anti-kindling more strongly, but less robustly with respect to variations of the CR stimulation frequency. Motivated by clinical constraints and inspired by the spacing principle of learning theory, in this computational study we propose a short-term dosage regimen that enables a robust anti-kindling effect of both RVS and SVS CR stimulation, also for those parameter values where RVS and SVS CR stimulation previously turned out to be ineffective. Intriguingly, for the vast majority of parameter values tested, spaced multishot CR stimulation with demand-controlled variation of stimulation frequency and intensity caused a robust and pronounced anti-kindling. In contrast, spaced CR stimulation with fixed stimulation parameters as well as singleshot CR stimulation of equal integral duration failed to improve the stimulation outcome. In the model network under consideration, our short-term dosage regimen enables to robustly induce long-term desynchronization at comparably short stimulation duration and low integral stimulation duration. Currently, clinical proof of concept is available for deep brain CR stimulation for Parkinson's therapy and acoustic CR stimulation for tinnitus therapy. Promising first in human data is available for vibrotactile CR stimulation for Parkinson's treatment. For the clinical development of these treatments it is mandatory to perform dose-finding studies to reveal optimal stimulation parameters and dosage regimens. Our findings can straightforwardly be tested in human dose-finding studies. PMID- 29706901 TI - Silencing of Chemosensory Protein Gene NlugCSP8 by RNAi Induces Declining Behavioral Responses of Nilaparvata lugens. AB - Chemosensory proteins (CSPs) play imperative functions in chemical and biochemical signaling of insects, as they distinguish and transfer ecological chemical indications to a sensory system in order to initiate behavioral responses. The brown planthopper (BPH), Nilaparvata lugens Stal (Hemiptera: Delphacidae), has emerged as the most destructive pest, causing serious damage to rice in extensive areas throughout Asia. Biotic characteristics like monophagy, dual wing forms, and annual long-distance migration imply a critical role of chemoreception in N. lugens. In this study, we cloned the full-length CSP8 gene from N. lugens. Protein sequence analysis indicated that NlugCSP8 shared high sequence resemblance with the CSPs of other insect family members and had the typical four-cysteine signature. Analysis of gene expression indicated that NlugCSP8 mRNA was specifically expressed in the wings of mated 3-day brachypterous females with a 175-fold difference compare to unmated 3-day brachypterous females. The NlugCSP8 mRNA was also highly expressed in the abdomen of unmated 5-day brachypterous males and correlated to the age, gender, adult wing form, and mating status. A competitive ligand-binding assay demonstrated that ligands with long chain carbon atoms, nerolidol, hexanal, and trans-2 hexenal were able to bind to NlugCSP8 in declining order of affinity. By using bioinformatics techniques, three-dimensional protein structure modeling and molecular docking, the binding sites of NlugCSP8 to the volatiles which had high binding affinity were predicted. In addition, behavioral experiments using the compounds displaying the high binding affinity for the NlugCSP8, revealed four compounds able to elicit significant behavioral responses from N. lugens. The in vivo functions of NlugCSP8 were further confirmed through the testing of RNAi and post-RNAi behavioral experiments. The results revealed that reduction in NlugCSP8 transcript abundance caused a decrease in behavioral response to representative attractants. An enhanced understanding of the NlugCSP8 is expected to contribute in the improvement of more effective and eco-friendly control strategies of BPH. PMID- 29706902 TI - Identification of Candidate Iron Transporters From the ZIP/ZnT Gene Families in the Mosquito Aedes aegypti. AB - Mosquito-transmitted viral pathogens, such as dengue and Zika, afflict tens of thousands of people every year. These viruses are transmitted during the blood feeding process that is required for mosquito reproduction, the most important vector being Aedes aegypti. While vertebrate blood is rich in protein, its high iron content is potentially toxic to mosquitoes. Although iron transport and sequestration are essential in the reproduction of vector mosquitoes, we discovered that culicine mosquitoes lack homologs of the common iron transporter NRAMP. Using a novel cell-based screen, we identified two ZIP and one ZnT genes as candidate iron transporters in the mosquito A. aegypti, the vector of dengue, Zika, and chikungunya. We determined the organ-specific expression pattern of these genes at critical time points in early reproduction. The result indicates modulation of these genes upon blood feeding, especially a ZIP13 homolog that is highly up-regulated after blood feeding, suggesting its importance in iron mobilization during blood digestion and reproduction. Gene silencing resulted in differential iron accumulation in the midgut and ovaries. This study sets a foundation for further investigation of iron transport and control strategies of this viral vector. PMID- 29706903 TI - High Molecular Weight Polymer Promotes Bone Health and Prevents Bone Loss Under Salmonella Challenge in Broiler Chickens. AB - As a consequence of rapid growth, broiler chickens are more susceptible to infection as well as bone fractures that result in birds being culled. Intestinal infection/inflammation has been demonstrated to promote bone loss in mice and humans. Given this link, we hypothesize that therapeutics that target the gut can benefit bone health. To test this, we infected broiler chickens (7 days old) with Salmonella and treated the birds with or without MDY, a non-absorbable mucus supplement known to benefit intestinal health, from day 1-21 or from day 14-21. Chicken femoral trabecular and cortical bone parameters were analyzed by microcomputed tomography at 21 days. Birds infected with Salmonella displayed significant trabecular bone loss and bone microarchitecture abnormalities that were specific to the femoral neck region, a common site of fracture in chickens. Histological analyses of the chicken bone indicated an increase in osteoclast surface/bone surface in this area indicating that infection-induced bone resorption likely causes the bone loss. Of great interest, treatment with MDY effectively prevented broiler chicken bone loss and architectural changes when given chronically throughout the experiment or for only a week after infection. The latter suggests that MDY may not only prevent bone loss but reverse bone loss. MDY also increased cortical bone mineral density in Salmonella-treated chickens. Taken together, our studies demonstrate that Salmonella-induced bone loss in broiler chickens is prevented by oral MDY. PMID- 29706905 TI - Positive Effects of an Anti-Aggression and De-Escalation Training on Ward Atmosphere and Subjective Safety May Depend on Previous Training Experience. AB - Anti-aggression and de-escalation (ADE) trainings of health-care professionals working on psychiatric inpatient wards have been shown to increase staff knowledge and confidence, which could be connected with higher subjective safety. Additionally, a potential reduction of aggressive incidents could improve ward atmosphere. Thus, the current study aimed to investigate the effects of ADE training on ward atmosphere and subjective safety. In 2015, an ADE training was established at the Psychiatric University Clinics (UPK), University of Basel. Nursing staff from 22 wards received theoretical and practical training over the course of 5 days. Ward atmosphere and subjective safety were assessed using the Essen Climate Evaluation Schema (EssenCES). A total of 46 people had been assessed in 2012 before training implementation (baseline), and 45 persons in 2016 after implementation. In the 2016 group, 23 people had previously participated in an ADE training, and 22 were first-time participants. Patients' coherence (p = 0.004), subjective safety (p = 0.004), and ward atmosphere (p = 0.001) were rated significantly higher by first-time ADE training participants compared to baseline, and patients' coherence (p = 0.029) and ward atmosphere (p = 0.011) were rated significantly higher by first-time ADE training participants than by nurses with prior ADE training. There were no significant differences regarding any EssenCES ratings by nurses with prior ADE training compared to baseline. ADE training was exclusively connected with higher ratings on most EssenCES scales for first-time participants. This indicates that the positive effects of ADE training may depend on previous training experience. PMID- 29706904 TI - Illness Perception of Patients with Functional Gastrointestinal Disorders. AB - Objective: To investigate the illness perception characteristics of Chinese patients with functional gastrointestinal disorders (FGID), and the mediating role between symptoms, psychopathology, and clinical outcomes. Methods: Six illness groups from four outpatient departments of a general hospital in China were recruited, including the FGID patient group. The modified and validated Chinese version of the illness perception questionnaire-revised was utilized, which contained three sections: symptom identity, illness representation, and causes. The 12-item short-form health survey was utilized to reflect the physical and mental health-related quality of life (HRQoL). The Toronto alexithymia scale was used to measure the severity of alexithymia. Additional behavioral outcome about the frequency of doctor visits in the past 12 months was measured. Pathway analyses with multiple-group comparisons were conducted to test the mediating role of illness perception. Results: Overall, 600 patients were recruited. The illness perceptions of FGID patients were characterized as with broad non gastrointestinal symptoms (6.8 +/- 4.2), a negative illness representation (more chronic course, worse consequences, lower personal and treatment control, lower illness coherence, and heavier emotional distress), and high numbers of psychological and culture-specific attributions. Fit indices of the three hypothesized path models (for physical and mental HRQoL and doctor-visit frequency, respectively) supported the mediating role of illness perceptions. For example, the severity of alexithymia and non-gastrointestinal symptoms had significant negative effect on mental quality of life through both direct (standardized effect: -0.085 and -0.233) and indirect (standardized effect: 0.045 and -0.231) influence via subscales of consequences, emotional representation, and psychological and risk factor attributions. Multi-group confirmatory factor analysis showed similar psychometric properties for FGID patients and the other disease group. Conclusion: The management of FGID patients should take into consideration dysfunctional illness perceptions, non gastrointestinal symptoms, and emotion regulation. PMID- 29706907 TI - Attentional Bias in Human Category Learning: The Case of Deep Learning. AB - Category learning performance is influenced by both the nature of the category's structure and the way category features are processed during learning. Shepard (1964, 1987) showed that stimuli can have structures with features that are statistically uncorrelated (separable) or statistically correlated (integral) within categories. Humans find it much easier to learn categories having separable features, especially when attention to only a subset of relevant features is required, and harder to learn categories having integral features, which require consideration of all of the available features and integration of all the relevant category features satisfying the category rule (Garner, 1974). In contrast to humans, a single hidden layer backpropagation (BP) neural network has been shown to learn both separable and integral categories equally easily, independent of the category rule (Kruschke, 1993). This "failure" to replicate human category performance appeared to be strong evidence that connectionist networks were incapable of modeling human attentional bias. We tested the presumed limitations of attentional bias in networks in two ways: (1) by having networks learn categories with exemplars that have high feature complexity in contrast to the low dimensional stimuli previously used, and (2) by investigating whether a Deep Learning (DL) network, which has demonstrated humanlike performance in many different kinds of tasks (language translation, autonomous driving, etc.), would display human-like attentional bias during category learning. We were able to show a number of interesting results. First, we replicated the failure of BP to differentially process integral and separable category structures when low dimensional stimuli are used (Garner, 1974; Kruschke, 1993). Second, we show that using the same low dimensional stimuli, Deep Learning (DL), unlike BP but similar to humans, learns separable category structures more quickly than integral category structures. Third, we show that even BP can exhibit human like learning differences between integral and separable category structures when high dimensional stimuli (face exemplars) are used. We conclude, after visualizing the hidden unit representations, that DL appears to extend initial learning due to feature development thereby reducing destructive feature competition by incrementally refining feature detectors throughout later layers until a tipping point (in terms of error) is reached resulting in rapid asymptotic learning. PMID- 29706906 TI - Editorial: Computers and Games for Mental Health and Well-Being. PMID- 29706909 TI - Recognizing Emily and Latisha: Inconsistent Effects of Name Stereotypicality on the Other-Race Effect. AB - A person's name may activate social category information, which has been shown to lead to stereotyping and discrimination in various contexts. However, no previous research has investigated the influence of names on more basic processes of person perception. We present a set of seven experimental studies examining the influence of names on face recognition, namely, on the other-race effect (i.e., the relative difficulty to recognize outgroup faces). White-American participants completed online recognition tasks with White ingroup faces and Black or Chinese outgroup faces. Outgroup faces were presented with typical outgroup names versus typical White names; White faces were presented with typical White names versus infrequent names. We expected better recognition of outgroup faces with typical White names compared to outgroup faces with typical outgroup names. Employing an internal meta-analysis, we observe overall evidence of a small but significant effect (dz = 0.11). However, the pattern of results across the seven studies is inconsistent. Given that particularly the high-powered pre-registered studies did not show an effect, we suggest that the effect should be interpreted with caution. We discuss that a small effect may still have important implications for real life as well as for theories of the ORE, emphasizing the importance of future research regarding the influence of name typicality on inter-group face perception. PMID- 29706908 TI - Event-Related-Potential (ERP) Correlates of Performance Monitoring in Adults With Attention-Deficit Hyperactivity Disorder (ADHD). AB - Introduction: Attention-deficit hyperactivity disorder (ADHD) is one of the most frequent neurodevelopmental disorders in children and tends to persist into adulthood. Evidence from neuropsychological, neuroimaging, and electrophysiological studies indicates that alterations of error processing are core symptoms in children and adolescents with ADHD. To test whether adults with ADHD show persisting deficits and compensatory processes, we investigated performance monitoring during stimulus-evaluation and response-selection, with a focus on errors, as well as within-group correlations with symptom scores. Methods: Fifty-five participants (27 ADHD and 28 controls) aged 19-55 years performed a modified flanker task during EEG recording with 64 electrodes, and the ADHD and control groups were compared on measures of behavioral task performance, event-related potentials of performance monitoring (N2, P3), and error processing (ERN, Pe). Adult ADHD Self-Report Scale (ASRS) was used to assess ADHD symptom load. Results: Adults with ADHD showed higher error rates in incompatible trials, and these error rates correlated positively with the ASRS scores. Also, we observed lower P3 amplitudes in incompatible trials, which were inversely correlated with symptom load in the ADHD group. Adults with ADHD also displayed reduced error-related ERN and Pe amplitudes. There were no significant differences in reaction time (RT) and RT variability between the two groups. Conclusion: Our findings show deviations of electrophysiological measures, suggesting reduced effortful engagement of attentional and error-monitoring processes in adults with ADHD. Associations between ADHD symptom scores, event related potential amplitudes, and poorer task performance in the ADHD group further support this notion. PMID- 29706910 TI - Development of an Online and Offline Integration Hypothesis for Healthy Internet Use: Theory and Preliminary Evidence. AB - The Internet has become an integral part of our daily life, and how to make the best use of the Internet is important to both individuals and the society. Based on previous studies, an Online and Offline Integration Hypothesis is proposed to suggest a framework for considering harmonious and balanced Internet use. The Integration Hypothesis proposes that healthier patterns of Internet usage may be achieved through harmonious integration of people's online and offline worlds. An online/offline integration is proposed to unite self-identity, interpersonal relationships, and social functioning with both cognitive and behavioral aspects by following the principles of communication, transfer, consistency, and "offline first" priorities. To begin to test the hypothesis regarding the relationship between integration level and psychological outcomes, data for the present study were collected from 626 undergraduate students (41.5% males). Participants completed scales for online and offline integration, Internet addiction, pros and cons of Internet use, loneliness, extraversion, and life satisfaction. The findings revealed that subjects with higher level of online/offline integration have higher life satisfaction, greater extraversion, and more positive perceptions of the Internet and less loneliness, lower Internet addiction, and fewer negative perceptions of the Internet. Integration mediates the link between extraversion and psychological outcomes, and it may be the mechanism underlying the difference between the "rich get richer" and social compensation hypotheses. The implications of the online and offline integration hypothesis are discussed. PMID- 29706911 TI - Motorized Recreation Sounds Influence Nature Scene Evaluations: The Role of Attitude Moderators. AB - Soundscape assessment takes many forms, including letting the consequences of the soundscape be an indicator of soundscape quality or value. As a result, much social science research has been conducted to better quantify problem soundscapes and the subsequent effects on humans exposed to them. Visual evaluations of natural environments are one area where research has consistently shown detrimental effects of noisy or anthropogenic soundscapes (e.g., those containing noise from motorized recreation), but the potential moderating role of individual attitudes toward elements within the soundscape has not been sufficiently explored. This study demonstrates that both pro-motorized recreation and pro motorized recreation management attitudes can alter the effect of motorized recreation noise on scenic evaluations in opposing directions. Pro-recreation attitudes lessen the effect of the soundscape, while pro-management attitudes heighten the negative effect of anthropogenic sounds on scenic evaluation. The implications for other areas of soundscape research, especially with regard to soundscape quality assessment through experienced outcomes, are discussed, including possible strategies for prioritizing known or relevant moderating variables. PMID- 29706912 TI - The Diaper Change Play: Validation of a New Observational Assessment Tool for Early Triadic Family Interactions in the First Month Postpartum. AB - The quality of family relations, observed during mother-father-infant triadic interactions, has been shown to be an important contributor to child social and affective development, beyond the quality of dyadic mother-child, father-child, and marital relationships. Triadic interactions have been well described in families with 3 month olds and older children using the Lausanne Trilogue Play (LTP). Little is known about the development of mother-father-baby interactions in the very 1st weeks postpartum, mostly because no specific observational setting or particular instrument had been designed to cover this age yet. To fill this gap, we adapted the LTP to create a new observational setting, namely the Diaper Change Play (DCP). Interactions are assessed using the Family Alliance Assessment Scales for DCP (FAAS-DCP). We present the validation of the DCP and its coding system, the FAAS-DCP. The three validation studies presented here (44 mother-father-child-triads) involve a sample of parents with 3-week-old infants recruited in two maternity wards (n = 32 and n = 12) in Switzerland. Infants from both sites were all healthy according to their APGAR scores, weight at birth, and scores on the NICU Network Neurobehavioral Scale (NNNS), which was additionally conducted on the twelve infants recruited in one of the maternity ward. Results showed that the "FAAS - DCP" coding system has good psychometric properties, with a good internal consistency and a satisfying reliability among the three independent raters. Finally, the "FAAS-DCP" scores on the interactive dimensions are comparable to the similar dimensions in the FAAS-LTP. The results showed that there is no statistically significant difference on scores between the "FAAS-DCP" and the "FAAS," which is consistent with previous studies underlying stability in triadic interaction patterns from pregnancy to 18 months. These first results indicated that the DCP is a promising observational setting, able to assess the development of the early family triadic functioning. The DCP and the FAAS-DCP offer to both clinicians and researchers a way to improve the understanding of the establishment of early family functioning as well as to study the young infant's triangular capacity. Perspectives for future research will be discussed. PMID- 29706913 TI - Understanding Conditionals in the East: A Replication Study of With Easterners. AB - The new probabilistic approaches to the natural language conditional imply that there is a parallel relation between indicative conditionals (ICs) "if s then b" and conditional bets (CBs) "I bet $1 that if s then b" in two aspects. First, the probability of an IC and the probability of winning a CB are both the conditional probability, P(s|b). Second, both an IC and a CB have a third value "void" (neither true nor false, neither wins nor loses) when the antecedent is false (!s). These aspects of the parallel relation have been found in Western participants. In the present study, we investigated whether this parallel is also present in Eastern participants. We replicated the study of Politzer et al. (2010) with Chinese and Japanese participants and made two predictions. First, Eastern participants will tend to engage in more holistic cognition and take all possible cases, including !s, into account when they judge the probability of conditional: Easterners may assess the probability of antecedent s out of all possible cases, P(s), and then may focus on consequent b out of s, P(b|s). Consequently, Easterners may judge the probability of the conditional, and of winning the bet, to be P(s) * P(b|s) = P(s & b), and false/losing the bet as P(s) * P(!b|s) = P(s & !b). Second, Eastern participants will tend to be strongly affected by context, and they may not show parallel relationships between ICs and CBs. The results indicate no cultural differences in judging the false antecedent cases: Eastern participants judged false antecedent cases as not making the IC true nor false and as not being winning or losing outcomes. However, there were cultural differences when asked about the probability of a conditional. Consistent with our hypothesis, Eastern participants had a greater tendency to take all possible cases into account, especially in CBs. We discuss whether these results can be explained by a hypothesized tendency for Eastern people to think in more holistic and context-dependent terms than Western people. PMID- 29706914 TI - Effect of Brief Mindfulness Induction on University Athletes' Sleep Quality Following Night Training. AB - Given the need to alleviate sleep problems confronting athletes, the present experiment, conducted as much as possible in a naturalistic fashion that mimics daily life, seeks to examine whether a brief mindfulness induction immediately prior to sleep following night training can improve athletes' sleep. A sample of university athletes (n = 80) was recruited and 63 of them were eligible to participate in this experiment. They were then randomly assigned into experimental group (n = 32) and control group (n = 31). Following night training and just prior to sleep, those in the experimental group received a self administered brief 6-min mindfulness induction via a video clip, whereas the control group participants viewed a similar 6-min video devoid of mindfulness induction passively. Questionnaire-based measures of training intensity, pre sleep arousal, state mindfulness, and sleep diary (i.e., level of rest, sleep duration, and overall sleep quality) were administered. Results showed that brief mindfulness induction reduced pre-sleep arousal, and improved level of rest and overall sleep quality, but not sleep duration. Pre-sleep arousal was also found to be a partial mediator in the relationship between the brief mindfulness induction and reported level of rest during sleep. These findings suggest that the brief mindfulness induction may be an effective approach for decreasing pre sleep arousal and improving sleep quality after night training among athletes. PMID- 29706915 TI - The Impact of Morphological Awareness on Word Reading and Dictation in Chinese Early Adolescent Readers With and Without Dyslexia. AB - This study investigated the role of morphological awareness in understanding Chinese word reading and dictation among Chinese-speaking adolescent readers in Hong Kong as well as the cognitive-linguistic profile of early adolescent readers with dyslexia. Fifty-four readers with dyslexia in Grades 5 and 6 were compared with 54 chronological age-matched (CA) typical readers on the following measures of cognitive-linguistic and literacy skills: morphological awareness, phonological awareness, visual-orthographic knowledge, rapid naming, vocabulary knowledge, verbal short-term memory (STM), Chinese word reading, and dictation (or spelling). The results indicated that early adolescent readers with dyslexia performed less well than the typical readers on all cognitive-linguistic and literacy measures except the phonological measures. Both groups' scores showed substantial correlations between morphological awareness and Chinese word reading and dictation. Visual-orthographic knowledge and rapid naming were also associated with dictation in early adolescent readers with and without dyslexia, respectively. Moderated multiple regression analyses further revealed that morphological awareness and rapid naming explained unique variance in word reading and dictation for the readers with dyslexia and typical readers separately after controlling readers' age and group effect. These results highlight the potential importance of morphological awareness and rapid naming in Chinese word reading and writing in Chinese early adolescents' literacy development and impairment. PMID- 29706916 TI - Development and Psychometric Evaluation of the Adaptive Functions of Music Listening Scale. AB - Music listening may serve many adaptive functions in everyday life. However, studies examining the relationship between the functions of music listening (FML) and wellbeing outcomes have produced mixed findings. The purpose of this study is to develop a new measure to assess music listening functions that is psychometrically robust, and suitable for outcomes-based research on music listening and wellbeing. Scale items were developed based on a literature review and a prior qualitative enquiry. The items were reviewed by four content experts in music psychology and scale development. Scale structure was investigated by EFA and CFA in two large samples of participants (N = 1,191, 17-66 years, M = 22.04, SD = 6.23, 326 males). Tests of dimensionality revealed a 46-item scale with 11 factors for the Adaptive Functions of Music Listening (AFML) scale. Namely, Stress Regulation, Anxiety Regulation, Anger Regulation, Loneliness Regulation, Rumination, Reminiscence, Strong Emotional Experiences, Awe and Appreciation, Cognitive Regulation, Identity, and Sleep FML. The scale and its subscales possess good internal consistency and construct validity. In line with theory and research on gender differences in FML, scores on factors representing affect regulation FML were significantly higher among female respondents. Supporting the concurrent validity of the AFML scale, factors were positively correlated with an existing measure of the FML-the Music USE questionnaire. Further evidence of construct validity derives from positive associations between affect regulation factor scores and level of reappraisal, and lack of association with suppression, as measured by the Emotion Regulation Questionnaire. Consistent with the view that adaptive FML are positively related to wellbeing, a number of factors, affect regulation factors in particular, were significantly positively correlated with subjective, psychological, and social wellbeing measures across two cross-sectional studies. PMID- 29706917 TI - Magnitude or Multitude - What Counts? AB - Recent studies revealed an association of low or high numbers (e.g., 1 vs. 9) and word semantics referring to entities typically found in upper or lower space (e.g., roof vs. root) indicating overlapping spatial representations. Another line of research revealed a similar association of grammatical number as a syntactic aspect of language and physical space: singular words were associated with left and plural words with right - resembling spatial-numerical associations of low numbers with left and high numbers with right. The present study aimed at integrating these lines of research by evaluating both types of spatial relations in one experiment. In a lexical decision task, pairs of a numerical cue and a subsequent plural noun were presented. For word with spatial associations (e.g., roofs vs. roots) number magnitude was expected to serve as a spatial cue. For spatially neutral words (e.g., tables) numbers were expected to cue multitude. Results showed the expected congruency-effect between the numbers and words with spatial associations (i.e., small numbers facilitate responses to down-words and high numbers to up-words). However, no effect was found for numbers and spatially neutral words. This seems to indicate that spatial aspects of word meaning may be related more closely to the magnitude of numbers than grammatical number is to the multitude reflected by numbers - at least in the current experimental setting, where only plural words were presented. PMID- 29706918 TI - Using Serial and Discrete Digit Naming to Unravel Word Reading Processes. AB - During reading acquisition, word recognition is assumed to undergo a developmental shift from slow serial/sublexical processing of letter strings to fast parallel processing of whole word forms. This shift has been proposed to be detected by examining the size of the relationship between serial- and discrete trial versions of word reading and rapid naming tasks. Specifically, a strong association between serial naming of symbols and single word reading suggests that words are processed serially, whereas a strong association between discrete naming of symbols and single word reading suggests that words are processed in parallel as wholes. In this study, 429 Grade 1, 3, and 5 English-speaking Canadian children were tested on serial and discrete digit naming and word reading. Across grades, single word reading was more strongly associated with discrete naming than with serial naming of digits, indicating that short high frequency words are processed as whole units early in the development of reading ability in English. In contrast, serial naming was not a unique predictor of single word reading across grades, suggesting that within-word sequential processing was not required for the successful recognition for this set of words. Factor mixture analysis revealed that our participants could be clustered into two classes, namely beginning and more advanced readers. Serial naming uniquely predicted single word reading only among the first class of readers, indicating that novice readers rely on a serial strategy to decode words. Yet, a considerable proportion of Grade 1 students were assigned to the second class, evidently being able to process short high-frequency words as unitized symbols. We consider these findings together with those from previous studies to challenge the hypothesis of a binary distinction between serial/sublexical and parallel/lexical processing in word reading. We argue instead that sequential processing in word reading operates on a continuum, depending on the level of reading proficiency, the degree of orthographic transparency, and word-specific characteristics. PMID- 29706919 TI - Working Together: Contributions of Corpus Analyses and Experimental Psycholinguistics to Understanding Conversation. AB - As conversation is the most important way of using language, linguists and psychologists should combine forces to investigate how interlocutors deal with the cognitive demands arising during conversation. Linguistic analyses of corpora of conversation are needed to understand the structure of conversations, and experimental work is indispensable for understanding the underlying cognitive processes. We argue that joint consideration of corpus and experimental data is most informative when the utterances elicited in a lab experiment match those extracted from a corpus in relevant ways. This requirement to compare like with like seems obvious but is not trivial to achieve. To illustrate this approach, we report two experiments where responses to polar (yes/no) questions were elicited in the lab and the response latencies were compared to gaps between polar questions and answers in a corpus of conversational speech. We found, as expected, that responses were given faster when they were easy to plan and planning could be initiated earlier than when they were harder to plan and planning was initiated later. Overall, in all but one condition, the latencies were longer than one would expect based on the analyses of corpus data. We discuss the implication of this partial match between the data sets and more generally how corpus and experimental data can best be combined in studies of conversation. PMID- 29706920 TI - Novice Shooters With Lower Pre-shooting Alpha Power Have Better Performance During Competition in a Virtual Reality Scenario. AB - Competition changes the environment for athletes. The difficulty of training for such stressful events can lead to the well-known effect of "choking" under pressure, which prevents athletes from performing at their best level. To study the effect of competition on the human brain, we recorded pilot electroencephalography (EEG) data while novice shooters were immersed in a realistic virtual environment representing a shooting range. We found a differential between-subject effect of competition on mu (8-12 Hz) oscillatory activity during aiming; compared to training, the more the subject was able to desynchronize his mu rhythm during competition, the better was his shooting performance. Because this differential effect could not be explained by differences in simple measures of the kinematics and muscular activity, nor by the effect of competition or shooting performance per se, we interpret our results as evidence that mu desynchronization has a positive effect on performance during competition. PMID- 29706921 TI - Patients With Very Mild Dementia May Confuse Objective Cognitive Impairments With Subjective Physical Health of Quality of Life: The Tome City Project in Japan. AB - Many elderly people with cognitive dysfunction may observe a decrease in their health levels and quality of life (QOL). The basic concept of QOL consists of several categories including physical functions and mental health. The QOL domain that is most important for elderly people is physical health and, to a lesser extent, psychological health, social relationships, and/ or the environment. Our aim was to explore the relationships between the subjective measure of QOL, an abbreviated version of the World Health Organization Quality of Life (WHOQOL BREF) scale, and the objective measure of impairment, Clinical Dementia Rating (CDR), among elderly people in a community. Totally, 178 community dwellers aged 75 years and above agreed to participate and completed the WHOQOL-BREF; 66 (32 males, 34 females) scored a CDR of 0 (healthy), 86 (33, 53) scored a CDR of 0.5 (questionable dementia or very mild dementia), and 26 (12, 14) scored a CDR of 1 and above (dementia). According to Pearson's correlation coefficient analysis (significance level, p < 0.05), the physical domain of the WHOQOL-BREF had significant statistical negative correlations with all CDR subscales. The CDR subscale of memory impairment had a significant statistical negative correlation with the WHOQOL-BREF subscales of the physical (r = -0.151, p = 0.044) and psychological (r = -0.232, p < 0.002) domains. The CDR subscale of home and hobbies impairment had significant statistical negative correlations with all WHOQOL-BREF subscales including the physical (r = -0.226, p = 0.002), psychological (r = -0.226, p = 0.002), social (r = -0.167, p = 0.026), and environmental (r = -0.204, p = 0.006) domains. Patients with very mild dementia may confuse cognitive impairment and physical disabilities. In the future, we need to systematically combine memory clinics and all departments related to the elderly for the successful early detection and rehabilitation of, and long-term care for, dementia. PMID- 29706922 TI - A Linear Empirical Model of Self-Regulation on Flourishing, Health, Procrastination, and Achievement, Among University Students. AB - This research aimed to analyze the linear bivariate correlation and structural relations between self-regulation -as a central construct-, with flow, health, procrastination and academic performance, in an academic context. A total of 363 college students took part, 101 men (27.8%) and 262 women (72.2%). Participants had an average age of 22 years and were between the first and fifth year of studies. They were from five different programs and two universities in Bogota city (Colombia). A validated ad hoc questionnaire of physical and psychological health was applied along with a battery of tests to measure self-regulation, procrastination, and flourishing. To establish an association relationship, Pearson bivariate correlations were performed using SPSS software (v. 22.0), and structural relationship predictive analysis was performed using an SEM on AMOS software (v. 22.0). Regarding this linear association, it was established that (1) self-regulation has a significant positive association on flourishing and overall health, and a negative effect on procrastination. Regarding the structural relation, it confirmed that (2) self-regulation is a direct and positive predictor of flourishing and health; (3) self-regulation predicts procrastination directly and negatively, and academic performance indirectly and positively; and (4) age and gender have a prediction effect on the analyzed variables. Implications, limitations and future research scope are discussed. PMID- 29706923 TI - Ego Depletion Does Not Interfere With Working Memory Performance. AB - Ego depletion happens if exerting self-control reduces a person's capacity to subsequently control themselves. Previous research has suggested that ego depletion not only interferes with subsequent self-control but also with working memory. However, recent meta-analytical evidence casts doubt onto this. The present study tackles the question if ego depletion does interfere with working memory performance. We induced ego depletion in two ways: using an e-crossing task and using a Stroop task. We then measured working memory performance using the letter-number sequencing task. There was no evidence of ego depletion interfering with working memory performance. Several aspects of our study render this null finding highly robust. We had a large and heterogeneous sample of N = 1,385, which provided sufficient power. We deployed established depletion tasks from two task families (e-crossing task and Stroop), thus making it less likely that the null finding is due to a specific depletion paradigm. We derived several performance scores from the working memory task and ran different analyses to maximize the chances of finding an effect. Lastly, we controlled for two potential moderators, the implicit theories about willpower and dispositional self-control capacity, to ensure that a possible effect on working memory is not obscured by an interaction effect. In sum, this experiment strengthens the position that ego depletion works but does not affect working memory performance. PMID- 29706924 TI - Metacognitive Therapy for Social Anxiety Disorder: An A-B Replication Series Across Social Anxiety Subtypes. AB - Cognitive behavioural therapy (CBT) is the treatment of choice for Social anxiety disorder (SAD). However, factors additional to those emphasised in CBT are the primary cause of psychological disorder according to the metacognitive model. Metacognitive Therapy (MCT) aims to target a perseverative thinking style named the cognitive attentional syndrome and its underlying metacognitive beliefs (beliefs about cognition). The present study aimed to explore the effects of generic MCT for SAD. Treatment related effects were evaluated using direct replication single case (A-B) methodology across three patients with different subtypes of SAD; performance type, generalised and generalised plus avoidant personality disorder, representing increasing SAD severity/complexity. All patients responded during treatment and achieved substantial symptom reductions which were largely maintained at 6 months' follow-up. Metacognitive therapy appears to be a suitable treatment and was associated with positive outcomes for patients with different presentations of SAD. PMID- 29706925 TI - The Indirect Path From Mindful Parenting to Emotional Problems in Adolescents: The Role of Maternal Warmth and Adolescents' Mindfulness. AB - Mindfulness has been demonstrated to have positive effects on children's emotional functioning, and adaptive parenting practices are associated with fewer emotional problems. However, the association between mindful parenting and adolescent emotional problems has not been studied much. In the current study, the indirect path from mindful parenting to adolescent emotional problems was examined, with maternal warmth and adolescent dispositional mindfulness as potential mediators. A sample of 168 mother-child dyads participated in this study. A serial indirect effects model showed mother's mindful parenting could decrease adolescent emotional problems through adolescent's perceived maternal warmth and their dispositional mindfulness. Findings of this study imply that intervention in mindful parenting may have benefits for adolescents' emotional problems through enhancing maternal warmth and children's trait mindfulness. PMID- 29706926 TI - Modulating the Oxytocin System During the Perinatal Period: A New Strategy for Neuroprotection of the Immature Brain? AB - Oxytocin is a neurohypophysal hormone known for its activity during labor and its role in lactation. However, the function of oxytocin (OTX) goes far beyond the peripheral regulation of reproduction, and the central effects of OTX have been extensively investigated, since it has been recognized to influence the learning and memory processes. OTX has also prominent effects on social behavior, anxiety, and autism. Interaction between glucocorticoids, OTX, and maternal behavior may have long-term effects on the developmental program of the developing brain subjected to adverse events during pre and perinatal periods. OTX treatment in humans improves many aspects of social cognition and behavior. Its effects on the hypothalamic-pituitary-adrenal axis and inflammation appear to be of interest in neonates because these properties may confer benefits when the perinatal brain has been subjected to injury. Indeed, early life inflammation and abnormal adrenal response to stress have been associated with an abnormal white matter development. Recent investigations demonstrated that OTX is involved in the modulation of microglial reactivity in the developing brain. This review recapitulates state-of-the art data supporting the hypothesis that the OTX system could be considered as an innovative candidate for neuroprotection, especially in the immature brain. PMID- 29706927 TI - TWEAK Receptor Deficiency Has Opposite Effects on Female and Male Mice Subjected to Neonatal Hypoxia-Ischemia. AB - Tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) is a multifunctional cytokine member of the TNF family. TWEAK binds to its only known receptor, Fn14, enabling it to activate downstream signaling processes in response to tissue injury. The aim of this study was to investigate the role of TWEAK signaling in neonatal hypoxia-ischemia (HI). We found that after neonatal HI, both TWEAK and Fn14 expression were increased to a greater extent in male compared with female mice. To assess the role of TWEAK signaling after HI, the size of the injury was measured in neonatal mice genetically deficient in Fn14 and compared with their wild-type and heterozygote littermates. A significant sex difference in the Fn14 knockout (KO) animals was observed. Fn14 gene KO was beneficial in females; conversely, reducing Fn14 expression exacerbated the brain injury in male mice. Our findings indicate that the TWEAK/Fn14 pathway is critical for development of hypoxic-ischemic brain injury in immature animals. However, as the responses are different in males and females, clinical implementation depends on development of sex-specific therapies. PMID- 29706928 TI - Repetitive Neonatal Erythropoietin and Melatonin Combinatorial Treatment Provides Sustained Repair of Functional Deficits in a Rat Model of Cerebral Palsy. AB - Cerebral palsy (CP) is the leading cause of motor impairment for children worldwide and results from perinatal brain injury (PBI). To test novel therapeutics to mitigate deficits from PBI, we developed a rat model of extreme preterm birth (<28 weeks of gestation) that mimics dual intrauterine injury from placental underperfusion and chorioamnionitis. We hypothesized that a sustained postnatal treatment regimen that combines the endogenous neuroreparative agents erythropoietin (EPO) and melatonin (MLT) would mitigate molecular, sensorimotor, and cognitive abnormalities in adults rats following prenatal injury. On embryonic day 18 (E18), a laparotomy was performed in pregnant Sprague-Dawley rats. Uterine artery occlusion was performed for 60 min to induce placental insufficiency via transient systemic hypoxia-ischemia, followed by intra-amniotic injections of lipopolysaccharide, and laparotomy closure. On postnatal day 1 (P1), approximately equivalent to 30 weeks of gestation, injured rats were randomized to an extended EPO + MLT treatment regimen, or vehicle (sterile saline) from P1 to P10. Behavioral assays were performed along an extended developmental time course (n = 6-29). Open field testing shows injured rats exhibit hypermobility and disinhibition and that combined neonatal EPO + MLT treatment repairs disinhibition in injured rats, while EPO alone does not. Furthermore, EPO + MLT normalizes hindlimb deficits, including reduced paw area and paw pressure at peak stance, and elevated percent shared stance after prenatal injury. Injured rats had fewer social interactions than shams, and EPO + MLT normalized social drive. Touchscreen operant chamber testing of visual discrimination and reversal shows that EPO + MLT at least partially normalizes theses complex cognitive tasks. Together, these data indicate EPO + MLT can potentially repair multiple sensorimotor, cognitive, and behavioral realms following PBI, using highly translatable and sophisticated developmental testing platforms. PMID- 29706929 TI - Neuromodulatory Effect of Thymoquinone in Attenuating Glutamate-Mediated Neurotoxicity Targeting the Amyloidogenic and Apoptotic Pathways. AB - Overexposure of the glutamatergic N-methyl-d-aspartate (NMDA) receptor to the excitatory neurotransmitter l-glutamic acid leads to neuronal cell death by excitotoxicity as a result of increased intracellular Ca2+, mitochondrial dysfunction, and apoptosis. Moreover, it was previously reported that prolonged activation of the NMDA receptor increased beta-amyloid (Abeta) levels in the brain. Thymoquinone (TQ), the active constituent of Nigella sativa seeds, has been shown to have potent antioxidant and antiapoptotic effects. The aim of the present study was to explore the neuromodulatory effects of different doses of TQ (2.5 and 10 mg/kg) against apoptotic cell death and Abeta formation resulting from glutamate administration in rats using vitamin E as a positive control. Behavioral changes were assessed using Y-maze and Morris water maze tests for evaluating spatial memory and cognitive functions. Caspase-3, Lactate dehydrogenase, Abeta-42, and cytochrome c gene expression were determined. TQ treated groups showed significant decreases in the levels of all tested biochemical and behavioral parameters compared with the glutamate-treated group. These findings demonstrated that TQ has a promising neuroprotective activity against glutamate-induced neurotoxicity and this effect is mediated through its anti-amyloidogenic, antioxidant, and antiapoptotic activities. PMID- 29706930 TI - A Preliminary Report on Brain-Derived Extracellular Vesicle as Novel Blood Biomarkers for Sport-Related Concussions. AB - The purpose of the study was to test the utility of unique panel of blood biomarkers as a means to reflect one's recovery process after sport-related neurotrauma. We established a panel of biomarkers that reacted positive with CD81 (extracellular vesicle marker) and various neuron- and glia-specific antigens [e.g., neurofilament light polypeptide (NF-L), tau, synaptosome-associated protein 25 (SNAP25), glial fibrillary acidic protein, and myelin basic protein]. We first evaluated test-retest reliabilities of brain-derived exosome markers, followed by an application of these markers in eight professional ice hockey players to detect cumulative neuronal burden from a single ice hockey season. During the season, two players were diagnosed with concussions by team physician based on an exhibition of symptoms as well as abnormality in balance and ocular motor testing. One player reached symptom-free status 7 days after the concussion, while the other player required 36 days for symptoms to completely resolve. Blood samples and clinical assessments including balance error scoring system and near point of convergence throughout recovery process were obtained. Biomarkers indicative of axonal damage, neuronal inflammation, and glial activation showed excellent test-retest reliabilities (intraclass correlation coefficient: 0.713-0.998, p's < 0.01). There was a statistically significant increase in the NF-L marker at post-season follow-up compared to pre-season baseline (Z = -2.100, P = 0.036); however the statistical significance did not withstand Bonferroni correction for multiple comparisons. In concussion cases, neuronal and microglia markers notably increased after concussions, with the unique expression patterns being similar to that of concussion recovery process. These longitudinal data coupled with excellent test-retest reliabilities of novel array of blood biomarkers potentially reflect the damage in neural cell structures and metabolic crisis due to concussion. However, future studies with larger sample size and appropriate control groups to evaluate sensitivity and specificity of these markers are needed. This preliminary case report suggests the potential utility of multimodal blood biomarkers for concussion prognosis and recovery assessment. PMID- 29706931 TI - Interaction of Sex and Diabetes on Outcome After Ischemic Stroke. AB - Background: The relationship between ischemic stroke (IS), diabetes mellitus (DM), and sex is intriguing. The aim of this study was to assess the effect modification of sex in the association between DM and short- and long-term disability and mortality in first-ever IS patients. Methods: In a retrospective, observational, hospital-based study of a prospective series including first-ever IS patients from January 2006 until July 2011, differences in 3-month and 5-year mortality, and disability between diabetic and non-diabetic patients [modified Rankin Scale (mRS) from 3 to 5] were analyzed by sex. Results: In total, 933 patients (36.3% with DM, 50.5% women) were included. Overall 3-month and 5-year mortality were 150 (16.1%) and 407 (44.1%), respectively. Adjusted for age, previous mRS, and stroke severity, patients with DM had significantly higher 3 month disability [hazard ratio (HR): 1.49 (95% confidence interval (CI): 1.39 1.70), p < 0.0001], 5-year disability [HR: 1.41 (95% CI: 1.07-1.86), p = 0.015], and 5-year mortality [HR: 1.48 (95% CI: 1.20-1.81), p < 0.0001], compared with the non-DM group. Compared with non-DM women, women with diabetes had worse 3 month disability [HR: 1.81 (95% CI: 1.33-2.46), p < 0.0001] and 5-year mortality [HR: 1.72 (95% CI: 1.30-2.20), p < 0.0001], and a trend for 5-year disability [HR: 1.40 (95% CI: 0.99-2.09), p = 0.057]. In men, DM had an effect on 3-month disability [HR: 1.45 (95% CI: 1.07-1.96), p = 0.018], a trend for 5-year disability [HR: 1.43 (95% CI: 0.94-2.19), p = 0.096], but no clear effect on 5 year mortality [HR: 1.22 (95% CI: 0.91-1.65), p = 0.186]. Conclusion: Sex has a modifier effect on mortality in first-ever IS diabetic patients. Long-term mortality is increased in diabetic women compared with non-diabetic women, a difference not observed in men. PMID- 29706932 TI - Potential Functions of IGFBP-2 for Ovarian Folliculogenesis and Steroidogenesis. AB - Ovarian follicles, as transient structural and functional complexes with the oocyte and the associated cells, determine the female reproductive cycle and thus fertility. Ovarian function is subject to the strict control of hormones and growth factors and thus regulated by auto-, para-, and endocrine mechanisms but influenced also by endogenous factors. During the waves of follicular growth and development, one follicle (monoovulatory) or a limited number of them (polyovulatory) are selected under hypothalamic-gonadal control for maturation until ovulation, resulting in the fertile oocyte. Subordinate follicles inevitably enter different stages of atresia. A number of studies have observed species-specific alterations of IGFBP-2 levels during the phases of growth and development or selection and atresia of follicles. IGFBP-2 is thus probably involved in the process of follicle growth, differentiation, and degeneration. This may occur on the levels of IGF-dependent and -independent growth control but also due to the control of steroidogenesis, e.g., via induction of aromatase expression. In mice, IGFBP-2 delayed reproductive development most probably by IGF-independent mechanisms. Because reproductive development is closely linked to the control of life- or health-span and energy metabolism, we feel that the time is right now to resume research on the effects of IGFBP-2 in the ovarian follicular compartment. PMID- 29706934 TI - Isotocin Regulates Growth Hormone but Not Prolactin Release From the Pituitary of Ricefield Eels. AB - The neurohypophyseal hormone oxytocin (Oxt) has been shown to stimulate prolactin (Prl) synthesis and release from the adenohypophysis in rats. However, little is known about the functional roles of Oxt-like neuropeptides in the adenohypophysis of non-mammalian vertebrates. In this study, cDNAs encoding ricefield eel oxytocin-like receptors (Oxtlr), namely isotocin (Ist) receptor 1 (Istr1) and 2 (Istr2), were isolated and specific antisera were generated, respectively. RT-PCR and Western blot analysis detected the presence of both Istr1 and Istr2 in the brain and pituitary, but differential expression in some peripheral tissues, including the liver and kidney, where only Istr1 was detected. In the pituitary, immunoreactive Istr1 and Istr2 were differentially distributed, with the former mainly in adenohypophyseal cell layers adjacent to the neurohypophysis, whereas the latter in peripheral areas of the adenohypophysis. Double immunofluorescent images showed that immunostaining of Istr1, but not Istr2 was localized to growth hormone (Gh) cells, but neither of them was expressed in Prl cells. Ist inhibited Gh release in primary pituitary cells of ricefield eels and increased Gh contents in the pituitary gland of ricefield eels at 6 h after in vivo administration. Ist inhibition of Gh release is probably mediated by cAMP, PKC/DAG, and IP3/Ca2+ pathways. In contrast, Ist did not affect either prl gene expression or Prl contents in primary pituitary cells. Results of this study demonstrated that Ist may not be involved in the regulation of Prl, but inhibit Gh release via Istr1 rather than Istr2 in ricefield eels, and provided evidence for the direct regulation of Gh cells by oxytocin-like neuropeptides in the pituitary of non mammalian vertebrates. PMID- 29706935 TI - Neonatal Overnutrition Increases Testicular Size and Expression of Luteinizing Hormone beta-Subunit in Peripubertal Male Rats. AB - Proper nutrition is important for growth and development. Maturation of the reproductive axis and the timing of pubertal onset can be delayed when insufficient nutrition is available, or possibly advanced with nutritional abundance. The childhood obesity epidemic has been linked to a secular trend in advanced puberty in some populations. The increase in circulating leptin that occurs in association with obesity has been suggested to act as a signal that an adequate nutritional status exists for puberty to occur, allowing activation of central mechanisms. However, obesity-associated hyperleptinemia is linked to decreased leptin sensitivity, at least in adults. Here, we analyzed whether neonatal overnutrition modifies the response to an increase in leptin in peripubertal male rats, as previously demonstrated in females. Wistar rats were raised in litters of 4 (neonatal overnutrition) or 12 pups (controls) per dam. Leptin was administered sc (3 ug/g body weight) at postnatal day 35 and the rats killed 45 min or 2 h later. Postnatal overfeeding resulted in increased body weight and circulating leptin levels; however, we found no overweight-related changes in the mRNA levels of neuropeptides involved in metabolism or reproduction. In contrast, pituitary expression of luteinizing hormone (LH) beta subunit was increased in overweight rats, as was testicular weight. There were no basal differences between L4 and L12 males or in their response to leptin administration in pSTAT3 levels in the hypothalamus at either 45 min or 2 h. In contrast, pJAK2 was found to be higher at 45 min in L4 compared to L12 males regardless of leptin treatment, while at 2 h it was higher in L4 leptin-treated males compared to L12 leptin-treated males, as well as L4 vehicle-treated rats. There were no changes in response to leptin administration in the expression of the neuropeptides analyzed. However, serum LH levels rose only in L4 males in response to leptin, but with no change in testosterone levels. In conclusion, the advancement in pubertal onset in males with neonatal overnutrition does not appear to be related to overt modifications in the central response to exogenous leptin during the peripubertal period. PMID- 29706936 TI - Oxidative Formation and Removal of Complexed Mn(III) by Pseudomonas Species. AB - The observation of significant concentrations of soluble Mn(III) complexes in oxic, suboxic, and some anoxic waters has triggered a re-evaluation of the previous Mn paradigm which focused on the cycling between soluble Mn(II) and insoluble Mn(III,IV) species as operationally defined by filtration. Though Mn(II) oxidation in aquatic environments is primarily bacterially-mediated, little is known about the effect of Mn(III)-binding ligands on Mn(II) oxidation nor on the formation and removal of Mn(III). Pseudomonas putida GB-1 is one of the most extensively investigated of all Mn(II) oxidizing bacteria, encoding genes for three Mn oxidases (McoA, MnxG, and MopA). P. putida GB-1 and associated Mn oxidase mutants were tested alongside environmental isolates Pseudomonas hunanensis GSL-007 and Pseudomonas sp. GSL-010 for their ability to both directly oxidize weakly and strongly bound Mn(III), and to form these complexes through the oxidation of Mn(II). Using Mn(III)-citrate (weak complex) and Mn(III)-DFOB (strong complex), it was observed that P. putida GB-1, P. hunanensis GSL-007 and Pseudomonas sp. GSL-010 and mutants expressing only MnxG and McoA were able to directly oxidize both species at varying levels; however, no oxidation was detected in cultures of a P. putida mutant expressing only MopA. During cultivation in the presence of Mn(II) and citrate or DFOB, P. putida GB-1, P. hunanensis GSL-007 and Pseudomonas sp. GSL-010 formed Mn(III) complexes transiently as an intermediate before forming Mn(III/IV) oxides with the overall rates and extents of Mn(III,IV) oxide formation being greater for Mn(III)-citrate than for Mn(III)-DFOB. These data highlight the role of bacteria in the oxidative portion of the Mn cycle and suggest that the oxidation of strong Mn(III) complexes can occur through enzymatic mechanisms involving multicopper oxidases. The results support the observations from field studies and further emphasize the complexity of the geochemical cycling of manganese. PMID- 29706937 TI - Aerobic Growth of Rhodococcus aetherivorans BCP1 Using Selected Naphthenic Acids as the Sole Carbon and Energy Sources. AB - Naphthenic acids (NAs) are an important group of toxic organic compounds naturally occurring in hydrocarbon deposits. This work shows that Rhodococcus aetherivorans BCP1 cells not only utilize a mixture of eight different NAs (8XNAs) for growth but they are also capable of marked degradation of two model NAs, cyclohexanecarboxylic acid (CHCA) and cyclopentanecarboxylic acid (CPCA) when supplied at concentrations from 50 to 500 mgL-1. The growth curves of BCP1 on 8XNAs, CHCA, and CPCA showed an initial lag phase not present in growth on glucose, which presumably was related to the toxic effects of NAs on the cell membrane permeability. BCP1 cell adaptation responses that allowed survival on NAs included changes in cell morphology, production of intracellular bodies and changes in fatty acid composition. Transmission electron microscopy (TEM) analysis of BCP1 cells grown on CHCA or CPCA showed a slight reduction in the cell size, the production of EPS-like material and intracellular electron transparent and electron-dense inclusion bodies. The electron-transparent inclusions increased in the amount and size in NA-grown BCP1 cells under nitrogen limiting conditions and contained storage lipids as suggested by cell staining with the lipophilic Nile Blue A dye. Lipidomic analyses revealed significant changes with increases of methyl-branched (MBFA) and polyunsaturated fatty acids (PUFA) examining the fatty acid composition of NAs-growing BCP1 cells. PUFA biosynthesis is not usual in bacteria and, together with MBFA, can influence structural and functional processes with resulting effects on cell vitality. Finally, through the use of RT (Reverse Transcription)-qPCR, a gene cluster (chcpca) was found to be transcriptionally induced during the growth on CHCA and CPCA. Based on the expression and bioinformatics results, the predicted products of the chcpca gene cluster are proposed to be involved in aerobic NA degradation in R. aetherivorans BCP1. This study provides first insights into the genetic and metabolic mechanisms allowing a Rhodococcus strain to aerobically degrade NAs. PMID- 29706938 TI - Improved Detection and Monitoring of Fungicide Resistance in Blumeria graminis f. sp. hordei With High-Throughput Genotype Quantification by Digital PCR. AB - The increased occurrence of triazole fungicide resistant strains of Blumeria graminis f. sp. hordei (Bgh) is an economic concern for the barley industry in Australia and elsewhere. High levels of resistance to triazoles in the field are caused by two separate point mutations in the Cyp51 gene, Y136F and S509T. Early detection of these mutations arising in pathogen field populations is important as this allows time for changes in fungicide practices to be adopted, thus mitigating potential yield losses due to fungicide failure and preventing the resistance from becoming dominant. A digital PCR (dPCR) assay has been developed for the detection and quantification of the Y136F and S509T mutations in the Bgh Cyp51 gene. Mutation levels were quantifiable as low as 0.2% in genomic DNA extractions and field samples. This assay was applied to the high throughput screening of Bgh field and bait trial samples from barley growing regions across Australia in the 2015 and 2016 growing seasons and identified the S509T mutation for the first time in the Eastern states of Australia. This is the first report on the use of digital PCR technology for fungicide resistance detection and monitoring in agriculture. Here we describe the potential application of dPCR for the screening of fungicide resistance mutations in a network of specifically designed bait trials. The combination of these two tools constitute an early warning system for the development of fungicide resistance that allows for the timely adjustment of management practices. PMID- 29706933 TI - The Role for Myc in Coordinating Glycolysis, Oxidative Phosphorylation, Glutaminolysis, and Fatty Acid Metabolism in Normal and Neoplastic Tissues. AB - That cancer cells show patterns of metabolism different from normal cells has been known for over 50 years. Yet, it is only in the past decade or so that an appreciation of the benefits of these changes has begun to emerge. Altered cancer cell metabolism was initially attributed to defective mitochondria. However, we now realize that most cancers do not have mitochondrial mutations and that normal cells can transiently adopt cancer-like metabolism during periods of rapid proliferation. Indeed, an encompassing, albeit somewhat simplified, conceptual framework to explain both normal and cancer cell metabolism rests on several simple premises. First, the metabolic pathways used by cancer cells and their normal counterparts are the same. Second, normal quiescent cells use their metabolic pathways and the energy they generate largely to maintain cellular health and organelle turnover and, in some cases, to provide secreted products necessary for the survival of the intact organism. By contrast, undifferentiated cancer cells minimize the latter functions and devote their energy to producing the anabolic substrates necessary to maintain high rates of unremitting cellular proliferation. Third, as a result of the uncontrolled proliferation of cancer cells, a larger fraction of the metabolic intermediates normally used by quiescent cells purely as a source of energy are instead channeled into competing proliferation-focused and energy-consuming anabolic pathways. Fourth, cancer cell clones with the most plastic and rapidly adaptable metabolism will eventually outcompete their less well-adapted brethren during tumor progression and evolution. This attribute becomes increasingly important as tumors grow and as their individual cells compete in a constantly changing and inimical environment marked by nutrient, oxygen, and growth factor deficits. Here, we review some of the metabolic pathways whose importance has gained center stage for tumor growth, particularly those under the control of the c-Myc (Myc) oncoprotein. We discuss how these pathways differ functionally between quiescent and proliferating normal cells, how they are kidnapped and corrupted during the course of transformation, and consider potential therapeutic strategies that take advantage of common features of neoplastic and metabolic disorders. PMID- 29706939 TI - Infectivity and RNA Persistence of a Norovirus Surrogate, the Tulane Virus, in Oysters. AB - Oysters, being filter feeders, can accumulate some human pathogens such as norovirus, a highly infectious calicivirus, most common cause of acute gastroenteritis worldwide. Accumulated virus decays over a period of days to weeks, possibly rendering contaminated oysters safe again. Sensitive molecular methods have been set up for shellfish analysis but without answering the question of infectious virus detection. Using the Tulane virus (TV), a norovirus surrogate that recognizes the same ligand as human norovirus in oyster tissues, the genome and infectious virus decay rates were estimated using inverse linear regression in a Bayesian framework for genome copies. Infectivity decreased faster than genome copies but infectious viruses were detected for several days. Quantifying the decrease in viral infectivity and genome detection in oysters over such a long period may help local authorities to manage production areas implicated in shellfish-borne outbreaks, and thus protect consumers. PMID- 29706940 TI - Cell Wall Structure of Coccoid Green Algae as an Important Trade-Off Between Biotic Interference Mechanisms and Multidimensional Cell Growth. AB - Coccoid green algae can be divided in two groups based on their cell wall structure. One group has a highly chemical resistant cell wall (HR-cell wall) containing algaenan. The other group is more susceptible to chemicals (LR-cell wall - Low resistant cell wall). Algaenan is considered as important molecule to explain cell wall resistance. Interestingly, cell wall types (LR- and HR-cell wall) are not in accordance with the taxonomic classes Chlorophyceae and Trebouxiophyceae, which makes it even more interesting to consider the ecological function. It was already shown that algaenan helps to protect against virus, bacterial and fungal attack, but in this study we show for the first time that green algae with different cell wall properties show different sensitivity against interference competition with the cyanobacterium Microcystis aeruginosa. Based on previous work with co-cultures of M. aeruginosa and two green algae (Acutodesmus obliquus and Oocystis marssonii) differing in their cell wall structure, it was shown that M. aeruginosa could impair only the growth of the green algae if they belong to the LR-cell wall type. In this study it was shown that the sensitivity to biotic interference mechanism shows a more general pattern within coccoid green algae species depending on cell wall structure. PMID- 29706941 TI - Novel Polymyxin Combination With Antineoplastic Mitotane Improved the Bacterial Killing Against Polymyxin-Resistant Multidrug-Resistant Gram-Negative Pathogens. AB - Due to limited new antibiotics, polymyxins are increasingly used to treat multidrug-resistant (MDR) Gram-negative bacteria, in particular carbapenem resistant Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Unfortunately, polymyxin monotherapy has led to the emergence of resistance. Polymyxin combination therapy has been demonstrated to improve bacterial killing and prevent the emergence of resistance. From a preliminary screening of an FDA drug library, we identified antineoplastic mitotane as a potential candidate for combination therapy with polymyxin B against polymyxin resistant Gram-negative bacteria. Here, we demonstrated that the combination of polymyxin B with mitotane enhances the in vitro antimicrobial activity of polymyxin B against 10 strains of A. baumannii, P. aeruginosa, and K. pneumoniae, including polymyxin-resistant MDR clinical isolates. Time-kill studies showed that the combination of polymyxin B (2 mg/L) and mitotane (4 mg/L) provided superior bacterial killing against all strains during the first 6 h of treatment, compared to monotherapies, and prevented regrowth and emergence of polymyxin resistance in the polymyxin-susceptible isolates. Electron microscopy imaging revealed that the combination potentially affected cell division in A. baumannii. The enhanced antimicrobial activity of the combination was confirmed in a mouse burn infection model against a polymyxin-resistant A. baumannii isolate. As mitotane is hydrophobic, it was very likely that the synergistic killing of the combination resulted from that polymyxin B permeabilized the outer membrane of the Gram-negative bacteria and allowed mitotane to enter bacterial cells and exert its antimicrobial effect. These results have important implications for repositioning non-antibiotic drugs for antimicrobial purposes, which may expedite the discovery of novel therapies to combat the rapid emergence of antibiotic resistance. PMID- 29706942 TI - Oral Administration of Recombinant Saccharomyces boulardii Expressing Ovalbumin CPE Fusion Protein Induces Antibody Response in Mice. AB - Saccharomyces boulardii, a subspecies of Saccharomyces cerevisiae, is a well known eukaryotic probiotic with many benefits for human health. In the present study, a recombinant strain of S. boulardii was prepared to use as a potential oral vaccine delivery vehicle. In this sense, a ura3 auxotroph strain of S. boulardii CNCM I-745 (known as S. cerevisiae HANSEN CBS 5926, Yomogi(r)) was generated using CRISPR/Cas9 methodology. Then a gene construct encoding a highly immunogenic protein, ovalbumin (OVA), was prepared and transformed into the ura3- S. boulardii. To facilitate the transport of the recombinant immunogen across the intestinal barrier, a claudin-targeting sequence from Clostridium perfringens enterotoxin (CPE) was added to the C-terminus of the expression cassette. The recombinant S. boulardii strain expressing the OVA-CPE fusion protein was then administered orally to a group of mice, and serum IgG and fecal IgA levels were evaluated by ELISA. Our results demonstrated that anti-OVA IgG in serum significantly increased in test group (P < 0.001) compared to control groups (receiving wild type S. boulardii or PBS), and the fecal IgA titer was significantly higher in test group (P < 0.05) than control groups. In parallel, a recombinant S. boulardii strain expressing the similar construct lacking C terminal CPE was also administered orally. The result showed an increased level of serum IgG in group receiving yeasts expressing the CPE negative construct compared to control groups; however, the fecal IgA levels did not increase significantly. In conclusion, our findings indicated that the yeast S. boulardii, as a delivery vehicle with possible immunomodulatory effects, and c-CPE, as a targeting tag, synergistically assist to stimulate systemic and local immunity. This proposed recombinant S. boulardii system might be useful in the expression of other antigenic peptides, making it as a promising tool for oral delivery of vaccines or therapeutic proteins. PMID- 29706943 TI - Antibacterial and Antibiofilm Activities of Psychorubrin, a Pyranonaphthoquinone Isolated From Mitracarpus frigidus (Rubiaceae). AB - Psychorubrin, a natural pyranonaphthoquinone found in different plants, has become an interesting compound in the search for new antimicrobial therapeutic agents. Here, we investigated the potential antagonistic activity of psychorubrin against planktonic and biofilm bacteria. First, psychorubrin was tested against several Gram-positive and Gram-negative bacteria strains by a broth microdilution susceptibility method. Second, bacterial killing assay, bacterial abundance, and membrane viability were evaluated. The nucleotide leakage assay was used to verify membrane destabilization while antibiofilm activities were analyzed by the effect on established biofilm, static biofilm formation, isolation of biofilm matrix assay and scanning electron microscopy. In parallel, the combinatorial effect of psychorubrin and chloramphenicol was evaluated by the checkerboard method. Psychorubrin was active against Gram-positive bacteria, showing rapid time-dependent kinetics of bacterial killing, amplified nucleotide leakage, and greater activity against the methicillin-resistant species (MRSA) Staphylococcus aureus 33591 and 33592 and Staphylococcus pyogenes 10096. Psychorubrin also interfered with the composition of the biofilm matrix by reducing the total content of carbohydrates and proteins. A synergic effect between psychorubrin and chloramphenicol was observed for S. aureus 33592 and S. pyogenes 10096 while an additive effect was detected for S. aureus 33591. Our findings demonstrate, for the first time, an antagonistic activity of psychorubrin against bacteria not only in their planktonic forms but also in biofilms, and identify bacterial membranes as primary targets for this compound. Based on these observations, psychorubrin has a good potential for the design of novel antimicrobial agents. PMID- 29706944 TI - Prediction of Cell-Penetrating Potential of Modified Peptides Containing Natural and Chemically Modified Residues. AB - Designing drug delivery vehicles using cell-penetrating peptides is a hot area of research in the field of medicine. In the past, number of in silico methods have been developed for predicting cell-penetrating property of peptides containing natural residues. In this study, first time attempt has been made to predict cell penetrating property of peptides containing natural and modified residues. The dataset used to develop prediction models, include structure and sequence of 732 chemically modified cell-penetrating peptides and an equal number of non-cell penetrating peptides. We analyzed the structure of both class of peptides and observed that positive charge groups, atoms, and residues are preferred in cell penetrating peptides. In this study, models were developed to predict cell penetrating peptides from its tertiary structure using a wide range of descriptors (2D, 3D descriptors, and fingerprints). Random Forest model developed by using PaDEL descriptors (combination of 2D, 3D, and fingerprints) achieved maximum accuracy of 95.10%, MCC of 0.90 and AUROC of 0.99 on the main dataset. The performance of model was also evaluated on validation/independent dataset which achieved AUROC of 0.98. In order to assist the scientific community, we have developed a web server "CellPPDMod" for predicting the cell-penetrating property of modified peptides (http://webs.iiitd.edu.in/raghava/cellppdmod/). PMID- 29706945 TI - Candida auris: Disinfectants and Implications for Infection Control. AB - Candida auris is a rapidly emerging pathogen and is able to cause severe infections with high mortality rates. It is frequently misidentified in most clinical laboratories, thus requiring more specialized identification techniques. Furthermore, several clinical isolates have been found to be multidrug resistant and there is evidence of nosocomial transmission in outbreak fashion. Appropriate infection control measures will play a major role in controlling the management and spread of this pathogen. Unfortunately, there are very few data available on the effectiveness of disinfectants against C. auris. Chlorine-based products appear to be the most effective for environmental surface disinfection. Other disinfectants, although less effective than chlorine-based products, may have a role as adjunctive disinfectants. A cleaning protocol will also need to be established as the use of disinfectants alone may not be sufficient for maximal decontamination of patient care areas. Furthermore, there are fewer data on the effectiveness of antiseptics against C. auris for patient decolonization and hand hygiene for healthcare personnel. Chlorhexidine gluconate has shown some efficacy in in vitro studies but there are reports of patients with persistent colonization despite twice daily body washes with this disinfectant. Hand hygiene using soap and water, with or without chlorhexidine gluconate, may require the subsequent use of alcohol-based hand sanitizer for maximal disinfection. Further studies will be needed to validate the currently studied disinfectants for use in real-world settings. PMID- 29706946 TI - The higBA Toxin-Antitoxin Module From the Opportunistic Pathogen Acinetobacter baumannii - Regulation, Activity, and Evolution. AB - Acinetobacter baumannii is one of the major causes of hard to treat multidrug resistant hospital infections. A. baumannii features contributing to its spread and persistence in clinical environment are only beginning to be explored. Bacterial toxin-antitoxin (TA) systems are genetic loci shown to be involved in plasmid maintenance and proposed to function as components of stress response networks. Here we present a thorough characterization of type II system of A. baumannii, which is the most ubiquitous TA module present in A. baumannii plasmids. higBA of A. baumannii is a reverse TA (the toxin gene is the first in the operon) and shows little homology to other TA systems of RelE superfamily. It is represented by two variants, which both are functional albeit exhibit strong difference in sequence conservation. The higBA2 operon is found on ubiquitous 11 Kb pAB120 plasmid, conferring carbapenem resistance to clinical A. baumannii isolates and represents a higBA variant that can be found with multiple sequence variations. We show here that higBA2 is capable to confer maintenance of unstable plasmid in Acinetobacter species. HigB2 toxin functions as a ribonuclease and its activity is neutralized by HigA2 antitoxin through formation of an unusually large heterooligomeric complex. Based on the in vivo expression analysis of gfp reporter gene we propose that HigA2 antitoxin and HigBA2 protein complex bind the higBA2 promoter region to downregulate its transcription. We also demonstrate that higBA2 is a stress responsive locus, whose transcription changes in conditions encountered by A. baumannii in clinical environment and within the host. We show elevated expression of higBA2 during stationary phase, under iron deficiency and downregulated expression after antibiotic (rifampicin) treatment. PMID- 29706947 TI - Circadian Disruption Changes Gut Microbiome Taxa and Functional Gene Composition. AB - Disrupted circadian rhythms and alterations of the gut microbiome composition were proposed to affect host health. Therefore, the aim of this research was to identify whether these events are connected and if circadian rhythm disruption by abnormal light-dark (LD) cycles affects microbial community gene expression and host vulnerability to intestinal dysfunction. Mice were subjected to either a 4 week period of constant 24-h light or of normal 12-h LD cycles. Stool samples were collected at the beginning and after the circadian rhythm disruption. A metatranscriptomic analysis revealed an increase in Ruminococcus torques, a bacterial species known to decrease gut barrier integrity, and a decrease in Lactobacillus johnsonii, a bacterium that helps maintain the intestinal epithelial cell layer, after circadian rhythm disruption. In addition, genes involved in pathways promoting host beneficial immune responses were downregulated, while genes involved in the synthesis and transportation of the endotoxin lipopolysaccharide were upregulated in mice with disrupted circadian cycles. Importantly, these mice were also more prone to dysfunction of the intestinal barrier. These results further elucidate the impact of light-cycle disruption on the gut microbiome and its connection with increased incidence of disease in response to circadian rhythm disturbances. PMID- 29706948 TI - Heavy Metal-Induced Expression of PcaA Provides Cadmium Tolerance to Aspergillus fumigatus and Supports Its Virulence in the Galleria mellonella Model. AB - Most of the metal transporters in Aspergillus fumigatus are yet uncharacterized. Their role in fungal metabolism and virulence remains unclear. This paper describes the novel PIB-type cation ATPase PcaA, which links metal homeostasis and heavy metal tolerance in the opportunistic human pathogen A. fumigatus. The protein possesses conserved ATPase motif and shares 51% amino acid sequence identity with the Saccharomyces cerevisiae cadmium exporter Pca1p. A pcaA deletion, an overexpression and a gfp-pcaA complementation strain of A. fumigatus were constructed and their heavy metal susceptibilities were studied. The pcaA knock out strain showed drastically decreased cadmium tolerance, however, its growth was not affected by the exposure to high concentrations of copper, iron, zinc, or silver ions. Although the lack of PcaA had no effect on copper adaption, we demonstrated that not only cadmium but also copper ions are able to induce the transcription of pcaA in A. fumigatus wild type Af293. Similarly, cadmium and copper ions could induce the copper exporting ATPase crpA. These data imply a general response on the transcriptomic level to heavy metals in A. fumigatus through the induction of detoxification systems. Confocal microscopy of the gfp pcaA complementation strain expressing functional GFP-PcaA supports the predicted membrane localization of PcaA. The GFP-PcaA fusion protein is located in the plasma membrane of A. fumigatus in the presence of cadmium ions. Virulence assays support a function of PcaA for virulence of A. fumigatus in the Galleria mellonella wax moth larvae model, which might be linked to the elimination of reactive oxygen species. PMID- 29706949 TI - A Shared Epitope of Collagen Type XI and Type II Is Recognized by Pathogenic Antibodies in Mice and Humans with Arthritis. AB - Background: Collagen XI (CXI) is a heterotrimeric molecule with triple helical structure in which the alpha3(XI) chain is identical to the alpha1(II) chain of collagen II (CII), but with extensive posttranslational modifications. CXI molecules are intermingled in the cartilage collagen fibers, which are mainly composed of CII. One of the alpha chains in CXI is shared with CII and contains the immunodominant T cell epitope, but it is unclear whether there are shared B cell epitopes as the antibodies tend to recognize the triple helical structures. Methods: Mice expressing the susceptible immune response gene Aq were immunized with CII or CXI. Serum antibody responses were measured, monoclonal antibodies were isolated and analyzed for specificity to CII, CXI, and triple helical collagen peptides using bead-based multiplex immunoassays, enzyme-linked immunosorbent assays, and Western blots. Arthritogenicity of the antibodies was investigated by passive transfer experiments. Results: Immunization with CII or CXI leads to a strong T and B cell response, including a cross-reactive response to both collagen types. Immunization with CII leads to severe arthritis in mice, with a response toward CXI at the chronic stage, whereas CXI immunization induces very mild arthritis only. A series of monoclonal antibodies to CXI were isolated and of these, the L10D9 antibody bound to both CXI and CII equally strong, with a specific binding for the D3 epitope region of alpha3(XI) or alpha1(II) chain. The L10D9 antibody binds cartilage in vivo and induced severe arthritis. In contrast, the L5F3 antibody only showed weak binding and L7D8 antibody has no binding to cartilage and did not induce arthritis. The arthritogenic L10D9 antibody bound to an epitope shared with CII, the triple helical D3 epitope. Antibody levels to the shared D3 epitope were elevated in the sera from mice with arthritis as well as in rheumatoid arthritis. Conclusion: CXI is immunologically not exposed in healthy cartilage but contains T and B cell epitopes cross-reactive with CII, which could be activated in both mouse and human arthritis and could evoke an arthritogenic response. PMID- 29706950 TI - Bullous Pemphigoid Triggered by Thermal Burn Under Medication With a Dipeptidyl Peptidase-IV Inhibitor: A Case Report and Review of the Literature. AB - Bullous pemphigoid (BP) is a common autoimmune blistering disease in which autoantibodies mainly target the hemidesmosomal component BP180 (also known as type XVII collagen) in basal keratinocytes. Various triggering factors are known to induce BP onset, including radiotherapy, burns, ultraviolet exposure, surgery, and the use of dipeptidyl peptidase-IV inhibitors (DPP4i), which are widely used antihyperglycemic drugs. Here, we present a case of BP triggered by a thermal burn under medication with DPP4i. A 60-year-old man with type II diabetes had been treated with the DPP4i linagliptin for 1 year. After the right forearm experienced a thermal burn, blisters developed around the burned area and gradually spread over the whole body with the production of autoantibodies targeting the non-NC16A domain of BP180. The diagnosis of BP was confirmed by immunohistopathological examination. Upon withdrawal of linagliptin and treatment with topical steroid and minocycline, complete remission was achieved after 4 months. Previously, 13 cases of BP that developed after thermal burns have been reported, and our case shared some of the clinical features of these thermal burn induced BP cases. Interestingly, the present case also showed the typical clinical, histopathological, and immunological features of the non-inflammatory type of DPP4i-associated BP (DPP4i-BP). Although the pathogenesis of BP remains uncertain, the present case suggests that DPP4i may trigger the onset of BP similarly to a thermal burn. In addition, the clinical and histopathological features of DPP4i-BP may be distinct from other types of BP. PMID- 29706951 TI - Transcriptional Modulation of Human Endogenous Retroviruses in Primary CD4+ T Cells Following Vorinostat Treatment. AB - The greatest obstacle to a cure for HIV is the provirus that integrates into the genome of the infected cell and persists despite antiretroviral therapy. A "shock and kill" approach has been proposed as a strategy for an HIV cure whereby drugs and compounds referred to as latency-reversing agents (LRAs) are used to "shock" the silent provirus into active replication to permit "killing" by virus-induced pathology or immune recognition. The LRA most utilized to date in clinical trials has been the histone deacetylase (HDAC) inhibitor-vorinostat. Potentially, pathological off-target effects of vorinostat may result from the activation of human endogenous retroviruses (HERVs), which share common ancestry with exogenous retroviruses including HIV. To explore the effects of HDAC inhibition on HERV transcription, an unbiased pharmacogenomics approach (total RNA-Seq) was used to evaluate HERV expression following the exposure of primary CD4+ T cells to a high dose of vorinostat. Over 2,000 individual HERV elements were found to be significantly modulated by vorinostat, whereby elements belonging to the ERVL family (e.g., LTR16C and LTR33) were predominantly downregulated, in contrast to LTR12 elements of the HERV-9 family, which exhibited the greatest signal, with the upregulation of 140 distinct elements. The modulation of three different LTR12 elements by vorinostat was confirmed by droplet digital PCR along a dose response curve. The monitoring of LTR12 expression during clinical trials with vorinostat may be indicated to assess the impact of this HERV on the human genome and host immunity. PMID- 29706952 TI - B Cell Modulation Strategies in Autoimmune Diseases: New Concepts. AB - B cells are major effector cells in autoimmunity through antibody production, T cell help and pro-inflammatory cytokine production. Major advances have been made in human B cell biology knowledge using rituximab and type II new anti-CD20 antibodies, anti-CD19 antibodies, anti-CD22 antibodies, autoantigen specific B cell depleting therapy (chimeric antigen receptor T cells), and B cell receptor signaling inhibition (Bruton's tyrosine kinase inhibitors). However, in certain circumstances B cell depleting therapy may lead to the worsening of the autoimmune disease which is in accordance with the existence of a regulatory B cell population. Current concepts and future directions for B cell modulating therapies in autoimmune diseases with a special focus on pemphigus are discussed. PMID- 29706953 TI - Conserved Bacterial-Binding Peptides of the Scavenger-Like Human Lymphocyte Receptor CD6 Protect From Mouse Experimental Sepsis. AB - Sepsis is an unmet clinical need constituting one of the most important causes of death worldwide, a fact aggravated by the appearance of multidrug resistant strains due to indiscriminate use of antibiotics. Host innate immune receptors involved in pathogen-associated molecular patterns (PAMPs) recognition represent a source of broad-spectrum therapies alternative or adjunctive to antibiotics. Among the few members of the ancient and highly conserved scavenger receptor cysteine-rich superfamily (SRCR-SF) sharing bacterial-binding properties there is CD6, a lymphocyte-specific surface receptor. Here, we analyze the bacterial binding properties of three conserved short peptides (11-mer) mapping at extracellular SRCR domains of human CD6 (CD6.PD1, GTVEVRLEASW; CD6.PD2 GRVEMLEHGEW; and CD6.PD3, GQVEVHFRGVW). All peptides show high binding affinity for PAMPs from Gram-negative (lipopolysaccharide; Kd from 3.5 to 3,000 nM) and Gram-positive (lipoteichoic acid; Kd from 36 to 680 nM) bacteria. The CD6.PD3 peptide possesses broad bacterial-agglutination properties and improved survival of mice undergoing polymicrobial sepsis in a dose- and time-dependent manner. Accordingly, CD6.PD3 triggers a decrease in serum levels of both pro-inflammatory cytokines and bacterial load. Interestingly, CD6.PD3 shows additive survival effects on septic mice when combined with Imipenem/Cilastatin. These results illustrate the therapeutic potential of peptides retaining the bacterial-binding properties of native CD6. PMID- 29706955 TI - Antibody Repertoires Identify beta-Tubulin as a Host Protective Parasite Antigen in Mice Infected With Trypanosoma cruzi. AB - Few studies investigate the major protein antigens targeted by the antibody diversity of infected mice with Trypanosoma cruzi. To detect global IgG antibody specificities, sera from infected mice were immunoblotted against whole T. cruzi extracts. By proteomic analysis, we were able to identify the most immunogenic T. cruzi proteins. We identified three major antigens as pyruvate phosphate dikinase, Hsp-85, and beta-tubulin. The major protein band recognized by host IgG was T. cruzi beta-tubulin. The T. cruzi beta-tubulin gene was cloned, expressed in E. coli, and recombinant T. cruzi beta-tubulin was obtained. Infection increased IgG reactivity against recombinant T. cruzi beta-tubulin. A single immunization of mice with recombinant T. cruzi beta-tubulin increased specific IgG reactivity and induced protection against T. cruzi infection. These results indicate that repertoire analysis is a valid approach to identify antigens for vaccines against Chagas disease. PMID- 29706956 TI - Embryonic Fibroblasts Promote Antitumor Cytotoxic Effects of CD8+ T Cells. AB - Adoptive CD8+ T cell therapy has emerged as an important modality for the treatment of cancers. However, the significant drawback of transfused T cells is their poor survival and functionality in response to tumors. To overcome this limitation, an important consideration is exploring a culture condition to generate superior antitumor cytotoxic T lymphocytes (CTLs) for adoptive therapy. Here, we provide a novel approach to generate potent CTL clones in mouse embryonic fibroblast-conditioned medium (MEF-CM). We found CTLs derived with MEF CM have higher potential in long-term persistence in tumor bearing and non-tumor bearing mice. Importantly, adoptive transfer of MEF-CM-cultured CTLs dramatically regressed tumor growth and prolonged mice survival. Characterization of MEF-CM cultured CTLs (effector molecules, phenotypes, and transcription factors) suggests that MEF-CM enhances the effector functions of CD8+ T cells in part by the upregulation of the T-box transcription factor eomesodermin. Consequently, MEF-CM enhances the intrinsic qualities of effector CD8+ T cells to augment antitumor immunity. PMID- 29706954 TI - A Serum Circulating miRNA Signature for Short-Term Risk of Progression to Active Tuberculosis Among Household Contacts. AB - Biomarkers that predict who among recently Mycobacterium tuberculosis (MTB) exposed individuals will progress to active tuberculosis are urgently needed. Intracellular microRNAs (miRNAs) regulate the host response to MTB and circulating miRNAs (c-miRNAs) have been developed as biomarkers for other diseases. We performed machine-learning analysis of c-miRNA measurements in the serum of adult household contacts (HHCs) of TB index cases from South Africa and Uganda and developed a c-miRNA-based signature of risk for progression to active TB. This c-miRNA-based signature significantly discriminated HHCs within 6 months of progression to active disease from HHCs that remained healthy in an independent test set [ROC area under the ROC curve (AUC) 0.74, progressors < 6 Mo to active TB and ROC AUC 0.66, up to 24 Mo to active TB], and complements the predictions of a previous cellular mRNA-based signature of TB risk. PMID- 29706957 TI - Microglia and Beyond: Innate Immune Cells As Regulators of Brain Development and Behavioral Function. AB - Innate immune cells play a well-documented role in the etiology and disease course of many brain-based conditions, including multiple sclerosis, Alzheimer's disease, traumatic brain and spinal cord injury, and brain cancers. In contrast, it is only recently becoming clear that innate immune cells, primarily brain resident macrophages called microglia, are also key regulators of brain development. This review summarizes the current state of knowledge regarding microglia in brain development, with particular emphasis on how microglia during development are distinct from microglia later in life. We also summarize the effects of early life perturbations on microglia function in the developing brain, the role that biological sex plays in microglia function, and the potential role that microglia may play in developmental brain disorders. Finally, given how new the field of developmental neuroimmunology is, we highlight what has yet to be learned about how innate immune cells shape the development of brain and behavior. PMID- 29706958 TI - One-Year Follow-Up of Natural Killer Cell Activity in Multiple Myeloma Patients Treated With Adjuvant Lenalidomide Therapy. AB - Multiple myeloma (MM) is a proliferation of tumoral plasma B cells that is still incurable. Natural killer (NK) cells can recognize and kill MM cells in vitro and can limit MM growth in vivo. Previous reports have shown that NK cell function is impaired during MM progression and suggested that treatment with immunomodulatory drugs (IMIDs) such as lenalidomide (LEN) could enhance it. However, the effects of IMIDs on NK cells have been tested mostly in vitro or in preclinical models and supporting evidence of their effect in vivo in patients is lacking. Here, we monitored NK cell activity in blood samples from 10 MM patients starting after frontline induction chemotherapy (CTX) consisting either of association of bortezomib-lenalidomide-dexamethasone (Velcade Revlimid Dexamethasone) or autologous stem-cell transplantation (SCT). We also monitored NK cell activity longitudinally each month during 1 year, after maintenance therapy with LEN. Following frontline chemotherapy, peripheral NK cells displayed a very immature phenotype and retained poor reactivity toward target cells ex vivo. Upon maintenance treatment with LEN, we observed a progressive normalization of NK cell maturation, likely caused by discontinuation of chemotherapy. However, LEN treatment neither activated NK cells nor improved their capacity to degranulate or to secrete IFN-gamma or MIP1-beta following stimulation with MHC-I-deficient or antibody-coated target cells. Upon LEN discontinuation, there was no reduction of NK cell effector function either. These results caution against the use of LEN as single therapy to improve NK cell activity in patients with cancer and call for more preclinical assessments of the potential of IMIDs in NK cell activation. PMID- 29706959 TI - Cathelicidin-Derived Antimicrobial Peptides Inhibit Zika Virus Through Direct Inactivation and Interferon Pathway. AB - Zika virus (ZIKV) is a neurotrophic flavivirus that is able to infect pregnant women and cause fetal brain abnormalities. Although there is a significant effort in identifying anti-ZIKV strategies, currently no vaccines or specific therapies are available to treat ZIKV infection. Antimicrobial peptides, which are potent host defense molecules in nearly all forms of life, have been found to be effective against several types of viruses such as HIV-1 and influenza A. However, they have not been tested in ZIKV infection. To determine whether antimicrobial peptides have anti-ZIKV effects, we used nine peptides mostly derived from human and bovine cathelicidins. Two peptides, GF-17 and BMAP-18, were found to have strong anti-ZIKV activities and little toxicity at 10 uM in an African green monkey kidney cell line. We further tested GF-17 and BMAP-18 in human fetal astrocytes, a known susceptible cell type for ZIKV, and found that GF 17 and BMAP-18 effectively inhibited ZIKV regardless of whether peptides were added before or after ZIKV infection. Interestingly, inhibition of type-I interferon signaling resulted in higher levels of ZIKV infection as measured by viral RNA production and partially reversed GF-17-mediated viral inhibition. More importantly, pretreatment with GF-17 and BMAP-18 did not affect viral attachment but reduced viral RNA early in the infection course. Direct incubation with GF-17 for 1 to 4 h specifically reduced the number of infectious Zika virions in the inoculum. In conclusion, these findings suggest that cathelicidin-derived antimicrobial peptides inhibit ZIKV through direct inactivation of the virus and via the interferon pathway. Strategies that harness antimicrobial peptides might be useful in halting ZIKV infection. PMID- 29706960 TI - Macrophage-Derived Extracellular Vesicles Induce Long-Lasting Immunity Against Hepatitis C Virus Which Is Blunted by Polyunsaturated Fatty Acids. AB - Extracellular vesicles (EVs) are increasingly recognized as important mediators of intercellular communication. In this study, we aimed to further characterize the role of macrophage-derived EVs in immune responses against hepatitis C virus (HCV) and the potential of polyunsaturated fatty acids (PUFAs) to modulate this modality of innate immunity. To this end, EVs were isolated from interferon stimulated macrophage cultures or from serum of patients with acute or chronic hepatitis C. EVs were characterized by electron microscopy, flow cytometry, RNA sequencing, and Western blot analysis. The effect of EVs on replication of HCV was assessed in coculture models. Functional analyses were performed to assess the impact of PUFAs on EV-mediated antiviral immunity. We found that macrophages secreted various cytokines shortly after stimulation with type I and II IFN, which orchestrated a fast but short-lasting antiviral state. This rapid innate immune answer was followed by the production of macrophage-derived EVs, which induced a late, but long-lasting inhibitory effect on HCV replication. Of note, exposure of macrophages to PUFAs, which are important regulators of immune responses, dampened EV-mediated antiviral immune responses. Finally, EVs from patients with hepatitis C exhibited long-lasting antiviral activities during IFN therapy as well. The antiviral effect of EVs from Caucasian and Japanese patients differed, which may be explained by different nutritional uptake of PUFAs. In conclusion, our data indicate that macrophage-derived EVs mediate long-lasting inhibitory effects on HCV replication, which may bridge the time until efficient adaptive immune responses are established, and which can be blunted by PUFAs. PMID- 29706962 TI - Variable Domain N-Linked Glycans Acquired During Antigen-Specific Immune Responses Can Contribute to Immunoglobulin G Antibody Stability. AB - Immunoglobulin G (IgG) can contain N-linked glycans in the variable domains, the so-called Fab glycans, in addition to the Fc glycans in the CH2 domains. These Fab glycans are acquired following introduction of N-glycosylation sites during somatic hypermutation and contribute to antibody diversification. We investigated whether Fab glycans may-in addition to affecting antigen binding-contribute to antibody stability. By analyzing thermal unfolding profiles of antibodies with or without Fab glycans, we demonstrate that introduction of Fab glycans can improve antibody stability. Strikingly, removal of Fab glycans naturally acquired during antigen-specific immune responses can deteriorate antibody stability, suggesting in vivo selection of stable, glycosylated antibodies. Collectively, our data show that variable domain N-linked glycans acquired during somatic hypermutation can contribute to IgG antibody stability. These findings indicate that introducing Fab glycans may represent a mechanism to improve therapeutic/diagnostic antibody stability. PMID- 29706961 TI - Regulatory T Cells As Potential Targets for HIV Cure Research. AB - T regulatory cells (Tregs) are a key component of the immune system, which maintain a delicate balance between overactive responses and immunosuppression. As such, Treg deficiencies are linked to autoimmune disorders and alter the immune control of pathogens. In HIV infection, Tregs play major roles, both beneficial and detrimental. They regulate the immune system such that inflammation and spread of virus through activated T cells is suppressed. However, suppression of immune activation also limits viral clearance and promotes reservoir formation. Tregs can be directly targeted by HIV, thereby harboring a fraction of the viral reservoir. The vital role of Tregs in the pathogenesis and control of HIV makes them a subject of interest for manipulation in the search of an HIV cure. Here, we discuss the origin and generation, homeostasis, and functions of Tregs, particularly their roles and effects in HIV infection. We also present various Treg manipulation strategies, including Treg depletion techniques and interventions that alter Treg function, which may be used in different cure strategies, to simultaneously boost HIV-specific immune responses and induce reactivation of the latent virus. PMID- 29706963 TI - Protective Role of the MER Tyrosine Kinase via Efferocytosis in Rheumatoid Arthritis Models. AB - Objective: Rheumatoid arthritis (RA) is a chronic and progressive joint disease. It appears that anti-inflammatory feedback mechanisms that could restrain joint inflammation and restore homeostasis are insufficient to perform this control. In this study, we investigated the contribution of the MER tyrosine kinase-mediated anti-inflammatory response on arthritis and whether targeting MER could be a valid approach to treat RA. Methods: KRN serum transfer arthritis (KRN STA) was induced in either Mertk-deficient mice or in mice that adenovirally overexpressed Pros1. Human synovial micromasses were treated with MER-specific antibodies or PROS1. Collagen-induced arthritis (CIA) mice were treated with MER-specific agonistic antibodies or by viral overexpression of Pros1. Results: Mertk-/- mice showed exacerbated arthritis pathology, whereas Pros1 overexpression diminished joint pathology in KRN STA. Human synovial micromasses challenged with MER specific antibodies enhanced the secretion of inflammatory cytokines, whereas stimulating MER with PROS1 reduced the secretion of these cytokines, confirming the protective role of MER. Next, we treated CIA mice with MER-specific agonistic antibodies, and this unexpectedly resulted in exacerbated arthritis pathology. This was associated with increased numbers of apoptotic cells in their knee joints and higher serum levels of interleukin (IL)-16C, a cytokine released by secondary necrotic neutrophils. Apoptotic cell numbers and IL-16C levels were enhanced during arthritis in Mertk-/- mice and reduced in Pros1-overexpressing mice. Conclusion: MER plays a protective role during joint inflammation and activating MER by its ligand PROS1 ameliorates disease. Treatment of mice with MER receptor agonistic antibodies is deleterious due to its counterproductive effect of blocking efferocytosis in the arthritic joint. PMID- 29706965 TI - Transcription Factor SOX5 Promotes the Migration and Invasion of Fibroblast-Like Synoviocytes in Part by Regulating MMP-9 Expression in Collagen-Induced Arthritis. AB - Objectives: Fibroblast-like synoviocytes (FLS) exhibit a unique aggressive phenotype in rheumatoid arthritis (RA). Increased FLS migration and subsequent invasion of the extracellular matrix are essential to joint destruction in RA. Our previous research reported that transcription factor SOX5 was highly expressed in RA-FLS. Here, the effects of SOX5 in RA-FLS migration and invasion will be investigated. Methods: The migration and invasion of RA-FLS were evaluated using a transwell chamber assay. The expression of several potential SOX5-targeted genes, including matrix metalloproteinases (MMP-1, 2, 3 and 9), chemokines (CCL4, CCL2, CCR5 and CCR2), and pro-inflammatory cytokines (TNF-alpha and IL-6), were examined in RA-FLS using SOX5 gain- and loss-of-function study. The molecular mechanisms of SOX5-mediated MMP-9 expressions were assayed by luciferase reporter gene and chromatin immunoprecipitation (ChIP) studies. The in vivo effect of SOX5 on FLS migration and invasion was examined using collagen induced arthritis (CIA) in DBA/1J mice. Results: Knockdown SOX5 decreased lamellipodium formation, migration, and invasion of RA-FLS. The expression of MMP 9 was the only gene tested to be concomitantly affected by silencing or overexpressing SOX5. ChIP assay revealed that SOX5 was bound to the MMP-9 promoter in RA-FLS. The overexpression of SOX5 markedly enhanced the MMP-9 promoter activity, and specific deletion of a putative SOX5-binding site in MMP-9 promoter diminished this promoter-driven transcription in FLS. Locally knocked down SOX5 inhibited MMP-9 expression in the joint tissue and reduced pannus migration and invasion into the cartilage in CIA mice. Conclusion: SOX5 plays a novel role in mediating migration and invasion of FLS in part by regulating MMP-9 expression in RA. PMID- 29706966 TI - Dysregulated CD25 and Cytokine Expression by gammadelta T Cells of Systemic Sclerosis Patients Stimulated With Cardiolipin and Zoledronate. AB - Objectives: gammadelta T cells, a non-conventional innate lymphocyte subset containing cells that can be activated by lipids and phosphoantigens, are abnormally regulated in systemic sclerosis (SSc). To further evaluate the significance of this dysregulation, we compared how exposure to an autoantigenic lipid, cardiolipin (CL), during co-stimulation with an amino-bisphosphonate (zoledronate, zol), affects the activation and cytokine production of SSc and healthy control (HC) gammadelta T cells. Methods: Expression of CD25 on Vgamma9+, Vdelta1+, and total CD3+ T cells in cultured peripheral blood mononuclear cells (PBMCs), their binding of CD1d tetramers, and the effect of monoclonal antibody (mAb) blockade of CD1d were monitored by flow cytometry after 4 days of in vitro culture. Intracellular production of IFNgamma and IL-4 was assessed after overnight culture. Results: Percentages of CD25+ among CD3+ and Vdelta1+ T cells were elevated significantly in short-term cultured SSc PBMC compared to HC. In SSc but not HC, CL and zol, respectively, suppressed %CD25+ Vgamma9+ and Vdelta1+ T cells but, when combined, CL + zol significantly activated both subsets in HC and partially reversed inhibition by the individual reagents in SSc. Importantly, Vdelta1+ T cells in both SSc and HC were highly reactive with lipid presenting CD1d tetramers, and a CD1d-blocking mAb decreased CL-induced enhancement of %SSc CD25+ Vdelta1+ T cells in the presence of zol. %IFNgamma+ cells among Vgamma9+ T cells of SSc was lower than HC cultured in medium, CL, zol, or CL + zol, whereas %IFNgamma+ Vdelta1+ T cells was lower only in the presence of CL or CL + zol. %IL 4+ T cells were similar in SSc and HC in all conditions, with the exception of being increased in SSc Vgamma9+ T cells in the presence of CL. Conclusion: Abnormal functional responses of gammadelta T cell subsets to stimulation by CL and phosphoantigens in SSc may contribute to fibrosis and immunosuppression, characteristics of this disease. PMID- 29706967 TI - Role of C-Reactive Protein at Sites of Inflammation and Infection. AB - C-reactive protein (CRP) is an acute inflammatory protein that increases up to 1,000-fold at sites of infection or inflammation. CRP is produced as a homopentameric protein, termed native CRP (nCRP), which can irreversibly dissociate at sites of inflammation and infection into five separate monomers, termed monomeric CRP (mCRP). CRP is synthesized primarily in liver hepatocytes but also by smooth muscle cells, macrophages, endothelial cells, lymphocytes, and adipocytes. Evidence suggests that estrogen in the form of hormone replacement therapy influences CRP levels in the elderly. Having been traditionally utilized as a marker of infection and cardiovascular events, there is now growing evidence that CRP plays important roles in inflammatory processes and host responses to infection including the complement pathway, apoptosis, phagocytosis, nitric oxide (NO) release, and the production of cytokines, particularly interleukin-6 and tumor necrosis factor-alpha. Unlike more recent publications, the findings of early work on CRP can seem somewhat unclear and at times conflicting since it was often not specified which particular CRP isoform was measured or utilized in experiments and whether responses attributed to nCRP were in fact possibly due to dissociation into mCRP or lipopolysaccharide contamination. In addition, since antibodies for mCRP are not commercially available, few laboratories are able to conduct studies investigating the mCRP isoform. Despite these issues and the fact that most CRP research to date has focused on vascular disorders, there is mounting evidence that CRP isoforms have distinct biological properties, with nCRP often exhibiting more anti-inflammatory activities compared to mCRP. The nCRP isoform activates the classical complement pathway, induces phagocytosis, and promotes apoptosis. On the other hand, mCRP promotes the chemotaxis and recruitment of circulating leukocytes to areas of inflammation and can delay apoptosis. The nCRP and mCRP isoforms work in opposing directions to inhibit and induce NO production, respectively. In terms of pro-inflammatory cytokine production, mCRP increases interleukin-8 and monocyte chemoattractant protein-1 production, whereas nCRP has no detectable effect on their levels. Further studies are needed to expand on these emerging findings and to fully characterize the differential roles that each CRP isoform plays at sites of local inflammation and infection. PMID- 29706968 TI - Long Non-Coding RNAs: Novel Players in Regulation of Immune Response Upon Herpesvirus Infection. AB - Herpesviruses have developed a variety of sophisticated immune evasion strategies to establish lifelong latent infection, including the use of long non-coding RNAs (lncRNAs). In this review, we summarize the lncRNA action modes, i.e., RNA protein, RNA-RNA, and RNA-DNA interactions, involved in regulating important aspects of immunity by controlling gene expression at various stages. Upon herpesvirus infection, host lncRNAs, such as nuclear paraspeckle assembly transcript 1, negative regulator of antiviral, and B-cell integration cluster have been functionally characterized as negative or positive antiviral regulators in the immune response. Herpesviruses have also evolved multiple strategies to modulate the host immune response using lncRNAs, such as latency-associated transcript, beta 2.7 RNA, 5 kb and 7.2 kb lncRNAs, Epstein-Barr virus-encoded non coding RNA, BamH I-A rightward transcripts, polyadenylated nuclear, and herpesvirus saimiri U-rich RNAs. We discuss the various mechanisms of immune related lncRNAs, and their diversified and important functions in the modulation of innate and adaptive immunity upon herpesvirus infection as well as in host pathogen interactions, which will facilitate our understanding of rational design of novel strategies to combat herpesvirus infection. PMID- 29706969 TI - Mesenchymal Stromal Cells and Their Extracellular Vesicles Enhance the Anti Inflammatory Phenotype of Regulatory Macrophages by Downregulating the Production of Interleukin (IL)-23 and IL-22. AB - Resolution-phase macrophage population orchestrates active dampening of the inflammation by secreting anti-inflammatory and proresolving products including interleukin (IL)-10 and lipid mediators (LMs). We investigated the effects of both human bone marrow-derived mesenchymal stromal cells (MSCs) and MSC-derived extracellular vesicles (MSC-EVs) on mature human regulatory macrophages (Mregs). The cytokines and LMs were determined from cell culture media of Mregs cultivated with MSCs and MSC-EVs. In addition, the alterations in the expression of cell surface markers and the phagocytic ability of Mregs were investigated. Our novel findings indicate that both MSC coculture and MSC-EVs downregulated the production of IL-23 and IL-22 enhancing the anti-inflammatory phenotype of Mregs and amplifying proresolving properties. The levels of prostaglandin E2 (PGE2) were substantially upregulated in MSC coculture media, which may endorse proresolving LM class switching. In addition, our results manifest, for the first time, that MSC-EVs mediate the Mreg phenotype change via PGE2. These data suggest that both human MSC and MSC-EVs may potentiate tolerance-promoting proresolving phenotype of human Mregs. PMID- 29706970 TI - H7N9 Avian Influenza Virus Is Efficiently Transmissible and Induces an Antibody Response in Chickens. AB - H7N9 viruses pose a threat to human health and they are no less harmful to the poultry industry than the H5N1 avian influenza viruses. However, the pathogenesis, transmissibility, and the host immune response of the H7N9 virus in chickens and mice remain unclear. In this study, we found that H7N9 viruses replicated in multiple organs of the chicken and viral shedding persisted up to 30 days postinoculation (DPI). The viruses were efficiently transmitted between chickens through direct contact. Notably, chickens infected with H7N9 had high antibody levels throughout the entire observation period and their antibody response lasted for 30 DPI. The expression levels of the pattern-recognition receptors and pro-inflammatory cytokines were found to be significantly upregulated in the brain using quantitative real-time PCR. The expression of TLR3, TLR7, MDA5, Mx, IL-1beta, IL-6, IFN-alpha, and IFN-gamma were also significantly different in the lungs of infected chickens. We found that the viruses isolated from these birds had low pathogenicity in mice, produced little weight loss and could only replicate in the lungs. Our findings suggested that the H7N9 viruses could replicate in chickens and mice and be efficiently transmitted between chickens, which presented a significant threat to human and poultry health. PMID- 29706964 TI - Crosstalk Between Peroxisome Proliferator-Activated Receptor Gamma and the Canonical WNT/beta-Catenin Pathway in Chronic Inflammation and Oxidative Stress During Carcinogenesis. AB - Inflammation and oxidative stress are common and co-substantial pathological processes accompanying, promoting, and even initiating numerous cancers. The canonical WNT/beta-catenin pathway and peroxisome proliferator-activated receptor gamma (PPARgamma) generally work in opposition. If one of them is upregulated, the other one is downregulated and vice versa. WNT/beta-catenin signaling is upregulated in inflammatory processes and oxidative stress and in many cancers, although there are some exceptions for cancers. The opposite is observed with PPARgamma, which is generally downregulated during inflammation and oxidative stress and in many cancers. This helps to explain in part the opposite and unidirectional profile of the canonical WNT/beta-catenin signaling and PPARgamma in these three frequent and morbid processes that potentiate each other and create a vicious circle. Many intracellular pathways commonly involved downstream will help maintain and amplify inflammation, oxidative stress, and cancer. Thus, many WNT/beta-catenin target genes such as c-Myc, cyclin D1, and HIF-1alpha are involved in the development of cancers. Nuclear factor-kappaB (NFkappaB) can activate many inflammatory factors such as TNF-alpha, TGF-beta, interleukin-6 (IL 6), IL-8, MMP, vascular endothelial growth factor, COX2, Bcl2, and inducible nitric oxide synthase. These factors are often associated with cancerous processes and may even promote them. Reactive oxygen species (ROS), generated by cellular alterations, stimulate the production of inflammatory factors such as NFkappaB, signal transducer and activator transcription, activator protein-1, and HIF-alpha. NFkappaB inhibits glycogen synthase kinase-3beta (GSK-3beta) and therefore activates the canonical WNT pathway. ROS activates the phosphatidylinositol 3 kinase/protein kinase B (PI3K/Akt) signaling in many cancers. PI3K/Akt also inhibits GSK-3beta. Many gene mutations of the canonical WNT/beta-catenin pathway giving rise to cancers have been reported (CTNNB1, AXIN, APC). Conversely, a significant reduction in the expression of PPARgamma has been observed in many cancers. Moreover, PPARgamma agonists promote cell cycle arrest, cell differentiation, and apoptosis and reduce inflammation, angiogenesis, oxidative stress, cell proliferation, invasion, and cell migration. All these complex and opposing interactions between the canonical WNT/beta-catenin pathway and PPARgamma appear to be fairly common in inflammation, oxidative stress, and cancers. PMID- 29706972 TI - Structural Insight Into the Role of Mutual Polymorphism and Conservatism in the Contact Zone of the NFR5-K1 Heterodimer With the Nod Factor. AB - Sandwich-like docking configurations of the heterodimeric complex of NFR5 and K1 Vicia sativa receptor-like kinases together with the putative ligand, Nod factor (NF) of Rhizobium leguminosarum bv. viciae, were modeled and two of the most probable configurations were assessed through the analysis of the mutual polymorphisms and conservatism. We carried out this analysis based on the hypothesis that in a contact zone of two docked components (proteins or ligands) the population polymorphism or conservatism is mutual, i.e., the variation in one component has a reflected variation in the other component. The population material of 30 wild-growing V. sativa (leaf pieces) was collected from a large field (uncultivated for the past 25-years) and pooled; form this pool, 100 randomly selected cloned fragments of NFR5 gene and 100 of K1 gene were sequenced by the Sanger method. Congruence between population trees of NFR5 and K1 haplotypes allowed us to select two respective haplotypes, build their 3D structures, and perform protein-protein docking. In a separate simulation, the protein-ligand docking between NFR5 and NF was carried out. We merged the results of the two docking experiments and extracted NFR5-NF-K1 complexes, in which NF was located within the cavity between two receptors. Molecular dynamics simulations indicated two out of six complexes as stable. Regions of mutual polymorphism in the contact zone of one complex overlapped with known NF structural variations produced by R. leguminosarum bv. viciae. A total of 74% of the contact zone of another complex contained mutually polymorphic and conservative areas. Common traits of the obtained two stable structures allowed us to hypothesize the functional role of three-domain structure of plant LysM RLKs in their heteromers. PMID- 29706971 TI - In Planta Functional Analysis and Subcellular Localization of the Oomycete Pathogen Plasmopara viticola Candidate RXLR Effector Repertoire. AB - Downy mildew is one of the most destructive diseases of grapevine, causing tremendous economic loss in the grape and wine industry. The disease agent Plasmopara viticola is an obligate biotrophic oomycete, from which over 100 candidate RXLR effectors have been identified. In this study, 83 candidate RXLR effector genes (PvRXLRs) were cloned from the P. viticola isolate "JL-7-2" genome. The results of the yeast signal sequence trap assay indicated that most of the candidate effectors are secretory proteins. The biological activities and subcellular localizations of all the 83 effectors were analyzed via a heterologous Agrobacterium-mediated Nicotiana benthamiana expression system. Results showed that 52 effectors could completely suppress cell death triggered by elicitin, 10 effectors could partially suppress cell death, 11 effectors were unable to suppress cell death, and 10 effectors themselves triggered cell death. Live-cell imaging showed that the majority of the effectors (76 of 83) could be observed with informative fluorescence signals in plant cells, among which 34 effectors were found to be targeted to both the nucleus and cytosol, 29 effectors were specifically localized in the nucleus, and 9 effectors were targeted to plant membrane system. Interestingly, three effectors PvRXLR61, 86 and 161 were targeted to chloroplasts, and one effector PvRXLR54 was dually targeted to chloroplasts and mitochondria. However, western blot analysis suggested that only PvRXLR86 carried a cleavable N-terminal transit peptide and underwent processing in planta. Many effectors have previously been predicted to target organelles, however, to the best of our knowledge, this is the first study to provide experimental evidence of oomycete effectors targeted to chloroplasts and mitochondria. PMID- 29706973 TI - The Sequenced Angiosperm Genomes and Genome Databases. AB - Angiosperms, the flowering plants, provide the essential resources for human life, such as food, energy, oxygen, and materials. They also promoted the evolution of human, animals, and the planet earth. Despite the numerous advances in genome reports or sequencing technologies, no review covers all the released angiosperm genomes and the genome databases for data sharing. Based on the rapid advances and innovations in the database reconstruction in the last few years, here we provide a comprehensive review for three major types of angiosperm genome databases, including databases for a single species, for a specific angiosperm clade, and for multiple angiosperm species. The scope, tools, and data of each type of databases and their features are concisely discussed. The genome databases for a single species or a clade of species are especially popular for specific group of researchers, while a timely-updated comprehensive database is more powerful for address of major scientific mysteries at the genome scale. Considering the low coverage of flowering plants in any available database, we propose construction of a comprehensive database to facilitate large-scale comparative studies of angiosperm genomes and to promote the collaborative studies of important questions in plant biology. PMID- 29706974 TI - A Systems Modeling Approach to Forecast Corn Economic Optimum Nitrogen Rate. AB - Historically crop models have been used to evaluate crop yield responses to nitrogen (N) rates after harvest when it is too late for the farmers to make in season adjustments. We hypothesize that the use of a crop model as an in-season forecast tool will improve current N decision-making. To explore this, we used the Agricultural Production Systems sIMulator (APSIM) calibrated with long-term experimental data for central Iowa, USA (16-years in continuous corn and 15-years in soybean-corn rotation) combined with actual weather data up to a specific crop stage and historical weather data thereafter. The objectives were to: (1) evaluate the accuracy and uncertainty of corn yield and economic optimum N rate (EONR) predictions at four forecast times (planting time, 6th and 12th leaf, and silking phenological stages); (2) determine whether the use of analogous historical weather years based on precipitation and temperature patterns as opposed to using a 35-year dataset could improve the accuracy of the forecast; and (3) quantify the value added by the crop model in predicting annual EONR and yields using the site-mean EONR and the yield at the EONR to benchmark predicted values. Results indicated that the mean corn yield predictions at planting time (R2 = 0.77) using 35-years of historical weather was close to the observed and predicted yield at maturity (R2 = 0.81). Across all forecasting times, the EONR predictions were more accurate in corn-corn than soybean-corn rotation (relative root mean square error, RRMSE, of 25 vs. 45%, respectively). At planting time, the APSIM model predicted the direction of optimum N rates (above, below or at average site-mean EONR) in 62% of the cases examined (n = 31) with an average error range of +/-38 kg N ha-1 (22% of the average N rate). Across all forecast times, prediction error of EONR was about three times higher than yield predictions. The use of the 35-year weather record was better than using selected historical weather years to forecast (RRMSE was on average 3% lower). Overall, the proposed approach of using the crop model as a forecasting tool could improve year-to-year predictability of corn yields and optimum N rates. Further improvements in modeling and set-up protocols are needed toward more accurate forecast, especially for extreme weather years with the most significant economic and environmental cost. PMID- 29706976 TI - MFS Transporters and GABA Metabolism Are Involved in the Self-Defense Against DON in Fusarium graminearum. AB - Trichothecene mycotoxins, such as deoxynivalenol (DON) produced by the fungal pathogen, Fusarium graminearum, are not only important for plant infection but are also harmful to human and animal health. Trichothecene targets the ribosomal protein Rpl3 that is conserved in eukaryotes. Hence, a self-defense mechanism must exist in DON-producing fungi. It is reported that TRI (trichothecene biosynthesis) 101 and TRI12 are two genes responsible for self-defense against trichothecene toxins in Fusarium. In this study, however, we found that simultaneous disruption of TRI101 and TRI12 has no obvious influence on DON resistance upon exogenous DON treatment in F. graminearum, suggesting that other mechanisms may be involved in self-defense. By using RNA-seq, we identified 253 genes specifically induced in DON-treated cultures compared with samples from cultures treated or untreated with cycloheximide, a commonly used inhibitor of eukaryotic protein synthesis. We found that transporter genes are significantly enriched in this group of DON-induced genes. Of those genes, 15 encode major facilitator superfamily transporters likely involved in mycotoxin efflux. Significantly, we found that genes involved in the metabolism of gamma aminobutyric acid (GABA), a known inducer of DON production in F. graminearum, are significantly enriched among the DON-induced genes. The GABA biosynthesis gene PROLINE UTILIZATION 2-2 (PUT2-2) is downregulated, while GABA degradation genes are upregulated at least twofold upon treatment with DON, resulting in decreased levels of GABA. Taken together, our results suggest that transporters influencing DON efflux are important for self-defense and that GABA mediates the balance of DON production and self-defense in F. graminearum. PMID- 29706975 TI - Manipulation of Light Signal Transduction Factors as a Means of Modifying Steroidal Glycoalkaloids Accumulation in Tomato Leaves. AB - Steroidal glycoalkaloids (SGAs) are cholesterol-derived specialized metabolites produced by Solanaceous plant species. They contribute to pathogen defense but are considered as anti-nutritional compounds and toxic to humans. Although the genes involved in the SGA biosynthetic pathway have been successfully cloned and identified, transcription factors regulating this pathway are still poorly understood. We report that silencing tomato light signal transduction transcription factors ELONGATED HYPOCOTYL 5 (SlHY5) and PHYTOCHROME INTERACTING FACTOR3 (SlPIF3), by virus-induced gene silencing (VIGS), altered glycoalkaloids levels in tomato leaves compared to control plant. Electrophoretic mobility shift assay (EMSA) and Chromatin immunoprecipitation (ChIP) analysis confirmed that SlHY5 and SlPIF3 bind to the promoter of target genes of GLYCOALKALOID METABOLISM (GAME1, GAME4, GAME17), affecting the steady-state concentrations of transcripts coding for SGA pathway enzymes. The results indicate that light-signaling transcription factors HY5 and PIF3 regulate the abundance of SGAs by modulating the transcript levels of these GAME genes. This insight into the regulation of SGA biosynthesis can be used for manipulating the level of these metabolites in crops. PMID- 29706977 TI - Joint Exploration of Favorable Haplotypes for Mineral Concentrations in Milled Grains of Rice (Oryza sativa L.). AB - Grain minerals in rice, especially those in milled grains, are important sources of micro-nutrition elements, such as iron (Fe), zinc (Zn), manganese (Mn), copper (Cu), and selenium (Se), and of toxic heavy metal elements, especially cadmium (Cd), for populations consuming a rice diet. To date, the genetic mechanism underlying grain mineral concentrations (GMCs) in milled grain remains largely unknown. In this report, we adopted a set of 698 germplasms consisting of two subsets [indica/Xian (X-set) and japonica/Geng (G-set)], to detect quantitative trait loci (QTL) affecting GMC traits of Fe, Zn, Cd, Mn, Cu, and Se in milled grains. A total of 47 QTL regions, including 18 loci and 29 clusters (covering 62 Cd loci), responsible for the GMCs in milled grains were detected throughout the genome. A joint exploration of favorable haplotypes of candidate genes was carried out as follows: (1) By comparative mapping, 10 chromosome regions were found to be consistent with our previously detected QTL from linkage mapping. (2) Within eight of these regions on chromosomes 1, 4, 6, 7, and 8, candidate genes were identified in the genome annotation database. (3) A total of 192 candidate genes were then submitted to further haplotype analysis using million-scale single nucleotide polymorphisms (SNPs) from the X-set and the G-set. (4) Finally, 37 genes (19.3%) were found to be significant in the association between the QTL targeting traits and the haplotype variations by pair-wise comparison. (5) The phenotypic values for the haplotypes of each candidate were plotted. Three zinc finger (like) genes within two candidate QTL regions (qFe6-2 and qZn7), and three major GMC traits (Fe, Zn, and Cd) were picked as sample cases, in addition to non exhausted cross validations, to elucidate this kind of association by trait value plotting. Taken together, our results, especially the 37 genes with favorable haplotype variations, will be useful for rice biofortification molecular breeding. PMID- 29706978 TI - Exploring Cell Wall Composition and Modifications During the Development of the Gynoecium Medial Domain in Arabidopsis. AB - In Arabidopsis, the gynoecium, the inner whorl of the flower, is the female reproductive part. Many tissues important for fertilization such as the stigma, style, transmitting tract, placenta, ovules, and septum, comprising the medial domain, arise from the carpel margin meristem. During gynoecium development, septum fusion occurs and tissues form continuously to prepare for a successful pollination and fertilization. During gynoecium development, cell wall modifications take place and one of the most important is the formation of the transmitting tract, having a great impact on reproductive competence because it facilitates pollen tube growth and movement through the ovary. In this study, using a combination of classical staining methods, fluorescent dyes, and indirect immunolocalization, we analyzed cell wall composition and modifications accompanying medial domain formation during gynoecium development. We detected coordinated changes in polysaccharide distribution through time, cell wall modifications preceding the formation of the transmitting tract, mucosubstances increase during transmitting tract formation, and a decrease of mannan distribution. Furthermore, we also detected changes in lipid distribution during septum fusion. Proper cell wall composition and modifications are important for postgenital fusion of the carpel (septum fusion) and transmitting tract formation, because these tissues affect plant reproductive competence. PMID- 29706979 TI - Forest Soil Phosphorus Resources and Fertilization Affect Ectomycorrhizal Community Composition, Beech P Uptake Efficiency, and Photosynthesis. AB - Phosphorus (P) is an important nutrient, whose plant-available form phosphate is often low in natural forest ecosystems. Mycorrhizal fungi mine the soil for P and supply their host with this resource. It is unknown how ectomycorrhizal communities respond to changes in P availability. Here, we used young beech (Fagus sylvatica L.) trees in natural forest soil from a P-rich and P-poor site to investigate the impact of P amendment on soil microbes, mycorrhizas, beech P nutrition, and photosynthesis. We hypothesized that addition of P to forest soil increased P availability, thereby, leading to enhanced microbial biomass and mycorrhizal diversity in P-poor but not in P-rich soil. We expected that P amendment resulted in increased plant P uptake and enhanced photosynthesis in both soil types. Young beech trees with intact soil cores from a P-rich and a P poor forest were kept in a common garden experiment and supplied once in fall with triple superphosphate. In the following summer, labile P in the organic layer, but not in the mineral top soil, was significantly increased in response to fertilizer treatment. P-rich soil contained higher microbial biomass than P poor soil. P treatment had no effect on microbial biomass but influenced the mycorrhizal communities in P-poor soil and shifted their composition toward higher similarities to those in P-rich soil. Plant uptake efficiency was negatively correlated with the diversity of mycorrhizal communities and highest for trees in P-poor soil and lowest for fertilized trees. In both soil types, radioactive P tracing (H333PO4) revealed preferential aboveground allocation of new P in fertilized trees, resulting in increased bound P in xylem tissue and enhanced soluble P in bark, indicating increased storage and transport. Fertilized beeches from P-poor soil showed a strong increase in leaf P concentrations from deficient to luxurious conditions along with increased photosynthesis. Based on the divergent behavior of beech in P-poor and P-rich forest soil, we conclude that acclimation of beech to low P stocks involves dedicated mycorrhizal community structures, low P reserves in storage tissues and photosynthetic inhibition, while storage and aboveground allocation of additional P occurs regardless of the P nutritional status. PMID- 29706980 TI - A RAD-Based Genetic Map for Anchoring Scaffold Sequences and Identifying QTLs in Bitter Gourd (Momordica charantia). AB - Genetic mapping is a basic tool necessary for anchoring assembled scaffold sequences and for identifying QTLs controlling important traits. Though bitter gourd (Momordica charantia) is both consumed and used as a medicinal, research on its genomics and genetic mapping is severely limited. Here, we report the construction of a restriction site associated DNA (RAD)-based genetic map for bitter gourd using an F2 mapping population comprising 423 individuals derived from two cultivated inbred lines, the gynoecious line 'K44' and the monoecious line 'Dali-11.' This map comprised 1,009 SNP markers and spanned a total genetic distance of 2,203.95 cM across the 11 linkage groups. It anchored a total of 113 assembled scaffolds that covered about 251.32 Mb (85.48%) of the 294.01 Mb assembled genome. In addition, three horticulturally important traits including sex expression, fruit epidermal structure, and immature fruit color were evaluated using a combination of qualitative and quantitative data. As a result, we identified three QTL/gene loci responsible for these traits in three environments. The QTL/gene gy/fffn/ffn, controlling sex expression involved in gynoecy, first female flower node, and female flower number was detected in the reported region. Particularly, two QTLs/genes, Fwa/Wr and w, were found to be responsible for fruit epidermal structure and white immature fruit color, respectively. This RAD-based genetic map promotes the assembly of the bitter gourd genome and the identified genetic loci will accelerate the cloning of relevant genes in the future. PMID- 29706981 TI - Increase in Artemisia annua Plant Biomass Artemisinin Content and Guaiacol Peroxidase Activity Using the Arbuscular Mycorrhizal Fungus Rhizophagus irregularis. AB - The main objective of this study was to investigate Artemisia annua plant property variations in terms of plant biomass, glandular trichome numbers, artemisinin production and Guaiacol peroxidase (GPOX) activity when plants are in mutualism with AMF. According to the results, A. annua mutualism with AMF significantly increased the most important and pharmaceutically relevant factors of fresh and dry plant biomass. This increase, especially in the biomass of plant herba (leaves), was 30% higher during the vegetation period and remained high (29% higher than for control) when plants were harvested at the end of the vegetation period. Similar differences in dry biomass were also detected. Glandular trichomas numbers increased by 40%, and the artemisinin content by 17% under AMF colonization. No effects due to AMF on chlorophyll variations were detected, while GPOX enzyme concentrations increased significantly under AMF colonization. Altogether the Artemisia plant properties with high pharmaceutically importance (fresh and dry biomass of leaves and artemisinin, number of trichomes and the artemisinin content) were significantly improved by AMF, the application in Artemisia cultivation can be an effective and cheap method. The high GPOX activity under AMF colonization indicate an enhanced oxidative stress alleviation, therefore a higher resistance to water deficiency, mechanisms important under climate conditions with low water supply where Artemisia is usually cultivated. PMID- 29706982 TI - An APETALA2 Homolog, RcAP2, Regulates the Number of Rose Petals Derived From Stamens and Response to Temperature Fluctuations. AB - Rosa chinensis, which is a famous traditional flower in China, is a major ornamental plant worldwide. Long-term cultivation and breeding have resulted in considerable changes in the number of rose petals, while most wild Rosaceae plants have only one whorl consisting of five petals. The petals of double flowers reportedly originate from stamens, but the underlying molecular mechanism has not been fully characterized. In this study, we observed that the number of petals of R. chinensis 'Old Blush' flowers increased and decreased in response to low- and high-temperature treatments, respectively, similar to previous reports. We characterized these variations in further detail and found that the number of stamens exhibited the opposite trend. We cloned an APETALA2 homolog, RcAP2. A detailed analysis of gene structure and promoter cis-acting elements as well as RcAP2 temporospatial expression patterns and responses to temperature changes suggested that RcAP2 expression may be related to the number of petals from stamen origin. The overexpression of RcAP2 in Arabidopsis thaliana transgenic plants may induce the transformation of stamens to petals, thereby increasing the number of petals. Moreover, silencing RcAP2 in 'Old Blush' plants decreased the number of petals. Our results may be useful for clarifying the temperature responsive mechanism involved in petaloid stamen production, which may be relevant for the breeding of new rose varieties with enhanced flower traits. PMID- 29706983 TI - Unraveling the Host Plant Alternation of Cacopsylla pruni - Adults but Not Nymphs Can Survive on Conifers Due to Phloem/Xylem Composition. AB - Plant sap feeding insects like psyllids are known to be vectors of phloem dwelling bacteria ('Candidatus Phytoplasma' and 'Ca. Liberibacter'), plant pathogens which cause severe diseases and economically important crop damage. Some univoltine psyllid species have a particular life cycle, within one generation they alternate two times between different host plant species. The plum psyllid Cacopsylla pruni, the vector of European Stone Fruit Yellows (ESFY), one of the most serious pests in European fruit production, migrates to stone fruit orchards (Prunus spp.) for mating and oviposition in early spring. The young adults of the new generation leave the Prunus trees in summer and emigrate to their overwintering hosts like spruce and other conifers. Very little is known about the factors responsible for the regulation of migration, reasons for host alternation, and the behavior of psyllids during their phase of life on conifers. Because insect feeding behavior and host acceptance is driven by different biotic factors, such as olfactory and gustatory cues as well as mechanical barriers, we carried out electrical penetration graph (EPG) recordings and survival bioassays with C. pruni on different conifer species as potential overwintering hosts and analyzed the chemical composition of the respective plant saps. We are the first to show that migrating psyllids do feed on overwintering hosts and that nymphs are able to ingest phloem and xylem sap of coniferous trees, but cannot develop on conifer diet. Analyses of plant saps reveal qualitative differences in the chemical composition between coniferous trees and Prunus as well as within conifer species. These differences are discussed with regard to nutritional needs of psyllid nymphs for proper development, overwintering needs of adults and restriction of 'Ca. P. prunorum' to Prunus phloem. PMID- 29706984 TI - Rivastigmine Improves Appetite by Increasing the Plasma Acyl/Des-Acyl Ghrelin Ratio and Cortisol in Alzheimer Disease. AB - Background: Weight loss accelerates cognitive decline and increases mortality in patients with dementia. While acetylcholinesterase (AChE) inhibitors are known to cause appetite loss, we sometimes encounter patients in whom switching from donepezil (AChE inhibitor) to rivastigmine (AChE and butyrylcholinesterase [BuChE] inhibitor) improves appetite. Since BuChE inactivates ghrelin, a potent orexigenic hormone, we speculated that rivastigmine improves appetite by inhibiting BuChE-mediated ghrelin inactivation. Methods: The subjects were patients with mild to moderate Alzheimer disease treated with either rivastigmine patch (n = 11) or donepezil (n = 11) for 6 months. Before and after treatment, we evaluated appetite (0, decreased; 1, slightly decreased; 2, normal; 3, slightly increased; 4, increased), cognitive function, and blood biochemical variables, including various hormones. Results: Rivastigmine treatment significantly improved appetite (from 1.6 +/- 0.5 to 2.6 +/- 0.7), whereas donepezil treatment did not (from 2.0 +/- 0.0 to 1.8 +/- 0.4). Simultaneously, rivastigmine, but not donepezil, significantly decreased the serum cholinesterase activity (from 304.3 +/- 60.5 to 246.8 +/- 78.5 IU/L) and increased the cortisol level (from 11.86 +/- 3.12 to 14.61 +/- 3.29 MUg/dL) and the acyl/des-acyl ghrelin ratio (from 4.03 +/- 2.96 to 5.28 +/- 2.72). The levels of leptin, insulin, total ghrel-in, and cognitive function were not significantly affected by either treatment. Conclusions: Our results suggest that compared with donepezil, rivastigmine has the advantage of improving appetite by increasing the acyl/des-acyl ghrelin ratio and cortisol level, thereby preventing weight loss. PMID- 29706985 TI - ABC Dementia Scale: A Quick Assessment Tool for Determining Alzheimer's Disease Severity. AB - Background: In this study, we examined the construct validity, concurrent validity concerning other standard scales, intrarater reliability, and changes in scores at 12 weeks of the previously developed ABC Dementia Scale (ABC-DS), a novel assessment tool for Alzheimer's disease (AD). Methods: Data were obtained from 312 patients diagnosed with either AD or mild cognitive impairment. The scores on the ABC-DS and standard scales were compared. Results: The 13 items of the ABC-DS are grouped into three domains, and the domain-level scores were highly correlated with the corresponding conventional scales. Statistically significant changes in assessment scores after 12 weeks were observed for the total ABC-DS scores. Conclusion: Our results demonstrate the ABC-DS to have good validity and reliability, and its usefulness in busy clinical settings. PMID- 29706986 TI - Prevalence of Mild Cognitive Impairment and Dementia in Saudi Arabia: A Community Based Study. AB - Introduction: The age of the population in Saudi Arabia is shifting toward elderly, which can lead to an increased risk of mild cognitive impairment (MCI) and dementia. Objective: The aim of this study is to determine the prevalence of cognitive impairment (MCI and dementia) among elderly patients in a community based setting in Riyadh, Saudi Arabia. Methods: In this cross-sectional study, we included patients aged 60 years and above who were seen in the Family Medicine Clinics affiliated with King Faisal Specialist Hospital and Research Centre. Patients with delirium, active depression, and patients with a history of severe head trauma in the past 3 months were excluded. Patients were interviewed during their regular visit by a trained physician to collect demographic data and to administer the validated Arabic version of the Montreal Cognitive Assessment (MoCA) test. Results: One hundred seventy-one Saudi patients were recruited based on a calculated sample size for the aim of this study. The mean age of included sample was 67 +/- 6 years. The prevalence of cognitive impairment was 45%. The prevalence of MCI was 38.6% and the prevalence of dementia was 6.4%. Age, low level of education, hypertension, and cardiovascular disease were risk factors for cognitive impairment. Conclusion: Prevalence of MCI and dementia in Saudi Arabia using MoCA were in the upper range compared to developed and developing countries. The high rate of risk factors for cognitive impairment in Saudi Arabia is contributing to this finding. PMID- 29706987 TI - Application of the DSM-5 Criteria for Major Neurocognitive Disorder to Vascular MCI Patients. AB - Aims: The DSM-5 introduced the term "major neurocognitive disorders" (NCDs) to replace the previous term "dementia." However, psychometric and functional definitions of NCDs are missing. We aimed to apply the DSM-5 criteria for diagnosing the transition to NCD to patients with mild cognitive impairment (MCI) and small vessel disease (SVD), and to define clinically significant thresholds for this transition. Methods: The functional and cognitive features of the NCD criteria were evaluated as change from baseline and operationalized according to hierarchically ordered psychometric rules. Results: According to the applied criteria, out of 138 patients, 44 were diagnosed with major NCD (21 with significant cognitive worsening in >=1 additional cognitive domain), 84 remained stable, and 10 reverted to normal. Single-domain MCI patients were the most likely to revert to normal, and none progressed to major NCD. The amnestic multiple-domain MCI patients had the highest rate of progression to NCD. Conclusion: We provide rules for the DSM-5 criteria for major NCD based on cognitive and functional changes over time, and define psychometric thresholds for clinically significant worsening to be used in longitudinal studies. According to these operationalized criteria, one-third of the MCI patients with SVD progressed to major NCD after 2 years, but only within the multiple-domain subtypes. PMID- 29706989 TI - Caregiver Burden in Semantic Dementia with Right- and Left-Sided Predominant Cerebral Atrophy and in Behavioral-Variant Frontotemporal Dementia. AB - Background: Caregiver burden is a serious concern for family caregivers of dementia patients, but its nature is unclear in patients with semantic dementia (SD). This study aimed to clarify caregiver burden for right- (R > L) and left sided (L > R) predominant SD versus behavioral-variant frontotemporal dementia (bvFTD) patients. Methods: Using the Japanese version of the Zarit Burden Interview (ZBI) and the Neuropsychiatric Inventory, we examined caregiver burden and behavioral and psychological symptoms of dementia (BPSD) in 43 first-visit outpatient/family caregiver dyads (bvFTD, 20 dyads; SD [L > R], 13 dyads; SD [R > L], 10 dyads). Results: We found a significant difference in ZBI score between the 3 diagnostic groups. Post hoc tests revealed a significantly higher ZBI score in the bvFTD than in the SD (L > R) group. The ZBI scores in the SD (L > R) and SD (R > L) groups were not significantly different, although the effect size was large. Caregiver burden was significantly correlated with BPSD scores in all groups and was correlated with activities of daily living and instrumental activities of daily living decline in the bvFTD and SD (R > L) groups. Conclusion: Caregiver burden was highest in the bvFTD group, comparatively high in the SD (R > L) group, and lowest in the SD (L > R) group. Adequate support and intervention for caregivers should be tailored to differences in caregiver burden between these patient groups. PMID- 29706988 TI - Time from Symptom Debut to Dementia Assessment by the Specialist Healthcare Service in Norway. AB - Objectives: We described the duration from symptom debut to assessment at specialist healthcare outpatient clinics for dementia in Norway and explored whether educational level was associated with time from symptom debut to dementia assessment. Methods: The study comprised 835 persons from a register for individuals with cognitive symptoms (NorCog). The outcome variable was time in months from symptom debut to assessment. The main independent variable was the number of years of education. Also age, gender, marital status, cognitive function, neuropsychiatric symptoms, assistance and location were assessed. Results: In an adjusted linear mixed model, a higher educational level was associated with a longer duration from symptom debut to assessment, where 5 additional years of education increased the time from symptom debut to consultation by 10%. Conclusion: The findings may perhaps be explained by the hypothesis that highly educated people may be able to compensate better for cognitive impairment, which is in line with a hypothesis of cognitive reserve. PMID- 29706990 TI - Inferring Variation in Copy Number Using High Throughput Sequencing Data in R. AB - Inference of copy number variation presents a technical challenge because variant callers typically require the copy number of a genome or genomic region to be known a priori. Here we present a method to infer copy number that uses variant call format (VCF) data as input and is implemented in the R package vcfR. This method is based on the relative frequency of each allele (in both genic and non genic regions) sequenced at heterozygous positions throughout a genome. These heterozygous positions are summarized by using arbitrarily sized windows of heterozygous positions, binning the allele frequencies, and selecting the bin with the greatest abundance of positions. This provides a non-parametric summary of the frequency that alleles were sequenced at. The method is applicable to organisms that have reference genomes that consist of full chromosomes or sub chromosomal contigs. In contrast to other software designed to detect copy number variation, our method does not rely on an assumption of base ploidy, but instead infers it. We validated these approaches with the model system of Saccharomyces cerevisiae and applied it to the oomycete Phytophthora infestans, both known to vary in copy number. This functionality has been incorporated into the current release of the R package vcfR to provide modular and flexible methods to investigate copy number variation in genomic projects. PMID- 29706991 TI - On Synchronizing Coupled Retinogeniculocortical Pathways: A Toy Model. AB - A Newman-Watts graph is formed by including random links in a regular lattice. Here, the emergence of synchronization in coupled Newman-Watts graphs is studied. The whole neural network is considered as a toy model of mammalian visual pathways. It is composed by four coupled graphs, in which a coupled pair represents the lateral geniculate nucleus and the visual cortex of a cerebral hemisphere. The hemispheres communicate with each other through a coupling between the graphs representing the visual cortices. This coupling makes the role of the corpus callosum. The state transition of neurons, supposed to be the nodes of the graphs, occurs in discrete time and it follows a set of deterministic rules. From periodic stimuli coming from the retina, the neuronal activity of the whole network is numerically computed. The goal is to find out how the values of the parameters related to the network topology affect the synchronization among the four graphs. PMID- 29706992 TI - NMDA Receptor Subunits Change after Synaptic Plasticity Induction and Learning and Memory Acquisition. AB - NMDA ionotropic glutamate receptors (NMDARs) are crucial in activity-dependent synaptic changes and in learning and memory. NMDARs are composed of two GluN1 essential subunits and two regulatory subunits which define their pharmacological and physiological profile. In CNS structures involved in cognitive functions as the hippocampus and prefrontal cortex, GluN2A and GluN2B are major regulatory subunits; their expression is dynamic and tightly regulated, but little is known about specific changes after plasticity induction or memory acquisition. Data strongly suggest that following appropriate stimulation, there is a rapid increase in surface GluN2A-NMDAR at the postsynapses, attributed to lateral receptor mobilization from adjacent locations. Whenever synaptic plasticity is induced or memory is consolidated, more GluN2A-NMDARs are assembled likely using GluN2A from a local translation and GluN1 from local ER. Later on, NMDARs are mobilized from other pools, and there are de novo syntheses at the neuron soma. Changes in GluN1 or NMDAR levels induced by synaptic plasticity and by spatial memory formation seem to occur in different waves of NMDAR transport/expression/degradation, with a net increase at the postsynaptic side and a rise in expression at both the spine and neuronal soma. This review aims to put together that information and the proposed hypotheses. PMID- 29706994 TI - Association of Three Polymorphisms rs11614913, rs2910146, and rs3746444 in miRNA 196a2, miRNA-146a, and miRNA-499 with Inflammatory Bowel Disease: A Systematic Review and Meta-Analysis. AB - Background: It has been found that single-nucleotide polymorphisms (SNPs) of microRNA might be involved in the development of inflammatory bowel diseases (IBDs). However, the related retrospective research has not been reported. In this work, we performed a meta-analysis to derive a more precise estimation of the associated relationship. Methods: We searched the studies on the association of SNPs of microRNA with the hereditary susceptibility of IBD in PubMed and Embase; eligible research was selected by screening the abstract and full text. The meta-analysis was performed based on the statistical software Stata 14.0, and besides, the odds ratio and 95% confidence interval were calculated to evaluate the strength of the association. Results: 159 papers were acquired from the PubMed and Embase databases, and five eligible articles containing nine case control studies were selected. In the study, we first found that the association between miRNA-196a2 rs11614913 and IBD was insignificant. Then, the susceptibility of miRNA-146a rs2910146 to IBD increased significantly in allelic comparison, homozygote model, heterozygote model, and dominant model. Moreover, a positive relationship between miRNA-499 rs3746444 and IBD was identified in the homozygote model. Conclusion: Our findings demonstrated that miRNA-146a rs2910146 (G>C) polymorphism was associated with the susceptibility to IBD and miRNA-196a2 rs11614913 (T>C) and miRNA-499 rs3746444 (A>G) did not reveal an obvious relationship with the IBD susceptibility. PMID- 29706995 TI - Tanshinone IIA Sodium Sulfonate Attenuates LPS-Induced Intestinal Injury in Mice. AB - Background: Tanshinone IIA sodium sulfonate (TSS) is known to possess anti inflammatory effects and has exhibited protective effects in various inflammatory conditions; however, its role in lipopolysaccharide- (LPS-) induced intestinal injury is still unknown. Objective: The present study is designed to explore the role and possible mechanism of TSS in LPS-induced intestinal injury. Methods: Male C57BL/6J mice, challenged with intraperitoneal LPS injection, were treated with or without TSS 0.5 h prior to LPS exposure. At 1, 6, and 12 h after LPS injection, mice were sacrificed, and the small intestine was excised. The intestinal tissue injury was analyzed by HE staining. Inflammatory factors (TNF alpha, IL-1beta, and IL-6) in the intestinal tissue were examined by ELISA and RT PCR. In addition, expressions of autophagy markers (microtubule-associated light chain 3 (LC3) and Beclin-1) were detected by western blot and RT-PCR. A number of autophagosomes were also observed under electron microscopy. Results: TSS treatment significantly attenuated small intestinal epithelium injury induced by LPS. LPS-induced release of inflammatory mediators, including TNF-alpha, IL 1beta, and IL-6, were markedly inhibited by TSS. Furthermore, TSS treatment could effectively upregulate LPS-induced decrease of autophagy levels, as evidenced by the increased expression of LC3 and Beclin-1, and more autophagosomes. Conclusion: The protective effect of TSS on LPS-induced small intestinal injury may be attributed to the inhibition of inflammatory factors and promotion of autophagy levels. The present study may provide novel insight into the molecular mechanisms of TSS on the treatment of intestinal injury. PMID- 29706993 TI - Instrumental or Physical-Exercise Rehabilitation of Balance Improves Both Balance and Gait in Parkinson's Disease. AB - We hypothesised that rehabilitation specifically addressing balance in Parkinson's disease patients might improve not only balance but locomotion as well. Two balance-training protocols (standing on a moving platform and traditional balance exercises) were assessed by assigning patients to two groups (Platform, n = 15, and Exercises, n = 17). The platform moved periodically in the anteroposterior, laterolateral, and oblique direction, with and without vision in different trials. Balance exercises were based on the Otago Exercise Program. Both platform and exercise sessions were administered from easy to difficult. Outcome measures were (a) balancing behaviour, assessed by both Index of Stability (IS) on platform and Mini-BESTest, and (b) gait, assessed by both baropodometry and Timed Up and Go (TUG) test. Falls Efficacy Scale-International (FES-I) and Parkinson's Disease Questionnaire (PDQ-8) were administered. Both groups exhibited better balance control, as assessed both by IS and by Mini BESTest. Gait speed at baropodometry also improved in both groups, while TUG was less sensitive to improvement. Scores of FES-I and PDQ-8 showed a marginal improvement. A four-week treatment featuring no gait training but focused on challenging balance tasks produces considerable gait enhancement in mildly to moderately affected patients. Walking problems in PD depend on postural instability and are successfully relieved by appropriate balance rehabilitation. This trial is registered with ClinicalTrials.gov NCT03314597. PMID- 29706996 TI - Does the Use of Nitroglycerin Patch Improve Local Anaesthetic Effects in Bier's Block? A Double-Blind Placebo Controlled Study. AB - Aim: The aim of the study was to assess the nitroglycerin patch as a new additive to Bier's block and its impact on the effects and dose of lidocaine. Methods: Forty patients of each sex belonging to ASA I or II underwent elective tendon repair surgeries of the forearm and hand. The patients were divided into two equal groups as follows: Group C received only lidocaine (1.5 mg/kg, 0.25%) and Group N received lidocaine (1.5 mg/kg, 0.25%) + 5 mg transcutaneous nitroglycerin patch. Onset and recovery times for sensory and motor block, visual analogue scale (VAS) scores for bandage pain, postoperative VAS score, analgesic requirements, patients' satisfaction, and surgeons' opinion were recorded. Results: Sensory block onset time was shorter in Group N (3.80 +/- 1.0) than that in Group C (5.72 +/- 1.46), and motor block onset time was shorter in Group N (10.72 +/- 1.93) than that in Group C (13.56 +/- 1.26). Sensory block recovery time was prolonged in Group N (10.56 +/- 1.12) than Group C (6.88 +/- 1.45), recovery time of motor block was prolonged in Group N (13.04 +/- 1.57) than Group C (11.96 +/- 1.72). Bandage pain had lower VAS scores in Group N. Postoperative VAS scores showed significant differences between both groups at the following points of measurement: 30 minutes, 1 hour, and 4 hours after bandage deflation. Postoperative analgesic effect was the longest in Group N (187.20 +/- 60.79 min) than Group C (51.60 +/- 25.28 min). Patients' satisfaction and surgeons' opinion were better in Group N than Group C. Conclusion: Supplementation of Bier's block with transcutaneous nitroglycerin patch reduces the lidocaine dose, the sensory and motor block onset times, VAS scores, and analgesic consumption intra- and postoperatively. Length of the block recovery times for the sensory and motor effects, duration of postoperative analgesic effect, and the first time to analgesic requirement improved the quality of Bier's block with better patients' satisfaction and surgeons' opinion and had no adverse effects. PMID- 29706997 TI - Influence of Handprint Culture Training on Compliance of Healthcare Workers with Hand Hygiene. AB - Objective: We aimed to study the effect of visual observation of bacterial growth from handprints on healthcare workers' (HCWs) compliance with hand hygiene (HH). Settings: Medical and postoperative cardiac surgery units. Design: Prospective cohort study. Subject: The study included 40 HCWs. Intervention: Each HCW was interviewed on 3 separate occasions. The 1st interview was held to obtain a handprint culture before and after a session demonstrating the 7 steps of HH using alcohol-based hand rub, allowing comparison of results before and after HH. A 2nd interview was held 6 weeks later to obtain handprint culture after HH. A 3rd interview was held to obtain a handprint culture before HH. One month before implementation of handprint cultures and during the 12-week study period, monitoring of HCWs for compliance with HH was observed by 2 independent observers. Main Results: There was a significant improvement in HH compliance following handprint culture interview (p < 0.001). The frequency of positive cultures, obtained from patients with suspected healthcare-associated infections, significantly declined (blood cultures: p = 0.001; wound cultures: p = 0,003; sputum cultures: p = 0.005). Conclusion: The visual message of handprint bacterial growth before and after HH seems an effective method to improve HH compliance. PMID- 29706999 TI - The Association between Serum Bilirubin Level and Electrochemical Skin Conductance in Chinese Patients with Type 2 Diabetes. AB - Bilirubin is an antioxidant and plays a protective role against cardiovascular and microvascular disease. The aim of this study is to explore the possible protective effect of bilirubin on small nerve function. A total of 265 Chinese patients with type 2 diabetes mellitus (T2DM) were enrolled in the study. Both SUDOSCAN and other traditional diabetic neuropathy examinations including neuropathy symptom score (NSS), the neuropathy disability score (NDS) and Michigan Neuropathy Screening Instrument (MNSI) scores were performed in all patients with T2DM. Blood bilirubin levels were tested in the study. Spearman correlation analysis and multivariate regression analysis were performed to determine the relation between bilirubin level and hands and feet ESC values. Spearman correlation analysis demonstrated a correlation between total bilirubin and ESC levels including hands (r = 0.165, P < 0.05) and feet (r = 0.122, P < 0.05) as well as between UCBil and ESC levels including both hands (r = 0.172, P < 0.05) and feet (r = 0.175, P < 0.05). Multivariate regression linear analyses showed both total bilirubin and UCBil level were independently associated with hands and feet ESC levels. All these results suggested a positive association between bilirubin level and ESC level, indicating a possible protective role of bilirubin in peripheral small nerve dysfunction of type 2 diabetes mellitus. PMID- 29706998 TI - Melatonin Treatment Improves Insulin Resistance and Pigmentation in Obese Patients with Acanthosis Nigricans. AB - Objective: This study aimed to determine the effects of melatonin on insulin resistance in obese patients with acanthosis nigricans (AN). Methods: A total of 17 obese patients with acanthosis nigricans were recruited in a 12-week pilot open trial. Insulin sensitivity, glucose metabolism, inflammatory factors, and other biochemical parameters before and after the administration of melatonin were measured. Results: After 12 weeks of treatment with melatonin (3 mg/day), homeostasis model assessment insulin resistance index (HOMA-IR) (8.99 +/- 5.10 versus 7.77 +/- 5.21, p < 0.05) and fasting insulin (37.09 5 +/- 20.26 MUU/ml versus 32.10 +/- 20.29 MUU/ml, p < 0.05) were significantly decreased. Matsuda index (2.82 +/- 1.54 versus 3.74 +/- 2.02, p < 0.05) was significantly increased. There were also statistically significant declines in the AN scores of the neck and axilla, body weight, body mass index, body fat, visceral index, neck circumference, waist circumference, and inflammatory markers. Conclusions: It was concluded that melatonin could improve cutaneous symptoms in obese patients with acanthosis nigricans by improving insulin sensitivity and inflammatory status. This trial is registered with ClinicalTrials.gov NCT02604095. PMID- 29707001 TI - Experience and Expectations of Ovarian Cancer Patients in Australia. AB - Some of the most significant advances in ovarian cancer treatment have been those that result in improvements in progression-free survival (PFS); however there is little research to understand the value that patients place on accessing therapies that result in PFS as a clinical outcome related to survivorship. This study therefore aimed to understand the experience and expectations of women with ovarian cancer in Australia in relation to quality of life (QoL) and treatment options. An online survey collected demographic information and 13 investigator derived structured interview questions were developed to understand the experience of women with ovarian cancer, their understanding of terminology associated with their condition, and expectations of future treatment. This study demonstrated that ovarian cancer patients equate PFS with being in remission and that patients expect QoL during that time to be good to excellent. Women in this study described excellent QoL as feeling positive and happy and not worrying about cancer, feeling fit and healthy without side effects, and being able to live life as they did before their diagnosis, including the absence of fear of progression or recurrence. It is therefore suggested that there is a positive relationship between PFS and QoL. While it is difficult to quantify QoL and further research is needed, the results of this study suggest that the minimum time that women with ovarian cancer expect in relation to treatments that result in PFS is approximately six months. In the absence of this information, decision makers are left to make assumptions about the value women place on access to therapeutics that increase PFS, which for this type of cancer is an important aspect of survivorship. PMID- 29707002 TI - Determination of Pyrethroids in Tea Brew by GC-MS Combined with SPME with Multiwalled Carbon Nanotube Coated Fiber. AB - A new method has been developed to simultaneously determine 7 pyrethroid residues in tea brew using gas chromatography-mass spectrometry (GC-MS) combined with solid phase microextraction (SPME) with multiwalled carbon nanotubes (MWCNTs) coated fiber. The MWCNTs coated fiber of SPME was homemade by using stainless steel wire as coating carrier and polyacrylonitrile (PAN) solution as adhesive glue. Under the optimized conditions, a good linearity was shown for bifenthrin, fenpropathrin, permethrin, and cyfluthrin in 1-50 ng mL-1 and for cypermethrin, fenvalerate, and deltamethrin in 5-50 ng mL-1. The correlation coefficients were in the range of 0.9948-0.9999. The average recoveries of 7 pyrethroids were 94.2% 107.3% and the relative standard deviations (RSDs) were less than 15%. The detection limit of the method ranged from 0.12 to 1.65 ng mL-1. The tea brew samples made from some commercial tea samples were analyzed. Among them, bifenthrin, fenpropathrin, and permethrin were found. The results show that the method is rapid and sensitive and requires low organic reagent consumption, which can be well used for the detection of the pyrethroids in tea brew. PMID- 29707003 TI - Evaluating the Agreement of Risk Categorization for Fetal Down Syndrome Screening between Ultrasound-Based Gestational Age and Menstrual-Based Gestational Age by Maternal Serum Markers. AB - Objective: To evaluate the agreement of risk categorization for Down syndrome screening between ultrasound scan-based gestational age (GA) and last menstrual period-based gestational age in both first and second trimesters by maternal serum markers. Methods: Data comprising 4,055 and 4,016 cases of first and second trimester screening were used. The maternal serum markers were analyzed using the ultrasound-based GA and menstrual age. The subjects whose menstrual age and ultrasound-based GA fell in different trimesters were excluded because the risk could not be calculated due to the different serum markers used in each trimester. The agreement of risk categorization for fetal Down syndrome was evaluated. Results: The agreement of Down syndrome screening in the first and the second trimesters were 92.7% and 89%, respectively. The study found a good agreement of risk categorization by Kappa index, which was 0.615 for the overall screening. The menstrual age had a slight decrease in the detection rate and a lower false-positive rate. Conclusion: Menstrual age is acceptable in cases of accurate last menstrual period. However, in places where ultrasonography is not readily available, gestational age estimation by menstrual age along with clinical examination that corresponds to the gestational age can be reliable. PMID- 29707000 TI - MicroRNA and Microvascular Complications of Diabetes. AB - In the last decade, miRNAs have received substantial attention as potential players of diabetes microvascular complications, affecting the kidney, the retina, and the peripheral neurons. Compelling evidence indicates that abnormally expressed miRNAs have pivotal roles in key pathogenic processes of microvascular complications, such as fibrosis, apoptosis, inflammation, and angiogenesis. Moreover, clinical research into innovative both diagnostic and prognostic tools suggests circulating miRNAs as possible novel noninvasive markers of diabetes microvascular complications. In this review, we summarize current knowledge and understanding of the role of miRNAs in the injury to the microvascular bed in diabetes and discuss the potential of miRNAs as clinical biomarkers of diabetes microvascular complications. PMID- 29707004 TI - Expansion of Gammadelta T Cells from Cord Blood: A Therapeutical Possibility. AB - Gammadelta (gammadelta) T cells are found in both blood and tissues and have antiviral and antitumor properties. The frequency of gammadelta T cells in umbilical cord blood (UCB) is low, and the majority express delta1, in contrast to blood, whereas the main subset is delta2gamma9 T cells. UCB gammadelta T cells are functionally immature, which together with their scarcity complicates the development of UCB gammadelta T cell therapies. We aimed to develop an effective expansion protocol for UCB gammadelta T cells based on zoledronate and IL-2. We found that culture with 5 MUM zoledronate and 200 IU IL-2/ml medium for 14 days promoted extensive proliferation. The majority of the cultured cells were gamma9delta2 T cells. The fold expansion of this, originally infrequent, subset was impressive (median and maximum fold change 253 and 1085, resp.). After culture, the cells had a polyclonal gammadelta T cell repertoire and the main memory subset was central memory (CD45RO+ CD27+). The cells produced cytokines such as IL-1B, IL-2, and IL-8 and displayed significant tumor-killing capacity. These results show that development of in vitro expanded UCB gammadelta T cell therapies is feasible. It could prove a valuable treatment modality for patients after umbilical cord blood transplantation. PMID- 29707005 TI - Efficacy of IANB and Gow-Gates Techniques in Mandibular Molars with Symptomatic Irreversible Pulpitis: A Prospective Randomized Double Blind Clinical Study. AB - Introduction: The aim of the present study was to compare the efficacy of the inferior alveolar nerve block (IANB) and Gow-Gates techniques in mandibular molars with symptomatic irreversible pulpitis. Methods and Materials: In this randomised, double-blind clinical trial, 80 patients referred to Mashhad Dental School, were randomly divided into two groups: IANB and Gow-Gates anaesthetic techniques using 2% lidocaine with 1:100000 epinephrine. After injection, if pain during caries/dentin removal and access cavity preparation was reported in each group, the patients once again were randomly allocated to receive buccal or lingual supplementary infiltration. Pain severity was evaluated using a visual analogue scale. The rates of positive aspiration and changes in heart rate were compared between the IANB and Gow-Gates. Paired and individual t-tests and the Mann-Whitney U-test were used to compare the reduction in pain severity. The level of significance was set at 0.05. Results: The success rates of anaesthesia in the Gow-Gates and IANB techniques were 50% and 42.5%, respectively with no significant difference (P=0.562). Supplementary infiltrations significantly reduced pain severity in all subgroups (P<0.05). Lingual infiltration resulted in a significantly greater reduction in pain severity in the IANB group than in the Gow-Gates group (P<0.05). No significant difference in heart rate or positive aspiration results was observed between groups (P>0.05). Conclusions: In the present study, the efficacy of the IANB and Gow-Gates techniques was comparable in mandibular molars with symptomatic irreversible pulpitis. Supplementary buccal and lingual infiltration significantly reduced pain severity. PMID- 29707006 TI - Radiographic Quality of Single vs. Multiple-Visit Root Canal Treatment Performed by Dental Students: A Case Control Study. AB - Introduction: The aim of this study was to compare the quality of root canal treatment provided by undergraduate dental students in relation to the number of dental visits. Methods and Materials: Root canal treatments done by 77 dental students were observed. For each student, one tooth treated in a single visit was matched and compared with a tooth treated in multiple visits. The effect of preoperative conditions on the quality of root canal treatment and the number of visits were analyzed. The quality of root canal treatment was determined by the following criteria: obturation length, density, taper, and presence of procedural errors. The data were statistically analyzed using an exact conditional logistic regression test, and the level of significance was set at 0.05. Results: There was no statistically significant association between single- and multiple-visit root canal treatment in terms of obturation length (P=0.263), obturation density (P=0.625), and obturation taper (P=1.00). The incidence of procedural errors in teeth which required a single visit (7.8%) was less but not significantly different from those treated in multiple visits (16.9%). The presence of preoperative conditions was not significantly associated with multiple-visit treatment. Conclusion: Within the limitations of the study, multiple-visit treatment was not associated with a better quality of root canal treatment compared to single-visit treatment. PMID- 29707007 TI - Correlation between the Periapical Index and Lesion Volume in Cone-beam Computed Tomography Images. AB - Introduction: The study aimed to correlate the Periapical Index (PAI), obtained by way of periapical radiographs, with the volume of chronic periapical lesion, obtained through cone-beam computed tomography (CBCT), in the permanent teeth. Methods and Materials: Radiographs and CBCT images were selected from 35 single rooted permanent teeth, with fully formed apices, with a diagnosis of pulp necrosis and chronic apical periodontitis that was radiographically visible. Two independent raters evaluated the radiographs on two separate occasions and classified the periapical lesions in accordance with Orstavik's PAI. The periapical lesion volume was calculated in the CBCT images. The correlation between the PAI and the lesion volume was calculated using Spearman's correlation test. Results: There was a positive, moderate correlation between the PAI and the volume (rs=0.596; P<0.001) where rs2 is equal to 0.355, showing that only 35% of the PAI variation was dependent upon the variation in periapical lesion volume. Conclusion: The radiographic evaluation of the periapical lesion does not reflect the lesion's volumetric characteristics as the volume had a moderate effect on the choice of PAI score. PMID- 29707008 TI - Intra-manufacture Diameter Variability of Rotary Files and Their Corresponding Gutta-Percha Cones Using Laser Scan Micrometre. AB - Introduction: Manufacturers offer gutta-percha (GP) cones matched with different sizes of endodontic files as an attempt to simplify the obturation process and create a tight seal in the canal. The purpose of this study was to evaluate whether intra-manufacture GP diameters matched the diameters of their corresponding files at different levels using laser micrometre. Methods and Materials: Twenty files and corresponding GP master cones of Reciproc R40 (40/0.06) (VDW, Munich, Germany), WaveOne Large(40/0.08)(Dentsply Maillefer, Ballaigues, Switzerland), ProTaper F3 (30/0.09) (Dentsply Maillefer, Ballaigues, Switzerland), and Mtwo 40/0.06 (VDW, Munich, Germany) were examined using laser micrometre (LSM 6000 by Mitutoyo, Japan) with accuracy of 1 nm to establish their actual diameter at D0, D1, D3 and D6. The data was analysed using the independent t-test. The differences were considered at 0.05. Results: The diameter of GP master cones was significantly larger than that of the corresponding files at all levels in all brands. ProTaper GP diameter was closest to the file diameter at D1 (GP=0.35, File=0.35 mm), and D3 (GP=0.48, File=0.49). Conclusion: Within the same manufacturer, GP cone diameters do not match the diameters of their corresponding files. Clinicians are advised to use a GP gauge to cut the tip so as to appropriate the diameter from a smaller sized GP cone. PMID- 29707009 TI - The Effect of Canal Preparation with Four Different Rotary Systems on Formation of Dentinal Cracks: An In Vitro Evaluation. AB - Introduction: Endodontic rotary systems may result in dentinal cracks. They may propagate to vertical root fracture that compromises the outcome of endodontic treatment. This study aimed to compare Neolix and Reciproc (single-file systems), Mtwo and ProTaper (conventional rotary systems) in terms of dentinal crack formation in root canal walls. Methods and Materials: This in vitro study was conducted on 110 extracted human single-rooted teeth. The teeth were randomly divided into four experimental groups (n=25) for root canal preparation with Neolix, Reciproc, Mtwo and ProTaper systems and two control groups (n=5). The first control group underwent root canal instrumentation with hand files while the second control group received no preparation and was only irrigated. After instrumentation, root canals were horizontally sectioned at 3, 6 and 9 mm from the apex and inspected under a stereomicroscope under 12* magnification for detection of cracks. The data were analyzed using Chi-square, GEE test and Bonferroni tests (P<0.05). Results: No crack was found in the control groups. All rotary systems caused dentinal cracks. ProTaper, Reciproc, Mtwo and Neolix caused cracks in 92%, 80%, 68% and 48% of samples. ProTaper caused significantly more cracks than Neolix and Mtwo (P<0.05). No significant differences were noted between other groups (P>0.05). Conclusion: All rotary systems cause dentinal cracks and it is significantly different in apical, middle and coronal third of the root. Neolix appears to be a suitable alternative to other rotary systems since use of this single-file system saves time and cost and minimizes trauma to dentinal walls. PMID- 29707010 TI - Extrusion of Irrigant in Open Apex Teeth with Periapical Lesions Following Laser Activated Irrigation and Passive Ultrasonic Irrigation. AB - Introduction: Sodium hypochlorite (NaOCl) irrigation is critical for the success of endodontic treatment and several agitation techniques have been developed to improve the efficacy of this irrigation. Using a combination of contrast medium and radiographic examination, this study evaluated NaOCl extrusion during agitation of irrigant. Development of pressure, which may result in apical extrusion of the irrigant, has been described during laser-activated irrigation (LAI) and passive ultrasonic irrigation (PUI). Methods and Materials: We examined 40 single root canals categorized as having open apices with apical lesions in 40 patients. For the final irrigation, the teeth were irrigated with a mixture of radiopaque contrast medium and 2.5% NaOCl in solution. The solution was activated for 60 sec in both groups [the Er, Cr: YSGG laser group (n=20) and the ultrasonic group (n=20)]. The teeth were imaged subsequently using radiography for the evaluation of contrast extrusion. Results: Radiopaque contrast medium was absent from the periapical tissues in all cases. Conclusion: Use of LAI or PUI appears to be safe as used currently in endodontic treatment. PMID- 29707011 TI - Bacterial Reduction after Gutta-Percha Removal with Single vs. Multiple Instrument Systems. AB - Introduction: The aim of this study was to evaluate the effectiveness of a reciprocating single-instrument system (Reciproc-REC) compared with combined continuously rotating multiple-instrument systems [D-Race (DR) and BioRace (BR)] in reducing Enterococcus faecalis (E.f.) after gutta-percha removal. Methods and Materials: Forty-six extracted human maxillary incisors were prepared and contaminated with E.f. strain (ATCC 29212) for 30 days. The samples were obturated and randomly divided into two experimental groups for gutta-percha removal (n=23): a REC group (R50) and a DR/BR group (DR1, DR2 and BR6). A standardized irrigation with 0.9% saline solution was performed. Root canal samples were taken with paper points before (S1) and after (S2) the removal of gutta-percha to establish bacterial quantification by culture. The time required for gutta-percha removal was also recorded. Positive and negative control groups (n=6) were used to test bacterial viability and control asepsis, respectively. Data were analysed using t-Student and one-way ANOVA tests (5% margin of error). Results: The mean percentage of bacterial reduction was significantly higher in DR/BR group (84.2%) than in REC group (72.3%) (P<0.05). The mean time for obturation removal was 74.00 sec in REC group and 107.53 sec in DR/BR group (P<0.05). Conclusion: The combined continuously rotating multiple-instrument system was more effective in reducing bacteria after the removal of gutta-percha than the single-instrument system. None of the tested systems was able to completely eliminate root canal infection after gutta-percha removal. Thus, additional techniques should be considered. PMID- 29707012 TI - Accuracy of Cone-beam Computed Tomography in Comparison with Standard Method in Evaluating Root Canal Morphology: An In Vitro Study. AB - Introduction: In order to successfully perform root canal treatment, thorough knowledge of the root canal anatomy is essential. Cone-beam computed tomography (CBCT) has the ability to improve our understanding of the root canal system. The goal of the present study was to compare the accuracy of CBCT in revealing the number and form of the root canals of different maxillary and mandibular teeth with clearing and staining method. Methods and Materials: CBCT images were taken from 80 extracted human teeth fixed in agar arch models. The number and configuration of the root canals of each tooth were determined by the two observers. Then the teeth were cleared and stained. Two endodontists evaluated the number and forms of the root canals. The accuracy of CBCT was determined and compared with clearing and staining by Fisher's exact test. The agreement of two methods in detection of the number and form of the root canals were evaluated by Kappa test, P<=0.05. Results: CBCT accurately detected the number of root canals in 129 (92.1%) of 140 roots and the form of the canals in 119 (85%) of the roots. There was no significant difference between the accuracy of CBCT in the detection of the number (P=0.13) and forms (P=0.4) of root canals of maxillary and mandibular teeth. The agreement between CBCT, and tooth clearing and staining in detection of the number of root canals was excellent in the maxilla (kappa=0.88+/ 0.05) and good in the mandible (kappa=0.720+/-0.097). The agreement between the two methods in demonstration of the form of root canals was good in both maxillary (kappa=0.73+/-0.07) and mandibular (kappa=0.67+/-0.09) teeth. Conclusion: CBCT provides accurate information about root canal morphology. Application of this technique could result in more successful endodontic treatments. PMID- 29707013 TI - The Effect of Resection Angle on Stress Distribution after Root-End Surgery. AB - Introduction: This study aimed to investigate the influence of the resection angle on the stress distribution of retrograde endodontic treated maxillary incisors under oblique-load application. Methods and Materials: A maxillary central incisor which was endodontically treated and restored with a fiber glass post was obtained in a 3-dimensional numerical model and distributed into three groups according to type of resection: control; restored with fiber post without retrograde obturation, R45 and R90 with 45o and 90o resection from tooth axial axis, respectively and restored with Fuji II LC (GC America). The numerical models received a 45o occlusal load of 200 N/cm2 on the middle of lingual surface. All materials and structures were considered linear elastic, homogeneous and isotropic. Numerical models were plotted and meshed with isoparametric elements, and the results were analyzed using maximum principal stress (MPS). Results: MPS showed greater stress values in the bone tissue for control group than the other groups. Groups with apicectomy showed acceptable stress distribution on the fiber post, cement layer and root dentin, presenting more improved values than control group. Conclusion: Apicectomy at 90o promotes more homogeneity on stress distribution on the fiber post, cement layer and root dentin, which suggests less probability of failure. However, due to its facility and stress distribution also being better than control group, apicectomy at 45 degrees could be a good choice for clinicians. PMID- 29707014 TI - Thermal Scanning of Dental Pulp Chamber by Thermocouple System and Infrared Camera during Photo Curing of Resin Composites. AB - Introduction: Due to thermal hazard during composite restorations, this study was designed to scan the pulp temperature by thermocouple and infrared camera during photo polymerizing different composites. Methods and Materials: A mesio-occlso distal (MOD) cavity was prepared in an extracted tooth and the K-type thermocouple was fixed in its pulp chamber. Subsequently, 1 mm increment of each composites were inserted (four composite types were incorporated) and photo polymerized employing either LED or QTH systems for 60 sec while the temperature was recorded with 10 sec intervals. Ultimately, the same tooth was hemisected bucco-lingually and the amalgam was removed. The same composite curing procedure was repeated while the thermogram was recorded using an infrared camera. Thereafter, the data was analyzed by repeated measured ANOVA followed by Tukey's HSD Post Hoc test for multiple comparisons (alpha=0.05). Results: The pulp temperature was significantly increased (repeated measures) during photo polymerization (P=0.000) while there was no significant difference among the results recorded by thermocouple comparing to infrared camera (P>0.05). Moreover, different composite materials and LCUs lead to similar outcomes (P>0.05). Conclusion: Although various composites have significant different chemical compositions, they lead to similar pulp thermal changes. Moreover, both the infrared camera and the thermocouple would record parallel results of dental pulp temperature. PMID- 29707015 TI - Effect of the Bone Graft on the Surface Microhardness of Endodontic Biomaterials. AB - Introduction: During periapical surgery, using of bone products in large endodontic lesions, is a treatment option that could affect the properties of the retro-filling endodontic material. The aim of present study was to evaluate the effect of Osteon II bone powder on the surface microhardness of calcium-enriched mixture (CEM) and mineral trioxide aggregate (MTA). Methods and Materials: Each material was mixed and carried into 40 sterile custom-made plastic cylinders. Half of the samples in each group were exposed to Osteon II. All cylinders were submerged in simulated tissue fluid and incubated at 37 degrees C and 100% relative humidity for 7 days. Surface microhardness values of each study group was attained using Vickers microhardness test. The data were analyzed statistically using two-way ANOVA and independent t-test at a significance level of 0.05. Results: The highest and lowest microhardness values were recorded in the MTA/without Osteon and MTA/with Osteon groups, respectively. Irrespective of the presence or absence of bone powder, the overall microhardness of CEM cement and MTA was not significantly different. In the MTA group, the presence of the powder resulted in a significant decrease (P<0.05) of the microhardness; however, its effect on CEM cement was not significant (P>0.05). Conclusion: Under the limitations of the present in vitro study, the presence of Osteon bone powder had no negative effect on the microhardness of CEM cement, contrary to its effect on MTA. PMID- 29707016 TI - Diagnostic Efficacy of Four Methods for Locating the Second Mesiobuccal Canal in Maxillary Molars. AB - Introduction: The major cause for failure of root canal therapy is the inability to recognize the presence of all canals of the root canal system. Auxiliary tools, such as magnifying loupe, operative microscope and computed tomography (CT) images are used to facilitate the location of canals. The objective of the present survey was to evaluate the diagnostic efficacy of four methods for detecting the second canal of mesiobuccal roots (MB2) of permanent maxillary molars. Methods and Material: A total of 147 extracted human maxillary molars were assessed. The floor of the pulp chamber was inspected by an endodontist to find MB2 canals. Analyses were performed without magnification (direct visual method), using a loupe (with 3.5* magnification), and using a microscope (with 16* magnification). A fourth analysis was conducted using cone-beam computed tomography (CBCT) images. Teeth were sectioned horizontally into three parts (cervical, medial and apical thirds) to confirm the presence of MB2 canals (reference standard method). Sensitivity, specificity, and positive/negative predictive values were calculated for each method. Results: No statistically significant differences were observed in the frequency of MB2 found between the microscope and the reference standard or between CBCT and the reference standard. CBCT had higher sensitivity (0.88), specificity (0.88), positive (0.84) and negative (0.91) predictive value than the other three methods. Conclusion: CBCT was the most accurate method for detecting the MB2 and it had a diagnostic efficacy similar to that of the reference standard method. PMID- 29707017 TI - Effects of Different Irrigation Solutions and Protocols on Mineral Content and Ultrastructure of Root Canal Dentine. AB - Introduction: The aim of this study was to evaluate the effect of different irrigating solutions and irrigation protocols on the chemical and physical structure of root dentin. Materials and Methods: Thirty extracted single-rooted human teeth were selected and then distributed into the following treatment groups (n=10): G1, saline solution (0.9% NaCl); G2, 2.5% NaOCl + 17% EDTA + 2.5% NaOCl; G3, 2.5% NaOCl + 9% Etidronate (HEBP) + 2.5% NaOCl; G4, mixture of 5% NaOCl + 18% HEBP; G5, 2.5% NaOCl + 17% EDTA + 0.9% NaCl, and G6, 2.5% NaOCl + 9% HEBP + 0.9% NaCl. The ultrastructure of dentin was characterized through scanning electron microscopy (SEM) and energy dispersive x-ray spectrometry (EDS) determined the chemical composition in terms of the calcium (Ca), phosphorus (P), magnesium (Mg) and potassium (K) content and the Ca/P ratio; and the crystalline phase was analyzed by x-ray diffraction (XRD). A descriptive analysis was performed on the ultrastructure and the crystallography data of dentin. Data analysis included a chemical composition analysis of variance (one-way ANOVA) and a subsequent multiple comparison test (Tukey's test). Results: Except for the control group, all groups showed morphological changes upon visualization with SEM. For EDS, G2 and G5 showed significant mineral loss and changes in the Ca/P ratio (P<0.05); the highest values of Ca and P were observed in G3, G4 and G6. Conclusion: All the irrigating solutions and irrigation protocols tested promoted changes in the morphology and physical and chemical composition of the dentin. However, no significant differences were observed crystallographically. PMID- 29707018 TI - Efficacy of Pre-Medication with Ibuprofen on Post-Operative Pain after Pulpotomy in Primary Molars. AB - Introduction: Pain management following dental procedures, particularly pulpotomies and extraction, is of great importance in pediatric dentistry. The aim of this study was to investigate the efficacy of pre-treatment with ibuprofen on post-operative pain following pulpotomy of primary molars. Methods and Materials: In a split mouth double-blinded randomized clinical trial, 49 children aging between 6-10 years old were given either ibuprofen or a placebo 45 min prior to the treatment. After pulpotomy and placement of a stainless steel crown (SSC), the pain level was evaluated using the Wong-Baker face visual analogue scale for up to 7 days post-treatment. McNemar and Wilcoxon tests were used for data analysis. Results: Forty-five patients were eligible to participate in this study. Pre-medication with ibuprofen significantly reduced pain during the first 24 h post-treatment (P=0.032). However, there was no significant difference in the pain levels between placebo and ibuprofen groups at 48 and 72 h post treatment (P=0.154 and P=0.197, respectively). The number of times patients needed analgesics in ibuprofen group was significantly lower compared to that in the placebo group (P=0.008). Conclusion: Pre-medication with ibuprofen resulted in less pain following pulpotomy and SSC placement in primary teeth. PMID- 29707019 TI - Micro-CT Evaluation of Gutta-Percha Removal by Two Retreatment Systems. AB - Introduction: The aim of the present ex vivo research was to compare the remaining filling material and the volumes of dentine removed after retreatment of curved canals with two rotary systems naming ProTaper Universal Retreatment and Mani NRT-GPR using micro-computed tomography (micro-CT). Methods and Material: Forty mandibular molars containing two completely separated canals, with curvature angle of 25-35 degrees and a curvature radius <10 mm were prepared to the Mtwo instrument 35/0.04 and filled with warm gutta-percha and AH Plus sealer. The teeth were randomly divided into 2 groups (n=20), according to the retreatment system evaluated: ProTaper Universal Retreatment (PR group) or Mani NRT-GPR (MR group). Retreatment was considered complete when the working length was reached and when smooth dentinal walls were observed, with no evidence of filling material adhered to instruments or in the irrigating solution. Preoperative and postoperative micro-CT images were obtained with an isotropic voxel size of 11.88 um to observe the volume of residual filling material in the canals and dentine removed after retreatment. Statistical analysis was performed by Student's t-test (P<0.05). Results: The mean percentage of remaining filling material was 12.96% for PR group and 24.26% for MR group (P=0.0056). The percentage of dentin removal was greater in the PR group (5.02%) than MR group (1.36%) (P=0.0028). Both systems failed to completely remove the filling material from the canals. Conclusion: ProTaper Universal Retreatment system was more effective than Mani NRT-GPR system regarding removal of root filling material and also removed significantly more dentine after retreatment of curved mesial root canals of mandibular molars. PMID- 29707020 TI - Effects of Reciproc, ProTaper Next and WaveOne Gold on Root Canal Walls: A Stereomicroscope Analysis. AB - Introduction: The aim of this study was to analyse the potential occurrence of dentinal defects after root canal preparation using three engine-driven instruments. Methods and Materials: Eighty permanent mandibular incisors were selected. Twenty teeth did not undergo preparation, and the remaining teeth were divided into three groups (n=20): Reciproc (REC), ProTaper Next (PTN) and WaveOne Gold (WOG). The samples were dyed with methylene blue, sectioned perpendicularly to the long axis in 3-, 6- and 9-mm slices and were finally observed under a stereomicroscope (under 25*). The absence/presence of dentinal defects was documented by two blind observers. The data were analysed using Pearson's chi squared test with a confidence level of 95% (P=0.05). The time to prepare the samples was recorded, and the groups were compared using F-test (ANOVA). Results: The control group did not present any defects, and the differences between the control and experimental groups were statistically significant (P<0.05). WOG, PTN and REC caused microcracks on 60%, 33.33% and 18.33% of the samples, respectively. No significant differences between the groups in the 3-mm sections (P=0.126) were observed. There were significant differences in the 6-mm (P=0.042) and 9-mm sections (P<0.001). When WOG and PTN were used to perform root canal preparation, a significant difference was found in the average time (P=0.047). Conclusion: All the used instruments caused dentinal defects in the root dentin. All the instruments were used to perform the preparation with a similar average time. PMID- 29707021 TI - The Antifungal Effect of Propolis Endodontic Irrigant with Three Other Irrigation Solutions in Presence and Absence of Smear Layer: An In Vitro Study. AB - Introduction: The aim of this in vitro study was to compare the antifungal effect of propolis as an endodontic irrigant agent with a mixture of doxycycline, citric acid, and a detergent mixture (MTAD), 2% chlorhexidine (CHX) and 3% sodium hypochlorite (NaOCl) against Candida albicans in presence and absence of smear layer. Methods and Materials: Extracted teeth with single canals (n=104) were prepared and randomly distributed into four experimental groups; 30% propolis, MTAD, 2% CHX and 3% NaOCl. Each group had two subgroups; with and without smear layer. The antifungal effectiveness was evaluated. The Kruskal-Wallis and Mann Whitney tests were used to compare the overall effectiveness of different treatments at significance level of 0.05. Results: Propolis, CHX and NaOCl had similar levels of effectiveness to each other against C. albicans, and these levels were not affected by the presence or absence of the smear layer. Each irrigant was significantly more effective than MTAD or saline solution. MTAD was less effective in the presence of the smear layer than in its absence. Conclusions: Propolis irrigation can produce root canals that are free of C. albicans, even in the presence of the smear layer. PMID- 29707022 TI - Canal Transportation and Centering Ability of ProTaper and SafeSider in Preparation of Curved Root Canals: A CBCT Evaluation. AB - Introduction: Maintaining the original central canal path is an important parameter in efficient root canal preparation. Instruments causing minimal changes in original canal path are preferred for this purpose. This study sought to compare canal transportation and centering ability of ProTaper and SafeSider instruments in curved mesiobuccal root canals of mandibular first molars using cone beam computed tomography (CBCT). Methods and Materials: In this experimental study, 30 mesiobuccal root canals of extracted human mandibular first molars with 20 degrees to 40 degrees curvature were randomly divided into two groups (n=15). After mounting in putty, preoperative CBCT scans were obtained of teeth. Root canals in group A were shaped using S1, S2, F1 and F2 of ProTaper system. Root canals in group B were instrumented to size 25 using SafeSider system according to the manufacturers' instructions. Postoperative CBCT scans were then obtained. The distance between the external root surface and internal canal wall was measured at the mesial and distal at 1, 3 and 7 mm from the apex. The values measured on primary and secondary CBCT scans were compared to assess possible changes in original central canal path and canal transportation. Data were compared using the t-test and repeated measure ANOVA. Results: ProTaper and SafeSider were significantly different in terms of canal transportation and centering ability, and ProTaper was significantly superior to SafeSider in this respect (P<0.001). Conclusion: ProTaper (in contrast to SafeSider) is well capable of maintaining the original central canal path with the least amount of transportation. PMID- 29707023 TI - How the Prevalence of Pulp Stone in a Population Predicts the Risk for Kidney Stone. AB - Introduction: Conflicting researches exist on relationship between pulp stones and systemic disorders. Nephrolithiasis is a common disease with severe pain and discomfort with increasing prevalence worldwide. The purpose of this study is to evaluate the correlation between pulp and kidney stones to help find a method for early detection of kidney stones. Methods and Materials: the sample of this case control study comprised of 154 subjects (77 patients with and 77 patients without kidney stone approved by sonographic examination). Two oral and maxillofacial radiologists evaluated their panoramic images for the presence of pulpal stones. Results: A total of 42.9% of subjects showed pulp stones. Most of the teeth with pulp stone in case and control groups were molars (86.30% and 72.97%, respectively). In the group with kidney stones, pulp stones were detected in 38 patients (49.4%), while in the control group, they were detected in 28 subjects (36.4%). Although there was not a significant relationship between the presence/absence of pulp stone and kidney stone (P=0.143), there was statistically significant association between number of teeth with pulp stone in a patient and the presence of kidney stone (P<0.013). The chance of having kidney stone is 5.78 times higher in the subjects having pulp stone in three teeth or more (>= 3 teeth). Conclusion: Although there is not a correlation between the presence of pulp and kidney stone, the chance of having kidney stone is 5.78 times higher in the subjects with >= 3 teeth having pulp stone. Thus, the number of teeth with pulp stone can serve as a predictor for possibility of having kidney stone. PMID- 29707024 TI - Anatomy of Permanent Mandibular First Molars in a Selected Iranian Population Using Cone-beam Computed Tomography. PMID- 29707025 TI - Cytotoxicity of Two Experimental Epoxy Resin-Based Sealers. AB - Introduction: Many endodontic sealers are available, but search for the ideal sealer continues. This study aimed to assess the cytotoxicity of two experimental endodontic sealers in comparison with AH-26 resin sealer. Methods and Materials: This in vitro study was conducted on conventional and experimental root canal sealers: AH-26, an epoxy resin experimental sealer A (ES-A) composed of calcium tungstate, zirconium oxide, aerosil, bismuth oxide, titanium oxide, hexamine and an epoxy resin and experimental sealer B (ES-B) with compositions similar to ES-A except for the presence of imidazoline as a catalyst. The experimental sealers containing nano-particles were mixed with 37.5% of an epoxy resin. The extraction of five samples of each experimental sealer (A, B) and AH-26 sealer were subjected to MTT assay in the form of set and fresh at 1, 24 and 72 h with 1, 10, 100% dilution according to the International Standard ISO:10993-2012. Data were analyzed using the one-way ANOVA. Results: The set ES-A had the least cytotoxicity from the first hour but the cytotoxicity of ES-B and AH-26 extraction decreased over time. In fresh form, except for 100% concentration, ES A showed the least cytotoxicity compared to the other two sealers. Conclusion: All three sealers had high cytotoxicity in 100% concentration but had low cytotoxicity in 10% and 1% concentrations. PMID- 29707026 TI - Endodontic Treatment of Complex Dens Invaginatus Teeth with Long Term Follow-Up Periods. AB - Dens invaginatus is characterized by invagination of enamel and dentin in the dental papilla prior to tissue calcification. This malformation commonly occurs in the maxillary lateral incisors. The present study reports two complex endodontic treatments in Oehlers' type II and III dens invaginatus, with periapical lesion and presence of bone resorption. In the reported cases, conventional endodontic therapy was successful and sufficient enough to eliminate the infectious process, allowing periapical bone neoformation and absence of symptomatology. Dens invaginatus is a relatively easy-to-diagnose dental malformation. However, it is necessary to know its radiographic aspects. The treatment results demonstrated that, although the cases of dens invaginatus of high complexity are challenging, an accurate diagnosis accompanied with proper endodontic treatment can avoid unnecessary surgical intervention and allow great chances of favorable prognosis in long term. PMID- 29707027 TI - Autotransplantation, Surgical Repositioning of Retained Canine, and Apical Filling of Two Incisors with Root Resorption. AB - The purpose is to show the autotransplantation and surgical repositioning of a retained canine, and the apical filling of central and lateral resorbed incisors from a 12-year-old female patient, healthy and with clinical absence of left maxillary canine. Radiographically, the retained canine between the resorbed central and lateral incisors was observed. Root canal treatment of the canine was performed after 8 weeks; apical curettage and placement of bovine graft in inter incisal zone was done after 4 months. During 6 months, orthodontic traction of the canine was carried out with no positive results, and 12 months after the autotransplantation, surgical repositioning was performed. Clinical-radiographic control at 30 days and 24 months showed absence of inflammation, restoration and integration of the tooth-supporting structures. Autotransplantation combined with surgical repositioning of the retained canine and the apical filling of two incisors achieved the harmonious, aesthetic, functional, dental and psychological preservation of the patient. PMID- 29707028 TI - Surgical Endodontics vs Regenerative Periodontal Surgery for Management of a Large Periradicular Lesion. AB - Treatment success of periodontal-endodontic lesions is dependent on the elimination of both disease causative factors, whether they exist separately or concurrently. This report presents successful endodontic management of a misdiagnosed large periradicular pathology, which had not resolved after a previous periodontal regenerative surgery. A patient complaining of discomfort in the left maxillary region was referred. He had undergone regenerative surgery for treatment of a large periradicular defect; however, there was no further amelioration of the clinical signs/symptoms. Radiographically, a large periradicular lesion filled with bone substitute materials was detected around tooth #25. The endodontic treatment of the tooth was imperfect; therefore, surgical endodontic retreatment was planned. During root-end surgery, the biopsy containing bone substitute materials was obtained. Root-end filling/sealing using calcium-enriched mixture cement was completed. The histopathological examination showed granulation tissues enclosing exogenous materials. In two-year radiographic evaluation, resolving lesion and complete bone healing was observed. The first fundamental step in the management of periradicular lesions is correct diagnosis of the lesion origin and set-by step of the treatment plan according to the main causative factor. Regenerative periodonttal surgery, without considering the defective apical seal, will only cause a painful procedure for the patient without any positive benefit. Following appropriate apical seal, the endodontic lesion healing can be anticipated. PMID- 29707029 TI - Cardiac myosin activators for heart failure therapy: focus on omecamtiv mecarbil. AB - Heart failure continues to be a major global health problem with a pronounced impact on morbidity and mortality and very limited drug treatment options especially with regard to inotropic therapy. Omecamtiv mecarbil is a first-in class cardiac myosin activator, which increases the proportion of myosin heads that are tightly bound to actin and creates a force-producing state that is not associated with cytosolic calcium accumulation. Phase I and phase II studies have shown that it is safe and well tolerated. It produces dose-dependent increases in systolic ejection time (SET), stroke volume (SV), left ventricular ejection fraction (LVEF), and fractional shortening. In the ATOMIC-AHF trial, intravenous (IV) omecamtiv mecarbil did not improve dyspnoea overall but may have improved it in a high-dose group of acute heart failure patients. It did, however, increase SET, decrease left ventricular end-systolic diameter, and was well tolerated. The COSMIC-HF trial showed that a pharmacokinetic-based dose-titration strategy of oral omecamtiv mecarbil improved cardiac function and reduced ventricular diameters compared to placebo and had a similar safety profile. It also significantly reduced plasma N-terminal-pro B-type natriuretic peptide compared with placebo. The GALACTIC-HF trial is now underway and will compare omecamtiv mecarbil with placebo when added to current heart failure standard treatment in patients with chronic heart failure and reduced LVEF. It is expected to be completed in January 2021. The ongoing range of preclinical and clinical research on omecamtiv mecarbil will further elucidate its full range of pharmacological effects and its clinical usefulness in heart failure. PMID- 29707030 TI - Complementary and Alternative Therapy of Rare Inflammatory/Autoimmune Diseases. PMID- 29707032 TI - Chromium-Containing Traditional Chinese Medicine, Tianmai Xiaoke Tablet, for Newly Diagnosed Type 2 Diabetes Mellitus: A Meta-Analysis and Systematic Review of Randomized Clinical Trials. AB - Objective: Chromium-containing traditional Chinese medicine Tianmai Xiaoke tablet (TMXKT) is approved for treating newly diagnosed type 2 diabetes mellitus (T2DM) in China. This review aimed to compile the evidence from randomized clinical trials (RCTs) and quantify the effects of TMXKT on newly diagnosed T2DM. Methods: Seven online databases were investigated up to March 20, 2017. The meta-analysis included RCTs investigating the treatment of newly diagnosed T2DM, in which TMXKT combined with conventional therapy was compared with placebo or conventional therapy. The risk of bias was evaluated using the Cochrane Collaboration tool. The estimated mean difference (MD) and the standardized mean difference were within 95% confidence intervals (CI) with respect to the interstudy heterogeneity. The outcomes were measured using fasting blood glucose (FBG), 2-h postprandial blood glucose (2hPG), glycosylated hemoglobin A1c (HbA1c), and body mass index (BMI) levels. Results: TMXKT combined with conventional therapy lowered FBG level (MD = -0.68, 95% CI -0.90 to -0.45, P < 0.00001), 2hPG (MD = 1.33, 95% CI -1.86 to -0.79, P < 0.00001), HbA1c (MD = -0.46, 95% CI -0.57 to 0.36, P < 0.00001), and BMI (MD = -0.77, 95% CI -1.12 to -0.41, P < 0.00001). Conclusions: TMXKT combined with conventional therapy is beneficial for patients with newly diagnosed T2DM. However, the effectiveness and safety of TMXKT are uncertain because of the limited number of trials and low methodological quality. Therefore, practitioners should be cautious when applying TMXKT in daily practice. Also, well-designed clinical trials are needed in the future. PMID- 29707031 TI - Mast Cells and Nerve Signal Conduction in Acupuncture. AB - Nerve and mast cells are densely distributed around acupoints in connective tissue. To explore the internal relations between them in acupuncture effect, we examined dorsal root potential (DRP) response to acupuncture at Zusanli (ST36) under sodium cromoglicate (DSCG, a mast cell stabilizer) intervention in anesthetized Sprague-Dawley (SD) rats. We used single unit nerve recording techniques to collect nerve signals from DRP afferent nerves for a 45-minute period that includes 4 stages, that is, base, drug absorption, acupuncture, and recovery stages. We analyzed the recorded signals from time-domain and frequency domain perspectives. The results showed that once acupuncture needle was inserted, twisting needle excited more nerves discharges than those at base discharges in ACU (from 35.1 +/- 7.2 to 47 +/- 9.2 Hz, P = 0.004), and there existed the same trend in Saline + ACU group (from 23.8 +/- 2.6 to 29.8 +/- 4.2 Hz, P = 0.059). There was no change of nerve discharges under twisting needle with injection of DSCG (from 34.8 +/- 5.3 to 34.7 +/- 4.4 Hz, P = 0.480). We conclude that acupuncture manipulation promotes neural signal production and DSCG could partly inhibit nerve discharges. PMID- 29707033 TI - Syzygium jambos Displayed Antibacterial and Antibiotic-Modulating Activities against Resistant Phenotypes. AB - The present study was designed to evaluate the antibacterial activities of methanol extracts of bark and leaves of Syzygium jambos, as well as their synergistic effects with selected antibiotics against drug-resistant Gram positive and Gram-negative bacteria. The crude extracts were subjected to qualitative phytochemical screening; broth microdilution method was used for antibacterial assays. Phytochemical studies indicate that leaves and bark extracts contained polyphenols, anthraquinones, tannins, and steroids. Extract of the leaves was active against all the 26 strains of Staphylococcus aureus and all the 21 strains of Gram-negative bacteria tested, within the minimum inhibitory concentration (MIC) range of 32-512 MUg/mL. The lowest MIC value of 32 MUg/mL was obtained with extract of the leaves against Staphylococcus aureus MRSA9 strain. In Gram-negative bacteria, the lowest MIC value of 64 MUg/mL was also obtained against Enterobacter aerogenes EA294 and Klebsiella pneumoniae K24 strains. Against S. aureus strains, antibiotic-modulating activity of extracts at MIC/2 towards more than 70% of the tested strains was obtained when leaves and bark extracts were tested in association with chloramphenicol (CHL). This was also the case when leaves extract was combined with CHL, kanamycin (KAN), tetracycline (TET), and erythromycin (ERY) and when bark extract was combined with ciprofloxacin (CIP), TET, and ERY against Gram-negative bacteria. In conclusion, this study demonstrated that Syzygium jambos has antibacterial and antibiotic modulating activities. PMID- 29707034 TI - Laser Acupuncture at Large Intestine 4 Compared with Oral Glucose Administration for Pain Prevention in Healthy Term Neonates Undergoing Routine Heel Lance: Study Protocol for an Observer-Blinded, Randomised Controlled Clinical Trial. AB - Background: Nonpharmacological strategies have actually become more important in neonatal pain management during routinely applied minor painful procedures. However, commonly used nonpharmacological strategies are inferior to orally administered sweet solutions. Therefore, we will compare laser acupuncture, as a recent nonpharmacological method, with the standard care of oral glucose solution for pain prevention. Methods: Ninety-five healthy term neonates will be allocated into one of two groups. Before routine heel lance for metabolic screening, one group will receive laser acupuncture at acupuncture point Large Intestine 4 (LI 4) bilaterally for 60 seconds per point (acupuncture group) and the other will receive the standard care with orally administered glucose solution (glucose group). The complete procedure of blood sampling will be recorded on video, excluding the intervention before heel lance. A paediatric nurse, blinded with respect to the allocation, will evaluate these video recordings and determine the Premature Infant Pain Profile (PIPP) for each neonate. Primary outcome will be the mean difference in PIPP scores between groups. Discussion: This observer blinded randomised controlled trial has been designed to explore potential advantages of laser acupuncture in the management of neonatal pain because more data are required to provide information about its efficacy and safety. Trial Registration: This trial is registered with DRKS00010122. PMID- 29707035 TI - Treatment of Danhong Injection Combined with Naoxintong Capsule in Acute Coronary Syndrome Patients Undergoing PCI Operation: Study for a Randomized Controlled and Double-Blind Trial. AB - Objective: This double-blind and randomized placebo-controlled trial evaluated the safety and efficacy of Danhong injection combined with Naoxintong capsule in patients with acute coronary syndrome (ACS) after percutaneous coronary intervention (PCI). Methods: ACS patients scheduled to undergo PCI (n = 130) were equally and randomly apportioned to either a treatment or control group. After PCI, the treatment group received Danhong injection combined with Naoxintong capsule for 12 weeks, while the control group was given placebo. Both groups were otherwise treated with conventional secondary prevention of coronary artery disease. The groups were primarily evaluated for clinical efficacy and cardiovascular events. Evaluative indicators of safety included adverse events, platelet count, and liver, renal, and blood coagulation functions. Result: No cardiovascular events or adverse reactions were observed in either group. The treatment group demonstrated better signs of clinical efficacy, including left ventricular ejection fraction, higher nitric oxide levels, and lower levels of endothelin-1 (ET-1) and von Willebrand factor (VWF). Conclusion: ACS patients treated with Danhong injection combined with Naoxintong capsule after PCI demonstrated better improvement with regard to markers associated with atherosclerosis and adverse cardiovascular events, without apparent adverse effects. Thus, Danhong injection combined with Naoxintong capsule was safe and effective for treating ACS patients after PCI. PMID- 29707036 TI - Effect of Chlorogenic Acid Intake on Cognitive Function in the Elderly: A Pilot Study. AB - Objective: To evaluate the effect of chlorogenic acids (CGAs) intake on cognitive function. Methods: In this pilot study, the Cogstate and CNS Vital Signs test batteries were used to evaluate cognitive function in 8 healthy elderly men and women complaining of subjective memory loss after a 6-month intake of a test beverage containing 330 mg of CGAs just before bedtime. Results: After a 6-month CGA intake period, significant improvement was observed in the One Back Test of the Cogstate, the Shifting Attention Test, and Finger Tapping Test as well as in the composite memory, verbal memory, complex attention, cognitive flexibility, executive function, and motor speed domains of the CNS Vital Signs test battery. Conclusion: A 6-month intake of CGAs may improve attentional, executive, and memory functions in the elderly with complaints of subjective memory loss. PMID- 29707037 TI - Efficacy and Safety of a Formulated Herbal Granula, Jiu Wei Zhen Xin, for Generalized Anxiety Disorder: A Meta-Analysis. AB - Background: The traditional Chinese medicine formula Jiu Wei Zhen Xin Granula (JWZXG) is prescribed to treat generalized anxiety disorder (GAD) in China. This study was to assess the efficacy and safety of JWZXG in patients with GAD. Method: Data were pooled from 14 randomized controlled trials involving the assessment of mean changes of Hamilton Anxiety Rating Scale (HAMA) total scores, response rates, adverse event rates, quality, publication bias, and risk of bias. Results: Pooled analysis showed no significant difference in response rate (risk ratio 1.01, 95% CI [0.93-1.08]; Z test = 0.17, P = 0.86) and no significant difference between JWZXG group and azapirones group (RR 0.69, 95% CI [0.45, 1.06]; Z test = 1.69, P = 0.09) in rate of adverse events. Though no difference exists between JWZXG group and azapirones group in HAMA total score from baseline, JWZXG group was inferior to selective serotonin reuptake inhibitors (SSRIs) group (WMD -0.93, 95% CI [-1.64, -0.23]; Z test = 2.6, P = 0.009) which had more adverse events than JWZXG group (RR 0.64, 95% CI [0.46, 0.89]; Z test = 2.63, P = 0.009). Conclusions: This meta-analysis preliminarily suggests that JWZXG is as effective as azapirones, though having the same possibility of suffering AEs. JWZXG was inferior to SSRIs but causes fewer AEs in the treatment of GAD. PMID- 29707038 TI - Calculating the Mean Amplitude of Glycemic Excursions from Continuous Glucose Data Using an Open-Code Programmable Algorithm Based on the Integer Nonlinear Method. AB - The mean amplitude of glycemic excursions (MAGE) is an essential index for glycemic variability assessment, which is treated as a key reference for blood glucose controlling at clinic. However, the traditional "ruler and pencil" manual method for the calculation of MAGE is time-consuming and prone to error due to the huge data size, making the development of robust computer-aided program an urgent requirement. Although several software products are available instead of manual calculation, poor agreement among them is reported. Therefore, more studies are required in this field. In this paper, we developed a mathematical algorithm based on integer nonlinear programming. Following the proposed mathematical method, an open-code computer program named MAGECAA v1.0 was developed and validated. The results of the statistical analysis indicated that the developed program was robust compared to the manual method. The agreement among the developed program and currently available popular software is satisfied, indicating that the worry about the disagreement among different software products is not necessary. The open-code programmable algorithm is an extra resource for those peers who are interested in the related study on methodology in the future. PMID- 29707040 TI - Incidence and mitigation of gastrointestinal events in patients with relapsing remitting multiple sclerosis receiving delayed-release dimethyl fumarate: a German phase IV study (TOLERATE). AB - Background: Gastrointestinal (GI) events are common adverse events (AEs) associated with delayed-release dimethyl fumarate (DMF), an approved treatment for relapsing-remitting multiple sclerosis (RRMS). The objective of the TOLERATE study was to evaluate GI tolerability and GI mitigation via symptomatic therapies in patients initiating DMF in a real-world clinical setting in Germany. Methods: TOLERATE was a multicentre, open-label, single-arm study performed at 25 German sites. Endpoints were frequency, severity, duration (all primary) and mitigation of GI-related events (secondary). Patients were instructed to take DMF according to the prescribing information for up to 12 weeks and to document GI events and intake of GI-symptomatic therapy on numerical rating scales, using eDiaries. Results: A total of 211 patients were included in the safety population (71% female; mean age 40 +/- 11 years). Of these, 185 patients (87.7%) reported GI related events, out of which nearly half received GI-symptomatic therapy (84/185; 45.4%). The most frequently reported GI events were upper abdominal pain, flatulence and nausea. GI-related events peaked during the first 3 weeks of therapy and rapidly decreased thereafter. The severity of GI events over 12 weeks according to the Modified Overall Gastrointestinal Symptom Scale were mild to moderate in the majority of patients reporting GI-related events and taking symptomatic GI medication (53.6%). Only 10% of all patients discontinued study treatment due to AEs in general, while 6.6% discontinued due to GI-related events. The severity of GI-related events decreased over time in patients who received symptomatic treatment with one or more medications (e.g. acid secretion blockers, antidiarrhoeals or antiemetics). Conclusion: Gastrointestinal events associated with delayed-release DMF were mainly mild to moderate in severity. Prevalence of GI events peaked during the first 3 weeks of therapy and rapidly faded thereafter. Although 44.9% of patients experiencing GI events used common GI symptomatic therapies, only 6.6% of patients discontinued DMF because of GI events, suggesting that GI events could be managed well with common symptomatic therapy. PMID- 29707041 TI - Commentary on the ECTRIMS-EAN guideline for pharmacological treatment of multiple sclerosis. PMID- 29707042 TI - Electrostatic Correlations in Polyelectrolyte Solutions. AB - The major attribute of polyelectrolyte solutions is that all chains are strongly correlated both electrostatically and topologically. Even in very dilute solutions such that the chains are not interpenetrating, the chains are still strongly correlated. These correlations are manifest in the measured scattering intensity when such solutions are subjected to light, X-ray, and neutron radiation. The behavior of scattering intensity from polyelectrolyte solutions is qualitatively different from that of solutions of uncharged polymers. Using the technique introduced by Sir Sam Edwards, and extending the earlier work by the author on the thermodynamics of polyelectrolyte solutions, extrapolation formulas are derived for the scattering intensity from polyelectrolyte solutions. The emergence of the polyelectrolyte peak and its concentration dependence are derived. The derived theory shows that there are five regimes. Published experimental data from many laboratories are also collected into a master figure and a comparison between the present theory and experiments is presented. PMID- 29707039 TI - Emerging concepts in non-invasive monitoring of Crohn's disease. AB - Inflammatory bowel disease (IBD) is an umbrella term for Crohn's disease (CD) and ulcerative colitis (UC). In light of evolving epidemiology of CD, its clinical management is still complex and remains a challenge for contemporary physicians. With the advent of new diagnostic and treatment paradigms, there is a growing need for new biomarkers to guide decision-making, differential diagnosis, disease activity monitoring, as well as prognosis. However, both clinical and endoscopic scoring systems, widely utilized for disease monitoring and prognosis, have drawbacks and limitations. In recent years, biochemical peptides have become available for IBD monitoring and more frequently used as surrogate markers of gut inflammation. Emerging concepts that revolve around molecular, stem cell, epigenetic, microbial or metabolomic pathways associated with vascular and epithelial gut barrier could lead to development of new CD biomarkers. Measurement of cell-derived microvesicles (MVs) in the blood of IBD patients is another emerging concept helpful in future disease management. In this review, we discuss novel concepts of non-invasive biomarkers, which may become useful in monitoring of CD activity and prognosis. We discuss metabolomics as a new powerful tool for clinicians to guide differential IBD diagnosis. In the coming years, new developments of prognostic tools are expected, aiming for breakthroughs in the management of patients with CD. PMID- 29707043 TI - Development and 10-year history of a biosimilar: the example of Binocrit(r). AB - Patent expirations for several biological products have prompted the development of alternative versions, termed 'biosimilars', which have comparable quality, safety and efficacy to a licensed biological medicine (also referred to as the 'reference' medicine). The first biosimilars developed in oncology were the supportive-care agents filgrastim and epoetin. Binocrit(r) (HX575) is a biosimilar version of epoetin alfa, indicated in the oncology setting for the treatment of chemotherapy-induced anemia (CIA). The process for development and approval of Binocrit(r) as a biosimilar included extensive analytical characterization and comparison with the reference epoetin alfa. This was followed by a clinical development program comprising phase I pharmacokinetic/pharmacodynamic studies to show bioequivalence to the reference medicine and a confirmatory phase III study to confirm therapeutic effectiveness in CIA. Since its approval, Binocrit(r) has been extensively used and studied in real-world clinical practice. The accumulated data confirm that Binocrit(r) is an effective and well-tolerated option for the treatment of CIA in patients with cancer. PMID- 29707044 TI - Enhanced Microchip Electrophoresis Separations Combined with Electrochemical Detection Utilizing a Capillary Embedded in Polystyrene. AB - The ability to use microchip-based electrophoresis for fast, high-throughput separations provides researchers with a tool for close-to real time analysis of biological systems. While PDMS-based electrophoresis devices are popular, the separation efficiency is often an issue due to the hydrophobic nature of PDMS. In this study, a hybrid microfluidic capillary device was fabricated to utilize the positive features of PDMS along with the electrophoretic performance of fused silica. A capillary loop was embedded in a polystyrene base that can be coupled with PDMS microchannels at minimal dead volume interconnects. A method for cleaning out the capillaries after a wet-polishing step was devised through the use of 3D printed syringe attachment. By comparing the separation efficiency of fluorescein and CBI-glycine with both a PDMS-based serpentine device and the embedded capillary loop device, it was shown that the embedded capillary loop device maintained higher theoretical plates for both analytes. A Pd decoupler with a carbon or Pt detection electrode were embedded along with the loop allowing integration of the electrophoretic separation with electrochemical detection. A series of catecholamines were separated to show the ability to resolve similar analytes and detect redox active species. The release of dopamine and norepinephrine from PC 12 cells was also analyzed showing the compatibility of these improved microchip separations with high ionic cell buffers associated with cell culture. PMID- 29707045 TI - In-silico Designing and Testing of Primers for Sanger Genome Sequencing of Dengue Virus Types of Asian Origin. AB - Rarity in reporting whole genome sequence of Dengue virus from dengue endemic countries leaves lacunae in understanding regional pattern of virus mutation and ultimately leading to non-understanding of transmission pattern and clinical outcomes emerging at regional levels. Due to inter-serotype genomic similarity and intra-serotype genomic diversity, appropriate designing of primer pairs appears as an exhaustive exercise. Present paper reports new Dengue virus type specific primer which may help in characterizing virus specific to Asian origin. Genomes of dengue virus serotypes of Asian region were searched and using advanced bioinformatics tools, serotype specific primers were designed and tested for their targeted amplification efficiency. 19 primers sets for DENV-1, 18 primer sets for DENV-2, 17 for DENV-3 and 18 for DENV-4 were designed. In-silico and experimental testing of the designed primers were performed on virus isolated from both clinical isolates and passaged cultures. While all 17 and 18 primer sets of DENV-3 and DENV-2 respectively yielded good quality sequencing results; in case of DENV-4, 16 out of 18 primer sets and in DENV-1, 16 out of 19 primer sets yielded good results. Average sequencing read length was 382 bases and around 82% nucleotide bases were Phred quality QV20 bases (representing an accuracy of circa one miscall every 100 bases) or higher. Results also highlighted importance of use of primer development algorithm and identified genomic regions which are conservative, yet specific for developing primers to achieve efficiency and specificity during experiments. PMID- 29707046 TI - De novo Assembly of the Burying Beetle Nicrophorus orbicollis (Coleoptera: Silphidae) Transcriptome Across Developmental Stages with Identification of Key Immune Transcripts. AB - Burying beetles (Nicrophorus spp.) are among the relatively few insects that provide parental care while not belonging to the eusocial insects such as ants or bees. This behavior incurs energy costs as evidenced by immune deficits and shorter life-spans in reproducing beetles. In the absence of an assembled transcriptome, relatively little is known concerning the molecular biology of these beetles. This work details the assembly and analysis of the Nicrophorus orbicollis transcriptome at multiple developmental stages. RNA-Seq reads were obtained by next-generation sequencing and the transcriptome was assembled using the Trinity assembler. Validation of the assembly was performed by functional characterization using Gene Ontology (GO), Eukaryotic Orthologous Groups (KOG), and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Differential expression analysis highlights developmental stage-specific expression patterns, and immunity-related transcripts are discussed. The data presented provides a valuable molecular resource to aid further investigation into immunocompetence throughout this organism's sexual development. PMID- 29707047 TI - Flexible intramedullary nailing versus nonoperative treatment for paediatric displaced midshaft clavicle fractures. AB - Purpose: The treatment of displaced midshaft clavicle fractures in children remains controversial. The purpose of our study was to compare the outcome of displaced midshaft clavicle fractures in children who were managed operatively by flexible intramedullary nailing (FIN) with nonoperative treatment. Methods: A prospective review of 31 children (mean age 10.5 years) with displaced midshaft clavicle fractures treated either by FIN or nonoperatively and with at least a six-month follow-up was undertaken. In all, 24 children underwent FIN and seven underwent nonoperative treatment. The patient outcomes included the Constant Murley score, Customer Satisfaction Questionnaire (CSQ-8), numeric pain rating scale, time to union and time to return to activity. Surgical complications were recorded. Results: The two groups were comparable with regards to age, gender and mechanism of injury. At six months of follow-up, the Constant-Murley (97.8 versus 94.7, p < 0.001) and CSQ-8 (29.1 versus 19.1, p < 0.001) scores were higher in the FIN group. Time to union and return to activity were significantly shorter in the FIN group (7.3 and 9.2 weeks versus 10.4 and 16.6 weeks respectively, p < 0.01). The only surgical complication was a FIN exchange for skin irritation due to nail prominence. Conclusion: FIN is a minimally invasive procedure for children with displaced midshaft clavicle fractures associated with shorter time to union, quicker return to activity and higher Constant-Murley and CSQ-8 scores when compared with nonoperative treatment. However, the difference in Constant Murley scores was not clinically significant. Furthermore, the advantages of FIN are at the expense of an increased complication rate of 12.5% (upper 95% confidence interval 33.3%). Level of Evidence: Therapeutic, II. PMID- 29707048 TI - Inpatient surgical treatment of paediatric proximal humerus fractures between 2000 and 2012. AB - Purpose: To estimate the rate of surgical treatment of paediatric proximal humerus fractures over time utilizing a large, publicly available national database. Methods: The Healthcare Cost and Utilization Project Kids' Inpatient Database was evaluated between the years 2000 and 2012. Proximal humerus fractures were identified using International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9 CM) diagnosis codes. ICD-9 CM procedure codes were used to identify patients who received surgical treatment. Univariable and multivariable logistic regression were used to determine variables associated with greater proportions of surgical treatment. All statistical analyses were performed utilizing SAS statistical software v.9.4. Statistical significance was set at p < 0.05. Results: A total of 7520 proximal humerus fracture admissions were identified; 3247 (43.2%) were treated surgically. The percentage of patients receiving surgery increased from 39.3% in 2000 to 46.4% in 2012 (p < 0.001). After adjustment for potential confounders, increased age, increased ICD-9 derived injury severity scores (ICISS) and more recent year were associated with an increased proportion of patients receiving surgical treatment (p < 0.001). Medicaid payer status (p < 0.001) and admission to a children's hospital (p = 0.045) were associated with a lower proportion of surgical treatment. Conclusion: The rate of operative treatment of paediatric proximal humerus fractures increased over time between 2000 and 2012. Increased surgical rates were independently associated with older age, increased ICISS, treatment at a non children's hospital and non-Medicaid insurance status. Further study is needed to provide evidence to support improved outcomes after operative treatment of paediatric proximal humerus fractures. Level of Evidence IV: PMID- 29707049 TI - Rate of displacement for Jakob Type 1 lateral condyle fractures treated with a cast. AB - Purpose: The aim of this retrospective study is to report the rate of displacement of Jakob Type 1 lateral condyle fractures that were initially treated in a cast. Methods: We performed a retrospective review of all patients that were treated for a non-displaced (Jakob Type 1 < 2 mm) lateral condyle fracture of the humerus at our institution between 2002 and 2015. Results: A total of 59 patients were initially treated with casting. Five fractures displaced and were converted to a closed pinning treatment plan with a conversion rate of 8.5%. There was a mean of 13.2 days (4 to 21) between treatment by initial casting and closed pinning. Conclusion: This study demonstrates an 8.5% displacement and conversion rate from cast treatment to closed pinning for initially non-displaced Jakob Type 1 lateral condyle fractures of the humerus. The internal oblique radiograph is most accurate to determine displacement. We recommend obtaining an internal oblique view at initial evaluation and at follow up in the cast for lateral condyle fractures. To minimize movement at the fracture site, we recommend treating Jakob Type 1 lateral condyle fractures with a long arm cast with the elbow at 90 degrees and the forearm in the supine position with a sling-loop design. Level of Evidence: IV - retrospective therapeutic study. PMID- 29707050 TI - Buckling down on torus fractures: has evolving evidence affected practice? AB - Purpose: The purpose of this study was to evaluate the management of paediatric torus fractures of the distal forearm in current practice in light of growing evidence supporting a 'minimalist' approach with splint immobilization and limited follow-up. We hypothesized that 'traditional' cast-based management has persisted despite alternative evidence. Methods: A retrospective review was performed of a consecutive series of paediatric patients diagnosed with torus fractures of the distal forearm between 2011 and 2014. Records were reviewed to abstract the type of immobilization (splint versus cast) prescribed at each visit, number of radiographic exams, duration of immobilization, number of clinical visits and complications. The primary outcome was the proportion of patients exclusively managed in splints. Injuries were grouped based on treatment into a cast group (CG) and a splint group (SG) for statistical analyses. Additionally, injuries were grouped by epoch of time to determine if immobilization usage patterns evolved. Results: A total of 240 forty injuries met criteria for inclusion. Of these, 16 (6.7%) were exclusively splinted (SG). Relative to the CG, the SG had fewer clinical visits (p < 0.001), fewer radiographic exams (p < 0.001) and a shorter total encounter time (p = 0.015). No change in immobilization use occurred over the study period. In all, 21 (9.4%) of the CG experienced complications. No clinically significant displacements occurred in either group. Conclusion: Cast utilization and frequent radiographic follow-up remain prevalent at our institution in the management of paediatric torus fractures. Splint-only management was associated with fewer clinical visits, fewer radiographic exams and a shorter total encounter time. Level of Evidence Level III: Therapeutic retrospective cohort study. PMID- 29707051 TI - Treatment strategy and long-term functional outcome of traumatic elbow dislocation in childhood: a single centre study. AB - Purpose: Traumatic elbow dislocation (TED) is the most common injury of large joints in children. There is an ongoing debate on the optimal treatment for TED. We aimed to assess the functional outcome after operative and nonoperative treatment of TED. Methods: We analysed the medical records of patients with TED treated at the University Children's Hospital, Basel, between March 2006 and June 2015. Functional outcome was assessed using the Mayo Elbow Performance Score (MEPS) and Quick Disabilities of the Arm, Shoulder and Hand (QuickDASH) Sport and Music Module score. These scores were compared between nonoperatively and operatively treated patients. Results: A total of 37 patients (mean age 10.2 years, 5.2 to 15.3) were included. Of these, 21 (56.8%) children had undergone nonoperative treatment, with 16 (43.2%) patients having had operative treatment. After a mean follow-up of 5.6 years (1.2 to 5.9), MEPS and QuickDASH Sport and Music Module scores in the nonoperative group and operative group were similar: MEPS: 97.1 points (SD 4.6) versus 97.2 points (SD 2.6); 95% confidence interval (CI)-2.56 to 2.03); p = 0.53; QuickDASH Sport and Music Module score: 3.9 points (SD 6.1) versus 3.1 points (SD 4.6); 95% CI 2.60 to 4.17; p = 0.94. We noted no significant differences regarding the long-term functional outcome between the subgroup of children treated operatively versus those treated nonoperatively for TED with accompanying fractures of the medial epicondyle and medial condyle. Conclusion: Functional outcome after TED was excellent, independent of the treatment strategy. If clear indications for surgery are absent, a nonoperative approach for TED should be considered. Level of evidence: Level III - therapeutic, retrospective, comparative study. PMID- 29707053 TI - Reliability and efficiency of three methods of calculating migration percentage on radiographs for hip surveillance in children with cerebral palsy. AB - Purpose: Hip surveillance programmes for children with cerebral palsy (CP) utilize the migration percentage (MP) measurement to initiate referrals and recommend treatment. This study assesses the reliability and efficiency of three methods of MP measurement on anteroposterior (AP) pelvis radiographs. Methods: A total of 20 AP pelvis radiographs (40 hips) of children with CP were measured by three raters on two occasions using three methods: digital measurement (DM) on a Picture Archiving and Communication System monitor, computer-aided measurement (CA) using a digital templating tool and mobile device application measurement (MA) using a freely available MP measurement tool. For each method, the time required to complete the MP measurement of both hips on each AP pelvis radiograph was measured. Intra-class correlation coefficient (ICC) was used to determine reliability, and analysis of variance was used to compare groups. Results: All three methods of determining MP showed excellent inter-rater and intra-rater reliability (ICC 0.976 to 0.989). The mean absolute difference in MP measurement was not significant between trials for a single rater (DM 2.8%, CA 1.9%, MA 2.2%) or between raters (DM 3.6%, CA 2.9%, MA 3.6%). The mean time to complete MP measurement was significantly different between methods, with DM = 151 seconds, CA = 73 seconds and MA = 80 seconds. Conclusion: All three MP measurement methods were highly reliable with clinically acceptable measurement error. The time required to measure a hip surveillance radiograph can be reduced by approximately 50% by utilizing a computer-based or mobile application-based MP measurement tool. Level of Evidence III: PMID- 29707052 TI - Systematic review of spica casting for the treatment of paediatric diaphyseal femur fractures. AB - Purpose: Paediatric femur fractures are commonly encountered and often successfully managed with spica casting. Despite spica casting's long history there is little formal guidance for optimal outcomes and no consolidation of existing literature. The purpose of this study is to review the available literature regarding the use of spica casting for the management of paediatric diaphyseal femur fractures. Methods: The PubMed database was queried for all research articles including the phrase "spica". A total of 788 abstracts were reviewed for relevance to the current study. Data was extracted from all available research studies which specified tolerance for fracture angulation or shortening in the cast. Additionally, all articles describing alternative materials, methods for spica application, and complications of spica casting were reviewed. Results: In all, 106 articles were found relevant to the management of diaphyseal femur fractures in the paediatric population. The aggregated, accepted fracture shortening decreased from 16 mm to 18 mm before age ten years to 12 mm to 14 mm after puberty. Aggregated, accepted angulation decreased from 14 degrees to 16 degrees varus/valgus and 18 degrees to 22 degrees pro/recurvatum before age two years, to 6 degrees to 8 degrees and 10 degrees to 12 degrees by puberty, respectively. The overall reported complication rate was 19.6%, with the most common complication being skin compromise in 8.2% of patients, followed by unacceptable angulation at the fracture site in 4.2% of patients and excessive limb shortening in 1.9% of patients. Conclusion: This article reviews the available spica casting literature and compiles the available data. Spica casting offers a safe, effective means for definitive management of paediatric diaphyseal femur fractures. Future research identifying the rate and pattern of remodelling as it relates to angulation and shortening at various patient ages, particularly beyond the aforementioned norms, would be valuable to identify true biological tolerances versus accepted expert opinion. Level of evidence Level II: Review of level II evidence. PMID- 29707054 TI - Age- and gender-specific variations of the epiphyseal tilt and epiphyseal angle in adolescents without hip pathology. AB - Purpose: To determine age-and gender-dependent variation of epiphyseal tilt and epiphyseal angle using CT in adolescents without hip pathology. Methods: Pelvic CT scans were obtained in 132 adolescents for evaluation of abdominal pain. Radially oriented planes around the femoral neck were reformatted and the epiphyseal tilt and angle were measured in the anterior, anterosuperior and superior planes. Variations in the tilt angle and epiphyseal angle were assessed by age group from 12 to 18 years and gender by using a linear mixed model analysis. Results: The epiphyseal tilt did not change (p = 0.97) with increasing age. Male patients exhibited smaller tilt angle in the anterosuperior plane (p = 0.003) but no difference was detected in the anterior (p = 0.17) or superior (p = 0.06) planes. The epiphyseal angle decreased with increasing age in the anterior (p = 0.03), anterosuperior (p = 0.001) and superior (p < 0.001) planes in male patients, with no variation in female patients (p = 0.92). Male patients had larger epiphyseal angles in the anterior (p = 0.02), anterosuperior (p < 0.001) and superior (p = 0.002) planes compared with female patients. Conclusion: We found no age-specific variations in the epiphyseal tilt and no difference in the epiphyseal tilt in male and female patients in the superior and anterior plane. The epiphyseal angle was smaller in female patients, however, the epiphyseal angle decreased with increasing age in male patients which corresponds to an increase in epiphyseal extension. The reference values reported in this study may serve as additional information in the evaluation of adolescents with hip pain and as reference for future studies investigating slipped capital femoral epiphysis and femoroacetabular impingement development. Level of Evidence: Level III Diagnostic Study. PMID- 29707055 TI - Diagnosing slipped capital femoral epiphysis amongst various medical specialists. AB - Purpose: To evaluate sensitivity, specificity and accuracy of a radiographic slipped capital femoral epiphysis (SCFE)-diagnosis among medical specialists. Methods: Three paediatricians, three paediatric radiologists and three paediatric orthopaedic surgeons completed two rounds of a survey of anteroposterior and frog leg lateral radiographs of patients with a diagnosis of SCFE (25), femoroacetabular impingement (four), Legg-Calve-Perthes (11) or no hip pathology (ten). Intra- and interobserver agreement among specialties regarding the diagnosis of a SCFE were assessed using Cohen's kappa coefficient (kappa). Diagnostic accuracy of SCFE relative to the benchmark, a combination of the radiographic diagnosis based on Klein's line, clinical symptoms and surgical treatment, was assessed computing sensitivity, specificity and accuracy. Results: Intraobserver agreement between the surveys was moderate among paediatricians (kappa-range, 0.44 to 0.52), moderate to almost perfect among orthopaedic surgeons (kappa-range, 0.79 to 0.88) and almost perfect among paediatric radiologists (kappa-range, 0.83 to 1.00). Interobserver agreement for survey 1 and 2 was slight among paediatricians (mean kappa, 0.19), substantial among orthopaedic surgeons (mean kappa, 0.77) and almost perfect among paediatric radiologists (mean kappa, 0.86). Sensitivity of SCFE-diagnosis was high among radiologists and orthopaedic surgeons (88% to 100% for both specialties), but lower for paediatricians (24% to 76%). Specificity was high among radiologists and orthopaedic surgeons (72% to 84%), however, variable among paediatricians (56% to 80%). Accuracy of a SCFE-diagnosis was highest in radiologists (84% to 92%), followed by orthopaedic surgeons (80% to 88%) and paediatricians (48% to 78%). Conclusion: SCFE can be detected on radiographs by different medical specialties. Intra- and interobserver agreement, specificity, sensitivity and accuracy for radiographic SCFE-diagnosis amongst paediatric radiologists and orthopaedic surgeons are better than that of general paediatricians. Level of Evidence: II. PMID- 29707056 TI - Characterization of proximal femoral anatomy in the skeletally-immature patient. AB - Purpose: The morphology of the proximal femur has been extensively studied in the adult population. However, no literature providing a comprehensive evaluation of the anatomy in paediatric patients exists. The current study aims to characterize such anatomy in skeletally-immature patients, examine potential differences between genders, and analyze how these anatomical parameters change with age. Methods: Cadaveric femurs from the Hamann-Todd Osteological Collection were examined. Specimens with open physes and no skeletal disease or deformity were included for analysis. Age and gender were recorded for each specimen. Each femur was photographed in standardized modified axial and anteroposterior views. In all, 14 proximal femoral anatomical parameters were measured from these photographs. Comparisons between genders and age were calculated. Results: A total of 43 femurs from ages four to 17 years met inclusion criteria. The majority were female (56%); no difference existed in age between genders (p = 0.62). The specimens had a neutral mean neck-shaft angle (130.7o) and anteversion (12.8o), and the sphericity of the ossified femoral heads was symmetrical. Male specimens had significantly higher alpha angles (p = 0.01), posterior offset (p = 0.02), neck width (p = 0.04) and head-neck length ratio (p = 0.02) values than female specimens. Strong positive correlations exist between length/size parameters and age, while negligible correlations were noted for angular measurements. Conclusions: This study establishes reference values for a comprehensive list of anatomical parameters for the skeletally-immature ossified proximal femur. It highlights gender differences in morphology and demonstrates that angular characteristics remain relatively stable while length parameters generally increase with age. Level of Evidence: Level III Diagnostic. PMID- 29707057 TI - Propionibacterium acnes infections in patients with idiopathic scoliosis: a case control study and review of the literature. AB - Purpose: Surgical site infection (SSI) caused by Propionibacterium acnes is an infrequent but devastating complication after spinal fusion. The purpose of this study was to identify risk factors for SSI with Propionibacterium acnes after spinal fusion for juvenile and adolescent idiopathic scoliosis (JIS and AIS). Methods: A case-control study was performed. Each case was matched 2:1 for age, gender and diagnosis. Retrospective chart review was performed to obtain relevant demographic, surgical and clinical data for all cases and controls. Statistical analysis included paired t-test and McNemar test, as well as exact logistic regression and robust regression models. Results: This study included ten infection cases (eight AIS, two JIS) and 20 controls (16 AIS, four JIS). In total, six infected cases presented within two weeks of the index procedure (acute infection) and four infected cases presented more than one year from the index procedure (delayed infection). The most common presentation for acute infections was wound drainage, while back pain was more common in delayed infections. All infections were successfully treated with surgical irrigation and debridement and postoperative antibiotics. Hardware was removed for patients with delayed infections. The strongest risk factor for infection was increased requirement for blood transfusion, but it did not reach statistical significance. Conclusion: SSI with Propionibacterium acnes is an important complication after spinal fusion for idiopathic scoliosis. These infections can be successfully treated, but larger studies are needed to further identify risk factors and establish standardized guidelines for the treatment and prevention of this complication. Level of Evidence Level III: PMID- 29707058 TI - T1-weighted MR imaging of bone marrow pattern in children with adolescent idiopathic scoliosis: a preliminary study. AB - Purpose: Distinct normal physiological patterns of fat conversion in vertebrae were described both for children and adults. Our aim was to evaluate the T1 weighted bone marrow pattern of the vertebral bodies in various sites along the scoliotic spine of children with adolescent idiopathic scoliosis (AIS). Methods: We retrospectively evaluated spine MRI studies of children with AIS. Scoliosis radiographs were assessed for type of curvature according to the Lenke classification. A paediatric neuroradiologist assessed the T1-weighted signal of vertebral bodies in comparison with the adjacent disc and distinct patterns of fatty conversion within the apical and stable vertebral bodies. Statistical assessment was performed. Results: MRI study of the spines of 75 children with AIS were assessed, 59 (79%) of whom were female, with an age range of nine to 19 years. The relative overall T1-weighted signal intensity of the vertebral body bone marrow relative to the intervertebral disc was hyperintense in 76% and isointense in 24%. Fatty conversion grade of the stable vertebra was higher than the apex vertebra (p = 0.0001). A significant tendency to have more advanced fat conversion patterns in the apex vertebra up to age 13.5 years old compared with adolescents above that (p = 0.015) was seen. Conclusion: This preliminary study suggests a different pattern of bone marrow conversion in AIS from the normal physiologic pattern described in the literature. Whether these changes are secondary to the biomechanics of the curved spine or may suggest that bone marrow maturation rate and content have a role in the pathogenesis of AIS remains to be further researched. Level of Evidence: Level III (Diagnostic Study). PMID- 29707059 TI - Posteromedial bowing of the tibia: a benign condition or a case for limb reconstruction? AB - Purpose: To review the initial deformity and subsequent remodelling in posteromedial bowing of the tibia and the outcome of limb reconstruction in this condition. Patients and Methods: In all, 38 patients with posteromedial bowing of the tibia presenting between 2000 and 2016 were identified. Mean follow-up from presentation was 78 months. A total of 17 patients underwent lengthening and deformity correction surgery, whilst three further patients are awaiting lengthening and deformity correction procedures. Results: The greatest correction of deformity occurred in the first year of life, but after the age of four years, remodelling was limited. The absolute leg-length discrepancy (LLD) increased throughout growth with a mean 14.3% discrepancy in tibial length. In the lengthening group, mean length gained per episode was 45 mm (35 to 60). Mean duration in frame was 192 days, with a mean healing index of 42.4 days/cm. Significantly higher rates of recurrence in LLD were seen in those undergoing lengthening under the age of ten years (p = 0.046). Four contralateral epiphysiodeses were also performed. Conclusion: Posteromedial bowing of the tibia improves spontaneously during the first years of life, but in 20/38 (53%) patients, limb reconstruction was indicated for significant residual deformity and/or worsening LLD. For larger discrepancies and persistent deformity, limb reconstruction with a hexapod external fixator should be considered as part of the treatment options. Level of evidence: Level IV (Case series). PMID- 29707060 TI - Patient-reported mobility function and engagement in young adults with cerebral palsy: a cross-sectional sample. AB - Purpose: To describe self-reported life satisfaction and motor function of young adults with cerebral palsy (CP). Methods: A total of 57 young adults with spastic CP classified as levels I (seven), II (25), III (16), IV (nine) by the Gross Motor Function Classification System, followed from childhood by our CP clinic, returned at a mean age of 27 years two months (SD 3 years 4 months). Self reported life satisfaction and mobility status were measured by the Pediatric Outcomes Data Collection Instrument (PODCI), Patient-Reported Outcomes Measurement Information System (PROMIS), Functional Mobility Scale (FMS) and a project questionnaire. Surgical history and childhood mobility were confirmed from medical records. Results: The Functional Mobility Scale demonstrated limited but stable mobility function from childhood to adulthood. The PROMIS and PODCI revealed limited motor function compared with a non-disabled normative reference (p < 0.05). Descriptive results showed high dependence on transportation, housing and income; although PROMIS subscales revealed satisfaction with social activities. Self-recall of childhood mobility function using the FMS correlated highly (r = 0.8; p < 0.0001) with historical records. Conclusion: Although functional mobility is limited and community independence is not fully achieved in young adults with CP, these participants maintained childhood levels of mobility function into young adulthood, were satisfied with social roles and had minimal reports of pain. Level of Evidence Level III: PMID- 29707062 TI - An Overview of a Smart Manufacturing System Readiness Assessment. AB - Smart manufacturing, today, is the ability to continuously maintain and improve performance, with intensive use of information, in response to the changing environments. Technologies for creating smart manufacturing systems or factories are becoming increasingly abundant. Consequently, manufacturers, large and small, need to correctly select and prioritize these technologies correctly. In addition, other improvements may be necessary to receive the greatest benefit from the selected technology. This paper proposes a method for assessing a factory for its readiness to implement those technologies. The proposed readiness levels provide users with an indication of their current factory state when compared against a reference model. Knowing this state, users can develop a plan to increase their readiness. Through validation analysis, we show that the assessment has a positive correlation with the operational performance. PMID- 29707061 TI - The efficacy of 16S ribosomal DNA sequencing in the diagnosis of bacteria from blood, bone and synovial fluid samples of children with musculoskeletal infections. AB - Background: Musculoskeletal infections are among the most common bacterial infections in children leading to hospitalization, invasive procedures and prolonged antibiotic administration. Blood, synovial and sometimes tissue cultures are essential for the diagnosis and treatment of musculoskeletal infections; 16S ribosomal DNA (rDNA) sequencing is a novel diagnostic tool for the detection of bacteria.While the yield of 16S rDNA sequencing in synovial fluid was previously assessed, data regarding the efficacy of this method from blood samples or partially treated children with suspected musculoskeletal infections is lacking.In this study we assessed the yield of 16S rDNA sequencing in blood, bone and synovial samples of children with musculoskeletal infections. Methods: Blood, synovial and bone samples were collected from children with suspected musculoskeletal infections and analyzed for the presence of 16S rDNA, the results were then compared with the benchmark microbial cultures. Results: During the study period, 41 children (18 boys and 23 girls) with suspected acute musculoskeletal infection were enrolled. A positive blood culture was found in 6/31 cases (19.4%) with methicillin-susceptible Staphylococcus aureus being the most commonly isolated bacterium. No significant 16S rDNA detection in blood samples was recorded.Synovial fluid culture was positive in 6/28 samples (21%), Kingella kingae being the most common pathogen. When using the 16S rDNA sequencing method, the rate of positive results in synovial fluid was higher with bacterial detection in 12/23 (52%) samples. The 16S rDNA sequencing method was also able to identify pathogens in samples taken from partially treated children where cultures were negative with 16S rDNA detection in 5/5 samples. Conclusion: Although 16S rDNA sequencing may increase the yield of bacterial detection in synovial samples of patients with musculoskeletal infections, there is no benefit from applying this method on blood samples. The 16S rDNA sequencing method may be particularly beneficial when antibiotic treatment was started prior to synovial fluid sampling. Level of Evidence: Level-II diagnostic study. PMID- 29707063 TI - Dehydration of bacterial cellulose and the water content effects on its viscoelastic and electrochemical properties. AB - Bacterial cellulose (BC) has interesting properties including high crystallinity, tensile strength, degree of polymerisation, water holding capacity (98%) and an overall attractive 3D nanofibrillar structure. The mechanical and electrochemical properties can be tailored upon incomplete BC dehydration. Under different water contents (100, 80 and 50%), the rheology and electrochemistry of BC were evaluated, showing a progressive stiffening and increasing resistance with lower capacitance after partial dehydration. BC water loss was mathematically modelled for predicting its water content and for understanding the structural changes of post-dried BC. The dehydration of the samples was determined via water evaporation at 37 degrees C for different diameters and thicknesses. The gradual water evaporation observed was well-described by the model proposed (R2 up to 0.99). The mathematical model for BC water loss may allow the optimisation of these properties for an intended application and may be extendable for other conditions and purposes. PMID- 29707064 TI - A general representation scheme for crystalline solids based on Voronoi tessellation real feature values and atomic property data. AB - Increasing attention has been paid to materials informatics approaches that promise efficient and fast discovery and optimization of functional inorganic materials. Technical breakthrough is urgently requested to advance this field and efforts have been made in the development of materials descriptors to encode or represent characteristics of crystalline solids, such as chemical composition, crystal structure, electronic structure, etc. We propose a general representation scheme for crystalline solids that lifts restrictions on atom ordering, cell periodicity, and system cell size based on structural descriptors of directly binned Voronoi-tessellation real feature values and atomic/chemical descriptors based on the electronegativity of elements in the crystal. Comparison was made vs. radial distribution function (RDF) feature vector, in terms of predictive accuracy on density functional theory (DFT) material properties: cohesive energy (CE), density (d), electronic band gap (BG), and decomposition energy (Ed). It was confirmed that the proposed feature vector from Voronoi real value binning generally outperforms the RDF-based one for the prediction of aforementioned properties. Together with electronegativity-based features, Voronoi-tessellation features from a given crystal structure that are derived from second-nearest neighbor information contribute significantly towards prediction. PMID- 29707066 TI - Single-graded CIGS with narrow bandgap for tandem solar cells. AB - Multi-junction solar cells show the highest photovoltaic energy conversion efficiencies, but the current technologies based on wafers and epitaxial growth of multiple layers are very costly. Therefore, there is a high interest in realizing multi-junction tandem devices based on cost-effective thin film technologies. While the efficiency of such devices has been limited so far because of the rather low efficiency of semitransparent wide bandgap top cells, the recent rise of wide bandgap perovskite solar cells has inspired the development of new thin film tandem solar devices. In order to realize monolithic, and therefore current-matched thin film tandem solar cells, a bottom cell with narrow bandgap (~1 eV) and high efficiency is necessary. In this work, we present Cu(In,Ga)Se2 with a bandgap of 1.00 eV and a maximum power conversion efficiency of 16.1%. This is achieved by implementing a gallium grading towards the back contact into a CuInSe2 base material. We show that this modification significantly improves the open circuit voltage but does not reduce the spectral response range of these devices. Therefore, efficient cells with narrow bandgap absorbers are obtained, yielding the high current density necessary for thin film multi-junction solar cells. PMID- 29707065 TI - 3D printing for soft robotics - a review. AB - Soft robots have received an increasing attention due to their advantages of high flexibility and safety for human operators but the fabrication is a challenge. Recently, 3D printing has been used as a key technology to fabricate soft robots because of high quality and printing multiple materials at the same time. Functional soft materials are particularly well suited for soft robotics due to a wide range of stimulants and sensitive demonstration of large deformations, high motion complexities and varied multi-functionalities. This review comprises a detailed survey of 3D printing in soft robotics. The development of key 3D printing technologies and new materials along with composites for soft robotic applications is investigated. A brief summary of 3D-printed soft devices suitable for medical to industrial applications is also included. The growing research on both 3D printing and soft robotics needs a summary of the major reported studies and the authors believe that this review article serves the purpose. PMID- 29707067 TI - PEGylated TiO2 nanoparticles mediated inhibition of cell migration via integrin beta 1. AB - Nanoparticles (NPs) elicit various physiological responses in cellular environment, and the effect of NPs on cell migration is of high interest. In this work, the effects of NPs on cell migration and their possible mechanisms were studied. Here, we showed that after exposure to pegylated titanium dioxide nanoparticles (TiO2-PEG NPs, where PEG stands for the polyethylene glycol), NCI H292 cells exhibited slower migration than control cells. Furthermore, larger NPs inhibited cell migration much stronger than smaller NPs. Following NP exposure, the cells showed decreased expression of integrin beta 1 and phosphorylated focal adhesion kinase (pFAK), and disrupted F-actin structures. We demonstrated that a possible mechanism involved NP-mediated promotion of the lysosomal degradation of integrin beta 1, thus leading to reduced expression of pFAK and cytoskeletal disruption and inhibited cell migration. Therefore, our results showed that inhibition of NCI-H292 cell migration by NPs is mediated through integrin beta 1, which provides useful information for the application of NPs in cancer therapy and related fields. PMID- 29707068 TI - Atomic-scale visualization of oxide thin-film surfaces. AB - The interfaces of complex oxide heterostructures exhibit intriguing phenomena not observed in their constituent materials. The oxide thin-film growth of such heterostructures has been successfully controlled with unit-cell precision; however, atomic-scale understandings of oxide thin-film surfaces and interfaces have remained insufficient. We examined, with atomic precision, the surface and electronic structures of oxide thin films and their growth processes using low temperature scanning tunneling microscopy. Our results reveal that oxide thin film surface structures are complicated in contrast to the general perception and that atomically ordered surfaces can be achieved with careful attention to the surface preparation. Such atomically ordered oxide thin-film surfaces offer great opportunities not only for investigating the microscopic origins of interfacial phenomena but also for exploring new surface phenomena and for studying the electronic states of complex oxides that are inaccessible using bulk samples. PMID- 29707069 TI - Opto-electronic characterization of third-generation solar cells. AB - We present an overview of opto-electronic characterization techniques for solar cells including light-induced charge extraction by linearly increasing voltage, impedance spectroscopy, transient photovoltage, charge extraction and more. Guidelines for the interpretation of experimental results are derived based on charge drift-diffusion simulations of solar cells with common performance limitations. It is investigated how nonidealities like charge injection barriers, traps and low mobilities among others manifest themselves in each of the studied cell characterization techniques. Moreover, comprehensive parameter extraction for an organic bulk-heterojunction solar cell comprising PCDTBT:PC70BM is demonstrated. The simulations reproduce measured results of 9 different experimental techniques. Parameter correlation is minimized due to the combination of various techniques. Thereby a route to comprehensive and accurate parameter extraction is identified. PMID- 29707070 TI - Triboelectric energy harvesting with surface-charge-fixed polymer based on ionic liquid. AB - A novel triboelectric energy harvester has been developed using an ionic liquid polymer with cations fixed at the surface. In this report, the fabrication of the device and the characterization of its energy harvesting performance are detailed. An electrical double layer was induced in the ionic liquid polymer precursor to attract the cations to the surface where they are immobilized using a UV-based crosslinking reaction. The finalized polymer is capable of generating an electrical current when contacted by a metal electrode. Using this property, energy harvesting experiments were conducted by cyclically contacting a gold surface electrode with the charge fixed surface of the polymer. Control experiments verified the effect of immobilizing the cations at the surface. By synthesizing a polymer with the optimal composition ratio of ionic liquid to macromonomer, an output of 77 nW/cm2 was obtained with a load resistance of 1 MOmega at 1 Hz. This tuneable power supply with a MUA level current output may contribute to Internet of Things networks requiring numerous sensor nodes at remote places in the environment. PMID- 29707071 TI - Gas formation and biological effects of biodegradable magnesium in a preclinical and clinical observation. AB - Magnesium alloys are biodegradable metals receiving increasing attention, but the clinical applications of these materials are delayed by concerns over the rapid corrosion rate and gas formation. Unlike corrosion, which weakens mechanical properties, the gas formation issue has received little attention. Therefore, we evaluated the gas formation and biological effects for Mg implants through preclinical (immersed in Earle's balanced salt solution and in vivo) and clinical studies. The immersion test examined the gas volume and composition. The in vivo study also examined gas volume and histological analysis. The clinical study examined the gas volume and safety after Mg screw metatarsal fixation. Gas was mainly composed of H2, CO and CO2. Maximum volumes of gas formed after 5 days for in vivo and 7 days in clinical study. Within the clinical examination, two superficial wound complications healed with local wound care. Osteolytic lesions in the surrounding metaphysis of the Mg screw insertion developed in all cases and union occurred at 3 months. Mg implants released gas with variable volumes and composition (H2, CO, and CO2), with no long-term toxic effects on the surrounding tissue. The implants enabled bone healing, although complications of wound breakdown and osteolytic lesions developed. PMID- 29707073 TI - Selective laser melting of high-performance pure tungsten: parameter design, densification behavior and mechanical properties. AB - Selective laser melting (SLM) additive manufacturing of pure tungsten encounters nearly all intractable difficulties of SLM metals fields due to its intrinsic properties. The key factors, including powder characteristics, layer thickness, and laser parameters of SLM high density tungsten are elucidated and discussed in detail. The main parameters were designed from theoretical calculations prior to the SLM process and experimentally optimized. Pure tungsten products with a density of 19.01 g/cm3 (98.50% theoretical density) were produced using SLM with the optimized processing parameters. A high density microstructure is formed without significant balling or macrocracks. The formation mechanisms for pores and the densification behaviors are systematically elucidated. Electron backscattered diffraction analysis confirms that the columnar grains stretch across several layers and parallel to the maximum temperature gradient, which can ensure good bonding between the layers. The mechanical properties of the SLM produced tungsten are comparable to that produced by the conventional fabrication methods, with hardness values exceeding 460 HV0.05 and an ultimate compressive strength of about 1 GPa. This finding offers new potential applications of refractory metals in additive manufacturing. PMID- 29707072 TI - Material challenges for solar cells in the twenty-first century: directions in emerging technologies. AB - Photovoltaic generation has stepped up within the last decade from outsider status to one of the important contributors of the ongoing energy transition, with about 1.7% of world electricity provided by solar cells. Progress in materials and production processes has played an important part in this development. Yet, there are many challenges before photovoltaics could provide clean, abundant, and cheap energy. Here, we review this research direction, with a focus on the results obtained within a Japan-French cooperation program, NextPV, working on promising solar cell technologies. The cooperation was focused on efficient photovoltaic devices, such as multijunction, ultrathin, intermediate band, and hot-carrier solar cells, and on printable solar cell materials such as colloidal quantum dots. PMID- 29707075 TI - Upper and Lower Gastrointestinal Endoscopic Findings in HIV-Infected Patients in the Era of Highly Active Antiretroviral Therapy. AB - Background: Endoscopic evaluation with biopsies are instrumental in the diagnosis and management of gastrointestinal (GI) disorders in the setting of human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS), especially in the era of highly active antiretroviral therapy (HAART). Methods: A retrospective chart review of 304 HIV-positive and 199 HIV-negative patients who had undergone upper and/or lower endoscopy in an urban community hospital from the years 2012 - 2017 was performed. Inclusion criteria included men and women between the ages of 45 to 75 years, which had undergone colonoscopies between within 2012 - 2017 and had tested positive for HIV. They were selected from that population if they had complete charts that included information regarding symptoms, viral load, cluster of differentiation 4 (CD4) count, prescribed HAART medication, findings from the upper and lower colonoscopy both from the gastroenterologist's report and pathologist's report. Only then would they be added to the pool of final selection that we could compute data from and draw conclusions. Results: Among HIV patients, those with less than 200 CD4 cells/uL counts had lower rates of diverticulosis and hemorrhoids, as compared with those with greater than 200 cells/uL counts. Other gross and histological findings (from either upper or lower endoscopy) were not statistically different between these two groups. In HIV-positive patients, gastritis, Helicobacter pylori (HP) infection, and esophagitis were significantly less common, while Candida esophagitis was more common. Among HIV patients taking different HAART regimens, the prevalence of peptic ulcers was significantly higher in those taking IIs than that in those who were not. Conclusions: Physicians should consider the possibility that the GI symptoms in HIV-infected patients on HAART may be due to an opportunistic infection, even when the CD4 count is more than 200 cells/uL and the viral load is low. PMID- 29707074 TI - Hepatobiliary Manifestations and Complications in Inflammatory Bowel Disease: A Review. AB - Liver and biliary track diseases are common extraintestinal manifestations of inflammatory bowel disease (IBD), reported both in Crohn's disease and ulcerative colitis, and may occur at any time during the natural course of the disease. Their etiology is mainly related to pathophysiological changes induced by IBD, and secondary, due to drugs used in IBD. Fatty liver is considered as the most frequent hepatobiliary manifestation in IBD, while primary sclerosing cholangitis (PSC) is the most correlated hepatobiliary disorder and is more prevalent in patients with ulcerative colitis. PSC can cause serious complications from the liver, biliary tree, and gallbladder and can lead to liver failure. Less frequently, IBD-associated hepatobiliary manifestations include cholelithiasis, granulomatous hepatitis, portal vein thrombosis, IgG4-related cholangiopathy, pyogenic liver abscess, hepatic amyloidosis and primary biliary cirrhosis. Most of the drugs used for IBD treatment may cause liver toxicity. Methotrexate and thiopurines carry the higher risk for hepatotoxicity, and in many cases, dose adjustment may normalize the liver biochemical tests. Reactivation of hepatitis B and C virus during immunosuppressive use, especially during use of biological agents, is a major concern, and adequate screening, vaccination and prophylactic treatment is warranted. PMID- 29707077 TI - Suspected Blood Indicator to Identify Active Gastrointestinal Bleeding: A Prospective Validation. AB - Background: The suspected blood indicator (SBI) function in the RAPID Reader v8.3 program was designed to quickly identify the presence of blood in video capsule endoscopy. While previous retrospective studies have shown that the SBI function was accurate in detecting the presence of active bleeding in the small bowel, its specificity and sensitivity were poor. Methods: An initial retrospective review (phase 1) compared 115 patients with active gastrointestinal bleeding seen on video capsule endoscopy (VCE) to 115 patients with no active bleeding seen on VCE to produce a highly accurate algorithm. A prospective study (phase 2) was then performed by applying the algorithm to 100 consecutive patients who received VCE for the following indications: obscure bleeding, iron deficiency anemia, melena, and hematochezia. Results: The initial retrospective review found that eight contiguous SBI markers had a specificity of 100% in identifying active gastrointestinal bleeding regardless of the total number of SBI markers, while two or more contiguous SBI markers had a sensitivity of 96.5%. Using a cutoff of eight contiguous SBI markers, the prospective arm found that there was a 100% sensitivity and specificity in detecting active gastrointestinal bleeding (P < 0.001). Conclusions: The SBI function can greatly facilitate the identification of active gastrointestinal bleeding on VCE by using eight contiguous SBI markers as a cutoff for active bleeding. PMID- 29707076 TI - Clinical Predictors for Repeat Hospitalizations in Left Ventricular Assist Device (LVAD) Patients With Gastrointestinal Bleeding. AB - Background: Patients implanted with left ventricular assist devices (LVAD) carry an increased risk of gastrointestinal bleeding (GIB), estimated at 25% in most studies. Significant efforts are employed in localizing and stopping the source of bleeding, but the rates of repeat hospitalization for GIB remain surprisingly high. Given the increasing incidence of LVAD-dependent end-stage heart failure and the excessive costs associated with repetitive endoscopic investigations, risk factors associated with re-bleeding need to be determined. The aim of our study was to investigate clinical predictors associated with repeat hospitalizations for GIB in patients implanted with a LVAD. Methods: We conducted a retrospective cohort using the prospectively assembled ventricular assist device database at the University of Alabama at Birmingham. We identified all end stage heart failure patients who were implanted with a continuous-flow (CF) LVAD between Jan 1, 2009 and Dec 31, 2013. We excluded pulsatile devices, biventricular assist devices (BiVADs), right ventricular assist devices (RVADs), and patients under 19 years of age. Results: There were 102 patients implanted with a CF-LVAD within the specified time period. With an average follow-up of 127 weeks, 32 (31.4%) patients developed GIB requiring 79 separate hospitalizations. Average time from LVAD implantation to first bleed was 343 days. The re-bleeding rate requiring readmission was 56.3% in those admitted with GIB, with eight (25%) of the patients necessitating multiple readmissions. The average hospital stay for a primary diagnosis of GIB was 9.45 days. Totally, 68 (86%) patients required endoscopic evaluation during their hospitalization, with 35 (44%) necessitating multiple procedures during the same admission. The average time to first endoscopy was 2.5 days with a median of 2 days. Patients receiving early endoscopy (< 48 h from admission) were 57% less likely to require future readmission for GIB compared to patients undergoing late endoscopy (> 48 h) (OR: 0.43, CI: 0.19 - 0.9). Other factors associated with repeat admissions for GIB included indication for LVAD (bridge to transplant had OR: 0.07, CI: 0.02 - 0.27), male gender (OR: 10.4, CI: 1.8 - 59), length of initial hospital stay (OR: 0.83, CI: 0.71 - 0.97), and INR on admission (OR: 3.6, CI: 1.46 - 8.8). Although not statistically significant, patients undergoing subsequent endoscopies during a single admission were 84% less likely to develop re-bleeding in the future (OR: 0.158, CI: 0.025 - 1.02). Conclusions: GIB in LVAD patients is a significant problem with high rates of readmission despite extensive endoscopic investigations and anticoagulant adjustments. Our experience revealed that early endoscopy, longer initial hospital stay, and better INR control were all associated with decreased rates of readmission for GIB in this population. These modifiable factors should be emphasized and addressed in the future to reduce the burdens associated with repeated hospitalizations. PMID- 29707078 TI - Assessment of Gastric Acidity by Conventional Endoscopy With Serological Gastric Markers. AB - Background: Gastric acidity could determine Helicobacter pylori (H. pylori) associated gastritis patterns. In reverse, H. pylori infection could lead disturbance in gastric acid secretion. We attempted to elucidate gastric acid status by conventional endoscopy with pepsinogen test. Methods: A total of 196 subjects who visited our health promotion center were consecutively enrolled and evaluated by conventional endoscopy, and blood examinations with pepsinogen I, II, and fasting serum gastrin were conducted. As a Japanese study suggested that in H. pylori-positive subjects the cutoff value was PG I/II ratio <= 2.7 for hypochlorhydia, PG I/II ratio >= 3.3 for hyperchlorhydria. Based on these serological data, we compared conventional endoscopic images with each acid level. Results: It showed that for hypoacidity, older age, and most of the H. pylori-associated endoscopic appearances featuring mucosal inflammation and more atrophy of corpus or antrum were in favor of hypoacidity in closed type. Mucosal appearances showing severe corpus atrophy and remnant gastritis with advanced background atrophy determine hypoacidity in open type. For hyperacidity, mucosal appearances featuring intact mucosa and less severe atrophy were associated with hyperacid status. Male gender, antrum camouflage were also involved in hyperacidity. Conclusions: Conventional endoscopy with pepsinogen test could be useful in gastric acid assessment. PMID- 29707079 TI - Prevalence of Hepatitis B Reactivation Among Chinese Individuals With Chronic Hepatitis C Treated With Pan-Oral Direct-Acting Antivirals. AB - Background: Clearance of hepatitis C virus (HCV) has been reported to induce the reactivation of hepatitis B virus (HBV). The aim of this study was to investigate the rate of HBV reactivation in HCV-infected Chinese patients who received treatment with pan-oral direct-acting antivirals (DAAs). Methods: Data from HCV subjects receiving oral DAA therapy were retrospectively collected from October 2015 to May 2017. Patients who were seropositive for HBsAg or anti-HBc were enrolled. The efficacy of DAAs, including end-of-treatment virologic response (ETVR) and sustained virologic response (SVR) 12, was recorded. HBV virologic reactivation was defined as a reappearance of HBsAg, or increased HBV DNA by at least one log10 IU/mL. HBV clinical reactivation was defined as virologic reactivation and serum alanine aminotransferase (ALT) over two-fold of the upper limit of normal. Results: There were 11 (7.2%) cases and 53 (34.6%) cases in the HBsAg group and the anti-HBc group among all 153 subjects. All individuals achieved ETVR and SVR12. There were no cases with reappearance of HBsAg during DAAs therapy. Among seven cases in the HBsAg group whose HBV DNA level was determined, HBV virological reactivation was detected in two subjects (28.6%). Among all 11 subjects in the HBsAg group, there was one (9.1%) case with HBV clinical reactivation, which was resolved following treatment with Entaclavir. The case with HBV clinical reactivation had a higher baseline HBV DNA viral load (1,380 IU/mL) compared with that of the other patients (20 - 296 IU/mL). Conclusion: HBV virological and clinical reactivation occurred in 28.5% and 9.1% of subjects with HBsAg seropositivity. No HBV reactivation was observed in the cases with past HBV infection. PMID- 29707080 TI - Direct-Acting Antivirals in Chronic Hepatitis C Genotype 4 Infection in Community Care Setting. AB - Background: Limited data exists comparing the safety, tolerability, and efficacy of direct-acting antivirals (DAAs) in patients with chronic hepatitis C genotype 4 (HCV GT-4) in the community practice setting. We aim to evaluate the treatment response of DAAs in these patients. Methods: All the HCV GT-4 patients treated with DAAs between January 2014 and October 2017 in a community clinic setting were retrospectively analyzed. Pretreatment baseline patient characteristics, treatment efficacy with sustained virologic response (SVR) at 12 weeks post treatment (SVR12), and adverse reactions were assessed. Results: Fifty-two patients of Middle Eastern (primarily Egyptian) descent were included in the study. Thirty-two patients were treated with ledipasvir/sofosbuvir (Harvoni(r)) +/- ribavirin, 12 patients were treated with ombitasvir/paritaprevir/ritonavir/dasabuvir (ViekiraPak(r)) +/- ribavirin, and eight patients were treated with sofosbuvir/Velpatasvir (Epclusa(r)). Ten patients (19.2%) had compensated cirrhosis. Overall, SVR at 12 weeks was achieved in 94% in patients who received one of the three DAA regimens (93.8% in Harvoni(r) group, 91.7 % in ViekiraPak(r) group and 100% in Epclusa(r) group). Prior treatment status and type of regimen used in the presence of compensated cirrhosis had no statistical significance on overall SVR achievement (P value = 0.442 and P value = 0.091, respectively). The most common adverse effect was fatigue (27%). Conclusions: In the real-world setting, DAAs are effective and well tolerated in patients with chronic HCV GT-4 infection with a high overall SVR rate of 94%. Large-scale studies are needed to further assess this SVR in these groups. PMID- 29707081 TI - Efficacy and Safety of Entecavir 0. 5 mg in Treating Naive Chronic Hepatitis B Virus Patients in Egypt: Five Years of Real Life Experience. AB - Background: The aim of the study was to evaluate the efficacy and safety of entecavir (ETV) among chronic hepatitis B (CHB) nucleos(t)ide-naive Egyptian patients. Methods: Forty-eight CHB patients on ETV were included. Males comprised 83.3% (40 cases), while females comprised 16.7% (eight cases). Minimum age was 19 years, while maximum age was 64 years. Hepatitis B envelope antigen (HBeAg) negative cases were 60.4%. HBeAg-positive cases were 39.6%. Factors including sex, positive HBeAg, baseline hepatitis B virus (HBV) DNA level, baseline alanine aminotransferase (ALT) and aspartate aminotransferase (AST), were evaluated in terms of their predictive role in treatment response, which was defined as a serum HBV DNA decrease of < 10 IU/mL. Results: Mean age of patients was 38.2 years; males were 83.3% and females were 16.7%. HBeAg-negative cases were 60.4%, while HBeAg-positive cases were 39.6%. Mean baseline DNA level was 44 * 106 IU/mL. Ultrasound results showed 14 cases had hepatomegaly, 10 cases had bright liver, seven cases had coarse liver, and eight cases had cirrhosis. Of the cases, 45.8% showed a negative PCR after the first 6 months of therapy to reach 64.6% by the end of the first year. HBV DNA undetectability reached 91.3% and 100% after 4 and 5 years, respectively for those who completed the study period. ALT reduction started after 6 months of treatment and reached 53.37% after 5 years. Similarly AST showed the same pattern of decline and reached 54.37% after 5 years. Only two cases achieved HBeAg seroconversion. Three patients experienced virological breakthrough and the three cases shared similar characteristics of being less than 40 years, with baseline HBV DNA of >= 105 IU/mL and positive HBeAg. None of the cases showed hepatitis B surface antigen (HBsAg) seroconversion. Conclusion: ETV proved to have a potent antiviral efficacy and safety in nucleoside/tide naive Egyptian patients. Rate of HBV DNA undetectability was higher in patients above 40 years of age and in patients who initially had a low viral load. ETV was well tolerated during the treatment period with a good overall safety profile. PMID- 29707082 TI - Trans-Hepatic Percutaneous Endoscopic Gastrostomy Tube Placement: A Case Report of A Rare Complication and Literature Review. AB - Percutaneous endoscopic gastrostomy (PEG) tubes have emerged as the standard of care for long-term enteral feeding. This procedure is relatively safe; however, complications do occur, and one of the most dreaded complications is trauma to the surrounding organs. Hepatic injury during PEG placement is an extremely rare complication of the PEG procedure, with a handful of cases described in the medical literature. We describe the case of an accidental trans-hepatic placement of a PEG tube in a 78-year-old morbidly obese female, even with excellent trans illumination and manual external pressure achieved during endoscopic placement. Post-procedure, cross-sectional imaging of the abdomen showed a gastrostomy tube traversing the lateral margin of the liver with adjacent small hematoma. Physical exam was unremarkable for abdominal tenderness or guarding/rigidity, and no blood or drainage was noted at the site of PEG insertion. Enteral nutrition was started after 24 h of PEG tube insertion and patient tolerated well with no complications. The patient was discharged to a nursing home but unfortunately died the following week to an unknown cause. PMID- 29707083 TI - Peutz-Jeghers Syndrome Presenting as Colonic Intussusception: A Rare Entity. AB - Peutz-Jeghers syndrome is an autosomal dominant inherited medical condition characterized by hyperpigmented mucocutaneous macules, hamartomatous polyps in the digestive tract, and with a greater risk of gastrointestinal and non gastrointestinal cancers. In fact, without appropriate medical surveillance, the lifetime risk for all cancers combined may be as high as 93%. The syndrome is rare, with estimates of incidence varying between 1 in 8,300 and 1 in 280,000 live births. Infrequently, individuals present for the first time with bowel obstruction secondary to intussusception. Here, we present an interesting case of a young Burmese man who, early on, showed traits of Peutz-Jeghers syndrome, including the characteristic hyperpigmented areas on the fingers and lips. Unfortunately, the diagnosis was not made until he later developed bowel obstruction caused by an intussusception, requiring exploratory laparoscopic bowel resection. A high index of suspicion is needed to diagnose accurately. However, early identification and close surveillance can lead to excellent prognosis in these individuals. PMID- 29707084 TI - Double Pylorus: Report of a Case With Endoscopic Follow-Up and Review of the Literature. AB - Double pylorus is a rare endoscopic finding that has been reported in 0.001% to 0.4% of upper gastrointestinal endoscopies and can be either congenital or acquired. Acquired double pylorus is usually an uncommon complication of peptic ulcer that erodes and creates a fistula between the duodenal bulb and the prepyloric antrum. We describe a case of a 67-year-old man who experienced mild epigastric pain and dyspepsia over the last 6 months. The patient periodically took nonsteroidal anti-inflammatory drugs (NSAIDs) due to joint pain. Esophagogastroduodenoscopy revealed gastritis and a double pylorus. An accessory channel connected the lesser curvature of the prepyloric antrum to the duodenal bulb and the endoscope was able to be passed through both of the ducts. The Helicobacter pylori quick test proved positive. Two years later, a follow-up endoscopy showed that fistula fused with normal pylorus and there was a single large opening. PMID- 29707085 TI - Enteral Nutrition With an Enteral Formula Containing Egg Yolk Lecithin After Percutaneous Endoscopic Gastrostomy: A Case Series. AB - The occurrence of diarrhea at the beginning of enteral nutrition complicates the continuation of enteral nutrition. Recently, studies in Japan indicated that diarrhea could be improved by changing the enteral formula to one that is emulsified with egg yolk lecithin. In this study, we administered the enteral formula K-2S plus, which is emulsified with egg yolk lecithin, to 15 patients (four men and 11 women; mean age, 79.9 +/- 2.0 years) after they had undergone a percutaneous endoscopic gastrostomy (PEG) to prevent the occurrence of diarrhea related to enteral nutrition. Two days after the PEG, the patients would receive 200 mL K-2S plus intermittently three times daily; thereafter, the amount of K-2S plus was increased according to the patient's condition. The administration rate was scheduled as 200 mL/h when 200 mL were administered at one time. For >= 300 mL, the scheduled administration rate was 300 mL/h. When we administered K-2S plus at the beginning of enteral nutrition after the PEG, the dose of the enteral formula could be increased without any occurrence of diarrhea or vomiting. Five patients had received intravenous nutrition before the PEG; thus, we were concerned about diarrhea in these patients. In conclusion, an enteral formula emulsified with egg yolk lecithin may be safely used at the time of enteral nutrition initiation without causing diarrhea. PMID- 29707087 TI - Elevated Neutrophil Gelatinase Lipocalin Levels Are Associated With Increased Oxidative Stress in Hemodialysis Patients. AB - Background: Administration of intravenous iron is an essential treatment of anemia in hemodialysis patients, but it may lead to oxidative stress and increased morbidity and mortality. There is evidence that neutrophil gelatinase associated lipocalin (NGAL) is protective against oxidative stress and thus the aim of the present study was to investigate the relationship between plasma NGAL and advanced oxidative protein products (AOPP) in hemodialysis patients treated with intravenous iron. Methods: In a prospective study, 47 hemodialysis patients (mean age 63 years, SD = 13.6; 40% women) were enrolled from two separate hospitals. Oxidative stress was induced by an intravenous administration of 100 mg iron saccharate 0.5 h after the start of dialysis. Blood samples were drawn at the beginning of the dialysis, 0.5 h after iron administration and at the end of dialysis. NGAL levels were measured from the first blood sample, AOPP levels were measured from all blood samples. Results: Our results showed that higher NGAL and AOPP levels at the beginning of the dialysis, prior to iron administration, significantly predicted higher levels of AOPP toward the end of dialysis, (beta = 0.355, SE = 0.054, P = 0.035; beta = 0.297, SE = 0.159, P = 0.043, respectively). Conclusions: Our results suggest that higher level of NGAL is a risk factor for oxidative stress, as measured by AOPP levels, in dialysis patients receiving intravenous iron. Our findings could identify dialysis patients who are at higher risk from iron supplementation via measurement of NGAL levels. PMID- 29707086 TI - Epigenetics of Metabolic Syndrome as a Mood Disorder. AB - Mood disorders comprise major depressive disorder (MDD), bipolar disorder (BD) and the milder forms of these two disorders. Reccurring MDD is also known as unipolar disorder. The distinction between unipolar and bipolar disorders was first suggested in 1957 by Leonard and was made official after support by several studies in 1980. Indeed, in 150 AD, Aretaeus of Cappadocia wrote "It seems to me that melancholia is the beginning and a part of mania". Additionally, Kraepelin, who proposed the first medical disease model in psychiatry a century ago, considered recurrent unipolar depression cases under the category of bipolar disorder and conceptualized spectrum disorders. Because today's classification systems conduct cross-sectional diagnosis, they do not consider family history, long-term characteristics and multidimensional approaches on symptoms. This method prioritizes reliability over validity and it rules out psychiatric disorders in etiology. Actually, a spectrum model which covers physical diseases is conceivable. The concept of epigenetics considers mood disorders, Alzheimer's disease, attention deficit and hyperactivity disorder, Carney syndrome, multiple endocrine neoplasia type I and II, breast and prostate cancers, carsinoid tumors, cerebrovascular and cardiovascular diseases and metabolic syndrome together. This review addressed the relationship between metabolic syndrome and mood disorders in this context along with genetic, clinical and environmental factors such as climate, geographic factors, migration and changeable lifestyles. Genetic and clinical variables are affective temperament, childhood trauma and use of antidepressants and antipsychotics. PMID- 29707088 TI - Impact of Dapagliflozin Therapy on Renal Protection and Kidney Morphology in Patients With Uncontrolled Type 2 Diabetes Mellitus. AB - Background: We examined whether the sodium-glucose cotransporter-2 inhibitor (SGLT2i) dapagliflozin can improve urine albumin-to-creatinine ratio (UACR) associated with a reduction in body weight or body fat in patients with type 2 diabetes mellitus (T2DM). Methods: We prospectively recruited T2DM patients having inadequate glycemic control (hemoglobin A1c (HbA1c) > 7.0%) not on SGLT2i therapy. We treated the patients with add-on dapagliflozin treatment or intensification of non-SGLT2 inhibitor therapies for 6 months. We measured UACR, urine N-acetyl-beta-glucosaminidase (uNAG), and body composition including total body fat mass (TBFM) as assessed by bioelectrical impedance analysis. We also investigated changes in length and radiation attenuation properties of the kidneys and abdominal fat area using computed tomography. Results: We enrolled 62 patients with a mean HbA1c of 8.0%. The HbA1c and fasting blood glucose were significantly decreased in both the dapagliflozin-group and non-SGLT2i-group, with no significant difference between the two groups. Dapagliflozin treatment, but not non-SGLT2i treatment, significantly decreased UACR and uNAG. The changes in UACR and uNAG were significantly greater in the dapagliflozin group compared with the non-SGLT2i group. Dapagliflozin treatment, but not non-SGLT2i treatment, significantly decreased the body weight, TBFM, and abdominal fat area and significantly increased kidney length and radiation attenuation. The percentage change in UACR was significantly correlated with changes in TBFM, but not with body weight. By multivariate logistic regression analysis, dapagliflozin treatment was significantly associated with the improvement of UACR. Conclusions: Add-on treatment with dapagliflozin exhibited significant renoprotective effects, with improvement of UACR and uNAG and increased kidney length and radiation attenuation in patients with uncontrolled T2DM. PMID- 29707090 TI - Recurrence Is Associated With Body Mass Index in Patients Undergoing a Single Level Lumbar Disc Herniation Surgery. AB - Background: The aim of the study was to assess the body mass index (BMI) and other risk factors associated with lumbar disc herniation (LDH) and clinical outcomes, in patients who undergo surgery for single-level LDH. Methods: This was a retrospective cohort study, affecting patients that underwent surgery for single-level LDH attending our hospital between July 2009 and January 2016. The mean follow-up period was 3.5 years (1 - 8 years). To maintain adequately sized groups for analysis, level L2-L3 and L3-L4 herniations were grouped as upper disc levels (group A) and level L4-L5 (group B) and L5-S1 (group C) herniations were analyzed individually. Disk herniation was graded on T2-weighted sagittal magnetic resonance images by using a five-point scale. Pain assessment was made using the visual analog scale (VAS). Results: Two hundred fifty-six (256) patients met study inclusion criteria. There were 138 males (53.9%) with a mean age of 55.3 +/- 12.9 years (range, 30 - 77). The association between A, B and C groups was analyzed, based on criteria such as age, sex, BMI, surgical techniques, diabetes, size of herniated disc, preoperative VAS, length of hospital stay, drop foot on admission, smoking, family history and history of injury to the lumbar spine, location of herniated disc (far lateral) and use of steroids. We found a statistically significant factor between groups in BMI (P = 0.006), family history (P = 0.001), location (far lateral) (P = 0.003) and history of injury to the lumbar spine (P = 0.003). Conclusions: There may be an association between severity of disc degeneration and BMI (overweight and obese adults). Furthermore, spine and neurosurgeons should be aware that BMI might be related to patients' outcome. PMID- 29707089 TI - Smoking Cessation Ameliorates Microalbuminuria With Reduction of Blood Pressure and Pulse Rate in Patients With Already Diagnosed Diabetes Mellitus. AB - Background: Smoking cessation in newly diagnosed type 2 diabetes patients is reported to be associated with amelioration of metabolic parameters and blood pressure (BP), and the reduction of microalbuminuria. The aim of this study is to demonstrate changes in BP, pulse rate (PR), and microalbuminuria in already diagnosed diabetes patients who quit smoking. Methods: We retrospectively evaluated diabetes outpatients who were habitual smokers, and who visited to our smoking cessation clinic. Patients were divided into two groups based on their smoking status at the termination of a 3-month smoking cessation program (smoking cessation group and smoking group), and analyzed systolic and diastolic BPs, PR, HbA1c, and body weight at the start date, and at 1, 3, 6, and 12 months thereafter. The urinary albumin-to-creatinine ratio was also measured at the start date and at 12 months. Results: Thirty-five patients met our criteria. Mean diabetes duration was 12 years. Eighteen patients (52%) quit smoking. Success or failure of smoking cessation depended on nicotine dependence rather than good or bad glycemic control. Both BP and PR decreased significantly after 1 month or later in the smoking cessation group without worsening HbA1c, while both parameters did not show any changes in the smoking group. Microalbuminuria was also ameliorated significantly at 12 months compared with that at the start date in the smoking cessation group (95.8 +/- 92.9 mg/gCr vs. 75.5 +/- 96.3 mg/gCr, P = 0.0059), while it did not show a significant change in the smoking group. (61.9 +/- 43.5 mg/gCr vs. 97.7 +/- 90.4 mg/gCr, P = 0.1039). Conclusions: Smoking cessation might cause a reduction in chronic kidney disease progression through ameliorating microalbuminuria without metabolic adverse effects in patients already diagnosed with diabetes mellitus. PMID- 29707091 TI - Sodium-Glucose Cotransporter 2 Inhibitors Reduce Prandial Insulin Doses in Type 2 Diabetic Patients Treated With the Intensive Insulin Therapy. AB - Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are anti-diabetic drugs which improve blood glucose control by blocking reabsorption of glucose from the proximal tubule of kidney. Anti-atherosclerotic properties and cardiovascular protective effects of SGLT2i have been demonstrated by recent studies; however, the efficacy and safety of addition of SGLT2i to the intensive insulin therapy remain largely unknown. Methods: We retrospectively picked up patients hospitalized for treatment of type 2 diabetes, who had been treated by the intensive insulin therapy and whose treatment using by SGLT2i started during their hospitalization. Such patients were picked up between June 2014 and May 2017 based on medical charts. Results: We found 12 eligible patients. Observation period was 10.2 +/- 4.7 days, and SGLT2i was started at 12.2 +/- 12.9 days after the admission. During observation period, nobody developed hypoglycemia. In spite of showing decrease of blood glucose (non-significant) before each meal, the addition of SGLT2i significantly reduced daily prandial insulin doses by approximately 4.6 units/day (-66%). The SGLT2i addition also decreased body weight by approximately 1.3 kg. Conclusion: Present study demonstrated that the addition of SGLT2i to intensive insulin therapy reduced prandial insulin doses and body weight, without the development of hypoglycemia. This result may be due to SGLT2i-mediated improvement of postprandial hyperglycemia by increasing urinary glucose excretion not via insulin secretion. PMID- 29707092 TI - Improved Outcomes Associated With the Use of Intravenous Acetaminophen for Management of Acute Post-Surgical Pain in Cesarean Sections and Hysterectomies. AB - Background: Post-surgical pain impacts many patient outcomes. Effective pain management increasingly relies on multimodal analgesia regimens in which acetaminophen (APAP) is a key component. The aim of our study was to examine the impact of oral APAP versus intravenous (IV) APAP as a component of post-surgical pain management after Cesarean sections and hysterectomies. Methods: A retrospective analysis of the Cerner HealthFacts(r) database (from January, 2011 to December, 2015) was conducted to compare outcomes of Cesarean section and hysterectomy surgery patients who received oral APAP to those who received IV APAP post-surgically. Length of stay (LOS), daily morphine milligram equivalent (MME) consumption, the presence of potential opioid-related adverse events (ORADEs), and total pharmacy costs were assessed. Adjusted results were derived using inverse probability weighted regression adjustment (IPW-RA) estimators based on covariates that included demographics, comorbidities, patient clinical characteristics, and hospital characteristics. Results: The study identified 29,124 Cesarean section patients (24,612 oral APAP; 4,512 IV APAP) and 9,767 hysterectomy surgery patients (5,586 oral APAP; 4,181 IV APAP). Compared to the oral APAP group, the IV APAP group had reductions in adjusted LOS (Cesarean section: -11.7% days (P < 0.001), hysterectomy: -11.8% days (P = 0.005)), lowered adjusted daily MME consumption from day 0 to day 3 (Cesarean section: -1.6 mg (P < 0.001), hysterectomy: -1.7 mg (P = 0.014)), and reduced risk of ORADEs for Cesarean sections (relative risk of 0.45, P < 0.001). Total pharmacy costs were not significantly different between the two APAP groups. Conclusions: Post surgical pain managed with IV APAP in patients undergoing Cesarean section or hysterectomy was associated with shorter LOS, reduced risk of ORADEs, and lower opioid consumption compared to patients managed with oral APAP, without adversely impacting total pharmacy costs. PMID- 29707093 TI - Pulsed Radiofrequency as a Minimally Invasive Treatment Option in Anterior Cutaneous Nerve Entrapment Syndrome: A Retrospective Analysis of 26 Patients. AB - Background: Chronic abdominal pain is occasionally due to entrapped intercostal nerve endings (ACNES, abdominal cutaneous nerve entrapment syndrome). If abdominal wall infiltration using an anesthetic agent is unsuccessful, a neurectomy may be considered. Pulsed radiofrequency (PRF) is a relatively new treatment option for various chronic pain syndromes. Evidence regarding a beneficial effect of this minimally invasive technique in ACNES is lacking. The aim was to assess the effectiveness of PRF treatment in ACNES patients. Methods: A series of ACNES patients undergoing PRF treatment between January 2014 and December 2015 in two hospitals were retrospectively evaluated. Pain was recorded prior to treatment and after 6 weeks using a numerical rating scale (NRS, 0 (no pain) to 10 (worst possible pain)). Successful treatment was defined as > 50% NRS pain reduction. Patient satisfaction was scored by patient global impression of change (PGIC, 1 = very much worse, to 7 = very much improved). Results: Twenty six patients were studied (17 women, median age 47 years, range 18 - 67 years). After 6 weeks, mean NRS score had dropped from 6.7 +/- 1.2 to 3.8 +/- 2.3 (P < 0.001). A mean 4.9 +/- 1.4 PGIC score was reported by then. Short term treatment success (6 - 8 weeks) was 50% (n = 13, 95% CI: 29 - 71), while 8% was pain-free on the longer term (median 15 months). Median effect duration was 4 months (range 2 - 26). Conclusions: PRF is temporarily effective in half of patients with ACNES. PRF is safe and may be favored in neuropathic pain syndromes as nerve tissue destruction is possibly limited. A randomized controlled trial determining the potential additional role of PRF in the treatment strategy for ACNES is underway. PMID- 29707094 TI - Depressed Women of Low Socioeconomic Status Have High Numbers of Physician Visits in the Year Before Pregnancy: Implications for Care. AB - Background: There is a higher prevalence of depression in women of low socioeconomic status (SES) than other women. Further, previous depression is the best predictor of future depression. Therefore, due to the negative effects of maternal depression on the fetus and subsequent child, particularly in combination with low SES, depression is ideally treated before pregnancy. During the year before pregnancy and by SES, we aimed to assess the odds of a physician visit associated with maternal depression and the mean number of physician visits in women by depressive status. Methods: We used population-based registry data of 243,933 women with 348,273 singleton live births in British Columbia from 1999 - 2009 and estimated family SES decile using tax-file data. Mixed effects logistic regression, adjusting for maternal age and parity, was used to calculate odds ratios and a two-sided, two-sample test was used to compare proportions. STATA 14 was used for analyses. Results: Compared to women of middle SES (Decile-6), women of low SES (from Decile-1, Decile-2) had higher odds of more than 20 physician visits whether depressed (aOR = 1.46 (95% CI: (1.15, 1.86); aOR = 1.26 (95% CI: (0.98, 1.61)) or non-depressed (aOR = 1.26 (95% CI: (1.13, 1.41); aOR = 1.24 (95% CI: (1.11, 1.38)) during the year before pregnancy. During pre-pregnancy, depressed women had more than three times the mean number of physician visits than non-depressed women: (8.56 (8.38, 8.73) versus (2.59 (2.57, 2.61), P < 0.00005. Conclusions: Physicians have ample opportunities to assess women of child-bearing age for depression and to refer for appropriate treatment. It is particularly important that physicians pay extra attention to identify depression in those of lower SES who are likely to become pregnant. Further, identifying depression and providing appropriate referral for treatment in all women who are likely to become pregnant, are already pregnant or are caring for children is important. In such a way, the possible negative effects of prenatal and post partum depression, along with the interactive effects of low SES on the child, might be reduced. PMID- 29707095 TI - A Case of a Reversible Neurologic Adverse Reaction to Apixaban Confirmed by Re Challenge. AB - Post-marketing reporting of adverse drug events is essential for new medications, as pre-FDA approval studies lack sufficient subject numbers to detect signals for rare events. Prescriptions for the novel oral anticoagulant factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) have equaled or exceeded those for vitamin K antagonists in many clinical settings requiring chronic anticoagulation, and those of injectable heparins for deep vein thrombosis prophylaxis. We report the case of a 60-year-old woman followed for permanent atrial fibrillation who was prescribed apixaban. She rapidly developed worsening neurologic symptoms of imbalance and non-vertiginous dizziness preventing her from walking, headache, diplopia, and confusion/disorientation. Her symptoms began to resolve after stopping the drug, with return to baseline function within 72 h. Unbeknownst to her cardiology care team, the patient chose to re-challenge herself with apixaban at the same dose, producing identical symptoms and again total symptom resolution within 24 h of drug discontinuation. When seen by her physician, her physical examination was unchanged from her pre-treatment baseline. Symptoms did not recur when switched to rivaroxaban therapy. PMID- 29707096 TI - Dissecting Vertebral Artery Aneurysm Presenting Regrowth After Stent-Assisted Coil Embolization in Acute Stage. AB - For a case of dissecting vertebral artery aneurysm (DVAA) in a dominant vertebral artery (VA) or posterior inferior cerebellar artery (PICA)-involving lesion, stent-assisted coil embolization (SACE) is an effective technique to preserve blood flow of the VA. A 41-year-old man presented with subarachnoid hemorrhage. Angiography demonstrated DVAA on the left VA just distal to the PICA, and the right VA was thinner than the left. For this case, SACE was performed to preserve the left VA and PICA. On the 10th day, angiography showed recurrence of the dissection. The dissected portion had thickened and extended to both distal and proximal sides involving the PICA origin and proximal portion to the PICA. A second endovascular embolization was performed and the recurrent dissecting aneurysm was embolized including the main VA cavity. In cases of DVAA, there is a possibility of recurrence after SACE, if a dissecting cavity remains unembolized. Therefore, total embolization is necessary under close observation from multiple angles, including the down-the-barrel view. PMID- 29707097 TI - Ice Nucleation Activity of Graphene and Graphene Oxides. AB - Aerosols can act as cloud condensation nuclei and/or ice-nucleating particles (INPs), influencing cloud properties. In particular, INPs show a variety of different and complex mechanisms when interacting with water during the freezing process. To gain a fundamental understanding of the heterogeneous freezing mechanisms, studies with proxies for atmospheric INPs must be performed. Graphene and its derivatives offer suitable model systems for soot particles, which are ubiquitous aerosols in the atmosphere. In this work, we present an investigation of the ice nucleation activity (INA) of different types of graphene and graphene oxides. Immersion droplet freezing experiments as well as additional analytical analyses, such as X-ray photoelectron spectroscopy, Raman spectroscopy, and transmission electron microscopy, were performed. We show within a group of samples that a highly ordered graphene lattice (Raman G band intensity >50%) can support ice nucleation more effectively than a lowly ordered graphene lattice (Raman G band intensity <20%). Ammonia-functionalized graphene revealed the highest INA of all samples. Atmospheric ammonia is known to play a primary role in the formation of secondary particulate matter, forming ammonium-containing aerosols. The influence of functionalization on interactions between the particle interface and water molecules, as well as on hydrophobicity and agglomeration processes, is discussed. PMID- 29707099 TI - Ordering of Air-Oxidized Decanethiols on Au(111). AB - Self-assembled monolayers (SAMs) of alkanethiols on gold are a commonly used platform for nanotechnology owing to their ease of preparation and high surface coverage. Unfortunately, the gold-sulfur bond is oxidized at ambient conditions which alters the stability and structure of the monolayer. We show using scanning tunneling microscopy and X-ray photoelectron spectroscopy that decanethiolate molecules oxidize into decanesulfonates that organize into a hitherto unknown striped phase. Air-exposed SAMs oxidize, as can be determined by a shift of the S 2p peak and the appearance of O 1s photoelectrons as part of the decanethiol monolayer transforms into a lamellae-like decanesulfonate structure when exposed to air. The herringbone structure of the Au(111) surface is preserved, indicating that the interaction between the molecules and the surface is rather weak as these findings are substantiated by density functional theory calculations. PMID- 29707098 TI - Optimum Particle Size for Gold-Catalyzed CO Oxidation. AB - The structure sensitivity of gold-catalyzed CO oxidation is presented by analyzing in detail the dependence of CO oxidation rate on particle size. Clusters with less than 14 gold atoms adopt a planar structure, whereas larger ones adopt a three-dimensional structure. The CO and O2 adsorption properties depend strongly on particle structure and size. All of the reaction barriers relevant to CO oxidation display linear scaling relationships with CO and O2 binding strengths as main reactivity descriptors. Planar and three-dimensional gold clusters exhibit different linear scaling relationship due to different surface topologies and different coordination numbers of the surface atoms. On the basis of these linear scaling relationships, first-principles microkinetics simulations were conducted to determine CO oxidation rates and possible rate determining step of Au particles. Planar Au9 and three-dimensional Au79 clusters present the highest CO oxidation rates for planar and three-dimensional clusters, respectively. The planar Au9 cluster is much more active than the optimum Au79 cluster. A common feature of optimum CO oxidation performance is the intermediate binding strengths of CO and O2, resulting in intermediate coverages of CO, O2, and O. Both these optimum particles present lower performance than maximum Sabatier performance, indicating that there is sufficient room for improvement of gold catalysts for CO oxidation. PMID- 29707100 TI - Scalable Bayesian nonparametric measures for exploring pairwise dependence via Dirichlet Process Mixtures. AB - In this article we propose novel Bayesian nonparametric methods using Dirichlet Process Mixture (DPM) models for detecting pairwise dependence between random variables while accounting for uncertainty in the form of the underlying distributions. A key criteria is that the procedures should scale to large data sets. In this regard we find that the formal calculation of the Bayes factor for a dependent-vs.-independent DPM joint probability measure is not feasible computationally. To address this we present Bayesian diagnostic measures for characterising evidence against a "null model" of pairwise independence. In simulation studies, as well as for a real data analysis, we show that our approach provides a useful tool for the exploratory nonparametric Bayesian analysis of large multivariate data sets. PMID- 29707101 TI - Towards a Multidimensional Approach to Bayesian Disease Mapping. AB - Multivariate disease mapping enriches traditional disease mapping studies by analysing several diseases jointly. This yields improved estimates of the geographical distribution of risk from the diseases by enabling borrowing of information across diseases. Beyond multivariate smoothing for several diseases, several other variables, such as sex, age group, race, time period, and so on, could also be jointly considered to derive multivariate estimates. The resulting multivariate structures should induce an appropriate covariance model for the data. In this paper, we introduce a formal framework for the analysis of multivariate data arising from the combination of more than two variables (geographical units and at least two more variables), what we have called Multidimensional Disease Mapping. We develop a theoretical framework containing both separable and non-separable dependence structures and illustrate its performance on the study of real mortality data in Comunitat Valenciana (Spain). PMID- 29707102 TI - The pivotal role of inflammation in scar/keloid formation after acne. AB - Most keloids are clinically observed as solid nodules or claw-like extensions. However, they appear hypoechoic on ultrasound images and are therefore easily confused with liquid features such as blood or vessels. The pathological manifestations of typical keloids also include prominent, thick blood vessels. The existing classification of scars fails to reflect the natural history of keloids. The outer characteristics of a typical keloid include bright red hyperplasia with abundant vessels, suggesting the importance of vascular components in the process of scar formation and prompting consideration of the role of inflammation in the development of granular hyperplasia. Additionally, we further considered the potential effectiveness of oral isotretinoin for severe keloids secondary to severe acne. We also explored different principles and applications related to 5-fluorouracil (5-FU), pulsed dye laser (PDL), and CO2 laser treatments for scars. PMID- 29707103 TI - NF-kappaB promotes the stem-like properties of leukemia cells by activation of LIN28B. AB - AIM: To examine whether nuclear factor kappa B (NF-kappaB) activity regulates LIN28B expression and their roles in leukemia stem cell (LSC)-like properties. METHODS: We used pharmacological inhibitor and cell viability assays to examine the relation between NF-kappaB and LIN28B. Western blot and qRT-PCR was employed to determine their protein and mRNA levels. Luciferase reporter was constructed and applied to explore the transcriptional regulation of LIN28B. We manipulated LIN28B level in acute myeloid leukemia (AML) cells and investigated LSC-like properties with colony forming and serial replating assays. RESULTS: This study revealed the relationship between NF-kappaB and LIN28B in AML cells through drug inhibition and overexpression experiments. Notably, inhibition of NF-kappaB by pharmacological inhibitors reduced LIN28B expression and decreased cell proliferation. We demonstrated that NF-kappaB binds to the -819 to -811 region of LIN28B promoter, and transcriptionally regulates LIN28B expression. LIN28B protein was significantly elevated in NFkappaB1 transfected cells compared to vector control. Importantly, ectopic expression of LIN28B partially rescued the self-renewal capacity impaired by pharmacological inhibition of NF-kappaB activity. CONCLUSION: These results uncover a regulatory signaling, NF kappaB/LIN28B, which plays a pivotal role in leukemia stem cell-like properties and it could serve as a promising intervening target for effective treatment of AML disease. PMID- 29707104 TI - The Effects of Synthesized Rhenium Acetylsalicylate Compounds on Human Astrocytoma Cell Lines. AB - Purpose: Because of the scarcity of suitable brain cancer drugs, researchers are frantically trying to discover novel and highly potent drugs free of side effects and drug-resistance. Rhenium compounds are known to be nontoxic and exhibit no drug resistance. For that reason, we have developed a series of novel rhenium acetylsalicylato (RAC or ASP) complexes to test their cytotoxicity on brain cancer cells. Also we have attempted to explore the DNAbinding properties of these compounds because many drugs either directly or indirectly bind to DNA. Methods: We have treated the RAC series compounds on human astrocytoma brain cancer cell lines and rat normal brain astrocyte cells and determined the efficacy of these complexes through in vitro cytotoxicity assay. We carried out the DNA-binding study through UV titrations of a RAC compound with DNA. Also we attempted to determine the planarity of the polypyridyl ligands of the RAC series compounds using DFT calculations. Results: RAC6 is more potent than any other RAC series compounds on HTB-12 human astrocytoma cancer cells as well as on Glioblastoma Multiforme D54 cell lines. In fact, The IC-50 value of RAC6 on HTB 12 cancer cells is approximately 2 MUM. As expected, the RAC series compounds were not active on normal cells. The DFT calculations on the RAC series compounds were done and suggest that the polypyridyl ligands in the complexes are planar. The UV-titrations of RAC9 with DNA were carried out. It suggests that RAC9 and possibly all RAC series compounds bind to minor grooves of the DNA. Conclusion: Because of the very low activity of RAC6 on normal cells and low lC50 value of on astrocytoma (HTB-12) cell lines, it is possible that RAC6 and its derivatives may potentially find application in the treatment of brain cancers. The DFT calculations and UV titrations suggest that RAC series compounds either bind to DNA intercalatively or minor grooves of the DNA or both. However, it is highly premature to make any definite statement in the absence of other techniques. PMID- 29707105 TI - Adherence to surveillance endoscopy following hospitalization for index esophageal variceal hemorrhage. AB - AIM: To investigate patient adherence to surveillance endoscopy after index esophageal variceal hemorrhage and the extent to which adherence influences outcomes. METHODS: We reviewed the records of patients with cirrhosis admitted to the medical intensive care unit between 2000 and 2014 for first time esophageal variceal hemorrhage treated with endoscopic variceal ligation who were subsequently discharged and scheduled for surveillance endoscopy at our medical center. Demographic and clinical data were obtained through the medical records, including etiology of cirrhosis, completion of variceal obliteration, attendance at surveillance endoscopy, zip code of primary residence, distance from home to hospital, insurance status, rehospitalization for variceal hemorrhage, beta blocker at discharge, pharmacologically treated psychiatric disorder, and transplant free survival. RESULTS: Of 99 consecutive survivors of esophageal variceal bleeding, the minority (33) completed variceal obliteration and fewer (12) adhered to annual surveillance. Completion of variceal obliteration was associated with fewer rehospitalizations for variceal rebleeding (27% vs 56%, P = 0.0099) and when rehospitalizations occurred, they occurred later in those who had completed obliteration (median 259 d vs 207 d, P = 0.0083). Incomplete adherence to endoscopic surveillance was associated with more rehospitalizations for variceal rebleeding compared to those fully adherent to annual endoscopic surveillance (51% vs 17%, P = 0.0328). Those adherent to annual surveillance were more likely to be insured privately or through Medicare compared to those who did not attend post-hospital discharge endoscopy (100% vs 63%, P = 0.0119). CONCLUSION: Most patients do not complete variceal obliteration after index esophageal variceal hemorrhage and fewer adhere to endoscopic surveillance, particularly the uninsured and those insured with Medicaid. PMID- 29707106 TI - Inhibition of aldose-reductase-2 by a benzofuroxane derivative bf-5m increases the expression of kcne1, kcnq1 in high glucose cultured H9c2 cardiac cells and sudden cardiac death. AB - Long QT syndrome (LQTS) is characterized by prolonged QT interval, leading to sudden cardiac death. Hyperglycemia is an important risk factor for LQTS, inhibiting the cardiac rapid component delayed rectifier K+ current (Iks), responsible for QT interval. We previously showed that the new ALR2 inhibitor BF 5m supplies cardioprotection from QT prolongation induced by high glucose concentration in the medium, reducing QT interval prolongation and preserving morphology. Here we investigated the effects of BF-5m on cell cytotoxicity and viability in H9c2 cells, and on cellular potassium ion channels expression. H9c2 cells were grown in medium with high glucose and high glucose plus the BF-5m by assessing the cytotoxic effects and the cell survival rate. In addition, KCNE1 and KCNQ1 expression in plasma and mitochondrial membranes were monitored. Also, the expression levels of miR-1 proved to suppress KCNQ1 and KCNE1, were analyzed. BF-5m treatment reduced the cytotoxic effects of high glucose on H9c2 cells by increasing cell survival rate and improving H9c2 morphology. Plasmatic KCNE1 and KCNQ1 expression levels were restored by BF-5m in H9c2 exposed to high glucose, down-regulating miR-1. These results suggest that BF-5m exerts cardioprotection from high glucose in rat heart ventricle H9c2 cells exposed to high glucose. PMID- 29707107 TI - Selective inhibition of BCL-2 is a promising target in patients with high-risk myelodysplastic syndromes and adverse mutational profile. AB - Somatic mutations in genes such as ASXL1, RUNX1, TP53 or EZH2 adversely affect the outcome of patients with myelodysplastic syndromes (MDS). Since selective BCL 2 inhibition is a promising treatment strategy in hematologic malignancies, we tested the therapeutic impact of ABT-199 on MDS patient samples bearing an adverse mutational profile. By gene expression, we found that the level of pro apoptotic BIM significantly decreased during MDS disease progression in line with an acquired resistance to cell death. Supporting the potential for ABT-199 treatment in MDS, high-risk MDS patient samples specifically underwent cell death in response to ABT-199 even when harbouring mutations in ASXL1, RUNX1, TP53 or EZH2. ABT-199 effectively targeted the stem- and progenitor compartment in advanced MDS harbouring mutations in ASXL1, RUNX1, TP53 or EZH2 and even proved effective in patients harbouring more than one of the defined high-risk mutations. Moreover, we utilized the protein abundance of BCL-2 family members in primary patient samples using flow cytometry as a biomarker to predict ABT-199 treatment response. Our data demonstrate that ABT-199 effectively induces apoptosis in progenitors of high-risk MDS/sAML despite the presence of adverse genetic mutations supporting the notion that pro-apoptotic intervention will hold broad therapeutic potential in high-risk MDS patients with poor prognosis. PMID- 29707108 TI - Glioblastoma-specific anti-TUFM nanobody for in-vitro immunoimaging and cancer stem cell targeting. AB - Glioblastoma multiforme (GBM) is the most common and lethal form of brain tumor. The prognosis for patients remains poor, despite the combination of new preoperative and intraoperative neuroimaging, radical surgery, and recent advances in radiotherapy and chemotherapy. To improve GBM therapy and patient outcome, sustained drug delivery to glioma cells is needed, while minimizing toxicity to adjacent neurons and glia cells. This might be achieved through an anti-proteomic approach based on nanobodies, the single-domain antigen-binding fragments of heavy-chain antibodies of the camelid adaptive immune system. We report here on the validation and quantification of a nanobody raised against mitochondrial translation elongation factor (TUFM). Differential expression of TUFM was examined in different GBM cell lines and GBM tissue at the protein and mRNA levels, as compared to their expression in neural stem cells and normal brain tissue. We further used in-silico modelling and immunocytochemistry to define the specificity of anti-TUFM nanobody (Nb206) towards GBM stem cells, as compared to GBM cell lines (U251MG and U87MG cells). Due to its specificity and pronounced inhibitory effect on GBM stem cell growth, we propose the use of this anti-TUFM nanobody for GBM in vitro immunoimaging and potentially also cancer stem cell targeting. PMID- 29707109 TI - MiR-21 over-expression and Programmed Cell Death 4 down-regulation features malignant pleural mesothelioma. AB - Background: Differential diagnosis between malignant pleural mesothelioma (MPM) and benign mesothelial conditions is still challenging and there is a lack of useful markers. Programmed cell death 4 (PDCD4) is a well-known tumor suppressor gene in several cancers, its post-transcriptional activity is directly controlled by miR-21, whose over-expression has been recently reported in MPM compared to normal mesothelium. Aim of this study was to test this suppressor gene as a possible new marker of malignant transformation in mesothelial cells, as well as a new prognostic marker. Methods: PDCD4 nuclear expression was assessed by immunohistochemistry (IHC) in 40 non-neoplastic pleural (NNP) and 40 MPM formalin fixed and paraffin-embedded specimens. PDCD4 and miR-21 expressions were analyzed by qRT-PCR in all cases. In situ hybridization (ISH) of miR-21 was performed in 5 representative cases of both groups. The prognostic relevance of PDCD4 was assessed in a public available gene expression dataset. Results: IHC showed that PDCD4 nuclear expression was significantly lower in MPM than in NNP. PDCD4 was down-regulated, whereas miR-21 was over-expressed in MPM cases compared to NNP ones. ISH detected miR-21 only in MPM specimens. Down-expression of PDCD4 was found significantly associated with short overall survival in publicly available data. Conclusions: These findings highlighted a switch between PDCD4 and miR-21 expression in MPM. Further studies should assess the diagnostic reliability of these two markers for MPM in biopsy and effusion specimens. PMID- 29707111 TI - 3D laparoscopic surgery: a prospective clinical trial. AB - Since it's introduction, laparoscopic surgery represented a real revolution in clinical practice. The use of a new generation three-dimensional (3D) HD laparoscopic system can be considered a favorable "hybrid" made by combining two different elements: feasibility and diffusion of laparoscopy and improved quality of vision. In this study we report our clinical experience with use of three dimensional (3D) HD vision system for laparoscopic surgery. Between 2013 and 2017 a prospective cohort study was conducted at the University Hospital of Palermo. We considered 163 patients underwent to laparoscopic three-dimensional (3D) HD surgery for various indications. This 3D-group was compared to a retrospective prospective control group of patients who underwent the same surgical procedures. Considerating specific surgical procedures there is no significant difference in term of age and gender. The analysis of all the groups of diseases shows that the laparoscopic procedures performed with 3D technology have a shorter mean operative time than comparable 2D procedures when we consider surgery that require complex tasks. The use of 3D laparoscopic technology is an extraordinary innovation in clinical practice, but the instrumentation is still not widespread. Precisely for this reason the studies in literature are few and mainly limited to the evaluation of the surgical skills to the simulator. This study aims to evaluate the actual benefits of the 3D laparoscopic system integrating it in clinical practice. The three-dimensional view allows advanced performance in particular conditions, such as small and deep spaces and promotes performing complex surgical laparoscopic procedures. PMID- 29707110 TI - Characterization of miRNA and their target gene during chicken embryo skeletal muscle development. AB - MicroRNAs (miRNAs) are non-coding RNAs that regulate mRNA expression by degradation or translational inhibition. We investigated the underlying molecular mechanisms of skeletal muscle development based on differentially expressed genes and miRNAs. We compared mRNA and miRNA from chicken skeletal muscle at embryonic day E11, E16 and one day post-hatch (P1). The interaction networks were constructed, according to target prediction results and integration analysis of up-regulated genes with down regulated miRNAs or down-regulated genes with up regulated miRNAs with |log2fold change| >= 1.75, P < 0.005. The miRNA-mRNA integration analysis showed high number of mRNAs regulated by a few number of miRNAs. In the E11_VS_E16, comparison group we identified biological processes including muscle maintenance, myoblast proliferation and muscle thin filament formation. The E11_VS_P1 group comparison included negative regulation of axon extension, sarcomere organization, and cell redox homeostasis and kinase inhibitor activity. The E16_VS_P1 comparison group contained genes for the negative regulation of anti-apoptosis and axon extension as well as glomerular basement membrane development. Functional in vitro assays indicated that over expression of miR-222a and miR-126-5p in DF-1 cells significantly reduced the mRNA levels of the target genes CPEB3 and FGFR3, respectively. These integrated analyses provide several candidates for future studies concerning miRNAs-target function on regulation of embryonic muscle development and growth. PMID- 29707113 TI - In silico prediction of targets for anti-angiogenesis and their in vitro evaluation confirm the involvement of SOD3 in angiogenesis. AB - Biocomputational network approaches are being successfully applied to predict and extract previously unknown information of novel molecular components of biological systems. In the present work, we have used this approach to predict new potential targets of anti-angiogenic therapies. For experimental validation of predictions, we made use of two in vitro assays related to two key steps of the angiogenic process, namely, endothelial cell migration and formation of "tubular-like" structures on Matrigel. From 7 predicted candidates, experimental tests clearly show that superoxide dismutase 3 silencing or blocking with specific antibodies inhibit both key steps of angiogenesis. This experimental validation was further confirmed with additional in vitro assays showing that superoxide dismutase 3 blocking produces inhibitory effects on the capacity of endothelial cells to form "tubular-like" structure within type I collagen matrix, to adhere to elastin-coated plates and to invade a Matrigel layer. Furthermore, angiogenesis was also inhibited in the en vivo aortic ring assay and in the in vivo mouse Matrigel plug assay. Therefore, superoxide dismutase 3 is confirmed as a putative target for anti-angiogenic therapy. PMID- 29707114 TI - An autophagy-related gene expression signature for survival prediction in multiple cohorts of hepatocellular carcinoma patients. AB - Prognostic signatures have been proposed as clinical tools to estimate prognosis in hepatocellular carcinoma (HCC), which is the second most common contributor to cancer-related death at present globally. Autophagy-related genes play a dynamic and fundamental role in HCC, but knowledge of their utility as prognostic markers is limited. Here, we facilitated univariate and multivariate Cox proportional hazards regression analyses to reveal that 3 autophagy-related genes (BIRC5, FOXO1 and SQSTM1) were closely related to the survival of HCC. Then, we generated a prognosis index (PI) for predicting overall survival (OS) based on the three genes, which was an independent prognostic indicator for the OS of HCC (HR = 1.930, 95% CI: 1.200-3.104, P = 0.007). The PI showed moderate performance for predicting the survival of HCC patients and its efficacy was validated by data from three microarrays (GSE10143, GSE10186 and GSE17856). Furthermore, we deeply mined the integrated large-scale datasets from public microarrays and immunohistochemistry to validate the overexpression of BIRC5 and SQSTM1 while down-regulated FOXO1 expression in HCC. Bioinformatic analysis offered the hypothesis that proliferative signals in high-risk HCC patients were disturbing and thereby facilitated inferior clinical outcomes. Collectively, the prognostic signature we proposed is a promising biomarker for monitoring outcome of HCC. Nevertheless, prospective experimental studies are needed to validate the clinical utility. PMID- 29707112 TI - Full in-frame exon 3 skipping of BRCA2 confers high risk of breast and/or ovarian cancer. AB - Germline pathogenic variants in the BRCA2 gene are associated with a cumulative high risk of breast/ovarian cancer. Several BRCA2 variants result in complete loss of the exon-3 at the transcript level. The pathogenicity of these variants and the functional impact of loss of exon 3 have yet to be established. As a collaboration of the COVAR clinical trial group (France), and the ENIGMA consortium for investigating breast cancer gene variants, this study evaluated 8 BRCA2 variants resulting in complete deletion of exon 3. Clinical information for 39 families was gathered from Portugal, France, Denmark and Sweden. Multifactorial likelihood analyses were conducted using information from 293 patients, for 7 out of the 8 variants (including 6 intronic). For all variants combined the likelihood ratio in favor of causality was 4.39*1025. These results provide convincing evidence for the pathogenicity of all examined variants that lead to a total exon 3 skipping, and suggest that other variants that result in complete loss of exon 3 at the molecular level could be associated with a high risk of cancer comparable to that associated with classical pathogenic variants in BRCA1 or BRCA2 gene. In addition, our functional study shows, for the first time, that deletion of exon 3 impairs the ability of cells to survive upon Mitomycin-C treatment, supporting lack of function for the altered BRCA2 protein in these cells. Finally, this study demonstrates that any variant leading to expression of only BRCA2 delta-exon 3 will be associated with an increased risk of breast and ovarian cancer. PMID- 29707115 TI - Clinical implication of a quantitative frailty assessment tool for prognosis in patients with urological cancers. AB - Objectives: Optimal tools for evaluating frailty among urological cancer patients remain unclear. We aimed to develop a quantitative frailty assessment tool comparing healthy individuals and urological cancer patients, and investigate the clinical implication of quantitative frailty on prognosis in urological cancer patients. Results: Gait speed, hemoglobin, serum albumin, exhaustion, and depression were significantly worse in patients with all types of cancers than in pair-matched controls. Frailty discriminant score (FDS) showed clear separation between controls and urological cancer patients, and significant association with the Fried criteria. Overall survivals were significantly shorter in patients with a higher score (>2.30) than in those with a lower score among nonprostate cancer (bladder, upper tract urothelial carcinoma, and renal cell carcinoma) patients. In prostate cancer patients, overall survivals were significantly shorter in patients with a higher score (>3.30) than in those with a lower score. Conclusions: FDS was significantly associated with frailty and prognosis in urological cancer patients. This tool for frailty assessment can help patients and physicians make more informed decisions. Further validation study is needed. Materials and Methods: Total 605 urological cancer patients presenting to our hospital underwent a prospective frailty assessment. Controls were selected from 2280 community-dwelling subjects. Frailty was assessed via physical status, blood biochemical tests, and mental status. We compared frailty variables between pair matched controls and urological cancer patients. We developed FDS using frailty variables, and compared with the Fried criteria. The influence of FDS on overall survivals was investigated by Kaplan-Meier analysis and Cox regression analysis. PMID- 29707116 TI - The role of particulate matters on methylation of IFN-gamma and IL-4 promoter genes in pediatric allergic rhinitis. AB - Allergic rhinitis (AR) is a chronic inflammatory disorder driven by T cell activation. How particulate matter contributes to epigenetic changes that in turn influence cytokine gene expression in CD4+T cells remains unclear. In this study, 105 children diagnosed with AR and 90 healthy controls were recruited to explore the possible mechanism of particulate matter (PM) on the epigenetic regulation of CD4+T IFN-gamma and IL-4 promoter genes. Daily average PM10 and PM2.5 were obtained from five state-controlled monitoring stations, and activity-based dynamic exposure and personal exposure data were collected. DNA methylation patterns of IFN-gamma and IL-4 promoter regions were analyzed using bisulfite sequencing. mRNA levels were detected by real-time quantitative reverse transcription polymerase chain reaction. We found that the methylation rate in IFN-gamma was higher in AR CD4+T cells than in the controls. IFN-gamma mRNA expression was significantly decreased in CD4+T cells, and negatively correlated with the mean methylation level of IFN-gamma. However, no correlation between IL 4 methylation and IL-4 mRNA expression was found. After adjusting for age, gender, exclusive breastfeeding within 4 months after birth and parental history of allergic disease, out data showed that PM2.5 exposure level was positively correlated with methylation level in IFN-gamma promoter region and decreased cytokine expression. We conclude that the effect of PM2.5 on pediatric AR may be mediated through epigenetic modification of IFN-gamma promoter region. PMID- 29707117 TI - Impact of tobacco smoking on the risk of developing 25 different cancers in the UK: a retrospective study of 422,010 patients followed for up to 30 years. AB - Background: The aim of this study was to analyze the impact of tobacco smoking on the risk of developing 25 different cancers in patients followed for up to 30 years in general practices in the UK. Methods: This study included all individuals with at least one visit to one of 196 general practitioners' offices in the UK between January 1988 and December 2008 (index date). Only individuals with documented smoking status were included. Smokers and non-smokers were matched (1:1) by age, gender, index year, body mass index, and physician. The main outcome of the study was the risk of cancer as a function of smoking status. Data regarding a total of 25 cancers were available for the present analysis. The risk of cancer was analyzed using Cox's regression model. Results: The present retrospective study included 211,005 smokers and 211,005 non-smokers. The mean age was 36.5 years (SD = 12.5 years) in men and 34.3 years (SD = 13.1 years) in women. There was a slightly positive association between smoking and any cancer in both men (HR = 1.07) and women (HR = 1.03). Smoking was further found to be positively associated with several cancers, such as liver cancer, bladder and kidney cancers, pancreas cancer, and lymphoma. By contrast, the use of tobacco was negatively associated with the risk of developing skin cancer, prostate cancer, multiple myeloma, endometrial carcinoma, or breast cancer. Conclusions: Smoking increased the overall risk of cancer in primary care practices in the UK. In addition, smoking was predominantly positively and less frequently negatively associated with numerous specific cancers. PMID- 29707118 TI - Identification of a serum biomarker panel for the differential diagnosis of cholangiocarcinoma and primary sclerosing cholangitis. AB - The non-invasive differentiation of malignant and benign biliary disease is a clinical challenge. Carbohydrate antigen 19-9 (CA19-9), leucine-rich alpha2 glycoprotein (LRG1), interleukin 6 (IL6), pyruvate kinase M2 (PKM2), cytokeratin 19 fragment (CYFRA21.1) and mucin 5AC (MUC5AC) have reported utility for differentiating cholangiocarcinoma (CCA) from benign biliary disease. Herein, serum levels of these markers were tested in 66 cases of CCA and 62 cases of primary sclerosing cholangitis (PSC) and compared with markers of liver function and inflammation. Markers panels were assessed for their ability to discriminate malignant and benign disease. Several of the markers were also assessed in pre diagnosis biliary tract cancer (BTC) samples with performances evaluated at different times prior to diagnosis. We show that LRG1 and IL6 were unable to accurately distinguish CCA from PSC, whereas CA19-9, PKM2, CYFRA21.1 and MUC5AC were significantly elevated in malignancy. Area under the receiver operating characteristic curves for these individual markers ranged from 0.73-0.84, with the best single marker (PKM2) providing 61% sensitivity at 90% specificity. A panel combining PKM2, CYFRA21.1 and MUC5AC gave 76% sensitivity at 90% specificity, which increased to 82% sensitivity by adding gamma glutamyltransferase (GGT). In the pre-diagnosis setting, LRG1, IL6 and PKM2 were poor predictors of BTC, whilst CA19-9 and C-reactive protein were elevated up to 2 years before diagnosis. In conclusion, LRG1, IL6 and PKM2 were not useful for early detection of BTC, whilst a model combining PKM2, CYFRA21.1, MUC5AC and GGT was beneficial in differentiating malignant from benign biliary disease, warranting validation in a prospective trial. PMID- 29707119 TI - IL-6 influences the polarization of macrophages and the formation and growth of colorectal tumor. AB - Macrophages play a crucial role in tumorigenesis depending upon the phenotype of macrophages found in tumor microenvironments. To date, how the tumor microenvironment affects the phenotypes of macrophages is not yet fully understood. In this study, we constructed a NIH3T3/Src cell line stably overexpresses the Src protein and found that conditioned medium from this cell line was able to induce polarization towards the M2 phenotype in primary bone marrow-derived macrophages (BMDM) and Ana-1 macrophages. Further investigation revealed that IL-6 produced by NIH3T3/Src cells plays a key role in M2 polarization. During the development of colorectal cancer in C57BL/6J-ApcMin/+ mice, increased IL-6 secretion in the interstitial fluid of the colorectal tissues was observed. Furthermore, tumorigenesis in IL-6tm1Kopf mice treated with AOM-DSS, an IL-6 knockout mouse strain, was significantly inhibited compared with the control group, suggesting the important role of IL-6 in promoting tumorigenicity. Our findings identify the target molecules and proinflammatory cytokines responsible for promoting polarization towards the M2 phenotype in macrophages present in tumor microenvironment, which may be useful for the design of novel therapeutic strategies for colorectal cancer. PMID- 29707120 TI - miRNA-based signatures in cerebrospinal fluid as potential diagnostic tools for early stage Parkinson's disease. AB - Parkinson's Disease is the second most common neurodegenerative disorder, affecting 1-2% of the elderly population. Its diagnosis is still based on the identification of motor symptoms when a considerable number of dopaminergic neurons are already lost. The development of translatable biomarkers for accurate diagnosis at the earliest stages of PD is of extreme interest. Several microRNAs have been associated with PD pathophysiology. Consequently, microRNAs are emerging as potential biomarkers, especially due to their presence in Cerebrospinal Fluid and peripheral circulation. This study employed small RNA sequencing, protein binding ligand assays and machine learning in a cross sectional cohort comprising 40 early stage PD patients and 40 well-matched controls. We identified a panel comprising 5 microRNAs (Let-7f-5p, miR-27a-3p, miR-125a-5p, miR-151a-3p and miR-423-5p), with 90% sensitivity, 80% specificity and 82% area under the curve (AUC) for the differentiation of the cohorts. Moreover, we combined miRNA profiles with hallmark-proteins of PD and identified a panel (miR-10b-5p, miR-22-3p, miR-151a-3p and alpha-synuclein) reaching 97% sensitivity, 90% specificity and 96% AUC. We performed a gene ontology analysis for the genes targeted by the microRNAs present in each panel and showed the likely association of the models with pathways involved in PD pathogenesis. PMID- 29707121 TI - FoxM1 is an independent poor prognostic marker and therapeutic target for advanced Middle Eastern breast cancer. AB - Breast cancer (BC) is the most common cause of cancer-related death in females in Saudi Arabia. BC in Saudi women tend to behave more aggressively than breast cancer in the West. Therefore, identification of new molecular targets and treatment strategies are highly warranted to improve patient outcome. FoxM1 has been shown to play a critical role in pathogenesis of various malignancies. In this study, we explored the prevalence and clinical implication of FoxM1 overexpression in Saudi breast cancer. FoxM1 protein overexpression was seen in 79% (770/975) of BC tissues and was associated with aggressive clinical parameters such as younger age (< 30 yrs) (p = 0.0172), high grade (p < 0.0001), mucinous histology (p < 0.0001) and triple negative phenotype (p < 0.0001). Overexpression of FoxM1 was significantly associated with activated AKT (p < 0.0001), Ki67 expression (p < 0.0001), VEGF (p < 0.0001), MMP-9 (p < 0.0001), XIAP (p < 0.0001) and Bcl-xL (p = 0.0300). Importantly, FoxM1 overexpression is found to be an independent prognostic marker in multivariate analysis in advanced stage (Stage III and IV) breast cancer (p = 0.0298). In vitro data using BC cell lines showed that down-regulation of FoxM1 using specific inhibitor, thiostrepton or siRNA inhibited cell migration, invasion and angiogenesis. In addition, treatment of BC cell lines with thiostrepton resulted in inhibition of proliferation and induction of apoptosis in a dose-dependent manner. In vivo, thiostrepton treatment regressed MDA-MB-231 cells generated xenografts via down regulation of FoxM1 and its downstream targets. Our results suggest that FoxM1 may be a potential therapeutic target for the treatment of aggressive breast cancers. PMID- 29707122 TI - Laser ablation is superior to TACE in large-sized hepatocellular carcinoma: a pilot case-control study. AB - Background: Limited therapies are available for large (>=40 mm) unresectable hepatocellular carcinoma (HCC). Currently, the standard treatment with transarterial chemoembolisation (TACE) is unsatisfactory with high recurrence rate and limited effect on survival. Laser Ablation (LA) has emerged as a relatively new technique characterized by high efficacy and good safety. This study is aimed to evaluate the efficacy of LA in comparison to TACE in patients with large HCC. Methods: Eighty-two patients with a single HCC nodule >=40 mm (BCLC stage A or B) were enrolled in this case-control study. Forty-one patients were treated with LA and 41 patients were treated with TACE. Response to therapy was evaluated according to the mRECIST criteria. Survival was calculated with Kaplan-Meier from the time of cancer diagnosis to death with values censored at the date of the last follow-up. Results: Twenty-six (63.4%) and 8 (19.5%) patients had a complete response after LA and TACE, respectively (p < 0.001). Subsequently we stratified the HCCs in 3 categories according to the nodule size: 40-50 mm, 51-60 mm, and >60 mm. LA resulted superior to TACE especially in nodules ranging between 51 and 60 mm in diameter, with a complete response rate post-LA and post-TACE of 75% and 14.3%, respectively (p = 0.0133). The 36 months cumulative survival rate in patients treated with LA and TACE was 55.4% and 48.8%, respectively. The disease recurrence rates after LA and TACE were 19.5% and 75.0%, respectively. Conclusions: LA is a more effective therapeutic option than TACE in patients with solitary large HCC. PMID- 29707123 TI - Undetectable or low (<1 ng/ml) postsurgical thyroglobulin values do not rule out metastases in early stage differentiated thyroid cancer patients. AB - Background: Differentiated thyroid cancer (DTC) work-up is based on (near)total thyroidectomy plus thyroid remnant ablation (TRA) with 131-radioiodine in many patients, and long-life follow-up. 131I-post therapy whole body scan (pT-WBS) and serum thyroglobulin (Tg) are used in identifying metastatic patients. Some authors have evaluated the possibility of using post-surgical Tg (ps-Tg) values in deciding for or against TRA. The aim of our study was to verify the diagnostic accuracy of 131I-pT-WBS and SPECT/CT imaging (post-therapeutic imaging) compared to serum Tg levels in detecting metastases in early stage of DTC patients. Results: Post-therapeutic imaging revealed metastases in 82 out of 570 (14.4%) patients. Metastases were successively confirmed by other diagnostic tools or by histology (sensitivity and PPV = 100%). Seventy-three out of 82 patients (90.2%) showed ps-Tg levels <=1 ng/ml. In fifty-four per cent of patients, serum Tg levels at TRA remained <=1 ng/ml. Conclusion: In conclusion, ps-Tg levels cannot be used in deciding for or against TRA. In early stage of DTC, post-therapeutic imaging (131I-pT-WBS and SPECT/CT) is an accurate method of detecting metastases, also in patients with stimulated serum Tg values <=1 ng/ml. Methods: We retrospectively reviewed the records of 570 consecutive patients affected by pT1 pT3 DTC (F = 450, M = 120), referred to our Nuclear Medicine Units in the last five years to perform TRA after (near)-total-thyroidectomy.All patients underwent TRA 3-4 months after thyroid surgery either in euthyroid or in hypothyroid state. Serum Tg values evaluated in post-surgical period and at TRA were matched with post-therapeutic imaging results. PMID- 29707124 TI - BRCA1/2 and TP53 mutation status associates with PD-1 and PD-L1 expression in ovarian cancer. AB - Checkpoint molecules such as programmed cell death protein-1 (PD-1) and its ligand PD-L1 are critically required for tumor immune escape. The objective of this study was to investigate tumoral PD-1 and PD-L1 mRNA-expression in a cohort of ovarian cancer (OC) patients in relation to tumor mutations. We analyzed mRNA expression of PD-1, PD-L1 and IFNG by quantitative real-time PCR in tissue of 170 patients with low grade-serous (LGSOC), high-grade serous (HGSOC), endometrioid and clear cell OC compared to 28 non-diseased tissues (ovaries and fallopian tubes) in relation to tumor protein 53 (TP53) and breast cancer gene 1/2 (BRCA1/2) mutation status. TP53-mutated OC strongly expressed PD-L1 compared to TP53 wild-type OC (p = 0.028) and BRCA1/2-mutated OC increasingly expressed PD-1 (p = 0.024) and PD-L1 (p = 0.012) compared to BRCA1/2 wild-type OC. For the first time in human, we noted a strong correlation between tumoral IFNG and PD-1 or PD L1 mRNA-expression, respectively (p < 0.001). OC tissue increasingly expressed PD 1 compared to healthy controls (vs. ovaries: p < 0.001; vs. tubes: p = 0.018). PD 1 and PD-L1 mRNA-expression increased with higher tumor grade (p = 0.008 and p = 0.027, respectively) and younger age (< median age, p = 0.001). Finally, in the major subgroup of our cohort, FIGO stage III/IV HGSOC, high PD-1 and PD-L1 mRNA expression was associated with reduced progression-free (p = 0.024) and overall survival (p = 0.049) but only in the univariate analysis. Our study suggests that in OC PD-1/PD-L1 mRNA-expression is controlled by IFNgamma and affected by TP53 and BRCA1/2 mutations. We suggest that these mutations might serve as potential predictive factors that guide anti-PD1/PD-L1 immunotherapy. PMID- 29707125 TI - The HNF-1beta-USP28-Claspin pathway upregulates DNA damage-induced Chk1 activation in ovarian clear cell carcinoma. AB - Transcription factor hepatocyte nuclear factor 1-beta (HNF-1beta) enhances checkpoint kinase 1 (Chk1) activation and promotes G2/M cell cycle progression in ovarian clear cell carcinoma (CCC) following exposure to diverse genotoxic agents including bleomycin. However, the underlying mechanism leading to checkpoint activation of HNF-1beta still remains largely unknown. To clarify the effects of HNF-1beta on cell cycle checkpoints, human CCC cell lines were transfected with siRNAs targeting HNF-1beta, Claspin, USP28, or a control vector. Ubiquitination and stabilization of Claspin protein by HNF-1beta was assessed by immunoprecipitation. Loss-of-function studies using RNAi-mediated gene silencing indicated that HNF-1beta facilitated the Claspin expression after treatment with a genotoxic agent bleomycin, resulting in accumulation of phosphorylated Chk1 (p Chk1) and promotion of survival in CCC cell lines. This study showed for the first time that USP28, a de-ubiquitinase crucial for Claspin expression, is one target gene of HNF-1beta. Knockdown of endogenous USP28 suppressed the Claspin expression and p-Chk1 activation and cell viability. Our findings identify a novel pathway of the HNF-1beta-USP28-Claspin-Chk1 axis in checkpoint signal amplification in response to DNA damage. Targeting this pathway may represent a putative, novel, anticancer strategy in ovarian CCC. PMID- 29707126 TI - HLA and killer cell immunoglobulin-like receptor (KIRs) genotyping in patients with acute viral encephalitis. AB - Introduction: The HLA genes, as well as the innate immune KIR genes, are considered relevant determinants of viral outcomes but no study, to our knowledge, has evaluated their role in the clinical setting of acute viral encephalitis. Results: Subjects with acute viral encephalitis in comparison to subjects without acute viral encephalitis showed a significantly higher frequency of 2DL1 KIR gene and AA KIR haplotypes and of HLA-C2 and HLA-A-Bw4 alleles. Subjects without acute viral encephalitis showed a higher frequency of interaction between KIR2DL2 and HLAC1. Multiple logistic regression analysis showed the detrimental effect of HLA-A haplotype and HLA-C1, HLA-A-BW4 HLA-B-BW4T alleles, whereas multiple logistic regression showed a protective effect of AB+BB KIR haplotype and a detrimental effect of interaction between KIR3DL1 and HLA-A Bw4. Discussion: Our findings of a lower frequency of activating receptors in patients with acute encephalitis compared to controls could result in a less efficient response of NK cells. This finding could represent a possible pathogenetic explanation of susceptibility to acute symptomatic encephalitis in patients with viral infection from potentially responsible viruses such as Herpes virus. Materials and Methods: 30 Consecutive patients with symptomatic acute viral encephalitis and as controls, 36 consecutive subjects without acute encephalitis were analyzed. The following KIR genes were analyzed, KIR2DL1, 2DL2, 2DL3, 2DL5, 3DL1, 3DL2, 3DL3, 2DL4, 2DS1, 2DS2, 2DS3, 2DS4, 2DS5, 3DS1, 2 pseudogenes (2DP1 and 3DP1) and the common variants of KIR2DL5 (KIR2DL5A, KIR2DL5B). PMID- 29707127 TI - Risk of sexual transmitted infection following bipolar disorder: a nationwide population-based cohort study. AB - Background: Bipolar disorder is a severe mental disorder associated with functional and cognitive impairment. Numerous studies have investigated associations between sexually transmitted infections (STIs) and psychiatric illnesses. However, the results of these studies are controversial. Objective: We explored the association between bipolar disorder and the subsequent development of STIs, including human immunodeficiency virus infection; primary, secondary, and latent syphilis; genital warts; gonorrhea; chlamydial infection; and trichomoniasis. Results: The bipolar cohort consisted of 1293 patients, and the comparison cohort consisted of 5172 matched control subjects without bipolar disorder. The incidence of subsequent STIs (hazard ratio (HR) = 2.23, 95% confidence interval (CI) 1.68-2.96) was higher among the patients with bipolar disorder than in the comparison cohort. Furthermore, female gender is a risk factor for acquisition of STIs (HR = 2.36, 95% CI 1.73-4.89) among patients with bipolar disorder. For individual STIs, the results indicated that the patients with bipolar disorder exhibited a markedly higher risk for subsequently contracting syphilis, genital warts, and trichomoniasis. Conclusions: Bipolar disorder might increase the risk of subsequent newly diagnosed STIs, including syphilis, genital warts, and trichomoniasis. Clinicians should pay particular attention to STIs in patients with bipolar disorder. Patients with bipolar disorder, especially those with a history of high-risk sexual behaviors, should be routinely screened for STIs. Methods: We identified patients who were diagnosed with bipolar disorder in the Taiwan National Health Insurance Research Database. A comparison cohort was constructed of patients without bipolar disorder who were matched with the bipolar cohort according to age and gender. The occurrence of subsequent new-onset STIs was evaluated in both cohorts. PMID- 29707128 TI - RANTES and IL-6 cooperate in inducing a more aggressive phenotype in breast cancer cells. AB - Both the CC chemokine ligand 5 (CCL5/RANTES) and interleukin-6 (IL-6), released by mesenchymal stem cells (MSCs) as well as by neoplastic cells, promote breast cancer cell progression through autocrine and paracrine mechanisms. In order to assess the effects of the simultaneous overexpression of RANTES and IL-6 on the tumor cell phenotype, we overexpressed both proteins in MCF-7 and MDA-MB-231 human breast cancer cell lines. MCF-7 cells co-expressing RANTES and IL-6 had a greater ability to form colonies in soft agar, compared to cells overexpressing RANTES or IL-6. In addition, both MCF-7 and MDA-MB-231 clones co-expressing RANTES and IL-6 showed a significantly higher ability to migrate and to invade. The analysis of phosphorylated ERK1/2, AKT and STAT3 signal transduction proteins revealed that several signaling pathways are simultaneously activated in cells overexpressing both factors. Finally, the overexpression of RANTES and IL-6 in MCF-7 cells significantly increased the in vivo tumor growth. Collectively, our data suggest that the simultaneous expression of IL-6 and RANTES produces a more aggressive phenotype in breast cancer cells and provide evidence that IL-6 and RANTES might represent potential targets for novel therapeutic strategies aimed to block the tumor-stroma interaction. PMID- 29707129 TI - Circulating programmed death ligand-1 (cPD-L1) in non-small-cell lung cancer (NSCLC). AB - Background: This study aimed at investigating feasibility of programmed death ligand-1 (PD-L1) testing in plasma samples of advanced NSCLC patients receiving first-line treatment, assessing whether circulating (c)PD-L1 levels were modified by the therapy and whether baseline cPD-L1 levels were associated with patients' clinical responses and survival outcome. Methods: Peripheral blood samples were collected from 16 healthy volunteers and 56 newly diagnosed NSCLC patients before and at 12th week during the course of first-line therapy. The level of PD-L1 was measured in plasma samples using the human (PD-L1/CD274) ELISA kit (CUSABIO, MD, USA). The Mann Whitney test or Fisher's test were used for comparisons. Survival analysis was performed using Kaplan Meyer method, providing median and p-value. Results: Baseline median cPD-L1 was 42.21 pg/ml (range 12.00-143.49) in NSCLC patients and 37.81 pg/ml (range 9.73-90.21) in healthy control cohort (p = 0.78). Median cPD-L1 increased in patients treated with first-line chemotherapy (63.20 pg/ml vs 39.34 pg/ml; p = 0.002), with no changes in patients exposed to non chemotherapy drugs (42.39 pg/ml vs 50.67 pg/ml; p = 0.398). Time to progression and overall survival were 4.4 vs 6.9 months (p = 0.062) and 8.8 vs 9.3 months (p = 0.216) in cPD-L1 positive vs cPD-L1 negative patients. Baseline cPD-L1 levels increased with the ascending number of metastatic sites, even if the association was not statistically significant (p = 0.063). Conclusions: This study showed that cPD-L1 testing is feasible, with chemotherapy influencing PD-L1 plasma levels. The possibility of using such test for predicting or monitoring the effect of immunotherapy or combination of chemotherapy and immunotherapy warrant further investigations. PMID- 29707130 TI - Sulforaphane suppresses oral cancer cell migration by regulating cathepsin S expression. AB - Sulforaphane has been demonstrated to exert numerous biological effects, such as neuroprotective, anti-inflammatory, and anticancer effects. However, the detailed effects of sulforaphane on human oral cancer cell migration and the underlying mechanisms remain unclear. In this study, we observed that sulforaphane attenuated SCC-9 and SCC-14 cell motility and invasiveness by reducing cathepsin S expression. Moreover, sulforaphane increased microtubule-associated protein 1 light chain 3 (LC3) conversion, and the knockdown of LC3 by siRNA increased cell migration ability. Regarding the mechanism, sulforaphane inhibited the cell motility of oral cancer cells through the extracellular signal-regulated kinase (ERK) pathway, which in turn reversed cell motility. In conclusion, sulforaphane suppress cathepsin S expression by inducing autophage through ERK signaling pathway. Thus, cathepsin S and LC3 may be new targets for oral cancer treatment. PMID- 29707132 TI - Molecular profiling of advanced breast cancer tumors is beneficial in assisting clinical treatment plans. AB - We used data obtained by Caris Life Sciences, to evaluate the benefits of tailoring treatments for a breast carcinoma cohort by using tumor molecular profiles to inform decisions. Data for 92 breast cancer patients from the commercial Caris Molecular Intelligence database was retrospectively divided into two groups, so that the first always followed treatment recommendations, whereas in the second group all patients received at least one drug after profiling that was predicted to lack benefit. The biomarker and drug associations were based on tests including fluorescent in situ hybridization and DNA sequencing, although immunohistochemistry was the main test used. Patients whose drugs matched those recommended according to their tumor profile had an average overall survival of 667 days, compared to 510 days for patients that did not (P=0.0316). In the matched treatment group, 26% of patients were deceased by the last time of monitoring, whereas this was 41% in the unmatched group (P=0.1257). We therefore confirm the ability of tumor molecular profiling to improve survival of breast cancer patients. Immunohistochemistry biomarkers for the androgen, estrogen and progesterone receptors were found to be prognostic for survival. PMID- 29707131 TI - Gene expression analyses determine two different subpopulations in KIT-negative GIST-like (KNGL) patients. AB - Introduction: There are limited findings available on KIT-negative GIST-like (KNGL) population. Also, KIT expression may be post-transcriptionally regulated by miRNA221 and miRNA222. Hence, the aim of this study is to characterize KNGL population, by differential gene expression, and to analyze miRNA221/222 expression and their prognostic value in KNGL patients. Methods: KIT, PDGFRA, DOG1, IGF1R, MIR221 and MIR222 expression levels were determined by qRT-PCR. We also analyzed KIT and PDGFRA mutations, DOG1 expression, by immunohistochemistry, along with clinical and pathological data. Disease-free survival (DFS) and overall survival (OS) differences were calculated using Log-rank test. Results: Hierarchical cluster analyses from gene expression data identified two groups: group I had KIT, DOG1 and PDGFRA overexpression and IGF1R underexpression and group II had overexpression of IGF1R and low expression of KIT, DOG1 and PDGFRA. Group II had a significant worse OS (p = 0.013) in all the series, and showed a tendency for worse OS (p = 0.11), when analyzed only the localized cases. MiRNA222 expression was significantly lower in a control subset of KIT-positive GIST (p < 0.001). OS was significantly worse in KNGL cases with higher expression of MIR221 (p = 0.028) or MIR222 (p = 0.014). Conclusions: We identified two distinct KNGL subsets, with a different prognostic value. Increased levels of miRNA221/222, which are associated with worse OS, could explain the absence of KIT protein expression of most KNGL tumors. PMID- 29707133 TI - Interactions among variants in TXA2R, P2Y12 and GPIIIa are associated with carotid plaque vulnerability in Chinese population. AB - Purpose: The associations between variants in platelet activation-relevant genes and carotid plaque vulnerability are not fully understood. The aim of the present study was to investigate the associations of the variants in platelet activation relevant genes and interactions among these variants with carotid plaque vulnerability. Results: There were no significant differences in the frequencies of genotypes of the 11 variants between patients and controls. Among 396 patients, 102 patients had not carotid plaque, 106 had VP, and 188 had SP. The 11 variants were not independently associated with risk of carotid plaque vulnerability after adjusting for potential confounding variables. However, the GMDR analysis showed that there were synergistic effects of gene-gene interactions among TXA2Rr s1131882, GPIIIa rs2317676 and P2Y12 rs16863323 on carotid plaque vulnerability. The high-risk interactions among the three variants were associated with high platelet activation, and independently associated with the risk of carotid plaque vulnerability. Methods: Eleven variants in platelet activation-relevant genes were examined using mass spectrometry methods in 396 ischemic stroke patients and 291controls. Platelet-leukocyte aggregates and platelet aggregation were also measured. Carotid plaques were assessed by B-mode ultrasound. According to the results of ultrasound, the patients were stratified into three groups: non-plaque group, vulnerable plaque (VP) group and stable plaque (SP) group. Furthermore, gene-gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR) methods. Conclusions: The rs1131882, rs2317676, and rs16863323 three-loci interactions may confer a higher risk of carotid plaque vulnerability, and might be potential markers for plaque instability. PMID- 29707134 TI - A Jurkat 76 based triple parameter reporter system to evaluate TCR functions and adoptive T cell strategies. AB - Adoptive T cell therapy using TCR transgenic autologous T cells has shown great potential for the treatment of tumor patients. Thorough characterization of genetically reprogrammed T cells is necessary to optimize treatment success. Here, we describe the generation of triple parameter reporter T cells based on the Jurkat 76 T cell line for the evaluation of TCR and chimeric antigen receptor functions as well as adoptive T cell strategies. This Jurkat subline is devoid of endogenous TCR alpha and TCR beta chains, thereby circumventing the problem of TCR miss-pairing and unexpected specificities. The resultant reporter cells allow simultaneous determination of the activity of the transcription factors NF kappaB, NFAT and AP-1 that play key roles in T cell activation. Human TCRs directed against tumor and virus antigens were introduced and reporter responses were determined using tumor cell lines endogenously expressing the antigens of interest or via addition of antigenic peptides. Finally, we demonstrate that coexpression of adhesion molecules like CD2 and CD226 as well as CD28 chimeric receptors represents an effective strategy to augment the response of TCR transgenic reporters to cells presenting cognate antigens. PMID- 29707135 TI - Capecitabine reverses tumor escape from anti-VEGF through the eliminating CD11bhigh/Gr1high myeloid cells. AB - The anti-VEGF humanized antibody bevacizumab suppresses various malignancies, but tumors can acquire drug resistance. Preclinical studies suggest myeloid-derived suppressor cells (MDSCs) may be associated with tumor refractoriness to anti-VEGF treatment. Here we report a novel mechanism of tumor escape from anti-VEGF therapy. Anti-VEGF treatment enhanced intratumoral recruitment of CD11bhigh/Gr 1high polymorphonuclear (PMN)-MDSCs in anti-VEGF-resistant Lewis lung carcinoma tumors. This effect was diminished by the anticancer agent capecitabine, a pro drug converted to 5-fluorouracil, but not by 5-fluorouracil itself. This process was mediated by enhanced intratumoral granulocyte-colony stimulating factor expression, as previously demonstrated. However, neither interleukin-17 nor Bv8, which were previously identified as key contributors to anti-VEGF resistance, was involved in this model. Capecitabine eliminated PyNPase-expressing MDSCs from both tumors and peripheral blood. Capecitabine treatment also reversed inhibition of both antitumor angiogenesis and tumor growth under anti-VEGF antibody treatment, and this effect partially inhibited in tumors implanted in mice deficient in both PyNPases. These results indicate that intratumoral granulocyte colony stimulating factor expression and CD11bhigh/Gr-1high PMN-MDSC recruitment underlie tumor resistance to anti-VEGF therapy, and suggest PyNPases are potentially useful targets during anti-angiogenic therapy. PMID- 29707136 TI - BNIP3 modulates the interface between B16-F10 melanoma cells and immune cells. AB - The hypoxia responsive protein BNIP3, plays an important role in promoting cell death and/or autophagy, ultimately resulting in a cancer type-dependent, tumour enhancer or tumour-suppressor activity. We previously reported that in melanoma cells, BNIP3 regulates cellular morphology, mitochondrial clearance, cellular viability and maintains protein expression of CD47, a pro-cancerous, immunosuppressive 'don't eat me' signal. Surface exposed CD47 is often up regulated by cancer cells to avoid clearance by phagocytes and to suppress immunogenic cell death (ICD) elicited by anticancer therapies. However, whether melanoma-associated BNIP3 modulates CD47-associated immunological effects or ICD has not been explored properly. To this end, we evaluated the impact of the genetic ablation of BNIP3 (i.e. BNIP3KD) in melanoma cells, on macrophage-based phagocytosis, polarization and chemotaxis. Additionally, we tested its effects on crucial determinants of chemotherapy-induced ICD (i.e. danger signals), as well as in vivo anticancer vaccination effect. Interestingly, loss of BNIP3 reduced the expression of CD47 both in normoxic and hypoxic conditions while macrophage phagocytosis and chemotaxis were accentuated only when BNIP3KD melanoma cells were exposed to hypoxia. Moreover, when exposed to the ICD inducer mitoxantrone, the loss of melanoma cell-associated BNIP3 did not alter apoptosis induction, but significantly prevented ATP secretion and reduced phagocytic clearance of dying cells. In line with this, prophylactic vaccination experiments showed that the loss of BNIP3 tends to increase the intrinsic resistance of B16-F10 melanoma cells to ICD-associated anticancer vaccination effect in vivo. Thus, normoxic vs. hypoxic and live vs. dying cell contexts influence the ultimate immunomodulatory roles of melanoma cell-associated BNIP3. PMID- 29707137 TI - CNPY2 inhibits MYLIP-mediated AR protein degradation in prostate cancer cells. AB - The androgen receptor (AR) is a ligand-dependent transcription factor that promotes prostate cancer (PC) cell growth through control of target gene expression. This report suggests that Canopy FGF signaling regulator 2 (CNPY2) controls AR protein levels in PC cells. We found that AR was ubiquitinated by an E3 ubiquitin ligase, myosin regulatory light chain interacting protein (MYLIP) and then degraded through the ubiquitin-proteasome pathway. CNPY2 decreased the ubiquitination activity of MYLIP by inhibition of interaction between MYLIP and UBE2D1, an E2 ubiquitin ligase. CNPY2 up-regulated gene expression of AR target genes such as KLK3 gene which encodes the prostate specific antigen (PSA) and promoted cell growth of PC cells. The cell growth inhibition by CNPY2 knockdown was rescued by AR overexpression. Furthermore, positive correlation of expression levels between CNPY2 and AR/AR target genes was observed in tissue samples from human prostate cancer patients. Together, these results suggested that CNPY2 promoted cell growth of PC cells by inhibition of AR protein degradation through MYLIP-mediated AR ubiquitination. PMID- 29707138 TI - Enhanced intratumoral expression of RNF2 is a favorable prognostic factor for patients with cutaneous melanoma? AB - Recent studies involving melanoma cell lines suggest that enhanced expression of epigenetic regulator RNF2 supports proliferation and promotes metastasis. However, it is not clear to what extent those data apply to disease progression and prognosis for melanoma patients. Therefore the aim of the present study was to assess the prognostic power of RNF2 intratumoral expression by melanoma cells. RNF2 was detected immunohistochemically in standard formalin-fixed paraffin embedded samples of 9 benign nevi, 60 melanomas and 24 nodal metastases. The lowest percentage of RNF2-positive melanocytes found in nevi was comparable to expression levels in normal skin. The RNF2 expression found in melanomas was significantly higher and it was even more enhanced in metastases. The increased occurrence of RNF2 expressing cells was positively correlated with longer patients' overall survival. Moreover, a negative correlation was found between intratumoral RNF2 expression and number of generated metastatic lesions. Our data indicate that development of melanoma is associated with significant changes in RNF2 intratumoral expression and imply that at least for some patients the enhancement of the expression levels of RNF2 in both primary and metastatic lesions may be considered a favorable prognostic factor in melanoma. PMID- 29707139 TI - Efficacy of prophylactic cranial irradiation in patients with limited-disease small-cell lung cancer who were confirmed to have no brain metastasis via magnetic resonance imaging after initial chemoradiotherapy. AB - Background: Prophylactic cranial irradiation (PCI) is recommended for patients with limited-disease small-cell lung cancer (LD-SCLC) who achieved good response to definitive chemoradiotherapy. However, most clinical studies lacked brain imaging scans before PCI. Our study aimed to investigate whether PCI has a survival benefit in patients who have no brain metastases (BM) confirmed via magnetic resonance imaging (MRI) before PCI. Results: Eighty patients were included in this study. Sixty patients received PCI (PCI group) and 20 patients did not (non-PCI group). OS was not significantly different between the two groups. The median OS time was 4.3 years (95% CI: 2.6 years-8.6 years) in the PCI group and was not reached (NR) (95% CI: 1.9 years-NR) in the non-PCI group (p = 0.542). Moreover, no differences were observed in the 3-year rates of PFS (46.2% and 44.4%, p = 0.720) and cumulative incidence of BM (24.0% vs. 27%, p = 0.404). Conclusions: Our result suggests that PCI may not have a survival benefit in patients with LD-SCLC confirmed to have no BM after initial therapy, even if patients achieve a good response to definitive chemoradiotherapy. Patients and Methods: We retrospectively evaluated patients with LD-SCLC who were confirmed to have no BM via MRI after initial chemoradiotherapy at the Shizuoka Cancer Center between September 2002 and August 2015. The overall survival (OS), progression free survival (PFS), and cumulative incidence of BM were estimated using the Kaplan-Meier method between patients who received PCI and those who did not. Propensity score matching was used to balance baseline characteristics. PMID- 29707140 TI - A phase 1 study of lirilumab (antibody against killer immunoglobulin-like receptor antibody KIR2D; IPH2102) in patients with solid tumors and hematologic malignancies. AB - Purpose: Anti-KIR monoclonal antibodies (mAbs) can enhance the antitumor responses of natural killer (NK) cells. We evaluated the safety of the anti-KIR2D mAb lirilumab in patients with various cancers. Experimental design: Thirty-seven patients with hematological malignancies (n = 22) or solid tumors (n = 15) were included in the study. Dose escalation (0.015 to 10 mg/kg) was conducted following a 3 + 3 design. Patients were scheduled to receive four cycles of treatment. In a second (extension) phase 17 patients were treated at 0.015 (n = 9) or 3 mg/kg (n = 8). Results: No dose-limiting toxicity was recorded. The most frequent lirilumab-related adverse events were pruritus (19%), asthenia (16%), fatigue (14%), infusion-related reaction (14%), and headache (11%), mostly mild or moderate. Pharmacokinetics was dose-dependent and linear, with minimal accumulation resulting from the 4-weekly repeated administrations. Full KIR occupancy (>95%) was achieved with all dosages, and the duration of occupancy was dose-related. No significant changes were observed in the number or distribution of lymphocyte subpopulations, nor was any reduction in the distribution of KIR2D positive NK cells. Conclusions: This phase 1 trial demonstrated the satisfactory safety profile of lirilumab up to doses that enable full and sustained blockade of KIR. PMID- 29707141 TI - The role of oxidative stress in activity of anticancer thiosemicarbazones. AB - Thiosemicarbazones are chelators of transition metals such as iron or copper whose anticancer potency is intensively investigated. Although two compounds from this class have entered clinical trials, their precise mechanism of action is still unknown. Recent studies have suggested the mobilization of the iron ions from a cell, as well as the inhibition of ribonucleotide reductase, and the formation of reactive oxygen species. The complexity and vague nature of this mechanism not only impedes a more rational design of novel compounds, but also the further development of those that are highly active that are already in the preclinical phase. In the current work, a series of highly active thiosemicarbazones was studied for their antiproliferative activity in vitro. Our experiments indicate that these complexes have ionophoric properties and redox activity. They appeared to be very effective generating reactive oxygen species and deregulating the antioxidative potential of a cell. Moreover, the genes that are responsible for antioxidant capacity were considerably deregulated, which led to the induction of apoptosis and cell cycle arrest. On the other hand, good intercalating properties of the studied compounds may explain their ability to cleave DNA strands and to also poison related enzymes through the formation of reactive oxygen species. These findings may help to explain the particularly high selectivity that they have over normal cells, which generally have a stronger redox equilibrium. PMID- 29707142 TI - PIK3CA mutation, reduced AKT serine 473 phosphorylation, and increased ERalpha serine 167 phosphorylation are positive prognostic indicators in postmenopausal estrogen receptor-positive early breast cancer. AB - Although endocrine therapy is the most important treatment option in estrogen receptor (ER)-positive breast cancer, new strategies, such as molecular targeted agents together with endocrine therapy are required to improve survival. PIK3CA is the most frequent mutated gene in ER-positive early breast cancers, and PIK3CA mutation status is reported to affect activation of AKT and ERalpha. Moreover, recent studies demonstrate that patients had a better prognosis when tumors expressed ER, androgen receptor (AR), and vitamin D receptor (VDR). In this study, we examined expression of AR and VDR, phosphorylation of AKT serine (Ser) 473 (AKT phospho-Ser473) and ERalpha Ser167 (ERalpha phospho-Ser167) by immunohistochemistry in ER-positive, HER2-negative early breast cancer. PIK3CA gene mutations were also detected in genomic DNA extracted from tumor blocks. Correlations between these biological markers, clinicopathological factors and prognosis were analyzed. Levels of AKT phospho-Ser473 were significantly higher in premenopausal women than in postmenopausal women. In contrast, AR expression was significantly higher in postmenopausal women than in premenopausal women. PIK3CA mutations were detected in 47% in premenopausal women and 47% in postmenopausal women. Postmenopausal women with PIK3CA wild-type tumors had significantly worse disease-free survival than patients with PIK3CA mutant tumors. Low levels of AKT phospho-Ser473 and high levels of ERalpha phospho Ser167 were strongly associated with increased disease-free survival in postmenopausal women. Evaluation of ERalpha activation, in addition to PIK3CA mutation status, might be helpful in identifying patients who are likely to benefit from endocrine therapy alone versus those who are not in postmenopausal ER-positive early breast cancer. PMID- 29707143 TI - The secondary prevention of stroke according to cytochrome P450 2C19 genotype in patients with acute large-artery atherosclerosis stroke. AB - Purpose: To investigated the effectiveness of antiplatelet agents for the secondary prevention of stroke according to CYP2C19 genotype in patients with ischemic stroke (IS). Methods: Between August 2009 and December 2011, 570 acute IS patients with acute large-artery atherosclerosis were randomly assigned to receive either combined clopidogrel and aspirin for the first 30 day, and clopidogrel thereafter (clopidogrel group, n=284) or aspirin monotherapy (aspirin group, n=286). CYP2C19 genotypes were measured and masked until the end-of-study. The primary outcome was a composite of IS, transient ischemic attack (TIA), myocardial infarction (MI), and death. Results: During the 5 years follow-up, the primary outcome occurred in 105 patients (18.4%) (71 had IS, 10 had TIA, 12 had MI, and 12 died). There were no significant differences in the primary outcome between clopidogrel group and aspirin group (16.5% vs. 20.3%) or between carriers of the CYP2C19 reduced-function alleles and noncarriers (21.8% vs.15.7%). In patients with aspirin therapy, CYP2C19 polymorphism was not associated with the primary outcome. However, in patients treated with clopidogrel, carriers of at least one CYP2C19 reduced-function allele had a 3-fold higher adjusted risk for primary outcome compared with noncarriers (95% confidence interval, 1.23 to 8.74). Conclusions: Among IS patients treated with clopidogrel, carriers of a reduced-function CYP2C19 allele had a significantly higher rate of adverse vascular events than did noncarriers. It should avoid prescribing clopidogrel to these patients with known CYP2C19 polymorphisms. PMID- 29707144 TI - Clinical importance of the EMSY gene expression and polymorphisms in ovarian cancer. AB - EMSY, a BRCA2-associated protein, is amplified and overexpressed in various sporadic cancers. This is the first study assessing the clinical impact of its expression and polymorphisms on ovarian cancer (OvCa) outcome in the context of the chemotherapy regimen used. In 134 frozen OvCa samples, we assessed EMSY mRNA expression with Reverse Transcription-quantitative PCR, and also investigated the EMSY gene sequence using SSCP and/or PCR-sequencing. Clinical relevance of changes in EMSY mRNA expression and DNA sequence was evaluated in two subgroups treated with either taxane/platinum (TP, n=102) or platinum/cyclophosphamide (PC, n=32). High EMSY expression negatively affected overall survival (OS), disease free survival (DFS) and sensitivity to treatment (PS) in the TP-treated subgroup (p-values: 0.001, 0.002 and 0.010, respectively). Accordingly, our OvCa cell line studies showed that the EMSY gene knockdown sensitized A2780 and IGROV1 cells to paclitaxel. Interestingly, EMSY mRNA expression in surviving cells was similar as in the control cells. Additionally, we identified 24 sequence alterations in the EMSY gene, including the previously undescribed: c.720G>C, p.(Lys240Asn); c.1860G>A, p.(Lys620Lys); c.246-76A>G; c.421+68A>C. In the PC-treated subgroup, a heterozygous genotype comprising five SNPs (rs4300410, rs3814711, rs4245443, rs2508740, rs2513523) negatively correlated with OS (p-value=0.009). The same SNPs exhibited adverse borderline associations with PS in the TP-treated subgroup. This is the first study providing evidence that high EMSY mRNA expression is a negative prognostic and predictive factor in OvCa patients treated with TP, and that the clinical outcome may hinge on certain SNPs in the EMSY gene as well. PMID- 29707145 TI - Circulating tumor DNA in early response assessment and monitoring of advanced colorectal cancer treated with a multi-kinase inhibitor. AB - Predictive biomarkers are eagerly awaited in advanced colorectal cancer (aCRC). Targeted sequencing performed on tumor and baseline plasma samples in 20 patients with aCRC treated with regorafenib identified 89 tumor-specific mutations of which >=50% are also present in baseline plasma. Droplet digital PCR (ddPCR) assays were optimized to monitor circulating tumor DNA (ctDNA) levels in plasmatic samples collected throughout the treatment course and showed the importance of using the absolute value for ctDNA rather than the mutant/wild type ratio in monitoring the therapy outcome. High baseline cell free DNA (cfDNA) levels are associated with shorter overall survival (OS) (HR 7.38, P=0.001). An early increase (D14) in mutated copies/mL is associated with a significantly worse PFS (HR 6.12, P=0.008) and OS (HR 8.02, P=0.004). These data suggest a high prognostic value for early ctDNA level changes and support the use of blood-born genomic markers as a tool for treatment. PMID- 29707146 TI - Aloe-emodin as drug candidate for cancer therapy. AB - As a leading cause of global mortality, cancer frequently cannot be cured due to the development of drug resistance. Therefore, novel drugs are required. Naturally occurring anthraquinones are mostly present in Rumex and Rhamnus species and are of interest because of their structural similarity to anthracyclines as well established anticancer drugs. In the present study, we focused on the structural elucidation of phytochemicals from R. acetosella as well as the investigation of cytotoxicity and modes of action of the main anthraquinone aglycons (emodin, Aloe-emodin, physcion, rhein). Resazurin reduction and protease viability marker assays were conducted to test their cytotoxicity. Microarray-based gene expression profiling was performed to identify cellular pathways affected by the compounds, which was validated by qPCR analyses and functional assays. Flow cytometry was used to measure cell cycle distribution, apoptosis and necrosis, induction of reactive oxygen species (ROS) and disruption of mitochondrial membrane potential (MMP). The comet assay was used to detect DNA damage. Aloe-emodin as the most cytotoxic compound revealed IC50 values from 9.872 MUM to 22.3 MUM in drug-sensitive wild-type cell lines and from 11.19 MUM to 33.76 MUM in drug-resistant sublines, was selected to investigate its mechanism against cancer. Aloe-emodin-induced S phase arrest, ROS generation, DNA damage and apoptosis. Microarray hybridization revealed a profile of deregulated genes in Aloe-emodin-treated CCRF-CEM cells with diverse functions such as cell death and survival, cellular growth and proliferation, cellular development, gene expression, cellular function and maintenance. Aloe-emodin as well as R. acetosella deserve further investigations as possible antineoplastic drug candidates. PMID- 29707147 TI - Molecular responses to therapeutic proteasome inhibitors in multiple myeloma patients are donor-, cell type- and drug-dependent. AB - Proteasome is central to proteostasis network functionality and its over activation represents a hallmark of advanced tumors; thus, its selective inhibition provides a strategy for the development of novel antitumor therapies. In support, proteasome inhibitors, e.g. Bortezomib or Carfilzomib have demonstrated clinical efficacy against hematological cancers. Herein, we studied proteasome regulation in peripheral blood mononuclear cells and erythrocytes isolated from healthy donors or from Multiple Myeloma patients treated with Bortezomib or Carfilzomib. In healthy donors we found that peripheral blood mononuclear cells express higher, as compared to erythrocytes, basal proteasome activities, as well as that proteasome activities decline during aging. Studies in cells isolated from Multiple Myeloma patients treated with proteasome inhibitors revealed that in most (but, interestingly enough, not all) patients, proteasome activities decline in both cell types during therapy. In peripheral blood mononuclear cells, most proteostatic genes expression patterns showed a positive correlation during therapy indicating that proteostasis network modules likely respond to proteasome inhibition as a functional unit. Finally, the expression levels of antioxidant, chaperone and aggresomes removal/autophagy genes were found to inversely associate with patients' survival. Our studies will support a more personalized therapeutic approach in hematological malignancies treated with proteasome inhibitors. PMID- 29707149 TI - Let-7b inhibits cancer-promoting effects of breast cancer-associated fibroblasts through IL-8 repression. AB - Cancer-associated fibroblasts (CAFs) are major players in the development and spread of breast carcinomas through non-cell-autonomous signaling. These paracrine effects are under the control of several genes and microRNAs. We present here clear evidence that let-7b, a tumor suppressor microRNA, plays key roles in the persistent activation of breast stromal fibroblasts and their functional interplay with cancer cells. We have first shown that let-7b is down regulated in CAFs as compared to their corresponding normal adjacent fibroblasts, and transient specific let-7b inhibition permanently activated breast fibroblasts through induction of the IL-6-related positive feedback loop. More importantly, let-7b-deficient cells promoted the epithelial-to-mesenchymal transition process in breast cancer cells in an IL-8-dependent manner, and also enhanced orthotopic tumor growth in vivo. On the other hand, overexpression of let-7b by mimic permanently suppressed breast myofibroblasts through blocking the positive feedback loop, which inhibited their paracrine pro-carcinogenic effects. Furthermore, we have shown that let-7b negatively controls IL-8, which showed higher expression in the majority of CAF cells as compared to their adjacent normal counterparts, indicating that IL-8 plays a major role in the carcinoma/stroma cross-talk. These findings support targeting active stromal fibroblasts through restoration of let-7b/IL-8 expression as a therapeutic option for breast carcinomas. PMID- 29707148 TI - Dual antiplatelet therapy with clopidogrel and aspirin increases mortality in 4T1 metastatic breast cancer-bearing mice by inducing vascular mimicry in primary tumour. AB - Platelet inhibition has been considered an effective strategy for combating cancer metastasis and compromising disease malignancy although recent clinical data provided evidence that long-term platelet inhibition might increase incidence of cancer deaths in initially cancer-free patients. In the present study we demonstrated that dual anti-platelet therapy based on aspirin and clopidogrel (ASA+Cl), a routine regiment in cardiovascular patients, when given to cancer-bearing mice injected orthotopically with 4T1 breast cancer cells, promoted progression of the disease and reduced mice survival in association with induction of vascular mimicry (VM) in primary tumour. In contrast, treatment with ASA+Cl or platelet depletion did reduce pulmonary metastasis in mice, if 4T1 cells were injected intravenously. In conclusion, distinct platelet-dependent mechanisms inhibited by ASA+Cl treatment promoted cancer malignancy and VM in the presence of primary tumour and afforded protection against pulmonary metastasis in the absence of primary tumour. In view of our data, long-term inhibition of platelet function by dual anti-platelet therapy (ASA+Cl) might pose a hazard when applied to a patient with undiagnosed and untreated malignant cancer prone to undergo VM. PMID- 29707150 TI - Structural characterization and in vivo pro-tumor properties of a highly conserved matrikine. AB - Elastin-derived peptides (EDPs) exert protumor activities by increasing tumor growth, migration and invasion. A number of studies have highlighted the potential of VGVAPG consensus sequence-derived elastin-like polypeptides whose physicochemical properties and biocompatibility are particularly suitable for in vivo applications, such as drug delivery and tissue engineering. However, among the EDPs, the influence of elastin-derived nonapeptides (xGxPGxGxG consensus sequence) remains unknown. Here, we show that the AGVPGLGVG elastin peptide (AG 9) present in domain-26 of tropoelastin is more conserved than the VGVAPG elastin peptide (VG-6) from domain-24 in mammals. The results demonstrate that the structural features of AG-9 and VG-6 peptides are similar. CD, NMR and FTIR spectroscopies show that AG-9 and VG-6 present the same conformation, which includes a mixture of random coils and beta-turn structures. On the other hand, the supraorganization differs between peptides, as demonstrated by AFM. The VG-6 peptide gathers in spots, whereas the AG-9 peptide aggregates into short amyloid like fibrils. An in vivo study showed that AG-9 peptides promote tumor progression to a greater extent than do VG-6 peptides. These results were confirmed by in vitro studies such as 2D and 3D proliferation assays, migration assays, adhesion assays, proteinase secretion studies and pseudotube formation assays to investigate angiogenesis. Our findings suggest the possibility that the AG-9 peptide present in patient sera may dramatically influence cancer progression and could be used in the design of new, innovative antitumor therapies. PMID- 29707151 TI - High levels of circulating endothelial progenitor cells in patients with diabetic retinopathy are positively associated with ARHGAP22 expression. AB - Diabetic retinopathy (DR) is a common microvascular complication of diabetes. Circulating endothelial progenitor cells (EPCs) are derived from bone marrow and are characterized by pathological retinal neovascularization. Rho GTPase Activating Protein 22 (ARHGAP22) is a DR susceptibility gene that interacts with its downstream regulatory protein ras-related C3 botulinum toxin substrate 1 (Rac1), to assist in endothelial cell angiogenesis and increasing capillary permeability. The aim of this study was to elucidate the relationship between ARHGAP22 expression and EPC levels in type 2 diabetes (T2D) patients with DR. Fifty T2D patients with DR were recruited. Circulating EPCs were characterized as CD31+/vascular endothelial growth factor-2+/CD45dim/CD133+ and were quantified using triple staining flow cytometry. Real-time polymerase chain reaction tests were used to quantify ARHGAP22 expression. We found that T2D patients with proliferative DR had significantly lower EPC levels than those with non proliferative DR (P = 0.028). T2D patients with EPC levels above the median value (> 4 cells/105 events) had higher levels of ARHGAP22 expression (P = 0.002). EPC levels were positively correlated with ARHGAP22 expression (r = 0.364, P = 0.009). Among T2D patients with DR, a higher expression of ARHGAP22 was associated with higher levels of EPCs. ARHGAP22 may be involved in the mobilization or active circulation of EPCs, thus contributing to neovascularization during DR development. PMID- 29707152 TI - Advance care planning and outcome in pediatric palliative home care. AB - Pediatric advance care planning seeks to ensure end-of-life care conforming to the patients/their families' preferences. To expand our knowledge of advance care planning and "medical orders for life-sustaining treatment" (MOLST) in pediatric palliative home care, we determined the number of patients with MOLST, compared MOLST between the four "Together for Short Lives" (TfSL) groups and analyzed, whether there was a relationship between the content of the MOLST and the patients' places of death. The study was conducted as a single-center retrospective analysis of all patients of a large specialized pediatric palliative home care team (01/2013-09/2016). MOLST were available in 179/198 children (90.4%). Most parents decided fast on MOLST, 99 (55.3%) at initiation of pediatric palliative home care, 150 (83.4%) within the first 100 days. MOLST were only changed in 7.8%. Eighty/179 (44.7%) patients decided on a Do Not Attempt Cardio-Pulmonary Resuscitation (DNACPR) order, 58 (32.4%) on treatment limitations of some kind and 41 (22.9%) wished for the entire spectrum of life sustaining measures (Full Code). Most TfSL group 1 families wanted DNACPR and most TfSL group 3/4 parents Full Code. The majority (84.9%) of all DNACPR patients died at home/hospice. Conversely, all Full Code patients died in hospital (80% in an intensive care setting). The circumstances of the childrens' deaths can therefore be predicted considering the content of the MOLST. Regular advance care planning discussions are thus a very important aspect of pediatric palliative home care. PMID- 29707154 TI - Similar expression profiles in CD34+ cells from chronic phase chronic myeloid leukemia patients with and without deep molecular responses to nilotinib. AB - The life expectancy of patients with chronic phase chronic myeloid leukemia on tyrosine kinase inhibitor therapy now approaches that of the general population. Approximately 60% of patients treated with second generation tyrosine kinase inhibitors achieve a deep molecular response, the prerequisite for a trial of treatment-free remission. Those patients unlikely to achieve deep molecular response may benefit from more intensive therapy up front. To identify biomarkers predicting deep molecular response we performed transcriptional profiling on CD34+ progenitor cells from newly diagnosed chronic phase chronic myeloid leukemia patients treated with nilotinib on a prospective clinical trial. Using unsupervised and targeted analytical strategies, we show that gene expression profiles are similar in patients with and without subsequent deep molecular response. This result is in contrast to the distinct expression signature of CD34+ chronic phase chronic myeloid leukemia patients failing to achieve a cytogenetic response on imatinib and suggests that deep molecular response to second-generation tyrosine kinase inhibitors is governed by the biology of more primitive chronic myeloid leukemia cells or extrinsic factors. PMID- 29707155 TI - Tissue miRNA 483-3p expression predicts tumor recurrence after surgical resection in histologically advanced hepatocellular carcinomas. AB - The choice of surgical treatment for hepatocellular carcinoma (HCC) depends on several prognostic variables, among which histological features, like microvascular invasion and tumor grade, are well established. This study aims to identify the tissue miRNAs predictive of recurrence after liver resection in "histologically advanced" HCC. We selected 54 patients: 15 retrospective resected patients without recurrence (group A), 19 retrospective resected patients with HCC recurrence (group B), and 20 prospective patients (group C), with 4 recurrence cases. All selected HCC were "histologically advanced" (high Edmondson grade and/or presence of microvascular invasion). A wide spectrum of miRNAs was studied with TaqMan Human microRNA Arrays; qRT-PCR assays were used to validate results on selected miRNAs; immunohistochemistry for IGF2 was applied to study the mechanism of miR-483-3p. As a result, a significant differential expression between group A and B was found for 255 miRNAs. Among them we selected miR-483-3p and miR-548e (P<0.001). As a single variable (group C), HCC with miR-483-3p downregulation (mean fold increase 0.21) had 44.4% of recurrence cases; HCC with miR-483-3p upregulation (mean fold increase 5.94) showed no recurrence cases (P=0.011). At immunohistochemistry (group C), the HCC with loss of cytoplasmic IGF2 expression showed a down-regulation of miR-483-3p (fold increase 0.57). In conclusion, in patients with "histologically advanced" HCC, the analysis of specific tissue miRNAs (particularly miR-483-3p) could help identify the recurrence risk and choose which treatment algorithm to implement (follow-up, resection or transplantation). This could have an important impact on patient survival and transplantation outcome, improving organ allocation. PMID- 29707153 TI - Diagnostic and prognostic biomarker potential of kallikrein family genes in different cancer types. AB - Purpose: The aim of this study was to compare and contrast the expression of all members of the Kallikrein (KLK) family of genes across 15 cancer types and to evaluate their utility as diagnostic and prognostic biomarkers. Results: Severe alterations were found in the expression of different Kallikrein genes across various cancers. Interestingly, renal clear cell and papillary carcinomas have similar kallikrein expression profiles, whereas, chromophobe renal cell carcinoma has a unique expression profile. Several KLK genes have excellent biomarker potential (AUC > 0.90) for chromophobe renal cell carcinoma (KLK2, KLK3, KLK4, KLK7, KLK15), renal papillary carcinoma (KLK1, KLK6, KLK7), clear cell renal cell carcinoma (KLK1, KLK6), thyroid carcinoma (KLK2, KLK4, KLK13, KLK15) and colon adenocarcinoma (KLK6, KLK7, KLK8, KLK10). Several KLK genes were significantly associated with mortality in clear cell renal cell carcinoma (KLK2: HR = 1.69; KLK4: HR = 1.63; KLK8: HR = 1.71; KLK10: HR = 2.12; KLK11: HR = 1.76; KLK14: HR = 1.86), papillary renal cell carcinoma (KLK6: HR = 3.38, KLK7: HR = 2.50), urothelial bladder carcinoma (KLK5: HR = 1.89, KLK6: HR = 1.71, KLK8: HR = 1.60), and hepatocellular carcinoma (KLK13: HR = 1.75). Methods: The RNA-seq gene expression data were downloaded from The Cancer Genome Atlas (TCGA). Statistical analyses, including differential expression analysis, receiver operating characteristic curves and survival analysis (Cox proportional-hazards regression models) were performed. Conclusions: A comprehensive analysis revealed the changes in the expression of different KLK genes associated with specific cancers and highlighted their potential as a diagnostic and prognostic tool. PMID- 29707156 TI - Dose-finding study of oxaliplatin associated to capecitabine-based preoperative chemoradiotherapy in locally advanced rectal cancer. AB - Introduction: Proper administration timing, dose-intensity, efficacy/toxicity ratio of oxaliplatin added to fluoropyrimidin should be improved to safely perform two-drugs intensive preoperative chemoradiotherapy in locally advanced rectal cancer (LARC). This dose-finding study investigated recommended oxaliplatin dose, safety of oxaliplatin/capecitabine regimen and preliminary activity. Methods: Schedule: oxaliplatin dose-levels, 35-40 mg/m2/week; capecitabine 825 mg/m2/ twice daily, radiotherapy on rectum/nodes, 50/45 Gy, 45 and 9 boost/45 Gy, in first 5 and subsequent patients, 5 days/week, respectively; for 5 weeks. Pathologic complete response (pCR) 10% was projected in order to positively affect clinical outcome. Results: Seventeen fit <75 years patients enrolled: median age 60; young-elderly 4 (23%); T3/T4, 15/2, N0/N1/N2, 7/9/1. At first dose-level, no dose-limiting toxicity (DLT). At second, 2 DLT, G3 mucositis, G3 thrombocytopenia, in 2/6 patients (33%). Oxaliplatin recommended dose, 40 mg/m2/week. Cumulative G3-4 toxicities: mucositis 6%, thrombocytopenia 6%. Limiting toxicity syndromes 18%, 25% in young-elderly, all single site. Objective response rate intent-to-treat 94%. Sphinter preservation 87%, pCR 6%. After 17 months follow-up, progression-free survival and overall survival were not reached. Conclusions: Oxaliplatin can be safely added to preoperative capecitabine-based chemoradiotherapy at the recommended dose 40 mg/m2/week, in LARC, with promising pCR and high activity. PMID- 29707157 TI - Microbiota effects on cancer: from risks to therapies. AB - Gut microbiota, a group of 1014 bacteria, eukaryotes and virus living in gastrointestinal tract, is crucial for many physiological processes in particular plays an important role in inflammatory and immune reactions. Several internal and external factors can influence this population, and shifts in their composition, have been demonstrated to contribute and affect different diseases. During dysbiosis several bacteria related to inflammation, one of the most necessary factors in carcinogenesis; it has been shown that some bacterial strains through deregulation of different signals/pathways may affect tumor development through the production of many factors. Gut microbiota might be considered as a holistic hub point for cancer development: direct and indirect involvements have been studying in several neoplasms such as colon rectal cancer, hepatocellular carcinoma and breast cancer. This review discuss over the evidence of crosstalk between gut microbiota and cancer, its ability to modulate chemotherapy, radiotherapy and immunotherapy, and the possibility that the intestinal microbial is a new target for therapeutic approaches to improve the prognosis and quality of life of cancer patients. PMID- 29707158 TI - Differential role of CXCR3 in inflammation and colorectal cancer. AB - Chemokines (CXCR3) and their ligands (CXCL9, CXCL10, and CXCL11) exert exquisite control over T-cell trafficking and are critical for activation, differentiation and effector T cell function. CXCR3 is important for CD4 Th1 cells, CD8 effectors, memory cells, and for the function of natural killer and natural killer T cells. The presence of high cytotoxic CXCR3 ligand expression on CD8 T cells in colorectal cancerous tissue has been well documented in the past. CXCR3 and its ligands are differentially expressed at sites of inflammation and within the tumors. Further, the expression of CXCR3 and its ligands has been correlated with both the presence of effector T cells within tumor tissue and disease-free survival of patients. However, effector T cell infiltration into primary and metastatic tumors is highly variable and, in fact, often absent. Thus, understanding why T cells fail to infiltrate into tumors and determining the way to improve effector T cell entry into tumors would be important advances in efforts to harness the power of the immune system to fight cancer. To this end, the recent exciting discovery that CXCR3 is functionally expressed on regulatory T cells and also induces the differentiation of peripheral CD4 T cells into regulatory T cells, might address the novel clinically relevant question of the therapeutic potential of the CXCR3 system. This is also coupled with the fact that increases in CXCR3 expression also improves effector T cell function. This review describes the differential role of CXCR3 induction on peripheral and tumor microenvironment inflammation. Further, this review, tied with important findings from our laboratory, demonstrates that polyphenols induce CXCR3 expression on regulatory T cells and increases CXCR3 ligands in the tumor microenvironment, which act together to suppress colorectal cancer through a differential mechanism discussed herewith. PMID- 29707159 TI - Phytochemicals as modulators of M1-M2 macrophages in inflammation. AB - Macrophages are critical mediators of the innate immune response against foreign pathogens, including bacteria, physical stress, and injury. Therefore, these cells play a key role in the "inflammatory pathway" which in turn can lead to an array of diseases and disorders such as autoimmune neuropathies and myocarditis, inflammatory bowel disease, atherosclerosis, sepsis, arthritis, diabetes, and angiogenesis. Recently, more studies have focused on the macrophages inflammatory diseases since the discovery of the two subtypes of macrophages, which are differentiated on the basis of their phenotype and distinct gene expression pattern. Of these, M1 macrophages are pro-inflammatory and responsible for inflammatory signaling, while M2 are anti-inflammatory macrophages that participate in the resolution of the inflammatory process, M2 macrophages produce anti-inflammatory cytokines, thereby contributing to tissue healing. Many studies have shown the role of these two subtypes in the inflammatory pathway, and their emergence appears to decide the fate of inflammatory signaling and disease progression. As a next step in directing the pro-inflammatory response toward the anti-inflammatory type after an insult by a foreign pathogen (e. g., bacterial lipopolysaccharide), investigators have identified many natural compounds that have the potential to modulate M1 to M2 macrophages. In this review, we provide a focused discussion of advances in the identification of natural therapeutic molecules with anti-inflammatory properties that modulate the phenotype of macrophages from M1 to M2. PMID- 29707162 TI - Correction: Long non-coding RNA HoxA-AS3 interacts with EZH2 to regulate lineage commitment of mesenchymal stem cells. AB - [This corrects the article DOI: 10.18632/oncotarget.11538.]. PMID- 29707161 TI - Immunotherapy in mucosal melanoma: a case report and review of the literature. AB - Background: Mucosal melanoma is a rare form of melanoma presenting variably as sores or unexplained bleeding located mainly in the head and neck region, anorectal region or female genital tract. Mucosal melanoma is usually diagnosed at an advanced stage and is characterized by an aggressive behavior. Surgery represents the mainstay of treatment for early stage melanomas, but for advanced disease there have been until recently very limited treatment options. Ipilimumab, a human monoclonal antibody directed against the cytotoxic T lymphocyte antigen 4, was the first treatment modality to demonstrate survival benefit in advanced malignant melanoma. Method: Description of a new case and review of the literature. Results: We present here a patient with mucosal melanoma with aggressive biological behavior and documented late response to ipilimumab. Conclusions: Ipilimumab represents an effective treatment option in selected patients with mucosal melanoma. PMID- 29707163 TI - Correction: A tissue factor-cascade-targeted strategy to tumor vasculature: a combination of EGFP-EGF1 conjugation nanoparticles with photodynamic therapy. AB - [This corrects the article DOI: 10.18632/oncotarget.12922.]. PMID- 29707160 TI - Pathogenic role for macrophage migration inhibitory factor in glioblastoma and its targeting with specific inhibitors as novel tailored therapeutic approach. AB - Macrophage Migration Inhibitory Factor (MIF) is a pro-inflammatory cytokine expressed by a variety of cell types. Although MIF has been primarily studied for its role in the pathogenesis of autoimmune diseases, it has also been shown to promote tumorigenesis and it is over expressed in various malignant tumors. MIF is able to induce angiogenesis, cell cycle progression, and to block apoptosis. As tailored therapeutic approaches for the inhibition of endogenous MIF are being developed, it is important to evaluate the role of MIF in individual neoplastic conditions that may benefit from specific MIF inhibitors. Along with this line, in this paper, we have reviewed the evidence of the involvement of MIF in the etiopathogenesis and progression of glioblastoma and the preclinical data suggesting the possible use of specific MIF inhibition as a potential novel therapeutic strategy for brain tumors. PMID- 29707164 TI - Outcomes after asystole events occurring during wearable defibrillator cardioverter use. AB - AIM: To examine whether wearable cardioverter defibrillator (WCD) alarms for asystole improve patient outcomes and survival. METHODS: All asystole episodes recorded by the WCD in 2013 were retrospectively analyzed from a database of device and medical record documentation and customer call reports. Events were classified as asystole episodes if initial presenting arrhythmia was asystole (< 10 beats/minor >= 5 s pause). Survival was defined as recovery at the scene or arrival to a medical facility alive, or not requiring immediate medical attention. Episodes occurring in hospitals, nursing homes, or ambulances were considered to be under medical care. Serious asystole episodes were defined as resulting in unconsciousness, hospital transfer, or death. RESULTS: Of the total 51933 patients having worn the WCD in 2013, there were 257 patients (0.5%) who had asystole episodes and comprised the study cohort. Among the 257 patients (74% male, median age 69 years), there were 264 asystole episodes. Overall patient survival was 42%. Most asystoles were considered "serious" (n = 201 in 201 patients, 76%), with a 26% survival rate. All 56 patients with "non-serious" asystole episodes survived. Being under medical care was associated with worse survival of serious asystoles. Among acute survivors, 20% later died during WCD use (a median 4 days post asystole episode). Of the 86 living patients at the end of WCD use period, 48 (56%) received ICD/pacemaker and 17 (20%) improved their condition. CONCLUSION: Survival rates after asystole in patients with WCD are higher than historically reported survival rates. Those under medical care at time of asystole exhibited lower survival. PMID- 29707165 TI - Preventive fraction of physical fitness on risk factors in cardiac patients: Retrospective epidemiological study. AB - AIM: To quantify the preventive fraction of physical fitness on the risk factors in patients with cardiovascular diseases (CVDs). METHODS: A total of 249 subjects (205 men and 44 women) suffering from CVD were categorized into four groups, according to their percentage of physical fitness. We calculated the odds ratio to obtain the preventive fraction in order to evaluate the impact of the physical fitness level on the risk factors (i.e., abdominal obesity, depression, diabetes, dyslipidemia, hypertension, obesity, overweight and smoking). RESULTS: It is observed that a normal physical fitness level is sufficient to induce a preventive action on abdominal obesity (38%), diabetes (12%), hypertension (33%), obesity (12%) and overweight (11%). Also, the preventive fraction increases with the level of physical fitness, in particular for hypertension (36%) and overweight (16%). A high physical fitness level does not necessarily induce a preventive action in most risk factors, excluding depression. CONCLUSION: This is the first study which demonstrates that reaching a normal physical fitness level is enough to induce a protection for some risk factors, despite having a CVD. PMID- 29707166 TI - Pre-deployment dissociation and personality as risk factors for post-deployment post-traumatic stress disorder in Danish soldiers deployed to Afghanistan. AB - Objective: This study investigated whether pre-deployment dissociation was associated with previously identified post-traumatic stress disorder (PTSD) symptom trajectories from before to 2.5 years after military deployment. Furthermore, it examined whether the tendency to dissociate, pre-deployment personality factors, conceptualized by the Big Five model, and previous trauma represented independent risk factors for post-deployment PTSD symptoms. Method: This prospective study included the entire team of 743 soldiers from the Danish Contingent of the International Security Assistance Force 7 deployed to Afghanistan in 2009. Data consisted of self-report measures and were collected six times: before deployment; during deployment; and 1-3 weeks, 2 months, 7 months and 2.5 years after homecoming. Results: The findings indicate significant associations between pre-deployment dissociation and six PTSD trajectories (p < 0.001, eta2 = 0.120). Based on mean differences in dissociation for the six trajectories, two main groups emerged: a group with high dissociation scores at pre-deployment, which had moderate PTSD symptom levels at pre-deployment and fluctuated over time; and a group with low dissociation scores at pre-deployment, which had low initial PTSD symptom levels and diverged over time. Our study also confirmed previous findings of a positive association between neuroticism and dissociation (r = 0.31, p < 0.001). This suggests that negative emotionality may be a vulnerability that enhances dissociative experiences, although a causal link cannot be concluded from the findings. Finally, pre-deployment dissociation, pre deployment neuroticism and a history of traumatic events, as independent factors, were significant predictors of post-deployment PTSD (p < 0.001, R2 = 0.158). Conclusions: The study emphasizes the multiplicity of factors involved in the development of PTSD, and group differences in dissociative symptoms support the heterogeneity in PTSD. Further, this study points to specific aspects of personality that may be targeted in a clinical setting and in pre-deployment assessments in the military. PMID- 29707167 TI - Anhedonia and emotional numbing in treatment-seeking veterans: behavioural and electrophysiological responses to reward. AB - Background: Anhedonia is a common symptom following exposure to traumatic stress and a feature of the PTSD diagnosis. In depression research, anhedonia has been linked to deficits in reward functioning, reflected in behavioural and neural responses. Such deficits following exposure to trauma, however, are not well understood. Objective: The current study aims to estimate the associations between anhedonia, PTSD symptom-clusters and behavioural and electrophysiological responses to reward. Methods: Participants (N = 61) were recruited among Danish treatment-seeking veterans at the Department of Military Psychology in the Danish Defence. Before entering treatment, participants were screened with symptom measurement instruments and participated in a joint behavioural electrophysiological experiment. The experimental paradigm consisted of a signal detection task aimed at assessing reward-driven learning. Simultaneous electrophysiological-recordings were analysed to evaluate neural responses upon receiving reward, as indicated by the Feedback-Related Negativity (FRN) component. Result: Anhedonia as conceptualized in depression correlated with behavioural learning (r = -0.28, p = .032). Neither anhedonia nor behavioural learning correlated with FRN. However, the anhedonia symptom cluster of PTSD did correlate with FRN (r = 0.29, p = .023). Extending upon this in an exploratory analysis, the specific PTSD-symptom emotional numbing was found to correlate moderately with FRN (r = 0.38, p = .003). Conclusion: The present data suggest that anhedonia in trauma-exposed individuals is related to the anticipatory aspect of reward, whereas the neural consummatory reward response seems unlinked. Interestingly, emotional numbing in the same population is related to the consummatory phase of reward, correlating with the FRN response. This suggests that anhedonia and emotional numbing in response to trauma might pertain to different phases of reward processing. PMID- 29707168 TI - Leadership and post-traumatic stress disorder: are soldiers' perceptions of organizational justice during deployment protective? AB - Background: Soldiers' perception of leadership during military deployment has gained research attention as a potentially modifiable factor to buffer against the development of postdeployment post-traumatic stress disorder (PTSD). Within nonmilitary research, the organizational justice (OJ) framework, i.e. distributive justice, procedural justice (PJ) and interactional justice (IJ), has been found to relate to mental health outcomes. Aspects of OJ may, therefore, be protective against PTSD. Objectives: We examined the prospective relationship between aspects of OJ, namely the perceptions of PJ and IJ by subordinate soldiers without leadership obligations in relationship to immediate superiors and PTSD. Method: Participants were soldiers (n = 245) deployed to Helmand Province in Afghanistan in 2009. Logistic regression procedures were used. The primary analysis measured PTSD cases using the Structured Clinical Interview for DSM-IV-TR Axis-I Disorder (SCID) 21/2 years after homecoming. PJ/IJ was measured during deployment with a 6-item composite measure ranging from 0 to 12. Supplementary primary analyses were performed with PJ/IJ measured before and immediately after deployment. A secondary PJ/IJ analysis also tested against four postdeployment measures with the Post-Traumatic Stress Disorder Checklist Civilian (PCL-C) dichotomized at screening symptom levels. Results: Higher levels of perceived PJ/IJ for soldiers without leadership obligations during deployment had a prospective relation (OR = 0.86, 95% CI = 0.75-0.98) with PTSD on the SCID 21/2 years after homecoming after adjustment for factors including predeployment PTSD symptoms, trauma and combat exposure, and state affectivity. Similar results were found by measuring PJ/IJ before (OR = 0.83, 95% CI = 0.71-0.95) but not immediately after homecoming (OR = 0.97, 95% CI = 0.85-1.11). A relationship with PTSD symptoms at the screening level at the four measurements of PCL-C was found, but only when predeployment PTSD symptoms were not controlled for. Conclusions: These results suggest that PJ/IJ exercised by superiors in relation to military deployments may protect subordinate soldiers against the development of postdeployment PTSD. PMID- 29707169 TI - Testing competing factor models of the latent structure of post-traumatic stress disorder and complex post-traumatic stress disorder according to ICD-11. AB - With the publication of the International Statistical Classification of Diseases and Related Health Problems, 11th edition (ICD-11) due for release in 2018, a number of studies have assessed the factorial validity of the proposed post traumatic stress disorder (PTSD) and complex (CPTSD) diagnostic criteria and whether the disorders are correlated but distinct constructs. As the specific nature of CPTSD symptoms has yet to be firmly established, this study aimed to examine the dimension of affect dysregulation as two separate constructs representing hyper-activation and hypo-activation. Seven alternative models were estimated within a confirmatory factor analytic framework using the International Trauma Questionnaire (ITQ). Data were analysed from a young adult sample from northern Uganda (n = 314), of which 51% were female and aged 18-25 years. Forty per cent of the participants were former child soldiers (n = 124) while the remainder were civilians (n = 190). The prevalence of CPTSD was 20.8% and PTSD was 13.1%. The results indicated that all models that estimated affective dysregulation as distinct but correlated constructs (i.e. hyper-activation and hypo-activation) provided satisfactory model fit, with statistical superiority for a seven-factor first-order correlated model. Furthermore, individuals who met the criteria for CPTSD reported higher levels of war experiences, symptoms of anxiety and depression, and somatic problems than those with PTSD only and no diagnosis. There was also a much larger proportion of former child soldiers that met the criteria for a CPTSD diagnosis. In conclusion, these results partly support the factorial validity of the ICD-11 proposals for PTSD and CPTSD in a non-Western culture exposed to mass violence. These findings highlight that more research is required across different cultural backgrounds before firm conclusions can be made regarding the factor structure of CPTSD using the ITQ. PMID- 29707170 TI - Tracheal collapse diagnosed by multidetector computed tomography: evaluation of different image analysis methods. AB - Background: The gold standard for diagnosing excessive tracheal collapse is still evaluation during bronchoscopy. Today, multidetector computed tomography (MDCT) is used to confirm a suspicion of abnormal tracheal collapse. There is no gold standard for computed tomography (CT) image analysis of tracheal collapse. Purpose: To evaluate four different methods for the diagnosis of tracheal collapse using the images obtained through MDCT to help clinicians evaluate the images in daily practice. Objectives: 374 consecutive high-resolution CT scans with full inspiratory and end-expiratory CT scans were retrospectively analyzed. Methods: The images were analyzed in four different ways. The degree of collapse was based on cross-sectional areas of individual locations or volumes of entire regions: (1) 1 cm above the carina, (2) the level of maximal collapse of the trachea, (3) the entire region from the carina to the thoracic inlet, and (4) the trachea and bronchial region as defined by the software. Results: We compared three existing and one new method for image analysis of tracheal collapse by MDCT. The prevalence of tracheal collapse varied from 10.7% to 19.5% in this cohort of patients suffering from mixed lung diseases when using an expiratory collapse of >=50% as a threshold. The four methods were comparable with highly significant Pearsons correlation coefficients (0.764-0.856). However, the four methods identified different patients with collapse of >=50%. There was no correlation between symptoms and the degree of collapse. Conclusion: The different methods identify tracheal collapse in different patients. Hence, the diagnosis of excessive tracheal collapse can not rely solely on MDCT images. Generally, there is a poor correlation between symptoms and the degree of collapse in the different methods. However, when using the maximal collapse, there is some correlation with symptoms. When in doubt regarding the diagnosis, further investigations, such as bronchoscopy, should be carried out. PMID- 29707171 TI - Study of respiratory chain dysfunction in heart disease. AB - The relentlessly beating heart has the greatest oxygen consumption of any organ in the body at rest reflecting its huge metabolic turnover and energetic demands. The vast majority of its energy is produced and cycled in form of ATP which stems mainly from oxidative phosphorylation occurring at the respiratory chain in the mitochondria. A part from energy production, the respiratory chain is also the main source of reactive oxygen species and plays a pivotal role in the regulation of oxidative stress. Dysfunction of the respiratory chain is therefore found in most common heart conditions. The pathophysiology of mitochondrial respiratory chain dysfunction in hereditary cardiac mitochondrial disease, the aging heart, in LV hypertrophy and heart failure, and in ischaemia-reperfusion injury is reviewed. We introduce the practicing clinician to the complex physiology of the respiratory chain, highlight its impact on common cardiac disorders and review translational pharmacological and non-pharmacological treatment strategies. PMID- 29707172 TI - Knowledge, attitude and practice of Iranian hypertensive patients regarding hypertension. AB - Introduction: This study aimed at evaluating knowledge and awareness of hypertension and the risk factors for hypertension among hypertensive patients. Methods: In this study, 110 hypertensive patients were enrolled and filled out two self-administered questionnaires. The first questionnaire was about the demographic characteristics and the second one was about the knowledge (n = 10), attitude (n = 9) and practice (n = 8). The internal consistency and the stability of the questionnaires were approved. The Mann-Whitney U test and Kruskal-Wallis and Spearman correlation coefficient were used for statistical analysis. Results: Seventy-three percent of participants know the normal range of hypertension. Most of the participants truly knew that stress (87.3%), obesity (70.9%) and aging (48.2%) are risk factors for hypertension. About 60% of participants knew the complications of uncontrolled hypertension. About 82.7% of participants believed that after adaptation of body to hypertension, there is no need to use antihypertensive drug. About 13.6% of participants measured their blood pressure daily and 11.8% of them measured it once a month. The educational level of participants was significantly associated with knowledge score (P = 0.01). There was a significant correlation between knowledge (P < 0.001) and attitude and also attitude and practice (P < 0.001) scores. Conclusion: These findings have important implications for developing proper and continuous self-management hypertension education programs in Iran which should mostly emphasize on the practical information about control and prevention programs. PMID- 29707174 TI - Development of a self-care program satisfaction questionnaire for cardiovascular patients in Iran. AB - Introduction: Evaluating patient satisfaction with self-care program can increase the likelihood of complying with treatment. There is no valid and reliable tool to be used in measuring Iranian patient's satisfaction with self-care program. So, this study intends to develop the patient satisfaction questionnaire in the context of cardiac rehabilitation and test its validity and reliability in Iranian patients. Methods: A cross-sectional study was conducted to develop and validate the patient satisfaction with self-care program questionnaire using structural modeling. A total of 155 cardiovascular patients referring to cardiovascular rehabilitation center in Isfahan were participated in this study. Construct and criterion validity, and test-retest reliability were used to validate the scale. Results: After reviewing literature and receiving expert' comments for items pooling as well as conducting exploratory factor analysis, 10 statements in the model remained which are loaded on 2 factors. These 2 subscales explained about 63 percent of variance of all constructs. The Cronbach's alpha coefficient ranged between 0.87 and 0.89 for the whole questionnaires and its subscales. Besides, scale had excellent stability (intraclass correlation = 0.86). Criterion validity analyzed through correlational analyses revealed significant relationships between the current scale and Patient Satisfaction Questionnaire Short Form (PSQ11). CFA revealed an acceptable overall fit for two factor model. Conclusion: The scale integrated 10 items in two dimension including patient satisfaction with rehabilitation program and patient satisfaction with personnel of rehabilitation team. In total, most of the psychometric properties of the 10-item patient satisfaction with self-care program scale achieved the standard level and were sufficient to recommend for cardiac rehabilitation settings. PMID- 29707173 TI - Analysis of the mutations in exon 10 of MEFV gene in patients with premature coronary heart disease in west Azerbaijan province of Iran. AB - Introduction: Premature coronary heart disease (PCHD) affects public health and leads to death. PCHD has several genetic and environmental risk factors. The aim of this study was to analysis of the mutations in exon 10 of MEFV gene in patients with PCHD in West Azerbaijan province of Iran. Methods: Totally 41 PCHD patients who were admitted to the cardiology unit of Sayedoshohada hospital (Urmia, Iran) enrolled in the study. Selection of the patients was done based on the strict criteria, that is, who had a minimum of one angiographically documented coronary artery with the stenosis of 50%. Mutations in exon 10 of MEFV gene were found by direct sequencing. Results: V726A, M680I, K695R, and A744S mutations with 2.44%, 1.22%, 1.22%, and 1.22%, allelic frequency were found, respectively. Five patients (12.2%) with PCHD carried at least one mutated MEFV allele. Heterozygote V726A was the most frequent mutation among tested cases (4.88%), followed by heterozygote M680I, heterozygote K695R, and heterozygote A744S. Conclusion: The results of the present study imply that the frequency of the MEFV gene exon 10 is significantly high in PCHD patients. This is the first report in its own kind in clinically diagnosed PCHD pa-tients of Iranian Azeri Turkish population. PMID- 29707175 TI - Comparative study of short-term cardiovascular autonomic control in cardiac surgery patients who underwent coronary artery bypass grafting or correction of valvular heart disease. AB - Introduction: Our aim was to perform a comparative study of short-term cardiovascular autonomic control in cardiac surgery patients who underwent coronary artery bypass grafting (CABG) or surgical correction of valvular heart disease (SCVHD ). Methods: The synchronous 15 minutes records of heart rate variability (HRV) and finger's photoplethysmographic waveform variability (PPGV) were performed in 42 cardiac surgery patients (12 women) aged 61.8 +/- 8.6 years (mean +/- standard deviation), who underwent CABG, and 36 patients (16 women) aged 54.2 +/- 14.9 years, who underwent SCVHD , before surgery and in 5-7 days after surgery. Conventional time and frequency domain measures of HRV and index S of synchronization between the slow oscillations in PPGV and HRV were analyzed. We also calculated personal dynamics of these indices after surgery. Results: We found no differences (R > 0.05) in all studied autonomic indices (preoperative and post-surgery) between studied patients' groups, except for the preoperative heart rate, which was higher in patients who underwent SCVHD (P = 0.013). We have shown a pronounced preoperative and post-surgery variability (magnitude of inter quartile ranges) of all autonomic indices in studied patients. In the cluster analysis based on cardiovascular autonomic indices (preoperative and post surgery), we divided all patients into two clusters (38 and 40 subjects) which did not differ in all clinical characteristics (except for the preoperative hematocrit, P = 0.038), index S, and all post-surgery HRV indices. First cluster (38 patients) had higher preoperative values of the HR, TP, HF, and HF%, and lower preoperative values of the LF% and LF/HF. Conclusion: The variability of cardiovascular autonomic indices in on-pump cardiac surgery patients (two characteristic clusters were identified based on preoperative indices) was not associated with their clinical characteristics and features of surgical procedure (including cardioplegia). PMID- 29707176 TI - Predictors of short-term mortality after acute stroke in East Azerbaijan province, 2014. AB - Introduction: Stroke is one of the important causes of death and disability in Iran. This study aimed to examine the factors influencing the short-term mortality of stroke in Northwest of Iran. Methods: Study population were all patients with confirming the diagnosis of the first-ever stroke who were hospitalized in two referral teaching hospitals from October 2013 to March 2015. They were followed up to 30 days after onset of stroke. A neurology year three resident was responsible for extracting the clinical data and assessment of stroke severity on admission using National Institute of Health Stroke Scale (NIHSS), and information about risk factors and socio-demographic factors were collected using face to face interview. Data were analysed using Cox proportional regression by STATA software version 14. Results: A total of 1036 consecutive patients with first-ever stroke were included in this study. Of them, 228 patients (22%) died within 30 days after stroke accordance. Advanced age was significantly associated with a hazard for early mortality (HR=1.05 95% CI 1.09 1.04), the inverse was true for education level; mortality decreased as the education level increased; it was 25.7 percent among illiterate and 14.3 among patients with higher education. The NIHSS score on admission for 30-days mortality and hemorrhagic stroke were associated with HR=1.11 (95% CI 1.09-1.13) and HR= 1.65 (95% CI 1.15-2.36) respectively. Conclusion: Advanced age, stroke subtype and high NIHSS score are the independent predictors of early mortality in this study. This provides important implications for the clinicians to target the high-risk patients for the specific therapies and management strategies. PMID- 29707177 TI - Identification of a novel non-sense mutation in TBX5 gene in pediatric patients with congenital heart defects. AB - Introduction: Congenital heart diseases (CHDs) are structural cardiovascular malformations that arise from abnormal development of the heart during the prenatal life. Mutations in the TBX5 gene, encoding T-box transcription factor, are a major cause of CHD. To evaluate the TBX5 mutations in hotspot exons in sporadic pediatric patients with CHD phenotypes, analytical case/control study performed in an Iranian cohort of unrelated patients with clinical diagnosis of congenital heart malformations. Methods: We investigated TBX5 coding exons 4, 5, 6 and 7 in 95 sporadic patients with CHD phenotypes and compared to 82 healthy controls using PCR-SSCP and DNA sequencing approaches. Results: We report here on a novel and heterozygote Non-sense mutation in exon 5 of TBX5, E128X (G14742T), in two Iranian children. This mutation locates inside the T-box and both of pediatric patients carrying this novel mutation suffer from severe heart malformations. The G14742T mutation leads to the substitution of glutamic acid (E) by stop codon (X) at residue 128, an evolutionarily conserved position in T box as well as in other species. The non-sense mutation of E128X was predicted to be pathogenic by Mutation Taster and Polyphen software programs. Conclusion: TBX5 E128X mutation results in a translational premature stop. This type of mutation results in a shortened protein that may function improperly and which cannot bind to other transcription factors; therefore, haploinsufficiency of TBX5 protein is presumably causing the severe cardiac malformations in these patients. PMID- 29707178 TI - CHA2DS2-VASc Score Predict No-Reflow Phenomenon in Primary Percutaneous Coronary Intervention in Primary Percutaneous Coronary Intervention. AB - Introduction: No-reflow is one of the major complications of primary PCI in patients with acute ST elevation myocardial infarction. This phenomenon is associated with adverse outcomes in these patients. In the current study, we evaluated the effectiveness of CHA2DS2-VASc score in predicting no-reflow phenomenon. CHA2DS2-VASc score is a risk stratification method to estimate the risk of thromboembolism in patients with atrial fibrillation. Methods: In total, 396 patients with ST elevation myocardial infarction who had undergone primary PCI were evaluated in our study. Based on post interventional TIMI flow rate results, the patients were divided into two groups: control group (294 patients) and no-reflow group (102 patients). The CHA2DS2-VASc score was calculated for each participant. Multivariate regression analysis was performed to determine the predictive value of this score. Results: Our findings showed that CHA2DS2-VASc score can predict no-reflow independently (odds ratio: 3.06, 95%, confidence interval: 2.23-4.21, P <0 .001). Moreover, lower systolic blood pressure, higher diastolic blood pressure, grade 0 initial TIMI flow rate and smaller stent size were other independent predictors of the no-reflow in our study. We also defined a cut off value of >= 2 for the CHA2DS2-VASc score in predicting the no-reflow with a sensitivity of 88% and specificity of 67%, area under curve: 0.83 with 95% CI (0.79-0.88). Conclusion: The CHA2DS2-VASc score could be used as a simple applicable tool in the prediction of no-reflow before primary PCI in the acute ST elevation myocardial infarction patients. PMID- 29707179 TI - Pigtail saves a twisted redo: successful management of chylopericardium after midline valve surgery. AB - Pericardial effusion after midline cardiac surgery may be transudative or exudative. The exudative infective or haemorrhagic variety requires early surgical intervention. However there are rare cases of collections like chylomediastinum which should be ruled out. Their low incidence prompts to establish protocol for evaluating postoperative pericardial collections, which includes echocardiography and biochemical analysis of aspirate. The same is important from the perspective of management as chylopericardium may be successfully managed without surgical intervention by aspiration, pig tail insertion, dietary and medical management, which we demonstrate through our rare case which occurred after midline double valve replacement. PMID- 29707180 TI - Accuracy of Guided Surgery via Stereolithographic Mucosa-Supported Surgical Guide in Implant Surgery for Edentulous Patient: a Systematic Review. AB - Objectives: The purpose of the present study is to systematically review the accuracy of implant placement with mucosa-supported stereolithographic surgical guide and to find out what factors can influence the accuracy. Material and Methods: An electronic literature search was performed through the MEDLINE (PubMed) and EMBASE databases. The articles are including human studies published in English from October 2008 to October, 2017. From the examination of selected articles, deviations between virtual planning and actual implant placement were analysed regarding the global apical, global coronal, and angulation position. Results: A total of 119 articles were reviewed, and 6 of the most relevant articles that are suitable to the criteria were selected. The present data included 572 implants and 93 patients. The result in the present systematic review shows that mean apical global deviation ranges from 0.67 (SD 0.34) mm to 2.19 (SD 0.83) mm, mean coronal global deviation ranges from 0.6 (SD 0.25) mm to 1.68 (SD 0.25) mm and mean angular deviation - from 2.6 degrees (SD 1.61 degrees ) to 4.67 degrees (SD 2.68 degrees ). Conclusions: It's clearly shown from most of the examined studies that the mucosa-supported stereolithographic surgical guide, showed not exceeding in apically 2.19 mm, in coronally 1.68 mm and in angular deviation 4.67 degrees . Surgeons should be aware of the possible linear and angular deviations of the system. Accuracy can be influenced by bone density, mucosal thickness, surgical techniques, type of jaw, smoking habits and implant length. Further studies should be performed in order to find out which jaw can have better accuracy and how the experience can influence the accuracy. PMID- 29707181 TI - Dental Stem Cells Harvested from Third Molars Combined with Bioactive Glass Can Induce Signs of Bone Formation In Vitro. AB - Objectives: The aim of this study was to assess the interaction of a bioactive glass scaffold with cells derived from dental pulp, dental follicle and periodontal ligament. Material and Methods: Impacted third molars were surgically removed from three young donors. Cells from the dental pulp, follicle and periodontal ligament tissues were isolated and expanded. Different cell populations were characterised using specific CD markers. Expanded pulp, follicle and periodontal cells were then seeded onto bioactive glass scaffolds and cultured in osteogenic medium or basic medium. Cell attachment, viability, proliferation and alkaline phosphatase activity were assessed. Results: This study revealed good biocompatibility of the specific bioactive glass configuration tested and the osteogenic induction of cells derived from dental pulp, dental follicle and periodontal ligament. Osteogenic medium seemed to increase the differentiation pattern and dental pulp stem cells showed the most positive results compared to periodontal ligament and dental follicle stem cells. Conclusions: Dental pulp stem cells combined with a bioactive glass scaffold and exposed to osteogenic medium in vitro represent a promising combination for future study of hard tissue regeneration in the cranio-maxillofacial skeleton. PMID- 29707182 TI - Immunohistochemical Study of Laminin-332 gamma2 Chain and MMP-9 in High Risk of Malignant Transformation Oral Lesions and OSCC. AB - Objectives: Oral squamous cell carcinoma is associated with alterations in basement membrane. Laminin-332 is present in basal lamina and performs multiple biologic effects by gamma2 chain. Matrix metalloproteinase acts disrupting extracellular components and was related to poor prognosis in cancer. Here, molecular profile of laminin-332 gamma2 chain and matrix metalloproteinase-9 was assessed in oral lesions. Material and Methods: The expression of laminin-332 gamma2 chain and matrix metalloproteinase-9 (MMP-9) was examined by immunohistochemistry in 10 patients with high risk of malignant transformation oral lesions and 26 cases of oral squamous cell carcinoma (OSCC). Associations between microscopic and clinicopathologic features were established. Results: Immunostaining of laminin-332 gamma2 chain in high risk oral lesions was most detected in basement membrane which is continuous, while the majority of OSCC cases showed a discontinuous membrane (P = 0.001). It was observed a positive reaction for gamma2 chain in invasive fronts and a higher expression in epithelial compartment of smoking patients with OSCC (P < 0.0001). In epithelium, MMP-9 expression was presented in all layers with no difference between lesions. However, an elevated immunostaining in stromal cells was associated with male patients (P = 0.0054), older than 60 years (P = 0.0101) and with OSCC. Conclusions: Present study results support the hypothesis of changes in molecules expression in high risk oral lesions and oral squamous cell carcinoma. A relation between clinical and molecule profile was observed. Those molecules may represent a useful tool to predict oral cancer behaviour. PMID- 29707183 TI - An Investigation of the Morphology of the Petrotympanic Fissure Using Cone-Beam Computed Tomography. AB - Objectives: The purpose of the present study was: a) to examine the visibility and morphology of the petrotympanic fissure on cone-beam computed tomography images, and b) to investigate whether the petrotympanic fissure morphology is significantly affected by gender and age, or not. Material and Methods: Using Newtom VGi (QR Verona, Italy), 106 cone-beam computed tomography examinations (212 temporomandibular joint areas) of both genders were retrospectively and randomly selected. Two observers examined the images and subsequently classified by consensus the petrotympanic fissure morphology into the following three types: type 1 - widely open; type 2 - narrow middle; type 3 - very narrow/closed. Results: The petrotympanic fissure morphology was assessed as type 1, type 2, and type 3 in 85 (40.1%), 72 (34.0%), and 55 (25.9%) cases, respectively. No significant difference was found between left and right petrotympanic fissure morphology (Kappa = 0.37; P < 0.001). Furthermore, no significant difference was found between genders, specifically P = 0.264 and P = 0.211 for the right and left petrotympanic fissure morphology, respectively. However, the ordinal logistic regression analysis showed that males tend to have narrower petrotympanic fissures, in particular OR = 1.58 for right and OR = 1.5 for left petrotympanic fissure. Conclusions: The current study lends support to the conclusion that an enhanced multi-planar cone-beam computed tomography yields a clear depiction of the petrotympanic fissure's morphological characteristics. We have found that the morphology is neither gender nor age-related. PMID- 29707184 TI - Lichen Sclerosus of the Upper Lip: Report of a Case, Utilizing Shikata's Modified Orcein Stain, and Review of the Literature. AB - Objectives: Lichen sclerosus is a rare chronic inflammatory disorder, affecting mainly the skin and the anogenital mucosa, while oral lesions can be the primary or the only manifestation of the disease. A rare case of oral lichen sclerosus, assessed histopathologically and histochemically, is presented, along with a thorough review of the English language literature. Material and Methods: A 32 year-old female presented an asymptomatic white patch affecting the skin and the mucosa of the upper lip, without other mucocutaneous involvement. A partial biopsy of the lesion was performed, along with the histochemical Shikata's modified orcein stain for elastin fibres detection. A literature review was also performed, discussing the epidemiological data, clinical presentation, and treatment modalities of all published cases with oral involvement. Results: The histopathological evaluation revealed the presence of acellular zone underneath the basal layer of the epithelium, accompanied by deep band-like chronic inflammation. Shikata's modified orcein stain exhibited scarcity or loss of elastin fibres in the acellular subepithelial area. The diagnosis of lichen sclerosus was made. Topical application of corticosteroids was prescribed and resolution of the lesion was observed. Literature review revealed that oral lichen sclerosus is predominantly presented in females, as asymptomatic lesions of the lips and buccal mucosa; few cases have extraoral manifestations and topical corticosteroids are the main treatment intervention. Conclusions: Despite its rarity, lichen sclerosus should be considered in the clinical and histopathological differential diagnosis of white patches of the oral mucosa. For rendering proper diagnosis, the histochemical Shikata's modified orcein stain is a useful assessment tool. PMID- 29707185 TI - The Evolving Role of Information Technology in Haemovigilance Systems. AB - This work provides an overview and appraisal of the general evolution of IS/IT in haemovigilance, from which lessons can be learned for its future strategic management. An electronic survey was conducted among the members of the International Haemovigilance Network to compile information on the mechanisms implemented to gather, process, validate, and store these data, to monitor haemovigilance activity, and to produce analytical reports. Survey responses were analysed by means of descriptive statistics, and comments/observations were considered in the final discussion. The answers received from 23 haemovigilance organizations show a direct relationship between the number of collected notifications (i.e., communication of adverse effects and events) and the technical specifications of the haemovigilance system in use. Notably, IT is used in the notification reception of 17 of these systems, out of which 8 systems are exclusively based on Web solutions. Most assessments of the evolution of IS/IT tend to focus on the scalability and flexibility of data gathering and reporting, considering the ever-changing requirements of haemovigilance. Data validation is poorly implemented, and data reporting has not reached its full potential. Web based solutions are seen as the most intuitive and flexible for a system-user interaction. PMID- 29707186 TI - A Novel Neural Network Model for Blood Pressure Estimation Using Photoplethesmography without Electrocardiogram. AB - The prevention, evaluation, and treatment of hypertension have attracted increasing attention in recent years. As photoplethysmography (PPG) technology has been widely applied to wearable sensors, the noninvasive estimation of blood pressure (BP) using the PPG method has received considerable interest. In this paper, a method for estimating systolic and diastolic BP based only on a PPG signal is developed. The multitaper method (MTM) is used for feature extraction, and an artificial neural network (ANN) is used for estimation. Compared with previous approaches, the proposed method obtains better accuracy; the mean absolute error is 4.02 +/- 2.79 mmHg for systolic BP and 2.27 +/- 1.82 mmHg for diastolic BP. PMID- 29707187 TI - Numerical Response Surfaces of Volume of Ablation and Retropulsion Amplitude by Settings of Ho:YAG Laser Lithotripter. AB - Objectives: Although laser lithotripsy is now the preferred treatment option for urolithiasis due to shorter operation time and a better stone-free rate, the optimal laser settings for URS (ureteroscopic lithotripsy) for less operation time remain unclear. The aim of this study was to look for quantitative responses of calculus ablation and retropulsion by performing operator-independent experiments to determine the best fit versus the pulse energy, pulse width, and the number of pulses. Methods: A lab-built Ho:YAG laser was used as the laser pulse source, with a pulse energy from 0.2 J up to 3.0 J and a pulse width of 150 MUs up to 1000 MUs. The retropulsion was monitored using a high-speed camera, and the laser-induced craters were evaluated with a 3-D digital microscope. The best fit to the experimental data is done by a design of experiment software. Results: The numerical formulas for the response surfaces of ablation speed and retropulsion amplitude are generated. Conclusions: The longer the pulse, the less the ablation or retropulsion, while the longer pulse makes the ablation decrease faster than the retropulsion. The best quadratic fit of the response surface for the volume of ablation varied nonlinearly with pulse duration and pulse number. PMID- 29707188 TI - Improved Multiscale Entropy Technique with Nearest-Neighbor Moving-Average Kernel for Nonlinear and Nonstationary Short-Time Biomedical Signal Analysis. AB - Analysis of biomedical signals can yield invaluable information for prognosis, diagnosis, therapy evaluation, risk assessment, and disease prevention which is often recorded as short time series data that challenges existing complexity classification algorithms such as Shannon entropy (SE) and other techniques. The purpose of this study was to improve previously developed multiscale entropy (MSE) technique by incorporating nearest-neighbor moving-average kernel, which can be used for analysis of nonlinear and non-stationary short time series physiological data. The approach was tested for robustness with respect to noise analysis using simulated sinusoidal and ECG waveforms. Feasibility of MSE to discriminate between normal sinus rhythm (NSR) and atrial fibrillation (AF) was tested on a single-lead ECG. In addition, the MSE algorithm was applied to identify pivot points of rotors that were induced in ex vivo isolated rabbit hearts. The improved MSE technique robustly estimated the complexity of the signal compared to that of SE with various noises, discriminated NSR and AF on single-lead ECG, and precisely identified the pivot points of ex vivo rotors by providing better contrast between the rotor core and the peripheral region. The improved MSE technique can provide efficient complexity analysis of variety of nonlinear and nonstationary short-time biomedical signals. PMID- 29707189 TI - A Review of Robotics in Neurorehabilitation: Towards an Automated Process for Upper Limb. AB - Robot-mediated neurorehabilitation is a growing field that seeks to incorporate advances in robotics combined with neuroscience and rehabilitation to define new methods for treating problems related with neurological diseases. In this paper, a systematic literature review is conducted to identify the contribution of robotics for upper limb neurorehabilitation, highlighting its relation with the rehabilitation cycle, and to clarify the prospective research directions in the development of more autonomous rehabilitation processes. With this aim, first, a study and definition of a general rehabilitation process are made, and then, it is particularized for the case of neurorehabilitation, identifying the components involved in the cycle and their degree of interaction between them. Next, this generic process is compared with the current literature in robotics focused on upper limb treatment, analyzing which components of this rehabilitation cycle are being investigated. Finally, the challenges and opportunities to obtain more autonomous rehabilitation processes are discussed. In addition, based on this study, a series of technical requirements that should be taken into account when designing and implementing autonomous robotic systems for rehabilitation is presented and discussed. PMID- 29707190 TI - Validity of Multisensor Array for Measuring Energy Expenditure of an Activity Bout in Early Stroke Survivors. AB - Introduction. Stroke survivors use more energy than healthy people during activities such as walking, which has consequences for the way exercise is prescribed for stroke survivors. There is a need for wearable device that can validly measure energy expenditure (EE) of activity to inform exercise prescription early after stroke. We aimed to determine the validity and reliability of the SenseWear-Armband (SWA) to measure EE and step-counts during activity <1 month after stroke. Materials and Methods. EE was measured using the SWA and metabolic cart and steps-counts were measured using the SWA and direct observation. Based on walking ability, participants performed 2x six-minute walks or repeated sit-to-stands. Concurrent validity and test-retest reliability were determined by calculating intraclass and concordance correlation coefficients. Results and Discussion. Thirteen participants walked; nine performed sit-to stands. Validity of the SWA measuring EE for both activities was poor (ICC/CCC < 0.40). The SWA overestimates EE during walking and underestimated EE during sit to-stands. Test-retest agreement showed an ICC/CCC of <0.40 and >0.75 for walking and sit-to-stand, respectively. However, agreement levels changed with increasing EE levels (i.e., proportional bias). The SWA did not accurately measure step counts. Conclusion. The SWA should be used with caution to measure EE of activity of mild to moderate stroke survivors <1 month after stroke. PMID- 29707191 TI - Environmental and Genetic Variables Influencing Mitochondrial Health and Parkinson's Disease Penetrance. AB - There is strong evidence that impairment of mitochondrial function plays a key role in the pathogenesis of PD. The two key PD genes related to mitochondrial function are Parkin (PARK2) and PINK1 (PARK6), and also mutations in several other PD genes, including SNCA, LRRK2, DJ1, CHCHD2, and POLG, have been shown to induce mitochondrial stress. Many mutations are clearly pathogenic in some patients while carriers of other mutations either do not develop the disease or show a delayed onset, a phenomenon known as reduced penetrance. Indeed, for several mutations in autosomal dominant PD genes, penetrance is markedly reduced, whereas heterozygous carriers of recessive mutations may predispose to PD in a dominant manner, although with highly reduced penetrance, if additional disease modifiers are present. The identification and validation of such modifiers leading to reduced penetrance or increased susceptibility in the case of heterozygous carriers of recessive mutations are relevant for a better understanding of mechanisms contributing to disease onset. We discuss genetic and environmental factors as well as mitochondrial DNA alterations and protein protein interactions, all involved in mitochondrial function, as potential causes to modify penetrance of mutations in dominant PD genes and to determine manifestation of heterozygous mutations in recessive PD genes. PMID- 29707192 TI - Evaluation of hearing level in patients on long term aspirin therapy. AB - INTRODUCTION: Aspirin is a routinely prescribed drug, most notably for cardiovascular diseases, such as myocardial ischemia. This cross sectional, comparative study study aims to explore differences in hearing status between the cardiovascular disease patients on aspirin therapy and age matched healthy controls. METHODS: The study population consisted of 182 patients with heart disease taking long term aspirin (i.e., for more than one year). The control population consisted of 221 age matched healthy controls who were not taking aspirin. RESULTS: Not aspirin, but the age of the patient was found to be the important risk factor for hearing loss. Conclusions: When confounding factors like age of the patient, hypertension and diabetes were taken into account, aspirin in its antiplatelet dose was not found to be the cause of any audiological problems like tinnitus and hearing loss. PMID- 29707194 TI - Rapid coral mortality following doldrums-like conditions on Iriomote, Japan. AB - Coral bleaching can be induced by many different stressors, however, the most common cause of mass bleaching in the field is high sea temperatures (SST). Here, we describe an unusual bleaching event that followed very calm sea conditions combined with higher than average sea surface temperatures (SST). Patterns of mortality differed from typical thermal bleaching in four ways: 1) mortality was very rapid; 2) the suite of species most affected was different; 3) tissue mortality in Acropora spp. was often restricted to the center of the colony; 4) the event occurred early in the summer. The two weeks prior to the event included 8 days where the average wind speed was less than 3 ms -1. In addition, SSTs in the weeks preceding this event were 1.0-1.5 degrees C higher than the mean for the last 30 years. We hypothesize that the lack of water movement induced by low wind speeds combined with high SST to cause colonies anoxic stress resulting in this unusual bleaching event. PMID- 29707195 TI - Case Report: A rare case of prosthetic valve infective endocarditis caused by Aerococcus urinae. AB - Infective endocarditis (IE) is a serious and life threatening cardiac condition, most commonly caused by staphylococci, streptococci, enterococci and rarely by HACEK organisms ( Haemophilus, Aggregatibacter, Cardiobacterium, Eikenella corrodens and Kingella). Here, we present a case of IE caused by Aerococcus urinae in a 75-year-old man with a bioprosthetic aortic valve. Aerococcus urinae is a gram-positive, catalase negative microorganism, and is usually an isolate of complicated urinary tract infections in the elderly male population. It is associated with high morbidity and mortality. Awareness of this organism as a cause of IE is important, since failure to recognize the condition may lead to adverse clinical outcomes and significant complications with even fatal outcome, as in this case. PMID- 29707193 TI - What do we know about grant peer review in the health sciences? AB - BACKGROUND: Peer review decisions award >95% of academic medical research funding, so it is crucial to understand how well they work and if they could be improved. METHODS: This paper summarises evidence from 105 relevant papers identified through a literature search on the effectiveness and burden of peer review for grant funding. RESULTS: There is a remarkable paucity of evidence about the overall efficiency of peer review for funding allocation, given its centrality to the modern system of science. From the available evidence, we can identify some conclusions around the effectiveness and burden of peer review. The strongest evidence around effectiveness indicates a bias against innovative research. There is also fairly clear evidence that peer review is, at best, a weak predictor of future research performance, and that ratings vary considerably between reviewers. There is some evidence of age bias and cronyism. Good evidence shows that the burden of peer review is high and that around 75% of it falls on applicants. By contrast, many of the efforts to reduce burden are focused on funders and reviewers/panel members. CONCLUSIONS: We suggest funders should acknowledge, assess and analyse the uncertainty around peer review, even using reviewers' uncertainty as an input to funding decisions. Funders could consider a lottery element in some parts of their funding allocation process, to reduce both burden and bias, and allow better evaluation of decision processes. Alternatively, the distribution of scores from different reviewers could be better utilised as a possible way to identify novel, innovative research. Above all, there is a need for open, transparent experimentation and evaluation of different ways to fund research. This also requires more openness across the wider scientific community to support such investigations, acknowledging the lack of evidence about the primacy of the current system and the impossibility of achieving perfection. PMID- 29707196 TI - Improving communication for interdisciplinary teams working on storage of digital information in DNA. AB - Close collaboration between specialists from diverse backgrounds and working in different scientific domains is an effective strategy to overcome challenges in areas that interface between biology, chemistry, physics and engineering. Communication in such collaborations can itself be challenging. Even when projects are successfully concluded, resulting publications - necessarily multi authored - have the potential to be disjointed. Few, both in the field and outside, may be able to fully understand the work as a whole. This needs to be addressed to facilitate efficient working, peer review, accessibility and impact to larger audiences. We are an interdisciplinary team working in a nascent scientific area, the repurposing of DNA as a storage medium for digital information. In this note, we highlight some of the difficulties that arise from such collaborations and outline our efforts to improve communication through a glossary and a controlled vocabulary and accessibility via short plain-language summaries. We hope to stimulate early discussion within this emerging field of how our community might improve the description and presentation of our work to facilitate clear communication within and between research groups and increase accessibility to those not familiar with our respective fields - be it molecular biology, computer science, information theory or others that might become relevant in future. To enable an open and inclusive discussion we have created a glossary and controlled vocabulary as a cloud-based shared document and we invite other scientists to critique our suggestions and contribute their own ideas. PMID- 29707197 TI - Case Report: Acute amyopathic dermatomyositis presenting with isolated facial edema. AB - A 45-year-old Asian man presented with acute-onset periorbital and facial edema associated with pyrexia. Muscle weakness was absent. Initial laboratory investigations showed an inflammatory reaction, while screening for infections was negative. Serum muscle enzyme levels were normal. He was hospitalized and treated empirically with antibiotics and corticosteroids, pending the result of facial skin and muscle biopsy. He showed a good clinical and laboratory response but an attempt to discontinue corticosteroids led to a prompt relapse of facial edema and pyrexia, associated with rising laboratory indices of inflammation. Biopsy findings were typical of dermatomyositis. Reintroduction of corticosteroid treatment resulted in complete clinical and laboratory remission. Facial edema as the sole clinical manifestation of dermatomyositis is extremely rare. There have been no previous reports of isolated facial edema in the setting of acute amyopathic dermatomyositis. A high level of suspicion is required to make the diagnosis in the absence of myopathy and the hallmark cutaneous manifestations of the disease (heliotrope rash, Gottron papules). PMID- 29707198 TI - Spatial band-pass filtering aids decoding musical genres from auditory cortex 7T fMRI. AB - Spatial filtering strategies, combined with multivariate decoding analysis of BOLD images, have been used to investigate the nature of the neural signal underlying the discriminability of brain activity patterns evoked by sensory stimulation -- primarily in the visual cortex. Reported evidence indicates that such signals are spatially broadband in nature, and are not primarily comprised of fine-grained activation patterns. However, it is unclear whether this is a general property of the BOLD signal, or whether it is specific to the details of employed analyses and stimuli. Here we performed an analysis of publicly available, high-resolution 7T fMRI on the response BOLD response to musical genres in primary auditory cortex that matches a previously conducted study on decoding visual orientation from V1. The results show that the pattern of decoding accuracies with respect to different types and levels of spatial filtering is comparable to that obtained from V1, despite considerable differences in the respective cortical circuitry. PMID- 29707199 TI - Epigenetic silencing of lncRNA MORT in 16 TCGA cancer types. AB - We have previously described a hominid-specific long non-coding RNA, MORT (also known as ZNF667-AS1, Gene ID: 100128252), which is expressed in all normal cell types, but epigenetically silenced during cancer-associated immortalization of human mammary epithelial cells. Initial analysis of The Cancer Genome Atlas (TCGA) showed that 15 of 17 cancer types, which represent the 10 most common cancers in women and men, display DNA methylation associated MORT silencing in a large fraction of their tumors. In this study we analyzed MORT expression and DNA methylation state in the remaining 16 TCGA cancer types not previously reported. Seven of the 16 cancer types showed DNA methylation linked MORT silencing in a large fraction of their tumors. These are carcinomas (cervical cancer, and cancers of esophagus, stomach, and bile duct), and the non-epithelial tumors mesothelioma, sarcoma, and uterine carcinosarcoma. Together with the findings from our previous report, MORT expression is silenced by aberrant DNA methylation in 22 of 33 of TCGA cancer types. These 22 cancers include most carcinoma types, blood derived cancers and sarcomas. In conclusion, results suggest that the MORT gene is one of the most common epigenetic aberrations seen in human cancer. Coupled with the timing of MORT gene silencing during in vitro epithelial cell immortalization and its occurrence early in the temporal arc of human carcinogenesis, this provides strong circumstantial evidence for a tumor suppressor role for MORT. PMID- 29707200 TI - Evaluation of portal pressure by doppler ultrasound in patients with cirrhosis before and after simvastatin administration - a randomized controlled trial. AB - Background: Portal hypertension is one of the most frequent complications of cirrhosis. beta-adrenergic blockers, with or without organic nitrates, are currently used as hypotensive agents. Statins such as simvastatin seem to be safe for patients with chronic liver diseases and exert multiple pleiotropic actions. This study aimed to assess PTH using Doppler ultrasound in patients with cirrhosis before and after simvastatin administration. Methods: This randomized controlled clinical trial was conducted on 40 patients with cirrhosis who were randomized into 2 groups: group I included 20 patients with cirrhosis who were administered 20 mg of simvastatin daily for 2 weeks and then 40 mg daily for another 2 weeks, and group II included 20 patients with cirrhosis who did not receive simvastatin as a control group. All patients underwent full clinical examination, laboratory investigations, and abdominal Doppler ultrasound at baseline and after 30 days to evaluate portal vein diameter, blood flow volume, direction and velocity of portal vein blood flow, hepatic artery resistance and pulsatility indices, splenic artery resistance index, portal hypertension index (PHI), liver vascular index, and modified liver vascular index (MLVI). Results: There was a highly significant decrease in the hepatic artery resistance index in group I, from 0.785 +/- 0.088 to 0.717 +/- 0.086 (P < 0.001). There was a significant decrease in the PHI in group I , from 3.915 +/- 0.973 m/sec to 3.605 +/- 1.168 m/sec (P = 0.024). Additionally, there was a significant increase in the MLVI in group I from 11.540 +/- 3.266 cm/sec to 13.305 +/- 3.222 cm/sec, an increase of 15.3% from baseline (P = 0.009). No significant adverse effects were detected. Conclusions: Simvastatin is safe and effective in lowering portal hypertension. [ClinicalTrials.gov Identifier: NCT02994485]. PMID- 29707201 TI - Taxa: An R package implementing data standards and methods for taxonomic data. AB - The taxa R package provides a set of tools for defining and manipulating taxonomic data. The recent and widespread application of DNA sequencing to community composition studies is making large data sets with taxonomic information commonplace. However, compared to typical tabular data, this information is encoded in many different ways and the hierarchical nature of taxonomic classifications makes it difficult to work with. There are many R packages that use taxonomic data to varying degrees but there is currently no cross-package standard for how this information is encoded and manipulated. We developed the R package taxa to provide a robust and flexible solution to storing and manipulating taxonomic data in R and any application-specific information associated with it. Taxa provides parsers that can read common sources of taxonomic information (taxon IDs, sequence IDs, taxon names, and classifications) from nearly any format while preserving associated data. Once parsed, the taxonomic data and any associated data can be manipulated using a cohesive set of functions modeled after the popular R package dplyr. These functions take into account the hierarchical nature of taxa and can modify the taxonomy or associated data in such a way that both are kept in sync. Taxa is currently being used by the metacoder and taxize packages, which provide broadly useful functionality that we hope will speed adoption by users and developers. PMID- 29707202 TI - A draft genome sequence for the Ixodes scapularis cell line, ISE6. AB - Background: The tick cell line ISE6, derived from Ixodes scapularis, is commonly used for amplification and detection of arboviruses in environmental or clinical samples. Methods: To assist with sequence-based assays, we sequenced the ISE6 genome with single-molecule, long-read technology. Results: The draft assembly appears near complete based on gene content analysis, though it appears to lack some instances of repeats in this highly repetitive genome. The assembly appears to have separated the haplotypes at many loci. DNA short read pairs, used for validation only, mapped to the cell line assembly at a higher rate than they mapped to the Ixodes scapularis reference genome sequence. Conclusions: The assembly could be useful for filtering host genome sequence from sequence data obtained from cells infected with pathogens. PMID- 29707203 TI - Repeated sessions of bilateral transcranial direct current stimulation on intractable tinnitus: a study protocol for a double-blind randomized controlled trial. AB - Background: Transcranial Direct Current Stimulation (tDCS) is reportedly a potential treatment option for chronic tinnitus. The main drawbacks of previous studies are short term follow up and focusing on the efficacy of single session tDCS. This study aims to investigate the therapeutic efficacy, adverse effects (AEs) and tolerability of repeated sessions of bilateral tDCS over auditory cortex (AC) on tinnitus symptoms Methods: This will be a double-blinded randomized placebo controlled parallel trial on patients (n=90) with intractable chronic tinnitus (> 2 years) randomly divided into three groups of anodal, cathodal, and sham tDCS. In the sham treatment, after 30 sec the device will be turned OFF without informing the patients. The tDCS protocol consists of 10 sessions (daily 20 min session; 2 mA current for 5 consecutive days per week and 2 consecutive weeks) applied through 35 cm 2 electrodes. The primary outcome is tinnitus handicap inventory (THI) which will be assessed pre- and post intervention and at one month follow-up. The secondary outcomes are tinnitus loudness and distress to be assessed using a visual analogue scale (VAS) pre intervention, and immediately, one hour, one week, and one month after last stimulation. The AEs and tolerability of patients will be evaluated after each session using a customized questionnaire. Possible interactions between the disease features and treatment response will be evaluated. Discussion: To our knowledge this is the first study to investigate the effects of repeated sessions of tDCS on chronic tinnitus symptoms with one month follow-up. In addition, the AEs, and tolerability of patients will be studied. In addition, the possible interactions between the disease specific features including the hearing loss, laterality, type of tinnitus, and treatment response will be evaluated. Trial registration: The study has been registered as a clinical trial in Iranian Registry of Clinical Trial ( IRCT2016110124635N6) on the 01/06/2017. PMID- 29707204 TI - Loss of Zbtb32 in NOD mice does not significantly alter T cell responses. AB - Background: We previously identified the transcriptional regulator Zbtb32 as a factor that can promote T cell tolerance in the Non-Obese Diabetic (NOD) mouse, a model of Type 1 diabetes. Antigen targeted to DCIR2 + dendritic cells (DCs) in vivo inhibited both diabetes and effector T cell expansion in NOD mice. Furthermore, Zbtb32 was preferentially induced in autoreactive CD4 T cells stimulated by these tolerogenic DCIR2 + DCs, and overexpression of Zbtb32 in islet-specific T cells inhibited the diabetes development by limiting T cell proliferation and cytokine production. Methods: To further understand the role of Zbtb32 in T cell tolerance induction, we have now used CRISPR to target the Zbtb32 gene for deletion directly in NOD mice and characterized the mutant mice. We hypothesized that the systemic loss of Zbtb32 in NOD mice would lead to increased T cell activation and increased diabetes pathogenesis. Results: Although NOD.Zbtb32 -/- male NOD mice showed a trend towards increased diabetes incidence compared to littermate controls, the difference was not significant. Furthermore, no significant alteration in lymphocyte number or function was observed. Importantly, in vitro stimulation of lymphocytes from NOD.Zbtb32 -/- mice did not produce the expected hypersensitive phenotype observed in other genetic strains, potentially due to compensation by homologous genes. Conclusions: The loss of Zbtb32 in the NOD background does not result in the expected T cell activation phenotype. PMID- 29707205 TI - Timely referral saves the lives of mothers and newborns: Midwifery led continuum of care in marginalized teagarden communities - A qualitative case study in Bangladesh. AB - Background: Prompt and efficient identification, referral of pregnancy related complications and emergencies are key factors to the reduction of maternal and newborn morbidity and mortality. As a response to this critical need, a midwifery led continuum of reproductive health care was introduced in five teagardens in the Sylhet division, Bangladesh during 2016. Within this intervention, professional midwives provided reproductive healthcare to pregnant teagarden women in the community. This study evaluates the effect of the referral of pregnancy related complications. Methods: A qualitative case study design by reviewing records retrospectively was used to explore the effect of deploying midwives on referrals of pregnancy related complications from the selected teagardens to the referral health facilities in Moulvibazar district of the Sylhet division during 2016. In depth analyses was also performed on 15 randomly selected cases to understand the facts behind the referral. Results: Out of a total population of 450 pregnant women identified by the midwives, 72 complicated mothers were referred from the five teagardens to the facilities. 76.4% of mothers were referred to conduct delivery at facilities, and 31.1% of them were referred with the complication of prolonged labour. Other major complications were pre-eclampsia (17.8%), retention of the placenta with post-partum hemorrhage (11.1%) and premature rupture of the membrane (8.9%). About 60% of complicated mothers were referred to the primary health care centre, and among them 14% of mothers were delivered by caesarean section. 94% deliveries resulted in livebirths and only 6% were stillbirths. Conclusions: This study reveals that early detection of pregnancy complications by skilled professionals and timely referral to a facility is beneficial in saving the majority of baby's as well as mother's lives in resource-poor teagardens with a considerable access barrier to health facilities. PMID- 29707206 TI - Recent advances in biologic therapy of asthma and the role in therapy of chronic rhinosinusitis. AB - Great strides have been made in the last five years in understanding the pathology of chronic rhinosinusitis (CRS). CRS is now accepted to be the end stage manifestation of inflammation resultant from various pathogenetic mechanisms. This has resulted in increasing recognition of distinct CRS endotypes. Such endotypes encompass a cluster of patients with similar pathogenic mechanisms that may have common therapeutic targets and responsiveness to interventions. The elucidation of mechanisms leading to the development of chronic upper (sino-nasal) airway inflammation has to some extent paralleled investigations of aberrant pathways operant in asthma. In this review, we focus on recent developments in understanding the innate immune pathways as well as adaptive (late) immune responses in CRS and asthma and their implication as potentially modifiable targets in CRS. Specific biologic therapy (that is, monoclonal antibodies targeting cytokines, cytokine receptors, or specific key molecules targeting inflammation) is an exciting proposition for the future of medical management of CRS. As of the writing of this article, the agents described are not approved for use in CRS; many have partial approval for use in asthma or are considered experimental. PMID- 29707207 TI - New technology to assess sleep apnea: wearables, smartphones, and accessories. AB - Sleep medicine has been an expanding discipline during the last few decades. The prevalence of sleep disorders is increasing, and sleep centers are expanding in hospitals and in the private care environment to meet the demands. Sleep medicine has evidence-based guidelines for the diagnosis and treatment of sleep disorders. However, the number of sleep centers and caregivers in this area is not sufficient. Many new methods for recording sleep and diagnosing sleep disorders have been developed. Many sleep disorders are chronic conditions and require continuous treatment and monitoring of therapy success. Cost-efficient technologies for the initial diagnosis and for follow-up monitoring of treatment are important. It is precisely here that telemedicine technologies can meet the demands of diagnosis and therapy follow-up studies. Wireless recording of sleep and related biosignals allows diagnostic tools and therapy follow-up to be widely and remotely available. Moreover, sleep research requires new technologies to investigate underlying mechanisms in the regulation of sleep in order to better understand the pathophysiology of sleep disorders. Home recording and non obtrusive recording over extended periods of time with telemedicine methods support this research. Telemedicine allows recording with little subject interference under normal and experimental life conditions. PMID- 29707208 TI - Retrospective cohort of pancreatic and Vater ampullary adenocarcinoma from a reference center in Mexico. AB - Introduction: Pancreatic ductal adenocarcinoma (PDAC) and ampulla of Vater adenocarcinomas (AVAC) are periampullary tumors. These tumors have overlapping symptoms and a common treatment, but present differences in their survival and biology. No recent studies in Mexico have been published that describe the clinicopathological characteristics of these tumors. Therefore, the aim of this study was to describe the clinicopathological characteristics of PDAC and AVAC in patients at a reference center in Mexico. Methods: A retrospective cohort of patients with PDAC or AVAC was analyzed at our institution (July 2007 to June 2016). Inferential analysis of the clinical data was performed with Student's t test or a chi2 test with odds ratios (OR) and confidence intervals (CI), depending on the variables. Overall survival was compared using Kaplan-Meier curves with log-rank p values. Results: Forty patients with PDAC and 76 with AVAC were analyzed, including 77 females and 39 males with a mean age of 60.6 years and a mean evolution time of 5.7 months. PDAC patients had more abdominal pain, a larger tumor size and more advanced stages than AVAC patients. In contrast, AVAC patients had more jaundice, a higher percentage of complete resections and higher overall survival. Up to 70% of patients were overweight. PDAC cohort included a higher proportion of smokers. Conclusions: Our cohort was slightly younger, had a larger percentage of females, and a greater percentage of obese patients than those in many international reports. A high proportion of PDAC patients are diagnosed in advanced stages and have a low likelihood of resectability. PMID- 29707210 TI - Microbial culturomics to isolate halophilic bacteria from table salt: genome sequence and description of the moderately halophilic bacterium Bacillus salis sp. nov. AB - Bacillus salis strain ES3T (= CSUR P1478 = DSM 100598) is the type strain of B. salis sp. nov. It is an aerobic, Gram-positive, moderately halophilic, motile and spore-forming bacterium. It was isolated from commercial table salt as part of a broad culturomics study aiming to maximize the culture conditions for the in depth exploration of halophilic bacteria in salty food. Here we describe the phenotypic characteristics of this isolate, its complete genome sequence and annotation, together with a comparison with closely related bacteria. Phylogenetic analysis based on 16S rRNA gene sequences indicated 97.5% similarity with Bacillus aquimaris, the closest species. The 8 329 771 bp long genome (one chromosome, no plasmids) exhibits a G+C content of 39.19%. It is composed of 18 scaffolds with 29 contigs. Of the 8303 predicted genes, 8109 were protein-coding genes and 194 were RNAs. A total of 5778 genes (71.25%) were assigned a putative function. PMID- 29707211 TI - Peptoniphilus lacydonensis sp. nov., a new human-associated species isolated from a patient with chronic refractory sinusitis. AB - Strain EL1T was isolated from a sinus sample of an 85-year-old man with chronic refractory sinusitis complicating ethmoidal adenocarcinoma. We studied its phenotypic and genomic characteristics. This is a Gram stain-positive, anaerobic and microaerophilic coccus. Cells are catalase negative, nonmotile and non-spore forming. The major fatty acids are saturated hexadecanoic acid (34%), unsaturated 9-octadecenoic acid (32%) and 9.12-octadecadienoic acid (21%). The 1.86 Mb long genome exhibits a 29.9% G+C content and contains 1750 protein-coding and 43 RNA genes. On the basis of these data, we propose the creation of the new human associated bacterial species Peptoniphilus lacydonensis sp. nov. PMID- 29707212 TI - Molecular characterization of chikungunya virus causing the 2017 outbreak in Dhaka, Bangladesh. AB - Chikungunya viruses from the 2017 outbreak in Dhaka, Bangladesh, were analysed phylogenetically. E1 sequences from 21 strains belonged to the Indian Ocean clade of the East/Central/South African (ECSA) genotype, forming a novel cluster with latest South Asian strains. They lacked the A226V substitution. PMID- 29707214 TI - Cervical myelocystocele: rare presentation of spinal dysraphism. PMID- 29707213 TI - Large-area synthesis of high-quality monolayer 1T'-WTe2 flakes. AB - Large-area growth of monolayer films of the transition metal dichalcogenides is of the utmost importance in this rapidly advancing research area. The mechanical exfoliation method offers high quality monolayer material but it is a problematic approach when applied to materials that are not air stable. One important example is 1T'-WTe2, which in multilayer form is reported to possess a large non saturating magnetoresistance, pressure induced superconductivity, and a weak antilocalization effect, but electrical data for the monolayer is yet to be reported due to its rapid degradation in air. Here we report a reliable and reproducible large-area growth process for obtaining many monolayer 1T'-WTe2 flakes. We confirmed the composition and structure of monolayer 1T'-WTe2 flakes using x-ray photoelectron spectroscopy, energy-dispersive x-ray spectroscopy, atomic force microscopy, Raman spectroscopy and aberration corrected transmission electron microscopy. We studied the time dependent degradation of monolayer 1T' WTe2 under ambient conditions, and we used first-principles calculations to identify reaction with oxygen as the degradation mechanism. Finally we investigated the electrical properties of monolayer 1T'-WTe2 and found metallic conduction at low temperature along with a weak antilocalization effect that is evidence for strong spin-orbit coupling. PMID- 29707215 TI - A critique of national solidarity in transnational organ sharing in Europe. AB - In this article, I critically examine the principle of national solidarity in organ sharing across national borders. More specifically, I analyse the policy foundations of solidarity in the transnational allocation of organs and its implementation in the system of national balance points adopted in Europe. I argue that the system of national balance points is based on statist collectivism and therefore is oriented more toward collective, rather than individual welfare. The same collective welfare rationale is also evident from leading policy statements about self-sufficiency in organ donation that seem to assume that cross-border organ sharing can be wrong if collective welfare is violated. This collectivist system of organ sharing can produce unjust results to individual candidates for organ transplantation. I propose several measures to reform the existing solidarity-based framework for the procurement and allocation of organs in order to balance the collective and the individual welfare of the donors and recipients of organs. I also discuss the implications of adopting that proposal. PMID- 29707216 TI - Cutting edges and weaving threads in the gene editing (YA)evolution: reconciling scientific progress with legal, ethical, and social concerns. AB - Gene-editing technology, such as CRISPR/Cas9, holds great promise for the advancement of science and many useful applications technology. This foundational technology enables modification of the genetic structure of any living organisms with unprecedented precision. Yet, in order to enhance its potential for societal benefit, it is necessary to adapt rules and produce adequate regulations. This requires an interdisciplinary effort in legal thinking. Any legislative initiative needs to consider both the benefits and the problematic aspects of gene editing, from a broader societal and value-based perspective. This paper stems from an interdisciplinary research project seeking to identify and discuss some of the most pressing legal implications of gene-editing technology and how to address these. While the questions raised by gene editing are global, laws and regulations are to a great extent bound by national borders. This paper presents a European perspective, written for a global audience, and intends to contribute to the global debate. The analysis will include brief references to corresponding USA rules in order to place these European debates in the broader international context. Our legal analysis incorporates interdisciplinary contributes concerning the scientific state of the art, philosophical thinking regarding the precautionary principle and dual-use issues as well as the importance of communication, social perception, and public debate. Focusing mainly in the main regulatory and patent law issues, we will argue that (a) general moratoriums and blank prohibitions do a disservice to science and innovation; (b) it is crucial to carefully consider a complex body of international and European fundamental rights norms applicable to gene editing; PMID- 29707217 TI - Assessing potential legal responses to medical ghostwriting: effectiveness and constitutionality. AB - Pharmaceutical companies are extensively involved in shaping medical knowledge to market their products to physicians and consumers. Specialized planning is undertaken to produce scientific articles driven by commercial interests. Rather than the listed authors, hidden analysts and publication management firms hired by pharmaceutical companies are often responsible for the content of scientific articles. Such ghostwriting practices raise serious concerns regarding the integrity of knowledge and thus demand urgent attention. This paper analyses the strategies of legal regulation on medical ghostwriting and their comparative advantages and disadvantages. Many of regulatory proposals suffer from a lack of effectiveness, whereas others are subject to constitutional concerns. The analysis in this paper offers insights into framing adequate regulation; it supports the strategy for reforming the structure of information production while calling for cautiousness in shaping its regulatory outline. In addition, this paper contributes to the analysis of First Amendment jurisprudence, suggesting that the judiciary should allow a certain amount of leeway for political branches to develop effective regulation. PMID- 29707218 TI - The generic drug user fee amendments: an economic perspective. AB - Since the vast majority of prescription drugs consumed by Americans are off patent ('generic'), their regulation and supply is of wide interest. We describe events leading up to the US Congress's 2012 passage of the Generic Drug User Fee Amendments (GDUFA I) as part of the Food and Drug Administration Safety and Innovation Act (FDASIA). Under GDUFA I, generic manufacturers agreed to pay approximately $300 million in fees each year of the five-year program. In exchange, the US Food and Drug Administration (FDA) committed to performance goals. We describe GDUFA I's FDA commitments, provisions, goals, and annual fee structure and compare it to that entailed in the authorization and implementation of GDUFA II on October 1, 2017. We explain how user fees required under GDUFA I erected barriers to entry and created scale and scope economies for incumbent manufacturers. Congress changed user fees under GDUFA II in part to lessen these incentives. In order to initiate and sustain user fees under GDUFA legislation, FDA requires the submission of self-reported data on generic manufacturers including domestic and foreign facilities. These data are public and our examination of them provides an unprecedented window into the recent organization of generic drug manufacturers supplying the US market. Our results suggest that generic drug manufacturing is increasingly concentrated and foreign. We discuss the implications of this observed market structure for GDUFA II's implementation among other outcomes. PMID- 29707219 TI - The app will see you now: mobile health, diagnosis, and the practice of medicine in Quebec and Ontario. AB - Mobile health applications are increasingly being used as tools of medicine. Outside of the clinic, some of these applications may contribute to diagnoses made absent a physician's care. We argue that this contravenes reservations of diagnosis to healthcare professionals in the law of two Canadian provinces: Quebec and Ontario. On the one hand, the law conceives of diagnosis in relatively broad terms. Drawing an association between symptoms and illness, for example, has been recognized in case law as sufficient. On the other hand, provincial law reserves diagnosis to physicians and other healthcare professionals. We argue that a number of health applications are capable of drawing associations between symptoms and disease and, in doing so, of delivering diagnoses in contravention of the law of Quebec and Ontario. This places mobile health applications in a poorly understood legal space. While prosecution is unlikely, the increasing ubiquity and technological sophistication of health applications promises to make such diagnosis widespread. We suggest that the legal status of such mobile health apps should be given serious attention. While our analysis focuses on the state of the law in Canada's largest provinces, we suggest that our argument will have implications in other jurisdictions. PMID- 29707220 TI - The impact of virtual reality on implicit racial bias and mock legal decisions. AB - Implicit racial biases are one of the most vexing problems facing current society. These split-second judgments are not only widely prevalent, but also are notoriously difficult to overcome. Perhaps most concerning, implicit racial biases can have consequential impacts on decisions in the courtroom, where scholars have been unable to provide a viable mitigation strategy. This article examines the influence of a short virtual reality paradigm on implicit racial biases and evaluations of legal scenarios. After embodying a black avatar in the virtual world, participants produced significantly lower implicit racial bias scores than those who experienced a sham version of the virtual reality paradigm. Additionally, these participants more conservatively evaluated an ambiguous legal case, rating vague evidence as less indicative of guilt and rendering more Not Guilty verdicts. As the first experiment of its kind, this study demonstrates the potential of virtual reality to address implicit racial bias in the courtroom setting. PMID- 29707221 TI - What do experimental simulations tell us about the effect of neuro/genetic evidence on jurors? PMID- 29707222 TI - The difficulty of discerning the effect of neuroscience: a peer commentary of Shen et al. 2018. PMID- 29707223 TI - Author's Response to Peer Commentaries: Brain-based mind reading: conceptual clarifications and legal applications. PMID- 29707224 TI - Spontaneous rupture of a renal artery pseudoaneurysm with no precipitating risk factor. AB - Renal artery pseudoaneurysm is a rare complication following renal interventional procedures or, although it may be spontaneous as described in this case. Clinicians should have a low threshold for early computer tomography (CT) imaging in cases of diagnostic uncertainty. PMID- 29707225 TI - A quantitative analysis of antipsychotic prescribing trends for the treatment of schizophrenia in England and Wales. AB - Objective: This study aims to assess the current antipsychotic prescribing trends for the treatment of schizophrenia and to compare them with available guidelines and research evidence. Design: An observational retrospective quantitative analysis. Setting: Data were collected from the prescribing cost analysis for the period between 2007 and 2014, including all drugs from the British National Formulary 4.2.1 and 4.2.2. Prescriptions were included from primary and secondary healthcare settings in England and Wales. Participants: None. Main outcome measures: Defined daily doses of antipsychotics were used to compare popularity of individual drugs and classes of antipsychotics. Results: There is a consistent increase in the proportion of atypical antipsychotics prescribed, compared to typical antipsychotics, between 2007 and 2014, with atypicals accounting for 79.9% of total antipsychotics prescribed in 2014. Conclusion: The consistent popularity of atypical antipsychotics is not concordant with the current National Institute for Health and Care Excellence guidelines for the treatment of schizophrenia or the most recent research evidence. PMID- 29707226 TI - A rare case of retroperitoneal synovial sarcoma. AB - Management of retroperitoneal soft tissue sarcomas is complex. Treatment is usually multimodal; involving surgery, chemotherapy and radiotherapy. PMID- 29707227 TI - Diabetes mellitus remission in a cat with pituitary-dependent hyperadrenocorticism after trilostane treatment. AB - Case summary: An 8-year-old male neutered Persian cat was presented with polyuria, polydipsia, polyphagia and muscle weakness associated with a 7 month history of diabetes mellitus (DM). The cat had initially been treated with neutral protamine Hagedorn (NPH) insulin 2 U q12h, followed by porcine lente insulin 2 U q12h and, most recently, 3 U glargine insulin q12h, without improvement of clinical signs. The cat also suffered from concurrent symmetrical bilateral alopecia of thorax and forelimbs, abdominal distension and lethargy. Hyperadrenocorticism (HAC), specifically pituitary-dependent HAC, was suspected and confirmed through abdominal ultrasonography demonstrating bilateral adrenal enlargement, and a low-dose dexamethasone suppression test using 0.1 mg/kg dexamethasone intravenously. Trilostane treatment (initially 10 mg/cat PO q24h then increased to 10 mg/cat PO q12h) was started and insulin sensitivity gradually improved, ultimately leading to diabetic remission after an increased in trilostane dose to 13mg/cat PO q12h, 14 months after the DM diagnosis and 7 months after the initiation of trilostane therapy. Relevance and novel information: DM in cats with HAC is a difficult combination of diseases to treat. To our knowledge this is the first reported case of diabetic remission in a feline patient with HAC as a result of treatment with trilostane. Further work should focus on whether fine-tuning of trilostane-treatment protocols in cats with concurrent DM and HAC could lead to a higher proportion of diabetic remissions in this patient group. PMID- 29707228 TI - Multiple sclerosis: Executive dysfunction, task switching and the role of attention. AB - Background: It has been suggested that switching ability might not be affected in multiple sclerosis (MS) as previously thought; however, whether this is true under more 'real-world' conditions when asymmetry in task difficulty is present has not been ascertained. Objective: The objective of this paper is to examine the impact of task difficulty asymmetry on task switching ability in MS. Method: An ocular motor (OM) paradigm that interleaves the simple task of looking towards a target (prosaccade, PS) with the cognitively more difficult task of looking away from a target (antisaccade, PS) was used. Two switching conditions: (1) PS switch cost, switching to a simple task from a difficult task (PS switch), relative to performing two simple tasks concurrently (PS repeat); (2) AS switch cost, switching to a difficult task from a simple task (AS switch) relative to performing two difficult tasks concurrently (AS repeat). Forty-five relapsing remitting MS patients and 30 control individuals were compared. Results: Controls and patients produced a similar magnitude PS switch cost, suggesting that task difficulty asymmetry does not detrimentally impact MS patients when transitioning from a more difficult task to a simpler task. However, MS patients alone found switching from the simpler PS trial to the more difficult AS trial easier (shorter latency and reduced error) than performing two AS trials consecutively (AS switch benefit). Further, MS patients performed significantly more errors than controls when required to repeat the same trial consecutively. Conclusion: MS patients appear to find the maintenance of task-relevant processes difficult not switching per se, with deficits exacerbated under increased attentional demands. PMID- 29707230 TI - A Tad pilus promotes the establishment and resistance of Vibrio vulnificus biofilms to mechanical clearance. AB - Vibrio vulnificus is autochthonous to estuaries and warm coastal waters. Infection occurs via open wounds or ingestion, where its asymptomatic colonization of seafood, most infamously oysters, provides a gateway into the human food chain. Colonization begins with initial surface contact, which is often mediated by bacterial surface appendages called pili. Type IV Tad pili are widely distributed in the Vibrionaceae, but evidence for a physiological role for these structures is scant. The V. vulnificus genome codes for three distinct tad loci. Recently, a positive correlation was demonstrated between the expression of tad-3 and the phenotypes of a V. vulnificus descendent (NT) that exhibited increased biofilm formation, auto-aggregation, and oyster colonization relative to its parent. However, the mechanism by which tad pilus expression promoted these phenotypes was not determined. Here, we show that deletion of the tad pilin gene (flp) altered the near-surface motility profile of NT cells from high curvature, orbital retracing patterns characteristic of cells actively probing the surface to low curvature traces indicative of wandering and diminished bacteria-surface interactions. The NT flp pilin mutant also exhibited decreased initial surface attachment, attenuated auto-aggregation and formed fragile biofilms that disintegrated under hydrodynamic flow. Thus, the tad-3 locus, designated iam, promoted initial surface attachment, auto-aggregation and resistance to mechanical clearance of V. vulnificus biofilms. The prevalence of tad loci in the Vibrionaceae suggests that they may play equally important roles in other family members. PMID- 29707231 TI - Preventing lower extremity injury in elite orienteerers: study protocol for a randomised controlled trial. AB - Background: The high physical load associated with running through uneven terrain contributes toorienteerers being exposed to high injury risk, where the majority of injuries are located in the lower extremities. Specific training programmes have been effective at reducing injury risk in sports. Yet no trial has been conducted in elite orienteering. The aim of this study is to investigate the effectiveness of a specific training programme in preventing lower extremity injury in adult elite orienteerers. Study design: Randomised controlled trial (RCT). Methods: Seventy-two Swedish elite orienteerers, aged 18-40 years, are allocated to an intervention or control group. The intervention group performs four specific exercises, with three difficult levels intensified every second week over the first 4 weeks, targeting strength, flexibility and coordination of the lower extremity. The exercises are completed four times a week (10 min per session) in conjunction with normal training over 14 weeks. Injury data are collected every second week using a valid injury questionnaire distributed by text messages over 14 weeks. The primary outcome is number of substantial injuries in the lower extremity. The secondary outcomes are incidence of ankle sprains and the average substantial injury prevalence across 14 weeks. Discussion: Due to high injury risk and lack of injury prevention trials in orienteering, an RCT investigating the effect of a specific exercise programme in preventing lower extremity injury is warranted. The results of this trial will be beneficial to orienteerers, clubs and federations, and increase our understanding on how lower extremity injuries can be prevented in a physically challenging sport. Trial registration number: NCT03408925. PMID- 29707232 TI - Baseline patient characteristics associated with response to biologic therapy in patients with psoriatic arthritis enrolled in the Corrona Psoriatic Arthritis/Spondyloarthritis Registry. AB - Objectives: To compare baseline characteristics between patients with psoriatic arthritis (PsA) who achieved and did not achieve minimal disease activity (MDA) with biologic therapy in the US-based Corrona Psoriatic Arthritis/Spondyloarthritis Registry. Methods: Patients with PsA aged >=18 years enrolled between March 2013 and March 2016 who were receiving biologics at enrolment (baseline), not in MDA and had >=2 follow-up visits were included. Patients were classified as those who remained on their index biologic and achieved MDA at the second follow-up visit (MDA achievers (MDA-A)) and those who did not (MDA non-achievers (MDA-NA)). Demographics, clinical characteristics, patient-reported outcomes and medication history were compared between groups. Results: Of 148 patients with PsA who met the inclusion criteria, 34 (23.0%) and 114 (77.0%) were classified as MDA-A and MDA-NA, respectively. At baseline, most patients (96.6%) were receiving tumour necrosis factor inhibitors, and both groups were similar in age, sex, race, medication history, enthesitis and dactylitis counts, disease duration and comorbidities. Compared with MDA-A, MDA NA had significantly worse mean tender joint count (7.2 vs 3.4), patient-reported pain (51.2 vs 35.7), patient-reported fatigue (54.1 vs 42.4), physical function (Health Assessment Questionnaire, 1.0 vs 0.6), Bath Ankylosing Disease Activity Index (5.0 vs 3.4) and Bath Ankylosing Spondylitis Functional Index (4.0 vs 2.0) scores (all p<0.05). Conclusions: Approximately one in four patients achieved MDA with their index biologic at the time of the second follow-up visit. Both groups were similar in several baseline demographic and clinical features; however, patients who did not achieve MDA generally had worse tender joint counts and patient-reported outcomes. PMID- 29707229 TI - Fighting biofilms with lantibiotics and other groups of bacteriocins. AB - Biofilms are sessile communities of bacteria typically embedded in an extracellular polymeric matrix. Bacterial cells embedded in biofilms are inherently recalcitrant to antimicrobials, compared to cells existing in a planktonic state, and are notoriously difficult to eradicate once formed. Avenues to tackle biofilms thus far have largely focussed on attempting to disrupt the initial stages of biofilm formation, including adhesion and maturation of the biofilm. Such an approach is advantageous as the concentrations required to inhibit formation of biofilms are generally much lower than removing a fully established biofilm. The crisis of antibiotic resistance in clinical settings worldwide has been further exacerbated by the ability of certain pathogenic bacteria to form biofilms. Perhaps the most notorious biofilm formers described from a clinical viewpoint have been methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermidis, Pseudomonas aeruginosa, Gardnerella vaginalis and Streptococcus mutans, the latter of which is found in oral biofilms. Due to the dearth of novel antibiotics in recent decades, compounded by the increasing rate of emergence of resistance amongst pathogens with a propensity for biofilm formation, solutions are urgently required to mitigate these crises. Bacteriocins are a class of antimicrobial peptides, which are ribosomally synthesised and often are more potent than their antibiotic counterparts. Here, we review a selection of studies conducted with bacteriocins with the ultimate objective of inhibiting biofilms. Overall, a deeper understanding of the precise means by which a biofilm forms on a substrate as well as insights into the mechanisms by which bacteriocins inhibit biofilms is warranted. PMID- 29707233 TI - Zika virus propagation and release in human fetal astrocytes can be suppressed by neutral sphingomyelinase-2 inhibitor GW4869. AB - Zika virus (ZIKV) is a neurotrophic flavivirus that is capable of infecting humans, leading to brain abnormalities during fetal development. The ZIKV infectivity in neural target cells remains poorly understood. Here, we found that ZIKV specifically infected glial fibrillary acidic protein- and S100B-positive primary human astrocytes derived from fetal brains. In contrast, neuron-specific Class III beta-tubulin (TuJ1)-positive neurons in the astrocyte cultures and SOX2 positive neural progenitor cells derived from the fetal brains were less susceptible to ZIKV infection compared with astrocytes. The infected astrocytes released competent viral particles and manifested programmed cell death with a progressive cytopathic effect. Interestingly, ZIKV infection in human fetal astrocytes induced a significant increase of extracellular vesicles (EVs). Treatment with GW4869, a specific inhibitor of neutral sphingomyelinase-2, decreased EV levels, suppressed ZIKV propagation, and reduced the release of infectious virions in astrocytes. Therefore, ZIKV infects primary human fetal astrocytes and the infection can be suppressed by neutral sphingomyelinase-2 inhibitor GW4869. Further investigation into sphingomyelin metabolism and EVs may provide insights to the therapeutic treatment of ZIKV infection. PMID- 29707234 TI - CRISPR-Cas12a-assisted nucleic acid detection. PMID- 29707235 TI - Detecting phenotype-driven transitions in regulatory network structure. AB - Complex traits and diseases like human height or cancer are often not caused by a single mutation or genetic variant, but instead arise from functional changes in the underlying molecular network. Biological networks are known to be highly modular and contain dense "communities" of genes that carry out cellular processes, but these structures change between tissues, during development, and in disease. While many methods exist for inferring networks and analyzing their topologies separately, there is a lack of robust methods for quantifying differences in network structure. Here, we describe ALPACA (ALtered Partitions Across Community Architectures), a method for comparing two genome-scale networks derived from different phenotypic states to identify condition-specific modules. In simulations, ALPACA leads to more nuanced, sensitive, and robust module discovery than currently available network comparison methods. As an application, we use ALPACA to compare transcriptional networks in three contexts: angiogenic and non-angiogenic subtypes of ovarian cancer, human fibroblasts expressing transforming viral oncogenes, and sexual dimorphism in human breast tissue. In each case, ALPACA identifies modules enriched for processes relevant to the phenotype. For example, modules specific to angiogenic ovarian tumors are enriched for genes associated with blood vessel development, and modules found in female breast tissue are enriched for genes involved in estrogen receptor and ERK signaling. The functional relevance of these new modules suggests that not only can ALPACA identify structural changes in complex networks, but also that these changes may be relevant for characterizing biological phenotypes. PMID- 29707236 TI - Subacute histopathological features in a case of varicella zoster virus myelitis and post-herpetic neuralgia. AB - Introduction: Post-herpetic neuralgia is a crippling complication of varicella zoster virus (VZV) reactivation, also known as zoster disease. In rare cases, VZV spreads to the spinal cord and causes myelitis. There is a paucity of data on spinal cord histopathology in the subacute phase of post-herpetic neuralgia and VZV myelitis. Case description: In this report, we present a case of post herpetic neuralgia in a patient who died 5 weeks after initiation of symptoms. Autopsy limited to the spinal cord revealed severe tissue vacuolization associated with macrophage and lymphocytic infiltration that was most intense in the right posterior horn, corresponding to an area of magnetic resonance imaging (MRI) T2-weighted hyperintensity. There was some extension of the inflammatory response to the ipsilateral posterior column, dorsolateral column, precentral gray matter, and contralateral lateral column. No significant axonal or myelin loss was observed. Nerve roots and meninges were free of significant inflammation. Discussion: Our findings provide histopathological insight into early subacute changes in post-herpetic neuralgia and suggest the involvement of the cord and subsequent macrophage and lymphocyte inflammatory response may lead to pain fiber irritation and the clinical pain syndrome of post-herpetic neuralgia. PMID- 29707237 TI - Pilot study of a training program to enhance transformational leadership in Spinal Cord Injury Peer Mentors. AB - Study design: Experimental, pragmatic design. Objectives: (1) To determine the effects of a transformational leadership (TFL) training program on spinal cord injury (SCI) peer mentors and their mentees; (2) To document characteristics of mentorship within a community-based SCI peer mentor program. Methods: In total 23 SCI peer mentors (70% male; M age = 47.4 +/- 12.1) were randomly allocated to an Experimental or Control condition. Experimental condition mentors received a half day TFL workshop and bi-weekly emailed information on using TFL in SCI peer mentorship. Sixteen SCI mentees (50% male; M age = 49.1 +/- 12.9) enrolled in the study and 9 completed measures of self-efficacy and their mentors' use of TFL and supportiveness at 3 and 6-months. Mentors completed monthly reports of mentorship activities. Setting: Community-based peer mentorship program in British Columbia, Canada. Results: There were no between-groups differences in mentee self efficacy, mentor use of TFL or mentor supportiveness. In the Experimental condition only, total mentorship time and sessions were positively correlated with mentors' use of TFL and supportiveness. Mentorship occurred in-person, by phone, text, and email and mentors discussed an average of 11 topics. Conclusions: The intervention did not increase SCI peer mentors' use of TFL relative to a Control condition. Nevertheless, there may be merit in coaching SCI peer mentors to use TFL given the positive correlations between mentorship time and sessions, TFL use, and perceived supportiveness of the mentor. Although inherently challenging, research involving community-based SCI peer mentorship programs provides opportunities for scientists and community organizations to extend knowledge of peer mentorship beyond the context of hospital-based programs. Sponsorship: Research supported by a SSHRC Partnership Development Grant. PMID- 29707238 TI - Open surgery for haemorrhoids in persons with spinal cord injury. AB - Study design: Pilot retrospective study on the outcome of open surgery for grade III and IV haemorrhoids in patients with SCI. Objective: Haemorrhoids and anal fissures are common in patients with spinal cord injury (SCI). Grade I to III haemorrhoids are usually managed medically or by surgical ligation. Grade III and IV haemorrhoids are treated with surgical haemorrhoidectomy in the general population, but not in patients with SCI, most probably due to fear of complications. Setting: Fondation Hopale, Berck-sur Mer, France. Methods: The surgical database was searched for open haemorrhoidectomies performed between 2007 and 2016. Seventeen patients were included. There were mostly males with complete paraplegia, mean age: 50 years and mean time since injury: 15.9 years. Open haemorrhoidectomy (Milligan and Morgan) was performed for isolated haemorrhoids (n = 4), and combined with Leopold Bellan procedure (posterior anoplasty and internal sphincterotomy) for associated anal fissures (n = 13). Short-term follow-up was performed by the surgeon (post-operative weeks 2 and 6), long-term follow-up by telephone interview (mean 5.7 years, SD 1.9). Results: At 6-weeks post-operative, no significant complications had occurred and all wounds had healed, however 1 patient had recurrence of anal fissure. At long-term follow up, 75% of patients reported a significant improvement in anorectal symptoms. Recurrences were reported by 5 patients: 3 haemorrhoids (18%) and 2 anal fissures (25%). Anal incontinence occurred in 1 patient who required an anal plug. All patients maintained the same bowel programs as pre-operative. Conclusions: Open surgery procedures were well tolerated and should be considered in persons with SCI. PMID- 29707239 TI - Falls, mobility, and physical activity after spinal cord injury: an exploratory study using photo-elicitation interviewing. AB - Study design: Exploratory qualitative study using photo-elicitation interviews. Objectives: To identify contributors to falls, as perceived by individuals with incomplete spinal cord injury, and describe the impact of perceived fall risk on mobility and physical activity. Setting: Participants' home and community environments. Methods: Eight individuals with chronic motor incomplete spinal cord injury participated. Participants took photographs of situations that increased/decreased their risk of falling, or depicted how this risk impacted mobility and physical activity. Photographs were discussed in semi-structured interviews. Inductive thematic analysis was used to describe participants' perceptions and experiences. Results: Photo-elicitation interviews identified four themes: (1) Perceived challenges were primarily environmental with biological (e.g., reduced strength) and behavioral (e.g., risk-taking) factors also identified. (2) Impact of perceived fall risk included moving slowly, avoiding balance-provoking activities, and feelings of frustration and/or fear. (3) Prevent falls: learn through experience included strategies used to avoid falls, which were learnt experientially and consisted of changes to behavior. (4) Factors mitigating impact of perceived fall risk included character traits (i.e., perseverance, optimism) and a desire for independence. Conclusions: Primarily environmental factors were perceived to contribute to fall risk and mainly behavioral strategies were adopted to mitigate the risk. Sponsorship: Physiotherapy Foundation of Canada. PMID- 29707240 TI - Dual function of peroxiredoxin I in lipopolysaccharide-induced osteoblast apoptosis via reactive oxygen species and the apoptosis signal-regulating kinase 1 signaling pathway. AB - Lipopolysaccharide (LPS)-induced osteoblast apoptosis is a prominent factor to the defect in periodontal tissue repair in periodontal disease. LPS challenge contributes to the production of reactive oxygen species (ROS) in periodontitis, and peroxiredoxin 1 (Prx1) is an antioxidant protein that protect cells against oxidative damage from ROS. Without LPS stimulation, apoptotic rates were higher in both Prx1 knockout (Prx1KO) and Prx1 overexpression (Prx1OE) cells compared with wild type. After LPS stimulation, intracellular ROS in Prx1KO cells showed the highest level and Prx1OE cells showed the least. Treatment with LPS significantly elevated the expression of Bax, Cyto-c, and caspase 3 in Prx1KO cells compared with wild type, although this could be completely abolished by NAC. In Prx1OE cells, the expression and activation of ASK1 were significantly increased, and this was slightly reduced by LPS stimulation. NQDI-1 completely abolished the increased phosphorylation of JNK and p38 and the expression of caspase 3 in LPS-stimulated cells. These results indicate that Prx1 eliminates intracellular ROS and exhibits a cytoprotective role in LPS-induced apoptosis. However, under physiological conditions, Prx1 overexpression acts as a H2O2 messenger, triggering the expression of ASK1 and its downstream cascades. PMID- 29707241 TI - KPT-330 inhibition of chromosome region maintenance 1 is cytotoxic and sensitizes chronic myeloid leukemia to Imatinib. AB - As tyrosine kinase inhibitors (e.g., Imatinib, IM) fail to induce long-term response in some chronic myeloid leukemia (CML), novel therapies targeting leukemia-dysregulated pathways are necessary. Nuclear-cytoplasmic trafficking of proteins play a key role in the development of leukemia and drug resistance. KPT 330 (Selinexor), an inhibitor of chromosome region maintenance 1 (CRM1, nuclear receptor exportin 1, XPO1), demonstrated activities against a few hematological malignancies. We examined the anti-leukemic efficacy of KPT-330 in IM-resistant CML. Cell viability was examined by MTS assay. Apoptosis and cell cycle were assessed by flow cytometry. CRM1 mRNA was detected by PCR. Expression of CRM1 protein and its cargo proteins were determined by western blot or immunofluorescent staining. Furthermore, we engrafted nude mice subcutaneously with IM-resistant CML K562G. Mice were treated with IM, KPT-330 alone or in combination. Expression of CRM1 in CML were markedly higher than control. KPT-330 inhibited proliferation, induced cell cycle arrest and apoptosis of K562 and K562G. IC50 of IM on K562G was reduced by KPT-330. Mechanistically, KPT-330 inhibited CRM1 and increased the nuclear/cytoplasm ratio of BCR-ABL and P27. p AKT was downregulated while p-STAT1 and caspase-3 were upregulated. Furthermore, KPT-330 showed anti-leukemic effect in primary IM-resistant CML with T315I mutation in CRM1-dependent manner. In K562G xenograft mice model, KPT-330 inhibited tumor growth and sensitized K562G to IM in vivo. To conclude, KPT-330 showed anti-leukemic activity and sensitized CML to IM in CRM1-dependent manner in vitro and in vivo. KPT-330 represents an alternative therapy for IM-refractory CML, warranting further investigation of CRM1 as therapeutic target. PMID- 29707242 TI - A Rift Valley fever virus Gn ectodomain-based DNA vaccine induces a partial protection not improved by APC targeting. AB - Rift Valley fever virus, a phlebovirus endemic in Africa, causes serious diseases in ruminants and humans. Due to the high probability of new outbreaks and spread to other continents where competent vectors are present, vaccine development is an urgent priority as no licensed vaccines are available outside areas of endemicity. In this study, we evaluated in sheep the protective immunity induced by DNA vaccines encoding the extracellular portion of the Gn antigen which was either or not targeted to antigen-presenting cells. The DNA encoding untargeted antigen was the most potent at inducing IgG responses, although not neutralizing, and conferred a significant clinical and virological protection upon infectious challenge, superior to DNA vaccines encoding the targeted antigen. A statistical analysis of the challenge parameters supported that the anti-eGn IgG, rather than the T-cell response, was instrumental in protection. Altogether, this work shows that a DNA vaccine encoding the extracellular portion of the Gn antigen confers substantial-although incomplete-protective immunity in sheep, a natural host with high preclinical relevance, and provides some insights into key immune correlates useful for further vaccine improvements against the Rift Valley fever virus. PMID- 29707243 TI - Economic evaluation of the Good School Toolkit: an intervention for reducing violence in primary schools in Uganda. AB - Introduction: This paper presents the cost and cost-effectiveness of the Good School Toolkit (GST), a programme aimed at reducing physical violence perpetrated by school staff to students in Uganda. Methods: The effectiveness of the Toolkit was tested with a cluster randomised controlled trial in 42 primary schools in Luwero District, Uganda. A full economic costing evaluation and cost effectiveness analysis were conducted alongside the trial. Both financial and economic costs were collected retrospectively from the provider's perspective to estimate total and unit costs. Results: The total cost of setting up and running the Toolkit over the 18-month trial period is estimated at US$397 233, excluding process monitor (M&E) activities. The cost to run the intervention is US$7429 per school annually, or US$15 per primary school pupil annually, in the trial intervention schools. It is estimated that the intervention has averted 1620 cases of past-week physical violence during the 18-month implementation period. The total cost per case of violence averted is US$244, and the annual implementation cost is US$96 per case averted during the trial. Conclusions: The GST is a cost-effective intervention for reducing violence against pupils in primary schools in Uganda. It compares favourably against other violence reduction interventions in the region. PMID- 29707244 TI - Forecasted impacts of a sofosbuvir-based national hepatitis C treatment programme on Egypt's hepatocellular cancer epidemic: simulation of alternatives. AB - Background: Egypt is experiencing a hepatocellular cancer (HCC) epidemic due to widespread hepatitis C virus (HCV) transmission. The use of sofosbuvir-related therapies producing improved treatment success has permitted an updated, nationwide, HCV treatment programme with expanded coverage. This study simulated the multidecade impacts of the new treatment programme on hepatitis and HCC. Methods: A Markov model of HCV infection and treatment analysed the HCV-related HCC epidemic between 2009 and 2050, using parameters based on peer-reviewed studies and expert opinion. Comparing the 'new' and 'old' scenarios, and with the old treatment programme being replaced or not by the new programme in 2015, the annual number, prevalence and incidence of HCC were simulated for representative Egypt populations including HCV-infected patients aged 15-59 years in 2008, healthy people aged 5-59 years in 2008 and 5-year-old children cohorts entering the population each year beginning in 2009. Averted HCC cases were calculated, and sensitivity analyses were performed. Results: Compared with the old scenario, the estimated number, prevalence and incidence of future HCC cases in the new scenario would peak earlier and at lower levels in 2025 (~29 000), 2023 (~28/100 000) and 2022 (~14/100 000), respectively. The new treatment programme is estimated to avert ~956 000 HCC cases between 2015 and 2050. Discussion: By reducing cancer cases and shortening the peak epidemic period, the new programme should substantially diminish the HCC epidemic across Egypt. Our timeline forecast for Egypt's HCC epidemic, and evaluation of various disease and programme components, should be useful to other countries that are developing policies to address HCV-related liver cancer prevention. PMID- 29707246 TI - The Nigeria Centre for Disease Control. PMID- 29707245 TI - Addressing the third delay: implementing a novel obstetric triage system in Ghana. AB - Institutional delivery has been proposed as a method for reducing maternal morbidity and mortality, but little is known about how referral hospitals in low resource settings can best manage the expected influx of patients. In this study, we assess the impact of an obstetric triage improvement programme on reducing hospital-based delay in a referral hospital in Accra, Ghana. An Active Implementation Framework is used to describe a 5-year intervention to introduce and monitor obstetric triage capabilities. Baseline data, collected from September to November 2012, revealed significant delays in patient assessment on arrival. A triage training course and monitoring of quality improvement tools occurred in 2013 and 2014. Implementation barriers led to the construction of a free-standing obstetric triage pavilion, opened January 2015, with dedicated midwives. Data were collected at three time intervals following the triage pavilion opening and compared with baseline including: referral indications, patient and labour characteristics, waiting time from arrival to assessment and the documentation of a care plan. An obstetric triage improvement programme reduced the median (IQR) patient waiting time from facility arrival to first assessment by a midwife from 40 min (15-100) to 5 min (2-6) (p<0.001) over the 5 year intervention. The triage pavilion enhanced performance resulting in the elimination of previous delays associated with the time of admission and disease acuity. Care plan documentation increased from 51% to 96%. Obstetric triage, when properly implemented, reduced delay in a busy, low-resource hospital. The implementation process was sustained under local leadership during transition to a new hospital. PMID- 29707247 TI - fastPACE Train-the-Trainer: A scalable new educational program to accelerate training in biomedical innovation, entrepreneurship, and commercialization. AB - Introduction: The Institute of Medicine recommended the advance of innovation and entrepreneurship training programs within the Clinical & Translational Science Award (CTSA) program; however, there remains a gap in adoption by CTSA institutes. The University of Michigan's Michigan Institute for Clinical & Health Research and Fast Forward Medical Innovation (FFMI) partnered to develop a pilot program designed to teach CTSA hubs how to implement innovation and entrepreneurship programs at their home institutions. Materials and methods: The program provided a 2-day onsite training experience combined with observation of an ongoing course focused on providing biomedical innovation, commercialization and entrepreneurial training to a medical academician audience (FFMI fastPACE). Results: All 9 participating CTSA institutes reported a greater connection to biomedical research commercialization resources. Six launched their own version of the FFMI fastPACE course or modified existing programs. Two reported greater collaboration with their technology transfer offices. Conclusion: The FFMI fastPACE course and training program may be suitable for CTSA hubs looking to enhance innovation and entrepreneurship within their institutions and across their innovation ecosystems. PMID- 29707248 TI - Training in patient-centered outcomes research for specific researcher communities. AB - A number of publications have discussed approaches to training the scientific workforce in comparative effectiveness research (CER) and patient-centered outcomes research (PCOR). To meet this need, funders have offered resources for developing educational materials and establishing training programs. To extend these efforts into specific researcher communities, the Agency for Healthcare Research and Quality developed an R25 Funding Opportunity Announcement that called for basic, advanced, and experiential training for a specific researcher community in collaboration with associated program partners. This paper describes the strategies developed by the 5 subsequently funded programs, their specific researcher communities and program partners, and the challenges associated with developing in-person and online programs. We focus on lessons learned that can be translated into developing training programs nationwide and on training for the special populations of interest. We also discuss the creation of a sustainable network for training and the conduct of comparative effectiveness research/patient-centered outcomes research in targeted communities. PMID- 29707249 TI - The Purdue Extension and Indiana CTSI's Community Health Partnerships collaboration: An innovative, generalizable, state-wide model to help communities build a culture of health. AB - The Indiana Clinical and Translational Sciences Institute's Community Engagement Partners-Purdue Extension collaborative model demonstrates tremendous potential for creating state-wide programmatic efforts and improvements in both the health culture and status of Indiana residents across the state. It can serve as a prototype not only for others interested in pursuing wide geographic health improvements through Clinical and Translational Sciences Award-Cooperative Extension partnerships but also for broader collaborations among United States Department of Agriculture, National Institutes of Health, Centers for Disease Control and Prevention, state and local health departments, and health foundation efforts to improve population health. PMID- 29707250 TI - The innovation scorecard for continuous improvement applied to translational science. AB - Introduction: This paper reports on the baseline stage of a qualitative evaluation of the application of the Innovative Scorecard (ISC) to the Clinical and Translational Science Award (CTSA) at the University of Texas Medical Branch (UTMB) at Galveston. The ISC is adopted from the established Balanced Scorecard system for strategic planning and performance management. In formulating the evaluation, we focused on the organizational identity literature. Methods: The initial evaluation consisted of a series of semi-structured interviews with 22 participants of the ISC Boot Camp conducted in July 2015. Results: The logic of grounded theory pointed to the clustering of perceptions of the ISC around respondents' occupational locations at UTMB. Administrators anticipate the expansion of planning activities to include a wider range of participants under the current CTSA award period (2015-2020) than under our first CTSA approval period (2009-2014). A common viewpoint among the senior scientists was that the scientific value of their work will continue to speak for itself without requiring the language of business. Junior scientists looked forward to the ISC's emphasis on increasingly horizontal leadership that will give them more access to and more control over their work and resources. Postdocs and senior staff welcomed increased involvement in the total research process at UTMB. Conclusion: The report concludes with strategies for future follow-up. PMID- 29707251 TI - Towards a practical model for community engagement: Advancing the art and science in academic health centers. AB - Introduction: Community engagement (CE) has become more prevalent among academic health centers (AHCs), with significant diversity in practices and language. The array of approaches to CE contributes to confusion among practitioners. Methods: We have reviewed multiple models of CE utilized by AHCs, Clinical and Translational Science Awards, and higher education institutions overall. Taking these models into consideration, we propose a comprehensive model of CE that encompasses a broader spectrum of activities and programs. Results: The CE Components Practical Model includes 5 components: Community Outreach and Service, Education, Clinical Care, Research, and Policy and Advocacy. The components are supported by the foundational elements within administrative functions and infrastructure. Conclusions: This model will accomplish the following: (1) reduce confusion about CE; (2) provide a broader understanding of CE; and (3) increase the ability of CE practitioners to interact with each other through this common reference and engage in advancing CE scholarship. PMID- 29707252 TI - A model for academic institution support for community-engaged research. PMID- 29707253 TI - RRApp, a robust randomization app, for clinical and translational research. AB - While junior clinical researchers at academic medical institutions across the US often desire to be actively engaged in randomized-clinical trials, they often lack adequate resources and research capacity to design and implement them. This insufficiency hinders their ability to generate a rigorous randomization scheme to minimize selection bias and yield comparable groups. Moreover, there are limited online user-friendly randomization tools. Thus, we developed a free robust randomization app (RRApp). RRApp incorporates 6 major randomization techniques: simple randomization, stratified randomization, block randomization, permuted block randomization, stratified block randomization, and stratified permuted block randomization. The design phase has been completed, including robust server scripts and a straightforward user-interface using the "shiny" package in R. Randomization schemes generated in RRApp can be input directly into the Research Electronic Data Capture (REDCap) system. RRApp has been evaluated by biostatisticians and junior clinical faculty at the Icahn School of Medicine at Mount Sinai. Constructive feedback regarding the quality and functionality of RRApp was also provided by attendees of the 2016 Association for Clinical and Translational Statisticians Annual Meeting. RRApp aims to educate early stage clinical trialists about the importance of randomization, while simultaneously assisting them, in a user-friendly fashion, to generate reproducible randomization schemes. PMID- 29707254 TI - Parenting stress and DNA methylation among African Americans in the InterGEN Study. AB - Introduction: General life stress has been associated with altered DNA methylation in individuals of African Ancestry, although the relationship between parenting stress and DNA methylation has not been described. The purpose of this study was to examine the relationship between maternal parenting stress and DNA methylation among African Ancestry mother-child dyads. Methods: We evaluated epigenome-wide DNA methylation relative to parenting stress in 74 mother-child dyads using linear mixed models. Results: Significant variation in maternal DNA methylation at 95 CpG sites was associated with level of parenting stress. Notably, we identified a change in DNA methylation associated with poly (ADP ribose) polymerase-1, which plays a key role in stress signaling. We did not identify any significant variation in child DNA methylation related to maternal parenting stress. Conclusions: However, DNA methylation patterns observed in children mirrored patterns observed in their mothers. The results suggest that differential maternal DNA methylation is associated with higher levels of parenting stress. PMID- 29707255 TI - Research coordinator networks and support models among academic health centers in the CTSA consortium. AB - Introduction: Research coordinators (RCs) are vital to the clinical research enterprise, ensuring research is conducted ethically, results are scientifically sound and human research subjects are protected. Given the absence of a prior systematic inquiry, we sought to understand the ways in which Clinical & Translational Science Award-funded academic health centers support RCs. Methods: Our survey asked questions about existing coordinator networks and where none existed, collected data on the characterization of resources and services provided to support RCs (outside of salary). Results: Findings show 4 mechanisms support RCs: identification of the workforce, professionalization of the position, dissemination of information, and offering of services. Conclusion: An academic health center that wishes to deliver research training and services to their RC workforce will need identification and communication structures in place before supportive activities can be effectively implemented. PMID- 29707256 TI - A content analysis of Clinical and Translational Science Award (CTSA) strategies for communicating about clinical research participation online. AB - Introduction: There is a dearth of literature providing guidance on how to effectively communicate about clinical research (CR). Methods: Using the transactional model of communication, a content analysis of the investigator (n=62) and participant (n=18) Web sites of institutions funded through the National Institutes of Health Clinical and Translational Science Award (CTSA) was conducted to identify their strategies (e.g., messages) for communicating about CR participation. Results: CTSAs targeted investigators with CR participation content across the main Web sites, although most CTSAs (n=55; 88.7%) also included CR participation content for participants. In total, 18 CTSAs (29%) hosted participant Web sites. Participant sites included 13 message types about CR participation (e.g., registry enrollment) and 5 additional channels (e.g., email, phone number) to communicate about CR. However, many CTSA participant Web sites excluded information explaining the CR process and offered CR content exclusively in English. Conclusion: CTSAs should identify their target audience and design strategies (e.g., messages, channels) accordingly. PMID- 29707257 TI - Using publication data to evaluate a Clinical and Translational Science Award (CTSA) career development program: Early outcomes from KL2 scholars. AB - Introduction: This study uses KL2 scholars' publications to evaluate the types of research the KL2 program supports and to assess the initial productivity and impact of its scholars. Methods: We illustrate the feasibility of 3 different approaches to bibliometrics, one viable method for determining the types of research a program or hub supports, and demonstrate how these data can be further combined with internal data records. Results: Gender differences were observed in the types of research scholars undertake. Overall KL2 scholars are performing well, with their publications being cited more than the norm for National Institutes of Health publications. Favorable results were also observed in scholars' continued engagement in research. Conclusion: This study illustrates that linking bibliometric data and data categorizing publications along the translational spectrum with a Clinical and Translational Science Award hub's internal data records is feasible and offers a number of innovative possibilities for the evaluation of a Clinical and Translational Science Award hub's programs and investigators. PMID- 29707258 TI - Improving readability of informed consents for research at an academic medical institution. AB - Introduction: The final rule for the protection of human subjects requires that informed consent be "in language understandable to the subject" and mandates that "the informed consent must be organized in such a way that facilitates comprehension." This study assessed the readability of Institutional Review Board approved informed consent forms at our institution, implemented an intervention to improve the readability of consent forms, and measured the first year impact of the intervention. Methods: Readability assessment was conducted on a sample of 217 Institutional Review Board-approved informed consents from 2013 to 2015. A plain language informed consent template was developed and implemented and readability was assessed again after 1 year. Results: The mean readability of the baseline sample was 10th grade. The mean readability of the post-intervention sample (n=82) was seventh grade. Conclusions: Providing investigators with a plain language informed consent template and training can promote improved readability of informed consents for research. PMID- 29707259 TI - Effectiveness and cost of recruiting healthy volunteers for clinical research studies using an electronic patient portal: A randomized study. AB - Introduction: It is not clear how to effectively recruit healthy research volunteers. Methods: We developed an electronic health record (EHR)-based algorithm to identify healthy subjects, who were randomly assigned to receive an invitation to join a research registry via the EHR's patient portal, letters, or phone calls. A follow-up survey assessed contact preferences. Results: The EHR algorithm accurately identified 858 healthy subjects. Recruitment rates were low, but occurred more quickly via the EHR patient portal than letters or phone calls (2.7 vs. 19.3 or 10.4 d). Effort and costs per enrolled subject were lower for the EHR patient portal (3.0 vs. 17.3 or 13.6 h, $113 vs. $559 or $435). Most healthy subjects indicated a preference for contact via electronic methods. Conclusions: Healthy subjects can be accurately identified from EHR data, and it is faster and more cost-effective to recruit healthy research volunteers using an EHR patient portal. PMID- 29707260 TI - Can composite digital monitoring biomarkers come of age? A framework for utilization. AB - Introduction: The application of digital monitoring biomarkers in health, wellness and disease management is reviewed. Harnessing the near limitless capacity of these approaches in the managed healthcare continuum will benefit from a systems-based architecture which presents data quality, quantity, and ease of capture within a decision-making dashboard. Methods: A framework was developed which stratifies key components and advances the concept of contextualized biomarkers. The framework codifies how direct, indirect, composite, and contextualized composite data can drive innovation for the application of digital biomarkers in healthcare. Results: The de novo framework implies consideration of physiological, behavioral, and environmental factors in the context of biomarker capture and analysis. Application in disease and wellness is highlighted, and incorporation in clinical feedback loops and closed-loop systems is illustrated. Conclusions: The study of contextualized biomarkers has the potential to offer rich and insightful data for clinical decision making. Moreover, advancement of the field will benefit from innovation at the intersection of medicine, engineering, and science. Technological developments in this dynamic field will thus fuel its logical evolution guided by inputs from patients, physicians, healthcare providers, end-payors, actuarists, medical device manufacturers, and drug companies. PMID- 29707261 TI - Rapid clinical diagnostic variant investigation of genomic patient sequencing data with iobio web tools. AB - Introduction: Computational analysis of genome or exome sequences may improve inherited disease diagnosis, but is costly and time-consuming. Methods: We describe the use of iobio, a web-based tool suite for intuitive, real-time genome diagnostic analyses. Results: We used iobio to identify the disease-causing variant in a patient with early infantile epileptic encephalopathy with prior nondiagnostic genetic testing. Conclusions: Iobio tools can be used by clinicians to rapidly identify disease-causing variants from genomic patient sequencing data. PMID- 29707262 TI - Climate Vulnerability and Human Migration in Global Perspective. AB - The relationship between climate change and human migration is not homogenous and depends critically on the differential vulnerability of population and places. If places and populations are not vulnerable, or susceptible, to climate change, then the climate-migration relationship may not materialize. The key to understanding and, from a policy perspective, planning for whether and how climate change will impact future migration patterns is therefore knowledge of the link between climate vulnerability and migration. However, beyond specific case studies, little is known about this association in global perspective. We therefore provide a descriptive, country-level portrait of this relationship. We show that the negative association between climate vulnerability and international migration holds only for countries least vulnerable to climate change, which suggests the potential for trapped populations in more vulnerable countries. However, when analyzed separately by life supporting sector (food, water, health, ecosystem services, human habitat, and infrastructure) and vulnerability dimension (exposure, sensitivity, and adaptive capacity), we detect evidence of a relationship among more, but not the most, vulnerable countries. The bilateral (i.e., country-to-country) migration show that, on average, people move from countries of higher vulnerability to lower vulnerability, reducing global risk by 15%. This finding is consistent with the idea that migration is a climate adaptation strategy. Still, ~6% of bilateral migration is maladaptive with respect to climate change, with some movement toward countries with greater climate change vulnerability. PMID- 29707263 TI - PCI or CABG for unprotected left main coronary artery disease?-new evidence justifies a change in perspective. PMID- 29707264 TI - Breast carcinoma is a multifactorial disease involving FOXN3, SINA3 and NEAT through repression of GATA3 and TJP. PMID- 29707265 TI - A richer understanding of intratumoral heterogeneity: single-cell genomics put it within reach. PMID- 29707266 TI - Immunotherapy after chemoradiotherapy in stage III non-small cell lung cancer: a new standard of care? PMID- 29707267 TI - Consolidation of immunotherapy becomes new standard of care in unresectable stage III non-small cell lung cancer. PMID- 29707268 TI - Different strategies of myocardial protection: the age of perfectionism. PMID- 29707269 TI - Causal role of rapid-eye-movement sleep on successful memory consolidation of fear extinction. PMID- 29707270 TI - Adequacy of intra-operative nodal staging during lung cancer surgery: a poorly achieved minimum objective. PMID- 29707271 TI - Pacific trial: a new ocean or an abnormal wave? PMID- 29707272 TI - Usefulness of robot-assisted surgery for lung cancer demonstrated from the patient's perspective. PMID- 29707273 TI - Surgery for mediastinal lymph node and early stage lung cancer: individualized practice based on clinical database. PMID- 29707274 TI - Should a therapeutic strategy be based on how the disease was diagnosed? PMID- 29707275 TI - Atelectrauma or volutrauma: the dilemma. PMID- 29707276 TI - Brain response to sleep-related attentional bias after cognitive-behavioral therapy in individuals with insomnia symptoms. PMID- 29707277 TI - Intratumoral heterogeneity of Notch1 expression in small cell lung cancer. PMID- 29707278 TI - Immune checkpoint blockade in esophageal squamous cell carcinoma: is it ready for prime time? PMID- 29707279 TI - Gene methylation in liquid biopsy and risk of recurrence in lung cancer. PMID- 29707280 TI - Report of the 2016-2017 ESTS-AME visiting fellow to the First Affiliated Hospital of Guangzhou University, China. PMID- 29707281 TI - What does the Acute Respiratory Distress Syndrome trial (ART) teach us?-it is time for precision medicine and precision trials in critical care! PMID- 29707282 TI - Targeted temperature management for non-shockable cardiac arrests: the debate must go on. PMID- 29707283 TI - Single agent anti PD-1 inhibitors in esophageal cancer-a first step in a new therapeutic direction. PMID- 29707284 TI - Does the hybrid algorithm has real impact on long-term outcomes or should only be used as a valuable approach for CTO crossing? PMID- 29707285 TI - Robotic-assisted thoracic surgery versus uniportal video-assisted thoracic surgery: is it a draw? PMID- 29707286 TI - In vitro assessment of cefoperazone-sulbactam based combination therapy for multidrug-resistant Acinetobacter baumannii isolates in China. AB - Background: Multidrug-resistant Acinetobacter baumannii (MDRAB) has emerged as an important pathogen of nosocomial infections. Even though cefoperazone-sulbactam is frequently used to treat MDRAB infections, this single-drug therapeutic approach often results in antibiotic resistance. Thus, combination therapy is preferred over single-drug therapy, particularly in the case of carbapenemase producing gram negative bacteria. The aim of this study was to investigate the efficacy of cefoperazone-sulbactam combined with either tigecycline or rifampicin against clinical isolates of MDRAB. Methods: One hundred and three MDRAB bacteria were isolated from patients in two hospitals in China. The Epsilomer test (E test) was used to determine the minimum inhibitory concentration (MIC) values for amikacin, ceftazidime, cefepime, levofloxacin, rifampicin, cefoperazone sulbactam, meropenem, tigecycline, and gentamicin against MDRAB isolates. In vitro effects of various antibiotic combinations were measured and the fractional inhibitory concentration index (FICI) was calculated for each drug combination. Results: Approximately 17.5% of the isolates were resistant to tigecycline, whereas more than 84.2% isolates were resistant to other antimicrobial agents tested in this study. Cefoperazone-sulbactam revealed remarkable synergistic effects when used in combination with either tigecycline or rifampicin. However, for the isolates with MICs lower than blood peak concentration after combination therapy, the ratio was lower in highly resistant isolates compared to the least resistant bacteria. Conclusions: In vitro cefoperazone-sulbactam in combination with tigecycline or rifampicin showed the highest synergistic or additive activity against MDRAB isolates. However, acquisition of highly antibiotic resistant bacteria may lessen the effectiveness of combination therapy. PMID- 29707287 TI - Peak expiratory flow among healthy children aged 5-14 years in China. AB - Background: Guidelines of the Global Initiative for Asthma recommend the use of peak expiratory flow (PEF) in the assessment and management of patients with asthma. However, normal PEF values for Chinese children have not been thoroughly investigated. Methods: This was a cross-sectional study of 3,169 healthy children aged 5-14 years from research centers in five cities of China: Guangzhou, Suzhou, Chengdu, Xi'an, and Beijing. We established pediatric reference values for PEF using a mini peak flow meter. PEF values recorded by the mini peak flow meter were compared with those obtained using a spirometer. Results: Height was the biometric variable with greatest correlation to PEF for both sexes. Significant differences were noted between males and females. The regression equation for boys was calculated as PEF =4.39* height (cm) -300.48 (R2 =0.76, P<0.001); for girls, this equation was PEF =4.13* height (cm) -278.04 (R2 =0.72, P<0.001). PEF values for Chinese children according to age were close to those of Irish, Turkish, and British children but were lower than those of children in Greece; PEF values according to height were similar to those of Turkish and Danish children but lower than values for children in Ireland. Conclusions: We established normal PEF values and developed predictive equations using linear regression analysis for Chinese children aged 5-14 years, while Greece and Ireland references were inappropriate for Chinese children. PMID- 29707288 TI - Early radiological response as predictor of overall survival in non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor mutations. AB - Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) are the standard treatment of advanced, EGFR-mutant non-small-cell lung cancer (NSCLC). Usually, radiographic assessment of response to chemotherapy is performed after the patient completes the second course of treatment. The optimal timing of response evaluation for patients receiving EGFR-TKIs is, however, not well-defined. The purpose of this study is to evaluate the association of an early radiological response (ERR) to TKIs by computed tomography (CT) with progression-free survival (PFS) and overall survival (OS) in advanced NSCLC patients with EGFR mutations. Methods: EGFR mutation status was analyzed retrospectively in a cohort of 360 NSCLC patients' between January 2009 and November 2014. Forty of them received treatment with TKI and therefore were included in the study. Response to TKI therapy was defined according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. ERR was defined as complete response (CR) or partial response (PR) at the first radiographic evaluation performed within 6-8 weeks after the beginning of the treatment. Results: Activating mutations in the tyrosine kinase domain of the EGFR gene were mainly exon 19 deletions. Thirty patients (75%) had ERR, 4 of those patients (10%) showed a PR on early CT achieving a CR in the long-term monitoring. Median PFS was longer in patients experiencing an ERR (10.9 vs. 2.4 months; HR: 0.42; 95% CI: 0.19-0.93; P=0.033) than those that did not [stable disease (SD) or progressive disease (PD)]. Median overall survival OS was also significantly increased in patients experiencing ERR (23.2 vs. 11.9 months; HR: 0.3; 95% CI: 0.15-0.85; P=0.021). Conclusions: ERR in patients treated with EGFR TKI therapy is associated with statistically significant PFS and OS, and could be a surrogate marker of efficacy in these patients. Moreover, ERR provides an early identification of patients not benefitting from TKI, despite the presence of activating EGFR mutations in which further efforts are needed to improve their prognosis. PMID- 29707289 TI - Fractures of the manubrium sterni: treatment options and a possible classification of different types of fractures. AB - Background: Sternum fractures are mostly located on the sternal corpus, seldom on the manubrium. Fractures of the sternal manubrium are, however, more frequently associated with severe concomitant injuries of thoracic organs, and therefore deserve special attention. In addition, in its function as a capstone in between the anterior chest wall and the shoulder girdle, it is exposed to a multiplicity of forces. Therefore the questions arise what types of fractures are observed in today's clinical practice, how to classify them and which treatment options are available. This study reports on different types of fractures which involve the manubrium sterni. Methods: Between January 2012 and October 2014, data was collected from all severely injured patients (ISS >=16), which received a CT scan of the thorax in our Level-I-Trauma Center and retrospectively analyzed concerning sternal fractures. Fracture type, collateral injuries, age, and information about the circumstances of the accident were noted. Results: Of 890 evaluable patients, 154 (17.3%) had a fracture of the sternum and 23 (2.6%) of the manubrium. Fractures of the manubrium appeared in following types: A-type transverse fracture (n=11) in 1st intercostal space by direct blunt trauma or flexion of the torso with sagittal instability; B-type-oblique fracture (n=9) by seat belt injury with rotatory instability; C-type-combined, more fragmentary fracture (n=3) by direct blunt trauma with simultaneous flexion of the torso and multi directional instability. Fractures only little dislocation were treated conservatively, and unstable fractures were surgically stabilized (n=10). Conclusions: In summary, three main types of fractures could be found. A-type fractures were stabilized with a longitudinal plate osteosynthesis and B-type fractures with transverse positioned plates. To treat complex C-type fractures, plates with a T- or H-form could be a good solution. Level of evidence: Level III retrospective prognostic cohort study. PMID- 29707290 TI - Age is major factor for predicting survival in patients with acute respiratory failure on extracorporeal membrane oxygenation: a Korean multicenter study. AB - Background: The proportion of elderly patients in the intensive care unit population is increasing. Although the Respiratory Extracorporeal Membrane Oxygenation Survival Prediction (RESP) score is widely used for survival prediction of extracorporeal membrane oxygenation (ECMO) patients, it is questionable whether the RESP score is applicable to older patients. The aim of this study was to investigate the applicability of the RESP score in Korean cohort. Methods: Data were retrospectively analyzed from 209 acute respiratory failure (ARF) patients treated with ECMO from 2014 to 2015 at 11 hospitals. A comparison of outcome prediction models was conducted and multivariate logistic regression analysis was performed to identify independent risk factors for hospital mortality. Results: In all patients, the median age was 58 (IQR, 45-65) years. Overall survival at hospital discharge was 45.9%, and veno-venous ECMO was used in 82.3% of patients. Patients older than 65 years treated with ECMO support were 51 with 31.4% of hospital survival. The PRedicting dEath for SEvere ARDS on VV-ECMO (PRESERVE) and RESP scores significantly predicted mortality in patients, with areas under the curve (AUCs) of 0.63 [95% confidence interval (CI), 0.54 0.72] and 0.66 (95% CI, 0.58-0.73), respectively. In multivariate logistic regression analysis, age is independent risk factor for hospital mortality [odds ratio 1.044 (95% CI, 1.020-1.068), P<0.001] with AUC of 0.67 (95% CI, 0.59-0.74). The RESP score was modified using reclassified age and the modified RESP score obtained AUC of 0.71 (95% CI, 0.63-0.78). Conclusions: The RESP score is significant model for predicting outcomes in a Korean ECMO population. Elderly patients had higher mortality, and age alone showed similar discrimination ability for prediction of mortality compared to the RESP score. PMID- 29707292 TI - Selective gene amplification to detect the T790M mutation in plasma from patients with advanced non-small cell lung cancer (NSCLC) who have developed epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) resistance. AB - Background: The epidermal growth factor receptor (EGFR) T790M mutation is associated with resistance to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non small cell lung cancer (NSCLC). However, tissues for the genotyping of the EGFR T790M mutation can be difficult to obtain in a clinical setting. The aims of this study were to evaluate a blood-based, non-invasive approach to detecting the EGFR T790M mutation in advanced NSCLC patients using the PointManTM EGFR DNA enrichment kit, which is a novel method for the selective amplification of specific genotype sequences. Methods: Blood samples were collected from NSCLC patients who had activating EGFR mutations and who were resistant to EGFR-TKI treatment. Using cell-free DNA (cfDNA) from plasma, EGFR T790M mutations were amplified using the PointManTM enrichment kit, and all the reaction products were confirmed using direct sequencing. The concentrations of plasma DNA were then determined using quantitative real-time PCR. Results: Nineteen patients were enrolled, and 12 patients (63.2%) were found to contain EGFR T790M mutations in their cfDNA, as detected by the kit. T790M mutations were detected in tumor tissues in 12 cases, and 11 of these cases (91.7%) also exhibited the T790M mutation in cfDNA samples. The concentrations of cfDNA were similar between patients with the T790M mutation and those without the mutation. Conclusions: The PointManTM kit provides a useful method for determining the EGFR T790M mutation status in cfDNA. PMID- 29707291 TI - Early changes in coagulation profiles and lactate levels in patients with septic shock undergoing extracorporeal membrane oxygenation. AB - Background: To investigate the impact of coagulation profiles and lactate levels in patients with septic shock undergoing extracorporeal membrane oxygenation (ECMO). Methods: A retrospective analysis of coagulation profiles, including disseminated intravascular coagulation (DIC) score, before and during 48 h of ECMO support [on day 0 (pre-ECMO), day 1, and day 2], was conducted in patients with septic shock undergoing ECMO. Results: A total of 37 patients were included, and 15 (40.5%) patients survived. The initial DIC scores did not change in either the pre-ECMO overt-DIC (n=15) or non-overt-DIC (n=22) group after ECMO commencement. However, the DIC scores were significantly higher, at all three time-points, in non-survivors than in survivors. Additionally, the lactate levels improved considerably in the pre-ECMO non-overt-DIC group and in survivors during ECMO support, but not in the pre-ECMO overt DIC group or non-survivors. On a multivariate analysis, the pre-ECMO DIC score was significantly associated with hospital death [odds ratio (OR), 3.935; 95% confidence interval (CI), 1.170 13.230]. Receiver operating characteristic (ROC) curves revealed that the combination of pre-ECMO DIC score plus lactate level was the best predictor of hospital death (area under the curve, 0.879; 0.771-0.987); patients with combined scores >9.35 (the optimal cut-off) exhibited a three-fold higher mortality rate than did those with lower scores (81.8% vs. 26.7%, P=0.001). Conclusions: During the early period of ECMO support, the coagulation profiles and lactate levels exhibited different trajectories in survivors and non-survivors. Furthermore, the pre-ECMO DIC score plus lactate level was the best predictor of hospital death. PMID- 29707293 TI - A population-based analysis of outcomes after radiotherapy in intensive care unit patients with lung cancer. AB - Background: As the value of radiotherapy (RT) in intensive care unit (ICU) patients with lung cancer is of uncertain efficacy, we evaluated characteristics, outcomes and RT utilization for such patients in Ontario, Canada. Methods: Multiple administrative databases were linked deterministically using unique encoded identifiers to identify eligible patients between April 1, 2007, and March 31, 2014. Differences in patient, treatment, institution and tumor characteristics between RT and non-RT groups at the level of episode of care were compared. Overall survival (OS) was evaluated using the Kaplan-Meier method, with differences compared using the log-rank test. Univariable and multivariable Cox proportional hazard modeling were performed to assess the effect of RT on survival. Results: RT was delivered in 133 episodes of care to 1.0% (n=131) of the 13,739 unique patients with lung cancer. RT delivery was associated with younger age (median 65 vs. 68, P<0.001), ventilation (79.8% vs. 38.2%, P<0.001) and longer ventilation duration (median 6 vs. 0 days, P<0.001). Pre-ICU disposition via transfer (35.3% vs. 9.7%) or the emergency room (ER) (28.6% vs. 21.9%) was more likely in the RT group (P<0.001). RT delivery varied, with half of the regions treating <=5 patients each. ICU discharge was common in both RT (n=75, 56.4%) and non-RT (n=10,405, 71.4%) cohorts. One-year OS was poor in both groups, but most notably in the RT group (11.3% vs. 42.4%). RT was associated with inferior 1-year OS on unadjusted modeling (HR =1.99, P<0.001), with ventilation and pre-ICU disposition adjusting this finding towards the null on multivariable modeling (HR =1.17, P=0.095). Conclusions: Major geographic disparities exist in the rare use of RT for lung cancer in the ICU. A significant proportion of patients receiving RT achieve discharge and a minority achieve prolonged survival, suggesting that RT use may not be futile. PMID- 29707294 TI - Lipoxin A4 regulates PM2.5-induced severe allergic asthma in mice via the Th1/Th2 balance of group 2 innate lymphoid cells. AB - Background: Urban particulate matter (PM) contributes to the increasing number of people with asthma, which is closely related to the development of industrialization. Especially, PM with an aerodynamic diameter of <2.5 um (PM2.5) enhances the risk of damaging respiratory organs. It has reported that PM2.5 induced pathological changes could be considered as a remarkable molecular mechanism of PM2.5-mediated cytotoxicity in respiratory disease and even lung cancer. Methods: In this study, we have investigated the effects of PM2.5 on ovalbumin (OVA)-induced asthma mice and the therapeutic effect of Lipoxin A4 (LXA4) on improving the poor pathology. Results: The exposure of PM2.5 showed that both cytokines of T helper-2 (Th2) cells and transcription factors of group 2 innate lymphoid cells (ILC2s) were significantly increased, and inflammatory cell infiltration occurred in lung tissue. The LXA4 was used to treat asthma, which was an effective option in reducing inflammatory cytokines and relieving pathological symptoms, probably by regulating the Th1/Th2 balance. Conclusions: These results suggest that PM2.5-induced inflammation plays a key role in the progression of asthma mice. In addition, LXA4 has a significant therapeutic effect on asthma, which indicates the direction for the treatment of asthma related inflammatory diseases. PMID- 29707295 TI - Percutaneous occluder device closure through femoral vein guidance by transthoracic echocardiography in adult atrial septal defect patients. AB - Background: This study aimed to summarize percutaneous occluder device closure of atrial septal defects (ASD) through the femoral vein, using guidance by transthoracic echocardiography under local anesthesia without radiation or fluoroscopic guidance. Methods: This was a case series of fourteen patients, 3 males and 11 females, diagnosed with central ASD, the diameter of the defect ranged from 9 to 32 mm, and the patients had no other heart malformations or organ dysfunction. The patients underwent a novel surgical technique of occluder device closure for ASD. The occluder closure procedures were completed through puncture of the femoral vein, and fluoroscopy-free catheter guidance by transthoracic echography without radiation. Results: All of the cases had successful closure of the ASD, without residual shunt or complications. The median operation time was 18.7+/-22.5 min (range, 12-56 min), with no ICU-stay time and a short hospital stay of 2.3+/-0.5 days (range, 1-3 days). All patients were followed up for 2 years and there were no cases of residual shunt. All occluders remained in place. Conclusions: Percutaneous occluder device closure of ASDs through the femoral vein with fluoroscopy-free guidance by transthoracic echography without radiation under local anesthesia could be an easy choice for some simple ASD patients, and may also be favored by cardiac surgeons. PMID- 29707296 TI - Sevoflurane did not show better protective effect on endothelial glycocalyx layer compared to propofol during lung resection surgery with one lung ventilation. AB - Background: The endothelial glycocalyx layer (EGL) coats the alveolar capillary endothelium and plays important roles in pulmonary vascular protection, modulation, and hemostasis. Ischemia-reperfusion, which occurs during lung resection surgery with one lung ventilation (OLV), can damage the EGL. Sevoflurane is known for its protective effect against ischemia-reperfusion injury. Therefore, we hypothesized that lung resection surgery produces EGL damage and sevoflurane protects the EGL better than the intravenous anesthetic propofol. Methods: Seventy-eight patients undergoing pulmonary resection were randomly allocated into the sevoflurane (n=38) and propofol (n=40) groups. All patients received OLV and protective ventilation under sevoflurane- or propofol based anesthesia. The concentrations of EGL injury markers (heparan sulfate and human syndecan-1) and an inflammatory marker (vascular cell adhesion molecule-1) were measured from blood samples drawn at five time points (after induction, 60 min after OLV, 120 min after OLV, end of OLV, and end of surgery). Results: OLV increased the concentrations of EGL injury markers; heparan sulfate concentrations increased from 120 minutes after OLV (120 minutes after OLV: sevoflurane, 13.3+/-6.8 ng/mL, P<0.05; propofol, 14.8+/-6.9 ng/mL, P<0.05). Human syndecan-1 concentrations also increased from 120 minutes after OLV (120 minutes after OLV: sevoflurane, 20.4+/-8.9 ng/mL, P<0.05; propofol, 20.5+/-11.8 ng/mL, P>0.05). However, no difference in EGL injury markers was observed between the sevoflurane and propofol groups at any time point. Vascular cell adhesion molecule-1 concentrations did not show any temporal changes in either group. Conclusions: Lung resection surgery with OLV produced EGL damage without any increase in inflammation. Although shedding of heparan sulfate induced by EGL injury during lung resection surgery with OLV, was less than propofol, it was not statistically significant. PMID- 29707297 TI - Atrial fibrillation is related to lower incidence of deep venous thrombosis in patients with pulmonary embolism. AB - Background: Atrial fibrillation (AF) is an established risk factor of left atrial thrombosis and systemic embolism. Traditionally pulmonary embolism (PE) is a recognized complication of deep vein thrombosis (DVT). However, whether AF is responsible for right atrial thrombosis and leads to PE has not been examined. Methods: We retrospectively analyzed medical records of patients with confirmed diagnosis of PE with AF (study group) from 2002-2015. Patients with PE without AF, matched by age and sex, served as controls (control group). The CHA2DS2-VASc and CHADS2 scores were classified into two categories, low-intermediate (<2 points) and high-risk (>=2 points). Results: A total of 330 patients (110 in study group and 220 in control group). The study group had significantly lower incidence of newly diagnosed DVT (21% vs. 44%, P<0.001), previous history of DVT (6% vs. 17%, P=0.006) and recent surgery or trauma (10% vs. 23%, P=0.004) compared to the control group. When stratified by the CHADS2 score, 49 patients (44.5%) were considered low-intermediate risk. This proportion significantly differed when stratified using CHA2DS2-VASc, in which 13 patients (13.6%) were considered low-intermediate risk, P<0.001. Conclusions: The incidence of DVT was much lower in the study group, suggesting the possibility of clots originated from the right heart that may increase the risk of PE. The CHA2DS2-VASc scoring system might be more sensitive for prediction and stratification of the PE in AF patients than the CHADS2 score. PMID- 29707298 TI - Effects of volume-controlled ventilation vs. pressure-controlled ventilation on respiratory function and inflammatory factors in patients undergoing video assisted thoracoscopic radical resection of pulmonary carcinoma. AB - Background: The best ventilation approach for patients undergoing video-assisted thoracic surgery (ATS) for pulmonary carcinoma remains undefined. This study aimed to assess hemodynamics, airway pressure, arterial blood gas, and inflammatory factors in patients undergoing VATS for pulmonary carcinoma under volume-controlled ventilation (VCV) or pressure-controlled ventilation (PCV). Methods: This was a prospective study of 60 patients with pulmonary carcinoma treated at a tertiary center in 2015-2016. The subjects were randomized to the VCV or PCV group after anesthesia and total lung ventilation (TLV). Hemodynamics and blood gas parameters were compared between the two groups pre-OLV (one-lung ventilation) (T1) and after 30 (T2), 60 (T3), and 120 (T4) minutes of OLV. Radial artery blood was collected to measure interleukin (IL)-6, IL-10, and tumor necrosis factor (TNF)-alpha levels. Results: Hemodynamic and blood gas parameters were similar between the two groups (all P>0.05). During OLV, airway resistance (RAW) was significantly lower in the PCV group compared with the VCV group at T2 (26.0+/-3.8 vs. 29.9+/-7.3 cmH2O/L/s), T3 (26.0+/-3.7 vs. 30.2+/-7.7 cmH2O/L/s), and T4 (25.8+/-4.1 vs. 29.6+/-6.7 cmH2O/L/s). Similar trends were found for peak pressure (Ppeak) and plateau pressure (Pplat). Mean pressure (Pmean) was similar between the two groups. Compared with the PCV group, TNF-alpha and IL-6 levels in the VCV group were significantly increased (all P<0.05). The levels of the anti inflammatory mediator IL-10 were higher in the PCV group compared with the VCV group. Conclusions: PCV for OLV during radical resection of pulmonary carcinoma by VATS could reduce Ppeak and downregulate pro-inflammatory factors, likely decreasing airway injury. PMID- 29707299 TI - Cold crystalloid versus warm blood cardioplegia in patients undergoing aortic valve replacement. AB - Background: Myocardial protection techniques during cardiac arrest have been extensively investigated in the clinical setting of coronary revascularization. Fewer studies have been carried out of patients affected by left ventricular hypertrophy, where the choice of type and temperature of cardioplegia remain controversial. We have retrospectively investigated myocardial injury and short term outcome in patients undergoing aortic valve replacement plus or minus coronary artery bypass grafting with using cold crystalloid cardioplegia (CCC) or warm blood cardioplegia (WBC). Methods: From January 2015 to October 2016, 191 consecutive patients underwent aortic valve replacement plus or minus coronary artery bypass grafting in normothermic cardiopulmonary bypass. Cardiac arrest was obtained with use of intermittent antegrade CCC group (n=32) or WBC group (n=159), according with the choice of the surgeon. Results: As compared with WBC group, in CCC group creatine-kinase-MB (CK-MB), cardiac troponin I (cTnI), aspartate aminotransferase (AST) release, and their peak levels, were lower during each time points of evaluation, with the greater statistically significant difference at time 0 (P<0.05, for all comparisons). A time 0, CK-MB/CK ratio >10% was 5.9% in CCC group versus 7.8% in WBC group (P<0.0001). At time 0 CK-MB/CK ratio >10% in patients undergoing isolated aortic valve replacement was 6.0% in CCC group versus 8.0% in WBC group (P<0.01). No any difference was found in perioperative myocardial infarction (0% versus 3.8%), postoperative (PO) major complications (15.6% versus 16.4%), in-hospital mortality (3.1% versus 1.3%). Conclusions: In aortic valve surgery a significant decrease of myocardial enzymes release is observed in favor of CCC, but this difference does not translate into different clinical outcome. However, this study suggests that in presence of cardiac surgical conditions associated with significant left ventricular hypertrophy, i.e., the aortic valve disease, a better myocardial protection can be achieved with the use of a cold rather than a warm cardioplegia. Therefore, CCC can be still safely used. PMID- 29707300 TI - Clinical results of multimodality therapy for esophageal cancer with distant metastasis. AB - Background: The purpose of this study is to evaluate outcomes in upfront local response and survival of patients with esophageal cancer and distant metastasis. Methods: This retrospective study included 34 patients (25 males) aged 42-92 years (median, 70 years) with a histological diagnosis of esophageal squamous cell cancer with distant metastasis. Staging was performed according to the UICC's TNM (6th edition) classification of malignant tumor. Results: The median survival time (MST) was 5 months. The 1-year overall survival (OS) was 20.6%. Improved OS was associated with receipt of surgery [hazard ratio (HR), 3.857; 95% CI, 1.142-13.024; P=0.030] on both univariate and multivariate analyses, and the MST was 11 months. The overall objective local response rate was 82%. Ten patients had complete response (CR), 18 had partial response (PR). The overall symptom response was 88% patients. Six had CR, 24 had PR. There was no significant difference in the objective and symptom response between <=50 and >50 Gy. Concurrent chemoradiotherapy (CCRT) with 50 Gy gave results of objective and symptom responses comparable to those of 60 Gy, which has been reported previously. Conclusions: CCRT with 50 Gy gave results comparable to those of 60 Gy, which has been reported previously, and the toxicity was acceptable. Our findings showed that a multimodality therapy that includes surgery may improve survival in only a select group. PMID- 29707301 TI - Lymph node metastases near the celiac trunk should be considered separately from other nodal metastases in patients with cancer of the esophagus or gastroesophageal junction after neoadjuvant treatment and surgery. AB - Background: The aim of the present study is to identify the incidence and prognostic significance of lymph node metastases near the celiac trunk in patients who underwent neoadjuvant chemo(radio)therapy followed by esophagectomy. Methods: Between March 1994 and September 2013 a total of 462 consecutive patients with cancer of the esophagus or gastroesophageal junction (GEJ) who underwent potentially curative esophageal resection after neoadjuvant chemotherapy (N=88; 19.0%) or neoadjuvant chemoradiotherapy (CRT) (N=374; 81.0%) were included. Results: Seventy one (15.4%) patients had truncal node metastases in the resection specimen. Metastases to these nodes occurred more frequently in male patients with adenocarcinoma and in tumors at the gastro-esophageal junction. A lower response to neoadjuvant treatment, higher ypT and ypN stages and a poorer grade of differentiation were significantly related with truncal node metastases. Patients with tumor positive truncal nodes had a worse median overall survival (17 vs. 55 months). In multivariate analysis, truncal node metastases were independently associated with a worse survival. Only 22 (31.0%) of the 71 patients with tumor positive truncal nodes were identified preoperatively with EUS or CT. In contrast, 37 patients had suspicious truncal nodes on EUS or CT, but metastases in the pathology specimen were absent. Conclusions: In the present study, it is demonstrated that positive truncal nodes in the resection specimen after neoadjuvant therapy, are associated with advanced tumor stages and are an independent factor for inferior survival. PMID- 29707302 TI - Prognostic and clinicopathological significance of platelet to lymphocyte ratio in esophageal cancer: a meta-analysis. AB - Background: The prognostic and clinicopathological significance of the platelet to lymphocyte ratio (PLR) has been studied in various cancers. However, studies examining the role of PLR in esophageal cancer have not yielded consistent results. The purpose of this meta-analysis was to study the prognostic and clinicopathological significance of PLR in esophageal cancer patients. Methods: We performed a literature search in three major databases: PubMed, Web of Science and Embase (up until May 1, 2017). The clinicopathologic significance of PLR and its prognostic significance were analyzed. Results: Our meta-analysis consisted of 13 studies with 4,621 patients. The pooled hazard ratios (HRs) showed that a high PLR was associated with poor survival of esophageal cancer [HR =1.283; 95% confidence interval (CI): 1.173-1.404; P<0.001]. Subgroup analysis revealed that elevated PLR was associated with poor survival in esophageal squamous cell carcinoma (HR =1.281; 95% CI: 1.098-1.493; P=0.002). The pooled odds ratio (OR) indicated that high PLR was also associated with the depth of tumor invasion (OR =1.543, 95% CI: 1.269-1.876, P<0.001), lymph node metastasis (OR =1.427, 95% CI: 1.195-1.705, P<0.001), tumor length (OR =1.81, 95% CI: 1.331-2.461, P<0.001), and Tumor stage (OR =1.459, 95% CI: 1.235-1.724, P<0.001). Conclusions: Our results demonstrate that elevated PLR was significantly associated with poor prognosis of esophageal cancer. Furthermore, the high PLR might predict worse clinicopathological features of esophageal cancer patients. PMID- 29707303 TI - A long-term evaluation of postoperative moist hands after R4/R4+5 sympathectomy for primary palmar hyperhidrosis. AB - Background: Thoracoscopic R4 sympathectomy has been recommended as a safe and effective surgical treatment procedure for primary palmar hyperhidrosis (PPH). However, approximately half of patients presented postoperative moist hands (PMH), and recurrence occurred individually. Therefore, more thorough long-term results should be evaluated. Methods: Between January 2005 and December 2014, 506 consecutive patients with palmar hyperhidrosis treated with either R4 or R4+5 were retrospectively reviewed and followed-up. Results: A total of 451 patients (89.1%) completed the follow-up with an average follow-up time of 30.7+/-25.4 months. Palmar sweating completely ceased in 178 patients (39.5%), whereas 215 (47.7%) achieved greater than 50% improvement, 43 (9.5%) achieved 20-50% improvement. Fifteen individuals (3.3%) experienced recurrence. The frequency of individuals achieving 100% improvement was significantly higher in the group R4+5 than in the group R4 (60.9% vs. 27.8%, respectively; P<0.001). A total of 321 patients (71.2%) showed compensatory hyperhidrosis with 290 (64.3%) and 29 (6.4%) experiencing mild or moderate types respectively. Two individuals (0.4%) suffered from severe type. The incidence of compensatory hyperhidrosis in the group R4+5 was significantly lower than the group R4 (63.8% vs. 73.7%, respectively; P=0.037). Regarding satisfaction, 345 (76.5%) and 83 (18.4%) patients were highly satisfied and partially satisfied with their surgical results, respectively. Six patients (1.3%) were dissatisfied, and 17 (3.8%) expressed regret for surgery. Conclusions: PMH occurred in over half of patients after R4 or R4+5 sympathectomy, but most of these patients were satisfied with the surgical results. R4+5 appears to be a better option for palmar hyperhidrosis with lower incidence of PMH and compensatory hyperhidrosis. PMID- 29707304 TI - Comparison of short-term outcomes for connective tissue disease-related interstitial lung disease and idiopathic pulmonary fibrosis after lung transplantation. AB - Background: Pulmonary involvement is common in connective tissue disease (CTD), and respiratory failure is a major cause of morbidity and mortality in CTD related interstitial lung disease (CTD-ILD). Lung transplantation is thus important for these patients. However, survival, outcomes, and management of these patients after transplantation have been debated. The aim of this study was to evaluate the outcomes for CTD-ILD compared to those for idiopathic pulmonary fibrosis (IPF) after lung transplantation. Methods: We performed a single-centre retrospective study of 62 patients with CTD-ILD or IPF who underwent lung transplantation at a tertiary hospital in South Korea between October 2012 and October 2016. Results: Patients with CTD-ILD (n=15) were younger (46 vs. 60 years, P=0.001) and were less likely to be male (33.3% vs. 76.6%, P=0.004) than were patients with IPF (n=47). The 1-year cumulative survival rate was 80.0% for CTD-ILD and 59.6% for IPF (log-rank P=0.394). There was no difference in the cumulative survival rate (log-rank P=0.613) of age- and sex-matched patients with CTD-ILD (n=15) and IPF (n=15). The incidence of primary graft dysfunction was similar (P=0.154), and 2 (18.2%) patients developed possible CTD flare. Conclusions: Patients with CTD-ILD and those with IPF who underwent lung transplantation had similar survival rates. PMID- 29707305 TI - Is closed thoracic drainage tube necessary for minimally invasive thoracoscopic esophagectomy? AB - Background: Closed thoracic drainage tube (CTDT) is a conventional treatment after esophagectomy, even after minimally invasive esophagectomy. Here, we report a single-center, retrospective study to explore the safety and necessity of CTDT after thoracoscopic-esophagectomy. Methods: From October 2015 and August 2016, 50 patients were enrolled and underwent thoracoscopic-esophagectomy in semi-prone position by same surgical team. Perioperative demographic and surgical parameters, and patients' satisfaction with or without CTDT after thoracoscopic esophagectomy were collected and analyzed. Results: All eligible patients (18 patients without CTDT and 32 patients with CTDT) were successfully underwent thoracoscopic procedures without conversion to open approach or major intraoperative complications and perioperative death. The two groups, with similar demographic parameters, had no statistically difference in thoracic operation time, blood loss, ICU stay, postoperative mobilization and oral feeding, and hospital stay. Also, the incidence of postoperative complications was similar with or without CTDT after esophagectomy. But, no-CTDT group had better post-operative satisfaction, including less pain scale scoring and better Norton scoring. Conclusions: This study demonstrated that the treatment of no CTDT after the minimally invasive thoracoscopic-esophagectomy is safe and feasible, might reduce the work intensity of medical stuff and lead to a better patients' experience. PMID- 29707306 TI - Different strategy of salvage esophagectomy between residual and recurrent esophageal cancer after definitive chemoradiotherapy. AB - Background: Clinical outcomes appear to differ between patients with residual or recurrent esophageal cancer after definitive chemoradiotherapy. We aimed to identify the patients most likely to benefit from this high-risk surgery, divided by the patients whose cancer was residual and recurrent groups, respectively. Methods: We retrospectively examined 100 cases of patients who failed to respond to definitive chemoradiotherapy for thoracic esophageal squamous cell carcinoma and subsequently underwent salvage transthoracic esophagectomy. Results: In hospital morbidity was similar in both groups. T status prior to administration of chemoradiotherapy correlated with survival in the group with residual cancer (P=0.010), but this relationship was not significant in the group with recurrent cancer (P=0.635). On the other hand, pathological T status showed a significant correlation with survival in both the residual (P<0.001) and recurrent groups (P=0.001). Patients with T3 disease in the recurrent group showed better survival, similar to T0-2 patients, while worse survival was demonstrated in the residual group. In the recurrent group, N status before chemoradiotherapy did not correlate with survival (P=0.895). Conclusions: Patients with residual cancer would have good prognosis by salvage esophagectomy in cases in which the cancer had not invaded to the adventitia at the time of chemoradiotherapy and surgery. Conversely, patients whose cancer was recurrent might benefit from salvage surgery if the cancer appears to be resectable. T and N status before chemoradiotherapy are not important factors in consideration of salvage esophagectomy in cases of recurrent cancer. PMID- 29707307 TI - Retrograde perfusion through superior vena cava reaches the brain during circulatory arrest. AB - Background: The optimal technique for brain perfusion during circulatory arrest remains controversial. Concern exists that retrograde cerebral perfusion (RCP) via the superior vena cava (SVC) is unable to perfuse the brain. We evaluated whether RCP blood circulates through the brain parenchyma in humans during deep hypothermic circulatory arrest (DHCA). We hypothesized that a significant difference in the levels of S-100beta (a protein with very high neuro sensitivity) between the blood infused in the SVC and the effluent blood returning in the left carotid artery (CA) during RCP, should be regarded as a sign of the circulation of RCP blood through the brain parenchyma. Methods: We enrolled 10 non-consecutive patients undergoing elective arch-surgery using DHCA and RCP. Circulating S-100beta levels were measured at baseline and immediately before DHCA. During DHCA and RCP the difference in S-100beta between the SVC and the CA was evaluated after 10 minutes of arrest and immediately before resumption of the circulation. S-100beta levels were evaluated using enzyme-linked immunosorbent assay (ELISA). Results: Mean DHCA duration was 22.4+/-7.9 minutes. Mean S-100beta level at baseline was 92.5+/-54.9 ug/L. After 10 minutes of DHCA the level of S-100beta in the CA was significantly higher than in the SVC (936.9+/-326.3 vs. 810.9+/-307.4 ug/L, P=0.0021). This difference was enhanced at the second DHCA sample (1113.8+/-334.2 vs. 920.5+/-340.0 ug/L, P=0.0002). There was a statistically significant correlation between the duration of DHCA and the percent difference in S-100beta level between the SVC and the CA (Pearson's correlation coefficient =0.902). Conclusions: RCP is able to perfuse the brain parenchyma in humans during DHCA. PMID- 29707308 TI - The clinical value of circulating tumour cells (CTCs) in patients undergoing pulmonary metastasectomy for metastatic colorectal cancer. AB - Background: Circulating tumour cells (CTCs) are a potential surrogate for distant metastasis and are considered a useful clinical prognostic marker for metastatic colorectal cancer (mCRC). This prospective study evaluated the preoperative CTC count as a prognostic factor for pulmonary metastasectomy in mCRC patients. Methods: Seventy-nine mCRC patients who underwent curative-intent pulmonary metastasectomy were included. Preoperatively, 7.5 mL of peripheral blood from each patient was quantitatively evaluated for CTCs with the CellSearch(r) system. The clinical significance of CTC count was evaluated according to Kaplan-Meier analyses and log-rank test. Multivariate analyses of the perioperative variables were performed. Results: The distribution of CTC counts were as follows; 0 in 66 patients (83.5%), 1 in eight patients (10.1%), 2 in three patients (3.8%), and 3 and 6 in one patient (1.3%). The patients with multiple CTCs (CTC count >=2) had significant shorter disease-free survival (DFS) (P=0.005, median DFS; 19.8 vs. 8.6 months) and overall survival (OS) (P=0.035, median DFS; not reached vs. 37.8 months), respectively. Multivariate analysis showed the patients with multiple CTCs had elevated risk of recurrence [hazard ratio (HR), 3.28; 95% confidence interval (CI), 1.24-8.67; P=0.017]. Conclusions: The detected rate of CTCs was quite low in mCRC patients who underwent pulmonary metastasectomy. The patient with multiple CTCs had shorter DFS in this study. The larger prospective clinical study is needed to establish the meaning of CTC in mCRC candidate for pulmonary metastasectomy. PMID- 29707310 TI - Right anterior mini-thoracotomy vs. conventional sternotomy for aortic valve replacement: a propensity-matched comparison. AB - Background: Right anterior mini-thoracotomy (MIAVR) is a promising technique for aortic valve replacement. We aimed at comparing its outcomes with those obtained in a propensity-matched group of patients undergoing sternotomy at our two high volume centers. Methods: Main clinical and operative data of patients undergoing aortic valve replacement between January 2010 and May 2016 were retrospectively collected. A total of 678 patients were treated with a standard full sternotomy approach, while MIAVR was performed in 502. Propensity score matching identified 363 patients per each group. Results: In-hospital mortality was not significantly different between the propensity-matched groups (1.7% in MIAVR patients vs. 2.2% in conventional sternotomy patients; P=0.79). No significant difference in the incidence of major post-operative complications was observed. Post-operative ventilation times (median 7, range 5-12 hours in MIAVR patients vs. median 7, range 5-12 in conventional sternotomy patients; P=0.72) were not significantly different between the two groups. Cardiopulmonary bypass time (61.0+/-21.0 vs. 65.9+/-24.7 min in conventional sternotomy group; P<0.01) and aortic cross clamping time (48.3+/-16.7 vs. 53.2+/-19.6 min in full sternotomy group; P<0.01) were shorter in MIAVR group. EuroSCORE (OR 1.52, 95% CI, 1.12-2.06; P<0.01) was found to be the only independent predictor of intra-hospital mortality in the whole propensity-matched population. Conclusions: Our experience shows that mini access isolated aortic valve surgery is a reproducible, safe and effective procedure with similar outcomes and no longer operative times compared to conventional sternotomy. PMID- 29707309 TI - Prognostic value of pre-transplant mean pulmonary arterial pressure in lung transplant recipients: a single-institution experience. AB - Background: Currently, lung transplantation (LTX) is considered to be a curative treatment option in patients with end-stage lung disease. Although pulmonary hypertension (PH), confirmed by cardiac catheterization, is a prognostic factor in patients undergoing LTX, the prognostic value of PH in Asian lung transplant recipients remains uncertain. In this study, we aimed to determine whether PH before LTX may serve as a prognostic factor for survival in Asian patients. Methods: The medical records of 50 patients [male, 27; female, 23; mean age, 51.0 (41.0-60.0) years], who received preoperative right heart catheterization (RHC) and echocardiography before single or double LTX at Severance Hospital between January 2010 and December 2014, were reviewed. The relationship between 1-year survival after LTX and PH [mean pulmonary arterial pressure (mPAP) >=25 mmHg at rest] was evaluated. Results: The mean right ventricular systolic pressure and mPAP were 48.5 (22.8) and 30.0 (24.0-40.0) mmHg. Of the 50 patients, 17 (34.0%) died within a year after LTX. The 1-year survival rate among patients with mPAP >=25 mmHg (58.8%) was lower than the survival rate among patients with mPAP <25 mmHg (87.5%). Pre-transplantation mPAP of >=25 mmHg was associated with post transplantation survival [hazard ratio (HR), 4.832; 95% confidence interval (CI), 1.080-21.608, P=0.039]. The presence of preoperative PH was also associated with an increased risk of postoperative complications. Conclusions: Confirmation of PH via preoperative cardiac catheterization was associated with the prognosis of the patient after LTX. Clinicians should consider the necessity for early transplantation surgery before the mPAP reaches >=25 mmHg. PMID- 29707311 TI - COP9 signalosome subunit CSN5, but not CSN6, is upregulated in lung adenocarcinoma and predicts poor prognosis. AB - Background: The COP9 signalosome (CSN) is an evolutionarily conserved complex composed of eight subunits (CSN1-CSN8). Among the CSN subunits, CSN5 and its dimerization partner CSN6 are the only two MPN (Mpr1-Pad1-N-terminal) domain containing subunits. These two subunits play essential roles in a variety of biological processes, such as cell cycle progression, protein stability and signal transduction. However, their expression patterns and clinical significance in lung cancer are not completely clear. Methods: We examined the expressions of both CSN5 and CSN6 in lung adenocarcinoma (LUAD) patients (n=59) using immunohistochemistry analysis, and correlated their expressions with clinicopathological characteristics. MTT cell proliferation assay was performed to determine the effect of CSN5 silencing or overexpression on the growth of lung cancer cells. Knock down or overexpression of CSN5 was confirmed by western blotting. Results: CSN5 expression was elevated in tumor cells, compared to the stromal compartment and adjacent normal epithelial cells. Interestingly, CSN5 was also expressed in the macrophages and lymphocytes adjacent to the tumors. Surprisingly, CSN6 was barely detected in the tumor cells of LUAD patients. Furthermore, we also demonstrated that higher levels of CSN5 were correlated with high tumor-node-metastasis (TNM) stage and worse clinical outcomes. Multivariate Cox regression analysis revealed CSN5 was an independently prognostic factor for LUAD patients. Additionally, in cellular model, depletion of CSN5 expression significantly suppressed the growth of lung cancer cells. Conclusions: COP9 signalosome subunit CSN5, but not CSN6, is upregulated in LUAD. Moreover, CSN5 is a critical regulator for the growth of lung cancer and represents an independent prognostic factor and a promising therapeutic target for LUAD patients. PMID- 29707312 TI - Establishment of animal model of gastroesophageal reflux disease by per-oral endoscopic tunneling: a preliminary study. AB - Background: Although a variety of antireflux procedures and medications are used to treat gastroesophageal reflux disease (GERD), reliable large-animal models of GERD that can be used to objectively compare the efficacy of these treatments are lacking. We developed a method to establish large animal models of GERD by endoscopic sphincterotomy to develop an endoscopic treatment for GERD. Methods: In this study six flesh swine carcasses were used. A full thickness incision was made at the esophageal site 5 cm above the dentate line by per-oral endoscopic tunneling. Esophageal radiography was conducted before and after surgery to observe changes at the site of the lower esophagus 5 cm above the dentate line and in the cardia. Results: There was no significant change in the diameter of the esophageal site 5 cm above the dentate line before and after surgery, while the cardiac orifice significantly relaxed after surgery and enabled the contrast agent to smoothly travel through. The difference in diameter was statistically significant (P<0.05). Conclusions: Our experiments showed that it is a minimally invasive and mature technology of establishing GERD animal models by using the per-oral endoscopic tunneling technique, and might be a new method to establishing GERD large animal models. PMID- 29707313 TI - Expression pattern of soluble triggering receptor expressed on myeloid cells-1 in mice with Acinetobacter baumannii colonization and infection in the lung. AB - Background: Acinetobacter baumannii (A. baumannii) is one of the most troublesome opportunistic pathogens associated with hospital-acquired pneumonia (HAP). It is important to be able to discriminate A. baumannii colonization from infection in its early stages so that effective antibiotics can be promptly applied. Recent studies have reported that the secretion of soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) is markedly upregulated in pneumonia and sepsis, but the expression pattern of sTREM-1 in A. baumannii colonization and infection in the lung has not been explored. Methods: C57BL/6J male mice were intraperitoneally injected with 1% streptozotocin for 5 consecutive days to establish diabetic models. Subsequently, aerosol inhalation of A. baumannii suspension was performed in these mice to induce pulmonary colonization or infection with saline as vehicle control. Mice were sacrificed and lung tissue was harvested on days 0, 1, 3, 5 and 7 after exposure. Pharyngeal swab culture, lung homogenate culture, and H&E staining of lung tissue were performed to assess the severity of infectious inflammation. sTREM-1 expressions in serum and lung supernatants, serum procalcitonin (PCT) and C-reactive protein (CRP) concentrations were measured by ELISA. Results: A. baumannii colonization and infection models were verified by pharyngeal swab culture, lung homogenate culture, and H&E staining. While sTREM-1 concentrations in mice with A. baumannii colonization remained unchanged in serum and lung supernatants, sTREM-1 expression levels in infected animals were significantly upregulated. In addition, serum sTREM-1 concentration was positively correlated with serum levels of PCT and CRP. Conclusions: Dynamic secretion of sTREM-1 is associated with the development of A. baumannii infection in the lung. Therefore, sTREM-1 expression level may be a promising biomarker for discriminating A. baumannii infection from colonization. PMID- 29707314 TI - Influence of lung resection volume on risk of primary spontaneous pneumothorax recurrence. AB - Background: Thoracoscopic stapled bullectomy is a popular procedure for the treatment of primary spontaneous pneumothorax (PSP) that has a relatively high postoperative recurrence rate. One reason for PSP recurrence is the formation of a new bulla around the staple line. We hypothesized that different resected specimen volumes might cause differences in staple line tension. In this study, we analyzed the relationship between postoperative pneumothorax recurrence and resected lung volume. Methods: Between April, 2009 and December 2013, 360 cases which underwent video-assisted thoracoscopic surgery (VATS) for PSP were selected. Recurrence after VATS was examined by electronic medical records and telephone survey. Resected volume and vertical area of specimen were calculated with the size of pathologic specimen. Results: A mean follow up period was 44.5+/ 24.4 months and recurrence rate was 11.1% (40/360). Large volume of resected specimen (>=16 cm3) (P=0.027 by the log-rank test) and larger vertical area of resected specimen (>=2.0 cm2) (P=0.003 by the log-rank test) showed significantly high recurrence rate. Cox regression analysis demonstrated that age [hazard ratio (HR), 0.083, P=0.006], vertical section area of resected specimen (HR, 1.239, P=0.020) and volume of resected pathology specimen (HR, 1.039, P=0.009) were independent risk factors of recurrence. Conclusions: Bulky resection during VATS for PSP increases the risk of recurrence. Large volume and vertical area of resected specimen are associated with greater tension in stapling line. Avoidance of wide resection and the firing of stapler after full collapse of lung are recommended for reducing the pneumothorax recurrence after VATS. PMID- 29707315 TI - Inflammation is related to preoperative hypoxemia in patients with acute Stanford type A aortic dissection. AB - Background: Preoperative hypoxemia is a frequent complication of acute Stanford type A aortic dissection (ATAAD). The aim of the present study was to determine which factors were associated with hypoxemia. Methods: A series of data were collected in a statistical analysis to evaluate preoperative hypoxemia in patients with ATAAD. After retrospectively analyzing data for 172 patients, we identified the risk factors for preoperative hypoxemia. Hypoxemia was defined by an arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) ratio of 200 or lower. Subsequent to identifying the patient population, a prospective study was conducted using ulinastatin as a preoperative intervention. The ulinastatin group received ulinastatin at a total dose of 300,000 units prior to surgery. All the pertinent factors were investigated through univariate and multiple logistic regression analysis. Results: The factors associated with preoperative hypoxemia in ATAAD comprised the following: body mass index (BMI) >=25; white blood cell count (WBC) and neutrophil counts; levels of C-reactive protein (CRP), D-dimer, and interleukin-6 (IL-6); ATAAD involving the celiac trunk, renal artery, or mesenteric artery. Logistic regression analysis showed that CRP and IL-6 levels were independent predictive factors. We found that ulinastatin effectively could improve oxygenation, since compared to the control group the oxygenation in the ulinastatin group was significantly improved. Conclusions: Systemic inflammatory reactions played a vital role in preoperative hypoxemia after the onset of ATAAD. The oxygenation of the patient could be improved significantly by inhibiting the inflammatory response prior to surgery. PMID- 29707316 TI - Single nucleotide polymorphisms of casitas B-lineage lymphoma proto-oncogene-b predict outcomes of patients with advanced non-small cell lung cancer after first line platinum based doublet chemotherapy. AB - Background: Casitas B-lineage lymphoma proto-oncogene-b (CBLB) influences the threshold of T cell activation and controlling peripheral T cell tolerance. In the present study, we hypothesize that potentially functional single nucleotide polymorphisms (SNPs) in CBLB are associated with clinical outcomes in patients advanced non-small cell lung cancer (NSCLC) treated with the first-line chemotherapy. Methods: We genotyped three SNPs (rs2305035, rs3772534 and rs9657904) at CBLB in 116 advanced NSCLC patients with progression free survival (PFS) data and 133 advanced NSCLC patients with overall survival (OS) data, and we assessed their associations, 95% confidence interval (CI), with clinical outcomes by using Cox proportional hazards regression analyses. In silico functional analysis was also performed for the SNPs under investigation. Results: We found that associations between the three SNPs and PFS/OS were not significant in the overall NSCLC patients. The rs2305035 AA genotype was associated with a worse PFS in female patients and those of non-smokers or light smokers (95% CI, 1.14-11.81, P=0.030; 95% CI, 1.42-10.24, P=0.008; and 95% CI, 1.39-9.93, P=0.009; respectively), compared with the GG+AA genotypes. We also found that the rs9657904 CC genotype was significantly associated with a worse OS than TT + TC genotypes in male advanced NSCLC patients. Further in silico functional analysis revealed that the rs965704 T allele was significantly associated with lower mRNA expression levels of the CBLB gene. Conclusions: Our findings identified two CBLB SNPs (rs2305035 and rs9657904) that were significantly associated with PFS and OS in several subgroups of Chinese advanced NSCLC patients after the first-line chemotherapy. PMID- 29707318 TI - The comparison of predictive factors regarding prognoses and invasion of thymic neuroendocrine tumors preoperatively and postoperatively. AB - Background: Thymic neuroendocrine tumors (TNT), in the anterior mediastinum, are extremely rare diseases which have significantly poor prognoses. Studies have rarely provided conclusive evidence of the prognostic factors of TNT. Standard therapies have been controversial. Methods: TNT patients (n=173) were enrolled from Surveillance, Epidemiology and End Results database (SEER). Univariate and multivariate analyses were utilized to evaluate predictive factors of prognoses. Logistic regression analysis was used to assess the plausible correlation between histological grade, and cancer invasion. Stratification analysis was used to evaluate the effectiveness of adjuvant therapies. Results: According to our analysis, local Masaoka stage, surgery, radiotherapy, and non-chemotherapy predicted better overall survival (OS) (P<0.05, for all) in 173 TNT patients. We found that the higher the histological grade of the tumor, the greater the rate of metastasis (P<0.05). The focus was on 125 surgically treated patients, who were females with poor prognostic factors of OS, upgraded histological grade, and advanced Masaoka stage (P<0.01, for all). The effectiveness of radiotherapy treatments had discrepancies at different clinical stages. In the local stage, radiotherapy caused significantly worse OS (P=0.011), while in the advanced stage, patients demonstrated significantly better OS with this treatment (P=0.028). Chemotherapy caused worse OS, primarily, in females (P=0.028). Conclusions: Surgery, Masaoka stage, and adjuvant treatments were prognostic factors. With surgically treated TNT, gender, histological grade, and Masaoka stage predicted significantly worse OS. Chemotherapy decreased female patients' OS. Radiotherapy significantly promoted advanced and local advanced patients' OS; however, it decreased local stage patients' OS. Predicted TNT invasiveness significantly correlated with histological grade. PMID- 29707317 TI - Unhealthy alcohol use is associated with postoperative complications in veterans undergoing lung resection. AB - Background: Lung resections carry a significant risk of complications necessitating the characterization of peri-operative risk factors. Unhealthy alcohol use represents one potentially modifiable factor. In this retrospective cohort study, the largest to date of lung resections in the Veterans Health Administration (VHA), we examined the association between unhealthy alcohol use and postoperative complications and mortality. Methods: Veterans Affairs Surgical Quality Improvement Program data recorded at 86 medical centers between 2007 and 2011 were used to identify 4,715 patients that underwent lung resection. Logistic regression models, adjusted for demographics and comorbidities, were fit to assess the association between unhealthy alcohol use (report of >2 drinks per day in the 2 weeks preceding surgery) and 30-day outcomes. Results: Among 4,715 patients that underwent pulmonary resection, 630 (13.4%) reported unhealthy alcohol use (>2 drinks/day). Overall, postoperative complications occurred in 896 (19.0%) patients, including pneumonia in 524 (11.1%). The rate of mortality was 2.6%. In adjusted analyses, complications were significantly more common among patients with unhealthy alcohol use [odds ratio (OR), 1.42; 95% confidence interval (CI), 1.15-1.74] including, specifically, pneumonia (OR, 1.69; 95% CI, 1.32-2.15). No statistically significant association was identified between unhealthy alcohol use and mortality (OR, 1.27; 95% CI, 0.75-2.02). In secondary analyses that stratified by smoking status at the time of surgery, drinking more than 2 drinks per day was associated with post-operative complications in patients reporting current smoking (OR, 1.51; 95% CI, 1.18-1.91) and was not identified in those reporting no current smoking at the time of surgery (OR, 1.23; 95% CI, 0.79-1.85). Conclusions: In this large VHA study, 13% of patients undergoing lung resection reported drinking more than 2 drinks per day in the preoperative period, which was associated with increased risk of post-operative complications. Unhealthy alcohol use may be an important target for perioperative risk-mitigation interventions, particularly in patients who report current smoking. PMID- 29707319 TI - Perioperative management and outcomes of minimally invasive esophagectomy: case study of a high-volume tertiary center in Taiwan. AB - Background: Mortality and complication rates for surgical esophagectomy remain high despite progress in surgical techniques and perioperative care. Minimally invasive surgery and intraoperative goal-directed fluid management are gaining popularity in Taiwan; however, perioperative complications and short-term outcomes have been rarely reported. In this retrospective study, we analyzed the surgical procedures performed as well as the perioperative outcomes and treatments after esophagectomy in a high-volume medical center in Taiwan. The goals of this study are to compare the complications and the following treatment between different surgical procedures and to analyze if any preoperative coexisting disease and anesthesia conduct might be associated with postoperative complications and hospitalization course. Methods: We retrospectively reviewed the data of all patients who had undergone esophagectomy and reconstruction in 2015. Patient characteristics, type of surgery performed, method of anesthesia, postoperative hospitalization course, and additional surgical interventions were reviewed and analyzed. Results: In total, 64 patients were included. Among them, 58 patients (90.6%) were reported squamous cell carcinoma, 33 patients (51.6%) received McKeown minimally invasive esophagectomy (MIE), and 20 (31.3%) received Ivor-Lewis MIE. The most common postoperative complications were pulmonary complications (18.7%), such as empyema and pleural effusion, dysrhythmias (14.1%), anastomosis leakage (14.1%), vocal cord paralysis (9.4%), gastric tube stenosis (4.7%), chyle leakage (4.7%), and acute kidney injury (AKI, 4.7%). Twenty-five percent of patients received secondary operative interventions for the aforementioned complications. Postoperative arrhythmia (P=0.042), pulmonary complications (P=0.009), and AKI (P=0.015) were significantly associated with prolonged intensive care unit (ICU) stays. Thirty-day and 90-day mortality rates were 3.1% and 4.7% respectively. Patients with preoperative arrhythmias have a higher risk of developing post-operative dysrhythmia (P=0.013) and lung complications (P=0.036). Patients with an underlying heart disease are at higher risk of post-op AKI (P=0.002) and second surgical intervention (P=0.013). Chronic kidney diseases are associated with post-op dysrhythmia (P=0.013), lung complications (P=0.036) and post-op AKI (P<=0.01). Although McKeown MIE bore a significantly longer surgical time and higher intraoperatively-infused crystalloid than did Ivor Lewis MIE, there were no significant differences regarding postoperative cardiothoracic complications and patient outcomes. Conclusions: Postoperative outcomes of McKeown MIE and Ivor-Lewis MIE were comparable in our center and short term outcomes were similar to those in previous reports. However, despite neoadjuvant concurrent chemoradiation therapy (CCRT), the use of minimally invasive techniques, and well-controlled anesthesia, the incidence of perioperative complications remains high. Our results suggest that patients with preoperative comorbidity of arrhythmia, heart diseases, and CKD are associated with more common post-operative complications. Furthermore, postoperative dysrhythmias, pulmonary complications, and AKI warrant special anesthetic and surgical care to prevent prolonged ICU stay. PMID- 29707320 TI - Robot-assisted thymectomy via subxiphoid approach: technical details and early outcomes. AB - Background: Trans-subxiphoid thoracoscopic thymectomy is a promising procedure but technically demanding associated with ergonomic discomfort. In order to facilitate this complex procedure, the authors present a modified trans subxiphoid thymectomy by the use of the Da Vinci robotic system. Methods: A 2-cm longitudinal incision for camera was made below the xiphoid process. Through this incision, the space among the posterior surface of the sternum, bilateral mediastinal pleura and diaphragm (extra pleural space) was enlarged blindly with a finger. Additional two operation holes were created below bilateral costal arches, and then two 8-mm robotic trocars were inserted into the extra pleural space. A third robotic instrument was placed in the 5th intercostal space after bilateral mediastinal pleura were dissected. The whole thymus was excised for patients with thymic tumor, and simultaneous resection of surrounding adipose tissues was performed for patients with myasthenia gravis. Clinical characteristics and early surgical outcomes of the patients were retrospectively collected and analyzed. Results: Between August 2016 and September 2017, 70 consecutive patients with myasthenia gravis or thymic neoplasm were successfully treated by the described surgical procedure. The median overall operative time was 115 (range, 60-150) min. The median hospital stay was 5 (range, 4-7) days. The median duration of chest tube was 3 (range, 1-8) days. The blood loss was minimal for all the patients. There was no mortality, conversion or postoperative complication during the postoperative and follow-up period. Conclusions: Based on our preliminary experience, the described technique of thymectomy is safe and feasible, and provides an optimal access for the robot camera and the instruments. PMID- 29707321 TI - Clinical significance of skipping mediastinal lymph node metastasis in N2 non small cell lung cancer. AB - Background: Lymph node metastasis is critical for the prognosis of non-small cell lung cancer (NSCLC) patients, and understanding of the pattern of lymph node metastasis is key to the treatment. We aim to investigate the N2 NSCLC patients without N1 lymph node involvement. Methods: From 1999 to 2005, a total of 803 patients with pN2 NSCLC were enrolled in this study. Among them, 137 pN2 patients with no metastasis at the hilar (N1) lymph nodes [skip (+) group] were compared with the other 666 patients [skip (-) group]. Results: The percentage of male, smoker and squamous cell carcinoma patients were significantly higher in the skip (+) group, (83.21% vs. 64.11%, P<0.001; 76.64% vs. 53.60%, P<0.001; 50.36% vs. 37.54%, P=0.007, respectively). Also, the primary tumor of skip (+) group patients were significantly more often located in the right upper and middle lobe (43.07% vs. 23.42%, 10.95% vs. 4.05%, P=0.001), and metastasis more frequently involved one lymph node station (75.18% vs. 49.55%, P<0.001). There was no significant difference in the number of total and N2 lymph node dissected. The postoperative survival of patients in both groups were also similar (P=0.379). Conclusions: Skipping mediastinal lymph node metastasis happens in about 17% of NSCLC patients with mediastinal lymph nodes metastasis but it is not a prognostic factor. PMID- 29707322 TI - Incremental cost-effectiveness of the second Xpert MTB/RIF assay to detect Mycobacterium tuberculosis. AB - Background: Due to the non-homogeneity of specimens collected from tuberculosis (TB) suspects, repeated Xpert MTB/RIF (Xpert) may have potential clinical benefits. Incremental cost-effectiveness was analyzed for the second Xpert assay to detect Mycobacterium tuberculosis (Mtb) and rifampicin (RIF) resistance. Methods: Specimens were collected from 1,063 pulmonary TB (PTB) and 398 extrapulmonary TB (EPTB) suspects, who had two Xpert tests sequentially within one week. The specimens were subjected to smear, culture, Xpert and drug susceptibility testing. Incremental cost-effectiveness of the serial Xpert assays was evaluated. Results: Among 813 Xpert-positive TB patients, 755 (92.87%) were identified by the first assay whereas the additional 58 (7.13%) were identified by the second assay. The second Xpert assay had higher incremental yield for smear-negative than for smear-positive specimens (12.07% vs. 1.84%, P<0.001), and higher incremental yield for EPTB than for PTB (10.71% vs. 4.65%, P=0.003). About 94.48% (137/145) of the RIF-resistant patients were identified by the first Xpert assay and 5.52% (8/145) were identified by the second Xpert assay. After the first assay, the incremental cost of performing a second Xpert was huge: US$22.82 vs. US$467.72 (P<0.001) and US$35.02 vs. US$291.87 (P<0.001) for PTB and EPTB, respectively. The incremental cost of performing a second Xpert is lower in smear negative than in smear-positive group in both PTB and EPTB. Conclusions: One Xpert assay is sufficient for smear-positive cases, and a second Xpert assay is beneficial not only for Mtb detection but also for RIF-resistant diagnosis for smear-negative TB suspects, whereas the incremental cost for the second Xpert is huge. PMID- 29707323 TI - Long-term survival without surgery in NSCLC patients with synchronous brain oligometastasis: systemic chemotherapy revisited. AB - Background: Among patients with metastatic non-small-cell lung cancer (NSCLC), patients with TNM stage N0 to N1 and brain oligometastases (BOM) (less than 5 metastases) as the sole distant lesion (N0-1 BOM) who receive surgical treatments for the primary and metastatic sites reportedly have a better prognosis. Little data is available regarding the outcomes of patients treated with only systemic chemotherapy for the primary site and definitive treatment for synchronous BOM, compared with the outcomes of patients receiving surgical treatment for the primary site. Methods: Stage IV NSCLC patients with or without N0-1 BOM, who underwent chemotherapy for the primary site between January 2000 and December 2010 were identified from the records of our institution. Results: Among 936 advanced NSCLC patients treated with systemic chemotherapy, 19 patients had N0-1 BOM at presentation. The median overall survival (OS) period of the N0-1 BOM patients was 16.0 months (95% CI, 11.8-20.2 months), while that of the N2-3 BOM + non-BOM patients was 14.5 months (95% CI, 13.2-15.8 months), compared with 7-9 months in previous reports. The median 3- and 5-year survival rates of the N0-1 BOM patients were 28% and 19%. Conclusions: The treatment outcomes of the N0-1 BOM patients who did not receive surgery for the primary site were better than those of the N2-3 BOM + non-BOM patients. A randomized trial evaluating the efficacy of surgery for the primary site in N0-1 BOM patients is warranted. PMID- 29707324 TI - Non-intubated thoracoscopic bullectomy under sedation is safe and comfortable in the perioperative period. AB - Background: Non-intubated thoracoscopic surgery can be performed under sedation using adjuvant regional anesthesia, however, the benefits of non-intubated thoracoscopic surgery under sedation have not yet been completely verified. In this study, we compare the perioperative safety and pain complaints of sedation without intubation in thoracoscopic bullectomy with that of conventional general anesthesia with double-lumen intubation and mechanical ventilation. Methods: Forty-one patients with primary spontaneous pneumothorax who were scheduled for thoracoscopic bullectomy were enrolled in this study. Twenty-one patients were under sedation anesthesia (SA group) and 20 patients were under general anesthesia (GA group). In SA group, sedation was done with dexmedetomidine (a loading dose of 1 ug/kg for 10 min and then maintained in dosages of 0.3-1 ug/kg/h) and ketamine (2-4 mg/kg/h intraoperatively). Meanwhile, in GA group, induction with propofol and rocuronium, intubation with double lumen endotracheal tube and maintenance with 1.0-2.5% sevoflurane was done. In both groups, thoracoscopic bullectomy was performed in the same manner and all operations were conducted by single surgeon. Time for anesthesia [including emergence time and post-anesthesia care unit (PACU) recovery time] and operation, postoperative pain, sore throat, hoarseness, adverse events (nausea, vomiting, hypotension and bradycardia), dose of rescue analgesic drug used for 24 hours post-operatively and perioperative arterial blood gas analysis were recorded. Results: The times for anesthesia, operation and emergence were significantly shorter in SA than GA. Incidence of sore throat were significantly lower in SA. The difference of other adverse events in the two groups was not significant. Conclusions: Our study demonstrated that compared to double-lumen intubation with general anesthesia, non-intubation with sedation for bullectomy for primary spontaneous pneumothorax was safe and efficient to reduce perioperative time. PMID- 29707325 TI - Subxiphoid and subcostal arch "Three ports" thoracoscopic extended thymectomy for myasthenia gravis. AB - Background: The approaches to thoracoscopic thymectomy in myasthenia gravis (MG) are debatable. We developed a novel approach via subxiphoid and subcostal arch, with a significantly shorter duration of operation and hospital stay, less estimated blood loss, and lower postoperative pain. Methods: From December 2012 to December 2014, 77 myasthenia gravis patients with or without thymoma underwent thoracoscopic extended thymectomy at our hospital. Among them, 41 patients were operated via the subxiphoid and subcostal arch approach and the other 36 via the conventional unilateral approach. The patient outcomes were retrospectively reviewed and evaluated. Results: The thoracoscopic extended thymectomy was performed safely via the subxiphoid and subcostal arch approach. In this approach, no drainage tube was inserted after operation except in the first two patients. Two of the 41 patients were switched to trans-sternal approach due to the tight adhesion between the thymoma and the left innominate vein. No major complications occurred. Compared with the unilateral approach, the duration of the procedure via subxiphoid and subcostal arch was significantly shorter, with less estimated blood loss, shorter hospital-stay and lower postoperative pain (P<0.001). The cosmetic scores were comparable between the two groups (P=0.369). Conclusions: The novel subxiphoid and subcostal arch approach is technically feasible and safe. It is an acceptable alternative to conventional thoracoscopic extended thymectomy. PMID- 29707327 TI - The curative effect of synthetic treatment for refractory acute myocardial infarction. AB - Background: This study aims to investigate the curative effect of synthetic treatment for refractory acute myocardial infarction (AMI). Methods: A total of 76 patients with coronary AMI accompanied by shock, who were treated with combined therapy from August 1999 to April 2017, were included into this study. Sixty patients received emergency percutaneous coronary intervention (PCI). Among these patients, 39 patients received intra-aortic balloon counterpulsation (IABP), eight patients had failed PCI underwent emergency off-pump coronary artery bypass (E-OPCAB), and eight patients were treated by hybrid cardiac surgery. Results: All patients were successfully rescued. However, two patients died afterward due to postoperative complications. Conclusions: For AMI patients complicated with shock, especially when emergency PCI fails or is difficult to perform, PCI + IABP, emergency E-OPCAB and hybrid cardiac surgery should be carried out, in order to achieve a good outcome and improve the success rate of rescue for this group of patients. Keywords: Acute myocardial infarction (AMI); emergency percutaneous coronary intervention (PCI); intra-aortic balloon counterpulsation (IABP); emergency off-pump coronary artery bypass (E-OPCAB); hybrid cardiac surgery. PMID- 29707326 TI - Spontaneous regionalization of esophageal cancer surgery: an analysis of the National Cancer Database. AB - Background: Esophagectomy patients are up to three times more likely to die after surgery when cared for at low-volume hospitals (LVHs). Increased awareness by patients and clinicians of the hazards of esophagectomy at LVHs, may inspire a "spontaneous regionalization" away from LVHs, yet the extent to which this has taken place is unclear. Methods: Retrospective analysis of patients undergoing esophagectomy for esophageal cancer in the National Cancer Database (NCDB) across two eras: 2004-2006 (Era 1) and 2010-2012 (Era 2). Primary outcomes included the proportion of patients at high-volume hospitals (HVHs) (>=13/year per Leapfrog Group), adjusted, and unadjusted 90-day mortality. Results: The NCDB captured 5,968 esophagectomy patients in Era 1 and 5,580 in Era 2, a 6.5% decrease (P<0.001). Fewer hospitals performed esophagectomies in Era 2 (756 vs. 663, P=0.014), yet the proportion of patients treated at LVHs declined slightly between eras (73% vs. 70%, P<0.001). Patients with high-risk attributes (e.g., advanced age, multiple comorbidities, etc.) were disproportionately treated at LVHs in both eras (77% Era 1, P<0.001, 73% Era 2, P=0.017). However, the 90-day mortality rate for patients with high-risk attributes decreased considerably between Eras at LVHs (19.3% to 12.3%, P<0.001). Conclusions: Spontaneous regionalization of esophageal cancer surgery has not occurred on a large scale, yet for high-risk patients, the hazards of being cared for at LVHs have dissipated. Further study is needed to optimize alignment of esophagectomy patients and hospitals. PMID- 29707328 TI - The prognostic value of positron emission tomography/computed tomography in pulmonary metastasectomy. AB - Background: Although positron emission tomography/computed tomography (PET/CT) findings are prognostic in lung cancer patients, the prognostic value of PET/CT findings in patients with pulmonary metastases has neither been comprehensively investigated nor clarified. The aims of this retrospective study were to evaluate the value of PET/CT and identify novel prognostic indicators for pulmonary metastasectomy. Methods: Between May 2004 and February 2017, 178 patients underwent PET/CT and resection of pulmonary metastases. After exclusion of patients who underwent biopsy only or duplicate cases, 142 patients were analyzed. Prognostic indicators, including PET/CT findings and outcomes were investigated. Results: The median follow-up time was 42 months. The primary tumor site was colorectal in 76, kidney in 14, head and neck in 13, breast in 12, stomach in 8, urinary tract in 7, and other organs in 12 patients. The median maximal standardized uptake value (SUVmax) was 4.6. The optimal cut-off value, determined by receiver operating characteristic (ROC) analysis, identified the following cut-off values: disease-free interval (DFI) (12 months; SUVmax =4.5). Univariable analysis revealed that DFI <=12 months, incomplete resection, and SUVmax >=4.5 were significant for poor outcome. Multivariable analysis revealed incomplete resection and SUVmax >=4.5 were significant for poor outcome. The 5 year survival rates of patients with SUVmax >=4.5 and SUVmax <4.5 were 51.6% and 74.0%, respectively. Conclusions: Analysis of patients undergoing pulmonary metastasectomy demonstrated that incomplete resection and an SUVmax >=4.5 are significant prognostic indicators. PET/CT findings should be included in estimations of these patients' prognosis. PMID- 29707329 TI - Feasible and promising modified trans-subxiphoid thoracoscopic extended thymectomy for patients with myasthenia gravis. AB - Background: We have used a promising, minimally invasive thoracoscopic technique of extended thymectomy for patients with myasthenia gravis (MG). The aim of this study was to report our promising technique, a modified single-port trans subxiphoid approach (MTXA) and to compare perioperative outcomes and effects on MG between our approach and sternotomy. Methods: We retrospectively reviewed records of all patients undergoing extended thymectomy for MG and/or thymoma between January 1, 2010 and December 31, 2016. The patients were divided into the MTXA group and Sternotomy group. Results: Of the 50 consecutive patients undergoing extended thymectomy for MG, finally, 13 patients undergoing our MTXA extended thymectomy technique were compared with 20 patients undergoing extended thymectomy via sternotomy. Intraoperative blood loss, postoperative length of stay, and C-reactive protein value on postoperative day 1 were significantly more favorable in the MTXA group than the Sternotomy group (P<0.0001, P=0.0040 and P=0.0073, respectively). Furthermore, no significant differences in the frequency of patients with improvement of their Quantitative Myasthenia Gravis score and/or MG-Activities of Daily Living scale, decrease in the serum level of acetylcholine receptor antibody, and dose reduction of oral prednisone were seen between the two groups. Conclusions: Our approach to extended thymectomy might be more favorable than sternotomy in patients with MG. PMID- 29707330 TI - Aberrant epithelial remodeling with impairment of cilia architecture in non cystic fibrosis bronchiectasis. AB - Background: Aberrant epithelial remodeling and/or abnormalities in mucociliary apparatus in airway epithelium contribute to infection and inflammation. It is uncertain if these changes occur in both large and small airways in non-cystic fibrosis bronchiectasis (non-CF bronchiectasis). In this study, we aim to investigate the histopathology and inflammatory profile in the epithelium of bronchi and bronchioles in bronchiectasis. Methods: Excised lung tissue sections from 52 patients with non-CF bronchiectasis were stained with specific cellular markers and analyzed by immunohistochemistry and immunofluorescence to assess the epithelial structures, including ciliated cells and goblet cells morphology. Inflammatory cell counts and ciliary proteins expression levels of centrosomal protein 110 (CP110) and dynein heavy chain 5, axonemal (DNAH5) were assessed. Results: Epithelial hyperplasia is found in both bronchi and bronchioles in all specimens, including hyperplasia and/or hypertrophy of goblet cells. The median cilia length is longer in hyperplastic epithelium [bronchi: 8.16 (7.03-9.14) um, P<0.0001; bronchioles: 7.46 (6.41-8.48) um, P<0.0001] as compared to non hyperplastic epithelium (bronchi: 5.60 um; bronchioles: 4.89 um). Hyperplastic epithelium is associated with overexpression of CP110 and decreased intensity of DNAH5 expression in both bronchial and bronchiolar epithelium. Though infiltration of neutrophils is predominant (63.0% in bronchi and 76.7% in bronchioles), eosinophilic infiltration is also present in the mucosa of bronchi (30.8%) and bronchioles (54.8%). Conclusions: Aberrant epithelial remodeling with impaired mucociliary architecture is present in both large and small airways in patients with refractory non-CF bronchiectasis. Future studies should evaluate the interplay between these individual components in driving chronic inflammation and lung damage in patients. PMID- 29707331 TI - Expression of TGF-beta receptor 1 and Smads in the tissues of primary spontaneous pneumothorax. AB - Background: Primary spontaneous pneumothorax (PSP) is a common disease which is often caused by the rupture of bullae in the lungs. The underlying pathogenesis of PSP remains unclear. Some molecules may be involved in the development of PSP potentially. The aim of this study was to investigate the expression of TGF-beta receptor 1 (TbetaR1), Smad2, Smad3 and Smad4 in the resected bullae of patients with PSP. Methods: From May 2015 to May 2016, 34 patients with PSP underwent video-assisted thoracoscopic surgery (VATS) bullectomy. Immunohistochemistry was performed to identify the expression of TbetaR1, Smad2, Smad3 and Smad4 in the resected pulmonary bullae tissues. The levels of these cytokines were calculated by immunoreactivity scoring system (IRS). Ten patients without pneumothorax associated disease were selected as the control group. Results: The analysis showed that the expression levels of TbetaR1, Smad2 and Smad4 were significantly higher in bullae tissues of patients with PSP than that in normal lung tissues (P=0.012, 0.031, 0.000 respectively). There was no significant difference between the expression level of Smad3 in bullae tissue of PSP patients and that in normal lung tissues of the control group (P=0.140). However, the absolute quantity of Smad3 expression in PSP bullae tissues was (4.2529+/-1.7193), scored by the IRS, which is higher than that in the control lung tissues (3.2600+/-2.2132). Also, the expression of TbetaR1, Smad2, Smad3 and Smad4 were not showed correlation with the clinical characteristics of PSP patients, such as age, sex, body mass index (BMI), recurrence and side of pneumothorax. Conclusions: TbetaR1, Smad2 and Smad4 highly expressed in bullae tissues of PSP patients. Our findings suggested that TbetaR1, Smad2 and Smad4 may be related to the development of PSP bullae. PMID- 29707332 TI - Medication regularity of pulmonary fibrosis treatment by contemporary traditional Chinese medicine experts based on data mining. AB - Background: Treatment of pulmonary fibrosis by traditional Chinese medicine (TCM) has accumulated important experience. Our interest is in exploring the medication regularity of contemporary Chinese medical specialists treating pulmonary fibrosis. Methods: Through literature search, medical records from TCM experts who treat pulmonary fibrosis, which were published in Chinese and English medical journals, were selected for this study. As the object of study, a database was established after analysing the records. After data cleaning, the rules of medicine in the treatment of pulmonary fibrosis in medical records of TCM were explored by using data mining technologies such as frequency analysis, association rule analysis, and link analysis. Results: A total of 124 medical records from 60 doctors were selected in this study; 263 types of medicinals were used a total of 5,455 times; the herbs that were used more than 30 times can be grouped into 53 species and were used a total of 3,681 times. Using main medicinals cluster analysis, medicinals were divided into qi-tonifying, yin tonifying, blood-activating, phlegm-resolving, cough-suppressing, panting calming, and ten other major medicinal categories. According to the set conditions, a total of 62 drug compatibility rules have been obtained, involving mainly qi-tonifying, yin-tonifying, blood-activating, phlegm-resolving, qi descending, and panting-calming medicinals, as well as other medicinals used in combination. Conclusions: The results of data mining are consistent with clinical practice and it is feasible to explore the medical rules applicable to the treatment of pulmonary fibrosis in medical records of TCM by data mining. PMID- 29707333 TI - Current outcomes of postrecurrence survival in patients after resection of non small cell lung cancer. AB - Background: Despite complete resection, patients with resectable non-small cell lung cancer (NSCLC) sometimes experience recurrence in various sites, generally with an unfavorable prognosis. Receptor tyrosine kinase inhibitors (TKIs) have produced a dramatic response in patients with advanced NSCLC harboring sensitive mutations. Methods: We retrospectively investigated 281 patients with recurrence who underwent complete resection of their NSCLC between January 2005 and December 2013 with tumors in which the status of epidermal growth factor receptor (EGFR) mutation, KRAS mutation, and anaplastic lymphoma kinase (ALK) rearrangement was confirmed. Clinicopathological factors, including mode of recurrence, oncogenic status, and postrecurrence survival (PRS), were reviewed. We aimed to investigate the prognostic factors of PRS by univariate and multivariate analyses. Results: Among the 281 patients, 135 patients (48.0%) with EGFR mutation, 33 (11.7%) with KRAS mutation, 13 (4.7%) with ALK rearrangement, and 100 (35.6%) with triple negative (TN) mutation were identified. Median survival time after recurrence was 26.1 months. In multivariate analysis, the presence of EGFR mutation, pStage I, the presence of both local and systemic therapies for recurrence, and longer time to recurrence (TTR) were significant favorable factors for PRS. With regard to the initial site of recurrence, the presence of pleural and/or bone recurrence reduced PRS significantly. The presence of pulmonary recurrence increased PRS, especially in patients with EGFR- or ALK-mutated tumors. Conclusions: This study documented the current outcomes of PRS. EGFR mutated status, pStage I, longer TTR and presence of multimodal therapy for recurrence were favorable factors for PRS. PMID- 29707334 TI - Prognostic implication of FEV1/FVC ratio for limited-stage small cell lung cancer. AB - Background: A proportion of patients with chronic obstructive pulmonary disease (COPD) may progress rapidly to small cell lung cancer (SCLC). As the forced expiratory volume in 1 second (FEV1)/forced volume vital capacity (FVC) ratio is usually impaired in patients with COPD, and given that the FEV1 and FVC are not necessarily related to lung cancer development, we performed this study to test our hypothesis that the FEV1/FVC ratio predicts survival of patients with limited stage (LS)-SCLC. Methods: We assessed 74 patients with LS-SCLC treated with chemoradiotherapy. The patients were divided into two FEV1/FVC ratio groups: <0.74 (n=24) and >=0.74 (n=50). Results: The 3-year overall survival (OS) and 3 year progression-free survival (PFS) rates were significantly lower in patients with FEV1/FVC <0.74 than in those with FEV1/FVC >=0.74 group (35.4% vs. 61.2%, P=0.0033; and 11.7% vs. 51.8%, P=0.0072, respectively). On multivariate analysis, the low FEV1/FVC group was independently associated with OS and PFS [hazard ratio (HR) (95% confidence interval): 2.15 (0.99-4.63), P=0.052; and 2.13 (1.04-4.39), P=0.039, respectively]. Conclusions: Pretreatment FEV1/FVC ratio appears to be a potential prognostic factor for patients with LS-SCLC. PMID- 29707335 TI - Impact of comorbidity burden on morbidity following thoracoscopic lobectomy: a propensity-matched analysis. AB - Background: Given the positive effect of a thoracoscopic approach on improving postoperative outcomes, it is reasonable to speculate whether an increased comorbidity burden is related to higher morbidity following thoracoscopic lobectomy. We sought to evaluate the impact of comorbidity burden on adverse postoperative outcomes in this patient population. Methods: A retrospective review of our institutional database included 512 patients undergoing thoracoscopic lobectomy for early-stage non-small cell lung cancer (NSCLC) from 2009 through 2016. Comorbidity burden was assessed by the Charlson comorbidity index (CCI) and classified as high (CCI >=3) or low (CCI <3) grade. Propensity score matching and random effects model were performed. Results: Patients included 228 women and 284 men with a median age of 67 years. High and low comorbidity burdens were found in 193 and 319 patients, respectively. The postoperative mortality, pulmonary and cardiovascular complication rates and overall morbidity in patients with high comorbidity burden were comparable to those with low comorbidity burden (1.6% vs. 0.6%, 9.3% vs. 8.5%, 6.2% vs. 6.0%, 24.4% vs. 22.9%, respectively). Similar results were seen after propensity score matching, which balanced differences in demographics and preoperative characteristics between the comorbidity groups. On the analyses of propensity matched data using generalized linear mixed model, a high comorbidity burden was not related to greater postoperative complication rates. Conclusions: Our results suggest that thoracoscopic lobectomy can be performed with low mortality and reasonable morbidity in lung cancer patients presenting with multiple comorbid diseases. The presence of a high comorbidity burden measured by CCI does not have a perceptible impact on adverse postoperative outcomes following thoracoscopic lobectomy. PMID- 29707336 TI - Values of aortic dissection detection risk score combined with ascending aorta diameter >40 mm for the early identification of type A acute aortic dissection. AB - Background: Type A acute aortic dissection (A-AAD), involving the ascending aorta, is a life-threatening disease. To detect A-AAD early and rapidly in patients with acute chest pain, especially in patients with acute myocardial infarction (AMI) secondary to A-AAD, we investigated values of combined use of the risk score and the ascending aorta diameter >40 mm for the early identification of A-AAD. Methods: Our study retrospectively encompassed 239 patients with acute chest pain on admission to our hospital between July 2010 and December 2016. The risk score was calculated according to the aortic dissection detection (ADD) risk score system, and the ascending aorta diameter was accurately obtained from the transthoracic echocardiography (TTE). Results: A risk score >=1 had an excellent sensitivity of 94.9% and a fair negative predictive value (NPV) of 77.8%, with a poor specificity of 8.7% and a positive predictive value (PPV) of 33.5% for the diagnosis of A-AAD. A risk score >=2 had an excellent specificity of 91.3% and a fair NPV of 73.1%, whereas it had a lower sensitivity of 30.8% and a PPV of 63.2%. A risk score >=1, combined with an ascending aorta diameter >40 mm, had a sensitivity, a specificity, a PPV, and an NPV of 84.6%, 87.6%, 76.7%, and 92.2% for the diagnosis of A-AAD, respectively. The combined use of a risk score >=2 and an ascending aorta diameter >40 mm had an excellent specificity of 98.1% and a PPV of 86.4%, a fair NPV of 72.8%, and a poor sensitivity of 24.4% for the detection of A-AAD. Moreover, the omission diagnostic rate for A-AAD was significantly decreased from 33.3% to 7.4% using a risk score >=1 combined with an ascending aorta diameter >40 mm in patients with AMI secondary to A-AAD. Conclusions: The combined use of an ADD risk score >=1 and an ascending aorta diameter >40 mm was highly indicative of A-AAD in patients presenting with acute chest pain, especially in patients with AMI secondary to A AAD, which urgently needed computed tomography angiography (CTA) or magnetic resonance imaging (MRI) to confirm the diagnosis of A-AAD. PMID- 29707338 TI - Virtual-assisted lung mapping (VAL-MAP) shortened surgical time of wedge resection. AB - Background: The detection of extremely small lung tumors has increased with the development of computed tomography. Resection of such tumors by thoracoscopy is often hindered due to the unclear location of the tumor. Various methods of preoperative determination of such lesions have been attempted, but without marked success. Here we used virtual-assisted lung mapping (VAL-MAP) to perform surgical resection of small lung lesions. Methods: We selected patients with pulmonary tumors that we anticipated to be difficult to identify during thoracoscopy and/or decide the resection line for sub-lobar lung resection. The wedge resections in the VAL-MAP group were compared to a group of patients who underwent wedge resection without VAL-MAP in 2013. Results: Surgery duration was significantly shorter in the VAL-MAP group (average: 76.4 min) than in the 2013 group (average: 108.6 min; P=0.000451), although the VAL-MAP group (average major axis: 9.6 mm) had smaller tumors (P=0.000032) and more pure ground-glass opacities (GGOs) (P=0.0000919) than the 2013 group (average major axis: 16.6 mm). Conclusions: The findings of this study indicate that VAL-MAP is efficacious. In particular, VAL-MAP resulted in a shorter surgery duration and has expanded the indications of resectable lesions. PMID- 29707339 TI - Effect of low molecular weight heparin on venous thromboembolism disease in thoracotomy patients with cancer. AB - Background: Much attention has been given to venous thromboembolism (VTE) disease, and many guidelines for prophylaxis have been published. However, there are few published data on patients who underwent thoracotomy. This study is to compare the effect of low molecular weight heparin (LMWH) combined mechanical approaches with mechanical approaches alone in prevention of VTE in the post thoracotomy cancer patients. Methods: This study used a prospective, randomized controlled design. Patients with cancer who were scheduled for thoracotomy were divided into two groups: group A and group B. In group A, patients were given intermittent pneumatic compression (IPC) and elastic stockings (ES) postoperatively. Additionally, at 24 hours post-operation, patients were subcutaneously injected with LMWH calcium (nadroparin calcium; GlaxoSmithKline, China) for 7 days. In group B, patients were only given postoperative IPC and ES. The primary end points were incidence of pulmonary embolism (PE), deep vein thrombosis (DVT), and the PE severity index (PESI) of PE patients. The secondary end points were hemoglobin (HGB), platelet (PLT), D-dimer, the PO2/FiO2 ratio (P/F) at postoperative day (POD) 7, the chest drainage time (CDT) and the length of stay (LOS) in hospital after operation. Results: A total of 90 patients were included in the final data analysis (40 patients in group A and 50 patients in group B). At POD7, the incidence of PE, DVT and PESI was 17.50%, 5.00% and 102.14+/-9.87, respectively, in group A. And 8.00%, 8.00% and 97.00+/-4.24, respectively, in group B. There were no significant differences between two groups (all P values were >0.05). There were no significant differences of HGB, PLT, D-dimer and P/F between two groups at the 7th day post operation (all P value >0.05). Conclusions: LMWH combined mechanical prophylaxis did not significant reduced the rate of VTE in thoracotomy cancer patients. PMID- 29707337 TI - An initial exploration for comprehensive assessment of IgG4-related lung disease: analyses on the cases enrolled from a systematic review. AB - Background: The existence of two diagnostic systems, the Boston and Japan criteria, for immunoglobulin G4-related disease (IgG4-RD) confuse the medical practice. We aimed to develop a comprehensive assessment based on the weight of each diagnostic item in the existing criteria to improve the diagnostic efficiency of Boston criteria. Methods: We assessed the patients enrolled by a systematic review of the literatures using the Boston criteria, Japan criteria and a tentative comprehensive assessment respectively, and evaluated the efficiency of each system and their consistency. Results: Our analysis showed that the distinction in pathological diagnostic items was similar for the Boston criteria (IgG4+/IgG+ ratio, P<0.01; the number of pathological features and IgG4+ count, P<0.001) and comprehensive assessment (IgG4+/IgG+ ratio and the number of pathological features, P<0.001; IgG4+ count, P<0.05). For the Japan criteria, a good distinction in the number of pathological features was demonstrated (P<0.05) but the difference in the IgG4+/IgG+ ratio and IgG4+ count was not significant. There was relatively poor consistency between the Boston and Japan criteria (Kappa =0.482, P<0.001), while there was good agreement (Kappa =0.811, P<0.001), but a significant difference (P=0.011, McNemar matching test), between the Boston criteria and comprehensive assessment. Conclusions: The current two diagnostic systems have poor consistency. Comprehensive assessment has good agreement with the Boston criteria, but can identify those cases in Boston Category 3 who could still be diagnosed as IgG4-related lung disease. Considering the weight of diagnostic items, the scoring system is a tentative exploration that should be improved with further experience in diagnosing IgG4-related lung disease. PMID- 29707340 TI - Antiplatelet and anticoagulant for prevention of reocclusion in patients with atrial fibrillation undergoing endovascular treatment for low extremity ischemia. AB - Background: The purpose of this study is to report the efficacy of the mono antiplatelet plus anticoagulation therapy for prevention of reocclusion in patients with atrial fibrillation (AF) undergoing endovascular treatment for lower extremity ischemia. Methods: From March 2014 to July 2016, 32 (21 males; range, 68-84 years) patients were submitted to endovascular therapy for low extremity ischemia with AF and all were treated with endovascular treatments to correct underlying lesions. Then 20 patients receive aspirin plus rivaroxaban post-operation and 12 patients receive aspirin plus warfarin to prevent reocclusion. Results: Complete reconstruction of occluded femopopliteal arteries with unimpeded blood flow to legs were successfully obtained in all 32 patients; 12 (37.5%) patients had acute ischemia, 17 (53.1%) patients had chronic ischemia, 3 (9.4%) patients had acute on chronic ischemia. Endovascular treatments including percutaneous transluminal angioplasty (PTA) and stenting were performed to correct residual lesions after the thrombolytic/thrombectomy procedure or to correct native lesions for chronic patients. All 32 patients showed significant improvements in symptoms and 4 patients improved completely. The mean ankle brachial index (ABI) had risen from 0.43+/-0.21 preoperatively to 0.81+/-0.16 postoperatively (P<0.01), and the primary patency rates were 88.9% at 12 months, and 81.5% at 24 months. No episodes of major bleeding and only one patient showed positive fecal occult blood tests during the follow-up. Conclusions: The mono antiplatelet plus anticoagulation therapy offers a safe and effective alternative for prevention of reocclusion in patients with AF undergoing endovascular treatment for lower extremity ischemic. PMID- 29707342 TI - Aortic arch repair under moderate hypothermic circulatory arrest with or without antegrade cerebral perfusion based on the extent of repair. AB - Background: For aortic-arch repair, moderate hypothermic circulatory arrest (HCA) have shown favorable outcomes over conventional deep HCA when coupled with antegrade cerebral perfusion (ACP); however, recent studies have shown that ACP may not be essential when circulatory arrest time is less than 30 minutes. This study aims to evaluate the stratified arch repair strategy of moderate HCA with or without ACP based on the extent of procedure. Methods: Consecutive 138 patients (63 female; mean age, 60.2+/-15.7 years) undergoing open arch repair due to acute aortic syndrome (n=69) or chronic aneurysm (n=69) from January 2012 through April 2017 were enrolled in this study. Stratified neuroprotective strategy was employed according to the extent of repair: hemi-arch repair (n=93) was performed under moderated HCA alone and total-arch repair (n=45) under moderate HCA combined with unilateral ACP. Results: Median total circulatory arrest and total procedural times were 8.0 minutes [interquartile range (IQR), 6.0-10.0] and 233.0 minutes (IQR, 196.0-290.0 minutes), respectively in the hemi arch group, and 25.0 minutes (IQR, 12.0-33.0 minutes) and 349.0 minutes (IQR, 276.0-406.0 minutes), respectively in the total-arch group. Early mortality occurred in 2 patients (1.4%) who underwent hemi-arch repair for acute aortic dissection. There was no permanent neurological injury, but 2 cases (1.4%) of temporary neurologic deficit in the hemi-arch group. Other complications included re-exploration for bleeding in 6 (4.3%), postoperative extracorporeal life support in 5 (3.6%) and new-dialysis in 6 (4.3%). Conclusions: Stratified cerebral perfusion strategy using moderate hypothermia for aortic-arch surgery based on the extent of arch repair showed satisfactory safety and reasonable efficiency. PMID- 29707341 TI - Short-term one-lung ventilation does not influence local inflammatory cytokine response after lung resection. AB - Background: One-lung ventilation (OLV) is a ventilation procedure used for pulmonary resection which may results in lung injury. The aim of this study was to evaluate the local inflammatory cytokine response from the dependent lung after OLV and its correlation to VT. The secondary aim was to evaluate the clinical outcome of each patient. Methods: Twenty-eight consecutive patients were enrolled. Ventilation was delivered in volume-controlled mode with a VT based on predicted body weight (PBW). 5 cmH2O positive end-expiratory pressure (PEEP) and FiO2 0.5 were applied. Bronchoalveolar lavage (BAL) was performed in the dependent lung before and after OLV. The levels of pro-inflammatory interleukins (IL-1alpha, IL-1beta, IL-6, IL-8), tumor necrosis factor alpha (TNFalpha), vascular endothelial growth factor (VEGF), endothelial growth factor (EGF), monocyte chemoattractant protein-1 (MCP-1) and anti-inflammatory cytokines, such as interleukins (IL-2, IL-4, IL-10) and interferon (IFN-gamma), were evaluated. Subgroup analysis: to analyze the VT setting during OLV, all patients were ventilated within a range of 5-10 mL/kg. Thirteen patients, classified as a conventional ventilation (CV) subgroup, received 8-10 mL/kg, while 15 patients, classified as a protective ventilation (PV) subgroup, received 5-7 mL/kg. Results: Cytokine BAL levels after surgery showed no significant increase after OLV, and no significant differences were recorded between the two subgroups. The mean duration of OLV was 64.44+/-21.68 minutes. No postoperative respiratory complications were recorded. The mean length of stay was for 4.00+/-1.41 days in the PV subgroup and 4.45+/-2.07 days in the CV group; no statistically significant differences were recorded between the two subgroups (P=0.511). Conclusions: Localized inflammatory cytokine response after OLV was not influenced by the use of different VT. Potentially, the application of PEEP in both ventilation strategies and the short duration of OLV could prevent postoperative complications. PMID- 29707343 TI - Retrospective study on video-assisted vs. open mediastinal lymphadenectomy for non-small cell lung cancer: a propensity-matched analysis. AB - Background: This retrospective study is designed to compare the surgical outcomes of mediastinal lymph node (MLN) dissection between the two groups of non-small cell lung cancer (NSCLC) patients underwent lung cancer surgery through video assisted thoracoscopic surgery (VATS) or thoracotomy, as well as classify the differences and identify the safer method between two groups. Methods: A total of 497 patients underwent pulmonary lobectomy and systemic MLN dissection were enrolled in this study. They were divided into VATS group (n=242) and traditional thoracotomy (TT) group (n=255). The VATS group received three-port VATS, while the thoracotomy group underwent posterior-lateral or muscle sparing thoracotomy. The range of MLN dissection included groups 2R, 4R, 7, 8, 9 in right-sided lung cancer surgery and groups 4L, 5, 6, 7, 8, 9 in left-sided. The two groups were matched at a ratio of 1:1 using the propensity score matching (PSM) method. Results: Out of 497 patients, 376 cases were matched for PSM, with 188 cases in each group. Baseline date did not get any significant difference between two groups. The average group number of MLN dissection in VATS group and TT group was 4.14 and 3.97, respectively. While the average amount of dissected lymph nodes in both groups were 16.63 and 17.32, respectively. Compare with the lymph node numbers among all the groups in TT group, only the number of group 7 though left approach (7L) in VATS group was statically significant. Besides, the operation time and postoperative length of hospital stay in VATS group were superior to those in TT group (P<0.05). No significant difference had been found in intraoperative blood loss, accessory surgical injury and postoperative complication between two groups. Conclusion: Compared with thoracotomy, systemic MLN dissection and pulmonary lobectomy via VATS has quicker recovery, less postoperative complication and length of hospital stay with similar surgical outcomes. Moreover, our findings also suggest thoracotomy has an advantage on the dissection of MLN in group 7L. PMID- 29707344 TI - Correlation and prognostic significance of PD-L1 and P53 expression in resected primary pulmonary lymphoepithelioma-like carcinoma. AB - Background: Aberrant expression of programmed cell death-ligand 1 (PD-L1) and protein 53 (P53) has been observed in various malignancies, and recently, the mechanism of PD-L1 regulation by P53 has been elucidated. We aimed to explore possible correlations between PD-L1 and P53 expression and the prognosis of patients with resected pulmonary lymphoepithelioma-like carcinoma (LELC). Methods: A total of 67 consecutive patients with primary pulmonary LELC who underwent radical resection from January 2003 to December 2014 were enrolled in our study. Membranous PD-L1 and nuclear P53 expression were detected by immunohistochemical staining (IHC). Results: Positive expression of PD-L1 in tumor cells (TCs), PD-L1 in tumor-infiltrating lymphocytes (TILs) and P53 was investigated in 44 patients (65.7%), 37 patients (55.2%), and 34 patients (50.7%), respectively. Using univariate and multivariable analysis, both PD-L1 (+) in TCs and P53 (+) were observed to be significantly independent prognostic factors associated with longer disease-free survival (DFS, P=0.037 and 0.039, respectively), along with early stage LELC (P=0.037), but had no association with overall survival (OS) (P>0.05). In the P53 (+) group, the rate of patients with PD-L1 (+) in TCs was significantly higher than in the P53 (-) group (85.3% vs. 45.5%, P=0.001). In addition, among the 45 patients who underwent adjuvant chemotherapy, DFS was significantly longer in patients with either PD-L1 (+) in TCs or P53 (+) (P=0.036 and 0.044, respectively). Conclusions: PD-L1 and P53 may be potential therapeutic targets for primary pulmonary LELC. PD-L1 (+) in TCs and P53 (+) were reliable predictors for longer DFS and benefits from adjuvant therapy in resected cases. Routine detection of these two indices in lung LELC may be warranted. PMID- 29707345 TI - HIV-negative pulmonary disease caused by nontuberculous mycobacteria in Southern Brazil: clinical and microbiological characterization. AB - Background: Nontuberculous mycobacteria (NTM) have been identified with increasing frequency in the clinical practice. The aim of this study was to characterize NTM isolates in respiratory specimens from patients with pulmonary disease and to correlate this with clinical/radiological findings, decision to start treatment and outcomes. Methods: A cross-sectional descriptive study was performed and included all patients who had at least one NTM isolated in respiratory specimens between 2011 and 2014. NTM culture was performed in liquid medium followed by immunochromatographic identification (anti-MPT64). Species identification was based on nucleic acid amplification followed by restriction analysis of a 441 bp fragment of the hsp65 gene (hsp65 PRA) and patients' records were reviewed. Results: From 14,394 cultures in 4 years, 590 (4.10%) grew NTM and 305 (51.7%) isolates were characterized till species level, representing 290 patients including those with and without human immunodeficiency virus (HIV) infection. Two hundred and eleven non-HIV patients had NTM isolated from respiratory specimens, 49 (23.2%) had criteria for active disease based on the American Thoracic Society (ATS) 2007. The majority was men above 51 years old and M. intracellulare was detected in 59.2% (29/49), followed by M. avium 14.3% (7/49), and M. abscessus 12.2% (6/49). Conclusions: Old age, nodular and nodular/bronchiectasis radiographic pattern, previous tuberculosis (TB) treatment and M. intracellulare were more frequent among NTM-disease patients compared to those only colonized. Positive culture and maintenance of clinical symptoms (poor outcome) was a rule when M. abscessus caused NTM-disease. Positive acid-fast smear in respiratory specimen is a strong predictor of disease. PMID- 29707346 TI - A comparison between two lung ventilation with CO2 artificial pneumothorax and one lung ventilation during thoracic phase of minimally invasive esophagectomy. AB - Background: To investigate the feasibility and safety of two lung ventilation with artificial pneumothorax in minimally invasive esophagectomy (MIE) through a comparison with conventional one lung ventilation. Methods: Eleven hundred and sixty-six patients with esophageal cancer, who underwent McKeown MIE in our center from February 2006 to December 2016, were studied retrospectively. Seven hundred and five patients who underwent one lung ventilation with double lumen endotracheal tube (DLET) were assigned to DLET group. Other 461 patients who underwent two lung ventilation with single lumen endotracheal tube (SLET) were assigned to SLET group. Clinical characteristics, surgical variables and complications were compared between two groups. Results: There were comparable patient characteristics in two groups. Surgical variables and complications were discussed between two groups. SLET group seemed to have shorter operative time, shorter postoperative hospital stay, and more harvested recurrent laryngeal nerve (RLN) lymph nodes than DLET group, which might be attributed to experienced surgeons. However, there were no significant differences of complications between two groups. Intraoperative clinical parameters were further studied. Before intubation and artificial pneumothorax, there were no significant differences between two groups, except diastolic blood pressure (DBP). With the application of artificial pneumothorax, patients in SLET group have obviously higher PO2, PCO2, and PetCO2 value, and slightly lower pH value and blood pressure during thoracic phase. After the thoracic phase, the changes induced by artificial pneumothorax in SLET group were gradually reversed and clinical parameters gradually return to normal level. Conclusions: Two lung ventilation with artificial pneumothorax is a safe and feasible choice during MIE. PMID- 29707347 TI - Appropriate lymphadenectomy significantly reduced recurrence after segmentectomy for patients with non-small cell lung cancer. AB - Background: Segmentectomy has been widely used for small-sized non-small cell lung cancer (NSCLC). The objective of this study is to determine the impact of number of harvested lymph nodes (LNs) on survival for patients undergoing segmentectomy. Methods: The clinicopathologic data of patients undergoing segmentectomy for NSCLC from July 2011 to December 2014 were retrospectively analyzed. Survival analysis was performed by Kaplan-Meier method and Cox regression analysis. Results: A total of 259 patients with NSCLC were eligible for analysis. Patients with harvested LN >=6 had higher frequency of nodal metastasis in pathologic examination (9.4% vs. 1.5%, P=0.005). The 3-year recurrence-free survival (RFS) of patients with harvested LN >=6 (90.2%) was significantly higher than that of patients with harvested LN <6 (73.7%, log-rank P=0.038). Multivariable Cox analysis identified harvested LN >=6 as an independent predictor for improved RFS [hazard ratio (HR) =0.35; 95% confidence interval (CI): 0.14-0.90; P=0.029]. There was no significant difference in RFS between patients with harvested LN station >=3 and <3 (log-rank P=0.34). Conclusions: The number of harvest LN >=6 was independently associated with improved RFS for NSCLC patients undergoing segmentectomy, supporting the National Comprehensive Cancer Network (NCCN) guidelines of appropriate LN sampling. PMID- 29707348 TI - Cerebral protection devices in transcatheter aortic valve replacement: a clinical meta-analysis of randomized controlled trials. AB - Background: Neurological complications after undergoing transcatheter aortic valve replacement (TAVR) may be reduced with cerebral protection (CP) devices. However, randomized controlled trials (RCTs) have failed to demonstrate convincing evidence of improvements in hard clinical endpoints in patients with CP. The aim of this study was to compare clinical outcomes of TAVR patients with and without CP devices. Methods: Electronic searches were performed using four electronic databases from their dates of inception to May 2017. RCTs that reported outcomes for patient cohorts that underwent TAVR procedures with and without CP were included. Crude odds ratios (ORs) and 95% confidence intervals were calculated using random effects model. Results: A total of five RCTs were included, totalling 643 patients, 386 of whom were randomized to TAVR + CP and 257 with TAVR only. The primary composite endpoint of all-cause mortality and stroke at 30 days was lower in patients undergoing CP devices compared to those patients with TAVR alone (OR, 0.54; 95% CI, 0.30 to 0.98). Use of CP devices was also associated with lower new total lesion volume (standardised mean difference, -0.49; 95% CI, -0.96 to -0.03). There was a non-significant reduction in the risk of secondary clinical endpoints of all-cause mortality, stroke, life-threatening bleed, acute kidney injury and major vascular complications in patients randomized to TAVR + CP. Conclusions: Use of CP devices in TAVR appears to be safe and may be associated with a reduction in stroke/death. PMID- 29707349 TI - Automatic detection of mycobacterium tuberculosis using artificial intelligence. AB - Background: Tuberculosis (TB) is a global issue that seriously endangers public health. Pathology is one of the most important means for diagnosing TB in clinical practice. To confirm TB as the diagnosis, finding specially stained TB bacilli under a microscope is critical. Because of the very small size and number of bacilli, it is a time-consuming and strenuous work even for experienced pathologists, and this strenuosity often leads to low detection rate and false diagnoses. We investigated the clinical efficacy of an artificial intelligence (AI)-assisted detection method for acid-fast stained TB bacillus. Methods: We built a convolutional neural networks (CNN) model, named tuberculosis AI (TB-AI), specifically to recognize TB bacillus. The training set contains 45 samples, including 30 positive cases and 15 negative cases, where bacilli are labeled by human pathologists. Upon training the neural network model, 201 samples (108 positive cases and 93 negative cases) were collected as test set and used to examine TB-AI. We compared the diagnosis of TB-AI to the ground truth result provided by human pathologists, analyzed inconsistencies between AI and human, and adjusted the protocol accordingly. Trained TB-AI were run on the test data twice. Results: Examined against the double confirmed diagnosis by pathologists both via microscopes and digital slides, TB-AI achieved 97.94% sensitivity and 83.65% specificity. Conclusions: TB-AI can be a promising support system to detect stained TB bacilli and help make clinical decisions. It holds the potential to relieve the heavy workload of pathologists and decrease chances of missed diagnosis. Samples labeled as positive by TB-AI must be confirmed by pathologists, and those labeled as negative should be reviewed to make sure that the digital slides are qualified. PMID- 29707350 TI - Treatment choice by patients with obstructive sleep apnea: data from two centers in China. AB - Background: Standard management has been recommended for obstructive sleep apnea (OSA) by several guidelines, but patient choice in the practical setting is unclear. Methods: A survey nested in two prospective cohort studies of OSA (enrollment: 2001-2010) in China. The last interview was conducted between July 2014 and May 2015, using a comprehensive 10-point questionnaire administered in a face-to-face or telephone interview, and assessed (I) whether the participant had received any OSA treatment; (II) why he or she had decided for or against treatment; (III) what treatment was received; (IV) whether the participant used continuous positive airway pressure (CPAP) or OA daily; and (V) the perceived efficacy of therapy. Results: A total of 4,097 subjects with a mean age of 45 years [37-55] responded to this survey, with a response rate of 79.4% (4,097/5,160); 2,779 subjects (67.8%) did not receive any treatment: 1,485 (53.4%) believed that their condition was not serious, despite severe OSA in 53.7% of the patients. A multivariate regression showed that the decision to receive treatment was associated with: age between 45-59 years [odds ratio (OR) 0.805, 95% CI: 0.691-0.936; P<0.001], female gender (OR 0.492, 95% CI: 0.383 0.631; P<0.001), severe OSA (OR 1.92, 95% CI: 1.01-3.64; P<0.001), hypertension (OR 1.414, 95% CI: 1.209-1.654; P<0.001) and diabetes (OR 1.760, 95% CI: 1.043 2.972; P=0.034). In subjects receiving treatment (n=1,318), 50.9% reported negative perceptions about the treatments. Conclusions: Nearly two thirds of Chinese patients choose not to receive treatment after OSA diagnosis, and nearly half are negative about their treatments for OSA. This requires clinical attention, and warrants further study in different geographic settings. PMID- 29707351 TI - Endobronchial ultrasound-guided transbronchial needle aspiration and cervical mediastinoscopy for mediastinal staging of non-small cell lung cancer: a retrospective comparison study. AB - Background: Invasive mediastinal lymph node staging is essential to resectable non-small cell lung cancer (NSCLC) patients. This retrospective study aimed to compare the diagnostic yield of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) against cervical mediastinoscopy (CMS) in radiologically enlarged mediastinal lymph nodes. Methods: Retrospective data were collected from January 2009 to March 2016. Suspected lung cancer patients with enlarged mediastinal lymph nodes (short axis >=10 mm), underwent EBUS-TBNA or CMS for invasive mediastinal staging were enrolled. Substantial radical resection with systematic mediastinal lymphadenectomy (SML) was used as the gold standard. Mediastinal lymph nodes diagnostic comparison and N staging analysis were conducted in this study. Results: Fifty-five patients received EBUS-TBNA and one hundred and ninety patients received CMS were included into the analysis set. In per case analysis, no significant differences were seen between EBUS-TBNA and CMS in N staging accuracy (83.6% vs. 78.9%, P=0.444). EBUS-TBNA had significantly higher sensitivity than CMS (82.4% vs. 47.6%, P=0.039) in malignant lymph nodes diagnosis. In lymph nodes diagnosis comparison (station #2, #4 and #7), both EBUS TBNA and CMS showed high diagnostic sensitivity, specificity and accuracy (82.4% vs. 94.7%, P=0.130; 97.4% vs. 100%, P=0.173; 98.8% vs. 92.9%, P=0.025; respectively), CMS had slightly better diagnostic accuracy rate than EBUS-TBNA. Malignant lymph nodes had longer short axis than benign nodes (mean 14.2 vs. 6.5 mm, P<0.001). In lymph nodes with a short axis >=15 mm, the malignant rate was 48.8%. More complications and injuries were found in patients receiving CMS. Conclusions: For clinically suspected lung cancers with enlarged mediastinal lymph nodes, both EBUS-TBNA and CMS are favorable invasive mediastinal staging options. EBUS-TBNA may be preferred for its higher malignant diagnostic sensitivity and fewer complications. PMID- 29707352 TI - Fifty years of coronary artery bypass grafting. AB - Coronary artery bypass grafting (CABG) remains the most common cardiac surgery performed today worldwide. The history of this procedure can be traced back for more than 100 years, and its development has been touched by several pioneers in the field of cardiac surgery, who have contributed with both their successes and failures. With ever increasing follow up and number of patients treated, thinking regarding optimal CABG technique evolves continually. This article reviews the history of CABG from its early experimental work to recent technological advances. PMID- 29707353 TI - Prospective registry database of patients with malignant mesothelioma: directions for a future Japanese registry-based lung cancer study. AB - Background: The International Association for the Study of Lung Cancer, in collaboration with members of the International Mesothelioma Interest Group (IMIG), developed a large international database and TNM-based system to study malignant pleural mesothelioma (MPM). However, this database has some limitations since it was a retrospective study and it was based predominantly on surgical cases. The Japanese Joint Committee of Lung Cancer Registry (JJCLCR) employs a project of prospective registry database of patients in Japan with MPM in order to clarify MPM's epidemiology, current management practices, and prognosis and also to investigate the potential capabilities to target the best patients for therapy. Methods: Tumor stage is described using the 7th and 8th versions of IMIG staging system. This prospective cohort study has been conducted from April 1, 2017 to March 31, 2019. Discussion: We will analyze the data in this registry to determine the most recent outcomes and trends related to MPM treatment in Japan. The present prospective study is expected to validate the 8th version of IMIG staging system, and to investigate whether tumor thickness is a reliable T descriptor. Trial registration: ClinicalTrials.gov Identifier: UMIN 000024664. PMID- 29707354 TI - Fiducial marker placement for stereotactic body radiation therapy via convex probe endobronchial ultrasound: a case series and review of literature. AB - Convex probe endobronchial ultrasound (CP-EBUS) and stereotactic body radiotherapy (SBRT) are valuable tools in the diagnosis, staging, and treatment of thoracic malignancies. With widespread clinical adoption, novel uses of CP EBUS beyond mediastinal diagnosis and staging continue to be discovered. SBRT is an attractive treatment strategy in early-stage lung cancer and oligo-metastatic disease of the chest when a surgical approach is either not feasible or desirable. Accurate application of SBRT is aided by the placement of radio-opaque fiducial markers (FM) to compensate for respiratory cycle movements. We describe eight patients with central thoracic lesions, either known or suspected to be malignant, who underwent EBUS bronchoscopy with lesion sampling and successful intralesional placement of modified FM via our technique, review the existing literature on this topic, and discuss the nuances of coding and billing aspects of FM placement. PMID- 29707356 TI - The role of local anaesthetic techniques in ERAS protocols for thoracic surgery. AB - The use of enhanced recovery after surgery (ERAS), as in other surgical specialties, is an emerging concept in cardio-thoracic surgery but there is still a lack of effective protocols to reduce the burden of surgery on the patient, shorten the period of postoperative recovery, and reduce the likelihood of chronic pain developing. The use of local anaesthetic (LA) techniques, such as thoracic epidural analgesia (TEA) and paravertebral blocks (PVB), as an adjunct to anaesthesia are considered key components, though there is little data for direct comparison of the techniques. This review aims to evaluate the role of LA techniques in a thoracic ERAS program through evidence from literature and considering aspects of clinical practice. We discuss how ERAS is adapting and evolving with the increasing use of video-assisted thoracoscopic surgery (VATS) is thoracic surgery. It also examines the advantages of multimodal, opioid sparing analgesia in the post-operative period to minimise the inflammatory response and improve functional recovery. LA techniques within ERAS protocols have the potential to hasten recovery when managed appropriately and to their full potential. PMID- 29707355 TI - Pneumatosis intestinalis in solid organ transplant recipients. AB - Pneumatosis intestinalis (PI) is an uncommon medical condition in which gas pockets form in the walls of the gastrointestinal tract. The mechanism by which this occurs is poorly understood; however, it is often seen as a sign of serious bowel ischemia, which is a surgical emergency. Since the early days of solid organ transplantation, PI has been described in recipients of kidney, liver, heart, and lung transplant. Despite the dangerous connotations often associated with PI, case reports dating as far back as the 1970s show that PI can be benign in solid organ transplant recipients. This is an important observation, as operative intervention in these patients carries greater risk than surgical procedures in the general population. The higher operative risks in the transplant population are partly due to their immunosuppressed status and poor wound healing. Furthermore, no clear consensus exists on the optimal management of PI. Various treatment strategies such as bowel rest, antibiotics, and parenteral feeding have been implemented with similar levels of success. With the increasing use of solid organ transplantation, PI is being recognized with increasing frequency. In this review, we provide a summary of the incidence, presentation, diagnosis, and management of PI, particularly as it affects recipients of solid organ transplantation. PMID- 29707357 TI - Transvenous phrenic nerve stimulation, a novel therapeutic approach for central sleep apnea. AB - Central sleep apnea (CSA) is common in heart failure (HF) patients. Traditional treatment of CSA, including continuous positive airway pressure (CPAP), adaptive servo ventilation (ASV), oxygen therapy, and CO2 inhalation, has respective limitations. Transvenous phrenic nerve stimulation (PNS), a novel therapeutic approach for CSA, was proved to be effective and safe. The remede(r) system and related transvenous PNS methods was approved by FDA in 2017, for treating moderate to severe CSA. PMID- 29707358 TI - Recent progress and market analysis of anticoagulant drugs. AB - This review describes epidemiology of thromboembolic disease in China and abroad, evaluates trends in the development of anticoagulant drugs, and analyzes the market situation based on large amounts of accumulated data. Specifically, we describe advances in clinical application of anticoagulants and analyze the most commonly used anticoagulants in the market systematically. PMID- 29707359 TI - Esophagectomy for benign disease. AB - Esophagectomy for benign disease is uncommonly used but it is an important option to consider in those patients who have lost function of this organ. Esophageal resection is, in fact considered as a last resort for benign disease, after multiple failed conservative treatments, when the primary disease is not amenable to other treatments and the esophagus has become non-functional leading to very poor quality of life. The indications for esophagectomy for benign diseases can be divided into three major categories: obstruction, perforation and dysmotility. The process leading to organ failure and the need for resection for each specific disease will be discussed in an attempt to provide guidance as to when an esophagectomy is appropriate. PMID- 29707361 TI - Ventricular tachycardia or artifact? AB - Electrocardiographic artifacts are extracardiac signals that may alter the electrocardiogram (ECG) generating false diagnoses. These artifacts may simulate pathologies on ECG's in healthy patients and result in long-term unnecessary or even deleterious treatments. On the other hand, to consider an arrhythmia as an artifact, may carry even worse consequences. PMID- 29707360 TI - Wild-type transthyretin cardiac amyloidosis (ATTRwt-CA), previously known as senile cardiac amyloidosis: clinical presentation, diagnosis, management and emerging therapies. AB - Cardiac amyloidosis is thought to be a rare group of diseases caused by extracellular deposition of misfolded proteins in the extracellular cardiac matrix resulting in heart failure with preserved ejection fraction (HFpEF). This review focuses on the similarities and differences between the pathophysiology, clinical presentation and diagnostic tests of wild-type transthyretin cardiac amyloidosis (ATTRwt-CA) compared to immunoglobulin light chain amyloidosis and hereditary cardiac amyloidosis. We address some obstacles to timely diagnosis and opportunities for management of the clinical symptoms as well as possibility of future novel disease modifying therapies. PMID- 29707362 TI - How to recognize silent atrial fibrillation in pacemakers and defibrillators-the value of atrial electrograms. AB - Today's pacemakers and defibrillators include diagnostic tools for detecting and treating cardiac arrhythmias like silent atrial fibrillation as atrial high rate episodes (AHREs). This diagnostic capability is crucial to prevent the potential embolic complications this AHREs are related to. However, sometimes data retrieved from diagnostic counters may be misleading reflecting limitations of detection algorithms, which must follow mathematical rules to classify events on a beat-to-beat basis. The incorporation of stored electrograms has been an important milestone in improving the diagnostic capabilities of these devices confirming the arrhythmia diagnosis. PMID- 29707363 TI - Asthma in the context of global alliance against respiratory diseases (GARD) in Turkey. PMID- 29707364 TI - Assessment of a respiratory face mask for capturing air pollutants and pathogens including human influenza and rhinoviruses. AB - Background: Prevention of infection with airborne pathogens and exposure to airborne particulates and aerosols (environmental pollutants and allergens) can be facilitated through use of disposable face masks. The effectiveness of such masks for excluding pathogens and pollutants is dependent on the intrinsic ability of the masks to resist penetration by airborne contaminants. This study evaluated the relative contributions of a mask, valve, and Micro Ventilator on aerosol filtration efficiency of a new N95 respiratory face mask. Methods: The test mask was challenged, using standardized methods, with influenza A and rhinovirus type 14, bacteriophage PhiChi174, Staphylococcus aureus (S. aureus), and model pollutants. The statistical significance of results obtained for different challenge microbial agents and for different mask configurations (masks with operational or nonoperational ventilation fans and masks with sealed Smart Valves) was assessed. Results: The results demonstrate >99.7% efficiency of each test mask configuration for exclusion of influenza A virus, rhinovirus 14, and S. aureus and >99.3% efficiency for paraffin oil and sodium chloride (surrogates for PM2.5). Statistically significant differences in effectiveness of the different mask configurations were not identified. The efficiencies of the masks for excluding smaller-size (i.e., rhinovirus and bacteriophage PhiChi174) vs. larger size microbial agents (influenza virus, S. aureus) were not significantly different. Conclusions: The masks, with or without features intended for enhancing comfort, provide protection against both small- and large-size pathogens. Importantly, the mask appears to be highly efficient for filtration of pathogens, including influenza and rhinoviruses, as well as the fine particulates (PM2.5) present in aerosols that represent a greater challenge for many types of dental and surgical masks. This renders this individual-use N95 respiratory mask an improvement over the former types of masks for protection against a variety of environmental contaminants including PM2.5 and pathogens such as influenza and rhinoviruses. PMID- 29707366 TI - Sleeve lobectomy for lung adenocarcinoma treated with neoadjuvant afatinib. AB - Afatinib, the second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has been postulated to be associated with improved inhibition of EGFR-dependent tumor growth compared with first-generation EGFR TKIs for advanced non-small cell lung cancer (NSCLC). We present a case of lung adenocarcinoma (cT3N0M0) treated with neoadjuvant afatinib and sleeve lobectomy. Because of the location of the tumor, reduced FEV1 value, and the presence of EGFR mutation, the patient was planned to be prescribed afatinib (30 mg daily) for 3 weeks as neoadjuvant therapy and underwent sleeve lobectomy to avoid pneumonectomy as much as possible. Although the patient presented with grade 3 diarrhea and dose reduction of afatinib to 20 mg daily was needed, several image findings showed a partial response of the tumor on Day 20. Oral administration of afatinib was discontinued on Day 22. A right upper sleeve lobectomy combined with partial resection of lower lobe was performed after oral administration of afatinib on Day 24. The patient's postoperative course was uneventful and she has been free of recurrence for 26 months. This strategy could reduce the risk of pneumonectomy with acceptable side effects. The treatment, clinical course and pathological findings of the patient are discussed. PMID- 29707365 TI - A rare case of renal angiomyolipoma involved both inferior vena cava and pulmonary arteries. AB - Angiomyolipoma is a benign mesenchymal tumour, which rarely involve inferior vena cava (IVC) and pulmonary arteries. Here we reported a 41-year-old man, who presented symptoms of chronic pulmonary embolism. After multiple images evaluation, a large tumour with the same properties as the pulmonary embolism was found in the right kidney. One-staged surgery to remove both pulmonary embolism and right kidney was performed. Histological study showed the tumour and embolism as angiomyolipoma. The present study reported a rare case with renal angiomyolipoma and both IVC and pulmonary arteries involvements, which provided a good example for differential diagnosis in the emergency department and treating a rare type of chronic pulmonary embolism after renal angiomyolipoma. PMID- 29707367 TI - Urokinase application for hemothorax in pulmonary mucormycosis. AB - We present an exemplary case of an immunocompromised patient with pulmonary mucormycosis successfully treated by a combination of surgical removal of the mucor and urokinase to control the recurring hemothorax. The use of urokinase in hemothoraces is a way to reduce repetitive surgeries in weak patients. PMID- 29707368 TI - Three-dimensional (3D) bronchial tree model for bronchial resection with pulmonary segmentectomy. AB - There has been an increase in pulmonary segmentectomy procedures because of increased numbers of individuals with small lung cancer. However, it is difficult to identify the correct bronchus during surgery even with pre-operative three dimensional (3D) computed tomography. We investigated using a 3D-printed model of the bronchi to prepare for bronchus resection during pulmonary segmentectomy. The model was useful to determine pre-operatively which bronchus should be transected, and being composed of a soft material it could be mobilized similarly to the actual bronchus during surgery. This simulation can increase surgeons' confidence to identify the correct bronchus during pulmonary segmentectomy. PMID- 29707369 TI - Isolated traumatic phrenic nerve injury treated with video-assisted thoracoscopic diaphragmatic plication-a case report. AB - Isolated traumatic phrenic nerve injury resulting from a stab wound to the neck is very rare. Herein, we report the case of a patient who was accidentally stabbed with garden shears that pierced her neck and penetrated the spinal canal. She sustained a right phrenic nerve injury complicated by diaphragm palsy and subsequent respiratory distress. We successfully treated the patient with video assisted thoracoscopic diaphragm plication. PMID- 29707370 TI - Successful repair of neonatal tricuspid regurgitation due to chordae rupture. AB - Neonatal rupture of the chordae of tricuspid valve with severe regurgitation is rare and disastrous. We report on a full-term female neonate presented with cyanosis caused by severe tricuspid regurgitation (TR) due to anterior leaflet chordal rupture. After initial stabilization by prostaglandin E1 infusion, successful early repair was achieved with artificial chordae implantation. The unique pathophysiology and the therapeutic strategy of this situation will be described. PMID- 29707371 TI - Successful extracorporeal cardiopulmonary resuscitation in a postpartum patient with amniotic fluid embolism. AB - Amniotic fluid embolism (AFE) is a rare but fatal obstetric emergency, which is characterized by a sudden cardiovascular collapse, respiratory failure, and disseminated intravascular coagulation (DIC). We report a case of sudden cardiac arrest due to an amniotic-fluid embolism which was successfully treated with veno arterial extracorporeal membrane oxygenation (ECMO). A 32-year-old female at 39.1 weeks of gestation was scheduled for induction labor. During labor, a sudden generalized tonic-clonic seizure was developed followed by dyspnea and hypotension. An immediate vaginal delivery was performed, and the baby was healthy. Despite the appropriate cardiopulmonary resuscitation, she became hypoxemic and experienced recurrent cardiovascular collapse. ECMO was applied promptly, and the patient became stable rapidly and was discharged without any complications. ECMO seems to be a proper treatment option for catastrophic amniotic-fluid embolism. PMID- 29707372 TI - A novel simple external fixation for securing silicone stent in patients with upper tracheal stenosis. AB - Upper tracheal stenosis is considered as a potentially life-threatening condition. Silicone stenting is an attractive treatment option for patients with upper tracheal stenosis. However, its use has been compromised by a major complication, stent migration. In the report, we introduced a novel external fixation of silicone stent which only needed one puncture site and involved a silicon chip as an anchoring device. All equipment and materials including the silicon chip were available in routine bronchoscopy suite. The method had been successfully performed in three patients with upper tracheal stenosis at our institution. And the patients were monitored for over 20 months after the intervention, and no spontaneous stent migration occurred. Therefore, we believe this is a simple and reliable approach for improving the outcome of silicone stenting in patients with upper tracheal stenosis and should be introduced in clinical practice. PMID- 29707373 TI - Antero mediastinal retrosternal goiter: surgical excision by combined cervical and hybrid robot-assisted approach. AB - Most intrathoracic goiters are located in the anterior mediastinum. Surgical resection is usually recommended in case of morbidity associated with the goiter's mass effect or for suspicion of malignancy difficult to diagnose without resection. Intrathoracic goiters are usually resected through a cervical approach, with sternotomy needed in selected cases. We report a case of antero mediastinal retrosternal goiter in old age patient undergoing surgical excision by combined cervical and hybrid robot-assisted approach. All steps of the thoracic procedure were completely performed using the da Vinci robot system with final extension of a port-site incision to extract the specimen. This approach provides more advantages than sternotomy regarding post operative clinical benefits and allows a more accurate surgical resection in the antero-superior mediastinum than conventional thoracoscopy. PMID- 29707374 TI - Successful surgical treatment of massive spontaneous hemothorax due to intrathoracic secondary degeneration of a neurofibroma from mediastinal involvement of type 1 neurofibromatosis. AB - Massive hemothorax caused by a mediastinal mass is extremely rare. Herein, we present a case of successful surgery for a massive hemothorax caused by intrathoracic cystic hemorrhagic degeneration of a neurofibroma in a patient with neurofibromatosis type 1 (NF1). A 44-year-old man with NF1 was admitted to our emergency department for chest pain and dyspnea. Image studies revealed a massive hemothorax caused by a posterior mediastinal mass adjacent to the descending aorta and the spinal canal. The tumor, located at the fourth to the sixth thoracic vertebra, had diffusely and extensively infiltrated around proliferative vessels. It was successfully excised via thoracostomy after aortic cross-clamping preparation. Final pathology revealed that the tumor was cystic hemorrhagic degeneration of a neurofibroma from mediastinal involvement of NF1. The patient had an uneventful postoperative course and was discharged on the 10th postoperative day. There was no recurrence of tumor or hemothorax six months after surgery. PMID- 29707375 TI - Transcatheter closure of a large patent ductus arteriosus using jugular access in an infant. AB - Trans-catheter device closure of patent ductus arteriosus (PDA) via femoral route is the commonly used, safe and effective procedure. Trans-jugular approach has been successfully used in older children with interrupted inferior vena cava. We report a case of successful occlusion of PDA using Amplatzer duct occluder (ADO) via trans-jugular approach following difficulties encountered in gaining femoral venous access. A 6-month-old male infant, weighing 8 kg was admitted for percutaneous catheter closure of PDA. Echocardiogram showed a 4.5 mm duct and left heart dilatation. Femoral venous access was not possible; therefore, we decided to use a trans-jugular approach. The duct was occluded using 8/6 mm ADO. Successful closure of the duct was confirmed with an aortogram. Post procedure echocardiogram showed no residual shunt across the duct. We highlight that trans catheter closure of PDA using jugular venous access is safe and effective even in infants. PMID- 29707376 TI - Is laryngeal mask airway general anesthesia feasible for minimally invasive esophagectomy? AB - Minimally invasive esophagectomy (MIE) has been identified as an oncological method with lower mortality and morbidity. This procedure is usually performed under general anesthesia using double endotracheal tube intubation and one-lung ventilation for a good visualization like other video-assisted thoracoscopic surgery (VATS). However, it is difficult to differentiate weather the postoperative hoarseness is caused by intubation or by recurrent laryngeal nerve injury during operation, and some complications related to intubation also are the focus of thoracic surgeons. Recently, VATS without tracheal intubation were reported to be feasible and safe in a series of VATS procedures, including management of pneumothorax, wedge resection of pulmonary tumors, excision of mediastinal tumors, lung reduction surgery and lobectomy. However, there is no report about its use in MIE. In December of 2012, we successfully applied nonintubated laryngeal mask airway (LMA) general anesthesia in MIE for three patients with esophageal cancer. Here, we retrospectively report the tentative results. PMID- 29707377 TI - Transaxillary uniportal video assisted thoracoscopic surgery for right upper lobectomy. AB - Uniportal video-assisted thoracic surgery (VATS) was growing popular since its first introduction. Based on the conventional uniportal VATS, we modified the technique and introduced transaxillary uniportal VATS lobectomy in this case report. In March 2017, transaxillary uniportal VATS was firstly attempted on a patient suffering from right upper lobe lesion at the Department of Thoracic Surgery, Zhongshan Hospital, Fudan University. A 4-cm single incision was made at the fossa axillaris paralleled to the skin folds, to which a soft wound protector was applied to reach the third intercostal space along the anterior axillary line. The right upper lobectomy was performed through the transaxillary incision. The surgery was accomplished without conversion to thoracotomy or application of extra incision. The truncus anterior artery, the upper lobe bronchus and upper pulmonary vein was mobilized and dissected in order. The target lobe was removed through the fossa axillaris incision. The operation duration was 110 minutes with limited blood loss. The patient was discharged 3 days post-operatively. Transaxillary uniportal VATS lobectomy is safe and feasible, and the procedure showed cosmetic advantages. Further studies based on larger population are required to determine these findings. PMID- 29707378 TI - Serial chest CT findings of intravascular large B-cell lymphoma of the lungs. PMID- 29707379 TI - Palliative ventilatory support: same knowledge, different goal. PMID- 29707380 TI - Look around the world, focus on Asia: the establishment of the Asia Society of Emergency and Critical Care Medicine. PMID- 29707381 TI - Comparing Pixel- and Object-Based Approaches in Effectively Classifying Wetland Dominated Landscapes. AB - Wetland ecosystems straddle both terrestrial and aquatic habitats, performing many ecological functions directly and indirectly benefitting humans. However, global wetland losses are substantial. Satellite remote sensing and classification informs wise wetland management and monitoring. Both pixel- and object-based classification approaches using parametric and non-parametric algorithms may be effectively used in describing wetland structure and habitat, but which approach should one select? We conducted both pixel- and object-based image analyses (OBIA) using parametric (Iterative Self-Organizing Data Analysis Technique, ISODATA, and maximum likelihood, ML) and non-parametric (random forest, RF) approaches in the Barguzin Valley, a large wetland (~500 km2) in the Lake Baikal, Russia, drainage basin. Four Quickbird multispectral bands plus various spatial and spectral metrics (e.g., texture, Non-Differentiated Vegetation Index, slope, aspect, etc.) were analyzed using field-based regions of interest sampled to characterize an initial 18 ISODATA-based classes. Parsimoniously using a three-layer stack (Quickbird band 3, water ratio index (WRI), and mean texture) in the analyses resulted in the highest accuracy, 87.9% with pixel-based RF, followed by OBIA RF (segmentation scale 5, 84.6% overall accuracy), followed by pixel-based ML (83.9% overall accuracy). Increasing the predictors from three to five by adding Quickbird bands 2 and 4 decreased the pixel-based overall accuracy while increasing the OBIA RF accuracy to 90.4%. However, McNemar's chi-square test confirmed no statistically significant difference in overall accuracy among the classifiers (pixel-based ML, RF, or object-based RF) for either the three- or five-layer analyses. Although potentially useful in some circumstances, the OBIA approach requires substantial resources and user input (such as segmentation scale selection-which was found to substantially affect overall accuracy). Hence, we conclude that pixel-based RF approaches are likely satisfactory for classifying wetland-dominated landscapes. PMID- 29707382 TI - Shape Memory Polymers Containing Higher Acrylate Content Display Increased Endothelial Cell Attachment. AB - Shape Memory Polymers (SMPs) are smart materials that can recall their shape upon the application of a stimulus, which makes them appealing materials for a variety of applications, especially in biomedical devices. Most prior SMP research has focused on tuning bulk properties; studying surface effects of SMPs may extend the use of these materials to blood-contacting applications, such as cardiovascular stents, where surfaces that support rapid endothelialization have been correlated to stent success. Here, we evaluate endothelial attachment onto the surfaces of a family of SMPs previously developed in our group that have shown promise for biomedical devices. Nine SMP formulations containing varying amounts of tert-Butyl acrylate (tBA) and Poly(ethylene glycol) dimethacrylate (PEGDMA) were analyzed for endothelial cell attachment. Dynamic mechanical analysis (DMA), contact angle studies, and atomic force microscopy (AFM) were used to verify bulk and surface properties of the SMPs. Human umbilical vein endothelial cell (HUVEC) attachment and viability was verified using fluorescent methods. Endothelial cells preferentially attached to SMPs with higher tBA content, which have rougher, more hydrophobic surfaces. HUVECs also displayed an increased metabolic activity on these high tBA SMPs over the course of the study. This class of SMPs may be promising candidates for next generation blood contacting devices. PMID- 29707383 TI - The association between asymptomatic and mild neurocognitive impairment and adherence to antiretroviral therapy among people living with human immunodeficiency virus. AB - Background: Asymptomatic cognitive impairment in human immunodeficiency virus (HIV)-infected patients has recently been recognised as part of HIV-associated neurocognitive disorders. This has been implicated as one of the causes of poor adherence to antiretroviral therapy (ART). Objective: To assess the association between neurocognitive impairment (asymptomatic and mild forms) and adherence to ART. Methods: This was a cross-sectional survey involving 218 participants consecutively sampled from those attending the HIV treatment clinic at Aga Khan University Hospital in Nairobi. Data collected included quantitative primary data on pre-defined baseline characteristics, neurocognitive assessment by Montreal Cognitive Assessment (MoCA) tool (Appendix 1), instrumental activities of daily living by Lawton score and objective and subjective adherence measures by medication possession ratio (MPR) and simplified medication adherence questionnaire (SMAQ) (see Appendix 2). Univariate and bivariate analyses were conducted to determine the strengths of association between predictor and the outcome variables. Results: Among the 218 participants in the study, a total of 69% had asymptomatic to mild neurocognitive impairment as assessed by the MoCA tool, while a total of 66% were determined as being adherent to ART by objective measures (by MPR) compared to subjective rates of 77% as assessed by SMAQ. However, no statistically significant association was observed between the presence of asymptomatic or mild neurocognitive impairment and likelihood of adherence to ART (p > 0.05). Conclusion: Even though asymptomatic and mild forms of cognitive impairment are prevalent in the population studied, there was no significant association between cognitive impairment and adherence to treatment. PMID- 29707384 TI - Human immunodeficiency virus infection predictors and genetic diversity of hepatitis B virus and hepatitis C virus co-infections among drug users in three major Kenyan cities. AB - Background: Drug users act as reservoirs and transmission channels for hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infections to the general population worldwide. Periodic epidemiological studies to monitor the prevalence and genetic diversity of these infections to inform on interventions are limited. Objective of the study: The objective of this study was to determine the predictors of HIV infection and genetic diversity of HBV and HCV among drug users in Kenya. Materials and methods: A cross-sectional study on previous drug use history among drug users was conducted in three Kenyan cities using a respondent-driven sampling method between January 2011 and September 2012. Blood samples were collected and analysed for the presence of HBV, HCV and HIV serological markers and to determine the genotypes of HBV and HCV. Results: The overall prevalence of HBV, HCV and HIV among drug users was 4.3%, 6.5% and 11.1%, respectively, with evidence of HBV/HIV, HCV/HIV and HBV/HCV/HIV co infections. The HBV circulating genotypes were A1 (69%) and D6 (19%), whereas HCV genotypes were 1a (72%) and 4a (22%). Injection drug use was a significant predictor of HIV/HCV infections. Younger age (30 years; aOR (adjusted odds ratio) = 0.50, 95% CI (confidence interval): 0.33-0.76; p < 0.001) and early sexual debut (aOR = 0.54, 95% CI: 0.40-0.82; p < 0.05) were negatively associated with detection of any of the three infections. Injecting drug use was positively associated with HCV infection (aOR = 5.37, 95% CI: 2.61-11.06; p < 0.001). Conclusion: This high level of genetic diversity exhibited by HBV and HCV isolates requires urgent implementation of harm reduction strategies and continuous monitoring for effective management of the patients. PMID- 29707385 TI - Similar HIV protection from four weeks of zidovudine versus nevirapine prophylaxis among formula-fed infants in Botswana. AB - Background: The World Health Organization HIV guidelines recommend either infant zidovudine (ZDV) or nevirapine (NVP) prophylaxis for the prevention of intrapartum mother-to-child HIV transmission (MTCT) among formula-fed infants. No study has evaluated the comparative efficacy of infant prophylaxis with twice daily ZDV versus once daily NVP in exclusively formula-fed HIV-exposed infants. Methods: Using data from the Mpepu Study, a Botswana-based clinical trial investigating whether prophylactic co-trimoxazole could improve infant survival, retrospective analyses of MTCT events and Division of AIDS (DAIDS) Grade 3 or Grade 4 occurrences of anaemia or neutropenia were performed among infants born full-term (>= 37 weeks gestation), with a birth weight >= 2500 g and who were formula-fed from birth. ZDV infant prophylaxis was used from Mpepu Study inception. A protocol modification mid-way through the study led to the subsequent use of NVP infant prophylaxis. Results: Among infants qualifying for this secondary retrospective analysis, a total of 695 (52%) infants received ZDV, while 646 (48%) received NVP from birth for at least 25 days but no more than 35 days. Confirmed intrapartum HIV infection occurred in two (0.29%) ZDV recipients and three (0.46%) NVP recipients (p = 0.68). Anaemia occurred in 19 (2.7%) ZDV versus 12 (1.9%) NVP (p = 0.36) recipients. Neutropenia occurred in 28 (4.0%) ZDV versus 21 (3.3%) NVP recipients (p = 0.47). Conclusions: Both ZDV and NVP resulted in low intrapartum transmission rates and no significant differences in severe infant haematologic toxicity (DAIDS Grade 3 or Grade 4) among formula-fed full-term infants with a birthweight >= 2500 g. PMID- 29707386 TI - Cognitive-behavioural theories and adherence: Application and relevance in antiretroviral therapy. AB - Background: Adherence in chronic disease conditions is described as the extent to which a person's behaviour corresponds to the prescribed medical advice of the healthcare provider. This is not limited to medication intake only but also includes acts such as following instructions regarding dietary or fluid restrictions and taking medicines at the prescribed times and intervals. Although adherence to antiretroviral therapy (ART) is a predictor of good clinical outcome among HIV-infected persons on ART, it is a major challenge and strict adherence is not very common. This article aims to examine the application and relevance of some cognitive-behavioural theories in antiretroviral therapy adherence. Methods: After doing a thorough literature review, contemporary theories of health behaviour at the individual and interpersonal levels referred to as cognitive behavioural theories were explored. This review highlights some aspects of the cognitive perspective of health behaviour theories as a good theoretical framework that could be used for organising thoughts about adherence and other health behaviours among patients on lifelong treatment such as ART. Results: Key concepts of these theories stipulate that behaviour is mediated by cognition i.e. knowledge and attitude affect the person's action. In addition, cognitive behavioural theories recognise knowledge alone as being insufficient to produce behavioural change; a person's perception, motivation, skills and social environment are all influential in the process of behavioural change. Conclusion: Prediction of medication adherence is complex, and health-related knowledge and beliefs alone are insufficient to achieve behaviour change, especially in chronic conditions such as HIV/AIDS. However, people can control or influence the events affecting their lives by integrating cognitive, social, and behavioural sub skills related to beliefs of personal efficacy in performing these skills. PMID- 29707387 TI - Completeness of the Road-to-Health Booklet and Road-to-Health Card: Results of cross-sectional surveillance at a provincial tertiary hospital. AB - Background: Accurate record-keeping is important for continuity and quality of care. Completing a child's Road-to-Health Booklet (RTHB), or the older, less detailed, Road-to-Health Card/Chart (RTHC), immediate interpretation thereof and appropriate action facilitates comprehensive care, which could contribute to a decline in child morbidity and mortality. Objective: This study aimed to assess the extent to which healthcare personnel working in catchment clinics of Kalafong Provincial Tertiary Hospital (KPTH), Tshwane district, South Africa, complete HIV related, sociodemographic, neonatal, growth and immunisation information in the RTHC and/or RTHB. Methods: A cross-sectional, quantitative record review was conducted. Data were extracted from 318 RTHCs and/or RTHBs of children attending KPTH for paediatric care. Data extraction focused on six main areas, namely documentation of HIV-related, neonatal, sociodemographic, anthropometric, immunisation and vitamin A-related information. During data analysis, age appropriate completeness scores were generated for each area and completeness of documentation in the RTHB and RTHC was assessed. Results: Data demonstrate significantly less unrecorded HIV-related information (maternal HIV status, timing of maternal HIV testing, timing of maternal antiretroviral therapy [ART] initiation, current maternal ART use and infant feeding decisions) in RTHBs compared with RTHCs (p < 001). Despite this, 24% of all RTHBs had no record of maternal HIV status and 67% of RTHBs from documented HIV-exposed infants had no record of maternal ART duration. Neonatal information completeness was similar between RTHBs and RTHCs, but socio-demographic completeness was significantly better in RTHBs compared with RTHCs (p = 0.006). Growth (especially weight), immunisation and vitamin A completeness was > 80% and similar between RTHBs and RTHCs. Length-for-age, weight-for-length and head circumference were plotted in < 5% of RTHBs and none of the RTHCs. Conclusion: Although completeness of key HIV related information was better in RTHBs compared with RTHCs, RTHB completeness was suboptimal. Healthcare personnel need reminders to utilise the RTHB optimally to improve continuity and quality of child healthcare. PMID- 29707388 TI - Risk factors and co-morbidities associated with changes in renal function among antiretroviral treatment-naive adults in South Africa: A chart review. AB - Introduction: Our systematic scoping review has demonstrated a research gap in antiretroviral treatment (ART) nephrotoxicity as well as in the long-term outcomes of renal function for patients on ART in South Africa. Bearing in mind the high prevalence of human immunodeficiency virus (HIV) in South Africa, this is of great concern. Objectives: To determine the risk factors and co-morbidities associated with changes in renal function in HIV-infected adults in South Africa. Methods: We conducted a retrospective study of 350 ART-naive adult patients attending the King Edward VIII HIV clinic, Durban, South Africa. Data were collected at baseline (pre-ART) and at six, 12, 18 and 24 months on ART. Renal function was assessed in the 24-month period using the Modification of Diet in Renal Disease equation and was categorised into normal renal function (estimated glomerular filtration rate [eGFR] >= 60), moderate renal impairment (eGFR 30-59), severe renal impairment (eGFR 15-29) and kidney failure (eGFR < 15 mL/min/1.73 m2). Generalised linear models for binary data were used to model the probability of renal impairment over the five time periods, controlling for repeated measures within participants over time. Risk ratios and 95% confidence intervals (CI) were reported for each time point versus baseline. Results: The cohort was 64% female, and 99% were Black. The median age was 36 years. At baseline, 10 patients had hypertension (HPT), six had diabetes, 61 were co-infected with tuberculosis (TB) and 157 patients had a high body mass index (BMI) with 25.4% being categorised as overweight and 19.4% as obese. The majority of the patients (59.3%) were normotensive. At baseline, the majority of the patients (90.4%) had normal renal function (95% CI: 86% - 93%), 7.0% (CI: 5% - 10%) had moderate renal impairment, 1.3% (CI: 0% - 3%) had severe renal impairment and 1.3% (CI: 0% - 3%) had renal failure. As BMI increased by one unit, the risk of renal impairment increased by 1.06 (CI: 1.03-1.10) times. The association of HPT with abnormal renal function was found to be insignificant, p > 0.05. The vast majority of patients were initiated on tenofovir disoproxil fumarate (TDF) (90.6%), in combination with lamivudine (3TC) (100%) and either efavirenz (EFV) (56.6%) or nevirapine (NVP) (43.4%). Conclusion: This study reports a low prevalence of baseline renal impairment in HIV-infected ART-naive outpatients. An improvement in renal function after the commencement of ART has been demonstrated in this population. However, the long-term outcomes of patients with HIV-related renal disease are not known. PMID- 29707389 TI - Making ward-based outreach teams an effective component of human immunodeficiency virus programmes in South Africa. AB - The implementation of ward-based outreach teams (WBOTs), comprised of community health workers (CHWs), is one of the three interventions of the South African National Department of Health's (NDoH) Primary Health Care (PHC) Re-engineering strategy for improving health outcomes. CHWs provide a necessary structure to contribute to successful implementation of the human immunodeficiency virus (HIV) programme in four ways: (1) prevention of HIV infection by health education, (2) linkage to care by health education and referrals, (3) adherence support and (4) identification of individuals who are failing treatment. However, CHW programme and HIV programme-specific barriers exist that need to be resolved in order to achieve maximum impact. These include a lack of stakeholder and community support for WBOTs, challenging work and operational environments, a lack of in-depth knowledge and skills, and socio-cultural barriers such as HIV-related stigma. Considering its promising structure, documentation of the WBOT contribution to healthcare overall, and the HIV programme in particular, is urgently warranted to successfully and sustainably incorporate it into the South African healthcare system. PMID- 29707390 TI - Comparison of Efficacy and Ocular Surface Disease Index Score between Bimatoprost, Latanoprost, Travoprost, and Tafluprost in Glaucoma Patients. AB - Aim: The purpose of this study is to evaluate and compare the efficacy of 4 prostaglandin analogues (PGAs) and to determine the incidence of ocular surface disease in newly diagnosed, primary open-angle glaucoma (POAG) patients started on one of those 4 PGAs: bimatoprost (benzalkonium chloride, BAK, 0.3 mg/mL), latanoprost (BAK 0.2 mg/mL), travoprost (polyquad), and tafluprost (BAK-free). Patients and Methods: In this single-center, open-label trial, 32 patients newly diagnosed with POAG were randomly started on one of the four PGAs. All patients underwent a complete ophthalmological exam at presentation and at 1, 3, and 6 months of follow-up. Dry eye disease (DED) was assessed using the original Ocular Surface Disease Index (OSDI) questionnaire, in order to evaluate the impact of the drops on the quality of life of patients. Results: The mean age was 60.06 years +/- 11.76. All four drugs equally and significantly reduced the intraocular pressure (IOP) with respect to the baseline IOP. There was a trend for a slightly greater reduction of IOP with bimatoprost, but the difference was not found to be statistically significant when compared to other PGAs. OSDI scores were significantly superior for travoprost (10.68 +/- 5.73) compared to the other three drugs (p < 0.05). Latanoprost caused the most significant eyelash growth and iris discoloration. Conjunctival hyperemia and superficial keratitis occurrence were similar in the four groups. Conclusion: All prostaglandin analogues equally and significantly reduce the IOP in patients with POAG. According to the results of the OSDI score, latanoprost seems to be the least tolerated among the four drugs. PMID- 29707391 TI - The Effect of Patient Characteristics and Sleep Quality on Visual Field Performance Reliability. AB - Purpose: To investigate the association of automated visual field (VF) reliability indices (false positive [FP], false negative [FN], and fixation loss [FL]) and sleep quality, VF experience, and age. Methods: Prospective, cross sectional study. Adult patients (age >= 18 years) completing automated VF testing were invited to participate. Baseline participant characteristics were obtained, and all participants were asked to complete the Pittsburgh Sleep Quality Index (PSQI) questionnaire. Nonparametric Spearman correlations and logistical regression models were performed. Results: 63 patients were enrolled. Lower PSQI score was correlated with higher percentage (%) FL in the right eye (p = 0.03). Fewer prior VF was significantly correlated with higher %FP in the right eye (p = 0.008). Older age was significantly correlated with higher %FN in the left eye (p = 0.01). Greater mean deviation (MD) and pattern standard deviation (PSD) were strongly correlated with higher %FN in the right (p = 0.02 and 0.002, resp.) and left eyes (p = 0.01 and 0.02, resp.). Conclusion: In this prospective, cross sectional study, worse MD and PSD are strongly correlated with increased FN in both eyes. Increased FN in the left eye associated with older age might be attributable to test fatigue. Worse sleep quality is associated with decreased FL in the right eye. PMID- 29707392 TI - Cardiovascular Risk Assessment in a Cohort of Newly Diagnosed Patients with Obstructive Sleep Apnea Syndrome. AB - Objectives: Obstructive sleep apnea syndrome (OSAS) is associated with increased cardiovascular morbidity and mortality. The aim of this study was to assess whether the 10-year risk for cardiovascular disease in newly diagnosed patients with OSAS is increased. Materials and Methods: Recently diagnosed, with polysomnography, consecutive OSAS patients were included. The Systematic Coronary Risk Evaluation (SCORE) and the Framingham Risk Score (FRS) were used to estimate the 10-year risk for cardiovascular disease. Results: Totally, 393 individuals (73.3% males), scheduled to undergo a polysomnographic study with symptoms indicative of OSAS, were enrolled. According to apnea-hypopnea index (AHI), subjects were divided in four groups: mild OSAS (AHI 5-14.9/h) was diagnosed in 91 patients (23.2%), moderate OSAS (AHI 15-29.9/h) in 58 patients (14.8%), severe OSAS (AHI > 30/h) in 167 patients (42.5%), while 77 individuals (19.6%) had an AHI < 5/h and served as controls. Increased severity of OSAS was associated with increased SCORE (p < 0.001) and FRS values (p < 0.001). More specifically, a significant correlation was observed both between AHI and SCORE (r=0.251, p < 0.001) and AHI and FRS values (r=0.291, p < 0.001). Furthermore, a negative correlation was observed between FRS values and sleep efficiency (r=-0.224, p=0.006). Conclusions: The 10-year risk for cardiovascular morbidity and mortality seems to increase with severity of OSAS. Physicians should bear this finding in mind, in order to seek for and consecutively eliminate risk factors for cardiovascular disease and to prevent future cardiovascular events in OSAS patients. PMID- 29707393 TI - The Association between Obesity and Cognitive Function in Otherwise Healthy Premenopausal Arab Women. AB - Objective: To examine the association between obesity and cognitive function in healthy premenopausal women. Methods: From a cohort of 220 women, 98 were randomly selected that provided complete data. Body composition was examined by dual-energy X-ray scan. All participants completed the Cambridge Neuropsychological Test Automated Battery (CANTAB) to assess cognitive performance in three domains: attention, memory, and planning executive function. The Reaction Time (RTI) test was used to assess motor and mental response speeds; the Stockings of Cambridge (SOC) test was used to assess planning executive function. For memory assessment, the Delayed Match to Sample (DMS), Pattern Recognition Memory (PRM), and Spatial Span (SSP) tests were used to assess forced choice recognition memory, visual pattern recognition memory, and working memory capacity, respectively. Results: 36 (36.7%) were morbidly obese, 22 (22.4%) obese, and 23 (23.5%) overweight. Performance on RTI and SOC planning ability were not associated with body mass index (BMI). DMS mean time to correct response, when stimulus is visible or immediately hidden (0 ms delay), was higher by 785 +/- 302 ms (milliseconds) (p=0.011) and 587 +/- 259 ms (p=0.026) in morbidly obese women compared to normal weight women. Memory span length was significantly lower in overweight (5.5 +/- 1.3, p=0.008) and obese women (5.6 +/- 1.6, p=0.007) compared to normal weight (6.7 +/- 0.9). DEXA-assessed body fat (%) showed similar associations as BMI, and latency to correct response on DMS and PRM was positively correlated with percentage of body fat, but not with VO2 max. Conclusion: In otherwise healthy premenopausal women, obesity did not impact accuracy on cognitive tasks related to attention, memory, or planning executive function, but morbid obesity was associated with higher latency to correct response on memory-specific tasks and lower memory span length. PMID- 29707394 TI - Percutaneous Coronary Intervention in a Patient with Right-Sided Heart: Invert the Views? AB - Situs inversus totalis considered a malposition syndrome is a very rare condition, occurring in 1 : 8000 births, usually without associated structural congenital heart disease. The diagnosis is often incidental as in this case, which presented with an acute coronary syndrome as a manifestationof multivessel coronary artery disease. Here, we present the challenges encountered during the diagnosis and management of this entity via percutaneous intervention. PMID- 29707395 TI - Fetal Sirenomelia Associated with an Abdominal Cyst Originating from a Saccular Cloaca. AB - A 40-year-old pregnant woman presented with a fetal abdominal cyst and oligohydramnios. Color Doppler scan revealed a single blood vessel from the fetal aorta into a single umbilical artery. Severe oligohydramnios limited ultrasonographic evaluation of the fetal lower limbs, kidneys, or bladder. The pregnancy was terminated; the fetus showed fused lower limbs, bulging abdomen, and absent external genitalia and was diagnosed with type III sirenomelia. On autopsy, no normal bladder was observed, but duodenal atresia, anorectal atresia, and right renal agenesis were found. An intra-abdominal cyst, diagnosed histologically as a saccular cloaca, occupied the abdominal cavity. Ultrasonographic diagnosis of fetal sirenomelia is difficult due to poor depiction of the lower limbs. A vitelline artery leading to a single umbilical artery and a fetal abdominal cyst occupying most of the abdominal cavity are considered fetal sirenomelia associated with large defects of the gastrointestinal and genitourinary tracts. PMID- 29707396 TI - Orbital Desmoid-Type Fibromatosis: A Case Report and Literature Review. AB - Purpose: Desmoid-type fibromatosis is a benign fibrous neoplasia originating from connective tissue, fascial planes, and musculoaponeurotic structures of the muscles. Currently, there is no evidence-based treatment approach available for desmoid fibromatosis. In this article, a case of a patient in the pediatric age affected by desmoid fibromatosis localized in the orbit is presented. The aim of the article is to describe this unusual and rare location for the desmoid fibromatosis and outline the principle phases in the decision-making process and the therapeutic alternatives for a patient affected by desmoid fibromatosis. Methods: The protocol of this review included study objectives, search strategy, and selection criteria. The primary end point of this study was to analyze the head and neck desmoid fibromatosis. The secondary end point was to identify the available therapies and assess their specific indications. Results: The mean age of patients was 18.9 years ranging from 0 to 66, and 52% were female. A bimodal age distribution was observed, and two age peaks were identified: 0-14 years (57%) and 28-42 years (18%). The most common involved areas were the mandible (25%) followed by the neck (21%). In 86% of the cases, the treatment was the surgical resection of the disease, and only in 5% of the cases, the surgical resection was followed by adjuvant radiotherapy. Conclusion: The orbital location is extremely rare, especially in the pediatric population. The management of desmoid fibromatosis is based on the function preservation and the maintenance of a good quality of life, but in case of symptomatic patients or aggressive course of the disease or risk of functional damages, the surgical approach may be considered. Therapeutic alternatives to surgical resection are radiotherapy and systemic therapy. PMID- 29707397 TI - Safe Administration of Ipilimumab, Pembrolizumab, and Nivolumab in a Patient with Metastatic Melanoma, Psoriasis, and a Previous Guillain-Barre Syndrome. AB - Background: Patients with autoimmune diseases were not evaluated in clinical trials with immune checkpoint inhibitors (ICIs), since a history of immune disorders, such as Guillain-Barre syndrome (GBS) and psoriasis, is one of the major risk factors for the development of immune-related adverse events (irAEs). This risk cannot be defined; therefore, physicians are called to manage these patients in clinical practice. Case Report: We report the case of a 62-year-old male patient affected by metastatic melanoma, with a history of GBS and psoriasis, and treated with sequential ipilimumab, pembrolizumab, and nivolumab, without significant toxicities. Conclusion: This case report supports that although a history of immune disorders is one of the major risk factors for development of irAEs, in some patients, it could be possible to safely administer sequential treatments with ICIs. A proper decision should be made, considering therapeutic options, disease-related risks, and those related to a recurrence of preexisting autoimmune disorders. PMID- 29707398 TI - Severe Bilateral Breast Mucinous Carcinoma with Bilateral Lungs and Cutaneous Metastasis: A Case Report and Literature Review. AB - The case of a female who had severe, rare, terminal breast mucinous carcinoma (BMC) and failed to receive surgery and chemotherapy was reported. The patient was diagnosed with pure BMC (ER++, PR++, CerbB-2-, and Ki-67 10%) accompanied with bilateral lungs, bilateral chest walls with skin ulcer (D = 14 cm), lymph nodes of bilateral armpits, and right supraclavicular metastases. ECOG (Eastern Cooperative Oncology Group) and NRS (Numeric Rating Scale) pain scores were 4 and 6, respectively. Because the patient refused traditional chemotherapy and radiotherapy on religious grounds, an herbal medicine containing Panax ginseng, Agrimonia pilosa, and white flower Patrinia herb was administered; extensive nursing for tumor debridement was also provided. Quality of Life (QOL) improved and pain reduced. Tumor-bearing survival time was prolonged. The present case dictates that herbal extract medicines and supportive treatment can be helpful for uncommon severe BMC as an appropriate alternative treatment. PMID- 29707399 TI - Placental Histomorphology in a Case of Double Trisomy 48,XXX,+18. AB - Background: Approximately 50% of early spontaneous abortions are found to have chromosomal abnormalities. In these cases, certain histopathologic abnormalities are suggestive of, although not diagnostic for, the presence of chromosomal abnormalities. However, placental histomorphology in cases of complex chromosomal abnormalities, including double trisomies, is virtually unknown. Case Report: We present the case of a 27-year-old G3P22002 female presenting at 19 weeks and 1 day of gestation by last menstrual period for scheduled prenatal visit. Ultrasound revealed a single fetus without heart tones and adequate amniotic fluid. Limited fetal measurements were consistent with estimated gestational age of 17 weeks. Labor was induced with misoprostol due to fetal demise. Autopsy revealed an immature female fetus with grade 1-2 maceration. The ears were low set and posteriorly rotated. The fingers were short bilaterally, and the right foot showed absence of the second and third digits. Evaluation of the organs showed predominantly marked autolysis consistent with retained stillbirth. Placental examination revealed multiple findings, including focal pseudovillous papilliform trophoblastic proliferation of the undersurface of the chorionic plate and clustering of perpendicularly oriented sclerotic chorionic villi in the chorion laeve, which have not been previously reported in cases of chromosomal abnormalities. Karyotype of placental tissue revealed a 48,XXX,+18 karyotype and the same double trisomy of fetal thymic tissue by FISH. Conclusion: In addition to convoluted outlines of chorionic villi, villous trophoblastic pseudoinclusions, and clusters of villous cytotrophoblasts, the previously unreported focal pseudovillous papilliform trophoblastic proliferation of the undersurface of the chorionic plate and clustering of perpendicularly oriented sclerotic chorionic villi in the chorion laeve were observed in this double trisomy case. More cases have to be examined to show if the histology is specific for this double trisomy. PMID- 29707400 TI - "Capgras" Delusions Involving Belongings, Not People, and Evolving Visual Hallucinations Associated with Occipital Lobe Seizures. AB - Capgras syndrome is characterized by the delusional belief that a familiar person has been replaced by a visually similar imposter or replica. Rarely, the delusional focus may be objects rather than people. Numerous etiologies have been described for Capgras to include seizures. Similarly, visual hallucinations, both simple and complex, can occur secondary to seizure activity. We present, to our knowledge, the first reported case of visual hallucinations and Capgras delusions for objects that developed secondary to new onset occipital lobe epilepsy. We then discuss the possible underlying neurologic mechanisms responsible for the symptomatology. PMID- 29707401 TI - A Rare but Fascinating Disorder: Case Collection of Patients with Schnitzler Syndrome. AB - Background: Schnitzler syndrome is a rare disorder characterized by a chronic urticarial rash and monoclonal gammopathy (IgM in more than 90% of the cases). It is difficult to distinguish from other neutrophilic urticarial dermatoses, and diagnosis is based on the Strasbourg criteria. Interleukin-1 is considered the key mediator, and interleukin-1 inhibitors are considered first line treatment. Here, we present two cases of Schnitzler syndrome, both successfully treated with anakinra. Objectives: To increase awareness regarding clinical presentation, diagnosis, and treatment of this rare disorder. Cases: We describe the clinical features and disease course of two patients with Schnitzler syndrome, diagnosed using the Strasbourg criteria. Both were treated with anakinra with remarkable response to therapy. Conclusion: Schnitzler syndrome is a rare and underdiagnosed disorder. High suspicion should be maintained in patients with chronic urticaria like dermatoses, intermittent fevers, and arthralgias. A serum protein electrophoresis and immunofixation should be performed in these patients. The diagnosis is important to recognize as Schnitzler syndrome is associated with malignancy. A lymphoproliferative disorder develops in about 20% of patients at an average of 7.6 years after onset of symptoms. Thus, patients warrant long-term follow-up. IL-1 inhibitors are extremely effective in relieving symptoms and are considered first line therapy. PMID- 29707402 TI - Molecularly specific detection of bacterial lipoteichoic acid for diagnosis of prosthetic joint infection of the bone. AB - Discriminating sterile inflammation from infection, especially in cases of aseptic loosening versus an actual prosthetic joint infection, is challenging and has significant treatment implications. Our goal was to evaluate a novel human monoclonal antibody (mAb) probe directed against the Gram-positive bacterial surface molecule lipoteichoic acid (LTA). Specificity and affinity were assessed in vitro. We then radiolabeled the anti-LTA mAb and evaluated its effectiveness as a diagnostic imaging tool for detecting infection via immunoPET imaging in an in vivo mouse model of prosthetic joint infection (PJI). In vitro and ex vivo binding of the anti-LTA mAb to pathogenic bacteria was measured with Octet, ELISA, and flow cytometry. The in vivo PJI mouse model was assessed using traditional imaging modalities, including positron emission tomography (PET) with [18F]FDG and [18F]NaF as well as X-ray computed tomography (CT), before being evaluated with the zirconium-89-labeled antibody specific for LTA ([89Zr]SAC55). The anti-LTA mAb exhibited specific binding in vitro to LTA-expressing bacteria. Results from imaging showed that our model could reliably simulate infection at the surgical site by bioluminescent imaging, conventional PET tracer imaging, and bone morphological changes by CT. One day following injection of both the radiolabeled anti-LTA and isotype control antibodies, the anti-LTA antibody demonstrated significantly greater (P < 0.05) uptake at S. aureus-infected prosthesis sites over either the same antibody at sterile prosthesis sites or of control non-specific antibody at infected prosthesis sites. Taken together, the radiolabeled anti-LTA mAb, [89Zr]SAC55, may serve as a valuable diagnostic molecular imaging probe to help distinguish between sterile inflammation and infection in the setting of PJI. Future studies are needed to determine whether these findings will translate to human PJI. PMID- 29707403 TI - Histone demethylase LSD1 regulates bone mass by controlling WNT7B and BMP2 signaling in osteoblasts. AB - Multiple regulatory mechanisms control osteoblast differentiation and function to ensure unperturbed skeletal formation and remodeling. In this study we identify histone lysine-specific demethylase 1(LSD1/KDM1A) as a key epigenetic regulator of osteoblast differentiation. Knockdown of LSD1 promoted osteoblast differentiation of human mesenchymal stem cells (hMSCs) in vitro and mice lacking LSD1 in mesenchymal cells displayed increased bone mass secondary to accelerated osteoblast differentiation. Mechanistic in vitro studies revealed that LSD1 epigenetically regulates the expression of WNT7B and BMP2. LSD1 deficiency resulted in increased BMP2 and WNT7B expression in osteoblasts and enhanced bone formation, while downregulation of WNT7B- and BMP2-related signaling using genetic mouse model or small-molecule inhibitors attenuated bone phenotype in vivo. Furthermore, the LSD1 inhibitor tranylcypromine (TCP) could increase bone mass in mice. These data identify LSD1 as a novel regulator of osteoblast activity and suggest LSD1 inhibition as a potential therapeutic target for treatment of osteoporosis. PMID- 29707404 TI - Human papillomavirus clustering patterns among HIV-infected and HIV-uninfected adolescent females in South Africa. AB - The global burden of disease caused by both human immunodeficiency virus (HIV) and human papillomavirus (HPV) is the greatest in the developing world, with the highest rates in sub-Saharan Africa. South African women not only have high rates of infection with HPV, but also have high rates of multiple concurrent infections with two or more HPV genotypes, and are among the world's most vulnerable to developing invasive cervical cancer. HIV co-infection increases these risks. Understanding clustering patterns of concurrent HPV infections in this population has important implications for HPV screening and will help define vaccination strategies in the future as vaccines continue to be developed to target more HPV genotypes. Latent class analysis was used to identify four distinct patterns of HPV co-infection: individuals with at least one low risk HPV genotype, but no high-risk HPV (HR-HPV) infections; individuals with a disperse pattern of HR-HPV infections; individuals infected with members of the alpha-7 group, but not HPV 18; and individuals infected with HPV-16, but not HPV-18. In this analysis, although alpha-7 HPV infections were more prevalent among HIV-infected adolescents than their HIV-uninfected counterparts, overall clustering patterns were not different based on HIV status. PMID- 29707405 TI - Genetics of Refractory Rickets: Identification of Novel PHEX Mutations in Indian Patients and a Literature Update. AB - Refractory rickets is a genetic disorder that cannot be treated by vitamin D supplementation and adequate dietary calcium and phosphorus. Hereditary hypophosphatemic rickets is one of the major forms of refractory rickets in Indian children and caused due to mutations in the PHEX , FGF23 , DMP1 , ENPP1 , and SLC34A3 genes. This is the first study in India on a large number of patients reporting on mutational screening of the PHEX gene. Direct sequencing in 37 patients with refractory rickets revealed eight mutations in 13 patients of which 1 was nonsense, 2 were deletions, 1 was a deletion-insertion, and 4 were missense mutations. Of these mutations, four (c.566_567 delAG, c.651_654delACAT, c.1337delinsAATAA, and c.2048T > A) were novel mutations. This article discusses the mutations in Indian patients, collates information on the genetic causes of refractory rickets, and emphasizes the significance of genetic testing for precise diagnosis, timely treatment, and management of the condition, especially in developing countries. PMID- 29707406 TI - Three Mutations in the Bilateral Frontoparietal Polymicrogyria Gene GPR56 in Pakistani Intellectual Disability Families. AB - Bilateral frontoparietal polymicrogyria (BFPP, MIM 606854) is a heterogeneous autosomal recessive disorder of abnormal cortical lamination, leading to moderate to-severe intellectual disability (ID), seizure disorder, and motor difficulties, and caused by mutations in the G protein-coupled receptor 56 ( GPR56 ) gene. Twenty-eight mutations in 40 different families have been reported in the literature. The clinical and neuroimaging phenotype is consistent in these cases. The BFPP cortex consists of numerous small gyral cells, with scalloping of the cortical-white matter junction. There are also associated white matter, brain stem, and cerebellar changes. GPR56 is a member of an adhesion G protein-coupled receptor family with a very long N-terminal stalk and seven transmembrane domains. In this study, we identified three families from Pakistan, ascertained primarily for ID, with overlapping approximately 1 Mb region (chr16:56,973,335 57,942,866) of homozygosity by descent, including 24 RefSeq genes. We found three GPR56 homozygous mutations, using next-generation sequencing. These mutations include a substitutional variant, c.1460T > C; p.L487P, (chr16:57693480 T > C), a 13-bp insertion causing the frameshift and truncating mutation, p.Leu269Hisfs*21 (NM_005682.6:c.803_804insCCATGGAGGTGCT; Chr16: 57689345_57689346insCCATGGAGGTGCT), and a truncating mutation c.1426C > T; p.Arg476* (Chr16:57693446C > T). These mutations fully segregated with ID in these families and were absent in the Exome Aggregation Consortium database that has approximately 8,000 control samples of South Asian origin. Two of these mutations have been reported in ClinVar database, and the third one has not been reported before. Three families from Pakistan with GPR56 mutations have been reported before. With the addition of our findings, the total number of mutations reported in Pakistani patients now is six. These results increase our knowledge regarding the mutational spectrum of the GPR56 gene causing BFPP/ID. PMID- 29707407 TI - Variants Associated with Infantile Cholestatic Syndromes Detected in Extrahepatic Biliary Atresia by Whole Exome Studies: A 20-Case Series from Thailand. AB - Biliary atresia (BA) is the most severe form of obstructive cholangiopathy occurring in infants. Definitive diagnosis of BA usually relies on operative findings together with supporting pathological patterns found in the extrahepatic bile duct. In infancy, overlapping clinical patterns of cholestasis can be found in other diseases including biliary hypoplasia and progressive familial intrahepatic cholestasis. In addition, BA has been reported as a phenotype in some rare genetic syndromes. Unlike BA, other cholangiopathic phenotypes have their own established genetic markers. In this study, we used these markers to look for other cholestasis entities in cases diagnosed with BA. DNA from 20 cases of BA, diagnosed by operative findings and histopathology, were subjected to a study of 19 genes associated with infantile cholestasis syndromes, using whole exome sequencing. Variant selection focused on those with allele frequencies in dbSNP150 of less than 0.01. All selected variants were verified by polymerase chain reaction-direct sequencing. Of the 20 cases studied, 13 rare variants were detected in 9 genes: 4 in JAG1 (Alagille syndrome), 2 in MYO5B (progressive familial intrahepatic cholestasis [PFIC] type 6), and one each in ABCC2 (Dubin Johnson syndrome), ABCB11 (PFIC type 2), UG1A1 (Crigler-Najjar syndrome), MLL2 (Kabuki syndrome), RFX6 (Mitchell-Riley syndrome), ERCC4 (Fanconi anemia), and KCNH1 (Zimmermann-Laband syndrome). Genetic lesions associated with various cholestatic syndromes detected in cases diagnosed with BA raised the hypothesis that severe inflammatory cholangiopathy in BA may not be a distinct disease entity, but a shared pathology among several infantile cholestatic syndromes. PMID- 29707408 TI - A De Novo Xp11.23 Duplication in a Girl with a Severe Phenotype: Expanding the Clinical Spectrum. AB - The Xp11.22-p11.23 duplication syndrome was described in 2009 by Giorda et al and is characterized by intellectual disability, speech delay, and electroencephalography anomalies. We report a case of a 23-month-old girl who presented with epilepsy and global developmental delay and who had a small duplication at Xp11.23. The case we present here is the first case showing the clinical features of Xp11.22-p11.23 duplication syndrome only involving synovial sarcoma, X breakpoint ( SSX ) genes: SSX1 , SSX3 , SSX4 , and SSX9 . This case report contributes to an expanding clinical spectrum of Xp11.22-p11.23 duplication syndrome. PMID- 29707409 TI - Juvenile Idiopathic Arthritis Associated with Combined JP-HHT Syndrome: A Novel Phenotype Associated with a Novel Variant in SMAD4. AB - Juvenile polyposis (JP) syndrome is characterized by multiple hamartomatous polyps of the gastrointestinal tract. Hereditary hemorrhagic telangiectasia (HHT) is a vascular dysplasia characterized by telangiectasia in the skin, mucous membranes, and arteriovenous malformations in other organs. Individuals with JP HHT syndrome have variable features of both rare disorders, attributed to heterozygous mutations in the SMAD4 gene. Systemic juvenile idiopathic arthritis (JIA) is a severe, chronic disease marked by arthritis and systemic inflammation for which the cause remains unknown. JIA has never been described in association with SMAD4 -related disease. We describe a case of JP-HHT syndrome with a novel SMAD4 variant, c.1052A > T (p.D351V), in which the child also had JIA manifestation. PMID- 29707410 TI - A 2-Year-Old Child with Bilateral Ectopis Lentis and a Novel FBN1 Gene Variant Cys129Ser. AB - Marfan syndrome and dominant ectopia lentis are part of type 1 fibrillinopathies that are caused by FBN1 pathogenic variants. Making a diagnosis could be challenging due to the clinical overlap between these disorders. The revised Ghent criteria used for Marfan syndrome diagnosis helped in resolving some of the confusion, especially in younger children. We report on a case of bilateral ectopia lentis in a 2-year-old child with a normal echocardiogram. FBN1 sequencing revealed a novel likely pathogenic variant described as c.385T > A (p.Cys129Ser). The patient's father also has a history of bilateral ectopia lentis and his genetic analysis detected the same FBN1 variant as the proband. PMID- 29707411 TI - Case Report of Proliferative Peripheral Retinopathy in Two Familial Lissencephaly Infants with Miller-Dieker Syndrome. AB - A complete ophthalmic examination is not routinely performed on infants with Miller-Dieker syndrome (MDS, chromosome 17p13.3 microdeletion). The authors present the cases of four cousins with MDS who also carried a 16p13.3 microduplication (not associated with Rubinstein-Taybi syndrome). Retinopathy of prematurity-like proliferative peripheral retinopathy (PPR) was detected in two male first cousins, but was not detected in the female half-cousins. PPR in the first infant resolved by 4 months, but the second infant's PPR progressed, requiring photocoagulation followed by lens-sparing vitrectomy. While ocular abnormalities are more prevalent and severe in other lissencephalopathies, the PPR in these MDS infants underscores the sight-saving potential of performing an ophthalmologic exam with early molecular testing for all lissencephaly infants. PMID- 29707412 TI - Oral-Facial-Digital Syndrome Type 1: Oral Findings in a 6-Year-Old Girl. AB - Oral-facial-digital syndrome (OFDS) is a group of congenital anomalies with 13 different forms. OFDS type 1 (OFDS1) is a developmental genetic anomaly related to the X chromosome, that is often seen in girls, and affects the face, oral cavity, and extremities. In this study, we discuss the oral findings of a 6-year old girl with OFDS1 and her situation after 2.5 years. PMID- 29707413 TI - End-Stage Renal Failure Is an Independent Risk Factor for 1-Year Mortality After Hip Fracture Surgery. AB - Introduction: End-stage renal failure (ESRF) with its associated comorbidities increase postoperative mortality in hip fracture patients. This study investigated the association of ESRF with various comorbidities in patients on dialysis and assessed rates ESRF as an independent risk factor for all-cause postoperative 1- year mortality rates. Methods: This was a retrospective cohort study on patients aged 55 years and older who underwent their first nonpathological, low-energy hip fracture surgery at an Asian tertiary hospital from June 2007 to 2012. Patients were identified as cases with ESRF on dialysis (study group) or non-ESRF patients (controls). Various comorbidity factors and postoperative 1-year mortality status were obtained from institutional electronic medical records. Univariate and multivariate logistic regression were used to identify significant risk factors for all-cause, 1-year mortality. Results: With no loss to follow-up, the 1-year postoperative mortality rate was 19.6% for the 46 patients with ESRF on dialysis and 8.4% for non-ESRF controls (P = .028). Fisher exact test showed that hypertension, ischemic heart disease (IHD), diabetes mellitus (DM), anemia, cerebrovascular disease, and vascular disease were significantly associated with ESRF (P < .05). Multivariable logistic regression analysis identified ESRF (adjusted odds ratio[AOR] = 2.85, P = .021), cancer (AOR = 3.04, P = .003), IHD (AOR = 2.07, P = .020), DM (AOR = 2.03, P = .022), and age (AOR = 1.08, P <.0001) as independent risk factors for 1-year mortality following hip fracture surgery. The area under the receiver-operating characteristic curve (95% confidence interval) for the multivariable predictor of 1-year mortality was 0.75 (0.60-0.82). Conclusions: Although associated with multiple comorbidities, ESRF was found to be independently predictive of 1-year mortality in patients undergoing hip fracture surgery, second to cancer in terms of magnitude of risk posed. As ESRF is a negative prognostic factor for 1-year mortality after hip fracture surgery, its importance should be recognized with implications on preoperative counseling to patients about the increased risk and implications on fracture prevention. PMID- 29707414 TI - Treatment patterns, clinical and economic outcomes of patients with anaplastic lymphoma kinase-positive non-small cell lung cancer receiving ceritinib: a retrospective observational claims analysis. AB - Objective: To describe patient characteristics, treatment patterns, healthcare resource utilization (HRU), and costs among patients with anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer (NSCLC) receiving ceritinib in second or later line of therapy. Methods: Adult patients with NSCLC receiving ceritinib were identified from two large US claims databases (2006-2015). Patient characteristics, comorbidity profile, treatment patterns prior to ceritinib, and ceritinib dosing patterns were described. All-cause, HRU, and costs incurred during the observation period after ceritinib initiation were reported per patient per six months. Results: One hundred sixty-four patients were included (mean age 54.2 years, 57.3% female); the majority had metastatic disease (94.5%) and the average Charlson Comorbidity Index was 7.6. 150 (91.5%) patients received crizotinib prior to ceritinib - average crizotinib duration was 10.2 months and time between crizotinib discontinuation and ceritinib initiation was 2.1 months (median= 0; 25th-75th percentile= 0-0.8). Most patients (73.8%) initiated ceritinib on the recommended dose (750 mg) and maintained the dose until the end of the observation period (mean of 7.4 months) or ceritinib discontinuation; 61 (37.2%) patients discontinued ceritinib during the observation period. A total of 76 (46.3%) patients had at least one inpatient admission during the observation period after ceritinib initiation. Mean total healthcare cost per patient per six months was $111,468. Conclusions: Patients with ALK-positive NSCLC receiving ceritinib had a high comorbidity burden and generally started ceritinib on the recommended dose quickly after crizotinib discontinuation. Medical costs accounted for nearly a half of the total healthcare costs. PMID- 29707415 TI - Data Integration through Ontology-Based Data Access to Support Integrative Data Analysis: A Case Study of Cancer Survival. AB - To improve cancer survival rates and prognosis, one of the first steps is to improve our understanding of contributory factors associated with cancer survival. Prior research has suggested that cancer survival is influenced by multiple factors from multiple levels. Most of existing analyses of cancer survival used data from a single source. Nevertheless, there are key challenges in integrating variables from different sources. Data integration is a daunting task because data from different sources can be heterogeneous in syntax, schema, and particularly semantics. Thus, we propose to adopt a semantic data integration approach that generates a universal conceptual representation of "information" including data and their relationships. This paper describes a case study of semantic data integration linking three data sets that cover both individual and contextual level factors for the purpose of assessing the association of the predictors of interest with cancer survival using cox proportional hazard models. PMID- 29707416 TI - Health Information Needs and Health Seeking Behavior During the 2014-2016 Ebola Outbreak: A Twitter Content Analysis. AB - Introduction: For effective public communication during major disease outbreaks like the 2014-2016 Ebola epidemic, health information needs of the population must be adequately assessed. Through content analysis of social media data, like tweets, public health information needs can be effectively assessed and in turn provide appropriate health information to address such needs. The aim of the current study was to assess health information needs about Ebola, at distinct epidemic time points, through longitudinal tracking. Methods: Natural language processing was applied to explore public response to Ebola over time from July 2014 to March 2015. A total 155,647 tweets (unique 68,736, retweet 86,911) mentioning Ebola were analyzed and visualized with infographics. Results: Public fear, frustration, and health information seeking regarding Ebola-related global priorities were observed across time. Our longitudinal content analysis revealed that due to ongoing health information deficiencies, resulting in fear and frustration, social media was at times an impediment and not a vehicle to support health information needs. Discussion: Content analysis of tweets effectively assessed Ebola information needs. Our study also demonstrates the use of Twitter as a method for capturing real-time data to assess ongoing information needs, fear, and frustration over time. PMID- 29707417 TI - Are Soy Products Effective in DMD? AB - Introduction: In addition to their nutritional value, processed soy bean extracts contain several activities with potential therapeutic benefits. These include anti-oxidants, and tyrosine kinase and protease inhibitory activity. There are also anecdotal reports of health benefits of soy products in alleviating DMD symptoms. Methods: Mdx mice were fed a control soy-free diet or the same diet containing either a proprietary soy preparation (Haelan 951), purified soy isoflavones, purified Bowman-Birk protease inhibitor or a combination of isoflavones and Bowman-Birk inhibitor. Mice were tested for their wire hanging ability at the start of the diet regimen and every 4 weeks until week 12 of treatment. Results and Discussion: The diet containing Bowman-Birk inhibitor was the only one to show a significant and sustained improvement over the 12 weeks of the study. All other dietary additions; Haelan 951, isoflavones and isoflavones with Bowman-Birk inhibitor, were not significantly different from each other or from control. The effectiveness of Bowman-Birk inhibitor in mdx mice clearly warrants further study. PMID- 29707418 TI - DISCUSSING ANT1 ROLE IN AMYOTROPHIC LATERAL SCLEROSIS PATHOGENESIS. PMID- 29707419 TI - OLANZAPINE AND DIABETIC KETOACIDOSIS: WHAT IS THE UNDERLYING MECHANISM? PMID- 29707420 TI - PROLACTIN LEVELS IN PATIENTS WITH SCHIZOPHRENIA WHO WERE SWITCHED FROM DAILY TO ONCE-MONTHLY ARIPIPRAZOLE TREATMENT. PMID- 29707421 TI - Neuroscience is the Next Oncology. PMID- 29707422 TI - Modafinil for the Improvement of Patient Outcomes Following Traumatic Brain Injury. AB - Objective: The authors sought to assess the literature evidence on the efficacy of modafinil use in patients with fatigue or excessive daytime sleepiness (EDS) secondary to traumatic brain injury (TBI). Method of Research: A literature search of Medline and PubMed was performed using the EBSCOhost database. Primary literature, observational studies, meta-analyses, case reports, and systematic reviews were assessed for content regarding modafinil and psychostimulant use in patients with TBI. Of the 23 articles collected, three randomized, controlled studies, three observational studies, one case report, and two systematic reviews gave a description of modafinil use in TBI patients. Results and Conclusion: Modafinil is a central nervous system stimulant with well-established effectiveness in the treatment of narcolepsy and shift-work sleep disorder. There is conflicting evidence about the benefits of modafinil in the treatment of fatigue and EDS secondary to TBI. One randomized, controlled study states that modafinil does not significantly improve patient wakefulness, while another concludes that modafinil corrects EDS but not fatigue. An observational study provides evidence that modafinil increases alertness in fatigued patients with past medical history of brainstem diencephalic stroke or multiple sclerosis. Modafinil appears to have the potential to improve wakefulness in patients with TBI. A prospective, double-blinded, randomized, crossover trial of modafinil for the management of fatigue in ischemic stroke patients is currently being conducted, and further studies demonstrating consistent results are needed before making a conclusive decision. PMID- 29707423 TI - Effects of Statins and Cholesterol on Patient Aggression: Is There a Connection? AB - Overview: Psychiatric adverse effects, including aggression, have been reported with the use of statin medications; however, there is little data to support or refute the theory that statins or low serum cholesterol do in fact increase a patient's risk of aggression. Objective: This study examined 1) statin use and increased aggression, measured by the requirement of either emergent psychiatric intervention referred to as "Code Green" (CG) or "Restraint and Seclusion" (RS) and 2) cholesterol level and increased aggression in psychiatric inpatients. Materials and Methods: Patient charts from January 1, 2011, to December 31, 2015 were reviewed. Statin therapy, lipid panel, and requirement of a psychiatric emergency code CG or RS were noted. Inpatients who did not receive cholesterol lowering therapy were used as controls. Analyses of variance (ANOVAs) were used to examine the relationship between statin use and increased aggression. Results: Eleven (9.6%) patients receiving statins required a total of 57 CGs, and five (4.4%) required 27 RSs. Conversely, 33 (28.9%) patients not receiving statins required a total of 64 CGs, and 14 (12.3%) required 27 RSs. No statistically significant relationship between statin therapy and agitation was found as evidenced by a CG (F=0.068; p=0.795) or RS (F=0.001; p=1.000). A statistically significant relationship was found between total cholesterol level and requirement of a CG (F=1.435; p=0.029) or RS (F=2.89; p=0.000). Conclusion: It is evident that psychiatric inpatients with lower total cholesterol levels are at an increased risk for loss of behavioral control. PMID- 29707424 TI - Comorbid Insomnia and Psychiatric Disorders: An Update. AB - Insomnia is a clinical problem of significant public health importance. Insomnia can be a symptom or harbinger of other psychiatric disorders. Insomnia can also be comorbid with other psychiatric disorders, thereby adding to the medical burden and increasing the risk of psychiatric relapse. Insomnia can also be associated with medical and neurological disorders. Some medications can also cause insomnia. Treatment of insomnia can lead to positive outcomes, not only by alleviating symptoms and moderating these comorbid disorders, but by preventing new episodes. Therefore, it is vital to be aware of the relationship between insomnia and psychiatric illness. This article reviews this relationship and provides recommendations for management. PMID- 29707425 TI - Psychosis in a Child with Atypical Autism: A Case Report and a Brief Review of the Association of Psychosis and Autism. AB - Recent studies have shown that individuals with an autism spectrum disorder (ASD) are at an increased risk of developing psychosis. Diagnosing psychosis in such individuals can be challenging when they present with symptoms at a young age. A careful history and thorough assessment are essential for proper diagnosis to avoid mislabeling certain behavioral problems encountered among children with ASD. We present the case of a 12-year-old child with atypical autism who developed psychotic symptoms that led to a diagnostic dilemma. Proper exploration of early childhood history, prompt treatment with an antipsychotic medication, and social skill training led to resolution of psychotic symptoms and improvement in disruptive symptoms of autism. PMID- 29707426 TI - Is Electroconvulsive Therapy a Treatment for Depression Following Traumatic Brain Injury? AB - Traumatic brain injury (TBI) can be caused by blunt or penetrating injury to the head. The pathophysiological evolution of TBI involves complex biochemical and genetic changes. Common sequelae of TBI include seizures and psychiatric disorders, particularly depression. In considering pharmacologic interventions for treating post-TBI depression, it is important to remember that TBI patients have a higher risk of seizures; therefore, the benefits of prescribing medications that lower the seizure threshold need to be weighed against the risk of seizures. When post-TBI depression is refractory to pharmacotherapy, electroconvulsive therapy (ECT) could provide an alternative therapeutic strategy. Data remain sparse on using ECT in this seizure-prone population, but three case reports demonstrated good outcomes. Currently, not enough evidence exists to provide clinical recommendations for using ECT for treating post-TBI depression, and more research is needed to generate guidelines on how best to treat depression in TBI patients. However, the preliminary data on using ECT in patients with TBI are promising. If proven safe, ECT could be a powerful tool to treat post-TBI depression. PMID- 29707427 TI - Task Related Cerebral Blood Flow Changes of Patients with Chronic Fatigue Syndrome: An Arterial Spin Labeling Study. AB - Purpose: One hallmark of chronic fatigue syndrome (ME/CFS) is task related worsening of fatigue. Global brain hypoperfusion, abnormal regional activation, and altered functional connectivity of brain areas associated with cognition and memory have been reported but remain controversial. Methods: We enrolled 17 female participants fulfilling the CDC Criteria for ME/CFS and 16 matched healthy controls (HC). Using a 3T-Phillips Achieva MRI-scanner, pseudo-continuous arterial spin-labeling (pCASL), was used to study the dynamics of regional cerebral blood flow (rCBF) and their relationship to mental fatigue in ME/CFS patients and HC during a demanding cognitive task, i.e. modified Paced-Auditory Serial-Addition-Testing (PASAT). Results: ME/CFS subjects reported more fatigue than HC at baseline (p < .01). Global brain perfusion of ME/CFS and HC subjects was similar at rest. The PASAT resulted in significantly increased fatigue in ME/CFS participants and HC. Although not different between groups, overall CBF significantly increased over the first 3 min of the PASAT and then decreased thereafter. Regional CBF (rCBF) changes were significantly different between groups during the post-task recovery period. Whereas improvement of fatigue of ME/CFS subjects was associated with decreased rCBF in both superior temporal gyri (STG), precuneus, and fusiform gyrus, it was associated with increased rCBF in the same areas in HC. Conclusions: Our results suggest that ME/CFS is associated with normal global CBF at rest and during a strenuous task (PASAT); however rCBF of several brain regions associated with memory, goal-oriented attention, and visual function was differentially associated with recovery from fatigue in ME/CFS patients and HC. PMID- 29707429 TI - Reconciling the conservation of the purple swamphen (Porphyrio porphyrio) and its damage in Mediterranean rice fields through sustainable non-lethal techniques. AB - Resolving human-wildlife conflicts requires the assessment and implementation of appropriate technical measures that minimize negative impacts on socio-economic uses, including agriculture, and ensure the adequate protection of biological diversity. Rice paddies are widely distributed in the western Mediterranean region. Because of their high productivity, they can be a good habitat for waterbirds, including the purple swamphen Porphyrio porphyrio, particularly in areas where natural wetlands have been removed or reduced. As a result of its population growth, there have been increasing levels of damage caused by this species in rice fields due to stem-cutting and opening of bald patches in rice fields. With the aim of reducing damage, we evaluated the effectiveness of passive and active measures that would limit access to rice fields and deter/scare away purple swamphens in affected areas of the Ebro Delta (NE Spain). We selected the techniques according to the growth phase of rice and the activity of birds in the rice fields (perimeter fences and clearing vegetation around the rice plots during sprouting and growing phases, and falconry at maturation). There were positive results during the sprouting and growing phases thanks to fences and clearing vegetation, reducing the affected area by 37.8% between treatment and control plots. This would mean an economic savings of 18,550 ?/year in compensation payments by regional administrations including the investment in implementing and maintaining passive protection measures. Active deterrence through falconry did not reduce the level of damage. The analysis of purple swamphen home range, activity centers (centroids), and the proportion of locations in and outside of rice fields showed no differences before and after dissuasive practices. These results were influenced by multiple concurrent factors including weather, the structural configuration of the rice plots and their location. In summary, we recommend the establishment of protection measures (perimeter fences + clearing vegetation around the rice plots) to reduce the level of damage. PMID- 29707428 TI - RNAi-mediated knockdown of MTNR1B without disrupting the effects of melatonin on apoptosis and cell cycle in bovine granulose cells. AB - Melatonin is well known as a powerful free radical scavenger and exhibits the ability to prevent cell apoptosis. In the present study, we investigated the role of melatonin and its receptor MTNR1B in regulating the function of bovine granulosa cells (GCs) and hypothesized the involvement of MTNR1B in mediating the effect of melatonin on GCs. Our results showed that MTNR1B knockdown significantly promoted GCs apoptosis but did not affect the cell cycle. These results were further verified by increasing the expression of pro-apoptosis genes (BAX and CASP3), decreasing expression of the anti-apoptosis genes (BCL2 and BCL XL) and anti-oxidant genes (SOD1 and GPX4) without affecting cell cycle factors (CCND1, CCNE1 and CDKN1A) and TP53. In addition, MTNR1B knockdown did not disrupt the effects of melatonin in suppressing the GCs apoptosis or blocking the cell cycle. Moreover, MTNR1B knockdown did not affect the role of melatonin in increasing BCL2, BCL-XL, and CDKN1A expression, or decreasing BAX, CASP3, TP53, CCND1 and CCNE1 expression. The expression of MTNR1A was upregulated after MTNR1B knockdown, and melatonin promoted MTNR1A expression with or without MTNR1B knockdown. However, despite melatonin supplementation, the expression of SOD1 and GPX4 was still suppressed after MTNR1B knockdown. In conclusion, these findings indicate that melatonin and MTNR1B are involved in BCL2 family and CASP3 dependent apoptotic pathways in bovine GCs. MTNR1A and MTNR1B may coordinate the work of medicating the appropriate melatonin responses to GCs. PMID- 29707430 TI - Genetic divergence and fine scale population structure of the common bottlenose dolphin (Tursiops truncatus, Montagu) found in the Gulf of Guayaquil, Ecuador. AB - The common bottlenose dolphin, Tursiops truncatus, is widely distributed along the western coast of South America. In Ecuador, a resident population of bottlenose dolphins inhabits the inner estuarine area of the Gulf of Guayaquil located in the southwestern part of the country and is under threat from different human activities in the area. Only one genetic study on South American common bottlenose dolphins has been carried out to date, and understanding genetic variation of wildlife populations, especially species that are identified as threatened, is crucial for defining conservation units and developing appropriate conservation strategies. In order to evaluate the evolutionary link of this population, we assessed the phylogenetic relationships, phylogeographic patterns, and population structure using mitochondrial DNA (mtDNA). The sampling comprised: (i) 31 skin samples collected from free-ranging dolphins at three locations in the Gulf of Guayaquil inner estuary, (ii) 38 samples from stranded dolphins available at the collection of the "Museo de Ballenas de Salinas," (iii) 549 mtDNA control region (mtDNA CR) sequences from GenBank, and (iv) 66 concatenated sequences from 7-mtDNA regions (12S rRNA, 16S rRNA, NADH dehydrogenase subunit I-II, cytochrome oxidase I and II, cytochrome b, and CR) obtained from mitogenomes available in GenBank. Our analyses indicated population structure between both inner and outer estuary dolphin populations as well as with distinct populations of T. truncatus using mtDNA CR. Moreover, the inner estuary bottlenose dolphin (estuarine bottlenose dolphin) population exhibited lower levels of genetic diversity than the outer estuary dolphin population according to the mtDNA CR. Finally, the estuarine bottlenose dolphin population was genetically distinct from other T. truncatus populations based on mtDNA CR and 7-mtDNA regions. From these results, we suggest that the estuarine bottlenose dolphin population should be considered a distinct lineage. This dolphin population faces a variety of anthropogenic threats in this area; thus, we highlight its fragility and urge authorities to issue prompt management and conservation measures. PMID- 29707431 TI - A public dataset of overground and treadmill walking kinematics and kinetics in healthy individuals. AB - In a typical clinical gait analysis, the gait patterns of pathological individuals are commonly compared with the typically faster, comfortable pace of healthy subjects. However, due to potential bias related to gait speed, this comparison may not be valid. Publicly available gait datasets have failed to address this issue. Therefore, the goal of this study was to present a publicly available dataset of 42 healthy volunteers (24 young adults and 18 older adults) who walked both overground and on a treadmill at a range of gait speeds. Their lower-extremity and pelvis kinematics were measured using a three-dimensional (3D) motion-capture system. The external forces during both overground and treadmill walking were collected using force plates and an instrumented treadmill, respectively. The results include both raw and processed kinematic and kinetic data in different file formats: c3d and ASCII files. In addition, a metadata file is provided that contain demographic and anthropometric data and data related to each file in the dataset. All data are available at Figshare (DOI: 10.6084/m9.figshare.5722711). We foresee several applications of this public dataset, including to examine the influences of speed, age, and environment (overground vs. treadmill) on gait biomechanics, to meet educational needs, and, with the inclusion of additional participants, to use as a normative dataset. PMID- 29707432 TI - Shifting reef fish assemblages along a depth gradient in Pohnpei, Micronesia. AB - Mesophotic coral ecosystems (MCEs) continue to be understudied, especially in island locations spread across the Indo-Pacific Ocean. Pohnpei is the largest island in the Federated States of Micronesia, with a well-developed barrier reef, and steep slopes that descend to more than 1,000 m. Here we conducted visual surveys along a depth gradient of 0 to 60 m in addition to video surveys that extend to 130 m, with 72 belt transects and 12 roving surveys using closed circuit rebreathers, to test for changes in reef fish composition from shallow to mesophotic depths. We observed 304 fish species across 47 families with the majority confined to shallow habitat. Taxonomic and trophic positions at 30 m showed similar compositions when compared against all other depths. However, assemblages were comprised of a distinct shallow (<30 m) and deep (>30 m) group, suggesting 30 m as a transition zone between these communities. Shallow specialists had a high probability of being herbivores and deep specialists had a higher probability of being planktivores. Acanthuridae (surgeonfishes), Holocentridae (soldierfishes), and Labridae (wrasses) were associated primarily with shallow habitat, while Pomacentridae (damselfishes) and Serranidae (groupers) were associated with deep habitat. Four species may indicate Central Pacific mesophotic habitat: Chromis circumaurea, Luzonichthys seaver, Odontanthias borbonius, and an undescribed slopefish (Symphysanodon sp.). This study supports the 30 m depth profile as a transition zone between shallow and mesophotic ecosystems (consistent with accepted definitions of MCEs), with evidence of multiple transition zones below 30 m. Disturbances restricted to either region are not likely to immediately impact the other and both ecosystems should be considered separately in management of reefs near human population centers. PMID- 29707433 TI - A robust method for RNA extraction and purification from a single adult mouse tendon. AB - Background: Mechanistic understanding of tendon molecular and cellular biology is crucial toward furthering our abilities to design new therapies for tendon and ligament injuries and disease. Recent transcriptomic and epigenomic studies in the field have harnessed the power of mouse genetics to reveal new insights into tendon biology. However, many mouse studies pool tendon tissues or use amplification methods to perform RNA analysis, which can significantly increase the experimental costs and limit the ability to detect changes in expression of low copy transcripts. Methods: Single Achilles tendons were harvested from uninjured, contralateral injured, and wild type mice between three and five months of age, and RNA was extracted. RNA Integrity Number (RIN) and concentration were determined, and RT-qPCR gene expression analysis was performed. Results: After testing several RNA extraction approaches on single adult mouse Achilles tendons, we developed a protocol that was successful at obtaining high RIN and sufficient concentrations suitable for RNA analysis. We found that the RNA quality was sensitive to the time between tendon harvest and homogenization, and the RNA quality and concentration was dependent on the duration of homogenization. Using this method, we demonstrate that analysis of Scx gene expression in single mouse tendons reduces the biological variation caused by pooling tendons from multiple mice. We also show successful use of this approach to analyze Sox9 and Col1a2 gene expression changes in injured compared with uninjured control tendons. Discussion: Our work presents a robust, cost effective, and straightforward method to extract high quality RNA from a single adult mouse Achilles tendon at sufficient amounts for RT-qPCR as well as RNA-seq. We show this can reduce variation and decrease the overall costs associated with experiments. This approach can also be applied to other skeletal tissues, as well as precious human samples. PMID- 29707434 TI - Association between vitamin D concentrations and knee pain in patients with osteoarthritis. AB - Objectives: Osteoarthritis (OA) and vitamin D deficiency are common health conditions in older people. Whether vitamin D concentration is associated with knee OA is controversial. In this study, we aimed to determine the association between serum concentrations of vitamin D and osteoarthritic knee pain. Subjects and Methods: Vitamin D concentrations were measured with the 25 hydroxyvitamin D test in patients presenting with clinical symptoms of primary knee osteoarthritis. Osteoarthritis was graded on the Kellgren-Lawrence grading scale from anteroposterior and lateral radiographs. Height, weight, and body mass index (BMI) were recorded. Patients completed a 10-cm visual analogue scale (VAS) for indicating pain and the Western Ontario and McMaster Universities Arthritis Index (WOMAC). Vitamin D concentration was defined as severely deficient (<10 ng/mL), insufficient (10 to 19 ng/mL), or normal (20 to 50 ng/mL). Results: Of 149 patients (133 women), the mean age was 63.6 years. Mean vitamin D concentration was 11.53 ng/mL, and 90% patients were vitamin D deficient. Mean WOMAC score was 57.2, and VAS pain score was 7.5. Kellgren-Lawrence grade was 2 for 10 patients, grade 3 for 61, and grade 4 for 88. Mean BMI was 33.4. Mean values of VAS, WOMAC, and BMI did not differ by vitamin D status. Conclusion: Serum vitamin D concentration is not associated with knee pain in patients with osteoarthritis. PMID- 29707435 TI - Genome comparison implies the role of Wsm2 in membrane trafficking and protein degradation. AB - Wheat streak mosaic virus (WSMV) causes streak mosaic disease in wheat (Triticum aestivum L.) and has been an important constraint limiting wheat production in many regions around the world. Wsm2 is the only resistance gene discovered in wheat genome and has been located in a short genomic region of its chromosome 3B. However, the sequence nature and the biological function of Wsm2 remain unknown due to the difficulty of genetic manipulation in wheat. In this study, we tested WSMV infectivity among wheat and its two closely related grass species, rice (Oryza sativa) and Brachypodium distachyon. Based on the phenotypic result and previous genomic studies, we developed a novel bioinformatics pipeline for interpreting a potential biological function of Wsm2 and its ancestor locus in wheat. In the WSMV resistance tests, we found that rice has a WMSV resistance gene while Brachypodium does not, which allowed us to hypothesize the presence of a Wsm2 ortholog in rice. Our OrthoMCL analysis of protein coding genes on wheat chromosome 3B and its syntenic chromosomes in rice and Brachypodium discovered 4,035 OrthoMCL groups as preliminary candidates of Wsm2 orthologs. Given that Wsm2 is likely duplicated through an intrachromosomal illegitimate recombination and that Wsm2 is dominant, we inferred that this new WSMV-resistance gene acquired an activation domain, lost an inhibition domain, or gained high expression compared to its ancestor locus. Through comparison, we identified that 67, 16, and 10 out of 4,035 OrthoMCL orthologous groups contain a rice member with 25% shorter or longer in length, or 10 fold more expression, respectively, than those from wheat and Brachypodium. Taken together, we predicted a total of 93 good candidates for a Wsm2 ancestor locus. All of these 93 candidates are not tightly linked with Wsm2, indicative of the role of illegitimate recombination in the birth of Wsm2. Further sequence analysis suggests that the protein products of Wsm2 may combat WSMV disease through a molecular mechanism involving protein degradation and/or membrane trafficking. The 93 putative Wsm2 ancestor loci discovered in this study could serve as good candidates for future genetic isolation of the true Wsm2 locus. PMID- 29707437 TI - Expression and characterization of a potential exopolysaccharide from a newly isolated halophilic thermotolerant bacteria Halomonas nitroreducens strain WB1. AB - The halophilic bacterial strain WB1 isolated from a hydrothermal vent was taxonomically characterized using multiple proxies, as Halomonas nitroreducens strain WB1. When grown on malt extract/yeast extract (MY) medium, it produced large quantities of exopolysaccharide (EPS). The polymer was synthesized at a higher rate during the log and early stationary phases. The anionic polysaccharide is primarily composed of glucose, mannose, and galactose. The studied EPS was highly viscous and had pseudoplastic nature. The EPS was found to be a mixture of three polysaccharides under FT-IR, which makes it less labile to environmental diagenesis. It also has emulsifying and antioxidant activity along with the binding capacity to heavy metals. The EPS has unique and interesting physical and chemical properties, which are different from earlier reported exo polysaccharides produced by different bacterial genus. This suggests that the extreme geological niches like hypersaline, hyperthermal, hypothermal, and oligophilic environments, which are not well studied so far, can offer extensive and potential resources for medical, biotechnological and industrial applications. The study clearly showed that the thermal springs from the temperate region can be a potent source of many such industrially important microbial genera and need further detailed studies to be carried out. PMID- 29707436 TI - Strain-level genetic diversity of Methylophaga nitratireducenticrescens confers plasticity to denitrification capacity in a methylotrophic marine denitrifying biofilm. AB - Background: The biofilm of a methanol-fed, fluidized denitrification system treating a marine effluent is composed of multi-species microorganisms, among which Hyphomicrobium nitrativorans NL23 and Methylophaga nitratireducenticrescens JAM1 are the principal bacteria involved in the denitrifying activities. Strain NL23 can carry complete nitrate (NO[Formula: see text]) reduction to N2, whereas strain JAM1 can perform 3 out of the 4 reduction steps. A small proportion of other denitrifiers exists in the biofilm, suggesting the potential plasticity of the biofilm in adapting to environmental changes. Here, we report the acclimation of the denitrifying biofilm from continuous operating mode to batch operating mode, and the isolation and characterization from the acclimated biofilm of a new denitrifying bacterial strain, named GP59. Methods: The denitrifying biofilm was batch-cultured under anoxic conditions. The acclimated biofilm was plated on Methylophaga specific medium to isolate denitrifying Methylophaga isolates. Planktonic cultures of strains GP59 and JAM1 were performed, and the growth and the dynamics of NO[Formula: see text], nitrite (NO[Formula: see text]) and N2O were determined. The genomes of strains GP59 and JAM1 were sequenced and compared. The transcriptomes of strains GP59 and JAM1 were derived from anoxic cultures. Results: During batch cultures of the biofilm, we observed the disappearance of H. nitrativorans NL23 without affecting the denitrification performance. From the acclimated biofilm, we isolated strain GP59 that can perform, like H. nitrativorans NL23, the complete denitrification pathway. The GP59 cell concentration in the acclimated biofilm was 2-3 orders of magnitude higher than M. nitratireducenticrescens JAM1 and H. nitrativorans NL23. Genome analyses revealed that strain GP59 belongs to the species M. nitratireducenticrescens. The GP59 genome shares more than 85% of its coding sequences with those of strain JAM1. Based on transcriptomic analyses of anoxic cultures, most of these common genes in strain GP59 were expressed at similar level than their counterparts in strain JAM1. In contrast to strain JAM1, strain GP59 cannot reduce NO[Formula: see text] under oxic culture conditions, and has a 24-h lag time before growth and NO[Formula: see text] reduction start to occur in anoxic cultures, suggesting that both strains regulate differently the expression of their denitrification genes. Strain GP59 has the ability to reduce NO[Formula: see text] as it carries a gene encoding a NirK-type NO[Formula: see text] reductase. Based on the CRISPR sequences, strain GP59 did not emerge from strain JAM1 during the biofilm batch cultures but rather was present in the original biofilm and was enriched during this process. Discussion: These results reinforce the unique trait of the species M. nitratireducenticrescens among the Methylophaga genus as facultative anaerobic bacterium. These findings also showed the plasticity of denitrifying population of the biofilm in adapting to anoxic marine environments of the bioreactor. PMID- 29707439 TI - The Low DIEP Flap for Breast Reconstruction. AB - Supplemental Digital Content is available in the text. PMID- 29707438 TI - Geologic and anthropogenic sources of contamination in settled dust of a historic mining port city in northern Chile: health risk implications. AB - Chile is the leading producer of copper worldwide and its richest mineral deposits are found in the Antofagasta Region of northern Chile. Mining activities have significantly increased income and employment in the region; however, there has been little assessment of the resulting environmental impacts to residents. The port of Antofagasta, located 1,430 km north of Santiago, the capital of Chile, functioned as mineral stockpile until 1998 and has served as a copper concentrate stockpile since 2014. Samples were collected in 2014 and 2016 that show elevated concentrations of As, Cu, Pb, and Zn in street dust and in residents' blood (Pb) and urine (As) samples. To interpret and analyze the spatial variability and likely sources of contamination, existent data of basement rocks and soil geochemistry in the city as well as public-domain airborne dust were studied. Additionally, a bioaccessibility assay of airborne dust was conducted and the chemical daily intake and hazard index were calculated to provide a preliminary health risk assessment in the vicinity of the port. The main conclusions indicate that the concentrations of Ba, Co, Cr, Mn, Ni, and V recorded from Antofagasta dust likely originate from intrusive, volcanic, metamorphic rocks, dikes, or soil within the city. However, the elevated concentrations of As, Cd, Cu, Mo, Pb, and Zn do not originate from these geologic outcrops, and are thus considered anthropogenic contaminants. The average concentrations of As, Cu, and Zn are possibly the highest in recorded street dust worldwide at 239, 10,821, and 11,869 mg kg-1, respectively. Furthermore, the contaminants As, Pb, and Cu exhibit the highest bioaccessibilities and preliminary health risk indices show that As and Cu contribute to elevated health risks in exposed children and adults chronically exposed to dust in Antofagasta, whereas Pb is considered harmful at any concentration. Therefore, an increased environmental awareness and greater protective measures are necessary in Antofagasta and possibly other similar mining port cities in developing countries. PMID- 29707440 TI - Assessment of Functional Rhinoplasty with Spreader Grafting Using Acoustic Rhinomanometry and Validated Outcome Measurements. AB - Background: Rhinoplasty is 1 of the most common aesthetic and reconstructive plastic surgical procedures performed within the United States. Yet, data on functional reconstructive open and closed rhinoplasty procedures with or without spreader graft placement are not definitive as only a few studies have examined both validated measurable objective and subjective outcomes of spreader grafting during rhinoplasty. The aim of this study was to utilize previously validated measures to assess objective, functional outcomes in patients who underwent open and closed rhinoplasty with spreader grafting. Methods: We performed a retrospective review of consecutive rhinoplasty patients. Patients with internal nasal valve insufficiency who underwent an open and closed approach rhinoplasty between 2007 and 2016 were studied. The Cottle test and Nasal Obstruction Symptom Evaluation survey was used to assess nasal obstruction. Patient-reported symptoms were recorded. Acoustic rhinometry was performed pre- and postoperatively. Average minimal cross-sectional area of the nose was measured. Results: One hundred seventy-eight patients were reviewed over a period of 8 years. Thirty eight patients were included in this study. Of those, 30 patients underwent closed rhinoplasty and 8 open rhinoplasty. Mean age was 36.9 +/- 18.4 years. The average cross-sectional area in closed and open rhinoplasty patients increased significantly (P = 0.019). There was a functional improvement in all presented cases using the Nasal Obstruction Symptom Evaluation scale evaluation. Conclusions: Closed rhinoplasty with spreader grafting may play a significant role in the treatment of nasal valve collapse. A closed approach rhinoplasty including spreader grafting is a viable option in select cases with objective and validated functional improvement. PMID- 29707441 TI - Genetic Requirement of talin1 for Proliferation of Cranial Neural Crest Cells during Palate Development. AB - Background: Craniofacial malformations are among the most common congenital anomalies. Cranial neural crest cells (CNCCs) form craniofacial structures involving multiple cellular processes, perturbations of which contribute to craniofacial malformations. Adhesion of cells to the extracellular matrix mediates bidirectional interactions of the cells with their extracellular environment that plays an important role in craniofacial morphogenesis. Talin (tln) is crucial in cell-matrix adhesion between cells, but its role in craniofacial morphogenesis is poorly understood. Methods: Talin gene expression was determined by whole mount in situ hybridization. Craniofacial cartilage and muscles were analyzed by Alcian blue in Tg(mylz2:mCherry) and by transmission electron microscopy. Pulse-chase photoconversion, 5-ethynyl-2'-deoxyuridine proliferation, migration, and apoptosis assays were performed for functional analysis. Results: Expression of tln1 was observed in the craniofacial cartilage structures, including the palate. The Meckel's cartilage was hypoplastic, the palate was shortened, and the craniofacial muscles were malformed in tln1 mutants. Pulse-chase and EdU assays during palate morphogenesis revealed defects in CNCC proliferation in mutants. No defects were observed in CNCC migration and apoptosis. Conclusions: The work shows that tln1 is critical for craniofacial morphogenesis in zebrafish. Loss of tln1 leads to a shortened palate and Meckel's cartilage along with disorganized skeletal muscles. Investigations into the cellular processes show that tln1 is required for CNCC proliferation during palate morphogenesis. The work will lead to a better understanding of the involvement of cytoskeletal proteins in craniofacial morphogenesis. PMID- 29707442 TI - The Functional Impact of Breast Reconstruction: An Overview and Update. AB - As rates of bilateral mastectomy and immediate reconstruction rise, the aesthetic and psychosocial benefits of breast reconstruction are increasingly well understood. However, an understanding of functional outcome and its optimization is still lacking. This endpoint is critical to maximizing postoperative quality of life. All reconstructive modalities have possible functional consequences. Studies demonstrate that implant-based reconstruction impacts subjective movement, but patients' day-to-day function may not be objectively hindered despite self-reported disability. For latissimus dorsi flap reconstruction, patients also report some dysfunction at the donor site, but this does not seem to result in significant, long-lasting limitation of daily activity. Athletic and other vigorous activities are most affected. For abdominal free flaps, patient perception of postoperative disability is generally not significant, despite the varying degrees of objective disadvantage that have been identified depending on the extent of rectus muscle sacrifice. With these functional repercussions in mind, a broader perspective on the attempt to ensure minimal functional decline after breast surgery should focus not only on surgical technique but also on postoperative rehabilitation. Early directed physical therapy may be an instrumental element in facilitating return to baseline function. With the patient's optimal quality of life as an overarching objective, a multifaceted approach to functional preservation may be the answer to this continued challenge. This review will examine these issues in depth in an effort to better understand postoperative functional outcomes with a focus on the younger, active breast reconstruction patient. PMID- 29707443 TI - The National Surgical Quality Improvement Program 30-Day Challenge: Microsurgical Breast Reconstruction Outcomes Reporting Reliability. AB - Background: The aim was to assess reliability of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) 30-day perioperative outcomes and complications for immediate, free-tissue transfer breast reconstruction by direct comparisons with our 30-day and overall institutional data, and assessing those that occur after 30 days. Methods: Data were retrieved for consecutive immediate, free-tissue transfer breast reconstruction patients from a single-institution database (2010-2015) and the ACS-NSQIP (2011-2014). Multiple logistic regressions were performed to compare adjusted outcomes between the 2 datasets. Results: For institutional versus ACS-NSQIP outcomes, there were no significant differences in surgical-site infection (SSI; 30-day, 3.6% versus 4.1%, P = 0.818; overall, 5.3% versus 4.1%, P = 0.198), wound disruption (WD; 30 day, 1.3% versus 1.5%, P = 0.526; overall, 2.3% versus 1.5%, P = 0.560), or unplanned readmission (URA; 30-day, 2.3% versus 3.3%, P = 0.714; overall, 4.6% versus 3.3%, P = 0.061). However, the ACS-NSQIP reported a significantly higher unplanned reoperation (URO) rate (30-day, 3.6% versus 9.5%, P < 0.001; overall, 5.3% versus 9.5%, P = 0.025). Institutional complications consisted of 5.3% SSI, 2.3% WD, 5.3% URO, and 4.6% URA, of which 25.0% SSI, 28.6% WD, 12.5% URO, and 7.1% URA occurred at 30-60 days, and 6.3% SSI, 14.3% WD, 18.8% URO, and 42.9% URA occurred after 60 days. Conclusion: For immediate, free-tissue breast reconstruction, the ACS-NSQIP may be reliable for monitoring and comparing SSI, WD, URO, and URA rates. However, clinicians may find it useful to understand limitations of the ACS-NSQIP for complications and risk factors, as it may underreport complications occurring beyond 30 days. PMID- 29707444 TI - Applications of Computer Technology in Complex Craniofacial Reconstruction. AB - Background: To demonstrate our use of advanced 3-dimensional (3D) computer technology in the analysis, virtual surgical planning (VSP), 3D modeling (3DM), and treatment of complex congenital and acquired craniofacial deformities. Methods: We present a series of craniofacial defects treated at a tertiary craniofacial referral center utilizing state-of-the-art 3D computer technology. All patients treated at our center using computer-assisted VSP, prefabricated custom-designed 3DMs, and/or 3D printed custom implants (3DPCI) in the reconstruction of craniofacial defects were included in this analysis. Results: We describe the use of 3D computer technology to precisely analyze, plan, and reconstruct 31 craniofacial deformities/syndromes caused by: Pierre-Robin (7), Treacher Collins (5), Apert's (2), Pfeiffer (2), Crouzon (1) Syndromes, craniosynostosis (6), hemifacial microsomia (2), micrognathia (2), multiple facial clefts (1), and trauma (3). In select cases where the available bone was insufficient for skeletal reconstruction, 3DPCIs were fabricated using 3D printing. We used VSP in 30, 3DMs in all 31, distraction osteogenesis in 16, and 3DPCIs in 13 cases. Utilizing these technologies, the above complex craniofacial defects were corrected without significant complications and with excellent aesthetic results. Conclusion: Modern 3D technology allows the surgeon to better analyze complex craniofacial deformities, precisely plan surgical correction with computer simulation of results, customize osteotomies, plan distractions, and print 3DPCI, as needed. The use of advanced 3D computer technology can be applied safely and potentially improve aesthetic and functional outcomes after complex craniofacial reconstruction. These techniques warrant further study and may be reproducible in various centers of care. PMID- 29707445 TI - Treatment of Painful Nerves in the Abdominal Wall Using Processed Nerve Allografts. AB - Neuromas can be a debilitating cause of pain and often negatively affect patients' quality of life. One effective method of treatment involves surgical resection of the painful neuroma and use of a processed nerve allograft to repair the injured nerve segment. Giving the nerve "somewhere to go and something to do" has been shown to effectively alleviate pain in upper and lower extremities. We present the first report of this concept to treat a painful neuroma of the abdominal wall that developed following a laparoscopic gastric bypass. The neuroma was excised, and the affected nerve was reconstructed using a processed nerve allograft as an interposition graft, with resolution of pain and gradual return of normal sensation. Patient-reported outcomes were measured using the Patient Reported Outcomes Measurement Information System. Neuroma excision with concurrent interposition grafting using processed nerve allografts may be a promising method of treatment for postsurgical painful neuromas of the trunk. PMID- 29707446 TI - Pyoderma Gangrenosum Secondary to Severe Congenital Neutropenia. AB - We encountered a case of a man who was diagnosed with severe congenital neutropenia as a child and presented at the age of 45 years with pyoderma gangrenosum (PG) of the lower leg. PG associates with an underlying systemic disease, most commonly inflammatory bowel, rheumatic, or hematological disease or malignancy. However, in many cases, the underlying disease was not known. Surgery can trigger PG. The histopathological features of PG were nonspecific, and diagnosis requires excluding other conditions that have a similar appearance. Our analyses showed that the PG in our case was secondary to severe congenital neutropenia, which had promoted an infection of keratinous cysts. The patient bore a mutation in the ELANE gene encoding neutrophil elastase. Only 1 other case of neutropenia-associated PG has been reported previously: the association was only suspected. The present complex case was effectively treated by systemic treatment of the neutropenia with granulocyte colony-stimulating factor and regional surgical treatment. Histology of the excised tissue revealed keratinous cysts that were diffusely distributed with inflammatory granulation tissue. We believe that the rupture of the walls of the keratinous cysts may have caused the PG. At the time of writing (3 years since the initial presentation), the PG has not recurred. This case shows the importance of performing detailed examinations, including blood tests, to determine the disease underlying PG. This was because if the underlying disease was identified, its treatment was likely to promote healing of the wound after local surgery and prevent recurrence. PMID- 29707447 TI - Debride and See: Use of Uterine Curette for Wound Bed Debridement before Skin Grafting. AB - Supplemental Digital Content is available in the text. PMID- 29707448 TI - Eliminating Preoperative Lymphoscintigraphy in Extremity Melanomas. AB - Background: Preoperative lymphoscintigraphy (LSG) is an imaging procedure routinely used to identify the draining nodal basin in melanomas. At our institute, we have traditionally performed preoperative LSG followed by intraoperative LSG for logistical and evaluative reasons. We sought to determine if preoperative LSG could be safely eliminated in the treatment of extremity melanomas, which exhibit consistent and predictable lymphatic drainage patterns. Methods: We reviewed the Yale Melanoma Registry 1308012545 for cutaneous extremity melanomas treated at our institution. From this registry, we calculated the incidence of atypical lymph node drainage patterns outside the axillary and inguinal regions. Based on these data, we eliminated preoperative LSG in 21 cases (8 upper extremities and 13 lower extremities). Additionally, we calculated the potential hospital charge reduction of forgoing preoperative LSG. Results: Upper and lower extremity melanomas treated at our institution exhibited atypical lymph node drainage at a rate of 3.4% and 2.0%, respectively. The sites of atypical drainage were to the epitrochlear and popliteal regions. In all 21 cases where preoperative LSG was eliminated, we were able to correctly identify the sentinel lymph node. The potential hospital charge reduction of forgoing preoperative LSG totaled $2,393. Conclusions: Preoperative LSG can be safely eliminated in the management of upper and lower extremity melanomas. Exceptions may be considered for primary lesions of the posterior calf, ankle, and heel as well as for patients with history of prior surgery or radiation. Forgoing preoperative LSG results in a hospital charge reduction of $2,393 and provides additional benefits to the patient. Ultimately, there is potential for significant charge reduction if applied across health care systems. PMID- 29707449 TI - Cleft Palate Fistula Closure Utilizing Acellular Dermal Matrix. AB - Fistulas represent failure of cleft palate repair. Secondary and tertiary fistula repair is challenging, with high recurrence rates. In the present retrospective study, we review the efficacy of using acellular dermal matrix as an interposition layer for cleft palate fistula closure in 20 consecutive patients between 2013 and 2016. Complete fistula closure was obtained in 16 patients; 1 patient had asymptomatic recurrent fistula; 2 patients had partial closure with reduction of fistula size and minimal nasal regurgitation; 1 patient developed a recurrent fistula without changes in symptoms (success rate of 85%). We conclude that utilizing acellular dermal matrix for cleft palate fistula repair is safe and simple with a high success rate. PMID- 29707450 TI - Development of "Core Syllabus" for Facial Anatomy Teaching to Aesthetic Physicians: A Delphi Consensus. AB - Background: A detailed understanding of facial anatomy, specifically the vascular framework, is crucial for delivering safe nonsurgical aesthetic procedures. To date, there is no core document based on consensus for the teaching of facial anatomy to aesthetic physicians exists. The aim of this study was to ascertain the most critical anatomical structures for avoiding disastrous complications during nonsurgical aesthetic procedures. Methods: After a detailed literature review, Delphi questionnaire was developed listing 154 anatomical structures of the face and neck for consensus review. Thirty-five international experts in surgical and nonsurgical facial aesthetics were invited to complete an online survey designed to rank the relevance of each anatomical element on a Likert scale from 1 (not at all important) to 4 (very important) or 5 (no opinion). Consensus for items included in the core syllabus was predefined as achieving a Cronbach's alpha >= 0.90 and an agreement score of >= 80%. Results: Thirty-four international experts (97.14%) completed the iterative online Delphi survey. The consensus among the specialists polled was achieved after 1 round of the survey (Cronbach's alpha = 0.94). The expert panel reached an agreement score of >= 80% on 137 of the 154 anatomical structures listed. Conclusion: The outcome of this Delphi study represents an essential first step in systematizing an evidence based facial anatomy "Core Syllabus" for the teaching of aesthetic physicians and practitioners. This "Core Syllabus" will act as a blueprint for the educators while crafting a program. PMID- 29707451 TI - Accurate Prediction of Submental Lymph Nodes Using Magnetic Resonance Imaging for Lymphedema Surgery. AB - Background: Submental lymph node transfer has proved to be an effective approach for the treatment of lymphedema. This study was to investigate the anatomy and distribution of vascularized submental lymph node (VSLN) flap using magnetic resonance imaging (MRI) and their clinical outcome. Methods: Fifteen patients who underwent 19 VSLN flap transfers for upper or lower limb lymphedema were retrospectively analyzed. The number of submental lymph nodes was compared among preoperative MRI, preoperative sonography, intraoperative finding, postoperative sonography, and postoperative computed tomography angiography. The outcome was compared between preoperatively and postoperatively. Results: All 19 VSLN flaps survived. Two hundred fifteen lymph nodes were identified in 30 submandibular regions by MRI. The mean number of submental lymph nodes on preoperative MRI was 7.2 +/- 2.4, on preoperative sonography was 3.2 +/- 1.1, on intraoperative finding was 3.1 +/- 0.6, postoperative sonography was 4.6 +/- 1.8, and postoperative CTA was 5.2 +/- 1.9. Sixty-one percent of the lymph nodes were located in the central two-quarters of the line drawn from the mental protuberance to the mandibular angle. The actual harvest rate of submental lymph nodes was 72.2%. At a 12-month follow-up, mean episodes of cellulitis were improved from 2.7 +/- 0.6 to 0.8 +/- 0.2 (P < 0.01); mean of circumferential difference was improved 3.2 +/- 0.4 cm (P < 0.03). The overall lymphedema quality of-life was improved 4.9 +/- 0.3 (P < 0.04). Conclusions: The preoperative MRI is a useful tool for the detection of mean 7.2 submental lymph nodes. Mean 72.2% of submental lymph nodes can be successfully transferred for extremity lymphedema with optimal functional recovery. PMID- 29707452 TI - Pedicled Descending Branch Latissimus Dorsi Mini-flap for Repairing Partial Mastectomy Defect: A New Technique. AB - Volume loss is 1 of the major factors influencing cosmetic outcomes of breast after partial mastectomy (PM), especially for smaller breasts, and therefore, volume replacement is critical for optimizing the final aesthetic outcome. We present a novel technique of raising a pedicled descending branch latissimus dorsi (LD) mini-flap for reconstruction of PM defects via an axillary incision. After PM, the LD mini-flap is harvested through the existing axillary incision of the axillary dissection or the sentinel lymph node biopsy. The descending branches of thoracodorsal vessels and nerve are carefully identified and isolated. The transverse branches are protected to maintain muscle innervation and function. The LD muscle is then undermined posteriorly and inferiorly to create a submuscular pocket and a subcutaneous pocket between LD muscle and superficial fascia. Once the submuscular plane is created, the muscle is divided along the muscle fibers from the deep surface including a layer of fat above the muscle. Finally, the LD mini-flap is transferred to the breast defect. Given the limited length and mobility of the LD mini-flap, this approach is best utilized for lateral breast defects. However, for medial defects, the lateral breast tissue is rearranged to reconstruct the medial breast defect, and an LD mini-flap is then used to reconstruct the lateral breast donor site. This technique can therefore be employed to reconstruct all quadrants of the breast and can provide aesthetic outcomes without scars on the back, with minimal dysfunction of LD muscle. PMID- 29707454 TI - Virtual Incision Pattern Planning using Three-Dimensional Images for Optimization of Syndactyly Surgery. AB - Syndactyly is a congenital condition characterized by fusion of the fingers. If not treated correctly during infancy, syndactyly may hinder the normal development of hand function. Many surgical techniques have been developed, with the main goal to create a functional hand with the smallest number of operative corrections. Therefore, exact preoperative planning of the reconstructive procedure is essential. An imaging method commonly used for preoperative planning is 3-dimensional (3D) surface imaging. The goal of this study was to implement the use of this technique in hand surgery, by designing a virtual planning tool for a desyndactylization procedure based on 3D hand images. A 3D image of a silicon syndactyly model was made on which the incision pattern was virtually designed. A surgical template of this pattern was printed, placed onto the silicon model and delineated. The accuracy of the transfer from the virtual delineation toward the real delineation was calculated, resulting in a mean difference of 0.82 mm. This first step indicates that by using 3D images, a virtual incision pattern can be created and transferred back onto the patient successfully in an easy and accurate way by using a template. Thereafter, 3D hand images of 3 syndactyly patients were made, and individual virtual incision patterns were created. Each pattern was transferred onto the patient by using a 3D printed template. The resulting incision pattern needed minor modifications by the surgeon before the surgery was performed. Further research and validation are necessary to develop the virtual planning of desyndactylization procedures. PMID- 29707453 TI - Management of High-energy Avulsive Ballistic Facial Injury: A Review of the Literature and Algorithmic Approach. AB - Background: High-energy avulsive ballistic facial injuries pose one of the most significant reconstructive challenges. We conducted a systematic review of the literature to evaluate management trends and outcomes for the treatment of devastating ballistic facial trauma. Furthermore, we describe the senior author's early and definitive staged reconstructive approach to these challenging patients. Methods: A Medline search was conducted to include studies that described timing of treatment, interventions, complications, and/or aesthetic outcomes. Results: Initial query revealed 41 articles, of which 17 articles met inclusion criteria. A single comparative study revealed that early versus delayed management resulted in a decreased incidence of soft-tissue contracture, required fewer total procedures, and resulted in shorter hospitalizations (level 3 evidence). Seven of the 9 studies (78%) that advocated delayed reconstruction were from the Middle East, whereas 5 of the 6 studies (83%) advocating immediate or early definitive reconstruction were from the United States. No study compared debridement timing directly in a head-to-head fashion, nor described flap selection based on defect characteristics. Conclusions: Existing literature suggests that early and aggressive intervention improves outcomes following avulsive ballistic injuries. Further comparative studies are needed; however, although evidence is limited, the senior author presents a 3-stage reconstructive algorithm advocating early and definitive reconstruction with aesthetic free tissue transfer in an attempt to optimize reconstructive outcomes of these complex injuries. PMID- 29707455 TI - Bilateral Sciatic Neuropathy following Gluteal Augmentation With Autologous Fat Grafting. AB - As gluteal augmentation continues to gain in popularity among patients seeking aesthetic enhancements, a thorough knowledge of the postoperative complications associated with this procedure is crucial. This case report concerns a 31-year old woman who suffered bilateral foot drop secondary to sciatic neuropathy and as a result was wheelchair-bound for several months, following gluteal autologous fat grafting in the Dominical Republic. One year later, the patient had persistent left foot drop and sensory deficits. This is a devastating but seldom reported complication that all plastic surgeons need to be aware of when performing this operation. PMID- 29707456 TI - Perineal Reconstruction with a Diamond-shaped Perforator Flap: A Case Report. AB - Reconstruction of perineal defects is a challenging procedure. Various surgical techniques have been proposed. Compared with traditional myocutaneous flaps, pedicled perforator flaps are believed to be a less invasive option for perineal reconstruction, with better functional and cosmetic results. We present the case of a 47-year-old woman with a perianal Paget's disease who underwent surgical excision of the lesion. The reconstructive technique was a pedicled flap based on an internal pudendal skin perforator artery. The flap was designed in a diamond shaped pattern. Six months after the operation, the patient is disease-free with successful aesthetic and functional results. A polygonal diamond-shaped flap is an easy and reliable choice for perineal reconstruction, offering better adjustment in the perianal region and avoidance of the curvilinear perianal incision (which often leads to anal stenosis). PMID- 29707457 TI - Lateral Branch of the Thoracodorsal Nerve (LaT Branch) Transfer for Biceps Reinnervation. AB - In cases of significant upper extremity trauma, the thoracodorsal nerve is a reliable secondary option for the restoration of elbow flexion. In all previous descriptions, however, the entire nerve is transferred. We describe a case utilizing the lateral thoracodorsal nerve (LaT) branch for biceps reinnervation with an associated cadaver study. Transfer of the LaT branch to the biceps branch was performed on a patient who had sustained a traumatic brachial plexus injury that left him without elbow flexion. Also, 4 cadavers (8 upper extremities) were dissected to identify the bifurcation of the thoracodorsal nerve and confirm the feasibility of transferring the LaT branch to the biceps motor branch. Axon counts of the thoracodorsal proper, LaT branch, musculocutaneous proper, and the biceps branch were also obtained. A bifurcation of the thoracodorsal nerve was present in all cadaver specimens, with an average distance of 7.5 cm (range, 6.2 9.8 cm) from the insertion of the latissimus dorsi muscle. Axon counts revealed a donor-to-recipient ratio of 0.85:1. Follow-up of our patient at 1 year showed improvement of elbow flexion manual muscle testing grade from 0 to 4/5. Furthermore, electromyography at 1 year confirmed biceps reinnervation and showed normal readings of the latissimus compared with preoperative electromyography. Transfer of the LaT branch is a viable and minimally morbid option for biceps reinnervation after traumatic branchial plexus injury. Further follow-up of our patient and larger prospective studies are needed to understand the true potential of this nerve transfer. PMID- 29707458 TI - Ketorolac May Increase Hematoma Risk in Reduction Mammaplasty: A Case-control Study. AB - Background: Ketorolac is a potent nonsteroidal anti-inflammatory drug that has valuable analgesic properties but also a hypothetical risk of increased bleeding due to inhibition of platelet activation. The clinical significance of this risk, however, is unclear when it is used after reduction mammaplasty. Our study objective was to therefore examine the association between ketorolac exposure and hematoma occurrence after breast reduction surgery. We hypothesized that there was no association between ketorolac exposure and hematoma occurrence in breast reduction surgery. Methods: A case-control design was used. Data from charts of all reduction mammaplasties that developed hematomas requiring surgical evacuation (cases) at our university-based hospitals were retrieved and matched to data from charts of reduction mammaplasty patients who did not indicate this complication (controls). Matching occurred in a 1:1 ratio based on 4 criteria: age, body mass index, institution, and preexisting hypertension. Charts were reviewed for retrospective information on exposure to ketorolac. Odds ratio (OR) was calculated with an OR > 1 favoring an association. Results: From 2002 to 2016, 40 cases of hematoma met inclusion criteria and were matched with 40 controls (N = 80). Cases had a significantly lower body mass index than controls; however, the other baseline patient demographics were similar between the 2 groups. There was an association between hematoma formation and exposure to ketorolac (OR, 2.4; 95% confidence interval, 0.8-7.4; P = 0.114) and a trend for greater risk of hematoma formation, although this was not statistically significant. Conclusions: Based on this level 3 evidence, there appears to be an association between perioperative ketorolac exposure and hematoma after breast reduction surgery, but it was not statistically significant. Although this study was adequately powered, the OR of 2.4 was associated with a wide confidence interval. A larger sample size may increase the precision of the results and may also make the association definitive. PMID- 29707459 TI - Surface Areas of Textured Breast Implants: Implications for the Biofilm Theory of Capsule Formation. AB - Background: Increased surface area of mammary implants is suggested as a causative agent for the development of biofilms, which may lead to capsular contraction. The aim of this study was to quantify the surface areas of round implants of different textures and examine how these data can be interpreted with regard to clinical observation. Methods: Surface areas of textured round breast implants were calculated from previously reported confocal scanning microscopic assessment, and dimensions sourced from 3 breast implant manufacturers (McGhan, Mentor, and Silimed). Statistical comparisons were made between manufacturers for different implant volumes, profiles, and texturing. Results: There was a difference in surface area between manufacturers for all implant profiles and between manufacturers for equivalent volume implants (F (3, 253) = 2,828.87; P < 0.001). Silimed polyurethane implants (mean area = 6.12 * 106 mm2) was the highest. Natrelle (mean area = 1.2 * 106 mm2) was the next highest, followed by Siltex (mean area = 4.8 * 105 mm2). Mentor smooth implants (mean area = 4 * 104 mm2) had the lowest mean surface area. There were no differences in surface area between the different profiles for Siltex, Silimed polyurethane, and Mentor smooth implants of the same volume. Conclusions: The increased surface area produced by texturing, although different between manufacturers, seems to provide protection against capsular contraction. Correlation with clinical data indicates that the surface area alone cannot account for these differences. Smooth implants, which have the smallest surface area have the highest incidence of capsular contraction. These data are at odds with the biofilm theory of capsular contraction. PMID- 29707460 TI - Comparing the Outcome of Different Biologically Derived Acellular Dermal Matrices in Implant-based Immediate Breast Reconstruction: A Meta-analysis of the Literatures. AB - Background: Acellular dermal matrices (ADMs) have been used extensively in implant-based breast reconstruction. It was reported that due to the different sources and processing methods, the outcomes of ADMs in implant-based breast reconstructions are expected to differ. We designed this study to statistically analyze and discuss the outcome of 3 commonly used ADMs, Alloderm, Strattice, and Surgimend in implant-based breast reconstruction. Methods: Comprehensive review of the literatures searched on electronic databases was done to identify studies published between 2006 and 2017 comparing the outcome of ADMs. Pooled random effect estimates for each complication and 95% confidence interval (CI) were calculated. One-way analysis of variance and Bonferroni test were used to compare statistical significance between and within groups, respectively. Multiple linear regression was done to include confounding factors and R statistic program for forest plot. Results: Twenty-one studies met the inclusion with a total of 1,659, 999, and 912 breasts reconstructions in Alloderm, Strattice, and Surgimend, respectively. Seven complications extracted including major and minor infection, seroma, implant loss, hematoma, capsular contracture, and localized erythema. Pooled total complication rates were 23.82% (95% CI, 21.18-26.47%) in Strattice, 17.98% (95% CI, 15.49-20.47%) in Surgimend, 16.21% (95% CI, 14.44-17.99%) in Alloderm. Seroma rate was the highest in Strattice group (8.61%; 95% CI, 6.87 10.35%). There was no statistical significance between and within groups. Conclusion: Although Strattice exhibited a higher overall pooled complication rate compared with Alloderm and Surgimend, the incidence of individual complication varies between studies. A cost analysis of different ADMs may aid in choosing the type of ADMs to be used. PMID- 29707461 TI - Partial Versus Total Trapeziectomy Thumb Arthroplasty: An Expertise-based Feasibility Study. AB - Background: There are numerous surgical techniques for the treatment of first carpometacarpal joint osteoarthritis, however, controversy exists as to whether outcomes differ between techniques. This feasibility study aimed to determine if a large-scale, health-related quality of life and functional outcomes study comparing 2 surgical techniques, complete trapeziectomy with ligament reconstruction and tendon interposition (T + LRTI) versus partial trapeziectomy and tendon interposition (PT + TI) arthroplasty, is possible. Methods: Patients with advanced stage arthritis (Eaton stages II-IV) of the thumb were invited to undergo either T + LRTI or PT + TI at 1 of the 2 hand surgery practices. Feasibility outcomes included: (1) Process: recruitment rate; (2) Resources: eligibility rate, eligibility criteria, retention, and compliance rates (completion of health-related quality of life questionnaires, Disabilities of the Arm, Shoulder, and Hand, EuroQol-5D-3L, and SF-36, and functional measurements, grip, key pinch, and tip pinch strength, at 1-week preoperatively and 1, 3, 6, and 12 months postoperatively); (3) Management: determining the practices' commitment to the study; and (4) Scientific: calculation of the variances and treatment effect sizes (ES) of differences between procedures. Data from baseline measurements and 6-month follow-up were used for analysis. Results: Sixty patients were screened, of which 34 (57%) were eligible for surgery. Twenty-one (81%) of the 26 ineligible patients were excluded due to previous or additional planned surgical procedures on the same hand, particularly carpal tunnel release (n = 17). Twenty patients consented; 12 in the T + LRTI and 8 in the PT + TI group. The highest completion rate for the 3 questionnaires and the functional measurements, for both groups was at 6-month time point. Compliance rates for questionnaire completion at 6-months were calculated at 50% and 75% for the T + LRTI and PT + TI group, respectively. Functional measurement completion rate was 50% and 63% for T + LRTI and PT + TI groups, respectively. Treatment ES were group dependent, with Disabilities of the Arm, Shoulder, and Hand, EuroQol-5D-3L usual activities and anxiety/depression showing a large ES in the PT + TI group; the T + LRTI group showed large ES in EQ-5D state of health today. Conclusions: Authors conclude that a large-scale study is feasible and dependent on: (1) increasing sample size to account for the high attrition rate; (2) liberalizing inclusion criteria to include patients with carpal tunnel syndrome; (3) allotting more time at follow-up visits to ensure completion of all measurements; and (4) increasing staff involvement (ie, develop rapport with patients and maintain stability with research assistants). PMID- 29707462 TI - Three-dimensional Printed Surgical Simulator for Kirschner Wire Placement in Hand Fractures. AB - Closed reduction and percutaneous pinning (CRPP) of hand fractures can be a deceptively challenging procedure that requires significant hands-on time to teach and learn. We created a realistic three-dimensional simulator that can be used for teaching junior residents the CRPP. Computer-aided design and computer aided manufacturing (CAD/CAM) software was used to create a three-dimensional hand model incorporating several common hand fractures: Bennett's fracture, transverse fifth metacarpal neck, and transverse second proximal phalanx. Three dimensional printing was used to create molds in which the bones and soft tissue were poured. A polyurethane foam was utilized for the bones with iron incorporated to render them radiopaque, whereas silicone of varying viscosities was used for the soft tissues. Five plastic surgery residents and 5 consultants evaluated the model. Individuals then completed an anonymous 12-question survey evaluating the model based on realism, educational utility, and overall usefulness. Survey responses obtained from both residents and consultants were strongly in favor of the simulator. Average realism was graded as 4.48/5 by residents and 4.68/5 by consultants. Average educational utility was graded as 5/5 by residents and 4.95/5 by consultants. Average overall usefulness was graded as 5/5 by both groups. We created an anatomically accurate and realistic simulator for CRPP of hand fractures that was low cost and easily reproducible. Initial feedback was encouraging in regard to realism, educational utility, and overall usefulness. PMID- 29707463 TI - Demonstration of the Effectiveness of Augmented Reality Telesurgery in Complex Hand Reconstruction in Gaza. AB - Augmented reality (AR) is defined as "a technology that superimposes a computer generated image on a user's view of the real world, thus providing a composite view."1 This case report describes how emerging AR telesurgery technologies may be used to facilitate international surgeon-surgeon collaboration and training. Here, we illustrate how a remote surgeon in Beirut, Lebanon, was able to offer assistance to a surgeon in Gaza, Palestine, during a complex hand reconstruction case following a bomb-blast injury in an 18-year-old male. We discuss the implications of AR technology on the future of global surgery and how it may be used to reduce structural inequities in access to safe surgical care. PMID- 29707464 TI - One-stage Pelnac Reconstruction in Full-thickness Skin Defects with Bone or Tendon Exposure. AB - Dermal regeneration template, such as Integra and Pelnac, was originally designed for treating large area burn injury by inducing regeneration of dermis. To date, it has been widely applied in various acute and chronic wound sites. The present study demonstrated that application of artificial dermis alone induced 1-stage wound healing for wounds with bone or tendon exposure that should usually be repaired by flap surgery. Eight patients who presented with skin defects with bone and/or tendon exposure were treated by 1-stage Pelnac approach. All wounds healed within 20 weeks without skin graft or flap surgery. The wound area was reconstructed by nearly normal skin structure and linear scar. In the case of scalp defect, evidence of hair follicle cell migration and regeneration during healing process was observed. Thereby, the 1-stage Pelnac reconstitution can be considered as a novel method for inducing regrowth of epidermis and hair follicles to cure large full-thickness skin defect with bone and tendon exposure in 1 stage. PMID- 29707465 TI - Improvement of Symptoms after Lymphaticovenous Anastomosis in Patients with Abdominal Wall Lymphedema. AB - At our institution, we performed a lymphaticovenous anastomosis in patients with primary or secondary abdominal lymphedema. Patients report good outcomes and feel relieved of their complaints. To obtain good results, it is important to have decent knowledge on the anatomical state of the lymphatic system. In general, the lymphatic system of the lower abdomen can be compared with the system of the upper legs. According to our current case results, the abdominal area might be susceptible to lymphaticovenous anastomosis procedure. Further research should be performed to confirm the effect of the intervention and the imaging techniques to monitor the improvements. PMID- 29707466 TI - Quantifying Soft Tissue Shape and Symmetry: Patients with Cleft Lip/Palate and Facial Paralysis. AB - Background: The objective of this study was to demonstrate simple three dimensional analyses of facial soft tissue shape and asymmetry. Methods: There were 2 study samples: one retrospective comprised patients with repaired cleft lip and palate (CL/P) and control subjects; and the other prospective comprised patients with unilateral facial paralysis (FP) and control subjects. The data collected were digitized three-dimensional facial landmarks. Scores for shape and asymmetry of subjects' faces and for different facial regions were generated using Procrustes methods. Pivotal bootstrap methods and analysis of variance were used to test for significant differences in the scores between the patients and controls, and plots of the scores were generated to compare differences among the subjects. Results: (1) Shape scores: The CL/P patients demonstrated significant overall and regional facial differences (P <= 0.01). The patients were further from the control mean, especially those with unilateral CL/P. Patients with FP demonstrated significant differences (P <= 0.05) for the lower face only. (2) Asymmetry scores: CL/P and FP patients demonstrated significant overall and regional facial differences (CL/P, P <= 0.0001; FP, P <= 0.01). CL/P and FP patients were more asymmetric and were further from the control mean, and patients with unilateral CL/P were more asymmetric than the bilateral CL/P patients. Conclusion: Clinicians can use the analyses to isolate differences and/or changes in the face due to shape or asymmetry, or a combination of both; based on the score plots, the extent of the shape and asymmetry differences can be compared among subjects and the extent of changes due to surgery measured. PMID- 29707467 TI - Staged Prosthetic Reconstruction with Fat Grafting for Severe Depressive Breast Deformation after Breast-conserving Therapy. AB - Breast-conserving therapy, where radiotherapy is performed after partial mastectomy, is a widely used surgical method that can preserve most of the breast tissue without increasing the recurrence rate of breast cancer. However, without reconstruction, asymmetry of the breast occurs due to the tissue defect and radiation fibrosis, producing in poor cosmetic results. In this case study, we performed staged prosthetic breast reconstruction combined with fat grafting for severe depressive deformation of the breast after breast-conserving therapy. The first surgery involved insertion of a tissue expander and fat grafting, second surgery was the reduction of injected saline volume and fat grafting, and third surgery involved exchange for an implant and fat grafting. The skin in the depressed area, which had atrophied, became soft and flexible; deformation was also improved, and the patient was satisfied with the aesthetic outcome. It is expected that fat grafting will fertilize and qualitatively improve the damaged tissue due to irradiation, reducing the complications related to the tissue expander and implant. We believe that it will be possible to correct a breast deformity after breast-conserving therapy using a tissue expander and implant, which had not been considered as a solution. The results showed that the present method can be an option for delayed reconstruction after breast-conserving therapy. PMID- 29707468 TI - Unrecognized Cell Torpidity as a Risk Factor in Elective Plastic Surgery. AB - Supplemental Digital Content is available in the text. PMID- 29707469 TI - Creation of a Central Under Flap Pocket Allows Secondary Implant Augmentation of Perforator Flap Breast Reconstruction. AB - Background: When a single perforator flap does not provide adequate volume or projection for satisfactory breast reconstruction, the addition of an implant may be considered at the time of second-stage revisions. Dissection of an implant pocket beneath the flap may lead to the inadvertent injury of the flap pedicle as the tissue planes have been obscured by tissue ingrowth. The authors present a technique in which the boundaries of the implant pocket are predetermined at the time of flap reconstruction allowing an implant to be inserted at the second stage in ideal position with greater ease of dissection and minimal risk to the flap pedicle. Methods: Forty patients (80 bilateral perforator flap breast reconstructions) treated with the creation of central under flap pocket technique in anticipation of subsequent sub flap implant augmentation within an 18-month period were assessed retrospectively. Results: Sixty-eight patients with flaps (85%) went on to receive secondary augmentation with silicone implants. The average percentage increase in volume contributed by the implant was 41%. The undersurface of the acellular dermal matrix was readily identified, and its medial most extent safely determined, allowing the expeditious recreation of the predelineated central under-flap implant pocket. No flap pedicles were injured during the process, and the implants were placed in a favorable position providing maximum projection to the reconstruction. No subsequent development of fat necrosis was identified after augmentation. Conclusion: The creation of central under flap pocket technique allows for safe, effective, and expedient delayed implant augmentation of perforator flap breast reconstruction. PMID- 29707470 TI - Retrieval of ice cloud properties using an optimal estimation algorithm and MODIS infrared observations. Part I: Forward model, error analysis, and information content. AB - An optimal estimation (OE) retrieval method is developed to infer three ice cloud properties simultaneously: optical thickness (tau), effective radius (reff ), and cloud-top height (h). This method is based on a fast radiative transfer (RT) model and infrared (IR) observations from the MODerate resolution Imaging Spectroradiometer (MODIS). This study conducts thorough error and information content analyses to understand the error propagation and performance of retrievals from various MODIS band combinations under different cloud/atmosphere states. Specifically, the algorithm takes into account four error sources: measurement uncertainty, fast RT model uncertainty, uncertainties in ancillary datasets (e.g., atmospheric state), and assumed ice crystal habit uncertainties. It is found that the ancillary and ice crystal habit error sources dominate the MODIS IR retrieval uncertainty and cannot be ignored. The information content analysis shows that, for a given ice cloud, the use of four MODIS IR observations is sufficient to retrieve the three cloud properties. However, the selection of MODIS IR bands that provide the most information and their order of importance varies with both the ice cloud properties and the ambient atmospheric and the surface states. As a result, this study suggests the inclusion of all MODIS IR bands in practice since little a priori information is available. PMID- 29707472 TI - Bilateral Supratentorial Subdural Hematomas after Craniotomy for Posterior Fossa Tumor Removal. AB - A 69-year-old man was admitted to the emergency department with headache and dizziness. He was submitted to brain computed tomography (CT) which showed a tumor in the right cerebellar hemisphere, findings which were subsequently confirmed with magnetic resonance imaging (MRI). He underwent a paramedian suboccipital craniotomy for removal of the mass. Histology confirmed the presence of a hemangiopericytoma. The patient was discharged 5 days postoperatively with improvement in his symptoms. Fifteen days later, he presented with gait difficulties. Clinical examination revealed positive Mingazzini sign on his left side. He was submitted to brain MRI which revealed bilateral subdural hematomas on late subacute stage with mass effect and midline shift caused by the largest on the right. The patient underwent burr hole evacuation of the right subdural hematoma. The postoperative CT showed evacuation of the right chronic subdural hematoma. Two days postoperatively, the patient's symptoms improved. PMID- 29707471 TI - Modeled Full-Flight Aircraft Emissions Impacts on Air Quality and Their Sensitivity to Grid Resolution. AB - Aviation is a unique anthropogenic source with four-dimensional varying emissions, peaking at cruise altitudes (9-12 km). Aircraft emission budgets in the upper troposphere lower stratosphere region and their potential impacts on upper troposphere and surface air quality are not well understood. Our key objective is to use chemical transport models (with prescribed meteorology) to predict aircraft emissions impacts on the troposphere and surface air quality. We quantified the importance of including full-flight intercontinental emissions and increased horizontal grid resolution. The full-flight aviation emissions in the Northern Hemisphere contributed ~1.3% (mean, min-max: 0.46, 0.3-0.5 ppbv) and 0.2% (0.013, 0.004-0.02 MUg/m3) of total O3 and PM2.5 concentrations at the surface, with Europe showing slightly higher impacts (1.9% (O3 0.69, 0.5-0.85 ppbv) and 0.5% (PM2.5 0.03, 0.01-0.05 MUg/m3)) than North America (NA) and East Asia. We computed seasonal aviation-attributable mass flux vertical profiles and aviation perturbations along isentropic surfaces to quantify the transport of cruise altitude emissions at the hemispheric scale. The comparison of coarse (108 * 108 km2) and fine (36 * 36 km2) grid resolutions in NA showed ~70 times and ~13 times higher aviation impacts for O3 and PM2.5 in coarser domain. These differences are mainly due to the inability of the coarse resolution simulation to capture nonlinearities in chemical processes near airport locations and other urban areas. Future global studies quantifying aircraft contributions should consider model resolution and perhaps use finer scales near major aviation source regions. PMID- 29707473 TI - Hemangioma of the Cavernous Sinus: A Case Series. AB - Introduction Cavernous sinus hemangiomas (CSHs) are rare, vascular, extra-axial tumors that are diagnosed with a combination of imaging and biopsy. We describe the clinical presentations, imaging findings, and management of two male patients with CSHs. Case Report Case 1 describes a 57-year-old man who presented with vision changes and cranial nerve palsies. Initial imaging and surgical biopsy were nondiagnostic. Follow-up Tc-99m tagged red blood cell (RBC) imaging supported CSH diagnosis. He was treated with surgical resection and radiotherapy. Case 2 describes a 57-year-old man who presented with chronic headache. Imaging findings were suggestive of CSH. He underwent endoscopic endonasal surgical resection and a final diagnosis of CSH was made via biopsy. Discussion CSHs often present with headache, vision changes, and cranial nerve palsies. Characteristic findings of a T2 hyperintense lesion with homogeneous contrast enhancement has been described in the literature. There is also a role for tagged RBC imaging studies in the setting of nondiagnostic imaging and biopsy. Surgical resection can be difficult due to tumor vascularity and encasement of internal carotid arteries. Stereotactic radiosurgery and adjuvant radiotherapy can play a role in the treatment of patients who have inoperable lesions or subtotal resections. PMID- 29707474 TI - Vitamin A and D in allergy: from experimental animal models and cellular studies to human disease. AB - Introduction: Vitamins A and D are able to modulate innate and adaptive immune responses and may therefore influence the development and the course of allergic diseases. Materials and methods: This article reviews the current evidence for the experimental effects of vitamins A and D in vivo in animal models and on immune cells in vitro, and discusses their translational implication. A systematic literature search over the last 10 years was performed using MEDLINE and PubMed databases. Results: Deficiencies of vitamin A or vitamin D in mouse models of allergic asthma seem to exacerbate allergic symptoms along with enhanced lung inflammation and Th2 cytokine production. In contrast, supplementation regimes especially with vitamin D were able to attenuate symptoms in therapeutic mouse models. The active metabolites retinoic acid (RA) and 1,25 dihydroxyvitamin D3 (VD3) induced tolerogenic dendritic cells (DCs) and up regulated T-regulatory cells in the allergic sensitization phase, which likely contributes to tolerance induction. Additionally, RA and VD3 maintained the stability of eosinophils and mast cells in the effector phase, thereby reducing allergic mediator release. Thus, both active vitamin metabolites RA and VD3 are able to influence allergic immune responses at several immunological sites. Conclusion: Animal studies predict that vitamin A and D may also be attractive players in the control of allergy in humans. Whether these experimental observations can be translated to the human situation remains open, as results from clinical trials are controversial. PMID- 29707475 TI - Liquid Biopsy in Rare Cancers: Lessons from Hemangiopericytoma. AB - Hemangiopericytoma (HPT) is a rare mesenchymal tumor of fibroblastic type and for its rarity is poorly studied. The most common sites of metastatic disease in patients with intracranial HPT are the bone, liver, and lung, suggestive for an hematogenous dissemination; for this reason, we investigated, for the first time, the presence of circulating tumor cells (CTCs) in hemangiopericytoma patient by CellSearch(r) and SceenCell(r) devices. Peripheral blood samples were drawn and processed by CellSearch, an EpCAM-dependent device, and ScreenCell(r), a device size based. We found nontypical CTCs by CellSearch system and the immunofluorescence analysis performed on CTCs isolate by ScreenCell demonstrated the presence of single CTCs and CTC clusters. The molecular characterization of single CTCs and CTC clusters, using antibodies directed against EpCAM, CD34, cytokeratins (8, 18, and 19), and CD45, showed a great heterogeneity in CTC clusters. We believe that the present study may open a new scenario in the rare tumors: the introduction of the liquid biopsy and the molecular characterization of circulating tumor cells could lead to personalized targeted treatments and also for rare tumors. PMID- 29707476 TI - Evaluation of perampanel as monotherapy for focal seizures: Experience from open label extension studies. AB - Perampanel, a selective, non-competitive alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid (AMPA) receptor antagonist, is approved for adjunctive treatment of focal seizures, with or without secondarily generalized seizures, and for primary generalized tonic-clonic seizures in patients with epilepsy aged >= 12 years. Perampanel was recently approved for monotherapy use for focal seizures in the U.S.A. Anti-seizure drug monotherapy may be preferable to polytherapy, which is generally associated with increased toxicity, non compliance, and cost. Here, we report cases where patients had converted to perampanel monotherapy during open-label extension (OLEx) portions of 9 Phase II and III studies. Of 2245 patients who enrolled in the OLEx studies, we identified 7 patients with drug-resistant focal seizures who discontinued all non-perampanel anti-seizure drugs and were maintained on perampanel monotherapy for >= 91 days until the end of data cut-off. Patients received perampanel monotherapy for up to 1099 days (157 weeks), most at a modal dose of 12 mg. Seizure data were available for 6 patients, of whom 5 had a >= 90% reduction in overall seizure frequency between baseline and their last 13-week period of monotherapy (3 were seizure free). Perampanel monotherapy was generally well tolerated and the safety profile during perampanel monotherapy was consistent with clinical and post-marketing experience in the adjunctive setting. This analysis included a small proportion of patients with highly drug-resistant focal seizures who converted to monotherapy during OLEx studies. While these limited data are encouraging in suggesting that perampanel might be useful as a monotherapy, further studies are required to explore outcomes in a less drug-resistant population, where a larger proportion of patients might benefit from monotherapy. PMID- 29707477 TI - Multispectral photoacoustic microscopy and optical coherence tomography using a single supercontinuum source. AB - We report on the use of a single supercontinuum (SC) source for multimodal imaging. The 2-octave bandwidth (475-2300 nm) makes the SC source suitable for optical coherence tomography (OCT) as well as for multispectral photoacoustic microscopy (MPAM). The IR band centered at 1310 nm is chosen for OCT to penetrate deeper into tissue with 8 mW average power on the sample. The 500-840 nm band is used for MPAM. The source has the ability to select the central wavelength as well as the spectral bandwidth. An energy of more than 35 nJ within a less than 50 nm bandwidth is achieved on the sample for wavelengths longer than 500 nm. In the present paper, we demonstrate the capabilities of such a multimodality imaging instrument based on a single optical source. In vitro mouse ear B-scan images are presented. PMID- 29707478 TI - Visualization of murine lymph vessels using photoacoustic imaging with contrast agents. AB - Metastasis frequently occurs even in the early stage of breast cancer. This research studied the feasibility of using photoacoustic (PA) imaging for identifying metastasis in the lymph vessels of mice. The photoacoustic efficiency of various contrast agents was investigated, and the influence of scattered light was evaluated by using a lymph vessel phantom. The lymph vessels of mice were then visualized using the selected contrast agents: indocyanine green (ICG) and gold nanorods (AuNR). The attenuation of the PA imaging was -1.90 dB/mm, whereas that of the fluorescence imaging was -4.45 dB/mm. The results indicate the potential of identifying sentinel lymph nodes by using PA imaging with these contrast agents. PMID- 29707480 TI - All-optical extravascular laser-ultrasound and photoacoustic imaging of calcified atherosclerotic plaque in excised carotid artery. AB - Photoacoustic (PA) imaging may be advantageous as a safe, non-invasive imaging modality to image the carotid artery. However, calcification that accompanies atherosclerotic plaque is difficult to detect with PA due to the non-distinct optical absorption spectrum of hydroxyapatite. We propose reflection-mode all optical laser-ultrasound (LUS) imaging to obtain high-resolution, non-contact, non-ionizing images of the carotid artery wall and calcification. All-optical LUS allows for flexible acquisition geometry and user-dependent data acquisition for high repeatability. We apply all-optical techniques to image an excised human carotid artery. Internal layers of the artery wall, enlargement of the vessel, and calcification are observed with higher resolution and reduced artifacts with nonconfocal LUS compared to confocal LUS. Validation with histology and X-ray computed tomography (CT) demonstrates the potential for LUS as a method for non invasive imaging in the carotid artery. PMID- 29707479 TI - Towards optimized naphthalocyanines as sonochromes for photoacoustic imaging in vivo. AB - In this paper we establish a methodology to predict photoacoustic imaging capabilities from the structure of absorber molecules (sonochromes). The comparative in vitro and in vivo screening of naphthalocyanines and cyanine dyes has shown a substitution pattern dependent shift in photoacoustic excitation wavelength, with distal substitution producing the preferred maximum around 800 nm. Central ion change showed variable production of photoacoustic signals, as well as singlet oxygen photoproduction and fluorescence with the optimum for photoacoustic imaging being nickel(II). Our approach paves the way for the design, evaluation and realization of optimized sonochromes as photoacoustic contrast agents. PMID- 29707481 TI - Brugada-type electrocardiogram changes associated with nitroprusside toxicity. PMID- 29707482 TI - Mahaim pathway tachycardia versus bystander ventricular tachycardia: A distinction without a difference. PMID- 29707483 TI - Slow pathway modification for treatment of pseudo-pacemaker syndrome due to first degree atrioventricular block with dual atrioventricular nodal physiology. PMID- 29707484 TI - Abolition of diaphragmatic stimulation and restoration of left ventricular pacing by nonsurgical withdrawal of the left ventricular lead: Report of two cases. PMID- 29707485 TI - Graves' disease-induced complete heart block and asystole. PMID- 29707486 TI - Subcutaneous implantable cardioverter-defibrillator implantation in a patient with bilateral pectoral deep brain stimulators. PMID- 29707487 TI - Catheter ablation of the slow pathway as a treatment for severe sinus node dysfunction in a patient with incessant atrioventricular nodal reentry tachycardia. PMID- 29707488 TI - Intravenous sotalol for conversion of atrial flutter in infants. PMID- 29707489 TI - Inside-out abrasion and contained conductor cable externalization in a defibrillation lead with asymmetric conductor cable lumen distribution. PMID- 29707490 TI - A rare case of acute myocardial infarction during extraction of a septally placed implantable cardioverter-defibrillator lead. PMID- 29707491 TI - Erratum. AB - [This corrects the article DOI: 10.1016/j.hrcr.2016.07.009.]. PMID- 29707492 TI - Segmented socioeconomic adaptation of New Eastern European professionals in the United States. AB - This study examines the socioeconomic adaptation of post-1991 Eastern European professionals in the United States. The data were obtained from the pooled 2006 2010 American Community Surveys. The analysis includes recent immigrants between ages of 25-65 who have at least an associate's degree. Skilled immigrants in professional or managerial occupations are compared with non-professionals or managers to examine and compare socioeconomic outcomes. The findings presented in this study support the segmented assimilation theory and reveal cross-group and cross-country disparities in socioeconomic adaptation. Despite the high amount of human capital, Eastern European skilled immigrants tend to have a lower share of professionals and managers than other groups. Their average income is lower than the income of some other groups in the analysis, especially immigrants from Northern and Western Europe, suggesting these immigrants experience difficulties in transferring human capital. Among the three largest Eastern European groups - Russia, Ukraine, and Poland - there is a clear hierarchy in socioeconomic status with Russian professionals having the highest educational attainment and income, followed by immigrants from Ukraine and Poland. Results also revealed gender differences in socioeconomic adaptation. Women from Eastern Europe are highly professional, but they tend to be concentrated in different occupations than men, leading to a significant gender-wage gap. The effect of selected individual and country-level characteristics on skilled immigrants' socioeconomic adaptation is discussed. PMID- 29707493 TI - Biochemical effects of commercial feedstuffs on the fry of climbing perch (Anabas testudineus) and its impact on Swiss albino mice as an animal model. AB - This study assesses the biochemical effects of commercially available fish feedstuffs on the fry of climbing perch (Anabas testudineus). Subsequently, its impact on experimental animal, Swiss albino mice, is also examined. In order to access the impact of commercial fish feed and feed consumption fish on the experimental animal, the proximate, biochemical and histopathological analyses were done using standard methods. The proximate composition as well as the concentrations of Pb, Ni, Mn, As, Zn, and Cd in the fish feed, different parts of the A. testudineus fish and different parts of the A. testudineus fish-treated experimental mice liver, were all determined using Energy Dispersive X-ray Fluorescence (EDXRF) Spectrometry. The highest levels of Cr, Pb and As were observed in the liver of Swiss albino mice treated with FFT2 and FFBB2 and their concentrations were 0.156, 0.491, 0.172 MUg/g and 0.166, 0.771, 0.157 MUg/g respectively. No significant changes of protein, fat, crude fiber, moisture and ash contents were observed after proximate composition analysis of fish feeds, A. testudineus and A. testudineus treated experimental mice. Significant amounts of heavy metals (Cr, Mn, Zn Cu, Ni) were found in fish feed, different parts of A. testudineus fish and in the experimental mice. However, remarkably high amounts were observed in the A. testudineus fish's head and bone with body parts. Biochemical analysis of blood samples of A. testudineus fish treated experimental mice indicated that the cholesterol, TG, LDL and glucose levels were significantly higher. Yet no significant alteration in the HDL level was observed when compared to the control. In histopathological analysis, a remarkable degeneration was observed in the liver and kidney of A. testudineus treated mice. It can therefore be concluded that although A. testudineus has nutritional benefits the quality of this fish may be compromised as a consequence of contamination through various anthropogenic activities. This analysis suggests the commercial fish feed producers must take special caution to reduce the toxic metals in various fish feed products and make it nutritionally rich and safe for fish to eat. Finally, it needs to be safe for human consumption as well. PMID- 29707494 TI - Guest Editor Introduction. PMID- 29707495 TI - A reassessment of tracheal substitutes-a systematic review. AB - Background: Tracheal substitutes remain an active area of research. For rare patients with large or complex defects that cannot be repaired primarily, replacement of the airway may represent the only treatment option. The present systematic review aims to assess the clinical successes and setbacks of current methods of airway replacement. Methods: Systematic review using Medline and PubMed from 01 January 2000 to 01 October 2017 focusing on clinical translation of circumferential or near circumferential (>270 degrees ) tracheal substitutes. Studies were identified using key phrases including terms such as "tracheal replacement", "tracheal regeneration", "tracheal transplant", "tracheal tissue engineering", and "tracheal substitution". Animal or non-clinical studies were excluded. Reviews were included if they contained clinical updates. Results: Twenty-one studies were included in assessment comprising a mix of case reports, case studies, and a single review with clinical updates on prior studies. Since 2001, 41 patients have undergone a reported circumferential or near circumferential tracheal substitution through four underlying methodologies including allotransplantation, autologous tissue reconstruction, bioprosthetic reconstruction, and tissue engineered reconstruction. Each modality has unique advantages and disadvantages with varying success in clinical application. Conclusions: The need for tracheal substitution remains a difficult clinical problem without an ideal prosthetic or graft material. While various modalities have had limited clinical success, further laboratory work is necessary before tracheal substitutes can become widely adopted, especially in the case of tissue engineered conduits, which have been setback by premature clinical translation. PMID- 29707497 TI - Imaging of the trachea. AB - Numerous benign and malignant tracheal diseases may affect the trachea primarily and secondarily. While the posterior anterior (PA) and lateral chest radiograph is the conventional study for initial evaluation of the trachea and central airways, findings may not always be apparent on conventional radiographs, and further evaluation with cross sectional imaging is usually necessary. Computed tomography (CT) is the imaging modality of choice for imaging the trachea and bronchi. Familiarity with the imaging appearances of the normal and diseased trachea will enhance diagnostic evaluation. PMID- 29707498 TI - Management of laryngotracheal trauma. AB - Laryngotracheal trauma is a rare but potentially life-threatening injury. It is usually seen in multiple-trauma patients and can go unrecognized and undertreated due to its scarcity. The presenting symptoms often do not correlate with the severity of the injury and injuries may range from an endolaryngeal hematoma to a complete tracheal transection. Accurate diagnosis of the extent of the injury can be achieved with a combination of high resolution computed tomography, flexible fiber optic laryngoscopy and flexible bronchoscopy. Treatment may include observation with symptomatic management, reduction and repair of laryngeal skeletal fractures, or complete tracheal or laryngeal reconstruction. Endolaryngeal stents are reserved for use in cases of significant mucosal trauma or injuries that disrupt the anterior commissure of the larynx. The most important goal in management is to first secure and reconstruct the airway. Once this has been achieved, the long-term goal of treatment is to restore the voice and swallowing mechanism. PMID- 29707496 TI - Secondary tracheal tumors: a systematic review. AB - Background: Secondary tracheal tumors arise from mural invasion by primary tumors in adjacent organs, metastatic lymph nodes or blood-born metastasis from distant sites. This systematic review aims to assess the presentation, management options, and clinical outcomes of these uncommon non-tracheal malignancies. Methods: Electronic searches of the MEDLINE database were performed to identify case series and individual case reports of tracheal invasion by primary non tracheal tumors or metastatic disease. All English-language studies with available abstracts or articles containing primary data were included. Results: From 1978 to 2017, a total of 160 case reports or case series identified 2,242 patients with invasion of the trachea by tumors of adjacent organs (n=1,853) or by metastatic lymph nodes or hematogenous spread (n=389). Common primary sites of origin were thyroid, esophagus, and lung, and the most common presentation was metachronous (range of interval: 0 to 564 months) with dyspnea, neck mass, voice change and/or hemoptysis. A majority of patients in case reports (77.9%) and case series (66.0%) underwent resection and the most common reported operation was segmental tracheal resection. Fewer patients underwent bronchoscopic intervention (21.7%) and radiation was used in 32.2% of patients. Complications after bronchoscopic treatment included bleeding, granulation tissue, and retained secretions, while anastomotic leak, unplanned tracheostomy, and new recurrent laryngeal nerve paralysis were observed after surgical resection. The rate of 30 day mortality was low (0.01-1.80%). Median survival was higher in patients with thyroid malignancy and in patients who underwent surgical management. Follow-up time ranged from 0.03 to 183 months. Conclusions: Patients with tracheal invasion by metastatic or primary non-tracheal malignancies should be assessed for symptoms, tumor grade, tumor recurrence and concurrent metastases to decide on optimal surgical, bronchoscopic or noninterventional therapy. Clinical experience suggests that palliative endoscopic intervention for tracheal obstruction by metastasis-bearing lymph nodes is underreported. PMID- 29707499 TI - Cervical exenteration. AB - Cervical exenteration is a radical procedure for the treatment of locally invasive cancers of the trachea, esophagus, or thyroid, as well as recurrent tumors at the site of a tracheal stoma, and occasionally for benign disease. Exenteration involves removal of the larynx, pharynx, esophagus, and trachea, as well as associated lymphatic tissue. The tracheal stump is brought up as a cervical or mediastinal tracheostomy, depending on the length and the location of the distal resection site. The alimentary tract can be reconstructed with several types of conduits, but most commonly the stomach or left colon are used. Tension on the innominate artery must be avoided when repositioning the trachea to prevent innominate artery erosion. Tension on the artery can be addressed by either dividing the vessel or by transposing the trachea inferior and lateral to the innominate artery and vein. Overall, cervical exenteration is associated with a significant risk of morbidity, including anastomotic leak, innominate artery erosion, and tracheostomy dehiscence with subsequent mediastinitis, as well as the potential for postoperative death. Nevertheless, in highly selected patients, it can provide an unparalleled opportunity for either cure or palliation, with functional results equivalent to that of total laryngectomy. PMID- 29707500 TI - Functional outcome after (laryngo)tracheal resection and reconstruction for acquired benign (laryngo)tracheal stenosis. AB - Background: In this study we focus on functional outcomes after (laryngo)tracheal resection and reconstruction for acquired benign (laryngo)tracheal stenosis, with a specific interest in the impact of laryngeal involvement on postoperative outcome. Methods: All patients who underwent (laryngo)tracheal surgery for benign pathology between 1996 and 2017 in our centre were included in this retrospective study. Surgical outcomes were procedural success rate, and airway- and voice related complications. Functional results were assessed using (standardized) questionnaires for quality of life, sensation of dyspnea, swallowing function, and voice perception. Results: Of 119 consecutive patients, 47 underwent laryngotracheal resection and reconstruction and 72 underwent segmental tracheal surgery (78% with an end-to-end tracheal anastomosis and 22% with a cricotracheal anastomosis). Overall success rate was 92% and was similar for all groups, with an overall significant improvement in quality of life when compared to the preoperative situation. However, after laryngotracheal surgery, airway-related complications were more common when compared to segmental resections with an end to-end tracheal anastomosis (30% versus 7%, P=0.003). Additionally, early voice alterations without recurrent nerve palsy were reported twice as often (34% versus 16%, P=0.034) and voice quality experienced during follow-up was significantly worse when compared to segmental resections. Overall response rate to the questionnaires on functional outcome was 63%. Conclusions: (Laryngo)tracheal surgery is safe and beneficial, with significant functional improvement during mid- and long-term follow-up. However, laryngeal involvement is a predictor for increased surgical airway-related complications. Additionally, voice alterations without recurrent nerve palsy are far more common after laryngotracheal resection and are a serious handicap. This aspect is underexposed in current literature and deserves further attention during preoperative counseling and patient follow-up. However, the results on functional outcome of this current study should be interpreted with caution due to the somewhat low response rate of the questionnaires. PMID- 29707501 TI - Prevention and management of complications following tracheal resections-lessons learned at the Massachusetts General Hospital. AB - Tracheal surgery has developed and evolved over the last 50 years, becoming an integral part of the clinical practice of modern thoracic surgeons. Today, surgeons can safely and effectively operate on most patients suffering from post intubation tracheal stenosis, tracheal tumors and other pathologies that result in an abnormal shape and function of the central airways. The Massachusetts General Hospital (MGH) in Boston witnessed first-hand the birth and growth of tracheal surgery under Dr. Hermes Grillo, becoming a reference center and accumulating one of the largest institutional experiences in the world. This vast experience of the management of patients with tracheal pathologies has allowed our group at MGH to refine the care of these patients, including their judicious preoperative evaluation, meticulous surgical treatment, and dedicated postoperative care. However, this experience has also provided valuable lessons on the potential complications that can arise after tracheal surgery. Here, we attempt to accumulate our institutional knowledge and experience to provide a summary of the key aspects to prevent complications following tracheal resections. Unfortunately, complications can occur despite strict adherence to the core principles of tracheal surgery, and therefore, we also highlight our institutional experience with the early recognition and management of the most common and dreaded complications. PMID- 29707502 TI - Overview of malignant tracheal tumors. AB - Malignant airway tumors present particular challenges for surgeons, namely: to distinguish symptoms from those of the more frequent benign airway diseases; to separate metastatic disease from the uncommon primary tumors; and to consider curative resection in appropriate candidates. Here, we present a critical review of tracheal malignant obstruction, focusing on the evaluation of a patient with malignant airway tumor, patient selection for resection and the predictors of long-term survival. The new development in primary tracheal tumors is an old story, that of making physicians aware that resection rates in epidemiologic studies remain low, mainly because opportunities for resection are missed. PMID- 29707503 TI - Surgical anatomy of the trachea. AB - Anatomy as the foundation of surgery is a concept no better exemplified than by the history of tracheal surgery. Incremental advancements in our understanding of the trachea's position, structure, blood supply and adjacent organs each allowed for stepwise improvements in the thoracic surgeon's ability to address upper airway disease. As such, the mastery of tracheal anatomy is fundamental to those clinicians responsible for treating such ailments. In this article, tracheal anatomy is reviewed and points critical to the thoracic surgeon are highlighted. The structure and location of the trachea, the blood supply to the trachea, and the trachea's spatial relationship to critical mediastinal organs are presented. This material provides the groundwork for understanding all aspects of tracheal surgery today. PMID- 29707504 TI - Tracheobronchoplasty for tracheomalacia. AB - Tracheobronchomalacia is an uncommon acquired disorder of the central airways. Common symptoms include dyspnea, constant coughing, inability to raise secretions and recurrent respiratory infections. Evaluation includes an inspiratory expiratory chest computed tomography (dynamic CT), an awake functional bronchoscopy and pulmonary function studies. Patients with significant associated symptoms and severe collapse on CT and bronchoscopy are offered membraneous wall plication. Tracheobronchoplasty is performed through a right thoracotomy. The posterior airway is exposed after the azygous vein is ligated. The posterior wall of the trachea (and usually both main bronchi) is plicated to a sheet of thick acellular dermis (or polypropylene mesh) with a series of 4 mattress sutures of 4 0 sutures from the thoracic inlet to the bottom of the trachea to re-shape the trachea and restore the normal D shape. Patients report generally good results with improvement of their symptoms. Quality of life is usually improved while pulmonary function tests usually are not improved. PMID- 29707505 TI - Acute airway management. AB - Acute airway management has challenged clinicians for nearly four millennia. History underscores the discoveries of surgeons and anesthesiologists, whose advances in technology and surgical technique have transformed management algorithms from primarily surgical tracheostomy, to transoral endotracheal intubation under direct laryngoscopy. Despite this progress and a better understanding of airway anatomy, physiology and pathogenesis of disease, the acute airway, whether obstructed, traumatically disrupted, or externally compressed, remains a life-threatening challenge. The role of all clinicians in acute airway management is patient stability and emergent control of the airway to ensure patency as well as adequate oxygenation and ventilation. The standard of care remains transoral intubation under direct laryngoscopy with use of indirect laryngoscopy as a first adjunct. If unsuccessful, surgical intubation of the trachea via cricothyroidotomy with subsequent conversion to open tracheostomy is the procedure of choice. While there is growing support for the use of percutaneous tracheostomy as an alternative to surgical intubation of the trachea after failed transoral intubation, the potential for damage to critical neck structures and longer time-to-intubation must be considered. In this perspective, we provide a history of acute airway management, highlighting milestones in the fields of airway surgery and anesthesia. We present a review of current medical and surgical approaches to managing the acute airway, including the risks, benefits and appropriateness of each approach with respect to patient stability, available equipment, clinician training and patient outcomes. We conclude with an emphasis on the role of the thoracic surgeon in prevention and the critical nature of regular surveillance of patients with chronic, partial tracheal obstruction. PMID- 29707506 TI - Airway stents. AB - Stents and tubes to maintain the patency of the airways are commonly used for malignant obstruction and are occasionally employed in benign disease. Malignant airway obstruction usually results from direct involvement of bronchogenic carcinoma, or by extension of carcinomas occurring in the esophagus or the thyroid. External compression from lymph nodes or metastatic disease from other organs can also cause central airway obstruction. Most malignant airway lesions are surgically inoperable due to advanced disease stage and require multimodality palliation, including stent placement. As with any other medical device, stents have significantly evolved over the last 50 years and deserve an in-depth understanding of their true capabilities and complications. Not every silicone stent is created equal and the same holds for metallic stents. Herein, we present an overview of the topic as well as some of the more practical and controversial issues surrounding airway stents. We also try to dispel the myths surrounding stent removal and their supposed use only in central airways. At the end, we come to the long-held conclusion that stents should not be used as first line treatment of choice, but after ruling out the possibility of curative surgical resection or repair. PMID- 29707507 TI - Bioprosthetics and repair of complex aerodigestive defects. AB - Aerodigestive defects involving the trachea, bronchi and esophagus are a result of prolonged intubation, operative complications, congenital defects, trauma, radiation and neoplastic disease. The vast majority of these defects may be repaired primarily. Rarely, due the size of the defect, underlying complexity, or unfavorable patient characteristics, primary repair is not possible. One alternative to primary repair is bioprosthetic repair. Materials such as acellular dermal matrix and aortic homograft have been used in a variety of applications, including closure of tracheal, bronchial and esophageal defects. Herein, we review the use of bioprosthetics in the repair of aerodigestive defects, along with the unique advantages and disadvantages of these repairs. PMID- 29707508 TI - Tracheal release maneuvers. AB - Tracheal resection and reconstruction has been slow to develop in the field of thoracic surgery. The ability to perform a low tension, well-vascularized anastomosis with good outcomes has improved with understanding of tracheal blood supply and the ability to perform tracheal release maneuvers. Laryngeal and suprahyoid release maneuvers can be helpful for cervical tracheal resections, while hilar and pericardial release maneuvers can be beneficial in thoracic tracheal resections. Simple maneuvers such as neck flexion and dissection of the avascular pretracheal plane can also be used to improve anastomotic tension. In this paper, we will review the indications, technical considerations and results of performing cervical and intrathoracic tracheal release maneuvers during tracheal resection and reconstruction. PMID- 29707509 TI - Idiopathic subglottic stenosis: techniques and results. AB - Idiopathic subglottic stenosis is a rare condition of unknown etiology characterized by circumferential stenosis in the subglottic larynx and upper trachea. Historically, patients were treated with dilation or ablation, however this approach has proven to be largely palliative and often leads to recurrence and the need for tracheostomy. A single-staged laryngotracheal resection and reconstruction is now the preferred definitive treatment for idiopathic subglottic stenosis and can be performed with excellent patient outcomes and rare subsequent progression of the disease. Avoiding anastomotic tension and devascularization are important technical keys to minimizing complications. PMID- 29707510 TI - Tracheal stenosis-resection and reconstruction. PMID- 29707511 TI - Carinal resections. PMID- 29707513 TI - Tracheal tumors. PMID- 29707512 TI - Surgical management of tracheoesophageal fistula. PMID- 29707514 TI - An analysis of trunk kinematics and gait parameters in people with stroke. AB - Background: Approximately two out of three people with stroke experience gait problems. Trunk movement control and symmetry is an important prerequisite for functional walking gait. Movement control, measured objectively as kinematics during walking gait, is rarely investigated. Objective: To describe the three dimensional (3D) kinematics of the trunk during gait in people with stroke, including key spatiotemporal characteristics. Methodology: A total of 17 adults with stroke who met the inclusion criteria were selected to participate in this cross-sectional pilot study. An eight-camera T-10 Vicon system with Nexus 1.8 software (Vicon Motion System Limited, Oxford, UK) was used to analyse the 3D kinematics of the trunk during self-selected walking speed. Trunk kinematics throughout the gait cycle and spatiotemporal parameters were extracted using custom-built scripts in MATLAB used at the Stellenbosch University Movement Analysis Laboratory. Stata Version 12.1 software was used to assess differences in trunk kinematics between the affected and unaffected sides during gait using the Sign test (statistical significance level p < 0.05). Results: Participants achieved functional gait speeds although they presented with asymmetrical trunk kinematics. During the full gait cycle, there were statistically significant differences of trunk motion between the affected and unaffected sides in the coronal plane (p < 0.001). There were statistically significant differences in the trunk kinematics between the affected side and unaffected sides at initial contact (p < 0.001) and foot off (p < 0.049) in the coronal plane as well as at initial contact (p < 0.000) and foot off (p < 0.013) in the transverse plane. Conclusion: This pilot study found significant asymmetry in trunk motion between the affected and unaffected sides that varied across the gait cycle. This suggests the trunk may need to be targeted in clinical gait retraining post stroke. PMID- 29707515 TI - The postural stability of children with foetal alcohol spectrum disorders during one-leg stance: A feasibility study. AB - Background: Postural control may be impaired in children with foetal alcohol spectrum disorders (FASD). The study assessed the protocol feasibility in terms of (1) recruiting children with FASD in a rural, small town; (2) using the measurement instruments in a real-life setting; (3) the one-leg standing (OLS) task and (4) presenting preliminary results on postural stability of children with and without FASD. Methods: Nine-year-old children diagnosed with and without FASD were invited to participate. Twenty-eight children performed OLS. Feasibility outcomes included recruitment, measurement instrument use and task instruction. Postural stability outcomes included standing duration, centre of pressure (COP) and body segment acceleration. Results: Participants recruitment was feasible in terms of the (1) ability to sample a reasonable participant number in a rural town setting and the capacity to increase the sample size if more schools are included in the sampling frame and (2) use of assent and consent forms that were appropriate for this population. The measurement instruments were user-friendly, cost-effective and time-efficient. Instructions for the task require amendment to address foot placement of the non-weight-bearing leg. There was a significant difference between cases and controls on mean COP velocity (p = 0.001) and the pelvis segment acceleration in the mediolateral direction (p = 0.01) and the anteroposterior direction (p = 0.027). The control children took longer to achieve postural control. The girls demonstrated a significant difference for the COP anteroposterior displacement (p = 0.008) and velocity (p = 0.049). Conclusions: The recruitment of children with and without FASD in a rural, small town and the administration of measurement instruments in a real life, school-based setting was feasible. However, the verbal instructions for the task require revision. The male control group took longer to achieve postural control because the task was performed differently between the two groups. However, the case girls were slower to achieve postural control than control girls though performing the task similarly. PMID- 29707517 TI - 'How deep are your pockets?' Autoethnographic reflections on the cost of raising a child with autism. AB - Background: In this article, we reflected on our experience of the cost of parenting a child with autism, including our ongoing search for educational and therapeutic intervention. Objectives: We aimed to give an academic insight into the state of autism education and care in South Africa as seen by us, with special attention to its cost and sustainability. Methods: Using evocative autoethnography as storied scholarship together with critical autism studies, we reflected on stories of the past 5 years since our son's diagnosis. Results: Our experiences agree with international studies that establish autism as the most expensive disability. In addition to the high costs of diagnosis, existing intervention and support approaches are unaffordable for the majority of South Africans. We recommend that teachers should be trained to participate in early screening and diagnosis, as well as co-therapists, to strengthen the implementation of inclusive education. Conclusion: The kind of autism intervention currently offered in South Africa is financially and socially unsustainable. Instead of positioning autism as an individual or family dilemma, it should be addressed as an educational and societal issue. Future research should explore cost-effective options for a developing country context, while promoting best practice within inclusive settings. PMID- 29707516 TI - Communication rehabilitation in sub-Saharan Africa: The role of speech and language therapists. AB - Background: Workforce factors present a significant barrier to the development of rehabilitation services for people with communication disabilities in sub-Saharan Africa (SSA). Exploring how the work of speech and language therapists (SLTs) in the region is organised and delivered can provide insight into existing services, areas for future workforce development and improved rehabilitation access for people with communication disability. Objectives: This paper describes the employment and service provision patterns and work roles of a sample of SLTs in SSA. Method: A broad, purpose-designed, mixed-methods survey was designed to collect data from SLTs living in Anglophone countries of SSA. Descriptive statistics and qualitative content analysis were undertaken. This paper reports on a subset of data from the wider survey. Results: A description of the employment and work roles of the 33 respondents to the survey and characteristics of their service users is presented. SLTs were commonly employed within private and not-for-profit sectors and frequently worked in temporary jobs. SLTs engaged in a range of work roles, including capacity building and training others. Services were provided by SLTs across age ranges, health conditions and settings, with paediatric, urban services commonly reported. Costs for service users and urban-centred services give indications of barriers to service access. Conclusion: Knowledge of the way in which speech and language therapy services are organised and provided has the potential to shape the development of communication disability rehabilitation in SSA. This research has identified a range of issues requiring consideration as the profession develops and grows. PMID- 29707518 TI - Lessons from the pilot of a mobile application to map assistive technology suppliers in Africa. AB - A pilot project to develop and implement a mobile smartphone application (App) that tracks and maps assistive technology (AT) availability in southern Africa was launched in Botswana in 2016. The App was developed and tested through an iterative process. The concept of the App (AT-Info-Map) was well received by most stakeholders within the pilot country, and broader networks. Several technical and logistical obstacles were encountered. These included high data costs; difficulty in accessing AT information from the public healthcare sector, the largest supplier of AT; and the high human resource demand of collecting and keeping up-to-date device-level information within a complex and fragmented supply sector that spans private, public and civil society entities. The challenges were dealt with by keeping the data burden low and eliminating product level tracking. The App design was expanded to include disability services, contextually specific AT categories and make navigation more intuitive. Long-term sustainability strategies like generating funding through advertisements on the App or supplier usage fees must be explored. Outreach and sensitisation programmes about both the App and AT in general must be intensified. The project team must continually strengthen partnerships with private and public stakeholders to ensure ongoing project engagement. The lessons learnt might be of value to others who wish to embark on initiatives in AT and/or implement Apps in health or disability in southern Africa and in low-resourced settings around the world. PMID- 29707520 TI - DNA Damage Inducible Transcript 4 Gene: The Switch of the Metabolism as Potential Target in Cancer. AB - DNA damage inducible transcript 4 (DDIT4) gene is expressed under stress situations turning off the metabolic activity triggered by the mammalian target of rapamycin (mTOR). Several in vitro and in vivo works have demonstrated the ability of DDIT4 to generate resistance to cancer therapy. The link between the metabolism suppression and aggressiveness features of cancer cells remains poorly understood since anti-mTOR agents who are part of the repertoire of drugs used for systemic treatment of cancer achieving variable results. Interestingly, the high DDIT4 expression is associated with worse outcomes compared to tumors with low DDIT4 expression, seen in a wide variety of solid and hematological tumors, which suggests the driver role of this gene and provide the basis to target it as part of a new therapeutic strategy. In this review, we highlight our current knowledge about the biology of DDIT4 and its role as a prognostic biomarker, encompassing the motives for the development of target drugs against DDIT4 as a better target than mTOR inhibitors. PMID- 29707519 TI - Molecular Signatures of High-Grade Cervical Lesions. AB - Cervical cancer is the fourth most common neoplasia in women and the infection with human papilloma virus (HPV) is its necessary cause. Screening methods, currently based on cytology and HPV DNA tests, display low specificity/sensitivity, reducing the efficacy of cervical cancer screening programs. Herein, molecular signatures of cervical cytologic specimens revealed by liquid chromatography-mass spectrometry (LC-MS), were tested in their ability to provide a metabolomic screening for cervical cancer. These molecules were tested whether they could clinically differentiate insignificant HPV infections from precancerous lesions. For that, high-grade squamous intraepithelial lesions (HSIL)-related metabolites were compared to those of no cervical lesions in women with and without HPV infection. Samples were collected from women diagnosed with normal cervix (N = 40) and from those detected with HSIL from cytology and colposcopy (N = 40). Liquid-based cytology diagnosis, DNA HPV-detection test, and LC-MS analysis were carried out for all the samples. The same sample, in a customized collection medium, could be used for all the diagnostic techniques employed here. The metabolomic profile of cervical cancer provided by LC-MS was found to indicate unique molecular signatures for HSIL, being two ceramides and a sphingosine metabolite. These molecules occurred independently of women's HPV status and could be related to the pre-neoplastic phenotype. Statistical models based on such findings could correctly discriminate and classify HSIL and no cervical lesion women. The results showcase the potential of LC-MS as an emerging technology for clinical use in cervical cancer screening, although further validation with a larger sample set is still necessary. PMID- 29707521 TI - Evaluation by Flow Cytometry of Mature Monocyte Subpopulations for the Diagnosis and Follow-Up of Chronic Myelomonocytic Leukemia. AB - Chronic myelomonocytic leukemia (CMML) is a myelodysplastic/myeloproliferative neoplasm, characterized by persistent monocytosis and dysplasia in at least one myeloid cell lineage. This persistent monocytosis should be distinguished from the reactive monocytosis which is sometimes observed in a context of infections or solid tumors. In 2015, Selimoglu-Buet et al. observed an increased percentage of classical monocytes (CD14+/CD16- >94%) in the peripheral blood (PB) of CMML patients. In this study, using multiparametric flow cytometry (MFC), we assessed the monocytic distribution in PB samples and in bone marrow aspirates from 63 patients with monocytosis or CMML suspicion, and in seven follow-up blood samples from CMML patients treated with hypomethylating agents (HMA). A control group of 12 healthy age-matched donors was evaluated in parallel in order to validate the analysis template. The CMML diagnosis was established in 15 cases in correlation with other clinical manifestations and biological tests. The MFC test for the evaluation of the repartition of monocyte subsets, as previously described by Selimoglu-Buet et al. showed a specificity of 97% in blood and 100% in marrow samples. Additional information regarding the expression of intermediate MO2 monocytes percentage improved the specificity to 100% in blood samples allowing the screening of abnormal monocytosis. The indicative thresholds of CMML monocytosis were different in PB compared to BM samples (classical monocytes >95% for PB and >93% for BM). A decrease of monocyte levels in PB and BM, along with a normalization of monocytes distribution, was observed after treatment in 4/7 CMML patients with favorable evolution. No significant changes were observed in 3/7 patients who did not respond to HMA therapy and also presented unfavorable molecular prognostic factors at diagnosis (ASXL1, TET2, and IDH2 mutations). Considering its simplicity and robustness, the monocyte subsets evaluation by MFC provides relevant information for CMML diagnosis. PMID- 29707522 TI - Early Lymphocyte Loss and Increased Granulocyte/Lymphocyte Ratio Predict Systemic Spread of Streptococcus pyogenes in a Mouse Model of Acute Skin Infection. AB - Background: Group A streptococci may induce lymphopenia, but the value of lymphocyte loss as early biomarkers for systemic spread and severe infection has not been examined systematically. Methods: We evaluated peripheral blood cell indices as biomarkers for severity and spread of infection in a mouse model of Streptococcus pyogenes skin infection, using two isolates of greatly differing virulence. Internal organs were examined histologically. Results: After subcutaneous inoculation, strain AP1 disseminated rapidly to peripheral blood and internal organs, causing frank sepsis. In contrast, seeding of internal organs by 5448 was mild, this strain could not be isolated from blood, and infection remained mostly localized to skin. Histopathologic examination of liver revealed microvesicular fatty change (steatosis) in AP1 infection, and examination of spleen showed elevated apoptosis and blurring of the white pulp/red pulp border late (40 h post infection) in AP1 infection. Both strains caused profound lymphopenia, but lymphocyte loss was more rapid early in AP1 infection, and lymphocyte count at 6 h post infection was the most accurate early marker for AP1 infection (area under the receiver operator curve [AUC] = 0.93), followed by the granulocyte/lymphocyte ratio (AUC = 0.89). Conclusions: The results suggest that virulence of S. pyogenes correlates with the degree of early lymphopenia and underscore the value of peripheral blood indices to predict severity of bacterial infections in mice. Early lymphopenia and elevated granulocyte/lymphocyte ratio merit further investigation as biomarkers for systemic spread of S. pyogenes skin infections in humans and, possibly, related pyogenic streptococci in humans and animals. PMID- 29707523 TI - List of guest reviewers. PMID- 29707524 TI - The Value of Ozone in CT-Guided Drainage of Multiloculated Pyogenic Liver Abscesses: A Randomized Controlled Study. AB - Objective: This study was designed to compare the effects of catheter drainage alone and combined with ozone in the management of multiloculated pyogenic liver abscess (PLA). Methods: The prospective study included 60 patients diagnosed with multiloculated PLA. All patients were randomly divided into two groups: catheter drainage alone (group I) and catheter drainage combined with ozone (group II). Drainage was considered successful when (1) the abscess cavity was drained and (2) clinical symptoms were resolved. Kruskal-Wallis nonparametric test was used to compare the success rates, length of stay (LOS), and need for further surgery of the two groups. P < 0.05 indicates significant difference. Results: All patients' catheters were successfully placed under CT guidance. Group I was treated with catheters alone and group II was treated with catheters and ozone. The success rates of groups I and II were 86% and 96%, respectively (P < 0.05). And compared with group II, the duration of fever in group I was longer (P < 0.05), and the LOS was also longer (P < 0.05). Conclusion: Catheter drainage combined with ozone is an effective and safe treatment in multiloculated PLA. The Clinical Registration Number is ChiCTR1800014865. PMID- 29707525 TI - RAS/BRAF Circulating Tumor DNA Mutations as a Predictor of Response to First-Line Chemotherapy in Metastatic Colorectal Cancer Patients. AB - Background: Since circulating tumor DNA (ctDNA) offers clear advantages as a minimally invasive method for tumor monitoring compared with tumor tissue, we aimed to evaluate genotyping ctDNA using a next-generation sequencing- (NGS-) based panel to identify the prognostic value of mutation status in metastatic colorectal cancer (mCRC) patients with primary tumor resected and with subsequent lines of treatment in this study. Methods: 76 mCRC patients treated in Beijing Chao-Yang Hospital from 2011 to 2017 were enrolled. Genotyping of RAS/BRAF in tumor tissue and ctDNA was determined by ARMS PCR and with a 40-gene panel using NGS, respectively. Patient clinicopathologic features and RAS/BRAF gene mutation status were evaluated by survival analysis for disease-free survival (DFS) and progression-free survival (PFS). Results: Among 76 patients, KRAS distributions were not significantly correlated with any clinicopathologic features. The concordance between tumor tissue and ctDNA KRAS mutation was 81.25%. Mutations of RAS/BRAF had no significant impact on DFS after surgery (hazard ratio (HR), 1.205; 95% CI, 0.618 to 2.349; P = 0.5837) but prognosticated poorer PFS in subsequent first-line therapy (HR, 3.351; 95% CI, 1.172 to 9.576; P = 0.024). Conclusion: ctDNA was comparable with tumor tissue for mutation detection. RAS/BRAF mutations detected in ctDNA predict a worse PFS in mCRC patients with first-line chemotherapy. Our results provide support for the prognostic value of RAS/BRAF ctDNA mutation detection in mCRC patients. PMID- 29707526 TI - Combination Immunotherapy Approaches for Pancreatic Cancer Treatment. AB - Pancreatic ductal adenocarcinoma is a lethal malignant disease with a very low medium survival. Currently, metastatic pancreatic cancer poorly responds to conventional treatments and exhibits an acute resistance to most chemotherapy. Few approaches have been shown to be effective for metastatic pancreatic cancer treatment. Novel therapeutic approaches to treat patients with pancreatic adenocarcinoma are in great demand. Last decades, immunotherapies have been evaluated in clinical trials and received great success in many types of cancers. However, it has very limited success in treating pancreatic cancer. As pancreatic cancer poorly responds to many single immunotherapeutic agents, combination immunotherapy was introduced to improve efficacy. The combination therapies hold great promise for enhancing immune responses to achieve better therapeutic effects. This review summarizes the existing and potential combination immunotherapies for the treatment of pancreatic cancer. PMID- 29707527 TI - Treating Hypotension in Preterm Neonates With Vasoactive Medications. AB - Preterm neonates often have hypotension which may be due to various etiologies. While it is controversial to define hypotension in preterm neonates, various vasoactive medications are commonly used to provide the cardiovascular support to improve the blood pressure, cardiac output, or to treat shock. However, the literature on the systemic and regional hemodynamic effects of these antihypotensive medications in neonates is deficient and incomplete, and cautious translation of findings from other clinical populations and animal studies is required. Based on a literature search on published reports, meta-analytic reviews, and selected abstracts, this review discusses the current available information on pharmacologic actions, clinical effects, and side effects of commonly used antihypotensive medications including dopamine, dobutamine, epinephrine, norepinephrine, vasopressin, and milrinone in preterm neonates. PMID- 29707528 TI - Changes in Near-Infrared Spectroscopy After Congenital Cyanotic Heart Surgery. AB - Background: Since oxygen saturation from pulse oximetry (SpO2) and partial pressure of arterial oxygen (PaO2) are observed to improve immediately after surgical correction of cyanotic congenital heart disease (CHD), we postulate that cerebral (CrO2) and somatic (SrO2) oximetry also improves immediately post correction. We aim to prospectively examine CrO2 and SrO2, before, during, and after surgical correction as well as on hospital discharge in children with cyanotic CHD to determine if and when these variables increase. Methods: This is a prospective observational trial. Eligibility criteria included children below 18 years of age with cyanotic CHD who required any cardiac surgical procedure. CrO2 and SrO2 measurements were summarized at six time-points for comparison: (1) pre-cardiopulmonary bypass (CPB); (2) during CPB; (3) post-CPB; (4) Day 1 in the pediatric intensive care unit (PICU); (5) Day 2 PICU; and (6) discharge. Categorical and continuous variables are presented as counts (percentages) and median (interquartile range), respectively. Results: Twenty-one patients were analyzed. 15 (71.4%) and 6 (28.6%) patients underwent corrective and palliative surgeries, respectively. In the corrective surgery group, SpO2 increased immediately post-CPB compared to pre-CPB [99 (98, 100) vs. 86% (79, 90); p < 0.001] and remained in the normal range through to hospital discharge. Post-CPB CrO2 did not change from pre-CPB [72.8 (58.8, 79.0) vs. 72.1% (63.0, 78.3); p = 0.761] and even decreased on hospital discharge [60.5 (53.6, 62.9) vs. 72.1% (63.0, 78.3); p = 0.005]. Post-CPB SrO2 increased compared to pre-CPB [87.3 (77.2, 89.5) vs. 72.7% (65.6, 77.3); p = 0.001] but progressively decreased during PICU stay to a value lower than baseline at hospital discharge [66.9 (57.3, 76.9) vs. 72.7% (65.6, 77.3); p = 0.048]. Conclusion: CrO2 and SrO2 did not increase after corrective surgery of cyanotic CHD even up to hospital discharge. Future larger studies are required to validate these findings. (This study is registered with ClinicalTrials.gov ID: NCT02417259.). PMID- 29707529 TI - Nephrolithiasis and Nephrocalcinosis in Childhood-Risk Factor-Related Current and Future Treatment Options. AB - Nephrolithiasis, urolithiasis, and nephrocalcinosis (NC) have become common causes of hospitalization and referral to pediatric outpatient clinics. It is of utmost importance to start with diagnostic evaluation directly after the first passage of a kidney stone, or if NC is diagnosed, in each pediatric patient. This is necessary, as in about 80% of children a metabolic reason for stone disease is detected. Current treatment options are scarce and mainly include general measures like an increased fluid intake or elevating the solubility of a lithogenic substance. According to the given lithogenic risk factor(s), specific treatment options are available and are being summarized in this review. Furthermore, an outlook on potential future treatment options, including innovative strategies such as mRNA-based or recombinant enzyme substitution therapy, is given. PMID- 29707530 TI - Shape-Up and Eat Right Families Pilot Program: Feasibility of a Weight Management Shared Medical Appointment Model in African-Americans With Obesity at an Urban Academic Medical Center. AB - Objectives: Disparities in obesity care exist among African-American children and adults. We sought to test the feasibility of a pilot program, a 1-year family based intervention for African-American families with obesity [shape up and eat right (SUPER)], adopting the shared medical appointment model (SMA) at an urban safety net hospital. Outcomes: Primary outcomes: (1) family attendance rate and (2) program satisfaction. Secondary outcomes: change in body mass index (BMI), eating behaviors, and sedentary activity. Methods: Adult parents (BMI >= 25 kg/m2) >=18 years and their child(ren) (BMI >= 85th percentile) ages 6-12 years from adult or pediatric weight management clinics were recruited. One group visit per month (n = 12) consisting of a nutrition and exercise component was led by a nurse practitioner and registered dietitian. Height and weight were recorded during each visit. Participants were queried on program satisfaction, food logs and exercise journals, Food Stamp Program's Food Behavior, and the Expanded Food and Nutrition Education Program food checklists. Results: Thirteen participants from lower socioeconomic zip codes consented [n = 5 mothers mean age 33 years, BMI of 47.4 kg/m2 (31.4-73.6 kg/m2); n = 8 children; mean age 9 years, BMI of 97.6th percentile (94-99th percentile); 60% enrolled in state Medicaid]. Average individual attendance was 23.4% (14-43%; n = 13); monthly session attendance rates declined from 100 to 40% by program completion; two families completed the program in entirety. Program was rated (n = 5 adults) very satisfactory (40%) and extremely satisfactory (60%). Pre-intervention, families rated their eating habits as fair and reported consuming sugar-sweetened beverages or sports drinks, more so than watching more than 1 h of television (p < 0.002) or video game/computer activity (p < 0.006) and consuming carbonated sodas (p < 0.004). Post-intervention, reducing salt intake was the only statistically significant variable (p < 0.029), while children watched fewer hours of television and spent less time playing video games (from average 2 to 3 h daily; p < 0.03). Conclusion: Attendance was lower than expected though children seemed to decrease screen time and the program was rated satisfactory. Reported socioeconomic barriers precluded families from attending most sessions. Future reiterations of the intervention could be enhanced with community engagement strategies to increase participant retention. PMID- 29707531 TI - Morphometric Magnetic Resonance Imaging Study in Children With Primary Monosymptomatic Nocturnal Enuresis. AB - Objective: Primary monosymptomatic nocturnal enuresis (PMNE) refers to bed wetting in children who have no other lower urinary tract symptoms and are never dry for more than 6 months. Our previous studies demonstrated that children with PMNE exhibited brain functional abnormalities compared with healthy controls; however, researches on the abnormalities in gray matter were limited. This study aimed to investigate brain structural changes in gray matter of children with PMNE using magnetic resonance imaging (MRI). Methods: Gray matter volumes (GMVs) and gyrification indices (GIs) were calculated using voxel-based and surface based morphometry analyses of structural MRI data acquired from 26 children with PMNE and 28 healthy children. To identify between-group differences in gray matter, two-sample t-tests were conducted on GMV and GI images separately. Results: Compared with the controls, children with PMNE showed significantly increased GMVs in the supplementary motor area and medial prefrontal cortex regions (mean GMV in PMNE: 0.54 +/- 0.07 l; mean GMV in controls: 0.50 +/- 0.06 l) and reduced GIs in the right precuneus (mean GI in PMNE: 25.74 degrees +/- 2.34 degrees ; mean GI in controls: 27.97 degrees +/- 1.79 degrees ). Conclusion: Children with PMNE showed abnormal GMVs in frontal lobe and GIs in precuneus, and these changes might be involved in the pathological mechanism of PMNE. PMID- 29707532 TI - Association of Cytochrome CYP1A1 Gene Polymorphisms and Tobacco Smoking With the Risk of Breast Cancer in Women From Iraq. AB - Background: CYP1A1 gene polymorphisms and tobacco smoking are among several risk factors for various types of cancers, but their influence on breast cancer remains controversial. We analyzed the possible association of CYP1A1 gene polymorphisms and tobacco smoking-related breast cancer in women from Iraq. Materials and methods: In this case-control study, gene polymorphism of CYP1A1 gene (CYP1A1m1, T6235C and CYP1A1m2, A4889G) of 199 histologically verified breast cancer patients' and 160 cancer-free control women's specimens were performed by using PCR-based restriction fragment length polymorphism. Results: Three genotype frequencies (TT, TC, and CC) of CYP1A1m1T/C appeared in 16.1, 29.6, and 54.3% of women with breast cancer, respectively, compared with 41.2, 40, and 18.8% in the control group, respectively. CYP1A1m1 CC genotype and C allele were significantly associated with increased risks for breast cancer in patients (54.3 and 69%, respectively) compared with controls (18.8 and 39%, respectively). While the three genotype frequencies (AA, AG, and GG) of CYP1A1m2A/G were detected in 20.1, 31.2, and 48.7% in patients compared with 46.3, 40.6, and 13.1% in controls, respectively. The frequency of GG genotypes and G allele was significantly higher in patients (48.7 and 64%, respectively) than in the controls (13.1 and 33%, respectively). Smoking women having either CC or GG genotypes showed a highly significant association with increased risk of breast cancer [odds ratio (OR) = 1.607, 95% confidence interval (CI) 0.91-1.64, p = 0.0001, and OR, 1.841, 95% CI, 0.88-1.67, p = 0.0001, respectively]. On the other hand, the T and A alleles of predominantly seen in healthy smoking women (83 and 85%, p = 0.0001, respectively). Conclusion: These findings indicated that both C and G alleles of CYP1A1m1 and m2 were significantly associated with elevated risk of breast cancer in Iraqi women, while the T and A alleles were predominantly seen in healthy controls which may indicate their protective role. The C and G association with breast cancer incidence was more prevalent among tobacco smoking patients. These polymorphisms may be used as biomarkers of breast cancer in women from Iraq. PMID- 29707533 TI - Persuasiveness of Statistics and Patients' and Mothers' Narratives in Human Papillomavirus Vaccine Recommendation Messages: A Randomized Controlled Study in Japan. AB - Background: The human papillomavirus (HPV) vaccination percentage among age eligible girls in Japan is only in the single digits. This signals the need for effective vaccine communication tactics. This study aimed to examine the influence of statistical data and narrative HPV vaccination recommendation massages on recipients' vaccination intentions. Methods: This randomized controlled study covered 1,432 mothers who had daughters aged 12-16 years. It compared message persuasiveness among four conditions: statistical messages only; narrative messages of a patient who experienced cervical cancer, in addition to statistical messages; narrative messages of a mother whose daughter experienced cervical cancer, in addition to statistical messages; and a control. Vaccination intentions to have one's daughter(s) receive the HPV vaccine before and after reading intervention materials were assessed. Statistical analysis was conducted using analysis of variance with Tukey's test or Games-Howell post hoc test, and analysis of covariance with Bonferroni correction. Results: Vaccination intentions after intervention in the three intervention conditions were higher than the control condition (p < 0.001). A mother's narrative messages in addition to statistical messages increased HPV vaccination intention the most of all tested intervention conditions. A significant difference in the estimated means of intention with the covariate adjustment for baseline value (i.e., intention before intervention) was found between a mother's narrative messages in addition to statistical messages and statistical messages only (p = 0.040). Discussion: Mothers' narrative messages may be persuasive when targeting mothers for promoting HPV vaccination. This may be because mothers can easily relate to and identify with communications from other mothers. However, for effective HPV vaccine communication, further studies are needed to understand more about persuasive differences in terms of statistics, narratives, and narrators. Directions for future research are also suggested. PMID- 29707534 TI - Photo-Responsive Graphene and Carbon Nanotubes to Control and Tackle Biological Systems. AB - Photo-responsive multifunctional nanomaterials are receiving considerable attention for biological applications because of their unique properties. The functionalization of the surface of carbon nanotubes (CNTs) and graphene, among other carbon based nanomaterials, with molecular switches that exhibit reversible transformations between two or more isomers in response to different kind of external stimuli, such as electromagnetic radiation, temperature and pH, has allowed the control of the optical and electrical properties of the nanomaterial. Light-controlled molecular switches, such as azobenzene and spiropyran, have attracted a lot of attention for nanomaterial's functionalization because of the remote modulation of their physicochemical properties using light stimulus. The enhanced properties of the hybrid materials obtained from the coupling of carbon based nanomaterials with light-responsive switches has enabled the fabrication of smart devices for various biological applications, including drug delivery, bioimaging and nanobiosensors. In this review, we highlight the properties of photo-responsive carbon nanomaterials obtained by the conjugation of CNTs and graphene with azobenzenes and spiropyrans molecules to investigate biological systems, devising possible future directions in the field. PMID- 29707535 TI - Evidence That Speciation of Oxovanadium Complexes Does Not Solely Account for Inhibition of Leishmania Acid Phosphatases. AB - Leishmaniasis is an endemic disease affecting a diverse spectra of populations, with 1.6 million new cases reported each year. Current treatment options are costly and have harsh side effects. New therapeutic options that have been previously identified, but still underappreciated as potential pharmaceutical targets, are Leishmania secreted acid phosphatases (SAP). These acid phosphatases, which are reported to play a role in the survival of the parasite in the sand fly vector, and in homing to the host macrophage, are inhibited by orthovanadate and decavanadate. Here, we use L. tarentolae to further evaluate these inhibitors. Using enzyme assays, and UV-visible spectroscopy, we investigate which oxovanadium starting material (orthovanadate or decavanadate) is a better inhibitor of L. tarentolae secreted acid phosphatase activity in vitro at the same total moles of vanadium. Considering speciation and total vanadium concentration, decavanadate is a consistently better inhibitor of SAP in our conditions, especially at low substrate:inhibitor ratios. PMID- 29707536 TI - Fast and Simple Microwave Synthesis of TiO2/Au Nanoparticles for Gas-Phase Photocatalytic Hydrogen Generation. AB - The fabrication of small anatase titanium dioxide (TiO2) nanoparticles (NPs) attached to larger anisotropic gold (Au) morphologies by a very fast and simple two-step microwave-assisted synthesis is presented. The TiO2/Au NPs are synthesized using polyvinylpyrrolidone (PVP) as reducing, capping and stabilizing agent through a polyol approach. To optimize the contact between the titania and the gold and facilitate electron transfer, the PVP is removed by calcination at mild temperatures. The nanocatalysts activity is then evaluated in the photocatalytic production of hydrogen from water/ethanol mixtures in gas-phase at ambient temperature. A maximum value of 5.3 mmol.[Formula: see text]h-1 (7.4 mmol.[Formula: see text]h-1) of hydrogen is recorded for the system with larger gold particles at an optimum calcination temperature of 450 degrees C. Herein we demonstrate that TiO2-based photocatalysts with high Au loading and large Au particle size (~50 nm) NPs have photocatalytic activity. PMID- 29707537 TI - Inertial Sensor Measurements of Upper-Limb Kinematics in Stroke Patients in Clinic and Home Environment. AB - Background: Upper-limb impairments in stroke patients are usually measured in clinical setting using standard clinical assessment. In addition, kinematic analysis using opto-electronic systems has been used in the laboratory setting to map arm recovery. Such kinematic measurements cannot capture the actual function of the upper extremity in daily life. The aim of this study is to longitudinally explore the complementarity of post-stroke upper-limb recovery measured by standard clinical assessments and daily-life recorded kinematics. Methods: The study was designed as an observational, single-group study to evaluate rehabilitation progress in a clinical and home environment, with a full-body sensor system in stroke patients. Kinematic data were recorded with a full-body motion capture suit during clinical assessment and self-directed activities of daily living. The measurements were performed at three time points for 3 h: (1) 2 weeks before discharge of the rehabilitation clinic, (2) right after discharge, and (3) 4 weeks after discharge. The kinematic analysis of reaching movements uses the position and orientation of each body segment to derive the joint angles. Newly developed metrics for classifying activity and quality of upper extremity movement were applied. Results: The data of four stroke patients (three mildly impaired, one sever impaired) were included in this study. The arm motor function assessment improved during the inpatient rehabilitation, but declined in the first 4 weeks after discharge. A change in the data (kinematics and new metrics) from the daily-life recording was seen in in all patients. Despite this worsening patients increased the number of reaches they performed during daily life in their home environment. Conclusion: It is feasible to measure arm kinematics using Inertial Measurement Unit sensors during daily life in stroke patients at the different stages of rehabilitation. Our results from the daily life recordings complemented the data from the clinical assessments and illustrate the potential to identify stroke patient characteristics, based on kinematics, reaching counts, and work area. Clinical Trial Registration: https://clinicaltrials.gov, identifier NCT02118363. PMID- 29707538 TI - Insulin-Like Growth Factor Axis Expression in Dental Pulp Cells Derived From Carious Teeth. AB - The insulin-like growth factor (IGF) axis plays an important role in dental tissue regeneration and most components of this axis are expressed in human dental pulp cells (DPCs). In our previous study, we analyzed IGF axis gene expression in DPCs and demonstrated a novel role of IGF binding protein (IGFBP)-2 and -3 in coordinating mineralized matrix formation in differentiating DPCs. A more recent study from our laboratory partially characterized dental pulp stem cells from teeth with superficial caries (cDPCs) and showed that their potential to differentiate odontoblasts and/or into osteoblasts is enhanced by exposure to the mild inflammatory conditions characteristic of superficial caries. In the present study, we examine whether changes apparent in IGF axis expression during osteogenic differentiation of healthy DPCs are also apparent in DPCs derived from carious affected teeth. PMID- 29707540 TI - Lymphoma and Lymphomagenesis in Primary Sjogren's Syndrome. AB - Primary Sjogren's syndrome (pSS) is a systemic autoimmune disease mainly affecting exocrine glands and leading to impaired secretory function. The clinical picture is dominated by signs and symptoms of mucosal dryness and the course of the disease is mild and indolent in the majority of cases. However, a subgroup of patients can also experience extraglandular manifestations that worsen the disease prognosis. pSS patients are consistently found to have a higher risk of developing non-Hodgkin lymphoma (NHL) compared with patients with other autimmune disorders and to the general population. NHL is the most severe comorbidity that can occur in pSS, therefore recent research has aimed to identify reliable clinical, serological, and histological biomarkers able to predict NHL development in these subjects. This review article encompasses the body of evidence published so far in this field highlighting the challenges and pitfalls of different biomarkers within clinical practice. We also provide an overview of epidemiological data, diagnostic procedures, and evidence-based treatment strategies for NHL in pSS. PMID- 29707541 TI - Personalized Hydration Strategy Attenuates the Rise in Heart Rate and in Skin Temperature Without Altering Cycling Capacity in the Heat. AB - The optimal hydration plan [i.e., drink to thirst, ad libitum (ADL), or personalized plan] to be adopted during exercise in recreational athletes has recently been a matter of debate and, due to conflicting results, consensus does not exist. In the present investigation, we tested whether a personalized hydration strategy based on sweat rate would affect cardiovascular and thermoregulatory responses and exercise capacity in the heat. Eleven recreational male cyclists underwent two familiarization cycling sessions in the heat (34 degrees C, 40% RH) where sweat rate was also determined. A fan was used to enhance sweat evaporation. Participants then performed three randomized time-to exhaustion (TTE) trials in the heat with different hydration strategies: personalized volume (PVO), where water was consumed, based on individual sweat rate, every 10 min; ADL, where free access to water was allowed; and a control (CON) trial with no fluids. Blood osmolality and urine-specific gravity were measured before each trial. Heart rate (HR), rectal, and skin temperatures were monitored throughout trials. Time to exhaustion at 70% of maximal workload was used to define exercise capacity in the heat, which was similar in all trials (p = 0.801). Body mass decreased after ADL (p = 0.008) and CON (p < 0.001) and was maintained in PVO trials (p = 0.171). Participants consumed 0 ml in CON, 166 +/- 167 ml in ADL, and 1,080 +/- 166 ml in PVO trials. The increase in mean body temperature was similar among trials despite a lower increase in skin temperature during PVO trial in comparison with CON (2.1 +/- 0.6 vs. 2.9 +/- 0.5 degrees C, p = 0.0038). HR was lower toward the end of TTE in PVO (162 +/- 8 bpm) in comparison with ADL (168 +/- 12 bpm) and CON (167 +/- 10 bpm), p < 0.001. In conclusion, a personalized hydration strategy can reduce HR during a moderate to high intensity exercise session in the heat and halt the increase in skin temperature. Despite these advantages, cycling capacity in the heat remained unchanged. PMID- 29707539 TI - The Emerging Field of Epitranscriptomics in Neurodevelopmental and Neuronal Disorders. AB - Analogous to DNA methylation and histone modifications, RNA modifications represent a novel layer of regulation of gene expression. The dynamic nature and increasing number of RNA modifications offer new possibilities to rapidly alter gene expression upon specific environmental changes. Recent lines of evidence indicate that modified RNA molecules and associated complexes regulating and "reading" RNA modifications play key roles in the nervous system of several organisms, controlling both, its development and function. Mutations in several human genes that modify transfer RNA (tRNA) have been linked to neurological disorders, in particular to intellectual disability. Loss of RNA modifications alters the stability of tRNA, resulting in reduced translation efficiency and generation of tRNA fragments, which can interfere with neuronal functions. Modifications present on messenger RNAs (mRNAs) also play important roles during brain development. They contribute to neuronal growth and regeneration as well as to the local regulation of synaptic functions. Hence, potential combinatorial effects of RNA modifications on different classes of RNA may represent a novel code to dynamically fine tune gene expression during brain function. Here we discuss the recent findings demonstrating the impact of modified RNAs on neuronal processes and disorders. PMID- 29707542 TI - Effects of the Brown Seaweed Laminaria japonica Supplementation on Serum Concentrations of IgG, Triglycerides, and Cholesterol, and Intestinal Microbiota Composition in Rats. AB - The intestinal microbial communities play critical roles in various aspects of body function of the host. Prebiotics, such as dietary fiber, can affect health of the host by altering the composition of intestinal microbiota. Although brown seaweed Laminaria japonica is rich in dietary fiber, studies on its prebiotic potential are quite rare. In this study, basal diet (control), basal diet supplemented with dried L. japonica (DLJ), heat-treated dried L. japonica (HLJ), or heated dried L. japonica with added fructooligosaccharide (FHLJ) was fed to rats for 16 weeks. Serum concentrations of IgG, triglyceride, and cholesterol were measured. In addition, the intestinal microbiota composition was analyzed by high-throughput sequencing of 16S rRNA gene. As compared to the control group, DLJ, HLJ, and FHLJ groups showed significantly higher serum IgG concentration, but had lower weight gain and serum triglyceride concentration. Moreover, DLJ, HLJ, and FHLJ groups showed lower Fimicutes to Bacteroidetes ratio when compared with the control group. As compared with the control group, obesity-associated bacterial genera (Allobaculum, Turicibacter, Coprobacillus, Mollicute, and Oscilibacter), and the genera with pathogenic potentials (Mollicute, Bacteroides, Clostridium, Escherichia, and Prevotella) decreased while leanness-associated genera (Alistipes, Bacteroides, and Prevotella), and lactic acid bacterial genera (Subdoligranulum, Streptococcus, Lactobacillus, Enterococcus, and Bifidobacterium) increased in all treatment groups. On the contrary, butyric acid producing genera including Subdoligranulum, Roseburia, Eubacterium, Butyrivibrio, and Anaerotruncus increased significantly only in FHLJ group. The overall results support multiple prebiotic effects of seaweed L. japonica on rats as determined by body weight reduction, enhanced immune response, and desirable changes in intestinal microbiota composition, suggesting the great potential of L. japonica as an effective prebiotic for promotion of host metabolism and reduction of obesity in humans. PMID- 29707543 TI - Modeling-Based Investigation of the Effect of Noise in Cellular Systems. AB - Noise is pervasive in cellular biology and inevitably affects the dynamics of cellular processes. Biological systems have developed regulatory mechanisms to ensure robustness with respect to noise or to take advantage of stochasticity. We review here, through a couple of selected examples, some insights on possible robustness factors and constructive roles of noise provided by computational modeling. In particular, we focus on (1) factors that likely contribute to the robustness of oscillatory processes such as the circadian clocks and the cell cycle, (2) how reliable coding/decoding of calcium-mediated signaling could be achieved in presence of noise and, in some cases, enhanced through stochastic resonance, and (3) how embryonic cell differentiation processes can exploit stochasticity to create heterogeneity in a population of identical cells. PMID- 29707544 TI - "Guidelines Recommendations on the Treatment of Tricuspid Regurgitation. Where Are We and Where Do We Go With Transcatheter Valve Intervention". AB - Tricuspid regurgitation (TR) is an important clinical problem because it is frequent and carries a poor prognosis when it is left uncorrected. However, there is still a lack of awareness of tricuspid disease in the medical community. The indications for evaluation and surgical interventions in patients with TR were recently updated in the ESC/EACTS guidelines. Transcatheter tricuspid valve intervention (TTVI), almost exclusively valve repair, is at an early stage of development as only a few hundreds of patients have been treated. The first-in man valve implantation was very recently performed. The recent ESC/EACTS Guidelines state that "The potential role of transcatheter tricuspid valve treatment in high-risk patients needs to be determined". We shall review here which lessons of interest for TTVI can be learned from the Guidelines as regards evaluation and indications for surgery and try to imagine what could be the place of TTVI in the Guidelines in the future. PMID- 29707547 TI - Rapid development of minimally invasive spinal surgery: exciting advancements and challenges. PMID- 29707545 TI - A Review of Bunyamwera, Batai, and Ngari Viruses: Understudied Orthobunyaviruses With Potential One Health Implications. AB - Bunyamwera (BUNV), Batai (BATV), and Ngari (NRIV) are mosquito-borne viruses of the Bunyamwera serogroup in the Orthobunyavirus genus of the Bunyaviridae family. These three viruses have been found to cause disease in both livestock animals, avian species, and humans. Thus, these viruses pose a potential threat to human public health, animal health, and food security. This is especially the case in the developing nations, where BUNV and NRIV are found, mainly in Africa. BUNV and BATV are fairly well characterized, while NRIV is not well characterized owing to only sporadic detection in human and animal populations in Africa. Reassortment is common among bunyaviruses, but NRIV is believed to be the only natural reassortant of the Bunyamwera serogroup. It resulted from a combination of BUNV S and L segments and the BATV M segment. This indicates at least some level co circulation of BUNV and BATV, which have no historically been reported to overlap in geographic distributions. But as these viruses are undercharacterized, there remains a gap in the understanding of how such reassortment could occur, and the consequences of such. Due to their combined wide range of hosts and vectors, geographic distributions, potential severity of associated diseases, and potential for transmissibility between vertebrate hosts, these viruses represent a significant gap in knowledge with important One Health implications. The goal of this review is to report available knowledge of and identify potential future directions for study of these viruses. As these are collectively understudied viruses, there is a relative paucity of data; however, we use available studies to discuss different perspectives in an effort to promote a better understanding of these three viruses and the public and One Health threat(s) they may pose. PMID- 29707546 TI - In Vitro and In Vivo Characterization of a Typical and a High Pathogenic Bovine Viral Diarrhea Virus Type II Strains. AB - Non-cytopathic (ncp) type 2 bovine viral diarrhea virus (BVDV-2) is widely prevalent in Argentina causing high mortality rates in cattle herds. In this study, we characterized an Argentinean ncp BVDV-2 field isolate (98-124) compared to a high-virulence reference strain (NY-93), using in silico analysis, in vitro assays, and in vivo infections of colostrum-deprived calves (CDC) to compare pathogenic characters and virulence. In vitro infection of bovine peripheral blood mononuclear cells (PBMC) with BVDV 98-124 induced necrosis shortly after infection while NY-93 strain increased the apoptotic rate in infected cells. Experimental infection of CDC (n = 4 each) with these strains caused an enteric syndrome. High pyrexia was detected in both groups. Viremia and shedding were more prolonged in the CDC infected with the NY-93 strain. In addition, NY-93 infection elicited a severe lymphopenia that lasted for 14 days, whereas 98-124 strain reduced the leukocyte counts for 5 days. All infected animals had a diminished lymphoproliferation activity in response to a mitogen. Neutralizing and anti-NS3 antibodies were detected 3 weeks after infection in all infected calves. Virulence was associated with a more severe clinical score, prolonged immune-suppression, and a greater window for transmission. Studies of apoptosis/necrosis performed after in vitro PBMC infection also revealed differences between both strains that might be correlated to the in vivo pathogenesis. Our results identified 98-124 as a low-virulence strain. PMID- 29707548 TI - Minimally invasive spine surgery for degenerative spine disease and deformity correction: a literature review. AB - During the last two decades, minimally invasive techniques and instruments in spine surgery have undergone serious development in all fields. Specific advantages of these minimally invasive methods have put them forward in spine surgery in recent times. Preservation of important anatomical structures of the spine is a major factor for the evolution of these procedures. The lower prevalence of complications and faster rehabilitation of patients are some of the advantages of minimally invasive spine surgery (MISS). Due to the increasing use of minimally invasive methods in the clinical practice worldwide, there is a strong need for clarification of basic principles, tips and tricks, complications, and clinical outcomes. This review is an effort to provide a better understanding of some of these procedures. PMID- 29707549 TI - Percutaneous endoscopic cervical discectomy: a technical review. AB - The treatment of cervical disc herniations has evolved in the last 2 decades. While the anterior cervical discectomy and fusion continues being the gold standard for the treatment of radicular pain triggered by cervical disc herniation, other surgical approaches have been developed. Percutaneous endoscopic cervical discectomy has demonstrated the ability to decompress the exiting nerve root and dural sac correctly and encouraging clinical outcomes has been reported in the literature. One of the most important advantages offered by the endoscopic technique is the capability to resolve the patient's symptoms without the need for interbody fusion. Also, a specific and selective decompression under continuous visualization with minimal surgery-related trauma can be achieved. There are two percutaneous endoscopic cervical discectomy approaches: anterior and posterior. The decision to perform each other depends on pathology site. However, the endoscopic technique requires previous surgical training, a steep learning curve, and proper patient selection. The development of new hardware such as endoscopes with better optics, lighting systems, and endoscopic surgical tools have allowed using endoscopic techniques in more complex cases. The objective of this review is the technical description of the anterior and posterior percutaneous endoscopic cervical discectomy. PMID- 29707551 TI - Minimally invasive surgery for thoracolumbar spinal trauma. AB - The indications for operative intervention after thoracolumbar spine trauma have been well described. Advances in minimally invasive techniques, including percutaneous pedicle screw fixation and mini-open anterolateral retractor-based approaches can improve surgical outcomes when appropriately applied by reducing blood loss, operative duration and post-operative pain. Moreover, they allow for theoretical advantages by preservation of muscular and skeletal blood supply and innervation that is typically lost during the muscular dissection of open approaches. For thoracolumbar spine fractures, percutaneous fixation allows for internal bracing of unstable fractures during healing while maintaining sagittal alignment. In instances of neurological compromise from fracture retropulsion, corpectomies may be required, and mini-open lateral approaches adopted from degenerative disease applications allow for a minimally invasive manner to treat the defect. These further allow for placement of wide rectangular-footprint expandable vertebral body replacement devices to provide anterior column support. We believe this allows for lower rates of subsidence and helps to maintain the biomechanical integrity necessary to prevent post-traumatic malalignment and kyphosis. Together, these minimally invasive techniques combined supply the spine surgeon with a minimally invasive armamentarium to treat nearly all thoracolumbar spine trauma. Surgeons should be comfortable with the strengths and shortcomings of these approaches in order to successfully apply them for this pathology. PMID- 29707550 TI - Complications on minimally invasive oblique lumbar interbody fusion at L2-L5 levels: a review of the literature and surgical strategies. AB - Fusion is the cornerstone in the treatment of an unstable degenerative lumbar spinal disease. Various techniques have been developed. Amongst these techniques exists the oblique lumbar interbody fusion (OLIF), which is the ante-psoas approach. Adequate restoration of disc height with large cages placed in the intervertebral space, indirect decompression, and correction of sagittal and coronal alignment can be achieved with OLIF procedure with the advantage of minimal risk for the psoas muscle and lumbar plexus. Nevertheless, this technique entails complications directly associated with the anatomical location where the fusion takes place. This surgical area is a window between the left lateral border of the aorta, or the left common iliac artery, and the anterior belly of the left psoas muscle. Vascular complications associated with the injury of the main vessels, segmental artery or iliolumbar vein of the lumbar spine have been reported, as well as urologic lesions due to ureter transgression, amongst others. Although these complications have been described in the literature, an article that complements this information with technical advice for its avoidance is yet to be published. This article is a review of the most frequent complications associated with the OLIF procedure in L2-L5 lumbar levels, as well as a description of technical strategies for the prevention of such complications. PMID- 29707552 TI - Minimally invasive versus conventional spine surgery for vertebral metastases: a systematic review of the evidence. AB - One of the major determinants of surgical candidacy in patients with symptomatic spinal metastases is the ability of the patient to tolerate the procedure associated morbidity. In other pathologies, minimally invasive (MIS) procedures have been suggested to have lower intra-operative morbidity while providing similar outcomes. We conducted a systematic review of the PubMed library searching for articles that directly compared the operative and post-operative outcomes of patients treated for symptomatic spinal metastases. Inclusion criteria were articles reporting two or more cases of patients >18 years old treated with MIS or open approaches for spinal metastases. Studies reporting results in spinal metastases patients that could not be disentangled from other pathologies were excluded. Our search returned 1,568 articles, of which 9 articles met the criteria for inclusion. All articles were level III evidence. Patients treated with MIS approaches tended to have lower intraoperative blood loss, shorter operative times, shorter inpatient stays, and fewer complications relative to patients undergoing surgeries with conventional approaches. Patients in the MIS and open groups had similar pain improvement, neurological improvement, and functional outcomes. Recent advances in MIS techniques may reduce surgical morbidity while providing similar symptomatic improvement in patients treated for spinal metastases. As a result, MIS techniques may expand the pool of patients with spinal metastases who are candidates for operative management. PMID- 29707553 TI - Minimally invasive anterior, lateral, and oblique lumbar interbody fusion: a literature review. AB - Lumbar interbody fusion involves insertion of a structural graft into an intervertebral disc space to promote bony arthrodesis. It is a well-established surgical strategy for multiple spinal disorders ranging from degenerative conditions to trauma, neoplastic diseases, and deformities requiring correction. Since the inception of lumbar interbody fusion, the most established techniques have been two posterior approaches, the posterior lumbar interbody fusion (PLIF) and the transforaminal lumbar interbody fusion (TLIF). Within the past 15 years, multiple anterolateral approaches to the spine have become widely adopted. These approaches can be performed minimally invasively and spare disruption of the paraspinal muscles and posterior spinal column while enabling wide exposure of the disc space for insertion of interbody grafts much larger than PLIF and TLIF instrumentation. This review highlights three minimally invasive anterolateral approaches: the anterior lumbar interbody fusion (ALIF), the transpsoas lateral lumbar interbody fusion (LLIF), and prepsoas or anterior to the psoas oblique lumbar interbody fusion (OLIF). Relevant topics for discussion and comparison include patient selection, surgical techniques, outcomes, and complications for the three surgical approaches. PMID- 29707554 TI - Comparison of minimally invasive and open transforaminal lumbar interbody fusion in the treatment of single segmental lumbar spondylolisthesis: minimum two-year follow up. AB - Background: Compare the efficacy and safety of minimally invasive and open transforaminal lumbar interbody fusion (TLIF) in the treatment of single segmental lumbar spondylolisthesis. Methods: From 2010-01 to 2015-10, in total, 167 patients with single segmental spondylolisthesis treated by TLIF were included, 79 cases in minimally invasive TLIF (MI-TLIF) group and 88 cases in open TLIF group. The peri-operative parameters of operative time, estimated blood loss and length of postoperative hospital stay was recorded, as well as complications. Visual Analogue Scale (VAS) of low back pain and leg pain, and Oswestry Disability Index (ODI) were used to assess the pain and functional outcomes at pre-operatively, 3 months/1 year/2 years/5 years after operation. The radiographic parameters of posterior height of the intervertebral space and segmental lordosis were measured too. Results: No significantly difference was found at baseline characteristic data of age, gender ratio, the percentage of degenerative and isthmic spondylolisthesis, the percentage of slip, and segmental distribution between MI-TLIF and open TLIF groups. MI-TLIF group had less estimated intra-operative blood loss (163.7+/-49.6 mL) than open TLIF group (243.3+/-70.2 mL, P<0.001) and had shorter post-operative hospital stay (5.8+/ 1.4 days) than open TLIF group (7.3+/-2.9 days, P<0.001). Both MI-TLIF and open TLIF can significantly reduce the VAS of low back pain, VAS of leg pain, ODI, and improve the posterior height of the intervertebral space and segmental lordosis, but no significantly difference was found of them between two groups. Conclusions: Our study suggests that MI-TLIF is a safe and effective choice in the treatment of lower grade lumbar spondylolisthesis (grade II or less), and it has advantages of less blood loss, postoperative hospital stay when compared to open TLIF. PMID- 29707555 TI - Lumbar disc reherniation after transforaminal lumbar endoscopic discectomy. AB - Background: Transforaminal lumbar endoscopic discectomy is a minimally invasive surgical procedure that can be performed in awake patients through an incision less than 1 cm. The procedure requires very little bony removal to access the herniated disc material because the approach is through the foramen, and only a small amount of the superior articulating process is removed to access Kambin's triangle. This study describes our experience with transforaminal endoscopic lumbar decompression (TELD) for the treatment of lumbar disc herniation. We evaluate the risk for reherniation in the first year after surgery and the characteristics of the patients who experience reherniation. Methods: We describe the technique for the transforaminal endoscopic approach to treat lumbar disc herniations. Retrospectively, a series of 141 consecutive patients, who were operated on with lumbar radiculopathy, was analyzed. We excluded patients who had previous surgery at the lumbar level, surgeries done for disease adjacent to a fusion, and surgeries done for spondylolisthesis. A total of 84 consecutive patients were included who had single level lumbar non-revision surgery and at least 1-year follow up. Results: A series of 46 consecutive male and 38 female patients with an average age of 57.4 years (range, 28-87 years old) who underwent transforaminal endoscopic treatment for lumbar disc herniations between 2014 and 2016 is presented. Four patients required microdiscectomy due to reherniation at 5 months, 8 months, 9 months, and 10 months postoperatively. All the patients in the series improved immediately following their endoscopic procedures, and no patients presented with symptoms suggestive of reherniation until 5 months after their initial endoscopic surgery. Patients with reherniation tended to be young: 31, 45, 48, and 49 years of age: all less than the average patient age who underwent endoscopic surgery. Conclusions: Transforaminal endoscopic surgical access to lumbar disc herniations is an ultra-minimally invasive approach for the treatment lumbar degenerative disc disease. It allows for neural decompression by removing disc and foraminal pathology with minimal bone removal. This minimal bone removal prevents iatrogenic destabilization. However, the 1-year reherniation rate presented here is 4.7%. This suggests that the benefit of this technique may be that it is ultra-minimally invasive, but it may only be equal, not superior to microdiscectomy in its rate of reherniation. PMID- 29707556 TI - The outcomes of percutaneous kyphoplasty in treatment of the secondary osteoporotic vertebral compression factures: a case-control study. AB - Background: To investigate the outcomes of using percutaneous kyphoplasty in the treatment of the secondary osteoporotic vertebral compression fractures. Methods: Eighty-one patients had the secondary single segmental osteoporotic vertebral compression fractures after the initial fractures and treated by percutaneous kyphoplasty were reviewed, 74 of them had minimum 2 years follow-up were included in this study. The 74 patients with primary osteoporotic vertebral compression fractures treated by percutaneous kyphoplasty at the same time period were matched as control group in 1:1 ratio. Visual Analogue Scales (VAS) and Oswestry Disability Index (ODI) were used to assess the back pain and functional outcomes. The kyphotic angulation (KA) and compression ratio (CR) of the fractured vertebra was measured too. Results: Both the secondary fracture group and control group had significantly relieved back pain, improved functional outcomes, corrected KA and restored CR after operation, but no difference was found between two groups. Conclusions: Our findings suggest that percutaneous kyphoplasty is an effective and safe procedure for patients with secondary single segmental osteoporotic vertebral compression fractures; it can achieve similar clinical outcomes to the primary osteoporotic vertebral compression fractures. PMID- 29707557 TI - Prepsoas oblique lateral lumbar interbody fusion in deformity surgery. AB - Interbody fusions are routinely used in deformity surgery to achieve both coronal and sagittal correction and attain increased fusion rates. Minimally invasive interbody techniques, including the prepsoas approach, are being utilized to decrease tissue disruption, blood loss, and patient morbidity with similar outcomes compared to traditional surgery. The prepsoas oblique lateral interbody fusion, accesses the spine between the iliac arteries or aorta and psoas muscle, and allows for exposure of the lumbar spine while avoiding some complications commonly seen with a direct lateral approach. Navigation can assist the surgeon for surgical planning, ensuring appropriate placement of the interbody graft, and with placement of posterior pedicle screws. In correctly selected patients, these minimally invasive procedures can achieve excellent deformity correction and outcomes. PMID- 29707558 TI - Limitations and complications of minimally invasive spinal surgery in adult deformity. AB - Minimally invasive spine (MIS) surgery has rapidly progressed from simple short segment fusions to large adult deformity corrections, with radiographic and clinical outcomes as good as those of open surgery. Anterior longitudinal ligament release (ALLR) and anterior column realignment (ACR) have been key advancements in the ability to correct deformity using MIS techniques. However, patient selection and appropriate preoperative workup is critical to obtain good outcomes and for complication avoidance. Despite favorable outcomes in spinal deformity surgery, MIS techniques are limited in (I) pronounced cervical or thoracic deformity; (II) patients with prior fusion mass; and (III) severe sagittal imbalance necessitating Schwab 5 osteotomy or higher. Guidelines for proper patient selection are needed to guide MIS spine surgeons in choosing the right candidate. PMID- 29707559 TI - Highlights from the First Annual Spinal Navigation, Emerging Technologies and Systems Integration Meeting. AB - This paper provides a detailed report of the "First Annual Spinal Navigation, Emerging Technologies and Systems Integration" meeting held December 3, 2016 at the Seattle Science Foundation. PMID- 29707560 TI - Planning for a Nondriving Future: Behaviors and Beliefs Among Middle-Aged and Older Drivers. AB - Despite the reality of older adults living many years after driving cessation, few prepare for the eventuality; empirically, planning for a nondriving future has not been directly quantified or explored. The following study quantifies 1) the extent of current drivers' planning, 2) specific planning behaviors, 3) beliefs about benefits of planning, 4) drivers' intention to plan more for future transportation needs, and 5) group differences associated with planning. In a predominantly female, black, urban sample of current drivers ages 53-92, fewer than half (42.1%) had planned at all for a nondriving future, with correspondingly low levels of planning behaviors reported. However, over 80% believed planning would help them meet their needs post-cessation and transition emotionally to being a nondriver. Most (85%) intended to plan more in the future as well, indicating further potential openness to the topic. Drivers who planned were older, drove less frequently, limited their driving to nearby places, reported less difficulty believing they would become a nondriver, and expected to continue driving three years less than non-planners. These findings suggest that drivers' perceived nearness to driving cessation impacts planning for future transportation needs, and existing perceived benefits of planning may provide leverage to motivate action. PMID- 29707561 TI - Integrated respiratory and palliative care may improve outcomes in advanced lung disease. AB - The unaddressed palliative care needs of patients with advanced, nonmalignant, lung disease highlight the urgent requirement for new models of care. This study describes a new integrated respiratory and palliative care service and examines outcomes from this service. The Advanced Lung Disease Service (ALDS) is a long term, multidisciplinary, integrated service. In this single-group cohort study, demographic and prospective outcome data were collected over 4 years, with retrospective evaluation of unscheduled healthcare usage. Of 171 patients included, 97 (56.7%) were male with mean age 75.9 years and 142 (83.0%) had chronic obstructive pulmonary disease. ALDS patients had severely reduced pulmonary function (median (interquartile range (IQR)) forced expiratory volume in 1 s 0.8 (0.6-1.1) L and diffusing capacity of the lung for carbon monoxide 37.5 (29.0-48.0) % pred) and severe breathlessness. All patients received nonpharmacological breathlessness management education and 74 (43.3%) were prescribed morphine for breathlessness (median dose 9 mg.day-1). There was a 52.4% reduction in the mean number of emergency department respiratory presentations in the year after ALDS care commenced (p=0.007). 145 patients (84.8%) discussed and/or completed an advance care plan. 61 patients died, of whom only 15 (24.6%) died in an acute hospital bed. While this was a single-group cohort study, integrated respiratory and palliative care was associated with improved end-of-life care and reduced unscheduled healthcare usage. PMID- 29707562 TI - The clinical utility of lung clearance index in early cystic fibrosis lung disease is not impacted by the number of multiple-breath washout trials. AB - The lung clearance index (LCI) from the multiple-breath washout (MBW) test is a promising surveillance tool for pre-school children with cystic fibrosis (CF). Current guidelines for MBW testing recommend that three acceptable trials are required. However, success rates to achieve these criteria are low in children aged <7 years and feasibility may improve with modified pre-school criteria that accepts tests with two acceptable trials. This study aimed to determine if relationships between LCI and clinical outcomes of CF lung disease differ when only two acceptable MBW trials are assessed. Healthy children and children with CF aged 3-6 years were recruited for MBW testing. Children with CF also underwent bronchoalveolar lavage fluid collection and a chest computed tomography scan. MBW feasibility increased from 46% to 75% when tests with two trials were deemed acceptable compared with tests where three acceptable trials were required. Relationships between MBW outcomes and markers of pulmonary inflammation, infection and structural lung disease were not different between tests with three acceptable trials compared with tests with two acceptable trials. This study indicates that pre-school MBW data from two acceptable trials may provide sufficient information on ventilation distribution if three acceptable trials are not possible. PMID- 29707563 TI - COPD: time to improve its taxonomy? AB - Due to well-conducted epidemiological studies and advances in genetics, molecular biology, translational research, the advent of computed tomography of the lungs and bioinformatics, the diagnosis of chronic obstructive pulmonary disease (COPD) as a single entity caused by susceptibility to cigarette smoke is no longer tenable. Furthermore, the once-accepted concept that COPD results from a rapid and progressive loss of lung function over time is not true for a sizeable proportion of adults with the disease. Now we know that some genetic predisposition and/or different environmental interactions (nutritional, infectious, pollution and immunological) may negatively modulate post-natal lung development and lead to poorly reversible airflow limitation later in life, consistent with COPD. We believe it is time to rethink the taxonomy of this disease based on the evidence at hand. To do so, we have followed the principles outlined in the 1980s by J.D. Scadding who proposed that diseases can be defined by four key characteristics: 1) clinical description (syndrome), 2) disorder of structure (morbid anatomy), 3) disorder of function (pathophysiology) and 4) causation (aetiology). Here, we propose a pragmatic approach to the taxonomy of COPD based on different processes that result in a similar syndromic presentation. It can accommodate changes over time, as the pathobiology that may lead to COPD expands. We hope that stakeholders in the field may find it useful to better define the patients now boxed into one single entity, so that specific studies can be designed and conducted for each type of COPDs. PMID- 29707564 TI - Comparative Study between Ethanolic and beta-Cyclodextrin Assisted Extraction of Polyphenols from Peach Pomace. AB - Peach byproducts are often regarded as food waste despite their high content in health-promoting components. Amongst the latter, polyphenols are bioactive molecules with significant health benefits. The present study investigated an eco friendly and cost-effective method using a GRAS food additive, beta-cyclodextrin (beta-CD), for the recovery of polyphenols from peach pomace. beta-CD assisted extraction of polyphenols was compared to that of conventional solvent (ethanol) extraction at the same concentrations (10 mg/mL, 20 mg/mL, 30 mg/mL, 40 mg/mL, and 50 mg/mL) in terms of quality (antiradical activity) and quantity. The extract obtained by 50 mg/mL beta-CD assisted extraction showed the highest polyphenol (0.72 mg GAE/g DM) and flavonoid (0.35 mg catechin/g of DM) concentrations as maximal antiradical activity (6.82%) and a noted antibacterial activity. Our results showed the competitiveness of beta-CD assisted extraction to recover a high quantity and quality of polyphenols from peach pomace suggesting beta-CD as a green alternative method for phenolic extraction. PMID- 29707565 TI - Maternal Body Mass Index and Anovaginal Distance in Active Phase of Term Labor. AB - Introduction: To evaluate if there was a difference in the anovaginal distance (AVD) measured by transperineal ultrasound between obese and normal weight women. Material and Methods: A prospective observational study including 207 primiparous women at term in first stage of labor. Transperineal ultrasound with a vaginal probe was used to measure the AVD. Maternal, pregnancy, and delivery characteristics potentially associated with perineal thickness were extracted from woman's medical records. The participants were divided into three BMI groups based on maternal weight in early pregnancy: normal weight (BMI < 25), overweight (BMI 25-29.9), and obesity (BMI >= 30). Obese and overweight women were compared with normal weight women regarding the AVD. Results: The mean AVD was 24.3, 24.9, and 27.0 mm in the normal weight, overweight, and obesity group, respectively. There were no group differences in background characteristics. The AVD was significantly longer in obese women compared with normal weight women (p = 0.018). Conclusions: The observed longer AVD in obese women might be protective of the anal sphincter complex, explaining lower rates of anal sphincter injuries in this group. Further studies are indicated to evaluate whether the length of the AVD plays a role in the risk assessment of obstetric anal sphincter injury. The trial is registered in ClinicalTrials.gov and the trial registration ID is NCT03149965. PMID- 29707566 TI - Histopathological Breast Cancer Image Classification by Deep Neural Network Techniques Guided by Local Clustering. AB - Breast Cancer is a serious threat and one of the largest causes of death of women throughout the world. The identification of cancer largely depends on digital biomedical photography analysis such as histopathological images by doctors and physicians. Analyzing histopathological images is a nontrivial task, and decisions from investigation of these kinds of images always require specialised knowledge. However, Computer Aided Diagnosis (CAD) techniques can help the doctor make more reliable decisions. The state-of-the-art Deep Neural Network (DNN) has been recently introduced for biomedical image analysis. Normally each image contains structural and statistical information. This paper classifies a set of biomedical breast cancer images (BreakHis dataset) using novel DNN techniques guided by structural and statistical information derived from the images. Specifically a Convolutional Neural Network (CNN), a Long-Short-Term-Memory (LSTM), and a combination of CNN and LSTM are proposed for breast cancer image classification. Softmax and Support Vector Machine (SVM) layers have been used for the decision-making stage after extracting features utilising the proposed novel DNN models. In this experiment the best Accuracy value of 91.00% is achieved on the 200x dataset, the best Precision value 96.00% is achieved on the 40x dataset, and the best F-Measure value is achieved on both the 40x and 100x datasets. PMID- 29707567 TI - HOTAIR Is a Potential Novel Biomarker in Patients with Congenital Heart Diseases. AB - Objective: To investigate the expression of HOX transcript antisense RNA (HOTAIR) in cardiac tissues and plasma of patients with congenital heart diseases (CHDs). Methods: qRT-PCR was used to detect the expression of HOTAIR in right atrial appendage tissues of 16 patients with CHDs and 14 patients with rheumatic valvular heart diseases (RVHDs), as well as in plasma of 36 normal people and 90 patients with CHDs including 36 cases of ASD, 23 cases of VSD, and 31 cases of PDA. Besides, the proteins interacting with HOTAIR were obtained from databases. Results: The HOTAIR expression in cardiac tissues of CHDs group was significantly higher than that of the RVHDs group (P < 0.01). Compared with the control group, the expression of plasma HOTAIR in the ASD group, the VSD group, and the PDA group was all remarkably upregulated (P < 0.01), whereas there was no relationship between HOTAIR and pulmonary arterial hypertension and defects size. Databases show that HOTAIR is associated with polycomb repressive complex 2 (PRC2) which contributes to heart development. Conclusion: The levels of HOTAIR were increased in cardiac tissues and plasma of patients with CHDs. HOTAIR is a potential novel diagnostic biomarker in patients with CHDs. PMID- 29707569 TI - A Longitudinal Study for the Empirical Validation of an Etiopathogenetic Model of Internet Addiction in Adolescence Based on Early Emotion Regulation. AB - Several etiopathogenetic models have been conceptualized for the onset of Internet Addiction (IA). However, no study had evaluated the possible predictive effect of early emotion regulation strategies on the development of IA in adolescence. In a sample of N = 142 adolescents with Internet Addiction, this twelve-year longitudinal study aimed at verifying whether and how emotion regulation strategies (self-focused versus other-focused) at two years of age were predictive of school-age children's internalizing/externalizing symptoms, which in turn fostered Internet Addiction (compulsive use of the Web versus distressed use) in adolescence. Our results confirmed our hypotheses demonstrating that early emotion regulation has an impact on the emotional behavioral functioning in middle childhood (8 years of age), which in turn has an influence on the onset of IA in adolescence. Moreover, our results showed a strong, direct statistical link between the characteristics of emotion regulation strategies in infancy and IA in adolescence. These results indicate that a common root of unbalanced emotion regulation could lead to two different manifestations of Internet Addiction in youths and could be useful in the assessment and treatment of adolescents with IA. PMID- 29707568 TI - Current Concepts of Neurodegenerative Mechanisms in Alzheimer's Disease. AB - Neurodegenerative diseases are hereditary or sporadic conditions that result in the progressive loss of the structure and function of neurons as well as neuronal death. Although a range of diseases lie under this umbrella term, Alzheimer's disease (AD) and Parkinson's disease (PD) are the most common neurodegenerative diseases that affect a large population around the globe. Alzheimer's disease is characterized by the abnormal accumulation of extracellular amyloid-beta plaques and intraneuronal neurofibrillary tangles in brain regions and manifests as a type of dementia in aged individuals that results in memory loss, multiple cognitive abnormalities, and intellectual disabilities that interfere with quality of life. Since the discovery of AD, a wealth of new information has emerged that delineates the causes, mechanisms of disease, and potential therapeutic agents, but an effective remedy to cure the diseases has not been identified yet. This could be because of the complexity of the disease process, as it involves various contributing factors that include environmental factors and genetic predispositions. This review summarizes the current understanding on neurodegenerative mechanisms that lead to the emergence of the pathology of AD. PMID- 29707570 TI - Whole Body Vibration Retards Progression of Atherosclerosis via Insulin-Like Growth Factor 1 in Apolipoprotein E-Deficient Mice. AB - Whole body vibration (WBV) has a marked impact on lipid metabolism and the endocrine system, which is related to the progression of atherosclerosis (AS). To investigate the effects of WBV, we measured the atherosclerotic plaque area of apolipoprotein E-knockout (ApoE-/-) AS mice, which were trained by WBV (15 Hz, 30 min) for 12 weeks. Simultaneously, serum levels of lipids, insulin-like growth factor 1 (IGF-1), insulin-like growth factor 1 receptor (IGF-1R), interleukin 6 (IL-6), and the mRNA and protein levels of the same in the aorta were compared between the control and WBV groups. The results indicated that WBV significantly reduced the atherosclerotic plaque area with lower very low-density lipoprotein (VLDL) and oxidized low-density lipoprotein (ox-LDL) in the blood. Moreover, the levels of IGF-1 in serum and expression of IL-6, IGF-1R, and p-IGF-1R protein in the mice aorta decreased significantly in the WBV group. In addition, we found that serum IGF-1 in mice increased to the highest concentration in 30 min after WBV for 10, 30, 60, and 120 minutes. These results suggested that appropriate WBV may delay the progression of AS, which was associated with acutely elevated serum IGF-1 and lower levels of IGF-1 and IL-6 in the aorta for long-term treatment. PMID- 29707572 TI - Adolescent Internet Abuse: A Study on the Role of Attachment to Parents and Peers in a Large Community Sample. AB - Adolescents are the main users of new technologies and their main purpose of use is social interaction. Although new technologies are useful to teenagers, in addressing their developmental tasks, recent studies have shown that they may be an obstacle in their growth. Research shows that teenagers with Internet addiction experience lower quality in their relationships with parents and more individual difficulties. However, limited research is available on the role played by adolescents' attachment to parents and peers, considering their psychological profiles. We evaluated in a large community sample of adolescents (N = 1105) the Internet use/abuse, the adolescents' attachment to parents and peers, and their psychological profiles. Hierarchical regression analyses were conducted to verify the influence of parental and peer attachment on Internet use/abuse, considering the moderating effect of adolescents' psychopathological risk. Results showed that adolescents' attachment to parents had a significant effect on Internet use. Adolescents' psychopathological risk had a moderating effect on the relationship between attachment to mothers and Internet use. Our study shows that further research is needed, taking into account both individual and family variables. PMID- 29707571 TI - Engineering Tissues without the Use of a Synthetic Scaffold: A Twenty-Year History of the Self-Assembly Method. AB - Twenty years ago, Dr. Francois A. Auger, the founder of the Laboratory of Experimental Organogenesis (LOEX), introduced the self-assembly technique. This innovative technique relies on the ability of dermal fibroblasts to produce and assemble their own extracellular matrix, differing from all other tissue engineering techniques that use preformed synthetic scaffolds. Nevertheless, the use of the self-assembly technique was limited for a long time due to its main drawbacks: time and cost. Recent scientific breakthroughs have addressed these limitations. New protocol modifications that aim at increasing the rate of extracellular matrix formation have been proposed to reduce the production costs and laboratory handling time of engineered tissues. Moreover, the introduction of vascularization strategies in vitro permits the formation of capillary-like networks within reconstructed tissues. These optimization strategies enable the large-scale production of inexpensive native-like substitutes using the self assembly technique. These substitutes can be used to reconstruct three dimensional models free of exogenous materials for clinical and fundamental applications. PMID- 29707573 TI - Impact of Health Education on Knowledge and Behaviors toward Infectious Diseases among Students in Gansu Province, China. AB - Objectives: Infectious disease knowledge and behaviors are key elements that ensure student health and safety. This study explores the impact of health education on student knowledge and behaviors toward infectious diseases and determines the factors affecting infectious diseases knowledge and behaviors among students in Gansu, China. Methods: A cross-sectional study and three sampling methods were used in two counties, 12 schools, and 32 classes in Gansu, China, from 2012 to 2013. Collected data included the following: (1) sociodemographic characteristics of 2002 students (1001 participants in the intervention group and 1001 in the control group); (2) accuracy of student knowledge and behaviors toward infectious diseases based on comparison of intervention and control groups through X2 test; and (3) mean scores on knowledge and behavior of students with different characteristics toward infectious diseases, as analyzed through analysis of variance (ANOVA). Multiple linear regression was conducted to analyze factors affecting student knowledge and behaviors toward infectious diseases. Results: Statistically significant differences were observed among eight items of infectious disease transmission and treatment knowledge between intervention and control groups (P < 0.001). Average accuracies of knowledge and behaviors toward infectious diseases reached 72.23% and 60.03%. Significant differences were observed in six items on student behavior in rural and urban areas (P < 0.001). Health education, household register, and county affected scores of student knowledge and behaviors toward infectious diseases (P < 0.05). Gender and education level also affected scores of student behaviors toward infectious diseases (P < 0.001). Conclusions: Health education contributes to student knowledge and behaviors toward infectious diseases. Students in the control group need intensified health education on infectious diseases. Health education needs to pay particular attention to rural students, all male students, and students at senior high school level living on campus. PMID- 29707574 TI - Analysis of Managing Safety in Small Enterprises: Dual-Effects of Employee Prosocial Safety Behavior and Government Inspection. AB - This paper aims to promote a national and international occupational health and safety (OHS) intervention for small and medium enterprises (SMEs) within internal and external resources. Based on the characteristics of small SME management, the work environment and occupational health may be positively affected by the dual effects of employees and government. Evolutionary game theory is utilized to identify relevant interactions among the government, small enterprises, and employees. Furthermore, dynamic simulations of the evolutionary game model are used to explore stability strategies and to identify modes of equilibrium. PMID- 29707575 TI - Optical Coherence Tomography Angiography versus Dye Angiography in Age-Related Macular Degeneration: Sensitivity and Specificity Analysis. AB - Introduction: Optical coherence tomography angiography (OCTA) could be a valid tool to detect choroidal neovascularization (CNV) in neovascular age-related macular degeneration (nAMD), allowing the analysis of the type, the morphology, and the extension of CNV in most of the cases. Purpose: To determine the sensitivity and specificity of OCTA in detecting CNV secondary to nAMD, compared to fluorescein angiography (FA) and indocyanine green angiography (ICGA). Methods: Prospective observational study. Patients with suspected nAMD were recruited between May and December 2016. Patients underwent FA, ICGA, spectral domain OCT, and OCTA (AngioVue, Optovue, Inc.). Sensitivity and specificity of FA, with or without ICGA, were assessed and compared with OCTA. Results: Seventy eyes of 70 consecutive patients were included: 32 eyes (45.7%) with type I CNV, 8 eyes (11.4%) with type II CNV, 4 eyes (5.7%) with type III CNV, 6 eyes (8.6%) with mixed type I and type II CNV, and 20 eyes (28.6%) with no CNV. Sensitivity of OCTA was 88% and specificity was 90%. Concordance between FA/ICGA and OCTA was very good (0,91; range 0,81-1,00). Conclusions: OCTA showed high sensitivity and specificity for detection of CNV. Concordance between OCTA and gold-standard dye based techniques was excellent. OCTA may represent a first-line noninvasive method for the diagnosis of nAMD. PMID- 29707576 TI - Establishment of a Gene Detection System for Hotspot Mutations of Hearing Loss. AB - Hearing loss is an etiologically heterogeneous trait with a high incidence in China. Though conventional newborn hearing screening program has been widely adopted, gene detection can significantly improve the means of early discovering genetic risk factors. Thus, simple and efficient methods with higher sensitivity and lower cost for detecting hotspot mutations of hearing loss are urgently requested. Here we established a mutation detection system based on multiple fluorescent probe technique, which can detect and genotype nine hotspot mutations of four prominent hearing loss-related genes in two reactions on a four-channel real-time PCR instrument, including GJB2 (rs750188782, rs80338943, rs1110333204, and rs80338939), GJB3 (rs74315319), SLC26A4 (rs111033313 and rs121908362), and mtDNA 12S rRNA (rs267606617 and rs267606619). This system is with high sensitivity that enables detecting as low as 10 DNA copies samples per reaction. A comparison study in 268 clinical samples showed that the detection system had 100% concordance to Sanger sequencing. Besides, blood and saliva samples can be directly detected without DNA extraction process, which greatly simplifies the manipulation. The new system with high sensitivity, accuracy, and specimen type compatibility can be expectedly a reliable tool in clinical application. PMID- 29707577 TI - Association of Androgen Excess with Glucose Intolerance in Women with Polycystic Ovary Syndrome. AB - Women with polycystic ovary syndrome (PCOS) show high prevalence of glucose intolerance. This study aimed to investigate the association of androgen excess with glucose intolerance in PCOS. A total of 378 women with PCOS participated in the study. Free androgen index (FAI) was selected as indicator of hyperandrogenism. Insulin sensitivity was assessed by 1/homeostasis model assessment of insulin resistance (1/HOMA-IR) and Matsuda insulin sensitivity index (ISIM); beta-cell function was assessed by disposition index (DI). We found that women with glucose intolerance had higher FAI levels compared to women with normal glucose tolerance (NGT) (prediabetes 6.2, T2DM 7.9 versus NGT 5.0, resp.; p < 0.001). Furthermore, there was a direct association between FAI levels and frequency of glucose intolerance (OR = 2.480, 95% CI 1.387-4.434), even after adjusting for age, BMI, waist circumference, hypertension, fasting insulin, testosterone, SHBG, and family history of diabetes. In addition, with FAI increase, glycosylated hemoglobin (HbA1c), plasma glucose concentrations, and serum insulin levels increased, while insulin sensitivity and beta-cell function decreased. Our results suggested that androgen excess indicated by high FAI levels might serve as indicator of glucose intolerance, as it might promote insulin resistance and beta-cell dysfunction in women with PCOS. PMID- 29707578 TI - Analysis of Bacterial Community Structure of Activated Sludge from Wastewater Treatment Plants in Winter. AB - Activated sludge bulking is easily caused in winter, resulting in adverse effects on effluent treatment and management of wastewater treatment plants. In this study, activated sludge samples were collected from different wastewater treatment plants in the northern Xinjiang Uygur Autonomous Region of China in winter. The bacterial community compositions and diversities of activated sludge were analyzed to identify the bacteria that cause bulking of activated sludge. The sequencing generated 30087-55170 effective reads representing 36 phyla, 293 families, and 579 genera in all samples. The dominant phyla present in all activated sludge were Proteobacteria (26.7-48.9%), Bacteroidetes (19.3-37.3%), Chloroflexi (2.9-17.1%), and Acidobacteria (1.5-13.8%). Fifty-five genera including unclassified_f_Comamonadaceae, norank_f_Saprospiraceae, Flavobacterium, norank_f_Hydrogenophilaceae, Dokdonella, Terrimonas, norank_f_Anaerolineaceae, Tetrasphaera, Simplicispira, norank_c_Ardenticatenia, and Nitrospira existed in all samples, accounting for 60.6-82.7% of total effective sequences in each sample. The relative abundances of Saprospiraceae, Flavobacterium, and Tetrasphaera with the respective averages of 12.0%, 8.3%, and 5.2% in bulking sludge samples were higher than those in normal samples. Filamentous Saprospiraceae, Flavobacterium, and Tetrasphaera multiplied were the main cause for the sludge bulking. Redundancy analysis (RDA) indicated that influent BOD5, DO, water temperature, and influent ammonia had a distinct effect on bacterial community structures. PMID- 29707579 TI - Cognitive Behavior Therapy as Augmentation for Sertraline in Treating Patients with Persistent Postural-Perceptual Dizziness. AB - Background: Persistent postural-perceptual dizziness (PPPD) is a common vestibular disorder. This study was conducted to assess whether the addition of cognitive behavior therapy (CBT) could significantly improve the efficacy and acceptability of sertraline in treating PPPD. Methods: PPPD patients were recruited and randomly assigned to control and experiment groups. Patients in both groups received sertraline 50-200 mg/day, and only patients in the experiment group received CBT (twice a week, one hour per time). The treatment was continued for eight weeks. At baseline, week 2, week 4, and week 8, the 25 item Dizziness Handicap Inventory (DHI), Hamilton Anxiety Rating Scale (HARS), and Hamilton Depression Rating Scale (HDRS) were used to assess the self perceived handicapping effects caused by PPPD, anxiety, and depressive symptoms, respectively. The dose of sertraline used and the adverse events in both groups were recorded and analyzed. Results: In total, 91 PPPD patients were randomly assigned to the control group (n = 45) and experiment group (n = 46). After eight weeks of treatment, the average DHI scores, HDRS scores, and HARS scores were significantly decreased in both groups. But compared to the control group, the experiment group had significantly lower average DHI score, HDRS score, and HARS score at weeks 4 and 8. Moreover, the dose of sertraline used in the experiment group was significantly lower than that in the control group, and adverse events occurred more frequently in the control group than in the experiment group (48.9% versus 26.1%, p = 0.025). Conclusion: These results demonstrated that the addition of CBT could significantly improve the efficacy and acceptability of sertraline in treating PPPD and reduce the dose of sertraline used. PMID- 29707581 TI - An Overview of Meta-Analyses of Endovascular Bridging Therapies for Acute Ischemic Stroke. AB - Background: Acute Ischemic Stroke (AIS) is a common cause of death worldwide and the leading cause of long-term severe disability. Endovascular bridging therapies (EBT), including endovascular thrombectomy (ET) and intra-arterial thrombolytic (IAT), have been recommended to realize a favorable functional outcome for AIS patients. Methods: An overview of meta-analyses of primary randomized controlled trial (RCT) studies was performed evaluating EBT for AIS patients compared with usual care. Results: Ten meta-analyses were included in this overview. ET was associated with a higher incidence of achieving functional outcome improvement, defined as a modified Rankin scale of 0 to 1 (mRS, p = 0.003), 0 to 2 (p < 0.00001), and 0 to 3 (p = 0.005). The risk of symptomatic intracranial hemorrhage (sICH) rate and all-cause mortality were similar between the two groups. Moreover, IAT treatment was also related to significantly improved outcomes in terms of the mRS score (p < 0.05), but no significant difference in rates of sICH and mortality within 90 days. Conclusions: In conclusion, our analysis supports that EBT, regardless of format (e.g., ET or IAT), is superior to the best medical therapy alone (e.g., IVT) in terms of mRS score in patients with AIS. In addition, the safety of EBT is similar to IVT. PMID- 29707580 TI - Chronic Unpredictable Mild Stress Causing Cardiac and Thoracic Spinal Cord Electrophysiological Abnormalities May Be Associated with Increased Cardiac Expression of Serotonin and Growth-Associated Protein-43 in Rats. AB - Background: The aim of this study was to investigate the potential mechanisms by which chronic unpredictable mild stress (CMS) might induce cardiovascular disease. Methods: Twenty male Sprague-Dawley rats (weighing 180-250 g) were divided into the CMS group (CMS for 3 weeks) and control group (n = 10/group). Sucrose solution consumption, sucrose solution preference rate, and the open field test (horizontal and vertical movements) were used to confirm the establishment of the CMS model. Heart rate was determined in Langendorff-perfused hearts, and field action potential duration (FAPD) was measured in cardiac atrial tissue, cardiac ventricular tissue, and thoracic spinal cord segments 1-5. The expressions of serotonin (5-HT) and growth-associated protein-43 (GAP-43) in cardiac ventricular tissue were analyzed using immunohistochemistry and immunofluorescence. Results: Compared with the control group, sucrose solution consumption, sucrose solution preference rate, horizontal movement, and vertical movement were significantly lower in the CMS group (P < 0.01). The CMS group exhibited significant decreases in atrial and ventricular FAPDs (P < 0.05), as well as significant increases in heart rates (P < 0.05) and T1-5 spinal cord FAPD (P < 0.01), as compared with the control group. The expressions of 5-HT and GAP 43 in cardiac ventricular tissue were significantly higher in the CMS group than in controls (P < 0.01). Conclusions: CMS causes cardiac and T1-5 spinal cord electrophysiological abnormalities as well as increased cardiac expression of 5 HT and GAP-43, indicating that CMS could potentially increase the risk of cardiovascular disease. PMID- 29707582 TI - Vitamin D Ameliorates Impaired Wound Healing in Streptozotocin-Induced Diabetic Mice by Suppressing Endoplasmic Reticulum Stress. AB - Background: This study is designed to investigate whether vitamin D promotes diabetic wound healing and explore the potential mechanism which may be involved in the healing process. Material and Methods: Human umbilical vein endothelial cells (HUVECs) were treated with 200 MUg/ml of advanced glycation end product modified human serum albumin (AGE-HSA) and 250 mg/dl of glucose with vitamin D. Cell viability was analyzed using the CCK-8 assay, and the apoptosis rate was measured using flow cytometry. Endogenous markers of ER stress were quantified using Western blot and a real-time polymerase chain reaction. Diabetic mice were treated with vitamin D (100 ng/kg per day) for 14 days. The ulcer area and ulcerative histology were detected dynamically. Results: Vitamin D administration not only decreased the apoptosis rate but also increased cell viability. Furthermore, the expression of endogenous markers of ER stress was downregulated as a result of vitamin D treatment. Vitamin D supplementation significantly accelerated wound healing of diabetic mice and improved the healing quality. Further studies showed that reduced ER stress was associated with the positive outcome. Conclusion: These results suggest that vitamin D may ameliorate impaired wound healing in diabetic mice by suppressing ER stress. PMID- 29707583 TI - Ultrasonographic Characterization of the db/db Mouse: An Animal Model of Metabolic Abnormalities. AB - The availability of an animal model able to reliably mirror organ damage occurring in metabolic diseases is an urgent need. These models, mostly rodents, have not been fully characterized in terms of cardiovascular, renal, and hepatic ultrasound parameters, and only sparse values can be found in literature. Aim of this paper is to provide a detailed, noninvasive description of the heart, vessels, liver, and kidneys of the db/db mouse by ultrasound imaging. Sixteen wild type and thirty-four db/db male mice (11-week-old) were studied. State-of the-art ultrasound technology was used to acquire images of cardiovascular, renal, and hepatic districts. A set of parameters describing function of the selected organs was evaluated. db/db mice are characterized by systolic and diastolic dysfunction, confirmed by strain analysis. Abdominal aortic and carotid stiffness do not seem to be increased in diabetic rodents; furthermore, they are characterized by a smaller mean diameter for both vessels. Renal microcirculation is significantly compromised, while liver steatosis is only slightly higher in db/db mice than in controls. We offer here for the first time an in vivo detailed ultrasonographic characterization of the db/db mouse, providing a useful tool for a thoughtful choice of the right rodent model for any experimental design. PMID- 29707584 TI - Rethinking the Viability and Utility of Inhaled Insulin in Clinical Practice. AB - Despite considerable advances in pharmacotherapy and self-monitoring technologies in the last decades, a large percentage of adults with diabetes remain unsuccessful in achieving optimal glucose due to suboptimal medication adherence. Contributors to suboptimal adherence to insulin treatment include pain, inconvenience, and regimen complexity; however, a key driver is hypoglycemia. Improvements in the PK/PD characteristics of today's SC insulins provide more physiologic coverage of basal and prandial insulin requirements than regular human insulin; however, they do not achieve the rapid on/rapid off characteristics of endogenously secreted insulin seen in healthy, nondiabetic individuals. Pulmonary administration of prandial insulin represents an attractive option that overcomes limitations of SC insulin by providing more a rapid onset of action and a faster return of action to baseline levels than SC administration of rapid-acting insulin analogs. This article reviews the unique PK/PD properties of a novel inhaled formulation that support its use in patient populations with T1D or T2D. PMID- 29707585 TI - Physical Activity and Sedentary Patterns among Metabolically Healthy Individuals Living with Obesity. AB - Background: Some individuals living with obesity are free from typical cardiometabolic risk factors and are termed metabolically healthy obese (MHO). The patterns of physical activity and sedentary behaviors among MHO are currently unknown. Methods: This study includes 414 youth (12-18 years old), 802 adults (19 44 years old), and 1230 older adults (45-85 years old) living with obesity from the 2003-2004 or 2005-2006 NHANES cycles. Time spent in bouts of 1, 5, 10, 30, and 60 minutes for moderate-to-vigorous physical activity (MVPA) and sedentary time was measured objectively using accelerometers. Participants were categorized as MHO if they had no cardiometabolic risk factors above the identified thresholds (triglycerides, high-density lipoprotein cholesterol, systolic blood pressure, diastolic blood pressure, and glucose). Results: The proportion of MHO was 19%, 14%, and 12% in youth, adults, and older adults, respectively. MHO adults displayed a higher 1-minute bout of MVPA per day compared to non-MHO (p = 0.02), but no difference was observed for MVPA and sedentary behavior patterns for youth and older adults. When adjusted for confounders, all bouts of sedentary behavior patterns in youth were significantly associated with being classified as MHO. Conclusion: This study suggests that greater sedentary time is associated with cardiometabolic risk factors in youth even if they are physically active. PMID- 29707586 TI - The Relationship between Diabetes-Related Complications and Obstructive Sleep Apnea in Type 2 Diabetes. AB - This study explored the relationship between obstructive sleep apnea (OSA) and the presence of any diabetes-related complications in type 2 diabetes and whether this was mediated by hypertension. Secondly, the relationship between OSA severity and estimated glomerular filtration rate (eGFR) was investigated. A total of 131 patients participated. OSA was diagnosed using a home monitor, and severity was measured by apnea-hypopnea index (AHI) and oxygen desaturation index (ODI). OSA was found in 75.6% of the participants, 40.5% with moderate-to-severe degree. Any diabetes-related complications (retinopathy, neuropathy, nephropathy, or coronary artery disease) were present in 55.5%, and 70.2% of the participants had hypertension. Mediation analysis indicated that, compared to those with mild or no OSA, those with moderate-to-severe OSA were 3.05 times more likely to have any diabetes-related complications and that this relationship was mediated by the presence of hypertension. After adjusting for confounders, ODI (B = -0.036, p = 0.041), but not AHI, was significantly associated with lower eGFR. In conclusion, moderate-to-severe OSA was related to the presence of any diabetes-related complications in type 2 diabetes, and the relationship was mediated by hypertension. The severity of intermittent hypoxia was associated with lower eGFR. Whether OSA treatment will delay or reduce diabetes-related complications should be investigated. PMID- 29707587 TI - The Relationship between Social Capital and Quality of Life among Patients Referring to Diabetes Centers in Isfahan, Iran. AB - Background: Studies have shown that the relationship between social capital (SC) and quality of life (QOL) has an important role in care, prevention, and treatment of some patients. The present study was conducted with the aim to determine the relationship between social capital and QOL of patients with type 2 diabetes. Materials and Methods: This descriptive, correlational study was conducted on 215 individuals selected through quota sampling. To assess social capital, the Social Capital Questionnaire was used, and to evaluate the QOL of patients with type 2 diabetes, the Diabetes Quality of Life (DQOL) Brief Clinical Inventory was used. Data were analyzed using the Pearson correlation and regression analysis. Results: A significant relationship was observed between QOL and social capital in patients with diabetes. Moreover, social capital explained 14% of variance in QOL and with the addition of other accompanying diseases, this was increased to 19%. Conclusion: The results of this study can be useful for health care providers to improve the health of patients with diabetes. They also help patients to better manage and cope with their illness. PMID- 29707589 TI - Substance Use and the Number of Male Sex Partners by African American and Puerto Rican Women. AB - Background: In the United States (US), there are 19 million new sexually transmitted disease (STD) infections each year. Untreated STDs can lead to serious long-term adverse health consequences, especially for young women. Centers for Disease Control and Prevention estimates that undiagnosed and untreated STDs cause at least 24,000 women in the US each year to become infertile. This clearly is a public health issue of great concern for young women. Materials and Methods: The current cross-sectional study included a community sample consisting of 343 female participants (50% African Americans, 50% Puerto Ricans) at their mean age of 39 years. Regression analyses were conducted to examine the associations of time-varying factors within-person (e.g., substance use) and fixed effects factors between-persons (e.g., race/ethnicity) with the number of male sexual partners. Results: Alcohol use (b=0.14, p<0.01), cannabis use (b=1.10, p<0.01), marital status - unmarried (b= 0.16, p<0.05), and race/ethnicity - African American (b=-0.20, p<0.01) were significantly related to having a higher number of male sex partners in the past year. Conclusions: From a public health perspective, treatment and prevention programs for sexual risk behavior focused on substance use as well as socio cultural factors (i.e., marital status, race/ethnicity) may be more effective than programs focused only on substance use. PMID- 29707588 TI - Development of Safe and Non-Self-Immunogenic Mucosal Adjuvant by Recombinant Fusion of Cholera Toxin A1 Subunit with Protein Transduction Domain. AB - Potential use of cholera toxin (CT) as a mucosal vaccine adjuvant has been documented in a variety of animal models. However, native CT is highly toxic to be used as a mucosal adjuvant in humans. Here, we demonstrate a new approach to generate a mucosal adjuvant by replacing the B subunit of CT with HIV-1 Tat protein transduction domain (PTD), which efficiently delivers fusion proteins into the cell cytoplasm by unspecific binding to cell surface. We compared the adjuvanticity and toxicity of Tat PTD-CTA1-Tat PTD (TCTA1T) with those of CT. Our results indicate that intranasal (i.n.) delivery of ovalbumin (OVA) with TCTA1T significantly augments the OVA-specific systemic and mucosal antibody responses to levels comparable to those seen with CT adjuvant. Moreover, in vivo cytotoxic T lymphocyte activity elicited by TCTA1T was significantly higher than that elicited by a mutant TCTA1T (TmCTA1T) lacking ADP-ribosyltransferase function. In addition, coadministration of influenza M2 protein with TCTA1T conferred near complete protection against lethal influenza virus challenge. Importantly, TCTA1T, in contrast to CT, did not induce serum IgG antibody responses to itself and was shown to be nontoxic. These results suggest that TCTA1T may be a safe and effective adjuvant when given by mucosal routes. PMID- 29707590 TI - Reverse Takotsubo Cardiomyopathy Following Exploratory Laparotomy. AB - Reverse takotsubo cardiomyopathy is an uncommon cardiomyopathy characterized by reversible regional wall motion abnormalities in the basilar segment of the left ventricle. This happens in the absence of any coronary artery pathology. Although it shares some pathogenic mechanisms with its more common variant, takotsubo cardiomyopathy, differences exist in terms of echocardiographic features, demographics, clinical manifestations, laboratory features, and prognosis. Cases of postoperative reverse takotsubo cardiomyopathy are less described in the literature. Herein, we report a case of reverse takotsubo cardiomyopathy in a 44 year-old woman occurring after exploratory laparotomy. PMID- 29707591 TI - Miliary Tuberculosis Presenting With Meningitis in a Patient Treated With Mycophenolate for Lupus Nephritis: Challenges in Diagnosis and Review of the Literature. AB - Tuberculosis is one of the top 10 causes of death worldwide according to the World Health Organization. Central nervous system involvement is usually the least common presentation of tuberculosis occurring in about 1% of all cases but yet can have very devastating outcomes. Lupus nephritis is one of the most common complications of systemic lupus erythematosus with up to two thirds of patients presenting with some degree of renal dysfunction. The mainstay of treatment is glucocorticoids; however, to sustain remission, steroid sparing agents such as cyclophosphamide, azathioprine and mycophenolate mofetil are used. Such patients, in addition to their baseline dysfunctional immune system, have a heightened risk of infections due to these drugs. In this article, we present a young woman who had recently been started on mycophenolate mofetil for control of class V lupus nephritis who presented with headaches, sinus pressure, and fevers. She had a protracted course of hospitalization as she failed to improve clinically and to respond to conventional therapy for acute bacterial sinusitis and meningitis. She was empirically started on antitubercular therapy 9 days after hospitalization. The diagnosis was not confirmed until day 18, the day results of cerebrospinal fluid acid-fast bacillus culture was reported. This case is reported to highlight the challenges in diagnosing Mycobacterium tuberculosis infection in an immunocompromised state and to demonstrate that its presentation can mimic numerous other conditions. Clinicians must maintain a high index of suspicion of Mycobacterium tuberculosis infection in such patients who present with nonspecific or unexplainable symptoms. PMID- 29707593 TI - Spontaneous Coronary Artery Dissection: A Case Series of 9 Patients With Literature Review. AB - Spontaneous coronary artery dissection is an increasingly recognized nonatherosclerotic cause of acute coronary syndrome. Reports regarding the prognosis and natural history of this disease are limited. In addition to the diagnostic difficulty, this condition poses a significant therapeutic challenge due to the lack of specific management guidelines. We present here a case series of 9 patients with spontaneous coronary artery dissection. Additionally, this article reviews the incidence, clinical characteristics, risk factors, diagnostic modalities, therapeutic approaches, and patterns of recurrence in patients with spontaneous coronary artery dissection. PMID- 29707592 TI - Varicella Pneumonia: Case Report and Review of a Potentially Lethal Complication of a Common Disease. AB - Varicella zoster virus causes varicella (chickenpox). It can be reactivated endogenously many years later to cause herpes zoster (shingles). Although varicella is usually a benign disease in healthy children, it resulted in over 11 000 hospitalizations and over 100 deaths every year, in all ages, in the United States. Morbidity was considerably worse in older teenagers and adults. Between 5% and 15% of cases of adult chickenpox will produce some form of pulmonary illness. Progression to pneumonia risk factors include pregnancy, age, smoking, chronic obstructive pulmonary disease, and immunosuppression. Typically, pulmonary symptoms occur 1 to 6 days after varicella zoster infection. They often include cough, fever, and dyspnea. Treatment is a 7-day course of intravenous acyclovir for varicella pneumonia. Early intervention may modify the course of this complication. This review illustrates practical features with a case of a 34 year-old female with severe varicella pneumonia. Despite the lack of significant past medical history and absence of immunosuppression, her pneumonia worsened and by using continuous positive airway pressure mask, intubation was avoided. More important, the radiographic progression of severe varicella pneumonia is shown. This highlights how a common disease of varicella can progress in an adult and manifest with significant organ malfunction. PMID- 29707594 TI - Can Patients Practice Strenuous Sports After Uncemented Ceramic-on-Ceramic Total Hip Arthroplasty? AB - Background: Patients are often concerned about returning to sports after total hip arthroplasty (THA). Purpose: To (1) evaluate sports participation and motivation rates in a large cohort of patients who underwent uncemented THA with ceramic-on-ceramic bearings and (2) determine whether patients' participation was associated with their motivation for each sport, preoperative demographics, or patient-reported outcomes. Study Design: Case-control study; Level of evidence, 3. Methods: We surveyed 1310 patients (aged <75 years) who underwent uncemented ceramic-on-ceramic THA and collected levels of motivation and participation for 22 different sports as well as patient-reported outcome measure scores. A total of 1042 patients (1206 hips) returned questionnaires; the mean age at index surgery was 60.6 +/- 8.8 years. Results: At least 51% of patients participated regularly or frequently in at least 1 light sport, 73% in at least 1 moderate sport, and 20% in at least 1 strenuous sport. Sports participation was strongly correlated with motivation (r = 0.97, P < .001) but not with level of discomfort (r = 0.22, P = .292). Participation in strenuous sports was significantly associated with age, body mass index, and sex. There were significant differences among patients who practiced various categories of sports as determined using the Oxford Hip Score (P = .008), but not with regard to the Forgotten Joint Score (P = .054). Conclusion: Only 20% of patients practiced strenuous sports regularly or frequently after THA, regardless of pain or discomfort. Participation in sports after THA is strongly correlated with motivation but not with level of discomfort. Longer term studies with a greater focus on complications and survival are necessary to determine whether high-impact sports compromise patient safety or implant longevity. PMID- 29707595 TI - Trends in the Body Mass Index of Pediatric and Adult Patients Undergoing Anterior Cruciate Ligament Reconstruction. AB - Background: The body mass index (BMI) in the United States (US) is rising and may be contributing to increased anterior cruciate ligament reconstruction (ACLR) rates. It is currently unknown whether the BMI is increasing in patients who undergo ACLR. Purpose: To determine whether (1) the BMI changed in pediatric and adult patients who previously underwent ACLR or revision ACLR over a 10-year eligibility period, (2) the BMI changed at a greater rate in pediatric or adult patients, and (3) the percentage of overweight and obese patients in the ACLR population was different than that of the general overweight population. Study Design: Case series; Level of evidence, 4. Methods: A retrospective investigation of patients who underwent ACLR by 6 surgeons from June 3, 2005, to June 3, 2015, was conducted. Patients were divided into pediatric (<18 years) and adult (>=18 years) categories. BMI at the time of surgery was defined as underweight (<18.5 kg/m2), normal (18.5-24.9 kg/m2), overweight (25.0-29.9 kg/m2), and obese (>=30.0 kg/m2). Patients with an indeterminate BMI were excluded. Comparisons of overweight and obese patients were made with general population trends determined by the Centers for Disease Control and Prevention (CDC) in a single US state. Pearson (R) and Spearman (Rs) correlations were used to determine correlations, Student t tests were used for 2-variable comparisons, analyses of variance were used for multivariable comparisons, and analyses of covariance were used for comparing linear relationships. Results: There were 1305 patients (733 male, 572 female; 409 pediatric, 896 adult) included. Adults requiring surgical revision demonstrated a strong positive correlation with respect to BMI over time (Rs = 0.906, P < .01). No other statistically significant trends in the BMI over time were found. The proportion of overweight pediatric patients undergoing ACLR was significantly greater than that of the general overweight pediatric population (P < .05), and the proportion of obese pediatric and adult patients in the general population was greater than that of the obese patients in the study cohort (P < .05). Conclusion: Between 2005 and 2015, the BMI for pediatric and adult patients who underwent ACLR did not demonstrate a significant change over time. However, there was a statistically significant strong positive correlation for increasing BMI in adult patients requiring revision, although the mean BMI in patients who underwent revision was less than that of the general population. In addition, the percentage of overweight pediatric patients undergoing ACLR was significantly greater than that of the general population of overweight patients in a single US state reported by the CDC. PMID- 29707596 TI - Radial Head Changes in Osteochondritis Dissecans of the Humeral Capitellum. AB - Background: Osteochondritis dissecans (OCD) of the elbow has almost exclusively been described in the humeral capitellum, with only a small number of reports describing secondary osteochondral changes in the radial head. Hypothesis: The authors hypothesized that concomitant radial head lesions (RHLs) would be seen with capitellar OCD and that patients with RHLs would present with more advanced capitellar OCD lesions and would respond better to procedures restoring articular congruity. Study Design: Cohort study; Level of evidence, 2. Methods: A total of 86 elbows from 82 patients (39 female patients; mean +/- SD age, 13.8 +/- 2.2 years; age range, 9.8-23.6 years) were treated for capitellar OCD and enrolled in a prospective registry. Clinical and radiographic data were compared between those with and without RHLs, with a median follow-up of 10.8 months (interquartile range, 6.2-17.1 months). Magnetic resonance imaging was used to characterize and measure RHLs and OCD lesions. Postoperative clinical results were compared between patients who underwent drilling and those who had osteochondral autograft transplantation surgery (OATS). Results: RHLs were present in 26 (30%) elbows-17 in the dominant arm. Edema was seen in 22 elbows; 17 had involvement of the anterior third of the radial epiphysis. Cysts were present in 4 elbows: 2 in the anterior third and 2 in the middle third. Blunting of the normal concave contour of the radial epiphysis was present in 10 elbows in the anterior third. Demographic and presenting clinical features were similar between those with and without RHLs. RHLs were more commonly seen in Nelson grade 4 OCD lesions (P = .04) as compared with elbows without RHLs. Elbows with RHLs that underwent OATS (n = 9) trended toward greater improvement in forearm range of motion (P = .058) and fewer persistent mechanical symptoms (P = .06) postoperatively as compared with elbows having RHLs that underwent drilling. There were no postoperative differences in elbows without RHLs that underwent OATS versus drilling. Conclusion: RHLs were seen in one-third of elbows with capitellar OCD. Lesions predominantly occurred in the anterior RH in patients with more advanced capitellar lesions. Short-term clinical follow-up suggested greater improvement in range of motion and resolution of mechanical symptoms for patients with RHLs who were treated with OATS than with drilling. PMID- 29707597 TI - A mass spectrometric method for quantification of tryptophan-derived uremic solutes in human serum. AB - In addition to various physiologic roles, emerging evidence strongly points to pathogenic roles of tryptophan and of its metabolites, especially in diseases such as renal failure. Accurate estimation of levels of these metabolites in blood is important to mechanistically probe their contribution to disease pathogenesis, while clinically, such a panel can be used to risk stratify patients for a clinical phenotype. Herein, we describe a comprehensive liquid chromatography-mass spectrometry (LC/MS)-based method to determine the level of tryptophan and its metabolites (kynurenine, kynurenic acid, xanthurenic acid, anthranilic acid, indoxyl sulfate and indoxyl acetate). Human sera samples were processed through a C18 column followed by application of a binary gradient and quantitation by MS/MS. The linearity, lower limit of detection, inter- and intraassay variabilities and recovery were determined, yielding a precise, reproducible method for all the metabolites. Unlike previous studies, we further validated these methods in a well-characterized set of human sera from end stage renal disease patients compared to age-, gender- and ethnic-background matched human controls. Overall, we report an optimized LC/MS-based estimation of a comprehensive panel of tryptophan-derived metabolites with quality features within FDA standards, underscoring their readiness for translational use. PMID- 29707598 TI - A Novel Single-Nucleotide Polymorphism Loop Mediated Isothermal Amplification Assay for Detection of Artemisinin-Resistant Plasmodium falciparum Malaria. AB - Background: Artemisinin-resistant malaria (ARM) remains a significant threat to malaria elimination. In the Greater Mekong subregion, the prevalence of ARM in certain regions has reached greater than 90%. Artemisinin-resistant malaria is clinically identified by delayed parasite clearance and has been associated with mutations in the propeller domain of the kelch 13 gene. C580Y is the most prevalent mutation. The detection of ARM currently relies on labor-intensive and time-consuming methods such as clinical phenotyping or in vitro susceptibility testing. Methods: We developed a novel single-nucleotide polymorphism loop mediated isothermal amplification (SNP-LAMP) test method for the detection of the C580Y mutation using a novel primer design strategy. Results: The SNP-LAMP was 90.0% sensitive (95% confidence interval [CI], 66.9-98.3) and 91.9% specific (95% CI, 82.6-96.7) without knowledge of the parasite load and was 100% sensitive (95% CI, 79.9-100) and 97.3% specific (95% CI, 89.7-99.5) when the parasitemia was within the assay dynamic range. Tests with potential application near-to-patient such as SNP-LAMP may be deployed in low- and middle-income and developed countries. Conclusions: Single-nucleotide polymorphism LAMP can serve as a surveillance tool and guide treatment algorithms for ARM in a clinically relevant time frame, prevent unnecessary use of additional drugs that may drive additional resistance, and avoid longer treatment regimens that cause toxicity for the patient. PMID- 29707600 TI - Preclinical Development of a Lentiviral Vector for Gene Therapy of X-Linked Severe Combined Immunodeficiency. AB - X-linked severe combined immunodeficiency (SCID-X1) is caused by mutations in the interleukin-2 receptor gamma chain gene (IL2RG), and it is characterized by profound defects in T, B, and natural killer (NK) cell functions. Transplantation of hematopoietic stem/progenitor cells (HSPCs) genetically corrected with early murine leukemia retrovirus (MLV)-derived gammaretroviral vectors showed restoration of T cell immunity in patients, but it resulted in vector-induced insertional oncogenesis. We developed a self-inactivating (SIN) lentiviral vector carrying a codon-optimized human IL2RG cDNA driven by the EF1alpha short promoter (EFS-IL2RG), and we tested its efficacy and safety in vivo by transplanting transduced Il2rg-deficient Lin- HSPCs in an Il2rg-/-/Rag2-/- mouse model. The study showed restoration of T, B, and NK cell counts in bone marrow and peripheral blood and normalization of thymus and spleen cellularity and architecture. High-definition insertion site analysis defined the EFS-IL2RG genomic integration profile, and it showed no sign of vector-induced clonal selection or skewing in primarily and secondarily transplanted animals. The study enables a phase I/II clinical trial aimed at restoring both T and B cell immunity in SCID-X1 children upon non-myeloablative conditioning. PMID- 29707601 TI - An Assay that Predicts In Vivo Efficacy for DNA Aptamers that Stimulate Remyelination in a Mouse Model of Multiple Sclerosis. AB - Multiple sclerosis (MS) is a debilitating disease for which regenerative therapies are sought. We have previously described human antibodies and DNA aptamer-streptavidin conjugates that promote remyelination after systemic injection into mice infected by Theiler's murine encephalomyelitis virus. Here, we report an in vitro assay of myelin binding with results that correlate with remyelination outcome in vivo, as shown for data from a set of DNA aptamer complexes of different size and formulation. This in vitro assay will be valuable for future screening of MS regenerative therapies targeting remyelination. PMID- 29707599 TI - Prevalence and Evolution of Renal Impairment in People Living With HIV in Rural Tanzania. AB - Background: We assessed the prevalence, incidence, and predictors of renal impairment among people living with HIV (PLWHIV) in rural Tanzania. Methods: In a cohort of PLWHIV aged >=15 years enrolled from January 2013 to June 2016, we assessed the association between renal impairment (estimated glomerural filtration rate < 90 mL/min/1.73 m2) at enrollment and during follow-up with demographic and clinical characteristcis using logistic regression and Cox proportional hazards models. Results: Of 1093 PLWHIV, 172 (15.7%) had renal impairment at enrollment. Of 921 patients with normal renal function at baseline, 117 (12.7%) developed renal impairment during a median follow-up (interquartile range) of 6.2 (0.4-14.7) months. The incidence of renal impairment was 110 cases per 1000 person-years (95% confidence interval [CI], 92-132). At enrollment, logistic regression identified older age (adjusted odds ratio [aOR], 1.79; 95% CI, 1.52-2.11), hypertension (aOR, 1.84; 95% CI, 1.08-3.15), CD4 count <200 cells/mm3 (aOR, 1.80; 95% CI, 1.23-2.65), and World Health Organization (WHO) stage III/IV (aOR, 3.00; 95% CI, 1.96-4.58) as risk factors for renal impairment. Cox regression model confirmed older age (adjusted hazard ratio [aHR], 1.85; 95% CI, 1.56-2.20) and CD4 count <200 cells/mm3 (aHR, 2.05; 95% CI, 1.36-3.09) to be associated with the development of renal impairment. Conclusions: Our study found a low prevalence of renal impairment among PLWHIV despite high usage of tenofovir and its association with age, hypertension, low CD4 count, and advanced WHO stage. These important and reassuring safety data stress the significance of noncommunicable disease surveillance in aging HIV populations in sub-Saharan Africa. PMID- 29707602 TI - Enhanced Production of Exosome-Associated AAV by Overexpression of the Tetraspanin CD9. AB - Research on cell-free vesicles revealed a multitude of characteristics, in particular of microvesicles and exosomes, that range from their potential as biomarkers to a function in horizontal transfer of genetic information from cell to cell and also include supportive functions in viral infection. Exosome associated adeno-associated viruses (exo-AAVs) are of particular interest for the past couple of years, because they introduced a new source of highly potent recombinant AAVs with improved features, including accelerated transduction rates and more efficient immune escape. However, key factors like the mode of action, efficiency of production, or engineering of exo-AAVs remain elusive to a large extent. Here, we used the established system of CD9 overexpression to boost the exosome output of AAV producing HEK-AAV cells. The CD9-powered high-exosome environment was established during exo-AAV1 production, and we could demonstrate that the yield of exo-AAVs dramatically increased when compared to standard exo AAVs. Furthermore, we report that exo-AAV-CD9GFP was more efficient in transduction of cells in the same titer ranges as standard exo-AAVs. Our results provide a technological approach for the generation of exo-AAVs with superior performance. PMID- 29707603 TI - The Biological Activity of AAV Vectors for Choroideremia Gene Therapy Can Be Measured by In Vitro Prenylation of RAB6A. AB - Choroideremia (CHM) is a rare, X-linked recessive retinal dystrophy caused by mutations in the CHM gene. CHM is ubiquitously expressed in human cells and encodes Rab escort protein 1 (REP1). REP1 plays a key role in intracellular trafficking through the prenylation of Rab GTPases, a reaction that can be reproduced in vitro. With recent advances in adeno-associated virus (AAV) gene therapy for CHM showing gene replacement to be a promising approach, an assay to assess the biological activity of the vectors is of the uttermost importance. Here we sought to compare the response of two Rab proteins, RAB27A and RAB6A, to the incorporation of a biotinylated lipid donor in a prenylation reaction in vitro. First, we found the expression of REP1 to be proportional to the amount of recombinant AAV (rAAV)2/2-REP1 used to transduce the cells. Second, prenylation of RAB6A appeared to be more sensitive to REP1 protein expression than prenylation of RAB27A. Moreover, the method was reproducible in other cell lines. These results support the further development of a prenylation reaction using a biotinylated lipid donor and RAB6A to assess the biological activity of AAV vectors for CHM gene therapy. PMID- 29707606 TI - Measurement of ROS in Caenorhabditis elegans Using a Reduced Form of Fluorescein. AB - Oxidative stress is implicated in the pathogenesis of various neurodegenerative diseases, including Alzheimer's disease. Oxidative stress is a result of a disruption of the equilibrium between antioxidants and oxidants, in favor of oxidants. Since mitochondria are major sites of production and reduction of reactive oxygen species (ROS), measurement of ROS levels can help us determine if mitochondrial functional integrity has been compromised. In this protocol, we describe a method to measure the level of ROS in the nematode Caenorhabditis elegans, using chloromethyl-2,7'-dichlorodihydrofluorescein diacetate (CM H2DCFDA). PMID- 29707604 TI - CYP-450 Epoxygenase Derived Epoxyeicosatrienoic Acid Contribute To Reversal of Heart Failure in Obesity-Induced Diabetic Cardiomyopathy via PGC-1 alpha Activation. AB - We have previously shown that an Epoxyeicosatrienoic Acid (EET) -agonist has pleiotropic effects and reverses cardiomyopathy by decreasing inflammatory molecules and increasing antioxidant signaling. We hypothesized that administration of an EET agonist would increase Peroxisome proliferator-activated receptor-gamma coactivator (PGC-1alpha), which controls mitochondrial function and induction of HO-1 and negatively regulates the expression of the proinflammatory adipokines CCN3/NOV in cardiac and pericardial tissues. This pathway would be expected to further improve left ventricular (LV) systolic function as well as increase insulin receptor phosphorylation. Measurement of the effect of an EET agonist on oxygen consumption, fractional shortening, blood glucose levels, thermogenic and mitochondrial signaling proteins was performed. Control obese mice developed signs of metabolic syndrome including insulin resistance, hypertension, inflammation, LV dysfunction, and increased NOV expression in pericardial adipose tissue. EET agonist intervention decreased pericardial adipose tissue expression of NOV, while normalized FS, increased PGC 1alpha, HO-1 levels, insulin receptor phosphorylation and improved mitochondrial function, theses beneficial effect were reversed by deletion of PGC-1alpha. These studies demonstrate that an EET agonist increases insulin receptor phosphorylation, mitochondrial and thermogenic gene expression, decreased cardiac and pericardial tissue NOV levels, and ameliorates cardiomyopathy in an obese mouse model of the metabolic syndrome. PMID- 29707607 TI - Analysis of Mitochondrial Structure in the Body Wall Muscle of Caenorhabditis elegans. AB - Mitochondrial function is altered in various pathologies, highlighting the crucial role mitochondria plays in maintaining cellular homeostasis. Mitochondrial structure undergoes constant fission and fusion in response to changing cellular environment. Due to this, analyzing mitochondrial structure could provide insight into the physiological state of the cell. In this protocol, we describe a method to analyze mitochondrial structure in body wall muscles in the nematode Caenorhabditis elegans, using both transgenic and dye-based approaches. PMID- 29707605 TI - Scaling up to study brca2: the zeppelin zebrafish mutant reveals a role for brca2 in embryonic development of kidney mesoderm. AB - Specialized renal epithelial cells known as podocytes are essential components of the filtering structures within the kidney that coordinate the process of removing waste from the bloodstream. Podocyte loss initiates many human kidney diseases as it triggers subsequent damage to the kidney, leading to progressive loss of function that culminates with end stage renal failure. Podocyte morphology, function and gene expression profiles are well conserved between zebrafish and humans, making the former a relevant model to study podocyte development and model kidney diseases. Recently, we reported that whole genome sequencing of the zeppelin (zep) zebrafish mutant, which exhibits podocyte abrogation, revealed that the causative lesion for this defect was a splicing mutation in the breast cancer 2, early onset (brca2) gene. This was a surprising and novel discovery, as previous research on brca2/BRCA2 in a number of vertebrate animal models had not implicated an explicit role for this gene in kidney mesoderm development. Interestingly, the abrogation of the podocyte lineage in zep mutants was also accompanied by the formation of a larger interrenal (IR) gland, which is analogous to the adrenal gland in mammals, and suggested a fate switch between the renal and inter renal mesodermal derivatives. Mirroring these findings, knockdown of brca2 also recapitulated the loss of podocytes and increased IR population. In addition, brca2 overexpression was sufficient to partially rescue podocytes in zep mutants, and induced ectopic podocyte formation in wild-type embryos. Interestingly, immunofluorescence studies indicated that zep mutants had elevated P-h2A.X levels, suggesting that DNA repair is dysfunctional in these animals and contributes to the zep phenotype. Moving forward, this unique zebrafish mutant provides a new model to further explore how brca2 contributes to the development of tissues including the kidney mesoderm-roles which may have implications for renal diseases as well. PMID- 29707608 TI - Intestinal perforation after surgical treatment for incisional hernia: iatrogenic or idiopathic? AB - Intestinal perforation (IP) is a life-threatening gastroenterological condition requiring urgent surgical care, which may present itself as an uncommon complication following incisional hernia repair surgery, most often because of iatrogenic traumatism occurring during the procedure. However, we report a case where a spontaneous onset can be hypothesised. A 60-years-old patient underwent repair of an abdominal laparocele, through rectus abdominis muscle plasty, 5 years after development of an incisional hernia due to exploratory laparotomy for the treatment of acute appendicitis. Xipho-pubic scar was excised and umbilicus and supra-umbilical hernia sac dissected, a linear median incision was performed along the sub-umbilical linea alba, reaching preperitoneal plane to assess any intestinal loop adherence to the abdominal wall. After limited viscerolysis, abdominal wall defect was corrected by 'rectus abdominis muscle plasty' and umbilicus reconstruction by Santanelli technique. Postoperative course was uneventful until Day 29, with sudden onset of epigastric pain, fever and bulge. Sixty cubic centimeter pus was drained percutaneously and cavity was rinsed with a 50% H2O2 and H2O V-V solution until draining clear fluid. Symptoms recurred two days later, while during rinsing presented dyspnoea. X-Ray and CT scan diagnosed IP, and she underwent under emergency an exploratory laparotomy, leading to right hemicolectomy extended to last ileal loops and middle third of the transverse, right monolateral salpingo-ovariectomy and a temporary ileostomy by general surgeon. Twenty-three days later an ileostomy reversal surgery was performed and 8 days after she was discharged. At latest follow-up patient showed fair conditions, complaining abdominal pain and diarrhoea, attributable to the extensive intestinal resection. IP following incisional hernia repair, is reported as uncommon and early postoperative complication. In our case, the previous regular postoperative course with late onset lead us to hypothesise a possible idiopathic etiopathogenesis, because of a strangulation followed by gangrene and abscess formation, which might begin before the incisional hernia repair and unnoticed at the time surgery was performed. PMID- 29707609 TI - Development of a primary melanoma in situ within a full-thickness skin graft overlying a free muscle flap: a case report. AB - The development of a primary melanoma within the confines of free tissue transfer is a rare occurrence. In this report, we describe the development of a primary melanoma in situ within a full-thickness skin graft overlying a free latissimus dorsi muscle flap used to cover a scalp defect. PMID- 29707610 TI - Axillary artery pseudoaneurysm and distal ulnar embolization in collegiate pitcher: a case report and review. AB - Twenty five-year-old pitcher presented with acute right middle and index finger numbness and coolness. Angiogram showed a 5mm axillary pseudoaneurysm and near complete occlusion of ulnar and common interosseous artery, ulnar side of the palmar arch, and ulnar digital artery. Patient deferred surgery, treatment with tPA and heparin succeeded in reperfusion. PMID- 29707611 TI - Monitoring B-cell repopulation after depletion therapy in neurologic patients. AB - Objective: To determine the factors that influence B-cell repopulation after B cell depletion therapy in neurologic patients and derive recommendations for monitoring and dosing of patients. Methods: In this study, we determined the association of body surface area (BSA; calculated by body weight and height with the Dubois formula), sex, pretreatment therapy, age, CSF data, and white blood cell counts with the risk and timing of B-cell repopulation, defined as 1% CD19+ cells (of total lymphocytes), following 87 B cell-depleting anti-CD20 treatment cycles of 45 neurologic patients (28 women; mean age +/- SD, 44.5 +/- 15.0 years). Results: Patients with a larger BSA had a higher probability to reach 1% CD19+ cells than those with a smaller BSA (p < 0.05) following B-cell depletion therapy, although those patients had received BSA-adapted doses of rituximab (375 mg/m2). Sex, pretreatment, age, CSF data, or absolute lymphocyte and leukocyte counts during treatment did not significantly influence CD19+ B-cell recovery in the fully adjusted models. Intraindividual B-cell recovery in patients with several treatment cycles did not consistently change over time. Conclusions: B cell repopulation after depletion therapy displays both high inter- and intra individual variance. Our data indicate that a larger BSA is associated with faster repopulation of B cells, even when treatment is adapted to the BSA. A reason is the routinely used Dubois formula, underestimating a large BSA. In these patients, there is a need for a higher therapy dose. Because B-cell count dependent therapy regimes are considered to reduce adverse events, B-cell monitoring will stay highly relevant. Patients' BSA should thus be determined using the Mosteller formula, and close monitoring should be done to avoid resurgent B cells and disease activity. PMID- 29707612 TI - Fracture load of colored and non-colored high translucent zirconia three-unit fixed dental prosthesis frameworks. AB - Aim: The use of colored translucent zirconia may enable restorations of a more natural tooth-like appearance than previous opaque white zirconia. The shift from non-colored to colored zirconia may however entail a risk of reduced strength. The aim of the present study was to compare fracture load and fracture mode of fixed dental prostheses frameworks made of colored translucent zirconia to that of non-colored controls. Methods: A total of forty three-unit FDP frameworks were manufactured from two different high translucent zirconia materials (Zenostar, Wieland Dental, and DD cubeX2, Dental Direkt). Each group contained two subgroups, one colored and one non-colored. Coloring was performed before final sintering using two different infiltration techniques. All FDPs underwent an artificial aging process in the form of heat treatment, thermocycling and preloading whereafter the specimens were subjected to load until fracture. Fracture load and mode was registered. Results: For one of the zirconia materials, Zenostar, the non-colored frameworks showed significantly higher fracture loads (p < .0001) compared to its colored counterpart. No significant difference (p > .05) was found between colored and non-colored frameworks in the other zirconia material, DD cubeX2. All FDPs fractured through the connector. Some fractures ran through the mesial and some through the distal side of the connector but there were no significant differences in fracture mode between groups. Conclusion: Coloring before sintering of high-translucent zirconia may decrease the fracture load of FDP frameworks for certain materials and techniques. Fracture mode however, does not appear to be affected. PMID- 29707614 TI - Comparison of inter- and intra-observer variability of breast density assessments using the fourth and fifth editions of Breast Imaging Reporting and Data System. AB - Background: Breast density is a well-known independent risk factor for breast cancer and can significantly affect the sensitivity of screening mammograms. Objective: We aimed to evaluate the intra- and inter-observer consistencies of breast density assessments using methods outlined in the fourth and fifth editions of the American College of Radiology (ACR) Breast Imaging Reporting and Data System (BI-RADS) guidelines to determine which method is more reliable. Materials and methods: Three radiologists with subspecialties in breast imaging defined breast density in 72 mammograms four times each: twice using the fourth edition of the ACR BI-RADS guidelines and twice using the fifth edition. The intra- and inter-observer agreements were calculated and compared for each method. Results: The weighted kappa values for the overall intra-observer agreement were 0.955 (95% confidence interval [CI]: 0.931-0.980) and 0.938 (95% CI: 0.907-0.968) when breast densities were assessed according to criteria outlined in the fourth and fifth ACR BI-RADS editions, respectively. The difference between these values was not statistically significant (p = .4). The overall Fleiss-Cohen (quadratic) weighted kappa for inter-observer agreement were 0.623 (95% CI: 0.517-0.729) and 0.702 (95% CI: 0.589-0.815) when breast densities were assessed according to criteria outlined in the fourth and fifth ACR BI-RADS editions, respectively. The difference between these values was not statistically significant (p = .32). Similarly, there were no significant differences in the evaluation of breast density (overall) when comparing breast density assignment using criteria outlined in the fourth and fifth ACR BI-RADS edition (p = .582). Conclusion: The ACR BI-RADS guideline is an acceptable method to classify breast density, resulting in substantial inter-observer agreements using criteria outlined in both the fourth and fifth editions. The intra-observer agreement was nearly perfect for radiologists using criteria outlined in both sets of guidelines. Moreover, although the percentage of women who were classified as having dense breasts was higher when radiologists used the fifth edition of ACR BI-RADS guidelines than when they used the fourth edition, this difference was not statistically significant. PMID- 29707613 TI - An overview of development and status of fiber-reinforced composites as dental and medical biomaterials. AB - Fibr-reinforced composites (FRC) have been used successfully for decades in many fields of science and engineering applications. Benefits of FRCs relate to physical properties of FRCs and versatile production methods, which can be utilized. Conventional hand lamination of prefabricated FRC prepregs is utilized still most commonly in fabrication of dental FRC devices but CAD-CAM systems are to be come for use in certain production steps of dental constructions and medical FRC implants. Although metals, ceramics and particulate filler resin composites have successfully been used as dental and medical biomaterials for decades, devices made out of these materials do not meet all clinical requirements. Only little attention has been paid to FRCs as dental materials and majority of the research in dental field has been focusing on particulate filler resin composites and in medical biomaterial research to biodegradable polymers. This is paradoxical because FRCs can potentially resolve many of the problems related to traditional isotropic dental and medical materials. This overview reviews the rationale and status of using biostable glass FRC in applications from restorative and prosthetic dentistry to cranial surgery. The overview highlights also the critical material based factors and clinical requirement for the succesfull use of FRCs in dental reconstructions. PMID- 29707615 TI - Finding cancer in mammograms: if you know it's there, do you know where? AB - Humans can extract considerable information from scenes, even when these are presented extremely quickly. The ability of an experienced radiologist to rapidly detect an abnormality on a mammogram may build upon this general capacity. Although radiologists have been shown to be able to detect an abnormality 'above chance' at short durations, the extent to which abnormalities can be localised at brief presentations is less clear. Extending previous work, we presented radiologists with unilateral mammograms, 50% containing a mass, for 250 or 1000 ms. As the female breast varies with respect to the level of normal fibroglandular tissue, the images were categorised into high and low density (50% of each), resulting in difficult and easy searches, respectively. Participants were asked to decide whether there was an abnormality (detection) and then to locate the mass on a blank outline of the mammogram (localisation). We found both detection and localisation information for all conditions. Although there may be a dissociation between detection and localisation on a small proportion of trials, we find a number of factors that lead to the underestimation of localisation including stimulus variability, response imprecision and participant guesses. We emphasise the importance of taking these factors into account when interpreting results. The effect of density on detection and localisation highlights the importance of considering breast density in medical screening. PMID- 29707616 TI - Rostrocaudal Areal Patterning of Human PSC-Derived Cortical Neurons by FGF8 Signaling. AB - The cerebral cortex is subdivided into distinct areas that have particular functions. The rostrocaudal (R-C) gradient of fibroblast growth factor 8 (FGF8) signaling defines this areal identity during neural development. In this study, we recapitulated cortical R-C patterning in human pluripotent stem cell (PSC) cultures. Modulation of FGF8 signaling appropriately regulated the R-C markers, and the patterns of global gene expression resembled those of the corresponding areas of human fetal brains. Furthermore, we demonstrated the utility of this culture system in modeling the area-specific forebrain phenotypes [presumptive upper motor neuron (UMN) phenotypes] of amyotrophic lateral sclerosis (ALS). We anticipate that our culture system will contribute to studies of human neurodevelopment and neurological disease modeling. PMID- 29707617 TI - Detection of endogenous S1292 LRRK2 autophosphorylation in mouse tissue as a readout for kinase activity. AB - Parkinson's disease-linked mutations in LRRK2 enhance the kinase activity of the protein, therefore targeting LRRK2 kinase activity is a promising therapeutic approach. Phosphorylation at S935 of LRRK2 and of its Rab GTPase substrates have proven very useful biomarkers to monitor its kinase activity. Complementary to these approaches autophosphorylation of LRRK2 can be used as a direct kinase activity readout but to date detection of autophosphorylation at endogenous levels in vivo has been limited. We developed a fractionation-based enrichment method to successfully detect endogenous S1292 LRRK2 autophosphorylation in mouse tissues and highlight S1292 as a physiological readout candidate for LRRK2 kinase activity in vivo. PMID- 29707618 TI - Transplantation of a Liver Allograft From a Hepatitis C Virus Seropositive Donor With Previous Sustained Virologic Response to an Uninfected Recipient Suffering Steroid Refractory Acute Graft Rejection With No Evidence of HCV Transmission. AB - Background: The goal of treating chronic hepatitis C virus (HCV) infection is sustained virologic response (SVR). There is concern that despite achieving SVR, replication-competent HCV may be sequestered at low levels within the liver and could theoretically reactivate with immunosuppression. We report transplantation of a HCV-seropositive liver donor, who achieved SVR, into a seronegative patient without HCV reactivation despite profound immunosuppression. Method: Retrospective chart review. Results: We present a 21-year-old male who was HCV seronegative and received a liver transplant from a donor who had been treated for HCV and achieved SVR. The liver recipient, despite developing severe acute graft rejection and undergoing intense immunosuppression with T cell-depleting antibodies, did not become HCV RNA-positive with a follow up period of 8 months. The recipient was HCV seronegative before transplant, but became HCV seropositive immediately posttransplant. The antibodies were undetectable after 97 days, in keeping with a passive antibody transmission or B lymphocyte transmission with the graft. Conclusions: To the best of our knowledge, this is the first reported case of an HCV seropositive liver allograft transplanted into an HCV-negative recipient who subsequently received intense immunosuppression. This case, therefore, is an encouraging and novel step in liver transplantation, and demonstrates that SVR may be closer to a true "cure" of HCV in the donor population and that, even in circumstances of very potent immunosuppression in the recipient, this SVR is sustained. PMID- 29707619 TI - Differences in Proinflammatory Cytokines and Monocyte Subtypes in Older as Compared With Younger Kidney Transplant Recipients. AB - Background: The number of elderly patients with end-stage kidney disease requiring kidney transplantation continues to grow. Evaluation of healthy older adults has revealed proinflammatory changes in the immune system, which are posited to contribute to age-associated illnesses via "inflamm-aging." Immunologic dysfunction is also associated with impaired control of infections. Whether these immunologic changes are found in older kidney transplant recipients is not currently known, but may have important implications for risk for adverse clinical outcomes. Methods: Three months after transplant, innate immune phenotype was evaluated by flow cytometry from 60 kidney transplant recipients (22 older [>=60 years] and 38 younger [<60 years old]). Multiplex cytokine testing was used to evaluate plasma cytokine levels. Younger patients were matched to older patients based on transplant type and induction immune suppression. Results: Older kidney transplant recipients demonstrated decreased frequency of intermediate monocytes (CD14++CD16+) compared with younger patients (1.2% vs 3.3%, P = 0.007), and a trend toward increased frequency of proinflammatory classical monocytes (CD14++CD16-) (94.5% vs 92.1%) (P = 0.065). Increased levels of interferon-gamma (IFN-gamma) were seen in older patients. Conclusions: In this pilot study of kidney transplant recipients, we identified differences in the innate immune system in older as compared with younger patients, including increased levels of IFN-gamma. This suggests that age associated nonspecific inflammation persists despite immune suppression. The ability to apply noninvasive testing to transplant recipients will provide tools for patient risk stratification and individualization of immune suppression regimens to improve outcomes after transplantation. PMID- 29707620 TI - Outcome of Patients With Small Vessel Vasculitis After Renal Transplantation: National Database Analysis. AB - Background: Small vessel vasculitis commonly affects the kidney and can progress to end-stage renal disease. The goal of this study is to compare outcomes of patients who received a renal transplant as a result of small vessel vasculitis (group A) with those who received kidney transplants because of other causes (group B). Methods: This is a retrospective analysis of United Network for Organ Sharing registry data for adult primary kidney transplants from January 2000 to December 2014. Group A patients (N = 2196) were compared with a group B (N = 6588); groups were case matched for age, race, sex, donor type, and year of transplant in a 1:3 ratio. Results: Renal and patient survivals were better in the group A (P < 0.001). New-onset diabetes after transplant developed in 8.3% of the group A and 11.3% of group B (P < 0.001). Seventeen (0.8%) patients in group A developed recurrent disease. Of these, 7 patients had graft failure, 3 of which were due to disease recurrence. Group A patients had significantly higher risk of developing posttransplant solid organ malignancies (11.3% vs 9.3%, P = 0.006) and lymphoproliferative disorder (1.3% vs 0.8%, P = 0.026). Independent predictors of graft failure and patient mortality were recipients' morbid obesity, diabetes, age, and dialysis duration (hazard ratio of 1.7, 1.4, 1.1/10 years, and 1.1/year for graft failure, and 1.7, 1.7, 1.6/10 years and 1.1/year for patient mortality, respectively). Conclusions: Renal transplantation in patients with has favorable long-term graft and patient outcomes with a low disease recurrence rate. However, they may have a higher risk of developing posttransplant malignancies. PMID- 29707621 TI - Improved Glucose Tolerance in a Kidney Transplant Recipient With Type 2 Diabetes Mellitus After Switching From Tacrolimus To Belatacept: A Case Report and Review of Potential Mechanisms. AB - The introduction of immunosuppressant belatacept, an inhibitor of the CD28-80/86 pathway, has improved 1-year outcomes in kidney transplant recipients with preexistent diabetes mellitus and has also reduced the risk of posttransplant diabetes mellitus. So far, no studies have compared a tacrolimus-based with a belatacept-based immunosuppressive regimen with regard to improving glucose tolerance after kidney transplantation. Here, we present the case of a 54-year old man with type 2 diabetes mellitus who was converted from belatacept to tacrolimus 1 year after a successful kidney transplantation. Thereafter, he quickly developed severe hyperglycemia, and administration of insulin was needed to improve metabolic control. Six months after this episode, he was converted back to belatacept because of nausea, diarrhea, and hyperglycemia. After switching back to belatacept and within 4 days after stopping tacrolimus glucose tolerance improved and insulin therapy could be discontinued. Although belatacept is considered less diabetogenic than tacrolimus, the rapid improvement of glucose tolerance after switching to belatacept is remarkable. In this article, the potential mechanisms of this observation are discussed. PMID- 29707622 TI - Improved Health-Related Quality of Life in Older Kidney Recipients 1 Year After Transplantation. AB - Background: We aimed to evaluate changes in health-related quality of life (HRQoL) in patients 65 years or older from time of kidney transplantation (KTx) until 1 year postengraftment. Methods: A single-center prospective study was conducted. HRQoL was measured pre-KTx and at 2, 6, and 12 months postengraftment using self-reported Kidney Disease and Quality of Life short-form version 1.3. Intraindividual scores before and after KTx were evaluated. Liu Comorbidity Index was registered at enlisting. short-form-36 scores were additionally compared with scores from an age-matched population. Results: From January 1, 2013, until November 30, 2016, a total of 289 waitlisted patients were included. By September 1, 2017, 134 had reached 1 year postengraftment, and valid questionnaires were available in 120 (90%) patients. Mean age at KTx was 71.6 years (+/-4.3 years), 71% were male. Living donor was used in 21%, and preemptive KTx was performed in 30% of the recipients. Median waiting time for KTx from deceased donor was 16 months (range, 0.6-50.5 months). A total of 79 (66%) recipients had a Liu Comorbidity Index score of 3 or less.All HRQoL scores except the domain social function improved at 2 months postengraftment and remained stable or continued to improve at 1 year.HRQoL scores 12 months postengraftment were similar to those described in an age-matched general population except for the domain social function which remained at a significantly lower level. Time in dialysis was the most important variable associated with impaired HRQoL postengraftment. Conclusions: HRQoL scores showed clinically significant improvement in older KTx recipients 1 year posttransplant. PMID- 29707623 TI - Early Allograft Dysfunction Is Associated With Higher Risk of Renal Nonrecovery After Liver Transplantation. AB - Early allograft dysfunction (EAD) identifies allografts with marginal function soon after liver transplantation (LT) and is associated with poor LT outcomes. The impact of EAD on post-LT renal recovery, however, has not been studied. Data on 69 primary LT recipients (41 with and 28 without history of renal dysfunction) who received renal replacement therapy (RRT) for a median (range) of 9 (13-41) days before LT were retrospectively analyzed. Primary outcome was renal nonrecovery defined as RRT requirement 30 days from LT. Early allograft dysfunction developed in 21 (30%) patients, and 22 (32%) patients did not recover renal function. Early allograft dysfunction was more common in the renal nonrecovery group (50% vs 21%, P = 0.016). Multivariate logistic regression analysis demonstrated that EAD (odds ratio, 7.25; 95% confidence interval, 2.0 25.8; P = 0.002) and baseline serum creatinine (odds ratio, 3.37; 95% confidence interval, 1.4-8.1; P = 0.007) were independently associated with renal nonrecovery. History of renal dysfunction, duration of renal dysfunction, and duration of RRT were not related to renal recovery (P > 0.2 for all). Patients who had EAD and renal nonrecovery had the worst 1-, 3-, and 5-year patient survival, whereas those without EAD and recovered renal function had the best outcomes (P < 0.001). Post-LT EAD was independently associated with renal nonrecovery in LT recipients on RRT for a short duration before LT. Furthermore, EAD in the setting of renal nonrecovery resulted in the worst long-term survival. Measures to prevent EAD should be undertaken in LT recipients on RRT at time of LT. PMID- 29707624 TI - Neurological Sequelae and Clinical Outcomes After Lung Transplantation. AB - Background: Neurological complications are common after lung transplantation. However, no large cohort studies have examined the incidence, predictors, and clinical significance of neurological events sustained by lung transplant recipients. Methods: We conducted a retrospective cohort analysis of a consecutive series of lung transplant recipients, transplanted at Duke University Medical Center between May 2014 and February 2017 (n = 276). Early neurological complications (ie, occurring during the first week after transplant) were documented by transplant mental health specialists and included delirium, ischemic injury, and posterior reversible encephalopathy syndrome. Analyses accounted for age, native disease, sex, type of transplant, lung allocation score, and primary graft dysfunction. The objectives of the study were to characterize the prevalence and predictors of early neurological sequelae (NSE), occurring during the first week posttransplant, and the association between NSE and subsequent clinical outcomes, including length of stay and mortality. Results: Neurological sequelae were common, occurring in 123 (45%) patients. Fifty-seven patients died over a follow-up interval of 2.1 years. The most common NSE were postoperative delirium (n = 110 [40%]) and posterior reversible encephalopathy syndrome (n = 12 [4%]), followed by stroke/transient ischemic attack and neurotoxicity. Higher lung allocation score was the strongest predictor of delirium. The presence of a NSE was associated with longer length of hospital stay (32 days vs 17 days, P < 0.001) and greater mortality (hazard ratio, 1.90; 95% confidence interval, 1.09-3.32], P = 0.024), with the greatest mortality risk occurring approximately 2 years after transplantation. Conclusions: Neurological events are relatively common after lung transplantation and associated with adverse clinical outcomes. PMID- 29707625 TI - Composite Mesenchymal Stromal Cell Islets: Implications for Transplantation via the Clinically Preferred Intraportal Route. PMID- 29707626 TI - Single Graft Utilization From Donors With Severe Acute Kidney Injury After Circulatory Death. AB - Chronic shortages of organs for transplantation have led to the use of marginal kidneys from donors after circulatory death with acute kidney injury (AKI), but the utilization of kidneys with severe AKI is not well established. We retrospectively analyzed eight kidney transplantation (KTx) cases from donation after circulatory death (DCD) with terminal creatinine (t-Cr) concentrations higher than 10.0 mg/dL and/or oliguria for more than 5 days (AKI network criteria: stage III). Although all patients showed delayed graft function, no cases of primary nonfunction (PNF) were found. Five patients maintained stable renal function for approximately 15.5, 10, 10, 5, and 0.5 years after KTx. Only 1 patient showed biopsy-proven acute rejection. Also, 2 patients developed graft failure: one attributable to chronic antibody mediated rejection at 11.3 years after KTx, and one attributable to recurrence of IgA nephropathy at 4.6 years after KTx. Kidneys with AKI stage III yielded great outcomes without the risk of primary nonfunction and rejection. Although the AKI kidneys were associated with delayed graft function, these results suggest that even the most severe kidneys with AKI stage III from DCD donors can be considered a valid alternative for recipients on a waiting list for KTx. PMID- 29707627 TI - Identifying Barriers to Preemptive Kidney Transplantation in a Living Donor Transplant Cohort. AB - Background: Despite substantial evidence demonstrating clear benefit, rates of preemptive kidney transplantation (PreKTx) remain low in the United States. Our goal was to identify barriers to PreKTx. Methods: Using a telephone-administered questionnaire including questions about barriers, timing of referral, timing of education, we retrospectively studied first living donor kidney transplant recipients (2006-2010) at Mayo Clinic, Rochester, MN. Of 235 patients, 145 (62%) responded to the questionnaire (74 PreKTx and 71 non-PreKTx). We compared categorical data with Fisher exact test and median times with Wilcoxon rank sum test. Results: Polycystic kidney disease (PCKD), longer median time between diagnosis and transplant, and time between education about transplant and transplant correlated with PreKTx (P < 0.01). The presence of at least 1 patient identified barrier (lack of referral, financial barriers, medical barriers, no identified living donor and donor evaluation delays) was associated with non PreKTx (0.034) though no single barrier predominated. Age, education level, insurance status and source of referral (primary care, nephrology, and nonphysician referral) were not associated with the rate of PreKTx. Univariate logistic regression identified white race, PCKD, and increased time from diagnosis as factors favoring PreKTx; PCKD and increased time remained significant factors after multivariate analysis. Conclusions: Even among a patient population that is primarily white, educated, and has a spouse or first degree relative donor, PreKTx rates remain concerningly low. Increased time between diagnosis or education and transplant are predictors of PreKTx. Greater emphasis on transplant education earlier in the stages of chronic kidney disease and community outreach from transplant centers may help to increase the rate of PreKTx. PMID- 29707629 TI - Comparison of the WarmCloud and Bair Hugger Warming Devices for the Prevention of Intraoperative Hypothermia in Patients Undergoing Orthotopic Liver Transplantation: A Randomized Clinical Trial. AB - Background: The avoidance of hypothermia is vital during prolonged and open surgery to improve patient outcomes. Hypothermia is particularly common during orthotopic liver transplantation (OLT) and associated with undesirable physiological effects that can adversely impact on perioperative morbidity. The KanMed WarmCloud (Bromma, Sweden) is a revolutionary, closed-loop, warm-air heating mattress developed to maintain normothermia and prevent pressure sores during major surgery. The clinical effectiveness of the WarmCloud device during OLT is unknown. Therefore, we conducted a randomized controlled trial to determine whether the WarmCloud device reduces hypothermia and prevents pressure injuries compared with the Bair Hugger underbody warming device. Methods: Patients were randomly allocated to receive either the WarmCloud or Bair Hugger warming device. Both groups also received other routine standardized multimodal thermoregulatory strategies. Temperatures were recorded by nasopharyngeal temperature probe at set time points during surgery. The primary endpoint was nasopharyngeal temperature recorded 5 minutes before reperfusion. Secondary endpoints included changes in temperature over the predefined intraoperative time points, number of patients whose nadir temperature was below 35.5 degrees C and the development of pressure injuries during surgery. Results: Twenty-six patients were recruited with 13 patients randomized to each group. One patient from the WarmCloud group was excluded because of a protocol violation. Baseline characteristics were similar. The mean (standard deviation) temperature before reperfusion was 36.0 degrees C (0.7) in the WarmCloud group versus 36.3 degrees C (0.6) in the Bairhugger group (P = 0.25). There were no statistical differences between the groups for any of the secondary endpoints. Conclusions: When combined with standardized multimodal thermoregulatory strategies, the WarmCloud device does not reduce hypothermia compared with the Bair Hugger device in patients undergoing OLT. PMID- 29707630 TI - Tacrolimus-Induced Hyponatremia in Lung Transplant Recipients: A Case Series. AB - Background: Lung transplant recipients are treated with a 3-drug immunosuppressive regimen that consists of a calcineurin inhibitor, an antiproliferative agent, and a corticosteroid. Calcineurin inhibitors are the backbone of this regimen, and tacrolimus is used more often than cyclosporine, because tacrolimus is the more potent of the two agents. Tacrolimus-induced hyponatremia has been described among kidney transplant recipients, but not among lung transplant recipients. Methods: We conducted a retrospective chart review of patients who underwent lung transplant at our institution and went on to develop severe hyponatremia. Results: We identified 5 lung transplant recipients who developed severe hyponatremia after lung transplantation (median nadir, 117 mEq/L; interquartile range, 116-119 mEq/L). Time to development of hyponatremia ranged from 3 to 85 days posttransplant. Hyponatremia persisted in these patients despite fluid restriction, salt tablets, diuretics, and fludrocortisone therapy. Hyponatremia resolved in 3 patients and significantly improved in 2 patients after they were switched from a tacrolimus-based immunosuppressive regimen to a cyclosporine-based regimen. Conclusion: Transitioning from a tacrolimus- to a cyclosporine-based immunosuppressive regimen may resolve or improve severe hyponatremia in lung transplant recipients. PMID- 29707628 TI - Poor Patient and Graft Outcome After Induction Treatment by Antithymocyte Globulin in Recipients of a Kidney Graft After Nonrenal Organ Transplantation. AB - Background: End-stage renal failure occurs in a substantial number of patients having received a nonrenal transplantation (NRT), for whom a kidney transplantation is needed. The medical strategy regarding the use of immunosuppression (IS) for a kidney graft in patients after an NRT is not well established. The prekidney grafts long-term IS advocates for a mild induction, such as using anti-IL-2R antibodies, whereas addition of new incompatibilities and anti-HLA preimmunization may suggest using stronger IS such as induction by polyclonal antithymocyte globulins (ATG). Methods: We performed Cox multivariate and propensity score analysis of our validated transplant database to study the impact of the type of induction therapy on kidney graft survival of recipients of a kidney graft after NRT. Results: We report here that kidney transplantation after NRT treated with an ATG induction has a poorer outcome (kidney and recipient survival) than that with an anti-IL-2R induction. After accounting for potential baseline differences with a multivariate Cox model, or by adjusting on a propensity score, we found that despite patients having received ATG cumulate more risk factors, ATG appears independently involved. As animal-derived biotherapeutics induce antiglycan antibodies and particularly anti-N glycolylneuraminic acid (Neu5Gc) IgGs which may activate endothelial cells in patients and grafts, we also investigated the magnitude and the nature of the anti-Neu5Gc elicited by the induction and showed that induction was associated with a shift in anti-Neu5Gc IgG repertoire. Possible reasons and mechanisms of a deleterious ATG usage in these patients are discussed. Conclusions: Our study suggests that ATG induction after a kidney transplantation in recipients already under maintenance IS for a NRT should be used cautiously. PMID- 29707631 TI - Polymer Microneedle Mediated Local Aptamer Delivery for Blocking the Function of Vascular Endothelial Growth Factor. AB - Overexpression of proteins in the body can cause severe diseases and other physiological disturbances. The development of protein blockers and local delivery systems would offer opportunities for addressing the health problems caused by protein overexpression. Nucleic acid aptamers are an emerging class of ligands with the potential to block proteins effectively; however, little effort has been made in developing polymer systems for local aptamer delivery. In this work, polymer microneedles capable of delivering DNA aptamers locally to inhibit the function of vascular endothelial growth factor (VEGF) were developed and studied. The presence of anti-VEGF aptamer in the polymer matrix did not change the apparent mechanical strength of the microneedles. Once in contact with a physiological solution, the polymer microneedles quickly dissolved, generating a high concentration of anti-VEGF aptamer in the surrounding local microenvironment. Aptamer delivery by way of dissolving polymer microneedles in a tissue phantom reduced VEGF-mediated endothelial cell tube formation. Thus, aptamer-loaded polymer microneedles hold great potential as a therapeutic tool for the treatment of human diseases resulting from protein overexpression. PMID- 29707632 TI - Crystal structure and equation of state of Fe-Si alloys at super-Earth core conditions. AB - The high-pressure behavior of Fe alloys governs the interior structure and dynamics of super-Earths, rocky extrasolar planets that could be as much as 10 times more massive than Earth. In experiments reaching up to 1300 GPa, we combine laser-driven dynamic ramp compression with in situ x-ray diffraction to study the effect of composition on the crystal structure and density of Fe-Si alloys, a potential constituent of super-Earth cores. We find that Fe-Si alloy with 7 weight % (wt %) Si adopts the hexagonal close-packed structure over the measured pressure range, whereas Fe-15wt%Si is observed in a body-centered cubic structure. This study represents the first experimental determination of the density and crystal structure of Fe-Si alloys at pressures corresponding to the center of a ~3-Earth mass terrestrial planet. Our results allow for direct determination of the effects of light elements on core radius, density, and pressures for these planets. PMID- 29707633 TI - Insight into structural remodeling of the FlhA ring responsible for bacterial flagellar type III protein export. AB - The bacterial flagellum is a supramolecular motility machine. Flagellar assembly begins with the basal body, followed by the hook and finally the filament. A carboxyl-terminal cytoplasmic domain of FlhA (FlhAC) forms a nonameric ring structure in the flagellar type III protein export apparatus and coordinates flagellar protein export with assembly. However, the mechanism of this process remains unknown. We report that a flexible linker of FlhAC (FlhAL) is required not only for FlhAC ring formation but also for substrate specificity switching of the protein export apparatus from the hook protein to the filament protein upon completion of the hook structure. FlhAL was required for cooperative ring formation of FlhAC. Alanine substitutions of residues involved in FlhAC ring formation interfered with the substrate specificity switching, thereby inhibiting filament assembly at the hook tip. These observations lead us to propose a mechanistic model for export switching involving structural remodeling of FlhAC. PMID- 29707634 TI - Moving chairs in Starbucks: Observational studies find rice-wheat cultural differences in daily life in China. AB - Traditional paddy rice farmers had to share labor and coordinate irrigation in a way that most wheat farmers did not. We observed people in everyday life to test whether these agricultural legacies gave rice-farming southern China a more interdependent culture and wheat-farming northern China a more independent culture. In Study 1, we counted 8964 people sitting in cafes in six cities and found that people in northern China were more likely to be sitting alone. In Study 2, we moved chairs together in Starbucks across the country so that they were partially blocking the aisle (n = 678). People in northern China were more likely to move the chair out of the way, which is consistent with findings that people in individualistic cultures are more likely to try to control the environment. People in southern China were more likely to adjust the self to the environment by squeezing through the chairs. Even in China's most modern cities, rice-wheat differences live on in everyday life. PMID- 29707635 TI - Most atolls will be uninhabitable by the mid-21st century because of sea-level rise exacerbating wave-driven flooding. AB - Sea levels are rising, with the highest rates in the tropics, where thousands of low-lying coral atoll islands are located. Most studies on the resilience of these islands to sea-level rise have projected that they will experience minimal inundation impacts until at least the end of the 21st century. However, these have not taken into account the additional hazard of wave-driven overwash or its impact on freshwater availability. We project the impact of sea-level rise and wave-driven flooding on atoll infrastructure and freshwater availability under a variety of climate change scenarios. We show that, on the basis of current greenhouse gas emission rates, the nonlinear interactions between sea-level rise and wave dynamics over reefs will lead to the annual wave-driven overwash of most atoll islands by the mid-21st century. This annual flooding will result in the islands becoming uninhabitable because of frequent damage to infrastructure and the inability of their freshwater aquifers to recover between overwash events. This study provides critical information for understanding the timing and magnitude of climate change impacts on atoll islands that will result in significant, unavoidable geopolitical issues if it becomes necessary to abandon and relocate low-lying island states. PMID- 29707636 TI - The delivery of water by impacts from planetary accretion to present. AB - Dynamical models and observational evidence indicate that water-rich asteroids and comets deliver water to objects throughout the solar system, but the mechanisms by which this water is captured have been unclear. New experiments reveal that impact melts and breccias capture up to 30% of the water carried by carbonaceous chondrite-like projectiles under impact conditions typical of the main asteroid belt impact and the early phases of planet formation. This impactor derived water resides in two distinct reservoirs: in impact melts and projectile survivors. Impact melt hosts the bulk of the delivered water. Entrapment of water within impact glasses and melt-bearing breccias is therefore a plausible source of hydration features associated with craters on the Moon and elsewhere in the solar system and likely contributed to the early accretion of water during planet formation. PMID- 29707638 TI - Observations of biogenic ion-induced cluster formation in the atmosphere. AB - A substantial fraction of aerosols, which affect air quality and climate, is formed from gaseous precursors. Highly oxygenated organic molecules (HOMs) are essential to grow the newly formed particles and have been evidenced to initiate ion-induced nucleation in chamber experiments in the absence of sulfuric acid. We investigate this phenomenon in the real atmosphere using an extensive set of state-of-the-art ion and mass spectrometers deployed in a boreal forest environment. We show that within a few hours around sunset, HOMs resulting from the oxidation of monoterpenes are capable of forming and growing ion clusters even under low sulfuric acid levels. In these conditions, we hypothesize that the lack of photochemistry and essential vapors prevents the organic clusters from growing past 6 nm. However, this phenomenon might have been a major source of particles in the preindustrial atmosphere and might also contribute to particle formation in the future and consequently affect the climate. PMID- 29707637 TI - Guns, germs, and trees determine density and distribution of gorillas and chimpanzees in Western Equatorial Africa. AB - We present a range-wide assessment of sympatric western lowland gorillas Gorilla gorilla gorilla and central chimpanzees Pan troglodytes troglodytes using the largest survey data set ever assembled for these taxa: 59 sites in five countries surveyed between 2003 and 2013, totaling 61,000 person-days of fieldwork. We used spatial modeling to investigate major drivers of great ape distribution and population trends. We predicted density across each taxon's geographic range, allowing us to estimate overall abundance: 361,900 gorillas and 128,700 chimpanzees in Western Equatorial Africa-substantially higher than previous estimates. These two subspecies represent close to 99% of all gorillas and one third of all chimpanzees. Annual population decline of gorillas was estimated at 2.7%, maintaining them as Critically Endangered on the International Union for Conservation of Nature and Natural Resources (IUCN) Red List. We quantified the threats to each taxon, of which the three greatest were poaching, disease, and habitat degradation. Gorillas and chimpanzees are found at higher densities where forest is intact, wildlife laws are enforced, human influence is low, and disease impacts have been low. Strategic use of the results of these analyses could conserve the majority of gorillas and chimpanzees. With around 80% of both subspecies occurring outside protected areas, their conservation requires reinforcement of anti-poaching efforts both inside and outside protected areas (particularly where habitat quality is high and human impact is low), diligent disease control measures (including training, advocacy, and research into Ebola virus disease), and the preservation of high-quality habitat through integrated land-use planning and implementation of best practices by the extractive and agricultural industries. PMID- 29707640 TI - Footprints preserve terminal Pleistocene hunt? Human-sloth interactions in North America. AB - Predator-prey interactions revealed by vertebrate trace fossils are extremely rare. We present footprint evidence from White Sands National Monument in New Mexico for the association of sloth and human trackways. Geologically, the sloth and human trackways were made contemporaneously, and the sloth trackways show evidence of evasion and defensive behavior when associated with human tracks. Behavioral inferences from these trackways indicate prey selection and suggest that humans were harassing, stalking, and/or hunting the now-extinct giant ground sloth in the terminal Pleistocene. PMID- 29707639 TI - Neuronal noise as an origin of sleep arousals and its role in sudden infant death syndrome. AB - In addition to regular sleep/wake cycles, humans and animals exhibit brief arousals from sleep. Although much is known about consolidated sleep and wakefulness, the mechanism that triggers arousals remains enigmatic. Here, we argue that arousals are caused by the intrinsic neuronal noise of wake-promoting neurons. We propose a model that simulates the superposition of the noise from a group of neurons, and show that, occasionally, the superposed noise exceeds the excitability threshold and provokes an arousal. Because neuronal noise decreases with increasing temperature, our model predicts arousal frequency to decrease as well. To test this prediction, we perform experiments on the sleep/wake behavior of zebrafish larvae and find that increasing water temperatures lead to fewer and shorter arousals, as predicted by our analytic derivations and model simulations. Our findings indicate a previously unrecognized neurophysiological mechanism that links sleep arousals with temperature regulation, and may explain the origin of the clinically observed higher risk for sudden infant death syndrome with increased ambient temperature. PMID- 29707641 TI - Interpersonal Psychotherapy for Adolescents With Mood and Behavior Dysregulation: Evidence-Based Case Study. AB - Interpersonal psychotherapy for depressed adolescents, an evidence-based psychotherapy, has been adapted for youth with chronic irritability and excessive reactivity (i.e., temper outbursts), to create Interpersonal Psychotherapy for Mood and Behavior Dysregulation (IPT-MBD). Youth with chronic irritability and excessive reactivity were originally conceptualized as severe mood dysregulation (SMD) and in the Diagnostic and Statistical Manual of Mental Disorders (5th ed.) as disruptive mood dysregulation disorder. Because outbursts are the most prominent symptom, behavioral management strategies are typically a common focus of treatment. These outbursts, along with other mood symptoms, result in significant impairment in multiple domains, with a particularly adverse impact on interpersonal functioning. For this reason improving relationships is an important target for treatment. We present an evidence-based case study of an adolescent who met research criteria for SMD and who received the IPT-MBD intervention as part of a research study. Monthly ratings assessing severity and improvement of SMD symptoms were conducted by an independent evaluator. This adolescent had an overall improvement in SMD symptoms, attended all scheduled therapy sessions, and parent and teen reported satisfaction with the treatment. We discuss factors that may influence the effectiveness of this treatment. PMID- 29707642 TI - Oxygen and Oxygen Toxicity: The Birth of Concepts. AB - Molecular dioxygen (O2) is an essential element of aerobic life, yet incomplete reduction or excitation of O2 during aerobic metabolisms generates diverse oxygen containing reactive species, commonly known as reactive oxygen species (ROS). On the one hand, ROS pose a serious threat to aerobic organisms via inducing oxidative damage to cellular constituents. On the other hand, these reactive species, when their generation is under homeostatic control, also play important physiological roles (e.g., constituting an important component of immunity and participating in redox signaling). This article defines oxygen and the key facts about oxygen, and discusses the relationship between oxygen and the emergence of early animals on Earth. The article then describes the discovery of oxygen by three historical figures and examines the birth of the concepts of oxygen toxicity and the underlying free radical mechanisms. The article ends with a brief introduction to the emerging field of ROS-mediated redox signaling and physiological responses. PMID- 29707643 TI - Defining ROS in Biology and Medicine. AB - Utilization of molecular oxygen by aerobic organisms inevitably results in the formation of a number of oxygen-containing reactive species that are collectively known as reactive oxygen species (ROS). ROS play important roles in both physiology and pathophysiology of aerobic life. The field of 'ROS biology and medicine' deals with the involvement of ROS and related species in contemporary biology and medicine. The purpose of this article is to survey common terms and concepts in ROS biology and medicine. It also introduces the 'ROS paradigm' so as to provide a conceptual framework for understanding the rapidly evolving field of ROS biology and medicine. PMID- 29707644 TI - Innovative Bioluminometric Quantification of Cancer Cell Load in Target Organs: Implications for Studying Anticancer Drugs, Including ROS Enhancers. AB - Animal models are essential for developing effective drugs for treating human cancer. Examination of the formation of lung surface foci of B16-F10 melanoma cells is a widely used animal model for studying cancer metastasis and drug intervention. This model, however, suffers from several drawbacks, including its non-quantitative nature and inability to yield information on cancer cell load inside the target organ. Here we report the development of a highly sensitive, bioluminescence-based method for quantifying melanoma cell load in mouse lungs following intravenous injection of luciferase-expressing B16-F10 melanoma cells. This method could readily detect as few as 1-10 cells in the samples and enable quantification of cancer cell load before the formation of surface foci in mouse lungs following metastasis of intravenously inoculated B16-F10 melanoma cells. This innovative bioluminometry-based method has important implications for studying anticancer drugs, including naturally occurring redox-active quinones that generate reactive oxygen species to kill cancer cells. PMID- 29707645 TI - Doxorubicin Redox Biology: Redox Cycling, Topoisomerase Inhibition, and Oxidative Stress. AB - Doxorubicin (also called Adriamycin) is effective in treating a wide range of human cancers and currently considered as one of the most important drugs in cancer chemotherapeutics. The clinical use of doxorubicin is, however, associated with dosage-dependent cardiotoxicity and development of heart failure, which diminish the therapeutic index of this widely used anticancer drug. This article first surveys key research findings on doxorubicin redox biology that may impact its cardiotoxicity as well as anticancer activity. It then discusses emerging concepts, especially the topoisomerase IIb-p53-mitochondrion axis that may lead to the development of mechanistically based novel strategies to protect against cardiotoxicity and enhance the effectiveness of doxorubicin therapy. PMID- 29707646 TI - Nrf2 Signaling in Macrophages. AB - The nuclear factor E2-related factor 2 (Nrf2) is known as the chief regulator of cellular antioxidant defenses as well as a suppressor of inflammation. Macrophages act as major players in inflammatory responses. Because oxidative stress and inflammation are two intertwined processes, the anti-inflammatory activity of Nrf2 signaling is believed to result from its upregulation of cellular antioxidant defenses via the antioxidant response element-driven transcription. In a recent article published in Nature Communications (May 23, 2016; doi: 10.1038/ncomms11624), Kobayashi et al. reported that Nrf2 suppresses transcriptional upregulation of pro-inflammatory cytokines independent of its role in regulating cellular antioxidants and redox status. This study by Kobayashi et al. provides novel insights into the molecular basis of Nrf2 acting as a suppressor of inflammation. PMID- 29707647 TI - Fluorescence-Based Assays for Measuring Doxorubicin in Biological Systems. AB - Detection and measurement of doxorubicin in biological systems, including body fluids, cells, and tissues, are instrumental in understanding the mechanisms of action of this widely used drug in treating cancer as well as in causing adverse effects. In this article, we, for the first time, characterized the use of fluorescence-based techniques, including fluorescence spectrometry, microscopy, and flow cytometry in measuring and/or detecting doxorubicin in biological systems, including cell lysates and cultured intact cells. We showed that doxorubicin has a maximum excitation and emission wavelength of 470 and 560 nm, respectively. The detection sensitivity by fluorescence spectrometry is less than 0.1 MUM in buffers and cell lysates. Fluorescence microscopy demonstrated the readily detection of concentration-dependent accumulation of doxorubicin in cultured cells via either green or red fluorescence, but with green fluorescence showing a higher sensitivity of detection. Flow cytometry also revealed sensitive detection of doxorubicin accumulation in cell suspensions in a concentration dependent manner. The readily and sensitive measurement and detection of doxorubicin by the above three fluorescence-based techniques has important implications in studying the cellular dynamics of doxorubicin in both cancer and normal cells under various experimental conditions. PMID- 29707648 TI - Bridging the Chasm: Challenges, Opportunities, and Resources for Integrating a Dissemination and Implementation Science Curriculum into Medical Education. AB - Background: Physicians are charged with implementing evidence-based medicine, yet few are trained in the science of Dissemination and Implementation (D&I). In view of the potential of evidence-based training in D&I to help close the gap between research and practice, the goal of this review is to examine the importance of D&I training in medical education, describe challenges to implementing such training, and provide strategies and resources for building D&I capacity. Methods: We conducted (1) a systematic review to identify US-based D&I training efforts and (2) a critical review of additional literature to inform our evaluation of the challenges and opportunities of integrating D&I training in medical education. Results: Out of 269 unique articles reviewed, 11 described US based D&I training. Although vibrant and diverse training opportunities exist, their capacity is limited, and they are not designed to meet physicians' needs. Synthesis of relevant literature using a critical review approach identified challenges inherent to changing medical education, as well as challenges related to D&I science. Finally, selected strategies and resources are available for facilitating incorporation of D&I training into medical education and overcoming existing challenges. Conclusions: Integrating D&I training in the medical education curriculum, and particularly in residency and fellowship training, holds promise for bridging the chasm between scientific discoveries and improved patient care and outcomes. However, unique challenges should be addressed, including the need for greater evidence. PMID- 29707649 TI - Tracking Active Learning in the Medical School Curriculum: A Learning-Centered Approach. AB - Background: Medical education is moving toward active learning during large group lecture sessions. This study investigated the saturation and breadth of active learning techniques implemented in first year medical school large group sessions. Methods: Data collection involved retrospective curriculum review and semistructured interviews with 20 faculty. The authors piloted a taxonomy of active learning techniques and mapped learning techniques to attributes of learning-centered instruction. Results: Faculty implemented 25 different active learning techniques over the course of 9 first year courses. Of 646 hours of large group instruction, 476 (74%) involved at least 1 active learning component. Conclusions: The frequency and variety of active learning components integrated throughout the year 1 curriculum reflect faculty familiarity with active learning methods and their support of an active learning culture. This project has sparked reflection on teaching practices and facilitated an evolution from teacher centered to learning-centered instruction. PMID- 29707650 TI - Using an Audience Response System Smartphone App to Improve Resident Education in the Pediatric Intensive Care Unit. AB - In the Pediatric Intensive Care Unit (PICU), most teaching occurs during bedside rounds, but technology now provides new opportunities to enhance education. Specifically, smartphone apps allow rapid communication between instructor and student. We hypothesized that using an audience response system (ARS) app can identify resident knowledge gaps, guide teaching, and enhance education in the PICU. Third-year pediatric residents rotating through the PICU participated in ARS-based education or received traditional teaching. Before rounds, experimental subjects completed an ARS quiz using the Socrative app. Concomitantly, the fellow leading rounds predicted quiz performance. Then, discussion points based on the incorrect answers were used to guide instruction. Scores on the pre-rotation test were similar between groups. On the post-rotation examination, ARS participants did not increase their scores more than controls. The fellow's prediction of performance was poor. Residents felt that the method enhanced their education whereas fellows reported that it improved their teaching efficiency. Although there was no measurable increase in knowledge using the ARS app, it may still be a useful tool to rapidly assess learners and help instructors provide learner centered education. PMID- 29707651 TI - Using circulating tumor cells to advance precision medicine in prostate cancer. AB - The field of CTC enrichment has seen many emerging technologies in recent years, which have resulted in the identification and monitoring of clinically relevant, CTC-based biomarkers that can be analyzed routinely without invasive procedures. Several molecular platforms have been used to investigate the molecular profile of the disease, from high throughput gene expression analyses down to single cell biological dissection. The established presence of CTC heterogeneity nevertheless constitutes a challenge for cell isolation as the several subpopulations can potentially display different molecular characteristics; in this scenario, careful consideration must be given to the isolation approach, whereas methods that discriminate against certain subpopulations may result in the exclusion of CTCs that carry biological relevance. In the context of prostate cancer (PC), CTC molecular interrogation can enable longitudinal monitoring of key biological features during treatment with substantial clinical impact, as several biomarkers could predict tumor response to AR signaling inhibitors (abiraterone, enzalutamide) or standard chemotherapy (taxanes). Thus, CTCs represent a valuable opportunity to personalize medicine in current clinical practice. PMID- 29707652 TI - Community-level antibiotic access and use (ABACUS) in low- and middle-income countries: Finding targets for social interventions to improve appropriate antimicrobial use - an observational multi-centre study. AB - In many low- and middle-income countries (LMICs), a poor link between antibiotic policies and practices exists. Numerous contextual factors may influence the degree of antibiotic access, appropriateness of antibiotic provision, and actual use in communities. Therefore, improving appropriateness of antibiotic use in different communities in LMICs probably requires interventions tailored to the setting of interest, accounting for cultural context. Here we present the ABACUS study (AntiBiotic ACcess and USe), which employs a unique approach and infrastructure, enabling quantitative validation, contextualization of determinants, and cross-continent comparisons of antibiotic access and use. The community infrastructure for this study is the INDEPTH-Network (International Network for the Demographic Evaluation of Populations and Their Health in Developing Countries), which facilitates health and population research through an established health and demographic surveillance system. After an initial round of formative qualitative research with community members and antibiotic suppliers in three African and three Asian countries, household surveys will assess the appropriateness of antibiotic access, provision and use. Results from this sample will be validated against a systematically conducted inventory of suppliers. All potential antibiotic suppliers will be mapped and characterized. Subsequently, their supply of antibiotics to the community will be measured through customer exit interviews, which tend to be more reliable than bulk purchase or sales data. Discrepancies identified between reported and observed antibiotic practices will be investigated in further qualitative interviews. Amartya Sen's Capability Approach will be employed to identify the conversion factors that determine whether or not, and the extent to which appropriate provision of antibiotics may lead to appropriate access and use of antibiotics. Currently, the study is ongoing and expected to conclude by 2019. ABACUS will provide important new insights into antibiotic practices in LMICs to inform social interventions aimed at promoting optimal antibiotic use, thereby preserving antibiotic effectiveness. PMID- 29707653 TI - Methyl donor deficient diets cause distinct alterations in lipid metabolism but are poorly representative of human NAFLD. AB - Background: Non-alcoholic fatty liver disease (NAFLD) is a global health issue. Dietary methyl donor restriction is used to induce a NAFLD/non-alcoholic steatohepatitis (NASH) phenotype in rodents, however the extent to which this model reflects human NAFLD remains incompletely understood. To address this, we undertook hepatic transcriptional profiling of methyl donor restricted rodents and compared these to published human NAFLD datasets. Methods: Adult C57BL/6J mice were maintained on control, choline deficient (CDD) or methionine/choline deficient (MCDD) diets for four weeks; the effects on methyl donor and lipid biology were investigated by bioinformatic analysis of hepatic gene expression profiles followed by a cross-species comparison with human expression data of all stages of NAFLD. Results: Compared to controls, expression of the very low density lipoprotein (VLDL) packaging carboxylesterases ( Ces1d, Ces1f, Ces3b) and the NAFLD risk allele Pnpla3 were suppressed in MCDD; with Pnpla3 and the liver predominant Ces isoform, Ces3b, also suppressed in CDD. With respect to 1-carbon metabolism, down-regulation of Chka, Chkb, Pcty1a, Gnmt and Ahcy with concurrent upregulation of Mat2a suggests a drive to maintain S-adenosylmethionine levels. There was minimal similarity between global gene expression patterns in either dietary intervention and any stage of human NAFLD, however some common transcriptomic changes in inflammatory, fibrotic and proliferative mediators were identified in MCDD, NASH and HCC. Conclusions: This study suggests suppression of VLDL assembly machinery may contribute to hepatic lipid accumulation in these models, but that CDD and MCDD rodent diets are minimally representative of human NAFLD at the transcriptional level. PMID- 29707654 TI - First report of the presence of L1014S Knockdown-resistance mutation in Anopheles gambiae s.s and Anopheles coluzzii from Togo, West Africa. AB - Background: To optimize the success of insecticide-based malaria control intervention, knowledge of the distribution of Anopheles gambiae species and insecticide resistance mechanisms is necessary. This paper reported an updated data on pyrethroids/DDT resistance in the An. gambiae s.l population from Togo. Methods: From December 2013 to April 2015, females of indoor-resting An. gambiae s.l were captured in three locations belonging to three different ecological zones. Resistance to DDT, permethrin and deltamethrin was screened in F1 progeny of collected mosquitoes using WHO susceptibility tests. The identification of species of An. gambiae complex and the detection of kdr and ace.1 R allele were carried out using DNA-based molecular techniques. Results:An. gambiae from Kovie and Nangbeto were highly resistant to DDT and permethrin with mortalities rate ranging from 0.83% to 1.58% for DDT and zero to 8.54% for permethrin. Mosquitoes collected in Nangbeto displayed 81.53% mortality with deltamethrin. An. coluzzii and An. gambiae s.s were found in sympatry in Nangbeto and Mango . The allelic frequency of L1014F was high, ranging from 66 to 100% in both An. coluzzii and An. gambiae s.s. For the first time we detected the L1014S allele in both An. coluzzii and An. gambiaes.s. from Togo at the frequency ranging from 5% to 13% in all the sites. The kdr N1575Y was present at various frequencies in both species ranging from 10% to 45%. Both An. gambiae s.s. and An. coluzzii shared the ace1 R mutation in all investigated sites with allelic frequency ranging from 4% to 16%. Conclusion: These results showed that multiple mutations are involved in insecticides resistance in An. gambiae populations from Togo including the kdr L1014F, L1014S, and N1575Y and ace.1 R G119S mutations. PMID- 29707655 TI - The neural determinants of age-related changes in fluid intelligence: a pre registered, longitudinal analysis in UK Biobank. AB - Background: Fluid intelligence declines with advancing age, starting in early adulthood. Within-subject declines in fluid intelligence are highly correlated with contemporaneous declines in the ability to live and function independently. To support healthy aging, the mechanisms underlying these declines need to be better understood. Methods: In this pre-registered analysis, we applied latent growth curve modelling to investigate the neural determinants of longitudinal changes in fluid intelligence across three time points in 185,317 individuals (N=9,719 two waves, N=870 three waves) from the UK Biobank (age range: 39-73 years). Results: We found a weak but significant effect of cross-sectional age on the mean fluid intelligence score, such that older individuals scored slightly lower. However, the mean longitudinal slope was positive, rather than negative, suggesting improvement across testing occasions. Despite the considerable sample size, the slope variance was non-significant, suggesting no reliable individual differences in change over time. This null-result is likely due to the nature of the cognitive test used. In a subset of individuals, we found that white matter microstructure (N=8839, as indexed by fractional anisotropy) and grey-matter volume (N=9931) in pre-defined regions-of-interest accounted for complementary and unique variance in mean fluid intelligence scores. The strongest effects were such that higher grey matter volume in the frontal pole and greater white matter microstructure in the posterior thalamic radiations were associated with higher fluid intelligence scores. Conclusions: In a large preregistered analysis, we demonstrate a weak but significant negative association between age and fluid intelligence. However, we did not observe plausible longitudinal patterns, instead observing a weak increase across testing occasions, and no significant individual differences in rates of change, likely due to the suboptimal task design. Finally, we find support for our preregistered expectation that white- and grey matter make separate contributions to individual differences in fluid intelligence beyond age. PMID- 29707656 TI - Cervical Human Papillomavirus genotypes in HIV-infected women: a cross-sectional analysis of the VALHIDATE study. AB - Introduction: Primary-prevention by prophylactic vaccination against HPV-related cancers and HPV-based screening programs are based on HPV-type distribution in immunocompetent individuals. HIV-infected women are at high risk of invasive HPV disease sustained by a broader range of HPV-types and have higher multi-type infection rates than immunocompetent hosts. Methods: This is a cross-sectional analysis of High Risk HPV (HR HPV) type distribution in 805 HIV+ women (HIW) compared with a control group of 1402 immunocompetent HIV- women (SPW) enrolled in the VALHIDATE study in order to define HPV type-specific distribution according to cytology. Results: HIW had a 3.8, 3.6, and 2.7 times higher risk of atypical squamous cells of undetermined significance (ASCUS), low-grade squamous intraepithelial lesion (LSIL) and high grade squamous intraepithelial lesion (HSIL) than SPW respectively. HPV-DNA prevalence was 28.4% in HIW and 11.81% in SPW (p<0.0001). The prevalence of infection increased from normal cytology to HSIL both in HIW (from 21.45% to 90.91%) and SPW (from 9.54% to 75%). The OR for women with normal cytology of having a positive HPV-DNA test result of was 2.6 times higher in HIW than in SPW. The cumulative prevalence of HPV-16/18 in HSIL is much lower in HIW (36.4+/-28.4) than SPW (62.5+/-33.5). Conclusions: A higher prevalence of infection and broader HPV type distribution were observed in HIV+ women compared to the general population. More than 60% of HSIL lesions of HIW patients are caused by single or multi-type infections from non-HPV16/18 HPVs. The potential 9v-HPV vaccine coverage could be even higher than that expected for the general population given the wide panel of HPV-types observed in the HSIL of HIV+ women. PMID- 29707657 TI - Knowledge, attitudes and practices (KAP) towards vaccinations in the school settings: an explorative survey. AB - Background: Past researches have shown that schoolteachers' (STs) interventions maximize the consent for vaccination programs. European data regarding knowledge, attitudes and practices of STs towards vaccination are otherwise lacking. Objectives: The aim of this study was therefore to evaluate knowledge and attitudes of STs regarding vaccinations in a sample from North Italy. Material and methods: In this cross sectional study, 154 STs from Lombardy region (Northern Italy) responded to a specific questionnaire assessing their attitude towards vaccination and vaccine related knowledge. Results: In general, 88.3% of subjects were somehow favourable to vaccinations. The main reason for declining vaccination was the risk of side effects whereas the main reason to be vaccinated was to avoid to be infected by VPDs (67.6%). Main information sources were health professionals (75.3%), and new media (13.1%), and the latter were STs more frequently associated with a negative attitude towards vaccinations (p < 0.001). Eventually, regression analysis identified risk perception as positively associated with propensity towards vaccinations, both for Students- and STs recommended vaccinations (B = 0.372, 95% CI 0.247 to 0.496 and B = 0.005, 95%CI 0.004 to 0.006, respectively). Conclusions: Our results are consistent with previous reports suggesting a significant knowledge gap in STs, with the risk perception of infectious diseases as the main predictor for vaccine propensity. Moreover, the better knowledge of official vaccination recommendations and policies among STs identifying Health Professionals as information source enlightens the role of the School Physicians and Occupational Physicians, whose intervention may ultimately increase the vaccination acceptance and vaccination rates. PMID- 29707658 TI - Age- and risk-related appropriateness of the use of available influenza vaccines in the Italian elderly population is advantageous: results from a budget impact analysis. AB - Introduction: Nowadays, four different types of influenza vaccines are available in Italy: trivalent (TIV), quadrivalent (QIV), MF59-adjuvanted (aTIV) and intradermal TIV (idTIV) inactivated vaccines. Recently, a concept of the appropriateness (i.e. according to the age and risk factors) of the use of different vaccines has been established in Italy. We conducted a budget impact analysis of switching to a policy, in which the Italian elderly (who carry the major disease burden) received the available vaccines according to their age and risk profile. Methods: A novel budget impact model was constructed with a time horizon of one influenza season. In the reference scenario the cohort of Italian elderly individuals could receive either available vaccine according to 2017/18 season market share. The alternative scenario envisaged the administration of TIV/QIV to people aged 65-74 years and at low risk of developing influenza related complications, while aTIV/idTIV were allocated to high-risk 65-74-year olds and all subjects aged >= 75 years. Results: Switching to the alternative scenario would result in both significant health benefits and net budget savings. Particularly, it would be possible to prevent an additional 8201 cases of laboratory-confirmed influenza, 988 complications, 355 hospitalizations and 14 deaths. Despite the alternative strategy being associated with slightly higher vaccination costs, the total savings derived from fewer influenza events completely resets this increase with net budget savings of ? 0.13 million. Conclusions: An immunization policy in which influenza vaccines are administered according to the age and risk profile of Italian elderly individuals is advisable. PMID- 29707659 TI - Practicing health promotion in primary care -a reflective enquiry. AB - Introduction: Health promotion is an integral part of routine clinical practice. The physicians' role in improving the health status of the general population, through effective understanding and delivery of health promotion practice, is evident throughout the international literature. Data from India suggest that physicians have limited skills in delivering specific health promotion services. However, the data available on this is scarce. This study was planned to document the current health promotion knowledge, perception and practices of local primary care physicians in Odisha. Methods: An exploratory study was planned between the months of January - February 2013 in Odisha among primary care physicians working in government set up. This exploratory study was conducted, using a two-step self administered questionnaire, thirty physicians practicing under government health system were asked to map their ideal and current health promotion practice, and potential health promotion elements to be worked upon to enhance the practice. Results: The study recorded a significant difference between the mean of current and ideal health promotion practices. The study reported that physicians want to increase their practice on health education. Conclusion: We concluded that inclusion of health promotion practices in routine care is imperative for a strong healthcare system. It should be incorporated as a structured health promotion module in medical curriculum as well. PMID- 29707660 TI - Changes in the incidence and antimicrobial susceptibility of healthcare associated infections in a New York hospital system, 2006-2012. AB - Introduction: National efforts to curtail healthcare-associated infections (HAI) proliferated recently, though data detailing progress over time are limited. This retrospective cohort study aims to describe changes in incidence and antimicrobial susceptibility of HAI in four New York City hospitals over seven years. Methods: Electronic data were collected retrospectively for all patients discharged from 2006 through 2012. Previously validated computerized algorithms based on National Healthcare Safety Network criteria detected bloodstream infections, pneumonia, surgical site infections, and urinary tract infections with Enterococcus spp., Staphylococcus aureus, Streptococcus pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumoniae. Antimicrobial susceptibilities were obtained from electronic laboratory records. Logistic regression was used to assess changes in odds of acquiring an HAI and odds of antimicrobial resistance over time, controlling for age, gender, severity of illness, previous hospitalizations, and admission source. Results: In total, 19,052 HAI were identified among 761,426 discharges. HAI rates fell for all organisms, all infection types, and within all hospitals. Odds of acquiring an HAI decreased significantly over time for all organisms. Resistance levels were stable for Enterococcus spp., S. aureus, A. baumannii, and S. pneumoniae. Multidrug resistance increased for P. aeruginosa and decreased for K. pneumoniae, though imipenem resistance among K. pneumoniae climbed sharply in 2011. Conclusions: This study suggests that HAI incidence rates are falling, possibly due to increased federal, state and local attention to healthcare quality and patient safety. Though we found no substantial reductions in resistance, recent national attention towards antimicrobial stewardship may precipitate a change in coming years. PMID- 29707661 TI - VIM-Klebsiella oxytoca outbreak in a Neonatal Intensive Care Unit. This time it wasn't the drain. AB - Objective: We describe an outbreak of VIM-carbapenemase Klebsiella oxytoca (VIM Kox) in a NICU. Materials and methods: Prospective Epidemiological Surveillance:Systematically (weekly screening cultures) or on admission, if the patient had a history of previous colonization by VIM-Kox.Clinical cultures, done if infection was suspected.Other possible microorganism sources were investigated: their mothers (rectal microbiota), milk packages and preparation apparata in the lactodietary section, echocardiagram transductors, cribs, the sinks (faucets and drains), washing bowls, etc.Molecular typing was performed using the DiversiLab (bioMerieux) system on all VIM-Kox isolated from environment or patients (one by neonate). Results: We identified 20 VIM-Kox cases, the most only presented colonization, but 4 showed infection. Three of the ten sinks (drains) in our NICU, were positive for VIM-Kox. Another four drains harbored P.aeruginosa, S. maltophilia and/or Enterobacter sp. Nevertheless the VIM-Kox bacteria in the sinks (drains) were not the same as those in the patients, who showed three different strains. Conclusions: A VIM-Kox colonization or infection outbreak in a NICU is described. Rather than environment, not even drains, the source of the outbreak was other patients. The outbreak was relatively brief, as a result of the rapidness with which appropriate measures were taken and followed. PMID- 29707662 TI - Molecular analysis of immune evasion cluster (IEC) genes and intercellular adhesion gene cluster (ICA) among methicillin-resistant and methicillin-sensitive isolates of Staphylococcus aureus. AB - Introduction: Resistance to antibiotics and presence of virulence factors play an important role in increased mortality associated with infection due to Staphylococcus aureus. In this study, we determine antibiotic resistance pattern, presence of the icaADBC locus as well as biofilm formation and distribution and diversity the immune evasion cluster (IEC) genes in clinical isolate of S. aureus from Kerman, Iran. Materials and methods: During 15 months, 100 clinical isolates S. aureus recovered from different patients were admitted to Kerman University affiliated hospitals. Resistance to different antibiotic agents was determined by disk diffusion method. Phenotypic method was used to the determination of biofilm formation ability and methicillin-resistance S. aureus (MRSA). Polymerase chain reaction technique (PCR) was used to the detection of nuc, mecA, icaA, icaD, icaB, icaC, scn, sea, sak, sep and chp genes. Results: Forty-four isolates were considered as MRSA and all of isolates were sensitive to vancomycin and linezolid. Our results showed, 77.2% (34/44) of MRSA and 8.9 % (5/56) of MSSA isolates were multidrug resistant. The predominant IEC variant was type B and our results displayed that 77.7% of the MRSA isolates harbor loci icaD and mecA. There was no significant difference in production biofilm between MSSA and MRSA isolates (P >= 0.05). There was significant difference in presence IEC types between MSSA and MRSA isolates (P = 0.000). Conclusions: The presence of icaADBC locus may not be a determining factor for biofilm formation in Staphtlocooci and other mechanisms might be involved in this process.The high prevalence IEC types in MSSA isolates can indicate that the presence of these genes can be an advantage for pathogenesis of these isolates in different infections. PMID- 29707663 TI - Ultraviolet germicidal irradiation in tap water contaminated by Aspergillus spp. AB - We investigated the effect of ultraviolet germicidal irradiation (UVI) from a low pressure mercury lamp on several pathogenic Aspergillus spp. including A. flavipes, A. flavus, A. fumigatus, A. glaucus, A. nidulans, A. niger, A. terreus, A. ustus and A. versicolor suspended in tap water under laboratory-scale conditions. It was shown that within 10 s of exposure, time species such as A. glaucus, A. niudulans and A. ustus were completely inactivated, while 40 s were needed for the elimination of all the species tested. A. flavus and A. niger were found to be less susceptible than other species. Based on these results we conclude that UV disinfection could effectively inactivate Aspergillus spp. in tap water. Such disinfection could be used to reduce potential exposure of high risk patients to fungal aerosols, particularly in hospital settings, where point of-use (POU) UV light devices could be installed to provide safe water at a very low cost. PMID- 29707664 TI - Food safety knowledge, attitude and practices of meat handler in abattoir and retail meat shops of Jigjiga Town, Ethiopia. AB - A cross-sectional survey was carried out among 91 meat handlers by using structured questionnaire to determine the food safety knowledge, attitude and practices in abattoir and retail meat shops of Jigjiga Town. The result shows that majority of the meat handlers were illiterate (30.8%) and primary school leaver (52.7%), and no one went through any food safety training except one meat inspector. The food-handlers' knowledge and safety practices were below acceptable level with the mean score of 13.12 +/- 2.33 and 7.7 +/- 2.1 respectively. Only few respondents knew about Staphylococcus aureus (3.3% correct answer), hepatitis A virus (19.8% correct answer), and E. coli (5.5% correct answer) as food borne pathogens. About 64% of meat handlers have good attitude about safety of food with mean of total score 14.4 +/- 2. All respondents answer correctly questions about proper meat handling and hand washing but they did not translate into strict food hygiene practices. Chi2 analysis testing for the association between knowledge, attitude and practices did not show any significant association. It may be due to meat handlers' below acceptable level safety practices regardless of sociodemographic characteristics, knowledge and attitude. However, there was strong association between level of education and knowledge, and knowledge and hand washing (p < 0.05). There was also association between age and knowledge though it was not statistically significant. Thus, continuous education and hands on training for meat handlers that can enhance good safety practices through better understanding and positive attitude. PMID- 29707665 TI - Helminths and heavy metals in soils from a dumpsite in Ibadan city, Nigeria. AB - Waste generation is inevitable because humans continue to generate waste due to increase in population, urbanization and advancement in technology. This generation of waste is of public health concern especially when the waste materials are deposited on dumpsites. This study assessed the helminths and heavy metal content of Awotan dumpsite in Ibadan city. Surface soils (0-15cm depth) of the dumpsite were randomly sampled at different dumpsite areas with the aid of a quadrat. Helminth content was determined using the zinc floatation method and the heavy metal concentrations of the soil were determined using Atomic Absorption Spectrophotometry (AAS). Some physicochemical properties of the soil were also determined. Results showed that the dumpsite soil was slightly alkaline with an average pH of 8.1 +/- 0.2 while the overall mean electrical conductivity, temperature, moisture content and height above sea level were 545.9 +/- 235.3MUS/cm, 32.6 +/- 2.2oC, 17.2 +/- 4.8 % and 236+/-4.6 m respectively. The overall prevalence of soil helminths was 10.4% with Ascaris lumbricoides being more prevalent (8.8%). The heavy metal concentration of the soil followed the trend Pb (709.7+/- 1574.9mg/g) > Cu (316 +/- 227.1mg/g) > Cr (48.8 +/- 17.7mg/g) > Cd (9.7 +/- 10.9mg/g). There was a low overall prevalence of soil helminths. However, the heavy metal concentrations exceeded USEPA permissible limits providing a possible source for underground water contamination in residential areas around the dumpsite. Human settlements close to the dumpsite should be discouraged by the government. PMID- 29707666 TI - Detection of ochratoxin A in human breast milk in Jiroft city, south of Iran. AB - Background and Purpose: Breastfeeding plays an important role in the growth and development of infants. However, breast milk may be contaminated with various mycotoxins. Ochratoxin A is one of the most important mycotoxins with nephrotoxic, carcinogenic, teratogenic, genotoxic, and immunotoxic properties. Thus, we carried out this study to determine the concentration of ochratoxin A in human breast milk in Jiroft, Kerman Province, south of Iran. Materials and Methods: Eighty-four human breast milk samples were collected from mothers visiting the number one clinic in Jiroft city. Enzyme-linked immunosorbent assay (ELISA) was used to detect ochratoxin A in the samples. Results: Ochratoxin A was found in all the tested samples at a concentration ranging from 0.11 to 7.34 ng/ml. The mean concentration of ochratoxin A in the samples was 1.99+/-1.34 ng/ml. Fourteen samples contained ochratoxin A at concentrations exceeding the quantitation limit (3 ng/ml). Conclusion: The results of this study showed that infants are exposed to ochratoxin A in our region. In cases exceeding the quantitation limit, the infant's body cannot detoxify the toxin. Therefore, the infant can be affected by various illnesses such as nephropathy, immune system deficiency, and different types of cancer. PMID- 29707667 TI - Identification of fungal causative agents of rhinosinusitis from Mashhad, Iran. AB - Background and Purpose: Rhinosinusitis is a common disorder, influencing approximately 20% of the population at some time of their lives. It was recognized and reported with expanding recurrence over the past two decades worldwide. Undoubtedly, correct diagnosis of fungi in patients with fungal rhinosinusitis affects the treatment planning and prognosis of the patients. Identification of the causative agents using the standard mycological procedures remains difficult and time-consuming. Materials and Methods: Based on clinical and radiological parameters, 106 patients suspected of fungal rhinosinusitis were investigated in this cross-sectional prospective study from April 2012 to March 2016 at an otorhinolaryngology department. In this study, internal transcribed spacer (ITS) and calmodulin (CaM) sequencing were respectively validated as reliable techniques for the identification of Mucorales and Aspergillus to species level (both agents of fungal rhinosinusitis). Results: Of these, 63 (59.4%) patients were suspected of allergic fungal rhinosinusitis (AFRS), 40 (37.7%) patients suspected of acute invasive fungal rhinosinusitis (AIFRS), and 3 (2.8%) patients suspected of mycetoma. In patients suspected of AFRS, AIFRS, and mycetoma only 7, 29, and 1 had positive fungal culture, respectively. After ITS and CaM sequencing, Aspergillus flavus was the most common species isolated from non-invasive forms, and A. flavus and Rhizopus oryzae were more frequently isolated from invasive forms. Conclusion: Aspergillus flavus is the most common agent of fungal rhinosinusitis in Iran, unlike most other reports from throughout the world stating that A. fumigatus is the most frequent causative agent of this disease. PMID- 29707668 TI - Comparison of CHROMagar, polymerase chain reaction-restriction fragment length polymorphism, and polymerase chain reaction-fragment size for the identification of Candida species. AB - Background and Purpose: The epidemiological alteration in the distribution of Candida species, as well as the significantly increasing trend of either intrinsic or acquired resistance of some of these fungi highlights the need for a reliable method for the identification of the species. Polymerase chain reaction (PCR) is one of the methods facilitating the quick and precise identification of Candida species. The aim of this study was to compare the efficiency of CHROMagar, PCR-restriction fragment length polymorphism (PCR-RFLP), and PCR fragment size polymorphism (PCR-FSP) assays in the identification of Candida species to determine the benefits and limitations of these methods. Materials and Methods: This study was conducted on 107 Candida strains, including 20 standard strains and 87 clinical isolates. The identification of the isolates was accomplished by using CHROMagar as a conventional method. The PCR-RFLP assay was performed on the entire internal transcribed spacer (ITS) region of ribosomal DNA (rDNA), and the consequent enzymatic digestion was compared with PCR-FSP results in which ITS1 and ITS2 regions were separately PCR amplified. In both molecular assays, yeast identification was carried out through the specific electrophoretic profiles of the PCR products. Results: According to the results, the utilization of CHROMagar resulted in the identification of 29 (33.3%) Candida isolates, while the PCR-RFLP and PCR-FSP facilitated the identification of 83 (95.4%) and 80 (91.9%) clinical isolates, respectively. The obtained concordances between CHROMagar and PCR-RFLP, between CHROMagar and PCR-FSP, as well as between PCR RFLP and PCR-FSP were 0.23, 0.20, and 0.77, respectively. Conclusion: The recognition of the benefits and limitations of PCR methods allows for the selection of the most efficient technique for a fast and correct differentiation. The PCR-RFLP and PCR-FSP assays had satisfactory concordance. The PCR-FSP provides a rapid, technically simple, and cost-effective method for the identification of Candida species. Nevertheless, to accurately differentiate among the taxonomically related species, PCR-RFLP should be implemented. PMID- 29707669 TI - Effect of biogenic selenium nanoparticles on ERG11 and CDR1 gene expression in both fluconazole-resistant and -susceptible Candida albicans isolates. AB - Background and Purpose: Candida albicans is the most common Candida species (sp.) isolated from fungal infections. Azole resistance in Candida species has been considerably increased in the last decades. Given the toxicity of the antimicrobial drugs, resistance to antifungal agents, and drug interactions, the identification of new antifungal agents seems essential. In this study, we assessed the antifungal effects of biogenic selenium nanoparticles on C. albicans and determined the expression of ERG11 and CDR1 genes. Materials and Methods: Selenium nanoparticles were synthesized with Bacillus sp. MSH-1. The ultrastructure of selenium nanoparticles was evaluated with a transmission electron microscope. The antifungal susceptibility test was performed according to the modified Clinical and Laboratory Standards Institute M27-A3 standard protocol. The expression levels of the CDR1 and ERG11 genes were analyzed using the quantitative real-time polymerase chain reaction (PCR) assay. Results: The azole-resistant C. albicans and wild type C. albicans strains were inhibited by 100 and 70 ug/mL of selenium nanoparticle concentrations, respectively. The expression of CDR1 and ERG11 genes was significantly down-regulated in these selenium nanoparticle concentrations. Conclusion: As the findings indicated, selenium nanoparticles had an appropriate antifungal activity against fluconazole resistant and -susceptible C.albicans strains. Accordingly, these nanoparticles reduced the expression of CDR1 and ERG11 genes associated with azole resistance. Further studies are needed to investigate the synergistic effects of selenium nanoparticles using other antifungal drugs. PMID- 29707670 TI - Morphological changes and induction of antifungal resistance in Aspergillus fumigatus due to different CO2 levels. AB - Background and Purpose: Aspergillosis is one of the most common opportunistic fungal infections in immunocompromised and neutropenic patients. Aspergillus fumigatus (A. fumigatus) is the most common causative agent of this infection. Due to variable CO2 concentrations that pathogens are exposed to during the infection process and to understand the role of CO2, we examined the effects of various CO2 concentrations as one of the environmental factors on morphological changes and induction of antifungal resistance in A. fumigatus. Materials and Methods: A. fumigatus strains were cultured and incubated under 1%, 3%, 5%, and 12% CO2 atmospheres, each time for one, two, and four weeks. The control culture was maintained for one week without CO2 atmosphere. Morphological changes were investigated and antifungal susceptibility test was performed according to the recommendations of the Clinical and Laboratory Standards Institute (CLSI) M38-A2 document. The results of different CO2 atmospheres were compared with that of the control sample. Results: We found that 1%, 3%, 5%, and 12% CO2 atmospheres were associated with morphological colony changes. Macroscopically, the colonies were shallow dark green, smooth, crisp to powdery with reduced growth; microscopic examination revealed the absence of conidiation. The induction of antifungal resistance in the susceptible strains to itraconazole, voriconazole, and amphotericin B increased after exposure to 12% CO2 atmosphere and four weeks of incubation. The MIC values for itraconazole, voriconazole, and amphotericin B were 16 g/ml, 1 g/ml, and 16 g/ml, respectively. These values for the control group were 0.125 g/ml, 0.125 g/ml, and 2 g/ml, respectively. Conclusion: Exposure to different CO2 atmospheres induced morphological changes in A. fumigatus, it seems to increase the MIC values, as well. In parallel, resistance to both itraconazole and voriconazole was also observed. PMID- 29707671 TI - Otomycosis in Damascus, Syria: Etiology and clinical features. AB - Background and Purpose: Otomycosis is a fungal infection that frequently involves the external auditory canal. The epidemiologic data on the etiologic agents of otomycosis in Syria are very limited. In this study, we aimed to determine the fungal agents, gender distribution, and clinical presentation of otomycosis. Materials and Methods: Two hundred and ninety nine patients (153 [51.17%] male and 146 [48.83%] female) clinically prediagnosed as otomycosis were studied at Al mouassat University Hospital and ENT Crescent Syrian Clinic. Clinical samples were collected from the ear discharges and cultured on Sabouraud Agar. Results: Otomycosis was diagnosed in 70 (23.4%) cases, with the highest prevalence in males aged 16-75 years (73.6%). The isolation rates of mold and yeast fungi were 75.7% and 24.3%, respectively. The most common presentations were otorrhea (98.66%), otalgia (18.06%), and hearing loss (6.35%). Our results showed that 64.28% of otomycosis agents were Aspergillus species. A.niger was the most common agent (45.7%), and 24.3% of the pathogens were C.albicans. Conclusion: Otomycosis agents most commonly belonged to the genus of Aspergillus followed by Candida, which should be seriously considered by physicians for appropriate treatment. PMID- 29707672 TI - Evaluation of esterase and hemolysin activities of different Candida species isolated from vulvovaginitis cases in Lorestan Province, Iran. AB - Background and Purpose: Annually affecting millions of women, vulvovaginal candidiasis (VVC) is commonly described by signs and symptoms of vulvovaginal inflammation in the presence of Candida species. Today, the detection of the virulence factors plays a major role in the understanding of pathogenesis of candidiasis and helps produce new anticandidial drugs to improve its treatment efficiency. Herein, we aimed to evaluate the esterase and hemolysin activities of the vaginal isolates of Candida and their relationship with the presence of VVC. Materials and Methods: One-hundred vaginal clinical specimens were randomly collected during September-December 2016. The target population consisted of married women suspected of VVC who presented to health centers in Lorestan Province, Iran. In this study, the esterase activity and hemolysin production of Candida clinical isolates were evaluated using the Tween 80 opacity test and the plate assay, respectively. Results: The most frequent Candida species was C. albicans (66; 66%), followed by C. glabrata (11; 11%) and C. tropicalis (11; 11%). The highest esterase activity was found in C. krusei (75%), followed by C. albicans (68.2%) and C. glabrata (54.5%). The greater part of the positive esterase isolates had Pz 4+ scores. Among the Candida species, C. albicans (22.7%), C. glabrata (63.6%), and C. krusei (50%) were found to have the highest rates of alpha, beta, and gamma hemolysin production, respectively. The level of hemolytic activity in 51% of the Candida species was Pz 4+ scores. Conclusion: According to our results, the higher expression rates of both enzymes in C. albicans species relative to those of non-albicans Candidate species can partly reflect the role of the virulence factors involved in C. albicans pathogenicity. PMID- 29707673 TI - Phytochemical analysis and docking study of compounds present in a polyherbal preparation used in the treatment of dermatophytosis. AB - Background and Purpose: Soleshine is a polyherbal preparation established in the market for the treatment of cracks and tinea pedis, which is applied externally. This preparation is composed of the extracts of indigenous plants, namely Azadirachta indica, Lawsonia alba, and Shorea robusta, mixed with castor oil and sesame oil. In the present study, an attempt was made to identify the constituents of soleshine and identify some potential drug-like molecules that can inhibit important drug targets of the dermatophytes using molecular docking method. Materials and Methods: The active ingredients of polyherbal preparation were identified with the aid of gas chromatography-mass spectrometry (GC-MS). Two major compounds were selected based on the retention time and percentage of the area covered in the graph for docking study. The three-dimensional structures of 1,3-beta-glucan synthase, chitinase, fungalysin, and lumazine synthase were derived by homology modelling using MODELLER software, version 9.0. The docking of the ligand and receptor was performed using iGEMDOCK and AutodockVina software. The physicochemical properties, lipophilicity, hydrophilicity, and drug likeness properties were obtained from the Swiss ADME online server tool. Results: The GC-MS analysis demonstrated the presence of different phytochemical compounds in the extract of polyherbal preparation. A total of 20 compounds were identified, among which 3,7-dimethyl-2,6-octadienaland 2-pentene-2-methyl were the major compounds. Regarding 3,7-dimethyl-2,6-octadienal, the covered area and height were 40.15% and 46.17%, respectively. These values were 31.90% and 23.33% for 2-pentene-2-methyl, respectively. These two major compounds had an excellent binding affinity and obeyed the rules for the drug likeness and lead likeness. Conclusion: As the findings indicated, the two major ingredients present in soleshine showed a good antifungal activity as they inhibited the enzymes responsible for the survival of fungal organism; furthermore, they were appropriate for the lead molecules. PMID- 29707674 TI - Microsatellite genotyping of clinical Candida parapsilosis isolates. AB - Background and Purpose: Candida parapsilosis is a predominant species found in nosocomial infection, particularly in hospitalized patients. The molecular epidemiology of the clinical strains of this species has not been well studied. The present study was performed with the aim of investigating the microsatellite genotyping of Candida parapsilosis among the Iranian clinical isolates. Materials and Methods: This study was conducted on 81 independent clinical C. parapsilosis isolates that were genotyped by using a panel of six microsatellite markers. Results: The short tandem repeat (STR) typing of clinical C. parapsilosis isolates demonstrated 68 separate genotypes, among which 57 genotypes were observed once and the remaining 11 cases were identified for multiple times. The Simpson's diversity index for the panel of combined six markers yielded a diversity index of 0.9951. The heterogeneity was observed among the Iranian and the Netherlands clinical C. parapsilosis isolates. Conclusion: As the findings indicated, the clinical C. parapsilosis isolates from Iran showed a high genetic diversity. It can be concluded that molecular epidemiology could be useful for screening during outbreak investigation where C. parapsilosis is involved. PMID- 29707675 TI - Identification of Candida species isolated from vulvovaginitis using matrix assisted laser desorption ionization-time of flight mass spectrometry. AB - Background and Purpose: Vulvovaginal candidiasis (VVC) is a common problem in women. The purpose of this study was to identify Candida isolates by matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) from women with vulvovaginitis that were referred to Ghaem Hospital, Mashhad, Iran. Materials and Methods: This study was conducted on 65 clinical samples isolated from women that were referred to Ghaem Hospital. All specimens were identified using phenotyping techniques, such as microscopy and culture on Sabouraud dextrose agar and corn meal agar. In addition, all isolates were processed for MALDI-TOF MS identification. Results: Out of the 65 analyzed isolates, 61 (94%) samples were recognized by MALDI-TOF MS. However, the remaining four isolates (6%) had no reliable identification. According to the results, C. albicans (58.5%) was the most frequently isolated species, followed by C. tropicalis (16.9%), C. glabrata (7.7%), C. parapsilosis (7.7%), and guilliermondii (3.1%). Conclusion: As the findings indicated, MALDI TOF MS was successful in the identification of clinical Candida species. C. albicans was identified as the most common Candida species isolated from the women with VVC. Moreover, C. tropicalis was the most common species among the non-albicans Candida species. PMID- 29707676 TI - Mycological aspects of onychomycosis in Khuzestan Province, Iran: A shift from dermatophytes towards yeasts. AB - Background and Purpose: Onychomycosis is fungal infection of the nails with an overall increasing incidence, worldwide. The epidemiological aspects of onychomycosis in Khuzestan, Iran, have not been established. In this study, we aimed to evaluate the clinical and mycological status of fungal nail infection in Khuzestan Province, Iran. Materials and Methods: The study population included 433 patients (143 males vs. 290 females). Nail samples underwent primary direct microscopy and culture. The isolated yeasts and dermatophytes were then subjected to additional molecular identification by r-DNA ITS-RFLP. Identification of some non-dermatophytic molds (NDMs) and unknown yeasts was accomplished by ITS and beta-tubulin sequencing. Results: Onychomycosis was confirmed in 154 patients (males: 36.4%; n=56 vs. females: 63.6%; n=98), whose age ranged from 2 to 85 years, with the highest prevalence in the age group of 41-50 years. Infection mostly occurred due to yeasts (57.15%), with Candida albicans as the most frequent (29.35%) species, followed by C. parapsilosis (13.8%) and C. tropicalis (4.5%). Dermatophytes were isolated in 38.35% of the cases; the most common isolates were found to be Trichophyton interdigitale (21.1%), Epidermophyton floccosum (10.5%), T. rubrum (5.25%), and Microsporum canis (1.5%). NDMs were isolated from 4.5% of the cases with Aspergillus spp. as the most common agent. Dermatophytes and NDMs were more frequently seen in toenails, whereas yeasts mostly infected fingernails. Fingernail onychomycosis was significantly more prevalent among females than in males (P<0.05). Conclusion: The study highlights that in Khuzestan province, the causative agents of onychomycosis have shifted from dermatophytes to yeasts. PMID- 29707677 TI - Patulin contamination in apple products marketed in Shiraz, Southern Iran. AB - Background and Purpose: Patulin is one of the important mycotoxins, produced by a wide range of molds, including Penicillium, Aspergillus, and Bysochlamys. Patulin is mainly found in the rotten parts of fruits and vegetables, such as apples, pears, peach, apricots, and grapes. Currently, the Codex Alimentarius and Food and Drug Administration have recommended a maximum level of 50 ug/L patulin for apple products. The purpose of this study was to investigate patulin contamination of apple juice and cans in 75 samples collected from 15 manufacturers in Shiraz, southern Iran. Materials and Methods: The detection of patulin was accomplished using a high-performance liquid chromatography with an ultraviolet detector. Results: A total of 38 apple juice samples (53%) and 17 apple cans (45%) were contaminated with patulin. Overall 50% and 3% of the apple juice and apple cans samples had a patulin level of > 3 ug/L. Conclusion: Although the maximum level of patulin in our samples was considerably lower than the permitted level established by the European Union (i.e., 50 ug/L), the high incidence of this mycotoxin in our samples should be lessen by improving their good manufacturing practice. PMID- 29707678 TI - Cardiomyocyte Lineage Specification in Adult Human Cardiac Precursor Cells Via Modulation of Enhancer-Associated Long Noncoding RNA Expression. AB - The mechanisms controlling differentiation in adult cardiac precursor cells (CPCs) are still largely unknown. In this study, CPCs isolated from the human heart were found to produce predominantly smooth muscle cells but could be redirected to the cardiomyocyte fate by transient activation followed by inhibition of NOTCH signaling. NOTCH inhibition repressed MIR-143/145 expression, and blocked smooth muscle differentiation. Expression of the microRNAs is under control of CARMEN, a long noncoding RNA associated with an enhancer located in the MIR-143/145 locus and target of NOTCH signaling. The CARMEN/MIR-145/143 axis represents, therefore, a promising target to favor production of cardiomyocytes in cell replacement therapies. PMID- 29707679 TI - The Annual Reproductive Cycle of Silurus microdorsalis, a Korean Endemic Species. AB - The annual reproductive cycle of the Korean endemic slender catfish, Silurus microdorsalis, was examined histologically regarding water temperature and day length of habitat, gonadosomatic index (GSI), and development characteristics of female and male gonads. The maximum GSI value was found in May, 1.23+/-0.33 and 11.77+/-3.23 for male and female respectively (habitat water temperature 21.5 degrees C/13.59hr day length). On the other hand, the minimal level was 0.63+/ 0.10 in July (26.5 degrees C/14.17) for male and 1.36+/-0.08 in October (20 degrees C/11.2hr) for female. We compared and calculated the stages of testis and ovary development process in order to determine the germ cell development characteristics and the reproductive cycle. According to results, we classified the annual reproductive cycle of the slender catfish into five stages: Growing phase (December-February), Mature phase (March-April), Ripe and spawning phase / Releasing phase in male (May-June), Degenerative phase (July-August), and Resting phase (September-November). PMID- 29707680 TI - Osteological Development of the Larvae and Juvenile of Bullhead torrent catfish, Liobagrus obesus. AB - This study was conducted to investigate the skeletal development of bullhead torrent catfish, Liobagrus obesus larvae and to utilize them as basic data for the taxonomic study of Liobagrus larvae. Skeletal development was observed by being divided into cranium, visceral skeleton, shoulder girdle bone, pelvic girdle bone and vertebra. On the first day after hatching, the pre-larvae had an average total length of 7.92 mm, and a line-shaped parasphenoid ossified in the cranium. In the jaw bone, the dentary supporting the lower jaw and the maxillary supporting the upper jaw were ossified. In the anterior abdominal vertebrae of the vertebra, seven centrums began to ossify and five neural spines ossified simultaneously. On the 3 day after hatching, pre-larvae had an average total length of 8.95 mm, and the prefrontal ossified in cranium. The number of abdominal vertebrae was increased to 14, and three parapophysis developed from the front side. On the 24th day after hatching, post-larvae had an average total length of 15.2 mm and the epural bone ossified in coccyx. The parhypural bone was ossified, and ossification of coccyx and pelvic girdle bone was completed. On the 30th day after hatching, the average total length of the juvenile was 17.8 mm, and the ossification of cranium and visceral skeleton was all completed while the preorbital and three suborbitals were ossified in the orbital region of the cranium. PMID- 29707681 TI - Hershberger Assays for Di-2-ethylhexyl Phthalate and Its Substitute Candidates. AB - In the present study, we employed Hershberger assay to determine possible androgenic or antiandrogenic activities of three di-2-ethylhexyl phthalate (DEHP) substitute candidates. The assay was carried out using immature castrated Sprague Dawley male rats. After 7 days of the surgery, testosterone propionate (TP, 0.4 mg/kg/day) and test materials (low dose, 40 mg/kg/day; high dose, 400 mg/kg/day) were administered for 10 consecutive days by subcutaneous (s.c.) injection and oral gavage, respectively. Test materials were DEHP, 2-ethylhexyl oleate (IOO), 2 ethylhexyl stearate (IOS) and triethyl 2-acetylcitrate (ATEC). The rats were necropsied, and then the weights of five androgen-dependent tissues [ventral prostate, seminal vesicle, coagulating glands, levator ani-bulbocavernosus (LABC) muscle, paired Cowper's glands, and glans penis] and four androgen-insensitive tissues (kidney, adrenal glands, spleen and liver) were measured. All test materials including DEHP did not exhibit any androgenic activity in the assay. On the contrary, antiandrogen-like activities were found in all test groups, and the order of the intensity was ATEC < DEHP < ISO < IOO in the five androgen-sensitive tissues. There was no statistical difference between low dose treatment and high dose treatment of all replacement candidate groups. In DEHP groups, high dose treatment exhibited significant weight gains in LABC and Glan Penis. There was no statistical difference in androgen-insensitive tissue measurements. Since the effects of ATEC treatment on the accessory sex organs were much less or not present at all when compared to those of DEHP, ATEC could be a strong candidate to replace DEHP. IOO treatment brought most severe weight reduction in all of androgen-sensitive tissues, so this material should be excluded for further screening of DEHP substitute selection. PMID- 29707682 TI - Expressional Patterns of Connexin Isoforms in the Rat Epididymal Fat during Postnatal Development. AB - In the multicellular tissue, cell-cell interaction is important for a precise control of its function. The exchange of signaling molecules between adjacent cells via connexon allows the functional harmony of cells in the tissue. The present research was to determine the presence and expressional patterns of connexin (Cx) isoforms in the rat epididymal fat during postnatal development using quantitative real-time polymerase chain reaction (PCR) analysis. Of 13 Cx isoforms examined, expression of 11 Cx isoforms in the epididymal fat during postnatal development was detected. These Cx isoforms include Cx26, Cx31, Cx31.1, Cx32, Cx33, Cx36, Cx37, Cx40, Cx43, Cx45, and Cx50. Expressional levels of all Cx isoforms at 1 and 2 years of age were significantly higher than those at the early postnatal ages, such as 7 days, 14 days, and 24 days of ages. Except Cx33 and Cx43, the transcript levels of rest Cx isoforms at 1 year of age were significantly lower than that at 2 years of age. In addition, expressional patterns of Cx isoforms between 7 days and 5 months of ages generally varied according to the isoform. The existence of various Cx isoforms in the rat epididymal fat has been identified and expression of each Cx isoform in the epididymal fat during postnatal development has shown a particular pattern, distinguishable from the others. To our knowledges, this is the first report showing expressional patterns of Cx isoforms at transcript level in the epididymal fat at various postnatal ages. PMID- 29707683 TI - Early Life History of Rhodeus Fish (R. uyekii and R. ocellatus) in the Nakdong River Water System. AB - The purpose of this study is to investigate the early life history of the Rhodeus fish, Rhodeus uyekii and R. ocellatus, in the Nakdong River to use as the preliminary data for the systematic study. The embryos used in the study were fertilized eggs (embryo) and larvae after artificial fertilization. The long diameter of the eggs of the R. uyekii was 3.39-3.97 mm (average 3.68+/-0.41 mm, n=30) and the short diameter was 1.36-1.55 mm (average 1.45+/-0.13 mm, n=30). The long diameter of the eggs of the R. ocellatus was 2.53-2.71 mm (average 2.62+/ 0.12 mm, n=30) and the short diameter was 1.47-1.60 mm (average 1.53+/-0.09 mm, n=30). Hatching time was 48 hours for the R. uyekii and 50 hours for the R. ocellatus given that the average water temperature was 21.5 degrees C. The hatched larvae were 4.95-5.00 mm (average 4.98+/-0.04 mm, n=5) for the R. uyekii and the total length was 3.66-3.69 mm (average 3.67+/-0.02 mm, n=5) for the R. ocellatus. R. uyekii was found to be 15.5-15.8 mm at total length (average 15.6+/ 0.21 mm, n=5) on the 56 days after hatching with the number of dorsal fins being iii-9, anal fins iii-10, ventral fins iii-5. The R. ocellatus was found to be 15.8-16.0 mm (average 15.9+/-0.14 mm, n=5) at total length on the 58 days with the number of dorsal fins being iii-11, anal fins iii-12 and ventral fins iii-5 where the number of all fin stalks reached maximum. PMID- 29707684 TI - Signal Transduction of Eel Luteinizing Hormone Receptor (eelLHR) and Follicle Stimulating Hormone Receptor (eelFSHR) by Recombinant Equine Chorionic Gonadotropin (rec-eCG) and Native eCG. AB - Previous studies showed that recombinant equine chorionic gonadotropin (rec eCGbeta/alpha) exhibits both follicle-stimulating hormone (FSH) and luteinizing hormone (LH)-like activities in rat LHR- and FSHR-expressing cells. In this study, we analyzed signal transduction by eelFSHR and eelLHR upon stimulation with rec-eCGbeta/alpha and native eCG. The cyclic adenosine monophosphate (cAMP) stimulation in CHO-K1 cells expressing eelLHR was determined upon exposure to different doses (0-1,450 ng/mL) of rec-eCGbeta/alpha and native eCG. The EC50 values of rec-eCGbeta/alpha and native eCG were 172.4 and 786.6 ng/mL, respectively. The activity of rec-eCGbeta/alpha was higher than that of native eCG. However, signal transduction in the CHO PathHunter Parental cells expressing eelFSHR was not enhanced by stimulation with both agonist rec-eCGbeta/alpha and native eCG. We concluded that rec-eCGbeta/alpha and native eCG were completely active in cells expressing eelLHR, similar to the activity in the mammalian cells expressing LHRs. However, rec-eCGbeta/alpha and native eCG did not invoke any signaling response in the cells expressing eelFSHR. These results suggest that eCG has a potent activity in cells expressing eelLHR. Thus, we also suggest that rec-eCGbeta/alpha can induce eel maturation by administering gonadotropic reagents (LH), such as salmon pituitary extract. PMID- 29707685 TI - Differential Expression of Cyclic AMP-Response Element Binding Protein Zhangfei (CREBZF) in the Mouse Testis during Postnatal Development. AB - Cyclic AMP-response element binding protein zhangfei (CREBZF), a member of ATF/CREB (activating transcription factor/ cAMP response element binding protein) family, regulates numerous cellular functions and development of cells by interacting transcription factors. This study discovered the expression pattern of CREBZF in seminiferous tubule of testes during the postnatal development of mice. In testis, CREBZF mRNA expression was the highest among other organs. Immunofluorescence analyses showed that the CREBZF was specifically expressed on spermatocyte but not in spermatogonia and Sertoli cells in seminiferous epithelium of mouse testis. Semi-quantitative polymerase chain reaction (PCR) analysis showed that CREBZF transcript level was significantly elevated during postnatal development of mouse testis. Confocal imaging analysis indicated that the protein expression of CREBZF in seminiferous tubule remained low until postnatal day (PD) 14, and was dramatically increased in PD 21. Interestingly, only one type of the spermatocyte expressed CREBZF specifically among SCP3 positive spermatocytes. Taken together, these results suggest that CREBZF may be novel putative marker of the spermatocyte and regulate meiosis during postnatal development of mice. PMID- 29707686 TI - Analysis of Endoplasmic Reticulum (ER) Stress Induced during Somatic Cell Nuclear Transfer (SCNT) Process in Porcine SCNT Embryos. AB - This study investigates the endoplasmic reticulum (ER) stress and subsequent apoptosis in duced during somatic cell nuclear transfer (SCNT) process of porcine SCNT embryos. Porcine SCNT and in vitro fertilization (IVF) embryos were sampled at 3 h and 20 h after SCNT or IVF and at the blastocyst stage for mRNA extraction. The x-box binding protein 1 (Xbp1) mRNA and the expressions of ER stress-associated genes were confirmed by RT-PCR or RT-qPCR. Apoptotic gene expression was analyzed by RT-PCR. Before commencing SCNT, somatic cells treated with tunicamycin (TM), an ER stress inducer, confirmed the splicing of Xbp1 mRNA and increased expressions of ER stress-associated genes. In all the embryonic stages, the SCNT embryos, when compared with the IVF embryos, showed slightly increased expression of spliced Xbp1 (Xbp1s) mRNA and significantly increased expression of ER stress-associated genes (p<0.05). In all stages, apoptotic gene expression was slightly higher in the SCNT embryos, but not significantly different from that of the IVF embryos except for the Bax/Bcl2L1 ratio in the 1 cell stage (p<0.05). The result of this study indicates that excessive ER stress can be induced by the SCNT process, which induce apoptosis of SCNT embryos. PMID- 29707687 TI - Nonmonotonic Effects of Chronic Low-Dose Di(2-ethylhexyl) Phthalate on Gonadal Weight and Reproductive. AB - Endocrine disruptors have been concerned in toxicology but now challenged as physiological point especially concerned with exposing dose and period. In this study the low-dose chronic administration of di(2-ethylhexyl) phthaltae (DEHP) during reproductive period was examined to evaluate the possible roles. Adult male and female CD-1 mice were exposed to DEHP with drinking water containing 133 1g/L and 1,330 /g/L DEHP in water according to OECD 433 guide line and sacrificed just after weaning. The weights of uterus and ovary were decreased by drinking of 1,330 /g/L DEHP water. There was not adverse effects on either accumulated mating rate and mating rate depend on estrus stage, pregnancy duration, and sex ration at birth. However, the accumulated rate of successful delivery and litter size were significantly high at 1,330 dg/L DEHP water. The number of epididymal sperm was significantly increased by drinking of 1,330 g/L DEHP water. In addition, the number of follicles (primary, secondary, tertiary) were more many than control at 1,330 /g/L DEHP water drunk mother. Though further studies are needed to identify what are the mechanism of DEHP in folliculogenesis and spermatogenesis. From this study we firstly report the effect of low-dose chronic administration of DEHP with drinking could change the ovarian follicle population size and spermatogenesis rate. Put together, those finding is different from previous high dose effects and suggest the physiological role of DEHP in gonads and uterus. PMID- 29707688 TI - Regulation of Cyclic AMP-Response Element Binding Protein Zhangfei (CREBZF) Expression by Estrogen in Mouse Uterus. AB - CREBZF (cAMP-response element binding protein zhangfei) is a member of ATF/CREB family, and which regulates various cellular functions by suppressing major factors with direct interaction. In this study, we have examined the expression of CREBZF on mouse endometrium during uterus estrous cycles and estrogen (E2) treatment. In uterus, CREBZF mRNA expression was higher than other organs and mRNA and protein of CREBZF was increased in proestrus phase and decreased in estrus phase. The expression of CREBZF in 3-weeks old mouse uterus was reduced by E2 injection in endometrium. In addition, the expression of progesterone receptor, a marker of E2 in ovariectomized mice was found to be strongly expressed in stroma, while CREBZF was only expressed in epithelium. Also, we conformed that E2-suppressed CREBZF was restored by co-injection of ICI 182,780, an estrogen receptor antagonist. Overall, these results suggest that CREBZF is regulated by estrogen and involved in ER signaling pathway in mouse uterus. PMID- 29707689 TI - New Ambulatory Hysteroscopic Septoplasty using Ballooning in a Woman with Complete Septate Uterus: A Case Report. AB - A 40-year-old G1 P0 L0 A1 woman was referred to our clinic with 6-year history of infertility. Before visiting the clinic, she had 3 cycles of In-Vitro Fertilization (IVF) procedures (2 cycles of Controlled Ovarian Stimulation-IVF and 1 cycle of frozen-thawed Embryo Transfer (ET)) at other clinic. She had medical history of abortion at early gestation following FET (frozen-thawed-ET). The patient had complete type of septate uterus, double cervix and longitudinal vaginal septum. Vaginal septotomy was done first and 1 month later, hysteroscopic septoplasty was followed using ballooning filled with dye. After septoplasty, we inserted ballooning and left for several days to compress septal endometrium on the septectomy area. All procedures were done in the ambulatory operating room without laparoscopy or admission. 3 months later, she had in vitro fertilization embryo transfer (IVF-ET) and FET procedures in our clinic. She had successful pregnancy and now is at 22 weeks of gestation. New ambulatory septoplasty using dye-filled ballooning is easy, safe and minimally invasive surgery for treatment of complete septate uterus. PMID- 29707690 TI - Temperature Dependent of Mitotic Interval for Grass Puffer, Takifugu niphobles. AB - The objective of this study was to determine the mitotic intervals (tau0) of two consecutive cell divisions and synchronous embryonic cleavage in grass puffer, Takifugu niphobles at different water temperatures (18, 20, 22, and 24C). The color of the fertilized egg was light yellowish. The egg type was demersal and unadhesive. Egg weight was 0.09+/-0.002 mg. The sizes of unfertilized eggs were smaller than fertilized eggs in major axis and minor axis at 20C (p<0.05). The size of the fertilized egg of 18C water temperature group at the blastodisc stage was the smallest (p<0.05), but no significant differences were observed in the other water temperatures group except 18C water temperature group (p>0.05). The first cleavage stages at 18, 20, 22, and 24C were at 75, 90, 105, and 120 mins, respectively. As water temperature was increased, embryonic development and formation time of the first cleavage furrow were accelerated. There were negative correlation between tau0 and water temperature for grass puffer (Y=-1.225X+70.05, R2=0.988, n=10, where Y was tau0 and X was temperature). This study confirmed that successful hatching of grass puffer was related to water temperature. Chromosome manipulation will be helpful for this species using cleavage frequency and tau0. PMID- 29707691 TI - A rare case of Clostridium septicum aortitis with colon adenocarcinoma. AB - Clostridium septicum aortitis is a rare, highly morbid condition typically accompanied by malignant disease, such as hematologic cancer or colon adenocarcinoma. Presenting symptoms commonly described include acute onset of abdominal pain, nausea, and fevers. Prompt diagnosis of infectious aortitis is critical to prevent deadly complications, such as sepsis and vascular catastrophe. The described management largely involves surgical resection of the infected aorta, debridement, and arterial revascularization through extra anatomic bypass or aortic graft placement. PMID- 29707692 TI - Successful surgical resection of giant arteriovenous malformation in supraclavicular fossa. AB - A 42-year-old woman with a large congenital giant arteriovenous malformation in the left supraclavicular fossa underwent surgical resection. Although endovascular treatment was initially planned, it was impossible to occlude the multiple feeding arteries (transverse cervical, clavicular branch of left internal mammary, thoracoacromial, anterior/posterior circumflex humeral), and the anatomy was difficult. After removal of the left clavicle, the arteriovenous malformation was exposed. Care was taken to not injure the brachial plexus, and each feeding artery was ligated, followed by division of the drainage veins. The postoperative course was uneventful, and no sign of recurrence has been seen. PMID- 29707693 TI - CatSper: A Unique Calcium Channel of the Sperm Flagellum. AB - To overcome egg protective vestments and ensure successful fertilization, mammalian spermatozoa switch symmetrical progressive motility to a powerful, whip like flagellar motion, known as hyperactivation. The latter is triggered by a calcium influx through the sperm-specific, voltage-dependent, and alkalization activated calcium channel of sperm - CatSper. The channel comprises nine subunits which together form a heteromeric complex. CatSper-deficient male mice and men with mutations in CatSper genes are infertile. This calcium channel is regulated by various endogenous compounds, such as steroids, prostaglandins, endocannabinoids, and intracellular pH. Being a sperm-specific ion channel that is not expressed anywhere else in the body, CatSper represents an ideal target for the development of female and even male contraceptives. In this review, we discuss the recent advances in studying CatSper functional properties and discuss future steps that are required to take in order to achieve a deep understanding of the molecular basis of CatSper function. PMID- 29707694 TI - Analysis of immune-related genes during Nora virus infection of Drosophila melanogaster using next generation sequencing. AB - Drosophila melanogaster depends upon the innate immune system to regulate and combat viral infection. This is a complex, yet widely conserved process that involves a number of immune pathways and gene interactions. In addition, expression of genes involved in immunity are differentially regulated as the organism ages. This is particularly true for viruses that demonstrate chronic infection, as is seen with Nora virus. Nora virus is a persistent non-pathogenic virus that replicates in a horizontal manner in D. melanogaster. The genes involved in the regulation of the immune response to Nora virus infection are largely unknown. In addition, the temporal response of immune response genes as a result of infection has not been examined. In this study, D. melanogaster either infected with Nora virus or left uninfected were aged for 2, 10, 20 and 30 days. The RNA from these samples was analyzed by next generation sequencing (NGS) and the resulting immune-related genes evaluated by utilizing both the PANTHER and DAVID databases, as well as comparison to lists of immune related genes and FlyBase. The data demonstrate that Nora virus infected D. melanogaster exhibit an increase in immune related gene expression over time. In addition, at day 30, the data demonstrate that a persistent immune response may occur leading to an upregulation of specific immune response genes. These results demonstrate the utility of NGS in determining the potential immune system genes involved in Nora virus replication, chronic infection and involvement of antiviral pathways. PMID- 29707695 TI - Serum heat shock protein 70 in preeclampsia and normal pregnancy: A systematic review and meta-analysis. AB - Background: Preeclampsia, a severe complication of human pregnancy is one of the main causes of maternal, fetal, and neonatal morbidity and mortality with unclear pathogenesis. Heat shock protein 70 (HSP70) is one of the factors that can mediate cytoprotective, antiapoptotic, and immune regulatory effects. Objective: This meta-analysis was performed with aim to evaluate HSP70 in preeclampsia and normal pregnancy. Materials and Methods: The original publications reporting the serum HSP70 levels in preeclampsia and normal pregnancies published before November 2015 were identified by searching PubMed Central, Scopus, and ISI Web of Knowledge databases by two researchers, separately. The keywords were" preeclampsia" and "HSP70" or "Heat shock protein 70" Statistical analyses were performed using STATA software (version 11). Results: Out of 127 studies, seven eligible case-control studies were identified which consists of 350 preeclampsia and 429 normal pregnancies. Our pooled analysis of data from 7 studies which met the inclusion criteria, provides evidence that there is a significant association between HSP70 and preeclampsia. Cochran's test results showed the heterogeneity of the studies (p<0.001) and the I2 index was 91%. The standardized mean differences (SMD) based on a random effect model with trim and fill method was 0.92 (95% CI: 0.33-1.51); also there was a significant association between HSP70 and preeclampsia (Z=3.07, p=0.002). Conclusion: The results showed that serum HSP70 concentration was significantly higher in preeclamptic patients than the control group. Therefore HSP70 may be identified as a diagnostic factor. PMID- 29707696 TI - Clonal Bifurcation of Foxp3 Expression Visualized in Thymocytes and T Cells. AB - Regulatory T cells (Tregs) are crucial for suppressing autoimmunity and inflammation mediated by conventional T cells. To be useful, some Tregs should have overlapping specificity with relevant self-reactive or pathogen-specific clones. Whether matching recognition between Tregs and non-Tregs might arise through stochastic or deterministic mechanisms has not been addressed. We tested the hypothesis that some Tregs that arise in the thymus or that are induced during Ag-driven expansion of conventional CD4+ T cells might be clonally related to non-Tregs by virtue of asymmetric Foxp3 induction during cell division. We isolated mouse CD4+ thymocytes dividing in vivo, wherein sibling cells exhibited discordant expression of Foxp3 and CD25. Under in vitro conditions that stimulate induced Tregs from conventional mouse CD4+ T cells, we found a requirement for cell cycle progression to achieve Foxp3 induction. Moreover, a substantial fraction of sibling cell pairs arising from induced Treg stimulation also contained discordant expression of Foxp3. Division-linked yet asymmetric induction of Treg fate offers potential mechanisms to anticipate peripheral self reactivity during thymic selection as well as produce precise, de novo counterregulation during CD4+ T cell-mediated immune responses. PMID- 29707697 TI - Joint Segmentation of Multiple Thoracic Organs in CT Images with Two Collaborative Deep Architectures. AB - Computed Tomography (CT) is the standard imaging technique for radiotherapy planning. The delineation of Organs at Risk (OAR) in thoracic CT images is a necessary step before radiotherapy, for preventing irradiation of healthy organs. However, due to low contrast, multi-organ segmentation is a challenge. In this paper, we focus on developing a novel framework for automatic delineation of OARs. Different from previous works in OAR segmentation where each organ is segmented separately, we propose two collaborative deep architectures to jointly segment all organs, including esophagus, heart, aorta and trachea. Since most of the organ borders are ill-defined, we believe spatial relationships must be taken into account to overcome the lack of contrast. The aim of combining two networks is to learn anatomical constraints with the first network, which will be used in the second network, when each OAR is segmented in turn. Specifically, we use the first deep architecture, a deep SharpMask architecture, for providing an effective combination of low-level representations with deep high-level features, and then take into account the spatial relationships between organs by the use of Conditional Random Fields (CRF). Next, the second deep architecture is employed to refine the segmentation of each organ by using the maps obtained on the first deep architecture to learn anatomical constraints for guiding and refining the segmentations. Experimental results show superior performance on 30 CT scans, comparing with other state-of-the-art methods. PMID- 29707698 TI - Analyzing the Usage of Standards in Radiation Therapy Clinical Studies. AB - Standards for scoring adverse effects after radiation therapy (RT) is crucial for integrated, consistent, and accurate analysis of toxicity results at large scale and across multiple studies. This project aims to investigate the usage of the three most commonly used standards in published RT clinical studies by developing a text-mining based analysis method. We develop and compare two text-mining methods, one based on regular expressions and one based on Naive Bayes Classifier, to analyze published full articles in terms of their adoption of standards in RT. The full dataset includes published articles identified in MEDLINE between January 2010 and August 2015. A radiation oncology physician reviewed all the articles in the training/validation subset and produced the usage trending data manually as gold standard for validation. The regular expression based method reported classifications and overall usage trends that are comparable to those of the domain expert. The CTCAE standard is becoming the overall most commonly used standards over time, but the pace of adoption seems very slow. Further examination of the results indicates that the usage vary by disease type. It suggests that further efforts are needed to improve and harmonize the standards for adverse effects scoring in RT research community. PMID- 29707699 TI - Health System Factors Influencing Partner Notification for STIs and HIV in Lilongwe Malawi. A Pre-intervention Phase Assessment for a Quality Improvement Project. AB - Introduction: Despite its wide use, passive partner notification (PN) has a low yield of sexual partners influenced by patient-related and health system (HS) factors. Methods: We conducted a qualitative study and clinic observations during a pre-intervention phase of a quality improvement (QI) project to identify HS factors that influenced passive PN at Bwaila STI unit (BSU) in Lilongwe Malawi from January to February 2016. We conducted 15 in-depth interviews with health workers and clinic observations for six clinic flow and PN processes at the clinic. Results: The majority of health workers felt that the lack of incentives for sexual partners or couples who presented to the clinic was the most important negative HS factor that influenced passive PN. We observed an average clinic start time of 09:02 hours. The average duration of the group health talk was 56 minutes and there was no difference in the time spent at the clinic between index cases and partners (1 hour 41 minutes versus 1 hour 36 minutes respectively). Discussion: Lack of incentives for sexual partners or couples was the most important HS factors that impacted the yield of sexual partners. Interventions focusing on designing simple non-monetary incentives and QI of passive PN should be encouraged. PMID- 29707700 TI - Multiple Sclerosis Lesion Segmentation Using Joint Label Fusion. AB - This paper adapts the joint label fusion (JLF) multi-atlas image segmentation algorithm to the problem of multiple sclerosis (MS) lesion segmentation in multi modal MRI. Conventionally, JLF requires a set of atlas images to be co-registered to the target image using deformable registration. However, given the variable spatial distribution of lesions in the brain, whole-brain deformable registration is unlikely to line up lesions between atlases and the target image. As a solution, we propose to first pre-segment the target image using an intensity regression based technique, yielding a set of "candidate" lesions. Each "candidate" lesion is then matched to a set of similar lesions in the atlas based on location and size; and deformable registration and JLF are applied at the level of the "candidate" lesion. The approach is evaluated on a dataset of 74 subjects with MS and shown to improve Dice similarity coefficient with reference manual segmentation by 12% over intensity regression technique. PMID- 29707701 TI - Semi-Supervised Approach to Monitoring Clinical Depressive Symptoms in Social Media. AB - With the rise of social media, millions of people are routinely expressing their moods, feelings, and daily struggles with mental health issues on social media platforms like Twitter. Unlike traditional observational cohort studies conducted through questionnaires and self-reported surveys, we explore the reliable detection of clinical depression from tweets obtained unobtrusively. Based on the analysis of tweets crawled from users with self-reported depressive symptoms in their Twitter profiles, we demonstrate the potential for detecting clinical depression symptoms which emulate the PHQ-9 questionnaire clinicians use today. Our study uses a semi-supervised statistical model to evaluate how the duration of these symptoms and their expression on Twitter (in terms of word usage patterns and topical preferences) align with the medical findings reported via the PHQ-9. Our proactive and automatic screening tool is able to identify clinical depressive symptoms with an accuracy of 68% and precision of 72%. PMID- 29707702 TI - Joker de Bruijn: Sequence Libraries to Cover All k-mers Using Joker Characters. PMID- 29707703 TI - Positive-unlabeled convolutional neural networks for particle picking in cryo electron micrographs. PMID- 29707704 TI - Integration of single-molecule detection with magnetic separation for multiplexed detection of DNA glycosylases. AB - We combine single-molecule detection with magnetic separation for simultaneous measurement of human 8-oxoG DNA glycosylase 1 (hOGG1) and uracil DNA glycosylase (UDG) based on excision repair-initiated endonuclease IV (Endo IV)-assisted signal amplification. This method can sensitively detect multiple DNA glycosylases, and it can be further applied for the simultaneous measurement of enzyme kinetic parameters and screening of both hOGG1 and UDG inhibitors. PMID- 29707705 TI - Copper(i)-catalysed regio- and diastereoselective intramolecular alkylboration of terminal allenes via allylcopper(i) isomerization. AB - We report the first copper(i)-catalysed intramolecular alkylboration of terminal allenes with an alkyl halide moiety. The reaction provides alkenylboronates bearing a four-membered ring structure with high regio- and diastereocontrol. A possible reaction mechanism is proposed, involving the facile isomerization of an allylcopper(i) intermediate. A DFT study explains the experimental regio- and diastereoselectivity. PMID- 29707706 TI - Solid state electrochemiluminescence from homogeneous and patterned monolayers of bifunctional spirobifluorene. AB - Electrochemiluminescence (ECL) generated by a monolayer of a spirobifluorene derivative covalently bound onto an indium tin oxide (ITO) substrate is reported for the first time. Our approach allows the efficient preparation homogeneous and patterned substrates through micromolding in capillaries (MIMIC), and opens novel scenarios for multicolour ECL applications. PMID- 29707707 TI - Ultra-thin wrinkled NiOOH-NiCr2O4 nanosheets on Ni foam: an advanced catalytic electrode for oxygen evolution reaction. AB - Here, we report the in situ electrochemical conversion of NiCr2O4 on Ni foam prepared using a hydrothermal strategy to give ultra-thin wrinkled NiOOH-NiCr2O4 amorphous-crystalline nanosheets on Ni foam (NiOOH-NiCr2O4/NF) via anode oxidation in 1.0 M KOH. Owing to the coordination of NiCr2O4 and NiOOH, NiOOH NiCr2O4/NF shows superior catalytic activity toward the oxygen evolution reaction (OER) with the demand of overpotential as low as 271 mV to drive a geometrical current density of 20 mA cm-2 under alkaline conditions. Notably, it also displays strong long-term electrochemical durability for at least 30 h. PMID- 29707708 TI - A DFT study on Zr-SBA-15 catalyzed conversion of ethanol to 1,3-butadiene. AB - Density functional theory (DFT) calculations have been used to elucidate the influence of the surface properties of Zr-SBA-15 on the conversion of ethanol to 1,3-butadiene at the molecular level. To identify the critical reactive intermediates of ethanol catalysis to catalytically form 1,3-butadiene on the Zr SBA-15 surface, the model of Zr-SBA-15 was first built. The overall enthalpy energy surface was explored for the highly-debated reaction mechanisms, including Toussaint's aldol condensation mechanism and Fripiat's Prins mechanism. It was found that ethanol dehydration to form ethylene possessed a lower energy barrier than dehydrogenation to yield acetaldehyde, which means they are competing reactive pathways. C-C bond coupling to form acetaldol (3-hydroxybutanal) proceeds with a 2.15 eV forward reaction barrier. Direct reaction of ethylene and acetaldehyde proceeds with a free energy barrier of 2.90 eV suggesting that Prins condensation hardly occurs. The results here provide a first glimpse into the overall mechanism of 1,3-butadiene formation on Zr-SBA-15 reactive sites in light of the variety of proposed mechanistic pathways mostly based on conventional homogenous organic chemistry reactions. PMID- 29707709 TI - Dependence of hot electron transfer on surface coverage and adsorbate species at semiconductor-molecule interfaces. AB - Developing a molecular-level understanding of how a hot electron transfer process can be enhanced at semiconductor-molecule interfaces is central to advancing various future technologies. Using first-principles quantum dynamics simulations, we investigate how surface coverage and molecular adsorbate species influence the hot electron transfer at semiconductor-molecule interfaces. Counterintuitively, hot electron transfer from the semiconductor to molecules was found to be lessened with increased surface coverage because the inter-molecular interaction changes nonadiabatic couplings across the semiconductor and adsorbed molecules. The adsorbate molecular species itself was found to be an important factor in hot electron transfer not simply because of the energy level alignments at the interface, but also because the transfer is quite sensitive to nonadiabatic couplings. Our work shows that relatively minor variations of the couplings could lead to significant changes in hot electron transfer characteristics at semiconductor-molecule interfaces. Controlling nonadiabatic couplings must be part of developing a molecular-level "design principle" for enhancing hot electron transfer in addition to the well-recognized importance of energy level alignments. PMID- 29707710 TI - Coumarin-diene photoswitches for rapid and efficient isomerization with visible light. AB - We have developed 7-diethylaminocoumarin-based chromophores that photoisomerize with visible light. These photoswitches possess many desirable attributes, including large extinction coefficients (18 600-59 100 M-1 cm-1), high quantum yields (0.45-0.50) and resistance to photofatigue. Additionally, time-resolved spectroscopy indicates that both isomerization reactions are complete in less than 1 ns. PMID- 29707711 TI - Tightly bound polyelectrolytes enhance enzyme proteolysis and destroy amyloid aggregates. AB - The use of polyelectrolytes is a prospective approach to form nanocomplexes to transport different compounds including proteins. In many cases, the bound protein should be digested after delivery to the target. In the present work, we studied proteolysis of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the complexes with polyelectrolytes. We have found polyanions to enhance the proteolytic degradation of GAPDH by proteinase K and thermolysin. This effect seems to be caused by destabilization of the protein structure. However, this destabilization is reversible since the release of the enzyme from the complexes with polymers (even tightly bound with the protein such as sulfated polymers and supercharged pyridinium polycations) was accompanied by partial or complete reactivation of GAPDH, depending on the polymers and conditions. Finally, we observed that complexation with sulfated polymers enhances the proteolytic degradation of prion fibrils by proteinase K. The obtained results can be useful for treatment of pathologies associated with amyloid aggregation. PMID- 29707713 TI - A rationally designed self-standing V2O5 electrode for high voltage non-aqueous all-solid-state symmetric (2.0 V) and asymmetric (2.8 V) supercapacitors. AB - The maximum capacitive potential window of certain pseudocapacitive materials cannot be accessed in aqueous electrolytes owing to the low dissociation potential of 1.2 V possessed by water molecules. However, the inferior pseudocapacitance exhibited by the commonly used electrode materials when integrated with non-aqueous electrolytes still remains a challenge in the development of supercapacitors (SC). Proper selection of materials for the electrode and a rational design process are indeed important to overcome these practical intricacies so that such systems can perform well with non-aqueous electrolytes. We address this challenge by fabricating a prototype all-solid state device designed with high-capacitive V2O5 as the electrode material along with a Li-ion conducting organic electrolyte. V2O5 is synthesized on a pre treated carbon-fibre paper by adopting an electrochemical deposition technique that effects an improved contact resistance. A judicious electrode preparation strategy makes it possible to overcome the constraints of the low ionic and electrical conductivities imposed by the electrolyte and electrode material, respectively. The device, assembled in a symmetrical fashion, achieves a high specific capacitance of 406 F g-1 (at 1 A g-1). The profitable aspect of using an organic electrolyte is also demonstrated with an asymmetric configuration by using activated carbon as the positive and V2O5 as the negative electrode materials, respectively. The asymmetric device displays a wide working-voltage window of 2.8 V and delivers a high energy density of 102.68 W h kg-1 at a power density of 1.49 kW kg-1. Moreover, the low equivalent series resistance of 9.9 Omega and negligible charge transfer resistance are observed in the impedance spectra, which is a key factor that accounts for such an exemplary performance. PMID- 29707712 TI - Coexisting order and disorder within a common 40-residue amyloid-beta fibril structure in Alzheimer's disease brain tissue. AB - Fibrils formed by 40- and 42-residue amyloid-beta (Abeta40 and Abeta42) peptides exhibit molecular-level structural polymorphisms. A recent screen of fibrils derived from brain tissue of Alzheimer's disease patients revealed a single predominant Abeta40 polymorph. We present solid state nuclear magnetic resonance (ssNMR) data that define its coexisting structurally ordered and disordered segments. PMID- 29707714 TI - Two-step chiral transfer from d-penicillamine to metallosupramolecular ionic crystals. AB - Treatment of a racemic RhIII4ZnII4 complex, (Delta)4/(Lambda)4 [Zn4O{Rh(aet)3}4]6+ (aet = 2-aminoethanethiolate), with d-penicillaminate (d-pen) gave optically pure ionic crystals composed of (Lambda)4-[Zn4O{Rh(aet)3}4]6+ and LambdaD-[Rh(d-pen)3]3-via intramolecular and intermolecular chiral transfers from d-pen. PMID- 29707715 TI - Effects of bovine lactoferrin on l-DOPA absorption and metabolism in mice. AB - Bioactive natural products, habitually ingested with milk or its derivative nutrients, have been studied for their bioavailability. In this study, we investigated the effects of the co-administration of bovine milk-derived lactoferrin (bLF) and bioactive products, with a focus on catechol-O methyltransferase (COMT), an enzyme in the catechol metabolism. bLF showed inhibitory activity on COMT in vitro, and acidic pretreatment of bLF enhanced its inhibitory activity. Moreover, partially digested products of bLF by pepsin retained inhibitory activity. Based on these results, bLF was co-administered with levodopa (l-DOPA), which is a catechol compound and a precursor of dopamine, and the effect of bLF on l-DOPA absorption and metabolism was investigated in a mouse model. The co-administration of l-DOPA and bLF alone showed no effect on the concentration of l-DOPA in plasma. However, with the additional administration of carbidopa, the concentration of l-DOPA was significantly enhanced. Furthermore, the ratio of l-DOPA/3-O-methyldopa significantly increased. On the other hand, casein, which is a major milk protein, was not effective. In addition, COMT activity in the intestines was lowered with bLF administration. We concluded that the co-administration of bLF and carbidopa enhances the concentration of l-DOPA. PMID- 29707716 TI - Structure and dynamics of water at water-graphene and water-hexagonal boron nitride sheet interfaces revealed by ab initio sum-frequency generation spectroscopy. AB - We simulate sum-frequency generation (SFG) spectra of isotopically diluted water at the water-graphene and water-hexagonal boron-nitride (hBN) sheet interfaces, using ab initio molecular dynamics simulations. A sharp 'dangling' O-D peak around ~2640 cm-1 appearing in both simulated SFG spectra evidences that both graphene and hBN are hydrophobic. The dangling O-D peak is 10 cm-1 red-shifted at the water-hBN interface relative to the peak at the water-graphene interface. This frequency difference gives a stronger O-DN intermolecular interaction between water and hBN than the O-DC interaction between water and graphene. Accordingly, the anisotropy decay of such a dangling O-D group slows down near hBN compared with near graphene, illustrating that the dynamics of the dangling O D group are also affected by the stronger O-DN interaction than the O-DC interaction. We discuss molecular-level insights into the structure and dynamics of interfacial water in the context of the friction of hBN and graphene. PMID- 29707717 TI - Vibrations of the p-chlorofluorobenzene cation. AB - The vibrations of the ground state cation (X[combining tilde]2B1) of para chlorofluorobenzene (pClFB) have been investigated using zero-electron-kinetic energy (ZEKE) spectroscopy. ZEKE spectra were recorded using different vibrational levels of the S1 state as intermediate levels, for which assignments were put forward in an earlier paper [W. D. Tuttle, A. M. Gardner, and T. G. Wright, Chem. Phys. Lett., 2017, 684, 339]. These different intermediate levels dramatically modify the Franck-Condon factors for the ionization step. The adiabatic ionization energy (AIE) for pClFB was measured as 72 919 +/- 5 cm-1, and analysis of the vibrational structure in the ZEKE spectra allowed further interrogation of the assignments of the REMPI spectrum. Assignment of the vibrational structure has been achieved by comparison with corresponding spectra of related molecules, via quantum chemical calculations, and via shifts in bands between the spectra of the 35Cl and 37Cl isotopologues. In this way it was possible to assign twenty out of the thirty vibrational modes of the ground state pClFB+ cation. Additionally, evidence for Fermi resonances between some vibrational levels was found in the S1 state, but no large-scale intramolecular vibrational redistribution (IVR) was seen in the spectra here. Finally, we discuss trends in AIE shifts for benzenes with one or two halogen atoms or methyl substituents. PMID- 29707718 TI - A Cu2Se-Cu2O film electrodeposited on titanium foil as a highly active and stable electrocatalyst for the oxygen evolution reaction. AB - Many nonprecious metal-selenide-based materials have been reported as electrocatalysts with high activity for the oxygen evolution reaction (OER). Herein, a hybrid catalyst film composed of Cu2Se and Cu2O nanoparticles directly grown on Ti foil (Cu2Se-Cu2O/TF) was prepared through a simple and fast cathodic electrodeposition method. Surprisingly, this electrode required a relatively low overpotential of 465 mV to achieve a catalytic current density of 10 mA cm-2 for the OER in 0.2 M carbonate buffer (pH = 11.0). Furthermore, a long-term constant current electrolysis test confirmed the high durability of the Cu2Se-Cu2O/TF anode at a current density of 10 mA cm-2 over 20 h. The XRD, TEM and XPS analysis of the sample after the OER indicated that a CuO protective layer formed on the surface of the Cu2Se-Cu2O catalyst, which effectively suppressed further oxidation of the Cu2Se-Cu2O catalyst during the OER and resulted in sustained catalytic oxidation of water. PMID- 29707719 TI - COSMO-RI-ADC(2) excitation energies and excited state gradients. AB - We present an implementation of analytic gradients for electronically excited states for the algebraic-diagrammatic construction through second order, ADC(2), in combination with the conductor-like screening model (COSMO) as an implicit solvent model. The implementation uses a post-SCF reaction field scheme for the coupling between the environment and the quantum system which retains the computational efficiency of the gas-phase RI-ADC(2) calculations. Applying this approach, we computed solvatochromic shifts for UV absorption and fluorescence transitions of 4-(N,N-dimethylamino)benzonitrile using equilibrium geometries for the ground and the first excited states optimized in the presence of acetonitrile as solvent. Furthermore, we investigated the excited state energies and geometries of the 2-iodobenzimidazolium.triflate ion pair in aqueous solution as an example where solvent effects have a large influence on the structure and the UV spectrum. PMID- 29707720 TI - Origins of halogen effects in bioorthogonal sydnone cycloadditions. AB - Halogen substituents increase sydnone cycloaddition reactivities substantially. Fluoro-sydnones are superior to bromo- and chloro-sydnones, and can achieve extremely high second-order rate constants with strained alkynes. Computational studies have revealed the fluorine substituent increases the reactivity of sydnone mainly by lowering its distortion energy. PMID- 29707721 TI - The influence of the sample dispersion on a solid surface in the thermal spin transition of [Fe(pz)Pt(CN)4] nanoparticles. AB - The thermal spin transition of [Fe(pz)Pt(CN)4], pz = pyrazine, nanoparticles is compared with the one of the microcrystalline powder by magnetic susceptibility measurements, absorption spectroscopy and X-ray powder diffraction (XRPD) using synchrotron radiation. The thermal transition shows less cooperativity when decreasing the size due to the reduction of cluster formation. Surprisingly, the dispersion of the nanoparticles on a surface entails important effects on the spin crossover properties of the system. These effects are simulated and explained within the framework of the mechanoelastic model. PMID- 29707722 TI - Hydrogenation of silyl formates: sustainable production of silanol and methanol from hydrosilane and carbon dioxide. AB - A new process for simultaneously obtaining two chemical building blocks, methanol and silanol, was realized starting from silyl formates which can be derived from silane and carbon dioxide. Understanding the reaction mechanism enabled us to improve the reaction efficiency by the addition of a small amount of methanol. PMID- 29707723 TI - Carbohydrate binding through first- and second-sphere coordination within aromatic oligoamide metallofoldamers. AB - Aromatic oligoamide capsules that fold upon metal binding recognize carbohydrate guests in solution as evidenced by CD and NMR titrations. Crystallographic data reveal that, besides their structural role, metal ions also contribute to guest recognition through either first- or second-sphere coordination. PMID- 29707724 TI - Correction: A novel nanomissile targeting two biomarkers and accurately bombing CTCs with doxorubicin. AB - Correction for 'A novel nanomissile targeting two biomarkers and accurately bombing CTCs with doxorubicin' by Yu Gao et al., Nanoscale, 2017, 9, 5624-5640. PMID- 29707725 TI - Automated characterization and assembly of individual nanowires for device fabrication. AB - The automated sorting and positioning of nanowires and nanotubes is essential to enabling the scalable manufacturing of nanodevices for a variety of applications. However, two fundamental challenges still remain: (i) automated placement of individual nanostructures in precise locations, and (ii) the characterization and sorting of highly variable nanomaterials to construct well-controlled nanodevices. Here, we propose and demonstrate an integrated, electric-field based method for the simultaneous automated characterization, manipulation, and assembly of nanowires (ACMAN) with selectable electrical conductivities into nanodevices. We combine contactless and solution-based electro-orientation spectroscopy and electrophoresis-based motion-control, planning and manipulation strategies to simultaneously characterize and manipulate multiple individual nanowires. These nanowires can be selected according to their electrical characteristics and precisely positioned at different locations in a low conductivity liquid to form functional nanodevices with desired electrical properties. We validate the ACMAN design by assembling field-effect transistors (FETs) with silicon nanowires of selected electrical conductivities. The design scheme provides a key enabling technology for the scalable, automated sorting and assembly of nanowires and nanotubes to build functional nanodevices. PMID- 29707726 TI - CaMoO4 nanosheet arrays for efficient and durable water oxidation electrocatalysis under alkaline conditions. AB - It is highly desirable to design and develop earth-abundant electrocatalysts for efficient and durable oxygen evolution reaction (OER) under alkaline conditions. In this communication, we demonstrate the development of CaMoO4 nanosheet arrays on nickel foam (CaMoO4/NF) as a durable high-performance non-noble-metal electrocatalyst for the OER. CaMoO4/NF shows high catalytic activity and needs an overpotential of only 345 mV to attain a geometrical catalytic current density of 50 mA cm-2 in 1.0 M KOH. Notably, it also shows high long-term electrochemical durability for at least 25 h. PMID- 29707727 TI - Foam flow in a model porous medium: II. The effect of trapped gas. AB - Gas trapping is an important mechanism in both Water or Surfactant Alternating Gas (WAG/SAG) and foam injection processes in porous media. Foams for enhanced oil recovery (EOR) can increase sweep efficiency as they decrease the gas relative permeability, and this is mainly due to gas trapping. However, gas trapping mechanisms are poorly understood. Some studies have been performed during corefloods, but little work has been carried out to describe the bubble trapping behaviour at the pore scale. We have carried out foam flow tests in a micromodel etched with an irregular hexagonal pattern. Image analysis of the foam flow allowed the bubble centres to be tracked and local velocities to be obtained. It was found that the flow in the micromodel is dominated by intermittency and localized zones of trapped gas. The quantity of trapped gas was measured both by considering the fraction of bubbles that were trapped (via velocity thresholding) and by measuring the area fraction containing immobile gas (via image analysis). A decrease in the quantity of trapped gas was observed for both increasing total velocity and increasing foam quality. Calculations of the gas relative permeability were made with the Brooks Corey equation, using the measured trapped gas saturations. The results showed a decrease in gas relative permeabilities, and gas mobility, for increasing fractions of trapped gas. It is suggested that the shear thinning behaviour of foam could be coupled to the saturation of trapped gas. PMID- 29707728 TI - Photoactivation of imatinib-antibody conjugate using low-energy visible light from Ru(ii)-polypyridyl cages. AB - Ru(ii)-polypyridyl cages with sterically bulky bidentate ligands provide efficient photochemical release of the anticancer drug imatinib using low energy visible light, imparting spatiotemporal control over drug bioavailability. The light-activated drug release is maintained when the Ru(ii) cage is covalently coupled to an antibody, which is expected to localize selectively on the tumor. PMID- 29707729 TI - A new strategy to synthesize anisotropic SmCo5 nanomagnets. AB - We report a simple strategy to synthesize anisotropic SmCo5 nanoplates. The strategy involves the pre-synthesis of 125 * 12 nm Sm(OH)3 nanorods and 10 nm Co nanoparticles followed by the self-assembly of these nanorods and nanoparticles into Sm(OH)3-Co nanocomposites. Once embedded in a CaO matrix, the nanocomposite is subjected to high temperature (850 degrees C) annealing in the presence of Ca, leading to the formation of 125 * 10 nm SmCo5 nanoplates, which are dispersible in ethanol, allowing the alignment in epoxy resin under a 20 kOe magnetic field. The aligned SmCo5 nanoplates show a square hysteresis behavior with room temperature coercivity reaching 30.1 kOe, which is among the highest values ever reported for SmCo5 made from chemical methods. This work provides a new approach to high-performance anisotropic SmCo5 for permanent magnetic applications. PMID- 29707730 TI - A robust multifunctional ligand-controlled palladium-catalyzed carbonylation reaction in water. AB - A novel, hydrophilic and recyclable methoxypolyethylene glycol (PEG)-modulated s triazine-based multifunctional Schiff base/N,P-ligand L9 was prepared and used in Pd-catalyzed Heck-type carbonylative coupling reactions, affording diverse chalcone derivatives and 1,4-dicarbonyl esters in good yields. PMID- 29707731 TI - Why Does a Universal Anti-Bullying Program Not Help All Children? Explaining Persistent Victimization During an Intervention. AB - Although anti-bullying interventions are often effective, some children continue to be victimized. To increase knowledge of potential factors that might impede children's benefiting from an anti-bullying intervention, we examined potential reasons for individual differences in victimization trajectories during a group based anti-bullying intervention. Data stem from a five-wave survey among 9122 children (7-12 years old; grades 2-5) who participated in the KiVa anti-bullying intervention (n = 6142) or were in control schools (n = 2980 children). Three trajectories were found in the intervention sample, representing children who experienced stable high, decreasing, or stable low/no victimization. A two trajectory model of high and low trajectories represented the control sample best. Multinomial regressions on the intervention sample showed that children who experienced particularly high levels of peer rejection, internalizing problems, and lower quality parent-child relationships decreased less in victimization; thus these characteristics appeared to contribute to persistent victimization. The results call for tailored strategies in interventions aiming to reduce victimization for more children. PMID- 29707732 TI - A PDMS Device Coupled with Culture Dish for In Vitro Cell Migration Assay. AB - Cell migration and invasion are important factors during tumor progression and metastasis. Wound-healing assay and the Boyden chamber assay are efficient tools to investigate tumor development because both of them could be applied to measure cell migration rate. Therefore, a simple and integrated polydimethylsiloxane (PDMS) device was developed for cell migration assay, which could perform quantitative evaluation of cell migration behaviors, especially for the wound healing assay. The integrated device was composed of three units, which included cell culture dish, PDMS chamber, and wound generation mold. The PDMS chamber was integrated with cell culture chamber and could perform six experiments under different conditions of stimuli simultaneously. To verify the function of this device, it was utilized to explore the tumor cell migration behaviors under different concentrations of fetal bovine serum (FBS) and transforming growth factor (TGF-beta) at different time points. This device has the unique capability to create the "wound" area in parallel during cell migration assay and provides a simple and efficient platform for investigating cell migration assay in biomedical application. PMID- 29707733 TI - Statistical Optimization of 1,3-Propanediol (1,3-PD) Production from Crude Glycerol by Considering Four Objectives: 1,3-PD Concentration, Yield, Selectivity, and Productivity. AB - This study investigated the biological conversion of crude glycerol generated from a commercial biodiesel production plant as a by-product to 1,3-propanediol (1,3-PD). Statistical analysis was employed to derive a statistical model for the individual and interactive effects of glycerol, (NH4)2SO4, trace elements, pH, and cultivation time on the four objectives: 1,3-PD concentration, yield, selectivity, and productivity. Optimum conditions for each objective with its maximum value were predicted by statistical optimization, and experiments under the optimum conditions verified the predictions. In addition, by systematic analysis of the values of four objectives, optimum conditions for 1,3-PD concentration (49.8 g/L initial glycerol, 4.0 g/L of (NH4)2SO4, 2.0 mL/L of trace element, pH 7.5, and 11.2 h of cultivation time) were determined to be the global optimum culture conditions for 1,3-PD production. Under these conditions, we could achieve high 1,3-PD yield (47.4%), 1,3-PD selectivity (88.8%), and 1,3-PD productivity (2.1/g/L/h) as well as high 1,3-PD concentration (23.6 g/L). PMID- 29707734 TI - Genomic and biological characterization of Newcastle disease viruses isolated from migratory mallards (Anas platyrhynchos). AB - Given the global evolutionary dynamics of Newcastle disease viruses (NDVs), it is imperative to continue extensive surveillance, routine monitoring and characterization of isolates originating from natural reservoirs (waterfowls). In this report, we isolated and characterized two virulent NDV strains from clinically healthy mallard (Anas platyrhynchos). Both isolates had a genome of 15,192 nucleotides encoding six genes in an order of 3'-NP-P-M-F-HN-L-5'. The biological characteristics (mean death time: 49.5-50 hr, EID50108.5 ml-1) and presence of a typical cleavage site in the fusion (F) protein (112R-R-Q-K-R?F117) confirmed the velogenic nature of these isolates. Phylogenetic analysis classified both isolates as members of genotype VII within class-II. Furthermore, based upon the hypervariable region of the F gene (375 nt), isolates showed clustering within sub-genotype VIIi. Similarity index and parallel comparison revealed a higher nucleotide divergence from commonly used vaccine strains; LaSota (21%) and Mukteswar (17%). A comparative residues analysis with representative strains of different genotypes, including vaccine strains, revealed a number of substitutions at important structural and functional domains within the F and hemagglutinin-neuraminidase (HN) proteins. Together, the results highlight consistent evolution among circulating NDVs supporting extensive surveillance of the virus in waterfowl to better elucidate epidemiology, evolutionary relationships and their impacts on commercial and backyard poultry. PMID- 29707735 TI - Clinical analysis of 90 cases of malignant lacrimal sac tumor. AB - PURPOSE: To investigate the pathology, clinical manifestations, and potential risk factors associated with the prognosis of malignant lacrimal sac tumors. In addition, the treatment outcomes and complications were also evaluated. METHODS: Ninety cases of malignant lacrimal sac tumors were retrospectively analyzed at our hospital. Pathological classifications, clinical manifestations, risk factors, and follow-up time were documented. The outcomes and complications were evaluated and compared among the various treatment modalities. RESULTS: The median follow-up time was 50 months (range, 3-258 months). The 5-year overall survival (OS) and progression-free survival (PFS) for all cases were 85.7 and 77.9%, respectively. The 5-year OS and PFS for 69 cases of squamous cell carcinoma were 87.6 and 76.3%, and which were 80.4 and 72.4% for 21 cases of non squamous cell carcinoma, respectively. There was no difference of 5-year OS and PFS between squamous cell carcinoma and non-squamous cell carcinoma (p = 0.350 and p = 0.946). Positive lymph node status was associated with worse OS (p < 0.001) and PFS (p = 0.020). For the 23.3% of cases (21/90) treated with the definitive radiotherapy, the outcomes were equivalent to that of surgery combined with radiotherapy, with the incidence of treatment-related visual acuity complication not being significant. The addition of chemotherapy to the treatment course had a marginal and non-significant improvement in OS and distant metastasis-free survival. CONCLUSIONS: Lymph node status was found to be a key factor for prognosis. Advanced tumors could benefit from multimodality treatment, with radiotherapy playing an important role. However, the role of chemotherapy requires further investigation. PMID- 29707736 TI - Cost-effectiveness of antimicrobial prophylaxis for children in the RIVUR trial. AB - PURPOSE: We evaluated the cost-effectiveness of antimicrobial prophylaxis to prevent recurrent UTIs in children with vesicoureteral reflux based on the RIVUR trial. MATERIALS AND METHODS: A decision tree model compared strategies of antimicrobial prophylaxis vs. placebo in children with reflux using results from the RIVUR trial. Risk reduction was 50% based on intention to treat analysis. Costs were based on Medicare reimbursement and data in literature. The model incorporated costs of medications, imaging and complications such as pyelonephritis, likelihood of surgery and loss of work. One- and two-way sensitivity analyses were performed evaluating the effect of changing variables on the cost-effectiveness of antibiotic prophylaxis in preventing recurrent UTIs. RESULTS: Mean costs were higher for treatment vs. placebo at $3092 and $2932, respectively, with 12.7 fewer infections per 100 children. One-way sensitivity analyses showed that antibiotics would be cost equivalent if the yearly medical cost was $386, rate of recurrent UTI increased to 32%, antibiotic risk reduction was 63%, or rate of pyelonephritis in the placebo group was 48%. Two-way analyses modifying antibiotic cost, risk reduction of antibiotics and probability of infection showed areas where antibiotics could be more cost-effective than placebo. CONCLUSIONS: Antibiotic prophylaxis is associated with marginally higher costs compared with placebo, but significantly fewer infections. A slight decrease in antibiotic cost or increase in recurrent UTIs on placebo may result in prophylaxis being more cost-effective. We recognize that the marginal overall cost in antibiotics may have a substantial impact on the quality of life for the individual patient and family. PMID- 29707737 TI - Cardiovascular Risk in Breast Cancer Patients Receiving Estrogen or Progesterone Antagonists. AB - PURPOSE OF REVIEW: The purpose of this review is to summarize the current literature on estrogen and progesterone antagonists and their effects on the cardiovascular system. RECENT FINDINGS: Estrogen and progesterone antagonists reduce cancer-related recurrence and mortality in women with ER-positive breast cancer. Recent studies, however, suggest that women with early stage breast cancer are more likely to die of cardiovascular disease than recurrent breast cancer. Estrogen antagonists have been shown to reduce endothelial function, to increase lipid profiles and to alter body composition accelerating atherosclerotic changes. While clinical trial data demonstrates mixed results of the impact of estrogen antagonists on cardiovascular risk, there is a growing body of evidence that estrogen suppression and estrogen antagonists result in biologic effects on the endothelium, altering lipid profiles and accelerating the risk of atherosclerosis. Further longitudinal work however is needed. PMID- 29707739 TI - SPR 2018. PMID- 29707738 TI - Central nervous system localisation of chronic lymphocytic leukaemia, description of two very distinct cases and a review of the literature. AB - Central nervous system (CNS) localisation of chronic lymphocytic leukaemia (CLL) can induce various neurological symptoms. Unfamiliarity with this manifestation causes diagnostic delay. We present two cases of leptomeningeal CLL. These cases and our literature review emphasise that CNS localisation of CLL should be considered in patients with any neurological symptom, irrespectively of the stage and systemic activity of CLL. PMID- 29707740 TI - Biotechnology applied to fish reproduction: tools for conservation. AB - This review discusses the new biotechnological tools that are arising and promising for conservation and enhancement of fish production, mainly regarding the endangered and the most economically important species. Two main techniques, in particular, are available to avoid extinction of endangered fish species and to improve the production of commercial species. Germ cell transplantation technology includes a number of approaches that have been studied, such as the transplantation of embryo-to-embryo blastomere, embryo-to-embryo differentiated PGC, larvae to larvae and embryo differentiated PGC, transplantation of spermatogonia from adult to larvae or between adults, and oogonia transplantation. However, the success of germ cell transplantation relies on the prior sterilization of fish, which can be performed at different stages of fish species development by means of several protocols that have been tested in order to achieve the best approach to produce a sterile fish. Among them, fish hybridization and triploidization, germline gene knockdown, hyperthermia, and chemical treatment deserve attention based on important results achieved thus far. This review currently used technologies and knowledge about surrogate technology and fish sterilization, discussing the stronger and the weaker points of each approach. PMID- 29707741 TI - Myocardial Energetics and Heart Failure: a Review of Recent Therapeutic Trials. AB - PURPOSE OF REVIEW: Several novel therapeutics being tested in patients with heart failure are based on myocardial energetics. This review will provide a summary of the recent trials in this area, including therapeutic options targeting various aspects of cellular and mitochondrial metabolism. RECENT FINDINGS: Agents that improve the energetic balance in myocardial cells have the potential to improve clinical heart failure status. The most promising therapies currently under investigation in this arena include (1) elamipretide, a cardiolipin stabilizer; (2) repletion of iron deficiency with intravenous ferrous carboxymaltose; (3) coenzyme Q10; and (4) the partial adenosine receptor antagonists capadenoson and neladenosone. Myocardial energetics-based therapeutics are groundbreaking in that they utilize novel mechanisms of action to improve heart failure symptoms, without causing the adverse neurohormonal side effects associated with current guideline-based therapies. The drugs appear likely to be added to the heart failure therapy armamentarium as adjuncts to current regimens in the near future. PMID- 29707742 TI - DNA sequences confirm low specificity to definitive host and wide distribution of the cat pathogen Platynosomum illiciens (= P. fastosum) (Trematoda: Dicrocoeliidae). AB - Although feline platynosomosis has been commonly reported in several parts of the world, the taxonomy and epidemiological chain related to cat liver flukes remain controversial. In this study, nuclear ribosomal ITS, 28S, and mitochondrial cox1 sequences obtained for Platynosomum illiciens from cat, marmoset, lizard, and snail found naturally infected in Brazil reveal no significant molecular differences between these isolates. Moreover, sequence data confirm that Brazilian P. illiciens from different hosts is conspecific with parasites obtained from cats in Vietnam, supporting wide distribution of the species. The lack of pronounced specificity of P. illiciens to definitive hosts is confirmed here for the first time using molecular approach. The results are discussed in context of the epizootology of platynosomosis. PMID- 29707743 TI - Cost-Effectiveness of Second-Line Endocrine Therapies in Postmenopausal Women with Hormone Receptor-positive and Human Epidermal Growth Factor Receptor 2 negative Metastatic Breast Cancer in Japan. AB - BACKGROUND: Exemestane (EXE), exemestane + everolimus (EXE + EVE), toremifene (TOR), and fulvestrant (FUL) are second-line endocrine therapies for postmenopausal hormone receptor-positive (HR +)/human epidermal growth factor receptor 2-negative (HER2 -) metastatic breast cancer (mBC) in Japan. Although the efficacy of these therapies has been shown in recent studies, cost effectiveness has not yet been determined in Japan. OBJECTIVE: This study aimed to examine the cost-effectiveness of second-line endocrine therapies for the treatment of postmenopausal women with HR + and HER2 - mBC. METHODS: A Markov model was developed to analyze the cost-effectiveness of the therapies over a 15 year time horizon from a public healthcare payer's perspective. The efficacy and utility parameters were determined via a systematic search of the literature. Direct medical care costs were used. A discount rate of 2% was applied for costs and outcomes. Subgroup analysis was performed for non-visceral metastasis. A series of sensitivity analyses, including probabilistic sensitivity analysis (PSA) and threshold analysis were performed. RESULTS: Base-case analyses estimated incremental cost-effectiveness ratios (ICERs) of 3 million and 6 million Japanese yen (JPY)/quality-adjusted life year (QALY) gained for TOR and FUL 500 mg relative to EXE, respectively. FUL 250 mg and EXE + EVE were dominated. The overall survival (OS) highly influenced the ICER. With a willingness-to-pay (WTP) threshold of 5 million JPY/QALY, the probability of TOR being cost-effective was the highest. Subgroup analysis in non-visceral metastasis revealed 0.4 and 10% reduction in ICER from the base-case results of FUL5 500 mg versus EXE and TOR versus EXE, respectively, while threshold analysis indicated EVE and FUL prices should be reduced 73 and 30%, respectively. CONCLUSION: As a second-line therapy for postmenopausal women with HR +/HER2 - mBC, TOR may be cost-effective relative to other alternatives and seems to be the most favorable choice, based on a WTP threshold of 5 million JPY/QALY. FUL 250 mg is expected to be as costly and effective as EXE. The cost-effectiveness of EXE + EVE and FUL 500 mg could be improved by a large price reduction. However, the results are highly sensitive to the hazard ratio of OS. Policy makers should carefully interpret and utilize these findings. PMID- 29707744 TI - TRPV4-Mediated Anti-nociceptive Effect of Suberanilohydroxamic Acid on Mechanical Pain. AB - Biological effects of suberanilohydroxamic acid (SAHA) have mainly been observed in the context of tumor suppression via epigenetic mechanisms, but other potential outcomes from its use have also been proposed in different fields such as pain modulation. Here, we tried to understand whether SAHA modulates specific pain modalities by a non-epigenetic unknown mechanism. From 24 h Complete Freund's Adjuvant (CFA)-inflamed hind paws of mice, mechanical and thermal inflammatory pain indices were collected with or without immediate intraplantar injection of SAHA. To examine the action of SAHA on sensory receptor-specific pain, transient receptor potential (TRP) ion channel-mediated pain indices were collected in the same manner of intraplantar treatment. Activities of primarily cultured sensory neurons and heterologous cells transfected with TRP channels were monitored to determine the molecular mechanism underlying the pain modulating effect of SAHA. As a result, immediate and localized pretreatment with SAHA, avoiding an epigenetic intervention, acutely attenuated mechanical inflammatory pain and receptor-specific pain evoked by injection of a TRP channel agonist in animal models. We show that a component of the mechanisms involves TRPV4 inhibition based on in vitro intracellular Ca2+ imaging and electrophysiological assessments with heterologous expression systems and cultured sensory neurons. Taken together, the present study provides evidence of a novel off-target action and its mechanism of SAHA in its modality-specific anti nociceptive effect and suggests the utility of this compound for pharmacological modulation of pain. PMID- 29707745 TI - Antinuclear Antibody-Positive Juvenile Idiopathic Arthritis Despite IRAK-4 Deficiency. PMID- 29707746 TI - Chronic Cadmium Exposure Accelerates the Development of Atherosclerosis and Induces Vascular Dysfunction in the Aorta of ApoE-/- Mice. AB - Cadmium exposure is related to cardiovascular diseases, including hypertension, atherosclerosis, increased oxidative stress, endothelial dysfunction, and specific biochemical changes induced by this metal. Thus, we aimed to investigate whether cadmium exposure induces endothelial dysfunction, accelerates atherosclerotic plaque formation in the aorta, and enhances oxidative stress in apolipoprotein E knockout (ApoE-/-) mice. Experiments were performed in 14-week old male wild-type and ApoE-/- mice. ApoE-/- mice received cadmium (CdCl2 100 mg/L in drinking water for 28 days) or vehicle (distilled water). After treatment, vascular reactivity to phenylephrine, acetylcholine, and sodium nitroprusside was analyzed using isolated aorta. Bone marrow cells were isolated to assess the production of nitric oxide and reactive oxygen and nitrogen species. ApoE-/- cadmium-treated mice had higher cholesterol levels than non exposed mice. Cadmium exposure decreased the vasodilatation response to acetylcholine in aortic ring of ApoE-/- mice, though no changes in phenylephrine or sodium nitroprusside responses were observed. L-NAME reduced vasodilator responses to acetylcholine; this effect was lower in ApoE-/- cadmium-treated mice, suggesting reduction in nitric oxide (NO) bioavailability. Moreover, in bone marrow cells, cadmium decreased cytoplasmic levels of NO and increased superoxide anions, hydrogen peroxide, and peroxynitrite in ApoE-/- mice. Morphological analysis showed that cadmium exposure increased plaque deposition in the aorta by approximately 3-fold. Our results suggest that cadmium exposure induces endothelial dysfunction in ApoE-/- mice. Moreover, cadmium increased total cholesterol levels, which may promote the early development of atherosclerosis in the aorta of ApoE-/- mice. Our findings support the hypothesis that cadmium exposure might increase the risk of atherosclerosis. PMID- 29707747 TI - Comparison of Human Denuded Amniotic Membrane and Porcine Small Intestine Submucosa as Scaffolds for Limbal Mesenchymal Stem Cells. AB - Blinding corneal scarring is usually treated with allogeneic graft tissue. Nevertheless, the global shortage of donors leaves millions of patients in need of therapy. Traditional tissue engineering strategies involves the combination of cells, growth factors, and scaffolds that can supply cellular biological components allowing to restore the tissue function. The mesenchymal stem cells found in the limbal stroma (L-MSCs) have a self-renewal potential for multilineage differentiation. Thus, in this work we compared the potential of human amniotic membrane (hAM) and porcine small intestine submucosa (SIS) as scaffolds for L-MSCs, aiming at potential applications in corneal regeneration. For that, L-MSCs were seeded on hAM and SIS and we analyzed their viability, actin cytoskeleton, nuclei morphology, cell density, adhesion and surface markers. Our results showed that cells adhered and integrated into both membranes with a high cell density, an important characteristic for cell therapy. However, due to its transparency, the hAM allowed a better observation of L-MSCs. In addition, the analysis of surface markers expression on L-MSCs after two weeks showed a slight increase in the percentages of negative markers for MSCs grown on SIS membrane. Thus, considering a long-term culture, the hAM was considered better in maintaining the MSCs phenotype. Regarding the function as scaffolds, SIS was as efficient as the amniotic membrane, considering that these two types of biological matrices maintained the cell viability, actin cytoskeleton, nuclei morphology and mesenchymal phenotype, without causing cell death. Therefore, our data in vitro provides evidence for future pre-clinical studies were these membranes can be used as a support to transport mesenchymal stem cells to the injured area, creating a kind of temporary curative, allowing the release of bioactive molecules, such as cytokines and growth factors and then promoting the tissue regeneration, both in human and veterinary medicine. PMID- 29707748 TI - Factors Influence the Acceptance of Surgical Treatment in Chinese Bariatric Surgery Candidates. AB - BACKGROUND: The prevalence of obesity and obesity-related disorders is rapidly increasing among the Chinese populations. Bariatric surgery is becoming more and more popular in China, yet little cases were performed compared with western countries. The acceptance of this new treatment modality in Chinese bariatric surgery candidates was seldom studied. OBJECTIVE: To investigate the factors affecting the choice of bariatric surgery in Chinese patients with obesity and metabolic disorders, so as to promote the popularization of bariatric surgery in developing countries like China METHODS: Patients with obesity and related metabolic disorders meet the indications for bariatric surgery in the Department of Metabolic and Bariatric Surgery in the First Affiliated Hospital of Jinan University between January 2016 and April 2017 were asked to answer a questionnaire about the demographics of the patients, social economic status, present and past history, family history, etc. The data collected and the relationship of the acceptance of bariatric surgery were analyzed. RESULTS: There were 157 patients (51 males, 32.5%; 106 females, 67.5%) with mean BMI 38.7 +/- 8.1 kg/m2 answered the questionnaire. One hundred twenty-three of them (78%) accepted bariatric surgery. By univariate analysis, it was found that patients' weight, BMI, family support, medical insurance, past surgical history, family history of T2DM, and obesity-related comorbidities and symptoms are correlated with the acceptance of bariatric surgery. By multivariate analysis, it was found that patients' weight (P = 0.024), BMI (P = 0.007), family support (P < 0.001), medical insurance (P < 0.001), past surgical history (P = 0.011), family history of T2DM (P = 0.020), and obesity-related comorbidities and symptoms (P = 0.030) are statistically significant and were positively correlated with the acceptance of bariatric surgery. Age, height, gender, history of smoking and alcohol consumption, family history of obesity, history of hypertension and T2DM, education level, and marital status were not statistically significant (P < 0.05). CONCLUSIONS: Patients with heavier weight, higher BMI, family support, medical insurance reimbursement, past surgical history, family history of T2DM, and obesity-related comorbidities and symptoms are more likely to consider bariatric surgery in Chinese bariatric surgery candidates. It will be important to provide appropriate healthcare education and support to patients focusing on both obesity-related health risks and options of surgical treatment so to improve their acceptance of bariatric surgery. PMID- 29707749 TI - Changes of biotoxicity in food waste fermentation wastewater treated by a membrane bioreactor system. AB - The biotoxicity of industrial effluents has attracted much concern in the wastewater treatment process. This research performed the biological treatment of the wastewater generated from food waste fermentation by anaerobic/anaerobic/anoxic/aerobic-membrane bioreactor (A3-MBR) system aiming at the meet of discharge standards and elimination of ecological risks to aquatic environment. The results showed that the A3-MBR could effectively remove pollutants such as COD, TN, ammonia, and TP in the wastewater. The study of biotoxicity revealed that the acute toxicity was mainly contained in the polar and mid-polar fractions of the wastewater, and the remained acute toxicity was less than 0.6 TU, much lower than the secondary effluent of domestic wastewater treatment plant. The genotoxicity was found abundantly in the polar fractions and less in mid-polar fractions, and a relatively low genotoxicity (0.086 MUg 4 NQO/L) was obtained in the final effluent of the treatment system. The fulvic acid-like compounds and humic acid-like compounds were the main cause of the acute toxicity, while the aromatic proteins and soluble microbial by-products mainly resulted in the genotoxicity in the wastewater. PMID- 29707750 TI - Immunolocalization and changes of 17beta-estradiol during ovarian development of Chinese mitten crab Eriocheir Sinensis. AB - 17beta-estradiol (E2) is important for crustacean ovarian development. This study aims to investigate the distribution and change pattern of E2 in the ovary, hepatopancreas, thoracic ganglion and brain ganglion as well as Vg-mRNA expression level during ovarian development of Chinese mitten crab Eriocheir sinensis. Results showed that strongly positive signals of E2 were mainly distributed in follicle cells of ovaries for all developmental stages as well as oocyte cytoplasm of stages III to V ovaries. In hepatopancreas, the E2-positive signal was mainly detected in the cytoplasm and nucleus of fibrillar cells and the nucleus of resorptive cells, while the maximum fluorescence intensity was observed in stage III hepatopancreas. On the contrary, the E2 immunoreactivities in nervous tissues were relatively stable during ovarian development. Moreover, the changing pattern of E2 concentration was similar within hemolymph, ovary and hepatopancreas during the ovarian development. From stages I to III, the E2 content in three tissues increased significantly, then decreased gradually until stage V. As for the Vg-mRNA expression level in hepatopancreas and ovaries, an increasing trend was found in ovaries but no significant difference was detected during the period of ovarian stages III to V. Hepatopancreatic Vg-mRNA expression level increased significantly during stages I to IV and dramatically decreased at stage V. In conclusion, our study suggests that ovary, hepatopancreas, hemolymph and nervous tissues are the target organs of E2 in E. sinensis and E2 concentrations in different tissues are closely related to vitellogenesis in ovary and hepatopancreas during ovarian development. PMID- 29707751 TI - Carbodiimide-mediated immobilization of acidic biomolecules on reversed-charge zwitterionic sensor chip surfaces. AB - The carbodiimide-mediated amine coupling of protein ligands to sensor chips coated with anionic polycarboxylate hydrogels, such as carboxymethyl dextran, is the predominant covalent immobilization procedure utilized in optical biosensors, namely surface plasmon resonance (SPR) biosensors. Usually, electrostatic interactions at a slightly acidic pH and low ionic strength are employed to efficiently accumulate neutral and basic ligands on the chip surface, which are then covalently coupled by surface-bound active N-hydroxysuccinimide (NHS) esters. Unfortunately, this approach is not suitable for acidic proteins or other ligands with low isoelectric points (IEPs), such as nucleic acids, because the charge density of the polycarboxylates is greatly reduced at acidic pH or because electrostatic attraction cannot be achieved. To overcome these drawbacks, we have established a charge-reversal approach that allows the preconcentration of acidic proteins above their IEPs. A precisely controlled amount of tertiary amines is applied to reverse the previous anionic surface charge while maintaining carbodiimide compatibility with future protein immobilization. The mechanism of this reversed-charge immobilization approach was demonstrated employing protein A as a model protein and using attenuated total reflectance Fourier transform infrared spectroscopy, dynamic contact angle measurements, colorimetric quantification, and SPR analysis to characterize surface derivatization. Furthermore, even though it had previously proven impossible to preconcentrate DNA electrostatically and to covalently couple it to polyanionic chip surfaces, we demonstrated that our approach allowed DNA to be preconcentrated and immobilized in good yields. Graphical abstract Principle of the covalent immobilization of acidic ligands on reversed-charge zwitterionic sensor chip surfaces. PMID- 29707752 TI - Real-time monitoring of endogenous cysteine levels in living cells using a CD based ratiometric fluorescent nanoprobe. AB - A simple and readily available fluorescent probe is needed for the real-time monitoring of endogenous cysteine (Cys) levels in living cells, as such a probe could be used to study the role of Cys in related diseases. Herein, we report the first fluorescent probe based on carbon dots (CDs-FITA) for the selective and ratiometric imaging of endogenous Cys in live cells. In this ratiometric fluorescent probe, a fluorescein derivative (FITA) that recognizes Cys is covalently linked to the surfaces of carbon dots (CDs); employing CDs greatly improves the water solubility of the probe. Acrylate on FITA is selectively cleaved by Cys in aqueous solution under mild conditions, leading to a dramatic increase in the fluorescence from fluorescein. The probe therefore allows the highly selective ratiometric fluorescent detection of Cys even in the presence of various interferents. The as-prepared CDs-FITA showed excellent performance when applied to detect Cys in blood serum. In addition, due to its negligible cytotoxicity, the CDs-FITA can also be utilized for the real-time monitoring of endogenous cysteine (Cys) levels in living cells. Graphical abstract Illustration of the CD-based probe for Cys imaging in living cells. PMID- 29707753 TI - Identification of acetylated derivatives of zearalenone as novel plant metabolites by high-resolution mass spectrometry. AB - Zearalenone (ZEN) major biotransformation pathways described so far are based on glycosylation and sulfation, although acetylation of trichothecenes has been reported as well. We investigated herein the ZEN acetylation metabolism route in micropropagated durum wheat leaf, artificially contaminated with ZEN. We report the first experimental evidence of the formation of novel ZEN acetylated forms in wheat, attached both to the aglycone backbone as well as on the glucose moiety. Thanks to the advantages provided by high-resolution mass spectrometry, identification and structure annotation of 20 metabolites was achieved. In addition, a preliminary assessment of the toxicity of the annotated metabolites was performed in silico focusing on the toxicodynamic of ZEN group toxicity. All the metabolites showed a worse fitting within the estrogen receptor pocket in comparison with ZEN. Nevertheless, possible hydrolysis to the respective parent compounds (i.e., ZEN) may raise concern from the health perspective because these are well-known xenoestrogens. These results further enrich the biotransformation profile of ZEN, providing a helpful reference for assessing the risks to animals and humans. Graphical abstract ?. PMID- 29707754 TI - Selective detection of copper ion in complex real samples based on nitrogen-doped carbon quantum dots. AB - Highly selective nitrogen-doped carbon quantum dots (ND-CQDs) for copper ion (Cu2+) determination were synthesized by a solvent-free pyrolysis of citric acid and histidine. The resultant ND-CQDs display a stable bright blue fluorescence with a satisfactory product yield of 56% and quantum yield of 16%. The ND-CQDs not only show good photostability under continuous UV irradiation, but are also dramatically stable against extreme ionic strengths. The solid powders of the ND CQDs re-dispersed in water still maintain a strong blue fluorescence after storing at room temperature for 6 months. The ND-CQDs can be employed to selectively detect Cu2+ in a wide linear range of 0.6-30 MUM. The detection limit is as low as 0.19 MUM. The ND-CQDs were applied for Cu2+ detection in environmental water samples, fruit juice samples, and urine sample. Satisfactory recoveries of 96-102% with relative standard deviations below 3% were obtained. The research provided a promising prospect for selective detection of Cu2+ in the complex matrix. Graphical abstract Schematic illustration of the preparation of the ND-CQDs and its detection mechanism to Cu2. PMID- 29707755 TI - A simple and reliable new microchip electrophoresis method for fast measurements of imidazole dipeptides in meat from different animal species. AB - Microchip electrophoresis (ME) was applied for the separation of two physiologically important imidazole dipeptides-carnosine and anserine. The capacitively coupled contactless conductivity detector (C4D) was employed for quantification of both dipeptides after separation in a new home-built ME unit. The separation parameters were optimized as follows to enable quantitative, baseline separation of both dipeptides: injection time 16 s, injection voltage 900 V/cm, and separation voltage 377.1 V/cm. The C4D detector responded linearly to both imidazole dipeptides in the range 0-20 mg L-1. The known addition methodology was applied to test the accuracy of the measurement of imidazole dipeptides in a complex sample. The recoveries for measurement of carnosine in the mixture ranged from 96.1 to 105.0%, whereas those for anserine amounted to 96.6 to 102.0%. This method was also applied to real biological samples. The results exhibited a satisfactory agreement with a standard HPLC method. The proposed ME method represents a cheap, fast, and simple alternative to the existing, more complicated and expensive HPLC methods. This method does not demand either the optical detectors nor tedious derivatization of sample, which are unavoidable in HPLC methods. The method was succesfuly applied for animal species determination in unknown meat samples using the carnosine/anserine ratio, and subsequently, it could be used in a food fraud prevention process. Graphical abstract Microchip electrophoresis portable device with a C4D detector for determination of imidazole dipeptides in model samples and real meat samples from different animal species. PMID- 29707756 TI - Comment on "Photobiomodulation delays the onset of skeletal muscle fatigue in a dose-dependent manner". PMID- 29707758 TI - Whipple Disease Presenting as Cystic Brain Tumor: Case Report and Review of the Literature. AB - Although neurological features are commonly encountered in Whipple"s disease (WD), presentation with purely neurological patterns is uncommon. Exclusive confinement to the central nervous system (CNS) is extremely rare. In these cases, the development of an isolated cerebral mass is exceptional. In the present paper, the authors describe a case of a 68-year-old man who presented with partial seizures. The neurological examination was normal. The imaging showed a cystic lesion. This tumor-like lesion was removed by performing frontal craniotomy. A histopathological investigation revealed the presence of numerous perivascular foamy histiocytes infiltrating the brain parenchyma. The majority of these histiocytes showed Periodic acid-schiff (PAS)-positive intense staining, which is distinctive feature of cerebral WD. The diagnosis was confirmed by polymerase chain reaction (PCR) analysis of cerebrospinal fluid. There were no gastrointestinal symptoms and no PAS inclusions in intestinal mucosa. The patient received Ceftriaxone intravenously followed by oral trimethoprime sulfamethoxazole (TMP-SMZ) for 12 months and recovered well. This case illustrates atypical WD, confined exclusively to the central nervous system. PMID- 29707757 TI - Transcutaneous oxygen pressure as a predictor for short-term survival in patients with type 2 diabetes and foot ulcers: a comparison with ankle-brachial index and toe blood pressure. AB - AIMS: Ankle-brachial index (ABI) is the most commonly used test when diagnosing peripheral vascular disease and is considered a marker for cardiovascular risk. Transcutaneous oxygen pressure (TcPO2), a test associated with microvascular function, has in several studies shown better correlation with diabetic foot ulcer (DFU) healing. Whether a low TcPO2 could be a marker for mortality in the high-risk population of DFU patients has not been evaluated before. The aim of this study was to evaluate the predictive value of TcPO2 in comparison with ABI and toe blood pressure (TBP) on 1-year mortality in type 2 diabetes patients with DFU. METHODS: Type 2 diabetes patients aged <= 90 years, with one DFU who attended our multidisciplinary DFU-unit during year 2013-2015 and were screened with TcPO2, ABI and TBP were retrospectively evaluated. One-year mortality was assessed from the national death register in Sweden. RESULTS: A total of 236 patients (30% women) with a median age of 76 (69-82) years were evaluated in this study. Within 1 year, 14.8% of the patients died. TcPO2 < 25 mmHg was associated with a higher 1-year mortality compared with TcPO2 >= 25 mmHg (27.7 vs. 11.6%, p = 0.003). TBP and ABI did not significantly influence 1-year mortality. In a Cox regression analysis adjusted for confounders, TcPO2 was independently predicting 1-year mortality with a hazard ratio for TcPO2 < 25 mmHg of 2.8 (95% CI 1.34 5.91, p = 0.006). CONCLUSIONS: This study indicates that a low TcPO2 is an independent prognostic marker for 1-year mortality among patients with type 2 diabetes and DFU. PMID- 29707759 TI - Impact of duration of induction therapy on survival in newly diagnosed multiple myeloma patients undergoing upfront autologous stem cell transplantation. AB - The optimal duration of induction therapy (IT) in transplant-eligible multiple myeloma (MM) patients in not well defined, resulting in a wide variation in clinical practice. The objective of our study was to determine whether the duration of IT in patients undergoing upfront autologous stem cell transplantation (ASCT) has an impact on progression-free survival (PFS) in the era of proteasome inhibitors and immunomodulatory drugs. A total of 596 patients who underwent ASCT at Mayo Clinic between 2007 and 2014 were included. The patients were divided into two cohorts based on the duration of IT: IT <= 4 and IT > 4 months. At a median follow-up of 54.5 months from ASCT, the median PFS in the IT <= 4 group was 28 months [95% confidence interval (CI), 25-33], compared to 26 months in the IT > 4 group (95% CI, 24-31) [P = 0.605]. There was no significant difference in overall survival (OS) in the two groups (P = 0.904). The lack of impact of IT duration on PFS and OS was consistent in subgroups with high-risk features at diagnosis (International Staging System III or high-risk cytogenetics) and different depths of pre-transplant response [>=very good partial response (VGPR) and A) polymorphism. Among both male and female participants who consumed alcohol less than weekly (n = 69,519; 211 EC cases), low active or inactive ALDH2 was not associated with increased EC risk [HRs (95% CIs): GA vs. GG 0.75 (0.54, 1.04); AA vs. GG 1.01 (0.46, 2.20)]. Among male weekly alcohol consumers, both flushing response [n = 59,380; 501 EC cases; HRs (95% CIs): "soon after drinking" vs. "no" flushing response 1.45 (1.05, 2.01)] and rs671 [n = 10,692; 94 EC cases; GA vs. GG 3.31 (1.94, 5.67)] were associated with EC risk. The increased EC risk associated with "soon" response or rs671 GA was apparent in men consuming alcohol >=30g/d. Among male daily consumers, the HRs (95% CIs) for EC associated with 15g/d of alcohol were 1.28 (1.15, 1.44) for "soon" response [vs. other responses: 1.12 (1.09, 1.15); pinteraction = 0.047; n = 36,401, 425 EC cases] and 1.41 (1.08, 1.82) for rs671 GA [vs. GG: 1.16 (1.06, 1.27); pinteraction = 0.493; n = 6,607, 80 EC cases]. Self-reported flushing response had low sensitivity (56.8%) and high specificity (88.4%) in identifying rs671 A allele among male weekly alcohol consumers. In conclusion, low-activity ALDH2 was associated with increased EC risk among male heavy alcohol consumers. More accurate measurement of alcohol-related EC risk allows better achievement of precision prevention. PMID- 29707773 TI - Wells syndrome: a case of successful treatment with omalizumab. PMID- 29707774 TI - Early-stage Hodgkin lymphoma in the modern era: simulation modelling to delineate long-term patient outcomes. AB - We developed a novel simulation model integrating multiple data sets to project long-term outcomes with contemporary therapy for early-stage Hodgkin lymphoma (ESHL), namely combined modality therapy (CMT) versus chemotherapy alone (CA) via 18 F-fluorodeoxyglucose positron emission tomography response-adaption. The model incorporated 3-year progression-free survival (PFS), probability of cure with/without relapse, frequency of severe late effects (LEs), and 35-year probability of LEs. Furthermore, we generated estimates for quality-adjusted life years (QALYs) and unadjusted survival (life years, LY) and used model projections to compare outcomes for CMTversusCA for two index patients. Patient 1: a 25-year old male with favourable ESHL (stage IA); Patient 2: a 25-year-old female with unfavourable ESHL (stage IIB). Sensitivity analyses assessed the impact of alternative assumptions for LE probabilities. For Patient 1, CMT was superior to CA (CMT incremental gain = 0.11 QALYs, 0.21 LYs). For Patient 2, CA was superior to CMT (CA incremental gain = 0.37 QALYs, 0.92 LYs). For Patient 1, the advantage of CMT changed minimally when the proportion of severe LEs was reduced from 20% to 5% (0.15 QALYs, 0.43 LYs), whereas increasing the severity proportion for Patient 2's LEs from 20% to 80% enhanced the advantage of CA (1.1 QALYs, 6.5 LYs). Collectively, this detailed simulation model quantified the long-term impact that varied host factors and alternative contemporary treatments have in ESHL. PMID- 29707776 TI - Epitope spread in chronic mucosal GVHD: mucous membrane pemphigoid resolution with rituximab. PMID- 29707775 TI - Impact of HPV-vaccination on outcome of cervical cytology screening in Denmark - a register based cohort study. AB - 4vHPV-vaccination has been tested in randomized controlled trials under almost ideal conditions, and studies of real-life use have compared outcome between vaccinated and unvaccinated women from the same birth cohort and mostly before screening age. Here we present the first - to our knowledge - evaluation of the impact of the 4vHPV-vaccination in real-life without selection bias in the reported data. The study has been carried out by comparing the results after first cervical screening between an HPV-vaccinated and an unvaccinated birth cohort, consisting of women born in Denmark in 1993 and 1983, respectively. Cytology data covering an 8-year period, from the age of 15 (age of HPV vaccination) to age 23 (age of invitation to first cervical screening), were retrieved from the Danish National Pathology Register. Abnormal cytology, defined as atypical squamous cell of undetermined significance and worse (ASCUS+) was detected in 9.4% of women born in 1993 as compared with 9.0% of women born in 1983; RR = 1.04 (95% CI 0.96-1.12), p = 0.29. Detection of high grade squamous intraepithelial lesion (HSIL) was statistically significantly lower in the 1993 than in the 1983 cohort, RR = 0.6 (95% CI 0.5-0.7), p <0.0001, while the opposite pattern was seen for ASCUS RR = 1.4 (95% CI 1.2-1.6), p <0.0001. The decrease in HSIL means that more women can be spared referral for colposcopy and biopsy. The increase of ASCUS could be explained by transition from conventional to liquid based cytology, but this observation requires further monitoring. This article is protected by copyright. All rights reserved. PMID- 29707777 TI - Hypertrophic cardiomyopathy in a Clydesdale gelding. AB - CASE REPORT: A 7-year-old Clydesdale gelding was referred with a history of progressive lethargy and ventral oedema. The horse developed diarrhoea after treatment with antibiotics by the referring veterinarian. History, clinical signs, imaging and laboratory findings were consistent with hypertrophic cardiomyopathy complicated by antibiotic-associated colitis. Progression of clinical signs prompted euthanasia and the antemortem diagnosis of hypertrophic cardiomyopathy was confirmed at postmortem examination. CONCLUSION: Primary HCM is reported as rare in horses, but specific descriptions are lacking. The history, clinical, laboratory and postmortem findings in this case supported a diagnosis of HCM, complicated by antibiotic-associated colitis. PMID- 29707778 TI - Electroconvulsive therapy increases brain volume in major depression: a systematic review and meta-analysis. AB - OBJECTIVE: The main purpose of this review was to synthesise evidence on ECT's effects on brain's structure. METHOD: A systematic literature review of longitudinal studies of depressed patients treated with ECT using magnetic resonance imaging (MRI) and meta-analysis of ECT's effect on hippocampal volume. RESULTS: Thirty-two studies with 467 patients and 285 controls were included. The MRI studies did not find any evidence of ECT-related brain damage. All but one of the newer MRI volumetric studies found ECT-induced volume increases in certain brain areas, most consistently in hippocampus. Meta-analysis of effect of ECT on hippocampal volume yielded pooled effect size: g = 0.39 (95% CI = 0.18-0.61) for the right hippocampus and g = 0.31 (95% CI = 0.09-0.53) for the left. The DTI studies point to an ECT-induced increase in the integrity of white matter pathways in the frontal and temporal lobes. The results of correlations between volume increases and treatment efficacy were inconsistent. CONCLUSION: The MRI studies do not support the hypothesis that ECT causes brain damage; on the contrary, the treatment induces volume increases in fronto-limbic areas. Further studies should explore the relationship between these increases and treatment effect and cognitive side effects. PMID- 29707779 TI - Alpha-1 antitrypsin deficiency panniculitis: clinical and pathologic characteristics of 10 cases. AB - BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) may be associated with liver and lung disease and rarely causes panniculitis. OBJECTIVE: We evaluated the clinicopathologic and laboratory findings of AATD panniculitis in 10 patients. METHODS: We conducted a retrospective review of all cases of AATD panniculitis at Mayo Clinic, Rochester, MN, from 1989 to 2016. RESULTS: Ten patients with AATD panniculitis were included. Seven of ten were women. Clinical lesions were most commonly nodular (100%), erythematous (90%), ulcerated (90%), and painful (90%) subcutaneous nodules and plaques. Extracutaneous associations were rare. PiZZ phenotype was most commonly identified (50%). Histopathologically, lobular panniculitis (80%) with associated septal involvement (60%) and a predominant neutrophilic infiltrate (100%) were most common. Treatments varied; dapsone and alpha-1 proteinase inhibitor infusions were each used in five (50%) patients, respectively. In patients with greater than 6-month follow-up (n = 4), one patient continued to have disease activity despite treatment. CONCLUSION: AATD panniculitis should be considered in the differential for a painful, ulcerative panniculitis with a predominantly neutrophilic histopathologic infiltrate. Diagnosis can be made with clinicopathologic correlation and genetic and laboratory evaluations. Serum AAT level and phenotype assists in diagnosing patients with suspected AATD panniculitis. PMID- 29707780 TI - Diagnostic performance of prothrombin time point-of-care to detect acute traumatic coagulopathy on admission: experience of 522 cases in trauma center. AB - BACKGROUND: Early identification of acute traumatic coagulopathy is a key challenge during initial management to determine whether to initiate early hemostatic support. We assessed the performance of prothrombin time (PT) at point of-care in trauma patients to detect moderate and severe coagulopathy on admission. STUDY DESIGN AND METHODS: All admitted consecutive trauma patients were analyzed retrospectively between April 2014 and July 2015. PT was measured on admission with both a PT point-of-care device (PTr-CGK) and a standard coagulation test (PTr-STD). The results for PTr-CGK and PTr-STD were compared using analysis of agreement, precision, and accuracy. The diagnostic performance of PTr-CGK to predict coagulopathy was established by analysis of receiver operating characteristic curves. The predictive performance of different thresholds and risk factors for misclassification were also studied. RESULTS: Over a 16-month period, 522 patients were included. PTr-CGK estimated PTr-STD with a bias of 0.00 (95% confidence interval [CI], -0.48 to 0.50) and a precision of 0.25. The optimal threshold was 1.4 to predict severe coagulopathy (sensitivity 81% [95% CI, 68%-94%], negative predictive value 98% [95% CI, 97% 99%]), and 1.2 for moderate coagulopathy (sensitivity 80% [95% CI, 72%-88%], negative predictive value 94% [95% CI, 91%-96%]). A low PTr-CGK in the presence of severity criteria (Injury Severity Score >= 16, Trauma Associated Severe Hemorrhage score >= 12, hemoglobin level < 7 g/dL, fibrinogen level < 2 g/L, base deficit >= 6 mmol/L) was strongly associated with a false-negative risk. CONCLUSIONS: The PT point-of-care device is reliable and accurate for the early identification of coagulopathic trauma patients. PMID- 29707781 TI - Driving working memory with frequency-tuned noninvasive brain stimulation. AB - Frequency-tuned noninvasive brain stimulation is a recent approach in cognitive neuroscience that involves matching the frequency of transcranially applied electromagnetic fields to that of specific oscillatory components of the underlying neurophysiology. The objective of this method is to modulate ongoing/intrinsic brain oscillations, which correspond to rhythmic fluctuations of neural excitability, to causally change behavior. We review the impact of frequency-tuned noninvasive brain stimulation on the research field of human working memory. We argue that this is a powerful method to probe and understand the mechanisms of memory functions, targeting specifically task-related oscillatory dynamics, neuronal representations, and brain networks. We report the main behavioral and neurophysiological outcomes published to date, in particular, how functionally relevant oscillatory signatures in signal power and interregional connectivity yield causal changes of working memory abilities. We also present recent developments of the technique that aim to modulate cross frequency coupling in polyrhythmic neural activity. Overall, the method has led to significant advances in our understanding of the mechanisms of systems neuroscience, and the role of brain oscillations in cognition and behavior. We also emphasize the translational impact of noninvasive brain stimulation techniques in the development of therapeutic approaches. PMID- 29707782 TI - Functional decoupling of melatonin suppression and circadian phase resetting in humans. AB - KEY POINTS: There is assumed to be a monotonic association between melatonin suppression and circadian phase resetting induced by light exposure. We tested the association between melatonin suppression and phase resetting in humans. Sixteen young healthy participants received nocturnal bright light (~9500 lux) exposure of continuous or intermittent patterns, and different durations ranging from 12 min to 6.5 h. Intermittent exposure patterns showed significant phase shifts with disproportionately less melatonin suppression. Each and every bright light stimulus in an intermittent exposure pattern induced a similar degree of melatonin suppression, but did not appear to cause an equal magnitude of phase shift. These results suggest that phase shifts and melatonin suppression are functionally independent such that one cannot be used as a proxy measure of the other. ABSTRACT: Continuous experimental light exposures show that, in general, the conditions that produce greater melatonin suppression also produce greater phase shift, leading to the assumption that one can be used as a proxy for the other. We tested this association in 16 healthy individuals who participated in a 9-day inpatient protocol by assessing melatonin suppression and phase resetting in response to a nocturnal light exposure (LE) of different patterns: (i) dim light control (<3 lux; n = 6) or (ii) two 12-min intermittent bright light pulses (IBL) separated by 36 min of darkness (~9500 lux; n = 10). We compared these results with historical data from additional LE patterns: (i) dim-light control (<3 lux; n = 11); (ii) single continuous bright light exposure of 12 min (n = 9), 1.0 h (n = 10) or 6.5 h (n = 6); or (iii) an IBL light pattern consisting of six 15-min pulses with 1.0 h dim-light recovery intervals between them during a total of 6.5 h (n = 7). All light exposure groups had significantly greater phase-delay shifts than the dim-light control condition (P < 0.0001). While a monotonic association between melatonin suppression and circadian phase shift was observed, intermittent exposure patterns showed significant phase shifts with disproportionately less melatonin suppression. Each and every IBL stimulus induced a similar degree of melatonin suppression, but did not appear to cause an equal magnitude of phase shift. These results suggest unique specificities in how light-induced phase shifts and melatonin suppression are mediated such that one cannot be used as a proxy measure of the other. PMID- 29707783 TI - High immunogenicity of red blood cell antigens restricted to the population of African descent in a cohort of sickle cell disease patients. AB - BACKGROUND: Sickle cell disease (SCD) patients undergo multiple red blood cell (RBC) transfusions and are regularly exposed to low-prevalence (LP) antigens specific to individuals of African descent. This study evaluated the prevalence of antibodies against LP antigens in SCD patients and the need to identify these antibodies in everyday practice. STUDY DESIGN AND METHODS: Plasma from 211 SCD patients was tested with RBCs expressing the following LP antigens: RH10 (V), RH20 (VS), RH23 (DW ), RH30 (Goa ), KEL6 (Jsa ), and MNS6 (He). RESULTS: Nine LP antibodies were found in eight patients (3.8%): five anti-RH23, two anti-RH30, and two anti-MNS6. The exposure risk, calculated for each LP antigen, was below 3% per RBC unit, for all antigens tested. Thus, in this cohort of transfused SCD patients, the prevalence of LP antibodies was similar to that of antibodies against antigens of the FY, JK, and MNS blood group systems. These findings also reveal the occurrence of anti-RH23 in SCD patients. No anti-RH20 or anti-KEL6 were found, despite the high frequency of mismatch situations. CONCLUSION: These results highlight the immunogenicity of these LP antigens, and the evanescence of antibodies against LP antigens. They also highlight the importance of appropriate pretransfusion testing for patients frequently transfused, who are likely to be exposed to multiple types of blood group antigens. PMID- 29707784 TI - Fragment-based quantum mechanical calculation of protein-protein binding affinities. AB - The electrostatically embedded generalized molecular fractionation with conjugate caps (EE-GMFCC) method has been successfully utilized for efficient linear scaling quantum mechanical (QM) calculation of protein energies. In this work, we applied the EE-GMFCC method for calculation of binding affinity of Endonuclease colicin-immunity protein complex. The binding free energy changes between the wild-type and mutants of the complex calculated by EE-GMFCC are in good agreement with experimental results. The correlation coefficient (R) between the predicted binding energy changes and experimental values is 0.906 at the B3LYP/6-31G*-D level, based on the snapshot whose binding affinity is closest to the average result from the molecular mechanics/Poisson-Boltzmann surface area (MM/PBSA) calculation. The inclusion of the QM effects is important for accurate prediction of protein-protein binding affinities. Moreover, the self-consistent calculation of PB solvation energy is required for accurate calculations of protein-protein binding free energies. This study demonstrates that the EE-GMFCC method is capable of providing reliable prediction of relative binding affinities for protein-protein complexes. (c) 2018 Wiley Periodicals, Inc. PMID- 29707785 TI - Predictive rhythmic tapping to isochronous and tempo changing metronomes in the nonhuman primate. AB - Beat entrainment is the ability to entrain one's movements to a perceived periodic stimulus, such as a metronome or a pulse in music. Humans have a capacity to predictively respond to a periodic pulse and to dynamically adjust their movement timing to match the varying music tempos. Previous studies have shown that monkeys share some of the human capabilities for rhythmic entrainment, such as tapping regularly at the period of isochronous stimuli. However, it is still unknown whether monkeys can predictively entrain to dynamic tempo changes like humans. To address this question, we trained monkeys in three tapping tasks and compared their rhythmic entrainment abilities with those of humans. We found that, when immediate feedback about the timing of each movement is provided, monkeys can predictively entrain to an isochronous beat, generating tapping movements in anticipation of the metronome pulse. This ability also generalized to a novel untrained tempo. Notably, macaques can modify their tapping tempo by predicting the beat changes of accelerating and decelerating visual metronomes in a manner similar to humans. Our findings support the notion that nonhuman primates share with humans the ability of temporal anticipation during tapping to isochronous and smoothly changing sequences of stimuli. PMID- 29707786 TI - Temporal dynamics of maintenance in young and old adults. AB - The present study investigated the time course of refreshing in young and old adults by analyzing the influence of memory load on response times for the processing of concurrent information. One to five squares sequentially displayed in random locations had to be memorized. Before the serial recall of the squares' locations, participants performed self-paced parity judgments on sequentially presented numbers. Trials without squares-not requiring memorization, but only parity judgments-constituted the control condition. Response times of parity judgments were separated for responses to the first digit and for responses to subsequent digits. In young adults, the results provided evidence for consolidation and refreshing, namely, the linear increase of first and subsequent response times with memory load. For old adults, a different pattern emerged: (1) the mean response time for the first digit processing was longer with memorization than without, probably reflecting task-switching rather than consolidation; and (2) in contrast to young adults, memory load did not affect subsequent response times, suggesting a deficit in the initiation of refreshing. Overall, findings support the hypothesis of impaired refreshing in aging. PMID- 29707787 TI - Force constant decomposition for penta-coordinated XH3 Cl2- (X = C, Si, Ge) structures. AB - Based on the energy decomposition analysis of an interacting system, we propose a method for force constant decomposition analysis with respect to the specific normal coordinate. Using the presented method, we examined the penta-coordinated XH3Cl2- system (X = C, Si, Ge), which possesses a three-center four-electron bond. The origin of the difference in the stability of the penta-coordinated D3h structures was clearly shown to be the effect of electron delocalization polarization term. (c) 2018 Wiley Periodicals, Inc. PMID- 29707788 TI - Extracorporeal photopheresis in the treatment of acute graft-versus-host disease: a single-center experience. AB - BACKGROUND: Steroid-refractory acute graft-versus-host disease (aGVHD) is a serious complication after hematopoietic stem cell transplantation. The long-term outcome of the patients is poor. Various immunosuppressive agents have been proposed as the second-line therapy but none of them has turned out more effective than the others. Extracorporeal photopheresis (ECP) is a treatment option that does not predispose the patients to severe side effects of the immunosuppressive drugs. STUDY DESIGN AND METHODS: We analyzed the treatment results of ECP in 52 patients with steroid-refractory or steroid-dependent aGVHD. Eighty-one percent of the patients suffered from a severe, Grade III or IV, aGVHD. ECP was started alone as the second-line treatment in 23 patients and in combination with an immunosuppressive drug in 18 patients. Eleven patients received ECP as the third-line or later treatment. RESULTS: A total of 62% of the patients responded, with 48% achieving complete response. In the patients with complete or partial response, the probabilities of survival at 4 years were 54 and 17%, respectively. The outcome of nonresponders was poor. The 1-year overall survivals of the patients with ECP as the second-line treatment either alone or in combination with an immunosuppressive drug or as the third-line treatment were 51, 28, and 18%, respectively. In multivariate analysis, starting ECP no later than 10 days after the start of the first-line treatment correlated with a good response and a consequent survival benefit. CONCLUSION: Extracorporeal photopheresis is an effective and well-tolerated treatment that should be considered as a second-line treatment for aGVHD. PMID- 29707789 TI - OK/basigin expression on red blood cells varies between blood donors and correlates with binding of recombinant Plasmodium falciparum reticulocyte-binding protein homolog 5. AB - BACKGROUND: Recently, basigin (BSG), which carries OK antigens on red blood cells (RBCs), was reported to be the receptor of the Plasmodium falciparum reticulocyte binding protein homolog 5 (PfRh5). BSG-PfRh5 is the only essential receptor ligand pair in P. falciparum invasion that is known to date. However, the kind of OK/BSG polymorphism involved in the selection pressure caused by P. falciparum malaria has not been determined. STUDY DESIGN AND METHODS: Blood samples were collected to detect the expression of OK/BSG. The coding region of PfRh5 was cloned and expressed. Enzyme-linked immunosorbent assay-based erythrocyte binding assay was used to measure the recombinant PfRh5 (rPfRh5) binding of RBCs with different OK/BSG expressions. Sequencing of the BSG gene and quantification of the BSG mRNA were performed for selected samples. The candidate microRNAs (miRNAs), which might target the BSG gene, were obtained by miRNA sequencing. Dual-Luciferase reporter assay and overexpression of identified miRNAs were performed in K562 cells. RESULTS: The rPfRh5 was successfully expressed and verified. The OK/BSG expression levels varied among blood donors and were strongly associated with rPfRh5 binding. No single-nucleotide polymorphism was related to the OK/BSG expression. A potential BSG regulator, miR-501-3p, was identified by miRNA sequencing and Dual-Luciferase assay, but was not proven to regulate the expression of BSG in K562 cells. CONCLUSION: Although the mechanism of OK/BSG expression and regulation on RBCs has not been fully clarified, our findings suggest that the OK/BSG expression levels on RBCs might be related to P. falciparum invasion. Moreover, posttranscriptional regulation might play a role in controlling the OK/BSG expression. PMID- 29707790 TI - Time of metastatic disease presentation and volume of disease are prognostic for metastatic hormone sensitive prostate cancer (mHSPC). AB - BACKGROUND: Currently, there is no universally accepted prognostic classification for patients (pts) with metastatic hormone sensitive prostate cancer (mHSPC) treated with androgen deprivation therapy (ADT). Subgroup analyses demonstrated that pts with low volume (LV), per CHAARTED trial definition, mHSPC, and those who relapse after prior local therapy (PLT) have longer overall survival (OS) compared to high volume (HV) and de-novo (DN), respectively. Using a hospital based registry, we aimed to assess whether a classification based on time of metastatic disease (PLT vs DN) and disease volume (LV vs HV) are prognostic for mHSPC pts treated with ADT. METHODS: A retrospective cohort of consecutive patients with mHSPC treated with ADT between 1990 and 2013 was selected from the prospectively collected Dana-Farber Cancer Institute database and categorized as DN or PLT and HV or LV, at time of ADT start. Primary and secondary endpoints were OS and time to castration-resistant prostate cancer (CRPC), respectively, which were measured from date of ADT start using Kaplan-Meier method. Multivariable Cox proportional hazards models using known prognostic factors was used. RESULTS: The analytical cohort consisted of 436 patients. The median OS and time to CRPC for PLT/LV were 92.4 (95%CI: 80.4-127.2) and 25.6 (95%CI: 21-35.7) months and 43.2 (95%CI: 37.2-56.4) and 12.2 (95%CI: 9.8-14.8) months for DN/HV, respectively, whereas intermediate values were observed for PLT/HV and DN/LV. A robust gradient for both outcomes was observed (Trend test P < 0.0001) in the four groups. In a multivariable analysis, DN presentation, HV, and cancer-related pain were independent prognostic factors. CONCLUSIONS: In our hospital-based registry, time of metastatic presentation and disease volume were prognostic for mHSPC pts treated with ADT. This simple prognostic classification system can aid patient counseling and future trial design. PMID- 29707791 TI - Theoretical insights on the inhibition mechanism of a class A Serine Hydrolase by avibactam. AB - The inhibition mechanism of CTX-M-15 class A serine hydrolase by the inhibitor avibactam is addressed by a combined molecular dynamics (MD) and quantum mechanics/molecular mechanics (QM/MM) approach postulating that the residue Ser70 is the sole reacting residue, that is, itself may play the role of the acid-base species required for the enzyme inhibition. Other residues located in the active site have key participation in the positioning of the inhibitor in the right conformation to favor the attack of Ser70, in addition to the stabilization of the transition state by electrostatic interactions with avibactam. The results validate the hypothesis and show that the reaction follows an asynchronous concerted mechanism, in which the nucleophilic attack of the hydroxyl oxygen of Ser70 precedes the protonation of the amidic nitrogen and ring opening. The calculated activation barrier is 16 kcal/mol in agreement with the experimental evidence. (c) 2018 Wiley Periodicals, Inc. PMID- 29707792 TI - Maintenance of pre-existing DNA methylation states through recurring excess-light stress. AB - The capacity for plant stress priming and memory and the notion of this being underpinned by DNA methylation-mediated memory is an appealing hypothesis for which there is mixed evidence. We previously established a lack of drought induced methylome variation in Arabidopsis thaliana (Arabidopsis); however, this was tied to only minor observations of physiological memory. There are numerous independent observations demonstrating that photoprotective mechanisms, induced by excess-light stress, can lead to robust programmable changes in newly developing leaf tissues. Although key signalling molecules and transcription factors are known to promote this priming signal, an untested question is the potential involvement of chromatin marks towards the maintenance of light stress acclimation, or memory. Thus, we systematically tested our previous hypothesis of a stress-resistant methylome using a recurring excess-light stress, then analysing new, emerging, and existing tissues. The DNA methylome showed negligible stress-associated variation, with the vast majority attributable to stochastic differences. Yet, photoacclimation was evident through enhanced photosystem II performance in exposed tissues, and nonphotochemical quenching and fluorescence decline ratio showed evidence of mitotic transmission. Thus, we have observed physiological acclimation in new and emerging tissues in the absence of substantive DNA methylome changes. PMID- 29707793 TI - Interleukin-6 induces VEGF secretion from prostate cancer cells in a manner independent of androgen receptor activation. AB - BACKGROUND: The reduced androgen-sensitivity of prostate cancer (PCa) cells is an important clinical development because of its association with the cells' progression to castration-resistant prostate cancer (CRPC). During androgen deprivation therapy (ADT), stroma-derived growth factors and cytokines can activate the androgen receptor (AR). For example, IL-6 is a multifunctional cytokine that is involved in the malignancy of PCa cells through AR activation. In the present study, we used an androgen-sensitive human PCa cell line (LNCaP) and its sublines to investigate the relationship between the responsiveness of PCa cells to IL-6 treatment and the cellular AR signaling pathway. METHODS: The androgen-low-sensitive F10 and E9 cells were obtained from LNCaP cells by limiting dilution method in regular culture condition. In contrast, the androgen insensitive AIDL cells were established from LNCaP cells by continuous passaging in hormone-depleted condition. Original carcinoma-associated fibroblasts (CAFs) PCaSC-8 and PCaSC-9 cells were isolated from needle biopsy samples of PCa patients. RESULTS: In fibroblasts derived from PCa patients, IL-6 secretion was generally higher than that observed with normal fibroblasts. In contrast, IL-6 secretion was not detected in LNCaP and its sublines. The soluble IL-6 receptor was detected in PCa cells but not in fibroblasts. IL-6 treatment suppressed cell growth of LNCaP, F10, and E9 cells but not AIDL cells and it was accompanied with neuroendocrine-like differentiation. Induction of PSA secretion was observed in IL-6-treated LNCaP and F10 cells. VEGF secretion was strongly induced in IL-6 treated LNCaP and AIDL cells. IL-6-induced VEGF secretion was significantly suppressed by a PI3K inhibitor (LY294002) and it was accompanied by inhibited phosphorylation of Akt. CONCLUSIONS: Our results suggest that IL-6 might induce VEGF secretion from PCa cells in a manner independent of AR activation. To prevent IL-6-induced VEGF secretion, inhibition of the PI3K/AKT signaling pathway could be an important pharmacological goal regardless of ADT. PMID- 29707795 TI - Harmless, friendly and lethal: antibiotic misuse in relation to the unpredictable bacterium Group A streptococcus. AB - Evidence-based treatment guidelines for managing infections in health care are promoted as tools to prevent unnecessary use of antibiotics. Antibiotic misuse has been examined as regards the doctor-patient relation and the social context of medical practice. Less attention has been paid to how the very conceptualisation of human-microbial relations may influence understandings of antibiotic misuse. The article examines a medical controversy concerning guidelines for managing throat infection and antibiotic treatment in Sweden. It demonstrates how this controversy unfolds around two different ways of relating to a specific bacterium - Group A Streptococcus. The analysis shows how two 'microbiopolitics', involving different understandings of human-microbial relations, are created in the controversy and how different antibiotic prescribing practices are justified. By focusing on Group A Streptococcus, which is commonly observed, but also unpredictable and potentially dangerous, the article provides new insights into the relations between bacteria, humans and policy in an age of antimicrobial resistance. It argues, in particular, that the definition of antibiotic misuse is unstable and consequently that policy measures aimed at reducing misuse must be related to how specific infections and bacteria are conceptualised in the actual context the policy addresses. PMID- 29707794 TI - Mechanical and moisture barrier properties of corn distarch phosphate film influenced by modified microcry stalline corn straw cellulose. AB - BACKGROUND: In this paper, a novel modified microcrystalline corn straw cellulose (MMCSC) was prepared by ultrasonic/microwave-assisted treatment. Effective incorporation of MMCSC into corn distarch phosphate (CDP)-based composite films was investigated. RESULTS: As the proportion of MMCSC was increased, tensile strength increased initially before decreasing, and the elongation at break always decreased. The composite film of MMCSC20 showed the lowest water vapor permeability (2.917 * 10-7 g m-1 h-1 Pa-1 ). The measurement of surface color showed that by the increasing of the MMCSC proportion in composite films, the L* and b* values and the total color difference (DeltaE* ) increased, while a* values decreased. Fourier transform infrared spectroscopy and X-ray diffraction analysis indicated that, with the incorporation of MMCSC, the stable structure of the films was enhanced through cross-linking and the crystallinity was increased. A scanning electron microscopy study revealed the surface microstructure of films (MMCSC0-MMCSC30) was smooth and homogeneous, and there was no distinct separation in the matrix of composite films. CONCLUSION: The incorporation of suitable MMCSC could improve the properties of composite films. The CDP-MMCSC films, which are completely biodegradable and environmental friendly, have a high potential to be used for food packaging. (c) 2018 Society of Chemical Industry. PMID- 29707796 TI - Calculating particle pair potentials from fluid-state pair correlations: Iterative ornstein-zernike inversion. AB - An iterative Monte Carlo inversion method for the calculation of particle pair potentials from given particle pair correlations is proposed in this article. The new method, which is best referred to as Iterative Ornstein-Zernike Inversion, represents a generalization and an improvement of the established Iterative Boltzmann Inversion technique (Reith, Putz and Muller-Plathe, J. Comput. Chem. 2003, 24, 1624). Our modification of Iterative Boltzmann Inversion consists of replacing the potential of mean force as an approximant for the pair potential with another, generally more accurate approximant that is based on a trial bridge function in the Ornstein-Zernike integral equation formalism. As an input, the new method requires the particle pair correlations both in real space and in the Fourier conjugate wavenumber space. An accelerated iteration method is included in the discussion, by which the required number of iterations can be greatly reduced below that of the simple Picard iteration that underlies most common implementations of Iterative Boltzmann Inversion. Comprehensive tests with various pair potentials show that the new method generally surpasses the Iterative Boltzmann Inversion method in terms of reliability of the numerical solution for the particle pair potential. (c) 2018 Wiley Periodicals, Inc. PMID- 29707797 TI - Can very early music interventions promote at-risk infants' development? AB - Music and musical activities are often a natural part of parenting. As accumulating evidence shows, music can promote auditory and language development in infancy and early childhood. It may even help to support auditory and language skills in infants whose development is compromised by heritable conditions, like the reading deficit dyslexia, or by environmental factors, such as premature birth. For example, infants born to dyslexic parents can have atypical brain responses to speech sounds and subsequent challenges in language development. Children born very preterm, in turn, have an increased likelihood of sensory, cognitive, and motor deficits. To ameliorate these deficits, we have developed early interventions focusing on music. Preliminary results of our ongoing longitudinal studies suggest that music making and parental singing promote infants' early language development and auditory neural processing. Together with previous findings in the field, the present studies highlight the role of active, social music making in supporting auditory and language development in at-risk children and infants. Once completed, the studies will illuminate both risk and protective factors in development and offer a comprehensive model of understanding the promises of music activities in promoting positive developmental outcomes during the first years of life. PMID- 29707798 TI - Exposure, hazard, and survival analysis of diffusion on social networks. AB - Sociologists, economists, epidemiologists, and others recognize the importance of social networks in the diffusion of ideas and behaviors through human societies. To measure the flow of information on real-world networks, researchers often conduct comprehensive sociometric mapping of social links between individuals and then follow the spread of an "innovation" from reports of adoption or change in behavior over time. The innovation is introduced to a small number of individuals who may also be encouraged to spread it to their network contacts. In conjunction with the known social network, the pattern of adoptions gives researchers insight into the spread of the innovation in the population and factors associated with successful diffusion. Researchers have used widely varying statistical tools to estimate these quantities, and there is disagreement about how to analyze diffusion on fully observed networks. Here, we describe a framework for measuring features of diffusion processes on social networks using the epidemiological concepts of exposure and competing risks. Given a realization of a diffusion process on a fully observed network, we show that classical survival regression models can be adapted to estimate the rate of diffusion, and actor/edge attributes associated with successful transmission or adoption, while accounting for the topology of the social network. We illustrate these tools by applying them to a randomized network intervention trial conducted in Honduras to estimate the rate of adoption of 2 health-related interventions-multivitamins and chlorine bleach for water purification-and determine factors associated with successful social transmission. PMID- 29707799 TI - Granulocyte antibodies in male blood donors: can they trigger transfusion-related acute lung injury? AB - BACKGROUND: White blood cell-associated antibodies can lead to transfusion related acute lung injury (TRALI). Female donors with a history of pregnancies have been identified as a main cause for these antibodies. Male or female donors without a history of pregnancy are considered as safe donors. STUDY DESIGN AND METHODS: Following the identification of two TRALI cases associated with blood products from male donors, we investigated the frequency of granulocyte-specific and human leukocyte antigen (HLA) antibodies in the entire blood donor population using a high throughput automated flow-cytometry-based granulocyte immunofluorescence test (Flow-GIFT). We investigated sera from 14,343 whole blood donors (female, n = 6974, 48.7%; male, n = 7369, 51.3%) using automated Flow GIFT. Of the female blood donors, 60.4% had a history of pregnancy. Positive sera were retested by the standard granulocyte immunofluorescence test and granulocyte agglutination test. For the detection of HLA Class I and II immunoglobulin G antibodies, we used a commercial screening enzyme-linked immunosorbent assay. RESULTS: We detected in 924 (21.9%) of the 4212 females with a history of pregnancy antibodies against granulocyte antigens (n = 62, 1.5%), HLA Class I and/or II antigens (n = 864, 20.5%). Notably, in 3.5% (n = 96) of 2762 females without a history of pregnancy and in 2.1% (n = 154) of 7369 males antibodies against granulocyte antigens (n = 13, 0.47% and n = 45, 0.6%), HLA Class I and/or II (n = 83, 3% and n = 109, 1.4%, respectively), were also detected. CONCLUSION: Human neutrophil antigen antibodies are rare in male and females without a history of pregnancy compared to females with a history of pregnancy, but their relevance is not negligible. PMID- 29707800 TI - An open library of relativistic core electron density function for the QTAIM analysis with pseudopotentials. AB - Based on two-component relativistic atomic calculations, a free electron density function (EDF) library has been developed for nearly all the known ECPs of the elements Li (Z = 3) up to Ubn (Z = 120), which can be interfaced into modern quantum chemistry programs to save the .wfx wavefunction file. The applicability of this EDF library is demonstrated by the analyses of the quantum theory of atoms in molecules (QTAIM) and other real space functions on HeCuF, PtO42+, OgF4 , and TlCl3 (DMSO)2 . When a large-core ECP is used, it shows that the corrections by EDF may significantly improve the properties of some density derived real space functions, but they are invalid for the wavefunction-depending real space functions. To classify different chemical bonds and especially some nonclassical interactions, a list of universal criteria has also been proposed. (c) 2018 Wiley Periodicals, Inc. PMID- 29707801 TI - Stop the war on DXA! AB - Dual-energy X-ray absorptiometry (DXA) is a versatile technology that is widely used in clinical practice in the management of osteoporosis and other skeletal diseases. It is a safe and inexpensive procedure that measures bone mineral density (BMD) to diagnose osteoporosis, assess fracture risk, and monitor osteoporosis treatment. However, DXA has been subjected to recurring claims that it is overutilized, too expensive, and not helpful in patient management. In recent years, there has been a decline in the number of office-based DXA facilities, a reduction in BMD tests performed, and fewer women being diagnosed and treated for osteoporosis, despite aging of the population with more people at risk for fractures. Here, we identify some of the challenges to DXA, which in the aggregate amount to a disturbing war on DXA and, as a result, a threat to good patient care. We suggest potential strategies to restore DXA to its proper role in osteoporosis management. PMID- 29707802 TI - The effects of verbal and spatial memory load on children's processing speed. AB - Examining the impact of maintenance on processing speed allows us to test whether storage and processing resources are shared. Comparing these relationships in children of different ages allows further insight into whether one or multiple resources for these operations must be assumed and whether remembering is proactive throughout childhood. We tested 185 4- to 6- and 8- to 10-year-old children using adaptive complex span tasks, in which simple judgments were interleaved between to-be-remembered items. The adaptiveness of our tasks ensured that all participants frequently correctly recalled the items. If storage and processing require a single resource, and if participants serially reactivate the memoranda between processing episodes, processing response times should increase with serial position of the processing judgment within lists. We observed different within-list dynamics for each age group. Older children's processing judgments slowed gradually when more than two memory items were maintained. By contrast, younger children showed no evidence of slower processing with increasing memory load. Our results support models of working memory that assume that some common resource is responsible for verbal and spatial storage and processing. They also support the notion that remembering becomes more proactive as children mature. PMID- 29707803 TI - Radiosynthesis of microtubule-targeted theranostic methyl N-[5-(3' radiohalobenzoyl)-1H-benzimidazol-2-yl]carbamates. AB - Microtubules are a target for a broad spectrum of drugs used as chemotherapeutics to treat hematological malignancies and solid tumors. Most of these drugs have significant dose-limiting toxicities including peripheral neuropathies that can be debilitating and permanent. In an ongoing effort to develop safer and more effective drugs, benzimidazole-based compounds are being developed as replacement for vincristine and similar agents. In this report, we describe radiosyntheses of novel microtubule-targeting methyl N-[5-(3'-radiohalobenzoyl)-1H-benzimidazol-2 yl]carbamates 4 that are intended as potential imaging agents and molecular radiotherapeutics. 125 I- and 131 I-radiolabeled derivatives were prepared either by direct radioiodination of methyl N-(6-benzoyl-1H-benzimidazol-2-yl)carbamate 1 or radioiododestannylation of the corresponding stannane precursor 3. The direct radioiodination was conducted in a solution of 1 in triflic acid and produced after ~1 hour at elevated temperatures and HPLC purification on average 62% of the no-carrier added products 125 I-4 and 131 I-4. Radioiododestannylation of 3' trimethylstannane 3 proceeded with ease at room temperature in the presence of H2 O2 as the oxidant and produced no-carrier-added 125 I-4 and 131 I-4 in high isolated yields, on average 85%. The radiohalodestannylation protocol is universal and can be applied to other radiohalides including 124 I to produce 124 I-4, a positron emission tomography agent, and 211 At to produce 211 At-4, an alpha-particle emitting radiotherapeutic. PMID- 29707804 TI - Compressed sensing for high-resolution nonlipid suppressed 1 H FID MRSI of the human brain at 9.4T. AB - PURPOSE: The aim of this study was to apply compressed sensing to accelerate the acquisition of high resolution metabolite maps of the human brain using a nonlipid suppressed ultra-short TR and TE 1 H FID MRSI sequence at 9.4T. METHODS: X-t sparse compressed sensing reconstruction was optimized for nonlipid suppressed 1 H FID MRSI data. Coil-by-coil x-t sparse reconstruction was compared with SENSE x-t sparse and low rank reconstruction. The effect of matrix size and spatial resolution on the achievable acceleration factor was studied. Finally, in vivo metabolite maps with different acceleration factors of 2, 4, 5, and 10 were acquired and compared. RESULTS: Coil-by-coil x-t sparse compressed sensing reconstruction was not able to reliably recover the nonlipid suppressed data, rather a combination of parallel and sparse reconstruction was necessary (SENSE x t sparse). For acceleration factors of up to 5, both the low-rank and the compressed sensing methods were able to reconstruct the data comparably well (root mean squared errors [RMSEs] <= 10.5% for Cre). However, the reconstruction time of the low rank algorithm was drastically longer than compressed sensing. Using the optimized compressed sensing reconstruction, acceleration factors of 4 or 5 could be reached for the MRSI data with a matrix size of 64 * 64. For lower spatial resolutions, an acceleration factor of up to R~4 was successfully achieved. CONCLUSION: By tailoring the reconstruction scheme to the nonlipid suppressed data through parameter optimization and performance evaluation, we present high resolution (97 uL voxel size) accelerated in vivo metabolite maps of the human brain acquired at 9.4T within scan times of 3 to 3.75 min. PMID- 29707806 TI - Analysis of dual tree M-band wavelet transform based features for brain image classification. AB - PURPOSE: The most complex organ in the human body is the brain. The unrestrained growth of cells in the brain is called a brain tumor. The cause of a brain tumor is still unknown and the survival rate is lower than other types of cancers. Hence, early detection is very important for proper treatment. METHODS: In this study, an efficient computer-aided diagnosis (CAD) system is presented for brain image classification by analyzing MRI of the brain. At first, the MRI brain images of normal and abnormal categories are modeled by using the statistical features of dual tree m-band wavelet transform (DTMBWT). A maximum margin classifier, support vector machine (SVM) is then used for the classification and validated with k-fold approach. RESULTS: Results show that the system provides promising results on a repository of molecular brain neoplasia data (REMBRANDT) with 97.5% accuracy using 4th level statistical features of DTMBWT. CONCLUSION: Viewing the experimental results, we conclude that the system gives a satisfactory performance for the brain image classification. PMID- 29707805 TI - Intestinal absorption of glucose in mice as determined by positron emission tomography. AB - KEY POINTS: The goal was to determine the importance of the sodium-glucose cotransporter SGLT1 and the glucose uniporter GLUT2 in intestinal glucose absorption during oral glucose tolerance tests (OGTTs) in mice. Glucose absorption was determined in mice using positron emission tomography and three non-metabolizable glucose probes: one specific for SGLTs, one specific for GLUTs, and one a substrate for both SGLTs and GLUTs. Absorption was determined in wild type, Sglt1-/- and Glut2-/- mice. Gastric emptying was a rate-limiting step in absorption. SGLT1, but not GLUT2, was important in fast glucose absorption. In the absence of SGLT1 or GLUT2, the oral glucose load delivered to the small intestine was slowly absorbed. Oral phlorizin only inhibited the fast component of glucose absorption, but it contributed to decreasing blood glucose levels by inhibiting renal reabsorption. ABSTRACT: The current model of intestinal absorption is that SGLT1 is responsible for transport of glucose from the lumen into enterocytes across the brush border membrane, and GLUT2 for the downhill transport from the epithelium into blood across the basolateral membrane. Nevertheless, questions remain about the importance of these transporters in vivo. To address these questions, we have developed a non-invasive imaging method, positron emission tomography (PET), to monitor intestinal absorption of three non-metabolized glucose tracers during standard oral glucose tolerance tests (OGTTs) in mice. One tracer is specific for SGLTs (alpha-methyl-4-[18 F]fluoro-4-deoxy-d-glucopyranoside; Me-4FDG), one is specific for GLUTs (2-deoxy 2-[18 F]fluoro-d-glucose; 2-FDG), and one is a substrate for both SGLTs and GLUTs (4-deoxy-4-[18 F]fluoro-d-glucose; 4-FDG). OGTTs were conducted on adult wild type, Sglt1-/- and Glut2-/- mice. In conscious mice, OGTTs resulted in the predictable increase in blood glucose that was blocked by phlorizin in both wild type and Glut2-/- animals. The blood activity of both Me-4FDG and 4-FDG, but not 2-FDG, accompanied the changes in glucose concentration. PET imaging during OGTTs further shows that: (i) intestinal absorption of the glucose load depends on gastric emptying; (ii) SGLT1 is important for the fast absorption; (iii) GLUT2 is not important in absorption; and (iv) oral phlorizin reduces absorption by SGLT1, but is absorbed and blocks glucose reabsorption in the kidney. We conclude that in standard OGTTs in mice, SGLT1 is essential in fast absorption, GLUT2 does not play a significant role, and in the absence of SGLT1 the total load of glucose is slowly absorbed. PMID- 29707807 TI - Clinical outcomes of atherectomy prior to percutaneous coronary intervention: A comparison of outcomes following rotational versus orbital atherectomy (COAP-PCI study). AB - BACKGROUND: Because of the challenges in treating calcified coronary artery disease (CAD), lesion preparation has become increasingly important prior to percutaneous coronary intervention (PCI). Despite growing data for both rotational atherectomy (RA) and orbital atherectomy (OA), there have been no multicenter studies comparing the safety and efficacy of both. We sought to examine the clinical outcomes of patients with calcified CAD who underwent atherectomy. METHODS: A total of 39 870 patients from five tertiary care hospitals who had PCI from January 2011 to January 2017 were identified. 907 patients who had RA or OA were included. This multicenter, prospectively collected observational analysis compared OA and RA. The primary end-point was myocardial infarction and safety outcomes including significant dissection, perforation, cardiac tamponade, and vascular complications. Propensity score matching (1:1) was performed to reduce selection bias. RESULTS: After matching, 546 patients were included in the final analysis. The primary endpoint, myocardial infarction occurred less frequently with OA compared to RA (6.7% vs 13.8%, P <= 0.01) in propensity score matched cohorts. Procedural safety outcomes were comparable between the groups. The secondary outcome of death on discharge occurred less in the OA group as compared with RA (0% vs 2.2%, P = 0.01). Fluoroscopy time was less in patients who were treated with OA (21.9 vs 25.6 min, P <= 0.01). Additional secondary outcomes were comparable between groups. CONCLUSION: In this non-randomized, multicenter comparison of contemporary atherectomy devices, OA was associated with significantly decreased in-hospital myocardial infarction and mortality after propensity score matching with decreased fluoroscopy time. PMID- 29707808 TI - Pooled diagnostic accuracy of resting distal to aortic coronary pressure referenced to fractional flow reserve: The importance of resting coronary physiology. AB - INTRODUCTION: Both resting and hyperemic physiologic methods to guide coronary revascularization improve cardiovascular outcomes compared with angiographic guidance alone. Fractional flow reserve (FFR) remains underutilized due to concerns regarding hyperemia, prompting study of resting distal to aortic coronary pressure (Pd/Pa). Pd/Pa is a vasodilator-free resting index unlike FFR. While Pd/Pa is similar to another resting index, instantaneous wave-free ratio (iFR), it is a whole-cycle measurement not limited to the wave-free diastolic period. Pd/Pa is not validated clinically although multiple accuracy studies have been performed. Our meta-analysis examines the overall diagnostic accuracy of Pd/Pa referenced to FFR, the accepted invasive standard of ischemia. METHODS: We searched PubMed, EMBASE, Central, ProQuest, and Web of Science databases for full text articles published through August 9, 2017 addressing the diagnostic accuracy of Pd/Pa referenced to FFR < 0.80. The following keywords were used: "distal coronary artery pressure" OR "Pd/Pa" AND "fractional flow reserve" OR "FFR." RESULTS: In total, 14 studies comprising 7004 lesions were identified. Pooled diagnostic accuracy estimates of Pd/Pa versus FFR < 0.80 were: sensitivity, 0.77 (95% CI, 0.75-0.78); specificity, 0.82 (0.81-0.83); positive likelihood ratio, 4.7 (3.3-6.6); negative likelihood ratio, 0.29 (0.24-0.34); diagnostic odds ratio, 18.1 (14.4-22.6); area under the summary receiver-operating characteristic curve of 0.88; and diagnostic accuracy of 0.80 (0.76-0.83). CONCLUSIONS: Pd/Pa shows adequate agreement with FFR as a resting index of coronary stenosis severity without the undesired effects and cost of hyperemic agents. Pd/Pa has the potential to guide coronary revascularization with easier application and availability compared with iFR and FFR. PMID- 29707809 TI - Hepatobiliary and Pancreatic: Nivolumab-related cholangiopathy. PMID- 29707810 TI - Identification and characterization of GRIP domain Golgin PpImh1 from Pichia pastoris. AB - Budding yeast Pichia pastoris has highly advanced secretory pathways resembling mammalian systems, an advantage that makes it a suitable model system to study vesicular trafficking. Golgins are large Golgi-resident proteins, primarily reported to play role in cargo vesicle capture, but details of such mechanisms are yet to be deciphered. Golgins that localize to the Golgi via their GRIP domain, a C-terminal Golgi anchoring domain, are known as GRIP domain Golgins. In this present study, we have identified and functionally characterized a homologue of one such GRIP domain Golgin protein, Imh1, from the budding yeast P. pastoris. We have demonstrated that the GRIP domain present at the C-terminal of P. pastoris Imh1 (PpImh1) functions as its Golgi-targeting sequence. Using a combination of yeast two-hybrid analysis, dynamic light scattering and electron microscopy, we have shown that PpImh1 can self-associate and form a homodimer. Analysis of purified recombinant PpImh1 by CD spectroscopy indicates the presence of an 85% alpha-helical structure, a characteristic of high-content alpha-helical coiled-coil sequences normally present in other Golgin family proteins. Two hybrid analysis indicated self-interaction between C-terminal fragments, yet N terminal fragments do not mediate any such form of self-interaction, suggesting that PpImh1 may form a parallel dimer. Electron microscopy data indicates that PpImh1 forms extended rod-like homo-dimeric molecules with splayed N-terminal end which can act as a tether for capturing vesicles. Our study provides the first evidence in support of the dimeric Y-shaped structure for any Golgin in the budding yeast. PMID- 29707812 TI - In Memoriam: Terry B. Strom. PMID- 29707811 TI - Exploring relationships between body condition score, body fat, activity level and inflammatory biomarkers. AB - Obesity is associated with inflammatory disorders in humans, including degenerative joint disease. While obesity is endemic in horses, its relationship to equine degenerative joint disease has not been explored. The current study sought to describe relationships between: body weight (BW), body condition score (BCS), lameness grade (AAEP), total body fat mass (kg; FM) and fat per cent (FP) [multifrequency bioelectrical impedance analysis (mfBIA)], age, gender, activity level (AL), synovial fluid (SF) and plasma (PL) PGE2 and glycosaminoglycan (GAG) in horses. During this field investigation, the BCS (of nine) of 54 horses at multiple farms in southern Ontario, Canada, was determined. Horses were categorized as thin (BCS=3/9; n = 6), moderate (BCS=4 or 5/9; n = 18), overweight (BCS=6 or 7/9; n = 19) or obese (BCS=8 or 9/9; n = 11). Total fat mass (kg) and body fat% was measured using mfBIA, lameness was assessed (AAEP lameness scale) and synovial fluid was collected via aseptic arthrocentesis from the left intercarpal joint for assessment of inflammatory biomarkers (PGE2 , GAG). Means were compared with a one-way ANOVA; correlation coefficients were calculated using a Spearman Rank Order Correlation to reveal correlations between variables. BCS was positively correlated with BW, FM, FP, AL and PL-PGE2 . BW was also significantly positively correlated with PL-PGE2 . It is concluded that BCS is significantly correlated with PL-PGE2 , due in part to the combined effect of AL and body condition. Net inflammatory effects of body fat on risk for joint disease require further study. PMID- 29707813 TI - Microstructural correlates of 3D steady-state inhomogeneous magnetization transfer (ihMT) in the human brain white matter assessed by myelin water imaging and diffusion tensor imaging. AB - PURPOSE: To compare the recently introduced inhomogeneous magnetization transfer (ihMT) technique with more established MRI techniques including myelin water imaging (MWI) and diffusion tensor imaging (DTI), and to evaluate the microstructural attributes correlating with this new contrast method in the human brain white matter. METHODS: Eight adult healthy volunteers underwent T1 weighted, ihMT, MWI, and DTI imaging on a 3T human scanner. The ihMT ratio (ihMTR), myelin water fraction (MWF), fractional anisotropy (FA), radial diffusivity (RD), axial diffusivity (AD), and mean diffusivity (MD) values were calculated from different white matter tracts. The angle ( theta) between the directions of the principal eigenvector, as measured by DTI, and the main magnetic field was calculated for all voxels from various fiber tracts. The ihMTR was correlated with MWF and DTI metrics. RESULTS: A strong correlation was found between ihMTR and MWF (rho = 0.77, P < 0.0001). This was followed by moderate to weak correlations between ihMTR and DTI metrics: RD (rho = -0.30, P < 0.0001), FA (rho = 0.20, P < 0.0001), MD (rho = -0.19, P < 0.0001), AD (rho = 0.02, P < 0.0001). A strong correlation was found between ihMTR and theta (rho = -0.541, P < 0.0001). CONCLUSION: The strong correlation with myelin water imaging and its low coefficient of variation suggest that ihMT has the potential to become a new structural imaging marker of myelin. The substantial orientational dependence of ihMT should be taken into account when evaluating and quantitatively interpreting ihMT results. PMID- 29707814 TI - Antera 3D capabilities for pore measurements. AB - BACKGROUND: The cause of enlarged pores remains obscure but still remains of concern for women. To complement subjective methods, bioengineered methods are needed for quantification of pores visibility following treatments. The study objective was to demonstrate the suitability of pore measurements from the Antera 3D. MATERIAL AND METHODS: Pore measurements were collected on 22 female volunteers aged 18-65 years with the Antera 3D, the DermaTOP and image analysis on photographs. Additionally, 4 raters graded pore size on photographs on a scale 0-5. Repeatability of Antera 3D parameters was ascertained and the benefit of a pore minimizer product on the cheek was assessed on a sub panel of seven female volunteers. RESULTS: Pore parameters using the Antera were shown to depict pore severity similar to raters on photographs, except for Max Depth. Mean pore volume, mean pore area and count were moderately correlated with DermaTOP parameters (up to r = .50). No relationship was seen between the Antera 3D and pore visibility analysis on photographs. The most repeatable parameters were found to be mean pore volume, mean pore area and max depth, especially for the small and medium filters. The benefits of a pore minimizer product were the most striking for mean pore volume and mean pore area when using the small filter for analysis, rather than the medium/large ones. CONCLUSION: Pore measurements with the Antera 3D represent a reliable tool for efficacy and field studies, with an emphasis of the small filter for analysis for the mean pore volume/mean pore area parameters. PMID- 29707815 TI - Dietary concentrate level affects the feed sorting behaviour of lambs. AB - The objective of this study was to evaluate the effect of forage concentration on sorting, nutrient intake and feeding behaviour of growing lambs. Twelve weaned lambs were exposed, in a crossover design with 7-day periods, to each of two treatment diets: (i) lower-concentrate diet (LC; 40.0% concentrate) and (ii) a higher-concentrate diet (HC; 60.0% concentrate). Alfalfa hay was used as forage source. Sorting was determined by subjecting fresh feed and ort samples to particle separation and expressing the actual intake of each particle fraction as a percentage of the predicted intake of that fraction. Lambs sorted against long particles (>19 mm) on both treatments. On the LC diet, lambs sorted for medium particles, whereas animals fed the HC diet did not sort for or against medium particles. Lambs sorted for fine particles (<1.18 mm) on both treatments (p < .05). The extent of sorting for the fine particles was greater on the LC diet compared with the HC diet (p < .05). Dry matter intake was increased by increasing the concentrate content of the diet. Intake per visit and eating rate increased, and total chewing time was decreased in lambs fed HC diet. In conclusion, lambs sorted most against the longest particles and for the fine particles. Furthermore, feed sorting behaviour is affected by the forage level, and lambs sorted more for the fine particles in the LC diet. PMID- 29707816 TI - Tissue and plasma antioxidant status in response to dietary methionine concentration and source in broilers. AB - This study hypothesized that plasma and tissue antioxidant status of broilers is positively influenced when dietary Met concentrations exceed, and negatively when they go below NRC recommendations. In addition, different Met sources are hypothesized to affect the antioxidant defence system differently. Day-old male Cobb-500 broilers (n = 336) were allotted to seven groups and phase-fed three wheat-soya bean meal-based basal diets during days 1-10, 11-21 and 22-35. The basal diets (Met- group, Met + Cys concentration 15% below NRC recommendations) were supplemented with 0.10%, 0.25% or 0.40% Met either as DL-Met (DLM) or DL-2 hydroxy-4-(methylthio) butanoic acid (DL-HMTBA) (equimolar comparison). Growth performance and carcass weights were lower in the Met- group compared to the groups whose diets met or exceeded Met requirements. The antioxidant defence system was not influenced by the Met source. However, in the liver, concentrations of glutathione increased with increasing dietary Met concentrations. Tocopherol concentrations in the liver at days 10 and 21 were lower in the Met- group than in the groups supplemented with Met. However, liver concentrations of thiobarbituric acid reactive substances (TBA-RS) and protein carbonyls (PC) were largely not influenced by dietary Met concentration. Plasma tocopherol concentrations at day 35 were lower, and those of TBA-RS and PC at day 35 were higher in Met- group than in the groups fed the Met-supplemented diets. In jejunum, but not in liver, relative mRNA abundances and activities of superoxide dismutase, catalase and glutathione peroxidase were higher in the Met- group than in the groups fed Met-supplemented diets. These data indicate that suboptimum supply of Met results in decreased antioxidant concentrations in plasma and body tissues, and increases oxidative stress in the jejunum mucosa. However, supplementation of Met in excess of the requirements (based on NRC) compared to diets adequate in Met + Cys did not influence the antioxidant defence system. PMID- 29707817 TI - Additivity of standardized ileal digestibility of amino acids in mixed diets containing multiple protein sources for growing pigs fed three crude protein levels. AB - This study was conducted to investigate the effect of dietary crude protein (CP) levels of semi-purified diets on the additivity of values for standardized ileal digestibility (SID) of amino acids (AA) in mixed diets from multiple protein sources for growing pigs. A total of 28 barrows (initial BW, 66.4 +/- 1.3 kg) were surgically fitted with simple T-cannulas at the distal ileum and assigned to a replicated 14 * 4 incomplete Latin square design with 14 diets and 4 periods. The 14 experimental diets consisted of a nitrogen-free diet; a corn-based diet (80 g CP/kg); nine semi-purified diets containing soya bean meal (SBM), canola meal (CM) or corn distillers dried grains with solubles (cDDGS), each type (protein source) of semi-purified diets supplied 80, 120 or 160 g CP/kg, respectively; three mixed diets based on corn, SBM, CM and cDDGS formulated to contain 120, 160 and 200 g CP/kg respectively. Pigs were fed each of the 14 diets during a seven-day period, and ileal digesta were collected from 08:00 a.m to 6:00 p.m on day 6 and 7. Chromic oxide was added as an indigestible marker. Results indicated that the SID of CP and AA were not affected by CP levels (p > .05). Values for SID of AA were additive (p > .05) with the exception of His and Lys; Arg and Lys; Arg, Lys, Thr, Asp, Cys and Gly in the mixed diets containing 120, 160 and 200 g CP/kg respectively (p < .05). In conclusion, additivity of SID values of AA in the mixed diets at different CP levels was not affected by the CP levels of semi-purified diets for growing pigs. Therefore, it is recommended that SID values of AA should be used to formulate practical diets containing multiple ingredients for pigs. PMID- 29707818 TI - A sensitivity analysis for missing outcomes due to truncation by death under the matched-pairs design. AB - The matched-pairs design enables researchers to efficiently infer causal effects from randomized experiments. In this paper, we exploit the key feature of the matched-pairs design and develop a sensitivity analysis for missing outcomes due to truncation by death, in which the outcomes of interest (e.g., quality of life measures) are not even well defined for some units (e.g., deceased patients). Our key idea is that if 2 nearly identical observations are paired prior to the randomization of the treatment, the missingness of one unit's outcome is informative about the potential missingness of the other unit's outcome under an alternative treatment condition. We consider the average treatment effect among always-observed pairs (ATOP) whose units exhibit no missing outcome regardless of their treatment status. The naive estimator based on available pairs is unbiased for the ATOP if 2 units of the same pair are identical in terms of their missingness patterns. The proposed sensitivity analysis characterizes how the bounds of the ATOP widen as the degree of the within-pair similarity decreases. We further extend the methodology to the matched-pairs design in observational studies. Our simulation studies show that informative bounds can be obtained under some scenarios when the proportion of missing data is not too large. The proposed methodology is also applied to the randomized evaluation of the Mexican universal health insurance program. An open-source software package is available for implementing the proposed research. PMID- 29707819 TI - Effects of pure plant secondary metabolites on methane production, rumen fermentation and rumen bacteria populations in vitro. AB - In this study, the effects of seven pure plant secondary metabolites (PSMs) on rumen fermentation, methane (CH4 ) production and rumen bacterial community composition were determined. Two in vitro trials were conducted. In trial 1, nine concentrations of 8-hydroxyquinoline, alpha-terpineol, camphor, bornyl acetate, alpha-pinene, thymoquinone and thymol were incubated on separate days using in vitro 24-hr batch incubations. All compounds tested demonstrated the ability to alter rumen fermentation parameters and decrease CH4 production. However, effective concentrations differed among individual PSMs. The lowest concentrations that reduced (p < .05) CH4 production were as follows: 8 mg/L of 8 hydroxyquinoline, 120 mg/L of thymoquinone, 240 mg/L of thymol and 480 mg/L of alpha-terpineol, camphor, bornyl acetate and alpha-pinene. These concentrations were selected for use in trial 2. In trial 2, PSMs were incubated in one run. Methane was decreased (p < .05) by all PSMs at selected concentrations. However, only 8-hydroxyquinoline, bornyl acetate and thymoquinone decreased (p < .05) CH4 relative to volatile fatty acids (VFAs). Based on denaturing gradient gel electrophoresis analysis, different PSMs changed the composition of bacterial communities to different extents. As revealed by Ion Torrent sequencing, the effects of PSMs on relative abundance were most pronounced in the predominant families, especially in Lachnospiraceae, Succinivibrionaceae, Prevotellaceae, unclassified Clostridiales and Ruminococcaceae. The CH4 production was correlated negatively (-.72; p < .05) with relative abundance of Succinivibrionaceae and positively with relative abundance of Ruminococcaceae (.86; p < .05). In summary, this study identified three pure PSMs (8hydroxyquinoline, bornyl acetate and thymoquinone) with potentially promising effects on rumen CH4 production. The PSMs tested in this study demonstrated considerable impact on rumen bacterial communities even at the lowest concentrations that decreased CH4 production. The findings from this study may help to elucidate how PSMs affect rumen bacterial fermentation. PMID- 29707820 TI - Evaluation of sex-related changes in skin topography and structure using innovative skin testing equipment. AB - BACKGROUND: Evaluation of skin condition on the basis of parametrization and objective measurements of the parameters has become obligatory. The aim of this study was to assess sex-related changes in skin topography and structure using the skin testing equipment. MATERIALS AND METHODS: The study was carried out on the group of 40 volunteers (20 females and 20 males) of the mean age 24 +/- 3 years. The skin parameters were measured using 3 devices: Visioscan(r) VC 98 (skin topography), Visioline(r) VL 650 (skin macro relief) and Ultrascan UC22 (ultrasound imaging of the skin). All measurements were performed on the inner part of the left forearm. RESULTS: The skin parameters measured revealed significant differences in skin surface and structure between females and males. The skin of all women subjects was more homogenous in its structure with the presence of more abundant superficial skin lines and wrinkles in comparison to male skin. The higher number of skin furrows in the skin of women is in agreement with literature reports claiming that men's skin has lower number of wrinkles which are deeper and more pronounced. Ultrasound imaging of the skin indicated greater thickness and lower density of the dermis of men subjects compared to those of females. CONCLUSION: Non-invasive methods of skin testing using new and advanced equipment have provided a possibility of objective parametrization and evaluation of sex-related changes in skin topography and structure. PMID- 29707821 TI - Evaluation of the molecular lipid organization in millimeter-sized stratum corneum by synchrotron X-ray diffraction. AB - BACKGROUND: The aim of this study was to investigate whether the lamellar and lateral structure of intercellular lipid of stratum corneum (SC) can be evaluated from millimeter-sized SC (MSC) by X-ray diffraction. MATERIALS AND METHODS: A 12 mm * 12 mm SC sheet from hairless mouse was divided into 16 pieces measuring 3 mm * 3 mm square. From another sheet, 4 pieces of ultramillimeter-sized SC (USC:1.5 mm * 1.5 mm square) were prepared. Small and wide-angle X-ray diffraction (SAXD and WAXD) measurements were performed on each piece. For MSC and USC, changes in the lamellar and lateral structure after the application of d-limonene were measured. RESULTS: The intensity of SAXD peaks due to the lamellar phase of long periodicity phase (LPP) and WAXD peaks due to the lateral hydrocarbon chain packing structures varied in MSC and USC pieces, although over the 12 mm * 12 mm SC sheet. These results indicated that the intercellular lipid components and their proportion appeared nearly uniform. Application of d-limonene on MSC and USC piece with strong peaks in SAXD and the WAXD resulted in the disappearance of peaks due to the lamellar phase of LPP and decrease in peak intensity for the lateral hydrocarbon chain-packing structures. These changes are consistent with normal-sized sample results. CONCLUSION: We found that the selection of a sample piece with strong diffraction peaks due to the lamellar and lateral structure enabled evaluation of the SC structure in small-sized samples by X-ray diffraction. PMID- 29707822 TI - When and how to use Q methodology to understand perspectives in conservation research. AB - Understanding human perspectives is critical in a range of conservation contexts, for example, in overcoming conflicts or developing projects that are acceptable to relevant stakeholders. The Q methodology is a unique semiquantitative technique used to explore human perspectives. It has been applied for decades in other disciplines and recently gained traction in conservation. This paper helps researchers assess when Q is useful for a given conservation question and what its use involves. To do so, we explained the steps necessary to conduct a Q study, from the research design to the interpretation of results. We provided recommendations to minimize biases in conducting a Q study, which can affect mostly when designing the study and collecting the data. We conducted a structured literature review of 52 studies to examine in what empirical conservation contexts Q has been used. Most studies were subnational or national cases, but some also address multinational or global questions. We found that Q has been applied to 4 broad types of conservation goals: addressing conflict, devising management alternatives, understanding policy acceptability, and critically reflecting on the values that implicitly influence research and practice. Through these applications, researchers found hidden views, understood opinions in depth and discovered points of consensus that facilitated unlocking difficult disagreements. The Q methodology has a clear procedure but is also flexible, allowing researchers explore long-term views, or views about items other than statements, such as landscape images. We also found some inconsistencies in applying and, mainly, in reporting Q studies, whereby it was not possible to fully understand how the research was conducted or why some atypical research decisions had been taken in some studies. Accordingly, we suggest a reporting checklist. PMID- 29707823 TI - Origin and Control of Orientation of Phosphorescent and TADF Dyes for High Efficiency OLEDs. AB - It has been known for decades that the emitting dipole orientation (EDO) of emitting dyes influences the outcoupling efficiency of organic light-emitting diodes (OLEDs). However, the EDO of dopants, especially phosphorescent dopants, has been studied less than that of neat films and polymer emitting layers (EMLs) due to the lack of an apparent driving force for aligning the dopants in amorphous host films. Recently, however, even globular-shaped Ir complexes have been reported to have a preferred orientation in doped films and OLEDs. External quantum efficiencies (EQEs) higher than 30% have also been demonstrated using phosphorescent and thermally activated delayed fluorescent dyes (TADF) doped in EMLs. Here, recent results on the EDO of phosphorescent and TADF dyes doped in host films, and highly efficient OLEDs using these dyes are reviewed. The origin and control of the orientation of phosphors are discussed, followed by a discussion of future strategies to achieve EQEs of over 60% without a light extraction layer, from the material point of view. PMID- 29707824 TI - Psychometric evaluation of the Orofacial Pain Scale for Non-Verbal Individuals as a screening tool for orofacial pain in people with dementia. AB - OBJECTIVE: The aim of this study was to describe the psychometric evaluation of the Orofacial Pain Scale for Non-Verbal Individuals (OPS-NVI) as a screening tool for orofacial pain in people with dementia. BACKGROUND: The OPS-NVI has recently been developed and needs psychometric evaluation for clinical use in people with dementia. The pain self-report is imperative as a reference standard and can be provided by people with mild-to-moderate cognitive impairment. METHODS: The presence of orofacial pain during rest, drinking, chewing and oral hygiene care was observed in people with mild cognitive impairment (MCI) and dementia using the OPS-NVI. Participants who were considered to present a reliable self-report were asked about pain presence, and in all participants, the oral health was examined by a dentist for the presence of potential painful conditions. After item-reduction, inter-rater reliability and criterion validity were determined. RESULTS: The presence of orofacial pain in this population was low (0%-10%), resulting in an average Positive Agreement of 0%-100%, an average Negative Agreement of 77%-100%, a sensitivity of 0%-100% and a specificity of 66%-100% for the individual items of the OPS-NVI. At the same time, the presence of oral problems, such as ulcers, tooth root remnants and caries was high (64.5%). CONCLUSION: The orofacial pain presence in this MCI and dementia population was low, resulting in low scores for average Positive Agreement and sensitivity and high scores for average Negative Agreement and specificity. Therefore, the OPS NVI in its current form cannot be recommended as a screening tool for orofacial pain in people with MCI and dementia. However, the inter-rater reliability and criterion validity of the individual items in this study provide more insight for the further adjustment of the OPS-NVI for diagnostic use. Notably, oral health problems were frequently present, although no pain was reported or observed, indicating that oral health problems cannot be used as a new reference standard for orofacial pain, and a regular oral examination by care providers and oral hygiene care professionals remains indispensable. PMID- 29707825 TI - Performance of intraclass correlation coefficient (ICC) as a reliability index under various distributions in scale reliability studies. AB - Many published scale validation studies determine inter-rater reliability using the intra-class correlation coefficient (ICC). However, the use of this statistic must consider its advantages, limitations, and applicability. This paper evaluates how interaction of subject distribution, sample size, and levels of rater disagreement affects ICC and provides an approach for obtaining relevant ICC estimates under suboptimal conditions. Simulation results suggest that for a fixed number of subjects, ICC from the convex distribution is smaller than ICC for the uniform distribution, which in turn is smaller than ICC for the concave distribution. The variance component estimates also show that the dissimilarity of ICC among distributions is attributed to the study design (ie, distribution of subjects) component of subject variability and not the scale quality component of rater error variability. The dependency of ICC on the distribution of subjects makes it difficult to compare results across reliability studies. Hence, it is proposed that reliability studies should be designed using a uniform distribution of subjects because of the standardization it provides for representing objective disagreement. In the absence of uniform distribution, a sampling method is proposed to reduce the non-uniformity. In addition, as expected, high levels of disagreement result in low ICC, and when the type of distribution is fixed, any increase in the number of subjects beyond a moderately large specification such as n = 80 does not have a major impact on ICC. PMID- 29707826 TI - Pulmonary hypertension is not a risk factor for grade 3 primary graft dysfunction after lung transplantation. AB - Grade 3 primary graft dysfunction (PGD3) represents the most important risk factor for patient mortality during the first year after lung transplantation (LTX). We investigated whether pretransplant pulmonary hypertension (PH) is a risk factor for the development of PGD3. This retrospective, single-center cohort study included 96 candidates undergoing right heart catheterization (RHC) prior to being listed for LTX between March 2000 and October 2015. Based on their mean pulmonary artery pressure (mPAP) levels, the patients were classified into 3 groups: (1) <25 mm Hg, (2) 25-34 mm Hg and (3) >=35 mm Hg. Forty-seven patients were classified in group 1, 31 in group 2, and 18 in group 3. Fifteen recipients (16%, 95%-CI 8-23) developed PGD3. In the univariate analysis, the diagnosis of interstitial lung disease (ILD) compared to COPD (OR: 7.06, P = .005), blood transfusion >1000 mL during surgery (OR: 5.25, P = .005), the need for intra operative cardio-pulmonary bypass (CPB) or extra-corporeal membrane oxygenation (ECMO) (OR: 4, P = .027), mPAP (OR 1.06, P = .007) and serum high density lipoprotein-cholesterol (HDL-C) (OR 0.09, P = .005) were associated with PGD3. In the multivariable logistic regression analysis, only HDL-C (OR 0.10, P = .016) was associated with PGD3 based on our single-center cohort data analysis. PMID- 29707828 TI - Enhanced immunity in intradermal vaccination by novel hollow microneedles. AB - BACKGROUND: The intradermal (ID) route for vaccination represents an effective alternative to subcutaneous (SC)/intramuscular administration to induce protective immunity. However, a critical issue associated with ID vaccination is the precise delivery of solution in the upper dermis, which ensures enhanced immunity. METHODS: We fabricated a hollow microneedle unit made of poly-glycolic acid by injection molding and bonding, and created a dedicated prototype injector. To ensure ID delivery of solution, the injected site was macroscopically and microscopically examined. Serum immunoglobulin G antibody production was measured by enzyme immunoassay and compared in groups of rats following either ID delivery with microneedles or SC administration with a 27-G stainless needle of graded vaccine doses. RESULTS: The unit used a tandem array of six microneedles, each with a side delivery hole, and a conduit inside for solution. Microneedles installed in the injector punctured the skin with the aid of a spring. Injection of solution formed a wheal due to ID distribution. Histologically, a wedge-shaped skin defect in the upper skin corresponded to each puncture site. Antibody titers following vaccinations on days 1 and 8 were significantly higher with ID injection than with SC delivery on day 15 and every 7 days thereafter until day 36 with mumps vaccination, and until day 36 with varicella vaccination. CONCLUSIONS: The microneedle unit presented here delivered solution intradermally without any difficulty and evoked antibody responses against viruses even with the reduced vaccine volume. Our findings confirm promising results of ID delivery as an immunogenic option to enhance vaccination efficacy. PMID- 29707827 TI - Self-Assembly of Transition Metal Oxide Nanostructures on MXene Nanosheets for Fast and Stable Lithium Storage. AB - Recently, a new class of 2D materials, i.e., transition metal carbides, nitrides, and carbonitrides known as MXenes, is unveiled with more than 20 types reported one after another. Since they are flexible and conductive, MXenes are expected to compete with graphene and other 2D materials in many applications. Here, a general route is reported to simple self-assembly of transition metal oxide (TMO) nanostructures, including TiO2 nanorods and SnO2 nanowires, on MXene (Ti3 C2 ) nanosheets through van der Waals interactions. The MXene nanosheets, acting as the underlying substrate, not only enable reversible electron and ion transport at the interface but also prevent the TMO nanostructures from aggregation during lithiation/delithiation. The TMO nanostructures, in turn, serve as the spacer to prevent the MXene nanosheets from restacking, thus preserving the active areas from being lost. More importantly, they can contribute extraordinary electrochemical properties, offering short lithium diffusion pathways and additional active sites. The resulting TiO2 /MXene and SnO2 /MXene heterostructures exhibit superior high-rate performance, making them promising high-power and high-energy anode materials for lithium-ion batteries. PMID- 29707829 TI - A Dual-Stimuli-Responsive Sodium-Bromine Battery with Ultrahigh Energy Density. AB - Stimuli-responsive energy storage devices have emerged for the fast-growing popularity of intelligent electronics. However, all previously reported stimuli responsive energy storage devices have rather low energy densities (<250 Wh kg-1 ) and single stimuli-response, which seriously limit their application scopes in intelligent electronics. Herein, a dual-stimuli-responsive sodium-bromine (Na//Br2 ) battery featuring ultrahigh energy density, electrochromic effect, and fast thermal response is demonstrated. Remarkably, the fabricated Na//Br2 battery exhibits a large operating voltage of 3.3 V and an energy density up to 760 Wh kg 1 , which outperforms those for the state-of-the-art stimuli-responsive electrochemical energy storage devices. This work offers a promising approach for designing multi-stimuli-responsive and high-energy rechargeable batteries without sacrificing the electrochemical performance. PMID- 29707830 TI - ESRD-induced dyslipidemia-Should management of lipid disorders differ in dialysis patients? AB - Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Although numerous modifiable risk factors in the pathogenesis of CVD and its associated mortality have been identified, dyslipidemia remains to be a key focus for therapy. In this regard, significant progress has been made in reducing cardiovascular mortality via the use of lipid-lowering agents such as HMG CoA reductase inhibitors (statins). Yet, despite the disproportionate risk of CVD and mortality in patients with advanced chronic and end stage renal disease (ESRD), treatment of dyslipidemia in this patient population has not been associated with a notable improvement in outcomes. Furthermore, observational studies have not consistently found an association between dyslipidemia and poor outcomes in patients with ESRD. However, it is imperative that examination of dyslipidemia and its association with outcomes take place in the context of the many factors that are unique to kidney disease and may contribute to the abnormalities in lipid metabolism in patients with ESRD. Understanding these intricacies and distinct features will be vital not only to the interpretation of the available clinical data in regards to outcomes, but also to the individualization of lipid therapy in ESRD. In this review, we will examine the nature and underlying mechanisms responsible for dyslipidemia, the association of serum lipids and lipoprotein concentrations with outcomes and the results of major trials targeting cholesterol (mainly statins) in patients with ESRD. PMID- 29707831 TI - Aligning Ag Nanowires by a Facile Bioinspired Directional Liquid Transfer: Toward Anisotropic Flexible Conductive Electrodes. AB - Recent years have witnessed the booming development of transparent flexible electrodes (TFEs) for their applications in electronics and optoelectronic devices. Various strategies have thus been developed for preparing TFEs with higher flexibility and conductivity. However, little work has focused on TFEs with anisotropic conductivity. Here, a facile strategy of directional liquid transfer is proposed, guided by a conical fibers array (CFA), based on which silver nanowires (AgNWs) are aligned on a soft poly(ethylene terephthalate) substrate in large scale. After further coating a second thin layer of the conductive polymer poly(3,4-ethylenedioxythiophene):poly(styrenesulfonate), a TFE with notable anisotropic conductivity and excellent optical transmittance of 95.2% is prepared. It is proposed that the CFA enables fine control over the receding of the three-phase contact line during the dewetting process, where AgNWs are guided and aligned by the as-generated directional stress. Moreover, anisotropic electrochemical deposition is enabled where the Cu nanoparticles deposit only on the oriented AgNWs, leading to a surface with anisotropic wetting behavior. Importantly, the approach enables alignment of AgNWs via multiple directions at one step. It is envisioned that the as-developed approach will provide an optional approach for simple and low-cost preparation of TFE with various functions. PMID- 29707832 TI - Dealing with competing risks in clinical trials: How to choose the primary efficacy analysis? AB - We investigate different primary efficacy analysis approaches for a 2-armed randomized clinical trial when interest is focused on a time to event primary outcome that is subject to a competing risk. We extend the work of Friedlin and Korn (2005) by considering estimation as well as testing and by simulating the primary and competing events' times from both a cause-specific hazards model as well as a joint subdistribution-cause-specific hazards model. We show that the cumulative incidence function can provide useful prognostic information for a particular patient but is not advisable for the primary efficacy analysis. Instead, it is preferable to fit a Cox model for the primary event which treats the competing event as an independent censoring. This is reasonably robust for controlling type I error and treatment effect bias with respect to the true primary and competing events' cause-specific hazards model, even when there is a shared, moderately prognostic, unobserved baseline frailty for the primary and competing events in that model. However, when it is plausible that a strongly prognostic frailty exists, combining the primary and competing events into a composite event should be considered. Finally, when there is an a priori interest in having both the primary and competing events in the primary analysis, we compare a bivariate approach for establishing overall treatment efficacy to the composite event approach. The ideas are illustrated by analyzing the Women's Health Initiative clinical trials sponsored by the National Heart, Lung, and Blood Institute. PMID- 29707833 TI - Site-Selective Catalysis of a Multifunctional Linear Molecule: The Steric Hindrance of Metal-Organic Framework Channels. AB - The site-selective reaction of a multifunctional linear molecule requires a suitable catalyst possessing both uniform narrow channel to limit the molecule rotation and a designed active site in the channel. Recently, nanoparticles (NPs) were incorporated in metal-organic frameworks (MOFs) with the tailorable porosity and ordered nanochannel, which makes these materials (NPs/MOFs) highly promising candidates as catalytic nanoreactors in the field of heterogeneous catalysis. Inspired by a "Gondola" sailing in narrow "Venetian Canal" without sufficient space for a U-turn, a simple heterogeneous catalyst based on NPs/MOFs is developed that exhibits site-selectivity for the oxidation of diols by restricting the random rotation of the molecule (the "Gondola") in the limited space of the MOF channel (the narrow "Venetian Canal"), thereby protecting the middle functional group via steric hindrance. This strategy is not limited to the oxidation of diols, but can be extended to the site-selective reaction of many similar multifunctional linear molecules, such as the reduction of alkadienes. PMID- 29707834 TI - Analysis of diffusion tensor measurements of the human cervical spinal cord based on semiautomatic segmentation of the white and gray matter. AB - BACKGROUND: Segmentation of the gray and white matter (GM, WM) of the human spinal cord in MRI images as well as the analysis of spinal cord diffusivity are challenging. When appropriately segmented, diffusion tensor imaging (DTI) of the spinal cord might be beneficial in the diagnosis and prognosis of several diseases. PURPOSE: To evaluate the applicability of a semiautomatic algorithm provided by ITK-SNAP in classification mode (CLASS) for segmenting cervical spinal cord GM, WM in MRI images and analyzing DTI parameters. STUDY TYPE: Prospective. SUBJECTS: Twenty healthy volunteers. SEQUENCES: 1.5T, turbo spin echo, fast field echo, single-shot echo planar imaging. ASSESSMENT: Three raters segmented the tissues by manual, CLASS, and atlas-based methods (Spinal Cord Toolbox, SCT) on T2 -weighted and DTI images. Masks were quantified by similarity and distance metrics, then analyzed for repeatability and mutual comparability. Masks created over T2 images were registered into diffusion space and fractional anisotropy (FA) values were statistically evaluated for dependency on method, rater, or tissue. STATISTICAL TESTS: t-test, analysis of variance (ANOVA), coefficient of variation, Dice coefficient, Hausdorff distance. RESULTS: CLASS segmentation reached better agreement with manual segmentation than did SCT (P < 0.001). Intra- and interobserver repeatability of SCT was better for GM and WM (both P < 0.001) but comparable with CLASS in entire spinal cord segmentation (P = 0.17 and P = 0.07, respectively). While FA values of whole spinal cord were not influenced by choice of segmentation method, both semiautomatic methods yielded lower FA values (P < 0.005) for GM than did the manual technique (mean differences 0.02 and 0.04 for SCT and CLASS, respectively). Repeatability of FA values for all methods was sufficient, with mostly less than 2% variance. DATA CONCLUSION: The presented semiautomatic method in combination with the proposed approach to data registration and analyses of spinal cord diffusivity can potentially be used as an alternative to atlas-based segmentation. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1217 1227. PMID- 29707835 TI - Influence of Physicochemical Properties of Lipopeptide Adjuvants on the Immune Response: A Rationale for Engineering a Potent Vaccine. AB - Adjuvant development and understanding the physicochemical properties of particles and interpreting the subsequent immunological responses is a challenge faced by many researchers in the vaccine field. We synthesized and investigated the physicochemical properties and immunogenicity of a library of multiple epitope self-adjuvant lipopeptides in a novel asymmetric arrangement. Vaccine candidates were synthesized using a combination of solid-phase peptide synthesis and copper-mediated click chemistry. In vivo studies showed that vaccine constructs containing a single OVA CD8+ T-cell epitope and two N-terminally located C16 lipid moieties were more effective at generating robust cellular immune responses compared to the same molecule containing multiple copies of the OVA CD8+ T-cell epitope with or without the C16 moieties. Furthermore, attachment of the two C16 lipids to the N-terminus provoked formation of long beta-sheet fibrils and was shown to induce a higher CD8+ donor T-cell frequency and IFN gamma secretion, compared to vaccine constructs with an internal lipid placement. A regression analysis indicated that particle secondary structure had a significant impact on CD8+ donor T-cell frequency and cytolytic activity. In addition, IFN-gamma production was influenced significantly by particle shape. The findings of this research will impact the future design of a vaccine intended to elicit cellular immune responses. PMID- 29707836 TI - Lack of evidence for human serum albumin as major source of HEV infections. PMID- 29707837 TI - Self-Assembled "Breathing" Grana-Like Cisternae Stacks. AB - Membranes in cells display elaborate, dynamic morphologies intimately tied to defined cellular functions. Cisternae stacks are a common membrane morphology in cells widely found in organelles. However, compared with the well-studied spherical cell membrane mimics, cisternae stacks as organelle membrane mimics are greatly neglected because of the difficulty of fabricating this unique structure. Herein, the grana-like cisternae stacks are assembled via the reorganization of stacked microsized bicelles to mimic grana functions. The cisternae stacks are connected by fusion regions between adjacent cisternae. The number of cisternae can be controlled from ~4 to 15 by the variation of ethanol volume percentage. Under the stimulation of solvent or negatively charged nanoparticles, the cisternae stacks can reversibly compress and expand, similar to the "breathing" property of natural grana. During the "breathing" process, nanoparticles are reversibly captured and released. Frequency resonance energy transfer is realized on the cisternae stacks trapped with two kinds of quantum dots. The cisternae stacks provide advanced membrane model for cell biotechnology, and clues for the shaping of organelles composed of cisternae. The ability of the cisternae stacks to capture materials enables them to possibly be applied in biomimetics and the design of advanced functional materials. PMID- 29707838 TI - Metal-Free 2D/2D Phosphorene/g-C3 N4 Van der Waals Heterojunction for Highly Enhanced Visible-Light Photocatalytic H2 Production. AB - The generation of green hydrogen (H2 ) energy using sunlight is of great significance to solve the worldwide energy and environmental issues. Particularly, photocatalytic H2 production is a highly promising strategy for solar-to-H2 conversion. Recently, various heterostructured photocatalysts with high efficiency and good stability have been fabricated. Among them, 2D/2D van der Waals (VDW) heterojunctions have received tremendous attention, since this architecture can promote the interfacial charge separation and transfer and provide massive reactive centers. On the other hand, currently, most photocatalysts are composed of metal elements with high cost, limited reserves, and hazardous environmental impact. Hence, the development of metal-free photocatalysts is desirable. Here, a novel 2D/2D VDW heterostructure of metal free phosphorene/graphitic carbon nitride (g-C3 N4 ) is fabricated. The phosphorene/g-C3 N4 nanocomposite shows an enhanced visible-light photocatalytic H2 production activity of 571 umol h-1 g-1 in 18 v% lactic acid aqueous solution. This improved performance arises from the intimate electronic coupling at the 2D/2D interface, corroborated by the advanced characterizations techniques, e.g., synchrotron-based X-ray absorption near-edge structure, and theoretical calculations. This work not only reports a new metal-free phosphorene/g-C3 N4 photocatalyst but also sheds lights on the design and fabrication of 2D/2D VDW heterojunction for applications in catalysis, electronics, and optoelectronics. PMID- 29707839 TI - Fabric Organic Electrochemical Transistors for Biosensors. AB - Flexible fabric biosensors can find promising applications in wearable electronics. However, high-performance fabric biosensors have been rarely reported due to many special requirements in device fabrication. Here, the preparation of organic electrochemical transistors (OECTs) on Nylon fibers is reported. By introducing metal/conductive polymer multilayer electrodes on the fibers, the OECTs show very stable performance during bending tests. The devices with functionalized gates are successfully used as various biosensors with high sensitivity and selectivity. The fiber-based OECTs are woven together with cotton yarns successfully by using a conventional weaving machine, resulting in flexible and stretchable fabric biosensors with high performance. The fabric sensors show much more stable signals in the analysis of moving aqueous solutions than planar devices due to a capillary effect in fabrics. The fabric devices are integrated in a diaper and remotely operated by using a mobile phone, offering a unique platform for convenient wearable healthcare monitoring. PMID- 29707840 TI - Perineural invasion: Independent prognostic factor in oral cancer that warrants adjuvant treatment. AB - BACKGROUND: Controversy exists regarding the administration of adjuvant radiotherapy (RT) when perineural invasion (PNI) is the only adverse histological feature. The purpose of this study was to evaluate the impact of PNI on the survival of patients with oral cavity squamous cell carcinoma (SCC). METHODS: A retrospective study of 1524 treatment naive patients with oral cavity SCC who underwent surgery from January 2012 to March 2015 was conducted. Survival analysis was performed using Cox regression model. RESULTS: The incidence of PNI was 20.3% and higher in tongue cancers (odds ratio 2.43). The PNI significantly affected both disease-free survival (DFS; hazard ratio [HR] 1.84) as well as overall survival (OS; HR 1.7). Patients with early node-negative oral cavity SCC with PNI are more likely to develop recurrences and have mortality (HR 2.79 for DFS; HR 2.54 for OS). However, the addition of adjuvant radiation in these patients showed improvement in survival (p = .022). Forest plot analysis showed a trend toward poor survival across all subgroups in patients with PNI. CONCLUSION: Aggressive treatment of the primary cancer with the coincident management of the neck is important in the presence of PNI. The PNI worsens survival and warrants intensification of adjuvant treatment. PMID- 29707841 TI - Activatable Semiconducting Theranostics: Simultaneous Generation and Ratiometric Photoacoustic Imaging of Reactive Oxygen Species In Vivo. AB - Enhancing the generation of reactive oxygen species (ROS) is an effective anticancer strategy. However, it is a great challenge to control the production and to image ROS in vivo, both of which are vital for improving the efficacy and accuracy of cancer therapy. Herein, an activatable semiconducting theranostic nanoparticle (NP) platform is developed that can simultaneously enhance ROS generation while self-monitoring its levels through ratiometric photoacoustic (PA) imaging. The NP platform can further guide in vivo therapeutic effect in tumors. The theranostic NP platform is composed of: (i) cisplatin prodrug and ferric ion catalyst for ROS generation, a part of combination cancer therapy; and (ii) a ratiometric PA imaging nanoprobe consisting of inert semiconducting perylene-diimide (PDI) and ROS activatable near-infrared dye (IR790s), used in ratiometric PA imaging of ROS during cancer treatment. Ratiometric PA signals are measured at two near-infrared excitation wavelengths: 680 and 790 nm for PDI and IR790s, respectively. The measurements show highly accurate visualization of * OH generation in vivo. This novel ROS responsive organic theranostic NP allows not only synergistic cancer chemotherapy but also real-time monitoring of the therapeutic effect through ratiometric PA imaging. PMID- 29707842 TI - Socio-economic disadvantage is associated with heavier drinking in high but not middle-income countries participating in the International Alcohol Control Study. AB - INTRODUCTION AND AIMS: To investigate if socio-economic disadvantage, at the individual- and country-level, is associated with heavier drinking in some middle and high-income countries. DESIGN AND METHODS: Surveys of drinkers were undertaken in some high- and middle-income countries. Participating countries were Australia, England, New Zealand, Scotland (high-income) and Peru, Thailand and Vietnam (middle-income). Disadvantage at the country-level was defined as per World Bank (categorised as middle-or high-income); individual-level measures were (i) years of education and (ii) whether and individual was under or over the poverty line in each country. Measures of heavier drinking were (i) proportion of drinkers that consumed 8+ drinks and (ii) three drinking risk groups (lower, increasing and higher). Multi-level logistic regression models were used. RESULTS: Individual-level measures of disadvantage, lower education and living in poverty, were associated with heavier drinking, consuming 8+ drinks on a typical occasion or drinking at the higher risk level, when all countries were considered together. Drinkers in the middle-income countries had a higher probability of consuming 8+ drinks on a typical occasion relative to drinkers in the high-income countries. Interactions between country-level income and individual-level disadvantage were undertaken: disadvantaged drinkers in the middle-income countries were less likely to be heavier drinkers relative to those with less disadvantage in the high-income countries. DISCUSSION AND CONCLUSIONS: Associations between socio-economic disadvantage and heavier drinking vary depending on country-level income. These findings highlight the value of exploring cross-country differences in heavier drinking and disadvantage and the importance of including country-level measurements to better elucidate relationships. PMID- 29707843 TI - Children with kawasaki disease present elevated stiffness of great arteries: Phase-contrast MRI study. AB - BACKGROUND: Patients with diagnosed Kawasaki disease (KD) are known to develop extracardiac vascular lesions and are prone to accelerated stiffening of medium size arteries. PURPOSE: To noninvasively evaluate great vessel (central aorta and main pulmonary artery (MPA)) stiffness using phase-contrast MRI (PC-MRI). STUDY TYPE: Retrospective review. SUBJECTS: Thirty-three patients with previously diagnosed KD and 15 control subjects underwent PC-MRI evaluation. FIELD STRENGTH/SEQUENCE: A free-breathing PC-MRI sequence was applied with Cartesian encoding and retrospective sorting using a 1.5 or 3.0T system. ASSESSMENT: We evaluated regionally specific vessel stiffness using pulse-wave velocity (PWV) and relative area change (RAC) at the ascending aorta, descending aorta, and MPA. STATISTICAL TESTS: Hemodynamics among patients with KD and controls were compared using Student's t-test, Wilcoxon Rank-sum, and chi2 . Additional group-specific comparisons were performed using Kruskal-Wallis or one-way analysis of variance (ANOVA). RESULTS: Patients with KD showed elevated PWV in both ascending (5.0 +/- 1.2 vs. 2.4 +/- 0.5, P < 0.001) and descending aorta (4.4 +/- 2.1 vs. 2.8 +/- 0.8, P < 0.001). RAC was correspondingly reduced in both segments (both P < 0.01). PWV measured in MPA was increased in KD patients (2.2 +/- 0.5 vs. 1.5 +/- 0.6, P = 0.045) while the RAC was reduced (34 +/- 6 vs. 47 +/- 3, P = 0.045). There were no associations between considered vessel stiffness indices and respective ventricular size and function, functional indices, and no correlations were observed with KD severity markers. DATA CONCLUSION: Patients with KD have elevated great vessel stiffness measured at the chronic stage of the disease. Accelerated stiffness process does not appear to affect biventricular function in youth Level of Evidence: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1228-1236. PMID- 29707844 TI - Additional palmaroproximal-palmarodistal oblique radiographic projections improve accuracy of detection and characterization of equine flexor cortical lysis. AB - Radiographic flexor cortical lysis indicates advanced degenerative change and its earlier recognition may improve case outcome. Aims of this prospective, diagnostic accuracy study were to determine effects of radiographic beam angle and observer on accuracy of lesion detection. The sample included 36 limbs from 31 horses. Palmaroproximal-palmarodistal oblique (skyline) radiographs were acquired at standard (n = 38) and more shallow (alternate) angles (n = 58). Images were independently reviewed by four experience levels of five observers each (n = 20) for the presence and severity of flexor cortical lysis. Observers also reported their confidence in these answers. Responses were compared based on seeing a standard skyline or multiple projections. The definitive presence (or absence) and severity of lysis was based upon radiologist consensus agreement. When assessed by observer, the identification of lysis and the assessment of its severity was most similar to that of radiologists when observers of all levels of experience were able to view multiple skyline projections (P = 0.399, P = 0.174). Using multiple views to detect lysis resulted in improved sensitivity (85.3% vs. 97.2%, P < 0.001), decreased specificity (82.8% vs. 74.5%, P = 0.03), and improved interobserver agreement (86.0% vs. 90.2%, P = 0.21). On average, observers of all levels of experience became more confident viewing multiple projections (P < 0.001). Skyline radiographs using a flatter angle of incidence improve radiographic detection and characterization of flexor cortical lysis severity, may allow the beam to be tangential to the more distal portion of the navicular bone, and are recommended when flexor cortical lysis is suspected. PMID- 29707845 TI - Ultra-high-b radial diffusion-weighted imaging (UHb-rDWI) of human cervical spinal cord. AB - BACKGROUND: Injury in the cervical spinal cord (CSC) can lead to varying degrees of neurologic deficit and persistent disability. Diffusion tensor imaging (DTI) is a promising method to evaluate white matter integrity and pathology. However, the conventional DTI results are limited with respect to the specific details of neuropathology and microstructural architecture. In this study we used ultrahigh b radial-DWI (UHb-rDWI) with b-values ranging from 0 to ~7500 s/mm2 and calculated decay constant (DH ) at the high b-values, which gives much deeper insight about the microscopic environment of CSC white matter. PURPOSE: To evaluate a novel diffusion MRI, UHb-rDWI technique for imaging of the CSC. STUDY TYPE: Longitudinal. SUBJECTS: Four healthy controls, each scanned twice. FIELD STRENGTH/SEQUENCE: 3T/2D single shot diffusion-weighted stimulated echo planar imaging with reduced field of view. ASSESSMENT: The signal from each pixel of b0 (b = 0) and b-value (b ? 0) images were fitted to a biexponential function and normalized. The signal-b curve is obtained by dividing the latter curve by the former. DH was obtained from the curve at b >4000 s/mm2 . A Monte-Carlo Simulation (MCS) was performed to investigate how DH changes upon the increased water-exchange at the CSC. RESULTS: The signal-b curves plotted at multiple levels of healthy CSC are almost identical on two successive scans and show a biexponential decay behavior: fast exponential decay at lower b-values and much slower decay at UHb-values. The mean values of DH were measured as (0.0607 +/- 0.02531) *10-3 and (0.0357 +/- 0.02072) *10-3 s/mm2 at the lateral funiculus and posterior column, respectively. MCS of diffusion MRI shows that the DH is elevated by increased water exchange between the intra- and extraaxonal spaces. DATA CONCLUSION: UHb-rDWI signal-b plots of the normal CSC were highly reproducible on successive scans and their biexponential decay behavior can be used to characterize normal spinal white matter. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018. PMID- 29707846 TI - Atom-by-Atom Fabrication of Monolayer Molybdenum Membranes. AB - Fabrication of materials in the monolayer regime to acquire fascinating physical properties has attracted enormous interest during the past decade, and remarkable success has been achieved for layered materials adopting weak interlayer van der Waals forces. However, the fabrication of monolayer metal membranes possessing strong intralayer bonding remains elusive. Here, suspended monolayer Mo membranes are fabricated from monolayer MoSe2 films via selective electron beam (e-beam) ionization of Se atoms by scanning transmission electron microscopy (STEM). The nucleation and subsequent growth of the Mo membranes are triggered by the formation and aggregation of Se vacancies as seen by atomic resolution sequential STEM imaging. Various novel structural defects and intriguing self-healing characteristics are unveiled during the growth. In addition, the monolayer Mo membrane is highly robust under the e-beam irradiation. It is likely that other metal membranes can be fabricated in a similar manner, and these pure metal-based 2D materials add to the diversity of 2D materials and introduce profound novel physical properties. PMID- 29707847 TI - Signatures of local adaptation along environmental gradients in a range-expanding damselfly (Ischnura elegans). AB - Insect distributions are shifting rapidly in response to climate change and are undergoing rapid evolutionary change. We investigate the molecular signatures underlying local adaptation in the range-expanding damselfly, Ischnura elegans. Using a landscape genomic approach combined with generalized dissimilarity modelling (GDM), we detect selection signatures on loci via allelic frequency change along environmental gradients. We analyse 13,612 single nucleotide polymorphisms (SNPs), derived from restriction site-associated DNA sequencing (RADseq), in 426 individuals from 25 sites spanning the I. elegans distribution in Sweden, including its expanding northern range edge. Environmental association analysis (EAA) and the magnitude of allele frequency change along the range expansion gradient revealed significant signatures of selection in relation to high maximum summer temperature, high mean annual precipitation and low wind speeds at the range edge. SNP annotations with significant signatures of selection revealed gene functions associated with ongoing range expansion, including heat shock proteins (HSP40 and HSP70), ion transport (V-ATPase) and visual processes (long-wavelength-sensitive opsin), which have implications for thermal stress response, salinity tolerance and mate discrimination, respectively. We also identified environmental thresholds where climate-mediated selection is likely to be strong, and indicate that I. elegans is rapidly adapting to the climatic environment during its ongoing range expansion. Our findings empirically validate an integrative approach for detecting spatially explicit signatures of local adaptation along environmental gradients. PMID- 29707848 TI - Assessment of a high-SNR chemical-shift-encoded MRI with complex reconstruction for proton density fat fraction (PDFF) estimation overall and in the low-fat range. AB - BACKGROUND: Improving the signal-to-noise ratio (SNR) of chemical-shift-encoded MRI acquisition with complex reconstruction (MRI-C) may improve the accuracy and precision of noninvasive proton density fat fraction (PDFF) quantification in patients with hepatic steatosis. PURPOSE: To assess the accuracy of high SNR (Hi SNR) MRI-C versus standard MRI-C acquisition to estimate hepatic PDFF in adult and pediatric nonalcoholic fatty liver disease (NAFLD) using an MR spectroscopy (MRS) sequence as the reference standard. STUDY TYPE: Prospective. POPULATION/SUBJECTS: In all, 231 adult and pediatric patients with known or suspected NAFLD. FIELD STRENGTH/SEQUENCE: PDFF estimated at 3T by three MR techniques: standard MRI-C; a Hi-SNR MRI-C variant with increased slice thickness, decreased matrix size, and no parallel imaging; and MRS (reference standard). ASSESSMENT: MRI-PDFF was measured by image analysts using a region of interest coregistered with the MRS-PDFF voxel. STATISTICAL TESTS: Linear regression analyses were used to assess accuracy and precision of MRI-estimated PDFF for MRS-PDFF as a function of MRI-PDFF using the standard and Hi-SNR MRI-C for all patients and for patients with MRS-PDFF <10%. RESULTS: In all, 271 exams from 231 patients were included (mean MRS-PDFF: 12.6% [SD: 10.4]; range: 0.9 41.9). High agreement between MRI-PDFF and MRS-PDFF was demonstrated across the overall range of PDFF, with a regression slope of 1.035 for the standard MRI-C and 1.008 for Hi-SNR MRI-C. Hi-SNR MRI-C, compared to standard MRI-C, provided small but statistically significant improvements in the slope (respectively, 1.008 vs. 1.035, P = 0.004) and mean bias (0.412 vs. 0.673, P < 0.0001) overall. In the low-fat patients only, Hi-SNR MRI-C provided improvements in the slope (1.058 vs. 1.190, P = 0.002), mean bias (0.168 vs. 0.368, P = 0.007), intercept ( 0.153 vs. -0.796, P < 0.0001), and borderline improvement in the R2 (0.888 vs. 0.813, P = 0.01). DATA CONCLUSION: Compared to standard MRI-C, Hi-SNR MRI-C provides slightly higher MRI-PDFF estimation accuracy across the overall range of PDFF and improves both accuracy and precision in the low PDFF range. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 29707849 TI - 3D-Printable Photochromic Molecular Materials for Reversible Information Storage. AB - The formulation of advanced molecular materials with bespoke polymeric ionic liquid matrices that stabilize and solubilize hybrid organic-inorganic polyoxometalates and allow their processing by additive manufacturing, is effectively demonstrated. The unique photo and redox properties of nanostructured polyoxometalates are translated across the scales (from molecular design to functional materials) to yield macroscopic functional devices with reversible photochromism. These properties open a range of potential applications including reversible information storage based on controlled topological and temporal reduction/oxidation of pre-formed printed devices. This approach pushes the boundaries of 3D printing to the molecular limits, allowing the freedom of design enabled by 3D printing to be coupled with the molecular tuneability of polymerizable ionic liquids and the photoactivity and orbital engineering possible with hybrid polyoxometalates. PMID- 29707850 TI - Creating Lithium-Ion Electrolytes with Biomimetic Ionic Channels in Metal-Organic Frameworks. AB - Solid-state electrolytes are the key to the development of lithium-based batteries with dramatically improved energy density and safety. Inspired by ionic channels in biological systems, a novel class of pseudo solid-state electrolytes with biomimetic ionic channels is reported herein. This is achieved by complexing the anions of an electrolyte to the open metal sites of metal-organic frameworks (MOFs), which transforms the MOF scaffolds into ionic-channel analogs with lithium-ion conduction and low activation energy. This work suggests the emergence of a new class of pseudo solid-state lithium-ion conducting electrolytes. PMID- 29707851 TI - Should I stay or should I go? Nurses' wishes to leave nursing homes and home nursing. AB - AIMS: This study investigates the prevalence of nurses' wishes to leave work in elderly care services and aims to explain differences between younger and older nurses. BACKGROUND: Health-and-care services, and specifically elderly care services, experience problems recruiting and retaining nurses. METHOD: A nationwide survey among nurses in Norway with 4,945 nurses aged 20-73 (mean age = 41.8), 95% female. Structural equation modelling was used, analysing the whole sample as well as analysing younger and older nurses as separate groups. RESULTS: Of the nurses surveyed, 25% wanted to work outside elderly care services and 25% were uncertain. The wish to leave was much more frequent among younger nurses. Reported working conditions were a strong predictor of the wish to leave, and a much stronger predictor among younger nurses than older nurses in nursing homes. CONCLUSIONS: Working conditions are a major predictor of nurses' wishes to leave elderly care services, especially among younger nurses in nursing homes. IMPLICATIONS FOR NURSING MANAGEMENT: Attempts to reduce turnover in elderly care services need to address the working conditions for younger nurses, for instance by reducing the time young nurses work in isolation. PMID- 29707852 TI - Dentinal tubule occluding capability of nano-hydroxyapatite; The in-vitro evaluation. AB - In this in-vitro study, the effectiveness of experimental pure nano hydroxyapatite (nHAP) and 1%, 2%, and 3% F- doped nano-HAp on dentine tubule occlusion was investigated. And also, the cytotoxicity of materials used in the experiment was evaluated. Nano-HAp types were synthesized by the precipitation method. Forty dentin specimens were randomly divided into five groups of; 1-no treatment (control), 2-specimens treated with 10% pure nano-HAp and 3, 4, 5 specimens treated with 1%, 2%, and 3% F- doped 10% nano-HAp, respectively. To evaluate the effectiveness of the materials used; pH, FTIR, and scanning electron microscopy evaluations were performed before and after degredation in simulated body fluid. To determine cytotoxicity of the materials, MTT assay was performed. Statistical evaluations were performed with F and t tests. All of the nano-HAp materials used in this study built up an effective covering layer on the dentin surfaces even with plugs in tubules. It was found that this layer had also a resistance to degradation. None of the evaluated nano-HAp types were have toxicity. Fluoride doping showed a positive effect on physical and chemical stability until a critical value of 1% F- . The all evaluated nano-HAp types may be effectively used in dentin hypersensitivity treatment. The formed nano-HAp layers were seem to resistant to hydrolic deletion. The pure and 1% F- doped nano HAp showed the highest biocompatibility thus it was assessed that pure and 1% F- doped materials may be used as an active ingredient in dentin hypersensitivity agents. PMID- 29707853 TI - Blood utilisation in a developing society: what is the best index of efficiency? AB - OBJECTIVES: To assess blood usage for elective surgery in a developing country as a first step towards developing a maximum surgical blood-ordering schedule (MSBOS). BACKGROUND: Cross-match:transfusion (C/T) ratio, transfusion index (Ti ) and transfusion ratio (T%) are standard indices of efficient blood usage for elective surgical procedures. The MSBOS assigns surgical procedures to Group and Cross Match (GXM) and Group and Save (G&S) categories. Non-use probability (NUP) is the percentage of blood that is requested but not used. Trinidad and Tobago (TTO) has a transfusion service that predominantly uses family replacement (F/R) donors. MATERIALS/METHODS: C/T ratio, Ti , T% and NUP were retrospectively calculated for 304 elective surgical procedures performed at a tertiary medical institution in TTO between 1st January and 15th May 2013. RESULTS: For 17 types of surgical procedure, C/T ratio was <2.5 for 10, T% >= 30 for 10 and Ti >= 0.5 for 12, suggesting efficiency, significant blood use and a requirement for GXM for most operations. However, the majority of these procedures qualify for G&S when performed under conditions that guarantee ready access to blood in an emergency. A substantial proportion of issued blood was returned unused to the blood bank, giving an NUP of 39.7%. CONCLUSION: NUP was the most sensitive measure of efficiency. C/T ratio, T% and Ti must be interpreted in the context of the blood donation system. An internationally accepted value of NUP that equates to efficient blood use should be adopted. PMID- 29707854 TI - Dual-Function Electrocatalytic and Macroporous Hollow-Fiber Cathode for Converting Waste Streams to Valuable Resources Using Microbial Electrochemical Systems. AB - Dual-function electrocatalytic and macroporous hollow-fiber cathodes are recently proposed as promising advanced material for maximizing the conversion of waste streams such as wastewater and waste CO2 to valuable resources (e.g., clean freshwater, energy, value-added chemicals) in microbial electrochemical systems. The first part of this progress report reviews recent developments in this type of cathode architecture for the simultaneous recovery of clean freshwater and energy from wastewater. Critical insights are provided on suitable materials for fabricating these cathodes, as well as addressing some challenges in the fabrication process with proposed strategies to overcome them. The second and complementary part of the progress report highlights how the unique features of this cathode architecture can solve one of the intrinsic bottlenecks (gas-liquid mass transfer limitation) in the application of microbial electrochemical systems for CO2 reduction to value-added products. Strategies to further improve the availability of CO2 to microbial catalysts on the cathode are proposed. The importance of understanding microbe-cathode interactions, as well as electron transfer mechanisms at the cathode-cell and cell-cell interface to better design dual-function macroporous hollow-fiber cathodes, is critically discussed with insights on how the choice of material is important in facilitating direct electron transfer versus mediated electron transfer. PMID- 29707855 TI - Random forests of interaction trees for estimating individualized treatment effects in randomized trials. AB - Assessing heterogeneous treatment effects is a growing interest in advancing precision medicine. Individualized treatment effects (ITEs) play a critical role in such an endeavor. Concerning experimental data collected from randomized trials, we put forward a method, termed random forests of interaction trees (RFIT), for estimating ITE on the basis of interaction trees. To this end, we propose a smooth sigmoid surrogate method, as an alternative to greedy search, to speed up tree construction. The RFIT outperforms the "separate regression" approach in estimating ITE. Furthermore, standard errors for the estimated ITE via RFIT are obtained with the infinitesimal jackknife method. We assess and illustrate the use of RFIT via both simulation and the analysis of data from an acupuncture headache trial. PMID- 29707856 TI - Enteric neural stem cell therapies for enteric neuropathies. AB - BACKGROUND: Enteric neuropathies exist as a wide range of human disorders which impact on gastrointestinal motility. Current standard therapies for enteric neuropathies are limited to surgical resection or manipulation (eg, myotomy) of affected gut segments or medical management including both therapy (eg, prokinetic pharmacotherapy) and support such as parenteral nutrition. However, such treatments often result in poor prognosis and significant morbidity. The current limitations in treatment options for enteric neuropathies underline the need for alternative approaches to treat these devastating diseases. Recent advances have highlighted the potential of enteric neural stem cells as a possible treatment option for regenerative medicine, in such cases. PURPOSE: The purpose of this review is to provide an up-to-date synopsis of the enteric neural stem cell research field. Here, we review in detail the initial characterization of enteric neural stem cells, early preclinical studies validating their use in murine models through to the most recent findings of therapeutic rescue of diseased gut tissue. We additionally pose a number of questions regarding these recent findings which will need to be addressed prior to clinical translation of this exciting cellular therapeutic. PMID- 29707857 TI - Self-Healing Proton-Exchange Membranes Composed of Nafion-Poly(vinyl alcohol) Complexes for Durable Direct Methanol Fuel Cells. AB - Proton-exchange membranes (PEMs) that can heal mechanical damage to restore original functions are important for the fabrication of durable and reliable direct methanol fuel cells (DMFCs). The fabrication of healable PEMs that exhibit satisfactory mechanical stability, enhanced proton conductivity, and suppressed methanol permeability via hydrogen-bonding complexation between Nafion and poly(vinyl alcohol) (PVA) followed by postmodification with 4-carboxybenzaldehyde (CBA) molecules is presented. Compared with pure Nafion, the CBA/Nafion-PVA membranes exhibit enhanced mechanical properties with an ultimate tensile strength of ~20.3 MPa and strain of ~380%. The CBA/Nafion-PVA membrane shows a proton conductivity of 0.11 S cm-1 at 80 degrees C, which is 1.2-fold higher than that of a Nafion membrane. The incorporated PVA gives the CBA/Nafion-PVA membranes excellent proton conductivity and methanol resistance. The resulting CBA/Nafion-PVA membranes are capable of healing mechanical damage of several tens of micrometers in size and restoring their original proton conductivity and methanol resistance under the working conditions of DMFCs. The healing property originates from the reversibility of hydrogen-bonding interactions between Nafion and CBA-modified PVA and the high chain mobility of Nafion and CBA-modified PVA. PMID- 29707858 TI - On-Chip Spiral Waveguides for Ultrasensitive and Rapid Detection of Nanoscale Objects. AB - Ultrasensitive and rapid detection of nano-objects is crucial in both fundamental studies and practical applications. Optical sensors using evanescent fields in microcavities, plasmonic resonators, and nanofibers allow label-free detection down to single molecules, but practical applications are severely hindered by long response time and device reproducibility. Here, an on-chip dense waveguide sensor to monitor single unlabeled nanoparticles in a strong optical evanescent field is demonstrated. The spiral nanowaveguide design enables two orders of magnitude enhancement in sensing area compared to a straight waveguide, significantly improving the particle capture ability and shortening the target analysis time. In addition, the measurement noise is suppressed to a level of 10 4 in the transmitted power, pushing the detection limit of single particles down to the size of 100 nm. The waveguide sensor on the silicon-on-isolator platform can be fabricated reproducibly by the conventional semiconductor processing and compatible with surface functionalization chemistries and microfluidics, which could lead to widespread use for sensing in environmental monitoring and human health. PMID- 29707860 TI - Narrative intelligence in nursing: Storying patient lives in dementia care. AB - This paper examines narrative approaches to care within the context of dementia. It reviews the function of stories and explores some of the narrative genres that shape the cultural perceptions of dementia. We argue that narrative intelligence within healthcare is an important element in nurturing communal self-identity for people living with dementia. Listening and responding to stories and the cultural framework that this encompasses is an embodied action that is not just related to cognitive recall but situates us within a cultural community. People with dementia may have challenges in maintaining narrative legitimacy in the face of fractured stories and incoherent narratives. Health professionals can offer support in reframing and presenting counterstories that maintain identities that can potentially be marginalised, silenced and open to narrative foreclosure. This process requires health professionals to be attentive and responsive to how patients with dementia and their supporters construct and position the stories they tell and the meaning(s) they attach to them. PMID- 29707859 TI - Does early exposure to caffeine promote smoking and alcohol use behavior? A prospective analysis of middle school students. AB - BACKGROUND AND AIMS: Despite the negative consequences associated with caffeine use among children and youth, its use is increasingly widespread among middle school students. Cross-sectional studies reveal links between caffeine and other substance use. The potential for caffeine use to confer increased vulnerability to substance use, however, has not been investigated using prospective designs. We hypothesized that caffeine use at baseline would be associated positively with increased alcohol use, drunkenness, smoking and e-cigarette use. DESIGN: Prospective cohort study with 12 months separating baseline from follow-up. SETTING: West Virginia, USA. PARTICIPANTS: Middle school students (6th and 7th grades; n = 3932) in three West Virginia (WV) counties provided data at baseline and follow-up 12 months later. MEASUREMENTS: Youth self-reported their use of caffeine from multiple sources (e.g. soda, energy drinks, coffee and tea), cigarette smoking, electronic cigarette use, alcohol use and drunkenness. FINDINGS: Cross-lagged path models for individual substance use categories provided a good fit to the data. Controlling for demographic variables and other substance use at baseline, caffeine at time 1 (T1) was associated positively with T2 cigarette smoking (beta = 0.27, P = 0.001), e-cigarette use (beta = 0.21, P = 0.001), alcohol use (beta = 0.17, P = 0.001) and drunkenness (beta = 0.15, P = 0.001). Conversely, non-significant relations emerged between three of four substances at T1 and caffeine at T2. Positive relations were found between e cigarette use at T1 and caffeine use at T2 (beta = 0.07, P = 0.006). These findings were supported by an omnibus model with all substances included. Specifically, significant relations were observed between caffeine at T1 and all substance use outcomes at T2, whereas no significant relations were observed between substance use and caffeine over time. CONCLUSIONS: Caffeine may promote early use of other types of substances among middle school-aged adolescents. PMID- 29707861 TI - Perioperative replacement therapy in haemophilia B: An appeal to "B" more precise. AB - INTRODUCTION: Haemophilia B is caused by a deficiency of coagulation factor IX (FIX) and characterized by bleeding in muscles and joints. In the perioperative setting, patients are treated with FIX replacement therapy to secure haemostasis. Targeting of specified FIX levels is challenging and requires frequent monitoring and adjustment of therapy. AIM: To evaluate perioperative management in haemophilia B, including monitoring of FIX infusions and observed FIX levels, whereby predictors of low and high FIX levels were assessed. METHODS: In this international multicentre study, haemophilia B patients with FIX < 0.05 IU mL-1 undergoing elective, minor or major surgical procedures between 2000 and 2015 were included. Data were collected on patient, surgical and treatment characteristics. Observed FIX levels were compared to target levels as recommended by guidelines. RESULTS: A total of 255 surgical procedures were performed in 118 patients (median age 40 years, median body weight 79 kg). Sixty percent of FIX levels within 24 hours of surgery were below target with a median difference of 0.22 IU mL-1 [IQR 0.12-0.36]; while >6 days after surgery, 59% of FIX levels were above target with a median difference of 0.19 IU mL-1 [IQR 0.10 0.39]. Clinically relevant bleeding complications (necessity of a second surgical intervention or red blood cell transfusion) occurred in 7 procedures (2.7%). CONCLUSION: This study demonstrates that targeting of FIX levels in the perioperative setting is complex and suboptimal, but although this bleeding is minimal. Alternative dosing strategies taking patient and surgical characteristics as well as pharmacokinetic principles into account may help to optimize and individualize treatment. PMID- 29707862 TI - The development of fast-mapping and novel word retention strategies in monolingual and bilingual infants. AB - The mutual exclusivity (ME) assumption is proposed to facilitate early word learning by guiding infants to map novel words to novel referents. This study assessed the emergence and use of ME to both disambiguate and retain the meanings of novel words across development in 18-month-old monolingual and bilingual children (Experiment 1; N = 58), and in a sub-group of these children again at 24 months of age (Experiment 2: N = 32). Both monolinguals and bilinguals employed ME to select the referent of a novel label to a similar extent at 18 and 24 months. At 18 months, there were also no differences in novel word retention between the two language-background groups. However, at 24 months, only monolinguals showed the ability to retain these label-object mappings. These findings indicate that the development of the ME assumption as a reliable word learning strategy is shaped by children's individual language exposure and experience with language use. PMID- 29707864 TI - Training with a three-dimensional multiple object-tracking (3D-MOT) paradigm improves attention in students with a neurodevelopmental condition: a randomized controlled trial. AB - The efficacy of attention training paradigms is influenced by many factors, including the specificity of targeted cognitive processes, accuracy of outcome measures, accessibility to specialized populations, and adaptability to user capability. These issues are increasingly significant when working with children diagnosed with neurodevelopmental conditions that are characterized by attentional difficulties. This study investigated the efficacy of training attention in students with neurodevelopmental conditions using a novel three dimensional Multiple Object-Tracking (3D-MOT) task. All students (ages 6-18 years) performed the Conners Continuous Performance Task (CPT-3) as a baseline measure of attention. They were then equally and randomly assigned to one of three groups: a treatment group, (3D-MOT); an active control group (visual strategy/math-based game, 2048); and a treatment as usual group. Students were trained on their respective tasks for a total of 15 training sessions over a five week period and then reassessed on the CPT-3. Results showed that post-training CPT-3 performance significantly improved from baseline for participants in the treatment group only. This improvement indicates that training with 3D-MOT increased attentional abilities in students with neurodevelopmental conditions. These results suggest that training attention with a non-verbal, visual-based task is feasible in a school setting and accessible to atypically developing students with attentional difficulties. PMID- 29707863 TI - Glucagon-like peptide-1 receptor expression in the human eye. AB - Semaglutide is a human glucagon-like peptide-1 (GLP-1) analogue that is in development for the treatment of type 2 diabetes. In the pre-approval cardiovascular outcomes trial SUSTAIN 6, semaglutide was associated with a significant increase in the risk of diabetic retinopathy (DR) complications vs placebo. GLP-1 receptor (GLP-1R) expression has previously been demonstrated in the retina in animals and humans; however, antibodies used to detect expression have been documented to be non-specific and fail to detect the GLP-1R using immunohistochemistry (IHC), a problem common for many G-protein coupled receptors. Using a validated GLP-1R antibody for IHC and in situ hybridization for GLP-1R mRNA in normal human eyes, GLP-1Rs were detected in a small fraction of neurons in the ganglion cell layer. In advanced stages of DR, GLP-1R expression was not detected at the protein or mRNA level. Specifically, no GLP-1R expression was found in the eyes of people with long-standing proliferative DR (PDR). In conclusion, GLP-1R expression is low in normal human eyes and was not detected in eyes exhibiting advanced stages of PDR. PMID- 29707865 TI - Co-designing for quality: Creating a user-driven tool to improve quality in youth mental health services. AB - BACKGROUND: Although high quality mental health care for children and youth is a goal of many health systems, little is known about the dimensions of quality mental health care from users' perspectives. We engaged young people, caregivers and service providers to share experiences, which shed light on quality dimensions for youth mental health care. METHODS: Using experience-based co design, we collected qualitative data from young people aged 16-24 with a mental disorder (n = 19), identified caregivers (n = 12) and service providers (n = 14) about their experiences with respect to youth mental health services. Experience data were collected using multiple approaches including interviews, a suite of online and smartphone applications (n = 22), and a co-design event (n = 16) and analysed to extract touch points. These touch points were used to prioritize and co-design a user-driven prototype of a questionnaire to provide feedback to service providers. FINDINGS: Young people, caregiver and service provider reports of service experiences were used to identify aspects of care quality at eight mental health service contact points: Access to mental health care; Transfer to/from hospital; Intake into hospital; Services provided; Assessment and treatment; Treatment environment; and Caregiver involvement in care. In some cases, low quality care was harmful to users and their caregivers. Young people co-designed a prototype of a user-driven feedback questionnaire to improve quality of service experiences that was supported by service providers and caregivers at the co-design event. CONCLUSION: By using EBCD to capture in-depth data regarding experiences of young people, their caregivers and service providers, study participants have begun to establish a baseline for acceptable quality of mental health care for young people. PMID- 29707866 TI - Dorzagliatin (HMS5552), a novel dual-acting glucokinase activator, improves glycaemic control and pancreatic beta-cell function in patients with type 2 diabetes: A 28-day treatment study using biomarker-guided patient selection. AB - AIMS: To investigate the pharmacokinetics and pharmacodynamics of a dual-acting glucokinase activator, dorzagliatin, and its safety, tolerability and effect on pancreatic beta-cell function in Chinese patients with type 2 diabetes (T2D). MATERIALS AND METHODS: A total of 24 T2D patients were selected, utilizing a set of predefined clinical biomarkers, and were randomized to receive dorzagliatin 75 mg twice or once daily (BID, QD respectively) for 28 days. Changes in HbA1c and glycaemic parameters from baseline to Day 28 were assessed. In addition, changes in beta-cell function from baseline to Day 32 were evaluated. RESULTS: Significant reductions in HbA1c were observed in both regimens on Day 28 (-0.79%, 75 mg BID; -1.22%, 75 mg QD). Similar trends were found in the following parameters, including reductions from baseline in fasting plasma glucose by 1.20 mmol/L and 1.51 mmol/L, in 2-hour postprandial glucose by 2.48 mmol/L and 5.03 mmol/L, and in glucose AUC0-24 by 18.59% and 20.98%, for the BID and QD groups, respectively. Both regimens resulted in improvement in beta-cell function as measured by steady state HOMA 2 parameter, %B, which increased by 36.31% and 40.59%, and by dynamic state parameter, DeltaC30 /DeltaG30 , which increased by 24.66% and 167.67%, for the BID and QD groups, respectively. Dorzagliatin was well tolerated in both regimens, with good pharmacokinetic profiles. CONCLUSIONS: Dorzagliatin treatment for 28 days in Chinese T2D patients, selected according to predefined biomarkers, resulted in significant improvement in beta-cell function and glycaemic control. The safety and pharmacokinetic profile of dorzagliatin supports a subsequent Phase II trial design and continued clinical development. PMID- 29707867 TI - Combination of fractional carbon dioxide laser with narrow band ultraviolet B to induce repigmentation in stable vitiligo: A comparative study. AB - BACKGROUND: Despite the numerous treatment modalities available for vitiligo, responses to treatment are still unsatisfactory. For this reason, new treatment modalities and approaches are needed. OBJECTIVE: To evaluate the efficacy and safety of fractional carbon dioxide (CO2 ) laser therapy followed by narrow band ultraviolet-B (NB-UVB) phototherapy on stable resistant vitiligo. SUBJECTS AND METHODS: Thirty-two patients with stable bilateral vitiligo were enrolled. For each patient, one side of the body was treated with NB-UVB in addition to two sessions of fractional CO2 laser performed at 2-months interval (laser side), while the other side was treated with NB-UVB alone (control side). NB-UVB was administrated twice weekly for 4 months. Outcomes were evaluated objectively based on standard digital photographs, patient satisfaction, and adverse effects. RESULTS: There was statistically significant improvement in the repigmentation in laser side compared to control side. Noticeable adverse events, such as infection, scarring, and Koebner phenomenon were not found in any patient. CONCLUSIONS: Fractional CO2 laser therapy combined with NB-UVB phototherapy could be used effectively and safely as an alternative modality for the treatment of vitiligo. It shortens the duration of NB-UVB therapy and is expected to increase patient compliance. PMID- 29707869 TI - Informed Molecular Design of Conjugated Oligoelectrolytes To Increase Cell Affinity and Antimicrobial Activity. AB - Membrane-intercalating conjugated oligoelectrolytes (COEs) are emerging as potential alternatives to conventional, yet increasingly ineffective, antibiotics. Three readily accessible COEs, belonging to an unreported series containing a stilbene core, namely D4, D6, and D8, were designed and synthesized so that the hydrophobicity increases with increasing side-chain length. Decreased aqueous solubility correlates with increased uptake by E. coli. The minimum inhibitory concentration (MIC) of D8 is 4 MUg mL-1 against both E. coli and E. faecalis, with an effective uptake of 72 %. In contrast, the MIC value of the shortest COE, D4, is 128 MUg mL-1 owing to the low cellular uptake of 3 %. These findings demonstrate the application of rational design to generate efficacious antimicrobial COEs that have potential as low-cost antimicrobial agents. PMID- 29707868 TI - Transarterial chemoembolization in children to treat unresectable hepatocellular carcinoma. AB - Children with unresectable HCC have a dismal prognosis and few approved treatment options. TACE is an effective treatment option for adults with HCC, but experience in children is very limited. Retrospective analysis was performed of 8 patients aged 4-17 years (4 male, mean 12.5 years) who underwent TACE for unresectable HCC. Response to TACE was evaluated by change in AFP, RECIST and tumor volume, PRETEXT, and transplantation eligibility by UCSF and Milan criteria. Post-procedure mean follow-up was 8.2 years. Mean overall change in tumor volume for the 8 patients was 51%. Percent change in AFP ranged from a decrease of 100% to an increase of 89.3%, with a mean change of -49.6%. Two patients did not undergo resection or transplantation and died of progressive disease. Six patients underwent orthotopic liver transplantation with mean first TACE-to-transplant interval of 141 days (range 11-514). Following transplantation, 5 patients were alive at the end of the follow-up period and one died of recurrent disease. Based on our initial experience, TACE for children with unresectable HCC appears to be a safe and effective method for managing hepatic tumor burden and for downstaging and bridging to liver transplantation. PMID- 29707870 TI - Polypeptides with High Zwitterion Density for Safe and Effective Therapeutics. AB - The commonly used "stealth material" poly(ethylene glycol) (PEG) effectively promotes the pharmacokinetics of therapeutic cargos while reducing their immune response. However, recent studies have suggested that PEG could induce adverse reactions, including the emergence of anti-PEG antibodies and tissue histologic changes. An alternative stealth material with no or less immunogenicity and organ toxicity is thus urgently needed. We designed a polypeptide with high zwitterion density (PepCB) as a stealth material for therapeutics. Neither tissue histological changes in liver, kidney, or spleen, nor abnormal behavior, sickness or death was induced by the synthesized polymer after high-dosage administration for three months in rats. When conjugated to a therapeutic protein uricase, the uricase-PepCB bioconjugate showed significantly improved pharmacokinetics and immunological properties compared with uricase-PEG conjugates. PMID- 29707871 TI - Effects of dietary lysine levels and lighting conditions on intramuscular fat accumulation in growing pigs. AB - This study was conducted to test our hypothesis that intramuscular fat (IMF) accumulation increases in pigs fed on a low lysine diet during the dark period than those fed on the same diet during the light period. Using barrows aged 6 weeks, we monitored whether serum glucose and insulin levels were affected by light conditions. Two diets with different levels of lysine, 0.78% (LL diet) and 1.37% (control diet) were prepared. Eight pigs were fed on the diet during the light period, while the remaining pigs were fed during the dark period. The pigs were fed either the LL diet or the control diet. Although IMF contents of Longissimus dorsi (LD) muscle were higher in the pigs fed on a LL diet (p < .05), the light conditions had no effect. Low dietary lysine caused reduction in serum glucose levels (p < .05) and serum insulin levels (p = .0613). However, they were also unaffected by the lighting conditions. To gain further insights, we determined the messenger RNA levels of insulin receptor, insulin receptor substrate 1, acetyl CoA carboxylase, and fatty acid synthase in LD and Rhomboideus muscles and in the liver. PMID- 29707872 TI - Platelet-rich plasma on female androgenetic alopecia: Tested on 10 patients. AB - BACKGROUND: Recently, platelet-rich plasma (PRP) injection has been proposed as a potential adjuvant therapy to treat androgenetic alopecia. AIMS: Investigate the efficacy, tolerability, and clinical improvement of PRP for the treatment of female AGA. PATIENTS/METHODS: A total of 10 female patients affected by AGA and not responding to treatment with minoxidil and/or oral antiandrogens were enrolled. The clinical improvement was evaluated by pull test, global photographs, and Trichoscan at weeks 9, 12, and 24, and hair measurements were performed at baseline and 12 and 24 weeks after the first session. RESULTS: After 24 weeks, the median relative percentage change (%RC) for all the parameters of hair density was mostly positive. After 12 weeks, the medium hair diameter in frontal area showed a significant increase (%RD = 12.5, with P-value < .05), and after 24 weeks (%RD = 14.6, P-value < .05), the vellus relative change instead showed a decrease, especially in the front and the central area, while for the vertex, the decrease was mainly visible at the end (-6.6%). No adverse events were reported. CONCLUSION: Platelet-rich plasma injections have a positive therapeutic effect on hair density and hair diameter improvement. PMID- 29707873 TI - Association between clinical characteristics, quality of life, and sleep quality in patients with periorbital hyperchromia. AB - INTRODUCTION: Periorbital hyperchromia (POH) is a multifactorial condition, precipitated or aggravated by sleep disorders, which negatively affects quality of life (QoL). The aim of this study was to evaluate the impact of POH on QoL, sleep quality, and dissatisfaction of affected patients. METHODS: In this cross sectional study of male and female patients over 18 years, participants were examined, their demographic data were registered, and Dermatology Quality of Life Index (DLQI), Pittsburgh Sleep Quality Index (PSQI-BR), and Visual Analogue Scale (VAS) were used to assess dissatisfaction. RESULTS: Patients (n = 100) were mostly women (91%) with a mean age of 36.9 years and POH duration of 18.32 years. Phototypes II (24%) and III (60%) were predominant. A total of 33% reported 4-6 hours and 66% reported over 6 hours of sleep per night. POH was classified as mild (59%), moderate (37%), or severe (4%). Mean dissatisfaction with POH was 6.9, PSQI was 6.04, and DLQI was 4.92. There was a significant difference in the dissatisfaction scale (P < .005) between men and women. Women reported worse QoL (P < .001) and higher dissatisfaction (P < .0001). A correlation between DLQI and disease duration was found. CONCLUSION: Periorbital hyperchromia negatively impacts patients' QoL. Dissatisfaction is directly related to disease severity. PMID- 29707875 TI - A practical approach and algorithm for intensifying beyond basal insulin in type 2 diabetes. AB - Despite the availability of long-term data demonstrating the benefits of timely and aggressive intensification of antihyperglycaemic regimens among individuals with type 2 diabetes, intensification beyond basal insulin continues to be suboptimal and a global challenge. This review summarizes the evidence surrounding the various options of advancing glucose-lowering management beyond basal insulin and provides a practical algorithm to assist in optimizing patient care and enhancing glycaemic target achievements. PMID- 29707874 TI - Total elbow arthroplasty in haemophilia. AB - INTRODUCTION: Advanced haemophilic arthropathy of the elbow can be a devastating manifestation of severe haemophilia with significant implications for activities of daily living. AIM: To summarize the currently available data on total elbow arthroplasty (TEA) for haemophilic arthropathy of the elbow, to draw comparisons to TEA for other indications, and to outline some considerations regarding TEA in this unique population. METHODS: A narrative review of the literature has been performed. RESULTS: The scant data regarding outcomes of TEA for haemophilic arthropathy are limited to small case series and case reports. A review of the available literature shows that, while pain relief and patient satisfaction are promising, variable outcomes with significant complications and infection rates may discourage routine use of TEA for haemophilic arthropathy of the elbow. CONCLUSION: While patients with severe haemophilic arthropathy of the elbow are likely to make gains in terms of pain control and range of motion following TEA, there are insufficient data to routinely recommend its use. Complication and infection rates are concerning, and the lack of survival analysis data makes it difficult to quantify the benefit to the patient in light of the risks and resources involved in the procedure. PMID- 29707876 TI - Maintenance dose conversion between oral risperidone and paliperidone palmitate 1 month: Practical guidance based on pharmacokinetic simulations. AB - AIM: We assessed the dosage strengths of paliperidone palmitate 1-month (PP1M) long-acting injectable resulting in similar steady-state (SS) exposures to the dosage strengths of oral risperidone using pharmacokinetic (PK) simulations. METHODS: Population PK simulations of SS PK were performed using the PK models of oral risperidone and PP1M. The concentrations of active moiety (risperidone + paliperidone) from risperidone were compared to paliperidone concentrations resulting from PP1M administration. Similarity was assessed via graphical evaluation of median and 90% prediction intervals of SS PK profiles over 28 days. RESULTS: Oral risperidone doses of 1, 2, 3, 4, and 6 mg/d are expected to result in similar SS PK as PP1M doses of 25, 50, 75, 100, and 150 mg eq. (which correspond to 39, 78, 117, 156, and 234 mg of paliperidone palmitate) respectively (ie 25-fold dose conversion factor from oral risperidone to PP1M). CONCLUSIONS: This study provides clinicians with a practical guidance to establish suitable maintenance dose levels of PP1M and oral risperidone when transitioning patients from one formulation to another. PMID- 29707877 TI - Evidence-based treatment for gynoid lipodystrophy: A review of the recent literature. AB - Gynoid lipodystrophy (GLD) is a structural, inflammatory, and biochemical disorder of the subcutaneous tissue causing alterations in the topography of the skin. Commonly known as "cellulite," GLD affects up to 90% of women, practically in all stages of the life cycle, beginning in puberty. It is a clinical condition that considerably affects the patients' quality of life. It is a frequent reason for consultation, although the patients resort to empirical, improvised, nonevidence-based treatments which discourage and can be a source of frustration not only because of the lack of results but also due to the complications derived from those treatments. In this article, a panel of experts from different specialties involved in the management of this clinical skin disorder presents the results of a systematic literature search and of the consensus discussion of the evidence obtained from different treatments currently available. The analysis was divided into topical, systemic, noninvasive, and minimally invasive treatments. PMID- 29707878 TI - MicroRNA-223 inhibits lipopolysaccharide-induced inflammatory response by directly targeting Irak1 in the nucleus pulposus cells of intervertebral disc. AB - This study was aimed to research the effect of miR-223 on the inflammatory responses induced by lipopolysaccharide (LPS) in nucleus pulposus (NP) cells of rat intervertebral disc. Isolated rat NP cells were induced by LPS. Reverse transcriptase quantitative real-time polymerase chain reaction was used to detect gene expression. To detect protein expression, Western blot and enzyme-linked immunosorbent assay experiments were applied. The putative targeting relationship between miR-223 and Irak1 was determined using dual-luciferase reporter gene assay. We found that miR-223 was downregulated in LPS-induced NP cells. MiR-223 upregulated the expression of extracellular matrix-related genes (Aggrecan and Collagen II). Matrix degrading enzymes (ADAMTS4, ADAMTS5, MMP3 and MMP13), NO reaction-associated proteins (PGE2, COX-2 and INOS) and the expression of nuclear factor (NF)-kappaB signaling-related proteins were downregulated after miR-233 overexpression. In addition, luciferase reporter assays demonstrated that miR-223 directly targeted Irak1. MiR-223 overexpression could inhibit NF-kappaB signaling by targeting Irak1, and finally suppress the LPS-induced inflammation in NP cells. (c) 2018 IUBMB Life, 70(6):479-490, 2018. PMID- 29707879 TI - Recent Advances in Polyanhydride Based Biomaterials. AB - This review focusses on recent developments of polyanhydrides, a class of degradable synthetic biopolymers. Polyanhydrides have been used as carriers for controlled delivery of drugs. A polyanhydride copolymer of carboxyphenoxy propane and sebacic acid has been used in Gliadel brain tumor implants for the controlled delivery of carmustine or bis-chloroethylnitrosourea. They are easy and inexpensive to synthesize (especially scale up). However, polyanhydrides possess a short shelf-life. Hydrolytic cleavage and anhydride interchanges lower their molecular weights during storage. One of the highlights in recent developments of polyanhydride chemistry is the discovery of alternating copolymers having extended shelf-life. Other highlights include their applications in biomedical electronics, vaccine delivery, and nano/micro particulate delivery systems. This review examines approaches for polyanhydride synthesis followed by their recent developments in biomedical applications. PMID- 29707880 TI - Risk factors for adverse maternal and perinatal outcomes in women with preeclampsia: analysis of 1396 cases. AB - Preeclampsia is a major cause of adverse maternal and perinatal outcomes, but how to identify women and fetuses at increased risk for later adverse events is a challenge. This study aimed to investigate the risk factors for adverse maternal and perinatal outcomes in women with preeclampsia. Data from 1396 women with preeclampsia were retrospectively collected and analyzed. Eighteen candidate risk factors and 12 adverse outcomes were investigated. The following factors were found to be significantly associated with at least one adverse outcome: maternal age 35 years or older, multiple birth, the usage of assisted reproductive technology, living in a rural area, history of pregnancy-induced hypertension, male fetus, multigravida, or having polycystic ovary syndrome, hemolysis, elevated liver enzymes, and low platelet count syndrome, intrahepatic cholestasis of pregnancy, cardiovascular disease, gestational diabetes mellitus, systemic lupus erythematosus, thyroid disease, or liver disease. Compared with patients without any identified risk factors, patients with preeclampsia with three or more risk factors were at increased risk for severe adverse outcomes. Those findings demonstrated that maternal risk factors could be used as indicators supplementary to clinical symptoms and laboratory test results for the risk assessment in women with preeclampsia. PMID- 29707881 TI - Prophylactic treatment of bleeding episodes in children <12 years with moderate to severe hereditary factor X deficiency (FXD): Efficacy and safety of a high purity plasma-derived factor X (pdFX) concentrate. AB - BACKGROUND: Hereditary factor X (FX) deficiency (FXD) affects 1:500 000-1:1 000 000 people worldwide. A novel, high-purity plasma-derived FX concentrate (pdFX) is available in the United States and European Union as replacement therapy for FXD, but data are scarce on pdFX use in children <12 years. AIM: This prospective, open-label phase 3 study assessed the safety, efficacy and pharmacokinetics of pdFX in children <12 years with moderate/severe FXD. METHODS: Subjects aged <12 years with basal plasma FX activity (FX:C) <5 IU/dL received pdFX as prophylactic and on-demand treatment, with doses adjusted to maintain FX:C > 5 IU/dL. After >=26 weeks and >=50 exposure days, investigators rated pdFX efficacy for preventing/decreasing bleeds. Secondary endpoints included number and severity of bleeds, trough FX:C and incremental recovery. Safety parameters were adverse events (AEs), inhibitor development and changes in laboratory parameters. RESULTS: The study enrolled 9 subjects (0-5 years, n = 4; 6-11 years, n = 5) with severe (n = 8) or moderate (n = 1) FXD. At end of study, investigators rated pdFX efficacy excellent for all subjects. Ten bleeds occurred (n = 3 subjects; 6 major, 3 minor, 1 unassessed for severity). Trough FX:C levels remained >5 IU/dL for all subjects after the last dose adjustment study visit. Mean incremental recovery was significantly lower for younger vs older subjects (1.53 vs 1.91 IU/dL per IU/kg; P = .001). All AEs were unrelated to treatment; no inhibitor development or clinically significant changes in laboratory parameters were observed. CONCLUSIONS: These results demonstrate the efficacy and safety of pdFX for treating children <12 years with moderate/severe hereditary FXD. PMID- 29707882 TI - Dietitians' opinions regarding refeeding syndrome, clinical guidelines and extended scope of practice. AB - AIM: Refeeding syndrome (RFS) prevalence rates vary across studies depending on the criteria used for assessment and identification. For registered dietitians, the assessment and management of RFS is highly reliant on daily serum electrolyte values; however, registered dietitians working within Australia do not currently possess laboratory test ordering privileges. We aimed to examine the opinions of registered dietitians regarding RFS identification, management and guidelines and the option of using extended scope of practice to order electrolyte monitoring autonomously. METHODS: A multi-method action research approach was used, incorporating two projects. The first was a survey examining Australian registered dietitians' (n = 187) opinions regarding RFS identification, management and guidelines, and autonomous electrolyte monitoring. To establish if results were similar internationally, an interview was conducted with 22 registered dietitians working within 10 different countries. Data were analysed using chi-square tests and thematic analysis. RESULTS: Australian registered dietitians (75%) identify patients at risk of RFS at a high rate of more than once per fortnight, with 74% reporting that they have previously worked with a patient diagnosed with RFS. Results varied internationally, with respondents from eight countries reporting that RFS is a problem within acute care versus respondents from five countries having never treated a patient with RFS. The majority (>=89%) of registered dietitians desire new guidelines and the option to order patient electrolyte monitoring autonomously. CONCLUSIONS: Our findings suggest that more stringent tools for the identification of RFS are necessary. There was limited uniformity across countries, and updated practice guidelines are needed. PMID- 29707883 TI - Evaluation of selected skin parameters following the application of 5% vitamin C concentrate. AB - BACKGROUND: Ascorbic acid is a substance with confirmed anti-free-radical properties. It triggers the collagen synthesis, has a depigmenting effect and seals blood vessels. All these properties have a significant effect of the skin's appearance. The characteristic traits of capillary skin include telangiectasias as well as erythema, which might consolidate in the future, along with the feeling of burning and increased skin sensitivity. OBJECTIVES: Study and evaluation of selected parameters of capillary skin after the application of 5% vitamin C concentrate throughout the period of 6 weeks with the use of instrumental tests and questionnaires. METHODS: The research was conducted on a group of 30 women ranging from 30 to 60 years of age with capillary skin indicating visible signs of erythematous plaques. The concentrate was applied once a day. Analyses of skin conditions were conducted four times: before the launch of the research D(0), after two 2D(14), after four 4D(28), and after 6 D(42) weeks of application. The research was conducted with the use of Mexameter MPA equipment, which was used to measure changes in the intensity of erythematous plaques. The depth of wrinkles was measured by PRIMOS system (two times D0 and 6D(42). The research also used VISIA system which allowed to perform visual and numeral skin analyses. Each research was finalized with a questionnaire which provided a subjective evaluation of the examined product among participants. RESULTS: Significant reduction in erythema has been widely recorded. After 2 weeks, erythema dropped by 9%. After 4 weeks, it decreased by 16% and by 21% after 6 weeks. The concentrate's efficiency in diminishing erythematous plaques was confirmed by photographs generated by VISIA photograph system. Thanks to PRIMOS, decrease in both depth and volume of nasolabial folds was recorded in 87% of participants after 6 weeks of research. CONCLUSION: 5% vitamin C concentrate is effective in treating capillary and photograph-aging skin. It decreases erythema and telangiectasias as well as triggers the shallowing of skin wrinkles. PMID- 29707885 TI - 9th World Congress of the World Institute of Pain (WIP). PMID- 29707884 TI - Accounting for spatially heterogeneous conditions in local-scale surveillance strategies: case study of the biosecurity insect pest, grape phylloxera (Daktulosphaira vitifoliae (Fitch)). AB - BACKGROUND: Surveillance strategies are often standardized and completed on grid patterns to detect pest incursions quickly; however, it may be possible to improve surveillance through more targeted observation that accounts for landscape heterogeneity, dispersal and the habitat requirements of the invading organism. We simulated pest spread at a local scale, using grape phylloxera (Daktulosphaira vitifoliae (Fitch)) as a case study, and assessed the influence of incorporating spatial heterogeneity into surveillance compared with current, standard surveillance strategies. RESULTS: Time to detection and spread within and beyond the vineyard were reduced by conducting surveys that target sampling effort in soil that is highly suitable for the invading pest in comparison with standard surveillance strategies. However, these outcomes were dependent on the virulence level of phylloxera because phylloxera is a complex pest with multiple genotypes that influence spread and detectability. CONCLUSION: Targeting surveillance strategies based on local-scale spatial heterogeneity can decrease the time to detection without increasing the survey cost, and surveillance that targets highly suitable soil is the most efficient strategy for detecting new incursions. In addition, combining targeted surveillance strategies with buffer zones and hygiene procedures, and updating surveillance strategies as additional species information becomes available, will further decrease the risk of pest spread. (c) 2018 Society of Chemical Industry. PMID- 29707886 TI - Telomerase reverse transcriptase suppression inhibits cell proliferation and promotes cell apoptosis in hepatocellular cancer. AB - We aimed to investigate the role of telomerase reverse transcriptase (TERT) in hepatocellular cancer (HCC) cells. R software was used for differential expressed gene analysis. Western blot and quantitative real time polymerase chain reaction (qRT-PCR), respectively, were used to detect protein expression and mRNA level of TERT in tumor cell lines. Real-time quantitative telomeric repeat amplification protocol assay, MTT assay, colony formation assay, and flow cytometry (FCM) assay were used to analyze the telomerase activity, viability, proliferation, cell cycle progression and apoptosis of HCC cells. The proliferation ratio of HCC cells transfected with TERT-siRNA was significantly decreased compared with control group. Plate clone results suggested that the number of colonies also decreased in TERT-siRNA group. FCM results showed that more cells were arrested in G0/G1 phase and apoptosis rate increased in TERT-siRNA group compared with control group. TERT suppression inhibited cell proliferation but promoted cell cycle arrest and cell apoptosis. (c) 2018 IUBMB Life, 70(7):642-648, 2018. PMID- 29707887 TI - Research Progress in MnO2 -Carbon Based Supercapacitor Electrode Materials. AB - With the serious impact of fossil fuels on the environment and the rapid development of the global economy, the development of clean and usable energy storage devices has become one of the most important themes of sustainable development in the world today. Supercapacitors are a new type of green energy storage device, with high power density, long cycle life, wide temperature range, and both economic and environmental advantages. In many industries, they have enormous application prospects. Electrode materials are an important factor affecting the performance of supercapacitors. MnO2 -based materials are widely investigated for supercapacitors because of their high theoretical capacitance, good chemical stability, low cost, and environmental friendliness. To achieve high specific capacitance and high rate capability, the current best solution is to use MnO2 and carbon composite materials. Herein, MnO2 -carbon composite as supercapacitor electrode materials is reviewed including the synthesis method and research status in recent years. Finally, the challenges and future development directions of an MnO2 -carbon based supercapacitor are summarized. PMID- 29707888 TI - Mycobacterium tuberculosis Reporter Strains as Tools for Drug Discovery and Development. AB - Reporter strains have proven to be powerful tools to study Mycobacterium tuberculosis (Mtb) physiology. Transcriptional and translational reporter strains are engineered by fusing a readout gene, encoding a fluorescent, luminescent or enzymatic protein, downstream of a promoter or in-frame with a gene of interest. When the reporter is expressed, it generates a signal that acts as a synthetic phenotype, enabling the study of physiologies that might have otherwise been hidden. This review will discuss approaches for generating reporter strains in Mtb and how they can be used as tools for high-throughput genetic and small molecule screening and as biomarkers for examining Mtb responses to drug or immune stresses during animal infections. Fluorescent reporter strains have an added benefit in that they can be used for single-cell studies both in vitro and in vivo, thus enabling the study of mechanisms underlying phenotypic heterogeneity. Recent examples of the use of Mtb reporter strains will be presented with a focus on how they can be used as tools for drug discovery and development. (c) 2018 IUBMB Life, 70(9):818-825, 2018. PMID- 29707889 TI - Resistance selection of indoxacarb in Helicoverpa armigera (Hubner) (Lepidoptera: Noctuidae): cross-resistance, biochemical mechanisms and associated fitness costs. AB - BACKGROUND: The cotton bollworm Helicoverpa armigera is a worldwide insect pest with the ability to develop resistance to many insecticides. Indoxacarb, a sodium channel blocker, is an important insecticide that is used to control H. armigera. Cross-resistance, metabolic mechanisms and life history traits were established for an indoxacarb-selected (IND-SEL) population of H. armigera. RESULTS: After 11 generations of selection, the susceptibility to indoxacarb was decreased by 4.43 fold and the estimated realized heritability (h2 ) was only 0.072. Interestingly, the IND-SEL population was more susceptible to methoxyfenozide and abamectin than the susceptible population. The activities of cytochrome P450 monooxygenase (P450) and carboxyl esterase (CarE) were significantly increased in IND-SEL H. armigera. Thus, susceptibility to indoxacarb was increased by piperonyl butoxide and S,S,S-tributyl phosphorothioate, showing synergistic ratios of 2.54- and 1.82 fold, respectively. Moreover, the IND-SEL population had a reduced relative fitness (0.67), with a lower growth rate and fecundity than the susceptible population. CONCLUSIONS: Evidence from this study suggests that decreased susceptibility to indoxacarb may be associated with fitness costs in H. armigera and enhanced activities of P450 and CarE may be important detoxification mechanisms in the development of indoxacarb resistance. Methoxyfenozide and abamectin can be rotationally used to manage indoxacarb resistance. (c) 2018 Society of Chemical Industry. PMID- 29707890 TI - Phase-Engineered Type-II Multimetal-Selenide Heterostructures toward Low-Power Consumption, Flexible, Transparent, and Wide-Spectrum Photoresponse Photodetectors. AB - Phase-engineered type-II metal-selenide heterostructures are demonstrated by directly selenizing indium-tin oxide to form multimetal selenides in a single step. The utilization of a plasma system to assist the selenization facilitates a low-temperature process, which results in large-area films with high uniformity. Compared to single-metal-selenide-based photodetectors, the multimetal-selenide photodetectors exhibit obviously improved performance, which can be attributed to the Schottky contact at the interface for tuning the carrier transport, as well as the type-II heterostructure that is beneficial for the separation of the electron-hole pairs. The multimetal-selenide photodetectors exhibit a response to light over a broad spectrum from UV to visible light with a high responsivity of 0.8 A W-1 and an on/off current ratio of up to 102 . Interestingly, all transparent photodetectors are successfully produced in this work. Moreover, the possibility of fabricating devices on flexible substrates is also demonstrated with sustainable performance, high strain tolerance, and high durability during bending tests. PMID- 29707891 TI - Dimension-Based Design of Melt Electrowritten Scaffolds. AB - The electrohydrodynamic stabilization of direct-written fluid jets is explored to design and manufacture tissue engineering scaffolds based on their desired fiber dimensions. It is demonstrated that melt electrowriting can fabricate a full spectrum of various fibers with discrete diameters (2-50 um) using a single nozzle. This change in fiber diameter is digitally controlled by combining the mass flow rate to the nozzle with collector speed variations without changing the applied voltage. The greatest spectrum of fiber diameters was achieved by the simultaneous alteration of those parameters during printing. The highest placement accuracy could be achieved when maintaining the collector speed slightly above the critical translation speed. This permits the fabrication of medical-grade poly(epsilon-caprolactone) into complex multimodal and multiphasic scaffolds, using a single nozzle in a single print. This ability to control fiber diameter during printing opens new design opportunities for accurate scaffold fabrication for biomedical applications. PMID- 29707892 TI - Increased neutrophil-lymphocyte ratio independently predicts poor survival in non metastatic triple-negative breast cancer patients. AB - Inflammation plays an important role in tumor initiation, progression, and metastasis. The neutrophil-lymphocyte ratio (NLR) is widely used to evaluate global inflammation in various tumor types. However, the prognostic role of NLR in non-metastatic triple-negative breast cancer (TNBC) patients was poorly known. The aim of this study was to explore the association between pre-treatment NLR and survival in TNBC patients. Data were collected for patients with stages I-III TNBC from 2006 to 2013 at Linyi Central Hospital to analyze pre-treatment NLR and survival. Overall survival (OS) and disease-free survival (DFS) were estimated by the Kaplan-Meier method, and Cox analysis was performed to determine clinicopathological parameters for their prognostic relevance. A total of 406 patients were eligible. Patients with NLR lower than 2.85 exhibited significantly higher OS (P < 0.001) and DFS (P < 0.001) than patients with higher NLR. Higher pre-treatment NLR was independently correlated with poor OS and DFS, with hazard ratios of 2.69 (95% confidence interval [CI]: 1.94-3.72, P = 0.001) and 2.13 (95% CI: 1.68-2.65, P = 0.008), respectively, in the Cox proportional multivariate hazard model. In conclusion, our results indicate that pre-treatment NLR may be correlated with OS and DFS in early-stage TNBC patients, and that it may have considerable clinical applications. (c) 2018 IUBMB Life, 70(6):529-535, 2018. PMID- 29707893 TI - 2D Metal Chalcogenides Incorporated into Carbon and their Assembly for Energy Storage Applications. AB - 2D metal chalcogenides have become a popular focus in the energy storage field because of their unique properties caused by their single-atom thicknesses. However, their high surface energy and van der Waals attraction easily cause serious stacking and restacking, leading to the generation of more inaccessible active sites with rapid capacity fading. The hybridization of 2D metal chalcogenides with highly conductive materials, particularly, incorporating ultrasmall and few-layered metal chalcogenides into carbon frameworks, can not only maximize the exposure of active sites but also effectively avoid their stacking and aggregation during the electrochemical reaction process. Therefore, a satisfactory specific capacity will be achieved with a long cycle life. In this Concept, the representative progress on such intriguing nanohybrids and their applications in energy storage devices are mainly summarized. Finally, an outlook of the future development and challenges of such nanohybrids for achieving an excellent energy storage capability is also provided. PMID- 29707894 TI - Advancements in Copper Nanowires: Synthesis, Purification, Assemblies, Surface Modification, and Applications. AB - Copper nanowires (CuNWs) are attracting a myriad of attention due to their preponderant electric conductivity, optoelectronic and mechanical properties, high electrocatalytic efficiency, and large abundance. Recently, great endeavors are undertaken to develop controllable and facile approaches to synthesize CuNWs with high dispersibility, oxidation resistance, and zero defects for future large scale nano-enabled materials. Herein, this work provides a comprehensive review of current remarkable advancements in CuNWs. The Review starts with a thorough overview of recently developed synthetic strategies and growth mechanisms to achieve single-crystalline CuNWs and fivefold twinned CuNWs by the reduction of Cu(I) and Cu(II) ions, respectively. Following is a discussion of CuNW purification and multidimensional assemblies comprising films, aerogels, and arrays. Next, several effective approaches to protect CuNWs from oxidation are highlighted. The emerging applications of CuNWs in diverse fields are then focused on, with particular emphasis on optoelectronics, energy storage/conversion, catalysis, wearable electronics, and thermal management, followed by a brief comment on the current challenges and future research directions. The central theme of the Review is to provide an intimate correlation among the synthesis, structure, properties, and applications of CuNWs. PMID- 29707895 TI - Gamma irradiation of ocular melanoma and lymphoma cells in the presence of gold nanoparticles: in vitro study. AB - The aim of this work was to determine whether conjugation of cultivated choroidal melanoma and Burkitt's lymphoma cells with gold nanoparticles (GNPs) is beneficial for these series of ocular cancer patients. GNPs are radiosensitizers and can sensitize tumors to radiotherapy.This application has been examined in several tumor types, but not in choroidal melanoma. This study shows the results of in vitro study on the choroidal melanoma and also Burkitt's lymphoma cells in the presence of GNPs during continuous gamma irradiation. Cytotoxicity of GNPs were assessed for five different concentrations then cultured melanoma and Burkitt's lymphoma cells were irradiated with a Gamma source in the presence and absence of NPs. Incubation of melanoma cells with GNP concentrations below 100 MUg/ml, accompanied by gamma irradiation, increased cell death (P value = 0.016) . In the absence of irradiation, GNPs at these concentrations did not affect cultured melanoma cell metabolism. Reduced cell viability resulted from a significant increase in absorbed energy by the tumor. Moreover, GNP concentrations higher than 200 MUg/ml induced cytotoxicity in melanoma cells. Cytotoxicity assay in GNPs-loaded Burkitt's lymphoma cells showed a slight decrease in cell viability at 50 MUg/ml and clear cytotoxicity at concentrations higher than 100 MUg/ml (P value = 0.035). Concentration and proper injection doses of GNPs in sensitive tissues such as the human eye are important variables yet to be determined.This is the first report of choroidal melanoma dosimetry performed in the presence of GNPs and provides valuable insights into future therapeutic approaches. Further in vitro study with more different sizes and concentrations is needed to determine the optimum size and concentration before any clinical research in this regard. PMID- 29707896 TI - Correlation between serum IL-17A level and SALT score in patients with alopecia areata before and after NB-UVB therapy. AB - BACKGROUND: There is strong evidence that alopecia areata is of immunological background; Interleukin-17 (IL-17) is a Th17 pro-inflammatory cytokine that has been allied to the pathogenesis of different autoimmune and inflammatory diseases. OBJECTIVE: This study aimed to measure serum IL-17A in patients with alopecia areata, and to study associations between IL-17A levels and disease severity before and after Narrowband-Ultraviolet B (NB-UVB), patient gender and age. METHODS: Twenty patients with AA of the scalp were treated with (NB-UVB), and 15 healthy subjects' age and sex matched were enrolled as controls. Patients were assessed clinically by SALT score. Assay of serum levels of IL-17A by ELISA was done in patients and controls. RESULTS: The mean level of IL-17A was (15.63 A +/- 10.89 Pg/mL) in AA patient group, and (16.50 A +/- 5.02 Pg/mL) in control group. No statistically significant correlation was detected between SALT score and IL-17A level before (NB-UVB) treatment while a significant negative correlation between SALT score and IL-17A level was observed after treatment (r = -.448, P = .047). Mean SALT score for patients was (14.03 A +/- 13.48), and correlated positively with age (r = .446, P = .049). CONCLUSION: Although (NB UVB) is an immune-modulatory type of treatment for alopecia areata of mild efficacy especially if it's used alone, it has shown significant decrease in serum IL-17A level among patients, and correlation to disease severity. PMID- 29707897 TI - Upregulated lncRNA ADAMTS9-AS2 suppresses progression of lung cancer through inhibition of miR-223-3p and promotion of TGFBR3. AB - In this study, we aimed at investigating effects of lncRNA ADAMTS9-AS2 on lung cancer progression through regulating miR-223-3p and TGFBR3 expressions. Expressions of ADAMTS9-AS2 in lung cancer tissues and cell lines were determined by reverse transcriptase polymerase chain reaction (qRT-PCR). TargetScan and miRcode were used to predict the targeting relationships, respectively. The luciferase reporter system was used to verify that the relationship among ADAMTS9 AS2, TGFBR3 and miR-223-3p. Western blot assay tested the protein level changes in TGFBR3. Cell proliferation was determined by CCK-8 assay. Cell cycle and cell apoptosis were detected by flow cytometry assay, and migration and invasion were determined by transwell assay. Tumor xenograft model was developed to study the influence of ADAMTS9-AS2 on tumor growth in vivo. qRT-PCR results demonstrated that lncADAMTS9-AS2 was lowly expressed in lung cancer tissues. High expression of ADAMTS9-AS2 in lung cancer cells significantly reduced proliferation ability and inhibited migration, as well as elevating their apoptosis rate. In vivo assay found that ADAMTS9-AS2 suppressed the lung tumor growth. Bioinformatics predicted that miR-223-3p bound directly to the ADAMTS9-AS2 and TGFBR3, which was later confirmed by luciferase reporter system. ADAMTS9-AS2 transfection increased TGFBR3 mRNA and protein expressions in lung cancer cells, but miR-223-3p transfection significantly decreased them. Besides, our results showed that miR 223-3p induced cellular apoptosis while TGFBR3 group showed the complete opposite effect. It was proved that ADAMTS9-AS2 and TGFBR3 were the direct genes of miR 223-3p. MiR-223-3p promotes proliferation, migration and invasion of lung cancer cells by targeting TGFBR3. Therefore, ADAMTS9-AS2, miR-223-3p and TGFBR3 may provide potential targets for the treatment of lung cancer patients. (c) 2018 IUBMB Life, 70(6):536-546, 2018. PMID- 29707898 TI - Three-dimensional porous poly(propylene fumarate)-co-poly(lactic-co-glycolic acid) scaffolds for tissue engineering. AB - Three-dimensional structural scaffolds have played an important role in tissue engineering, especially broad applications in areas such as regenerative medicine. We have developed novel biodegradable porous poly(propylene fumarate) co-poly(lactic-co-glycolic acid) (PPF-co-PLGA) scaffolds using thermally induced phase separation, and determined the effects of critical parameters such as copolymer concentration (6, 8, and 10 wt %) and the binary solvent ratio of dioxane:water (78/22, 80/20, 82/18 wt/wt %) on the fabrication process. The cloud point temperatures of PPF-co-PLGA changed in parallel with increasing copolymer concentration, but inversely with increasing dioxane content. The compressive moduli of the scaffolds increased with greater weight composition and dioxane:water ratio. Scaffolds formed using high copolymer concentrations and solvent ratios exhibited preferable biomineralization. All samples showed biodegradation capability in both accelerated solution and phosphate-buffered saline (PBS). Cell toxicity testing indicated that the scaffolds had good biocompatibility with bone and nerve cells, which adhered well to the scaffolds. Variations in the copolymer concentration and solvent ratio exercised a remarkable influence on morphology, mechanical properties, biomineralization, and biodegradation, but not on the cell viability and adhesion of the cross-linked scaffolds. An 8 to 10 wt % solute concentration and 80/20 to 82/18 wt/wt dioxane:water ratio were the optimum parameters for scaffold fabrication. PPF-co PLGA scaffolds thus possess several promising prospects for tissue engineering applications. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2507-2517, 2018. PMID- 29707899 TI - A Novel Approach to Realize Si-Based Porous Wire-In-Tube Nanostructures for High Performance Lithium-Ion Batteries. AB - Hollow inorganic nanostructures have drawn great attention due to their fascinating features, such as large surface area, high loading capacity, and high permeability. The formation, characterization, and application of partially and entirely hollow structure by applying a Si-based reactive ion deposition and etching method on silicon nanowire as a template are reported. This fabrication technique is extended to a stainless steel substrate to be used as the binder free anode for high capacity and high rate lithium-ion batteries. The electrochemical analyses exhibit that in addition to the high initial discharge capacity of 4125 mAh g-1 at a rate of C/16, the best performing electrode shows discharge/charge capacity of as high as 3302.14/2832.1 mAh g-1 , respectively, with an excellent charge capacity retention of 96.7% over 100 cycles at a rate density of 1 C. Even at a rate of 12 C, the as-designed structure is still able to deliver an impressive 1553 mAh g-1 , which probably is attributed to fast lithium diffusion in its hollow part and high porosity of Si and alumina layer. It is proved that the change in hollowness ratio significantly affects capacity retention and average coulombic efficiency of the lithium-ion cells. PMID- 29707900 TI - An Observational Case Series of Spinal Cord Stimulation Waveforms Visualized on Intraoperative Neuromonitoring. AB - INTRODUCTION: Intraoperative neuromonitoring for spinal cord stimulation uses electromyography (EMG) responses to determine myotomal coverage as a marker for dermatomal coverage. These responses are utilized to determine the orientation of the electrode. Somatosensory evoked potential (SSEP) collision testing can also be used in which sensory signals are decreased and/or eliminated when stimulation is activated. METHODS: Fifteen patients were observed in the study. Each manufacturer had a minimum of three patients. Those included were Abbott BurstDR waveform, Boston Scientific burst stimulation, Medtronic high-dose stimulation, and Nevro high-frequency waveform. Efficacy of therapy was determined by a successful trial. Analysis performed during the permanent implant, included findings with traditional tonic stimulation, specific waveform and stimulation platforms, amplitude differences, and findings for both EMG responses and SSEP collision testing. RESULTS: The Abbott BurstDR waveform produced the most findings. The amplitudes necessary to generate an observed EMG response were far lower than others, with a threshold of 10-20% of that seen in traditional tonic programming. The Medtronic high-dose programming and Nevro high-frequency waveform did not generate any observable EMG responses. Unique to Abbott BurstDR waveform was the onset of EMG activity in the distal muscle groups prior to proximal ones, as well as a hyperexcitability phenomenon acting as a primer generating signals at lower thresholds with more robust responses when returning to traditional tonic stimulation. EMG responses demonstrated propagation into one large EMG spike with BurstDR, while Boston Scientific burst stimulation had no propagation with separate spikes being consistent with traditional tonic stimulation. CONCLUSION: This observational series demonstrated distinct differences between the waveforms and stimulation alluding to different mechanisms of action. Nevro high-frequency and Abbott BurstDR waveforms appear to be most different in action from traditional tonic stimulation while Abbotts BurstDR appears to be the most energy efficient generating signals at the lowest thresholds with a propagating effect that leads to a hyperexcitable or primed stimulation state. PMID- 29707901 TI - Argatroban is stable in citrated whole blood for 24 hours. AB - INTRODUCTION: Argatroban is a direct thrombin inhibitor used as an anticoagulant for patients who have Heparin induced thrombocytopenia. Quantification can be performed using a dilute thrombin time or anti-iia assay. Our preferred method is Hemoclot Thrombin Inhibitor Assay (HTI).To the best of our knowledge, no one has published on the stability of plasma argatroban in whole citrated blood at room temperature. METHODS: Forty matched samples obtained from 4 patients receiving argatroban. 1 mL of the whole blood was removed from the sample into a labelled plastic tube and left on the laboratory bench at room temperature for 24 hours prior to centrifugation. The remaining sample was spun at 2000 g for 10 minutes and the plasma aliquoted off and labelled 0 hour and stored at -80 degrees C prior to testing. At 24 hours the plastic tube containing whole blood was centrifuged at 2000 g for 10 minutes and the plasma aliquoted off and labelled 24 hours and stored at -80 degrees C prior to testing. HTI assay was used for plasma argatroban determination. RESULTS: The lowest argatroban level obtained was 0.16 MUg/mL at 0 hour; 0.18 MUg/mL at 24 hours from the same pair, the highest argatroban level obtained was 1.72 MUg/mL at 0 hour;1.76 MUg/mL for the same pair at 24 hours. The mean result for 0 hour was 0.57 MUg/mL and 0.60 MUg/mL at 24 hours. CONCLUSION: This study proposes that patients receiving treatment in hospitals who cannot provide a dedicated argatroban plasma concentration method could have their samples sent on whole blood within 24 hours of venepuncture to a laboratory who could provide the test. PMID- 29707902 TI - The impact of cognitive impairment in dementia on self-care domains in diabetes: A systematic search and narrative review. AB - Self-management is integral to effective chronic disease management. Cognitive impairments (CogImp) associated with dementia have not previously been reviewed in diabetes mellitus (DM) self-care. The aims of this study are to know (1) whether CogImp associated with dementia impact self-care and (2) whether specific CogImp affects key DM self-care processes. A systematic literature search with a narrative review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. This review examined studies published from January, 2000 to February, 2016 describing the relationship between cognition and DM self-care domains in community dwelling older adults with dementia/CogImp. Eight studies met inclusion criteria. Decrements in all self-care domains were associated with CogImp. Problem solving was related to reduced disease knowledge (OR 0.87, 95% CI = 0.49-1.55), resulting in poorer glycemic control. Decision-making impairments manifested as difficulties in adjusting insulin doses, leading to more hospital admissions. People without CogImp were better able to find/utilize resources by adhering to recommended management (OR 1.03, 95% CI = 1.02-1.05). A lack of interaction with health care providers was demonstrated through reduced receipt of important routine investigation including eye examinations (ARR = 0.85, 95% CI = 0.85-0.86), HbA1c testing (ARR = 0.96, 95% CI = 0.96-0.97), and LDL-C testing (ARR = 0.91, 95% CI = 0.901-0.914). People without CogImp had better clinic attendance (OR 2.17, 95% CI = 1.30-3.70). Action taking deficits were apparent through less self-testing of blood sugar levels (20.2% vs 24.4%, P = 0.1) resulting in poorer glycemic control, self-care, and more frequent micro/macrovascular complications. Persons with diabetes and CogImp, particularly in domains of learning, memory and executive function, were significantly impaired in all self-care tasks. PMID- 29707903 TI - Patterned Arrays of Functional Lateral Heterostructures via Sequential Template Directed Printing. AB - The precise integration of microscale dots and lines with controllable interfacing connections is highly important for the fabrication of functional devices. To date, the solution-processible methods are used to fabricate the heterogeneous micropatterns for different materials. However, for increasingly miniaturized and multifunctional devices, it is extremely challenging to engineer the uncertain kinetics of a solution on the microstructures surfaces, resulting in uncontrollable interface connections and poor device performance. Here, a sequential template-directed printing process is demonstrated for the fabrication of arrayed microdots connected by microwires through the regulation of the Rayleigh-Taylor instability of material solution or suspension. Flexibility in the control of fluidic behaviors can realize precise interface connection between the micropatterns, including the microwires traversing, overlapping or connecting the microdots. Moreover, various morphologies such as circular, rhombic, or star shaped microdots as well as straight, broken or curved microwires can be achieved. The lateral heterostructure printed with two different quantum dots displays bright dichromatic photoluminescence. The ammonia gas sensor printed by polyaniline and silver nanoparticles exhibits a rapid response time. This strategy can construct heterostructures in a facile manner by eliminating the uncertainty of the multimaterials interface connection, which will be promising for the development of novel lateral functional devices. PMID- 29707904 TI - Investigation of EBT3 radiochromic film's response to humidity. AB - PURPOSE: The aim of this work is to investigate the effects of immersing EBT3 radiochromic film in water and to evaluate its contribution to the total uncertainty in dose determination. MATERIALS AND METHODS: We used 3 cm * 3 cm EBT3 radiochromic films irradiated in the range of 0-70 Gy to study the impact of water immersion on the change in net optical density. These films were placed in a water container for a period of 24 h. The net optical density was measured before (0 h) and after of the immersion in water (1, 3, 6, 12, 18, and 24 h). The absorbance spectrum of the EBT3 radiochromic film was measured at 0 h and 24 h after immersion in water. The uncertainty in dose determination due to the effects of keeping the EBT3 radiochromic film submerged in water at 0, 1, and 24 h were recorded in the red, green, and blue channels. RESULTS: We observed an increase in the net optical density as an effect on the film due to its immersion in water. The penetration of the water at the edges of the radiochromic film was observed to be a function of time during which the film remained in the water. On the other hand, the penetration of water at the edges of the film was found to be independent of irradiation dose. CONCLUSIONS: EBT3 radiochromic film is found more resistant to water penetration through the edges than its predecessors. However, there is evidence that suggest that liquid water damage the Nylon cover layer of the film by changing its optical properties. Therefore, it is recommended to build a new calibration curve for radiochromic films for a specific situation involving dose measurements in liquid water. PMID- 29707905 TI - Human herpesvirus 8 infection DNA positivity is associated with low insulin secretion: A case-control study in a sub-Saharan African population with diabetes. AB - BACKGROUND: Viruses have been considered potential triggers for the development of diabetes. This study assessed insulin secretion and insulin sensitivity in human herpesvirus 8 (HHV8)-infected and uninfected sub-Saharan African people with diabetes. METHODS: In all, 173 people with non-autoimmune diabetes were enrolled consecutively: 124 with type 2 diabetes mellitus (T2DM) and 49 with ketosis-prone diabetes (KPD) admitted in hyperglycemic crisis. Those with KPD were further subdivided into those with new-onset ketotic-phase KPD (n = 34) or non-ketotic phase KPD (n = 15). All participants were screened for HHV8-specific antibodies and genomic DNA. Blood samples were collected for analysis of fasting glucose, HbA1c, lipid profile, and C-peptide, with insulin resistance and secretion estimated by homeostasis model assessment. RESULTS: Among the 173 diabetic participants, 88 (50.9%) were positive for HHV8 antibodies (Ac-HHV8+), including 15 (8.7%) positive for HHV8 DNA (DNA-HHV8+). The seroprevalence of HHV8 was similar between T2DM (55.6%) and KPD (61.2%) subjects. Of those with and without ketotic-phase KPD, 35.3% and 46.7% were Ac-HHV8+, respectively. Body mass index was significantly in lower DNA-HHV8+ than DNA-HHV8- subjects. Low-density lipoprotein and total cholesterol were significantly higher, but C-peptide and homeostatic model assessment of beta-cell function (HOMA-beta) were significantly lower in DNA-HHV8+ than DNA-HHV8- participants. After excluding DNA-HHV8+ participants, triglyceride concentrations were significantly higher in Ac-HHV8+ (n = 73) than Ac-HHV8- (n = 85) subjects. In contrast, HOMA-beta was significantly higher among Ac-HHV8+ than Ac-HHV8- participants. CONCLUSIONS: In the present study, HHV8 DNA positivity was associated with low insulin secretion in this sub-Saharan African diabetes population. PMID- 29707906 TI - Detecting signatures of a sponge-associated lifestyle in bacterial genomes. AB - Sponges interact with diverse and rich communities of bacteria that are phylogenetically often distinct from their free-living counterparts. Recent genomics and metagenomic studies have indicated that bacterial sponge symbionts also have distinct functional features from free-living bacteria; however, it is unclear, if such genome-derived functional signatures are common and present in different symbiont taxa. We therefore compared here a large set of genomes from cultured (Pseudovibrio, Ruegeria and Aquimarina) and yet-uncultivated (Synechococcus) bacteria found in either sponge-associated or free-living sources. Our analysis revealed only very few genera-specific functions that could be correlated with a sponge-associated lifestyle. Using different sets of sponge associated and free-living bacteria for each genus, we could however show that the functions identified as 'sponge-associated' are dependent on the reference comparison being made. Using simulation approaches, we show how this influences the robustness of identifying functional signatures and how evolutionary divergence and genomic adaptation can be distinguished. Our results highlight the future need for robust comparative analyses to define genomic signatures of symbiotic lifestyles, whether it is for symbionts of sponges or other host organisms. PMID- 29707907 TI - Secondary Hyperparathyroidism and Protein-Energy Wasting in End-Stage Renal Disease. AB - Protein-energy wasting (PEW), a syndrome involving adverse changes in nutrition and body composition, is a serious problem associated with morbidity and mortality in patients with end-stage renal disease (ESRD). The pathogenesis of PEW is multifactorial, and the underlying mechanisms are not fully understood. However, recent translational work has provided compelling evidence for a causal role of parathyroid hormone (PTH) in the pathogenesis of adipose tissue browning and increased energy expenditure, a critical component of PEW in ESRD. These results provide a biological explanation for the clinical association between secondary hyperparathyroidism (SHPT) and PEW in hemodialysis patients and may serve as an additional rationale for treating SHPT. Large-scale clinical and epidemiological studies should determine the clinical significance of SHPT as a contributor to PEW and establish the optimal management of SHPT to ameliorate PEW. PMID- 29707909 TI - Evolving concepts in classification of systemic vasculitis: where are we and what is the way forward? PMID- 29707908 TI - Why Do Mice Overeat High-Fat Diets? How High-Fat Diet Alters the Regulation of Daily Caloric Intake in Mice. AB - OBJECTIVE: Ad libitum high-fat diets (HFDs) spontaneously increase caloric intake in rodents, which correlates positively with weight gain. However, it remains unclear why rodents overeat HFDs. This paper investigated how changing the proportion of diet that came from HFDs might alter daily caloric intake in mice. METHODS: Mice were given 25%, 50%, or 90% of their daily caloric need from an HFD, along with ad libitum access to a low-fat rodent chow diet. Food intake was measured daily to determine how these HFD supplements impacted total daily caloric intake. Follow-up experiments addressed the timing of HFD feeding. RESULTS: HFD supplements did not alter total caloric intake or body weight. In a follow-up experiment, mice consumed approximately 50% of their daily caloric need from an HFD in 30 minutes during the light cycle, a time when mice do not normally consume food. CONCLUSIONS: An HFD did not disrupt regulation of total daily caloric intake, even when up to 90% of total calories came from the HFD. However, HFDs increased daily caloric intake when provided ad libitum and were readily consumed by mice outside of their normal feeding cycle. Ad libitum HFDs appear to induce overconsumption beyond the mechanisms that regulate daily caloric intake. PMID- 29707910 TI - Disagreement between service-users and clinicians assessment of physical health during early psychosis. AB - AIMS: Physical illnesses account for the majority of excess deaths following psychosis; access to care and treatment is inequitable and schizophrenia has now been dubbed the life-shortening disease. We compared service-users and clinician's perspectives of their physical health assuming that one of the fundamental issues in prompting screening and treatment is the view that health is poor. METHODS: Data comprising sample characteristics, diagnosis, symptoms, insight, antecedents to psychosis and physical health perspectives were obtained prospectively as part of a larger epidemiological study of first-episode psychosis. We compared physical health perspectives between service-users and clinicians and examined clinical correlates. RESULTS: Contrary to our expectations, we found that service-users reported poorer physical health over time than clinicians did. CONCLUSION: Reconciling service-users and clinician's views of physical health may be an important step towards collaborative care and improving access to better quality healthcare for serious mental illness. PMID- 29707912 TI - Cell Surface MHC Class I Expression Is Limited by the Availability of Peptide Receptive "Empty" Molecules Rather than by the Supply of Peptide Ligands. AB - While antigen processing and presentation (APP) by the major histocompatibility complex class I (MHC-I) molecules have been extensively studied, a question arises as to whether the level of MHC-I expression is limited by the supply of peptide-receptive (empty) MHC molecules, or by the availability of peptide ligands for loading. To this end, the effect of interferons (IFNs) on the MHC peptidomes of human breast cancer cells (MCF-7) were evaluated. Although all four HLA allotypes of the MCF-7 cells (HLA-A*02:01, B*18, B*44, and C*5) present peptides of similar lengths and C-termini, which should be processed similarly by the proteasome and by the APP chaperones, the IFNs induced differential modulation of the HLA-A, B, and C peptidomes. In addition, overexpression of recombinant soluble HLA-A*02:01, introduced to compete with the identical endogenous membrane-bound HLA-A*02:01 for peptides of the MCF-7 cells, did not alter the expression level or the presented peptidome of the membrane-bound HLA A*02:01. Taken together, these results indicate that a surplus supply of peptides is available inside the ER for loading onto the MHC-I peptide-receptive molecules, and that cell surface MHC-I expression is likely limited by the availability of empty MHC molecules. PMID- 29707911 TI - An investigation into the use of radiographer abnormality detection systems by Queensland public hospitals. AB - INTRODUCTION: A Radiographer Abnormality Detection System (RADS), such as the 'red dot system', involves radiographers highlighting the presence of potential acute abnormalities on radiographs in the emergency setting. The literature suggests little additional training is required of radiographers to participate in such a system, posing little impact on current workflow while remaining a cost effective, easy-to-implement program. However, its use outside the United Kingdom is sporadic. The purpose of this study was to investigate the frequency of use of a RADS in Queensland public hospitals. METHODS: A cross-sectional web-based questionnaire was developed and distributed to 28 medical imaging department directors throughout metropolitan, rural and remote Queensland (Australia) public hospitals. The results of this survey were analysed using conventional descriptive statistics of response frequencies and the percentage of the sample. RESULTS: The questionnaire was completed by 25 radiography directors (89% response rate). Sixteen percent of respondents, all metropolitan-based, indicated a RADS was in operation (n = 4/25; 16%). Respondents without a RADS (n = 21/21; 100%) expressed interest in a trial. Just over half (n = 13/25; 52%) of the respondents believed their staff members were not trained appropriately to implement a RADS successfully. CONCLUSION: This study found an infrequent use of RADSs in Queensland public hospitals. This finding presents a unique opportunity for medical imaging professionals to enhance communication between the facets of a multidisciplinary emergency team via the implementation of RADS complemented by a radiographer commenting system. PMID- 29707913 TI - A simple method for combining binomial counts or proportions with hazard ratios for evidence synthesis of time-to-event data. AB - In studies with time-to-event data, outcomes may be reported as hazard ratios (HR) or binomial counts/proportions at a specific time point. If the intent is to synthesise evidence by performing a meta-analysis or network meta-analysis (NMA) using the HR as the measure of treatment effect, studies that only report binomial data cannot be included in the network. Methods for converting binomial data to HRs were investigated, so that studies reporting binomial data only could be included in a network of HR data. Estimating the log HR is relatively straightforward under the assumptions of proportional hazards and minimal censoring at the binomial data time point. Estimating the standard error of the log HR is harder, but a simple method based on using a Taylor series expansion to approximate the variance is proposed. Thus, we have 2 easy-to-calculate equations for the log HR and variance. The performance of the method was assessed using simulations and data from a NMA of multiple sclerosis treatments. In the simulation, our binomial method produced very similar HRs to those from survival analysis when censoring rates were low, and also when censoring rates were high but the event rate was low. In all situations, it outperformed using relative risk to approximate the HR. In the NMA, results were consistent between reported HRs and HRs derived from binomial data for studies that reported both types of data. This method may be useful for easily incorporating trials reporting binomial data into an evidence synthesis of HR data, under certain assumptions. PMID- 29707914 TI - Analysis of the changes in scalp hair angles: In vivo and in vitro comparison before and after tumescence. AB - OBJECTIVES: To estimate the hair shaft exit angles and also to check the effect of tumescence on the hair angles. MATERIALS AND METHODS: Ten patients undergoing first session of strip hair restoration were included. The strip was marked at the level of external occipital protuberance and superior nuchal line. Three hairs were marked, one near upper end, one near lower end, and one in the middle. About 10 mL of 0.5% xylocaine with adrenaline was used with the needle in the subdermal level. The hair angles were measured. After the strip harvest, small slivers were prepared and photographed. The hair shaft exit angles of the three hairs were calculated using the computer software. The Kruskal-Wallis test and multiple comparisons (Bonferroni's correction) were used to analyze the data statistically. RESULTS: The mean age of the patients was 23.4 years. The average preinjection (in vivo) hair angle was 52.82 degrees with 52.96 degrees in upper hairs (43.2 degrees -61.2 degrees ), 51.77 degrees in middle hairs (43.4 degrees -61.3 degrees ), and 53.72 degrees in lower hairs (38.4 degrees -61.3 degrees ). The average postinjection (in vivo) hair angle was 65.34 degrees with 65.05 degrees in upper hairs (55.1 degrees -86.4 degrees ), 65.63 degrees in the middle hairs (56.4 degrees -71.2 degrees ), and 65.35 degrees in the lower hairs (51.3 degrees -75.2 degrees ). Similarly, the postexcision (in vitro) hair angles was 71.91 degrees with 70.83 degrees in upper hairs (range, 56.8 degrees -95.7 degrees ), 72.19o in middle hairs (64.3 degrees -78.5 degrees ), and 72.71 degrees in the lower hairs (63.9 degrees -81.4 degrees ). CONCLUSION: The proper assessment of hair angles is very important and can be altered by the injection technique. PMID- 29707915 TI - Development of an organ-specific insert phantom generated using a 3D printer for investigations of cardiac computed tomography protocols. AB - INTRODUCTION: An ideal organ-specific insert phantom should be able to simulate the anatomical features with appropriate appearances in the resultant computed tomography (CT) images. This study investigated a 3D printing technology to develop a novel and cost-effective cardiac insert phantom derived from volumetric CT image datasets of anthropomorphic chest phantom. METHODS: Cardiac insert volumes were segmented from CT image datasets, derived from an anthropomorphic chest phantom of Lungman N-01 (Kyoto Kagaku, Japan). These segmented datasets were converted to a virtual 3D-isosurface of heart-shaped shell, while two other removable inserts were included using computer-aided design (CAD) software program. This newly designed cardiac insert phantom was later printed by using a fused deposition modelling (FDM) process via a Creatbot DM Plus 3D printer. Then, several selected filling materials, such as contrast media, oil, water and jelly, were loaded into designated spaces in the 3D-printed phantom. The 3D-printed cardiac insert phantom was positioned within the anthropomorphic chest phantom and 30 repeated CT acquisitions performed using a multi-detector scanner at 120 kVp tube potential. Attenuation (Hounsfield Unit, HU) values were measured and compared to the image datasets of real-patient and Catphan(r) 500 phantom. RESULTS: The output of the 3D-printed cardiac insert phantom was a solid acrylic plastic material, which was strong, light in weight and cost-effective. HU values of the filling materials were comparable to the image datasets of real-patient and Catphan(r) 500 phantom. CONCLUSIONS: A novel and cost-effective cardiac insert phantom for anthropomorphic chest phantom was developed using volumetric CT image datasets with a 3D printer. Hence, this suggested the printing methodology could be applied to generate other phantoms for CT imaging studies. PMID- 29707916 TI - Association between Parathyroid Hormone and Cardiovascular Disease. AB - Although parathyroid hormone is known to be related with calcium and phosphate metabolism, it has been also reported to have several effects on the cardiovascular system including heart and vessels. However, the detailed pathophysiological mechanisms remain unclear. Clinical studies have indicated that parathyroid hormone is associated with cardiovascular events and mortality not only in patients with chronic kidney disease but also in those without chronic kidney disease. As a possible mechanism, it is thought that parathyroid hormone is associated with the renin-angiotensin-aldosterone system and has direct effects on the cardiovascular system. Therefore, we should pay attention to not only the control of serum phosphate and calcium levels but also the control of serum parathyroid hormone levels, especially in patients with chronic kidney disease. PMID- 29707917 TI - Evidence of Powassan/deer tick virus in adult black-legged ticks (Ixodes scapularis) recovered from hunter-harvested white-tailed deer (Odocoileus virginianus) in Pennsylvania: A public health perspective. AB - Studies reporting tick infection rates for Powassan virus (POWV), an emerging zoonotic arthropod-borne pathogen responsible for POWV disease in the Commonwealth of Pennsylvania, are limited. To determine the presence and ascertain a statewide prevalence of POWV, ticks were collected from 9,912 hunter harvested white-tailed deer (Odocoileus virginianus) heads presented to six regional Pennsylvania Game Commission Chronic Wasting Disease sampling stations in early December of 2013, 2014 and 2015. Of the 2,973 ticks recovered, 1,990 (66.9%) were identified as adult Ixodes scapularis (black-legged tick). The 1,990 I. scapularis ticks were PCR-tested for the presence of POWV. The ticks had a statewide Powassan/deer tick virus infection rate of 0.05%, providing evidence of this pathogen in Pennsylvania's adult I. scapularis ticks and supporting the need for more comprehensive pathogen prevalence assessment strategies, as well as increased public health awareness for this emerging zoonotic arthropod-borne pathogen of public health concern. PMID- 29707919 TI - Optimising lameness detection in dairy cattle by using handheld infrared thermometers. AB - Lameness is one of the most serious economic and welfare issues in the dairy industry. Early detection of lameness can be difficult, but provision of early treatment is crucial. Previous studies have used infrared thermography to show that increased foot temperature (FT) is associated with lameness and foot lesions. However, poor accuracy has limited the management application potential. This study analysed ambient-temperature (AT)-adjusted foot-surface temperatures and temperature differences between the hind feet of individual cows to enhance lameness detection. Cow FTs were recorded on a 990-cow farm using an infrared thermometer fortnightly for 6 months. Additionally, mobility level was scored using the AHDB Dairy 4-point scale. The averages of FTs and ATs were 23.83 +/- 0.03 degrees C and 13.99 +/- 1.60 degrees C, respectively. The FT of cows with lameness was significantly higher than that of cows without lameness (P < 0.001). Increases in FTs correlated with the mobility score (MS) (P < 0.001). According to receiver operating characteristic (ROC) curves, the optimal threshold based on actual FTs was 23.3 degrees C with 78.5% sensitivity and 39.2% specificity. However, the ROC curve for the AT-adjusted FT and FT difference parameters showed minimal improvements over the FT in detecting lameness. In conclusion, the infrared thermometer results demonstrated the association between elevated FTs and lameness, but further improvements to this detection technique will be required before it can be implemented as a management tool for detecting cows that could benefit from treatment. With additional validation, the technique could be used as a screening device to identify cows in need of further assessment. PMID- 29707918 TI - The combined effect of high-intensity intermittent training and vitamin D supplementation on glycemic control in overweight and obese adults. AB - High-intensity intermittent training (HIIT) has been shown to reduce the risk of chronic conditions including the development of type 2 diabetes mellitus (T2DM). Independently, a low vitamin D status has also been linked to the prevalence of T2DM. The aim of this study was to investigate if there was a synergistic metabolic effect of HIIT and vitamin D supplementation on glycemic control. A total of 20 male and female participants (age, 34 +/- 9 year; BMI, 31.4 +/- 2.8 kg.m-2 ) completed 6 weeks HIIT, and were randomized to ingest 100 MUg.day-1 of vitamin D3 or placebo. Response to an oral glucose tolerance test (OGTT) was determined at baseline and at 72 h postintervention. Glucose tolerance was improved as a result of the HIIT intervention, shown through a reduction in glucose and insulin concentrations during the OGTT, accompanied by a decrease in glucose (829 +/- 110 to 786 +/- 139 mmol.h-1 .L-1 ; P = 0.043) and insulin (8101 +/- 4755-7024 +/- 4489 mU.h-1 .L-1 ; P = 0.049) area under the curve (AUC). Supplementation increased 25-hydroxyvitamin D3 concentration by 120% to a sufficiency status (P < 0.001). However, the consumption of vitamin D3 seemed to attenuate the glucose response during an OGTT. Triglyceride content was lowered following the intervention (P = 0.025). There was no effect of the intervention on insulin sensitivity (IS) indices: ISIMatsuda and HOMA-IR. Our findings demonstrate that HIIT improves glucose tolerance in nondiabetic overweight and obese adults; however vitamin D3 supplementation did not proffer any additional positive effects on the measured indices of metabolic health. PMID- 29707920 TI - Highly Tough Bioinspired Ternary Hydrogels Synergistically Reinforced by Graphene/Xonotlite Network. AB - The application fields of hydrogels are often severely limited by their weak mechanical performance. It is therefore highly demanded to develop an effective strategy to fabricate mechanically strong hydrogels. Herein, a kind of bioinspired ternary hydrogel consisting of graphene oxide (GO) nanosheets, xonotlite nanowires, and polyacrylamide (PAM) is constructed under the synergy of hydrogen bonding-induced GO/xonotlite network and the penetrated PAM chain network. Benefiting from the effective energy dissipation mechanism caused by double-network structural design and the strong hydrogen bonding interaction between two nanobuilding blocks, the gel exhibits a high toughness of 22 MJ m-3 at an elongation of 2750%. Even notched with 1/4 size, it still holds a large extensibility of 2180% its initial length. These high-performance hydrogels could be of great interest in the fields of tissue engineering and biomedical areas. PMID- 29707921 TI - Obesity, Weight Loss, and Progression of Disability in Rheumatoid Arthritis. AB - OBJECTIVE: Cross-sectional studies have demonstrated that obese patients with rheumatoid arthritis (RA) often report greater disability. The longitudinal effects of obesity, however, are not well-characterized. We evaluated associations between obesity, weight loss, and worsening of disability in patients of 2 large registry studies, which included patients who were followed for longer periods of time. METHODS: This study included patients with RA from the National Data Bank for Rheumatic Diseases (FORWARD) (n = 23,323) and the Veterans Affairs RA (VARA) registry study (n = 1,697). Results of the Health Assessment Questionnaire (HAQ) or Multidimensional HAQ (MD-HAQ) were recorded through follow-up. Significant worsening of disability was defined as an increase of >0.2 in HAQ or MD-HAQ scores. The Cox proportional hazards model was used to evaluate the risk of worsening of disability from baseline and to adjust for demographics, baseline disability, comorbidity, disease duration, and other disease features. RESULTS: At enrollment, disability scores were higher among severely obese patients compared to those who were overweight both in FORWARD (beta = 0.17 [95% confidence interval (95% CI) 0.14, 0.20]; P < 0.001) and in the VARA registry (beta = 0.17 [95% CI 0.074, 0.27]; P = 0.001). In multivariable models, patients who were severely obese at enrollment had a greater risk of progressive disability compared to overweight patients in FORWARD (HR 1.25 [95% CI 1.18, 1.33] P < 0.001) and in the VARA registry (HR 1.33 [95% CI 1.07, 1.66]; P = 0.01). Weight loss following enrollment was also associated with a greater risk in both cohorts. In the VARA registry, associations were independent of other clinical factors, including time-varying C-reactive protein and swollen joint count. CONCLUSION: Severe obesity is associated with a more rapid progression of disability in RA. Weight loss is also associated with worsening disability, possibly due to it being an indication of chronic illness and the development of age-related or disease-related frailty. PMID- 29707922 TI - Regulation of inflammatory mediator expression in bovine endometrial cells: effects of lipopolysaccharide, interleukin 1 beta, and tumor necrosis factor alpha. AB - An abnormal uterine environment can influence maternal-fetal communication, conception rate and disrupt normal embryo development, thereby affecting fertility and the reproductive performance of dairy cows. Animal variability means that development of endometrial cell lines with appropriate characteristic are required. We evaluated the effect of an infectious agent (i.e., bacterial lipopolysaccharide; LPS) and proinflammatory mediators (i.e., Interleukin 1 beta; IL-1beta, and tumor necrosis factor alpha; TNFalpha) on inflammatory mediator gene expression and production by bovine endometrial epithelial (bEEL) and stromal (bCSC) cell lines. Expression of CXCL8/IL8, IL1A, IL1B, and IL6 cytokine genes was significantly upregulated in both epithelial and stromal cells when treated with LPS and IL-1beta. LPS treatment of epithelial cells (compared with treatment by IL-1beta and TNFalpha) exhibited greater CXCL8/IL8, IL1A, IL1B, and IL6 cytokine gene expression. Whereas, in stromal cells, IL-1beta treatment (compared with LPS and TNFalpha) exhibited greater CXCL8/IL8, IL1A, IL1B, and IL6 cytokine gene expression. Interestingly, bEEL and bCSC cells treated with IL 1beta increased IL1B gene expression, suggesting that IL-1beta may act unusually in an autocrine-positive feedback loop. Cytokine production was stimulated by these agents in both cell types. We suggest that the characteristics of these two cell lines make them excellent tools for the study of intrauterine environment. PMID- 29707923 TI - Hypertensive Disorders in Pregnant Women Receiving Fertility Treatments. AB - Hypertensive disorders (HDs) as the most prevalent medical problem during pregnancy, predispose the patient to a lot of comorbidities and may even cause maternal or fetal death. The rate of infertility has been increasing in recent decades. So, we collected and summarized data about the co-existence of these two entities and found that HDs are somewhat more common in women receiving fertility treatments regardless of pathophysiologic correlation of infertility and hypertension or older age and chance of multiple pregnancies. PMID- 29707924 TI - The Effect of Cognitive Behavioral Therapy on Marital Quality among Women. AB - Background: Marital quality reflects the individual's overall evaluation of marital relationship. The aim of study was examine the effect of cognitive behavioral counseling on marital quality among women. MATERIALS AND METHODS: The experimental study was a randomized clinical trial with two groups, on 198 qualified women who referred to selected health care centers in Hamadan, Iran in 2016. The intervention participants attended four 90-minute sessions of cognitive behavioral counseling. Demographic information questionnaire and marital quality scale [Revised Dyadic Adjustment Scale (RDAS)] were completed by the two groups before and after the intervention. To perform the comparisons, t test, Chi-square test and Fisher's test, Logistic Regression and covariance analysis were used. Covariance analysis or change analysis were employed. Statistical analysis was done using SPSS Software, version 21.0. The significance level was set at 5% (P<0.05). RESULTS: According to the results of the present study, the mean age in the control group and the intervention group was 23.58 +/- 7.54 and 35.04 +/- 7.91 years old, respectively. Covariance analysis was utilized to examine the marital quality scores. In this analysis, after modification of the variables of age, marital quality score of agreement and satisfaction before the intervention, and income status, the total marital quality score experienced a significant change in all dimensions (P<0.05) and the mean scores increased remarkably. Moreover, according to the cut-off point of the dimensions, the scores of all dimensions increased remarkably and the proportion of individuals with high marital quality before and after the intervention changed significantly (P<0.05). CONCLUSION: Due to the role of sexual relations in stabilizing marriage, cognitive behavioral consultation was effective in improving marital quality especially after agreement and can be used in health care centers in order to improve the relationship between couples and reduce divorce rates (Registration number: IRCT201610209014N125). PMID- 29707925 TI - Evaluating The Impact of Risk Factors on Birth Weight and Gestational Age: A Multilevel Joint Modeling Approach. AB - Background: Abnormalities in birth weight and gestational age cause several adverse maternal and infant outcomes. Our study aims to determine the potential factors that affect birth weight and gestational age, and their association. MATERIALS AND METHODS: We conducted this cross-sectional study of 4415 pregnant women in Tehran, Iran, from July 6-21, 2015. Joint multilevel multiple logistic regression was used in the analysis with demographic and obstetrical variables at the first level, and the hospitals at the second level. RESULTS: We observed the following prevalence rates: preterm (5.5%), term (94%), and postterm (0.5%). Low birth weight (LBW) had a prevalence rate of 4.8%, whereas the prevalence rate for normal weight was 92.4, and 2.8% for macrosomia. Compared to term, older mother's age [odds ratio (OR)=1.04, 95% confidence interval (CI): 1.02-1.07], preeclampsia (OR=4.14, 95% CI: 2.71-6.31), multiple pregnancy (OR=18.04, 95% CI: 9.75- 33.38), and use of assisted reproductive technology (ART) (OR=2.47, 95% CI: 1.64-33.73) were associated with preterm birth. Better socioeconomic status (SES) was responsible for decreased odds for postterm birth compared to term birth (OR=0.53, 95% CI: 0.37-0.74). Cases with higher maternal body mass index (BMI) were 1.02 times more likely for macrosomia (95% CI: 1.01-1.04), and male infant sex (OR=1.78, 95% CI: 1.21-2.60). LBW was related to multiparity (OR=0.59, 95% CI: 0.42-0.82), multiple pregnancy (OR=17.35, 95% CI: 9.73-30.94), and preeclampsia (OR=3.36, 95% CI: 2.15-5.24). CONCLUSION: Maternal age, SES, preeclampsia, multiple pregnancy, ART, higher maternal BMI, parity, and male infant sex were determined to be predictive variables for birth weight and gestational age after taking into consideration their association by using a joint multilevel multiple logistic regression model. PMID- 29707926 TI - Attitude of Law and Medical Students to Oocyte Donation. AB - Background: Among the young generation, medical and law students' attitude towards third party reproduction is very important because they will be directly involved in restricting or developing the programs that will support it in the future. The aim of this survey was to investigate attitude of law and medical students to oocyte donation and key aspects of this kind of third party. MATERIALS AND METHODS: In analytical cross-sectional study, 345 medical and law students were randomly selected using stratified sampling. Data was collected using attitude toward donation- oocyte (ATOD-O) questionnaire. Responses were on a 5-point Likert scale. Data were analyzed according to established statistical approach by Heeren and D'Agostino. RESULTS: The majority of the participants agreed with oocyte donation being the last choice for infertility treatment. There was a significant difference between medical students and law students regarding the acceptance of oocyte donation (3.23 vs. 3.53, P=0.025). In addition, female participants were more tolerant on receiving donated oocytes from their sisters than male participants (3.01 vs. 2.58, P=0.002) and finally, a higher number of the participants had a positive attitude towards anonymity of the donor and the recipient to one another (3.93 vs. 3.86, P=0.580). The vast majority of female students believed that the oocyte recipient naturally likes that child (P<0.0001). CONCLUSION: In the current study, a great majority of law and medical students support oocyte donation as an alternative way of starting a family. There is an interest among female students in donating oocytes anonymously. The majority believed that the oocyte recipient family will like the donor oocyte child naturally. PMID- 29707927 TI - Relationship between Quality of Life, Relationship Beliefs and Attribution Style in Infertile Couples. AB - Background: Many infertile couples experience psychological distress and suffer from impaired quality of life. Generally, when couples are dealing with uncontrolled events such as infertility, it is important to manage it well and to use the suitable coping style; so this can represent an example of attribution style. The purpose of this study is to investigate the quality of life, relationship beliefs and attribution style in infertile couples. MATERIALS AND METHODS: This cross-sectional study consisted of 50 infertile couples, who were at least 18 years of age and could read and write in Persian. Participants provided demographic and general characteristics and completed the quality of life (SF-12), relationship belief inventory (RBI) and attribution style (ASQ) forms. Data was analyzed by the paired t test, Pearson correlation tests and multiple linear regression analysis, using SPSS version 22 statistical software. RESULTS: Overall, 50 infertile couples participated in our study. The males had a significantly higher score for quality of life compared to the females (P=0.019). In RBI subscales except "Disagreement is Destructive" all others significantly higher in wives than husbands. All subscales of RBI had a negative correlation with the quality of life. The quality of life had a significant correlation with positive internal (r=0.213, P=0.033). The adjusted regression model showed that the quality of life for males was higher than in females (beta=-3.098, P=0.024). CONCLUSION: The current data indicate that in infertile couples, the husbands have a higher quality of life in comparison to their wives. Also, all subscales of relationship beliefs have a negative correlation with the quality of life, but in attribution style, just internal attribution style for positive events is associated with the quality of life. In general, there is a correlation between relationship beliefs and the quality of life in infertile couples. PMID- 29707928 TI - Evaluation of Factors Associated with Sexual Function in Infertile Women. AB - Background: Infertility is a major and problem influencing different aspects of couples life, especially those of women. Sexual dysfunction is the silent partner of infertility. This study aimed to identify the above-mentioned factors to make necessary decisions and perform efficient interventions to improve the sexual health of infertile women. This study investigated the factors influencing sexual dysfunction in infertile women in Mashhad, Iran. MATERIALS AND METHODS: This cross-sectional study was conducted on 85 infertile women visiting governmental Infertility Clinic and Research Center in Mashhad, Iran. The convenience sampling method was used in this study. The research tools included a demographic and infertility information form, a sexual self-efficacy questionnaire based on Schwarzer's General Self-Efficacy Scale, Female Sexual Function Index (FSFI), and Evaluation and Nurturing Relationship Issues, Communication, and Happiness (ENRICH) Marital Satisfaction Scale. The descriptive statistical tests and logistic regression method were used to analyze data. RESULTS: The mean age of women was 31.18 +/- 5.56 years old. The majority of participants (36.7%) had higher educations, and 60% of them were housewives. Most of their husbands (49.4%) were self-employed. The mean period of infertility awareness was 6.02 +/- 4.47 years, and the mean period of infertility treatment was 4.11 +/- 4.46 years. The following variables influenced the sexual function of infertile women: sexual self-efficacy, sexual satisfaction, marital satisfaction, the educational level of both wife and husband, income, satisfaction with spouse appearance, and the high costs of infertility treatment. CONCLUSION: The findings indicated that some factors such as sexual self-efficacy, marital satisfaction, sexual satisfaction, education, and cost of infertility treatment are associated with sexual function in infertile women. PMID- 29707929 TI - The Persian Version of Fertility Adjustment Scale: Psychometric Properties. AB - Background: Infertility is a common clinical problem. Psychological adjustment to infertility refers to changing the viewpoint and attitude of an infertile person toward infertility problems, treatments and possible outcomes. The present study aims to prepare a valid and reliable scale for assessing the psychological adjustment to infertility, by determining the cultural adaptation, validity and reliability of the Persian version of the Fertility Adjustment Scale. MATERIALS AND METHODS: This is a cross-sectional study performed to localize and validate the Fertility Adjustment Scale, in which 40 infertile women and 40 healthy subjects (fertile or having children) were detected by a gynecologist and the subjects who completed the Fertility Adjustment Scale (FAS) questionnaire were recruited. This study had four steps: in the first step, the literature was reviewed, in the second step, the scale was translated, in the third step, the content and construct validity indicators were calculated, and in the fourth step, reliability of the scale was validated. RESULTS: The mean (+/- SE and range) of fertility adjustment total scores in the infertile group and the control group were 43.2 (1.2 and 27-57) and 42.3 (1.5 and 18-57), respectively (P=0.623). The content validity was good according to Content Validity Index score (0.7-0.8). A two-component structure was extracted from factor analysis which approximately justifies 52.0% of the cumulative variations. A Cronbach's alpha value of 0.68 showed moderate reliability. CONCLUSION: The results of this study revealed that the infertility adjustment scale is a useful tool for the analysis of psychological reactions towards infertility problems and evaluation of the consequences of treating this social-clinical problem. PMID- 29707930 TI - Relationship between Health Literacy and Sexual Function and Sexual Satisfaction in Infertile Couples Referred to The Royan Institute. AB - Background: Health science and technology today is a rapidly growing field. Health is a multifaceted concept influenced by several factors, and health literacy is essential to deal properly with the current situation. In this study, the association between health literacy and sexual function and sexual satisfaction were investigated in 2016. MATERIALS AND METHODS: This descriptive and correlational study was conducted on 193 couples in the Royan Institute, Tehran. Data collection instruments were three standard questionnaires which included the Test of Functional Health Literacy, the Female Sexual Function Index (FSFI) and the International Index of Erectile Function, and the Iranian version of the Sexual Satisfaction Scale. The data were analyzed using SPSS-v23 software at a significance level of 0.05. RESULTS: Marginal health literacy, 49.7% among men and 44.1% among women, was more common than adequate or inadequate health literacy. Erectile function for the majority of men was appropriate (53.3%), compared to 16.6% who had perfect function and 30.1% for whom function was less than appropriate. The majority of women (57.0%) had sexual dysfunction. One hundred and three (53.3%) men had appropriate sexual function and 57% of women had normal sexual function. The greater proportion of men (50.8%) and women (46.1%) had good, rather than very good or less than good, sexual satisfaction. The results of chi-square tests indicated that greater health literacy was associated with higher levels of sexual function and sexual satisfaction among men and women. However, application of the Cramer's V test indicates that the strength of these associations is moderate to weak. CONCLUSION: Health literacy was marginal among most couples and its adverse impacts on sexual function and sexual satisfaction were confirmed. Accordingly, it is recommended that plans be developed to promote health literacy among infertile couples. PMID- 29707931 TI - Difference between Primary and Secondary Infertility in Morocco: Frequencies and Associated Factors. AB - Background: The main objective of this survey was to determine the difference between primary and secondary infertility in Morocco and the associated factors among women, who are referred to public and private health centers in Morocco. MATERIALS AND METHODS: In this cross-sectional study, 619 infertile women referring to public and private health centers in Marrakech-Safi region, were selected by simple random sampling method. This study was conducted between 1 October 2013 and 31 December 2015. Socio-economic status, demographic characteristics, couple's age, nutritional status and other data related to both male and female reproductive organs were collected by a questionnaire. Logistic regression was used to identify the associated factors to infertility. Statistical significance was set at 0.05. RESULTS: The rates of primary and secondary infertility were 67.37, and 32.63%, respectively. Multivariate analysis identified a model with three significant predictive factors of secondary infertility: duration of marriage [odds ratio (OR)=12.263: 2.289-65.685], socio economic status (OR=3.83: 1.011-14.70) and the ages of women (OR=1.268: 1.038 1.549). CONCLUSION: The causes of primary and secondary infertility were not always a woman's problem, but both man and woman contribute to infertility. Multiple regression analysis showed that women's age, duration of marriage, and socioeconomic status are predictive variables that decrease the chance of fertility among women with secondary infertility. PMID- 29707932 TI - The Association of PPARgamma Pro12Ala and C161T Polymorphisms with Polycystic Ovary Syndrome and Their Influence on Lipid and Lipoprotein Profiles. AB - Background: The aim of present study was to clarify the role of the peroxisome proliferator-activated receptor (PPAR) gamma Pro12Ala and C161T polymorphisms in the pathogenesis of polycystic ovary syndrome (PCOS) and their influence on lipid and lipoprotein profiles of patients. MATERIALS AND METHODS: The present cross sectional study consisted of 50 women with PCOS, who referred to the Kermanshah University of Medical Sciences Clinic between April and October 2015, and 233 unrelated age-matched healthy women from the same region (West Iran). The PPARgamma Pro12Ala and PPARgamma C161T polymorphisms were genotyped using the polymerase chain reaction-restriction fragment length polymorphism method. Fasting blood sugar (FBS), serum triglycerides (TG), cholesterol, low density lipoprotein- cholesterol (LDL-C), high density lipoproteincholesterol (HDL-C) and estradiol levels were measured. RESULTS: The serum level of estradiol was significantly lower in PCOS patients compared to healthy women. The PPARgamma Pro12Ala (CG) genotype increased the risk of PCOS 2.96-fold. The frequency of the PPARgamma T allele (at C161T) was 21% in patients and 17.2% in controls with no significant difference (P=0.52). In all studied individuals, the PPARgamma CG genotype was associated with significantly higher levels of TG. However, significantly lower levels of total cholesterol and LDL-C were observed in PPARgamma TT individuals compared with those with the CC genotype. Within the PCOS group, the PPARgamma CG genotype was significantly associated with lower levels of estradiol compared with the CC genotype. Also, the CG genotype was significantly associated with higher levels of TG when compared with the CC genotype. CONCLUSION: Our study shows that, unlike PPARgamma C161T, PPARgamma Pro12Ala is associated with the risk of PCOS. Also, we found that the lipid and lipoprotein profiles significantly vary based on PPARgamma Pro12Ala and C161T genotypes. PMID- 29707933 TI - Molecular Evidence of Chlamydia trachomatis Infection and Its Relation to Miscarriage. AB - Background: Chlamydia trachomatis (CT) infection is the most common sexually transmitted disease in the world that can persist and also ascend in the genital tract. This intracellular and silent infection is related to some adverse pregnancy outcomes, such as miscarriage. The aims of this study were to explore the best CT screening tests using blood and vaginal samples and to investigate the correlation between CT infection and the incidence of miscarriage. MATERIALS AND METHODS: This case-control study was done in October 2013 through June 2014, using purposive sampling from 157 female participants with or without a history of miscarriage. The samples were taken after each participant had signed a letter of consent and had completed a questionnaire. To achieve the objectives of this study, polymerase chain reaction (PCR) and enzyme-linked immunosorbent assay (ELISA) tests were performed on vaginal swabs and blood samples, respectively. RESULTS: PCR results showed a significantly higher CT infection rate in the miscarriage group compared to the control group (11.3 vs. 0%, P=0.007). Anti-CT IgG and IgA antibodies were found in 4.2 and 2.1% of cases in the miscarriage group, and in 1.7 and 6.7% of cases in the control group, respectively (P>0.05). Despite lower humoral responses in this study, positive samples were detected only by one of the following techniques; PCR, ELISA IgA and ELISA IgG. It also should be noted that PCR worked best in terms of detection. CONCLUSION: Based on the obtained data, there is a strong association between molecular evidence of CT infection and miscarriage. A higher rate of CT detection in molecular tests compared to serological assays suggests that PCR could be used as the first choice assay for detection of C. trachomatis. However, the importance of serological tests in detecting potential past CT infection or upper genital infection not amenable to sampling is undeniable. PMID- 29707934 TI - Melatonin Improves The Developmental Competence of Goat Oocytes. AB - Background: DNA methylation is one the epigenetic mechanisms, which is critically involved in gene expression. This phenomenon is mediated by DNA methyl transferases and is affected by environmental stress, including in vitro maturation (IVM) of oocytes. Melatonin, as an antioxidant, may theoretically be involved in epigenetic regulation via reductions of reactive oxygen species. This study was performed to investigate DNA methylation and the possibility of goat oocyte development after treatment with different concentrations of melatonin. MATERIALS AND METHODS: This experimental study was performed to investigate DNA methylation and the possibility of goat oocyte development after treatment with different concentrations of melatonin. For this purpose, oocytes with granulated cytoplasm were selected and co-cultured with at least two layers of cumulus cells in maturation medium with 10-6 M, 10-9 M, 10-12 M and 0-M (as control group) of melatonin. Nucleus status, glutathione content and developmental competence of the oocytes in each experimental group were assessed. Also, expression of genes associated with DNA methylation, including DNA methyltransferase 1 (DNMT1), DNA methyltransferase 3b (DNMT3b) and DNA methyltransferase 3a (DNMT3a) was evaluated by quantitative real time-polymerase chain reaction (RT-PCR). RESULTS: According to our findings, the percentage of oocytes that reached the M-II stage significantly increased in the 10-12 M group (P<0.05). Also, a significant elevation of glutathione content was observed in melatonin-treated oocytes (P<0.05). Analysis of blastocyst formation revealed that developmental competence of the oocytes was higher than the control group (P<0.05). It was observed that melatonin treatment decreased expression levels of DNA methyltransferases (DNMTs) and global DNA methylation (P<0.05). In addition, the expression of melatonin receptor1A (MTNR1A) was detected in both cumulus and oocyte by RT-PCR. CONCLUSION: The results suggested that in goat model melatonin affects DNA methylation pattern, leading to an improvement in the developmental competence of the oocytes. PMID- 29707935 TI - Do Serum Vitamin D Levels Have Any Effect on Intrauterine Insemination Success? AB - Background: Recent studies have shown that vitamin D has an essential role in the reproductive system. In this study, we aimed to investigate the effect of vitamin D levels in patients undergoing ovulation induction (OI), and subsequent intrauterine insemination (IUI) procedure. MATERIALS AND METHODS: One hundred and four infertile and one hundred and three fertile women were recruited in this cross-sectional study which was conducted in a tertiary level maternity hospital. Infertile patients were divided into pregnant and non-pregnant subgroups after treatment. Individual characteristics and 25-hydroxyvitamin D3 [25 (OH) D3] levels were compared between the groups. RESULTS: The vast majority of our study population consisted of women who had vitamin D deficiency (96.6%). There was no statistically significant difference between infertile and fertile groups in terms of serum 25 (OH) D3 levels (P=0.512). Similarly, no significant difference was observed between the pregnant and non-pregnant subgroups of infertile patients regarding 25 (OH) D3 levels (P=0.267). CONCLUSION: There is no association between female infertility and serum vitamin D levels. Vitamin D does not predict pregnancy in infertile women undergoing OI with IUI. Further research which will provide a comparison between much more women who have deficient and sufficient 25 (OH) D3 levels is warranted. PMID- 29707936 TI - Effects of Varicocelectomy on Serum Testosterone Levels among Infertile Men with Varicocele. AB - Background: The main purpose of this study is to evaluate the effects of varicocelectomy on serum testosterone levels and semen quality in infertile men who suffer from varicocele. MATERIALS AND METHODS: This prospective study enrolled 115 subjects with clinical varicocele grades II and III and 240 fertile men as the control group. Total volume of testosterone serum level (ng/dl) and semen quality were compared before and after microscopic varicocelectomy. We normalized testosterone serum levels for age, grade, and testis size basis. SPSS 20 software was used to analyze the data. All results of continuous variables were reported as mean +/- SD. Statistical significance was set at a P<0.05. RESULTS: The mean ages of individuals who participated in the treatment (32.2 +/- 5.23) and control (32.8 +/- 5.27) groups were similar. There were similar mean values for adjusted testosterone levels between the varicocele (567 +/- 222 ng/ml) and control (583 +/- 263 ng/ml) groups. In the varicocele group, the adjusted testosterone levels insignificantly increased to 594 +/- 243 ng/ml. Among semen parameters, only mean sperm concentration significantly increased after varicocelectomy. CONCLUSION: Despite increases in sperm concentration, adjusted testosterone levels did not significantly improve after varicocelectomy. PMID- 29707938 TI - Novel LAMA2 Gene Mutations Associated with Merosin-Deficient Congenital Muscular Dystrophy AB - Background: Merosin-deficient congenital muscular dystrophy (MDC1A) is a rare autosomal recessive genetic disease occurred due to mutations in the LAMA2 gene. This study investigated the molecular genetics of three Iranian MDC1A patients who manifested hypotonia, muscle weakness at birth, elevated levels of creatine kinase, and normal magnetic resonance imaging before the age of six months Methods: Peripheral blood samples were collected from three unrelated patients and their families after obtaining informed written consents. Genomic DNA was extracted and sequenced using next-generation sequencing, followed by Sanger confirmation. Results: Sequencing results revealed a known missense mutation, c.8665G>A, and two novel heterozygous sequencing variants affecting splicing, c.397-4_c.478del and c.7452-1G>A, in the LAMA2 gene. Reverse transcriptase-PCR analysis showed that a new intronic variant, c.7452-1G>A, produced aberrant splicing pattern in the patient. Conclusion: This study expands the mutation spectrum of LAMA2 and assists in the diagnosis, genetic counseling, and prenatal diagnosis of the affected families. PMID- 29707937 TI - Detection of Y Chromosome Microdeletions and Hormonal Profile Analysis of Infertile Men undergoing Assisted Reproductive Technologies. AB - Background: Y chromosome deletions (YCDs) in azoospermia factor (AZF) region are associated with abnormal spermatogenesis and may lead to azoospermia or severe oligozoospermia. Assisted reproductive technologies (ART) by intracytoplasmic sperm injection (ICSI) and testicular sperm extraction (TESE) are commonly required for infertility management of patients carrying YCDs. The aim of this study was to estimate the frequency of YCDs, to find the most frequent variant in infertile men candidate for ART and to compare YCD distribution with a control fertile group. The semen parameters, hormonal profiles and ART outcomes of the infertile group were studied. MATERIALS AND METHODS: This case-control study consisted of 97 oligozoospermic or non-obstructive azoospermic (NOA) infertile men, who had undergone ART, as the case group and 100 fertile men as the control group. DNA samples were extracted from blood samples taken from all 197 participants and YCDs were identified by multiplex polymerase chain reaction (PCR) of eight known sequence-tagged sites. The chi-square test was used to compare the mean values of hormone and sperm parameters between the two groups. P<0.05 was considered statistically significant. RESULTS: No YCD was detected in the control group. However, 20 out of 97 (20.6%) infertile men had a YCD. AZFc, AZFbc and AZFabc deletions were detected in 15 (75%), four (20%) and one (5%) YCD positive patients. No fertilization or clinical pregnancy was seen following ICSI in this sub-group with YCD. The mean level of FSH was significantly higher in the group with YCD (28.45 +/- 22.2 vs. 4.8 +/- 3.17 and 10.83 +/- 7.23 in YCD negative patients with and without clinical pregnancy respectively). CONCLUSION: YCD is frequent among NOA men and YCD screening before ART and patient counseling is thus strongly recommended. PMID- 29707939 TI - Immobilized Ferrous Ion and Glucose Oxidase on Graphdiyne and Its Application on One-Step Glucose Detection. AB - Graphdiyne (GDY) is a novel two-dimensional (2D) carbon allotrope with sp hybridized carbon atoms and hexagonal rings. Because of its unique structure and electronic property, GDY was reported as a promising candidate applied in energy storage, catalysis, biosensing and so on. However, using GDY as a platform to immobilize metal ion or enzyme was still not reported. Here, we presented a GDY based composite with dual-enzyme activity by immobilizing ferrous ion and glucose oxidase onto GDY sheet. GDY showed great adsorption capacity and maintained the high catalytic activity of ferrous ion. The ferrous ion preferred to adsorb in between the neighboring two C-C triple bonds of GDY with lower adsorption energy (-5.64 eV) if compared to graphene (-1.69 eV). Meanwhile, GDY exhibited the ability of adsorbing glucose oxidase while did not obviously influence the structure and catalytic activity of the enzyme. The as-prepared composite was successfully used in one-step blood glucose detection. This work provides a new insight on ion and enzyme immobilization by 2D material. PMID- 29707940 TI - O-O Radical Coupling: From Detailed Mechanistic Understanding to Enhanced Water Oxidation Catalysis. AB - A deeper mechanistic understanding of the key O-O bond formation step of water oxidation by the [Ru(bda)(L)2] (bdaH2 = 2,2'-bipyridine-6,6'-dicarboxylic acid; L is a pyridine or isoquinoline derivative) family of catalysts is reached through harmonious experimental and computational studies of two series of modified catalysts with systematic variations in the axial ligands. The introduction of halogen and electron-donating substituents in [Ru(bda)(4-X-py)2] and [Ru(bda)(6-X isq)2] (X is H, Cl, Br, and I for the pyridine series and H, F, Cl, Br, and OMe for the isoquinoline series) enhances the noncovalent interactions between the axial ligands in the transition state for the bimolecular O-O coupling, resulting in a lower activation barrier and faster catalysis. From detailed transition state calculations in combination with experimental kinetic studies, we find that the main contributor to the free energy of activation is entropy due to the highly organized transition states, which is contrary to other reports. Previous work has considered only the electronic influence of the substituents, suggesting electron-withdrawing groups accelerate catalysis, but we show that a balance between polarizability and favorable pi-pi interactions is the key, leading to rationally devised improvements. Our calculations predict the catalysts with the lowest Delta G? for the O-O coupling step to be [Ru(bda)(4-I-py)2] and [Ru(bda)(6,7-(OMe)2-isq)2] for the pyridine and isoquinoline families, respectively. Our experimental results corroborate these predictions: the turnover frequency for [Ru(bda)(4-I-py)2] (330 s-1) is a 10-fold enhancement with respect to that of [Ru(bda)(py)2], and the turnover frequency for [Ru(bda)(6-OMe isq)2] reaches 1270 s-1, two times faster than [Ru(bda)(isq)2]. PMID- 29707941 TI - Ultrathin WO3.0.33H2O Nanotubes for CO2 Photoreduction to Acetate with High Selectivity. AB - Artificial photosynthesis from CO2 reduction is severely hampered by the kinetically challenging multi-electron reaction process. Oxygen vacancies (Vo) with abundant localized electrons have great potential to overcome this limitation. However, surface Vo usually have low concentrations and are easily oxidized, causing them to lose their activities. For practical application of CO2 photoreduction, fabricating and enhancing the stability of Vo on semiconductors is indispensable. Here we report the first synthesis of ultrathin WO3.0.33H2O nanotubes with a large amount of exposed surface Vo sites, which can realize excellent and stable CO2 photoreduction to CH3COOH in pure water under solar light. The selectivity for acetum generation is up to 85%, with an average productivity of about 9.4 MUmol g-1 h-1. More importantly, Vo in the catalyst are sustainable, and their concentration was not decreased even after 60 h of reaction. Quantum chemical calculations and in situ DRIFT studies revealed that the main reaction pathway might be CO2 -> *COOH -> (COOH)2 -> CH3COOH. PMID- 29707942 TI - DNA Adduct Formation in the Lungs and Brain of Rats Exposed to Low Concentrations of [13C2]-Acetaldehyde. AB - Air pollution is a major environmental risk for human health. Acetaldehyde is present in tobacco smoke and vehicle exhaust. In this study, we show that [13C2] acetaldehyde induces DNA modification with the formation of isotopically labeled 1, N2-propano-2'-deoxyguanosine adducts in the brain and lungs of rats exposed to concentrations of acetaldehyde found in the atmosphere of megacities. The adduct, with the addition of two molecules of isotopically labeled acetaldehyde [13C4]-1, N2-propano-dGuo, was detected in the lung and brain tissues of exposed rats by micro-HPLC/MS/MS. Structural confirmation of the products was unequivocally performed by nano-LC/ESI+-HRMS3 analyses. DNA modifications induced by acetaldehyde have been regarded as a key factor in the mechanism of mutagenesis and may be involved in the cancer risks associated with air pollution. PMID- 29707943 TI - In-Plane Anisotropic Photoconduction in Nonpolar Epitaxial a-Plane GaN. AB - Nonpolar a-plane GaN epitaxial films were grown on an r-plane sapphire using the plasma-assisted molecular beam epitaxy system, with various nitrogen plasma power conditions. The crystallinity of the films was characterized by high-resolution X ray diffraction and reciprocal space mapping. Using the X-ray "rocking curve-phi scan", [0002], [1-100], and [1-102] azimuth angles were identified, and interdigitated electrodes along these directions were fabricated to evaluate the direction-dependent UV photoresponses. UV responsivity ( R) and internal gain ( G) were found to be dependent on the azimuth angle and in the order of [0002] > [1-102] > [1-100], which has been attributed to the enhanced crystallinity and lowest defect density along [0002] azimuth. The temporal response was very stable irrespective of growth conditions and azimuth angles. Importantly, response time, responsivity, and internal gain were 210 ms, 1.88 A W-1, and 648.9%, respectively, even at a bias as low as 1 V. The results were validated using the Silvaco Atlas device simulator, and experimental observations were consistent with simulated results. Overall, the photoresponse is dependent on azimuth angles and requires further optimization, especially for materials with in-plane crystal anisotropy. PMID- 29707944 TI - High Field Asymmetric Waveform Ion Mobility Spectrometry in Nontargeted Bottom-up Proteomics of Dried Blood Spots. AB - Despite the great potential of dried blood spots (DBS) as a source of endogenous proteins for biomarker discovery, the literature relating to nontargeted bottom up proteomics of DBS is sparse, primarily due to the inherent complexity and very high dynamic range associated with these samples. Here, we present proof-of concept results in which we have coupled high field asymmetric waveform ion mobility spectrometry (FAIMS) with liquid chromatography-tandem mass spectrometry (LC-MS/MS) for nontargeted bottom-up proteomics of DBS with the aim of addressing these challenges. We, and others, have previously demonstrated the benefits of FAIMS more generally in proteomics including improved signal-to-noise and extended proteome coverage, and the aim of the current work was to extend those benefits specifically to DBS. The DBS samples were either extracted by the more traditional manual "punch and elute" approach or by an automated liquid surface extraction (LESA) approach prior to trypsin digestion. The resulting samples were analyzed by LC-MS/MS and LC-FAIMS-MS/MS analysis. The results show that the total number of proteins identified increased by ~50% for the punch and elute samples and ~45% for the LESA samples in the LC-FAIMS-MS/MS analysis. For both the punch and elute samples and the LESA samples, ~30% of the total proteins identified were observed in both the LC-MS/MS and the LC-FAIMS-MS/MS data sets, illustrating the complementarity of the approaches. Overall, this work demonstrates the benefits of inclusion of FAIMS for nontargeted proteomics of DBS. PMID- 29707945 TI - Tetramethylpiperidine N-Oxyl (TEMPO), Phthalimide N-Oxyl (PINO), and Related N Oxyl Species: Electrochemical Properties and Their Use in Electrocatalytic Reactions. AB - N-Oxyl compounds represent a diverse group of reagents that find widespread use as catalysts for the selective oxidation of organic molecules in both laboratory and industrial applications. While turnover of N-oxyl catalysts in oxidation reactions may be accomplished with a variety of stoichiometric oxidants, N-oxyl reagents have also been extensively used as catalysts under electrochemical conditions in the absence of chemical oxidants. Several classes of N-oxyl compounds undergo facile redox reactions at electrode surfaces, enabling them to mediate a wide range of electrosynthetic reactions. Electrochemical studies also provide insights into the structural properties and mechanisms of chemical and electrochemical catalysis by N-oxyl compounds. This review provides a comprehensive survey of the electrochemical properties and electrocatalytic applications of aminoxyls, imidoxyls, and related reagents, of which the two prototypical and widely used examples are 2,2,6,6-tetramethylpiperidine N-oxyl (TEMPO) and phthalimide N-oxyl (PINO). PMID- 29707946 TI - Analysis and Chemistry of Novel Protein Oxidation Markers in Vivo. AB - Proteins continually undergo spontaneous oxidation reactions, which lead to changes in structure and function. The quantitative assessment of protein oxidation adducts provides information on the level of exposure to reactive precursor compounds with a high oxidizing potential and reactive oxygen species (ROS). In the present work, we introduce N6-(2-hydroxyethyl)lysine as a novel marker based on the ratio of glycolaldehyde and its oxidized form glyoxal. The high analytical potential was proven with a first set of patients undergoing hemodialysis versus healthy controls, in comparison with well-established parameters for oxidative stress. In vitro experiments with N1- t-BOC-lysine and N1- t-BOC-arginine enlightened the mechanistic relationship of glycolaldehyde and glyoxal. Oxidation was strongly dependent on the catalytic action of the epsilon amino moiety of lysine. Investigations on the formation of N6-carboxymethyl lysine revealed glycolaldehyde-imine as the more reactive precursor, even though an additional oxidative step is required. As a result, a novel and very effective alternative mechanism was unraveled. PMID- 29707947 TI - Over-Stoichiometry in Heavy Metal Oxides: The Case of Iono-Covalent Tantalum Trioxides. AB - Oxides of tantalum (common examples including TaO, TaO2, and Ta2O5) are key oxide materials for modern electronic devices, such as dynamic random-access memory and field effect transistors. Of late, new forms of stable tantalum oxides have been proposed as two-dimensional nanosheet structures with a nonconventional stoichiometry of TaO3 via soft-chemical delamination of RbTaO3. However, not much is known about the elusive nanosheet-structured TaO3, unlike other closely related common trioxides of W and Mo. In this work, using first-principles density functional theory calculations, we have studied various TaO3 structures as inspired from previous theoretical and experimental studies and discuss their properties with respect to the more conventional oxide of tantalum, Ta2O5. We have calculated their thermodynamics and lattice properties and have found a new stable-layered beta-TaO3 and its exfoliated monolayer phase (beta'). By further analyzing their electronic structures, we discuss the mixed iono-covalent bonding characteristics in the TaO3 phases, challenging the conventional formal oxidation state model for metal oxides. Finally, we propose how these new TaO3 oxide materials may be potentially useful in photodevice applications. PMID- 29707948 TI - A Modular Approach to the Synthesis of gem-Disubstituted Cyclopropanes. AB - A diastereoselective, Pd-catalyzed Suzuki-Miyaura coupling reaction of geminal bis(boryl)cyclopropanes has been developed. The reaction offers a highly modular approach to the synthesis of tertiary cyclopropylboronic esters. The resulting boronic esters may be further functionalized to afford a range of gem disubstituted cyclopropanes, which represent an important structural motif in the pharmaceutical industry. Sequential Suzuki-Miyaura cross-coupling reactions of gem-bis(boryl)cyclopropanes are also reported. The coupling protocols are compatible with a broad range of functionalized aryl and heteroaryl bromides. PMID- 29707949 TI - Covalent and Non-covalent Conjugation of Few-Layered Graphene Oxide and Ruthenium(II) Complex Hybrids and Their Energy Transfer Modulation via Enzymatic Hydrolysis. AB - Pyrene-containing ruthenium(II) tris-bipyridine complexes have been prepared. These complexes have been non-covalently attached onto the few-layered graphene oxide (GO) sheets through their high binding affinity for flat pi-surfaces. Alternatively, the reduced graphene oxide (rGO) sheets have also been covalently functionalized with the ruthenium(II) tris-bipyridine complex. The prepared conjugates have been characterized by transmission electron microscopy (TEM), energy-dispersive X-ray analysis (EDX), X-ray diffraction (XRD), atomic force microscopy (AFM), Raman spectroscopy, thermogravimetric analysis (TGA), and UV visible absorption spectroscopy. The energy transfer properties of the resulted conjugates between the graphene and transition metal complexes have been studied via esterase hydrolysis. The energy transfer efficiencies were found to vary with the separation between the donor and the acceptor units. PMID- 29707950 TI - Deciphering the Underlying Metabolomic and Lipidomic Patterns Linked to Thermal Acclimation in Saccharomyces cerevisiae. AB - Temperature is one of the most critical parameters for yeast growth, and it has deep consequences in many industrial processes where yeast is involved. Nevertheless, the metabolic changes required to accommodate yeast cells at high or low temperatures are still poorly understood. In this work, the ultimate responses of these induced transcriptomic effects have been examined using metabolomics-derived strategies. The yeast metabolome and lipidome have been characterized by 1D proton nuclear magnetic resonance spectroscopy and ultra-high performance liquid chromatography-mass spectrometry at four temperatures, corresponding to low, optimal, high, and extreme thermal conditions. The underlying pathways that drive the acclimation response of yeast to these nonoptimal temperatures were evaluated using multivariate curve resolution alternating least-squares. The analysis revealed three different thermal profiles (cold, optimal, and high temperature), which include changes in the lipid composition, secondary metabolic pathways, and energy metabolism, and we propose that they reflect the acclimation strategy of yeast cells to low and high temperatures. The data suggest that yeast adjusts membrane fluidity by changing the relative proportions of the different lipid families (acylglycerides, phospholipids, and ceramides, among others) rather than modifying the average length and unsaturation levels of the corresponding fatty acids. PMID- 29707951 TI - Synthesis of Halomethyl Isoxazoles/Cyclic Nitrones via Cascade Sequence: 1,2 Halogen Radical Shift as a Key Link. AB - A novel iminoxyl radical-promoted dichotomous regioselective 5-exo-trig cyclization onto vinylic halogen/1,2-halogen radical shift sequence is developed for the synthesis of halomethyl isoxazoles/cyclic nitrones using beta-halo beta,gamma- and gamma-halo-gamma,delta-unsaturated ketoximes as the substrates and PhI(OAc)2/TEMPO as the oxidation system. DFT calculations reveal that a halogen-bridged three-membered ring transition state is involved in the 1,2-Cl /Br-atom shift, while the 1,2-I atom migration can be taken into account with an elimination/readdition mechanism. The migration ability was indicated to be ranked in the following order: I > Br > Cl. PMID- 29707952 TI - Structural Elucidation and Biomimetic Synthesis of (+/-)-Cochlactone A with Anti Inflammatory Activity. AB - A pair of new natural meroterpenoids, (+/-)-cochlactone A (1) possessing a bicyclo[4.4.0]decane ring system with a gamma-lactone fragment, was isolated from Ganoderma cochlear. To further confirm their absolute configurations, a high yielding, one-step biomimetic synthesis of (+/-)-cochlactone A (1) from ganomycin C (3) was conducted. In addition, a new compound, (+/-)-cochlactone B (2), featuring a bicyclo[3.3.1]decane fragment fused to a gamma-lactone moiety was synthesized. Their structures were determined using spectroscopic data, X-ray diffraction crystallography, and electronic circular dichroism (ECD) analyses. Furthermore, a plausible reaction mechanism for the formation of 1 and 2 was proposed. Compounds (+)-2 and (+/-)-2 showed inhibitory effects against Staphylococcus aureus with MIC50 values of 41.1 +/- 0.1 and 64.0 +/- 2.6 MUg/mL, respectively. Meanwhile, (+/-)-1, (-)-1, (+)-2, and (+/-)-2 displayed significant anti-inflammatory activities (IC50: 5.9 +/- 0.1, 6.1 +/- 0.2, 12.1 +/- 0.4, and 18.7 +/- 1.9 MUM, respectively). PMID- 29707953 TI - Ir(III)-Catalyzed Oxidative Annulation of Phenylglyoxylic Acids with Benzo[ b]thiophenes. AB - An Ir(III)-catalyzed oxidative annulation of phenylglyoxylic acids with benzo[ b]thiophenes for the construction of benzothieno[3,2- c][2]benzopyranones in one step is disclosed. Three C-H cleavages and C-C/C-O bond formations are involved in this reaction. This protocol features a relatively broad substrate scope, good functional group tolerance, good regioselectivities, mild reaction conditions, and scale-up synthesis. PMID- 29707954 TI - Biocompatible Surface-Coated Probe for in Vivo, in Situ, and Microscale Lipidomics of Small Biological Organisms and Cells Using Mass Spectrometry. AB - Lipidomics is a significant way to understand the structural and functional roles that lipids play in biological systems. Although many mass spectrometry (MS) based lipidomics strategies have recently achieve remarkable results, in vivo, in situ, and microscale lipidomics for small biological organisms and cells have not yet been obtained. In this article, we report a novel lipidomics methodology for in vivo, in situ, and microscale investigation of small biological organisms and cells using biocompatible surface-coated probe nanoelectrospray ionization mass spectrometry (BSCP-nanoESI-MS). A novel biocompatible surface-coated solid-phase microextration (SPME) probe is prepared, which possesses a probe-end diameter of less than 5 MUm and shows excellent enrichment capacity toward lipid species. In vivo extraction of living biological organisms (e.g., zebrafishes), in situ sampling a precise position of small organisms (e.g., Daphnia magna), and even microscale analysis of single eukaryotic cells (e.g., HepG2) are easily achieved by the SPME probe. After extraction, the loaded SPME probe is directly applied for nanoESI-MS analysis, and a high-resolution mass spectrometer is employed for recording spectra and identifying lipid species. Compared with the conventional direct infusion shotgun MS lipidomics, our proposed methodology shows a similar result of lipid profiles but with simpler sample pretreatment, less sample consumption, and shorter analytical times. Lipidomics of zebrafish, Daphnia magna, and HepG2 cell populations were investigated by our proposed BSCP-nanoESI MS methodology, and abundant lipid compositions were detected and identified and biomarkers were obtained via multivariate statistical analysis. PMID- 29707955 TI - Do schizotypy dimensions reflect the symptoms of schizophrenia? AB - OBJECTIVE: The personality characteristics and symptoms observed in schizophrenia are postulated to lie on a continuum, with non-clinical manifestations referred to as schizotypy. High schizotypy behaviours are argued to correspond with the three main clusters of symptoms in schizophrenia: positive, negative and cognitive/disorganised symptoms, yet there is limited empirical evidence to support this. This study aimed to investigate whether schizotypy dimensions significantly correlate with their respective schizophrenia symptomatology in the largest sample to date. METHODS: A total of 361 adults (103 patients with schizophrenia/schizoaffective disorder and 258 healthy controls) were assessed for schizotypy using the Oxford-Liverpool Inventory of Feelings and Experiences. The MATRICS Consensus Cognitive Battery supplemented by the Stroop task and Wisconsin Card Sorting Test was administered to all participants to obtain objective measurements of cognition. Schizophrenia symptomatology was assessed using the Positive and Negative Syndrome Scale in patients only. RESULTS: The results demonstrated significant correlations between the Oxford-Liverpool Inventory of Feelings and Experiences positive and negative subscales and their respective Positive and Negative Syndrome Scale subscales only, indicating that positive and negative schizotypy dimensions across patients and controls accurately reflect the respective schizophrenia symptomatology observed in patients. Cognitive performance did not correlate with cognitive/disorganised symptom dimensions of the Oxford-Liverpool Inventory of Feelings and Experiences or the Positive and Negative Syndrome Scale, indicating that cognitive impairment is an independent symptom dimension that requires objective cognitive testing. CONCLUSION: Collectively, the findings provide empirical evidence for the continuum theory and support the use of schizotypy as a model for investigating schizophrenia. PMID- 29707957 TI - A Health Plan's Journey to Identifying Meaningful Quality Measures. AB - The number of quality measures in health care is overwhelming, and reporting requirements are inconsistent. Value-based payments emphasize the need to prioritize quality measures and align across organizations. This article describes the process Humana undertook to reduce the quality measurement burden, refine measure consistency across the organization, ensure alignment with national standards, and relate quality measures to improved health outcomes within the health plan. Of the 1100 measures identified in use at Humana, 699 were duplicative or inconsistent. The biggest challenge was reaching consensus on similar measures while staying within regulatory and accrediting agency constraints. After review, physicians, quality experts, and business leaders prioritized 208 quality measures grounded in evidence, supported by credible organizations, and impactful to health outcomes. A governance committee was created to provide ongoing, proactive quality measure review. These efforts allow Humana to better support value-based payments by reducing complexity and helping physicians focus on meaningful measures. PMID- 29707958 TI - Comparing Upper Airway Stimulation to Expansion Sphincter Pharyngoplasty: A Single University Experience. AB - INTRODUCTION: Expansion sphincter pharyngoplasty (ESP) is a surgical option for patients with obstructive sleep apnea (OSA). Upper airway stimulation (UAS) is an alternative that has shown success in initial outcomes studies. We compare outcomes of a cohort of patients undergoing UAS to ESP. METHODS: We compared demographic and polysomnographic data of the UAS to ESP cohorts. We also calculated the proportion of patients achieving surgical success. RESULTS: The ESP cohort consisted of 33 patients. The mean preoperative Apnea-Hypopnea Index (AHI), O2 nadir, Epworth Sleepiness Scale (ESS), and BMI were 36.47 +/- 20.01, 82.63 +/- 5.37, 10.69 +/- 4.42, and 29.6 +/- 4.49, which improved to 13.47 +/- 18.74, 84.84 +/- 5.48, 7.00 +/- 5.81, and 29.92 +/- 4.59 postoperatively. There was a 63.64% success rate. The UAS cohort consisted of 75 patients. The mean preoperative AHI, O2 nadir, ESS, and BMI were 36.76 +/- 20.72, 80.24 +/- 8.43, 11.18 +/- 4.16, and 29.50 +/- 3.96, which improved to 7.25 +/- 11.19, 88.71 +/- 3.25, 5.36 +/- 3.35, and 29.36 +/- 3.68 postoperatively. The success rate was 86.67%. We found a significant difference in gender, age, preoperative AHI, postoperative AHI, postoperative O2 nadir, surgical success, and patients reaching an AHI less than 10 and 5. CONCLUSION: Upper airway stimulation is a new surgical option for select patients with OSA showing comparable or improved outcomes to a cohort of patients undergoing ESP. PMID- 29707959 TI - Acute changes in muscle thickness and pennation angle in response to work-matched concentric and eccentric isokinetic exercise. AB - Acute changes in muscle architecture influenced by muscle swelling might be associated with chronic adaptations to resistance exercise, including skeletal muscle growth. Concentric (CON) and eccentric (ECC) muscle actions both play a role in hypertrophic processes, but the influence of each on acute indices of muscle swelling (i.e., muscle thickness (MT) and pennation angle (PA)) remains relatively unknown. Therefore, this study compared the acute changes in MT and PA in response to work-matched CON versus ECC isokinetic exercise. Twelve university aged students performed 2 bouts of maximal isokinetic knee extensions at 120 degrees .s-1 on the same day: 50 CON followed by a work-matched ECC bout (~5000 J; 28 +/- 5 reps) with the contralateral limb. Ultrasound images were captured from the middle and distal sites of the vastus lateralis before and immediately after each exercise bout. From these images, MT and PA were measured. Middle and distal MT (11% and 14%, respectively; p < 0.001) and middle PA (39%, p < 0.001) increased only after CON. In addition, changes in MT were strongly related to the amount of total work performed (r = 0.76) during CON. Our results suggest that when the workload is matched between CON and ECC muscle actions performed at a moderate velocity, CON actions seem to be a more potent stimulus for inducing acute changes in MT and PA. PMID- 29707960 TI - The phosphoinositide 3-kinase pathway and glycogen synthase kinase-3 positively regulate the activity of metal-responsive transcription factor-1 in response to zinc ions. AB - Metal-responsive transcription factor-1 (MTF-1) is a metal-regulatory transcription factor essential for induction of the genes encoding metallothioneins (MTs) in response to transition metal ions. Activation of MTF-1 is dependent on the interaction of zinc with the zinc fingers of the protein. In addition, phosphorylation is essential for MTF-1 transactivation. We previously showed that inhibition of phosphoinositide 3-kinase (PI3K) abrogated Mt expression and metal-induced MTF-1 activation in human hepatocellular carcinoma (HCC) HepG2 and mouse L cells, thus showing that the PI3K signaling pathway positively regulates MTF-1 activity and Mt gene expression. However, it has also been reported that inhibition of PI3K has no significant effects on Mt expression in immortalized epithelial cells and increases Mt expression in HCC cells. To further characterize the role of the PI3K pathway on the activity of MTF-1, transfection experiments were performed in HEK293 and HepG2 cells in presence of glycogen synthase kinase-3 (GSK-3), mTOR-C1, and mTOR-C2 inhibitors, as well as of siRNAs targeting Phosphatase and TENsin homolog (PTEN). We showed that inhibition of the mTOR-C2 complex inhibits the activity of MTF-1 in HepG2 and HEK293 cells, while inhibition of the mTOR-C1 complex or of PTEN stimulates MTF-1 activity in HEK293 cells. These results confirm that the PI3K pathway positively regulates MTF-1 activity. Finally, we showed that GSK-3 is required for MTF-1 activation in response to zinc ions. PMID- 29707961 TI - Influenza vaccine acceptance and health beliefs among Korean kidney transplant patients. AB - Kidney transplantation (KT) patients are at a higher risk than the general population for influenza virus infection. Although vaccination is primarily recommended for KT patients, little is known about the influenza vaccination rate and related health beliefs in South Korea. The influence of health beliefs on influenza vaccination among KT patients has never been explored. This study aimed to identify influenza vaccine acceptance and association with health beliefs among KT patients. A total of 180 patients who underwent a KT were recruited from an organ transplant center in Korea. Data were collected through structured questionnaires, which were analyzed using descriptive statistics and binary logistic regression. Approximately 47.2% of the participants received influenza vaccination. Previous influenza vaccination, lower perceived barriers, higher perceived benefits, older age, and longer duration after transplantation influenced influenza vaccine acceptance. The results suggest that various strategies are needed for increasing acceptance of influenza vaccination among KT patients. Getting vaccinated for influenza after KT might be crucial for the annual vaccinations. Improving benefits and decreasing barriers perceived by KT patients may contribute to increasing the acceptance. Education on influenza vaccination should be emphasized particularly for young patients under 45 years and up to 10 years after KT. PMID- 29707962 TI - Assessment of depression and anxiety in patients before and after percutaneous coronary intervention: A step forward in cardiac rehabilitation? PMID- 29707963 TI - Global warming and heart disease prevention. PMID- 29707964 TI - The gut microbiota and heart disease prevention. PMID- 29707965 TI - An Enriched Environment Ameliorates Oxidative Stress and Olfactory Dysfunction in Parkinson's Disease with alpha-Synucleinopathy. AB - Parkinson's disease (PD) features nonmotor symptoms such as olfactory dysfunction referred to as hyposmia, an initial sign of disease progression. Metabolic dysfunction can contribute to neurodegenerative diseases, and various xenobiotics and endogenous compounds are also involved in the pathogenesis of PD. Although aerobic exercise was found to induce preservation or improvement in olfactory function in PD patients in a recent study, the exact underlying mechanism for this effect is not clear. We aimed to investigate the influence of an enriched environment (EE) on olfactory dysfunction especially via metabolic pathways related to detoxification enzymes. Eight-month-old transgenic (Tg) PD mice that overexpress human A53T alpha-synuclein (alpha-syn) were randomly allocated to an EE or standard conditions for 2 mo. The buried food test showed that EE group had significantly improved olfactory function compared to the control group. Reverse transcription polymerase chain reaction (PCR) and real-time quantitative PCR showed that expression of the detoxification enzymes-- cytochrome P450 family 1 subfamily A member 2, paraoxonase 1, alcohol dehydrogenase 1, UDP glucuronosyltransferase family 2 member A1 complex locus, aldehyde oxidase homolog 2, and aldehyde glutathione peroxidase 6--was significantly increased in the olfactory bulb (OB) of the PD control group, but these enzymes were normalized in the EE group. Immunohistochemical staining of the OB showed that oxidative stress and nitrated alpha-syn were significantly increased in the control group but decreased in the EE group. In conclusion, we suggest that exposure to an EE decreases both oxidative stress and nitrated alpha-syn, resulting in normalized detoxification enzymes and amelioration of olfactory dysfunction. PMID- 29707966 TI - The effect of exercise training in symptomatic patients with grown-up congenital heart disease: a review. AB - INTRODUCTION: The number of grown-up congenital heart disease (GUCH) patients is steadily increasing. Unfortunately, the majority of these patients suffer from late sequelae, with heart failure being the most common cause of death. Exercise training is beneficial and safe in patients with acquired heart failure, as well as in asymptomatic GUCH patients. However, its effect remains unknown in symptomatic GUCH patients. This could cause reticence on positive sports advice, with possible counterproductive effects. Areas covered: A review of current literature was performed to evaluate the effect of exercise training in symptomatic (NYHA>=2) GUCH patients. The search yielded a mere three studies including symptomatic patients, and another six studies including also patients in NYHA 1 without making clear distinction between the NYHA subgroups. Expert commentary: Suboptimal trial designs, low patient numbers, and homogeneity of investigated cardiac anomalies make this review insufficient to draw definite conclusions. However, all studies describe overall positive effects of exercise training in symptomatic GUCH patients in terms of exercise capacity and quality of life. There were no safety concerns. Larger-scaled, randomized controlled trials are needed to obtain certainty. PMID- 29707967 TI - Where there's smoke, there's fire: focal points for risk communication. AB - Large fires involving hazardous materials are often characterized by failing crisis communication. In this study, we compared opinions of experts regarding the risks of major fires to lay beliefs using a mental models approach. Amongst lay people this revealed relevant knowledge gaps and beliefs in opposition to those held by experts. While, experts considered the chance of getting cancer from inhaling smoke from a chemical fire extremely small, most lay people thought that even at a great distance, the chance of getting cancer to be large. To improve crisis communication about risk in a case of large chemical fires, and reduce the potential for messages to be misunderstood, distrusted or dismissed, we recommend a clarification of cancer risk in communications about public health emergencies such as chemical fires, for which lay people equate even small exposures to carcinogenic chemicals make one more likely to get cancer later in life. PMID- 29707969 TI - Letter to the Editor: androgenetic alopecia; drug safety and therapeutic strategies. PMID- 29707968 TI - Electroencephalography Findings in Crohn's Disease. AB - OBJECTIVES: Crohn's Disease (CD) is a chronic systemic inflammatory disease associated with various extraintestinal manifestations, including seizure as a neurological finding. In this study, the prevalence of seizure and electroencephalographic abnormalities in patients with CD was investigated. MATERIALS AND METHODS: This study involved 41 patients with CD (female/male: 25/16) and 39 subjects in the control group (female/male: 25/14). Patients in the CD group were diagnosed and monitored according to the European Crohn's and Colitis Organization diagnostic criteria. The control group was composed of healthy subjects with similar age and sex as the CD group. Seizures were classified according to the criteria of the International League Against Epilepsy. Electroencephalography (EEG) was performed for all patients with CD and for healthy subjects. Seizure prevalence and EEG findings were also compared. RESULTS: One patient in the CD group had history of seizures. EEG abnormality was significantly higher in the CD group (16/41, 39%) ( P = .001). The most common EEG abnormality was intermittent generalized slow wave abnormality in theta frequency. DISCUSSION: Our study indicated that CD was associated with EEG abnormalities rather than seizure. The results also indicated that EEG was a potential indicator for detecting subclinical neurological abnormalities in CD. PMID- 29707970 TI - Orthopaedic In-Training Examination Resources and Residency Training for the Foot and Ankle Domain. AB - BACKGROUND: Residency programs use the annual Orthopaedic In-Training Examination (OITE) prepared by the American Academy of Orthopaedic Surgeons (AAOS) to monitor resident progress and prepare them for the part 1 of the American Board of Orthopaedic Surgeons (ABOS) Certifying Examination. The purpose of this study was to determine resources residents currently use to prepare for the OITE and also to learn about their perception of training they receive in the foot and ankle subspecialty in their program and their interest in foot and ankle fellowship after residency. METHODS: An anonymous survey was sent to both allopathic programs and osteopathic residents to learn what resources residents used to study for the OITE, preparatory question sets, on-call resources, their perception on training received in foot and ankle surgery, and their intent to pursue fellowship training. RESULTS: A total of 130 residents participated in the survey. The majority of residents in allopathic and osteopathic residencies used Orthobullets (OB) to prepare for the OITE and use this resource while on-call. Most residents also used OB question sets to study along with the AAOS self assessment examinations. In total, 43.2% of osteopathic residents felt they did not get enough exposure to foot and ankle subspecialty while in training, in contrast to 31.2% of allopathic residents. A total of 35% of all orthopaedic surgery residents felt they lacked enough exposure to foot and ankle orthopaedic surgery. Only 7 residents (6%, 6 allopathic, 1 osteopathic) intended to pursue a foot and ankle fellowship following graduation. CONCLUSION: Online resources such as OB continue to be frequently used by residents for preparation for the OITE. Greater than one-third of orthopaedic residents feel they do not get enough exposure to foot and ankle orthopaedic surgery. Improvement in this area could be helped by continued endeavors from the American Orthopaedic Foot and Ankle Society such as the Visiting Professor Program and Resident Scholarship Program. LEVELS OF EVIDENCE: Level V: Single Cross-Sectional Study. PMID- 29707972 TI - Corrigendum. PMID- 29707971 TI - Human Multilineage-differentiating Stress-Enduring Cells Exert Pleiotropic Effects to Ameliorate Acute Lung Ischemia-Reperfusion Injury in a Rat Model. AB - Posttransplantation lung ischemia-reperfusion (IR) injuries affect both patient survival and graft function. In this study, we evaluated the protective effects of infused human multilineage-differentiating stress-enduring (Muse) cells, a novel, easily harvested type of nontumorigenic endogenous reparative stem cell, against acute IR lung injury in a rat model. After a 2-h warm IR injury induction in a left rat lung, human Muse cells, human mesenchymal stem cells (MSCs), and vehicle were injected via the left pulmonary artery after reperfusion. Functionality, histological findings, and protein expression were subsequently assessed in the injured lung. In vitro, we also compared human Muse cells with human MSCs in terms of migration abilities and the secretory properties of protective substances. The arterial oxygen partial pressure to fractional inspired oxygen ratio, alveolar-arterial oxygen gradient, left lung compliance, and histological injury score on hematoxylin-eosin sections were significantly better in the Muse group relative to the MSC and vehicle groups. Compared to MSCs, human Muse cells homed more efficiently to the injured lung, where they suppressed the apoptosis and stimulated proliferation of host alveolar cells. Human Muse cells also migrated to serum from lung-injured model rats and produced beneficial substances (keratinocyte growth factor [KGF], hepatocyte growth factor, angiopoietin-1, and prostaglandin E2) in vitro. Western blot of lung tissue confirmed high expression of KGF and their target molecules (interleukin 6, protein kinase B, and B-cell lymphoma-2) in the Muse group. Thus, Muse cells efficiently ameliorated lung IR injury via pleiotropic effects in a rat model. These findings support further investigation on the use of human Muse cells for lung IR injury. PMID- 29707973 TI - Identifying and prioritizing concerns associated with prosthetic devices for use in a benefit-risk assessment: a mixed-methods approach. AB - OBJECTIVE: We identified and prioritized concerns reported by stakeholders associated with novel upper-limb prostheses. METHODS: An evidence review and key informant engagement, identified 62 concerns with upper-limb prostheses with implantable components. We selected 16 concerns for inclusion in a best-worst scaling (BWS) prioritization survey. Focus groups and BWS were used to engage stakeholders at a public meeting on prostheses. In 16 BWS choice tasks, attendees selected the most and least influential concern when choosing an upper-limb prosthesis. Aggregate data were analyzed using choice frequencies and conditional logit analysis. Latent class analysis examined heterogeneity in priorities. Estimates were adjusted to importance ratios which indicate how influential each concern is in the decision making process. RESULTS: Forty-seven (47) stakeholders from diverse backgrounds completed the BWS survey (response rate 51%). On aggregate, the most influential concern was reliability of the device (importance ratio: 13%), and least influential was the concern of an outdated device (importance ratio: 1%). Latent class analysis identified two classes with approximately 50% of participants each. The first class was most influenced by effectiveness of the device. The second class was most influenced by minimizing risks. CONCLUSION: In this pilot, we identified heterogeneity in how participants prioritize concerns for upper-limb prostheses. PMID- 29707974 TI - Mass spectrometric analysis of glycosylated viral proteins. AB - INTRODUCTION: Viral diseases contribute much to human and animal suffering and enormous efforts are directed at developing appropriate vaccines for protection. Glycoproteins constitute much of the viral surfaces and are obvious targets for such vaccine development. This review describes mass spectrometric methods used for the structural determination of these compounds. Areas covered: The review describes the structures of the N- and O-linked glycans found on glycoproteins and mass spectrometric methods for their ionization and fragmentation. The steps, such as determination of glycan attachment sites and the structures of the attached glycans following their release from the glycoproteins are described and examples are given of the uses of the various analytical methods using mainly influenza, Ebola and HIV as representative examples. Also included are tables listing work on many other viruses. Expert commentary: Recent technological advances, such as the introduction of ion mobility techniques, have greatly improved analyses in this area and have enabled larger amounts of information to be gathered in shorter time periods on ever smaller amounts of material. Such techniques should greatly accelerate the discovery of vaccine targets and lead to the production of vaccines for diseases not currently available. PMID- 29707976 TI - Corrigendum. PMID- 29707975 TI - Synthesis and biological evaluation of certain hydrazonoindolin-2-one derivatives as new potent anti-proliferative agents. AB - In connection with our research program on the development of novel indolin-2-one based anticancer candidates, herein we report the design and synthesis of different series of hydrazonoindolin-2-ones 3a-e, 5a-e, 7a-c, and 10a-l. The synthesised derivatives were in vitro evaluated for their anti-proliferative activity towards lung A-549, colon HT-29, and breast ZR-75 human cancer cell lines. Compounds 5b, 5c, 7b, and 10e emerged as the most potent derivatives with average IC50 values of 4.37, 2.53, 2.14, and 4.66 uM, respectively, which are superior to Sunitinib (average IC50 = 8.11 uM). Furthermore, compounds 7b and 10e were evaluated for their effects on cell cycle progression and levels of phosphorylated retinoblastoma (Rb) protein in the A-549 cancer cell line. Moreover, 7b and 10e inhibited the cell growth of the multidrug-resistant lung cancer NCI-H69AR cell line with IC50 = 16 uM. In addition, the cytotoxic activities of 7b and 10e were assessed towards three non-tumorigenic cell lines (Intestine IEC-6, Breast MCF-10A, and Fibroblast Swiss-3t3) where both compounds displayed mean tumor selectivity index (1.6 and 1.8) higher than that of Sunitinib (1.4). PMID- 29707977 TI - Ghosts of inventions: Patent law's digital mediations. AB - This article examines the shifts in the material ordering of inventions in patent law organization and their effects on the meaning and scope of inventions as intellectual property. Formats and media are constitutive of the establishment and stabilization of inventions as objects of intellectual property. Modern patent law's materiality had been dominated by paper documents but ever more consists of digital images, files, and networked data. The article traces and analyzes such effects of digital media on the meaning of intellectual/intangible property and argues that inventions increasingly matter as digital data in the legal realm. PMID- 29707978 TI - The use of process mapping in healthcare quality improvement projects. AB - Introduction Process mapping provides insight into systems and processes in which improvement interventions are introduced and is seen as useful in healthcare quality improvement projects. There is little empirical evidence on the use of process mapping in healthcare practice. This study advances understanding of the benefits and success factors of process mapping within quality improvement projects. Methods Eight quality improvement projects were purposively selected from different healthcare settings within the UK's National Health Service. Data were gathered from multiple data-sources, including interviews exploring participants' experience of using process mapping in their projects and perceptions of benefits and challenges related to its use. These were analysed using inductive analysis. Results Eight key benefits related to process mapping use were reported by participants (gathering a shared understanding of the reality; identifying improvement opportunities; engaging stakeholders in the project; defining project's objectives; monitoring project progress; learning; increased empathy; simplicity of the method) and five factors related to successful process mapping exercises (simple and appropriate visual representation, information gathered from multiple stakeholders, facilitator's experience and soft skills, basic training, iterative use of process mapping throughout the project). Conclusions Findings highlight benefits and versatility of process mapping and provide practical suggestions to improve its use in practice. PMID- 29707979 TI - Systemic Monotherapy Treatments for Generalized Pustular Psoriasis: A Systematic Review. AB - Generalized pustular psoriasis (GPP) is a rare but serious and difficult to treat cutaneous disease, with high morbidity and mortality rates. Despite the numerous treatment regimens available, the overall quality of evidence-based research is limited with a lack of an algorithmic approach available. In this review, we aim to evaluate the current level of evidence regarding the efficacy and safety/tolerability of systemic monotherapies available in the treatment of GPP. A comprehensive MEDLINE, EMBASE, and PubMed search of clinical studies examining systemic monotherapy treatment options for GPP was conducted. In total, 31 studies met eligibility criteria. Described treatment modalities included retinoids, cyclosporine, biologics, and dapsone. Despite the lack of high-quality evidence or a well-accepted treatment algorithm for GPP, systemic retinoids, cyclosporine, biologics, and dapsone are all possible first-line agents, with retinoids being one of the best-supported treatment options and biologics as an emerging therapeutic field with great potential requiring additional data. However, the final choice of treatment should be considered within the unique context of each patient. PMID- 29707980 TI - Psychosocial health mediates the gratitude-physical health link. AB - There is now a growing body of research demonstrating the physical health benefits of being grateful. However, research has only just began to explore the mechanisms accounting for this gratitude-health relationship. This study examines the relationship between dispositional gratitude and self-reported physical health symptoms, and explores whether this relationship is explained through reduced levels of perceived loneliness and stress. This study employed a cross sectional design with a sample of 607 healthy adults. Serial mediation analysis revealed that the positive effect of gratitude on physical health was significantly mediated by lower reported levels of perceived loneliness and stress. These findings are important given evidence that gratitude can be cultivated, and may serve to buffer against stress and loneliness and improve somatic health symptoms in the general population. PMID- 29707982 TI - Molecular markers in disease detection and follow-up of patients with non-muscle invasive bladder cancer. AB - INTRODUCTION: Diagnosis and surveillance of non-muscle invasive bladder cancer (NMIBC) is mainly based on endoscopic bladder evaluation and urine cytology. Several assays for determining additional molecular markers (urine-, tissue- or blood-based) have been developed in recent years but have not been included in clinical guidelines so far. Areas covered: This review gives an update on different molecular markers in the urine and evaluates their role in patients with NMIBC in disease detection and surveillance. Moreover, the potential of recent approaches such as DNA methylation assays, multi-panel RNA gene expression assays and cell-free DNA analysis is assessed. Expert commentary: Most studies on various molecular urine markers have mainly focused on a potential replacement of cystoscopy. New developments in high throughput technologies and urine markers may offer further advantages as they may represent a non-invasive approach for molecular characterization of the disease. This opens new options for individualized surveillance strategies and may help to choose the best therapeutic option. The implementation of these technologies in well-designed clinical trials is essential to further promote the use of urine diagnostics in the management of patients with NMIBC. PMID- 29707981 TI - PMN-MDSC and arginase are increased in myeloma and may contribute to resistance to therapy. AB - OBJECTIVES: Despite improvement in overall response due to the introduction of the first-in-class proteasome inhibitor bortezomib (btz), multiple myeloma (MM) is still an incurable disease due to the immune-suppressive bone marrow (BM) environment. Thus, the authors aimed to identify the role of CD11b+CD15+CD14-HLA DR- granulocytic-like myeloid-derived suppressor cells (PMN-MDSC) in MM patients treated up-front with novel agents. METHODS: In MM cell lines and primary cells derived by patients affected by MGUS and MM, we investigated sensitivity to bortezomib and lenalidomide in presence of Arg-1 and PMN-MDSC. RESULTS: The authors found that PMN-MDSC and their function through increased arginase-1 (Arg 1) are associated with MM progression. When the authors assessed cell viability of the human myeloma cell lines MM1.s, OPM2 and U266 treated with 5-20 nM btz for 24 h in PMN-MDSC conditioned media, they disclosed that amount of Arg-1 and Arg-1 inhibition could affect btz sensitivity in-vitro. PMN-MDSC and Arg-1 were increased in peripheral blood of newly diagnosed MM patients compared to healthy subjects. PMN-MDSC and arginase were reduced after exposure to lenalidomide-based regimen but increased after btz-based treatment. CONCLUSION: In MM, Arg-1 is mainly expressed by PMN-MDSC. PMN-MDSC and Arg-1 are reduced in vivo after lenalidomide but not bortezomib treatment. PMID- 29707983 TI - Response to the letter to the editor; Androgenetic alopecia; drug safety and therapeutic strategies. PMID- 29707984 TI - The influence of early radiolucent lines appearing on femoral head penetration into HXLPE cemented sockets. AB - INTRODUCTION: This study investigates differences in femoral head penetration between highly cross-linked polyethylene (HXLPE) cemented sockets both with and without radiolucent lines (RLLs) in the early postoperative phase and at 5 years follow-up. METHODS: There were 35 patients (37 hips), mean age of 66.8 years, who underwent total hip arthroplasty (THA) using highly HXLPE cemented sockets. They were divided into 2 groups based on postoperative the early appearance of RLLs. Femoral head penetrations on both anteroposterior- and Lauenstein-view radiographs were evaluated, and the mean polyethylene (PE) wear rate was calculated based on femoral head penetrations between 2 and 5 years. RESULTS: Femoral head penetrations in the proximal direction were 0.075 mm and 0.150 mm in the RLL and non-RLL groups at 1 year postoperatively ( p = 0.019). At 5 years measured penetration was 0.107 mm and 0.125 mm in the RLL and non-RLL groups, respectively ( p = 0.320). The mean PE wear rates in anteroposterior-view were 0.008 mm/year and 0.003 mm/year in the RLL and non-RLL groups ( p = 0.390) and those in Lauenstein-view were 0.010 mm/year and 0.005 mm/year, respectively ( p = 0.239). CONCLUSIONS: In the RLL group, the PE bedding-in was less compared with those in the non-RLL group. Additionally, the mean PE wear rate in the RLL group tended to be higher than that in the non-RLL group. The distribution of stress loading through the cement may differ according to whether early RLLs appear. PMID- 29707985 TI - How can multi criteria decision analysis support value assessment of pharmaceuticals? - Findings from a systematic literature review. AB - INTRODUCTION: As budget constraints become more and more visible, there is growing recognition for greater transparency and greater stakeholders' engagement in the pharmaceuticals' pric-ing&reimbursement (P&R) decision making. New frameworks of drugs' value assessments are searched for. Among them, the multi criteria decision analysis (MCDA) receives more and more attention. In 2014, ISPOR established Task Force to provide methodological recommendations for MCDA utilization in the health care decision making. Still, there is not so much knowledge about the real life experience with MCDA's adaptation to the P&R processes. Areas covered: A systematic literature review was performed to understand the rationale for MCDA adaptation, methodology used as well as its impact on P&R outcomes. Expert commentary: In total 102 hits were found through the search of databases, out of which 18 publications were selected. Although limited in scope, the review highlighted how MCDA can im-prove the decision making processes not only regarding pricing & reimbursement but also contribute to the the risk benefit assessment as well as optimization of treatment outcomes. Still none of re-viewed studies did report how MCDA results actually impacted the real life settings. PMID- 29707986 TI - Gender specificity improves the early-stage detection of clear cell renal cell carcinoma based on methylomic biomarkers. AB - AIM: The two genders are different ranging from the molecular to the phenotypic levels. But most studies did not use this important information. We hypothesize that the integration of gender information may improve the overall prediction accuracy. MATERIALS & METHODS: A comprehensive comparative study was carried out to test the hypothesis. The classification of the stages I + II versus III + IV of the clear cell renal cell carcinoma samples was formulated as an example. RESULTS & CONCLUSION: In most cases, female-specific model significantly outperformed both-gender model, as similarly for the male-specific model. Our data suggested that gender information is essential for building biomedical classification models and even a simple strategy of building two gender-specific models may outperform the gender-mixed model. PMID- 29707987 TI - Adjuvant therapy for advanced renal cell carcinoma. AB - INTRODUCTION: Locally advanced, non-metastatic renal cell carcinoma (RCC) is conventionally managed with surgery. However, patients are at a high risk of RCC recurrence and have poor survival outcomes. An effective adjuvant systemic treatment is needed to improve on these outcomes. Targeted molecular and immune based therapies have been investigated, or are under investigation, but their role in this setting remains unclear. Areas covered: A comprehensive search of PubMed and ClinicalTrials.gov was performed for relevant literature. The following topics pertinent to adjuvant therapy in RCC were evaluated: strategies for patient selection, cytokine-based immunotherapy, vaccine therapy, VEGF and non-VEGF targeted molecular agents, and immune checkpoint inhibitors. Expert commentary: Strong evidence for the incorporation of adjuvant therapy in high risk RCC is lacking. Multiple targeted molecular therapies have been examined with only one approved for use. Genetic and molecular-based prognostic models are needed to determine who may benefit from adjuvant therapy. Developing adjuvant therapy strategies in the future depends on the results of important ongoing trials with immunotherapy and targeted agents. PMID- 29707988 TI - Purification processes of xenogeneic bone substitutes and their impact on tissue reactions and regeneration. AB - Xenogeneic bone substitute materials are widely used in oral implantology. Prior to their clinical use, purification of the former bone tissue has to be conducted to ensure the removal of immunogenic components and pathogens. Different physicochemical methods are applied for purification of the donor tissue, and temperature treatment is one of these methods. Differences in these methods and especially the application of different temperatures for purification may lead to different material characteristics, which may influence the tissue reactions to these materials and the related (bone) healing process. However, little is known about the different material characteristics and their influences on the healing process. Thus, the aim of this mini-review is to summarize the preparation processes and the related material characteristics, safety aspects, tissue reactions, resorbability and preclinical and clinical data of two widely used xenogeneic bone substitutes that mainly differ in the temperature treatment: sintered (cerabone(r)) and non-sintered (Bio-Oss(r)) bovine-bone materials. Based on the summarized data from the literature, a connection between the material induced tissue reactions and the consequences for the healing processes are presented with the aim of translation into their clinical application. PMID- 29707989 TI - Diagnostic usefulness of bronchoalveolar lavage fluid xpert MTB/RIF in pauci bacillary pulmonary tuberculosis. PMID- 29707990 TI - Interproximal grinding (disking) of caries in primary molars, attitudes and the extent utilized in a Swedish County. AB - OBJECTIVE: To assess the occurrence of interproximal grinding as a caries therapy in primary molars, to what degree grinding replaced conventional restorative caries therapy, to what extent anaesthesia was used while grinding and to assess open comments about attitudes about grinding. MATERIALS AND METHODS: A questionnaire was sent to 108 public dental service clinics with questions concerning the use of grinding as a therapy and alternative to restorative treatment, the use of anaesthesia prior to conventional caries therapy and grinding, respectively. In addition, a content analysis of open comments about grinding was performed. RESULTS: Grinding had been performed in 96% of the clinics. Two-thirds of the dentists used grinding as an alternative to conventional restorative treatment at some point. Most dentists used anaesthesia prior to restorative therapy. Prior to grinding, the frequency of anaesthesia was lower (median 5.0) than for conventional restorative therapy (median 8.7) (p < .001). The open comment analysis revealed complex reasons for the use of grinding. CONCLUSIONS: Grinding has been widely practiced in parts of Sweden, is presently a technique employed by a multitude of dentists, and that anaesthesia is used less frequently prior to grinding, in comparison to conventional restorative therapy. Dentist considered grinding as a treatment option in specific situations. PMID- 29707991 TI - Sleep beliefs and attitudes and the association with insomnia among psychiatric outpatients. AB - BACKGROUND: While it has been demonstrated that dysfunctional sleep beliefs can contribute to sleep disturbances, less is known about it in psychiatric patients and the role these beliefs play in influencing sleep. AIMS: To examine maladaptive sleep cognition among psychiatric patients and to assess its association with insomnia. METHOD: Participants were outpatients (n = 400) recruited from a tertiary psychiatric hospital. The Dysfunctional Beliefs and Attitudes about Sleep (DBAS-16) scale was administered to examine sleep-related cognitions in different domains. Clinical insomnia was assessed using the Insomnia Severity Index. Factors associated with DBAS were explored using linear regression and the association between DBAS scores and insomnia was tested using logistic regression. RESULTS: Among psychiatric patients, factors associated with the DBAS domains were ethnicity, educational attainment, psychiatric comorbidity, and consumption of sleep medication. Higher dysfunctional sleep beliefs were associated with insomnia. The association was particularly prominent in the mood disorder diagnostic group. CONCLUSIONS: Dysfunctional sleep beliefs were associated with insomnia among psychiatric patients. Addressing these maladaptive cognitions is critical in alleviating sleep problems in psychiatric patients. PMID- 29707992 TI - Angiopoietin-2 level as a tool for cardiovascular risk stratification in hypertensive type 2 diabetic subjects. AB - OBJECTIVES: This observational cross-sectional study aimed to investigate the relationship between serum Angiopoietin-2 (Ang-2) levels and cardiovascular (CVD) risk factors in drug controlled hypertensive diabetic subjects without cardiovascular complications. METHODS: All subjects were evaluated for fasting blood glucose (FBG), HbA1c, liver enzymes, lipid profile and serum Ang-2. RESULTS: Mean serum Ang-2 level was significantly higher in hypertensive diabetic subjects. In bivariate analysis in diabetic subjects with cardiovascular risk factors, Ang-2 positively correlated with waist circumference, body mass index (BMI), systolic blood pressure (SBP), FBG, HbA1c and triglycerides. In multivariate linear regression analysis, this association remained significant with FBG and triglycerides. Ang-2 levels were independently associated with CVD risk factors in drug controlled Type 2 diabetes (T2D) subjects. CONCLUSIONS: Further detailed studies in larger population with more attention is needed to consider Ang-2 level as a tool for CVD risk stratification in hypertensive diabetic subjects. PMID- 29707993 TI - Procalcitonin as a postoperative marker in the follow-up of patients affected by medullary thyroid carcinoma. AB - AIM: Due to the limits of calcitonin, other markers are warranted to better manage medullary thyroid carcinoma patients, and procalcitonin has been reported as promising. Here we aimed to evaluate procalcitonin as a marker of medullary thyroid carcinoma in the post-treatment follow-up. METHODS: Medullary thyroid carcinoma patients previously treated by thyroidectomy were enrolled. After complete imaging work-up (i.e. ultrasonography, computed tomography, magnetic resonance and 18FDG-PET-CT) we identified patients with structural recurrent/persistent medullary thyroid carcinoma (active medullary thyroid carcinoma) and subjects with no evidence of disease. Then, both calcitonin and procalcitonin were measured and their performance analyzed. RESULTS: The final series included 55 medullary thyroid carcinoma patients treated and followed-up for about five years. Of these, 43 were assessed as no evidence of disease, and 12 as active medullary thyroid carcinoma. The median value of procalcitonin was significantly higher ( P < 0.0001) in active medullary thyroid carcinoma patients (3.10 ng/mL) than in those with no evidence of disease (0.10 ng/mL). Also, calcitonin levels of active medullary thyroid carcinoma (96.7 pg/mL) were significantly ( P < 0.0001) higher than that of no evidence of disease (2.0 pg/mL). At the receiver operating characteristic curve analysis, the optimal cut off of procalcitonin was >=0.32 ng/mL with 92% sensitivity and 98% specificity, while the most accurate threshold of calcitonin was >=12.0 pg/mL with 100% sensitivity and 91% specificity. There was no active medullary thyroid carcinoma with simultaneously negative results of procalcitonin and calcitonin. CONCLUSIONS: Procalcitonin is reliable in discriminating medullary thyroid carcinoma patients with active disease from those with no evidence of disease. We suggest using procalcitonin as complementary to calcitonin to follow-up medullary thyroid carcinoma patients. PMID- 29707995 TI - Is there a link between female asthma and a reduction in fertility? PMID- 29707994 TI - High expression of Aurora-B is correlated with poor prognosis and drug resistance in non-small cell lung cancer. AB - OBJECTIVE: Aurora kinase B (Aurora-B) is a crucial regulator of accurate mitosis. Abnormal Aurora-B expression is associated with aneuploidy and has been implicated in the pathogenesis and drug resistance in a variety of human cancers. However, little evidence is available regarding the role of Aurora-B in regulating drug response in non-small cell lung cancer (NSCLC), which is the most common type of lung cancer, and is characterized with poor prognosis and high mortality. METHOD: In the current study, we investigated the association of Aurora-B with the prognosis of NSCLC patients, and we also used the latest CRISPR/Cas9 system to explore the regulatory role of Aurora-B in NSCLC cells developing resistance to cisplatin (CDDP) and paclitaxel. RESULTS: We found that Aurora-B was correlated with significantly reduced overall survival and disease free survival in NSCLC patients. Aurora-B overexpression was also observed in NSCLC cells developing impaired response to both CDDP and paclitaxel. Moreover, we found, for the first time, that Aurora-B may impair NSCLC drug response by disturbing cell proliferation and inhibiting p53-related DNA damage response and apoptotic pathway, while the knockout of Aurora-B resensitized NSCLC cells to chemo drugs by ensuring correct chromosome segregation and restoring p53 expression. CONCLUSIONS: Our results demonstrated the association of Aurora-B with chemoresistance in NSCLC, which may finally contribute to the poor prognosis of NSCLC patients. We also suggested Aurora-B as a promising therapeutic target in NSCLC treatment. PMID- 29707996 TI - Impact of age of onset of psychosis and engagement in higher education on duration of untreated psychosis. AB - BACKGROUND: The average age of onset of psychosis coincides with the age of college enrollment. Little is known about the impact of educational engagement on DUP in a college-aged population. AIMS: To determine DUP, and the impact of educational engagement, for college-aged participants of the RAISE study (n = 404). METHOD: We conducted secondary data analyses on the publicly available RAISE dataset. Subsamples were analyzed to determine the impact of age and educational engagement on DUP. RESULTS: DUP was significantly shorter (p < 0.02) for participants who were college-aged (18-22 years, n = 44) and engaged in post secondary education (median = 12 weeks, mean = 29 weeks) compared with participants who were college-aged and not engaged in higher education (n = 92, median = 29 weeks, mean = 44 weeks). CONCLUSIONS: Educational engagement appears to be associated with a shorter DUP. This may be partially explained by the presence of on-site wellness centers in college settings. However, even among young people who engaged in post-secondary education DUP was still at, or beyond, the upper limit of WHO recommendations in this group. Future research exploring how colleges could improve their capacity to detect and refer at risk students for treatment at an earlier stage is recommended. PMID- 29707998 TI - Quality of Life Among Children and Adolescents With Tourette Disorder and Comorbid ADHD: A Clinical Controlled Study. AB - OBJECTIVE: To examine (a) the quality of life (QOL) in children with Tourette's disorder (TD) and ADHD (TD + ADHD) compared with ADHD without tics (ADHD alone) and (b) the effects of the severity of tics, ADHD symptoms, comorbid diagnoses, and family functioning on QOL. METHOD: The assessments included the Kiddie Schedule for Affective Disorders and Schizophrenia, Yale Global Tic Severity Scale, ADHD Rating Scale, Pediatric Quality of Life Inventory, and Family Assessment Device. RESULTS: The TD + ADHD group had poorer psychosocial QOL. Agreement between child and parent ratings was higher in the TD + ADHD group, and children reported higher scores than their parents in both groups. Severity of tics and ADHD symptoms had stronger negative associations with parent-reported than child-reported QOL. Significant positive correlations were detected between QOL and family functioning in both groups. CONCLUSION: Children with TD + ADHD have lower QOL than their peers with ADHD alone. Family functioning seems to affect QOL in both groups. PMID- 29707997 TI - Effect of combination sildenafil and gemfibrozil on cisplatin-induced nephrotoxicity; role of heme oxygenase-1. AB - BACKGROUND/AIM: Cisplatin-induced nephrotoxicity in large proportion of patients. The aim of this work is to clarify the effect of combination of sildenafil and gemfibrozil on cisplatin-induced nephrotoxicity either before or after cisplatin treatment and determination of nephrotoxicity predictors among the measured tissue markers. METHODS: Thirty two adult male albino rats were divided into four equal groups (G) GI control, GII received cisplatin, GIII received sildenafil and gemfibrozil before cisplatin, GIV received sildenafil and gemfibrozil after cisplatin. Creatinine and urea were measured and animals were sacrificed and kidney was taken for histopathology. The following tissue markers were measured, heme oxygenase-1 (HO-1) activity, reduced glutathione, quantitative (real-time polymerase chain reaction) RT-PCR for gene expression of tumor necrosis factor alpha (TNF-alpha) and endothelial nitric oxide synthase (ENOS) level. RESULTS: GII developed AKI demonstrated by significantly high urea and creatinine and severe diffuse (80-90%) tubular necrosis. TNF-alpha was highly and significantly elevated while the rest of tissue markers were significantly reduced in GI1 compared to other groups. GIV showed better results compared to GIII. There was a significant positive correlation between creatinine and TNF-alpha when combining GI and GII while there were significant negative correlation between creatinine and other tissue markers in same groups. Linear regression analysis demonstrated that HO-1 was the independent predictor of AKI demonstrated by elevated creatinine among GI and GII. CONCLUSIONS: Combination of sildenafil and gemfibrozil can be used in treatment of cisplatin-induced nephrotoxicity. HO-1 is a promising target for prevention and/or treatment of cisplatin-induced nephrotoxicity. PMID- 29707999 TI - An Examination of Blood Cell Membrane Potential as a Diagnostic Test of Attention Deficit Disorder in Children. AB - OBJECTIVE: To reexamine previous findings that reported that blood cells' membrane potential ratios (MPRsTM) differ between youth with ADHD and controls and to determine whether psychostimulants affect MPRsTM. METHOD: Forty-four youth (ages 6-17) with ADHD (not currently taking psychostimulants; n = 24) and controls ( n = 20) completed the Mini-International Neuropsychiatric Interview 7 (MINI 7) and a blood draw to determine MPRTM. Youth with ADHD provided another blood draw 30 days after receiving psychostimulants. RESULTS: MPRTM values of participants with ADHD who were not taking stimulants were not significantly different from those of the controls. MPR'sTM sensitivity was 79.2% and specificity 25.0%. Among youth with ADHD, there was a trending association between lower MPRsTM and taking stimulants (compared with baseline). CONCLUSION: Results neither replicate prior findings nor support MPRs'TM utility in diagnosing ADHD in youth. We identified possible MPRTM changes after participants with ADHD began stimulants. Further studies are needed to establish the clinical significance of this finding. PMID- 29708001 TI - Drama review: "watch me vanish": formlessness and the immersive psychiatric phenomenology of Sarah Kane's "4.48 Psychosis". PMID- 29708002 TI - Might robotic-assisted surgery become commonplace in endometrial cancer treatment? PMID- 29708000 TI - Working Memory and Intraindividual Variability in Response Time Mediate Fluid Intelligence Deficits Associated With ADHD Symptomology. AB - OBJECTIVE: To determine if decreased fluid intelligence was associated with ADHD, and was mediated by deficits in working memory and intraindividual variability in motor responding. METHOD: The present study tested 142 young adults from the general population on a range of working memory, response time, and fluid intelligence tasks, and an ADHD self-report symptoms questionnaire. RESULTS: Total and hyperactive ADHD symptoms correlated significantly and negatively with fluid intelligence, but this association was fully mediated by both working memory and intraindividual variability in response time. However, inattentive symptoms were not associated with fluid intelligence. CONCLUSION: These results have important implications for clinicians using speeded psychometric tests as part of their assessment battery, working memory interventions for ADHD patients that focus on performance improvement without controlling for response consistency, and also demonstrate potential differences in the neuropsychological profiles of ADHD subtypes. PMID- 29708003 TI - "Chipping away": non-consumer researcher perspectives on barriers to collaborating with consumers in mental health research. AB - BACKGROUND: Collaboration between researchers who have lived experience of mental illness and services (consumer researchers) and mental health researchers without (other mental health researchers) is an emergent development in research. Inclusion of consumer perspectives is crucial to ensuring the ethics, relevancy and validity of mental health research; yet widespread and embedded consumer collaboration of this nature is known to be impeded by attitudinal and organisational factors. Limited research describes consumer researchers' experiences of barriers. Other mental health researchers are key players in the co-production process yet there is also a paucity of research reporting their views on barriers to collaborating with consumers. AIMS: To explore other researchers' views and experiences on partnering with consumer mental health researchers in Australia and New Zealand. METHODS: Exploratory qualitative design. Eleven semi-structured interviews were conducted with mental health researchers. Interviews were recorded, transcribed and thematically analysed. RESULTS: Four themes concerning barriers to collaborating with consumers (hierarchies, status quo, not understanding, paternalism), and one theme on addressing the barriers (constantly chipping away) were identified. CONCLUSIONS: It is suggested that multifaceted strategies for advancing collaboration with consumers are most effective. It is imperative to attend to several barriers simultaneously to redress the inherent power disparity. PMID- 29708004 TI - Traumatic glioblastoma: commentary and suggested mechanism. AB - The role of head trauma in the development of glioblastoma is highly controversial and has been minimized since first put forward. This is not unexpected because skull injuries are overwhelmingly more common than glioblastoma. This paper presents a commentary based on the contributions of James Ewing, who established a major set of criteria for the recognition of an official relationship between trauma and cancer. Ewing's criteria were very stringent. The scholars who succeeded Ewing have facilitated the characterization of traumatic brain injuries since the introduction of computed tomography and magnetic resonance imaging. Discussions of the various criteria that have since developed are now being conducted, and those of an unnecessarily limiting nature are being highlighted. Three transcription factors associated with traumatic brain injury have been identified: p53, hypoxia-inducible factor-1alpha, and c MYC. A role for these three transcription factors in the relationship between traumatic brain injury and glioblastoma is suggested; this role may support a cause-and-effect link with the subsequent development of glioblastoma. PMID- 29708005 TI - MicroRNA-based therapeutics in central nervous system injuries. AB - Central nervous system (CNS) injuries, such as stroke, traumatic brain injury (TBI) and spinal cord injury (SCI), are important causes of death and long-term disability worldwide. MicroRNA (miRNA), small non-coding RNA molecules that negatively regulate gene expression, can serve as diagnostic biomarkers and are emerging as novel therapeutic targets for CNS injuries. MiRNA-based therapeutics include miRNA mimics and inhibitors (antagomiRs) to respectively decrease and increase the expression of target genes. In this review, we summarize current miRNA-based therapeutic applications in stroke, TBI and SCI. Administration methods, time windows and dosage for effective delivery of miRNA-based drugs into CNS are discussed. The underlying mechanisms of miRNA-based therapeutics are reviewed including oxidative stress, inflammation, apoptosis, blood-brain barrier protection, angiogenesis and neurogenesis. Pharmacological agents that protect against CNS injuries by targeting specific miRNAs are presented along with the challenges and therapeutic potential of miRNA-based therapies. PMID- 29708006 TI - Cyclophosphamide immunomodulation of TB-associated cerebral vasculitis. PMID- 29708007 TI - Corrigendum. AB - Gary, R., Dunbar, S. B., Higgins, M., Butts, B., Corwin, E., Hepburn, K., ... Miller, A. H. (2018). An Intervention to Improve Physical Function and Caregiver Perceptions in Family Caregivers of Persons With Heart Failure. Journal of Applied Gerontology. E pub ahead of print 19 January 2018. DOI: 10.1177/0733464817746757 In this article, the acknowledgment for the funder in the funding statement was missing. The correct funding statement is given below. The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work is supported in part by the National Institutes of Health National Institute of Nursing Research grant no. P01 1PO1NR011587 (PI-E. Corwin), Advancing Translational Sciences of the National Institutes of Health under award no. UL1TR000454 (D. Stephens), and the Atlanta Veterans Administration Medical Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or the Veterans Administration. This study is registered at www.clinicaltrials.gov (NCT01188070). The online version of this article has been corrected. PMID- 29708008 TI - Masculinity, Social Connectedness, and Mental Health: Men's Diverse Patterns of Practice. AB - Men's mental health has remained undertheorized, particularly in terms of the gendered nature of men's social relations. While the importance of social connections and strong supportive networks for improving mental health and well being is well documented, we know little about men's social support networks or how men go about seeking or mobilizing social support. An in-depth understanding of the gendered nature of men's social connections and the ways in which the interplay between masculinity and men's social connections can impact men's mental health is needed. Fifteen life history interviews were undertaken with men in the community. A theoretical framework of gender relations was used to analyze the men's interviews. The findings provide rich insights into men's diverse patterns of practice in regards to seeking or mobilizing social support. While some men differentiated between their social connections with men and women, others experienced difficulties in mobilizing support from existing connections. Some men maintained a desire to be independent, rejecting the need for social support, whereas others established support networks from which they could actively seek support. Overall, the findings suggest that patterns of social connectedness among men are diverse, challenging the social science literature that frames all men's social relationships as being largely instrumental, and men as less able and less interested than women in building emotional and supportive relationships with others. The implications of these findings for promoting men's social connectedness and mental health are discussed. PMID- 29708010 TI - The effects of spiritual care on quality of life and spiritual well-being among patients with terminal illness: A systematic review. AB - BACKGROUND: Terminal illness not only causes physical suffering but also spiritual distress. Spiritual care has been widely implemented by healthcare professionals to assist patients coping with spiritual distress. However, the effects of spiritual care need to be clear. AIM: To evaluate the effects of spiritual care on quality of life and spiritual well-being among patients with terminal illness. DESIGN: Systematic review according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidance. DATA SOURCES: A comprehensive search was conducted in nine electronic databases from date of inception to May 2017. Hand searches of the bibliographies of relevant articles were also performed. The studies were independently reviewed by two investigators who scored them for methodological quality using the Cochrane Risk of Bias Tool. RESULTS: No statistical pooling of outcomes was performed and a narrative summary was chosen to describe the included studies. A total of 19 studies with 1548 participants were identified in the systematic review, corresponding to seven kinds of interventions. The risk of bias for these studies were all rated as moderate. A majority of studies indicated that spiritual care had a potential beneficial effect on quality of life and spiritual well-being among patients with terminal illness. CONCLUSION: It is suggested that healthcare professionals integrate spiritual care with usual care in palliative care. When providing spiritual care, healthcare professionals should take into consideration patients' spiritual needs, preference, and cultural background. More multicenter and disciplinary studies with rigorous designs are needed in the future. PMID- 29708009 TI - High-Frequency Ultrasound Imaging-Guided Wedge Resection: An Effective Treatment for Paraurethral Duct Dilatation Following Gonococcal Paraurethral Duct Infection in Men. AB - This study was performed to evaluate the therapeutic effects of wedge resection on male paraurethral duct dilatation following gonococcal paraurethral duct infection. Twenty-six men with paraurethral duct dilatation following gonococcal paraurethral duct infection were enrolled. Their lesions underwent wedge resection after examination using an ACUSON X300 ultrasound system. The anesthetic method, surgical duration, intraoperative blood loss, wound healing time, complications, sequelae, and curative effect were assessed. All 26 men received local infiltration anesthesia. The mean surgical duration was 18.65 +/- 2.50 min (range, 14-23 min), the mean intraoperative blood loss was 10.50 +/- 1.68 ml (range, 8-14 ml), and the mean wound healing time was 14.73 +/- 1.31 days (range, 13-17 days). The lesions were cured in all patients (100%). The postoperative wounds healed in all patients. No complications or glans defects were observed in any patients. The study identifies that high-frequency ultrasound imaging-guided wedge resection is an effective and safe therapy for paraurethral duct dilatation following gonococcal paraurethral duct infection in men. PMID- 29708012 TI - 2nd Asia-Pacific Conference of the Society for Medical Decision Making. PMID- 29708011 TI - Mild cognitive impairment and prospective memory: translating the evidence into neuropsychological practice. AB - OBJECTIVE: There has been a recent rapid development of research characterizing prospective memory performance in mild cognitive impairment (MCI) in older age. However, this body of literature remains largely separated from routine clinical practice in neuropsychology. Furthermore, there is emerging evidence of effective interventions to improve prospective memory performance. Therefore, our objective in this article was to offer a clinical neuropsychological perspective on the existing research in order to facilitate the translation of the evidence-base into clinical practice. METHOD: By conducting a critical review of the existing research related to prospective memory and MCI, we highlight how this data can be introduced into clinical practice, either within diagnostic assessment or clinical management. CONCLUSIONS: Prospective memory is impaired in older adults with MCI, with a pattern of performance that helps with differential diagnosis from healthy aging. Clinical neuropsychologists are encouraged to add prospective memory assessment to their toolbox for diagnostic evaluation of clients with MCI. Preliminary findings of prospective memory interventions in MCI are promising, but more work is required to determine how different approaches translate to increasing independence in everyday life. PMID- 29708013 TI - Factors Influencing the Prevalence of Animal Cruelty During Adolescence. AB - Adolescents' interactions with animals are of increasing interest and their beneficial developmental outcomes are well known. However, negative interactions such as perpetrating cruelty toward animals during childhood and adolescence have been related with child abuse, domestic violence, and later interpersonal violence. Cruelty toward animals by adolescents has been reported predominately in criminal and clinical samples, and links have been made between animal cruelty and interpersonal violence. However, studies often lack a clear definition of animal cruelty and the animal involved. The present study addresses methodological shortcomings by providing a clear definition of the cruelty acts and the animals involved and the time frame within which cruelty acts have been taken place. Therefore, we investigated the prevalence of animal cruelty of 979 British adolescents (419 male, 497 female, Mage = 15.1 +/- 1.57 years) by means of a survey questionnaire administered in school. Animal cruelty was investigated encompassing deliberate and nondeliberate cruelty acts, a clear definition of the target animals was included and a time frame was provided. Furthermore, acceptability of animal cruelty, engaging in antisocial behavior, and family affluence were investigated. Results show high reliabilities for the measures applied. Exploratory factor analysis reveals different types of animal cruelty. Gender differences were observed for deliberate and accidental cruelty acts, with boys reporting higher levels than girls. Younger adolescents reported higher accidental cruelty acts than older ones. Acceptance of animal cruelty played a significant role in predicting animal cruelty, together with antisocial behaviors and place of living. The present study shows for the first time the importance of distinguishing between different types of animal cruelty and defining the animals involved. PMID- 29708014 TI - The difficulties of discharging hospice patients to care homes at the end of life: A focus group study. AB - BACKGROUND: Discharge from inpatient palliative care units to long-term care can be challenging. In the United Kingdom, hospice inpatients move to a care home if they no longer require specialist palliative care and cannot be discharged home. There is evidence to suggest that patients and families find the prospect of such a move distressing. AIM: To investigate the issues that arise when patients are transferred from hospice to care home at the end of life, from the perspective of the hospice multidisciplinary team. DESIGN: A qualitative study, using thematic analysis to formulate themes from focus group discussions with hospice staff. SETTING/PARTICIPANTS: Five focus groups were conducted with staff at five UK hospices. Participants included multidisciplinary team members involved in discharge decisions. All groups had representation from a senior nurse and doctor at the hospice, with group size between three and eight participants. All but one group included physiotherapists, occupational therapists and family support workers. RESULTS: A major focus of group discussions concerned dilemmas around discharge. These included (1) ethical concerns (dilemmas around the decision, lack of patient autonomy and allocation of resources); (2) communication challenges; and (3) discrepancies between the ideals and realities of hospice palliative care. CONCLUSION: Hospice palliative care unit staff find discharging patients to care homes necessary, but often unsatisfactory for themselves and distressing for patients and relatives. Further research is needed to understand patients' experiences concerning moving to care homes for end of life care, in order that interventions can be implemented to mitigate this distress. PMID- 29708016 TI - What We Choose to Emphasize. PMID- 29708015 TI - Park use and physical activity among adolescent girls at two time points. AB - This longitudinal study described park usage and assessed the contribution of parks to moderate to vigorous physical activity (MVPA) among adolescent girls. High school girls from California (n = 131) and Minnesota (n = 134) wore a global positioning system (GPS) monitor and accelerometer for 6 consecutive days at two time points, one year apart. Park visits were classified by linking the GPS, accelerometer, and park and built environment data around home and school locations into a geographic information system. At baseline, 20% of girls visited a park at least once (mean 0.1 times/day), which was similar one year later (19%, mean 0.1 times/day). Girls lived a mean Euclidean distance of 0.2 miles to the nearest park at both times. Among all park visits, the mean Euclidean distance of the park visited was 4.1 (baseline) and 3.9 miles (follow-up). The average duration of park visits was higher at baseline (63.9 minutes) compared to follow up (38.4 minutes). On days when a park was visited, MVPA was higher than on days when a park was not visited. On average, 1.9% (baseline) and 2.8% (follow-up) of MVPA occurred in parks. In this study, parks were an under-used resource for adolescent girls, particularly for MVPA. PMID- 29708017 TI - 16th Biennial European Meeting of the Society for Medical Decision Making: ESMDM Meeting Abstracts. PMID- 29708018 TI - 37th Annual Meeting of the Society for Medical Decision Making. PMID- 29708019 TI - Measuring pulmonary arterial compliance: mission impossible? Insights from a novel in vivo continuous-flow based experimental model. AB - Arterial compliance (C) is related to the elasticity, size, and geometrical distribution of arteries. Compliance is a determinant of the load that impedes ventricular ejection. Measuring compliance is difficult, particularly in the pulmonary circulation in which resistive and compliant vessels overlap. Comparing different methods for quantification of compliance to a method that involves a continuous flow might help to identify the optimal method. Pulmonary arterial compliance was computed in six pigs based on the stroke volume to pulse pressure ratio, diastolic decay exponential fitting, area method, and the pulse pressure method (PPM). Compliance measurements were compared to those obtained under continuous flow conditions through a right ventricular bypass (Heartware Inc., Miami Lakes, FL, USA). Compliance was computed for various flows using diastolic decay exponential fitting after an abrupt interruption of the pump. Under the continuous flow conditions, resistance (R) was a decreasing function of the flow, and the fitting to P = e-t/RC yielded a pulmonary time constant (RC) of 2.06 s ( +/- 0.48). Compliance was an increasing function of flow. Steady flow inter method comparisons of compliance under pulsatile flow conditions showed large discrepancies and values (7.23 +/- 4.47 mL/mmHg) which were lower than those obtained under continuous flow conditions (10.19 +/- 1 0.31 mL/mmHg). Best agreement with steady flow measurements is obtained with the diastolic decay method. Resistance and compliance are both flow-dependent and are inversely related in the pulmonary circulation. The dynamic nature of the pulsatile flow may induce a non-uniformly distributed compliance, with an influence on the methods of measurement. PMID- 29708020 TI - " The Worst Thing Was...": Prostate Cancer Patients' Evaluations of Their Diagnosis and Treatment Experiences. AB - The objective of the current study was to identify the patient-perceived "worst aspects" of their diagnostic and treatment processes for prostate cancer (PCa) so as to inform targeted interventions aimed at reducing patient anxiety and depression. Two hundred and fifty-two patients who had received their diagnoses less than 8 years ago answered a postal survey about (a) background information, (b) their own descriptions of the worst aspects of their diagnosis and treatment, and (c) their ratings of 13 aspects of that process for (i) how these aspects made them feel stressed, anxious, and depressed and (ii) how they affected their relationships with significant others. They also answered standardized scales of anxiety and depression. The worst aspects reported by patients were receiving the initial diagnosis of PCa, plus the unknown outcome of that diagnosis, because of the possibility of death, loss of quality of life and/or partner, and the shock of the diagnosis. The most common coping strategy was to "just deal with it," but participants also thought that more information would help. Principal contributors to feeling stressed, anxious, and depressed were also the diagnosis itself, followed by surgery treatment effects. The aspects that most affected relationships were receiving the diagnosis and the side effects of hormone therapy. The identification of these specific worst aspects of the PCa experience provides a set of potential treatment and prevention "targets" for psychosocial care in PCa patients. PMID- 29708021 TI - Association Between Erectile Dysfunction and Subsequent Prostate Cancer Development: A Population-Based Cohort Study With Double Concurrent Comparison Groups. AB - Recent studies indicate that erectile dysfunction (ED) and prostate cancer share common potential risk factors such as chronic inflammation, prostatitis, cigarette smoking, obesity, a high animal fat diet, sedentarism, and depression. There is great interest in knowing if ED is associated with prostate cancer. This study aimed to investigate if men afflicted with ED harbor an increased risk of prostate cancer, utilizing two concurrent comparison groups, constructed from the Taiwan NHIRD, with up to 8 years' follow-up. Among men with no preexisting prostate cancer, an ED group of 3,593 men >= 40 years of age and two non-ED comparison groups of 14,372 men from the general population, 1:4 matched by age and index date (GENPOP); and 3,594 men with clinical benign prostatic hyperplasia (BPH), matched by similar criteria were assembled. A Cox model was constructed to calculate the adjusted hazard ratio (aHR) after controlling for age, socioeconomic factors, and various medical comorbidities. During the 11,449 person-year follow-up for the ED group, 24 incident prostate cancer developed. During the 44,486 and 11,221 person-year follow-up for the GENPOP and the BPH group, respectively, there were 33 and 25 incidents of prostate cancer. The ED group demonstrated a 2.6-fold greater risk of prostate cancer than that by the GENPOP with an aHR of 2.63 (95% confidence interval [CI] [1.51, 4.59], p < .001). There was no significant difference in risk between ED and BPH group (aHR = 0.83, 95% CI [0.46, 1.48]). This concurrent, double comparison, longitudinal study revealed a positive association between ED and subsequent prostate cancer incidence. PMID- 29708023 TI - Textbook descriptions of people with psychosis - some ethical aspects. AB - BACKGROUND: Textbooks are central for the education of professionals in the health field and a resource for practitioners already in the field. OBJECTIVES: This article focuses on how 12 textbooks in psychiatric nursing and psychiatry, published in Norway between 1877 and 2012, describe and present people with psychosis. RESEARCH DESIGN: We used qualitative content analysis. Ethical considerations: The topic is published textbooks, made available to be read by students, teachers and professionals, and no ethical approval was required. FINDINGS: The analysis shows that all 12 textbooks describe and present people who are considered as psychotic from a 'perspective from above'. In this perspective, the readers are learning about psychosis in the professional's language and from the author's viewpoint. Most often the textbooks communicate a universal image of people with psychosis, a description that fits with the diagnostic criteria. The analysis also shows that two textbooks in psychiatric nursing combined this perspective with a 'perspective from within'. Here, the readers are learning about psychosis from the patients' own viewpoint. The authors communicate a personal, psychotic universe that differs from various people, even if they have the same diagnosis, and the descriptions are focusing on the patient as a whole person. DISCUSSION AND CONCLUSION: Drawing partly on Rita Charon's writings about narrative knowledge in the health field, and partly on insights from Martha Nussbaum and her concept of narrative imagination, we argue that mental health professionals need to learn about, understand and fathom what patients go through by reading, listening to and acknowledging the patients' own stories and experiences. Cultivating the capacity for empathy and compassion are at the very heart of moral performance in the mental health field. A valuable moral resource in that regard is leading textbooks and how they describe and present people with severe mental illness. PMID- 29708022 TI - The impact of right ventricular pressure and function on survival in patients with pulmonary vein stenosis. AB - Pulmonary vein stenosis (PVS) is associated with pulmonary hypertension (PH), but there is little information regarding the impact of PH on right ventricular (RV) systolic function and survival. We conducted a retrospective cohort study of our patients to explore this and other aspects of pulmonary hemodynamics with PVS. RV function was assessed using qualitative two-dimensional echocardiography. The ratio of systolic pulmonary artery (PA) and aortic pressures (PA:Ao) at cardiac catheterization reflected pulmonary hemodynamics. Reactivity testing employed inhaled nitric oxide + 100% fiO2, or 100% fiO2 only; "reactivity" was a >= 20% decrease in PA:Ao. There were 105 PVS patients, although not all had data at every time point. (1) The mean PA:Ao at first cardiac catheterization (n = 77) was 0.79 +/- 0.36; at last catheterization (n = 54), PA:Ao = 0.69 +/- 0.30; 90% had systolic PAP > one-half systemic. Survival was shorter with PA:Ao > 0.5. (2) Differences in survival relative to RV dysfunction on the first echocardiogram were not significant, although they were using the last echocardiogram. (3) The magnitude of RV dysfunction was positively correlated with PA:Ao. (4) Balloon dilation of PV acutely decreased PA:Ao (-0.13 +/- 0.37, P = 0.03 [n = 40 patients]). 5. Of 20 patients tested, 13 were acutely reactive to vasodilators. PH is a major feature of PVS. Reduced RV function and PA:Ao appear to be predictors of survival. Given the importance of PH in this disease, clinical studies of PVS treatments should include measures of PAP and RV function as important variables of interest. PMID- 29708024 TI - How American Nurses Association Code of Ethics informs genetic/genomic nursing. AB - Members of the Ethics and Public Policy Committee of the International Society of Nurses in Genetics prepared this article to assist nurses in interpreting the American Nurses Association (2015) Code of Ethics for Nurses with Interpretive Statements (Code) within the context of genetics/genomics. The Code explicates the nursing profession's norms and responsibilities in managing ethical issues. The nearly ubiquitous application of genetic/genomic technologies in healthcare poses unique ethical challenges for nursing. Therefore, authors conducted literature searches that drew from various professional resources to elucidate implications of the code in genetic/genomic nursing practice, education, research, and public policy. We contend that the revised Code coupled with the application of genomic technologies to healthcare creates moral obligations for nurses to continually refresh their knowledge and capacities to translate genetic/genomic research into evidence-based practice, assure the ethical conduct of scientific inquiry, and continually develop or revise national/international guidelines that protect the rights of individuals and populations within the context of genetics/genomics. Thus, nurses have an ethical responsibility to remain knowledgeable about advances in genetics/genomics and incorporate emergent evidence into their work. PMID- 29708025 TI - The use of arts interventions for mental health and wellbeing in health settings. AB - AIMS: This literature review aims to illustrate the variety and multitude of studies showing that participation in arts activities and clinical arts interventions can be beneficial for citizens with mental and physical health problems. The article is focused on mental health benefits because this is an emerging field in the Nordic countries where evidence is demanded from national health agencies that face an increasing number of citizens with poor mental health and a need for non-medical interventions and programmes. METHODS: A total of 20 articles of interest were drawn from a wider literature review. Studies were identified through the search engines: Cochrane Library, Primo, Ebscohost, ProQuest, Web of Science, CINAHL, PsycINFO, PubMed and Design and Applied Arts Index. Search words included the following: arts engagement + health/hospital/recovery, arts + hospital/evidence/wellbeing, evidence-based health practice, participatory arts for wellbeing, health + poetry/literature/dance/singing/music/community arts, arts health cost effectiveness and creative art or creative activity + health/hospital/recovery/mental health. The inclusion criteria for studies were (1) peer review and (2) empirical data. RESULTS: The studies document that participation in activities in a spectrum from clinical arts interventions to non clinical participatory arts programmes is beneficial and an effective way of using engagement in the arts to promote holistic approaches with health benefits. Engagement in specially designed arts activities or arts therapies can reduce physical symptoms and improve mental health issues. CONCLUSION: Based on the growing evidence of the arts as a tool for enhancing mental health wellbeing, and in line with the global challenges in health, we suggest that participatory arts activities and clinical arts interventions are made more widely available in health and social settings. It is well-documented that such activities can be used as non-medical interventions to promote public health and wellbeing. PMID- 29708026 TI - Evacuation of Swedish survivors after the 2004 Southeast Asian tsunami: The survivors' perspective and symptoms of post-traumatic stress. AB - AIMS: Following the 2004 Southeast Asian tsunami, Swedish authorities received public criticism for slow implementation of rescue work. Meanwhile, data are scarce on survivors' perspectives and potential mental health symptoms associated with timing of evacuation. Therefore, the aim of this study was to investigate survivors' contentment with evacuation time and whether duration at disaster site following the 2004 tsunami was associated with post-traumatic stress symptoms (PTSS) and psychological morbidity. METHODS: Of 10,116 Swedish tsunami survivors who returned to Sweden in the first 3 weeks post tsunami, 4910 (49%) answered a questionnaire 14 months later including questions on evacuation time, contentment with evacuation time and PTSS (Impact of Event Scale). We used logistic regression to calculate odds ratios (OR) and 95% confidence intervals (95% CI) of PTSS by timing of evacuation adjusting for gender, age, education, various indicators of trauma exposure and pre-tsunami psychiatric diagnoses. RESULTS: More than half of the survivors (53%) were content with evacuation time while 33% wanted later evacuation and 13% earlier evacuation. Compared with those evacuated 14-21 days post tsunami, individuals evacuated at day 1-4 presented with increased odds of PTSS (crude OR 3.0, 95% CI 2.0-4.5; and multivariable adjusted OR 2.0, 95% CI 1.3-3.0) and impaired mental health (crude OR 1.7, 95% CI 1.2-2.4; and multivariable adjusted OR 1.4 95% CI 1.0-2.0). CONCLUSIONS: One-third of Swedish tsunami survivors preferred a later evacuation from disaster sites. These findings call for further studies, with prospective designs, to disentangle the causal direction of the association between evacuation time and PTSS. PMID- 29708028 TI - Adolescent self-rated health predicts general practice attendance in adulthood: Results from the Young-HUNT1 survey. AB - AIMS: Self-rated health (SRH) is a predictor of future health. However, the association between SRH in adolescence and health problems and health care utilization in adulthood has rarely been investigated. The aim of this study was to examine adolescent SRH as a predictor of general practitioner consultations in adulthood. METHODS: SRH was registered in the Young-HUNT1 survey in 1995-1997 ( N=8828, mean age 16 years, 88% participation rate). General practitioner consultations during 2006-2014 were obtained from a national claims database. The predictive value of adolescent SRH on general practitioner consultations in adulthood was analysed by regression models estimating the relative risks (RR) for the total number of consultations and consultations for psychological, gastrointestinal, musculoskeletal or respiratory problems. Age, sex and baseline measures of chronic disease and health care attendance were used as the adjusting variables. RESULTS: SRH was reported as 'very good' by 28.4%, 'good' by 60.6% and 'not good' by 11.0% of the respondents. The increases in consultation rates were 21% (RR 1.21, 95% CI 1.15-1.27) and 52% (RR 1.52, 95% CI 1.40-1.64) when comparing respondents with 'very good' SRH to those with 'good' and 'not good' SRH, respectively. We also demonstrated a dose-response association between adolescent SRH and general practitioner consultations for psychological, gastrointestinal, musculoskeletal or respiratory problems. CONCLUSIONS: SRH in adolescence is a predictor for general practitioner consultations in adult life. Previous research shows that SRH is influenced by factors such as well-being, health behaviour, functional status and body satisfaction. Intervention studies are needed to evaluate whether population-based and clinical interventions can improve SRH by improving these factors among adolescents. PMID- 29708029 TI - Relevant research from orthodontic journals: sleep apnoea. PMID- 29708030 TI - The concept and measurement of fathers' stimulating play: a review. AB - Reviews of attachment research point to fathers' capacity to provide for a secure child-parent attachment relationship; a suggested mechanism for the development of this relationship may be sensitive and challenging play interactions. This review synthesises research on fathers' challenging and stimulating play by mapping the variation in construct definitions and reporting on the association of fathers' stimulating play with child outcomes. Using search terms such as "father", "stimulating"and "challenging", 26 studies were identified, including 16 longitudinal studies, which assessed the association between father-child stimulating or challenging play, and child outcomes. Five categories of stimulating play were derived from the analysis,ranging on a continuum of activation and complexity. Most studies reported positive associations with children's cognitive, psycho social and physical development. The discussion highlights the variation in the operationalisation of challenging and stimulating play, and suggestions for future research on the function of fathers' play interactions are made. PMID- 29708031 TI - The use of RemoweLL oxygenator-integrated device in the prevention of the complications related to aortic valve surgery in the elderly patient: Preliminary results. AB - Background The effects of fat microembolization due to cardiopulmonary bypass are well known in cardiac surgery. Our aim is to evaluate the use of the RemoweLL device (Eurosets, Medolla, Italy) during elective aortic valve replacement in elderly patients (>70 years old) to rate its biochemical and clinical effects. The RemoweLL device is an oxygenator-integrated reservoir which combines two strategies for fat emboli and leucocytes removal: filtration and supernatant elimination. Methods Forty-four elderly patients were enrolled and assigned randomly to a Group A (standard device) and a Group B (RemoweLL). Biochemical effects were evaluated by blood samples, which were tested for white blood cells, neutrophils, protein SP-100 and interleukin 6 besides standard lab tests. Our clinical endpoints were any type of neurological, cardiac, respiratory, gastrointestinal or renal complications, and length of stay in the intensive care unit. Statistical analysis was carried out with chi square test for non parametric data; t test and analysis of variance for repeated measures were used for parametric data. Results Group B showed lower levels of white blood cells, neutrophils, interleukin 6 and protein SP-100 immediately and 24 hours after the operation. Group B also showed a lower amount of neurocognitive type II dysfunction even if the length of stay in the ICU did not change. Conclusions The RemoweLL system is safe and effective in reducing inflammatory response to cardiopulmonary bypass and it could be a useful tool in minimizing negative effects of cardiopulmonary bypass; however, it does not seem to have any effect on elderly patients' hospital stay. PMID- 29708033 TI - The role of genetic testing in the prevention of acute aortic dissection. AB - Although much has been learned about disease of the thoracic aorta, most diagnosis of thoracic aortic aneurysm (TAA) is still incidental. The importance of the genetic aspects in thoracic aortic disease is overwhelming, and today different mutations which cause TAA or alter its natural history have been discovered. Technological advance has made available testing which detects genetic mutations linked to TAA. This article analyses the genetic aspects of TAA and describes the possible role of genetic tests in the clinical setting in preventing devastating complications of TAA. PMID- 29708032 TI - Studies on sporadic non-syndromic thoracic aortic aneurysms: 1. Deregulation of Jagged/Notch 1 homeostasis and selection of synthetic/secretor phenotype smooth muscle cells. AB - Background Sporadic non-syndromic thoracic aortic aneurysms (SNSTAAs) are less well understood than familial non-syndromic or syndromic ones. The study aimed at defining the peculiar morphologic and molecular changes occurring in the media layer of SNSTAAs. Design This study was based on a single centre design. Methods Media layer samples taken from seven carefully selected SNSTAAs and seven reference patients (controls) were investigated via quantitative polymerase chain reaction, proteomics-bioinformatics, immunoblotting, quantitative histology, and immunohistochemistry/immunofluorescence. Results In SNSTAAs media, aortic smooth muscle cells numbers were halved due to an apoptotic process coupled with a negligible cell proliferation. Cystathionine gamma-lyase was diffusely up regulated. Surviving aortic smooth muscle cells exhibited diverging phenotypes: in inner- and outer-media contractile cells prevailed, having higher contents of smooth-muscle-alpha-actin holoprotein (45-kDa) and of caspase-3-cleaved smooth muscle-alpha-actin 25-kDa fragments; in mid-media, aortic smooth muscle cells exhibited a synthetic/secretor phenotype, down-regulating vimentin, but up regulating glial fibrillary acidic protein, trans-Golgi network 46 protein, Jagged1 (172-kDa) holoprotein, and Jagged1's receptor Notch1. Extracellular soluble Jagged1 (42-kDa) fragments accumulated. Conclusions In SNSTAAs, there is a relentless aortic smooth muscle cells attrition caused by the up-regulated cystathionine gamma-lyase. In mid-media, synthetic/secretor aortic smooth muscle cells intensify Jagged1/NOTCH1 signalling in the attempt to counterbalance the weakened aortic wall, due to aortic smooth muscle cells net loss and mechanical stress. Synthetic/secretor aortic smooth muscle cells are apoptosis-prone, and the accruing thrombin-cleaved Jagged1 fragments counteract the otherwise useful effects of Jagged1/NOTCH1 signalling, thus hampering tissue homeostasis/remodelling, and aortic smooth muscle cells adhesion, differentiation, and migration. PMID- 29708034 TI - Aortic centres should represent the standard of care for acute aortic syndrome. AB - Background Existing evidence suggests that patients affected by acute aortic syndromes (AAS) may benefit from treatment at dedicated specialized aortic centres. The purpose of the present study was to perform a meta-analysis to evaluate the impact aortic service configuration has in clinical outcomes in AAS patients. Methods The design was a quantitative and qualitative review of observational studies. We searched PubMed/ MEDLINE, EMBASE, and Cochrane Library from inception to the end of December 2017 to identify eligible articles. Areas of interest included hospital and surgeon volume activity, presence of a multidisciplinary thoracic aortic surgery program, and a dedicated on-call aortic team. Participants were patients undergoing repair for AAS, and odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were adopted for synthesizing hospital/30-day mortality. Results A total of 79,131 adult patients from a total of 30 studies were obtained. No randomized studies were identified. Pooled unadjusted ORs showed that patients treated in high-volume centres or by high volume surgeons were associated with lower mortality rates (OR 0.51; 95% CI 0.46 0.56, and OR 0.41, 95% CI 0.25-0.66, respectively). Pooled adjusted estimates for both high-volume centres and surgeons confirmed these survival benefits (adjusted OR, 0.56; 95% CI 0.45-0.70, respectively). Patients treated in centres that introduced a specific multidisciplinary aortic program and a dedicated on-call aortic team also showed a significant reduction in mortality (OR 0.31; 95% CI 0.19-0.5, and OR 0.37; 95% CI 0.15-0.87, respectively). Conclusions We found that specialist aortic care improves outcomes and decreases mortality in patients affected by AAS. PMID- 29708035 TI - Gender differences in outcomes after aortic aneurysm surgery should foster further research to improve screening and prevention programmes. AB - Background Gender-related biases in outcomes after thoracic aortic surgery are an important factor to consider in the prevention of potential complications related to aortic diseases and in the analysis of surgical results. Methods The aim of this study is to provide an up-to-date review of gender-related differences in the epidemiology, specific risk factors, outcome, and screening and prevention programmes in aortic aneurysms. Results Female patients affected by aortic disease still have worse outcomes and higher early and late mortality than men. It is difficult to plan new specific strategies to improve outcomes in women undergoing major aortic surgery, given that the true explanations for their poorer outcomes are as yet not clearly identified. Some authors recommend further investigation of hormonal or molecular explanations for the sex differences in aortic disease. Others stress the need for quality improvement projects to quantify the preoperative risk in high-risk populations using non-invasive tests such as cardiopulmonary exercise testing. Conclusions The treatment of patients classified as high risk could thus be optimised before surgery becomes necessary by means of numerous strategies, such as the administration of high-dose statin therapy, antiplatelet treatment, optimal control of hypertension, lifestyle improvement with smoking cessation, weight loss and careful control of diabetes. Future efforts are needed to understand better the gender differences in the diagnosis, management and outcome of aortic aneurysm disease, and for appropriate and modern management of female patients. PMID- 29708036 TI - Studies on sporadic non-syndromic thoracic aortic aneurysms: II. Alterations of extra-cellular matrix components and focal adhesion proteins. AB - Background Sporadic non-syndromic thoracic aortic aneurysms (SNSTAAs) are less well understood than familial non-syndromic or syndromic ones. Here, we focused on morphologic and molecular changes of the extracellular matrix of the tunica media of SNSTAAs. Design Single centre design. Methods Surgical media samples from seven SNSTAAs and seven controls underwent quantitative polymerase chain reaction, proteomics-bioinformatics, immunoblotting, histology and immunohistochemistry analysis. Results A down-regulation of Decorin mRNA with unchanged protein levels associated with a remarkable increase of collagen fibres. A reduced and distorted network of elastic fibres partnered with an attenuated expression of microfibril-associated glycoprotein1 despite the rise of MFAP2 gene-encoded mRNA levels. An increasingly proteolysed paxillin (55 kDa PXN), a focal adhesion protein, combined with an upregulated 62 kDa PXN holoprotein, without changes in amount and phosphorylation of focal adhesion kinase (pp125FAK). The upregulation of SPOCK2-encoded Testican2 proteoglycan and of ectodysplasin (EDA) protein was coupled with a down-regulation of EDA2 receptor (EDA2R). Conclusions Several tunica media extracellular matrix-related changes favour SNSTAA development. A steady level of decorin and a microfibril associated glycoprotein1 protein shortage cause the assembly of structurally defective collagen and elastic fibres. Up-regulation of PXN holoproteins perturbs PXN/pp125FAK interaction and focal adhesion functioning. Testican2 up-regulation suppresses the membrane-type matrix metalloproteinase inhibiting activities of other SPOCK family members thus enhancing extracellular matrix proteolysis. Finally, the altered EDA*EDA2R signalling would impact on the remodelling of SNSTAA tunica media. Altogether, our results pave the way to a deeper molecular understanding of SNSTAAs necessary to identify their early diagnostic biochemical markers. PMID- 29708037 TI - Thoracic endovascular aortic repair to treat uncomplicated Stanford type B aortic dissection: The surgeon's dilemma to preventing future complications. AB - Uncomplicated type B aortic dissections have traditionally been managed non operatively with aggressive blood pressure control. However, the best medical treatment is associated with a considerable risk of disease progression to complicated dissection or aneurysmal degeneration of the affected aortic segment. Thoracic endovascular aortic repair could prevent long-term complications but, because the dissected aorta is vulnerable, it is a high-risk procedure performed in asymptomatic patient. Therefore, endovascular treatment is not a solution for all patients and it should be performed only in the subgroup prone to developing progression of the disease and future complications. A number of studies have suggested several prognostic factors of early or late adverse events such as the patency of the false lumen in the follow-up, an initial aortic diameter >=4 cm with a patent false lumen, an initial false lumen diameter >=22 mm in the proximal descending aorta, visceral involvement and recurrent or refractory pain or hypertension. Partial false lumen thrombosis and a proximal entry tear size >10 mm have also been suggested to be associated with an increased rate of aortic growth. We need randomised trials focused on these prognostic factors to reach level 1, class A recommendation for the optimal timing of intervention. Meanwhile, we have to discuss with the patient the pro and cons of this prophylactic, low-invasive but high-risk treatment to personalise medical care and provide the optimal risk-to-benefit ratio. PMID- 29708040 TI - Fear of Recurrence in Turkish Breast Cancer Survivors: A Qualitative Study. AB - PURPOSE: Fear of recurrence (FOR) of cancer is a distressing symptom and can negatively affect breast cancer survivors' quality of life and psychological well being. The purpose of this qualitative study was to explore Turkish breast cancer survivors' experiences related to FOR. DESIGN: The data were collected through semistructured interviews, which were conducted with 12 breast cancer survivors. RESULTS: The data were categorized into four themes: the quality of fear, triggers, effects on life, and coping. FOR survivors' lives in multiple aspects, and the women found it difficult to manage their fear. IMPLICATIONS: Nurses should be aware of FOR in survivors during follow-up care. In addition, it is essential to consider the impact of FOR on life, and survivors should be referred to appropriate resources and support services. PMID- 29708038 TI - Comparison of hemiarthroplasty and total hip arthroplasty in elderly patients with displaced femoral neck fractures. AB - Objective This study was performed to compare the clinical and radiological outcomes of displaced femoral neck fractures (FNFs) treated with either hemiarthroplasty or total hip arthroplasty (THA) in elderly patients. Morbidity and mortality were also evaluated. Methods Twenty-two patients who underwent hemiarthroplasty and 16 patients who underwent THA for treatment of Garden type 3 4 FNFs from 2012 to 2015 were enrolled in this study. All patients were >65 years of age. Cox regression analysis was performed for mortality evaluation. Results The postoperative blood loss volume, decrease in the hemoglobin level, and transfusion rate were significantly higher in the THA group. The univariate mortality risk was higher in patients with a Charlson comorbidity score of >4, American Society of Anesthesiologists score of >2, Singh index of <3, and postoperative hospitalization of >1 week. Conclusion This study revealed no significant difference in the short-term clinical and radiological results between cementless hemiarthroplasty and THA in elderly patients with displaced FNFs. However, morbidity and mortality were associated with the presence of additional systemic diseases. THA is the preferred surgical technique in patients with displaced FNFs and low comorbidities. PMID- 29708041 TI - Comparative analysis of Klebsiella pneumoniae strains isolated in 2012-2016 that differ by antibiotic resistance genes and virulence genes profiles. AB - The antibacterial resistance and virulence genotypes and phenotypes of 148 non duplicate Klebsiella pneumoniae strains collected from 112 patients in Moscow hospitals in 2012-2016 including isolates from the respiratory system (57%), urine (30%), wounds (5%), cerebrospinal fluid (4%), blood (3%), and rectal swab (1%) were determined. The majority (98%) were multidrug resistant (MDR) strains carrying blaSHV (91%), blaCTX-M (74%), blaTEM (51%), blaOXA (38%), and blaNDM (1%) beta-lactamase genes, class 1 integrons (38%), and the porin protein gene ompK36 (96%). The beta-lactamase genes blaTEM-1, blaSHV-1, blaSHV-11, blaSHV-110, blaSHV-190, blaCTX-M-15, blaCTX-M-3, blaCTX-M-55, blaOXA-48, blaOXA-244, and blaNDM-1 were detected; class 1 integron gene cassette arrays (aadA1), (dfrA7), (dfrA1-orfC), (aadB-aadA1), (dfrA17-aadA5), and (dfrA12-orfF-aadA2) were identified. Twenty-two (15%) of clinical K. pneumoniae strains had hypermucoviscous (HV) phenotype defined as string test positive. The rmpA gene associated with HV phenotype was detected in 24% of strains. The intrapersonal mutation of rmpA gene (deletion of one nucleotide at the polyG tract) was a reason for negative hypermucoviscosity phenotype and low virulence of rmpA positive K. pneumoniae strain KPB584. Eighteen virulent for mice strains with LD50 <= 104 CFU were attributed to sequence types ST23, ST86, ST218, ST65, ST2174, and ST2280 and to capsular types K1, K2, and K57. This study is the first report about hypervirulent K. pneumoniae strain KPB2580-14 of ST23K1 harboring extended-spectrum beta-lactamase CTX-M-15 and carbapenemase OXA-48 genes located on pCTX-M-15-like and pOXA-48-like plasmids correspondingly. PMID- 29708043 TI - Skill-Based and Planned Active Play Versus Free-Play Effects on Fundamental Movement Skills in Preschoolers. AB - Fundamental movement skill interventions are important for promoting physical activity, but the optimal intervention model for preschool children remains unclear. We compared two 8-week interventions, a structured skill-station and a planned active play approach, to a free-play control condition on pre- and postintervention fundamental movement skills. We also collected data regarding program attendance and perceived enjoyment. We found a significant interaction effect between intervention type and time. A Tukey honest significant difference analysis supported a positive intervention effect showing a significant difference between both interventions and the free-play control condition. There was a significant between-group difference in group attendance such that mean attendance was higher for both the free-play and planned active play groups relative to the structured skill-based approach. There were no differences in attendance between free-play and planned active play groups, and there were no differences in enjoyment ratings between the two intervention groups. In sum, while both interventions led to improved fundamental movement skills, the active play approach offered several logistical advantages. Although these findings should be replicated, they can guide feasible and sustainable fundamental movement skill programs within day care settings. PMID- 29708042 TI - The epidemiology of 5-methoxy- N, N-dimethyltryptamine (5-MeO-DMT) use: Benefits, consequences, patterns of use, subjective effects, and reasons for consumption. AB - BACKGROUND/AIM: 5-Methoxy- N,N-dimethyltryptamine (5-MeO-DMT) is a psychoactive compound found in several plants and in high concentrations in Bufo alvarius toad venom. Synthetic, toad, and plant-sourced 5-MeO-DMT are used for spiritual and recreational purposes and may have psychotherapeutic effects. However, the use of 5-MeO-DMT is not well understood. Therefore, we examined patterns of use, motivations for consumption, subjective effects, and potential benefits and consequences associated with 5-MeO-DMT use. METHODS: Using internet-based advertisements, 515 respondents ( Mage=35.4. SD=11.7; male=79%; White/Caucasian=86%; United States resident=42%) completed a web-based survey. RESULTS: Most respondents consumed 5-MeO-DMT infrequently ( 0.23) in lateral heel pressure, age, weight, height, BMI and military selection test. A logistic regression model predicted MSKI significantly (p= 0.03) with an accuracy of 34.50% of all MSK injury and 76.70% of the non-injured group with an overall accuracy of 69.50%. CONCLUSION: The logistic regression model combining the three risk factors was capable of predicting 34.5% of all MSKI. A specific biomechanical profile, slow 1.5 mile run time and current smoking status were identified as predictors of subsequent MSKI development. The proposed model could include evaluation of other potential risk factors and if validated then further enhance the specificity, sensitivity and applicability. PMID- 29708076 TI - Recent Progress of Marine Polypeptides as Anticancer Agents. AB - BACKGROUND: Marine environment constitutes an almost infinite resource for novel anticancer drug discovery. The biodiversity of marine organisms provides a rich source for the discovery and development of novel anticancer peptides in the treatment of human cancer. Marine peptides represent a new opportunity to obtain lead compounds in biomedical field, particularly for cancer therapy. OBJECTIVE: Providing an insight of the recent progress of patented marine peptides and presenting information about the structures and mechanistic mode of anticancer activities of these marine peptides. METHODS: We reviewed recent progress on the patented anticancer peptides from marine organisms according to their targets on different signal pathways. This work focuses on relevant recent patents (2010 2018) that entail the anticancer activity with associated mechanism and related molecular diversity of marine peptides. The related cellular signaling pathways for novel peptides that induce apoptosis and affect tubulin-microtubule equilibrium, angiogenesis and kinase activity that are related to the anticancer and related pharmacological properties are also discussed. RESULTS: The recent patents (2010-2018) of marine peptides with anticancer activity were reviewed, and the anticancer activity of marine peptides with associated mechanism and related molecular diversity of marine peptides were also discussed. CONCLUSION: Marine peptides possess chemical diversity and display potent anticancer activity via targeting different signal pathways. Some of the marine peptides are promising to be developed as novel anticancer agents. PMID- 29708077 TI - Emerging Drugs for the Treatment of Breast Cancer Brain Metastasis: A Review of Patent Literature. AB - BACKGROUND: Despite dramatic advances in cancer treatment that lead to long-term survival, there is an increasing number of patients presenting with clinical manifestations of cerebral metastasis in breast cancer, for whom only palliative treatment options exist. OBJECTIVE: The present review based on researches aims to provide identification of recent patens of breast cancer brain metastasis that may have application in improving cancer treatment. METHODS: Recent patents regarding the breast cancer brain metastasis were obtained from USPTO patent databases, Esp@cenet, Patentscope and Patent Inspiration(r). RESULTS: A total of 55 patent documents and 35 drug targets were recovered. Of these, a total of 45 patents and 10 patents were biotech drugs and chemical drugs, respectively. Among the target drugs analyzed were neurotrophin-3, protocadherin 7, CXCR4, PTEN, GABA receptor 3, L1CAM, PI3K-Akt / mTOR, VEGFR2, Claudin-5, Occludin, and NKG2A, among others. CONCLUSION: In this study, we found 35 drug targets for metastasis to the brain in breast cancer, with 60% of them including only one patent, which establishes that this area of research is very recent, and that these targets have recently been linked to metastasis to the brain. On the other hand, 19 drug targets, among them VEGF, VEGFR2, CXCL12, and CXCR4, have been addressed for the first time until 6 years ago, confirming that the development of drugs for brain metastasis in breast cancer is an incipient area, but with interesting potential. Interestingly, the stage of inside the brain, was the stage with the lowest amount of drug targets, which places it as a priority for research and drug development. PMID- 29708078 TI - Generating the evidence for risk reduction: a contribution to the future of food based dietary guidelines. AB - A major advantage of analyses on the food group level is that the results are better interpretable compared with nutrients or complex dietary patterns. Such results are also easier to transfer into recommendations on primary prevention of non-communicable diseases. As a consequence, food-based dietary guidelines (FBDG) are now the preferred approach to guide the population regarding their dietary habits. However, such guidelines should be based on a high grade of evidence as requested in many other areas of public health practice. The most straightforward approach to generate evidence is meta-analysing published data based on a careful definition of the research question. Explicit definitions of study questions should include participants, interventions/exposure, comparisons, outcomes and study design. Such type of meta-analyses should not only focus on categorical comparisons, but also on linear and non-linear dose-response associations. Risk of bias of the individual studies of the meta-analysis should be assessed, rated and the overall credibility of the results scored (e.g. using NutriGrade). Tools such as a measurement tool to assess systematic reviews or ROBIS are available to evaluate the methodological quality/risk of bias of meta-analyses. To further evaluate the complete picture of evidence, we propose conducting network meta analyses (NMA) of intervention trials, mostly on intermediate disease markers. To rank food groups according to their impact, disability-adjusted life years can be used for the various clinical outcomes and the overall results can be compared across the food groups. For future FBDG, we recommend to implement evidence from pairwise and NMA and to quantify the health impact of diet-disease relationships. PMID- 29708079 TI - Barriers to cancer nutrition therapy: excess catabolism of muscle and adipose tissues induced by tumour products and chemotherapy. AB - Cancer-associated malnutrition is driven by reduced dietary intake and by underlying metabolic changes (such as inflammation, anabolic resistance, proteolysis, lipolysis and futile cycling) induced by the tumour and activated immune cells. Cytotoxic and targeted chemotherapies also elicit proteolysis and lipolysis at the tissue level. In this review, we summarise specific mediators and chemotherapy effects that provoke excess proteolysis in muscle and excess lipolysis in adipose tissue. A nutritionally relevant question is whether and to what degree these catabolic changes can be reversed by nutritional therapy. In skeletal muscle, tumour factors and chemotherapy drugs activate intracellular signals that result in the suppression of protein synthesis and activation of a transcriptional programme leading to autophagy and degradation of myofibrillar proteins. Cancer nutrition therapy is intended to ensure adequate provision of energy fuels and a complete repertoire of biosynthetic building blocks. There is some promising evidence that cancer- and chemotherapy-associated metabolic alterations may also be corrected by certain individual nutrients. The amino acids leucine and arginine provided in the diet at least partially reverse anabolic suppression in muscle, while n-3 PUFA inhibit the transcriptional activation of muscle catabolism. Optimal conditions for exploiting these anabolic and anti-catabolic effects are currently under study, with the overall aim of net improvements in muscle mass, functionality, performance status and treatment tolerance. PMID- 29708080 TI - Immunohistochemical observation of local inflammatory cell infiltration in the host-tissue reaction site of human hydatid cysts. AB - The aim of this study was to evaluate the pattern of local immune cell infiltration in human cystic echinococcosis (CE) by identifying the subtypes of immune cells using immunohistochemistry (IHC). Fifty surgically removed hydatid cyst samples and surrounding tissues were collected from patients referred to Al Zahra Hospital, Isfahan, Iran. IHC was performed on the surrounding host tissue of hydatid cysts using anti-human CD3, CD19, CD8, CD4, CD68, CD56, Ki-67 and Foxp3 (forkhead box P3) antibodies. The results were then compared to hepatocellular carcinoma and chronic hepatitis. In the host-tissue reaction site of liver hydatid cysts, a distinct pattern of local immune cell response, which outwardly consisted of a pack of the fibrous elements, a layer of palisading macrophages, an eosinophil-containing layer and a layer of accumulated lymphocytes, was observed. However, in some cases there were no positive cells for CD56+ natural killer cells and Foxp3+ regulatory T cells. The CD3+ T cells were the predominant inflammatory cells in all groups, followed by CD19+ B cells. It can be concluded that different immune cells are involved in the local response to human hydatid cysts. PMID- 29708081 TI - Predictors of Antimicrobial Stewardship Program Recommendation Disagreement. AB - OBJECTIVETo identify predictors of disagreement with antimicrobial stewardship prospective audit and feedback recommendations (PAFR) at a free-standing children's hospital.DESIGNRetrospective cohort study of audits performed during the antimicrobial stewardship program (ASP) from March 30, 2015, to April 17, 2017.METHODSThe ASP included audits of antimicrobial use and communicated PAFR to the care team, with follow-up on adherence to recommendations. The primary outcome was disagreement with PAFR. Potential predictors for disagreement, including patient-level, antimicrobial, programmatic, and provider-level factors, were assessed using bivariate and multivariate logistic regression models.RESULTSIn total, 4,727 antimicrobial audits were performed during the study period; 1,323 PAFR (28%) and 187 recommendations (15%) were not followed due to disagreement. Providers were more likely to disagree with PAFR when the patient had a gastrointestinal infection (odds ratio [OR], 5.50; 95% confidence interval [CI], 1.99-15.21), febrile neutropenia (OR, 6.14; 95% CI, 2.08-18.12), skin or soft-tissue infections (OR, 6.16; 95% CI, 1.92-19.77), or had been admitted for 31-90 days at the time of the audit (OR, 2.08; 95% CI, 1.36-3.18). The longer the duration since the attending provider had been trained (ie, the more years of experience), the more likely they were to disagree with PAFR recommendations (OR, 1.02; 95% CI, 1.01-1.04).CONCLUSIONSEvaluation of our program confirmed patient-level predictors of PAFR disagreement and identified additional programmatic and provider-level factors, including years of attending experience. Stewardship interventions focused on specific diagnoses and antimicrobials are unlikely to result in programmatic success unless these factors are also addressed.Infect Control Hosp Epidemiol 2018;806-813. PMID- 29708082 TI - Time-series analysis of tuberculosis from 2005 to 2017 in China. AB - Seasonal autoregressive integrated moving average (SARIMA) has been used to model nationwide tuberculosis (TB) incidence in other countries. This study aimed to characterise monthly TB notification rate in China. Monthly TB notification rate from 2005 to 2017 was used. Time-series analysis was based on a SARIMA model and a hybrid model of SARIMA-generalised regression neural network (GRNN) model. A decreasing trend (3.17% per years, P < 0.01) and seasonal variation of TB notification rate were found from 2005 to 2016 in China, with a predominant peak in spring. A SARIMA model of ARIMA (0,1,1) (0,1,1)12 was identified. The mean error rate of the single SARIMA model and the SARIMA-GRNN combination model was 6.07% and 2.56%, and the determination coefficient was 0.73 and 0.94, respectively. The better performance of the SARIMA-GRNN combination model was further confirmed with the forecasting dataset (2017). TB is a seasonal disease in China, with a predominant peak in spring, and the trend of TB decreased by 3.17% per year. The SARIMA-GRNN model was more effective than the widely used SARIMA model at predicting TB incidence. PMID- 29708083 TI - Phenotypical resistance correlation networks for 10 non-typhoidal Salmonella subpopulations in an active antimicrobial surveillance programme. AB - Antimicrobials play a critical role in treating cases of invasive non-typhoidal salmonellosis (iNTS) and other diseases, but efficacy is hindered by resistant pathogens. Selection for phenotypical resistance may occur via several mechanisms. The current study aims to identify correlations that would allow indirect selection of increased resistance to ceftriaxone, ciprofloxacin and azithromycin to improve antimicrobial stewardship. These are medically important antibiotics for treating iNTS, but these resistances persist in non-Typhi Salmonella serotypes even though they are not licensed for use in US food animals. A set of 2875 Salmonella enterica isolates collected from animal sources by the National Antimicrobial Resistance Monitoring System were stratified in to 10 subpopulations based on serotype and host species. Collateral resistances in each subpopulation were estimated as network models of minimum inhibitory concentration partial correlations. Ceftriaxone sensitivity was correlated with other beta-lactam resistances, and less commonly resistances to tetracycline, trimethoprim-sulfamethoxazole or kanamycin. Azithromycin resistance was frequently correlated with chloramphenicol resistance. Indirect selection for ciprofloxacin resistance via collateral selection appears unlikely. Density of the ACSSuT subgraph resistance aligned well with the phenotypical frequency. The current study identifies several important resistances in iNTS serotypes and further research is needed to identify the causative genetic correlations. PMID- 29708084 TI - Age bias in survey sampling and implications for estimating HIV prevalence in men who have sex with men: insights from mathematical modelling. AB - Respondent-driven sampling (RDS) is widely used to estimate HIV prevalence in men who have sex with men (MSM). Mathematical models that are calibrated to these data may be compromised if they fail to account for selection biases in RDS surveys. To quantify the potential extent of this bias, an agent-based model of HIV in South Africa was calibrated to HIV prevalence and sexual behaviour data from South African studies of MSM, first reweighting the modelled MSM population to match the younger age profile of the RDS surveys (age-adjusted analysis) and then without reweighting (unadjusted analysis). The model estimated a median HIV prevalence in South African MSM in 2015 of 34.6% (inter-quartile range (IQR): 31.4-37.2%) in the age-adjusted analysis, compared with 26.1% (IQR: 24.1-28.4%) in the unadjusted analysis. The median lifetime risk of acquiring HIV in exclusively homosexual men was 88% (IQR: 82-92%) in the age-adjusted analysis, compared with 76% (IQR: 64-85%) in the unadjusted analysis. These results suggest that RDS studies may under-estimate the exceptionally high HIV prevalence rates in South African MSM because of over-sampling of younger MSM. Mathematical models that are calibrated to these data need to control for likely over-sampling of younger MSM. PMID- 29708085 TI - Weekly Checks Improve Real-Time Prehospital ECG Transmission in Suspected STEMI. AB - : IntroductionField identification of ST-elevation myocardial infarction (STEMI) and advanced hospital notification decreases first-medical-contact-to-balloon (FMC2B) time. A recent study in this system found that electrocardiogram (ECG) transmission following a STEMI alert was frequently unsuccessful.HypothesisInstituting weekly test ECG transmissions from paramedic units to the hospital would increase successful transmission of ECGs and decrease FMC2B and door-to-balloon (D2B) times. METHODS: This was a natural experiment of consecutive patients with field-identified STEMI transported to a single percutaneous coronary intervention (PCI)-capable hospital in a regional STEMI system before and after implementation of scheduled test ECG transmissions. In November 2014, paramedic units began weekly test transmissions. The mobile intensive care nurse (MICN) confirmed the transmission, or if not received, contacted the paramedic unit and the department's nurse educator to identify and resolve the problem. Per system-wide protocol, paramedics transmit all ECGs with interpretation of STEMI. Receiving hospitals submit patient data to a single registry as part of ongoing system quality improvement. The frequency of successful ECG transmission and time to intervention (FMC2B and D2B times) in the 18 months following implementation was compared to the 10 months prior. Post implementation, the time the ECG transmission was received was also collected to determine the transmission gap time (time from ECG acquisition to ECG transmission received) and the advanced notification time (time from ECG transmission received to patient arrival). RESULTS: There were 388 patients with field ECG interpretations of STEMI, 131 pre-intervention and 257 post intervention. The frequency of successful transmission post-intervention was 73% compared to 64% prior; risk difference (RD)=9%; 95% CI, 1-18%. In the post intervention period, the median FMC2B time was 79 minutes (inter-quartile range [IQR]=68-102) versus 86 minutes (IQR=71-108) pre-intervention (P=.3) and the median D2B time was 59 minutes (IQR=44-74) versus 60 minutes (IQR=53-88) pre intervention (P=.2). The median transmission gap was three minutes (IQR=1-8) and median advanced notification time was 16 minutes (IQR=10-25). CONCLUSION: Implementation of weekly test ECG transmissions was associated with improvement in successful real-time transmissions from field to hospital, which provided a median advanced notification time of 16 minutes, but no decrease in FMC2B or D2B times. D'ArcyNT, BossonN, KajiAH, BuiQT, FrenchWJ, ThomasJL, ElizarrarazY, GonzalezN, GarciaJ, NiemannJT. Weekly checks improve real-time prehospital ECG transmission in suspected STEMI. Prehosp Disaster Med. 2018;33(3):245-249. PMID- 29708087 TI - Determinants of folic acid supplement use outside national recommendations for pregnant women: results from the Growing Up in New Zealand cohort study. AB - OBJECTIVE: To evaluate the sociodemographic and lifestyle factors associated with insufficient and excessive use of folic acid supplements (FAS) among pregnant women. DESIGN: A pregnancy cohort to which multinomial logistic regression models were applied to identify factors associated with duration and dose of FAS use. SETTING: The Growing Up in New Zealand child study, which enrolled pregnant women whose children were born in 2009-2010. SUBJECTS: Pregnant women (n 6822) enrolled into a nationally generalizable cohort. RESULTS: Ninety-two per cent of pregnant women were not taking FAS according to the national recommendation (4 weeks before until 12 weeks after conception), with 69 % taking insufficient FAS and 57 % extending FAS use past 13 weeks' gestation. The factors associated with extended use differed from those associated with insufficient use. Consistent with published literature, the relative risks of insufficient use were increased for younger women, those with less education, of non-European ethnicities, unemployed, who smoked cigarettes, whose pregnancy was unplanned or who had older children, or were living in more deprived households. In contrast, the relative risks of extended use were increased for women of higher socio-economic status or for whom this was their first pregnancy and decreased for women of Pacific v. European ethnicity. CONCLUSIONS: In New Zealand, current use of FAS during pregnancy potentially exposes pregnant women and their unborn children to too little or too much folic acid. Further policy development is necessary to reduce current socio-economic inequities in the use of FAS. PMID- 29708086 TI - The value of chest X-ray in the Scottish Referral Guidelines for suspected head and neck cancer in 2144 patients. AB - OBJECTIVE: In Scotland, patients with suspected head and neck cancer are referred on the basis of the Scottish Referral Guidelines for Suspected Cancer, rather than the National Institute for Health and Care Excellence guidelines. A chest X ray should be requested by the general practitioner at the same time as referral for persistent hoarseness. The evidence for this is level 4. METHODS: This audit identified adherence to this recommendation and X-ray results. All 'urgent suspicion of cancer' referrals to the ENT department in the National Health Service Greater Glasgow and Clyde for 2015-2016 were audited. RESULTS: Persistent hoarseness for more than 3 weeks instigated referral in 318 patients (15.7 per cent). Chest X-ray was performed in 120 patients (38 per cent), which showed: no abnormality in 116 (96.7 per cent), features of infection in 2 (1.7 per cent) and something else in 2 patients (1.7 per cent). No chest X-ray altered the management of a patient. CONCLUSION: Performance of chest X-ray does not alter management and its removal from the Scottish Referral Guidelines for Suspected Cancer is recommended. PMID- 29708088 TI - Nutrition and public health in medical education in the UK: reflections and next steps. AB - OBJECTIVE: Doctors play an important role in the identification of nutritional disorders and as advocates for a healthy diet, and although the key tenets of good nutrition education for medical students have been discussed, reports on implementation are sparse. The present commentary responds to a gap in UK medical students' understanding of nutrition and public health and suggests ways to improve it. DESIGN: We review literature about nutrition education in medical schools and discuss a 6-week elective in public health nutrition for medical students. We discuss suggested competencies in nutrition and compare means of students' confidence and knowledge before and after. SETTING: A nutrition and public health elective in a UK medical school, discussing advocacy, motivational interviewing, supplements, nutritional deficits, parenteral nutrition, obesity services. We utilised multidisciplinary teaching approaches including dietitians, managers and pharmacists, and students implemented a public health activity in a local school. SUBJECTS: Fifteen final-year medical students were enrolled; sixty school pupils participated in the public health activity. RESULTS: The students were not confident in nutrition competencies before and were taught less than European counterparts. Students enjoyed the course, had improved knowledge, and felt more confident in interviewing and prescribing supplements. Feedback from the local school was positive. CONCLUSIONS: Students in our UK medical school were not confident in their required competencies within the confines of the current educational programme. An elective course can improve medical students' knowledge. Similar courses could be implemented in other medical schools to improve nutrition and public health knowledge and practice in future doctors. PMID- 29708089 TI - Need for improved public health protection of young people wanting body piercing: evidence from a look-back exercise at a piercing and tattooing premises with poor hygiene practices, Wales (UK) 2015. AB - Following a cluster of serious pseudomonas skin infections linked to a body piercing and tattooing premises, a look-back exercise was carried out to offer clients a screen for blood-borne viruses. Of those attending for screening 72% (581/809) had a piercing procedure in the premises of interest: 94 (16%) were under 16 years of age at the time of screening. The most common site of piercing was ear (34%), followed by nose (27%), nipple (21%) and navel (21%). A small number (<5) tested positive for hepatitis B and C, with no evidence this was linked to the premises. However, 36% (211/581) of clients reported a skin infection associated with their piercing. Using data from client forms, 36% provided a false age. Those aged under 16 years (OR 4.5, 95% CI 2.7-7.7) and those receiving a piercing at an intimate site (OR 2.1, 95% CI 1.3-3.6) were more likely to provide a false age. The findings from this exercise were used to support the drafting of the Public Health (Wales) Bill which proposed better regulation of piercing premises and the need to provide proof of being 18 years of age or over before having a piercing of an intimate site. PMID- 29708090 TI - Couples' psychological adjustment to twin parenthood: mode of conception (spontaneous versus assisted reproduction) and gender differences. AB - : AimTo examine whether mode of conception and gender are associated with parents' psychological adjustment across the transition to twin parenthood. BACKGROUND: There is limited knowledge on the psychological adjustment of couples to twin parenthood during pregnancy and early postpartum, especially for fathers. The available research suggests that first-time mothers of twins conceived by assisted reproduction techniques (ART) may experience lower psychosocial well being than mothers of spontaneously conceived (SC) twins. METHODS: A total of 41 couples expecting twins, 25 of whom conceived spontaneously and 16 conceived by assisted reproduction techniques, completed measures of depressive and anxiety symptoms, marital relationship, attitudes to sex, and attitudes to pregnancy and the baby.FindingsART parents showed a decline in marital relationship quality, no changes in attitudes to pregnancy and the baby and no changes in attitudes to sex over the postpartum. In contrast, SC parents did not change their perception of the marital relationship, reported more positive attitudes to pregnancy and the baby, and more positive attitudes to sex over the postpartum. Compared with the other groups (SC mothers and fathers, ART fathers), ART mothers exhibited a higher increase in depressive and anxiety symptoms from pregnancy to postpartum and only anxiety symptoms exhibited a decline trend over the postpartum. These findings suggest that ART parents may experience more psychological difficulties during the transition to twin parenthood than SC parents. ART mothers, in particular, appear to be more at risk of high levels of postpartum depressive symptoms. PMID- 29708091 TI - Impact of 2018 Changes in National Healthcare Safety Network Surveillance for Clostridium difficile Laboratory-Identified Event Reporting. PMID- 29708092 TI - More Than a Cold: Hospital-Acquired Respiratory Viral Infections, Sick Leave Policy, and A Need for Culture Change. PMID- 29708093 TI - Addressing religion and spirituality in the intensive care unit: A survey of clinicians. AB - OBJECTIVE: Studies have shown that when religious and spiritual concerns are addressed by the medical team, patients are more satisfied with their care and have lower healthcare costs. However, little is known about how intensive care unit (ICU) clinicians address these concerns. The objective of this study was to determine how ICU clinicians address the religious and spiritual needs of patients and families. METHOD: We performed a cross-sectional survey study of ICU physicians, nurses, and advance practice providers (APPs) to understand their attitudes and beliefs about addressing the religious and spiritual needs of ICU patients and families. Each question was designed on a 4- to 5-point Likert scale. A total of 219 surveys were collected over a 4-month period.ResultA majority of clinicians agreed that it is their responsibility to address the religious/spiritual needs of patients. A total of 79% of attendings, 74% of fellows, 89% of nurses, and 83% of APPs agreed with this statement. ICU clinicians also feel comfortable talking to patients about their religious/spiritual concerns. In practice, few clinicians frequently address religious/spiritual concerns. Only 14% of attendings, 3% of fellows, 26% of nurses, and 17% of APPs say they frequently ask patients about their religious/spiritual needs.Significance of resultsThis study shows that ICU clinicians see it as their role to address the religious and spiritual needs of their patients, and report feeling comfortable talking about these issues. Despite this, a minority of clinicians regularly address religious and spiritual needs in clinical practice. This highlights a potential deficit in comprehensive critical care as outlined by many national guidelines. PMID- 29708094 TI - Urea changes oocyte competence and gene expression in resultant bovine embryo in vitro. AB - SummaryNutrition influences the microenvironment in the proximity of oocyte and affects early embryonic development. Elevated blood urea nitrogen, even in healthy dairy cows, is associated with reduced fertility and there is high correlation between blood urea levels and follicular fluid urea levels. Using a docking calculation (in silico), urea showed a favorable binding activity towards the ZP-N domain of ZP3, that of ZP2, and towards the predicted full-length sperm receptor ZP3. Supplementation of oocyte maturation medium with nutrition-related levels of urea (20 or 40 mg/dl as seen in healthy dairy cows fed on low or high dietary protein, respectively) dose-dependently increased: (i) the proportion of oocytes that remained uncleaved; and (ii) oocyte degeneration; and reduced cleavage, blastocyst and hatching rates. High levels of urea induced shrinkage in oocytes, visualised using scanning electron microscopy. Urea downregulated NANOG while dose-dependently upregulating OCT4, DNMT1, and BCL2 expression. Urea at 20 mg/dl induced BAX expression. Using mathematical modelling, the rate of oocyte degeneration was sensitive to urea levels; while cleavage, blastocyst and hatching rates exhibited negative sensitivity. The present data imply a novel role for urea in reducing oocyte competence and changing gene expression in the resultant embryos. PMID- 29708095 TI - Etiologies of the Relationships Among Body Mass Index and Cold-Heat Patterns: A Twin Study. AB - The phenotypic relationships between body mass index (BMI) and cold-heat patterns have been frequently reported, but the etiology of these relationships remains unknown. We previously demonstrated that the cold pattern (CP) and the heat pattern (HP) were heritable traits. In the present study, we explored underlying genetic and environmental structures of the relationships among BMI and the CP and the HP. Twins (N = 1,752) drawn from the South Korean twin registry completed a cold-heat pattern questionnaire via a telephone interview. The phenotypic correlations among the three phenotypes were moderate but significant. Cross twin, cross-trait correlations among BMI and the CP and the HP were consistently greater in monozygotic than in dizygotic twins, suggesting the presence of genetic effects on the relationships between BMI and the two patterns. A trivariate Cholesky model was applied to the raw data. The results indicated that the phenotypic relationship between the HP and BMI was completely determined by common genetic influences, while the relationship between the CP and BMI was explained by both common genetic and common individual-specific environmental influences. The genetic correlation between the HP and the CP was not significant, suggesting that the two patterns may be genetically independent from each other. Genetic correlations were 0.31 between the HP and BMI, and -0.22 between the CP and BMI. The individual-specific environmental correlation was 0.22 between HP and CP, and between CP and BMI. PMID- 29708096 TI - The role of DNA methylation in ageing and cancer. AB - The aim of the present review paper is to survey the literature related to DNA methylation, and its association with cancer and ageing. The review will outline the key factors, including diet, which modulate DNA methylation. Our rationale for conducting this review is that ageing and diseases, including cancer, are often accompanied by aberrant DNA methylation, a key epigenetic process, which is crucial to the regulation of gene expression. Significantly, it has been observed that with age and certain disease states, DNA methylation status can become disrupted. For instance, a broad array of cancers are associated with promoter specific hypermethylation and concomitant gene silencing. This review highlights that hypermethylation, and gene silencing, of the EN1 gene promoter, a crucial homeobox gene, has been detected in various forms of cancer. This has led to this region being proposed as a potential biomarker for diseases such as cancer. We conclude the review by describing a recently developed novel electrochemical method that can be used to quantify the level of methylation within the EN1 promoter and emphasise the growing trend in the use of electrochemical techniques for the detection of aberrant DNA methylation. PMID- 29708097 TI - Adherence to Emergency Public Health Measures for Bioevents: Review of US Studies. AB - The frequency of bioevents is increasing worldwide. In the United States, as elsewhere, control of contagion may require the cooperation of community members with emergency public health measures. The US general public is largely unfamiliar with these measures, and our understanding of factors that influence behaviors in this context is limited. The few previous reviews of research on this topic focused on non-US samples. For this review, we examined published research on the psychosocial influences of adherence in US sample populations. Of 153 articles identified, only 9 met the inclusion criteria. Adherence behaviors were categorized into 2 groups: self-protective behaviors (personal hygiene, social distancing, face mask use, seeking out health care advice, and vaccination) and protecting others (isolation, temperature screening, and quarantine). A lack of uniformity across studies regarding definitions and measures was noted. Only 5 of the 9 articles reported tests of association between adherence with emergency measures and psychosocial factors; perceived risk and perceived seriousness were found to be significantly associated with adherence or adherence intentions. Although it is well documented that psychosocial factors are important predictors of protective health behaviors in general, this has not been rigorously studied in the context of bioevents. (Disaster Med Public Health Preparedness. 2018;12:528-535). PMID- 29708098 TI - Snapshot: Targeting Macrophages as a Candidate for Tissue Regeneration. AB - Macrophages are a specific mononuclear cell group abundant in almost every organ of higher animals. This group is a pivotal part of the immune system and is involved in immune responses against exogenous antigen invasion. Recently, accumulating evidence has demonstrated that macrophages participate in wound repair and tissue regeneration. In this review, we will first introduce the influences of regeneration after injury in various tissues and organs among macrophage-depleted animal models. Second, the possible relationship between macrophages and reparation capacities will be discussed. Finally, we provide a general idea about the roles of macrophages in the injury- regeneration process and then discuss the current challenges and prospects of their clinical application. The information compiled here may be useful for regenerative research and may promote macrophages as a therapeutic target in regenerative medicine. PMID- 29708099 TI - Impact of ionization equilibrium on electrokinetic flow of weak electrolytes in nanochannels. AB - Weak electrolyte transport in nanochannels or nanopores has been actively explored in recent experiments. In this paper, we establish a new electrokinetic model where the ionization balance effect of weak electrolytes is outlined, and performed numerical calculations for H3PO4 concentration-biased nanochannel systems. By considering the roles of local chemical equilibrium in phosphorous acid ionization, the simulation results show quantitative agreement with experimental observations. Based on the model, we predict that enhanced energy harvesting capacity could be accomplished by utilizing weak electrolytes compared to the conventional strong electrolyte approaches in a concentration gradient based power-generating system. PMID- 29708100 TI - Resistive switching of organic-inorganic hybrid devices of conductive polymer and permeable ultra-thin SiO2 films. AB - We propose a resistive switching device composed of conductive polymer (PEDOT:PSS) and SiO2 ultra-thin films. The SiO2 film was fabricated from silsesquioxane polymer nanosheets as a resistive switching layer. Devices with metal (Ag or Au)?SiO2?PEDOT:PSS architecture show good resistive switching performance with set-reset voltages as low as several hundred millivolts. The device properties and the working mechanism were investigated by varying the electrode material, surrounding atmosphere, and SiO2 film thickness. Results show that resistive switching is based on water and ion migration at the PEDOT:PSS?SiO2 interface. PMID- 29708101 TI - Focus on sub-10 nm nanofabrication. PMID- 29708102 TI - Aqueous synthesis of L-cysteine and mercaptopropionic acid co-capped ZnS quantum dots with dual emissions. AB - In this paper, L-cysteine (L-cys) and mercaptopropionic acid (MPA) co-capped ZnS quantum dots (QDs) with dual emissions have been successfully synthesized by a one-pot aqueous-phase synthesis method. The intensities of the dual emissions could be controlled by regulating the molar ratio of L-cys to MPA, and the fluorescence color also turned from blue to yellow accordingly. The relationship between the ligands and fluorescence was investigated and the results indicated that L-cys could cause two emissions and MPA improved the emission intensity. In addition, the L-cys-MPA co-capped ZnS QDs showed high photostability under UV irradiation. Therefore, the L-cys-MPA co-capped ZnS QDs, which show the dual emissions and tunable emission intensities, have great potentials for use in ratiometric fluorescence sensors and multicolor bioimaging. PMID- 29708104 TI - The limits of historical sociology: Temporal borders and the reproduction of the 'modern' political present. AB - This article develops a poststructuralist critique of the historical sociology of International Relations project. While the historical sociology of International Relations project claims to offer a more nuanced understanding of the state and the international, this article argues that it lacks critical reflection on the notion of a common ground on which 'history' and 'sociology' can successfully be combined. In order to problematize this 'ground', the article turns to Jacques Derrida's critique of attempts to solve the history-structure dichotomy by finding a perfect combination of historicist and structuralist modes of explanation. Exploring the implications of Derrida's critique, the article considers how the combination of 'history' and 'sociology' can be linked to a sovereign politics of time, which reaffirms rather than challenges the limits of the 'modern' political present and its relationship to the past, as well as the future. In response, it is suggested that a more radical critique is needed, one that seeks to disrupt the 'modern' political present and the contingent ground on which it rests. PMID- 29708103 TI - Retrospective Study to Compare Frozen-Thawed Embryo Transfer with Fresh Embryo Transfer on Pregnancy Outcome Following Intracytoplasmic Sperm Injection for Male Infertility. AB - BACKGROUND With the development of assisted reproductive technology, there is increasing evidence that frozen-thawed (FT) embryo transfer achieves a better outcome when compared with fresh embryo transfer in different types of infertile individuals. This aim of this study was to investigate the effect of FT embryo transfer for intracytoplasmic sperm injection (ICSI) on pregnancy outcome in assisted reproductive technology for male infertility. MATERIAL AND METHODS A total of 516 embryo transfer cycles (286 fresh embryo transfer cycles and 230 FT embryo transfer cycles) were studied, in which ICSI treatment was performed for the first time because of male infertility. The women in the study were normal or had Fallopian tube abnormalities. The clinical data and pregnancy outcomes of these two study groups were compared. RESULTS The implantation rate, pregnancy rate, and multiple birth rate of the FT embryo transfer group were similar when compared with the fresh embryo transfer group. The live birth rate of the FT embryo transfer group was significantly greater when compared with the fresh embryo transfer group (P<0.05). The rate of miscarriage of the FT embryo transfer group was 6.52%, which was significantly less than that of the fresh embryo transfer group (14.01%) (P<0.05). The gestational age and neonatal birth weight were not significantly different between the two groups (P>0.05). CONCLUSIONS FT embryo transfer was an effective and safe treatment for patients undergoing ICSI, which improved the live birth rate and reduced the rate of miscarriage. PMID- 29708105 TI - Messy interviews: changing conditions for politicians' visibility on the web. AB - This article provides an updated analysis relating to John B. Thompson's argument about political visibility and fragility. It does so in light of recent years' development of communication technologies and the proliferation of nonbroadcasting media organizations producing TV. Instances of a new mediated encounter for politicians is analyzed in detail - the live web interview - produced and streamed by two Swedish tabloids during election campaigning 2014. It is argued that the live web interview is not yet a recognizable 'communicative activity type' with an obvious set of norms, rules, and routines. This fact makes politicians more intensely exposed to moments of mediated fragility which may be difficult to control. The most crucial condition that changes how politicians are able to manage their visibility is the constantly rolling 'non-exclusive' live camera which does not give the politician any room for error. The tabloids do not seem to mind 'things going a bit wrong' while airing; rather, interactional flaws are argued to be part and parcel of the overall web TV performance. PMID- 29708106 TI - Emergency Management and Tourism Stakeholder Responses to Crises: A Global Survey. AB - This article examines the contested area of the responsibility for destinations and tourists, within emergency settings. It incorporates a Delphi-Scenario technique to facilitate a structured discussion of emergency management for different destination stakeholders. The Delphi exercise engaged 123 senior international stakeholders, from 9 different industry sectors, across 34 countries to provide a global perspective. The study's principal focus is on the notion of emergency management, to identify the challenges that stakeholders would face within a disaster scenario. The exercise asked stakeholders to identify with whom the responsibility rests for 18 distinct disaster-related activities. The study proposes a responsibility allocation building-block framework that could help speed up the emergency management responses by "knowing who is going to do what" with a particular focus on dealing with international tourists as a community in a disaster zone. PMID- 29708107 TI - Sounding ruins: reflections on the production of an 'audio drift'. AB - This article is about the use of audio media in researching places, which I term 'audio geography'. The article narrates some episodes from the production of an 'audio drift', an experimental environmental sound work designed to be listened to on a portable MP3 player whilst walking in a ruinous landscape. Reflecting on how this work functions, I argue that, as well as representing places, audio geography can shape listeners' attention and bodily movements, thereby reworking places, albeit temporarily. I suggest that audio geography is particularly apt for amplifying the haunted and uncanny qualities of places. I discuss some of the issues raised for research ethics, epistemology and spectral geographies. PMID- 29708108 TI - Understanding the effects of decompaction maintenance on the infill state and play performance of third-generation artificial grass pitches. AB - Third generation artificial grass pitches have been observed to get harder over time. The maintenance technique of rubber infill decompaction is intended to help slow, or reverse, this process. At present, little is understood about either the science of the infill compaction process or the efficacy of decompaction maintenance. The objective of this study was to measure the changes in rubber infill net bulk density, force reduction (impact absorption) and vertical ball rebound under various levels of compactive effort in controlled laboratory-based testing. The assessments were repeated after the systems had been raked to simulate the decompaction maintenance techniques. These tests defined the limits of compaction (loose to maximally compacted) in terms of the change in rubber infill net bulk density, force reduction and vertical ball rebound. Site testing was also undertaken at four third generation pitches immediately pre and post decompaction, to determine the measurable effects in the less well controlled field environment. Rubber infill net bulk density was found to increase as compactive effort increased, resulting in increased hardness. Decompacting the surface was found to approximately fully reverse these effects. In comparison, the site measurements demonstrated similar but notably smaller magnitudes of change following the decompaction process suggesting that the field state pre and post decompaction did not reach the extremes obtained in the laboratory. The findings suggest that rubber infill net bulk density is an important parameter influencing the hardness of artificial grass and that decompactions can be an effective method to reverse compaction related hardness changes. PMID- 29708109 TI - An Exploratory Study of Residents' Perception of Place Image: The Case of Kavala. AB - Studies on place image have predominantly focused on the tourists' destination image and have given limited attention to other stakeholders' perspectives. This study aims to address this gap by focusing on the notion of residents' place image, whereby it reviews existing literature on residents' place image in terms of whether common attributes can be identified, and examines the role of community-focused attributes in its measurement. Data collected from a sample of 481 Kavala residents (Greece) were subjected to exploratory and confirmatory factor analysis. The study reveals that the existing measurement tools have typically emphasized destination-focused attributes and neglected community focused attributes. This study contributes to the residents' place image research by proposing a more holistic measurement, which consisted of four dimensions: physical appearance, community services, social environment, and entertainment opportunities. The study also offers practical insights for developing and promoting a tourist place while simultaneously enhancing its residents' quality of life. PMID- 29708110 TI - Protocol and the post-human performativity of security techniques. AB - This article explores the deployment of exercises by the United Kingdom Fire and Rescue Service. Exercises stage, simulate and act out potential future emergencies and in so doing help the Fire and Rescue Service prepare for future emergencies. Specifically, exercises operate to assess and develop protocol; sets of guidelines which plan out the actions undertaken by the Fire and Rescue Service in responding to a fire. In the article I outline and assess the forms of knowledge and technologies, what I call the 'aesthetic forces', by which the exercise makes present and imagines future emergencies. By critically engaging with Karen Barad's notion of post-human performativity, I argue that exercises provide a site where such forces can entangle with one another; creating a bricolage through which future emergencies are evoked sensually and representatively, ultimately making it possible to experience emergencies in the present. This understanding of exercises allows also for critical appraisal of protocol both as phenomena that are produced through the enmeshing of different aesthetic forces and as devices which premise the operation of the security apparatus on contingency. PMID- 29708111 TI - The 'abnormal' state: Identity, norm/exception and Japan. AB - The term 'abnormal' has frequently been used to describe post-war Japan. Together with the idea that the country will, or should have to, 'normalise' its foreign and security policy, it has been reproduced in both academia and Japanese society. Why is Japan branded as 'abnormal', and from where does the desire to 'normalise' it come? Drawing on a relational concept of identity, and the distinction between norm and exception, this article argues that the 'abnormality normalisation nexus' can be understood in terms of three identity-producing processes: (1) the process whereby the Japanese Self is socialised in US/'Western' norms, ultimately constructing it as an Other in the international system; (2) the process whereby the Japanese Self imagines itself as 'legitimately exceptional' (what is called 'exceptionalisation'), but also 'illegitimately abnormal' - both of which are epitomised by Japan's 'pacifism'; and (3) the process whereby both the Self's 'negative abnormality' and China/Asia are securitised in attempts to realise a more 'normal' (or super-normal) Japanese Self. How Japan is inter subjectively constructed on a scale between 'normal' and 'abnormal' enables and constrains action. Although Japan has not remilitarised nearly as much in the 2000s as is often claimed, these processes might very well forebode an exceptional decision to become 'normal' and therefore more significant steps towards remilitarisation. PMID- 29708112 TI - Atmospheres of progress in a data-based school. AB - In this article, I seek to extend the geographies of education, youth and young people by offering an account of the significant shifts taking place in contemporary English state education around the production and use of data. I present material from pupils, for whom the changes are putatively made, whose voices are absent in existing educational and sociological literature on data in schools. I do this through an exploration of one specific feature of school datascapes: the use of data to create and maintain a sense of 'progress'. This is not progress solely as developmental fact, logic, ideology or discourse but as felt. This article draws attention to profound changes to cultures of education that are evinced in relation to contemporary proliferations of data, contributes to theorisations of affective atmospheres in geography and how they come to be known (as a question of both experience and method), and it advances a novel theorisation of progress 'after the affective turn'. PMID- 29708113 TI - Mind-modelling with corpus stylistics in David Copperfield. AB - We suggest an innovative approach to literary discourse by using corpus linguistic methods to address research questions from cognitive poetics. In this article, we focus on the way that readers engage in mind-modelling in the process of characterisation. The article sets out our cognitive poetic model of characterisation that emphasises the continuity between literary characterisation and real-life human relationships. The model also aims to deal with the modelling of the author's mind in line with the modelling of the minds of fictional characters. Crucially, our approach to mind-modelling is text-driven. Therefore we are able to employ corpus linguistic techniques systematically to identify textual patterns that function as cues triggering character information. In this article, we explore our understanding of mind-modelling through the characterisation of Mr. Dick from David Copperfield by Charles Dickens. Using the CLiC tool (Corpus Linguistics in Cheshire) developed for the exploration of 19th century fiction, we investigate the textual traces in non-quotations around this character, in order to draw out the techniques of characterisation other than speech presentation. We show that Mr. Dick is a thematically and authorially significant character in the novel, and we move towards a rigorous account of the reader's modelling of authorial intention. PMID- 29708114 TI - Exploring the Constraint Profile of Winter Sports Resort Tourist Segments. AB - Many studies have confirmed the importance of market segmentation both theoretically and empirically. Surprisingly though, no study has so far addressed the issue from the perspective of leisure constraints. Since different consumers face different barriers, we look at participation in leisure activities as an outcome of the negotiation process that winter sports resort tourists go through, to balance between related motives and constraints. This empirical study reports the findings on the applicability of constraining factors in segmenting the tourists who visit winter sports resorts. Utilizing data from 1,391 tourists of winter sports resorts in Greece, five segments were formed based on their constraint, demographic, and behavioral profile. Our findings indicate that such segmentation sheds light on factors that could potentially limit the full utilization of the market. To maximize utilization, we suggest customizing marketing to the profile of each distinct winter sports resort tourist segment that emerged. PMID- 29708115 TI - The history of a habit: jogging as a palliative to sedentariness in 1960s America. AB - This article provides an account of the emergence of jogging as mass physical fitness practice in America in the 1960s. It explores how jogging was configured as a physical fitness activity suitable for sedentary middle-aged men and women. Jogging developed as a counter to the ill-effects of habits entrained by the increasingly sedentary lifestyles of modern industrialized urban and suburban dwellers. The paper traces the development of jogging as a defined exercise routine at the University of Oregon, Eugene, Oregon. Focusing on the moment when jogging is 'invented' as a recognizable fitness practice tells a great deal about the origin of contemporary regimes of physical fitness for the middle-aged population and how they have evolved. It also points to the significance of understanding how the shaping of corporeal habits play into the making of (1) individual bodies, (2) common practices of corporeal care and activity, and (3) environments of physical activity. PMID- 29708116 TI - Geographies of education, volunteering and the lifecourse: the Woodcraft Folk in Britain (1925-75). AB - This article extends the current scholarly focus within the geographies of education and the geographies of children, youth and families through an original examination of the Woodcraft Folk - a British youth organization founded in 1925 that aimed to create a world built on equality, friendship and peace. This article illustrates how voluntary uniformed youth organizations had a much wider spatial remit and more complex institutional geographies than have been hitherto acknowledged, with their active involvement in the training of adults (namely parents and volunteers) as well as the education of children and young people. Drawing on archival research and a range of sources, the article explores the Woodcraft Folk's philosophies and political activities across its first 50 years, and in doing so, makes two central academic contributions to the discipline. First, the article provides a timely focus on training and its analytical purchase for geographers as part of a growing body of work on the geographies of education. Second, the article shows how geographers can account for both children and adults' geographies in institutional spaces, in this case through mapping out the enlivened historical geographies of voluntarism across the lifecourse. This article demonstrates the complex and often fluid relationship between formal and informal education, as well as the important connections between parenting and volunteering. Overall, the article reflects on the subsequent challenges and opportunities for researchers concerned with debates on education, youth and volunteering within geography and beyond. PMID- 29708117 TI - Treatment of malignant pleural mesothelioma: lessons learned and quo vadis? PMID- 29708118 TI - Adjuvant EGFR TKI therapy for resectable non-small cell lung cancer: new era for personalized medicine. PMID- 29708119 TI - The borderscape of Punta Tarifa: concurrent invisibilisation practices at Europe's ultimate peninsula. AB - This contribution aims to provide a cultural-geographical reading of the borderscape of Punta Tarifa: the southernmost point of so-called continental Europe and a key site vis-a-vis material and representational Euro-African (dis)connections. It is argued that Punta Tarifa harbours a complex process of symbolic and functional invisibilisation that turns this border landscape into a highly significant scenario within the ongoing European Union bordering process. This invisibilisation process is twofold. On the one hand, it lies with the selective public neglecting/ignoring of a crucial historical episode which challenges mainstream readings of Europe's cultural heritage (the arrival of Tarif and Islam to Tarifa in the year 710). On the other hand, it concerns the veiling of the implemented migration management practices and, more precisely, the opacity surrounding the Migrant Detention Centre situated by Punta Tarifa. Having explored the case of Punta Tarifa, we suggest that a cultural-geographical reading - and hence the shedding of some light - on these and other similar invisibilisation processes is paramount in order to neutralise symbolic and functional exclusionary practices which lie at the heart of current European Union external bordering dynamics. PMID- 29708120 TI - Resilience 2.0: social media use and (self-)care during the 2011 Norway attacks. AB - Departing from the understanding that resilience is a technique of self organization during emergencies, this article provides a study on the way in which the use of social media influenced and engendered societal resilience practices during the 2011 Norway attacks. It builds on the concepts of governmentality and mediality to discuss how the interplay between social media and its users created new forms of self-initiated and mediated emergency governance. Empirically, it draws on material from 20 in-depth interviews with Norwegians who explained and reflected upon their social media use during the attacks. The article presents an overview of the different functions that social media assumed in the process of dealing with the attacks and discusses these vis a-vis their related challenges. It draws conclusions about the way in which resilience practices and the resilient subject are influenced by the networked character of 2.0 technologies. PMID- 29708121 TI - "The Work Must Go On": The Role of Employee and Managerial Communication in the Use of Work-Life Policies. AB - The Netherlands is characterized by extensive national work-life regulations relative to the United States. Yet, Dutch employees do not always take advantage of existing work-life policies. Individual and focus group interviews with employees and managers in three (public and private) Dutch organizations identified how employee and managerial communication contributed to acquired rules concerning work-life policies and the interpretation of allocative and authoritative resources for policy enactment. Analyses revealed differences in employees' and managers' resistance to policy, the binds and dilemmas experienced, and the coordination of agreements and actions to complete workloads. There are also differences between public and private contexts in the enactment of national and organizational policies, revealing how national (e.g., gender) and organizational (e.g., concertive control) mechanisms play out in employee and managerial communication that determine the use of work-life policies. PMID- 29708122 TI - Doing comic geographies. AB - This article reflects on how notions of 'the comic' may be of added value to geographers' research. It is formed around the idea that there are aspects of space and society that are by nature incongruous and unsuitable to be understood through frameworks of scholarship that privilege 'reason' and objectivity above all else. The author thus reflects on how these notions of 'the comic' as a mode of thought can be applied to understanding different fields of research. Ultimately, the article draws out how using this comic mode also forms an 'inward' reflective process which can help to understand the often complicated positions that researchers hold. This article thus calls for an inclusion of the often otherwise ignored comic aspects of the world into scholarship so that we, as geographers, may provide fuller and more human critical analyses of space, culture and society. PMID- 29708123 TI - Becoming ecological citizens: connecting people through performance art, food matter and practices. AB - Engaging the interest of Western citizens in the complex food connections that shape theirs' and others' personal wellbeing around issues such as food security and access is challenging. This article is critical of the food marketplace as the site for informing consumer behaviour and argues instead for arts-based participatory activities to support the performance of ecological citizens in non commercial spaces. Following the ongoing methodological and conceptual fascination with performance, matter and practice in cultural food studies, we outline what the ecological citizen, formed through food's agentive potential, does and could do. This is an ecological citizen, defined not in its traditional relation to the state but rather to the world of humans and non-humans whose lives are materially interconnected through nourishment. The article draws on the theories of Berlant, Latour, Bennett and Massumi. Our methodology is a collaborative arts-led research project that explored and juxtaposed diverse food practices with artist Paul Hurley, researchers, community partners, volunteers and participants in Bristol, UK. It centred on a 10-day exhibition where visitors were exposed to a series of interactive explorations with and about food. Our experience leads us to outline two steps for enacting ecological citizenship. The first step is to facilitate sensory experiences that enable the agential qualities of foodstuffs to shape knowledge making. The second is to create a space where people can perform, or relate differently, in unusual manners to food. Through participating in the project and visiting the exhibition, people were invited to respond not only as 'ethical consumers' but also as 'ecological citizens'. This participatory approach to research can contribute to understandings of human-world entanglements. PMID- 29708124 TI - Microvascular obstruction in ST elevation myocardial infarction patients undergoing primary percutaneous coronary intervention: another frontier to conquer? PMID- 29708125 TI - European integration in crisis? Of supranational integration, hegemonic projects and domestic politics. AB - The European Union is facing multiple challenges. Departing from mainstream theory, this article adopts a fresh approach to understanding integration. It does so by taking two theoretical steps. The first introduces the structure agency debate in order to make explicit the relationship between macro structures, the institutional arrangements at European Union level and agency. The second proposes that the state of integration should be understood as the outcome of contestation between competing hegemonic projects that derive from underlying social processes and that find their primary expression in domestic politics. These two steps facilitate an analysis of the key areas of contestation in the contemporary European Union, illustrated by an exploration of the current crisis in the European Union, and open up the development of an alternative, critical, theory of integration. PMID- 29708126 TI - Is IR going extinct? AB - A global extinction crisis may threaten the survival of most existing life forms. Influential discourses of 'existential risk' suggest that human extinction is a real possibility, while several decades of evidence from conservation biology suggests that the Earth may be entering a 'sixth mass extinction event'. These conditions threaten the possibilities of survival and security that are central to most branches of International Relations. However, this discipline lacks a framework for addressing (mass) extinction. From notions of 'nuclear winter' and 'omnicide' to contemporary discourses on catastrophe, International Relations thinking has treated extinction as a superlative of death. This is a profound category mistake: extinction needs to be understood not in the ontic terms of life and death, but rather in the ontological context of be(com)ing and negation. Drawing on the work of theorists of the 'inhuman' such as Quentin Meillassoux, Claire Colebrook, Ray Brassier, Jean-Francois Lyotard and Nigel Clark, this article provides a pathway for thinking beyond existing horizons of survival and imagines a profound transformation of International Relations. Specifically, it outlines a mode of cosmopolitics that responds to the element of the inhuman and the forces of extinction. Rather than capitulating to narratives of tragedy, this cosmopolitics would make it possible to think beyond the restrictions of existing norms of 'humanity' to embrace an ethics of gratitude and to welcome the possibility of new worlds, even in the face of finitude. PMID- 29708127 TI - From voice to voices: identifying a plurality of Muslim sources in the news media. AB - This article identifies a qualitative change in the diversity of actors who represent Muslims in British news media. Hitherto, the literature discussing Muslims and the media has tended to characterize media organizations as institutions which portray Muslims in an essentialized, monolithic way. In contrast, I propose in this article that the process of representation is more complex, including greater agency and engaging a wider diversity of Muslims than the prevailing literature suggests. Sociological studies distinguish between official and unofficial sources who help determine the representations that journalists employ in their texts, and I apply this to Muslim communities in Glasgow. Using qualitative methods drawn from media production analysis, including participant-observation and ethnographic interviews, I identify a shift from a 'gatekeeper' model of representing the community to that of a plurality of sources, which reveals and insists on the diversity of Muslim communities and voices. I will show why a wider range of actors emerged to speak publicly, what differentiates them and how they position themselves as representatives of Muslims. This focus on producers and on source strategies brings fresh insights into a field dominated by content analysis and a 'media-centric' approach. PMID- 29708128 TI - Introducing Jus ante Bellum as a cosmopolitan approach to humanitarian intervention. AB - Cosmopolitans often argue that the international community has a humanitarian responsibility to intervene militarily in order to protect vulnerable individuals from violent threats and to pursue the establishment of a condition of cosmopolitan justice based on the notion of a 'global rule of law'. The purpose of this article is to argue that many of these cosmopolitan claims are incomplete and untenable on cosmopolitan grounds because they ignore the systemic and chronic structural factors that underwrite the root causes of these humanitarian threats. By way of examining cosmopolitan arguments for humanitarian military intervention and how systemic problems are further ignored in iterations of the Responsibility to Protect, this article suggests that many contemporary cosmopolitan arguments are guilty of focusing too narrowly on justifying a responsibility to respond to the symptoms of crisis versus demanding a similarly robust justification for a responsibility to alleviate persistent structural causes. Although this article recognizes that immediate principles of humanitarian intervention will, at times, be necessary, the article seeks to draw attention to what we are calling principles of Jus ante Bellum (right before war) and to stress that current cosmopolitan arguments about humanitarian intervention will remain insufficient without the incorporation of robust principles of distributive global justice that can provide secure foundations for a more thoroughgoing cosmopolitan condition of public right. PMID- 29708129 TI - The direction of travel to better outcomes for patients with oesophago-gastric cancer. PMID- 29708130 TI - What is the best pain control after thoracic surgery? PMID- 29708131 TI - Validating guideline concordant care in lung cancer also validates good surgical judgement and skill. PMID- 29708132 TI - The evolving understanding of immunoediting and the clinical impact of immune escape. PMID- 29708133 TI - Slumdog romance: Facebook love and digital privacy at the margins. AB - Facebook has consolidated its position as the one-stop-shop for social activity among the poor in the global South. Sex, romance, and love are key motivations for mobile and Internet technology usage among this demographic, much like the West. Digital romance is a critical context through which we gain fresh perspectives on Internet governance for an emerging digital and globalizing public. Revenge porn, slut-shaming, and Internet romance scams are a common and growing malady worldwide. Focusing on how it manifests in diverse digital cultures will aid in the shaping of new Internet laws for a more inclusive cross cultural public. In specific, this article examines how low-income youth in two of the BRICS (Brazil, Russia, India, China and South Africa) nations - Brazil and India - exercise and express their notions on digital privacy, surveillance, and trust through the lens of romance. This allows for a more thorough investigation of the relationship between sexuality, morality, and governance within the larger Facebook ecology. As Facebook becomes the dominant virtual public sphere for the world's poor, we are compelled to ask whether inclusivity of the digital users comes at the price of diversity of digital platforms. PMID- 29708134 TI - British torture in the 'war on terror'. AB - Despite long-standing allegations of UK involvement in prisoner abuse during counterterrorism operations as part of the US-led 'war on terror', a consistent narrative emanating from British government officials is that Britain neither uses, condones nor facilitates torture or other cruel, inhuman or degrading treatment and punishment. We argue that such denials are untenable. We have established beyond reasonable doubt that Britain has been deeply involved in post 9/11 prisoner abuse, and we can now provide the most detailed account to date of the depth of this involvement. We argue that it is possible to identify a peculiarly British approach to torture in the 'war on terror', which is particularly well-suited to sustaining a narrative of denial. To explain the nature of UK involvement, we argue that it can be best understood within the context of how law and sovereign power have come to operate during the 'war on terror'. We turn here to the work of Judith Butler, and explore the role of Britain as a 'petty sovereign', operating under the state of exception established by the US executive. UK authorities have not themselves suspended the rule of law so overtly; indeed, they have repeatedly insisted on their commitment to it. Nevertheless, they have been able to construct a rhetorical, legal and policy 'scaffold' that has enabled them to demonstrate at least procedural adherence to human rights norms while, at the same time, allowing UK officials to acquiesce in the arbitrary exercise of sovereignty over individuals who are denied any access to appropriate representation or redress in compliance with the rule of law. PMID- 29708135 TI - Meet the new boss: lung cancer staging. PMID- 29708136 TI - Updated statistics of lung and bronchus cancer in United States (2018). PMID- 29708137 TI - Protection of lung oxidative injury by remote ischemic preconditioning: a study of exhaled water during pulmonary lobectomy. PMID- 29708138 TI - Zebrafish as experimental model to establish the contribution of mutant p53 and ID4 to breast cancer angiogenesis in vivo. PMID- 29708139 TI - Use of antibiotics in the ambulance for sepsis patients: is earlier really better? PMID- 29708140 TI - Lobectomy versus segmentectomy and wedge resection in the treatment of stage I non-small cell lung cancer. PMID- 29708141 TI - Inequivalence of non-aggressiveness in clinically diagnosed lung cancers and overdiagnosis in lung cancer screening trials. PMID- 29708142 TI - Thresholds, triggers or requirements-time to look beyond the transfusion trials. PMID- 29708143 TI - Combination immuno-oncology therapy with immune checkpoint blockers targeting PD L1, PD-1 or CTLA4 and epigenetic drugs targeting MYC and immune evasion for precision medicine. PMID- 29708144 TI - Dynamic stroke risk scores of atrial fibrillation. PMID- 29708145 TI - Utility of computed tomography lung cancer screening and the management of computed tomography screen-detected findings. PMID- 29708146 TI - A novel survival prediction model of ECMO in acute respiratory distress syndrome: things to consider for optimal use. PMID- 29708147 TI - Deep learning and medical imaging. PMID- 29708148 TI - Novel insights and recent discoveries on the genetics and pathogenesis of malignant mesothelioma. PMID- 29708149 TI - Treatment of hepatic metastases from medullary thyroid cancer with transarterial embolisation. AB - Transarterial chemoembolisation (TACE) is well established in the treatment of primary hepatocellular carcinoma and of metastatic disease from colorectal and neuroendocrine tumours. There are few published studies on the effectiveness of treating hepatic metastases from medullary thyroid carcinoma with chemoembolisation and none to our knowledge utilising bland particle transarterial embolisation (TAE). Here we describe the management of multifocal hepatic metastases from medullary thyroid cancer in a 39-year-old woman who underwent bland particle TAE with a biochemical and radiological response and discuss the potential for a wider scope of clinical application for bland TAE in hepatic metastases. PMID- 29708150 TI - Multifocal adenocarcinoma: perspectives, assumptions and elephants. PMID- 29708151 TI - Remote ischemic preconditioning in patients undergoing pulmonary lobectomy: we are on the right path. PMID- 29708152 TI - Circulating microRNAs as an emerging biomarker for acute aortic dissection diagnosis-comparing with prior biomarkers. PMID- 29708153 TI - Erratum to bronchial interrupted suture anastomosis for video-assisted thoracic surgery (VATS) right upper lobe resection. AB - [This corrects the article DOI: 10.21037/jtd.2017.08.21.]. PMID- 29708154 TI - Predicting outcome of venovenous ECMO: look outside the lung! PMID- 29708155 TI - Guidelines for stereotactic body radiation therapy treatment of lung cancer highlight important research questions: what is the next step? PMID- 29708156 TI - Perspectives on stereotactic body radiotherapy for early-stage non-small cell lung cancer: a maturing treatment modality. PMID- 29708157 TI - In vitro labelling and detection of mesenchymal stromal cells: a comparison between magnetic resonance imaging of iron-labelled cells and magnetic resonance spectroscopy of fluorine-labelled cells. AB - Background: Among the various stem cell populations used for cell therapy, adult mesenchymal stromal cells (MSCs) have emerged as a major new cell technology. These cells must be tracked after transplantation to monitor their migration within the body and quantify their accumulation at the target site. This study assessed whether rat bone marrow MSCs can be labelled with superparamagnetic iron oxide (SPIO) nanoparticles and perfluorocarbon (PFC) nanoemulsion formulations without altering cell viability and compared magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) results from iron-labelled and fluorine labelled MSCs, respectively. Methods: Of MSCs, 2 * 106 were labelled with Molday ION Rhodamine-B (MIRB) and 2 * 106 were labelled with Cell Sense. Cell viability was evaluated by trypan blue exclusion method. Labelled MSCs were divided into four samples containing increasing cell numbers (0.125 * 106, 0.25 * 106, 0.5 * 106, 1 * 106) and scanned on a 7T MRI: for MIRB-labelled cells, phantoms and cells negative control, T1, T2 and T2* maps were acquired; for Cell Sense labelled cells, phantoms and unlabelled cells, a 19F non-localised single-pulse MRS sequence was acquired. Results: In total, 86.8% and 83.6% of MIRB-labelled cells and Cell Sense-labelled cells were viable, respectively. MIRB-labelled cells were visible in all samples with different cell numbers; pellets containing 0.5 * 106 and 1 * 106 of Cell Sense-labelled cells showed a detectable 19F signal. Conclusions: Our data support the use of both types of contrast material (SPIO and PFC) for MSCs labelling, although further efforts should be dedicated to improve the efficiency of PFC labelling. PMID- 29708158 TI - NUTRIREA-2 trial finds that early enteral nutrition and early parenteral nutrition do not differ with regards to major clinical outcomes. PMID- 29708159 TI - New concepts in the treatment of malignant pleural mesothelioma. PMID- 29708160 TI - Do we need complementary locoregional analgesia in patients undergoing minimally invasive thoracic surgical procedures? PMID- 29708161 TI - Best practice for sepsis. PMID- 29708162 TI - Current perspectives for the size measurement of screening-detected lung nodules. PMID- 29708163 TI - Malignant pleural mesothelioma: some progress, but still a long way from cure. PMID- 29708164 TI - Predictive tools in VVECMO patients: handicap or benefit for clinical practice? PMID- 29708165 TI - Should the ART trial change our practice? PMID- 29708166 TI - Extending the curve: survival of EGFR-mutated lung cancer patients in the 21st century. PMID- 29708167 TI - Multimodal ultrasound tomography for breast imaging: a prospective study of clinical feasibility. AB - Background: To describe the clinical set-up and evaluate the feasibility of multimodal ultrasound tomography (MUT) for breast imaging. Methods: Thirty-two consecutive patients referred for breast imaging and 24 healthy volunteers underwent MUT. In the 32 patients, the examination discomfort was compared to that of mammography (n = 31), handheld ultrasound (HUS) (n = 27) and magnetic resonance imaging (MRI) (n = 4) on a scale from 1 (lowest discomfort) to 10 (highest discomfort). MUT investigation time was recorded. Findings automatically detected by MUT were correlated with conventional imaging and biopsy results. Results: Breast MUT was well tolerated by all 56 participants; 55 bilateral exams were uneventful. During one exam, the digitalisation card failed and the exam was successfully repeated within three days. Mean examination discomfort was 1.6 (range = 1-5) for MUT, 1.5 (range = 1-5) for HUS, 5.3 (range = 3-7) for MRI, and 6.3 (range = 1-10) for mammography. MUT examination time was 38 +/- 6 min (mean +/- standard deviation). In the patients referred for breast imaging, MUT detected four lesions and indicated malignancy in three of these cases. These findings were confirmed by additional imaging and biopsy. Conclusion: MUT is feasible in a clinical context considering examination time and patient acceptance. These interesting initial diagnostic findings warrant further studies. PMID- 29708168 TI - International trends in the clinical epidemiology of malignant pleural mesothelioma. PMID- 29708169 TI - Letter to: acute respiratory distress syndrome in traumatic brain injury: how do we manage it? PMID- 29708170 TI - Trends in radiology and experimental research. AB - European Radiology Experimental, the new journal launched by the European Society of Radiology, is placed in the context of three general and seven radiology specific trends. After describing the impact of population aging, personalized/precision medicine, and information technology development, the article considers the following trends: the tension between subspecialties and the unity of the discipline; attention to patient safety; the challenge of reproducibility for quantitative imaging; standardized and structured reporting; search for higher levels of evidence in radiology (from diagnostic performance to patient outcome); the increasing relevance of interventional radiology; and continuous technological evolution. The new journal will publish not only studies on phantoms, cells, or animal models but also those describing development steps of imaging biomarkers or those exploring secondary end-points of large clinical trials. Moreover, consideration will be given to studies regarding: computer modelling and computer aided detection and diagnosis; contrast materials, tracers, and theranostics; advanced image analysis; optical, molecular, hybrid and fusion imaging; radiomics and radiogenomics; three-dimensional printing, information technology, image reconstruction and post-processing, big data analysis, teleradiology, clinical decision support systems; radiobiology; radioprotection; and physics in radiology. The journal aims to establish a forum for basic science, computer and information technology, radiology, and other medical subspecialties. PMID- 29708172 TI - Current PD-L1 immunohistochemistry for non-small cell lung cancer. PMID- 29708171 TI - The MRI characteristics of the no-flow region are similar in reperfused and non reperfused myocardial infarcts: an MRI and histopathology study in swine. AB - Background: The no-flow region (NF) visualised by magnetic resonance imaging (MRI) in myocardial infarction (MI) has been explained as the product of reperfusion-injury-induced microvascular obstruction. However, a similar MRI phenomenon occurs in non-reperfused MI. Accordingly, our purpose was to compare the MRI and histopathologic characteristics of the NF in reperfused and non reperfused MIs. Methods: Reperfused (n = 7) and non-reperfused MIs (n = 7) were generated in swine by percutaneous balloon occlusion and microsphere embolisation techniques. Four days post-MI, animals underwent myocardial T2-mapping, early and serial late gadolinium enhancement MRI. MI and NF were compared between the models using the independent samples t test. Serial measurements were analysed using repeated measures analysis of variance. Triphenyltetrazolium chloride (TTC) macroscopic and microscopic histopathologic assessment was also performed. Results: The MI size in the reperfused and non-reperfused groups was 17.1 +/- 3.4 ml and 19.4 +/- 8.1 ml, respectively (p = 0.090), in agreement with TTC assessment (p = 0.216; p = 0.484), and the NF size was 7.7 +/- 2.4 ml and 8.1 +/- 1.9 ml, respectively (P = 0.211). Compared to the reference 2-min post-contrast measurement, the NF size was significantly reduced at 20 min in the reperfused group and at 25 min in the non-reperfused group (both p < 0.001). Nevertheless, the NF was still detectable at 45 min after injection. No significant T2 difference was observed between the groups (p > 0.326). Histopathologic assessment revealed extensive calcification and hemosiderin deposition in the NF of the reperfused MI, but not in the non-reperfused MI. Conclusions: The NF in non-reperfused and reperfused MIs have similar characteristics on MRI despite the different pathophysiologic and underlying histopathologic conditions, indicating that the presence of the NF alone cannot differentiate between these two types of MI. PMID- 29708173 TI - Uncertainties from a worldwide survey on antiepileptic drug withdrawal after seizure remission. AB - Background: We sought to determine differences in practice for discontinuation of antiepileptic drugs (AEDs) after seizure remission and stimulate the planning and conduction of withdrawal trials. Methods: We utilized a worldwide electronic survey that included questions about AED discontinuation for 3 paradigmatic cases in remission: (1) focal epilepsy of unknown etiology, (2) temporal lobe epilepsy after surgery, and (3) juvenile myoclonic epilepsy. We analyzed 466 complete questionnaires from 53 countries, including the United States. Statistical analysis included chi2 and multivariate logistic regression. Results: Case 1: responders in practice for <10 years were less likely to taper AEDs: odds ratio (OR) (95% confidence interval [CI]) 0.52 (0.32-0.85), p = 0.02. The likelihood of stopping AEDs was higher among doctors treating children: OR (95% CI): 11.41 (2.51-40.13), p = 0.002. Doctors treating children were also more likely to stop after 2 years or less of remission: OR (95% CI): 6.91 (2.62-19.31), p = 0.002, and the same was observed for US physicians: OR (95% CI): 1.61 (1.01-2.57), p = 0.0049. Case 2: responders treating children were more likely to taper after 1 year or less of postoperative remission, with the goal of discontinuing all medications: OR (95% CI): 1.91 (1.09-3.12), p = 0.015, and so were US-based responders: OR (95% CI): 1.73 (1.21-2.41), p = 0.003. Case 3: epileptologists were less likely to withdraw the medication: OR (95% CI): 0.56 (0.39-0.82), p = 0.003, and so were those in practice for 10 or more years: OR (95% CI): 0.54 (0.31-0.95), p = 0.025. Conclusions: We observed several differences in practice for AED withdrawal after seizure remission that highlight global uncertainty. Trials of AED discontinuation are needed to provide evidence-based guidance. PMID- 29708174 TI - Diffusion tensor imaging in the musculoskeletal and peripheral nerve systems: from experimental to clinical applications. AB - Magnetic resonance imaging (MRI) is a well-established imaging modality which is used in all districts of the musculoskeletal and peripheral nerve systems. More recently, initial studies have applied multiparametric MRI to evaluate quantitatively different aspects of musculoskeletal and peripheral nerve diseases, thus providing not only images but also numbers and clinical data. Besides 1H and 31P magnetic resonance spectroscopy, diffusion-weighted imaging (DWI) and blood oxygenation level-dependent imaging, diffusion tensor imaging (DTI) is a relatively new MRI-based technique relying on principles of DWI, which has traditionally been used mainly for evaluating the central nervous system to track fibre course. In the musculoskeletal and peripheral nerve systems, DTI has been mostly used in experimental settings, with still few indications in clinical practice. In this review, we describe the potential use of DTI to evaluate different musculoskeletal and peripheral nerve conditions, emphasising the translational aspects of this technique from the experimental to the clinical setting. PMID- 29708176 TI - Multifocal ground-glass opacities: multifocal origin versus intrapulmonary metastasis. PMID- 29708175 TI - Evaluation of the rabbit liver by direct portography and contrast-enhanced computed tomography: anatomical variations of the portal system and hepatic volume quantification. AB - Background: The study was aimed at: (1) describing the incidence of anatomic variations of the portal system in the rabbit using direct portography; and (2) estimating the liver volume and caudate lobe volume by using contrast-enhanced computed tomography (CECT) in the same animal model. Methods: Forty-six New Zealand white rabbits were included. All of them underwent direct portography and unenhanced CECT. Conventional liver rabbit portal system anatomy (type 1) consisted of the bifurcation of the main portal vein (MPV) into the right portal vein (RPV) and left portal vein (LPV), which subsequently divided into medial left portal vein and lateral left portal vein. Trifurcation of the LPV was considered type 2. The LPV that divides into four smaller branches was classified as type 3. Other configurations of the portal system, including particular cases of MPV branching, were grouped as type 4. Liver lobes were manually segmented. Results: The incidence of each type of portal system anatomy was: type 1, 67.4%; type 2, 15.2%; type 3, 13.0%); and type 4, 4.3%. The mean volume of the caudate lobe was 19.1 ml +/- 5.7 ml and of the cranial lobes it was 66.7 ml +/- 13.7 ml, and the total liver volume was 85.7 ml +/- 16.7 ml. Conclusions: In New Zealand white rabbits, type 1 is the prevalent type of portal system, liver volume is about 86 ml, and the caudate and cranial lobes are separated. This information could be important when planning experimental rabbit liver procedures. PMID- 29708177 TI - The long and winding road to translation for imaging biomarker development: the case for arterial spin labelling (ASL). AB - Radiology is facing many challenges nowadays, and certainly needs to keep up with the fast pace of developments taking place in this field. This editorial aims at drawing the attention of the reader to the current establishment of quantitative imaging biomarkers, in particular through the efforts of the Quantitative Imaging Biomarker Alliance (QIBA) from the Radiological Society of North America (RSNA), as well as the European Imaging Biomarker Alliance (EIBALL) from the European Society of Radiology (ESR). The case of arterial spin labelling (ASL) is used as an example of the long and winding road to translate a good imaging technique into a clinically relevant imaging biomarker. PMID- 29708178 TI - Evaluation of bone mineral density of the lumbar spine using a novel phantomless dual-energy CT post-processing algorithm in comparison with dual-energy X-ray absorptiometry. AB - Background: Current techniques for evaluation of bone mineral density (BMD) commonly require phantom calibration. The purpose of this study was to evaluate a novel algorithm for phantomless in vivo dual-energy computed tomography (DECT) based assessment of BMD of the lumbar spine in comparison with dual-energy X-ray absorptiometry (DEXA). Methods: Data from clinically indicated DECT and DEXA examinations within two months comprising the lumbar spine of 47 patients were retrospectively evaluated. By using a novel automated dedicated post-processing algorithm for DECT, the trabecular bone of lumbar vertebrae L1-L4 was selected and analysed. Linear correlation was analysed using Pearson's product-moment correlation coefficient for the comparison of the results from DECT and DEXA. Results: A total of 186 lumbar vertebrae in 47 patients (mean age, 58 years; age range, 24-85 years) were analysed, 24 men (mean age, 55 years; age range, 24-85 years) and 23 women (mean age, 59 years; age range, 31-80 years). Mean BMD of L1 L4 determined with DEXA was 0.985 g/cm2 and 20/47 patients (42.6%) showed an osteoporotic BMD (T score lower than - 2.5) of at least two vertebrae. Average DECT-based BMD of L1-L4 was 86.8 mg/cm3. Regression analysis demonstrated a lack of correlation between DECT- and DEXA-based BMD values with a Pearson's product moment correlation coefficient r = 0.4205. Conclusions: Dedicated post-processing of DECT data using a novel algorithm for retrospective phantomless BMD assessment of the trabecular bone of lumbar vertebrae from clinically indicated DECT examinations is feasible. PMID- 29708179 TI - Differentiation of vestibular schwannomas from meningiomas of the internal auditory canal using perilymphatic signal evaluation on T2-weighted gradient-echo fast imaging employing steady state acquisition at 3T. AB - Background: Our aim was to confirm the usefulness of the perilymphatic signal changes on T2-weighted (T2W) gradient-echo sequence to differentiate vestibular schwannomas from internal auditory canal (IAC) meningiomas, through a compartmental analysis of inner ear fluids signal intensity. Methods: A total of 203 patients with all criteria for typical vestibular schwannoma on T1-weighted contrast-enhanced sequences were retrospectively enrolled (190 schwannomas and 13 meningiomas). All patients underwent a T2W gradient-echo steady state free precession (SSFP) acquisition at 3T. Two radiologists analysed the signal intensity of the perilymph (cistern and cochlea) and endolymph (saccule and utricle) using a region of interest-based method for obtaining ratios between the analysed structures and the cerebrospinal fluid (CSF). Results: Obstructive vestibular schwannomas showed a markedly decreased perilymphatic signal in both cistern and cochlea; the cistern/CSF ratio (Ci/CSF) was 0.62. The decrease was more moderate in IAC meningiomas (Ci/CSF = 0.81). For Ci/CSF > 0.70, the tumour was more likely a meningioma, with a 92% sensitivity and 83% specificity. No endolymphatic signal changes were observed. Conclusion: The pronounced decrease in perilymphatic signal on a T2W SSFP sequence in obstructive vestibular schwannoma provides a new tool to differentiate schwannomas from IAC meningiomas, which may be useful to overcome the insufficiencies of morphological analysis. PMID- 29708180 TI - Stereotactic body radiation therapy vs. surgery in early-stage non-small cell lung cancer: lessons learned, current recommendations, future directions. PMID- 29708181 TI - Semi-quantitative evaluation of signal intensity and contrast-enhancement in Modic changes. AB - Background: Semi-quantitative evaluation of Modic changes (MCs) has recently been proposed as a way to standardise and increase repeatability of clinical studies. This study is aimed at developing semi-quantitative measures of enhancement, given by contrast agent injection, on T1-weighted images in MCs, and to investigate their reliability and relation with MC types. Methods: Thirty-seven subjects suffering from low back pain underwent T1-weighted and T2-weighted turbo spin-echo sequences. Five minutes after the injection of a paramagnetic contrast agent, a second T1-weighted sequence was acquired. Regions of interest (ROIs) corresponding to MCs were selected manually on the unenhanced image; control ROIs in the "healthy" bone marrow were selected. For each ROI, the mean signal intensity (SI) of unenhanced pixels and the mean absolute and normalised difference in SI between unenhanced and contrast-enhanced pixels values were calculated. Results: A total of 103 MCs were recognised and 61 were semi quantitatively analysed: 16 type I, 34 type II and 11 type I/II. Regarding controls, MCs I showed a lower SI on the unenhanced T1-weighted images and a marked contrast enhancement (CE); MCs II showed a higher SI than controls on unenhanced images and a lower or comparable CE; and MCs I/II presented an intermediate SI on the unenhanced images and a marked CE. Inter-rater and intra rater agreements were found to be excellent or substantial. Conclusions: Semi quantitative measurements could differentiate MC types in terms of unenhanced SI and of CE with respect to "healthy" bone marrow. PMID- 29708182 TI - Neurologist-patient communication about epilepsy in the United States, Spain, and Germany. AB - Background: Effective communication between patients and their health care providers is recognized as critically important to improve the quality of health services for individuals with epilepsy. We aimed to describe in-office neurologist-patient conversations about epilepsy and focus on disease identification, shared decision-making, and care planning. Methods: Transcripts and audio recordings of conversations between patients and neurologists in the United States, Spain, and Germany were analyzed linguistically in the topic areas of epilepsy identification and diagnosis, disease education, treatments, and care planning. Analyses included word-level assessments, topic switching, strategies of information elicitation, identification of topics discussed, quantification of questions asked, and assessment of types of questions asked. Results: Conversations of 17 neurologists in the United States, 12 in Spain, and 6 in Germany, with 50, 20, and 16 patients, respectively, were analyzed. Neurologists tended to utilize an event-based, patient-friendly vocabulary to refer to seizures, and in the United States, they avoided using the term "epilepsy." Regardless of who initiated the treatment discussion, the neurologists in all 3 countries were unilaterally responsible for the treatment decision and choice of medication. When describing a new medication, neurologists most often discussed potential side effects but did not review potential benefits. Neurologists rarely defined seizure control and did not ask patients what seizure control meant to them. Conclusions: We identified opportunities related to vocabulary, decision making, and treatment goal setting that could be targeted to improve neurologist patient communication about epilepsy, and ultimately, the overall treatment experience and outcomes for patients. PMID- 29708183 TI - Imaging of the saccule for the diagnosis of endolymphatic hydrops in Meniere disease, using a three-dimensional T2-weighted steady state free precession sequence: accurate, fast, and without contrast material intravenous injection. AB - Background: Endolymphatic hydrops can be studied on magnetic resonance imaging (MRI) using images acquired 4 h after intravenous injection of Gd-chelate. Our aim was to compare high-resolution T2-weighted images of the saccule in normal subjects with histological sections from cadavers and to identify its changes in Meniere disease, compared to healthy volunteers. Methods: Sixty-four healthy volunteers without any otologic disease and 64 patients who fulfilled all the criteria for unilateral Meniere disease underwent 3 T MRI using a T2-weighted steady state free precession (SSFP) sequence, without contrast material injection. Images of healthy volunteers were compared with histological sections of normal inner ears from premature foetuses and compared with volunteers. Results: The normal saccule was easily visible on T2-weighted images in volunteers, with a normal maximal height of 1.6 mm (1.4 +/- 0.1 mm, mean +/- standard deviation) and a good correlation with reference histological sections, while in Meniere disease the saccule was dilated in 52/62 patients (84%), with a saccular height greater than 1.6 mm (1.69 +/- 0.24 mm, p = 0.001), found in 45/52 patients (86%). An associated increased width (greater than 1.4 mm) was found in 23/52 patients (44%). A round shape or the non-visualisation of the saccule were also found in 2/52 (4%) and in 5/62 patients (8%), respectively. Conclusions: A T2-weighted sequence is an easy method to diagnose Meniere disease. Saccular abnormalities were found in 84% of the cases: elongation (height > 1.6 mm) in 86%, increased saccular width in 44%, or a missing saccule in 8%. PMID- 29708184 TI - MicroRNAs in acute aortic dissection. PMID- 29708185 TI - Precision of manual two-dimensional segmentations of lung and liver metastases and its impact on tumour response assessment using RECIST 1.1. AB - Background: Response evaluation criteria in solid tumours (RECIST) has significant limitations in terms of variability and reproducibility, which may not be independent. The aim of the study was to evaluate the precision of manual bi-dimensional segmentation of lung, liver metastases, and to quantify the uncertainty in tumour response assessment. Methods: A total of 520 segmentations of metastases from six livers and seven lungs were independently performed by ten physicians and ten scientists on CT images, reflecting the variability encountered in clinical practice. Operators manually contoured the tumours, firstly independently according to the RECIST and secondly on a preselected slice. Diameters and areas were extracted from the segmentations. Mean standard deviations were used to build regression models and 95% confidence intervals (95% CI) were calculated for each tumour size and for limits of progressive disease (PD) and partial response (PR) derived from RECIST 1.1. Results: Thirteen aberrant segmentations (2.5%) were observed without significant differences between the physicians and scientists; only the mean area of liver tumours (p = 0.034) and mean diameter of lung tumours (p = 0.021) differed significantly. No difference was observed between the methods. Inter-observer agreement was excellent (intra-class correlation >0.90) for all variables. In liver, overlaps of the 95% CI with the 95% CI of limits of PD or PR were observed for diameters above 22.7 and 37.9 mm, respectively. An overlap of 95% CIs was systematically observed for area. No overlaps were observed in lung. Conclusions: Although the experience of readers might not affect the precision of segmentation in lung and liver, the results of manual segmentation performed for tumour response assessment remain uncertain for large liver metastases. PMID- 29708186 TI - Noninvasive assessment and quantification of tumour vascularisation using MRI and CT in a tumour model with modifiable angiogenesis - An animal experimental prospective cohort study. AB - Background: To investigate vascular-related pathophysiological characteristics of two human lung cancers with modifiable vascularisation using MRI and CT. Methods: Tumour xenografts with modifiable vascularisation were established in 71 rats (approval by the Animal Care Committee was obtained) by subcutaneous transplantation of two human non-small-cell lung cancer (NSCLC) cells (A549, H1299) either alone or co-transplanted with vascular growth promoters. The vascularity of the tumours was assessed noninvasively by MRI diffusion-weighted imaging (DWI), T2-weighted, and time-of-flight (TOF) sequences) as well as contrast-enhanced CT (CE-CT), using clinical scanners. As a reference standard, histological examinations (CD-31, fluorescent beads) were done after explantation. Results: Microvessel density (MVD) was higher in co-transplanted tumours (171 +/- 19 number/mm2) than in non-co-transplanted tumours (111 +/- 11 number/mm2; p = 0.002). Co-transplanted tumours showed higher growth rates and larger tumour vessels at TOF-MRI as well as larger necrotic areas at CE-CT. In co transplanted tumours, DWI revealed higher cellularity (lower minimal ADCdiff 166 +/- 15 versus 346 +/- 27 mm2/s * 10-6; p < 0.001), highly necrotic areas (higher maximal ADCdiff 1695 +/- 65 versus 1320 +/- 59 mm2/s * 10-6; p < 0.001), and better-perfused tumour stroma (higher ADCperf 723 +/- 36 versus 636 +/- 51 mm2/s * 10-6; p = 0.005). Significant correlations were found using qualitative and quantitative parameters: maximal ADCperf and MVD (r = 0.326); maximal ADCdiff and relative necrotic volume on CE-CT (r = 0.551); minimal ADCdiff and MVD (r = 0.395). Conclusions: Pathophysiological differences related to vascular supply in two human lung cancer cell lines with modifiable vascularity are quantifiable with clinical imaging techniques. Imaging parameters of vascularisation correlated with the results of histology. DWI was able to characterise both the extent of necrosis and the level of perfusion. PMID- 29708187 TI - Investigation of aquaporins and apparent diffusion coefficient from ultra-high b values in a rat model of diabetic nephropathy. AB - Background: To assess kidney damage in a rat model of type-2 diabetic nephropathy based on apparent diffusion coefficient (ADC) data obtained from ultra-high b values and discuss its relationship to the expression of aquaporins (AQPs). Methods: This study was approved by the institutional Animal Care and Use Committee. Thirty male Sprague-Dawley rats were randomised into two groups: (1) untreated controls and (2) diabetes mellitus (DM). All rats underwent diffusion weighted imaging (DWI) with 18 b-values (0-4500 s/mm2). Maps of low ADC (ADClow), standard ADC (ADCst) and ultra-high ADC (ADCuh) were calculated from low b-values (0-200 s/mm2), standard b-values (300-1500 s/mm2) and ultra-high b-values (1700 4500 s/mm2), respectively. The expression of AQPs in the kidneys was studied using immunohistochemistry. Laboratory parameters of diabetic and kidney functions, ADClow, ADCst, ADCuh, and the optical density (OD) of AQP expression in the two groups were compared using an independent t test. Correlations between ADCs and the OD of AQP expression were evaluated by Pearson's correlation analysis. Results: ADCuh were significantly higher in the cortex (CO), outer stripe of the outer medulla (OS) and inner stripe of the outer medulla (IS), and the OD values of AQ-2 were significantly higher in the OS, IS and inner medulla (IM) in DM animals compared with control animals. ADCuh and OD values of AQP-2 expression were positively correlated in the OS, IS and IM of the kidney. Conclusions: ADCuh may work as useful metrics for early detection of kidney damage in diabetic nephropathy and may be associated with AQP-2 expression. PMID- 29708188 TI - Commentary: Geographic Variations in the Incidence of Glioblastoma and Prognostic Factors Predictive of Overall Survival in US Adults from 2004-2013. PMID- 29708189 TI - Vestibular evoked myogenic potential testing: Payment policy review for clinicians and payers. AB - Purpose of review: A recent American Academy of Neurology Evidence-Based Practice Guideline on vestibular myogenic evoked potential (VEMP) testing has described superior canal dehiscence syndrome (SCDS) and evaluated the merits of VEMP in its diagnosis. SCDS is an uncommon but now well-recognized cause of dizziness and auditory symptoms. This article familiarizes health care providers with this syndrome and the utility and shortcomings of VEMP as a diagnostic test and also explores payment policies for VEMP. Recent findings: In carefully selected patients with documented history compatible with the SCDS, both high-resolution temporal bone CT scan and VEMP are valuable aids for diagnosis. Payers might be unfamiliar with both this syndrome and VEMP testing. Summary: It is important to raise awareness of VEMP and its possible indications and the rationale for coverage of VEMP testing. Payers may not be readily receptive to VEMP coverage if this test is used in an undifferentiated manner for all common vestibular and auditory symptoms. PMID- 29708190 TI - 3-T MRI implant safety: heat induction with new dual-channel radiofrequency transmission technology. AB - We aimed to investigate whether different transmission settings of the dual transmit technology may influence the amount of heat induction around an implant material dependent on its location within the magnetic field. Metallic hip implants were positioned in the magnet of a 3-T scanner at various lateral offset positions in relation to the magnetic axis in a body-phantom tank filled with polyacrylic acid gel. The temperature increase close to the implants was measured during turbo spin-echo scanning using dual-channel parallel radiofrequency (RF) transmission with circular in comparison to elliptic RF polarization. Circularly polarized transmission (CPT) induced higher temperature increases (maximum 6.2 degrees C) than elliptically polarized transmission (EPT) (maximum 1.5 degrees C). The heat induction was dependent on the distance to the isocenter with increased heating by increased distance to the isocenter. EPT showed lower heating around implants compared to the CPT as commonly used in single transmission system; further, less heating was observed for both transmission settings closer to the magnet isocenter. PMID- 29708191 TI - Use of the Hourglass peripheral embolisation device: early experiences. AB - We evaluated a novel intravascular plug, the Hourglass peripheral embolisation device (PED). We describe, for the first time, the use of this device and discuss its potential applications. The device was deployed in nine patients over a six month period at a single institution by two different operators. Five patients underwent renal artery embolisation, three underwent gonadal vein embolisation for a varicocele, and a single patient underwent embolisation of the gastroduodenal artery. We recorded the indications, success rate, and the procedure-related complication rate in all patients. We also evaluated the satisfaction of the operators with the device using a post-procedure evaluation form. Technical success was achieved in 9/9 (100%) cases. Unanimous feedback was obtained from the operators (100% agreement). The usability of the delivery system, device deployment, and device visibility under fluoroscopy were rated as easy in 9/9 (100%) cases. The ease of repositioning was rated as good in both cases where this was attempted. The device trackability was rated as good in 9/9 (100%) cases. There were no procedure-related complications. The Hourglass PED is potentially useful for the embolisation of small-to-medium sized vessels. PMID- 29708192 TI - Intra-voxel incoherent motion MRI of the living human foetus: technique and test retest repeatability. AB - Background: Our purpose was to test the within-subject (test-retest) reproducibility of the perfusion fraction, diffusion coefficient, and pseudo diffusion coefficient measurements in various foetus organs and in the placenta based on the intra-voxel incoherent motion (IVIM) principle. Methods: In utero diffusion-weighted IVIM magnetic resonance imaging (MRI) was performed in 15 pregnant women (pregnancy age 21-36 weeks) on 1.5-T and 3.0-T clinical scanners with b-factors in the range of 0-900 s/mm2 in 16 steps. A bi-exponential model was fitted on the volume-averaged diffusion values. Perfusion fraction (f), diffusion coefficient (d), and pseudo-diffusion coefficient (D*) were calculated. Within-subject reproducibility was evaluated as test-retest variability (VAR %) of the IVIM parameters in the foetal frontal cortex, frontal white matter, cerebellum, lungs, kidneys, liver, and in the placenta. Results: For the foetal lungs, liver and the placenta, test-retest variability was in the range of 14-20% for f, 12-14% for d, and 17-25% for D*. The diffusion coefficients of the investigated brain regions were moderately to highly reproducible (VAR 5-15%). However, f and D* showed inferior reproducibility compared to corresponding measures for the lungs, liver, and placenta. The IVIM parameters of the foetal kidney were revealed to be highly variable across scans. Conclusions: IVIM MRI potentially provides a novel method for examining microvascular perfusion and diffusion in the developing human foetus. However, reproducibility of perfusion and diffusion parameters depends greatly upon data quality, foetal and maternal movements, and foetal-specific image post-processing. PMID- 29708193 TI - Comparison of the rebuilding effects of different computed tomography scanners and reconstructive settings for the five-line sign in normal interlobular fissures. AB - Background: Based on the images generated from two multi-slice computed tomography (CT) scanners, we intended to compare the five-line sign of normal interlobular fissures produced on axial or oblique maximum intensity projection (MIP) reconstructions using different algorithms. Methods: Two groups of 50 subjects underwent either 16-slice or 256-slice spiral unenhanced chest CT. None of them in either group displayed any abnormality. For each case, maximum intensity projection (MIP) data were used to calculate the axial or oblique projection using four algorithms: standard axial, standard oblique, high resolution axial, and high-resolution oblique algorithm. The results were then used to reconstruct images of six locations of the lung. The clarity of the five line sign of the reconstructed MIPs for the interlobular fissures was determined and graded as 1 (unclear), 2 (barely clear), or 3 (clear). Comparisons of the rate and the degree of clarity were performed using non-parametric tests. Results: Data from both the 16-slice and 256-slice CT revealed that the standard oblique algorithm was the best among the four methods for presenting clear images of the five-line sign (p < 0.001), whereas the high-resolution axial algorithm was the worst. In addition, the two CT units exhibited no significant differences in the clarity of the five-line sign (p = 0.273). Conclusions: The standard oblique algorithm was the best approach to reveal the five-line sign of normal lung fissures. Both 16-slice and 256-slice CT were effective for reconstructing the sign. PMID- 29708194 TI - A simple method for low-contrast detectability, image quality and dose optimisation with CT iterative reconstruction algorithms and model observers. AB - Background: The aim of this work was to evaluate detection of low-contrast objects and image quality in computed tomography (CT) phantom images acquired at different tube loadings (i.e. mAs) and reconstructed with different algorithms, in order to find appropriate settings to reduce the dose to the patient without any image detriment. Methods: Images of supraslice low-contrast objects of a CT phantom were acquired using different mAs values. Images were reconstructed using filtered back projection (FBP), hybrid and iterative model-based methods. Image quality parameters were evaluated in terms of modulation transfer function; noise, and uniformity using two software resources. For the definition of low contrast detectability, studies based on both human (i.e. four-alternative forced choice test) and model observers were performed across the various images. Results: Compared to FBP, image quality parameters were improved by using iterative reconstruction (IR) algorithms. In particular, IR model-based methods provided a 60% noise reduction and a 70% dose reduction, preserving image quality and low-contrast detectability for human radiological evaluation. According to the model observer, the diameters of the minimum detectable detail were around 2 mm (up to 100 mAs). Below 100 mAs, the model observer was unable to provide a result. Conclusion: IR methods improve CT protocol quality, providing a potential dose reduction while maintaining a good image detectability. Model observer can in principle be useful to assist human performance in CT low-contrast detection tasks and in dose optimisation. PMID- 29708195 TI - Can portable tomosynthesis improve the diagnostic value of bedside chest X-ray in the intensive care unit? A proof of concept study. AB - Portable bedside chest X-ray (CXR) is an important and frequently used tool in the intensive care unit (ICU). Unfortunately, the diagnostic value of portable CXR is often low due to technical limitations and suboptimal patient positioning. Additionally, abnormalities in the chest may be hidden on the projection image by overlapping anatomy and devices such as endotracheal tubes, lines and catheters. Digital tomosynthesis (DTS) can solve the problem of anatomical overlap. In DTS, several low-dose X-ray images from different angles are acquired and subsequently used by a reconstruction algorithm to compute section images along planes parallel to the detector. However, a portable device to be used for portable bedside chest DTS is not on the market yet. In this work, we discuss modifications to a portable X-ray device to enable portable DTS and illustrate the potential of portable DTS to improve the diagnostic value of bedside CXR in the ICU. A simulation, based on computed tomography scans, is presented. Our experiments comparing portable DTS with conventional bedside CXR showed a substantially improved detection of pneumothorax and other abnormalities. PMID- 29708196 TI - Choreic movement in striatal infarction: Involvement in cortico-striato-nigral disconnection. PMID- 29708198 TI - Water-enhanced antegrade MR pyelography in pregnancy: a novel radiation-free approach. AB - Our aim was to determine if water-enhanced antegrade magnetic resonance (MR) pyelography can be an alternative to conventional antegrade pyelography in pregnant patients who require percutaneous nephrostomy placement for urosepsis and/or obstructive uropathy. The pregnant patient was placed supine in a 1.5-T MRI scanner seven days after percutaneous nephrostomy placement using ultrasound. Serial axial and coronal T2-weighted echo-planar fast spin-echo sequences were performed before and after injection of the catheter. The right nephrostomy catheter hub was sterilised using chlorhexidine. Sixty millilitres of sterile water were slowly injected. No Gd-based contrast agent was utilised due to safety concerns for the foetus. MR antegrade pyelography demonstrated the level of ureteric obstruction and the absence of renal calculi using sterile water as a contrast medium injected through a percutaneous nephrostomy followed by T2 weighted imaging. Air bubbles in the injected solution were differentiated from calculi due to their mobility on serial scans and their anti-dependent position. Water-enhanced antegrade MR pyelography was a safe and effective method of imaging the pregnant patient. It served as an alternative to conventional antegrade pyelography and minimised potential risks to the foetus. PMID- 29708197 TI - Manganese-enhanced MRI for the detection of metastatic potential in colorectal cancer. AB - Background: To study manganese superoxide dismutase (MnSOD) expression, manganese enhanced magnetic resonance imaging (MEMRI) appearance and its relation to metastatic potential in colorectal cancer (CRC). Methods: CRC cells SW620, HCT116, LoVo, SW480, DLD-1, HCT15, Caco-2 and their normal counterpart CCD841 CoN were chosen, based on differential aggressiveness, to undergo Western blot analysis for assessment of MnSOD expression, reported as proportion of readings to internal reference (glyceraldehyde-3-phosphate-dehydrogenase). Based on the results of the invasion assay, HCT15, DLD-1, LoVo and SW620 cells and corresponding xenografts underwent MEMRI. The differences of average T1-value shortening were compared. Results: MnSOD expression in SW620, HCT116, LoVo, SW480, DLD-1, HCT15, Caco-2 and CCD841 CoN cells (0.255 +/- 0.018 (mean +/- standard deviation), 0.289 +/- 0.028, 0.438 +/- 0.028, 0.337 +/- 0.025, 0.777 +/- 0.031, 1.045 +/- 0.038, 0.163 +/- 0.035 and 0.185 +/- 0.038, respectively) was not correlated with Invasion Index (22.6 +/- 0.7, 17.0 +/- 0.6, 20.9 +/- 0.6, 9.7 +/- 0.4, 7.5 +/- 0.3, 8.3 +/- 0.2, 12.6 +/- 0.5 and 0) (r = - 0.204, p = 0.627). In highly aggressive cells (SW620, LoVo), T1 shortening (289.33 +/- 0.57, 268.45 +/- 6.87 ms, respectively) was greater than that in lower counterparts (148.68 +/ 3.99 ms in DLD-1, 128.60 +/- 1.96 in HCT15) (p < 0.001). Both 5- and 10-mm group SW620 and/or LoVo tumours showed greater T1 shortening (>=600 ms) than DLD-1 and HCT15 (<=350 ms) (p < 0.001, p = 0.005, p = 0.010). Conclusions: MEMRI has the potential to noninvasively distinguish different metastatic potential CRCs. However, the MnSOD expression is not correlated to malignant potential in CRC cells. PMID- 29708199 TI - Investigation into cardiac sympathetic innervation during the commencement of haemodialysis in patients with chronic kidney disease. AB - Background: Patients with chronic kidney disease (CKD) who undergo chronic haemodialysis (HD) show altered sympathetic tone, which is related to a higher cardiovascular mortality. The purpose of this study was to investigate the effect of transition from pre-HD to HD on cardiac sympathetic innervation. Methods: Eighteen patients aged 58 +/- 18 years (mean +/- standard deviation [SD]), 13 males and five females, with stage 5 CKD and nine healthy control subjects aged 52 +/- 17 (mean +/- SD), three males and six females, were included in this prospective study between May 2010 and December 2013. All patients underwent 123I labelled meta-iodobenzylguanidine (123I-MIBG) scintigraphy for cardiac sympathetic innervation and electrocardiographically gated adenosine stress and rest 99mTc-labelled tetrofosmin single-photon emission computed tomography for myocardial perfusion imaging prior to (pre-HD) and 6 months after the start of HD. Results of 123I-MIBG scans in patients were compared to controls. Impaired cardiac sympathetic innervation was defined as late heart-to-mediastinum ratio (HMR) < 2.0. Results: Mean late HMR was lower in patients during HD (2.3) than in controls (2.9) (p = 0.035); however, in patients it did not differ between pre-HD and after the start of HD. During HD, two patients showed new sympathetic innervation abnormalities, and in three patients innervation abnormalities seemed to coincide with myocardial perfusion abnormalities. Conclusions: CKD patients show cardiac sympathetic innervation abnormalities, which do not seem to progress during the maintenance HD. The relationship between sympathetic innervation abnormalities and myocardial perfusion abnormalities in HD patients needs further exploration. PMID- 29708200 TI - Breast MRI radiomics: comparison of computer- and human-extracted imaging phenotypes. AB - Background: In this study, we sought to investigate if computer-extracted magnetic resonance imaging (MRI) phenotypes of breast cancer could replicate human-extracted size and Breast Imaging-Reporting and Data System (BI-RADS) imaging phenotypes using MRI data from The Cancer Genome Atlas (TCGA) project of the National Cancer Institute. Methods: Our retrospective interpretation study involved analysis of Health Insurance Portability and Accountability Act compliant breast MRI data from The Cancer Imaging Archive, an open-source database from the TCGA project. This study was exempt from institutional review board approval at Memorial Sloan Kettering Cancer Center and the need for informed consent was waived. Ninety-one pre-operative breast MRIs with verified invasive breast cancers were analysed. Three fellowship-trained breast radiologists evaluated the index cancer in each case according to size and the BI RADS lexicon for shape, margin, and enhancement (human-extracted image phenotypes [HEIP]). Human inter-observer agreement was analysed by the intra-class correlation coefficient (ICC) for size and Krippendorff's alpha for other measurements. Quantitative MRI radiomics of computerised three-dimensional segmentations of each cancer generated computer-extracted image phenotypes (CEIP). Spearman's rank correlation coefficients were used to compare HEIP and CEIP. Results: Inter-observer agreement for HEIP varied, with the highest agreement seen for size (ICC 0.679) and shape (ICC 0.527). The computer-extracted maximum linear size replicated the human measurement with p < 10-12. CEIP of shape, specifically sphericity and irregularity, replicated HEIP with both p values < 0.001. CEIP did not demonstrate agreement with HEIP of tumour margin or internal enhancement. Conclusions: Quantitative radiomics of breast cancer may replicate human-extracted tumour size and BI-RADS imaging phenotypes, thus enabling precision medicine. PMID- 29708201 TI - Measurement of jugular foramen diameter using MRI in multiple sclerosis patients compared to control subjects. AB - Background: Multiple sclerosis (MS) is a chronic disease of the central nervous system. As an association between MS and reduced cerebral venous blood drainage was hypothesised, our aim was to compare the size of the jugular foramina in patients with MS and in control subjects. Methods: Ethics committee approval was received for this retrospective case-control study. We collected imaging and clinical data of 53 patients with MS (23 men, mean age 45 +/- 9 years) and an age/gender-matched control group of 53 patients without MS (23 men, mean age 46 +/- 10 years). The minimal diameter of both jugular foramina was measured on T1 weighted contrast-enhanced axial magnetic resonance images; the two diameters were summed. Student t test and Spearman correlation coefficient were used for analysis. Reproducibility was estimated using the Bland-Altman method. Results: The mean diameter of the right foramen in patients with MS (6.3 +/- 1.6 mm) was 10% smaller than that of the controls (7.0 +/- 1.4 mm) (p = 0.020); the mean diameter of the left foramen in patients with MS (5.6 +/- 1.3 mm) was 7% smaller than that of the controls (6.0 +/- 1.3 mm) (p = 0.089). The sum of the diameters of both jugular foramina in patients with MS (mean 11.9 +/- 2.3 mm) was 8% smaller (p = 0.009) than that of the controls (mean 13.0 +/- 2.1 mm). The differences in diameters between patients with relapsing-remitting MS and patients with secondary progressive MS were not significant (p >= 0.332). There was no significant correlation between foramen diameters and the expanded disability status scale (p >= 0.079). Intra-reader and inter-reader reproducibility were 91% and 88%, respectively. Conclusions: Jugular foramen diameter in patients with MS was 7-10% smaller than that in controls, regardless of the MS disease course. PMID- 29708202 TI - Breast DCE-MRI: lesion classification using dynamic and morphological features by means of a multiple classifier system. AB - Background: In breast magnetic resonance imaging (MRI) analysis for lesion detection and classification, radiologists agree that both morphological and dynamic features are important to differentiate benign from malignant lesions. We propose a multiple classifier system (MCS) to classify breast lesions on dynamic contrast-enhanced MRI (DCE-MRI) combining morphological features and dynamic information. Methods: The proposed MCS combines the results of two classifiers trained with dynamic and morphological features separately. Twenty-six malignant and 22 benign breast lesions, histologically proven, were analysed. The lesions were subdivided into two groups: training set (14 benign and 18 malignant) and testing set (8 benign and 8 malignant). Volumes of interest were extracted both manually and automatically. We initially considered a feature set including 54 morphological features and 98 dynamic features. These were reduced by means of a selection procedure to delete redundant parameters. The performance of each of the two classifiers and of the overall MCS was compared with pathological classification. Results: We obtained an accuracy of 91.7% on the testing set using automatic segmentation and combining the best classifier for morphological features (decision tree) and for dynamic information (Bayesian classifier). With implementation of the MCS, an increase in accuracy of 12.5% and of 31.3% was obtained compared with the accuracy of the Bayesian classifier tested with dynamic features and with that of the decision tree tested with morphological parameters, respectively. Conclusions: An MCS can optimise the accuracy for breast lesion classification combining morphological features and dynamic information. PMID- 29708203 TI - A new method for estimating patient body weight using CT dose modulation data. AB - Background: Body weight (BW) is a relevant metric in emergency care. However, visual/physical methods to estimate BW are unreliable. We have developed a method for estimating BW based on effective mAs (mAseff) from computed tomography (CT) dose modulation. Methods: The mAseff of CT examinations was correlated with the BW of 329 decedents. Linear regression analysis was used to calculate an equation for BW estimation based on the results of decedents with a postmortem interval (PMI) < 4 days (n = 240). The equation was applied to a validation group of 125 decedents. Pearson correlation and t-test statistics were used. Results: We found an overall strong correlation between mAseff and BW (r = 0.931); r values ranged from 0.854 for decedents with PMI >= 4 days to 0.966 for those with PMI < 4 days; among the latter group, r was 0.974 for females and 0.960 for males and 0.969 in the presence and 0.966 in the absence of metallic implants (all correlations with p values < 0.001). The estimated BW was equal to 3.732 + (0.422 * mAseff) - (3.108 * sex index), where the sex index is 0 for males and 1 for females. The validation group showed a strong correlation (r = 0.969) between measured BW and the predicted BW, without significant differences overall (p = 0.119) as well as in female (p = 0.394) and in male decedents (p = 0.196). No outliers were observed. Conclusions: CT dose modulation is a rapid and reliable method for BW estimation with potential use in clinical practice, in particular in emergency settings. PMID- 29708204 TI - Through the HoloLensTM looking glass: augmented reality for extremity reconstruction surgery using 3D vascular models with perforating vessels. AB - Precision and planning are key to reconstructive surgery. Augmented reality (AR) can bring the information within preoperative computed tomography angiography (CTA) imaging to life, allowing the surgeon to 'see through' the patient's skin and appreciate the underlying anatomy without making a single incision. This work has demonstrated that AR can assist the accurate identification, dissection and execution of vascular pedunculated flaps during reconstructive surgery. Separate volumes of osseous, vascular, skin, soft tissue structures and relevant vascular perforators were delineated from preoperative CTA scans to generate three dimensional images using two complementary segmentation software packages. These were converted to polygonal models and rendered by means of a custom application within the HoloLensTM stereo head-mounted display. Intraoperatively, the models were registered manually to their respective subjects by the operating surgeon using a combination of tracked hand gestures and voice commands; AR was used to aid navigation and accurate dissection. Identification of the subsurface location of vascular perforators through AR overlay was compared to the positions obtained by audible Doppler ultrasound. Through a preliminary HoloLens-assisted case series, the operating surgeon was able to demonstrate precise and efficient localisation of perforating vessels. PMID- 29708205 TI - Simultaneous dual-contrast multi-phase liver imaging using spectral photon counting computed tomography: a proof-of-concept study. AB - Background: To assess the feasibility of dual-contrast spectral photon-counting computed tomography (SPCCT) for liver imaging. Methods: We present an SPCCT in silico study for simultaneous mapping of the complementary distribution in the liver of two contrast agents (CAs) subsequently intravenously injected: a gadolinium-based contrast agent and an iodine-based contrast agent. Four types of simulated liver lesions with a characteristic arterial and portal venous pattern (haemangioma, hepatocellular carcinoma, cyst, and metastasis) are presented. A material decomposition was performed to reconstruct quantitative iodine and gadolinium maps. Finally, a multi-dimensional classification algorithm for automatic lesion detection is presented. Results: Our simulations showed that with a single-scan SPCCT and an adapted contrast injection protocol, it was possible to reconstruct contrast-enhanced images of the liver with arterial distribution of the iodine-based CA and portal venous phase of the gadolinium based CA. The characteristic patterns of contrast enhancement were visible in all liver lesions. The approach allowed for an automatic detection and classification of liver lesions using a multi-dimensional analysis. Conclusions: Dual-contrast SPCCT should be able to visualise the characteristic arterial and portal venous enhancement with a single scan, allowing for an automatic lesion detection and characterisation, with a reduced radiation exposure. PMID- 29708206 TI - Average absorbed breast dose in mammography: a new possible dose index matching the requirements of the European Directive 2013/59/EURATOM. AB - Background: The new European Directive 2013/59/EURATOM requires that patients are informed about the risk associated with ionising radiation and that detailed information on patient exposure is included in the radiological report. This implies a revision of the routinely used dose indexes to obtain quantities related to individual exposure evaluable from acquisition parameters. Here we propose a new mammography dose index consistent with the average glandular dose (AGD). Methods: An equation has been developed for calculating the average absorbed breast dose (2ABD). It depends on incident air kerma ka,i and on energy absorption coefficient MUen; ka,i can be calculated for each anode-filter combination, based on kVp, mAs, the yield of the tube used Ytb , and the breast thickness d; MUen depends on kVp and has been evaluated for each anode-filter combination. 2ABD has been compared to AGD evaluated by Dance or Wu methods, which represent the reference standards, for 20 patients of our university hospital. Results: The incident air kerma ka,i , calculated as a function of kVp, mAs, Ytb and d, was in good agreement with the same quantity directly measured: the relative uncertainty is < 0.10. The results of the comparison between 2ABD and AGD evaluated by both Dance and Wu methods appear to be consistent within the uncertainties. Conclusions: 2ABD is easily evaluable for each mammogram from the acquisition parameters. It can be proposed as a new suitable dose index, consistent with AGD, matching the requirements of the 2013 European Directive. PMID- 29708207 TI - SSRI-associated bruxism: A systematic review of published case reports. AB - Purpose of review: Antidepressant-associated movement disorders are a well described phenomenon. However, antidepressant-associated bruxism, jaw pain, or jaw spasm, while reported in dental literature, is less commonly recognized among neurologists. We summarize the clinical features and treatment of antidepressant associated bruxism and associated jaw pain through a systematic review of case reports. Recent findings: Antidepressant-associated bruxism may occur in pediatric and adult patients, most commonly among female patients. Patients may develop symptoms with short-term and long-term antidepressant use. Fluoxetine, sertraline, and venlafaxine were the most commonly reported offending agents. Symptoms may begin within 3-4 weeks of medication initiation and may resolve within 3-4 weeks of drug discontinuation, addition of buspirone, or substitution with another pharmacologic agent. The incidence of this phenomenon is unknown. Summary: Bruxism associated with antidepressant use is an underrecognized phenomenon among neurologists, and may be treated with the addition of buspirone, dose modification, or medication discontinuation. PMID- 29708209 TI - Magnetisation transfer as a biomarker for chronic airway fibrosis in a mouse lung transplantation model. AB - Background: Chronic airway fibrosis (CAF) is the most prevalent complication in human lung transplant recipients. The aim of the study is to evaluate magnetisation transfer (MT) as a biomarker of developing CAF of lung transplants in a mouse model. Methods: Lung transplantation was performed in 48 mice, applying major or minor histocompatibility mismatches between strains for the induction of CAF. MT measurements were performed in vivo with systematic variation of off-resonance frequencies and flip angle of the MT prepulse. MT ratios (MTRs) were compared for lungs showing CAF and without CAF. Results: Seven out of 24 animals (29%) showed a pattern of CAF at histology. All mice developing CAF also showed signs of acute rejection, whereas none of the lungs showed signs of other post-transplant complications. After lung transplantation, pulmonary infiltration was a frequent finding (14 out of 24) exhibiting a higher MTR (24.8% +/- 4.5%) compared to well-ventilated lungs (12.3% +/- 6.9%, p = 0.001) at 8000 Hz off-resonance frequency, 3000 degrees flip angle. In infiltrated lung tissue exhibiting CAF, lower MTR values (21.8% +/- 5.7%) were found compared to infiltrated lungs showing signs of acute rejection alone (26.5% +/- 2.9%, p = 0.028), at 8000 Hz, 3000 degrees flip angle. The highest MTR values were observed at 3000 degrees flip angle, using a 1000 Hz off-resonance frequency. Conclusion: MTR might serve as a tool for the detection of CAF in infiltrated lung tissue. PMID- 29708208 TI - Apathy and functional disability in behavioral variant frontotemporal dementia. AB - Background: Behavioral variant frontotemporal dementia (bvFTD) has profound consequences on patients and their families. In this multicenter study, we investigated the contribution of cognitive and neuropsychiatric factors to everyday function at different levels of overall functional impairment. Methods: In a retrospective cross-sectional study, 109 patients with bvFTD from 4 specialist frontotemporal dementia centers (Australia, England, India, and Brazil) were included. The measures administered evaluated everyday function (Disability Assessment for Dementia [DAD]), dementia staging (Clinical Dementia Rating [CDR]), general cognition (Addenbrooke's Cognitive Examination-revised [ACE-R]), and neuropsychiatric symptoms (Neuropsychiatric Inventory [NPI]). Patients were then subdivided according to functional impairment on the DAD into mild, moderate, severe, and very severe subgroups. Three separate multiple linear regression analyses were run, where (1) total DAD, (2) basic activities of daily living (BADL), and (3) instrumental activities of daily living (IADL) scores were dependent variables; ACE-R total score and selected NPI domains (agitation/aggression, euphoria, apathy, disinhibition, irritability, aberrant motor behavior) were used as independent variables. Age, sex, education, and country of origin were controlled for in the analyses. Results: Cognitive deficits were similar across the mild, moderate, and severe subgroups but significantly worse in the very severe subgroup. NPI domain scores (agitation/aggression, euphoria, apathy, disinhibition, irritability, aberrant motor behavior) did not differ across the DAD subgroups. In the multiple regression analyses, a model including ACE-R and NPI apathy explained 32.5% of the variance for total DAD scores. For IADL, 35.6% of the variance was explained by the ACE-R only. No model emerged for BADL scores. Conclusions: Cognitive deficits and apathy are key contributors to functional disability in bvFTD but factors underlying impairment in BADLs remain unclear. Treatments targeting reduction of disability need to address apathy and cognitive impairment to ensure greater efficacy, especially in regards to IADLs. PMID- 29708210 TI - Optical imaging of the breast: evaluation of deoxyhemoglobin concentration alteration in 166 patients with suspicious breast lesions. AB - Background: We investigated the performance of optical imaging evaluating deoxyhemoglobin concentration alteration (DeHCA) in breast tissues. Methods: We enrolled all consecutive patients from January 2015 to October 2016 with clinically suspicious and/or BI-RADS grade 3-5 lesions at mammography or ultrasound (US). Patients underwent optical imaging (ComfortScan) to evaluate for DeHCA. The reference standard was pathology from a surgical specimen for malignant lesions, pathology from a surgical specimen or core needle biopsy for benign lesions, and negative follow-up for contralateral negative breasts. Non parametric statistics, receiver operating characteristic, and linear discrimination analyses were performed. Results: Of 334 enrolled patients, 168 (50%) were excluded for technical problems and 166 (50%) (median age 52 years) were analyzed totaling 331 breasts and 176 lesions. Of these, 75 were benign (median size 19 mm) and 101 malignant (median size 20 mm). The median DeHCA score in malignant lesions (0.95, interquartile range [IQR] 1.00-0.87) was higher (p < 0.001) than in benign lesions (0.80, IQR 0.95-0.70). Using the optimal cutoff (0.85), DeHCA score was less accurate than mammography, US, and their combination, with 78% sensitivity, 52% specificity, 40% positive predictive value (PPV), and 85% negative predictive value (NPV); using a 0.8 cutoff, sensitivity reached 93% and NPV 91%, but specificity fell to 32% and PPV to 37%. The accuracy of DeHCA score linearly combined with mammography or US was higher than that of DeHCA score alone (p < 0.001) and not significantly higher than that of mammography or US alone. Conclusions: DeHCA score was significantly higher in malignant than in benign lesions, but its accuracy was significantly lower than that of mammography or US. Future refinements are needed. PMID- 29708211 TI - Postsurgical cortical myoclonus responsive to perampanel. PMID- 29708212 TI - Myocardial tissue characterization by combining late gadolinium enhancement imaging and percent edema mapping: a novel T2 map-based MRI method in canine myocardial infarction. AB - Background: Assessing the extent of ischemic and reperfusion-associated myocardial injuries remains challenging with current magnetic resonance imaging (MRI) techniques. Our aim was to develop a tissue characterization mapping (TCM) technique by combining late gadolinium enhancement (LGE) with our novel percent edema mapping (PEM) approach to enable the classification of tissue represented by MRI voxels as healthy, myocardial edema (ME), necrosis, myocardial hemorrhage (MH), or scar. Methods: Six dogs underwent closed-chest myocardial infarct (MI) generation. Serial MRI scans were performed post-MI on days 3, 4, 6, 14, and 56, including T2 mapping and LGE. Dogs were sacrificed on day 4 (n = 4, acute MI) or day 56 (n = 2, chronic MI). TCMs were generated based on a voxel classification algorithm taking into account signal intensity from LGE and T2-based estimation of ME. TCM-based MI and MH were validated with post mortem triphenyl tetrazolium chloride (TTC) staining. Pearson's correlation and Bland-Altman analyses were performed. Results: The MI, ME, and MH measured by TCM were 13.4% [25th-75th percentile 1.6-28.8], 28.1% [2.1-37.5] and 4.3% [1.0-11.3], respectively. TCM measured higher MH and MI compared to TTC (p = 0.0033 and p = 0.0007, respectively). MH size was linearly correlated with MI size by both MRI (r = 0.9528, p < 0.0001) and TTC (r = 0.9625, p < 0.0001). MH quantification demonstrated good agreement between TCM and TTC (r = 0.8766, p < 0.0001, 2.4% overestimation by TCM). A similar correlation was observed for MI size (r = 0.9429, p < 0.0001, 6.1% overestimation by TCM). Conclusions: Preliminary results suggest that the TCM method is feasible for the in vivo localization and quantification of various MI-related tissue components. PMID- 29708214 TI - Achieving high value care for all and the perverse incentives of 340B price agreements. AB - Section 340B of the Public Health Service Act requires drug manufacturers to enter into price agreements with the Department of Health and Human Services. These agreements result in variation in the price paid to acquire a drug by sector, which complicates the price used in cost-effectiveness analyses. We describe the transactions and sectors in a 340B agreement using a multiple sclerosis drug. Cost-effectiveness estimates were calculated for the drug using drug prices from the manufacturer and payer perspective. We found the amount paid to the manufacturer (340B price) was a good value ($118,256 per quality-adjusted life-year); however, from the payer drug cost perspective, good value ($196,683 per quality-adjusted life-year) was not achieved. Given that emerging value frameworks incorporate cost-effectiveness, these price variations may have downstream negative consequences, including inaccurate coverage and reimbursement policy recommendations. Upcoming policy changes to the 340B program should incentivize pricing schemes hinged on transparency and value. PMID- 29708213 TI - Photoacoustic imaging of tumour vascular permeability with indocyanine green in a mouse model. AB - Background: We analysed the haemodynamics of indocyanine green (ICG) in mouse organs and tumours and evaluated responses to anti-angiogenic agents in an allograft tumour mouse model by photoacoustic imaging. Methods: Thirty-six male mice (aged 10-14 weeks; body weight 20-25 g) were used. Real-time photoacoustic imaging of organs and tumours after intravenous injection of ICG was conducted in mice until 10 min after ICG injection. ICG distribution in tumour tissues was assessed by immunohistochemical staining and observation of ICG-derived fluorescence. Vascular permeability changes induced by the vascular endothelial growth factor (VEGF)-blocking agent VEGF-trap on tumour photoacoustic signals were studied. Results: The photoacoustic signals in salivary glands and tumours after intravenous injection of iCG (0.604 +/- 0.011 and 0.994 +/- 0.175 [mean +/- standard deviation], respectively) were significantly increased compared with those in the liver, kidney, and great vessel (0.234 +/- 0.043, 0.204 +/- 0.058 and 0.127 +/- 0.040, respectively; p < 0.010). In tumours, the photoacoustic signal increased within 30 s after ICG injection in a dose-dependent manner (r2 = 0.899) and then decreased gradually. ICG was found to extravasate in tumour tissues. In VEGF-trap-treated mice, the photoacoustic signal in the tumour decreased at the early phase before inhibition of tumour growth was detected (0.297 +/- 0.052 vs 1.011 +/- 0.170 in the control; p < 0.001). Conclusions: Photoacoustic imaging with ICG administration demonstrated extravasation of ICG in mouse organs and tumours, indicating the potential for early detection of changes in vascular permeability during cancer therapy. PMID- 29708216 TI - Carotid ergotism with retinal ischemia. PMID- 29708215 TI - Simultaneous wood and metal particle detection on dark-field radiography. AB - Background: Currently, the detection of retained wood is a frequent but challenging task in emergency care. The purpose of this study is to demonstrate improved foreign-body detection with the novel approach of preclinical X-ray dark field radiography. Methods: At a preclinical dark-field x-ray radiography, setup resolution and sensitivity for simultaneous detection of wooden and metallic particles have been evaluated in a phantom study. A clinical setting has been simulated with a formalin fixated human hand where different typical foreign-body materials have been inserted. Signal-to-noise ratios (SNR) have been determined for all test objects. Results: On the phantom, the SNR value for wood in the dark field channel was strongly improved by a factor 6 compared to conventional radiography and even compared to the SNR of an aluminium structure of the same size in conventional radiography. Splinters of wood < 300 MUm in diameter were clearly detected on the dark-field radiography. Dark-field radiography of the formalin-fixated human hand showed a clear signal for wooden particles that could not be identified on conventional radiography. Conclusions: x-ray dark-field radiography enables the simultaneous detection of wooden and metallic particles in the extremities. It has the potential to improve and simplify the current state-of-the-art foreign-body detection. PMID- 29708217 TI - Multiple sclerosis management and reproductive changes: A guide for general neurologists. AB - Purpose of review: Multiple sclerosis (MS) disease activity and symptoms are tied to hormonal changes. This review explains the current standard of care in MS at various stages of a woman's reproductive life and helps neurologists answer patients' most common questions surrounding MS care and fertility, pregnancy, and menopause. Recent findings: Recent work has focused on MS risk and exacerbation with variables related to reproductive health. Management of disease-modifying therapies prenatally and postnatally is also a focus. Summary: This review is a concise, practical guide for general neurologists caring for women with MS. MS is a disease that requires adaptation of management as a woman moves through reproductive stages. With proper planning and management, pregnancy is safe for women with MS. We describe the current standard of care based on trials, when available, and on expert opinion. PMID- 29708219 TI - [Bioethics and environmental justice in the health of the Andean residents of Peru]. AB - This article attempts to capture the bioethical-environmental panorama of the health in the residents who live on the Peruvian highlands, highlighting the inequity in access to health services that exist in this region and reflecting on the possible historical and current contextual causes that have originated differences between Inca-Andean settler and modern-Andean settler. The change in the view of the world about the environment and natural resources, the decline of justice approach, loss of solidarity, welfare, and respect to human being and nature. Besides, we describe health from a historical scenario of this region, where Public health has and will have as a challenge the application of programs that respond to the specific needs of this population, with a focus on the environment. PMID- 29708218 TI - Stroke code simulation benefits advanced practice providers similar to neurology residents. AB - Background: Advanced practice providers (APPs) are important members of stroke teams. Stroke code simulations offer valuable experience in the evaluation and treatment of stroke patients without compromising patient care. We hypothesized that simulation training would increase APP confidence, comfort level, and preparedness in leading a stroke code similar to neurology residents. Methods: This is a prospective quasi-experimental, pretest/posttest study. Nine APPs and 9 neurology residents participated in 3 standardized simulated cases to determine need for IV thrombolysis, thrombectomy, and blood pressure management for intracerebral hemorrhage. Emergency medicine physicians and neurologists were preceptors. APPs and residents completed a survey before and after the simulation. Generalized mixed modeling assuming a binomial distribution was used to evaluate change. Results: On a 5-point Likert scale (1 = strongly disagree and 5 = strongly agree), confidence in leading a stroke code increased from 2.4 to 4.2 (p < 0.05) among APPs. APPs reported improved comfort level in rapidly assessing a stroke patient for thrombolytics (3.1-4.2; p < 0.05), making the decision to give thrombolytics (2.8 vs 4.2; p < 0.05), and assessing a patient for embolectomy (2.4-4.0; p < 0.05). There was no difference in the improvement observed in all the survey questions as compared to neurology residents. Conclusion: Simulation training is a beneficial part of medical education for APPs and should be considered in addition to traditional didactics and clinical training. Further research is needed to determine whether simulation education of APPs results in improved treatment times and outcomes of acute stroke patients. PMID- 29708220 TI - Topological Network Analysis of Electroencephalographic Power Maps. AB - Meditation practice as a non-pharmacological intervention to provide health related benefits has generated much neuroscientific interest in its effects on brain activity. Electroencephalogram (EEG), an imaging modality known for its inexpensive procedure and excellent temporal resolution, is often utilized to investigate the neuroplastic effects of meditation under various experimental conditions. In these studies, EEG signals are routinely mapped on a topographic layout of channels to visualize variations in spectral powers within certain frequency ranges. Topological data analysis (TDA) of the topographic power maps modeled as graphs can provide different insight to EEG signals than standard statistical methods. A highly effective TDA technique is persistent homology, which reveals topological characteristics of a power map by tracking feature changes throughout a filtration process on the graph structure of the map. In this paper, we propose a novel inference procedure based on filtrations induced by sublevel sets of the power maps of high-density EEG signals. We apply the pipeline to simulated and real data, where we compare the persistent homological features of topographic maps of spectral powers in high-frequency bands of EEG signals recorded on long-term meditators and meditation-naive practitioners. PMID- 29708221 TI - Relationships between full-day arm movement characteristics and developmental status in infants with typical development as they learn to reach: An observational study. AB - Background: Advances in wearable sensor technology now allow us to quantify the number, type and kinematic characteristics of bouts of infant arm movement made across a full day in the natural environment. Our aim here was to determine whether the amount and kinematic characteristics of arm movements made across the day in the natural environment were related to developmental status in infants with typical development as they learned to reach for objects using their arms. Methods: We used wearable sensors to measure arm movement across days and months as infants developed arm reaching skills. In total, 22 infants with typical development participated, aged between 38 and 203 days. Of the participants, 2 infants were measured once and the other 20 infants were measured once per month for 3 to 6 visits. The Bayley Scales of Infant Development was used to measure developmental level. Results: Our main findings were: 1) infant arm movement characteristics as measured by full-day wearable sensor data were related to Bayley motor, cognitive and language scores, indicating a relationship between daily movement characteristics and developmental status; 2) infants who moved more had larger increases in language and cognitive scores across visits; and 3) larger changes in movement characteristics across visits were related to higher motor scores. Conclusions: This was a preliminary, exploratory, small study of the potential importance of infant arm movement characteristics as measured by full-day wearable sensor data. Our results support full-day arm movement activity as an area of interest for future study as a biomarker of neurodevelopmental status and as a target for early intervention. PMID- 29708222 TI - When multiple sclerosis and X-linked adrenoleukodystrophy are tangled: A challenging case. PMID- 29708223 TI - Using light microscopy for diagnosing the cause of a case of acute stroke. PMID- 29708224 TI - Neurologic provider views on patient-reported outcomes including depression screening. AB - Background: We sought to assess neurologic provider satisfaction with the systematic electronic collection of patient-reported outcome measures (PROMs) for both disease-specific measures and depression screening (Patient Health Questionnaire [PHQ-9]). Methods: A web-based survey was sent to 299 staff physicians and advanced practice providers on the staff email list of a large group neurologic practice, of whom 206 used the PROM system. The survey consisted of 11 questions with Likert response options regarding perceived usefulness of PROM collection; usefulness of PROM data for clinical care, quality, and research activities according to provider age group and type; and perceived usefulness between disease-specific information and the PHQ-9 depression screen. Results: Of those who use the PROM system, 73.3% (151/206) responded. PROM collection was useful for patient care (strongly agree or agree 59.6%), research (strongly agree or agree 68.5%), and to a lesser extent, quality improvement (strongly agree or agree 48.6%). Providers aged 66-75 years believed PROM data were less useful for research (p < 0.01). PROM collection affected patient interactions or clinical management (always or usually 34.6% for disease-specific information and 31.3% for the PHQ-9). Responses were similar concerning perceived clinical usefulness (strongly agree or agree 67.3%) for center-selected disease-specific PROMs and the mandated PHQ-9 (69.8%). Conclusions: Providers favorably viewed systematic electronic collection of PROMs in neurologic patients. A mandated depression screening was perceived as favorably as center-selected disease-specific information and should be considered when implementing PROMs in neurologic practice. PMID- 29708226 TI - Partners in enhancing functional ability and well-being. PMID- 29708225 TI - Effectiveness of alternative dose fingolimod for multiple sclerosis. AB - Background: Fingolimod is a daily oral medication used to treat relapsing multiple sclerosis (MS). Clinicians often adopt less frequent dosing for patients with profound drug-induced lymphopenia or other adverse events. Data on the effectiveness of alternate dose fingolimod are limited. Methods: We conducted a multicenter, retrospective, observational study at 14 sites and identified 170 patients with MS taking alternate doses of fingolimod for >=1 month. Clinical and radiologic outcomes were collected and compared during daily and alternate fingolimod dosing. Results: Profound lymphopenia (77%), liver function abnormalities (9%), and infections (7%) were the most common reasons for patients to switch to alternate fingolimod dosing. The median follow-up was 12 months on daily dose and 14 months on alternate dose. Most patients (64%) took fingolimod every other day during alternate dosing. Disease activity was similar on alternate dose compared to daily dose: annualized relapse rate was 0.1 on daily dose vs 0.2 on alternate dose (p = 0.25); proportion of patients with contrast enhancing MRI lesions was 7.6% on daily vs 9.4% on alternate (p = 0.55); proportion of patients with cumulative MS activity (clinical and radiologic disease) was 13.5% on daily vs 18.2% on alternate (p = 0.337). Patients who developed contrast-enhancing lesions while on daily dose were at higher risk for breakthrough disease while on alternate dose fingolimod (odds ratio 11.4, p < 0.001). Conclusions: These data support the clinical strategy of alternate dosing of fingolimod in patients with good disease control but profound lymphopenia or other adverse events while on daily dose. Classification of Evidence: This study provides Class IV evidence that for patients with MS on daily dose fingolimod with adverse events, alternate dose fingolimod is associated with disease activity similar to daily dose fingolimod. PMID- 29708227 TI - Midbrain meningioma causing subacute parkinsonism. PMID- 29708228 TI - Erratum. AB - [This corrects the article DOI: 10.22037/iej.v13i1.18507.]. PMID- 29708229 TI - The 340B benefit program: Why we should care about both its intentions and outcomes. PMID- 29708230 TI - Correction: Atlas for the OMERACT thumb base osteoarthritis MRI scoring system (TOMS--). AB - [This corrects the article DOI: 10.1136/rmdopen-2017-000583.][This corrects the article DOI: 10.1136/rmdopen-2017-000583.]. PMID- 29708231 TI - Sickle cell disease, fat embolism syndrome, and "starfield" pattern on MRI. PMID- 29708232 TI - CHANGES IN RESTING SALIVARY TESTOSTERONE, CORTISOL AND INTERLEUKIN-6 AS BIOMARKERS OF OVERTRAINING. AB - Background: Overtraining (OVT) is a concern for many athletes. Immunological (increased interleukin-6 [IL-6]) and hormonal (increased cortisol [C], decreased free testosterone [fT]) biomarkers have been analyzed during training to detect OVT development. Methods: This study determined if resting levels of salivary IL 6, T, and C change during a pre-season resistance training (RT) program in 20 Division I American football players (mean +/- SD: age = 19.1 +/- 1.1 years; height = 185.4 +/- 6.7 cm; mass = 102.0 +/- 22.2 kg; body fat = 14.7 +/- 7.6%). 1RM squat, bench press and Olympic-style clean, IL-6, C and T were assessed at baseline (WK1), week 4 (WK4), week 6 (WK6) along with psychological status (PS) to determine affective state. Results: 1RM (bench press: 121.6 +/- 36.3 kg vs. 127.4 +/- 35.9 kg, squat: 187.2 +/- 30.2 kg, 190.9 +/- 28.1 kg, clean: 116.8 +/- 14.6 kg, vs. 119.2 +/- 14.5 kg), IL-6 (1.42 +/- 1.77 pg/mL vs. 5.60 +/- 12.57 pg/mL) and C (2.57 +/- 2.46 nmol/L vs. 5.33 +/- 4.94) increased signihcantly from WK1 to WK6 (p < .05), fT decreased signihcantly (417.44 +/- 83.63 pmol/Lvs. 341.10 +/- 87.79 pmol/L) from WK1 to WK6 (p < .05). PS was minimally affected during the study. Signihcant biomarker changes were detected, but no OVT was induced (i.e. performance improved). Conclusion: Therefore, directional changes in these biomarkers may not be sufficiently reflective of OVT in RT programs. PMID- 29708233 TI - Bioanalytical method development and validation of HPLCUV assay for the quantification of SHetA2 in mouse and human plasma: Application to pharmacokinetics study. AB - Background: SHetA2 is an oral anticancer agent being investigated for cancer treatment and prevention. The aim of this study was to develop and validate a simple, cost-effective, and sensitive HPLC-UV method for the quantification of SHetA2 in biological samples and to apply the method to pharmacokinetic studies of the drug. Methods: Sample preparation for mouse and human plasmas involved liquid-liquid precipitation and extraction using chilled acetonitrile with 2, 3 Diphenylquinoxaline as an internal standard. The separation of SHetA2 and internal standard was achieved via Waters XBridgeTM BEH 130 C18 (3.5 MUm, 2.1*150 mm) column coupled with a Waters XBridgeTM C-18 (3.5 MUm, 2.1*10 mm) guard column using 65% v/v acetonitrile: distilled water as a mobile phase in an isocratic mode with a flow rate of 0.18 ml/min. The analytes were eluted at a detection wavelength of 341 nm at a column temperature of 25 degrees C. Results: The method was validated across a range of 5-1000 ng/ml for SHetA2 in plasma, with a lower limit of quantification of 5 ng/ml. The method showed high recovery in human (79.9-81.8%) and mouse (95.4-109.2%) plasma with no matrix effect. The intra- and inter-day accuracy and precision studies demonstrated that the method was specific, sensitive, and reliable. Stability studies showed that SHetA2 is stable for 20 h postoperatively in the auto sampler, and for six weeks at -80 degrees C in plasma. Repetitive freezing and thawing may be avoided by preparing the aliquots and storing them at -80 degrees C. The developed method was successfully applied to study the plasma pharmacokinetics of SHetA2 in tumor-bearing nude mice after intravenous and oral administration. Conclusion: A novel method for quantifying SHetA2 in mouse and human plasmas has been validated and is being applied for pharmacokinetic evaluation of SHetA2 in tumor-bearing mice. The developed method will be utilized for the quantification of SHetA2 in clinical studies. PMID- 29708234 TI - [Rare diseases: laying out some challenges]. PMID- 29708236 TI - PREDICTING ADOLESCENTS' QUALITY OF LIFE USING DISCRIMINAT ANALYSIS. AB - Psychosocial functioning and depression is associated with a wide range of impacts on adolescents' quality of life. In Nigeria, studies assessing the importance of psychosocial functioning and depression in distinguishing between the categories of quality of life and classifying adolescents into these categories have been limited in literature. This study investigated the domains of psychosocial functioning and child depression that significantly distinguish between the categories of quality of life and also classify into these groups. Data for 2019 adolescents aged 10-19 were obtained in a Benue State cross sectional study. Preliminary analyses on their socio-demographic information were performed using descriptive statistics. Differences between categories (groups) of Quality of Life (low, moderate and excellent) on the basis of the attributes of the adolescents in terms of their psychosocial functioning and depression status , indicating which attributes contribute most to group separation were investigated using discriminant analysis. Chi-square analysis was used to assess the association between socio-demographic characteristics of the adolescents and levels of Quality of Life. The inter-relationships between the domains of Quality of Life and the adolescents age, position in the family, domains of psychosocial functioning and child depression status was assessed using correlation analysis. Prosocial behaviour (F=82.41, p<0.001) and ineffectiveness (F=31.19, p<0.001) were strong significant discriminating variables that predict adolescents' levels of total quality of life. Adolescent's psychosocial functioning and depression status relates with their physical health, psychological health, social relationship, environmental health and total quality of life. PMID- 29708235 TI - Cutaneous Leishmaniasis: Update on Vaccine Development. AB - Leishmaniasis is an important disease mediated by the protozoan parasite Leishmania via the bite of the female sandfly insect vector. Leishmaniasis is endemic in the tropical and subtropical regions. The most common form of the disease is cutaneous leishmaniasis, which affects more than 10 million people worldwide and includes at least 1.5 million new cases every year. So far, treatment of the disease relies on unsatisfactory chemotherapy that can be complicated by the rising appearance of drug-resistant parasites. Furthermore, it is challenging to achieve solid control of the insect vector and animal reservoir. Therefore, the development of a safe and effective vaccine is urgently needed for the treatment and prevention of leishmaniasis. This review focuses on the recent advances in the development of a safe vaccine that could be used for prevention and treatment of cutaneous leishmaniasis. A short outlook for future research efforts is also presented. PMID- 29708237 TI - Correction to: A Randomized Controlled Trial of a Mini Low-Carbohydrate Diet and an Energy-Controlled Diet Among Japanese Patients With Type 2 Diabetes. AB - [This corrects the article DOI: 10.14740/jocmr3281w.]. PMID- 29708238 TI - Quantitative analysis of multiple high-resolution mass spectrometry images using chemometric methods: quantitation of chlordecone in mouse liver. AB - In this work, a chemometrics-based strategy is developed for quantitative mass spectrometry imaging (MSI). In this regard, quantification of chlordecone as a carcinogenic organochlorinated pesticide (C10Cll0O) in mouse liver using the matrix-assisted laser desorption ionization MSI (MALDI-MSI) method is used as a case study. The MSI datasets corresponded to 1, 5 and 10 days of mouse exposure to the standard chlordecone in the quantity range of 0 to 450 MUg g-1. The binning approach in the m/z direction is used to group high resolution m/z values and to reduce the big data size. To consider the effect of bin size on the quality of results, three different bin sizes of 0.25, 0.5 and 1.0 were chosen. Afterwards, three-way MSI data arrays (two spatial and one m/z dimensions) for seven standards and four unknown samples were column-wise augmented with m/z values as the common mode. Then, these datasets were analyzed using multivariate curve resolution-alternating least squares (MCR-ALS) using proper constraints. The resolved mass spectra were used for identification of chlordecone in the presence of a complex background and interference. Additionally, the augmented spatial profiles were post-processed and 2D images for each component were obtained in calibration and unknown samples. The sum of these profiles was utilized to set the calibration curve and to obtain the analytical figures of merit (AFOMs). Inspection of the results showed that the lower bin size (i.e., 0.25) provides more accurate results. Finally, the obtained results by MCR for three datasets were compared with those of gas chromatography-mass spectrometry (GC-MS) and MALDI-MSI. The results showed that the MCR-assisted method gives a higher amount of chlordecone than MALDI-MSI and a lower amount than GC-MS. It is concluded that a combination of chemometric methods with MSI can be considered as an alternative way for MSI quantification. PMID- 29708239 TI - Gold-doped silver nanoclusters with enhanced photophysical properties. AB - We detail the characterization of atomically precise, luminescent silver and gold bimetallic nanoclusters (Ag and AgAuNCs) grown in the presence of bidentate lipoic acid (LA, the oxidized form) and dihydrolipoic acid (DHLA, the reduced form) ligands. We found that while doping AuNCs with Ag or Cu precursors using up to a 50% molar fraction (during growth) did not lead to any photoluminescence enhancement, doping of AgNCs with Au resulted in a six-fold enhancement of the PL emission compared to undoped AgNCs. The effect of doping is also reflected in the optical absorption and PL excitation spectra of the gold-doped NCs (AgAuNCs), where a clear blue shift in the absorbance features with respect to the pure AgNCs has been measured. Mass spectrometry measurements using ESI-MS showed that the AgNCs and Au-doped AgNCs had the compositions Ag29(DHLA)12 and Ag28Au(DHLA)12, respectively. The bimetallic nature of the AgAuNC cores was further supported by X-ray Photoelectron Spectroscopy (XPS) measurements. Data showed that the binding energies of the Ag and Au atoms measured from the nanoclusters were shifted with respect to those of the Ag and Au metals. Furthermore, the change in the Ag binding energy was affected by the presence of Au atoms. DOSY-NMR measurements performed on both sets of nanoclusters yielded no change in the hydrodynamic radius measured for either set of NCs when capped with the same ligands. PMID- 29708240 TI - A facile graphene oxide-based fluorescent nanosensor for the in situ "turn-on" detection of telomerase activity. AB - A facile and sensitive method for the quantitative detection of telomerase and in situ imaging of intracellular telomerase is developed by using a graphene oxide (GO)-based fluorescent nanosensor. The nanosensor consists of a fluorescent DNA (P1) adsorbed on the GO surface. Here, GO serves not only as a fluorescence quencher but also as a carrier to successfully transport P1 into cancer cells as a signal reporter. P1 is a dye-labeled single-stranded DNA complementary to the telomeric repeated sequence, and initially the combination of P1 and GO exhibits minimal background fluorescence. When telomerase extends its repeat units of TTAGGG on the 3'-end of the primer-DNA, the fluorescence of P1 is subsequently recovered because the telomeric repeated sequence can hybridize with P1 and liberate it from the GO surface. This method enables the determination of telomerase activity down to 10 cells. For the in situ detection of telomerase, upon endocytosis of the P1/GO combinatorial probe into living cancer cells, the intracellular telomerase extends its primer to produce the telomeric repeated sequence and then turns on the fluorescence of P1, which can be directly monitored by confocal laser scanning microscopy. The feasibility of the assay is further investigated by treating with telomerase-related drugs, and the results demonstrate its potential in antitumor drug screening and cancer therapy evaluation. PMID- 29708241 TI - Photoinduced proton transfer inside an engineered green fluorescent protein: a stepwise-concerted-hybrid reaction. AB - Photoactivated proton transfer (PT) wire is responsible for the glow of green fluorescent protein (GFP), which is crucial for bioimaging and biomedicine. In this work, a new GFP-S65T/S205V double mutant is developed from wild-type GFP in which the PT wire is significantly modified. We implement femtosecond transient absorption (fs-TA) and femtosecond stimulated Raman spectroscopy (FSRS) to delineate the PT process in action. The excited state proton transfer proceeds on the ~110 ps timescale, which infers that the distance of one key link (water to T203) in the PT wire of GFP-S205V is shortened by the extra S65T mutation. The rise of an imidazolinone ring deformation mode at ~871 cm-1 in FSRS further suggests that this PT reaction is in a concerted manner. A ~4 ps component prior to large-scale proton dissociation through the PT wire is also retrieved, indicative of some small-scale proton motions and heavy-atom rearrangement in the vicinity of the chromophore. Our work provides deep insights into the novel hybrid PT mechanism in engineered GFP and demonstrates the power of tunable FSRS methodology in tracking ultrafast photoreactions with the desirable structural specificity in physiological environments. PMID- 29708242 TI - Co-delivery of timolol and hyaluronic acid from semi-circular ring-implanted contact lenses for the treatment of glaucoma: in vitro and in vivo evaluation. AB - Glaucoma is a chronic disease, which is currently treated using frequent high dose applications of an eye drop solution; this method is tedious, and most of patients are non-compliant to it. Contact lenses are emerging as a convenient option to sustain the release of ophthalmic drugs. However, the incorporation of a drug/formulation changes the optical and physical properties of contact lenses. Contact lens users have also reported pink eye syndrome; this makes contact lenses unsuitable to be accepted as a medical device. The objective of the present study was to design novel timolol and hyaluronic acid (comfort agent) loaded semi-circular ring-implanted contact lenses that could uphold the release at therapeutic rates without compromising the critical lens properties. The drug loaded rings were individually implanted within the periphery of the contact lenses using modified cast-moulding technology. Atomic force microscopy showed an average roughness of 12.38 nm for the implanted lens that was significantly lower as compared to that of the Freshlook contact lenses (116.27 nm). A major amount of timolol was leached (from 46.47 to 58.79%) during the monomer extraction and moist sterilization (autoclave) steps; therefore, the lenses were sterilized by radiation and packaged under dry conditions (dehydrated). The in vitro release data showed sustained release of timolol and hyaluronic acid up to 96 h. The in vivo drug release study on rabbit eyes showed the presence of timolol in tear fluid up to 72 h. The in vivo pharmacodynamics studies showed a reduction in IOP till 144 h with a low drug loading (154 MUg) as compared to the case of a single instillation eye drop solution (250 MUg). This study has demonstrated the successful application of implantation technology to co-deliver timolol and hyaluronic acid from contact lenses for an extended period of time to treat glaucoma. PMID- 29708243 TI - In situ preparation of MgCo2O4 nanosheets on Ni-foam as a binder-free electrode for high performance hybrid supercapacitors. AB - A binder-free, MgCo2O4 nanosheet-like architecture was prepared on Ni-foam using a hydrothermal method. MgCo2O4/Ni-foam was characterized by X-ray diffraction, field emission scanning electron microscopy (FESEM), and transmission electron microscopy techniques. The FESEM image revealed a nanosheet array-like architecture. The MgCo2O4 nanosheets grown on Ni-foam exhibited the maximum specific capacity of 947 C g-1 at a specific current of 2 A g-1. Approximately 96% of the specific capacity was retained from the maximum specific capacity after 5000 continuous charge-discharge cycles. This hybrid device exhibited a maximum specific capacity of 52 C g-1 at a specific current of 0.5 A g-1, and also exhibited a maximum specific energy of 12.99 W h kg-1 at a specific power of 448.7 W kg-1. These results confirmed that the binder-free MgCo2O4 nanosheets grown on Ni-foam are a suitable positive electrode material for hybrid supercapacitors. PMID- 29708244 TI - Optimal control of orientation and entanglement for two dipole-dipole coupled quantum planar rotors. AB - Optimal control simulations are performed for orientation and entanglement of two dipole-dipole coupled identical quantum rotors. The rotors at various fixed separations lie on a model non-interacting plane with an applied control field. It is shown that optimal control of orientation or entanglement represents two contrasting control scenarios. In particular, the maximally oriented state (MOS) of the two rotors has a zero entanglement entropy and is readily attainable at all rotor separations. Whereas, the contrasting maximally entangled state (MES) has a zero orientation expectation value and is most conveniently attainable at small separations where the dipole-dipole coupling is strong. It is demonstrated that the peak orientation expectation value attained by the MOS at large separations exhibits a long time revival pattern due to the small energy splittings arising form the extremely weak dipole-dipole coupling between the degenerate product states of the two free rotors. Moreover, it is found that the peak entanglement entropy value attained by the MES remains largely unchanged as the two rotors are transported to large separations after turning off the control field. Finally, optimal control simulations of transition dynamics between the MOS and the MES reveal the intricate interplay between orientation and entanglement. PMID- 29708245 TI - Highly stable protein immobilization via maleimido-thiol chemistry to monitor enzymatic activity. AB - Immobilizing enzymes for biocatalysis offers many advantages, including easy separation of the enzyme from the product and repeated and continuous use. ATR FTIR spectroscopy is a versatile tool to monitor immobilized enzymes and has been applied to many proteins. However, while the common and convenient immobilization via oligohistidine on mono-NTA layers is adequate for the measurement of difference spectra induced by ligand binding or photochemistry, it lacks the long term stability that is necessary for monitoring biocatalysis. Here, we report a new immobilization methodology based on maleimido-thiol chemistry. A 12 mercaptododecanoic acid NHS ester monolayer is reacted with 1-(2-aminoethyl) maleimide to build a thiol reactive surface. Subsequently, NTA-C16-thiol is covalently attached and finally oligohistidine tagged enzymes were immobilized to this surface, which remained bound with a five times higher EC50-value compared to typical mono-NTA layers. To demonstrate the high potential of the surface we analysed decarboxylation reactions catalyzed by arylmalonate decarboxylase. With ATR-FTIR both the enzyme and its substrate conversion can be monitored label free. Correct folding of the enzyme can be evaluated based on the amide band of the immobilized enzyme. In addition, the infrared absorption spectra of educt and product are monitored in real time. We show that hybrid hard-soft multivariate curve resolution improves separation of the product and educt spectra from other effects during the experiments, leading to clean kinetic traces and reaction rates for the catalytic process. Our approach can in principle be extended to any enzyme and is ideally suited for the development of biocatalysts. PMID- 29708246 TI - Development of non-orthogonal 3D-printed scaffolds to enhance their osteogenic performance. AB - Three-dimensional (3D)-printed polycaprolactone (PCL)-based scaffolds have been extensively proposed for Tissue Engineering (TE) applications. Currently, the majority of the scaffolds produced are not representative of the complex arrangement of natural structures, since the internal morphologies follow an orthogonal and regular pattern. In order to produce scaffolds that more closely replicate the structure of the extracellular matrix (ECM) of tissues, herein both circular and sinusoidal scaffolds were fabricated and compared to their conventional orthogonal counterparts. This is an innovative, versatile and efficient strategy to 3D print PCL scaffolds with unique curved geometries. The morphology and the mechanical behavior of the scaffolds were assessed. The biological response was analyzed by evaluating the cell seeding efficiency, cell adhesion, proliferation, and osteogenic activity of an osteoblastic-like cell line seeded in these scaffolds. The scaffolds were designed and produced to have a similar porosity of about 56%. The non-orthogonal structures demonstrated lead to higher values of Young's modulus, both under dry conditions and when immersed in PBS. Moreover, the biological data corroborate that non-orthogonal scaffolds influence the cellular responses in a positive manner, namely in the osteogenic activity when compared with the orthogonal controls. These results suggest that introducing less orthogonal elements, which better mimic the tissue ECM and architecture, may have a positive influence on the cellular behavior, being a potential strategy to address bone tissue engineering applications. PMID- 29708247 TI - New Ni4Na2-phenylgermsesquioxane architecture: synthesis, structure and slow dynamic behaviour. AB - The first Ni(ii)-based metallagermaniumsesquioxane cage compound [(PhGeO1.5)10(NiO)4(NaO0.5)2] presents a sandwich-like structure where two germsesquioxane cages are linked through an {NiO}4 core and exhibits slow dynamics of the magnetization. PMID- 29708248 TI - Iodine-catalyzed oxidative annulation of 3-cyanoacetylindoles with benzylamines: facile access to 5-(3-indolyl)oxazoles. AB - An iodine-catalyzed oxidative annulation of 3-cyanoacetylindoles with benzylamines has been developed. This reaction enables the convenient synthesis of a variety of 5-(3-indolyl)oxazoles under mild conditions with broad functional group compatibility. PMID- 29708249 TI - Interrogation of biosynthetic pathways of the cruciferous phytoalexins nasturlexins with isotopically labelled compounds. AB - The discovery of the first non-indolyl cruciferous phytoalexins nasturlexins A and B together with cyclonasturlexin and brassinin, all chemical defenses of watercress plants (Nasturtium officinale R. Br.), revealed the co-occurrence of two parallel defense pathways, the tryptophan (Trp) pathway and the phenylalanine (Phe) pathway in crucifers. Similar to watercress, winter cress (Barbarea vulgaris R. Br.) and upland cress [B. verna (P. Mill.) Aschers] produce Phe derived phytoalexins, the nasturlexins C and D together with their counterpart sulfoxides. A detailed chemical understanding of the biosynthetic pathways of these phytoalexins facilitates their metabolic engineering. To this end, the biosynthetic pathways of cyclonasturlexin, nasturlexins A-D and corresponding sulfoxides in cress plants were investigated using isotopically labelled compounds. Except for the carbon atom of the thiomethyl groups of nasturlexins, the origin of all carbon atoms and nitrogen of nasturlexins was established to be homophenylalanine. A detailed map of the biosynthetic intermediates between phenylethyl isothiocyanates and nasturlexins A-D and sulfoxides in upland cress, winter cress and watercress is proposed. An application beyond these findings could lead to "designer crops" containing a wider range of chemical defenses that could make such crops more resistant to pests and diseases, a greatly advantageous trait. PMID- 29708250 TI - Spectroelectrochemical study of the AMP-Ag+ and ATP-Ag+ complexes using silver mesh electrodes. AB - In this study, electrochemical reaction mechanism of adenosine monophosphate (AMP) and adenosine triphosphate (ATP) on a silver mesh was investigated in acetate buffer using spectroelectrochemical technique. The results indicate that AMP (or ATP) can form a complex with silver ion originating from a silver mesh when a positive potential was applied. In these complexes, silver ion coordinates with AMP or ATP via their phosphate group. However, when a negative potential was applied, the formed complex disappeared. The complex reaction is therefore an electrochemically reversible process. Further studies using surface-enhancement Raman spectroscopy (SERS) have shown that AMP (or ATP) has a parallel or perpendicular orientation to the silver mesh surface, which is governed by their different binding sites (adenine ring, ribose, and phosphate groups). Herein, the adenine nucleotide-silver mesh surface complexes have displayed a promising biosensing capacity. PMID- 29708251 TI - Facile Cu(ii)-mediated conjugation of thioesters and thioacids to peptides and proteins under mild conditions. AB - The bioconjugation of peptide derivatives such as polypeptides, peptide-based probes and proteins is a vibrant area in many scientific fields. However, reports on metal-mediated chemical methods towards native peptides especially non engineering protein modification under mild conditions are still limited. Herein, we describe a novel Cu(ii)-mediated strategy for the conjugation of thioesters/thioacids to peptides under mild conditions with high functional group tolerance. Based on this strategy, polypeptides, even peptide-based fluorescent probes, can be efficiently constructed. Finally, the selective modification of lysine residues of native Ub with thioesters could be realized and complete conjugation of Ub could be achieved even under equivalent Cu(ii). These promising results could greatly expand Cu(ii)-mediated reaction strategies on chemical biology and molecular imaging. PMID- 29708252 TI - DNA aptamers from whole-cell SELEX as new diagnostic agents against glioblastoma multiforme cells. AB - Glioma is a cancer derived from transformed glial cells, which are often invasive and display a heterogeneous cell population. Currently, no trustworthy biomarkers for the detection and risk stratification of glioma have been discovered. The objective of the present research was to select DNA aptamers to facilitate early diagnosis and effective therapy of glioma. Using cell-SELEX, three aptamers (WYZ 37, WYZ-41, WYZ-50), which can specifically recognize the molecular differences between target cells T98G and negative cells SVGp12, were identified. The best binding sequences WYZ-41 and WYZ-50 were optimized in length, resulting in aptamer sequences WYZ-41a and WYZ-50a. The Kd values of the aptamers WYZ-41a and WYZ-50a against the target cell line were found to be 1.0 +/- 0.2 nM and 2.8 +/- 0.6 nM, respectively, which are better than the Kds for full-length aptamers WYZ 41 and WYZ-50. Flow cytometry analysis results show that the aptamers WYZ-41a and WYZ-50a do not influence each other in mutual binding, and that they effectively detect the target even in complex mixtures, such as undiluted fetal bovine serum (FBS) and cerebral spinal fluid (CSF), indicating that aptamers WYZ-41a and WYZ 50a have excellent potential as aptamer pairs to improve the accuracy of glioma diagnosis. PMID- 29708253 TI - 808 nm-triggered optical thermometry based on up-conversion luminescence of Nd3+/Yb3+/Er3+ doped MIn2O4 (M = Ca, Sr and Ba) phosphors. AB - Optical thermometry based on up-conversion (UC) fluorescent intensity ratio (FIR) with 808 nm excitation is preferable in water-rich environments, and investigation of the ambiguous intrinsic influencing factors on host-dependent sensitivity is a prerequisite for the development of highly sensitive thermometry. Herein, MIn2O4:Nd3+/Yb3+/Er3+ (M = Ca, Sr, and Ba) microcrystals with low phonon energy are synthesized via a sol-gel method. Intense UC luminescence with tunable emission color from green to red is obtained by controlling the Yb3+ content, and the UC mechanisms and successive energy transfer of Nd3+ -> Yb3+ -> Er3+ are elaborated using lifetime measurements. The thermal sensing properties of the samples based on the thermally coupled levels (4S3/2/2H11/2) of Er3+ are assessed, and their sensitivities increase gradually with an increase in temperature and reach the maximum of about 0.0048, 0.0033 and 0.0058 K-1 at 490 K for M = Ca, Sr, and Ba, respectively. By analysing the host structure, site symmetry of M2+ ions and characteristics of the M-O bonds, it is proposed that the higher Ca-O bond covalency in CaIn2O4 leads to better sensitivity than SrIn2O4 with the same structure, and the optimal sensitivity in BaIn2O4 is mainly attributed to the specific local crystal field of the Ba2+ site with higher ligancy and longer chemical bonds. These results provide insight for the selection of appropriate matrix materials to achieve higher temperature detection sensitivity. PMID- 29708254 TI - Regulating the emission of tetraphenylethenes by changing the alkoxyl linkage length between two neighboring phenyl moieties. AB - Alkoxyl linkages with different carbon lengths are employed to link the two neighboring ortho carbons of the two phenyl moieties at the same ethylene carbon of the tetraphenylethene framework, resulting in successful regulation of the molecular conformation and in turn the emission properties. PMID- 29708255 TI - A cyano-bridged Cu(i)-based organic framework coupled with the C-C bond cleavage of acetonitrile for selective and sensitive sensing of Fe3+ ions. AB - A cyano-bridged Cu(i) organic framework based on [Cu6(CN)6]n was synthesized, in which cyano anions were generated in situ from the C-C bond cleavage of acetonitrile. The as-synthesized compound displays orange-red luminescence and is further proven to be a promising Fe3+ luminescent sensor with high selectivity and sensitivity. PMID- 29708256 TI - A novel approach to sesquiterpenoid benzoxazole synthesis from marine sponges: nakijinols A, B and E-G. AB - Nakijinols A, B and analogues E through G, which are structurally unique and biologically significant sesquiterpenoid benzoxazoles, can be efficiently obtained in a highly unified manner from the sesquiterpenoid quinone, smenospongine. The starting material is accessible from the (+)-5-methyl Wieland Miescher ketone. The synthetic method features strategic construction of the requisite dihydroxylated benzoxazole substructure via the ring closure of the N (2-hydroxyphenyl)-formamide or -acetamide moiety. The synthesis of nakijinols is reported here for the first time. The absolute configurations of nakijinols A and E were also established. PMID- 29708257 TI - Consecutive Lossen rearrangement/transamidation reaction of hydroxamic acids under catalyst- and additive-free conditions. AB - The Lossen rearrangement is a classic process for transforming activated hydroxamic acids into isocyanate under basic or thermal conditions. In the current report we disclosed a consecutive Lossen rearrangement/transamidation reaction in which unactivated hydroxamic acids were converted into N-substituted formamides in a one-pot manner under catalyst- and additive-free conditions. One feature of this novel transformation is that the formamide plays triple roles in the reaction by acting as a readily available solvent, a promoter for additive free Lossen rearrangement, and a source of the formyl group in the final products. Acyl groups other than formyl could also be introduced into the product when changing the solvent to other low molecular weight aliphatic amide derivatives. The solvent-promoted Lossen rearrangement was better understood by DFT calculations, and the intermediacy of isocyanate and amine was supported well by experiments, in which the desired products were obtained in excellent yields under similar conditions. Not only monosubstituted formamides were synthesized from hydroxamic acids, but also N,N-disubstituted formamides were obtained when secondary amines were used as precursors. PMID- 29708258 TI - Ultrathin tellurium dioxide: emerging direct bandgap semiconductor with high mobility transport anisotropy. AB - An effectively large bandgap and a high carrier mobility of two dimensional (2D) crystals are crucial in emerging materials for nanoelectronics. A previously unexplored two-dimensional material, monolayer TeO2, is proposed to have high stability, a wide direct gap and high carrier mobility, based on first-principles calculations. Our results show that 2D TeO2 is both thermally and dynamically stable. In addition, it is easily exfoliated from its bulk counterpart, a natural layered mineral tellurite. Importantly, 2D TeO2 always exhibits a direct bandgap when thinning from bulk (3.32 eV) to monolayer (3.70 eV), an energy range not covered by previously reported 2D materials. Furthermore, monolayer TeO2 is exceptional in high transport anisotropy, possessing not only high electron mobility (of the order of 1000 cm2 V-1 s-1) but also exceptionally high hole mobility (up to 9100 cm2 V-1 s-1). All these findings make 2D TeO2 a promising candidate for both power electronics and short-wavelength optoelectronic applications. PMID- 29708259 TI - Roll-to-roll fabrication of integrated PDMS-paper microfluidics for nucleic acid amplification. AB - Microfluidic-based integrated molecular diagnostic systems, which are automated, sensitive, specific, user-friendly, robust, rapid, easy-to-use, and portable, can revolutionize future medicine. Current research and development largely relies on polydimethylsiloxane (PDMS) to fabricate microfluidic devices. Since the transition from the proof-of-principle phase to clinical studies requires a vast number of integrated microfluidic devices, there is a need for a high-volume manufacturing method of silicone-based microfluidics. Here we present the first roll-to-roll (R2R) thermal imprinting method to fabricate integrated PDMS-paper microfluidics for molecular diagnostics, which allows production of tens of thousands of replicates in an hour. In order to validate the replicated molecular diagnostic platforms, on-chip amplification of viral ribonucleic acid (RNA) with loop-mediated isothermal amplification (LAMP) was demonstrated. These low-cost, rapid and accurate molecular diagnostic platforms will generate a wide range of applications in preventive personalized medicine, global healthcare, agriculture, food, environment, water monitoring, and global biosecurity. PMID- 29708260 TI - Unraveling aminophosphine redox mechanisms for glovebox-free InP quantum dot syntheses. AB - The synthesis of colloidal indium phosphide quantum dots (InP QDs) has always been plagued by difficulties arising from limited P3- sources. Being effectively restricted to the highly pyrophoric tris(trimethylsilyl) phosphine (TMS3P) creates complications for the average chemist and presents a significant risk for industrially scaled reactions. The adaptation of tris(dialkylamino) phosphines for these syntheses has garnered attention, as these new phosphines are much safer and can generate nanoparticles with competitive photoluminescence properties to those from (TMS)3P routes. Until now, the reaction mechanics of this precursor were elusive due to many experimental optimizations, such as the inclusion of a high concentration of zinc salts, being atypical of previous InP syntheses. Herein, we utilize density functional theory calculations to outline a logical reaction mechanism. The aminophosphine precursor is found to require activation by a zinc halide before undergoing a disproportionation reaction to self-reduce this P(iii) material to a P(-iii) source. We use this understanding to adapt this precursor for a two-pot nanoparticle synthesis in a noncoordinating solvent outside of glovebox conditions. This allowed us to generate spherical InP/ZnS nanoparticles possessing fluorescence quantum yields >55% and lifetimes as fast as 48 ns, with tunable emission according to varying zinc halide acidity. The development of high quality and efficient InP QDs with this safer aminophosphine in simple Schlenk environments will enable a broader range of researchers to synthesize these nontoxic materials for a variety of high-value applications. PMID- 29708261 TI - A cancer specific oxaliplatin-releasing Pt(iv)-prodrug. AB - We prepared a Pt(iv)-prodrug, which under cancer specific conditions (elevated concentration of reactive oxygen species, ROS) releases a DNA-binding drug oxaliplatin as well as ROS-amplifying drugs p-quinone methide and N alkylferrocenium. Due to the concerted action of these components, an excellent anticancer effect was achieved: IC50 = 0.4 +/- 0.1 MUM for human ovarian carcinoma A2780 cells. Importantly, the prodrug was found to be 45-fold less toxic to normal cells (HDFa). PMID- 29708262 TI - Bipolar magnetic semiconductors among intermediate states during the conversion from Sc2C(OH)2 to Sc2CO2 MXene. AB - MXenes represent a new family of two-dimensional materials that have attracted considerable attention in recent years. Because of the remarkably different structures of Sc2C(OH)2 and Sc2CO2 MXene and their recently reported properties, this study explored the structural evolution and mechanism of chemical conversion between these two MXenes. Using first-principles density functional theory (DFT), the mechanism for dehydrogenation/hydrogenation is investigated by gradually removing/adding surface hydrogen atoms for Sc2C(OH)2/Sc2CO2 supercells. Employing three different supercells (2 * 2 * 1, 3 * 3 * 1 and 4 * 4 * 1), intermediate states Sc2C(OH)xO2-x with varying hydrogen content x (0.0625<=x <= 1.94) are obtained. The results show that the trend is to minimize the difference in the number of hydrogen atoms and the distance between them on the two sides of the monolayer. This feature is found to be generally applicable to other functional groups of MXenes during surface conversion. Analysis of these structures shows that all the oxygen, carbon and scandium atoms remain in essentially the same locations as in Sc2C(OH)2 until atoms rearrange in the carbon layer at sufficiently low x. Regarding the electronic properties, the behavior of the rearranged configurations is found to depend on the structure, moving beyond the conventional model of p-type doping induced by dehydrogenation. Bipolar magnetic semiconductors (BMSs) are identified from these rearranged configurations by the inhomogeneous distribution of hydrogen atoms on the different sides and x values approximately in the range of 0.188 <= x <= 0.812. Findings from this study suggest that the intrinsic spin-polarized semiconducting characteristics of Sc2C(OH)xO2-x are expected to be experimentally observable if samples are prepared as nanoscale flakes. The current results indicate that Sc-based MXene may be a promising material for nanoscale spintronic devices. PMID- 29708263 TI - Parameters and functional analysis of the deep epaxial muscles in the thoracic, lumbar and sacral regions of the equine spine. AB - The epaxial muscles produce intervertebral rotation in the transverse, vertical and axial axes. These muscles also counteract the movements induced by gravitational and inertial forces and movements produced by antagonistic muscles and the intrinsic muscles of the pelvic limb. Their fascicles are innervated by the dorsal branch of the spinal nerve, which corresponds to the metamere of its cranial insertion in the spinous process. The structure allows the function of the muscles to be predicted: those with long and parallel fibres have a shortening function, whereas the muscles with short and oblique fibres have an antigravity action. In the horse, the multifidus muscle of the thoracolumbar region extends in multiple segments of two to eight vertebral motion segments (VMS). Functionally, the multifidus muscle is considered a spine stabiliser, maintaining VMS neutrality during spine rotations. However, there is evidence of the structural and functional heterogeneity of the equine thoracolumbar multifidus muscle, depending on the VMS considered, related to the complex control of the required neuromuscular activity. Osteoarticular lesions of the spine have been directly related to asymmetries of the multifidus muscle. The lateral (LDSM) and medial (MDSM) dorsal sacrocaudal muscles may be included in the multifidus complex, the function of which is also unclear in the lumbosacral region. The functional parameters of maximum force (Fmax ), maximum velocity of contraction (Vmax ) and joint moment (M) of the multifidus muscles inserted in the 4th, 9th, 12th and 17th thoracic and 3rd and 4th lumbar vertebrae of six horses were studied postmortem (for example: 4MT4 indicates the multifidus muscle that crosses four metameres with cranial insertion in the T4 vertebra). Furthermore, the structural and functional characteristics of LDSM and MDSM were determined. Data were analysed by analysis of variance (anova) in a randomised complete block design (P <= 0.05). For some muscles, the ordering of Vmax values was almost opposite to that of Fmax values, generally indicating antigravity or dynamic functions, depending on the muscle and VMS. The muscles 3MT12, 3ML3 and 4ML4 exhibited high Fmax and low Vmax values, indicating a stabilising action. The very long 7MT4 and 8MT4 multifidus had low Fmax and high Vmax values, suggesting a shortening action. However, some functional characteristics of interest did not fall within these general observations, also indicating a dual action. In summary, the results of the analysis of various structural and functional parameters confirm the structural and functional heterogeneity of the equine thoracolumbar multifidus complex, depending on the VMS, regardless of the number of metameres crossing each fascicle. To clarify the functions of the equine multifidus muscle complex, this study aimed to assess its functional parameters in thoracolumbar VMSs with different movement characteristics and in the MDSM and LDSM muscles, hypothesising that the functional parameters vary significantly when the VMS is considered. PMID- 29708264 TI - Psychological need frustration as a transdiagnostic process in associations of self-critical perfectionism with depressive symptoms and eating pathology. AB - OBJECTIVE: The identification of transdiagnostic risk factors and processes that explain the comorbidity between depressive symptoms and eating disorder symptoms is critical. We examined the mediating role of the frustration of adolescents' psychological needs for autonomy, competence, and relatedness in the association between self-critical perfectionism, depressive symptoms and eating disorder symptoms. METHOD: A cross-sectional study (N = 248; 58% female, mean age = 14 years) and a two-wave longitudinal study (N = 608; 59% female; mean age = 16 years) were conducted. RESULTS: At the level of inter-individual differences and intra-individual change, self-critical perfectionism was a robust predictor of both symptoms. After introducing need frustration as an underlying mechanism, the relation between self-critical perfectionism and the two types of symptoms, as well as the relation between the symptoms themselves, decreased. CONCLUSIONS: Need frustration represents a transdiagnostic vulnerability process that helps to explain why self-critical perfectionism relates to depressive symptoms and eating disorder symptoms. PMID- 29708265 TI - Interventions for preventing occupational irritant hand dermatitis. AB - BACKGROUND: Occupational irritant hand dermatitis (OIHD) causes significant functional impairment, disruption of work, and discomfort in the working population. Different preventive measures such as protective gloves, barrier creams and moisturisers can be used, but it is not clear how effective these are. This is an update of a Cochrane review which was previously published in 2010. OBJECTIVES: To assess the effects of primary preventive interventions and strategies (physical and behavioural) for preventing OIHD in healthy people (who have no hand dermatitis) who work in occupations where the skin is at risk of damage due to contact with water, detergents, chemicals or other irritants, or from wearing gloves. SEARCH METHODS: We updated our searches of the following databases to January 2018: the Cochrane Skin Specialised Register, CENTRAL, MEDLlNE, and Embase. We also searched five trials registers and checked the bibliographies of included studies for further references to relevant trials. We handsearched two sets of conference proceedings. SELECTION CRITERIA: We included parallel and cross-over randomised controlled trials (RCTs) which examined the effectiveness of barrier creams, moisturisers, gloves, or educational interventions compared to no intervention for the primary prevention of OIHD under field conditions. DATA COLLECTION AND ANALYSIS: We used the standard methodological procedures expected by Cochrane. The primary outcomes were signs and symptoms of OIHD developed during the trials, and the frequency of treatment discontinuation due to adverse effects. MAIN RESULTS: We included nine RCTs involving 2888 participants without occupational irritant hand dermatitis (OIHD) at baseline. Six studies, including 1533 participants, investigated the effects of barrier creams, moisturisers, or both. Three studies, including 1355 participants, assessed the effectiveness of skin protection education on the prevention of OIHD. No studies were eligible that investigated the effects of protective gloves. Among each type of intervention, there was heterogeneity concerning the criteria for assessing signs and symptoms of OIHD, the products, and the occupations. Selection bias, performance bias, and reporting bias were generally unclear across all studies. The risk of detection bias was low in five studies and high in one study. The risk of other biases was low in four studies and high in two studies.The eligible trials involved a variety of participants, including: metal workers exposed to cutting fluids, dye and print factory workers, gut cleaners in swine slaughterhouses, cleaners and kitchen workers, nurse apprentices, hospital employees handling irritants, and hairdressing apprentices. All studies were undertaken at the respective work places. Study duration ranged from four weeks to three years. The participants' ages ranged from 16 to 67 years.Meta-analyses for barrier creams, moisturisers, a combination of both barrier creams and moisturisers, or skin protection education showed imprecise effects favouring the intervention. Twenty-nine per cent of participants who applied barrier creams developed signs of OIHD, compared to 33% of the controls, so the risk may be slightly reduced with this measure (risk ratio (RR) 0.87, 95% confidence interval (CI) 0.72 to 1.06; 999 participants; 4 studies; low-quality evidence). However, this risk reduction may not be clinically important. There may be a clinically important protective effect with the use of moisturisers: in the intervention groups, 13% of participants developed symptoms of OIHD compared to 19% of the controls (RR 0.71, 95% CI 0.46 to 1.09; 507 participants; 3 studies; low-quality evidence). Likewise, there may be a clinically important protective effect from using a combination of barrier creams and moisturisers: 8% of participants in the intervention group developed signs of OIHD, compared to 13% of the controls (RR 0.68, 95% CI 0.33 to 1.42; 474 participants; 2 studies; low-quality evidence). We are uncertain whether skin protection education reduces the risk of developing signs of OIHD (RR 0.76, 95% CI 0.54 to 1.08; 1355 participants; 3 studies; very low-quality evidence). Twenty one per cent of participants who received skin protection education developed signs of OIHD, compared to 28% of the controls.None of the studies addressed the frequency of treatment discontinuation due to adverse effects of the products directly. However, in three studies of barrier creams, the reasons for withdrawal from the studies were unrelated to adverse effects. Likewise, in one study of moisturisers plus barrier creams, and in one study of skin protection education, reasons for dropout were unrelated to adverse effects. The remaining studies (one to two in each comparison) reported dropouts without stating how many of them may have been due to adverse reactions to the interventions. We judged the quality of this evidence as moderate, due to the indirectness of the results. The investigated interventions to prevent OIHD probably cause few or no serious adverse effects. AUTHORS' CONCLUSIONS: Moisturisers used alone or in combination with barrier creams may result in a clinically important protective effect, either in the long- or short-term, for the primary prevention of OIHD. Barrier creams alone may have slight protective effect, but this does not appear to be clinically important. The results for all of these comparisons were imprecise, and the low quality of the evidence means that our confidence in the effect estimates is limited. For skin protection education, the results varied substantially across the trials, the effect was imprecise, and the pooled risk reduction was not large enough to be clinically important. The very low quality of the evidence means that we are unsure as to whether skin protection education reduces the risk of developing OIHD. The interventions probably cause few or no serious adverse effects.We conclude that at present there is insufficient evidence to confidently assess the effectiveness of interventions used in the primary prevention of OIHD. This does not necessarily mean that current measures are ineffective. Even though the update of this review included larger studies of reasonable quality, there is still a need for trials which apply standardised measures for the detection of OIHD in order to determine the effectiveness of the different prevention strategies. PMID- 29708266 TI - Nerves and blood vessels in degenerated intervertebral discs are confined to physically disrupted tissue. AB - Nerves and blood vessels are found in the peripheral annulus and endplates of healthy adult intervertebral discs. Degenerative changes can allow these vessels to grow inwards and become associated with discogenic pain, but it is not yet clear how far, and why, they grow in. Previously we have shown that physical disruption of the disc matrix, which is a defining feature of disc degeneration, creates free surfaces which lose proteoglycans and water, and so become physically and chemically conducive to cell migration. We now hypothesise that blood vessels and nerves in degenerated discs are confined to such disrupted tissue. Whole lumbar discs were obtained from 40 patients (aged 37-75 years) undergoing surgery for disc herniation, disc degeneration with spondylolisthesis or adolescent scoliosis ('non-degenerated' controls). Thin (5-MUm) sections were stained with H&E and toluidine blue for semi-quantitative assessment of blood vessels, fissures and proteoglycan loss. Ten thick (30-MUm) frozen sections from each disc were immunostained for CD31 (an endothelial cell marker), PGP 9.5 and Substance P (general and nociceptive nerve markers, respectively) and examined by confocal microscopy. Volocity image analysis software was used to calculate the cross-sectional area of each labelled structure, and its distance from the nearest free surface (disc periphery or internal fissure). Results showed that nerves and blood vessels were confined to proteoglycan-depleted regions of disrupted annulus. The maximum distance of any blood vessel or nerve from the nearest free surface was 888 and 247 MUm, respectively. Blood vessels were greater in number, grew deeper, and occupied more area than nerves. The density of labelled blood vessels and nerves increased significantly with Pfirrmann grade of disc degeneration and with local proteoglycan loss. Analysing multiple thick sections with fluorescent markers on a confocal microscope allows reliable detection of thin filamentous structures, even within a dense matrix. We conclude that, in degenerated and herniated discs, blood vessels and nerves are confined to proteoglycan-depleted regions of disrupted tissue, especially within annulus fissures. PMID- 29708267 TI - Preventative and restorative safety behaviors: Effects on exposure treatment outcomes and risk for future anxious symptoms. AB - OBJECTIVES: Two studies investigated the differential effect of preventative and restorative safety behaviors on the treatment and development of anxiety and depression. METHOD: Study 1 investigated the impact of preventative and restorative safety behaviors in prolonged exposure therapy among US veterans with PTSD (N = 95). Study 2 was a 3-month prospective study investigating preventative and restorative safety behaviors as risk factors for anxious and depressive symptoms in a non-clinical sample (N = 84). RESULTS: The results of Study 1 showed that both preventative and restorative safety behaviors were associated with worse treatment outcomes (both PTSD symptoms and depressive symptoms). The results of Study 2 found that preventative, but not restorative, safety behaviors predicted increases in future anxious symptoms. Neither preventative nor restorative safety behaviors conferred risk for increases in future depression symptoms (anhedonia). CONCLUSIONS: Preventative and restorative safety behaviors impact PTSD treatment outcomes, while only preventative safety behaviors predict future anxiety. PMID- 29708268 TI - Ultrasonography in Undergraduate Medical Education: A Systematic Review. AB - OBJECTIVES: The purpose of this study was to conduct a systematic review of the evidence of educational outcomes associated with teaching ultrasonography (US) to medical students. METHODS: A review of databases through 2016 was conducted for research studies that reported data on teaching US to medical students. Each title and abstract were reviewed by teams of 2 independent abstractors to determine whether the article would be ordered for full-text review and subsequently by 2 independent authors for inclusion. Data were abstracted with a form developed a priori by the authors. RESULTS: Ninety-five relevant unique articles were included (of 6936 identified in the databases). Survey data showed that students enjoyed the US courses and desired more US training. Of the studies that assessed US-related knowledge and skill, most of the results were either positive (16 of 25 for knowledge and 24 of 58 for skill) or lacked a control (8 of 25 for knowledge and 27 of 58 for skill). The limited evidence (14 of 95 studies) of the effect of US training on non-US knowledge and skill (eg, anatomy knowledge or physical examination skill) was mixed. CONCLUSIONS: There is ample evidence that students can learn US knowledge and skills and that they enjoy and want US training in medical school. The evidence for the effect of US on external outcomes is limited, and there is insufficient evidence to recommend it for this purpose at this time. PMID- 29708269 TI - Use of permanent pacemaker systems as temporary pacemakers. PMID- 29708270 TI - Acute Acalculous Cholecystitis in Hospitalized Patients With Hematologic Malignancies and Prognostic Importance of Gallbladder Ultrasound Findings. AB - OBJECTIVES: Patients with hematologic malignancies, especially those with acute disease or those receiving intense chemotherapy, are known to develop acute acalculous cholecystitis (AAC). The aim of this study was to evaluate the diagnostic and prognostic value of the established ultrasound (US) diagnostic criteria for AAC in patients with acute hematologic malignancies who were clinically suspected to have AAC. METHODS: We retrospectively studied the US findings of the gallbladder in patients with hematologic malignancies and correlated these findings with the duration of clinical symptoms, complications, and gallbladder-specific mortality. The major criteria were a 3.5-mm or thicker wall, pericholecystic fluid, intramural gas, and a sloughed mucosal membrane. The minor criteria were echogenic bile and hydrops (gallbladder distension > 4 cm). Ultrasound findings were considered positive if they included 2 major criteria or 1 major and 2 minor criteria. RESULTS: Ninety-four (25.5%) of 368 patients with hematologic malignancies had clinical signs of AAC during their acute phase of illness or during intense chemotherapy. Forty-three (45.7%) of these 94 patients had AAC-positive test results based on US criteria. The mean duration of symptoms was significantly longer (7.8 days) in this group than among the patients with negative test results (3.9 days; P < .001). Patients with positive test results had a higher rate of complications or mortality (20.9%) than those with negative test results (0%; P < .001). CONCLUSIONS: Symptomatic patients who meet the US criteria for the diagnosis of AAC have a poor prognosis. Other patients require a close follow-up US examination within 1 week to detect early progression. PMID- 29708271 TI - Reciprocal loop of hypoxia-inducible factor-1alpha (HIF-1alpha) and metastasis associated protein 2 (MTA2) contributes to the progression of pancreatic carcinoma by suppressing E-cadherin transcription. AB - Metastasis-associated protein 2 (MTA2) is overexpressed in certain malignancies, and plays important roles in tumour metastasis and progression. The present study highlights the function of MTA2 in pancreatic carcinoma through its role as a deacetylator of hypoxia-inducible factor-1alpha (HIF-1alpha) and a cotranscriptional factor for E-cadherin expression. We found that overexpression of MTA2 promoted, and knockdown of MTA2 inhibited, the invasion and proliferation of pancreatic carcinoma cells both in vitro and in xenograft models in vivo. We also found that MTA2 is transcriptionally upregulated by HIF-1alpha through a hypoxia response element (HRE) of the MTA2 promoter in response to hypoxia. Reciprocally, MTA2 deacetylates HIF-1alpha and enhances its stability through interacting with histone deacetylase 1 (HDAC1). Consequently, HIF-1alpha recruits MTA2 and HDAC1 to the HRE of the E-cadherin promoter, by which E-cadherin transcription is repressed. In agreement with these experimental results, MTA2 is positively associated with HIF-1alpha, but inversely correlated with E-cadherin, in pancreatic carcinoma samples. Moreover, data from The Cancer Genome Atlas on 172 pancreatic carcinomas indicate an association between high expression of MTA2 and short overall survival. Taken together, our study identifies MTA2 as a critical hub and potential therapeutic target to inhibit the progression and metastasis of pancreatic carcinoma. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29708272 TI - Three Distinct Types of Microautophagy Based on Membrane Dynamics and Molecular Machineries. AB - Microautophagy is originally defined as lysosomal (vacuolar) membrane dynamics to directly enwrap and transport cytosolic components into the lumen of the lytic organelle. Molecular details of microautophagy had remained unknown until genetic studies in yeast identified a set of proteins required for the process. Subsequent studies with other experimental model organisms resulted in a series of discoveries that accompanied an expansion of the definition of microautophagy to also encompass endosomal membrane dynamics. These findings, however, still impose puzzling, non-integrated images as to the molecular mechanism of microautophagy. By reviewing recent studies on microautophagy in various experimental systems, we propose the classification of microautophagy into three types, as the basis for developing a comprehensive view of the process. PMID- 29708273 TI - A case of feline gastrointestinal eosinophilic sclerosing fibroplasia limited to the mesentery. AB - An entire, female, mixed-breed cat of unknown age was presented with a 6-week history of lethargy, anorexia and vomiting. There was an increase in the number of white blood cells in the blood, including neutrophils and eosinophils; moderate anaemia; ascites; and possible mesenteric peritonitis. Exploratory laparotomy revealed firm, multifocal small nodules in the mesentery. As the nodules were surgically unresectable, they were biopsied. Histologically, the nodules were composed of thin trabeculae of dense collagen fibres mixed with plump fibroblasts and numerous eosinophils, consistent with feline gastrointestinal eosinophilic sclerosing fibroplasia. Bacteria were not detected on histological examination of the nodules and cytology of the ascites. Remission of disease occurred following treatment with prednisolone and ciclosporin A for 22 days and antibiotics for 40 days. After remission, ciclosporin A was administered for 236 days and then discontinued. Eosinophilia also resolved after treatment with ciclosporin A. The cat is still alive and in good condition on day 689. This report describes what may be an atypical case of feline gastrointestinal eosinophilic sclerosing fibroplasia, lacking involvement of the gastrointestinal tract, and was apparently cured by treatment that involved ciclosporin A. PMID- 29708274 TI - Congenital pleuroperitoneal hernia presenting as gastrothorax in five cavalier King Charles spaniel dogs. AB - Five cavalier King Charles spaniels were examined for acute onset of respiratory distress. Thoracic radiographs demonstrated diaphragmatic hernia and tension gastrothorax, visible as a distended stomach occupying the left caudal thoracic cavity. Exploratory midline coeliotomy confirmed congenital pleuroperitoneal diaphragmatic hernia with herniation and dilatation of the stomach. The hernia configuration was consistent in all cases, with a defect affecting the left diaphragmatic crus. Congenital pleuroperitoneal diaphragmatic hernia is a rare condition caused by a defect in the dorsolateral diaphragm. Defects of the left crus of the diaphragm could result in the herniation of the stomach into the thoracic cavity with possible subsequent tension gastrothorax. Cavalier King Charles spaniels may have a predisposition to this condition. Tension gastrothorax is an acute life-threatening consequence of gastric herniation through a diaphragmatic defect that must be promptly recognised and surgically treated. PMID- 29708275 TI - A Rare Congenital Anomaly: Double Bladders on 2- and 3-Dimensional Ultrasound Imaging. PMID- 29708276 TI - Eyelid allergic contact dermatitis after intravitreal injections of anti-vascular endothelial growth factor: What is the culprit? A report of 3 cases. PMID- 29708277 TI - Revising the FP Quality of Care Framework in the Context of Rights-based Family Planning. AB - Nearly three decades ago, Bruce articulated a client-centered quality of care (QoC) framework for family planning services. The term quality has since then been used in many rights-based frameworks for health, reproductive health, and family planning. This commentary compares the concept of quality used in many of these frameworks to reconcile the elements of the FP QoC framework with the use of quality in various rights frameworks. We propose five modifications to the original FP QoC framework to better align it with the treatment of quality in the rights-based approaches and the way quality in family planning has been applied in practice. PMID- 29708278 TI - An outbreak of toxoplasmosis in squirrel monkeys (Saimiri sciureus) in South Korea. AB - BACKGROUND: Toxoplasma gondii (T. gondii) is an intracellular protozoan parasite that can infect warm-blooded animals including humans. New World monkeys, such as squirrel monkeys, are more susceptible to T. gondii than Old World monkeys, often developing fatal disease. METHODS: In this study, seven of thirteen dead squirrel monkeys at Seoul Grand Park were tested to find the cause of sudden death. RESULTS: The main histopathological findings included interstitial pneumonia, necrotizing hepatitis, and splenitis. Periodic acid-Schiff staining of liver, spleen, and lung revealed cyst structures consistent with bradyzoites. Amplification of the B1 gene was detected in the liver or spleen of all monkeys. Additionally, a restriction fragment length polymorphism assay and phylogenetic analysis of the GRA6 amplicon revealed a consistent clustering with the type II strain of T. gondii. CONCLUSIONS: This study is the first report of T. gondii infection of squirrel monkeys in Korea, and the first report of type II T. gondii based on GRA6 analysis in Korea. PMID- 29708279 TI - CDKN2A loss and PIK3CA mutation in myoepithelial-like metaplastic breast cancer. AB - Metaplastic breast carcinoma comprises a heterogeneous group of tumours with poorly understood pathogenesis. A subset of metaplastic breast cancers show myoepithelial differentiation and constitute a morphological spectrum with ill defined borders from fibromatosis-like spindle cell carcinoma to myoepithelial carcinoma. In a series of 34 metaplastic breast cancers with spindle cell and myoepithelial differentiation, we found recurrent genetic aberrations, which set them apart from other metaplastic breast cancers and suggest a unique pathogenesis. The majority of cases (28 of 34 patients; 82.4%) showed distinct chromosomal loss in the 9p21.3 region, including CDKN2A and CDKN2B. Biallelic loss of the CDKN2A/B region was found in 50% of deleted cases. Expression of the cyclin-dependent kinase inhibitor CDKN2A (p16) was missing in all samples affected by 9p21.3 loss. Other genomic alterations frequently occurring in triple negative and metaplastic breast cancer were absent or found in only a minority of cases. Gains of whole chromosome 5 and chromosomal region 5p were observed in nine cases, and were associated with recurrences (p < 0.001). In 64.3% of cases, 9p21.3 loss was accompanied by concurrent PIK3CA mutation. Both genomic abnormalities were also detectable in adenomyoepitheliomas (4/12), which are considered to represent the precursor lesion of myoepithelial metaplastic breast cancer. In adenomyoepithelioma, PIK3CA mutation was present in both luminal epithelial and myoepithelial cells, whereas p16 loss was found only in the latter. We conclude that 9p21.3 (CDKN2A) loss and PIK3CA mutation characterize a subgroup of metaplastic breast cancers with myoepithelial and spindle cell differentiation. Myoepithelial cells in adenomyoepithelioma may show identical aberrations. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29708280 TI - Association Between Shear Wave Elastography of Virtual Touch Tissue Imaging Quantification Parameters and the Ki-67 Proliferation Status in Luminal-Type Breast Cancer. AB - OBJECTIVES: To evaluate the association between shear wave elastography parameters using virtual touch tissue imaging quantification (VTIQ) and the Ki-67 index in luminal-type breast cancer. METHODS: Eighty-one patients with 82 lesions of pathologic confirmed luminal-type breast cancer underwent virtual touch tissue imaging quantification examination before surgery between December 2015 and June 2016. Patients were divided into 2 groups according to the Ki-67 index (>=14% versus < 14%), which is used to define luminal type B and luminal type A, respectively. The mean shear wave velocity (SWVmean ) and lesion-to-adjacent tissues ratio (SWV ratio) were calculated for each lesion. RESULTS: The SWVmean , SWV ratio, histologic grade, axillary lymph node involvement, and lymphovascular invasion showed a significant positive association with a high Ki-67 index (all P < .05). Receiver operating characteristic curve analysis for the differential diagnosis between high (>=14%) and low (<14%) Ki-67 groups displayed that the optimal cutoff value for SWVmean and SWV ratio were 3.99 meters per second and 2.861, with sensitivity 94% and 72%, specificity 40.6% and 56.2%, and area under the receiver operating characteristic curve of 0.689 and 0.651, respectively. Univariate analysis showed that SWVmean (P = .005), SWV ratio (P = .029), histologic grade (P = .011), presence of axillary node involvement (P = .004), and lymphovascular invasion (P = .008) were significantly associated with high Ki 67 status. Multivariable analysis displayed that SWVmean (hazard ratio [HR], 1.459, 95% confidence interval [CI], 1.028-2.072; P = .035), histologic grade (HR, 4.105; 95% CI, 1.142-14.763; P = .031), and presence of axillary node involvement (HR, 3.75; 95% CI, 1.228-11.453; P = .020) maintained significance for predicting high Ki-67 status. CONCLUSIONS: The SWVmean using the virtual touch tissue imaging quantification method showed significant correlation with the Ki-67 index, suggesting the potential to assess tumor proliferation status in luminal-type breast cancer with a noninvasive manner. PMID- 29708282 TI - Ultrasonographic and Mammographic Findings of Male Breast Disease. AB - Most male breast diseases are benign, although malignancies can also occur. Gynecomastia, the most common abnormality in the male breast, has characteristic imaging findings differentiating it from cancer. Fewer than 1% of patients with breast cancer are men, but the incidence of male breast cancer is increasing worldwide. Additionally, breast cancer often presents at a more advanced stage in men than in women due to delayed diagnosis. Understanding imaging features of male breast disease is important for an accurate diagnosis and optimal care. This article reviews ultrasonography and mammography findings of benign and malignant diseases of the male breast. PMID- 29708281 TI - Pharmacokinetics, safety and tolerability of OBE022, a selective prostaglandin F2alpha receptor antagonist tocolytic: A first-in-human trial in healthy postmenopausal women. AB - AIMS: Preterm birth remains a significant risk for later disability. The selective inhibition of the prostaglandin F2alpha receptor has significant advantages for a tocolytic. The prodrug OBE022 and its metabolite OBE002 are novel prostaglandin F2alpha receptor antagonists under development for treating preterm labour. METHODS: We performed a prospective, first in human, Phase I, dose escalation, placebo-controlled, randomized trial at a clinical trial site in the UK. Placebo, single ascending doses of 10, 30, 100, 300, 1000 or 1300 mg, and multiple ascending doses over 7 days of 100, 300 or 1000 mg day-1 ; were administered to postmenopausal female volunteers. Food interaction was additionally evaluated. RESULTS: Subjects tolerated OBE022 well at all single and multiple doses. No clinically relevant changes in safety parameters were shown and there were no serious adverse events. Observations showed that prodrug OBE022 was readily absorbed and rapidly converted into its equally active stable metabolite OBE002. The plasma level of OBE002 rose with increasing doses, reaching exposure levels that were anticipated to be clinically relevant within 1 h following administration. There was no clinically significant food interaction, with peak exposures reduced to 80% and area under the curve staying bioequivalent. The mean half-life of OBE002 ranged between 8 and 11 h following administration of a single dose and 22-29 h after multiple doses. CONCLUSIONS: Administration of OBE022 was safe and had favourable pharmacokinetic characteristics and no clinically relevant interaction with food. Our results allow further investigation of OBE022 in preterm labour patients. PMID- 29708283 TI - Trichilemmal Cyst: Clinical and Sonographic Features. AB - OBJECTIVES: In this study, we retrospectively reviewed the clinical and sonographic features of patients with trichilemmal cysts. METHODS: Sonographic findings of 54 cases of trichilemmal cysts were retrospectively analyzed from 50 patients, including 4 cases of proliferating trichilemmal cysts. Associated factors of internal calcification-positive cases were also evaluated. RESULTS: The mean age of the 50 patients was 43.4 years (range, 15-80 years) and the female-to-male ratio was 1.3. Overall, 68% of the trichilemmal cysts in the 54 lesions were located in the scalp, and 15% were located in the extremities. All 54 lesions were preoperatively examined by sonography and showed well-defined, oval-shaped structures located in subcutaneous soft tissues close to the dermis. Of the 54 lesions, 72% were hypoechoic masses, 89% were heterogeneous, and 65% had internal calcification. Among the internal calcification-positive cases, the mean age of the patients was 43.4 years, and the female-to-male ratio was 0.6. Of these lesions, 83% were located in the scalp. We did not find any significant association between calcification, age, or sex (P = .993 and P = .99); however, lesions present in the scalp were significantly associated with internal calcification (P = .005). 81% of the 54 lesions displayed posterior enhancement. but the color Doppler sonography of all lesions revealed no vascularization. CONCLUSIONS: Trichilemmal cysts should be considered to diagnose of well-defined, hypoechoic lesions with internal calcification and posterior sound enhancement in the subcutaneous soft tissues of the scalp or extremities upon sonography. PMID- 29708284 TI - Supersonic Shear Imaging Elastography in Skeletal Muscles: Relationship Between In Vivo and Synthetic Fiber Angles and Shear Modulus. AB - OBJECTIVES: To verify a relationship between the pennation angle of synthetic fibers and muscle fibers with the shear modulus (MU) generated by Supersonic shear imaging (SSI) elastography and to compare the anisotropy of synthetic and in vivo pennate muscle fibers in the x2 -x3 plane (probe perpendicular to water surface or skin). METHODS: First, the probe of Aixplorer ultrasound scanner (v.9, Supersonic Imagine, Aix-en-Provence, France) was placed in 2 positions (parallel [aligned] and transverse to the fibers) to test the anisotropy in the x2 -x3 plane. Subsequently, it was inclined (x1 -x3 plane) in relation to the fibers, forming 3 angles (18.25 degrees , 21.55 degrees , 36.86 degrees ) for synthetic fibers and one (approximately 0 degrees ) for muscle fibers. RESULTS: On the x2 -x3 plane, MU values of the synthetic and vastus lateralis fibers were significantly lower (P < .0001) at the transverse probe position than the longitudinal one. In the x1 -x3 plane, the MU values were significantly reduced (P < .0001) with the probe angle increasing, only for the synthetic fibers (approximately 0.90 kPa for each degree of pennation angle). CONCLUSIONS: The pennation angle was not related to the MU values generated by SSI elastography for the in vivo lateral head of the gastrocnemius and vastus lateralis muscles. However, a MU reduction with an angle increase in the synthetic fibers was observed. These findings contribute to increasing the applicability of SSI in distinct muscle architecture at normal or pathologic conditions. PMID- 29708285 TI - Design, synthesis, and molecular docking study of 3H-imidazole[4,5-c]pyridine derivatives as CDK2 inhibitors. AB - A novel series of imidazo[4,5-c]pyridine-based CDK2 inhibitors were designed from the structure of CYC202 via scaffold hopping strategy. These compounds were synthesized and biologically evaluated for their CDK2 inhibitory and in vitro anti-proliferation potential against cancer cell lines. Several compounds exhibited potent CDK2 inhibition with IC50 values of less than 1 uM. The most potent compound 5b showed excellent CDK2 inhibitory (IC50 = 21 nM) and in vitro anti-proliferation activity against three different cell lines (HL60, A549, and HCT116). The molecular docking and dynamic studies portrayed the potential binding mechanism between 5b and CDK2, and several key interactions between them were observed, which would be the reason for its potent CDK2 inhibitory and anti proliferation activities. Therefore, the pyridin-3-ylmethyl moiety would serve as an excellent pharmacophore for the development of novel CDK2 inhibitors for targeted anti-cancer therapy. PMID- 29708286 TI - Controlling CO2 -Responsive Behaviors of Polymersomes Self-Assembled by Coumarin Containing Star Polymer via Regulating Its Crosslinking Pattern. AB - An oligo(ethylene glycol)-based star polymer of N2 -(OEG-C)3 with fluorescent coumarin as hydrophobic end groups and dual tertiary amines as the star center is designed and synthesized. Owing to its amphiphilic nature of N2 -(OEG-C)3 , it will self-assemble into hollow vesicles with coumarin groups dispersed in the hydrophobic membrane and exhibits CO2 -responsive behavior due to the protonation of amine centers with CO2 . More importantly, coumarin moieties can either form non-crosslinking with gamma-cyclodextrin via the 2/1 host-guest inclusion, or covalently photodimerized by 365 nm light, offering a tunable crosslinking pattern in the hydrophobic membrane and thus adjusting its CO2 -stimulated reorganization and disassembly behaviors of these vesicles in aqueous solution. PMID- 29708287 TI - Nurse practitioner integration: Qualitative experiences of the change management process. AB - AIM: The aim of this qualitative research was to explore perceptions of organisational change related to the integration of nurse practitioners from key nursing stakeholders. BACKGROUND: The ongoing delivery of effective and efficient patient services is reliant upon the development and sustainability of nurse practitioner roles. Examination of the factors contributing to the underutilization of nurse practitioner roles is crucial to inform future management policies. A change management theory is used to reveal the complexity involved. METHOD: Qualitative interviews were undertaken using a purposive sampling strategy of key stakeholders. Thematic analysis was undertaken and key themes were correlated to the theoretical framework. RESULTS: The results confirm the benefits of nurse practitioner roles, but suggest organisational structures and embedded professional cultures present barriers to full role optimization. Complicated policy processes are creating barriers to the integration of nurse practitioner roles. CONCLUSION: The findings increase understanding of the links between strategic planning, human resource management, professional and organisational cultures, governance and politics in change management. Effective leadership drives the change process through the ability to align key components necessary for success. Sustainability of nurse practitioners relies on recognition of their full potential in the health care team. IMPLICATIONS FOR NURSING MANAGEMENT: The results of this study highlight the importance of management and leadership in the promotion of advanced nursing skills and experience to better meet patient outcomes. The findings reinforce the potential of nurse practitioners to deliver patient centred, timely and efficient health care. PMID- 29708288 TI - Analytical performance of the various acquisition modes in Orbitrap MS and MS/MS. AB - Quadrupole Orbitrap instruments (Q Orbitrap) permit high-resolution mass spectrometry-based full scan acquisitions and have a number of acquisition modes where the quadrupole isolates a particular mass range prior to a possible fragmentation and high-resolution mass spectrometry-based acquisition. Selecting the proper acquisition mode(s) is essential if trace analytes are to be quantified in complex matrix extracts. Depending on the particular requirements, such as sensitivity, selectivity of detection, linear dynamic range, and speed of analysis, different acquisition modes may have to be chosen. This is particularly important in the field of multi-residue analysis (eg, pesticides or veterinary drugs in food samples) where a large number of analytes within a complex matrix have to be detected and reliably quantified. Meeting the specific detection and quantification performance criteria for every targeted compound may be challenging. It is the aim of this paper to describe the strengths and the limitations of the currently available Q Orbitrap acquisition modes. In addition, the incorporation of targeted acquisitions between full scan experiments is discussed. This approach is intended to integrate compounds that require an additional degree of sensitivity or selectivity into multi-residue methods. PMID- 29708289 TI - Safety and efficacy of HCV eradication during etanercept treatment for severe psoriasis. AB - Treatment of severe psoriasis in HCV positive patients is challenging, because several psoriasis medications have a toxic effect on the liver, and interferon alpha, used to treat hepatitis, can induce worsening of psoriatic lesions. TNF alpha inhibitors seem to be a safe and effective option in HCV positive psoriatic patients, but there are concerns about long-term safety, impact on liver fibrosis progression and risk of immune-mediated liver injury. With regard to HCV treatment, new direct-acting antiviral therapies (DAA) seem to be extremely effective, with minimal side effects, but little is known about possible interactions with other medications, particularly with biologics. We report the case of a psoriatic patient, in treatment with Etanercept, who needed to undergo HCV eradication with Daclastavir and Sofosbuvir because of worsening liver fibrosis due to chronic hepatitis C. The present treatment produced excellent results in terms of HCV eradication and control of psoriatic lesions, without side effects. PMID- 29708290 TI - The role of unregulated care providers in home care: A scoping review. AB - AIM AND BACKGROUND: Health care needs of individuals living in the community are increasing. To meet the rising need, unregulated care providers are providing more complex patient care. The aim of this review is to articulate the unregulated care provider role by identifying patient care activities offered by unregulated care providers in home care. METHODS: A scoping review was conducted. One thousand and eleven published manuscripts were identified in CINAHL, Ageline and MEDLINE. Eleven additional manuscripts were identified through hand searching. Manuscripts were screened for relevancy and data were abstracted to address the research question. RESULTS: Twenty-eight studies originating from Canada, Sweden, Belgium, UK, USA and New Zealand were included. Three categories of patient care activities provided by unregulated care providers were found: (1) personal care and core skills; (2) delegated tasks and added skills; and (3) specialty roles. CONCLUSION: Unregulated care providers predominantly provide assistance with personal care and activities of daily living. However, unregulated care providers also provide care outside their training, including care once provided by nurses. IMPLICATIONS FOR NURSING MANAGEMENT: Guidelines clearly articulating responsibilities of nurses transferring care activities to unregulated care providers should be developed. Processes and policies regarding evaluation and supervision of unregulated care providers providing added skills should be developed to ensure appropriate monitoring and support. PMID- 29708291 TI - Phenotypic and functional analysis of bovine peripheral blood dendritic cells before parturition by a novel purification method. AB - Dendritic cells (DCs) are specialized antigen presenting cells specializing in antigen uptake and processing, and play an important role in the innate and adaptive immune response. A subset of bovine peripheral blood DCs was identified as CD172a+ /CD11c+ /MHC (major histocompatibility complex) class II+ cells. Although DCs are identified at 0.1%-0.7% of peripheral blood mononuclear cells (PBMC), the phenotype and function of DCs remain poorly understood with regard to maintaining tolerance during the pregnancy. All cattle used in this study were 1 month before parturition. We have established a novel method for the purification of DCs from PBMC using magnetic-activated cell sorting, and purified the CD172a+ /CD11c+ DCs, with high expression of MHC class II and CD40, at 84.8% purity. There were individual differences in the expressions of CD205 and co-stimulatory molecules CD80 and CD86 on DCs. There were positive correlations between expression of cytokine and co-stimulatory molecules in DCs, and the DCs maintained their immune tolerance, evidenced by their low expressions of the co stimulatory molecules and cytokine production. These results suggest that before parturition a half of DCs may be immature and tend to maintain tolerance based on the low cytokine production, and the other DCs with high co-stimulatory molecules may already have the ability of modulating the T-cell linage. PMID- 29708293 TI - Using connectivity to identify climatic drivers of local adaptation: a response to Macdonald et al. AB - Macdonald et al. (Ecol. Lett., 21, 2018, 207-216) proposed an analytical framework for identifying evolutionary processes underlying trait-environment relationships observed in natural populations. Here, we propose an expanded and refined framework based on simulations and bootstrap-based approaches, and we elaborate on an important statistical caveat common to most datasets. PMID- 29708292 TI - Longitudinal association between eating frequency and hemoglobin A1c and serum lipids in diabetes in the SEARCH for Diabetes in Youth study. AB - BACKGROUND: Few studies have evaluated the prospective association of eating frequency with HbA1c levels and cardiovascular disease risk markers among youth with diabetes. OBJECTIVE: To examine the 5-year longitudinal association of eating frequency with HbA1c and serum lipid levels among youth with type 1 diabetes (T1D) or type 2 diabetes (T2D). METHODS: One-thousand and forty-nine youth (>=10-year old) with incident T1D (n = 821) or T2D (n = 228) who participated in the SEARCH for Diabetes in Youth study were included. Eating frequency (<=3, 4-5, or 6-10 times/d) measured at baseline and follow-up visits was related to HbA1c and serum lipid levels measured repeatedly over 5 years. RESULTS: Increased eating frequency was associated with larger increases in HbA1c among youth T1D. For example, for youth with T1D who ate <=3 times/d at the outset and ate 6-10 times/d 5 years later, the longitudinal model predicted greater absolute increases in HbA1c (2.77%); whereas for youth with T1D who ate 6 10 times/d at the outset and ate <=3 times/d 5 years later, the model predicted lesser absolute increases in HbA1c (1.33%). Eating frequency was not associated with changes in serum lipid levels among youth with T1D or T2D. CONCLUSIONS: Youth with T1D who increased their eating frequency vs those who decreased it had larger increases in HbA1c over 5 years. PMID- 29708295 TI - The safety of St John's wort (Hypericum perforatum) in pregnancy and lactation: A systematic review of rodent studies. AB - Herbal products are popular among women during the perinatal period. St John's wort (SJW), Hypericum perforatum, is a common remedy for mild depression, a problem prevalent in this population. Although the safety of herbal products must be investigated, ethical issues constrain intervention studies in humans. Hence, animal studies often inform clinical decisions. The objective of this study is to systematically review rodent studies assessing the safety of SJW during the perinatal period. A literature search to November 10, 2017, identified 10 rodent studies that met a priori inclusion criteria. Study quality was evaluated according to both the Systematic Review Centre for Laboratory animal Experimentation tool for assessing bias and recommendations for appropriate reporting of herbal medicine research. Significant methodological limitations were found in each of the studies reviewed. These limitations include the lack of botanical verification and omission of extract characterization, inadequate explanation of dosage rationale, and absence of bias limiting protocols. Critical appraisal with contemporary tools indicates that each of the reviewed studies lacks appropriate rigour, rendering the results unreliable. Despite this, these papers are used in the rationale for recommending or contraindicating SJW during pregnancy and lactation. PMID- 29708294 TI - Combined effect of apigenin and ferulic acid on frozen-thawed boar sperm quality. AB - The main aim of the present study was to evaluate the cryoprotective effect of apigenin (AP) and ferulic acid (FA) on boar sperm during cryopreservation. AP and FA were both demonstrated to be high-efficiency antioxidants and had not previously been used to protect sperm from cryodamage. As boar sperm is sensitive to oxidative stress, suitable antioxidants are still needed for improving frozen thawed sperm quality. With this purpose, semen samples coming from five boars were used in this study. Ejaculates of five boars were mixed and split into 16 aliquots, in which different doses of AP and FA were added separately or together. The motility, the plasma membrane integrity, the mitochondrial activity, the acrosomal integrity, the antioxidase activities and the malondialdehyde concentration of the frozen-thawed boar sperm were assessed. The results suggested that both AP and FA significantly improved the frozen-thawed boar sperm quality in all these aspects when they were added to the freezing extender separately, while the highest improvement was recorded when the extender was supplemented with 0.1 mmol/L AP plus 0.15 mmol/L FA. These findings demonstrated that supplementation of freezing extender with both AP and FA had a combined, beneficial effect on frozen-thawed boar sperm. PMID- 29708297 TI - Sleep habits in adolescents with type 1 diabetes: Variability in sleep duration linked with glycemic control. AB - OBJECTIVE: To describe adolescents' sleep on school and weekend nights using multiple methods and to examine the links between sleep variability, quality, and duration with diabetes indicators. METHODS: Adolescents with type 1 diabetes (N = 65, mean age = 15.0, 52.3% female, mean HbA1c = 8.9% or 74 mmol/mol) wore an actigraph and kept daily diaries recording sleep, activities, and blood glucose monitoring (BGM) habits for at least 7 days. Average daily BGM and blood glucose (BG) levels were obtained through glucometer downloads. HbA1c was obtained as part of clinic visits. Adolescents completed a sleep quality questionnaire (Pittsburgh sleep quality index [PSQI]), and adolescents and caregivers reported on adherence to diabetes treatment. RESULTS: Adolescents reported a mean PSQI global score of 5.37, which is above the clinical cutoff for poor sleep quality. Actigraphy data revealed that mean adolescent total sleep time was 6:54 (h:min), and participants slept more on weekend nights than on school nights (P < .001). Additionally, variability in sleep duration was significantly related to HbA1c, frequency of BGM, and average BG. Total sleep time and self-reported sleep quality were not significantly associated with adherence or glycemic control. CONCLUSIONS: Few adolescents with type 1 diabetes met recommendations for sleep duration, and many reported poor sleep quality. We identified significant associations between variability in sleep duration with poorer glycemic control and less frequent BGM, supporting the need to consider sleep patterns as a modifiable factor that may affect adherence and glycemic control. PMID- 29708296 TI - Effect of supplemental dietary slow-release urea on growth performance and physiological status of dairy heifers. AB - We examined the effect of supplemental dietary slow-release urea on the growth performance and physiological status of 16 dairy Holstein heifers (10 months of age, 322 +/- 10 kg). The heifers were offered a formulated isocaloric and isonitrogenous 70:30 roughage : concentrate ration and were assigned randomly to one of four levels of slow-release urea supplementation (0% [U0 ], 1% [U1 ], 1.5% [U1.5 ] and 2% [U2 ] dry matter [DM]). The total study lasted 95 days, which included a 20 days adaptation period. Dry matter intake (DMI) of U2 was lower than the intakes of U0 and U1 (p < .05), while average daily gains (ADG) of U1 and U1.5 were higher than U0 and U2 (p < .05). Rumen volatile fatty acids concentration did not differ among the four treatments, while ammonia nitrogen concentration increased with an increase in urea level (p < .05). Serum blood urea nitrogen concentration was lower in U1.5 than in U0 and U2 while serum free fatty acids concentration in U2 was higher than in the other three treatments (p < .05). We concluded that the addition of urea at a level of 1.5 to 2.0% DM resulted in a reduction in DMI but the addition of 1.0%-1.5% urea resulted in the highest ADG, with no negative effects on rumen fermentation and health status of the calves. PMID- 29708298 TI - Cationic Polymer-Mediated CRISPR/Cas9 Plasmid Delivery for Genome Editing. AB - Delivery of CRISPR (clustered regularly interspaced short palindromic repeats)/CRISPR-associated protein-9 (Cas9) represents a major hurdle for successful clinical translation of genome editing tools. Owing to the large size of plasmids that encode Cas9 and single-guide RNA (sgRNA), genome editing efficiency mediated by current delivery carriers is still unsatisfactory to meet the requirement for its real applications. Herein, cationic polymer polyethyleneimine-beta-cyclodextrin (PC), known to be efficient for small plasmid transfection, is reported to likewise mediate efficient delivery of plasmid encoding Cas9 and sgRNA. Whereas PC can condense and encapsulate large plasmids at high N/P ratio, the delivery of plasmid results in efficient editing at two genome loci, namely, hemoglobin subunit beta (19.1%) and rhomboid 5 homolog 1 (RHBDF1) (7.0%). Sanger sequencing further confirms the successful genome editing at these loci. This study defines a new strategy for the delivery of the large plasmid encoding Cas9/sgRNA for efficient genome editing. PMID- 29708299 TI - Arsenic trioxide induces growth inhibition and death in human pulmonary artery smooth muscle cells accompanied by mitochondrial O2*- increase and GSH depletion. AB - Arsenic trioxide (ATO; As2 O3 ) induces cell death in various cells via oxidative stress. Expose to chronic arsenic is involved in the development of vascular diseases. However, little is known about the cytotoxic effects of ATO on human normal vascular smooth muscle cells (VSMCs). Thus, in this study, we investigated the effects of ATO on cell growth and death in human pulmonary artery smooth muscle (HPASM) cells in relation to reactive oxygen species (ROS) and glutathione (GSH) levels. ATO treatment decreased the growth of HPASM cells with an IC50 of ~30-50 MUM at 24 h, and ATO induced HPASM cell death via apoptosis or necrosis dependent on the doses of it at this time. Treatment with 50 MUM ATO did not increase ROS levels at the early time points, but it significantly increased mitochondrial O2*- levels at 24 h. ATO also induced GSH depletion in HPASM cells. N-acetyl cysteine (NAC; a well-known antioxidant) did not significantly affect apoptotic cell death, ROS levels, or GSH depletion in ATO-treated HPASM cells. However, l-buthionine sulfoximine (BSO; an inhibitor of GSH synthesis) intensified mitochondrial O2*- levels in ATO-treated HPASM cells, and significantly increased cell death and GSH depletion in these cells as well. In summary, we provided the first evidence that ATO inhibited the growth of HPASM cells, and induced apoptotic and/or necrotic cell death in these cells, accompanied by increases in mitochondrial O2*- level and GSH depletion. PMID- 29708301 TI - Enhanced chemiluminescence of the fluorescein-KIO4 system by CdTe quantum dots for determination of catechol. AB - In this paper, a novel chemiluminescence (CL) system was introduced based on the use of CdTe quantum dots (QDs) with the mixture solutions of fluorescein and potassium periodate (KIO4 ) in alkaline medium. The CL signal of an ultra-weak system was strongly enhanced in the presence of QDs. The application of CdTe QDs fluorescein-KIO4 system is reported for the first time. It was found that catechol had a diminishing effect on the CL reaction. Under optimal experimental conditions, CL intensity decreased linearly in a 1 to 100 MUM catechol concentration range, with a 0.18 MUM detection limit. A possible reaction mechanism was proposed according to the results of kinetic analyses, CL spectra, ultraviolet-visible and fluorescence spectra. The results pointed to an efficient energy transfer between the CL energy donor CdTe QDs and acceptor fluorescein. Finally, the CL method was successfully applied to the determination of catechol in environmental water samples. PMID- 29708300 TI - GABA tea attenuates cardiac apoptosis in spontaneously hypertensive rats (SHR) by enhancing PI3K/Akt-mediated survival pathway and suppressing Bax/Bak dependent apoptotic pathway. AB - Cardiomyocyte apoptosis is the major risk factor for the development of heart failure (HF). The purpose of this study was to evaluate the effects of Gamma aminobutyric acid (GABA) tea on hypertension-induced cardiac apoptotic pathways in spontaneously hypertensive rats (SHR). In order to reveal the mechanisms, 36 male SHR at eight weeks of age, 200 g were divided into six groups. One group was fed water as a control group. Other rats were administered one of the following treatments: GABA tea at dose 150 and 300 mg/kg/day as low GABA tea (LGT) and high GABA tea (HGT) groups, respectively, pure GABA at dose 150 and 300 mg/kg/day as LG and HG groups, respectively, green tea (GT) as control of LGT and HGT groups. After 12 weeks, cardiac tissues were analyzed by histological analysis, western blotting, and TUNEL assays. GABA tea, GT, and pure GABA decreased hypertension induced cardiac abnormalities, including abnormal myocardial architecture. In addition, GABA tea, GT, and pure GABA dramatically increased anti-apoptotic protein, Bcl2. Furthermore, GABA tea, GT, and pure GABA also decreased activated caspase 9 and activated-caspase 3. Additionally, the survival associated protein IGF-I and PI3K/Akt were enhanced in cardiac tissues upon treatment. Our results showed an optimistic anti-apoptotic and pro-survival effects of GABA tea treatment against hypertensive rat hearts. PMID- 29708302 TI - Congenital dysfibrinogenaemia assessed by whole blood thromboelastography. AB - INTRODUCTION: Congenital dysfibrinogenaemia (CD) is a rare hereditary blood disorder, and thromboelastography (TEG) can comprehensively assess the clotting function of patients. However, only few studies have focussed on the application of TEG in CD. We aim to investigate the clinical value of TEG in congenital CD. METHODS: We performed TEG and routine coagulation tests, including plasma prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), functional fibrinogen (Fg) concentration (Clauss method) and Fg concentration (PT-derived method) tests, in 17 patients with CD (experimental group) and 28 healthy individuals (control group). RESULTS: In the TEG test, the coagulation time was significantly longer and the angle value was significantly smaller in the experimental group than that in the control group (3.73 +/- 1.73 minutes vs 1.99 +/- 0.49 minutes; 52.39 degrees +/-11.6 degrees vs 65.69 degrees +/-4.43 degrees ; P < .05 for both); the coagulation index was significantly decreased in the experimental group when compared to the control group (-0.86 +/- 2.85 vs 1.29 +/- 1.53) (P < .05), but the maximum amplitude was not significantly different (P > .05). In the coagulation test, compared with the control group, TT was significantly longer (11.59 +/- 0.93 minutes vs 32.34 +/- 7.1 minutes; P < .05) and the functional Fg concentration was significantly lower (3.17 +/- 0.59 g/L vs 0.56 +/- 0.18 g/L; P < .05) in the experimental group, whereas there were no differences in APTT, PT and Fg concentrations (P > .05). CONCLUSION: TEG is highly accurate for detecting coagulation function in patients with CD, with the thromboelastographic coagulation time and angle reflecting a reduced Fg activity, thereby facilitating diagnosis and differential diagnosis of CD and coagulation status evaluation of patients with CD. PMID- 29708303 TI - Utility of Von Pechman synthesis of coumarin reaction for development of spectrofluorimetric method for quantitation of salmeterol xinafoate in pharmaceutical preparations and human plasma. AB - Simple, precise and selective spectrofluorimetric technique was evolved for quantitation of selective beta2 agonist drug namely salmeterol xinafoate (SAL). Utilizing its phenolic nature, a method was described based on the reaction of the studied drug with ethyl acetoacetate (EAA) to yield extremely fluorescent coumarin product which can be detected at 480 nm (lambdaex = 420 nm). The procedure obeys Beer's law with a correlation coefficient of r = 0.9999 in the concentration range between 500 and 5000 ng ml-1 with and 177 ng ml-1 for limit of detection (LOD) and limit of quantification (LOQ), respectively. Diverse reaction variables influencing the firmness and formation of the coumarin product were accurately examined and modified to ensure greatest sensitivity of the procedure. The proposed technique was performed and examined according to the US Food and Drug Administration (FDA) guidelines for bio-analytical methods and was efficiently applied for quantitation of SAL in both pharmaceutical preparations (% recovery = 100.06 +/- 1.07) and spiked human plasma (% recovery = 96.64-97.14 +/- 1.01-1.52). PMID- 29708304 TI - Casein kinase 2 inhibition impairs spontaneous and oxytocin-induced contractions in late pregnant mouse uterus. AB - NEW FINDINGS: What is the central question of this study? Does the inhibition of the protein kinase casein kinase 2 (CK2) alter the uterine contractility? What is the main finding and its importance? Inhibition of CK2 impaired the spontaneous and oxytocin-induced contractility in late pregnant mouse uterus. This finding suggests that CK2 is a novel pathway mediating oxytocin-induced contractility in the uterus and thus opens up the possibility for this class of drugs to be developed as a new class of tocolytics. ABSTRACT: The protein kinase casein kinase 2 (CK2) is a ubiquitously expressed serine or threonine kinase known to phosphorylate a number of substrates. The aim of this study was to assess the effect of CK2 inhibition on spontaneous and oxytocin-induced uterine contractions in 19 day pregnant mice. The CK2 inhibitor CX-4945 elicited a concentration dependent relaxation in late pregnant mouse uterus. CX-4945 and another selective CK2 inhibitor, apigenin, also inhibited the oxytocin-induced contractile response in late pregnant uterine tissue. Apigenin also blunted the prostaglandin F2alpha response, but CX-4945 did not. Casein kinase 2 was located in the lipid raft fractions of the cell membrane, and disruption of lipid rafts was found to reverse its effect. The results of the present study suggest that CK2, located in lipid rafts of the cell membrane, is an active regulator of spontaneous and oxytocin-induced uterine contractions in the late pregnant mouse. PMID- 29708305 TI - Validation of the Mission(r) PTCoagulation Monitoring point-of-care device for the outpatient management of patients on long-term warfarin therapy. PMID- 29708306 TI - Comparison of neutrophil distribution patterns in Jordans' anomaly among major automated hematology analyzers. PMID- 29708307 TI - Inkjet-Spray Hybrid Printing for 3D Freeform Fabrication of Multilayered Hydrogel Structures. AB - Here, a new bioprinting process by combining drop-on-demand inkjet printing with a spray-coating technique, which enables the high-resolution, high-speed, and freeform fabrication of large-scale cell-laden hydrogel structures is reported. Hydrogel structures with various shapes and composed of different materials, including alginate, cellulose nanofiber, and fibrinogen, are fabricated using the inkjet-spray printing. To manufacture cell-friendly hydrogel structures with controllable stiffness, gelatine methacryloyl is saponified to stabilize jet formation and is subsequently mixed with sodium alginate to prepare blend inks. The hydrogels crosslinked from the blend inks are characterized by assessing physical properties including the microstructure and mechanical stiffness and cellular responses including the cell viability, metabolic activity, and functionality of human dermal fibroblasts within the hydrogel. Cell-laden hydrogel structures are generated on a large scale and collagen type I secretion and spreading of cells within the hydrogels are assessed. The results demonstrate that the inkjet-spray printing system will ensure the formation of a cell-laden hydrogel structure with high shape fidelity in a rapid and reliable manner. Ultimately, the proposed printing technique and the blend bioink to be used to fabricate 3D laminated large-scale tissue equivalents that potentially mimic the function of native tissues is expected. PMID- 29708308 TI - Externalizing depression symptoms among Canadian males with recent suicidal ideation: A focus on young men. AB - AIM: The primary aim was to quantify, relative to older men, young men's externalizing of depression symptoms and past-month suicidal ideation. METHODS: A non-probability national sample of 1000 Canadian men self-reported internalizing and externalizing symptoms of depression and past-month suicidal ideation. Stratification quotas reflected Canadian census data to age and region. RESULTS: Young men (18-25 years) were at markedly higher risk of past-month suicidal ideation than were older men. When controlling for internalizing depression, a multivariate age * recent suicidal ideation interaction indicated higher externalizing of depression symptoms in young men relative to older men, especially for those reporting recent suicidal ideation (P < .001). Interactions were observed for drug use, anger and aggression, and risk-taking domains. A sizable proportion of younger men were uniquely identified by the MDRS-22. CONCLUSIONS: Screening tools that include assessment of externalizing symptoms may assist in improving detection of distress and suicide risk in young men. PMID- 29708309 TI - Pyrosynthesis of Na3 V2 (PO4 )3 @C Cathodes for Safe and Low-Cost Aqueous Hybrid Batteries. AB - Rechargeable hybrid aqueous batteries (ReHABs) have emerged as promising sustainable energy-storage devices because all components are environmentally benign and abundant. In this study, a carbon-wrapped sponge-like Na3 V2 (PO4 )3 nanoparticle (NVP@C) cathode is prepared by a simple pyrosynthesis for use in the ReHAB system with impressive rate capability and high cyclability. A high resolution X-ray diffraction study confirmed the formation of pure Na ion superionic conductor (NASICON) NVP with rhombohedral structure. When tested in the ReHAB system, the NVP@C demonstrated high rate capability (66 mAh g-1 at 32 C) and remarkable cyclability over 1000 cycles (about 72 % of the initial capacity is retained at 30 C). Structural transformation and oxidation change studies of the electrode evaluated by using in situ synchrotron X-ray diffraction and ex situ X-ray photoelectron spectroscopy, respectively, confirmed the high reversibility of the NVP@C electrode in the ReHAB system through a two-phase reaction. The combined strategy of nanosizing and carbon-wrapping in the NVP particles is responsible for the remarkable electrochemical properties. The pyrosynthesis technique appears to be a promising and feasible approach to prepare a high-performance electrode for safe and low-cost ReHAB systems as nextgeneration large-scale energy storage devices. PMID- 29708310 TI - Early intervention for everyone? A review of cross-cultural issues and their treatment in ultra-high-risk (UHR) cohorts. AB - AIM: Over the past 20 years, early management of psychosis has become both a research and policy priority. In Western countries, psychotic disorders appear more prevalent in migrant and minority ethnic groups than in native or dominant groups. Moreover, disparities exist in health conditions and access to care among immigrants and minority ethnic groups, compared with native-born and majority groups. Appropriate early detection tools are necessary for the different groups. METHODS: This systematic review provides a synthesis of the assessment and discussion of transcultural issues in ultra-high-risk (UHR) cohorts. The Medline database was searched via PubMed for peer-reviewed articles published in English from 1995 to 2017. All 79 studies included are prospective UHR cohort studies that used the Comprehensive Assessment of At-Risk Mental States (CAARMS). RESULTS: In UHR cohort studies that used the CAARMS, transcultural data (native language, ethnicity, place of birth, migration) are rarely collected, and inadequate ability to speak the dominant language is a common exclusion criterion. When they are included, the CAARMS scores differ between some minorities and the native-born majority group. CONCLUSIONS: This systematic review demonstrates barriers to the access to participation in early intervention research for migrants and ethnic minorities. This selection bias may result in lower validity for the CAARMS among these populations and thus in inadequate intervention programmes. Along with targeted studies, minorities' access to participation in UHR cohorts should be improved through 3 tools: interpreters at recruitment and for administration of CAARMS, a guide to cultural formulation and transcultural data collection. PMID- 29708311 TI - The Cloaked Self: Professional Decloaking and its Implications for Human Engagement in Nursing. AB - PURPOSE: Much of our practice as nurses is predicated on the development of a trusting relationship between patient and nurse. Through this, the nurse and patient can identify the issues which are challenging health, the desired outcomes of care and the interventions that will be enacted, by both parties, in order to achieve these outcomes. Often, though, both nurses and patients find it difficult to put aside the relative roles that they play in health care and the level of engagement that is possible may not be achieved. METHODS: In this theoretical paper, I will explore the importance of human engagement to nursing practice, drawing, in a reflective and personal manner, on experiences gained throughout my 30 years of providing nursing service. CONCLUSIONS: Human engagement is central to the practice of nursing, but if engagement is to be valid, it must involve a dialogic transaction between the nurse and patient such that both parties are changed and there is a commitment to journey together, as humans, in the hope of finding positive outcomes for both. PRACTICE IMPLICATIONS: In a time of increasing tendency to build boundaries between people and communities, it is imperative that nursing does not lose its most essential quality: the coming together of human beings in dialogic engagement. PMID- 29708312 TI - Cell behaviour during postembryonic pattern regulation in the insect abdomen (Oncopeltus fasciatus). I. Regeneration of segment borders AB - The confrontation of cells from the anterior region of an abdominal segment of Oncopeltus with those from the posterior region of the same or the adjacent segment results in the generation of a segment border. The behaviour of epidermal cells during this regulation is described. It consists primarily of cell division and transverse elongation of cells at the site of confrontation. This behaviour can be separated from any associated purely with wound healing because a similar sized wound to that used to ablate the segment border, performed within the segment, does not result in any cell division or elongation. The results are consistent with the view that there is a discontinuity in positional values at the segment border. The stability of such a discontinuity and the regeneration of segment borders are discussed in terms of there being a special population of cells at the segment border that have the property of isolating other cells with the maximum difference in positional values. PMID- 29708313 TI - Cell behaviour during postembryonic pattern regulation in the insect abdomen (Oncopeltus fasciatus). II. Intrasegmental regulation AB - Cells from different levels in the anteroposterior axis of an abdominal segment of Oncopeltus were confronted by scraping away the strip of epidermis that separated these levels. The cells migrate over the wound and meet in the centre. The subsequent behaviour of the epidermal cells was followed by preparing whole mounts of integument at various times after confrontation. These operations may lead to cell division and an alteration in cell shape at the confrontation site. The intensity of the induced cell behaviour pattern depends on which levels in the segment are confronted and the evidence suggests that it is directly related to the magnitude of the difference in positional values between confronted cells. The results can be explained by a nonlinear gradient of positional values within the segment with a crowding of values in the posterior region. It is also shown that segment border formation requires the confrontation of cells with a near maximum possible difference in positional values. PMID- 29708314 TI - Initiation of the proximodistal axis in insect legs AB - Much of the cell-cell communication that controls assignment of cell fates during animal development appears to be mediated by extracellular signaling molecules. The formation of the proximodistal (P/D) axis of the legs of flies is controlled by at least two such molecules, a Wnt and a TGFbeta, encoded by the wingless (wg) and decapentaplegic (dpp) genes, respectively. The P/D axis appears to be initiated from the site where cells expressing wg are in close association with those expressing dpp. Support for this hypothesis comes from two sources: classical grafting experiments in cockroaches and ectopic protein expression in Drosophila. PMID- 29708315 TI - Glypican-3 and Melanoma Antigen Genes 1 and 3 as Tumor Markers for Hepatocellular Carcinoma. AB - Hepatocellular carcinoma (HCC) is the commonest liver cancer; its incidence and prevalence are continuously increased. Glypican3 (GPC3), melanoma antigen-1, 3 genes (MAGE1 and 3) are tumor markers used in HCC. We evaluated their role in HCC detection and assessed their relation to tumor parameters. Three groups, HCC group, liver cirrhosis group and a control group were studied. AFP, GPC3, and MAGE1 and 3 mRNA were determined in all study subjects. Tissue GPC3 was examined in patients with HCC only. Serum AFP and GPC3 were elevated in HCC group compared to other groups (P < 0.000 and P < 0.001, respectively). AFP at cutoff 44.4ng/ml and GPC3 at cutoff 5.6ug/L resulted in 81% and 90.1% sensitivity, 73.3% and 92.6% specificity, respectively. The combined measurement of both increased the sensitivity and the specificity to 100% and 93.3%, respectively. GPC 3 was detected in tissues of 81.0% of the cases. MAGE-1 and MAGE-3 genes expression were detected in 61.9% and 52.4%, respectively in HCC cases but not in other groups. GPC3, MAGE1and 3 were increased with advanced tumor stage, size, and nodule numbers. We concluded that GPC3 is a promising diagnostic marker for HCC, and MAGE 1 and 3 could be helpful in early detection of extrahepatic metastasis of HCC. PMID- 29708316 TI - [Motor Imagery Electroencephalogram Feature Selection Algorithm Based on Mutual Information and Principal Component Analysis]. AB - Aiming at feature selection problem of motor imagery task in brain computer interface(BCI),an algorithm based on mutual information and principal component analysis(PCA)for electroencephalogram(EEG)feature selection is presented.This algorithm introduces the category information,and uses the sum of mutual information matrices between features under different motor imagery category to replace the covariance matrix.The eigenvectors of the sum matrix represent the direction of the principal components and the eigenvalues of the sum matrix are used to determine the dimensionality of principal components.2005 International BCI competition data set was used in our experiments,and four feature extraction methods were adopted,i.e.power spectrum estimation,continuous wavelet transform,wavelet packet decomposition and Hjorth parameters.The proposed feature selection algorithm was adopted to select and combine the most useful features for classification.The results showed that relative to the PCA algorithm,our algorithm had better performance in dimensionality reduction and in classification accuracy with the assistance of support vector machine classifier under the same dimensionality of principal components. PMID- 29708317 TI - [Three-class Motor Imagery Classification Based on Optimal Sub-band Features of Independent Components]. AB - In the study of the scalp electroencephalogram(EEG)-based brain-computer interface(BCI),individual differences and complex background noise are two main factors which affect the stability of BCI system.For different subjects,therefore,optimization of BCI system parameters is necessary,including the optimal designing of temporal and spatial filters parameters as well as the classifier parameters.In order to improve the accuracy of BCI system,this paper proposes a new BCI information processing method,which combines the optimization design of independent component analysis spatial filter(ICA-SF)with the multiple sub-band features of EEG signals.The four subjects' three-class motor imagery EEG(MI-EEG)data collected in different periods were analyzed with the proposed method.Experimental results revealed that,during the inner and outer cross validation of single subject as well as the subject-to-subject validation,the proposed multiple sub-band method always had higher average classification accuracy compared to those with single-band method,and the maximum difference could achieve 6.08% and5.15%,respectively. PMID- 29708318 TI - [Classifying Electroencephalogram Signal Using Under-determined Blind Source Separation and Common Spatial Pattern]. AB - One of the key problems of brain-computer interfaces(BCI)is low signal-to-noise ratio(SNR)of electroencephalogram(EEG)signals.It affects recognition performance.To remove the artifact and noise,block under-determined blind source separation method based on the small number of channels is proposed in this paper.The nonstationary EEG signals are turned into block stationary signals by piecewise.The mixing matrix is estimated by the second-order under-determined blind mixing matrix identification.Then,the beamformer based on minimum mean square error separates the original sources of signals.Eventually,the reconstructed EEG for mixed signals removes the unwanted components of source signals to achieve suppressing artifact.The experiment results on the real motor imagery BCI indicated that the block under-determined blind source separation method could reconstruct signals and remove artifact effectively.The accuracy of motor imagery task of BCI has been greatly improved. PMID- 29708319 TI - [Study on Electrocardiogram Signal De-noising Methods Based on Ensemble Empirical Mode Decomposition Decomposed by White Noise]. AB - Ensemble empirical mode decomposition(EEMD)is an effective method for non stationary signal analysis,such as electrocardiogram(ECG)signals.However,the precision and correctness of EEMD are affected by the two parameters,ratio of the added noise and ensemble number.The values of two parameters are set relying on experience and lacking of adaptability for uncertain signals.In order to solve these problems,we proposed a method based on white noise decomposed by EEMD in the present study shown in this paper.Empirical mode decomposition(EMD)was applied to decompose the signal to different intrinsic mode functions(IMFs)in the de-noising process.The white noise IMFs were selected to constitute high frequency part based on the character that the product of the energy density of white noise and its average period tended to be a constant.Then the two parameters of EEMD were adaptively obtained according to the criterion which was used to avoid modal aliasing.Experimental results showed that the method was an effective one for ECG signal de-noising. PMID- 29708320 TI - [An Improved Cubic Spline Interpolation Method for Removing Electrocardiogram Baseline Drift]. AB - The selection of fiducial points has an important effect on electrocardiogram(ECG)denoise with cubic spline interpolation.An improved cubic spline interpolation algorithm for suppressing ECG baseline drift is presented in this paper.Firstly the first order derivative of original ECG signal is calculated,and the maximum and minimum points of each beat are obtained,which are treated as the position of fiducial points.And then the original ECG is fed into a high pass filter with 1.5Hz cutoff frequency.The difference between the original and the filtered ECG at the fiducial points is taken as the amplitude of the fiducial points.Then cubic spline interpolation curve fitting is used to the fiducial points,and the fitting curve is the baseline drift curve.For the two simulated case test,the correlation coefficients between the fitting curve by the presented algorithm and the simulated curve were increased by 0.242and0.13 compared with that from traditional cubic spline interpolation algorithm.And for the case of clinical baseline drift data,the average correlation coefficient from the presented algorithm achieved 0.972. PMID- 29708321 TI - [Classification of Children with Attention-Deficit/Hyperactivity Disorder and Typically Developing Children Based on Electroencephalogram Principal Component Analysis and k-Nearest Neighbor]. AB - This paper aims to assist the individual clinical diagnosis of children with attention-deficit/hyperactivity disorder using electroencephalogram signal detection method.Firstly,in our experiments,we obtained and studied the electroencephalogram signals from fourteen attention-deficit/hyperactivity disorder children and sixteen typically developing children during the classic interference control task of Simon-spatial Stroop,and we completed electroencephalogram data preprocessing including filtering,segmentation,removal of artifacts and so on.Secondly,we selected the subset electroencephalogram electrodes using principal component analysis(PCA)method,and we collected the common channels of the optimal electrodes which occurrence rates were more than 90%in each kind of stimulation.We then extracted the latency(200~450ms)mean amplitude features of the common electrodes.Finally,we used the k-nearest neighbor(KNN)classifier based on Euclidean distance and the support vector machine(SVM)classifier based on radial basis kernel function to classify.From the experiment,at the same kind of interference control task,the attention deficit/hyperactivity disorder children showed lower correct response rates and longer reaction time.The N2 emerged in prefrontal cortex while P2 presented in the inferior parietal area when all kinds of stimuli demonstrated.Meanwhile,the children with attention-deficit/hyperactivity disorder exhibited markedly reduced N2 and P2amplitude compared to typically developing children.KNN resulted in better classification accuracy than SVM classifier,and the best classification rate was 89.29%in StI task.The results showed that the electroencephalogram signals were different in the brain regions of prefrontal cortex and inferior parietal cortex between attention-deficit/hyperactivity disorder and typically developing children during the interference control task,which provided a scientific basis for the clinical diagnosis of attention-deficit/hyperactivity disorder individuals. PMID- 29708322 TI - [Automatic Classification of Dry Cough and Wet Cough Based on Improved Reverse Mel Frequency Cepstrum Coefficients]. AB - Automatic classification of different types of cough plays an important role in clinical.In the previous research of cough classification or cough recognition,traditional Mel frequency cepstrum coefficients(MFCC)which extracts feature mainly from low frequency band is usually used as feature expression.In this paper,by analyzing the distributions of spectral energy of dry/wet cough,it is found that spectral difference of two types of cough exits mainly in middle frequency band and high frequency band.To better reflect the spectral difference of dry cough and wet cough,an improved method of extracting reverse MFCC is proposed.In this method,reverse Mel filter-bank in which filters are allocated in reverse Mel scale is adopted and is improved by placing filters only in the frequency band with high spectral energy.As a result,features are mainly extracted from the frequency band where two types of cough show both high spectral energy and distinguished difference.Detailed process of accessing improved reverse MFCC was introduced and hidden Markov models trained by 60 dry cough and 60 wet cough were used as cough classification model.Classification experiment results for 120 dry cough and 85 wet cough showed that,compared to traditional MFCC,better classification performance was achieved by the proposed method and the total classification accuracy was raised from 89.76%to 93.66%. PMID- 29708323 TI - [Analysis of Abnormal Muscular Coupling During Rehabilitation after Stroke]. AB - For the questions of deeply researching abnormal neuromuscular coupling and better evaluating motor function of stroke patients with motor dysfunction,an effective intermuscular coherence analysis method and index are studied to explore the neuromuscular oscillation and the pathomechanism of motor dysfunction,based on which an assessment standard of muscle function is established.Firstly,the contrastive analysis about the intermuscular coherence of antagonistic muscle of affected and intact upper limbs of stroke patients was conducted.Secondly,a significant indicator of Fisher's Z-transformed coherence significant indicator was defined to quantitatively describe the coupling differences in certain functional frequency domain between surface electromyogram(sEMG)of affected and intact sides.Further more,the relationship between intermuscular coherence and motor task was studied.Through the analysis of intermuscular coherence during elbow flexion-extension of affected and intact sides,we found that the intermuscular coherence was associated with motor task and the stroke patients exhibited significantly lower betaband intermuscular coherence in performing the task with their affected upper limbs.More conclusion can be drawn that beta-band intermuscular coherence has been found concerned with Fugle-Meyer scale,which indicates that betaband intermuscular coherence could be an index assisting in evaluating motor function of patients. PMID- 29708324 TI - [Controlling Epileptogenic Excitation Based on Neural Mass Model]. AB - Overexcitation of neurons in brain can lead to epilepsy seizures,and the key to control epilepsy seizures is to keep the balance between excitation and inhibition.In this paper,epileptiform index is presented to denote the seizure degree and used as control variable of PID controller to control epilepsy seizures.Neural mass model(NMM)is used as a test-bed to simulate the change of seizure degree with the increase of excitatory strength and two control strategies.Experimental results showed that the increase of excitatory strength could lead to a substantial increase of epileptiform index and trigger seizures.PID controller which is used to decrease excitatory strength or increase inhibitory strength can keep excitation-inhibition balance and inhibit epilepsy seizures.Epileptiform index can describe the linear and nonlinear feature of electroencephalogram(EEG)comprehensively,and PID controller is simple and independent of underlying physiological structure,which lays the foundation for its application in the clinic. PMID- 29708325 TI - [Preliminary Studies on the Hydrodynamic Behaviors and Mechanisms of Hepatic Vessel Perfusion Using Simple Vessel Models]. AB - The hydrodynamic behavior of the perfusion process(cleaning)of the liver endovascular before the operation was studied to provide a theoretical guidance to the relative operations.A straight and a curved first-class vascular entity model with foreign matter and the control equations of turbulence liquid in vessel was established.With the physical parameters of a medical infusion liquid measured,an estimation method of perfusion parameters as an example,the perfusion velocity was proposed.The simulation was performed by changing technical parameters of the perfusion.Based on the control equations of turbulent liquid in vessel and the preliminarily calculated results using the vessel model,the results fitted the values of the real operation.The simulation results showed clearly the fluid dynamics behavior around the foreign matter,for example the swirling flow.The results also showed the distribution of velocity of the fluid and the wall pressure of the vessels.With the increasing velocity of the entrance perfusion,the pressure and the velocity field were increased in the two types of the vessel model.The negative wall pressure and recirculation region appeared and located in the foreign matter.Because of influence of the shape,the fluid dynamics behavior in the curved vessel model was more complicated than that in the straight vessel model.The swirling flow and the phenomenon of stagnation of the perfusion fluid were more likely to appear in the curved vessel than in the straight vessel.The most important conclusion of this paper is that the appropriate perfusion velocity can be estimated using the methods proposed in this paper. PMID- 29708326 TI - Stilbenes from Veratrum maackii Regel Protect against Ethanol-Induced DNA Damage in Mouse Cerebellum and Cerebral Cortex. AB - Ethanol is a principle ingredient of alcoholic beverages with potential neurotoxicity and genotoxicity, and the ethanol-associated oxidative DNA damage in the central nervous system is well documented. Natural source compounds may offer new options to protect the brain against ethanol-induced genotoxicity. Veratrum maackii Regel is a toxic rangeland plant linked to teratogenicity which is also used in traditional Chinese medicine as "Lilu" and is reported to contain a family of compounds called stilbenes that can have positive biological activity. In this study, nine stilbenes were isolated from the aerial parts of V. maackii Regel, and their structures were identified as cis-mulberroside A (1), resveratrol-4,3'- O-beta-d-diglucopyranoside (2), mulberroside A (3), gentifolin K (4), resveratrol-3,5- O-beta-d-diglucopyranoside (5), oxyresveratrol- 4'- O beta-d-glucopyranoside (6), oxyresveratrol-3- O-beta-d-glucopyranoside (7), oxyresveratrol (8), and resveratrol (9) using ESI-MS and NMR techniques. The total concentration of extracted compounds 2-9 was 2.04 mg/g, suggesting that V. maackii Regel is a novel viable source of these compounds. In an in vivo comet assay, compounds 1-9 were observed to decrease DNA damage in mouse cerebellum and cerebral cortex caused by acute ethanol administration. Histological observation also revealed decreased brain injury in mice administered with compounds 1-9 after acute ethanol administration. The protective effects of compound 6 were associated with increasing T-SOD and GSH-PX activities and a decrease in NO and MDA concentrations. These findings suggest that these compounds are potent inhibitors of ethanol-induced brain injury possibly via the inhibition of oxidative stress and may be valuable leads for future therapeutic development. PMID- 29708327 TI - Graphdiyne-Doped P3CT-K as an Efficient Hole-Transport Layer for MAPbI3 Perovskite Solar Cells. AB - Here we reported the doping of graphdiyne in P3CT-K in MAPbI3 perovskite solar cells as hole-transport materials. The doping could improve the surface wettability of P3CT-K, and the resulting perovskite morphology was improved with homogeneous coverage and reduced grain boundaries. Simultaneously, it increased the hole-extraction mobility and reduced the recombination as well as improved the performance of devices. Therefore, a high efficiency of 19.5% was achieved based on improved short-circuit current and fill factor. In addition, hysteresis of the J- V curve was also obviously reduced. This work paves the way for the development of highly efficient perovskite solar cells. PMID- 29708328 TI - Dual-Responsive Metabolic Precursor and Light-Up AIEgen for Cancer Cell Bio orthogonal Labeling and Precise Ablation. AB - Metabolic glycoengineering of unnatural glycans with bio-orthogonal chemical groups and a subsequent click reaction with fluorescent probes have been widely used in monitoring various bioprocesses. Herein, we developed a dual-responsive metabolic precursor that could specifically generate unnatural glycans with azide groups on the membrane of targeted cancer cells with high selectivity. Moreover, a water-soluble fluorescent light-up probe with aggregation-induced emission (AIE) was synthesized, which turned its fluorescence on upon a click reaction with azide groups on the cancer cell surface, enabling special cancer cell imaging with low background signal. Furthermore, the probe can generate 1O2 upon light irradiation, fulfilling its dual role as an imaging and therapeutic agent for cancer cells. Therefore, the concepts of the cancer-cell-specific metabolic precursor cRGD-S-Ac3ManNAz and the AIE light-up probe are promising in bio orthogonal labeling and cancer-specific imaging and therapy. PMID- 29708329 TI - Imaging Tiny Hepatic Tumor Xenografts via Endoglin-Targeted Paramagnetic/Optical Nanoprobe. AB - Surgery is the mainstay for treating hepatocellular carcinoma (HCC). However, it is a great challenge for surgeons to identify HCC in its early developmental stage. The diagnostic sensitivity for a tiny HCC with a diameter less than 1.0 cm is usually as low as 10-33% for computed tomography (CT) and 29-43% for magnetic resonance imaging (MRI). Although MRI is the preferred imaging modality for detecting HCC, with its unparalleled spatial resolution for soft tissue, the commercially available contrast agent, such as Gd3+-DTPA, cannot accurately define HCC because of its short circulation lifetime and lack of tumor-targeting specificity. Endoglin (CD105), a type I membrane glycoprotein, is highly expressed both in HCC cells and in the endothelial cells of neovasculature, which are abundant at the tumor periphery. In this work, a novel single-stranded DNA oligonucleotide-based aptamer was screened by systematic evolution of ligands in an exponential enrichment assay and showed a high binding affinity ( KD = 98 pmol/L) to endoglin. Conjugating the aptamers and imaging reporters on a G5 dendrimer created an HCC-targeting nanoprobe that allowed the successful visualization of orthotopic HCC xenografts with diameters as small as 1-4 mm. Significantly, the invasive tumor margin was clearly delineated, with a tumor to normal ratio of 2.7 by near-infrared (NIR) fluorescence imaging and 2.1 by T1 weighted MRI. This multimodal nanoprobe holds promise not only for noninvasively defining tiny HCC by preoperative MRI but also for guiding tumor excision via intraoperative NIR fluorescence imaging, which will probably gain benefit for the patient's therapeutic response and improve the survival rate. PMID- 29708330 TI - Highly Sensitive Refractive Index Sensors with Plasmonic Nanoantennas-Utilization of Optimal Spectral Detuning of Fano Resonances. AB - We analyze and optimize the performance of coupled plasmonic nanoantennas for refractive index sensing. The investigated structure supports a sub- and super radiant mode that originates from the weak coupling of a dipolar and quadrupolar mode, resulting in a Fano-type spectral line shape. In our study, we vary the near-field coupling of the two modes and particularly examine the influence of the spectral detuning between them on the sensing performance. Surprisingly, the case of matched resonance frequencies does not provide the best sensor. Instead, we find that the right amount of coupling strength and spectral detuning allows for achieving the ideal combination of narrow line width and sufficient excitation strength of the subradiant mode, and therefore results in optimized sensor performance. Our findings are confirmed by experimental results and first order perturbation theory. The latter is based on the resonant state expansion and provides direct access to resonance frequency shifts and line width changes as well as the excitation strength of the modes. Based on these parameters, we define a figure of merit that can be easily calculated for different sensing geometries and agrees well with the numerical and experimental results. PMID- 29708331 TI - Effects of the 1- N-(4-Amino-2 S-hydroxybutyryl) and 6'- N-(2-Hydroxyethyl) Substituents on Ribosomal Selectivity, Cochleotoxicity, and Antibacterial Activity in the Sisomicin Class of Aminoglycoside Antibiotics. AB - Syntheses of the 6'- N-(2-hydroxyethyl) and 1- N-(4-amino-2 S-hydroxybutyryl) derivatives of the 4,6-aminoglycoside sisomicin and that of the doubly modified 1 N-(4-amino-2 S-hydroxybutyryl)-6'- N-(2-hydroxyethyl) derivative known as plazomicin are reported together with their antibacterial and antiribosomal activities and selectivities. The 6'- N-(2-hydroxyethyl) modification results in a moderate increase in prokaryotic/eukaryotic ribosomal selectivity, whereas the 1- N-(4-amino-2 S-hydroxybutyryl) modification has the opposite effect. When combined in plazomicin, the effects of the two groups on ribosomal selectivity cancel each other out, leading to the prediction that plazomicin will exhibit ototoxicity comparable to those of the parent and the current clinical aminoglycoside antibiotics gentamicin and tobramycin, as borne out by ex vivo studies with mouse cochlear explants. The 6'- N-(2-hydroxyethyl) modification restores antibacterial activity in the presence of the AAC(6') aminoglycoside modifying enzymes, while the 1- N-(4-amino-2 S-hydroxybutyryl) modification overcomes resistance to the AAC(2') class but is still affected to some extent by the AAC(3) class. Neither modification is able to circumvent the ArmA ribosomal methyltransferase-induced aminoglycoside resistance. The use of phenyltriazenyl protection for the secondary amino group of sisomicin facilitates the synthesis of each derivative and their characterization through the provision of sharp NMR spectra for all intermediates. PMID- 29708332 TI - New Insights into the Changes of the Proteome and Microbiome of Shrimp ( Litopenaeus vannamei) Stored in Acidic Electrolyzed Water Ice. AB - Acidic electrolyzed water (AEW) ice is a novel technique for prolonging the shelf life of foods, but there is limited knowledge of its preservation mechanism. A proteomics approach and 16S rRNA-based Illumina sequencing were employed to investigate the changes of key proteins and bacterial communities in shrimp stored in AEW ice and tap water ice (TW ice) for 7 days. Compared with TW ice, AEW ice markedly retards the degradation of myofibrillar proteins in shrimp, including myosin, actin, and tropomyosin. Moreover, sarcoplasmatic proteins that participate in the carbohydrate catabolic process and amino acid metabolism were also influenced. Furthermore, the growth of spoilage bacteria, which includes the genera Psychrobacter, Shewanella, and Flavobacterium, was significantly inhibited by AEW ice, and the inhibition rates at day 7 were 71.6, 47.8, and 100%, respectively ( p < 0.05). Further correlation analysis showed the links between spoilage bacteria and protein changes can be broken by AEW ice treatment. Collectively, our findings indicated AEW ice can improve the quality of shrimp via previously undescribed mechanisms, which retarded the degradation of myofibrillar proteins and inhibited the growth of spoilage bacteria. PMID- 29708333 TI - Reduction of RuVI=N to RuIII-NH3 by Cysteine in Aqueous Solution. AB - The reduction of metal nitride to ammonia is a key step in biological and chemical nitrogen fixation. We report herein the facile reduction of a ruthenium(VI) nitrido complex [(L)RuVI(N)(OH2)]+ (1, L = N, N'-bis(salicylidene)- o-cyclohexyldiamine dianion) to [(L)RuIII(NH3)(OH2)]+ by l-cysteine (Cys), an ubiquitous biological reductant, in aqueous solution. At pH 1.0-5.3, the reaction has the following stoichiometry: [(L)RuVI(N)(OH2)]+ + 3HSCH2CH(NH3)CO2 -> [(L)RuIII(NH3)(OH2)]+ + 1.5(SCH2CH(NH3)CO2)2. Kinetic studies show that at pH 1 the reaction consists of two phases, while at pH 5 there are three distinct phases. For all phases the rate law is rate = k2[1][Cys]. Studies on the effects of acidity indicate that both HSCH2CH(NH3+)CO2- and -SCH2CH(NH3+)CO2- are kinetically active species. At pH 1, the reaction is proposed to go through [(L)RuIV(NHSCH2CHNH3CO2H)(OH2)]2+ (2a), [(L)RuIII(NH2SCH2CHNH3CO2H)(OH2)]2+ (3), and [(L)RuIV(NH2)(OH2)]+ (4) intermediates. On the other hand, at pH around 5, the proposed intermediates are [(L)RuIV(NHSCH2CHNH3CO2)(OH2)]+ (2b) and [(L)RuIV(NH2)(OH2)]+ (4). The intermediate ruthenium(IV) sulfilamido species, [(L)RuIV(NHSCH2CHNH3CO2H)(OH2)]2+ (2a) and the final ruthenium(III) ammine species, [(L)RuIII(NH3)(MeOH)]+ (5) (where H2O was replaced by MeOH) have been isolated and characterized by various spectroscopic methods. PMID- 29708334 TI - Correction to In Vivo Imaging of Human Neuroinflammation. PMID- 29708335 TI - Inhibitive Effects of Quercetin on Myeloperoxidase-Dependent Hypochlorous Acid Formation and Vascular Endothelial Injury. AB - Myeloperoxidase (MPO) from activated neutrophils plays important roles in multiple human inflammatory diseases by catalyzing the formation of powerful oxidant hypochlorous acid (HOCl). As a major flavonoid in the human diet, quercetin has been suggested to act as antioxidant and anti-inflammatory agent in vitro and in vivo. In this study, we showed that quercetin inhibited MPO-mediated HOCl formation (75.0 +/- 6.2% for 10 MUM quercetin versus 100 +/- 5.2% for control group, P < 0.01) and cytotoxicity to endothelial cells in vitro, while this flavonoid was nontoxic to endothelial cell cultures ( P > 0.05, all cases). Moreover, quercetin inhibited HOCl generation by stimulated neutrophils (a rich source of MPO) and protected endothelial cells from neutrophils-induced injury. Furthermore, quercetin could inhibit HOCl-induced endothelial dysfunction such as loss of cell viability, and decrease of nitric oxide formation in endothelial cells ( P < 0.05, all cases). Consistent with these in vitro data, quercetin attenuated lipopolysaccharide-induced endothelial dysfunction and increase of MPO activity in mouse aortas, while this flavonoid could protect against HOCl mediated endothelial dysfunction in isolated aortas ( P < 0.05). Therefore, it was proposed that quercetin attenuated endothelial injury in inflammatory vasculature via inhibition of vascular-bound MPO-mediated HOCl formation or scavenging of HOCl. These data indicate that quercetin is a nontoxic inhibitor of MPO activity and MPO/neutrophils-induced cytotoxicity in endothelial cells and may be useful for targeting MPO-dependent vascular disease and inflammation. PMID- 29708336 TI - Controllable Spatial Configuration on Cathode Interface for Enhanced Photovoltaic Performance and Device Stability. AB - The molecular structure of cathode interface modification materials can affect the surface morphology of the active layer and key electron transfer processes occurring at the interface of polymer solar cells in inverted structures mostly due to the change of molecular configuration. To investigate the effects of spatial configuration of the cathode interfacial modification layer on polymer solar cells device performances, we introduced two novel organic ionic salts (linear NS2 and three-dimensional (3D) NS4) combined with the ZnO film to fabricate highly efficient inverted solar cells. Both organic ionic salts successfully decreased the surface traps of the ZnO film and made its work function more compatible. Especially NS4 in three-dimensional configuration increased the electron mobility and extraction efficiency of the interfacial film, leading to a significant improvement of device performance. Power conversion efficiency (PCE) of 10.09% based on NS4 was achieved. Moreover, 3D interfacial modification could retain about 92% of its initial PCE over 160 days. It is proposed that 3D interfacial modification retards the element penetration induced degradation without impeding the electron transfer from the active layer to the ZnO film, which significantly improves device stability. This indicates that inserting three-dimensional organic ionic salt is an efficient strategy to enhance device performance. PMID- 29708337 TI - Ligation and Reactivity of Methionine-Oxidized Cytochrome c. AB - Met80, one of the heme iron ligands in cytochrome c (cyt c), is readily oxidized to Met sulfoxide (Met-SO) by several biologically relevant oxidants. The modification has been suggested to affect both the electron-transfer (ET) and apoptotic functions of this metalloprotein. The coordination of the heme iron in Met-oxidized cyt c (Met-SO cyt c) is critical for both of these functions but has remained poorly defined. We present electronic absorption, NMR, and EPR spectroscopic investigations as well as kinetic studies and mutational analyses to identify the heme iron ligands in yeast iso-1 Met-SO cyt c. Similar to the alkaline form of native cyt c, Lys73 and Lys79 ligate to the ferric heme iron in the Met80-oxidized protein, but this coordination takes place at much lower pH. The ferrous heme iron is ligated by Met-SO, implying the redox-linked ligand switch in the modified protein. Binding studies with the model peptide microperoxidase-8 provide a rationale for alterations in ligation and for the role of the polypeptide packing in native and Met-SO cyt c. Imidazole binding experiments have revealed that Lys dissociation from the ferric heme in K73A/K79G/M80K (M80K#) and Met-SO is more than 3 orders of magnitude slower than the opening of the heme pocket that limits Met80 replacement in native cyt c. The Lys-to-Met-SO ligand substitution gates ET of ferric Met-SO cyt c with Co(terpy)22+. Owing to the slow Lys dissociation step, ET reaction is slow but possible, which is not the case for nonswitchable M80A and M80K#. Acidic conditions cause Lys replacement by a water ligand in Met-SO cyt c (p Ka = 6.3 +/ 0.1), increasing the intrinsic peroxidase activity of the protein. This pH driven ligand switch may be a mechanism to boost peroxidase function of cyt c specifically in apoptotic cells. PMID- 29708338 TI - Enhanced Monte Carlo Methods for Modeling Proteins Including Computation of Absolute Free Energies of Binding. AB - The generation of a complete ensemble of geometrical configurations is required to obtain reliable estimations of absolute binding free energies by alchemical free energy methods. Molecular dynamics (MD) is the most popular sampling method, but the representation of large biomolecular systems may be incomplete owing to energetic barriers that impede efficient sampling of the configurational space. Monte Carlo (MC) methods can possibly overcome this issue by adapting the attempted movement sizes to facilitate transitions between alternative local energy minima. In this study, we present an MC statistical mechanics algorithm to explore the protein-ligand conformational space with emphasis on the motions of the protein backbone and side chains. The parameters for each MC move type were optimized to better reproduce conformational distributions of 18 dipeptides and the well-studied T4-lysozyme L99A protein. Next, the performance of the improved MC algorithms was evaluated by computing absolute free energies of binding for L99A lysozyme with benzene and seven analogs. Results for benzene with L99A lysozyme from MD and the optimized MC protocol were found to agree within 0.6 kcal/mol, while a mean unsigned error of 1.2 kcal/mol between MC results and experiment was obtained for the seven benzene analogs. Significant advantages in computation speed are also reported with MC over MD for similar extents of configurational sampling. PMID- 29708339 TI - Structural Evolution of Metal (Oxy)hydroxide Nanosheets during the Oxygen Evolution Reaction. AB - Metal (oxy)hydroxides (MO xH y, M = Fe, Co, Ni, and mixtures thereof) are important materials in electrochemistry. In particular, MO xH y are the fastest known catalysts for the oxygen evolution reaction (OER) in alkaline media. While key descriptors such as overpotentials and activity have been thoroughly characterized, the nanostructure and its dynamics under electrochemical conditions are not yet fully understood. Here, we report on the structural evolution of Ni1-deltaCodeltaO xH y nanosheets with varying ratios of Ni to Co, in operando using atomic force microscopy during electrochemical cycling. We found that the addition of Co to NiO xH y nanosheets results in a higher porosity of the as-synthesized nanosheets, apparently reducing mechanical stress associated with redox cycling and hence enhancing stability under electrochemical conditions. As opposed to nanosheets composed of pure NiO xH y, which dramatically reorganize under electrochemical conditions to form nanoparticle assemblies, restructuring is not found for Ni1-deltaCodeltaO xH y with a high Co content. Ni0.8Fe0.2O xH y nanosheets show high roughness as-synthesized which increases during electrochemical cycling while the integrity of the nanosheet shape is maintained. These findings enhance the fundamental understanding of MO xH y materials and provide insight into how nanostructure and composition affect structural dynamics at the nanoscale. PMID- 29708340 TI - Electroporation of Skin Stratum Corneum Lipid Bilayer and Molecular Mechanism of Drug Transport: A Molecular Dynamics Study. AB - The electroporation technique has been used significantly to increase drug permeation through the skin. This technique relies on the application of short timed (microseconds to millisecond) electric fields (generally, order of 50--300 V) on the skin to create microscopic pores. However, the molecular mechanism of pore formation, resulting in an enhanced flux of active molecules through the skin, remains poorly understood. In this study, extensive atomistic molecular dynamics simulation of skin lipids [made up of ceramide (CER), cholesterol (CHOL), and free fatty acid (FFA)] has been performed at various external electric fields. We show for the first time the pore formation in the skin lipid bilayer during electroporation. We show the effect of the applied external electrical field (0.6-1.0 V/nm) on the pore formation dynamics in the lipid bilayer of different sizes (154, 616, and 2464 lipids) and compositions (CER/CHOL/FFA, 1:0:0, 1:0:1, 1:1:0, 1:1:1). The pore formation and resealing kinetics were different and were found to be highly dependent on the composition of the skin lipid bilayer. The pore formation time decreased with increase in the bilayer size. The pore sustaining electric field was found to be in the range of 0.20-0.25 V/nm for equimolar CER, CHOL, and FFA lipid bilayers. The skin lipid bilayer (1:1:1) sealed itself within 20 ns after the removal of the external electric field. We also present the molecular mechanism of enhancement of drug permeation in the presence of external field as compared to the passive diffusion. The molecular-level understanding obtained here could help in optimizing/designing the electroporation experiments for effective drug delivery. For a given skin composition and size of the drug molecule, the combination of pore formation time and pore growth model can be used to know a priori the desired electric field and time for the application of the electric field. PMID- 29708341 TI - Allosteric Self-Assembly of Coordinating Terthiophene Amphiphile for Triggered Light Harvesting. AB - Allosteric regulation is extensively employed by nature to achieve functional control of protein or deoxyribonucleic acid through triggered conformational change at a remote site. We report that a similar strategy can be utilized in artificial self-assembly to control the self-assembled structure and its function. We show that on binding of metal ions to the headgroup of an amphiphile TTC4L, the conformational change may lead to change of the dipole orientation of the energy donor at the chain end. This on the one hand leads to a drastically different self-assembled structure; on the other hand, it enables light harvesting between the donor-acceptor. Because the Forster resonance fluorescence transfer efficiency is gated by metal ions, controlling the feeding of metal ions allows switching on and off of light harvesting. We expect that using allosteric self-assembly, we will be able to create abundant structures with distinct function from limited molecules, which show prominent potential for the postorganic modification of the structure and function of self-assembled materials. PMID- 29708342 TI - Origin of the Reactive and Nonreactive Excited States in the Primary Reaction of Rhodopsins: pH Dependence of Femtosecond Absorption of Light-Driven Sodium Ion Pump Rhodopsin KR2. AB - KR2 is the first light-driven Na+-pumping rhodopsin discovered. It was reported that the photoexcitation of KR2 generates multiple S1 states, i.e., "reactive" and "nonreactive" S1 states at physiological pH, but their origin remained unclear. In this study, we examined the S1 state dynamics of KR2 using femtosecond time-resolved absorption spectroscopy at different pH's in the range from 4 to 11. It was found that the reactive S1 state is predominantly formed at pH >9, but its population drastically decreases with decreasing pH while the population of the nonreactive S1 state(s) increases. The pH dependence of the relative population of the reactive S1 state correlates very well with the pH titration curve of Asp116, which is the counterion of the protonated retinal Schiff base (PRSB) in KR2. This strongly indicates that the deprotonation/protonation of Asp116 is directly related to the generation of the multiple S1 states in KR2. The quantitative analysis of the time-resolved absorption data led us to conclude that the reactive and nonreactive S1 states of KR2 originate from KR2 proteins having a hydrogen bond between Asp116 and PRSB or not, respectively. In other words, it is the ground-state inhomogeneity that is the origin of the coexistence of the reactive and nonreactive S1 states in KR2. So far, the generation of multiple S1 states having a different photoreactivity of rhodopsins has been mainly explained with the branching of the relaxation pathway in the Franck-Condon region in the S1 state. The present study shows that the structural inhomogeneity in the ground state, in particular that of the hydrogen-bond network, is the more plausible origin of the reactive and nonreactive S1 states which have been widely observed for various rhodopsins. PMID- 29708344 TI - Synthetic Studies Toward Pactamycin Highlighting Oxidative C-H and Alkene Amination Technologies. AB - A strategy enabled by C-H and alkene amination technologies for synthesizing the aminocyclitol natural product, pactamycin, is disclosed. This work features two disparate approaches for assembling the five-membered ring core of the target, the first of which utilizes acyl anion catalysis and a second involving beta ketoester aerobic hydroxylation. Installation of the C3-N bond, one of three contiguous nitrogen centers, is made possible through Rh-catalyzed allylic C-H amination of a sulfamate ester. Subsequent efforts are presented to introduce the C1,C2 cis-diamino moiety en route to pactamycin, including carbamate-mediated alkene aziridination. In the course of these studies, assembly of the core of C2- epi-pactamycate, which bears the carbon skeleton and all of the requisite nitrogen and oxygen functional groups found in the natural product, has been achieved. PMID- 29708343 TI - Nanodroplets Impact on Rough Surfaces: A Simulation and Theoretical Study. AB - Impact of droplets is widespread in life, and modulating the dynamics of impinging droplets is a significant problem in production. However, on textured surfaces, the micromorphologic change and mechanism of impinging nanodroplets are not well-understood; furthermore, the accuracy of the theoretical model for nanodroplets needs to be improved. Here, considering the great challenge of conducting experiments on nanodroplets, a molecular dynamics simulation is performed to visualize the impact process of nanodroplets on nanopillar surfaces. Compared with macroscale droplets, apart from the similar relation of restitution coefficient with the Weber number, we found some distinctive results: the maximum spreading time is described as a power law of impact velocity, and the relation of maximum spreading factor with impact velocity or the Reynolds number is exponential. Moreover, the roughness of substrates plays a prominent role in the dynamics of impact nanodroplets, and on surfaces with lower solid fraction, the lower attraction force induces an easier rebound of impact nanodroplets. At last, on the basis of the energy balance, through modifying the estimation of viscous dissipation and surface energy terms, we proposed an improved model for the maximum spreading factor, which shows greater accuracy for nanodroplets, especially in the low-to-moderate velocity range. The outcome of this study demonstrates that a distinctive dynamical behavior of impinging nanodroplets, the fundamental insight, and more accurate prediction are very useful in the improvement of the hydrodynamic behavior of the nanodroplets. PMID- 29708345 TI - Unified Scaling of the Structure and Loading of Nanoparticles Formed by Diffusion Limited Coalescence. AB - The present study establishes the scaling laws describing the structure of spherical nanoparticles formed by diffusion-limited coalescence. We produced drug loaded nanoparticles from a poly(ethylene glycol)-poly(d,l-lactic acid) diblock polymer (PEG- b-PLA) by the nanoprecipitation method using different types of micromixing chambers to explore multiple mixing regimes and characteristic times. We first show that the drug loading of the nanoparticles is not controlled by the mixing time but solely by the drug-to-polymer ratio (D:P) in the feed and the hydrophobicity of the drug scaled via the partition coefficient P. We then procure compelling evidence that particles formed via diffusion/coalescence exhibit a relative distribution of PEG blocks between the particle core and its shell that depends only on mixing conditions (not on D:P). Scaling laws of PEG relative distribution and chain surface density were derived in different mixing regimes and showed excellent agreement with experimental data. In particular, results made evident that PEG blocks entrapment in the core of the particles occurs in the slow-mixing regime and favors the overloading (above the thermodynamic limit) of the particles with hydrophilic drugs. The present analysis compiles effective guidelines for the scale up of nanoparticles structure and properties with mixing conditions, which should facilitate their future translation to medical and industrial settings. PMID- 29708346 TI - Synthesis of Pyrimidopyrrolopyridazines via a Tandem Reaction of Heterocyclic Ketene Aminals with 1,2-Diaza-1,3-dienes. AB - A tandem reaction of heterocyclic ketene aminals and 1,2-diaza-1,3-dienes was developed for the expedient synthesis of pyrimidopyrrolopyridazine derivatives. This process involved an intramolecular conjugate addition followed by CuCl2 catalyzed hydrazone formation. PMID- 29708347 TI - Controlling Shape and Plasmon Resonance of Pt-Etched Au@Ag Nanorods. AB - Pt-based catalysts with novel structure have attracted great attention due to their outstanding performance. In this work, H2PtCl6 was used as both precursor and etching agent to realize the shape-controlled synthesis of Pt-modified Au@Ag nanorods (NRs). During the synthesis, the as-prepared Ag shell played a crucial role in both protecting the Au NRs from being etched away by PtCl62- and leading to an unusual growth mode of Pt component. The site-specified etching and/or growth depended on the concentration of H2PtCl6, where high-yield core-shell structure or dumbbell-like structure could be obtained. The shape-controlled synthesis also led to a tunable longitudinal surface plasmon resonance from ca. 649 to 900 nm. Meanwhile, the core-shell Pt-modified Au@Ag NRs showed approximately 4-fold enhancement in catalytic reduction reaction of p-nitrophenol than that of the Au NRs, suggesting the great potential for photocatalytic reaction. PMID- 29708348 TI - Layer-by-Layer Assembly of Free-Standing Nanofilms by Controlled Rolling. AB - A water surface not only provides a habitat to many living organisms but also opens up new possibilities to develop state-of-the-art technologies. Here, we show a technology for the layer-by-layer assembly of free-standing nanofilms by controlled rolling. The water surface is exploited as an ideal platform for rolling a nanofilm, allowing adhesion control and frictionless feeding. The nanofilm floating on the water surface is attached to a tube by van der Waals adhesion and is rolled up by the rotation of the tube. This method can assemble diverse film materials including metals, polymers, and two-dimensional materials, with an easy control of the number of layers. Furthermore, heterogeneous and spiral structures of the nanofilm are achieved. Various applications such as a stretchable tubular electrode, an electroactive polymer tube actuator, and a superelastic nanofilm tube are demonstrated. We believe this work can potentially lead to a breakthrough in the nanofilm assembly processes. PMID- 29708349 TI - Tuning Nanocrystal Surface Depletion by Controlling Dopant Distribution as a Route Toward Enhanced Film Conductivity. AB - Electron conduction through bare metal oxide nanocrystal (NC) films is hindered by surface depletion regions resulting from the presence of surface states. We control the radial dopant distribution in tin-doped indium oxide (ITO) NCs as a means to manipulate the NC depletion width. We find in films of ITO NCs of equal overall dopant concentration that those with dopant-enriched surfaces show decreased depletion width and increased conductivity. Variable temperature conductivity data show electron localization length increases and associated depletion width decreases monotonically with increased density of dopants near the NC surface. We calculate band profiles for NCs of differing radial dopant distributions and in agreement with variable temperature conductivity fits find NCs with dopant-enriched surfaces have narrower depletion widths and longer localization lengths than those with dopant-enriched cores. Following amelioration of NC surface depletion by atomic layer deposition of alumina, all films of equal overall dopant concentration have similar conductivity. Variable temperature conductivity measurements on alumina-capped films indicate all films behave as granular metals. Herein, we conclude that dopant-enriched surfaces decrease the near-surface depletion region, which directly increases the electron localization length and conductivity of NC films. PMID- 29708350 TI - [Human Papillomavirus - Role in Cervical Carcinogenesis and Methods of Detection]. AB - BACKGROUND: Persistent infection with high-risk human papillomavirus (HPV) strains, especially HPV 16 and HPV 18, is associated with the onset of various malignant diseases, including cervical carcinoma in women. HPV DNA testing is thus being implemented as a complementary method to standard cytological examination, mainly due to its increased sensitivity. AIM: This review outlines the role of HPV in cervical carcinogenesis, with a focus on the formation of cervical intraepithelial neoplasias (CIN1-3) and the molecular mechanism underlying cellular transformation. Current biomarkers used to screen premalignant lesions are described, including mRNA transcripts of the E6 and E7 genes, protein p16 (a cyclin-dependent kinase inhibitor that regulates cell cycle progression from G1 to S phase), altered DNA methylation patterns, and actions of specific microRNAs (short (18-22 bp), non-coding, single-stranded RNA molecules that regulate gene expression at the post-transcriptional level). This review also describes the advantages and drawbacks of commercial HPV tests, and depicts novel methods for more cost-effective and faster HPV diagnostics based on optical or electrochemical detection. CONCLUSION: Although great progress has been made, the incidence and mortality rates of cervical malignancies remain relatively high, especially in developing countries. Incorporation of HPV testing into routine screening programs could help to decrease mortality rates; however, the cost of such testing must be reduced if it is to compete with current cytology based examinations.Key words: HPV - cervical carcinoma - HPV testing - nucleic acid hybridization - mRNA - DNA methylation - microRNA This work was supported by MEYS-NPS I-LO1413 and GACR 17-08971S. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 25. 9. 2017Accepted: 26. 1. 2018. PMID- 29708351 TI - Long Non-coding RNAs as Regulators of the Mitogen-activated Protein Kinase (MAPK) Pathway in Cancer. AB - BACKGROUND: The mitogen-activated protein kinase (MAPK) pathway contributes to regulation of many cellular functions, such as cell proliferation and differentiation, mobility and apoptosis. Extracellular signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK) /p38 and ERK5 construct the three main modules in this pathway. The Raf-ERK1/2 and JNK cascades contribute in cell proliferation, migration, and survival and are principal regulators of malignant phenotype. This pathway is itself regulated by several outside signals as well as lateral signals from other pathways, which construct a complex network. Long non coding RNAs (lncRNAs) as principal modulators of gene expression at transcriptional and post-transcriptional levels also regulate this pathway. In addition, lncRNA signature can be used as biomarker and target of novel treatment strategies in cancer patients. AIM: To explore the role of lncRNAs in regulation of MAPK pathway. CONCLUSION: Considering the role of this pathway in the pathogenesis of several cancers, alterations in lncRNA expression lead to changes in MAPK pathway resulting in inhibition of apoptosis and induction of cell proliferation and migration. Moreover, some lncRNAs participate in cross-talk between MAPK and other cancer-related pathways, such as PI3K/Akt pathway through regulation of certain shared proteins between these pathways. Based on the availability of certain anticancer drugs that modulate this pathway, identification of lncRNAs that affect this pathway would help in establishment of effective therapies.Key words: RNA - long noncoding - mitogen-activated protein kinases - signal transduction. PMID- 29708352 TI - [Anogenital HPV Infection as the Potential Risk Factor for Oropharyngeal Carcinoma]. AB - BACKGROUND: Human papillomavirus (HPV) can cause cervical, other genital, anal, head, and neck cancers. The incidence of oropharyngeal squamous cell carcinoma (OSCC), the head and neck cancer most commonly caused by HPV infection, is increasing. The prevalence of oral HPV infections is considerably lower than that of genital HPV infections; however, infection of both sites is strongly associated with sexual behavior. Although the natural histories of cervical and oral HPV infections do not markedly differ, the virus seems to rarely infect oral and genital sites simultaneously. On the other hand, the standardized incidence ratio of OSCC is higher in cervical cancer patients than in other populations. Furthermore, women with OSCC have a significantly increased risk of developing HPV-related genital cancers. Administration of the HPV vaccine to both genders will undoubtedly dramatically change the epidemiology of HPV-related cancers. AIM: This work provides an overview of the literature and estimates the risk of OSCC in women with anogenital HPV infections. CONCLUSION: The biological relationship between different HPV-infected sites might be complex; however, the increased prevalence of HPV in oral samples of women positive for anogenital HPV indicates that such infections are unlikely to be independent of one another. Sexual activity likely affects the risk of concurrent anogenital and oral coinfections. However, it is also possible that one infection site provides a reservoir that can increase the risk of autoinoculation at anatomically distant locations or that coinfections develop as a result of other factors, such as immunodeficiency. Nevertheless, women with HPV-associated malignancy undoubtedly have a higher risk of developing OSCC.Key words: human papillomavirus - HPV - genital HPV infection - oral HPV infection - oropharyngeal squamous cell carcinoma - standardized incidence ratio - head and neck cancer This article was supported by by the project UNCE 204065 of Charles University. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 26. 8. 2017Accepted: 4. 1. 2018. PMID- 29708353 TI - [Treatment of Metastatic Renal Cell Carcinoma]. AB - INTRODUCTION: Renal cell cancer accounts for approximately 2-3% of all cases of malignancy. The incidence of kidney cancer in the Czech Republic is the highest in the world. Approximately 70% of renal cell carcinomas are clear-cell renal cancer. Various treatment options for metastatic renal cell cancer (mRCC) have been developed. Treatment regimens comprise antiangiogenic drugs in combination with vascular endothelial growth factor receptor inhibitors, mTOR inhibitors, and immunotherapy. AIM: This review provides an overview of the current treatment options for mRCC. Patients with a good performance status and a low systemic disease burden are candidates for cytoreductive nephrectomy. Ablative methods, such as stereotactic radiotherapy, can be used in patients with oligometastatic disease. Sunitinib and pazopanib are preferred first-line treatments for mRCC and provide similar outcomes. Second-line and higher line treatments markedly changed with the development of new drugs, such as cabozantinib and the immunotherapy nivolumab. The optimal treatment sequence for mRCC is discussed. Ongoing studies are evaluating combined treatments and searching for potential biomarkers. However, the tumor heterogeneity of renal cell cancer complicates the use of biomarkers. CONCLUSION: The results of clinical trials have markedly changed the treatment guidelines for mRCC. New strategies include combinatorial approaches, which mainly incorporate immunotherapy.Key words: renal cancer - targeted therapy - immunotherapy - metastases - biomarkers The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 19. 12. 2017Accepted: 7. 1. 2018. PMID- 29708354 TI - [New Approaches for Chemosensitivity Testing in Malignant Diseases]. AB - BACKGROUND: Due to the irreplaceable role of chemotherapy in cancer treatment, research has focused on improving the efficacies of individual drugs and minimizing, or completely suppressing, their negative side effects. Based on long term experience and the results of clinical trials, the selection of appropriate treatment is currently based on classical clinical diagnostic criteria, such as tumor size, grade, and the presence or absence of standard markers. However, complications arise due to variability between patients and tumor heterogeneity. Characterization of intratumoral heterogeneity and acquisition of more reliable drug performance indicators should improve personalized therapy. Development and selection of suitable models are therefore important issues in cancer research focused on predicting sensitivity to therapy. AIM: This work provides an overview of various chemosensitivity tests that have been previously employed and those that are currently used. Great emphasis is placed on comparing 2D and 3D cell culture models, since their importance and popularity are increasing. Particular attention is paid to in vivo systems, which have significantly improved recently and are tested in clinical trials to predict responses to therapy. CONCLUSION: This work provides a brief overview of chemosensitivity tests, focusing on the importance of individual tests and their application in decision-making and patient stratification to improve the clinical responses of patients and the development of targeted personalized therapy.Key words: cell culture techniques - personalized medicine - drug screening - biological models - tumor cell lines - carcinoma - cytotoxicity assays This work was supported by the project MEYSNPS I LO1413 and GACR 17-05838S. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 21. 9. 2017Accepted: 20. 12. 2017. PMID- 29708355 TI - [Quality of Life After High-dose Brachytherapy in Patients with Early Oral Carcinoma]. AB - BACKGROUND: The prevalence of head and neck tumors has continually increased over the past decades, which is a serious medical and social problem. This study retrospectively assessed the quality of life of patients with early-stage oral cavity tumors after high-dose rate (HDR) brachytherapy. MATERIAL AND METHODS: Quality of life was evaluated in 14 patients with early-onset oral cavity tumors who underwent HDR brachytherapy at the Department of Oncology and Radiotherapy, University Hospital Hradec Kralove. The standardized EORTC QLQ-C30 and EORTC QLQ H&N 35 questionnaires were used. Patients completed these questionnaires at 12 months after treatment. RESULTS: The general health status was scored 70 points using the EORTC QLQ-C30 questionnaire. Fatigue, insomnia, loss of appetite, dyspnea, and financial problems were the most severe problems reported. The main problems identified by the EORTC QLQ-H&N 35 questionnaire were weight gain, coughing, pain, sticky saliva, and difficulties eating in public. On the contrary, patients did not significantly suffer weight loss, speech impairments, difficulties in mouth opening or swallowing, or sensory problems. CONCLUSION: HDR brachytherapy is an effective treatment for early oral cancer that leaves patients with an acceptable quality of life. A prospective, multicentric study focused on the quality of life of patients with head and neck tumors is required.Key worlds: oral cancer - brachytherapy - quality of life This article was supported by grant PROGRES Q 40/13. The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 17. 1. 2018Accepted: 4. 2. 2018. PMID- 29708356 TI - MAPK/ERK signal pathway alterations in patients with Langerhans Cell Histiocytosis. AB - BACKGROUND: Clinical outcomes of Langerhans cell histiocytosis (LCH) are highly variable. It has been suggested that mitogen-activated protein kinase (MAPK) /extracellular signal-regulated kinases (ERK) signaling pathway might be activated in LCH patients. MATERIALS AND METHODS: We investigated KRAS, BRAF and NRAS mutations in patients with LCH by qPCR. RESULTS: Eight adult patients with LCH were treated at the National Cancer Institute, Kiev, Ukraine. Five patients received chemo plus radiation therapy and three patients received only chemotherapy, resp. (p < 0.05). All patients received LCH-I study protocol, six cycles in average. A BRAF c.1799T > A, p. V600E mutation was detected in 25% (2/8) of cases - 1 patient had an early relapse in 6 months, and 1 patient - stable disease. We did not find any BRAF, KRAS or NRAS mutations in three patients with late relapses (in 15, 24 and 46 months). Notably, KRAS mutations were not revealed in any LCH samples. The NRAS c.182A > G, p. Q61R mutation was found in two cases - one patient had LCH transformed to Hodgkins lymphoma, one patient had a refractory disease. Time to relapse rate (TTR) in patients with and without BRAF V600E gene mutation was 13 vs. 28 months, resp. (p < 0.05). TTR was 31.3 vs. 6.41 months in patients with absence and presence of NRAS mutation, p < 0.05. Multivariate analysis showed the presence of NRAS Q61R mutation was associated with poor event-free survival in LCH patients with HR of 6.1 (95% CI 0.2-12.6; p = 0.008). CONCLUSION: BRAF and NRAS mutations in LCH suggest a possibility of the disease being driven by the activation of the MAPK/ERK pathway. These oncogenic mutations provide new opportunities in understanding LCH pathogenesis and may be a potential target of therapy.Key words: Langerhans cell histiocytosis - mutations - prognostic factors - relapse - survival. PMID- 29708357 TI - Recent Trends in Survival of Testicular Cancer Patients - Nation-wide Population Based Study. AB - INTRODUCTION AND AIM: Survival of germ cell testicular cancer (TC) patients is better than for other malignancies and has not yet been exactly studied in the Slovak Republic. The aim of the study, based on the analyses of epidemiological data over time, was to present 5-year survival trends for germ cell TC patients. PATIENTS AND METHODS: Survival is assessed within the framework of a nation-wide retroprospective study among TC patients newly diagnosed between 1993-2007 (divided to three 5-year periods according the time of diagnosis - 1993-1997, 1998-2002 and 2003-2007). Standardized 5-year survival rates were calculated and compared between the periods using a widely accepted methodology. TC patients were divided into two groups (seminomas and non-seminomas histopathologically) and to two groups according the age at diagnosis (< 40 vs. 40 years). The demographic characteristics of TC patients were analyzed using descriptive statistics. Statistical analysis was carried out using Microsoft Excel 2013, statistical software STATISTICA and Joinpoint Regression Programe, Version 4.3.1.0. RESULTS: Five-year survival of TC patients (n = 2.748) diagnosed from 1993 to 2007 was 92.21%. TC patients diagnosed between 1993 and 1997 (n = 810) reached 5-year survival at 91.23%, between years 1998 and 2002 (n = 916) at 92.14% and between years 2003 and 2007 (n = 1.022) at 93.05%. There was not a statistically significant difference in survival among these three 5-year periods. Significant difference in 5-year survival was observed between seminomas and non-seminomas in each 5-year period. Compared with younger patients (age < 40 years), there was a significantly worse survival for TC patients (age 40 years) in all groups. CONCLUSION: Moderate improvement in survival for TC patients in the Slovak Republic is probably influenced by diagnostic and therapeutic progress, including multidisciplinary care and patients concentration in specialized centers. The long-term follow-up of TC survivors can also help to prevent late side effects of the treatment modalities and to detect second malignancies.Key words: testicular cancer - seminoma - non-seminoma - age at diagnosis - survival. PMID- 29708358 TI - Cutaneous and Subcutaneous Metastases of Adenocarcinoma as a Dominant Clinical Manifestation of Malignancy of Unknown Origin - a Case Report. AB - BACKGROUND: Cutaneous metastases occur in 0.6-10.4% of all patients with underlying malignancy. Among them, the site of origin remains unknown in 4.4 14.5% of all cases. CASE: The authors describe a 68-year-old man with widespread skin and soft tissue metastases appearing as the first and dominant clinical manifestation of oncologic disease. Physical examination and CT scans revealed multiple cutaneous and subcutaneous tumor nodules arising in the neck, chest, abdomen, lumbar region and right forearm, as well as in the gluteal and iliacus muscles and in the proximal part of the left thigh. Light microscopy confirmed a metastasis of adenocarcinoma exhibiting a tubuloglandular pattern and a slight mucin production. It was immunoreactive for cytokeratin 7 and carcinoembryonic antigen and negative for cytokeratin 20, CDX-2, TTF-1 and prostatic specific antigen. Based upon the histomorphology and immunophenotype, the pathologist suggested a primary tumor in the stomach or biliopancreatic tract. However, further clinical workup did not clearly identify a primary lesion. CONCLUSION: Determining the origin of cutaneous metastases might be a challenging issue for both clinicians and pathologists. The case we describe is uncommon because widespread skin and subcutaneous metastases appeared as the first and dominant clinical sign of adenocarcinoma, the origin of which has not been established. This unusual tumor behavior may suggest that a spreading and colonization of metastatic cancer cells in the skin and soft tissue may be a specific biologic process.Key words: skin metastases - malignancy of unknown origin - adenocarcinoma. PMID- 29708359 TI - Diagnostic, Prognostic and Predictive Immunohistochemistry in Malignant Melanoma of the Skin. PMID- 29708360 TI - The interplay of prior experience and motivation in great ape problem-solving (Gorilla gorilla, Pan paniscus, Pan troglodytes, and Pongo abelii). AB - Many primate species have a strong disposition to approach and manipulate objects in captivity. However, few studies have investigated what primates learn during free exploration of objects in the absence of rewards, and how previous problem solving performance influences subsequent exploration. We confronted members of each of the four nonhuman great ape species (N = 25) with the collapsible platform task that required subjects to drop a stone inside a tube to collapse a platform and release a reward. Subjects received four successive sessions with an empty apparatus (exploration driven by intrinsic motivation) followed by four with a baited apparatus (problem-solving driven by extrinsic motivation) or vice versa. Apes who first faced an empty apparatus solved the task more quickly in the baited condition than apes who started with this condition. Moreover, apes starting with the baited condition took longer to collapse the platform in the first trial than apes who started with the empty condition. This study suggests that apes exposed to an empty apparatus before the test gain information that is later used to solve the task in a more efficient manner. Thus, apes learn about action-outcome contingencies during free exploration. Moreover, it indicates that the presence of food rewards distracts apes and delays problem-solving because apes' attention is mainly focused on the food. (PsycINFO Database Record PMID- 29708361 TI - The effect of clustering on perceived quantity in humans (Homo sapiens) and in chicks (Gallus gallus). AB - Animals can perceive the numerosity of sets of visual elements. Qualitative and quantitative similarities in different species suggest the existence of a shared system (approximate number system). Biases associated with sensory properties are informative about the underlying mechanisms. In humans, regular spacing increases perceived numerosity (regular-random numerosity illusion). This has led to a model that predicts numerosity based on occupancy (a measure that decreases when elements are close together). We used a procedure in which observers selected one of two stimuli and were given feedback with respect to whether the choice was correct. One configuration had 20 elements and the other 40, randomly placed inside a circular region. Participants had to discover the rule based on feedback. Because density and clustering covaried with numerosity, different dimensions could be used. After reaching a criterion, test trials presented two types of configurations with 30 elements. One type had a larger interelement distance than the other (high or low clustering). If observers had adopted a numerosity strategy, they would choose low clustering (if reinforced with 40) and high clustering (if reinforced with 20). A clustering or density strategy predicts the opposite. Human adults used a numerosity strategy. Chicks were tested using a similar procedure. There were two behavioral measures: first approach response and final circumnavigation (walking behind the screen). The prediction based on numerosity was confirmed by the first approach data. For chicks, one clear pattern from both responses was a preference for the configurations with higher clustering. (PsycINFO Database Record PMID- 29708362 TI - Marijuana use by intimate partners: Does discrepant use impair relationship functioning? AB - Intimate couples with discrepant use of alcohol and other drugs experience poorer relationship functioning relative to couples with concordant use or nonuse. Within a sample of marijuana-using couples, we hypothesized that greater discrepancy in marijuana use frequency between partners would be associated with lower relationship satisfaction and perceived partner responsiveness and with greater conflict, negative interpersonal exchange, and psychological and physical aggression. The Actor Partner Interdependence Model (APIM) allowed us to account for the effects of each partner's marijuana use, as well as the discrepancy between partners' use, on his or her own perceptions of relationship functioning. Using multivariate, two-level models, we considered both between-couple and within-couple effects of partner marijuana discrepancy using 4 waves of data collected over 10 months. The sample consisted of heterosexual community couples (ages 18-30) in which at least one partner reported using marijuana two or more times per week. For several outcome measures, we observed negative within-couple discrepancy effects on reports of relationship functioning: at time points when absolute discrepancy in marijuana use was greater than typical for the couple, relationship functioning was poorer. The pattern was the same regardless of whether it was the male or female partner who used more frequently. There were also some negative between-couple effects associated with more frequent female use. Findings replicate and extend prior research on partner discrepancy by demonstrating the dynamic nature of these effects over time. (PsycINFO Database Record PMID- 29708363 TI - Parental warmth during childhood predicts coping and well-being in adulthood. AB - Numerous studies have shown that early life experiences can affect well-being later in life. Additionally, previous literature has emphasized the importance of exploring the role of mediators in developmental research (e.g., coping strategies). The present study used 3 waves of longitudinal data across 20 years from the national survey Midlife Development in the United States (N = 2,088) to examine the link between retrospectively reported parental warmth and well-being in adulthood by exploring 2 categories of coping strategies (emotion- and problem focused strategies) as possible mediators. Three cross-lagged panel models, exhibiting good fit, were conducted in Mplus. Significant indirect effects were found where both negative and positive affect (Time 2) partially mediated the association between perceived parental warmth (Time 1) and emotion-focused coping (Time 3). Further, evidence for bidirectional effects were shown by the observed significant indirect effects of problem-focused coping (Time 2) partially explaining the association between perceived parental warmth (Time 1) and eudaimonic well-being (Time 3) as well as eudaimonic well-being (Time 2) partially explaining the link between parental warmth (Time 1) and problem focused coping (Time 3). These findings suggest that it is important to consider early life experiences when examining both well-being and coping during adulthood. (PsycINFO Database Record PMID- 29708364 TI - "You're forgiven, but don't do it again!" Direct partner regulation buffers the costs of forgiveness. AB - Although forgiveness can have numerous benefits, it can also have a notable cost forgiveness can allow transgressors to continue behaving in ways that can be hurtful (McNulty, 2010, 2011). Accordingly, two studies tested the prediction that the implications of forgiveness for whether the partner transgresses or fails to behave benevolently depend on whether forgivers regulate partners away from future transgressions and toward benevolent behaviors. Study 1 was an experimental study of emerging adult couples in which participants were (a) asked to report their partners' tendencies to engage in partner-regulation behaviors, (b) led to believe their partners were either forgiving or unforgiving, and (c) given the opportunity to transgress against their partners. Study 2 was a longitudinal study of newlywed couples in which participants were (a) asked to report their tendencies to forgive their partners, (b) observed during problem solving discussions, and then (c) asked to report their satisfaction with their partners' considerateness every 6 months for 4 years. Both studies provided evidence that direct oppositional partner-regulation behaviors moderate the implications of forgiveness for partner behavior. Among intimates who demanded more change, forgiveness was associated with the partner transgressing less (Study 1) and compromising more (Study 2), as well as participants being more satisfied with their partners' considerateness over time (Study 2); among intimates who demanded less change, forgiveness was associated with these outcomes in the opposite direction. These findings suggest that supplementing forgiveness with partner-regulation behaviors can help nondistressed couples avoid the undesirable outcomes and maximize desirable outcomes associated with forgiveness. (PsycINFO Database Record PMID- 29708365 TI - Do day-to-day finances play a role in relationship satisfaction? A dyadic investigation. AB - Prior researchers have found consistent links between financial issues and relationship outcomes. Yet, because most research is cross-sectional or examines these constructs over longer periods of time (e.g., years), the microlevel processes of how and when these changes occur are unclear. In the present study, we use interdependence theory as a guide to examine the daily fluctuations of financial satisfaction and stress as well as their daily associations with relationship quality in married and unmarried heterosexual couples. Using a dyadic 14-day daily diary research design, we found both financial satisfaction and stress demonstrated significant within-person fluctuations, with women demonstrating greater volatility in financial satisfaction than men. Given that individuals varied in their perceptions of financial satisfaction and stress from day to day, we then examined how these fluctuations were associated with daily relationship satisfaction. We expected financial satisfaction would be positively associated with relationship satisfaction for both actors and partners, whereas financial stress would be negatively associated for both actors and partners. Hypotheses were partially supported. Unmarried women's daily financial satisfaction was associated with increased relationship quality for both themselves (marginal) as well as their partners. An unexpected pattern for unmarried men's financial satisfaction was found; their increased financial satisfaction was associated with decreased relationship satisfaction. Increased financial stress was associated with decreased relationship satisfaction for unmarried men and married women (actor effects). We discuss implications for research and practice. (PsycINFO Database Record PMID- 29708366 TI - Feasibility of implementing a recovery education center in a Veterans Affairs medical center. AB - OBJECTIVE: The purpose of this study was to determine the feasibility of implementing a recovery education program in a Veterans Affairs medical center. METHOD: This case study describes development and implementation of a mental health and wellness curriculum offered through a centralized location. Referral and utilization data (n = 781) from the first 18 months of implementation were used to evaluate feasibility. FINDINGS: Access to programming with zero exclusion was prioritized and average time from referral to enrollment was 9.6 days. Fifty six percent of veterans admitted to mental health services during the 18-month evaluation period were referred to the program, and this level of utilization continued to be sustained. A broad range of classes was available. Opportunities to change classes as recovery goals evolved was encouraged and data indicate veterans actively tailored their individual recovery curriculum. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Educational recovery programming was easily incorporated into a large integrated health facility, was well received, and offered greater opportunity for choice and individualization of recovery curriculum. (PsycINFO Database Record PMID- 29708367 TI - Defining "peerness": Developing peer supports for parents with mental illnesses. AB - TOPIC: This article addresses critical considerations in the development of peer supports for parents with mental illnesses, focusing on the question of what makes a peer a peer in the parent peer specialist domain. PURPOSE: The implementation and testing of parent peer supports requires specification of the critical components of the model, including the qualities, characteristics, and unique contributions of the parent peer specialist. SOURCES USED: Themes emerged in Parent Peer Specialist Project Advisory Group discussions, with members drawing from lived experience, practice expertise, and conversations with experts. In addition to literature review, strategic stakeholder interviews were conducted. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Lived experience of mental illness and family life, training, and ongoing support for parent peer specialists, along with key ingredients conveyed by perceived peer-parent similarity, will likely enhance the benefits of peer supports to parents and promote job satisfaction and career advancement for parent peer specialists. (PsycINFO Database Record PMID- 29708368 TI - Helping veterans achieve work: A Veterans Health Administration nationwide survey examining effective job development practices in the community. AB - OBJECTIVE: Veterans Health Administration vocational services assist veterans with mental illness to acquire jobs; one major component of these services is job development. The purpose of this study was to characterize the nature of effective job development practices and to examine perceptions and intensity of job development services. METHOD: A national mixed-methods online survey of 233 Veterans Health Administration vocational providers collected data regarding frequency of employer contacts, perceptions of job development ease/difficulty, and effective job development practices when dealing with employers. Qualitative responses elucidating effective practices were analyzed using content analysis. RESULTS: Vocational providers had a modest number of job development employer contacts across 2 weeks (M = 11.0, SD = 10.6) and fewer were face-to-face (M = 7.6, SD = 8.4). Over 70% of participants perceived job development to be difficult. Six major themes emerged regarding effective job development practices with employers: using an employer-focused approach; utilizing a targeted marketing strategy; engaging in preparation and follow-up; going about the employer interaction with genuineness, resilience, and a strong interpersonal orientation; serving as an advocate for veterans and educator of employers; utilizing specific employer-tailored strategies, such as arranging a one-on-one meeting with a decision maker and touring the business, individualizing a prescripted sales pitch, connecting on a personal level, and engaging in ongoing communication to solidify the working relationship. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Respondents highlight several potentially effective job development strategies; tools and resources may be developed around these strategies to bolster job development implementation and allow opportunities for fruitful employer interactions. (PsycINFO Database Record PMID- 29708369 TI - Automaticity of access to numerical magnitude and its spatial associations: The role of task and number representation. AB - Generally, people respond faster to small numbers with left-sided responses and large numbers with right-sided responses, a pattern known as the SNARC (spatial numerical association of response codes) effect. The SNARC effect is interpreted as evidence for amodal automatic access of magnitude and its spatial associations, because it occurs in settings where number is task-irrelevant and for different number formats. We report five studies designed to establish the degree to which activation of magnitude and its spatial associations is truly automatic and amodal. Based on the notion of autonomous automaticity, we hypothesized that the mere presence of a number form (to which participants made a color decision) would be sufficient to elicit the SNARC effect. However, we found no evidence of a SNARC effect for simple color decisions to Arabic digits (Experiment 1). There was a SNARC effect for color decision to digits when participants recognized the stimulus as a digit before responding (Experiment 2), participants viewed the digit for sufficient time before color onset (Experiments 3 and 5), or there was temporal uncertainty regarding color onset (Experiment 3). There was no SNARC effect for color decision to arrays of circles (Experiment 4), regardless of viewing time or temporal uncertainty. Overall, our results suggest that, while access to magnitude and its spatial associations is not automatic in an "all-or-none" sense, it is certainly at the strong end of automaticity, and that this automatic activation is modality dependent. Our findings are most supportive of conceptual coding accounts of the SNARC effect. (PsycINFO Database Record PMID- 29708370 TI - Uninformative contexts support word learning for high-skill spellers. AB - The current study investigated how high-skill spellers and low-skill spellers incidentally learn words during reading. The purpose of the study was to determine whether readers can use uninformative contexts to support word learning after forming a lexical representation for a novel word, consistent with instance based resonance processes. Previous research has found that uninformative contexts damage word learning; however, there may have been insufficient exposure to informative contexts (only one) prior to exposure to uninformative contexts (Webb, 2007; Webb, 2008). In Experiment 1, participants read sentences with one novel word (i.e., blaph, clurge) embedded in them in three different conditions: Informative (six informative contexts to support word learning), Mixed (three informative contexts followed by three uninformative contexts), and Uninformative (six uninformative contexts). Experiment 2 added a new condition with only three informative contexts to further clarify the conclusions of Experiment 1. Results indicated that uninformative contexts can support word learning, but only for high-skill spellers. Further, when participants learned the spelling of the novel word, they were more likely to learn the meaning of that word. This effect was much larger for high-skill spellers than for low-skill spellers. Results are consistent with the Lexical Quality Hypothesis (LQH) in that high-skill spellers form stronger orthographic representations which support word learning (Perfetti, 2007). Results also support an instance-based resonance process of word learning in that prior informative contexts can be reactivated to support word learning in future contexts (Bolger, Balass, Landen, & Perfetti, 2008; Balass, Nelson, & Perfetti, 2010; Reichle & Perfetti, 2003). (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29708371 TI - The Lackland Behavioral Questionnaire: The use of biographical data and statistical prediction rules for public safety screening. AB - Screening for public safety positions (e.g., police officers, fire fighters, military service members) is a difficult and challenging task. Notably, the military has been widely criticized because of the general lack of an empirically based system or program for mental health screening. The purpose of the present study is to describe the use of statistical prediction rules for this task. Prediction rules were derived and validated using U.S. Air Force (USAF) recruits in basic military training (N = 50,322). Items from the Lackland Behavioral Questionnaire were used as predictors. General attrition (discharge for any reason before completing term of service) and disciplinary offenses (including criminal charges) were used as outcomes. For trainees in the top 2% or 1% of the general attrition prediction rule, 63% and 68% were discharged before they completed their first 4 years. The base rate was 25%. Similarly, for trainees in the top 2% or 1% of the disciplinary offenses prediction rule, 35% and 39% had a significant disciplinary offense over the following 4 years. The base rate was 15.5%. The results suggest that we may be able to use biographical data inventories and statistical prediction rules to identify a small percentage of trainees in public safety fields with significant mental health or behavioral histories who are at elevated risk for general attrition and disciplinary offenses. (PsycINFO Database Record PMID- 29708372 TI - Using the Violence Risk Scale-Sexual Offense version in sexual violence risk assessments: Updated risk categories and recidivism estimates from a multisite sample of treated sexual offenders. AB - The present study sought to develop updated risk categories and recidivism estimates for the Violence Risk Scale-Sexual Offense version (VRS-SO; Wong, Olver, Nicholaichuk, & Gordon, 2003-2017), a sexual offender risk assessment and treatment planning tool. The overarching purpose was to increase the clarity and accuracy of communicating risk assessment information that includes a systematic incorporation of new information (i.e., change) to modify risk estimates. Four treated samples of sexual offenders with VRS-SO pretreatment, posttreatment, and Static-99R ratings were combined with a minimum follow-up period of 10-years postrelease (N = 913). Logistic regression was used to model 5- and 10-year sexual and violent (including sexual) recidivism estimates across 6 different regression models employing specific risk and change score information from the VRS-SO and/or Static-99R. A rationale is presented for clinical applications of select models and the necessity of controlling for baseline risk when utilizing change information across repeated assessments. Information concerning relative risk (percentiles) and absolute risk (recidivism estimates) is integrated with common risk assessment language guidelines to generate new risk categories for the VRS-SO. Guidelines for model selection and forensic clinical application of the risk estimates are discussed. (PsycINFO Database Record PMID- 29708374 TI - Surface filling-in and contour interpolation contribute independently to Kanizsa figure formation. AB - To explore mechanisms of object integration, the present experiments examined how completion of illusory contours and surfaces modulates the sensitivity of localizing a target probe. Observers had to judge whether a briefly presented dot probe was located inside or outside the region demarcated by inducer elements that grouped to form variants of an illusory, Kanizsa-type figure. From the resulting psychometric functions, we determined observers' discrimination thresholds as a sensitivity measure. Experiment 1 showed that sensitivity was systematically modulated by the amount of surface and contour completion afforded by a given configuration. Experiments 2 and 3 presented stimulus variants that induced an (occluded) object without clearly defined bounding contours, which gave rise to a relative sensitivity increase for surface variations on their own. Experiments 4 and 5 were performed to rule out that these performance modulations were simply attributable to variable distances between critical local inducers or to costs in processing an interrupted contour. Collectively, the findings provide evidence for a dissociation between surface and contour processing, supporting a model of object integration in which completion is instantiated by feedforward processing that independently renders surface filling-in and contour interpolation and a feedback loop that integrates these outputs into a complete whole. (PsycINFO Database Record PMID- 29708373 TI - The impact of substance use disorders on treatment engagement among justice involved veterans with posttraumatic stress disorder. AB - Veterans involved with the criminal justice system represent a particularly vulnerable population who experience high rates of both posttraumatic stress disorder (PTSD) and substance use disorders (SUD). This study sought to investigate whether having co-occurring SUD is a barrier to PTSD treatment. This is a retrospective observational study of a national sample of justice-involved veterans served by the Veterans Health Administration Veterans Justice Outreach program who had a diagnosis of PTSD (N = 27,857). Mixed effects logistic regression models with a random effect for facility (N = 141 medical centers) were utilized to estimate the odds of receiving each type of PTSD treatment as a function of having a SUD diagnosis. Results indicate that a majority of veterans with PTSD served by the Veterans Justice Outreach program have an SUD diagnosis (73%), and having a co-occurring SUD was associated with higher odds of receiving PTSD treatment, after adjusting for demographic differences. Although not without limitations, these results suggest that among justice-involved veterans enrolled in the Veterans Health Administration with PTSD, having an SUD comorbidity is not a barrier to PTSD treatment and may in fact facilitate access to PTSD treatment. (PsycINFO Database Record PMID- 29708375 TI - A physiologically based nonhomogeneous Poisson counter model of visual identification. AB - A physiologically based nonhomogeneous Poisson counter model of visual identification is presented. The model was developed in the framework of a Theory of Visual Attention (Bundesen, 1990; Kyllingsbaek, Markussen, & Bundesen, 2012) and meant for modeling visual identification of objects that are mutually confusable and hard to see. The model assumes that the visual system's initial sensory response consists in tentative visual categorizations, which are accumulated by leaky integration of both transient and sustained components comparable with those found in spike density patterns of early sensory neurons. The sensory response (tentative categorizations) feeds independent Poisson counters, each of which accumulates tentative object categorizations of a particular type to guide overt identification performance. We tested the model's ability to predict the effect of stimulus duration on observed distributions of responses in a nonspeeded (pure accuracy) identification task with eight response alternatives. The time courses of correct and erroneous categorizations were well accounted for when the event-rates of competing Poisson counters were allowed to vary independently over time in a way that mimicked the dynamics of receptive field selectivity as found in neurophysiological studies. Furthermore, the initial sensory response yielded theoretical hazard rate functions that closely resembled empirically estimated ones. Finally, supplied with a Naka-Rushton type contrast gain control, the model provided an explanation for Bloch's law. (PsycINFO Database Record PMID- 29708376 TI - Familiar size effects on reaction time: When congruent is better. AB - Familiar size is known to influence our perception of object's size and distance. In this study, we examined whether or not simple RTs (RTs) are also affected by prior knowledge of objects' size. In a series of experiments, participants were asked to respond as quickly as possible to briefly presented images of familiar objects, equated for luminance and retinal size. The effects of familiar size and object animacy on RTs were investigated under natural (Experiment 1) and reduced (Experiment 2) viewing conditions. Restricted viewing conditions were introduced to manipulate the availability of depth cues. A systematic effect of familiar size on RTs was considered for progressively "shrunken" (Experiment 3) and "enlarged" (Experiment 4) objects on the screen with respect to their familiar size. Measures of perceived size were also taken by means of a manual estimation task (Experiment 5). Results showed an effect of animacy on simple RTs: Participants were faster to respond to images of animals than nonanimals. An effect of familiar size on simple RTs was also observed under reduced viewing conditions only: Objects shown closer to their real-world size were detected significantly more quickly than those further from their familiar size. However, this familiar-size advantage did not reflect perceived size. Hence, simple RTs under reduced viewing conditions are modulated by the degree of compatibility between physical size and long-term representations of size. (PsycINFO Database Record PMID- 29708377 TI - Regularity and dimensional salience in temporal grouping. AB - How do pitch and duration accents combine to influence the perceived grouping of musical sequences? Sequence context influences the relative importance of these accents; for example, the presence of learned structure in pitch exaggerates the effect of pitch accents at the expense of duration accents despite being irrelevant to the task and not attributable to attention (Prince, 2014b). In the current study, two experiments examined whether the presence of temporal structure has the opposite effect. Experiment 1 tested baseline conditions, in which participants (N = 30) heard sequences with various sizes of either pitch or duration accents, which implied either duple or triple groupings (accent every two or three notes, respectively). Sequences either had regular temporal structure (isochronous) or not (irregular, via using random interonset intervals). Regularity enhanced the effect of duration accents but had negligible influence on pitch accents. The accent sizes that gave the most equivalent ratings across dimension and regularity levels were used in Experiment 2 (N = 33), in which sequences contained both pitch and duration accents that suggested either duple, triple, or neutral groupings. Despite controlling for the baseline effect of regularity by selecting equally effective accent sizes, regularity had additional effects on duration accents, but only for duple groupings. Regularity did not influence the effectiveness of pitch accents when combined with duration accents. These findings offer some support for a dimensional salience hypothesis, which proposes that the presence of temporal structure should foster duration accent effectiveness at the expense of pitch accents. (PsycINFO Database Record PMID- 29708378 TI - The affordance of catchability in running to intercept fly balls. AB - How do outfielders control their locomotor behavior in running to catch fly balls? This question has been the topic of many empirical studies. It is interesting that a little addressed but highly relevant issue in this regard is that of the influence of perceived catchability on locomotor control. We examined what factors determine catchability and whether catchability can be reliably perceived. We had participants run to catch fly balls that could either be catchable or uncatchable. Participants performed two tasks. In the catching task, they were instructed to attempt to catch the ball and to keep running even when they felt that a ball was uncatchable. In the judging task, they were instructed to call "no" as soon as they perceived a ball to be uncatchable. Using Generalized Linear Mixed Effects Regression (GLMER) on data from the catching task, we modeled catchability, identifying five behaviorally relevant agent environment variables that together explained 84.4% of the variance in catching performance. Next, we examined whether judgments of catchability were accurate. Using the GLMER-model, the catchability of every fly ball in the judging task was predicted and subsequently compared with participants' judgments. Participants were able to correctly judge the catchability of a fly ball on 85.4% of the trials. It is interesting that participants' judgments of fly balls to be uncatchable most often were given only after they had started running. Present findings provide a valuable step toward the formalization of an affordance-based control strategy for running to catch fly balls. (PsycINFO Database Record PMID- 29708379 TI - Audiovisual semantic interactions between linguistic and nonlinguistic stimuli: The time-courses and categorical specificity. AB - We examined the time-courses and categorical specificity of the crossmodal semantic congruency effects elicited by naturalistic sounds and spoken words on the processing of visual pictures (Experiment 1) and printed words (Experiment 2). Auditory cues were presented at 7 different stimulus onset asynchronies (SOAs) with respect to the visual targets, and participants made speeded categorization judgments (living vs. nonliving). Three common effects were observed across 2 experiments: Both naturalistic sounds and spoken words induced a slowly emerging congruency effect when leading by 250 ms or more in the congruent compared with the incongruent condition, and a rapidly emerging inhibitory effect when leading by 250 ms or less in the incongruent condition as opposed to the noise condition. Only spoken words that did not match the visual targets elicited an additional inhibitory effect when leading by 100 ms or when presented simultaneously. Compared with nonlinguistic stimuli, the crossmodal congruency effects associated with linguistic stimuli occurred over a wider range of SOAs and occurred at a more specific level of the category hierarchy (i.e., the basic level) than was required by the task. A comprehensive framework is proposed to provide a dynamic view regarding how meaning is extracted during the processing of visual or auditory linguistic and nonlinguistic stimuli, therefore contributing to our understanding of multisensory semantic processing in humans. (PsycINFO Database Record (c) 2018 APA, all rights reserved). PMID- 29708380 TI - Reconceptualizing perceptual load as a rate problem: The role of time in the allocation of selective attention. AB - In the literature about allocation of selective attention, a widely studied question is when will attention be allocated to information that is clearly irrelevant to the task at hand. The present study, by using convergent evidence, demonstrated that there is a trade-off between quantity of information present in a display and the time allowed to process it. Specifically, whether or not there is interference from irrelevant distractors depends not only on the amount of information present, but also on the amount of time allowed to process that information. When processing time is calibrated to the amount of information present, irrelevant distractors can be selectively ignored successfully. These results suggest that the perceptual load in the load theory of selective attention (i.e., Lavie, 2005) should be thought about as a dynamic rate problem rather than a static capacity limitation. The authors thus propose that rather than conceiving of perceptual load as a quantity of information, they should consider it as a quantity of information per unit of time. In other words, it is the relationship between the quantity of information in the task and the time for processing the information that determines the allocation of selective attention. Thus, the present findings extended load theory, allowing it to explain findings that were previously considered as counter evidence of load theory. (PsycINFO Database Record PMID- 29708381 TI - Do we know what we need? Preference for feedback about accurate performances does not benefit sensorimotor learning. AB - Previous research on skill acquisition has shown that learners seem to prefer receiving knowledge of results (KR) about those trials in which they have performed more accurately. In the present study, we assessed whether this preference leads to an advantage in terms of skill acquisition, transfer, and retention of their capacity to extrapolate the motion of decelerating objects during periods of visual occlusion. Instead of questionnaires, we adopted a more direct approach to investigate learners' preferences for KR. Participants performed 90 trials of a motion extrapolation task (acquisition phase) in which, every three trials, they could decide between receiving KR about their best or worst performance. Retention and transfer tests were carried out 24 hr after the acquisition phase, without KR, to examine the effects of the self-selected KR on sensorimotor learning. Consistent with the current literature, a preference for receiving KR about the most accurate performance was observed. However, participants' preferences were not consistent throughout the experiment as less than 10% (N = 40) selected the same type of KR in all their choices. Importantly, although preferred by most participants, KR about accurate performances had detrimental effects on skill acquisition, suggesting that learners may not always choose the KR that will maximize their learning experiences and skill retention. (PsycINFO Database Record PMID- 29708382 TI - Can vigilance tasks be administered online? A replication and discussion. AB - Recently, experimental studies of vigilance have been deployed using online data collection methods. This data collection strategy is not new to the psychological sciences, but it is relatively new to basic research assessing vigilance performance, as studies in this area of research tend to collect data in the laboratory or in the field. The present study partially replicated the results of a newly developed online vigilance task (Thomson, Besner, & Smilek, 2016). A sample of 130 participants completed the semantic vigilance task created by Thomson et al. (2016) in a research laboratory setting. The present results replicated Thomson et al. (2016) when nonparametric and corrected signal detection measures were used. We suggest that some vigilance tasks typically performed in the laboratory could be administered online. However, we encourage researchers to consider the following factors prior to studying vigilance performance online: (a) the type of vigilance task, (b) the length of the vigilance task, and (c) the signal detection indices most appropriate for their research. It is quite possible that some analyses may yield significant results, whereas other signal detection measures may not (i.e., parametric indices vs. nonparametric indices vs. "corrected" indices) and this point is discussed further in our article. (PsycINFO Database Record PMID- 29708383 TI - A note by any other name: Intonation context rapidly changes absolute note judgments. AB - Absolute pitch (AP) judgments, by definition, do not require a reference note, and thus might be viewed as context independent. Here, we specifically test whether short-term exposure to particular intonation contexts influences AP categorization on a rapid time scale and whether such context effects can change from moment to moment. In Experiment 1, participants heard duets in which a "lead" instrument always began before a "secondary" instrument. Both instruments independently varied on intonation (flat, in-tune, or sharp). Despite participants being instructed to judge only the intonation of the secondary instrument, we found that participants treated the lead instrument's intonation as "in-tune" and intonation judgments of the secondary instrument were relativized against this standard. In Experiment 2, participants heard a short antecedent context melody (flat, in-tune, or sharp) followed by an isolated target note (flat, in-tune, or sharp). Target note intonation judgments were once again relativized against the context melody's intonation, though only for notes that were experienced in the context or implied by the context key signature. Moreover, maximally contrastive intonation combinations of context and target engendered systematic note misclassifications. For example, a flat melody resulted in a greater likelihood of misclassifying a "sharp F-sharp" as a "G." These results highlight that both intonation and note category judgments among AP possessors are rapidly modified by the listening environment on the order of seconds, arguing against an invariant mental representation of the absolute pitches of notes. Implications for general auditory theories of perception are discussed. (PsycINFO Database Record PMID- 29708384 TI - The Least Costs Hypothesis: A rational analysis approach to the voluntary symbolic control of attention. AB - Here we propose a rational analysis account of voluntary symbolic attention control-the Least Costs Hypothesis (LCH)-that construes voluntary control as a decision between intentional cue use and unguided search. Consistent with the LCH, the present study showed that this decision is sensitive to variations in cue processing efficiency. In Experiment 1, observers demonstrated a robust preference for using "easy-to-process" arrow cues but not "hard-to-process" spatial word cues to satisfy an easy visual search goal; Experiment 2 showed that this preference persisted even when the temporal costs of cue processing were neutralized. Experiment 3 showed that observers reported this cue type preference outside the context of a speeded task, and Experiment 4 showed empirical measures of this bias to be relatively stable over the course of the task. Together with previous evidence suggesting that observers' decision between intentional cue use and unguided search is also influenced by variations in unguided search efficiency, these findings suggest that voluntary symbolic attention control is mediated by ongoing metacognitive evaluations of demand that are sensitive to perceived variations in the time, effort, and opportunity costs associated with each course of action. Thus, voluntary symbolic attention control is far more complex than previously held. (PsycINFO Database Record PMID- 29708385 TI - Age differences in adults' daily social interactions: An ecological momentary assessment study. AB - Prevailing research has suggested that social relationships get better with age, but this evidence has been largely based on studies with lengthy reporting intervals. Using an ecological momentary assessment approach, the present study examined age differences in several characteristics of social interactions as reported in near-real time: the frequency, quality, and partner type. Participants (N = 173) ages 20-79 years reported their social interactions at 5 random times throughout the day for 1 week. Results revealed that age was associated with higher frequency of interacting with family and lower frequency of interacting with peripheral partners. These age effects, however, became nonsignificant after accounting for contextual factors such as race, gender, education, employment status, family structure, and living arrangement. In contrast, a curvilinear relationship best characterized age differences in both positive and negative ratings of daily social interaction quality, with middle aged adults reporting the lowest positive ratings and older adults reporting the lowest negative ratings among all ages. Contextual factors did not account for these patterns of age differences in interaction quality. Furthermore, the intraindividual variability of interaction frequency with peripheral partners, partner diversity, and interaction quality (positivity and negativity) was lower among older adults than among younger adults. Findings from the present study portray a nuanced picture of social interactions in daily life and advance the understanding of social interactions across the life span. (PsycINFO Database Record PMID- 29708386 TI - Mindful vs. mind full: Processing strategies moderate the association between subjective aging experiences and depressive symptoms. AB - Recent evidence suggests that the longitudinal association between subjective aging experiences, that is, the way people perceive and evaluate their aging process, and well-being-related developmental outcomes depends on individual differences. We investigated the moderating role of two processing strategies, that is, mindfulness and negative repetitive thought (RT), for the association between subjective aging experiences and depressive symptoms in middle and old adulthood. Analyses were based on two measurements covering a 4.5-year interval (Time 1: 2012, N = 423; age range = 40-98 years; Time 2: 2017, N = 299; age range = 44-92 years). Subjective aging experiences were operationalized as awareness of age-related gains and losses. Data were analyzed by means of a latent change score model based on a structural equation modeling approach. Mindfulness buffered the harmful effect of high levels of awareness of age-related losses on change in depressive symptoms. Conversely, negative RT exacerbated the detrimental effect of high levels of awareness of age-related losses and low levels of awareness of age-related gains on change in depressive symptoms. With regard to the interplay between awareness of age-related gains and mindfulness, effects were less robust, although the direction of findings was consistent with theoretical considerations. Effects were comparable across middle-aged and older adults. Subjective aging experiences are not operating in isolation, but always need to be considered in the context of the way individuals are cognitively dealing with them. (PsycINFO Database Record PMID- 29708387 TI - Intervention delivery fidelity assessment of a counseling-based intervention for promoting smoking reduction and increasing physical activity. AB - OBJECTIVE: The aims of this study were to (1) develop an approach to assess the delivery fidelity of a complex intervention to simultaneously increase physical activity and reduce smoking and (2) use this approach to assess the variation of fidelity across the delivery of different intervention components of the intervention. METHOD: Audio recorded and transcribed sessions (90 in total) involving 30 participants and 3 health trainers delivering a one-to-one intervention were purposively sampled across health trainer (HT) and stage of treatment. The Dreyfus system for skill acquisition informed a scoring system based on 12 intervention processes and applied by three experts in health behavior change. Scores ranged from 0 to 2 (poor quality), 3 to 4 (reasonable quality), and 5 to 6 (expert level quality). Scores were averaged across coders and presented in relation to fidelity of both HT and the intervention component. RESULTS: The methods were successfully applied with recommendations for future application. Average scores for each item by each coder differed by up to +0.7 to -0.9 points indicating reasonable agreement. Mean scores for the three HTs were 2.9, 2.2, and 2.4, across all 12 intervention processes. The delivery of all intervention components for physical activity was scored lower (<3) than their respective counterparts for smoking reduction (>3; p < .001). CONCLUSIONS: Novel methods for assessing delivery fidelity were successfully applied and areas for improvement identified. Delivery fidelity was deemed to be of reasonable quality but was higher for smoking related intervention components over physical activity ones. (PsycINFO Database Record PMID- 29708389 TI - Stress-related eating, mindfulness, and obesity. AB - OBJECTIVE: This study explored how experiences of stress in adulthood, including the occurrence of stressful life events and psychosocial strains in various life domains, might be related to stress-related eating and indicators of obesity, including body mass index (BMI) and waist circumference. METHOD: Cross-sectional data were examined from 3,708 adults in the Midlife in the U.S. study (MIDUS II). RESULTS: Hierarchical regression analyses indicated that experiences of stress were associated with higher BMI and waist circumference, even after controlling for age, annual household income, education level, race, and sex, although the additional variance accounted for was small. A nonparametric bootstrapping approach indicated that stress-related eating mediated the association between experiences of stress and indicators of obesity. Moderated-mediation analyses indicated that the relationship between experiences of stress and stress-related eating was amplified for women and individuals with obesity in comparison to men and individuals without obesity. Mindfulness did not moderate the experiences of stress and stress-related eating association. CONCLUSIONS: These results provide further evidence of the contributions of psychosocial factors to chronic disease risk. (PsycINFO Database Record PMID- 29708388 TI - Does exercise aid smoking cessation through reductions in anxiety sensitivity and dysphoria? AB - OBJECTIVE: Research shows that high anxiety sensitivity (AS) and dysphoria are related to poor smoking cessation outcomes. Engaging in exercise may contribute to improvement in smoking cessation outcomes through reductions in AS and dysphoria. In the current study, we examined whether exercise can aid smoking cessation through reductions in AS and dysphoria. METHOD: Participants were sedentary and low activity adult daily smokers (N = 136) with elevated AS who participated in a randomized controlled trial comparing smoking cessation treatment (ST) plus an exercise intervention (ST + EX) to ST plus wellness education (ST + CTRL). Self-reported smoking status was assessed in-person weekly from baseline through week 16 (end of-treatment; EOT), at week 22 (4 months postquit day), and at week 30 (6 months postquit day), and verified biochemically. RESULTS: Results indicated that both AS and dysphoria at 6-month follow-up were significantly lower in the ST + EX group compared to the ST + CTRL group (controlling for baseline levels). Moreover, reductions in AS and dysphoria emerged as independent mechanisms of action explaining success in quitting. CONCLUSIONS: These novel findings offer clinically significant evidence suggesting that vigorous-intensity exercise can effectively engage affective constructs in the context of smoking cessation. (PsycINFO Database Record PMID- 29708390 TI - An integrated model of condom use in Sub-Saharan African youth: A meta-analysis. AB - OBJECTIVE: We tested an integrated social-cognitive model derived from multiple theories of the determinants of young people's condom use in Sub-Saharan Africa. The model comprised seven social-cognitive antecedents of condom use: Attitudes, norms, control, risk perceptions, barriers, intentions, and previous condom use. METHOD: We conducted a systematic search of studies including effects between at least one model construct and intended or actual condom use in young people from sub-Saharan African countries. Fifty-five studies comprising 72 independent data sets were included and subjected to random-effects meta-analysis. Demographic and methodological variables were coded as moderators. Hypotheses of the integrated model were tested using meta-analytic structural equation modeling. RESULTS: The meta-analysis revealed significant nontrivial sample-weighted correlations among most model constructs. Moderator analyses revealed differences in six correlations for studies that included a formative research component relative to studies that did not. There was little evidence of systematic moderation of relations among model constructs by other candidate moderators. Meta-analytic structural equation models revealed significant direct effects of attitudes, norms, and control on condom use intentions, and of intention, control, and barriers on condom use. Including past condom use increased explained variance in condom use intentions and behavior but did not attenuate model effects. There were also significant indirect effects of attitudes, norms, and control on condom use through intentions. CONCLUSIONS: Findings provide preliminary evidence to support the integrated condom use model in sub-Saharan African youth. The model provides guidance on potential targets for improving the effectiveness of condom promotion interventions. (PsycINFO Database Record PMID- 29708391 TI - Reply to Goulden et al.: Risk of Bias in Study of Varenicline and Cardiovascular Outcomes. PMID- 29708392 TI - Can We Manipulate the Evolutionary Biology of Pathogens for Clinical Benefit? PMID- 29708393 TI - Models of Ciliary Dysfunction: Time to Expand. PMID- 29708394 TI - Extracorporeal CO2 Removal May Improve Renal Function of Patients with Acute Respiratory Distress Syndrome and Acute Kidney Injury: An Open-Label, Interventional Clinical Trial. PMID- 29708395 TI - The Emerging Role of Neutrophils in Repair after Acute Lung Injury. AB - Neutrophils are key players in acute lung injury. Once recruited from the circulation, these cells release cytotoxic molecules that lead to tissue disruption, so their blockade has been advocated to prevent lung damage. However, lung injury also occurs during neutropenia and usually involves a very poor outcome. There is emerging evidence that neutrophils not only contribute to that early damage but also orchestrate later repair. Neutrophils promote epithelial proliferation and are a source of proteases, which are required for the processing of the collagen scar and facilitation of cell migration. This article reviews the effects of neutrophils in repair after acute lung injury, focusing on their role as biovectors for proteases and other molecules involved in tissue remodeling. PMID- 29708396 TI - Evaluation of characteristics of the craniofacial complex and dental maturity in girls with central precocious puberty. AB - OBJECTIVES: To identify unique characteristics of the craniofacial complex and dental maturity in girls with central precocious puberty (CPP). MATERIALS AND METHODS: This study included 34 Korean girls with idiopathic CPP (mean age, 8.6 +/- .5 years) and 28 normal healthy girls of the same chronological age. An initial evaluation of the growth pattern of the craniofacial complex and dental maturity was conducted by analyzing lateral cephalometric and panoramic radiographs. RESULTS: The mandibular ramus height (44.4 +/- 4.1 mm) and total mandibular length (10.8 +/- 4.3 mm) ( P = .004 and .021, respectively) were greater and the lower anterior facial height was lesser (63.2 +/- 2.4 mm) ( P = .040) in the CPP group than in the reference group. In addition, the gonial angle (12.9 +/- 6.1 degrees ; P = .045) and the mandibular plane angle (34.9 +/- 4.8 degrees ; P = .012) were smaller in girls with CPP than in normal healthy girls. All the mandibular teeth were more mature in girls with CPP ( P < .001). A strong positive correlation was observed between the mandibular tooth formation stages and the presence of CPP in girls ( r = .756 to .957; P < .001). CONCLUSIONS: CPP had an effect on the anteroposterior growth of the mandible in the craniofacial complex and the rotation of the mandibular plane angle. Early maturation of the mandibular teeth was observed in girls with CPP. PMID- 29708397 TI - Effects of growth hormone and functional appliance on mandibular growth in an adolescent rat model. AB - OBJECTIVES: To investigate the individual and synergistic effects of growth hormone (GH) and functional appliance (FA) on mandibular growth in an adolescent rat model. MATERIALS AND METHODS: Forty adolescent (6-week-old) female Wistar rats were randomly divided into four groups (10 rats in each group). The control group received a sham treatment (intra-abdominal injection of phosphate-buffered saline), the GH group received an intra-abdominal injection of recombinant human growth hormone, the FA group was treated with a mandibular advancement device, and the GH+FA group received both the GH and FA treatments. The amount of mandibular growth in each group was measured quantitatively using cone-bean computed tomography. The growth of condylar cartilage and expression of matrix metalloproteinases-1 and -13 (MMP-1 and MMP-13) and type II and X collagen (Col II and Col X) were assessed using histological staining and immunostaining techniques. RESULTS: After 4 weeks, there was significant mandibular growth in the FA group compared with the control group ( P < .05). The GH+FA group had significantly greater mandibular length, thickness of condylar cartilage, and expression of MMP-1, MMP-13, Col II, and Col X in the cartilage than the other groups ( P < .05). The GH+FA group and GH group had significantly greater weight than the FA and control groups ( P < .05). CONCLUSIONS: The FA as well as GH+FA stimulated mandibular growth in adolescent rats. PMID- 29708398 TI - Predicting Outcome in Idiopathic Pulmonary Fibrosis Using Automated Computed Tomography Analysis. PMID- 29708399 TI - IL-17 Strikes a Chord in Chronic Obstructive Pulmonary Disease Exacerbation. PMID- 29708400 TI - Shadow study: randomized comparison of clinic with video follow-up in glioma undergoing adjuvant temozolomide therapy. AB - AIM: This study was designed with a primary objective to study the rate of agreement in treatment plan and decisions between video follow-up (VF) and conventional clinic follow-up (CF). PATIENTS & METHODS: Adult patients with intermediate- to high-grade glioma on adjuvant temozolomide (TMZ) with facilities for live video call were invited to participate in the study. RESULTS: The concurrence in decision of administering TMZ between VF and CF was 100% (p < 0.00). The median cost incurred in VF was US$58.15 while that incurred in CF was US$131.23 (p < 0.00). CONCLUSION: VF can substitute CF during adjuvant TMZ administration (CTRI/2017/01/007626). PMID- 29708401 TI - Patterns of care and treatment outcomes of patients with astroblastoma: a National Cancer Database analysis. AB - AIM: To evaluate the use of chemotherapy and radiation, and their outcomes for patients with astroblastoma. PATIENTS & METHODS: This is a retrospective review of patients extracted from the National Cancer Database. We investigated overall survival (OS) using Kaplan-Meier curves. Cox proportional hazards models were used to correlate OS with risk variables and treatments. RESULTS: OS at 5 years was 79.5%. Patients with high-grade tumors were more likely to receive chemotherapy and radiation. Patients with high-grade astroblastoma who did not receive adjuvant radiation had poor survival. CONCLUSION: Patients with astroblastoma should be treated with curative intent. Radiation is likely beneficial in high-grade astroblastoma. The exact role of radiation and chemotherapy following surgical resection warrant further investigation. PMID- 29708402 TI - Risk of Bias in Study of Varenicline and Cardiovascular Outcomes. PMID- 29708403 TI - Detection of unknown primary tumor in patients presented with brain metastasis by F-18 fluorodeoxyglucose positron emission tomography/computed tomography. AB - AIM: F-18 fluorodeoxyglucose (FDG) PET/CT has several advantages in diagnosis of cancer of unknown primary with reported incremental diagnostic value. In this study, we evaluated the patients who were presented with multiple brain metastasis and unknown primary tumor. MATERIALS & METHODS: 31 patients (17 males, 14 females; mean: 56.1 +/- 14.22 years old) with diagnosis of brain metastasis according to histopathology and/or MRI were included into this retrospective study. RESULTS: The patients presented with hypermetabolic (n = 17; mean SUVmax: 11.6 +/- 6.9) or hypometabolic brain lesions with additional different metastatic sites in 13 patients (mean SUVmax: 9.03 +/- 4.02). The primary tumor was determined by FDG PET/CT in 20/26 patients (77%) (lung [n = 6], primary brain [n = 9], renal cell carcinoma [n = 2], skin [n = 1], breast [n = 1] and neuroendocrine tumor [n = 1]). CONCLUSION: New generation multislice scanners may provide higher detection ratios. The detection rate of FDG PET/CT might be higher than previously reported according to this study. PMID- 29708404 TI - BRAF inhibition with concomitant tumor treating fields for a multiply progressive pleomorphic xanthoastrocytoma. AB - Pleomorphic xanthoastrocytomas can be very resistant to treatment if they progress after standard therapy with surgery and radiation. We present the case of a patient with a multiply recurrent pleomorphic xanthoastrocytoma which demonstrated a sustained partial response to a combination regimen of the BRAF inhibitor vemurafenib and tumor treating fields. The regimen proved tolerable and efficacious in this case. PMID- 29708405 TI - Coffee Drinking and the Risk of Endometrial Cancer: An Updated Meta-Analysis of Observational Studies. AB - BACKGROUND: Several compounds contained in coffee have been found to suppress carcinogenesis in experimental studies. We conducted a dose-response meta analysis to assess the impact of coffee consumption on the risk of endometrial cancer. MATERIALS AND METHODS: We searched MEDLINE and EMBASE databases for studies published up to August 2016. Using random effects models, we estimated summary relative risks (RR) for cohort studies and odds ratios (OR) for case control studies with 95% confidence intervals (CI). Dose-response analyses were conducted by using generalized least square trend estimation. RESULTS: We identified 12 cohort studies and 8 case-control studies eligible for inclusion, contributing with 11,663 and 2,746 endometrial cancer cases, respectively. The summary RR for highest compared with lowest coffee intake was 0.74 (95% CI: 0.68 0.81; pheterogeneity = 0.09, I2 = 32%). The corresponding summary RR among cohort studies was 0.78 (95% CI: 0.71-0.85; pheterogeneity = 0.14, I2 = 31.9%) and 0.63 (95% CI: 0.53-0.76; pheterogeneity = 0.57, I2 = 0%) for case-control studies. One cup increment per day was associated with 3% risk reduction (95% CI: 2-4%) in cohort studies and 12% (95% CI: 5-18%) in case-control studies. After pooling the results from 5 cohort studies, the association remained significant only in women with body mass index over 30 (RR = 0.71, 95% CI: 0.61-0.81). CONCLUSION: The results from our meta-analysis strengthen the evidence of a protective effect of coffee consumption on the risk of EC and further suggest that increased coffee intake might be particularly beneficial for women with obesity. PMID- 29708406 TI - Public perspectives toward long-term care staff's interventions in the sexual relationships of residents with dementia. AB - : Background and objectives Sexual expression is an essential component of older adults' quality of life, including those with lower cognitive functioning. Issues have been raised with long-term care facility policies related to aspects of staff intervention, permissibility of degree of intimacy, and how involved partners of residents with cognitive decline may be in decision-making processes. RESEARCH DESIGN AND METHODS: This study used a multiple segment factorial vignette to explore the attitudes of the public toward a dementia-caused non spousal sexual relationship in a long-term care facility. Specific elements examined included the degree of intimacy, obligation of long-term care staff to intervene in the relationship, and the healthy spouse's disposition. Respondents ( N = 318) were contacted using a list-assisted random-digit dialing method and read a version of the vignette with the independent variables randomly generated. Two logistic regression models and one ordinal regression model were used to analyze the main effects of the independent design variables and respondent characteristics. Results The majority of respondents report the need for long term care staff to intervene in sexual relationships and an obligation to inform the healthy spouse of a resident's sexual relationship. Results suggest differences of opinion exist based on respondent characteristics of education and religiosity. Discussion and implications: Public opinion is in favor of long-term care facilities incorporating spousal involvement into decisions regarding a cognitively impaired resident's ability to engage in an intimate relationship. Implications for long-term care policy focusing on staff training about sexual expression and intervention in addition to incorporating the spouse into decision making processes are discussed. PMID- 29708407 TI - It takes time: Building relationships and understanding through an intergenerational ballet programme. AB - Individuals living in long-term residential care homes are often viewed through a negative lens. These residents have increasingly complex care needs, and their functional, communication and cognitive challenges can support conceptualizations of difference and disability perpetuating negative stereotypes of age and dementia. However, engaging in meaningful activities and relationships with older adults, including those with dementia, has been shown to promote positive attitudes. Specifically, intergenerational programming that provides opportunities for meaningful engagement between children and older adults has been shown to support positive emotional experiences through socializing and building relationships. This qualitative study explored the development of relationships between school-aged children and older adults with dementia living in a long-term residential care home. Residents in long-term care homes and children typically have limited opportunities to interact with each other; in this study, participating in an intergenerational dance programme provided an opportunity for meaningful relationships to develop. This paper focuses on the development of the children's attitudes and understandings of their much older dance partners. Seven girls between the ages of seven and nine participated in ballet classes with residents in a long-term care home for one hour each week over a six-month period. All of the residents had a diagnosis of moderate to advanced dementia. Further, all of the residents also had other chronic health issues such as cardiac, respiratory and/or neurological diseases. The children were interviewed at the baseline, three- and six-month intervals. Prior to beginning the dance programme, the children anticipated their dance partners to be unwell and unable. However, by the end of six months, the children described the residents much more positively highlighting their abilities and strengths. Over time, through participating in a structured intergenerational programme, the children's views of disability and difference disappeared as they formed dance partnerships and developed meaningful relationships. PMID- 29708408 TI - The arts and dementia: Emerging directions for theory, research and practice. PMID- 29708409 TI - The effect of high-polyphenol extra virgin olive oil on cardiovascular risk factors: A systematic review and meta-analysis. AB - The polyphenol fraction of extra-virgin olive oil may be partly responsible for its cardioprotective effects. The aim of this systematic review and meta-analysis was to evaluate the effect of high versus low polyphenol olive oil on cardiovascular disease (CVD) risk factors in clinical trials. In accordance with PRISMA guidelines, CINAHL, PubMed, Embase and Cochrane databases were systematically searched for relevant studies. Randomized controlled trials that investigated markers of CVD risk (e.g. outcomes related to cholesterol, inflammation, oxidative stress) were included. Risk of bias was assessed using the Jadad scale. A meta-analysis was conducted using clinical trial data with available CVD risk outcomes. Twenty-six studies were included. Compared to low polyphenol olive oil, high polyphenol olive oil significantly improved measures of malondialdehyde (MD: -0.07umol/L [95%CI: -0.12, -0.02umol/L]; I2: 88%; p = 0.004), oxidized LDL (SMD: -0.44 [95%CI: -0.78, -0.10umol/L]; I2: 41%; P = 0.01), total cholesterol (MD 4.5 mg/dL [95%CI: -6.54, -2.39 mg/dL]; p<0.0001) and HDL cholesterol (MD 2.37 mg/dL [95%CI: 0.41, 5.04 mg/dL]; p = 0.02). Subgroup analyses and individual studies reported additional improvements in inflammatory markers and blood pressure. Most studies were rated as having low-to-moderate risk of bias. High polyphenol oils confer some CVD-risk reduction benefits; however, further studies with longer duration and in non-Mediterranean populations are required. PMID- 29708412 TI - Illusion as a Basic Psychic Principle: Winnicott, Freud, Oedipus, and Trump. AB - Illusion can be viewed as a creative engagement with the world, and as a central psychic motivation and capacity, rather than as a form of self-deception. Winnicott and other Middle Group writers have understood integrative, imaginative illusion as an essential part of healthy living and psychosocial development. As such, it emerges and presents itself in a variety of ways, in transaction with the realities that support or degrade it. In its absence, varied difficulties in living ensue. To elaborate and illustrate this conceptualization, Freud's notion that the oedipus complex is resolved is reconsidered as a creative misreading of Sophocles' Oedipus trilogy, one based on the plausible illusion of a civilizing psychosocial development that would serve as a protective bastion against his experience of the political chaos and violence of the first decades of twentieth century European history. Finally, the place of illusion and disillusionment among those most disillusioned by the recent election of Donald Trump in the United States is considered in relation to the recent right-wing populist turn. PMID- 29708415 TI - The Psychotic Part of the Personality: Bion'S Expeditions into Unmapped Mental Life. AB - The psychotic part of the personality is seen as a multidimensional mental realm that is fully comprehensible only through intuition and tolerance of approximations, transience, and the notion of infinity. It is suggested that a major differentiating factor between the psychotic and nonpsychotic parts of the personality is the capacity to tolerate the infinite complexity of the human mind. With the use of mathematical concepts, Bion tries to describe the state of mind required of the analyst who endeavors to tread on psychotic territories of the personality. Bion is in effect trying to describe the intensity, violence, and fortitude of the transformation of the emotional experience generated by the psychotic as opposed to the nonpsychotic part of personality. Viewed from this vertex, transference is the path by which the unrepressed and unrepresentable unconscious can evolve and express itself. It is the function by which the individual can live through for the first time aspects of his mental life that have never been experienced. This is illustrated with a number of clinical vignettes highlighting different aspects of our capacity to get in touch with this nonsensuous realm of the psychoanalytic encounter. PMID- 29708417 TI - "The Fullness of the Infinite": Introduction to Disillusionment Papers. PMID- 29708416 TI - Disillusionment and Suicidality: When a Developmental Necessity Becomes a Clinical Challenge. AB - Both illusion and disillusion play an important role in development, fostering processes of going-on-being and separation (Winnicott 1960). The capacity to bear disillusionment is both a developmental necessity and an ongoing challenge. Disillusionment penetrates the sphere of illusion and invites the individual into an expanded encounter with shared realities. But when disillusionment becomes chronic and pervasive or is accompanied by severe psychic pain, then suicide is felt by some to be an urgent option for refusing or escaping this pain. Contextualized within a review of psychoanalytic developmental theories of disillusion, vignettes from a research study of participants who have survived a near lethal suicide attempt illuminate the phenomenon of suicide as an illusory solution to what feels like unbearable disillusionment. PMID- 29708419 TI - Illusionment and Disillusionment: Foundational Illusions and the Loss of a World. AB - One can only be disillusioned if once one lived within illusions-and so disillusionment is always after the fact ( apres coup or nachtraglich), as illusions come into view even as they are crumbling within. With a crisis of disillusionment-or existential disillusionment-one falls away from a coherence of meaning, revealing a system of intertwined fundamental illusions that had always been lived within and implicit, part of one's being-in-the-world, and that now seem broken, strange, and uncanny. This way of being that one recognizes only retrospectively may be called "illusionment," a state of being apprehended in the very process of its falling apart. That is, prior to disillusionment, there may not have been an illusion as such; rather, there was some overall effective enough, taken-for-granted coherence, an experience of world and being that now comes into view and seems broken precisely because it no longer holds together. For example, a sense of a common "we" might be revealed to be so flawed as to have been a fiction, a fantasy, a set of pervasive, interwoven illusions that one had once naively lived within as unquestioned beliefs. Severe disillusionment, then, carries with it a sense of falling out of the once taken-for-granted world, undermining a sense of solid existential grounding. Saturating all aspects of the psyche, traumatizing disillusionments may lead to a lifelong cascade of apres coup attempts to find new grounding in how to live, as one attempts to repair this world-broken-ness. PMID- 29708421 TI - Discussion: A Crisis of Disillusionment. PMID- 29708422 TI - Disillusioning Gender. AB - Illusions are not errors but erroneous beliefs motivated by wishful ideas and fantasies. To disillusion gender is to challenge the traditional Freudian construction that splits masculinity and femininity into agency versus passivity, the first with power, the second without. Disillusioning femininity as impotent frees up potency and power as generativity. Disillusioning masculinity as phallic and omnipotent opens the masculine subject to permeability and vulnerability. Illusions regarding the transgender include the idea that there are only two gender categories and the idea that gender identity is generated solely from an internal sense of self. The wish "to be seen as" or "to pass as" one gender or the other shows that social structures exceed the individual. At least for now, the disillusionment of gender with which we are left marks a tension between the internal sense of gender identity and the social structures of gender. PMID- 29708427 TI - Between Action and Inaction: The Space for Analytic Intimacy. PMID- 29708429 TI - US Food and Drug Administration Approval of Whole Slide Imaging for Primary Diagnosis: A Key Milestone Is Reached and New Questions Are Raised. AB - April 12, 2017 marked a significant day in the evolution of digital pathology in the United States, when the US Food and Drug Administration announced its approval of the Philips IntelliSite Pathology Solution for primary diagnosis in surgical pathology. Although this event is expected to facilitate more widespread adoption of whole slide imaging for clinical applications in the United States, it also raises a number of questions as to the means by which pathologists might choose to incorporate this technology into their clinical practice. This article from the College of American Pathologists Digital Pathology Committee reviews frequently asked questions on this topic and provides answers based on currently available information. PMID- 29708428 TI - Interpathologist Diagnostic Agreement for Non-Small Cell Lung Carcinomas Using Current and Recent Classifications. AB - CONTEXT.-: Measurement of interpathologist diagnostic agreement (IPDA) should allow pathologists to improve current diagnostic criteria and disease classifications. OBJECTIVES.-: To determine how IPDA for pathologists' diagnoses of non-small cell lung carcinoma (NSCLC) is affected by the addition of a set of mucin and immunohistochemical (IHC) stains to hematoxylin-eosin (H&E) alone, by recent NSCLC reclassifications, by simplification of these classifications, and by pathologists' practice location, pulmonary pathology expertise, practice duration, and lung carcinoma case exposure. DESIGN.-: We used a Web-based survey to present core images of 54 NSCLC cases to 22 practicing pathologists for diagnosis, initially as H&E only, then as H&E plus mucin and 4 IHC stains. Each case was diagnosed according to published 2004, 2011, and 2015 NSCLC classifications. Cohen's kappa was calculated for the 231 pathologist pairs as a measure of IPDA. RESULTS.-: Twenty-two pathologists diagnosed 54 NSCLC cases by using 4 published classifications. IPDA is significantly higher for H&E/mucin/IHC diagnoses than for H&E-only diagnoses. IPDA for H&E/mucin/IHC diagnoses is highest with the 2015 classification. IPDA is estimated higher after collapse of stated diagnoses into subhead or dichotomized classes. IPDA for H&E/mucin/IHC diagnoses with the 2015 World Health Organization classification is similar for community and academic pathologists, and is higher when pathologists have pulmonary pathology expertise, have more than 6 years of practice experience, or diagnose more than 100 new lung carcinoma cases per year. CONCLUSIONS.-: Higher IPDA is associated with use of mucin and IHC stains, with the 2015 NSCLC classification, and with pathologists' pulmonary pathology expertise, practice duration, and frequency of lung carcinoma cases. PMID- 29708430 TI - Report on the 18th Annual Land O'Lakes Bioanalytical Conference. AB - The 18th Annual Land O'Lakes Bioanalytical Conference, titled 'Cutting-Edge Bioanalytical Technologies and Concepts - Issues, Solutions and Practical Considerations for Applications in Novel and Emerging Modalities', was held 10-13 July 2017 in Madison, WI, USA. This Land O'Lakes Conference is presented each year by the Division of Pharmacy Professional Development within the School of Pharmacy at the University of Wisconsin-Madison (USA). The purpose of this conference is to provide an educational forum to discuss issues and applications associated with the analysis of xenobiotics, metabolites, biologics and biomarkers in biological matrices. The conference is designed to include and encourage an open exchange of scientific and methodological applications for bioanalysis. This report summarized the presentations at the 18th Annual Conference. PMID- 29708431 TI - Synthesis and evaluation of thiazolidinone-pyrazole conjugates as anticancer and antimicrobial agents. AB - AIM: To synthesize a series of new thiazolidinone-pyrazole hybrids (5a-o) and assess their anticancer (in vitro and in vivo) and antimicrobial activities. RESULTS: The compounds 5h (against Ehrlich ascites carcinoma cells), 5e and 5i (against the human breast cancer [MDA-MB231] cell line) exhibited potent anticancer activity. All the compounds except 5g and 5e found to be less toxic for the human dermal fibroblast cells. The effective interactions of the compounds in silico with MDM2 exemplified their inhibitory potency. The derivatives also showed moderate antimicrobial activity. CONCLUSION: The halogen atoms on various positions of the N-arylamino ring played an advantageous role in elevating the potency of the molecules. Thus, these conjugates could be used as a lead for further optimization to achieve promising therapeutics. PMID- 29708433 TI - Care and Culpability. PMID- 29708434 TI - Biopsy of ureteric lesions using a semi-rigid ureteroscope through a ureteric access sheath. PMID- 29708436 TI - PROLACTIN LEVELS DO NOT RISE AMONG TRANSGENDER WOMEN TREATED WITH ESTRADIOL AND SPIRONOLACTONE. AB - OBJECTIVE: Existing transgender treatment guidelines suggest that there is a need to monitor prolactin levels in patients receiving transfeminine hormone treatment. Also, recent studies suggest that use of cyproterone acetate as an adjunctive anti-androgen during transgender hormone treatment may elevate serum prolactin. We sought to determine whether the reported relationship between transfeminine estradiol treatment and hyperprolactinemia would be evident when the regimen used spironolactone as the adjunctive anti-androgen. METHODS: Estradiol levels, testosterone levels, prolactin levels, body mass index (BMI), and prescribed spironolactone dosage were extracted from the electronic medical records of 98 de-identified transgender women treated with estrogen therapy at the Endocrinology Clinic at Boston Medical Center (BMC). Up to 6 years of data were available for some patients. RESULTS: We found no statistically significant relationship between prolactin and any of the other measures. No estrogen dose associated elevations in prolactin were found. None of the patients were diagnosed with prolactinoma. CONCLUSION: Our data suggest that there may be no significant rise in prolactin when transgender women are treated with estrogen along with spironolactone as the adjunct anti-androgen. It may be unnecessary to monitor prolactin in patients on this treatment combination. ABBREVIATIONS: BMI = body mass index; BMC = Boston Medical Center; HT = hormone therapy. PMID- 29708435 TI - Heterogenic expression of stem cell markers in patient-derived glioblastoma spheroid cultures exposed to long-term hypoxia. AB - AIM: To investigate the time profile of hypoxia and stem cell markers in glioblastoma spheroids of known molecular subtype. MATERIALS & METHODS: Patient derived glioblastoma spheroids were cultured up to 7 days in either 2% or 21% oxygen. Levels of proliferation (Ki-67), hypoxia (HIF-1alpha, CA9 and VEGF) and stem cell markers (CD133, nestin and musashi-1) were investigated by immunohistochemistry. RESULTS: Hypoxia markers as well as CD133 and partially nestin increased in long-term hypoxia. The proliferation rate and spheroid size were highest in normoxia. CONCLUSION: We found differences in hypoxia and stem cell marker profiles between the patient-derived glioblastoma cultures. This heterogeneity should be taken into consideration in development of future therapeutic strategies. PMID- 29708437 TI - Adapting Maslow's Hierarchy of Needs as a Framework for Resident Wellness. AB - ISSUE: Burnout in graduate medical education is pervasive and has a deleterious impact on career satisfaction, personal well-being, and patient outcomes. Interventions in residency programs have often addressed isolated contributors to burnout; however, a more comprehensive framework for conceptualizing wellness is needed. EVIDENCE: In this article the authors propose Maslow's hierarchy of human needs (physiologic, safety, love/belonging, esteem, and self-actualization) as a potential framework for addressing wellness initiatives. There are numerous contributors to burnout among physician-trainees, and programs to combat burnout must be equally multifaceted. A holistic approach, considering both the trainees personal and professional needs, is recommended. Maslow's Needs can be adapted to create such a framework in graduate medical education. The authors review current evidence to support this model. IMPLICATIONS: This work surveys current interventions to mitigate burnout and organizes them into a scaffold that can be used by residency programs interested in a complete framework to supporting wellness. PMID- 29708438 TI - Outcomes of protocolised analgesia and sedation in a neurocritical care unit. AB - OBJECTIVES: Providing analgesia and sedation while allowing for neurological assessment is important in the neurocritical care unit (NCCU), yet data are limited about the effects of protocolised analgesia and sedation. We developed an analgesia-based sedation protocol and evaluated its effect on medication utilisation and costs in the NCCU. METHODS: We conducted a retrospective cohort study of patients who are mechanically ventilated and admitted to a 12-bed NCCU over four years. To compare outcomes, we used gamma and negative binomial regression models, and interrupted time-series sensitivity analyses. RESULTS: The study cohort consisted of 1197 patients: 576 pre-protocol and 621 post-protocol. The protocol resulted in an increase in fentanyl use [incidence rate ratio (IRR) = 2.8, (95% confidence limits (CLs) 1.9, 4.2)] and a decrease in propofol use (IRR = 0.8, CLs 0.6, 1.0). There was a decrease in fentanyl (cost ratio = 0.8, CLs 0.5, 1.1) and propofol costs (cost ratio = 0.6, CLs 0.5, 0.8). The sensitivity analyses results were similar. There was no effect on healthcare utilisation, healthcare costs, and in-hospital mortality. CONCLUSION: Protocolised analgesia and sedation increased analgesia use, decreased sedative use, and reduced medication-associated costs in the NCCU. Our results suggest that similar NCCUs should consider use of population-specific protocols to manage analgesia and sedation. PMID- 29708440 TI - Corrigendum. PMID- 29708441 TI - In Situ Blood Coagulum versus Sutures for Autograft Fixation after Pterygium Excision. AB - PURPOSE: To compare the outcomes of autograft fixation using patient's own blood coagulum and using sutures after pterygium excision. METHODS: In this prospective clinical study, 30 eyes of 30 patients with primary pterygium were randomly assigned into two groups: Group 1 (15 eyes) underwent autograft fixation with 10/0 nylon sutures and Group 2 (15 eyes) underwent autograft fixation by using in situ blood coagulum following pterygium excision. Primary outcome measure of this study was graft failure and displacement. Recurrence, the duration of surgery and patient discomfort were also evaluated. The patients were examined at day 1, day 7, month 1, month 6, and month 12. RESULTS: Mean duration of surgery was significantly less in Group 2 (mean duration 14 +/- 2 minutes) compared with Group 1 (mean duration 48 +/- 2 minutes). Graft failure and displacement were more common in Group 2 (13.3%) compared with Group 1 (6.7%). Recurrence was reported equally in both groups. Patient discomfort was found significantly more in Group 1 (foreign body sensation due to sutures.) Conclusions: Autograft fixation by using in situ blood coagulum after pterygium excision is an effective technique with less patient discomfort and shorter operation time. PMID- 29708439 TI - Acteoside relieves mesangial cell injury by regulating Th22 cell chemotaxis and proliferation in IgA nephropathy. AB - The existing therapies of IgA nephropathy are unsatisfying. Acteoside, the main component of Rehmannia glutinosa with anti-inflammatory and anti-immune effects, can improve urinary protein excretion and immune disorder. Th22 cell is involved in IgA nephropathy progression. This study was determined to explore the effect of acteoside on mesangial injury underlying Th22 cell disorder in IgA nephropathy. Serum Th22 cells and urine total protein of patients with IgA nephropathy were measured before and after six months treatment of Rehmannia glutinosa acteoside or valsartan. Chemotactic assay and co-culture assay were performed to investigate the effect of acteoside on Th22 cell chemotaxis and differentiation. The expression of CCL20, CCL22 and CCL27 were analyzed. To explore the effect of acteoside on mesangial cell injury induced by inflammation, IL-1, IL-6, TNF-alpha and TGF-beta1 were tested. Results showed that the proteinuria and Th22 lymphocytosis of patients with IgA nephropathy significantly improved after combination treatment of Rehmannia glutinosa acteoside and valsartan, compared with valsartan monotherapy. In vitro study further demonstrated that acteoside inhibit Th22 cell chemotaxis by suppressing the production of Th22 cell attractive chemokines, i.e., CCL20, CCL22 and CCL27. In addition, acteoside inhibited the Th22 cell proliferation. Co-culture assay proved that acteoside could relieve the overexpression of pro-inflammatory cytokines, and prevent the synthesis of TGF-beta1. TGF-beta1 level in mesangial cells was positively correlated with the Th22 cell. This research demonstrated that acteoside can alleviate mesangial cell inflammatory injury by modulating Th22 lymphocytes chemotaxis and proliferation. PMID- 29708442 TI - Psychological well-being in individuals living in the community with traumatic brain injury. AB - BACKGROUND: Well-being and quality of life issues remain a long-term problem for many individuals with traumatic brain injury (TBI). Meaningful activity is key to developing life satisfaction and a sense of contribution to society, yet individuals with TBI are often unable to return to competitive employment. OBJECTIVE: To describe the self-reported psychological well-being of a cohort of unemployed individuals living in the community at least 1 year post TBI with low life satisfaction. METHODS: Seventy-four unemployed individuals with low life satisfaction at least 1 year post TBI were administered measures of psychological well-being and cognitive functioning. RESULTS: This cohort of 74 participants demonstrated cognitive impairment and elevated levels of emotional distress. Significant bivariate relationships were noted among nearly all measures of well being, and associations were in the directions as expected. Individuals reported low life satisfaction and well-being. Two newer measures of well-being correlated with established measures used with this population. CONCLUSIONS: Individuals with TBI living in the community who are not employed but who seek to be productive reported low life satisfaction and well-being. This study highlights the need for interventions aimed at increasing productivity and meaning in life for individuals with TBI, and a broader understanding of psychological health after TBI. PMID- 29708443 TI - Maternal association and influence of DHFR 19 bp deletion variant predisposes foetus to anencephaly susceptibility: a family-based triad study. AB - OBJECTIVE: Previous studies have not used family-based methods to evaluate maternal-paternal genetic effects of the folate metabolizing enzyme, dihydro folate reductase (DHFR) essential during embryogenesis. Present study focuses on evaluating the association and influence of parental genetic effects of DHFR 19 bp deletion in the development of foetal neural tube defects (NTDs) using family based triad approach. MATERIALS AND METHODS: The study population (n = 924) including 124 NTD case-parent trios (n = 124 * 3 = 372) and 184 healthy control parent trios (n = 184 * 3 = 552) from Telangana, India, was genotyped for DHFR 19 bp deletion. Statistical analysis was used by SPSS and parent-of-origin effects (POE). RESULTS: Foetuses with deletion genotype (DD) were at risk of developing anencephaly (OR = 3.26, p = 0.020). Among parents, increased maternal risk of having an anencephaly foetus (OR = 2.66, p = 0.028) was observed in mothers with DD genotype. In addition, POE analysis also demonstrated higher risk of maternal transmission of the deletion allele to anencephaly foetus compared with paternal transmission (OR = 6.00, p = 0.016). Interestingly, maternal-paternal-offspring genotype incompatibility revealed maternal deletion genotype (DD) in association with paternal heterozygous deletion genotype (WD) significantly increased risk for NTDs (OR = 5.29, p = 0.013). CONCLUSIONS: This study, using family-based case parent and control-parent triad approach, is the first to report influence of maternal transmission of DHFR 19 bp deletion in the development of anencephaly in the foetus. PMID- 29708444 TI - Fulminant rebound of relapsing-remitting multiple sclerosis after discontinuation of dimethyl fumarate: A case report. AB - BACKGROUND: Rebound phenomena after discontinuation of different treatments for relapsing-remitting multiple sclerosis (RRMS) have previously been described. Systematic database research in PubMed did not show any report with relapse directly associated with dimethyl fumarate (DMF) cessation. CASE PRESENTATION: Here, we report on a 38-year-old Caucasian male patient suffering from a relatively mild course of RRMS who developed a fulminant clinical rebound 2 months after discontinuation of DMF therapy. Radiological alterations presented impressively with primarily spinal involvement. The patient received intensive care and multiple immunomodulating therapies. CONCLUSION: We report on this case to raise neurologist's awareness of complications of basic therapy discontinuation in RRMS. PMID- 29708445 TI - Latest in Vitro and in Vivo Assay, Clinical Trials and Patents in Cancer Treatment using Curcumin: A Literature Review. AB - Curcumin, the main active compound of the curcuma root, shows antioxidant, anti inflammatory, and antitumor properties which have been demonstrated in preclinical and clinical trials. Its antitumor activity is mediated by its ability to act directly on the tumor cell, activating apoptosis pathways and indirectly inhibiting the process of inflammation, angiogenesis, and metastasis in the tumor microenvironment. In addition, it has a preventive activity such as radio and/or chemosensitizer. These effects have been evident in in vitro assays but have also been corroborated in patient trials either through the isolated use of curcumin or through its association with other agents. Moreover, curcumin has demonstrated a low induction of side effects. Numerous patents have been developed in connection with the administration and use of curcumin against different types of cancer. All this justifies the interest for the development of new laboratory studies and especially of clinical trials to validate this compound as a dietary supplement in both the healthy and the oncological population. The present review aims to address the most recent in vitro investigations and the latest clinical trials and patents related to the curcumin agent to provide an up-to-date overview of the latest advances in relation to its antitumor effect. PMID- 29708446 TI - BRAF-mutant colorectal cancer, a different breed evolving. AB - INTRODUCTION: BRAF mutant colorectal cancer (BRAF MT CRC) is a unique category of colorectal tumour with peculiar molecular, pathological and clinical features and poor prognosis; despite recent research, BRAF mutation predictive value and standard treatment of BRAF MT CRC still have to be defined. In this review, we focused on this challenging topic. Areas covered: The potential use of BRAF mutational status among recent additional prognostic and predictive indicators and current treatment strategy in use in these patients is discussed. Moreover, implications and characteristics of new BRAF mutations other than BRAFV600E are analyzed. An in-deep outlook on the immediate future for clinical and translational research in this subgroup of patients is also presented, such as combination therapy with agents targeting the RAS/RAF/MEK/ERK pathway and standard chemotherapy in order to overcome resistance. We performed a research on Pubmed typing 'BRAF mutation', 'colorectal cancer', 'predictive and prognostic value', 'targeted therapy', 'BRAF inhibition'. Expert commentary: BRAFV600E mutation represents a strong, independent negative prognostic factor in II-III stage MSS CRC and mCRC. The best treatment still has to be identified; currently, in good performance status patients, an intensive-chemotherapy-combination remains the standard of care. Further investigations are warranted to explore new horizons to change BRAF MT mCRC outcomes. PMID- 29708447 TI - Prevalence and predictors of tobacco smoking in veterans and service members following traumatic brain injury rehabilitation: a VA TBIMS study. AB - OBJECTIVE: To identify prevalence and predictors of tobacco smoking among veterans and military service members (V/SM) with traumatic brain injury (TBI) admitted for rehabilitation. METHODS: Participants were drawn from the VA TBI Model Systems multicentre longitudinal research study. Tobacco smoking was assessed both preinjury and at 1- or 2-year post-TBI follow-up for 336 participants. RESULTS: Smoking prevalence was 32% preinjury and 28% at follow-up. Most participants had a stable smoking pattern but 12% of preinjury non-smokers became smokers at follow-up. Preinjury smoking was the strongest predictor of post-TBI smoking. Higher cognitive function also predicted smoking at follow-up. In univariate analyses, smoking was predicted by lower education, preinjury mental health (MH) history, selected TBI severity metrics, and higher functional status at rehabilitation hospital discharge (Disability Rating Scale [DRS] and motor subscale of the Functional Independence Measure [FIM]). CONCLUSION: Study findings may help clinicians and administrators recognize who is at high risk for smoking following TBI, to plan for in-hospital and postdischarge screening and interventions. PMID- 29708448 TI - Alcoholic steatohepatitis (ASH) and alcoholic hepatitis (AH): cascade of events, clinical aspects, and pharmacotherapy options. AB - INTRODUCTION: Clinicians caring for patients with alcoholic hepatitis (AH) are often confronted with the question of the best pharmacotherapy to be used. Areas covered: This article covers metabolic aspects of alcohol as the basis of understanding pharmacotherapy and to facilitate choosing the drug therapeutic options for patients with severe AH. Expert opinion: Alcoholic steatohepatitis (ASH) and alcoholic hepatitis (AH) as terms are often used interchangeably in scientific literature but a stringent differentiation is recommended for proper clarity. As opposed to ASH, the clinical course of AH is often severe and requires an effective drug treatment strategy, in addition to absolute alcohol abstinence and nutritional support. Drug options include corticosteroids as a first choice and pentoxifylline, an inhibitor of phosphodiesterase, as a second line therapy, especially in patients with contraindications for a corticosteroid therapy such as infections or sepsis. At seven days under corticosteroids, treatment should be terminated in non-responders, and patients must then be evaluated for liver transplantation. Pentoxifylline is not effective as a rescue therapy for these patients. Other treatments such as infliximab, propylthiouracil, N-acetylcysteine, silymarin, colchicine, insulin and glucagon, oxandrolone, testosterone, and polyunsaturated lecithin are not effective in severe AH. For liver transplantation, few patients will be eligible. PMID- 29708449 TI - Low clinical adoption of tumor genomic profiling: cause for concern? PMID- 29708451 TI - Maximizing the benefit of openness in publication planning and disclosure. PMID- 29708450 TI - Associations between Pain-Related Anxiety, Gender, and Prescription Opioid Misuse among Tobacco Smokers Living with HIV/AIDS. AB - BACKGROUND: People living with HIV/AIDS (PLWHA) who smoke cigarettes are vulnerable to greater pain and aberrant use of prescription pain medications. Prescription opioid misuse is highly prevalent among PLWHA and can lead to a variety of adverse outcomes. Pain-related anxiety, which has been implicated in the maintenance of both pain and tobacco dependence, may also play a role in prescription pain medication misuse. OBJECTIVES: This study aimed to test associations between pain-related anxiety and prescription opioid misuse. We hypothesized that, among those prescribed opioid medication, pain-related anxiety would be positively associated with current opioid misuse, and stated intentions to misuse prescription opioids in the future. We further hypothesized that these relations would be more pronounced among males (vs. females). METHODS: Participants included 61 PLWHA daily tobacco smokers with pain. Hierarchical regressions were used to test interactions between gender and pain-related anxiety on current and intended opioid misuse among those prescribed opioid medications. RESULTS: There was a significant interactive effect of pain-related anxiety and gender on opioid misuse, such that pain-related anxiety was positively associated with current opioid misuse among male (but not female) participants who were prescribed opioid medications. Among both males and females, pain-related anxiety was positively associated with intention to misuse prescription pain medications in the future. Conclusions/Importance: Additional research into the role of pain-related anxiety in prescription opioid misuse is warranted. This type of work may inform the development of tailored interventions for PLWHA smokers who are prescribed opioid pain medications. PMID- 29708452 TI - Original Abstracts from the 2018 European Meeting of ISMPP. PMID- 29708453 TI - Original Abstracts from the 14th Annual Meeting of ISMPP. PMID- 29708455 TI - [Formula: see text] Preface. PMID- 29708456 TI - The Association between Distress Tolerance and Alcohol Related Problems: The Pathway of Drinking to Cope. AB - Binge drinking (BD) and alcohol related problems (ARP) are highly prevalent among college students. However, current models examining ARP suggest drinking quantity only accounts for a portion of the variance, suggesting other variables contribute to ARP. Distress tolerance (DT), or the ability to withstand negative affect, is associated with alcohol misuse and may be an important mechanism related to ARP. However, studies have reported inconsistent findings on this association, which may be due to the use of only global scores to measure DT rather than specific DT components. Furthermore, the mechanisms underlying this association remain unknown. Drinking to cope with negative affect has been associated with both DT and ARP, suggesting it may be a mechanism explaining the relationship between DT and ARP. The current study examined the association between specific proposed DT components (i.e., tolerance, absorption, appraisal, and regulation) and drinking to cope and ARP in 147 college students who BD. A hierarchical linear regression was performed in order to examine which DT component best predicted ARP. Four follow-up mediation models were then tested to examine whether drinking to cope mediated the relationship between each DT component and ARP. Appraisal of DT was the only DT component that significantly predicted ARP, in the model controlling for drinking quantity and sex differences. Drinking to cope mediated the relationship between ARP and tolerance, absorption, and regulation, but not appraisal of DT. Implications for furthering our understanding of DT and treatment of BD as it relates to DT are explored. PMID- 29708457 TI - A proposed explanation for thunderstorm asthma and leukemia risk near high voltage power lines: a supported hypothesis. AB - Thunderstorm asthma and increased childhood leukemia risk near high-voltage power lines (HVPL) are occurrences whose mechanism of effect is not fully understood. This paper proposes and discusses a key similarity: both thunderstorms and HVPL generate a high enough electrical field in the environment to ionize nearby air and air-borne particles. I argue that the repeatedly demonstrated acute asthma response to pollen-laden air during thunderstorms is largely due to ionization of air-borne allergens, which adhere more readily and in greater quantity in the lungs than non-ionized particles. If these bind to mucous or phagocytic cells, it would enhance immune response. A rapid temperature drop and high ozone also seem to be drivers of thunderstorm asthma. This causal nexus provides strong support for the parallel situation of prolonged exposure to ionized particles near HVPL and an increased rate of childhood leukemia. Here, it is proposed that upwind carcinogens are ionized when passing HVPL and then residential and business areas. Published evidence for most steps are presented, but have not previously been published as a coherent whole, nor has it been suggested that the inhaled ionized micro-particle explanation for acute asthma may also explain development of childhood leukemia over time. The demonstrated series of events leading to increased deposition and retention of ionized particles in airways provides support for explaining both adverse health outcomes: acute thunderstorm asthma and increased risk of childhood leukemia near HVPL. Further support for this explanation of both outcomes is provided by effects of on-going proximity to highways. PMID- 29708458 TI - Use of 14C-glucose by primary cultures of mature rat epididymal adipocytes. Marked release of lactate and glycerol, but limited lipogenesis in the absence of external stimuli. AB - White adipose tissue can metabolize large amounts of glucose to glycerol and lactate. We quantitatively traced glucose label to lactate, glycerol and fats in primary cultures of mature rat epididymal adipocytes. Cells were incubated with 7/14 mM 14C-glucose for 24/48 h. Medium metabolites and the label in them and in cells' components were measured. Gene expression analysis was done using parallel incubations. Glucose concentration did not affect lactate efflux and most parameters. Glycerol efflux increased after 24 h, coinciding with arrested lipogenesis. Steady production of lactate was maintained in parallel to glycerogenesis. Changes in adipocyte metabolism were paralleled by gene expression. Glucose use for lipogenesis was minimal, and stopped (24 h-onwards) when glycerol efflux increased because of triacylglycerol turnover. Lactate steady efflux showed that anaerobic glycolysis was the main adipocyte source of energy. We can assume that adipose tissue may play a quantitatively significant effect on glycaemia, returning 3C fragments thus minimizing lipogenesis. PMID- 29708459 TI - Betanin exhibits significant potential as an antihyperglycemic and attenuating the glycoprotein components in streptozotocin-nicotinamide-induced experimental rats. AB - This study hypothesized to evaluate the effect of betanin, a chromoalkaloid on plasma and altered tissues glycoprotein components in streptozotocin-nicotinamide induced diabetic rats. Diabetes was induced by a single intraperitoneal (i.p.) injection of streptozotocin (45 mg/kg b.w.) dissolved in 0.1 M citrate buffer (pH 4.5) 15 min after the i.p. administration of nicotinamide (110 mg/kg b.w.). Experimental rats were administered betanin at the dose of 20 mg/kg b.w. and glibenclamide (600 ug/kg b.w.) once a day for 30 days. Diabetic rats revealed significant (p < 0.05) increase in the levels of glucose, HbA1C, hexose, hexosamine, sialic acid and fucose in the plasma; decrease in the levels of plasma insulin, Hb and sialic acid in the liver and kidney; significant (p < 0.05) increase in hexose, hexosamine and fucose in the liver and kidney. Moreover, periodic acid-Schiff staining of tissues revealed positive-stain accumulation in diabetic rats. On co-supplementation of betanin and glibenclamide to diabetic rats for the period of 30 days brought back the levels of plasma and tissues glycoprotein components. Based on the present study, we propose that betanin possesses significant protective effect on glycoprotein components in plasma and tissue of diabetic rats. PMID- 29708460 TI - Weighing the Pros and Cons of Using Alcohol Protective Behavioral Strategies: A Qualitative Examination among College Students. AB - BACKGROUND: Alcohol protective behavioral strategies (PBS) are behaviors engaged in immediately prior to, during, after, or instead of drinking with the explicit goal of reducing alcohol use, intoxication, and/or alcohol-related harms. Despite the quantitative support for alcohol PBS as a protective factor among college student drinkers, we know of no qualitative research aimed at determining college student drinkers' perceptions regarding the advantages and disadvantages of using PBS. OBJECTIVES: In the style of a decisional balance exercise, we asked college student drinkers (analytic n = 113) to identify 5 reasons they would not use PBS (cons) and 5 reasons they would use PBS (pros). METHOD: Participants (majority female, 77.0%) were recruited from a psychology department participant pool at a large, southeastern university in the United States. Within our analytic sample, participants on average consumed 6.38 (SD = 8.16) drinks per typical week of drinking and reported consuming alcohol on average 7.5 days (SD = 5.83) in the last 30 days. RESULTS: Using a descriptive phenomenological approach, we identified 2 themes for pros (prevention of specific negative alcohol-related consequences and general safety) and 4 themes for cons (goal conflict, ineffectiveness, difficulty of implementation, and negative peer/social repercussions). Overall, participants reported more pros than cons and this discrepancy (i.e., number of PBS pros minus number of PBS cons) was positively related to self-reported frequency of PBS use. Conclusions/Importance: Taken together, we hope that clinicians/researchers will probe individual's reasons for choosing to use (or not use) PBS in order to tailor or improve existing PBS-based interventions. PMID- 29708461 TI - Synthesis and evaluation of novel spiro derivatives for pyrrolopyrimidines as anti-hyperglycemia promising compounds. PMID- 29708462 TI - Effect of clarification process on the removal of pesticide residues in red wine and comparison with white wine. AB - The aim of this study was to determine the potential of seven clarifying agents to remove pesticides in red wine. The presence of pesticides in wine consists a great problem for winemakers and therefore, results on pesticide removal by clarification are very useful for taking a decision on the appropriate adsorbent. The selection of an efficient adsorbent can be based on data correlating pesticide removal in red wine to pesticides' properties, given the great number and variety of pesticides used. So, this experimental work is focused on the collection of results with regard to pesticide removal by clarification using a great number of pesticides and fining agents. A Greek red wine, fortified with single solutions and mixtures of 23 or 9 pesticides was studied. The seven fining agents, used at two concentrations, were activated carbon, bentonite, polyvinylpolypyrrolidone (PVPP), gelatin, egg albumin, isinglass-fish glue, and casein. Pesticides were selected with a wide range of properties (octanol-water partition coefficient (log Kow) 2.7-6.3 and water solubility 0.0002-142) and belong to 11 chemical groups. Solid phase extraction (SPE) followed by gas chromatography (GC) with electron capture detector (ECD) were performed to analyze pesticide residues of the clarified fortified wine. The correlation of the clarifying agents' effectiveness to pesticide's chemical structure and properties (log Kow, water solubility) was investigated. The antagonistic and/or synergistic effects, occurring among the pesticides in the mixtures, were calculated by indices. Pesticide removal effectiveness results of the red wine were compared to those obtained from a white wine under the same experimental conditions and discussed. The order of decreasing adsorbent effectiveness (mixture of 23 pesticides) was: activated carbon 40% > gelatin 23% > egg albumin 21% > PVPP 18% > casein 12% > bentonite 7%. Isinglass showed 12% removal at the highest permitted concentration. In the case of 9 pesticides mixture, the effectiveness was quite higher but the order remained the same compared to 23 pesticides mixture. The removal of each pesticide from its single solution was generally the highest (particularly for hydrophobic pesticides). Adsorption on fining agents is increased by increasing hydrophobicity and decreasing hydrophilicity of organic pesticide molecules. PMID- 29708463 TI - Synthesis, characterization and in vivo evaluation of cadmium telluride quantum dots toxicity in mice by toxicometabolomics approach. AB - Quantum dots (QDs) have widespread application in many fields such as medicine and electronics. The need for understanding the potentially harmful side effects of these materials becomes clear. In this study, the toxicity of cadmium telluride quantum dots (CdTe-QDs) and bulk Cd2+ has been investigated and compared by applying metabolomics methods. The datasets were 1H-NMR data from mice plasma which had been taken from four groups of mice in different time intervals. Then, the data were analyzed by applying chemometrics methods and the metabolites were found from Human Metabolome Database (HMDB). The results showed the significant change in the level of some metabolites especially estrogenic steroids in different groups with different amounts of received Cd. The findings also indicated that steroid hormone biosynthesis, lysine biosynthesis and taurine and hypotaurine metabolism are the most affected pathways by CdTe-QDs especially in estrogenic steroids. The over-representation analysis indicated that endoplasmic reticulum, gonads, and hepatocytes are most affected. Since the pattern of metabolite alteration of CdTe-QDs with equivalent Cd2+ was similar to those of CdCl2, it was postulated that beside Cd2+ effects, the toxicity of CdTe QDs is associated with other factors. PMID- 29708464 TI - Rebound disease in multiple sclerosis. PMID- 29708466 TI - Overexpression of sphingosine-1-phosphate receptors on reactive astrocytes drives neuropathology of multiple sclerosis rebound after fingolimod discontinuation. AB - We present the neuropathological description of an autoptic case of fatal rebound of disease activity after fingolimod discontinuation in a multiple sclerosis patient. MRI prior to the fatal outcome showed several large tumefactive demyelinating lesions. These lesions were characterized by prominent astrocytic gliosis, with a remarkable preponderance of large hypertrophic reactive astrocytes showing intense expression of sphingosine-1-phosphate receptor 1. Prominent astrocytic gliosis was also diffusely observed in the normal-appearing white matter. Dysregulated sphingosine-1-phosphate signaling on astrocytes following fingolimod withdrawal might represent a possible contributing mechanism to disease rebound and might account for the unusual radiological and neuropathological features observed in the present case. PMID- 29708467 TI - Does Narrative Feedback Enhance Children's Motor Learning in a Virtual Environment? AB - Augmented feedback has motivational and informational functions in motor learning, and is a key feature of practice in a virtual environment (VE). This study evaluated the impact of narrative (story-based) feedback as compared to standard feedback during practice of a novel task in a VE on typically developing children's motor learning, motivation and engagement. Thirty-eight children practiced navigating through a virtual path, receiving narrative or non-narrative feedback following each trial. All participants improved their performance on retention but not transfer, with no significant differences between groups. Self reported engagement was associated with acquisition, retention and transfer for both groups. A narrative approach to feedback delivery did not offer an additive benefit; additional affective advantages of augmented feedback for motor learning in VEs should be explored. PMID- 29708468 TI - Do transgender men have equal access to health care and engagement in preventive health behaviors compared to cisgender adults? AB - Using 2015 Behavioral Risk Factor Surveillance System data, this study investigates whether transgender men have equal access to health care and engagement in preventive health behaviors compared to cisgender adults in the U.S. and whether race/ethnicity, socioeconomic status, and rural residence moderate these relationships. Once controlling for sociodemographic factors, we do not find differences for transgender men. Rural transgender men were less likely to have a personal doctor or receive a blood cholesterol screening than their urban peers; transgender men with less education were more likely to have a cholesterol screening. We detail implications for social workers within health care. PMID- 29708469 TI - Hong Kong Chinese aging adults voice financial care expectations in changing family and sociocultural contexts: implications for policy and services. AB - Despite being one of the world's wealthiest cities, approximately one-third of Hong Kong older adults live below the poverty line. Innovatively using the Photovoice research method, this study invited 36 Hong Kong Chinese aging adults to photograph images and voice their concerns and expectations regarding financial care. Insufficient government support, diminishing family support, insecurity and fear regarding future finances, and strong desire for self sufficiency through early preparation and bridge employment were recurring themes observed in the participants' photographs and narratives. The shifting of the participants' financial care expectations from informal to formal sources in changing family and sociocultural contexts indicated that older people are in urgent need of policy reform from a needs-based to rights-based approach to foster empowerment and fulfill older people's rights of financial security, dignity and participation. Improving the retirement protection system should go hand in hand with encouraging family support and caregiving and creating age friendly working environment for older residents. The findings of this study may have crucial policy implications for Hong Kong and other aging societies, especially those that share similar filial piety values and have seemingly ungenerous welfare systems. PMID- 29708470 TI - Comparison of physical technologies for biomass control in biofilters treating gaseous toluene. AB - : Excessive accumulation of biomass within gas-phase biofilters often results in the deterioration of removal performance. Compared with chemical and biological technologies, physical technologies are more effective in removing biomass and inducing less inhibition of the biofilter performance. This study applied different physical technologies, namely, air sparging, mechanical mixing, and washing with water at various temperatures, to remove excess biomass in biofilters treating toluene. Filter pressure drop, removed dry biomass, biofilter performance, and microbial metabolic characteristics were analyzed to evaluate the effectiveness of the methods. Results showed that air sparging was inefficient for biomass removal (1 kg dry biomass/m3 filter), whereas mechanical mixing significantly inhibited removal efficiencies (<30%). Washing of the packing with fluids was feasible, and hot fluids can remove a large amount of biomass. However, hot fluids reduce microbial activity and inhibit removal performance. Washing of the packing with either 20 degrees C or 50 degrees C water showed efficiency as >3 kg dry biomass/m3 filter can be removed at both temperatures with removal efficiencies at approximately 40% after treatment. Finally, different technologies were compared and summarized to propose an optimized strategy of biomass control for industrial biofilters. IMPLICATIONS: This study is to apply different physical technologies, namely, air sparging, mechanical mixing, and washing with water of different temperatures, to remove the excess biomass in biofilters treating toluene. The filter pressure drop, removed dry biomass, biofilter performance, and microbial metabolic characteristics were all analyzed to evaluate the effectiveness of the methods. The results of this study provide useful information regarding biomass control of industrial biofilters. PMID- 29708472 TI - A closer look at the size of the gaze-liking effect: a preregistered replication. AB - This study is a direct replication of gaze-liking effect using the same design, stimuli and procedure. The gaze-liking effect describes the tendency for people to rate objects as more likeable when they have recently seen a person repeatedly gaze toward rather than away from the object. However, as subsequent studies show considerable variability in the size of this effect, we sampled a larger number of participants (N = 98) than the original study (N = 24) to gain a more precise estimate of the gaze-liking effect size. Our results indicate a much smaller standardised effect size (dz = 0.02) than that of the original study (dz = 0.94). Our smaller effect size was not due to general insensitivity to eye-gaze effects because the same sample showed a clear (dz = 1.09) gaze-cuing effect - faster reaction times when eyes looked toward vs away from target objects. We discuss the implications of our findings for future studies wishing to study the gaze liking effect. PMID- 29708471 TI - Effect of a Multi-Site Trial using Short Message Service (SMS) on Infant Feeding Practices and Weight Gain in Low-Income Minorities. AB - OBJECTIVE: To test the effects of weekly SMS for improving infant feeding practices and infant weight. METHODS: This was a multi-site randomized clinical trial in a convenience sample of 202 caregivers of healthy term infants 0-2 months participating in the WIC program in Puerto Rico and Hawaii. Participants were randomized to receive SMS about infant's general health issues (control) or SMS for improving feeding practices (intervention) for four months. Weight, length and infant feeding practices were assessed at baseline and four months later. RESULTS: A total of 170 participants completed the study (n = 86 control and n = 84 intervention). Baseline characteristics were similar between groups. At the end, exclusive breastfeeding rates were similar between groups (67.4% control and 59.1% intervention). Introduction of other foods and beverages, addition of foods to the bottle, placing infants to sleep with milk bottles, caregiver's method and response to feeding infants and distractions while feeding infants were similar between groups. Also, weight status or rate of weight gain was similar between groups. CONCLUSION: There were no significant improvements in feeding practices or in weight with the intervention. The timeline of the messages in relation to the targeted behavior may have affected the effectiveness of the intervention. Earlier dissemination of messages, higher level of intensity, longer intervention, additional contacts and inclusion of other caregivers may be needed to achieve the desired effects. PMID- 29708473 TI - Core Ethics for Health Professionals: Principles, Issues and Compliance. PMID- 29708474 TI - Converting between estimates of moderate-to-vigorous physical activity derived from raw accelerations measured at the wrist and from ActiGraph counts measured at the hip: the Rosetta Stone. AB - The ability to compare published group-level estimates of objectively measured moderate-to-vigorous physical activity (MVPA) across studies continues to increase in difficulty. The objective of this study was to develop conversion equations and demonstrate their utility to compare estimates of MVPA derived from the wrist and hip. Three studies of youth (N = 232, 9-12yrs, 50% boys) concurrently wore a hip-worn ActiGraph and a wrist-worn GENEActiv for 7-days. ActiGraph hip count data were reduced using four established cutpoints. Wrist accelerations were reduced using the Hildebrand MVPA 200 mg threshold. Conversion equations were developed on a randomly selected subsample of 132 youth. Equations were cross-validated and absolute error, absolute percent error, and modified Bland-Altman plots were evaluated for conversion accuracy. Across equations R2adj was 0.51-0.56 with individual-level absolute error in minutes ranging from 7 (wrist-to-hip Puyau) to 14.5 minutes (wrist-to-hip Freedson 3MET) and absolute percent differences ranging from 13.9%-24.5%. Group-level cross-validation to convert hip-to-wrist MVPA resulted in average absolute percent errors ranging from 3.1%-4.9%. Conversion of wrist-to-hip MVPA resulted in average absolute percent errors ranging from 3.0%-10.0%. We recommend the use of these equations to compare published estimates of MVPA between the wear-site cut-point combinations presented. PMID- 29708475 TI - Direct bioethanol production from brown macroalgae by co-culture of two engineered Saccharomyces cerevisiae strains. AB - A co-culture platform for bioethanol production from brown macroalgae was developed, consisting of two types of engineered Saccharomyces cerevisiae strains; alginate- and mannitol-assimilating yeast (AM1), and cellulase displaying yeast (CDY). When the 5% (w/v) brown macroalgae Ecklonia kurome was used as the sole carbon source for this system, 2.1 g/L of ethanol was produced, along with simultaneous consumption of alginate, mannitol, and glucans. PMID- 29708477 TI - Dribble Deficit: A novel method to measure dribbling speed independent of sprinting speed in basketball players. AB - Basketball tests assessing dribbling speed predicated on total performance times are influenced by sprinting speed. This study examines an approach termed Dribble Deficit to counter this limitation by examining the relationships between sprinting and dribbling speed during linear and change-of-direction (COD) tasks measured using total performance time and Dribble Deficit. Ten semi-professional basketball players completed linear sprints and COD sprints with and without dribbling. Dribble Deficit was calculated as the difference between the best time for each dribbling trial and corresponding non-dribbling trial for linear and COD sprints. Large to very large significant relationships (P < 0.05) were evident between linear sprint and dribble times (R = 0.64-0.77, R2 = 0.41-0.59), and between COD sprint and dribble times (R = 0.88, R2 = 0.77). Conversely, trivial small relationships were evident between linear sprint time and linear Dribble Deficit (R = 0.01-0.15, R2 = 0.00-0.02). A non-significant, moderate, negative relationship was observed between COD sprint time and COD Dribble Deficit (R = 0.45, R2 = 0.20). These findings indicate Dribble Deficit provides a more isolated measure of dribbling speed than tests using total performance times. Basketball practitioners may use Dribble Deficit to measure dribbling speed independent of sprint speed in test batteries. PMID- 29708476 TI - Antileishmanial activity of sulphonamide nanoemulsions targeting the beta carbonic anhydrase from Leishmania species. AB - The beta-carbonic anhydrase (CA, EC 4.2.1.1) from Leishmania spp. (LdcCA) is effectively inhibited by aromatic/heterocyclic sulphonamides, in the low nanomolar range, but no in vitro antileishmanial activity was detected for such compounds. We formulated some of these sulphonamides as nanoemulsions (NEs) in clove oil, and tested them in vitro against Leishmania infantum MHOM/BR/1974/PP75 and Leishmania amazonensis IFLA/BR/1967/PH8 strains. Interesting inhibitory concentrations IC50 were observed for some of the sulphonamides NEs, with IC50 as low as 3.90 uM (NE-3F) and 2.24 uM (NE-5B) for L. amazonensis and 3.47 uM (NE-5B) for L. infantum. Some of the investigated NEs displayed toxicity for macrophages beyond the parasites. For the same nonoemulsions, a selective index (SI) greater than for Amphotericin B. Haemolytic assay using human red blood cells indicate that the NEs were less cytotoxic than amphotericin B, a widely used antifungal agent. NEs demonstrated to be an excellent strategy for increasing the penetration of these hydrophilic drugs through membranes, with a huge increase of efficacy over the sulphonamide CA inhibitor (CAI) alone. PMID- 29708478 TI - Carbon biofixation and lipid composition of an acidophilic microalga cultivated on treated wastewater supplied with different CO2 levels. AB - This study evaluated productivity, CO2 biofixation, and lipid content in biomass of the acidophilic microalga Chlamydomonas acidophila LAFIC-004 cultivated with five different carbon dioxide concentrations. The influence of carbon dioxide concentration on nutrient removal and pH was also investigated. Treated wastewater (secondary effluent) was used as culture medium. Five experimental setups were tested: T-0% - injection of atmospheric air (0.038% CO2), T-5% (5% CO2), T-10% (10% CO2), T-15% (15% CO2) and T-20% (20% CO2). The T-5% and T-10% experiments showed the highest values of productivity and CO2 biofixation, and maximum biomass dry weight was 0.48 +/- 0.02 and 0.51 +/- 0.03 g L-1, respectively. This acidophilic microalga proved to be suitable for carbon biofixation and removal of nutrients from secondary effluent of wastewater treatment plants with high CO2 concentration. All assays were performed without pH control. This microalga species presented high lipid content. However, fatty acid methyl esters (FAME) are not suitable for biodiesel use. PMID- 29708480 TI - Preface. PMID- 29708481 TI - Editorial: The HIV/SIV Envelope Protein: From Structure To Function To Host Evasion. PMID- 29708482 TI - Abundance of enterovirus C in RD-L20B cell culture-negative stool samples from acute flaccid paralysis cases in Nigeria is geographically defined. AB - PURPOSE: We recently showed that enteroviruses (EVs) andenterovirus species C (EV C) in particular were abundant in faecal samples from children who had been diagnosed with acute flaccid paralysis (AFP) in Nigeria but declared to be EV free by the RD-L20B cell culture-based algorithm. In this study, we investigated whether this observed preponderance of EVs (and EV-Cs) in such samples varies by geographical region. METHODOLOGY: One hundred and eight samples (i.e. 54 paired stool suspensions from 54 AFP cases) that had previously been confirmed to be negative for EVs by the WHO-recommended RD-L20B cell culture-based algorithm were analysed. The 108 samples were made into 54 pools (27 each from North-West and South-South Nigeria). All were subjected to RNA extraction, cDNA synthesis and the WHO-recommended semi-nested PCR assay and its modifications. All of the amplicons were sequenced, and the enteroviruses identified, using the enterovirus genotyping tool and phylogenetic analysis. RESULTS: EVs were detected in 16 (29.63 %) of the 54 samples that were screened and successfully identified in 14 (25.93 %). Of these, 10 were from North-West and 4 were from South-South Nigeria. One (7.14 %), 2 (14.29 %) and 11 (78.57 %) of the strains detected were EV-A, EV B and EV-C, respectively. The 10 strains from North-West Nigeria included 7 EV types, namely CV-A10, E29, CV-A13, CV-A17, CV-A19, CV-A24 and EV-C99. The four EV types recovered from South-South Nigeria were E31, CV-A1, EV-C99 and EV-C116. CONCLUSION: The results of this study showed that the presence of EVs and consequently EV-Cs in AFP samples declared to be EV-free by the RD-L20B cell culture-based algorithm varies by geographical region in Nigeria. PMID- 29708483 TI - Sexual behaviour, HPV status and p16INK4a expression in oropharyngeal and oral cavity squamous cell carcinomas: a case-case comparison study. AB - A significant proportion of mucosal squamous cell carcinomas of the head and neck (HNSCC; particularly of the oropharynx) are directly attributable to the human papillomavirus (HPV). The increase in the incidence of HPV-related tumours has been postulated to be due to changing sexual practices in the community. We analysed 136 formalin-fixed paraffin-embedded squamous cell carcinomas from the oral cavity (n=40) and oropharynx (n=96) recruited from the Princess Alexandra Hospital (Brisbane, Australia). Samples were analysed for the presence of HPV DNA using a combination of mucosal HPV general primer GP+ PCR and sequencing; p16INK4a expression was assessed by immunohistochemistry. Each patient completed a questionnaire detailing their lifestyle factors, such as tobacco smoking and alcohol consumption, marital status, and sexual behaviour and history. The HPV DNA prevalence was 5 % in the oral cavity cancers and 72 % in the oropharyngeal cancers (P<0.0001). HPV-16 was the most commonly detected HPV type (found in 91 % of all HPV-positive tumours). There was a strong correlation between HPV DNA positivity and positive p16INK4a staining in oropharyngeal tumours (P<0.0001). Having an HPV-related tumour was associated with being married or having been married previously (P=0.046), an increasing number of passionate kissing partners (P=0.046), ever having given oral sex (P=0.0007) and an increasing number of oral sex partners (P=0.0015). This study found a higher prevalence of HPV in oropharyngeal compared to oral cavity tumours, with a strong association being identified between oral sex behaviours and HPV-positive tumours. Further research is needed to establish that vaccines will reduce the transmission and carriage of oropharyngeal HPV infections. PMID- 29708485 TI - Protein-protein interactions among the structural proteins of Chilo iridescent virus. AB - Chilo iridescent virus (CIV), officially named invertebrate iridescent virus 6 (IIV6), is a nucleocytoplasmic virus with a ~212-kb linear dsDNA genome that encodes 215 putative open reading frames (ORFs). Proteomic analysis has revealed that the CIV virion consists of 54 virally encoded proteins. In this study, we identified the interactions between the structural proteins using the yeast two hybrid system. We cloned 47 structural genes into both bait and prey vectors, and then analysed the interactions in Saccharomyces cerevisiae strain AH109. A total of 159 protein-protein interactions were detected between the CIV structural proteins. Only ORF 179R showed a self-association. Four structural proteins that have homologues in iridoviruses (118L, 142R, 274L and 295L) showed indirect interactions with each other. Seven proteins (138R, 142R, 361L, 378R, 395R, 415R and 453R) interacted with the major capsid protein 274L. The putative membrane protein 118L, a homologue of the frog virus 3/Ranagrylio virus 53R protein, showed direct interactions with nine other proteins (117L, 229L, 307L, 355R, 366R, 374R, 378R, 415R and 422L). The interaction between 118L and 415R was confirmed by a GST pull-down assay. These data indicate that 415R is a potential matrix protein connecting the envelope protein 118L with the major capsid protein 274L. PMID- 29708486 TI - Research in Pediatrics: Cincinnati Children's Hospital and Beyond. PMID- 29708487 TI - Referral and Diagnosis of Developmental Auditory Processing Disorder in a Large, United States Hospital-Based Audiology Service. AB - BACKGROUND: Children referred to audiology services with otherwise unexplained academic, listening, attention, language, or other difficulties are often found to be audiometrically normal. Some of these children receive further evaluation for auditory processing disorder (APD), a controversial construct that assumes neural processing problems within the central auditory nervous system. This study focuses on the evaluation of APD and how it relates to diagnosis in one large pediatric audiology facility. PURPOSE: To analyze electronic records of children receiving a central auditory processing evaluation (CAPE) at Cincinnati Children's Hospital, with a broad goal of understanding current practice in APD diagnosis and the test information which impacts that practice. RESEARCH DESIGN: A descriptive, cross-sectional analysis of APD test outcomes in relation to final audiologist diagnosis for 1,113 children aged 5-19 yr receiving a CAPE between 2009 and 2014. RESULTS: Children had a generally high level of performance on the tests used, resulting in marked ceiling effects on about half the tests. Audiologists developed the diagnostic category "Weakness" because of the large number of referred children who clearly had problems, but who did not fulfill the AAA/ASHA criteria for diagnosis of a "Disorder." A "right-ear advantage" was found in all tests for which each ear was tested, irrespective of whether the tests were delivered monaurally or dichotically. However, neither the side nor size of the ear advantage predicted the ultimate diagnosis well. Cooccurrence of CAPE with other learning problems was nearly universal, but neither the number nor the pattern of cooccurring problems was a predictor of APD diagnosis. The diagnostic patterns of individual audiologists were quite consistent. The number of annual assessments decreased dramatically during the study period. CONCLUSIONS: A simple diagnosis of APD based on current guidelines is neither realistic, given the current tests used, nor appropriate, as judged by the audiologists providing the service. Methods used to test for APD must recognize that any form of hearing assessment probes both sensory and cognitive processing. Testing must embrace modern methods, including digital test delivery, adaptive testing, referral to normative data, appropriate testing for young children, validated screening questionnaires, and relevant objective (physiological) methods, as appropriate. Audiologists need to collaborate with other specialists to understand more fully the behaviors displayed by children presenting with listening difficulties. To achieve progress, it is essential for clinicians and researchers to work together. As new understanding and methods become available, it will be necessary to sort out together what works and what doesn't work in the clinic, both from a theoretical and a practical perspective. PMID- 29708484 TI - Expanding an expanded genome: long-read sequencing of Trypanosoma cruzi. AB - Although the genome of Trypanosoma cruzi, the causative agent of Chagas disease, was first made available in 2005, with additional strains reported later, the intrinsic genome complexity of this parasite (the abundance of repetitive sequences and genes organized in tandem) has traditionally hindered high-quality genome assembly and annotation. This also limits diverse types of analyses that require high degrees of precision. Long reads generated by third-generation sequencing technologies are particularly suitable to address the challenges associated with T. cruzi's genome since they permit direct determination of the full sequence of large clusters of repetitive sequences without collapsing them. This, in turn, not only allows accurate estimation of gene copy numbers but also circumvents assembly fragmentation. Here, we present the analysis of the genome sequences of two T. cruzi clones: the hybrid TCC (TcVI) and the non-hybrid Dm28c (TcI), determined by PacBio Single Molecular Real-Time (SMRT) technology. The improved assemblies herein obtained permitted us to accurately estimate gene copy numbers, abundance and distribution of repetitive sequences (including satellites and retroelements). We found that the genome of T. cruzi is composed of a 'core compartment' and a 'disruptive compartment' which exhibit opposite GC content and gene composition. Novel tandem and dispersed repetitive sequences were identified, including some located inside coding sequences. Additionally, homologous chromosomes were separately assembled, allowing us to retrieve haplotypes as separate contigs instead of a unique mosaic sequence. Finally, manual annotation of surface multigene families, mucins and trans-sialidases allows now a better overview of these complex groups of genes. PMID- 29708488 TI - Understanding the Needs of Families of Children Who Are Deaf/Hard of Hearing with an Autism Spectrum Disorder. AB - BACKGROUND: There is a significant lack of evidence guiding our understanding of the needs of families of children who are deaf/hard of hearing (Deaf/HH) with an autism spectrum disorder (ASD). Much of our current knowledge is founded in case report studies with very small numbers of children with the dual diagnosis. PURPOSE: The purpose of this study was to gain an understanding of the factors relating to caregiver stress and needs (i.e., supports and interventions) in families of children who are Deaf/HH with ASD. RESEARCH DESIGN: Comparison groups of families of children who were Deaf/HH, families with a hearing child with ASD, and families of children who were Deaf/HH with ASD were administered standardized questionnaires of stress with brief qualitative questionnaires focusing on family identified needs. STUDY SAMPLE: Six families of children with the dual diagnosis, four families of children who were Deaf/HH, and three families of children with ASD. DATA COLLECTION AND ANALYSIS: Surveys included demographic and support questionnaires, the Parenting Stress Index (PSI), the Pediatric Hearing Impairment Caregiver Experience, and a qualitative questionnaire. RESULTS: Families of children who were Deaf/HH with ASD had a higher median total stress score on the PSI as compared to families of children who were Deaf/HH only (58.5 versus 41.5, respectively; p = 0.02) and higher Child Domain scores (60 versus 43, respectively; p = 0.02), indicating higher levels of stress in families of children with the dual diagnosis. The families of children who were Deaf/HH with ASD reported similar levels of stress as families of children with ASD. CONCLUSIONS: Families of children who are Deaf/HH with an ASD experience stress and describe similar needs and priorities as families of hearing children with ASD. This suggests the needs related to having an autism spectrum disorder are of high priority in families of children with the dual diagnosis. PMID- 29708489 TI - fMRI as a Preimplant Objective Tool to Predict Children's Postimplant Auditory and Language Outcomes as Measured by Parental Observations. AB - BACKGROUND: The trends in cochlear implantation candidacy and benefit have changed rapidly in the last two decades. It is now widely accepted that early implantation leads to better postimplant outcomes. Although some generalizations can be made about postimplant auditory and language performance, neural mechanisms need to be studied to predict individual prognosis. PURPOSE: The aim of this study was to use functional magnetic resonance imaging (fMRI) to identify preimplant neuroimaging biomarkers that predict children's postimplant auditory and language outcomes as measured by parental observation/reports. RESEARCH DESIGN: This is a pre-post correlational measures study. STUDY SAMPLE: Twelve possible cochlear implant candidates with bilateral severe to profound hearing loss were recruited via referrals for a clinical magnetic resonance imaging to ensure structural integrity of the auditory nerve for implantation. INTERVENTION: Participants underwent cochlear implantation at a mean age of 19.4 mo. All children used the advanced combination encoder strategy (ACE, Cochlear CorporationTM, Nucleus(r) Freedom cochlear implants). Three participants received an implant in the right ear; one in the left ear whereas eight participants received bilateral implants. Participants' preimplant neuronal activation in response to two auditory stimuli was studied using an event-related fMRI method. DATA COLLECTION AND ANALYSIS: Blood oxygen level dependent contrast maps were calculated for speech and noise stimuli. The general linear model was used to create z-maps. The Auditory Skills Checklist (ASC) and the SKI-HI Language Development Scale (SKI-HI LDS) were administered to the parents 2 yr after implantation. A nonparametric correlation analysis was implemented between preimplant fMRI activation and postimplant auditory and language outcomes based on ASC and SKI-HI LDS. Statistical Parametric Mapping software was used to create regression maps between fMRI activation and scores on the aforementioned tests. Regression maps were overlaid on the Imaging Research Center infant template and visualized in MRIcro. RESULTS: Regression maps revealed two clusters of brain activation for the speech versus silence contrast and five clusters for the noise versus silence contrast that were significantly correlated with the parental reports. These clusters included auditory and extra-auditory regions such as the middle temporal gyrus, supramarginal gyrus, precuneus, cingulate gyrus, middle frontal gyrus, subgyral, and middle occipital gyrus. Both positive and negative correlations were observed. Correlation values for the different clusters ranged from -0.90 to 0.95 and were significant at a corrected p value of <0.05. Correlations suggest that postimplant performance may be predicted by activation in specific brain regions. CONCLUSIONS: The results of the present study suggest that (1) fMRI can be used to identify neuroimaging biomarkers of auditory and language performance before implantation and (2) activation in certain brain regions may be predictive of postimplant auditory and language performance as measured by parental observation/reports. PMID- 29708490 TI - Audiology Assistants: Results of a Multicenter Survey. AB - BACKGROUND: Although audiologists have been using support personnel for over 45 yr, controversy and variability continue with respect to the entry-level education, training methods, and scope of practice. PURPOSE: As part of a larger clinical practices survey, this report focuses on use of audiology assistants (AAs) for pediatric settings and "life-span" facilities that had a significant population of pediatric patients. RESEARCH DESIGN: A questionnaire was sent to 116 facilities in geographically diverse locations. Of the 25 surveys returned, 22 had sufficient data to be included for analysis purposes. RESULTS: The majority of respondents assigned duties to AAs as follows: assisting with conditioned play audiometry and visual reinforcement audiometry, infection control, mail management, disposing of protected health information, ordering supplies, calling families, fielding family phone calls, and stocking supplies. In addition, of the nine pediatric facilities that used AAs and reported job duties, the majority assigned troubleshooting equipment and auditory brainstem response (ABR) screening. Two of the five life-span facilities that reported job duties assigned several duties not assigned by any of the pediatric facilities: pure-tone screening, earmold impressions, assisting with videonystagmography and ABR, and in-house hearing aid repairs. Of facilities that use AAs and reported staffing, the ratio of AAs to audiologists ranged from 0.03:1 to 1:0.37, with an average of 0.15 for life-span facilities and 0.17 for the pediatric facilities. Minimum educational levels required were reported as follows: high school (n = 8), college (n = 3), certificate (n = 1), and no requirement (n = 1). CONCLUSIONS: Within a small sample size of pediatric and life-span facilities, 14 of 22 centers used AAs to perform a variety of direct patient care, indirect patient care, and clerical duties. Based on the duties recommended within the American Speech-Language-Hearing Association guidelines and by many states, expanded employment of AAs, as well as expansion of assigned duties should be considered. Data are needed to determine the appropriate ratio of AAs to audiologists within different settings and to determine the impact of AAs for accessibility, productivity, and profitability. PMID- 29708491 TI - Video Head Impulse Testing in a Pediatric Population: Normative Findings. AB - BACKGROUND: The video head impulse test (vHIT) is a new tool being used in vestibular clinics to assess the function of all six semicircular canals (SCCs) by measuring the gain of the vestibulo-ocular reflex (VOR) in response to rapid head turns. Whereas vHIT has been validated in adults for all SCCs, there are few studies describing the normal response in children, particularly for stimulation of the vertical canals. PURPOSE: The purpose of this study was to characterize the normal vHIT response for all six SCCs in children aged 4-12 years. RESEARCH DESIGN: A cross-sectional prospective descriptive study. STUDY SAMPLE: Forty-one participants were categorized into one of four groups based on their age (4-6 years, 7-9 years, 10-12 years, and adults) with at least ten participants in each age group. DATA COLLECTION AND ANALYSIS: The ICS Impulse system (GN Otometrics, Schaumburg, IL) was used to perform vHIT on each participant. Lateral, anterior, and posterior SCCs were stimulated by thrusting the head in the plane of the canal being evaluated and resulting VOR gain measures were calculated as eye velocity divided by head velocity. VOR gain of the pediatric age groups was compared with adults for all SCCs. RESULTS: There were no significant differences in mean VOR gain between the three pediatric age groups for any SCC measured; thus, the pediatric data were combined into one group of 30 children for comparison with the adult group. Results showed that the pediatric group had significantly higher mean VOR gain than the adult group during left lateral SCC testing. A significantly lower mean VOR gain, however, was observed for the children compared with the adult participants for left anterior and right posterior (LARP) impulses. There was a large amount of variability in the data during right anterior and left posterior (RALP) impulse testing for both the pediatric and the adult groups, which was at least partially attributed to large pupil diameter in the younger participants. Test time decreased with an increase in age for all impulse conditions (lateral, RALP, and LARP). Several modifications were necessary to obtain adequate data on the pediatric participants. CONCLUSIONS: vHIT can be used to successfully measure the function of the lateral SCC in children as young as 4 years of age. Our results provide normative gain values that can be used when testing children with lateral vHIT. Care must be taken to obtain the most accurate measures and reduce variability when testing children, particularly with LARP and RALP. Our data would suggest that lower gain cutoffs should be used for LARP and RALP testing in children than the cutoffs used for lateral vHIT. Further research is warranted to study LARP and RALP response reliability and validity in children because of the highly variable VOR gains found in this population. Pediatric modifications for successfully administering vHIT and obtaining reliable results are discussed. PMID- 29708492 TI - Cochlear Microphonic and Summating Potential Responses from Click-Evoked Auditory Brain Stem Responses in High-Risk and Normal Infants. AB - BACKGROUND: Examination of cochlear and neural potentials is necessary to assess sensory and neural status in infants, especially those cared for in neonatal intensive care units (NICU) who have high rates of hyperbilirubinemia and thus are at risk for auditory neuropathy (AN). PURPOSE: The purpose of this study was to determine whether recording parameters commonly used in click-evoked auditory brain stem response (ABR) are useful for recording cochlear microphonic (CM) and Wave I in infants at risk for AN. Specifically, we analyzed CM, summating potential (SP), and Waves I, III, and V. The overall aim was to compare latencies and amplitudes of evoked responses in infants cared for in NICUs with infants in a well-baby nursery (WBN), both of which passed newborn hearing screening. RESEARCH DESIGN: This is a prospective study in which infants who passed ABR newborn hearing screening were grouped based on their birth history (WBN and NICU). All infants had normal hearing status when tested with diagnostic ABR at about one month of age, corrected for prematurity. STUDY SAMPLE: Thirty infants (53 ears) from the WBN [mean corrected age at test = 5.0 weeks (wks.)] and thirty two infants (59 ears) from the NICU (mean corrected age at test = 5.7 wks.) with normal hearing were included in this study. In addition, two infants were included as comparative case studies, one that was diagnosed with AN and another case that was diagnosed with bilateral sensorineural hearing loss (SNHL). DATA COLLECTION AND ANALYSIS: Diagnostic ABR, including click and tone-burst air- and bone-conduction stimuli were recorded. Peak Waves I, III, and V; SP; and CM latency and amplitude (peak to trough) were measured to determine if there were differences in ABR and electrocochleography (ECochG) variables between WBN and NICU infants. RESULTS: No significant group differences were found between WBN and NICU groups for ABR waveforms, CM, or SP, including amplitude and latency values. The majority (75%) of the NICU group had hyperbilirubinemia, but overall, they did not show evidence of effects in their ECochG or ABR responses when tested at about one-month corrected age. These data may serve as a normative sample for NICU and well infant ECochG and ABR latencies at one-month corrected age. Two infant case studies, one diagnosed with AN and another with SNHL demonstrated the complexity of using ECochG and otoacoustic emissions to assess the risk of AN in individual cases. CONCLUSIONS: CM and SPs can be readily measured using standard click stimuli in both well and NICU infants. Normative ranges for latency and amplitude are useful for interpreting ECochG and ABR components. Inclusion of ECochG and ABR tests in a test battery that also includes otoacoustic emission and acoustic reflex tests may provide a more refined assessment of the risks of AN and SNHL in infants. PMID- 29708493 TI - Ocular Vestibular Evoked Myogenic Potentials: Normative Findings in Children. AB - BACKGROUND: To add to the limited body of literature on ocular vestibular evoked myogenic potential (oVEMP) responses in children and to assess a different montage for oVEMP recording. PURPOSE: To evaluate the characteristics of the oVEMP response in children and compare the results with that of a group of healthy adults. RESEARCH DESIGN: Prospective descriptive study from a tertiary referral center. STUDY SAMPLE: Twenty-two children (mean age = 6.3 yr, standard deviation = +/-1.5, range = 3.5-8.9 yr) were recruited from families whose parent(s) were employed by the Cincinnati Children's Hospital Medical Center (CCHMC). Pediatric participants were categorized by age into three groups for data analysis. The comparison adult group of ten participants were members of the employee staff at CCHMC. DATA COLLECTION AND ANALYSIS: Audiometric assessment was completed in all participants. The latency, amplitude, and threshold of the oVEMP responses were recorded using a modified electrode montage with reference at the chin and compared between the pediatric and adult participants. RESULTS: All participants completed testing and had bilateral measurable oVEMP responses using a 105-dB nHL, 500-Hz tone burst stimulus. Comparison between right and left ears across all participants for each oVEMP characteristic found no statistically significant difference. oVEMP testing showed no significant differences with respect to latency, amplitude, interaural amplitude asymmetry, and threshold of response as a function of age. CONCLUSIONS: oVEMP responses for ages >=3 did not differ from responses in adults. PMID- 29708495 TI - All-atom molecular dynamics of the HBV capsid reveals insights into biological function and cryo-EM resolution limits. AB - The hepatitis B virus capsid represents a promising therapeutic target. Experiments suggest the capsid must be flexible to function; however, capsid structure and dynamics have not been thoroughly characterized in the absence of icosahedral symmetry constraints. Here, all-atom molecular dynamics simulations are leveraged to investigate the capsid without symmetry bias, enabling study of capsid flexibility and its implications for biological function and cryo-EM resolution limits. Simulation results confirm flexibility and reveal a propensity for asymmetric distortion. The capsid's influence on ionic species suggests a mechanism for modulating the display of cellular signals and implicates the capsid's triangular pores as the location of signal exposure. A theoretical image reconstruction performed using simulated conformations indicates how capsid flexibility may limit the resolution of cryo-EM. Overall, the present work provides functional insight beyond what is accessible to experimental methods and raises important considerations regarding asymmetry in structural studies of icosahedral virus capsids. PMID- 29708496 TI - Reduced expression of C/EBPbeta-LIP extends health and lifespan in mice. AB - Ageing is associated with physical decline and the development of age-related diseases such as metabolic disorders and cancer. Few conditions are known that attenuate the adverse effects of ageing, including calorie restriction (CR) and reduced signalling through the mechanistic target of rapamycin complex 1 (mTORC1) pathway. Synthesis of the metabolic transcription factor C/EBPbeta-LIP is stimulated by mTORC1, which critically depends on a short upstream open reading frame (uORF) in the Cebpb-mRNA. Here, we describe that reduced C/EBPbeta-LIP expression due to genetic ablation of the uORF delays the development of age associated phenotypes in mice. Moreover, female C/EBPbetaDeltauORF mice display an extended lifespan. Since LIP levels increase upon aging in wild type mice, our data reveal an important role for C/EBPbeta in the aging process and suggest that restriction of LIP expression sustains health and fitness. Thus, therapeutic strategies targeting C/EBPbeta-LIP may offer new possibilities to treat age related diseases and to prolong healthspan. PMID- 29708499 TI - Physics and performances of III-V nanowire broken-gap heterojunction TFETs using an efficient tight-binding mode-space NEGF model enabling million-atom nanowire simulations. AB - We report the capability to simulate in a quantum-mechanical atomistic fashion record-large nanowire devices, featuring several hundred to millions of atoms and a diameter up to 18.2 nm. We have employed a tight-binding mode-space NEGF technique demonstrating by far the fastest (up to 10 000 * faster) but accurate (error < 1%) atomistic simulations to date. Such technique and capability opens new avenues to explore and understand the physics of nanoscale and mesoscopic devices dominated by quantum effects. In particular, our method addresses in an unprecedented way the technologically-relevant case of band-to-band tunneling (BTBT) in III-V nanowire broken-gap heterojunction tunnel-FETs (HTFETs). We demonstrate an accurate match of simulated BTBT currents to experimental measurements in a 12 nm diameter InAs NW and in an InAs/GaSb Esaki tunneling diode. We apply our TB MS simulations and report the first in-depth atomistic study of the scaling potential of III-V GAA nanowire HTFETs including the effect of electron-phonon scattering and discrete dopant impurity band tails, quantifying the benefits of this technology for low-power low-voltage CMOS applications. PMID- 29708500 TI - Dimensional reduction of a general advection-diffusion equation in 2D channels. AB - Diffusion of point-like particles in a two-dimensional channel of varying width is studied. The particles are driven by an arbitrary space dependent force. We construct a general recurrence procedure mapping the corresponding two dimensional advection-diffusion equation onto the longitudinal coordinate x. Unlike the previous specific cases, the presented procedure enables us to find the one-dimensional description of the confined diffusion even for non conservative (vortex) forces, e.g. caused by flowing solvent dragging the particles. We show that the result is again the generalized Fick-Jacobs equation. Despite of non existing scalar potential in the case of vortex forces, the effective one-dimensional scalar potential, as well as the corresponding quasi equilibrium and the effective diffusion coefficient [Formula: see text] can be always found. PMID- 29708497 TI - Co-translational protein targeting facilitates centrosomal recruitment of PCNT during centrosome maturation in vertebrates. AB - As microtubule-organizing centers of animal cells, centrosomes guide the formation of the bipolar spindle that segregates chromosomes during mitosis. At mitosis onset, centrosomes maximize microtubule-organizing activity by rapidly expanding the pericentriolar material (PCM). This process is in part driven by the large PCM protein pericentrin (PCNT), as its level increases at the PCM and helps recruit additional PCM components. However, the mechanism underlying the timely centrosomal enrichment of PCNT remains unclear. Here, we show that PCNT is delivered co-translationally to centrosomes during early mitosis by cytoplasmic dynein, as evidenced by centrosomal enrichment of PCNT mRNA, its translation near centrosomes, and requirement of intact polysomes for PCNT mRNA localization. Additionally, the microtubule minus-end regulator, ASPM, is also targeted co translationally to mitotic spindle poles. Together, these findings suggest that co-translational targeting of cytoplasmic proteins to specific subcellular destinations may be a generalized protein targeting mechanism. PMID- 29708498 TI - Transcriptional profiling identifies strain-specific effects of caloric restriction and opposite responses in human and mouse white adipose tissue. AB - Caloric restriction (CR) has been extensively studied in rodents as an intervention to improve lifespan and healthspan. However, effects of CR can be strain- and species-specific. This study used publically available microarray data to analyze expression responses to CR in males from 7 mouse strains (C57BL/6J, BALB/c, C3H, 129, CBA, DBA, B6C3F1) and 4 tissues (epididymal white adipose tissue (eWAT), muscle, heart, cortex). In each tissue, the largest number of strain-specific CR responses was identified with respect to the C57BL/6 strain. In heart and cortex, CR responses in C57BL/6 mice were negatively correlated with responses in other strains. Strain-specific CR responses involved genes associated with olfactory receptors (Olfr1184, Olfr910) and insulin/IGF-1 signaling (Igf1, Irs2). In each strain, CR responses in eWAT were negatively correlated with those in human subcutaneous WAT (scWAT). In human scWAT, CR increased expression of genes associated with stem cell maintenance and vascularization. However, orthologous genes linked to these processes were down regulated in mouse. These results identify strain-specific CR responses limiting generalization across mouse strains. Differential CR responses in mouse versus human WAT may be due to differences in the depots examined and/or the presence of "thrifty genes" in humans that resist adipose breakdown despite caloric deficit. PMID- 29708501 TI - Special issue on self-interaction corrected functionals for solids and surfaces. PMID- 29708502 TI - Large enhancement of superconductivity in Zr point contacts. AB - For certain complex superconducting systems, the superconducting properties get enhanced under mesoscopic point contacts made of elemental non-superconducting metals. However, understanding of the mechanism through which such contact induced local enhancement of superconductivity happens has been limited due to the complex nature of such compounds. In this paper we present a large enhancement of superconducting transition temperature T c and superconducting energy gap Delta in a simple elemental superconductor Zr. While bulk Zr shows a critical temperature around 0.6 K, superconductivity survives at Ag/Zr and Pt/Zr point contacts up to 3 K with a corresponding five-fold enhancement of Delta. Further, the first-principles calculations on a model system provide useful insights. We show that the enhancement in superconducting properties can be attributed to a modification in the electron-phonon coupling accompanied by an enhancement of the density of states which involves the appearance of a new electron band at the Ag/Zr interfaces. PMID- 29708503 TI - Resonant magneto-acoustic switching: influence of Rayleigh wave frequency and wavevector. AB - We show on in-plane magnetized thin films that magnetization can be switched efficiently by 180 degrees using large amplitude Rayleigh waves travelling along the hard or easy magnetic axis. Large characteristic filament-like domains are formed in the latter case. Micromagnetic simulations clearly confirm that this multi-domain configuration is compatible with a resonant precessional mechanism. The reversed domains are in both geometries several hundreds of [Formula: see text], much larger than has been shown using spin transfer torque- or field driven precessional switching. We show that surface acoustic waves can travel at least 1 mm before addressing a given area, and can interfere to create magnetic stripes that can be positioned with a sub-micronic precision. PMID- 29708504 TI - Functionalization of group-14 two-dimensional materials. AB - The great success of graphene has boosted intensive search for other single-layer thick materials, mainly composed of group-14 atoms arranged in a honeycomb lattice. This new class of two-dimensional (2D) crystals, known as 2D-Xenes, has become an emerging field of intensive research due to their remarkable electronic properties and the promise for a future generation of nanoelectronics. In contrast to graphene, Xenes are not completely planar, and feature a low buckled geometry with two sublattices displaced vertically as a result of the interplay between sp2 and sp3 orbital hybridization. In spite of the buckling, the outstanding electronic properties of graphene governed by Dirac physics are preserved in Xenes too. The buckled structure also has several advantages over graphene. Together with the spin-orbit (SO) interaction it may lead to the emergence of various experimentally accessible topological phases, like the quantum spin Hall effect. This in turn would lead to designing and building new electronic and spintronic devices, like topological field effect transistors. In this regard an important issue concerns the electron energy gap, which for Xenes naturally exists owing to the buckling and SO interaction. The electronic properties, including the magnitude of the energy gap, can further be tuned and controlled by external means. Xenes can easily be functionalized by substrate, chemical adsorption, defects, charge doping, external electric field, periodic potential, in-plane uniaxial and biaxial stress, and out-of-plane long-range structural deformation, to name a few. This topical review explores structural, electronic and magnetic properties of Xenes and addresses the question of their functionalization in various ways, including external factors acting simultaneously. It also points to future directions to be explored in functionalization of Xenes. The results of experimental and theoretical studies obtained so far have many promising features making the 2D-Xene materials important players in the field of future nanoelectronics and spintronics. PMID- 29708505 TI - Optimization of ScSZ/GDC bilayer thin film electrolyte for anodic aluminum oxide supported low temperature solid oxide fuel cells. AB - Due to the poor chemical stability of CeO2-based materials, doped CeO2 electrolytes are generally used as a stabilized ZrO2 protection layer/doped CeO2 electrolyte bilayer structure. Since the ionic conductivity of stabilized ZrO2 materials is lower than that of doped CeO2 materials, the thickness of the ZrO2 protective layer needs to be optimized. Thus, in this study, nano-porous anodic aluminum oxide template based scandia stabilized zirconia (ScSZ)/gadolinia doped ceria (GDC) bilayer electrolyte low temperature solid oxide fuel cells (LT-SOFCs) are successfully fabricated and investigated. The optimized thickness of the ScSZ protection layer is revealed by physical and electrochemical characterizations to maximize the performance of LT-SOFCs. The 160 nm ScSZ/400 nm GDC bilayer electrolyte LT-SOFC achieves a maximum power density of 252 mW . cm-2 and an open circuit voltage of 1.02 V OCV at 450 degrees C. PMID- 29708506 TI - Effective NaBH4-exfoliated ultrathin multilayer Co(OH)2 nanosheets arrays and sulfidation for energy storage. AB - Facile engineering ultrathin nano structural materials is still a huge challenge for material science. Thereinto, the strategy of exfoliating shows great advantages. In this work, we develop a convenient approach to exfoliate Co(OH)2 nanosheets into ultrathin Co(OH)2 nanoflakes through NaBH4-exfoliation method. Moreover, the microstructures of the Co(OH)2 nanosheets are conveniently controlled by varying the exfoliation time. As a result, the obtained ultrathin Co(OH)2-72 h nanosheets deliver the excellent electrochemical performance. In order to improve the energy storage properties, the obtained ultrathin Co(OH)2 nanosheets are further modified to enhance the conductivity via sulfidation. Consequently, the synthesized Co(OH)2-72 h/CoS2 composites exhibit a specific capacitance of 2536 F g-1 at 1 A g-1, which is more outstanding than that of Co(OH)2-72 h. What's more, the Co(OH)2-72 h/CoS2 composites show a capacitance retention of 83.3% after 10 000 cycles. Besides, the assembled asymmetric supercapacitor displays a power density of 482 W kg-1 at an energy density of 36 Wh kg-1, demonstrating a large potential for application. PMID- 29708508 TI - Second-hit mosaic mutation in mTORC1 repressor DEPDC5 causes focal cortical dysplasia-associated epilepsy. AB - DEP domain-containing 5 protein (DEPDC5) is a repressor of the recently recognized amino acid-sensing branch of the mTORC1 pathway. So far, its function in the brain remains largely unknown. Germline loss-of-function mutations in DEPDC5 have emerged as a major cause of familial refractory focal epilepsies, with case reports of sudden unexpected death in epilepsy (SUDEP). Remarkably, a fraction of patients also develop focal cortical dysplasia (FCD), a neurodevelopmental cortical malformation. We therefore hypothesized that a somatic second-hit mutation arising during brain development may support the focal nature of the dysplasia. Here, using postoperative human tissue, we provide the proof of concept that a biallelic 2-hit - brain somatic and germline - mutational mechanism in DEPDC5 causes focal epilepsy with FCD. We discovered a mutation gradient with a higher rate of mosaicism in the seizure-onset zone than in the surrounding epileptogenic zone. Furthermore, we demonstrate the causality of a Depdc5 brain mosaic inactivation using CRISPR-Cas9 editing and in utero electroporation in a mouse model recapitulating focal epilepsy with FCD and SUDEP like events. We further unveil a key role of Depdc5 in shaping dendrite and spine morphology of excitatory neurons. This study reveals promising therapeutic avenues for treating drug-resistant focal epilepsies with mTORC1-targeting molecules. PMID- 29708507 TI - Granulocyte-CSF links destructive inflammation and comorbidities in obstructive lung disease. AB - Chronic obstructive pulmonary disease (COPD) is an incurable inflammatory lung disease that afflicts millions of people worldwide, and it is the fourth leading cause of death. Systemic comorbidities affecting the heart, skeletal muscle, bone, and metabolism are major contributors to morbidity and mortality. Given the surprising finding in large prospective clinical biomarker studies that peripheral white blood cell count is more closely associated with disease than inflammatory biomarkers, we probed the role of blood growth factors. Using the SHIP-1-deficient COPD mouse model, which manifests a syndrome of destructive lung disease and a complex of comorbid pathologies, we have identified a critical and unexpected role for granulocyte-CSF (G-CSF) in linking these conditions. Deletion of G-CSF greatly reduced airway inflammation and lung tissue destruction, and attenuated systemic inflammation, right heart hypertrophy, loss of fat reserves, and bone osteoporosis. In human clinical translational studies, bronchoalveolar lavage fluid of patients with COPD demonstrated elevated G-CSF levels. These studies suggest that G-CSF may play a central and unforeseen pathogenic role in COPD and its complex comorbidities, and identify G-CSF and its regulators as potential therapeutic targets. PMID- 29708509 TI - DEPDC5 takes a second hit in familial focal epilepsy. AB - Loss-of-function mutations in a single allele of the gene encoding DEP domain containing 5 protein (DEPDC5) are commonly linked to familial focal epilepsy with variable foci; however, a subset of patients presents with focal cortical dysplasia that is proposed to result from a second-hit somatic mutation. In this issue of the JCI, Ribierre and colleagues provide several lines of evidence to support second-hit DEPDC5 mutations in this disorder. Moreover, the authors use in vivo, in utero electroporation combined with CRISPR-Cas9 technology to generate a murine model of the disease that recapitulates human manifestations, including cortical dysplasia-like changes, focal seizures, and sudden unexpected death. This study provides important insights into familial focal epilepsy and provides a preclinical model for evaluating potential therapies. PMID- 29708510 TI - Tumor-secreted Pros1 inhibits macrophage M1 polarization to reduce antitumor immune response. AB - Tyro3, Axl, Mer (TAM) receptor tyrosine kinases reduce inflammatory, innate immune responses. We demonstrate that tumor-secreted protein S (Pros1), a Mer/Tyro3 ligand, decreased macrophage M1 cytokine expression in vitro and in vivo. In contrast, tumor cells with CRISPR-based deletion of Pros1 failed to inhibit M1 polarization. Tumor cell-associated Pros1 action was abrogated in macrophages from Mer- and Tyro3- but not Axl-KO mice. In addition, several other murine and human tumor cell lines suppressed macrophage M1 cytokine expression induced by IFN-gamma and LPS. Investigation of the suppressive pathway demonstrated a role for PTP1b complexing with Mer. Substantiating the role of PTP1b, M1 cytokine suppression was also lost in macrophages from PTP1b-KO mice. Mice bearing Pros1-deficient tumors showed increased innate and adaptive immune infiltration, as well as increased median survival. TAM activation can also inhibit TLR-mediated M1 polarization. Treatment with resiquimod, a TLR7/8 agonist, did not improve survival in mice bearing Pros1-secreting tumors but doubled survival for Pros1-deleted tumors. The tumor-derived Pros1 immune suppressive system, like PD-L1, was cytokine responsive, with IFN-gamma inducing Pros1 transcription and secretion. Inhibition of Pros1/TAM interaction represents a potential novel strategy to block tumor-derived immune suppression. PMID- 29708511 TI - Prometheus revisited. AB - The liver's extraordinary ability to regenerate has been known since the myth of Prometheus, but the mechanisms involved are still being discovered. Various small animal models have been used in this quest. Two of the most popular include partial hepatectomy (PHx), in which two-thirds of the liver mass is surgically removed to evoke a massive, immediate stimulus for regeneration, and prolonged exposure to toxins that kill liver cells more gradually, provoking chronic regenerative activity. In either case, multiple types of cells must interact effectively to repopulate the organ with functional mature hepatocytes and thus assure ultimate restoration of healthy liver structure and function. This complexity has confounded efforts to distinguish specific changes that occur in cells that repopulate the hepatocyte compartment from changes in other cell populations, including subpopulations of hepatocytes or hepatocyte precursors that do not become regenerative. In the current issue of the JCI, Wang et al. used translating ribosome affinity purification followed by high-throughput RNA sequencing (TRAP-seq) to isolate mRNAs from repopulating hepatocytes in order to profile gene expression specifically in the hepatocytes that regenerate the liver following toxic injury imposed by inherent byproducts of tyrosine metabolism. This innovative methodology can potentially be used to design therapeutic strategies for liver regeneration. PMID- 29708512 TI - Hypercholesterolemia induces T cell expansion in humanized immune mice. AB - Emerging data suggest that hypercholesterolemia has stimulatory effects on adaptive immunity and that these effects can promote atherosclerosis and perhaps other inflammatory diseases. However, research in this area has relied primarily on inbred strains of mice whose adaptive immune system can differ substantially from that of humans. Moreover, the genetically induced hypercholesterolemia in these models typically results in plasma cholesterol levels that are much higher than those in most humans. To overcome these obstacles, we studied human immune system-reconstituted mice (hu-mice) rendered hypercholesterolemic by treatment with adeno-associated virus 8-proprotein convertase subtilisin/kexin type 9 (AAV8 PCSK9) and a high-fat/high-cholesterol Western-type diet (WD). These mice had a high percentage of human T cells and moderate hypercholesterolemia. Compared with hu-mice that had lower plasma cholesterol, the PCSK9-WD mice developed a T cell mediated inflammatory response in the lung and liver. Human CD4+ and CD8+ T cells bearing an effector memory phenotype were significantly elevated in the blood, spleen, and lungs of PCSK9-WD hu-mice, whereas splenic and circulating regulatory T cells were reduced. These data show that moderately high plasma cholesterol can disrupt human T cell homeostasis in vivo. This process may not only exacerbate atherosclerosis, but also contribute to T cell-mediated inflammatory diseases in the hypercholesterolemia setting. PMID- 29708515 TI - Cardiac Magnetic Resonance Imaging of Cardiac Amyloidosis. PMID- 29708516 TI - Increased Prevalence of Metabolic Syndrome and Adipocytokine Levels in a Psoriatic Arthritis Cohort. AB - OBJECTIVE: The aims of this study were to evaluate the prevalence of metabolic syndrome (MetS) in psoriatic arthritis (PsA) patients according to the most recent definition in a Mediterranean population and to determine its association with biomarkers of inflammation and serum adipocytokine levels. METHODS: Demographic, clinical, and laboratory data were collected on 74 patients with PsA and 82 control subjects. The presence of MetS was determined according to the current "harmonization" definition. Serum adipocytokines were analyzed. Continuous variables were compared by t test and discrete variables by chi test. Multivariate regression models compared the association between the presence of MetS and the blood levels of adipocytokines. RESULTS: The prevalence of MetS was higher in PsA patients compared with the control group: 54.8% versus 36.6%, respectively (P = 0.02; odds ratio, 2.33; 95% confidence interval, 1.16-4.69). The main difference between the 2 groups was waist circumference. No association was found between MetS and parameters of articular and skin disease activity or treatment. Leptin levels and leptin/adiponectin ratio were higher in PsA patients compared with control subjects: 83.4 versus 51.7 ng/mL (P = 0.001) and 6.3 * 10 versus 4.1 * 10 (P = 0.015), respectively. There was no significant difference in the adiponectin levels between the groups. CONCLUSIONS: The prevalence of MetS was higher in PsA patients compared with non-PsA control subjects in this Mediterranean population. Clinicians caring for PsA patients ought to be aware of the increased risk of MetS in PsA patients, confirmed in different regions worldwide. The increased MetS seems to be linked to central obesity in these patients, and appropriate treatment recommendations are advised. PMID- 29708513 TI - DNA methyltransferase expression in triple-negative breast cancer predicts sensitivity to decitabine. AB - Triple-negative breast cancer (TNBC) is a heterogeneous disease with poor prognosis that lacks targeted therapies, especially in patients with chemotherapy resistant disease. Since DNA methylation-induced silencing of tumor suppressors is common in cancer, reversal of promoter DNA hypermethylation by 5-aza-2' deoxycytidine (decitabine), an FDA-approved DNA methyltransferase (DNMT) inhibitor, has proven effective in treating hematological neoplasms. However, its antitumor effect varies in solid tumors, stressing the importance of identifying biomarkers predictive of therapeutic response. Here, we focused on the identification of biomarkers to select decitabine-sensitive TNBC through increasing our understanding of the mechanism of decitabine action. We showed that protein levels of DNMTs correlated with response to decitabine in patient derived xenograft (PDX) organoids originating from chemotherapy-sensitive and resistant TNBCs, suggesting DNMT levels as potential biomarkers of response. Furthermore, all 3 methytransferases, DNMT1, DNMT3A, and DNMT3B, were degraded following low-concentration, long-term decitabine treatment both in vitro and in vivo. The DNMT proteins could be ubiquitinated by the E3 ligase, TNF receptor associated factor 6 (TRAF6), leading to lysosome-dependent protein degradation. Depletion of TRAF6 blocked decitabine-induced DNMT degradation, conferring resistance to decitabine. Our study suggests a potential mechanism of regulating DNMT protein degradation and DNMT levels as response biomarkers for DNMT inhibitors in TNBCs. PMID- 29708517 TI - Neuropathic Pain Component in Axial Spondyloarthritis and the Influence on Disease Burden. AB - OBJECTIVES: Patients with nonradiographic axial spondyloarthritis (nr-axSpA) and radiographic axSpA/ankylosing spondylitis (AS) have similar burden of disease; however, the potential influence of pain characteristics including the neuropathic pain (NeP) component has not been assessed yet. The aim of this study was first to assess frequency of NeP component in patients with axSpA and second to assess the potential influence of NeP on burden of disease. METHODS: Adult patients who met the Assessment of SpondyloArthritis International Society classification criteria for axSpA were consecutively recruited. Patients were evaluated using the Douleur Neuropathique en 4 Questions interview and painDETECT questionnaire and subgrouped as patients with and without NeP. RESULTS: Neuropathic pain component was present in 31.4% of patients with axSpA categorized according to Douleur Neuropathique en 4 Questions (31.6% in nr-axSpA vs 31.3% in AS, P = 0.964) and in 33.5% of patients categorized according to painDETECT (35.1% in nr-axSpA vs 32.8% in AS, P = 0.762). Pain characteristics were quite similar between patients with nr-axSpA and AS. Women tented to have more frequent NeP. Patients with NeP component had significantly higher scores in visual analog scale of pain, patient and physician global, fatigue, Bath Ankylosing Spondylitis Disease Activity Index, Ankylosing Spondylitis Disease Activity Score using C-reactive protein, depression, anxiety scores, and physical functions; poorer quality of life (QoL); and similar frequency of fibromyalgia compared with patients without NeP component. In multivariable analysis, having NeP was associated with QoL measures (Ankylosing Spondylitis Quality of Life and Short-Form 36 physical component score) and visual analog scale of fatigue. CONCLUSIONS: Nearly one third of patients with axSpA may have NeP component regardless of having nr-axSpA or AS. Neuropathic pain component may contribute worsened QoL and poorer patient-reported outcome data and should be kept in mind during patient evaluation. PMID- 29708514 TI - Systemic isradipine treatment diminishes calcium-dependent mitochondrial oxidant stress. AB - The ability of the Cav1 channel inhibitor isradipine to slow the loss of substantia nigra pars compacta (SNc) dopaminergic (DA) neurons and the progression of Parkinson's disease (PD) is being tested in a phase 3 human clinical trial. But it is unclear whether and how chronic isradipine treatment will benefit SNc DA neurons in vivo. To pursue this question, isradipine was given systemically to mice at doses that achieved low nanomolar concentrations in plasma, near those achieved in patients. This treatment diminished cytosolic Ca2+ oscillations in SNc DA neurons without altering autonomous spiking or expression of Ca2+ channels, an effect mimicked by selectively knocking down expression of Cav1.3 channel subunits. Treatment also lowered mitochondrial oxidant stress, reduced a high basal rate of mitophagy, and normalized mitochondrial mass - demonstrating that Cav1 channels drive mitochondrial oxidant stress and turnover in vivo. Thus, chronic isradipine treatment remodeled SNc DA neurons in a way that should not only diminish their vulnerability to mitochondrial challenges, but to autophagic stress as well. PMID- 29708518 TI - Polymyalgia Rheumatica and Autoimmune Inflammatory Syndrome Induced by Adjuvants Following Administration of Influenza Vaccine. PMID- 29708519 TI - "Don't Forget the Eagle's". PMID- 29708521 TI - Ethical Analysis and Policy Recommendations Regarding Domino Liver Transplantation. AB - Due to the widening gap between supply and demand, patients who need a liver transplant due to metabolic disease may be asked to serve as domino liver donors to have their native liver transplanted into another candidate. We here analyze the ethical problems surrounding informed consent for the implant and explant procedures in transplant candidates who will serve as domino donors, using the case of a child with maple syrup urine disease. We discuss the need for 2 distinct consent processes separated in time to ensure that potential domino donors (or their surrogates) give a truly voluntary consent. We propose a Domino Donor Advocate-based on the concept of the independent living donor advocate to help the patient and/or his or her surrogates consider the risks, benefits and alternatives. Finally, we evaluate the Organ Procurement and Transplantation Network policy regarding "therapeutic organ donation" and propose several modifications to ensure that the decision by the potential domino donor (and/or his or her surrogate) is voluntary and informed. PMID- 29708522 TI - Surveying the Literature: Synopsis of Recent Key Publications. PMID- 29708523 TI - Fabricating Degradable Thermoresponsive Hydrogels on Multiple Length Scales via Reactive Extrusion, Microfluidics, Self-assembly, and Electrospinning. AB - While various smart materials have been explored for a variety of biomedical applications (e.g., drug delivery, tissue engineering, bioimaging, etc.), their ultimate clinical use has been hampered by the lack of biologically-relevant degradation observed for most smart materials. This is particularly true for temperature-responsive hydrogels, which are almost uniformly based on polymers that are functionally non-degradable (e.g., poly(N-isopropylacrylamide) (PNIPAM) or poly(oligoethylene glycol methacrylate) (POEGMA)). As such, to effectively translate the potential of thermoresponsive hydrogels to the challenges of remote controlled or metabolism-regulated drug delivery, cell scaffolds with tunable cell-material interactions, theranostic materials with the potential for both imaging and drug delivery, and other such applications, a method is required to render the hydrogels (if not fully degradable) at least capable of renal clearance following the required lifetime of the material. To that end, this protocol describes the preparation of hydrolytically-degradable hydrazone crosslinked hydrogels on multiple length scales based on the reaction between hydrazide and aldehyde-functionalized PNIPAM or POEGMA oligomers with molecular weights below the renal filtration limit. Specifically, methods to fabricate degradable thermoresponsive bulk hydrogels (using a double barrel syringe technique), hydrogel particles (on both the microscale through the use of a microfluidics platform facilitating simultaneous mixing and emulsification of the precursor polymers and the nanoscale through the use of a thermally-driven self assembly and cross-linking method), and hydrogel nanofibers (using a reactive electrospinning strategy) are described. In each case, hydrogels with temperature responsive properties similar to those achieved via conventional free radical cross-linking processes can be achieved, but the hydrazone cross-linked network can be degraded over time to re-form the oligomeric precursor polymers and enable clearance. As such, we anticipate these methods (which may be generically applied to any synthetic water-soluble polymer, not just smart materials) will enable easier translation of synthetic smart materials to clinical applications. PMID- 29708524 TI - Subject-specific Musculoskeletal Model for Studying Bone Strain During Dynamic Motion. AB - Bone stress injuries are common in sports and military trainings. Repetitive large ground impact forces during training could be the cause. It is essential to determine the effect of high ground impact forces on lower-body bone deformation to better understand the mechanisms of bone stress injuries. Conventional strain gauge measurement has been used to study in vivo tibia deformation. This method is associated with limitations including invasiveness of the procedure, involvement of few human subjects, and limited strain data from small bone surface areas. The current study intends to introduce a novel approach to study tibia bone strain under high impact loading conditions. A subject-specific musculoskeletal model was created to represent a healthy male (19 years, 80 kg, 1,800 mm). A flexible finite element tibia model was created based on a computed tomography (CT) scan of the subject's right tibia. Laboratory motion capture was performed to obtain kinematics and ground reaction forces of drop-landings from different heights (26, 39, 52 cm). Multibody dynamic computer simulations combined with a modal analysis of the flexible tibia were performed to quantify tibia strain during drop-landings. Calculated tibia strain data were in good agreement with previous in vivo studies. It is evident that this non-invasive approach can be applied to study tibia bone strain during high impact activities for a large cohort, which will lead to a better understanding of injury mechanism of tibia stress fractures. PMID- 29708525 TI - Establishment of a Primary Culture of Patient-derived Soft Tissue Sarcoma. AB - Soft tissue sarcomas (STS) represent a spectrum of heterogeneous malignancies with a difficult diagnosis, classification, and management. To date, more than 50 histological subtypes of these rare solid tumors have been identified. Thus, due to their extraordinary diversity and low incidence, our understanding of the biology of these tumors is still limited. Patient-derived cultures represent the ideal platform to study STS pathophysiology and pharmacology. We thus developed a human preclinical model of STS starting from tumor specimens harvested from patients undergoing surgical resection. Patient-derived STS cell cultures were obtained from the surgical specimens by collagenase digestion and isolated by filtration. Cells were counted, seeded, and left for 14 days in standard monolayer cultures and then processed by downstream analysis. Before performing molecular or pharmaceutical analyses, the establishment of STS primary cultures was confirmed through the evaluation of cytomorphologic features and, when available, immunohistochemical markers. This method represents a useful tool 1) to study the natural history of these poorly explored malignancies and 2) to test the effects of different drugs in an effort to learn more about their mechanisms of action. PMID- 29708526 TI - Improving the Application of High Molecular Weight Biotinylated Dextran Amine for Thalamocortical Projection Tracing in the Rat. AB - High molecular weight biotinylated dextran amine (BDA) has been used as a highly sensitive neuroanatomical tracer for many decades. Since the quality of its labeling was affected by various factors, here, we provide a refined protocol for the application of high molecular weight BDA for studying optimal neural labeling in the central nervous system. After stereotactic injection of BDA into the ventral posteromedial nucleus (VPM) of the thalamus in the rat through a delicate glass pipette, BDA was stained with fluorescent streptavidin-Alexa (AF) 594 and counterstained with fluorescent Nissl stain AF500/525. On the background of green Nissl staining, the red BDA labeling, including neuronal cell bodies and axonal terminals, was more distinctly demonstrated in the somatosensory cortex. Furthermore, double fluorescent staining for BDA and the calcium-binding protein parvalbumin (PV) was carried out to observe the correlation of BDA labeling and PV-positive interneurons in the cortical target, providing the opportunity to study the local neural circuits and their chemical characteristics. Thus, this refined method is not only suitable for visualizing high quality neural labeling with the high molecular weight BDA through reciprocal neural pathways between the thalamus and cerebral cortex, but also will permit the simultaneous demonstration of other neural markers with fluorescent histochemistry or immunochemistry. PMID- 29708527 TI - A Multimodal Imaging Approach Based on Micro-CT and Fluorescence Molecular Tomography for Longitudinal Assessment of Bleomycin-Induced Lung Fibrosis in Mice. AB - Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease characterized by the progressive and irreversible destruction of lung architecture, which causes significant deterioration in lung function and subsequent death from respiratory failure. The pathogenesis of IPF in experimental animal models has been induced by bleomycin administration. In this study, we investigate an IPF-like mouse model induced by a double intratracheal bleomycin instillation. Standard histological assessments used for studying lung fibrosis are invasive terminal procedures. The goal of this work is to monitor lung fibrosis through noninvasive imaging techniques such as Fluorescent Molecular Tomography (FMT) and Micro-CT. These two technologies validated with histology findings could represent a revolutionary functional approach for real time non-invasive monitoring of IPF disease severity and progression. The fusion of different approaches represents a step further for understanding the IPF disease, where the molecular events occurring in a pathological condition can be observed with FMT and the subsequent anatomical changes can be monitored by Micro-CT. PMID- 29708528 TI - Installation Method to Enhance Quality Control for Fiber Reinforced Polymer Spike Anchors. AB - Fiber reinforced polymer (FRP) anchors are a promising way to enhance the performance of externally-bonded FRPs applied to existing structures, as they can delay or even prevent debonding failure. However, a major concern faced by designers is the premature failure of the anchors due to stress concentration. Poor installation quality and preparation of the clearance holes can result in stress concentration that provokes this premature failure. This paper deals with an installation method that aims to reduce the impact of the stress concentration and to provide a proper quality control of the preparation of the drill hole. The method involves three parts: the drilling and cleaning of the holes, the smoothing of the hole edges with a customized drill bit, and the installation of the anchor itself, including the impregnation of the anchor dowel and its insertion. Anchor fans (the free length of the spikes) are then bonded to the external FRP reinforcement. For the end anchorage, and in the case of reinforcements with multiple plies, it is recommended that the anchor fan be inserted between two plies to assist the stress-transfer mechanism. The proposed procedure is complemented with a design approach for spike anchors, based on an extensive database. It is proposed that the design follow a number of steps, namely: selection of the anchor diameter and subsequent tensile strength of the connector (that is to say, the anchor before fanning out the free end), evaluation of the reduction in the tensile strength due to bending, provision of enough embedment to prevent slippage failure, and consideration of the number and spacing of anchors for a given reinforcement. In this sense, it should be noted that further research is needed in order to obtain a general expression for the contribution of spike anchors to overall bond strength of FRP reinforcements. PMID- 29708529 TI - Ecosystem Fabrication (EcoFAB) Protocols for The Construction of Laboratory Ecosystems Designed to Study Plant-microbe Interactions. AB - Beneficial plant-microbe interactions offer a sustainable biological solution with the potential to boost low-input food and bioenergy production. A better mechanistic understanding of these complex plant-microbe interactions will be crucial to improving plant production as well as performing basic ecological studies investigating plant-soil-microbe interactions. Here, a detailed description for ecosystem fabrication is presented, using widely available 3D printing technologies, to create controlled laboratory habitats (EcoFABs) for mechanistic studies of plant-microbe interactions within specific environmental conditions. Two sizes of EcoFABs are described that are suited for the investigation of microbial interactions with various plant species, including Arabidopsis thaliana, Brachypodium distachyon, and Panicum virgatum. These flow through devices allow for controlled manipulation and sampling of root microbiomes, root chemistry as well as imaging of root morphology and microbial localization. This protocol includes the details for maintaining sterile conditions inside EcoFABs and mounting independent LED light systems onto EcoFABs. Detailed methods for addition of different forms of media, including soils, sand, and liquid growth media coupled to the characterization of these systems using imaging and metabolomics are described. Together, these systems enable dynamic and detailed investigation of plant and plant-microbial consortia including the manipulation of microbiome composition (including mutants), the monitoring of plant growth, root morphology, exudate composition, and microbial localization under controlled environmental conditions. We anticipate that these detailed protocols will serve as an important starting point for other researchers, ideally helping create standardized experimental systems for investigating plant-microbe interactions. PMID- 29708530 TI - Generation and Isolation of Cell Cycle-arrested Cells with Complex Karyotypes. AB - Chromosome mis-segregation leads to aneuploidy, a condition in which cells harbor an imbalanced chromosome number. Several lines of evidence strongly indicate that aneuploidy triggers genome instability, ultimately generating cells with complex karyotypes that arrest their proliferation. Isolation and characterization of cells harboring complex karyotypes are crucial to study the impact of an imbalanced chromosome number on cell physiology. To date, no methods have been established to reliably isolate such aneuploid cells. This paper provides a protocol for the enrichment and analysis of aneuploid cells with complex karyotypes utilizing standard, inexpensive tissue culture techniques. This protocol can be used to analyze several features of aneuploid cells with complex karyotypes including their induced senescence-associated secretory phenotype, pro inflammatory properties, and ability to interact with immune cells. Because cancer cells often harbor imbalances in chromosome number, it is crucial to decipher how aneuploidy impacts cell physiology in normal cells, with the ultimate goal of uncovering both its pro- and anti-tumorigenic effects. PMID- 29708531 TI - A Comprehensive Procedure to Evaluate the In Vitro Performance of the Putative Hemangioblastoma Neovascularization Using the Spheroid Sprouting Assay. AB - The inactivation of the von Hippel-Lindau (VHL) tumor suppressor gene plays a crucial role in the development of hemangioblastomas (HBs) within the human central nervous system (CNS). However, both the cytological origin and the evolutionary process of HBs (including neovascularization) remain controversial, and anti-angiogenesis for VHL-HBs, based on classic HB angiogenesis, have produced disappointing results in clinical trials. One major obstacle to the successful clinical translation of anti-vascular treatment is the lack of a thorough understanding of neovascularization in this vascular tumor. In this article, we present a comprehensive procedure to evaluate in vitro whether classic tumor angiogenesis exists in HBs, as well as its role in HBs. With this procedure, researchers can accurately understand the complexity of HB neovascularization and identify the function of this common form of angiogenesis in HBs. These protocols can be used to evaluate the most promising anti-vascular therapy for tumors, which has high translational potential either for tumors treatment or for aiding in the optimization of the anti-angiogenic treatment for HBs in future translations. The results highlight the complexity of HB neovascularization and suggest that this common form angiogenesis is only a complementary mechanism in HB neovascularization. PMID- 29708532 TI - Development of Recombinant Proteins to Treat Chronic Pain. AB - Chronic pain is difficult to treat and new approaches to resolve persistent pain are urgently needed. Anti-inflammatory cytokines are promising candidates for treating debilitating pain conditions due to their capacity to regulate aberrant neuro-immune interactions. However, physiologically they work in a network of various cytokines, and therefore their therapeutic effect may not be optimal when used as stand-alone drugs. To overcome this limitation, we developed a fusion protein of the anti-inflammatory cytokines IL4 and IL10. Here, we describe the methods for production and quality control of IL4-10 recombinant fusion protein and we test the effectiveness of the IL4-10 fusion protein to resolve pain in a mouse model of persistent inflammatory pain. PMID- 29708533 TI - A Simple and Efficient Method for In Vivo Cardiac-specific Gene Manipulation by Intramyocardial Injection in Mice. AB - Gene manipulation specifically in the heart significantly potentiate the investigation of cardiac disease pathomechanisms and their therapeutic potential. In vivo cardiac-specific gene delivery is commonly achieved by either systemic or local delivery. Systemic injection via tail vein is easy and efficient in manipulating cardiac gene expression by using recombinant adeno-associated virus 9 (AAV9). However, this method requires a relatively high amount of vector for efficient transduction, and may result in nontarget organ gene transduction. Here, we describe a simple, efficient, and time-saving method of intramyocardial injection for in vivo cardiac-specific gene manipulation in mice. Under anesthesia (without ventilation), the pectoral major and minor muscles were bluntly dissected, and the mouse heart was quickly exposed by manual externalization through a small incision at the fourth intercostal space. Subsequently, adenovirus encoding luciferase (Luc) and vitamin D receptor (VDR), or short hairpin RNA (shRNA) targeting VDR, was injected with a Hamilton syringe into the myocardium. Subsequent in vivo imaging demonstrated that luciferase was successfully overexpressed specifically in the heart. Moreover, Western blot analysis confirmed the successful overexpression or silencing of VDR in the mouse heart. Once mastered, this technique can be used for gene manipulation, as well as injection of cells or other materials such as nanogels in the mouse heart. PMID- 29708534 TI - Electric-field Control of Electronic States in WS2 Nanodevices by Electrolyte Gating. AB - A method of carrier number control by electrolyte gating is demonstrated. We have obtained WS2 thin flakes with atomically flat surface via scotch tape method or individual WS2 nanotubes by dispersing the suspension of WS2 nanotubes. The selected samples have been fabricated into devices by the use of the electron beam lithography and electrolyte is put on the devices. We have characterized the electronic properties of the devices under applying the gate voltage. In the small gate voltage region, ions in the electrolyte are accumulated on the surface of the samples which leads to the large electric potential drop and resultant electrostatic carrier doping at the interface. Ambipolar transfer curve has been observed in this electrostatic doping region. When the gate voltage is further increased, we met another drastic increase of source-drain current which implies that ions are intercalated into layers of WS2 and electrochemical carrier doping is realized. In such electrochemical doping region, superconductivity has been observed. The focused technique provides a powerful strategy for achieving the electric-filed-induced quantum phase transition. PMID- 29708535 TI - Whole-mount Clearing and Staining of Arabidopsis Flower Organs and Siliques. AB - Due to its formidable tools for molecular genetic studies, Arabidopsis thaliana is one of the most prominent model species in plant biology and, especially, in plant reproductive biology. However, plant morphological, anatomical, and ultrastructural analyses traditionally involve time-consuming embedding and sectioning procedures for bright field, scanning, and electron microscopy. Recent progress in confocal fluorescence microscopy, state-of-the-art 3-D computer-aided microscopic analyses, and the continuous refinement of molecular techniques to be used on minimally processed whole-mount specimens, has led to an increased demand for developing efficient and minimal sample processing techniques. In this protocol, we describe techniques for properly dissecting Arabidopsis flowers and siliques, basic clearing techniques, and some staining procedures for whole-mount observations of reproductive structures. PMID- 29708536 TI - Culturing of Retinal Pigment Epithelial Cells on an Ex Vivo Model of Aged Human Bruch's Membrane. AB - Aside from vitamins and antioxidants recommended by the Age-Related Eye Disease Study, there is no effective therapy for "dry," or atrophic age-related macular degeneration (AMD) which represents 90% of the cases. Therapies are needed to slow or retard the development of geographic atrophy (GA), and understanding Bruch's membrane pathology is part of this process. Alterations in human Bruch's membrane precede the progression of AMD by contributing to the damage of retinal pigment epithelial (RPE) cells. Given the lack of sufficient animal models to study AMD, ex vivo models of aged human Bruch's membrane serve as a useful tool to study the behavior of RPE cells from immortalized and primary cell lines as well as RPE lines derived from induced pluripotent stem cells (iPSCs). Here, we present a detailed method that allows one to determine the effects of RPE cell behavior seeded on harvested human Bruch's membrane explants from human donors, including attachment, apoptosis and proliferation, ability to phagocytize photoreceptor outer segments, establishment of polarity, and gene expression. This assay provides an ex vivo model of aged Bruch's membrane to assess the functional characteristics of RPE cells when seeded on aged/compromised extracellular matrix. PMID- 29708537 TI - A Protocol for Laboratory Housing of Turquoise Killifish (Nothobranchius furzeri). AB - The development of husbandry practices in non-model laboratory fish used for experimental purposes has greatly benefited from the establishment of reference fish model systems, such as zebrafish and medaka. In recent years, an emerging fish - the turquoise killifish (Nothobranchius furzeri) - has been adopted by a growing number of research groups in the fields of biology of aging and ecology. With a captive life span of 4 - 8 months, this species is the shortest-lived vertebrate raised in captivity and allows the scientific community to test - in a short time - experimental interventions that can lead to alterations of the aging rate and life expectancy. Given the unique biology of this species, characterized by embryonic diapause, explosive sexual maturation, marked morphological and behavioral sexual dimorphism - and their relatively short adult life span - ad hoc husbandry practices are in urgent demand. This protocol reports a set of key husbandry measures that allow optimal turquoise killifish laboratory care, enabling the scientific community to adopt this species as a powerful laboratory animal model. PMID- 29708538 TI - Electrically Conductive Scaffold to Modulate and Deliver Stem Cells. AB - Stem cell therapy has emerged as an exciting stroke therapeutic, but the optimal delivery method remains unclear. While the technique of microinjection has been used for decades to deliver stem cells in stroke models, this technique is limited by the lack of ability to manipulate the stem cells prior to injection. This paper details a method of using an electrically conductive polymer scaffold for stem cell delivery. Electrical stimulation of stem cells using a conductive polymer scaffold alters the stem cell's genes involved in cell survival, inflammatory response, and synaptic remodeling. After electrical preconditioning, the stem cells on the scaffold are transplanted intracranially in a distal middle cerebral artery occlusion rat model. This protocol describes a powerful technique to manipulate stem cells via a conductive polymer scaffold and creates a new tool to further develop stem cell-based therapy. PMID- 29708539 TI - Protein Digestion, Ultrafiltration, and Size Exclusion Chromatography to Optimize the Isolation of Exosomes from Human Blood Plasma and Serum. AB - Exosomes, a type of nanovesicle released from all cell types, can be isolated from any bodily fluid. The contents of exosomes, including proteins and RNAs, are unique to the cells from which they are derived and can be used as indicators of disease. Several common enrichment protocols, including ultracentrifugation, yield exosomes laden with soluble protein contaminants. Specifically, we have found that the most abundant proteins within blood often co-purify with exosomes and can confound downstream proteomic studies, thwarting the identification of low abundance biomarker candidates. Of additional concern is irreproducibility of exosome protein quantification due to inconsistent representation of non-exosomal protein levels. The protocol detailed here was developed to remove non-exosomal proteins that co-purify along with exosomes, adding rigor to the exosome purification process. Five methods were compared using paired blood plasma and serum from five donors. Analysis using nanoparticle tracking analysis and micro bicinchoninic acid protein assay revealed that a combined protocol utilizing ultrafiltration and size exclusion chromatography yielded the optimal vesicle enrichment and soluble protein removal. Western blotting was used to verify that the expected abundant blood proteins, including albumin and apolipoproteins, were depleted. PMID- 29708540 TI - Synthesis and Performance Characterizations of Transition Metal Single Atom Catalyst for Electrochemical CO2 Reduction. AB - This protocol presents both the synthesis method of the Ni single atom catalyst, and the electrochemical testing of its catalytic activity and selectivity in aqueous CO2 reduction. Different from traditional metal nanocrystals, the synthesis of metal single atoms involves a matrix material that can confine those single atoms and prevent them from aggregation. We report an electrospinning and thermal annealing method to prepare Ni single atoms dispersed and coordinated in a graphene shell, as active centers for CO2 reduction to CO. During the synthesis, N dopants play a critical role in generating graphene vacancies to trap Ni atoms. Aberration-corrected scanning transmission electron microscopy and three-dimensional atom probe tomography were employed to identify the single Ni atomic sites in graphene vacancies. Detailed setup of electrochemical CO2 reduction apparatus coupled with an on-line gas chromatography is also demonstrated. Compared to metallic Ni, Ni single atom catalyst exhibit dramatically improved CO2 reduction and suppressed H2 evolution side reaction. PMID- 29708541 TI - Deep Vein Thrombosis Induced by Stasis in Mice Monitored by High Frequency Ultrasonography. AB - Venous thrombosis is a common condition affecting 1 - 2% of the population, with an annual incidence of 1 in 500. Venous thrombosis can lead to death through pulmonary embolism or results in the post-thrombotic syndrome, characterized by chronic leg pain, swelling, and ulceration, or in chronic pulmonary hypertension resulting in significant chronic respiratory compromise. This is the most common cardiovascular disease after myocardial infarction and ischemic stroke and is a clinical challenge for all medical disciplines, as it can complicate the course of other disorders such as cancer, systemic disease, surgery, and major trauma. Experimental models are necessary to study these mechanisms. The stasis model induces consistent thrombus size and a quantifiable amount of thrombus. However, it is necessary to systematically ligate side branches of the inferior vena cava to avoid variability in thrombus sizes and any erroneous data interpretation. We have developed a non-invasive technique to measure thrombus size using ultrasonography. Using this technique, we can assess thrombus development and resolution over time in the same animal. This approach limits the number of mice required for quantification of venous thrombosis consistent with the principle of replacement, reduction, and refinement of animals in research. We have demonstrated that thrombus weight and histological analysis of thrombus size correlate with measurement obtained with ultrasonography. Therefore, the current study describes how to induce deep vein thrombosis in mice using the inferior vena cava stasis model and how to monitor it using high frequency ultrasound. PMID- 29708542 TI - A Simple Flow Cytometry Based Assay to Determine In Vitro Antibody Dependent Enhancement of Dengue Virus Using Zika Virus Convalescent Serum. AB - Antibody dependent enhancement of infection has been shown to play a major role in Dengue viral pathogenesis. Traditional assays that measure the capacity of antibodies or serum to enhance infection in impermissible cell lines have relied on using viral output in the media followed by plaque assays to quantify infection. More recently, these assays have examined Dengue virus (DENV) infection in the cell lines using fluorescently labeled antibodies. Both these approaches have limitations that restrict the widespread use of these techniques. Here, we describe a simple in vitro assay using Dengue virus reporter viral particles (RVPs) that express green fluorescent protein and K562 cells to examine antibody dependent enhancement (ADE) of DENV infection using serum that was obtained from rhesus macaques 16 weeks after infection with Zika virus (ZIKV). This technique is reliable, involves minimal manipulation of cells, does not involve the use of live replication competent virus, and can be performed in a high throughput format to get a quantitative readout using flow cytometry. Additionally, this assay can be easily adapted to examine antibody dependent enhancement (ADE) of other flavivirus infections such as Yellow Fever virus (YFV), Japanese Equine Encephalitis virus (JEEV), West Nile virus (WNV) etc. where RVPs are available. The ease of setting up the assay, analyzing the data, and interpreting results makes it highly amenable to most laboratory settings. PMID- 29708543 TI - Electrochemical Detection of Deuterium Kinetic Isotope Effect on Extracellular Electron Transport in Shewanella oneidensis MR-1. AB - Direct electrochemical detection of c-type cytochrome complexes embedded in the bacterial outer membrane (outer membrane c-type cytochrome complexes; OM c-Cyts) has recently emerged as a novel whole-cell analytical method to characterize the bacterial electron transport from the respiratory chain to the cell exterior, referred to as the extracellular electron transport (EET). While the pathway and kinetics of the electron flow during the EET reaction have been investigated, a whole-cell electrochemical method to examine the impact of cation transport associated with EET has not yet been established. In the present study, an example of a biochemical technique to examine the deuterium kinetic isotope effect (KIE) on EET through OM c-Cyts using a model microbe, Shewanella oneidensis MR-1, is described. The KIE on the EET process can be obtained if the EET through OM c-Cyts acts as the rate-limiting step in the microbial current production. To that end, before the addition of D2O, the supernatant solution was replaced with fresh media containing a sufficient amount of the electron donor to support the rate of upstream metabolic reactions, and to remove the planktonic cells from a uniform monolayer biofilm on the working electrode. Alternative methods to confirm the rate-limiting step in microbial current production as EET through OM c-Cyts are also described. Our technique of a whole-cell electrochemical assay for investigating proton transport kinetics can be applied to other electroactive microbial strains. PMID- 29708544 TI - Radiation Planning Assistant - A Streamlined, Fully Automated Radiotherapy Treatment Planning System. AB - The Radiation Planning Assistant (RPA) is a system developed for the fully automated creation of radiotherapy treatment plans, including volume-modulated arc therapy (VMAT) plans for patients with head/neck cancer and 4-field box plans for patients with cervical cancer. It is a combination of specially developed in house software that uses an application programming interface to communicate with a commercial radiotherapy treatment planning system. It also interfaces with a commercial secondary dose verification software. The necessary inputs to the system are a Treatment Plan Order, approved by the radiation oncologist, and a simulation computed tomography (CT) image, approved by the radiographer. The RPA then generates a complete radiotherapy treatment plan. For the cervical cancer treatment plans, no additional user intervention is necessary until the plan is complete. For head/neck treatment plans, after the normal tissue and some of the target structures are automatically delineated on the CT image, the radiation oncologist must review the contours, making edits if necessary. They also delineate the gross tumor volume. The RPA then completes the treatment planning process, creating a VMAT plan. Finally, the completed plan must be reviewed by qualified clinical staff. PMID- 29708545 TI - Generation of Human Nasal Epithelial Cell Spheroids for Individualized Cystic Fibrosis Transmembrane Conductance Regulator Study. AB - While the introduction of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator drugs has revolutionized care in Cystic Fibrosis (CF), the genotype-directed therapy model currently in use has several limitations. First, rare or understudied mutation groups are excluded from definitive clinical trials. Moreover, as additional modulator drugs enter the market, it will become difficult to optimize the modulator choices for an individual subject. Both of these issues are addressed with the use of patient-derived, individualized preclinical model systems of CFTR function and modulation. Human nasal epithelial cells (HNEs) are an easily accessible source of respiratory tissue for such a model. Herein, we describe the generation of a three-dimensional spheroid model of CFTR function and modulation using primary HNEs. HNEs are isolated from subjects in a minimally invasive fashion, expanded in conditional reprogramming conditions, and seeded into the spheroid culture. Within 2 weeks of seeding, spheroid cultures generate HNE spheroids that can be stimulated with 3',5'-cyclic adenosine monophosphate (cAMP)-generating agonists to activate CFTR function. Spheroid swelling is then quantified as a proxy of CFTR activity. HNE spheroids capitalize on the minimally invasive, yet respiratory origin of nasal cells to generate an accessible, personalized model relevant to an epithelium reflecting disease morbidity and mortality. Compared to the air-liquid interface HNE cultures, spheroids are relatively quick to mature, which reduces the overall contamination rate. In its current form, the model is limited by low throughput, though this is offset by the relative ease of tissue acquisition. HNE spheroids can be used to reliably quantify and characterize CFTR activity at the individual level. An ongoing study to tie this quantification to in vivo drug response will determine if HNE spheroids are a true preclinical predictor of patient response to CFTR modulation. PMID- 29708546 TI - Highly Efficient Gene Disruption of Murine and Human Hematopoietic Progenitor Cells by CRISPR/Cas9. AB - Advances in the hematopoietic stem cell (HSCs) field have been aided by methods to genetically engineer primary progenitor cells as well as animal models. Complete gene ablation in HSCs required the generation of knockout mice from which HSCs could be isolated, and gene ablation in primary human HSCs was not possible. Viral transduction could be used for knock-down approaches, but these suffered from variable efficacy. In general, genetic manipulation of human and mouse hematopoietic cells was hampered by low efficiencies and extensive time and cost commitments. Recently, CRISPR/Cas9 has dramatically expanded the ability to engineer the DNA of mammalian cells. However, the application of CRISPR/Cas9 to hematopoietic cells has been challenging, mainly due to their low transfection efficiencies, the toxicity of plasmid-based approaches and the slow turnaround time of virus-based protocols. A rapid method to perform CRISPR/Cas9-mediated gene editing in murine and human hematopoietic stem and progenitor cells with knockout efficiencies of up to 90% is provided in this article. This approach utilizes a ribonucleoprotein (RNP) delivery strategy with a streamlined three-day workflow. The use of Cas9-sgRNA RNP allows for a hit-and-run approach, introducing no exogenous DNA sequences in the genome of edited cells and reducing off-target effects. The RNP-based method is fast and straightforward: it does not require cloning of sgRNAs, virus preparation or specific sgRNA chemical modification. With this protocol, scientists should be able to successfully generate knockouts of a gene of interest in primary hematopoietic cells within a week, including downtimes for oligonucleotide synthesis. This approach will allow a much broader group of users to adapt this protocol for their needs. PMID- 29708547 TI - Identifying Transcription Factor Olig2 Genomic Binding Sites in Acutely Purified PDGFRalpha+ Cells by Low-cell Chromatin Immunoprecipitation Sequencing Analysis. AB - In mammalian cells, gene transcription is regulated in a cell type specific manner by the interactions of transcriptional factors with genomic DNA. Lineage specific transcription factors are considered to play essential roles in cell specification and differentiation during development. ChIP coupled with high throughput DNA sequencing (ChIP-seq) is widely used to analyze genome-wide binding sites of transcription factors (or its associated complex) to genomic DNA. However, a large number of cells are required for one standard ChIP reaction, which makes it difficult to study the limited number of isolated primary cells or rare cell populations. In order to understand the regulatory mechanism of oligodendrocyte lineage-specific transcription factor Olig2 in acutely purified mouse OPCs, a detailed method using ChIP-seq to identify the genome-wide binding sites of Olig2 (or Olig2 complex) is shown. First, the protocol explains how to purify the platelet-derived growth factor receptor alpha (PDGFRalpha) positive OPCs from mouse brains. Next, Olig2 antibody mediated ChIP and library construction are performed. The last part describes the bioinformatic software and procedures used for Olig2 ChIP-seq analysis. In summary, this paper reports a method to analyze the genome-wide bindings of transcriptional factor Olig2 in acutely purified brain OPCs. PMID- 29708548 TI - Using Mouse Oocytes to Assess Human Gene Function During Meiosis I. AB - Embryonic aneuploidy is the major genetic cause of infertility in humans. Most of these events originate during female meiosis, and albeit positively correlated with maternal age, age alone is not always predictive of the risk of generating an aneuploid embryo. Therefore, gene variants might account for incorrect chromosome segregation during oogenesis. Given that access to human oocytes is limited for research purposes, a series of assays were developed to study human gene function during meiosis I using mouse oocytes. First, messenger RNA (mRNA) of the gene and gene variant of interest are microinjected into prophase I arrested mouse oocytes. After allowing time for expression, oocytes are synchronously released into meiotic maturation to complete meiosis I. By tagging the mRNA with a sequence of a fluorescent reporter, such as green fluorescent protein (Gfp), the localization of the human protein can be assessed in addition to the phenotypic alterations. For example, gain or loss of function can be investigated by establishing experimental conditions that challenge the gene product to fix meiotic errors. Although this system is advantageous in investigating human protein function during oogenesis, adequate interpretation of results should be undertaken given that protein expression is not at endogenous levels and, unless controlled for (i.e. knocked out or down), murine homologs are also present in the system. PMID- 29708549 TI - An In Vitro Model to Study the Effect of 5-Aminolevulinic Acid-mediated Photodynamic Therapy on Staphylococcus aureus Biofilm. AB - Staphylococcus aureus (S. aureus) is a common human pathogen, which causes pyogenic and systemic infections. S. aureus infections are difficult to eradicate not only due to the emergence of antibiotic-resistant strains but also its ability to form biofilms. Recently, photodynamic therapy (PDT) has been indicated as one of the potential treatments for controlling biofilm infections. However, further studies are required to improve our knowledge of its effect on bacterial biofilms, as well as the underlying mechanisms. This manuscript describes an in vitro model of PDT with 5-aminolevulinic acid (5-ALA), a precursor of the actual photosensitizer, protoporphyrin IX (PpIX). Briefly, mature S. aureus biofilms were incubated with ALA and then exposed to light. Subsequently, the antibacterial effect of ALA-PDT on S. aureus biofilm was quantified by calculating the colony forming units (CFUs) and visualized by viability fluorescent staining via confocal laser scanning microscopy (CLSM). Representative results demonstrated a strong antibacterial effect of ALA-PDT on S. aureus biofilms. This protocol is simple and can be used to develop an in vitro model to study the treatment of S. aureus biofilms with ALA-PDT. In the future, it could also be referenced in PDT studies utilizing other photosensitizers for different bacterial strains with minimal adjustments. PMID- 29708550 TI - A Semantic Priming Event-related Potential (ERP) Task to Study Lexico-semantic and Visuo-semantic Processing in Autism Spectrum Disorder. AB - Individuals with autism spectrum disorder (ASD) have characteristic deficits in understanding the meaning of language, or semantic processing. However, some evidence indicates that semantic processing of non-linguistic stimuli is intact, suggesting that semantic deficits may be language-specific. To appropriately characterize semantic processing deficits in individuals with ASD, comparison of within-modality linguistic (e.g., written words) and non-linguistic (e.g., pictures) stimuli is required. This paper describes such a methodology that makes use of a semantic priming paradigm during concurrent recording of electroencephalographic (EEG) data. EEG provides a dynamic measure of brain activity that is well-suited to characterize subtle differences in semantic processing that may not be observable at the behavioral level. The semantic priming paradigm presents a prime picture or word (e.g., dog) followed by a target picture or word that is either related (e.g., cat) or unrelated (e.g., pencil) to the prime. This paradigm can thus be used to evaluate semantic processing across different modalities, and to compare lexico-semantic and visuo semantic processing abilities in individuals with ASD and how they might differ from TD individuals. The specific steps involved in creating the stimuli, performing the EEG testing, and analyzing the EEG data are discussed. Representative results illustrate how the N400 component of the event-related potential (ERP) is reduced following semantically-related prime-target pairs compared to unrelated pairs. Comparisons of the N400 between conditions, modalities, and groups can provide estimates of the success of semantic processing, and can thereby be used to characterize semantic deficits in individuals with ASD or other clinical populations. PMID- 29708551 TI - Assessing Lysosomal Alkalinization in the Intestine of Live Caenorhabditis elegans. AB - The nematode Caenorhabditis elegans (C. elegans) is a model system that is widely used to study longevity and developmental pathways. Such studies are facilitated by the transparency of the animal, the ability to do forward and reverse genetic assays, the relative ease of generating fluorescently labeled proteins, and the use of fluorescent dyes that can either be microinjected into the early embryo or incorporated into its food (E. coli strain OP50) to label cellular organelles (e.g. 9-diethylamino-5H-benzo(a)phenoxazine-5-one and (3-{2-[(1H,1'H-2,2' bipyrrol-5-yl-kappaN(1))methylidene]-2H-pyrrol-5-yl-kappaN}-N-[2 (dimethylamino)ethyl]propanamidato)(difluoro)boron). Here, we present the use of a fluorescent pH-sensitive dye that stains intestinal lysosomes, providing a visual readout of dynamic, physiological changes in lysosomal acidity in live worms. This protocol does not measure lysosomal pH, but rather aims to establish a reliable method of assessing physiological relevant variations in lysosomal acidity. cDCFDA is a cell-permeant compound that is converted to the fluorescent fluorophore 5-(and-6)-carboxy-2',7'-dichlorofluorescein (cDCF) upon hydrolysis by intracellular esterases. Protonation inside lysosomes traps cDCF in these organelles, where it accumulates. Due to its low pKa of 4.8, this dye has been used as a pH sensor in yeast. Here we describe the use of cDCFDA as a food supplement to assess the acidity of intestinal lysosomes in C. elegans. This technique allows for the detection of alkalinizing lysosomes in live animals, and has a broad range of experimental applications including studies on aging, autophagy, and lysosomal biogenesis. PMID- 29708552 TI - RNA Pull-down Procedure to Identify RNA Targets of a Long Non-coding RNA. AB - Long non-coding RNA (lncRNA), which are sequences of more than 200 nucleotides without a defined reading frame, belong to the regulatory non-coding RNA's family. Although their biological functions remain largely unknown, the number of these lncRNAs has steadily increased and it is now estimated that humans may have more than 10,000 such transcripts. Some of these are known to be involved in important regulatory pathways of gene expression which take place at the transcriptional level, but also at different steps of RNA co- and post transcriptional maturation. In the latter cases, RNAs that are targeted by the lncRNA have to be identified. That's the reason why it is useful to develop a method enabling the identification of RNAs associated directly or indirectly with a lncRNA of interest. This protocol, which was inspired by previously published protocols allowing the isolation of a lncRNA together with its associated chromatin sequences, was adapted to permit the isolation of associated RNAs. We determined that two steps are critical for the efficiency of this protocol. The first is the design of specific anti-sense DNA oligonucleotide probes able to hybridize to the lncRNA of interest. To this end, the lncRNA secondary structure was predicted by bioinformatics and anti-sense oligonucleotide probes were designed with a strong affinity for regions that display a low probability of internal base pairing. The second crucial step of the procedure relies on the fixative conditions of the tissue or cultured cells that have to preserve the network between all molecular partners. Coupled with high throughput RNA sequencing, this RNA pull-down protocol can provide the whole RNA interactome of a lncRNA of interest. PMID- 29708554 TI - Reconfigurable Microfluidic Channel with Pin-discretized Sidewalls. AB - Microfluidic components need to have various shapes to realize different key microfluidic functions such as mixing, separation, particle trapping, or reactions. A microfluidic channel that deforms even after fabrication while retaining the channel shape enables high spatiotemporal reconfigurability. This reconfigurability is required in such key microfluidic functions that are difficult to achieve in existing "reconfigurable" or "integrated" microfluidic systems. We describe a method for the fabrication of a microfluidic channel with a deformable sidewall consisting of a laterally aligned array of the ends of rectangular pins. Actuating the pins in their longitudinal directions changes the pins' end positions, and thus, the shape of discretized channel sidewalls.Pin gaps can cause unwanted leakage or adhesion to adjacent pins caused by meniscus forces. To close the pin gaps, we have introduced hydrocarbon-fluoropolymer suspension-based gap filler accompanied by an elastomeric barrier. This reconfigurable microfluidic device can generate strong temporal in-channel displacement flow, or can stop the flow in any region of the channel. This feature will facilitate, on demand, the handling of cells, viscous liquids, gas bubbles, and non-fluids, even if their existence or behavior is unknown at the time of fabrication. PMID- 29708553 TI - An Alternative Approach to Study Primary Events in Neurodegeneration Using Ex Vivo Rat Brain Slices. AB - Despite numerous studies that attempt to develop reliable animal models which reflecting the primary processes underlying neurodegeneration, very few have been widely accepted. Here, we propose a new procedure adapted from the well-known ex vivo brain slice technique, which offers a closer in vivo-like scenario than in vitro preparations, for investigating the early events triggering cell degeneration, as observed in Alzheimer's disease (AD). This variation consists of simple and easily reproducible steps, which enable preservation of the anatomical cytoarchitecture of the selected brain region and its local functionality in a physiological milieu. Different anatomical areas can be obtained from the same brain, providing the opportunity to perform multiple experiments with the treatments in question in a site-, dose-, and time-dependent manner. Potential limitations which could affect the outcomes related to this methodology are related to the conservation of the tissue, i.e., the maintenance of its anatomical integrity during the slicing and incubation steps and the section thickness, which can influence the biochemical and immunohistochemical analysis. This approach can be employed for different purposes, such as exploring molecular mechanisms involved in physiological or pathological conditions, drug screening, or dose-response assays. Finally, this protocol could also reduce the number of animals employed in behavioral studies. The application reported here has been recently described and tested for the first time on ex vivo rat brain slices containing the basal forebrain (BF), which is one of the cerebral regions primarily affected in AD. Specifically, it has been demonstrated that the administration of a toxic peptide derived from the C-terminus of acetylcholinesterase (AChE) could prompt an AD-like profile, triggering, along the antero-posterior axis of the BF, a differential expression of proteins altered in AD, such as the alpha7 nicotinic receptor (alpha7-nAChR), phosphorylated Tau (p-Tau), and amyloid beta (Abeta). PMID- 29708557 TI - The mechanism and regularity of quenching the effect of bases on fluorophores: the base-quenched probe method. AB - The base-quenched probe method for detecting single nucleotide polymorphisms (SNPs) relies on real-time PCR and melting-curve analysis, which might require only one pair of primers and one probe. At present, it has been successfully applied to detect SNPs of multiple genes. However, the mechanism of the base quenched probe method remains unclear. Therefore, we investigated the possible mechanism of fluorescence quenching by DNA bases in aqueous solution using spectroscopic techniques. It showed that the possible mechanism might be photo induced electron transfer. We next analyzed electron transfer or transmission between DNA bases and fluorophores. The data suggested that in single-stranded DNA, the electrons of the fluorophore are transferred to the orbital of pyrimidine bases (thymine (T) and cytosine (C)), or that the electron orbitals of the fluorophore are occupied by electrons from purine bases (guanine (G) and adenine (A)), which lead to fluorescence quenching. In addition, the electrons of a fluorophore excited by light can be transmitted along double-stranded DNA, which gives rise to stronger fluorescence quenching. Furthermore, we demonstrated that the quenching efficiency of bases is in the order of G > C >= A >= T and the capability of electron transmission of base-pairs in double-stranded DNA is in the order of CG[combining low line] >= GC[combining low line] > TA[combining low line] >= AT[combining low line] (letters representing bases on the complementary strand of the probe are bold and underlined), and the most common commercial fluorophores including FAM, HEX, TET, JOE, and TAMRA could be influenced by bases and are in line with this mechanism and regularity. PMID- 29708560 TI - Chlorination-promoted skeletal transformation of IPR C76 discovered via trifluoromethylation under the formation of non-IPR C76(CF3)nFm. AB - High-temperature chlorination of an Isolated-Pentagon Rule (IPR) D2-C76 fullerene followed by high-temperature trifluoromethylation of non-IPR C76 chlorides with CF3I unexpectedly resulted in a series of non-IPR C76(CF3)nFm compounds. X-ray diffraction study with the use of synchrotron radiation revealed the mixed CF3/F structures of non-classical, non-IPR C76(CF3)14, C76(CF3)14F2, and C76(CF3)16F6. PMID- 29708561 TI - Thermodynamics of faceted palladium(-gold) nanoparticles supported on rutile titania nanorods studied using transmission electron microscopy. AB - Many physical properties of nanoparticles (NPs) are driven by their equilibrium shape (ES). Thus, knowing the kinetic and thermodynamic parameters that affect the particle morphology is key for the rational design of NPs with targeted properties. Here, we report on the thermodynamic ES of supported monometallic palladium and bimetallic palladium-gold (Pd-Au) single-crystalline truncated nano octahedra (TOs) studied using aberration-corrected transmission electron microscopy (TEM). Monometallic palladium and bimetallic Pd62Au38 and Pd43Au57 TOs were grown by pulsed laser deposition on rutile titania (r-TiO2) nanorods exposing mainly (110) facets. Particle structure and dimension were first obtained from aberration-corrected high resolution TEM (HRTEM) images acquired parallel to the metal-oxide interface. By fitting an extended Wulff-Kaishev rule to the HRTEM data of the truncated octahedral thermodynamic ES in the size range of 2 to 5 nm, we secondly determined the interface and excess line energies associated with the particle-oxide-vacuum triple phase junction in Pd and Pd43Au57 TOs in the epitaxial relationship Pd(-Au)(111)101||r-TiO2(110)[1-1-1] and in Pd62Au38 TOs in the epitaxial relationship Pd62Au38(100)101||r-TiO2(110)[1 10]. Our results show a decrease in particle adhesion to the oxide support upon alloying Pd with Au. The loss in adhesion is tentatively attributed to an increase of the lattice strain induced at the metal-oxide interface as gold atoms are added to the palladium lattice. PMID- 29708562 TI - Multicomponent metal-organic framework derivatives for optimizing the selective catalytic performance of styrene epoxidation reaction. AB - Multicomponent metal-organic framework (MOF) derivatives have attracted strong interest in energy and environmental fields. However, most of the papers focus on single MOF derivatives; reports on multicomponent MOF derivatives and their catalytic studies are relatively few. Here, we report an easy-to-operate strategy to obtain multicomponent MOF derivatives by treating multicomponent MOFs under a suitable gas atmosphere and at high temperature. We used ZIF-67 as a template to introduce Zn and successfully obtained multicomponent MOFs. After carbonization, the multicomponent MOF derivatives with Co and CoO nanoparticles exhibit higher conversion of styrene (~99%), higher selectivity (~70%) and better stability compared to MOFs and single component MOF derivatives. PMID- 29708563 TI - Negative thermal expansion in molecular materials. AB - Negative thermal expansion (NTE), whereby lattices contract upon heating, is of considerable interest for its wide applications in many fields. Molecular materials have been widely investigated as catalysts, sensors, etc., which usually endure temperature vibration. NTE can become a substantial means for controlling the coefficients of thermal expansion. Molecular materials possess plentiful structures and can be easily decorated, making them ideal platforms for thermal expansion modification. In this feature article, we provide an overview of the recent developments in utilizing NTE in molecular materials and summarize some mechanisms leading to NTE. The discussion of NTE in molecular materials concerns many factors, including transverse vibration, geometric flexibility, host-guest interactions, spin crossover, molecular packing rearrangement and molecular conformational changes. PMID- 29708564 TI - Argentate(i) and (iii) complexes as intermediates in silver-mediated cross coupling reactions. AB - Despite the potential of silver to mediate synthetically valuable cross-coupling reactions, the operating mechanisms have remained unknown. Here, we use a combination of rapid-injection NMR spectroscopy, electrospray-ionization mass spectrometry, and quantum chemical calculations to demonstrate that these transformations involve argentate(i) and (iii) complexes as key intermediates. PMID- 29708565 TI - The interaction of the excited states of safranine-O with low generation carboxyl terminated PAMAM dendrimers in an aqueous medium. AB - The interaction of the singlet and triplet excited states of the synthetic dye safranine-O with carboxyl-terminated poly(amidoamine) (PAMAM) dendrimers was investigated in a buffer solution at pH 8. Low half-generation PAMAM dendrimers (G -0.5; G +0.5: G 1.5) were employed. The UV-vis absorption spectrum of the dye presents only a very small red shift in the presence of dendrimers. Fluorescence quenching was detected and it was interpreted by a static mechanism in terms of the association of the dye with the dendrimer. Laser flash photolysis experiments were carried out and transient absorption spectra of the triplet and radicals were obtained. The triplet state is quenched by the dendrimers with rate constants well below the diffusional limit. The quenching process was characterized as an electron transfer process and the quantum yield of radicals was estimated. It was found that radicals are formed with a high efficiency in the triplet quenching reaction. PMID- 29708566 TI - Clinical Performance of Ultra-Short Anatomic Cementless Versus Fourth-Generation Cemented Femoral Stems for Hip Replacement in Octogenarians. AB - The aim of this study was to determine how ultra-short anatomic cementless vs cemented femoral stems affect the survival of primary total hip arthroplasties in octogenarians. Specifically, the authors investigated whether ultra-short anatomic cementless and cemented femoral components would have similar (1) functional results, (2) radiographic results, (3) revision and survival rates, and (4) complication rates in octogenarians. The authors evaluated 93 consecutive octogenarians (98 hips) in the ultra-short stem group (mean age, 86.5+/-5.3 years) and 78 consecutive octogenarians (92 hips) in the cemented stem group (mean age, 85.7+/-5.8 years). The average follow-up was 8.1 years (range, 5-12 years) in the ultra-short anatomic cementless stem group and 7.8 years (range, 5 11 years) in the cemented stem group. Mean preoperative (39 vs 37 points) and postoperative (81 vs 83 points) Harris hip scores were similar in the 2 groups (P=.131 and .128, respectively). The incidence of thigh pain was 0% in both groups. At final follow-up, mean Western Ontario and McMaster Universities Osteoarthritis Index scores (18 vs 14 points) and University of California, Los Angeles activity scores (4.3 vs 4.5 points) were similar in the 2 groups. The revision rate was 3% (3 hips) in the ultra-short stem group and 3% (3 hips) in the cemented stem group. Survivorship of the femoral stem was 97.3% at 8.1 years in the ultra-short stem group and 97.9% at 7.8 years in the cemented stem group (P=.136). Ultra-short anatomic cementless and cemented stems obtained rigid fixation in octogenarians. However, the incidence of undisplaced periprosthetic calcar fracture intraoperatively was significantly higher (P=.003) in the cemented stem group. [Orthopedics. 2018; 41(4):e470-e478.]. PMID- 29708567 TI - Relationship of Blood Metal Ion Levels and Leukocyte Profiles in Patients With Articular Surface Replacement Metal-on-Metal Hip Replacement. AB - The purpose of this study was to compare blood leukocyte profiles and metal ion concentrations between hip resurfacing arthroplasty (articular surface replacement) patients with and without revision. A total of 25 articular surface replacement patients were recruited (10 with stable implants and 15 undergoing revision). Blood concentrations of chromium (Cr) and cobalt (Co) were measured. Flow cytometry was used to quantify the subpopulations of leukocytes, including CD14+ monocytes, CD16+ monocytes, CD3+ T-lymphocytes, CD19+ B-lymphocytes, CD4+ helper T-cells, and CD45+RA memory vs naive T-cells. Patients undergoing revision had higher blood Co (mean, 10.85 ug/L) and Cr (mean, 3.19 ug/L) levels than patients with stable implants (mean Co, 3.06 ug/L; mean Cr, 1.07 ug/L) (P<.05). The number of CD4+ helper T-cells was higher in patients with stable implants (mean, 842+/-311 cells/uL) than in patients undergoing revision (mean, 591+/-208 cells/uL) (P<.05). There was a significant association between total metal ion levels (Co+Cr) and the number of CD14+ monocytes (P=.045) and inflammatory CD16+ monocytes (P=.046). The authors observed that the increase in blood metal ions was associated with an increase in CD16+ monocytes. They believe that continued analysis of blood leukocyte profiles may be helpful in defining differences among failed articular surface replacement, stable articular surface replacement, and failed metal-on-polyethylene implants. [Orthopedics. 2018; 41(3):e424-e431.]. PMID- 29708568 TI - Preoperative Vitamin D Deficiency Is Associated With Higher Postoperative Complication Rates in Total Knee Arthroplasty. AB - The purpose of this study was to determine the relative incidence of postoperative complications in 25-hydroxyvitamin D (25D)-deficient and sufficient patients undergoing total knee arthroplasty (TKA). Patients who were either serum 25D deficient (25D <20 ng/mL) or 25D sufficient (25D >=20 ng/mL) 90 days prior to primary TKA from 2007 to 2016 were identified using the Humana administrative claims registry. The incidence of postoperative medical and surgical complications was determined by querying for relevant International Classification of Diseases, Ninth Revision and Current Procedural Terminology codes. Risk-adjusted odds ratios (ORs) were calculated using multivariate logistic regression with age, sex, and Charlson Comorbidity Index as covariates. In total, 868 of 6593 patients who underwent TKA from 2007 to 2016 were 25D deficient, corresponding to a 13.2% prevalence rate. On adjustment for age, sex, and Charlson Comorbidity Index, 25D-deficient patients had a higher incidence of postoperative stiffness requiring manipulation under anesthesia (OR, 1.69; 95% confidence interval [CI], 1.39-2.04; P<.001), surgical site infection requiring irrigation and debridement (OR, 1.76; 95% CI, 1.25-2.48; P=.001), and prosthesis explantation (OR, 2.97; 95% CI, 2.04-4.31; P<.001) at 1 year. Patients who were 25D deficient also had higher rates of postoperative deep venous thrombosis (OR, 1.80; 95% CI, 1.36-2.38; P<.001), myocardial infarction (OR, 2.11; 95% CI, 1.41 3.15; P<.001), and cerebrovascular accident (OR, 1.73; 95% CI, 1.17-2.57; P=.006). Thus, serum 25D levels below 20 ng/mL are associated with a higher incidence of postoperative complications and may be a perioperative modifiable risk factor in TKA. [Orthopedics. 2018; 41(4):e489-e495.]. PMID- 29708569 TI - Performance-Based Outcomes Following Lisfranc Injury Among Professional American Football and Rugby Athletes. AB - Professional National Football League (NFL) and rugby athletes have high rates of Lisfranc injuries. Although favorable return-to-play rates have been previously reported, a thorough assessment of postinjury performance is lacking. Professional NFL and rugby athletes who sustained a Lisfranc injury were identified using a well-established protocol confirmed by multiple sources of the public record. Return-to-play rate and time to return were determined for each athlete. League participation and game performance were collected 1 season prior to injury and up to 3 seasons after injury. Statistical analysis was performed, with P<=.05 being significant. A total of 47 athletes (NFL=35, rugby=12) with Lisfranc injuries were identified, having 23 ligamentous injuries and 24 fractures. Thirty-five (75%) were treated operatively. Among NFL players, 29 (83%) returned to play, taking 10.0+/-2.9 months to do so. Overall, NFL players started fewer games 2 and 3 seasons following surgery (P=.002 and .035, respectively) and showed a significant decline in performance 1 season after return compared with preinjury levels (21%; P=.05). Offensive players had a significantly greater decline in statistical performance compared with defensive counterparts (P=.02). Although professional NFL athletes return to play at a high rate (83%) following Lisfranc injury, their league participation and performance is significantly decreased on return. Ligamentous and bony injuries have similar prognoses; however, offensive players show greater declines in performance compared with defensive players. To best guide therapy, players, coaches, and team physicians should be aware of the impact of Lisfranc injuries on career performance and longevity. [Orthopedics. 2018; 41(4):e479-e482.]. PMID- 29708570 TI - Longer Operative Time Is Associated With Increased Adverse Events After Anterior Cervical Diskectomy and Fusion: 15-Minute Intervals Matter. AB - Little is known about the impact of operative time, as an independent and interval variable, on general health perioperative outcomes following anterior cervical diskectomy and fusion. Therefore, patients undergoing a 1-level anterior cervical diskectomy and fusion were identified in the American College of Surgeons National Surgical Quality Improvement Program. Operative time (as an interval variable) was tested for association with perioperative outcomes using a multivariate regression that was adjusted for differences in baseline characteristics. A total of 15,241 patients were included. Increased surgical duration was consistently correlated with a rise in any adverse event postoperatively, with each additional 15 minutes of operating time raising the risk for having any adverse event by an average of 10% (99.64% confidence interval, 3%-17%, P<.001). In fact, 15-minute increases in surgical duration were associated with incremental increases in the rates of venous thromboembolism, sepsis, unplanned intubation, extended length of hospital stay, and hospital readmission. Greater operative time, despite controlling for other patient variables, increases the risk for overall postoperative adverse events and multiple individual adverse outcomes. This increased risk may be attributed to anesthetic effects, physiologic stresses, and surgical site issues. Although it is difficult to fully isolate operative time as an independent variable because it may be closely related to the complexity of the surgical pathology being addressed, the current study suggests that surgeons should maximize operative efficiency as possible (potentially using strategies that have been shown to improve operative time in the 15-minute magnitude), without compromising the technical components of the procedure. [Orthopedics. 2018; 41(4):e483-e488.]. PMID- 29708571 TI - Reliability of the Anterior Humeral Line Index Compared With the Gartland Classification for Posteriorly Hinged Supracondylar Humerus Fractures. AB - The Gartland classification of pediatric supracondylar humerus (SCH) fractures is commonly used but inconsistently defined regarding type 1 and type 2 (posteriorly hinged) SCH fractures. This study examined the reliability of the anterior humeral line (AHL) index compared with the Gartland classification. Fifty consecutive SCH fractures on anteroposterior and lateral elbow radiographs in pediatric patients (age range, 18 months to 15 years) were classified by 11 observers (9 attendings and 2 residents) according to the Gartland classification (types 1, 2, and 3) and the AHL index (AHL0, AHL passes anterior to the capitellum; AHL1, anterior one-third capitellum; and AHL2, middle one-third capitellum), with recommendations for treatment (cast immobilization vs surgery). Five attendings repeated the evaluation 4 to 6 weeks later. Interobserver and intraobserver reliability were scored using kappa statistics. Interobserver agreement for AHL with AHL1 and AHL2 combined (AHL1/2) was substantial (kappa=0.68) and moderate (kappa=0.55) when differentiating between AHL1 and AHL2. Anterior humeral line intraobserver reliability was almost perfect (kappa=0.83). Overall interobserver agreement on Gartland fracture type was fair (kappa=0.36), with type 2 fractures having the lowest (kappa=0.27), and with substantial (kappa=0.71) intraobserver reliability. For treatment, the interobserver agreement was fair (kappa=0.39), with substantial intraobserver reliability (kappa=0.72). Observers agreed more when using the AHL index than when using the Gartland classification. Observers differed on the degree of extension in posteriorly hinged SCH fractures that requires closed reduction. The AHL index is a more consistent method than the Gartland classification in differentiating posteriorly hinged SCH fractures and may be useful in guiding treatment. [Orthopedics. 2018; 41(4):e502-e505.]. PMID- 29708572 TI - Relationship Between Foraminal Area and Degenerative Changes in the Lower Cervical Spine With Implications for C5 Nerve Root Palsy. AB - Preoperative foraminal stenosis at C4/5 is a predisposing risk factor for C5 nerve root palsy in elderly patients. However, the area of the C4/5 intervertebral foramen and its relationship to the extent of arthrosis and lower foraminal areas (C5/6 and C6/7) are unknown. The authors sought to compare the areas of the cervical intervertebral foramen at the C4/5, C5/6, and C6/7 levels, noting any differences across race or sex and the relationship between foraminal area and arthrosis grade. A total of 600 cervical foramina from an osseous collection were examined. One hundred specimens between the ages of 60 and 80 years were selected, 50 from each sex and race (white and African American). Foramina were photographed bilaterally at C4/5, C5/6, and C6/7. Vertical height and mid-sagittal width were digitally measured. The degree of arthrosis within each intervertebral foramen was graded by 2 of the authors independently using the Kellgren-Lawrence grading system. Average age of death for specimens was 69.3+/-5.9 years. The mean foraminal areas at C4/5 (P=.001) and C5/6 (P<.001) were significantly smaller than at C6/7. Whites had larger foraminal areas than African Americans at C4/5 (P=.05) and C6/7 (P=.01). Arthrosis grade was found to make a significant contribution to foraminal area at C4/5 (standardized beta= 0.267; P<.001), but not at C5/6 or C6/7. A higher grade of arthrosis was associated with a narrower intervertebral foramen at the C4/5 level in osseous specimens from elderly individuals. [Orthopedics. 2018; 41(4):e506-e510.]. PMID- 29708573 TI - Medial Compartment Decompression by Proximal Fibular Osteotomy: A Biomechanical Cadaver Study. AB - Medial compartment knee osteoarthritis is a painful and debilitating disease. A proximal fibular osteotomy is a novel, simple surgical technique that may reduce pain and improve function for patients with osteoarthritis. The purpose of this biomechanical cadaver study was to determine what effect proximal fibular osteotomy had on knee joint and ankle pressures and tibia strain. Ten matched pairs of cadaver legs were tested in compression to 1.1 times body weight comparing intact and with proximal fibular osteotomy at 0 degrees , 15 degrees , and 30 degrees of flexion. Sensors were inserted into the knee and ankle joint to measure pressure, force, and contact area. Strain was measured with a strain gage on the anterior medial tibia. In the medial compartment, the peak force, contact area, and pressure all decreased from intact to after fibular osteotomy, with significant differences at 15 degrees of flexion (P<.05). There were no significant differences in the lateral compartment for any measures. In the ankle joint, the peak force and pressure decreased from intact to after fibular osteotomy at all 3 flexion angles. There were no significant changes in strain in the tibia. Proximal fibular osteotomy decreases the pressure in the medial compartment of the knee, which may reduce knee pain and improve function in patients with medial compartment knee osteoarthritis. [Orthopedics. 2018; 41(4):e496-e501.]. PMID- 29708577 TI - For Geriatrics Health Care Professionals, #AGS18 Helps Trace Where We've Been, Where We're Going. PMID- 29708574 TI - Are Gerontological Nurses Ready for the Expression of Sexuality by Individuals With Dementia? PMID- 29708578 TI - Study of transected sciatic nerve repair by biodegradable membrane and betamethasone in adult albino wistar rats. AB - AIM: One of the major injuries of the nervous system is that of peripheral nerves. Although peripheral nerves show some capacity of regeneration after injury, the extent of regeneration is not remarkable. The present study aimed to evaluate the regeneration of the transected sciatic nerve by membrane and betamethasone in rats. MATERIAL AND METHODS: In this study twenty-eight adult male rats were divided into four equal groups including 1. Control group (Ctrl); 2. Betamethasone group (Beta); 3. Membrane group (Mem); 4. Membrane and Betamethasone group (Mem-Beta). Functional recovery was evaluated at 2, 4, 6 and 8 weeks post surgery. At 8 weeks after surgery, electromyographical (EMG) and histological assessments were performed. RESULTS: 8 weeks after surgery, sciatic functional index (SFI) and withdrawl reflex latency (WRL) reaction time were decreased significantly (p 0.05) in Mem+Beta group as compared to the control, beta and Mem groups respectively. In EMG test latency and amplitude of impulses improved in Mem+Beta group compared to other groups (p 0.05). Histological assessments performed at 8 weeks after surgery showed significant increase in the number of nerve fibers, diameter of nerve fibers and myelin thickness in Mem+Beta group as compared to the Ctrl, Beta and Mem groups (p 0.05). CONCLUSION: The results of the present study showed the positive effects of the chitosan membrane together with betamethasone on nerve regeneration of the transected sciatic nerve in a rat model. PMID- 29708579 TI - Evaluation of the Prognostic Importance of c-Myc and Bcl-2 Expressions and the Presence of Epstein-Barr Virus in Classical Hodgkin Lymphoma. AB - OBJECTIVE: Although classical Hodgkin lymphoma (cHL) has a relatively good prognosis, it also entails different treatment responses and involves patients who have different clinical courses. Our aim was to investigate c-Myc, Bcl-2 and EBV biomarkers in cHL and their relationship with the IPS score. MATERIAL AND METHOD: c-Myc and Bcl-2 immunohistochemical staining with EBER in situ hybridization (EBER-ISH) was applied to the paraffin sections of 94 cases diagnosed as cHL. These cases were classified into two groups as low and high clinical symptoms according to the International Prognostic Scores (IPS). RESULTS: Positive results were obtained in 83 (88.3%) cases with c-Myc and 39 (43.5%) cases with Bcl-2 while EBER-ISH was found positive in 42 (44.7%) cases. No difference was found between the groups of low/high IP scores with respect to the positive or negative results of EBER-ISH, Bcl-2 and c-Myc. When Bcl-2 and c Myc positive cases were grouped together and compared to the IP scores of the remaining cHL cases, again no difference was seen. Extranodal involvement and bone marrow involvement was observed in 25 (26.5%) and 9 (9.5%) cases, respectively. Similarly, no statistically significant differences was found between these groups according to their positivity with EBER-ISH, Bcl-2 and c Myc. CONCLUSION: We could not find any relationship between Bcl-2, c-Myc and EBER ISH positivity and the low/high IPS groups in cHL. New studies with larger series are needed in which more precise cut-off values are used and clinically and biologically heterogeneous groups of cHL patients are determined more clearly. PMID- 29708580 TI - Allergic contact dermatitis and diabetes medical devices: 2 clinical cases. PMID- 29708581 TI - A case of allergic contact dermatitis caused by goalkeeper gloves. PMID- 29708582 TI - Amyloidosis associated with skin popping: a case report and review of literature. PMID- 29708583 TI - Micro- and macroevolutionary adaptation through repeated loss of a complete metabolic pathway. AB - There is growing evidence for the convergent evolution of physically linked gene clusters encoding chemical defense pathways. Metabolic clusters are proposed to evolve because they ensure co-inheritance of all required genes where the defense is favored, and prevent inheritance of toxic partial pathways where it is not. This hypothesis rests on the assumption that clusters evolve in species where selection favors intraspecific polymorphism for the defense; however, they have not been examined in polymorphic species. We examined metabolic cluster evolution in relation to an adaptive polymorphism for cyanogenic glucoside (CNglc) production in clover. Using 163 accessions, we performed CNglc assays, BAC sequencing, Southern hybridizations and molecular evolutionary analyses. We find that the CNglc pathway forms a 138-kb cluster in white clover, and that the adaptive polymorphism occurs through presence/absence of the complete cluster. Component genes are orthologous to those in the distantly related legume Lotus japonicus. These findings provide empirical support for the co-inheritance hypothesis, and they indicate that adaptive CNglc variation in white clover evolves through recurrent deletions of the entire pathway. They further indicate that the shared ancestor of many important legume crops was likely cyanogenic and that this defense was lost repeatedly over the last 50 Myr. PMID- 29708584 TI - Whole genome sequencing reveals DICER1 as a candidate predisposing gene in familial Hodgkin lymphoma. PMID- 29708585 TI - When Treatment Establishes Diagnosis: A Case Report of Posttraumatic Chronic Paroxysmal Hemicrania. PMID- 29708586 TI - Oxygen supplementation for critically ill patients-A protocol for a systematic review. AB - BACKGROUND: In critically ill patients, hypoxaemia is a common clinical manifestation of inadequate gas exchange in the lungs. Supplemental oxygen is therefore given to all critically ill patients. This can result in hyperoxaemia, and some observational studies have identified harms with hyperoxia. The objective of this systematic review is to critically assess the evidence of randomised clinical trials on the effects of higher versus lower inspiratory oxygen fractions or targets of arterial oxygenation in critically ill adult patients. METHODS: We will search for randomised clinical trials in major international databases. Two authors will independently screen and select references for inclusion using Covidence, extract data and assess the methodological quality of the included randomised clinical trials using the Cochrane risk of bias tool. Any disagreement will be resolved by consensus. We will analyse the extracted data using Review Manager and Trial Sequential Analysis. To assess the quality of the evidence, we will create a 'Summary of Findings' table containing our primary and secondary outcomes using the GRADE assessment. DISCUSSION: Supplemental oxygen administration is widely recommended in international guidelines despite lack of robust evidence of its effectiveness. To our knowledge, no systematic review of randomised clinical trials has investigated the effects of oxygen supplementation in critically ill patients. This systematic review will provide reliable evidence to better inform future trialists and decision-makers on clinical practice on supplemental oxygen administration in critically ill patients. PMID- 29708587 TI - Use of radiological indicators to predict difficult laryngoscopy in patients with cervical spondylosis. PMID- 29708588 TI - Anti-arthritic properties of crude extract from Chenopodium ambrosioides L. leaves. AB - OBJECTIVES: To evaluate the effect of hydroalcoholic crude extract (HCE) from Chenopodium ambrosioides leaves on the development of type II collagen-induced arthritis (CIA) and on pro-inflammatory cytokine balance. METHODS: Collagen induced arthritis was induced in DBA1/J mice. On the 21st day, the mice were treated orally with HCE or methotrexate, daily. Six weeks after beginning the treatment, the following measures were determined: lymphoid organs cell numbers, percentage of blood cells, IL-6, IFN-gamma, TNF-alpha and IL-17 serum concentrations, activity of hepatic and kidney glutathione S-transferase, hepatic 7-ethoxyresorufin-O-deethylase activity, bone density and histopathology. KEY FINDINGS: Treatment of CIA mice with HCE 5 mg/kg (HCE5) reduced the percentage of neutrophils and macrophages and the number of bone marrow cells and increased the lymphocyte numbers and the inguinal lymph node cellularity. This treatment inhibited the serum concentration of IL-6 and TNF-alpha, which may be related to the preservation of bone density and to the slight thickening of periarticular tissues, with minimal fibrosis and fibroblast proliferation in the joints. The CIA group presented advanced articular erosion and synovial hyperplasia. Phytochemical analysis showed mainly flavonols. CONCLUSIONS: HCE5 presented anti arthritic potential and reduced IL-6 and TNF-alpha, which participate directly in the development and maintenance of the inflammatory process in rheumatoid arthritis. PMID- 29708590 TI - Standardised assessment of competence in Focused Assessment with Sonography for Trauma. AB - PURPOSE: The aim of this study was to develop and gather validity evidence for a standardised test of competence in Focused Assessment with Sonography for Trauma (FAST) and to define the appropriate cut-off point in simulation-based learning of the FAST protocol. METHODS: A 20-item simulation-based test for assessing competence in FAST was created. The test was administered to thirteen novices and twelve radiologists experienced in abdominal ultrasound diagnostics. The Contrasting Groups' method was used to establish a credible passing score. RESULTS: The internal consistency was high (Cronbach's alpha = 0.90) and the test had good discriminatory ability (P < .001). The mean score was 16.9 (95% CI: 15.5 18.3) in the experienced group and 8.0 (95% CI: 5.8-10.2) in the novice group, corresponding to 85% and 40% of the total score, respectively. A pass/fail standard of 14 points was established using the Contrasting Groups' method. CONCLUSIONS: The FAST simulation-based test provided valid assessment of competence in FAST. The FAST test could be used to guide training and ensure basic competence of physicians using FAST. PMID- 29708589 TI - Impaired modulation of postjunctional alpha1 - but not alpha2 -adrenergic vasoconstriction in contracting forearm muscle of postmenopausal women. AB - KEY POINTS: Contraction-mediated blunting of postjunctional alpha-adrenergic vasoconstriction (functional sympatholysis) is attenuated in skeletal muscle of ageing males, brought on by altered postjunctional alpha1 - and alpha2 adrenergic receptor sensitivity. The extent to which postjunctional alpha adrenergic vasoconstriction occurs in the forearms at rest and during exercise in postmenopausal women remains unknown. The novel findings indicate that contraction-mediated blunting of alpha1 - (via intra-arterial infusion of phenylephrine) but not alpha2 -adrenergic (via intra-arterial infusion of dexmedetomidine) vasoconstriction was attenuated in postmenopausal women compared to young women. Additional important findings revealed that postjunctional alpha adrenergic vasoconstrictor responsiveness at rest does not appear to be affected by age in women. Collectively, these results contribute to our understanding of local neurovascular control at rest and during exercise with age in women. ABSTRACT: Contraction-mediated blunting of postjunctional alpha-adrenergic vasoconstriction (functional sympatholysis) is attenuated in older males; however, direct confirmation of this effect remains unknown in postmenopausal women (PMW). The present study examined whether PMW exhibit augmented postjunctional alpha-adrenergic receptor vasoconstriction at rest and during forearm exercise compared to young women (YW). Eight YW (24 +/- 1 years) and eight PMW (65 +/- 1 years) completed a series of randomized experimental trials: (1) at rest, (2) under high flow (adenosine infusion) conditions and (3) during 6 min of forearm exercise at relative (20% of maximum) and absolute (7 kg) intensities. Phenylephrine (alpha1 -agonist) or dexmedetomidine (alpha2 -agonist) was administered during the last 3 min of each trial to elicit alpha-adrenergic vasoconstriction. Forearm vascular conductance (FVC) was calculated from blood flow and blood pressure. Vasoconstrictor responsiveness was identified as the change in FVC (%) during alpha-adrenergic agonist infusions from baseline (resting trial) or from steady-state conditions (high flow and exercise trials). During resting and high flow trials, the %FVC during alpha1 - and alpha2 -agonist stimulation was similar between YW and PMW. During exercise, alpha1 -mediated vasoconstriction was blunted in YW vs. PMW at relative (-6 +/- 2% vs. -15 +/- 3%) and absolute (-4 +/- 2% vs. -14 +/- 5%) workloads, such that blood flow and FVC were lower in PMW (P < 0.05 for all). Conversely, alpha2 -mediated vasoconstriction was similar between YW and PMW at relative (-22 +/- 3% vs. -22 +/- 4%; P > 0.05) and absolute (-19 +/- 3% vs. -18 +/- 4%; P > 0.05) workloads. Collectively, these findings demonstrate that despite similar alpha-adrenergic vasoconstrictor responsiveness at rest, PMW have a decreased ability to attenuate alpha1 -adrenergic vasoconstriction in contracting skeletal muscle. PMID- 29708591 TI - Alcohol, smoking, and risk of Her2-overexpressing and triple-negative breast cancer relative to estrogen receptor-positive breast cancer. AB - Epidemiological evidence is limited on how alcohol consumption and smoking are associated with risk of different subtypes of breast cancer, such as triple negative (TN) and human epidermal growth factor receptor 2-overexpressing (H2E) breast cancers, which may have different etiologies from more common luminal (estrogen receptor [ER+]) breast cancers. In this population-based case-case study, we evaluated the association between alcohol, smoking, and risk of H2E and TN breast cancer, compared with ER+ breast cancers, among women aged 20-69 years. Using polytomous regression, associations between alcohol consumption, smoking, and breast cancer risk were evaluated in 909 ER+, 1,290 TN, and 489 H2E breast cancer patients, with ER+ breast cancer patients as the reference group. Current alcohol consumption at diagnosis was associated with a lower risk of H2E breast cancer (odds ratio = 0.74, 95% confidence interval: 0.58-0.92) relative to ER+ cancers. No difference in association was observed by menopausal status. No association between alcohol consumption and TN breast cancer relative to ER+ breast cancer was observed. Women who smoked did not have an altered risk of TN or H2E breast cancer, relative to ER+ cancer. Our results suggest that alcohol is associated with lower risk of H2E breast cancer relative to ER+ breast cancer. This study adds to the body of epidemiologic evidence that breast cancer etiology differs by breast cancer subtype. PMID- 29708594 TI - Refractory feline sporotrichosis treated with itraconazole combined with potassium iodide. PMID- 29708593 TI - Downregulating aspen xylan biosynthetic GT43 genes in developing wood stimulates growth via reprograming of the transcriptome. AB - Xylan is one of the main compounds determining wood properties in hardwood species. The xylan backbone is thought to be synthesized by a synthase complex comprising two members of the GT43 family. We downregulated all GT43 genes in hybrid aspen (Populus tremula * tremuloides) to understand their involvement in xylan biosynthesis. All three clades of the GT43 family were targeted for downregulation using RNA interference individually or in different combinations, either constitutively or specifically in developing wood. Simultaneous downregulation in developing wood of the B (IRX9) and C (IRX14) clades resulted in reduced xylan Xyl content relative to reducing end sequence, supporting their role in xylan backbone biosynthesis. This was accompanied by a higher lignocellulose saccharification efficiency. Unexpectedly, GT43 suppression in developing wood led to an overall growth stimulation, xylem cell wall thinning and a shift in cellulose orientation. Transcriptome profiling of these transgenic lines indicated that cell cycling was stimulated and secondary wall biosynthesis was repressed. We suggest that the reduced xylan elongation is sensed by the cell wall integrity surveying mechanism in developing wood. Our results show that wood specific suppression of xylan-biosynthetic GT43 genes activates signaling responses, leading to increased growth and improved lignocellulose saccharification. PMID- 29708595 TI - Allergic contact dermatitis caused by Irganox 1076 used as antioxidant in non woven fabric. PMID- 29708592 TI - Meta-analysis comparing upfront surgery with neoadjuvant treatment in patients with resectable or borderline resectable pancreatic cancer. AB - BACKGROUND: Studies comparing upfront surgery with neoadjuvant treatment in pancreatic cancer may report only patients who underwent resection and so survival will be skewed. The aim of this study was to report survival by intention to treat in a comparison of upfront surgery versus neoadjuvant treatment in resectable or borderline resectable pancreatic cancer. METHODS: MEDLINE, Embase and the Cochrane Library were searched for studies reporting median overall survival by intention to treat in patients with resectable or borderline resectable pancreatic cancer treated with or without neoadjuvant treatment. Secondary outcomes included overall and R0 resection rate, pathological lymph node rate, reasons for unresectability and toxicity of neoadjuvant treatment. RESULTS: In total, 38 studies were included with 3484 patients, of whom 1738 (49.9 per cent) had neoadjuvant treatment. The weighted median overall survival by intention to treat was 18.8 months for neoadjuvant treatment and 14.8 months for upfront surgery; the difference was larger among patients whose tumours were resected (26.1 versus 15.0 months respectively). The overall resection rate was lower with neoadjuvant treatment than with upfront surgery (66.0 versus 81.3 per cent; P < 0.001), but the R0 rate was higher (86.8 (95 per cent c.i. 84.6 to 88.7) versus 66.9 (64.2 to 69.6) per cent; P < 0.001). Reported by intention to treat, the R0 rates were 58.0 and 54.9 per cent respectively (P = 0.088). The pathological lymph node rate was 43.8 per cent after neoadjuvant therapy and 64.8 per cent in the upfront surgery group (P < 0.001). Toxicity of at least grade III was reported in up to 64 per cent of the patients. CONCLUSION: Neoadjuvant treatment appears to improve overall survival by intention to treat, despite lower overall resection rates for resectable or borderline resectable pancreatic cancer. PROSPERO registration number: CRD42016049374. PMID- 29708597 TI - Pour Guess: The Effect of Glass Shape and an Ice Substitute on Alcohol Pouring and Estimation. AB - BACKGROUND: Research suggests that people are poor at estimating the amount of alcohol they have served themselves. Glass shape, the presence of ice, and alcohol consumption may influence the amount of alcohol people pour and estimate they have poured. The aim of these studies was to examine whether these factors would affect pouring behavior, in the laboratory and in real-world environments. METHODS: Across 4 studies, 1 laboratory study and 3 conducted during public engagement events, we tested the effect of glass shape (straight sided highball and tumbler glasses) and, using an ice substitute (whiskey stones), the effect of ice on pouring and estimating a self-defined typical drink. We also assessed the association between alcohol consumption and pouring accuracy. RESULTS: Overall, participants consistently overestimated their typical serving of alcohol, and poured more than 1 U.K. unit when pouring into an empty glass. Findings demonstrate no credible effect of glass shape or ice substitute on alcohol unit estimation or the amount of a typical serving. However, while alcohol consumption was not related to accuracy, the presence of an ice substitute improved accuracy when pouring a single U.K. unit. CONCLUSIONS: Given that participants overestimated the amount of alcohol in their typical alcoholic drink, self-report measures of alcohol consumption may be overstating the amount of alcohol individuals consume. Additionally, the presence of ice may improve accuracy when pouring standard servings (U.K. units) of alcohol. Therefore, self-report measures may be improved if the presence of ice is considered. PMID- 29708598 TI - Learning and Socializing Preferences in Hong Kong Chinese Children. AB - The impact of social group information on the learning and socializing preferences of Hong Kong Chinese children were examined. Specifically, the degree to which variability in racial out-group exposure affects children's use of race to make decisions about unfamiliar individuals (Chinese, White, Southeast Asian) was investigated. Participants (N = 212; Mage = 60.51 months) chose functions for novel objects after informants demonstrated their use; indicated with which peer group member to socialize; and were measured on racial group recognition, preference, and identification. Overall, children preferred in-group members, though out-group exposure and the relative social status of out-groups mattered as well. At a young age, children's specific experiences with different races influence how they learn and befriend others across racial group lines. PMID- 29708599 TI - In vivo tumor gene delivery using novel peptideticles: pH-responsive and ligand targeted core-shell nanoassembly. AB - Modulating cancer causing genes with nucleic acid based-molecules as cutting-edge approaches need efficient delivery systems to succeed in clinic. Herein, we report design and fabrication of a novel tissue penetrating peptideticle with charge-structure switching in tumor microenvironment for an effective gene delivery. The comparative in vitro studies indicate that peptideticles identify and bind to tumor endothelial cells and efficiently penetrate into multicellular tumor spheroid. In addition, negatively charged peptideticle at pH 7.4, prevent unwanted interaction while its sharp charge-structure switching at pH 6.2-6.9 (e.g. in tumor tissue) facilitates malignant cells penetration. More importantly, upon systemic administration into tumor bearing mice, peptideticles effectively localized in tumor tissue and delivered luciferase gene with a 200-fold higher efficiency compared to their non-pH-responsive counterparts. In conclusion, this study presents a robust nanoassembly of safe materials for high efficient tumor gene delivery. PMID- 29708596 TI - Knockout of the Gsta4 Gene in Male Mice Leads to an Altered Pattern of Hepatic Protein Carbonylation and Enhanced Inflammation Following Chronic Consumption of an Ethanol Diet. AB - BACKGROUND: Glutathione S-transferase A4-4 (GSTA4) is a key enzyme for removal of toxic lipid peroxidation products such as 4-hydroxynonenal (4-HNE). In this study, we examined the potential role of GSTA4 on protein carbonylation and progression of alcoholic liver disease by examining the development of liver injury in male wild-type (WT) SV/J mice and SV/J mice lacking functional GSTA4 (GSTA4-/- mice). METHODS: Adult male WT and GSTA4-/- mice were fed chow (N = 10 to 12) or high-fat Lieber-DeCarli liquid diets containing up to 28% calories as ethanol (EtOH) (N = 18 to 20) for 116 days. At the end of the study, half of the EtOH-fed mice were acutely challenged with an EtOH binge (3 g/kg given intragastrically) 12 hours before sacrifice. Carbonylation of liver proteins was assessed by immunohistochemical staining for 4-HNE adduction and by comprehensive liquid chromatography-tandem mass spectrometry (LC-MS/MS) of purified carbonylated proteins. RESULTS: Chronic EtOH intake significantly increased hepatic 4-HNE adduction and protein carbonylation, including carbonylation of ribosomal proteins. EtOH intake also resulted in steatosis and increased serum alanine aminotransferase. Hepatic infiltration with B cells, T cells, and neutrophils and mRNA expression of pro-inflammatory cytokines tumor necrosis factor (TNF)alpha and interferon (IFN)gamma was modest in WT mice. However, an EtOH binge increased hepatic necrosis, hepatic cell proliferation, and expression of TNFalpha mRNA (p < 0.05). EtOH treatment of GSTA4-/- mice increased B-cell infiltration and increased mRNA expression of TNFalpha and IFNgamma and of matrix remodeling markers MMP9, MMP13, and Col1A1 (p < 0.05). GSTA4-/- mice exhibited panlobular rather than periportal distribution of 4-HNE-adducted proteins and increased overall 4-HNE staining after EtOH binge. Comprehensive LC-MS of carbonylated proteins identified 1,022 proteins of which 189 were unique to the GSTA4-/- group. CONCLUSIONS: These data suggest long-term adaptation to EtOH in WT mice does not occur in GSTA4-/- mice. Products of lipid peroxidation appear to play a role in inflammatory responses due to EtOH. And EtOH effects on B-cell infiltration and autoimmune responses may be secondary to formation of carbonyl adducts. PMID- 29708602 TI - Lapse in Antibiotics Leads to Sepsis. PMID- 29708600 TI - Evaluation of the chemical and nutritional characteristics of almonds (Prunus dulcis (Mill). D.A. Webb) as influenced by harvest time and cultivar. AB - BACKGROUND: Several workers have studied the effect of harvest time on chemical and nutritional composition of almonds, but the results are partly conflicting, probably due to differences in the cultivars considered and to different agronomic and climatic conditions in the growing areas. In this paper, the influence of harvest time and cultivar on the chemical and nutritional composition of almonds (Prunus dulcis (Mill). D.A. Webb) were evaluated. Ten cultivars were considered, grown in the same orchard and subjected to the same agronomical regime. Almonds were collected at two different harvest times: (i) when the fruits were unripe, but already edible, and showed green and moist hull; and (ii) when the fruits were ripe, with dry brown hull. The analyses of proximate composition, fatty acid profile, total phenolic compounds, and antioxidant activity were carried out. RESULTS: Lipid content increased (P < 0.001) during ripening, while both protein and carbohydrate content decreased (P < 0.01). Fatty acid composition showed a not univocal behavior during ripening and was highly influenced by cultivar. Total phenolic compounds and antioxidant activity varied among cultivars but increased during ripening with the exception of cv Marcona. The 'Genco' and 'Francoli' cultivars were found to be phenolic rich. CONCLUSION: Harvest time and cultivar significantly influenced the chemical and nutritional composition of almonds. Genotype strongly influenced fatty acid composition and total phenolic compounds. The changes of bioactive compounds and antioxidant activity suggest that the synthesis of antioxidants also occurs in the last stage of ripening. Unripe almonds, a valuable niche product, showed interesting nutritional value. (c) 2018 Society of Chemical Industry. PMID- 29708601 TI - Cis-directed cleavage and nonstoichiometric abundances of 21-nucleotide reproductive phased small interfering RNAs in grasses. AB - Post-transcriptional gene silencing in plants results from independent activities of diverse small RNA types. In anthers of grasses, hundreds of loci yield noncoding RNAs that are processed into 21- and 24-nucleotide (nt) phased small interfering RNAs (phasiRNAs); these are triggered by miR2118 and miR2275. We characterized these 'reproductive phasiRNAs' from rice (Oryza sativa) panicles and anthers across seven developmental stages. Our computational analysis identified characteristics of the 21-nt reproductive phasiRNAs that impact their biogenesis, stability, and potential functions. We demonstrate that 21-nt reproductive phasiRNAs can function in cis to target their own precursors. We observed evidence of this cis regulatory activity in both rice and maize (Zea mays). We validated this activity with evidence of cleavage and a resulting shift in the pattern of phasiRNA production. We characterize biases in phasiRNA biogenesis, demonstrating that the Pol II-derived 'top' strand phasiRNAs are consistently higher in abundance than the bottom strand. The first phasiRNA from each precursor overlaps the miR2118 target site, and this impacts phasiRNA accumulation or stability, evident in the weak accumulation of this phasiRNA position. Additional influences on this first phasiRNA duplex include the sequence composition and length, and we show that these factors impact Argonaute loading. PMID- 29708605 TI - Surgical Site Infection Prevention in 2018 and Beyond. PMID- 29708603 TI - Evidence appraisal of Sandini M, Pinotti E, Persico I, Picone D, Bellelli G, Gianotti L. Systematic review and meta-analysis of frailty as a predictor of morbidity and mortality after major abdominal surgery.BJS Open. 2017;1(5):128 137. PMID- 29708606 TI - Back to Basics: Packaging Systems: 1.5 www.aornjournal.org/content/cme. PMID- 29708607 TI - Conducting a Surgical Site Infection Prevention Tracer. AB - Surgical site infections (SSIs) are the most common health care-associated infections in patients. Approximately half of SSIs are preventable when using evidence-based strategies; however, deviations from evidence-based practice can occur over time. Infection preventionists and perioperative staff members can help prevent these deviations by observing staff member practices using tracer methodology. Tracer methodology uses clinical information to follow patient care, treatment, or services provided throughout the care delivery system. The goal of tracer methodology for SSI prevention is to validate that organizational processes are promoting safer patient care. Using tracers, perioperative and infection prevention staff members can develop strategies to eliminate deviations from evidence-based practice, thereby helping to prevent SSIs and improve patient outcomes. PMID- 29708610 TI - Guideline Quick View: High-Level Disinfection. PMID- 29708609 TI - The Key to Safety: Inspire, Innovate, and Influence. PMID- 29708611 TI - Did You Know? PMID- 29708612 TI - An Incision Closure Bundle for Colorectal Surgery: 2.0 www.aornjournal.org/content/cme. PMID- 29708613 TI - Severe blood shortages reinforce the importance of reducing wastage. PMID- 29708614 TI - Designing a Culture of Safety in Perioperative Services. PMID- 29708616 TI - Kidney transplantation. PMID- 29708615 TI - Success of a Colorectal Surgical Site Infection Prevention Bundle in a Multihospital System. AB - Surgical site infections, readmissions, and extended hospital stays are risks for patients undergoing colon surgeries. These procedures are often urgent, and patients may have multiple comorbidities. Preoperative and postoperative steps to reduce the number of complications provide substantial benefits clinically, economically, and psychologically. We used a multidisciplinary, collaborative approach to identify best practices when developing and implementing a standardized approach to the management of patients undergoing elective colon surgery. Interventions included nutrition supplements and preoperative and postoperative protocols. Our management project showed a 74.6% reduction in readmissions, a 22.73% reduction in length of stay, an 85% reduction in colon surgical site infections measured by incidence (84.5% reduction) and standard infection ratio (54.55% reduction), and 95% compliance with the use of both order sets during an 18-month period. Applying standardized order sets for assessing and addressing patient comorbidities before colorectal surgery can result in a substantial and sustainable reduction in complications. PMID- 29708617 TI - Educational Opportunities. PMID- 29708619 TI - A Nurse's Accountability. PMID- 29708618 TI - Clinical Issues-May 2018: 1.2 www.aornjournal.org/content/cme. PMID- 29708620 TI - Implementation of a Wisconsin Division of Public Health Surgical Site Infection Prevention Champion Initiative. AB - Approximately 900 surgical site infections (SSIs) were reported to the Wisconsin Division of Public Health annually from 2013 to 2015, representing the most prevalent reported health care-associated infection in the state. Personnel at the Wisconsin Division of Public Health launched an SSI prevention initiative in May 2015 using a surgical care champion to provide surgical team peer-to-peer guidance through voluntary, nonregulatory, fee-exempt onsite visits that included presentations regarding the evidence-based surgical care bundle, tours of the OR and central processing areas, and one-on-one discussions with surgeons. The surgical care champion visited 10 facilities from August to December 2015, and at those facilities, SSIs decreased from 83 in 2015 to 47 in 2016 and the overall SSI standardized infection ratio decreased by 45% from 1.61 to 0.88 (P = .002), suggesting a statewide SSI prevention champion model can help lead to improved patient outcomes. PMID- 29708621 TI - Approaches to minimize blood product wastage. PMID- 29708622 TI - Evaluation of tacrolimus-related CYP3A5 genotyping in China: Results from the First External Quality Assessment Exercise. AB - BACKGROUND: Tacrolimus is the most widely used immunosuppressant in solid organ transplant patients. The cytochrome P450 3A5 (CYP3A5) has been proved to be associated with tacrolimus dose requirement. Molecular detection for CYP3A5 genotyping is demanded for the optimization of treatments of tacrolimus. METHODS: To achieve the consistency and accuracy of the testing results, the Chinese National Center for Clinical Laboratories (NCCL) organized a national external quality assessment(EQA) program to evaluate the performance of laboratories providing CYP3A5 genotyping. Ten validated DNA samples covering the common genetic polymorphisms of CYP3A5 were delivered to 33 voluntary laboratories, and their detecting results and clinical written reports were evaluated. RESULTS: Thirty-three datasets were received. The corresponding analytical sensitivity was 95.9% (285/297 challenges; 95% confidence interval: 93.0%-97.9%), and the analytical specificity was 95.3% (346/363; 95% confidence interval: 92.6%-97.2%). Thirty of the participating laboratories correctly identified the CYP3A5 allele status for all EQA samples. Three laboratories made genotyping errors, and 2 of them failed to detect any of the homozygotes such as *1/*1 and *3/*3. Twenty eight CYP3A5*3 tests reports were submitted, but many reports showed a shortage of essential information. No reports fulfilled all the consensus recommendations for pharmacogenetic test result reporting. CONCLUSION: The EQA program highlighted the necessity for an improvement in the accuracy of genotyping for some of the laboratories and a greater education on the reporting of CYP3A5 genotyping results. PMID- 29708623 TI - Eating disorders symptoms in sexual minority women: A systematic review. AB - BACKGROUND: Although the literature consistently shows increased levels of psychological distress in the gay population, less evidence-and with contrasting findings-is available with regard to lesbian women. The aim of the present study is to review the literature in the eating disorders (EDs) field in order to provide further data on the frequency of EDs symptoms in sexual minority women. METHOD: A systematic review of the studies identified by electronic database search (PubMed, Ovid, ScienceDirect, and Google Scholar) up to August 2017. RESULTS: Fourty-five studies were found, conducted on 372,256 women. Only 7 studies investigated patients with lifetime diagnosis of ED. As for the symptomatology of EDs, 39 studies were found, which presented huge differences in the scales used for the assessment (e.g., Eating Disorders Inventory and Eating Attitudes Test-26). CONCLUSIONS: A higher number of diagnoses of EDs were found in sexual minority women, with a symptomatology characterized by higher occurrence of binge eating and purging, as well as lower body dissatisfaction and drive for thinness, compared with heterosexual peers. PMID- 29708624 TI - Latent Profiles of Discrimination and Socialization Predicting Ethnic Identity and Well-Being Among Asian American Adolescents. AB - Ethnic identity is rooted in sociocultural processes, but little is known about how social interactions predict its longitudinal changes. Using data from 154 Asian American adolescents, latent profile analysis derived four typologies based on unfair treatment (i.e., discrimination, model minority stereotyping) and ethnic socialization (i.e., cultural socialization, preparation for bias, promotion of mistrust): Low Cultural Salience, High Cultural Salience with Marginalization, Culturally Prepared with Low Mistrust, and High Mistrust/Discrimination. Few gender or generational differences in profile membership were found. Positive outcomes were linked to adolescents attuned to both positive and negative experiences, Culturally Prepared with Low Mistrust, who reported increases in ethnic belonging and decreases in negative emotions. The implications for identity formation and adjustment are discussed. PMID- 29708625 TI - Role of the Wilms' tumor suppressor gene Wt1 in pancreatic development. AB - The Wilms tumor suppressor gene (Wt1) encodes a transcription factor involved in the development of a number of organs, but the role played by Wt1 in pancreatic development is unknown. The pancreas contains a population of pancreatic stellate cells (PSC) very important for pancreatic physiology. We described elsewhere that hepatic stellate cells originate from the WT1-expressing liver mesothelium. Thus, we checked if the origin of PSCs was similar. WT1 expression is restricted to the pancreatic mesothelium. Between embryonic day (E) 10.5 and E15.5, this mesothelium gives rise to mesenchymal cells that contribute to a major part of the PSC and other cell types including endothelial cells. Most WT1 systemic mutants show abnormal localization of the dorsal pancreas within the mesentery and intestinal malrotation by E14.0. Embryos with conditional deletion of WT1 between E9.5 and E12.5 showed normal dorsal pancreatic bud and intestine, but the number of acini in the ventral bud was reduced approximately 30% by E16.5. Proliferation of acinar cells was reduced in WT1 systemic mutants, but pancreatic differentiation was not impaired. Thus, mesothelial-derived cells constitute an important subpopulation of pancreatic mesodermal cells. WT1 expression is not essential for pancreas development, although it influences intestinal rotation and correct localization of the dorsal pancreas within the mesogastrium. Developmental Dynamics 247:924-933, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29708626 TI - Radiation chemists look at damage in redox proteins induced by X-rays. AB - The three-dimensional structure of proteins, especially as determined by X-ray crystallography, is critical to the understanding of their function. However, the X-ray exposure may lead to damage that must be recognized and understood to interpret the crystallographic results. This is especially relevant for proteins with transition metal ions that can be oxidized or reduced. The detailed study of proteins in aqueous solution by the technique of pulse radiolysis has provided a wealth of information on the production and fate of radicals that are the same as those produced by X-ray exposure. The results reviewed here illustrate how the products of the interaction of radiation with water or with solutes added to the crystallization medium, and with proteins themselves, are formed, and about their fate. Of particular focus is how electrons are produced and transferred through the polypeptide matrix to redox centers such as metal ions or to specific amino acid residues, for example, disulfides, and how the hydroxyl radicals formed may be converted to reducing equivalents or scavenged. PMID- 29708628 TI - Analysis of the immune response in infants hospitalized with viral bronchiolitis shows different Th1/Th2 profiles associated with respiratory syncytial virus and human rhinovirus. PMID- 29708627 TI - Effect of humic acids on intestinal viscosity, leaky gut and ammonia excretion in a 24 hr feed restriction model to induce intestinal permeability in broiler chickens. AB - The purpose of this study was to evaluate the effect of humic acids (HA) on intestinal viscosity, leaky gut and ammonia excretion in a 24 hr feed restriction (FR) model to induce intestinal permeability in chickens. One-day-old male Cobb Vantress broilers were randomly allocated to one of two groups (n = 25 chickens), with or without 0.2% of isolated HA from worm-compost, and placed in brooder batteries. Chicks had ad libitum access to water and feed for 14 days. Intestinal permeability was induced by 24 hr FR starting at 14 days. At 15 days of age, chickens in both groups were given an appropriate dose of fluorescein isothiocyanate dextran (FITC-d) by oral gavage. Intestine and liver samples were also collected to evaluate viscosity and bacterial translocation (BT), respectively. An increase (p < .05) in intestinal viscosity was observed in the experimental group consuming 0.2% of HA and was confirmed in a published in vitro digestion model that simulates the chemical and physical conditions of the crop, proventriculus and intestine of chickens. Furthermore, the treated group also showed a significant reduction in FITC-d, liver BT and ammonia in the manure. These results suggest that HA have a positive impact in intestinal integrity in chickens. PMID- 29708630 TI - A self-controlled study of intralesional injection of diprospan combined with topical timolol cream for treatment of thick superficial infantile hemangiomas. AB - Topical application of timolol cream is effective and convenient for treating superficial infantile hemangiomas. Intralesional injection of corticosteroids, such as diprospan, is useful for the treatment of superficia infantile hemangiomas without systemic side effects. We conducted a self-controlled study to investigate whether a combination of intralesional injection of diprospan with topical timolol 0.5% cream would be more efficient than timolol cream alone in thick superficial infantile hemangiomas. Thirty-eight patients with 39 thick superficial infantile hemangiomas were recruited. Each lesion was randomly divided into two equal parts: one part was treated with topical timolol 0.5% cream (timolol cream group), while the other part was treated with injection of diprospan combined with topical timolol 0.5% cream (combined treatment group). Infants were followed every 4 weeks to determine whether injections should be continued, and timolol cream was applied four times daily for 5 months. During 5 months of treatment, three specialist physicians were invited to evaluate the therapeutic effects. The combined treatment group showed better lesion involution than did the timolol cream group regarding lesion thickness and color of lesions. The combination of intralesional injection of diprospan with topical timolol 0.5% cream is a suitable and safe strategy for thick superficial infantile hemangiomas. PMID- 29708631 TI - Comparative proteomic analysis of hypothalamus tissue from Huoyan geese between pre-laying period and laying period using an iTRAQ-based approach. AB - The hypothalamus plays a central role in controlling poultry endocrine and reproductive activities. So far there is limited information focused on the proteome profiles of the hypothalamus from geese during different stages of the egg-laying cycle. In order to identify proteins regulating the egg-laying process of Huoyan geese, we investigated the proteome profiles of the hypothalamus from Huoyan geese during the laying period and pre-laying period by applying an isobaric tags for relative and absolute quantitation (iTRAQ)-based proteomic technology. A total number of 3,337 were identified and quantified, of which 18 were significantly up-regulated and 16 were significantly down-regulated. These differentially expressed proteins were subjected to bioinformatics analyses based on the Gene Ontology annotation and Kyoto Encyclopedia of Genes and Genomes pathway. Some of these were revealed to be involved in hormone and neurotransmitter secretion, exocytosis, calcium ion transport and synaptic transmission. Subsequently, excitatory amino acid transporter 2, complexin-1 and inositol 1,4,5-trisphosphate receptor, type 3 were confirmed at the messenger RNA level using quantitative real-time RT-PCR. Then, the abundance change of these proteins was verified further using Western blotting analysis. These data may aid in elucidating the molecular mechanism of higher laying performance in Huoyan geese. PMID- 29708632 TI - A concise guide to clinical reasoning. AB - What constitutes clinical reasoning is a disputed subject regarding the processes underlying accurate diagnosis, the importance of patient-specific versus population-based data, and the relation between virtue and expertise in clinical practice. In this paper, I present a model of clinical reasoning that identifies and integrates the processes of diagnosis, prognosis, and therapeutic decision making. The model is based on the generalized empirical method of Bernard Lonergan, which approaches inquiry with equal attention to the subject who investigates and the object under investigation. After identifying the structured operations of knowing and doing and relating these to a self-correcting cycle of learning, I correlate levels of inquiry regarding what-is-going-on and what-to-do to the practical and theoretical elements of clinical reasoning. I conclude that this model provides a methodical way to study questions regarding the operations of clinical reasoning as well as what constitute significant clinical data, clinical expertise, and virtuous health care practice. PMID- 29708633 TI - Utility of the immature granulocyte percentage for diagnosing acute appendicitis among clinically suspected appendicitis in adult. AB - BACKGROUND: Acute appendicitis is the most common cause of abdominal surgical emergencies that present at the emergency department (ED). Although early phase of acute appendicitis cannot induce systemic inflammatory responses, it may induce proliferation immature granulocyte before leukocytosis is occurred. Based on this, we hypothesized that IG% may be beneficial for detecting appendicitis, in addition to classic inflammatory markers including the WBC count, a left shift in neutrophils, and CRP, at no additional cost. METHODS: A retrospective observational study was conducted in a tertiary-care, university-affiliated hospital emergency department in adults (>18 years old) with suspected appendicitis from January 1, 2015 to December 31, 2016. The diagnostic performance of IG% and other inflammatory markers, namely white blood cell (WBC) count, proportion of neutrophils, and C-reactive protein (CRP), for acute appendicitis was evaluated. RESULTS: Of 403 patients, 204 (50.6%) were diagnosed with acute appendicitis and 45 (22.0%) had complicated appendicitis. All inflammatory markers, including WBC count, proportion of neutrophils, IG%, and CRP, were statistically different between the appendicitis and nonappendicitis group (P < .01). However, IG% was not clinically useful because the median IG% was the same (0.3 vs 0.3) between the appendicitis and nonappendicitis group. Moreover, the area under the curve for IG% was smaller than for other inflammatory markers (0.57, 0.51-0.63, P < .02). CONCLUSION: The diagnostic ability of IG% for appendicitis is insufficient, and it brings no additional benefit over other inflammatory markers. PMID- 29708634 TI - A case report of Dermanyssus gallinae infestation in three cats. AB - BACKGROUND: Dermanyssus gallinae is a major threat for the poultry industry; these mites also feed on the blood of many other birds, small mammals and potentially humans. HYPOTHESIS/OBJECTIVES: Three cats with dermatitis attributed to D. gallinae infestation. ANIMALS: Two 40-day-old kittens, living in a rural area, and one 7-year-old female indoor cat, were presented with a pruritic skin condition. METHODS: Mite specimens were collected from the cats and examined by light and scanning electron microscopy. Cytological and histological examinations of the skin lesions were performed. RESULTS: A diagnosis of D. gallinae infestation was made after identification of the mites. Histological findings were compatible with eosinophilic dermatitis. Clinical improvement was noted two weeks after treatment. CONCLUSIONS AND CLINICAL IMPORTANCE: The two kittens showed chronic blood loss which reflects the ability of D. gallinae mites to switch host. For the indoor cat, mites were presumed to be carried by birds regularly present on the balcony of the apartment. This demonstrates that mite infestation is possible even in urban areas, through contact with birds or their abandoned nests. When birds are not present, cats or other small mammals as well as humans, can be infested. PMID- 29708629 TI - Defining the molecular mechanisms of HIV-1 Tat secretion: PtdIns(4,5)P2 at the epicenter. AB - The human immunodeficiency virus type 1 (HIV-1) transactivator of transcription (Tat) protein functions both intracellularly and extracellularly. Intracellularly, the main function is to enhance transcription of the viral promoter. However, this process only requires a small amount of intracellular Tat. The majority of Tat is secreted through an unconventional mechanism by binding to phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2 ), a phospholipid in the inner leaflet of the plasma membrane that is required for secretion. This interaction is mediated by the basic domain of Tat (residues 48-57) and a conserved tryptophan (residue 11). After binding to PtdIns(4,5)P2 , Tat secretion diverges into multiple pathways, which we categorized as oligomerization-mediated pore formation, spontaneous translocation and incorporation into exosomes. Extracellular Tat has been shown to be neurotoxic and toxic to other cells of the central nervous system (CNS) and periphery, able to recruit immune cells to the CNS and cerebrospinal fluid, and alter the gene expression and morphology of uninfected cells. The effects of extracellular Tat have been examined in HIV-1 associated neurocognitive disorders (HAND); however, only a small number of studies have focused on the mechanisms underlying Tat secretion. In this review, the molecular mechanisms of Tat secretion will be examined in a variety of biologically relevant cell types. PMID- 29708635 TI - Shifting metabolic priorities among key protistan taxa within and below the euphotic zone. AB - A metatranscriptome study targeting the protistan community was conducted off the coast of Southern California, at the San Pedro Ocean Time-series station at the surface, 150 m (oxycline), and 890 m to link putative metabolic patterns to distinct protistan lineages. Comparison of relative transcript abundances revealed depth-related shifts in the nutritional modes of key taxonomic groups. Eukaryotic gene expression in the sunlit surface environment was dominated by phototrophs, such as diatoms and chlorophytes, and high abundances of transcripts associated with synthesis pathways (e.g., photosynthesis, carbon fixation, fatty acid synthesis). Sub-euphotic depths (150 and 890 m) exhibited strong contributions from dinoflagellates and ciliates, and were characterized by transcripts relating to digestion or intracellular nutrient recycling (e.g., breakdown of fatty acids and V-type ATPases). These transcriptional patterns underlie the distinct nutritional modes of ecologically important protistan lineages that drive marine food webs, and provide a framework to investigate trophic dynamics across diverse protistan communities. PMID- 29708636 TI - Securing a Supramolecular Architecture by Tying a Stopper Knot. AB - We report on a rotaxane-like architecture secured by the in situ tying of an overhand knot in the tris(2,6-pyridyldicarboxamide) region of the axle through complexation with a lanthanide ion (Lu3+ ). The increase in steric bulk caused by the knotting locks a crown ether onto the thread. Removal of the lutetium ion unties the knot, and when the axle binding site for the ring is deactivated, the macrocycle spontaneously dethreads. When the binding interaction is switched on again, the crown ether rethreads over the 10 nm length of the untangled strand. The overhand knot can be retied, relocking the threaded structure, by once again adding lutetium ions. PMID- 29708637 TI - Consistency of cybernetic variables with gene expression profiles: A more rigorous test. AB - Diauxic growth of Escherichia coli is driven by a host of internal, complex regulatory actions. In this classic scenario of cellular control, the cell employs a rational algorithm to modulate its metabolism in a competitive fashion. Cybernetic models of metabolism, whose development now spans three decades, were first formulated to describe regulation of cells in complex, multi-substrate environments. They modeled this scenario using the hypothesis that the formation of the enzymatic machinery is regulated to maximize a return on investment. While this assumption is made on the basis of logical arguments rooted in evolutionary principles, little effort has been taken to validate if enzymes are truly synthesized in the same fashion that is predicted by cybernetic variables. This work revisits the original cybernetic models describing diauxic growth and compares their predictions of enzyme synthesis control with time series gene expression data in microarray and qRT-PCR formats. Three separate studies are made for two different strains of E. coli. The first is for the growth of E. coli BW25113 on a mixture of glucose and acetate, whose gene expression changes are metered by microarray. Another is also for the sequential consumption of glucose and acetate but involves strain MG1655 and employs qRT-PCR. The final is for E. coli MG1655 on glucose and lactose. By demonstrating how cybernetic variables for induced enzyme synthesis mimic the behavior of transcriptional data, a strong argument for using cybernetic models is made. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:858-867, 2018. PMID- 29708638 TI - Defining the mechanistic binding of viral particles to a multi-modal anion exchange resin. AB - A multi-tiered approach to determine the binding mechanism of viral clearance utilizing a multi-modal anion exchange resin was applied to a panel of four viral species that are typically used in validating viral clearance studies (i.e., X MuLV, MVM, REO3, and PrV). First, virus spiked buffer-only experiments were conducted to evaluate the virus's affinity for single mode and multi-modal chromatography resins under different buffer conditions in a chromatography column setting. From these results we hypothesize that the mechanisms of binding of the viruses involve binding to both the hydrophobic and anionic functional groups. This mechanistic view agreed with the general surface characteristics of the different virus species in terms of isoelectric point and relative hydrophobicity values. This hypothesized mechanistic binding was then tested with commercially relevant, in-process materials, in which competitive binding occurred between the load components (e.g., viruses, target product, and impurities) and the resin. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:1019-1026, 2018. PMID- 29708639 TI - The distribution of active iron-cycling bacteria in marine and freshwater sediments is decoupled from geochemical gradients. AB - Microaerophilic, phototrophic and nitrate-reducing Fe(II)-oxidizers co-exist in coastal marine and littoral freshwater sediments. However, the in situ abundance, distribution and diversity of metabolically active Fe(II)-oxidizers remained largely unexplored. Here, we characterized the microbial community composition at the oxic-anoxic interface of littoral freshwater (Lake Constance, Germany) and coastal marine sediments (Kalo Vig and Norsminde Fjord, Denmark) using DNA-/RNA based next-generation 16S rRNA (gene) amplicon sequencing. All three physiological groups of neutrophilic Fe(II)-oxidizing bacteria were found to be active in marine and freshwater sediments, revealing up to 0.2% anoxygenic photoferrotrophs (e.g., Rhodopseudomonas, Rhodobacter, Chlorobium), 0.1% microaerophilic Fe(II)-oxidizers (e.g., Mariprofundus, Hyphomonas, Gallionella) and 0.3% nitrate-reducing Fe(II)-oxidizers (e.g., Thiobacillus, Pseudomonas, Denitromonas, Hoeflea). Active Fe(III)-reducing bacteria (e.g., Shewanella, Geobacter) were most abundant (up to 2.8%) in marine sediments and co-occurred with cable bacteria (up to 4.5%). Geochemical profiles of Fe(III), Fe(II), O2 , light, nitrate and total organic carbon revealed a redox stratification of the sediments and explained 75%-85% of the vertical distribution of microbial taxa, while active Fe-cycling bacteria were found to be decoupled from geochemical gradients. We suggest that metabolic flexibility, microniches in the sediments, or interrelationships with cable bacteria might explain the distribution patterns of active Fe-cycling bacteria. PMID- 29708641 TI - A Comparative Reengineering Study of cpADH5 through Iterative and Simultaneous Multisite Saturation Mutagenesis. AB - Positions identified in directed evolution campaigns or by (semi)rational design can be recombined iteratively or simultaneously. Iterative recombination has yielded many success stories and is beneficially used if screening capabilities are limited (four iterative SSMs generate 20*4=80 different enzyme variants). Simultaneous site saturation mutagenesis offers significantly higher diversity (204 =160 000 variants) and enables greater improvements to be found, especially if the selected positions are in close proximity to each other (cooperative effects). Here we report a first comprehensive comparison of iterative and simultaneous saturation of four residues in Candida parapsilosis alcohol dehydrogenase 5 (cpADH5) with methyl 3-hydroxyhexanoate as substrate. Screening of 7200 clones from 33 site saturation mutagenesis libraries (exploring 17 recombination paths) yielded the cpADH5 W286A variant, with a 82-fold improved initial activity toward methyl 3-hydroxyhexanoate. Screening 3500 clones from a single OmniChange library with four positions (C57, W116, L119, and W286; 1.8 % of the generated sequence space) yielded the cpADH5 C57V/W286S variant, with a 108-fold improvement in initial activity toward methyl 3-hydroxyhexanoate. A 1.8 % coverage of the sequence space of the simultaneous multisite saturation library was, in comparison to the investigated 17 recombination paths, sufficient to identify a cpADH5 variant with improved activity. PMID- 29708640 TI - Augmented reality for the surgeon: Systematic review. AB - INTRODUCTION: Since the introduction of wearable head-up displays, there has been much interest in the surgical community adapting this technology into routine surgical practice. METHODS: We used the keywords augmented reality OR wearable device OR head-up display AND surgery using PubMed, EBSCO, IEEE and SCOPUS databases. After exclusions, 74 published articles that evaluated the utility of wearable head-up displays in surgical settings were included in our review. RESULTS: Across all studies, the most common use of head-up displays was in cases of live streaming from surgical microscopes, navigation, monitoring of vital signs, and display of preoperative images. The most commonly used head-up display was Google Glass. Head-up displays enhanced surgeons' operating experience; common disadvantages include limited battery life, display size and discomfort. CONCLUSIONS: Due to ergonomic issues with dual-screen devices, augmented reality devices with the capacity to overlay images onto the surgical field will be key features of next-generation surgical head-up displays. PMID- 29708642 TI - Enhancing the chemiluminescence intensity of a KMnO4 formaldehyde system for estimating the total phenolic content in honey samples using a novel nanodroplet mixing approach in a microfluidics platform. AB - A novel mixing approach was utilized with a highly sensitive chemiluminescence (CL) method to determine the total phenolic content (TPC) in honey samples using an acidic potassium permanganate-formaldehyde system. The mixing approach was based on exploiting the mixing efficiency of nanodroplets generated in a microfluidic platform. Careful optimization of the instrument setup and various experimental conditions were employed to obtain excellent sensitivity. The mixing efficiency of the droplets was compared with the CL signal intensity obtained using the common serpentine chip design, with both approaches using at a total flow rate of 15 MUl min-1 ; the results showed that the nanodroplets provided 600% higher CL signal intensity at this low flow rate. Using the optimum conditions, calibration equations, limits of detection (LOD) and limits of quantification (LOQ) for gallic acid (GA), caffeic acid (CA), kaempferol (KAM), quercetin (QRC) and catechin (CAT) were obtained. The LOD ranged from 6.2 ppb for CA to 11.0 ppb for QRC. Finally, the method was applied for the determination of TPC in several local and commercial honey samples. PMID- 29708643 TI - Efficient and easily scalable protein folding strong anion exchange chromatography for renaturation and simultaneous purification of recombinant human asparaginase from E. coli. AB - Recombinant proteins are revolutionizing present day therapeutics. They are generally expressed as insoluble inclusion bodies in the E. coli and mis-folding, loss of protein, and high cost of down streaming are the hurdles in their recovery. For the first time, we are reporting the refolding with simultaneous purification of rhASP in E. coli using a single step utilizing protein folding strong anion exchange chromatography (PF-SAX). The purification method is also standardized for optimal concentration of solution additives, pH, and mobile phase composition. The results showed purification of rhASP with anion exchange chromatography was effective. Phosphate buffer and slightly alkaline pH produced significant recovery yields and purity profiles. The effect of solution additives such as arginine, glycerol, TMAO, sorbitol, dextran, glutamate, and fructose on rhASP renaturation is also investigated. Significant results were achieved using arginine-TMAO combination in terms of purity, recovery yield and specific activity of 99%, 78%, and 210 IU/mg, respectively. The work concludes that PF-SAX refolding method is superior to other conventional methods and it can be applied to large scale purification of rhASP produced in E. coli. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:1036-1044, 2018. PMID- 29708644 TI - Influence of the Hfq and Crc global regulators on the control of iron homeostasis in Pseudomonas putida. AB - Metabolically versatile bacteria use catabolite repression control to select their preferred carbon sources, thus optimizing carbon metabolism. In pseudomonads, this occurs through the combined action of the proteins Hfq and Crc, which form stable tripartite complexes at target mRNAs, inhibiting their translation. The activity of Hfq/Crc is antagonised by small RNAs of the CrcZ family, the amounts of which vary according to carbon availability. The present work examines the role of Pseudomonas putida Hfq protein under conditions of low level catabolite repression, in which Crc protein would have a minor role since it is sequestered by CrcZ/CrcY. The results suggest that, under these conditions, Hfq remains operative and plays an important role in iron homeostasis. In this scenario, Crc appears to participate indirectly by helping CrcZ/CrcY to control the amount of free Hfq in the cell. Iron homeostasis in pseudomonads relies on regulatory elements such as the Fur protein, the PrrF1-F2 sRNAs, and several extracytoplasmic sigma factors. Our results show that the absence of Hfq is paralleled by a reduction in PrrF1-F2 small RNAs. Hfq thus provides a regulatory link between iron and carbon metabolism, coordinating the iron supply to meet the needs of the enzymes operational under particular nutritional regimes. PMID- 29708645 TI - Keystone taxa predict compositional change in microbial communities. AB - The influence of biotic interactions on microbial community assembly is intensely debated. We hypothesized that keystone taxa, which influence community assembly through strong biotic interactions, are important for regulating microbial community composition. While highly connected microbes have been identified, evidence that these taxa act as keystones is lacking, because keystone status requires influence on whole-community dynamics. We address this gap, showing that small subsets of highly connected keystone taxa (generally 1%-5% of richness) can be optimal predictors of whole-community compositional change. In three long-term data sets, greater connectivity due to the presence of keystone taxa corresponded to lower compositional turnover. We further hypothesized that the influence of keystone taxa would be diminished when environmental disturbance was a strong driver of compositional change. We used two case studies of reference and disturbed communities to investigate how biotic and abiotic forces interact to shape community composition. Most of the same taxa were present in both the reference and disturbed communities, but keystone taxa had much greater explanatory power in the reference communities. Our results suggest that greater biotic connectivity arising from the presence of keystone taxa is stabilizing to community composition, and that keystone taxa can be good indicators of pending community shifts. PMID- 29708646 TI - The path of electron transfer to nitrogenase in a phototrophic alpha proteobacterium. AB - The phototrophic alpha-proteobacterium, Rhodopseudomonas palustris, is a model for studies of regulatory and physiological parameters that control the activity of nitrogenase. This enzyme produces the energy-rich compound H2 , in addition to converting N2 gas to NH3 . Nitrogenase is an ATP-requiring enzyme that uses large amounts of reducing power, but the electron transfer pathway to nitrogenase in R. palustris was incompletely known. Here, we show that the ferredoxin, Fer1, is the primary but not sole electron carrier protein encoded by R. palustris that serves as an electron donor to nitrogenase. A flavodoxin, FldA, is also an important electron donor, especially under iron limitation. We present a model where the electron bifurcating complex, FixABCX, can reduce both ferredoxin and flavodoxin to transfer electrons to nitrogenase, and we present bioinformatic evidence that FixABCX and Fer1 form a conserved electron transfer pathway to nitrogenase in nitrogen-fixing proteobacteria. These results may be useful in the design of strategies to reroute electrons generated during metabolism of organic compounds to nitrogenase to achieve maximal activity. PMID- 29708647 TI - Biosynthesis of abscisic acid in fungi: identification of a sesquiterpene cyclase as the key enzyme in Botrytis cinerea. AB - While abscisic acid (ABA) is known as a hormone produced by plants through the carotenoid pathway, a small number of phytopathogenic fungi are also able to produce this sesquiterpene but they use a distinct pathway that starts with the cyclization of farnesyl diphosphate (FPP) into 2Z,4E-alpha-ionylideneethane which is then subjected to several oxidation steps. To identify the sesquiterpene cyclase (STC) responsible for the biosynthesis of ABA in fungi, we conducted a genomic approach in Botrytis cinerea. The genome of the ABA-overproducing strain ATCC58025 was fully sequenced and five STC-coding genes were identified. Among them, Bcstc5 exhibits an expression profile concomitant with ABA production. Gene inactivation, complementation and chemical analysis demonstrated that BcStc5/BcAba5 is the key enzyme responsible for the key step of ABA biosynthesis in fungi. Unlike what is observed for most of the fungal secondary metabolism genes, the key enzyme-coding gene Bcstc5/Bcaba5 is not clustered with the other biosynthetic genes, i.e., Bcaba1 to Bcaba4 that are responsible for the oxidative transformation of 2Z,4E-alpha-ionylideneethane. Finally, our study revealed that the presence of the Bcaba genes among Botrytis species is rare and that the majority of them do not possess the ability to produce ABA. PMID- 29708648 TI - Enzymatic synthesis of ethyl esters from waste oil using mixtures of lipases in a plug-flow packed-bed continuous reactor. AB - This work describes the continuous synthesis of ethyl esters via enzymatic catalysis on a packed-bed continuous reactor, using mixtures of immobilized lipases (combi-lipases) of Candida antarctica (CALB), Thermomyces lanuginosus (TLL), and Rhizomucor miehei (RML). The influence of the addition of glass beads to the reactor bed, evaluation of the use of different solvents, and flow rate on reaction conditions was studied. All experiments were conducted using the best combination of lipases according to the fatty acid composition of the waste oil (combi-lipase composition: 40% of TLL, 35% of CALB, and 25% of RML) and soybean oil (combi-lipase composition: 22.5% of TLL, 50% of CALB, and 27.5% of RML). The best general reaction conditions were found to be using tert-butanol as solvent, and the flow rate of 0.08 mL min-1 . The combi-lipase reactors operating at steady state for over 30 days (720 h), kept conversion yields of ~50%, with average productivity of 1.94 gethyl estersgsubstrate-1 h-1 , regardless of the type of oil in use. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:952-959, 2018. PMID- 29708649 TI - Natural killer cell function predicts severe infection in kidney transplant recipients. AB - The aim of this study was to determine if natural killer cell number (CD3- /CD16+/- /CD56+/- ) and cytotoxic killing function predicts severity and frequency of infection in kidney transplant recipients. A cohort of 168 kidney transplant recipients with stable graft function underwent assessment of natural killer cell number and functional killing capacity immediately prior to entry into this prospective study. Participants were followed for 2 years for development of severe infection, defined as hospitalization for infection. Area under receiver operating characteristic (AUROC) curves were used to evaluate the accuracy of natural killer cell number and function for predicting severe infection. Adjusted odds ratios were determined by logistic regression. Fifty nine kidney transplant recipients (35%) developed severe infection and 7 (4%) died. Natural killer cell function was a better predictor of severe infection than natural killer cell number: AUROC 0.84 and 0.75, respectively (P = .018). Logistic regression demonstrated that after adjustment for age, transplant function, transplant duration, mycophenolate use, and increasing natural killer function (odds ratio [OR] 0.82, 95% confidence interval [CI] 0.74-0.90; P < .0001) but not natural killer number (OR 0.96, 95% CI 0.93-1.00; P = .051) remained significantly associated with a reduced likelihood of severe infection. Natural killer cell function predicts severe infection in kidney transplant recipients. PMID- 29708651 TI - Identification and characterization of the biotechnological potential of a wild strain of Paraconiothyrium sp. AB - The isolation and characterization of fungal strains from poorly described taxa allows undercover attributes of their basic biology useful for biotechnology. Here, a wild fungal strain (CMU-196) from recently described Paraconiothyrium genus was analyzed. CMU-196 was identified as Paraconiothyrium brasiliense by phylogenetic analysis of the rDNA internal transcribed spacer region (ITS). CMU 196 metabolized 57 out of 95 substrates of the Biolog FF microplates. Efficient assimilation of dextrins and glycogen indicates that CMU-196 is a good producer of amylolytic enzymes. It showed a remarkably assimilation of alpha-d-lactose, substrate described as inducer of cellulolytic activity but poorly assimilated by several fungi. Metabolically active mycelium of the strain decolorized broth supplemented with direct blue 71, Chicago sky blue and remazol brilliant blue R dyes. The former two dyes were also well removed from broth by mycelium inactivated by autoclaving. Both mycelia had low efficiency for removing fuchsin acid from broth and for decolorizing wastewater from the paper industry. CMU-196 strain showed extracellular laccase activity when potato dextrose broth was supplemented with Cu+2 , reaching a maximum activity of 46.8 (+/-0.33) U L-1 . Studied strain antagonized phytopathogenic Colletotrichum spp. fungi and Phytophthora spp. oomycetes in vitro, but is less effective towards Fusarium spp. fungi. CMU-196 antagonism includes overgrowing the mycelia of phytopathogens and growth inhibition, probably by hydrosoluble extracellular metabolites. The biotechnological potential of strain CMU-196 here described warrants further studies to have a more detailed knowledge of the mechanisms associated with its metabolic versatility, capacity for environmental detoxification, extracellular laccase production, and antagonism against phytopathogens. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:846-857, 2018. PMID- 29708650 TI - Efficacy and safety of dulaglutide monotherapy compared with glimepiride in East Asian patients with type 2 diabetes in a multicentre, double-blind, randomized, parallel-arm, active comparator, phase III trial. AB - AIMS: To compare the efficacy and safety of once-weekly glucagon-like peptide-1 receptor agonist dulaglutide 1.5 and 0.75 mg with glimepiride in East-Asian patients with type 2 diabetes (T2D). MATERIALS AND METHODS: In this phase III, multinational, multicentre, double-blind, randomized, parallel-arm, 26-week study, patients with inadequate glycaemic control were randomized 1:1:1 to once weekly dulaglutide 1.5 or 0.75 mg or daily glimepiride (1-3 mg/d). The primary endpoint was assessment of the non-inferiority of dulaglutide (1.5 mg), as measured by change in glycated haemoglobin (HbA1c), compared with glimepiride using a 0.4% non-inferiority margin. RESULTS: A total of 737 patients were randomized (dulaglutide 1.5 mg, n = 244; dulaglutide 0.75 mg, n = 248; glimepiride, n = 245). At week 26, both doses of dulaglutide were non-inferior and also superior to glimepiride for HbA1c reduction from baseline with a least squares mean difference of -6.34 mmol/mol (95% confidence interval [CI] -8.31, 4.26) or -0.58% (95% CI -0.76, -0.39) for dulaglutide 1.5 mg and -3.50 mmol/mol (95% CI -5.47, -1.42) or -0.32% (95% CI -0.50, -0.13) for dulaglutide 0.75 mg (P < .001). A greater proportion of patients in the dulaglutide 1.5 mg group achieved the HbA1c target of <53 mmol/mol (<7.0%) compared with the glimepiride group (74.1% vs 57.4%; P < .001). The mean body weight decreased (P < .005) and total hypoglycaemia rates were lower (P < .001) in the dulaglutide groups compared with the glimepiride group. The most common drug-related adverse events in both dulaglutide groups (>=5% of patients) included diarrhoea, nausea, increased lipase, decreased appetite, abdominal distension and vomiting. CONCLUSIONS: Dulaglutide (both doses) demonstrated superior glycaemic control vs glimepiride, with a favourable tolerability and safety profile in East-Asian patients with T2D. PMID- 29708652 TI - Information overload; a response to "Turn down for what? Patient outcomes associated with declining increased infectious risk kidneys". PMID- 29708653 TI - Characterization of a novel HLA-C allele, HLA-C*04:288, in an Italian patient. AB - The novel HLA-C*04:288 differs from HLA-C*04:01:01:06 by a single nucleotide substitution in exon 2. PMID- 29708654 TI - Adult periodontitis treated with a new device for subgingival lavage-a randomized controlled clinical trial using a split-mouth design. AB - OBJECTIVES: To evaluate in patients with untreated adult periodontitis, the effect of treatment with a novel pocket irrigator/evacuator device (IED) compared to conventional subgingival debridement (CPT), both provided during the initial phase of active periodontal therapy. METHODS: This study was an examiner-blind, randomized controlled clinical trial using a split-mouth design. Systemically healthy patients with adult periodontitis were selected. Full-mouth probing pocket depth (PPD), gingival bleeding on pocket probing scores (BOPP), gingival recession (REC) and dental plaque (PI) were assessed at baseline. All participants received oral hygiene instructions and supragingival prophylaxis including polishing. In 2 randomly assigned contra-lateral quadrants, approximal sites were irrigated with the IED, whereas in the other quadrants, CPT was provided. The CPT consisted of subgingival debridement using ultrasonic devices followed by the use of hand instruments. At 3 months post-treatment, the clinical parameters were re-assessed. RESULTS: Twenty-five patients met the inclusion criteria and were willing to participate. At 3 months post-treatment, the PPD and BOPP had significantly improved for both treatment modalities. Pockets of >=5 mm reduced by 0.64 mm in the IED group (P < .001), compared to a reduction of 0.82 mm for the CPT group (P < .001). With respect to the primary outcome parameter (PPD) and BI, the results with the IED were less pronounced. Between the test and control groups, no significant differences were observed for REC and PI. CONCLUSIONS: Oral hygiene instructions, supragingival prophylaxis and subgingival lavage with the IED resulted in a significant reduction in PPD and BOPP. However, the effect does not reach the results of CPT which included the subgingival use of ultrasonic and hand instruments. PMID- 29708655 TI - Effect of cobalt ions on the interaction between macrophages and titanium. AB - Inflammation and bone reduction around dental implants are described as peri implantitis and can be caused by an inflammatory response against bacterial products and toxins. Titanium (Ti) forms aggregates with serum proteins, which activate and cause release of the cytokine interleukin (IL-1beta) from human macrophages. It was hypothesized that cobalt (Co) ions can interact in the formation of pro-inflammatory aggregates, formed by titanium. To test this hypothesis, we differentiated THP-1 cells into macrophages and exposed them to Ti ions alone or in combination with Co ions to investigate if IL-1beta release and cytotoxicity were affected. We also investigated aggregate formation, cell uptake and human biopsies with inductively coupled plasma atomic emission spectroscopy and electron microscopy. Co at a concentration of 100 uM neutralized the IL-1beta release from human macrophages and affected the aggregate formation. The aggregates formed by Ti could be detected in the cytosol of macrophages. In the presence of Co, the Ti-induced aggregates were located in the cytosol of the cultured macrophages, but outside the lysosomal structures. It is concluded that Co can neutralize the Ti-induced activation and release of active IL-1beta from human macrophages in vitro. Also, serum proteins are needed for the formation of metal-protein aggregates in cell medium. Furthermore, the structures of the aggregates as well as the localisation after cellular uptake differ if Co is present in a Ti solution. Phagocytized aggregates with a similar appearance seen in vitro with Ti present, were also visible in a sample from human peri-implant tissue. (c) 2018 The Authors Journal of Biomedical Materials Research Part A Published by Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2518-2530, 2018. PMID- 29708656 TI - Electrodeposited Amorphous Tungsten-doped Cobalt Oxide as an Efficient Catalyst for the Oxygen Evolution Reaction. AB - Thin film of amorphous tungsten-doped cobalt oxide (W:CoO) was successfully grown on a conducting electrode via an electrochemical oxidation process employing a [Co(WS4 )2 ]2- deposition bath. The W:CoO catalyst displays an attractive performance for the oxygen evolution reaction in an alkaline solution. In an NaOH solution of pH 13, W:CoO operates with a moderate onset overpotential of 230 mV and requires 320 mV overpotential to generate a catalytic current density of 10 mA cm-2 . A low Tafel slope of 45 mV decade-1 was determined, indicating a rapid O2 -evolving kinetics. The as-prepared W:CoO belongs to the best cobalt oxide based catalysts ever reported for the oxygen evolution (OER) reaction. PMID- 29708657 TI - TiO2 nanoparticles disrupt cell adhesion and the architecture of cytoskeletal networks of human osteoblast-like cells in a size dependent manner. AB - Human exposure to titanium dioxide nanoparticles (nano-TiO2 ) is increasing. An internal source of nano-TiO2 is represented by titanium-based orthopedic and dental implants can release nanoparticles (NPs) upon abrasion. Little is known about how the size of NPs influences their interaction with cytoskeletal protein networks and the functional/homeostatic consequences that might follow at the implant-bone interface with regard to osteoblasts. We investigated the effects of size of anatase nano-TiO2 on SaOS-2 human osteoblast-like cells exposed to clinically relevant concentrations (0.05, 0.5, 5 mg/L) of 5 and 40 nm spherical nano-TiO2 . Cell viability and proliferation, adhesion, spread and migration were assessed, as well as the orientation of actin and microtubule cytoskeletal networks. The phosphorylation of focal adhesion kinase (p-FAKY397 ) and the expression of vinculin in response to nano-TiO2 were also assessed. Treatment with nano-TiO2 disrupted the actin and microtubule cytoskeletal networks leading to morphological modifications of SaOS-2 cells. The phosphorylation of p-FAKY397 and the expression of vinculin were also modified depending on the particle size, which affected cell adhesion. Consequently, the cell migration was significantly impaired in the 5 nm-exposed cells compared to unexposed cells. The present work shows that the orientation of cytoskeletal networks and the focal adhesion proteins and subsequently the adhesion, spread and migration of SaOS-2 cells were affected by the selected nano-TiO2 in a size dependent manner. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2582-2593, 2018. PMID- 29708659 TI - [Influence of Angle Variation between Right Hepatic Vein and Inferior Vena Cava on Inferior Vena Cava Diaphragm]. AB - Computational fluid dynamics was used to investigate the effect of the pathogenesis of membranous obstruction of inferior vena cava of Budd-Chiari syndrome with various angles between right hepatic vein and inferior vena cava.Mimics software was used to reconstruct the models from magnetic resonance imaging(MRI)angiograms of inferior vena cava,right hepatic vein,middle hepatic vein and left hepatic vein,and 3DMAX was used to construct the models of 30 degrees ,60 degrees ,90 degrees and 120 degrees angles between right hepatic vein and inferior vena cava,which was based on the reconstructed models.The model was conducted with clinical parameters in terms of wall shear stress distribution,static pressure distribution and blood velocity.The results demonstrated that the differences between wall shear stress and static pressure had statistical significance with various angles between right hepatic vein and inferior vena cava by SPSS.The pathogenesis of membranous obstruction of inferior vena cava had a correlation with the angles between right hepatic vein and inferior vena cava. PMID- 29708660 TI - [Influence of Different Abduction Angles of Hip Joint on Stress Distribution of Femoral Neck]. AB - The stress distribution and different abduction angles have a close relation to the hip joint.The purpose of this study is to provide biomechanical evidence for the treatment or precaution of hip joint injuries.A three-dimensional model of the hip was established through a series of processing based on the normal human hip joint computed tomograph(CT)image data which were applied to reverse engineering software Mimics14.0in this study.Firstly,a three-dimensional finite element model was generated with meshing and assigned material and then it was imported into the finite element analysis software Ansys13.0.At last the stress at the femoral neck was solved,computed and analyzed in the positive orthostatic position with 7hip abduction angles of the hip joint:0 degrees ,5 degrees ,10 degrees ,15 degrees ,20 degrees ,25 degrees ,and 30 degrees ,respectively.The results showed that the stresses of femoral neck and outer region were obviously higher than those of front and rear area of the neck of femur in the upright position or abduction of a different angle.With the increase of abduction angle,femoral neck in front of the regional stress value basically unchanged and rear area decreased,but the more obvious changes occurred in the outer region although the stress of inner and outer area also increased gradually.The hip abduction may cause changes in stress distribution because of the femoral neck stress mostly concentrated in the inner and outer cortex,and therefore it has an important role in guiding for hip surgery injury patients to choose the most reasonable solutions and prevention initiatives. PMID- 29708658 TI - Mining for Microbial Gems: Integrating Proteomics in the Postgenomic Natural Product Discovery Pipeline. AB - Natural products (NPs) are a major source of compounds for medical, agricultural, and biotechnological industries. Many of these compounds are of microbial origin, and, in particular, from Actinobacteria or filamentous fungi. To successfully identify novel compounds that correlate to a bioactivity of interest, or discover new enzymes with desired functions, systematic multiomics approaches have been developed over the years. Bioinformatics tools harness the rapidly expanding wealth of genome sequence information, revealing previously unsuspected biosynthetic diversity. Varying growth conditions or application of elicitors are applied to activate cryptic biosynthetic gene clusters, and metabolomics provide detailed insights into the NPs they specify. Combining these technologies with proteomics-based approaches to profile the biosynthetic enzymes provides scientists with insights into the full biosynthetic potential of microorganisms. The proteomics approaches include enrichment strategies such as employing activity-based probes designed by chemical biology, as well as unbiased (quantitative) proteomics methods. In this review, the opportunities and challenges in microbial NP research are discussed, and, in particular, the application of proteomics to link biosynthetic enzymes to the molecules they produce, and vice versa. PMID- 29708661 TI - [A Denoising Method for Low-dose Small-animal Computed Tomography Image Based on Globe Dictionary Learning]. AB - Considering the survival rate of small animals and the continuity of the experiments,high-dose X-ray shooting process is not suitable for the small animals in computed tomography(CT)experiments.But the low-dose process results with images might be polluted by noises which are not conducive for the experiments.In order to solve this problem,we in this paper introduce a global dictionary learning based denoising method to apply the promotion of the low dose CT image.We at first adopted the K-means singular value decomposition(K SVD)algorithm to train a global dictionary based on the high dose CT image.Then,the noise image could be decomposed into sparse component which was free from noise through the orthogonal matching pursuit(OMP)algorithm.Finally,the noisefree image could be achieved by reconstructing the image only with its sparse components.The experiments results showed that the method we proposed here could decrease the noise efficiently and remain the details,and it would help promote the low dose image quality and increase the survival rate of the small animals. PMID- 29708662 TI - [Automated Tissue Characterization of Intravascular Ultrasound Gray-scale Images]. AB - Automated characterization of different vessel wall tissues including atherosclerotic plaques,branchings and stents from intravascular ultrasound(IVUS)gray-scale images was addressed.The texture features of each frame were firstly detected with local binary pattern(LBP),Haar-like and Gabor filter in the present study.Then,a Gentle Adaboost classifier was designed to classify tissue features.The methods were validated with clinically acquired image data.The manual characterization results obtained by experienced physicians were adopted as the golden standard to evaluate the accuracy.Results indicated that the recognition accuracy of lipidic plaques reached 94.54%,while classification precision of fibrous and calcified plaques reached 93.08%.High recognition accuracy can be reached up to branchings 93.20% and stents 93.50%,respectively. PMID- 29708663 TI - [Automatic Segmentation of Four Dimensional Computed Tomography of Lung Tumor Based on Star Shape Prior and Graph Cuts]. AB - Lung four dimensional computed tomography(4D-CT)is of great value in tumor target localization and precise cancer radiotherapy.However,it is hard to segment tumors in 4D-CT data manually,since the data may contain a great number of slices with tumor.Meanwhile,auto-segmentation does not certainly guarantee the accuracy due to the complexity of images.Therefore,a new automatic segmentation technique based on Graph Cuts with star shape prior was proposed to increase automation and guarantee the accuracy of segmentation in our laboratory.Firstly,an object seed was selected in the image of initial phase and an initial target block was formed centering the selected seed.Then,the full search block-matching algorithm was adopted to obtain the most similar target block in the next phase and compute the motion field between them,and so on.Afterwards,the center seeds of each phase were obtained according to the motion fields,which would be set to the center point of star shape prior.Finally,tumors could be automatically segmented with Graph Cuts algorithm and star shape prior.Both qualitative and quantitative evaluation results showed that our approach could not only guarantee the accuracy of segmentation but also increase automation,compared with the traditional Graph Cuts algorithm. PMID- 29708664 TI - [Segmentation Method of Colour White Blood Cell Image Based on HSI Modified Space Information Fusion]. AB - This paper presents a kind of automatic segmentation method for white blood cell based on HSI corrected space information fusion.Firstly,the original cell image is transformed to HSI colour space conversion.Because the transformation formulas of H component piecewise function was discontinuous,the uniformity of uniform visual cytoplasm area in the original image was lead to become lower in this channel.We then modified formulas,and then fetched information of nucleus,cytoplasm,red blood cells and background region according to distribution characteristics of the H,S and I-channel,using the theory and method of information fusion to build fusion imageIand fusion imageII,which only contained cytoplasm and a small amount of interference,and fetched nucleus and cytoplasm respectively.Finally,we marked the nucleus and cytoplasm region and obtained the final result of segmentation.The simulation results showed that the new algorithm of image segmentation for white blood cell had high accuracy,robustness and universality. PMID- 29708665 TI - [Quantitative Segmentation and Measurement of Tooth from Computed Tomography Image Based on Regional Adaptive Deformation Model]. AB - For tooth segmentation problem on the three-dimensional computed tomography(CT)volume data,this paper proposes a regional adaptive deformable model for tooth structure measurement of CT images.The proposed method combines the automatic thresholding segmentation,CV active contour model,and graph cut.Firstly,we achieved the segmentation and location of dental crowns by automatic thresholding segmentation.And then by using the above segmentation result as the initial contour,we utilized active contour method to slice gradually the segment of remaining tooth.By incorporating active contour and graph-cut then,we realized the accurate segmentation for tooth root,which is the most difficult to be segmented.The experimental results showed that the proposed tooth structure measurement accurately and automatically segmented dental crowns from CT data,and then rapidly and accurately segmented the tooth neck and tooth root.The structure of tooth could be effectively segmented from CT data by using the proposed method.Experimental results indicated that the proposed method was rather robust and accurate,and could effectively assist the doctor for diagnosis in clinical treatment. PMID- 29708666 TI - [Experimental Study of Burst Strength for the Nonwovens]. AB - The burst strength is one of the most important characteristics for nonwovens.The strength of three kinds of the nonwoven were detected under four testing radius,including the wood spunlace nonwoven,the SpunbondMeltblown Spunbond(SMS)nonwoven and the melt nonwoven.The precise results of the SMS and the melt nonwoven could be received by removing the influence of the elastic membrane and the single-peak fitting.The influence of the testing radius to the strength results was also studied,and the semiempirical formula(q0=k/r3)was deduced using the elastic mechanics theory and testing data. PMID- 29708667 TI - [Preliminary Study on Comfortableness of Motorized Wheelchair Cushion]. AB - This paper aims to explore the thermal feelings of different cover materials effect on wheelchair cushion comfortableness,and to build a mathematical model for motorized wheelchair cushion comfortableness.By measuring temperature and humidity between the contact face of motorized wheelchair cushion and human body as well as the setting posture adjustment time while cushion cover materials are nylon cloth,leather,fishnets cloth.At the same time,each volunteer took a questionnaire about the comfort of different cushion cover materials.Results showed that fishnets cloth was most comfortable,leather was worst,while nylon cloth was in between the two.The experimental objective data were consistent with the subjective data.We built a back propagation(BP)neural network mathematical model for motorized wheelchair cushion comfortableness.This study will provide objective reference to motorized wheelchair for the designers and users. PMID- 29708668 TI - [Prediction of Antigen Epitopes of Associated Protein Rv2004c Latent-infected by Mycobacterium Tuberculosis]. AB - To screen new tuberculosis diagnostic antigens and vaccine candidates,we predicted the epitopes of Mycobacterium tuberculosis latent infection-associated protein Rv2004 cby means of bioinformatics.The homology between Rv2004 cprotein and human protein sequences was analyzed with BLAST method.The second structures,hydrophilicity,antigenicity,flexibility and surface probability of the protein were analyzed to predict B cell epitopes and T cell epitopes by Protean software of DNAStar software package.The Th epitopes were predicted by RANKPEP and SYFPEITHI supermotif method,the CTL epitopes were predicted by means of combination analyses of SYFPEITHI supermotif method,BIMAS quantitative motif method and NetCTL prediction method.The peptide sequences with higher scores were chosen as the candidate epitopes.Blast analysis showed that Rv2004 cprotein had low homology with human protein.This protein had abundant secondary structures through analysis of DNAStar software,the peptide segments with high index of hydrophilicity,antigenicity,surface probability and flexibility were widely distributed and were consistent with segments having beta turn or irregular coil.Ten candidates of B cell epitopes were predicted.The Th epitopes of Rv2004 cprotein were located after the 200 th amino acid.Of 37 Th cell epitopes predicted,there were more epitopes of HLA-DRB1*0401and HLA DRB1*0701phenotypes,and the MHC restrictive types of some Th cell epitopes exist cross overlap.Of 10 CTL epitopes predicted,there were more number and higher score of HLA-A2 restricted epitopes.Therefore MycobacteriumtuberculosisRv2004 cprotein is a protein antigen with T cell and B cell epitopes,and is expected to be a new target protein candidate for tuberculosis diagnosis and vaccine. PMID- 29708669 TI - [Quantitative Study on Angiogenesis Features of Human Lung Adenocarcinoma Xenografted into Nude Mouse Model Using Time-intensity Curve Parameters with Contrast Enhanced Ultrasonography]. AB - This research is to explore the perfusion time-intensity curve parameters of a lung adenocarcinoma xenograft into nude mouse model with contrast enhanced ultrasonography(CEUS);and to investigate the angiogenesis features of tumor at different growth time.Twenty one lung adenocarcinoma xenografted nude mice were divided into three groups and inculcated with human lung adenocarcinoa.Time window for examining CEUS were respectively in7-day,14-day and 28-day.The perfusion parameters including rise time(RT),peak intensity(PI),area under the curve(AUC)of lung tumor were obtained on CEUS images by using off-line software Q lab.Immunohistochemically staining for CD34 was used to observe the microvessel density(MVD).The 7-day group had the highest AUC and PI;AUC and PI of 14-day and 28-day group decreased gradually(P<0.05).RT was increased as tumor growth.In tumor with necrosis,AUC and PI of non-necrosis part were also larger than necrosis part(P<0.05).Immunohistochemically staining for CD34 of all tumors reflected that the density of microvessels in necrosis tumor was significantly higher than those without necrosis(7.50+/-3.44 vs.12.44+/-5.74,P=0.034).Pearson correlation indicated that PI was positively related with MVD(r=0.668,P=0.008).Lung adenocarcinoma perfusion characteristic can be accessed from time-intensity curve parameters by using noninvasively and non-radiative contrast enhanced ultrasonography.Time-intensity curve parameters including AUC,PI and RT may reflect tumor angiogenesis. PMID- 29708671 TI - [Medical Image Registration Method Based on a Semantic Model with Directional Visual Words]. AB - Medical image registration is very challenging due to the various imaging modality,image quality,wide inter-patients variability,and intra-patient variability with disease progressing of medical images,with strict requirement for robustness.Inspired by semantic model,especially the recent tremendous progress in computer vision tasks under bag-of-visual-word framework,we set up a novel semantic model to match medical images.Since most of medical images have poor contrast,small dynamic range,and involving only intensities and so on,the traditional visual word models do not perform very well.To benefit from the advantages from the relative works,we proposed a novel visual word model named directional visual words,which performs better on medical images.Then we applied this model to do medical registration.In our experiment,the critical anatomical structures were first manually specified by experts.Then we adopted the directional visual word,the strategy of spatial pyramid searching from coarse to fine,and the k-means algorithm to help us locating the positions of the key structures accurately.Sequentially,we shall register corresponding images by the areas around these positions.The results of the experiments which were performed on real cardiac images showed that our method could achieve high registration accuracy in some specific areas. PMID- 29708670 TI - [Development of An Implantable Optrode for Optogenetic Stimulation]. AB - In this study,an implantable optrode was developed for optogenetics stimulation of neural population in nuclei or multi-sites in neural circuits.The optrode was composed of base layer,micro-light emitting diode(LED)and coating layer.The base layer was a 150MUm thick polyimide substrate on which copper wires and contacts were fabricated by flexible printed circuit board processes.The micro-LED was soldered on the contacts using SnBi.ParyleneC was deposited over the optrode as the coating layer using a vacuum vapor deposition system.The optical output power was tested by optical power meter and the insulating property was tested using saline in the experiment.The stimulation function of the optrode was demonstrated through animal experiment.The width of the optrode was500MUm and the maximum thickness of the optrode was 310MUm at the LED position.The thickness of the parylene coating layer was about 1MUm.The maximum optical output power of optrode was 9.31 mW and the effective illumination area was a 3.03mm2 spherical cap at 650MUm deep in brain tissue.The optrode was still functional after 14 days in physiological saline.Conventional copper electrodes were used to verify the efficacy of the optrode for stimulation and robust spiking activities of the expressing Channelrhodopsin-2neurons in the entire cortex of a mouce were recorded.Obvious behavior change happened when light stimulation was applied to the expressing Channelrhodopsin-2neurons in the secondary motor cortex of the mice.The optrode has the characteristics of large effective illumination range,flexible in implantation and long-term implantable,which provide neural population in nuclei research a new tool. PMID- 29708672 TI - [A Novel Channel Selection Method for Brain-computer Interface Based on Relief SBS]. AB - Regarding to the channel selection problem during the classification of electroencephalogram(EEG)signals,we proposed a novel method,Relief-SBS,in this paper.Firstly,the proposed method performed EEG channel selection by combining the principles of Relief and sequential backward selection(SBS)algorithms.And then correlation coefficient was used for classification of EEG signals.The selected channels that achieved optimal classification accuracy were considered as optimal channels.The data recorded from motor imagery task experiments were analyzed,and the results showed that the channels selected with our proposed method achieved excellent classification accuracy,and also outperformed other feature selection methods.In addition,the distribution of the optimal channels was proved to be consistent with the neurophysiological knowledge.This demonstrates the effectiveness of our method.It can be well concluded that our proposed method,Relief-SBS,provides a new way for channel selection. PMID- 29708673 TI - [Detection of Weak Speech Signals from Strong Noise Background Based on Adaptive Stochastic Resonance]. AB - Traditional speech detection methods regard the noise as a jamming signal to filter,but under the strong noise background,these methods lost part of the original speech signal while eliminating noise.Stochastic resonance can use noise energy to amplify the weak signal and suppress the noise.According to stochastic resonance theory,a new method based on adaptive stochastic resonance to extract weak speech signals is proposed.This method,combined with twice sampling,realizes the detection of weak speech signals from strong noise.The parameters of the systema,b are adjusted adaptively by evaluating the signal-to-noise ratio of the output signal,and then the weak speech signal is optimally detected.Experimental simulation analysis showed that under the background of strong noise,the output signal-to-noise ratio increased from the initial value-7dB to about 0.86 dB,with the gain of signalto-noise ratio is 7.86 dB.This method obviously raises the signal-to-noise ratio of the output speech signals,which gives a new idea to detect the weak speech signals in strong noise environment. PMID- 29708674 TI - [An Improved Spectral Quaternion Interpolation Method of Diffusion Tensor Imaging]. AB - Diffusion tensor imaging(DTI)is a rapid development technology in recent years of magnetic resonance imaging.The diffusion tensor interpolation is a very important procedure in DTI image processing.The traditional spectral quaternion interpolation method revises the direction of the interpolation tensor and can preserve tensors anisotropy,but the method does not revise the size of tensors.The present study puts forward an improved spectral quaternion interpolation method on the basis of traditional spectral quaternion interpolation.Firstly,we decomposed diffusion tensors with the direction of tensors being represented by quaternion.Then we revised the size and direction of the tensor respectively according to different situations.Finally,we acquired the tensor of interpolation point by calculating the weighted average.We compared the improved method with the spectral quaternion method and the Log-Euclidean method by the simulation data and the real data.The results showed that the improved method could not only keep the monotonicity of the fractional anisotropy(FA)and the determinant of tensors,but also preserve the tensor anisotropy at the same time.In conclusion,the improved method provides a kind of important interpolation method for diffusion tensor image processing. PMID- 29708707 TI - [Wavelength Selection in Hemolytic Evaluation Systems with Spectrophotometry Detection]. AB - Spectrophotometry is a simple hemolytic evaluation method commonly used in new drugs,biomedical materials and blood products.It is for the quantitative analysis of the characteristic absorption peaks of hemoglobin.Therefore,it is essential to select the correct detection wavelength when the evaluation system has influences on the conformation of hemoglobin.Based on the study of changes in the characteristic peaks over time of the hemolysis supernatant in four systems,namely,cell culture medium,phosphate buffered saline(PBS),physiological saline and banked blood preservation solution,using continuous wavelength scanning,the selections of detection wavelength were proposed as follows.In the cell culture medium system,the wavelength of 415 nm should be selected within 4h;,near 408 nm should be selected within 4~72h.In PBS system,within 4h,541 nm,577nm or 415 nm should be selected;4~72h,541 nm,577nm or near 406 nm should be selected.In physiological saline system,within 4h,414 nm should be selected;4~72h,near 405 nm should be selected;within 12 h,541nm or 577 nm could also be selected.In banked blood preservation solution system,within 72 h,415nm,540 nm or 576 nm should be selected. PMID- 29708708 TI - [Application Progress of Three-dimensional Laser Scanning Technology in Medical Surface Mapping]. AB - The booming three-dimensional laser scanning technology can efficiently and effectively get spatial three-dimensional coordinates of the detected object surface and reconstruct the image at high speed,high precision and large capacity of information.Non-radiation,non-contact and the ability of visualization make it increasingly popular in three-dimensional surface medical mapping.This paper reviews the applications and developments of three-dimensional laser scanning technology in medical field,especially in stomatology,plastic surgery and orthopedics.Furthermore,the paper also discusses the application prospects in the future as well as the biomedical engineering problems it would encounter with. PMID- 29708709 TI - [The Differentiation of Mesenchymal Stem Cells into Pacemaker-like Cells]. AB - The biological pacemaker has become a new strategy in the treatment of severe bradycardias,in which a kind of ideal pacemaker cells is a pivotal factor.Here we reviewed the progress in the differentiation of bone-marrow mesenchymal stem cells and adipose-derived stem cells into pacemaker-like cells by means of gene transfer,chemical molecules,co-culture with other cells and specific culture media,and we also analyzed the potential issues to be solved when they are used as seeding cells of biological pacemaker. PMID- 29708710 TI - [Organogenesis Using Three-dimensional Culture Technology]. AB - A critical shortage of donor organs raises a question of needs for alternative organ sources for regenerative medicine.Over the last decade,three dimensional(3D)culture has become a new approach for organ regeneration.The 3Dculture takes significant advantages of cells spatial relationships between multiple cellular types and surrounding matrices of dynamic cellular interactions,which plays a key role in structural self-formation of complex organ buds.Here we present major classic cases of 3Dculture organ regeneration to show how it works,and then we try to find the way of future organ regeneration. PMID- 29708711 TI - [Research Progress in Mitochondria-associated Endoplasmic Reticulum Membrane and Its Application in Treatment of Diseases]. AB - The endoplasmic reticulum(ER)is physically connected to mitochondria through the specific sub-domain,called mitochondria-associated endoplasmic reticulum membranes(MAMs).These contacts are involved in calcium signaling,lipid transferring,mitochondrial fission and fusion and energy metabolism.Recently,MAMs alterations have been identified to associate with some diseases,including neurodegenerative diseases,obesity,cardiovascular diseases and cancer.Therefore,in this paper,we introduce the structure,function and detection methods of MAMs.Besides,we also summarize the potential role of MAMs in these diseases.In any case,the signaling at the MAMs might be a promising pharmacological target for several diseases. PMID- 29708712 TI - [Research Progress of Multi-Model Medical Image Fusion at Feature Level]. AB - Medical image fusion realizes advantage integration of functional images and anatomical images.This article discusses the research progress of multi-model medical image fusion at feature level.We firstly describe the principle of medical image fusion at feature level.Then we analyze and summarize fuzzy sets,rough sets,D-S evidence theory,artificial neural network,principal component analysis and other fusion methods' applications in medical image fusion and get summery.Lastly,we in this article indicate present problems and the research direction of multi-model medical images in the future. PMID- 29708713 TI - [Research Progress of Low Radiation Dose Computed Tomography Perfusion of the Liver]. AB - Liver computed tomography(CT)perfusion is a noninvasive imaging technology which can quantitatively investigate liver function,and it is mainly used in the diagnosis of liver tumors and assessment of liver function in the state of chronic liver diseases.The use of liver CT perfusion was limited in the past because of the high radiation dose.Now new technologies are exploited and they make it possible to reduce the radiation burden while maintaining the imaging quality.This article discusses the research progress of low radiation dose CT perfusion in 3aspects,including X-ray source,reconstruction algorithm,and improvement of CT scanners and optimization of scanning parameters.Although there are not too many studies of low radiation dose CT perfusion on liver now and many problems need to be solved,the clinical application of it will be very prospective. PMID- 29708714 TI - [Three-dimensional Structural Visualization of Subthalamic Nucleus for Deep Brain Stimulation]. AB - The effect of deep brain stimulation(DBS)surgery treatment for Parkinson's disease is determined by the accuracy of the electrodes placement and localization.The subthalamic nuclei(STN)as the implant target is small and has no clear boundary on the images.In addition,the intra-operative magnetic resonance images(MRI)have such a low resolution that the artifacts of the electrodes impact the observation.The three-dimensional(3D)visualization of STN and other nuclei nearby is able to provide the surgeons with direct and accurate localizing information.In this study,pre-and intra-operative MRIs of the Parkinson's disease patients were used to realize the 3Dvisualization.After making a co-registration between the high-resolution pre-operative MRIs and the low-resolution intraoperative MRIs,we normalized the MRIs into a standard atlas space.We used a special threshold mask to search the lead trajectories in each axial slice.After checking the location of the electrode contacts with the coronal MRIs of the patients,we reconstructed the whole lead trajectories.Then the STN and other nuclei nearby in the standard atlas space were visualized with the grey images of the standard atlas,accomplishing the lead reconstruction and nerve nuclei visualization near STN of all patients.This study provides intuitive and quantitative information to identify the accuracy of the DBS electrode implantation,which could help decide the post-operative programming setting. PMID- 29708715 TI - [Selection and Classification of Elastic Net Feature with Fused Electroencephalogram Features]. AB - Signal classification is a key of brain-computer interface(BCI).In this paper,we present a new method for classifying the electroencephalogram(EEG)signals of which the features are heterogeneous.This method is called wrapped elastic net feature selection and classification.Firstly,we used the joint application of time-domain statistic,power spectral density(PSD),common spatial pattern(CSP)and autoregressive(AR)model to extract high-dimensional fused features of the preprocessed EEG signals.Then we used the wrapped method for feature selection.We fitted the logistic regression model penalized with elastic net on the training data,and obtained the parameter estimation by coordinate descent method.Then we selected best feature subset by using 10-fold cross-validation.Finally,we classified the test sample using the trained model.Data used in the experiment were the EEG data from international BCI CompetitionIV.The results showed that the method proposed was suitable for fused feature selection with high dimension.For identifying EEG signals,it is more effective and faster,and can single out a more relevant subset to obtain a relatively simple model.The average test accuracy reached 81.78%. PMID- 29708716 TI - [Study on Sleep Staging Methods Based on Heart Rate Variability Analysis]. AB - In order to realize sleep staging automatically and conveniently,we used support vector machine(SVM)to analyze the correlation between heart rate variability and sleep stage experimentally.R-R intervals(RRIs)from 33 cases of sleep clinical data of Tianjin Thoracic Hospital were extracted and analyzed by principal component analysis(PCA).The SVM method was used to establish the model and predict the five sleep stages.The prediction accuracy of three-sleep-stage was higher than 80%,in contrast to sleep scoring annotations marked by physiological experts based on electroencephalogram(EEG)golden standard.The result showed that there was a good correlation between heart rate variability and sleep staging.This method is an important supplement to the traditional sleep staging method and has a great value for clinical application. PMID- 29708717 TI - [Study on Muscle Fatigue Property of Human Body in Shoulder Loaded Walking Based on Surface Electromyogram]. AB - We carried out study on surface electromyogram(sEMG)signal generated from cluster muscles in trunk and lower limbs on condition of human body walking with heavily burdened shoulder to explore functional status and fatigue property of human muscles and to offer an important reference for finding better ways of loading,improving the performance and design of backpack as well as weight bearing system more suitable for ergonomics.We measured and obtained surface electromyography signals from the primary muscles clusters in neck,shoulder,back and leg of20 test recipients loaded with different burdens on their shoulders.The eigenvalue of mean power frequency(MPF)were processed with SPSS 16.0.It could be concluded that with the increase of loading weights,male are more likely to be fatigued due to dramatic decrease of trapezius' MPF.While for the female test recipients,the cervical extensor muscles' MPF dropped significantly and were more easily fatigued.Moreover,there was a remarkable difference in terms of electromyography signal before and after the weight reaches certain limit(P<0.05).The maximum weight limit loaded on shoulders for man is 12% of the total bodyweight while such limit for woman is just 9%. PMID- 29708718 TI - Enhanced Lithium Storage Capacity of a Tetralithium 1,2,4,5 Benzenetetracarboxylate (Li4C10H2O8) Salt Through Crystal Structure Transformation. AB - Because of their low price, design flexibility, and sustainability, organic-based electrode materials are considered one of the most promising next-generation alternatives to inorganic materials in Li-ion batteries. However, a clear understanding of the changes in the molecular crystal structure during Li-ion insertion/extraction and its relationship to excess capacity (over theoretical capacity) is still lacking. Herein, the tetralithium 1,2,4,5 benzenetetracarboxylate (Li4C10H2O8, Li4BTC) salt was prepared using a simple ion exchange reaction at room temperature and under solvothermal conditions (100 degrees C). The solvothermally synthesized salt (Li4BTC-S) exhibited a well ordered nanosheet morphology, whereas the room-temperature salt (Li4BTC-R) was comprised of irregularly shaped particles. During the cycling of Li4BTC-S, molecular rearrangement occurred to reduce the stress caused by repeated Li-ion insertion/extraction, resulting in a change in the crystal structure from triclinic to monoclinic and an increased free volume. This contributed to an increase in the reversible capacity to 1016 mAh g-1 during the initial 25 cycles at 0.1 A g-1, and finally the capacity stabilized at ca. 600 mAh g-1 after 100 cycles, which is much higher than its theoretical capacity (234 mAh g-1). Compared with Li4BTC-R, Li4BTC-S delivered a higher reversible capacity of 190 mAh g-1 at a high current density of 2 A g-1, with an excellent long-term cyclability of up to 1000 cycles, which was attributed to the straight free volume columns and the low-charge-transfer limitation. PMID- 29708719 TI - Targetable Mesoporous Silica Nanoprobes for Mapping the Subcellular Distribution of H2Se in Cancer Cells. AB - Hydrogen selenide, a highly active reductant, is believed as a key molecule in the cytotoxicity of inorganic selenium compounds. However, the detail mechanism has hardly been studied because the distribution of H2Se in the subcellular organelles remains unclear. Herein, we exploited a series of novel targetable mesoporous silica nanoplatforms to map the distribution of H2Se in cytoplasm, lysosome, and mitochondria of cancer cells. The subcellular targeting moiety conjugated mesoporous silica nanoparticles were assembled with a near-infrared fluorescent probe (NIR-H2Se) for detecting endogenous H2Se in the corresponding organelles. The confocal fluorescence imaging of cancer cells induced by Na2SeO3 found out a higher concentration of H2Se accumulated only in mitochondria. Consequently, the H2Se burst in mitochondria-triggered mitochondrial collapse that led to cell apoptosis. Hence, the selenite-induced cytotoxicity in cancer cells associates with the alteration in mitochondrial function caused by high level of H2Se. These findings provide a new way to explore the tumor cell apoptosis signaling pathways induced by Na2SeO3, meanwhile, we propose a research strategy for tracking the biomolecules in the subcellular organelles and the correlative cellular function and related disease diagnosis. PMID- 29708720 TI - Pentiptycene-Based Polyurethane with Enhanced Mechanical Properties and CO2 Plasticization Resistance for Thin Film Gas Separation Membranes. AB - The development of thin film composite (TFC) membranes offers an opportunity to achieve the permeability/selectivity requirements for optimum CO2 separation performance. However, the durability and performance of thin film gas separation membranes are mostly challenged by weak mechanical properties and high CO2 plasticization. Here, we designed new polyurethane (PU) structures with bulky aromatic chain extenders that afford preferred mechanical properties for ultra thin-film formation. An improvement of about 1500% in Young's modulus and 600% in hardness was observed for pentiptycene-based PUs compared to the typical PU membranes. Single (CO2, H2, CH4, and N2) and mixed (CO2/N2 and CO2/CH4) gas permeability tests were performed on the PU membranes. The resulting TFC membranes showed a high CO2 permeance up to 1400 GPU (10-6 cm3(STP) cm-2 s-1 cmHg 1) and the CO2/N2 and CO2/H2 selectivities of about 22 and 2.1, respectively. The enhanced mechanical properties of pentiptycene-based PUs result in high performance thin membranes with the similar selectivity of the bulk polymer. The thin film membranes prepared from pentiptycene-based PUs also showed a twofold enhanced plasticization resistance compared to non-pentiptycene-containing PU membranes. PMID- 29708721 TI - Crystal Orientation-Dependent Reactivity of Oxide Surfaces in Contact with Lithium Metal. AB - Understanding ionic transport across interfaces between dissimilar materials and the intrinsic chemical stability of such interfaces is a fundamental challenge spanning many disciplines and is of particular importance for designing conductive and stable solid electrolytes for solid-state Li-ion batteries. In this work, we establish a surface science-based approach for assessing the intrinsic stability of oxide materials in contact with Li metal. Through a combination of experimental and computational insights, using Nb-doped SrTiO3 (Nb/STO) single crystals as a model system, we were able to understand the impact of crystallographic orientation and surface morphology on the extent of the chemical reactions that take place between surface Nb, Ti, and Sr upon reaction with Li. By expanding our approach to investigate the intrinsic stability of the technologically relevant, polycrystalline Nb-doped lithium lanthanum zirconium oxide (Li6.5La3Zr1.5Nb0.5O12) system, we found that this material reacts with Li metal through the reduction of Nb, similar to that observed for Nb/STO. These results clearly demonstrate the feasibility of our approach to assess the intrinsic (in)stability of oxide materials for solid-state batteries and point to new strategies for understanding the performance of such systems. PMID- 29708722 TI - Structural and Functional Components of the Skate Sensory Organ Ampullae of Lorenzini. AB - The skate, a cartilaginous fish related to sharks and rays, possesses a unique electrosensitive sensory organ known as the ampullae of Lorenzini (AoL). This organ is responsible for the detection of weak electric field changes caused by the muscle contractions of their prey. While keratan sulfate (KS) is believed to be a component of a jelly that fills this sensory organ and has been credited with its high proton conductivity, modern analytical methods have not been applied to its characterization. Surprisingly, total glycosaminoglycan (GAG) analysis demonstrates that the KS from skate jelly is extraordinarily pure, containing no other GAGs. This KS had a molecular weight of 20 to 30 kDa, consisting primarily of N-linked KS comprised mostly of a monosulfated disaccharide repeating unit, ->3) Gal (1->4) GlcNAc6S (1->. Proteomic analysis of AoL jelly suggests that transferrin, keratin, and mucin serve as KS core proteins. Actin and tropomyosin are responsible for assembling the macrostructure of the jelly, and parvalbumin alpha-like protein and calreticulin regulate calcium and potassium channels involved in the transduction of the electrical signal, once conducted down the AoL by the jelly, serving as the molecular basis for electroreception. PMID- 29708723 TI - Still Unconquered: Enantioselective Passerini and Ugi Multicomponent Reactions. AB - The Passerini three-component (P-3CR) and the Ugi four-component (U-4CR) are two of the most prominent isocyanide-based multicomponent reactions (IMCRs). The P 3CR transforms isocyanides, aldehydes (ketones), and carboxylic acids to alpha acyloxy carboxamides, while the U-4CR converts isocyanides, aldehydes (ketones), amines, and carboxylic acids to alpha-acetamido carboxamides. Conversion of the high energy formal divalent isocyano carbon into a tetravalent amide carbonyl carbon provides the driving force for these reactions. While the prototypical P 3CR and U-4CR provide linear adducts, many heterocycles and macrocycles are now readily synthesized by modifying these truly versatile reactions. As one stereocenter is generated by the nucleophilic addition of the isocyanide to the carbonyl and imine functions, the search for enantioselective versions of these reactions has become a much sought after goal among synthetic chemists. This seemingly trivial endeavor turns out to be extremely difficult to achieve, in sharp contrast to the remarkable progress documented in the field of asymmetric synthesis in general and catalytic enantioselective nucleophilic addition to C?X bond in particular. Since Denmark's first report in 2003 on the catalytic enantioselective Passerini two-component reaction of isocyanides with aldehydes, several Lewis acid (LA) and Bronsted acid-catalyzed enantioselective protocols have been developed. However, it is fair to say that truly catalytic enantioselective P-3CR and U-4CR with wide application scope remain elusive. In this Account, we summarize the progress recorded in this field over the past 15 years. We entered the field by investigating the enantioselective reaction of alpha-isocyanoacetamides with aldehydes and imines, which was previously developed in our lab for the synthesis of functionalized 5-aminooxazoles. Our initial experimental results, in conjunction with Domling's and Schreiber's earlier findings, prompted us to assume that the low turnover number in LA catalyzed asymmetric IMCRs is a main hurdle for enantioselectivity. We speculated that the LA incapable of forming chelates would be the catalyst of choice for enantioselectivity, the rational being that the P-3CR and the U-4CR afforded bidentate intermediates (alpha-hydroxy imidates, alpha-amino imidates) and products (alpha-acyloxy carboxamides, alpha-acetamido carboxamides) from nonchelating inputs. Therefore, the transfer of catalyst from these chelating intermediates or products to the monocoordinating starting materials would be difficult, hence the problem with catalyst turnover. This working hypothesis turned out to be a valuable guide that allowed us to develop Al-salen and Al phosphate-catalyzed enantioselective P-3CR and enantioselective construction of chiral heterocycles such as oxazoles and tetrazoles. Nevertheless, all our attempts to apply these LA catalysts to the Ugi reaction failed. Indeed, to date, no reports on the successful LA-catalyzed asymmetric Ugi-type reactions exist in the literature. However, significant progress has been made in recent years employing organocatalysts. We developed a chiral phosphoric acid (CPA)-catalyzed enantioselective three-component synthesis of 2-(1-aminoalkyl)-5-aminooxazoles, a four-component synthesis of epoxy-tetrahydropyrrolo[3,4- b]pyridin-5-ones and a Ugi four-center, three-component reaction of isocyanides, anilines, and 2 formylbenzoic acids for the synthesis of isoindolinones. Other groups have found that chiral dicarboxylic acid and BOROX are effective catalysts for truncated Ugi three-component reactions. PMID- 29708724 TI - Tailoring Emulsions for Controlled Lipid Release: Establishing in vitro-in Vivo Correlation for Digestion of Lipids. AB - The use of oil-in-water emulsions for controlled lipid release is of interest to the pharmaceutical industry in the development of poorly water soluble drugs and also has gained major interest in the treatment of obesity. In this study, we focus on the relevant in vitro parameters reflecting gastric and intestinal digestion steps to reach a reliable in vitro-in vivo correlation for lipid delivery systems. We found that (i) gastric lipolysis determines early lipid release and sensing. This was mainly influenced by the emulsion stabilization mechanism. (ii) Gastric mucin influences the structure of charge-stabilized emulsion systems in the stomach, leading to destabilization or gel formation, which is supported by in vivo magnetic resonance imaging in healthy volunteers. (iii) The precursor structures of these emulsions modulate intestinal lipolysis kinetics in vitro, which is reflected in plasma triglyceride and cholecystokinin concentrations in vivo. PMID- 29708725 TI - Control of Integrin Affinity by Confining RGD Peptides on Fluorescent Carbon Nanotubes. AB - Integrins are transmembrane receptors that mediate cell-adhesion, signaling cascades and platelet-mediated blood clotting. Most integrins bind to the common short peptide Arg-Gly-Asp (RGD). The conformational freedom of the RGD motif determines how strong and to which integrins it binds. Here, we present a novel approach to tune binding constants by confining RGD peptide motifs via noncovalent adsorption of single-stranded DNA (ssDNA) anchors onto single-walled carbon nanotubes (SWCNTs). Semiconducting SWCNTs display fluorescence in the near infrared (nIR) region and are versatile fluorescent building blocks for imaging and biosensing. The basic idea of this approach is that the DNA adsorbed on the SWCNT surface determines the conformational freedom of the RGD motif and affects binding affinities. The RGD motif was conjugated to different ssDNA sequences in both linear ssDNA-RGD and bridged ssDNA-RGD-ssDNA geometries. Molecular dynamics (MD) simulations show that the RGD motif in all the synthesized systems is mostly exposed to solvent and thus available for binding, but its flexibility depends on the exact geometry. The affinity for the human platelet integrin alphaIIbbeta3 could be modulated up to 15-fold by changing the ssDNA sequence. IC50 values varied from 309 nM for (C)20-RGD/SWCNT hybrids to 29 nM for (GT)15-RGD/SWCNT hybrids. When immobilized onto surface adhesion of epithelial cells increased 6 fold for (GT)15-RGD/SWCNTs. (GT)15-RGD/SWCNTs also increased the number of adhering human platelets by a factor of 4.8. Additionally, alphaIIbbeta3 integrins on human platelets were labeled in the nIR by incubating them with these ssDNA-peptide/SWCNT hybrids. In summary, we show that ssDNA-peptide hybrid structures noncovalently adsorb onto SWCNTs and serve as recognition units for cell surface receptors such as integrins. The DNA sequence affects the overall RGD affinity, which is a versatile and straightforward approach to tune binding affinities. In combination with the nIR fluorescence properties of SWCNTs, these new hybrid materials promise many applications in integrin targeting and bioimaging. PMID- 29708726 TI - Prospects for Fluorescence Nanoscopy. AB - Overcoming Abbe's diffraction limit has been a challenging task and one of great interest for biological investigations. The emergence of fluorescence nanoscopy circumvents the diffraction barrier with nearly limitless power for optical microscopy, which enables investigations of the microscopic world in the 1-100 nm range. Proposed variants, such as expansion microscopy (ExM), stimulated emission depletion microscopy (STED), and Airyscan, are innovative in three aspects: sampling, illumination, and detection. These techniques show increasing strength in bioimaging subcellular structures. In this Perspective, we highlight advances in and prospects of fluorescence nanoscopy. PMID- 29708727 TI - Superplastic Creep of Metal Nanowires from Rate-Dependent Plasticity Transition. AB - Understanding the time-dependent mechanical behavior of nanomaterials such as nanowires is essential to predict their reliability in nanomechanical devices. This understanding is typically obtained using creep tests, which are the most fundamental loading mechanism by which the time-dependent deformation of materials is characterized. However, due to existing challenges facing both experimentalists and theorists, the time-dependent mechanical response of nanowires is not well-understood. Here, we use atomistic simulations that can access experimental time scales to examine the creep of single-crystal face centered cubic metal (Cu, Ag, Pt) nanowires. We report that both Cu and Ag nanowires show significantly increased ductility and superplasticity under low creep stresses, where the superplasticity is driven by a rate-dependent transition in defect nucleation from twinning to trailing partial dislocations at the micro- or millisecond time scale. The transition in the deformation mechanism also governs a corresponding transition in the stress-dependent creep time at the microsecond (Ag) and millisecond (Cu) time scales. Overall, this work demonstrates the necessity of accessing time scales that far exceed those seen in conventional atomistic modeling for accurate insights into the time-dependent mechanical behavior and properties of nanomaterials. PMID- 29708728 TI - High-Performance Ultrathin Active Chiral Metamaterials. AB - Ultrathin active chiral metamaterials with dynamically tunable and responsive optical chirality enable new optical sensors, modulators, and switches. Herein, we develop ultrathin active chiral metamaterials of highly tunable chiroptical responses by inducing tunable near-field coupling in the metamaterials and exploit the metamaterials as ultrasensitive sensors to detect trace amounts of solvent impurities. To demonstrate the active chiral metamaterials mediated by tunable near-field coupling, we design moire chiral metamaterials (MCMs) as model metamaterials, which consist of two layers of identical Au nanohole arrays stacked upon one another in moire patterns with a dielectric spacer layer between the Au layers. Our simulations, analytical fittings, and experiments reveal that spacer-dependent near-field coupling exists in the MCMs, which significantly enhances the spectral shift and line shape change of the circular dichroism (CD) spectra of the MCMs. Furthermore, we use a silk fibroin thin film as the spacer layer in the MCM. With the solvent-controllable swelling of the silk fibroin thin films, we demonstrate actively tunable near-field coupling and chiroptical responses of the silk-MCMs. Impressively, we have achieved the spectral shift over a wavelength range that is more than one full width at half-maximum and the sign inversion of the CD spectra in a single ultrathin (1/5 of wavelength in thickness) MCM. Finally, we apply the silk-MCMs as ultrasensitive sensors to detect trace amounts of solvent impurities down to 200 ppm, corresponding to an ultrahigh sensitivity of >105 nm/refractive index unit (RIU) and a figure of merit of 105/RIU. PMID- 29708729 TI - Powerful Artificial Neural Network for Planar Chromatographic Image Evaluation, Shown for Denoising and Feature Extraction. AB - An artificial neural network (ANN) is presented as a new and superior technique for processing planar chromatography images. Though several algorithms are available for image processing in planar chromatography, the use of ANN has not been explored so far. It simulates how the human brain interprets images, and the intrinsic features of the image were captured on patches of pixels and successfully reconstructed afterward. The obtained high number of observations was a perfect basis for using ANN. As examples, three quite different data sets were processed with this new algorithm to demonstrate its versatility and benefits. Powerful features, which the ANN learned from the image data set, improved the quality of the analytical data. Thus, noise or inhomogeneous background of bioautograms was removed as demonstrated for salvia extracts, improving their bioquantifications. On colorful fluorescence chromatograms of further botanical extracts, the power and benefit of the feature extraction were demonstrated. Using ANN, videodensitometric results were improved. If compared to conventional digital processing, the resolution between two adjacent blue fluorescent bands increased from 0.95 to 1.18 or between two orange fluorescent bands from 0.77 to 1.57. The trueness of the new ANN was successfully verified by comparison with conventional densitometric results of the absorbance of separated tea extracts. The correlation coefficients of epigallocatechin gallate therein improved from 0.9889 with median filter to 0.9959 using this new ANN algorithm. The code was released open-source to the scientific community as a ready-to-use tool to exploit this potential, spread its usage, and boost improvements in planar chromatographic image evaluation. PMID- 29708730 TI - Development of a High-Resolution Laser Absorption Spectroscopy Method with Application to the Determination of Absolute Concentration of Gaseous Elemental Mercury in Air. AB - Isotope dilution-cold-vapor-inductively coupled plasma mass spectrometry (ID-CV ICPMS) has become the primary standard for measurement of gaseous elemental mercury (GEM) mass concentration. However, quantitative mass spectrometry is challenging for several reasons including (1) the need for isotopic spiking with a standard reference material, (2) the requirement for bias-free passive sampling protocols, (3) the need for stable mass spectrometry interface design, and (4) the time and cost involved for gas sampling, sample processing, and instrument calibration. Here, we introduce a high-resolution laser absorption spectroscopy method that eliminates the need for sample-specific calibration standards or detailed analysis of sample treatment losses. This technique involves a tunable, single-frequency laser absorption spectrometer that measures isotopically resolved spectra of elemental mercury (Hg) spectra of 6 1S0 <- 6 3P1 intercombination transition near lambda = 253.7 nm. Measured spectra are accurately modeled from first-principles using the Beer-Lambert law and Voigt line profiles combined with literature values for line positions, line shape parameters, and the spontaneous emission Einstein coefficient to obtain GEM mass concentration values. We present application of this method for the measurement of the equilibrium concentration of mercury vapor near room temperature. Three closed systems are considered: two-phase mixtures of liquid Hg and its vapor and binary two-phase mixtures of Hg-air and Hg-N2 near atmospheric pressure. Within the experimental relative standard uncertainty, 0.9-1.5% congruent values of the equilibrium Hg vapor concentration are obtained for the Hg-only, Hg-air, Hg-N2 systems, in confirmation with thermodynamic predictions. We also discuss detection limits and the potential of the present technique to serve as an absolute primary standard for measurements of gas-phase mercury concentration and isotopic composition. PMID- 29708731 TI - Capillary Electrophoresis Sensitivity Enhancement Based on Adaptive Moving Average Method. AB - In the present work, we demonstrate a novel approach to improve the sensitivity of the "out of lab" portable capillary electrophoretic measurements. Nowadays, many signal enhancement methods are (i) underused (nonoptimal), (ii) overused (distorts the data), or (iii) inapplicable in field-portable instrumentation because of a lack of computational power. The described innovative migration velocity-adaptive moving average method uses an optimal averaging window size and can be easily implemented with a microcontroller. The contactless conductivity detection was used as a model for the development of a signal processing method and the demonstration of its impact on the sensitivity. The frequency characteristics of the recorded electropherograms and peaks were clarified. Higher electrophoretic mobility analytes exhibit higher-frequency peaks, whereas lower electrophoretic mobility analytes exhibit lower-frequency peaks. On the basis of the obtained data, a migration velocity-adaptive moving average algorithm was created, adapted, and programmed into capillary electrophoresis data-processing software. Employing the developed algorithm, each data point is processed depending on a certain migration time of the analyte. Because of the implemented migration velocity-adaptive moving average method, the signal-to noise ratio improved up to 11 times for sampling frequency of 4.6 Hz and up to 22 times for sampling frequency of 25 Hz. This paper could potentially be used as a methodological guideline for the development of new smoothing algorithms that require adaptive conditions in capillary electrophoresis and other separation methods. PMID- 29708733 TI - Characterization of Virus Capsids and Their Assembly Intermediates by Multicycle Resistive-Pulse Sensing with Four Pores in Series. AB - Virus self-assembly is a critical step in the virus lifecycle. Understanding how viruses assemble and disassemble provides needed insight into developing antiviral pharmaceuticals. Few tools offer sufficient resolution to study assembly intermediates that differ in size by a few dimers. Our goal is to improve resistive-pulse sensing on nanofluidic devices to offer better particle size and temporal resolution to study intermediates and capsids generated along the assembly pathway. To increase the particle-size resolution of the resistive pulse technique, we measured the same, single virus particles up to a thousand times, cycling them back and forth across a series of nanopores by switching the polarity of the applied potential, i.e., virus ping-pong. Multiple pores in series provide a unique multipulse signature during each cycle that improves particle tracking and, therefore, identification of a single particle and reduces the number of cycles needed to make the requisite number of measurements. With T = 3 and T = 4 hepatitis B virus (HBV) capsids, we showed the standard deviation of the particle-size distribution decreased with the square root of the number of measurements and approached discriminating particles differing in size by single dimers. We then studied in vitro assembly of HBV capsids and observed that the ensemble of intermediates shift to larger sizes over 2 days of annealing. On the contrary, assembly reactions diluted to lower dimer concentrations an hour after initiation had fewer intermediates that persisted after the 2 day incubation and had a higher ratio of T = 4 to T = 3 capsids. These reactions indicate that labile T = 4 intermediates are formed rapidly, and dependent on conditions, intermediates may be trapped as metastable species or progress to yield complete capsids. PMID- 29708732 TI - Protein Cofactors Are Essential for High-Affinity DNA Binding by the Nuclear Factor kappaB RelA Subunit. AB - Transcription activator proteins typically contain two functional domains: a DNA binding domain (DBD) that binds to DNA with sequence specificity and an activation domain (AD) whose established function is to recruit RNA polymerase. In this report, we show that purified recombinant nuclear factor kappaB (NF kappaB) RelA dimers bind specific kappaB DNA sites with an affinity significantly lower than that of the same dimers from nuclear extracts of activated cells, suggesting that additional nuclear cofactors might facilitate DNA binding by the RelA dimers. Additionally, recombinant RelA binds DNA with relatively low affinity at a physiological salt concentration in vitro. The addition of p53 or RPS3 (ribosomal protein S3) increases RelA:DNA binding affinity 2- to >50-fold depending on the protein and ionic conditions. These cofactor proteins do not form stable ternary complexes, suggesting that they stabilize the RelA:DNA complex through dynamic interactions. Surprisingly, the RelA-DBD alone fails to bind DNA under the same solution conditions even in the presence of cofactors, suggesting an important role of the RelA-AD in DNA binding. Reduced RelA:DNA binding at a physiological ionic strength suggests that multiple cofactors might be acting simultaneously to mitigate the electrolyte effect and stabilize the RelA:DNA complex in vivo. Overall, our observations suggest that the RelA-AD and multiple cofactor proteins function cooperatively to prime the RelA-DBD and stabilize the RelA:DNA complex in cells. Our study provides a mechanism for nuclear cofactor proteins in NF-kappaB-dependent gene regulation. PMID- 29708734 TI - Noncanonical Radical SAM Enzyme Chemistry Learned from Diphthamide Biosynthesis. AB - Radical S-adenosylmethionine (SAM) enzymes are a superfamily of enzymes that use SAM and reduced [4Fe-4S] cluster to generate a 5'-deoxyadenosyl radical to catalyze numerous challenging reactions. We have reported a type of noncanonical radical SAM enzymes in the diphthamide biosynthesis pathway. These enzymes also use SAM and reduced [4Fe-4S] clusters, but generate a 3-amino-3-carboxypropyl (ACP) radical to modify the substrate protein, translation elongation factor 2. The regioselective cleavage of a different C-S bond of the sulfonium center of SAM in these enzymes comparing to canonical radical SAM enzymes is intriguing. Here, we highlight some recent findings in the mechanism of these types of enzymes, showing that the diphthamide biosynthetic radial SAM enzymes bound SAM with a distinct geometry. In this way, the unique iron of the [4Fe-4S] cluster in the enzyme can only attack the carbon on the ACP group to form an organometallic intermediate. The homolysis of the organometallic intermediate releases the ACP radical and generates the EF2 radial. PMID- 29708735 TI - Compartment-Specific Labeling of Bacterial Periplasmic Proteins by Peroxidase Mediated Biotinylation. AB - The study of the bacterial periplasm requires techniques with sufficient spatial resolution and sensitivity to resolve the components and processes within this subcellular compartment. Peroxidase-mediated biotinylation has enabled targeted labeling of proteins within subcellular compartments of mammalian cells. We investigated whether this methodology could be applied to the bacterial periplasm. In this study, we demonstrated that peroxidase-mediated biotinylation can be performed in mycobacteria and Escherichia coli. To eliminate detection artifacts from natively biotinylated mycobacterial proteins, we validated two alternative labeling substrates, tyramide azide and tyramide alkyne, which enable biotin-independent detection of labeled proteins. We also targeted peroxidase expression to the periplasm, resulting in compartment-specific labeling of periplasmic versus cytoplasmic proteins in mycobacteria. Finally, we showed that this method can be used to validate protein relocalization to the cytoplasm upon removal of a secretion signal. This novel application of peroxidase-mediated protein labeling will advance efforts to characterize the role of the periplasm in bacterial physiology and pathogenesis. PMID- 29708736 TI - Testing the N-Terminal Velcro Model of CooA Carbon Monoxide Activation. AB - CooAs are dimeric bacterial CO-sensing transcription factors that activate a series of enzymes responsible for CO oxidation. The crystal structure of Rhodospirillum rubrum (rrCooA) shows that the N-terminal Pro from monomer A of the dimer coordinates the heme of monomer B that locks rrCooA in the "off" state. When CO binds, it is postulated that the Pro is replaced with CO, resulting in a very large reorientation of the DNA binding domains required for specific binding to DNA. Crystal structures of the closely related CooA from Carboxydothermus hydrogenoformans (chCooA) are available, and in one of these, the CO-bound on state indicates that the N-terminal region that is displaced when CO binds provides contacts between the heme and DNA binding domains that hold the DNA binding domain in position for DNA binding. This has been termed the N-terminal velcro model of CooA activation. The study presented here tests this hypothesis by generating a disulfide mutant that covalently locks chCooA in the on-state. A simple fluorescence assay was used to measure DNA binding, and the S-S mutant was found to be in the on-state even without CO. We also determined the high resolution crystal structure of the apo-heme domain, and the resulting structure is very similar to the holo-heme-bound structure. This result shows that the heme binding motif forms a stable structure without heme or the DNA binding domain. PMID- 29708737 TI - A Novel Lipidomics Workflow for Improved Human Plasma Identification and Quantification Using RPLC-MSn Methods and Isotope Dilution Strategies. AB - Lipid identification and quantification are essential objectives in comprehensive lipidomics studies challenged by the high number of lipids, their chemical diversity, and their dynamic range. In this work, we developed a tailored method for profiling and quantification combining (1) isotope dilution, (2) enhanced isomer separation by C30 fused-core reversed-phase material, and (3) parallel Orbitrap and ion trap detection by the Orbitrap Fusion Lumos Tribid mass spectrometer. The combination of parallelizable ion analysis without time loss together with different fragmentation techniques (HCD/CID) and an inclusion list led to higher quality in lipid identifications exemplified in human plasma and yeast samples. Moreover, we used lipidome isotope-labeling of yeast (LILY)-a fast and efficient in vivo labeling strategy in Pichia pastoris-to produce (nonradioactive) isotopically labeled eukaryotic lipid standards in yeast. We integrated the 13C lipids in the LC-MS workflow to enable relative and absolute compound-specific quantification in yeast and human plasma samples by isotope dilution. Label-free and compound-specific quantification was validated by comparison against a recent international interlaboratory study on human plasma SRM 1950. In this way, we were able to prove that LILY enabled quantification leads to accurate results, even in complex matrices. Excellent analytical figures of merit with enhanced trueness, precision and linearity over 4-5 orders of magnitude were observed applying compound-specific quantification with 13C labeled lipids. We strongly believe that lipidomics studies will benefit from incorporating isotope dilution and LC-MSn strategies. PMID- 29708738 TI - The Helicobacter pylori HypA.UreE2 Complex Contains a Novel High-Affinity Ni(II) Binding Site. AB - Helicobacter pylori is a human pathogen that colonizes the stomach, is the major cause of ulcers, and has been associated with stomach cancers. To survive in the acidic environment of the stomach, H. pylori uses urease, a nickel-dependent enzyme, to produce ammonia for maintenance of cellular pH. The bacteria produce apo-urease in large quantities and activate it by incorporating nickel under acid shock conditions. Urease nickel incorporation requires the urease-specific metallochaperone UreE and the (UreFGH)2 maturation complex. In addition, the H. pylori nickel urease maturation pathway recruits accessory proteins from the [NiFe] hydrogenase maturation pathway, namely, HypA and HypB. HypA and UreE dimers (UreE2) are known to form a protein complex, the role of which in urease maturation is largely unknown. Herein, we examine the nickel-binding properties and protein-protein interactions of HypA and UreE2 using isothermal titration calorimetry and fluorometric methods under neutral and acidic pH conditions to gain insight into the roles played by HypA in urease maturation. The results reveal that HypA and UreE2 form a stable complex with micromolar affinity that protects UreE from hydrolytic degradation. The HypA.UreE2 complex contains a unique high-affinity (nanomolar) Ni2+-binding site that is maintained under conditions designed to mimic acid shock (pH 6.3). The data are interpreted in terms of a proposed mechanism wherein HypA and UreE2 act as co-metallochaperones that target the delivery of Ni2+ to apo-urease with high fidelity. PMID- 29708739 TI - Formation of N, N-Dimethylacrylamide by a Multicenter Hydrocarbamoylation of C2H2 with N, N-Dimethylformamide Activated by Ru5(MU5-C)(CO)15. AB - Hydrocarbamoylation of C2H2 by N, N-dimethylformamide (DMF) to N, N dimethylacrylamide was effected by a series of cluster-opening reactions with Ru5(MU5-C)(CO)15 (1). The reaction of 1 with DMF yielded the new complexes Ru5(MU5-C)(CO)14(MU-eta2-O?CNMe2)(MU-H) (2) and a minor coproduct Ru5(MU5 C)(CO)13(HNMe2)(MU-eta2-O?CNMe2)(MU-H) (3) by a cluster-opening activation of the formyl C-H bond of DMF. Compound 3 was obtained from 2 by a further reaction with DMF. Compound 3 reacted with C2H2 (1 atm, 70 degrees C) to yield Ru5(MU5 C)(CO)13(MU-eta3-O?CNMe2CHCH)(MU-H) (4) by the addition and coupling of C2H2 to the bridging dimethylformamido ligand. Compound 4 contains a sigma-pi coordinated, dimethylformamido-substituted vinyl ligand that bridges a Ru-Ru edge of an open Ru5C cluster. The formamido group is also coordinated to one of the metal atoms. The addition of CO (1 atm, 25 degrees C) to 4 yielded the CO adduct Ru5(MU5-C)(CO)14(eta2-O?CNMe2CH?CH)(MU-H) (5) containing a chelating dimethylacrylamido ligand, which released dimethylacrylamide by the reductive elimination of a C-H bond upon a further addition of CO (400 psi, 125 degrees C) with the re-formation of 1. All of the products were characterized by single crystal X-ray diffraction analyses. PMID- 29708740 TI - Earth-Abundant Mixed-Metal Catalysts for Hydrocarbon Oxygenation. AB - The oxygenation of aliphatic and aromatic hydrocarbons using earth-abundant Fe and Cu catalysts and "green" oxidants such as hydrogen peroxide is becoming increasingly important to atom-economical chemical processing. In light of this, we describe that dinuclear CuII complexes of pyrrolic Schiff-base macrocycles, in combination with ferric chloride (FeCl3), catalyze the oxygenation of pi activated benzylic substrates with hydroperoxide oxidants at room temperature and low loadings, representing a novel design in oxidation catalysis. Mass spectrometry and extended X-ray absorption fine structure analysis indicate that a cooperative action between CuII and FeIII occurs, most likely because of the interaction of FeCl3 or FeCl4- with the dinuclear CuII macrocycle. Voltammetric measurements highlight a modulation of both CuII and FeIII redox potentials in this adduct, but electron paramagnetic resonance spectroscopy indicates that any Cu-Fe intermetallic interaction is weak. High ketone/alcohol product ratios, a small reaction constant (Hammett analysis), and small kinetic isotope effect for H-atom abstraction point toward a free-radical reaction. However, the lack of reactivity with cyclohexane, oxidation of 9,10-dihydroanthracene, oxygenation by the hydroperoxide MPPH (radical mechanistic probe), and oxygenation in dinitrogen purge experiments indicate a metal-based reaction. Through detailed reaction monitoring and associated kinetic modeling, a network of oxidation pathways is proposed that includes "well-disguised" radical chemistry via the formation of metal-associated radical intermediates. PMID- 29708741 TI - Direct beta-Alkylation of Ketones and Aldehydes via Pd-Catalyzed Redox Cascade. AB - We report a direct beta-alkylation of ketones and aldehydes with simple alkyl bromides through a Pd-catalyzed redox-cascade strategy. The use of a Cu cocatalyst is important for improved efficiency. The reaction is redox-neutral, without the need for strong acids or bases. Both cyclic and acyclic ketones, as well as alpha-branched aldehydes, are suitable substrates for coupling with secondary and tertiary alkyl bromides. Concise formal synthesis of Zanapezil is achieved using this beta-alkylation method. PMID- 29708742 TI - Modeling Kinase Inhibition Using Highly Confident Data Sets. AB - : Protein kinases form a consistent class of promising drug targets, and several efforts have been made to predict the activities of small molecules against a representative part of the kinome. This study continues our previous work ( Bora , A. ; Avram , S. ; Ciucanu , I. ; Raica , M. ; Avram , S. Predictive Models for Fast and Effective Profiling of Kinase Inhibitors . J. Chem. Inf. MODEL: 2016 , 56 , 895 - 905 ; www.chembioinf.ro ) aiming to build and measure the performance of ligand-based kinase inhibitor prediction models. Here we analyzed kinase inhibitor pairs with multiple activity points extracted from the ChEMBL database and identified the main sources of inconsistency. Our results indicate that lower IC50 values are usually less affected by errors and reflect more accurately the structure-activity relationship of the molecules against the target, ideally for quantitative structure-activity relationship studies. Further, we modeled the activities of 104 kinases using unbiased target-specific activity points. The performance of predictors built on extended connectivity fingerprints (ECFP4) and two-dimensional pharmacophore fingerprints (PFPs) are compared by means of tolerance intervals (TIs) (95%/95%) in virtual screening (VS) and classification tasks using external random ( RandSets) and diversity-based ( DivSets) test sets. We found that the two encodings perform superior to each other on different kinases in VS and that PFP models perform consistently better in classifying actives (higher sensitivity). Next, we combined the two encodings into a single one (PFPECFP) and demonstrated that especially in VS (as indicated by the exponential receiver operating curve enrichment metric (eROCE)), for the vast majority of kinases the model performance increased compared with the individual fingerprint models. These findings are highlighted in the more challenging DivSets compared with RandSets. The current paper explores the boundaries of inhibitor predictors for individual kinases to enhance VS and ultimately aid the discovery of novel compounds with desirable polypharmacology. PMID- 29708743 TI - Utilization of a Nonemissive Triphosphine Ligand to Construct a Luminescent Gold(I)-Box That Undergoes Mechanochromic Collapse into a Helical Complex. AB - Luminescent gold(I) complexes ([Au6(Triphos)4Cl](PF6)5.2(CH3C6H5), [Au6(Triphos)4Cl](AsF6)5.8(CH3C6H5), and [Au6(Triphos)4Cl](SbF6)5.7(CH3C6H5) where Triphos = bis(2-diphenylphosphinoethyl)phenylphosphine) with a boxlike architecture have been prepared and crystallographically characterized. A chloride ion resides at the center of the box with two of the six gold(I) ions nearby. Mechanical grinding of blue luminescent crystals containing the cation, [Au6(Triphos)4Cl]5+, results in their conversion into amorphous solids with green emission that contain the bridged helicate cation, [MU-Cl{Au3(Triphos)2}2]5+. A mechanism of the mechanochromic transformation is proposed. The structures of the blue-emitting helicate, [Au3(Triphos)2](CF3SO3)3.4(CH3C6H5).H2O, and the green emitting bridged-helicate, [MU-Cl{Au3(Triphos)2}2](PF6)5.3CH3OH have been determined by single crystal X-ray diffraction. PMID- 29708744 TI - Positive Modulators of the N-Methyl-d-aspartate Receptor: Structure-Activity Relationship Study of Steroidal 3-Hemiesters. AB - Here, we report the synthesis of pregn-5-ene and androst-5-ene dicarboxylic acid esters and explore the structure-activity relationship (SAR) for their modulation of N-methyl-d-aspartate receptors (NMDARs). All compounds were positive modulators of recombinant GluN1/GluN2B receptors (EC50 varying from 1.8 to 151.4 MUM and Emax varying from 48% to 452%). Moreover, 10 compounds were found to be more potent GluN1/GluN2B receptor modulators than endogenous pregnenolone sulfate (EC50 = 21.7 MUM). The SAR study revealed a relationship between the length of the residues at carbon C-3 of the steroid molecule and the positive modulatory effect at GluN1/GluN2B receptors for various D-ring modifications. A selected compound, 20-oxo-pregnenolone hemiadipate, potentiated native NMDARs to a similar extent as GluN1/GluN2A-D receptors and inhibited AMPARs and GABAAR responses. These results provide a unique opportunity for the development of new steroid based drugs with potential use in the treatment of neuropsychiatric disorders involving hypofunction of NMDARs. PMID- 29708745 TI - The Neuronal Tau Protein Blocks in Vitro Fibrillation of the Amyloid-beta (Abeta) Peptide at the Oligomeric Stage. AB - In Alzheimer's disease, amyloid-beta (Abeta) plaques and tau neurofibrillary tangles are the two pathological hallmarks. The co-occurrence and combined reciprocal pathological effects of Abeta and tau protein aggregation have been observed in animal models of the disease. However, the molecular mechanism of their interaction remain unknown. Using a variety of biophysical measurements, we here show that the native full-length tau protein solubilizes the Abeta40 peptide and prevents its fibrillation. The tau protein delays the amyloid fibrillation of the Abeta40 peptide at substoichiometric ratios, showing different binding affinities toward the different stages of the aggregated Abeta40 peptides. The Abeta monomer structure remains random coil in the presence of tau, as observed by nuclear magnetic resonance (NMR), circular dichroism (CD) spectroscopy and photoinduced cross-linking methods. We propose a potential interaction mechanism for the influence of tau on Abeta fibrillation. PMID- 29708746 TI - Three-Fold Intramolecular Ring Closing Alkene Metatheses of Square Planar Complexes with cis Phosphorus Donor Ligands P(X(CH2) mCH?CH2)3 (X = -, m = 5-10; X = O, m = 3-5): Syntheses, Structures, and Thermal Properties of Macrocyclic Dibridgehead Diphosphorus Complexes. AB - Reactions of cis-PtCl2(P((CH2) mCH?CH2)3)2 and Grubbs' first generation catalyst and then hydrogenations afford cis- PtCl2(P((CH2) n)3 P) ( cis-2; n = 2 m + 2 = 12 (b), 14 (c), 16 (d), 18 (e), 20 (f), 22 (g); 6-40%), derived from 3-fold interligand metatheses. The phosphite complexes cis-PtCl2(P(O(CH2) m*CH?CH2)3)2 are similarly converted to cis- PtCl2(P(O(CH2) n*O)3 P) ( cis-5; n* = 8 (a), 10 (b), 12 (c), 10-20%). The substitution products cis- PtPh2(P((CH2) n)3 P) ( cis 6c,d) and cis- PtI2(P(O(CH2)10O)3 P) are prepared using Ph2Zn and NaI, respectively. Crystal structures of cis-2c,d,f, cis-5a,b, and cis-6c show one methylene bridge that roughly lies in the platinum coordination plane and two that are perpendicular. The thermal behavior of the complexes is examined. When the bridges are sufficiently long, they rapidly exchange via an unusual "triple jump rope" motion over the PtX2 moieties. NMR data establish Delta H?, Delta S?, and Delta G298K?/Delta G393K? values of 7.8 kcal/mol, -27.9 eu, and 16.1/18.8 kcal/mol for cis-2d, and a Delta G393K? of >=19.6 kcal/mol for the shorter bridged cis-2c. While cis-2c,g gradually convert to trans-2c,g at 150-185 degrees C in haloarenes, trans-2c,g give little reaction under analogous conditions, establishing the stability order trans > cis. Similar metathesis/hydrogenation sequences with octahedral complexes containing two cis phosphine ligands, fac-ReX(CO)3(P((CH2)6CH?CH2)3)2 (X = Cl, Br), give fac- ReX(CO)3( P(CH2)13 CH2)((CH2)14)( P(CH2)13 CH2) (19-50%), which are derived from a combination of interligand and intraligand metathesis. The relative stabilities of cis/ trans and other types of isomers are probed by combinations of molecular dynamics and DFT calculations. PMID- 29708747 TI - Precursor Manipulation in Glycopeptide Antibiotic Biosynthesis: Are beta-Amino Acids Compatible with the Oxidative Cyclization Cascade? AB - Natural products such as the glycopeptide antibiotics (GPAs, including vancomycin and teicoplanin) are of great pharmaceutical importance due to their use against Gram-positive bacteria such as methicillin-resistant Staphylococcus aureus. GPAs are assembled in a complex process based on nonribosomal peptide synthesis and late-stage, multistep cross-linking of the linear heptapeptide performed by cytochrome P450 monooxygenases. These P450 enzymes demonstrate varying degrees of substrate selectivity toward the linear peptide precursor, with limited information available about their tolerance regarding modifications to amino acid residues within the essential antibiotic core of the GPA. In order to test the acceptance of altered residues by the P450-catalyzed cyclization cascade, we have explored the use of beta-amino acids in both variable and highly conserved positions within GPA peptides. Our results indicate that the incorporation of beta-amino acids at the C-terminus of the peptide leads to a dramatic reduction in the efficiency of peptide cyclization by the P450s during GPA biosynthesis, whereas replacement of residue 3 is well tolerated by the same enzymes. These results show that maintaining the C-terminal 3,5-dihydroxyphenylglycine residue is of key importance to maintain the efficiency of this complex and essential enzymatic cross-linking process. PMID- 29708748 TI - Cascading Auto-oxidative Biproline Guanylations Form Optically Active Dispacamide Dimers and Permit an Eight-Step Synthesis of (-)-Ageliferin. AB - A nickel catalyzed synthesis of isomeric 3,3'-biproline esters is described. When those materials are doubly acylated with the acid chloride of pyrrole-2 carboxylic acid, they become susceptible to auto-oxidation in the presence of guanidine. Through proper staging of reaction conditions, it is possible to initiate two consecutive oxidative guanylations prior to in situ cycloisomerization to afford spirocyclic bis-glycocyamidines. This unique outcome reflects a cascade of no fewer than 10 reactions occurring sequentially in one flask. The chemistry provides rapid access to advanced intermediates useful for the preparation of complex, optically active pyrrole/imidazole alkaloids. PMID- 29708750 TI - Enantioselective Halo-oxy- and Halo-azacyclizations Induced by Chiral Amidophosphate Catalysts and Halo-Lewis Acids. AB - Catalytic enantioselective halocyclization of 2-alkenylphenols and enamides have been achieved through the use of chiral amidophosphate catalysts and halo-Lewis acids. Density functional theory calculations suggested that the Lewis basicity of the catalyst played an important role in the reactivity and enantioselectivity. The resulting chiral halogenated chromans can be transformed to alpha-Tocopherol, alpha-Tocotrienol, Daedalin A and Englitazone in short steps. Furthermore, a halogenated product with an unsaturated side chain may provide polycyclic adducts under radical cyclization conditions. PMID- 29708749 TI - Two Distinct Mechanisms for C-C Desaturation by Iron(II)- and 2-(Oxo)glutarate Dependent Oxygenases: Importance of alpha-Heteroatom Assistance. AB - Hydroxylation of aliphatic carbons by nonheme Fe(IV)-oxo (ferryl) complexes proceeds by hydrogen-atom (H*) transfer (HAT) to the ferryl and subsequent coupling between the carbon radical and Fe(III)-coordinated oxygen (termed rebound). Enzymes that use H*-abstracting ferryl complexes for other transformations must either suppress rebound or further process hydroxylated intermediates. For olefin-installing C-C desaturations, it has been proposed that a second HAT to the Fe(III)-OH complex from the carbon alpha to the radical preempts rebound. Deuterium (2H) at the second site should slow this step, potentially making rebound competitive. Desaturations mediated by two related l arginine-modifying iron(II)- and 2-(oxo)glutarate-dependent (Fe/2OG) oxygenases behave oppositely in this key test, implicating different mechanisms. NapI, the l Arg 4,5-desaturase from the naphthyridinomycin biosynthetic pathway, abstracts H* first from C5 but hydroxylates this site (leading to guanidine release) to the same modest extent whether C4 harbors 1H or 2H. By contrast, an unexpected 3,4 desaturation of l-homoarginine (l-hArg) by VioC, the l-Arg 3-hydroxylase from the viomycin biosynthetic pathway, is markedly disfavored relative to C4 hydroxylation when C3 (the second hydrogen donor) harbors 2H. Anchimeric assistance by N6 permits removal of the C4-H as a proton in the NapI reaction, but, with no such assistance possible in the VioC desaturation, a second HAT step (from C3) is required. The close proximity (<=3.5 A) of both l-hArg carbons to the oxygen ligand in an X-ray crystal structure of VioC harboring a vanadium based ferryl mimic supports and rationalizes the sequential-HAT mechanism. The results suggest that, although the sequential-HAT mechanism is feasible, its geometric requirements may make competing hydroxylation unavoidable, thus explaining the presence of alpha-heteroatoms in nearly all native substrates for Fe/2OG desaturases. PMID- 29708751 TI - Correction to Identification of Mutational Hot Spots for Substrate Diffusion: Application to Myoglobin. PMID- 29708752 TI - Probing Fe-V Bonding in a C3-Symmetric Heterobimetallic Complex. AB - Direct metal-metal bonding of two distinct first-row transition metals remains relatively unexplored compared to their second- and third-row heterobimetallic counterparts. Herein, a recently reported Fe-V triply bonded species, [V( iPrNPPh2)3FeI] (1; Kuppuswamy, S.; Powers, T. M.; Krogman, J. P.; Bezpalko, M. W.; Foxman, B. M.; Thomas, C. M. Vanadium-iron complexes featuring metal-metal multiple bonds. Chem. Sci. 2013, 4, 3557-3565), is investigated using high frequency electron paramagnetic resonance, field- and temperature-dependent 57Fe nuclear gamma resonance (Mossbauer) spectroscopy, and high-field electron electron double resonance detected nuclear magnetic resonance. From the use of this suite of physical methods, we have assessed the electronic structure of 1. These studies allow us to establish the effective g tensors as well as the Fe/V electro-nuclear hyperfine interaction tensors of the spin S = 1/2 ground state. We have rationalized these tensors in the context of ligand field theory supported by quantum chemical calculations. This theoretical analysis suggests that the S = 1/2 ground state originates from a single unpaired electron predominately localized on the Fe site. PMID- 29708753 TI - Spatially Controlled Noncovalent Functionalization of 2D Materials Based on Molecular Architecture. AB - Polymerizable amphiphiles can be assembled into lying-down phases on 2D materials such as graphite and graphene to create chemically orthogonal surface patterns at 5-10 nm scales, locally modulating functionality of the 2D basal plane. Functionalization can be carried out through Langmuir-Schaefer conversion, in which a subset of molecules is transferred out of a standing phase film on water onto the 2D substrate. Here, we leverage differences in molecular structure to spatially control transfer at both nanoscopic and microscopic scales. We compare transfer properties of five different single- and dual-chain amphiphiles, demonstrating that those with strong lateral interactions (e.g., hydrogen-bonding networks) exhibit the lowest transfer efficiencies. Since molecular structures also influence microscopic domain morphologies in Langmuir films, we show that it is possible to transfer such microscale patterns, taking advantage of variations in the local transfer rates based on the structural heterogeneity in Langmuir films. Nanoscale domain morphologies also vary in ways that are consistent with predicted relative transfer and diffusion rates. These results suggest strategies to tailor noncovalent functionalization of 2D substrates through controlled LS transfer. PMID- 29708754 TI - Quantitative Attachment of Bimetal Combinations of Transition-Metal Ions to the Surface of TiO2 Nanorods. AB - We report the sequential, quantitative loading of transition-metal ions (Cr3+, Mn2+, Fe2+, Co2+, Ni2+, and Cu2+) onto the surface of rod-shaped anatase TiO2 nanocrystals in bimetallic combinations (6 C2 = 15) to form M,M'-TiO2 nanocrystals. The materials were characterized with transmission electron microscopy (TEM), powder X-ray diffraction (XRD), elemental analysis, X-ray photoelectron spectroscopy (XPS), and UV-visible spectroscopy. TEM and XRD data indicate that the sequential adsorption of metal ions occurs with the retention of the phase and morphology of the nanocrystal. Atomistic models of the M,M'-TiO2 nanocrystals were optimized with density functional theory calculations. Calculated UV-visible absorption spectra and partial charge density maps of the donor and acceptor states for the electronic transitions indicate the importance of metal-to-metal charge transfer (MMCT) processes. PMID- 29708755 TI - Extended Charge-On-Particle Optimized Potentials for Liquid Simulation Acetone Model: The Case of Acetone-Water Mixtures. AB - It is well-known that classical molecular dynamics simulations of acetone-water mixtures lead to a strong phase separation when using most of the standard all atom force fields, despite the well-known experimental fact that acetone is miscible with water in any proportion at room temperature. We describe here the use of a charge-on-particle model for accounting for the induced polarization effect in acetone-water mixtures which can solve the demixing problem at all acetone molar fractions. The polarizability effect is introduced by means of a virtual site (VS) on the carbonyl group of the acetone molecule, which increases its dipole moment and leads to a better affinity with water molecules. The VS parameter is set by fitting the density of the mixture at different acetone molar fractions. The main novelty of the VS approach lies on the transferability and universality of the model because the polarizability can be controlled without modifying the force field adopted, like previous efforts did. The results are satisfactory also in terms of the transport properties, that is, diffusivity and viscosity coefficients of the mixture. PMID- 29708756 TI - Targeted Mass Spectrometry-Based Assays for Relative Quantification of 30 Brain Related Proteins and Their Clinical Applications. AB - Cerebrospinal fluid (CSF) is a promising clinical sample for identification of novel biomarkers for various neurological disorders. Considering its direct contact with brain tissue, CSF represents a valuable source of brain-related and brain-specific proteins. Multiple sclerosis is an inflammatory, demyelinating neurological disease affecting the central nervous system, and so far there are no diagnostic or prognostic disease specific biomarkers available in the clinic. The primary aim of the present study was to develop a targeted mass spectrometry assay for simultaneous quantification of 30 brain-related proteins in CSF and subsequently to demonstrate assay feasibility in neurological samples derived from multiple sclerosis patients. Our multiplex selected reaction monitoring assay had wide dynamic range (median fold range across peptides = 8.16 * 103) and high assay reproducibility (median across peptides CV = 4%). Candidate biomarkers were quantified in CSF samples from neurologically healthy individuals (n = 9) and patients diagnosed with clinically isolated syndrome (n = 29) or early multiple sclerosis (n = 15). PMID- 29708757 TI - Cu(I)-Catalyzed Aminative Aza-Annulation of Enynyl Azide using N Fluorobenzenesulfonimide: Synthesis of 5-Aminonicotinates. AB - An unprecedented copper-catalyzed aminative aza-annulation of enynyl azide using commercially available N-fluorobenzenesulfonimide (NFSI) as an amination reagent is described. The reaction proceeds via regioselective inter-/intramolecular diamination, incorporating one nitrogen from the NFSI and the other from the azide, to provide amino-substituted nicotinate derivatives in a single step with moderate to high yield. This method represents an efficient way to access diverse aminonicotinates through direct C-N bond-coupling processes. PMID- 29708758 TI - Amide-Directed Ru-Catalyzed Hydrodemethoxylation of ortho-Methoxy-Benzamides and Naphthamides: A D oM Reaction Counterpart. AB - A new ruthenium-catalyzed hydrodemethoxylation of ortho-methoxy-benzamides and naphthamides involving amide-directed C-OMe bond activation and hydride reduction is disclosed. The reaction is general, proceeding under RuH2(CO)(PPh3)3 catalysis using either triethylsilane (Et3SiH) or diisobutylaluminum hydride (DIBAL-H) as the reductant. The corresponding C-N hydrodeamination reaction is also briefly reported. PMID- 29708759 TI - Coupling Reagent for UV/vis Absorbing Azobenzene-Based Quantitative Analysis of the Extent of Functional Group Immobilization on Silica. AB - A methallylsilane coupling reagent, containing both a N-hydroxysuccinimidyl(NHS) ester group and a UV/vis absorbing azobenzene linker undergoes acid-catalyzed immobilization on silica. Analysis of the UV/vis absorption band associated with the azobenzene group in the adduct enables facile quantitative determination of the extent of loading of the NHS groups. Reaction of NHS-groups on the silica surface with amine groups of GOx and rhodamine can be employed to generate enzyme or dye-immobilized silica for quantitative analysis. PMID- 29708760 TI - A DNA-Based Nanocarrier for Efficient Gene Delivery and Combined Cancer Therapy. AB - The efficient delivery of a therapeutic gene into target tissues has remained a major obstacle in realizing a viable gene-based medicine. Herein, we introduce a facile and universal strategy to construct a DNA nanostructure-based codelivery system containing a linear tumor therapeutic gene (p53) and a chemotherapeutic drug (doxorubicin, DOX) for combined therapy of multidrug resistant tumor (MCF 7R). This novel codelivery system, which is structurally similar to a kite, is rationally designed to contain multiple functional groups for the targeted delivery and controlled release of the therapeutic cargoes. The self-assembled DNA nanokite achieves efficient gene delivery and exhibits effective inhibition of tumor growth in vitro and in vivo without apparent systemic toxicity. These structurally and chemically well-defined codelivery nanovectors provide a new platform for the development of gene therapeutics for not only cancer but also a wide range of diseases. PMID- 29708761 TI - In Situ High-Level Nitrogen Doping into Carbon Nanospheres and Boosting of Capacitive Charge Storage in Both Anode and Cathode for a High-Energy 4.5 V Full Carbon Lithium-Ion Capacitor. AB - To circumvent the imbalances of electrochemical kinetics and capacity between Li+ storage anodes and capacitive cathodes for lithium-ion capacitors (LICs), we herein demonstrate an efficient solution by boosting the capacitive charge storage contributions of carbon electrodes to construct a high-performance LIC. Such a strategy is achieved by the in situ and high-level doping of nitrogen atoms into carbon nanospheres (ANCS), which increases the carbon defects and active sites, inducing more rapidly capacitive charge-storage contributions for both Li+ storage anodes and PF6- storage cathodes. High-level nitrogen-doping induced capacitive enhancement is successfully evidenced by the construction of a symmetric supercapacitor using commercial organic electrolytes. Coupling a pre lithiated ANCS anode with a fresh ANCS cathode enables a full-carbon LIC with a high operating voltage of 4.5 V and high energy and power densities thereof. The assembled LIC device delivers high energy densities of 206.7 and 115.4 Wh kg-1 at power densities of 0.225 and 22.5 kW kg-1, respectively, as well as an unprecedented high-power cycling stability with only 0.0013% capacitance decay per cycle within 10 000 cycles at a high power output of 9 kW kg-1. PMID- 29708763 TI - Happy Father's Day: Be Important, Make a Difference! PMID- 29708762 TI - Improvements in Irritability with Open-Label Methylphenidate Treatment in Youth with Comorbid Attention Deficit/Hyperactivity Disorder and Disruptive Mood Dysregulation Disorder. AB - OBJECTIVE: The purpose of this open-label study was to examine the effects of long-acting methylphenidate (MPH) treatment on irritability and related emotional symptoms associated with disruptive mood dysregulation disorder (DMDD) in youth with comorbid attention-deficit/hyperactivity disorder (ADHD). METHODS: The sample included 22 medication-free male and female subjects (ages 9-15) who met criteria for both DMDD and ADHD. Participants underwent a 4-week trial of long acting MPH treatment (Concerta(r)), with weekly dosing increases until a therapeutic dose was reached. Repeated measures t-tests were used to compare pre- and posttreatment ratings of primary and secondary measures. The primary outcome was self-report irritability. Secondary outcomes included parent and child ratings of emotional frequency, emotional lability, and negative affect (NA). Multiple regression was used to examine the impact baseline hyperactivity, age, gender, race, socioeconomic status, or comorbid diagnosis had on treatment outcomes. RESULTS: Significant improvements (medium to large effect sizes) in child-rated irritability as well as parent and child ratings of emotional lability, NA, and anger were found. As anticipated, ADHD symptoms also improved. While a majority of the sample saw improvement in child-rated irritability (71%), symptoms worsened a small proportion (19%), and an even smaller portion experienced no change (10%). No demographics, psychiatric comorbidities, or severity of ADHD symptoms influenced treatment outcomes. CONCLUSIONS: Study findings suggest that MPH treatment significantly improved mood and emotional symptoms associated with DMDD comorbid with ADHD. These findings, coupled with good tolerability in this open-label pilot study supports further research into the use of MPH as a first-line treatment for DMDD. Future work examining MPH treatment of youth with DMDD with and without comorbid ADHD is needed. PMID- 29708765 TI - Analyzing Factors That Impact Breastfeeding Duration in the Postpartum Period: A Secondary Analysis of PRAMS Data. AB - BACKGROUND: Benefits of breastfeeding are well established. What is more, breastfeeding is associated with lower healthcare costs. More U.S. hospitals are adopting the World Health Organization's Ten Steps to Successful Breastfeeding; however, most hospitals fall short on key factors. OBJECTIVE: To our knowledge, this project is the first of its kind to use national-level data and a complex statistical modeling approach to identify a more complete picture of the variables related to breastfeeding duration within the postpartum period. METHODS: This secondary data analysis project used the Phase 7 Core PRAMS Research File (2012-2013) and the Standard Questions B1, B2, B3, and B4 variables in the statistical analysis. The outcome variable of interest was length of breastfeeding during the postpartum period. The postpartum period was defined as 8 weeks after delivery rather than the usual definition of 6 weeks to accommodate the way quit time is reported in the Pregnancy Risk Assessment Monitoring System (PRAMS) data. Univariate and multivariate analyses were conducted using PC SAS version 9.4. RESULTS: The multivariate analysis indicates that many of the modifiable factors associated with quitting breastfeeding within the postpartum period are hospital related. This pilot study reinforces the importance of 7 of the 10 Steps. CONCLUSIONS: These results underscore the importance of hospitals adopting evidence-based best practices for breastfeeding. The relationship found between Women, Infants, and Children receiving supplemental nutrition benefits and breastfeeding quit times requires further exploration. The study results also highlight the need to address modifiable factors that may be overlooked in traditional breastfeeding promotion efforts, such as depression and alcohol use. PMID- 29708764 TI - Human Milk Biomarkers of Secretory Activation in Breast Pump-Dependent Mothers of Premature Infants. AB - OBJECTIVE: Mothers of premature infants confront barriers to coming to volume (CTV; >=500 mL/day mother's own milk [MOM] by postpartum day 14), a strong predictor of continued MOM provision at neonatal intensive care unit (NICU) discharge. We sought to determine concentrations of secretory activation biomarkers (MOM sodium, total protein, lactose, and citrate) during the first 14 postpartum days and to describe relationships among these biomarkers, pumped MOM volume, CTV, and pumping frequency. STUDY DESIGN: This descriptive observational study collected serial MOM samples, pumped MOM volume, and pumping frequency during the first 14 postpartum days in 16 breast pump-dependent mothers who delivered <33 weeks gestation. Daily biomarker concentrations were compared to published normal values for mothers of term infants. Relationships among biomarkers, pumped MOM volume, and pumping frequency were determined. RESULTS: On postpartum day 5, only 40% of MOM samples revealed normal concentrations of all four biomarkers, and normalcy was not maintained throughout the first 14 days. All eight mothers (50%) who achieved CTV had normal concentrations for four biomarkers at 5.4 +/- 3.5 days postpartum and had more cumulative pumping sessions by day 5 (p = 0.03). A dose-response relationship between number of normal biomarkers and pumped MOM volume was demonstrated for postpartum days 3 (p = 0.01) and 5 (p = 0.04). CONCLUSION: Secretory activation is delayed in mothers who deliver prematurely and is closely tied to CTV, MOM volume, and pumping frequency. MOM biomarkers hold promise as objective research outcome measures and for point-of-care testing to identify and proactively manage mothers at risk for compromised lactation. PMID- 29708766 TI - Effect of Soft Tissue Techniques on Headache Impact, Disability, and Quality of Life in Migraine Sufferers: A Pilot Study. AB - OBJECTIVE: To determine the efficacy of suboccipital inhibitory techniques in people with migraine compared with a control treatment based on myofascial trigger point (MTrP) therapy and stretching. DESIGN: A randomized, double-blind controlled pilot trial was conducted. SETTINGS/LOCATION: University research laboratory. SUBJECTS: Forty-six adults diagnosed with migraine with over 6 months duration. INTERVENTIONS: Participants were randomized to receive either combined MTrP therapy and stretching (control group) or the control treatment plus suboccipital soft tissue inhibition (experimental group). Treatment was applied on four occasions over 8 weeks (one every 15 days), with a duration of 30 minutes per session in the experimental group and 20 min in the control group. OUTCOME MEASURES: The impact of headache was assessed with the Headache Impact Test (HIT 6), disability by the migraine disability assessment (MIDAS), and quality of life by the Short Form Health Survey (SF-36). Both groups were assessed at baseline and 1 week immediately after the end of treatment. RESULTS: The amount of change of the HIT-6 score and MIDAS scores were significantly different between groups (p < 0.05), although the SF-36 scores were not. The change in the HIT-6 score and MIDAS scores was greater in the experimental group. Both groups showed a reduction on the HIT-6 score (p < 0.001), MIDAS scores (p < 0.05), and SF-36 physical subscale, whereas the SF-36 mental subscale improved only in the experimental group (p < 0.001). CONCLUSION: Soft tissue techniques based on MTrP therapy and stretching were helpful for improving certain aspects of migraine, such as the impact and disability caused by the headache, and the frequency and intensity of headache; however, when combined with suboccipital soft tissue inhibition, the treatment effect was larger. PMID- 29708767 TI - A Fast Approximate Algorithm for Mapping Long Reads to Large Reference Databases. AB - Emerging single-molecule sequencing technologies from Pacific Biosciences and Oxford Nanopore have revived interest in long-read mapping algorithms. Alignment based seed-and-extend methods demonstrate good accuracy, but face limited scalability, while faster alignment-free methods typically trade decreased precision for efficiency. In this article, we combine a fast approximate read mapping algorithm based on minimizers with a novel MinHash identity estimation technique to achieve both scalability and precision. In contrast to prior methods, we develop a mathematical framework that defines the types of mapping targets we uncover, establish probabilistic estimates of p-value and sensitivity, and demonstrate tolerance for alignment error rates up to 20%. With this framework, our algorithm automatically adapts to different minimum length and identity requirements and provides both positional and identity estimates for each mapping reported. For mapping human PacBio reads to the hg38 reference, our method is 290 * faster than Burrows-Wheeler Aligner-MEM with a lower memory footprint and recall rate of 96%. We further demonstrate the scalability of our method by mapping noisy PacBio reads (each >=5 kbp in length) to the complete NCBI RefSeq database containing 838 Gbp of sequence and >60,000 genomes. PMID- 29708769 TI - Healing Waters? Commentary on Two Experimental Studies and a Review of Homeopathy Research. PMID- 29708768 TI - Fibroblast Growth Factor 10 Enhances the Developmental Efficiency of Somatic Cell Nuclear Transfer Embryos by Accelerating the Kinetics of Cleavage During In Vitro Maturation. AB - Somatic cell nuclear transfer (SCNT) is required for the generation of transgenic animals as disease models. During the in vitro development of SCNT embryos, the quality of matured oocytes is one of the major factors regulating the developmental potential of embryos. Time-lapse monitoring systems are new tools that assess the developmental capacity of embryos for use in embryo transfer. In this study, we investigated the effect of fibroblast growth factor 10 (FGF 10) on the developmental potential of SCNT embryos. After the in vitro maturation (IVM) of oocytes in IVM medium containing 10 ng/mL FGF 10 (10 F), the polar body extrusion rate was significantly higher than in the control. However, there was no difference in the percentage of fused embryos between the groups. The cleavage and blastocyst formation rates of embryos were significantly increased in the 10 F compared with the control. In addition, the total cell number was higher and the apoptotic index was lower in the 10 F than control at day 7. The messenger RNA (mRNA) expression of genes involved in apoptosis (baculoviral inhibitor of apoptosis repeat containing 5 [BIRC5] and caspase 3 [CASP3]) and development (octamer-binding transcription factor 4 [POU5F1] and sex determining region Y box 2 [SOX2]) increased after 10 F treatment. Furthermore, the kinetics of the first cleavage was faster and the percentage of embryos at cell block was significantly lower in the 10 F group than in the control. These results demonstrate that exposure of oocytes to FGF 10 during IVM promotes developmental competence. PMID- 29708770 TI - Drug delivery using microneedle patches: not just for skin. PMID- 29708771 TI - Serratia marcescens Colonization Causing Pink Breast Milk and Pink Diapers: A Case Report and Literature Review. AB - INTRODUCTION: Serratia marcescens is an opportunistic pathogen and common cause of infectious outbreaks in pediatric units, leading to both significant morbidity and mortality in immunocompromised hosts. Environmental and some clinical strains may produce a characteristic red pigment, prodigiosin. Colonization can hence turn breast milk and fecally-soiled diapers pink, which can lead otherwise unaffected patients to present to their physicians and also interrupt breastfeeding. No clear guidance exists regarding the outpatient management of breastfeeding mothers and infants colonized with S. marcescens. METHODS: Our aim was to understand the significance of pigment-producing S. marcescens colonization of breast milk and stools in healthy infants in the community setting. We describe the case of a healthy 9-week-old infant presenting with pink soiled diapers secondary to S. marcescens colonization and systematically review previously reported cases of infants diagnosed with pink diapers or milk published in PubMed between 1958 and 2017. RESULTS: Six publications describing seven additional mother-infant cases were selected for inclusion. In all, 8 mother-infant groups of colonization were reviewed, involving 10 infants (there were 2 sets of twins). Good clinical outcomes were reported in all cases regardless of whether antibiotic treatment was prescribed. CONCLUSION: Providers evaluating mother-infant dyads with S. marcescens colonization causing pink milk or pink infant soiled diapers should assess for manifestations of systemic infection. In the absence of evidence of clinical infection, expectant management is appropriate and continued breastfeeding can be supported. PMID- 29708772 TI - Evaluation of femoral perfusion using dynamic contrast-enhanced MRI after simultaneous initiation of electrical stimulation and steroid treatment in an osteonecrosis model. AB - This study aimed to evaluate femoral perfusion using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) for two weeks after the simultaneous initiation of electrical stimulation (ES) and steroid treatment in a steroid induced osteonecrosis (ON) model. A single dose of methylprednisolone was injected into 14 rabbits. Seven rabbits underwent ES (ES group), and seven rabbits did not (control group). DCE-MRI was performed before steroid administration and 1, 5, 10, and 14 days after steroid administration. Regions of interest were set in the bilateral proximal femora. The enhancement ratio, initial slope, and area under the curve were analyzed. These parameters were evaluated after steroid administration in each group and between the two groups, and the ratios of ON in both groups were compared. In the control group, the minimum values of all parameters decreased significantly after steroid administration (P < 0.05), but in the ES group, the parameters did not decrease. In the ES group, all parameter values were significantly increased on the 10th and 14th days (P < 0.05). All parameter values in the ES group were significantly higher than those in the control group on the 14th day (P < 0.05). In the control group, ON was detected in three of five rabbits (in three of ten femora). In the ES group, ON was not detected. These results suggest that increased femoral blood flow elicited by ES may be related to ON prevention after steroid administration. PMID- 29708773 TI - Efficacy of the Fun For Wellness Online Intervention to Promote Well-Being Actions: A Secondary Data Analysis. AB - OBJECTIVE: Fun For Wellness (FFW) is a new online intervention designed to promote growth in well-being by providing capability-enhancing learning opportunities (e.g., play an interactive game) to participants. The purpose of this study was to provide an initial evaluation of the efficacy of the FFW intervention to increase well-being actions. MATERIALS AND METHODS: The study design was a secondary data analysis of a large-scale prospective, double-blind, parallel-group randomized controlled trial. Data were collected at baseline and 30 and 60 days postbaseline. A total of 479 adult employees at a major university in the southeast of the United States of America were enrolled. Participants who were randomly assigned to the FFW group were provided with 30 days of 24-hour access to the intervention. A two-class linear regression model with complier average causal effect estimation was fitted to well-being actions scores at 30 and 60 days. RESULTS: Intent-to-treat analysis provided evidence that the effect of being assigned to the FFW intervention, without considering actual participation in the FFW intervention, had a null effect on each dimension of well-being actions at 30 and 60 days. Participants who complied with the FFW intervention, however, had significantly higher well-being actions scores, compared to potential compliers in the Usual Care group, in the interpersonal dimension at 60 days, and the physical dimension at 30 days. CONCLUSIONS: Results from this secondary data analysis provide some supportive evidence for both the efficacy of and possible revisions to the FFW intervention in regard to promoting well-being actions. PMID- 29708774 TI - Environmental Factors Related to a Semiarid Climate Influence the Freezability of Sperm from Collared Peccaries (Pecari tajacu Linnaeus, 1758). AB - The influence of environmental factors in a semiarid climate on characteristics of fresh and frozen/thawed sperm collected from collared peccaries (Pecari tajacu) was assessed. Semen from 11 male collared peccaries was collected by electroejaculation during the peaks of the dry and rainy periods while rainfall indices, air temperatures, relative humidity levels, and wind speeds were measured. The number, motility, morphology, osmotic response, and membrane integrity of sperm in the collected ejaculates were assessed. Samples were then frozen in liquid nitrogen, thawed, and reassessed. The rainfall index of the rainy period (73.2 mm) was significantly higher than that of the dry period (13.6 mm) and the relative humidity was significantly higher during the rainy period (74.6%) than it was during the dry period (66.8%). Air temperature and wind speed did not differ between the two periods. Characteristics of sperm in the fresh samples were not affected by environmental parameters. In contrast, computerized analysis revealed that sperm in samples frozen during the rainy period exhibited better post-thaw membrane integrity (28.6 +/- 6%), motility (29.5 +/- 7.7%), and rapid sperm population (13.7 +/- 6.2%) than did sperm in samples frozen during the dry period (23.4 +/- 3% membrane integrity, 14.6 +/- 4.1% motility, and 4.1 +/- 1.2% rapid sperm; p < 0.05). Other characteristics of the frozen/thawed sperm did not differ depending on the period in which they were collected. We demonstrated that environmental parameters did not affect the quality of fresh sperm, but could influence the freezability of sperm collected from collared peccaries raised under a semiarid climate. PMID- 29708775 TI - Moderator Roles of Optimism and Weight Control on the Impact of Playing Exergames on Happiness: The Perspective of Social Cognitive Theory Using a Randomized Controlled Trial. AB - OBJECTIVE: The literature on exergames has examined their impact on user perceived psychological health (i.e., user-perceived happiness), but little is known about whether such an impact depends on user characteristics. Therefore, this study used the perspective of social cognitive theory (SCT) to identify potential moderators (i.e., whether the user is optimistic or attempting to control his or her weight) of the impact of playing exergames on user-perceived happiness. MATERIALS AND METHODS: This large-scale randomized controlled trial recruited 337 college students (of whom 57.3% were female and all were aged 20-40 years) as participants. The participants were randomly assigned to the intervention group or the control group. Participants in the intervention group were asked to use an Xbox 360 to play 1 of 10 exergame programs for 30 minutes once a week for 2 weeks. Participants in the control group were not required to do so. Repeated-measures ANOVA was used for the analyses. RESULTS: The analytical results indicate that playing exergames helped to maintain happiness levels and prevented them from decreasing. The maintained happiness was more prominent among participants who were trying to control their weight, but did not differ between participants who were highly optimistic and those who were less optimistic. This study is the first using SCT to explain the contingent effect of playing exergames on user happiness. CONCLUSIONS: Exergames can maintain happiness among users, and such maintenance can be the strongest among users who are trying to control their weight. PMID- 29708776 TI - [Analysis of the Muscle Fatigue Based on Band Spectrum Entropy of Multi-channel Surface Electromyography]. AB - Exercise-induced muscle fatigue is a phenomenon that the maximum voluntary contraction force or power output of muscle is temporarily reduced due to muscular movement.If the fatigue is not treated properly,it will bring about a severe injury to the human body.With multi-channel collection of lower limb surface electromyography signals,this article analyzes the muscle fatigue by adoption of band spectrum entropy method which combined electromyographic signal spectral analysis and nonlinear dynamics.The experimental result indicated that with the increase of muscle fatigue,muscle signal spectrum began to move to low frequency,the energy concentrated,the system complexity came down,and the band spectrum entropy which reflected the complexity was also reduced.By monitoring the entropy,we can measure the degree of muscle fatigue,and provide an indicator to judge fatigue degree for the sports training and clinical rehabilitation training. PMID- 29708777 TI - Healthcare Encounters for Pokemon Go: Risks and Benefits of Playing. AB - OBJECTIVE: Our aim was to quantify the health risks and benefits of Pokemon Go, an augmented reality game played on the mobile phone utilizing real-world locations. MATERIALS AND METHODS: Healthcare encounters containing references to Pokemon Go in Kaiser Permanente Northern California (KPNC) from July 5, 2016 to November 5, 2016 were reviewed. Subjects were classified according to the nature of the healthcare encounter subsequent to playing Pokemon Go: adverse event/injury, self-reported benefit, or incidental mention. Comparisons were made using the Wilcoxon-Mann-Whitney nonparametric test where variables were continuous and the chi-squared or Fisher's exact test where variables were binomial. RESULTS: Of 222 Pokemon Go players reporting an adverse event or benefit, 75 (33.8%) experienced adverse events and 147 (66.2%) reported benefits. Among our cohort, 114 subjects (54.0%) were obese, and 62 (27.9%) were diabetic or prediabetic. More subjects reporting benefits had an endocrine-related comorbidity than those reporting injuries (40.1% vs. 16.0%, P < 0.001). Median family income was higher in the benefit group than in the adverse event group ($83,846 vs. $70,378, P = 0.027). Of 75 subjects having adverse events, 8 (10.7%) had severe injuries, including fractures and head trauma, with 4 (5.3%) having inpatient stays. Most adverse events were musculoskeletal or skin injuries (n = 51, 68.0%). CONCLUSIONS: Injuries were similar to those seen with other light-to moderate outdoor physical activities. Given KPNC's membership of 3.85 million, the number of severe injuries reported was low; this suggests that the game is safe to play. Pokemon Go may be reaching a population that requires increased physical activity. PMID- 29708779 TI - Genome-Wide Analysis of the Association of Transposable Elements with Gene Regulation Suggests that Alu Elements Have the Largest Overall Regulatory Impact. AB - Nearly half of the human genome is made up of transposable elements (TEs), and there is evidence that TEs are involved in gene regulation. In this study, we have integrated publicly available genomic, epigenetic, and transcriptomic data to investigate this in a genome-wide manner. A bootstrapping statistical method was applied to minimize confounder effects from different repeat types. Our results show that although most TE classes are primarily associated with reduced gene expression, Alu elements are associated with upregulated gene expression. Furthermore, Alu elements had the highest probability of any TE class contributing to regulatory regions of any type defined by chromatin state. This suggests a general model where clade-specific short interspersed elements (SINEs) may contribute more to gene regulation than ancient/ancestral TEs. Our exhaustive analysis has extended and updated our understanding of TEs in terms of their global impact on gene regulation and suggests that the most recently derived types of TEs, that is, clade- or species-specific SINES, have the greatest overall impact on gene regulation. PMID- 29708778 TI - Are Food Animals Responsible for Transfer of Antimicrobial-Resistant Escherichia coli or Their Resistance Determinants to Human Populations? A Systematic Review. AB - The role of farm animals in the emergence and dissemination of both AMR bacteria and their resistance determinants to humans is poorly understood and controversial. Here, we systematically reviewed the current evidence that food animals are responsible for transfer of AMR to humans. We searched PubMed, Web of Science, and EMBASE for literature published between 1940 and 2016. Our results show that eight studies (18%) suggested evidence of transmission of AMR from food animals to humans, 25 studies (56%) suggested transmission between animals and humans with no direction specified and 12 studies (26%) did not support transmission. Quality of evidence was variable among the included studies; one study (2%) used high resolution typing tools, 36 (80%) used intermediate resolution typing tools, six (13%) relied on low resolution typing tools, and two (5%) based conclusions on co-occurrence of resistance. While some studies suggested to provide evidence that transmission of AMR from food animals to humans may occur, robust conclusions on the directionality of transmission cannot be drawn due to limitations in study methodologies. Our findings highlight the need to combine high resolution genomic data analysis with systematically collected epidemiological evidence to reconstruct patterns of AMR transmission between food animals and humans. PMID- 29708780 TI - Bleeding Complications After Percutaneous Liver Biopsy: Do Subcapsular Lesions Pose a Higher Risk? AB - OBJECTIVE: The purpose of this study is to determine the incidence of moderate and severe bleeding complications after subcapsular liver mass biopsy and compare it with the incidences of such complications after nonsubcapsular liver mass biopsy and after random biopsy. MATERIALS AND METHODS: This retrospective review of ultrasound-guided liver biopsies was performed between January 2006 and February 2015. Biopsy type, needle size, the number of needle passes, and mass size and depth were recorded. A mass was categorized as subcapsular if it abutted the capsule and if the needle entered the mass directly without first traversing normal liver. Patients were observed postprocedurally, and the electronic medical record and findings from imaging performed within 1 month of the procedure were reviewed to assess for bleeding. Bleeding complications were categorized by size (with mild bleeding denoted by perihepatic blood <= 2 cm thick; moderate bleeding denoted by perihepatic blood > 2 cm thick, observation of blood elsewhere in the upper abdomen, or a combination of both findings; and severe bleeding denoted by blood extending into the lower abdomen, pelvis, or both). Bleeding rates were compared between groups using the Fisher exact test. RESULTS: Of a total of 1876 biopsies, 347 (18.5%) involved subcapsular masses, 760 (40.5%) involved nonsubcapsular masses, and 769 (41.0%) were random biopsies. There were no significant differences in biopsy type (p = 1.00), needle size (p = 0.12), or the number of needle passes (p = 0.10) when subcapsular and nonsubcapsular masses were compared. Thirteen moderate or severe bleeding complications (0.69%) occurred overall. The bleeding rate after subcapsular mass biopsy (3/347; 0.86%) was not statistically different from that noted after nonsubcapsular mass biopsy (5/760; 0.66%) (p = 0.71) or after random biopsy (5/769; 0.65%) (p = 0.71). CONCLUSION: Moderate and severe bleeding complications are rare after subcapsular liver mass biopsy, and their incidence is not significantly higher than that noted after nonsubcapsular mass biopsy or random biopsy. Biopsy of subcapsular lesions should no longer be considered contraindicated. PMID- 29708781 TI - Synergistic Role of Newer Techniques for Forensic and Postmortem CT Examinations. AB - OBJECTIVE: The aim of this article is to provide an overview of newer techniques and postprocessing tools that improve the potential impact of CT in forensic situations. CONCLUSION: CT has become a standard tool in medicolegal practice. Postmortem CT is an essential aid to the pathologist during autopsies. Advances in technology and software are constantly leading to advances in its performance. PMID- 29708782 TI - MRI, Clinical Examination, and Mammography for Preoperative Assessment of Residual Disease and Pathologic Complete Response After Neoadjuvant Chemotherapy for Breast Cancer: ACRIN 6657 Trial. AB - OBJECTIVE: The objective of our study was to determine the accuracy of preoperative measurements for detecting pathologic complete response (CR) and assessing residual disease after neoadjuvant chemotherapy (NACT) in patients with locally advanced breast cancer. SUBJECTS AND METHODS: The American College of Radiology Imaging Network 6657 Trial prospectively enrolled women with >= 3 cm invasive breast cancer receiving NACT. Preoperative measurements of residual disease included longest diameter by mammography, MRI, and clinical examination and functional volume on MRI. The accuracy of preoperative measurements for detecting pathologic CR and the association with final pathology size were assessed for all lesions, separately for single masses and nonmass enhancements (NMEs), multiple masses, and lesions without ductal carcinoma in situ (DCIS). RESULTS: In the 138 women with all four preoperative measures, longest diameter by MRI showed the highest accuracy for detecting pathologic CR for all lesions and NME (AUC = 0.76 and 0.84, respectively). There was little difference across preoperative measurements in the accuracy of detecting pathologic CR for single masses (AUC = 0.69-0.72). Longest diameter by MRI and longest diameter by clinical examination showed moderate ability for detecting pathologic CR for multiple masses (AUC = 0.78 and 0.74), and longest diameter by MRI and longest diameter by mammography showed moderate ability for detecting pathologic CR for tumors without DCIS (AUC = 0.74 and 0.71). In subjects with residual disease, longest diameter by MRI exhibited the strongest association with pathology size for all lesions and single masses (r = 0.33 and 0.47). Associations between preoperative measures and pathology results were not significantly influenced by tumor subtype or mammographic density. CONCLUSION: Our results indicate that measurement of longest diameter by MRI is more accurate than by mammography and clinical examination for preoperative assessment of tumor residua after NACT and may improve surgical planning. PMID- 29708783 TI - Prebiopsy Multiparametric MRI With Cancer-Negative Findings in Men With Suspected Prostate Cancer: Evaluation Using Prostate Imaging Reporting and Data System Version 2. AB - OBJECTIVE: The purpose of this study is to investigate the rates and characteristics of missed cancers at prebiopsy multiparametric MRI with cancer negative findings according to the Prostate Imaging Reporting and Data System (PI RADS) version 2 in men with suspected prostate cancer (PCa). MATERIALS AND METHODS: A total of 584 consecutive men (biopsy naive, n = 392; repeated biopsy, n = 192) with suspected PCa who underwent prebiopsy 3-T multipara-metric MRI, followed by subsequent biopsies, were enrolled. Cancer-positive findings were confirmed at systemic biopsies and cognitive MRI-targeted biopsies, whereas cancer-negative findings were confirmed at systemic biopsies performed during subsequent follow-up. Missing and detection rates of all PCa and clinically significant cancer according to five biopsy-based definitions were determined. The likelihood of PCa at multiparametric MRI was evaluated according to PI-RADS version 2, and the results were compared. RESULTS: Pathologically confirmed cancers were found in 25% of patients. Cancer-positive MRI findings were seen in 99 men (17%) and, of these, 85.9% had PCa. Of 485 men with cancer-negative MRI findings, a total of 61 (12.6%) had PCa, including 46 men in the biopsy-naive group and 15 men in the repeated-biopsy group. For clinically significant cancers, the rate of missed cancers at MRI was 0.1-6.0%, and the detection rate was 21.2-83.5%. For detecting PCa, multiparametric MRI had 96.8% specificity, 87.2% accuracy, and 87.4% negative predictive value. CONCLUSION: Prebiopsy 3-T multiparametric MRI with cancer-negative findings missed approximately 12.6% of cases of PCa, including 0.1-6.0% of clinically significant cancers in a cohort of biopsy-naive men and those who had undergone repeated biopsy. PMID- 29708784 TI - Lung Cancer Screening Guidelines: How Readable Are Internet-Based Patient Education Resources? AB - OBJECTIVE: Following the findings of the National Lung Screening Trial, several national societies from multiple disciplines have endorsed the use of low-dose chest CT to screen for lung cancer. Online patient education materials are an important tool to disseminate information to the general public regarding the proven health benefits of lung cancer screening. This study aims to evaluate the reading level at which these materials related to lung cancer screening are written. MATERIALS AND METHODS: The four terms "pulmonary nodule," "radiation," "low-dose CT," and "lung cancer screening" were searched on Google, and the first 20 online resources for each term were downloaded, converted into plain text, and analyzed using 10 well-established readability scales. If the websites were not written specifically for patients, they were excluded. RESULTS: The 80 articles were written at a 12.6 +/- 2.7 (mean +/- SD) grade level, with grade levels ranging from 4.0 to 19.0. Of the 80 articles, 62.5% required a high school education to comprehend, and 22.6% required a college degree or higher (>= 16th grade) to comprehend. Only 2.5% of the analyzed articles adhered to the recommendations of the National Institutes of Health and American Medical Association that patient education materials be written at a 3rd- to 7th-grade reading level. CONCLUSION: Commonly visited online lung cancer screening-related patient education materials are written at a level beyond the general patient population's ability to comprehend and may be contributing to a knowledge gap that is inhibiting patients from improving their health literacy. PMID- 29708785 TI - Interval Change in Diffusion and Perfusion MRI Parameters for the Assessment of Pseudoprogression in Cerebral Metastases Treated With Stereotactic Radiation. AB - OBJECTIVE: Apparent increases in the size of cerebral metastases after stereotactic radiosurgery (SRS) can be caused by pseudoprogression or true disease progression, which poses a diagnostic challenge at conventional MRI. The purpose of this study was to assess whether interval change in DWI and perfusion MRI parameters can differentiate pseudoprogression from progressive disease after treatment with SRS. MATERIALS AND METHODS: Patients with apparent growth of cerebral metastases after SRS treatment who underwent pre- and post-SRS DWI, dynamic susceptibility contrast (DSC)-MRI, and perfusion dynamic contrast enhanced (DCE)-MRI were retrospectively evaluated. Final assignment of pseudoprogression or progressive disease was determined at 6-month follow-up imaging using the Response Assessment in Neuro-Oncology Brain Metastases criteria. Mean values of apparent diffusion coefficient (ADC), DCE-MRI-derived volume transfer constant (Ktrans), and DSC-MRI-derived relative cerebral blood volume (CBV) from pre- and post-SRS MRI scans were compared between groups using univariate and regression analysis. Fisher exact test was used to compare interval change of imaging biomarkers. RESULTS: Of 102 cerebral metastases evaluated, 32 lesions in 29 patients met our inclusion criteria. The mean duration of follow-up was 7.2 months (range, 6-14 months). Twenty-two lesions were determined as pseudoprogression, and 10 lesions were determined as progressive disease using the Response Assessment in Neuro-Oncology Brain Metastases criteria at 6-month follow-up MRI. The interval change pattern of our imaging parameters matched the expected patterns of treatment response for ADC (23/32 lesions; 72%; p = 0.055; odds ratio, 5.1), Ktrans (24/32 lesions; 75%; p = 0.006; odds ratio, 19.2), and relative CBV (27/32 lesions; 84%; p = 0.001; odds ratio, 25.3). CONCLUSION: Pseudoprogression can be distinguished from disease progression in cerebral metastases treated with SRS via an interval decrease in relative CBV and Ktrans values. PMID- 29708786 TI - Differentiation Between Hepatocellular Carcinoma Showing Hyperintensity on the Hepatobiliary Phase of Gadoxetic Acid-Enhanced MRI and Focal Nodular Hyperplasia by CT and MRI. AB - OBJECTIVE: The purpose of this study is to identify points useful in the imaging differentiation of hepatocellular carcinoma (HCC) showing hyperintensity on the hepatobiliary phase of gadoxetic acid-enhanced MRI and focal nodular hyperplasia (FNH) and FNH-like nodules. MATERIALS AND METHODS: We enrolled consecutive 51 pathologically diagnosed HCCs that were hyperintense on hepatobiliary phase imaging (47 patients, including 44 with cirrhosis) and 10 FNHs and eight FNH-like nodules (16 patients, including five with cirrhosis). Imaging findings of dynamic CT and gadoxetic acid-enhanced MRI were assessed by two radiologists and compared between HCC and FNH. RESULTS: The apparent diffusion coefficient (ADC) was lower in hyperintense HCC than in FNH (p = 0.004). The enhancement patterns of hyperintense HCC and FNH at dynamic CT were significantly different (p < 0.0001), with 95.9% of HCCs and 22.2% of FNHs showing arterial phase enhancement with a washout pattern, and 4.1% of HCCs and 77.8% of FNHs showing arterial phase enhancement without a washout pattern. The frequency of coronalike enhancement was 84.3% in hyperintense HCCs versus 11.1% in FNHs (p < 0.0001). The signal distribution on the hepatobiliary phase was significantly different between hyperintense HCCs and FNHs (p = 0.0002). The frequency of a capsulelike rim was 88.2% versus 22.2%, that of a mosaic appearance was 72.5% versus 11.1%, and that of a central scar was 0% versus 55.6% in hyperintense HCCs versus FNHs (all p < 0.0001). Multivariate logistic regression analysis showed that ADC ratio (p = 0.03; odds ratio, 0.12) and enhancement pattern at dynamic CT (p = 0.04; odds ratio, 16.21) were the independent factors for differentiation between hyperintense HCC and FNH. CONCLUSION: For the diagnosis of hyperintense HCC differentiated from FNH and FNH-like nodule, arterial phase enhancement and washout pattern at dynamic CT and decrease of ADC ratio would be important findings. PMID- 29708787 TI - Self-care for older people with psoriasis. AB - Psoriasis affects 1.5% of the UK population and due to the ageing population it is more common in older people. The incidence of type II psoriasis peaks in patients between 57 and 62 years of age, and has different genetic markers. Chronic plaque psoriasis can be challenging for older people as the majority are treated in primary care and expected to self-manage. Community nurses can support older people with psoriasis and their families in understanding current evidence based psoriasis management, and finding solutions to these challenges. PMID- 29708788 TI - Does every contact count? PMID- 29708789 TI - District nursing renascent as Wales adopts safe staffing levels. AB - This article reflects on the history of the NHS in Wales and how this has led to its current structure. How this structure supports integrated working across primary, community and secondary care and how further integration with social care is moving forward and its direct effects on district nursing are explored. This article describes how district nursing is meeting these challenges. Support for district nurses as part of integrated multiprofessional teams is being developed to promote appropriately staffed teams centred on meeting the requirements of people within a designated area and ensuring that home is the best and first place of care. PMID- 29708790 TI - The calm before the 'perfect storm'. PMID- 29708791 TI - Dietary management of older people with diabetes. AB - Diabetes UK's revised nutrition guidelines for the prevention and management of diabetes, published recently, encourage education in self-management and include additional guidance for older people with diabetes. The incidence of diabetes in older people is increasing. Many older people with diabetes are healthy and mobile, and live in the community, but a number are frail and living in care homes. Those who are frail are at increased risk of malnutrition from a range of causes. Older people with diabetes should be assessed for malnutrition risk and referred to a dietitian if required. Management of these patients focuses on foods that are high in protein and energy foods. A case study gives an example of how a community nurse may be involved. PMID- 29708792 TI - Incontinence-associated dermatitis in older people: prevention and management. PMID- 29708793 TI - Clean intermittent self-catheterisation and multiple sclerosis. PMID- 29708794 TI - Best interest meetings. AB - Best interests is the standard by which the law judges the propriety of care and treatment for adults who lack decision making capacity. The Mental Capacity Act 2005 Code of Practice argues that the best way to decide on a person's best interests is through a multidisciplinary best interests meeting to enable all views, including those of the patient and their carers to be properly considered. In this article Richard Griffith considers the conduct of a best interest meeting and the role of district nurses in those meetings. PMID- 29708795 TI - Perspectives on the delegation of hygienic care in the context of home nursing: a qualitative study. AB - BACKGROUND: In light of current trends and healthcare evolutions, delegation of patient care from home nurses to health care assistants (HCAs) is increasingly important. Hygienic care is an essential component of nursing education and practice, yet it has rarely been the subject of scientific literature. AIM: To understand the opinions and experiences of home nurses and policy makers with regard to the meaning of hygienic care and the delegation of these acts in the context of home nursing. METHODS: A descriptive qualitative study (six focus groups with home nurses and two with policy makers from the Belgian home nursing sector). Content analysis of the data and the use of NVivo 11.0 software. FINDINGS: Hygienic care is a cyclical care process of continuously investing in a trusting relationship with a patient, assessing their care needs and ability for self-care and taking action and evaluating care as situations change. All of this must be mutally agreed with the patient and should consider their environment and lifestyle. The decision to delegate hygienic care is based on patient assessments and the patient's specific care needs using nursing diagnoses and indicators. Finally, barriers and facilitating factors for both delegating and providing hygienic care were addressed. CONCLUSION: Hygienic care is a crucial component of nursing care, that can be delegated to HCAs with the necessary supervision. PMID- 29708796 TI - Recruiting the next generation: applying a values-based approach to recruitment. AB - The qualified district nurse (DN) role demands high levels of leadership. Attracting the right candidates to apply for the Specialist Practice Qualification District Nursing (SPQDN) education programme is essential to ensure fitness to practice on qualification. Anecdotal evidence suggested that the traditional panel interview discouraged candidates from applying and a need to improve the quality of the overall interview process was identified by the authors. The University of Central Lancashire in partnership with Lancashire Care NHS Foundation Trust adopted the National Values Based Recruitment (VBR) Framework to select candidates to gain entry onto the SPQDN course. This involved using 'selection centres' of varying activities including a multiple mini interview, written exercise, group discussion, and portfolio review with scores attached to each centre. The ultimate aim of utilising VBR was to align personal and profession values to both the nursing profession and the Trust whilst allowing a fairer assessment process. An evaluation of the VBR recruitment process demonstrated 100% pass rate for the course and 100% satisfaction with the interview process reported by all 16 candidates over three academic years. Interviewer feedback showed deeper insight into the candidates' skills and values aligned with the core values and skills required by future District Nurse leaders within the Trust. PMID- 29708797 TI - Becoming aware of patients at risk of self-harm or suicide. PMID- 29708798 TI - Researching palliative care: remaining true to the ontological subjective of patients. PMID- 29708799 TI - Combined Tongue-Palate Fusion With Alveolar Bands in a Patient With Pierre Robin Sequence and Van der Woude Syndrome. AB - This report describes the presentation of a newborn male with circumferential tongue-palate fusion associated with cleft palate and alveolar bands. After intraoral adhesions lysis, the patient was diagnosed with Pierre Robin sequence. A family history of cleft lip and palate was noted, and interferon regulatory factor 6 ( IRF6) sequencing revealed a heterozygous variant, confirming the diagnosis of van der Woude syndrome. The disruption of IRF6 resulted in abnormal orofacial development including micrognathia and intraoral adhesions as well as tongue-palate fusion, then resulting in glossoptosis with airway obstruction and cleft palate. PMID- 29708801 TI - Erratum. AB - Kawamoto H. 2017 Whitaker Lecture: History of the American Society of Craniofacial Surgery. Cleft Palate Craniofac J. 2018;55:8-11. (Original DOI: 10.1177/1055665617740350 ) In the January 2018 issue of The Cleft Palate Craniofacial Journal, Table 3 on page 10 contained several errors. The corrected Table 3 appears below: [Table: see text]. PMID- 29708800 TI - Birth Prevalence of Orofacial Clefts in Kuwait From Hospital-Based Registration: Retrospective Study. AB - INTRODUCTION: Cleft lip and palate (CLAP) are the most common craniofacial anomalies and birth defects globally. Despite the fact that a tertiary care registry of clefts has existed in Kuwait since 2008, to date there is no published data regarding the prevalence of orofacial clefts in this population. OBJECTIVE: To tabulate the pattern of orofacial clefts from tertiary care center registration during 2009 through 2014 and to estimate the prevalence and trend using population-based records. METHODOLOGY: Data from all CLAP cases (born in Kuwait) registered in the central cleft center registry of the Al-Amiri hospital, Kuwait City, Kuwait, from January 2009 to December 2014 were obtained. Data regarding the type, severity, gender as well as nationality, parental consanguinity, and associated syndrome were obtained from medical records. Birth prevalence was tabulated against the population statistics for the period obtained from the central department of statistics. RESULT: A total of 202 CLAP patients were recorded in the study period with a mean birth prevalence of 0.57 per 1000 live births (95% confidence interval [CI] .57 +/- .23). The registry recorded 108 (53.2%) males and 94 (47.8%) females. Children born to Kuwaitis represented 53.7% of cases while those born to non-Kuwaitis represented 45.3%. The most common oral cleft was CLAP (47.3%), followed by cleft palate (30.5%), cleft lip (20.2%), and other facial clefts (2%). Other congenital anomalies were recognized in 33% of all cases. There were no statistically significant differences in oral cleft prevalence across gender or nationality. CONCLUSION: The prevalence of oral cleft in Kuwait appears to be similar to those of other Middle Eastern populations. PMID- 29708802 TI - Establishment of a Multiplex Loop-Mediated Isothermal Amplification Method for Rapid Detection of Sulfonamide Resistance Genes (sul1, sul2, sul3) in Clinical Enterobacteriaceae Isolates from Poultry. AB - Antimicrobial resistance genes play an important role in mediating resistance to sulfonamide in Gram-negative bacteria. While PCR is the current method to detect sulfonamide resistance genes (sul1, sul2, sul3), it is time-consuming and costly and there is an urgent need to develop a more convenient, simpler and rapid test for the sul. In this study, we describe a multiplex loop-mediated isothermal amplification (m-LAMP) assay we developed for the rapid and simultaneous detection of three sul. This m-LAMP assay successfully detected seven reference strains with different sul genotypes, but was negative for nine sul-negative reference strains. The m-LAMP products were verified by HinfI restriction enzyme digestion and the detection limit of the test was 0.5 pg genomic DNA per reaction. Testing 307 sulfonamide-resistant Enterobacteriaceae clinical isolates with the m-LAMP revealed all were positive for the sul with sul2 (79.5%) and sul1 (64.5%) being most prevalent, and sul3 the least (12.1%). Of the Enterobacteriaceae isolates tested, the Salmonella Indiana, a newly emerging serovar resistant to numerous antimicrobials, were most commonly positive with 33% having sul3. PMID- 29708803 TI - A 5-Year Follow-Up Study of the Treatment of Macular Edema Due to Retinal Vein Occlusion Using Dexamethasone Intravitreal Implants. AB - PURPOSE: To evaluate the long-term effects of intravitreal dexamethasone implants (IDIs) in eyes with macular edema (ME) due to retinal vein occlusion (RVO). METHODS: We reviewed the records of 10 patients followed for 5 years after they received their first IDI. The main outcome measures included changes in best corrected visual acuity (BCVA), central macular thickness (CMT), and central macular volume (CMV), and the incidence of side effects. RESULTS: Ten patients were included in the study with a mean follow-up of 65.51 months. Forty IDI injections were performed. An improvement in BCVA was observed after 92.5% of the IDI injections (P < 0.05), while the CMT and the CMV decreased significantly (P < 0.05) after 97.5% of the injections. After 27.5% of the injections, the intraocular pressure rose more than 10 mmHg and 3 of the 7 phakic patients required phacoemulsification surgery. CONCLUSION: IDI is an effective therapy for the treatment of ME secondary to RVO with a favorable long-term safety profile. PMID- 29708804 TI - Korean Red Ginseng Protects Against Mitochondrial Damage and Intracellular Inflammation in an Animal Model of Type 2 Diabetes Mellitus. AB - Korean red ginseng (KRG), a heat-processed Korean ginseng (Panax ginseng C.A. Meyer), has been used as a traditional medicine for its beneficial effects on hyperglycemia. This study aimed to investigate whether the antidiabetic action of KRG in an animal model of type 2 diabetes mellitus (DM) is partly mediated by prevention of mitochondrial dysfunction and intracellular inflammation. Four-week old C57BL/KsJ db/db mice (a genetic animal model of obese type 2 DM) and C57BL/KsJ db/+ mice were divided into three groups: db/+ mice (normoglycemic control group, n = 8), db/db mice (untreated DM group, n = 8), and db/db mice with KRG administration (KRG-treated DM group, n = 8). After 12 weeks, metabolic parameters of fasting blood glucose concentrations, hemoglobin A1c (HbA1c) level, insulin level, lipid profile, and leukocyte count were determined using high performance liquid chromatography. Mitochondrial DNA (mtDNA) copy number and inflammatory marker (interleukin-6, cyclooxygenase-2, and C-reactive protein) expression levels were measured in skeletal muscle tissue using quantitative real time PCR analysis. After 12 weeks of KRG treatment at 100 mg/kg, the fasting glucose, HbA1c, insulin, and low-density lipoprotein cholesterol concentrations were lower, whereas mtDNA copy numbers were higher in the KRG-treated DM group than in the untreated DM group. Compared with the untreated DM group, the messenger RNA expression levels of mitochondrial biogenesis-related transcription factors and inflammatory markers were lower in the KRG-treated DM group. In conclusion, KRG had a beneficial effect on the metabolic profile by preserving mitochondrial function and protecting against intracellular inflammation. PMID- 29708805 TI - Human urinary concentrations of monoisononyl phthalate estimated using physiologically based pharmacokinetic modeling and experimental pharmacokinetics in humanized-liver mice orally administered with diisononyl phthalate. AB - Diisononyl phthalate (DINP) used as a plasticizer is a mixture of compounds consisting of isononyl esters of phthalic acid. There are concerns about the bioaccumulation of such esters in humans. A [phenyl-U-14C]DINP mixture was synthesized and orally administered (50 mg/kg body weight) to control and humanized-liver mice and their pharmacokinetics were determined. Monoisononyl phthalate (MINP, a primary metabolite of DINP), oxidized MINP (isomers with hydroxy, carbonyl, and carboxy functional groups), and their glucuronides were detected in plasma from control and humanized-liver mice. Biphasic plasma concentration-time curves of MINP and its glucuronide were seen in control mice. In contrast, no such biphasic relationship was seen in humanized-liver mice, in which MINP and oxidized MINP were extensively excreted in the urine within 48 h. Animal biomonitoring equivalents of MINP and oxidized MINP from humanized-liver mice studies were scaled to human equivalents using known species allometric scaling factors with a simple physiologically based pharmacokinetic (PBPK) model. Estimated urinary oxidized MINP concentrations in humans were roughly consistent with reported concentrations of MINP (with a different side chain). The simplified PBPK model could estimate human urinary concentrations of MINP after ingestion of DINP and was capable of both forward and reverse dosimetry. PMID- 29708806 TI - Ashitaba (Angelica Keiskei) Exudate Prevents Increases in Plasminogen Activator Inhibitor-1 Induced by Obesity in Tsumura Suzuki Obese Diabetic Mice. AB - Angelica keiskei koidzumi (ashitaba) is consumed as a traditional folk medicine and health food in Japan. Ashitaba extract contains abundant flavonoids containing chalcones. Plasminogen activator inhibitor-1 (PAI-1) is the primary physiological inhibitor of tissue plasminogen activator. Excessive amounts of PAI 1 in plasma disrupt the fibrinolytic balance and promote a prothrombotic state with which thrombosis and cardiovascular diseases are associated. In the present study, we investigated the effects of ashitaba yellow exudate (AE) on enhanced PAI-1 levels in Tsumura Suzuki obese diabetic (TSOD) mice. AE significantly decreased food efficiency and plasma PAI-1 in TSOD mice but did not affect lean control Tsumura Suzuki nonobese (TSNO) mice. AE also decreased some parameters in the plasma, such as glucose, insulin, tumor necrosis factor alpha (TNF-alpha) and gains in body weight, subcutaneous, mesenteric fat weight in TSOD mice but had little effect on these parameters in TSNO mice. Levels of adipose PAI-1 were significantly higher in TSOD than in TSNO mice. Major sources of plasma PAI-1 are thought to be adipose tissue and liver. AE significantly suppressed PAI-1 protein levels in the livers of both TSOD and TSNO mice. These results suggest that AE decreased plasma PAI-1 levels by suppressing both the adipose tissue retention of PAI-1 protein and liver PAI-1 production in TSOD mice. Supplementing the diet with AE might help to prevent thrombotic diseases or alleviate the risk of thrombotic diseases as well as to suppress metabolic state in obese individuals. PMID- 29708807 TI - Breaking the Glass Ceiling of Overall Survival in Non-Small-Cell Lung Cancer. PMID- 29708808 TI - MIPSS70+ Version 2.0: Mutation and Karyotype-Enhanced International Prognostic Scoring System for Primary Myelofibrosis. PMID- 29708809 TI - Factors Influencing Overuse of Breast Cancer Screening: A Systematic Review. AB - BACKGROUND: Excessive breast cancer screening with mammography or other modalities often burdens patients with false-positive results and costs. Yet, screening patients beyond the age at which they will benefit or at too frequent intervals persists. This review summarizes the factors associated with overuse of breast cancer screening. METHODS: We searched Medline and Embase from January 1998 to March 2017 for articles addressing the overuse of breast cancer screening and hand-searched the reference lists of included articles. Studies were included if they were written in English, pertained to a U.S. population, and identified a factor associated specifically with overuse of breast imaging. Paired reviewers independently screened abstracts, extracted data, and assessed quality. RESULTS: We included 15 studies: 3 cohort, 5 cross-sectional, 6 surveys, and 1 in-depth interview. White women (non-Hispanic) were less vulnerable than other racial groups to overuse in 3 of 5 studies. Physician specialty was consistently associated with screening overuse in three of three studies. Abundant access to primary care and a patient desire for screening were associated with breast cancer screening overuse. Lower self-confidence, lower risk taking tendencies, higher perception of conflict in expert recommendations, and a belief in screening effectiveness were clinician traits associated with overuse of screening in the surveys. CONCLUSIONS: The literature supports that liberal access to care and clinicians' recommendations to screen, possibly influenced by conflicting guidelines, increase excessive breast cancer screening. Overuse might conceivably be reduced with more concordance across guidelines, physician education, patient involvement in decision-making, thoughtful insurance restrictions, and limitations on the supply of services; however, these will need careful testing regarding their impact. PMID- 29708810 TI - Ocular Toxicity Profile of ST-162 and ST-168 as Novel Bifunctional MEK/PI3K Inhibitors. AB - PURPOSE: ST-162 and ST-168 are small-molecule bifunctional inhibitors of MEK and PI3K signaling pathways that are being developed as novel antitumor agents. Previous small-molecule and biologic MEK inhibitors demonstrated ocular toxicity events that were dose limiting in clinical studies. We evaluated in vitro and in vivo ocular toxicity profiles of ST-162 and ST-168. METHODS: Photoreceptor cell line 661W and adult retinal pigment epithelium cell line ARPE-19 were treated with increasing concentrations of bifunctional inhibitors. Western blots, cell viability, and caspase activity assays were performed to evaluate MEK and PI3K inhibition and dose-dependent in vitro toxicity, and compared with monotherapy. In vivo toxicity profile was assessed by intravitreal injection of ST-162 and ST 168 in Dutch-Belted rabbits, followed by ocular examination and histological analysis of enucleated eyes. RESULTS: Retinal cell lines treated with ST-162 or ST-168 exhibited dose-dependent inhibition of MEK and PI3K signaling. Compared with inhibition by monotherapies and their combinations, bifunctional inhibitors demonstrated reduced cell death and caspase activity. In vivo, both bifunctional inhibitors exhibited a more favorable toxicity profile when compared with MEK inhibitor PD0325901. CONCLUSIONS: Novel MEK and PI3K bifunctional inhibitors ST 162 and ST-168 demonstrate favorable in vitro and in vivo ocular toxicity profiles, supporting their further development as potential therapeutic agents targeting multiple aggressive tumors. PMID- 29708811 TI - Gender Differences in Spinal Injuries: Causes and Location of Injury. AB - BACKGROUND: Spinal injury is common in trauma suffered by both men and women. A lesser degree of involvement of females with spinal trauma, or at least, the different nature of such injuries, has been suggested. It has been proposed that behavioral and structural characteristics may explain the differential type and severity of spinal injuries in women. We carried out this study to find women specific divergences in spinal traumatic lesions, including suspected mechanisms for their generation. METHODS: All patients with spinal injury, documented by the Trauma Registry at our Medical Center and using the AIS code 65XXXX.X for spinal fractures and dislocations, were evaluated. The women-associated analysis included data related to: type of spinal lesion, area affected, possible mechanisms, associated damage, surgical procedures, and complications. Male related data were collected for comparison. RESULTS: Between 2006 and 2010, 546 patients with traumatic spine injuries were documented. Of those, 30.6% were women (F:M-168:378). Average age was 43.5 years (women: 49.6 years and men: 40.1 years). Regarding the mechanisms of injury, women with spinal injuries were susceptible to falls from a standing position or had attempted suicide. However, men with similar lesions had a tendency to be more involved in motorcycle accidents or falls from height. Women involved in motor vehicle crashes showed statistically more significant lumbar spine lesions, whereas men in the same situation developed mainly cervical spine damage to a significant level. CONCLUSIONS: The characteristics of spinal injury in women, as opposed to men, stand out as divergent. The mechanisms of trauma and the site of injury differ significantly. We suggest this variance may be due, in part, to skeletal and muscular structure dissimilarity in women and in part to the spinal kinematics attending each group. PMID- 29708812 TI - Investigational drugs for the treatment of endometriosis, an update on recent developments. AB - INTRODUCTION: Endometriosis is a hormone-dependent benign chronic disease that requires a chronic medical therapy. Although currently available drugs are efficacious in treating endometriosis-related pain, some women experience partial or no improvement. Moreover, the recurrence of symptoms is expected after discontinuation of the therapies. Currently, new drugs are under intense clinical investigation for the treatment of endometriosis. Areas covered: This review aims to offer the reader a complete and updated overview on new investigational drugs and early molecular targets for the treatment of endometriosis. The authors describe the pre-clinical and clinical development of these agents. Expert opinion: Among the drugs under investigation, late clinical trials on gonadotropin-releasing hormone antagonists (GnRH-ant) showed the most promising results for the treatment of endometriosis. Aromatase inhibitors (AIs) are efficacious in treating endometriosis related pain symptoms but they cause significant adverse effects that limit their long-term use. New targets have been identified to produce drugs for the treatment of endometriosis, but the majority of these new compounds have only been investigated in laboratory studies or early clinical trials. Thus, further clinical research is required in order to elucidate their efficacy and safety in human. PMID- 29708813 TI - Comprehensive Adolescent Sexual Health: An Unmet Prevention Need. PMID- 29708814 TI - Protective Effect of the c-mpl Agonist Romiplostim on Megakaryocytopoiesis of Human CD34+ Hematopoietic Progenitor Cells Exposed to Ionizing Radiation. AB - A thrombopoiesis-stimulating protein, the myeloproliferative leukemia virus protooncogene (Mpl) ligand romiplostim (RP), is currently approved as a therapeutic agent for idiopathic thrombocytopenic purpura in many countries. Although the action of the initial MPL ligand thrombopoietin (TPO) on human megakaryocytic regeneration from irradiated human hematopoietic stem cells has been examined, there are few reports on the action of RP. In the present study, freshly prepared nonirradiated and 2-Gy X-irradiated human CD34 positive (CD34+) cells from placental umbilical cord blood were cultured with a combination of RP and various cytokines. As a result, the effect of RP on cell proliferation of nonirradiated CD34+ cells was found to be comparable to that of TPO. However, the stimulating activity of RP on megakaryocytic progenitor-derived colony formation was markedly lower compared with TPO. Regarding the action of RP with various cytokines, the present results showed that a combination of RP with interleukin-3 (IL-3) or IL-3 plus stem cell factor (SCF) showed a high regenerative effect on cell proliferation, megakaryopoiesis, thrombopoiesis, and megakaryocyte colony formation from X-irradiated CD34+ cells. The present study showed that human recombinant RP has potential effects on human megakaryocytic regeneration from X irradiated human CD34+ cells and synergistically acts with IL-3 and IL-3 plus SCF, just as observed with TPO. PMID- 29708815 TI - PI3K/AKT/mTOR pathway inhibitors inhibit the growth of melanoma cells with mTOR H2189Y mutations in vitro. AB - mTOR is an important therapeutic target in many types of cancers. In melanoma, the mTOR nonsynonymous mutation rate is up to 10.4%. However, mTOR inhibitors have shown limited effects in clinical trials of melanoma. Because mTOR mutations are distributed, not selecting patients with specific mTOR mutations may be the main reason for therapeutic failures. Our previous research found that mutations in the mTOR P2213S and S2215Y kinase domains resulted in gain-of-function and were sensitive to specific inhibitors. The purpose of this study was to test the effect of heterozygous/homozygous H2189Y mutations on downstream pathways and sensitivity to inhibitors. mTOR kinase activity was analyzed by western blot and a K-LISATM mTOR activity kit. The sensitivity of melanoma cells to inhibitors was tested by a proliferation assay. The expression of downstream pathway proteins was also analyzed by western blot. The results showed that heterozygous/homozygous H2189Y mutations were gain-of-function. The heterozygous H2189Y mutation was sensitive to the AKT inhibitor, AZD5363, and the phosphoinositide 3-kinase inhibitor, LY294002. The homozygous H2189Y mutation was sensitive to the mTOR inhibitor, everolimus, and the AKT inhibitors AZD5363 and MK-2206 2HCL,and the phosphoinositide 3-kinase inhibitor, LY294002. These results indicated that homozygous mutations in the kinase domain have a greater effect on protein function than heterozygous mutations. The mTOR kinase domain may play an important role in mTOR kinase activity and may be the target of selective inhibitors. Our study can facilitate the selection of appropriate inhibitors for patients in clinical trials. PMID- 29708816 TI - Immune response to influenza vaccination in children with cancer. AB - The aim of this study was to evaluate the ability of influenza immunization to evoke a protective immune response among children with cancer. We evaluated 75 children with cancer who received influenza vaccination. Hemagglutination Inhibition Antibody titers were determined before and after vaccination. The protective rates after vaccination were 79% for H1N1, 75% for H3N2 and 59% for influenza B virus whereas the seroconversion rates were 54%, 44% and 43% respectively. The differences pre- and post-vaccination were significant regardless the method which was used: seroprotection changes, seroconversion and geometric mean titers analyses. Variables such as the pre-vaccination antibody titers, the time when the responses were measured after the vaccination, the age and the type of malignancy as well as the absolute lymphocyte count were found to be correlated with the immune response but the findings were different for each vaccine subunit. In conclusion, influenza vaccination provides protection in a remarkable proportion of pediatric cancer patients whereas this protection is more obvious against H1N1 and H3N2 compared to influenza B. The immune response after vaccination is significant and seems to be influenced by a variety of factors. PMID- 29708817 TI - Montelukast inhibits hypoxia inducible factor-1alpha translation in prostate cancer cells. AB - Through regulating the expression of hundreds of genes, hypoxia-inducible factor 1(HIF-1) plays a critical role in hypoxic adaption of cancer cells and is considered as a target for cancer therapy. Here we show that montelukast, a clinical leukotriene receptor antagonist for the treatment of asthma, inhibits hypoxia or CoCl2-induced HIF-1alpha activation and reduces its protein expression in prostate cancer cells. However, the other two leukotriene receptor antagonists, pranlukast and zafirlukast, cannot decrease HIF-1alpha protein, which indicates that montelukast-induced downregulation of HIF-1alpha is not mediated by leukotriene receptor. Neither proteasome inhibitor MG132 nor the lysosomal inhibitor chloroquine (CQ) can block montelukast-induced downregulation of HIF-1alpha protein. Interestingly, GSK2606414, a PKR-like endoplasmic reticulum kinase (PERK) inhibitor, abrogates montelukast-induced downregulation of HIF-1alpha under hypoxic conditions. However, montelukast increases phosphorylation of eIF-2alpha at Ser51. Moreover, montelukast inhibits the proliferation of prostate cancer cells, which can be reversed by overexpression of HIF-1alpha protein. In conclusion, we identify montelukast may be used as a novel agent for the treatment of prostate cancer by decreasing HIF-1alpha protein translation. PMID- 29708818 TI - A Placebo-Controlled Double-Blind Study Demonstrates the Clinical Efficacy of a Novel Herbal Formulation for Relieving Joint Discomfort in Human Subjects with Osteoarthritis of Knee. AB - LI73014F2 is a novel composition prepared from extracts of Terminalia chebula fruit, Curcuma longa rhizome, and Boswellia serrata gum resin with synergistic benefit in 5-Lipoxygenase (5-LOX) inhibition. This herbal composition with strong anti-5-LOX activity exhibited significant pain relief as indicated through improvements in weight-bearing capacity in a monosodium iodoacetate-induced osteoarthritis (OA) model of Sprague-Dawley rats. A 90-day randomized, placebo controlled double-blind study evaluates the clinical efficacy and tolerability of LI73014F2 in the management of symptoms of OA of the knee (Clinical Trial Registration No. CTRI/2014/01/004338). Subjects, (n = 105), were randomized into three groups: placebo (n = 35), 200 mg/day of LI73014F2 (n = 35), and 400 mg/day of LI73014F2 (n = 35). All study participants were evaluated for pain and physical function by using standard tools, that is, Visual Analog Scale, Lequesne's Functional Index, and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) at the baseline (day 0) and on day 14 +/- 3, 30 +/- 3, 60 +/- 3, and at the end of the study (day 90 +/- 3). In addition, routine examinations on biochemical parameters in serum, urine, and hematological parameters were conducted on each visit to assess the safety of the study material. At the end of the trial period, LI73014F2 conferred significant pain relief, improved physical function, and quality of life in OA patients. In conclusion, preclinical and clinical data together strongly suggest that the herbal formulation LI73014F2 is a safe and effective intervention for management of joint discomfort, demonstrating efficacy as early as 14 days. PMID- 29708820 TI - Brain-to-Brain Synchrony and Learning Outcomes Vary by Student-Teacher Dynamics: Evidence from a Real-world Classroom Electroencephalography Study. AB - How does the human brain support real-world learning? We used wireless electroencephalography to collect neurophysiological data from a group of 12 senior high school students and their teacher during regular biology lessons. Six scheduled classes over the course of the semester were organized such that class materials were presented using different teaching styles (videos and lectures), and students completed a multiple-choice quiz after each class to measure their retention of that lesson's content. Both students' brain-to-brain synchrony and their content retention were higher for videos than lectures across the six classes. Brain-to-brain synchrony between the teacher and students varied as a function of student engagement as well as teacher likeability: Students who reported greater social closeness to the teacher showed higher brain-to-brain synchrony with the teacher, but this was only the case for lectures-that is, when the teacher is an integral part of the content presentation. Furthermore, students' retention of the class content correlated with student-teacher closeness, but not with brain-to-brain synchrony. These findings expand on existing social neuroscience research by showing that social factors such as perceived closeness are reflected in brain-to-brain synchrony in real-world group settings and can predict cognitive outcomes such as students' academic performance. PMID- 29708819 TI - Impact of Flow Rate, Collection Devices, and Extraction Methods on Tear Concentrations Following Oral Administration of Doxycycline in Dogs and Cats. AB - PURPOSE: Compare the precision of doxycycline quantification in tear fluid collected with either Schirmer strips or polyvinyl acetal (PVA) sponges following oral drug administration. METHODS: Three dogs and 3 cats were administered doxycycline orally at a dose of 4.2-5 mg/kg every 12 h for 6 consecutive days. At day 5 and 6, blood and tear fluid were sampled to capture doxycycline trough and maximal concentrations. Tear fluid was collected 3 times (spaced 10 min apart) at each session with the absorbent material placed in the lower conjunctival fornix until the 20-mm mark was reached (Schirmer strip, one eye) or for 1 min (PVA sponge, other eye). Tear extraction was performed with either centrifugation or elution in methanol. Doxycycline concentrations were measured with liquid chromatography-mass spectrometry. Low (100 ng/mL) and high (1,000 ng/mL) tear concentrations measured in vivo were spiked into each absorbent material in vitro to evaluate percentage drug recovery. RESULTS: After oral administration of doxycycline, the drug reached the tear compartment at concentrations of 45.1 900.7 ng/mL in cats and 45.4-632.0 ng/mL in dogs, representing a tear-to-serum ratio of 12% and 16%, respectively. Doxycycline tear concentrations were significantly more precise when tear collection was performed with Schirmer strips rather than PVA sponges (P = 0.007), but were not correlated with tear flow rate. In vitro doxycycline recovery was poor to moderate (<75%). CONCLUSIONS: Schirmer strips represent a good option for lacrimal doxycycline quantification, although the collection and subsequent extraction have to be optimized to improve drug recovery. PMID- 29708821 TI - Gamma Oscillatory Activity Related to Language Prediction. AB - Using magnetoencephalography, the current study examined gamma activity associated with language prediction. Participants read high- and low-constraining sentences in which the final word of the sentence was either expected or unexpected. Although no consistent gamma power difference induced by the sentence final words was found between the expected and unexpected conditions, the correlation of gamma power during the prediction and activation intervals of the sentence-final words was larger when the presented words matched with the prediction compared with when the prediction was violated or when no prediction was available. This suggests that gamma magnitude relates to the match between predicted and perceived words. Moreover, the expected words induced activity with a slower gamma frequency compared with that induced by unexpected words. Overall, the current study establishes that prediction is related to gamma power correlations and a slowing of the gamma frequency. PMID- 29708822 TI - Rifaximin is associated with modest, transient decreases in multiple taxa in the gut microbiota of patients with diarrhoea-predominant irritable bowel syndrome. AB - Rifaximin, a non-systemic antibiotic, is efficacious for the treatment of diarrhoea-predominant irritable bowel syndrome (IBS-D). Given the emerging association between the gut microbiota and IBS, this study examined potential effects of rifaximin on the gastrointestinal microbial community in patients with IBS-D. TARGET 3 was a randomised, double-blind, placebo-controlled, phase 3 study. Patients with IBS-D initially received open-label rifaximin 550 mg 3 times daily (TID) for 2 weeks. Patients who responded to the initial treatment and then relapsed were randomised to receive 2 repeat courses of rifaximin 550 mg TID or placebo for 2 weeks, with each course separated by 10 weeks. Stool samples were collected at the beginning and end of open-label treatment, at the beginning and end of the first double-blind treatment, and at the end of the study. As a secondary analysis to the TARGET 3 trial, the composition and diversity of the gut microbiota were assessed, from a random subset of patients, using variable 4 hypervariable region 16S ribosomal RNA gene sequencing. Samples from 103 patients were included. After open-label rifaximin treatment for 2 weeks, 7 taxa (e.g. Peptostreptococcaceae, Verrucomicrobiaceae, Enterobacteriaceae) had significantly lower relative abundance at a 10% false discovery rate threshold. The effects of rifaximin were generally short-term, as there was little evidence of significantly different changes in taxa relative abundance at the end of the study (up to 46 weeks) versus baseline. The results suggest that rifaximin has a modest, largely transient effect across a broad range of stool microbes. Future research may determine whether the taxa affected by rifaximin are causally linked to IBS-D. ClinicalTrials.gov identifier number: NCT01543178. PMID- 29708823 TI - Levels of potentially toxic metals in water, sediment and peat from Wonderfonteinspruit, North West Province, South Africa. AB - Environmental monitoring of the levels of potentially toxic metals is of importance because of possible adverse effects on living species. This study was conducted to assess the levels of Cd, Cr, Cu, Hg, Mn, Pb, U and V in water, sediment and peat samples collected from the region of Wonderfonteinspruit. Water samples were simply filtered and acidified with HNO3 prior to analysis. Sediment and peat were oven-dried, ground, sieved and mineralised using a microwave digestion system. Concentrations of the selected elements in all samples were determined by inductively coupled plasma-mass spectrometry. A Zeeman mercury analyser was also used for quantification of Hg in the same sediment and peat samples. The method validation was carried out using SRM 1643e water and BCR 320R sediment certified reference materials. The results showed no significant difference at 95% level of confidence between the certified and measured values after using the Student's t-test. The levels of Cd, Cr, Cu, Pb, V and U found in rivers and dams were lower than the tentative South African water quality range guideline for domestic and irrigation purposes. However, water from dams and certain rivers was unsuitable for irrigation and domestic use. PMID- 29708824 TI - The short-term improvements of enriched environment in behaviors and pathological changes of APP/PS1 mice via regulating cytokines. AB - OBJECTIVE: To study the effect of enriched environment (EE) on cognitive function and pathological changes in Alzheimer's disease (AD) mice. METHOD: 6-month-old of the male mice were divided into 3 groups (n = 8), the wild type C57BL/6 mice in the control group, the APP/PS1 transgenic mice of AD reared in either the standard environment or the EE. Mice were feeding for 8 weeks, and then moved into standard environment. The activity and cognitive function were measured by Open-field test and Morris-water Maze. Immunofluorescence was used to detect Abeta plaque, hydroxylamine colorimetric assay was used to detect the activity of Ach, ChAT and AchE, and ELISA was used to detect the Abeta protein and the inflammatory factors IL-1beta, IL-6, TNF-alpha and IFN-gamma in serum, as well as the trophic cytokines BDNF, NGF and IGF-1 in hippocampus. RESULT: Compared with the controls, the behaviors of AD mice were degraded, the Abeta deposition could be detected in the brain, the activity of Ach and ChAT decreased while the AchE increased, and the inflammatory factors increased significantly in serum while the trophic factors decreased in hippocampus. By means of rearing in EE, the activity and cognitive functions of AD mice were improved, and the Abeta plaques were significantly reduced. Meanwhile, the inflammatory factors in serum were reduced while the trophic cytokines increased. Besides, the cholinergic system in the brain were improved without statistic difference. However, 3 months later, these improvements in AD mice which were previously raised in EE disappeared. CONCLUSION: The EE can improve the behaviors of AD mice, reduce the Abeta deposition in the brain, regulate the levels of cytokines, and have benefit in pathological changes in AD, but these improvements are short-term. PMID- 29708825 TI - Elemental analysis and nutritional value of edible Trifolium (clover) species. AB - Trifolium species, commonly known as clover species, have a cosmopolitan distribution and, as such, are used in many different traditional systems of medicine and consumed by many communities all over the world. In this study, the elemental distribution and nutritional value of five edible Trifolium species, namely, Trifolium africanum, Trifolium burchellianum, Trifolium repens, Trifolium dubium and Trifolium pratense were investigated to evaluate the potential of these plant species to alleviate malnutrition, thereby contributing toward the fight against food insecurity. Trifolium species were found to be a rich alternate source of essential nutrients with concentrations of elements being in decreasing order of Ca > Mg > Fe > Mn > Zn > Se > Cu > Cr > Pb > Ni > Co > Cd > As and with adequate levels of lipids (4.2 to 8.6%), proteins (35.1 to 45.4%) and carbohydrates (26.7 to 47.0%). Trifolium species were found to be rich in Se (contributing greater than 516% toward its RDA) with T. dubium having a concentration of 0.53 mg 10 g-1, dry mass, which is higher than Brazil nuts. T. pratense was found to be the most suitable species for human consumption due to it having low levels of toxic metals (As, Cd and Pb) while being rich in macro- and micro-elements, especially Fe (7.84 mg 10 g-1, dry mass) and Se (0.36 mg 10 g 1, dry mass). PMID- 29708826 TI - Correlates of human papillomavirus (HPV) vaccination initiation and completion among 18-26 year olds in the United States. AB - PURPOSE: To examine correlates of HPV vaccination uptake in a nationally representative sample of 18-26-year-old adults. METHODS: Young adults aged 18-26 years were identified from the 2014 and 2015 National Health Interview Survey (n = 7588). Survey-weighted multivariable logistic regression models estimated sociodemographic factors associated with HPV vaccine initiation (>=1 dose) and completion (>=3 doses). RESULTS: Approximately 27% of study participants had initiated the HPV vaccine and 16% had completed the HPV vaccine. Participants were less likely to initiate the vaccine if they were men [(adjusted odds ratio) 0.19; (95% confidence interval) 0.16-0.23], had a high school diploma (0.40; 0.31 0.52) or less (0.46; 0.32-0.64) vs. college graduates, and were born outside the United States (0.52; 0.40-0.69). But, participants were more likely to initiate the HPV vaccine if they visited the doctor's office 1-5 times (2.09; 1.56-2.81), or >= 6 times (1.86; 1.48-2.34) within the last 12 months vs. no visits. Odds of completing HPV vaccine uptake followed the same pattern as initiation. And after stratifying the study population by gender and foreign-born status, these variables remained statistically significant. CONCLUSIONS: In our nationally representative study, only one out of six 18-26 year olds completed the required vaccine doses. Men, individuals with high school or less education, and those born outside the United States were less likely to initiate and complete the HPV vaccination. Our findings suggest that it may be useful to develop targeted interventions to promote HPV vaccination among those in the catch-up age range. PMID- 29708827 TI - Big Data and Dysmenorrhea: What Questions Do Women and Men Ask About Menstrual Pain? AB - BACKGROUND: Menstrual pain is highly prevalent among women of reproductive age. As the general public increasingly obtains health information online, Big Data from online platforms provide novel sources to understand the public's perspectives and information needs about menstrual pain. The study's purpose was to describe salient queries about dysmenorrhea using Big Data from a question and answer platform. MATERIALS AND METHODS: We performed text-mining of 1.9 billion queries from ChaCha, a United States-based question and answer platform. Dysmenorrhea-related queries were identified by using keyword searching. Each relevant query was split into token words (i.e., meaningful words or phrases) and stop words (i.e., not meaningful functional words). Word Adjacency Graph (WAG) modeling was used to detect clusters of queries and visualize the range of dysmenorrhea-related topics. We constructed two WAG models respectively from queries by women of reproductive age and bymen. Salient themes were identified through inspecting clusters of WAG models. RESULTS: We identified two subsets of queries: Subset 1 contained 507,327 queries from women aged 13-50 years. Subset 2 contained 113,888 queries from men aged 13 or above. WAG modeling revealed topic clusters for each subset. Between female and male subsets, topic clusters overlapped on dysmenorrhea symptoms and management. Among female queries, there were distinctive topics on approaching menstrual pain at school and menstrual pain-related conditions; while among male queries, there was a distinctive cluster of queries on menstrual pain from male's perspectives. CONCLUSIONS: Big Data mining of the ChaCha(r) question and answer service revealed a series of information needs among women and men on menstrual pain. Findings may be useful in structuring the content and informing the delivery platform for educational interventions. PMID- 29708828 TI - Single Session of Robotic Human Cadaver Training: The Immediate Impact on Urology Residents in a Teaching Hospital. AB - INTRODUCTION AND OBJECTIVE: To evaluate the immediate impact of robotic human cadaver training on the confidence with robotic surgery among urology residents. METHODS: After a preliminary survey assessing baseline skills, our institution's urology residents attended a single session of robotic training on fresh-frozen human cadavers, supervised by staff urologists. Post-training, both the residents and the supervisors were administered a survey querying the improvement of robotic skills and the sentiments toward the cadaver laboratory compared with alternative trainings (answers were given by Likert scale: 1 = negative/5 = positive). RESULTS: Twenty-two residents and five supervisors completed the surveys. Median residents' age was 32 years (IQR 29-33). Median year of residency was 4 (IQR 3-6). One hundred percent of the residents were familiar with robotics (86.4% had previous experience as bedside assistant; 90.9% have performed a median of 15 procedures at console). Post-training the residents evaluated their confidence with port placement and docking, EndoWrist(r) manipulation, Camera and Clutching, Fourth Arm Integration, and Needle Control and Driving with median scores of 4 (IQR 4-5), 4 (IQR 4-5), 4 (IQR 4-5), 4 (IQR 4-4), and 4 (IQR 3-4), with significant perceived improvement in all skills (P < .045). Almost all of them (86.4%) rated the cadaver training 5. When asked about the superiority of human cadaver training with respect to the virtual simulator and the pig laboratory, residents gave median scores of 5 (IQR 5-5) and 4 (IQR 3-5). At univariate analysis, increased experience with robotics was found to be inversely associated with improvement in the "camera and clutching" skill (P < .048). The supervisors felt that human cadaver training was effective in improving the residents' robotic skills (median answer of 5, IQR 4-5). CONCLUSIONS: Human cadaver robotic training demonstrated great acceptability among both the residents and the supervisors. It allowed for immediate improvement of the residents' robotic skills. PMID- 29708829 TI - The impact of testosterone replacement therapy on glycemic control, vascular function, and components of the metabolic syndrome in obese hypogonadal men with type 2 diabetes. AB - OBJECTIVE: This study set out to assess effects of testosterone replacement therapy (TRT) on parameters of metabolic syndrome and vascular function in obese hypogonadal males with type 2 diabetes mellitus (DM2). STUDY DESIGN: Fifty-five obese hypogonadal diabetic males on oral hypoglycemic treatment were enrolled into this one-year, double-blind, randomized, placebo-controlled clinical study. Group T (n = 28) was treated with testosterone undecanoate (1000 mg i.m. every 10 weeks) while group P (n = 27) received placebo. METHODS: Anthropometrical and vascular measurements - flow-mediated dilatation (FMD) and intima media thickness (IMT) - biochemical and hormonal blood sample analyses were performed at the start of the study and after one year. Derived parameters (BMI, HOMA-IR, calculated free testosterone (cFT) and bioavailable testosterone (BT)) were calculated. RESULTS: TRT resulted in reduction of HOMA-IR by 4.64 +/- 4.25 (p < .001), HbA1c by 0.94 +/- 0.88% points (p < .001), and an increase in FMD by 2.40 +/- 4.16% points (p = .005). CONCLUSION: TRT normalized serum testosterone levels, improved glycemic control and endothelial function while exerting no ill effects on the study population. PMID- 29708830 TI - Earthworms to assess the innocuousness of spent biomixtures employed for glyphosate degradation. AB - In this study, the innocuousness of different biomixtures employed for glyphosate degradation was tested through Eisenia fetida earthworms. Eight biomixtures were prepared with local materials: alfalfa straw (AS), wheat stubble (WS), river waste (RW) and two different soils (A and B). Each biomixture was divided into two equal portions: one without glyphosate application (control substrate) and the other was sprayed with a commercial glyphosate formulation of 1,000 mg glyphosate a.i. kg-1 biomixture (applied substrate). The bioassay started when all sprayed biomixtures reached high percentages of glyphosate degradation (spent biomixtures). Three parameters were studied: survival, adults and juveniles biomass and reproduction. The results allowed the identification of three biomixtures (AWS, BWS and BWSRW) for good maintenance and development of E. fetida. In addition, at the end of the bioassay two of the viable biomixtures (AWS and BWS) showed the highest performance of juvenile earthworms compared to a reference soil. The Principal Component Analysis (PCA) indicated that the biomixtures containing high silt and clay percentages and minor density renders higher values of earthworm growth and reproduction. Therefore, these innocuous biomixtures can be used as organic amendments or recycled materials for new treatments on biobeds. PMID- 29708831 TI - Pre-digestion to enhance volatile fatty acids (VFAs) concentration as a carbon source for denitrification in treatment of liquid swine manure. AB - Insufficient denitrification in biological treatment is often a result of the lack of a carbon source. In this study, use of the volatile fatty acids (VFAs) generated via pre-digestion as a carbon source to improve denitrification in sequencing batch reactor (SBR) treatment of liquid swine manure was investigated. The pre-digestion of swine manure was realized by storing the manure in a sealed container in room temperature and samples were taken periodically from the container to determine the VFA levels. The results showed that after 14 days of pre-digestion, the VFA level in the digested liquid was increased by 200%. A polynomial relationship for the VFA level in the digested manure with the digestion time was observed with a correlation coefficient being 0.9748. Two identical SBRs were built and operated on 8-h cycles in parallel, with one fed with pre-digested and the other raw swine manure. There were five phases included in each cycle, i.e., anaerobic (90 min), anoxic (150 min), anoxic/anaerobic (90 min), anoxic/aerobic (120 min), and settle/decant (30 min), and the feeding was split to 600 mL/200 mL and performed at the beginning of and 240 min into the cycle. The SBR fed on pre-digested swine manure achieved successful denitrification with only 0.35 mg/L nitrate left in the effluent, compared to 15.9 mg/L found in the effluent of the other SBR. Nitrite was not detected in the effluent from both SBRs. The results also indicated that there was no negative impact of feeding SBRs with the pre-digested liquid swine manure for treatment on the removal of other constituents such as total solids (TS), volatile solids (VS), suspended solids (SS), volatile suspended solids (VSS), and soluble chemical oxygen demand (COD). Therefore, anaerobic digestion as a pretreatment can be an effective way to condition liquid swine manure for SBR treatment to achieve sufficient nitrate removal. PMID- 29708832 TI - Antimicrobial Resistance of Thermotolerant Campylobacter Species Isolated from Humans, Food-Producing Animals, and Products of Animal Origin: A Worldwide Meta Analysis. AB - The objective of this meta-analysis was to summarize available information on the prevalence of antimicrobial-resistant Campylobacter species in humans, food producing animals, and products of animal origin. A number of multilevel random effect meta-analysis models were fitted to estimate mean occurrence rate of antimicrobial-resistant thermotolerant Campylobacter and to compare them throughout the years and among the species, food-producing animals (i.e., bovine, pigs, broilers, hen, goat, and sheep), country of origin, sample type, methodology to determine the antimicrobial susceptibility, and the species of Campylobacter. Among the considered antibiotics, thermotolerant Campylobacter showed the highest resistance to tetracycline (pool estimate [PE] = 0.493; 95% CI 0.466-0.519), nalidixic acid (PE = 0.385; 95% CI 0.348-0.423), and ciprofloxacin (PE = 0.376; 95% CI 0.339-0.415). In general, the prevalence of antimicrobial resistant Campylobacter spp. was higher in hen, broilers, and swine. Campylobacter coli showed a higher prevalence of antimicrobial resistance than Campylobacter jejuni. Independent of the antimicrobial evaluated, the disk diffusion method showed higher prevalence of antimicrobial-resistant Campylobacter than the methods based on the minimum inhibitory concentration estimation. The meta-analysis showed that the prevalence of antimicrobial resistant Campylobacter is relevant essentially in foods derived from hens and broilers, and it was observed worldwide. The prevalence of this pathogen is of public health importance and the increase in the prevalence of Campylobacter strains resistant to the antimicrobial of choice worsens the situation, hence, national authorities must monitor the situation in each country with the aim to establish the appropriate risk management measures. PMID- 29708833 TI - Chemoreception of botanical nematicides by Meloidogyne incognita and Caenorhabditis elegans. AB - Plant-parasitic nematodes, such as Meloidogyne incognita, cause serious damage to various agricultural crops worldwide, and their control necessitates environmentally safe measures. We have studied the effects of plant secondary metabolites on M. incognita locomotion, as it is an important factor affecting host inoculation inside the soil. We compared the effects to the respective behavioral responses of the model saprophytic nematode Caenorhabditis elegans. The tested botanical nematicides, all reported to be active against Meloidogyne sp. in our previous works, are small molecular weight molecules (acids, alcohols, aldehydes, and ketones). Here, we specifically report on the attractant or repellent properties of trans-anethole, (E,E)-2,4-decadienal, (E)-2-decenal, fosthiazate, and 2-undecanone. The treatments for both nematode species were made at sublethal concentration levels, namely, 1 mM (=1 of the HPV types. Statistical analysis showed: those with a history of abnormal pap smear/cervical neoplasia were likely to have a positive anti-HPV antibody result pre-vaccine to >= 1 of the 4 types, p = 0.035 Fisher's Exact Test. In general, HPV exposed women showed higher post vaccine GMTs than HPV unexposed women with higher point estimates. However, when examining the rise in titers using logistic regression, there was no evidence of an anamnestic response. CONCLUSION: Prior HPV infection and cervical neoplasia in SLE are linked with no anamnestic response to HPV vaccine. This supports not checking HPV-antibodies pre vaccine. Women with SLE should be vaccinated for HPV. PMID- 29708837 TI - Molecular Epidemiology of Vancomycin-Resistant Enterococcus faecalis and Enterococcus faecium Isolated from Clinical Specimens in the Northwest of Iran. AB - This study was conducted to investigate the phenotypic and genotypic characteristics of vancomycin-resistant Enterococcus faecalis and Enterococcus faecium. Antibiotic resistance and virulence genes in the aforementioned resistant isolates were studied using the epsilometer (E)-test and polymerase chain reaction (PCR). These isolates were subjected to typing by pulsed-field gel electrophoresis (PFGE). Thirty vancomycin-resistant enterococci (VRE; 18.75%) were isolated from a total of 160 various clinical specimens cultured for any bacterial growth. Of these, 11 (36.7%) isolates were identified as E. faecalis and 19 (63.3%) as E. faecium. Minimum inhibitory concentrations (MICs) of vancomycin, teicoplanin, and three alternative therapeutic options (linezolid, daptomycin, and quinupristin/dalfopristin) were determined using the E-test. Multiplex PCR was done for confirming species, identification of the resistant genotypes, and the detection of the virulence genes. Finally, the clonal relationship of all VRE strains was studied by PFGE. All VRE strains showed vancomycin MIC >=256 MUg/mL, and 27 (90%) isolates carried the vanA gene, whereas none of the isolates carried vanB. The most common resistance antibiotic pattern observed was toward rifampicin (n = 30 [100%]). Among all virulence genes studied, gelE (n = 28 [93.33%]) was found as the most prevalent virulent gene. VRE isolates exhibited 90%, 46.67%, 100%, and 66.67% resistance to teicoplanin, linezolid, quinupristin/dalfopristin, and daptomycin, respectively. Molecular typing demonstrated 16 PFGE types of VRE isolates (A-P). Although vanA was carried by most of the isolates, PFGE displayed small clonal dissemination among VR E. faecium and VR E. faecalis species. PMID- 29708836 TI - Development of new hepatitis E vaccines. AB - Hepatitis E virus (HEV) infection is an emerging zoonotic disease posing a severe threat to public health in the world, especially to pregnant women. Currently, no specific treatments are available for HEV infection. Therefore, it is crucial to develop vaccine to prevent this infection. Although several potential candidate vaccines against HEV have been studied for their immunogenicity and efficacy, only Hecolin(r) which is developed by Xiamen Innovax Biotech Co., Ltd. and approved by China Food and Drug Administration (CFDA) in 2012, is the licensed HEV vaccine in the world so far. Extensive studies on safety, immunogenicity and efficacy in phase III clinical trials have shown that Hecolin(r) is a promising vaccine for HEV prevention and control. In this article, the advances on HEV vaccine development and research are briefly reviewed. PMID- 29708839 TI - The effect of two bromfenvinphos impurities: BDCEE and beta-ketophosphonate on oxidative stress induction, acetylcholinesterase activity, and viability of human red blood cells. AB - Numerous research works have shown that synthesis of pesticides leads to the formation of impurities that may substantially enhance pesticide toxicity. In this study, the effect of manufacturing impurities of pesticide bromfenvinphos (BFVF) such as 1-bromo-2-(2,4-dichlorophenyl)-2-ethoxy ethene (BDCEE) and diethyl [2-(2,4-dichlorophenyl)-2-oxo-ethyl] phosphonate (beta-ketophosphonate) on human erythrocytes, being significantly exposed to xenobiotics has been studied. The cells were treated with the compounds studied in the concentrations ranging from 0.1 MUM to 250 MUM for 4 h. In order to assess the effect of BDCEE and beta ketophosphonate on red blood cells hemolytic changes, changes in cell size (FSC parameter) and oxidation of hemoglobin were studied. Moreover, alterations in reactive oxygen species (ROS) formation, reduced glutathione (GSH) level and acetylcholinesterase (AChE) activity were determined. BDCEE induced an increase in ROS level and caused strong oxidation of hemoglobin as well as a slight change in erythrocytes size and hemolysis, while it did not change GSH level and AChE activity. beta-ketophosphonate has not been shown to affect most parameters studied, but it strongly reduced AChE activity. Because changes in the parameters examined were noted at low concentrations of BFVF impurities (5-250 uM), those substances should not negatively affect on red blood cells of humans environmentally exposed to this pesticide. PMID- 29708840 TI - Prevalence and Antimicrobial Susceptibility of Ureaplasma spp. and Mycoplasma hominis in Asymptomatic Individuals in Korea. AB - This study investigated the prevalence and antibiotic resistance of Ureaplasma spp. and Mycoplasma hominis isolated from asymptomatic individuals in Korea. Endocervical swabs from women and urine from men, from a total of 5,781 asymptomatic individuals, were analyzed using a Mycoplasma IST2 Kit. Of the 4,825 specimens tested from females, 486 (10.1%) were positive culture. In these positive specimens, 437 (9.1%) were positive only for Ureaplasma spp., 17 (0.4%) were positive only for M. hominis, and 32 (0.7%) were positive for both Ureaplasma spp. and M. hominis. In males, of the 956 tested specimens, only 4 (0.42%) were positive for Ureaplasma spp. and no M. hominis colonization was identified. In antimicrobial susceptibility tests, more than 93.2% of both M. hominis and Ureaplasma spp. was susceptible to tetracycline, doxycycline, josamycin, and pristinamycin. However, M. hominis isolates were found to be highly resistant to erythromycin, azithromycin, and clarithromycin (82.4%, 70.6%, and 76.5%, respectively). Ofloxacin and ciprofloxacin, which have recently exhibited increasing resistance rates, showed rates of 17.7% and 35.3%, respectively, in M. hominis, and 50.6% and 27.4%, respectively, in Ureaplasma spp. In conclusion, accurate antimicrobial susceptibility tests of the genital mycoplasmas should be conducted for each case to select the appropriate antibiotics. Fluoroquinolone-based drugs should be avoided in the initial treatment of urogenital mycoplasmas because of the increasing rate of resistance to quinolones, although the susceptibility to tetracycline remains high in Korea. PMID- 29708838 TI - Intracellular Trafficking and Endosomal Release of Oligonucleotides: What We Know and What We Don't. AB - Understanding the cellular uptake and intracellular trafficking of oligonucleotides provides an important basic underpinning for the developing field of oligonucleotide-based therapeutics. Whether delivered as "free" oligonucleotides, as ligand-oligonucleotide conjugates, or in association with various nanocarriers, all forms of oligonucleotide enter cells by endocytosis and are initially ensconced within membrane-limited vesicles. Accordingly, the locus and extent of release to the cytosol and nucleus are key determinants of the pharmacological actions of oligonucleotides. A number of recent studies have explored the intracellular trafficking of various forms of oligonucleotides and their release from endomembrane compartments. These studies reveal a surprising convergence on an early-intermediate compartment in the trafficking pathway as the key locus of release for oligonucleotides administered in "free" form as well as those delivered with lipid complexes. Thus, oligonucleotide release from multivesicular bodies or from late endosomes seems to be the crucial endogenous process for attaining pharmacological effects. This intrinsic process of oligonucleotide release may be amplified by delivery agents such as lipid complexes or small molecule enhancers. PMID- 29708841 TI - Chemical indicators of exposure to polychlorodibenzo-p-dioxins, polychlorodibenzofurans and polychlorobiphenyls in breast milk samples from mothers residing in Trento, Italy, and neighboring country municipalities. AB - A human biomonitoring study was carried out in the province of Trento, northern Italy, on two groups of women residing in areas with presumably different levels of exposure to polychlorodibenzo-p-dioxins (PCDDs), polychlorodibenzofurans (PCDFs) and polychlorobiphenyls (PCBs). The aim was characterization of the possible impact of a steel plant and an urban environment on the internal doses of these contaminants. The areas investigated were the following: (i) the municipality of Borgo Valsugana, where a steel plant has been operating for the last 30 years, and (ii) the city of Trento. Ten women were enrolled from each area, and breast milk samples were collected from each woman. The amounts of PCDDs, PCDFs and PCBs were analyzed in all samples, and the data obtained were evaluated by descriptive and multivariate statistical approaches. For all samples, the concentrations observed were in the current acceptable concentration range observed in Europe. The descriptive statistics, however, clearly showed that some differences existed between the two groups: the PCDD, PCDF and DL-PCB concentrations were consistently higher in the Trento group of women living in the area surrounding the steel plant. Congener-profile analysis was carried out on both groups, and an appropriate multivariate approach, such as classical factor analysis (CFA), was used to investigate possible differential exposure sources. The application of this approach made it possible to show the quantitative and qualitative differences that characterized the two areas. PMID- 29708842 TI - Toxicity assessment of untreated/treated electroplating sludge using human and plant bioassay. AB - The purpose of this work was to assess the risk to the environment arising from the electroplating sludge from both chemical and toxicological point of view. Both approaches were used for the assessment of the treatment efficiency which consisted of CaO based solidification followed by thermal treatment at 400 degrees C. The elemental composition was determined in the bulk samples and the leachates of untreated sludge. The toxicity of the leachate was determined using two human colorectal adenocarcinoma cell lines (Caco-2 and SW 480) and Hordeum vulgare L. based plant bioassay. The same toxicity tests were employed to the leachate of the treated sludge. Untreated sludge showed extremely high cytotoxic effect to both human and plant bio-system in dose-dependent manner. The percentages higher than 0.5% and 0.05% of the leachate caused significant cytotoxic effect on Caco-2 and SW 480 cells, respectively. The percentages of the leachate higher than 0.05% also showed significant toxic effect to H. vulgare L. bio-system with complete arrest of seed germination following the treatment with 100% to 5% of the leachate. The leachate of the treated sludge showed no toxicity to any of the test systems confirming the efficiency and justification of the employed procedures for the detoxification of electroplating sludge. PMID- 29708843 TI - Cost-effectiveness of switching from trivalent to quadrivalent inactivated influenza vaccines for the at-risk population in Italy. AB - Seasonal influenza is caused by two subtypes of influenza A and two lineages of influenza B. Although trivalent influenza vaccines (TIVs) contain both circulating A strains, they contain only a single B-lineage strain. This can lead to mismatches between the vaccine and predominant circulating B lineages, a concern especially for at-risk populations. Quadrivalent influenza vaccines (QIVs) containing a strain from both B lineages have been developed to improve protection against influenza. Here, we used a cost-utility model to examine whether switching from TIV to QIV would be cost-effective for the at-risk population in Italy. Costs were estimated from the payer and societal perspectives. The discount rate for outcomes was 3.0%. Univariate and probabilistic sensitivity analyses were performed to examine the effects of variations in parameters. Switching from TIV to QIV in Italy was estimated to increase quality-adjusted life-years (QALYs) and produce cost savings, including ?1.6 million for hospitalization and approximately ?2 million in productivity. The incremental cost-effectiveness ratio was ?23,426 per QALY from a payer perspective and ?21,096 per QALY from a societal perspective. Switching to QIV was most cost-effective for individuals >= 65 years of age (?19,170 per QALY). Probabilistic sensitivity analysis showed that the switching from TIV to QIV would be cost-effective for > 91% of simulation at a maximum willingness-to-pay threshold of ?40,000 per QALY gained. Although the model did not take herd protection into account, it predicted that the switch from TIV to QIV would be cost-effective for the at-risk population in Italy. PMID- 29708844 TI - Chronic Toxicity Assessment of 2'-O-Methoxyethyl Antisense Oligonucleotides in Mice. AB - Advances in antisense oligonucleotide (ASO) chemistry and screening have enabled the design and selection of molecules that are optimized for a particular therapeutic application in terms of both potency and tolerability. The most-well studied of the chemically modified ASOs are single-stranded antisense inhibitors with phosphorothioate backbones and 2'-O-methoxyethyl modifications (2'-MOE ASO). The 2'-MOE chemical modification in the design of the ASO has conferred increased hybridization affinity, increased stability, and/or enhanced tissue residence time, resulting in better potency and pharmacokinetics. Compound screening and selection are also important in optimizing the tolerability of intended therapeutic antisense inhibitors. In this study, we report the chronic toxicity of multiple 2'-MOE ASOs in mice for several representative compounds that have progressed to later phases of clinical development. The results show that these 2'-MOE ASOs selected for development have consistent behavior between sequences, have tolerability profiles suitable for chronic administration, and exhibit a relative lack of progression of findings observed in subchronic studies in mice. PMID- 29708845 TI - The Role of Flies in the Maintenance of Antimicrobial Resistance in Farm Environments. AB - Flies play an important role as vectors in the transmission of antimicrobial resistant bacteria (ARB) and are hypothesized to transfer ARB between internal and external livestock housing areas. The aim of this study was to understand the role that flies may play in the maintenance of ARB in the farm environment. We first evaluated the fate of ingested antimicrobial-resistant Escherichia coli harboring a plasmid containing antimicrobial-resistance genes (ARGs) throughout the housefly (Musca domestica) life cycle, from adult to the subsequent F1 generation. Antimicrobial-resistant E. coli was isolated from different life cycle stages and ARG carriage quantified. The ingested E. coli persisted throughout the fly life cycle, and ARG carriage was maintained at a constant level in the housefly microbiota. To clarify the transmission of ARB from flies to livestock, 30-day-old chickens were inoculated with maggots containing antimicrobial-resistant E. coli. Based on the quantification of bacteria isolated from cecal samples, antimicrobial-resistant E. coli persisted in these chickens for at least 16 days. These results suggest that flies act as a reservoir of ARB throughout their life cycle and may therefore be involved in the maintenance and circulation of ARB in the farm environment. PMID- 29708846 TI - Distribution of Aminoglycoside-Modifying Enzymes and Molecular Analysis of the Coagulase Gene in Clinical Isolates of Methicillin-Resistant and Methicillin Susceptible Staphylococcus aureus. AB - Enzymatic alteration of aminoglycosides by aminoglycoside-modifying enzymes (AMEs) is the major mechanism of resistance to aminoglycosides. The purpose of this study was to determine the frequency of AME genes, staphylococcal chromosomal cassette mec (SCCmec) types, and molecular analysis of the coagulase (coa) gene in Staphylococcus aureus strains isolated from clinical specimens. Totally, 102 S. aureus were tested by disk diffusion and microbroth dilution methods for susceptibility to aminoglycosides. AMEs genes and SCCmec types were determined by multiplex polymerase chain reaction (PCR). For polymorphism analysis, the 3' end region of the coa gene was amplified by PCR and the products were then subjected to restriction digestion with HaeIII enzyme. Of the 102 S. aureus, 42 (41.2%) were methicillin-resistant S. aureus (MRSA). Thirty-five (83%) of MRSA strains were resistant to kanamycin, 32 (76.2%) to tobramycin, 30 (71.4%) to gentamicin, 25 (59.5%) to amikacin, and 10 (23.8%) to netilmicin. The aac(6') Ie-aph(2") was the most frequent gene among MRSA isolates 19 (45.2%), followed by aph(3')-IIIa 8 (19%), ant(4')-Ia 6 (14.3%), and aph(2")-Id 2 (4.8%). SCCmec types included type I 10 (23.8%), II 1 (2.4%), III 21 (50%), and IV 7 (16.7%). Three (7.2%) isolates were nontypeable. Digestion of the PCR products of the coa gene yielded 19 distinct restriction fragment length polymorphism patterns. In conclusion, given the alarming rate of resistance to aminoglycosides among MRSA, the monitoring of aminoglycoside resistance and AME genes should be performed to limit the spread of aminoglycoside resistance among MRSA isolates. Several variants of the coa gene were found in the studied isolates, although the majority of the MRSA isolates belonged to a limited number of coagulase types. PMID- 29708847 TI - Preliminary Study on the Antibacterial Activity of Essential Oils Alone and in Combination with Gentamicin Against Extended-Spectrum beta-Lactamase-Producing and New Delhi Metallo-beta-Lactamase-1-Producing Klebsiella pneumoniae Isolates. AB - AIM: The aim of the study was to investigate possible synergistic effects between several selected, commercially available essential oils and gentamicin against extended-spectrum beta-lactamase (ESBL)-producing and New Delhi metallo-beta lactamase-1 (NDM-1)-producing Klebsiella pneumoniae isolates. MATERIALS AND METHODS: ESBLs production was confirmed by double-disk synergy test. Isolates positive for blaNDM-1 gene were found among the tested strains. K. pneumoniae ATCC(r) BAA-1705TM strain was used as a control. The checkerboard method was applied to assess the synergistic and additive action of nine essential oils: caraway, fennel, peppermint, geranium, basil, clove, thyme, clary sage, and lavender, respectively, in combination with gentamicin. RESULTS: Our results indicated that peppermint oil combined with gentamicin showed synergistic activity against both control, ESBL-producing and NDM-1-producing isolates. Caraway essential oil demonstrated synergy with gentamicin toward ESBL-producing and additionally gentamicin-resistant strains. The additive effect was observed for gentamicin combined with thyme, fennel, basil, and clary sage. CONCLUSIONS: Because of their synergistic activity with gentamicin, peppermint, and caraway oils in particular, can be considered as an alternative or an addition for the control of infections with limited therapeutic options due to multidrug resistance. PMID- 29708848 TI - Clostridium difficile Infection in Trauma, Surgery, and Medical Patients Admitted to the Intensive Care Unit. AB - BACKGROUND: Clostridium difficile infection (CDI) causes significant morbidity and mortality rates, especially for patients in the intensive care unit (ICU). Data comparing trauma and surgery patients with CDI in the ICU with medical patients with CDI in the ICU are limited. METHODS: In a single-center study, we analyzed retrospective data from 25 trauma patients and 13 surgery patients aged 18 years or older who had CDI and had been admitted to the ICU. A comparison group of 156 medical patients aged 18 years or greater who had CDI and were admitted to the ICU also was identified. RESULTS: The trauma/surgery patients had a significantly higher mean number of ventilator days (13.5 +/- 9.3 vs. 7.3 +/- 7.2; p < 0.0004), Foley catheter days (11.9 +/- 6.8 vs. 8.0 +/- 7.9; p = 0.005), mean ICU length of stay (LOS) (12.34 +/- 9.7 vs. 5.9 +/- 5.9 days; p < 0.0003), and mean total LOS (16 +/- 9.3 vs. 10.7 +/- 8.4 days; p = 0.0008). However, the medical group had a significantly higher mean number of vasopressor days (2.07 +/ 3.51) than the trauma/surgery group (0.58 +/- 1.55; p < 0.0001). The overall survival rate was significantly higher in the trauma/surgery group than in the medical group (100% vs. 81%, respectively; p = 0.003). A higher percentage of patients in the trauma/surgery group received piperacillin/tazobactam before the diagnosis of CDI than the medical patients (58% vs. 37%, respectively; p = 0.02). The number of days that antibiotics were given prior to the development of CDI was greater in the trauma/surgery group than in the medical group (10.3 +/- 6.7 vs. 7.6 +/- 7.3 days; p = 0.04). Multiple logistic regression models determined ICU LOS (adjusted odds ratio [aOR] 1.27 days; 95% confidence interval [CI] 1.13 1.41), the presence of chronic obstructive pulmonary disease (COPD) (aOR 3.44; 95% CI 1.19-9.95), and piperacillin/tazobactam use (aOR 3.27; 95% CI 1.24-8.65) to be positively associated with CDI in the trauma/surgery group compared with the medical patients. CONCLUSIONS: Longer ICU stay, receipt of piperacillin/tazobactam, and having COPD were positively associated with CDI in trauma/surgery patients compared with medical patients. These findings suggest further consideration of the possibility of CDI should be given to patients admitted the surgical ICU for an extended period of time, receiving piperacillin/tazobactam, or having COPD. Additional evaluation of these factors in a larger patient sample is warranted. PMID- 29708849 TI - No Compelling Evidence that Preferences for Facial Masculinity Track Changes in Women's Hormonal Status. AB - Although widely cited as strong evidence that sexual selection has shaped human facial-attractiveness judgments, findings suggesting that women's preferences for masculine characteristics in men's faces are related to women's hormonal status are equivocal and controversial. Consequently, we conducted the largest-ever longitudinal study of the hormonal correlates of women's preferences for facial masculinity ( N = 584). Analyses showed no compelling evidence that preferences for facial masculinity were related to changes in women's salivary steroid hormone levels. Furthermore, both within-subjects and between-subjects comparisons showed no evidence that oral contraceptive use decreased masculinity preferences. However, women generally preferred masculinized over feminized versions of men's faces, particularly when assessing men's attractiveness for short-term, rather than long-term, relationships. Our results do not support the hypothesized link between women's preferences for facial masculinity and their hormonal status. PMID- 29708850 TI - Examination of the influence of phenyltrimethylammonium chloride (PTMA) concentration on acetochlor adsorption by modified montmorillonite. AB - The results presented in this paper show an impact of the concentration of the aromatic organic cation on the adsorption of acetochlor on the surface of the organic-modified montmorillonite. Natural montmorillonite from Bogovina (Boljevac municipality, Serbia) was used for organic modification in this experiment. Cation exchange capacity of this montmorillonite (86 mmol 100 g-1 of clay) was determined using the methylene blue method. In pretreatment, montmorillonite was modified with NaCl. For the purpose of organic modification, three different concentrations of phenyltrimethylammonium chloride (PTMA) have been selected, based on calculated CEC value: 43 mmol 100 g-1 of clay (0.5 CEC), 86 mmol 100 g-1 of clay (1 CEC) and 129 mmol 100 g-1 of clay (1.5 CEC). The changes in the properties of the inorganic and organic modified montmorillonite were examined using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR) and batch equilibrium method. Freundlich coefficients show higher uptake of the herbicide by montmorillonite modified with PTMA, compared to inorganic-modified montmorillonite. The results also indicate the influence of the organic cation concentration on the adsorption of the selected herbicide. PMID- 29708853 TI - A method to reduce heat strain while clad in encapsulating outerwear. AB - The use of personal protective equipment (PPE) increases the risk of heat related maladies. A means to enhance heat dissipation capacity of individuals clad in PPE would be of benefit. The glabrous skin regions of the hands, face, and feet are portals for direct heat transfer between the body core and the external environment. The effects of PPE outerwear and palmar glabrous skin cooling on heat storage were assessed. Subjects engaged in fixed load treadmill exercise in a thermoneutral environment (Ta = 20-24 degrees C) or rested in a hot environment (45 +/- 0.5 degrees C). The use of PPE outerwear increased the rate of core temperature rise by five-fold during vigorous exercise. Palm cooling using a stationary water circulation system attenuated the rate of core temperature rise by 30-60% during rest and light, moderate, and vigorous exercise while wearing PPE outerwear. However, the subjects were tethered to the system. A wearable cooling system was devised that allowed free range of motion and unrestricted mobility. The wearable system provided thermal benefits equivalent to the use of the tethering cooling system. With optimization, this wearable cooling technique could neutralize the negative thermoregulatory effects of wearing PPE while engaged in light workload activities such as those encountered by healthcare professionals working in infectious disease treatment centers. For individuals working at higher workloads, such as firefighters, a wearable glabrous skin-based cooling system could extend work bout duration as well as enhance heat loss during episodic recovery periods. PMID- 29708852 TI - Fab is the most efficient format to express functional antibodies by yeast surface display. AB - Multiple formats are available for engineering of monoclonal antibodies (mAbs) by yeast surface display, but they do not all lead to efficient expression of functional molecules. We therefore expressed four anti-tumor necrosis factor and two anti-IpaD mAbs as single-chain variable fragment (scFv), antigen-binding fragment (Fab) or single-chain Fabs and compared their expression levels and antigen-binding efficiency. Although the scFv and scFab formats are widely used in the literature, 2 of 6 antibodies were either not or weakly expressed. In contrast, all 6 antibodies expressed as Fab revealed strong binding and high affinity, comparable to that of the soluble form. We also demonstrated that the variations in expression did not affect Fab functionality and were due to variations in light chain display and not to misfolded dimers. Our results suggest that Fab is the most versatile format for the engineering of mAbs. PMID- 29708851 TI - Radial-Artery or Saphenous-Vein Grafts in Coronary-Artery Bypass Surgery. AB - BACKGROUND: The use of radial-artery grafts for coronary-artery bypass grafting (CABG) may result in better postoperative outcomes than the use of saphenous-vein grafts. However, randomized, controlled trials comparing radial-artery grafts and saphenous-vein grafts have been individually underpowered to detect differences in clinical outcomes. We performed a patient-level combined analysis of randomized, controlled trials to compare radial-artery grafts and saphenous-vein grafts for CABG. METHODS: Six trials were identified. The primary outcome was a composite of death, myocardial infarction, or repeat revascularization. The secondary outcome was graft patency on follow-up angiography. Mixed-effects Cox regression models were used to estimate the treatment effect on the outcomes. RESULTS: A total of 1036 patients were included in the analysis (534 patients with radial-artery grafts and 502 patients with saphenous-vein grafts). After a mean (+/-SD) follow-up time of 60+/-30 months, the incidence of adverse cardiac events was significantly lower in association with radial-artery grafts than with saphenous-vein grafts (hazard ratio, 0.67; 95% confidence interval [CI], 0.49 to 0.90; P=0.01). At follow-up angiography (mean follow-up, 50+/-30 months), the use of radial-artery grafts was also associated with a significantly lower risk of occlusion (hazard ratio, 0.44; 95% CI, 0.28 to 0.70; P<0.001). As compared with the use of saphenous-vein grafts, the use of radial-artery grafts was associated with a nominally lower incidence of myocardial infarction (hazard ratio, 0.72; 95% CI, 0.53 to 0.99; P=0.04) and a lower incidence of repeat revascularization (hazard ratio, 0.50; 95% CI, 0.40 to 0.63; P<0.001) but not a lower incidence of death from any cause (hazard ratio, 0.90; 95% CI, 0.59 to 1.41; P=0.68). CONCLUSIONS: As compared with the use of saphenous-vein grafts, the use of radial artery grafts for CABG resulted in a lower rate of adverse cardiac events and a higher rate of patency at 5 years of follow-up. (Funded by Weill Cornell Medicine and others.). PMID- 29708855 TI - Novel Epigenomic Biomarkers of Male Infertility Identified by Methylation Patterns of CpG Sites Within Imprinting Control Regions of H19 and SNRPN Genes. AB - Male infertility is an important global health burden that can benefit from novel biomarkers and diagnostics innovation. Aberrant methylation of the imprinted genes H19 and SNRPN (small nuclear ribonucleoprotein polypeptide N) in sperm DNA has been implicated in abnormal sperm parameters and male infertility. However, whether certain methylation patterns of one or multiple CpG sites within an imprinted gene are pathological for multiple sperm defects remains poorly understood. To examine the diagnostic potential of certain methylation patterns of CpG sites for multiphenotype defects in human sperm, the sperm DNA methylation patterns of individual CpG sites within imprinting control regions (ICRs) of imprinted genes H19 and SNRPN were measured by bisulfite pyrosequencing in a Han Chinese population sample: 39 oligoasthenozoospermia (OA) patients, 36 asthenoteratozoospermia (AT) patients, and 50 normozoospermia (N) controls. A partial least squares discriminant analysis model was built with the CpG sites as independent variables. Among the 16 CpG sites screened, the methylation patterns of eight CpG sites within H19-ICR (CpG sites 1, 6-9, 12 and 15-16), and eight CpG sites within SNRPN-ICR (CpG sites 2, 5-6, 8-10, 13, and 16) correctly classified 74.4% and 72.0% of the samples in terms of male fertile status, respectively. Furthermore, by combination of these 16 selected CpG sites within ICRs of H19 and SNRPN, 88.0% of the samples could be successfully classified. Our study demonstrates that methylation profiles of CpG sites within ICRs of imprinted genes H19 and SNRPN may potentially serve as epigenomic biomarkers for assessment of infertility in men with multiple sperm defects. Further studies in independent population samples are called for diagnostic significance of methylation patterns of CpG sites within imprinted genes. PMID- 29708856 TI - Empirical data in support of a skin notation for methyl chloride. AB - This article presents the first empirical experimental data on the skin absorption of methyl chloride gas using an in vitro technique and human skin. Methyl chloride is a commonly used industrial agent that is known to be an inhalational hazard but is also reported to be absorbed through human skin in amounts that contribute substantially to systemic intoxication. As a result, is has been assigned a skin notation by the ACGIH. Other than predictive models, there is a general paucity of experimental data on the skin absorption of methyl chloride and therefore a distinct lack of empirical evidence in the open literature to support the assignment of a skin notation for this chemical. This study found that methyl chloride permeates through human epidermis when exposed at high atmospheric concentrations within relatively short timeframes. Therefore, providing important initial empirical evidence in support of the assignment of a skin notation. PMID- 29708857 TI - Exploiting the Dynamics of Soft Materials for Machine Learning. AB - Soft materials are increasingly utilized for various purposes in many engineering applications. These materials have been shown to perform a number of functions that were previously difficult to implement using rigid materials. Here, we argue that the diverse dynamics generated by actuating soft materials can be effectively used for machine learning purposes. This is demonstrated using a soft silicone arm through a technique of multiplexing, which enables the rich transient dynamics of the soft materials to be fully exploited as a computational resource. The computational performance of the soft silicone arm is examined through two standard benchmark tasks. Results show that the soft arm compares well to or even outperforms conventional machine learning techniques under multiple conditions. We then demonstrate that this system can be used for the sensory time series prediction problem for the soft arm itself, which suggests its immediate applicability to a real-world machine learning problem. Our approach, on the one hand, represents a radical departure from traditional computational methods, whereas on the other hand, it fits nicely into a more general perspective of computation by way of exploiting the properties of physical materials in the real world. PMID- 29708858 TI - How Does Infection with Human Papillomavirus 16 and 18 Impact on DNA Damage and Repair in Cervical Cells and Peripheral Blood? AB - Human papillomavirus (HPV) infection is one of the most common sexually transmitted diseases worldwide and a prime cause of cervical cancer. The HPV DNA is detected in approximately 80-90% of all cervical cancers, with HPV 16 and 18 being the high risk conferring human carcinogens. DNA damage and diminished DNA repair mechanisms are potential biological surrogates of HPV infection that warrant further research in different tissues and populations. Notably, we do not know the extent to which the high risk HPV 16 and 18 differentially affect cervical cells versus other systems such as peripheral blood lymphocytes (PBLs). We evaluated DNA damage and repair in women who tested positive for HPV 16 or HPV 18 and healthy control women without HPV 16 or HPV 18 infection. We found that the DNA damage as measured by the Comet assay was markedly greater in cervical cells of women with HPV 16 (mean: 8.1 as% DNA in tail, 95% CI: 7.6-8.7) or HPV 18 infection (mean: 9.6, 95% CI: 8.9-10.2) than controls (mean: 6.7, 95% CI: 6.2 7.4) (p < 0.05). By contrast, in PBLs, we did not find a significant difference in DNA damage between women with HPV 16 or 18 infection versus controls, as measured by the Comet assay or the Conventional Chromosomal Aberration analysis (p > 0.05). We observed, however, the DNA repair capacity, as measured by the X ray induced challenge (XRC) assay, was significantly impaired in PBLs from women with HPV 16 or 18 infection compared to controls (p < 0.05). This is the first comparative study, to the best of our knowledge, suggesting that the cervical swab cells might be better suited than peripheral lymphocytes as biosamples for detection of HPV 16 or 18 biological effects on DNA damage. In addition, these findings suggest that the Comet assay performed only in PBLs may potentially lead to false negative diagnosis of DNA damage. Taken together, these observations contribute to development of future diagnostic innovation and precision sampling strategies for robust detection of the biological effects of HPV 16 or 18 in women. We conclude by a brief discussion of implications for HPV clinical diagnostics and precision medicine innovation. PMID- 29708859 TI - Bioimpedance patterns and bioelectrical impedance vector analysis (BIVA) of road cyclists. AB - Bioelectrical impedance vector-analysis (BIVA) describes cell-mass, cell function and hydration status of an individual or a group. The goal of the present investigation was to provide bioelectrical impedance data for 525 male road cyclists (155 professionals, 79 elite, 59 elite-youth, and 232 amateurs) at the time of their optimal performance level. Data were plotted on the resistance reactance (R-Xc) graph to characterize cyclists group vectors using BIVA. Compared to the general male population, the mean vector position of the road cyclists indicates a higher body cell mass (BCM) and phase angle (p<0.001). The vector position of the high-performance, compared to the amateur cyclists showed similar patterns with higher BCM and phase angles and higher reactance values for the high-performance athletes (p<0.001). The bio-impedance data were used to calculate the 50%, 75%, and 95% tolerance ellipses of each group of cyclists. The characteristic vector positions of the road cyclists indicate normal hydration and greater muscle mass and function of the high-performance cyclists compared to amateur cyclists and the normal population. The cyclists specific tolerance ellipses, particularly the high-performance cyclists might be used for classifying a cyclist according to the individual vector position and to define target vector regions for lower level cyclists. PMID- 29708860 TI - Why Hate the Good Guy? Antisocial Punishment of High Cooperators Is Greater When People Compete To Be Chosen. AB - When choosing social partners, people prefer good cooperators (all else being equal). Given this preference, people wishing to be chosen can either increase their own cooperation to become more desirable or suppress others' cooperation to make them less desirable. Previous research shows that very cooperative people sometimes get punished ("antisocial punishment") or criticized ("do-gooder derogation") in many cultures. Here, we used a public-goods game with punishment to test whether antisocial punishment is used as a means of competing to be chosen by suppressing others' cooperation. As predicted, there was more antisocial punishment when participants were competing to be chosen for a subsequent cooperative task (a trust game) than without a subsequent task. This difference in antisocial punishment cannot be explained by differences in contributions, moralistic punishment, or confusion. This suggests that antisocial punishment is a social strategy that low cooperators use to avoid looking bad when high cooperators escalate cooperation. PMID- 29708861 TI - Occupational exposures of flour dust and airborne chemicals at bakeries in Taiwan. AB - Walk-through surveys were carried out for bakeries in this study to determine the environmental characteristics of bakeries in Taiwan. Questionnaires were administrated to discover whether job-related asthma-like symptoms occurred among workers. Air sampling and analysis were also performed. The results show that the levels of inhalable flour dust ranged from 0.01-0.83 mg m-3 with an average of 0.27 mg m-3. Among the samples collected, 23% of them had concentrations higher than the ACGIH TLV-TWA (0.5 mg m-3), which indicated that inhalable flour dust was an important air pollutant for bakery workers in Taiwan. Airborne chemicals such as diacetyl, acetoin, 2,3-pentanedione, 2,3-hexanedione, 2,3-heptanedione, furfural, and acetaldehyde were also found in various levels in this study. The concentrations of acetaldehyde measured in these bakeries were 37-83 times higher than what have been reported from other studies for residential areas and Chinese restaurants. In addition, the concentrations of total VOCs in the working areas of the bakeries were over 21 times higher than the levels determined in the non working areas. Based on our results, there appears to be a need to improve the air quality of the working environments of bakeries in Taiwan. PMID- 29708862 TI - Assessment of nitrogen oxides and ground-level ozone behavior in a dense air quality station network: Case study in the Lesser Antilles Arc. AB - This paper presents a study on ground-level ozone (O3), nitrogen oxides (NOx = NO + NO2) concentrations, and their variabilities in the ambient air of three sites of a tropical archipelago that is moderately urbanized. Statistical analysis was performed on a quite complete (>80%) set of 5 years of measurements (2008-2012). There are few studies on those pollutants and their seasonal behavior in the Caribbean area, where pollution level and cities configuration are different from megacities. Analyses are focused on pollutant variations at the scale of the day, the week, and the seasons, using hourly data. The observations show that NOx concentrations are more elevated during the wet season, whereas O3 concentrations are higher in the dry season. Amplitudes of ozone cycles are strongly influenced by meteorological conditions (temperature, global radiation, and wind speed) and prevailing levels of NOx. An ozone weekend effect is detected with the highest amplitude in the city, where anthropogenic activity is the lowest during the weekend. Due to the nature and the origin of pollutants, NOx shows higher variability than O3 in the time series. Our results evince the need for continuous measurements of volatile organic compounds (VOCs) in order to better quantify their contribution in O3 formation in an insular context where numerous natural sources have been identified. Implications: Statistical analyses of observed NOx and O3 concentrations for 5 years for a typical low industrialized site of the Caribbean area have been done. Air quality for those components is correct based on the standards of the World Health Orgaization, pollutant source spatial distributions, and level of industrialization. Observations show the same patterns as in megacities but also a strong impact of weather conditions and road traffic. Behaviors of O3 cannot be fully explained without VOCs monitoring. Localization and type of AQS should be reconsidered to improve the accuracy of concentrations of the pollutant and better understand their behaviors. PMID- 29708864 TI - First-Time Detection of Porcine Reproductive and Respiratory Syndrome Virus and Porcine Circovirus 2 in an Albanian Farrow-to-Finish Herd. AB - The purpose of this case report is to describe for the first time concurrent porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus 2 (PCV-2) infections in a commercial farrow-to-finish pig farm in Albania, as well as the phylogenetical analysis of isolated PRRSV strain. The present study reports on a farrow-to-finish commercial pig farm, located in South Albania. In a percentage of about 40% of weaners in each batch (60-70 piglets per batch), clinical signs, including fever, severe respiratory signs, wasting, jaundice, rough hairy coat, palpable inguinal lymphadenopathy, and high mortality rate, were performed. The clinical signs of sows included sporadic premature farrowings (22%), with increased number of stillbirth (3.3%) and weak piglets (4.1%) based on the record system of the farm. Blood samples were obtained from 8 sows (4 lactating and 4 dry-period sows), 25 piglets of 5 different batches (5 at 15-20 days, 5 at 40 days, 5 at 50 days, 5 of 60 days, and 5 of 70 days), and 5 finishers of 130-150 days of age. Moreover, tissue samples were collected from five weaners at 20-70 days of age. Histopathological examination of lung and lymph node sections revealed findings compatible with PRRSV and PCV-2 infection. Pigs between 15 and 130-140 days of age were positive for type 1 (European) PRRSV and pigs between 50 and 130-140 days of age were positive for PCV-2. Blood serum samples were tested by real-time polymerase chain reaction (PCR) for PCV-2 and one real-time reverse transcription-PCR-positive sample was selected for subsequent complete ORF5 (Gp5) gene sequencing. The results of this case report confirm the detection of PRRSV and PCV-2 concurrent infection in an Albanian farrow-to-finish pig farm. The full-length ORF5 sequence of the detected PRRSV strain (named "Mursi/AL/15") was successfully determined, revealing high nucleotide identity with other type 1 European isolates. PMID- 29708863 TI - Addressing the growing opioid and heroin abuse epidemic: a call for medical school curricula. AB - Substance abuse is a growing public health concern in the USA (US), especially now that the US faces a national drug overdose epidemic. Over the past decade, the number of drug overdose deaths has rapidly grown, largely driven by increases in prescription opioid-related overdoses. In recent years, increased heroin and illicitly manufactured fentanyl overdoses have substantially contributed to the rise of overdose deaths. Given the role of physicians in interacting with patients who are at risk for or currently abusing opioids and heroin, it is essential that physicians are aware of this issue and know how to respond. Unfortunately, medical school curricula do not devote substantial time to addiction education and many physicians lack knowledge regarding assessment and management of opioid addiction. While some schools have modified curricula to include content related to opioid prescription techniques and pain management, an added emphasis about the growing role of heroin and fentanyl is needed to adequately address the epidemic. By adapting curricula to address the rising opioid and heroin epidemic, medical schools have the potential to ensure that our future physicians can effectively recognize the signs, symptoms, and risks of opioid/heroin abuse and improve patient outcomes. This article proposes ways to include heroin and fentanyl education into medical school curricula and highlights the potential of simulation-based medical education to enable students to develop the skillset and emotional intelligence necessary to work with patients struggling with opioid and heroin addiction. This will result in future doctors who are better prepared to both prevent and recognize opioid and heroin addiction in patients, an important step in helping reduce the number of addicted patients and address the drug overdose epidemic. PMID- 29708865 TI - Assessing the Digital Divide Among Low-Income Perinatal Women: Opportunities for Provision of Health Information and Counseling. AB - OBJECTIVES: Technology-based health interventions may provide a means to reach low-income perinatal women and improve outcomes for both mother and infant, yet little is known about technology access and interest among this population. This study explored interest, attitudes, and concerns regarding technology to deliver health information and interventions. METHODS: Between May and October 2014, a cross-sectional study of 161 low-income pregnant and/or postpartum mothers (up to 1 year) was conducted, assessing attitudes and behaviors regarding the current use of devices and receptivity to interventions delivered through devices. Participants (ages 18-41) were pregnant or postpartum and able to read and comprehend English. Women were recruited from waiting areas at two urban clinics affiliated with the local health department in a Midwestern city in the United States. Surveys included 46 questions and were completed at the time of invitation. Descriptive statistics, independent sample t test, or chi-square for independence tests were completed using SPSS (version 23). RESULTS: Participants from this sample were mostly African American (60%) and had a mean age of 26 years. Most were postpartum (67%). The majority of the sample used mobile phones (most being smartphones), with less access and use of computers and tablets. CONCLUSION: A moderate level of interest in utilizing technology for health related information and interventions was found, with concerns related to privacy and time. PMID- 29708866 TI - The Characterization of Monoclonal Antibodies to Mouse TLT-1 Suggests That TLT-1 Plays a Role in Wound Healing. AB - Platelets play a vital role in hemostasis and inflammation. The membrane receptor TREM-like transcript-1 (TLT-1) is involved in platelet aggregation, bleeding, and inflammation, and it is localized in the alpha-granules of platelets. Upon platelet activation, TLT-1 is released from alpha-granules both in its transmembrane form and as a soluble fragment (sTLT-1). Higher levels of sTLT-1 have been detected in the plasma of patients with acute inflammation or sepsis, suggesting an important role for TLT-1 during inflammation. However, the roles of TLT-1 in hemostasis and inflammation are not well understood. We are developing the mouse model of TLT-1 to mechanistically test clinical associations of TLT-1 in health and disease. To facilitate our studies, monoclonal murine TLT-1 (mTLT 1) antibodies were produced by the immunization of a rabbit using the negatively charged region of the mTLT-1 extracellular domain 122PPVPGPREGEEAEDEK139. In the present study, we demonstrate that two selected clones, 4.6 and 4.8, are suitable for the detection of mTLT-1 by western blot, immunoprecipitation, immunofluorescent staining, flow cytometry and inhibit platelet aggregation in aggregometry assays. In addition, we found that the topical administration of clone 4.8 delayed the wound healing process in an experimental burn model. These results suggest that TLT-1 plays an important role in wound healing and because both clones specifically detect mTLT-1, they are suitable to further develop TLT 1 based models of inflammation and hemostasis in vivo. PMID- 29708867 TI - Development of Monoclonal Antibodies Specifically Recognizing the Nonstructural Protein 12 of Type 2 Porcine Reproductive and Respiratory Syndrome Virus. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) is one of the most important viral pathogens that has caused tremendous economic losses to the swine industry worldwide. Although extensive research has been focused on PRRSV, little is known about the structure and biological functions of individual nonstructural viral proteins, especially the nonstructural protein 12 (Nsp12). In this study, we generated and identified the monoclonal antibody (mAb) against PRRSV Nsp12. Six strains of hybridoma cells named 2B10, 2B12, 5E1, 5G6, 5E7, and 8B2 secreting anti-Nsp12 mAbs were obtained by the hybridoma technique. All the mAbs were specifically reacted with PRRSV by indirect immunofluorescence assay and four of them (2B12, 5E1, 5G6, and 5E7) were specifically reacted by Western blot. Furthermore, the 5E7 specifically recognized multiple type 2 PRRSV strains, including highly pathogenic and classical PRRSV strains, but not type 1 PRRSV strain. Taken together, the mAbs against Nsp12 provide a valuable tool to specifically recognize type 2 PRRSV as a diagnostic reagent and study the biological function of Nsp12 in the future. PMID- 29708868 TI - Multiple Tolerization Reduces Antibody Binding Against Tolerogen Cells: Implications for the Production of Monoclonal Antibodies. AB - We report an immunization technique that can update the production of monoclonal antibodies (mAbs): the multiple tolerization subtractive immunization (MTSI). A total of 10 BALB/C mice were used. Animals in group 1 received one inoculation of RWPE-1 cells (nontumoral), followed by cyclophosphamide, and then received serial inoculations of nonirradiated PC3 cells (tumoral). Animals in group 2 received our MTSI protocol, as follows: one inoculation of RWPE-1 cells, followed by cyclophosphamide (Cy). This whole tolerization step was repeated three other times, with 14-day intervals between the last Cy exposure and the next RWPE-1 cell inoculation. Finally, the animals received the same nonirradiated PC3 cell exposure as group 1. Blood was taken from each animal, and their polyclonal sera individually tested against the nontumoral RWPE-1 cells in flow cytometry. We found out that, after the MTSI was employed, the serum of the immunized animals, in group 2, contained considerably less antibodies that reacted against the tolerogenic cells, compared with the serum of the animals that underwent regular subtractive immunization. We showed that, by repeating the tolerization cycles, the polyclonal antibodies produced by mice have a reduced specificity toward common/immunodominant epitopes present at nontumoral cells, and thus this technique can be readily used by others in studies involving murine mAb protocols. PMID- 29708869 TI - Delayed Cholecystectomy for Acute Cholecystitis in Elderly Patients Treated Primarily with Antibiotics or Percutaneous Drainage of the Gallbladder. AB - BACKGROUND: In high-risk patients with acute cholecystitis, antibiotics with or without percutaneous drainage of the gallbladder followed by delayed cholecystectomy (DC) can be performed. This study aimed to review our current management of elderly patients with acute cholecystitis treated with DC. METHODS: All consecutive patients older than 70 with acute cholecystitis treated primarily with antibiotics with or without percutaneous drainage followed by DC between 2006 and 2015 were retrospectively reviewed. RESULTS: Overall 105 elderly patients had acute cholecystitis with planned DC. Ninety-three patients had antibiotherapy alone at first. Twenty-eight patients needed percutaneous drainage either in intention to treat (n = 12) or due to failure of antibiotic treatment (n = 16). Nine (32%) versus 11 patients (12%) required an emergency cholecystectomy (EC) due to failure of percutaneous drainage or antibiotic treatment, respectively. Eighteen patients (64%) underwent DC after percutaneous drainage. Postoperative morbidity was 39% (7/18) after DC in the percutaneous drainage group, and 1 patient died. Compared to DC after antibiotherapy (n = 53), elderly patients who underwent DC after percutaneous drainage (n = 18) had longer median hospital stay (10 days versus 3 days, P = .001) and higher postoperative complications (7/18 versus 6/53, P = .015). CONCLUSION: In elderly patients with acute cholecystitis, DC can be a good alternative to EC. However, after percutaneous drainage DC is associated with high complication rate and long hospital stay. PMID- 29708870 TI - Validation of Freezing-of-Gait Monitoring Using Smartphone. AB - BACKGROUND: Freezing of gait (FOG) is a commonly observed motor symptom for patients with Parkinson's disease (PD). The symptoms of FOG include reduced step lengths or motor blocks, even with an evident intention of walking. FOG should be monitored carefully because it not only lowers the patient's quality of life, but also significantly increases the risk of injury. INTRODUCTION: In previous studies, patients had to wear several sensors on the body and another computing device was needed to run the FOG detection algorithm. Moreover, the features used in the algorithm were based on low-level and hand-crafted features. In this study, we propose a FOG detection system based on a smartphone, which can be placed in the patient's daily wear, with a novel convolutional neural network (CNN). METHODS: The walking data of 32 PD patients were collected from the accelerometer and gyroscope embedded in the smartphone, located in the trouser pocket. The motion signals measured by the sensors were converted into the frequency domain and stacked into a 2D image for the CNN input. A specialized CNN model for FOG detection was determined through a validation process. RESULTS: We compared our performances with the results acquired by the previously reported settings. The proposed architecture discriminated the freezing events from the normal activities with an average sensitivity of 93.8% and a specificity of 90.1%. CONCLUSIONS: Using our methodology, the precise and continuous monitoring of freezing events with unconstrained sensing can assist patients in managing their chronic disease in daily life effectively. PMID- 29708871 TI - Spino-pelvic radiological parameters in normal Indian population. AB - INTRODUCTION: There is increasing emphasis on the sagittal spino-pelvic alignment and its interpretation is of critical importance in the management of spinal disorders. A cross-sectional study of several spino-pelvic radiographic parameters was conducted to determine the physiological values of these parameters, to calculate the variations of these parameters according to epidemiological data, and to study the relationships among these parameters. MATERIAL AND METHOD: Fifty normal healthy volunteers (29 males and 21 females) with no history of back pain were selected and were subjected to standing sagittal spino-pelvic radiographs. All the measurements of various radiographic parameters were performed with use of a software program. A statistical analysis was done to study the relationships among them. RESULTS: The mean values of pelvic incidence (PI) and lumbar Lordosis Angle (LLA) were 48.52 +/- 8.99 and 58.78 +/- 9.51, respectively. There was statistical difference between male and female parameters in LLA, lumbo-sacral angle (LSA), sacral horizontal angle (SHA), sacral inclination angle (SIA), sacropelvic angle (PRS1), pelvisacral angle (PSA), and PI. A majority of parameters had higher values for female subjects when compared to male subjects. PI was positively correlated with LLA, pelvic angle (PA), pelvic overhang (PO), pelvic tilt (PT), sacrofemoral distance (SFD), SHA, and sacropelvic translation (SPT), which were highly significant, whereas LLA was positively correlated with SHA and SIA only. PI and LLA were both negatively correlated with PSA, pelvic thickness (PTH), and PRS1. CONCLUSIONS: This study presents the various spino-pelvic radiographic parameter values of a sample of the normal asymptomatic Indian population. There was significant difference in radiographic parameters between males and females in about half of the parameters studied in the sample. The values obtained are comparable with the values presented as normal in the literature. A comparison of the study results with data published about other populations revealed no differences in any of the pelvic parameters between the Indian, Brazilian, and Korean populations. PMID- 29708872 TI - Analysis of on-surface and in-air movement in handwriting of subjects with Parkinson's disease and atypical parkinsonism. AB - The purpose of this paper is to emphasize the importance of in-air movement besides on-surface movement for handwriting analysis. The proposed method uses a classification of drawing healthy subjects and subjects with Parkinson's disease, according to their on-surface and in-air handwriting parameters during their writing on a graphical tablet. Experimental results on real data sets demonstrate that the highest accuracy of subject's classification was obtained by combining both on-surface and in-air kinematic parameters. PMID- 29708873 TI - Simple gastric motility assessment method with a single-channel electrogastrogram. AB - Surface electrogastrography (EGG) is a non-invasive technique that is used to record myoelectrical activity of the stomach using cutaneous electrodes placed on the abdomen. Gastric motility assessment by EGG is a candidate for standard clinical procedure based on the quantification of parameters characteristic of gastric motility disorders. Despite its noticeable benefits, EGG is not widely implemented in clinical practice. The main reasons are: (1) lack of standardization of electrode placement, (2) time-consuming diagnostic procedures and (3) a complex multi-channel recording setup. We proposed a methodology in which an easy-to-use single-channel EGG, with a less time-consuming protocol (<1 h), would provide sufficient information for gastric motility assessment. Recordings from the three anatomical landmarks in 20 healthy young subjects were compared under two conditions, fasting and postprandial by evaluating the dominant frequency (DF). Our results showed that there is a statistically significant increase of DF after meal ingestion (p<0.05) in each of the three channels. However, when the study group was divided into two subgroups based on body mass index (BMI), the most appropriate recording location was above the body of the stomach (according to statistical significance p=7.82*10-6). We showed that a less time-consuming recording session with light meal intake could be used for the assessment of gastric myoelectrical activity (GMA). PMID- 29708874 TI - Electro-spun PLA-PEG-yarns for tissue engineering applications. AB - Electro-spinning is widely used in tissue-engineered applications mostly in form of non-woven structures. The development of e-spun yarn opens the door for textile fabrics which combine the micro to nanoscale dimension of electro-spun filaments with three-dimensional (3D) drapable textile fabrics. Therefore, the aim of the study was the implementation of a process for electro-spun yarns. Polylactic acid (PLA) and polyethylene glycol (PEG) were spun from chloroform solutions with varying PLA/PEG ratios (100:0, 90:10, 75:25 and 50:50). The yarn samples produced were analyzed regarding their morphology, tensile strength, water uptake and cytocompatibility. It was found that the yarn diameter decreased when the funnel collector rotation was increasd, however, the fiber diameter was not influenced. The tensile strength was also found to be dependent on the PEG content. While samples composed of 100% PLA showed a tensile strength of 2.5+/ 0.7 cN/tex, the tensile strength increased with a decreasing PLA content (PLA 75%/PEG 25%) to 6.2+/-0.5 cN/tex. The variation of the PEG content also influenced the viscosity of the spinning solutions. The investigation of the cytocompatibility with endothelial cells was conducted for PLA/PEG 90:10 and 75:25 and indicated that the samples are cytocompatible. PMID- 29708875 TI - Detecting molecular forms of antithrombin by LC-MRM-MS: defining the measurands. PMID- 29708876 TI - Quantification of vanillylmandelic acid, homovanillic acid and 5 hydroxyindoleacetic acid in urine using a dilute-and-shoot and ultra-high pressure liquid chromatography tandem mass spectrometry method. AB - BACKGROUND: Urinary vanillylmandelic acid (VMA) and homovanillic acid (HVA) are biomarkers for the diagnosis and follow-up of neuroblastoma, whereas urinary 5 hydroxyindoleacetic acid (5-HIAA) is used to assess a carcinoid tumor. These analytes are conventionally analyzed in a single run by chromatography (LC) coupled with electrochemical detection (LC-ECD) using commercial kits. A rapid dilute-and-shoot LC tandem mass spectrometry (LC-MS/MS) assay was validated in order to replace the LC-ECD method and therefore improve analytical specificity and throughput. METHODS: Sample preparation was carried out by dilution of the urine sample with a solution containing the deuterated internal standards. The separation was achieved on an ultra-high pressure LC system with MS detection using a triple quadrupole mass spectrometer. The method was validated according to the current EMA and FDA guidelines. RESULTS: The full chromatographic run was achieved in 8 min. The method validation showed excellent linearity (r2>0.999 for all three analytes), precision (CV <15%), negligible matrix effect (recoveries >90%), low carryover (<1%) and LLOQ of 0.25, 0.4 and 0.4 MUM for VMA, HVA and 5 HIAA, respectively. Deming fits and Bland-Altman analyses showed no significant differences between the values obtained between the two assays. CONCLUSIONS: The LC-MS/MS method proposed in this study is fast and robust, and the simple sample preparation saves time and avoids the additional costs of dedicated kits used for the LC-ECD assays by switching to LC-MS/MS. Additionally, the near-perfect correlation observed herein between both assays allows the previously established reference ranges to be maintained. PMID- 29708877 TI - External quality assessment schemes for glucose measurements in Germany: factors for successful participation, analytical performance and medical impact. AB - BACKGROUND: Determination of blood glucose concentration is one of the most important measurements in clinical chemistry worldwide. Analyzers in central laboratories (CL) and point-of-care tests (POCT) are both frequently used. In Germany, regular participation in external quality assessment (EQA) schemes is mandatory for laboratories performing glucose testing. METHODS: Glucose testing data from the two German EQAs "Reference Institute for Bioanalytics" (RfB) and "INSTAND - Gesellschaft zur Forderung der Qualitatssicherung in medizinischen Laboratorien" (Instand) were analyzed from 2012 to 2016. Multivariable odds ratios (OR) for the probability to reach a "good" result were calculated. Imprecision and bias were determined and clinical risk of measurement errors estimated. RESULTS: The device employed was the most important variable required for a "good" performance in all EQAs. Additional participation in an EQA for CL automated analyzers improved performance in POCT EQAs. The reciprocal effect was less pronounced. New participants performed worse than experienced participants especially in CL EQAs. Imprecision was generally smaller for CL, but some POCT devices reached a comparable performance. Large lot-to-lot differences occurred in over 10% of analyzed cases. We propose the "bias budget" as a new metric to express the maximum allowable bias that still carries acceptable medical risk. Bias budgets were smallest and clinical risks of errors greatest in the low range of measurement 60-115 mg/dL (3.3-6.4 mmol/L) for most devices. CONCLUSIONS: EQAs help to maintain high analytical performances. They generate important data that serve as the foundation for learning and improvement in the laboratory healthcare system. PMID- 29708878 TI - Unstable haemoglobin variant Hb Leiden is detected on Sysmex XN-Series analysers. PMID- 29708879 TI - Fibroblast growth factor 23 and renal function among young and healthy individuals. AB - BACKGROUND: Fibroblast growth factor 23 (FGF-23), an osteocyte hormone involved in the regulation of phosphate metabolism, is associated with incident and progressive chronic kidney disease. We aimed to assess the association of FGF-23 with renal parameters, vascular function and phosphate metabolism in a large cohort of young and healthy individuals. METHODS: Healthy individuals aged 25-41 years were included in a prospective population-based study. Fasting venous blood and morning urinary samples were used to measure plasma creatinine, cystatin C, endothelin-1, phosphate and plasma FGF-23 as well as urinary creatinine and phosphate. Multivariable regression models were constructed to assess the relationship of FGF-23 with parameters of renal function, endothelin-1 and fractional phosphate excretion. RESULTS: The median age of 2077 participants was 37 years, 46% were males. The mean estimated glomerular filtration rate (eGFR - CKD-EPI creatinine-cystatin C equation) and fractional phosphate excretion were 110 mL/min/1.73 m2 and 8.7%, respectively. After multivariable adjustment, there was a significant inverse relationship of FGF-23 with eGFR (beta per 1 log-unit increase -3.81; 95% CI [-5.42; -2.20]; p<0.0001). Furthermore, we found a linear association between FGF-23 and endothelin-1 (beta per 1 log-unit increase 0.06; [0.01, 0.11]; p=0.01). In addition, we established a significant relationship of FGF-23 with fractional phosphate excretion (beta per 1 log-unit increase 0.62; [0.08, 1.16]; p=0.03). CONCLUSIONS: Increasing plasma FGF-23 levels are strongly associated with decreasing eGFR and increasing urinary phosphate excretion, suggesting an important role of FGF-23 in the regulation of kidney function in young and healthy adults. PMID- 29708880 TI - Diagnostic laboratory tests for systemic autoimmune rheumatic diseases: unmet needs towards harmonization. PMID- 29708881 TI - Perceptions of sexual abstinence among Muslim adolescent girls in southern Thailand. AB - Background Sex before marriage among Muslim adolescents is becoming a serious issue in Muslim societies exemplified by an increasing incidence of teenage pregnancy. Sexual abstinence is an optimal goal for adolescent health from an Islamic perspective. Muslim adolescent girls' perceptions have not been investigated, therefore, we lack understanding of their strengths and the risks that may contribute to outcomes such as pregnancy or sexually transmitted infections. Objective The purpose of this investigation was to characterize Muslim adolescent girls' perceptions of sexual abstinence. Methodology This participatory action study was conducted at an Islamic school in southern Thailand. Twenty-five girls, ages 12-14 years old, were purposively selected to participate in the study. Content analysis was used for data analysis. Results Two salient themes were discovered that characterize Muslim adolescent girls' perceptions about sexual abstinence: sexual abstinence is a means of self protection and sex outside marriage is restricted by Islam, but it seems to be difficult to adhere to. Conclusions Religious values, family and peers play a central role in shaping thoughts and decisions about abstaining from sex. The integration of religious principles with building practical refusal skills, is needed to promote Muslim adolescent health. PMID- 29708882 TI - Does it take a village? Fostering gender equity among early adolescents in Nepal. AB - Background Gender inequity contributes to a range of poor health outcomes. Early adolescence presents a window of opportunity for gender transformative interventions to shift inequitable gender norms, attitudes and behaviors. Objective The objective of this study is to evaluate a set of individual, family and community interventions to increase gender equity among very young adolescents (VYAs) in rural Nepal. Methods Two communities received the individual-level Choices intervention as well the family and community Voices and Promises interventions (CVP). Two comparison communities received only Choices. Samples of 1200 VYAs and 600 parents were interviewed at baseline before implementation and at end line 1 year later. Results In both CVP and Choices only areas most measures of gender norms, attitudes, and behaviors improved, suggesting a positive effect of the individual-level intervention. Increases in norms, attitudes, and behaviors reported by VYAs were generally greater in CVP areas compared to Choices areas, suggesting an added benefit from the family and community interventions. Parent-reported measures did not demonstrate an intervention effect of the family and community interventions. Uneven evaluation results, particularly among parents, may reflect implementation challenges such as the compressed 3-month intervention period due to the 2015 earthquakes and subsequent political unrest. Conclusion Overall findings are encouraging and suggest that adding family and community interventions may improve gender equity. PMID- 29708883 TI - Graves' disease following allogenic hematopoietic stem cell transplantation for severe aplastic anemia: case report and literature review. AB - BACKGROUND: Similar autoimmune processes (defective T-cell function) take place during the pathogenesis of aplastic anemia (AA) and Graves' disease (GD). Antithyroid drugs used for the management of GD may induce AA and GD may occur following treatment of severe aplastic anemia (SAA). CASE PRESENTATION: Clinical and laboratory investigations were performed for an 11-year-and-2-month-old girl who was referred for bilateral exophthalmus and abnormal thyroid function tests. She had been diagnosed as having severe acquired AA at the age of 8 years and had been treated with allogenic hematopoietic stem cell transplantation from her healthy human leukocyte antigen-matched sibling donor. Clinical examination revealed a weight of 32.6 kg (-0.88 standard deviation [SD] score); height, 145.7 cm (-0.14 SD score); body mass index 15.5 kg/m2 (-1.01 SD score); heart rate, 110/min; blood pressure, 128/74 mmHg; bilateral exophthalmos and an enlarged thyroid gland. The laboratory workup showed hemoglobin of 11.1 g/dL; white blood cells, 7500/mL; platelets, 172,000/mL; free thyroxine (FT4), 4.80 ng/dL (normal, 0.5-1.51); free triiodothyronine (FT3), 17.7 pg/mL (normal, 2.5-3.9); thyrotropin (TSH), 0.015 mIU/mL (normal, 0.38-5.3); antithyroglobulin peroxidase (TPO) antibody, 61.7 IU/mL (normal, 0-9); antithyroglobulin (TG) antibody, <0.9 IU/mL (normal, 0-4) and thyrotropin (TSH) receptor antibodies 14 U/L (normal, 0-1). Doppler ultrasonography showed diffuse enlargement of the thyroid gland and increased vascularity. She was treated with methimazole (0.6 mg/kg/day). L thyroxine treatment was also needed (50 MUg/day). Thrombocytopenia developed during follow-up. A thyroidectomy was performed for definitive treatment at the 14th month of treatment. CONCLUSIONS: The association of hyperthyroidism and AA in the pediatric age group is rare. The long-term use of antithyroid drugs and radioactive iodine should be avoided due to their hematologic toxic side effects. PMID- 29708884 TI - Serum sFlt-1/PlGF ratio has better diagnostic ability in early- compared to late onset pre-eclampsia. AB - BACKGROUND: To establish gestational specific cutoffs for the soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor (PlGF) ratio as a diagnostic tool for pre-eclampsia (PE) in an Asian population. METHODS: 82 subjects (48 PE patients and 34 controls) were recruited. sFlt-1 and PlGF were analysed on the Roche Cobas e411 analyzer and their ratio was calculated. Diagnostic performance was evaluated using receiver-operating characteristics (ROC) curves. Optimal cutoffs for sFlt-1/PlGF ratio were determined for different gestation phases. RESULTS: The most optimal cut-off for the study group is 32 with a sensitivity and specificity of 85.1% and 100% and Youden Index (J) of 0.85. Applying this cutoff for early-onset PE (EO-PE), sensitivity increased to 95.8% while specificity remains at 100% (J=0.96). However, for late onset PE (LO PE), sensitivity decreases to 73.9% while specificity remains at 100% (J=0.74). Two cutoffs were further determined for EO-PE and LO-PE - the first focusing on high sensitivity; the second focusing on high specificity. For EO-PE, cutoff <17 yielded sensitivity of 100% and specificity of 94.4% (J=0.94) while cutoff >=32 yielded sensitivity of 95.8% and specificity of 100% (J=0.95). For LO-PE, cutoff <22 has a sensitivity of 82.6% and a specificity of 91.7% (J=0.74) while cutoff >=32 yielded sensitivity of 73.9% and specificity of 100% (J=0.74). CONCLUSION: While our study found an overall cutoff at 32 regardless of gestation age, it has limited diagnostic accuracy for LO-PE in our study. Multiple cutoffs focusing on either high sensitivity or high specificity enhance the performance of the sFlt 1/PlGF ratio as a diagnostic tool for PE and contribute to the identification of women at risk of PE in our Asian region. PMID- 29708885 TI - A transformative icon for modern perinatology. PMID- 29708886 TI - Noise-robust assessment of SNP array based CNV calls through local noise estimation of log R ratios. AB - Arrays based on single nucleotide polymorphisms (SNPs) have been successful for the large scale discovery of copy number variants (CNVs). However, current CNV calling algorithms still have limitations in detecting CNVs with high specificity and sensitivity, especially in case of small (<100 kb) CNVs. Therefore, this study presents a simple statistical analysis to evaluate CNV calls from SNP arrays in order to improve the noise-robustness of existing CNV calling algorithms. The proposed approach estimates local noise of log R ratios and returns the probability that a certain observation is different from this log R ratio noise level. This probability can be triggered at different thresholds to tailor specificity and/or sensitivity in a flexible way. Moreover, a comparison based on qPCR experiments showed that the proposed noise-robust CNV calls outperformed original ones for multiple threshold values. PMID- 29708887 TI - Twelve-month clinical outcomes of acute non-ST versus ST-segment elevation myocardial infarction patients with reduced preprocedural thrombolysis in myocardial infarction flow undergoing percutaneous coronary intervention. AB - BACKGROUND: Reduced preprocedural thrombolysis in myocardial infarction (TIMI) flow in patients with ST-segment elevation myocardial infarction (STEMI) is known to be associated with increased mortality. However, clinical implications of reduced preprocedural TIMI flow in patients with non-ST-segment elevation myocardial infarction (NSTEMI) have not been fully elucidated as yet. The aim of the present study was to compare the clinical influence of reduced preprocedural TIMI flows between patients with STEMI and NSTEMI undergoing percutaneous coronary intervention (PCI). METHODS: From the Korea Acute Myocardial Infarction Registry, a total of 7336 AMI patients with angiographically confirmed reduced preprocedural TIMI flow (TIMI 0/1) during PCI were selected and divided into STEMI (n=4852) and NSTEMI (n=2484) groups. The 12-month composite of total death, nonfatal myocardial infarction, coronary artery bypass graft, and repeated PCI was compared between the two groups. RESULTS: After adjustment of baseline confounders by propensity score stratification, the NSTEMI group had lower incidences of major adverse cardiac events than the STEMI group (7.15 vs. 11.19%; hazard ratio: 0.63; 95% confidence interval: 0.47-0.84; P=0.001) at 12 months, which was largely attributable to the lower incidences of total deaths (2.43 vs. 3.99%; P=0.04) and repeated PCI (3.81 vs. 6.41%; P=0.01). CONCLUSION: Among AMI patients with TIMI 0/1, patients with NSTEMI had better outcomes compared with those of patients with STEMI on the basis of the incidences of 12-month outcomes. This could be attributable to lower total death and repeated revascularization in patients with NSTEMI. PMID- 29708889 TI - In Response to: Cancers of the Esophagus and Stomach: Potential Mechanisms Behind the Beneficial Influence of Physical Activity. PMID- 29708888 TI - Urine Reagent Strips Are Inaccurate for Assessing Hypohydration: A Brief Report. AB - OBJECTIVE: To assess the diagnostic ability of urine reagent strips to identify hypohydration based on urine specific gravity (USG). DESIGN: This study examined the agreement of USG between strips and refractometry with Bland-Altman, whereas the diagnostic ability of the strips to assess hypohydration was performed by receiver operating characteristic analysis. SETTING: Arkansas high school football preseason practice. PARTICIPANTS: Four hundred fourteen fresh urine samples were analyzed. MAIN OUTCOME MEASURES: Urine specific gravity was assessed by both reagent strips and refractometry. Cutoffs of >1.020 and >1.025 were used for identifying hypohydration. RESULTS: Bland-Altman analysis showed agreement of the 2 methods. Overall diagnostic ability of the urine strip to identify hypohydration was fair (area under the curve 72%-78%). However, the sensitivity to correctly identify hypohydration was poor (63%-71%), and the specificity of correctly identifying euhydration was poor to fair (68%-83%). CONCLUSION: The urine strip method is not valid for assessing hypohydration. PMID- 29708890 TI - Antithrombotic drugs in cardiovascular medicine: a year in review. AB - PURPOSE OF REVIEW: To provide an up to date review of the most recent randomized clinical trials in the field of antithrombotic drugs for cardiovascular diseases. RECENT FINDINGS: In 2017, low-dose anti-Xa treatment added to aspirin proved to be more efficacious than either treatment alone in patients with stable atherosclerotic disease despite the increase in nonfatal bleeding events. Furthermore, anticoagulation strategy during coronary interventions was again tested in a registry-based trial and showed comparable efficacy and safety between heparin alone and bivalirudin. Data from safety trials demonstrated lower risk of bleeding with dual antithrombotic therapy compared with triple antithrombotic therapy following coronary intervention, albeit these trials were underpowered for efficacy. Although still in its infancy, the role of antithrombotic treatment following transcatheter aortic valve replacement (TAVR) has been investigated in small trials with evidence that a single antiplatelet drug may be noninferior to dual antiplatelet therapy with a better safety profile. SUMMARY: In this review, we discuss the most recent clinical trials investigating antithrombotic drugs for cardiovascular diseases published in 2017. PMID- 29708891 TI - Frequency and Acceptability of Adverse Events After Anterior Cervical Discectomy and Fusion: A Survey Study From the Cervical Spine Research Society. AB - PURPOSE: Anterior cervical discectomy and fusion has a low but well-established profile of adverse events. The goal of this study was to gauge surgeon opinion regarding the frequency and acceptability of these events. METHODS: A 2-page survey was distributed to attendees at the 2015 Cervical Spine Research Society (CSRS) meeting. Respondents were asked to categorize 18 anterior cervical discectomy and fusion-related adverse events as either: "common and acceptable," "uncommon and acceptable," "uncommon and sometimes acceptable," or "uncommon and unacceptable." Results were compiled to generate the relative frequency of these responses for each complication. Responses for each complication event were also compared between respondents based on practice location (US vs. non-US), primary specialty (orthopedics vs. neurosurgery) and years in practice. RESULTS: Of 150 surveys distributed, 115 responses were received (76.7% response rate), with the majority of respondents found to be US-based (71.3%) orthopedic surgeons (82.6%). Wrong level surgery, esophageal injury, retained drain, and spinal cord injury were considered by most to be unacceptable and uncommon complications. Dysphagia and adjacent segment disease occurred most often, but were deemed acceptable complications. Although surgeon experience and primary specialty had little impact on responses, practice location was found to significantly influence responses for 12 of 18 complications, with non-US surgeons found to categorize events more toward the uncommon and unacceptable end of the spectrum as compared with US surgeons. CONCLUSIONS: These results serve to aid communication and transparency within the field of spine surgery, and will help to inform future quality improvement and best practice initiatives. PMID- 29708892 TI - Continuous Negative Abdominal Pressure Reduces Ventilator-induced Lung Injury in a Porcine Model. AB - BACKGROUND: In supine patients with acute respiratory distress syndrome, the lung typically partitions into regions of dorsal atelectasis and ventral aeration ("baby lung"). Positive airway pressure is often used to recruit atelectasis, but often overinflates ventral (already aerated) regions. A novel approach to selective recruitment of dorsal atelectasis is by "continuous negative abdominal pressure." METHODS: A randomized laboratory study was performed in anesthetized pigs. Lung injury was induced by surfactant lavage followed by 1 h of injurious mechanical ventilation. Randomization (five pigs in each group) was to positive end-expiratory pressure (PEEP) alone or PEEP with continuous negative abdominal pressure (-5 cm H2O via a plexiglass chamber enclosing hindlimbs, pelvis, and abdomen), followed by 4 h of injurious ventilation (high tidal volume, 20 ml/kg; low expiratory transpulmonary pressure, -3 cm H2O). The level of PEEP at the start was ~7 (vs. ~3) cm H2O in the PEEP (vs. PEEP plus continuous negative abdominal pressure) groups. Esophageal pressure, hemodynamics, and electrical impedance tomography were recorded, and injury determined by lung wet/dry weight ratio and interleukin-6 expression. RESULTS: All animals survived, but cardiac output was decreased in the PEEP group. Addition of continuous negative abdominal pressure to PEEP resulted in greater oxygenation (PaO2/fractional inspired oxygen 316 +/- 134 vs. 80 +/- 24 mmHg at 4 h, P = 0.005), compliance (14.2 +/- 3.0 vs. 10.3 +/- 2.2 ml/cm H2O, P = 0.049), and homogeneity of ventilation, with less pulmonary edema (~10% less) and interleukin-6 expression (~30% less). CONCLUSIONS: Continuous negative abdominal pressure added to PEEP reduces ventilator-induced lung injury in a pig model compared with PEEP alone, despite targeting identical expiratory transpulmonary pressure. PMID- 29708893 TI - Recent approaches to provision of mental healthcare in refugee populations. AB - PURPOSE OF REVIEW: The present review provides an overview of key issues and concepts on the provision of mental healthcare to refugees with mental health conditions. RECENT FINDINGS: Several barriers to mental healthcare for refugees have been described, and principles for good mental care in this group have been framed. Evidence for specific interventions for refugees is available for trauma related mental health problems. The best evidence is available for psychosocial interventions for the treatment of posttraumatic stress disorder. SUMMARY: The worldwide increase in the number of refugees and the substantial burden of psychological distress and mental health problems associated with this condition has led to an increased research and policy interest for optimizing the provision of effective mental healthcare. To date, with the exception of trauma-related conditions, there is almost no evidence on the efficacy of psychosocial interventions for anxiety and depressive conditions, and there is no information on how mental healthcare should be embedded into existing health and social care services. Existing research and implementation activities will hopefully contribute to better characterize the effective components and elements of mental healthcare programmes for refugees. PMID- 29708894 TI - Alcohol drinking and problems in young populations: the challenge in Asia. AB - PURPOSE OF REVIEW: The current article reviews recent research (from 2016 onward) on drinking behaviors and alcohol-related problems among young people in Asia with an emphasis on population-based evidence. RECENT FINDINGS: Recent evidence concerning underage drinking in Asia was limited to certain countries and societies with most data derived from cross-sectional surveys. Measures of alcohol drinking or problems were less sophisticated. The prevalence of recent alcohol drinking varies widely with the highest estimates reported in Hong Kong and Korea (~21%). Certain emotional, behavioral, and cognitive characteristics have been linked with increased drinking behaviors, including internalizing or externalizing problems. Parents (or family) are the most studied predictors within the domain of socioenvironmental characteristics, whereas little attention has been paid to the macro environments (e.g., media, alcohol advertisement, and alcohol control policy/regulations). SUMMARY: Research on underage drinking behaviors in Asia is urgently needed, particularly in some emerging markets. Follow-up studies with longitudinal measurements and large diverse samples will provide a better understanding of developmental stage-dependent and ever-changing macroenvironmental factors, as well as possible mechanisms. PMID- 29708895 TI - Offspring of parents with mood disorders: time for more transgenerational research, screening and preventive intervention for this high-risk population. AB - PURPOSE OF REVIEW: Offspring of parents with mood disorders (major depressive and bipolar disorder) are at increased risk for developing mood disorders. In this review, an overview regarding the intergenerational transmission of mood disorders, screening, and preventive intervention is given for this vulnerable group. RECENT FINDINGS: Offspring of parents with depression have a 40% chance of developing a depression, whereas offspring of parents with bipolar disorder have a 10% chance of developing a bipolar disorder by adulthood. Studies into the intergenerational transmission of mood disorders show that children of parents with mood disorders have increased biological dysregulation and neuropsychosocial impairments. Although there is a clear need for early identification of those at the highest risk, there are few systematic attempts in mental health care to screen children of parents with mood disorders. Lastly, preventive interventions seem to be effective in reducing depressive symptoms of children of parents with depression; however, those effects are small and short-lived. SUMMARY: Offspring of parents with mood disorders constitute a vulnerable group at high risk of mood disorders. More research needs to be conducted regarding mechanisms of the intergenerational transmission. Moreover, screening and preventive interventions for these offspring should be systematically evaluated and implemented. PMID- 29708896 TI - How the pathologist can aid in the assessment of gastroesophageal reflux disease. AB - PURPOSE OF REVIEW: To provide new concepts regarding the early pathologic changes of gastroesophageal reflux disease (GERD) that are associated with damage to the lower esophageal sphincter (LES). RECENT FINDINGS: A body of evidence exists that cardiac mucosa is a metaplastic esophageal epithelium rather than a normal gastric epithelium. Recent studies in asymptomatic volunteers suggest a potential mechanism for cardiac metaplasia in the squamous epithelium of the esophagus. SUMMARY: The concept that cardiac mucosa is esophageal, not gastric, suggests that the widely accepted endoscopic definition of the gastroesophageal junction (GEJ) is incorrect. I propose that the true GEJ is the proximal extent of gastric oxyntic epithelium. If there is cardiac mucosa lining proximal rugal folds, that cardiac mucosa-lined region is the dilated distal esophagus, not the proximal stomach. The dilated distal esophagus is the pathologic expression of damage to the abdominal segment of the LES. This concept suggests a new test for measuring damage to the abdominal LES and a new understanding of the disease of GERD based on the measured amount of LES damage. This opens the door to new research and change in objectives in the management of reflux disease from control of symptoms to prevention of complications such as Barrett's esophagus and adenocarcinoma. PMID- 29708897 TI - Conservative management of neonatal cerebral sinovenous thrombosis with coexisting thrombophilia. AB - : Neonatal cerebral sinovenous thrombosis (CSVT) comprises approximately 50% of all pediatric-related CSVT. Although guidelines support anticoagulation in pediatric CSVT, the role of anticoagulation in neonatal CSVT remains controversial. This case report details the course of a neonate diagnosed with extensive CSVT and concurrent bilateral thalamic and intraventricular hemorrhage. Due to existing hemorrhage at the time of diagnosis, anticoagulation therapy was not administered. Despite coexisting protein C and antithrombin deficiency, CSVT resolved spontaneously, and neurodevelopmental follow-up after 13 years suggests a good prognosis. Although our case had a positive outcome, the association between the use of anticoagulation with concurrent hemorrhage and long-term outcome in neonatal CSVT has not been investigated in prospective studies to firmly guide optimum treatment. Current literature and guidelines for the treatment of neonatal CSVT are reviewed in this article. Until robust studies are available, expert opinion recommends anticoagulation in a stable neonate with CSVT. PMID- 29708898 TI - Activated partial thromboplastin time derivative curves: helpful diagnostic tool in mixing test interpretation. AB - : The mixing test is used to evaluate whether prolonged activated partial thromboplastin time (APTT) is due to an inhibitor or a factor deficiency. The coagulation reaction is demonstrated with APTT derivative curves on the ACL TOP series. We aimed to determine the utility of APTT derivative curves in the mixing test process. The plasma of a patient was mixed with normal plasma in a 1 : 1 ratio and APTT assay was performed with SynthASil reagent. We observed roughness, biphasic and shoulder patterns in derivative curves during the mixing test. An extended laboratory investigation revealed a positive lupus anticoagulant, low factors XI and IX activities. Along with mixing test cut-off limits, we recommend analysing changes in APTT derivative curves to minimize erroneous interpretations of the mixing test. Derivative curves display either a normalizing pattern in factor deficiencies or an atypical pattern in the presence of lupus anticoagulant. PMID- 29708899 TI - The return of PRO 140, a CCR5-directed mAb. AB - PURPOSE OF REVIEW: Although antiretroviral therapy has become more potent and tolerable, adherence remains a barrier to continuous viral suppression and new approaches are needed. PRO 140 is a C-C chemokine receptor 5 (CCR5)-directed mAb with potential for weekly subcutaneous dosing. This review discusses data from the PRO 140 clinical development program including emerging data from ongoing efficacy studies. RECENT FINDINGS: Phase II development of PRO 140 began over a decade ago, and recently initiated phase IIb and III trials are ongoing in study participants with virologic failure and as monotherapy maintenance in virologically suppressed study participants. PRO 140 previously demonstrated potency against CCR5-tropic virus in parenteral formulations with excellent short term safety and tolerability, and low potential for tropism shifts or resistance. Studies are ongoing in treatment-experienced patients with multidrug resistant virus and as monotherapy maintenance in virologically suppressed patients. Partial data are available from these studies. To date, only a small number of study participants have achieved durable success on monotherapy maintenance. SUMMARY: PRO 140 has demonstrated antiviral potency, a high barrier to resistance, and a promising short-term safety profile. Ongoing trials are exploring efficacy against CCR5-tropic virus resistant to current antiretroviral therapy and safety and efficacy as monotherapy maintenance in individuals with viral suppression. PMID- 29708900 TI - Fertility, IVF and reproductive genetics. AB - PURPOSE OF REVIEW: Telomere attrition and dysfunction has become a well established pathway involved in organismal aging, not only because it imposes a limitation to cell division and therefore, tissue regeneration but also because telomere homeostasis influences other pathways involved in aging. However, the implication of telomere biology in ovarian aging and fertility is barely starting to be unveiled. RECENT FINDINGS: During the last years, mounting evidence in favor of the relationship between the accumulation of short telomeres and ovarian senescence has emerged. Telomere attrition and the loss of telomerase activity in ovarian cell types is a common characteristic of female infertility. SUMMARY: Recent findings regarding telomere attrition in the ovary open the possibility of both, finding new molecular biomarkers related to telomere homeostasis that make possible the early detection of ovarian dysfunction before the ovarian reserve has vanished, and the search of new therapies to preserve or set up ovarian cell types so that new and better quality oocytes can be generated in aged ovaries to improve IVF outcomes. PMID- 29708901 TI - Metabolism of the oocyte and the preimplantation embryo: implications for assisted reproduction. AB - PURPOSE OF REVIEW: To discuss the common aspects of energy generation in the cell, substrate utilization by the oocyte and the preimplantation embryos, metabolic characteristics of the reproductive tract, and how metabolic characteristics of an embryo can be exploited to assess viability. RECENT FINDINGS: Utilization of pyruvate, lactate and glucose by the oocyte and the preimplantation embryo seems to be tightly controlled by the most essential molecular regulatory pathways. SUMMARY: Accumulating data on the metabolic needs of the preimplantation embryo and the substrate concentrations in the reproductive tract guide us in improving in-vitro culture conditions, and provide potential biomarkers of embryo viability. PMID- 29708902 TI - The case against endometrial ablation for treatment of heavy menstrual bleeding. AB - PURPOSE OF REVIEW: Endometrial ablation is a common treatment for heavy menstrual bleeding, but serious limitations and long-term complications exist. Our purpose is to summarize the use of endometrial ablation devices, potential short-term and long-term complications, cost effectiveness, and quality of life in relation to alternative treatments. RECENT FINDINGS: There is insufficient evidence to strongly recommend one endometrial ablation device over another. Providers should consider and discuss with their patients, complications including risk of future pregnancy, endometrial cancer, and hysterectomy for continued bleeding or pain. Patient selection is key to reducing postablation pain and failure; patients with a history of tubal ligation and dysmenorrhea should consider alternative treatments. All patients should also be counseled that the levonorgestrel intrauterine device is a cost-effective alternative with higher quality of life and fewer complications. Hysterectomy is definitive treatment with higher quality of life and fewer complications. SUMMARY: Although endometrial ablation can offer adequate symptom control for patients who have failed medical therapy, desire uterine preservation, or who are high-risk surgical candidates, patients should be appropriately selected and counseled regarding the potential for treatment failure and long-term complications. PMID- 29708903 TI - Managing the late effects of chemoradiation on swallowing: bolstering the beginning, minding the middle, and cocreating the end. AB - PURPOSE OF REVIEW: Late dysphagia has a profound impact on quality of life in patients treated with chemoradiation therapy for advanced head and neck cancer and the number of survivors is growing. Traditional treatment methods are not uniformly successful in reducing the swallow impairment in these patients. RECENT FINDINGS: Manifestations of late dysphagia are complex and do not follow a uniform trajectory. Patient's experience of eating and engagement in treatment is critical given the complex, variable nature of late dysphagia. Novel swallow treatment methods target respiratory function including coordination and strength as well as patient adherence. SUMMARY: Head and neck cancer survivors deserve routine and fastidious surveillance beyond the 5-year survival point with respect to swallow function if the enormous biopsychosocial burden of late dysphagia is to be addressed. PMID- 29708904 TI - Pre-operative evaluation of the adult patient undergoing elective noncardiac surgery: updated guideline from the European Society of Anaesthesiology: Direction and not directives. PMID- 29708905 TI - Pre-operative evaluation of adults undergoing elective noncardiac surgery: Updated guideline from the European Society of Anaesthesiology. AB - : The purpose of this update of the European Society of Anaesthesiology (ESA) guidelines on the pre-operative evaluation of the adult undergoing noncardiac surgery is to present recommendations based on the available relevant clinical evidence. Well performed randomised studies on the topic are limited and therefore many recommendations rely to a large extent on expert opinion and may need to be adapted specifically to the healthcare systems of individual countries. This article aims to provide an overview of current knowledge on the subject with an assessment of the quality of the evidence in order to allow anaesthesiologists all over Europe to integrate - wherever possible - this knowledge into daily patient care. The Guidelines Committee of the ESA formed a task force comprising members of the previous task force, members of ESA scientific subcommittees and an open call for volunteers was made to all individual active members of the ESA and national societies. Electronic databases were searched from July 2010 (end of the literature search of the previous ESA guidelines on pre-operative evaluation) to May 2016 without language restrictions. A total of 34 066 abtracts were screened from which 2536 were included for further analysis. Relevant systematic reviews with meta-analyses, randomised controlled trials, cohort studies, case-control studies and cross sectional surveys were selected. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to assess the level of evidence and to grade recommendations. The final draft guideline was posted on the ESA website for 4 weeks and the link was sent to all ESA members, individual or national (thus including most European national anaesthesia societies). Comments were collated and the guidelines amended as appropriate. When the final draft was complete, the Guidelines Committee and ESA Board ratified the guidelines. PMID- 29708906 TI - Intra-operative cutaneous temperature monitoring with zero-heat-flux technique (3M SpotOn) in comparison with oesophageal and arterial temperature: A prospective observational study. AB - BACKGROUND: Continuous monitoring of core temperature is essential during major surgery as a way of improving patient safety. Oesophageal probes or specific arterial catheters are invasive methods used in this setting. A new noninvasive device based on zero-heat-flux (ZHF) technique (SpotOn) seems promising but has been poorly investigated during rapid core temperature changes (RCTC). OBJECTIVE: To assess the accuracy of a SpotOn sensor vs. an oesophageal probe or specific arterial catheter during a slow change in core temperature of less than 1 degrees C within 30 min and RCTC >= 1 degrees C within 30 min. DESIGN: Prospective observational study. SETTING: Operating rooms at the University Hospital of Poitiers, France. PATIENTS: Fifty patients scheduled for major abdominal surgery under general anaesthesia were enrolled from June 2015 to March 2016. Data from 49 patients were finally analysed. Among these, 15 patients were treated with hyperthermic intraperitoneal chemotherapy. INTERVENTION: Each patient had a ZHF sensor placed on the skin surface of the forehead (TempZHF) and an oesophageal probe (TempEso) used as a reference method. Twenty-two patients also had a thermodilution arterial catheter (TempArt) placed in the axillary artery. MAIN OUTCOME MEASURES: Core temperature was continuously recorded from the three devices after induction of anaesthesia. Comparison of temperature measurements between methods was made using the Bland and Altman method during two separate periods according to the speed of core temperature changes. RESULTS: Compared with TempEso, bias and limits of agreement for TempZHF were 0.1 +/- 0.5 degrees C during slow core temperature changes periods and 0.6 +/- 1.8 degrees C during RCTC periods (P = 0.0002). Compared with TempArt, these values were -0.1 +/- 0.4 and 0.5 +/- 1.7 degrees C, respectively (P = 0.0039). The ZHF sensor was well tolerated. CONCLUSION: A SpotOn sensor using the ZHF method seems reliable for core temperature monitoring during abdominal surgery when variations in core temperature are slow rather than rapid. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02869828. PMID- 29708907 TI - The emergency paediatric surgical airway: A systematic review. AB - BACKGROUND: Although an emergency surgical airway is recommended in the guidelines for a paediatric cannot intubate, cannot oxygenate (CICO), there is currently no evidence regarding the best technique for this procedure. OBJECTIVE: To review the available literature on the paediatric emergency surgical airway to give recommendations for establishing a best practice for this procedure. DESIGN: Systematic review: Considering the nature of the original studies, a meta analysis was not possible. DATA SOURCES: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cumulative Index to Nursing and Allied Health Literature, Web of Science, Google Scholar and LILACS databases. ELIGIBILITY CRITERIA: Studies addressing the paediatric emergency surgical airway and reporting the following outcomes: time to tracheal access, success rate, complications and perceived ease of use of the technique were included. Data were reported using a Strengths, Weaknesses, Opportunities and Threats analysis. Strengths and Weaknesses describe the intrinsic (dis)advantages of the techniques. The opportunities and threats describe the (dis)advantage of the techniques in the setting of a paediatric CICO scenario. RESULTS: Five studies described four techniques: catheter over needle, wire-guided, cannula or scalpel technique. Mean time for placement of a definitive airway was 44 s for catheter over needle, 67.3 s for the cannula and 108.7 s for the scalpel technique. No time was reported for the wire-guided technique. Success rates were 43 (10/23), 100 (16/16), 56 (87/154) and 88% (51/58), respectively. Complication rates were 34 (3/10), 69 (11/16), 36 (55/151) and 38% (18/48), respectively. Analysis shows: catheter over needle, quick but with a high failure rate; wire-guided, high success rate but high complication rate; cannula, less complications but high failure rate; scalpel, high success rate but longer procedural time. The available data are limited and heterogeneous in terms of reported studies; thus, these results need to be interpreted with caution. CONCLUSION: The absence of best practice evidence necessitates further studies to provide a clear advice on best practice management for the paediatric emergency surgical airway in the CICO scenario. PMID- 29708909 TI - Shared Decision Making in the Care of Children with Autism Spectrum Disorder. PMID- 29708908 TI - Anteverting Bernese periacetabular osteotomy in the treatment of neurogenic hip dysplasia in cerebral palsy. AB - All patients with hypertonic cerebral palsy undergoing Bernese periacetabular osteotomy (PAO) between 2005 and 2014 were reviewed. Clinical and radiographic parameters, including the cerebral palsy hip classification and anterior and posterior wall indices were collected to assess acetabular reorientation. Twenty (83%) of 24 procedures involved the correction of posterolateral acetabular insufficiency and were 'anteverting PAOs'. All 20 experienced improvements in radiographic indices. Eleven (58%) of 19 PAOs in ambulatory patients were performed in the setting of other multilevel orthopedic surgery. The anteverting PAO is successful in correcting the posterolateral acetabular insufficiency present in spastic hip dysplasia, and can be performed in conjunction with a single-event multilevel surgery. PMID- 29708910 TI - Primary cardiac lymphoma: the role of multimodality imaging. PMID- 29708911 TI - Closure of patent foramen ovale or medical therapy alone for secondary prevention of cryptogenic cerebrovascular events. AB - AIMS: About one-third of ischemic stroke are cryptogenic. Paradoxical embolism through patent foramen ovale (PFO) has been identified as a possible cause of cryptogenic stroke. Therefore, PFO closure has been considered for secondary prevention of cryptogenic stroke. However, randomized clinical trials (RCTs) comparing PFO closure versus medical therapy led to conflicting results. Our objectives were to examine if PFO closure is superior to medical therapy alone for secondary prevention of cryptogenic stroke and to investigate whether PFO closure is associated with an increased incidence of atrial fibrillation/atrial flutter (AFL). METHODS: The authors systematically searched MEDLINE for RCTs that compared PFO closure with medical therapy. Efficacy outcome was cerebrovascular event (CVE) recurrence and safety outcome was new-onset atrial fibrillation/AFL. The outcomes of interest were investigated according to device type with subgroup analyses and meta-regression. RESULTS: The authors included eight RCTs constituting 4114 patients. Patients who underwent PFO closure had a lower risk of CVE recurrence compared with medically treated patients [relative risk (RR): 0.56; 95% confidence interval (CI) 0.40-0.80; P = 0.001; I = 30%]. This protective effect was consistent across the different device types. Patients who underwent PFO closure developed more frequently atrial fibrillation/AFL (RR 4.96; 95% CI 2.74-8.99; P < 0.00001; I = 0%), which was mainly transient and within 1 month. Atrial fibrillation/AFL risk was consistent according to device types, although marginally significant in the Amplatzer subgroup. CONCLUSION: PFO closure might have a role in secondary CVE prevention of patients with PFO and cryptogenic stroke. However, it is associated with an increased incidence of new onset atrial fibrillation/AFL especially within 1 month. PMID- 29708912 TI - Chemotherapy-induced cardiotoxicity: new insights into mechanisms, monitoring, and prevention. AB - : Chemotherapy-induced cardiotoxicity (CTX) remains a determining factor for the quality of life and mortality of patients treated with potentially cardiotoxic drugs. Considerable advances have been made in this field with increase in awareness regarding chemotherapy-induced CTX, which has changed the treatment approach to include cardiovascular risk among the first factors to be evaluated before therapy. Moreover, a better understanding of the pathophysiology of chemotherapy-induced CTX has also facilitated early identification of patients at risk with the help of new imaging technologies. The newly developed imaging tools in cardio-oncology have led to the introduction of novel parameters for evaluation of myocardial function. This, together with a renewed standardization of measurements, has increased the adherence to monitoring protocols. With respect to treatment and prevention, researchers have started focusing attention on the development of new strategies as well as new cardioprotective agents that will play a crucial role in the prevention of CTX in the near future. PMID- 29708913 TI - Case Report of an Awake Craniotomy in a Patient With Eisenmenger Syndrome. AB - We present a detailed report of an awake craniotomy for recurrent third ventricular colloid cyst in a patient with severe pulmonary arterial hypertension in the setting of Eisenmenger syndrome, performed 6 weeks after we managed the same patient for a more conservative procedure. This patient has a high risk of perioperative mortality and may be particularly susceptible to perioperative hemodynamic changes or fluid shifts. The risks of general anesthesia induction and emergence must be balanced against the risks inherent in an awake craniotomy on a per case basis. PMID- 29708914 TI - Intrathecal Baclofen Injection to Avoid Withdrawal in a Multiple Sclerosis Patient Undergoing Lumbar Spine Surgery: A Case Report. AB - Spasticity of spinal or cerebral origin is frequently treated with baclofen. Treatment interruption initially results in rebound spasticity; life-threatening withdrawal symptoms may follow. Severe rebound spasticity of leg muscles occurred in a multiple sclerosis patient after a 10-hour long perioperative pause of oral baclofen intake. In a subsequent spine surgery, recurrence was prevented by substituting a cumulative 12-hour oral baclofen dose with an intraoperative intrathecal injection. Administration of intrathecal baclofen during prolonged surgery in patients dependent on oral baclofen may improve patient comfort and prevent early withdrawal symptoms. The most optimal conversion ratio from oral to intrathecal baclofen is still undetermined. PMID- 29708915 TI - Should Percussion Pacing Have a Role in Perioperative Advanced Cardiac Life Support?: A Case Report. AB - Percussion pacing involves using one's fist to repeatedly strike a patient's left sternal border in a rhythmic manner. The resulting increase in ventricular pressure can trigger myocardial depolarization and subsequent contraction. We describe the successful treatment of acute preoperative symptomatic sinus bradycardia with percussion pacing in a 63-year-old patient scheduled for placement of a gastric feeding tube after trauma involving spinal cord injury. Although no longer included in current advanced cardiovascular life support guidelines, percussion pacing may be a suitable alternative to chest compressions in multitrauma cases where the force of compressions could cause further complications. PMID- 29708916 TI - Venovenous Extracorporeal Membrane Oxygenation to Prolong Pregnancy: A Case Report. AB - We report a gravida in fulminant acute respiratory distress syndrome, mechanically ventilated at 27 weeks estimated gestational age, who further deteriorated into severe combined hypercarbic, hypoxemic respiratory failure. At 30 weeks estimated gestational age, she was placed on venovenous extracorporeal membrane oxygenation (ECMO) because of refractory respiratory failure. Her physical status improved without fetal deterioration. She was managed expectantly in an effort to allow continued fetal maturation. Six days later, complications of ECMO (pulmonary hemorrhage) led to emergent abdominal delivery of a living male child. She was successfully weaned from ECMO 8 days later. The implications of ECMO during pregnancy are discussed. PMID- 29708917 TI - Epidural Anesthesia to Facilitate Organ Blood Flow During the First Penile Transplantation in the United States: A Case Report. AB - Regional anesthesia has been used to help create local sympathectomy and improve blood flow in plastic surgery procedures involving tissue grafts and flaps. However, anesthetic techniques that reduce systemic vascular resistance must be used with caution in patients with aortic stenosis (AS). Combined neuraxial and general anesthesia with careful titration of the local anesthetic dose can be a safe approach for patients with AS undergoing microvascular procedures. We present the anesthetic management of the first North American penile transplant, on an obese patient with moderate AS. PMID- 29708918 TI - Adjusting Pediatric Endotracheal Tube Depths Relative to the Cricoid by Using Longitudinal Ultrasound Images of the Saline-Inflated Cuff in the Trachea: Two Case Reports. AB - Cuff positions of endotracheal tubes should be confirmed to ensure safe anesthesia. However, determining the cuff positions relative to the cricoid by using chest radiography or fiberoptic bronchoscopy is difficult. We identified the cephalad edges of saline-inflated pediatric endotracheal tube cuffs relative to the cricoid on longitudinal ultrasound images over the larynx and trachea in 2 children. Thereafter, we adjusted the endotracheal tube depths and confirmed the cuff positions relative to the cricoid. Longitudinal ultrasound images over the larynx and trachea can help confirm the distance from the caudal edge of the cricoid to the saline-inflated cuff. PMID- 29708919 TI - The Use of Liposomal Bupivacaine in Erector Spinae Plane Block to Minimize Opioid Consumption for Breast Surgery: A Case Report. AB - The erector spinae plane block is a novel interfascial plane block that can provide thoracic and abdominal analgesia. We describe a patient with opioid intolerance scheduled for breast surgery who received an erector spinae plane block with liposomal bupivacaine as well as a supplemental T1 paravertebral block resulting in profound analgesia throughout her postoperative course. This case report demonstrates that use of liposomal bupivacaine in the erector spinae plane block can be successful in providing extended duration postoperative analgesia and minimizing systemic opioid requirements. PMID- 29708920 TI - Airway Management in a Patient With Tracheal Disruption due to Penetrating Neck Trauma With Hollow Point Ammunition: A Case Report. AB - Rapid sequence induction and intubation was performed for a patient in respiratory distress after a gunshot wound to the neck. Resistance was noted distal to vocal cords. With a bronchoscope unavailable, the endotracheal tube was advanced with a corkscrew maneuver. Subcutaneous emphysema had developed. The endotracheal tube was advanced into the right mainstem with adequate ventilation. Imaging illustrated tracheoesophageal injury. The patient was emergently explored. An intraluminal bullet was removed, lateral wall tracheal defect was repaired, and a tracheostomy was placed. The intubating provider should secure the airway by the method they are most comfortable, have high suspicion of airway injury, and prepare to manage airway disruption. PMID- 29708921 TI - Point-of-Care Ultrasound in the Periarrest Setting-Lessons Learned: A Case Report. AB - Point-of-care ultrasound may elucidate reversible causes of cardiac arrest, and its use is supported by international guidelines in the periarrest setting. We present a case in which the treatment of cardiac arrest caused tension pneumothoraces and cardiac tamponade by pneumopericardium. Both pneumothorax and tamponade were expected to be identified with ultrasound, but were not. Subcutaneous emphysema precluded the diagnosis of pneumothorax. Cardiac imaging was false negative for tamponade, because the latter was caused by air and not fluid. Diagnoses are not to be excluded with inconclusive point-of-care ultrasound examinations, which should prompt further clinical evaluation and imaging. PMID- 29708922 TI - RETINA. PMID- 29708923 TI - Predicting cardiovascular disease in familial hypercholesterolemia. AB - PURPOSE OF REVIEW: Familial hypercholesterolemia is a frequent genetic disease associated with a high lifetime risk of cardiovascular disease (CVD). Statins are the cornerstone of treatment of familial hypercholesterolemia; however, with the advent of novel LDL-cholesterol lowering therapies, it has become necessary to identify familial hypercholesterolemia subjects presenting a significant residual CVD risk. The aim of this review is to provide an update on the recent literature concerning cardiovascular risk stratification in familial hypercholesterolemia. RECENT FINDINGS: Recently, several clinical and genetic factors have been shown to be independent predictors of CVD in familial hypercholesterolemia. These include clinical scores such as the Montreal-FH-SCORE, novel protein biomarkers, carotid plaque score and genetic predictors such as genetic risk scores as well as single-nucleotide polymorphisms. SUMMARY: Although there has been recent progress in cardiovascular risk stratification in familial hypercholesterolemia, there is still a need to further refine our knowledge concerning phenotype modifiers in this disease. Indeed, current known predictors do not explain the entirety of cardiovascular risk. More precise individual risk stratification in familial hypercholesterolemia could help to better tailor the proper therapy for each patient. PMID- 29708924 TI - Can we still learn from the Seven Countries Study? AB - PURPOSE OF REVIEW: The Seven Countries Study (SCS) of Cardiovascular Diseases started midway last century and was the pioneer investigation of coronary heart disease (CHD) at international level. The 16 cohorts of middle-aged men enrolled in eight nations of seven countries allowed to show large differences of CHD incidence and mortality across different cultures, partly explained by average levels of serum cholesterol and dietary habits, that is, Western type patterns in the high-risk populations, and Mediterranean or Oriental type in Southern Europe and Japan. Later, critics to the validity of the study were largely based on fake news, wrong or distorted information uncritically transmitted in a cascade of media. RECENT FINDINGS: Recent analyses based on 45-50 years of follow-up showed and confirmed that diet patterns were associated with all-cause mortality and age at death; that multivariate coefficients of major risk factors of CHD were not heterogeneous across different populations and cultures; that analysis of competing risks of CHD versus other conditions identified serum cholesterol as the critical determinant; that true CHD manifestations had different determinants compared with Heart Diseases of Uncertain Etiology frequently confused with CHD. SUMMARY: The SCS can still teach investigators and scholars of cardiovascular epidemiology, if old contributions are carefully read and interpreted; it is still recognized as the seminal study in this area at international level although it had limits as any other study but represented the first step into the identification of the relationship of diet with CHD and mortality across populations, and of the Mediterranean diet. PMID- 29708925 TI - Unexplained reciprocal regulation of diabetes and lipoproteins. AB - PURPOSE OF REVIEW: Type 2 diabetes is associated with a characteristic dyslipidemia that may exacerbate cardiovascular risk. The causes of, and the effects of new antihyperglycemia medications on, this dyslipidemia, are under investigation. In an unexpected reciprocal manner, lowering LDL-cholesterol with statins slightly increases the risk of diabetes. Here we review the latest findings. RECENT FINDINGS: The inverse relationship between LDL-cholesterol and diabetes has now been confirmed by multiple lines of evidence. This includes clinical trials, genetic instruments using aggregate single nucleotide polymorphisms, as well as at least eight individual genes - HMGCR, NPC1L1, HNF4A, GCKR, APOE, PCKS9, TM6SF2, and PNPLA3 - support this inverse association. Genetic and pharmacologic evidence suggest that HDL-cholesterol may also be inversely associated with diabetes risk. Regarding the effects of diabetes on lipoproteins, new evidence suggests that insulin resistance but not diabetes per se may explain impaired secretion and clearance of VLDL-triglycerides. Weight loss, bariatric surgery, and incretin-based therapies all lower triglycerides, whereas SGLT2 inhibitors may slightly increase HDL-cholesterol and LDL-cholesterol. SUMMARY: Diabetes and lipoproteins are highly interregulated. Further research is expected to uncover new mechanisms governing the metabolism of glucose, fat, and cholesterol. This topic has important implications for treating type 2 diabetes and cardiovascular disease. PMID- 29708926 TI - Pain management after photorefractive keratectomy. AB - PURPOSE OF REVIEW: To review current concepts regarding the mechanisms of postoperative pain after photorefractive keratectomy (PRK) and review available treatment options. RECENT FINDINGS: Many clinical studies have established the safety and efficacy of different topical and systematic therapeutic agents and techniques for the treatment of postoperative pain after PRK, especially topical nonsteroidal anti inflammatory agents and oral nonsteroidal and narcotic medications. New therapeutic agents and techniques are continuously studied, introducing new agents and comparing teh efficacy of different regimens. Postoperative pain severity varies widely between patients, and no single strategy has been proven best for acute pain management. SUMMARY: To date, the literature supports the use of topical agents such as nonsteroidal anti inflammatory medications (NSAIDs) and diluted topical anesthetics in combination with oral agents such as opiates and NSAIDs for acute pain management. The use of local agents and techniques is preferred due to their less significant side effect profile. The use of systemic opiate agents is reserved for breakthrough pain. PMID- 29708927 TI - Cytomegalovirus keratitis. AB - PURPOSE OF REVIEW: Cytomegalovirus (CMV) keratitis, albeit an uncommon manifestation of this ubiquitous pathogen, can lead to devastating ocular morbidity. Timely diagnosis and appropriate treatment are also unfortunately uncommon. The purpose of this review is to discuss recently published literature regarding the epidemiology, pathophysiology, diagnosis, and therapy of CMV keratitis. RECENT FINDINGS: Classic clinical presentations of CMV keratitis are known; however, current investigations further elucidate characteristics of typical versus atypical disease. Ongoing research stems beyond utilizing PCR analysis towards targeted diagnostic studies with advanced imaging modalities as well as modern genotyping techniques. Strong clinical acumen combined with appropriate handling of these modern technologies are proving invaluable for rapid diagnosis and treatment of this virulent pathogen. SUMMARY: The current recommended treatment for CMV keratitis is systemic ganciclovir. Astute clinicians must consider this diagnosis in any patient with keratitis, anterior uveitis, and intraocular hypertension. Novel diagnostic techniques should be combined with clinical exam findings to accurately and efficiently diagnose, treat, and monitor progression. PMID- 29708928 TI - Revisiting monovision for presbyopia. AB - PURPOSE OF REVIEW: Presbyopia is an inevitable age-related loss of accommodation that results in spectacle dependence with common everyday near-vision tasks. Many surgical approaches to presbyopic correction have been investigated, with monovision correction being amongst the most common and attractive options. In this article, we will review the advantages and disadvantages of the new modalities of presbyopic monovision correction. RECENT FINDINGS: New methods such as mini-monovision, corneal inlays, and multifocal corneal ablation aim to maximize stereopsis and decrease the anisometropic side effects of conventional monovision. These include inlays such as the KAMRA and Raindrop, and phakic intraocular lenses such as the hole ICL. Newer corneal laser refractive procedures such as small incision lenticule extraction have also shown good outcomes with monovision. Pseudophakic monovision using standard monofocal lenses still provides good results. SUMMARY: Monovision for presbyopic correction continues to provide promising results. There are a number of new devices and techniques that have shown good visual acuity outcomes, patient satisfaction and spectacle independence. PMID- 29708929 TI - Surgical management of herpetic keratitis. AB - PURPOSE OF REVIEW: The purpose of this review is to discuss the options for, and recent developments in, the surgical treatment of herpes keratitis. Although the mainstay of treatment of herpetic keratitis is topical or oral antiviral agents, surgical intervention may be necessary for corneal melting or long-term complications such as scarring, lipid keratopathy, necrotizing keratitis, and neurotrophic keratitis. RECENT FINDINGS: There are a number of surgical therapies available for herpes keratitis. Preferred therapeutic modalities differ based on the size, causation, and location of the infection but consist of either replacement of the infected tissue or structural support of the tissue to allow healing. Incremental improvements in the existing treatment modalities have made them more effective, easier, and safer, whereas novel therapies such as corneal neurotization are starting to be described in ophthalmic literature. SUMMARY: Several options are available for surgically managing the complications of herpes keratitis. Ophthalmologists should select the optimal procedure based on the individual patient's situation. VIDEO ABSTRACT: http://links.lww.com/COOP/A28. PMID- 29708930 TI - Management of chronic complications associated with herpes zoster ophthalmicus. AB - PURPOSE OF REVIEW: Herpes zoster ophthalmicus (HZO) has the potential to cause significant visual morbidity and functional disability in patients with recalcitrant disease, keratitis, and postherpetic neuralgia. This article will review the current methods of prevention and treatment of anterior segment related chronic complications of HZO. RECENT FINDINGS: HZO-related anterior segment ocular complications can range to include conjunctivitis, keratitis, and uveitis that can all be difficult to manage. Furthermore, many clinicians differ in their approach to disease management given the relative lack of large randomized controlled trials to guide therapy. The goal in managing complications of HZO is to reduce visual morbidity and to improve analgesia, and here, we present current recommendations for the management of anterior segment complications of HZO. SUMMARY: Recent advances in vaccine technology and the initiation of the Zoster Eye Disease Study improve the possibility of reducing the burden of disease while also further standardizing management of HZO. PMID- 29708931 TI - Recent advances in wavefront-guided LASIK. AB - PURPOSE OF REVIEW: Laser vision correction remains an active area of research, and there have been many recent advances in the field. The purpose of this review is to provide an update on the recent advances for one of the most common methods of laser vision correction, wavefront-guided laser in-situ keratomileusis (LASIK). RECENT FINDINGS: Recent technological advancements in wavefront aberrometry are largely responsible for the improved visual outcomes that have been recently reported. In addition, improvements in femtosecond and excimer laser technology, used in flap creation and corneal ablation, have been shown to provide superior results when compared to microkeratomes and earlier lasers. Wavefront-guided LASIK appears to have advantages over some other keratorefractive modalities in terms of visual acuity, predictability, astigmatism correction, and subjective visual symptoms. Nonetheless, there may be some limitations in highly aberrated corneas, and also in biomechanical stability relative to other available platforms. SUMMARY: Improvements in wavefront aberrometry, and also femtosecond and excimer lasers, have continued to improve our ability to correct refractive errors. Wavefront-guided LASIK remains a well tolerated and effective keratorefractive procedure, with a trend toward superiority. Nonetheless, further studies comparing this modality to others are needed to define the role each can serve. PMID- 29708932 TI - Adenoviral keratitis: a review of the epidemiology, pathophysiology, clinical features, diagnosis, and management. AB - PURPOSE OF REVIEW: Adenoviral keratitis is a common and bothersome ocular infection that produces a lot of burden on healthcare systems and patients. The goal of this article is to provide a review of the topic, with an emphasis on current attempts at advancing strategies in diagnosis and management. RECENT FINDINGS: Sixty-eight articles and one textbook published on adenoviral keratitis were reviewed. The findings on the epidemiology, pathophysiology, clinical features, diagnosis, and management were summarized. Any contradicting opinions for which the literature was unclear were either omitted or recorded as lacking strong evidence. SUMMARY: Although significant effort has been made to develop new methods for diagnosis and management, adenoviral keratitis is predominantly diagnosed clinically with prevention being the mainstay of management. The use of newer DNA analysis techniques and topical anti-inflammatory agents for treatment of corneal infiltrates show promising results, but a better understanding of the pathogenesis and clinical features can lead to more targeted methods of diagnosis and therapy. PMID- 29708933 TI - Diagnostic and Therapeutic Challenges. PMID- 29708934 TI - POSTERIOR STAPHYLOMAS IN EYES WITH RETINITIS PIGMENTOSA WITHOUT HIGH MYOPIA. AB - PURPOSE: To describe features of posterior staphylomas in nonhighly myopic eyes with retinitis pigmentosa (RP). METHODS: The retrospective observational case series study included patients with RP and an axial length of <26.5 mm and searched for eyes with posterior staphylomas. All study participants underwent fundus photography and optical coherence tomography. RESULTS: The study identified 13 eyes of 7 patients with a narrow macular staphyloma. Mean age was 40.9 +/- 17.9 years (range 9-62 years) and mean axial length was 24.90 +/- 0.69 mm. The staphyloma edges corresponded to the margin between the retinal atrophic area in the fundus midperiphery and the relatively unaffected fundus center. On vertically orientated optical coherence tomography images, the staphyloma edges showed a slight inward protrusion of the sclera and a ring-like localized choroidal thinning with choroidal rethickening in direction toward the fovea and toward the periphery of the fundus. The upper and lower staphyloma edges did not differ in steepness. The thickness of the subfoveal choroid (138.6 m +/- 50.1 um) was thinner than the normal range after adjusting for age and axial length in all eyes. Two eyes with advanced RP in the macula showed a subfoveal choroidal thickness of 95 um and 88 um. CONCLUSION: Narrow macular staphylomas can occur in nonhighly myopic eyes with RP and, in contrast to staphylomas in highly myopic eyes, show a less marked thinning of the subfoveal choroid. The occurrence of posterior staphylomas in nonhighly myopic eyes with RP may provide hints to unravel the etiology of posterior staphyloma formation. PMID- 29708935 TI - External Drainage of Subretinal Fluid During Vitrectomy for Rhegmatogenous Retinal Detachment. PMID- 29708936 TI - Frequency of Complications During Preparation of Corneal Lamellae Used in Posterior Lamellar Keratoplasty Using the Pneumodissection Technique (Big Bubble). AB - PURPOSE: To determine the frequency of formation of various types of bubbles and the potential impact of donor and lamella parameters on this frequency, and to identify possible risk factors of unsuccessful "big-bubble" creation in preparation of pre-Descemet endothelial keratoplasty and Descemet membrane endothelial keratoplasty with peripheral stromal support. METHODS: Donor age and sex, death to preservation time (DPT), storage time, presence of corneal scars (mainly a condition after cataract surgery), and endothelial cell density of 256 donor corneas were assessed before Descemet membrane endothelial keratoplasty with peripheral stromal support or pre-Descemet endothelial keratoplasty lamella preparation using the big-bubble technique. RESULTS: Mean donor age was 62.3 +/- 8.5 years (28.3% women and 71.7% men). Mean endothelial cell density of the donor graft was 2866 +/- 255 cells/mm. Mean DPT was 10.12 +/- 4.88 hours, and mean storage time of the transplant before surgery was 6.5 +/- 4.8 days. Corneal scars were present in 17 donor grafts (6.6%) after cataract surgery. Eleven corneas were devalued because of Descemet membrane rupture during preparation (4.3%). In 182 corneas, standard bubble type I was created (71.7%); in 27 corneas, bubble type II was created; eventually, both types of bubbles formed simultaneously (10.5%); in 47 corneas, no bubble was created (18.4%). CONCLUSIONS: We identified higher endothelial cell density, shorter DPT, and the presence of corneal scars after cataract surgery as risk factors threatening successful bubble formation. The only risk factor for creating type II bubbles was higher donor age in our study. PMID- 29708937 TI - Epithelial Recurrent Erosion Dystrophy Secondary to COL17A1 c.3156C>T Mutation in a Non-white Family. AB - PURPOSE: To report the identification of the collagen, type XVII, alpha 1 (COL17A1) c.3156C>T mutation associated with epithelial recurrent erosion dystrophy (ERED) in a Thai family. METHODS: Slit-lamp examination was performed to determine the affected status of each member of a Thai family, with multiple members demonstrating scattered Bowman layer opacities. After genomic deoxyribonucleic acid (DNA) was isolated from saliva, polymerase chain reaction (PCR) amplification and Sanger sequencing were performed to screen COL17A1 and exons 4 and 12 of the transforming growth factor beta-induced gene. RESULTS: The 67-year-old proband and her 4 siblings were examined by slit-lamp biomicroscopy, which identified bilateral subepithelial opacities in the proband and in one of the 4 siblings. In both the proband and the affected sister, screening of the COL17A1 gene identified a heterozygous c.3156C>T synonymous mutation that has been previously demonstrated to introduce a cryptic splice donor site, likely leading to aberrant splicing of COL17A1. This mutation was not identified in the unaffected siblings, and no mutations were identified in exons 4 and 12 of the transforming growth factor beta-induced gene in any of the screened family members. CONCLUSIONS: ERED associated with a COL17A1 mutation has been previously reported in only 6 families, all white. Identification of the c.3156C>T mutation, previously identified in 5 of these 6 families, in the Thai family we report indicates conservation of the genetic basis of ERED across different races and underscores the importance of ophthalmologists around the globe being familiar with ERED, which has only recently become a recognized corneal dystrophy. PMID- 29708938 TI - Endothelial Keratoplasty at an Early Stage of the Progressive Iris Atrophy Variant of Irido Corneal Endothelial Syndrome: Can It Avert the Need for Glaucoma Surgery Intervention? PMID- 29708939 TI - Outcomes of Thermal Pulsation Treatment for Dry Eye Syndrome in Patients With Sjogren Disease. AB - PURPOSE: To evaluate the clinical outcomes of thermal pulsation treatment in patients with meibomian gland dysfunction (MGD) and dry eye secondary to Sjogren disease. METHODS: Twenty-four eyes from 13 patients with previously diagnosed Sjogren disease who presented to our institution with dry eye symptoms and had thermal pulsation treatment were prospectively followed up. Patients underwent comprehensive slit-lamp examination, including MGD grading, gland oil flow, corneal and conjunctival staining scores, and tear break-up time (TBUT). Tear osmolarity was tested before and after treatment. RESULTS: The average patient age was 62.4 years (range, 31-78 yrs); 12 were women and 1 a man. The average meibomian gland oil flow score showed an increase from pretreatment 0.71 to 1.75 at 1 year posttreatment (range 9-15 months) (P = 0.001). The average corneal staining score decreased from a pretreatment grade of 1.04 to a posttreatment grade of 0.36 (P < 0.001). The average conjunctival staining score decreased from a pretreatment grade of 1.5 to a posttreatment grade of 0.48 (P < 0.001). The average tear break-up time improved from 3.8 seconds before treatment to 7.5 seconds after thermal pulsation treatment (P < 0.001). There was no statistically significant change in the tear osmolarity or Ocular Surface Disease Index score. CONCLUSIONS: Our findings suggest that MGD is an important contributor to dry eye disease in patients with Sjogren disease and should not be overlooked when considering treatment options. Thermal pulsation is a therapeutic option for patients with Sjogren disease who have MGD and dry eye symptoms. After a single treatment, patients exhibited increased oil flow and tear break-up time with an associated decrease in corneal and conjunctival staining. PMID- 29708940 TI - Chronic pain in survivors of childhood cancer: a developmental model of pain across the cancer trajectory. PMID- 29708942 TI - A bifunctional-biased mu-opioid agonist-neuropeptide FF receptor antagonist as analgesic with improved acute and chronic side effects. AB - Opioid analgesics, such as morphine, oxycodone, and fentanyl, are the cornerstones for treating moderate to severe pain. However, on chronic administration, their efficiency is limited by prominent side effects such as analgesic tolerance and dependence liability. Neuropeptide FF (NPFF) and its receptors (NPFF1R and NPFF2R) are recognized as an important pronociceptive system involved in opioid-induced hyperalgesia and analgesic tolerance. In this article, we report the design of multitarget peptidomimetic compounds that show high-affinity binding to the mu-opioid receptor (MOPr) and NPFFRs. In vitro characterization of these compounds led to identification of KGFF03 and KGFF09 as G-protein-biased MOPr agonists with full agonist or antagonist activity at NPFFRs, respectively. In agreement with their biased MOPr agonism, KGFF03/09 showed reduced respiratory depression in mice, as compared to the unbiased parent opioid agonist KGOP01. Chronic subcutaneous administration of KGOP01 and KGFF03 in mice rapidly induced hyperalgesia and analgesic tolerance, effects that were not observed on chronic treatment with KGFF09. This favorable profile was further confirmed in a model of persistent inflammatory pain. In addition, we showed that KGFF09 induced less physical dependence compared with KGOP01 and KGFF03. Altogether, our data establish that combining, within a single molecule, the G protein-biased MOPr agonism and NPFFR antagonism have beneficial effects on both acute and chronic side effects of conventional opioid analgesics. This strategy can lead to the development of novel and potent antinociceptive drugs with limited side effects on acute and chronic administration. PMID- 29708941 TI - High-fat diet exacerbates postoperative pain and inflammation in a sex-dependent manner. AB - Obesity is often associated with increased pain, but little is known about the effects of obesity and diet on postoperative pain. In this study, effects of diet and obesity were examined in the paw incision model, a preclinical model of postoperative pain. Long-Evans rats were fed high-fat diet (40% calories from butter fat) or low-fat normal chow. Male rats fed high-fat diet starting 6 weeks before incision (a diet previously shown to induce markers of obesity) had prolonged mechanical hypersensitivity and an overall increase in spontaneous pain in response to paw incision, compared with normal chow controls. Diet effects in females were minor. Removing high-fat diet for 2 weeks before incision reversed the diet effects on pain behaviors, although this was not enough time to reverse high-fat diet-induced weight gain. A shorter (1 week) exposure to high-fat diet before incision also increased pain behaviors in males, albeit to a lesser degree. The 6-week high-fat diet increased macrophage density as examined immunohistochemically in lumbar dorsal root ganglion even before paw incision, especially in males, and sensitized responses of peritoneal macrophages to lipopolysaccharide stimuli in vitro. The nerve regeneration marker growth associated protein 43 (GAP43) in skin near the incision (day 4) was higher in the high-fat diet group, and wound healing was delayed. In summary, high-fat diet increased postoperative pain particularly in males, but some diet effects did not depend on weight gain. Even short-term dietary manipulations, that do not affect obesity, may enhance postoperative pain. PMID- 29708943 TI - Pain as a threat to the social self: a motivational account. PMID- 29708944 TI - Multivariate machine learning distinguishes cross-network dynamic functional connectivity patterns in state and trait neuropathic pain. AB - Communication within the brain is dynamic. Chronic pain can also be dynamic, with varying intensities experienced over time. Little is known of how brain dynamics are disrupted in chronic pain, or relates to patients' pain assessed at various timescales (eg, short-term state vs long-term trait). Patients experience pain "traits" indicative of their general condition, but also pain "states" that vary day to day. Here, we used network-based multivariate machine learning to determine how patterns in dynamic and static brain communication are related to different characteristics and timescales of chronic pain. Our models were based on resting-state dynamic functional connectivity (dFC) and static functional connectivity in patients with chronic neuropathic pain (NP) or non-NP. The most prominent networks in the models were the default mode, salience, and executive control networks. We also found that cross-network measures of dFC rather than static functional connectivity were better associated with patients' pain, but only in those with NP features. These associations were also more highly and widely associated with measures of trait rather than state pain. Furthermore, greater dynamic connectivity with executive control networks was associated with milder NP, but greater dynamic connectivity with limbic networks was associated with greater NP. Compared with healthy individuals, the dFC features most highly related to trait NP were also more abnormal in patients with greater pain. Our findings indicate that dFC reflects patients' overall pain condition (ie, trait pain), not just their current state, and is impacted by complexities in pain features beyond intensity. PMID- 29708945 TI - A 'musculoskeletal look' to sarcopenia: Where do/should the physical and rehabilitation medicine physicians (physiatrists) stand? PMID- 29708946 TI - Comments on: 'Effects of walking trainings on walking function among stroke survivors: a systematic review'. PMID- 29708947 TI - Comment on the Letter to the Editor by Mohammad Alwardat and Mohammad Etoom on 'Effects of walking trainings on walking function among stroke survivors: a systematic review'. PMID- 29708948 TI - Leveraging the clinical collaborative model to drive value improvement. AB - PURPOSE OF REVIEW: Physician-led quality improvement collaboratives have emerged across surgical disciplines as a means to measure and subsequently improve the quality and cost of care. In this review, we will provide an overview of recent successes within quality improvement collaboratives, as well as discuss future opportunities for such initiatives. RECENT FINDINGS: Successful quality improvement collaboratives have coupled data registries with a collegial environment to achieve data-driven improvements in care across diverse practice settings. Such efforts have a track record for accomplishing specific patient safety gains, and have more recently addressed complex care scenarios where data and consensus building have been leveraged to clarify optimal care pathways. Collaboratives are currently exploring mechanisms to meaningfully impact increasingly complex elements of care delivery, such as individual surgeon performance. SUMMARY: Quality improvement collaboratives are in a unique position to understand patterns in care across populations, lead evidence-based assessments of variation in quality, and to attempt to intervene to improve outcomes based on the data they accumulate. As healthcare increasingly shifts to emphasize quality of care, physician-led collaboratives represent an important mechanism to drive improvement. PMID- 29708949 TI - The genomics of renal cell carcinoma and its role in renal mass biopsy. AB - PURPOSE OF REVIEW: Large-scale genomic profiling has shed new light on the molecular underpinnings of renal cell carcinoma (RCC), spurring a much needed refinement of RCC subclassification based on an integrative assessment of histopathologic features and molecular alterations. At the same time, renal mass biopsies have become increasingly commonplace, necessitating ancillary tools to help guide clinical management. Herein, we briefly review our current understanding of RCC genomics, highlighting areas of possible clinical utility, as well as potential limitations, for renal mass biopsies. RECENT FINDINGS: Distinct RCC subtypes harbor characteristic molecular features, including somatic mutations, copy number alterations, and genomic rearrangements. Existing ancillary tools, including fluorescent in-situ hybridization and immunohistochemistry, may be useful for diagnostic subclassification. Recurrent secondary molecular alterations in clear cell RCC (BAP1, SETD2, PBRM1, and TP53) and papillary RCC (CDKN2A) may be associated with poor prognosis; however, intratumoral genomic heterogeneity may limit the clinical utility of these molecular biomarkers in renal mass biopsies. SUMMARY: Recent technological advances have the potential to fundamentally alter the clinical management of RCC by leveraging our increasing understanding of RCC genomics to assess hundreds of molecular biomarkers simultaneously. Additional focused molecular analyses of renal mass biopsy cohorts are needed prior to widespread implementation of molecular biomarker assays. PMID- 29708950 TI - Granulosa Cell Tumors of the Ovary With Prominent Thecoma-like Foci: A Report of 16 Cases Emphasizing the Ongoing Utility of the Reticulin Stain in the Modern Era. AB - Sixteen adult granulosa cell tumors which had conspicuous zones of cells with pale cytoplasm imparting a resemblance to thecoma are reported. The neoplasms occurred in patients from 38 to 86 yr of age, the majority being over 55 yr of age. Ten tumors were incidental findings, the remainder being associated with symptoms or signs related to an adnexal mass. All the tumors were unilateral, typically small, usually under 5 cm, with only 3 being larger. With 1 exception they were uniformly solid and were typically entirely or focally yellow on sectioning. Microscopic examination typically showed a nodular pattern of growth constituted by cells with moderate to abundant pale cytoplasm; the cells resembled those seen in most thecomas. The nodules occasionally became confluent and focally a diffuse pattern was seen. Typical foci of adult granulosa cell neoplasia in the form of foci of conspicuous epithelial differentiation were absent or rare in most cases but were seen in subtle form in 6 cases and overtly in 3. A few tumors had other features seen in some thecomas, hyaline plaques, sclerosis, and calcification. Reticulin stains were examined in 13 cases and showed that the thecoma-like foci exhibited a dearth of reticulum indicating that those areas were predominantly of granulosa cell nature. Most adult granulosa cell tumors have cells with scant cytoplasm; occasional tumors have abundant eosinophilic cytoplasm, so-called luteinized adult granulosa cell tumors. That some granulosa cell tumors have the cytoplasmic features described herein has occasionally been noted but the resemblance to thecoma has not been emphasized to the best of our knowledge and in the past such tumors may have been misdiagnosed as thecoma, the referral diagnosis in 6 of our cases. A reticulin stain is of crucial aid in indicating the epithelial nature of the thecoma-like foci in these cases. Given the small size of the majority of the tumors the distinction between a small adult granulosa cell tumor and thecoma does not have significant prognostic or therapeutic implications in most cases but awareness of this feature of a small subset of adult granulosa cell tumors is warranted. Our findings have import to the diagnosis of thecoma which is uncommon if strict criteria, including exclusion of granulosa tumors of the type described, are used. PMID- 29708951 TI - Predatory Journals: Author Beware! PMID- 29708955 TI - Deprescribing in older people: why it matters in routine clinical practice. PMID- 29708956 TI - Optimal management of cancer patients with acute coronary syndrome. AB - Cancer at various stages and therapy is observed in about 15% of patients with acute coronary syndrome (ACS). Current guidelines for invasive and conservative treatment of ACS cannot be applied to all patients with cancer. The choice of antiplatelet and anticoagulant drugs should be individualized with clopidogrel as a key P2Y12 inhibitor in this population. Major challenges of therapy in patients with ACS and cancer include limitations for the use of the recommended antithrombotic therapy (particularly in case of cancer-related thrombocytopenia or when anticoagulation is needed due to concomitant atrial fibrillation or venous thromboembolism), the management of bleeding complications, eligibility criteria for cancer surgery, and reinitiation of chemotherapy or radiotherapy after ACS. This review summarizes the current evidence and our own experience in the treatment of ACS in cancer patients. Since prognosis has considerably improved in many cancer patients in the last decade, optimal therapy of ACS may increase the life expectancy and reduce the risk of adverse coronary events after ACS in this high-risk population. PMID- 29708957 TI - Transbronchial lung cryobiopsy guided by endobronchial ultrasound radial miniprobe in interstitial lung diseases: preliminary results of a prospective study. PMID- 29708958 TI - Analysis of growth hormone levels in the blood of patients with drug-resistant depression. PMID- 29708959 TI - Interleukin 27 in bronchoalveolar lavage fluid in patients with non- small cell lung cancer. PMID- 29708960 TI - Interleukin 27 in bronchoalveolar lavage fluid in patients with non- small cell lung cancer. Authors' reply. PMID- 29708961 TI - Cellular Mechanisms of Hepatoprotection Mediated by M2-Like Macrophages. AB - BACKGROUND Acute liver injury in the setting of hepatic fibrosis is an intriguing and still unsettled issue. We previously have demonstrated the protective effects conferred by M2-like macrophages in the fibrotic liver. In the present work, we further decipher the cellular mechanisms governing this hepatoprotection. MATERIAL AND METHODS Macrophages were isolated from control mice (M0 macrophages), then polarized into M1 or M2 phenotype using IFN-gamma or IL-4, respectively. Conditioned media (CM) from M0, M1, and M2 macrophages were harvested and applied to M1 macrophages. Cell apoptosis was evaluated by immunostaining and real-time PCR. Similarly, human monocyte-derived macrophages were isolated and polarized, then M0, M1, and M2 CM were applied to HL-7702 or HepG2 cells followed by apoptosis induction. Cell apoptosis was assessed by flow cytometry. RESULTS For the mouse conditioned medium experiment, stronger expression of cleaved caspase 3 and higher Bax/Bcl-2 mRNA ratio were found in M1 macrophages pretreated with M2 CM compared to those in M1 macrophages pretreated with M0 or M1 CM. Similarly, exposure of HL-7702 and HepG2 cells to either M0 or M1 CM had no significant effect on cell apoptosis. Nevertheless, the frequency of hepatocyte apoptosis was substantially reduced in HL-7702 (from 32.23+/-2.99 to 15.37+/-0.69 for Annexin V+/PI+ staining, p<0.01) and HepG2 cells (from 36.1+/ 7.26 to 15.2+/-1.2 for Annexin V+/PI+ staining, p<0.01) with M2 CM pretreatment. CONCLUSIONS M2-like macrophages exert their hepatoprotective effect by promoting M1-like macrophage apoptosis but protecting against hepatocyte apoptosis. PMID- 29708962 TI - Mib1 prevents Notch Cis-inhibition to defer differentiation and preserve neuroepithelial integrity during neural delamination. AB - The vertebrate neuroepithelium is composed of elongated progenitors whose reciprocal attachments ensure the continuity of the ventricular wall. As progenitors commit to differentiation, they translocate their nucleus basally and eventually withdraw their apical endfoot from the ventricular surface. However, the mechanisms allowing this delamination process to take place while preserving the integrity of the neuroepithelial tissue are still unclear. Here, we show that Notch signaling, which is classically associated with an undifferentiated state, remains active in prospective neurons until they delaminate. During this transition period, prospective neurons rapidly reduce their apical surface and only later down-regulate N-Cadherin levels. Upon Notch blockade, nascent neurons disassemble their junctions but fail to reduce their apical surface. This disrupted sequence weakens the junctional network and eventually leads to breaches in the ventricular wall. We also provide evidence that the Notch ligand Delta-like 1 (Dll1) promotes differentiation by reducing Notch signaling through a Cis-inhibition mechanism. However, during the delamination process, the ubiquitin ligase Mindbomb1 (Mib1) transiently blocks this Cis-inhibition and sustains Notch activity to defer differentiation. We propose that the fine-tuned balance between Notch Trans-activation and Cis-inhibition allows neuroepithelial cells to seamlessly delaminate from the ventricular wall as they commit to differentiation. PMID- 29708964 TI - Antibiotic combination efficacy (ACE) networks for a Pseudomonas aeruginosa model. AB - The spread of antibiotic resistance is always a consequence of evolutionary processes. The consideration of evolution is thus key to the development of sustainable therapy. Two main factors were recently proposed to enhance long-term effectiveness of drug combinations: evolved collateral sensitivities between the drugs in a pair and antagonistic drug interactions. We systematically assessed these factors by performing over 1,600 evolution experiments with the opportunistic nosocomial pathogen Pseudomonas aeruginosa in single- and multidrug environments. Based on the growth dynamics during these experiments, we reconstructed antibiotic combination efficacy (ACE) networks as a new tool for characterizing the ability of the tested drug combinations to constrain bacterial survival as well as drug resistance evolution across time. Subsequent statistical analysis of the influence of the factors on ACE network characteristics revealed that (i) synergistic drug interactions increased the likelihood of bacterial population extinction-irrespective of whether combinations were compared at the same level of inhibition or not-while (ii) the potential for evolved collateral sensitivities between 2 drugs accounted for a reduction in bacterial adaptation rates. In sum, our systematic experimental analysis allowed us to pinpoint 2 complementary determinants of combination efficacy and to identify specific drug pairs with high ACE scores. Our findings can guide attempts to further improve the sustainability of antibiotic therapy by simultaneously reducing pathogen load and resistance evolution. PMID- 29708963 TI - Automated evaluation of quaternary structures from protein crystals. AB - A correct assessment of the quaternary structure of proteins is a fundamental prerequisite to understanding their function, physico-chemical properties and mode of interaction with other proteins. Currently about 90% of structures in the Protein Data Bank are crystal structures, in which the correct quaternary structure is embedded in the crystal lattice among a number of crystal contacts. Computational methods are required to 1) classify all protein-protein contacts in crystal lattices as biologically relevant or crystal contacts and 2) provide an assessment of how the biologically relevant interfaces combine into a biological assembly. In our previous work we addressed the first problem with our EPPIC (Evolutionary Protein Protein Interface Classifier) method. Here, we present our solution to the second problem with a new method that combines the interface classification results with symmetry and topology considerations. The new algorithm enumerates all possible valid assemblies within the crystal using a graph representation of the lattice and predicts the most probable biological unit based on the pairwise interface scoring. Our method achieves 85% precision (ranging from 76% to 90% for different oligomeric types) on a new dataset of 1,481 biological assemblies with consensus of PDB annotations. Although almost the same precision is achieved by PISA, currently the most popular quaternary structure assignment method, we show that, due to the fundamentally different approach to the problem, the two methods are complementary and could be combined to improve biological assembly assignments. The software for the automatic assessment of protein assemblies (EPPIC version 3) has been made available through a web server at http://www.eppic-web.org. PMID- 29708965 TI - Topological and statistical analyses of gene regulatory networks reveal unifying yet quantitatively different emergent properties. AB - Understanding complexity in physical, biological, social and information systems is predicated on describing interactions amongst different components. Advances in genomics are facilitating the high-throughput identification of molecular interactions, and graphs are emerging as indispensable tools in explaining how the connections in the network drive organismal phenotypic plasticity. Here, we describe the architectural organization and associated emergent topological properties of gene regulatory networks (GRNs) that describe protein-DNA interactions (PDIs) in several model eukaryotes. By analyzing GRN connectivity, our results show that the anticipated scale-free network architectures are characterized by organism-specific power law scaling exponents. These exponents are independent of the fraction of the GRN experimentally sampled, enabling prediction of properties of the complete GRN for an organism. We further demonstrate that the exponents describe inequalities in transcription factor (TF) target gene recognition across GRNs. These observations have the important biological implication that they predict the existence of an intrinsic organism specific trans and/or cis regulatory landscape that constrains GRN topologies. Consequently, architectural GRN organization drives not only phenotypic plasticity within a species, but is also likely implicated in species-specific phenotype. PMID- 29708966 TI - Role of heterotrimeric Galpha proteins in maize development and enhancement of agronomic traits. AB - Plant shoot systems derive from the shoot apical meristems (SAMs), pools of stems cells that are regulated by a feedback between the WUSCHEL (WUS) homeobox protein and CLAVATA (CLV) peptides and receptors. The maize heterotrimeric G protein alpha subunit COMPACT PLANT2 (CT2) functions with CLV receptors to regulate meristem development. In addition to the sole canonical Galpha CT2, maize also contains three eXtra Large GTP-binding proteins (XLGs), which have a domain with homology to Galpha as well as additional domains. By either forcing CT2 to be constitutively active, or by depleting XLGs using CRISPR-Cas9, here we show that both CT2 and XLGs play important roles in maize meristem regulation, and their manipulation improved agronomic traits. For example, we show that expression of a constitutively active CT2 resulted in higher spikelet density and kernel row number, larger ear inflorescence meristems (IMs) and more upright leaves, all beneficial traits selected during maize improvement. Our findings suggest that both the canonical Galpha, CT2 and the non-canonical XLGs play important roles in maize meristem regulation and further demonstrate that weak alleles of plant stem cell regulatory genes have the capacity to improve agronomic traits. PMID- 29708967 TI - Metabolite profiling for biomarkers in Schistosoma haematobium infection and associated bladder pathologies. AB - BACKGROUND: Metabolic fingerprinting analysis can offer insights into underlying reactions in a biological system; hence it is crucial to the understanding of disease pathogenesis and could provide useful tools for discovering biomarkers. We sought to examine the urine and plasma metabolome in individuals affected by urogenital schistosomiasis and its associated-bladder pathologies. METHODOLOGY: Blood and midstream urine were obtained from volunteers who matched our inclusion criteria among residents from Eggua, southwestern Nigeria. Samples were screened by urinalysis, microscopy, PCR and ultrasonography, and categorised as advanced (urogenital schistosomiasis associated-bladder pathologies), infection-only (urogenital schistosomiasis alone) and controls (no infection and no pathology). Metabolites were extracted and data acquired with ultra high-performance liquid chromatography coupled with Thermo Q-Exactive orbitrap HRMS. Data was analysed with MetaboAnalyst, Workflow4Metabolomics, HMDB, LipidMaps and other bioinformatics tools, with univariate and multivariate statistics for metabolite selection. PRINCIPAL FINDINGS: There were low levels of host sex steroids, and high levels of several benzenoids, catechols and lipids (including ganglioside, phosphatidylcholine and phosphatidylethanolamine), in infection-only and advanced cases (FDR<0.05, VIP>2, delta>2.0). Metabolites involved in biochemical pathways related to chorismate production were abundant in controls, while those related to choline and sphingolipid metabolism were upregulated in advanced cases (FDR<0.05). Some of these human host and Schistosoma haematobium molecules, including catechol estrogens, were good markers to distinguish infection-only and advanced cases. CONCLUSIONS: Altered glycerophospholipid and sphingolipid metabolism could be key factors promoting the development of bladder pathologies and tumours during urogenital schistosomiasis. PMID- 29708968 TI - Estimation of the dispersal distances of an aphid-borne virus in a patchy landscape. AB - Characterising the spatio-temporal dynamics of pathogens in natura is key to ensuring their efficient prevention and control. However, it is notoriously difficult to estimate dispersal parameters at scales that are relevant to real epidemics. Epidemiological surveys can provide informative data, but parameter estimation can be hampered when the timing of the epidemiological events is uncertain, and in the presence of interactions between disease spread, surveillance, and control. Further complications arise from imperfect detection of disease and from the huge number of data on individual hosts arising from landscape-level surveys. Here, we present a Bayesian framework that overcomes these barriers by integrating over associated uncertainties in a model explicitly combining the processes of disease dispersal, surveillance and control. Using a novel computationally efficient approach to account for patch geometry, we demonstrate that disease dispersal distances can be estimated accurately in a patchy (i.e. fragmented) landscape when disease control is ongoing. Applying this model to data for an aphid-borne virus (Plum pox virus) surveyed for 15 years in 605 orchards, we obtain the first estimate of the distribution of flight distances of infectious aphids at the landscape scale. About 50% of aphid flights terminate beyond 90 m, which implies that most infectious aphids leaving a tree land outside the bounds of a 1-ha orchard. Moreover, long-distance flights are not rare-10% of flights exceed 1 km. By their impact on our quantitative understanding of winged aphid dispersal, these results can inform the design of management strategies for plant viruses, which are mainly aphid-borne. PMID- 29708969 TI - Microdeletion on chromosome 8p23.1 in a familial form of severe Buruli ulcer. AB - Buruli ulcer (BU), the third most frequent mycobacteriosis worldwide, is a neglected tropical disease caused by Mycobacterium ulcerans. We report the clinical description and extensive genetic analysis of a consanguineous family from Benin comprising two cases of unusually severe non-ulcerative BU. The index case was the most severe of over 2,000 BU cases treated at the Centre de Depistage et de Traitement de la Lepre et de l'Ulcere de Buruli, Pobe, Benin, since its opening in 2003. The infection spread to all limbs with PCR-confirmed skin, bone and joint infections. Genome-wide linkage analysis of seven family members was performed and whole-exome sequencing of both patients was obtained. A 37 kilobases homozygous deletion confirmed by targeted resequencing and located within a linkage region on chromosome 8 was identified in both patients but was absent from unaffected siblings. We further assessed the presence of this deletion on genotyping data from 803 independent local individuals (402 BU cases and 401 BU-free controls). Two BU cases were predicted to be homozygous carriers while none was identified in the control group. The deleted region is located close to a cluster of beta-defensin coding genes and contains a long non-coding (linc) RNA gene previously shown to display highest expression values in the skin. This first report of a microdeletion co-segregating with severe BU in a large family supports the view of a key role of human genetics in the natural history of the disease. PMID- 29708970 TI - Histone acetyltransferase TGF-1 regulates Trichoderma atroviride secondary metabolism and mycoparasitism. AB - Some filamentous fungi of the Trichoderma genus are used as biocontrol agents against airborne and soilborne phytopathogens. The proposed mechanism by which Trichoderma spp. antagonizes phytopathogens is through the release of lytic enzymes, antimicrobial compounds, mycoparasitism, and the induction of systemic disease-resistance in plants. Here we analyzed the role of TGF-1 (Trichoderma Gcn Five-1), a histone acetyltransferase of Trichoderma atroviride, in mycoparasitism and antibiosis against the phytopathogen Rhizoctonia solani. Trichostatin A (TSA), a histone deacetylase inhibitor that promotes histone acetylation, slightly affected T. atroviride and R. solani growth, but not the growth of the mycoparasite over R. solani. Application of TSA to the liquid medium induced synthesis of antimicrobial compounds. Expression analysis of the mycoparasitism related genes ech-42 and prb-1, which encode an endochitinase and a proteinase, as well as the secondary metabolism-related genes pbs-1 and tps-1, which encode a peptaibol synthetase and a terpene synthase, respectively, showed that they were regulated by TSA. A T. atroviride strain harboring a deletion of tgf-1 gene showed slow growth, thinner and less branched hyphae than the wild-type strain, whereas its ability to coil around the R. solani hyphae was not affected. Deltatgf-1 presented a diminished capacity to grow over R. solani, but the ability of its mycelium -free culture filtrates (MFCF) to inhibit the phytopathogen growth was enhanced. Intriguingly, addition of TSA to the culture medium reverted the enhanced inhibition growth of Deltatgf-1 MFCF on R. solani at levels compared to the wild-type MFCF grown in medium amended with TSA. The presence of R. solani mycelium in the culture medium induced similar proteinase activity in a Deltatgf-1 compared to the wild-type, whereas the chitinolytic activity was higher in a Deltatgf-1 mutant in the absence of R. solani, compared to the parental strain. Expression of mycoparasitism- and secondary metabolism related genes in Deltatgf-1 was differentially regulated in the presence or absence of R. solani. These results indicate that histone acetylation may play important roles in the biocontrol mechanisms of T. atroviride. PMID- 29708972 TI - Analysis of LCT-13910 genotypes and bone mineral density in ancient skeletal materials. AB - The relation of LCT-13910 genotypes and bone mineral density (BMD) has been the subject of modern-day human population studies, giving inconsistent results. In the present study we analyze for the first time a relation of LCT-13910 genotypes and BMD in historical skeletal individuals. Ancient population might be a model for testing this association due to elimination of non-natural factors affecting bone density. Among 22 medieval individuals from Sanok churchyard (South-Eastern Poland; dated from XIV to XVII c. AD) we identified 4 individuals with osteoporosis (mean BMD = 0.468 g/cm2, SD = 0.090), 10 individuals with osteopenia (mean BMD = 0.531 g/cm2, SD = 0.066) and 8 individuals with normal BMD values (mean BMD = 0,642 g/cm2, SD = 0.060). Analyses of BMD and LCT-13910 genotypes revealed that mean BMD was the highest (0.583 g/cm2, SD = 0.065) in the individuals with lactose tolerance genotypes (TT and CT). We also found possible association of lower BMD at the radius and CC genotypes due to higher but not statistically significant frequency of osteoporosis in the lactose intolerant group (p = 0.60). Statistically significant correlation was found between BMD and females aged 20-35 years, with tendency to reduce BMD with age (p = 0.02). PMID- 29708971 TI - Indirect ELISA based on Hendra and Nipah virus proteins for the detection of henipavirus specific antibodies in pigs. AB - Hendra virus (HeV) and Nipah virus (NiV) belong to the genus Henipavirus in the family Paramyxoviridae. Henipavirus infections were first reported in the 1990's causing severe and often fatal outbreaks in domestic animals and humans in Southeast Asia and Australia. NiV infections were observed in humans in Bangladesh, India and in the first outbreak in Malaysia, where pigs were also infected. HeV infections occurred in horses in the North-Eastern regions of Australia, with singular transmission events to humans. Bats of the genus Pteropus have been identified as the reservoir hosts for henipaviruses. Molecular and serological indications for the presence of henipa-like viruses in African fruit bats, pigs and humans have been published recently. In our study, truncated forms of HeV and NiV attachment (G) proteins as well as the full-length NiV nucleocapsid (N) protein were expressed using different expression systems. Based on these recombinant proteins, Enzyme-linked Immunosorbent Assays (ELISA) were developed for the detection of HeV or NiV specific antibodies in porcine serum samples. We used the NiV N ELISA for initial serum screening considering the general reactivity against henipaviruses. The G protein based ELISAs enabled the differentiation between HeV and NiV infections, since as expected, the sera displayed higher reactivity with the respective homologous antigens. In the future, these assays will present valuable tools for serosurveillance of swine and possibly other livestock or wildlife species in affected areas. Such studies will help assessing the potential risk for human and animal health worldwide by elucidating the distribution of henipaviruses. PMID- 29708973 TI - Calibration and testing of a Raman hyperspectral imaging system to reveal powdered food adulteration. AB - The potential adulteration of foodstuffs has led to increasing concern regarding food safety and security, in particular for powdered food products where cheap ground materials or hazardous chemicals can be added to increase the quantity of powder or to obtain the desired aesthetic quality. Due to the resulting potential health threat to consumers, the development of a fast, label-free, and non invasive technique for the detection of adulteration over a wide range of food products is necessary. We therefore report the development of a rapid Raman hyperspectral imaging technique for the detection of food adulteration and for authenticity analysis. The Raman hyperspectral imaging system comprises of a custom designed laser illumination system, sensing module, and a software interface. Laser illumination system generates a 785 nm laser line of high power, and the Gaussian like intensity distribution of laser beam is shaped by incorporating an engineered diffuser. The sensing module utilize Rayleigh filters, imaging spectrometer, and detector for collection of the Raman scattering signals along the laser line. A custom-built software to acquire Raman hyperspectral images which also facilitate the real time visualization of Raman chemical images of scanned samples. The developed system was employed for the simultaneous detection of Sudan dye and Congo red dye adulteration in paprika powder, and benzoyl peroxide and alloxan monohydrate adulteration in wheat flour at six different concentrations (w/w) from 0.05 to 1%. The collected Raman imaging data of the adulterated samples were analyzed to visualize and detect the adulterant concentrations by generating a binary image for each individual adulterant material. The results obtained based on the Raman chemical images of adulterants showed a strong correlation (R>0.98) between added and pixel based calculated concentration of adulterant materials. This developed Raman imaging system thus, can be considered as a powerful analytical technique for the quality and authenticity analysis of food products. PMID- 29708975 TI - High prevalence of G3 rotavirus in hospitalized children in Rawalpindi, Pakistan during 2014. AB - Rotavirus A species (RVA) is the leading cause of severe diarrhea among children in both developed and developing countries. Among different RVA G types, humans are most commonly infected with G1, G2, G3, G4 and G9. During 2003-2004, G3 rotavirus termed as "new variant G3" emerged in Japan that later disseminated to multiple countries across the world. Although G3 rotaviruses are now commonly detected globally, they have been rarely reported from Pakistan. We investigated the genetic diversity of G3 strains responsible RVA gastroenteritis in children hospitalized in Rawalpindi, Pakistan during 2014. G3P[8] (18.3%; n = 24) was detected as the most common genotype causing majority of infections in children less than 06 months. Phylogenetic analysis of Pakistani G3 strains showed high amino acid similarity to "new variant G3" and G3 strains reported from China, Russia, USA, Japan, Belgium and Hungary during 2007-2012. Pakistani G3 strains belonged to lineage 3 within sub-lineage 3d, containing an extra N-linked glycosylation site compared to the G3 strain of RotaTeqTM. To our knowledge, this is the first report on the molecular epidemiology of G3 rotavirus strains from Pakistan and calls for immediate response measures to introduce RV vaccine in the routine immunization program of the country on priority. PMID- 29708974 TI - Quantitative analysis reveals crosstalk mechanisms of heat shock-induced attenuation of NF-kappaB signaling at the single cell level. AB - Elevated temperature induces the heat shock (HS) response, which modulates cell proliferation, apoptosis, the immune and inflammatory responses. However, specific mechanisms linking the HS response pathways to major cellular signaling systems are not fully understood. Here we used integrated computational and experimental approaches to quantitatively analyze the crosstalk mechanisms between the HS-response and a master regulator of inflammation, cell proliferation, and apoptosis the Nuclear Factor kappaB (NF-kappaB) system. We found that populations of human osteosarcoma cells, exposed to a clinically relevant 43 degrees C HS had an attenuated NF-kappaB p65 response to Tumor Necrosis Factor alpha (TNFalpha) treatment. The degree of inhibition of the NF kappaB response depended on the HS exposure time. Mathematical modeling of single cells indicated that individual crosstalk mechanisms differentially encode HS mediated NF-kappaB responses while being consistent with the observed population level responses. In particular "all-or-nothing" encoding mechanisms were involved in the HS-dependent regulation of the IKK activity and IkappaBalpha phosphorylation, while others involving transport were "analogue". In order to discriminate between these mechanisms, we used live-cell imaging of nuclear translocations of the NF-kappaB p65 subunit. The single cell responses exhibited "all-or-nothing" encoding. While most cells did not respond to TNFalpha stimulation after a 60 min HS, 27% showed responses similar to those not receiving HS. We further demonstrated experimentally and theoretically that the predicted inhibition of IKK activity was consistent with the observed HS dependent depletion of the IKKalpha and IKKbeta subunits in whole cell lysates. However, a combination of "all-or-nothing" crosstalk mechanisms was required to completely recapitulate the single cell data. We postulate therefore that the heterogeneity of the single cell responses might be explained by the cell intrinsic variability of HS-modulated IKK signaling. In summary, we show that high temperature modulates NF-kappaB responses in single cells in a complex and unintuitive manner, which needs to be considered in hyperthermia-based treatment strategies. PMID- 29708976 TI - Factors associated with visual field defects of optic disc drusen. AB - PURPOSE: To investigate the prevalence and risk factors for visual field defect in patients with optic disc drusen (ODD). METHODS: We assessed the visual field status of patients with ODD whose diagnosis were confirmed by spectral-domain optical coherence tomography (SD-OCT). Visual field defects were classified as normal, enlarged blind spot, or other defects. ODD were classified into either type 1 (without hyperreflective border and heterogenic internal reflectance) or type 2 (with hyperreflective border and lower internal reflectance). The prevalence and risk factors for each visual field defect was analyzed using logistic regression analysis and classification and regression tree (CART) modeling. RESULTS: Of the 40 eyes with ODD, 33 (83%) eyes were categorized as type 1 and 7 (17%) eyes were categorized as type 2 ODD. Regarding the visual field defects, 19 (48%) eyes showed normal visual field, 11 (28%) eyes showed enlarged blind spot, and 9 (24%) eyes showed other defects. The latter was more frequent in type 2 ODD (P = 0.001). Logistic regression analysis revealed that the factor associated with other defects was the thinning of the average retinal nerve fiber layer (RNFL) (per 10 MUm decrease, OR = 3.436, P = 0.004), and the factor associated with enlarged blind spot was the height of ODD (per 100 MUm increase, OR = 3.956, P = 0.023). CART modeling revealed that the average RNFL thickness lesser than 85.5 MUm, and then the ODD height larger than 348 MUm were the best split-up factors for predicting the type of visual field defects. CONCLUSIONS: In this study, one-quarter of ODD patients showed abnormal visual field defect other than enlarged blind spot. These other visual field defects appeared to be associated with the axonal loss in the eyes with type 2 ODD. PMID- 29708977 TI - Population prevalence and distribution of ankle pain and symptomatic radiographic ankle osteoarthritis in community dwelling older adults: A systematic review and cross-sectional study. AB - OBJECTIVES: To identify by systematic review published prevalence estimates of radiographic ankle osteoarthritis (OA) and to subsequently estimate the prevalence of ankle pain and symptomatic, radiographic ankle OA within community dwelling older adults from North Staffordshire, UK. METHODS: Electronic databases were searched using terms for ankle, osteoarthritis and radiography. Data regarding population, radiographic methods, definitions and prevalence estimates of ankle OA were extracted from papers meeting predetermined selection criteria. Adults aged >=50 years and registered with four general practices in North Staffordshire were mailed a health questionnaire. Ankle pain in the previous month was determined using a foot and ankle pain manikin. Respondents reporting pain in or around the foot in the last 12 months were invited to attend a research clinic where weight-bearing, antero-posterior and lateral ankle radiographs were obtained and scored for OA using a standardised atlas. Prevalence estimates for ankle pain and symptomatic, radiographic ankle OA were calculated using multiple imputation and weighted logistic regression, and stratified by age, gender and socioeconomic status. RESULTS: Eighteen studies were included in the systematic review. The methods of radiographic classification of ankle OA were poorly reported and showed heterogeneity. No true general population prevalence estimates of radiographic ankle OA were found, estimates in select sporting and medical community-dwelling populations ranged from 0.0-97.1%. 5109 participants responded to the health survey questionnaire (adjusted response 56%). Radiographs were obtained in 557 participants. The prevalence of ankle pain was 11.7% (10.8,12.6) and symptomatic, radiographic ankle OA grade>=2 was 3.4% (2.3, 4.5) (grade>=1: 8.8% (7.9,9.8); grade = 3: 1.9% (1.0,2.7). Prevalence was higher in females, younger adults (50-64 years) and those with routine/manual occupations. CONCLUSION: No general population prevalence estimates of radiographic ankle OA were identified in the published literature. Our prevalence study found that ankle pain was common in community dwelling older adults, whereas moderate to severe symptomatic, radiographic ankle OA occurred less frequently. Further investigations of the prevalence of ankle OA using more sensitive imaging modalities are warranted. PMID- 29708978 TI - Frequency and distribution of 152 genetic disease variants in over 100,000 mixed breed and purebred dogs. AB - Knowledge on the genetic epidemiology of disorders in the dog population has implications for both veterinary medicine and sustainable breeding. Limited data on frequencies of genetic disease variants across breeds exists, and the disease heritage of mixed breed dogs remains poorly explored to date. Advances in genetic screening technologies now enable comprehensive investigations of the canine disease heritage, and generate health-related big data that can be turned into action. We pursued population screening of genetic variants implicated in Mendelian disorders in the largest canine study sample examined to date by examining over 83,000 mixed breed and 18,000 purebred dogs representing 330 breeds for 152 known variants using a custom-designed beadchip microarray. We further announce the creation of MyBreedData (www.mybreeddata.com), an online updated inherited disorder prevalence resource with its foundation in the generated data. We identified the most prevalent, and rare, disease susceptibility variants across the general dog population while providing the first extensive snapshot of the mixed breed disease heritage. Approximately two in five dogs carried at least one copy of a tested disease variant. Most disease variants are shared by both mixed breeds and purebreds, while breed- or line specificity of others is strongly suggested. Mixed breed dogs were more likely to carry a common recessive disease, whereas purebreds were more likely to be genetically affected with one, providing DNA-based evidence for hybrid vigor. We discovered genetic presence of 22 disease variants in at least one additional breed in which they were previously undescribed. Some mutations likely manifest similarly independently of breed background; however, we emphasize the need for follow up investigations in each case and provide a suggested validation protocol for broader consideration. In conclusion, our study provides unique insight into genetic epidemiology of canine disease risk variants, and their relevance for veterinary medicine, breeding programs and animal welfare. PMID- 29708979 TI - Development and characterization of carboxy-terminus specific monoclonal antibodies for understanding MUC16 cleavage in human ovarian cancer. AB - MUC16 is overexpressed in ovarian cancer and plays important roles in invasion and metastasis. Previously described monoclonal antibodies against cell surface expressed MUC16 recognize the N-terminal tandemly repeated epitopes present in cancer antigen 125 (CA125). MUC16 is cleaved at a specific location, thus, releasing CA125 into the extracellular space. Recent reports have indicated that the retained carboxy-terminal (CT) fragment of MUC16 might play an important role in tumorigenicity in diverse types of cancers. However, limited data is available on the fate and existence of CT fragment on the surface of the cancer cell. Herein, we characterize two monoclonal antibodies (mAbs) showing specificity to the retained juxtamembrane region of MUC16. For the first time, we demonstrate that MUC16 is cleaved in ovarian cancer cells (NIH:OVCAR-3 [OVCAR-3]) and that the cleaved MUC16 subunits remain associated with each other. Immunohistochemical analyses on different grades of ovarian tumor tissues indicated differential reactivity of CA125 and MUC16 CT mAbs. The CA125 (M11) mAb detected 32/40 (80%), while the CT mAb (5E6) detected 33/40 (82.5%) of total ovarian cancer cases. For serous and serous papillary cases, the CA125 (M11) mAb stained 27/31 cases (87%), while CT mAb (5E6) stained 29/31 cases (93.5%). The CT mAb(s) accurately predict expression of MUC16 since their epitopes are not tandemly repeated and their reactivity may not be dependent on O-linked glycosylation. These antibodies can serve as valuable reagents for understanding MUC16 cleavage and may also serve as potential therapeutic agents for treatment of ovarian cancer. PMID- 29708980 TI - Springboard to an academic career-A national medical student research program. AB - Over the last decades there has been a decline in the recruitment of medical students into academia in all medical fields. Concurrently, medical research has increasingly included other disciplines in multidisciplinary convergence, introducing an unmet recruitment gap and requirement for medical researchers. To counteract the trend and recruit students to academic medicine, a national intercalated Medical Student Research Program (MSRP) was established in Norway in 2002. A preliminary evaluation in 2009 suggested that the MSRP had resulted in recruitment, but could not conclude on a lasting effect beyond graduation in a study that did not include any controls. These results led us to hypothesize that the MSRP could increase the number of PhD degrees and attract medical students towards academic medicine. Adopting a case cohort design, we here report that the intercalated MSRP had a significant impact of the throughput of physician scientists to PhD, by increasing the rate of PhD completion 10-fold (p<0.001). Moreover, almost twice as many MSRP physicians reported an academic aspiration (49% vs 22%, p<0.001). Results suggested that an MSRP-like approach could efficiently address the unmet recruitment gap and strengthen the medical disciplines in medical research. PMID- 29708981 TI - Exotic species as models to understand biocultural adaptation: Challenges to mainstream views of human-nature relations. AB - A central argument in the research on traditional knowledge, which persists in the scientific literature, is that the entrance of exotic plants in local medical systems is directly associated with acculturation. However, this logic has put an end for a long period to efforts to understand why such species have so successfully entered socio-ecological systems or even their real role in such systems. This study provides evidence that (1) in some socio-environmental contexts, exotic medicinal species usually confer greater adaptive advantages to local populations, and (2) despite their general importance, exotic species only excel in medical systems when cost-benefit ratio is favorable to them. Thus, in order to avoid the loss of knowledge about native plants and to ensure biocultural conservation, it is necessary to create strategies to amplify the advantages of these species. PMID- 29708982 TI - FSI simulation of CSF hydrodynamic changes in a large population of non communicating hydrocephalus patients during treatment process with regard to their clinical symptoms. AB - 3D fluid-structure interaction modelling was utilized for simulation of 13 normal subjects, 11 non-communicating hydrocephalus (NCH) patients at pre-treatment phase, and 3 patients at five post-treatment phases. Evaluation of ventricles volume and maximum CSF pressure (before shunting) following results validation indicated that these parameters were the most proper hydrodynamic indices and the NCH type doesn't have any significant effect on changes in two indices. The results confirmed an appropriate correlation between these indices although the correlation decreased slightly after the occurrence of disease. NCH raises the intensity of vortex and pulsatility (2.4 times) of CSF flow while the flow remains laminar. On day 18 after shunting, the CSF pressure decreased 81.0% and all clinical symptoms of patients vanished except for headache. Continuing this investigation during the treatment process showed that maximum CSF pressure is the most sensitive parameter to patients' clinical symptoms. Maximum CSF pressure has decreased proportional to the level of decrease in clinical symptoms and has returned close to the pressure range in normal subjects faster than other parameters and simultaneous with disappearance of patients' clinical symptoms (from day 81 after shunting). However, phase lag between flow rate and pressure gradient functions and the degree of CSF pulsatility haven't returned to normal subjects' conditions even 981 days after shunting and NCH has also caused a permanent volume change (of 20.1%) in ventricles. Therefore, patients have experienced a new healthy state in new hydrodynamic conditions after shunting and healing. Increase in patients' intracranial compliance was predicted with a more accurate non-invasive method than previous experimental methods up to more than 981 days after shunting. The changes in hydrodynamic parameters along with clinical reports of patients can help to gain more insight into the pathophysiology of NCH patients. PMID- 29708983 TI - Botanical-chemical formulations enhanced yield and protection against Bipolaris sorokiniana in wheat by inducing the expression of pathogenesis-related proteins. AB - Two experiments (pot and field experiments) were conducted in two consecutive years to evaluate the protective effects of botanical-chemical formulations on physiological, biochemical performance and grain yield of wheat inoculated with Bipolaris sorokiniana. We compared different formulations comprising Calotropis procera, Jacaranda mimosifolia, Thevetia peruviana extracts, chemical fungicide (mefenoxam) and salicylic acid to modulate the defense system of wheat host plants. Among the selected plant species J. mimosifolia aqueous and methanolic leaf extracts (1.2% w/v) resulted in 96 to 97% inhibition against B. sorokiniana. Both in pot and field experiments, among all the formulations of selected plant extracts the combined formulation of JAF2 (J. mimosifolia 0.6%)+MFF2 (mefenoxam 0.1%) lowered the dose of chemical fungicide required to reduce the leaf spot blotch disease. The same formulation induced resistance in wheat apparently through the accumulation of peroxidase, polyphenol oxidase, protease, acid invertase, chitinase and phenylalanine ammonia lyase. This formulation also stimulated the defense-related gene expression of PR-proteins. The same treatment gave even more increase (48%, 12% and 22%) in no. of grains/spike, grains weight and grain yield, than the MFF1 (mefenoxam 0.2%). We conclude that foliar application of J. mimosifolia leaf extract with very low dose of chemical fungicide (J. mimosifolia 0.6%+mefenoxam 0.1%) is a promising approach for the management of leaf blight and spot blotch in wheat. PMID- 29708984 TI - The effects of individual status and group performance on network ties among teammates in the National Basketball Association. AB - For individuals, status is derived both from their personal attributes and the groups with whom they are affiliated. Depending on the performance of their groups, the status of individuals may benefit or suffer from identifying closely with the group. When the group excels, high-status members potentially receive much of the credit and increased status. Conversely, high-status members of underperforming groups potentially suffer disproportionate declines in their status relative to the low-status group members. We therefore predict an interaction between group performance and individual status on the willingness to associate with the group and its members. We test our prediction by examining social media ties among teammates in the National Basketball Association. Specifically, we investigate the "following" ties of teammates on Twitter at the end of the 2014-2015 season. Elections to All-Star games are used to measure the status of players, and team performance is measured by recent success in the postseason playoffs. The results show that compared to high-status players on successful teams, high-status players on underperforming teams are less likely to follow their teammates. This result aligns with research on status inconsistency, suggesting that individuals deemphasize their group affiliation when it jeopardizes their individual status. An additional contribution is the advancement of the probit Social Relations Model for the analysis of binary ties in social networks. PMID- 29708985 TI - Economic and clinical burden of viral hepatitis in California: A population-based study with longitudinal analysis. AB - BACKGROUND: Economic burden of HBV and HCV infection are trending upwards. AIMS: Compare hepatitis B virus (HBV) and hepatitis C virus (HCV) related hospital admission rates, charges, mortality rates, causes of death in a US population based study. METHODS: Retrospective cohort analysis of HBV and HCV patients from the California Office of Statewide Health Planning and Development (2006-2013) database. RESULTS: A total of 23,891 HBV and 148,229 HCV patients were identified. Across the 8-year period, the mean increase for all-cause ($1,863 vs $1,388) and liver-related hospitalization charges ($1,175 vs $675) were significantly higher for the HBV cohort compared to the HCV cohort. HBV patients had significantly higher liver-related hospital charges per person per year than HCV patients after controlling for covariates ($123,239 vs $111,837; p = 0.002). Compared to HCV patients, adjusted mortality hazard ratio was slightly lower in HBV patients (relative risk = 0.96; 95% CI 0.94-0.99). The major causes and places of death were different. The three major causes of death for HBV were: other malignant neoplasms (35%), cardiovascular disease/other circulatory disorders (17%), and liver-related disease (15%) whereas for HCV patients were: liver-related disease (22%), other malignant neoplasms (20%), and cardiovascular disease (16%). Regarding the place of death, 53% of HBV patients and 44% of HCV patients died in hospital inpatient, respectively. CONCLUSIONS: HBV patients incurred higher liver-related hospital charges and higher mean increase for all cause and liver-related hospitalization charges over the 8-year period compared to HCV patients. HBV patients had slightly lower mortality rate and their major causes and places of death were noticeably different from HCV patients. PMID- 29708986 TI - A model for studying the energetics of sustained high frequency firing. AB - Regulating membrane potential and synaptic function contributes significantly to the energetic costs of brain signaling, but the relative costs of action potentials (APs) and synaptic transmission during high-frequency firing are unknown. The continuous high-frequency (200-600Hz) electric organ discharge (EOD) of Eigenmannia, a weakly electric fish, underlies its electrosensing and communication. EODs reflect APs fired by the muscle-derived electrocytes of the electric organ (EO). Cholinergic synapses at the excitable posterior membranes of the elongated electrocytes control AP frequency. Based on whole-fish O2 consumption, ATP demand per EOD-linked AP increases exponentially with AP frequency. Continual EOD-AP generation implies first, that ion homeostatic processes reliably counteract any dissipation of posterior membrane ENa and EK and second that high frequency synaptic activation is reliably supported. Both of these processes require energy. To facilitate an exploration of the expected energy demands of each, we modify a previous excitability model and include synaptic currents able to drive APs at frequencies as high as 600 Hz. Synaptic stimuli are modeled as pulsatile cation conductance changes, with or without a small (sustained) background conductance. Over the full species range of EOD frequencies (200-600 Hz) we calculate frequency-dependent "Na+-entry budgets" for an electrocyte AP as a surrogate for required 3Na+/2K+-ATPase activity. We find that the cost per AP of maintaining constant-amplitude APs increases nonlinearly with frequency, whereas the cost per AP for synaptic input current is essentially constant. This predicts that Na+ channel density should correlate positively with EOD frequency, whereas AChR density should be the same across fish. Importantly, calculated costs (inferred from Na+-entry through Nav and ACh channels) for electrocyte APs as frequencies rise are much less than expected from published whole-fish EOD-linked O2 consumption. For APs at increasingly high frequencies, we suggest that EOD-related costs external to electrocytes (including packaging of synaptic transmitter) substantially exceed the direct cost of electrocyte ion homeostasis. PMID- 29708987 TI - Phagocytic response of astrocytes to damaged neighboring cells. AB - This study aims to understand the phagocytic response of astrocytes to the injury of neurons or other astrocytes at the single cell level. Laser nanosurgery was used to damage individual cells in both primary mouse cortical astrocytes and an established astrocyte cell line. In both cases, the release of material/substances from laser-irradiated astrocytes or neurons induced a phagocytic response in near-by astrocytes. Propidium iodide stained DNA originating from irradiated cells was visible in vesicles of neighboring cells, confirming phagocytosis of material from damaged cortical cells. In the presence of an intracellular pH indicator dye, newly formed vesicles correspond to acidic pH fluorescence, thus suggesting lysosome bound degradation of cellular debris. Cells with shared membrane connections prior to laser damage had a significantly higher frequency of induced phagocytosis compared to isolated cells with no shared membrane. The increase in phagocytic response of cells with a shared membrane occurred regardless of the extent of shared membrane (a thin filopodial connection vs. a cell cluster with significant shared membrane). In addition to the presence (or lack) of a membrane connection, variation in phagocytic ability was also observed with differences in injury location within the cell and distance separating isolated astrocytes. These results demonstrate the ability of an astrocyte to respond to the damage of a single cell, be it another astrocyte, or a neuron. This single-cell level of analysis results in a better understanding of the role of astrocytes to maintain homeostasis in the CNS, particularly in the sensing and removal of debris in damaged or pathologic nervous tissue. PMID- 29708988 TI - Dynamic linear modeling of monthly electricity demand in Japan: Time variation of electricity conservation effect. AB - After the severe nuclear disaster in Fukushima, which was triggered by the Great East Japan earthquake in March 2011, nuclear power plants in Japan were temporarily shut down for mandatory inspections. To prevent large-scale blackouts, the Japanese government requested companies and households to reduce electricity consumption in summer and winter. It is reported that the domestic electricity demand had a structural decrease because of the electricity conservation effect (ECE). However, quantitative analysis of the ECE is not sufficient, and especially time variation of the ECE remains unclear. Understanding the ECE is important because Japan's NDC (nationally determined contribution) assumes the reduction of CO2 emissions through aggressive energy conservation. In this study, we develop a time series model of monthly electricity demand in Japan and estimate time variation of the ECE. Moreover, we evaluate the impact of electricity conservation on CO2 emissions from power plants. The dynamic linear model is used to separate the ECE from the effects of other irrelevant factors (e.g. air temperature, economic production, and electricity price). Our result clearly shows that consumers' electricity conservation behavior after the earthquake was not temporary but became established as a habit. Between March 2011 and March 2016, the ECE on industrial electricity demand ranged from 3.9% to 5.4%, and the ECE on residential electricity demand ranged from 1.6% to 7.6%. The ECE on the total electricity demand was estimated at 3.2%-6.0%. We found a seasonal pattern that the residential ECE in summer is higher than that in winter. The emissions increase from the shutdown of nuclear power plants was mitigated by electricity conservation. The emissions reduction effect was estimated at 0.82 MtCO2-2.26 MtCO2 (-4.5% on average compared to the zero-ECE case). The time-varying ECE is necessary for predicting Japan's electricity demand and CO2 emissions after the earthquake. PMID- 29708989 TI - Toothbrushing Systematics Index (TSI) - A new tool for quantifying systematics in toothbrushing behaviour. AB - Systematics is considered important for effective toothbrushing. A theoretical concept of systematics in toothbrushing and a validated index to quantify it using observational data is suggested. The index consists of three components: completeness (all areas of the dentition reached), isochronicity (all areas brushed equally long) and consistency (avoiding frequent alternations between areas). Toothbrushing should take a sufficient length of time; therefore, this parameter is part of the index value calculation. Quantitative data from video observations were used including the number of changes between areas, number of areas reached, absolute brushing time and brushing time per area. These data were fed into two algorithms that converted the behaviour into two index values (each with values between 0 and 1) and were summed as the Toothbrushing Systematics Index (TSI) value; 0 indicates completely unsystematic and 2 indicates perfectly systematic brushing. The index was developed using theoretical data. The data matrices revealed the highest values when all areas are reached and brushed equally long. Few changes occurred between the areas when the brushing duration was >=90 s; the lowest values occurred under opposite conditions. Clinical applicability was tested with data from re-analysed videos from an earlier intervention study aiming to establish a pre-defined toothbrushing sequence. Subjects who fully adopted this sequence had a baseline TSI of 1.30+/-0.26, which increased to 1.74+/-0.09 after the intervention (p<=0.001). When the participants who only partially adopted the sequence were included, the respective values were 1.25+/-0.27 and 1.69+/-0.14 (p<=0.001). The suggested new TS-index can cover a variety of clinically meaningful variations of systematic brushing, validly quantifies the changes in toothbrushing systematics and has discriminative power. PMID- 29708990 TI - Increasing educational inequalities in self-rated health in Brazil, 1998-2013. AB - The objectives of this study are to analyze the associations between educational levels and poor self-rated health (SRH) among adults in Brazil and to assess trends in the prevalence of poor self-rated health across educational groups between 1998 and 2013. Individual-level data came from the 1998, 2003 and 2008 Brazilian National Household Survey and the 2013 National Health Survey. We estimate prevalence rates of poor SRH by education. Using multivariable regressions, we assess the associations between educational levels and poor self rated health. We use these regressions to predict the estimated ratios between the prevalence rates of those in low vs. high education in order to assess if relative changes in poor SRH have narrowed over time. Finally, we tested for statistically significant time trends in adult chronic disease inequalities by education. Results indicate a clear educational gradient in poor SRH. Prevalence ratios show that Brazilian adults with no education have levels of poor SRH that are 7 to 9 times higher than those with some college or more. The difference between those with lowest and highest education increased from 1998 to 2013. Compared to those with no education, there were increases in the prevalence of poor SRH among those with primary and secondary incomplete as well as among those with secondary complete in 2008 and 2013. In conclusion, there is a positive association between poor SRH and low education. Brazil has many social and geographic inequalities in health. Even though educational levels are increasing, there is no improvement in the general subjective health of Brazilians. Health inequalities by race and region highlight the need to improve the health of socially disadvantaged groups in Brazil. Addressing chronic conditions and mental health is needed to improve self-perceptions of health in Brazil as well. PMID- 29708991 TI - DNA microarray-based assessment of virulence potential of Shiga toxin gene carrying Escherichia coli O104:H7 isolated from feedlot cattle feces. AB - Escherichia coli O104:H4, a hybrid pathotype reported in a large 2011 foodborne outbreak in Germany, has not been detected in cattle feces. However, cattle harbor and shed in the feces other O104 serotypes, particularly O104:H7, which has been associated with sporadic cases of diarrhea in humans. The objective of our study was to assess the virulence potential of Shiga toxin-producing E. coli (STEC) O104:H7 isolated from feces of feedlot cattle using DNA microarray. Six strains of STEC O104:H7 isolated from cattle feces were analyzed using FDA-E. coli Identification (ECID) DNA microarray to determine their virulence profiles and compare them to the human strains (clinical) of O104:H7, STEC O104:H4 (German outbreak strain), and O104:H21 (milk-associated Montana outbreak strain). Scatter plots were generated from the array data to visualize the gene-level differences between bovine and human O104 strains, and Pearson correlation coefficients (r) were determined. Splits tree was generated to analyze relatedness between the strains. All O104:H7 strains, both bovine and human, similar to O104:H4 and O104:H21 outbreak strains were negative for intimin (eae). The bovine strains were positive for Shiga toxin 1 subtype c (stx1c), enterohemolysin (ehxA), tellurite resistance gene (terD), IrgA homolog protein (iha), type 1 fimbriae (fimH), and negative for genes that code for effector proteins of type III secretory system. The six cattle O104 strains were closely related (r = 0.86 0.98) to each other, except for a few differences in phage related and non annotated genes. One of the human clinical O104:H7 strains (2011C-3665) was more closely related to the bovine O104:H7 strains (r = 0.81-0.85) than the other four human clinical O104:H7 strains (r = 0.75-0.79). Montana outbreak strain (O104:H21) was more closely related to four of the human clinical O104:H7 strains than the bovine O104:H7 strains. None of the bovine E. coli O104 strains carried genes characteristic of E. coli O104:H4 German outbreak strain and unlike other human strains were also negative for Shiga toxin 2. Because cattle E. coli O104:H7 strains possess stx1c and genes that code for enterohemolysin and a variety of adhesins, the serotype has the potential to be a diarrheagenic foodborne pathogen in humans. PMID- 29708992 TI - Genetic profiling of young and aged endothelial progenitor cells in hypoxia. AB - Age is a major risk factor for diseases caused by ischemic hypoxia, such as stroke and coronary artery disease. Endothelial progenitor cells (EPCs) are the major cells respond to ischemic hypoxia through angiogenesis and vascular remodeling. However, the effect of aging on EPCs and their responses to hypoxia are not well understood. CD34+ EPCs were isolated from healthy volunteers and aged by replicative senescence, which was to passage cells until their doubling time was twice as long as the original cells. Young and aged CD34+ EPCs were exposed to a hypoxic environment (1% oxygen for 48hrs) and their gene expression profiles were evaluated using gene expression array. Gene array results were confirmed using quantitative polymerase chain reaction, Western blotting, and BALB/c female athymic nude mice hindlimb ischemia model. We identified 115 differentially expressed genes in young CD34+ EPCs, 54 differentially expressed genes in aged CD34+ EPCs, and 25 common genes between normoxia and hypoxia groups. Among them, the expression of solute carrier family 2 (facilitated glucose transporter), member 1 (SLC2A1) increased the most by hypoxia in young cells. Gene set enrichment analysis indicated the pathways affected by aging and hypoxia most, including genes "response to oxygen levels" in young EPCs and genes involved "chondroitin sulfate metabolic process" in aged cells. Our study results indicate the key factors that contribute to the effects of aging on response to hypoxia in CD34+ EPCs. With the potential applications of EPCs in cardiovascular and other diseases, our study also provides insight on the impact of ex vivo expansion might have on EPCs. PMID- 29708994 TI - Profiles of patient and tumour characteristics in relation to health-related quality of life after oesophageal cancer surgery. AB - Strong deterioration in health-related quality of life (HRQOL) is a major concern in a sub-group of long-term oesophageal cancer survivors. This study aimed to identify potential clustering of patients and tumour variables that predicts such deterioration. Patient and tumour variables were collected in a prospective cohort of patients who underwent surgery for oesophageal cancer in Sweden 2001 2005. Latent cluster analysis identified statistically significant clustering of these variables. Multivariable logistic regression adjusted for age, BMI, tumour stage and marital status was used to determine odds ratios (ORs) with 95% confidence intervals (CIs) between patient profiles and HRQOL at 3 and 5 years from surgery. Among 155 included patients at 3 years, three patient profiles were identified: 1) 'reference profile' (males, younger age, employed, upper secondary education, co-habitating, urban dwellers, adenocarcinoma and advanced tumour stage) (n = 47;30%), 2) 'adenocarcinoma profile' (middle age, unemployed/retired, males, low education, co-habitating, adenocarcinoma, advanced tumour stage, tumour in lower oesophagus/cardia, and co-morbidities (n = 79;51%), and 3) 'squamous-cell carcinoma profile' (unemployed/retired, middle-age, males, low BMI, urban dwellers, squamous-cell carcinoma, tumour in upper/middle oesophagus (n = 29;19%). These profiles did not differ regarding most HRQOL measures. Exceptions were the squamous-cell carcinoma profile, reporting more constipation (OR = 5.69; 95%CI: 1.34-24.28) and trouble swallowing saliva (OR = 4.87; 95%CI: 1.04-22.78) and the adenocarcinoma profile reporting more dyspnoea (OR = 2.60; 95%CI: 1.00-6.77) and constipation (OR = 3.31; 95%CI: 1.00-10.97) compared to the reference profile. Three distinct patient profiles were identified but these could not explain the substantial deterioration in HRQOL observed in the sub sample of survivors. PMID- 29708993 TI - Alcohol use, abuse and dependence in an older European population: Results from the MentDis_ICF65+ study. AB - BACKGROUND: Alcohol use disorders (AUD) in older people have been the subject of increasing interest in Europe and worldwide. However, thus far, no reliable data exist regarding the prevalence of AUD in people over the age of 65 years in Europe. OBJECTIVE: To assess the current (past month), 12-month and lifetime prevalence of alcohol use, abuse and dependence in people aged 65-84 years. STUDY DESIGN: The MentDis_ICF65+ study was a representative stepwise cross-sectional survey that was conducted in six European and associated cities (Hamburg, Germany; Ferrara, Italy; London/Canterbury, England; Madrid, Spain; Geneva, Switzerland and Jerusalem, Israel). METHOD: In total, 3,142 community-dwelling people aged between 65 and 84 years who lived in participating cities were assessed with an age-sensitive diagnostic interview (CIDI65+). RESULTS: The prevalence of lifetime alcohol use was 81% for the overall sample. The observed AUD (DSM-IV-TR) prevalence was as follows: current, 1.1%; 12-month, 5.3% and lifetime, 8.8%. Alcohol consumption and AUD were more prevalent in males, and a significant interaction between gender and city was observed; greater gender differences in the prevalence of these disorders were observed in Hamburg, London/Canterbury and Geneva in comparison to the other cities. The prevalence of lifetime alcohol consumption and 12-month AUD tended to be lower in older persons. CONCLUSION: The results highlight the appropriateness of using age adjusted diagnostic tools (CIDI65+) to identify alcohol use and AUD in older people. Different alcohol use patterns were observed in males and females. The results seem to indicate the presence of different alcohol use patterns between northern and southern European countries. Specialized services are proposed, including brief and/or more intensive interventions framed intensive and more simple interventions framed in stepped care strategies, to improve the social and health resources available for older people across Europe. PMID- 29708995 TI - Temporal evolution of HIV sero-discordancy patterns among stable couples in sub Saharan Africa. AB - INTRODUCTION: Objective was to examine the temporal variation of HIV sero discordancy in select representative countries (Kenya, Lesotho, Mali, Niger, Tanzania, and Zimbabwe) in sub-Saharan Africa at different HIV epidemic scales. A sero-discordant couple is defined as a stable couple (SC) in which one partner is HIV-positive while the other is HIV-negative. METHODS: A deterministic compartmental mathematical model was constructed to describe HIV transmission dynamics. The model was pair-based, that is explicitly modeling formation of SCs and infection dynamics in both SCs and in single individuals. The model accommodated for different forms of infection statuses in SCs. Using population based nationally-representative epidemiologic and demographic input data, historical (1980-2014) and future (2015-2030) trends of sero-discordancy and other demographic and epidemiologic indicators were projected throughout HIV epidemic phases. RESULTS: As the epidemics emerged, about 90% of SCs affected by HIV were sero-discordant. This proportion declined to 45%-88% at epidemic peak and stabilized as the epidemics started their natural decline. The largest reductions in sero-discordancy were in high HIV-prevalence countries. As the epidemics further declined with antiretroviral therapy (ART) scale-up, the proportion of sero-discordant couples among HIV-affected couples was projected to increase to 70%-92% by 2030. The proportion of sero-discordant couples among all SCs increased as the epidemics emerged and evolved, then peaked at 2%-20% as the epidemics peaked, and then declined as the epidemics declined to reach 0.3%-16% by 2030. CONCLUSIONS: Sero-discordancy patterns varied with the evolution of the epidemics, and were affected by both epidemic phase and scale. The largest variations were found in high HIV-prevalence countries. The fraction of stable couples that are sero-discordant, as opposed to being sero-concordant positive, was projected to increase with ART scale-up and further HIV incidence decline over the coming two decades. These findings inform strategic planning and resource allocation for interventions among sero-discordant couples. PMID- 29708996 TI - Mild cognitive dysfunction of caregivers and its association with care recipients' end-of-life plans and preferences. AB - Little is known about the association between cognitive dysfunction among informal caregivers and patients' plans and preferences for patients' end of life care. We report on the frequency of cognitive dysfunction among both patients and caregivers and examine associations between caregivers' cognitive screening scores and end of life plans and preferences of patients with advanced cancer. The current sample was derived from a National Cancer Institute- and National Institute of Mental Health-funded study of patients with distant metastasis who had disease progression on at least first-line chemotherapy, and their informal caregivers (n = 550 pairs). The Pfeiffer Short Portable Mental Status, a validated cognitive screen, was administered to patients and caregivers. Patients were interviewed about their end of life plans and preferences. Logistic regression models regressed patients' advance care planning and treatment preferences on caregivers' cognitive screen scores. Patients' cognitive screen scores were included as covariates. Most caregivers (55%) were spouses. Almost 30% of patients scored worse on the cognitive screen than their caregivers and 12% of caregivers scored worse than the patients. For each additional error that caregivers made on the cognitive screen, patients were more likely (AOR = 1.59, p = 0.002) to report that they preferred that everything possible be done to keep them alive and were less likely (AOR = 0.75, p = 0.04) to have a living will or a health care proxy/durable power of attorney. Worse caregiver cognitive screening scores were associated with higher likelihood of patients' reporting that they wanted everything done to save their lives and a lower likelihood of having a living will or other type of advanced care plan. Future studies should confirm these findings in other populations and determine the mechanisms that may underlie the identified relationships. PMID- 29708998 TI - Copenhagen Psychosocial Questionnaire - A validation study using the Job Demand Resources model. AB - AIM: This study aims at investigating the nomological validity of the Copenhagen Psychosocial Questionnaire (COPSOQ II) by using an extension of the Job Demands Resources (JD-R) model with aspects of work ability as outcome. MATERIAL AND METHODS: The study design is cross-sectional. All staff working at public dental organizations in four regions of Sweden were invited to complete an electronic questionnaire (75% response rate, n = 1345). The questionnaire was based on COPSOQ II scales, the Utrecht Work Engagement scale, and the one-item Work Ability Score in combination with a proprietary item. The data was analysed by Structural Equation Modelling. RESULTS: This study contributed to the literature by showing that: A) The scale characteristics were satisfactory and the construct validity of COPSOQ instrument could be integrated in the JD-R framework; B) Job resources arising from leadership may be a driver of the two processes included in the JD-R model; and C) Both the health impairment and motivational processes were associated with WA, and the results suggested that leadership may impact WA, in particularly by securing task resources. CONCLUSION: In conclusion, the nomological validity of COPSOQ was supported as the JD-R model-can be operationalized by the instrument. This may be helpful for transferral of complex survey results and work life theories to practitioners in the field. PMID- 29708997 TI - Effect of post-discharge virtual wards on improving outcomes in heart failure and non-heart failure populations: A systematic review and meta-analysis. AB - BACKGROUND: Unplanned hospital admissions in high-risk patients are common and costly in an increasingly frail chronic disease population. Virtual Wards (VW) are an emerging concept to improve outcomes in these patients. PURPOSE: To evaluate the effect of post-discharge VWs, as an alternative to usual community based care, on hospital readmissions and mortality among heart failure and non heart failure populations. DATA SOURCES: Ovid MEDLINE, EMBASE, PubMed, the Cochrane Database of Systematic Reviews, SCOPUS and CINAHL, from inception through to Jan 31, 2017; unpublished data, prior systematic reviews; reference lists. STUDY SELECTION: Randomized trials of post-discharge VW versus community based, usual care that reported all-cause hospital readmission and mortality outcomes. DATA EXTRACTION: Data were reviewed for inclusion and independently extracted by two reviewers. Risk of bias was assessed using the Cochrane Collaboration risk of bias tool. DATA SYNTHESIS: In patients with heart failure, a post-discharge VW reduced risk of mortality (six trials, n = 1634; RR 0.59, 95% CI = 0.44-0.78). Heart failure related readmissions were reduced (RR 0.61, 95% CI = 0.49-0.76), although all-cause readmission was not. In contrast, a post discharge VW did not reduce death or hospital readmissions for patients with undifferentiated high-risk chronic diseases (four trials, n = .3186). LIMITATIONS: Heterogeneity with respect to intervention and comparator, lacking consistent descriptions and utilization of standardized nomenclature for VW. Some trials had methodologic shortcomings and relatively small study populations. CONCLUSIONS: A post-discharge VW can provide added benefits to usual community based care to reduce all-cause mortality and heart failure-related hospital admissions among patients with heart failure. Further research is needed to evaluate the utility of VWs in other chronic disease settings. PMID- 29708999 TI - Phenotypic plasticity of life-history traits of a calanoid copepod in a tropical lake: Is the magnitude of thermal plasticity related to thermal variability? AB - According to the Climatic Variability Hypothesis [CVH], thermal plasticity should be wider in organisms from temperate environments, but is unlikely to occur in tropical latitudes where temperature fluctuations are narrow. In copepods, food availability has been suggested as the main driver of phenotypic variability in adult size if the range of temperature change is less than 14 degrees C. Leptodiaptomus garciai is a calanoid copepod inhabiting Lake Alchichica, a monomictic, tropical lake in Mexico that experiences regular, narrow temperature fluctuations but wide changes in phytoplankton availability. We investigated whether the seasonal fluctuations of temperature and food produce phenotypic variation in the life-history traits of this tropical species. We sampled L. garciai throughout a year and measured female size, egg size and number, and hatching success, along with temperature and phytoplankton biomass. The amplitude of the plastic responses was estimated with the Phenotypic Plasticity Index. This index was also computed for a published dataset of 84 copepod populations to look if there is a relationship between the amplitude of the phenotypic plasticity of adult size and seasonal change in temperature. The temperature annual range in Lake Alchichica was 3.2 degrees C, whereas phytoplankton abundance varied 17 fold. A strong pattern of thermal plasticity in egg size and adult female size followed the inverse relationship with temperature commonly observed in temperate environments, although its adaptive value was not demonstrated. Egg number, relative reproductive effort and number of nauplii per female were clearly plastic to food availability, allowing organisms to increase their fitness. When comparing copepod species from different latitudes, we found that the magnitude of thermal plasticity of adult size is not related to the range of temperature variation; furthermore, thermal plasticity exists even in environments of limited temperature variation, where the response is more intense compared to temperate populations. PMID- 29709000 TI - Control of Pem protein level by localized maternal factors for transcriptional regulation in the germline of the ascidian, Halocynthia roretzi. AB - Localized maternal mRNAs play important roles in embryogenesis, e.g. the establishment of embryonic axes and the developmental cell fate specification, in various animal species. In ascidians, a group of maternal mRNAs, called postplasmic/PEM RNAs, is localized to a subcellular structure, called the Centrosome-Attracting Body (CAB), which contains the ascidian germ plasm, and is inherited by the germline cells during embryogenesis. Posterior end mark (Pem), a postplasmic/PEM RNAs member, represses somatic gene expression in the germline during cleavage stages by inhibition of RNA polymerase II activity. However, the functions of other postplasmic/ PEM RNAs members in germline formation are largely unknown. In this study, we analyzed the functions of two postplasmic/PEM RNAs, Popk-1 and Zf-1, in transcriptional regulation in the germline cells. We show that Popk-1 contributes to transcriptional quiescence by controlling the size of the CAB and amount of Pem protein translated at the CAB. Our studies also indicated that zygotic expression of a germline gene starts around the onset of gastrulation and that the decrease of Pem protein is necessary and sufficient for the zygotic germline gene expression. Finally, further studies showed that the decrease of the Pem protein level is facilitated by Zf-1. Taken together, we propose that postplasmic/PEM RNAs such as Popk-1 and Zf-1 control the protein level of the transcriptional repressor Pem and regulate its transcriptional state in the ascidian germline. PMID- 29709001 TI - Long-term in vitro culture and preliminary establishment of chicken primordial germ cell lines. AB - Primordial germ cells (PGCs) are precursors of functional gametes and can be used as efficient transgenic tools and carriers in bioreactors. Few methods for long term culture of PGCs are available. In this study, we tested various culture conditions for PGCs, and used the optimum culture system to culture chicken gonad PGCs for about three hundred days. Long-term-cultured PGCs were detected and characterized by karyotype analysis, immunocytochemical staining of SSEA-1, c kit, Sox2, cDAZL, and quantitative RT-PCR for specific genes like Tert, DAZL, POUV, and NANOG. Cultured PGCs labeled with PKH26 were reinjected into Stage X recipient embryos and into the dorsal aorta of Stage 14-17 embryos to assay their ability of migration into the germinal crescent and gonads, respectively. In conclusion, the most suitable culture system for PGCs is as follows: feeder layer cells treated with 20 MUg/mL mitomycin C for 2 hours, and with 50% conditioned medium added to the factor culture medium. PGCs cultured in this system retain their pluripotency and the unique ability of migration without transformation, indicating the successful preliminary establishment of chicken primordial germ cell lines and these PGCs can be considered for use as carriers in transgenic bioreactors. PMID- 29709003 TI - Mindset switching increases the use of 'want-based' over 'should-based' behaviors. AB - This study examines the consequences of mindset switching on behavioral choices in want/should conflicts. Building on the insights of the ego depletion literature, we propose that mindset switching depletes individuals' self-control resources and therefore prompts the choice of want behavior, which provides immediate pleasure, over should behavior, which provides long-term utility. Four laboratory experiments with university students that stimulated individuals to switch mindsets were conducted to test our hypotheses. Experiment 1 demonstrated that switching between individualist and collectivist mindsets increased the subjects' tendency to prefer popular magazines over scientific journals. Experiment 2 replicated the results by testing the relationship between an abstract/concrete mindset-switching task and want/should online behavioral choices. The mediating effect of ego depletion was also supported. Experiment 3 retested the main effect of language-switching on reading choices, and the mediating effect of ego-depletion. Experiment 3 also tested the moderating effect of the Need for Cognition, and eliminated the alternative explanation of cognitive fatigue. In Experiment 4, actual food choices were used as the direct measure of want/should behaviors to test the robustness of our findings. The results consistently supported our hypotheses that mindset switching has significant effects on behavioral choices in terms of overindulgence, such as increasing want behavior and thus foregoing should behavior. PMID- 29709002 TI - B cells response directed against Cut4 and CFP21 lipolytic enzymes in active and latent tuberculosis infections. AB - BACKGROUND: Better understanding of the immune response directed against Mycobacterium tuberculosis (Mtb) is critical for development of vaccine strategies and diagnosis tests. Previous studies suggested that Mtb enzymes involved in lipid metabolism, are associated with persistence and/or reactivation of dormant bacilli. METHODS: Circulating antibodies secreting cells (ASCs), memory B cells, and antibodies directed against Cut4 (Rv3452) and CFP21 (Rv1984c) antigens were explored in subjects with either active- or latent-tuberculosis (LTB), and in Mtb-uninfected individuals. RESULTS: Circulating anti-Cut4 ASCs were detected in 11/14 (78.6%) subjects from the active TB group vs. 4/17 (23.5%) from the LTB group (p = 0.001). Anti-CFP21 ASCs were found in 11/14 (78.6%) active TB vs. in 5/17 (29.4%) LTB cases (p = 0.01). Circulating anti-Cut4 and anti-CFP21 ASCs were not detected in 38 Mtb uninfected controls. Memory B cells directed against either Cut4 or CFP21 were identified in 8/11 (72.7%) and in 9/11 (81.8%) subjects with LTB infection, respectively, and in 2/6 Mtb uninfected individuals (33.3%). High level of anti-Cut4 and anti-CFP21 IgG were observed in active TB cases. CONCLUSION: Circulating IgG SCs directed against Cut4 or CFP21 were mostly detected in patients presenting an active form of the disease, suggesting that TB reactivation triggers an immune response against these two antigens. PMID- 29709004 TI - MCU-knockdown attenuates high glucose-induced inflammation through regulating MAPKs/NF-kappaB pathways and ROS production in HepG2 cells. AB - Mitochondrial Ca2+ is a key regulator of organelle physiology and the excessive increase in mitochondrial calcium is associated with the oxidative stress. In the present study, we investigated the molecular mechanisms linking mitochondrial calcium to inflammatory and coagulative responses in hepatocytes exposed to high glucose (HG) (33mM glucose). Treatment of HepG2 cells with HG for 24 h induced insulin resistance, as demonstrated by an impairment of insulin-stimulated Akt phosphorylation. HepG2 treatment with HG led to an increase in mitochondrial Ca2+ uptake, while cytosolic calcium remained unchanged. Inhibition of MCU by lentiviral-mediated shRNA prevented mitochondrial calcium uptake and downregulated the inflammatory (TNF-alpha, IL-6) and coagulative (PAI-1 and FGA) mRNA expression in HepG2 cells exposed to HG. The protection from HG-induced inflammation by MCU inhibition was accompanied by a decrease in the generation of reactive oxygen species (ROS). Importantly, MCU inhibition in HepG2 cells abrogated the phosphorylation of p38, JNK and IKKalpha/IKKbeta in HG treated cells. Taken together, these data suggest that MCU inhibition may represent a promising therapy for prevention of deleterious effects of obesity and metabolic diseases. PMID- 29709005 TI - Single nucleotide polymorphisms in A4GALT spur extra products of the human Gb3/CD77 synthase and underlie the P1PK blood group system. AB - Contrary to the mainstream blood group systems, P1PK continues to puzzle and generate controversies over its molecular background. The P1PK system comprises three glycosphingolipid antigens: Pk, P1 and NOR, all synthesised by a glycosyltransferase called Gb3/CD77 synthase. The Pk antigen is present in most individuals, whereas P1 frequency is lesser and varies regionally, thus underlying two common phenotypes: P1, if the P1 antigen is present, and P2, when P1 is absent. Null and NOR phenotypes are extremely rare. To date, several single nucleotide polymorphisms (SNPs) have been proposed to predict the P1/P2 status, but it has not been clear how important they are in general and in relation to each other, nor has it been clear how synthesis of NOR affects the P1 phenotype. Here, we quantitatively analysed the phenotypes and A4GALT transcription in relation to the previously proposed SNPs in a sample of 109 individuals, and addressed potential P1 antigen level confounders, most notably the red cell membrane cholesterol content. While all the SNPs were associated with the P1/P2 blood type and rs5751348 was the most reliable, we found large differences in P1 level within groups defined by their genotype and substantial intercohort overlaps, which shows that the P1PK blood group system still eludes full understanding. PMID- 29709006 TI - Facilitators and barriers to non-medical prescribing - A systematic review and thematic synthesis. AB - INTRODUCTION: Non-medical prescribing has the potential to deliver innovative healthcare within limited finances. However, uptake has been slow, and a proportion of non-medical prescribers do not use the qualification. This systematic review aimed to describe the facilitators and barriers to non-medical prescribing in the United Kingdom. METHODS: The systematic review and thematic analysis included qualitative and mixed methods papers reporting facilitators and barriers to independent non-medical prescribing in the United Kingdom. The following databases were searched to identify relevant papers: AMED, ASSIA, BNI, CINAHL, EMBASE, ERIC, MEDLINE, Open Grey, Open access theses and dissertations, and Web of Science. Papers published between 2006 and March 2017 were included. Studies were quality assessed using a validated tool (QATSDD), then underwent thematic analysis. The protocol was registered with PROSPERO (CRD42015019786). RESULTS: Of 3991 potentially relevant identified studies, 42 were eligible for inclusion. The studies were generally of moderate quality (83%), and most (71%) were published 2007-2012. The nursing profession dominated the studies (30/42). Thematic analysis identified three overarching themes: non-medical prescriber, human factors, and organisational aspects. Each theme consisted of several sub themes; the four most highly mentioned were 'medical professionals', 'area of competence', 'impact on time' and 'service'. Sub-themes were frequently interdependent on each other, having the potential to act as a barrier or facilitator depending on circumstances. DISCUSSION: Addressing the identified themes and subthemes enables strategies to be developed to support and optimise non-medical prescribing. Further research is required to identify if similar themes are encountered by other non-medical prescribing groups than nurses and pharmacists. PMID- 29709008 TI - Design a software real-time operation platform for wave piercing catamarans motion control using linear quadratic regulator based genetic algorithm. AB - This work presents optimal linear quadratic regulator (LQR) based on genetic algorithm (GA) to solve the two degrees of freedom (2 DoF) motion control problem in head seas for wave piercing catamarans (WPC). The proposed LQR based GA control strategy is to select optimal weighting matrices (Q and R). The seakeeping performance of WPC based on proposed algorithm is challenged because of multi-input multi-output (MIMO) system of uncertain coefficient problems. Besides the kinematical constraint problems of WPC, the external conditions must be considered, like the sea disturbance and the actuators (a T-foil and two flaps) control. Moreover, this paper describes the MATLAB and LabVIEW software plats to simulate the reduction effects of WPC. Finally, the real-time (RT) NI CompactRIO embedded controller is selected to test the effectiveness of the actuators based on proposed techniques. In conclusion, simulation and experimental results prove the correctness of the proposed algorithm. The percentage of heave and pitch reductions are more than 18% in different high speeds and bad sea conditions. And the results also verify the feasibility of NI CompactRIO embedded controller. PMID- 29709007 TI - Chikungunya virus infection in Aruba: Diagnosis, clinical features and predictors of post-chikungunya chronic polyarthralgia. AB - BACKGROUND: Chikungunya virus (CHIKV) emerged in Aruba for the first time in 2014. We studied the clinical presentation of acute CHIKV infection and the contribution of serologic and molecular assays to its diagnosis. In a cohort of confirmed CHIKV cases, we analysed the frequency, duration and predictors of post chikungunya chronic polyarthralgia (pCHIK-CPA), defined as joint pains lasting longer than 6 weeks or longer than 1 year. METHODOLOGY: Patient sera obtained within 10 days of symptom onset were tested for CHIKV, using an indirect immunofluorescence test for the detection of CHIKV-specific Immunoglobulin M (IgM) and post-hoc, by reverse-transcription polymerase chain reaction (RT-PCR). CHIKV was isolated from selected samples and genotyped. For confirmed CHIKV cases, clinical data from chart review were complemented by a Telephone survey, conducted 18-24 months after diagnosis. When joint pain was reported, the duration, presence of inflammatory signs, type and number of joints affected, were recorded. Joint involvement was scored according to the 2010 'American College of Rheumatology/ European League Against Rheumatism' criteria for seronegative rheumatoid arthritis (ACR-score). Risk factors for pCHIK-CPA were identified by logistic regression. PRINCIPAL FINDINGS: Acute CHIKV infection was diagnosed in 269 of 498 sera, by detection of IgM (n = 105), by RT-PCR (n = 59), or by both methods (n = 105). Asian genotype was confirmed in 7 samples. Clinical data were complete for 171 of 248 (69.0%) patients, aged 15 years or older (median 49.4 [35.0-59.6]). The female-to-male ratio was 2.2. The main acute symptoms were arthralgia (94%), fever (85%), myalgia (85%), headache (73%) and rash (63%). In patients with arthralgia (n = 160), pCHIK-CPA longer than 6 weeks was reported by 44% and longer than 1 year by 26% of cases. Inflammatory signs, stiffness, edema and redness were frequent (71%, 39% and 21%, respectively). Joints involved were knees (66%), ankles (50%), fingers (52%), feet (46%), shoulders (36%), elbows (34%), wrists (35%), hips (31%), toes (28.1%) and spine (28.1%). Independent predictors of pCHIK-CPA longer than 1 year were female gender (OR 5.9, 95%-CI [2.1-19.6]); high ACR-score (7.4, [2.7-23.3]), and detection of CHIKV-RNA in serum beyond 7 days of symptom onset (6.4, [1.4-34.1]. CONCLUSIONS: We identified 269 CHIKV patients after the first outbreak of Asian genotype CHIKV in Aruba in 2014-2015. RT-PCR yielded 59 (28%) additional CHIKV diagnoses compared to IgM antibody detection alone. Arthralgia, fever and skin rash were the dominant acute phase symptoms. pCHIK-CPA longer than 1 year affected 26% of cases and was predicted by female gender, high ACR-score and CHIKV-RNA detection beyond 7 days of symptom onset. PMID- 29709009 TI - NF2 signaling pathway plays a pro-apoptotic role in beta-adrenergic receptor stimulated cardiac myocyte apoptosis. AB - METHODS AND RESULTS: Treatment of adult rat ventricular myocytes (ARVMs) with beta-AR agonist (isoproterenol) for 15 min increased phosphorylation (serine-518) and sumoylation of NF2. Co-immunoprecipitation assay confirmed beta-AR-stimulated sumoylation of NF2. beta-AR stimulation enhanced nuclear translocation of phosphorylated and sumoylated NF2. Specific inhibition of beta1-AR and protein kinase A (PKA) decreased beta-AR-stimulated increase in NF2 post-translational modifications, while inhibition of beta2-AR had no effect. Activation of adenylyl cyclase using forskolin (FSK) mimicked the effects of beta-AR stimulation. beta AR stimulation and expression of wild-type (WT)-NF2 using adenoviruses increased phosphorylation of mammalian sterile like kinase-1/2 (MST1/2) and yes activated protein (YAP), downstream targets of NF2. Knockdown of NF2 using siRNA in H9C2 cardiomyocytes decreased beta-AR-stimulated increase in NF2 and YAP phosphorylation. siRNA-mediated knockdown of NF2 decreased beta-AR-stimulated increase in apoptosis, while expression of WT-NF2 induced apoptosis in ARVMs. Expression of WT-NF2 stimulated the mitochondrial death pathway as evidenced by activation of c-Jun N-terminal Kinases (JNKs), and increase in cytosolic cytochrome c levels and Bax expression. CONCLUSION: beta-AR stimulation affects post-translational modifications of NF2 via the involvement beta1-AR/PKA/cAMP pathway, and NF2 plays a pro-apoptotic role in beta-AR-stimulated myocyte apoptosis via the phosphorylation (inactivation) of YAP and involvement of mitochondrial death pathway. PMID- 29709010 TI - Amelioration of CCl4 induced liver injury in swiss albino mice by antioxidant rich leaf extract of Croton bonplandianus Baill. AB - The progress in industrialization has blessed mankind with a technologically superior lifestyle but poor management of industrial waste has in turn poisoned nature. One such chemical is carbon tetra chloride (CCl4), which is a potent environmental toxin emitted from chemical industries and its presence in the atmosphere is increasing at an alarming rate. Presence of CCl4 in human body is reported to cause liver damage through free radical mediated inflammatory processes. Kupffer cells present in the liver are potentially more sensitive to oxidative stress than hepatocytes. Kuffer cells produced tumor necrosis factor alpha (TNF-alpha) in response to reactive oxygen species (ROS), that might further cause inflammation or apoptosis. In this study hepatoprotective capacity of antioxidant rich extract of Croton bonplandianus Baill. (CBL) was evaluated on CCl4 induced acute hepatotoxicity in murine model. Hydro-methanolic extract of C. bonplandianus leaf was used for evaluation of free radical scavenging activity. Liver cells of experimental mice were damaged using CCl4 and subsequently hepatoprotective potential of the plant extract was evaluated using series of in vivo and in-vitro studies. In the hepatoprotective study, silymarin was used as a positive control. Antioxidant enzymes, pro-inflammatory markers, liver enzymatic and biochemical parameters were studied to evaluate hepatoprotective activity of Croton bonplandianus leaf extract. Free radical scavenging activity of CBL extract was also observed in WRL-68 cell line. The phytochemicals identified by GCMS analysis were scrutinized using in-silico molecular docking procedure. The results showed that CBL extract have potent free radical scavenging capacity. The biochemical parameters were over expressed due to CCl4 administration, which were significantly normalized by CBL extract treatment. This finding was also supported by histopathological evidences showing less hepatocellularnecrosis, inflammation and fibrosis in CBL and silymarin treated group, compared to CCl4 group. ROS generated due to H2O2 in WRL-68 cell line were normalize in the highest group (200 MUg/ml) when compared with control and negative control (CCl4) group. After molecular docking analysis, it was observed that the compound alpha amyrin present in the leaf extract of C. bonplandianus has better potentiality to protect hepatocellular damages than the standard drug Silymarin. The present study provided supportive evidence that CBL extract possesses potent hepatoprotective capacity by ameliorating haloalkane induced liver injury in the murine model. The antioxidant and anti-inflammatory activities also affirm the same. The synergistic effects of the phytochemicals present in CBL are to be credited for all the hepatoprotective activity claimed above. PMID- 29709011 TI - Muscle wasting in osteoarthritis model induced by anterior cruciate ligament transection. AB - This study aimed to investigate the molecular pathways involved in muscle wasting in an animal model of osteoarthritis (OA) induced by anterior cruciate ligament transection (ACLT) in rats. Reduction of protein syntheses, increased proteolysis and impaired muscle regeneration are important pathways related to muscle wasting, and myogenin, MyoD, myostatin and MuRF-1 are some of their markers. Female Wistar rats were allocated into two groups: OA (submitted to the ACLT) and SHAM (submitted to surgery without ACLT). Nociception, spontaneous exploratory locomotion and body weight of animals were evaluated weekly. Twelve weeks after the disease induction, animals were euthanized, and the right knee joints were collected. Gastrocnemius muscle of the right hind paw were dissected and weighed. Gastrocnemius was used for evaluation of muscle atrophy and expression of IL 1beta, TNF-alpha, Pax7, myogenin, MyoD, myostatin and MuRF-1. Histopathology of the knee confirmed the development of the disease in animals of OA group. Gastrocnemius of OA animals showed a reduction of about 10% in area and an increased IL-1beta expression compared to animals of SHAM group. Expression of myostatin was increased in OA group, while myogenin expression was decreased. TNF alpha, Pax7, MuRF-1 and MyoD expression was similar in both OA and SHAM groups. Nociception was significantly elevated in OA animals in the last two weeks of experimental period. Spontaneous exploratory locomotion, body weight and weight of gastrocnemius showed no difference between OA and SHAM groups. Gastrocnemius atrophy in OA induced by ACLT involves elevated expression of IL-1beta within the muscle, as well as increased expression of myostatin and decreased expression of myogenin. Therefore, muscle wasting may be linked to impaired muscle regeneration. PMID- 29709012 TI - Discontinuation risk comparison among 'real-world' newly anticoagulated atrial fibrillation patients: Apixaban, warfarin, dabigatran, or rivaroxaban. AB - Discontinuation of oral anticoagulants may expose non-valvular atrial fibrillation (NVAF) patients to an increased risk of stroke. This study describes the real-world discontinuation rates and compared the risk of drug discontinuation among NVAF patients initiating apixaban, warfarin, dabigatran, or rivaroxaban. This retrospective cohort study evaluated newly-anticoagulated NVAF patients in the MarketScan(r) data population from 01/01/2012 through 12/31/2014. Discontinuation was defined as a lack of subsequent prescription of the index drug within 30 days after the last supply day of the last prescription. A Cox model was used to estimate the hazard ratio (HR) of discontinuation, adjusted for age, sex, and comorbidities. Among 45,361 eligible NVAF patients, 15,461 (34.1%) initiated warfarin; 7,438 (16.4%) apixaban; 4,661 (10.3%) dabigatran; and 17,801 (39.2%) initiated rivaroxaban treatment. Compared to warfarin, patients who initiated dabigatran (adjusted HR [aHR]: 0.84, 95% confidence interval [CI]: 0.80 0.87, P<0.001), rivaroxaban (aHR: 0.70, 95% CI: 0.68-0.73, P<0.001), or apixaban (aHR: 0.57, 95% CI: 0.55-0.60, P<0.001) were 16%, 30%, and 43% less likely to discontinue treatment, respectively. When compared to apixaban, patients who initiated dabigatran (aHR: 1.46, 95% CI: 1.38-1.54, P<0.001) or rivaroxaban (aHR: 1.23, 95% CI: 1.17-1.28, P<0.001) were more likely to discontinue treatment. Among newly-anticoagulated NVAF patients in the real-world setting, initiation on rivaroxaban, dabigatran, or apixaban was associated with a significantly lower risk of discontinuation compared to warfarin. When compared to apixaban, patients who initiated treatment with warfarin, dabigatran, or rivaroxaban were more likely to discontinue treatment. PMID- 29709013 TI - Prevalence of and risk factors for low bone mineral density in Spanish treated HIV-infected patients. AB - OBJECTIVES: Several studies have involved antiretroviral therapy in the pathogenesis of low bone mineral density (BMD), while others have not confirmed this association. In this study we analyze the impact of HIV status, traditional risk factors and antiretroviral therapy in BMD in an HIV-infected population living in Madrid. MATERIAL AND METHODS: We performed a cross-sectional analysis of 107 individuals infected with HIV and exposed to antiretroviral treatment to estimate the prevalence of decreased BMD. Bone mineral density of lumbar spine and femoral neck was measured by dual-energy X-ray absorptiometry. In a multivariate analysis variables related with HIV status, antiretroviral drugs and traditional risk factors were included. RESULTS: Low BMD was diagnosed in 63 participants (58.9%), including osteoporosis in 11 (10%). At least one cause of osteoporosis was identified in 43 patients (40%), with a deficiency of vitamin D in 86 (89%) and secondary hyperparathyroidism in 30 (28%). In multivariate analysis, increasing age, a treatment based on boosted PI and tenofovir DF, and previous exposure to tenofovir were identified as independent risk factors for a decreased BMD in both lumbar spine and femoral neck. CONCLUSIONS: We have confirmed a high prevalence of reduced BMD, which is favoured by ritonavir boosted PI and TDF. Bone safety should continue to be evaluated in clinical trials and cohort studies in order to demonstrate that the new drugs offer additional advantages regarding the impact on BMD. PMID- 29709014 TI - Correction: Serologic and behavioral risk survey of workers with wildlife contact in China. AB - [This corrects the article DOI: 10.1371/journal.pone.0194647.]. PMID- 29709015 TI - Efficacy of fluorides and CPP-ACP vs fluorides monotherapy on early caries lesions: A systematic review and meta-analysis. AB - The study aimed to evaluate the efficacy of the combination of CPP-ACP and fluorides compared with fluorides monotherapy on patients with early caries lesions. The Medline, Embase and Cochrane databases up to August 2017 were scanned, with no restrictions. Studies satisfied the guideline of randomised controlled trials (RCTs), the patients with early caries lesions and data considering the efficacy of fluorides and CPP-ACP versus fluorides alone were selected. There was no language restriction during the literature search process, however, only papers in English or Chinese were included during the selection process. Outcome variables include laser fluorescence, quantitative light-induced fluorescence, lesion area and visual inspection scores. Mean differences were calculated during the data extraction process. Ten studies including 559 patients were selected in the meta-analysis. Fluorides combined with CPP-ACP achieved the same efficacy for early caries lesions on smooth surfaces compared with fluorides monotherapy (mean difference: -13.90, 95% confidence interval: [-39.25, 11.46], P = 0.28), and the combination treatment showed significantly better efficacy than fluorides monotherapy for occlusal early caries lesions (mean difference: -21.02, 95% confidence interval: [-27.94, -14.10], P<0.01). However, further well designed studies are still needed. PMID- 29709016 TI - EBV persistence without its EBNA3A and 3C oncogenes in vivo. AB - The oncogenic Epstein Barr virus (EBV) infects the majority of the human population and usually persists within its host for life without symptoms. The EBV oncoproteins nuclear antigen 3A (EBNA3A) and 3C (EBNA3C) are required for B cell transformation in vitro and are expressed in EBV associated immunoblastic lymphomas in vivo. In order to address the necessity of EBNA3A and EBNA3C for persistent EBV infection in vivo, we infected NOD-scid gammacnull mice with reconstituted human immune system components (huNSG mice) with recombinant EBV mutants devoid of EBNA3A or EBNA3C expression. These EBV mutants established latent infection in secondary lymphoid organs of infected huNSG mice for at least 3 months, but did not cause tumor formation. Low level viral persistence in the absence of EBNA3A or EBNA3C seemed to be supported primarily by proliferation with the expression of early latent EBV gene products transitioning into absent viral protein expression without elevated lytic replication. In vitro, EBNA3A and EBNA3C deficient EBV infected B cells could be rescued from apoptosis through CD40 stimulation, mimicking T cell help in secondary lymphoid tissues. Thus, even in the absence of the oncogenes EBNA3A and 3C, EBV can access a latent gene expression pattern that is reminiscent of EBV persistence in healthy virus carriers without prior expression of its whole growth transforming program. PMID- 29709017 TI - Structural and functional dissection of differentially expressed tomato WRKY transcripts in host defense response against the vascular wilt pathogen (Fusarium oxysporum f. sp. lycopersici). AB - The WRKY transcription factors have indispensable role in plant growth, development and defense responses. The differential expression of WRKY genes following the stress conditions has been well demonstrated. We investigated the temporal and tissue-specific (root and leaf tissues) differential expression of plant defense-related WRKY genes, following the infection of Fusarium oxysporum f. sp. lycopersici (Fol) in tomato. The genome-wide computational analysis revealed that during the Fol infection in tomato, 16 different members of WRKY gene superfamily were found to be involved, of which only three WRKYs (SolyWRKY4, SolyWRKY33, and SolyWRKY37) were shown to have clear-cut differential gene expression. The quantitative real time PCR (qRT-PCR) studies revealed different gene expression profile changes in tomato root and leaf tissues. In root tissues, infected with Fol, an increased expression for SolyWRKY33 (2.76 fold) followed by SolyWRKY37 (1.93 fold) gene was found at 24 hrs which further increased at 48 hrs (5.0 fold). In contrast, the leaf tissues, the expression was more pronounced at an earlier stage of infection (24 hrs). However, in both cases, we found repression of SolyWRKY4 gene, which further decreased at an increased time interval. The biochemical defense programming against Fol pathogenesis was characterized by the highest accumulation of H2O2 (at 48 hrs) and enhanced lignification. The functional diversity across the characterized WRKYs was explored through motif scanning using MEME suite, and the WRKYs specific gene regulation was assessed through the DNA protein docking studies The functional WRKY domain modeled had beta sheets like topology with coil and turns. The DNA protein interaction results revealed the importance of core residues (Tyr, Arg, and Lys) in a feasible WRKY-W-box DNA interaction. The protein interaction network analysis revealed that the SolyWRKY33 could interact with other proteins, such as mitogen-activated protein kinase 5 (MAPK), sigma factor binding protein1 (SIB1) and with other WRKY members including WRKY70, WRKY1, and WRKY40, to respond various biotic and abiotic stresses. The STRING results were further validated through Predicted Tomato Interactome Resource (PTIR) database. The CELLO2GO web server revealed the functional gene ontology annotation and protein subcellular localization, which predicted that SolyWRKY33 is involved in amelioration of biological stress (39.3%) and other metabolic processes (39.3%). The protein (SolyWRKY33) most probably located inside the nucleus (91.3%) with having transcription factor binding activity. We conclude that the defense response following the Fol challenge was accompanied by differential expression of the SolyWRKY4(?), SolyWRKY33(?) and SolyWRKY37(?) transcripts. The biochemical changes are occupied by elicitation of H2O2 generation and accumulation and enhanced lignified tissues. PMID- 29709018 TI - Phospholipase A2 activity during the replication cycle of the flavivirus West Nile virus. AB - Positive-sense RNA virus intracellular replication is intimately associated with membrane platforms that are derived from host organelles and comprised of distinct lipid composition. For flaviviruses, such as West Nile virus strain Kunjin virus (WNVKUN) we have observed that these membrane platforms are derived from the endoplasmic reticulum and are rich in (at least) cholesterol. To extend these studies and identify the cellular lipids critical for WNVKUN replication we utilized a whole cell lipidomics approach and revealed an elevation in phospholipase A2 (PLA2) activity to produce lyso-phosphatidylcholine (lyso PChol). We observed that the PLA2 enzyme family is activated in WNVKUN-infected cells and the generated lyso-PChol lipid moieties are sequestered to the subcellular sites of viral replication. The requirement for lyso-PChol was confirmed using chemical inhibition of PLA2, where WNVKUN replication and production of infectious virus was duly affected in the presence of the inhibitors. Importantly, we could rescue chemical-induced inhibition with the exogenous addition of lyso-PChol species. Additionally, electron microscopy results indicate that lyso-PChol appears to contribute to the formation of the WNVKUN membranous replication complex (RC); particularly affecting the morphology and membrane curvature of vesicles comprising the RC. These results extend our current understanding of how flaviviruses manipulate lipid homeostasis to favour their own intracellular replication. PMID- 29709019 TI - The SecA2 pathway of Mycobacterium tuberculosis exports effectors that work in concert to arrest phagosome and autophagosome maturation. AB - To subvert host defenses, Mycobacterium tuberculosis (Mtb) avoids being delivered to degradative phagolysosomes in macrophages by arresting the normal host process of phagosome maturation. Phagosome maturation arrest by Mtb involves multiple effectors and much remains unknown about this important aspect of Mtb pathogenesis. The SecA2 dependent protein export system is required for phagosome maturation arrest and consequently growth of Mtb in macrophages. To better understand the role of the SecA2 pathway in phagosome maturation arrest, we identified two effectors exported by SecA2 that contribute to this process: the phosphatase SapM and the kinase PknG. Then, utilizing the secA2 mutant of Mtb as a platform to study effector functions, we identified specific steps in phagosome maturation inhibited by SapM and/or PknG. By identifying a histidine residue that is essential for SapM phosphatase activity, we confirmed for the first time that the phosphatase activity of SapM is required for its effects on phagosome maturation in macrophages. We further demonstrated that SecA2 export of SapM and PknG contributes to the ability of Mtb to replicate in macrophages. Finally, we extended our understanding of the SecA2 pathway, SapM, and PknG by revealing that their contribution goes beyond preventing Mtb delivery to mature phagolysosomes and includes inhibiting Mtb delivery to autophagolysosomes. Together, our results revealed SapM and PknG to be two effectors exported by the SecA2 pathway of Mtb with distinct as well as cumulative effects on phagosome and autophagosome maturation. Our results further reveal that Mtb must have additional mechanisms of limiting acidification of the phagosome, beyond inhibiting recruitment of the V-ATPase proton pump to the phagosome, and they indicate differences between effects of Mtb on phagosome and autophagosome maturation. PMID- 29709020 TI - Rapid identification of tomato Sw-5 resistance-breaking isolates of Tomato spotted wilt virus using high resolution melting and TaqMan SNP Genotyping assays as allelic discrimination techniques. AB - In tomato, resistance to Tomato spotted wilt virus (TSWV) is conferred by the dominant gene, designated Sw-5. Virulent Sw-5 resistance breaking (SRB) mutants of TSWV have been reported on Sw-5 tomato cultivars. Two different PCR-based allelic discrimination techniques, namely Custom TaqManTM SNP Genotyping and high resolution melting (HRM) assays, were developed and compared for their ability to distinguish between avirulent (Sw-5 non-infecting, SNI) and SRB biotypes. TaqMan assays proved to be more sensitive (threshold of detection in a range of 50-70 TSWV RNA copies) and more reliable than HRM, assigning 25 TSWV isolates to their correct genotype with an accuracy of 100%. Moreover, the TaqMan SNP assays were further improved developing a rapid and simple protocol that included crude leaf extraction for RNA template preparations. On the other hand, HRM assays showed higher levels of sensitivity than TaqMan when used to co-detect both biotypes in different artificial mixtures. These diagnostic assays contributed to gain preliminary information on the epidemiology of TSWV isolates in open field conditions. In fact, the presented data suggest that SRB isolates are present as stable populations established year round, persisting on both winter (globe artichoke) and summer (tomato) crops, in the same cultivated areas of Southern Italy. PMID- 29709022 TI - Correction: Prescribing patterns and associated factors of antibiotic prescription in primary health care facilities of Kumbo East and Kumbo West Health Districts, North West Cameroon. AB - [This corrects the article DOI: 10.1371/journal.pone.0193353.]. PMID- 29709021 TI - Validity of a point-of-care nerve conduction device for polyneuropathy identification in older adults with diabetes: Results from the Canadian Study of Longevity in Type 1 Diabetes. AB - OBJECTIVE: Point-of-care nerve conduction devices (POCD) have been studied in younger patients and may facilitate screening for polyneuropathy in non specialized clinical settings. However, performance may be impaired with advanced age owing to age-related changes in nerve conduction. We aimed to evaluate the validity of a POCD as a proxy for standard nerve conduction studies (NCS) in older adults with type 1 diabetes (T1D). METHODS: Sural nerve amplitude potential (AMP) and sural nerve conduction velocity (CV) was measured in 68 participants with >= 50 years T1D duration and 71 controls (from age/sex-matched subgroups) using POCD and NCS protocols. Agreement was determined by the Bland-Altman method, and validity was determined by receiver operating characteristic curves. RESULTS: T1D were 53% female, aged 66+/-8yr and had diabetes duration 54yr[52,58]. Controls were 56%(p = 0.69) female and aged 65+/-8yr(p = 0.36). Mean AMPPOCD and CVPOCD for the 139 participants was 7.4+/-5.8MUV and 45.7+/-11.2m/s and mean AMPNCS and CVNCS was 7.2+/-6.1MUV and 43.3+/-8.3m/s. Mean difference of AMPPOCD-AMPNCS was 0.3+/-3.8MUV and was 2.3+/-8.5m/s for CVPOCD-CVNCS. A AMPPOCD of <=6MUV had 80% sensitivity and 80% specificity for identifying abnormal AMPNCS, while a CVPOCD of <=44m/s had 81% sensitivity and 82% specificity to identify abnormal CVNCS. Abnormality in AMPPOCD or CVPOCD was associated with 87% sensitivity, while abnormality in both measures was associated with 97% specificity for polyneuropathy identification. CONCLUSIONS: The POCD has strong agreement and diagnostic accuracy for identification of polyneuropathy in a high risk subgroup and thus may represent a sufficiently accurate and rapid test for routinely detecting those with electrophysiological dysfunction. PMID- 29709024 TI - Uncovering inequality through multifractality of land prices: 1912 and contemporary Kyoto. AB - Multifractal analysis offers a number of advantages to measure spatial economic segregation and inequality, as it is free of categories and boundaries definition problems and is insensitive to some shape-preserving changes in the variable distribution. We use two datasets describing Kyoto land prices in 1912 and 2012 and derive city models from this data to show that multifractal analysis is suitable to describe the heterogeneity of land prices. We found in particular a sharp decrease in multifractality, characteristic of homogenisation, between older Kyoto and present Kyoto, and similarities both between present Kyoto and present London, and between Kyoto and Manhattan as they were a century ago. In addition, we enlighten the preponderance of spatial distribution over variable distribution in shaping the multifractal spectrum. The results were tested against the classical segregation and inequality indicators, and found to offer an improvement over those. PMID- 29709025 TI - Correction: Acute Infectious Gastroenteritis Potentiates a Crohn's Disease Pathobiont to Fuel Ongoing Inflammation in the Post-Infectious Period. AB - [This corrects the article DOI: 10.1371/journal.ppat.1005907.]. PMID- 29709023 TI - Relationship between brain plasticity, learning and foraging performance in honey bees. AB - Brain structure and learning capacities both vary with experience, but the mechanistic link between them is unclear. Here, we investigated whether experience-dependent variability in learning performance can be explained by neuroplasticity in foraging honey bees. The mushroom bodies (MBs) are a brain center necessary for ambiguous olfactory learning tasks such as reversal learning. Using radio frequency identification technology, we assessed the effects of natural variation in foraging activity, and the age when first foraging, on both performance in reversal learning and on synaptic connectivity in the MBs. We found that reversal learning performance improved at foraging onset and could decline with greater foraging experience. If bees started foraging before the normal age, as a result of a stress applied to the colony, the decline in learning performance with foraging experience was more severe. Analyses of brain structure in the same bees showed that the total number of synaptic boutons at the MB input decreased when bees started foraging, and then increased with greater foraging intensity. At foraging onset MB structure is therefore optimized for bees to update learned information, but optimization of MB connectivity deteriorates with foraging effort. In a computational model of the MBs sparser coding of information at the MB input improved reversal learning performance. We propose, therefore, a plausible mechanistic relationship between experience, neuroplasticity, and cognitive performance in a natural and ecological context. PMID- 29709027 TI - A comprehensive phylogeny of auxin homeostasis genes involved in adventitious root formation in carnation stem cuttings. AB - Understanding the functional basis of auxin homeostasis requires knowledge about auxin biosynthesis, auxin transport and auxin catabolism genes, which is not always directly available despite the recent whole-genome sequencing of many plant species. Through sequence homology searches and phylogenetic analyses on a selection of 11 plant species with high-quality genome annotation, we identified the putative gene homologs involved in auxin biosynthesis, auxin catabolism and auxin transport pathways in carnation (Dianthus caryophyllus L.). To deepen our knowledge of the regulatory events underlying auxin-mediated adventitious root formation in carnation stem cuttings, we used RNA-sequencing data to confirm the expression profiles of some auxin homeostasis genes during the rooting of two carnation cultivars with different rooting behaviors. We also confirmed the presence of several auxin-related metabolites in the stem cutting tissues. Our findings offer a comprehensive overview of auxin homeostasis genes in carnation and provide a solid foundation for further experiments investigating the role of auxin homeostasis in the regulation of adventitious root formation in carnation. PMID- 29709026 TI - Immunophenotypic characterization of CSF B cells in virus-associated neuroinflammatory diseases. AB - Intrathecal antibody synthesis is a well-documented phenomenon in infectious neurological diseases as well as in demyelinating diseases, but little is known about the role of B cells in the central nervous systems. We examined B cell and T cell immunophenotypes in CSF of patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) compared to healthy normal donors and subjects with the other chronic virus infection and/or neuroinflammatory diseases including HIV infection, multiple sclerosis (MS) and progressive multifocal leukoencephalopathy. Antibody secreting B cells (ASCs) were elevated in HAM/TSP patients, which was significantly correlated with intrathecal HTLV-1-specific antibody responses. High frequency of ASCs was also detected in patients with relapsing-remitting multiple sclerosis (RRMS). While RRMS patients showed significant correlations between ASCs and memory follicular helper CD4+ T cells, CD4+CD25+ T cells were elevated in HAM/TSP patients, which were significantly correlated with ASCs and HTLV-1 proviral load. These results highlight the importance of the B cell compartment and the associated inflammatory milieu in HAM/TSP patients where virus-specific antibody production may be required to control viral persistence and/or may be associated with disease development. PMID- 29709029 TI - Correction: Nanoscopic X-ray fluorescence imaging and quantification of intracellular key-elements in cryofrozen Friedreich's ataxia fibroblasts. AB - [This corrects the article DOI: 10.1371/journal.pone.0190495.]. PMID- 29709028 TI - Mapping the characteristics of network meta-analyses on drug therapy: A systematic review. AB - BACKGROUND: Network meta-analysis (NMA) is a new tool developed to overcome some limitations of pairwise meta-analyses. NMAs provide evidence on more than two comparators simultaneously. This study aimed to map the characteristics of the published NMAs on drug therapy comparisons. METHODS: A systematic review of NMAs comparing pharmacological interventions was performed. Searches in Medline (PubMed) and Scopus along with manual searches were conducted. The main characteristics of NMAs were systematically collected: publication metadata, criteria for drug inclusion, statistical methods used, and elements reported. A methodological quality score with 25 key elements was created and applied to the included NMAs. To identify potential trends, the median of the publication year distribution was used as a cut-off. RESULTS: The study identified 365 NMAs published from 2003 to 2016 in more than 30 countries. Randomised controlled trials were the primary source of data, with only 5% including observational studies, and 230 NMAs used a placebo as a comparator. Less than 15% of NMAs were registered in PROSPERO or a similar system. One third of studies followed PRISMA and less than 9% Cochrane recommendations. Around 30% presented full-search strategies of the systematic review, and 146 NMAs stated the selection criteria for drug inclusion. Over 75% of NMAs presented network plots, but only half described their geometry. Statistical parameters (model fit, inconsistency, convergence) were properly reported by one third of NMAs. Although 216 studies exhibited supplemental material, no data set of primary studies was available. The methodological quality score (mean 13.9; SD 3.8) presented a slightly positive trend over the years. CONCLUSION: The map of the published NMAs emphasises the potential of this tool to gather evidence in healthcare, but it also identified some weaknesses, especially in the report, which limits its transparency and reproducibility. PMID- 29709030 TI - Initial evaluation of thyroid dysfunction - Are simultaneous TSH and fT4 tests necessary? AB - OBJECTIVE: Guidelines for thyroid function evaluation recommend testing TSH first, then assessing fT4 only if TSH is out of the reference range (two-step), but many clinicians initially request both TSH and fT4 (one-step). Given limitations of previous studies, we aimed to compare the two-step with the one step approach in an unselected community-dwelling study population, and develop a prediction score based on clinical parameters that could identify at-risk patients for thyroid dysfunction. DESIGN: Cross-sectional analysis of the population-based Busselton Health Study. METHODS: We compared the two-step with the one-step approach, focusing on cases that would be missed by the two-step approach, i.e. those with normal TSH, but out-of-range fT4. We used likelihood ratio tests to identify demographic and clinical parameters associated with thyroid dysfunction and developed a clinical prediction score by using a beta coefficient based scoring method. RESULTS: Following the two-step approach, 93.0% of all 4471 participants had normal TSH and would not need further testing. The two-step approach would have missed 3.8% of all participants (169 of 4471) with a normal TSH, but a fT4 outside the reference range. In 85% (144 of 169) of these cases, fT4 fell within 2 pmol/l of fT4 reference range limits, consistent with healthy outliers. The clinical prediction score that performed best excluded only 22.5% of participants from TSH testing. CONCLUSION: The two-step approach may avoid measuring fT4 in as many as 93% of individuals with a very small risk of missing thyroid dysfunction. Our findings do not support the simultaneous initial measurement of both TSH and fT4. PMID- 29709031 TI - Gadoxetic acid-enhanced magnetic resonance imaging to predict paritaprevir induced hyperbilirubinemia during treatment of hepatitis C. AB - BACKGROUND: Paritaprevir inhibits organic anion-transporting polypeptide (OATP)1B1 and OATP1B3, which transport bilirubin. Hyperbilirubinemia is an adverse event reported during hepatitis C treatment. Gadoxetic acid is also transported by OATP1B1/1B3. We evaluated whether the enhancement effect in gadoxetic acid-enhanced magnetic resonance (MR) imaging could predict the plasma concentration of paritaprevir and might anticipate the development of hyperbilirubinemia. METHODS: This prospective study evaluated 27 patients with hepatitis C who underwent gadoxetic acid-enhanced MR imaging prior to treatment with ombitasvir, paritaprevir, and ritonavir. The contrast enhancement index (CEI), a measure of liver enhancement during the hepatobiliary phase, was assessed. Plasma trough concentrations, and concentrations at 2, 4, and 6 h after dosing were determined 7 d after the start of treatment. RESULTS: Seven patients (26%) developed hyperbilirubinemia (>= 1.6 mg/dl). Paritaprevir trough concentration (Ctrough) was significantly higher in patients with hyperbilirubinemia than in those without (p = 0.022). We found an inverse relationship between CEI and Ctrough (r = 0.612, p = 0.001), while there was not a significantly weak inverse relationship between AUC0-6 h and CEI (r = -0.338, p = 0.085). The partial correlation coefficient between CEI and Ctrough was -0.425 (p = 0.034), while excluding the effects of albumin and the FIB-4 index. Receiver operating characteristic (ROC) curve analysis showed that the CEI was relatively accurate in predicting hyperbilirubinemia, with area under the ROC of 0.882. Multivariate analysis showed that the CEI < 1.61 was the only independent predictor related to the development of hyperbilirubinemia, with an odds ratio of 9.08 (95% confidence interval 1.05-78.86, p = 0.046). CONCLUSIONS: Hepatic enhancement with gadoxetic acid was independently related to paritaprevir concentration and was an independent pretreatment factor in predicting hyperbilirubinemia. Gadoxetic acid-enhanced MR imaging can therefore be useful in determining the risk of paritaprevir-induced hyperbilirubinemia. PMID- 29709032 TI - Correction: Optimization of prophylaxis for hemophilia A. AB - [This corrects the article DOI: 10.1371/journal.pone.0192783.]. PMID- 29709034 TI - Correction: Genetic factors affecting EBV copy number in lymphoblastoid cell lines derived from the 1000 Genome Project samples. AB - [This corrects the article DOI: 10.1371/journal.pone.0179446.]. PMID- 29709033 TI - Viral targeting of TFIIB impairs de novo polymerase II recruitment and affects antiviral immunity. AB - Viruses have evolved a plethora of mechanisms to target host antiviral responses. Here, we propose a yet uncharacterized mechanism of immune regulation by the orthomyxovirus Thogoto virus (THOV) ML protein through engaging general transcription factor TFIIB. ML generates a TFIIB depleted nuclear environment by re-localizing it into the cytoplasm. Although a broad effect on gene expression would be anticipated, ML expression, delivery of an ML-derived functional domain or experimental depletion of TFIIB only leads to altered expression of a limited number of genes. Our data indicate that TFIIB is critically important for the de novo recruitment of Pol II to promoter start sites and that TFIIB may not be required for regulated gene expression from paused promoters. Since many immune genes require de novo recruitment of Pol II, targeting of TFIIB by THOV represents a neat mechanism to affect immune responses while keeping other cellular transcriptional activities intact. Thus, interference with TFIIB activity may be a favourable site for therapeutic intervention to control undesirable inflammation. PMID- 29709035 TI - Does the use of outdoor fitness equipment by older adults qualify as moderate to vigorous physical activity? AB - Despite the rapid worldwide expansion of parks with outdoor fitness equipment (OFE), no objective data regarding the intensity of activity associated with using OFE are available. Hence, this study quantified the energy expenditure and intensity of physical activity by examining four outdoor fitness devices widely used by older adults and provides objective evidence-based intensity references for the Compendium of Physical Activities. Sixteen older adults (mean age: 70.7 +/- 5.6 yr) equipped with a portable metabolic system for measuring energy expenditure and activity intensity completed tasks while walking or using four types of OFE. Descriptive statistics and repeated-measures ANOVA with the Bonferroni post hoc test were employed. The energy expenditure and activity intensity for using an air walker at tempos of 80, 100, and 120 bpm were 50.78 +/ 14.76 (2.81 +/- 0.85), 59.62 +/- 14.23 (3.26 +/- 0.82), and 65.62 +/- 18.27 (3.55 +/- 1.02) cal/kg/min (METs), respectively. The induced energy and intensity output values for a ski machine were 54.00 +/- 14.31 (3.02 +/- 0.87), 68.87 +/- 22.74 (3.82 +/- 1.35), and 74.55 +/- 23.39 (4.05 +/- 1.35) cal/kg/min (METs), at 80, 100, and 120 bpm, respectively. The energy output for a waist twister at 60 bpm was 38.43 +/- 20.16 cal/kg/min (2.05 +/- 1.15 METs), and that for a double arm stretch at 80 bpm was 31.05 +/- 12.58 cal/kg/min (1.63 +/- 0.70 METs). These findings indicate that activity on the ski machine and air walker could be considered to have moderate intensity, whereas the intensity of activity on the waist twister and double arm stretch was significantly lower than that for walking at either 3.2 km/h or 4 km/h and could be considered only light intensity. The MET values for the OFE were lower than those for similar indoor fitness equipment. The results of this study provide crucial implications for public health practices concerning the development of active living environments. PMID- 29709036 TI - Insectivorous bat reproduction and human cave visitation in Cambodia: A perfect conservation storm? AB - Cave roosting bats represent an important component of Southeast Asian bat diversity and are vulnerable to human disturbance during critical reproductive periods (pregnancy, lactation and weaning). Because dramatic growth of cave tourism in recent decades has raised concerns about impacts on cave bats in the region, we assessed the reproductive phenology of two insectivorous species (Hipposideros larvatus sensu lato and Taphozous melanopogon) at three caves in Cambodia for 23 months in 2014-2016 and evaluated human visitation to these sites between 2007 and 2014. Despite the differing foraging strategies employed by the two taxa, the temporal consistency observed in proportions of pregnant, lactating and juvenile bats indicates that their major birth peaks coincide with the time of greatest cave visitation annually, particularly for domestic visitors and namely during the Cambodian new year in April. They also reflect rainfall patterns and correspond with the reproductive phenology of insectivorous cave bats in Vietnam. These findings were predictable because 1) insect biomass and thus food availability for insectivorous bats are optimal for ensuring survival of young following this period, and 2) the Khmer new year is the most significant month for religious ceremonies and thus domestic cave visitation nationally, due to the abundance of Buddhist shrines and temples in Cambodian caves. While the impact of visitor disturbance on bat population recruitment cannot be empirically assessed due to lack of historical data, it is nonetheless likely to have been considerable and raises a conservation concern. Further, because growing evidence suggests that insectivorous cave bats exhibit reproductive synchrony across continental Southeast Asia where countless cave shrines are heavily frequented during April in Theravada Buddhist countries (e.g., Myanmar, Thailand, Cambodia and Laos), our results may have wider applicability in the region. We consequently advocate for increased emphasis on sustainable cave management practices in Cambodia and further investigations to determine whether our findings present a broader concern for cave bat conservation in Southeast Asia. PMID- 29709037 TI - Correction: Histone demethylase LSD1 restricts influenza A virus infection by erasing IFITM3-K88 monomethylation. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006773.]. PMID- 29709038 TI - HCMV triggers frequent and persistent UL40-specific unconventional HLA-E restricted CD8 T-cell responses with potential autologous and allogeneic peptide recognition. AB - Immune response against human cytomegalovirus (HCMV) includes a set of persistent cytotoxic NK and CD8 T cells devoted to eliminate infected cells and to prevent reactivation. CD8 T cells against HCMV antigens (pp65, IE1) presented by HLA class-I molecules are well characterized and they associate with efficient virus control. HLA-E-restricted CD8 T cells targeting HCMV UL40 signal peptides (HLA EUL40) have recently emerged as a non-conventional T-cell response also observed in some hosts. The occurrence, specificity and features of HLA-EUL40 CD8 T-cell responses remain mostly unknown. Here, we detected and quantified these responses in blood samples from healthy blood donors (n = 25) and kidney transplant recipients (n = 121) and we investigated the biological determinants involved in their occurrence. Longitudinal and phenotype ex vivo analyses were performed in comparison to HLA-A*02/pp65-specific CD8 T cells. Using a set of 11 HLA-E/UL40 peptide tetramers we demonstrated the presence of HLA-EUL40 CD8 alphabetaT cells in up to 32% of seropositive HCMV+ hosts that may represent up to 38% of total circulating CD8 T-cells at a time point suggesting a strong expansion post infection. Host's HLA-A*02 allele, HLA-E *01:01/*01:03 genotype and sequence of the UL40 peptide from the infecting strain are major factors affecting the incidence of HLA-EUL40 CD8 T cells. These cells are effector memory CD8 (CD45RAhighROlow, CCR7-, CD27-, CD28-) characterized by a low level of PD-1 expression. HLA-EUL40 responses appear early post-infection and display a broad, unbiased, Vbeta repertoire. Although induced in HCMV strain-dependent, UL4015-23 specific manner, HLA-EUL40 CD8 T cells are reactive toward a broader set of nonapeptides varying in 1-3 residues including most HLA-I signal peptides. Thus, HCMV induces strong and life-long lasting HLA-EUL40 CD8 T cells with potential allogeneic or/and autologous reactivity that take place selectively in at least a third of infections according to virus strain and host HLA concordance. PMID- 29709040 TI - Pediatric Frontalis Suspension With Braided Polyester: A Comparison of Two Techniques. AB - PURPOSE: To demonstrate the benefits of using braided polyester in the management of severe or recurrent ptosis in children and young adults and to compare the efficacy of two surgical techniques. METHODS: Retrospective, non-randomized record review of 30 patients (43 eyelid procedures) affected by congenital or acquired severe ptosis who underwent frontalis suspension with braided polyester from 2008 to 2016. Two surgical techniques were compared: the base-down triangle and the Fox pentagon, both of which were performed using a closed technique. Functional success was defined as clearing of the visual axis. Complications and results were examined. RESULTS: Functional success was obtained in 39 eyes of 43 procedures. Marginal reflex distance increased an average of 2.51 mm with the base-down triangle technique and 1.70 mm with the Fox pentagon technique (P = .05). The vertical palpebral fissure height increased an average of 4.60 mm with the base-down triangle technique and 2.45 mm with the Fox pentagon technique (P < .001). Mean follow-up duration was 38.6 months. Complications included untied suture (n = 2), suture dehiscence (n = 1), cellulitis (n = 2), and granuloma (n = 1). CONCLUSIONS: Braided polyester was found to be a safe, effective, easy-to handle, and low-cost sling material for frontalis suspension and should be considered for clinical use, especially in developing countries where the cost and availability of other materials represents a significant barrier to treatment. In the authors' experience, the base-down triangle technique appeared superior to the Fox pentagon technique. [J Pediatr Ophthalmol Strabismus. 2018;55(4):229-233.]. PMID- 29709041 TI - Infantile Exotropia and Developmental Delay. AB - PURPOSE: To evaluate a group of infants with this disorder to determine the long term outcome of surgery and to assess the need for neurologic evaluations. METHODS: This interventional case series reviewed the records of infants who underwent surgery for the treatment of exotropia with onset during the first year of life. The preoperative ophthalmic and systemic findings, treatment, and developmental and ophthalmic outcomes were reviewed. Surgery was considered successful if the horizontal deviation was less than 10 prism diopters (PD). Developmental assessments were obtained at each visit. RESULTS: Twenty-six patients presented between age 2 and 10 months with exotropia ranging from 20 to 95 PD. Ten (38%) patients had a developmental delay that was recognized at the first visit, 9 of whom had a systemic diagnosis at that time; the other patients remained developmentally normal during a mean follow-up of 7 years. Age at surgery ranged from 4 to 18 months. Surgery was successful in 10 (38%) of 26 patients after 1 surgery and in an additional 13 (50%) of 26 patients after a second surgery. CONCLUSIONS: In this study, the need for more than 1 surgery was higher in infantile exotropia when compared to other forms of childhood strabismus, but most children achieved good alignment with one or two surgeries. Developmental delay is common in patients with infantile exotropia, but this was usually recognized at the time of the initial evaluation. In the current patients, routine neurologic screening or imaging of these otherwise developmentally normal infants was not required. [J Pediatr Ophthalmol Strabismus. 2018;55(4):225-228.]. PMID- 29709039 TI - Varicella zoster virus productively infects human natural killer cells and manipulates phenotype. AB - Varicella zoster virus (VZV) is a ubiquitous human alphaherpesvirus, responsible for varicella upon primary infection and herpes zoster following reactivation from latency. To establish lifelong infection, VZV employs strategies to evade and manipulate the immune system to its advantage in disseminating virus. As innate lymphocytes, natural killer (NK) cells are part of the early immune response to infection, and have been implicated in controlling VZV infection in patients. Understanding of how VZV directly interacts with NK cells, however, has not been investigated in detail. In this study, we provide the first evidence that VZV is capable of infecting human NK cells from peripheral blood in vitro. VZV infection of NK cells is productive, supporting the full kinetic cascade of viral gene expression and producing new infectious virus which was transmitted to epithelial cells in culture. We determined by flow cytometry that NK cell infection with VZV was not only preferential for the mature CD56dim NK cell subset, but also drove acquisition of the terminally-differentiated maturity marker CD57. Interpretation of high dimensional flow cytometry data with tSNE analysis revealed that culture of NK cells with VZV also induced a potent loss of expression of the low-affinity IgG Fc receptor CD16 on the cell surface. Notably, VZV infection of NK cells upregulated surface expression of chemokine receptors associated with trafficking to the skin -a crucial site in VZV disease where highly infectious lesions develop. We demonstrate that VZV actively manipulates the NK cell phenotype through productive infection, and propose a potential role for NK cells in VZV pathogenesis. PMID- 29709042 TI - Immediate Postoperative Alignment Measurements as a Predictor of Alignment Stability in Fixed Suture Strabismus Surgery. AB - PURPOSE: To evaluate the use of immediate postoperative alignment measurements as a predictor of future alignment stability in fixed suture strabismus surgery. METHODS: Forty-seven patients were prospectively evaluated after undergoing horizontal or vertical rectus muscle surgery using a fixed suture technique. Alignment measurements were taken approximately 1 hour, 1 to 3 weeks, and 2 to 3 months postoperatively. A Spearman correlation coefficient was used to compare measurements from the immediate postoperative period to the 2- to 3-month postoperative period. Patients with dissociated strabismus, only oblique muscle surgery, or poor vision in one or both eyes precluding precise alternate cover test were excluded. RESULTS: Mean age of all patients was 46.7 years (range: 12 to 86 years). Twenty-two patients underwent surgery for exotropia: 19 for esotropia and 6 for hypertropia. Mean alignment for all surgeries was 2 prism diopters (PD) undercorrection in the immediate postoperative period, which was similar to the mean of 4.6 PD undercorrection at 2 to 3 months postoperatively. However, the Spearman correlation between the immediate postoperative and 2- to 3 month postoperative measurements was 0.18 for all surgeries, 0.03 for exotropia, 0.56 for esotropia, and 0.40 for hypertropia. The overall success rate, defined as 8 PD or less of horizontal deviation and 4 PD or less of vertical deviation, was 77% at 2 to 3 months postoperatively. CONCLUSIONS: The relationship between immediate postoperative alignment and future alignment stability in fixed suture strabismus surgery has not been previously defined. The current study demonstrated that although the surgical success rate was reasonably good, poor correlation occurred between the alignment immediately postoperatively and 2 to 3 months postoperatively. [J Pediatr Ophthalmol Strabismus. 2018;55(4):240-244.]. PMID- 29709043 TI - Pediatric Eales Disease: An Indian Tertiary Eye Center Experience. AB - PURPOSE: To report the clinical profiles, etiologies, treatment modalities, and outcomes for Eales disease in patients younger than age 16 years in India. METHODS: Retrospective review of medical records of patients with Eales disease who had a minimum 5-year follow-up period. RESULTS: A total of 25 eyes of 13 patients were included. Of these 13 patients, 12 (94%) had bilateral Eales disease and 11 (84.6%) were men. Mean patient age was 14.1 years (range: 11 to 16 years). Diminution of vision (36%) was the most common presenting complaint, followed by both diminutions of vision and floaters (32%). Sclerosed vessels were seen in all eyes, and 21 (84%) eyes had active periphlebitis at presentation. Neovascularization elsewhere was seen in 20 (80%) eyes and neovascularization of the optic disc was seen in 1 (4%) eye. Veno-venous shunts were found in 12 (48%) eyes, and 18 (72%) eyes had vitreous hemorrhage. All eyes received photocoagulation; 84.6% of patients received oral steroids, with 7.7% of patients treated with azathioprine and 38.4% treated with anti-tubercular therapy. Vitrectomy was performed in 36% of eyes for non-clearing vitreous hemorrhage and tractional retinal detachment. Vision improved in 7 (28%) eyes, was stable in 12 (48%) eyes, and worsened in 6 (24%) eyes. Recurrence of the disease more than five times during the 5-year follow-up period occurred in 20% of patients. CONCLUSIONS: Recurrent vasculitis and vitreous hemorrhage in children should raise the suspicion of pediatric Eales disease. [J Pediatr Ophthalmol Strabismus. 2018;55(4):270-274.]. PMID- 29709044 TI - Congenital Nasolacrimal Duct Obstruction and Its Association With the Mode of Birth. AB - PURPOSE: To assess the association of congenital nasolacrimal duct obstruction (CNLDO) with mode of birth (vaginal or cesarean). METHODS: This study was a prospective interventional case series of 200 consecutive cases of CNLDO presenting at a tertiary care center. Data collected include demographics, mode of delivery, elective or emergency cesarean section, primary or secondary cesarean sections, type of CNLDO (simple or complex), management, and outcomes. Statistical significance was set at a P value of less than .05. RESULTS: Of the 200 consecutive patients, 97 (48.5%) were vaginal deliveries and 103 (51.5%) were cesarean sections. Of the 103 cesarean section patients, 57 (55.3%) were primary cesarean sections and the remaining were secondary cesarean sections. Based on the type of CNLDO, 172 (86%) were simple CNLDO. In general, the current study did not find any significant association between the incidence of CNLDO and mode of delivery. Among the complex CNLDO cohort (n = 28), a significant association was found with cesarean section delivery (P = .016); however, no such association was noted when the patients were analyzed with regard to their age at presentation. CONCLUSIONS: The current study did not find an overall significant association between CNLDO and the mode of delivery; however, the subset of patients with complex CNLDO showed a significant association with cesarean section. [J Pediatr Ophthalmol Strabismus. 2018;55(4):266-268.]. PMID- 29709045 TI - Clinical Research on the Efficacy of Modified Surgery for Esotropia Fixus With High Myopia. AB - PURPOSE: To investigate the efficacy of a modified surgical procedure for esotropia fixus with high myopia. METHODS: Thirteen patients (15 eyes) with esotropia fixus and high myopia who underwent the Jensen procedure for superior and lateral rectus muscles at Southwest Hospital between February 2014 and December 2015 were retrospectively analyzed. Intraoperatively, the superior rectus and lateral rectus muscles were separated up to 12 to 14 mm posterior to their respective insertion. A medial rectus large recession or rectus tenotomy was performed based on the degree of fibrosis of the medial rectus muscle. Postoperative examinations were performed at 1 day, 2 weeks, 3 months, and 6 months. RESULTS: On the first postoperative day, 12 eyes (10 patients) were in the primary position (80.0%), 2 eyes (2 patients) exhibited 5 degrees to 10 degrees esotropia (13.3%), and 1 eye (1 patient) exhibited 15 degrees esotropia (6.7%). At the 2-week follow up, 1 eye (1 patient) was lost to follow-up, 9 eyes (7 patients) were in the primary position (64.3%), 3 eyes (3 patients) exhibited 10 degrees esotropia (21.4%), and 2 eyes (2 patients) exhibited 15 degrees to 20 degrees esotropia (14.3%). At the 3-month follow-up, the patient whose ocular alignment was 20 degrees esotropia at 2 weeks was found to have developed 30 degrees esotropia; no change was observed in the other patients. A remarkable improvement in ocular motility was observed in all patients. CONCLUSIONS: The Jensen procedure for the union of the superior rectus and lateral rectus muscles, using two pairs of sutures applied 12 to 14 mm posterior to their respective insertions, yielded favorable outcomes. [J Pediatr Ophthalmol Strabismus. 2018;55(4):219-224.]. PMID- 29709046 TI - Prevalence and predictors of readmissions among adults with cystic fibrosis in the United States. AB - INTRODUCTION: Patients with Cystic Fibrosis (CF) have increasing rates of hospitalization. We analyzed the burden and predictors of thirty-day readmission among patients with CF in the U.S. MATERIAL AND METHODS: Nationwide Readmission Database (NRD) 2013 was used to identify adults with CF who were hospitalized. These individuals were followed to determine the prevalence of readmission within thirty days of index discharge. Cox proportional hazard regression was used to identify independent predictors of readmission. RESULTS: There were 14,616 index admissions of adults with CF in 2013. Of these, 2,606 (17.8%) patients were readmitted within 30 days of discharge. Female sex and chronic anemia were independent predictors of readmission. The most common causes of readmission were pulmonary exacerbation (31%), lung transplant complications (5.2%), and septicemia (3.4%). CONCLUSION: Readmissions are frequent among adults with CF and contribute to significant healthcare burden and cost among this population. PMID- 29709047 TI - Vitamin D status of severe COPD patients with chronic respiratory failure. AB - INTRODUCTION: The aim of the study was to measure the concentrations of vitamin D in serum of COPD patients with chronic respiratory failure in comparison to healthy control group. The correlation between the levels of vitamin D in serum and the selected clinical, spirometric and blood gas parameters was the additional aim of the study. MATERIAL AND METHODS: The study included 61 patients with diagnosed COPD in stadium of chronic respiratory failure (45 men and 16 women) and 37 healthy controls (19 men and 18 women). The following procedure were performed in all studied subjects: detailed history (especially: daily activity, diet, tobacco and alcohol use), post-bronchodilator spirometry, assessment of 25(OH)D in serum and for COPD group only blood gas analysis. Recruitment for the study was conducted from November to April. Statistical analysis was performed using the following statistical methods: t-Student test, Mann-Whitney U test, Spearman correlation test and Chi-kwadrat test. RESULTS: There was no significant differences between COPD and control group for the levels of 25(OH)D in serum. Median and lower; upper quartile were respectively following: 24,75 nmol/l (16,9; 36,4) vs. 24,06 nmol/l (16,3; 37,2), p=0,69. Vitamin D deficiency was present in 60 COPD patients (98,3% of all patients) and in 36 control group subject (97,3% of all healthy volunteers). The difference was not statistically significant. The levels of vitamin D in serum did not significantly correlated with any of studied parameters (spirometry, blood gas, age, the level of activity, BMI, tobacco smoke exposure and others). However, the level of activity in COPD group correlated positively with spirometry values and negatively with age and number of exacerbations. CONCLUSION: The results of the study showed that in autumn-winter time in Poland there are very frequent deficiency of vitamin D in serum not only in COPD patients in respiratory failure stage but also in elderly healthy persons. However, in contrary to expectations the deficiency of vitamin D in COPD patients with respiratory failure were similar to that seen in healthy persons. PMID- 29709048 TI - Coping with stress by mothers of children and adolescents with cystic fibrosis. AB - INTRODUCTION: Studies of coping with stress of parents of children with cystic fibrosis (CF) are relatively rare and their results are inconsistent. The aim of the work was to determine the strategies of coping with stress of Polish mothers of children and adolescents with CF. MATERIAL AND METHODS: The research was conducted in the group of 89 Polish mothers of children with CF (0-18) and used the Brief COPE by Carver in the Polish adaptation by Juczynski and Oginska-Bulik (2009). The data were compared with the normative results obtained from Polish adults. RESULTS: The strategies of coping most often used by mothers of children with CF are as follows: active coping, planning and acceptance. A comparison of mean results obtained in the research group and mean results of adults in Polish population revealed that mothers of ill children significantly more often use: active coping, planning, positive reframing, acceptance, religion, seeking of instrumental support and venting. They less often use sense of humour and take psychoactive substance. Use of problem- -oriented strategies dominated over use of coping strategies focusing on emotions. CONCLUSION: Social support provided to mothers of children with CF should be oriented on strengthening cognitive strategies of coping with stress. PMID- 29709049 TI - Pulmonary tuberculosis mimicking lung cancer progression after 10 years of cancer remission. AB - Differentiation between pulmonary tuberculosis and lung cancer is often challenging for clinicians, especially that both conditions can coexist. This is due to the fact that the clinical and radiological symptoms of both diseases can be similar. Our case report presents a patient who was treated for advanced lung cancer 10 years earlier and currently has been hospitalized again because of a strong clinical and radiological suspicion of the cancer progression, but whose final diagnosis was tuberculosis. PMID- 29709050 TI - Acrometastasis due to lung adenocarcinoma. AB - We are presenting a case of acrometastasis in a male patient with lung adenocarcinoma. Acrometastases accumulate for 0.1% of all metastatic bone lesions and can be the first manifestation of cancer in approximately 10% of cases. The main clinical manifestations are tenderness, intermittent pain, functional impairment, erythema, heat and swelling of the affected part. Lung cancer is the main primary malignancy which causes acrometastases. Although the lesions can be recognized in x-rays or CT scans, the gold standard for the diagnosis is MRI scan in which the full extension of the tumor can be evaluated.The diagnosis is usually confirmed by fine-needle biopsy of the affected bone. In the presence of acrometastases, prognosis is very poor and palliative treatment is usually recommended. This case shows that patients at risk for lung cancer should be screened intensively when they develop persistent digital symptoms. PMID- 29709051 TI - Thoracic ultrasound for the detection of rib metastases of non-small cell lung cancer. AB - Transthoracic ultrasound has lately emerged as a useful diagnostic tool for respiratory physicians in the diagnosis of diverse pulmonary diseases, usually including pleural effusion and pneumothorax. However, the use of chest ultrasound may be also critical in the evaluation of chest wall diseases. Therefore, we present an interesting case of a patient with metastases of lung cancer to the rib, detected during the chest wall ultrasound examination. By representing a non invasive, surface-imaging technique with several advantages, chest ultrasound may evolve to a valid, bed-side diagnostic tool for the diagnosis and follow up of lung cancer with metastases in the chest wall. PMID- 29709052 TI - Can vitamin D help in achieving asthma control? Vitamin D "revisited'': an updated insight. AB - Asthma - a prolonged respiratory disease related with hyper-responsiveness and increased inflammation of airways; affects millions peoples worldwide. Vitamin D possess anti-inflammatory and immunomodulatory activities. Its deficiency (the level less than 20 ng/mL in the serum) is found to be related to occurrence of pulmonary diseases including bacterial and viral infections and asthma. Some studies indicate that low levels of vitamin D in the serum are related to reduced lung function and increased airway inflammation as well as overall poor results in asthmatic patients. Thus, it provides positive relation between vitamin D and asthma. Increased prevalence of asthma over the past decades causes elevated interest in vitamin D supplementation that is even reported as a ,,potential therapeutic option''. Unfortunately, results of clinical trials are inconsistent and do not provide supportive information about positive role of vitamin D in asthma. Little or even no effect of supplementation of vitamin D in improvement of onset, symptoms or progression of asthma was found in comprehensive interventional studies in adults, children and pregnant woman. This review critically summarized the last years evidence of a relation between vitamin D and asthma in adults, children and pregnant women. PMID- 29709053 TI - Bronchoscopy in diagnosis of haemoptysis. PMID- 29709054 TI - Is bronchoscopy always justified in diagnosis of haemoptysis? Response to the letter of Tamura et al. PMID- 29709055 TI - Interventions for investigating and identifying the causes of stillbirth. AB - BACKGROUND: Identification of the causes of stillbirth is critical to the primary prevention of stillbirth and to the provision of optimal care in subsequent pregnancies. A wide variety of investigations are available, but there is currently no consensus on the optimal approach. Given their cost and potential to add further emotional burden to parents, there is a need to systematically assess the effect of these interventions on outcomes for parents, including psychosocial outcomes, economic costs, and on rates of diagnosis of the causes of stillbirth. OBJECTIVES: To assess the effect of different tests, protocols or guidelines for investigating and identifying the causes of stillbirth on outcomes for parents, including psychosocial outcomes, economic costs, and rates of diagnosis of the causes of stillbirth. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (31 August 2017), ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) (15 May 2017). SELECTION CRITERIA: We planned to include randomised controlled trials (RCTs), quasi-RCTs, and cluster-RCTs. We planned to include studies published as abstract only, provided there was sufficient information to allow us to assess study eligibility. We planned to exclude cross-over trials.Participants included parents (including mothers, fathers, and partners) who had experienced a stillbirth of 20 weeks' gestation or greater.This review focused on interventions for investigating and identifying the causes of stillbirth. Such interventions are likely to be diverse, but could include:* review of maternal and family history, and current pregnancy and birth history;* clinical history of present illness;* maternal investigations (such as ultrasound, amniocentesis, antibody screening, etc.);* examination of the stillborn baby (including full autopsy, partial autopsy or noninvasive components, such as magnetic resonance imaging (MRI), computerised tomography (CT) scanning, and radiography);* umbilical cord examination;* placental examination including histopathology (microscopic examination of placental tissue); and* verbal autopsy (interviews with care providers and support people to ascertain causes, without examination of the baby).We planned to include trials assessing any test, protocol or guideline (or combinations of tests/protocols/guidelines) for investigating the causes of stillbirth, compared with the absence of a test, protocol or guideline, or usual care (further details are presented in the Background, see Description of the intervention).We also planned to include trials comparing any test, protocol or guideline (or combinations of tests/protocols/guidelines) for investigating the causes of stillbirth with another, for example, the use of a limited investigation protocol compared with a comprehensive investigation protocol. DATA COLLECTION AND ANALYSIS: Two review authors assessed trial eligibility independently. MAIN RESULTS: We excluded five studies that were not RCTs. There were no eligible trials for inclusion in this review. AUTHORS' CONCLUSIONS: There is currently a lack of RCT evidence regarding the effectiveness of interventions for investigating and identifying the causes of stillbirth. Seeking to determine the causes of stillbirth is an essential component of quality maternity care, but it remains unclear what impact these interventions have on the psychosocial outcomes of parents and families, the rates of diagnosis of the causes of stillbirth, and the care and management of subsequent pregnancies following stillbirth. Due to the absence of trials, this review is unable to inform clinical practice regarding the investigation of stillbirths, and the specific investigations that would determine the causes.Future RCTs addressing this research question would be beneficial, but the settings in which the trials take place, and their design, need to be given careful consideration. Trials need to be conducted with the utmost care and consideration for the needs, concerns, and values of parents and families. Assessment of longer-term psychosocial variables, economic costs to health services, and effects on subsequent pregnancy care and outcomes should also be considered in any future trials. PMID- 29709056 TI - Minority Stress and Same-Sex Relationship Satisfaction: The Role of Concealment Motivation. AB - Most lesbian, gay, and bisexual (LGB) people want a stable, satisfying romantic relationship. Although many of the predictors of relationship outcomes are similar to those of heterosexual couples, same-sex couples face some additional challenges associated with minority stress that also impact upon relationship quality. Here, we investigate the association between minority stressors and relationship quality in a sample of 363 adults (M age = 30.37, SD = 10.78) currently in a same-sex romantic relationship. Internalized homophobia and difficulties accepting one's LGB identity were each negatively associated with relationship satisfaction via heightened concealment motivation. We also examined the protective role of identity affirmation on relationship quality, finding a direct positive relationship between the two variables. Minority stressors were negatively associated with couple relationship satisfaction via heightened concealment motivation. The finding that identity affirmation directly predicted increased couple satisfaction also highlights the important role of protective factors in same-sex couple relationships. PMID- 29709057 TI - The Role of Dyadic Coping on the Marital and Emotional Adjustment of Couples With Infertility. AB - Infertility is a challenging experience, affecting individual and couples' adjustment. However, the way the members of the couple support each other may affect the experience of infertility and their adjustment. This study aimed to investigate the role of dyadic coping by oneself and by the partner in the association between the impact of infertility and dyadic and emotional adjustment (anxiety and depression) to infertility. In this cross-sectional study, a total of 134 participants (67 couples with infertility) completed self-report questionnaires assessing infertility-related stress, dyadic coping, dyadic adjustment, and depression and anxiety symptoms. A path analysis examined the direct and indirect effects between the impact of infertility in one's life and dyadic and emotional adjustment. There is an indirect effect of the impact of infertility in one's life on dyadic adjustment through men's perceived dyadic coping efforts employed by the self (dyadic coping by oneself) and women's perceived dyadic coping efforts of the partner (dyadic coping by the partner). Regarding the emotional adjustment of infertile couples, infertility stress impact had an indirect effect only on depressive symptoms through men's dyadic coping by oneself. The results highlight the importance of men's dyadic coping strategies for the marital adjustment of couples as well as for men's emotional adjustment. Findings emphasize the importance of involving men in the fertility treatment process, reinforcing the dyadic nature of infertility processes. PMID- 29709059 TI - Health worker migration and migrant healthcare: Seeking cosmopolitanism in the NHS. AB - The U.K.'s National Health Service (NHS) is critically reliant on staff from overseas, which means that a sizeable number of U.K. healthcare professionals have received their training at the cost of other states, whose populations are urgently in need of healthcare professionals. At the same time, while healthcare is widely seen as a primary good, many migrants are unable to access the NHS without charge, and anti-immigration political trends are likely to further reduce that access. Both of these topics have received close attention in the global health ethics literature. In this article, I make the novel move of suggesting that these two seemingly disparate issues should be folded into the same moral narrative. The 'brain drain' upon which the NHS and its users depend derives from the same gradient of wealth, security, and opportunity that produces migrants who require the NHS. I endorse moral cosmopolitanism as a lens for understanding patients' right to healthcare regardless of nationality or immigration status. I argue that the NHS in its current formulation effectively enacts a partial cosmopolitanism in its reliance on medical workers from abroad, but could more meaningfully instantiate that cosmopolitanism were it to offer the same healthcare to migrants as it does to citizens. PMID- 29709058 TI - Cellular ATP levels are affected by moderate and strong static magnetic fields. AB - Mitochondrion is the major cellular energy producing organelle that is at the boundary between chemical reactions and physical processes. Although mitochondria have been shown to be affected by physical methods such as nonthermal plasma, whether static magnetic field (SMF) could also affect them is still unclear. Here we used rat adrenal PC12 cells to compare SMFs of different intensities for their effects on ATP (adenosine-5'-triphosphate), the major energy source produced by mitochondria, which is essential for various cellular processes. Our results show that although 0.26 or 0.50 T SMFs did not affect ATP, 1 T and 9 T SMFs affected ATP level differently and time-dependently. Moreover, SMF-induced ATP level fluctuations are correlated with mitochondrial membrane potential changes. Our study provides insights not only into understanding various cellular effects of SMFs, but also the potential clinical applications of SMFs. Bioelectromagnetics. 39:352-360, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29709060 TI - Effects of 1.8 GHz radiofrequency field on microstructure and bone metabolism of femur in mice. AB - To investigate the effects of 1.8 GHz radiofrequency (RF) field on bone microstructure and metabolism of femur in mice, C57BL/6 mice (male, age 4 weeks) were whole-body exposed or sham exposed to 1.8 GHz RF field. Specific absorption rates of whole body and bone were approximately 2.70 and 1.14 W/kg (6 h/day for 28 days). After exposure, microstructure and morphology of femur were observed by microcomputed tomography (micro-CT), Hematoxylin and Eosin (HE) and Masson staining. Subsequently, bone parameters were calculated directly from the reconstructed images, including structure model index, bone mineral density, trabecular bone volume/total volume, connectivity density, trabecular number, trabecular thickness, and trabecular separation. Biomarkers that reflect bone metabolism, such as serum total alkaline phosphatase (ALP), bone-specific alkaline phosphatase (BALP), and tartrate-resistant acid phosphatase 5b (TRACP 5b), were determined by biochemical assay methods. Micro-CT and histology results showed that there was no significant change in bone microstructure and the above parameters in RF group, compared with sham group. The activity of serum ALP and BALP increased 29.47% and 16.82%, respectively, in RF group, compared with sham group (P < 0.05). In addition, there were no significant differences in the activity of serum TRACP-5b between RF group and sham group. In brief, under present experimental conditions, we did not find support for an effect of 1.8 GHz RF field on bone microstructure; however, it might promote metabolic function of osteoblasts in mice. Bioelectromagnetics. 39:386-393, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29709061 TI - Fidelity Failures in Brief Strategic Family Therapy for Adolescent Drug Abuse: A Clinical Analysis. AB - As evidence-based family treatments for adolescent substance use and conduct problems gain traction, cutting edge research moves beyond randomized efficacy trials to address questions such as how these treatments work and how best to disseminate them to community settings. A key factor in effective dissemination is treatment fidelity, which refers to implementing an intervention in a manner consistent with an established manual. While most fidelity research is quantitative, this study offers a qualitative clinical analysis of fidelity failures in a large, multisite effectiveness trial of Brief Strategic Family Therapy (BSFT) for adolescent drug abuse, where BSFT developers trained community therapists to administer this intervention in their own agencies. Using case notes and video recordings of therapy sessions, an independent expert panel first rated 103 cases on quantitative fidelity scales grounded in the BSFT manual and the broader structural-strategic framework that informs BSFT intervention. Because fidelity was generally low, the panel reviewed all cases qualitatively to identify emergent types or categories of fidelity failure. Ten categories of failures emerged, characterized by therapist omissions (e.g., failure to engage key family members, failure to think in threes) and commissions (e.g., off-model, nonsystemic formulations/interventions). Of these, "failure to think in threes" appeared basic and particularly problematic, reflecting the central place of this idea in structural theory and therapy. Although subject to possible bias, our observations highlight likely stumbling blocks in exporting a complex family treatment like BSFT to community settings. These findings also underscore the importance of treatment fidelity in family therapy research. PMID- 29709062 TI - Management of newly diagnosed high-risk and intermediate-risk follicular lymphoma with 90 Y ibritumomab tiuxetan in a phase II study. AB - Five-year overall survival for high-risk Follicular Lymphoma International Prognostic Index follicular lymphoma is only approximately 50% compared with 90% for low risk. To evaluate an approach to improve upon this poor outcome, we completed an exploratory phase II trial of intensified treatment for patients with intermediate and high-risk follicular lymphoma. Front-line treatment with chemo-immunotherapy consisting of rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone was followed by radio- immunotherapy with 90-Yttrium ibritumomab tiuxetan consolidation, and 2 years of rituximab maintenance. The 5 year overall survival for intermediate and high-risk patients was 88% and 83%, respectively. Of 33 enrolled patients, 3 were off study before receiving radio immunotherapy. Three months post radio-immunotherapy, 28/33 (85%) patients had achieved complete response including 6 patients who had only a partial response to chemo-immunotherapy and converted to complete response after radio immunotherapy. The 5-year progression-free survival for intermediate and high risk was 79% and 58%, respectively. Nine of 19 patients with molecular markers patients remain in molecular and clinical complete remission with a median follow up of 48 months (range 3-84 months). Post radio-immunotherapy, hematologic toxicities were mostly grade 1 and 2. However, asymptomatic grade 3 or 4 thrombocytopenia and neutropenia occurred in 11%-36% and 10%-24% of patients, respectively. Myelodysplastic syndrome occurred in 1 patient 4 years post treatment. Whereas many patients had prolonged B-cell reduction and low immunoglobulin levels post treatment, previous immunities to rubella were maintained. More aggressive upfront approaches such as this may benefit higher risk follicular lymphoma, but confirmatory trials are required. http://www.clinicaltrials.gov: NCT01446562. PMID- 29709063 TI - Evaluation of behaviour of Lachancea thermotolerans biocontrol agents on grape fermentations. AB - : Previous researches have showed that Lachancea thermotolerans strains RCKT4 and RCKT5 inhibited the growth of Aspergillus. However, currently, there are no data on their nutritional preferences, as a possible substrate competitor against Saccharomyces cerevisiae, and their effects on fermentation. In this work, we observed that the biocontrol yeasts and S. cerevisiae BSc203, based on the utilization of 16 carbonate sources, revealed significant differences in the nutritional profile (biocontrol yeasts NS:0.25, BSc203 NS:0.56). Lachancea thermotolerans strains did not occupy the same niche as that of BSc203 (NOI:0.44). The biocontrol agents and BSc203 presented similar competitive attitude in terms of the sugar, ethanol and sulphite tolerances. During fermentation, the biocontrol yeasts were found to tolerate up to 12% v/v ethanol, 250 mg ml-1 of total SO2 and 30 degrees Brix sugar. In mixed cultures, L. thermotolerans strains did not negatively affect the growth of BSc203 and the wine quality, except when RCKT4 was initially inoculated at a high proportion in the mixed culture 1MSK4 (1%BSc203/99%RCKT4), resulting in a lower production of CO2 and ethanol, in comparison with pure BSc203. RCKT5, at a high proportion, in 1MSK5 (1%BSc203/99%RCKT5) presented promising oenological properties. This fermentation showed lower acetic acid contents and higher total acidity than pure BSc203. SIGNIFICANCE AND IMPACT OF THE STUDY: Generally it is not evaluated if the biofungicide yeasts sprayed on vegetables alter the quality of the fermented products. This work focused on the importance of assessing the possible effects of yeast-based fungicides used in vineyards on grape fermentation, especially on Saccharomyces cerevisiae growth. In this context, the competition between biofungicide yeasts and S. cerevisiae under winemaking conditions is investigated. PMID- 29709064 TI - Effects of moderate intensity static magnetic fields on osteoclastic differentiation in mouse bone marrow cells. AB - Although we recently demonstrated that static magnetic fields (SMFs) of 3, 15, and 50 mT stimulate osteoblastic differentiation, the effects of SMFs on osteoclastogenesis are still poorly understood. This study focused on the suppressive effects of SMFs on receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclastogenesis and bone resorption. Direct SMFs inhibit RANKL induced multinucleated osteoclast formation, tartrate-resistant acid phosphatase activity, and bone resorption in mouse bone marrow-derived macrophage cells. The conditioned medium from osteoblasts treated with SMFs also resulted in the inhibition of osteoclast differentiation as well as resorption. The RANKL-induced expression of osteoclast-specific transcription factors, such as c-Fos and NFATc1, was remarkably downregulated by SMF at 15 mT. In addition, SMF inhibited RANKL-activated Akt, glycogen synthase kinase 3beta (GSK3beta), extracellular signal-regulated kinase, c-jun N-terminal protein kinase, mitogen-activated protein kinase (MAPK), and nuclear factor-kappaB (NF-kappaB) formation. These findings indicate that SMF-mediated attenuation of RANKL-induced Akt, GSK3beta, MAPK, and NF-kappaB pathways could contribute to the direct and indirect inhibition of osteoclast formation and bone resorption. Therefore, SMFs could be developed as a therapeutic agent against periprosthetic or peri-implant osteolysis. Additionally, these could be used against osteolytic diseases such as osteoporosis and rheumatoid arthritis. Bioelectromagnetics. 39:394-404, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29709065 TI - Probing chemical space of tick-borne encephalitis virus reproduction inhibitors with organoselenium compounds. AB - Tick-borne encephalitis virus (TBEV), a member of the genus Flavivirus, is the leading cause of arboviral neuroinfections in Europe. Only a few classes of the nucleoside and non-nucleoside inhibitors were investigated against TBEV reproduction. Paving the way to previously unexplored areas of anti-TBEV chemical space, we assessed the inhibition of TBEV reproduction in the plaque reduction assay by various compounds derived from cyanothioacetamide and cyanoselenoacetamide. Compounds from seven classes, including 4-(alkylthio)-2 aryl-3-azaspiro[5.5]undec-4-ene-1,1,5-tricarbonitriles, 3-arylamino-2-(selenazol 2-yl)acrylonitriles, ethyl 6-(alkylseleno)-5-cyano-2-oxo-1,2-dihydropyridine-3 carboxylates, 6-(alkylseleno)-2-oxo-1,4,5,6-tetrahydropyridine-3-carbonitriles, 2 (alkylseleno)-5-oxo-1,4,5,6,7,8-hexahydroquinoline-3-carbonitriles, 8-selenoxo 3,5,7,11-tetraazatricyclo[7.3.1.02,7 ]tridec-2-ene-1,9-dicarbonitriles, and selenolo[2,3-b]quinolines, inhibited TBEV reproduction with EC50 values in the micromolar range while showing moderate cytotoxicity and no inhibition of enterovirus reproduction. Thus, new scaffolds with promising anti-TBEV activity were found. PMID- 29709066 TI - Heritable L1 Retrotransposition Events During Development: Understanding Their Origins: Examination of heritable, endogenous L1 retrotransposition in mice opens up exciting new questions and research directions. AB - The retrotransposon Long Interspersed Element 1 (LINE-1 or L1) has played a major role in shaping the sequence composition of the mammalian genome. In our recent publication, "Heritable L1 retrotransposition in the mouse primordial germline and early embryo," we systematically assessed the rate and developmental timing of de novo, heritable endogenous L1 insertions in mice. Such heritable retrotransposition events allow L1 to exert an ongoing influence upon genome evolution. Here, we place our findings in the context of earlier studies, and highlight how our results corroborate, and depart from, previous research based on human patient samples and transgenic mouse models harboring engineered L1 reporter genes. In parallel, we outline outstanding questions regarding the stage specificity, regulation, and functional impact of embryonic and germline L1 retrotransposition, and propose avenues for future research in this field. PMID- 29709067 TI - The pathogenicity of IL-33 on steroid-resistant eosinophilic inflammation via the activation of memory-type ST2+ CD4+ T cells. AB - The lungs are the primary organs of the respiratory system in many animals and have unique epithelial barrier systems to protect the host from continuous invasion of various harmful particles, such as viruses and bacteria. IL-33, a member of the IL-1 family of cytokines, is released from epithelial cells in the mucosal organs and drives the type 2 immune response by activating a number of immune cells in cases of helminth infection. However, IL-33 derived from epithelial cells also causes various allergic diseases via the activation of ST2 positive immune cells, including memory-type (CD62Llow CD44hi ) ST2+ CD4+ T cells in the lung. Recent studies have revealed that the type 2 inflammation induced by IL-33 is steroid resistant. Steroid resistance causes severe chronic inflammatory diseases, such as intractable asthma. In this review, we will discuss the impact of ST2+ CD4+ T cells on shaping the pathology of IL-33-induced eosinophilic inflammation. We will also highlight the mechanism underlying steroid resistance in eosinophilic pneumonia. A better understanding of the cellular and molecular mechanisms underlying steroid resistance is crucial for the development of new therapeutic strategies for intractable allergic diseases. PMID- 29709068 TI - Normalizing Gas-Chromatography-Mass Spectrometry Data: Method Choice can Alter Biological Inference. AB - We demonstrate how different normalization techniques in GC-MS analysis impart unique properties to the data, influencing any biological inference. Using simulations, and empirical data, we compare the most commonly used techniques (Total Sum Normalization 'TSN'; Median Normalization 'MN'; Probabilistic Quotient Normalization 'PQN'; Internal Standard Normalization 'ISN'; External Standard Normalization 'ESN'; and a compositional data approach 'CODA'). When differences between biological classes are pronounced, ESN and ISN provides good results, but are less reliable for more subtly differentiated groups. MN, TSN, and CODA approaches produced variable results dependent on the structure of the data, and are prone to false positive biomarker identification. In contrast, PQN exhibits the lowest false positive rate, though with occasionally poor model performance. Because ESN requires extensive pre-planning, and offers only mixed reliability, and ISN, TSN, MN, and CODA approaches are prone to introducing artefactual differences, we recommend the use of PQN in GC-MS research. PMID- 29709069 TI - Predicting suicide attempts in adolescents with longitudinal clinical data and machine learning. AB - BACKGROUND: Adolescents have high rates of nonfatal suicide attempts, but clinically practical risk prediction remains a challenge. Screening can be time consuming to implement at scale, if it is done at all. Computational algorithms may predict suicide risk using only routinely collected clinical data. We used a machine learning approach validated on longitudinal clinical data in adults to address this challenge in adolescents. METHODS: This is a retrospective, longitudinal cohort study. Data were collected from the Vanderbilt Synthetic Derivative from January 1998 to December 2015 and included 974 adolescents with nonfatal suicide attempts and multiple control comparisons: 496 adolescents with other self-injury (OSI), 7,059 adolescents with depressive symptoms, and 25,081 adolescent general hospital controls. Candidate predictors included diagnostic, demographic, medication, and socioeconomic factors. Outcome was determined by multiexpert review of electronic health records. Random forests were validated with optimism adjustment at multiple time points (from 1 week to 2 years). Recalibration was done via isotonic regression. Evaluation metrics included discrimination (AUC, sensitivity/specificity, precision/recall) and calibration (calibration plots, slope/intercept, Brier score). RESULTS: Computational models performed well and did not require face-to-face screening. Performance improved as suicide attempts became more imminent. Discrimination was good in comparison with OSI controls (AUC = 0.83 [0.82-0.84] at 720 days; AUC = 0.85 [0.84-0.87] at 7 days) and depressed controls (AUC = 0.87 [95% CI 0.85-0.90] at 720 days; 0.90 [0.85-0.94] at 7 days) and best in comparison with general hospital controls (AUC 0.94 [0.92-0.96] at 720 days; 0.97 [0.95-0.98] at 7 days). Random forests significantly outperformed logistic regression in every comparison. Recalibration improved performance as much as ninefold - clinical recommendations with poorly calibrated predictions can lead to decision errors. CONCLUSIONS: Machine learning on longitudinal clinical data may provide a scalable approach to broaden screening for risk of nonfatal suicide attempts in adolescents. PMID- 29709070 TI - Pulsed electromagnetic field therapy in the treatment of pain and other symptoms in fibromyalgia: A randomized controlled study. AB - Low-energy pulsed electromagnetic field (PEMF) therapy has been suggested as a promising therapy to increase microcirculation, which is of great concern in patients with fibromyalgia. This study evaluated the effectiveness of PEMF therapy on the treatment of fibromyalgia. A group of 108 women with fibromyalgia were allocated to a 12-week treatment period with an active Bio-Electro-Magnetic Energy-Regulation (BEMER) device and a similar treatment period with an inactive device. Each patient received active and sham treatments in a random order. Pain and stiffness were assessed on a visual analog scale (VAS, scale 0-100 mm), and functional status was assessed by the Fibromyalgia Impact Questionnaire (FIQ). Mean VAS pain scores before the active and sham treatment periods were 66 (SD 22) and 63 (SD 22), respectively. After treatment periods, mean VAS pain scores had decreased significantly in active treatment, -12, 95% CI [-18, -6], and in sham treatment, -11, 95% CI [-17, -5]. Similarly, the decrease in stiffness and FIQ index after both treatments was statistically significant. However, per-protocol analysis showed no differences between active and sham treatments at any of the outcomes. This study demonstrated that low-energy PEMF therapy was not efficient in reducing pain and stiffness or in improving functioning in women with fibromyalgia. Bioelectromagnetics. 39:405-413, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29709071 TI - The effect of the implementation of low price medicine policy on medicine price in China: A retrospective study. AB - In an effort to relieve the pressure of drug shortages, the Chinese government implemented Low-price Medicines (LPM) policy to raise the price cap in July 2014. The purpose of this study is to examine the effect of the implementation of this policy on drug price in China. Price data of 491 LPM, including 218 low-price chemical medicines (LPCM) and 273 low-price traditional Chinese medicines (LPTCM), were collected from 699 hospitals. We used interrupted time series design to identify the variation of monthly Laspeyres Indexes (LI) and Paasche Indexes (PI) for LPM, LPCM, and LPTCM. The result demonstrated that although LPM expenditures increased, the proportion of LPM expenditures accounting for all medicine expenditures fell from 3.6% to 3.2%. After the implementation of LPM policy, there was a significant increasing trend in LPM-PI, LPCM-PI, and LPTCM PI. The trend in LPM-LI and LPCM-LI was found from descending to rising. However, for LPTCM, the trend in the LI remained to decrease after the policy implementation. Despite the LPM policy had an increasing impact on the LPM drug price, the proportion of LPM expenditures accounting for all medicine expenditures did not increase. More efforts are needed in the future to promote the rational drug use in China. PMID- 29709072 TI - Numerical evaluation of human exposure to WiMax patch antenna in tablet or laptop. AB - The use of wireless communication devices, such as tablets or laptops, is increasing among children. Only a few studies assess specific energy absorption rate (SAR) due to exposure from wireless-enabled tablets and laptops, in particular with Worldwide Interoperability for Microwave Access (WiMax) technology. This paper reports the estimation of the interaction between an E shaped patch antenna (3.5 GHz) and human models, by means of finite-difference time-domain (FDTD) method. Specifically, four different human models (young adult male, young adult female, pre-teenager female, male child) in different exposure conditions (antenna at different distances from the human model, in different positions, and orientations) were considered and whole-body, 10 and 1 g local SAR and magnetic field value (Bmax) were evaluated. From our results, in some worst case scenarios involving male and female children's exposure, the maximum radiofrequency energy absorption (hot spots) is located in more sensitive organs such as eye, genitals, and breast. Bioelectromagnetics. 39:414-422, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29709073 TI - iPSCs from an Endangered Mammalian Species Could Elucidate the Mechanism of Sex Determination with Evolutionary Y Chromosome Loss. PMID- 29709074 TI - Mitochondrial Outer Membrane Channels: Emerging Diversity in Transport Processes. AB - Mitochondrial function and biogenesis depend on the transport of a large variety of proteins, ions, and metabolites across the two surrounding membranes. While several specific transporters are present in the inner membrane, transport processes across the outer membrane are less understood. Recent studies reveal that the number of outer membrane channels and their transport mechanisms are more diverse than originally thought. Four protein-conducting channels promote transport of distinct sets of precursor proteins across and into the outer membrane. The voltage-dependent anion channel (VDAC) forms the major channel for small hydrophilic molecules. In addition, three channels with yet unknown substrate specificity exist in the outer membrane. In this review, we outline the emerging functional diversity, selectivity, and regulation of mitochondrial outer membrane channels. The presence of several channel-forming proteins challenges the traditional view that the outer membrane forms an unspecific size-exclusion filter for the flux of small hydrophilic molecules. PMID- 29709075 TI - Reduction of the geomagnetic field delays Arabidopsis thaliana flowering time through downregulation of flowering-related genes. AB - Variations in magnetic field (MF) intensity are known to induce plant morphological and gene expression changes. In Arabidopsis thaliana Col-0, near null magnetic field (NNMF, i.e., <100 nT MF) causes a delay in the transition to flowering, but the expression of genes involved in this response has been poorly studied. Here, we showed a time-course quantitative analysis of the expression of both leaf (including clock genes, photoperiod pathway, GA20ox, SVP, and vernalization pathway) and floral meristem (including GA2ox, SOC1, AGL24, LFY, AP1, FD, and FLC) genes involved in the transition to flowering in A. thaliana under NNMF. NNMF induced a delayed flowering time and a significant reduction of leaf area index and flowering stem length, with respect to controls under geomagnetic field. Generation experiments (F1 - and F2 -NNMF) showed retention of flowering delay. The quantitative expression (qPCR) of some A. thaliana genes expressed in leaves and floral meristem was studied during transition to flowering. In leaves and flowering meristem, NNMF caused an early downregulation of clock, photoperiod, gibberellin, and vernalization pathways and a later downregulation of TSF, AP1, and FLC. In the floral meristem, the downregulation of AP1, AGL24, FT, and FLC in early phases of floral development was accompanied by a downregulation of the gibberellin pathway. The progressive upregulation of AGL24 and AP1 was also correlated to the delayed flowering by NNMF. The flowering delay is associated with the strong downregulation of FT, FLC, and GA20ox in the floral meristem and FT, TSF, FLC, and GA20ox in leaves. Bioelectromagnetics. 39:361-374, 2018. (c) 2018 The Authors. Bioelectromagnetics Published by Wiley Periodicals, Inc. PMID- 29709076 TI - Two cases of generalized pustular psoriasis complicated by IgG4-related disease. PMID- 29709077 TI - Use of platelet transfusions prior to lumbar punctures or epidural anaesthesia for the prevention of complications in people with thrombocytopenia. AB - BACKGROUND: People with a low platelet count (thrombocytopenia) often require lumbar punctures or an epidural anaesthetic. Lumbar punctures can be diagnostic (haematological malignancies, subarachnoid haematoma, meningitis) or therapeutic (spinal anaesthetic, administration of chemotherapy). Epidural catheters are placed for administration of epidural anaesthetic. Current practice in many countries is to correct thrombocytopenia with platelet transfusions prior to lumbar punctures and epidural anaesthesia, in order to mitigate the risk of serious procedure-related bleeding. However, the platelet count threshold recommended prior to these procedures varies significantly from country to country. This indicates significant uncertainty among clinicians regarding the correct management of these patients. The risk of bleeding appears to be low, but if bleeding occurs it can be very serious (spinal haematoma). Consequently, people may be exposed to the risks of a platelet transfusion without any obvious clinical benefit.This is an update of a Cochrane Review first published in 2016. OBJECTIVES: To assess the effects of different platelet transfusion thresholds prior to a lumbar puncture or epidural anaesthesia in people with thrombocytopenia (low platelet count). SEARCH METHODS: We searched for randomised controlled trials (RCTs), non-randomised controlled trials (nRCTs), controlled before-after studies (CBAs), interrupted time series studies (ITSs), and cohort studies in CENTRAL (the Cochrane Library 2018, Issue 1), MEDLINE (from 1946), Embase (from 1974), the Transfusion Evidence Library (from 1950), and ongoing trial databases to 13 February 2018. SELECTION CRITERIA: We included RCTs, nRCTs, CBAs, ITSs, and cohort studies involving transfusions of platelet concentrates, prepared either from individual units of whole blood or by apheresis, and given to prevent bleeding in people of any age with thrombocytopenia requiring insertion of a lumbar puncture needle or epidural catheter.The original review only included RCTs. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane for including RCTs, nRCTs, CBAs, and ITSs. Two review authors independently assessed studies for eligibility and risk of bias and extracted data. Results were only expressed narratively. MAIN RESULTS: We identified no completed or ongoing RCTs, nRCTs, CBAs, or ITSs. No studies included people undergoing an epidural procedure. No studies compared different platelet count thresholds prior to a procedure.In this update we identified three retrospective cohort studies that contained participants who did and did not receive platelet transfusions prior to lumbar puncture procedures. All three studies were carried out in people with cancer, most of whom had a haematological malignancy. Two studies were in children, and one was in adults.The number of participants receiving platelet transfusions prior to the lumbar puncture procedures was not reported in one study. We therefore only summarised in a narrative form the relevant outcomes from two studies (150 participants; 129 children and 21 adults), in which the number of participants who received the transfusion was given.We judged the overall risk of bias for all reported outcomes for both studies as 'serious' based on the ROBINS-I tool.No procedure related major bleeding occurred in the two studies that reported this outcome (2 studies, 150 participants, no cases, very low-quality evidence).There was no evidence of a difference in the risk of minor bleeding (traumatic tap) in participants who received platelet transfusions before a lumbar puncture and those who did not receive a platelet transfusion before the procedure (2 studies, 150 participants, very low-quality evidence). One of the 14 adults who received a platelet transfusion experienced minor bleeding (traumatic tap; defined as at least 500 x 106/L red blood cells in the cerebrospinal fluid); none of the seven adults who did not receive a platelet transfusion experienced this event. Ten children experienced minor bleeding (traumatic taps; defined as at least 100 x 106/L red blood cells in the cerebrospinal fluid), six out of the 57 children who received a platelet transfusion and four out of the 72 children who did not receive a platelet transfusion.No serious adverse events occurred in the one study that reported this outcome (1 study, 21 participants, very low-quality evidence).We found no studies that evaluated all-cause mortality within 30 days from the lumbar puncture procedure, length of hospital stay, proportion of participants who received platelet transfusions, or quality of life. AUTHORS' CONCLUSIONS: We found no evidence from RCTs or non-randomised studies on which to base an assessment of the correct platelet transfusion threshold prior to insertion of a lumbar puncture needle or epidural catheter. There are no ongoing registered RCTs assessing the effects of different platelet transfusion thresholds prior to the insertion of a lumbar puncture or epidural anaesthesia in people with thrombocytopenia. Any future study would need to be very large to detect a difference in the risk of bleeding. A study would need to be designed with at least 47,030 participants to be able to detect an increase in the number of people who had major procedure-related bleeding from 1 in 1000 to 2 in 1000. The use of a central data collection register or routinely collected electronic records (big data) is likely to be the only method to systematically gather data relevant to this population. PMID- 29709079 TI - Expression of unique chimeric human papilloma virus type 16 (HPV-16) L1-L2 proteins in Pichia pastoris and Hansenula polymorpha. AB - Cervical cancer is ranked the fourth most common cancer in women worldwide. Despite two prophylactic vaccines being commercially available, they are unaffordable for most women in developing countries. We compared the optimized expression of monomers of the unique HPV type 16 L1-L2 chimeric protein (SAF) in two yeast strains of Pichia pastoris, KM71 (Muts ) and GS115 (Mut+ ), with Hansenula polymorpha NCYC 495 to determine the preferred host in bioreactors. SAF was uniquely created by replacing the h4 helix of the HPV-16 capsid L1 protein with an L2 peptide. Two different feeding strategies in fed-batch cultures of P. pastoris Muts were evaluated: a predetermined feed rate vs. feeding based on the oxygen consumption by maintaining constant dissolved oxygen levels (DO stat). All cultures showed a significant increase in biomass when methanol was fed using the DO stat method. In P. pastoris the SAF concentrations were higher in the Muts strains than in the Mut+ strains. However, H. polymorpha produced the highest level of SAF at 132.10 mg L-1 culture while P. pastoris Muts only produced 23.61 mg L-1 . H. polymorpha showed greater potential for the expression of HPV-16 L1/L2 chimeric proteins despite the track record of P. pastoris as a high-level producer of heterologous proteins. PMID- 29709078 TI - Titanium nanoparticles influence the Akt/Tor signal pathway in the silkworm, Bombyx mori, silk gland. AB - Various nanoparticles, such as silver nanoparticles (AgNPs) and titanium nanoparticles (TiO2 NPs) are increasingly used in industrial processes. Because they are released into the environment, research into their influence on the biosphere is necessary. Among its other effects, dietary TiO2 NPs promotes silk protein synthesis in silkworms, which prompted our hypothesis that TiO2 NPs influence protein kinase B (Akt)/Target of rapamycin (Tor) signaling pathway (Akt/Tor) signaling in their silk glands. The Akt/Tor signaling pathway is a principle connector integrating cellular reactions to growth factors, metabolites, nutrients, protein synthesis, and stress. We tested our hypothesis by determining the influence of dietary TiO2 NPs (for 72 h) and, separately, of two Akt/Tor pathway inhibitors (LY294002 and rapamycin) on expression of Akt/Tor signaling pathway genes and proteins in the silk glands. TiO2 NPs treatments led to increased accumulation of mRNAs for Akt, Tor1 and Tor2 by 1.6-, 12.1-, and 4.8 fold. Dietary inhibitors led to 2.6- to 4-fold increases in mRNAs encoding Akt and substantial decreases in mRNAs encoding Tor1 and Tor2. Western blot analysis showed that dietary TiO2 NPs increased the phosphorylation of Akt and its downstream proteins. LY294002 treatments led to inhibition of Akt phosphorylation and its downstream proteins and rapamycin treatments similarly inhibited the phosphorylation of Tor-linked downstream proteins. These findings support our hypothesis that TiO2 NPs influence Akt/Tor signaling in silk glands. The significance of this work is identification of specific sites of TiO2 NPs actions. PMID- 29709080 TI - Lipidomic Study of Precursors of Endocannabinoids in Freshwater Bryozoan Pectinatella magnifica. AB - Freshwater bryozoan Pectinatella magnifica was collected from a sand pit (South Bohemia). The total lipids after extraction from lyophilized bryozoans were analyzed using high-performance liquid chromatography/high-resolution negative tandem electrospray mass spectrometry. A total of 19 lipid classes were identified, including N-acyl-substituted phospholipids, that is, N acylphosphatidylethanolamine and N-acylphosphatidylserine in their plasmenyl forms. Based on gas chromatography/mass spectrometry of 3-pyridylcarbonyl (picolinyl) esters, a very unusual fatty acid was identified, namely 24:7n-3 (all cis-3,6,9,12,15,18,21-tetracosaheptaenoic acid). The presence of polyunsaturated fatty acids in individual classes is very specific: arachidonic and eicosapentaenoic acids being predominantly bound as amides in N-acyl phospholipids, that is, diacyl-N-acylphosphatidylethanolamines (NAPtdEtn), plasmenyl-N-acylphosphatidyl ethanolamines (PlsNAPtdEtn), diacyl-N acylphosphatidylserines (NAPtdSer), and plasmenyl-N-acylphosphatidylserines (PlsNAPtdSer). While 24:6n-3 was identified in the sn-2 position of several phospholipids, 24:7n-3 was identified in only two plasmalogens, that is, PlsNAPtdEtn and PlsNAPtdSer. Thanks to the tandem mass spectrometry, we managed to identify the position of all acyl groups in both diacyl- and also in alkenyl acyl-(plasmenyl) molecular species of N-acylphospholipids. The identification of the molecular species of N-acyl-substituted phosphatidylethanolamine and phosphatidylserine, including their plasmalogen forms, in the freshwater bryozoan P. magnifica has enabled the identification of endogenous cannabinoid precursors. PMID- 29709081 TI - How Ancient Sex Drove Mammalian Lineage Evolution. PMID- 29709082 TI - Enhanced Exciton and Photon Confinement in Ruddlesden-Popper Perovskite Microplatelets for Highly Stable Low-Threshold Polarized Lasing. AB - At the heart of electrically driven semiconductors lasers lies their gain medium that typically comprises epitaxially grown double heterostuctures or multiple quantum wells. The simultaneous spatial confinement of charge carriers and photons afforded by the smaller bandgaps and higher refractive index of the active layers as compared to the cladding layers in these structures is essential for the optical-gain enhancement favorable for device operation. Emulating these inorganic gain media, superb properties of highly stable low-threshold (as low as ~8 uJ cm-2 ) linearly polarized lasing from solution-processed Ruddlesden-Popper (RP) perovskite microplatelets are realized. Detailed investigations using microarea transient spectroscopies together with finite-difference time-domain simulations validate that the mixed lower-dimensional RP perovskites (functioning as cladding layers) within the microplatelets provide both enhanced exciton and photon confinement for the higher-dimensional RP perovskites (functioning as the active gain media). Furthermore, structure-lasing-threshold relationship (i.e., correlating the content of lower-dimensional RP perovskites in a single microplatelet) vital for design and performance optimization is established. Dual wavelength lasing from these quasi-2D RP perovskite microplatelets can also be achieved. These unique properties distinguish RP perovskite microplatelets as a new family of self-assembled multilayer planar waveguide gain media favorable for developing efficient lasers. PMID- 29709083 TI - Nanopatched Graphene with Molecular Self-Assembly Toward Graphene-Organic Hybrid Soft Electronics. AB - Increasing the mechanical durability of large-area polycrystalline single-atom thick materials is a necessary step toward the development of practical and reliable soft electronics based on these materials. Here, it is shown that the surface assembly of organosilane by weak epitaxy forms nanometer-thick organic patches on a monolayer graphene surface and dramatically increases the material's resistance to harsh postprocessing environments, thereby increasing the number of ways in which graphene can be processed. The nanopatched graphene with the improved mechanical durability enables stable operation when used as transparent electrodes of wearable strain sensors. Also, the nanopatched graphene applied as an electrode modulates the molecular orientation of deposited organic semiconductor layers, and yields favorable nominal charge injection for organic transistors. These results demonstrate the potential for use of self-assembled organic nanopatches in graphene-based soft electronics. PMID- 29709085 TI - Strong Preference of the Redox-Neutral Mechanism over the Redox Mechanism for the TiIV Catalysis Involved in the Carboamination of Alkyne with Alkene and Diazene. AB - Titanium catalysis generally prefers redox-neutral mechanisms. Yet it has been reported that titanium could promote bond formations in a way similar to reductive elimination. Accordingly, redox catalytic cycles involving TiIV /TiII cycling have been considered. By studying, as an example, the carboamination of alkynes with alkenes and azobenzene catalyzed by the [TiIV ]=NPh imido complex, we performed DFT computations to gain an understanding of how the "abnormal" catalysis takes place, thereby allowing us to clarify whether the catalysis really follows TiIV /TiII redox mechanisms. The reaction first forms an azatitanacyclohexene by alkyne addition to the [TiIV ]=NPh bond, followed by alkene insertion. The azatitanacyclohexene can either undergo Calpha -Cgamma coupling, to afford bicyclo[3.1.0]imine, or beta-H elimination, to yield a [TiIV ]-H hydride, which then undergoes Calpha =Cbeta or Cgamma =Cdelta insertion to give an alpha,beta- or beta,gamma-unsaturated imine, respectively. Both the geometric and electronic structures indicate that the catalytic cycles proceed through redox-neutral mechanisms. The alternative redox mechanisms (e.g., by N-H or C-H reductive elimination) are substantially less favorable. We concluded that electronically, the TiIV catalysis intrinsically favors the redox-neutral mechanism, because a redox pathway would involve TiII structures either in the triplet ground state or in the high-lying open-shell singlet state, but the involvement of triplet TiII structures is spin-forbidden and that of singlet TiII structures is energetically disadvantageous. PMID- 29709084 TI - Metal-Organic Frameworks as Catalyst Supports: Influence of Lattice Disorder on Metal Nanoparticle Formation. AB - Because of their high tunability and surface area, metal-organic frameworks (MOFs) show great promise as supports for metal nanoparticles. Depending on the synthesis route, MOFs may contain defects. Here, we show that highly crystalline MIL-100(Fe) and disordered Basolite(r) F300, with identical iron 1,3,5 benzenetricarboxylate composition, exhibit very divergent properties when used as a support for Pd nanoparticle deposition. While MIL-100(Fe) shows a regular MTN zeotype crystal structure with two types of cages, Basolite(r) F300 lacks long range order beyond 8 A and has a single-pore system. The medium-range configurational linker-node disorder in Basolite(r) F300 results in a reduced number of Lewis acid sites, yielding more hydrophobic surface properties compared to hydrophilic MIL-100(Fe). The hydrophilic/hydrophobic nature of MIL-100(Fe) and Basolite(r) F300 impacts the amount of Pd and particle size distribution of Pd nanoparticles deposited during colloidal synthesis and dry impregnation methods, respectively. It is suggested that polar (apolar) solvents/precursors attractively interact with hydrophilic (hydrophobic) MOF surfaces, allowing tools at hand to increase the level of control over, for example, the nanoparticle size distribution. PMID- 29709086 TI - Di-(2-picolyl)-N-(2-quinolinylmethyl)amine-Functionalized Triarylboron: Lewis Acidity Enhancement and Fluorogenic Discrimination Between Fluoride and Cyanide in Aqueous Solution. AB - Triarylboron-based Lewis acids as fluoride sensors face a stimulating academic challenge because of the high hydration enthalpy of fluoride, and are usually influenced by a competing response for cyanide ion. Herein, we present a new triarylborane functionalized by a metal-ion ligand, di-(2-picolyl)-N-(2 quinolinylmethyl)amine, with subsequent metalation. In aqueous solution, this triarylborane (QB) can capture fluoride and cyanide anions through chelation induced by the synergy of boron and metal ions. Moreover, this triarylborane moiety acts as a fluorescent reporter of the binding, allowing for discrimination between fluoride and cyanide anions through dual-channel fluorescence changes. The different chelation models and fluorogenic responses of this sensor toward F- and CN- were verified by the single-crystal structures of 2-to-2 adduct for KCN and 1-to-1 for KF. PMID- 29709088 TI - Disulfuryl Dichloride ClSO2 OSO2 Cl: A Conformation and Polymorphism Chameleon. AB - Disulfuryl dichloride ClSO2 OSO2 Cl was characterized by vibrational spectroscopy in the gaseous and liquid phase as well as in the Ar-matrix. By varying the temperature, certain bands could be assigned to several conformers. Gas-phase electron diffraction revealed a dominance of the anti-conformer at ambient temperature. The same conformation was found in the solid state. Via the in situ technique for crystallization, not less than four different modifications were identified. Among these different modifications, the structural parameters of the molecules remain relatively constant, but the aggregation pattern changes. Although the molecules aggregate by chlorine???oxygen contacts in each modification, the geometrical parameters of these interaction show significant differences and were evaluated and are in part inconsistent with the halogen bonding concept. PMID- 29709087 TI - Identification of sarcomeric variants in probands with a clinical diagnosis of arrhythmogenic right ventricular cardiomyopathy (ARVC). AB - AIMS: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by ventricular arrhythmias and sudden death. Currently 60% of patients meeting Task Force Criteria (TFC) have an identifiable mutation in one of the desmosomal genes. As much overlap is described between other cardiomyopathies and ARVC, we examined the prevalence of rare, possibly pathogenic sarcomere variants in the ARVC population. METHODS: One hundred and thirty-seven (137) individuals meeting 2010 TFC for a diagnosis of ARVC, negative for pathogenic desmosomal variants, TMEM43, SCN5A, and PLN were screened for variants in the sarcomere genes (ACTC1, MYBPC3, MYH7, MYL2, MYL3, TNNC1, TNNI3, TNNT2, and TPM1) through either clinical or research genetic testing. RESULTS: Six probands (6/137, 4%) were found to carry rare variants in the sarcomere genes. These variants have low prevalence in controls, are predicted damaging by Polyphen-2, and some of the variants are known pathogenic hypertrophic cardiomyopathy mutations. Sarcomere variant carriers had a phenotype that did not differ significantly from desmosomal mutation carriers. As most of these probands were the only affected individuals in their families, however, segregation data are noninformative. CONCLUSION: These data show variants in the sarcomere can be identified in individuals with an ARVC phenotype. Although rare and predicted damaging, proven functional and segregational evidence that these variants can cause ARVC is lacking. Therefore, caution is warranted in interpreting these variants when identified on large next-generation sequencing panels for cardiomyopathies. PMID- 29709089 TI - Tetraacylstannanes as Long-Wavelength Visible-Light Photoinitiators with Intriguing Low Toxicity. AB - The first tetraacylstannanes Sn[(CO)R]4 (R=2,4,6-trimethylphenyl (1 a) and 2,6 dimethylphenyl (1 b)), a class of highly efficient Sn-based photoinitiators, were synthesized. The formation of these derivatives was confirmed by NMR spectroscopy, mass spectrometry, and X-ray crystallography. The UV/Vis absorption spectra of 1 a, b reveal a significant redshift of the longest wavelength absorption compared to the corresponding germanium compounds. In contrast to the known toxicity of organotin derivatives, the AMES test and cytotoxicity studies reveal intriguing low toxicity. The excellent performance of 1 as photoinitiators is demonstrated by photobleaching (UV/Vis) and NMR/CIDNP investigations, as well as photo-DSC studies. PMID- 29709091 TI - Palladium-Catalyzed Enantioselective Arylation of Racemic Ketones to Form Bridged Bicycles via Dynamic Kinetic Resolution. AB - Enantioselective alpha-arylation of racemic ketones containing existing alpha' stereocenters is reported for the first time via base-induced dynamic kinetic resolution. Bridged bicyclic rings are formed in good ee values, which are difficult to obtain otherwise. Furthermore, reactions in DMSO-d6 resulted in extensive deuteration of both alpha- and alpha'-positions in the products, thus supporting a pathway involving rapid, reversible deprotonation of ketones under catalytic conditions. PMID- 29709090 TI - Copper(I)-Catalyzed Enantio- and Diastereodivergent Borylative Coupling of Styrenes and Imines. AB - We report copper(I)-catalyzed enantio- and diastereodivergent borylative coupling of styrenes and imines to produce enantiomerically-enriched alpha,beta-dibranched gamma-boryl amine derivatives. Each of the four possible stereoisomers of the products, derived from the two contiguous stereocenters, was selectively accessible by choosing a proper chiral ligand for the copper catalyst. This method, which combines catalyst-controlled stereodivergency and constitutional divergency derived from the lynchpin motif (i.e., the C-B bond), offers a strategy for addressing the construction of molecular structural diversity concomitant with precise chirality control. PMID- 29709092 TI - The vaginal microbiome amplifies sex hormone-associated cyclic changes in cervicovaginal inflammation and epithelial barrier disruption. AB - PROBLEM: Susceptibility to HIV is associated with the menstrual cycle and vaginal microbiome, but their collective impact on vaginal inflammation remains unclear. Here, we characterized the cervicovaginal proteome, inflammation, and microbiome community structure and function during the menstrual cycle. METHOD OF STUDY: Cervicovaginal secretions were collected from regularly cycling women (n = 16) at median day 10, 16, and 24 of each menstrual cycle and analyzed by mass spectrometry, 16S rRNA gene sequencing, and a multiplex bead array immunoassay. Follicular, ovulatory, and luteal phases were defined by serum sex hormone levels. RESULTS: Ovulation showed the largest mucosal proteome changes, where 30% and 19% of the 406 human proteins identified differed compared to the luteal and follicular phases, respectively. Neutrophil/leukocyte migration pathways were lowest during ovulation and peaked in the luteal phase, while antimicrobial and epithelial barrier promoting proteins were highest during ovulation. Vaginal microbial community structure and function did not vary significantly during the menstrual cycle, with the majority consistently Lactobacillus-dominant (63%) or non-Lactobacillus-dominant (25%). Fluctuations in the epithelial barrier protein RPTN between the ovulatory and luteal phase were amplified in women with Gardnerella vaginalis and anaerobic bacteria and reduced when Lactobacillus was dominant. CONCLUSION: This small study demonstrates that sex hormones modulate neutrophil/leukocyte inflammation, barrier function, and antimicrobial pathways in the female genital tract with the strongest changes occurring during ovulation. The data further suggest a microbiome context for hormone-driven changes in vaginal immunity which may have implications for HIV susceptibility. PMID- 29709093 TI - Magnesium sulfate differentially modulates fetal membrane inflammation in a time dependent manner. AB - PROBLEM: Chorioamnionitis and infection-associated inflammation are major causes of preterm birth. Magnesium sulfate (MgSO4 ) is widely used in obstetrics as a tocolytic; however, its mechanism of action is unclear. This study sought to investigate how MgSO4 modulates infection-associated inflammation in fetal membranes (FMs), and whether the response was time dependent. METHOD OF STUDY: Human FM explants were treated with or without bacterial lipopolysaccharide (LPS); with or without MgSO4 added either: 1 hour before LPS; at the same time as LPS; 1 hour post-LPS; or 2 hours post-LPS. Explants were also treated with or without viral dsRNA and LPS, alone or in combination; and MgSO4 added 1 hour post LPS After 24 hours, supernatants were measured for cytokines/chemokines; and tissue lysates measured for caspase-1 activity. RESULTS: Lipopolysaccharide induced FM inflammation by upregulating the secretion of a number of inflammatory cytokines/chemokines. Magnesium sulfate administered 1-hour post-LPS inhibited FM secretion of IL-1beta, IL-6, G-CSF, RANTES, and TNFalpha. Magnesium sulfate administered 2 hours post-LPS augmented FM secretion of these factors as well as IL-8, IFNgamma, VEGF, GROalpha and IP-10. Magnesium sulfate delivered 1- hour post-LPS inhibited LPS-induced caspase-1 activity, and inhibited the augmented IL 1beta response triggered by combination viral dsRNA and LPS. CONCLUSION: Magnesium sulfate differentially modulates LPS-induced FM inflammation in a time dependent manner, in part through its modulation of caspase-1 activity. Thus, the timing of MgSO4 administration may be critical in optimizing its anti inflammatory effects in the clinical setting. MgSO4 might also be useful at preventing FM inflammation triggered by a polymicrobial viral-bacterial infection. PMID- 29709095 TI - Irreversible electroporation-Let's keep it cool. PMID- 29709094 TI - Accelerated Thermal Depolymerization of Cyclic Polyphthalaldehyde with a Polymeric Thermoacid Generator. AB - Thermally triggerable polymer films that degrade at modest temperatures (~85 degrees C) are created from a blend of cyclic polyphthalaldehyde (cPPA) and a polymeric thermoacid generator, poly(vinyl tert-butyl carbonate sulfone) (PVtBCS). PVtBCS depolymerizes when heated, generating acid which initiates the depolymerization of cPPA into volatile byproducts. The mass loss onset for 2 wt% PVtBCS/cPPA is 22 degrees C lower than the onset for neat cPPA alone in dynamic thermogravimetric analysis experiments. Increased concentrations of PVtBCS increase the rate of depolymerization of cPPA. Raman spectroscopy reveals that the monomer, o-phthalaldehyde, is the main depolymerization product of the acid catalyzed depolymerization of cPPA. The PVtBCS/cPPA blend is a promising material for the design and manufacture of transient electronic packaging and polymers. PMID- 29709096 TI - 17OHP-C in patients with spontaneous preterm labor and intact membranes: is there an effect according to the presence of intra-amniotic inflammation? AB - PROBLEM: It is not known whether 17-alpha-hydroxyprogesterone caproate (17OHP-C) is effective for preventing preterm delivery with an episode of preterm labor (PTL) with or without intra-amniotic inflammation/infection. METHODS OF STUDY: This was a retrospective cohort study. One hundred and seven PTL patients were selected and divided into a 17OHP-C group (use of 17OHP-C: n = 53) and a no treatment group (no use of 17OHP-C: n = 54). Moreover, the patients were divided into three subgroups (subgroup A: without intra-amniotic inflammation, B: with mild intra-amniotic inflammation, and C: with severe intra-amniotic inflammation) according to their level of amniotic interleukin (IL)-8, and perinatal prognosis was analyzed. RESULTS: Interval from admission to delivery (days) in the 17OHP-C group (76 [13-126], n = 34) was significantly longer than that in the no treatment group (50 [8-104], n = 33; P = .012) in subgroup B. In cases without intra-amniotic microbes in subgroup B, a significant prolongation of gestational days was associated with the 17OHP-C group (79 [13-126], n = 25) compared with the no-treatment group (50 [8-104], n = 29; P = .029). However, there were no significant differences in subgroups A or C. CONCLUSION: 17OHP-C could prolong gestational period in limited PTL cases with sterile mild intra-amniotic inflammation. PMID- 29709097 TI - Autophagy: The multi-purpose bridge in viral infections and host cells. AB - Autophagy signaling pathway is involved in cellular homeostasis, developmental processes, cellular stress responses, and immune pathways. The aim of this review is to summarize the relationship between autophagy and viruses. It is not possible to be fully comprehensive, or to provide a complete "overview of all viruses". In this review, we will focus on the interaction of autophagy and viruses and survey how human viruses exploit multiple steps in the autophagy pathway to help viral propagation and escape immune response. We discuss the role that macroautophagy plays in cells infected with hepatitis C virus, hepatitis B virus, rotavirus gastroenteritis, immune cells infected with human immunodeficiency virus, and viral respiratory tract infections both influenza virus and coronavirus. PMID- 29709098 TI - Unresponsiveness to meglumine antimoniate in anthroponotic cutaneous leishmaniasis field isolates: analysis of resistance biomarkers by gene expression profiling. AB - BACKGROUND: Resistance to antimonials is a fundamental determinant of treatment failure in anthroponotic cutaneous leishmaniasis (ACL). Detection of reliable molecular markers to distinguish unresponsive and responsive parasites is critical for consolidating strategies to monitor drug efficacy. METHODS: We analysed the expression of five major antimony resistance-associated genes that is aquaglyceroporin1 (AQP1), gamma-glutamylcysteine synthetase (gamma-GCS), multidrug resistance protein A (MRPA), trypanothione reductase (TR) and thiol dependent reductase 1 (TDR1), in unresponsive and responsive Leishmania tropica field isolates by quantitative real-time PCR in comparison with sensitive and resistant reference strains. RESULTS: Gene expression analysis showed the down regulation of AQP1, gamma-GCS and TDR1 by a factor of 1.9, 1.7 and 3.55, respectively, in unresponsive isolates vs. responsive ones. The average RNA expression level of MRPA increased by a factor of 1.9 in the unresponsive group. Isolates exhibited a strong positive linear correlation between gene expression of AQP1 and gamma-GCS. A negative correlation between the AQP1 and gamma-GCS expression level and lesion duration in responsive patients indicated the potential role in diagnosing drug-unresponsive parasites in endemic areas of ACL. CONCLUSION: In cases of inconclusive outcomes of resistance tests in clinical isolates, expression analysis of a set of influential genes can be beneficial to identify distinctive biomarkers between antimony-unresponsive and responsive parasites. PMID- 29709099 TI - Biomarker-based phenotyping of myocardial fibrosis identifies patients with heart failure with preserved ejection fraction resistant to the beneficial effects of spironolactone: results from the Aldo-DHF trial. AB - BACKGROUND: Myocardial fibrosis is characterized by excessive cross-linking and deposition of collagen type I and is involved in left ventricular stiffening and left ventricular diastolic dysfunction (LVDD). We investigated whether the effect of spironolactone on LVDD in patients with heart failure with preserved ejection fraction (HFpEF) depends on its effects on collagen cross-linking and/or deposition. METHODS AND RESULTS: We investigated 381 HFpEF patients from the multicentre, randomized, placebo-controlled Aldo-DHF trial with measures of the E:e' ratio. The ratio of serum carboxy-terminal telopeptide of collagen type I to serum matrix metalloproteinase-1 (CITP:MMP-1, an inverse index of myocardial collagen cross-linking) and serum carboxy-terminal propeptide of procollagen type I (PICP, a direct index of myocardial collagen deposition) were determined at baseline and after 1-year treatment with spironolactone 25 mg once daily or placebo. Patients were classified by CITP:MMP-1 and PICP tertiles at baseline. While CITP:MMP-1 tertiles at baseline interacted (P < 0.05) with spironolactone effect on E:e', PICP tertiles did not. In fact, while spironolactone treatment did not modify E:e' in patients with lower CITP:MMP-1 levels, this ratio was significantly reduced in the remaining spironolactone-treated patients. In addition, PICP was unchanged in patients with lower CITP:MMP-1 levels but was reduced in the remaining spironolactone-treated patients. CONCLUSIONS: A biochemical phenotype of high collagen cross-linking identifies HFpEF patients resistant to the beneficial effects of spironolactone on LVDD. It is suggested that excessive collagen cross-linking, which stabilizes collagen type I fibres, diminishes the ability of spironolactone to reduce collagen deposition in these patients. PMID- 29709100 TI - A comparison of effectiveness among frequent treatments of recurrent spontaneous abortion: A Bayesian network meta-analysis. AB - OBJECTIVE: A comprehensive network meta-analysis was designed to clarify contradictions and offer valuable clinical guidance in the treatment of recurrent spontaneous abortion (RSA). METHOD: The included clinical trials were selected from the relevant medical journal databases and screened. Treatments were ranked by the surface under the cumulative ranking curve. Heat plots were constructed to analyze the inconsistency between direct data and network results, and adjusted funnel plots were constructed to assess publication bias. RESULTS: Forty-nine randomized controlled trials involving a total of 8496 RSA patients were selected. With placebo as control, corticosteroid plus low dose aspirin (LDA) plus unfractionated heparin (UFH), granulocyte colony-stimulating factor (G-CSF) alone, and LDA plus low molecular weight heparin (LMWH) all demonstrated effectiveness in increasing successful live birth rates and reducing the incidences of miscarriage. However, no treatment was demonstrably superior to placebo in terms of pregnancy success. For all 3 endpoints (live birth, abortion and success pregnancy), the adjusted funnel plots were symmetric to zero and indicated no publication bias. In terms of live birth and abortion rates, no treatment outperformed placebo in patients with antiphospholipid syndrome. CONCLUSION: In consideration of live birth and abortion rates, corticosteroid plus LDA plus UFH appeared to be the optimum treatment strategy; G-CSF was second, followed by LDA with LMWH, LDA plus LMWH plus intravenous immunoglobulin, corticosteroid with LDA and others. Subgroup analysis demonstrated no benefit of antithrombotic therapy in patients with antiphospholipid syndrome. PMID- 29709101 TI - Genotype-phenotype relationship and risk stratification in loss-of-function SCN5A mutation carriers. AB - INTRODUCTION: Loss-of-function (LoF) mutations in the SCN5A gene cause multiple phenotypes including Brugada Syndrome (BrS) and a diffuse cardiac conduction defect. Markers of increased risk for sudden cardiac death (SCD) in LoF SCN5A mutation carriers are ill defined. We hypothesized that late potentials and fragmented QRS would be more prevalent in SCN5A mutation carriers compared to SCN5A-negative BrS patients and evaluated risk markers for SCD in SCN5A mutation carriers. METHODS: We included all SCN5A loss-of-function mutation carriers and SCN5A-negative BrS patients from our center. A combined arrhythmic endpoint was defined as appropriate ICD shock or SCD. RESULTS: Late potentials were more prevalent in 79 SCN5A mutation carriers compared to 39 SCN5A-negative BrS patients (66% versus 44%, p = .021), while there was no difference in the prevalence of fragmented QRS. PR interval prolongation was the only parameter that predicted the presence of a SCN5A mutation in BrS (OR 1.08; p < .001). Four SCN5A mutation carriers, of whom three did not have a diagnostic type 1 ECG either spontaneously or after provocation with a sodium channel blocker, reached the combined arrhythmic endpoint during a follow-up of 44 +/- 52 months resulting in an annual incidence rate of 1.37%. CONCLUSION: LP were more frequently observed in SCN5A mutation carriers, while fQRS was not. In SCN5A mutation carriers, the annual incidence rate of SCD was non-negligible, even in the absence of a spontaneous or induced type 1 ECG. Therefore, proper follow-up of SCN5A mutation carriers without Brugada syndrome phenotype is warranted. PMID- 29709103 TI - Coordination of Be and Mg Centres by HCN Ligands - Be...N and Mg...N Interactions. AB - omegaB97XD/aug-cc-pVTZ calculations were performed for clusters of Z2+ cations (Z=Be and Mg) and HCN molecules (up to six molecules). The clusters of Be(CH3 )2 and Mg(CH3 )2 with HCN species were also calculated to analyse the influence of the Be/Mg-C formally covalent bonds on interactions of Be or Mg centre with ligands. The beryllium and magnesium centres possess different areas of a positive electrostatic potential that depend on a number of HCN ligands in the cluster considered. Numerous correlations between geometrical, energetic and topological parameters of the clusters considered are discussed since various theoretical approaches are applied; Quantum Theory of 'Atoms in Molecules', Natural Bond Orbital method and decomposition of the energy of interaction. The Be/Mg...N interactions classified as beryllium and magnesium bonds possess numerous characteristics which are known for the hydrogen bonds. Different types of coordination of Be and Mg centres analysed here exist also in crystal structures. PMID- 29709102 TI - General Syntheses of Nanotubes Induced by Block Copolymer Self-Assembly. AB - Amphiphilic block copolymer templating strategies are extensively used for syntheses of mesoporous materials. However, monodisperse tubular nanostructures are limited. Here, a general method is developed to synthesize monodisperse nanotubes with narrow diameter distribution induced by self-assembly of block copolymer. 3-Aminophenol (AP) and formaldehyde (F) polymerize and self-assemble with cylindrical PS-b-PEO micelles into worm-like PS-b-PEO@APF composites with uniform diameter (49 +/- 3 nm). After template extraction, worm-like APF polymer nanotubes are formed. The structure and morphology of the polymer nanotubes can be tuned by regulating the synthesis conditions. Furthermore, PS-b-PEO@APF composites are uniformly converted to isomorphic carbon nanotubes with large surface area of 662 m2 g-1 , abundant hierarchical porous frameworks and nitrogen doping. The synthesis can be extended to silica nanotubes. These findings open an avenue to the design of porous materials with controlled structural framework, composition, and properties for a wide range of applications. PMID- 29709104 TI - Solvent-Controlled Synthesis of Highly Luminescent Carbon Dots with a Wide Color Gamut and Narrowed Emission Peak Widths. AB - Carbon dots (CDs) have tremendous potential applications in bioimaging, biomedicine, and optoelectronics. By far, it is still difficult to produce photoluminescence (PL) tunable CDs with high quantum yield (QY) across the entire visible spectrum and narrow the emission peak widths of CDs close to those of typical quantum dots. In this work, a series of CDs with tunable emission from 443 to 745 nm, quantum yield within 13-54%, and narrowed full width at half maximum (FWHM) from 108 to 55 nm, are obtained by only adjusting the reaction solvents in a one-pot solvothermal route. The distinct optical features of these CDs are based on their differences in the particle size, and the content of graphitic nitrogen and oxygen-containing functional groups, which can be modulated by controlling the dehydration and carbonization processes during solvothermal reactions. Blue, green, yellow, red, and even pure white light emitting films (Commission Internationale de L'Eclairage (CIE)= 0.33, 0.33, QY = 39%) are prepared by dispersing one or three kinds of CDs into polyvinyl alcohol with appropriate ratios. The near-infrared emissive CDs are excellent fluorescent probes for both in vitro and in vivo bioimaging because of their high QY in water, long-term stability, and low cytotoxicity. PMID- 29709105 TI - Enantioselective Mukaiyama-Michael Reaction Catalyzed by a Chiral Rhodium Complex Based on Pinene-Modified Pyridine Ligands. AB - The rhodium complex Lambda-Rh1 containing chiral pinene-modified pyridine ligands is prepared through a two-step synthetic procedure; it exhibits excellent reactivity and enantiocontrol towards the enantioselective Mukaiyama-Michael reaction of alpha,beta-unsaturated 2-acyl imidazoles with silyl enol ethers, affording enantioenriched 1,5-dicarbonyl compounds in good yields (up to 99 %) with excellent enantioselectivities (up to 99 % ee). PMID- 29709106 TI - Selectivity Control on Hydrogenation of Substituted Nitroarenes through End-On Adsorption of Reactants in Zeolite-Encapsulated Platinum Nanoparticles. AB - Platinum nanoparticles encapsulated into zeolite Y (Pt@Y catalyst) exhibit excellent catalytic selectivity in the hydrogenation of substituted nitroarenes to form the corresponding aromatic amines, even after complete conversion. With the hydrogenation of p-chloronitrobenzene as a model, the role of zeolite encapsulation toward perfect selectivity can be attributed to constraint of the substrate adsorbed on the platinum surface in an end-on conformation. This conformation results in the activation of only one adsorbed group, with little influence on the other one in the molecule. Owing to a much lower apparent activation energy of Pt@Y for the hydrogenation of a separately adsorbed nitro group than that of the adsorbed chloro group, the Pt@Y catalyst can prevent hydrodechlorination of p-chloronitrobenzene under mild conditions. Moreover, such a conformation results in a reduced adsorption energy of target p-chloroaniline on the platinum surface; thus suppressing the reactivity of hydrodechlorination of p-chloroaniline to circumvent further C-Cl bond breakage. PMID- 29709107 TI - Embedding Carbon Nitride into a Covalent Organic Framework with Enhanced Photocatalysis Performance. AB - We report a new strategy to construct porous carbon nitride (PCN) by embedding a heptazine unit-the primary building block of carbon nitride-into the backbone of a covalent organic framework (COF). The strategy results in a new type of PCN which bears a fibrous morphology, high surface area and wide visible absorption. The photocatalytic performance was evaluated by photodegradation of an organic dye. We found that the introduction of the heptazine unit has a prominent effect on the catalytic activity, which demonstrates an effective strategy to prepare carbon nitride materials. This work opens up a new way for the preparation of carbon nitride for photocatalysis applications. PMID- 29709108 TI - Uniform Luminous Perovskite Nanofibers with Color-Tunability and Improved Stability Prepared by One-Step Core/Shell Electrospinning. AB - A one-step core/shell electrospinning technique is exploited to fabricate uniform luminous perovskite-based nanofibers, wherein the perovskite and the polymer are respectively employed in the core and the outer shell. Such a coaxial electrospinning technique enables the in situ formation of perovskite nanocrystals, exempting the needs of presynthesis of perovskite quantum dots or post-treatments. It is demonstrated that not only the luminous electrospun nanofibers can possess color-tunability by simply tuning the perovskite composition, but also the grain size of the formed perovskite nanocrystals is largely affected by the perovskite precursor stoichiometry and the polymer solution concentration. Consequently, the optimized perovskite electrospun nanofiber yields a high photoluminescence quantum yield of 30.9%, significantly surpassing the value of its thin-film counterpart. Moreover, owing to the hydrophobic characteristic of shell polymer, the prepared perovskite nanofiber is endowed with a high resistance to air and water. Its photoluminescence intensity remains constant while stored under ambient environment with a relative humidity of 85% over a month and retains intensity higher than 50% of its initial intensity while immersed in water for 48 h. More intriguingly, a white light emitting perovskite-based nanofiber is successfully fabricated by pairing the orange light-emitting compositional perovskite with a blue light-emitting conjugated polymer. PMID- 29709109 TI - Clinical outcomes of a stepped care program for borderline personality disorder. AB - OBJECTIVE: This study examines the clinical outcomes of two clinics for borderline personality disorder (BPD) in a naturalistic setting, offering a stepped care model with both short-term (ST) treatment lasting 12 weeks and extended care (EC) up to 24 months. METHODS: A total of 479 patients attending the ST clinic and 145 attending the EC clinic were assessed on depression, impulsivity, self-esteem, emotion dysregulation, substance abuse, self-harm and suicidality. RESULTS: There were significant reductions in all symptoms in both clinics with the exception that substance abuse was only reduced in the EC clinic. On all symptoms, no significant differences in magnitude of changes were observed between patients who stayed in EC clinic for 6-12 months in comparison to those who stayed for 18-24 months. CONCLUSIONS: These results support the concept that for the majority of patients with BPD, brief treatment can be effective. While some patients still need longer treatment, the results are encouraging for brief treatment as a first step for the majority of patients with BPD. While this study adds to the weight of evidence to support ST interventions for patients with BPD, further research using a control group is needed. Copyright (c) 2018 John Wiley & Sons, Ltd. PMID- 29709111 TI - C-H Alkenylation of Pyrroles by Electronically Matching Ligand Control. AB - Directing group and substrate control strategies have frequently been employed for the regioselective C-H alkenylation of acid- and oxidant-sensitive pyrrole heterocycles. We developed an undirected, aerobic strategy for the C-H alkenylation of N-alkylpyrroles by ligand control. For C2-alkenylation of electron-rich N-alkylpyrroles, an electrophilic palladium catalyst derived from Pd(OAc)2 and 4,5-diazafluoren-9-one (DAF) was used. Alternatively, a combination of Pd(OAc)2 and a mono-protected amino acid ligand, Ac-Val-OH, was useful for C5 alkenylation of N-alkylpyrroles possessing electron-withdrawing groups at the C2 position. This approach based on the electronic effects of heterocycles and catalysts can rapidly provide a wide range of alkenyl pyrroles from readily available N-alkylpyrroles and alkenes. PMID- 29709113 TI - Chaos theory and fractals. PMID- 29709110 TI - Making lineage decisions with biological noise: Lessons from the early mouse embryo. AB - Understanding how individual cells make fate decisions that lead to the faithful formation and homeostatic maintenance of tissues is a fundamental goal of contemporary developmental and stem cell biology. Seemingly uniform populations of stem cells and multipotent progenitors display a surprising degree of heterogeneity, primarily originating from the inherent stochastic nature of molecular processes underlying gene expression. Despite this heterogeneity, lineage decisions result in tissues of a defined size and with consistent proportions of differentiated cell types. Using the early mouse embryo as a model we review recent developments that have allowed the quantification of molecular intercellular heterogeneity during cell differentiation. We first discuss the relationship between these heterogeneities and developmental cellular potential. We then review recent theoretical approaches that formalize the mechanisms underlying fate decisions in the inner cell mass of the blastocyst stage embryo. These models build on our extensive knowledge of the genetic control of fate decisions in this system and will become essential tools for a rigorous understanding of the connection between noisy molecular processes and reproducible outcomes at the multicellular level. We conclude by suggesting that cell-to-cell communication provides a mechanism to exploit and buffer intercellular variability in a self-organized process that culminates in the reproducible formation of the mature mammalian blastocyst stage embryo that is ready for implantation into the maternal uterus. This article is categorized under: Gene Expression and Transcriptional Hierarchies > Cellular Differentiation Establishment of Spatial and Temporal Patterns > Regulation of Size, Proportion, and Timing Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics Gene Expression and Transcriptional Hierarchies > Quantitative Methods and Models. PMID- 29709114 TI - Minimizing publication bias. PMID- 29709112 TI - A Five-Year Study of the Efficacy of Purified CD34+ Cell Therapy for Angiitis Induced No-Option Critical Limb Ischemia. AB - Angiitis-induced critical limb ischemia (AICLI) patients constitute a remarkable proportion of no-option critical limb ischemia (CLI) patients. Stem cell therapy has become an innovative and promising option for no-option CLI patients. As one of these promising stem cell therapies, purified CD34+ cell transplantation (PuCeT) has shown favorable short-term results. However, the long-term efficacy of PuCeT has yet to be reported. This study evaluates the long-term efficacy of PuCeT in AICLI patients. Twenty-seven AICLI patients were enrolled from May 2009 to December 2011. Granulocyte colony-stimulating factor (G-CSF) and enoxaparin sodium were administered for 5 days. On day 5, CD34+ cell isolation was performed, and cells were transplanted by intramuscular injection. The primary endpoint, major-amputation-free survival rate (MAFS), as well as secondary endpoints, such as peak pain-free walking time (PPFWT) and the Wong-Baker FACES pain rating scale score (WFPRSS), were routinely evaluated during the 5-year follow-up period. The endpoints were as follows: the MAFS was 88.89%; PPFWT increased from 3 +/- 3 to 17 +/- 6 minutes; WFPRSS decreased from 7 +/- 2 to 0.3 +/- 1.7; the ulcer healing rate was 85.71%; the recurrence rate was 11.11%; and SF-36v2 scores were significantly improved at 5 years after PuCeT. The rate of labor recovery 5 years after PuCeT was 65.38%, and no severe adverse effect was observed during the treatment. PuCeT demonstrated long-term efficacy and durability as a treatment of AICLI not only in achieving limb salvage but also in recovering the labor competence and improving the quality of life of patients. Stem Cells Translational Medicine 2018;7:583-590. PMID- 29709115 TI - Looking backwards into the Future of Orthodontics. PMID- 29709117 TI - Orthodontic Education. PMID- 29709116 TI - Australian Orthodontists: are they "with it". PMID- 29709118 TI - The role of the foundation in Australian Orthodontic education. PMID- 29709119 TI - Orthodontics in general practice: part 1. Scope and limits related to orthodontic education. PMID- 29709120 TI - Who says that child needs orthodontic treatment? PMID- 29709121 TI - The history of dental hygienists in Australia and their use in orthodontic practice. PMID- 29709122 TI - Brackets, epitopes and flash memory cards: a futuristic view of clinical orthodontics. AB - Orthodontics continues to be a profession anchored in traditional technology using appliances that cause inflammatory periodontal ligament (PDL) responses. Existing concepts of biological tooth movement based largely on histological tissue observations and the application of physical principles require major reassessment. In the next millennium, the genome revolution and knowledge of protein production and control could lead to the genetic correction of dentofacial anomalies and pain-free, biomolecular methods of malocclusion correction and long-term stability. A fundamental change is likely to be the abolition of bracket systems and their replacement with preprogrammed microchips driven by computers, and the control of PD[ blood vessels and cells by pharmacological targeting. Future survival of the profession will depend on a radically different specialist who will be educated with a postgraduate curriculum based on molecular biology and computer engineering. PMID- 29709123 TI - What is the truth behind the smile? AB - A number of arguments surround orthodontics and orthodontic treatment and this article aims to discuss the current thinking and evidence base associated with these controversies. PMID- 29709124 TI - 3D facial and dento-alveolar imaging. AB - This article reviews three-dimensional (1D) surface scanning contrasted with 3D imaging. Precise techniques are now available for capture of the face and craniofacial structures as well as improved introoral scanning for the production of virtual 3D casts of the dentition. Facial and intraoral scanners have established an accuracy that makes them viable for use in the clinical and research arenas. Three-dimensional imaging is a field of rapid change and currently-available scanners will doubtlessly be surpassed in the near future. Although there is much overlap between the capabilities of different proprietary systems, there are subtle, yet significant, differences between manufacturers. The differences have the potential to make a purchased scanner not fulfil expectations as much for reasons of software compatibility and integration, as for clinical usability and accuracy. PMID- 29709125 TI - Management of missing mandibular second premolars: a review. AB - Tooth agenesis is the most common developmental dental anomaly and it is frequently associated with other dento-skeletal disturbances, such as structural variations of other teeth, late dental eruption, transpositions and crowding. Except for the third molars, the mandibular second premolars are the most commonly missing teeth. Oral rehabilitation of patients with missing mandibular premolars often requires a multi-disciplinary approach, and usually results in prolonged treatment time and a greater burden of care. An understanding of the aetiology and clinical features of hypodlontia is essential for the planning phase and the outcome of treatment. The purpose of the present review is, therefore, to discuss the aetiology of hypodlontia as well as to evaluate the clinical options available for the treatment of missing mandibular second premolars. An insight into future research directions and their clinical applications will also be discussed. PMID- 29709126 TI - Orthodontic considerations for impacted and ectopic teeth. AB - This review article describes the changing approach to the management of various impacted teeth. Currently, more third molars are being retained, and it is likely that more patients will develop impactions than a generation ago because of non extraction orthodontic treatment plans. There are still valid reasons for the surgical removal of selected third molars during the teenage years, during which time impaction can be anticipated to avoid the higher rate of morbidity associated with later removal. Palatally-impacted canines (PIC] can now often be managed with interceptive and non-surgical approaches, which are attractive options. The various approaches addressed in the literature are discussed. PMID- 29709127 TI - The effect of paper patching on aural fullness of unknown aetiology. AB - : The effect of paper patching on aural fullness of unknown aetiology. OBJECTIVE: To assess the effect of paper patching on aural fullness. METHODOLOGY: We conducted a prospective, single-blind, placebo-controlled study using urn randomization. Twenty-two patients presenting with the complaint of aural fullness, without middle-ear pathology, were recruited from a secondary referral centre. The tested intervention was the application of paper patches on specified areas of the tympanic membrane. The main outcome measure was the change in subjective symptoms of average aural fullness and peak aural fullness, based on differences between pre- and post-intervention measurements on a scale from 0 to 10. RESULTS: Paper patching led to significant improvement in subjective symptom scores. In the treatment group, the change in average aural fullness was -2.00 (SD 2.00, p = 0.006), and the change in peak fullness was -1.77 (SD 2.49, p = 0.01). In the placebo group, these values were -0.13 (SD 1.55, p = 0.72) and +0.33 (SD 1.10, p = 0.37), respectively. No major adverse effects were reported. CONCLUSION: After one week of treatment, paper patching showed a beneficial effect on aural fullness of vague or unknown aetiology. PMID- 29709128 TI - The incidence of hypothyroidism after radiotherapy for head and neck cancer. AB - : The incidence of hypothyroidism after radiotherapy for head and neck cancer. OBJECTIVES: To identify the incidence of radiation-induced hypothyroidism (HT) after head and neck radiotherapy.Furthermore, we wanted to correlate patient and treatment characteristics with the incidence of HT in order to identify predictive factors for radiation-induced HT. METHODOLOGY: We examined the values of thyrotropin, i.e., the thyroid-stimulating hormone (TSH), in head and neck cancer patients who received a combination treatment of radiotherapy and chemotherapy between 2005 and 2012. HT was defined as having a TSH value of > 10 mIU/L or whenever the patient started to take substitution therapy after treatment. We correlated the radiotherapy mean dose to the thyroid gland (Dmean), the pretreatment volume of the thyroid gland, sex, age, type of concomitant treatment, tumour localization, and T and N classification with the incidence of HT. RESULTS: We were able to obtain data from 72 patients. From these 72 patients, 48 (66%) had a normal thyroid function and 25 (34%) had developed HT. The mean follow-up for these patients was 55 months (range: 21 to 103 months). Out of the 25 patients with HT, 8 (32%) were diagnosed within the first year of follow-up. Increasing Dmean is a significant risk factor for developing HT. Increasing thyroid volume, on the other hand, was correlated with less HT in our patient cohort. CONCLUSIONS: In our study, the incidence of HT is 34%. We also noticed that HT can even develop shortly after treatment. Patients with a higher Dmean to the thyroid gland and lower pretreatment thyroid gland volumes are more at risk. PMID- 29709129 TI - Human papilloma virus detection in oropharyngeal cancer with gargle samples. AB - : Human papilloma virus detection in oropharyngeal cancer with gargle samples. OBJECTIVE: human papilloma virus (HPV) is a major risk factor for oropharyngeal squamous cell carcinoma (OPSCC) and knowledge of a patient's HPV status is clinically important in terms of treatment and prognosis. The practicality of using oral gargle samples to reliably detect HPV in patients with OPSCC remains unclear. Therefore, we evaluated the feasibility of HPV detection in gargle samples of OPSCC patients using an HPV-dedicated nucleic acid amplification test (cobas 4800 HPV Test; Roche Diagnostics K.K.). METHODOLOGY: 15 patients with histologically proven OPSCC were evaluated from May 2014 to March 2015. Swab sam- ples served as positive controls and were tested using both the Hybrid Capture II HPV Test (HC-II; Digene Corporation) and the cobas 4800 HPV Test. Oral gargle samples were tested using the cobas 4800 HPV Test. Five of the 15 patients were confirmed to be HPV-positive by a combination of p16 immunohistochemistry, HPV DNA in situ hybridization and nucleic acid amplification. RESULTS: the sensitivity and specificity of the gargling method were 60% and 100%, respectively. No false-positives were obtained. Detection of HPV in two very small tumours rising from the base of the tongue was difficult and these cases were overlooked as HPV-negative. CONCLUSIONS: use of the gargling method to determine HPV positivity in OPSCC patients appears feasible, except in patients with very small tumours. Real-time polymerase chain reaction using gargle samples may have greater clinical efficacy than the swabbing method. PMID- 29709130 TI - Induction chemotherapy followed by supracricoid partial laryngectomy (SCPL) with cricohyoidoepiglottopexy (CHEP) in T3NO arytenoid fixation-related glottic cancer. AB - : Induction chemotherapy followed by supracricoid partial laryngectomy (SCPL) with cricohyoidoepiglottopexy (CHEF) in T3NO arytenoid fixation-related glottic cancer. OBJECTIVE: Arytenoid fixation in the larynx has been considered a contraindication for performing organ preservation surgery (OPS). We present a retrospective series of cases of arytenoid fixation-related T3N0 glottic cancer treated by neoadjuvant chemotherapy followed by OPS. MATERIAL: Retrospective review of 19 patients (from 2008 to 2012) with T3NO glottic cancer who received two cycles of neoadjuvant chemotherapy with a combination of paclitaxel, cisplatin and 5-fluoruracil (PPF), with a 21-day interval between each cycle, followed by supracricoid partial laryngectomy (SCPL) with cricohyoidoepiglottopexy (CHEP). RESULTS: Sixteen patients with a mean age of 56.4 years received neoadjuvant chemotherapy with a clinical response (7 partial response/9 complete response) and radiologic response by computed tomography (CT) (7 partial response/7 complete response/2 cases without CT) were treated with SCPL-CHEP and removal of the arytenoid cartilage in the tumour site (10 left/6 right), bilateral neck dissection of levels II to V and searching of the Delphian node. There was one patient who died after a recurrence in the larynx and who also had an additional concomitant second primary tumour, and a second patient with a second primary tumour in the lung, who is still alive after treatment. Disease-free survival (DFS) was 82.5% at 5 years and overall survival (OS) was 80% at 5 years. CONCLUSION: Neoadjuvant chemotherapy proved beneficial in patients waiting for surgery, helped maximize the oncologic benefit of the surgery provided (good local control using SCPL with CHEP), improved regional and distant control, minimized side effects by avoiding treatment with radiotherapy whenever possible, and proved feasible even in the presence of ipsilateral arytenoid fixation. Our results are encouraging, although a multi-centre randomized clinical trial should be performed in order to identify the true impact of this approach. PMID- 29709131 TI - Airway intervention in cases of acute epiglottitis. AB - : Airway intervention in cases of acute epiglottitis.Problem/objectives: In cases of acute epiglottitis, indications for airway intervention have not been established. In the present study, we reviewed patients with acute epiglottitis to identify clinical factors, which suggest airway intervention should be performed. METHODOLOGY: Patients with acute epiglottitis admitted to The Jikei University Daisan Hospital (Tokyo) from 2004 to 2013 were identified. Patients' characteristics, histories, laryngoscopic findings and laboratory findings were reviewed and analysed. RESULTS: Of the 83 patients (82 adults and one adolescent) in the sample, 16 (19%) underwent airway intervention and conservative treatment. The factors that were significantly more likely to have been present in patients who received airway intervention were odynophagia, drooling, hoarseness, muffled voice, dyspnoea, swelling of the posterior side of the epiglottis, less than 50% of the glottis area being visible with laryngoscopy, and a high white blood cell (WBC) count. The only factor that was shown by multiple logistic regression analysis to be distinctively predictive of airway intervention was "less than 50% of the glottis area being visible" (P = .000, odds ratio = 23.630, sensitivity = 86.6%, specificity = 78.6%, predictive accuracy = 85.2%). CONCLUSIONS: When considering whether airway intervention should be performed in cases of acute epiglottitis, the most important clinical factor is the laryngoscopic finding that "less than 50% of the glottis area being visible." Other important clinical factors to consider are odynophagia, drooling, hoarseness, muffled voice, dyspnoea, swelling of the posterior side of the epiglottis and a high WBC count. PMID- 29709132 TI - Comparison of the cough reflex test and water swallowing test in healthy participants and neurological patients. AB - : Comparison of the cough reflex test and water swallowing test in healthy participants and neurological patients. BACKGROUND: Silent aspiration is poorly identified by traditional clinical swallowing evaluations. Recently, sevral studies have proposed the use of a cough reflex test (CRT) for screening patients at risk of aspirations. The first aithis study is to investigate the CRT thresholds of citric acid concentration for identifying cough responses in healthy participants and neurological patients. The second aim is to compare the results of the CRT with the water swallowing test (WST), a standard screening test for identifying cough responses in neurological patients. METHODS: The CRT and then the WST were administered to 100 neurological patients and 100 healthy participants. For the CRT, we administered incremental solutions of citric acid interspersed with placebo doses. We used the results of the CRT in healthy participants to define a citric acid concentration cut-off, which could be used with neurological patients as a screening for aspirations. RESULTS: As all controls coughed at a concentration of 0.1 mol/L, this was used as a cut-off in patients to identify coughing as a screening for aspiration risk. Patients showed cough reflexes at concentrations significantly higher than controls (p=0 .001). The WST was not administered to 17 patients, due to cognitive deficits and severe clinical conditions. Thirty six patients had a cough response above the screening cut-off (> 0.1 mol/L), 25 of which (30.1%) also had a positive cough response during the WST. CONCLUSION: The CRT correlated significantly with the WST. Unlike the WST, the CRT could be easily administered to severely impaired patients. Our results indicate the use of the CRT as a screening test for silent aspirators. PMID- 29709133 TI - Assessment and management of presumed branchial cleft cysts: our experience. AB - : Assessment and management of presumed branchial cleft cysts: our experience. OBJECTIVES: The aim was to assess the accuracy of diagnosis and management of presumed branchial cleft cysts in our centre. METHODOLOGY: Retrospective review of patients with a clinical diagnosis of branchial cleft cyst at B arts Health NHS Trust from 2009 to 2015. RESULTS: 67 patients underwent surgical excision for presumed branchial cysts. Ninety per cent were histologically confirmed, 7% demonstrated cystic metastatic squamous cell carcinoma, and 3% lymph node metastases from papillary thyroid cancer. No patient had pre-operative Multi Disciplinary Team (MDT) discussion. Pre-operative FNA had a positive predictive value of 90% (95% Cl 0.82-0.95). Age >40 years (p=0.02) and presence of lymph nodes (p=0.02) carried a higher risk of malignancy. CONCLUSIONS: Patients >40 years with or without multiple lymph nod 'es on imaging should be treated as presumed meta- static cancer. Consideration should be given to concurrent panendoscopy and intra-operative frozen section +/- selective neck dissection after discussion at the Head & Neck MDT. PMID- 29709134 TI - The microbiology of normal non-inflamed sinuses. AB - : The microbiology of normal non-inflamed sinuses. OBJECTIVES: The presence of organisms in the healthy sinus was uncertain for many decades. This review summarizes the studies that have explored the microbiology of normal non-inflamed sinuses using conventional microbiological culture methods and non-culture molecular techniques, and discusses the potential implications of these for the treatment and prevention of sinus inflammation. METHODOLOGY: A literature search of the Cochrane Library, EMBASE, TRIP, and MEDLINE databases was conducted from their inception (1993 for the Cochrane Library, 1980 for EMBASE, 1997 for TRIP, and 1966 for MEDLINE) to 25th June 2016. RESULTS: Studies that used adequate microbiological methods demonstrated the presence of aerobic and anaerobic bacterial flora in healthy non-inflamed sinuses. These organisms may participate in sinus inflammation if the right circumstances arise. Recent data suggest that the host response or lack of response to normal sinus flora may be central to the development of sinus inflammation. CONCLUSIONS: Healthy non-inflamed sinuses are colonized by rich and diverse populations of aerobic and anaerobic bacterial flora. These organisms may participate in sinus inflammation if the right circumstances arise. The host response or lack of response to the normal sinus flora may be central to the development of sinus inflammation. Corynebacterium tuberculostearicum seems to have a potential pathogenic role, while certain probiotics may have a protective effect. Modulation of the sinus flora by topical antimicrobial and/or probiotic organisms which may interfere with the growth of potential bacterial and fungal pathogens may be used to prevent and treat sinus inflammation. PMID- 29709135 TI - Periostin: a novel biomarker for chronic rhinosinusitis. AB - : Periostin: a novel biomarker for chronic rhinosinusitis. OBJECTIVES: Rhinosinusitis is characterized by inflammation of the sinuses, resulting in particular symptoms. This study aims to investigate the feasibility of periostin as a biomarker for chronic rhinosinusitis. METHODOLOGY: The mucosal tissues of the ethmoid sinus were sampled from 12 patients with chronic rhinosinusitis without nasal polyps (CRsNP) and 25 with chronic rhinosinusitis with nasal polyps (CRwNP). Inferior turbinate biopsy was performed in 15 patients with a deviation of the nasal septum (DNS). Immunohistochemical (IHC) staining was performed to assess the distribution of periostin. Quantitative reverse transcription polymerase chain reaction (RT-PCR) was conducted to detect the expression of periostin mRNA in nasal tissue specimens. The serum concentration of periostin was measured using enzyme-linked immunosorbent assay (ELISA). Correlation analysis among periostin mRNA in nasal mucosa, IHC staining score of periostin, serum concentration of periostin and proportion of blood eosinophils was performed. RESULTS: The serum concentration of periostin and the IHC staining score of nasal mucosa from CRSsNP and CRSwNP patients were significantly higher than those in DNS counterparts (both P <0.01). The levels of periostin mRNA in CRSsNP and CRSwNP patients were slightly increased, but did not significantly differ from that in the DNS group (both P >0.05). The IHC staining score and serum concentration of periostin were correlated with the proportion of eosinophils in blood (P<0.05 and P <0.0 1). CONCLUSION: Periostin can be used as a novel biomarker for chronic rhinosinusitis, which provides a potential target for individualized therapy of chronic rhinosinusitis. PMID- 29709136 TI - Corticosteroid hypersensitivity in allergic rhinitis. AB - : Corticosteroid hypersensitivity in allergic rhinitis. BACKGROUND: intranasal corticosteroid (IC) is the most effective treatment method in allergic rhinitis patients who are unresponsive to antihistamines. The literature reports an approximate 20% treatment failure for instances where IC is used for the treatment allergic rhinitis. Hypersensitivity reaction to corticosteroids may be one of the causes of this treatment failure. OBJECTIVE: to discover the incidence and confounding factors of corticosteroid hypersensitivity in patients with allergic rhinitis. METHODS: after 31 patients were excluded, 150 consecutive patients who were prospectively evaluated in our outpatient clinics with the diagnosis of allergic rhinitis and 50 age- and sex- matched healthy volunteers were included in this study. To diagnose allergic rhinitis, the symptoms of patients and a skin prick test were used. A skin patch test was used to determine corticosteroid hypersensitivity. Total IgE values and total eosinophil count were obtained for all patients. Total symptom scores were calculated for the severity of symptoms and to determine the response to therapy using intranasal corticosteroids. RESULTS: the incidence of corticosteroid hypersensitivity determined via the skin patch test was 14.0% (21 out of 150 patients). A difference was observed for patch test positivity results between the study and control groups (14% vs. 0%, respectively). Serum IgE levels and total eosinophil count were higher among patients who had corticosteroid hypersensitivity (p:0.005 and p:0.004, respectively). Patients unresponsive to intranasal corticosteroids had a higher incidence of corticosteroid hypersensitivity (71.4% vs. 4.4%, p<0.00 1). CONCLUSION: our study is the largest to date investigating CH in patients with allergic rhinitis and patients with allergic rhinitis have been found to have a high incidence (14%) of corticosteroid hypersensitivity, which may affect the response of patients to intranasal corticosteroid treatment. PMID- 29709137 TI - Smell functions in patients with multiple sclerosis: a prospective case-control study. AB - : Smell functions in patients with multiple sclerosis: a prospective case-control study. OBJECTIVES: The aim of this study is to evaluate the smell function in patients with multiple sclerosis (MS). METHODS: Twenty subjects (six males, 14 females) who were diagnosed as having MS, based on the 2010 Revised McDonald criteria, and 20 healthy individuals (six males, 14 females) were included in this study. In order to measure smell identification abilities, each subject completed the 12-item Brief Smell Identification Test (BSIT). Central and peripheral regions of smell were measured using cranial magnetic resonance (MR) images. The central regions of smell (the temporal lobe insular gyrus and the corpus amygdala) and the peripheral regions of smell (the olfactory bulb, tract and sulcus) were examined in the cranial MR images. Regions of smell were also evaluated for the presence of MS lesions (plaques). RESULTS: The total BSIT scores of the subjects in the MS group were found to be significantly lower than those of the control group (p<0.05). In the MS group, measurement values of the central regions of smell (right corpus amygdala diameter, right and left corpus amygdala) were significantly higher than those of the control group (p<0.05). There were no MS 'lesions in the peripheral regions of smell, but MS lesions were observed in the central regions: the right temporal lobe insular gyrus (four patients, 20.0%); the left temporal lobe insular gyrus (two patients, 10.0%); and the right corpus amygdala (one patient, 5.0%). While these results are not sufficient for statistical analysis, the total smell scores of these patients were found to be low. CONCLUSION: There is a deterioration in the smell functions of patients with MS. Therefore, we highly recommend that ENT specialists use the easily accessible and reliable BSIT for the diagnosis of smell disorders. PMID- 29709138 TI - Isolated laryngeal leishmaniasis in an immunocompetent patient: a case report. AB - : Isolated laryngeal leishmaniasis in an immunocompetent patient: a case report. OBJECTIVE: Isolated laryngeal Leishmaniasis presents neither explicit laryngeal lesions nor specific symptoms. In fact, it may mimic many inflammatory and neoplastic diseases. Considering the low incidence of this atypical localization, laryngeal Leishmaniasis, is rarely contemplated by physicians in differential diagnoses of laryngeal tumour lesions. We present the case of a 62-year-old immunocompetent subject who developed a single Leishmania mucosal lesion on the left vocal cord, simulating a laryngeal cancer. METHODS: A case report and discussion of the clinical case by referring to the literature. RESULTS: Specific therapy with miltefosine led to clinical and endoscopic improvement. We had no relapse after three years of follow-up. CONCLUSIONS: This clinical case highlights the need to consider isolated laryngeal Leishmaniasis in the differential diagnoses of laryngeal tumour lesions, even in immunocompetent subjects who live in endemic zones, in order to ensure an early and correct therapeutic approach. PMID- 29709139 TI - Radiation-induced carcinosarcoma of the submandibular gland: case report and review of literature. AB - Radiation-induced carcinosarcoma of the submandibular gland: case report and review of literature. Radiation-induced carcinosarcoma (RICS) of the head and neck is a very rare and extremely aggressive entity. We present the case of a 60 year-old man diagnosed with a T2N2cM0 squamous cell carcinoma at the right base of the tongue (BOT). The patient was treated with neoadjuvant chemotherapy and 3D conformal radiotherapy (3D-CRT) to the BOT and bilateral neck. He developed left submandibular firmness five years after treatment, initially diagnosed as radiation-induced fibrosis. The increasing size of the left submandibular mass two years later prompted further imaging, which showed a 2.2x1.8 cm mass in the left submandibular region in the previously irradiated field. This was diagnosed as a radiation-induced submandibular gland malignancy. This is the first reported case of a RICS in the submandibular gland and demonstrates the importance of early workup and evaluation of submandibular gland pathology in a patient with a history of radiation for a head and neck malignancy. PMID- 29709140 TI - [Automatical Assessment of Fetal Status Based on Fuzzy Theory and Euclidean Distance]. AB - Computer analysis of cardiotocography(CTG)is very significant to evaluate fetal status.However,current computer analysis based on traditional classification criteria is not ideal.In order to improve the accuracy of fetal status assessment,we proposed a new method.The new method improves the classification criteria and uses fuzzy set to represent the CTG parameters.And then feature vector is formed by that set to represent the CTG signal.By calculating and comparing the Euclidean distance between the signal feature vector and the standard state feature vector,the corresponding fetal status of the signal can be determined.Experiments showed that compared to the results of the first expert,the accuracy rate of new method was 88.3% which was higher than that(69.9%)of the traditional method,and the false positive rate of new method was 7.2% which was much lower than that(34.9%)of traditional methods.While compared to the results of the second expert,the accuracy of new method was 90.3% which was higher than that(66.0%)of the traditional method,and the false positive rate of new method was 9.0% which was well below the 38.2% of the traditional method.Thus the new method is reliable and effective. PMID- 29709141 TI - [Study on Prediction Model of Soft Tissue Deformation during Needle Insertion]. AB - Polyvinyl alcohol(PVA)hydrogel was made for simulating human's soft tissue in our experiment.The image acquisition device is composed of an optical platform,a camera and its bracket and a light source.In order to study the law of soft tissue deformation under flexible needle insertion,markers were embedded into the soft tissue and their displacements were recorded.Based on the analysis of displacements of markers in Xdirection and Ydirection,back propagation(BP)neural network was employed to model the displacement of Ydirection for the markers.Compared to the experimental data,fitting degree of the neural network model was above 95%,the maximum relative error for valid data was limited to 30%,and the maximum absolute error was 0.8mm.The BP neural network model was beneficial for predicting soft tissue deformation quantitatively.The results showed that the model could effectively improve the accuracy of flexible needle insertion into soft tissue. PMID- 29709142 TI - [Comparison of Characteristics between Different Turning Strategies]. AB - Turning gait is very common in daily lives.However,study of turning is still limited.For researching the differences of the walking characteristics between straight gait and turning gait and between different turning strategies,and for analyzing the endopathic factor,this study selected 10 healthy young men to perform straight walking and 90 degrees turning using two turning strategies(outside leg turning and inside leg turning).The Vicon capture system and plantar pressure capture system were used to measure gait parameters and plantar pressure parameters at the same time.The study showed that stride velocity reduced while stride time and proportion of stance time increased when turning was compared to straight walking.Inside leg turning strategy needed stronger muscle controlling and could promote turning,while outside leg turning strategy was more stable.This results will offer data for projecting gait of biped robot and provide reference value for walking rehabilitation training design and development of walking assistive equipments,etc. PMID- 29709144 TI - [Design and Optimization of Microfluidic Chips Used for Mixing Cryoprotectants]. AB - Microfluidic chips can be used to realize continuous cryoprotectants(CPA)loading/unloading for oocytes,reducing osmotic damage and chemical toxicity of CPA.In this study,five different Y-shape microfluidic chips were fabricated to realize the continuous CPA loading/unloading.The effects of flow rate,entrance angle,aspect ratio and turning radius of microchannels on the mixing efficiency of microfluidic chips were analyzed quantitatively.The experimental results showed that with the decrease of flow rates,the increase of aspect ratios and the decrease of turning raradius of microchannel,the mixing length decreased and the mixing velocity was promoted,while the entrance angle had little effect on the mixing efficiency.However,the operating conditions and structural parameters of the chips in practical application should be determined based on an overall consideration of CPA loading/unloading time and machining accuracy.These results would provide a reference to the application of microfluidic chip in CPA mixing. PMID- 29709143 TI - [Study on Finite Element Analysis Method for the Pre-operative Planning of Bernese Periacetabular Osteotomy]. AB - We developed a three-dimensional finite element model of development dysplasia of hip(DDH)of a patient.And then we performed virtual Bernese periacetabular osteotomy(PAO)by rotating the acetabular bone with different angle so as to increase femoral head coverage and distribute the contact pressure over the cartilage surface.Using finite element analysis method,we analyzed contact area,contact pressure,and von Mises stress in the acetabular cartilage to determine the effect of various rotation angle.We also built a normal hip joint model.Compared to the normal hip joint model,the DDH models showed stress concentration in the acetabular edge,and higher stress values.Compared to the DDH models,the post-PAO models showed decreases in the maximum values of von Mises stress and contact pressure while we increased the contact area.An optimal position could be achieved for the acetabulum that maximizes the contact area while minimizing the contact pressure and von Mises stress in the acetabular cartilage.These would provide theoretical bases to pre-operative planning. PMID- 29709145 TI - [Influence of Water Content on the Biotribological Behavior of Bone Tissue]. AB - In the present study,swine thighbone samples with different water contents were prepared through process of dehydration.The influence of water content on the biotribological behavior of the bone tissue was studied with nanoindentation test,reciprocating sliding test and impact wear test.It is shown that the water contents had significant influence on the mechanical properties and biotribological behavior of the swine thighbone samples.In this experiment condition,with decreasing water content,the hardness and elastic modulus of the swine thighbone samples increased,while the tribological properties significantly decreased.The viscoelasticity of bone tissue decreased with decreasing water content,which mainly resulted in different wear mechanisms of the bone tissue samples under applied loading. PMID- 29709146 TI - [Tumor Data Interacted System Design Based on Grid Platform]. AB - In order to satisfy demands of massive and heterogeneous tumor clinical data processing and the multi-center collaborative diagnosis and treatment for tumor diseases,a Tumor Data Interacted System(TDIS)was established based on grid platform,so that an implementing virtualization platform of tumor diagnosis service was realized,sharing tumor information in real time and carrying on standardized management.The system adopts Globus Toolkit 4.0tools to build the open grid service framework and encapsulats data resources based on Web Services Resource Framework(WSRF).The system uses the middleware technology to provide unified access interface for heterogeneous data interaction,which could optimize interactive process with virtualized service to query and call tumor information resources flexibly.For massive amounts of heterogeneous tumor data,the federated stored and multiple authorized mode is selected as security services mechanism,real-time monitoring and balancing load.The system can cooperatively manage multi-center heterogeneous tumor data to realize the tumor patient data query,sharing and analysis,and compare and match resources in typical clinical database or clinical information database in other service node,thus it can assist doctors in consulting similar case and making up multidisciplinary treatment plan for tumors.Consequently,the system can improve efficiency of diagnosis and treatment for tumor,and promote the development of collaborative tumor diagnosis model. PMID- 29709147 TI - [Construction of a Recombinant Lac Z Gene in Yeast Cell for Rapid Detection of Tetracycline Antibiotics]. AB - Two vectors were used to construct the recombinant gene yeast cell that can be used to bioassay of the pollution of tetracycline antibiotics in the environment.In the expression vector,the GPD(glyceraldehyde-3-phosphate dehydrogenase)promoter was used to drive the gene expression of tetracycline repressor protein(TR)fused with V5 antigen epitope gene,while in the reporter vector,the tetracycline response element(TRE)was used to regulate Lac Z report gene expression.The specificity and the sensitivity of the recombinant gene yeast cell were evaluated respectively by different concentrations of tetracycline antibiotics and non-tetracycline antibiotics.The results showed that there were significant dose effect relationships between the tetracycline antibiotics and the yeast cells,while non-tetracycline antibiotics showed no dose effect relationships with this biosensor.It is illustrated that the recombinant yeast cells can be used to monitor the tetracycline antibiotic pollution on the environment. PMID- 29709148 TI - [Effects of Etomidate on mRNA Expression of Ion Channels in Daphnia Pulex]. AB - Ion channels are involved in the mechanism of anesthetic action and side effect.The transcription and expression of ion channel genes can be modulated by general anesthetics.The adverse effect of continuous infusion of etomidate has been concerned.However,the effects of etomidate on mRNA expressions of ion channel genes remain unclear.In this study,we exposed Daphnia pulexin 250MUmol/L of etomidate for 240 min and observed the change of heart rate,phototactic behavior and blood glucose during the period of exposure,as well as the mRNA expressions of 120 ion channel genes at the end of the experiment.Compared to the controls,heart rate,phototactic behavior and blood glucose were not influenced by 250MUmol/L of etomidate.According to the quantitative PCR results,18 of 120Daphnia pulexion channel genes transcripts were affected by persistent 240 min exposure to 250MUmol/L of etomidate:2genes were upregulated and 16 genes were down-regulated,suggesting that etomidate showed effects on many different ion channels in transcription level.Systematical exploration of transcriptional changes of ion channels could contribute to understanding of the pharmacological mechanism of etomidate. PMID- 29709149 TI - [Effect of Chit-oligosaccharide/Collagen Composite Gels on Pre-osteoblastic MC3T3 E1s Differentiation]. AB - Chit-oligosaccharide(COS)is a low-molecular,water-soluble mass with higher biological activity,which can be absorbed by human body easily and interact with cells directly.Based on the excellent biological properties of collagen(Col)and COS,a series of Col and COS composite hydrogel(Col/COSn)was constructed in this study.The effect of composite hydrogel on cells proliferation,differentiation and related osteogenic gene expression was evaluated on pre-osteoblast MC3T3-E1 s.The experimental results showed that all the Col/COS composite gels could promote the growth of MC3T3-E1 s,proliferation and bone related gene expression compared to that of pure Col gels.And there was significant difference among the composite hydrogel groups with different degrees of polymerization of COS.The effect of the composite gel which contained chitotetraose(COS4)or chitohexaose(COS6)on the cells proliferation was better than that of other groups,while on cells differentiation and related osteogenic gene expression the composite gel contained chitopentaose(COS5)was the best in all the groups. PMID- 29709150 TI - [Effect of Biaxial Tensile Strain on Expression of Osteogenic Specificity Markers of Rat Bone Marrow-derived Mesenchymal Stem Cells in Vitro]. AB - The purpose of this study was to investigate the effect of biaxial tensile strain on the osteogenic differentiation of rat bone marrow mesenchymal stem cells(rBMSCs)in vitro.The rBMSCs were isolated from tibia and femur of 4weeks-old Sprague-Dawley(SD)rats.The rBMSCs were cultured in DMEM-LG complete culture medium and grew to subconfluence in the cell culture device for loading tensile strain.The biaxial tensile strain was applied to the rBMSCs for periods of 2,4and 6hours every day,respectively,lasting 3days.The amplitude of biaxial tensile strain applied to the rBMSCs were 1%,2% and 5%respectively,at a frequency of 1Hz.Unstrained rBMSCs were used as blank control(control group).The rBMSCs cultured with DMEM-LG complete culture medium containing100nmol/Lbeta Estradiol(E2)were used as positive control.The mRNA expression of alkaline phosphatase(ALP),collagen typeI(ColI),Runt-related transcription factor 2(Runx2)and osteocalcin(OCN)was examined with real-time quantitative PCR and the protein expression of ALP,ColI,Runx2 and OCN was detected with Western blot method.The results showed as follws:(1)The mRNA and protein expression of the ALP,ColI,Runx2,OCN were significantly higher in rBMSCs of the E2 group than those in the control group(P<0.05).(2)The mRNA and protein expression level of the ALP,Runx2 were higher markedly in the 1% tensile strain groups than those in the control group(P<0.05),but lower than those in the E2group(P<0.05).(3)The mRNA and protein expression level of the ALP,ColI,Runx2,OCN were significantly higher in the 2% tensile strain groups than those in the control group(P<0.05),and the mRNA and protein expression level of ColI and Runx2 in the group applied with2% amplitude of tensile strain for 4h/d was significantly higher than those in E2group(P<0.05).(4)The mRNA and protein expression level of the ALP,ColI,Runx2 were significantly higher in the groups applied with 5% amplitude of tensile strain for 2h/d or for 4h/d than those in the control group(P<0.05).In our study,E2 and mechanical stimulation played an important role in the regulation of differentiation of rBMSCs into osteoblasts,and the manner applied with the 2%amplitude of tensile strain for 4h/d,lasting 3days was an optimal stimulus for up-regulating the mRNA and protein expression of ALP,ColI,Runx2,OCN of rBMSCs. PMID- 29709151 TI - [Effects of Chlorpyrifos on Dopaminergic Neuronal Viability with Activation of Microglia]. AB - Excessive microglial activation and subsequent neuroinflammation lead to neuronal cell death,which are involved in the pathogenesis and progression of several neurodegenerative diseases such as Parkinson's disease.The objective of this study was to determine the involvement of chlorpyrifos(CPF)in the activation of microglia and production of inflammatory factors in response to CPF stimulation and the influence on the viability of dopaminergic(DA)neurons.We detected the change of BV-2cells morphology and expression of inducible nitric oxide(iNOS),cyclooxygenase-2(COX-2)mRNA and protein level upon CPF stimulation(0,1,3,6,12,24h)in BV-2(mouse brain microglia)cells by reverse transcription polymerase chain reaction(RT-PCR)or Western blot.We randomly assigned BV-2cells into CPF,menstruum dimethysulfoxide(DMSO)and normal saline(NS)groups.We stimulated The BV-2cells in the CPF group with CPF,and we stimulated the two control groups with DMSO or NS for 12 hours,respectively.We then collected the used culture media from the culture dishes and centrifuged it to remove the detached cells.Then,we used the supernatants as microglial conditioned media.We treated SH-SY5 Yneurons with various groups of microglial conditioned media for 24 hours.We observed the effect of conditioned media collected from BV-2cell on the viability of dopaminergic cell lines SH-SY5 Yusing MTT assay.We found that inflammatory factors iNOS,COX-2mRNA and protein levels were up-regulated upon CPF stimulation.Conditioned media from BV-2upon CPF stimulation is toxic to SH-SY5 Y.It might be concluded that the exposure to CPF may induce dopaminergic neuronal damage by the activation of inflammatory response,and a mechanism may be involved in Parkinson's disease pathogenesis. PMID- 29709152 TI - [Study on Potential Role of Calreticulin in Pressure Overload Induced Cardiac Hypertrophy]. AB - This study aims to investigate the role of calreticulin in(CRT)pressure overload induced cardiac hypertrophy.In our study,cardiac hypertrophy was induced by left ventricular pressure overload in male SD rats subjected to transverse aortic constriction(TAC)operation.Expression of gene and protein of calreticulin,markers of cardiac hypertrophy and endoplasmic reticulum stress(ERS)were measured with real-time qPCR and Western blot respectively.Meanwhile,atorvastatin(a known ERS inhibitor)and calreticulin-specific small interference ribonucleic acid(siRNA)were used to inhibit the expression of ERS and calreticulin respectively.The experimental data demonstrated that the gene and protein levels of calreticulin,hypertrophic and ERS markers were increased significantly in the heart tissues of TAC rat models after 4weeks.Moreover,atorvastatin administration improved the cardiac function and reduced the expression of calreticulin and ERS markers in TAC rats.In addition,cultured primary neonatal rat cardiomyocytes(NCMs)were treated with norepinephrine(NE),angiotensionII(AngII)or isoprenaline(ISO)to induce hypertrophic phenotype and ERS.The expression of hypertrophic markers was reduced in NCMs transfected with calreticulin-siRNA.The results suggested that calreticulin might be a promising target for the treatment of cardiac hypertrophy. PMID- 29709153 TI - [Screening the Optimal Time of Sinusoidal Alternating Electromagnetic Field for the Bone Biomechanical Properties of Rat]. AB - The present research is to investigate the time effect of sinusoidal electromagnetic fields(SEMFs)at different exposure time on the biomechanical properties in rats,and to find a best time for improving biomechanical properties.Forty female SD rats were randomly divided into five groups,i.e.control group,45 min SEMFs group,90 min SEMFs group,180 min SEMFs group,and 270 min SEMFs group.In addition to the control group,other groups were exposed to 50 Hz and 0.1mT magnetic field every day for the corresponding time periods.After eight weeks,bone mineral density(BMD),bone biomechanics,bone tissue morphology,micro-CT and pathological examination were performed.The results showed that there was no abnormal pathological finding in the experimental groups.In the 90 min SEMFs group,BMD,femur maximum load,elastic modulus,yield strength,trabecular number(Tb.N),trabecular thickness(Tb.Th)and trabecular area(Tb.Ar)percentage were all significantly higher than those in the control group(P<0.01),and trabecular separation(Tb.Sp)was significantly lower than that of the control group(P<0.01).However,for other experimental groups,some indices showed statistical significance compared to the control group(P<0.05),but some did not(P>0.05).This study showed that under 50 Hz and 0.1 mT SEMFs,90 min is the best time that can effectively increase bone mineral density,improve the bone tissue microstructure organization and the biomechanical properties. PMID- 29709154 TI - [Voxel-Based Morphometry in Medicated-naive Boys with Attention deficit/hyperactivity Disorder(ADHD)]. AB - Attention-deficit/hyperactivity disorder(ADHD)is one of the most common neuro developmental disorders occurring in childhood,characterized by symptoms of age inappropriate inattention,hyperactivity/impulsivity,and the prevalence is higher in boys.Although gray matter volume deficits have been frequently reported for ADHD children via structural magnetic resonance imaging,few of them had specifically focused on male patients.The present study aimed to explore the alterations of gray matter volumes in medicated-naive boys with ADHD via a relatively new voxel-based morphometry technique.According to the criteria of DSM IV-TR,43medicated-naive ADHD boys and 44age-matched healthy boys were recruited.The magnetic resonance image(MRI)scan was performed via a 3T MRI system with three-dimensional(3D)spoiled gradient recalled echo(SPGR)sequence.Voxel based morphometry with diffeomorphic anatomical registration through exponentiated lie algebra in SPM8 was used to preprocess the3DT1-weighted images.To identify gray matter volume differences between the ADHD and the controls,voxelbased analysis of whole brain gray matter volumes between two groups were done via two sample t-test in SPM8 with age as covariate,threshold at P<0.001.Finally,compared to the controls,significantly reduced gray matter volumes were identified in the right orbitofrontal cortex(peak coordinates[-2,52, 25],t=4.01),and bilateral hippocampus(Left:peak coordinates[14,0, 18],t=3.61;Right:peak coordinates[-14,15,-28],t=3.64)of ADHD boys.Our results demonstrated obvious reduction of whole brain gray matter volumes in right orbitofrontal cortex and bilateral hippocampus in boys with ADHD.This suggests that the abnormalities of prefrontal-hippocampus circuit may be the underlying cause of the cognitive dysfunction and abnormal behavioral inhibition in medicatednaive boys with ADHD. PMID- 29709156 TI - [A Voxel-wise imaging analysis method for early evaluation of tumor treatment response]. AB - To solve the problem that the method based on tumor morphology or overall average parameters of tumor cannot conduct the early evaluation of tumor treatment response,we proposed a voxel-wise method.The voxel-wise method uses the method combining rigid and elastic registration algorithm to align the tumor area before and after treatment on the images which are acquired by the dynamic contrast enhanced magnetic resonance imaging(DCEMRI).We calculated voxel-wise volume transport constant(Ktrans)using pharmacokinetic model,and designed a threshold d to get the volume fraction of voxels which Ktrans increased significantly(F+),Ktrans decreased significantly(F-)or had no significant change(F0).Linear regression analysis was performed to get the correlation between volume fractions and pathological tumor cell necrosis rate(TCNR).We then determined the ability of volume fractions to evaluate treatment response at early stage by receiver operating characteristic(ROC)curve analysis.We performed experiments on 10 patients with soft tissue sarcomas.The results indicated that F had significant negative correlation with TCNR(R2=0.832 8,P=0.000 2),F0 has significant positively correlation with TCNR(R2=0.788 4,P=0.000 6).In addition,F (AUC=0.905,P=0.053),F0(AUC=0.857,P=0.087)had a good ability in early tumor treatment response evaluation.Therefore,F- and F0 can be used as effective imaging biomarkers for early evaluation of tumor treatment. PMID- 29709155 TI - [Research on Residual Aberrations Correction with Adaptive Optics Technique in Patients Undergoing Orthokeratology]. AB - We conducted this study to explore the influence of the ocular residual aberrations changes on contrast sensitivity(CS)function in eyes undergoing orthokeratology using adaptive optics technique.Nineteen subjects' nineteen eyes were included in this study.The subjects were between 12 and 20years(14.27+/ 2.23years)of age.An adaptive optics(AO)system was adopted to measure and compensate the residual aberrations through a 4-mm artificial pupil,and at the same time the contrast sensitivities were measured at five spatial frequencies(2,4,8,16,and 32 cycles per degree).The CS measurements with and without AO correction were completed.The sequence of the measurements with and without AO correction was randomly arranged without informing the observers.A two interval forced-choice procedure was used for the CS measurements.The paired t test was used to compare the contrast sensitivity with and without AO correction at each spatial frequency.The results revealed that the AO system decreased the mean total root mean square(RMS)from 0.356MUm to 0.160MUm(t=10.517,P<0.001),and the mean total higher-order RMS from 0.246MUm to 0.095MUm(t=10.113,P<0.001).The difference in log contrast sensitivity with and without AO correction was significant only at 8cpd(t=-2.51,P=0.02).Thereby we concluded that correcting the ocular residual aberrations using adaptive optics technique could improve the contrast sensitivity function at intermediate spatial frequency in patients undergoing orthokeratology. PMID- 29709157 TI - [Study on Abnormal Topological Properties of Structural Brain Networks of Patients with Depression Comorbid with Anxiety]. AB - This paper is aimed to analyze the topological properties of structural brain networks in depressive patients with and without anxiety and to explore the neuropath logical mechanisms of depression comorbid with anxiety.Diffusion tensor imaging and deterministic tractography were applied to map the white matter structural networks.We collected 20 depressive patients with anxiety(DPA),18 depressive patients without anxiety(DP),and 28 normal controls(NC)as comparative groups.The global and nodal properties of the structural brain networks in the three groups were analyzed with graph theoretical methods.The result showed that1 the structural brain networks in three groups showed small-world properties and highly connected global hubs predominately from association cortices;2DP group showed lower local efficiency and global efficiency compared to NC group,whereas DPA group showed higher local efficiency and global efficiency compared to NC group;3significant differences of network properties(clustering coefficient,characteristic path lengths,local efficiency,global efficiency)were found between DPA and DP groups;4DP group showed significant changes of nodal efficiency in the brain areas primarily in the temporal lobe and bilateral frontal gyrus,compared to DPA and NC groups.The analysis indicated that the DP and DPA groups showed nodal properties of the structural brain networks,compared to NC group.Moreover,the two diseased groups indicated an opposite trend in the network properties.The results of this study may provide a new imaging index for clinical diagnosis for depression comorbid with anxiety. PMID- 29709158 TI - [Affective Stress Rating Method Based on Improved Hidden Markov Model]. AB - To solve the defect which is recognizing but not rating the stress,or rating but not considering the influence of the previous stress state to the current state of the existing affective stress evaluation method,this paper proposes an approach of affective stress rating model on electrocardiogram(ECG).An affective stress rating algorithm based on hidden Markov model(HMM)was established with the theory of affective computing.The individual's affective stress was rated using this affective rating model combining the investigation questionnaire.Features like complexity and approximate entropy of ECG were used in the model,and a matching process suggested that it improved the accuracy of affective stress rating.The result of the experiment illustrated that the model considering the environmental factors and the influence of previous stress state to the current state was an effective method in affective stress rating,and the accuracy of rating was improved by this affective stress rating method. PMID- 29709159 TI - [Investigation into Feasibility of Congestive Heart Failure Diagnosis Based on Analysis of Very Short-term Heart Rate Variability]. AB - The analysis parameters for the characterization of heart rate variability(HRV)within a very short time(< 1min)usually exhibit complicate variation patterns over time,which may easily interfere the judgment to the status of the cardiovascular system.In this study,long-term HRV sequence of 41 cases of healthy people(control group)and 25 cases of congestive heart failure(CHF)patients(experimental group)was divided into multiple segments of very short time series.The variation coefficient of the same HRV parameter under multiple segments of very short time series and the testing proportion with statistically significant differences under multiple interclass t-test were calculated.On this account,part of HRV analysis parameters under very short time were discussed to reveal the stability of difference of the cardiovascular system function under different status.Furthermore,with analyzing the receiver operating characteristic(ROC)curve and modeling the artificial neural network(ANN),the classification effects of these parameters between the control group and the experimental group were assessed.The results demonstrated that1 the indices of entropy of degree distribution based on the complex network analysis had a lowest variation coefficient and was sensitive to the pathological status(in 79.75% cases,there has statistically significant differences between the control group and experimental group),which can be served as an auxiliary index for clinical doctor to diagnose for CHF patient;2after conducting ellipse fitting to Poincare plot,in 98.5% cases,there had statistically significant differences for the ratio of ellipse short-long axis(SDratio)between the control group and the experimental group;when modeling the ANN and solely adopting SDratio,the classification accuracy to the control group and experimental group was 71.87%,which demonstrated that SDratio might be acted as the intelligent diagnosis index for CHF patients;3 however,more sensitive and robust indices were still needed to find out for the very-short HRV analysis and for the diagnosis of CHF patients as well. PMID- 29709160 TI - [Application of an Adaptive Inertia Weight Particle Swarm Algorithm in the Magnetic Resonance Bias Field Correction]. AB - An adaptive inertia weight particle swarm algorithm is proposed in this study to solve the local optimal problem with the method of traditional particle swarm optimization in the process of estimating magnetic resonance(MR)image bias field.An indicator measuring the degree of premature convergence was designed for the defect of traditional particle swarm optimization algorithm.The inertia weight was adjusted adaptively based on this indicator to ensure particle swarm to be optimized globally and to avoid it from falling into local optimum.The Legendre polynomial was used to fit bias field,the polynomial parameters were optimized globally,and finally the bias field was estimated and corrected.Compared to those with the improved entropy minimum algorithm,the entropy of corrected image was smaller and the estimated bias field was more accurate in this study.Then the corrected image was segmented and the segmentation accuracy obtained in this research was 10% higher than that with improved entropy minimum algorithm.This algorithm can be applied to the correction of MR image bias field. PMID- 29709161 TI - [Design of Flow Cytometry Self-cleaning System]. AB - In order to solve the problem of the micro flow cell clogging,and to improve the reliability of the flow cytometry system,a new method was proposed for hydrodynamic self-cleaning system.By analyzing the flow cell focus principle,we considered that to obtain stable single cell flow,the stable pressure in the flow chamber must be ensured.Therefore,we established a diagnosis method of clogging by the pressure detecting,and designed a self-cleaning system.Then we built up corresponding experimental systems.Experiments and testing showed that the selfcleaning system could improve the flow and resolve the clogging problem. PMID- 29709162 TI - [Research Progress of Regulation of Hypoxia-mediated Signaling Pathways on Epithelial-Mesenchymal Transition of Tumor Cells]. AB - Hypoxic microenvironment always exists in solid tumors,and it closely relates to the development and metastasis of solid tumor.As a main transcription factor responding to hypoxic environment,hypoxia-inducible factor(HIF)can promote tumor cell proliferation,survival,angiogenesis,and epithelial-mesenchymal transition(EMT),etc.EMT is a biological process that epithelial phenotype was transformed into mesenchymal phenotype,which is mainly associated with its signaling pathways,transcription factors,inflammatory factors and miRNAs,and plays a vital role in tumor invasion and metastasis.This paper summarizes the effects of hypoxia signaling pathway,Wnt/beta-catenin signaling pathway,Notch signaling pathway,NF-kappaB signaling pathway,Hedgehog(Hh)signaling pathway and PI3K/Akt signaling pathway on the EMT of tumor cells. PMID- 29709163 TI - [Mechanoresponsive microRNA]. AB - Mechanoresponsive microRNAs are a type of miRNAs which are sensitive or responsive to mechanical strain applied to them,their expression levels were changed after mechanical loading,thus affecting the expression levels of mRNA and proteins they regulated.Up to now,some mechanoresponsive miRNAs have been discovered in physiological or pathological tissues or organs.However,these discoveries are usually limited,and they are not able to guide clinical practice well.According to this situation,this paper summarizes research findings of mechanoresponsive miRNAs,and provides directions for clinical practice and further researches. PMID- 29709164 TI - [Research Progress of microRNA Influences on Colorectal Cancer]. AB - microRNA(miRNA)is a kind of RNAs which involves in the regulation of proliferation,invasion and metastasis of tumors.It also closely connects to the colorectal cancer.This article reviews the relationship between miRNA and proliferation,invasion,metastasis,diagnosis and treatment of colorectal cancer. PMID- 29709165 TI - [Surface Modification and Applications of Cardiovascular Stent]. AB - Cardiovascular disease is one of the most common causes of death.Coronary artery stent implantation has been the most important method to cure coronary disease and inhibit angiostegnosis.However,restenosis and thrombus at the site of implanting cardiovascular devices remains a significant problem in the practice of interventional cardiology.Recently,lots of studies have revealed that endothelial impairment is considered as one of the most important mechanisms contributing to restenosis.As a result,the method of accelerating endothelial regeneration at the injury site could prevent restenosis and thrombus.Considering the surface modification of cardiovascular stent implantation,this paper summarizes the progress on this direction,especially for the prevention of cardiovascular restenosis.Furthermore,this paper also proposes the methods and the future developing prospects for accelerating in vivo re-endothelialization at the site of intravascular stent with different biological molecules. PMID- 29709166 TI - [Computer-aided Prognosis for Breast Cancer Based on Hematoxylin & Eosin Histopathology Image]. AB - Quantitatively analyzing hematoxylin &eosin(H&E)histopathology images is an emerging field attracting increasing attentions in recent years.This paper reviews the application of computer-aided image analysis in breast cancer prognosis.The traditional prognosis based on H&E histopathology image for breast cancer is firstly sketched,followed by a detailed description of the workflow of computer-aided prognosis including image acquisition,image preprocessing,regions of interest detection and object segmentation,feature extraction,and computer aided prognosis.In the end,major technical challenges and future directions in this field are summarized. PMID- 29709167 TI - [Research Progress of Graphene and Derivatives Nanocomposite in Orthopedics Application]. AB - Graphene and its derivatives have good physical and chemical properties and biological properties,which can promote stem cell proliferation and osteogenic differentiation,and it has antibacterial properties and drug release property.Therefore,it has broad application prospects in the field of orthopedic biomaterials.This paper mainly introduces the research progress of graphene nanocomposite materials applied in the aspects of bone tissue engineering scaffold,bone repair,bone graft materials,etc.in order to provide desirable information for the future application basis and clinical research. PMID- 29709168 TI - Biodegradable Nanocomposite Antimicrobials for the Eradication of Multidrug Resistant Bacterial Biofilms without Accumulated Resistance. AB - Infections caused by multidrug-resistant (MDR) bacteria are a rapidly growing threat to human health, in many cases exacerbated by their presence in biofilms. We report here a biocompatible oil-in-water cross-linked polymeric nanocomposite that degrades in the presence of physiologically relevant biomolecules. These degradable nanocomposites demonstrated broad-spectrum penetration and elimination of MDR bacteria, eliminating biofilms with no toxicity to cocultured mammalian fibroblast cells. Notably, serial passaging revealed that bacteria were unable to develop resistance toward these nanocomposites, highlighting the therapeutic promise of this platform. PMID- 29709170 TI - Mathematical Modeling of RNA-Based Architectures for Closed Loop Control of Gene Expression. AB - Feedback allows biological systems to control gene expression precisely and reliably, even in the presence of uncertainty, by sensing and processing environmental changes. Taking inspiration from natural architectures, synthetic biologists have engineered feedback loops to tune the dynamics and improve the robustness and predictability of gene expression. However, experimental implementations of biomolecular control systems are still far from satisfying performance specifications typically achieved by electrical or mechanical control systems. To address this gap, we present mathematical models of biomolecular controllers that enable reference tracking, disturbance rejection, and tuning of the temporal response of gene expression. These controllers employ RNA transcriptional regulators to achieve closed loop control where feedback is introduced via molecular sequestration. Sensitivity analysis of the models allows us to identify which parameters influence the transient and steady state response of a target gene expression process, as well as which biologically plausible parameter values enable perfect reference tracking. We quantify performance using typical control theory metrics to characterize response properties and provide clear selection guidelines for practical applications. Our results indicate that RNA regulators are well-suited for building robust and precise feedback controllers for gene expression. Additionally, our approach illustrates several quantitative methods useful for assessing the performance of biomolecular feedback control systems. PMID- 29709169 TI - Influence of Storage on the Stability of Toxic Pyrrolizidine Alkaloids and Their N-Oxides in Peppermint Tea, Hay, and Honey. AB - 1,2-Dehydropyrrolizidine alkaloids (PA) and PA- N-oxides (PANO) are phytotoxins, which presumably occur in more than 6,000 plant species worldwide. Plants containing PA/PANO are responsible for various food and feed poisonings recorded for decades. Main reasons of exposition of consumers and livestock are contaminations of food and animal feed with parts, seeds, pollen, or nectar of PA containing plants. Concerning stability, effects of processing on PA were mainly investigated in the past. The current study examined the behavior of PA/PANO in unprocessed matrices peppermint tea, hay, and honey during storage. Blank samples were fortified with PA/PANO or contaminated with blueweed ( Echium vulgare) and ragwort ( Senecio jacobaea) and stored for 182 d. The time-series analysis using liquid chromatography-tandem mass spectrometry (LC-MS/MS) confirmed that all 25 analyzed PA/PANO compounds remained stable in herbal samples. However, the results showed a very fast decrease of PANO in honey samples within hours. These results were discussed with respect to potential consequences for health risk assessment. PMID- 29709171 TI - Bovine Serum Albumin and Fibrinogen Adsorption at the 316L Stainless Steel/Aqueous Interface. AB - The binding of bovine serum albumin (BSA) to a 316L stainless steel surface from a buffer solution has been characterized using neutron reflectometry and quartz crystal microbalance measurements; coverage at all concentrations up to a near physiological concentration was found to be relatively low (<20%); the protein followed a two-step isotherm adsorption model type and the overall thickness at the higher concentrations (around 80 A) suggested possible multilayering and/or protein unfolding. As it has been postulated that BSA may inhibit the further adsorption of another blood plasma protein-fibrinogen-the effects of preadsorbing BSA on fibrinogen adsorption were examined, first by prior physisorption of BSA to the stainless steel surface and second by pretreating the stainless steel with a layer of sodium dodecyl sulfate (SDS) to render it more hydrophobic. Although the preadsorption of BSA to an untreated stainless steel surface did slightly decrease the amount of fibrinogen adsorbed initially, it had no inhibiting effect if a solution containing solely fibrinogen subsequently flowed through. In contrast, the SDS-treated surface yielded both an increased BSA adsorption and consistently decreased fibrinogen adsorption. PMID- 29709172 TI - Simultaneous Analysis of Seven Biomarkers of Oxidative Damage to Lipids, Proteins, and DNA in Urine. AB - The determination of oxidative stress biomarkers (OSBs) is useful for the assessment of health status and progress of diseases in humans. Whereas previous methods for the determination of OSBs in urine were focused on a single marker, in this study, we present a method for simultaneous determination of biomarkers of oxidative damage to lipids, proteins, and DNA. 2,4-Dinitrophenylhydrazine (DNPH) derivatization followed by solid phase extraction (SPE) and high performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) allowed the determination of 8-hydroxy-2'-deoxyguanosine (8-OHdG), o- o'-dityrosine (diY), malondialdehyde (MDA), and four F2-isoprostane isomers: 8-iso prostaglandinF2alpha (8-PGF2alpha), 11beta-prostaglandinF2alpha (11-PGF2alpha), 15( R)-prostaglandinF2alpha (15-PGF2alpha), and 8-iso,15( R)-prostaglandinF2alpha (8,15-PGF2alpha) in urine. Derivatization with DNPH and SPE was optimized to yield greater sensitivity and selectivity for the analysis of target chemicals. The limits of detection of target analytes in urine were below 30 pg mL-1. The assay intra- and interday variability was below 16% of the relative standard deviation, and the recoveries of target chemicals spiked into synthetic urine were near 100%. The method was applied to the analysis of 21 real urine samples, and the analytes were found at a detection frequency of 85% for 8-PGF2alpha and 15-PGF2alpha, 71% for 11-PGF2alpha, 81% for 8,15-PGF2alpha, and 100% for diY, 8 OHdG, and MDA. This method offers simultaneous determination of multiple OSBs of different molecular origin in urine samples selectively with high accuracy and precision. PMID- 29709174 TI - Temperature- and Phase-Dependent Phonon Renormalization in 1T'-MoS2. AB - Polymorph engineering of 2H-MoS2, which can be achieved by alkali metal intercalation to obtain either the mixed 2H/1T' phases or a homogeneous 1T' phase, has received wide interest recently, since this serves as an effective route to tune the electrical and catalytic properties of MoS2. As opposed to an idealized single crystal-to-single crystal phase conversion, the 2H to 1T' phase conversion results in crystal domain size reduction as well as strained lattices, although how these develop with composition is not well understood. Herein, the evolution of the phonon modes in Li-intercalated 1T'-MoS2 (Li xMoS2) are investigated as a function of different 1T'-2H compositions. We observed that the strain evolution in the mixed phases is revealed by the softening of four Raman modes, Bg ( J1), Ag ( J3), E12g, and A1g, with increasing 1T' phase composition. Additionally, the first-order temperature coefficients of the 1T' phonon mode vary linearly with increasing 1T' composition, which is explained by increased electron-phonon and strain-phonon coupling. PMID- 29709173 TI - Photophysics of Thermally-Assisted Photobleaching in "Giant" Quantum Dots Revealed in Single Nanocrystals. AB - Quantum dots (QDs) are steadily being implemented as down-conversion phosphors in market-ready display products to enhance color rendering, brightness, and energy efficiency. However, for adequate longevity, QDs must be encased in a protective barrier that separates them from ambient oxygen and humidity, and device architectures are designed to avoid significant heating of the QDs as well as direct contact between the QDs and the excitation source. In order to increase the utility of QDs in display technologies and to extend their usefulness to more demanding applications as, for example, alternative phosphors for solid-state lighting (SSL), QDs must retain their photoluminescence emission properties over extended periods of time under conditions of high temperature and high light flux. Doing so would simplify the fabrication costs for QD display technologies and enable QDs to be used as down-conversion materials in light-emitting diodes for SSL, where direct-on-chip configurations expose the emitters to temperatures approaching 100 degrees C and to photon fluxes from 0.1 W/mm2 to potentially 10 W/mm2. Here, we investigate the photobleaching processes of single QDs exposed to controlled temperature and photon flux. In particular, we investigate two types of room-temperature-stable core/thick-shell QDs, known as "giant" QDs for which shell growth is conducted using either a standard layer-by-layer technique or by a continuous injection method. We determine the mechanistic pathways responsible for thermally-assisted photodegradation, distinguishing effects of hot-carrier trapping and QD charging. The findings presented here will assist in the further development of advanced QD heterostructures for maximum device lifetime stability. PMID- 29709175 TI - Epitaxial-Growth-Induced Junction Welding of Silver Nanowire Network Electrodes. AB - In this study, we developed a roll-to-roll Ag electroplating process for metallic nanowire electrodes using a galvanostatic mode. Electroplating is a low-cost and facile method for deposition of metal onto a target surface with precise control of both the composition and the thickness. Metallic nanowire networks [silver nanowires (AgNWs) and copper nanowires (CuNWs)] coated onto a polyethylene terephthalate (PET) film were immersed directly in an electroplating bath containing AgNO3. Solvated silver ions (Ag+ ions) were deposited onto the nanowire surface through application of a constant current via an external circuit between the nanowire networks (cathode) and a Ag plate (anode). The amount of electroplated Ag was systematically controlled by changing both the applied current density and the electroplating time, which enabled precise control of the sheet resistance and optical transmittance of the metallic nanowire networks. The optimized Ag-electroplated AgNW (Ag-AgNW) films exhibited a sheet resistance of ~19 Omega/sq at an optical transmittance of 90% (550 nm). A transmission electron microscopy study confirmed that Ag grew epitaxially on the AgNW surface, but a polycrystalline Ag structure was formed on the CuNW surface. The Ag-electroplated metallic nanowire electrodes were successfully applied to various electronic devices such as organic light-emitting diodes, triboelectric nanogenerators, and a resistive touch panel. The proposed roll-to-roll Ag electroplating process provides a simple, low-cost, and scalable method for the fabrication of enhanced transparent conductive electrode materials for next generation electronic devices. PMID- 29709176 TI - Ultrasensitive Detection of Escherichia coli O157:H7 by Immunomagnetic Separation and Selective Filtration with Nitroblue Tetrazolium/5-Bromo-4-chloro-3-indolyl Phosphate Signal Amplification. AB - Here, we report an enhanced colorimetric method using enzymatic amplification with nitroblue tetrazolium (NBT)/5-bromo-4-chloro-3-indolyl phosphate (BCIP) precipitation for the ultrasensitive detection of Escherichia coli O157:H7 through immunomagnetic separation-selective filtration. Biotinylated anti- E. coli O157:H7 antibody and streptavidin-alkaline phosphatase were conjugated to the surface of magnetic nanoparticles, and E. coli O157:H7-conjugates complexes remained on the membrane filter surface. The resultant light brown spots on the membrane filter were amplified with NBT/BCIP solution to yield enzyme-catalyzed precipitation, which increased with an increasing E. coli O157:H7 concentration. E. coli O157:H7 was detected in pure samples with limits of detection of 10 and 6.998 colony-forming units (CFU)/mL through visual observation and measurement of optical density, respectively. The proposed method was applied to a lettuce sample inoculated with selective E. coli O157:H7, which was detected within 55 min without cross-reactivity to non-target bacteria. This enhanced colorimetric method has potential for on-site detection of food contaminants and environmental pollutants. PMID- 29709177 TI - Nonplanar Macrocycle Consisting of Four Pyridine and Phenol Units Connected with Acetylene Bonds Displaying Preferential Binding to Maltoside over Monosaccharides. AB - A nonplanar macrocycle consisting of four pyridine-acetylene-phenol units was developed as a host for saccharide guest molecules. The macrocycle was found to strongly associate with a lipophilic maltose derivative, with an association constant of 107 M-1, over monosaccharide derivatives, for which much smaller association constants were determined, ranging from 103 M-1 to 104 M-1. The macrocycle was found to adopt a boat-like conformation, encapsulating beta-d maltoside in a twisted manner through approximately seven intermolecular hydrogen bonds. PMID- 29709178 TI - Structural Dependence and Spectroscopic Evidence of Methane Dissolution in Ionic Liquids. AB - High methane dissolution capacity in a liquid is important for methane storage and transformation. In this work, methane solubility in different ionic liquids (ILs) was studied and was found associated with IL's structural and physical properties. In imidazolium-based ILs, ILs containing C-F and long alkyl chain showed high methane solubility mainly due to lower surface tension and molar density. Reducing the surface tension of solvent by adding 0.16 mol of trimethyl 1-propanaminium iodide (FC-134) with respect to [Bmim][NTf2] increased methane solubility by 39.3%. In situ high-pressure attenuated total reflection Fourier transform infrared spectroscopic results indicated a reversible process of methane dissolution in the ILs. The antisymmetric C-H stretching band of dissolved methane in ILs showed highly prominent rotational-vibrational bands with high intensity and narrow half-peak width compared to gaseous methane. Induced interaction between methane and IL resulted in increased dipole variation strength and reduced methane molecular symmetry. The constant antisymmetric C-H stretching peak at 3016.85 cm-1 revealed an unconstrained methane rotation in the stable physical and chemical environment of IL. Methane insertion into the IL's intranetwork space needs activation energy to overcome the interaction of cation anion network. Kinetic analysis of methane in [Bmim][NTf2] and [Bmim][HSO4] at different temperatures indicated that methane dissolution in these two ILs was a reversible first-order and very weak endothermic process and that methane dissolution required high activation energy in ILs with stronger cation-anion interaction. PMID- 29709179 TI - Probing Cytochrome c Folding Transitions upon Phototriggered Environmental Perturbations Using Time-Resolved X-ray Scattering. AB - Direct tracking of protein structural dynamics during folding-unfolding processes is important for understanding the roles of hierarchic structural factors in the formation of functional proteins. Using cytochrome c (cyt c) as a platform, we investigated its structural dynamics during folding processes triggered by local environmental changes (i.e., pH or heme iron center oxidation/spin/ligation states) with time-resolved X-ray solution scattering measurements. Starting from partially unfolded cyt c, a sudden pH drop initiated by light excitation of a photoacid caused a structural contraction in microseconds, followed by active site restructuring and unfolding in milliseconds. In contrast, the reduction of iron in the heme via photoinduced electron transfer did not affect conformational stability at short timescales (<1 ms), despite active site coordination geometry changes. These results demonstrate how different environmental perturbations can change the nature of interaction between the active site and protein conformation, even within the same metalloprotein, which will subsequently affect the folding structural dynamics. PMID- 29709180 TI - Surface Properties of Fluorite in Presence of Water: An Atomistic Investigation. AB - Density functional theory simulations, including a correction for dispersive interactions, were performed to investigate the adsorption of water on the main cleavage plane of the fluorite, namely, the (111) surface. In the case of a single molecule of water, we observe that the molecular form is preferred over the dissociated one, and absorbs on the surface with an energy of -55 kJ mol-1, including a significant contribution from the dispersion forces. Also, we show that the substitution of a fluorine atom by a hydroxyl group on the surface of fluorite is not energetically favorable. Then, the hydration of the surface in function of the coverage by water molecules was studied in a systematic way. It was shown that the geometries involving the formation of a cluster of water molecules on the surface, with half of the molecules adsorbed, are the most favorable. Finally, ab initio molecular dynamics conducted at 300 K confirms the trends observed at 0 K, albeit the adsorption energies are reduced by about 10 kJ mol-1. Also, we observe that once put in the interaction with a large number of water molecules, half of the calcium atoms at the surface are in close interaction with a water molecule, whereas the rest of the molecules are further away but present a relatively well-defined structure showing similarities with the one of water clusters. PMID- 29709182 TI - Chemical Synthesis of the Repeating Unit of Type II Group B Streptococcus Capsular Polysaccharide. AB - The first chemical synthesis of the repeating unit of serotype II group B Streptococcus capsular polysaccharide, a branched heptasaccharide alpha-Neu p5Ac (2->3)-beta-d-Gal p-(1->4)-beta-d-GlcN pAc-(1->3)-{[beta-d-Gal p-(1->6)]-beta-d Gal p}-(1->4)-beta-d-Glc p-(1->3)-beta-d-Glc p-(1->, was achieved by convergent [4+2+1] glycosylation, after probing different synthetic strategies and overcoming a series of difficulties. The title compound was designed to carry a free amino group at its downstream end to enable further regioselective elaboration. This work also revealed that the alpha-Neu5Ac-(2->3)-beta-d-Gal-(1 >4)-beta-d-GlcNAc motif, which is common in natural glycans, had a low reactivity as glycosyl donors, so it was rather difficult to directly couple this trisaccharide with sterically hindered acceptors. The motif was efficiently constructed via on-site glycan elongation using properly protected GlcN and alpha Neu5Ac-(2->3)-beta-d-Gal as consecutive glycosyl donors. PMID- 29709181 TI - Observation of Ultrafast Vibrational Energy Transfer in Fibrinogen and Fibrin Fibers. AB - We study the secondary structure of the blood protein fibrinogen using two dimensional infrared spectroscopy. With this technique, we identify the amide I' vibrational modes of the antiparallel beta-sheets and turns of fibrinogen. We observe ultrafast energy flow among these amide I' vibrational modes with a time constant of ~7 ps. This energy transfer time constant does not change significantly upon fibrin fiber formation, indicating that the secondary structure of the fibrinogen monomers remains largely unchanged in the polymerization process. PMID- 29709183 TI - Binary Strengthening and Toughening of MXene/Cellulose Nanofiber Composite Paper with Nacre-Inspired Structure and Superior Electromagnetic Interference Shielding Properties. AB - With the growing popularity of electrical communication equipment, high performance electromagnetic interference (EMI) shielding materials are widely used to deal with radiation pollution. However, the large thickness and poor mechanical properties of many EMI shielding materials usually limit their applications. In this study, ultrathin and highly flexible Ti3C2T x (d-Ti3C2T x, MXene)/cellulose nanofiber (CNF) composite paper with a nacre-like lamellar structure is fabricated via a vacuum-filtration-induced self-assembly process. By the interaction between one-dimensional (1D) CNFs and two-dimensional (2D) d Ti3C2T x MXene, the binary strengthening and toughening of the nacre-like d Ti3C2T x/CNF composite paper has been successfully achieved, leading to high tensile strength (up to 135.4 MPa) and fracture strain (up to 16.7%), as well as excellent folding endurance (up to 14 260 times). Moreover, the d-Ti3C2T x/CNF composite paper exhibits high electrical conductivity (up to 739.4 S m-1) and excellent specific EMI shielding efficiency (up to 2647 dB cm2 g-1) at an ultrathin thickness (minimum thickness 47 MUm). The nacre-inspired strategy in this study offers a promising approach for the design and preparation of the strong integrated and flexible MXene/CNF composite paper, which may be applied in various fields such as flexible wearable devices, weapon equipment, and robot joints. PMID- 29709184 TI - Phase Engineering in Quasi-2D Ruddlesden-Popper Perovskites. AB - Quasi-2D Ruddlesden-Popper (RP) halide perovskites have drawn intensive research interest because they possess superior ambient stability while retaining excellent device performance as compared to their pure 2D or 3D counterparts. By phase engineering strategy, quasi-2D perovskites can fall into three types-large- n 2D perovskite, 2D:3D mixed perovskite, and 3D/2D bilayer perovskite. This Perspective discusses the modulation of phase composition, hierarchical distribution, and crystal orientation in quasi-2D perovskites, aiming to uncover the correlation between morphological structure, band alignment, and charge recombination. A perspective of phase engineering in 2D RP-type perovskite materials is then given toward the concurrent stability and device efficiency. PMID- 29709185 TI - Phosphorescence Kinetics of Singlet Oxygen Produced by Photosensitization in Spherical Nanoparticles. Part II. The Case of Hypericin-Loaded Low-Density Lipoprotein Particles. AB - The phosphorescence kinetics of singlet oxygen produced by photosensitized hypericin (Hyp) molecules inside low-density lipoprotein (LDL) particles was studied experimentally and by means of numerical and analytical modeling. The phosphorescence signal was measured after short laser pulse irradiation of aqueous Hyp/LDL solutions. The Hyp triplet state lifetime determined by a laser flash-photolysis measurement was 5.3 * 10-6 s. The numerical and the analytical model described in part I of the present work (DOI: 10.1021/acs.jpcb.8b00658) were used to analyze the observed phosphorescence kinetics of singlet oxygen. It was shown that singlet oxygen diffuses out of LDL particles on a time scale shorter than 0.1 MUs. The total (integrated) concentration of singlet oxygen inside LDL is more than an order of magnitude smaller than the total singlet oxygen concentration in the solvent. The time course of singlet oxygen concentrations inside and outside the particles was calculated using simplified representations of the LDL internal structure. The experimental phosphorescence data were fitted by a linear combination of these concentrations using the emission factor E (the ratio of the radiative singlet oxygen depopulation rate constants inside and outside LDL) as a fitting parameter. The emission factor was determined to be E = 6.7 +/- 2.5. Control measurements were carried out by adding sodium azide, a strong singlet oxygen quencher, to the solution. PMID- 29709186 TI - AACID: Anisotropy of the Asymmetric Magnetically Induced Current Density Tensor. AB - Molecular magnetic properties, such as the magnetizability, the magnetic shielding, and the current strength, all stem from the asymmetric current density tensor. The anisotropy of that tensor, previously defined from its symmetric component only, is a scalar field expected to bear useful information on molecular structure. A more general anisotropy has here been defined, considering the full asymmetric tensor and its eigenvalues in the complex plane. Computations on a few prototypical aromatic molecules show that the anisotropy of the full tensor highlights previously missed structural features and also changes in a more regular way with bond length, as compared to the already known anisotropy of the symmetric component of the tensor. PMID- 29709187 TI - Integrating Dispersants in Oil Spill Response in Arctic and Other Icy Environments. AB - Future oil exploration and marine navigation may well extend into the Arctic Ocean, and government agencies and responders need to plan for accidental oil spills. We argue that dispersants should play an important role in these plans, since they have substantial logistical benefits, work effectively under Arctic conditions, and stimulate the rapid biodegradation of spilled oil. They also minimize the risk of surface slicks to birds and mammals, the stranding of oil on fragile shorelines and minimize the need for large work crews to be exposed to Arctic conditions. PMID- 29709188 TI - Phosphorescence Kinetics of Singlet Oxygen Produced by Photosensitization in Spherical Nanoparticles. Part I. Theory. AB - The singlet oxygen produced by energy transfer between an excited photosensitizer (pts) and ground-state oxygen molecules plays a key role in photodynamic therapy. Different nanocarrier systems are extensively studied to promote targeted pts delivery in a host body. The phosphorescence kinetics of the singlet oxygen produced by the short laser pulse photosensitization of pts inside nanoparticles is influenced by singlet oxygen diffusion from the particles to the surrounding medium. Two theoretical models are presented in this work: a more complex numerical one and a simple analytical one. Both the models predict the time course of singlet oxygen concentration inside and outside of the spherical particles following short-pulse excitation of pts. On the basis of the comparison of the numerical and analytical results, a semiempirical analytical formula is derived to calculate the characteristic diffusion time of singlet oxygen from the nanoparticles to the surrounding solvent. The phosphorescence intensity of singlet oxygen produced in pts-loaded nanocarrier systems can be calculated as a linear combination of the two concentrations (inside and outside the particles), taking the different phosphorescence emission rate constants into account. PMID- 29709189 TI - IR Spectra of (HCOOH)2 and (DCOOH)2: Experiment, VSCF/VCI, and Ab Initio Molecular Dynamics Calculations Using Full-Dimensional Potential and Dipole Moment Surfaces. AB - We report quantum VSCF/VCI and ab initio molecular dynamics (AIMD) calculations of the IR spectra of (HCOOH)2 and (DCOOH)2, using full-dimensional, ab initio potential energy and dipole moment surfaces (PES and DMS). These surfaces are fits, using permutationally invariant polynomials, to 13 475 ab initio CCSD(T) F12a electronic energies and MP2 dipole moments. Here "AIMD" means using these ab initio potential and dipole moment surfaces in the MD calculations. The VSCF/VCI calculations use all (24) normal modes for coupling, with a four-mode representation of the potential. The quantum spectra align well with jet-cooled and room-temperature experimental spectra over the spectral range 600-3600 cm-1. Analyses of the complex O-H and C-H stretch bands are made based on the mixing of the VSCF/VCI basis functions. The comparisons of the AIMD IR spectra with both experimental and VSCF/VCI ones provide tests of the accuracy of the AIMD approach. These indicate good accuracy for simple bands but not for the complex O H stretch band, which is upshifted from experimental and VSCF/VCI bands by roughly 300 cm-1. In addition to testing the AIMD approach, the PES, DMS, and VSCF/VCI calculations for formic acid dimer provide opportunities for testing other methods to represent high-dimensional data and other methods that perform postharmonic vibrational calculations. PMID- 29709190 TI - Thiolate-Protected Trimetallic Au~20Ag~4Pd and Au~20Ag~4Pt Alloy Clusters with Controlled Chemical Composition and Metal Positions. AB - The mixing of heteroelements in metal clusters is a powerful approach to generate new physical/chemical properties and functions. However, as the kinds of elements increase, control of the chemical composition and geometric structure becomes difficult. We succeeded in the compositionally selective synthesis of phenylethanethiolate-protected trimetallic Au~20Ag~4Pd and Au~20Ag~4Pt clusters, Au~20Ag~4Pd(SC2H4Ph)18 and Au~20Ag~4Pt(SC2H4Ph)18. Single-crystal X-ray structural analysis revealed the precise position of each metal element in these metal clusters. Reacting with thiol at an elevated temperature was found to be important to direct the metal elements to the most stable positions. The electronic structures of these trimetallic clusters become more discretized than those of the related bimetallic clusters due to orbital splitting. PMID- 29709191 TI - Cation-Dependent Light-Induced Halide Demixing in Hybrid Organic-Inorganic Perovskites. AB - Mixed cation metal halide perovskites with increased power conversion efficiency, negligible hysteresis, and improved long-term stability under illumination, moisture, and thermal stressing have emerged as promising compounds for photovoltaic and optoelectronic applications. Here, we shed light on photoinduced halide demixing using in situ photoluminescence spectroscopy and in situ synchrotron X-ray diffraction (XRD) to directly compare the evolution of composition and phase changes in CH(NH2)2CsPb-halide (FACsPb-) and CH3NH3Pb halide (MAPb-) perovskites upon illumination, thereby providing insights into why FACs-perovskites are less prone to halide demixing than MA-perovskites. We find that halide demixing occurs in both materials. However, the I-rich domains formed during demixing accumulate strain in FACsPb-perovskites but readily relax in MA perovskites. The accumulated strain energy is expected to act as a stabilizing force against halide demixing and may explain the higher Br composition threshold for demixing to occur in FACsPb-halides. In addition, we find that while halide demixing leads to a quenching of the high-energy photoluminescence emission from MA-perovskites, the emission is enhanced from FACs-perovskites. This behavior points to a reduction of nonradiative recombination centers in FACs-perovskites arising from the demixing process and buildup of strain. FACsPb-halide perovskites exhibit excellent intrinsic material properties with photoluminescence quantum yields that are comparable to MA-perovskites. Because improved stability is achieved without sacrificing electronic properties, these compositions are better candidates for photovoltaic applications, especially as wide bandgap absorbers in tandem cells. PMID- 29709192 TI - Enhanced Photoresponse in Metasurface-Integrated Organic Photodetectors. AB - In this work, we experimentally demonstrate metasurface-enhanced photoresponse in organic photodetectors. We have designed and integrated a metasurface with broadband functionality into an organic photodetector, with the goal of significantly increasing the absorption of light and generated photocurrent from 560 up to 690 nm. We discuss how the metasurface can be integrated with the fabrication of an organic photodiode. Our results show large gains in responsivity from 1.5* to 2* between 560 and 690 nm. PMID- 29709193 TI - Three-Dimensional Printing of Cytocompatible, Thermally Conductive Hexagonal Boron Nitride Nanocomposites. AB - Hexagonal boron nitride (hBN) is a thermally conductive yet electrically insulating two-dimensional layered nanomaterial that has attracted significant attention as a dielectric for high-performance electronics in addition to playing a central role in thermal management applications. Here, we report a high-content hBN-polymer nanocomposite ink, which can be 3D printed to form mechanically robust, self-supporting constructs. In particular, hBN is dispersed in poly(lactic- co-glycolic acid) and 3D printed at room temperature through an extrusion process to form complex architectures. These constructs can be 3D printed with a composition of up to 60% vol hBN (solids content) while maintaining high mechanical flexibility and stretchability. The presence of hBN within the matrix results in enhanced thermal conductivity (up to 2.1 W K-1 m-1) directly after 3D printing with minimal postprocessing steps, suggesting utility in thermal management applications. Furthermore, the constructs show high levels of cytocompatibility, making them suitable for use in the field of printed bioelectronics. PMID- 29709194 TI - Inhibition of Human Amylin Aggregation and Cellular Toxicity by Lipoic Acid and Ascorbic Acid. AB - More than 30 human degenerative diseases result from protein aggregation such as Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM). Islet amyloid deposits, a hallmark in T2DM, are found in pancreatic islets of more than 90% of T2DM patients. An association between amylin aggregation and reduction in beta cell mass was also established by post-mortem studies. A strategy in preventing protein aggregation-related disorders is to inhibit the protein aggregation and associated toxicity. In this study, we demonstrated that two inhibitors, lipoic acid and ascorbic acid, significantly inhibited amylin aggregation. Compared to amylin (15 MUM) as 100%, lipoic acid and ascorbic acid reduced amylin fibril formation to 42.1 +/- 17.2% and 42.9 +/- 12.8%, respectively, which is confirmed by fluorescence and TEM images. In cell viability tests, both inhibitors protected RIN-m5f beta-cells from the toxicity of amylin aggregates. At 10:1 molar ratio of lipoic acid to amylin, lipoic acid with amylin increased the cell viability to 70.3%, whereas only 42.8% RIN-m5f beta-cells survived in amylin aggregates. For ascorbic acid, an equimolar ratio achieved the highest cell viability of 63.3% as compared to 42.8% with amylin aggregates only. Docking results showed that lipoic acid and ascorbic acid physically interact with amylin amyloidogenic region (residues Ser20-Ser29) via hydrophobic interactions; hence reducing aggregation levels. Therefore, lipoic acid and ascorbic acid prevented amylin aggregation via hydrophobic interactions, which resulted in the prevention of cell toxicity in vitro. PMID- 29709195 TI - Intracellular Drug Bioavailability: Effect of Neutral Lipids and Phospholipids. AB - Intracellular unbound drug concentrations are the pharmacologically relevant concentrations for targets inside cells. Intracellular drug concentrations are determined by multiple processes, including the extent of drug binding to intracellular structures. The aim of this study was to evaluate the effect of neutral lipid (NL) and phospholipid (PL) levels on intracellular drug disposition. The NL and/or PL content of 3T3-L1 cells were enhanced, resulting in phenotypes (in terms of morphology and proteome) reminiscent of adipocytes (high NL and PL) or mild phospholipidosis (only high PL). Intracellular bioavailability ( Fic) was then determined for 23 drugs in these cellular models and in untreated wild-type cells. A higher PL content led to higher intracellular drug binding and a lower Fic. The induction of NL did not further increase drug binding but led to altered Fic due to increased lysosomal pH. Further, there was a good correlation between binding to beads coated with pure PL and intracellular drug binding. In conclusion, our results suggest that PL content is a major determinant of drug binding in cells and that PL beads may constitute a simple alternative to estimating this parameter. Further, the presence of massive amounts of intracellular NLs did not influence drug binding significantly. PMID- 29709196 TI - Pharmacological Characterization of the RPMI 2650 Model as a Relevant Tool for Assessing the Permeability of Intranasal Drugs. AB - The RPMI 2650 cell line has been described as a potent model of the human nasal mucosa. Nevertheless, pharmacological data are still insufficient, and the role of drug efflux transporters has not been fully elucidated. We therefore pursued the pharmacological characterization of this model, initially investigating the expression of four well-known adenosine triphosphate [ATP]-binding cassette (ABC) transporters (P-glycoprotein (P-gp), multidrug resistance associated protein (MRP)1, MRP2, and breast cancer resistance protein (BCRP)) by means of ELISA and immunofluorescence staining. The functional activity of the selected transporters was assessed by accumulation studies based on specific substrates and inhibitors. We then performed standardized bidirectional transport experiments under air liquid interface (ALI) culture conditions, using four therapeutic compounds of local intranasal relevance in upper airway diseases. Protein expression of P-gp, MRP1, MRP2, and BCRP was detected at the membrane of the RPMI 2650 cells. In addition, all four transporters exhibited functional activity at the cellular level. In the bidirectional transport experiments, the RPMI 2650 model was able to accurately discriminate the four therapeutic compounds according to their physicochemical properties. The ABC transporters tested did not play a major role in the efflux of these compounds at the barrier level. In conclusion, the RPMI 2650 model represents a promising tool for assessing the nasal absorption of drugs on the basis of preclinical pharmacological data. PMID- 29709197 TI - Dynamic Covalent Silica Nanoparticles for pH-Switchable Pickering Emulsions. AB - Dynamic covalent surfactants have been recently reported for preparation of pH switchable emulsions [ Sun , D. Langmuir , 2017 , 33 , 3040 ]. In this study, dynamic covalent silica (SiO2-B) nanoparticles of switchable wettability were fabricated by a pH-responsive dynamic (covalent) imine bond between hydrophilic amino silica (SiO2-NH2) nanoparticles and hydrophobic benzaldehyde molecules. The properties of SiO2-B were characterized by Fourier transform infrared spectroscopy, elemental analysis, contact angle measurement, and zeta potential measurement. The hydrophilicity and hydrophobicity of SiO2-B were shown to be readily switchable by adjusting pH between 7.8 and 3.5. At pH 7.8, SiO2-B was partially hydrophobic and adsorbed at oil-water interface to stabilize O/W Pickering emulsions, which were characterized by electrical conductivity, optical microscopy, and confocal laser scanning microscopy. Upon lowering the pH to 3.5, the dynamic covalent bond is dissociated to convert partially hydrophobic SiO2-B into highly hydrophilic SiO2-NH2 and surface-inactive benzaldehyde. Both of them desorb from oil-water interface, resulting in a rapid oil-water separation of the Pickering emulsions. Alternating stabilization and phase separation of the Pickering emulsions over 3 cycles were demonstrated by adjusting the pH. The pH switchable Pickering emulsions show great potential in application to effective oil-water separation of emulsions. PMID- 29709198 TI - Active Tuning of Spontaneous Emission by Mie-Resonant Dielectric Metasurfaces. AB - Mie-resonant dielectric metasurfaces offer comprehensive opportunities for the manipulation of light fields with high efficiency. Additionally, various strategies for the dynamic tuning of the optical response of such metasurfaces were demonstrated, making them important candidates for reconfigurable optical devices. However, dynamic control of the light-emission properties of active Mie resonant dielectric metasurfaces by an external control parameter has not been demonstrated so far. Here, we experimentally demonstrate the dynamic tuning of spontaneous emission from a Mie-resonant dielectric metasurface that is situated on a fluorescent substrate and embedded into a liquid crystal cell. By switching the liquid crystal from the nematic state to the isotropic state via control of the cell temperature, we induce a shift of the spectral position of the metasurface resonances. This results in a change of the local photonic density of states, which, in turn, governs the enhancement of spontaneous emission from the substrate. Specifically, we observe spectral tuning of both the electric and magnetic dipole resonances, resulting in a 2-fold increase of the emission intensity at lambda ~ 900 nm. Our results demonstrate a viable strategy to realize flat tunable light sources based on dielectric metasurfaces. PMID- 29709200 TI - Ancient Biomolecules and Evolutionary Inference. AB - Over the past three decades, studies of ancient biomolecules-particularly ancient DNA, proteins, and lipids-have revolutionized our understanding of evolutionary history. Though initially fraught with many challenges, today the field stands on firm foundations. Researchers now successfully retrieve nucleotide and amino acid sequences, as well as lipid signatures, from progressively older samples, originating from geographic areas and depositional environments that, until recently, were regarded as hostile to long-term preservation of biomolecules. Sampling frequencies and the spatial and temporal scope of studies have also increased markedly, and with them the size and quality of the data sets generated. This progress has been made possible by continuous technical innovations in analytical methods, enhanced criteria for the selection of ancient samples, integrated experimental methods, and advanced computational approaches. Here, we discuss the history and current state of ancient biomolecule research, its applications to evolutionary inference, and future directions for this young and exciting field. PMID- 29709201 TI - Telehealth and autism: A systematic search and review of the literature. AB - PURPOSE: Research interest in telehealth and autism spectrum disorder (ASD) has grown. There is a need to review the literature to allow speech-language pathologists (SLPs) and other service providers to consider applicability to their settings. The aim of this review was to examine the nature and outcomes of studies examining telehealth assessment and/or intervention in ASD. METHOD: A systematic search of the literature was undertaken, with 14 studies meeting inclusion criteria. The authors extracted information from each included article, including participant characteristics, technology used, measures and reported outcomes. Quality review of articles was undertaken. RESULT: The 284 participants with ASD across the 14 included studies ranged in age from 19 months to adulthood. The quality of the studies varied. A range of services were provided via telehealth, including diagnostic assessments, early intervention and language therapy. Results suggested that services delivered via telehealth were equivalent to services delivered face to face, and superior to comparison groups without telehealth sessions. CONCLUSION: The findings suggest there may be a range of benefits in using telehealth with individuals with ASD, their families, and teachers. Further research, however, is required particularly regarding the use of telehealth directly with children with ASD for assessment and intervention. PMID- 29709202 TI - Inferring Causal Relationships Between Risk Factors and Outcomes from Genome-Wide Association Study Data. AB - An observational correlation between a suspected risk factor and an outcome does not necessarily imply that interventions on levels of the risk factor will have a causal impact on the outcome (correlation is not causation). If genetic variants associated with the risk factor are also associated with the outcome, then this increases the plausibility that the risk factor is a causal determinant of the outcome. However, if the genetic variants in the analysis do not have a specific biological link to the risk factor, then causal claims can be spurious. We review the Mendelian randomization paradigm for making causal inferences using genetic variants. We consider monogenic analysis, in which genetic variants are taken from a single gene region, and polygenic analysis, which includes variants from multiple regions. We focus on answering two questions: When can Mendelian randomization be used to make reliable causal inferences, and when can it be used to make relevant causal inferences? PMID- 29709199 TI - The MRE11-RAD50-NBS1 Complex Conducts the Orchestration of Damage Signaling and Outcomes to Stress in DNA Replication and Repair. AB - Genomic instability in disease and its fidelity in health depend on the DNA damage response (DDR), regulated in part from the complex of meiotic recombination 11 homolog 1 (MRE11), ATP-binding cassette-ATPase (RAD50), and phosphopeptide-binding Nijmegen breakage syndrome protein 1 (NBS1). The MRE11 RAD50-NBS1 (MRN) complex forms a multifunctional DDR machine. Within its network assemblies, MRN is the core conductor for the initial and sustained responses to DNA double-strand breaks, stalled replication forks, dysfunctional telomeres, and viral DNA infection. MRN can interfere with cancer therapy and is an attractive target for precision medicine. Its conformations change the paradigm whereby kinases initiate damage sensing. Delineated results reveal kinase activation, posttranslational targeting, functional scaffolding, conformations storing binding energy and enabling access, interactions with hub proteins such as replication protein A (RPA), and distinct networks at DNA breaks and forks. MRN biochemistry provides prototypic insights into how it initiates, implements, and regulates multifunctional responses to genomic stress. PMID- 29709203 TI - Cystic Fibrosis Disease Modifiers: Complex Genetics Defines the Phenotypic Diversity in a Monogenic Disease. AB - In many respects, genetic studies in cystic fibrosis (CF) serve as a paradigm for a human Mendelian genetic success story. From recognition of the condition as a heritable pathological entity to implementation of personalized treatments based on genetic findings, this multistep pathway of progress has focused on the genetic underpinnings of CF clinical disease. Along this path was the recognition that not all CFTR gene mutations produce the same disease and the recognition of the complex, multifactorial nature of CF genotype-phenotype relationships. The non- CFTR genetic components (gene modifiers) that contribute to variation in phenotype are the focus of this review. A multifaceted approach involving candidate gene studies, genome-wide association studies, and gene expression studies has revealed significant gene modifiers for multiple CF phenotypes. The bold challenges for the future are to integrate the findings into our understanding of CF pathogenesis and to use the knowledge to develop novel therapies. PMID- 29709204 TI - Ancient Genomics of Modern Humans: The First Decade. AB - The first decade of ancient genomics has revolutionized the study of human prehistory and evolution. We review new insights based on prehistoric modern human genomes, including greatly increased resolution of the timing and structure of the out-of-Africa expansion, the diversification of present-day non-African populations, and the earliest expansions of those populations into Eurasia and America. Prehistoric genomes now document population transformations on every inhabited continent-in particular the effect of agricultural expansions in Africa, Europe, and Oceania-and record a history of natural selection that shapes present-day phenotypic diversity. Despite these advances, much remains unknown, in particular about the genomic histories of Asia (the most populous continent) and Africa (the continent that contains the most genetic diversity). Ancient genomes from these and other regions, integrated with a growing understanding of the genomic basis of human phenotypic diversity, will be in focus during the next decade of research in the field. PMID- 29709206 TI - Closing the Loop: From Motor Neuroscience to Neurorehabilitation. AB - The fields of human motor control, motor learning, and neurorehabilitation have long been linked by the intuition that understanding how we move (and learn to move) leads to better rehabilitation. In reality, these fields have remained largely separate. Our knowledge of the neural control of movement has expanded, but principles that can directly impact rehabilitation efficacy remain somewhat sparse. This raises two important questions: What can basic studies of motor learning really tell us about rehabilitation, and are we asking the right questions to improve the lives of patients? This review aims to contextualize recent advances in computational and behavioral studies of human motor learning within the framework of neurorehabilitation. We also discuss our views of the current challenges facing rehabilitation and outline potential clinical applications from recent theoretical and basic studies of motor learning and control. PMID- 29709207 TI - Viral Strategies for Targeting the Central and Peripheral Nervous Systems. AB - Recombinant viruses allow for targeted transgene expression in specific cell populations throughout the nervous system. The adeno-associated virus (AAV) is among the most commonly used viruses for neuroscience research. Recombinant AAVs (rAAVs) are highly versatile and can package most cargo composed of desired genes within the capsid's ~5-kb carrying capacity. Numerous regulatory elements and intersectional strategies have been validated in rAAVs to enable cell type specific expression. rAAVs can be delivered to specific neuronal populations or globally throughout the animal. The AAV capsids have natural cell type or tissue tropism and trafficking that can be modified for increased specificity. Here, we describe recently engineered AAV capsids and associated cargo that have extended the utility of AAVs in targeting molecularly defined neurons throughout the nervous system, which will further facilitate neuronal circuit interrogation and discovery. PMID- 29709205 TI - Long-Term Plasticity of Neurotransmitter Release: Emerging Mechanisms and Contributions to Brain Function and Disease. AB - Long-lasting changes of brain function in response to experience rely on diverse forms of activity-dependent synaptic plasticity. Chief among them are long-term potentiation and long-term depression of neurotransmitter release, which are widely expressed by excitatory and inhibitory synapses throughout the central nervous system and can dynamically regulate information flow in neural circuits. This review article explores recent advances in presynaptic long-term plasticity mechanisms and contributions to circuit function. Growing evidence indicates that presynaptic plasticity may involve structural changes, presynaptic protein synthesis, and transsynaptic signaling. Presynaptic long-term plasticity can alter the short-term dynamics of neurotransmitter release, thereby contributing to circuit computations such as novelty detection, modifications of the excitatory/inhibitory balance, and sensory adaptation. In addition, presynaptic long-term plasticity underlies forms of learning and its dysregulation participates in several neuropsychiatric conditions, including schizophrenia, autism, intellectual disabilities, neurodegenerative diseases, and drug abuse. PMID- 29709209 TI - Anxiety, Depression, and Decision Making: A Computational Perspective. AB - In everyday life, the outcomes of our actions are rarely certain. Further, we often lack the information needed to precisely estimate the probability and value of potential outcomes as well as how much effort will be required by the courses of action under consideration. Under such conditions of uncertainty, individual differences in the estimation and weighting of these variables, and in reliance on model-free versus model-based decision making, have the potential to strongly influence our behavior. Both anxiety and depression are associated with difficulties in decision making. Further, anxiety is linked to increased engagement in threat-avoidance behaviors and depression is linked to reduced engagement in reward-seeking behaviors. The precise deficits, or biases, in decision making associated with these common forms of psychopathology remain to be fully specified. In this article, we review evidence for which of the computations supporting decision making are altered in anxiety and depression and consider the potential consequences for action selection. In addition, we provide a schematic framework that integrates the findings reviewed and will hopefully be of value to future studies. PMID- 29709210 TI - The Dynamic Basis of Respiratory Rhythm Generation: One Breath at a Time. AB - Rhythmicity is a universal timing mechanism in the brain, and the rhythmogenic mechanisms are generally dynamic. This is illustrated for the neuronal control of breathing, a behavior that occurs as a one-, two-, or three-phase rhythm. Each breath is assembled stochastically, and increasing evidence suggests that each phase can be generated independently by a dedicated excitatory microcircuit. Within each microcircuit, rhythmicity emerges through three entangled mechanisms: ( a) glutamatergic transmission, which is amplified by ( b) intrinsic bursting and opposed by ( c) concurrent inhibition. This rhythmogenic triangle is dynamically tuned by neuromodulators and other network interactions. The ability of coupled oscillators to reconfigure and recombine may allow breathing to remain robust yet plastic enough to conform to nonventilatory behaviors such as vocalization, swallowing, and coughing. Lessons learned from the respiratory network may translate to other highly dynamic and integrated rhythmic systems, if approached one breath at a time. PMID- 29709211 TI - Neural Circuits of Sexual Behavior in Caenorhabditis elegans. AB - The recently determined connectome of the Caenorhabditis elegans adult male, together with the known connectome of the hermaphrodite, opens up the possibility for a comprehensive description of sexual dimorphism in this species and the identification and study of the neural circuits underlying sexual behaviors. The C. elegans nervous system consists of 294 neurons shared by both sexes plus neurons unique to each sex, 8 in the hermaphrodite and 91 in the male. The sex specific neurons are well integrated within the remainder of the nervous system; in the male, 16% of the input to the shared component comes from male-specific neurons. Although sex-specific neurons are involved primarily, but not exclusively, in controlling sex-unique behavior-egg-laying in the hermaphrodite and copulation in the male-these neurons act together with shared neurons to make navigational choices that optimize reproductive success. Sex differences in general behaviors are underlain by considerable dimorphism within the shared component of the nervous system itself, including dimorphism in synaptic connectivity. PMID- 29709212 TI - Memory Allocation: Mechanisms and Function. AB - Memories for events are thought to be represented in sparse, distributed neuronal ensembles (or engrams). In this article, we review how neurons are chosen to become part of a particular engram, via a process of neuronal allocation. Experiments in rodents indicate that eligible neurons compete for allocation to a given engram, with more excitable neurons winning this competition. Moreover, fluctuations in neuronal excitability determine how engrams interact, promoting either memory integration (via coallocation to overlapping engrams) or separation (via disallocation to nonoverlapping engrams). In parallel with rodent studies, recent findings in humans verify the importance of this memory integration process for linking memories that occur close in time or share related content. A deeper understanding of allocation promises to provide insights into the logic underlying how knowledge is normally organized in the brain and the disorders in which this process has gone awry. PMID- 29709213 TI - Relationship power and HIV risk among young Black men who have sex with men in the Southern United States. AB - Background: The purpose of this study was to examine the impact of relationship power on HIV risk behaviour among young Black men who have sex with men (MSM) in the Southern US. Methods: Data from 425 Black/African American males aged 18-29 years who reported recent anal intercourse with a male partner were analysed. Five selected measures of relationship power were tested for correlation and association with protected receptive anal intercourse using contingency tables and logistic regression analysis. Results: Acts of 100% protected receptive anal intercourse were common (n=277, 65.2%). Men who reported low barriers to condom negotiation were significantly more likely to report protected acts (P<0.001). Men who reported 100% protected acts were less likely to report financial dependence on male sexual partners and serosorting behaviour (12.0% vs 20.7%, P=0.02; 31.5% vs 49.8%, P<0.001 respectively). Conclusion: Future efforts should further examine the role of relationship power in HIV risk among young Black MSM, including the intersection of individual, dyadic and social-structure risks. PMID- 29709208 TI - A Guide to Emerging Technologies for Large-Scale and Whole-Brain Optical Imaging of Neuronal Activity. AB - The mammalian brain is a densely interconnected network that consists of millions to billions of neurons. Decoding how information is represented and processed by this neural circuitry requires the ability to capture and manipulate the dynamics of large populations at high speed and high resolution over a large area of the brain. Although the use of optical approaches by the neuroscience community has rapidly increased over the past two decades, most microscopy approaches are unable to record the activity of all neurons comprising a functional network across the mammalian brain at relevant temporal and spatial resolutions. In this review, we survey the recent development in optical technologies for Ca2+ imaging in this regard and provide an overview of the strengths and limitations of each modality and its potential for scalability. We provide guidance from the perspective of a biological user driven by the typical biological applications and sample conditions. We also discuss the potential for future advances and synergies that could be obtained through hybrid approaches or other modalities. PMID- 29709214 TI - Variant proteins stimulate more IgM+ GC B-cells revealing a mechanism of cross reactive recognition by antibody memory. AB - Vaccines induce memory B-cells that provide high affinity secondary antibody responses to identical antigens. Memory B-cells can also re-instigate affinity maturation, but how this happens against antigenic variants is poorly understood despite its potential impact on driving broadly protective immunity against pathogens such as Influenza and Dengue. We immunised mice sequentially with identical or variant Dengue-virus envelope proteins and analysed antibody and germinal-centre (GC) responses. Variant protein boosts induced GCs with a higher proportion of IgM+ B cells. The most variant protein re-stimulated GCs with the highest proportion of IgM+ cells with the most diverse, least mutated V-genes and with a slower but efficient serum antibody response. Recombinant antibodies from GC B-cells showed a higher affinity for the variant antigen than antibodies from a primary response, confirming a memory origin. This reveals a new process of antibody memory, that IgM memory cells with fewer mutations participate in secondary responses to variant antigens, demonstrating how the hierarchical structure of B-cell memory is used and indicating the potential and limits of cross-reactive antibody based immunity. PMID- 29709215 TI - Welcome to ISCT 2018 Montreal. PMID- 29709216 TI - Genetic studies and alcoholic liver disease. PMID- 29709217 TI - Glycogenic hepatopathy. AB - BACKGROUND: Glycogenic hepatopathy (GH) is a disorder associated with uncontrolled diabetes mellitus, most commonly type 1, expressed as right upper quadrant abdominal pain, hepatomegaly and increased liver enzymes. The diagnosis may be difficult, because laboratory and imaging tests are not pathognomonic. Although GH may be suggested based on clinical presentation and imaging studies, the gold standard for diagnosis is a liver biopsy, showing a significant accumulation of glycogen within the hepatocytes. GH may be diagnosed also after elevated liver enzymes in routine blood tests. GH usually regresses after tight glycemic control. Progression to end-stage liver disease has never been reported. This review aims to increase the awareness to this disease, to suggest a pathway for investigation that may reduce the use of unnecessary tests, especially invasive ones. DATA SOURCES: A PubMed database search (up to July 1, 2017) was done with the words "glycogenic hepatopathy", "hepatic glycogenosis", "liver glycogenosis" and "diabetes mellitus-associated glycogen storage hepatopathy". Articles in which diabetes mellitus-associated liver glycogen accumulation was described were included in this review. RESULTS: A total of 47 articles were found, describing 126 patients with GH. Hepatocellular disturbance was more profound than cholestatic disturbance. No synthetic failure was reported. CONCLUSIONS: GH may be diagnosed conservatively, based on corroborating medical history, physical examination, laboratory tests, imaging studies and response to treatment, even without liver biopsy. In case of doubt about the diagnosis or lack of clinical response to treatment, a liver biopsy may be considered. There is no role for noninvasive tests like fibroscan or fibrotest for the diagnosis of GH or for differentiation of this situation from nonalcoholic fatty liver disease. PMID- 29709218 TI - Clues to predict incidental gallbladder cancer. AB - BACKGROUND: Consequences of incidental gallbladder cancer (iGBC) following cholecystectomy may include repeat operation (depending on T stage) and worse survival (if bile spillage occurred), both avoidable if iGBC were suspected preoperatively. METHODS: A retrospective single-institution review was done. Ultrasound images for cases and controls were blindly reviewed by a radiologist. Chi-square and Student's t tests, as well as logistic regression and Kaplan-Meier analyses were used. A P <= 0.01 was considered significant. RESULTS: Among 5796 cholecystectomies performed 2000-2013, 26 (0.45%) were iGBC cases. These patients were older (75.61 versus 52.27 years), had more laparoscopic-to-open conversions (23.1% versus 3.9%), underwent more imaging tests, had larger common bile duct diameter (7.13 versus 5.04 mm) and higher alkaline phosphatase. Ultrasound imaging showed that gallbladder wall thickening (GBWT) without pericholecystic fluid (PCCF), but not focal-versus-diffuse GBWT, was associated significantly with iGBC (73.9% versus 47.4%). On multivariable logistic regression analysis, GBWT without PCCF, and age were the strongest predictors of iGBC. The consequences iGBC depended significantly on intraoperative bile spillage, with nearly all such patients developing carcinomatosis and significantly worse survival. CONCLUSIONS: Besides age, GBWT, dilated common bile duct, and elevated alkaline phosphatase, number of preoperative imaging modalities and the presence of GBWT without PCCF are useful predictors of iGBC. Bile spillage causes poor survival in patients with iGBC. PMID- 29709219 TI - Bugbee flexible electrocautery facilitates choledochoscopic biopsy, fulguration, and debulking of a high grade intraductal papillary neoplasm of the bile duct. PMID- 29709221 TI - Corrigendum to "The novel mineralocorticoid receptor antagonist finerenone in diabetic kidney disease: Progress and challenges" [Metabolism 65 (2016) 1342 1349]. PMID- 29709220 TI - [Summit meeting of Cali. VII Iberoamerican of Family Medicine]. PMID- 29709222 TI - The Negative Health Consequences of Anti-Immigration Policies. PMID- 29709223 TI - Individual-Level and Ecological Studies. PMID- 29709224 TI - Agency, Adolescence, and Motor Vehicle Crash Risk. PMID- 29709225 TI - U.S. Adolescent Street Racing and Other Risky Driving Behaviors. AB - PURPOSE: We examined demographic characteristics and risky driving behaviors associated with street racing among adolescents in the NEXT Generation Health Study (N = 2,395). METHOD: Binomial logistic regression tested associations between demographics and driving in a street race (DSR) or being a passenger in a street race (PSR). Sequential logistic regression tested the robustness of the association between DSR and crashes. RESULTS: Hispanic/Latino, non-Hispanic Black/African-American, and mixed-race participants were more likely to engage in DSR. Males were more likely and teens with moderate socioeconomic status were less likely to engage in DSR and PSR. DSR was associated with other risky driving behaviors in bivariate models but was not independently associated with crashes after sequential modeling. CONCLUSIONS: Among adolescents, those who are male, racial/ethnic minorities, or low socioeconomic status may be at higher risk of DSR. However, overall driving risk might explain the association between DSR engagement and higher crash risk. PMID- 29709226 TI - Physical Activity and Sociodemographic Correlates of Adolescent Exergamers. AB - PURPOSE: Exergame use (or active video games that promote physical activity [PA]) has the potential to increase PA in youth, but there is a scarcity of information about PA of youth who are current exergamers. The current study examined PA behaviors in exergamers versus nonexergamers. METHODS: Adolescents (N = 2,793; mean age = 14.4 +/- 2.0 years) participating in EAT 2010 (Eating and Activity in Teens) self-reported sociodemographic characteristics and exergaming and PA behavior. Height and weight were measured. RESULTS: Both male and female exergamers tended to be younger and black compared with nonexergamers (p < .001). Generally, exergamers did not report significantly more PA than nonexergamers, except for female exergamers who engaged in more vigorous PA than female nonexergamers (p < .01; 1.3 +/- .05 h/wk vs. 1.6 +/- .06 h/wk, respectively). CONCLUSIONS: PA behavior in exergamers is similar to PA behavior in nonexergamers. However, when targeting vigorous PA, exergaming may be an innovative and appealing intervention strategy for adolescent girls. PMID- 29709227 TI - Arthur J. Moss, MD-A giant who changed cardiology. PMID- 29709228 TI - Leadership Letter. PMID- 29709229 TI - Defibrillation testing is mandatory in patients with subcutaneous implantable cardioverter-defibrillator to confirm appropriate ventricular fibrillation detection. AB - BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) remains a new technology requiring accurate assessment of the various aspects of its functioning. Isolated cases of delayed sensing of ventricular arrhythmia have been described. OBJECTIVE: The purpose of this multicenter study was to assess the quality of sensing during induced ventricular fibrillation (VF). METHODS: One hundred thirty-seven patients underwent induction of VF at the end of the S-ICD implantation. RESULTS: VF induction was successful in 133 patients (97%). Mean time to first therapy was 16.2 +/- 3.1 seconds, with a substantial range from 12.5 to 27.0 seconds. Four different detection profiles were arbitrarily defined: (1) optimal detection (n = 39 [29%]); (2) undersensing with moderate prolongation of time to therapy (<18 seconds; n = 68 [51%]); (3) undersensing with significant prolongation of the time to therapy (>18 seconds; n = 19 [14%]); and (4) absence of therapy or prolonged time to therapy related to noise oversensing (n = 7 [6%]). In some of the patients in the last group, despite induction of VF the initial counter was never filled, the device did not charge the capacitors, and the shock was not delivered because of a sustained diagnosis of noise (n = 5). A manual shock by the device or an external shock had to be delivered to restore the sinus rhythm. CONCLUSION: Our study demonstrated a marked sensing delay leading to prolonged time to therapy in a large number of S-ICD patients. A few worrisome cases of noise oversensing inhibiting the therapies were detected. These results support the need for systematic intraoperative defibrillation testing. PMID- 29709230 TI - Fusion during entrainment at the cavotricuspid isthmus: What is the mechanism? PMID- 29709231 TI - Anterior myocardial infarction with high-degree AV block in a 62-year-old man. PMID- 29709232 TI - Preventive Medicine: A hidden asset for building a dominant culture of prevention. AB - We explore three issues related to the practice of preventive medicine. First, how does the dearth of preventive medicine physicians on state licensure boards affect quality of medical care? Second, should a process be established to assess the training and skills of candidates for population health positions, like the "credentialing" or "privilege-granting" process used by hospitals and health systems for clinical positions? And third, how should the pervasive lack of recognition of preventive medicine as a bona fide medical specialty be addressed? In exploring these issues, we conclude that preventive medicine physicians are critical to the US health care ecosystem at every level, and to building a dominant culture of prevention. Preventive medicine physicians are actively engaged in the practice of medicine and should be party to the same licensure, credentialing, and privilege-granting procedures as all other specialties. Further, we raise a call to action to our profession to define and raise awareness of preventive medicine, participate in state licensure boards, and establish clear standards of practice for which we are uniquely trained and capable. PMID- 29709233 TI - Mapping the historical development of physical activity and health research: A structured literature review and citation network analysis. AB - Little has been published about the historical development of scientific evidence in the physical activity (PA) and public health research field. The study aimed to examine the evolution of knowledge in this field. A structured literature review using formal citation network analysis methods was conducted in June-2016. Using a list of influential PA publications identified by domain experts, a snowball sampling technique was used to build a compact citation network of 141 publications that represents the backbone of the field. Articles were coded by study type and research team characteristics, then analyzed by visualizing the citation network and identifying research clusters to trace the evolution of the field. The field started in the 1950s, with a health sciences focus and strong North American and European leadership. Health outcome studies appeared most frequently in the network and policy and interventions least. Critical articles on objective measurement and public policy have influenced the progress from an emphasis on health outcomes research at early stages in the field to the more recent emerging built environment and global monitoring foci. There is only modest cross-citation across types of study. To our knowledge, this paper is the first to systematically describe the development of research on PA and public health. The key publications include fundamental ideas that remain citable over time, but notable research and dissemination gaps exist and should be addressed. Increasing collaboration and communication between study areas, encouraging female researchers, and increasing studies on interventions, evaluation of interventions and policy are recommended. PMID- 29709234 TI - Mapping the historical development of research in physical activity and health: Providing a platform for future research. AB - This editorial is a commentary on the review paper by Ramirez Varela et al. entitled "Mapping the historical development of physical activity and health research: a structured literature review and citation network analysis." This editorial highlights the significance and implications of this review, with a particular focus on future research and policy directions. PMID- 29709236 TI - Radiofrequency ablation versus surgical resection for multiple HCCs meeting the Milan criteria: propensity score analyses of 10-year therapeutic outcomes. AB - AIM: To assess the long-term therapeutic outcomes of radiofrequency ablation (RFA) versus surgical resection (SR) as a first-line treatment for patients meeting the Milan criteria with multiple hepatocellular carcinomas (HCCs). MATERIALS AND METHODS: This retrospective study was approved by the institutional review board and the requirement for informed consent was waived. Between January 2004 and December 2009, among 3,441 patients with treatment-naive HCCs, 88 patients meeting the Milan criteria with multiple HCCs (Barcelona Clinic Liver Cancer [BCLC] A stage) who underwent either RFA (n=62) or SR (n=26) were included. Recurrence-free survival (RFS) and overall survival (OS) rates were compared by using propensity score matching. In addition, multivariate analysis was performed for assess the prognostic factor. RESULTS: Matching yielded 20 matched pairs of patients. In the two matched groups, the RFS rates were 30% and 30% at 5- and 10-years, respectively, in the RFA group and 60% and 48.6% in the SR group (p=0.054). The corresponding OS rates were 63.3% and 46.1% in the RFA group and 100% and 73.6% in the SR group, respectively (p=0.061). In multivariate analysis, treatment type was independently associated with RFS (hazard ratio [HR]=0.51; p=0.043) whereas it was not a statistically significant factor for OS (HR=0.50; p=0.088). CONCLUSION: In patients meeting the Milan criteria with multiple HCCs (BCLC A stage), SR may provide better RFS compared to RFA. PMID- 29709235 TI - [Tunisian National Protocol for Adult Hodgkin's Lymphoma Treatment: Results of a therapeutic regimen adapted to the 2-cycle CT response, about 444 patients]. AB - OBJECTIVE: In Tunisia, the management of Adult Hodgkin's Lymphoma (HL) has been standardized since 1999. We propose in this study to report the therapeutic results of the national protocol of adult HL treatment (MDH2008). PATIENTS AND METHODS: Our study is prospective multicenter interesting 444 patients followed for HL between July 2008 and June 2013 and treated according to the MDH2008 protocol. The median age of our patients was 30 years. B symptoms were present in 62.8 % of our patients. According to the Ann Arbor classification, our patients were in stages I, II, III and IV in 3 %, 42 %, 26 % and 29 %, respectively. The MDH2008 protocol is based on a strategy adapted to the therapeutic response to 2 cycles of chemotherapy. RESULTS: Response>=75 % to 2 courses of chemotherapy was achieved in 43 % of patients and the response rate at the end of treatment was 92.1 %. Forty-eight patients (11.4 %) had primary failure. In the multi-variant study, bulky mediastinal mass (IMT>=0.35) was an independent predictive factor of primary failure (P: 0.000). Nineteen toxic deaths (4.35 %) were reported. The relapse rate was 7.8 %. Event free survival, relapse-free survival and overall survival at 5years were 75 %, 89 % and 90 %, respectively. Adaptation of the treatment to the 2 cycles response was effective in unfavorable early stages and advanced stages. CONCLUSION: Compared to MDH2002 (second version of Tunisian prospective protocol), the MDH2008 reduced the primary failure rate, the rate of toxic deaths with escalated BEACOPP and the rate of relapse in Tunisian patients. PMID- 29709237 TI - An optimised repetition time (TR) for cine imaging of uterine peristalsis on 3 T MRI. AB - AIM: To determine the optimal repetition time (TR) of cine imaging for uterine peristalsis on 3 T magnetic resonance imaging (MRI). MATERIALS AND METHODS: Twenty-three young female volunteers (age range: 23-28 years, mean: 24.91+/-1.12 years) underwent 3 T MRI for uterine peristalsis in the periovulatory phase. A midsagittal section of their uteri was scanned using a single-shot fast spin echo sequence with TR of 2 seconds (Cine2s) and 4 seconds (Cine4s) for 3 minutes. Subjective image-quality scores, signal-to-noise ratios (SNRs), and contrast-to noise ratios (CNRs) of these MRI images were evaluated by two radiologists independently. The number, direction, and intensity of uterine peristalsis in the MRI images with two TRs were compared at 15 times the actual speed. RESULTS: The SNRendometrium (263.14+/-91.54) and CNRendometrium -junction zone (134.30+/ 46.91) in Cine4s were significantly higher than those in Cine2s (209.01+/-96.53, 104.05+/-50.19; p=0.042, 0.015, respectively); however, no significant differences were found in other objective indexes and subjective image quality score (p>0.05). In addition, the peristaltic number of Cine2s (7.13+/-1.58) was significantly higher than that in Cine4s (5.30+/-1.06). Cine2s could identify peristaltic directions more clearly than Cine4s; however, no significant difference was observed in the intensity of uterine peristalsis between Cine2s and Cine4s (p=0.509). CONCLUSION: At 3 T MRI, the number and direction of endometrium peristalsis could was displayed better using Cine2s than Cine4s, with the uncompromised image quality. PMID- 29709238 TI - Alleged "sonic attack" supported by poor neuropsychology. PMID- 29709240 TI - Hygroscopic expansion of self-adhesive resin cements and the integrity of all ceramic crowns. AB - OBJECTIVE: Low pH neutralization and subsequent remnant hydrophilicity can lead to hygroscopic expansion of self-adhesive resin cements (SARCs) after water storage. The aim of this in vitro study was to investigate the effects of hygroscopic expansion of SARCs, used as luting and partial core build-up material, on integrity and cement gap thickness increase of all-ceramic CAD/CAM crowns. METHODS: Human third molars (n=48) were prepared and anatomical all ceramic CAD/CAM crowns were manufactured (VITABLOCS Mark II, VITA Zahnfabrik). Crowns internal surfaces were HF etched and silanized. The prepared teeth with their respective crowns were divided into 6 groups (n=8). In groups 1, 3 and 5 the coronal dentin was removed to simulate a partial core build-up. Groups 1 and 2 were luted with iCEM (Heraeus Kulzer), 3 and 4 with RelyX Unicem 2 Automix (3M), 5 and 6 with Variolink Esthetic DC (Ivoclar Vivadent). All specimens were dual cured and stored in distilled water at 37 degrees C. Crown integrity was controlled at baseline and in regular intervals until 180 days. Cement gap thickness was measured using an optical 3D scanner (ATOS Triple scan, GOM) at baseline and after 180 days. Crown integrity was statistically analysed using Kaplan-Meier survival analysis and cement gap thickness increase using two-way ANOVA (alpha=0.05). RESULTS: After 180 days storage, crack formation was observed in all specimens of group 1 (mean survival time of 85.5 days), in one specimen of group 2 and in two specimens of group 4. Two-way ANOVA analysis revealed a statistically significant interaction between material type and build-up on cement gap size increase for iCEM. SIGNIFICANCE: Within the limits of this study, the application of SARCs with low pH neutralization as partial build-up material under CAD/CAM crowns is not recommended for clinical use. PMID- 29709239 TI - Cytosine methylation predicts renal function decline in American Indians. AB - Diabetic nephropathy accounts for most of the excess mortality in individuals with diabetes, but the molecular mechanisms by which nephropathy develops are largely unknown. Here we tested cytosine methylation levels at 397,063 genomic CpG sites for association with decline in the estimated glomerular filtration rate (eGFR) over a six year period in 181 diabetic Pima Indians. Methylation levels at 77 sites showed significant association with eGFR decline after correction for multiple comparisons. A model including methylation level at two probes (cg25799291 and cg22253401) improved prediction of eGFR decline in addition to baseline eGFR and the albumin to creatinine ratio with the percent of variance explained significantly improving from 23.1% to 42.2%. Cg22253401 was also significantly associated with eGFR decline in a case-control study derived from the Chronic Renal Insufficiency Cohort. Probes at which methylation significantly associated with eGFR decline were localized to gene regulatory regions and enriched for genes with metabolic functions and apoptosis. Three of the 77 probes that were associated with eGFR decline in blood samples showed directionally consistent and significant association with fibrosis in microdissected human kidney tissue, after correction for multiple comparisons. Thus, cytosine methylation levels may provide biomarkers of disease progression in diabetic nephropathy and epigenetic variations contribute to the development of diabetic kidney disease. PMID- 29709241 TI - In vitro and in vivo studies of anti-bacterial copper-bearing titanium alloy for dental application. AB - OBJECTIVE: A novel copper-bearing titanium alloy (Ti-Cu) was fabricated for dental application that is expected to efficiently restrain the growth of bacteria and discourage biofilm formation. The aim of this study was to investigate both the antibacterial activity and biofilm inhibition of Ti-Cu alloy in vitro, and the antibacterial effect of Ti-Cu implant in early stage of peri implantitis in vivo. METHODS: Staphylococcus aureus and Escherichia coli were selected to evaluate the antibacterial activity of Ti-Cu alloy and Ti served as control. The antibacterial rate, attached bacteria and developed biofilms were studied from quantitative antibacterial test, biofilm observation and bacterial morphological examination. Electrochemical tests were used to investigate the corrosion property of Ti-Cu alloy. Furthermore, both Ti and Ti-Cu dental implants were manufactured and then implanted in the mandibular premolar sites of beagle dogs for 3 months with ligature-infected treatment. Implant-tissue samples were prepared for radiographic analysis, Micro-CT evaluation and histological examination. RESULTS: Ti-Cu alloy was found to efficiently kill the attached bacteria by ways of damaging cell membranes and cell walls and strongly inhibit the biofilm formation. However, Ti-Cu alloy had excellent corrosion resistance similar with Ti. Further, Ti-Cu dental implants showed superior capacities of inhibiting the bone resorption caused by bacterial infection and enhancing bone formation. SIGNIFICANCE: Ti-Cu alloy strongly inhibited biofilm formation in vitro and prevented bacterial infection associated with dental implant in vivo, making it great potential for application in dental implants with excellent antibacterial viability and positive effect against bone resorption induced by peri-implantitis. PMID- 29709242 TI - Advancing Fenton and photo-Fenton water treatment through the catalyst design. AB - The review is devoted to modern Fenton, photo-Fenton, as well as Fenton-like and photo-Fenton-like reactions with participation of iron species in liquid phase and as heterogeneous catalysts. Mechanisms of these reactions were considered that include hydroxyl radical and oxoferryl species as the reactive intermediates. The barriers in the way of application of these reactions to wastewater treatment were discussed. The following fundamental problems need further research efforts: inclusion of more mechanism steps and quantum calculations of all rate constants lacking in the literature, checking the outer sphere electron transfer contribution, determination of the causes for the key changes in the homogeneous Fenton reaction mechanism with a change in the reagents concentration. The key advances for Fenton reactions implementation for the water treatment are related to tremendous hydrodynamical effects on the catalytic activity, design of ligands for high rate and completeness of mineralization in short time, and design of highly active heterogeneous catalysts. While both homogeneous and heterogeneous Fenton and photo-Fenton systems are open for further improvements, heterogeneous photo-Fenton systems are most promising for practical applications because of the inherent higher catalyst stability. Modern methods of quantum chemistry are expected to play a continuously increasing role in development of such catalysts. PMID- 29709243 TI - Role of TAVR in pure native valvular aortic regurgitation: A new paradigm. PMID- 29709244 TI - SCN5A mutation type and topology are associated with the risk of ventricular arrhythmia by sodium channel blockers. AB - BACKGROUND: Ventricular fibrillation in patients with Brugada syndrome (BrS) is often initiated by premature ventricular contractions (PVCs). Presence of SCN5A mutation increases the risk of PVCs upon exposure to sodium channel blockers (SCB) in patients with baseline type-1 ECG. In patients without baseline type-1 ECG, however, the effect of SCN5A mutation on the risk of SCB-induced arrhythmia is unknown. We aimed to establish whether presence/absence, type, and topology of SCN5A mutation correlates with PVC occurrence during ajmaline infusion. METHODS AND RESULTS: We investigated 416 patients without baseline type-1 ECG who underwent ajmaline testing and SCN5A mutation analysis. A SCN5A mutation was identified in 88 patients (S+). Ajmaline-induced PVCs occurred more often in patients with non-missense mutations (Snon-missense) or missense mutations in transmembrane or pore regions of SCN5A-encoded channel protein (Smissense-TP) than patients with missense mutations in intra-/extracellular channel regions (Smissense-IE) and patients without SCN5A mutation (S-) (29%, 24%, 9%, and 3%, respectively; P<0.001). The proportion of patients with ajmaline-induced BrS was similar in different mutation groups but lower in S- (71% Snon-missense, 63% Smissense-TP, 70% Smissense-IE, and 34% S-; P<0.001). Logistic regression indicated Snon-missense and Smissense-TP as predictors of ajmaline-induced PVCs. CONCLUSIONS: SCN5A mutation is associated with an increased risk of drug-induced ventricular arrhythmia in patients without baseline type-1 ECG. In particular, Snon-missense and Smissense-TP are at high risk. PMID- 29709245 TI - [Persistence, internalization and translocation of Escherichia coli O157:H7, O157:H16 and O105ab in plants and tomato fruits (Solanum lycopersicum L.)]. AB - The presence of pathogenic bacteria, such as Escherichia coli affects the quality and safety of vegetables that are consumed fresh and is associated with serious health problems. The objective of this study was to determine if three different strains of E. coli can penetrate and remain in plants and tomato fruits. A completely randomized experimental design was followed for which a tomato crop ("Cid" variety) was established under greenhouse conditions and three treatments were evaluated, T1 (E. coli O157:H7), T2 (E. coli from tomato cultivation [EcT] O157:H16), T3 (E. coli from spinach cultivation [EcH] O105ab) and a T4 control, with 100 plants each and four forms of inoculation: in the substrate, steam, petiole and the peduncle. Samples were carried out in vegetative stage, flowering, fruiting and physiological maturity to quantify in petri dish CFU/g and know if the bacteria managed to move around and recover in root, stem, flower and fruit. The phylogenetic groups that corresponded to the bacteria recovered were confirmed by biochemical tests, serotyping and PCR. At 120 days the recovery of bacteria in the plant was 23% (E. coli O157:H7), 28% (EcT O157:H16) and 55% (EcH O105ab) whit inoculation to the substrate while the inoculation by puncture the recovery was (in the same order) of 5%, 3%, and 4% at 30 days; 37%, 35% and 30% at 90 days; and 42%, 39% and 13% at 65 days. The strains submit the ability to enter the tomato plant and to stay in it and transported to the fruit, without producing that indicate their presence. PMID- 29709246 TI - Infections in patients with chronic lymphocytic leukaemia: Mitigating risk in the era of targeted therapies. AB - Chronic lymphocytic leukaemia (CLL) is the most common leukaemia with infections a leading cause of morbidity and mortality. Recently there has been a paradigm shift from the use of chemo-immunotherapies to agents targeting specific B lymphocyte pathways. These agents include ibrutinib, idelalisib and venetoclax. In this review, the risks and timing of infections associated with these agents are described, taking into account disease and treatment status. Treatment with ibrutinib as monotherapy or in combination with chemo-immunotherapies is not associated with additional risk for infection. In contrast, the use of idelalisib is associated with a 2-fold risk for severe infection and opportunistic infections. Venetoclax does not appear to be associated with additional infection risk. The evolving spectrum of pathogens responsible infections in CLL patients, especially those with relapsed and refractory disease are described, and prevention strategies (prophylaxis, monitoring and vaccination) are proposed. PMID- 29709248 TI - Identifying risk profiles in liver transplant candidates and implications for induction immunosuppression. AB - Changes in recipient and donor characteristics are redefining the role of induction in liver transplant recipients. Older recipients are more common, with greater concomitant comorbidity. Moderate or severe renal dysfunction is now estimated to affect 40% of liver transplant recipients. Donors are also becoming older, and other factors such as more frequent non-alcoholic fatty liver disease (NAFLD) compromise the quality of some grafts. Rejection rates are now relatively low (~10%) but some patients have a markedly increased risk such as younger recipients and those undergoing re-transplantation. Induction immunosuppression is associated with a significant reduction in rejection risk but due to various factors universal induction is not justified. Steroid-free therapy without induction increases the risk of biopsy-proven acute rejection (BPAR) but randomized trials have shown that induction with an interleukin-2 antagonist receptor (IL-2RA) agent or with rabbit antithymocyte globulin (rATG) maintains immunosuppressive efficacy in steroid-free regimens. Delayed calcineurin inhibitor (CNI) initiation (e.g. to days 4-5 post-transplant) can prevent deterioration of renal function during the first year post-transplant, but requires induction with an IL-2RA agent or rATG to maintain early immunosuppressive efficacy. IL-2RA induction may be inadequate to ensure a low risk of rejection in a steroid-free regimen combined with delayed tacrolimus. Randomized trials of CNI withdrawal at month 1 post-transplant have only achieved an acceptable rate of BPAR when induction is administered. In terms of safety, an increased rate of infection does not seem to be a concern. The most recent large scale analyses have not indicated any evidence for an increased risk of malignancy, or specifically post-transplant lymphoproliferative disease. In summary, the place of induction in the management of liver transplant patients is becoming established. Selective use in high-risk individuals to avoid graft rejection is still relevant, but the key rationale for induction is to facilitate steroid-sparing and CNI-sparing regimens to reduce long-term complications. PMID- 29709247 TI - Blocking "don't eat me" signal of CD47-SIRPalpha in hematological malignancies, an in-depth review. AB - Hematological malignancies express high levels of CD47 as a mechanism of immune evasion. CD47-SIRPalpha triggers a cascade of events that inhibit phagocytosis. Preclinical research supports several models of antibody-mediated blockade of CD47-SIRPalpha resulting in cell death signaling, phagocytosis of cells bearing stress signals, and priming of tumor-specific T cell responses. Four different antibody molecules designed to target the CD47-SIRPalpha interaction in malignancy are currently being studied in clinical trials: Hu5F9-G4, CC-90002, TTI-621, and ALX-148. Hu5F9-G4, a humanized anti-CD47 blocking antibody is currently being studied in four different Phase I trials. These studies may lay the groundwork for therapeutic bispecific antibodies. Bispecific antibody (CD20 CD47SL) fusion of anti-CD20 (Rituximab) and anti-CD47 also demonstrated a synergistic effect against lymphoma in preclinical models. This review summarizes the large body of preclinical evidence and emerging clinical data supporting the use of antibodies designed to target the CD47-SIRPalpha interaction in leukemia, lymphoma and multiple myeloma. PMID- 29709249 TI - Migration and health in the world: a global public health perspective. PMID- 29709250 TI - Migration and health-seeing past the hype, hysteria and labels. PMID- 29709251 TI - Direct incorporation and extension of a fluorescent nucleotide through rolling circle DNA amplification for the detection of microRNA 24-3P. AB - We designed and synthesized several fluorescent nucleotides from thiophene, anthracene and pyrene, which have different sizes, and screened their incorporation and extension capability during the rolling circle amplification of DNA. The thiophene-based fluorescent nucleotide (dUthioTP) could highly incorporate and extended into the rolling circle DNA product, while other fluorescent nucleotides (dUanthTP, and dUpyrTP) could not. This dUthioTP fluorescent nucleotide could be used for the detection of miRNA 24-3P, which is related PRRSV. This direct labeling system during rolling circle DNA amplification exhibited an increased fluorescence signal showing gel formation for the detection of miRNA 24-3P. This direct labeling system is a very simple and cost-efficient method for the detection miRNA 24-3P and also exhibited highly sensitive and selective detection properties. PMID- 29709252 TI - 1,2,4-Triazolsulfone: A novel isosteric replacement of acylsulfonamides in the context of NaV1.7 inhibition. AB - Recently, the identification of several classes of aryl sulfonamides and acyl sulfonamides that potently inhibit NaV1.7 and demonstrate high levels of selectivity over other NaV isoforms have been reported. The fully ionizable nature of these inhibitors has been shown to be an important part of the pharmacophore for the observed potency and isoform selectivity. The requirement of this functionality, however, has presented challenges associated with optimization toward inhibitors with drug-like properties and minimal off-target activity. In an effort to obviate these challenges, we set out to develop an orally bioavailable, selective NaV1.7 inhibitor, lacking these acidic functional groups. Herein, we report the discovery of a novel series of inhibitors wherein a triazolesulfone has been designed to serve as a bioisostere for the acyl sulfonamide. This work culminated in the delivery of a potent series of inhibitors which demonstrated good levels of selectivity over NaV1.5 and favorable pharmacokinetics in rodents. PMID- 29709254 TI - Systematic Outcome Documentation and Potential Impact of New International Delineation Guidelines for Head and Neck Contouring Peer Review. PMID- 29709253 TI - 2-Methylacrylamide as a bioisoster of thiourea group for 1,3-dibenzylthioureido TRPV1 receptor antagonists. AB - In order to replace thiourea group with the more drug-like moiety for 1,3 dibenzylthioureas having TRPV1 antagonist activity, we introduced a set of functional groups between the two aromatic rings based on bioisosteric replacement. The synthesized bioisosteres of 1,3-dibenzylthioureas were tested for their antagonist activities on TRPV1 by 45Ca2+-influx assay using neonatal rat cultured spinal sensory neurons. Among the tested 14 kinds of bioisosters, 2 methylacrylamide group was the best candidate to replace thiourea group. Compound 7c, 2-methylacrylamide analog of ATC-120, showed as potent as ATC-120 in its antagonist activity. In addition, 2-methylacrylamide analog 7e having vinyl moiety showed the most potent activity with 0.022 MUM of IC50 value, indicating that thiourea group of 1,3-dibenzylthioureas could be replaced to 2 methylacrylamide without loss of their potencies. PMID- 29709255 TI - Mapping Effector-Phenotype Landscapes in KRAS-Driven Cancers. AB - Oncogenic KRAS can activate numerous effector pathways to drive malignant progression. However, the relationships between specific effectors and oncogenic phenotypes, and the extent to which these relationships vary across heterogeneous tumors, are incompletely understood. Recently in Cell Reports, a team of scientists described an innovative, combinatorial siRNA-based approach to functionally link KRAS effectors and phenotypes in a large panel of cancer cell lines. Central to this work was the identification of two major subtypes of KRAS mutant cancers with distinct effector landscapes and tractable therapeutic vulnerabilities. PMID- 29709256 TI - Turning Cold Tumors Hot by Blocking TGF-beta. AB - Novel immune therapeutic tools are rapidly expanding the anticancer arsenal. Despite this progress, patients with colorectal cancer (CRC) that spreads to vital parts of the body still have a dismal outcome. Transforming growth factor beta (TGF-beta) plays a pivotal role in the development of CRC and metastasis. Important new work by Tauriello and colleagues has revealed that inhibition of TGF-beta prevents tumor metastasis by enhancing a cytotoxic T cell response, suggesting that TGF-beta inhibition is a promising pro-immunogenic therapy. PMID- 29709257 TI - Improved Pathological Examination of Tumors with 3D Light-Sheet Microscopy. AB - Light-sheet microscopy offers new possibilities to efficiently visualize large tissue samples in three dimensions. Volumetric 3D imaging can uncover detailed information about the inner landscape of tumors, which can improve cancer diagnosis and therapy. This Forum article highlights the advantages of using light-sheet microscopy for pathological examinations of intact tumor specimens. PMID- 29709258 TI - Development versus Evolution in Cancer Biology. AB - The terms 'development' and 'evolution' are both used to describe the unfolding of the carcinogenic process. However, there is increasing awareness of an essential difference in the meanings of these two terms with reference to cancer. We discuss evidence suggesting that the concepts of development and evolution are both pertinent to the description of carcinogenesis; however, they appropriately apply to distinct phases of a multistep process. Such a distinction bears important implications for the study and management of cancer. PMID- 29709259 TI - Cancer CRISPR Screens In Vivo. AB - Clustered regularly interspaced short palindromic repeats (CRISPR) screening is a powerful toolset for investigating diverse biological processes. Most CRISPR screens to date have been performed with in vitro cultures or cellular transplant models. To interrogate cancer in animal models that more closely recapitulate the human disease, autochthonous direct in vivo CRISPR screens have recently been developed that can identify causative drivers in the native tissue microenvironment. By empowering multiplexed mutagenesis in fully immunocompetent animals, direct in vivo CRISPR screens enable the rapid generation of patient specific avatars that can guide precision medicine. This Opinion article discusses the current status of in vivo CRISPR screens in cancer and offers perspectives on future applications. PMID- 29709260 TI - Noninvasive PET Imaging of T cells. AB - The rapidly evolving field of cancer immunotherapy recently saw the approval of several new therapeutic antibodies. Several cell therapies, for example, chimeric antigen receptor-expressing T cells (CAR-T), are currently in clinical trials for a variety of cancers and other diseases. However, approaches to monitor changes in the immune status of tumors or to predict therapeutic responses are limited. Monitoring lymphocytes from whole blood or biopsies does not provide dynamic and spatial information about T cells in heterogeneous tumors. Positron emission tomography (PET) imaging using probes specific for T cells can noninvasively monitor systemic and intratumoral immune alterations during experimental therapies and may have an important and expanding value in the clinic. PMID- 29709261 TI - Cancer as a Matter of Fat: The Crosstalk between Adipose Tissue and Tumors. AB - Obesity has been linked to the increased risk and aggressiveness of many types of carcinoma. A state of chronic inflammation in adipose tissue (AT), resulting in genotoxic stress, may contribute to carcinogenesis and cancer initiation. Evidence that AT plays a role in cancer aggressiveness is solid and mounting. During cancer progression, tumor cells engage in a metabolic symbiosis with adjacent AT. Mature adipocytes provide adipokines and lipids to cancer cells, while stromal and immune cells from AT infiltrate carcinomas and locally secrete paracrine factors within the tumor microenvironment. This review focuses on the crosstalk between AT and tumor cells that promotes tumor growth and increases cellular lipid metabolism, metastasis, and chemoresistance. PMID- 29709262 TI - New Therapies in Head and Neck Cancer. AB - Head and neck squamous cell carcinoma (HNSCC) is a common malignancy with high rates of mortality and morbidity. Beginning with cetuximab, investigators continue to optimize antibody technology to target cell-surface receptors that promote HNSCC growth. Small molecules and oligonucleotides have also emerged as therapeutic inhibitors of key receptor-mediated signaling pathways. Although many such therapies have been disappointing in clinical trials as single agents, they continue to be studied in combination with standard therapies. Approvals of pembrolizumab and nivolumab opened a new era of immunotherapy that aims to stimulate antitumor immunity in the tumor microenvironment. Immunotherapies are being intensively investigated in new HNSCC clinical trials, with the goal of optimizing the therapeutic potential of this new class of anticancer agent. PMID- 29709263 TI - Sedentary Behavior and the Risk of Depression in Patients With Acute Coronary Syndromes. AB - Although there is good evidence that sedentary behavior is associated with poor health outcomes in healthy persons and patients with cardiovascular disease, the mental health consequences of sedentary behavior have not been widely studied. In this report, we conducted a cross-sectional analysis to examine the relation of self-reported sedentary behavior and depression in a sample of 4,043 hospitalized men and women with acute coronary syndrome enrolled in a randomized clinical trial in rural China. Sedentary behavior was assessed by self-report, and depression was assessed with the Patient Health Questionnaire-9 (PHQ-9); a subset of 1,209 patients also completed the Beck Depression Inventory-II. Results revealed that greater sedentary behavior was associated with higher levels of depressive symptoms measured by both the PHQ-9 (p <0.001) and the Beck Depression Inventory-II (p <0.001). Compared with patients who reported that they were seldom sedentary, patients reporting that they were frequently sedentary were 4.7 times (odds ratio 4.73, 95% confidence interval 2.71 to 8.24) more likely to be clinically depressed defined as PHQ-9 scores >=10 after adjusting for demographic factors, lifestyle behaviors, clinical characteristics, and in-hospital treatments. In conclusion, greater sedentary behavior is significantly related to greater depression in Chinese patients with acute coronary syndrome, independent of physical activity. These findings suggest that strategies to reduce sedentary behavior may improve medical outcomes and reduce risk for depression. PMID- 29709264 TI - Assessing and addressing cardiovascular risk in young women. PMID- 29709265 TI - American Academy of Nursing on policy: Recommendations in response to mass shootings. PMID- 29709266 TI - ? AB - We are reporting the case of an 82-year-old Yemeni patient, renal transplant recipient who was admitted to our institution and who subsequently developed disseminated infection with Saprochaete capitata. This pathogenic fungus is rarely reported in patients with solid organ trans-plants. Saprochaete capitata is an emerging fungal pathogen, ubiquitously spread in the environment. This is the second case to our knowledge of infection with Saprochaete capitata in a renal transplant patient. Our patient was treated for multiple nosocomial infections with prolonged antibiotic courses. He succumbed to the infection with Saprochaete capitate after several weeks spent in the intensive care unit. PMID- 29709267 TI - Orbital cellulitis secondary to a fungal sinusitis caused by Scopulariopsis: The first case in Tunisia. AB - We report a case of invasive fungal sinusitis caused by Scopulariopsis in 57 year old man who had recurrence of orbital cellulitis. CT-scan and magnetic resonance imaging found an orbital cellulitis associated to a left frontal sinusitis with bone erosion and calcification. Patient was treated by surgical debridement and voriconazole. Culture of excised tissue was positive for Scopulariopsis. PMID- 29709268 TI - Literature Review: Assessment of Opioid-related Sedation and the Pasero Opioid Sedation Scale. AB - PURPOSE: To examine sedation scales and monitoring practices, specifically evaluating utilization of the Pasero Opioid Sedation Scale (POSS) in the clinical setting. DESIGN: Literature review. METHODS: A thorough review of the literature was conducted using three databases from January 2009 to June 2016. FINDINGS: A total of six articles were selected for the review; three descriptive survey based design, two quasi-experimental design, and one evidence-based practice project. Three articles evaluated implementation of the POSS in a postanesthesia care unit, pediatric clinical unit or pediatric intensive care unit, and in general care areas. CONCLUSIONS: The POSS is an effective tool to assess sedation and increase confidence among nurses. PMID- 29709269 TI - Polysulfide protects midbrain dopaminergic neurons from MPP+-induced degeneration via enhancement of glutathione biosynthesis. AB - Polysulfides are endogenous sulfur-containing molecular species that may regulate various cellular functions. Here we examined the effect of polysulfides exogenously applied to rat midbrain slice cultures, to address their potential neuroprotective actions. Na2S3 at concentrations of 10 MUM or higher prevented 1 methyl-4-phenylpyridinium (MPP+)-induced loss of dopaminergic neurons. Na2S4 at 10 MUM also protected dopaminergic neurons from MPP+ cytotoxicity, whereas Na2S and Na2S2 at the same concentration had no significant effect. We also found that Na2S3 (10 MUM) prevented MPP+-induced increase in intracellular reactive oxygen species as detected by 2',7'-dichlorofluorescein fluorescence. In addition, the protective effect of Na2S3 was abolished by l-buthionine sulfoximine, an inhibitor of glutathione synthesis. In cellular models of neurons (SH-SY5Y cells) and glial cells (C6 cells), Na2S3 (30 and 100 MUM) increased expression of mRNAs encoding the subunits of glutamate cysteine ligase, the rate-limiting enzyme for glutathione biosynthesis. Consistently, the cellular content of total glutathione was increased by Na2S3, and the effect was more prominent in SH-SY5Y cells than in C6 cells. These results suggest that polysulfides are efficient neuroprotectants superior to monosulfur species such as H2S and HS-, and that the neuroprotective effect of polysulfides is mediated by upregulation of glutathione biosynthesis. PMID- 29709271 TI - Prophylactic mesh augmentation: Patient selection, techniques, and early outcomes. AB - BACKGROUND: Incisional hernias (IH) following abdominal surgery are frequent and morbid. Prophylactic mesh augmentation (PMA) has emerged as a technique to reduce IH formation. We aim to report patient selection, techniques and early outcomes after PMA. METHODS: Retrospective chart review identified descriptive characteristics, risk factors, operative technique, and early post-operative outcomes for PMA patients and matched non-PMA patients between January 1, 2016 and October 31, 2017. RESULTS: 18 consecutive PMA cases were performed (55.6% female, mean age 54.3 years and mean BMI = 29.5 kg/m2). 88.9% of patients had at least two high-risk features for IH. Zero PMA patients developed IH compared to 5.3% non-PMA patients (p = 0.314) (6-months mean follow-up). No difference in surgical site occurrences (SSO) were identified between the two groups. CONCLUSIONS: Early results are encouraging, demonstrating PMA is safe with equivocal SSO. Further studies are needed to assess if the reduction in IH formation is statistically significant with longer follow-up. PMID- 29709270 TI - Selectivity of Ca2+ channel blockers for dilator actions on the isolated lower esophageal sphincter and aorta from rats. AB - We compared dilator actions of representative four Ca2+ channel blockers on the isolated lower esophagus sphincter (LES) and thoracic aorta from rats. Verapamil, diltiazem, nifedipine and cilnidipine suppressed KCl-induced contractions of LES and thoracic aorta in a concentration-dependent manner. The order of selectivity for LES, which was calculated as ratio of IC50 value for thoracic aorta divided by that for LES, was diltiazem > verapamil > nifedipine > cilnidipine. These results suggest that diltiazem more preferentially dilates the LES whereas cilnidipine is expected to have lower potential risk of gastroesophageal dysfunction during the antihypertensive therapy. PMID- 29709272 TI - Value of ultrasound-guided fine needle aspiration in diagnosing axillary lymph node recurrence after breast cancer surgery. AB - BACKGROUND: This article aims to assess the diagnostic performance of ultrasound guided fine needle aspiration (US-FNA) in diagnosing axillary lymph node (ALN) recurrence in patients with a history of breast cancer. METHODS: From January 2005 to June 2015, 231 US-FNA examinations performed for suspicious axillary lesions in 218 patients with a history of breast cancer were included. Diagnostic performance of US-FNA for ALN recurrence were evaluated. RESULTS: Of the 231 US FNA examinations, 172 (74.5%) obtained negative and 59 (25.5%) obtained positive cytological results. All US-FNA-negative axillary lesions were considered imaging cytology concordant and underwent follow-up, with one false-negative result (false negative rate, 1.6% [1/60]). The overall sensitivity, specificity, PPV and NPV of US-FNA for diagnosing ALN recurrence/metastasis per examination were 98.3% (59/60), 100% (171/171), 100% (59/59) and 99.4% (171/172). When excluding nine patients with newly developed contralateral breast cancer, the sensitivity, specificity, PPV and NPV of US-FNA for diagnosing ALN recurrence was 98.1% (51/52),100% (170/170),100% (51/51) and 99.4% (170/171). CONCLUSIONS: US-FNA is a reliable method for diagnosing axillary recurrence in patients with a history of breast cancer. PMID- 29709274 TI - Land degradation: a solution is possible. PMID- 29709273 TI - How to deal with rectal lesions more than 15 cm from the anal verge through transanal endoscopic microsurgery. AB - BACKGROUND: The aim of this study is to assess postoperative morbidity and mortality in tumors with a proximal margin 15 cm or more from the anal verge operated with transanal endoscopic microsurgery (TEM). METHODS: This observational study of consecutive rectal tumor patients undergoing TEM was carried out from July 2004 to June 2017. We compared the results of rectal tumors at distances of >=15 cm (group A) and <15 cm (group B) from the anal verge. RESULTS: During the study period 667 patients were included: 118 in group A and 549 in group B. In the comparative analysis there were no significant differences in morbidity (p = 0.23), mortality (p = 0.32) or free margin involvement (p = 0.545). Differences were observed in terms of lesion size (p < 0.001), surgical time (p < 0.001) and peritoneal cavity perforation, which were all increased in group A. CONCLUSION: TEM for lesions in the rectosigmoid junction is feasible and is not associated with higher morbidity or mortality. PMID- 29709276 TI - Redesigning public health for planetary health. PMID- 29709275 TI - Challenges and opportunities in planetary health for primary care providers. PMID- 29709277 TI - Growing water insecurity and dengue burden in the Americas. PMID- 29709278 TI - Cross-cutting principles for planetary health education. PMID- 29709279 TI - The Lancet Countdown UK case study. PMID- 29709280 TI - Cognition impact of sand and dust storms highlights future research needs? PMID- 29709281 TI - Environmental and socioeconomic drivers in infectious disease. PMID- 29709283 TI - Correction to Lancet Planet Health 2018; 2: e147-48. PMID- 29709282 TI - Bringing the planet into the generalist practice: a form of preventive care. PMID- 29709284 TI - The Lancet Countdown on health benefits from the UK Climate Change Act: a modelling study for Great Britain. AB - BACKGROUND: Climate change poses a dangerous and immediate threat to the health of populations in the UK and worldwide. We aimed to model different scenarios to assess the health co-benefits that result from mitigation actions. METHODS: In this modelling study, we combined a detailed techno-economic energy systems model (UK TIMES), air pollutant emission inventories, a sophisticated air pollution model (Community Multi-scale Air Quality), and previously published associations between concentrations and health outcomes. We used four scenarios and focused on the air pollution implications from fine particulate matter (PM2.5), nitrogen dioxide (NO2) and ozone. The four scenarios were baseline, which assumed no further climate actions beyond those already achieved and did not meet the UK's Climate Change Act (at least an 80% reduction in carbon dioxide equivalent emissions by 2050 compared with 1990) target; nuclear power, which met the Climate Change Act target with a limited increase in nuclear power; low greenhouse gas, which met the Climate Change Act target without any policy constraint on nuclear build; and a constant scenario that held 2011 air pollutant concentrations constant until 2050. We predicted the health and economic impacts from air pollution for the scenarios until 2050, and the inequalities in exposure across different socioeconomic groups. FINDINGS: NO2 concentrations declined leading to 4 892 000 life-years saved for the nuclear power scenario and 7 178 000 life-years saved for the low-greenhouse gas scenario from 2011 to 2154. However, the associations that we used might overestimate the effects of NO2 itself. PM2.5 concentrations in Great Britain are predicted to decrease between 42% and 44% by 2050 compared with 2011 in the scenarios that met the Climate Change Act targets, especially those from road traffic and off-road machinery. These reductions in PM2.5 are tempered by a 2035 peak (and subsequent decline) in biomass (wood burning), and by a large, projected increase in future demand for transport leading to potential increases in non-exhaust particulate matter emissions. The potential use of biomass in poorly controlled technologies to meet the Climate Change Act commitments would represent an important missed opportunity (resulting in 472 000 more life-years lost from PM2.5 in the low greenhouse gas scenario and 1 122 000 more life-years lost in the nuclear power scenario from PM2.5 than the baseline scenario). Although substantial overall improvements in absolute amounts of exposure are seen compared with 2011, these outcomes mask the fact that health inequalities seen (in which socioeconomically disadvantaged populations are among the most exposed) are projected to be maintained up to 2050. INTERPRETATION: The modelling infrastructure created will help future researchers explore a wider range of climate policy scenarios, including local, European, and global scenarios. The need to strengthen the links between climate change policy objectives and public health imperatives, and the benefits to societal wellbeing that might result is urgent. FUNDING: National Institute for Health Research. PMID- 29709285 TI - Prenatal exposure to sand and dust storms and children's cognitive function in China: a quasi-experimental study. AB - BACKGROUND: While there is evidence that sand and dust storms can have adverse health effects, the effects of such storms on children's cognitive function has not been explored. We examined whether prenatal exposure to sand and dust storms affects children's cognitive function and, if so, whether harmful effects of sand and dust storms vary by the trimester of exposure. METHODS: This study used nationally representative data from the China Family Panel Studies between 2010 and 2014 and data on sand and dust storms from the national Sand and Dust Weather Almanac. We selected four indicators of children's cognitive function: mathematics test scores, word-recognition test scores, the age the child began speaking in whole sentences, and the age the child began counting from one to ten. Since the annual incidence of sand and dust storms is highly variable and is largely unpredictable, we used a region-and-year fixed-effect model to compare the cognitive function of children born in the same region and year but with varying amounts of prenatal exposure to sand and dust storms. We also investigated whether the effect of sand and dust storms varied by the specific month of prenatal exposure. FINDINGS: We included 1236 observations for the analysis of mathematics and word-recognition test scores, 2693 observations in the analysis of the age the child began speaking in whole sentences, and 1951 observations for the analysis of the age the child began counting from one to ten. Every 10 additional days of prenatal exposure to sand and dust storms was associated with a 0.20 SD (95% CI 0.06 to 0.35, p=0.009) reduction in word test scores, 0.04 (-0.00 to 0.09, p=0.089) additional months to begin speaking in sentences, and 0.14 (0.03 to 0.25, p=0.021) additional months to begin counting, but was not significantly associated with mathematics test scores (reduction of 0.02 SD, -0.19 to 0.15). 10 additional days of prenatal exposure to sand and dust storms in the seventh gestational month was associated with a 0.18 SD (0.10 to 0.25) reduction in mathematics test scores, a 0.34 SD (0.18 to 0.50) reduction in word test scores, an additional 0.33 months (0.07 to 0.59) to begin speaking in sentences, and an additional 0.20 months (0.04 to 0.35) to begin counting. INTERPRETATION: Our results suggest that protecting pregnant women from the effects of sand and dust storms in the critical periods of fetal brain development could generate benefits for the cognitive function of the next generation. FUNDING: None. PMID- 29709287 TI - [Which place occupies the free drug sample in the prescription of the physicians in Morocco?] AB - OBJECTIVES: Do the state of affairs of the perception of free drug samples by a group of prescribers of drugs in the Morocco. METHODS: This was a cross-sectional study of 381 physicians practising in different sectors (public, private) using a self-administered anonymous questionnaire, conducted between December 2016 and March 2017. The questionnaire focused on assessing the general knowledge of prescriber on free drug sample, medical visit of medical representative of pharmaceutical laboratory, drug prescribing and free drug sample use. RESULTS: In total, 381 prescribers were interviewed. Sex M/F ratio was 0.53 with a mean age of 37.4+/-11.2 years exerting mainly in the public sector in urban areas. According to surveyed prescribers, the drug specialties presented as free drug sample occupied 52.1 percent of their prescription. The main interest in having the free drug sample was to help the patient at low socioeconomic level but it influences the physician's prescription. CONCLUSION: This survey puts in perspective the place of the free drug sample in the medical prescription with prescribers, in order to raise awareness about the ability of free drug sample to influence the medical prescription although it allows to help the patient low socio-economic level. PMID- 29709286 TI - Use of geographically weighted logistic regression to quantify spatial variation in the environmental and sociodemographic drivers of leptospirosis in Fiji: a modelling study. AB - BACKGROUND: Leptospirosis is a globally important zoonotic disease, with complex exposure pathways that depend on interactions between human beings, animals, and the environment. Major drivers of outbreaks include flooding, urbanisation, poverty, and agricultural intensification. The intensity of these drivers and their relative importance vary between geographical areas; however, non-spatial regression methods are incapable of capturing the spatial variations. This study aimed to explore the use of geographically weighted logistic regression (GWLR) to provide insights into the ecoepidemiology of human leptospirosis in Fiji. METHODS: We obtained field data from a cross-sectional community survey done in 2013 in the three main islands of Fiji. A blood sample obtained from each participant (aged 1-90 years) was tested for anti-Leptospira antibodies and household locations were recorded using GPS receivers. We used GWLR to quantify the spatial variation in the relative importance of five environmental and sociodemographic covariates (cattle density, distance to river, poverty rate, residential setting [urban or rural], and maximum rainfall in the wettest month) on leptospirosis transmission in Fiji. We developed two models, one using GWLR and one with standard logistic regression; for each model, the dependent variable was the presence or absence of anti-Leptospira antibodies. GWLR results were compared with results obtained with standard logistic regression, and used to produce a predictive risk map and maps showing the spatial variation in odds ratios (OR) for each covariate. FINDINGS: The dataset contained location information for 2046 participants from 1922 households representing 81 communities. The Aikaike information criterion value of the GWLR model was 1935.2 compared with 1254.2 for the standard logistic regression model, indicating that the GWLR model was more efficient. Both models produced similar OR for the covariates, but GWLR also detected spatial variation in the effect of each covariate. Maximum rainfall had the least variation across space (median OR 1.30, IQR 1.27-1.35), and distance to river varied the most (1.45, 1.35-2.05). The predictive risk map indicated that the highest risk was in the interior of Viti Levu, and the agricultural region and southern end of Vanua Levu. INTERPRETATION: GWLR provided a valuable method for modelling spatial heterogeneity of covariates for leptospirosis infection and their relative importance over space. Results of GWLR could be used to inform more place-specific interventions, particularly for diseases with strong environmental or sociodemographic drivers of transmission. FUNDING: WHO, Australian National Health & Medical Research Council, University of Queensland, UK Medical Research Council, Chadwick Trust. PMID- 29709288 TI - Is the Bishop-Koop procedure useful in severe jejunoileal atresia? AB - PURPOSE: The aim of this study was to report our experience using the Bishop-Koop procedure for the treatment of various surgical problems of jejunoileal atresia including luminal discrepancy, complex meconium peritonitis, type IIIb and type IV atresia which we defined as severe jejunoileal atresia. METHODS: This retrospective study was performed on the patients with severe jejunoileal atresia who underwent Bishop-Koop procedure at a tertiary center in China over a five year of period. The mortality, complication rate, nutrition status and the risk factors for postoperative adverse outcomes were explored. RESULTS: A total of 41 neonates underwent the Bishop-Koop procedure. The median duration of the hospital stay and total parenteral nutrition and the point at which oral feeding was initiated postoperatively were 24 days (95% CI =18.99-29.01), 13 days (95% CI = 9.03-16.97) and 11 days (95% CI = 10.17-11.83) respectively. The mortality rate was 7.32% (3/41). The complication rate was 41.4% (17/41) including anastomotic leak, intestinal obstruction, high output stoma and cholestasis. The weight for age Z-score at stoma closure was restored to normal levels (-0.86, 95% confidence interval (CI) = -1.44, -0.28). The main factor associated with adverse outcomes in severe jejunoileal atresia was premature delivery (odds ratio (OR) = 4.44, 95% CI = 1.06-18.67). CONCLUSIONS: Bishop-Koop procedure appears to be a technically efficient method for severe jejunoileal atresia, although larger studies are needed to compare Bishop-Koop procedure and other operation techniques. TYPE OF STUDY: Therapeutic. LEVEL OF EVIDENCE: Level IV. PMID- 29709289 TI - Macroscopic features of prostate cancer. AB - This study investigates the macroscopic features of prostate cancers in unfixed prostatic tissue. For the study 514 radical prostatectomy specimens received at the Karolinska University Hospital were examined. The glands were bisected horizontally prior to fixation. Features on the cut surface of the prostate that were considered conclusive or suspicious for cancer were seen in 52% and 24% of specimens, respectively. In microscopic sections from these areas substantial cancers (>=2 mm) were found in 94% and 69%, of glands, respectively. When no cancer was seen grossly, substantial cancers were still identified histologically in 56% of cases on the cut surface of the prostate. Of substantial tumours 58% had distinct gross findings and 20% were considered to be suspicious for cancer on macroscopic examination. It was noted that gross assessment of the tumour diameter usually underestimated the microscopic extent of the tumour (p < 0.001). Of tumours that could be identified conclusively, 30% were tan, 30% white, 16% yellow and 24% orange. Transition zone tumours were most often orange (61%) while peripheral zone tumours were usually tan or white (35% and 33%). All macroscopically identifiable cancers were poorly circumscribed. Among substantial cancers, transition zone tumours were less frequently visualised than peripheral zone tumours (33% and 13%, respectively; p < 0.001). Findings conclusive for cancer macroscopically usually predict microscopic cancer, but substantial cancers may be present even if no cancer is seen grossly. Transition zone tumours are more difficult than peripheral zone tumours to visualise macroscopically. PMID- 29709290 TI - The use of routinely collected patient-reported outcome measures in rheumatoid arthritis. AB - This study systematically reviewed commonly used patient-reported outcome measures (PROMs) for rheumatoid arthritis (RA), routinely collected in clinical practice, and evaluated objectives of their use. An additional survey conducted among identified RA registries provided additional information about collection of PROMs. Medline Ovid and Embase were searched for observational studies using data of RA registries/cohorts, published between 2011 and 2016. The search combined a validated search algorithm for PROMs and RA. Study characteristics, objective, registry, country, type of PROMs collected, and time interval of collection were systematically recorded. The survey asked about PROMs collected by the registries, timing, response rates, and barriers to collection. Ninety eight articles from 15 countries were identified making use of 37 registries and large cohorts. Thirty-three PROMs were collected routinely, with VAS, EQ-5d and HAQ being the most used tools. Health domains reported the most were functional assessment, pain and patient global assessment. Despite the wide variety of collected PROMs, foci of the articles were similar and reported results narrow. This review suggests rethinking the role of PROMs in rheumatology research to use this information as broadly as possible, including evaluation of treatments, economic analyses, and decision-making based on patients' experiences at system, provider, and physician level. PMID- 29709291 TI - Underutilization of brachytherapy and disparities in survival for patients with cervical cancer in California. AB - PURPOSE: The treatment for locally advanced cervical cancer is external beam radiation (EBRT), concurrent chemotherapy, and brachytherapy (BT). We investigated demographic and socioeconomic factors that influence trends in BT utilization and disparities in survival. METHODS: Using the California Cancer Registry, cervical cancer patients FIGO IB2-IVA from 2004 to 2014 were identified. We collected tumor, demographic and socioeconomic (SES) factors. We used multivariable logistic regression analysis to determine predictors of use of BT. Using Cox proportional hazards, we examined the impact of BT vs EBRT boost on cause specific (CSS) and overall survival (OS). RESULTS: We identified 4783 patients with FIGO stage 11% IB2; 32% II, 54% III, 3% IVA. Nearly half (45%) of patients were treated with BT, 18% were treated with a EBRT boost, and 37% had no boost. Stage II and III were more likely to be treated with BT (p = 0.002 and p = 0.0168) vs Stage IB2. As patients aged, the use of BT decreased. Using multivariate analysis, BT impacted CCS (HR 1.16, p = 0.0330) and OS (HR 1.14, p = 0.0333). Worse CSS was observed for black patients (p = 0.0002), low SES (p = 0.0263), stage III and IVA (p < 0.0001. Black patients, low and middle SES had worse OS, (p = 0.0003). CONCLUSIONS: The utilization of BT in locally advanced cervical cancer was low at 45%, with a decrease in CSS and OS. Black patients and those in low SES had worse CSS. As we strive for outcome improvement in cervical cancer, we need to target increasing access and disparities for quality and value. PMID- 29709292 TI - Patterns of lateral enamel growth in Homo naledi as assessed through perikymata distribution and number. AB - Perikymata, incremental growth lines visible on tooth enamel surfaces, differ in their distribution and number among hominin species, although with overlapping patterns. This study asks: (1) How does the distribution of perikymata along the lateral enamel surface of Homo naledi anterior teeth compare to that of other hominins? (2) When both perikymata distribution and number are analyzed together, how distinct is H. naledi from other hominins? A total of 19 permanent anterior teeth (incisors and canines) of H. naledi were compared, by tooth type, to permanent anterior teeth of other hominins: Australopithecus afarensis, Australopithecus africanus, Paranthropus robustus, Paranthropus boisei, Homo ergaster/Homo erectus, other early Homo, Neandertals, and modern humans, with varying sample sizes. Repeated measures analyses of the percentage of perikymata per decile of reconstructed crown height yielded several statistically significant differences between H. naledi and other hominins. Canonical variates analysis of percentage of perikymata in the cervical half of the crown together with perikymata number revealed that, in 8 of 19 cases, H. naledi teeth were significantly unlikely to be classified as other hominins, while exhibiting least difference from modern humans (especially southern Africans). In a cross validated analysis, 68% of the H. naledi teeth were classified as such, while 32% were classified as modern human (most often southern African). Of 313 comparative teeth use for this analysis, only 1.9% were classified as H. naledi. What tends to differentiate H. naledi anterior tooth crowns from those of most other hominins, including some modern humans, is strongly skewed perikymata distributions combined with perikymata numbers that fall in the middle to lower ranges of hominin values. H. naledi therefore tends toward a particular combination of these features that is less often seen in other hominins. Implications of these data for the growth and development of H. naledi anterior teeth are considered. PMID- 29709293 TI - Mandibular ramus shape variation and ontogeny in Homo sapiens and Homo neanderthalensis. AB - As the interface between the mandible and cranium, the mandibular ramus is functionally significant and its morphology has been suggested to be informative for taxonomic and phylogenetic analyses. In primates, and particularly in great apes and humans, ramus morphology is highly variable, especially in the shape of the coronoid process and the relationship of the ramus to the alveolar margin. Here we compare ramus shape variation through ontogeny in Homo neanderthalensis to that of modern and fossil Homo sapiens using geometric morphometric analyses of two-dimensional semilandmarks and univariate measurements of ramus angulation and relative coronoid and condyle height. Results suggest that ramus, especially coronoid, morphology varies within and among subadult and adult modern human populations, with the Alaskan Inuit being particularly distinct. We also identify significant differences in overall anterosuperior ramus and coronoid shapes between H. sapiens and H. neanderthalensis, both in adults and throughout ontogeny. These shape differences are subtle, however, and we therefore suggest caution when using ramus morphology to diagnose group membership for individual specimens of these taxa. Furthermore, we argue that these morphologies are unlikely to be representative of differences in masticatory biomechanics and/or paramasticatory behaviors between Neanderthals and modern humans, as has been suggested by previous authors. Assessments of ontogenetic patterns of shape change reveal that the typical Neanderthal ramus morphology is established early in ontogeny, and there is little evidence for divergent postnatal ontogenetic allometric trajectories between Neanderthals and modern humans as a whole. This analysis informs our understanding of intraspecific patterns of mandibular shape variation and ontogeny in H. sapiens and can shed further light on overall developmental and life history differences between H. sapiens and H. neanderthalensis. PMID- 29709294 TI - Occurrence, profile and spatial distribution of UV-filters and musk fragrances in mussels from Portuguese coastline. AB - The increasing production and consumption of Personal Care Products (PCPs), containing UV-filters and musk fragrances, has led to its widespread presence in the aquatic environment which can cause harmful effects to the aquatic organisms due to its intrinsic toxicity. This study aims to evaluate the degree of contamination of wild mussels along the entire Portuguese coastline, continually exposed in their habitat to different contaminants. For this purpose, approximately 1000 mussel specimens were sampled during one year in seven different locations, along the Portuguese coastline. Simultaneous quantification of five UV-filters and seven musks in mussels was achieved by a Quick, Easy, Cheap, Effective, Rugged and Safe (QuEChERS) extraction procedure combined with dispersive liquid-liquid microextraction (DLLME) followed by gas chromatography with mass spectrometry (GC-MS) analysis. Ten out of the twelve target analytes were found in the analysed samples, highlighting the presence of AHTN (tonalide), EHS (2-ethylhexylsalicylate) and EHMC (2-ethylhexyl 4-methoxycinnamate) in all positive samples (93%). Overall, the results obtained indicate a widespread contamination of wild mussels along Portuguese coastline, all over the year. UV filters were more frequently detected (90%) than musk fragrances (70%) and also quantified at higher levels, with average total concentrations reaching 1155.8 ng/g (dw) against 397.7 ng/g (dw) respectively. A high correlation was observed between the most densely populated and industrialized locations and the higher levels of musks and UV-filters found. In other hand, lower levels of PCPs were found in protected areas. As expected, an increase in UV-filters levels was observed after the summer, likely due to the intense period of recreational activities. PMID- 29709295 TI - Activation of Mechanosensitive Transient Receptor Potential/Piezo Channels in Odontoblasts Generates Action Potentials in Cocultured Isolectin B4-negative Medium-sized Trigeminal Ganglion Neurons. AB - INTRODUCTION: Various stimuli to the dentin surface elicit dentinal pain by inducing dentinal fluid movement causing cellular deformation in odontoblasts. Although odontoblasts detect deformation by the activation of mechanosensitive ionic channels, it is still unclear whether odontoblasts are capable of establishing neurotransmission with myelinated A delta (Adelta) neurons. Additionally, it is still unclear whether these neurons evoke action potentials by neurotransmitters from odontoblasts to mediate sensory transduction in dentin. Thus, we investigated evoked inward currents and evoked action potentials form trigeminal ganglion (TG) neurons after odontoblast mechanical stimulation. METHODS: We used patch clamp recordings to identify electrophysiological properties and record evoked responses in TG neurons. RESULTS: We classified TG cells into small-sized and medium-sized neurons. In both types of neurons, we observed voltage-dependent inward currents. The currents from medium-sized neurons showed fast inactivation kinetics. When mechanical stimuli were applied to odontoblasts, evoked inward currents were recorded from medium-sized neurons. Antagonists for the ionotropic adenosine triphosphate receptor (P2X3), transient receptor potential channel subfamilies, and Piezo1 channel significantly inhibited these inward currents. Mechanical stimulation to odontoblasts also generated action potentials in the isolectin B4-negative medium-sized neurons. Action potentials in these isolectin B4-negative medium-sized neurons showed a short duration. Overall, electrophysiological properties of neurons indicate that the TG neurons with recorded evoked responses after odontoblast mechanical stimulation were myelinated Adelta neurons. CONCLUSIONS: Odontoblasts established neurotransmission with myelinated Adelta neurons via P2X3 receptor activation. The results also indicated that mechanosensitive TRP/Piezo1 channels were functionally expressed in odontoblasts. The activation of P2X3 receptors induced an action potential in the Adelta neurons, underlying a sensory generation mechanism of dentinal pain. PMID- 29709296 TI - Efficacy of Corticosteroids on Postoperative Endodontic Pain: A Systematic Review and Meta-analysis. AB - INTRODUCTION: The purpose of this systematic review and meta-analysis was to evaluate the effectiveness of corticosteroids on postoperative endodontic pain and to determine/adjust between-trial heterogeneity using meta-regression analysis. METHODS: A systematic literature search was conducted to identify randomized clinical trials using corticosteroids to manage postoperative endodontic pain in adults. The outcome measure was pain intensity scores at 6, 12, and 24 hours postoperatively. Standardized mean differences (SMDs) with their 95% confidence intervals (CIs) were estimated using the random effect inverse variance method. The level of significance was set at P < .05. Meta-regression analysis was also performed to examine the associations between effect sizes and study-level covariates. RESULTS: Eighteen randomized clinical trials, comprising 1088 patients, were included. Corticosteroids significantly reduced the incidence of postoperative pain in endodontic patients at 6 hours (SMD = -1.03; 95% CI, 1.55 to -0.51; P = .000), 12 hours (SMD = -1.089; 95% CI, -1.71 to -0.46; P = .001), and 24 hours (SMD = -0.957; 95% CI, -1.34 to -0.56; P = .000). Meta regression analysis showed that the type and dose of drug, performing intention to-treat analysis, and using rescue medication could significantly influence the effect size at different time points. CONCLUSIONS: Corticosteroids had a postoperative pain-reducing effect in endodontic patients, and the choice of drug regimens could be an important predictor of pain reduction. PMID- 29709297 TI - Effect of Nonsteroidal Anti-inflammatory Drug as an Oral Premedication on the Anesthetic Success of Inferior Alveolar Nerve Block in Treatment of Irreversible Pulpitis: A Systematic Review with Meta-analysis and Trial Sequential Analysis. AB - INTRODUCTION: Successful anesthesia with an inferior alveolar nerve block (IANB) is imperative for treating patients with irreversible pulpitis in mandibular teeth. This systematic review assessed the efficacy of nonsteroidal anti inflammatory drugs (NSAIDs) as oral premedications on the success of IANBs in irreversible pulpitis. METHODS: Three databases were searched to identify randomized clinical trials (RCTs) published up until September 2017. Retrieved RCTs were evaluated using the revised Cochrane Risk of Bias Tool. The primary efficacy outcome of interest was the success rate of IANB anesthesia. Meta analytic estimates (risk ratio [RR] with 95% confidence intervals [CIs]) performed using a random effects model and publication bias determined using funnel plot analysis were assessed. Random errors were evaluated with trial sequential analyses, and the quality of evidence was appraised using a Grading of Recommendations, Assessment, Development and Evaluation approach. RESULTS: Thirteen RCTs (N = 1034) were included. Eight studies had low risk of bias. Statistical analysis of good-quality RCTs showed a significant beneficial effect of any NSAID in increasing the anesthetic success of IANBs compared with placebo (RR = 1.92; 95% CI, 1.55-2.38). Subgroup analyses showed a similar beneficial effect for ibuprofen, diclofenac, and ketorolac (RR = 1.83 [95% CI, 1.43-2.35], RR = 2.56 [95% CI, 1.46-4.50], and RR = 2.07 [95% CI, 1.47-2.90], respectively). Dose-dependent ibuprofen >400 mg/d (RR = 1.85; 95% CI, 1.39-2.45) was shown to be effective; however, ibuprofen <=400 mg/d showed no association (RR = 1.78; 95% CI, 0.90-3.55). TSA confirmed conclusive evidence for a beneficial effect of NSAIDs for IANB premedication. The Grading of Recommendations, Assessment, Development and Evaluation approach did not reveal any concerns regarding the quality of the results. CONCLUSIONS: Oral premedication with NSAIDs and ibuprofen (>400 mg/d) increased the anesthetic success of IANBs in patients with irreversible pulpitis. PMID- 29709298 TI - [Important weight loss in a 63 year-old man]. PMID- 29709299 TI - [Biosimilars in Internal Medicine: Needed in-depth knowledge to best prescribe]. PMID- 29709300 TI - Foot longitudinal arches in obese, overweight and normal weight females who differ in age. AB - Nowadays, excessive body weight is the cause of death of more people than malnutrition. Obesity is a growing health problem worldwide, which also results in a considerable number of movement dysfunctions, including degenerative changes and foot pain. The study aimed to assess the effect of overweight and obesity on the height of foot arches in females aged 10-84 years, as well as to establish which factor - age or BMI - affected the height of medial longitudinal arch (MLA) to a greater extent. Three groups of females (96 pupils, 86 young adults and 88 seniors) were selected to participate in the study. The participants' height and weight were measured, their BMI calculated and their body weight status categorized as normal weight, overweight or obesity. The height of foot arches was assessed using the Arch Index (AI). According to the value of the AI, the foot was defined as high-arched, normal or flat. Differences in participants' AI were determined in their age and weight status groups. Correlations between BMI and AI were calculated for the whole study sample and age groups. The analysis used the Shapiro-Wilk test, the Kruskal-Wallis test and Pearson's linear correlation. Overweight or obesity prevailed in 31% of pupils, 4.7% of young adults and in 77% of seniors. Pupils and young adults had often the high-arched foot. Flat feet were mostly observed in seniors and were common in obese individuals. BMI significantly correlated with the height of the foot arch but their age did not. Excessive body weight contributes to the development of flat feet to a greater extent than age. PMID- 29709302 TI - The Cosmologic continuum from physics to consciousness. AB - Reduction of developmental biology to self-referential cell-cell communication offers a portal for understanding fundamental mechanisms of physiology as derived from physics through quantum mechanics. It is argued that self-referential organization is implicit to the Big Bang and its further expression is a recoil reaction to that Singularity. When such a frame is considered, in combination with experimental evidence for the importance of epigenetic inheritance, the unicellular state can be reappraised as the primary object of selection. This framework provides a significant shift in understanding the relationship between physics and biology, providing novel insights to the nature and origin of consciousness. PMID- 29709301 TI - Primary isolated intracranial Rosai-Dorfman disease: Report of a rare case and review of the literature. AB - BACKGROUND: Intracranial involvement is an uncommon manifestation of Rosai Dorfman disease (RDD) and had been rarely reported. In this study, we explore clinical characteristics, imageology manifestations and pathological features of primary intracranial RDD so as to improve the understanding for this disease. METHODS: One case (16-years-old boy) with primary intracranial RDD was analyzed and studied retrospectively by MRI features, histopathological observation and immunohistochemical staining, and the related literatures were reviewed. RESULTS: The case was single lesion and involved the dura of the left middle cranial fossa base, which was iso-hypo signal intensity on T1WI and hypointense on T2WI and FLAIR image. The lesion was a homogeneous contrast enhancement mass with dural tail sign and had peritumoral brain edema. Pathological analysis showed the lesion consisted of variable numbers of mature lymphocytes, plasma cells and neutrophils. The characteristic histiocytes were emperipolesis and positively expressed for S-100 and CD-68 and negatively expressed for CD-1a by immunohistochemical analysis. Based on clinical presentations and histological findings after surgical excision, a final diagnosis of primary intracranial RDD was made. CONCLUSION: Primary intracranial RDD, especially located in the cranial base, is exceptionally rare, which hard to be distinguished with meningoma by imageology and clinical manifestations, but could be diagnosed by pathological and immunohistochemical examinations. Surgery is of the most importance treatment and prognosis is optimistic for this disease. PMID- 29709303 TI - Assessment of longitudinal systolic function using tissue motion annular displacement in healthy dogs. AB - INTRODUCTION: Left ventricular systolic function is one of the main parameters studied in echocardiography. Longitudinal systolic function, however, is less commonly evaluated in routine examinations but may provide early information on systolic dysfunction. The movement of the mitral annulus toward the apex has already been determined as a method for evaluation of longitudinal systolic function in dogs, but the study of this movement by speckle tracking with the tissue motion annular displacement (TMAD) technique has not yet been evaluated. ANIMALS: One hundred fifty-three client-owned healthy dogs. METHODS: Cross sectional study. One hundred fifty-three client-owned healthy dogs underwent physical examination, electrocardiography, blood pressure measurement, and a standard and speckle tracking echocardiography. Systolic function was evaluated by global longitudinal strain (GLS) and TMAD. These parameters were compared with the standard echocardiographic data. RESULTS: A correlation was found between GLS, TMAD, and body weight. Tissue motion annular displacement and GLS were significantly correlated (p < 0.001) with other surrogates of systolic function, including ejection fraction and fractional shortening. There were no differences in TMAD between sexes. The coefficient of variation (CV) of the intraobserver evaluation in the global TMAD (CV 4.44) was slightly higher than that in the GLS (CV 3.74). Also, TMAD was not influenced by heart rhythm and could be acquired more rapidly than GLS. CONCLUSIONS: Tissue motion annular displacement is a rapid and reproducible method for the assessment of left ventricle longitudinal function in healthy dogs. However, more studies are needed to validate the real clinical applicability of TMAD in animals with heart diseases. PMID- 29709304 TI - Galanin decreases spontaneous resting contractions and potentiates acetyl choline induced contractions of goldfish gut. AB - Galanin (GAL) is a 29 amino acid peptide, first identified from the porcine intestine and widely distributed within the brain and peripheral tissues. Among GAL biological functions, its role as a potent appetite-stimulating peptide is probably the most studied. With galanin's established role in the modulation of food intake in fish, this study aims to evaluate the effects of GAL on the intestinal motility of the goldfish, Carassius auratus, using an organ bath system. Our results found that application of GAL to the organ bath causes a significant concentration-dependent decrease in the amplitude of spontaneous contractions of goldfish gut. Preincubations of intestinal strips with acetylcholine (ACh) and GAL showed that GAL increases the force of ACh-induced contractions of the goldfish gut. These results provide the first evidence for a role of GAL in gut motility in goldfish. This also suggests a crosstalk between the effects of GAL and ACh in such functions, thus pointing to a putative joint role between the two molecules. These findings offer novel information that strengthens the role of the galaninergic system in fish feeding. PMID- 29709305 TI - Training in EUS and ERCP: standardizing methods to assess competence. PMID- 29709306 TI - Research methods in nursing students' Bachelor's theses in Sweden: A descriptive study. AB - BACKGROUND: During the nursing programme in Sweden, students complete an independent project that allows them to receive both a professional qualification as a nurse and a Bachelor's degree. This project gives students the opportunity to develop and apply skills such as critical thinking, problem-solving and decision-making, thus preparing them for their future work. However, only a few, small-scale studies have analysed the independent project to gain more insight into how nursing students carry out this task. OBJECTIVES: The aim of the present study was to describe the methods, including ethical considerations and assessment of data quality, applied in nursing students' independent Bachelor's degree projects in a Swedish context. DESIGN: A descriptive study with a quantitative approach. METHODS: A total of 490 independent projects were analysed using descriptive statistics. RESULTS: Literature reviews were the predominant project form. References were often used to support the analysis method. They were not, however, always relevant to the method. This was also true of ethical considerations. When a qualitative approach was used, and data collected through interviews, the participants were typically professionals. In qualitative projects involving analysis of biographies/autobiographies or blogs participants were either persons with a disease or next of kin of a person with a disease. CONCLUSIONS: Although most of the projects were literature reviews, it seemed unclear to the nursing students how the data should be analysed as well as what ethical issues should be raised in relation to the method. Consequently, further research and guidance are needed. In Sweden, independent projects are not considered research and are therefore not required to undergo ethics vetting. However, it is important that they be designed so as to avoid possible research ethics problems. Asking persons about their health, which occurred in some of the empirical projects, may therefore be considered questionable. PMID- 29709307 TI - Students' approaches to learning in a clinical practicum: A psychometric evaluation based on item response theory. AB - BACKGROUND: The investigation of learning approaches in the clinical workplace context has remained an under-researched area. Despite the validation of learning approach instruments and their applications in various clinical contexts, little is known about the extent to which an individual item, that reflects a specific learning strategy and motive, effectively contributes to characterizing students' learning approaches. OBJECTIVES: This study aimed to measure nursing students' approaches to learning in a clinical practicum using the Approaches to Learning at Work Questionnaire (ALWQ). DESIGN: Survey research design was used in the study. SETTINGS AND PARTICIPANTS: A sample of year 3 nursing students (n = 208) who undertook a 6-week clinical practicum course participated in the study. METHODS: Factor analyses were conducted, followed by an item response theory analysis, including model assumption evaluation (unidimensionality and local independence), item calibration and goodness-of-fit assessment. RESULTS: Two subscales, deep and surface, were derived. Findings suggested that: (a) items measuring the deep motive from intrinsic interest and deep strategies of relating new ideas to similar situations, and that of concept mapping served as the strongest discriminating indicators; (b) the surface strategy of memorizing facts and details without an overall picture exhibited the highest discriminating power among all surface items; and, (c) both subscales appeared to be informative in assessing a broad range of the corresponding latent trait. The 21-item ALWQ derived from this study presented an efficient, internally consistent and precise measure. CONCLUSIONS: Findings provided a useful psychometric evaluation of the ALWQ in the clinical practicum context, added evidence to the utility of the ALWQ for nursing education practice and research, and echoed the discussions from previous studies on the role of the contextual factors in influencing student choices of different learning strategies. They provided insights for clinical educators to measure nursing students' approaches to learning and facilitate their learning in the clinical practicum setting. PMID- 29709308 TI - A bi-level environmental impact assessment framework for comparing construction and demolition waste management strategies. AB - Several pioneering life cycle assessment (LCA) studies have been conducted in the past to assess the environmental impact of specific methods for managing mineral construction and demolition waste (MCDW), such as recycling the waste for use in concrete. Those studies focus on comparing the use of recycled MCDW and that of virgin components to produce materials or systems that serve specified functions. Often, the approaches adopted by the studies do not account for the potential environmental consequence of avoiding the existing or alternative waste management practices. The present work focuses on how product systems need to be defined in recycling LCA studies and what processes need to be within the system boundaries. A bi-level LCA framework is presented for modelling alternative waste management approaches in which the impacts are measured and compared at two scales of strategy and decision-making. Different functional units are defined for each level, all of which correspond to the same flow of MCDW in a cascade of product systems. For the sole purpose of demonstrating how the framework is implemented an illustrative example is presented, based on real data and a number of simplifying assumptions, which compares the impacts of a number of potential MCDW management strategies in New York City. PMID- 29709309 TI - A systematic review on the composting of green waste: Feedstock quality and optimization strategies. AB - Green waste (GW) is an important fraction of municipal solid waste (MSW). The composting of lignocellulosic GW is challenging due to its low decomposition rate. Recently, an increasing number of studies that include strategies to optimize GW composting appeared in the literature. This literature review focuses on the physicochemical quality of GW and on the effect of strategies used to improve the process and product quality. A systematic search was carried out, using keywords, and 447 papers published between 2002 and 2018 were identified. After a screening process, 41 papers addressing feedstock quality and 32 papers on optimization strategies were selected to be reviewed and analyzed in detail. The GW composition is highly variable due to the diversity of the source materials, the type of vegetation, and climatic conditions. This variability limits a strict categorization of the GW physicochemical characteristics. However, this research established that the predominant features of GW are a C/N ratio higher than 25, a deficit in important nutrients, namely nitrogen (0.5-1.5% db), phosphorous (0.1-0.2% db) and potassium (0.4-0.8% db) and a high content of recalcitrant organic compounds (e.g. lignin). The promising strategies to improve composting of GW were: i) GW particle size reduction (e.g. shredding and separation of GW fractions); ii) addition of energy amendments (e.g. non-refined sugar, phosphate rock, food waste, volatile ashes), bulking materials (e.g. biocarbon, wood chips), or microbial inoculum (e.g. fungal consortia); and iii) variations in operating parameters (aeration, temperature, and two-phase composting). These alternatives have successfully led to the reduction of process length and have managed to transform recalcitrant substances to a high-quality end-product. PMID- 29709310 TI - Plasma methods for metals recovery from metal-containing waste. AB - Metal-containing waste, a kind of new wastes, has a great potential for recycling and is also difficult to deal with. Many countries pay more and more attention to develop the metal recovery process and equipment of this kind of waste as raw material, so as to solve the environmental pollution and comprehensively utilize the discarded metal resources. Plasma processing is an efficient and environmentally friendly way for metal-containing waste. This review mainly discuss various metal-containing waste types, such as printed circuit boards (PCBs), red mud, galvanic sludge, Zircon, aluminium dross and incinerated ash, and the corresponding plasma methods, which include DC extended transferred arc plasma reactor, DC non-transferred arc plasma torch, RF thermal plasma reactor and argon and argon-hydrogen plasma jets. In addition, the plasma arc melting technology has a better purification effect on the extraction of useful metals from metal-containing wastes, a great capacity of volume reduction of waste materials, and a low leaching toxicity of solid slag, which can also be used to deal with all kinds of metal waste materials, having a wide range of applications. PMID- 29709311 TI - A Simulation model for estimating methane oxidation and emission from landfill cover soils. AB - Quantification of methane (CH4) oxidation and emission from landfill cover soils is important for evaluating measures to mitigate anthropogenic greenhouse gas emissions. In this study, a model that combines the multicomponent diffusive equation and Darcy's law, coupled with the dual Monod kinetic equation, was established to simulate CH4 transport, oxidation and emission in landfill cover soils. Sensitivity analysis was performed to illustrate the influence of model parameters on CH4 transport, oxidation and emission. The model was then applied to predict CH4 emissions from several column experiments. The results of the sensitivity analysis showed that a high CH4 oxidation rate can be obtained with a high Vmax of cover soil, even for a low cover soil thickness, and that oxidation efficiency is constant when the thickness of the cover soil becomes greater than a threshold value. The simulated results fitted well with the measured values, confirming that the new model provides a reliable method for estimating CH4 emissions from landfills. PMID- 29709312 TI - Comparison of disk diffusion and agar dilution methods for gentamicin susceptibility testing of Neisseria gonorrhoeae. AB - Gentamicin is a promising antibiotic for the treatment of multidrug-resistant gonorrhea. The aim of this study was to analyze the suitability and reliably of disk diffusion to monitor the susceptibility to gentamicin. We studied 237 Neisseria gonorrhoeae isolates obtained in 2013 and 2015. Reference MICs were correlated with inhibition zone diameters (in millimeters) of gentamicin 10 ug disks manufactured by BBL and Oxoid. The Pearson correlation between disk diffusion and agar dilution was r = -.68 (P < 0.001) for BBL disk and r = -.71 (P < 0.001) for Oxoid disk. No very major or major discrepancies were detected. However, a high percentage of minor discrepancies was observed (44.7%, BBL disk) and (21.9%, Oxoid disk). By adjusting the susceptible breakpoint to S >= 17 mm, the minor discrepancies rate was reduced to 19.4% (BBL disk) and 10.1% (Oxoid disk). The disk diffusion may be a screening method in clinical laboratories to detect the gentamicin susceptibility of N. gonorrhoeae. PMID- 29709313 TI - Re: Michael B. Atkins, Elizabeth R. Plimack, Igor Puzanov, et al. Axitinib in Combination with Pembrolizumab in Patients with Advanced Renal Cell Cancer: A Non randomised, Open-label, Dose-finding, and Dose-expansion Phase 1b Trial. Lancet Oncol 2018;19:405-15. PMID- 29709314 TI - Radial artery pulse waveform analysis based on curve fitting using discrete Fourier series. AB - BACKGROUND AND OBJECTIVES: Radial artery pulse diagnosis has been playing an important role in traditional Chinese medicine (TCM). For its non-invasion and convenience, the pulse diagnosis has great significance in diseases analysis of modern medicine. The practitioners sense the pulse waveforms in patients' wrist to make diagnoses based on their non-objective personal experience. With the researches of pulse acquisition platforms and computerized analysis methods, the objective study on pulse diagnosis can help the TCM to keep up with the development of modern medicine. METHODS: In this paper, we propose a new method to extract feature from pulse waveform based on discrete Fourier series (DFS). It regards the waveform as one kind of signal that consists of a series of sub components represented by sine and cosine (SC) signals with different frequencies and amplitudes. After the pulse signals are collected and preprocessed, we fit the average waveform for each sample using discrete Fourier series by least squares. The feature vector is comprised by the coefficients of discrete Fourier series function. RESULTS: Compared with the fitting method using Gaussian mixture function, the fitting errors of proposed method are smaller, which indicate that our method can represent the original signal better. The classification performance of proposed feature is superior to the other features extracted from waveform, liking auto-regression model and Gaussian mixture model. CONCLUSIONS: The coefficients of optimized DFS function, who is used to fit the arterial pressure waveforms, can obtain better performance in modeling the waveforms and holds more potential information for distinguishing different psychological states. PMID- 29709315 TI - Salvage HDR Brachytherapy: Multiple Hypothesis Testing Versus Machine Learning Analysis. AB - PURPOSE: Salvage high-dose-rate brachytherapy (sHDRB) is a treatment option for recurrences after prior radiation therapy. However, only approximately 50% of patients benefit, with the majority of second recurrences after salvage brachytherapy occurring distantly. Therefore, identification of characteristics that can help select patients who may benefit most from sHDRB is critical. Machine learning may be used to identify characteristics that predict outcome following sHDRB. We aimed to use machine learning to identify patient characteristics associated with biochemical failure (BF) following prostate sHDRB. METHODS AND MATERIALS: We analyzed data for 52 patients treated with sHDRB for locally recurrent prostate cancer after previous definitive radiation therapy between 1998 and 2009. Following pathologic confirmation of locally recurrent disease without evidence of metastatic disease, 36 Gy in 6 fractions was administered to the prostate and seminal vesicles. BF following sHDRB was defined using the Phoenix definition. Sixteen different clinical risk features were collected, and machine learning analysis was executed to identify subpopulations at higher risk of BF. Decision tree-based algorithms including classification and regression trees, MediBoost, and random forests were constructed. RESULTS: Patients were followed up for a minimum of 5 years after sHDRB. Those with a fraction of positive cores >=0.35 and a disease-free interval <4.12 years after their initial radiation treatment experienced a higher failure rate after sHDRB of 0.75 versus 0.38 for the rest of the population. CONCLUSIONS: Using machine learning, we have identified that patients with a fraction of positive cores >=0.35 and a disease-free interval <4.1 years might be associated with a high risk of BF following sHDRB. PMID- 29709316 TI - Estrous Cycle Manipulation in Dogs. AB - Since 1939, scientists have studied estrous cycle manipulation in dogs resulting in more articles published in this field that any other area of canine reproduction. Estrous cycle manipulation in dogs must be safe and reliable. Dopamine agonists, gonadotropin-releasing hormone agonists, and gonadotropins are hormones that have been used for estrus induction in bitches but each treatment has advantages and disadvantages. Despite widespread availability of these medications throughout the rest of the world, there are no drugs currently labeled for canine estrus induction in the United States. PMID- 29709317 TI - Estrus Suppression in Dogs. AB - Since 1952, scientists have studied estrus suppression in dogs. Estrus suppression in dogs must be safe and reliable. Medications used for estrus suppression in bitches include gonadotropin-releasing hormone (GnRH) agonists, GnRH antagonists, progestogens, and androgens. Despite widespread availability of these medications throughout the rest of the world, there are no drugs currently labeled for canine estrus induction in the United States. PMID- 29709318 TI - Allergic myocardial infarction following recombinant human insulin. AB - BACKGROUND: Allergic myocardial infarction is a rare clinical entity. OBJECTIVES: Although a few number of case reports with severe anaphylactic reactions to recombinant human insulin have been reported, allergic myocardial infarction, known as Kounis Syndrome, has not been reported before. METHODS: Herein, we report a 57-year-old woman with myocardial infarction, referred for urticarial rash, chest pain, and palpitations developed after the first subcutaneous dose of recombinant human insulin. RESULTS: The patient treated with antihistamines and steroids and discharged from hospital in a good condition. CONCLUSIONS: Physicians should be aware of allergic myocardial infarction. The diagnosis of Kounis Syndrome should be entertained when allergic symptoms, electrocardiographic changes, and high cardiac enzymes accompany acute-onset chest pain. All patients admitted to the emergency department with chest pain and ST elevation on electrocardiography should be asked about allergic insults. PMID- 29709319 TI - 2nd trimester miscarriage following decidual polypectomy. PMID- 29709320 TI - Reactivation of Hepatitis B virus in kidney transplant recipients with previous clinically resolved infection: A single-center experience. AB - BACKGROUND: Hepatitis B virus (HBV) reactivation in kidney transplant recipients (KTR) involves important morbidity and mortality. Despite being more common in patients who are HBsAg-positive, it may occur in patients with clinically resolved infection (HBsAg-negative and anti-HBc-positive), in whom the presence of the protective anti-HB antibody is thought to decrease the risk of reactivation. Data regarding reactivation rates in this population are scarce. OBJECTIVE: To retrospectively evaluate the risk of HBV reactivation in KTR with previously resolved infection. MATERIAL AND METHODS: Retrospective cohort study including patients who underwent a kidney transplant between January 1994 and December 2014 with resolved HBV infection at the time of transplantation (anti HBc seropositivity without detectable HBsAg, with or without anti-HB-positive antibodies and normal liver enzymes). RESULTS: Out of 966 patients, 95 patients with evidence of resolved HBV infection were analyzed, of which 86 had a titer of anti-HBs >10mIU/ml. Mean follow-up time was 93 months; 12 patients had lost anti HBs. Two patients showed evidence of reactivation. Risk factors associated with loss of anti-HBs were elderly age (>60) and occurrence of acute graft rejection (p<0.05). CONCLUSION: The risk of HBV reactivation in KTR with previously resolved infection is not negligible at 2%. Elderly age and acute rejection were associated with loss of anti-HBs, and these patients may benefit from closer monitoring of HBV DNA levels. Routine serology and/or HBV viral load monitoring in HBsAg-negative, anti-HBc-positive patients is recommended and should be emphasized in these patients. PMID- 29709321 TI - Learning Research Ethics; Why It Matters. PMID- 29709322 TI - Artificial sight: A therapeutic alternative for the future. PMID- 29709323 TI - Treatments of tenosynovial giant cell tumours of the temperomandibular joint: a report of three cases and a review of literature. AB - Tenosynovial giant cell tumours (TGCTs) are benign lesions affecting synovial joints. The classified subtypes are localized and diffuse. They seldom occur in the temporomandibular joint (TMJ). The aim of this study is to report on three new cases and to review the literature. One patient had surgical debulking with adjuvant external beam radiation therapy (EBRT). After 1year of follow-up, no evidence of disease was presented. The second patient was misdiagnosed and treated with denosumab. Debulking with adjuvant EBRT followed. Ten months postoperatively, no disease progression was seen. The third patient received systemic nilotinib and remained stable for over 5years. The literature review included 106 cases of which 95 had diffuse subtype. Most patients, had surgical excision. Thirteen (14%) patients received adjuvant EBRT. Eleven (14%) recurrences were identified. After 1-, 5- and 10 years of follow-up, an overall progression-free survival (PFS) of 99% (95% confidence interval (CI) 0.96-1), 80% (95% CI 0.68-0.94), 67% (95% CI 0.51-0.90) was calculated, respectively. Treatments for diffuse-TGCT-TMJ should be individualized depending on age, severity of symptoms, extent of disease and progression, expected mutilation of surgical interference, and current systemic treatment options. In stable disease a 'wait and see' policy, is a viable option. Additional treatments should be reserved for symptomatic, irresectable tumours or residual disease after surgical treatment with persistent complaints. PMID- 29709324 TI - The clinical outcome of skeletal anchorage in interceptive treatment (in growing patients) for class III malocclusion. AB - A systematic review of the literature was performed regarding the clinical outcome (effectiveness) of bone anchorage devices in interceptive treatment for class III malocclusion. A search of Embase, PubMed and Web of Science databases yielded 285 papers. An additional two articles were retrieved through manual searching of the reference lists. After initial abstract selection, 32 potentially eligible articles were screened in detail, resulting in a final number of eight articles included in this review. Insufficient evidence was found regarding the effects of skeletal anchorage in interceptive class III treatment to support definitive conclusions on long-term skeletal effects and stability. In the short term, it seems that bone anchors can provide more skeletal effect with less dentoalveolar compensations and less unwanted vertical changes. This does not always exclude the use of a face mask. The use of miniscrews as skeletal anchorage device does not seem to provide more skeletal effect, although it could minimize the unwanted dental effects in the upper jaw. No information regarding the need for orthognathic surgery, orthodontic treatment time or patient compliance and complications was found in the selected articles. PMID- 29709326 TI - Ten years of observations and demographics of hemimandibular hyperplasia and elongation. AB - INTRODUCTION: The full epidemiology and etiology of hemimandibular hyperplasia (HH) has not yet been clarified. In most cases it starts before puberty and results in various forms of dento-alveolar and skeletal discrepancies. This study is the first attempt at evaluating and describing some of the authors' key experiences, clinical philosophical approach, and gathered demographic data on hemimandibular hyperplasia and hemimandibular elongation (HE) among the Polish population. MATERIAL AND METHOD: A total of 45 patients (M = 8; F = 37; p < 0.05) with HE (n = 16; 35.6%; p < 0.05), HH (n = 28; 62.2%; p < 0.05), or HH + HE (n = 1; 2.2%; p > 0.05) had been diagnosed and treated. Epidemiological, geographical, and clinical data concerning the occurrence and treatment protocols in these mandibular malformations were measured in the Polish study groups. RESULTS: Women more often suffered from these mandibular malformations (82-87%). The occurrence of the first symptoms was highest at the age of 13-15 years and was statistically significant for both sides (p < 0.05). The disorders were found earlier in young girls, therefore an early compensatory orthodontic treatment in some cases had been used with a limited degree of success (p > 0.05). All values of bone scintigraphy were significant (p < 0.001). CONCLUSIONS: A very fast growth with visible major asymmetry and enlarged condylar head should be an indication for condylectomy. Women's expectations from surgery and treatment are more demanding than men's, a fact that is connected with the predominance of females in the study group. Almost all possible treatment alternatives are not only related with the degree of skeletal deformity, but also with the patient's willingness to undergo any necessary treatment protocols, which in most cases involve more than one stage. Skeletal scintigraphy tests are an important factor in estimating bone growth and possible surgical approaches in these disorders. PMID- 29709327 TI - Early intensive rehabilitation after oral cancer treatment. AB - PURPOSE: The treatment of oral cancer requires an effective rehabilitation strategy such as an early intensive rehabilitation (EIR) program. MATERIALS AND METHODS: The medical records and data of 41 patients who participated in an EIR program and 20 control group patients were analyzed. These patients all underwent surgical resection of the primary tumor followed by microsurgical reconstruction using free flaps. The length of stay (LOS) at the acute care hospital was compared between the two groups. Four indexes were used to evaluate the effectiveness of the EIR program. RESULTS: EIR patients stayed an average of 11.6 fewer days at the acute care hospital. All indexes showed significant improvements (p < 0.001). The Barthel Index (BI) and the Early Intensive Rehabilitation Barthel Index (EIR-BI) improved by 36.0 and 103.6 points, respectively. At discharge, the Bogenhausener Dysphagia Score (BODS) had improved to a score of 11.0 compared to the 13.9 at admission. EIR patients had a Work Ability Index (WAI) score of 25.7. CONCLUSION: Length of stay at the acute care hospital can be reduced using early intensive rehabilitation if patients are transferred to an intensive rehabilitation clinic early. PMID- 29709325 TI - 3D biomaterial matrix to support long term, full thickness, immuno-competent human skin equivalents with nervous system components. AB - Current commercially available human skin equivalents (HSEs) are used for relatively short term studies (~1 week) due in part to the time-dependent contraction of the collagen gel-based matrix and the limited cell types and skin tissue components utilized. In contrast, here we describe a new matrix consisting of a silk-collagen composite system that provides long term, stable cultivation with reduced contraction and degradation over time. This matrix supports full thickness skin equivalents which include nerves. The unique silk-collagen composite system preserves cell-binding domains of collagen while maintaining the stability and mechanics of the skin system for long-term culture with silk. The utility of this new composite protein-based biomaterial was demonstrated by bioengineering full thickness human skin systems using primary cells, including nerves and immune cells to establish an HSE with a neuro-immuno-cutaneous system. The HSEs with neurons and hypodermis, compared to in vitro skin-only HSEs controls, demonstrated higher secretion of pro-inflammatory cytokines. Proteomics analysis confirmed the presence of several proteins associated with inflammation across all sample groups, but HSEs with neurons had the highest amount of detected protein due to the complexity of the model. This improved, in vitro full thickness HSE model system utilizes cross-linked silk-collagen as the biomaterial and allows reduced reliance on animal models and provides a new in vitro tissue system for the assessment of chronic responses related to skin diseases and drug discovery. PMID- 29709328 TI - The value of histological grading of biopsy and resection specimens in early stage oral squamous cell carcinomas. AB - INTRODUCTION: In oral squamous cell carcinoma (OSCC) the differentiation grade of the tumor is determined on the biopsy and the resection specimen. The relation between tumor grade, nodal metastasis and survival is debatable. The aims of this study were to determine the correlation between differentiation grade of the biopsy and the resection specimen. Furthermore, we wanted to correlate tumor differentiation grade with nodal stage and survival. PATIENTS AND METHODS: One hundred and forty-five patients with OSCC staged as T1-2, N0 of the tongue, floor of mouth or cheek with primary resection of the tumor were examined. Biopsy and resection specimen were histologically re-assessed with regard to differentiation grade, as well as infiltrative, peri-neural and vascular invasive growth. RESULTS: This study showed a poor correlation between differentiation grade in the incisional biopsy and the resection specimen of the same tumor. No significant relation between differentiation grade of the resection specimen and nodal involvement, as well as overall and disease-specific survival was found. CONCLUSION: In early OSCC the differentiation grade determined by biopsy is of little predictive value for the grading of the resection specimen. Poor differentiation grade could not be related to the presence of nodal metastasis or survival and seems not to have any prognostic value concerning outcome. Treatment planning must be related to these findings. PMID- 29709329 TI - Cranial growth in infants?A longitudinal three-dimensional analysis of the first months of life. AB - PURPOSE: In the first months of life, any deviation from a physiological growth pattern can cause skull deformity. As there has not been any longitudinal three dimensional (3D) study investigating the physiological growth of the infant skull, the aim of the present study was to acquire such data. MATERIALS AND METHODS: We performed 3D stereophotogrammetric scans of 40 infants without cranial asymmetry at four regular 2-month intervals from the 4th to the 10th month of age. Six growth-related parameters (circumference, length, width, height, cephalic index [CI; width-length ratio] and total head volume) were used to analyse skull growth longitudinally. RESULTS: With exception of the CI, all parameters showed significant increases, with maximum percentage growth from the 4th to the 6th month. The CI initially remained unchanged until the 6th month, before showing a significant reduction that continued throughout the study period. Male infants had larger heads than female infants, but a similar width length ratio at all measurement times. CONCLUSION: This prospective study is the first longitudinal 3D analysis to examine the physiological growth dynamics of infants' heads within the first months of life. Understanding patterns of skull growth in all three dimensions is important for gaining further insights into physiological and pathophysiological skull development. PMID- 29709330 TI - Does volumetric measurement of cervical lymph nodes serve as an imaging biomarker for locoregional recurrence of oral squamous cell carcinoma? AB - INTRODUCTION: Recent studies highlighted the prognostic superiority of lymph node volume towards the conventional N Classification. However, data on the importance of neck lymph node volume, obtained by semiautomatic segmentation of CT images, do not exist for locoregional recurrence in patients with oral squamous cell carcinoma (OSCC). METHODS: Retrospective chart review of 100 patients, who were diagnosed and treated between 2006-2014. Inclusion criteria were patients with treatment-naive oral squamous cell carcinoma and primarily curative intended surgery with negative resection margins, for whom a preoperative computed tomography (CT) of the head and neck region was performed. Furthermore, comprehensive neck dissection (level I-V) due to ipsilateral lymph node metastasis was chosen as inclusion criterion. Exclusion criteria were neoadjuvant chemoradiotherapy, T4b classification, perioperative death, unresectable disease, synchronous malignancy, follow-up < 3 months and inadequate information to correctly determine clinicopathological characteristics. RESULTS: Pathological N Classification (p = 0.001), central necrosis (p = 0.008) and lymph node volume (p < 0.001) significantly affected locoregional recurrence (p < 0.001). Multivariate analysis indicated N Classification (p = 0.06) and volume (p < 0.001) as indepedent risk factors for locoregional recurrence. CONCLUSION: Volumetric measurement serves as a better risk stratification tool than the conventional N Classification for OSCC. A lymph node volume of more than 6.86 cm3 goes along with a 20-fold higher risk for locoregional failure. PMID- 29709331 TI - The importance of lymph node ratio for patients with mandibular infiltration of oral squamous cell carcinoma. AB - PURPOSE: Lymph node ratio (LNR) essentially improves assessment of prognosis and therapeutic decision making for patients with oral squamous cell carcinoma, as it considers both the number of positive lymph nodes and the number of dissected lymph nodes. Mandibular infiltration by oral squamous cell carcinoma is a vital clinicopathological feature, significantly worsens prognosis. However, to the best of our knowledge, data on the influence of LNR on prognosis for patients with OSCC and mandibular infiltration are not available. MATERIALS AND METHODS: A retrospective chart review of 89 patients with treatment-naive oral squamous cell carcinoma and histopathologically proven mandibular infiltration (pT4a) was performed. Exclusion criteria were primarily curative intended surgery (radical tumor resection, neck dissection and segmental mandibulectomy) with negative resection margins. Exclusion criteria were neoadjuvant chemoradiotherapy, erosive infiltration of the mandible, T4b classification, perioperative death, unresectable disease, synchronous malignancy, follow-up <3 months, and inadequate information to correctly determine clinicopathological characteristics. RESULTS: We observed a significant correlation on univariate analysis between locoregional recurrence and pathologic N classification (p = 0.004), perineural invasion (p = 0.005) and lymph node ratio (p < 0.001). On multivariate analysis, lymph node ratio (p = 0.028) was shown to be an independent indicator for locoregional recurrence. CONCLUSION: LNR predicted locoregional recurrence better than the conventional nodal staging system and therefore might serve as a more precise risk stratification tool. LNR >7% led to a 11.419-fold higher risk for locoregional recurrence of patients with mandibular infiltration due to OSCC. PMID- 29709332 TI - Surgical indication of Furlow palatoplasty to treat submucous cleft palate. AB - This study investigated the effects of Furlow palatoplasty on children with submucous cleft palate (SMCP) and identified surgical indications by comparing SMCP and control patients. Twenty-three SMCP children (average age 28.9 months) who were nonsyndromic and underwent surgery between April 2010 and December 2016 were included. Facial computed tomography (CT) was performed preoperatively and at least 1 year postoperatively after a language test. Facial CT measurements were taken for 140 children aged 0-6 years without deformities (control group). Later surgery was associated with more severe nasality. In the coronal view, the difference in the maxillary tuberosity before and after surgery was 3.8 mm (p < 0.05). The height and width of the palatal arch (HNP and WNP) were well maintained (p > 0.05), whereas the angle of the levator veli palatini muscle (ALM) increased (p < 0.05). The nasopharynx was close to normal postoperatively. The distance between the medial pterygoid plates, the HNP, and the WNP were larger in SMCP patients preoperatively (p < 0.05), but these differences disappeared after surgery (p > 0.05). The ALM in SMCP patients was narrower preoperatively, but became flatter postoperatively (p < 0.05), indicating the repositioning of the levator muscle, with improvement of the velopharyngeal function. Furlow palatoplasty is indicated if the HNP and WNP values are larger, and the ALM value is less, in patients with SMCP than in those without. PMID- 29709333 TI - Gender differences in morphological and functional outcomes after mandibular setback surgery. AB - PURPOSE: The aim of this study was to examine and compare morphological and functional outcomes after either isolated mandibular setback or bimaxillary surgery in males and females. MATERIALS AND METHODS: A retrospective study was done on 52 patients, in whom surgical correction for mandibular prognathism was performed either by isolated mandibular setback (30 cases) or by bimaxillary surgery (22 cases). Morphological changes were studied using cephalograms and functional changes studied using impulse oscillometry (IOS) taken before surgery (T0), 3 months (T1) and 1 year after surgery (T2). Also 3% oxygen desaturation index (ODI) was measured at T0 and T2. RESULT: Posterior airway space decreased significantly in both groups and both sexes but more so in males after mandibular setback surgery and in females after bimaxillary surgery. Changes in supine R20 (central airway resistance at 20 Hz) and supine R5 (total airway resistance at 5 Hz) in IOS statistically significantly increased in the period T0-T1 in males compared with females after mandibular setback surgery (p < 0.05). CONCLUSION: Gender dimorphism is present according to morphological and functional outcomes, with males at a higher risk for obstructive sleep apnea (OSA) after mandibular setback surgery and females after bimaxillary surgery; however, compensatory changes act as a barrier against this. PMID- 29709334 TI - Socioeconomic status and access to care and the incidence of a heart failure diagnosis in the inpatient and outpatient settings. AB - PURPOSE: Despite well-documented associations of socioeconomic status with incident heart failure (HF) hospitalization, little information exists on the relationship of socioeconomic status with HF diagnosed in the outpatient (OP) setting. METHODS: We used Poisson models to examine the association of area-level indicators of educational attainment, poverty, living situation, and density of primary care physicians with incident HF diagnosed in the inpatient (IP) and OP settings among a cohort of Medicare beneficiaries (n = 109,756; 2001-2013). RESULTS: The age-standardized rate of HF incidence was 35.8 (95% confidence interval [CI], 35.1-36.5) and 13.9 (95% CI, 13.5-14.4) cases per 1000 person years in IP and OP settings, respectively. The incidence rate differences (IRDs) per 1000 person-years in both settings suggested greater incidence of HF in high- compared to low-poverty areas (IP IRD = 4.47 [95% CI, 3.29-5.65], OP IRD = 1.41 [95% CI, 0.61-2.22]) and in low- compared to high-education areas (IP IRD = 3.73 [95% CI, 2.63-4.82], OP IRD = 1.72 [95% CI, 0.97-2.47]). CONCLUSIONS: Our results highlight the role of area-level social determinants of health in the incidence of HF in both the IP and OP settings. These findings may have implications for HF prevention policies. PMID- 29709335 TI - US ethnic group differences in self-management in the 2nd diabetes attitudes, wishes and needs (DAWN2) study. AB - AIMS: Understanding the relationship between ethnicity and self-management is important due to disparities in healthcare access, utilization, and outcomes among adults with type 2 diabetes from different ethnic groups in the US. METHODS: Self-reports of self-management and interest in improving self management from US people with diabetes (PWD) in the 2nd Diabetes Attitudes, Wishes and Needs (DAWN2) study, a multinational, multi-stakeholder survey, were analyzed, including 447 non-Hispanic White, 241 African American, 194 Hispanic American, and 173 Chinese American PWD (>18 years). RESULTS: Overall, self management behavior was highest for medication taking and lowest for physical activity. Non-Hispanic Whites had lowest physical activity and highest adherence to insulin therapy. Chinese Americans had lowest foot care and highest healthy eating. Overall, interest was highest for improving healthy eating and physical activity. Chinese Americans and Hispanic Americans were more interested than non Hispanic Whites in improving most self-management behaviors. Chinese Americans were more interested than African Americans in improving most self-management behaviors. Healthcare providers telling PWD that their A1c needs improvement was associated with lower self-rated glucose control, which was associated with higher PWD interest in improving self-management behaviors. CONCLUSIONS: Diabetes care providers should use patient-centered approaches and consider ethnicity in tailoring self-management support. PMID- 29709336 TI - Short-term metabolic control and sleep in children and adolescents with type 1 diabetes mellitus. AB - AIMS: The aim of this study was to examine sleep in T1D children and in healthy controls by polysomnographic (PSG) examination and to determine the influence of short-term metabolic compensation on sleep quality and sleep disordered breathing (SDB). METHODS: The prospective cross-sectional study included 44 T1D subjects and 60 healthy controls, aged 10-19 years. Subjects underwent anthropometric measurements, laboratory testing and standard overnight in-laboratory video polysomnography with continuous glucose monitoring (CGM). RESULTS: No significant differences were found in total sleep time, sleep efficiency, percentage of sleep stages and respiratory parameters between T1D and healthy group. T1D children with more optimal short-term metabolic control (AvgSG < 10 mmol/l, n = 18) had a significantly lower apnea-hypopnea index (AHI) (0.3(0-0.5) vs. 0.6 (0.2-0.9) events/h, p < 0.05)and respiratory arousal index (0(0-0,1) vs. 0.2(0-0.3)), p < 0.01) compared to children with suboptimal short-term control(n = 26), no significant differences were found in parameters of sleep architecture. Obstructive sleep apnea (OSA) was diagnosed in only one T1D patient, nine T1D children had mild central apnea. CONCLUSIONS: There may be an association between short-term metabolic compensation and SDB in T1D children without chronic complications, obesity or overweight and hypoglycemia. Further research is needed to confirm this result. PMID- 29709337 TI - Corrigendum to "The importance of boron in biological systems" [J. Trace Elem. Med. Biol. 45 (2018) 156-162]. PMID- 29709339 TI - Prognostic factors and treatment outcomes of malignant pleural mesothelioma in Eastern Asian patients - A Taiwanese study. AB - BACKGROUND/PURPOSE: There are scarce reports on the prognostic factors and treatment outcomes of patients with malignant pleural mesothelioma (MPM) in Asia. This study aimed to address these matters in a real-world setting. METHODS: Medical records of patients with histologically proven MPM diagnosed between 1977 and 2016 at the National Taiwan University Hospital were reviewed. Variables including age, gender, performance status, asbestos exposure, smoking history, histology subtype, staging, and treatment received were recorded. All patients were followed until death or March 1st, 2017. Survival and prognostic factors were analyzed by the Kaplan-Meir method and the Cox proportional hazard model. RESULTS: A total of 93 patients was identified, including 65 men and 28 women. An increasing trend of MPM cases diagnosed was observed in the past 40 years. Stage I/II disease (HR 0.24, 95% CI 0.13-0.46) and epithelioid histology (HR 0.42, 95% CI 0.23-0.75) were associated with favorable prognosis, whereas age >=70 years (HR 2.66, 95% CI 1.36-5.22) and ECOG >=2 (HR 5.03, 95% CI 2.69-9.4) were poor prognostic factors. After adjustment for prognostic factors, surgery in stage I III MPM (HR 0.36, 95% CI 0.15-0.83) and systemic therapy in stage III/IV disease (HR 0.42, 95% CI 0.19-0.94) conferred a survival benefit. CONCLUSION: This is one of the largest case series of MPM reported in Asia outside of Japan. Prognostic factors in the study population included age, performance status, stage, and histology subtype. Surgery in potentially resectable disease and systemic therapy in advanced MPM confer a survival benefit in Asian patients. PMID- 29709338 TI - Omitting radiotherapy in women >= 65 years with low-risk early breast cancer after breast-conserving surgery and adjuvant endocrine therapy is safe. AB - PURPOSE: The aim of this study was to verify if radiotherapy (RT) safely can be omitted in older women treated for estrogen-receptor positive early breast cancer with breast-conserving surgery (BCS) and endocrine therapy (ET). PATIENTS AND METHODS: Eligibility criteria were: consecutive patients with age >=65 years, BCS + sentinel node biopsy, clear margins, unifocal T1N0M0 breast cancer tumor, Elston-Ellis histological grade 1 or 2 and estrogen receptor-positive tumor. After informed consent, adjuvant ET for 5 years was prescribed. Primary endpoint was ipsilateral breast tumor recurrence (IBTR). Secondary endpoints were contralateral breast cancer and overall survival. RESULTS: Between 2006 and 2012, 603 women were included from 14 Swedish centers. Median age was 71.1 years (range 65-90). After a median follow-up of 68 months 16 IBTR (cumulative incidence at five-year follow-up; 1.2%, 95% CI, 0.6% to 2.5%), 6 regional recurrences (one combined with IBTR), 2 distant recurrences (both without IBTR or regional recurrence) and 13 contralateral breast cancers were observed. There were 48 deaths. One death (2.1%) was due to breast cancer and 13 (27.1%) were due to other cancers (2 endometrial cancers). Five-year overall survival was 93.0% (95% CI, 90.5% to 94.9%). CONCLUSION: BCS and ET without RT seem to be a safe treatment option in women >= 65 years with early breast cancer and favorable histopathology. The risk of IBTR is comparable to the risk of contralateral breast cancer. Moreover, concurrent morbidity dominates over breast cancer as leading cause of death in this cohort with low-risk breast tumors. PMID- 29709340 TI - IL-1beta induced IL-8 and uPA expression/production of dental pulp cells: Role of TAK1 and MEK/ERK signaling. AB - BACKGROUND/PURPOSE: Interleukin 1 beta (IL-1beta) is a pro-inflammatory cytokine involved in the inflammatory processes of dental pulp. IL-8 and urokinase plasminogen activator (uPA) are two inflammatory mediators. However, the role of transforming growth factor beta-activated kinase-1 (TAK1) and mitogen-activated protein kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathways in responsible for the effects of IL-1beta on IL-8 and uPA expression/secretion of dental pulp cells are not clear. METHODS: Human dental pulp cells were exposed to IL-1beta with/without pretreatment with 5z-7 oxozeaneaeol (a TAK1 inhibitor) or U0126 (a MEK/ERK inhibitor). TAK1 activation was determined by immunofluorescent staining. The protein expression of IL-8 was tested by western blot. The expression of IL-8 and uPA mRNA was studied by reverse transcriptase-polymerase chain reaction (RT-PCR). The secretion of IL-8 and uPA was measured by enzyme-linked immunosorbent assay. RESULTS: Exposure of dental pulp cells to IL-1beta (0.1-10 ng/ml) stimulated IL-8 and uPA expression. IL-1beta also induced IL-8 and uPA secretion of dental pulp cells. IL-1beta stimulated p-TAK1 activation of pulp cells. Pretreatment and co-incubation of pulp cells by 5z-7oxozeaenol (1 and 2.5 MUM) and U0126 (10 and 20 MUM) prevented the IL-1beta-induced IL-8 and uPA expression. 5z-7oxozeaenol and U0126 also attenuated the IL-1beta-induced IL-8 and uPA secretion. CONCLUSION: IL-1beta is important in the pathogenesis of pulpal inflammatory diseases and repair via stimulation of IL-8 and uPA expression and secretion. These events are associated with TAK1 and MEK/ERK signaling. Blocking of TAK1 and MEK/ERK signaling has potential to control inflammation of dental pulp. PMID- 29709341 TI - Inhibition of miR-21 ameliorates excessive astrocyte activation and promotes axon regeneration following optic nerve crush. AB - Optic nerve injury is a leading cause of irreversible visual impairment worldwide and can even cause blindness. Excessive activation of astrocytes has negative effects on the repair and recovery of retinal ganglion cells following optic nerve injury. However, the molecular and cellular mechanisms underlying astrocyte activation after optic nerve injury remain largely unknown. In the present study, we explored the effects of microRNA-21 (miR-21) on axon regeneration and flash visual evoked potential (F-VEP) and the underlying mechanisms of these effects based on astrocyte activation in the rat model of optic nerve crush (ONC). To the best of our knowledge, this article is the first to report that inhibition of miR 21 enhances axonal regeneration and promotes functional recovery in F-VEP in the rat model of ONC. Furthermore, inhibition of miR-21 attenuates excessive astrocyte activation and glial scar formation, thereby promoting axonal regeneration by regulating the epidermal growth factor receptor (EGFR) pathway. In addition, we observed that the expression of tissue inhibitor of metalloproteinase-3, a target gene of miR-21, was inhibited during this process. Taken together, these findings demonstrate that inhibition of miR-21 regulates the EGFR pathway, ameliorating excessive astrocyte activation and glial scar progression and promoting axonal regeneration and alleviating impairment in F-VEP function in a model of ONC. This study's results suggest that miR-21 may represent a therapeutic target for optic nerve injury. PMID- 29709342 TI - Simultaneous detection of anions and cations in mineral water by two dimensional ion chromatography. AB - A two dimensional ion chromatography (2D-IC) method was improved for the simultaneous determination of six cations and seven anions using one-valve switching after injection and conductivity detector. The trap conditions and valve-switch timing were optimized. The method has good accuracy and sensitivity for the simultaneous separation of inorganic anions and cations with a mean correlation coefficient of >0.99, repeatability of 0.60%-3.0% for eight replicates, reproducibility of 0.78%-3.1%, and spiked recovery rate of 88.7% 110%. The method was successfully applied to the analysis of inorganic anions and cations in four kinds of mineral water and can completely satisfy the demand of water quality monitoring. PMID- 29709343 TI - Increased Risk of Thrombosis Associated with Peripherally Inserted Central Catheters Compared with Conventional Central Venous Catheters in Children with Leukemia. AB - OBJECTIVE: To study the risk of catheter-associated thrombosis (CAT) between peripherally inserted central catheters (PICCs) and tunneled central venous catheters in children with leukemia. STUDY DESIGN: We analyzed all PICCs and conventional tunneled catheters placed in patients aged <18 years and admitted to our institute for leukemia treatment between February 2008 and April 2014. Cases of symptomatic CAT were confirmed by ultrasound and treated with low-molecular weight heparin. RESULTS: During the study period, 157 PICCs and 138 conventional tunneled catheters were placed in 192 patients with leukemia. CAT incidence was 1.5% (n = 2) in the conventional tunneled catheter group and 10.2% (n = 16) in the PICC group. The OR for CAT occurrence after PICC vs conventional tunneled catheter placement was 5.6 (95% CI, 1.2-26.5). CONCLUSION: Our results suggest that the use of PICCs in children with leukemia increases the risk of CAT in comparison with the use of conventional tunneled catheters. Further randomized controlled studies are needed to characterize this risk and to better define indications. PMID- 29709344 TI - Insufficient Sleep and Incidence of Dental Caries in Deciduous Teeth among Children in Japan: A Population-Based Cohort Study. AB - OBJECTIVES: To examine whether late bedtime and short nighttime sleep duration at age 18 months are associated with risk of caries in deciduous teeth. STUDY DESIGN: Population-based cohort study using health check-up data of 71 069 children born in Kobe City, Japan, who were free of caries at age 18 months and had information on sleep variables at age 18 months and records of dental examinations at age 3 years. Sleep variables were assessed by standardized parent reported questionnaires, and the incidence of caries in deciduous teeth was defined as the occurrence of at least 1 decayed, missing, or filled tooth assessed by qualified dentists without radiographs. Logistic regression was used to estimate the effects of late bedtime and short sleep duration on dental caries with adjustment for clinical and lifestyle characteristics. RESULTS: Overall, 11 343 (16.0%) cases of caries were observed at age 3 years. aORs for children with late or irregular bedtimes compared with those with bedtimes before 21:00 were 1.26 (95% CI 1.19-1.33), 1.48 (1.38-1.58), 1.74 (1.58-1.92), 1.90 (1.58-2.29), and 1.66 (1.53-1.81) for bedtimes at 21:00, 22:00, 23:00, 0:00, and irregular bedtime, respectively. aORs for children with short or irregular sleep duration compared with those with sleep duration of >=11 hours were 1.30 (95% CI 1.15 1.47), 1.16 (1.09-1.24), 1.11 (1.05-1.18), and 1.35 (1.25-1.46) for sleep duration of <= 8, 9, 10 hours, and irregular sleep duration, respectively. CONCLUSIONS: In this exploratory study, late bedtime and short sleep duration were both consistently associated with increased risk of caries in deciduous teeth. PMID- 29709345 TI - The Jones Criteria for the Diagnosis of Acute Rheumatic Fever: Updated but Not Abandoned. PMID- 29709346 TI - A Link between Nutritional and Growth States in Pediatric Patients with Functional Gastrointestinal Disorders. AB - OBJECTIVE: To investigate nutritional status and growth status of pediatric patients with functional gastrointestinal disorders (FGIDs) and to examine the relationship between nutritional status and linear growth in these children. STUDY DESIGN: In total, 102 pediatric patients diagnosed with functional constipation (FC), irritable bowel syndrome (IBS), or functional abdominal pain (FAP) in years 2013-2015 were subjected to anthropometric measurements. Anthropometry comprised body height, leg and trunk lengths, body weight, mid upper arm circumference, and 3 skinfold thicknesses. Body fat percentage was obtained with bioelectrical impedance analysis. Indices of the nutritional status and body proportions were calculated and adjusted for age and sex. RESULTS: Excessive body weight and excessive fatness were the most common in children with IBS. Being underweight was most common in children with FAP, but fat deficiency was similarly frequent in the FAP and in FC groups. Short stature was the most common in children with FC. Children with IBS were the best nourished and the tallest for age and sex due to increased trunk length. Body height and linear body proportions adjusted for age and sex were positively associated with body weight and body fatness in the total sample. CONCLUSIONS: Children with FGIDs present various linear growth abnormalities that are associated with body weight and body fatness. Although excessive body weight and body fat are common in children with IBS, pediatricians should be aware of the risk of malnutrition in children with other FGIDs. PMID- 29709347 TI - Achieving Stability in Oxygenation: Servo-Controlled Oxygen Environment as a First Step to Fully Automated Oxygen Control? PMID- 29709348 TI - Malaria Summit London 2018. PMID- 29709349 TI - Corrections. PMID- 29709350 TI - Hepatic fibrosis: It is time to go with hepatic stellate cell-specific therapeutic targets. AB - Hepatic fibrosis is a pathological lesion, characterized by the progressive accumulation of extracellular matrix (ECM) in the perisinusoidal space and it is a major problem in chronic liver diseases. Phenotypic activation of hepatic stellate cells (HSC) plays a central role in the progression of hepatic fibrosis. Retardation of proliferation and clearance of activated HSCs from the injured liver is an appropriate therapeutic strategy for the resolution and treatment of hepatic fibrosis. Clearance of activated HSCs from the injured liver by autophagy inhibitors, proapoptotic agents and senescence inducers with the high affinity toward the activated HSCs may be the novel therapeutic strategy for the treatment of hepatic fibrosis in the near future. PMID- 29709352 TI - Radial Head Fracture Fixation Using Tripod Technique With Headless Compression Screws. AB - Radial head and neck fractures are one of the most common elbow fractures, comprising 2% to 5% of all fractures, and 30% of elbow fractures. Although uncomplicated Mason type I fractures can be managed nonsurgically, Mason type II IV fractures require additional intervention. Mason type II-III fractures with 3 or fewer fragments are typically treated with open reduction and internal fixation using 2 to 3 lag screws. Transverse radial neck involvement or axial instability with screw-only fixation has historically required the additional use of a mini fragment T-plate or locking proximal radius plate. More recently, less invasive techniques such as the cross-screw and tripod techniques have been proposed. The purpose of this paper is to detail and demonstrate the proper implementation of the tripod technique using headless compression screws. PMID- 29709351 TI - Expression of hepatic Wnt5a and its clinicopathological features in patients with hepatocellular carcinoma. AB - BACKGROUD: Wingless-type MMTV integration site family member 5a (Wnt5a) is involved in carcinogenesis. However, little data are available in Wnt5a signaling with hepatocellular carcinoma (HCC). In the present study, we investigated the expression of hepatic Wnt5a in HCC and the role of Wnt5a in HCC progression and outcome. METHODS: Wnt5a expression and cellular distribution in HCCs and their matched paracancerous tissues from 87 patients were analyzed with tissue microarray and immunohistochemistry and compared with hepatic Wnt3a signaling. Wnt5a expression was categorized into low or high based on immunohistochemistry. Overall survival rate of HCC patients was estimated in correlation with the hepatic Wnt5a level using Kaplan-Meier method; the survival difference between patients with low and those with high Wnt5a was compared with log-rank test; and prognostic analysis was carried out with Cox regression. RESULTS: Total incidence of Wnt5a expression in the HCC tissues was 70.1%, which was significantly lower (chi2 = 13.585, P < 0.001) than that in their paracancerous tissues (88.5%). Significant difference of Wnt5a intensity was found between HCC and their paracancerous tissues (Z = 8.463, P < 0.001). Wnt5a intensity was inversely correlated with Wnt3a signaling (r = -0.402, P < 0.001) in HCC tissues. A decrease of Wnt5a expression in relation to the clinical staging from stage I to IV and low or no staining at advanced HCC were observed. Wnt5a level was related to periportal embolus (chi2 = 11.069, P < 0.001), TNM staging (chi2 = 8.852, P < 0.05), 5-year survival (chi2 = 4.961, P < 0.05), and confirmed as an independent prognosis factor of HCC patients (hazard ratio: 1.957; 95% confidence interval: 1.109-3.456; P < 0.05). CONCLUSIONS: The decrease of hepatic Wnt5a signaling is associated with HCC progression and poor prognosis. PMID- 29709353 TI - Comment on: effects of gastric bypass followed by a randomized study of physical training on markers of coagulation activation, fibrin clot properties and fibrinolysis. PMID- 29709355 TI - Discussion. PMID- 29709356 TI - Tricuspid valve replacement in failing Fontan circulation with severe ventricular dysfunction: The road not taken? PMID- 29709354 TI - Simple versus complex degenerative mitral valve disease. AB - OBJECTIVES: At a center where surgeons favor mitral valve (MV) repair for all subsets of leaflet prolapse, we compared results of patients undergoing repair for simple versus complex degenerative MV disease. METHODS: From January 1985 to January 2016, 6153 patients underwent primary isolated MV repair for degenerative disease, 3101 patients underwent primary isolated MV repair for simple disease (posterior prolapse), and 3052 patients underwent primary isolated MV repair for complex disease (anterior or bileaflet prolapse), based on preoperative echocardiographic images. Logistic regression analysis was used to generate propensity scores for risk-adjusted comparisons (n = 2065 matched pairs). Durability was assessed by longitudinal recurrence of mitral regurgitation and reoperation. RESULTS: Compared with patients with simple disease, those undergoing repair of complex pathology were more likely to be younger and female (both P values < .0001) but with similar symptoms (P = .3). The most common repair technique was ring/band annuloplasty (3055/99% simple vs 3000/98% complex; P = .5), followed by leaflet resection (2802/90% simple vs 2249/74% complex; P < .0001). Among propensity-matched patients, recurrence of severe mitral regurgitation 10 years after repair was 6.2% for simple pathology versus 11% for complex pathology (P = .007), reoperation at 18 years was 6.3% for simple pathology versus 11% for complex pathology, and 20-year survival was 62% for simple pathology versus 61% for complex pathology (P = .6). CONCLUSIONS: Early surgical intervention has become more common in patients with degenerative MV disease, regardless of valve prolapse complexity or symptom status. Valve repair was associated with similarly low operative risk and time-related survival but less durability in complex disease. Lifelong annual echocardiographic surveillance after MV repair is recommended, particularly in patients with complex disease. PMID- 29709357 TI - Discussion. PMID- 29709358 TI - Transcatheter tricuspid valve replacement with a self-expanding bioprosthesis. PMID- 29709359 TI - Minimally invasive mitral valve surgery is associated with excellent resource utilization, cost, and outcomes. AB - OBJECTIVES: Minimally invasive mitral valve surgery (mini-MVR) has numerous associated benefits. However, many studies fail to include greater-risk patients. We hypothesized that a minimally invasive approach in a representative cohort provides excellent outcomes with reduced resource utilization. METHODS: Mitral valve surgical records from 2011 to 2016 were paired with institutional financial records. Patients were stratified by approach and propensity-score matched to balance preoperative difference. The primary outcomes of interest were resource utilization including cost, discharge to a facility, and readmission. RESULTS: A total of 478 patients underwent mitral surgery (21% mini-MVR) and were balanced after matching (n = 74 per group), with 18% of patients having nondegenerative mitral disease. Outcomes were excellent with similar rates of major morbidity (9.5% mini-MVR vs 10.8% conventional, P = .78). Mini-MVR cases had lower rates of transfusion (11% vs 27%, P = .01) and shorter ventilator times (3.7 vs 6.0 hours, P < .0001). Mean total hospital cost was equivalent ($49,703 vs $54,970, P = .235) with mini-MVR having lower ancillary ($1645 vs $2652, P = .001) and blood costs ($383 vs $1058, P = .001). These savings were offset by longer surgical times (291 vs 234 minutes, P < .0001) with greater surgical ($7645 vs $7293, P = .0001) and implant costs ($1148 vs $748, P = .03). Rates of discharge to a facility (9.6% vs 16.2%) and readmission (9.6% vs 4.1%) were not statistically different. CONCLUSIONS: In a real-world cohort, mini-MVR continues to demonstrate excellent results with a favorable resource utilization profile. Greater surgical and implant costs with mini-MVR are offset by decreased transfusions and ancillary needs leading to equivalent overall hospital cost. PMID- 29709360 TI - The fate of the abdominal aorta after endovascular treatment in chronic Debakey IIIb aneurysm. AB - OBJECTIVES: We sought to identify the risk factors for abdominal aortic remodeling after thoracic endovascular aortic repair in patients with chronic DeBakey IIIb aneurysm. METHODS: From 2012 to 2016, 70 patients underwent thoracic endovascular aortic repair for chronic DeBakey IIIb aneurysm. The abdominal aortic diameter was measured at 3 different levels (celiac trunk, renal artery, and infrarenal aorta). Abdominal aorta status was classified as expansion or stable. Expansion status was assigned when the abdominal aortic diameter was increased over 5 mm at least 1 level. Otherwise, it was classified as stable status. Forty-six of 70 patients underwent more than 2 postoperative imaging studies. In those patients (n = 46), abdominal aortic volume was measured from celiac trunk to inferior mesenteric artery. A linear mixed-effect model was used to analyze the overall fate of abdominal aortic volume. RESULTS: No in-hospital mortality occurred. The mean follow-up and imaging follow-up duration were 26 and 17 months, respectively. Sixty-one patients (87.1%) demonstrated thoracic false lumen thrombosis. Although false-lumen thrombosis was achieved, 15 patients (24.6%) demonstrated the expansion status. In volumetric analysis, the total abdominal aortic volume was increasing over time (0.603 cm3/mo; P < .001) and the residual intima tears were identified as an independent anatomic risk factor for an enlarged abdominal aorta. CONCLUSIONS: An enlarged abdominal aorta in chronic DeBakey IIIb aneurysm can be frequently recognized even after successful endovascular treatment. The residual intima tears were the only identified risk factor for change in a dissected abdominal aneurysm. We suggest careful abdominal aorta evaluation and additional procedures on the false lumen if necessary. PMID- 29709361 TI - Partial thromboplastin time is more predictive of bleeding than anti-Xa levels in heparinized pediatric patients after cardiac surgery. AB - OBJECTIVES: Anticoagulation with unfractionated heparin (UFH) after pediatric cardiac surgery can be monitored using either activated partial thromboplastin time (aPTT) or anti-factor Xa activity (anti-Xa). However, correlation of bleeding with either of these laboratory values has not been established. We sought to determine the correlation between bleeding events and aPTT and anti-Xa in patients who undergo anticoagulation after congenital heart surgery. METHODS: We prospectively studied pediatric patients treated with UFH after cardiac surgery over an 11-month period. Bleeding events were prospectively assessed and adjudicated. The highest aPTT and corresponding anti-Xa for the 24 hours before bleeding events were collected to assess for association with bleeding. Statistical analysis was performed using generalized additive logistic regression. RESULTS: A total of 202 patients received UFH over 1488 patient-days. The median age at surgery was 0.4 years (interquartile range, 0.1-2.2). A total of 45 major or clinically relevant bleeding events were observed. The correlation between aPTT and anti-Xa was of moderate strength (R = 0.58; P < .001). The odds of bleeding increased significantly when aPTT exceeded 150 (odds ratio, 1.71 per 10-second increase in aPTT, 95% confidence interval, 1.21-2.42; P = .003). Anti Xa was not associated with bleeding (odds ratio, 1.11 per 0.1 IU/mL increase, 95% confidence interval, 0.89-1.29; P = .34). CONCLUSIONS: In heparinized pediatric patients after cardiac surgery, increased risk of bleeding is more closely associated with elevated aPTT levels than elevated anti-Xa levels. In addition to anti-Xa, monitoring of aPTT levels should be considered during titration of UFH in pediatric patients after cardiac surgery. PMID- 29709362 TI - Modified technique for Melody valve implantation in the mitral position. PMID- 29709363 TI - Staged ventricular recruitment in patients with borderline ventricles and large ventricular septal defects. AB - OBJECTIVES: Patients with borderline ventricles and ventricular septal defects (VSDs) who have previously undergone single ventricle palliation might be candidates for staged ventricular recruitment with the ultimate goal of biventricular conversion. This study aimed to determine the effect of atrial septal defect (ASD) restriction without VSD closure on ventricular growth in patients with borderline right or left ventricles and VSDs. METHODS: Patients with borderline ventricles and VSD who underwent a staged ventricular recruitment procedure with strategies to increase blood flow through hypoplastic ventricle via ASD restriction without VSD closure after single ventricle palliation were retrospectively reviewed. Pre- and postrecruitment ventricular volumes were compared using Wilcoxon signed rank test. RESULTS: A total of 21 patients underwent staged ventricular recruitment via ASD restriction without VSD closure at median age of 20.0 months (interquartile range [IQR], 8.0-52.5 months). At a median of 9.0 months (IQR, 8.0-11.8 months) after the recruitment procedure, there were increases in the median indexed ventricular diastolic volume (31.7 mL/m2 [IQR, 24.5-37.1] to 48.5 mL/m2 [IQR, 38.4-58.0; P < .01]), median indexed systolic volume (13.3 mL/m2 [IQR, 9.7-18.7] to 19.5 mL/m2 [IQR, 16.8-29.7]; P < .01), and the median indexed stroke volume (18.4 mL/m2 [IQR, 14.8-21.1] to 28.1 mL/m2 [IQR, 21.3-31.8]; P < .01). Biventricular conversion was ultimately performed in 14 (67%). Two patients died after biventricular conversion. CONCLUSIONS: Staged ventricular recruitment via ASD restriction without VSD closure is associated with growth of the hypoplastic ventricle. In patients who are deemed high-risk for single ventricle, this approach might facilitate eventual biventricular conversion. Further studies are needed to identify optimal candidates for this approach. PMID- 29709364 TI - Effect of the number of lymph nodes examined on the survival of patients with stage I non-small cell lung cancer who undergo sublobar resection. AB - OBJECTIVES: Early stage lung cancer is being detected at a higher frequency with the implementation of screening programs. At the same time, medically complex patients with multiple comorbidities are presenting for surgery, with a concomitant rise in rates of sublobar resection. We sought to examine the effect of sampling lymph nodes on the outcomes of patients who undergo sublobar resection for small (<2 cm) stage I non-small cell lung cancer (NSCLC). METHODS: All patients in the Surveillance, Epidemiology, and End Results database from 2004 to 2013 with small (<2 cm) stage I NSCLC who underwent sublobar resection (wedge/segmentectomy) and no other cancer history were included. The association of the number of lymph nodes examined (LNE; categories none, 1-3, 4-6, 7-9, >9) with the overall survival as well as disease-specific survival were examined using univariate as well as multivariate analyses while controlling for covariates such as age, size (<1 cm, >1 cm), grade, histology (adenocarcinoma vs others), and extent of resection (wedge/segmentectomy). RESULTS: Data from 3916 eligible patients were analyzed. Seven hundred fifteen patients (18.3%) had segmentectomy. No lymph nodes were examined in 49% and 23% of wedge resection and segmentectomy patients, respectively. Among all eligible patients, 1132 (29%), 474 (12%), 228 (6%), and 328 (8%) patients had 1 to 3, 4 to 6, 7 to 9 and >9 LNE, respectively. Univariate analyses showed significant associations between overall and disease-specific survivals with age, grade, histology, sex, extent of surgery, and LNE. The association between the number of LNE and survival remained significant even after adjusting for significant covariates including extent of sublobar resection (hazard ratio for groups with LNE 1-3, 4-6, 7-9, and >9 compared with 0 LNE were 0.79, 0.77, 0.68, and 0.45 for overall survival; P < .001) and 0.85, 0.77, 0.71, and 0.44 for disease-specific survival (P < .05), respectively. In multivariate modeling, LNE was retained as a significant variable and extent of resection was not. In patients in whom at least 1 lymph node was examined, extent of resection was not predictive of outcome. CONCLUSIONS: Many patients having sublobar resection for early stage NSCLC in the United States do not have a single lymph node removed for pathologic examination. The number of LNE is associated with improved survival, presumably due to avoidance of mis-staging. This association seems greater than the association with extent of resection (segmentectomy vs wedge resection). Appropriate lymph node examination remains an important part of resection for lung cancer even if the resection is sublobar. PMID- 29709365 TI - Protein Losses and Urea Nitrogen Underestimate Total Nitrogen Losses in Peritoneal Dialysis and Hemodialysis Patients. AB - OBJECTIVE: Muscle wasting is associated with increased mortality and is commonly reported in dialysis patients. Hemodialysis (HD) and peritoneal dialysis (PD) treatments lead to protein losses in effluent dialysate. We wished to determine whether changes in current dialysis practice had increased therapy-associated nitrogen losses. DESIGN: Cross-sectional cohort study. METHODS: Measurement of total protein, urea and total nitrogen in effluent dialysate from 24-hour collections from PD patients, and during haemodiafiltration (HDF) and haemodialysis (HD) sessions. SUBJECTS: One hundred eight adult dialysis patients. INTERVENTION: Peritoneal dialysis, high-flux haemodialysis and haemodiafiltration. MAIN OUTCOME MEASURE: Total nitrogen and protein losses. RESULTS: Dialysate protein losses were measured in 68 PD and 40 HD patients. Sessional losses of urea (13.9 [9.2-21.1] vs. 4.8 [2.8-7.8] g); protein (8.6 [7.2 11.1] vs. 6.7 [3.9-11.1] g); and nitrogen (11.5 [8.7-17.7] vs. 4.9 [2.6-9.5] g) were all greater for HD than PD, P < .001. Protein-derived nitrogen was 71.9 (54.4-110.4) g for HD and 30.8 (16.1-59.6) g for PD. Weekly protein losses were lower with HD 25.9 (21.5-33.4) versus 46.6 (27-77.6) g/week, but nitrogen losses were similar. We found no difference between high-flux HD and HDF: urea (13.5 [8.8-20.6] vs. 15.3 [10.5-25.5] g); protein (8.8 [7.3-12.2] vs. 7.6 [5.8-9.0] g); and total nitrogen (11.6 [8.3-17.3] vs. 10.8 [8.9-22.5] g). Urea nitrogen (UN) only accounted for 45.1 (38.3-51.0)% PD and 63.0 (55.3-62.4)% HD of total nitrogen losses. CONCLUSION: Although sessional losses of protein and UN were greater with HD, weekly losses were similar between modalities. We found no differences between HD and HDF. However, total nitrogen losses were much greater than the combination of protein and UN, suggesting greater nutritional losses with dialysis than previously reported. PMID- 29709366 TI - Databases for surgical health services research: National Health and Nutrition Examination Survey. PMID- 29709367 TI - Inhibition of necroptosis attenuates lung injury and improves survival in neonatal sepsis. AB - BACKGROUND: Neonatal sepsis represents a unique therapeutic challenge owing to an immature immune system. Necroptosis is a form of programmed cell death that has been identified as an important mechanism of inflammation-induced cell death. Receptor-interacting protein kinase 1 plays a key role in mediating this process. We hypothesized that pharmacologic blockade of receptor-interacting protein kinase 1 activity would be protective in neonatal sepsis. METHODS: Sepsis was induced in C57BL/6 mouse pups (5-7 days old) by intraperitoneal injection of adult cecal slurry. At 1 hour after cecal slurry injection, the receptor interacting protein kinase 1 inhibitor necrostatin-1 (10 ug/g body weight) or vehicle (5% dimethyl sulfoxide in phosphate buffered saline) was administered via retro-orbital injection. At 20 hours after cecal slurry injection, blood and lung tissues were collected for various analyses. RESULTS: At 20 hours after sepsis induction, vehicle-treated pups showed a marked increase in serum levels of interleukin 6, interleukin 1-beta, and interleukin 18 compared to sham. With necrostatin-1 treatment, serum levels of interleukin 6, interleukin 1-beta, and interleukin 18 were decreased by 77%, 81%, and 63%, respectively, compared to vehicle. In the lungs, sepsis induction resulted in a 232-, 10-, and 2.8-fold increase in interleukin 6, interleukin 1-beta, and interleukin 18 mRNA levels compared to sham, while necrostatin-1 treatment decreased these levels to 40-, 4 , and 0.8-fold, respectively. Expressions of the neutrophil chemokines keratinocyte chemoattractant and macrophage-inflammatory-protein-2 were also increased in the lungs in sepsis, while necrostatin-1 treatment decreased these levels by 81% and 61%, respectively, compared to vehicle. In addition, necrostatin-1 treatment significantly improved the lung histologic injury score and decreased lung apoptosis in septic pups. Finally, treatment with necrostatin 1 increased the 7-day survival rate from 0% in the vehicle-treated septic pups to 29% (P = .11). CONCLUSION: Inhibition of receptor-interacting protein kinase 1 by necrostatin-1 decreases systemic and pulmonary inflammation, decreases lung injury, and increases survival in neonatal mice with sepsis. Targeting the necroptosis pathway might represent a new therapeutic strategy for neonatal sepsis. PMID- 29709368 TI - Empiric transfusion strategies during life-threatening hemorrhage. AB - BACKGROUND: Resuscitation guided by thrombelastography improves survival after injury. If bleeding is rapid, however, or if no thrombelastography data are available, the optimal strategy remains controversial. Our current practice gives fresh frozen plasma and red blood cells (1:2) empirically in patients with life threatening hemorrhage, with subsequent administration based on rapid thrombelastography. We identified patients at risk of massive transfusion at 1 hour, examined their initial rapid thrombelastography, and used this value to provide empiric recommendations about transfusions. METHODS: Massive transfusion was defined as >4 units of red blood cells in the first hour. Patients managed by a trauma activation (2014-2017) had an admission rapid thrombelastography analyzed to determine what proportion met thresholds for administration of cryoprecipitate or platelets. RESULTS: Overall, 35 patients received >4 units of red blood cells in the first hour. Based on the admission rapid thrombelastography, 37% met criteria for both platelets and cryoprecipitate, 35% for either platelets or cryoprecipitate and 29% for neither. Kaplan-Meier analysis showed a significant delay in the administration of cryoprecipitate and platelets compared to fresh frozen plasma. CONCLUSION: Patients who require >4 units of red blood cells within the first hour should receive cryoprecipitate and platelets if thrombelastography results are not available. Point-of-care devices are needed for optimal care of trauma-induced-coagulopathy, but these data offer guidance in their absence. PMID- 29709369 TI - Palliative Care Training and Decision-Making for Patients with Advanced Cancer: A Comparison of Surgeons and Medical Physicians. AB - BACKGROUND: Surgical decision-making in patients with advanced cancer requires careful thought and deliberation to balance the high risks with the potential palliative benefits. We sought to compare surgical decision-making and palliative care training among surgeons and medical physicians who commonly treat advanced cancer patients. We hypothesized that surgeons will report less palliative care training compared with medical physicians, and deficits in palliative care training will be associated with more aggressive treatment recommendations in clinical scenarios of advanced cancer patients with symptomatic surgical conditions. STUDY DESIGN: Practicing surgeons, medical oncologists, intensivists, and palliative care physicians from a large urban city and its surrounding areas were surveyed with a 32-item questionnaire consisting of a survey addressing palliative care training and 4 clinical vignettes depicting patients with advanced cancer and symptomatic surgical conditions. RESULTS: Of the 299 physicians surveyed, 102 responded (response rate 34.1%). Surgeons reported fewer hours of palliative care training during residency, fellowship, and continuing medical education combined (median 10, IQR 2-15) compared with medical oncologists (median 30, IQR 20-80) and medical intensivists (median 50 IQR 30 100), P < .05. Additionally, 20% of surgeons reported no history of any palliative care training. Analysis of physician recommendations for treatment of the 4 clinical vignettes showed minimal consensus regardless of physician specialty. Absence of palliative care training was associated with recommending major operative intervention more frequently compared with physicians with >=40 hours of palliative care training (0.7 +/- 0.7 vs 1.6 +/- 0.8, P =.01). CONCLUSION: Substantial deficiencies in palliative care training persist among surgeons and are associated with more aggressive recommendations for treatment for the selected scenarios presented in patients with advanced cancer. These findings highlight the need for greater efforts systemwide in palliative care education among surgeons, including incorporation of a structured palliative care training curriculum in graduate and continuing surgical education. PMID- 29709370 TI - Development of models to predict early post-transplant recurrence of hepatocellular carcinoma that also integrate the quality and characteristics of the liver graft: A national registry study in China. AB - BACKGROUND: Donor characteristics and graft quality were recently reported to play an important role in the recurrence of hepatocellular carcinoma after liver transplantation. Our aim was to establish a prognostic model by using both donor and recipient variables. METHODS: Data of 1,010 adult patients (training/validation: 2/1) undergoing primary liver transplantation for hepatocellular carcinoma were extracted from the China Liver Transplant Registry database and analyzed retrospectively. A multivariate competing risk regression model was developed and used to generate a nomogram predicting the likelihood of post-transplant hepatocellular carcinoma recurrence. RESULTS: Of 673 patients in the training cohort, 70 (10.4%) had hepatocellular carcinoma recurrence with a median recurrence time of 6 months (interquartile range: 4-25 months). Cold ischemia time was the only independent donor prognostic factor for predicting hepatocellular carcinoma recurrence (hazard ratio = 2.234, P = .007). The optimal cutoff value was 12 hours when patients were grouped according to cold ischemia time at 2-hour intervals. Integrating cold ischemia time into the Milan criteria (liver transplantation candidate selection criteria) improved the accuracy for predicting hepatocellular carcinoma recurrence in both training and validation sets (P < .05). A nomogram composed of cold ischemia time, tumor burden, differentiation, and alpha-fetoprotein level proved to be accurate and reliable in predicting the likelihood of 1-year hepatocellular carcinoma recurrence after liver transplantation. Additionally, donor anti-hepatitis B core antibody positivity, prolonged cold ischemia time, and anhepatic time were linked to the intrahepatic recurrence, whereas older donor age, prolonged donor warm ischemia time, cold ischemia time, and ABO incompatibility were relevant to the extrahepatic recurrence. CONCLUSION: The graft quality integrated models exhibited considerable predictive accuracy in early hepatocellular carcinoma recurrence risk assessment. The identification of donor risks can further help understand the mechanism of different patterns of recurrence. PMID- 29709371 TI - Neuroendoscopic septostomy: Indications and surgical technique. AB - BACKGROUND: Endoscopic septostomy is the treatment of choice for monolateral obstruction of the foramen of Monro. Common causes of this condition include: neoplasms, hemorrages, infections, congenital atresia, idiopathic occlusion. METHOD: All the steps for performing a safe endoscopic pellucidotomy are presented. A brief discussion about the most common technical variations and their rationale is added. CONCLUSION: Endoscopic pellucidotomy is a safe and effective treatment when a thorough understanding of anatomy is achieved. PMID- 29709372 TI - Transoral migration of the inferior end of a ventriculoperitoneal shunt: A case report with literature review. AB - Ventriculoperitoneal (VP) shunt surgery is the most widely used technique for the treatment of hydrocephalus. However, it can incur certain complications. Beside frequent complications (infection, obstruction), migration of the peritoneal catheter is a rare but dangerous complication. This report presents the case of a 4-year-old boy who had undergone VP shunt for hydrocephalus. One month later, the patient presented with protrusion of the peritoneal catheter through his mouth. He underwent another procedure to remove the peritoneal catheter, retaining the original ventricular catheter and valve chamber. Progression was favorable. To the best of our knowledge, only 7 cases of VP shunt transoral extrusion were reported, but many risk factors were identified. Bowel perforation is a serious complication of VP shunt surgery, sometimes leading to fatal outcome. PMID- 29709373 TI - Rosette-forming glioneural tumor in the tectal plate: Endoscopic diagnosis and conservative management. AB - We present the case of a 29 year-old male with a tumor involving the mesencephalic tectum with associated hydrocephalus. Third ventriculocisternostomy was performed along with endoscopic biopsy; this provided adequate sampling of the tumor and enabled diagnosis of rosette-forming glioneural tumor (RGNT). The patient was followed for 48 months without progression of the disease. We review the features of the previous eight cases described in the literature and discuss the advantages of a minimally invasive approach and conservative management. PMID- 29709374 TI - Translating Current Bioanalytical Techniques for Studying Corona Activity. AB - The recent discovery of the biological corona is revolutionising our understanding of the in vivo behaviour of nanomaterials. Accurate analysis of corona bioactivity is essential for predicting the fate of nanomaterials and thereby improving nanomedicine design. Nevertheless, current biotechniques for protein analysis are not readily adaptable for analysing corona proteins, given that their conformation, activity, and interaction may largely differ from those of the native proteins. Here, we introduce and propose tailor-made modifications to five types of mainstream bioanalytical methodologies. We specifically illustrate how these modifications can translate existing techniques for protein analysis into competent tools for dissecting the composition, bioactivity, and interaction (with both nanomaterials and the tissue) of corona formed on specific nanomaterial surfaces. PMID- 29709375 TI - Purulent lymphadenitis caused by Staphylococcus argenteus, representing the first Japanese case of Staphylococcus argenteus (multilocus sequence type 2250) infection in a 12-year-old boy. AB - Staphylococcus argenteus is a novel species separated from a strain of coagulase positive, non-pigmented S. aureus. Although S. argenteus has been reported to occur globally, multilocus sequence type (ST) 2250 is mainly found in Northeastern Thailand. Because conventional biochemical testing misidentifies this pathogen as S. aureus, multilocus sequence typing (MLST) or nucA sequencing is recommended to distinguish between S. argenteus and S. auereus. The patient was a previously healthy 12-year-old boy who was admitted because of right inguinal lymphadenitis and cellulitis. Although intravenous cefazolin was administered, his lymphadenitis worsened and formed an abscess on day 6 of hospitalization. Incision and drainage were performed on day 7 of hospitalization. Cefazolin was changed to oral cefaclor, and the patient was successfully treated over a period of 5 weeks. No recurrence was observed throughout 12-months of follow-up. He had a history of right axillary lymph node abscess 2 months before this admission, which was successfully treated with incision, drainage, and antibiotic therapy. He has lived in Japan since birth and never traveled abroad. He had no opportunity to interact with foreigners. His immune function, especially neutrophil function, was tested and we did not find any dysfunction. First, methicillin-sensitive S. aureus was misidentified from the abscess culture. Subsequently, the causative agent was re-identified as S. argenteus ST2250 based on MLST. To our knowledge, this is the first case of S. argenteus ST2250 infection in Japan. This pathogen should be taken into consideration in the diagnosis if the patient has atypical non-pigmented S. aureus. PMID- 29709376 TI - The biology of fracture healing in osteoporosis and in the presence of anti osteoporotic drugs. AB - Compromised bone strength in osteoporosis predisposes patients to an increased fracture risk. The management of these fractures is complicated due to the poor bone quality, which may lead to inadequate fixation strength and stability. While a number of studies using osteoporotic animal models have shown a detrimental impact on fracture healing, clinical evidence regarding whether fracture healing is impaired in the presence of osteoporosis is complicated by numerous associated conditions including advancing age. The mechanism of some anti-osteoporotic medications creates concern about a potential detrimental impact on fracture healing, while others appear to enhance fracture healing. The current evidence indicates that the beneficial effects of anti-osteoporosis treatment exceeds any concerns about possible adverse consequences on fracture healing in most circumstances. PMID- 29709377 TI - High energy injury is a risk factor for preoperative venous thromboembolism in the patients with hip fractures: A prospective observational study. AB - BACKGROUND: The purpose of this study was to identify the incidence of preoperative venous thromboembolism (VTE), and determine if high energy hip fracture affects preoperative VTE occurrence. METHODS: Three-hundred nine patients (244 low and 61 high energy injuries) treated between March 2015 and March 2017 were included in this study. Indirect multidetector computed tomographic venography for the detection of preoperative VTE was performed at admission. The incidence of preoperative VTE was compared between high and low energy injury hip fractures. Logistic regression analysis was used to identify independent risk factors for preoperative VTE. RESULTS: The overall incidence of preoperative VTE was 18.4% (56 of 305 patients). Preoperative VTE was identified in 17 (27.9%) and 39 (16.0%) patients in the high and low energy injury groups, respectively (p = 0.034). Multivariate logistic regression analysis showed that high energy injury, history of VTE, and myeloproliferative disease were significant predictive factors of preoperative VTE (OR = 2.451; 95% CI = 1.227 4.896, OR = 11.174; 95% CI = 3.500-35.673, OR = 6.936; 95% CI = 1.641-29.321, respectively) CONCLUSION: Because high energy hip fracture is significantly associated with preoperative VTE occurrence, preoperative evaluation and proper thromboprophylaxis should be performed for patients with a high-energy hip fracture. PMID- 29709379 TI - In reply to "A Long-Awaited Guideline for the Delineation of Primary Tumor in Head and Neck Cancer, and a Few Concerns about It" by Sezin Yuce Sari et al. PMID- 29709378 TI - A secondary analysis of FDG spatio-temporal consistency in the randomized phase II PET-boost trial in stage II-III NSCLC. AB - PURPOSE: FDG-PET scans have shown spatial consistency in NSCLC patients before and following chemoradiotherapy, implying radioresistance. We hypothesized that patients, who received FDG-PET redistributed dose painting, would demonstrate reduced spatial consistency when compared to registered patients or to escalated dose treatment. METHODS: Stage II-IIIB, inoperable NSCLC patients were randomized in a phase II trial (NCT01024829) to (chemo)radiotherapy of either homogeneous boosting to the primary tumor, or redistributed inhomogeneous boosting to the GTV subvolume (FDG-SUV > 50% SUVmax). Patients who could not be boosted (>=72 Gy) received 66 Gy in 24 fractions. Spatial consistency of pre-treatment and post treatment (3 months) FDG-PET scans was measured by various overlap fraction thresholds. RESULTS: 66/82 patients analyzed received randomized treatment in the trial. Thresholds of 50% SUVmax pre-treatment and 70% SUVmax post-treatment yielded a median overlap fraction of 0.63 [interquartile range: 0.15-0.93], with similar results for other thresholds. No significant differences were found among overlap fractions of the treatment groups. A high incidence of FDG-uptake in normal lung (grade-1 pneumonitis: 73%) was found post-treatment. CONCLUSION: FDG redistributed boosting did not reduce FDG spatial consistency from pre-treatment to post-treatment, which was highly variable among patients. The study found high numbers of patients with lung inflammation after treatment. PMID- 29709380 TI - Calorie intake and short-term survival of critically ill patients. AB - BACKGROUND & AIMS: The association between calorie supply and outcome of critically ill patients is unclear. Results from observational studies contradict findings of randomized studies, and have been questioned because of unrecognized confounding by indication. The present study wanted to re-examine the associations between the daily amount of calorie intake and short-term survival of critically ill patients using several novel statistical approaches. METHODS: 9661 critically ill patients from 451 ICUs were extracted from an international database. We examined associations between survival time and three pragmatic nutritional categories (I: <30% of target, II: 30-70%, III: >70%) reflecting different amounts of total daily calorie intake. We compared hazard ratios for the 30-day risk of dying estimated for different hypothetical nutrition support plans (different categories of daily calorie intake during the first 11 days after ICU admission). To minimize indication bias, we used a lag time between nutrition and outcome, we particularly considered daily amounts of calorie intake, and we adjusted results to the route of calorie supply (enteral, parenteral, oral). RESULTS: 1974 patients (20.4%) died in hospital before day 30. Median of daily artificial calorie intake was 1.0 kcal/kg [IQR 0.0-4.1] in category I, 12.3 kcal/kg [9.4-15.4] in category II, and 23.5 kcal/kg [19.5-27.8] in category III. When compared to a plan providing daily minimal amounts of calories (category I), the adjusted minimal hazard ratios for a delayed (from day 5-11) or an early (from day 1-11) mildly hypocaloric nutrition (category II) were 0.71 (95% confidence interval [CI], 0.54 to 0.94) and 0.56 (95% CI, 0.38 to 0.82), respectively. No substantial hazard change could be detected, when a delayed or an early, near target calorie intake (category III) was compared to an early, mildly hypocaloric nutrition. CONCLUSIONS: Compared to a severely hypocaloric nutrition, a mildly hypocaloric nutrition is associated with a decreased risk of death. In unselected critically ill patients, this risk cannot be reduced further by providing amounts of calories close to the calculated target. STUDY REGISTRATION: ID number ISRCTN17829198, website http://www.isrctn.org. PMID- 29709381 TI - Re: Retroseptal transconjunctival approach for fractures of the zygomaticomaxillary complex: a retrospective study. PMID- 29709382 TI - Numbness of the lower lip does not adversely affect quality of life or patients' satisfaction after mandibular orthognathic surgery. AB - Measures of patient-reported quality of life (QoL) are increasingly being used to tailor services that are funded by Clinical Commissioning Groups (CCG) in England. Mandibular osteotomies may result in altered sensation of the lower lip, but we know of limited evidence about the resulting effect on QoL. The modified Bristol orthognathic patient outcomes questionnaire was given to patients who had mandibular osteotomies at the Queen Elizabeth Hospital, Birmingham, between March 2006 and April 2016. Questionnaires were collected at the final orthognathic postoperative appointment. The significance of the difference in QoL between those who had altered sensation of the lower lip and those who did not was compared using a two-tailed t test. During this period 170 patients had mandibular orthognathic operations. Completed questionnaires were received from 117 of those patients (69%) during this period, after a follow up of about six months. We found no significant difference between the perceived benefits of treatment between the 41 who had altered sensation and the 74 who did not (p=0.30). Only 5/41 who reported residual numbness six months postoperatively stated that they would not choose to have the same treatment again. In conclusion, orthognathic surgery results in an appreciable improvement in QoL and should continue to be funded by CCG in England. Contrary to the perception of some clinicians, those patients with residual numbness of the lip did not have significantly poorer QoL. Future interpretation of the data will be improved if they are collected both before and after the operation. PMID- 29709383 TI - "Flipped classrooms" in training in maxillofacial surgery: preparation before the traditional didactic lecture? AB - While virtual learning environments (VLE) can be used in medical education as stand-alone educational interventions, they can also be used in preparation for traditional "face-to-face" training sessions as part of a "flipped classroom" model. We sought to evaluate the introduction of this model in a single module on maxillofacial radiology from a course on trauma skills. Course delegates were randomised into two groups: one was given access to an e-learning resource (test group) and the other attended a traditional didactic lecture (control group). Knowledge and confidence were assessed before and after the course with a 20 question single-best-answer paper and a 10-situation 100mm visual analogue scale (VAS) paper, respectively. All participants were then given free access to the VLE for 30days and were invited to take part in an e-survey. Neither group showed improvements in the single-best-answer scores, but both groups showed comparable improvements in VAS (control: median (range) values improved from 40.8 (17.7 82.5) mm to 62.8 (35.3-88.7) mm, p=0.001; test group: from 47.7 (10.9-58.1) mm to 60.5 (32.4-75.6) mm, p=0.005). Half of the respondents stated that they preferred the "flipped classroom" approach, and 22/22 stated that they would be "likely" or "very likely" to use an e-learning resource with expanded content. The "flipped classroom" approach was well received and there were comparable improvements in confidence. As maxillofacial radiology lends itself to online instruction with its reliance on the recognition of patterns, and problem-based approach to learning, a piloted e-learning resource could be developed in this area. PMID- 29709384 TI - Current thinking in medical education research: an overview. AB - Medical education is fast becoming a separate focus, and together with their clinical commitments, many clinicians now seek higher qualifications and professional accreditation in the field. Research is also developing, and there is a need for evidence-based practice in education, just as in clinical work. This review gives an overview of research into medical education, and explains the fundamentals of educational theory and the specific considerations for the quantitative and qualitative research methods that pertain to it. It also explains the application of these methods to two growing areas of research: technology-enhanced learning (TEL) and normative ethics in training. PMID- 29709385 TI - Detection of Helicobacter pylori in drinking water treatment plants in Bogota, Colombia, using cultural and molecular techniques. AB - Helicobacter pylori is one of the most common causes of chronic bacterial infection in humans, and a predisposing factor for peptic ulcer and gastric cancer. The infection has been consistently associated with lack of access to clean water and proper sanitation. H. pylori has been detected in surface water, wastewater and drinking water. However, its ability to survive in an infectious state in the environment is hindered because it rapidly loses its cultivability. The aim of this study was to determine the presence of cultivable and therefore viable H. pylori in influent and effluent water from drinking water treatment plants (DWTP). A total of 310 influent and effluent water samples were collected from three drinking water treatment plants located at Bogota city, Colombia. Specific detection of H. pylori was achieved by culture, qPCR and FISH techniques. Fifty-six positive H. pylori cultures were obtained from the water samples. Characteristic colonies were covered by the growth of a large number of other bacteria present in the water samples, making isolation difficult to perform. Thus, the mixed cultures were submitted to Fluorescent in situ Hybridization (FISH) and qPCR analysis, followed by sequencing of the amplicons for confirmation. By qPCR, 77 water samples, both from the influent and the effluent, were positive for the presence of H. pylori. The results of our study demonstrate that viable H. pylori cells were present in both, influent and effluent water samples obtained from drinking water treatment plants in Bogota and provide further evidence that contaminated water may act as a transmission vehicle for H. pylori. Moreover, FISH and qPCR methods result rapid and specific techniques to identify H. pylori from complex environmental samples such as influent water. PMID- 29709386 TI - 9th annual international water and health seminar: We get what we give: Water reuse coalesces prominent water and health topics. PMID- 29709387 TI - The fork in the road: A laryngeal filter airway foreign body. AB - OBJECTIVE: Upper aero-digestive tract foreign body management can be complicated and life threatening in both adult and pediatric populations. The variation seen with foreign bodies including shape, material, and duration of ingestion can impact clinical decision making and management. The objective of this report is to demonstrate a complicated case of upper airway obstruction by a plastic fork. METHOD: This case report presents an adult with ingestion of an intact plastic fork with acute laryngeal and cervical esophageal obstruction. The position of the fork precluded intubation as it was blocking the laryngeal inlet. RESULTS: The report illustrates successful nasolaryngoscopy pre-operative evaluation, multi-disciplinary team airway management and subsequent operative airway management and fork removal. CONCLUSION: Despite various concerns by both the Otolaryngology and Anesthesia services for airway establishment, sedation allowing for spontaneous ventilation through the fork prongs and adequate analgesia for direct laryngoscopy yielded successful removal of a plastic fork from the upper airway. PMID- 29709388 TI - Assessment of auditory discrimination in hearing-impaired patients. AB - Hearing loss can impair auditory discrimination, especially in noisy environments, requiring greater listening effort, which can impact socio occupational life. To assess the impact of hearing loss in noisy environments, clinicians may use subjective or objective methods. Subjective methods, such as speech audiometry in noise, are used in clinical practice to assess reported discomfort. Objective methods, such as cortical auditory evoked potentials (CAEPs), are mainly used in research. Subjective methods mainly comprise speech audiometry in noise, in which the signal-to-noise ratio can be varied so as to determine the individual speech recognition threshold, with and without hearing rehabilitation, the aim being to highlight any improvement in auditory performance. Frequency discrimination analysis is also possible. Objective methods assess auditory discrimination without the patient's active participation. One technique used for patients with auditory rehabilitation is the study of auditory responses by CAEPs. This electrophysiological examination studies cortical auditory rehabilitation oddball paradigms, enabling wave recordings such as mismatch negativity, P300 or N400, and analysis of neurophysiological markers according to auditory performance. The present article reviews all these methods, in order to better understand and evaluate the impact of hearing loss in everyday life. PMID- 29709389 TI - Unusual presentation of emphysematous pyelonephritis with extension to the scrotum and leg. PMID- 29709391 TI - Optimized Target-AID system efficiently induces single base changes in zebrafish. PMID- 29709392 TI - Antibiotics by Subcutaneous Route: A Safe and Efficient Alternative. PMID- 29709390 TI - Amazing Diversity in Biochemical Roles of Fe(II)/2-Oxoglutarate Oxygenases. AB - Since their discovery in the 1960s, the family of Fe(II)/2-oxoglutarate-dependent oxygenases has undergone a tremendous expansion to include enzymes catalyzing a vast diversity of biologically important reactions. Recent examples highlight roles in controlling chromatin modification, transcription, mRNA demethylation, and mRNA splicing. Others generate modifications in tRNA, translation factors, ribosomes, and other proteins. Thus, oxygenases affect all components of molecular biology's central dogma, in which information flows from DNA to RNA to proteins. These enzymes also function in biosynthesis and catabolism of cellular metabolites, including antibiotics and signaling molecules. Due to their critical importance, ongoing efforts have targeted family members for the development of specific therapeutics. This review provides a general overview of recently characterized oxygenase reactions and their key biological roles. PMID- 29709393 TI - Validity of administrative data in identifying complex surgical site infections from a population-based cohort after primary hip and knee arthroplasty in Alberta, Canada. AB - BACKGROUND: Surgical site infections (SSIs) are a substantial burden to healthcare systems in North America. Administrative data is one method though which these may be identified, but the accuracy of using such data is uncertain. METHODS: We followed a population-based cohort of patients who received primary hip/knee arthroplasty in Alberta, Canada, for whom a comprehensive Infection Prevention and Control (IPC) prospective surveillance methodology was used to track SSIs. Patients were also followed using International Classification of Diseases, Tenth Revision (ICD-10) codes. We assessed the sensitivity/specificity and positive/negative predictive values of ICD-10 codes compared to IPC surveillance. RESULTS: Between April 1, 2012, and March 31, 2015, 24,512 people received hip/knee arthroplasty. Of these, 258 (1.05%) had a complex SSI found by IPC surveillance. Sensitivity and specificity of ICD-10 codes in identifying complex SSIs after hip/knee arthroplasty were 85.3% (95% confidence interval [CI] 80.3%-89.4%) and 99.5% (95% CI 99.4%-99.6%), respectively. Positive and negative predictive values were 63.6% (95% CI 58.3%-68.7%) and 99.8% (95% CI 99.8%-99.9%), respectively. DISCUSSION: Administrative data have reasonable testing characteristics for identifying complex SSIs after arthroplasty. For centers without prospective surveillance programs, this could be useful in identifying hospitals with frequent complex SSIs after arthroplasty. CONCLUSIONS: A comprehensive IPC surveillance program is superior at detecting SSIs after arthroplasty. PMID- 29709395 TI - PPCM and type II autoimmune polyglandular syndrome. PMID- 29709394 TI - Clinical practice guidelines for fertility preservation in young women undergoing gonadotoxic treatment: an overview and critical appraisal of methodological quality and content. AB - RESEARCH QUESTION: What is the methodological quality and content of internationally available clinical practice guidelines (CPGs) on fertility preservation (FP) care in adult women? DESIGN: Internationally available CPGs on FP care in adult women were identified after conducting an extensive literature search and consulting (inter)national key experts. The methodological quality of the CPGs was appraised by an (inter)national panel of experts using the Appraisal of Guidelines for Research and Evaluation (AGREE) II instrument. The content of the best CPGs, scoring >=60% for the domain 'Rigour of development' of the AGREE II instrument, was extracted and categorized according to their topic. RESULTS: Thirty of the 1808 documents found were included. After consulting (inter)national key experts, 30 CPGs were included, six of which scored >=60% for their 'Rigour of development'. The number of FP-related topics discussed by these six CPGs ranged from 4 to 12. The number of recommendations provided by the CPGs on these topics varied. The number of topics to which >=5 recommendations were dedicated ranged from 0 to 4 between CPGs. CONCLUSION: CPGs on the subject of FP care are available, but there is room for improvement in quality and content. Although written for use in daily practice, the CPGs can also be used to develop quality indicators to monitor the quality of current FP care or to evaluate future improvement initiatives. PMID- 29709396 TI - Rivaroxaban plus Percutaneous catheter-directed treatment for a patient with massive pulmonary embolism and colporrhagia. AB - Massive pulmonary embolism (PE) is defined by acute PE with sustained systemic arterial hypotension that is below 90 mm Hg for at least 15 min or requires inotropic agents (Jaff et al., 2011). For patients with absolute contraindications to thrombolysis, interventional treatment requires the removal of obstructing thrombi from the main pulmonary arteries to facilitate RV recovery and improve symptoms and survival (European Respiratory Society et al., 2014). For patients with acute PE, anticoagulation is recommended, with the objective of preventing both early death and recurrent symptomatic or fatal VTE. Rivaroxaban, an oral factor Xa inhibitor and a new oral anticoagulants, shows effective anticoagulation within hours of administration. It has a fixed-dose regimen, and requires no laboratory monitoring (EINSTEIN-PE Investigators et al., 2012). However, the efficacy and safety of rivaroxaban plus catheter-directed treatment for massive PE and bleeding is unknown. This case demonstrated that a combination of catheter-directed treatment and rivaroxaban was safe and effective in for the treatment of severe PE with vaginal bleeding. PMID- 29709397 TI - Prognosis value of partial arterial oxygen pressure in patients with septic shock subjected to pre-hospital invasive ventilation. AB - OBJECTIVE: Mechanical ventilation can help improve the prognosis of septic shock. While adequate delivery of oxygen to the tissue is crucial, hyperoxemia may be deleterious. Invasive out-of-hospital ventilation is often promptly performed in life-threatening emergencies. We propose to determine whether the arterial oxygen pressure (PaO2) at the intensive care unit (ICU) admission is associated with mortality in patients with septic shock subjected to pre-hospital mechanical ventilation. METHODS: We performed a monocentric retrospective observational study on 77 patients. PaO2 was measured at ICU admission. The primary outcome was mortality at day 28 (D28). RESULTS: Forty-nine (64%) patients were included. The mean PaO2 at ICU admission was 153 +/- 77 and 202 +/- 82 mm Hg for alive and deceased patients respectively. Mortality concerned 18% of patients for PaO2 < 100, 25% for 100 < PaO2 < 150 and 57% for a PaO2 > 150 mm Hg. PaO2 was significantly associated with mortality at D28 (p = 0.04). Using propensity score analysis including SOFA score, pre-hospital duration, lactate, and prehospital fluid volume expansion, association with mortality at D28 only remained for PaO2 > 150 mm Hg (p = 0.02, OR [CI95] = 1.59 [1.20-2.10]). CONCLUSIONS: In this study, we report a significant association between hyperoxemia at ICU admission and mortality in patients with septic shock subjected to pre-hospital invasive mechanical ventilation. The early adjustment of the PaO2 should be considered for these patients to avoid the toxic effects of hyperoxemia. However, blood gas analysis is hard to get in a prehospital setting. Consequently, alternative and feasible measures are needed, such as pulse oximetry, to improve the management of pre-hospital invasive ventilation. PMID- 29709399 TI - STEMI-like pulmonary embolism: Is it the time for a multimodality approach? PMID- 29709398 TI - Alternatives to opioids for pain management in the emergency department decreases opioid usage and maintains patient satisfaction. AB - OBJECTIVE: The objective of this study was to assess opioid use in an emergency department following the development and implementation of an alternative to opioids (ALTO)-first approach to pain management. The study also assessed how implementation affected patient satisfaction scores. METHODS: This study compared data collected from October to December of 2015 (prior to implementation) to data collected between October and December of 2016 (after the intervention had been implemented). Emergency department visits during the study timeframe were included. Opioid reduction was measured in morphine equivalents (ME) administered per visit. Secondary outcomes on patient satisfaction were gathered using the Press Ganey survey. RESULTS: Intravenous (IV) opioid administration during the study period decreased by >20%. The predicted mean ME use in 2016 was 0.25 ME less when compared to 2015 (95% CI -0.27 to -0.23). Estimated use for patients in the pre-implementation period was 1.45 ME mgs (SD 0.88), and 1.13 ME mg (SD 0.69) for patients in the post-implementation period. Patient satisfaction scores using the Press Ganey Scale also were assessed. There was no significant difference in the scores between 2015 and 2016 when patients were asked "How well was you pain controlled?" (-0.94, 95% CI -5.29 to 3.4) and "How likely are you to recommend this emergency department?" (-1.55, 95% CI -5.26 to 2.14). CONCLUSION: In conclusion, by using an ALTO-first, multimodal treatment approach to pain management, participating clinicians were able to significantly decrease the use of IV opioids in the emergency department. Patient satisfaction scores remained unchanged following implementation. PMID- 29709400 TI - Aortic dissection presenting with acute pulmonary edema. AB - BACKGROUND: Acute aortic dissection is a cardiovascular emergency with high mortality that necessitates prompt diagnosis and immediate treatment. Though asymmetric extremity pulses/blood pressures and mediastinal widening on chest roentgenogram are often clues to diagnosis, aortic regurgitation (AR) of variable degrees could be the only sign on initial assessment. Mostly resulting from dilated aortic ring with valvular insufficiency, the AR could be caused by different pathogenic mechanisms. Herein we report a case of Stanford type A aortic dissection presenting with acute pulmonary edema. Physical examination detected severe AR murmur and bedside echocardiogram confirmed prolapsed dissecting intima flap with interference of aortic valve closure as a specific mechanism. CASE PRESENTATION: A 36-year-old man presented with rapidly progressive dyspnea within hours. Physical examination disclosed a grade IV/VI diastolic murmur at aortic area and left parasternal border. Immediate bedside echocardiography revealed an onion-shaped aortic root with a dissecting intima flapping to-and-fro in between aortic root and left ventricular outflow tract, thus interfering with aortic valve closure and resulting in severe AR. Chest computed tomography confirmed a Stanford type A aortic dissection with the dilated aortic root well hidden in cardiac silhouette, making chest roentgenogram difficult for diagnosis. Emergency operation with Bentall procedure was performed smoothly and the patient was discharged uneventfully later. CONCLUSIONS: Acute pulmonary edema resulting from severe AR is a specific presentation of aortic dissection. New-onset AR murmur, either caused by aortic ring dilatation or prolapsed intima flap interfering with aortic valve closure, may serve as a clue to timely correct diagnosis. PMID- 29709401 TI - The usage of Ambu(r) AuraGainTM laryngeal mask airway by the lifeguards. PMID- 29709402 TI - WASP (Write a Scientific Paper) using Excel - 11: Test characteristics. AB - The calculation of various test characteristics may be required as part of a data analysis exercise. This paper explains how to set up these calculations in Microsoft Excel in order to obtain sensitivity, specificity, positive and negative predictive values, diagnostic accuracy and prevalence. PMID- 29709403 TI - Improving diabetes care among patients with severe mental illness: A systematic review of the effect of interventions. AB - BACKGROUND AND AIM: Individuals with severe mental illness (SMI) who suffer from type 2 diabetes (T2DM) are likely to be sub-optimally treated for their physical condition. This study aimed to review the effect of interventions in this population. METHODS: A systematic search in five databases was conducted in July 2017. RESULTS: Seven studies on multi-faced interventions were included. These comprised nutrition and exercise counselling, behavioural modelling and increased disease awareness aiming to reduce HbA1c, fasting plasma glucose, body mass index and weight. CONCLUSION: Non-pharmacologic interventions in individuals with SMI and T2DM could possibly improve measures of diabetes care, although with limited clinical impact. PMID- 29709404 TI - Microbiology of French military casualties repatriated from overseas for an open traumatic injury. AB - BACKGROUND: This study aimed to describe the microbiological epidemiology of repatriated French soldiers with an open traumatic injury, and to measure the proportion of multidrug-resistant bacteria (MDRB). METHODS: Retrospective study including all French soldiers repatriated in 2011 and 2012 in Parisian military hospitals for open traumatic injury. Results of clinical samples and MDRB screening were collected. The antibiotic susceptibility was assessed using the agar disk diffusion method. Characterization of resistance mechanisms was performed using PCR. Genotyping of extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL-E) isolates was performed using rep-PCR. RESULTS: A total of 139 patients were included; 70% of them were repatriated from Afghanistan. At admission, 24/88 were positive for MDRB (28%), mainly ESBL-E but no carbapenemase-producing Enterobacteriaceae and vancomycin-resistant Enterococcus faecium were identified. Forty-five patients had lesion sample collection, and 28/45 had a positive culture. The most frequently isolated pathogens were Enterobacter cloacae, Pseudomonas aeruginosa, and Escherichia coli. For eight patients, a MDRB was isolated from the wound, mainly ESBL-E (7/8) but also one methicillin-resistant Staphylococcus aureus and one imipenem resistant Acinetobacter baumannii. Among ESBL-E, the PCR evidenced the high prevalence of CTX-M15 enzymes. Rep-PCR performed on the 23 ESBL-producing E. coli isolates highlighted numerous profiles. CONCLUSIONS: Controlling the spread of ESBL-E is currently challenging for French Armed Forces. Despite any evidence of an epidemic clone, a high-level compliance with hygiene precautions is required throughout the chain of care to avoid cross contamination. PMID- 29709405 TI - Influence of obesity and metabolic syndrome on clinical outcomes of ST-segment elevation myocardial infarction in men undergoing primary percutaneous coronary intervention. AB - BACKGROUND: The correlation between obesity and metabolic syndrome (MetS) and its impact on cardiovascular disease remains unclear. This study aims to investigate the impact of metabolic status and obesity on clinical outcomes of male patients with ST-segment elevation myocardial infarction (STEMI). METHODS: Data from the Korea Acute Myocardial Infarction Registry-National Institutes of Health registry were used to evaluate the impact of obesity and MetS on patients undergoing primary percutaneous coronary intervention (PPCI) from November 2005 to November 2015. Patients were grouped according to the presence or absence of obesity and MetS ('obese-/MetS-', 'obese-/MetS+', 'obese+/MetS-', or 'obese+/MetS+', respectively). All-cause death and major adverse cardiac events (MACE) were recorded during 12 months of follow-up. RESULTS: A total of 14,357 patients were included. Multivariate analysis showed that the presence of MetS was an independent risk factor for all-cause death (HR 2.08, 95% CI 1.30-3.31, p=0.002) and cardiovascular death (HR 2.44, 95% CI 1.33-4.46, p=0.004) at 12 months among normal weight patients. The protective effect of obesity was observed, compared with the obese-/MetS+ group, in terms of all-cause death (HR 0.50, 95% CI 0.31 0.81, p=0.005) and cardiovascular death (HR 0.52, 95% CI 0.28-0.96, p=0.038; vs. total obese individuals), but it might have disappeared compared with the obese /MetS- group. The rate of MACE did not differ significantly according to category by obesity and MetS. CONCLUSIONS: The obesity paradox has not been observed between obese and normal weight patients without MetS. Risk stratification on the basis of the presence or absence of MetS is not a clinically useful indicator of outcome in obese male patients with STEMI after PPCI. PMID- 29709406 TI - Massive organ embolization from primary aortic thrombosis. AB - A 49-year-old woman was hospitalized for acute left foot arterial ischemia. Arterial Doppler revealed occlusion of the dorsalis pedis and posterior tibial arteries. A computed tomography angiography performed to assess abdominal pain showed hepatic, splenic, renal and pancreatic infarctions. A splenic artery embolism and a small aortic wall thrombus at the celiac trunk were identified. No radiological signs of aortic atherosclerosis were found. No predisposing conditions for secondary aortic thrombosis or intracardiac embolic sources were detected. It was determined that primary aortic thrombosis, a rare though potentially serious condition, was to blame. Isolated aortic mural thrombosis therapy is not well established, although systemic anticoagulation, thrombolysis, thromboaspiration, endovascular stent grafting and surgical thrombectomy have been attempted with varying success. In our patient, systemic anticoagulation therapy was initiated and resulted in aortic thrombus resolution. Close clinical follow-up is crucial, as the aortic thrombus can recur despite anticoagulation and aggressive control of the atherosclerotic risk factors. PMID- 29709407 TI - Minimization of Radial Forearm Flap Donor-Site Scar Using Endoscopy and Allogeneic Dermal Matrix. AB - Radial forearm free flaps are widely used for soft tissue reconstruction in the oral cavity. However, preparation of the vascular pedicle leaves long undesirable scars. Extensive scar formation also occurs at the skin defect site. Over recent years, endoscopic surgery has been increasingly used for minimally invasive procedures. We report 4 cases involving the formation of radial forearm free flaps using endoscopy and an alloplastic skin graft, resulting in minimal scar formation and favorable results. PMID- 29709408 TI - Multiple Endocrine Neoplasia Type 2b (MEN2B) in a 9-Year-Old Female. AB - Multiple endocrine neoplasia (MEN) is an uncommon genetic syndrome transmitted as an autosomal dominant condition characterized by multiple tumors or hyperplasia of neuroendocrine tissues. MEN type 2b (MEN2B) often has clinical signs of marfanoid facial appearance and mucosal neuromas of the head. This report describes the diagnosis of MEN2B in a previously undiagnosed 9 year old who presented for biopsy of an oral lesion. PMID- 29709409 TI - Screening/surveillance programs for pancreatic cancer in familial high-risk individuals: A systematic review and proportion meta-analysis of screening results. AB - BACKGROUND/OBJECTIVES: Screening/surveillance programs for pancreatic cancer (PC) in familial high-risk individuals (FPC-HRI) have been widely reported, but their merits remain unclear. The data reported so far are heterogeneous-especially in terms of screening yield. We performed a systematic review and meta-analysis of currently available data coming from screening/surveillance programs to evaluate the proportion of screening goal achievement (SGA), overall surgery and unnecessary surgery. METHODS: We searched MEDLINE, Embase, PubMed and the Cochrane Library database from January 2000 to December 2016to identify studies reporting results of screening/surveillance programs including cohorts of FPC HRI. The main outcome measures were weighted proportion of SGA, overall surgery, and unnecessary surgery among the FPC-HRI cohort, using a random effects model. SGA was defined as any diagnosis of resectable PC, PanIN3, or high-grade dysplasia intraductal papillary mucinous neoplasm (HGD-IPMN). Unnecessary surgery was defined as any other final pathology. RESULTS: In a meta-analysis of 16 studies reporting on 1551 FPC-HRI cases, 30 subjects (1.82%), received a diagnosis of PC, PanIN3 or HGD-IPMNs. The pooled proportion of SGA was 1.4%(95% CI 0.8-2, p < 0.001, I2 = 0%). The pooled proportion of overall surgery was 6%(95% CI 4.1-7.9, p < 0.001, I2 = 60.91%). The pooled proportion of unnecessary surgery was 68.1%(95% CI 59.5-76.7, p < 0.001, I2 = 4.05%); 105 subjects (6.3%) received surgery, and the overall number of diagnoses from non-malignant specimens was 156 (1.5 lesion/subject). CONCLUSIONS: The weighted proportion of SGA of screening/surveillance programs published thus far is excellent. However, the probability of receiving surgery during the screening/surveillance program is non-negligible, and unnecessary surgery is a potential negative outcome. PMID- 29709410 TI - The complicated 'Yes': Decision-making processes and receptivity to lung cancer screening among head and neck cancer survivors. AB - OBJECTIVE: Shared decision making (SDM) is recommended when offering lung cancer screening (LCS)-which presents challenges with tobacco-related cancer survivors because they were excluded from clinical trials. Our objective was to characterize head and neck cancer (HNC) survivors' knowledge, attitudes, and beliefs toward LCS and SDM. METHODS: Between November 2017 and June 2018, we conducted semi-structured qualitative interviews with 19 HNC survivors, focusing on patients' cancer and smoking history, receptivity to and perceptions of LCS, and decision-making preferences RESULTS: Participants were receptive to LCS, referencing their successful HNC outcomes. They perceived that LCS might reduce uncertainty and emphasized the potential benefits of early diagnosis. Some expressed concern over costs or overdiagnosis, but most minimized potential harms, including false positives and radiation exposure. Participants preferred in-person LCS discussions, often ideally with their cancer specialist. CONCLUSION AND PRACTICE IMPLICATIONS: HNC survivors may have overly optimistic expectations for LCS, and clinicians need to account for this in SDM discussions. Supporting these patients in making informed decisions will be challenging because we lack clinical data on the potential benefits and harms of LCS for cancer survivors. While some patients prefer discussing LCS with their cancer specialists, the ability of specialists to support high-quality decision making is uncertain. PMID- 29709411 TI - "We Don't Want to be Judged": Perceptions about Professional Help and Attitudes Towards Help-Seeking among Pregnant and Postpartum Mexican-American Adolescents. AB - PURPOSE: The purpose of this qualitative study is to understand how depression is recognized, as well as perceptions of professional help and attitudes concerning perinatal depression among pregnant and postpartum (perinatal) Mexican-American adolescents. DESIGN AND METHODS: This qualitative descriptive study used deductive and inductive content analysis to analyze data. Categories and subcategories describing the mental health literacy of perinatal Mexican-American adolescents concerning perinatal depression are presented. A convenience sample of 20 perinatal Mexican-American adolescents between the ages of 15 and 19 years were interviewed. Participants were recruited from parenting classes across urban high-schools in Southwestern United States. RESULTS: Adolescents expressed difficulties in recognizing perinatal depression. Depressive symptoms were identified through self-appraisals or the appraisal of others. Establishing rapport with empathetic health care providers facilitated trust among adolescents. Fear of judgement was the most common response and prevented help seeking. Lack of trust, normalization of depression, and reluctance with disclosing symptoms were also indicated by participants. CONCLUSIONS: Stigma concerning perinatal depression was identified as a barrier for help-seeking among participants who were already experiencing criticism due to their pregnancy status. The quality of interactions with health providers may hinder or facilitate adolescents from professional help-seeking. PRACTICE IMPLICATIONS: Active engagement and collaboration with Mexican-American adolescents are indicated in identification and treatment of perinatal depression. Integration of mental health services in primary care settings is suggested to facilitate help seeking for perinatal depression. Mental Health First Aid may be utilized to improve knowledge and decrease stigma concerning perinatal depression among Mexican-American adolescents. PMID- 29709412 TI - Phytochemical profile and pharmacological activity of Aegle marmelos Linn. AB - Aegle marmelos Linn. (Rutaceae), commonly known as "bael" in Nepal and India, is a valuable medicinal plant and is considered sacred by the Hindus. It is used to cure several diseases in the Indian traditional medicine system of Ayurveda and has had similar uses among many ethnic communities residing in Indian subcontinent for over 5000 years. Its leaves, bark, stem, fruits and seeds have been used for various medicinal purposes. Bael fruits are especially effective in the treatment of chronic diarrhea, dysentery and peptic ulcers, while they are also useful as a laxative and cure for respiratory infections. Scientific studies have validated many of the ethnomedicinal uses of A. marmelos, which include antibacterial, antiviral, antidiarrheal, gastroprotective, anti-ulcerative colitis, hepatoprotective, antidiabetic, cardioprotective and radioprotective effects. Recently, this plant has also received attention as an anticancer agent for the treatment of various types of cancers. Thus, this review focuses on scientific evidence verifying the important pharmacological activity such as antioxidant, antidiabetic, antimicrobial, hepatoprotective, cardioprotective and anticancer activity of A. marmelos. PMID- 29709413 TI - The radiocapitellar synovial fold: a lateral anatomic landmark for sizing radial head arthroplasty. AB - BACKGROUND: Successful radial head arthroplasty relies on reproduction of anatomy. We hypothesized that the radiocapitellar synovial fold could serve as a reference point in radial head prosthesis sizing. Our study aimed to define the relationship between the synovial fold and the radial head in elbows with and without lateral ulnar collateral ligament (LUCL) injury. MATERIALS AND METHODS: We performed magnetic resonance imaging evaluation of 34 elbows to determine the normal relationship between the radiocapitellar synovial fold and the radial head. Next, we used cadaveric dissections to evaluate the anatomic relationships with the LUCL intact and disrupted, as well as in the setting of sizing with a radial head prosthesis. The fold-to-radial head distance (FRHD) was measured on all images and analyzed to determine the relationship of the synovial fold and radial head. RESULTS: The FRHD in cadavers with an intact LUCL and native radial head measured an average of 1.5 mm proximal to the radial head. With the LUCL disrupted and a native radial head, the FRHD measured an average of 1.2 mm proximal to the radial head. The mean difference between the groups was 0.5 mm (P = .031), suggesting that the fold migrated distally in the cadavers with a disrupted LUCL. CONCLUSION: The radiocapitellar synovial fold may be a helpful landmark for radial head sizing. The synovial fold is always just proximal to the articular surface of the radial head. Using this information, the surgeon can prevent overlengthening as the implant should not be placed proximal to the fold. PMID- 29709414 TI - Contractile property measurement of the torn supraspinatus muscle using real-time tissue elastography. AB - HYPOTHESIS: In the restoration of shoulder abduction, decreased contractility of the torn rotator cuff muscle may be a cause of a poor result. The aim of this study was to investigate the relationship between the contractile property of the torn supraspinatus muscle measured by real-time tissue elastography and the Goutallier stage as modified by Fuchs et al. METHODS: The muscular hardness of the torn supraspinatus muscle was measured in 32 patients at rest and during isometric contraction with the shoulder abducted to 60 degrees in the scapular plane. The muscular hardness was calculated as the strain ratio. Fatty degeneration was assessed according to the modified Goutallier stage. Because the activity value (defined as the difference between the strain ratio at rest and the strain ratio during isometric contraction) estimated the contractile property of the muscle, stepwise multiple regression analysis was used to compare the activity value with age, sex, side, time from injury onset to obtaining the measurements, and modified Goutallier stage. RESULTS: The mean activity value was 0.26 +/- 0.16. Fatty degeneration of the supraspinatus muscle was grade 0 in 5 patients, grade 1 in 16, grade 2 in 10, and grade 3 in 1. The activity value was significantly correlated only with the modified Goutallier stage (r = -0.78, P < .001). CONCLUSION: The contractile property of the supraspinatus muscles decreased with an increase in the modified Goutallier stage. Real-time tissue elastography can measure the contractile property of the muscles before surgery and thus may be a predictor for the resulting restoration of lost muscle function. PMID- 29709415 TI - Biomechanical comparison of glenoid implants with adaptable and fixed backside curvatures in anatomic total shoulder arthroplasty. AB - BACKGROUND: We evaluated the biomechanical effects and potential advantages of glenoid implants with adaptable backside curvature radii and compared them with standard implants having fixed backside curvatures in anatomic total shoulder arthroplasty (aTSA) for primary glenohumeral osteoarthritis with uniconcave glenoids. METHODS: A glenoid implant with adaptable backside curvatures (Aequalis PerFORM, Tornier SAS, Montbonnot, France) was compared with its previous model having a fixed curvature radius. Virtual aTSAs were performed in 24 patients from preoperative shoulder computed tomography data sets, using both implants in each patient. For all 48 simulated aTSAs, we first measured the glenoid bone reaming depth, subchondral bone quality after reaming, and implant backside surface and then the predicted cement stress, bone-cement interfacial stress, and bone strain at 60 degrees of arm abduction. These biomechanical quantities were tested for differences between adaptable and fixed implants and for correlations between preoperative measurements and postoperative predictions. RESULTS: Adaptable glenoid implants induced a significant decrease in cement stress (P = .008), bone cement interfacial stress (P = .045), and bone strain (P = .039), particularly for glenoids with curvature radii larger than 40 mm. However, these biomechanical effects were not significantly correlated with an increase in subchondral glenoid bone quality. CONCLUSIONS: Our study confirms the presumed biomechanical advantages of adaptable glenoid implants, even though the effects were not directly due to the adaptation of the backside curvature radius. Benefits were more pronounced for glenoids with large curvature radii. Our initial biomechanical findings should now be corroborated with large-scale clinical studies. PMID- 29709417 TI - Department of Error. PMID- 29709418 TI - The Palestinian March: return to dialogue. PMID- 29709416 TI - The Palestinian Day of Return: from a short day of commemoration to a long day of mourning. PMID- 29709419 TI - BIOACTIVE GLASS S53P4: a new opportunity for the treatment in the diabetic foot osteomyelitis. PMID- 29709421 TI - Correlates of immune and clinical activity of novel cancer vaccines. AB - Cancer vaccines are solely meant to amplify the pool of type 1 cytokine oriented CD4+ and CD8+ T cells that recognize tumor antigen and ultimately foster control and destruction of a growing tumor. They are not designed to deal with all aspects of immune ignorance, exclusion, suppression and escape that are generally in place in patients with cancer and may prevent the T cells to enter the tumor or to exert their effector function. This simple fact prompted for a reappraisal of the many recent trials in which therapeutic cancer vaccines have been examined as monotherapy. In this review, I focus on trials examining therapeutic cancer vaccines at different stages of existing disease. The analysis of vaccine-induced immune responses and clinical activity of therapeutic cancer vaccines revealed four levels of evidence for vaccine efficacy. The lowest levels, reflect the many trials in which the strength of the tumor-reactive T cell response of vaccinated patients is associated with better clinical outcome or change in tumor marker. The highest levels indicate occasional regressions of tumors and metastases after vaccination or reflect a stronger clinical impact of vaccine in a randomized trial. A whole series of trials in which vaccine-induced tumor immunity correlates with the clinical impact of cancer vaccines in premalignant diseases, settings of low tumor burden or tumor regressions in patients with cancer, form an attest to the fact that cancer vaccines work. While the current number of true clinical responders in each cancer trial is too low for firm conclusions on immune correlates of clinical reactivity in cancer, extrapolation of the results from vaccinated patients with pre-cancers suggest a requirement of broad type 1 T cell reactivity. PMID- 29709420 TI - Outcome of patients with cardiac amyloidosis admitted to an intensive care unit for acute heart failure. AB - BACKGROUND: The outcome of cardiac amyloidosis (CA) has been reported mainly in stable populations; limited data are available in patients referred for acute heart failure (AHF) to an intensive cardiac care unit (ICCU). AIMS: To address the characteristics and outcomes of patients with confirmed CA admitted to an ICCU for AHF and then to identify the predictors of evolution to cardiogenic shock. METHODS: All patients with CA referred to an ICCU for AHF between 2009 and 2015 were included. The clinical endpoint was 3-month death. Data from the population with cardiogenic shock, obtained in a stable haemodynamic state, were matched with data from a control group to determine predictors of evolution to cardiogenic shock. RESULTS: Among the 421 patients followed for CA in our expert centre, 46 patients (mean age: 64+/-14 years; 65% light-chain [AL] CA) were referred to the ICCU for AHF (n=26 with cardiogenic shock). At 3 months, death occurred in 24 (52%) patients, mostly in the cardiogenic shock group (n=21/26, 81%). Most deaths occurred 5 days [interquartile range 3-9 days] after catecholamine infusion and 50% occurred in patients aged<65 years. The majority of deaths were reported in patients with AL CA (n=19/24, 79%). Independent variables associated with in-hospital mortality were cardiogenic shock and uraemia level. N-terminal prohormone of B-type natriuretic peptide (NT-proBNP) concentration obtained in a stable haemodynamic state was the only predictor of short-term evolution to cardiogenic shock (odds ratio: 8.7, 95% confidence interval: 2.2-34.6), with an optimal cut-off of 4040pg/mL (sensitivity=92%; specificity=81%). CONCLUSIONS: The study confirms the dramatic mortality associated with CA when presenting as cardiogenic shock and underlines the limited efficiency of conventional treatments. Given the rapid occurrence of death in a young population, an alternative strategy to dobutamine support should be investigated in patients with elevated NT-proBNP concentration. PMID- 29709422 TI - Arthroscopic Subtalar Arthrodesis: Does the Type of Fixation Modify Outcomes? AB - The goal of the present study was to analyze a modified American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot scale score, time to union, and the incidence of fusion after isolated arthroscopic posterior subtalar arthrodesis using either 1 or 2 screws of different diameters. We reviewed a consecutive series of 65 patients, mean age 50.0 +/- 15.6 years, including 38 males (58.5%) and 27 females (41.5%), who had undergone arthrodesis from May 2004 to February 2011. The mean follow-up duration was 57.5 (range 24 to 105) months. The patients were divided into 3 groups according to the fixation method used: group 1 (n = 12; 18.5%) underwent fixation with one 6.5-mm screw; group 2 (n = 40; 61.5%) with one 7.3-mm screw; and group 3 (n = 13; 20%) with two 7.3-mm screws. An overall statistically significant (p <.0001) improvement was seen in the modified AOFAS scale score for all 3 fixation groups; however, the difference was not statistically significant (p = .79) among the fixation groups. Fusion was achieved in 62 patients (95.4%) after a mean of 12.1 (range 9 to 16) weeks. The difference in the time to union was not statistically significant (p = .781) among the fixation groups. Nine patients (13.8%) experienced complications, and nonunion was significantly (p = .005) more prevalent in the single 6.5-mm screw group. In conclusion, all 3 screw configurations led to improved modified AOFAS scale scores, although nonunion was more common among patients fixed with a single 6.5-mm screw. PMID- 29709423 TI - Basic and clinical aspects of antimuscarinic agents used to treat overactive bladder. AB - Antimuscarinic agents are now widely used as the pharmacological therapy for overactive bladder (OAB) because neuronal (parasympathetic nerve) and non neuronal acetylcholine play a significant role for the bladder function. In this review, we will highlight basic and clinical aspects of eight antimuscarinic agents (oxybutynin, propiverine, tolterodine, solifenacin, darifenacin, trospium, imidafenacin, and fesoterodine) clinically used to treat urinary dysfunction in patients with OAB. The basic pharmacological characteristics of these eight antimuscarinic agents include muscarinic receptor subtype selectivity, functional bladder selectivity, and muscarinic receptor binding in the bladder and other tissues. The measurement of drug-receptor binding after oral administration of these agents allows for clearer understanding of bladder selectivity by the integration of pharmacodynamics and pharmacokinetics under in vivo conditions. Their central nervous system (CNS) penetration potentials are also discussed in terms of the feasibility of impairments in memory and cognitive function in elderly patients with OAB. The clinical aspects of efficacy focus on improvements in the daytime urinary frequency, nocturia, bladder capacity, the frequency of urgency, severity of urgency, number of incontinence episodes, OAB symptom score, and quality of life (QOL) score by antimuscarinic agents in patients with OAB. The safety of and adverse events caused by treatments with antimuscarinic agents such as dry mouth, constipation, blurred vision, erythema, fatigue, increased sweating, urinary retention, and CNS adverse events are discussed. A dose dependent relationship was observed with adverse events, because the risk ratio generally increased with elevations in the drug dose of antimuscarinic agents. Side effect profiles may be additive to or contraindicated by other medications. PMID- 29709424 TI - Preclinical pharmacokinetics of a recombinant humanized rabbit anti-VEGF monoclonal antibody in rabbits and monkeys. AB - TMAB001 is a humanized rabbit monoclonal antibody (mAb) designed to bind and neutralize human vascular endothelial growth factor (VEGF)-165. The purpose of the study was to investigate the pharmacokinetics (PK) and ocular tissue distribution after a single intravitreal (IVT) dose in rabbits and monkeys. Rabbits (2.5 mg/eye; n = 40) and monkeys (2.5 mg/eye; n = 12) received TMAB001 as a bilateral IVT dose. TMAB001 concentrations were measured in ocular tissues in all rabbits and monkeys by enzyme-linked immunosorbent assay (ELISA). TMAB001 and VEGF concentrations were measured in serum of monkeys by ELISA. Following a single bilateral IVT injection of TMAB001 2.5 mg/eye, the highest concentration was in vitreous humor, followed by retina and choroid, and the lowest concentration was in lens. In rabbits, TMAB001 was still detectable in ocular tissues at day 21 after single IVT dose, with the highest level in the vitreous humor and then retina, with longest t1/2 in aqueous humor and shortest t1/2 in choroid. In monkeys, tmax in serum was 43 h and t1/2 was approximately 5.5 days. Cmax in serum was much lower than that in vitreous, nearly 1/200. After IVT injection of TMAB001, total VEGF concentrations in serum and ocular tissues increased over time. VEGF concentration in retina and choroid increased over time, up to 336 h after administration. This study demonstrated that TMAB001 could reach the drug target sites-retina and choroid after a single bilateral IVT administration in rabbits and monkeys, with a long t1/2 in vitreous humor. TMAB001 also showed strong capability to neutralize VEGF. The study further confirmed that full-length antibodies can also efficiently diffuse and distribute in ocular tissues. PMID- 29709425 TI - A study of inter-individual variability in the Phase II metabolism of xenobiotics in human skin. AB - Understanding skin metabolism is key to improve in vitro to in vivo extrapolations used to inform risk assessments of topically applied products. However, published literature is scarce and usually covers a limited and non representative number of donors. We developed a protocol to handle and store ex vivo skin samples post-surgery and prepare skin S9 fractions to measure the metabolic activity of Phase II enzymes. Preincubation of an excess of cofactors at 37 degrees C for fifteen minutes in the S9 before introduction of the testing probe, greatly increased the stability of the enzymes. Using this standardised assay, the rates of sulphation (SULT) and glucuronidation (UGT) of 7 hydroxycoumarin, methylation (COMT) of dopamine and N-acetylation (NAT) of procainamide were measured in the ng/mg protein/h (converted to ng/cm2/h) range in eighty-seven individuals. Glutathione conjugation (GST) of 1-chloro-2,4 dinitrobenzene was assessed in a smaller pool of fifty donors; the metabolic rate was much faster and measured over six minutes using a different methodology to express rates in MUg/mg protein/min (converted to MUg/cm2/min). A comprehensive statistical analysis of these results was carried out, separating donors by age, gender and metabolic rate measured. PMID- 29709426 TI - The activation of STIM1 mediates S-phase arrest and cell death in paraquat induced acute lung intoxication. AB - Calcium signaling and oxidative stress are tightly linked to cell cycle and cell death in response to a number of stress conditions. Recent study indicated that stromal interaction molecule 1 (STIM1) is the endoplasmic reticulum calcium sensor. However, the regulatory mechanisms and the role of STIM1 in paraquat (PQ) induced acute lung intoxication remain elusive. The aim of this study was to explore the molecular and cellular mechanisms of PQ induced acute intoxication in the lung, and further determine whether calcium signaling and reactive oxygen species (ROS) participate in the regulatory mechanism. Our data demonstrated that PQ (500 MUM, 24 h) induced intracellular ROS production and enhanced store operated calcium entry (SOCE) activity which is correlated to STIM1 activation. In addition, PQ (500 MUM, 24-48 h) caused accelerated cell cycle G1/S transition and then arrested in S phase. While knock-outing STIM1 by CRISPR-CAS9 in 16HBE or inhibiting STIM1 mediated SOCE activation ameliorated cell death caused by acute PQ treatment, which also leaded to alleviating the cell accumulation in S phase through the modulation the expression of cyclinD1, p21, cyclinA2 and CDK2. In conclusion, STIM1 plays an important role in PQ induced cell cycle arrest and cell death in acute lung injury, which may provide us a new potential opportunity to target paraquat induced intoxication. PMID- 29709428 TI - Developmental outcome in a group of twins: Relation to perinatal factors and general movements. AB - BACKGROUND: The quality of general movements (GMs) has proven to have predictive value for the developmental outcome, but this has not yet been studied in twins. AIMS: Our aim was to analyse the quality of GMs and neurological and developmental outcome in relation to the gestational age (GA), mode of conception and other perinatal risk factors in a group of twins. STUDY DESIGN: The documentation of twins referred for follow-up in the period from 1998 to 2016 was studied retrospectively. Data concerning the quality of GMs, perinatal risk factors and developmental outcome were analysed. SUBJECTS: Eighty-nine twin pairs, GA from 24 to 38 weeks (median 35.0; IQR 3), birth weight 670 g-3820 g (median 2323; IQR 645) were included. OUTCOME MEASURES: Results of neurological, psychological and speech/language development and school outcome were analysed. RESULTS: GMs at term age and at three to four months postterm age did not differ with regard to the mode of conception. Preterm birth was significantly related to GMs at three to four months postterm age. At term age, GMs were significantly related to neurological outcome, while at three to four months postterm age, GMs were related to both the neurological and psychological outcome. Difficulties in speech/language development were diagnosed in almost half of the children, more frequently in boys and children with lower Apgar scores. CONCLUSION: The study highlights the value of GMs for predicting the developmental outcome in twins and indicates the importance of developmental, especially speech/language, follow-up in twins. PMID- 29709429 TI - Mild ventriculomegaly from fetal consultation to neurodevelopmental assessment: A single center experience and review of the literature. AB - OBJECTIVE: The aim of our study was to determine the outcome of fetuses with isolated mild ventriculomegaly, with prenatal imaging work-up, prenatal consultation, delivery and clinical follow-up performed in a single tertiary referring center. METHODS: Fetuses with isolated and non-progressive mild ventriculomegaly (10-15 mm) were included in the study. Inclusion criteria were as follows: singleton pregnancies, normal chromosomal analysis, normal serological evaluation of TORCH, fetal ultrasound and MRI excluding additional CNS or extra-CNS malformations. The prenatal consultation consisted in discussing the prognosis of ventriculomegaly, according to the literature. The postnatal follow-up protocol included a neuroradiological investigation (cranial ultrasound or MRI), neurological and pediatric examinations. The Griffiths Scales were used to assess the neurodevelopmental outcome. RESULTS: Thirty newborns were included in follow-up. The postnatal neuroradiological investigations confirmed the ventriculomegaly as an isolated finding in all cases except one. Nineteen children were available for formal neurodevelopmental testing. In our case series, 93.3% of the children had a favorable outcome or mild anomalies. Two children (6.6%) with mild ventriculomegaly were diagnosed as having rare genetic conditions. The Griffiths developmental quotients were normal (mean General Quotient 98.3) at the latest assessment (mean age 20.8 months) in all but one case. DISCUSSION: Most children in our case series had a favorable outcome, as described in the literature. Even though a large quantity of data is now available on ventriculomegaly, fetal consultation remains challenging and requires caution. The diagnostic work-up of pregnancies diagnosed with mild ventriculomegaly must be very meticulous and include TORCH evaluation, microarray, serial ultrasounds to exclude progression, and a fetal MRI. However, despite accurate screening, there are more complex conditions in which ventriculomegaly can be the only non-specific finding in fetal life, making postnatal follow up mandatory. PMID- 29709427 TI - ABCC6 mutations and early onset stroke: Two cases of a typical Pseudoxanthoma Elasticum. AB - Pseudoxanthoma elasticum (PXE) is a rare genetic disorder characterized by fragmented and mineralized elastic fibers in the mid-dermis of the skin, eye, digestive tract and cardiovascular system. Clinical presentation includes typical skin lesions, ocular angioid streaks, and multisystem vasculopathy. The age of onset varies considerably from infancy to old age, but the diagnosis is usually made in young adults due to frequent absence of pathognomonic skin and ocular manifestations in early childhood. We report two children with PXE presenting with isolated multisystem vasculopathy and early-onset stroke. In the first patient, diagnosis was delayed until typical dermatologic alterations appeared; in the second patient, next-generation sequencing (NGS) study led to early diagnosis and specific follow-up, underlying the crucial role in idiopathic pediatric stroke of early genetic testing using NGS-based panels. PMID- 29709430 TI - Evaluation of anatomical and round breast implant aesthetics and preferences in Dutch young lay and plastic surgeon cohort. AB - BACKGROUND: Literature remains inconclusive on the attractiveness and natural aspect of anatomical breast implants, and thus far, studies have failed to demonstrate the visible difference in implants that are in practice compared to those that are round. This study was undertaken to evaluate (1) whether lay and professional participants can distinguish between breasts augmented with either round or anatomical breast implants and (2) their opinion with regard to naturalness and attractiveness of these augmented breasts. METHODS: Twenty breast augmentations (10 anatomical and 10 round implants), each depicted by two postoperative pictures, were scored by 100 lay participants and 15 plastic surgeons. Implant volume ranged from 275 to 400 g. Ptotic or malformed breasts were excluded. Finally, they had to score the most natural, unnatural, attractive, and unattractive breast shapes on a schematic depiction of breast types with varying upper poles. RESULTS: The rate of correct implant identifications was 74.0% (1480/2000 observations, p < 0.001) in the lay and 67.3% (202/300 observations, p < 0.001) in the surgeon cohort. Breasts with anatomical implants were rated as significantly more natural (3.3 +/- 1.0 vs. 2.6 +/- 1.0, p < 0.001 and 3.3 +/- 1.0 vs. 2.2 +/- 0.9, p < 0.001, respectively) and more attractive (3.1 +/- 1.0 vs. 2.6 +/- 1.0, p < 0.001 and 3.6 +/- 0.9 vs. 2.7 +/- 0.9, p < 0.001, respectively) versus round implants by both lay participants and surgeons. Participants preferred breasts with a neutral or slightly negative upper pole contour. CONCLUSION: Participants were able to distinguish between the results achieved with either anatomical or round textured Allergan breast implants and found augmented breasts with the anatomical implants more natural and attractive. PMID- 29709431 TI - Women's experience of midwife-led counselling and its influence on childbirth fear: A qualitative study. AB - BACKGROUND: Women with childbirth fear have been offered counseling by experienced midwives in Sweden for decades without evidence for its effectiveness, in terms of decrease in childbirth fear. Women are usually satisfied with the counselling. However, there is a lack of qualitative data regarding women's views about counselling for childbirth fear. AIM: To explore women's experiences of midwife-led counselling for childbirth fear. METHOD: A qualitative interview study using thematic analysis. Twenty-seven women assessed for childbirth fear who had received counselling during pregnancy at three different hospitals in Sweden were interviewed by telephone one to two years after birth. FINDINGS: The overarching theme 'Midwife-led counselling brought positive feelings and improved confidence in birth' was identified. This consisted of four themes describing 'the importance of the midwife' and 'a mutual and strengthening dialogue' during pregnancy. 'Coping strategies and support enabled a positive birth' represent women's experiences during birth and 'being prepared for a future birth' were the women's thoughts of a future birth. CONCLUSIONS: In this qualitative study, women reported that midwife-led counselling improved their confidence for birth through information and knowledge. The women experienced a greater sense of calm and preparedness, which increased the tolerance for the uncertainty related to the birthing process. This, in turn, positively affected the birth experience. Combined with a feeling of safety, which was linked to the professional support during birth, the women felt empowered. The positive birth experience strengthened the self-confidence for a future birth and the childbirth fear was described as reduced or manageable. PMID- 29709432 TI - Veiled midwifery in the baby factory - A grounded theory study. AB - BACKGROUND: Midwives' professional role has been changing drastically over time, from handling births in home settings to being part of a team in labour wards in hospitals. This demands a greater effort of interprofessional collaboration in childbirth care. AIM: Explore midwives' work in a hospital-based labour ward from the perspectives of other professions, working in the same ward. METHOD: Classical grounded theory, using a constant comparative analysis, was applied to focus group interviews with obstetricians, assistant nurses and managers to explore their views of midwifery work during childbirth. FINDINGS: The substantive theory of 'veiled midwifery' emerged as an explanation of the social process between the professions in the 'baby factory' context. The other professionals perceive midwifery through a veil that filters the reality and only permits fragmentary images of the midwives' work. The main concern for the other professions was that the midwives were 'marching to own drum'. The midwives were perceived as both in dissonance with the baby factory, and therefore hard to control, or, alternatively more compliant with the prevailing rhythm. This caused an unpredictability and led to feelings of frustration and exclusion. Which in turn resulted in attempts to cooperate and gain access to the midwifery world, by using three unveiling strategies: Streamlining, Scrutinising and Collaborating admittance. CONCLUSIONS: Findings provide a theoretical conceptualisation of a 'veiled midwifery 'that causes problems for the surrounding team. This generates a desire to streamline and control midwifery in order to increase interprofessional collaboration. PMID- 29709433 TI - Low Serum Testosterone is Present in Nearly Half of Men Undergoing Artificial Urinary Sphincter Placement. AB - OBJECTIVES: To report the prevalence of low serum testosterone (LST) in men undergoing artificial urinary sphincter (AUS) placement at a single high-volume institution. METHODS: We retrospectively reviewed all men undergoing AUS procedures by a single surgeon from January 2015 to January 2018 to identify men with pretreatment total serum testosterone levels. LST was defined as less than 280 ng/dL. Patients with only posttreatment testosterone levels were excluded. Demographic characteristics and clinical outcomes were compared between men with and without LST. RESULTS: Among 113 patients who underwent AUS with pretreatment serum testosterone levels drawn an average of 2.2 months before AUS surgery, 45.1% (51 of 113) met criteria for LST, including 18 patients on androgen deprivation therapy. The rate of primary LST was 34.7% (33 of 95). The median total serum testosterone level among men with LST was 118 ng/dL (interquartile range 6-211), and 413 mg/dL (interquartile range 333-550) in the normal serum testosterone group. There were no differences in patient age, history of radiation, erectile dysfunction, or other comorbidities between the groups. Body mass index was higher in the LST group compared to normal serum testosterone (30 vs 27 kg/m2, P = .001). Cuff size and rates of transcorporal cuff placement were similar between groups. CONCLUSION: Nearly one-half of men with stress urinary incontinence undergoing AUS placement present with LST. While AUS cuff erosion appears to be more common in men with LST, further study is needed to determine if treating LST will reduce cuff erosion rates. PMID- 29709434 TI - No Effect of Music on Anxiety and Pain During Transrectal Prostate Biopsies: A Randomized Trial. AB - OBJECTIVE: To investigate the effect of ambient music on anxiety and pain in men undergoing prostate biopsies. MATERIALS AND METHODS: Between September 2015 and June 2016, men undergoing office transrectal prostate biopsy at our institution were randomly assigned to music (n = 85) or control (n = 97) groups. We examined clinical characteristics, pathologic variables, and baseline anxiety using the Trait Instrument of State-Trait Anxiety Inventory. Primary outcomes included anxiety assessed by State Instrument of STAI (STAI-S) and pain using a visual analog scale. RESULTS: There were no significant differences in baseline characteristics between the music and control groups, including median age, prostate-specific antigen, use of magnetic resonance imaging-guided biopsies, or Trait Instrument of State-Trait Anxiety Inventory. The majority (93%) of patients indicated they desired music in their prebiopsy survey. There were no significant differences in STAI-S (33.7 +/- 8.9 vs 34.4 +/- 9.9, P = .6), pain score (2.3 +/- 2.1 vs 2.0 +/- 2.1, P = .3), or vital signs between the music and control groups, respectively. There were also no differences in STAI-S, visual analog scale, or vital signs between groups when stratified by age, prostate-specific antigen, or number of previous biopsies. Men who received music were more likely to request music for future prostate biopsy, compared to men who did not (93% vs 83%, P = .07, respectively). CONCLUSION: This randomized study showed no difference in anxiety or pain scores for patients who had ambient music during transrectal prostate biopsy. Future studies are needed to discern the influence of details including method of music delivery, music type, and utilization of adjunct relaxation tools. PMID- 29709435 TI - Arterial Fistula With Severe Hematuria After Ileal Conduit Diversion. AB - Iliac-urinary fistula is a rare cause of severe hematuria after urinary diversion. Indwelling stents and advanced atherosclerosis may be risk factors. Angiography with embolization is usually resolutive. PMID- 29709436 TI - Extracorporeal Membrane Oxygenation: Beyond Cardiac Surgery and Intensive Care Unit: Unconventional Uses and Future Perspectives. AB - Extracorporeal membrane oxygenation (ECMO) is used with increasing frequency to treat severe cardiac or respiratory failure as it can provide respiratory only or combined circulatory and respiratory support. Despite efforts aimed at increasing its diffusion however, ECMO is currently reserved, usually as last resort, in very severe cases, which are managed almost exclusively in the intensive care unit (ICU). Recent improvements in both technology and patients' management is leading to constant improvement in patients' outcome, especially in centers with a high caseload volume and after ensuring careful patients' selection. Moreover, since short ECMO runs are associated with limited complications, there are now several potential situations outside the ICU and outside the cardiac surgery setting where ECMO is being (or could be) successfully employed to provide cardio respiratory support, including: high-risk structural heart interventions, ventricular tachycardia ablation, cesarean section, trauma, and, most interestingly, non-cardiac elective procedures in patients at high risk for perioperative cardiac or respiratory complications. Given the increased availability and the good outcomes of ECMO, when carefully employed, we are thus moving towards a future in which no patient should be denied diagnostic or therapeutic procedure exclusively due to high cardiorespiratory risk. PMID- 29709437 TI - The Effects of an Open-Lung Approach During One-Lung Ventilation on Postoperative Pulmonary Complications and Driving Pressure: A Descriptive, Multicenter National Study. AB - OBJECTIVE: Thoracic surgical procedures are associated with an increased risk of postoperative pulmonary complications (PPCs), which seem to be related directly to intraoperative driving pressure. The authors conducted this study to describe the incidence of PPCs in patients in whom an individualized open-lung approach was applied during one-lung ventilation. DESIGN: This was a prospective, multicenter, national descriptive study. SETTING: Thoracic surgery patients undergoing one-lung ventilation. PARTICIPANTS: Eligible participants were included consecutively from October 1, 2016, to September 30, 2017. A total of 690 patients were included. INTERVENTIONS: An individualized open-lung approach that consisted of an alveolar recruitment maneuver followed by a positive end expiratory pressure adjusted to best respiratory system compliance was performed in all patients. MEASUREMENTS AND MAIN RESULTS: Preoperative and intraoperative data were recorded; the primary outcome was a description of the incidence of PPCs in these patients during the first 7 postoperative days. The patients were mainly male, and half of them had a high risk of PPCs (ARISCAT score exceeding 44). Eleven percent of participants developed a PPC within the first postoperative week. The mean open lung positive end-expiratory pressure was 8 +/- 3 cmH2O. When compared with pre-open lung approach values, the open-lung approach significantly decreased the driving pressure (14 +/- 4 cmH2O v 11 +/- 3 cmH2O; p < 0.001) and increased dynamic compliance (30 +/- 10 mL/cmH2O v 43 +/-15 mL/cmH2O; p < 0.001). CONCLUSIONS: The low incidence of PPCs in patients who underwent an open-lung approach during one-lung ventilation compared with that reported for other thoracic surgery series and the decrease in the driving pressure in these patients justify an additional randomized controlled trial to compare the open-lung approach with the standard protective strategy of low tidal volume and low positive end-expiratory pressure. PMID- 29709438 TI - Bridgemanian space constancy as a precursor to extended cognition. AB - A few decades ago, cognitive psychologists generally took for granted that the reason we perceive our visual environment as one contiguous stable whole (i.e., space constancy) is because we have an internal mental representation of the visual environment as one contiguous stable whole. They supposed that the non contiguous visual images that are gathered during the brief fixations that intervene between pairs of saccadic eye movements (a few times every second) are somehow stitched together to construct this contiguous internal mental representation. Determining how exactly the brain does this proved to be a vexing puzzle for vision researchers. Bruce Bridgeman's research career is the story of how meticulous psychophysical experimentation, and a genius theoretical insight, eventually solved this puzzle. The reason that it was so difficult for researchers to figure out how the brain stitches together these visual snapshots into one accurately-rendered mental representation of the visual environment is that it doesn't do that. Bruce discovered that the brain couldn't do that if it tried. The neural information that codes for saccade amplitude and direction is simply too inaccurate to determine exact relative locations of each fixation. Rather than the perception of space constancy being the result of an internal representation, Bruce determined that it is the result of a brain that simply assumes that external space remains constant, and it rarely checks to verify this assumption. In our extension of Bridgeman's formulation, we suggest that objects in the world often serve as their own representations, and cognitive operations can be performed on those objects themselves, rather than on mental representations of them. PMID- 29709439 TI - Vasodilator effects and putative guanylyl cyclase stimulation by 2-nitro-1 phenylethanone and 2-nitro-2-phenyl-propane-1,3-diol on rat aorta. AB - Compounds containing a nitro group may reveal vasodilator properties. Several nitro compounds have a NO2 group in a short aliphatic chain connected to an aromatic group. In this study, we evaluated in rat aorta the effects of two nitro compounds, with emphasis on a putative recruitment of the soluble guanylate cyclase (sGC) pathway to induce vasodilation. Isolated aortic rings were obtained from male Wistar rats to compare the effects induced by 2-nitro-1-phenylethanone (NPeth) or 2-nitro-2-phenyl-propane-1,3-diol (NPprop). In aortic preparations contracted with phenylephrine or KCl, NPeth and NPprop induced vasorelaxant effects that did not depend on the integrity of vascular endothelium. NPeth had a lesser vasorelaxant efficacy than NPprop and only the NPprop effects were inhibited by pretreatment with the sGC inhibitors, 1H-[1,2,4]oxadiazolo[4,3 a]quinoxalin-1-one (ODQ) or methylene blue. In an ODQ-preventable manner, NPprop inhibited the contractile component of the phenylephrine-induced response mediated by intracellular Ca2+ release or by extracellular Ca2+ recruitment through receptor- or voltage-operated Ca2+ channels. In contrast, NPprop was inert against the transient contraction induced by caffeine in Ca2+-free medium. In an ODQ-dependent manner, NPprop inhibited the contraction induced by the protein kinase C activator phorbol 12,13-dibutyrate or by the tyrosine phosphatase inhibitor sodium orthovanadate. In silico docking analysis of a sGC homologous protein revealed preferential site for NPprop. In conclusion, the nitro compounds NPeth and NPprop induced vasorelaxation in rat aortic rings. Aliphatic chain substituents selectively interfered in the ability of these compounds to induce vasorelaxant effects, and only NPprop relaxed aortic rings via a sGC pathway. PMID- 29709440 TI - The 2018 ISHLT/APM/AST/ICCAC/STSW recommendations for the psychosocial evaluation of adult cardiothoracic transplant candidates and candidates for long-term mechanical circulatory support. AB - The psychosocial evaluation is well-recognized as an important component of the multifaceted assessment process to determine candidacy for heart transplantation, lung transplantation, and long-term mechanical circulatory support (MCS). However, there is no consensus-based set of recommendations for either the full range of psychosocial domains to be assessed during the evaluation, or the set of processes and procedures to be used to conduct the evaluation, report its findings, and monitor patients' receipt of and response to interventions for any problems identified. This document provides recommendations on both evaluation content and process. It represents a collaborative effort of the International Society for Heart and Lung Transplantation (ISHLT) and the Academy of Psychosomatic Medicine, American Society of Transplantation, International Consortium of Circulatory Assist Clinicians, and Society for Transplant Social Workers. The Nursing, Health Science and Allied Health Council of the ISHLT organized a Writing Committee composed of international experts representing the ISHLT and the collaborating societies. This Committee synthesized expert opinion and conducted a comprehensive literature review to support the psychosocial evaluation content and process recommendations that were developed. The recommendations are intended to dovetail with current ISHLT guidelines and consensus statements for the selection of candidates for cardiothoracic transplantation and MCS implantation. Moreover, the recommendations are designed to promote consistency across programs in the performance of the psychosocial evaluation by proposing a core set of content domains and processes that can be expanded as needed to meet programs' unique needs and goals. PMID- 29709441 TI - State of the Research Enterprise in IR and Recommendations for the Future: Proceedings from the Society of Interventional Radiology Foundation Investigator Development Task Force. PMID- 29709442 TI - Gas chromatography coupled with mass spectrometry-based metabolomics for the classification of tempe from different regions and production processes in Indonesia. AB - Tempe, a fermented soybean originally from Indonesia, is an excellent protein source with high nutritional quality. Differences in the production process and unique fermentation condition in different regions result in varieties of tempe. Despite its high cultural and economic values, there are very few studies on the characterization of tempe based on the differences of production process and geographical origin. Metabolomics is a powerful tool assessing food quality, food safety, and determination of origin and varietal differences. In this study, metabolomics is applied for the study of Indonesian tempe obtained from various regions and different production processes. Seventeen samples were collected from 6 different cities in Java Island, which were produced by local tempe crafters (traditional), semi-modern industry and modern industry. Untargeted metabolomics by gas chromatography coupled with mass spectrometry (GC/MS) was implemented to discriminate various kinds of tempe and identify metabolites that are associated with these differences. Results showed that tempe produced in different places clustered together according to the cities and their production category. Sugars and amino acids groups were found to be primary compounds that contributed to this result. This is the first report that address the metabolic differences between different varieties of tempe from different regions and production processes. The knowledge from this study is important for future development of tempe production. PMID- 29709443 TI - Upregulation of LncRNA FEZF-AS1 is associated with advanced clinical stages and family history of cancer in patients with NSCLC. AB - Antisense RNA (AS) is a type of long non-coding RNAs that functions as a post transcriptional regulatory element on regulating parental coding gene expression via directly binding to complementary mRNA sequences. We aimed to investigate the effect of the AS to FEZF1 gene on non-small cell lung cancer (NSCLC) development. The expression level of lncRNA FEZF-AS1 and FEZF1 was determined by the quantitative Real-time PCR in 160 cases of NSCLC tissues and their adjacent non tumour tissues. We found that lncRNA FEZF-AS1 was significantly up-regulated in tumour tissues when compared to the adjacent non-cancerous tissues (P = 0.001), and it's high expression correlated with advanced stages (P = 0.002) and Tumour Family History (P = 0.029). Meanwhile, In 58 cases of NSCLC tissues the expression of lncRNA FEZF-AS1 was positively associated with that of FEZF1expression (r = 0.8810, p = 1.6575E-20). By GEPIA database analysis, we also found that the expression of lncRNA FEZF-AS1 and FEZF1 were significantly higher in tumour tissues than those of the adjacent non-cancerous tissues in 969 NSCLC patients (P < 0.05), and lncRNA FEZF-AS1 was positively correlated with FEZF1 (r = 0.90, P < 0.001). These results suggest that lncRNA FEZF-AS1 relate to the progression of lung cancer patients and it may be a potential target for cancer therapy. PMID- 29709444 TI - Food Choice Drivers in the Context of the Nutrition Transition in Delhi, India. AB - OBJECTIVE: To understand factors that influence the process of food decision making among urban Indian women in the context of the nutrition transition. DESIGN: Mixed methods. METHODS: Semistructured interviews and sorting of 12 a priori hypothesized drivers into categories of always, sometimes, and never influencing food choice. SETTING: Delhi, India. PARTICIPANTS: Thirty-eight women aged 20-35 years selected from the roster of a prospective cohort study. PHENOMENON OF INTEREST: Drivers of food choice. ANALYSIS: Interviews were transcribed verbatim and translated, then analyzed using an iterative, constant comparative process. Differences in pile sort rankings across tertiles of body mass index and wealth index were tested using Fisher exact tests. RESULT: Four primary themes emerged: (1) family influence; (2) cultural perceptions, with 3 subthemes of beliefs relating to (a) outside food and less healthful food, (b) seasonality, and (c) hometown food; (3) convenience, with 3 subthemes of (a) decisions regarding procurement of food, (b) not having time to cook, resulting in eating out or purchasing premade foods, and (c) eating whatever is available at home or is left over from previous meals; and (4) habit, with 2 subthemes of (a) subconscious decisions and (b) food roots. Responses from the pile sort activity revealed perceptions that food safety and health most influence food choice whereas marketing and advertisements least influence it. CONCLUSIONS AND IMPLICATIONS: Young adult women in Delhi seem to rely on preferences of their families, habits and perceptions established in childhood, convenience, and food safety and health when making choices about food. These aspects of decision making should be targeted in future interventions aimed at improving dietary intake in this population. PMID- 29709445 TI - Predominant bacteria and patterns of antibiotic susceptibility in urinary tract infection in children with spina bifida. AB - BACKGROUND: Urinary tract infection is more common in children with spina bifida (SB) than neurologically intact children, and Escherichia coli is the most common urinary pathogen in the general pediatric population. Less is known of the pathogens responsible for urinary tract infections (UTI) in the pediatric SB population or their evolving antimicrobial resistance patterns. The goal of this study is to determine the epidemiology and antimicrobial resistance patterns of SB-associated urinary pathogens. METHODS: Between January 1996 and August 2013, 231 patients aged 1 month to 18 years were identified with a diagnosis of SB-NB and at least one symptomatic urinary tract infection (UTI) event (Table). Two hundred and thirty-one normally voiding children with a single symptomatic UTI were age-matched based on age at diagnosis of UTI at a 1:1 ratio. Chi-square tests and Generalized Estimating Equation analysis, controlling for clinicopathological factors, were performed to compare rates of pathogen associations with UTI between groups and likelihood of UTI with multi-drug resistant (MDR) organisms. RESULTS: Children in the SB-NB group had a higher rate of non-E. coli UTI compared with controls (64% vs. 41%, p < 0.01), particularly associated with Klebsiella species the SB-NB group had an overall higher infection rate with MDR organisms (21% vs. 10%, p < 0.01) and E. coli isolates, with a trend towards increased rates of antibiotic resistance to aminoglycosides, fluoroquinolones, cephalosporins, extended spectrum beta-lactams, and TMP-SMZ. Additionally, patients in the SB-NB group had a 10-fold increase of urosepsis with 57% of events caused by MDR organisms. CONCLUSIONS: Children with SB-NB are more likely to have non-E. coli UTI, UTIs with MDR organisms, and urosepsis than the general pediatric population. PMID- 29709446 TI - The effect of exercise on vaccine-related pain, anxiety and fear during HPV vaccinations in adolescents. AB - INTRODUCTION: With increased school-based vaccinations for improved coverage rates and practicality, the World Health Organization (WHO) recently endorsed research to identify possible interventions to reduce vaccine-related pain in mass clinical and school-based settings. In particular, the lack of research in adolescents indicate a particular need in this population. Acute exercise has analgesic effects and has been used as a behavioural adjuvant to vaccination. Here, we examine the effect of exercise on vaccine-related pain, anxiety and fear in adolescents, during a school-based program for HPV vaccinations. METHODS: 116 students (Female: 61, Male: 55) aged 11-13 years were randomly allocated to either an Exercise (n = 60) or Control (n = 56) group. All participants completed demographic and Trait-anxiety questionnaires prior to receiving the vaccine according to usual care. The Exercise group also performed upper body exercise for 15 min prior to receiving the vaccine. Immediately after the vaccine administration, all participants reported on pain, anxiety and fear at the time of receiving the vaccine. RESULTS: Female adolescents in the Exercise group reported significantly less pain (3.64; 95% CI, 2.98-4.30) than Controls (4.58; 95% CI, 3.96-5.19; p = 0.04). Further, females reported greater pain and anxiety than males in the Control group but not the Exercise group. CONCLUSION: This study supports the use of exercise prior to vaccine administration, especially in female adolescents who are particularly vulnerable to negative experiences during vaccination procedures. Furthermore, the ease of application, as well as the benefit of exercise, provides support for the use of simple exercise prior to vaccination in mass vaccination settings. Clinical trial registry: ANZCTR, ACTRN12614001185651. PMID- 29709447 TI - A Phase III randomised trial of the immunogenicity and safety of quadrivalent versus trivalent inactivated subunit influenza vaccine in adult and elderly subjects, assessing both anti-haemagglutinin and virus neutralisation antibody responses. AB - BACKGROUND: Trivalent influenza vaccines (TIVs) offer substantial protection against matching B-strains, however, protection against alternate-lineage B strains may be enhanced by adding a second B-strain in quadrivalent influenza vaccines (QIVs). In this Phase III, double-blind, multicentre, randomised study, the immunogenicity and safety of subunit inactivated QIV versus TIV was assessed in adult (aged >=18 to <=60 years) and elderly (aged >=61 years) subjects by analysing a combination of haemagglutinin inhibition (HI) and virus neutralisation (VN). METHODS: Subjects (n = 1980) were recruited off season (2015/2016) from 20 centres in five European countries and randomised to receive either QIV (n = 1538), TIV with B-strain of the Victoria lineage (n = 221) or TIV with B-strain of the Yamagata lineage (n = 221). The primary aim was to demonstrate non-inferiority of QIV to TIV for immunogenicity against matched influenza strains based on post-vaccination HI titres. Secondary aims were to show superiority of QIV to TIV for immunogenicity against alternate-lineage B strains and to characterise the immune response by reverse cumulative distribution (RCD) curves of antibody titres and derived serological parameters for HI and VN. Reactogenicity and occurrence of adverse events were assessed post vaccination. RESULTS: QIV elicited a non-inferior immune response for matched strains (upper limit of 95% CI for HI geometric mean ratios [GMRs] <1.5) and a superior response for alternate-lineage B-strains (HI GMRs < 1; p < 0.0001) versus TIV. RCD curves demonstrated that post-vaccination HI and VN titres were higher for QIV versus TIV for both alternate-lineage B-strains. Seroconversion rates and geometric mean fold increases of the VN assay were consistent with the HI assay for all strains in QIV. Reporting rates of local and systemic reactions were similar in both vaccine groups. CONCLUSIONS: QIV was non-inferior in immunogenicity to TIV for matched strains and superior to the alternate-lineage B strains in TIV. Safety and tolerability profiles of QIV and TIV were comparable. PMID- 29709448 TI - Evaluation of the association of pneumococcal conjugate vaccine immunization and density of nasopharyngeal bacterial colonization using a multiplex quantitative polymerase chain reaction assay. AB - BACKGROUND: Nasopharyngeal bacterial colonization is a pre-requisite for developing bacterial mucosal and invasive disease. Pneumococcal conjugate vaccine (PCV) immunization of children reduces their risk of colonization by vaccine serotypes, which could affect the biome of the nasopharynx in relation to colonization by other bacteria. This study evaluated the association of PCV immunization on the prevalence density of nasopharyngeal colonization by common, potentially pathogenic bacteria. METHODS: A multiplex qPCR assay was used to evaluate bacterial nasopharyngeal colonization by 7-valent PCV (PCV7) serotypes, non-vaccine serotypes (NVT), Haemophilus influenzae, Staphylococcus aureus, Moraxella catarrhalis, and Neisseria meningitidis in PCV7-vaccinated and PCV unvaccinated African children at two time points. RESULTS: PCV7 vaccination was associated with a higher prevalence of NVT and H. influenzae at 9 and 16 months, respectively. While the prevalence of S. aureus was higher in PCV7-vaccinated children at 9 months, no difference was found at 16 months. The density of PCV7 serotypes (3.8 vs. 3.4 log10; p = 0.048), NVT (3.6 vs. 3.1 log10; p = 0.018), H. influenzae (4.34 vs. 3.86 log10; p = 0.008), M. catarrhalis (3.52 vs. 2.98 log10; p < 0.001) and S. aureus (4.02 vs. 3.06 log10; p = 0.02) was higher among PCV vaccinated compared to PCV-unvaccinated children at 9 months, although, this difference diminished at 16 months of age. CONCLUSION: The reduction in PCV7 serotype colonization impacted on colonization prevalence and density of other bacterial species of the nasopharynx. The clinical relevance of this needs further exploration in relation to mucosal and invasive disease outcomes, as well as for higher valency PCV vaccines. PMID- 29709449 TI - Signalling mechanism(s) of epithelial-mesenchymal transition and cancer stem cells in tumour therapeutic resistance. AB - : Epithelial-mesenchymal transition (EMT) leads to tumour progression, including tumour metastasis, disease recurrence and therapy resistance. Cancer stem cells (CSCs) are a small group of cells that have the ability to undergo self-renewal and heterogeneous differentiation, which play a key role in the occurrence and development of cancer. EMT can promote tumour cells to develop stem cell characteristics, which makes tumours more difficult to treat. Therefore, exploring the role of EMT and CSCs in the metastasis of cancer is of great significance to guide tumour treatment and prognosis. In this review, we discuss EMT and CSCs in cancer progression and therapeutic resistance, with a special focus on the common characteristics and relationships between these processes, to explore the crucial relationships in the development of improved anti-tumour therapies. AREAS COVERED: In this brief review article, the author has searched PubMed and Wikipedia for original research and reviewed articles to gather current information on the association of CSCs and EMT with therapeutic resistance characteristics, cancer growth and metastasis, which are believed to be regulated by the TGF-beta, Wnt, Hedgehog (Hh), beta-catenin, STAT3, Notch, and Nanog signalling pathways and other factors (miRNAs, microenvironment and additional cytokines). PMID- 29709450 TI - The combination of 5 serum markers compared to FibroScan to predict significant liver fibrosis in patients with chronic hepatitis B virus. AB - BACKGROUND: We evaluated the performance of serum hyaluronan (HA), procollagen type III N-terminal peptide (PIIINP), type IV collagen (IVC), laminin (LN), alanine aminotransferase (ALT), and aspartate aminotransferase (AST), compared to transient elastography (FibroScan) in predicting significant liver fibrosis. METHODS: We therefore determined 4 serum fibrosis markers, FibroScan and liver biopsy in 70 consecutive adult patients with chronic hepatitis B. According to a modified Scheuer scoring system, significant fibrosis was defined as fibrosis stage >=S2. We compared serum fibrosis markers to histological staging and FibroScan results using Spearman correlation analysis and area under receiver operating characteristic (ROC) curves (AUROCs). RESULTS: Of the 212 patients who had the results of FibroScans and four serum fibrosis markers for HBV, 70 had concurrent liver biopsy. Significant liver fibrosis was found in 24/70 patients. The serum levels of HA, PIIINP, IVC, LN, ALT, AST was all positively correlated with fibrosis stage of Liver biopsy. The coefficients with stages were respectively 0.468, 0.392, 0.538, 0.213, 0.350, 0.375. There was a significant difference between mild fibrosis (=S2), excluding LN, in the levels of these 5 serum makers (P < .05). AUROC for FibroScans and HA, PIIINP, IVC, LN, ALT, AST to correctly allocate patients to histological fibrosis stage >= S2 was 0.866, 0.784, 0.738, 0.827, 0.630, 0.713 and 0.728 respectively. Since LN shows the worst performance of the others. We decided to check the performance of the combination of HA, PIIINP, CIV, ALT, AST, excluding LN, to distinguish fibrosis stages. The index of the histological fibrosis stage >= S2, combining the 5 serum markers, significantly improved diagnostic performance (AUROC = 0.861) compared to the use of 5 serum markers alone in all HBV patients. CONCLUSION: The combination of the 5 serum markers and FibroScan performed equally well in predicting significant fibrosis. The combination of the 5 serum markers is a reliable noninvasive method to predict significant liver fibrosis in patients with CHB. So, it provide another choice rather than FibroScan in predicting significant liver fibrosis. PMID- 29709451 TI - Development of an enzymatic assay to measure lactate in perchloric acid precipitated cerebrospinal fluid. AB - BACKGROUND: Individuals with inherited deficiencies of the pyruvate dehydrogenase complex or the respiratory chain complex can have increased concentrations of cerebrospinal fluid (CSF) lactate. Such measurements are clinical useful when measured in conjunction with pyruvate in order to calculate the lactate:pyruvate (L:P) ratio, a useful surrogate of cytosolic redox status. CSF pyruvate is measured in a protein-free supernatant prepared by the addition of CSF to perchloric acid while lactate is measured in untreated CSF. Utilizing the same sample for both lactate and pyruvate measurements is desirable. OBJECTIVE: To develop a method to measure lactate in perchloric-acid precipitated CSF and validate the L:P ratio as calculated from the analysis of both analytes in the same sample. METHODS: Samples were prepared by the addition of 1 mL CSF to 2 mL 8% (w/v) cold perchloric acid, incubated on ice for 10 min, then centrifuged to obtain a protein-free supernatant. Lactate was measured by its oxidation to pyruvate and hydrogen peroxide using lactate oxidase and the absorbance of the resulting chromogen determined at 540 nm on a Roche cobas c501 chemistry analyzer. Method accuracy, linearity, imprecision and sensitivity were determined and a reference interval was verified. RESULTS: To assess accuracy, this method was compared to lactate determined in unaltered CSF at another laboratory using 41 specimens with lactate concentrations from 0.6-11.9 mmol/L. Linear regression produced a slope of 1.09 and y-intercept of 0.26 (R2 = 1.00). Recovery was performed by ad-mixes of a high lactate standard and a CSF pool in different ratios to create a set of 19 samples prior to preparing protein-free supernatants. Recovery was 94.6-100% (mean +/- SD was 97.4 +/- 1.4%) at lactate concentrations of 2.68 to 12.63 mmol/L. Linearity was determined by combining two supernatants with low and high lactate concentrations in different ratios to create a set of six samples (0.15-12.70 mmol/L) that were tested in duplicate. Linear regression generated a slope of 1.01, y-intercept of -0.04 (R2 = 1.00). Precision was verified by analyzing quality control materials (acid-treated lactate standard) in 3 replicates each day for 5 days. Within-laboratory imprecision was 2.3% at 1.5 mmol/L and 1.5% at 10.5 mmol/L. The limit of blank was 0.05 mmol/L as determined by the mean added to three standard deviations determined from 10 replicates of perchloric-acid treated saline pool. The limit of detection was determined to be 0.12 mmol/L calculated from 10 replicates of a patient sample treated with perchloric-acid. The manufacturer's reference interval of 1.1-2.4 mmol/L was verified using 20 residual patient CSF samples. CONCLUSIONS: CSF lactate can be measured with accuracy and precision using the same perchloric-acid treated sample that is used for pyruvate. PMID- 29709452 TI - Diagnostic and therapeutic profiles of serum bile acids in women with intrahepatic cholestasis of pregnancy-a pseudo-targeted metabolomics study. AB - BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP), as a pregnancy-specific liver disorder, obtains increasing recognition due to a series of adverse outcomes. ICP is generally characterized by pruritus and jaundice, and closely related to abnormalities in the metabolism and disposition of bile acids composition. Because of its elusive pathogenesis, ICP has become an intractable issue to be diagnosed and managed for obstetricians. Analysis of metabolic profile could reveal the state of small-molecule metabolites systematically and provide comprehensively metabolic information for diseases. We developed a pseudo targeted approach to perform metabolomic analysis of bile acids in serum using an ultra-performance liquid chromatography-triple quadrupole time-of-flight tandem mass spectrometry (UPLC-Triple TOF-MS/MS) method. METHODS: We investigated the metabolites of bile acids in 55 healthy pregnant women, 42 women with ICP and 11 women with ICP who persisted to accept ursodeoxycholic acid (UDCA) therapy. RESULTS: The metabolic profiles of serum bile acids were significantly altered in ICP group compared with the control group. A screened potential combination biomarker, with a high diagnostic efficiency (area under the curve = 0.996, Youden index = 0.940), was superior to total bile acids for the diagnosis of ICP. CONCLUSIONS: The profiles of serum bile acids in women with ICP became more clear under the UDCA therapy, and were fully recovered after the delivery. PMID- 29709453 TI - LC-Q-TOF-MS based plasma metabolomic profile of subclinical pelvic inflammatory disease: A pilot study. AB - BACKGROUND: No index for non-invasive diagnosis of subclinical pelvic inflammatory disease (PID) is available at this time. Here we carried out a plasma metabolomic study to search for potential biomarkers to facilitate its non invasive diagnosis. METHOD: The metabolites in plasma were detected by using an LC-Q-TOF-MS method. The metabolic profiles of subclinical PID patients and healthy controls were discriminated by multivariate analysis. 30 patients and 28 controls were enrolled for PLS-DA model construction, and further 8 patients and 8 controls were employed for model validation. Univariate analysis was performed to evaluate potential biomarkers. RESULTS: The metabolic profiles of subclinical PID patients were different from those of healthy controls in a PLS-DA model, and this model was validated by permutation test and could accurately classify further 16 samples in T-prediction. Eleven differentiating metabolites, with the variable importance in the project >1 and corrected P < 0.05, were found as potential biomarkers. These metabolites included eight lipids, p-cresol, 3 indolepropionic acid and indoxylsulfuric acid. Among them, lysophosphatidic acid (16,0/0:0) showed a highest AUC value of receiver operating characteristic curve (0.855), with sensitivity of 89.3% and specificity of 73.3%. CONCLUSION: Through an LC-Q-TOF-MS based metabolomic analysis on subclinical PID, this study reports the potential plasma biomarkers which may be helpful for its non-invasive diagnosis. PMID- 29709454 TI - Are There Differences between Women who Choose Elective Repeat Caesarean Versus Trial of Labour in St. John's, NL? AB - OBJECTIVES: To compare the demographic and clinical characteristics between women who chose elective repeat Caesarean section (ERCS) versus trial of labour after Caesarean section (TOLAC) in St. John's, Newfoundland and Labrador (NL). METHODS: We conducted a retrospective case control study of women with live singleton gestations delivering at term in St. John's, NL between January 1, 2001 and December 31, 2014. Inclusion criteria were women who had a previous single lower segment Caesarean section (LSCS). TOLAC, successful TOLAC, and VBAC rates were calculated. Demographic and clinical characteristics were compared between women who chose ERCS versus TOLAC. Univariate analyses and multiple logistic regression analyses were performed, and adjusted odds ratios (aOR) and 95% CIs were calculated. RESULTS: A total of 1579 women were included, of whom 160 (10.1%) chose TOLAC, with 107 resulting in successful VBAC (67% successful TOLAC rate). The overall VBAC rate was 6.8%. Women who chose ERCS compared with those who chose TOLAC were more likely to be obese (aOR 3.20, 95% CI 1.85-5.54, P < 0.001), less likely to have had GA at delivery greater than 40 weeks (aOR 0.13, 95% CI 0.08-0.21, P < 0.001), less likely to have had a previous vaginal delivery (aOR 0.40, 95% CI 0.20-0.80, P < 0.001), and less likely to have had the previous CS for breech presentation (aOR 0.51, 95% CI 0.33-0.80, P = 0.003). CONCLUSIONS: The overall TOLAC and VBAC rates in St. John's are low when compared with reported national rates. The successful TOLAC rate is within the expected range reported in the literature. Differences exist between women who chose ERCS compared with TOLAC. PMID- 29709455 TI - The Approach to Peripartum Management of Anticoagulation: A Multidisciplinary Survey. AB - OBJECTIVE: This study sought to determine whether there is practice variation in the treatment and prevention of acute venous thromboembolism (VTE) in pregnant patients, potentially to prioritize future studies. BACKGROUND: The risk of VTE during pregnancy is five-fold that of the non-pregnant state. Guidance is often lacking for the treatment and prophylaxis of VTE because there are few RCTs. METHODS: The study used a cross-sectional study design using a self-administered electronic questionnaire consisting of 11 case scenarios that were sent to hematologists, maternal-fetal medicine specialists, obstetricians and gynaecologists, and internal medicine specialists across Canada. RESULTS: A total of 254 participants responded to the survey and 193 (76%) completed the survey, 158 of whom indicated that they were involved in the decision to anticoagulate these patients. Anticoagulation of patients with superficial venous thrombosis during pregnancy, monitoring of low-molecular-weight heparin antepartum, and discontinuation of this agent at the time of delivery were the scenarios associated with the largest variability of responses. For the management of acute VTE antepartum, most participants favoured a once-daily regimen, although internists more so than obstetrics and gynaecology physicians (94.7% vs. 73.7%). Cesarean section was not perceived to be a procedure with a marked increased risk of thrombosis to warrant thromboprophylaxis because most physicians elected not to offer thromboprophylaxis for this scenario. However, obesity and severe preeclampsia with Cesarean section led to the predominant use of thromboprophylaxis, at 80.0% and 68.4%, respectively. CONCLUSION: Prospective studies addressing peripartum management where significant discrepancies exist are warranted. PMID- 29709456 TI - Drug Registries and Approval of Drugs: Promises, Placebo, or a Real Success? AB - PURPOSE: As part of the approval process, regulatory authorities often require postauthorization studies that involve patient registries; it is unknown, however, whether such registry studies are adequately completed. We investigated whether registry studies for new drugs were performed as agreed at time of approval. METHODS: This study reviewed protocols and follow-up reports for 73 registry studies that were proposed for 43 drugs approved by the Committee for Medicinal Products for Human Use in Europe in the period 2007 to 2010. RESULTS: The data lock point of January 1, 2016, was taken to allow a 5-year follow-up period for each drug after approval. At that time, 2 studies (3%) in registries had been finalized, 19 registries (26%) had not enrolled any patients, and 52 studies (71%) were ongoing. The median enrollment was 31% (interquartile range [IQR], 6-104) of the required number of patients for 41 registry studies that had a predefined sample size, 30% (IQR, 2-101) for nonimposed registries, and 61% (IQR, 18-144) for imposed registries. IMPLICATIONS: Enrollment of patients into postapproval registries is poor, although the results for imposed registries seem better. Currently, registries only have a limited impact on resolving gaps in the knowledge of a drug's benefits and risks at time of marketing authorization. PMID- 29709457 TI - Diabetic Peripheral Neuropathy: Epidemiology, Diagnosis, and Pharmacotherapy. AB - PURPOSE: Diabetic peripheral neuropathy (DPN) is the commonest cause of neuropathy worldwide, and its prevalence increases with the duration of diabetes. It affects approximately half of patients with diabetes. DPN is symmetric and predominantly sensory, starting distally and gradually spreading proximally in a glove-and-stocking distribution. It causes substantial morbidity and is associated with increased mortality. The unrelenting nature of pain in this condition can negatively affect a patient's sleep, mood, and functionality and result in a poor quality of life. The purpose of this review was to critically review the current literature on the diagnosis and treatment of DPN, with a focus on the treatment of neuropathic pain in DPN. METHODS: A comprehensive literature review was undertaken, incorporating article searches in electronic databases (EMBASE, PubMed, OVID) and reference lists of relevant articles with the authors' expertise in DPN. This review considers seminal and novel research in epidemiology; diagnosis, especially in relation to novel surrogate end points; and the treatment of neuropathic pain in DPN. We also consider potential new pharmacotherapies for painful DPN. FINDINGS: DPN is often misdiagnosed and inadequately treated. Other than improving glycemic control, there is no licensed pathogenetic treatment for diabetic neuropathy. Management of painful DPN remains challenging due to difficulties in personalizing therapy and ascertaining the best dosing strategy, choice of initial pharmacotherapy, consideration of combination therapy, and deciding on defining treatment for poor analgesic responders. Duloxetine and pregabalin remain first-line therapy for neuropathic pain in DPN in all 5 of the major published guidelines by the American Association of Clinical Endocrinologists, American Academy of Neurology, European Federation of Neurological Societies, National Institute of Clinical Excellence (United Kingdom), and the American Diabetes Association, and their use has been approved by the US Food and Drug Administration. IMPLICATIONS: Clinical recognition of DPN is imperative for allowing timely symptom management to reduce the morbidity associated with this condition. PMID- 29709458 TI - Prognostic Significance of Clinicopathologic Features in Patients With Breast Ductal Carcinoma-in-Situ Who Received Breast-Conserving Surgery. AB - PURPOSE: To identify whether a certain group of breast ductal carcinoma-in-situ (DCIS) patients can be treated with breast-conserving surgery (BCS) alone; to analyze the clinicopathologic features of DCIS and tamoxifen administration in patients treated with BCS who developed ipsilateral breast tumor recurrence (IBTR). PATIENTS AND METHODS: Data for 375 women with breast DCIS who underwent BCS at our institute between June 2003 and October 2010 were analyzed. The patients were divided into different categories according to the recurrence risk predicted using the California/Van Nuys Prognostic Index (USC/VNPI) score (4-6, 7 9, and 10-12), Eastern Cooperative Oncology Group (ECOG) E5194 criteria, or combined risk features with USC/VNPI score and ECOG E5194 criteria. The IBTR and disease-free survival (DFS) rates were calculated by the Kaplan-Meier method. The prognostic effects of age, tumor size, tumor grade, margin width, estrogen receptor status, USC/VNPI score, low-risk characteristics, and tamoxifen use were evaluated by log-rank tests. RESULTS: Of the patients, 168 were treated with breast irradiation after BCS and 207 were not. The patients who were treated with radiotherapy (RT) tended to be younger (< 40 years), to have higher USC/VNPI scores (7-9), and to meet the ECOG E5194 non-cohort 1 criteria. The 7-year risk of IBTR was 6.2% (n = 11) in the patients who received irradiation and 9.0% (n = 22) in those who did not. DFS rates were better in the patients who underwent RT than in those who did not (93.3% vs. 88.5%, P = .056). Among the patients who underwent BCS alone, age >= 40 years, margin width > 10 mm, USC/VNPI scores 4-6, ECOG E5194 cohort 1 criteria, estrogen receptor-positive status, and tamoxifen use predicted lower IBTR and better DFS rates. In the multivariate analysis, combined low-risk characteristics (USC/VNPI scores 4-6 and meeting the ECOG E5194 cohort 1 criteria) were identified as an independent prognostic factor of lower IBTR (P = .028) and better DFS (P = .005). CONCLUSION: RT reduces the risk of IBTR after BCS for DCIS of the breast. Patients with combined low-risk characteristics (USC/VNPI scores 4-6 and meeting the ECOG E5194 cohort 1 criteria) may be adequately treated with BCS alone. PMID- 29709459 TI - Progressive Chronic Retinal Axonal Loss Following Acute Methanol-induced Optic Neuropathy: Four-Year Prospective Cohort Study. AB - PURPOSE: To study the dynamics and clinical determinants of chronic retinal nerve fiber layer thickness (RNFL) loss after methanol-induced optic neuropathy. DESIGN: Prospective cohort study. METHODS: All patients underwent complete ophthalmic evaluation including spectral-domain optical coherence tomography 3 times during 4 years of observation: 4.9 (+/-0.6), 25.0 (+/-0.6), and 49.9 (+/ 0.5) months after discharge. PARTICIPANTS: Eighty-four eyes of 42 survivors of methanol poisoning, mean age (standard deviation) of 45.7 (+/-4.4) years; and 82 eyes of 41 controls, mean age 44.0 (+/-4.2) years. MAIN OUTCOME MEASURES: Global and temporal RNFL loss. RESULTS: Abnormal RNFL thickness was registered in 13 of 42 (31%) survivors of methanol poisoning and chronic axonal loss in 10 of 42 (24%) patients. Significant decrease of global/temporal RNFL thickness during the observation period was found in the study population compared to the controls (P < .001). The risk estimate of chronic global RNFL loss for arterial blood pH < 7.3 at admission was 11.65 (95% confidence interval 1.91-71.12) after adjusting for age and sex. The patients with chronic axonal degeneration demonstrated progressive visual loss in 7 of 10 cases. The patients with abnormal RNFL thickness had magnetic resonance signs of brain damage in 10 of 13 vs 8 of 29 cases with normal RNFL thickness (P = .003). Signs of brain hemorrhages were present in 7 of 13 patients with abnormal RNFL thickness vs 5 of 29 cases with normal RNFL thickness (P = .015). CONCLUSIONS: Methanol-induced optic neuropathy may lead to chronic retinal axonal loss during the following years. Arterial blood pH on admission is the strongest predictor of chronic RNFL thickness decrease. Chronic retinal neurodegeneration is associated with the progressive loss of visual functions and necrotic brain lesions. PMID- 29709461 TI - Different biochemical patterns in type II and type III mixed cryoglobulinemia in HCV positive patients. AB - BACKGROUND: Reversible cryoprecipitability of proteins is observed as a concomitant feature of immune complex formation. Mixed cryoglobulinemia (MC) is systemic vasculitis, associated with mixed IgM and IgG cryoglobulins (CGs) showing rheumatoid factor (RF) activity. It is frequently associated with hepatitis C virus (HCV). This study investigates the presence of IgG RF and anti nuclear antibodies (ANA) in cryoprecipitates of patients with type III and type II MC, to understand the biochemical patterns associated with different types of MC to a greater degree. METHODS: Sera from 70 HCV untreated patients with type III or type II MC were tested by immunofixation for IgG3 and through ELISA for IgG RF. Cryoprecipitates were analysed for ANA by indirect immunofluorescence to identify specific patterns. RESULTS: After stratification according to MC type, the ANA patterns between type II and type III MC were statistically different. IgG3 levels and IgG-RF positivity were significantly higher in type III cryoprecipitate. We observed a higher positivity of IgG3 and a significant difference between the liver fibrosis stage, ANA and IgG-RF in the cryoprecipitate. CONCLUSION: Results show a combination of biochemical markers and autoantibodies associated to mixed cryoglobulinemia; these findings could be further investigated in order to ascertain their usefulness in assessing the risk for the development of mixed cryoglobulinemia. PMID- 29709460 TI - Endoscopic papillary large balloon dilation in patients with large biliary stones and periampullary diverticula: Results of a multicentric series. AB - INTRODUCTION: Stone extraction represents the most frequent indication for endoscopic retrograde cholangiopancreatography (ERCP). Endoscopic papillary large balloon dilation (EPLBD) is a recent introduced approach consisting of an endoscopic papillary large balloon dilation following limited endoscopic sphyncterotomy (ES), which has been proven to be safe and effective for extraction of large common bile duct (CBD) stones. Peri-ampullary diverticula (PAD) are described in 10-20% of patients undergoing ERCP. Aim of our study is to evaluate efficacy and safety of EPLBD for the extraction of large biliary stones in patients with PAD. METHODS: The prospectively collected endoscopy databases of 4 Italian ERCP high-volume centers were reviewed retrospectively, and all consecutive patients with an instrumental diagnosis of large biliary stones and PAD, between September 2014 and October 2016, were included in this study. RESULTS: Eighty-one patients (36 males, median age 75 years) were treated between September 2014 and October 2016. Deep biliary cannulation was reached in 78/80 patients. Successful extraction was achieved in 74/78 patients at the first attempt. AEs occurred in 8 patients (1 severe). Younger age, stone size and incomplete stone extraction were significantly associated with AEs. CONCLUSIONS: EPLBD is an effective and safe technique in patients with PAD and large biliary stones, which avoids the need of other techniques, thereby reducing the risks of adverse events. PMID- 29709462 TI - Faecal high mobility group box 1 in children with celiac disease: A pilot study. AB - BACKGROUND: Celiac disease (CD) is a gluten-related immunological disorder resulting in inflammatory enteropathy. AIMS: We assessed a stool marker of intestinal inflammation, the HMGB1 protein, in children with CD on a gluten free diet (GFD) at baseline and at follow up (FU). METHODS: Thirty-nine children were investigated at diagnosis and at FU. Traditional serum markers of CD (anti transglutaminase and anti-endomysial antibodies) and faecal HMGB1 (by enzyme linked immunosorbent assay and immunoblotting) were tested. RESULTS: There was a marked increase at baseline in both serum anti-transglutaminase IgA (anti-tTGAs) and faecal HMGB1; the latter being undetectable in controls. A strong correlation occurred between the two markers. At 12-month FU in 24 patients on GFD, HMGB1 decreased in all subjects, yet still being detectable in six children: high anti tTGAs where evident in three, while the three with normal anti-tTGAs were complaining of intestinal symptoms and reported a low GFD adherence. CONCLUSIONS: Faecal HMGB1 is a valuable marker of intestinal inflammation and may have a role in complementing serology in the management of CD children. Future studies including larger patient cohorts and small bowel mucosa histology will be designed to assess the relationship between faecal HMGB1 levels and duodeno jejunal histopathology. PMID- 29709463 TI - Rethinking foundations of language from a multidisciplinary perspective. AB - The issue of language foundations has been of great controversy ever since it was first raised in Lenneberg's (1967) monograph Biological Foundations of Language. Based on a survey of recent findings relevant to the study of language acquisition and evolution, we propose that: (i) the biological predispositions for language are largely domain-general, not necessarily language-specific or human-unique; (ii) the socio-cultural environment of language serves as another important foundation of language, which helps shape language components, induce and drive language shift; and (iii) language must have coevolved with the cognitive mechanisms associated with it through intertwined biological and cultural evolution. In addition to theoretical issues, this paper also evaluates the primary approaches recently joining the endeavor of studying language foundations and evolution, including human experiments and computer simulations. Most of the evidence surveyed in this paper comes from a variety of disciplines, and methodology therein complements each other to form a global picture of language foundations. These reflect the complexity of the issue of language foundations and the necessity of taking a multidisciplinary perspective to address it. PMID- 29709464 TI - Dynamic contrast-enhanced MRI of orbital and anterior visual pathway lesions. AB - PURPOSE: The accurate diagnosis of orbital and anterior visual pathway lesions has clinical significance. We determined whether dynamic contrast-enhanced MRI could differentiate benign from malignant lesions and compared model-independent and model-dependent methods of data analysis. METHODS: We retrospectively reviewed dynamic contrast-enhanced MRI studies of 37 enhancing orbital and anterior visual pathway lesions. The data were processed using model-independent analysis and model-dependent analysis using a 2-compartment pharmacokinetic model. The time-signal intensity curve and semiquantitative parameters from the model-independent method (area under the curve [AUC] after the initial 60, 90, and 120 s; time to peak; maximum signal enhancement ratio; maximum slope of increase; and washout ratio) and the quantitative parameters from the model dependent method (Ktrans, kep, and ve) were derived for comparison with pathologic diagnoses. RESULTS: The time-signal intensity curves demonstrated different perfusion characteristics and were classified into 4 types. All the lesions that demonstrated curve types 1 and 4 were benign, while type 3 lesions were significantly associated with malignancy (P = 0.001). AUC60, AUC90, AUC120, and kep were significantly lower in benign lesions than in malignant lesions (P = 0.020, 0.018, 0.015, and 0.018, respectively). Receiver operating characteristic analysis indicated that AUC120 yielded the best diagnostic accuracy (area under the curve, 0.80; 95% CI, 0.64-0.96) in differentiating between benign and malignant lesions. CONCLUSIONS: Dynamic contrast-enhanced MRI is useful in evaluating orbital and anterior visual pathway lesions. The model-independent analysis method is equivalent to the model-dependent method in differentiating benign from malignant lesions. PMID- 29709465 TI - Huntington's disease pattern of transcriptional dysregulation in the absence of mutant huntingtin is produced by knockout of neuronal GLT-1. AB - GLT-1 is the major glutamate transporter in the brain, and is expressed in astrocytes and in axon terminals in the hippocampus, cortex, and striatum. Neuronal GLT-1 accounts for only 5-10% of total brain GLT-1 protein, and its function is uncertain. In HD, synaptic dysfunction of the corticostriate synapse is well-established. Transcriptional dysregulation is a key feature of HD. We hypothesized that deletion of neuronal GLT-1, because it is expressed in axon terminals in the striatum, might produce a synaptopathy similar to that present in HD. If true, then some of the gene expression changes observed in HD might also be observed in the neuronal GLT-1 knockout. In situ hybridization using 33P labeled oligonucleotide probes was carried out to assess localization and expression of a panel of genes known to be altered in expression in HD. We found changes in the expression of cannabinoid receptors 1 and 2, preproenkaphalin, and PDE10A in the striatum of mice in which the GLT-1 gene was inactivated in neurons by expression of synapsin-Cre, compared to wild-type littermates. These changes in expression were observed at 12 weeks of age but not at 6 weeks of age. No changes in DARPP-32, PDE1B, NGFIA, or beta-actin expression were observed. In addition, we found widespread alteration in expression of the dynamin 1 gene. The changes in expression in the neuronal GLT-1 knockout of genes thought to exemplify HD transcriptional dysregulation suggest an overlap in the synaptopathy caused by neuronal GLT-1 deletion and HD. These data further suggest that specific changes in expression of cannabinoid receptors, preproenkephalin, and PDE10A, considered to be the hallmark of HD transcriptional dysregulation, may be produced by an abnormality of glutamate homeostasis under the regulation of neuronal GLT-1, or a synaptic disturbance caused by that abnormality, independently of mutation in huntingtin. PMID- 29709466 TI - The communication experience of tracheostomy patients with nurses in the intensive care unit: A phenomenological study. AB - OBJECTIVES: To describe the experience and sources of comfort and discomfort in tracheostomy patients, when they communicate with nurses in the Intensive Care Unit. RESEARCH METHODOLOGY/DESIGN: Benner's interpretive phenomenology. Data were collected through: a) semi-structured interviews conducted with the patients after leaving the intensive care unit; b) participant observation; c) situated interviews with intensive care nurses. SETTING: The intensive care unit of a hospital in Northern Italy. FINDINGS: Eight patients and seven nurses were included in this study. Two main themes were identified 1) feeling powerless and frustrated due to the impossibility to use voice to communicate; 2) facing continual misunderstanding, resignation, and anger during moments of difficulty and/or communication misunderstandings. The main communication discomfort factors were: struggling with not knowing what was happening, feeling like others had given up on me, living in isolation and feeling invisible. The main comfort factors were: being with family members, feeling reassured by having a call bell nearby and nurses' presence. CONCLUSIONS: This study highlights the important role of communication in tracheostomy patients in intensive care and how closely it is linked to all the aspects of a person's life, which cannot be underestimated as just not being able to use one's voice. PMID- 29709467 TI - Use of the CAM-ICU during daily sedation stops in mechanically ventilated patients as assessed and experienced by intensive care nurses - A mixed-methods study. AB - BACKGROUND: Mechanically ventilated patients are at risk of developing delirium, which increases mortality and prolongs their stay in the Intensive Care Unit (ICU). AIM: To investigate the assessment of delirium by ICU nurses and their experiences of using the Confusion Assessment Method for Intensive Care Unit (CAM ICU) in mechanically ventilated patients during daily sedation stops. METHODS: The study employed an explanatory sequential mixed-methods design. The data (n = 30) were collected by two nurses who assessed the same patient (n = 15) using the tool. Data from the nurses' assessments were analysed by means of frequency analysis, while the interviews were analysed phenomenographically using Dahlgren and Fallberg's seven categories. FINDINGS: Four pairs of nurses made similar assessments, three pairs had differing assessments and in eight pairs, one of the nurses did not fill in the form properly. The interviews revealed variations in ICU nurses' preparation for, views on and use of the CAM-ICU. CONCLUSION: Assessment and use of the CAM-ICU revealed variations, indicating the necessity of identifying barriers within the ICU team. ICU nurses need training in the use of the CAM-ICU and support in their decision-making. The individual nurse must take responsibility for updating their knowledge and for following guidelines. PMID- 29709468 TI - Glycated hemoglobin targets and glycemic control: Link with lipid, uric acid and kidney profile. AB - AIMS: To compare uric acid, lipid, and kidney profile along with management and complications of Indonesian diabetic patients with good and poor glycemic control based on glycated hemoglobin profile. MATERIALS AND METHODS: Data was obtained from medical records of Internal Medicine Clinic in Hermina Podomoro General Hospital for the period January-December 2015. Subjects were grouped into good and poor glycemic control groups based on their glycated hemoglobin (HbA1c) levels. RESULTS: Fifty-five subjects were obtained with an average age of 54 years, 29 with good glycemic control and 26 with poor glycemic control. All glycemic parameters were worse in poor compared to good glycemic control group (p < 0.05). Similar averages of urea, creatinine, uric acid, low-density lipoprotein (LDL) and a lower average of high-density lipoprotein (HDL) were found between both groups with statistically non-significant differences (p > 0.05). Main comorbidities were dyslipidemia, hypertension, and nephropathy. Fatty liver disease, urinary tract infection and neuropathy was also reported. Most patients were prescribed with oral anti-diabetics. CONCLUSION: Diabetic patients regardless of glycemic control according to current guidelines have a greater average lipid and kidney profile than the optimum target. Therefore both are equally at greater risk for cardiovascular diseases, nephropathy, and other diabetic complications. Greater patient monitoring of these parameters is recommended to lower the risk of comorbidities and complications. PMID- 29709469 TI - Effect of Resident Involvement on Morbidity and Mortality Following Thoracic Endovascular Aortic Repair. AB - OBJECTIVE: To evaluate the effect of resident involvement in thoracic endovascular aortic repair (TEVAR). SUMMARY OF BACKGROUND DATA: Although the influence of resident intraoperative involvement in several types of surgical procedures has been reported, the effect of resident participation in TEVAR is unknown. We evaluated patient outcomes in resident-involved TEVAR procedures. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database was analyzed for TEVAR performed from 2010 to 2012. Current procedural terminology codes were used to identify adult patients (>=18 y) who underwent TEVAR. Patients were grouped into those with and without resident involvement. Descriptive and binomial logistic statistics were used to determine the effect of resident involvement on post-TEVAR outcomes. p values < 0.05 were considered statistically significant. RESULTS: A total of 676 patients met inclusion criteria for this study. Of these, 517 (76.5%) had residents involved. Overall mortality was 9.8%, with no significant difference between the 2 groups (p = 0.88). Resident involvement was not a significant predictor of any post-TEVAR complication. Postoperative pneumonia (3.5% vs 6.9%, p = 0.06), prolonged mechanical ventilation (11.8% vs 11.9%, p = 0.96), stroke (2.7% vs 5.7%, p = 0.07), urinary tract infection (3.3% vs 4.4%, p = 0.50), progressive renal insufficiency (1.2% vs 2.5%, p = 0.22), acute renal failure (4.1% vs 5.0%, p = 0.60), cardiac arrest (2.9% vs 5.0%, p = 0.20), myocardial infarction (1.7% vs 1.9%, p = 0.91), deep venous thrombosis (1.7% vs 1.3%, p = 0.67), red blood cells transfusions (29.2% vs 36.5%, p = 0.08), sepsis (2.9% vs 4.4%, p = 0.35), septic shock (1.9% vs 3.8%, p = 0.18), and unplanned reintubation (8.7% vs 9.4%, p = 0.78) were not significantly affected. Additionally, resident involvement did not significantly affect operative time (176.1 +/- 122.8 min vs 180.3 +/- 119.1 min, p = 0.71) and anesthesia time (282.1 +/- 146.6 min vs 278.3 +/- 140.5 min, p = 0.78). CONCLUSIONS: The participation of residents in TEVAR did not significantly affect all 30-day patient outcomes. Resident involvement in TEVAR is safe and should be encouraged. MINI ABSTRACT: This study evaluated the effect of resident participation on postoperative outcomes of thoracic endovascular aortic repair (TEVAR) using the American College of Surgeons National Surgical Quality Improvement (ACS-NSQIP) database. Results showed that resident involvement in TEVAR does not negatively affect patient outcomes. PMID- 29709470 TI - Uncovering transcription factor and microRNA risk regulatory pathways associated with osteoarthritis by network analysis. AB - Osteoarthritis (OA) is the most common form of joint disease. The development of inflammation have been considered to play a key role during the progression of OA. Regulatory pathways are known to play crucial roles in many pathogenic processes. Thus, deciphering these risk regulatory pathways is critical for elucidating the mechanisms underlying OA. We constructed an OA-specific regulatory network by integrating comprehensive curated transcription and post transcriptional resource involving transcription factor (TF) and microRNA (miRNA). To deepen our understanding of underlying molecular mechanisms of OA, we developed an integrated systems approach to identify OA-specific risk regulatory pathways. In this study, we identified 89 significantly differentially expressed genes between normal and inflamed areas of OA patients. We found the OA-specific regulatory network was a standard scale-free network with small-world properties. It significant enriched many immune response-related functions including leukocyte differentiation, myeloid differentiation and T cell activation. Finally, 141 risk regulatory pathways were identified based on OA-specific regulatory network, which contains some known regulator of OA. The risk regulatory pathways may provide clues for the etiology of OA and be a potential resource for the discovery of novel OA-associated disease genes. PMID- 29709471 TI - Mm9_circ_009056 enhances osteogenesis by targeting BMP7 via CGRP-mediated miR-22 3p. AB - Circular RNAs (circRNAs) are noncoding RNAs that can function as miRNA sponges, post-transcriptionally regulating the expression of genes. Here, we report a novel positive function of mm9_circ_009056 during osteogenesis in regulating bone morphogenetic protein 7 (BMP7) through miR-22-3p. First, we found that calcitonin gene-related peptide (CGRP) had great osteogenesis function on MC3T3 cells. Then aberrant expression of mm9_circ_009056 were confirmed in CGRP-induced cells. Furthermore, the expression of mm9_circ_009056 was up-regulated in the CGRP induced cells, whereas miR-22-3p was obviously decreased. Silencing of mm9_circ_009056 increased the expression of miR-22-3p and decreased the gene and protein levels of BMP7, RUNX2. Cells proliferation and growth were also inhibited following silengcing. The protein levels of BMP7 and RUNX2 decreased after mimics transfection and increased after inhibitors transfection. In summary, mm9_circ_009056 may function as a sponge for miR-22-3p to regulate osteogenesis in CGRP-induced cells. PMID- 29709472 TI - Activation of TGR5 promotes mitochondrial biogenesis in human aortic endothelial cells. AB - Impairment of mitochondrial biogenesis has been associated with vascular pathophysiology. The G-protein-coupled receptor (TGR5) is an important mediator of bile acid signaling and glucose metabolism. However, the effects of TGR5 on mitochondrial biogenesis in endothelial cells remain elusive. In this study, we found that activation of TGR5 using its specific agonist taurolithocholic acid (TLCA) promoted the expression of PGC-1alpha, a master regulator of mitochondrial biogenesis in human aortic endothelial cells (HAECs). Additionally, activation of TGR5 increased the expression of PGC-1alpha target genes, such as NRF1 and TFAM. Indeed, we found that TLCA treatment promoted mitochondrial biogenesis by increasing mitochondrial mass, mitochondrial-to-nuclear DNA (mtDNA/nDNA), COX-I expression, and cytochrome c oxidase activity in HAECs. Notably, our results displayed that activation of TGR5 resulted in a functional gain in mitochondria by increasing the rate of respiration and ATP production. Mechanistically, we found that TLCA treatment activated the transcriptional factor CREB by inducing the phosphorylation of CREB at Ser133. Using the PKA/CREB inhibitor H89 abolished the effects of TLCA on PGC-1alpha, NRF1 and TFAM expression as well as the increase in mtDNA/nDNA and ATP production. These findings suggest that activation of TGR5 promoted mitochondrial biogenesis in endothelial cells, which is mediated by the CREB/PGC-1alpha signaling pathway. PMID- 29709473 TI - MiR-502 mediates esophageal cancer cell TE1 proliferation by promoting AKT phosphorylation. AB - Esophageal cancer is one of the most common cancers in the world and esophageal squamous cell carcinoma is one of the two main types in esophageal cancer. MicroRNA is a small non-coding RNA molecule functions in many different cancers including esophageal cancer. We found miR-502 was up-regulated in esophageal tissues, which indicated miRNA-502 may play important roles in esophageal cancer. In this study, we used esophageal cancer cell line TE1 as an in vitro model for investigating the role of miR-502 in promoting the proliferation of the cancer cells. We found that overexpressing miR-502 in TE1 cells promoted the proliferation and inhibited the apoptosis induced by dox. Down-regulating miR-502 made the opposite phenomenon. Furthermore, western blot showed that miR-502 enhanced the phosphorylation levels of AKT pathways, which may be the mechanism of the overgrowth for esophageal cancer cell. Our data provide the evidence of a role for miR-502 in the regulation the proliferation of esophageal cancer cell through promoting the phosphorylation of AKT signaling. Due to its ability to promote the overgrowth of esophageal cancer cell, miR-502 may be a novel target for esophageal cancer therapeutic. PMID- 29709474 TI - Keratinocyte growth factor protects endometrial cells from oxygen glucose deprivation/re-oxygenation via activating Nrf2 signaling. AB - Oxygen and glucose deprivation (OGD)-re-oxygenation (OGDR) exposure to endometrial cells mimics ischemia-reperfusion injury. The present study tests the potential effect of keratinocyte growth factor (KGF) on the process. We show that KGF receptor KGFR is expressed in human endometrial T-HESC cells and primary murine endometrial cells. KGF pre-treatment protected endometrial cells from OGDR, inhibiting cell viability reduction and cell death. KGF attenuated OGDR induced programmed necrosis in endometrial cells. Significantly, KGF activated Nrf2 signaling, causing Nrf2 Ser-40 phosphorylation, protein stabilization, nuclear translocation to promote anti-oxidant gene (HO1, NOQ1 and GCLC) expression. Nrf2 silencing (by targeted shRNAs) or CRISPR/Cas9 knockout almost abolished KGF-induced endometrial cell protection against OGDR. Furthermore, KGF activated Akt-mTOR signaling in endometrial cells. Whereas Akt-mTOR inhibitors (LY294002, AZD2014 and RAD001) abolished KGF-induced Nrf2 activation and anti OGDR cytoprotection. Together, KGF protects endometrial cells from OGDR via activating Akt-mTOR-Nrf2 signaling. PMID- 29709475 TI - TNIP1 alleviates hepatic ischemia/reperfusion injury via the TLR2-Myd88 pathway. AB - Hepatic ischemia/reperfusion (I/R) injury induces oxidative stress, hepatocyte apoptosis, and release of inflammatory cytokines, which together causes liver damage and even organ dysfunction. TNF-alpha-induced protein 3-interacting protein 1 (TNIP1) reportedly decreases expression of genes associated with stress response and inflammation. Thus, we investigated the effects of TNIP1 on hepatic cells injury caused by hypoxia/reoxygenation (H/R). Reduced expression of TNIP1 was determined in I/R mice compared to normal mice. Then, TNIP1 transgene mice were used to determine the effects of TNIP1 on mice after treatment for I/R. In the normal transgene (NTG) group, serum liver damage markers alanine aminotransferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH) and gamma glutamyl transferase (GGT) in I/R mice significantly increased compared to the sham-operated mice. However, in the TNIP1 transgene (TNIP1-TG) group, those levels in I/R mice were reduced than that in NTG mice. Additionally, cell viability and apoptosis in the hepatic cell line L02 were detected after H/R treatment, MTT assay showed that cell viability was inhibited after H/R treatment, but reversed after ad-TNIP1 transfection. Cell apoptosis also was inhibited after ad-TNIP1 transfection, as shown by the caspase-3 and caspase-9 levels and Bcl-2 and Bax values. Furthermore, TNIP1 overexpression also attenuated the inflammatory response of L02 cells after H/R treatment. Finally, treatment with TNIP1 reduced the elevated expression of TLR2, TLR4, and Myd88 after H/R injury, but overexpression of TLR4 reversed the effects of TNIP1. In conclusion, TNIP1 may protect H/R-induced hepatic cell injury by inhibiting the TLR4/Myd88 pathway. PMID- 29709476 TI - Different mitochondrial fragmentation after irradiation with X-rays and carbon ions in HeLa cells and its influence on cellular apoptosis. AB - Although mitochondria are known to play an important role in radiation-induced cellular damage, the mechanisms by which ionizing radiation modulates mitochondrial dynamics are largely unknown. In this study, human cervical carcinoma cell line HeLa was used to demonstrate the different modes of mitochondrial network in response to different quality radiations such as low linear energy transfer (LET) X-rays and high-LET carbon ions. Mitochondria fragmented into punctate and clustered ones upon carbon ion irradiation in a dose and LET-dependent manner, which was associated with apoptotic cell death. In contrast, low-dose X-ray irradiation promoted mitochondrial fusion while mitochondrial fission was detected until the radiation dose was more than 1 Gy. This fission was driven by ERK1/2-mediated phosphorylation of Drp1 on Serine 616. Inhibition of mitochondrial fragmentation suppressed the radiation-induced apoptosis and thus enhanced the resistance of cells to carbon ions and high-dose X-rays, but not for cells irradiated with X-rays at the low dose. Our results suggest that radiations of different qualities cause diverse changes of mitochondrial dynamics in cancer cells, which play an important role in determining the cell fate. PMID- 29709477 TI - Spindle pole body component 25 homolog expressed by ECM stiffening is required for lung cancer cell proliferation. AB - Accumulating evidence has shown that matrix stiffening in cancer tissue by the deposition of extracellular matrix (ECM) is closely related with severe tumor progression. However, much less is known about the genes affected by matrix stiffness and its signaling for cancer progression. In the current research, we investigated the differential gene expression of a non-small lung adenocarcinoma cell line, H1299, cultured under the conditions of soft (~0.5 kPa) and stiff (~40 kPa) matrices, mimicking the mechanical environments of normal and cancerous tissues, respectively. For integrated transcriptome analysis, the genes identified by ECM stiffening were compared with 8248 genes retrieved from The Cancer Genome Atlas Lung Adenocarcinoma (TCGA). In stiff matrix, 29 genes were significantly upregulated, while 75 genes were downregulated. The screening of hazard ratios for these genes using the Kaplan-Meier Plotter identified 8 genes most closely associated with cancer progression under the condition of matrix stiffening. Among these genes, spindle pole body component 25 homolog (SPC25) was one of the most up-regulated genes in stiff matrix and tumor tissue. Knockdown of SPC25 in H1299 cells using shRNA significantly inhibited cell proliferation with downregulation of the expression of checkpoint protein, Cyclin B1, under the condition of stiff matrix whereas the proliferation rate in soft matrix was not affected by SPC25 silencing. Thus, our findings provide novel key molecules for studying the relationship of extracellular matrix stiffening and cancer progression. PMID- 29709478 TI - Low expression level of HMBOX1 in high-grade serous ovarian cancer accelerates cell proliferation by inhibiting cell apoptosis. AB - Homeobox-containing 1 (HMBOX1) has been described as a transcription factor involved in the occurrence of some tumors, but its roles in ovarian cancer have never been reported. Here we aimed to investigate the roles of HMBOX1 on high grade serous ovarian carcinoma (HGSOC). In this present study, HMBOX1 expression was decreased in HGSOC tissues and ovarian cancer cell lines (HO8910 and A2780) compared with ovarian surface epithelial tissues or normal human ovarian surface epithelial cell line (HOSEpiC). The cell proliferation of HOSEpiC was weaker than ovarian cancer cell lines. By altering the expression of HMBOX1 in A2780 and HOSEpiC, we demonstrated that HMBOX1 inhibited the cell proliferation and promoted the cell apoptosis. Furthermore, our study revealed that HMBOX1 downregulated the expression of anti-apoptotic proteins (Bcl-2, Bcl-xL), raised the expression of pro-apoptotic-regulated proteins (Bad, Bax), apoptotic executionior (Caspase3), and P53. In conclusion, HMBOX1 played important roles in occurrence of HGSOC through regulation of proliferation and apoptosis, which implied that HMBOX1 might serve as a new therapeutic target for HGSOC. PMID- 29709479 TI - Modulation of Angiopoietin 2 release from endothelial cells and angiogenesis by the synaptic protein Neuroligin 2. AB - The synaptic protein Neuroligin 2, similarly to its isoform Neuroligin 1, is produced by endothelial cells, but its activity in the vascular context remains unknown. This study aimed at verifying the hypothesis that Neuroligin 2, in parallel with its extraneuronal involvement in pancreatic beta cells exocytosis, modulated cytokine release from endothelial cells and consequently angiogenesis. We used in vitro approaches to modulate Neuroligin 2 expression and Neuroligin 2 null mice to test our hypotheses. In vitro, upon VEGF stimulation, Neuroligin 2 silencing strongly reduces Angiopoietin 2 release in the medium and increases the endothelial cell retention of Weibel Palade Bodies, the specialized organelles that store Angiopoietin 2 and various other cytokines. On the contrary, Neuroligin 2 overexpression almost depletes cells of Weibel Palade Bodies, independent of VEGF. In vivo, both the retina and tumor xenografts grown in NLGN2 null mice display an immature vasculature, with lower pericyte coverage and lower Tie2 phosphorylation. At the molecular level NLGN2 colocalizes with its neuronal partner collibystin, a CDC42 guanine nucleotide exchange factor, which is also expressed by endothelial cells and in turn modulates Angiopoietin 2 release. Neuroligin 2, an inhibitory synaptic protein, modulates a peculiar aspect of vascular function and could represent a novel target of therapy in various fields, from tumor angiogenesis to vascular diseases. PMID- 29709480 TI - Effects of enzymes on elastic modulus of low-density lipoproteins were investigated using atomic force microscopy. AB - Oxidation of low-density lipoproteins (LDLs) induces development of cardiovascular disease. Recently, reports of studies using atomic force microscopy (AFM) have described that the elastic modulus of metal-induced oxidized LDLs is lower than the modulus before oxidation. However, the mechanisms of change of the elastic modulus have not been well investigated. We postulated that disorder of the LDL structure might decrease the elastic modulus. This study measured the elastic modulus of LDLs before and after enzyme treatment with V8 protease, alpha-chymotrypsin, and phospholipase A2. After LDLs were obtained from serum by ultracentrifugation, LDLs or enzyme-treated LDLs were physically absorbed. They were crowded on a mica surface. Although V8 protease and alpha chymotrypsin did not induce the elastic modulus change, treatment with PLA2 decreased the elastic modulus. The LDL particle size did not change during the enzyme treatment. Results suggest that disordering of the lipid structure of the LDL might contribute to the elastic modulus change. Results show that AFM might be a useful tool to evaluate disorders of complex nanoscale particle structures from lipids and proteins such as lipoproteins. PMID- 29709481 TI - Fam83h mutation inhibits the mineralization in ameloblasts by activating Wnt/beta catenin signaling pathway. AB - FAM83H was identified as the major causative gene for autosomal dominant hypocalcified amelogenesis imperfect (ADHCAI). The pathogenic mechanism of FAM83H in ADHCAI remains elusive. The present study aims to investigate the effect of Fam83h mutation on the mineralization of mouse ameloblast cell line LS8 and to explore the possible pathogenesis of ADHCAI. Lentivirus package was performed for the plasmids with mouse Fam83h mutant cDNA (c.1186C > T, M3) and empty vector (Control) and transfected into LS8, which were divided into M3-FLAG and Control groups. Immunoprecipitation, western-blot and immunofluorescence were performed to detect the expression and subcellular localization of Fam83 h, CK1alpha and beta-catenin. ALP activity, ALP staining, expression of the mineralization factors were detected in two groups during mineralization induction. Expression of the mineralization factors was also detected in M3-FLAG and LS8 exposing to pyrvinium pamoate. Compared with the Control, the Fam83h mutation altered the expression and localization of Fam83 h, CK1alpha and beta-catenin in LS8, inhibited the mineralization and down-regulated the expression of mineralization factors in M3-FLAG. Pyrvinium pamoate, an inhibitor of the Wnt/beta-catenin signaling pathway, up-regulated expression of mineralization factors in LS8 and rescued the inhibited mineralization in M3-FLAG. The results indicated that the Fam83h mutation could inhibit the mineralization in ameloblasts by activating Wnt/beta-catenin signaling pathway. PMID- 29709483 TI - Novel phosphorelay-dependent control of ZFP36L1 protein during the cell cycle. AB - The ZFP36 family is a prototypical member of a highly conserved group of proteins with CCCH-type RNA-binding domains, whose functional role and regulatory mechanism in mitotic cells remain obscure. In this study, we provide the first evidence that ZFP36L1 phosphorylation is modulated in a cell cycle-dependent manner. The C-terminal region of ZFP36L1 is critical for its cell cycle-dependent phosphorylation of this protein. We also suggest that the phosphorelay-dependent regulation of ZFP36L1 influences mitotic spindle organization. Thus, our data demonstrate a new class of regulatory mechanism for CCCH-type zinc-finger proteins in cell cycle control. PMID- 29709484 TI - Protein disulfide isomerase enhances tissue factor-dependent thrombin generation. AB - Protein disulfide isomerase (PDI) plays an important role in fibrin generation in vivo, but the underlying mechanism remains largely unknown. In this study, using thrombin generation assay (TGA), we investigated whether PDI contributes to tissue factor (TF)-mediated thrombin generation. Human peripheral blood mononuclear cells (PBMCs) were treated with 100 ng/ml lipopolysaccharide (LPS), the expression of TF on cell surface was analyzed by flow cytometry. After incubation with an inhibitory anti-TF antibody, recombinant PDI protein or a PDI inhibitor PACMA31, LPS-stimulated human PBMCs were incubated with human plasma, and thrombin generation was assessed by Ceveron Alpha TGA and a fluorescent thrombin substrate. Bone marrow mononuclear cells isolated from PDI-knockout and wild-type mice were stimulated by LPS, followed by measurement of thrombin generation. LPS stimulation increased expression of TF on PBMCs, and thrombin generation. Inhibitory anti-TF antibody almost completely suppressed thrombin generation of LPS-stimulated PBMCs, suggesting that thrombin generation was TF dependent. Recombinant PDI protein increased thrombin generation, while PACMA31 attenuated thrombin generation. Compared with control cells, PDI-deficient marrow mononuclear cells had less capacity in thrombin generation. Taken together, these data suggest that PDI enhances TF-dependent thrombin generation. PMID- 29709485 TI - Endometriosis surgery and preservation of fertility, what surgeons should know. AB - Colorectal surgeons often participate in the multidisciplinary management of young females with endometriosis. Complications of endometriosis as well as its management often result in infertility since they can involve all pelvic organs including the procreative organs: uterus, ovaries and fallopian tubes. Complete excision of all endometriotic lesions should not be performed at the expense of irreversible destruction of the procreative organs; definitive infertility should not be the price to pay in order to obtain an improvement of the painful symptoms caused by endometriosis. Surgery for ovarian endometriomas should be specifically adapted to the patient's desire for future conception and to her preoperative ovarian reserve. Two main techniques are used to treat ovarian endometriomas: ovarian cystectomy excises the wall of the cyst while ablation consists of destruction of the internal surface of the cyst. The use of mono polar or biolar coagulation for cyst ablation is strongly contra-indicated. Ablation using laser or plasma energy has resulted in comparable rates of post-operative pregnancy to those obtained by ovarian cystectomy. Patients who wish to delay their attempt to conceive for some period of time, should be placed on long-term oral contraception with prevention of menstruation to reduce the risk of recurrent endometriosis. When surgery for colorectal endometriosis is necessary, the laparoscopic approach increases the chances of spontaneous conception compared to laparotomy. Surgery for deep-seated endometriosis has been accompanied by a high rate of spontaneous conception and successful pregnancy and does not seem to decrease the chances for conception by in vitro fertilization. PMID- 29709482 TI - Spatial localisation of Discoidin Domain Receptor 2 (DDR2) signalling is dependent on its collagen binding and kinase activity. AB - Discoidin Domain Receptor 2 (DDR2) is a collagen-binding receptor tyrosine kinase that initiates delayed and sustained tyrosine phosphorylation signalling. To understand the molecular basis of this unique phosphorylation profile, here we utilise fluorescence microscopy to map the spatiotemporal localisation of DDR2 and tyrosine phosphorylated proteins upon stimulation with collagen. We show that cellular phosphorylated proteins are localised to the interface where DDR2 is in contact with collagen and not in the early endosomes or lysosomes. We find that DDR2 localisation is independent of integrin activation and the key DDR2 signalling effector SHC1. Structure-function analysis reveals that DDR2 mutants defective for collagen binding or kinase activity are unable to localise to the cell surface, demonstrating for the first time that both collagen binding and kinase functions are required for spatial localisation of DDR2. This study provides new insights into the underlying structural features that control DDR2 activation in space and time. PMID- 29709486 TI - Preservation of fertility in surgery of benign and borderline malignant ovarian tumors. AB - Benign ovarian tumors occur in 7% of women during their procreative years and involve both organic and functional tumors. The average age of onset for borderline ovarian tumors is ten years younger than that for ovarian cancers. Women with benign and borderline malignant ovarian tumors are therefore more likely to be affected by fertility issues. The causal link between infertility and benign ovarian tumor stems more from the therapeutic strategies adopted than from the histological nature of the benign ovarian tumor. The question of fertility preservation must therefore be addressed in the management of these patients through respect for "correct" surgical indications, through gestures centered around ovarian preservation, and finally, if necessary, by recourse to fertility preservation techniques. PMID- 29709487 TI - Urea Improves Stability of Inactivated Polio Vaccine Serotype 3 During Lyophilization and Storage in Dried Formulations. AB - Stable formulations of inactivated polio vaccine (IPV) could reduce cold-chain requirements and increase distribution of the vaccine to developing countries. Recently, significant improvement in thermal stability of IPV vaccines has been achieved by including urea in lyophilized formulations. In the present study, we investigated the effects of urea on recovery of potency of IPV after lyophilization and storage at 37 degrees C and the correlation of potency recovery with key biophysical properties of IPV. By dynamic light scattering and transmission light microscopy, we found that loss of potency appeared to be due to agglomeration of virus particles during lyophilization and that moderate concentrations (e.g., 0.4 M) of urea reduced agglomeration and improved potency recovery. In addition, the relative thermal stability of the viron proteins was assessed after rehydration with temperature-dependent intrinsic fluorescence. Lyophilization of formulations without urea and postdrying storage resulted in reduced apparent melting temperatures in rehydrated samples. In formulations with urea, the rehydrated samples had thermal transitions and melting temperatures that were similar to those observed in aqueous control samples. Overall, the results indicated that in IPV formulations, urea improved potency recovery by inhibiting viron particle agglomeration and reducing denaturation of viron proteins. PMID- 29709488 TI - Spectral Reflectance Measurement of Evaporating Chemical Films: Initial Results and Application to Skin Permeation. AB - The present study has 2 aims. First, the method of spectral reflectance was used to measure evaporation rates of thin (~25-300 MUm) films of neat liquid volatile organic chemicals exposed to a well-regulated wind speed u. Gas-phase evaporation mass transfer coefficient (kevap) measurements of 10 chemicals, 9 of which were measured at similar u, are predicted (slope of log-log data = 1.01; intercept = 0.08; R2 = 0.996) by a previously proposed mass transfer correlation. For one chemical, isoamyl alcohol, the dependence of kevap on u0.52 was measured, in support of the predicted exponent value of 1/2. Second, measured kevap of nicotine was used as an input in analytical models based on diffusion theory to estimate the absorbed fraction (Fabs) of a small dose (5 MUL/cm2) applied to human epidermis in vitro. The measured Fabs was 0.062 +/- 0.023. Model-estimated values are 0.066 and 0.115. Spectral reflectance is a precise method of measuring kevap of liquid chemicals, and the data are well described by a simple gas-phase mass transfer coefficient. For nicotine under the single exposure condition measured herein, Fabs is well-predicted from a theoretical model that requires knowledge of kevap, maximal dermal flux, and membrane lag time. PMID- 29709489 TI - Application of Empirical Phase Diagrams for Multidimensional Data Visualization of High-Throughput Microbatch Crystallization Experiments. AB - Protein phase diagrams are a tool to investigate the cause and consequence of solution conditions on protein phase behavior. The effects are scored according to aggregation morphologies such as crystals or amorphous precipitates. Solution conditions affect morphologic features, such as crystal size, as well as kinetic features, such as crystal growth time. Commonly used data visualization techniques include individual line graphs or phase diagrams based on symbols. These techniques have limitations in terms of handling large data sets, comprehensiveness or completeness. To eliminate these limitations, morphologic and kinetic features obtained from crystallization images generated with high throughput microbatch experiments have been visualized with radar charts in combination with the empirical phase diagram method. Morphologic features (crystal size, shape, and number, as well as precipitate size) and kinetic features (crystal and precipitate onset and growth time) are extracted for 768 solutions with varying chicken egg white lysozyme concentration, salt type, ionic strength, and pH. Image-based aggregation morphology and kinetic features were compiled into a single and easily interpretable figure, thereby showing that the empirical phase diagram method can support high-throughput crystallization experiments in its data amount as well as its data complexity. PMID- 29709490 TI - Mental health multimorbidity and poor quality of life in patients with schizophrenia. AB - OBJECTIVE: While "dual diagnosis" involving both psychiatric and substance use disorders has long been a focus of schizophrenia research, recent studies have advocated for a shift of focus to multimorbidity, addressing comorbidity from both additional psychiatric disorders and substance use disorders. We hypothesized that more extensive mental health multimorbity would be associated with poorer quality of life (QOL) and functioning, and that additional psychiatric comorbidity in schizophrenia would have similar adverse effects on QOL as substance use comorbidity. METHODS: Participants with schizophrenia in the NIMH-funded Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) were classified using baseline diagnostic data into four groups: 1) monomorbid schizophrenia: 2) additional psychiatric comorbidity, 3) additional substance use comorbidity, and 4) both additional psychiatric and substance use comorbidity. Mixed models compared groups on self-reported QOL (SF-12 and Lehman QOLI) and rater-evaluated QOL (the Quality of Life Scale) using baseline, 6, 12 and 18 month follow-up data. RESULTS: As hypothesized, patients with schizophrenia alone had a better QOL than those with any multimorbidity; patients with both psychiatric and substance use comorbidities had a worse QOL than those with fewer comorbidities; and patients with comorbid substance use alone were not significantly worse off than those with comorbid psychiatric disorder. CONCLUSION: The multimorbidity framework more richly differentiates complex clinical presentations of schizophrenia than the current dual diagnosis concept and deserves further study as to its etiology, consequences, and treatment. PMID- 29709491 TI - Resting-state network connectivity and metastability predict clinical symptoms in schizophrenia. AB - BACKGROUND: The functional architecture of resting-state networks (RSNs) is defined by their connectivity and metastability. Disrupted RSN connectivity has been amply demonstrated in schizophrenia while the role of metastability remains poorly defined. Here, we undertake a comprehensive characterisation of RSN organization in schizophrenia and test its contribution to the clinical profile of this disorder. METHODS: We extracted RSNs representing the default mode (DMN), central executive (CEN), salience (SAL), language (LAN), sensorimotor (SMN), auditory (AN) and visual (VN) networks from resting-state functional magnetic resonance imaging data obtained from patients with schizophrenia (n = 85) and healthy individuals (n = 48). For each network, we computed its functional cohesiveness and integration and used the Kuramoto order parameter to compute metastability. We used stepwise multiple regression analyses to test these RSN features as predictors of symptom severity in patients. RESULTS: RSN features respectively explained 14%, 17%, 12% and 5% of the variance in positive, negative, anxious/depressive and agitation/disorganization symptoms. Lower functional integration between the DMN, CEN and SMN primarily contributed to positive symptoms. The functional properties of the SAL network were key predictors of all other symptom dimensions; specifically, lower cohesiveness of the SAL, lower integration of this network with the LAN and higher integration with the CEN respectively contributed to negative, anxious/depressive and disorganization symptoms. Increased SAL metastability was associated with negative symptoms. CONCLUSIONS: These results confirm the primacy of the SAL network for schizophrenia and demonstrate that abnormalities in RSN connectivity and metastability are significant predictors of schizophrenia-related psychopathology. PMID- 29709492 TI - Fibrillin microfibrils and proteases, key integrators of fibrotic pathways. AB - Supramolecular networks composed of multi-domain ECM proteins represent intricate cellular microenvironments which are required to balance tissue homeostasis and direct remodeling. Structural deficiency in ECM proteins results in imbalances in ECM-cell communication resulting often times in fibrotic reactions. To understand how individual components of the ECM integrate communication with the cell surface by presenting growth factors or providing fine-tuned biomechanical properties is mandatory for gaining a better understanding of disease mechanisms in the quest for new therapeutic approaches. Here we provide an overview about what we can learn from inherited connective tissue disorders caused primarily by mutations in fibrillin-1 and binding partners as well as by altered ECM processing leading to defined structural changes and similar functional knock-in mouse models. We will utilize this knowledge to propose new molecular hypotheses which should be tested in future studies. PMID- 29709493 TI - Immune parameters in different age classes of captive male Steller's eiders (Polysticta stelleri). AB - The immune system is important for host defense against antigens, but little is known about Steller's eider (Polysticta stelleri) immunology. This study compared hematological parameters, serum protein levels, lymphocyte proliferation, heat shock protein levels and oxidative damage in four different age classes of captive male Steller's eiders. The hatch year cohort had significantly higher total white blood cell and lymphocyte counts. The second year cohort had significantly higher albumin, alpha globulins and lymphocyte proliferation, and significantly lower beta globulin levels. The 9 year old males had a significantly higher IgY:IgY(DeltaFc) ratio. The oldest eiders in the study, 14 + year old males, had significantly higher serum IgY, pre-albumin and glutathione reductase activity, and the lowest lymphocyte proliferation. This study provided a baseline of immune parameters in captive male Steller's eiders, and the results suggested the parameters were influenced by age-related changes. PMID- 29709494 TI - Pyloric sphincter characteristics using EndoFLIP(r) in gastroparesis. AB - INTRODUCTION AND AIMS: Pyloric sphincter abnormalities may be detected in gastroparesis. Botulinum toxin A (BoNT/A) injection into the pylorus has been used to treat gastroparesis with varying results. The aim of the present article was to assess whether pyloric sphincter characteristics using the endoscopic functional lumen imaging probe (EndoFLIP(r)) with impedance planimetry in patients with gastroparesis correlated with symptoms, gastric emptying, and therapeutic response to pyloric sphincter BoNT/A injection. METHODS: EndoFLIP(r) study was performed on patients undergoing gastroparesis treatment with BoNT/A. The gastroparesis cardinal symptom index (GCSI) was applied prior to treatment and at post-treatment weeks 2, 4, 8, and 12. RESULTS: Forty-four patients were enrolled (30 with idiopathic gastroparesis, 14 with diabetic gastroparesis). Smaller pyloric diameter, cross-sectional area (CSA), and distensibility correlated with worse vomiting and retching severity at baseline. Greater gastric retention tended to correlate with decreased CSA and pyloric distensibility. BoNT/A treatment resulted in a significant decrease in the GCSI score at 2 and 4 weeks after treatment, but not at post-treatment weeks 8 or 12. Nausea, early satiety, postprandial fullness, and upper abdominal pain improved up to 12 weeks, whereas loss of appetite, stomach fullness, and stomach visibly larger improved only up to 4 weeks. Retching and vomiting failed to improve. Greater pyloric compliance at baseline correlated with greater improvement in early satiety and nausea at 8 weeks and greater pyloric distensibility correlated with improvement in upper abdominal pain. CONCLUSIONS: EndoFLIP(r) characteristics of the pylorus provided important pathophysiologic information in patients with gastroparesis, in relation to symptoms, gastric emptying, and predicting the response to treatment directed at the pylorus. PMID- 29709495 TI - Morphological changes induced by intraprostatic PSA-based vaccine in prostate cancer biopsies (phase I clinical trial). AB - Immunotherapy is a novel treatment for many tumors including prostate cancer. Little is known about the histological changes in prostate biopsies caused by the prostate-specific antigen (PSA)-based vaccine. This study evaluated the histopathological effects in prostate biopsies of recombinant fowlpox (rF) virus based vaccine engineered to present the PSA and 3 costimulatory molecules (collectively labeled as PSA-TRICOM). This vaccine has shown that it can break tolerance of the PSA, and its administration directly into a tumor enables the affected tumor cells to act as antigen-presenting cells activating new T cells and broadening the immune response to recognize and kill tumor. We studied 10 patients with recurrent prostate cancer who had failed radiation therapy and/or androgen-deprivation therapy. Pre- and posttreatment biopsies were compared. Posttreatment biopsies induced 8 cases with residual adenocarcinoma despite evidences of treatment effect and inflammation, 2 cases did not show any residual tumor, and 1 one case did not have any inflammatory infiltrate or any evidence of treatment effect. The inflammatory infiltrate varied from mild to severe and was composed of mononuclear cells. Greater numbers of infiltrating CD8+ lymphocytes were identified around prostatic glands and within the epithelial lining. The most remarkable feature was the presence of increased eosinophils around the glands and stroma. Three cases showed areas of necrosis surrounded by lymphocytes and palisading epithelioid macrophages arranged in granuloma-like pattern with multinucleated giant cells. This description of these morphological changes induced by the PSA-TRICOM will help to interpret the results of future intratumoral vaccine therapy trials. PMID- 29709496 TI - Molecular markers associated with development and progression of potentially premalignant oral epithelial lesions: Current knowledge and future implications. AB - Identification and management of potentially premalignant oral epithelial lesions (PPOELs) at highest risk of malignant transformation holds great promise for successful secondary prevention of oral squamous cell carcinoma, potentially reducing oral cancer morbidity and mortality. However, to date, neither clinical nor histopathologic validated risk predictors that can reliably predict which PPOELs will definitively progress to malignancy have been identified. In addition, the management of PPOELs remains a major challenge. Arguably, progress in the prevention and treatment of oral premalignancy and cancer will require improved understanding of the underlying molecular mechanisms, facilitating the discovery of diagnostic, prognostic, and predictive markers, as well as the identification of novel targeted therapeutics. This review provides a synopsis of the molecular biomarkers that have been studied in PPOELs and have been correlated with the presence and grade of dysplasia and/or their propensity to undergo malignant transformation to oral squamous cell carcinoma. The emphasis is on highlighting new emerging research fields, particularly epigenetic events, including methylation and micro-RNA regulation. Several promising biomarkers are highlighted. Current limitations and challenges are discussed. Recommendations for future focused research areas, to validate and promote clinically useful applications, are offered. PMID- 29709498 TI - Clinical and biomechanical changes following a 4-month toe-out gait modification program for people with medial knee osteoarthritis: a randomized controlled trial. AB - OBJECTIVE: To compare changes in knee pain, function, and loading following a 4 month progressive walking program with or without toe-out gait modification in people with medial tibiofemoral knee osteoarthritis. DESIGN: Individuals with medial knee osteoarthritis were randomized to a 4-month program to increase walking activity with (toe-out) or without (progressive walking) concomitant toe out gait modification. The walking program was similar between the two groups, except that the gait modification group was trained to walk with 15 degrees more toe-out. Primary outcomes included: knee joint pain (WOMAC), foot progression angles and knee joint loading during gait (knee adduction moment (KAM)). Secondary outcomes included WOMAC function, timed stair climb, and knee flexion moments during gait. RESULTS: Seventy-nine participants (40 in toe-out group, 39 in progressive walking group) were recruited. Intention-to-treat analysis showed no between-group differences in knee pain, function, or timed stair climb. However, the toe-out group exhibited significantly greater changes in foot progression angle (mean difference = -9.04 degrees (indicating more toe-out), 95% CI: -11.22 degrees , -6.86 degrees ; P < 0.001), late stance KAM (mean difference = -0.26 %BW*ht, 95% CI: -0.39 %BW*ht, -0.12 %BW*ht, P < 0.001) and KAM impulse (-0.06 %BW*ht*s, 95% CI: -0.11 %BW*ht*s, -0.01 %BW*ht*s; P = 0.031) compared to the progressive walking group at follow-up. The only between-group difference that remained at a 1-month retention assessment was foot progression angle, with greater changes in the toe-out group (mean difference = -6.78 degrees , 95% CI: -8.82 degrees , -4.75 degrees ; P < 0.001). CONCLUSIONS: Though both groups experienced improvements in self-reported pain and function, only the toe out group experienced biomechanical improvements. TRIALS REGISTRY NUMBER: NCT02019108. PMID- 29709497 TI - Reduced Cortical Excitability, Neuroplasticity, and Salivary Cortisol in 11-13 Year-Old Children Born to Women with Gestational Diabetes Mellitus. AB - BACKGROUND: Children exposed to gestational diabetes mellitus (GDM) in utero are at increased risk of neurodevelopmental difficulties, including autism and impaired motor control. However, the underlying neurophysiology is unknown. METHODS: Using transcranial magnetic stimulation, we assessed cortical excitability, long-term depression (LTD)-like neuroplasticity in 45 GDM-exposed and 12 control children aged 11-13 years. Data were analysed against salivary cortisol and maternal diabetes severity and treatment (insulin [N = 22] or metformin [N = 23]) during pregnancy. FINDINGS: GDM-exposed children had reduced cortical excitability (p = .003), LTD-like neuroplasticity (p = .005), and salivary cortisol (p < .001) when compared with control children. Higher maternal insulin resistance (IR) before and during GDM treatment was associated with a blunted neuroplastic response in children (p = .014) and this was not accounted for by maternal BMI. Additional maternal and neonatal measures, including fasting plasma glucose and inflammatory markers, predicted neurophysiological outcomes. The metformin and insulin treatment groups had similar outcomes. INTERPRETATION: These results suggest that GDM can contribute to subtle differences in child neurophysiology, and possibly cortisol secretion, persisting into early adolescence. Importantly, these effects appear to occur during second trimester, before pharmacologic treatment typically commences, and can be predicted by maternal insulin resistance. Therefore, earlier detection and treatment of GDM may be warranted. Metformin appears to be safe for these aspects of neurodevelopment. PMID- 29709499 TI - In thumb base osteoarthritis structural damage is more strongly associated with pain than synovitis. AB - OBJECTIVE: Osteoarthritis in thumb base joints (first carpometacarpal (CMC-1), scaphotrapeziotrapezoid (STT)) is prevalent and disabling, yet focussed studies are scarce. Our aim was to investigate associations between ultrasonographic and magnetic resonance imaging (MRI) inflammatory features, radiographic osteophytes, and thumb base pain in hand osteoarthritis patients. DESIGN: Cross-sectional analyses were performed in cohorts with MRI (n = 202) and ultrasound measurements (n = 87). Pain upon thumb base palpation was assessed. Radiographs were scored for CMC-1/STT osteophytes. Synovial thickening, effusion and power Doppler signal in CMC-1 joints were assessed with ultrasound. MRIs were scored for synovitis and bone marrow lesions (BMLs) in CMC-1 and STT joints using OMERACT-TOMS. Associations between ultrasound/MRI features, osteophytes, and thumb base pain were assessed. Interaction between MRI features and osteophytes was explored. RESULTS: In 289 patients (mean age 60.2, 83% women) 139/376 thumb bases were painful. Osteophyte presence was associated with pain (MRI cohort: odds ratio (OR) 5.1 (2.7-9.8)). Ultrasound features were present in 25-33% of CMC-1 joints, though no associations were seen with pain. MRI-synovitis and BMLs grade >=2 were scored in 25% and 43% of thumb bases, and positively associated with pain (OR 3.6 (95% CI 1.7-7.6) and 3.0 (1.6-5.5)). Associations attenuated after adjustment for osteophyte presence. Combined presence of osteophytes and MRI-synovitis had an additive effect. CONCLUSIONS: Ultrasonographic and MRI inflammatory features were often present in the thumb base. Osteophytes were more strongly associated with thumb base pain than inflammatory features, in contrast to findings in finger OA studies, supporting thumb base osteoarthritis as a distinct phenotype. PMID- 29709500 TI - Maturation of vocal emotion recognition: Insights from the developmental and neuroimaging literature. AB - Emotions are implicitly expressed in both facial expressions and prosodic components of vocal communication. The ability to recognize nonverbal cues of emotion is an important feature of social competence that matures gradually across childhood and adolescence. Compared to the extensive knowledge about the development of emotion recognition (ER) from facial displays of emotion, relatively little is known about the maturation of this ability in the auditory domain. The current review provides an overview of knowledge about the development of vocal emotion recognition from behavioural studies, and neural mechanisms that might contribute to this maturational process. Youth are thought to reach adult-like vocal ER ability in early or late adolescence. At a neural level, several structural and functional changes occur in the adolescent brain that may impact the representation of emotional information. However, there is a paucity of developmental neuroimaging work directly examining neural prosody processing in youth. We speculate that brain areas relevant to vocal perception in adults may undergo age-related changes that map onto increased vocal ER capacity. PMID- 29709501 TI - Spurious testosterone laboratory results in a patient taking synthetic alkaline phosphatase (asfotase alfa). AB - OBJECTIVES: We report a case of discordant total and free testosterone values in a patient with hypogonadism and juvenile hypophosphatasia after he initiated treatment with asfotase alfa, recombinant tissue non-specific alkaline phosphatase. METHODS: Total testosterone was evaluated using immunoassay pre and post initiation of therapy with asfotase alfa, and free testosterone was evaluated using radioimmunoassay and LC-MS/MS while on asfotase alfa therapy. RESULTS: Total testosterone measured by immunoassay was normal prior to therapy with asfotase alfa, and was low post initiation of therapy. During the same time frame, free testosterone measured using RAI and total testosterone measured using LC-MS/MS were normal on asfotase alfa therapy. This suggests assay interference with the total testosterone immunoassay. CONCLUSION: When laboratory results are discordant or do not match the clinical impression, the possibility of assay interference should be considered. Alternative laboratory methods free of the interference should be selected to evaluate these patients. HUMAN GENES DISCUSSED IN THE PAPER: ALPL gene, Approved name: Alkaline phosphatase, liver/bone/kidney, Synonym: Tissue non-specific alkaline phosphatase (TNSAP). PMID- 29709502 TI - Is the Venner-PneuX Endotracheal Tube System a Cost-Effective Option for Post Cardiac Surgery Care? AB - BACKGROUND: Ventilator-associated pneumonia (VAP) is common and costly. In a recent randomized controlled trial, the Venner-PneuX (VPX) endotracheal tube system (Qualitech Healthcare Limited, Maidenhead, United Kingdom) was found to be superior to standard endotracheal tubes (SET) in preventing VAP. However, VPX is considerably more expensive. We evaluated the costs and benefits of VPX to determine whether replacing SET with VPX is a cost-effective option for intensive care units. METHODS: We developed a decision analytic model to compare intubation with VPX or SET for patients requiring mechanical ventilation after cardiac operations. The model was populated with existing evidence on costs, effectiveness, and quality of life. Cost-effectiveness and cost-utility analyses were conducted from a National Health Service hospital perspective. Uncertainty was assessed through deterministic and probabilistic sensitivity analyses. RESULTS: Compared with SET, VPX is associated with an expected cost saving of L738 per patient. VPX led to a small increase in quality-adjusted life years, indicating that the device is overall less costly and more effective than SET. The probability of VPX being cost-effective at L30,000 per quality-adjusted life year is 97%. VPX would cease to be cost-effective if (1) it led to a risk reduction smaller than 0.02 compared with SET, (2) the acquisition cost of VPX was as high as L890, or (3) the cost of treating a case of VAP was lower than L1,450. CONCLUSIONS: VPX resulted in improved outcomes and savings that far offset the cost of the device, suggesting that replacing SET with VPX is overall beneficial. Findings were robust to extreme values of key variables. PMID- 29709503 TI - A Systemic Review and Meta-Analysis of Sutureless Aortic Valve Replacement Versus Transcatheter Aortic Valve Implantation. AB - BACKGROUND: Sutureless aortic valve replacement (SU-AVR) and transcatheter aortic valve implantation (TAVI) are increasingly adopted methods to treat high-risk patients with severe aortic valve stenosis. We conducted a systematic review and meta-analysis to compare the clinical outcomes between these two recent methods to treat aortic valve disease. METHODS: We systematically searched multiple databases (January 2000 to October 2016) to identify original studies comparing clinical outcome between SU-AVR and TAVI. End points studied were early mortality, development of paravalvular leak, early stroke, bleeding events, and the need for pacemaker insertion. A random-effect inverse-variance weighted analysis was performed. Event rates were compared as odds ratio (OR) and 95% confidence interval (CI). RESULTS: The meta-analysis included seven observational studies comprising 617 SU-AVR and 621 TAVI patients. Early mortality was 2.5% and 5% in the SU-AVR and TAVI cohorts, respectively (OR, 0.52; 95% CI, 0.30 to 0.90; p = 0.02; I2 = 2%). Postprocedural significant paravalvular leak was much lower after SU-AVR (OR, 0.18l; 95% CI, 0.11 to 0.30; p < 0.0001). Postprocedural stroke (OR, 0.71; 95% CI, 0.24 to 2.08; p = 0.53) and the need for pacemaker insertion (OR, 0.884; 95% CI, 0.364 to 2.18; p = 0.7) were comparable between the two cohorts. CONCLUSIONS: Our meta-analysis of observational studies demonstrates that early mortality is lower after SU-AVR than after TAVI in selected patients. The rates of stroke and pacemaker implant are comparable between procedures; however, the incidence of paravalvular leak is higher after TAVI. PMID- 29709504 TI - The pleiotropic transcriptional regulator COUP-TFI plays multiple roles in neural development and disease. AB - Transcription factors are expressed in a dynamic fashion both in time and space during brain development, and exert their roles by activating a cascade of multiple target genes. This implies that understanding the precise function of a transcription factor becomes a challenging task. In this review, we will focus on COUP-TFI (or NR2F1), a nuclear receptor belonging to the superfamily of the steroid/thyroid hormone receptors, and considered to be one of the major transcriptional regulators orchestrating cortical arealization, cell-type specification and maturation. Recent data have unraveled the multi-faceted functions of COUP-TFI in the development of several mouse brain structures, including the neocortex, hippocampus and ganglionic eminences. Despite NR2F1 mutations and deletions in humans have been linked to a complex neurodevelopmental disease mainly associated to optic atrophy and intellectual disability, its role during the formation of the retina and optic nerve remains unclear. In light of its major influence in cortical development, we predict that its haploinsufficiency might be the cause of other cognitive diseases, not identified so far. Mouse models offer a unique opportunity of dissecting COUP-TFI function in different regions during brain assembly; hence, the importance of comparing and discussing common points linking mouse models to human patients' symptoms. PMID- 29709505 TI - Effects of pulse width, waveform and current direction in the cortex: A combined cTMS-EEG study. AB - BACKGROUND: the influence of pulse width, pulse waveform and current direction on transcranial magnetic stimulation (TMS) outcomes is of critical importance. However, their effects have only been investigated indirectly with motor-evoked potentials (MEP). By combining TMS and EEG it is possible to examine how these factors affect evoked activity from the cortex and compare that with the effects on MEP. OBJECTIVE: we used a new controllable TMS device (cTMS) to vary systematically pulse width, pulse waveform and current direction and explore their effects on global and local TMS-evoked EEG response. METHODS: In 19 healthy volunteers we measured (1) resting motor threshold (RMT) as an estimate of corticospinal excitability; (2) global mean field power (GMFP) as an estimate of global cortical excitability; and (3) local mean field power (LMFP) as an estimate of local cortical excitability. RESULTS: RMT was lower with monophasic posterior-to-anterior (PA) pulses that have a longer pulse width (p < 0.001). After adjusting for the individual motor threshold of each pulse type we found that (a) GMFP was higher with monophasic pulses (p < 0.001); (b) LMFP was higher with longer pulse width (p = 0.015); (c) early TEP polarity was modulated depending on the current direction (p = 0.01). CONCLUSIONS: Despite normalizing stimulus intensity to RMT, we found that local and global responses to TMS vary depending on pulse parameters. Since EEG responses can vary independently of the MEP, titrating parameters of TMS in relation to MEP threshold is not a useful way of ensuring that a constant set of neurons is activated within a cortical area. PMID- 29709506 TI - Motor asymmetry and neuromelanin imaging: Concordance in Parkinson's disease. AB - BACKGROUND: The onset of motor symptoms in Parkinson's disease (PD) is characteristically asymmetric and correlates with dopaminergic deficit of contralateral basal ganglia. This study explored the concordance between motor asymmetry and changes of substantia nigra pars compacta (SNc) using neuromelanin sensitive imaging. METHODS: Forty-four subjects with PD and fifteen healthy controls were included in this study. Clinical laterality (CL) was based on the motor sub scores of the Unified Parkinson's Disease Rating Scale-Part III. All subjects underwent neuromelanin-sensitive imaging and imaging laterality (IL) was based on the differences between contrast ratios of the right and left lateral SNc. Concordance was evaluated by correlating CL and IL. RESULTS: Motor asymmetry at disease onset was reported in 97.72% of subjects with PD, of which 65.90% reported right-sided onset. Forty-three subjects were right-handed and 68.18% reported onset of symptoms on dominant side. Right CL was observed in 59.09%, left CL in 40.90%, right IL in 11.36% and left IL in 88.63%. Concordance was established in 61.36%, majority of whom had a combination of right CL and left IL. In healthy controls, a significantly lower contrast ratio of the left lateral SNc was also noted. CONCLUSIONS: Handedness may correlate with motor asymmetry and left hemisphere may have a predilection for neurodegeneration. The finding of significant neuronal loss of left SNc in controls warrants further evaluation for better understanding of motor asymmetry in PD. Neuromelanin sensitive imaging can be a useful tool to study the relationship between motor asymmetry and nigrostriatal dysfunction. PMID- 29709507 TI - Anosognosia for cognitive and behavioral symptoms in Parkinson's disease with mild dementia and mild cognitive impairment: Frequency and neuropsychological/neuropsychiatric correlates. AB - INTRODUCTION: Anosognosia is a multidimensional phenomenon with detrimental effects on patients' illness course, therapy compliance and quality of life. We aimed at investigating anosognosia for cognitive and behavioral symptoms in Parkinson's Disease (PD) with dementia (PDD) and, for the first time, in PD with Mild Cognitive Impairment (MCI-PD). METHODS: Community dwelling subjects (47 mild PDD, 136 multidomain MCI-PD (mdMCI-PD), 5 single domain MCI-PD (sdMCI-PD), and 197 PD without cognitive impairment (noCI-PD) were enrolled in a cross-sectional design study. All the subjects were administered the Anosognosia Questionnaire for Dementia, the Mental Deterioration Battery and a number of neuropsychiatric inventories. RESULTS: A diagnosis of anosognosia was made in 36% of patients with mild PDD and 16% with mdMCI-PD, whether it was negligible in sdMCI-PD and noCI PD. Higher severity of anosognosia for cognitive impairment was also found in PDD and in mdMCI-PD. SdMCI-PD had the lower severity of anosognosia for cognitive impairment. Higher anosognosia for cognitive impairment was associated to lower depression in noCI-PD (r = -0.227, p = 0.0013) and mdMCI-PD (r = -0.266, p = 0.0016), and to reduced hedonic tone in noCI-PD (r = -0.191, p = 0.0071). Greater anosognosia was associated to lower executive performances in PDD (r = 0.424, p = 0.0074). CONCLUSIONS: Anosognosia for non-motor symptoms is frequent in PD patients with mild dementia or mdMCI. Results confirm the role of neuropsychiatric characteristics in anosognosia also in PD, the high prevalence of anosognosia in neurodegenerative illnesses and suggest a common pathogenic path for anosognosia in different neurodegenerative and psychiatric disorders. PMID- 29709508 TI - Genomic characterization of a RdRp-recombinat nebovirus strain with a novel VP1 genotype. AB - Nebovirus is a new genus within the family Caliciviridae and is a causative agent of calf diarrhea. The limited nebovirus genomic sequences that are currently available has hampered understanding of nebovirus genetic evolution. The aim of the present study was to determine the genomic characterization of strain Bo/LZB 1/17/CH, which was previously identified as being similar to the novel genotype strain Bo/DijonA216/06/FR based on partial capsid sequences. Our results show that the complete RNA genome of strain Bo/LZB-1/17/CH is 7453 nucleotides (nt) in length and shares 79.0%-83.5% nt identity with all available nebovirus genomes in the GenBank database. A phylogenetic analysis based on its complete genome sequence revealed that strain Bo/LZB-1/17/CH clustered into an independent branch. Two interesting characteristics were observed in the genome of strain Bo/LZB-1/17/CH. First, the major capsid protein (VP1) of strain Bo/LZB-1/17/CH shares 96.6% amino acid (aa) identity with strain Bo/DijonA216/06/FR but shares only 75.2%-76.8% aa identity with other nebovirus strains and has an even lower identity in the P2 domain (61.1%-65% aa identity). Second, the RNA-dependent RNA polymerase (RdRp) of strain Bo/LZB-1/17/CH is more closely related to NB-like strains than it is to strain Bo/DijonA216/06/FR, and a recombination event was identified within the 3' end of the RdRp in strain Bo/LZB-1/17/CH. In conclusion, the results in this study indicate that strain Bo/LZB-1/17/CH may represent a novel nebovirus strain. To the best of our knowledge, this is the first description of a recombinant event in nebovirus RdRp. PMID- 29709509 TI - Notch3 is involved in adipogenesis of human adipose-derived stromal/stem cells. AB - Human adipose-derived stromal/stem cells (hASCs) have tremendous therapeutic potential and the ability to offer insight into human development and disease. Here we subject human ASCs to siRNA-mediated knockdown of Notch3 cultured under both self-renewing and adipogenic differentiation conditions. Self-renewal was monitored by assessing viability and proliferation rates through staining and alamarBlue assays, respectively. Adipogenesis was measured through Oil-Red O staining, western blot, and quantitative real-time RT-PCR that determined expression levels of multipotency and adipogenic markers over time. Notch3 was expressed in self-renewing hASCs but knockdown, as validated by qRT-PCR and western blot, showed no impact on cell viability, as measured through live-dead staining, or cell proliferation rates, as measured through alamarBlue assays. However, although Notch3 expression was observed to increase during adipogenesis, in the absence of Notch3 there was a significant increase in hASC adipogenesis as demonstrated through an increased number of lipid vesicles, and increased expression of adipogenic markers ppar-gamma, adiponectin, fabp4, and plin2. Although Notch3 is only one of four Notch receptors expressed on the surface of hASCs, this receptor appears important for proper regulation of adipogenic differentiation, possibly serving as a negative regulator to prevent inappropriate adipogenesis or promote other lineage commitments of ASCs. PMID- 29709511 TI - Maternal pomegranate juice attenuates maternal inflammation-induced fetal brain injury by inhibition of apoptosis, neuronal nitric oxide synthase, and NF-kappaB in a rat model. AB - BACKGROUND: Maternal inflammation is a risk factor for neonatal brain injury and future neurological deficits. Pomegranates have been shown to exhibit anti inflammatory, anti-apoptotic and anti-oxidant activities. OBJECTIVE: We hypothesized that pomegranate juice (POM) may attenuate fetal brain injury in a rat model of maternal inflammation. STUDY DESIGN: Pregnant rats (24 total) were randomized for intraperitoneal lipopolysaccharide (100 MUg/kg) or saline at time 0 at 18 days of gestation. From day 11 of gestation, 12 dams were provided ad libitum access to drinking water, and 12 dams were provided ad libitum access to drinking water with pomegranate juice (5 mL per day), resulting in 4 groups of 6 dams (saline/saline, pomegranate juice/saline, saline/lipopolysaccharide, pomegranate juice/lipopolysaccharide). All dams were sacrificed 4 hours following the injection and maternal blood and fetal brains were collected from the 4 treatment groups. Maternal interleukin-6 serum levels and fetal brain caspase 3 active form, nuclear factor-kappaB p65, neuronal nitric oxide synthase (phosphoneuronal nitric oxide synthase), and proinflammatory cytokine levels were determined by enzyme-linked immunosorbent assay and Western blot. RESULTS: Maternal lipopolysaccharide significantly increased maternal serum interleukin-6 levels (6039 +/- 1039 vs 66 +/- 46 pg/mL; P < .05) and fetal brain caspase 3 active form, nuclear factor-kappaB p65, phosphoneuronal nitric oxide synthase, and the proinflammatory cytokines compared to the control group (caspase 3 active form 0.26 +/- 0.01 vs 0.20 +/- 0.01 U; nuclear factor-kappaB p65 0.24 +/- 0.01 vs 0.1 +/- 0.01 U; phosphoneuronal nitric oxide synthase 0.23 +/- 0.01 vs 0.11 +/- 0.01 U; interleukin-6 0.25 +/- 0.01 vs 0.09 +/- 0.01 U; tumor necrosis factor alpha 0.26 +/- 0.01 vs 0.12 +/- 0.01 U; chemokine (C-C motif) ligand 2 0.23 +/- 0.01 vs 0.1 +/- 0.01 U). Maternal supplementation of pomegranate juice to lipopolysaccharide-exposed dams (pomegranate juice/lipopolysaccharide) significantly reduced maternal serum interleukin-6 levels (3059 +/- 1121 pg/mL, fetal brain: caspase 3 active form (0.2 +/- 0.01 U), nuclear factor-kappaB p65 (0.22 +/- 0.01 U), phosphoneuronal nitric oxide synthase (0.19 +/- 0.01 U) as well as the brain proinflammatory cytokines (interleukin-6, tumor necrosis factor alpha and chemokine [C-C motif] ligand 2) compared to lipopolysaccharide group. CONCLUSION: Maternal pomegranate juice supplementation may attenuate maternal inflammation-induced fetal brain injury. Pomegranate juice neuroprotective effects might be secondary to the suppression of both the maternal inflammatory response and inhibition of fetal brain apoptosis, neuronal nitric oxide synthase, and nuclear factor-kappaB activation. PMID- 29709510 TI - Subjective but Not Objective Sleep is Associated with Subsyndromal Anxiety and Depression in Community-Dwelling Older Adults. AB - OBJECTIVE: To examine the relationship between subclinical anxiety and depressive symptoms and objective sleep architecture measures and subjective sleep reports in older adults. METHODS: Community-dwelling older adults (N = 167) self-rated their current severity of anxiety symptoms, depressive symptoms, daytime sleepiness, and global sleep quality. Participants received overnight ambulatory polysomnography to assess sleep architecture. Multivariate linear regression models examined associations between anxiety and depressive symptoms and objective and subjective sleep measures. RESULTS: Significant findings emerged for subjective sleep, with higher depression and anxiety scores associated with worse global sleep quality and greater anxiety scores associated with greater daytime sleepiness. No significant associations were observed between subclinical levels of anxiety or depressive symptoms with sleep architecture. CONCLUSION: Subclinical levels of late-life anxiety and depression have distinct associations with subjective sleep disturbance. Findings implicate subjective measures of sleep quality and daytime sleepiness as stronger trait markers for subthreshold psychiatric symptoms than objective sleep biomarkers. PMID- 29709512 TI - Changes in circular RNA expression patterns during human foetal brain development. AB - Circular RNAs (circRNAs) are a recently identified class of long non-coding RNAs and their expression is regulated in a tissue- and developmental stage-specific manner. Recent studies indicate the potential regulatory role that circRNAs may have, particularly in the brain, where they are most abundant. This study aims to elucidate changes in circRNA patterns during human embryonic brain development. We detected a number of differentially expressed genes that showed distinct expression profiles for circular and linear transcripts despite having originated from the same genes, implicating a dichotomy in the regulation of these two RNA species. Altogether our study showed that circular and linear RNAs have independent expression patterns, and that circular transcriptomes from different developing stages have distinct characteristics in terms of transcript abundance and isoform diversity. PMID- 29709513 TI - Differential circular RNAs expression in ovary during oviposition in honey bees. AB - Circular RNAs (circRNAs) are non-coding RNAs newly identified and play important roles in RNA regulation. The mechanism and function of circRNAs have been reported in some species. However, little is known regarding circRNAs in honey bees. In this study, we analyzed circRNAs through bioinformatics, and predicted 12,211 circRNAs in the ovary of honey bee queens. 1340, 175 and 100 circRNAs were differentially expressed in comparisons of egg-laying queens vs virgin queens, egg-laying inhibited queens vs egg-laying queens and egg-laying recovery queens vs egg-laying inhibited queens. Further, functional annotation of differentially expressed circRNAs revealed several pathways that are closely related to ovary activation and oviposition, including insulin secretion and calcium signaling pathways. Moreover, the potential interactions among circRNAs, miRNAs, lncRNAs and mRNAs were investigated. Ame_circ_0005197 and ame_circ_0016640 were observed to sponge several reproductive related miRNAs. These findings demonstrate that circRNAs have potential effects in ovary activation and oviposition of honey bees. PMID- 29709514 TI - Genome engineering in ornamental plants: Current status and future prospects. AB - Ornamental plants, like roses, carnations, and chrysanthemums, are economically important and are sold all over the world. In addition, numerous cut and garden flowers add colors to homes and gardens. Various strategies of plant breeding have been employed to improve traits of many ornamental plants. These approaches span from conventional techniques, such as crossbreeding and mutation breeding, to genetically modified plants. Recently, genome editing has become available as an efficient means for modifying traits in plant species. Genome editing technology is useful for genetic analysis and is poised to become a common breeding method for ornamental plants. In this review, we summarize the benefits and limitations of conventional breeding techniques and genome editing methods and discuss their future potential to accelerate the rate breeding programs in ornamental plants. PMID- 29709515 TI - 5-Methoxyindole-2-carboxylic acid (MICA) suppresses Abeta-mediated pathology in C. elegans. AB - Alzheimer's disease (AD) is an age-related disease characterized by loss of memory and disrupted thinking that is associated with altered energy metabolism. Variants of an important enzyme of energy metabolism, dihydrolipoamide dehydrogenase (dld), have been genetically linked to late-onset AD. Moreover, reduced activity of DLD-containing enzyme complexes is associated with AD progression. To understand how energy metabolism influences AD progression, we exposed C. elegans expressing human Abeta peptide to the chemical inhibitor of DLD, 2-methoxyindole-5-carboxylic acid (MICA). Expression of human Abeta in C. elegans causes a variety of pathologies that can be used to monitor the efficacy of treatments against proteotixicity. We found that MICA alleviated the Abeta induced paralysis and improved cholinergic neurotransmission in C. elegans that express Abeta in muscle cells. MICA also reduced both hypersensitivity to serotonin and perturbation of chemotaxis associated with neuronal expression of human Abeta. Furthermore, low doses of MICA helped to alleviate an Abeta-mediated decrease in fecundity. Protection against AD pathogenesis by MICA in the C. elegans model was associated with a decrease in Abeta oligomerization that could be reversed by the calcium ionophore, A23187. MICA also caused a decrease in oxidative stress, which could also contribute to the protective effect of MICA against Abeta toxicity. PMID- 29709516 TI - Cancer-associated fibroblasts-stimulated interleukin-11 promotes metastasis of gastric cancer cells mediated by upregulation of MUC1. AB - Cancer-associated fibroblasts (CAFs) are major components of the tumor stroma and regulators of tumor progression. However, the molecular mechanism by which CAFs promote gastric cancer progression should be further explored. In our study, we found that interleukin-11 (IL-11) secretion was significantly increased when CAFs were co-cultured with gastric cancer cells. Co-culture system-derived IL-11 promoted the migration and invasion of gastric cancer cells, whereas the increase of migration and invasion was attenuated by a neutralizing antibody of IL-11 or inhibition of JAK/STAT3 and MAPK/ERK pathways with specific inhibitors. Taken together, these results revealed that CAFs play a significant role in the gastric cancer progression in the tumor microenvironment through IL-11-STAT3/ERK signaling by upregulating MUC1. Also, IL-11 targeted therapy can achieve an effective treatment against gastric cancer indirectly by exerting their action on stromal fibroblasts. PMID- 29709517 TI - Maximally informative next experiments for nonlinear models. AB - Mathematical modeling is a powerful tool in systems biology; we focus here on improving the reliability of model predictions by reducing the uncertainty in model dynamics through experimental design. Model-based experimental design is a process by which experiments can be systematically chosen to reduce dynamic uncertainty in a given model. We discuss the Maximally Informative Next Experiment (MINE) method for group-wise selection of points in an experimental design and present a convergence result for MINE with nonlinear models. As an application, we illustrate the method on polynomial regression and an ODE model for immune system dynamics. The MINE criterion sequentially determines experiments that can be conducted to best refine model dynamics. PMID- 29709518 TI - The association between prenatal bisphenol A exposure and birth weight: a meta analysis. AB - The association between prenatal BPA exposure and birth weight is controversial. Here, a meta-analysis was performed to estimate the association between prenatal BPA exposure and birth weight. We searched literature addressing the association of interest in relevant databases. Data were independently extracted and analyzed using partial regression coefficient (beta) and/or odds ratio (OR) and their 95% confidence intervals (CIs). We identified 140 references and included 8 studies. Based on the results of meta-analysis, the association between prenatal BPA exposure and continuous birth weight was estimated to be 4.42 g (95% CI: -8.83 to 17.67 g) when comparing the highest vs. the lowest BPA concentration. Findings from this study indicated that prenatal BPA exposure was not statistically associated with continuous birth weight. However, more evidence, based on large prospective cohort studies, is required to provide conclusive evidence on whether or not prenatal BPA exposure is associated with birth weight. PMID- 29709520 TI - OGG1 Ser326Cys polymorphism, HIV, obesity and air pollution exposure influences adverse birth outcome susceptibility, within South African Women. AB - The global HIV and obesity epidemics are major public health concerns; particularly as both are associated with increased risk of adverse birth outcomes. Despite extensive research, their combined effect, in terms of birth outcomes, has not been investigated. A single-nucleotide polymorphism (SNP) within 8-oxoguanine glycosylase 1 (OGG1) (Ser326Cys) has been suggested to affect body mass indices and therefore could predispose South African (SA) women to adverse effects of obesity. This study investigated the associations of OGG1 Ser326Cys SNP in relation to HIV and obesity on the susceptibility of low birthweight (LBW) and pre-term birth (PTB) in SA women exposed to ambient air pollution living in Durban. In our study population, the OGG1 SNP was associated with HIV and obesity. Wild-type (CC)-carrying patients had increased susceptibility for HIV-associated LBW and PTB. Co-morbid HIV and obese patients delivered neonates with decreased birthweights. Living within the heavily polluted south-Durban and carrying the CC-genotype increased the risk for PTB within our study population. PMID- 29709521 TI - Balance Control and Energetics of Powered Exoskeleton-Assisted Sit-to-Stand Movement in Individuals With Paraplegic Spinal Cord Injury. AB - OBJECTIVE: To quantify the effects of initial hip angle and angular hip velocity settings of a lower-limb wearable robotic exoskeleton (WRE) on the balance control and mechanical energy requirements in patients with paraplegic spinal cord injuries (SCIs) during WRE-assisted sit-to-stand (STS). DESIGN: Observational, cross-sectional study. SETTING: A university hospital gait laboratory with an 8-camera motion analysis system, 3 forceplates, a pair of instrumented crutches, and a WRE. PARTICIPANTS: Patients (N=12) with paraplegic SCI. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The inclination angle (IA) of the body's center of mass (COM) relative to the center of pressure (COP), and the rate of change of IA (RCIA) for balance control, and the mechanical energy and forward COM momentum before and after seat-off for energetics during WRE-assisted STS were compared between conditions with 2 initial hip angles (105 degrees and 115 degrees ) and 3 initial hip angular velocities (800, 1000, 1200 rpm). RESULTS: No interactions between the main factors (ie, initial hip angle vs angular velocity) were found for any of the calculated variables. Greater initial hip angle helped the patients with SCI move the body forward with increased COM momentum but reduced RCIA (P<.05). With increasing initial angular hip velocity, the IA and RCIA after seat-off (P<.05) increased linearly while total mechanical energy reduced linearly (P<.05). CONCLUSIONS: The current results suggest that a greater initial hip angle with smaller initial angular velocity may provide a favorable compromise between momentum transfer and balance of the body for people with SCI during WRE-assisted STS. The current data will be helpful for improving the design and clinical use of the WRE. PMID- 29709519 TI - Cardiopulmonary consequences of gestational toxicant exposure: Symposium overview at the 56th annual SOT meeting, Baltimore, MD. AB - Xenobiotic exposures affect the maternal and/or in utero environment resulting in impairments in fetal development. During the period of rapid fetal growth, developing cardiovascular systems are especially vulnerable to their environment. Furthermore, fetal exposures can evoke changes in epigenetic signatures that result in permanent modifications in gene expression. This symposium focused on the intersection between maternal and fetal exposure and the developing cardiovascular system. The impact of maternal exposures on prenatal development is of major concern for regulatory agencies given the unique vulnerability of the embryo/fetus to environmental factors, the importance of vascular biology to maternal-fetal interactions, and the adverse consequences of vascular disruption to children's health. Speakers provided data from diverse exposures: nanomaterials, particulate matter or air pollution (PM2.5), nicotine, and environmental chemicals. The current findings related to susceptible gestational windows for cardiovascular development and epigenetic, transcriptomic, toxicokinetic, and toxicodynamic changes in vascular physiology and cardiac function. In response to these concerns, new concepts in predictive modeling and risk assessment associated with in utero exposures were presented as future avenues of research within developmental toxicology. Finally, current applications using an Adverse Outcome Pathway framework for developmental toxicity were presented to integrate data from in vitro profiling of chemical libraries (e.g. ToxCastTM) with computational models for in silico toxicology. In summary, this symposium addressed the significant threats to cardiovascular health that are associated with fetal/perinatal exposures, and offered new insights into the predictive, mechanistic, and risk assessment strategies in developmental toxicology. PMID- 29709522 TI - Feasibility and Preliminary Validation of an Online Version of the Ohio State University Traumatic Brain Injury Identification Method. AB - OBJECTIVE: To test the feasibility and validity of an online version of an established interview designed to determine a lifetime history of traumatic brain injury (TBI). DESIGN: Cross-sectional. SETTING: General community. PARTICIPANTS: A volunteer sample of individuals (N= 265) from the general population across the United States. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE(S): Online version of the Ohio State University Traumatic Brain Injury Identification Method, Rivermead Postconcussion Symptoms Questionnaire (RPQ), Patient-Reported Outcomes Measurement Information System Cognitive Concerns Scale. RESULTS: The measure was completed by 89.4% of the sample with most participants completing the measure in <8 minutes. After controlling for age, sex, psychiatric history, drug or alcohol history, and history of developmental disability, worst TBI severity was significantly associated with scores on the RPQ, F(2,230)=4.56, P=.011, and having a TBI within the past 2 years was associated with higher scores on the cognitive factor subscale of the RPQ, F(1,75)=7.7, P=.007. CONCLUSIONS: The online administration of the Ohio State University Traumatic Brain Injury Identification Method appears to be feasible in the general population. Preliminary validity was demonstrated for the indices of worst TBI severity and time since most recent TBI. PMID- 29709523 TI - Knee Arthroplasty Patients Predicted Versus Actual Recovery: What Are Their Expectations About Time of Recovery After Surgery and How Long Before They Can Do the Tasks They Want to Do? AB - OBJECTIVES: (1) To determine evidence-based guidance for the length of time to return to specific valued functional and leisure activities after knee arthroplasty (KA). (2) To determine what patients feel are the most important functional or leisure activities to recover after KA. (3) To collect information about patients' expectations and compare them to the actual time it takes to return. DESIGN: Prospective longitudinal cohort observational survey. SETTING: Specialist orthopedic hospital. PARTICIPANTS: Patients (N=99) with osteoarthritis or rheumatoid arthritis (mean=69.9y [range 44-88]) listed for total knee arthroplasty (TKA) or unicompartmental knee arthroplasty. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Valued activities list (VAL) used to select activities patients expect to return to and report the actual time taken to return. RESULTS: Participants in unicompartmental knee arthroplasty group returned to the 6 most popular valued activities (walking >1km, stair climbing, housework, driving, gardening, and kneeling) 8%-33% more quickly than TKA group, and they were satisfied with performing these activities sooner on average (4% 18%) than the TKA group. The percentage of participants satisfied at 12 months postsurgery ranged from 96% returning to housework to 36% returning to kneeling. The Wilcoxon signed-rank test was used to compare the expected time and the actual time to return: Housework (Z=-5.631, P<.05, effect size=0.64) and swimming (Z=-3.209, P<.05, effect size=0.59) were quicker than expected, and walking >1 km (Z=-2.324, P<.05, effect size=0.27) was slower than expected. CONCLUSIONS: A more tailored and personalized approach with consideration of prior level of activity and comorbidities must be taken into account and adequately discussed to help bridge the gap between the expected and actual recovery time. PMID- 29709524 TI - Evidence of Generalized Muscle Stiffness in the Presence of Latent Trigger Points Within Infraspinatus. AB - OBJECTIVE: To evaluate stiffness of infraspinatus muscle tissue, both with and without latent trigger points, using ultrasound shear wave elastography (SWE). The primary hypothesis is that muscle with a latent trigger point will demonstrate a discrete region of increased shear wave speed. The secondary hypothesis is that shear wave speed (SWS) in the region with the trigger point will be higher in patients compared with controls, and will be similar between the two groups in the uninvolved regions. DESIGN: Case-control. SETTING: Hospital based outpatient physical therapy center. PARTICIPANTS: Convenience sample (N=18) of patients (6 female, 3 male, mean age=44) (range=31-61y) diagnosed with latent trigger points in infraspinatus and matched controls without trigger points. MAIN OUTCOME MEASURES: Shear wave speed (m/s). RESULTS: SWS of the latent trigger point (mean=4.09+/-SD1.4 m/s) did not differ from the adjacent muscle tissue (3.92+/-1.6 m/s, P>.05), but was elevated compared to corresponding tissue in controls (2.8+/-0.75 m/s, P=.02). SWS was generally greater in patients' uninvolved tissue (3.83+/-1.6 m/s) when compared to corresponding tissue in controls (2.62+/-0.2 m/s, P=.05). CONCLUSION: Although discrete regions of increased SWS corresponding to the trigger point were not observed in patients, evidence of generally increased muscle stiffness in infraspinatus was exhibited compared to healthy controls. Further study of additional muscles with SWE is warranted. PMID- 29709525 TI - Tracking Changes in Participation With Participation Measurement Scale in Community-Dwelling Stroke Survivors in Africa. AB - OBJECTIVE: To investigate responsiveness of the Participation Measurement Scale (PM-Scale) for the measurement of participation of stroke survivors. DESIGN: A 6 month observational study with 3 evaluation time points. Responsiveness of the PM Scale was investigated over a period of 6 months. SETTING: Rehabilitation centers. PARTICIPANTS: Stroke survivors (N =64); mean age +/- SD, 56.9+/-12.6 years; sex, 45 men (70%). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Participants were evaluated using the PM-Scale. The modified Rankin Scale was used to categorize the overall disability level for each participant. RESULTS: The mixed-effect model analysis showed a significant difference in the participation over time (chi2=35.04; df=2; P<.001). In addition, the model exhibited significant effects of the sex, age, and disability at enrollment on the subjects' participation levels. Furthermore, the PM-Scale detected different levels of changes in the entire cohort over time (small change, effect size [ES]=0.33; moderate change, ES=0.67; and large change, ES=1). The PM-Scale also facilitated the classification of the participants into discriminative categories such as important improvement (t score>=1.96; 1.8<=ES<=2.13), moderate improvement (024 mm Hg, alternative glaucoma procedure following ECP, or occurrence of visually significant complications. Analysis was performed to estimate risk factors for failure. RESULTS: A total of 27 aphakic and 8 pseudophakic eyes were included. Pretreatment IOP averaged 33.9 +/- 7.9 mm Hg. Final IOP after a mean follow-up period of 7.2 years was 18.9 +/- 8.8 mm Hg (P < 0.001). The success rate was 54% (19/35 eyes). The failure rate was not increased in pseudophakic patients relative to aphakic patients. Patients with single ECP demonstrated preserved visual acuity from baseline to final follow-up. CONCLUSIONS: In this patient cohort, with average follow-up period of 7.2 years, ECP was useful in the treatment of pediatric GFCS. PMID- 29709536 TI - Caged noble metals: Encapsulation of a cytotoxic platinum(II)-gold(I) compound within the ferritin nanocage. AB - The encapsulation of Pt and Au-based anticancer agents within a protein cage is a promising way to enhance the selectivity of these potential drugs. Here a cytotoxic organometallic compound containing platinum(II) and gold(I) has been encapsulated within a ferritin nanocage (AFt). Inductively plasma coupled mass spectrometry data, collected to evaluate the amount of Pt and Au within the cage, indicate disruption of the starting heterobimetallic complex upon encapsulation within the nanocage. The drug-loaded protein (Pt(II)/Au(I)-AFt) has been characterized by UV-Vis spectroscopy, circular dichroism and X-ray diffraction analysis. Data indicate that the protein maintains its fold upon encapsulation of the metallodrug and that Au(I) and Pt(II)-containing fragments are encapsulated within the AFt cage, with Au(I) ion that binds the side chain of Cys126 and Pt(II) in the bulk, respectively. The in vitro cytotoxicity of Pt(II)Au(I)-AFt, as well as that of the free heterobimetallic complex, has been comparatively evaluated on human cervix and breast cancer cells and against cardiomyoblasts and keratinocytes non-tumorigenic cells. Our data demonstrate that it is possible to obtain a protein nanocarrier containing both Pt and Au atoms starting from a bimetallic compound, opening the way for the design and development of new potential drugs based on protein nanocarriers. PMID- 29709537 TI - Anti-thrombogenicity and permeability of polyethersulfone hollow fiber membrane with sulfonated alginate toward blood purification. AB - The main aim of this study was to evaluate the suitability of sulfonated alginate as a modifying agent to enhance the hemocompatibility of self-fabricated polyethersulfone (PES) hollow fiber membrane for blood detoxification. Sodium alginate was sulfonated with a degree of 0.6 and immobilized on the membrane via surface amination and using glutaraldehyde as cross-linking agent. Coating layer not only improved the membrane surface hydrophilicity, but also induced -39.2 mV negative charges on the surface. Water permeability of the modified membrane was enhanced from 67 to 95 L/m2.h.bar and flux recovery ratio increased more than 2 fold. Furthermore, the modified membrane presented higher platelet adhesion resistance (reduced by more than 90%) and prolonged coagulation time (35 s for APTT and 14 s for PT) in comparison with the pristine PES hollow fiber membrane, which verified the improved anti-thrombogenicity of the modified membrane. On the other hand, obtained membrane after 3 h coating could remove up-to 60% of the uremic toxins. According to the obtained data, sulfonated alginate can be a promising modifying agent for the future blood-contacting membrane and specially blood purification issues. PMID- 29709538 TI - Bioaccessibility and inhibitory effects on digestive enzymes of carnosic acid in sage and rosemary. AB - In this study, the aim was to determine the bioaccessibilities of carnosic acid in sage and rosemary and in vitro inhibitory effects of these samples on lipid and starch digestive enzymes by evaluating the lipase, alpha-amylase and alpha glucosidase enzyme inhibition activities. The content of carnosic acid in rosemary (18.72 +/- 0.33 mg/g) was found to be higher than that content of that in sage (3.76 +/- 0.13 mg/g) (p < 0.05). The carnosic acid bioaccessibilities were found as 45.10 +/- 1.88% and 38.32 +/- 0.21% in sage and rosemary, respectively. The tested sage and rosemary showed inhibitory activity against alpha-glucosidase (Concentration of inhibitor required to produce a 50% inhibition of the initial rate of reaction - IC50 88.49 +/- 2.35, 76.80 +/- 1.68 MUg/mL, respectively), alpha-amylase (IC50 107.65 +/- 12.64, 95.65 +/- 2.73 MUg/mL, respectively) and lipase (IC50 6.20 +/- 0.63, 4.31 +/- 0.62 MUg/mL, respectively). Furthermore, to the best of our knowledge, this is the first work that carnosic acid standard equivalent inhibition capacities (CAEIC50) for these food samples were determined and these values were in agreement with the IC50 values. These results show that sage and rosemary are potent inhibitors of lipase, alpha-amylase and alpha-glucosidase digestive enzymes. PMID- 29709539 TI - Research on homology modeling, molecular docking of the cellulase and highly expression of the key enzyme (Bgl) in Pichia pastoris. AB - Cellulose is the most abundant and renewable biological resource on earth. As nonrenewable resources are becoming scarce, cellulose is expected to become a major raw material for food, energy, fuel and other products. 1,4-beta glucosidase (Bgl), as a kind of cellulose, can be degraded cellulose into industrial available glucose. In this study, we constructed mutants of Bgl with enhanced activity based on homology modeling, molecular docking, and the site directed mutagenesis of target residues to modify spatial positions, steric hindrances, or hydrophilicity/hydrophobicity. On the basis of the high-activity mutations were got (N347S and G235 M) by using site-directed mutagenesis and screening methods and introduced in the Pichia pastoris expression system, the enzymatic properties of mutant enzymes were analysed. Assays of the activity of the purified Bgl revealed that the two mutants exhibited increased activity. The pPICZalphaA-G235 M and pPICZalphaA-N347S mutants exhibited a >33.4% and 44.8% increase in specific activity respectively, with similar pH, temperature and metal ion requirements, compared to wild-type Bgl. These findings would be good foundation for improving production properties of Bgl in the future. PMID- 29709540 TI - Implications of Pharmacogenomics to the Management of IBS. AB - The objectives are to review the role of pharmacogenomics in drug metabolism of medications typically used in patients with irritable bowel syndrome (IBS) focusing predominantly on cytochrome P450 metabolism. Other aims are to provide examples of genetic variation of receptors or intermediary pathways that are targets for IBS drugs and to critically appraise the situations where precision medicine is impacting health in IBS. Pharmacogenomics impacts both pharmacokinetics and pharmacodynamics. Although large clinical trials have not incorporated testing for genetic variations that could impact the efficacy of medications in IBS, there are therapeutic advantages to inclusion of pharmacogenomics testing for individual patients, as has been demonstrated particularly in the treatment with central neuromodulators in psychiatry practice. Clinical practice in IBS is moving in the same direction with the aid of commercially available tests focused on drug metabolism. Specific mechanisms leading to pathophysiology of IBS are still poorly characterized, relative to diseases such as cancer and inflammatory bowel disease, and, therefore, pharmacogenomics related to drug pharmacodynamics is still in its infancy and requires extensive future research. With increased attention to pharmacogenomics affecting drug metabolism, it is anticipated that pharmacogenomics will impact care of IBS. PMID- 29709541 TI - The physiological orienting response in female adolescents with borderline personality disorder. AB - BACKGROUND: The reflexive startle- and orienting-response have been widely studied in psychiatric disorders. Existing evidence in patients with borderline personality disorder (BPD) is mixed, and limited to adults. The present study addressed clinical correlates of the psychophysiological orienting response in adolescents with BPD. METHODS: Female adolescents (13-19 years) with BPD (n = 30), healthy controls (HC; n = 34), and psychiatric clinical controls (CC; n = 53) participated in the trial. Orienting response was induced using acoustic startle-probes (sinus tones) while heart rate (HR) and skin conductance (SCR) were continuously recorded. Besides clinical interviews, the assessment included self-reports on depressive symptoms, anxiety, dissociation and psychopathological distress. RESULTS: On a group level, relative habituation of the HR-response (regression slope) significantly differed between groups (F(2,114) = 3.74, p = 0.027), with significant contrasts (p = 0.026, Sidak corrected) comparing CC (slope 0.04 +/- 0.41) and BPD (slope 0.28 +/- 0.40). On a dimensional level, relative HR habituation was significantly correlated with the number of BPD diagnostic criteria endorsed (r(117) = 0.183, p = 0.049) and symptoms of dissociation (r(116) = 0.193, p = 0.038), indicating that delayed HR habituation across probes was associated with greater BPD symptom severity. Analyses of SCR showed no significant findings. CONCLUSION: Findings provide preliminary support for altered habituation of the HR orienting response in adolescent BPD, associated with BPD severity - in particular dissociative experiences. Dissociative experiences may alter the automatic defensive response early in the course of BPD, providing a potential pathway to exaggerated emotional responding in BPD. PMID- 29709542 TI - A survey of current approaches to thyroid nodules and thyroid operations. AB - INTRODUCTION: Thyroid nodules are commonly seen. Our aim is to learn the behaviors and operational attitudes of surgeons approaching the thyroid nodules. In a literature search, our study is the first and only study performed merely on surgeons. MATERIALS- METODS: This cross-sectional study was done between June 2014-January 2015. The questionnaire consists of 25 questions. Initially, general questions consisting of demographic findings were asked. In step 2, questions consisting of the index case and case variants were asked. Results were compared with American Thyroid Association, European Thyroid Association guidelines, and Australia survey results. In the last step, questions about thyroid operations were asked. RESULTS: A total of 301 surgeons responded to the survey. The response rate was approximately 20%. Thirty nine were female and 262 were male. For the question that asks the diameter of the thyroid nodule that will require a thyroid fine needle aspiration biopsy (TFNAB), 47.5% of the surgeons will require a TFNAB for 1-2 cm solid nodules. 40.15% of the surgeons required a TFNAB regardless of size. 46.1% of the surgeons who required a TFNAB between 1 and 2 cm solid nodules also required scintigraphy at diagnosis of suppressed TSH case variant. CONCLUSION: In this survey, we identified differences from up-to-date guidelines about approaching thyroid nodules and perioperative thyroid surgery. From our perspective, surgeons need updated training requirements. This can be done with updated seminars across the country. Thereby approaches may become standard and consequently patients may have qualified services. PMID- 29709543 TI - Hematopoietic reconstitution after autologous hematopoietic stem cell transplantation: do CD45 (+) CD34 (+) CD38 (-) progenitors really matter in real life? PMID- 29709544 TI - Identification and suppression of epidermal growth factor receptor variant III signaling in fibroblast-like synoviocytes from aggressive rheumatoid arthritis by the mimotope. AB - Epidermal growth factor receptor (EGFR) signaling has been reported to play a vital role in the pathogenesis of rheumatoid arthritis (RA). In current study, we sought to observe whether the active immunization induced by the mimotope could recognize EGFR, inhibit their signaling and disrupt the pathogenic behavior of fibroblast-like synoviocytes (FLS) from RA patients. We prepared a linked EGFR mimotope and performed series of experiments to detect whether the mimotope could induce the desired immune responses. To our surprises, we detected the expression of EGFR variant III (EGFRvIII), but not EGFR in the synovial tissues and FLS from patients with aggressive RA by the linked EGFR mimotope-induced antibodies (LEMIA). Meanwhile, LEMIA could inhibit the signaling caused by the autophosphorylation of EGFRvIII in the FLS. The proliferation, migration, invasion and anti-apoptosis capabilities of the EGFRvIII-expressed FLS were disrupted by LEMIA. These results suggest that EGFRvIII signaling may participate in the malignant behaviors of FLS from aggressive RA. Meanwhile, the linked EGFR mimotope could be used to detect the expression of EGFRvIII and developed to be a potential therapy agent against the aggressive FLS. PMID- 29709545 TI - DPP9 enzymatic activity in hematopoietic cells is dispensable for mouse hematopoiesis. AB - Dipeptidyl peptidase 9 (DPP9) is a ubiquitously expressed intracellular prolyl peptidase implicated in immunoregulation. However, its physiological relevance in the immune system remains largely unknown. We investigated the role of DPP9 enzyme in immune system by characterizing DPP9 knock-in mice expressing a catalytically inactive S729A mutant of DPP9 enzyme (DPP9ki/ki mice). DPP9ki/ki mice show reduced number of lymphoid and myeloid cells in fetal liver and postnatal blood but their hematopoietic cells are fully functional and able to reconstitute lymphoid and myeloid lineages even in competitive mixed chimeras. These studies demonstrate that inactivation of DPP9 enzymatic activity does not lead to any perturbations in mouse hematopoiesis. PMID- 29709546 TI - Purification of native Sigma class glutathione transferase from Fasciola hepatica. AB - Fascioliasis is a parasitic disease of grazing livestock and a threat to global food security by significantly reducing the production value of sheep, goats and cattle. Moreover, the zoonotic parasite is also a re-emerging food borne threat to human populations. Driven by climate change, the prevalence of fascioliasis is set to increase. Efforts to control the main causative agent, Fasciola hepatica, are hampered by short lived chemotherapy approaches that are becoming increasingly obsolete due to therapeutic failure and resistance. A protective vaccine is urgently needed. A recombinant form of Sigma class glutathione transferase (Hematopoietic Prostaglandin D synthase) from F. hepatica (FhGSTS1) with confirmed prostaglandin synthase activity shows immune-modulation activity via suppression of Th17 responses in host dendritic cells. In vaccine trials recombinant FhGSTS1 reduces liver pathology but not worm burden. Native FhGSTS1 is yet to be tested for immune-modulation activities or for vaccine potential, primarily due to the technical difficulty in purifying FhGST-S1 away from the other more abundant GST members in F. hepatica cytosol. This paper reports a pipeline for the purification of native FhGSTS1 using a two-step process consisting of glutathione-agarose affinity and cationic exchange chromatography. The methodology allows for the isolation of purified and active FhGSTS1 or Sigma GSTs from other sources for analytical biochemical and immunological studies. PMID- 29709547 TI - Differential tissue distribution of Trypanosoma cruzi during acute experimental infection: Further evidence using natural isolates. AB - In the present work, we evaluated the effect of mixed Trypanosoma cruzi infections, studying the biological distribution of the different parasites in blood, heart and skeletal muscle during the acute phase. Albino Swiss mice were infected with different parasite strain/isolates or with a combination of them. The parasites in the different tissues were typified through specific PCR, population variability was analyzed through RFLP studies and parasitological and histopathological parameters were evaluated. We found a predominance of TcII and TcVI in all tissues samples respect to TcV and different parasite populations were found in circulation and in the tissues from the same host. These results verify the distribution of parasites in host tissues from early stages of infection and show biological interactions among different genotypes and populations of T. cruzi. PMID- 29709548 TI - The META score for differentiating metastatic from osteoporotic vertebral fractures: an independent agreement assessment. AB - BACKGROUND CONTEXT: Differentiating osteoporotic vertebral fractures (OVFs) from metastatic vertebral fractures (MVFs) is an important clinical challenge. A novel magnetic resonance imaging (MRI)-based score (the META score) was described, aiming to differentiate OVF from MVF. This score showed an almost perfect agreement by the group developing it, but an independent agreement evaluation is pending. PURPOSE: We aimed to perform an independent inter- and intraobserver agreement evaluation of the META score and to test the score's capability of differentiating OVF from MVF. STUDY DESIGN: This is an agreement study of the META score. METHODS: Sixty-four patients with confirmed OVF or MVF were assessed by six independent evaluators (three spine surgeons and three fellowship-trained radiologists) using the META score. We used the intraclass correlation coefficient (ICC) to determine the overall inter-and intraobserver agreement, and the kappa statistic (kappa) to express the agreement for each individual score criterion. The score accuracy was determined by calculating the area under the receiver operating characteristic curve. Finally, we used kappa to evaluate the agreement among raters to determine whether the fracture was OVF or MVF. RESULTS: The overall interobserver agreement was poor [ICC=0.10 (0.02-0.20)]; spine surgeons [ICC=0.75 (0.66-0.83)] had better agreement than radiologists did [ICC=0.05 (-0.08 to 0.21)]. The intraobserver agreement was poor [ICC=0.17 (0.01 0.32)]; both spine surgeons [ICC=0.21 (0.05-0.41)] and radiologists had a poor agreement [ICC=0.03 (-0.29 to 0.27)]. The agreement for each specific criterion varied from kappa=0.24 to kappa=0.60. The area under the receiver operating characteristic curve was 0.58 (0.64 for spine surgeons and 0.52 for radiologists, p<.01). CONCLUSIONS: The interobserver agreement using the META score was adequate for spine surgeons but not for other potential users (radiologists); the intraobserver agreement was poor. Further studies are thus necessary before the use of this score is recommended. PMID- 29709549 TI - Use of the subcutaneous lumbar spine (SLS) index as a predictor for surgical complications in lumbar spine surgery. AB - BACKGROUND CONTEXT: Lumbar spine surgeries require adequate exposure to visualize key structures and limited exposure can make surgery more technically difficult, thus increasing the potential for complications. Body mass index and body mass distribution have been shown to be associated with worse surgical outcomes. PURPOSE: This study aims to further previous investigations in elucidating the predictive nature of body mass distribution with peri- and postoperative complications in lumbar surgery. STUDY DESIGN/SETTING: This is a retrospective study conducted at a single institution. PATIENT SAMPLE: Two hundred eighty-five patients who underwent lumbar laminectomy, laminotomy, or posterior lumbar interbody fusion or transforaminal lumbar interbody fusion procedures between 2013 and 2016. OUTCOME MEASURES: Magnetic resonance imaging (MRI) results and electronic medical records were reviewed for measurements and relevant complications. METHODS: Previously known risk factors were identified and MRI measurements of subcutaneous adipose depth (SAD) relative to spinous process height (SPH) were measured at the surgical site to generate the subcutaneous lumbar spine (SLS) index. This measurement was then analyzed in association with recorded surgical complications. RESULTS: The SLS index was found to be a significant risk factor for total complications (0.292, p=.041), perioperative complications (0.202, p=.015), and need for revision surgery (0.285, p<.001). The SAD alone proved to be negatively associated with perioperative complications ( 0.075, p=.034) and need for revision surgery (-0.104, p=.001), with no predictive association seen for total or postoperative complications. Linear regression revealed an SLS index of 3.43 as a threshold value associated with a higher risk of total complications, 5.8 for perioperative complications, and 3.81 for the need for revision surgeries. CONCLUSION: Body mass distribution of the surgical site as indicated by SAD to SPH (SLS index) is significantly associated with increasing risk of postoperative and perioperative complications as well as increased likelihood for necessary revision surgery. This relationship was shown to be a more accurate indication of perioperative risk than previous standards of body mass index and SAD alone, and may allow spine surgeons to assess surgical risk when considering lumbar spine surgery using simple calculations from standard preoperative MRI results. PMID- 29709550 TI - Is the behavior of disc replacement adjacent to fusion affected by the location of the fused level in hybrid surgery? AB - BACKGROUND CONTEXT: Hybrid surgery (HS), consisting of cervical disc arthroplasty (CDA) at the mobile level, along with anterior cervical discectomy and fusion at the spondylotic level, could be a promising treatment for patients with multilevel cervical degenerative disc disease (DDD). An advantage of this technique is that it uses an optimal procedure according to the status of each level. However, information is lacking regarding the influence of the relative location of the replacement and the fusion segment in vivo. PURPOSE: We conducted the present study to investigate whether the location of the fusion affected the behavior of the disc replacement and adjacent segments in HS in vivo. STUDY DESIGN: This is an observational study. PATIENT SAMPLE: The numbers of patients in the arthroplasty-fusion (AF) and fusion-arthroplasty (FA) groups were 51 and 24, respectively. OUTCOME MEASURES: The Japanese Orthopedic Association (JOA), Neck Disability Index (NDI), and Visual Analog Scale (VAS) scores were evaluated. Global and segmental lordosis, the range of motion (ROM) of C2-C7, and the operated and adjacent segments were measured. Fusion rate and radiological changes at adjacent levels were observed. METHODS: Between January 2010 and July 2016, 75 patients with cervical DDD at two contiguous levels undergoing a two level HS were retrospectively reviewed. The patients were divided into AF and FA groups according to the locations of the disc replacement. Clinical outcomes were evaluated according to the JOA, NDI, and VAS scores. Radiological parameters, including global and segmental lordosis, the ROM of C2-C7, the operated and adjacent segments, and complications, were also evaluated. RESULTS: Although the JOA, NDI, and VAS scores were improved in both the AF and the FA groups, no significant differences were found between the two groups at any follow-up point. Both groups maintained cervical lordosis, but no difference was found between the groups. Segmental lordosis at the fusion segment was significantly improved postoperatively (p<.001), whereas it was maintained at the arthroplasty segment. The ROM of C2-C7 was significantly decreased in both groups postoperatively (AF p=.001, FA p=.014), but no difference was found between the groups. The FA group exhibited a non-significant improvement in ROM at the arthroplasty segment. The ROM adjacent to the arthroplasty segment was increased, although not significantly, whereas the ROM adjacent to the fusion segment was significantly improved after surgery in both groups (p<.001). Fusion was achieved in all patients. No significant difference in complications was found between the groups. CONCLUSIONS: In HS, cephalic or caudal fusion segments to the arthroplasty segment did not affect the clinical outcomes and the behavior of CDA. However, the ROM of adjacent segments was affected by the location of the fusion segment; segments adjacent to fusion segments had greater ROMs than segments adjacent to arthroplasty segments. PMID- 29709551 TI - Predictive model for distal junctional kyphosis after cervical deformity surgery. AB - BACKGROUND CONTEXT: Distal junctional kyphosis (DJK) is a primary concern of surgeons correcting cervical deformity. Identifying patients and procedures at higher risk of developing this condition is paramount in improving patient selection and care. PURPOSE: The present study aimed to develop a risk index for DJK development in the first year after surgery. STUDY DESIGN/SETTING: This is a retrospective review of a prospective multicenter cervical deformity database. PATIENT SAMPLE: Patients over the age of 18 meeting one of the following deformities were included in the study: cervical kyphosis (C2-7 Cobb angle>10 degrees ), cervical scoliosis (coronal Cobb angle>10 degrees ), positive cervical sagittal imbalance (C2-C7 sagittal vertical axis (SVA)>4 cm or T1-C6>10 degrees ), or horizontal gaze impairment (chin-brow vertical angle>25 degrees ). OUTCOME MEASURES: Development of DJK at any time before 1 year. METHODS: Distal junctional kyphosis was defined by both clinical diagnosis (by enrolling surgeon) and post hoc identification of development of an angle<-10 degrees from the end of fusion construct to the second distal vertebra, as well as a change in this angle by <-10 degrees from baseline. Conditional Inference Decision Trees were used to identify factors predictive of DJK incidence and the cut-off points at which they have an effect. A conditional Variable-Importance table was constructed based on a non-replacement sampling set of 2,000 Conditional Inference Trees. Twelve influencing factors were found; binary logistic regression for each variable at significant cutoffs indicated their effect size. RESULTS: Statistical analysis included 101 surgical patients (average age: 60.1 years, 58.3% female, body mass index: 30.2) undergoing long cervical deformity correction (mean levels fused: 7.1, osteotomy used: 49.5%, approach: 46.5% posterior, 17.8% anterior, 35.7% combined). In 2 years after surgery, 6% of patients were diagnosed with clinical DJK; however, 23.8% of patients met radiographic definition for DJK. Patients with neurologic symptoms were at risk of DJK (odds ratio [OR]: 3.71, confidence interval [CI]: 0.11-0.63). However, no significant relationship was found between osteoporosis, age, and ambulatory status with DJK incidence. Baseline radiographic malalignments were the most numerous and strong predictors for DJK: (1) C2-T1 tilt>5.33 (OR: 6.94, CI: 2.99 16.14); (2) kyphosis<-50.6 degrees (OR: 5.89, CI: 0.07-0.43); (3) C2-C7 lordosis<-12 degrees (OR: 5.7, CI: 0.08-0.41); (4) T1 slope minus cervical lordosis>36.4 (OR: 5.6, CI: 2.28-13.57); (5) C2-C7 SVA>56.3 degrees (OR: 5.4, CI: 2.20-13.23); and (6) C4_Tilt>56.7 (OR: 5.0, CI: 1.90-13.1). Clinically, combined approaches (OR: 2.67, CI: 1.21-5.89) and usage of Smith-Petersen osteotomy (OR: 2.55, CI: 1.02-6.34) were the most important predictors of DJK. CONCLUSIONS: In a surgical cohort of patients with cervical deformity, we found a 23.8% incidence of DJK. Different procedures and patient malalignment predicted incidence of DJK up to 1 year. Preoperative T1 slope-cervical lordosis, cervical kyphosis, SVA, and cervical lordosis all strongly predicted DJK at specific cut off points. Knowledge of these factors will potentially help direct future study and strategy aimed at minimizing this potentially dramatic occurrence. PMID- 29709552 TI - How social media, training, and demographics influence online reviews across three leading review websites for spine surgeons. AB - BACKGROUND CONTEXT: The future of health care is consumer driven with a focus on outcome metrics and patient feedback. Physician review websites have grown in popularity and are guiding patients to certain health-care providers, for better or worse. No prior study has specifically evaluated Internet reviews of spine surgeons, determined if social media (SM) correlates with patient reviews, or evaluated Google as a physician review website. PURPOSE: This study aimed to evaluate patient satisfaction scores for spine surgeons in Florida using leading physician ratings websites. STUDY DESIGN: A retrospective study was carried out. SAMPLE POPULATION: The sample comprised spine surgeons with a review on Healthgrades.com (HG), Vitals.com (V), or Google.com (G) online rating websites as of August 17, 2017. OUTCOME MEASURES: Number of ratings, number of comments, overall rating, patient-reported wait times, physician website presence, and physician SM presence were the outcome measures. METHODS: Using the directory of registered North American Spine Society physicians, we identified all spine surgeons practicing in Florida (137 orthopedic trained; 78 neurosurgery trained). Surgeon demographics and ratings data were collected from three physician rating websites (HG, V, G) from July 19, 2017 to August 17, 2017. Using only the first 10 search results from Google.com we then identified if the surgeon had accounts on Facebook (FB), Twitter (TW), or Instagram (IG). RESULTS: Nearly every surgeon in this cohort had either an institutional or personal website (98.1%), and 38.6% had at least one SM outlet of our three reviewed. Both personal and institutional website presence significantly correlated with higher G scores. Spine surgeons with a searchable account on FB, TW, or IG made up 35.4%, 10.2%, and 0.5% of the cohort, respectively. Surgeons with an SM presence had a significantly higher number of ratings and comments on HG, V, and G, but not overall scores. In multivariable analysis, only V showed a significant inverse correlation between overall score and age, private institution, and orthopedic surgery training. Wait times >30 minutes were significantly associated with worse overall scores across all three review sites. Overall ratings between HG, V, and G all had significantly positive correlations on Pearson correlation analysis. CONCLUSION: Social media presence correlates with patient communication in the form of number of ratings and comments, yet does not impact overall scores, suggesting social media may influence patient feedback. Longer wait times are indicative of lower scores across all three platforms. Overall ratings from all three websites correlate significantly with each other, indicating agreement between physician ratings across different platforms. Understanding the factors that optimize a patient's overall experience with a physician is an important and emerging outcome measure for the future of patient-centered health care. PMID- 29709553 TI - Chronic preoperative opioid use is a risk factor for increased complications, resource use, and costs after cervical fusion. AB - BACKGROUND CONTEXT: As health-care transitions to value-based models, there has been an increased focus on patient factors that can influence peri- and postoperative adverse events, resource use, and costs. Many studies have reported risk factors for systemic complications after cervical fusion, but none have studied chronic opioid therapy (COT) as a risk factor. PURPOSE: The objective of this study was to answer the following questions from a large cohort of patients who underwent primary cervical fusion for degenerative pathology: (1) What is the patient profile associated with preoperative COT? (2) Is preoperative COT a risk factor for 90-day systemic complications, emergency department (ED) visits, readmission, and 1-year adverse events? (3) What are the risk factors and 1-year adverse events related to long-term postoperative opioid use? (4) How much did payers reimburse for management of complications and adverse events? STUDY DESIGN: This is a retrospective review of Humana commercial insurance data (2007 Q3 2015). PATIENT SAMPLE: The patient sample included 29,101 patients undergoing primary cervical fusion for degenerative pathology. METHODS: Patients and procedures of interest were included using International Classification of Diseases (ICD) coding. Patients with opioid prescriptions for >6 months before surgery were considered as having preoperative COT. Patients with continued opioid use until 1-year after surgery were considered as long-term users. Descriptive analysis of patient cohorts has been done. Multiple-variable logistic regression analyses adjusting for approach, number of levels of surgery, discharge disposition, and comorbidities were done to answer first three study questions. Reimbursement data from insurers have been reported to answer our fourth study question. RESULTS: Of the entire cohort, 6,643 (22.8%) had preoperative COT. Preoperative COT was associated with a higher risk of 90-day wound complications (odds ratio [OR] 1.39, 95% confidence interval [CI]: 1.16 1.66), all-cause 90-day ED visits (adjusted OR 1.22, 95% CI: 1.13-1.32), and pain related ED visits (adjusted OR 1.39, 95% CI: 1.24-1.55). Patients who had preoperative COT were more likely to receive epidural or facet joint injections within 1 year after surgery (adjusted OR 1.68, 95% CI: 1.47-1.92). These patients were also more likely to undergo a repeat cervical fusion within a year than patients who did not have preoperative COT (adjusted OR 1.21, 95% CI: 1.01-1.43). Preoperative COT had a higher likelihood of long-term use after surgery (adjusted OR 4.72, 95% CI: 4.41-5.06). Long-term opioid use after surgery was associated with a higher risk of new-onsetconstipation (adjusted OR 1.34, 95% CI: 1.22 1.48). The risk of complications and adverse events was not found to be significant in patients with <3 months of preoperative opioid use or those who stopped opioids for at least 6 weeks before surgery. The cost of additional resource use for medications, ED visits, constipation, injections, and revision fusion ranged from $623 to $27,360 per patient. CONCLUSIONS: Preoperative opioid use among patients who underwent cervical fusion increases complication rates, postoperative opioid usage, health-care resource use, and costs. These risks may be reduced by restricting the duration of preoperative opioid use or weaning off before surgery. Better understanding and management of pain in the preoperative period with judicious use of opioids is critical to enhance outcomes after cervical fusion surgery. PMID- 29709554 TI - Decompression surgery improves gait quality in patients with symptomatic lumbar spinal stenosis. AB - BACKGROUND CONTEXT: We aimed to fully understand the extent of limitations associated with symptomatic lumbar spinal stenosis (LSS) and the functional outcome of its treatment, including not only function during daily activities (eg, using the 6-minute walk test [6MWT]) but also the quality of function that should be objectively assessed. PURPOSE: This study was performed to test the hypothesis that the Oswestry Disability Index (ODI) score, the walking distance during the 6MWT (6-minute walking distance [6MWD]), and gait quality (spatiotemporal parameters and gait asymmetry) will improve postoperatively and achieve normal values; to determine if changes in gait parameters correlate with changes in Oswestry Disability Index (ODI) score; and to ascertain if patients' gait quality will diminish during the 6MWT, reflected by changes in gait parameters during the 6MWT. STUDY DESIGN/SETTING: This is a prospective observational study with intervention. PATIENT SAMPLE: The sample comprised patients with symptomatic LSS. OUTCOME MEASURES: The ODI score, gait quality (spatiotemporal and asymmetry), and walking performance (walking distance during the 6MWT) were the outcome measures. METHODS: Patients with symptomatic LSS were analyzed on the day before surgery and 10 weeks and 12 months postoperatively. Functional disability in daily life was assessed by the ODI. Spatiotemporal and kinematic gait parameters were recorded with an inertial sensor system during the 6MWT, and the 6MWD was determined. Gait asymmetry was defined as 100*|right left|/(0.5*(|right+left|)). RESULTS: The ODI decreased by 17.9% and 23.9% and 6MWD increased by 21 m and 26 m from baseline to 10-week and 12-month follow-up, respectively. Gait quality did not change during the 6MWT at any assessment or between assessments. Compared with the control group, patients walked less during the 6MWT, and gait quality differed between patients and the control group at baseline and 10-week follow-up but not at 12-month follow-up. Change in gait quality explained 39% and 73% of variance in change in ODI from baseline to 10 week and to 12-month follow-up, respectively. CONCLUSIONS: Changes in gait quality explained a large portion of variance in changes in the ODI, indicating that patients with symptomatic LSS perceive their compromised gait quality as functional limitations. Gait data obtained by instrumented gait analysis contain information on gait quality that can be helpful for evaluating functional limitations in patients with LSS, the outcome of decompression surgery, and the development of patient-specific rehabilitation regimens. PMID- 29709555 TI - Genetic screening of male patients with primary hypogammaglobulinemia can guide diagnosis and clinical management. AB - The precise diagnosis of an immunodeficiency is sometimes difficult to assess, especially due to the large spectrum of phenotypic variation reported among patients. Common variable immunodeficiency disorders (CVID) do not have, for a large part, an identified genetic cause. The identification of a causal genetic mutation is important to confirm, or in some cases correct, the diagnosis. We screened >150 male patients with hypogammaglobulinemia for mutations in three genes involved in pediatric X-linked primary immunoglobulin deficiency: CD40LG, SH2D1A and BTK. The SH2D1A screening allowed to reclassify two individuals with an initial CVID presentation as XLP after mutations identification. All these mutations were associated with a lack of protein expression. In addition, 4 patients with a primary diagnosis of CVID and one with a primary IgG subclass deficiency were requalified as XLA after identifying BTK mutations. Interestingly, two out of these 5 patients carried a damaging coding BTK mutation associated with a lower, but detectable, BTK expression in monocytes, suggesting that a dysfunctional protein explains the disease phenotype in these patients. In conclusion, our results advocate to include SH2D1A and BTK in newly developed targeted NGS genetic testing, to contribute to providing the most appropriate medical treatment and genetic counselling. PMID- 29709556 TI - GoldCLIP: Gel-omitted Ligation-dependent CLIP. AB - Protein-RNA interaction networks are essential to understand gene regulation control. Identifying binding sites of RNA-binding proteins (RBPs) by the UV crosslinking and immunoprecipitation (CLIP) represents one of the most powerful methods to map protein-RNA interactions in vivo. However, the traditional CLIP protocol is technically challenging, which requires radioactive labeling and suffers from material loss during PAGE-membrane transfer procedures. Here we introduce a super-efficient CLIP method (GoldCLIP) that omits all gel purification steps. This nonisotopic method allows us to perform highly reproducible CLIP experiments with polypyrimidine tract-binding protein (PTB), a classical RBP in human cell lines. In principle, our method guarantees sequencing library constructions, providing the protein of interest can be successfully crosslinked to RNAs in living cells. GoldCLIP is readily applicable to diverse proteins to uncover their endogenous RNA targets. PMID- 29709558 TI - Bursectomy versus omentectomy alone for resectable gastric cancer (JCOG1001): a phase 3, open-label, randomised controlled trial. AB - BACKGROUND: The role of bursectomy, in which the peritoneal lining covering the pancreas and the anterior plane of the transverse mesocolon are dissected, has long been controversial for preventing peritoneal metastasis. We investigated the survival benefit of bursectomy in patients with resectable gastric cancer. METHODS: This phase 3, open-label, randomised controlled trial was done at 57 hospitals in Japan. Patients aged 20-80 years who had cT3(SS)-cT4a(SE) histologically proven gastric adenocarcinoma with an Eastern Cooperative Oncology Group performance status of 0 or 1 and body-mass index less than 30 kg/m2 and who did not have distant metastasis or bulky lymph nodes were randomly assigned (1:1) during surgery to receive omentectomy alone (non-bursectomy) or bursectomy. Randomisation was done by telephone or website to the Japan Clinical Oncology Group Data Center and used a minimisation method with a random component to adjust for institution, cT status (T3 vs T4a), and type of gastrectomy (distal vs total). Both groups had total or distal gastrectomy with D2 lymphadenectomy. The primary endpoint was overall survival, analysed in the intention-to-treat population. The study is registered with UMIN-CTR, number UMIN000003688. FINDINGS: Between June 1, 2010, and March 30, 2015, 1503 patients were enrolled based on preoperative inclusion and exclusion criteria. Intraoperative inclusion and exclusion criteria were met in 1204 patients, of which 602 were allocated to the non-bursectomy group and 602 were allocated to the bursectomy group. At the planned second interim analysis on Sept 17, 2016, the JCOG Data and Safety Monitoring Committee independently reviewed the results and recommended their early publication on the basis of futility because overall survival was lower in the bursectomy group than the non-bursectomy group, and because the predictive probability of overall survival being significantly higher in bursectomy than non bursectomy patients at the final analysis was only 12.7%. 5-year overall survival was 76.7% (95% CI 72.0-80.6) in the non-bursectomy group and 76.9% (72.6-80.7) in the bursectomy group (hazard ratio 1.05, 95% CI 0.81-1.37, one-sided p=0.65). 64 (11%) of 601 in the non-bursectomy group and 77 (13%) of 600 patients in the bursectomy group had grade 3-4 operative morbidity. Pancreatic fistula was significantly more common in the bursectomy group than in the non-bursectomy group (29 [5%] vs 15 [2%]; p=0.032). Six deaths occurred either in hospital or within 1 month of surgery: five in the non-bursectomy group and one in the bursectomy group. INTERPRETATION: Bursectomy did not provide a survival advantage over non-bursectomy. D2 dissection with omentectomy alone should be done as a standard surgery for resectable cT3-T4a gastric cancer. FUNDING: Japan Agency for Medical Research and Development, the Ministry of Health, Labour and Welfare of Japan, and the National Cancer Centre Research and Development Fund. PMID- 29709559 TI - The end of bursectomy for gastric cancer? PMID- 29709560 TI - Contributing factors to mortality rates of pulmonary tuberculosis in intensive care units. AB - BACKGROUND: Tuberculosis (TB) remains an important health problem worldwide. TB patients sometimes require intensive care unit (ICU) treatment. The aim of this study is to establish special features and mortality rates of pulmonary TB patients in ICUs and identify the factors contributing to ICU mortality. METHODS: Medical records of adult patients (>18 years) with a diagnosis of TB who were admitted to the ICU of a referral hospital for chest diseases between 2004 and 2010 were reviewed retrospectively. Demographic characteristics, comorbidities, APACHE II scores, symptoms, radiologic appearance of the disease, bacteriological and laboratory investigations, need and type of mechanical ventilation support (invasive, non-invasive), characteristics related to ICU stay, length of ICU stay, mortality and factors affecting mortality were recorded and analysed. RESULTS: Forty patients (33 male) with active pulmonary TB with a median age of 55 years (43-63 years) and a median APACHE II score of 22 (17-26) were followed up in the ICU. Patients who needed invasive mechanical ventilation had significantly longer ICU stays than patients who were treated with non-invasive ventilation or medical therapy (Log rank p = 0.014). Mortality was 72.5%. The only independent risk factor for mortality was having an APACHE II score >=18. CONCLUSION: The mortality of TB patients who needed ICU support remains high. This higher mortality rate seems related to multi-organ failure, requiring invasive mechanical ventilation and high APACHE II scores. PMID- 29709561 TI - Selective recovery of RNAs from bacterial pathogens after their internalization by human host cells. AB - Selective RNA extractions are required when studying bacterial gene expression within complex mixtures of pathogens and human cells, during adhesion, internalization and survival within the host. New technologies should be developed and implemented to enrich the amount of bacterial RNAs since the majority of RNAs are from the eukaryotic host cells, requiring high read depth coverage to capture the bacterial transcriptomes in dual-RNAseq studies. This will improve our understanding about bacterial adaptation to the host cell defenses, and about how they will adapt to an intracellular life. Here we present an RNA extraction protocol to selectively enrich the lowest bacterial RNA fraction from a mixture of human and bacterial cells, using zirconium beads, with minimal RNA degradation. Zirconium beads have higher capacity to extract bacterial RNAs than glass beads after pathogen internalization. We optimized the beads size and composition for an optimal bacterial lysis and RNA extraction. The protocol was validated on two human cell lines, differentiated macrophages and osteoblasts, with either Gram-positive (Staphylococcus aureus) or -negative (Salmonella typhimurium) bacteria. Relative to other published protocols, yield of total RNA recovery was significantly improved, while host cell infection was performed with a lower bacterial inoculum. Within the host, bacterial RNA recovery yields were about six-fold lower than an RNA extraction from pure bacteria, but the quality of the RNA recovered was essentially similar. Bacterial RNA recovery was more efficient for S. aureus than for S. typhimurium, probably due to their higher protection by the Gram-positive cell walls during the early step of eukaryotic cell lysis. These purified bacterial RNAs allow subsequent genes expression studies in the course of host cell-bacteria interactions. PMID- 29709557 TI - Structural Insights into N6-methyladenosine (m6A) Modification in the Transcriptome. AB - More than 100 types of chemical modifications in RNA have been well documented. Recently, several modifications, such as N6-methyladenosine (m6A), have been detected in mRNA, opening the window into the realm of epitranscriptomics. The m6A modification is the most abundant modification in mRNA and non-coding RNA (ncRNA). At the molecular level, m6A affects almost all aspects of mRNA metabolism, including splicing, translation, and stability, as well as microRNA (miRNA) maturation, playing essential roles in a range of cellular processes. The m6A modification is regulated by three classes of proteins generally referred to as the "writer" (adenosine methyltransferase), "eraser" (m6A demethylating enzyme), and "reader" (m6A-binding protein). The m6A modification is reversibly installed and removed by writers and erasers, respectively. Readers, which are members of the YT521-B homology (YTH) family proteins, selectively bind to RNA and affect its fate in an m6A-dependent manner. In this review, we summarize the structures of the functional proteins that modulate the m6A modification, and provide our insights into the m6A-mediated gene regulation. PMID- 29709562 TI - Novel cyclo-peptides inhibit Ebola pseudotyped virus entry by targeting primed GP protein. AB - Ebola virus (EBOV) causes fatal hemorrhagic fever with high death rates in human. Currently, there are no available clinically-approved prophylactic or therapeutic treatments. The recently solved crystal structure of cleavage-primed EBOV glycoprotein (GPcl) in complex with the C domain of endosomal protein Niemann Pick C1 (NPC1) provides a new target for the development of EBOV entry inhibitors. In this work, a computational approach using docking and molecular dynamic simulations is carried out for the rational design of peptide inhibitors. A novel cyclo-peptide (Pep-3.3) was identified to target at the late stage of EBOV entry and exhibit specific inhibitory activity against EBOV-GP pseudotyped viruses, with 50% inhibitory concentration (IC50) of 5.1 MUM. In vitro binding assay and molecular simulations revealed that Pep-3.3 binds to GPcl with a KD value of 69.7 MUM, through interacting with predicted residues in the hydrophobic binding pocket of GPcl. Mutation of predicted residues T83 caused resistance to Pep-3.3 inhibition in viral infectivity, providing preliminary support for the model of the peptide binding to GPcl. This study demonstrates the feasibility of inhibiting EBOV entry by targeting GPcl with peptides. PMID- 29709563 TI - Characterization and structure-activity relationship analysis of a class of antiviral compounds that directly bind dengue virus capsid protein and are incorporated into virions. AB - Dengue viruses (DENV) are endemic pathogens of tropical and subtropical regions and cause significant morbidity and mortality worldwide. Although a partially effective vaccine is in use in several countries in which DENV are endemic, no antiviral therapeutics are approved for combating DENV-associated disease. Herein, we report the characterization of novel small molecule inhibitors of DENV replication, VGTI-A3 and VGTI-A3-03, as well as structure-activity relationship analysis of the molecules using a panel of chemical analogs. VGTI-A3 and VGTI-A3 03 are highly virus-specific, with greatest activity against DENV serotype 2. Further analysis revealed that treatment of infected cells with VGTI-A3-03 does not inhibit viral RNA replication or secretion of viral particles. Rather, the infectivity of secreted particles from A3-03 treated cells is significantly diminished compared to particles secreted from control cells. Elicitation of VGTI A3-03-resistant mutants demonstrated a clear binding pocket in the capsid molecule at the dimerization interface. Additionally, we show that VGTI-A3-03 is incorporated into virus particles released from infected cells. In summary, these data provide detailed analysis of a potentially useful class of anti-DENV inhibitors and further identify a region of the viral capsid protein as a druggable target for other therapeutic approaches. PMID- 29709564 TI - Peptides P4 and P7 derived from E protein inhibit entry of dengue virus serotype 2 via interacting with beta3 integrin. AB - Dengue virus (DENV) infection has become a severe public health problem worldwide. However, there is no specific antiviral drug available yet. In this study, we found that DENV serotype 2 (DENV2) infection enhanced the expression of beta3 integrin on human umbilical vein endothelial cells (HUVECs) and that DENV2 antigens co-localized with beta3 integrin. DENV2 envelope protein (E) directly interacted with beta3 integrin, and their interacting sites were located at domain III of E protein (EDIII). Several synthetic peptides were designed based on the amino acid sequence of EDIII, and peptides P4 and P7 could inhibit DENV2 entry into HUVECs in a dose-dependent manner. The inhibitory concentration (IC50) of the two peptides was 19.08 +/- 2.52 MUM for P4 and 12.86 +/- 5.96 MUM for P7. Moreover, P7 containing an FG-loop, but not P4, could also inhibit DENV1 entry into HUVECs. Our results suggest a novel mechanism in which interaction between beta3 integrin and EDIII is involved in DENV entry. The findings on the inhibitory effect of the peptides on viral entry have significance for anti-DENV drug design. PMID- 29709565 TI - Cupping Therapy and Animal Research: The Progress. PMID- 29709566 TI - Organic components of airborne dust influence the magnitude and kinetics of dendritic cell activation. AB - Bioaerosol exposure in highly contaminated occupational settings is associated with an increased risk of disease. Yet, few determinants allow for accurate prediction of the immunopathogenic potential of complex bioaerosols. Since dendritic cells are instrumental to the initiation of immunopathological reactions, we studied how dendritic cell activation was modified in response to individual agents, combined microbial agents, or air sample eluates from highly contaminated environmental settings. We found that combinations of agents accelerated and enhanced the activation of in vitro-generated murine bone marrow derived dendritic cell cultures, when compared to individual agents. We also determined that endotoxins are not sufficient to predict the potential of air samples to induce bone marrow-derived dendritic cell activation, especially when endotoxin levels are low. Importantly, bone marrow-derived dendritic cell activation stratified samples from three environmental settings (swine barns, dairy barns, and wastewater treatment plants) according to their air quality status. As a whole, these results support the notion that the interplay between bioaerosol components impacts on their ability to activate dendritic cells and that bone marrow-derived dendritic cell cultures are promising tools to study the immunomodulatory impact of air samples and their components. PMID- 29709567 TI - [Culture conditions for gametes and embryos: Which culture medium? Which impact on newborn?] AB - Many studies have examined the impact of cell/embryo culture media on the development of human embryo during IVF process, but few studies have followed up and compared the effects of these culture media on the developmental outcome of children conceived by IVF. As recurrent experimental evidence from animal studies suggests potential long-term effects of embryo culture media on the health outcome of IVF-conceived children, more studies are needed to clarify the role of the culture media and mechanisms underlying such effects. In human, however, the effects of culture media are difficult to pinpoint due to complications stem from both the influence of maternal nutrition during the gestational period and the parental genetic. Based on a simple review of the literature integrating animal experimentations and human clinic studies, we suggest that the composition of culture medium should be considered beyond the character of unique or sequential medium, corresponding to "let embryo choose" or "back to nature" respectively. Instead, we suggest that the main components of embryo culture media should be considered from the point of view of metabolic consequences and potential epigenetic effects. Given that energetic metabolites can regulate epigenetic machinery, we hypothesize that metabolic abnormalities linked to morphological abnormalities could reveal epigenetic defects in embryos. PMID- 29709568 TI - Semicarbazone derivatives as urease inhibitors: Synthesis, biological evaluation, molecular docking studies and in-silico ADME evaluation. AB - A series of hydrazinecarboxamide derivatives were synthesized and examined against urease for their inhibitory activity. Among the series, the 1-(3 fluorobenzylidene)semicarbazide (4a) (IC50 = 0.52 +/- 0.45 uM), 4u (IC50 = 1.23 +/- 0.32 uM) and 4h (IC50 = 2.22 +/- 0.32 uM) were found most potent. Furthermore, the molecular docking study was also performed to demonstrate the binding mode of the active hydrazinecarboxamide with the enzyme, urease. In order to estimate drug likeness of compounds, in silico ADME evaluation was carried out. All compounds exhibited favorable ADME profiles with good predicted oral bioavailability. PMID- 29709569 TI - The effect of sleep deprivation on emotional memory consolidation in participants reporting depressive symptoms. AB - Sleep has been shown to play a crucial role in the consolidation of emotionally salient memories. However, the influence of sleep, and Sleep Deprivation (SD), on emotional memory consolidation in depressive individuals remains elusive. For this experiment we recruited two groups of healthy students, one reporting mild to-severe depressive symptoms, and another reporting minimal/no depressive symptoms (assessed using the Beck Depression Inventory; BDI-II). We measured recognition performance for positive, neutral and negative images before and after a 12 h overnight retention interval, during which participants either remained awake in the laboratory or returned home to sleep normally. We found a significant depressive symptomatology group * sleep condition * image valence interaction on memory consolidation across the 12 h retention interval [F(2, 98) = 3.12, p = .049, etap2 = 0.060]. We also found that depressive participants who slept normally consolidated significantly more negative and neutral images across the 12 h retention interval than depressive participants who were sleep deprived [t(24) = 2.35, p = .028, t(24) = 2.79, p = .010, respectively]. Our preliminary results indicate that SD may impair the consolidation of negative and neutral memories in depressive participants, but not in participants reporting minimal/no depressive symptoms. PMID- 29709570 TI - Zinc-mediated Reversible Multimerization of Hsp31 Enhances the Activity of Holding Chaperone. AB - Hsp31 protein, belonging to the DJ-1/ThiJ/PfpI superfamily, increases the survival of Escherichia coli under various stresses. While it was reported as a holding chaperone, Hsp31 was also shown to exhibit the glyoxalase III activity in subsequent study. Here, we describe our finding that Hsp31 undergoes a Zn+2 mediated multimerization (HMWZinc), resulting in an enhanced chaperone activity. Furthermore, it was shown that the formation of HMWZinc is reversible such that the oligomer dissociates into the native dimer by EDTA incubation. We attempted to determine the structural change involving the transition between the native dimer and HMWZinc by adding Ni+2, which is Zn+2-mimetic, producing a potential intermediate structure. An analysis of this intermediate revealed a structure with hydrophobic interior exposed, due to an unfolding of the N-terminal loop and the C-terminal beta-to-alpha region. A treatment with hydrogen peroxide accelerated HMWZinc formation, so that the Hsp31C185E mutant rendered the formation of HMWZinc even at 45 degrees C. However, the presence of Zn+2 in the catalytic site antagonizes the oxidation of C185, implying a negative role. Our results suggest an unprecedented mechanism of the enhancing chaperone activity by Hsp31, in which the reversible formation of HMWZinc occurs in the presence of heat and Zn+2 ion. PMID- 29709571 TI - Virus Entry: Looking Back and Moving Forward. AB - Research over a period of more than half a century has provided a reasonably accurate picture of mechanisms involved in animal virus entry into their host cells. Successive steps in entry include binding to receptors, endocytosis, passage through one or more membranes, targeting to specific sites within the cell, and uncoating of the genome. For some viruses, the molecular interactions are known in great detail. However, as more viruses are analyzed, and as the focus shifts from tissue culture to in vivo experiments, it is evident that viruses display considerable redundancy and flexibility in receptor usage, endocytic mechanism, location of penetration, and uncoating mechanism. For many viruses, the picture is still elusive because the interactions that they engage in rely on sophisticated adaptation to complex cellular functions and defense mechanisms. PMID- 29709572 TI - An Overlapping Region between the Two Terminal Folding Units of the Outer Surface Protein A (OspA) Controls Its Folding Behavior. AB - Although many naturally occurring proteins consist of multiple domains, most studies on protein folding to date deal with single-domain proteins or isolated domains of multi-domain proteins. Studies of multi-domain protein folding are required for further advancing our understanding of protein folding mechanisms. Borrelia outer surface protein A (OspA) is a beta-rich two-domain protein, in which two globular domains are connected by a rigid and stable single-layer beta sheet. Thus, OspA is particularly suited as a model system for studying the interplays of domains in protein folding. Here, we studied the equilibria and kinetics of the urea-induced folding-unfolding reactions of OspA probed with tryptophan fluorescence and ultraviolet circular dichroism. Global analysis of the experimental data revealed compelling lines of evidence for accumulation of an on-pathway intermediate during kinetic refolding and for the identity between the kinetic intermediate and a previously described equilibrium unfolding intermediate. The results suggest that the intermediate has the fully native structure in the N-terminal domain and the single layer beta-sheet, with the C terminal domain still unfolded. The observation of the productive on-pathway folding intermediate clearly indicates substantial interactions between the two domains mediated by the single-layer beta-sheet. We propose that a rigid and stable intervening region between two domains creates an overlap between two folding units and can energetically couple their folding reactions. PMID- 29709574 TI - Detection of blaOXA-48 and clonal relationship in carbapenem resistant K. pneumoniae isolates at a tertiary care center in Western Turkey. AB - BACKGROUND: Klebsiella pneumoniae is an important nosocomial pathogen that can lead to high morbidity and mortality. ESBL and carbapenamase producing strains may cause epidemic situations. The aim of our study was to investigate the molecular epidemiology and clonal relationship between carbapenem resistant K. pneumoniae strains isolated from our hospital during a three month period. METHODS: Fourteen carbapenem resistant K. pneumoniae strains isolated during April 1st-June 30th 2013 were included. The identification and the antibiotic susceptibility of the strains were studied by Vitek 2 Compact (Biomerieux, France) system. The carbapenemase production of the isolates were investigated by Modified Hodge assay. The blaOXA of the strains was investigated by in house PCR. The clonal relationship between the isolates were studied by pulsed-field gel electrophoresis (PFGE) and automatized repetitive extragenic palindromic PCR (Rep PCR, DiversiLab sistemi, Biomerieux, France) methods. RESULTS: All the K. pneumoniae isolates were carbapenem resistant; they were all susceptible to gentamycin and colistin. All of them had blaOXA-48. The genotyping analysis revealed that eight isolates were in the same cluster both by Rep-PCR (similarity border >=95%) and PFGE (Tennover criteriae) analysis. The other isolates did not belong to any other clusters. The strains that are in the same cluster are isolated from the Anesthesiology Intensive Care Unit during a three month period. The cluster ration by both methods was 57%. CONCLUSIONS: All K. pneumoniae strains possessed blaOXA-48. The clonal spreading was particularly detected in Anesthesiology Intensive Care Unit. Molecular epidemiological monitorization of nosocomial pathogens may prevent the spread of these multidrug resistant pathogens. PMID- 29709575 TI - Arrhythmia genetics: Not dark and lite, but 50 shades of gray. PMID- 29709576 TI - Leadless pacemaker versus transvenous single-chamber pacemaker therapy: A propensity score-matched analysis. AB - BACKGROUND: The recent introduction of leadless pacemakers (PMs) was aimed to eliminate transvenous lead- and pocket-related complications. While the initial results with the leadless PMs seem promising, the nonrandomized nature, limited implant experience of operators, and short follow-up period of these studies preclude a simple comparison to transvenous PMs. OBJECTIVES: The objective of this study was to provide a balanced comparison of leadless and transvenous single-chamber PM therapies through a propensity score-matched analysis. METHODS: Leadless patients from 3 experienced leadless implant centers were propensity score-matched to VVI-R patients from a contemporary prospective multicenter transvenous PM registry. The primary outcome was device-related complications that required invasive intervention during mid-term follow-up. Separate analyses including and excluding PM advisory-related complications were performed. RESULTS: A total of 635 patients were match-eligible (leadless: n = 254; transvenous: n = 381), of whom 440 patients (median age 78 years; interquartile range 70-84 years; 61% men) were successfully matched (leadless: n = 220 vs transvenous: n = 220). The complication rate at 800 days of follow-up was 0.9% (95% confidence interval [CI] 0%-2.2%) in the leadless group vs 4.7% (95% CI 1.8% 7.6%) in the transvenous group when excluding PM advisory-related complications (P = .02). When including these PM advisory-related complications, the complication rate at 800 days increased to 10.9% (95% CI 4.8%-16.5%) in the leadless group vs 4.7% (95% CI 1.8%-7.6%) in the transvenous group (P = .063). CONCLUSION: This study reveals favorable complication rates for leadless compared to transvenous single-chamber pacing therapy at mid-term follow-up in a propensity score-matched cohort. When including PM advisory-related complications, this advantage is no longer observed. PMID- 29709577 TI - Endocardial ablation of ventricular ectopic beats arising from the basal inferoseptal process of the left ventricle. AB - BACKGROUND: Idiopathic ventricular ectopy (VE) shows predilection to sites within the left ventricular (LV) base such as the outflow tract/aortic sinuses, LV summit, and areas adjacent to the aortomitral continuity. We characterize VE arising from the inferior septum of the LV base that was successfully managed by LV endocardial ablation from the inferoseptal recess of the LV. OBJECTIVE: The purpose of this study was to determine the incidence, electrocardiographic (ECG) findings, electrophysiological findings, and anatomical features associated with VE arising from the basal inferoseptal process of the LV (ISP-LV) ablated using an LV endocardial approach via the inferoseptal recess of the LV. METHODS: A total of 425 consecutive patients undergoing VE ablation between January 1, 2012 and December 31, 2016 at 3 centers were evaluated. Demographic characteristics, ECG findings, and procedural data were analyzed for patients with ISP-LV VEs. RESULTS: Seven (1.5%) had a site of origin from the ISP-LV. Common ECG findings were a right bundle branch block concordant pattern or an atypical left bundle branch block early transition pattern, suggestive of a basal origin with a left superior axis, a biphasic QRS complex in lead aVR, and a small s wave in lead V6. Earliest activation was seen in an area below the outflow tract accessed from the inferoseptal recess inferior to the His bundle. In 3 cases, transient junctional rhythm was seen during ablation. All cases were ablated successfully with no complications. CONCLUSION: VE arising from the ISP-LV represents a distinct subset of idiopathic arrhythmia and can be successfully treated by endocardial catheter ablation from the inferoseptal recess. They share common surface ECG and electrophysiological findings with special anatomical features that need recognition for successful catheter ablation. PMID- 29709573 TI - Roles for neuronal and glial autophagy in synaptic pruning during development. AB - The dendritic protrusions known as spines represent the primary postsynaptic location for excitatory synapses. Dendritic spines are critical for many synaptic functions, and their formation, modification, and turnover are thought to be important for mechanisms of learning and memory. At many excitatory synapses, dendritic spines form during the early postnatal period, and while many spines are likely being formed and removed throughout life, the net number are often gradually "pruned" during adolescence to reach a stable level in the adult. In neurodevelopmental disorders, spine pruning is disrupted, emphasizing the importance of understanding its governing processes. Autophagy, a process through which cytosolic components and organelles are degraded, has recently been shown to control spine pruning in the mouse cortex, but the mechanisms through which autophagy acts remain obscure. Here, we draw on three widely studied prototypical synaptic pruning events to focus on two governing principles of spine pruning: 1) activity-dependent synaptic competition and 2) non-neuronal contributions. We briefly review what is known about autophagy in the central nervous system and its regulation by metabolic kinases. We propose a model in which autophagy in both neurons and non-neuronal cells contributes to spine pruning, and how other processes that regulate spine pruning could intersect with autophagy. We further outline future research directions to address outstanding questions on the role of autophagy in synaptic pruning. PMID- 29709579 TI - New insights in the in vitro characterisation and molecular modelling of the P glycoprotein inhibitory promiscuity. AB - The presence of several binding sites for both substrates and inhibitors is yet a poorly explored thematic concerning the assessment of the drug-drug interactions risk due to interactions of multiple drugs with the human transport protein P glycoprotein (P-gp or MDR1, gene ABCB1). In this study we measured the inhibitory behaviour of a set of known drugs towards P-gp by using three different probe substrates (digoxin, Hoechst 33,342 and rhodamine 123). A structure-based model was built to unravel the different substrates binding sites and to rationalize the cases where drugs were not inhibiting all the substrates. A separate set of experiments was used to validate the model and confirmed its suitability to either detect the substrate-dependent P-gp inhibition and to anticipate proper substrates for in vitro experiments case by case. The modelling strategy described can be applied for either design safer drugs (P-gp as antitarget) or to target specific sub-site inhibitors towards other drugs (P-gp as target). PMID- 29709578 TI - B-type natriuretic peptide and risk of sudden death in patients with hypertrophic cardiomyopathy. AB - BACKGROUND: The association between B-type natriuretic peptide (BNP) levels and sudden cardiac death in patients with hypertrophic cardiomyopathy (HCM) remains unclear. OBJECTIVE: This study evaluated the effect of elevated BNP levels on sudden death risk in a cohort of patients with HCM. METHODS: This study included 346 patients with HCM. Plasma BNP levels were measured at the initial evaluation. RESULTS: The median (interquartile range) BNP level in the study patients was 197.2 (84.4-353.3) pg/mL. During a median (interquartile range) follow-up period of 8.4 (4.2-12.5) years, 37 patients (10.7%) experienced the combined end point of sudden death or potentially lethal arrhythmic events, including 11 patients with sudden death (3.2%), 8 resuscitated after cardiac arrest, and 18 with appropriate implantable defibrillator shocks. Time-dependent receiver operating characteristic curve analysis of the prognostic value of BNP for the combined end point showed that the Harrell's concordance index was 0.748 and the optimal BNP cutoff point was 312 pg/mL. Patients with high BNP levels (>312 pg/mL) were at a significantly higher risk of sudden death (Gray test, P = .001) and the combined end point (Gray test, P < .001) than were patients with low BNP levels (<=312 pg/mL). Multivariable analysis that included BNP levels and established risk factors for sudden death showed that high BNP levels were an independent determinant of the combined end point (adjusted hazard ratio 5.71; 95% confidence interval 2.86-11.4; P < .001). CONCLUSION: Elevated BNP levels may be associated with sudden death and the combination of sudden death or potentially lethal arrhythmic events in patients with HCM. PMID- 29709580 TI - Increased conflict-induced slowing, but no differences in conflict-induced positive or negative prediction error learning in patients with schizophrenia. AB - People with schizophrenia (PSZ) often fail to pursue rewarding activities despite largely intact in-the-moment hedonic experiences. Deficits in effort-based decision making in PSZ may be related to enhanced effects of cost or reduced reward, i.e., through the amplification of negative prediction errors or by dampened positive prediction errors (here, positive and negative prediction errors refer to outcomes that are better or worse than expected respectively). We administered a modified Simon task to people with schizophrenia (PSZ; N = 46) and healthy controls (N = 32). The modification included a reinforcement learning component, where positive and negative prediction errors are dampened or boosted through the use of cognitively-effortful response conflict. EEG was recorded concurrently to investigate potential differences in conflict enhanced mid frontal theta power between PSZ and controls. We found an enhanced effect of response conflict on response time in people with schizophrenia, but no discernible difference in conflict processing as reflected by the lack of a difference in theta-power enhancement to conflict in mid-frontal regions. Using the reinforcement learning transfer phase of the modified Simon task, PSZ also showed clear deficits in selecting the most rewarding stimulus during the 'easy' (most discriminable in terms of value) stimulus contrasts. However, we failed to find a difference between patients and controls in their gain or avoidance learning bias, nor did these biases correlate with negative symptoms. Previous studies had failed to find significant conflict effects on the Simon task likely due to its modest effect size. Our results show that PSZ do indeed possess subtle impairments in response-conflict, suggesting an increase in cognitive effort required for appropriate responding. In addition, while the lack of an overt positive or negative prediction error bias (i.e., a bias towards punishment or reward learning) was unexpected, it is consistent with recent work showing intact estimation of value when the reinforcement learning system is isolated from other contributors to value learning. PMID- 29709581 TI - The neuroscience of empathy - from past to present and future. PMID- 29709582 TI - Differential effects of sustained and transient effort triggered by reward - A combined EEG and pupillometry study. AB - In instrumental task contexts, incentive manipulations such as posting reward on successful performance usually trigger increased effort, which is signified by effort markers like increased pupil size. Yet, it is not fully clear under which circumstances incentives really promote performance, and which role effort plays therein. In the present study, we compared two schemes of associating reward with a Flanker task, while simultaneously acquiring electroencephalography (EEG) and pupillometry data in order to explore the contribution of effort-related processes. In Experiment 1, reward was administered in a block-based fashion, with series of targets in pure reward and no-reward blocks. The results imply increased sustained effort in the reward blocks, as reflected in particular in sustained increased pupil size. Yet, this was not accompanied by a behavioral benefit, suggesting a failure of translating increased effort into a behavioral pay-off. In Experiment 2, we introduced trial-based cues in order to also promote transient preparatory effort application, which indeed led to a behavioral benefit. Again, we observed a sustained pupil-size increase, but also transient ones. Consistent with this, the EEG data of Experiment 2 indicated increased transient preparatory effort preceding target onset, as well as reward modulations of target processing that arose earlier than in Experiment 1. Jointly, our results indicate that incentive-triggered effort can operate on different time-scales, and that, at least for the current task, its transient (and largely preparatory) form is critical for achieving a behavioral benefit, which may relate to the temporal dynamics of the catecholaminergic systems. PMID- 29709583 TI - Seeing action simulation as it unfolds: The implicit effects of action scenes on muscle contraction evidenced through the use of a grip-force sensor. AB - Action simulation is a cognitive process that mentally simulates a motor act without performing it in the true external world. Simulation mechanisms play a key role in perceiving, feeling and understanding actions executed by others. However, very little is known about the process dynamics because of the absence of a behavioral tool to probe directly the action simulation process as it unfolds. Twenty-seven healthy adults were required to hold a force sensor in a relaxed pinch-grip while viewing action videos of different intensities: wait (null); touch (low); move (medium); crush (high). When contrasting the variations in grip force (GFv) across conditions, results indicated that GFv started to increase and peaked respectively 200 and 400 ms after the moment of effector object contact. In the wait condition, GFv remained flat throughout the trial confirming an absence of simulation engagement. Peak GFv was greater for the high and medium than for the low intensity videos suggesting greater brain activity overflow to the peripheral motor system when simulating more effortful body movements. These effects were negatively correlated with the motor imagery abilities of the participants, with greater GFv in the poor imagers as determined by the Movement Imagery Questionnaire. Our results confirm the possibility of using a non-invasive grip force sensor to detect not only when individuals are cognitively engaged in action simulation but also to reveal the dynamics of the process. With various sets of videos, this paradigm offers new perspectives in the study of action simulation and its role in human cognition. PMID- 29709584 TI - Resuscitative Endovascular Balloon Occlusion of the Aorta: Implementation and Preliminary Results at an Academic Level I Trauma Center. AB - BACKGROUND: Resuscitative endovascular balloon occlusion of the aorta (REBOA) is a novel method of controlling subdiaphragmatic hemorrhage while improving hemodynamic stability. This procedure achieves many of the goals of resuscitative thoracotomy (RT), but is less invasive. Here, we present the initial experience with REBOA at a level 1 academic trauma center. STUDY DESIGN: We performed a retrospective review. Orientation of surgeons and residents to REBOA was accomplished by an educational program including a hands-on simulation session (1.5 hours). Surgeons were not required to attend an external training course. Operating room personnel were oriented with a slide presentation. Initially, a 12 Fr introducer and aortic occlusion balloon were used. Subsequently, a 7-Fr device was used. All REBOAs were performed in a dedicated hybrid operating room. Resuscitative thoracotomy was performed in the trauma bays and operating room. RESULTS: During a 21-month period (June 2015 to March 2017), 16 patients (Injury Severity Score [ISS] 38.6 +/- 22.3, Glasgow Coma Scale [GCS] 8.9 +/- 5.9, lactate 4.91 +/- 3.26 mmol/L) had REBOA placed. All patients were hemodynamically unstable (systolic blood pressure 96.5 +/- 9.3 mmHg) due to hemorrhage. Preoperative hemoglobin ranged from 5 to 14.4 mg/dL. Etiology of hemorrhage was blunt trauma (n = 11), penetrating injury (n = 2), and nontraumatic mechanisms (n = 3). After REBOA, hemodynamic status improved in 10 of 16 patients. Fourteen patients survived the initial operative intervention and 6 survived 30 days; REBOA was successfully performed in all patients. One survivor developed a common femoral pseudoanuerysm. Survival for RT (ISS 31.3 +/- 11.25) during same period was 0%. CONCLUSIONS: Resuscitative endovascular balloon occlusion of the aorta is an effective method of improving hemodynamic status in patients with sub diaphragmatic hemorrhage. Extensive training is not required to implement a REBOA program, and REBOA is a useful technique for trauma surgeons. PMID- 29709586 TI - Large group size promotes the evolution of cooperation in the mutual-aid game. AB - Our society is based on group cooperation, but this remains an unsolved problem from the viewpoint of evolutionary biology and the social sciences. Group cooperation is often studied through the public goods game, and it has been shown that large group size never promotes the evolution of cooperation. We consider the mutual-aid game, in which one member of the group is chosen randomly as the aid recipient, and other members decide whether to help the recipient. This game can describe the early stage of insurance provision in England, for example. With reference to existing indirect reciprocity studies, we investigate what promotes the evolution of cooperation in the mutual-aid game by means of replicator equations and agent-based simulations. Our key findings are as follows. In a multilateral relationship in which members play the mutual-aid game in a group whose size is greater than two, once two or more defectors are in bad standing, they remain bad under the rule that a donor's bad reputation remains bad, whether or not the donor helps a recipient with a bad reputation. Then, cooperators never help them, and mutation helps the invasion of rare cooperators more when the group size is larger in the finite population, even when implementation and perception errors occur. Meanwhile, this rule never helps the invasion in the bilateral relationship in which the group size is two. Our results suggest that large group cooperation can be sustainable if social institutions are equipped with systems such as those in the mutual-aid game. PMID- 29709585 TI - Emerging role of viral vectors for circuit-specific gene interrogation and manipulation in rodent brain. AB - Over the past half century, novel tools have allowed the characterization of myriad molecular underpinnings of neural phenomena including synaptic function, neurogenesis and neurodegeneration, membrane excitability, and neurogenetics/epigenetics. More recently, transgenic mice have made possible cell type-specific explorations of these phenomena and have provided critical models of many neurological and psychiatric diseases. However, it has become clear that many critical areas of study require tools allowing the study and manipulation of individual neural circuits within the brain, and viral vectors have come to the forefront in driving these circuit-specific studies. Here, we present a surface level review of the general classes of viral vectors used for study of the brain, along with their suitability for circuit-specific studies. We then cover in detail a new long-lasting, retrograde expressing form of herpes simplex virus termed LT-HSV that has become highly useful in circuit-based studies. We detail some of its current uses and propose a variety of future uses for this critical new tool, including circuit-based transgene overexpression, gene editing, and gene expression profiling. PMID- 29709587 TI - The influence of the DNA torque on the dynamics of transcription bubbles in plasmid PTTQ18. AB - In this work, we study numerically the influence of the DNA torque on the movement of transcription bubbles in the potential field formed by the sequence of plasmid PTTQ18. To imitate the movement, we apply a modified sine-Gordon equation with the two additional terms that describe the effects of dissipation and the action of the DNA torsion torque, and with the coefficients that depend on the sequence of bases. We obtain the trajectories of the transcription bubbles and investigate the dependence of the trajectories on the initial bubble velocity and the DNA torsion torque. It is shown that not the initial bubble velocity but the DNA torsion torque governs the trajectories of the transcription bubbles. PMID- 29709588 TI - Potential of siRNA-albumin complex against cancer. AB - RNA interference is a highly specific as well as efficient technology for gene therapy application in molecular oncology. The present study was planned to develop an efficient and stable tumor selective delivery mechanism for siRNA gene therapy for the purpose of both diagnosis as well as therapy. We have used 20 Male wistar rats for the formation of colon cancer model and utilized albumin as carrier molecule for the delivery of siRNA against vascular endothelial growth factor receptor 2 (VEGF R2). The study results confirmed efficient delivery of siRNA at tumor site as confirmed by tagging of siRNA-albumin complex with 99mTC. Moreover, the expression of VEGF also showed decline after efficient delivery of siRNA at tumor site. The study concluded that albumin is an efficient molecule for the efficient delivery of siRNA at tumor sites. PMID- 29709589 TI - Effect of the alkyl group in the piperazine N-substitution on the therapeutic action of rifamycins: A drug-membrane interaction study. AB - In this work, we studied the effects of the N-alkyl group (methyl, cyclopentyl) in the piperazine ring of, respectively, rifampicin (RIF) and rifapentine (RPT) to correlate this substitution with their differential pharmacokinetic properties and overall clinical performance. Since this group is their only structural change, and given that they share the same pharmacological target, differences in their therapeutic behavior may respond to this asset, particularly in their interaction with lipid membranes across the organism. In this study, surface pressure-area isotherms, as well as spectroscopic and microscopic techniques of characterization of phospholipid monolayers at the air/water interface were used to gain insight into drug-membrane interactions. Differences in the affinity for lipid membranes for both drugs, given by the vibration frequency of characteristic chemical groups in the lipid, as well as by reflectivity and mean molecular area of the monolayer, seem to be due to the N-alkyl substituent and can contribute to provide a molecular explanation as why they pose different choices in the chemotherapy against the deadliest infectious disease, tuberculosis. PMID- 29709590 TI - Impairment of the intestine barrier function in Litopenaeus vannamei exposed to ammonia and nitrite stress. AB - Intestine barrier serves as the front-line of shrimp defense, which rely on its structural integrity, microbial composition, and mucus immune compounds. Mucins are the major organic components of the intestine mucus layer that contribute to the immunity of intestine mucus. In this study, we examined the histological structure, microbial composition, and mucin genes expression in the intestines of Litopenaeus vanmei under three different conditions: control, ammonia stress, and nitrite stress for 72 h. H&E stain showed that ammonia and nitrite stress exposure both damaged the intestine mucosal tissue. High-throughput 16S rDNA sequencing revealed that two stresses exposure decreased the bacterial diversity, and altered the composition of intestine microbial. Specifically, the dominant bacterial phyla Bacteroidetes abundance was increased, while Proteobacteria and Planctomycetes were decreased; at the genus level, Formosa abundance was increased and Photobacterium was decreased, opportunistic pathogens including Nautella and Pseudoalteromonas was also increased. Intestine mucus immune genes including mucin-2 and mucin-19 were up-regulated, while mucin-1, mucin-5AC, and mucin-5B were down-regulated in two stress exposure groups. These results revealed that ammonia and nitrite stress harmed the intestine barrier function of L. vannamei by damaging the mucosal tissue, disrupting the composition of intestine microbial, and suppressing the immune function. PMID- 29709591 TI - Molecular characterization of glutaminyl-peptide cyclotransferase(QPCT)in Scylla paramamosain and its role in Vibrio alginolyticus and white spot syndrome virus (WSSV) infection. AB - Glutaminyl-peptide cyclotransferase (QPCT) catalyzes the posttranslational modification of an N-terminal glutamate of proteins to pyroglutamate. This renders the protein more resistant to protease degradation, more susceptible to hydrophobic interactions, aggregation, and neurotoxic. In this study, we evaluated the influence of QPCT in the crab Scylla paramamosain infected with white spot syndrome virus (WSSV) or with Vibrio alginolyticus. A cDNA clone, encompassing the entire 2445 bp of the S. paramamosain QPCT gene, containing a 1113 bp open reading frame (ORF) encoding a 370 amino acid protein was cloned from S. paramamosain. Real-time PCR indicated that QPCT was primarily expressed in the digestive tract of S. paramamosain, was up-regulated in hemocytes after infection with V. alginolyticus, and down-regulated in hemocytes after infection with WSSV. Knockdown of QPCT expression by double-stranded RNA (QPCT-dsRNA) resulted in down-regulation of prophenoloxidase (proPO) and crustin antimicrobial peptide, whereas myosin-II-essential-light-chain-like-protein was significantly up-regulated in hemocytes at 24 h post QPCT-dsRNA treatment. WSSV challenge in crabs treated with QPCT-dsRNA resulted in a reduction in viral burden and in the apoptotic rate of crab hemocytes, while the phagocytic activity of crab hemocytes and overall mortality rate were increased. This suggests that WSSV might take advantage of QPCT to benefit its replication. In contrast, V. alginolyticus infection in crabs treated with QPCT-dsRNA indicated that the apoptotic rate and phagocytic activity of hemocytes, and overall incidence of mortality, were increased compared to mock-treated animals, indicating that QPCT might be a resistance factor in bacterial infection. These results increase our understanding of the function of QPCT and its role in the innate immunity of S. paramamosain. PMID- 29709592 TI - The skin immune response of rainbow trout, Oncorhynchus mykiss (Walbaum), associated with puffy skin disease (PSD). AB - Puffy skin disease (PSD) is an emerging skin condition which affects rainbow trout, Oncorhynchus mykiss (Walbaum). The transmission pattern of PSD suggests an infectious aetiology, however, the actual causative infectious agent(s) remain(s) unknown. In the present study, the rainbow trout epidermal immune response to PSD was characterised. Skin samples from infected fish were analysed and classified as mild, moderate or severe PSD by gross pathology and histological assessment. The level of expression of 26 immune-associated genes including cytokines, immunoglobulins and cell markers were examined by TaqMan qPCR assays. A significant up-regulation of the gene expression of C3, lysozyme, IL-1beta and T bet and down-regulation of TGFbeta and TLR3 was observed in PSD fish compared to control fish. MHCI gene expression was up-regulated only in severe PSD lesions. Histological examinations of the epidermis showed a significant increase in the number of eosinophil cells and dendritic melanocytes in PSD fish. In severe lesions, mild diffuse lymphocyte infiltration was observed. IgT and CD8 positive cells were detected locally in the skin of PSD fish by in situ hybridisation (ISH), however, the gene expression of those genes was not different from control fish. Total IgM in serum of diseased animals was not different from control fish, measured by a sandwich ELISA, nor was significant up regulation of IgM gene expression in PSD lesions observed. Taken together, these results show activation of the complement pathway, up-regulation of a Th17 type response and eosinophilia during PSD. This is typical of a response to extracellular pathogens (i.e. bacteria and parasites) and allergens, commonly associated with acute dermatitis. PMID- 29709594 TI - Reliability of IOTA score and ADNEX model in the screening of ovarian malignancy in postmenopausal women. AB - BACKGROUND: The IOTA (International Ovarian Tumor Analysis) group has developed the ADNEX (Assessment of Different NEoplasias in the adneXa) model to predict the risk that an ovarian mass is benign, borderline or malignant. This study aimed to test reliability of these risks prediction models to improve the performance of pelvic ultrasound and discriminate between benign and malignant cysts. MATERIAL AND METHODS: Postmenopausal women with an adnexal mass (including ovarian, para ovarian and tubal) and who underwent a standardized ultrasound examination before surgery were included. Prospectively and retrospectively collected data and ultrasound appearances of the tumors were described using the terms and definitions of the IOTA group and tested in accordance with the ADNEX model and were compared to the final histological diagnosis. RESULTS: Of the 107 menopausal patients recruited between 2011 and 2016, 14 were excluded (incomplete inclusion criteria). Thus, 93 patients constituted a cohort in whom 89 had benign cysts (83 ovarian and 6 tubal or para-ovarian cysts), 1 had border line tumor and 3 had invasive ovarian cancers (1 at first stage, 1 at advanced stage and 1 metastatic tumor in the ovary). The overall prevalence of malignancy was 4.3%. Every benign ovarian cyst was classified as probably benign by IOTA score which showed also a high specificity with the totality of probably malignant lesion proved malignant by histological exam. The limit of this score was the important rate of not classified or undetermined cysts. However, the malignancy risks calculated by ADNEX model allowed identifying the totality of malignancy. Thus, the combination of the two methods of analysis showed a sensitivity and specificity rates of respectively 100% and 98%. Evaluation of malignancy risks by these 2 tests highlighted a negative predictive value of 100% (there was no case of false negative) and a positive predictive value of 80%. DISCUSSION AND CONCLUSION: On the basis of our findings, the IOTA classification and the ADNEX multimodal algorithm used as risks prediction models can improve the performance of pelvic ultrasound and discriminate between benign and malignant cysts in postmenopausal women, especially for undetermined lesions. PMID- 29709593 TI - A novel toll-like receptor from Mytilus coruscus is induced in response to stress. AB - Toll-like receptor (TLR) is considered to be an evolutionarily conserved transmembrane protein which promotes the Toll signal pathway to active the expression of transcription factors in the innate immunity of the organism. In this study, a full length of TLR homologue of 2525bp in Mytilus coruscus (named as McTLR-a, GenBank accession no: KY940571) was characterized. Its ORF was 1815 bp with a 5'untranslated region (UTR) of 128 bp and a 3'UTR of 582 bp, encoding 602 amino acid residues with a calculated molecular weight of 70.870 kDa (pI = 6.10). BLASTn analysis and phylogenetic relationship strongly suggested that this cDNA sequence was a member of TLR family. Quantitative real time RT-PCR showed that constitutive expression of McTLR-a was occurred, with increasing order in hemocyte, gonad, mantle, adducter, gill and hepatopancreas. Bacterial infection and heavy metals stimulation up-regulated the expression of McTLR-a mRNA in hepatopancreas with time-dependent manners. The maximum expression appeared at 12 h after pathogenic bacteria injection, with approximately 22-fold in Aeromonas hydrophila and 17-fold in Vibrio parahemolyticus higher than that of the blank group. In heavy metals stress group, they all reached peaks at 3d, while the diverse concentration caused the maximum expression were different. The highest expression reached approximately 7-fold higher than the blank in low concentration of Pb2+ exposure. In Cu2+ treated group, it reached the peak (approximately 12-fold higher than the blank)in middle concentration. These results indicated that McTLR-a might be involved in the defense response and had a significant role in mediating the environmental stress. PMID- 29709595 TI - Activated hyaluronan metabolism in the tumor matrix - Causes and consequences. AB - Hyaluronan accumulates in the stroma of several solid tumors and promotes their progression. Both enhanced synthesis and fragmentation of hyaluronan are required as a part of this inflammatory process resembling wound healing. Increased expression of the genes of hyaluronan synthases (HAS1-3) are infrequent in human tumors, while posttranslational modifications that activate the HAS enzymes, and glucose shunted to the UDP-sugar substrates HASs, can have crucial contributions to tumor hyaluronan synthesis. The pericellular hyaluronan influences virtually all cell-cell and cell-matrix interactions, controlling migration, proliferation, apoptosis, epithelial to mesenchymal transition, and stem cell functions. The catabolism by hyaluronidases and free radicals appears to be as important as synthesis for the inflammation that promotes tumor growth, since the receptors mediating the signals create specific responses to hyaluronan fragments. Targeting hyaluronan metabolism shows therapeutic efficiency in animal experiments and early clinical trials. PMID- 29709596 TI - Vascular aspects of the Ehlers-Danlos Syndromes. AB - The Ehlers-Danlos Syndromes comprise a heterogeneous group of rare monogenic conditions that are characterized by joint hypermobility, skin and vascular fragility and generalized connective tissue friability. The latest classification recognizes 13 clinical subtypes, with mutations identified in 19 different genes. Besides defects in fibrillar collagens (collagen types I, III and V), their modifying enzymes (ADAMTS-2, lysylhydroxylase 1 (LH1)), and molecules involved in collagen folding (FKBP22), defects have recently been identified in other constituents of the extracellular matrix (e.g. Tenascin-X, collagen type XII), enzymes involved in glycosaminoglycan biosynthesis (beta4GalT7 and beta3GalT6), dermatan 4-O-sulfotransferase-1 (D4ST1), dermatan sulfate epimerase (DSE)), (putative) transcription factors (ZNF469, PRDM5), components of the complement pathway (C1r, C1s) and an intracellular Zinc transporter (ZIP13). Easy bruising is, to a variable degree, present in all subtypes of EDS. A variable bleeding tendency, manifesting e.g. as gum bleeding, menometrorraghia, postnatal or peri operative hemorrhage is observed in many EDS-patients of varying EDS subtypes. Life-threatening arterial aneurysms, dissections and ruptures of medium-sized and large arteries are a hallmark of the vascular subtype of EDS, caused by a molecular defect in collagen type III, an important constituent of blood vessel walls and hollow organs. They may however also occur in other EDS subtypes, especially in classical EDS, caused by defects in type V collagen or, rarely, type I collagen, and in kyphoscoliotic EDS, caused by defects in LH1 or FKBP22. These manifestations of vascular fragility and bleeding are usually attributed to fragility of the blood vessel walls and the perivascular connective tissues, but the molecular pathomechanisms underlying these complications are poorly studied. This review summarizes current knowledge on manifestations of vascular fragility in the different EDS subtypes. PMID- 29709597 TI - Developmental evolution and developmental plasticity of the olfactory epithelium and olfactory skills in Mexican cavefish. AB - The fish Astyanax mexicanus comes in two forms: the normal surface-dwelling (SF) and the blind depigmented cave-adapted (CF) morphs. Among many phenotypic differences, cavefish show enhanced olfactory sensitivity to detect amino-acid odors and they possess large olfactory sensory organs. Here, we questioned the relationship between the size of the olfactory organ and olfactory capacities. Comparing olfactory detection abilities of CF, SF and F1 hybrids with various olfactory epithelium (OE) sizes in behavioral tests, we concluded that OE size is not the only factor involved. Other possibilities were envisaged. First, olfactory behavior was tested in SF raised in the dark or after embryonic lens ablation, which leads to eye degeneration and mimics the CF condition. Both absence of visual function and absence of visual organs improved the SF olfactory detection capacities, without affecting the size of their OE. This suggested that developmental plasticity occurs between the visual and the olfactory modalities, and can be recruited in SF after visual deprivation. Second, the development of the olfactory epithelium was compared in SF and CF in their first month of life. Proliferation, cell death, neuronal lifespan, and olfactory progenitor cell cycling properties were identical in the two morphs. By contrast, the proportions of the three main olfactory sensory neurons subtypes (ciliated, microvillous and crypt) in their OE differed. OMP-positive ciliated neurons were more represented in SF, TRPC2-positive microvillous neurons were proportionately more abundant in CF, and S100-positive crypt cells were found in equal densities in the two morphs. Thus, general proliferative properties of olfactory progenitors are identical but neurogenic properties differ and lead to variations in the neuronal composition of the OE in SF and CF. Together, these experiments suggest that there are at least two components in the evolution of cavefish olfactory skills: (1) one part of eye-dependent developmental phenotypic plasticity, which does not depend on the size of the olfactory organ, and (2) one part of developmental evolution of the OE, which may stem from embryonic specification of olfactory neurons progenitor pools. PMID- 29709598 TI - Transcriptomics of dorso-ventral axis determination in Xenopus tropicalis. AB - Amphibian embryos provide a powerful system to study early cell fate determination because their eggs are externally fertilised, large, and easy to manipulate. Ultraviolet (UV) or lithium chloride (LiCl) treatment are classic embryonic manipulations frequently used to perturb specification of the dorso ventral (DV) axis by affecting the stability of the maternal Wnt mediator beta catenin. Such treatments result in the formation of so-called ventralised or dorsalised embryos. Although these phenotypes have been well described with respect to their morphology and some aspects of gene expression, their whole transcriptomes have never been systematically characterised and compared. Here we show that at the early gastrula stage UV-treated embryos are transcriptionally more closely related to untreated embryos than to LiCl-treated embryos. Transcriptional comparisons with dissected ventral and dorsal regions of unperturbed gastrula embryos indicate that UV and LiCl treatments indeed enrich for ventral and dorsal cells, respectively. However, these treatments also affect the balance of neural induction in the ectodermal germ layer, with LiCl stimulating pro-neural BMP inhibition and UV preferentially generating epidermis because of elevated BMP levels. Thus the transcriptomes of UV- and LiCl-treated embryos can best be described as ventro-epidermalised and dorso-neuralised. These descriptions notwithstanding, our profiling reveals several hitherto uncharacterized genes with differential expression along the DV axis. At least one of these genes, a RNF220-like ubiquitin ligase, is activated dorsally by beta catenin. Our analysis of UV/LiCl-mediated axis perturbation will enhance the mechanistic understanding of DV axis determination in vertebrates. PMID- 29709600 TI - Characterization of somatic embryogenesis initiated from the Arabidopsis shoot apex. AB - Somatic embryogenesis is one of the best examples of the remarkable developmental plasticity of plants, in which committed somatic cells can dedifferentiate and acquire the ability to form an embryo and regenerate an entire plant. In Arabidopsis thaliana, the shoot apices of young seedlings have been reported as an alternative tissue source for somatic embryos (SEs) besides the widely studied zygotic embryos taken from siliques. Although SE induction from shoots demonstrates the plasticity of plants more clearly than the embryo-to-embryo induction system, the underlying developmental and molecular mechanisms involved are unknown. Here we characterized SE formation from shoot apex explants by establishing a system for time-lapse observation of explants during SE induction. We also established a method to distinguish SE-forming and non-SE-forming explants prior to anatomical SE formation, enabling us to identify distinct transcriptome profiles of these two explants at SE initiation. We show that embryonic fate commitment takes place at day 3 of SE induction and the SE arises directly, not through callus formation, from the base of leaf primordia just beside the shoot apical meristem (SAM), where auxin accumulates and shoot-root polarity is formed. The expression domain of a couple of key developmental genes for the SAM transiently expands at this stage. Our data demonstrate that SE forming and non-SE-forming explants share mostly the same transcripts except for a limited number of embryonic genes and root genes that might trigger the SE initiation program. Thus, SE-forming explants possess a mixed identity (SAM, root and embryo) at the time of SE specification. PMID- 29709602 TI - Structure, dynamics, and biochemical characterization of ADF/cofilin Twinstar from Drosophilamelanogaster. AB - BACKGROUND: Twinstar is an ADF/cofilin family protein, which is expressed by the tsr gene in Drosophila melanogaster. Twinstar is one of the main regulators of actin cytoskeleton remodelling and is essential for vital cellular processes like cytokinesis and endocytosis. METHODS: We have characterized the structure and dynamics of Twinstar by solution NMR spectroscopy, the interaction of Twinstar with rabbit muscle actin by ITC, and biochemical activities of Twinstar through different biochemical assays using fluorescence spectroscopy and ultra centrifugation. RESULTS: The solution structure of Twinstar shows characteristic ADF-H fold with well-formed G/F-site and F-site for interaction with actin. The structure possesses an extended F-loop, which is rigid at the base, but flexible towards its apical region. Twinstar shares similar dynamics for the G/F-site with C. elegans homologs, UNC-60A and UNC-60B. However, the dynamics of its F-loop are different from its C. elegans homologs. Twinstar shows strong affinity for ADP-G Actin and ATP-G-Actin with Kds of ~7.6 nM and ~0.4 MUM, respectively. It shows mild F-actin depolymerizing activity and stable interaction with F-actin with a Kd of ~5.0 MUM. It inhibits the rate of the nucleotide exchange in a dose dependent manner. CONCLUSION: On the basis of structure, dynamics, and biochemical activity, Twinstar can be taken to execute its biochemical role by facilitating directional growth and maintenance of length of actin filaments. GENERAL SIGNIFICANCE: This study characterizes the structure, backbone dynamics, and biochemical activities of Twinstar of Drosophila, which provides an insight into the regulation of actin dynamics in the member of phylum insecta. PMID- 29709601 TI - The left-right asymmetry of liver lobation is generated by Pitx2c-mediated asymmetries in the hepatic diverticulum. AB - Internal organs exhibit left-right asymmetric sizes, shapes and anatomical positions, but how these different lateralities develop is poorly understood. Here we use the experimentally tractable Xenopus model to uncover the morphogenetic events that drive the left-right asymmetrical lobation of the liver. On the right side of the early hepatic diverticulum, endoderm cells become columnar and apically constricted, forming an expanded epithelial surface and, ultimately, an enlarged right liver lobe. In contrast, the cells on the left side become rounder, and rearrange into a compact, stratified architecture that produces a smaller left lobe. Side-specific gain- and loss-of-function studies reveal that asymmetric expression of the left-right determinant Pitx2c elicits distinct epithelial morphogenesis events in the left side of the diverticulum. Surprisingly, the cellular events induced by Pitx2c during liver development are opposite those induced in other digestive organs, suggesting divergent cellular mechanisms underlie the formation of different lateralities. PMID- 29709603 TI - Photodynamic therapy for Hidradenitis Suppurativa/acne inversa: Case report. AB - Hidradenitis suppurativa/acne inversa (HS/AI) is a type of chronic suppurative inflammatory reaction of the hair follicles characterized by recurrent dermal abscesses, sinus tracts and scars. So far, there has not been any prospective study proving the efficacy and safety of photodynamic therapy for the disease. In this report, one case of HS/AI achieved resolution of skin lesions, ulcer healing and disappearance of symptoms after nine treatments with 5-aminolevulinic acid photodynamic therapy (ALA-PDT). PMID- 29709604 TI - Ex vivo assessment of synergic effect of chlorhexidine for enhancing antimicrobial photodynamic therapy efficiency on expression patterns of biofilm associated genes of Enterococcus faecalis. AB - BACKGROUND: It has clearly been demonstrated that Enterococcus faecalis, as a persistent microorganism, is the major agent in the etiopatogeny of endodontic infections. Recently, the limitations of conventional endodontic therapy have given rise to many attempts to introduce antimicrobial photodynamic therapy (aPDT) as an alternative treatment. The aim of this study was to analyze the ex vivo effect of aPDT in combination with 2.0% chlorhexidine (CHX) as a conventional therapy on colony count and expression patterns of genes associated with biofilm formation of E. faecalis. MATERIALS AND METHODS: A total of 125 extracted human single-rooted teeth were divide into six groups (A-F; n = 20) and were incubated with E. faecalis. Group A- photosensitizer (indocyanine green [ICG]); B- diode laser; C- aPDT; D- 2.0% CHX; E- aPDT with photosensitizer modified by 2.0% CHX; and F- control group (no procedure was performed). Five remaining teeth were used to confirm the presence of E. faecalis biofilm via scanning electron microscope. Counts of colony forming units (CFUs) in each group were evaluated separately and quantitative real-time PCR (qRT-PCR) was then applied to monitor genes expression of fsrC, efa, and gelE involved in E. faecalis biofilm. RESULTS: The results showed that none of the tested groups achieved eradication or inhibition of biofilm. On the other hand, aPDT + 2.0% CHX, 2.0% CHX, and ICG- mediated aPDT groups showed significantly less CFU/mL than ICG and diode laser groups. The group with the lowest CFU/mL count was the aPDT + 2.0% CHX, being statistically different from all other groups that could decrease the expression levels of efa, gelE, and fsrC genes 6.8-, 8.3-, and 12.1 fold, respectively. CONCLUSION: Based on the results, the synergism effect of ICG aPDT with 2.0% CHX leads to modulation of the virulence of E. faecalis strains biofilm model by suppressing the expression of the genes associated with biofilm formation. PMID- 29709605 TI - Catalase A is involved in the response to photooxidative stress in Pseudomonas aeruginosa. AB - BACKGROUND: Pseudomonas aeruginosa is the etiological agent of systemic and skin infections that are often difficult to treat. Photodynamic therapy (PDT) and, more recently, phototherapy (PT), are emerging among antimicrobial treatments to be combined with antibiotics. Visible light, either alone or combined with a photosensitizer (PS), elicits photooxidative stress that induces microbial death. The response of bacteria to phototherapy seems to involve the antioxidant machinery. This study relies on the effects of detoxifying catalase A (KatA) in response to PDT and PT-induced photooxidative stress. METHODS: The photo- and photodynamic inactivation experiments have been targeted at P. aeruginosa PAO1 and its isogenic derivative katA- mutant. The microorganisms were irradiated by a wide-spectrum halogen-tungsten lamp or light-emitting diodes (LEDs). Two photosensitizers, Tetrakis-(1-methyl-4-pyridyl)-21H, 23porphine, tetra-p-tosylate (TMPyP) porphyrin and Toluidine Blue O (TBO), were applied as part of the photodynamic approach. RESULTS: P. aeruginosa katA- mutant was more sensitive than wild-type strain PAO1 to wide-spectrum light and blue LED (464 nm) treatments. The complementation of KatA, in katA- mutant, restored the light response of wild-type PAO1. Upon TBO treatment and irradiation by visible light (halogen lamp or LED), the sensitivity of katA- mutant was significant higher (p = 0.028 and p = 0.045, respectively) than that of the PAO1 strain. CONCLUSIONS: This study provides the first description of KatA in the response to photooxidative stress induced by photo- and photodynamic therapy. PMID- 29709606 TI - Effect of photodynamic therapy as an adjuvant to non-surgical periodontal therapy: Periodontal and metabolic evaluation in patients with type 2 diabetes mellitus. AB - BACKGROUND: This pilot study aimed to evaluate the effect of antimicrobial photodynamic therapy (aPDT) as an adjuvant to non-surgical periodontal therapy (NSPT) on periodontal status and glycemic control in patients with type 2 diabetes mellitus and generalized chronic periodontitis. METHODS: Twelve patients were evaluated at five time points: during the preparation of the patient (T0), during the treatment phase (T1) and after 30 (T2), 90 (T3) and 180 (T4) days. The patients had a mean age of 52.2 years and a 9.58-year history of diabetes, on average, and were divided into two randomized treatment groups: 6 patients received NSPT combined with aPDT (G1) and 6 patients received only NSPT (G2). The aPDT was applied associating the photosensitizing agent methylene blue (10 mg/ ml) with a red laser (660 nm-40 mW). The total time of exposure was 2 min per tooth. RESULTS: Whitin the limitation of this study, the results showed that the plaque index reduced significantly only in the control group (p = 0.02) at T2 (30 days). For bleeding on probing, both groups showed a significant reduction between T1 and T2, with no difference between groups G1 and G2. Regarding the probing depth, there were no differences between groups, but the parameters decreased over time when compared to T1. The glycated haemoglobin and fructosamine levels did not significantly differ between or within the groups at any time point. CONCLUSION: When NSPT was combined with aPDT, no additional benefits were observed for the periodontal and metabolic clinical parameters. PMID- 29709607 TI - Test-retest reliability of the Battery for the Assessment of Auditory Sensorimotor and Timing Abilities (BAASTA). AB - Perceptual and sensorimotor timing skills can be thoroughly assessed with the Battery for the Assessment of Auditory Sensorimotor and Timing Abilities (BAASTA). The battery has been used for testing rhythmic skills in healthy adults and patient populations (e.g., with Parkinson disease), showing sensitivity to timing and rhythm deficits. Here we assessed the test-retest reliability of the BAASTA in 20 healthy adults. Participants were tested twice with the BAASTA, implemented on a tablet interface, with a 2-week interval. They completed 4 perceptual tasks, namely, duration discrimination, anisochrony detection with tones and music, and the Beat Alignment Test (BAT). Moreover, they completed motor tasks via finger tapping, including unpaced and paced tapping with tones and music, synchronization-continuation, and adaptive tapping to a sequence with a tempo change. Despite high variability among individuals, the results showed good test-retest reliability in most tasks. A slight but significant improvement from test to retest was found in tapping with music, which may reflect a learning effect. In general, the BAASTA was found a reliable tool for evaluating timing and rhythm skills. PMID- 29709599 TI - Autophagy in C. elegans development. AB - Autophagy involves the sequestration of cytoplasmic contents in a double-membrane structure referred to as the autophagosome and the degradation of its contents upon delivery to lysosomes. Autophagy activity has a role in multiple biological processes during the development of the nematode Caenorhabditis elegans. Basal levels of autophagy are required to remove aggregate prone proteins, paternal mitochondria, and spermatid-specific membranous organelles. During larval development, autophagy is required for the remodeling that occurs during dauer development, and autophagy can selectively degrade components of the miRNA induced silencing complex, and modulate miRNA-mediated silencing. Basal levels of autophagy are important in synapse formation and in the germ line, to promote the proliferation of proliferating stem cells. Autophagy activity is also required for the efficient removal of apoptotic cell corpses by promoting phagosome maturation. Finally, autophagy is also involved in lipid homeostasis and in the aging process. In this review, we first describe the molecular complexes involved in the process of autophagy, its regulation, and mechanisms for cargo recognition. In the second section, we discuss the developmental contexts where autophagy has been shown to be important. Studies in C. elegans provide valuable insights into the physiological relevance of this process during metazoan development. PMID- 29709608 TI - Predictive coding of the statistical parameters of uncertain rewards by orbitofrontal neurons. AB - Uncertain reward outcomes are characterised by statistical parameters that capture the numerical values of the underlying probability distributions of reward values, including the expected value, risk (variance) and probability. Here we show coding of an integrated expected value signal by single orbitofrontal neurons in response to visual cues predicting uncertain rewards. Separate subpopulations of orbitofrontal neurons predominantly code the prediction of one statistical parameter with few neurons showing combined coding. These signals are likely combined with subjective value signals to inform learning and decision making under conditions of uncertainty. PMID- 29709609 TI - Physiological identification of cortico-striatal projection neurons for song control in Bengalese finches. AB - The avian song system is a group of brain areas specialized for vocal learning and production of song. A major cortical control area, HVC, projects both to a motor output circuit and to a striatal area in the anterior forebrain pathway. These projections are made by two groups of neurons, with mainly distinct roles in either programming vocal production or regulating vocal plasticity. In order to distinguish these two types of projection neurons in singing birds, we recorded unit activity in HVC of anesthetized birds, while stimulating in the anterior forebrain nucleus Area X. HVC units identified in this way had a distinct spike waveform, with a much longer duration positive peak than an initial negative one. We further found that units with a very similar spike waveform were phasically active during singing, firing at specific points of a limited number of song syllables. These units were also less active when birds only heard their own song, during the same syllables. While similar results from anesthetized and awake recordings have been reported in previous studies, the combination of both types of experiments here may be useful as a basis for identifying HVC neurons projecting to Area X based on their spike waveforms, and aid further study of their role in song learning and control. PMID- 29709610 TI - Effects of HIV-1 TAT protein and methamphetamine exposure on visual discrimination and executive function in mice. AB - Mild neurocognitive impairments are common in people with human immunodeficiency virus (HIV) infection. HIV-encoded proteins, such as trans-activator of transcription (TAT), contribute to neuropathology and cognitive function in medicated subjects. The combination of TAT and comorbid methamphetamine use may further impair neurocognitive function in HIV-positive individuals by affecting dopaminergic systems in the brain. The current study examined the effects of TAT protein expression and methamphetamine exposure on cognitive function and dopamine systems in mice. Transgenic mice with inducible brain expression of the TAT protein were exposed to a binge methamphetamine regimen. TAT expression was induced via a doxycycline-containing diet during the final stage of the regimen and maintained throughout cognitive testing. Learning and executive function were assessed using an operant visual discrimination protocol, with a strategy switch and reversal. TAT expression and methamphetamine exposure improved visual discrimination learning. Combined TAT expression and methamphetamine exposure increased perseverative errors during reversal learning. TAT expression altered reversal learning by improving early stage, but impairing late stage, learning. TAT expression was also associated with an increase in dopamine transporter expression in the caudate putamen. These results highlight that TAT expression and methamphetamine exposure likely affect a range of selective cognitive processes, with some potentially improving function under certain conditions. PMID- 29709611 TI - The effects of acute foot shock stress on empathy levels in rats. AB - Empathy defined as the ability to understand and the share the feelings, thoughts, and attitudes of another, is an important skill in survival and reproduction. Among many factors that affect empathy include psychological stress, anxiety states. The aim of this study was to investigate the impact of acute psychological stress on empathic behavior and its association with oxytocin and vasopressin levels in amygdala and prefrontal cortex. Rats were subjected to 0.2 mA (low) and 1.6 mA (high) intensity of foot shock stress for duration of 20 min. Empathic behavior was found to be improved as a response to low intensity stress, but not to high intensity stress. As a response to lower intensity stress, vasopressin was increased in prefrontal cortex and amygdala; oxytocin was increased in only prefrontal cortex, and corticosterone levels increased in general. Anxiety indicators did not change in low intensity stress group yet; high intensity stress group demonstrated a lesser degree of anxiety response. High intensity stress group stayed unexpectedly more active in middle area of elevated plus maze test equipment, which may support impaired executive decision making abilities in the setting of high anxiety states. Further research is needed to investigate gender effects, the role of dopaminergic system and other stress related pathways in acute stress. PMID- 29709612 TI - Toxicological assessment of silica-coated iron oxide nanoparticles in human astrocytes. AB - Iron oxide nanoparticles (ION) have great potential for an increasing number of medical and biological applications, particularly those focused on nervous system. Although ION seem to be biocompatible and present low toxicity, it is imperative to unveil the potential risk for the nervous system associated to their exposure, especially because current data on ION effects on human nervous cells are scarce. Thus, in the present study potential toxicity associated with silica-coated ION (S-ION) exposure was evaluated on human A172 glioblastoma cells. To this aim, a complete toxicological screening testing several exposure times (3 and 24 h), nanoparticle concentrations (5-100 MUg/ml), and culture media (complete and serum-free) was performed to firstly assess S-ION effects at different levels, including cytotoxicity - lactate dehydrogenase assay, analysis of cell cycle and cell death production - and genotoxicity - H2AX phosphorylation assessment, comet assay, micronucleus test and DNA repair competence assay. Results obtained showed that S-ION exhibit certain cytotoxicity, especially in serum-free medium, related to cell cycle disruption and cell death induction. However, scarce genotoxic effects and no alteration of the DNA repair process were observed. Results obtained in this work contribute to increase the knowledge on the impact of ION on the human nervous system cells. PMID- 29709614 TI - Investigation of phase transitions of saturated phosphocholine lipid bilayers via molecular dynamics simulations. AB - Lipid bilayers play an important role in biological systems as they protect cells against unwanted chemicals and provide a barrier for material inside a cell from leaking out. In this paper, nearly 30 MUs of molecular dynamics (MD) simulations were performed to investigate phase transitions of 1,2-dimyristoyl-sn-glycero-3 phosphocholine (DMPC) and 1,2-dipalmitoyl-sn-glycero-phosphocholine (DPPC) lipid bilayers from the liquid crystalline (Lalpha) to the ripple (Pbeta) and to the gel phase (Lbeta). Our MD simulations accurately predict the main transition temperature for the single-component bilayers. A key focus of this work is to quantify the structure of the Pbeta phase for DMPC and compare with measures from x-ray experiments. The Pbeta major arm has similar structure to that of the Lbeta, while the thinner minor arm has interdigitated chains and the transition region between these two regions has large chain splay and disorder. At lower temperatures, our MD simulations predict the formation of the Lbeta phase with tilted fatty acid chains. The Pbeta and Lbeta phases are studied for mixtures of DMPC and DPPC and compare favorably with experiment. Overall, our MD simulations provide evidence for the relevancy of the CHARMM36 lipid force field for structures and add to our understanding of the less-defined Pbeta phase. PMID- 29709615 TI - Common proteomic profiles of induced pluripotent stem cell-derived three dimensional neurons and brain tissue from Alzheimer patients. AB - : We established a unique platform for proteomic analysis of cultured three dimensional (3D) neurons and brain tissue from Alzheimer's disease (AD) patients. We collected peripheral blood mononuclear cells (PBMC), converted PBMC to induced pluripotent stem cell (iPSC) lines, and differentiated the iPSC into human 3D neuro-spheroids. The postmortem brain tissue from the superior frontal cortex, inferior frontal cortex and cerebellum area of the AD patients was compared to the same regions from the control subjects. Proteomic analysis of 3D neuro spheroids derived from AD subjects revealed the alteration of a number of proteins involved in axon growth, mitochondrial function, and antioxidant defense. Similar analysis of post-mortem AD brain tissue revealed significant alteration in proteins involved in oxidative stress, neuro-inflammation, along with proteins related to axonal injury. These results clearly indicate that the dysfunction of 3D neurons from AD patients in our in vitro environment is comparable to the post-mortem AD brain tissue in vivo. In conclusion, our study revealed a number of candidate proteins that have important implications in AD pathogenesis and supports the notion that the iPSC-derived 3D neuronal system functions as a model to examine novel aspects of AD pathology. SIGNIFICANCE: In this study, we present a unique platform for proteomic analysis of induced pluripotent stem cell-derived three dimensional (3D) neurons and compare the results to those from three regions of post-mortem brain tissue from Alzheimer's disease patients and normal control subjects. Our results show that the dysfunction of 3D neurons from AD patients in our in vitro environment is comparable to the post-mortem AD brain tissue in vivo. Our results revealed several candidate proteins that have important implications in AD pathogenesis. PMID- 29709616 TI - Cellular delivery of doxorubicin mediated by disulfide reduction of a peptide dendrimer bioconjugate. AB - In this study, we developed a peptide-dendrimer-drug conjugate system for the pH triggered direct cytosolic delivery of the cancer chemotherapeutic doxorubicin (DOX) using the pH Low Insertion Peptide (pHLIP). We synthesized a pHLIP dendrimer-DOX conjugate in which a single copy of pHLIP displayed a generation three dendrimer bearing multiple copies of DOX via disulfide linkages. Biophysical analysis showed that both the dendrimer and a single DOX conjugate inserted into membrane bilayers in a pH-dependent manner. Time-resolved confocal microscopy indicate the single DOX conjugate may undergo a faster rate of membrane translocation, due to greater nuclear localization of DOX at 24 h and 48 h post delivery. At 72 h, however, the levels of DOX nuclear accumulation for both constructs were identical. Cytotoxicity assays revealed that both constructs mediated ~80% inhibition of cellular proliferation at 10 uM, the dendrimer complex exhibited a 17% greater cytotoxic effect at lower concentrations and greater than three-fold improvement in IC50 over free DOX. Our findings show proof of concept that the dendrimeric display of DOX on the pHLIP carrier (1) facilitates the pH-dependent and temporally-controlled release of DOX to the cytosol, (2) eliminates the endosomal sequestration of the drug cargo, and (3) augments DOX cytotoxicity relative to the free drug. PMID- 29709617 TI - Exploring gelatin nanoparticles as novel nanocarriers for Timolol Maleate: Augmented in-vivo efficacy and safe histological profile. AB - The use of gelatin has been gaining recognition in ocular delivery for its safety profile and biocompatible properties. Timolol Maleate (TM) is an anti-glaucoma drug possessing poor corneal penetration while causing eye irritation making it an ideal candidate for novel nanoparticulate systems. Timolol Maleate loaded Gelatin Nanoparticles (GNPs) were prepared using the double desolvation method utilizing glutaraldehyde as the crosslinking agent. Optimization of the nanoparticles was achieved through a full-factorial design. An optimum formulation possessing particle size of 205 nm, zetapotential of 12.5 mV and an entrapment efficiency of 74.72% was selected. TEM imaging of the optimized nanoparticles was performed and the stability was tracked over 6 months. The in vitro release studies showed a burst effect followed by a sustained profile. The selected formulae were tested in-vivo and compared to a Timolol marketed product on albino rabbits and were proven superior regarding intraocular pressure lowering and sustained efficacy. The prepared nanoparticles successfully passed Draize irritancy test and showed normal histology. These data indicate that the prepared GNPs possessed all needed qualities of a successful ocular system; corneal affinity, suitable particle size, high entrapment efficiency, sustained release, good stability, efficient lowering of intraocular pressure, high drug bioavailability and lack of irritancy. PMID- 29709613 TI - Impact of membrane curvature on amyloid aggregation. AB - The misfolding, amyloid aggregation, and fibril formation of intrinsically disordered proteins/peptides (or amyloid proteins) have been shown to cause a number of disorders. The underlying mechanisms of amyloid fibrillation and structural properties of amyloidogenic precursors, intermediates, and amyloid fibrils have been elucidated in detail; however, in-depth examinations on physiologically relevant contributing factors that induce amyloidogenesis and lead to cell death remain challenging. A large number of studies have attempted to characterize the roles of biomembranes on protein aggregation and membrane mediated cell death by designing various membrane components, such as gangliosides, cholesterol, and other lipid compositions, and by using various membrane mimetics, including liposomes, bicelles, and different types of lipid nanodiscs. We herein review the dynamic effects of membrane curvature on amyloid generation and the inhibition of amyloidogenic proteins and peptides, and also discuss how amyloid formation affects membrane curvature and integrity, which are key for understanding relationships with cell death. Small unilamellar vesicles with high curvature and large unilamellar vesicles with low curvature have been demonstrated to exhibit different capabilities to induce the nucleation, amyloid formation, and inhibition of amyloid-beta peptides and alpha-synuclein. Polymorphic amyloidogenesis in small unilamellar vesicles was revealed and may be viewed as one of the generic properties of interprotein interaction-dominated amyloid formation. Several mechanical models and phase diagrams are comprehensively shown to better explain experimental findings. The negative membrane curvature-mediated mechanisms responsible for the toxicity of pancreatic beta cells by the amyloid aggregation of human islet amyloid polypeptide (IAPP) and binding of the precursors of the semen-derived enhancer of viral infection (SEVI) are also described. The curvature-dependent binding modes of several types of islet amyloid polypeptides with high-resolution NMR structures are also discussed. PMID- 29709619 TI - Hematopoietic insults damage bone marrow niche by activating p53 in vascular endothelial cells. AB - Hematopoietic stem cells (HSCs) are exposed to various insults such as genotoxic stress, inflammation, and infection, which have a direct effect. These insults deplete, cause a functional decline in, and promote HSC aging and transformation. However, the impact of hematopoietic insults on niche cells remains largely unknown. We have reported previously that p53 is activated in blood vessels by various stresses, including hypoxia, inflammation, and aging, and contributes to tissue dysfunction and metabolic abnormalities. We hypothesized that hematopoietic insults also affect the bone marrow (BM) vascular niche. Here, we demonstrate that p53 becomes activated in BM endothelial cells upon hematopoietic stresses such as irradiation and chemotherapeutic treatments. The conditional activation of p53 in VE-cadherin+ vascular niche cells by deleting Mdm2 induces the expression of p53 target genes specifically in vascular endothelial cells, resulting in the dilation and collapse of vascular endothelial cells and reductions in perivascular mesenchymal stromal cell numbers. Consequently, hematopoietic stem cells (HSCs) fail to maintain dormancy, mobilize to the periphery, and are depleted significantly. Our results indicate that various hematopoietic insults affect HSCs, not only directly, but also indirectly by altering vascular integrity, which is critical for perivascular niche formation and maintenance of HSCs. PMID- 29709620 TI - Changes in tibial bone microarchitecture in female recruits in response to 8 weeks of U.S. Army Basic Combat Training. AB - BACKGROUND: U.S. Army Basic Combat Training (BCT) is a physically-demanding program at the start of military service. Whereas animal studies have shown that increased mechanical loading rapidly alters bone structure, there is limited evidence of changes in bone density and structure in humans exposed to a brief period of unaccustomed physical activity. PURPOSE: We aimed to characterize changes in tibial bone density and microarchitecture and serum-based biochemical markers of bone metabolism in female recruits as a result of 8 weeks of BCT. METHODS: We collected high-resolution peripheral quantitative computed tomographic images of the distal tibial metaphysis and diaphysis (4% and 30% of tibia length from the distal growth plate, respectively) and serum markers of bone metabolism before and after BCT. Linear mixed models were used to estimate the mean difference for each outcome from pre- to post-BCT, while controlling for race/ethnicity, age, and body mass index. RESULTS: 91 female BCT recruits volunteered and completed this observational study (age = 21.5 +/- 3.3 yrs). At the distal tibial metaphysis, cortical thickness, trabecular thickness, trabecular number, bone volume/total volume, and total and trabecular volumetric bone density (vBMD) increased significantly by 1-2% (all p < 0.05) over the BCT period, whereas trabecular separation, cortical tissue mineral density (TMD), and cortical vBMD decreased significantly by 0.3-1.0% (all p < 0.05). At the tibial diaphysis, cortical vBMD and cortical TMD decreased significantly (both -0.7%, p < 0.001). Bone strength, estimated by micro finite element analysis, increased by 2.5% and 0.7% at the distal tibial metaphysis and diaphysis, respectively (both p < 0.05). Among the biochemical markers of bone metabolism, sclerostin decreased ( 5.7%), whereas bone alkaline phosphatase, C-telopeptide cross-links of type 1 collagen, tartrate-resistance acid phosphatase, and 25(OH)D increased by 10-28% (all p < 0.05). CONCLUSION: BCT leads to improvements in trabecular bone microarchitecture and increases in serum bone formation markers indicative of new bone formation, as well as increases in serum bone resorption markers and decreases in cortical vBMD consistent with intracortical remodeling. Together, these results demonstrate specific changes in trabecular and cortical bone density and microarchitecture following 8 weeks of unaccustomed physical activity in women. PMID- 29709621 TI - Workforce Trends and Analysis of Selected Pediatric Subspecialties in the United States. AB - OBJECTIVE: To update pediatric subspecialty workforce data to support evidence based legislation and public policy decisions by replicating the American Academy of Pediatrics' 1998 Future of Pediatric Education (FOPE II) workforce survey. METHODS: A descriptive and comparative analysis of survey responses from 9950 US pediatric subspecialists who completed an electronic survey. RESULTS: Pediatric subspecialists are working fewer hours and spending less of their time in direct patient care than they did in 1998 but the mean hours worked differs significantly according to subspecialty. Most subspecialists continue to be board certified, white, non-Hispanic men, although the percentage who are women and from minority groups has increased. The proportion of subspecialists practicing in an academic medical center has increased since 1998. Thirty percent of pediatric subspecialists reported appointment wait times of >2 weeks and pediatric subspecialists in developmental pediatrics, endocrinology, and neurology identified much longer wait times than other subspecialists. CONCLUSION: The demographic and practice characteristics of pediatric subspecialists have changed since the FOPE II survey and access to subspecialty care in a family's community remains a challenge. However, pediatric subspecialties are not monolithic and solutions to workforce shortages will need to take into account these differences to improve access to subspecialty care. PMID- 29709618 TI - An action video game for the treatment of amblyopia in children: A feasibility study. AB - The gold-standard treatment for childhood amblyopia remains patching or penalizing the fellow eye, resulting in an average of about a one line (0.1 logMAR) improvement in visual acuity following ~120 h of patching in children 3-8 years old. However, compliance with patching and other treatment options is often poor. In contrast, fast-paced action video games can be highly engaging, and have been shown to yield broad-based improvements in vision and attention in adult amblyopia. Here, we pilot-tested a custom-made action video game to treat children with amblyopia. Twenty-one (n = 21) children (mean age 9.95 +/- 3.14 [se]) with unilateral amblyopia (n = 12 anisometropic and n = 9 strabismic) completed 20 h of game play either monocularly, with the fellow eye patched (n = 11), or dichoptically, with reduced contrast to the fellow eye (n = 10). Participants were assessed for visual acuity (VA), stereo acuity and reading speed at baseline, and following 10 and 20 h of play. Additional exploratory analyses examined improvements after 6-10 weeks of completion of training (follow up). Following 20 h of training, VA improved, on average, by 0.14 logMAR (~38%) for the dichoptic group and by 0.06 logMAR (~15%) for the monocular group. Similarly, stereoacuity improved by 0.07 log arcsec (~17%) following dichoptic training, and by 0.06 log arcsec (~15%) following monocular training. Across both treatment groups, 7 of the 12 individuals with anisometropic amblyopia showed improvement in stereoacuity, whereas only 1 of the 9 strabismic individuals improved. Most improvements were largely retained at follow-up. Our feasibility study therefore suggests that the action video game approach may be used as an effective adjunct treatment for amblyopia in children, achieving results similar to those of the gold-standard treatment in shorter duration. PMID- 29709622 TI - Adverse Childhood Experiences and Young Adult Health Outcomes Among Youth Aging Out of Foster Care. AB - OBJECTIVE: Former youth in foster care (YFC) are at greater risk of chronic health conditions than their peers. Although research in general population samples has shown a dose-response relationship between adverse childhood experiences (ACEs) and adult health outcomes, few studies have conducted similar analyses in highly stress-exposed populations such as YFC. In this study we used person-centered latent class analysis methods to examine the relationship between different profiles of ACE exposures and divergent health trajectories among this high-risk population. METHODS: Data are from longitudinal research that followed transition-age YFC from age 17 to 26 (N = 732). Using 3 subgroups previously identified by their ACEs histories-complex, environmental, and lower adversity groups-we applied group mean statistics to test for differences between the groups for physical and sexual health outcomes in young adulthood. RESULTS: In contrast to previous research that showed that the environmental group was at the highest risk of criminalbehavior outcomes, for most of the physical and sexual health risk outcomes evaluated in this study, the complex adversity group had the highest risk. CONCLUSIONS: This study shows that there are subgroups of YFC, which each have a distinct profile of risk in young adulthood, with the complex group being at highest risk of the physical and sexual health risk outcomes evaluated. Findings strongly suggest the need for targeted strategies to promote screening for ACEs and chronic health conditions, linkage to adult health care, and continuity of care for adolescents and young adults in foster care to offset these trajectories. PMID- 29709623 TI - Kisspeptin modulates pain sensitivity of CFLP mice. AB - Kisspeptin, a hypothalamic neuropeptide, is a member of the RF-amide family, which have been known to modify pain sensitivity in rodents. The aim of the present study was to investigate the effect of kisspeptin-13 (KP-13), an endogenous derivative of kisspeptin, on nociception in adult male and female CFLP mice and the possible interaction of KP-13 with morphine on nociception. Mice were injected with different doses of KP-13, 30, 60 and 120 min after of which the nociceptive sensitivity were assessed via the tail-flick test. To investigate the receptor involved in the mediation a kisspeptin receptor antagonist (KP-234) pretreatment was applied before KP-13 administration. Furthermore, we investigated the effect of KP-13 on the acute antinociceptive effect of morphine, on acute morphine tolerance and on naloxone-precipitated withdrawal. Last, the Von Frey test was used in order to assess KP-13's effect on mechanical nociception. Our results showed that KP-13 decreased the nociceptive threshold of both males and females independent of sex, which was prevented by KP-234. Furthermore, KP-13 treatment depressed the acute antinociceptive effect of morphine and attenuated the development of morphine tolerance. KP-13 also induced a mechanical hypersensitivity. These data underlie kisspeptin's hyperalgesic action and argues for the role of kisspeptin receptor 1 in the mediation of its action. Furthermore, our results suggest that central KP-13 administration can modify the acute effects of morphine. PMID- 29709624 TI - The antimicrobial and anti-endotoxic peptide AmyI-1-18 from rice alpha-amylase and its [N3L] analog promote angiogenesis and cell migration. AB - In our previous studies, we showed that AmyI-1-18 and its single amino acid substituted analogs have antimicrobial, anti-inflammatory, and anti-endotoxic activities and cause little or no hemolysis or cytotoxicity. In this study, we investigated the potential of these peptides to promote proliferation, angiogenesis (tube formation), and migration in human umbilical vein endothelial cells (HUVECs). Among five single amino acid-substituted analogs, [N3L]AmyI-1-18 induced cell proliferation in a concentration-dependent manner with similar efficacy to AmyI-1-18. In tube formation assays, AmyI-1-18 and [N3L]AmyI-1-18 had angiogenic activities at 1 MUM and their effects were similar to those of LL-37. Moreover, scratch migration assays showed that AmyI-1-18, [N3L]AmyI-1-18, and LL 37 promote cell migration with optimum concentrations of 10, 1, and 0.1 MUM, respectively. Subsequently, we performed tube formation assays using HUVECs pretreated with SU5416, which is an inhibitor of vascular endothelial growth factor (VEGF) receptors, and revealed that AmyI-1-18 and [N3L]AmyI-1-18 induce angiogenesis by activating VEGF receptors. Similarly, after pretreating HUVECs with mitomycin C, which inhibits cell proliferation, [N3L]AmyI-1-18 significantly contributed to wound closure in scratch migration assays. Moreover, enhancements of hydrophobicity following substitution of AmyI-1-18 asparagine with leucine led to greater increases in cell migration. The present data indicate that both peptides, particularly [N3L]AmyI-1-18, are candidates for use as wound healing agents. PMID- 29709625 TI - Dynamic functional connectivity markers of objective trait mindfulness. AB - While mindfulness is commonly viewed as a skill to be cultivated through practice, untrained individuals can also vary widely in dispositional mindfulness. Prior research has identified static neural connectivity correlates of this trait. Here, we use dynamic functional connectivity (DFC) analysis of resting-state fMRI to study time-varying connectivity patterns associated with naturally varying and objectively measured trait mindfulness. Participants were selected from the top and bottom tertiles of performers on a breath-counting task to form high trait mindfulness (HTM; N = 21) and low trait mindfulness (LTM; N = 18) groups. DFC analysis of resting state fMRI data revealed that the HTM group spent significantly more time in a brain state associated with task-readiness - a state characterized by high within-network connectivity and greater anti correlations between task-positive networks and the default-mode network (DMN). The HTM group transitioned between brain states more frequently, but the dwell time in each episode of the task-ready state was equivalent between groups. These results persisted even after controlling for vigilance. Across individuals, certain connectivity metrics were weakly correlated with self-reported mindfulness as measured by the Five Facet Mindfulness Questionnaire, though these did not survive multiple comparisons correction. In the static connectivity maps, HTM individuals had greater within-network connectivity in the DMN and the salience network, and greater anti-correlations between the DMN and task-positive networks. In sum, DFC features robustly distinguish HTM and LTM individuals, and may be useful biological markers for the measurement of dispositional mindfulness. PMID- 29709626 TI - Cortical depth dependent population receptive field attraction by spatial attention in human V1. AB - Visual spatial attention concentrates neural resources at the attended location. Recently, we demonstrated that voluntary spatial attention attracts population receptive fields (pRFs) toward its location throughout the visual hierarchy. Theoretically, both a feed forward or feedback mechanism could underlie pRF attraction in a given cortical area. Here, we use sub-millimeter ultra-high field functional MRI to measure pRF attraction across cortical depth and assess the contribution of feed forward and feedback signals to pRF attraction. In line with previous findings, we find consistent attraction of pRFs with voluntary spatial attention in V1. When assessed as a function of cortical depth, we find pRF attraction in every cortical portion (deep, center and superficial), although the attraction is strongest in deep cortical portions (near the gray-white matter boundary). Following the organization of feed forward and feedback processing across V1, we speculate that a mixture of feed forward and feedback processing underlies pRF attraction in V1. Specifically, we propose that feedback processing contributes to the pRF attraction in deep cortical portions. PMID- 29709627 TI - Multi-task prediction of infant cognitive scores from longitudinal incomplete neuroimaging data. AB - Early postnatal brain undergoes a stunning period of development. Over the past few years, research on dynamic infant brain development has received increased attention, exhibiting how important the early stages of a child's life are in terms of brain development. To precisely chart the early brain developmental trajectories, longitudinal studies with data acquired over a long-enough period of infants' early life is essential. However, in practice, missing data from different time point(s) during the data gathering procedure is often inevitable. This leads to incomplete set of longitudinal data, which poses a major challenge for such studies. In this paper, prediction of multiple future cognitive scores with incomplete longitudinal imaging data is modeled into a multi-task machine learning framework. To efficiently learn this model, we account for selection of informative features (i.e., neuroimaging morphometric measurements for different time points), while preserving the structural information and the interrelation between these multiple cognitive scores. Several experiments are conducted on a carefully acquired in-house dataset, and the results affirm that we can predict the cognitive scores measured at the age of four years old, using the imaging data of earlier time points, as early as 24 months of age, with a reasonable performance (i.e., root mean square error of 0.18). PMID- 29709628 TI - Simultaneous resting-state FDG-PET/fMRI in Alzheimer Disease: Relationship between glucose metabolism and intrinsic activity. AB - Simultaneously evaluating resting-state brain glucose metabolism and intrinsic functional activity has potential to impact the clinical neurosciences of Alzheimer Disease (AD). Indeed, integrating such combined information obtained in the same physiological setting may clarify how impairments in neuroenergetic and neuronal function interact and contribute to the mechanisms underlying AD. The present study used this multimodality approach to investigate, by means of a hybrid PET/MR scanner, the coupling between glucose consumption and intrinsic functional activity in 23 patients with AD-related cognitive impairment ranging from amnestic mild cognitive impairment (MCI) to mild-moderate AD (aMCI/AD), in comparison with a group of 23 healthy elderly controls. Between-group (Controls > Patients) comparisons were conducted on data from both imaging modalities using voxelwise 2-sample t-tests, corrected for partial-volume effects, head motion, age, gender and multiple tests. FDG-PET/fMRI relationships were assessed within and across subjects using Spearman partial correlations for three different resting-state fMRI (rs-fMRI) metrics sensitive to AD: fractional amplitude of low frequency fluctuations (fALFF), regional homogeneity (ReHo) and group independent component analysis with dual regression (gICA-DR). FDG and rs-fMRI metrics distinguished aMCI/AD from controls according to spatial patterns analogous to those found in stand-alone studies. Within-subject correlations were comparable across the three rs-fMRI metrics. Correlations were overall high in healthy controls (rho = 0.80 +/- 0.04), but showed a significant 17% reduction (p < 0.05) in aMCI/AD patients (rho = 0.67 +/- 0.05). Positive across-subject correlations were overall moderate (rho = 0.33 +/- 0.07) and consistent across rs-fMRI metrics. These were confined around AD-target posterior regions for metrics of functional connectivity (ReHo and gICA-DR). In contrast, FDG/fALFF correlations were distributed in the frontal gyrus, thalami and caudate nuclei. Taken together, these results support the presence of bioenergetic coupling between glucose utilization and rapid transmission of neural information in healthy ageing, which is substantially reduced in aMCI/AD, suggesting that abnormal glucose utilization is in some way linked to communication breakdown among brain regions impacted by the underlying pathological process. PMID- 29709629 TI - Occurrence of Campylobacter in retail meat in Lahore, Pakistan. AB - Campylobacter, one of the emerging zoonotic pathogens, is worldwide in distribution. This thermo-tolerant pathogen is one of the leading causes of diarrhea and gastroenteritis in humans. The main sources of infection are contaminated meat and meat products. A cross-sectional study was conducted to estimate the prevalence of Campylobacter species in retail meat in the Lahore district of Pakistan from September 2014 to January 2015. A total of 600 samples (200 samples each of beef, mutton, and chicken) were collected from retail shops through convenience sampling and preceded for Campylobacter contamination using the ISO 10272-1:2006 (E) method. Campylobacter was present in all three types of meat; the highest prevalence being recorded in chicken meat (29%) followed by mutton (18%) and beef (15.5%). Campylobacters were isolated from 125 (20.8%) samples out of the 600 meat samples. Campylobacter jejuni was more common (74.4%) than C. coli (25.6%). The highest number of Campylobacters were isolated in September (25/125) and November (23/125) while low numbers were isolated in October and December with isolates rate of (17/125) and (19/125), respectively. The highest prevalence was seen in the oldest and overpopulated town of Data Gunj Bakhsh 16% (20/125) while lowest prevalence was seen in a newer and least populated town of Gulburg (7/125). These results indicate that Campylobacter species are circulating in various meat sources in Lahore and that it may pose a threat to public health. PMID- 29709630 TI - Space-time clusters and co-occurrence of chikungunya and dengue fever in Colombia from 2015 to 2016. AB - Vector-borne diseases (VBDs) infect over one billion people and are responsible for over one million deaths each year, globally. Chikungunya (CHIK) and Dengue Fever (DENF) are emerging VBDs due to overpopulation, increases in urbanization, climate change, and other factors. Colombia has recently experienced severe outbreaks of CHIK AND DENF. Both viruses are transmitted by the Aedes mosquitoes and are preventable with a variety of surveillance and vector control measures (e.g. insecticides, reduction of open containers, etc.). Spatiotemporal statistics can facilitate the surveillance of VBD outbreaks by informing public health officials where to allocate resources to mitigate future outbreaks. We utilize the univariate Kulldorff space-time scan statistic (STSS) to identify and compare statistically significant space-time clusters of CHIK and DENF in Colombia during the outbreaks of 2015 and 2016. We also utilize the multivariate STSS to examine co-occurrences (simultaneous excess incidences) of DENF and CHIK, which is critical to identify regions that may have experienced the greatest burden of VBDs. The relative risk of CHIK and DENF for each Colombian municipality belonging to a univariate and multivariate cluster is reported to facilitate targeted interventions. Finally, we visualize the results in a three dimensional environment to examine the size and duration of the clusters. Our approach is the first of its kind to examine multiple VBDs in Colombia simultaneously, while the 3D visualizations are a novel way of illustrating the dynamics of space-time clusters of disease. PMID- 29709631 TI - Independent and interactive effect of plant- and mammalian- based odors on the response of the malaria vector, Anopheles gambiae. AB - Several studies have shown that odors of plant and animal origin can be developed into lures for use in surveillance of mosquito vectors of infectious diseases. However, the effect of combining plant- and mammalian-derived odors into an improved lure for monitoring both nectar- and blood-seeking mosquito populations in traps is yet to be explored. Here we used both laboratory dual choice olfactometer and field assays to investigate responses of the malaria vector, Anopheles gambiae, to plant- and mammalian-derived compounds and a combined blend derived from these two odor sources. Using subtractive bioassays in dual choice olfactometer we show that a 3-component terpenoid plant-derived blend comprising (E)-linalool oxide, beta-pinene, beta-ocimene was more attractive to females of An. gambiae than (E)-linalool oxide only (previously found attractive in field trials) and addition of limonene to this blend antagonized its attractiveness. Likewise, a mammalian-derived lure comprising the aldehydes heptanal, octanal, nonanal and decanal, was more preferred than (E)-linalool oxide. Surprisingly, combining the plant-derived 3-component blend with the mammalian derived 4 component blend attracted fewer females of An. gambiae than the individual blends in laboratory assays. However, this pattern was not replicated in field trials, where we observed a dose-dependent effect on trap catches while combining both blends with significantly improved trap catches at higher doses. The observed dose-dependent attractiveness for An. gambiae has practical implication in the design of vector control strategies involving kairomones from plant- and mammalian-based sources. PMID- 29709632 TI - Characterization of Simulium (Simulium) hackeri Edwards (Diptera: Simuliidae) from Malaysia: Morphological description of the pupa and larva, and DNA barcoding. AB - Simulium (Simulium) hackeri Edwards, 1928 of the Simulium variegatum species group from Malaysia was described initially based on the female specimen from Cameron Highlands, Pahang. In the present study, the pupa and larva of this species are described for the first time. Their morphological characters resemble those of the Simulium variegatum species-group by having six gill filaments per side, abdomen with dorsal spine-combs at least on segments 7 and 8, cocoon with wall-pocket shaped and with or without an anterodorsal projection. Postgenal cleft of the larva medium-sized, rarely small, ventral papillae small or absent. The DNA barcode of this species is also reported herein. PMID- 29709633 TI - Human-specific features of the G-quadruplex in the androgen receptor gene promoter: A comparative structural and dynamics study. AB - The androgen receptor (AR) promoter contains guanine-rich regions that are able to fold into polymorphic G-quadruplex (GQ) structures, and whose deletion decreases AR gene transcription. Our attention was focused on this region because of the frequent termination of sequencing reactions during promoter methylation studies. UV and circular dichroism (CD) spectroscopy of synthetic oligonucleotides encompassing these guanine-rich regions suggested a parallel quadruplex topology with three guanine quartets and three side loops in the three cases. Melting curves revealed a lower thermostability of the human GQ compared to the rat/mouse QG structures, which is attributed to the presence of a longer central loop in the former. One molecular model is proposed for the highly similar sequences in the rat/mouse. Due to the polymorphism resulting from possible arrangements of the guanine tracts, two models were derived for the human GQ. Molecular dynamics (MD) simulations determined that both models for the human GQ had higher flexibility and lower stability than the rodent GQ models. These properties result from the presence of a longer central loop in the human GQ models, which contains 11 and 13 nucleotides, in comparison to the 2 nucleotide long loop in the rat/mouse GQ. Overall, the unveiled structural and dynamics features provide sufficient detail for the intelligent design of drugs targeting the human AR promoter. PMID- 29709634 TI - Delineating the regulation of estrogen and androgen receptor expression by sex steroids during rat spermatogenesis. AB - Estrogen receptors (ERalpha and beta) and androgen receptor (AR) regulate various critical processes during spermatogenesis. Since spermatogenesis is very sensitive to hormonal stimuli and perturbations, it is important to understand the regulation of expression of these receptors by sex steroid hormones. Although many studies have reported deregulation of steroid receptors on endocrine disruption, there is no consensus on the regulation of their expression by steroid hormones during spermatogenesis, and a lack of clear understanding of the mechanism of regulation. Here, we evaluated the receptor expressions in a well established exogenous estradiol administration model. We then investigated the mechanisms by which the individual receptors regulate their expression by binding to the respective hormone response elements upstream of these receptor genes. By further employing in vitro and in vivo models of ER and AR stimulation or antagonism, we delineated their regulation in a receptor subtype-specific manner. Our results indicate that ERalpha positively regulates expression of both the ERs; whereas, ERbeta and AR negatively regulate expression of both ERbeta and AR by direct binding to upstream regulatory regions. The perturbations in the levels of steroid receptors could be an important factor contributing to spermatogenic defects and male sub-fertility after estradiol and ER agonist treatment. Our study delineates the direct contribution of the individual steroid receptors in the regulation of their own expression. PMID- 29709635 TI - Identification of genomic ATP binding cassette (ABC) transporter genes and Cd responsive ABCs in Brassica napus. AB - The plant ATP binding cassette (ABC) transporters are one of the integral membrane proteins responsible for uptake and allocation of a wide range of metabolites and xenobiotics including heavy metals (e.g. zinc, manganese and cadmium). They play multiple roles in plant growth, development and environmental stress responses. Although the ABC transporters have been identified in model plants such as Arabidopsis and rice, they are have not been annotated and identified in rapeseed (Brassica napus) and also, little is known about functionality of these metal transporters. B. napus is an important oil crop ranking the third largest source of vegetable oil worldwide. Importantly, it is long considered as a desirable candidate for phytoremediation owning to its massive dry weight productivity and moderate Cd accumulation. In this study, we identified 314 ABC protein genes from B. napus using bioinformatics and high throughput sequencing. Eight subfamilies including ABCA-G and ABCI have been categorized. The ABCG proteins constitute the largest subfamily with 116 members, and the ABCB and ABCC subfamilies ranks second and third with 69 and 47 members, respectively. Analyses of ABCs in B. napus genome reveal that their evolutional expansion was through localized allele duplications. Most of the ABC genes (74.2%, 233/314) were validated by RNA-sequencing rapeseed seedlings. Among the 233 profiled BnaABCs, 132 genes were differentially expressed (>1.5 fold change, p < 0.05) and 84 genes were significantly induced under Cd stress. Analyses of specific cis-elements in the upstream of eight representative genes show diverse motifs, which potentially respond to environmental stress, hormone responsiveness and other development signals. PMID- 29709636 TI - Genomic structure, expression pattern and polymorphisms of GILT in golden pompano Trachinotus ovatus (Linnaeus 1758). AB - The interferon-g-inducible lysosomal thiol reductase (GILT) plays a significant character in the processing and presentation of MHC class II restricted antigen (Ag) by catalyzing disulfide bond reduction in mammals. To explore the function of GILT in the immune system of fish, we cloned a GILT gene homologue from Trachinotus ovatus, the full-length cDNA of GILT, which consisted of 2, 747 bp with a 771 bp open reading frame, encoding a protein of 256 amino acids. Moreover, similar to other species GILT gene, 7 exons and 6 introns were identified in T. ovatus, the deduced protein also possessed a representative characteristic of known GILT proteins. The result of real-time quantitative PCR showed that GILT mRNA was dramatically expressed in immune-associated tissues, such as spleen (p < 0.01) and kidney (p < 0.05). Bacterial challenge revealed that GILT mRNA level remarkably up-regulation in liver, spleen, kidney and intestine after induction with Photobacterium damsela. Furthermore, based on cloned sequences and genome BLAST, only one SNP site (ToGILT-S1-g.148C>G) was identified, and the allele C was significantly associated with high susceptibility (HS) group, nevertheless, the allele G was dramatically associated with high-resistance (HR) group, indicating potential application for disease resistant breeding selection in T. ovatus. PMID- 29709637 TI - Seasonal changes in the communities of photosynthetic picoeukaryotes in Ofunato Bay as revealed by shotgun metagenomic sequencing. AB - Small photosynthetic eukaryotes play important roles in oceanic food webs in coastal regions. We investigated seasonal changes in the communities of photosynthetic picoeukaryotes (PPEs) of the class Mamiellophyceae, including the genera Bathycoccus, Micromonas and Ostreococcus, in Ofunato Bay, which is located in northeastern Japan and faces the Pacific Ocean. The abundances of PPEs were assessed over a period of one year in 2015 at three sampling stations, KSt. 1 (innermost bay area), KSt. 2 (middle bay area) and KSt. 3 (bay entrance area) at depths of 1 m (KSt. 1, KSt. 2 and KSt. 3), 8 m (KSt. 1) or 10 m (KSt. 2 and KSt. 3) by employing MiSeq shotgun metagenomic sequencing. The total abundances of Bathycoccus, Ostreococcus and Micromonas were in the ranges of 42-49%, 35-49% and 13-17%, respectively. Considering all assayed sampling stations and depths, seasonal changes revealed high abundances of PPEs during the winter and summer and low abundances during late winter to early spring and late summer to early autumn. Bathycoccus was most abundant in the winter, and Ostreococcus showed a high abundance during the summer. Another genus, Micromonas, was relatively low in abundance throughout the study period. Taken together with previously suggested blooming periods of phytoplankton, as revealed by chlorophyll a concentrations in Ofunato Bay during spring and autumn, these results for PPEs suggest that greater phytoplankton blooming has a negative influence on the seasonal occurrences of PPEs in the bay. PMID- 29709638 TI - Molecular cloning of a plasma membrane aquaporin in Stipa purpurea, and exploration of its role in drought stress tolerance. AB - Stipa purpurea is widely distributed on the Tibetan Plateau, and has high drought resistance. Plasma membrane intrinsic proteins are a type of aquaporin. They regulate the movement of water and are associated with plant protective reactions to biotic and abiotic stresses. We characterized a plasma membrane intrinsic protein from S. purpurea (SpPIP1) and elucidated its role in molecular aspects of the plant's response to drought stress. The full-length open reading frame of SpPIP1 was 870 bp and encoded 289 amino acids. The transcript level of SpPIP1 was higher in the root of S. purpurea than in the flower, leaf and stem. The level of SpPIP1 transcript increased significantly when treated with drought treatment. Subcellular localization result showed that SpPIP1 was localized in the plasma membrane. Ectopic expression of SpPIP1 in Arabidopsis thaliana resulted in plants with higher tolerance to drought treatment. SpPIP1 of S. purpurea may mediate plant response to arid environments. PMID- 29709639 TI - DNMT1 mediated promoter methylation of GNAO1 in hepatoma carcinoma cells. AB - Hepatocellular carcinoma (HCC) is one of the most lethal and prevalent cancers worldwide and has recently become the second most common cause of cancer-related deaths in men of developing countries. Guanine nucleotide-binding protein (G protein) has been reported to be associated with the early process of HCC. In our previous study, GNAO1, one of members of G protein, was found to be down regulated in HCC. Thus, the present study aimed to throw light upon the mechanism of the abnormal expression of GNAO1 in HCC. First, qPCR results from two HCC cell lines (SMMC-7721 and QGY-7703) confirmed the down-expression of GNAO1, followed by the validation of the methylation status of the promoter region by bisulfite sequence PCR (BSP). Moreover, 5-Aza-2'-deoxycytidine (DAC) with Trichostatin A (TSA) treatment made it much clear that GNAO1 transcription was inhibited by promoter hypermethylation, contributing to its low expression. It was further revealed that the silencing effect was regulated by methyltransferase 1 (DNMT1), and was further enhanced by transforming growth factor beta (TGF-beta). In addition, the up-regulation of GNAO1 with the help of recombinant plasmid was also found to accelerate cell apoptosis, confirmed by flow cytometry and western blotting analysis. All these results above indicated that the promoter hypermethylation of GNAO1 might play an important role in HCC, suggesting that it might be used as a promising biomarker for HCC diagnosis and targeted therapy. PMID- 29709640 TI - Metagenome-based diversity analyses suggest a strong locality signal for bacterial communities associated with oyster aquaculture farms in Ofunato Bay. AB - Ofunato Bay, in Japan, is the home of buoy-and-rope-type oyster aquaculture activities. Since the oysters filter suspended materials and excrete organic matters into the seawater, bacterial communities residing in its vicinity may show dynamic changes depending on the oyster culture activities. We employed a shotgun metagenomic technique to study bacterial communities near oyster aquaculture facilities at the center of the bay (KSt. 2) and compared the results with those of two other localities far from the station, one to the northeast (innermost bay, KSt. 1) and the other to the southwest (bay entrance, KSt. 3). Seawater samples were collected every month from January to December 2015 from the surface (1 m) and deeper (8 or 10 m) layers of the three locations, and the sequentially filtered fraction on 0.2-MUm membranes was sequenced on an Illumina MiSeq system. The acquired reads were uploaded to MG-RAST for KEGG functional abundance analysis, while taxonomic analyses at the phylum and genus levels were performed using MEGAN after parsing the BLAST output. Discrimination analyses were then performed using the ROC-AUC value of the cross validation, targeting the depth (shallow or deep), locality [(KSt. 1 + KSt. 2) vs. KSt 3; (KSt. 1 + KSt. 3) vs. KSt. 2 or the (KSt. 2 + KSt. 3) vs. KSt. 1] and seasonality (12 months). The matrix discrimination analysis on the adjacent 2 continuous seasons by ROC-AUC, which was based on the datasets that originated from different depths, localities and months, showed the strongest discrimination signal on the taxonomy matrix at the phylum level for the datasets from July to August compared with those from September to June, while the KEGG matrix showed the strongest signal for the datasets from March to June compared with those from July to February. Then, the locality combination was subjected to the same ROC-AUC discrimination analysis, resulting in significant differences between KSt. 2 and KSt. 1 + KSt. 3 on the KEGG matrix. These results suggest that aquaculture activities markedly affect bacterial functions. PMID- 29709642 TI - Secondhand smoke exposure increased the need for inhaled corticosteroids in children with asthma. PMID- 29709641 TI - Transcriptome profiling analysis revealed co-regulation of multiple pathways in jujube during infection by 'Candidatus Phytoplasma ziziphi'. AB - BACKGROUND: Jujube witches' broom (JWB), caused by a phytoplasma, devastates jujube tree (Ziziphus jujuba) growth and production in Asia. Although host responses to phytoplasmas are studied at the phenotypic, physiological, biochemical and molecular levels, it remains unclear how a host plant responds at the molecular level during the primary stage of infection. METHODS: To understand the response of the jujube tree to JWB infection, leaves were sampled at different times during the phytoplasma infection. Transcriptomic analyses at six stages were performed to reveal how phytoplasma infection affects Chinese jujube gene expression through the determination of the key differentially expressed genes (DEGs), and their related pathways. Quantitative real-time PCR was applied to validate 10 differentially expressed genes at different JWB phytoplasma infection stages. RESULTS: A total of 25,067 unigenes were mapped to jujube genome reference sequences. In the first infection stage (0-2 weeks after grafting (WAG), a total of 582 jujube genes were differentially regulated but no visible symptoms appeared. Quite a few DEGs related to abscisic acid (ABA) and cytokinin (CTK) were down-regulated, while some related to jasmonic acid (JA) and salicylic acid (SA) were up-regulated, Genes related to plant-pathogen interaction were also differentially expressed. In the second infection stage (37 39WAG), witches' broom symptoms were visible, and a total of 4373 DEGs were identified. Genes involved in biosynthesis and signal transduction of ABA, brassinosteroid (BR), CTK, ethylene (ET), and auxin (IAA), GA, JA and SA, plant pathogen interaction, flavonoid biosynthesis genes were significantly regulated, suggesting that jujube trees activated defense factors related to SA, JA, ABA and secondary metabolites to defend against phytoplasma infection. By the third infection stage (48-52WAG), serious symptoms occurred and 3386 DEGs were identified. Most DEGs involved in biosynthesis and signal transduction of JA, SA and GA were up-regulated, while those relating to ABA were down-regulated. Genes involved in plant-pathogen interaction were up- or down-regulated, while phenylpropanoid and flavonoid biosynthesis genes were significantly up-regulated. Meanwhile, DEGs involved in photosynthesis, chlorophyll and peroxisome biosynthesis, and carbohydrate metabolism were down-regulated. These results suggested that phytoplasma infection had completely destroyed jujube trees' defense system and had disturbed chlorophyll synthesis and photosynthetic activity in the infected leaves at the late stage, resulting in yellow leaves and other JWB symptoms. DISCUSSION: The results in this report suggested that phytohormone biosynthesis and signal transduction, photosynthesis, and secondary metabolism all played important roles in the battle between colonization and defense in the interaction between Ca. Phytoplasma ziziphi and jujube. PMID- 29709644 TI - Performance monitoring in the medial frontal cortex and related neural networks: From monitoring self actions to understanding others' actions. AB - Action is a key channel for interacting with the outer world. As such, the ability to monitor actions and their consequences - regardless as to whether they are self-generated or other-generated - is of crucial importance for adaptive behavior. The medial frontal cortex (MFC) has long been studied as a critical node for performance monitoring in nonsocial contexts. Accumulating evidence suggests that the MFC is involved in a wide range of functions necessary for one's own performance monitoring, including error detection, and monitoring and resolving response conflicts. Recent studies, however, have also pointed to the importance of the MFC in performance monitoring under social conditions, ranging from monitoring and understanding others' actions to reading others' mental states, such as their beliefs and intentions (i.e., mentalizing). Here we review the functional roles of the MFC and related neural networks in performance monitoring in both nonsocial and social contexts, with an emphasis on the emerging field of a social systems neuroscience approach using macaque monkeys as a model system. Future work should determine the way in which the MFC exerts its monitoring function via interactions with other brain regions, such as the superior temporal sulcus in the mentalizing system and the ventral premotor cortex in the mirror system. PMID- 29709645 TI - Perivascular fibrosis and the microvasculature of the heart. Still hidden secrets of pathophysiology? AB - Perivascular fibrosis, the deposition of connective tissue around the vessels, has been demonstrated crucially involved in the development of cardiac dysfunction. Although cardiac fibrosis has been shown to be reversible under certain experimental conditions, effective anti-fibrotic therapies remain largely elusive. Therefore, perivascular fibrosis currently represents a major therapeutic target for cardiovascular diseases. The main topic of this review will be to address the mechanisms underlying perivascular fibrosis of the vasculature within the myocardium, with a special focus on perivascular fibrosis of small vessels, microvascular dysfunction and disease. PMID- 29709643 TI - Development of a tool predicting severity of allergic reaction during peanut challenge. AB - BACKGROUND: Reliable prognostic markers for predicting severity of allergic reactions during oral food challenges (OFCs) have not been established. OBJECTIVE: To develop a predictive algorithm of a food challenge severity score (CSS) to identify those at higher risk for severe reactions to a standardized peanut OFC. METHODS: Medical history and allergy test results were obtained for 120 peanut allergic participants who underwent double-blind, placebo-controlled food challenges. Reactions were assigned a CSS between 1 and 6 based on cumulative tolerated dose and a severity clinical indicator. Demographic characteristics, clinical features, peanut component IgE values, and a basophil activation marker were considered in a multistep analysis to derive a flexible decision rule to understand risk during peanut of OFC. RESULTS: A total of 18.3% participants had a severe reaction (CSS >4). The decision rule identified the following 3 variables (in order of importance) as predictors of reaction severity: ratio of percentage of CD63hi stimulation with peanut to percentage of CD63hi anti-IgE (CD63 ratio), history of exercise-induced asthma, and ratio of forced expiratory volume in 1 second to forced vital capacity (FEV1/FVC) ratio. The CD63 ratio alone was a strong predictor of CSS (P < .001). CONCLUSION: The CSS is a novel tool that combines dose thresholds and allergic reactions to understand risks associated with peanut OFCs. Laboratory values (CD63 ratio), along with clinical variables (exercise-induced asthma and FEV1/FVC ratio) contribute to the predictive ability of the severity of reaction to peanut OFCs. Further testing of this decision rule is needed in a larger external data source before it can be considered outside research settings. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02103270. PMID- 29709647 TI - The Rainwater Rock-pool Dinoflagellate Nottbeckia ochracea gen. et comb. nov. (syn.: Hemidinium ochraceum) - A Fine-structural and Molecular Study with Emphasis on the Motile Stage. AB - The rarely recorded dinoflagellate Hemidinium ochraceum Levander was isolated from a rainwater rock-pool in Finland and the motile stage studied by light- and electron microscopy and molecular sequencing. The ultrastructure of the motile stage revealed several features not previously observed in other dinoflagellates, e.g. thecal plates with inwards 'knobs' and a peculiar corrugated left sulcal plate. The apparent lack of the R2 and R4 flagellar roots was also unusual. The typical plate tabulation was 4', 2a, 8", cx, 4c,?s, 3''', cy, 1p, 2"", cx and cy being extra plates associated with the cingulum, but intraspecific variations were observed in shape and number of plates. Phylogenetic analyses of nuclear encoded LSU rDNA and concatenation of LSU and SSU rDNA sequences showed that H. ochraceum was only distantly related to Hemidinium nasutum (the type species of Hemidinium). The immotile coccoid stage resembled Gloeodinium montanum and a weakly supported relationship between the two was only inferred in the analyses based on LSU rDNA. Hemidinium ochraceum showed some resemblance to Rufusiella insignis sensu Richards, but the true identity of this species and of genus Rufusiella is uncertain. A new genus, Nottbeckia, is erected to accommodate H. ochraceum, as Nottbeckia ochracea gen. et comb. nov. PMID- 29709646 TI - Cytotoxicity of 18 Cameroonian medicinal plants against drug sensitive and multi factorial drug resistant cancer cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Recommendations have been made stating that ethnopharmacological usages such as immune and skin disorders, inflammatory, infectious, parasitic and viral diseases should be taken into account if selecting plants for anticancer screening, since these reflect disease states bearing relevance to cancer or cancer-like symptoms. Cameroonian medicinal plants investigated in this work are traditionally used to treat cancer or ailments with relevance to cancer or cancer-like symptoms. AIM OF THE STUDY: In this study, 21 methanol extracts from 18 Cameroonian medicinal plants were tested in leukemia CCRF-CEM cells, and the best extracts were further tested on a panel of human cancer cell lines, including various multi-drug-resistant (MDR) phenotypes. Mechanistic studies were performed with the three best extracts. MATERIALS AND METHODS: Resazurin reduction assay was used to evaluate cytotoxicity and ferroptotic effects of methanol extracts from different plants. Flow cytometry was used to analyze cell cycle, apoptosis, mitochondrial membrane potential (MMP), and reactive oxygen species (ROS) of extracts from Curcuma longa rhizomes (CLR), Lycopersicon esculentum leaves (LEL), and Psidium guajava bark (PGB). RESULTS: In a pre-screening of all extracts, 13 out of 21 (61.9%) had IC50 values below 80 ug/mL. Six of these active extracts displayed IC50 values below 30 ug/mL: Cola pachycarpa leaves (CPL), Curcuma longa rhizomes (CLR), Lycopersicon esculentum leaves, Persea americana bark (PAB), Physalis peruviana twigs (PPT) and Psidium guajava bark (PGB). The best extracts displayed IC50 values from 6.25 ug/mL (against HCT116 p53-/-) to 10.29 ug/mL (towards breast adenocarcinoma MDA MB-231-BCRP cells) for CLR, from 9.64 ug/mL (against breast adenocarcinoma MDA-MB 231 cells) to 57.74 ug/mL (against HepG2 cells) for LEL and from 1.29 ug/mL (towards CEM/ADR5000 cells) to 62.64 ug/mL (towards MDA-MB-231 cells) for PGB. CLR and PGB induced apoptosis in CCRF-CEM cells via caspases activation, MMP depletion and increase ROS production whilst LEL induced apoptosis mediated by caspases activation and increase ROS production. CONCLUSION: The best botanicals tested were CLR and LEL, which are worth to be explored in more detail to fight cancers including MDR phenotypes. PMID- 29709648 TI - A public health approach to Canada's opioid crisis. PMID- 29709649 TI - Lysine production from the sugar alcohol mannitol: Design of the cell factory Corynebacterium glutamicum SEA-3 through integrated analysis and engineering of metabolic pathway fluxes. AB - The amino acid lysine is among the world's most important biotechnological products, and enabling its manufacture from the most attractive new materials is an ever-present challenge. In this study, we describe a cell factory of Corynebacterium glutamicum, which produces lysine from mannitol. A preliminary mutant C. glutamicum SEA-1 obtained by the deletion of the mannitol repressor MtlR in the glucose-based, lysine-producing strain C. glutamicum LYS-12 produced only small amounts of lysine. This limitation was due to a significant accumulation of fructose and a limited NADPH supply, which caused a low flux of only 6% into the oxidative pentose phosphate (PP) pathway. Subsequent expression of fructokinase slightly increased production but failed to substantially redirect the flux from the Emden-Meyerhof-Parnas (EMP) pathway to the PP pathway. This suggested the design of C. glutamicum SEA-3, which overexpressed the NADP dependent glyceraldehyde 3-phosphate dehydrogenase GapN from Streptococcus mutans and coupled the EMP pathway flux to NADPH formation. When grown on mannitol, the SEA-3 strain had a lysine yield of 0.24 mol mol-1 and a specific productivity of 1.3 mmol g-1 h-1, approximately 60% and 75% higher, respectively, than those of the basic producer SEA-1. A computational pathway analysis revealed that this design would potentially enable a lysine yield of 0.9 mol mol-1, providing room for further development. Our findings open new avenues for lysine production from marine macroalgae, which is farmed globally as an attractive third-generation renewable resource. Mannitol is a major constituent of these algae (up to 30% and higher) and can be easily extracted from their biomass with hot water. PMID- 29709650 TI - Decentralization, healthcare access, and inequality in Mpumalanga, South Africa. AB - Healthcare access and utilization remain key challenges in the Global South. South Africa represents this given that more than twenty years after the advent of democratic elections, the national government continues to confront historical systems of spatial manipulation that generated inequities in healthcare access. While the country has made significant advancements, governmental agencies have mirrored international strategies of healthcare decentralization and focused on local provision of primary care to increase healthcare access. In this paper, we show the significance of place in shaping access and health experiences for rural populations. Using data from a structured household survey, focus group discussions, qualitative interviews, and clinic data conducted in northeast South Africa from 2013 to 2016, we argue that decentralization fails to resolve the uneven landscapes of healthcare in the contemporary period. This is evidenced by the continued variability across the study area in terms of government-sponsored healthcare, and constraints in the clinics in terms of staffing, privacy, and patient loads, all of which challenge the access-related assumptions of healthcare decentralization. PMID- 29709651 TI - Sensory nerve disturbance in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is the most common motor neuron disorder, characterized by the selective degeneration of upper and lower motor neurons. The common clinical symptoms of ALS are caused by the degeneration and dysfunction of motor neurons. With the progression of our understanding of the pathogenesis of the disease, an increasing number of extramotor phenotypes have been linked to ALS. It has long been believed that sensory neurons localized in the dorsal root ganglia are not involved in ALS. In addition, sensory nerve injury can clearly be considered as an important basis that does not support the diagnosis of ALS. However, accumulating evidence has revealed abnormalities in sensory neurons in both ALS patients and mouse models. This review summarizes the discoveries related to sensory nerve disturbance in ALS, which may provide insightful information that will help us better diagnose and understand the disease. PMID- 29709652 TI - Preparation of an efficient and safe polymeric-magnetic nanoparticle delivery system for sorafenib in hepatocellular carcinoma. AB - AIMS: Superparamagnetic iron oxide nanoparticles (SPIONs), as drug delivery vehicles, offer to eliminate the concerns associated with hydrophobic anti-cancer agents. The current study was intended to fabricate a SPION based delivery system for sorafenib that can simultaneously enable targeted delivery of sorafenib and expand its therapeutic index against hepatocellular carcinoma (HCC). MAIN METHODS: Co-precipitation and physical entrapment methods were employed for the synthesis of sorafenib loaded PVA coated SPIONs. Physicochemical characterizations were done using TEM, XRD, FTIR, Raman spectra and VSM measurements. The superior activity of nanoconjugate was demonstrated by AO/EB staining, FACS, immunofluorescence and Western blot. The safety of the sorafenib conjugated nanoparticles were verified in Wistar rats. KEY FINDINGS: The synthesized nanoparticles were in the size range of 5-15 nm. The adsorption of PVA to the SPIONs and the conjugation of sorafenib to the nanocarrier were confirmed by XRD, FTIR and Raman spectra analyses. VSM study ascertained the superparamagnetic nature of the nanoconjugate. Cellular uptake studies suggested its efficient entrapment in HepG2 cells. MTT assay showed that the cytotoxicity of sorafenib loaded PVA/SPIONs was comparable or higher than free sorafenib. The activation of apoptosis and autophagy pathways in HepG2 by the nanoconjugate was evidenced. Acute toxicity testing in Wistar rats supported the safe administration of the nanoconjugate and established its localization in animal tissues by Perl's Prussian Blue reaction. SIGNIFICANCE: The novel combination of sorafenib with PVA/SPIONs showed better anticancer efficiency than free sorafenib demonstrative of its potential in cancer chemotherapy. PMID- 29709654 TI - The role of HBV-induced autophagy in HBV replication and HBV related-HCC. AB - Hepatitis B virus (HBV) is infecting about 364 million people around the world. It can cause various diseases, such as chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC). However, the present anti-viral treatment in clinics is limited; studies for new therapies are highly desired. Autophagy is a crucial and major catabolic process in the maintenance of normal intracellular homeostasis in host cells. Host cells use this unique process to degrade and recycle long-lived proteins, damaged organelles, and various pathogens for keeping the normal physiological functions. Recently, published studies indicated that HBV can induce autophagy in host cells; this autophagic response is involved in viral replication and pathogenesis. Several viral proteins, such as surface and X proteins, are assumed to be responsible for inducing autophagy in HBV infection. This review briefly summarizes some important mechanisms involved in HBV-induced autophagy and provides a novel perspective on therapies of HBV infection and HBV-related HCC. PMID- 29709653 TI - Oleic acid protects saturated fatty acid mediated lipotoxicity in hepatocytes and rat of non-alcoholic steatohepatitis. AB - : Aim This study aims to demonstrate the protective effects of monounsaturated oleic acid (OA) against saturated palmitic acid (PA) induced cellular lipotoxicity in hepatocytes and rats with non-alcoholic steatohepatitis (NASH). MAIN METHODS: Human hepatoma cell line HepG2 cells and neonatal rat primary hepatocytes were treated with PA or/and OA for 24 h. SD rats were fed with high fat diet (HFD) to induce NASH. From the 16th w, the HFD was full or half replaced by olive oil to observe the protective effects. KEY FINDINGS: In vitro, OA substantially alleviated PA induced cellular apoptosis, oxidative stress, ER stress, mitochondrial dysfunction, as well as inflammation in hepatocytes. In vivo, only olive oil supplementation had no detrimental effects, while HFD developed NASH in normal rats. Full replacement of HFD with olive oil had profoundly reversed NASH. Noteworthily, half replacement of HFD with olive oil (a mixed diet) has ameliorated NASH injury as well. It strikingly changed the hepatic histology from macrovesicular-steatosis into entire microvesicular steatosis, and significantly reduced inflammation, ballooning and fibrosis. SIGNIFICANCE: Our study has demonstrated in both hepatocytes and NASH rats that oleic acids had great potential to combat the saturated fatty acids induced hepatic lipotoxicity. Only half replacement of HFD by monounsaturated fatty acids rich diet still had significant therapeutic outcome in NASH rats. Redirecting the toxic saturated fatty acids into triglyceride storage and reduction of cholesterol accumulation might be the possible explanation of OA driven protection in this scenario. PMID- 29709655 TI - Preoperative predictors of patient satisfaction after carpal tunnel release. AB - BACKGROUND: We investigated preoperative factors among demographic and clinical characteristics, as well as psychological factors that influence postoperative patient satisfaction, with the goal of assisting preoperative patient consultation for CTR. MATERIALS AND METHODS: We included 92 hands from 60 patients diagnosed with idiopathic carpal tunnel syndrome. We selected the following factors as possible preoperative predictors for patient satisfaction: age, sex, duration of symptoms, static two-point discrimination, the Semmes Weinstein monofilament test, grip strength, electrophysiological category and scores for the Boston Carpal Tunnel Questionnaire, the Pain Anxiety Symptoms scale and the Center for the Epidemiological Study of Depression scale. We used a cumulative logit model with generalized estimation equations to identify the predictors of patient satisfaction after CTR. RESULTS: Univariate analyses demonstrated significant correlations of patient satisfaction with age, preoperative grip power and preoperative CES-D. Multivariate analyses showed that age and preoperative CES-D scores were significantly correlated with patient satisfaction. CONCLUSION: Age and depression level were preoperative predictors influencing satisfaction after CTR. LEVELS OF EVIDENCE: IV. PMID- 29709656 TI - Surgical treatment of idiopathic pes planovalgus in paediatric patients. AB - Idiopathic pes planus is common and usually physiologic. Decompensation, when it occurs, may be obvious or on the contrary difficult to identify, raising challenges in patient selection for surgical treatment. The physical examination of a child with pes planus must include an evaluation in the supine position, which helps to adjust the amount of correction during surgery. The many reported surgical procedures include repositioning (talus-reseating, subtalar implants and calcaneo-stop screw), osteotomies and joint fusions. The primary treatment goal is to achieve full architectural correction of the deformity. Selection of the procedure depends on patient age and reducibility of the deformity. The joint lines should be preserved whenever possible. Triceps surae contracture should be sought and corrected if found. PMID- 29709657 TI - Recovery of early neural spikes from stimulation electrodes using a DC-coupled low gain high resolution data acquisition system. AB - BACKGROUND: Neural responses to electrical stimulation provide valuable information to probe and study the network function. Especially, recording neural responses from the stimulated site provides improved neural interfacing method. However, it is difficult to measure short-delayed responses at the stimulated electrode due to the saturation of the amplifier after stimulation which is called "stimulus artifact". Despite the advances in handling stimulation artifacts, it is still very challenging to deal with the artifacts if one tries to stimulate and record from the same electrode. NEW METHOD: In this paper, we developed a system consisting of 24 bit ADC and low gain DC-amplifier which allows us to record the entire responses including saturation-free stimulus artifact and neural responses with excellent resolution. RESULTS: Our approach showed saturation-free recording after stimulation, which makes it possible to recover neural spike as early as in 2 ms at the stimulating electrode with digital elimination methods. COMPARISON WITH EXISTING METHODS: With our system we could record neural signals after stimulation that was difficult with high gain and high pass filtered recording system due to amplifier saturation. CONCLUSIONS: Our new system can enhance interface performance with its higher robustness and with simple system configuration. PMID- 29709658 TI - Acute prediction of outcome and cognitive-communication impairments following traumatic brain injury: The influence of age, education and site of lesion. AB - BACKGROUND: Communication impairment following a traumatic brain injury (TBI) has been well documented, yet information regarding communication skills in the acute period following the injury is limited in the literature. Also, little is known about the influence of TBI severity (mild, moderate or severe) on cognitive communication impairments and how these impairments are related to short-term functional outcome. The goal of this study was to assess the performance of adults with mild, moderate and severe TBI on different language tests and to determine how this performance is related to functional capacity. We also aimed to explore which variables among age, sex, education, TBI severity and site of cerebral damage would predict initial language impairments. METHODS: Several language tests were administered to a sample of 145 adult patients with TBI of a range of severities admitted to an acute care service and to 113 healthy participants from the community. RESULTS: TBI patients of a range of severities performed poorly on all language tests in comparison to the healthy controls. In addition, patients with mild TBI performed better than the moderate and severe groups, except on the reading test and on the semantic naming test. In addition, their performance on verbal fluency, conversational discourse and procedural discourse tasks predicted acute functional outcome. Finally, age, education and TBI severity and site of lesion predicted some language performance. A left temporal lesion was associated with poorer performance in conversational discourse and auditory comprehension tasks, a left frontal lesion with a decrease in the verbal fluency results and a right parietal lesion with decreased auditory comprehension and reasoning skills. CONCLUSION: Health care professionals working in the acute care setting should be aware of the possible presence of cognitive communication impairments in patients with TBI, even for those with mild TBI. These deficits can lead to functional communication problems and assistance may be required for tasks frequently encountered in acute care requiring intact comprehension and expression. PMID- 29709659 TI - Mitigating the risks of global spread of Lassa fever at the 2018 Hajj pilgrimage. PMID- 29709660 TI - VT storm in remote myocardial infarction: Is it all in the genes? PMID- 29709661 TI - Effect of intermittent shear stress on corneal epithelial cells using an in vitro flow culture model. AB - PURPOSE: The aim of this study was to establish and to evaluate an in vitro model for culturing human telomerase-immortalized corneal epithelial (hTCEpi) cells under adjustable medium flow mimicking the movements of the tear film on the ocular surface. METHODS: Using an IBIDI pump system, cells were cultured under unidirectional, continuous or oscillating, discontinuous medium flow. Cell surface and cytoskeletal architecture were investigated by scanning electron microscopy and immunofluorescence. Gene expression of e-cadherin, occludin, tight junction protein (TJP), desmoplakin, desmocollin and mucins was investigated by real-time PCR. Protein expression of desmoplakin, TJP, occludin and e-cadherin was analyzed by western blot and localization was detected by immunofluorescence. Rose bengal staining was used to assess mucin (MUC) barrier integrity. MUC1, -4 and -16 proteins were localized by immunofluorescence. RESULTS: Medium flow induced shear stress dramatically changed cellular morphology of hTCEpi. Cells subjected to discontinuous shear stress displayed the typical flattened, polygonal cell shape of the superficial layer of stratified squamous epithelia. Cell surfaces showed less bulging under shear stress and less extracellular gaps. The mRNA expression of E-cadherin, occludin and TJP were increased under oscillatory medium flow. Desmoplakin and occludin protein were upregulated under oscillatory shear stress. Stress fiber formation was not aligned to flow direction. MUC1, -4, and -16 protein were localized under all culture conditions, a regulation on mRNA expression was not detectable. Rose Bengal uptake was diminished under unidirectional conditions. CONCLUSION: Our findings suggest that shear stress as it occurs at the ocular surface during blinking exerts marked effects on corneal epithelial cells, such as changes in cellular morphology and expression of cell junctions. The described model may be useful for in vitro investigations of ocular surface epithelia as it represents a much more physiologic reproduction of the in vivo situation than the commonly applied static culture conditions. PMID- 29709662 TI - The effects of recurrent physical abuse on the co-development of behavior problems and posttraumatic stress symptoms among child welfare-involved youth. AB - The primary aim of the current study was to examine the longitudinal effects of ongoing physical abuse on the co-development of externalizing behavior problems and posttraumatic stress (PTS) symptoms among child welfare-involved adolescents. Using three waves of data from the National Survey of Child and Adolescent Well Being, we performed unconditional and conditional parallel process latent growth curve modeling in a structural equation modeling framework. The study sample included 491 adolescents who were between 11 and 13 years of age at baseline. Higher levels of initial PTS symptoms were associated with higher levels of externalizing behavior problems, but the rate of change in PTS symptoms were not significantly associated with the rate of change in externalizing behavior problems over time. Although physical abuse was concurrently associated with both externalizing behavior problems and PTS symptoms at all assessment points, there were no lagged effects. Additionally, we found that physical abuse indirectly affects subsequent development of externalizing behavior problems and PTS symptoms through ongoing physical abuse. Findings highlight the comorbidity of externalizing behaviors and PTS symptoms among early adolescents in the child welfare system, underlining the importance of screening for and addressing these problems simultaneously. Findings also point to the need for continued assessment of and protection from ongoing physical abuse during adolescence. PMID- 29709663 TI - Predictors of maternal support following children's sexual abuse disclosures. AB - Despite the importance of parental support following children's sexual abuse (CSA) disclosures, there is a dearth of research regarding the predictors of support. Much of the prior literature is limited by the use of small sample sizes, measures of support without adequately reported psychometric properties, and inadequate or inconsistent definitions of support, which hinders the ability to accurately identify key predictors. Further, some potentially important predictors of parental support remain unexplored, including child-reported abuse stressors (e.g., family conflict, nonsupportive disclosure responses). The present study aimed to better delineate predictors of maternal belief and emotional support by examining the links between child, maternal, and family factors, and abuse characteristics as reported by both mothers and children. Two hundred and forty-seven treatment-seeking children (M age = 9.24, SD = 3.74) and their non-offending mothers were included in the study. Select demographic factors (i.e., child's age, minority status), abuse characteristics (i.e., use of penetration, repeated CSA incidents, and amount of CSA characteristics known), and child-reported abuse stressors were tied to levels of maternal belief and/or emotional support. Maternal and family characteristics were unrelated to support. The child's age and whether the abuse occurred more than once remained robust predictors of both aspects of support in multivariate analyses. The amount of CSA information known to the mother predicted emotional support, which may signal the utility of increasing parental knowledge of the abuse to bolster their emotional support. Findings indicate that there are several factors that may influence levels of maternal support, and children who experience certain types of CSA may be at greater risk for lower levels of belief and support. PMID- 29709664 TI - Outcomes and Prognostic Factors in Men Receiving Androgen Deprivation Therapy for Prostate Cancer Recurrence after Radical Prostatectomy. AB - PURPOSE: We sought to determine clinicopathological factors associated with early progression in men on androgen deprivation therapy as well as cancer specific and overall survival. We also assessed whether certain prostate specific antigen thresholds at androgen deprivation therapy initiation are associated with poorer outcomes. MATERIALS AND METHODS: We identified 2,418 men with rising prostate specific antigen after undergoing radical prostatectomy at a single institution between 1987 and 2007 in a prospectively maintained registry. Early progression was defined as clinical progression within 2 years of initiating androgen deprivation therapy. The primary study outcome was cancer specific and overall survival. RESULTS: The risk of early progression while on androgen deprivation therapy was lower for prostate specific antigen doubling time 3 to less than 9 months (OR 0.19) and less than 9 months or longer (OR 0.10, each p <0.001) prior to androgen deprivation therapy. Independent predictors of cancer specific survival were metastatic disease at androgen deprivation therapy initiation (HR 2.60), prostate specific antigen 5 to 50 ng/ml (HR 2.68) and 50 ng/ml or greater (HR 4.33), and doubling time 3 to less than 9 months (HR 0.54) and 9 months or longer (HR 0.45, all p <0.001). Independent predictors of overall survival were prostate specific antigen 5 to 50 ng/ml (HR 3.10) and 50 ng/ml or greater (HR 5.20, each p <0.001). CONCLUSIONS: In men in whom androgen deprivation therapy was initiated for relapse after radical prostatectomy prostate specific antigen doubling time less than 3 months and prostate specific antigen 5 ng/ml or greater were adverse prognostic factors for early progression and cancer specific survival. Prostate specific antigen 5 ng/ml or greater also predicted shorter overall survival. Longer doubling time and prostate specific antigen less than 5 ng/ml were associated with lower risk and these men may not require immediate androgen deprivation therapy. PMID- 29709665 TI - Symptomatic Venous Thromboembolism is Associated with Inferior Survival among Patients Undergoing Nephrectomy with Inferior Vena Cava Tumor Thrombectomy for Renal Cell Carcinoma. AB - PURPOSE: We investigated the incidence and survival impact of symptomatic venous thromboembolism after nephrectomy with inferior vena cava tumor thrombectomy. MATERIALS AND METHODS: We retrospectively reviewed the records of 183 patients who underwent nephrectomy with inferior vena cava tumor thrombectomy (level I-IV) for renal cell carcinoma between 2000 and 2010. Postoperative venous thromboembolism was defined as symptomatic bland thrombus or embolism confirmed on imaging. The cumulative incidence of venous thromboembolism was estimated by the Kaplan-Meier method. Associations of clinicopathological features with time to thromboembolism after surgery and all cause mortality were evaluated on multivariable analysis with Cox models. RESULTS: Symptomatic venous thromboembolism developed in 55 patients a median of 23 days (IQR 5-142) postoperatively, including pulmonary thrombosis in 24, deep venous thrombosis in 17, bland inferior vena cava thrombosis in 13 and portal vein thrombosis in 1. The cumulative incidence of thromboembolism 30, 90 and 365 days following surgery was 17%, 22% and 27%, respectively. A history of smoking (HR 2.15, 95% CI 1.09 4.24, p = 0.028), ECOG (Eastern Cooperative Oncology Group) performance status 1 or greater (HR 2.15, 95% CI 1.17-3.93, p = 0.013), hypercoagulability disorder (HR 5.12, 95% CI 1.93-13.59, p = 0.001) and bulky lymphadenopathy at surgery (HR 4.84, 95% CI 1.87-12.51, p = 0.001) was significantly associated with an increased risk of venous thromboembolism on multivariable analysis. Postoperative venous thromboembolism was significantly associated with an increased risk of all cause mortality (HR 1.53, 95% CI 1.04-2.23, p = 0.029). CONCLUSIONS: Venous thromboembolism after nephrectomy and tumor thrombectomy is common within 90 days of surgery. Symptomatic venous thromboembolism in this population is independently associated with a greater risk of mortality. PMID- 29709666 TI - Involuntary polymodal imagery involving olfaction, audition, touch, taste, and vision. AB - Percepts and urges often enter consciousness involuntarily. The Reflexive Imagery Task (RIT) reveals how high-level cognitions, too, can enter consciousness involuntarily. In the task, the eliciting stimuli are visual (e.g., picture of a cat), and the involuntary imagery is verbal (e.g., the subvocalization "cat"). The generalizability of the RIT effect has been questioned because verbal imagery is an easily elicited form of imagery. Do such effects arise for other kinds of imagery? It is known that imagery is more elicitable in some senses (e.g., vision) than in other senses (e.g., olfaction). We found such differences in an RIT in which food items were presented as orthographic stimuli or as drawings. Although subjects were instructed to suppress mental imagery, involuntary imagery still arose: Olfactory (effect in ~40% of trials), taste (~54%), touch (~60%), and visual/auditory (~79%). Of theoretical import, effects were comparable when the eliciting stimuli were orthographs or visual objects. PMID- 29709667 TI - Synthesis of Ag nanoparticles decoration on magnetic carbonized polydopamine nanospheres for effective catalytic reduction of Cr(VI). AB - More discrete and active Ag nanoparticles (Ag NPs) were fabricated by decorating them on the surface of magnetic nanoparticles encapsulated in carbonized polydopamine nanospheres (M/C-PDA/Ag) via in-situ solid-state decomposition process. The morphology, structure, surface compositions and textural properties of the M/C-PDA and M/C-PDA/Ag catalyst were characterized. The results revealed a dispersion of Ag NPs with average particle size of less than 50 nm on C-PDA nanospheres uniformly embedded with Fe3C NPs of only 3-5 nm in size. With the synergistic effect of Ag NPs, nitrogen doping, and hierarchical mesopores, M/C PDA/Ag displayed a superior catalytic capability for catalytic reduction of toxic Cr(VI) to less-toxic Cr(III) by formic acid as a reductant. Moreover, M/C-PDA/Ag maintained good physicochemical structure and stable activity even after several cycles of reactions. According to the results, the simple synthetic strategy, good stability, highly catalytic activity, and easy magnetic separation property of M/C-PDA/Ag hybrid make it serve as a promising environmentally friendly catalyst for the elimination of Cr(VI). PMID- 29709668 TI - Facile green synthetic graphene-based Co-Fe Prussian blue analogues as an activator of peroxymonosulfate for the degradation of levofloxacin hydrochloride. AB - A kind of Co-Fe Prussian blue analogues (Co-Fe PBAs), cobalt hexacyanoferrate Co3[Fe(CN)6]2, and graphene oxide (GO) were combined to synthesize magnetically separable Co-Fe PBAs@rGO nanocomposites through a simple two-step hydrothermal method. The crystalline structure, morphology and textural properties of the Co Fe PBAs@rGO nanocomposites were characterized. The catalytic performance of the nanocomposites was evaluated by PMS activation, with Levofloxacin Hydrochloride (LVF) as the target contaminant. Synergistic interactions between the Co-Fe PBAs and rGO prevented the aggregation of the Co-Fe PBAs nanoparticles, which resulted in enhanced degradation efficiencies. The influence of several critical parameters was investigated, including the reaction temperature, PMS and Co-Fe PBAs@rGO catalyst concentrations, solution pH and salt content. LVF degradation was favored at higher catalyst and PMS concentrations, high temperatures, and in neutral or weak acidic solutions. Sulphate radicals were the dominant active species in the Co-Fe PBAs@rGO/PMS system. In addition, the Co-Fe PBAs@rGO exhibited no significant decrease in LVF degradation efficiency following five catalytic cycles. Thus, the as-prepared Co-Fe PBAs@rGO nanocomposite catalyst might be applied to the removal of hard-to-degrade organics owing to its high catalytic ability to activate PMS, as well as its good reusability and recyclability. PMID- 29709669 TI - Does reduced zona pellucida binding protein 2 (ZPBP2) expression on chromosome 17q21 protect against asthma? PMID- 29709671 TI - Biological exacerbation clusters demonstrate asthma and chronic obstructive pulmonary disease overlap with distinct mediator and microbiome profiles. AB - BACKGROUND: Exacerbations of asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous. OBJECTIVE: We sought to investigate the sputum cellular, mediator, and microbiome profiles of both asthma and COPD exacerbations. METHODS: Patients with severe asthma or moderate-to-severe COPD were recruited prospectively to a single center. Sputum mediators were available in 32 asthmatic patients and 73 patients with COPD assessed at exacerbation. Biologic clusters were determined by using factor and cluster analyses on a panel of sputum mediators. Patterns of clinical parameters, sputum mediators, and microbiome communities were assessed across the identified clusters. RESULTS: The asthmatic patients and patients with COPD had different clinical characteristics and inflammatory profiles but similar microbial ecology. Three exacerbation biologic clusters were identified. Cluster 1 was COPD predominant, with 27 patients with COPD and 7 asthmatic patients exhibiting increased blood and sputum neutrophil counts, proinflammatory mediators (IL-1beta, IL-6, IL-6 receptor, TNF alpha, TNF receptors 1 and 2, and vascular endothelial growth factor), and proportions of the bacterial phylum Proteobacteria. Cluster 2 had 10 asthmatic patients and 17 patients with COPD with increased blood and sputum eosinophil counts, type 2 mediators (IL-5, IL-13, CCL13, CCL17, and CCL26), and proportions of the bacterial phylum Bacteroidetes. Cluster 3 had 15 asthmatic patients and 29 patients with COPD with increased type 1 mediators (CXCL10, CXCL11, and IFN gamma) and proportions of the phyla Actinobacteria and Firmicutes. CONCLUSIONS: A biologic clustering approach revealed 3 subgroups of asthma and COPD exacerbations, each with different percentages of patients with overlapping asthma and COPD. The sputum mediator and microbiome profiles were distinct between clusters. PMID- 29709672 TI - Of pleiotropy and trajectories: Does the TGF-beta pathway link childhood asthma and chronic obstructive pulmonary disease? AB - The study of developmental trajectories is where epigenetics truly shines. The "epi" in epigenetics captures the fact that although epigenetic processes also preside over the maintenance and termination of gene expression, the unfolding and remodeling of chromatin architecture are especially critical to prepare genes for regulated transcription. These properties imply being on a path, a trajectory to events that will occur later thanks to epigenetic programming. Thus epigenetics is about timed and timely events. In this article we discuss epigenetic and genetic evidence from several independent studies of asthma, chronic obstructive pulmonary disease, and lung function, which converge to highlight a potential role of the TGF-beta gene pathway in these processes. These results raise the possibility that at least in a subset of subjects, these conditions might be functionally connected in ways that need to be further defined but that likely reflect the uniquely pleiotropic nature of TGF-beta pathway genes, particularly their ability to control both lung development and immune responses essential for regulation and inflammation. Further characterization of this pathway in longitudinally phenotyped populations might unmask novel trajectories to lung disease that begin in utero and unfold into old age. PMID- 29709673 TI - Dignity or Dignities? When a Concept Has Multiple Meanings. PMID- 29709674 TI - Nurse Ratings of Dignity Deserve Dignity. PMID- 29709675 TI - Good Death. PMID- 29709676 TI - Liver stiffness measurement in the primary care setting detects high rates of advanced fibrosis and predicts liver-related events in hepatitis C. AB - BACKGROUND & AIMS: As many as 70% of individuals with chronic hepatitis C (CHC) are managed solely in primary care. The aims of this study were to determine the prevalence of elevated liver stiffness measurement (LSM) in a cohort of community managed patients with CHC and to evaluate predictors of advanced liver disease and liver-related events. METHODS: A prospective cohort of adult patients with CHC were recruited from 21 primary care practices throughout Victoria, Australia. Inclusion criteria included the presence of CHC for >6 months, no recent (<18 months) specialist input and no history of hepatocellular carcinoma. Clinical assessment, LSM and phlebotomy were carried out in primary care. A hospital cohort was recruited for comparison. Participants were followed longitudinally and monitored for liver-related events. RESULTS: Over 26 months, 780 community patients were recruited and included in the analysis. The median LSM was 6.9 kPa in the community, with 16.5% of patients at risk of advanced fibrosis (LSM >=12.5 kPa); of these 8.5% had no laboratory features of advanced liver disease. The proportion at risk of cirrhosis was no different between the community and hospital cohorts (p = 0.169). At-risk alcohol consumption, advancing age, elevated body mass index and alanine aminotransferase were independent predictors of elevated LSM. Over a median follow-up of 15.2 months, liver-related events occurred in 9.3% of those with an LSM >=12.5 kPa. An LSM of 24 kPa had the highest predictive power for liver-related events (hazard ratio152; p <0.001). CONCLUSION: The prevalence of advanced fibrosis, as determined by LSM, in primary care managed CHC is significant and comparable to a hospital cohort. Furthermore, this study supports the use of LSM as a community screening tool in a CHC population and indicates a possible role in predicting liver-related events. LAY SUMMARY: The prevalence of advanced liver disease in primary care managed hepatitis C is unknown. Our data suggests that rates of advanced fibrosis in the community are significant (16.5%), often underdiagnosed and comparable to rates seen in specialist referral centres. Liver stiffness measurement is a feasible community screening tool prior to hepatitis C therapy and can predict liver related adverse events. PMID- 29709677 TI - JNK1 induces hedgehog signaling from stellate cells to accelerate liver regeneration in mice. AB - BACKGROUND & AIMS: To improve outcomes of two-staged hepatectomies for large/multiple liver tumors, portal vein ligation (PVL) has been combined with parenchymal transection (associating liver partition and portal vein ligation for staged hepatectomy [coined ALPPS]) to greatly accelerate liver regeneration. In a novel ALPPS mouse model, we have reported paracrine Indian hedgehog (IHH) signaling from stellate cells as an early contributor to augmented regeneration. Here, we sought to identify upstream regulators of IHH. METHODS: ALPPS in mice was compared against PVL and additional control surgeries. Potential IHH regulators were identified through in silico mining of transcriptomic data. c-Jun N-terminal kinase (JNK1 [Mapk8]) activity was reduced through SP600125 to evaluate its effects on IHH signaling. Recombinant IHH was injected after JNK1 diminution to substantiate their relationship during accelerated liver regeneration. RESULTS: Transcriptomic analysis linked Ihh to Mapk8. JNK1 upregulation after ALPPS was validated and preceded the IHH peak. On immunofluorescence, JNK1 and IHH co-localized in alpha-smooth muscle actin positive non-parenchymal cells. Inhibition of JNK1 prior to ALPPS surgery reduced liver weight gain to PVL levels and was accompanied by downregulation of hepatocellular proliferation and the IHH-GLI1-CCND1 axis. In JNK1-inhibited mice, recombinant IHH restored ALPPS-like acceleration of regeneration and re-elevated JNK1 activity, suggesting the presence of a positive IHH-JNK1 feedback loop. CONCLUSIONS: JNK1-mediated induction of IHH paracrine signaling from hepatic stellate cells is essential for accelerated regeneration of parenchymal mass. The JNK1-IHH axis is a mechanism unique to ALPPS surgery and may point to therapeutic alternatives for patients with insufficient regenerative capacity. LAY SUMMARY: Associating liver partition and portal vein ligation for staged hepatectomy (so called ALPPS), is a new two-staged approach to hepatectomy, which induces an unprecedented acceleration of liver regeneration, enabling treatment of patients with liver tumors that would otherwise be considered unresectable. Herein, we demonstrate that JNK1-IHH signaling from stellate cells is a key mechanism underlying the regenerative acceleration that is induced by ALPPS. PMID- 29709670 TI - Blood eosinophil count thresholds and exacerbations in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Eosinophilic airway inflammation in patients with chronic obstructive pulmonary disease (COPD) is associated with exacerbations and responsivity to steroids, suggesting potential shared mechanisms with eosinophilic asthma. However, there is no consistent blood eosinophil count that has been used to define the increased exacerbation risk. OBJECTIVE: We sought to investigate blood eosinophil counts associated with exacerbation risk in patients with COPD. METHODS: Blood eosinophil counts and exacerbation risk were analyzed in patients with moderate-to-severe COPD by using 2 independent studies of former and current smokers with longitudinal data. The Genetic Epidemiology of COPD (COPDGene) study was analyzed for discovery (n = 1,553), and the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study was analyzed for validation (n = 1,895). A subset of the ECLIPSE study subjects were used to assess the stability of blood eosinophil counts over time. RESULTS: COPD exacerbation risk increased with higher eosinophil counts. An eosinophil count threshold of 300 cells/MUL or greater showed adjusted incidence rate ratios for exacerbations of 1.32 in the COPDGene study (95% CI, 1.10-1.63). The cutoff of 300 cells/MUL or greater was validated for prospective risk of exacerbation in the ECLIPSE study, with adjusted incidence rate ratios of 1.22 (95% CI, 1.06 1.41) using 3-year follow-up data. Stratified analysis confirmed that the increased exacerbation risk associated with an eosinophil count of 300 cells/MUL or greater was driven by subjects with a history of frequent exacerbations in both the COPDGene and ECLIPSE studies. CONCLUSIONS: Patients with moderate-to severe COPD and blood eosinophil counts of 300 cells/MUL or greater had an increased risk exacerbations in the COPDGene study, which was prospectively validated in the ECLIPSE study. PMID- 29709678 TI - Lysyl oxidase-like protein 2 (LOXL2) modulates barrier function in cholangiocytes in cholestasis. AB - BACKGROUND & AIMS: The lysyl oxidase-like protein 2 (LOXL2) promotes stabilization of the extracellular matrix, chemotaxis, cell growth and cell mobility. We aimed to (i) identify stimuli of LOXL2 in cholangiopathies, (ii) characterize the effects of LOXL2 on biliary epithelial cells' (BECs) barrier function, (iii) compare LOXL2 expression in primary sclerosing cholangitis (PSC), primary biliary cholangitis, and disease controls, and (iv) to determine LOXL2 expression and its cellular sources in four mouse models of cholangiopathies. METHODS: Cultured murine BECs were challenged with well-known triggers of cellular senescence, hypoxia, phospholipid-deficient Abcb4-/- mouse bile and chenodeoxycholic acid and investigated for LOXL2, SNAIL1 and E-cadherin expression and transepithelial electrical resistance with and without LOX inhibition. In vivo, LOXL2 expression was studied in PSC livers, and controls and mouse models. We compared LOXL2 serum levels in patients with PSC, secondary SC, primary biliary cholangitis, and controls. RESULTS: Cellular senescence, hypoxia, Abcb4-/- bile and chenodeoxycholic acid induced LOXL2 and SNAIL1 expression, repressed E-cadherin expression, and significantly reduced transepithelial electrical resistance in BECs. Notably, all of the pathological changes could be recovered via pharmacological LOX-inhibition. Mouse models showed induced LOXL2 expression in the portal region and in association with ductular reaction. LOXL2 serum levels were significantly elevated in patients with cholangiopathies. In PSC, LOXL2 expression was located to characteristic periductal onion skin-type fibrosis, ductular reaction, Kupffer cells, and fibrotic septa. Importantly, in PSC, LOXL2 overexpression was paralleled by E-cadherin loss in BECs from medium sized bile ducts. CONCLUSIONS: Reactive BECs produce LOXL2, resulting in increased tight junction permeability, which can be ameliorated by pharmacological LOX-inhibition in vitro. Reactive BECs, portal myofibroblasts, and Kupffer cells are the main sources of LOXL2 in cholangiopathies. LAY SUMMARY: In this study, we investigate the role of lysyl oxidase-like protein 2 (LOXL2), an enzyme pivotal in the development of organ fibrosis, in the pathogenesis of cholangiopathies (diseases of bile ducts), such as primary sclerosing cholangitis. We found LOXL2 to be expressed in association with bile duct epithelial injury and uncovered mechanisms for its upregulation and the subsequent effects in vitro and in vivo. Our findings support testing of anti LOXL2 treatment strategies for patients with primary sclerosing cholangitis. PMID- 29709679 TI - Molecular profiling of subclinical inflammatory lesions in long-term surviving adult liver transplant recipients. AB - BACKGROUND & AIMS: Subclinical inflammatory changes are commonly described in long-term transplant recipients undergoing protocol liver biopsies. The pathogenesis of these lesions remains unclear. The aim of this study was to identify the key molecular pathways driving progressive subclinical inflammatory liver allograft damage. METHODS: All liver recipients followed at Hospital Clinic Barcelona who were >10 years post-transplant were screened for participation in the study. Patients with recurrence of underlying liver disease, biliary or vascular complications, chronic rejection, and abnormal liver function tests were excluded. Sixty-seven patients agreed to participate and underwent blood and serological tests, transient elastography and a liver biopsy. Transcriptome profiling was performed on RNA extracted from 49 out of the 67 biopsies employing a whole genome next generation sequencing platform. Patients were followed for a median of 6.8 years following the index liver biopsy. RESULTS: Median time since transplantation to liver biopsy was 13 years (10-22). The most frequently observed histological abnormality was portal inflammation with different degrees of fibrosis, present in 45 biopsies (67%). Two modules of 102 and 425 co expressed genes were significantly correlated with portal inflammation, interface hepatitis and portal fibrosis. These modules were enriched in molecular pathways known to be associated with T cell mediated rejection. Liver allografts showing the highest expression levels for the two modules recapitulated the transcriptional profile of biopsies with clinically apparent rejection and developed progressive damage over time, as assessed by non-invasive markers of fibrosis. CONCLUSIONS: A large proportion of adult liver transplant recipients who survive long-term exhibit subclinical histological abnormalities. The transcriptomic profile of these patients' liver tissue closely resembles that of T cell mediated rejection and may result in progressive allograft damage. LAY SUMMARY: A large proportion of adult liver transplant recipients who survive for a long time exhibit subclinical histological abnormalities. The expression profile (a measurement of the activity of genes) of liver tissue from a large fraction of these patients closely resembles the profile of T cell mediated rejection. Liver allografts showing the highest expression levels of rejection related genes developed progressive damage over time. PMID- 29709680 TI - Liver - master and servant of serum proteome. AB - Hepatocytes synthesise the majority of serum proteins. This production occurs in the endoplasmic reticulum (ER) and is adjusted by complex local and systemic regulatory mechanisms. Accordingly, serum levels of hepatocyte-made proteins constitute important biomarkers that reflect both systemic processes and the status of the liver. For example, C-reactive protein is an established marker of inflammatory reaction, whereas transferrin emerges as a liver stress marker and an attractive mortality predictor. The high protein flow through the ER poses a continuous challenge that is handled by a complex proteostatic network consisting of ER folding machinery, ER stress response, ER-associated degradation and autophagy. Various disorders disrupt this delicate balance and result in protein accumulation in the ER. These include chronic hepatitis B infection with overproduction of hepatitis B surface antigen or inherited alpha1-antitrypsin deficiency that give rise to ground glass hepatocytes and alpha1-antitrypsin aggregates, respectively. We review these ER storage disorders and their downstream consequences. The interaction between proteotoxic stress and other ER challenges such as lipotoxicity is also discussed. Collectively, this article aims to sharpen our view of liver hepatocytes as the central hubs of protein metabolism. PMID- 29709681 TI - Class III obesity is a risk factor for the development of acute-on-chronic liver failure in patients with decompensated cirrhosis. AB - BACKGROUND & AIMS: Acute-on-chronic liver failure (ACLF) is a syndrome of systemic inflammation and organ failures. Obesity, also characterized by chronic inflammation, is a risk factor among patients with cirrhosis for decompensation, infection, and mortality. Our aim was to test the hypothesis that obesity predisposes patients with decompensated cirrhosis to the development of ACLF. METHODS: We examined the United Network for Organ Sharing (UNOS) database, from 2005-2016, characterizing patients at wait-listing as non-obese (body mass index [BMI] <30), obese class I-II (BMI 30-39.9) and obese class III (BMI >=40). ACLF was determined based on the CANONIC study definition. We used Cox proportional hazards regression to assess the association between obesity and ACLF development at liver transplantation (LT). We confirmed our findings using the Nationwide Inpatient Sample (NIS), years 2009-2013, using validated diagnostic coding algorithms to identify obesity, hepatic decompensation and ACLF. Logistic regression evaluated the association between obesity and ACLF occurrence. RESULTS: Among 387,884 patient records of decompensated cirrhosis, 116,704 (30.1%) were identified as having ACLF in both databases. Multivariable modeling from the UNOS database revealed class III obesity to be an independent risk factor for ACLF at LT (hazard ratio 1.24; 95% CI 1.09-1.41; p <0.001). This finding was confirmed using the NIS (odds ratio 1.30; 95% CI 1.25-1.35; p <0.001). Regarding specific organ failures, analysis of both registries demonstrated patients with class I-II and class III obesity had a greater prevalence of renal failure. CONCLUSION: Class III obesity is a newly identified risk factor for ACLF development in patients with decompensated cirrhosis. Obese patients have a particularly high prevalence of renal failure as a component of ACLF. These findings have important implications regarding stratifying risk and preventing the occurrence of ACLF. LAY SUMMARY: In this study, we identify that among patients with decompensated cirrhosis, class III obesity (severe/morbid obesity) is a modifiable risk factor for the development of acute-on-chronic liver failure (ACLF). We further demonstrate that regarding the specific organ failures associated with ACLF, renal failure is significantly more prevalent in obese patients, particularly those with class III obesity. These findings underscore the importance of weight management in cirrhosis, to reduce the risk of ACLF. Patients with class III obesity should be monitored closely for the development of renal failure. PMID- 29709682 TI - Low subcutaneous adiposity associates with higher mortality in female patients with cirrhosis. AB - BACKGROUND & AIMS: Two major body compartments, skeletal muscle and adipose tissue, exhibit independent functions. We aimed to explore the prognostic significance of skeletal muscle, visceral and subcutaneous adipose tissue, according to sex, in patients with cirrhosis assessed for liver transplantation (LT). METHODS: CT images taken at the 3rd lumbar vertebra from 677 patients were quantified for three body composition indexes (cm2/m2), visceral adipose tissue index, subcutaneous adipose tissue index (SATI), and skeletal muscle index (SMI). Cox proportional and competing-risk analysis hazard models were conducted to assess associations between mortality and body composition. RESULTS: The majority of patients were male (67%) with a mean age of 57 +/- 7 years, model for end stage liver disease (MELD) score of 14 +/- 8 and mean body mass index of 27 +/- 6 kg/m2. Despite similar body mass index between the sexes, male patients had greater SMI (53 +/- 12 vs. 45 +/- 9 cm2/m2), whereas SATI (67 +/- 52 vs. 48 +/- 37 cm2/m2) was higher in females (p <0.001 for each). In sex stratified multivariate analyses after adjustment for MELD score and other confounding variables, SATI in females (hazard ratio [HR] 0.99; 95% CI 0.98-1.00; p = 0.01) and SMI in males (HR 0.98; 95% CI 0.96-1.00; p = 0.02) were significant predictors of mortality. Female patients with low SATI (<60 cm2/m2) had a higher risk of mortality (HR 2.06; 95% CI 1.08-3.91; p = 0.03). Using competitive risk analysis in female patients listed for LT, low SATI was also an independent predictor of mortality (subdistribution HR 2.80; 95% CI 1.28-6.12; p = 0.01) after adjusting for MELD, and other confounding factors. CONCLUSIONS: A lower SATI is associated with higher mortality in female patients with cirrhosis. Subcutaneous adipose tissue has a favorable metabolic profile - low SATI may reflect depletion of this major energy reservoir, leading to poor clinical outcomes. LAY SUMMARY: We looked at the importance of two of the main body compartments, skeletal muscle and adipose tissue (fat) on the prognosis of males and females with end-stage liver disease. Lower amounts of subcutaneous fat but not visceral fat (around internal organs), are associated with higher mortality in female patients with end-stage liver disease. However, low skeletal muscle predicts mortality in male patients with end-stage liver disease. PMID- 29709683 TI - A single preovulatory administration of ulipristal acetate affects the decidualization process of the human endometrium during the receptive period of the menstrual cycle. AB - In order to get further information on the effects of ulipristal acetate (UPA) upon the process of decidualization of endometrium, a functional analysis of the differentially expressed genes in endometrium (DEG) from UPA treated-versus control-cycles of normal ovulatory women was performed. A list of 1183 endometrial DEG, from a previously published study by our group, was submitted to gene ontology, gene enrichment and ingenuity pathway analyses (IPA). This functional analysis showed that decidualization was a biological process overrepresented. Gene set enrichment analysis identified LIF, PRL, IL15 and STAT3 among the most down-regulated genes within the JAK STAT canonical pathway. IPA showed that decidualization of uterus was a bio-function predicted as inhibited by UPA. The results demonstrated that this selective progesterone receptor modulator, when administered during the periovulatory phase of the menstrual cycle, may affect the molecular mechanisms leading to endometrial decidualization in response to progesterone during the period of maximum embryo receptivity. PMID- 29709684 TI - The re-emerging of orf virus infection: A call for surveillance, vaccination and effective control measures. AB - Orf disease is known to be enzootic among small ruminants in Asia, Africa, and some other parts of the world. The disease caused by orf virus is highly contagious among small ruminant species. Unfortunately, it has been neglected for decades because of the general belief that it only causes a self-limiting disease. On the other hand, in the past it has been reported to cause huge cumulative financial losses in livestock farming. Orf disease is characterized by localized proliferative and persistent skin nodule lesions that can be classified into three forms: generalized, labial and mammary or genitals. It can manifest as benign or malignant types. The later type of orf can remain persistent, often fatal and usually causes a serious outbreak among small ruminant population. Morbidity and mortality rates of orf are higher especially in newly infected kids and lambs. Application of antibiotics together with antipyretic and/or analgesic is highly recommended as a supportive disease management strategy for prevention of subsequent secondary microbial invasion. The presence of various exotic orf virus strains of different origin has been reported in many countries mostly due to poorly controlled cross-border virus transmission. There have been several efforts to develop orf virus vaccines and it was with variable success. The use of conventional vaccines to control orf is a debatable topic due to the concern of short term immunity development. Following re-infection in previously vaccinated animals, it is uncommon to observe the farms involved to experience rapid virus spread and disease outbreak. Meanwhile, cases of zoonosis from infected animals to animal handler are not uncommon. Despite failures to contain the spread of orf virus by the use of conventional vaccines, vaccination of animals with live orf virus is still considered as one of the best choice. The review herein described pertinent issues with regard to the development and use of potential effective vaccines as a control measure against orf virus infection. PMID- 29709685 TI - Biocontrol and plant stimulating potential of novel strain Bacillus sp. PPM3 isolated from marine sediment. AB - In the current study, the biocontrol potential of a novel strain Bacillus sp. PPM3 isolated from marine sediment from the Red Sea in Hurghada, Egypt is recognized. This novel strain was selected out of 32 isolates based on its ability to suppress the growth of four plant pathogenic fungi: Aspergillus flavus, Fusarium graminearum, Mucor sp. and Alternaria sp. The new marine strain was identified and characterized by phenotypic and molecular approaches. The culture filtrate of Bacillus sp. PPM3 suppressed the growth and spore germination of all tested fungi in vitro with the highest value of inhibition reported for Mucor sp. (97.5%). The antifungal effect of the culture filtrate from the strain PPM3 was due to production of highly stable secondary metabolites resistant to extreme pH, temperature and enzymatic treatments. A PCR analysis confirmed the expression of genes involved in the synthesis of antifungal lipopeptides: iturin, bacillomycin D, mycosubtilin and surfactin. In a greenhouse experiment strain PPM3 effectively reduced disease incidence of F. graminearum in maize plants and displayed additional plant growth stimulating effect. The results show that novel marine strain PPM3 could have a potential in commercial application as biocontrol agent for treatment of various plant diseases caused by soil-borne and postharvest pathogenic fungi. PMID- 29709686 TI - Dual functions of a 4-hydroxyphenylpyruvate dioxygenase for Vibrio splendidus survival and infection. AB - Vibrio splendidus is a well-documented pathogenic bacterium that can trigger different diseases, including skin ulcer syndrome in Apostichopus japonicus. In our previous study, a gene named Vshppd encoding a 4-hydroxyphenylpyruvate dioxygenase homologue was cloned from pathogenic V. splendidus, and validated to be responsible for the haemolysis activities of V. splendidus. In this study, Vshppd was determined to participate in the catabolism of tyrosine and promote pyomelanin production in Escherichia coli BL21 (DE3) harboring Vshppd. The purified melanin pigment displayed obvious antimicrobial activity against E. coli and Micrococcus luteus and protective effect on V. splendidus under ultraviolet irradiation. As an important virulence factor, Vshppd was further determined to be cytotoxic to the coelomocyte of A. japonicus and cell viability decreased to approximately 68%, 77%, 54% and 44% when 50, 60, 80 and 100 MUL of purified rVshppd was present, respectively. To better understand the potential effect of Vshppd mediated oxidative stress, we injceted A. japonicus with the rVshppd, which showed significantly stimulatory effects on the expression of oxidative stress related genes catalase (cat), glutathione S-transferase (gst), glutathione peroxidase (gpx), heat shock protein 70 (hsp70) of A. japonicus. At 48 h, the expression level of cytochrome P450 (cyp450) was down-regulated compared with that treated with BSA. It was suggested that Vshppd exhibited cytotoxicity via altering the oxidative stress. Our result indicated that Vshppd was not only involved in the self-protection, but also contributed to the pathogenesis of V. splendidus by modulating the oxidative stress imbalance in A. japonicus. PMID- 29709687 TI - Three polypeptides screened from phage display random peptide library may be the receptor polypeptide of Mycoplasma genitalium adhesion protein. AB - Mycoplasma genitalium adhesion protein (MgPa) is a major adhesin of M. genitalium, a human pathogen associated with a series of genitourinary tract diseases. MgPa plays a very important role in M. genitalium adhering to the host cells. However, the exact receptor peptides or proteins of MgPa are still poorly understood so far. Three polypeptides (V-H-W-D-F-R-Q-W-W-Q-P-S), (D-W-S-S-W-V -Y R-D-P-Q-T) and (H-Y-I-D-F-R-W) were previously screened from a phage display random peptide library using recombinant MgPa (rMgPa) as a target molecule. In this study, three polypeptides were artificially synthesized and investigated as to whether they are potential receptors of MgPa. We found that rMgPa specifically bound to three synthesized polypeptides as determined via an indirect enzyme linked immunosorbent assay (ELISA). Moreover, three polypeptides were further identified by indirect immunofluorescence microscopy (IFM). We confirmed that rMgPa and M. genitalium can adhere to SV-HUC-1 cells in vitro and that anti-rMgPa antibody and three synthesized polypeptides can partially inhibit the adherence of rMgPa and M. genitalium to SV-HUC-1 cells. In summary, these three polypeptides may be the essential receptor peptides of MgPa, and may aid in enhancing the understanding of biological function of MgPa and the possible pathogenic mechanism of M. genitalium. PMID- 29709688 TI - Bacterial diversity in the feces of dogs with CPV infection. AB - Canine parvovirus (CPV) is a contagious disease in dogs that has high morbidity and mortality. In cases of infection, the pups tend to have a higher mortality and more severe clinical symptoms than the adult dogs because the dehydration is difficult for pups to bear. Following the natural infection, there is a rapid antibody response neutralizing the extracellular virus. As a result, virus titers in tissue and feces become markedly reduced. Hence, it is important to have an effective symptomatic therapy of supporting animals to survive in the early stages of CPV infection. Furthermore, the co-infection with bacteria could increase the severity of lesions and clinical signs as well. In this paper, we obtained the bacterial diversity in feces of CPV infected dogs with the enrichment of five bacteria genera (Shigella, Peptoclostridium, Peptostreptococcus, Streptococcus, Fusobacterium). These microorganisms may partly result in the intestinal pathology of the infection. In summary, the discussion of the bacterial biodiversity in feces of CPV infected dogs provides further insights into the pathology of CPV disease and the targets of developing more effective treatment strategies. PMID- 29709689 TI - A newly emerged focus of zoonotic cutaneous leishmaniasis in South-western Iran. AB - Leishmaniasis is rising in many countries, including Iran, due to climate change, refugee crises, urbanization and etc. The aim of this study was to explore the epidemiology, extent and identity of Leishmania species in a newly emerged focus in Abdanan County, Ilam Province, South-western Iran. This study was performed as a descriptive cross-sectional study by a systematic house-to-house approach. The Leishmania species was identified by RFLP-PCR and sequencing. Altogether, 46799 individuals consisting of 22907 (48.9) female and 23892 (51.1%) male were interviewed and physically examined for the presence of skin lesions. Overall, the incidence rate was 0.34% (n = 160). All age groups were affected and the incidence rate was the highest in <10 years of age group (0.49%) and the lowest in >50 years old individuals (0.15%), although there was no significant difference regarding the sex and age. The majority of patients had one lesion (47.5%) on hands (56%) and most of the cases occurred in Abdanan city (%54) in summer. Based on the RFLP-PCR analysis, all the Leishmania isolates were L. major of single genotype. A newly emerged focus of zoonotic CL caused by L. major occurred in South-western of Iran. Multiple risk factors created this epidemic area. Further studies on the vector and reservoir are crucial needed to provide evidences to select the prophylactic and therapeutic measures for future control strategies. PMID- 29709691 TI - Reconstructing the phylogenetic history of the tribe Leucocoryneae (Allioideae): Reticulate evolution and diversification in South America. AB - At present, the Allioideae is included within the Amaryllidaceae, which is an economically important bulb crop subfamily that includes onion, garlic, and ornamental species worldwide. The Allioideae includes four tribes geographically disjunct namely: Allieae, widespread in the northern hemisphere, tribe Tulbaghieae distributed in South Africa, and tribes Leucocoryneae and Gilliesieae are endemic to South America. Although we agree with the current tribal circumscription of the Leucocoryneae including Beauverdia, Ipheion, Latace, Leucocoryne, Nothoscordum, and Tristagma, there are still taxonomic and phylogenetic uncertainties regarding the monophyly, phylogenetic relationships, and divergence time of several lineages in a biogeographic context. In this study, a comprehensive molecular phylogeny of the tribe Leucocoryneae was inferred based on nuclear ribosomal ITS and plastid (ndhF and matK) sequences. We used Bayesian inference and maximum parsimony analyses to predict ancestor descendant relationships. Our results confirmed the monophyly of the four tribes of subfamily Allioideae. Similarly, within the Leucocoryneae, Ipheion, Leucocoryne, and Nothosocordum Sect. Inodorum were also monophyletic; Tristagma and Nothoscordum would be monophyletic if including Ipheion and Beauverdia, respectively. Network analyses were implemented to reveal putative scenarios of reticulate evolution. Both, current and ancestral hybridization events have presumably occurred among species of Nothoscordum Sect. Nothoscordum and Beauverdia favored by spatial overlapping of populations, flowering synchrony and a puzzling pattern of cytogenetic attributes. The estimation of divergence time indicates that the tribe Leucocoryneae originated in the Late Oligocene in southern South America with possible ancestors in Africa. Most crown lineages within the tribe diversified in conjunction with biogeographical events during the Late Miocene to Pliocene. We posit that new suitable environments available after the Andean uplift and during the Age of the Southern Plains provided the favorable geographic setting for the major lineages of Leucocoryneae in southern Pampas, extra-Andean Patagonia, Andean mountains, and in Chile. Hybridization, polyploidization, and Robertsonian translocations of chromosomes have been the driving forces and major sources of speciation in the evolution of tribe Leucocoryneae. PMID- 29709690 TI - Study of serum bactericidal and splenic activity of Total-OMP- CagA combination from Brucella abortus and Helicobacter pylori in BALB/c mouse model. AB - BACKGROUND: Brucella is a Gram-negative and facultative intracellular organism that causes brucellosis, a common zoonotic disease. Over 500,000 people are annually affected by brucellosis. Brucella is highly infectious through inhalation route; for this reason it is used for biological warfare aims. This study aimed to study the serum bactericidal and splenic activity of Total-OMP-r CagA immunogens from Brucella abortus and Helicobacter pylori in a BALB/c mouse model. METHODS: Immunization of BALB/c mice was performed with immunogenic proteins three times subcutaneously (S.C.) at 14-day intervals. The protective effects of two component vaccines with CpG adjuvant were evaluated after mice were challenged with H. pylori ss1 and Brucella abortus strain 544. The specific IgG1 and IgG2a antibodies in sera were assessed using ELISA test. For measuring the antigen-specific IL-4, IL-12 and IFN-gamma responses in sera of immunized mice after challenge, RT-PCR technique was applied. Twenty days after the challenge, mice were killed then gastric, splenic and serum samples were assessed and bacterial colony count was measured based on the pour plate count agar. RESULTS: The results indicated that rCagA + OMP decreased bacterial colonization in these tissues, and significant difference was observed between test and control groups (p value?0.001). CONCLUSION: Our results showed that the combination vaccine was effective against an oral exposure and the bacterial burden in the spleen, serum and gastric tissues were reduced in mice immunized with the Total- OMP-CagA. PMID- 29709692 TI - Turning one into five: Integrative taxonomy uncovers complex evolution of cryptic species in the harvester ant Messor "structor". AB - Seed harvesting ants are ecosystem engineers that shape vegetation, nutrient cycles, and microclimate. Progress in ecological research is, however, slowed down by poor species delimitation. For example, it has not been resolved to date, how many species the European harvester ant Messor "structor" (Latreille, 1798) represents. Since its first description, splitting into additional taxa was often proposed but not accepted later on due to inconsistent support from morphology and ecology. Here, we took an iterative integrative-taxonomy approach - comparing multiple, independent data sets of the same sample - and used traditional morphometrics, Wolbachia symbionts, mitochondrial DNA, amplified fragment length polymorphism, and ecological niche modelling. Using the complementarity of the data sets applied, we resolved multiple, strong disagreements over the number of species, ranging from four to ten, and the allocation of individuals to species. We consider most plausible a five-species hypothesis and conclude the taxonomic odyssey by redescribing Messor structor, M. ibericus Santschi, 1925, and M. muticus (Nylander, 1849) stat.rev., and by describing two new species, M. ponticus sp.n. and M. mcarthuri sp.n. The evolutionary explanations invoked in resolving the various data conflicts include pronounced morphological crypsis, incomplete lineage-sorting or ongoing cospeciation of endosymbionts, and peripatric speciation - these ants' significance to evolutionary biology parallels that to ecology. The successful solution of this particular problem illustrates the usefulness of the integrative approach to other systematic problems of comparable complexity and the importance of understanding evolution to drawing correct conclusions on species' attributes, including their ecology and biogeography. PMID- 29709693 TI - Metagenomic identification, genetic characterization and genotyping of porcine sapoviruses. AB - Sapoviruses (SaVs), belonging to the genus Sapovirus of the family Caliciviridae, were known as the enteric pathogen causing acute gastroenteritis. SaVs have been detected in humans and several animals including pigs and some porcine SaVs showed close sequence relationship with human strains suggesting the possibility of interspecies transmission. Here, we sequenced the genomes of two porcine SaVs (with strain names of p38 and SH1703) using the metagenomic analyses and traditional RT-PCR methods. Phylogenetic trees were constructed based on the complete genome, the full-length VP 1 nucleotide and amino acid sequences to group those two strains. The two porcine SaV strains, p38 and SH1703, detected in this study, were classified as genogroup III and genogroup VII, respectively. These two strains showed similar genomic organization with that of other SaVs. We firstly divided SaVs into 51 genotypes within 19 genogroups. Our data are helpful for genetic characterization and classification of newly detected SaVs worldwide. PMID- 29709694 TI - Dehiscence of a Low Transverse Cesarean Scar by a Submucous Myoma in a Nongravid Uterus. PMID- 29709695 TI - Non-infective endocarditis: Expanding the phenotype of giant cell arteritis. PMID- 29709696 TI - IMSYC immunologic synovitis score: A new score for synovial membrane characterization in inflammatory and non-inflammatory arthritis. AB - OBJECTIVES: Krenn synovitis Score has been developed by Krenn et al. in order to assess synovitis severity and is used in synovial research. Cell signature of synovial tissue can be studied using immunohistochemistry and is of interest as a biomarker for both prognosis and prediction of response to treatment. However, no synovitis score including immunohistochemistry exists yet. In order to answer this unmet need, we propose a new Immunologic Synovitis score (IMSYC) adding 5 components to the Krenn score: CD68, CD3, CD20, CD31 and Ki67 immunostaining. In this study, we aimed to validate this new IMSYC by studying its diagnostic performances in a well-defined collection of synovial samples. METHODS: Synovial samples from patients were obtained during surgical procedures. CD68, CD3, CD20, CD31 and KI67 immunohistochemistry were performed. RESULTS: In total, 77 patients were included. In total, 45 were females, mean age was 63.1 years. Forty had inflammatory arthritis, mainly rheumatoid arthritis (31/40). Non inflammatory arthritis group included 35 patients with mainly osteoarthritis. Mean Krenn score and IMSYC were significantly higher in the inflammatory group (P<0.001). ROC analysis of diagnostic performances determined the score of 13.5 out of 24 as the cut-off that gave the best ratio for discrimination between inflammatory and non inflammatory arthritis with a sensitivity of 71.8% and specificity of 98%. CONCLUSION: We propose a new synovitis score including immunohistochemistry. This score has a better sensitivity and specificity than the Krenn score and represents a more functional synovitis evaluation. IMSYC could be further used in better categorizing synovial tissue phenotype and give a basis for tissue driven therapy. PMID- 29709697 TI - Pseudo-malignant osteolysis of the pelvis: Unusual pattern of pubic bone fracture. PMID- 29709698 TI - Extensive lytic tuberculosis of the humeral head. PMID- 29709699 TI - Burden of severe spondyloarthritis in France: A nationwide assessment of prevalence, associated comorbidities and cost. AB - OBJECTIVES: To estimate the number of patients with severe spondyloarthritis (SpA) in France, describe their comorbidities and document and value their healthcare resource consumption. METHODS: Data were retrieved from an insurance claims database covering a 1/97 random sample of the French population. All patients benefiting from full insurance coverage ("ALD") for severe SpA in 2012 (including cases with structural damage and/or frequent flares) were identified, together with a control group frequency-matched by age and gender. Severe comorbidities were documented through ALD categories. Healthcare resource consumption was documented and valued from the payer's perspective. Rates of comorbidities and costs were compared in SpA patients versus controls using non parametric testing. RESULTS: Overall, 827 patients with ALD status for severe SpA were identified (control group: n=2.481), corresponding to a prevalence rate of 0.18% [0.17-0.19] for SpA with ALD in the general population. Severe comorbidities more frequent in patients with SpA than in controls included inflammatory bowel disorders (odds ratio: 15.0 [6.2-36.2]), hypertension (2.5 [1.6-3.9]), atrial fibrillation (4.3 [1.9-9.6]) and major depressive disorder (2.1 [1.3-3.6]). Mean per capita annual direct healthcare expenditure was 3.6 [3.2-4.1]-fold higher in SpA patients (?6,122 [?5,838-?6,406]) than in controls (?1,682 [?1,566-?1,798]). Extrapolating to all patients in France, total healthcare cost attributable to severe SpA patients was ?391 [?355-?426] million, with medication accounting for 53.8% of this cost. CONCLUSIONS: The burden of severe SpA in France is substantial, due to the high prevalence, high direct costs and associated comorbidities. PMID- 29709700 TI - Epidemiology of stroke: findings from a community-based survey in rural Bangladesh. AB - OBJECTIVES: This study was designed to determine the epidemiology of stroke in a rural population of Bangladesh. STUDY DESIGN: In a cross-sectional study, we surveyed stroke patients. METHODS: The survey was conducted in a rural community of Bangladesh from January 2016 to June 2016. All community members 15 years and older in a surveillance system were included in this study. The Questionnaire for Verifying Stroke-Free Status was used to screen stroke cases at household level which were again examined by the neurologist for confirmatory diagnosis. RESULTS: The prevalence of stroke was 1.96 (95% confidence interval [CI] 1.69-2.26) per 1000 population. The highest prevalence was 9.65 (95% CI 7.42-12.33) per 1000 population, identified among patients aged 65-79 years. Males had higher prevalence (2.38 per 1000 population) than females (1.55 per 1000 population). Of the 24% of patients who had radiological examination (magnetic resonance imaging and computed tomography scan) reports, 17.2% of stroke cases were ischemic, 4.8% were intracerebral, and about 1.1% were subarachnoid. The ratio of infarction to hemorrhage was 2.91. Approximately 67% of patients were diagnosed as hypertensive, and 37% of patients had elevated blood glucose level. While 15% of patients were found to be overweight or obese, 45% of patients had raised blood cholesterol level. More than 10% of patients reported that they had heart disease before the occurrence of stroke. About 40% of patients had the history of tobacco consumption. CONCLUSIONS: The prevalence of stroke is higher among elderly and male populations. A significant proportion of patients presented with hypertension and/or diabetes. PMID- 29709701 TI - Co-targeting of BET proteins and HDACs as a novel approach to trigger apoptosis in rhabdomyosarcoma cells. AB - Histone acetylation marks exert essential functions in regulating gene expression. These marks are written by histone acetyltransferases (HATs), removed by histone deacetylases (HDACs) and read by e.g. BET proteins. While BET inhibitors are promising new anticancer drugs, little is yet known about their antitumor activity in rhabdomyosarcoma (RMS). We therefore investigated the efficacy of the prototypic BET inhibitor JQ1 alone or in combination with other epigenetic modifiers, namely HDAC inhibitors (HDACIs). Here, we discover a synergistic interaction of the panBET inhibitor JQ1 together with various HDACIs, i.e. Quisinostat (JNJ-26481585), Vorinostat (SAHA), Entinostat (MS-275) and Panobinostat (LBH589), inducing apoptosis in RMS cells, whereas JQ1 as single agent exhibits little cytotoxicity. Calculation of combination index (CI) confirmed the synergism of this combination. Importantly, JQ1 and JNJ-26481585 act in concert to suppress colony formation and to trigger apoptosis in an in vivo model. Mechanistic studies revealed that combination of JQ1 and JNJ-26481585 cooperatively upregulates BIM and BMF, while downregulating BCL-xL. This shifted ratio of pro- and antiapoptotic BCL-2 proteins engages activation of BAX and BAK and increases caspases-3 and -7 activity. Individual silencing of BIM or NOXA, overexpression of BCL-2 or MCL-1 as well as addition of the caspase inhibitor zVAD.fmk significantly rescue JQ1/JNJ-26481585-induced apoptosis. Thus, co targeting of histone acetylation by concomitant inhibition of HDAC and BET proteins synergistically induces mitochondrial apoptosis by shifting the ratio of pro- and antiapoptotic BCL-2 proteins towards apoptosis. These findings indicate that combinatorial use of BET and HDACIs may represent a promising new strategy for the treatment of RMS. PMID- 29709702 TI - Tumor-released exosomal circular RNA PDE8A promotes invasive growth via the miR 338/MACC1/MET pathway in pancreatic cancer. AB - Circular RNA (circ-RNA) and exosomes have recently been shown to play important roles in different tumors. However, the functions and regulatory mechanisms of exosomal circ-RNA in pancreatic ductal adenocarcinoma (PDAC) tumor progression remain unclear. Here, we identified a circular RNA (circ-PDE8A) from liver metastatic PDAC cells by microarray analysis, detected its expression levels in clinical tissues and found that high circ-PDE8A expression was correlated with lymphatic invasion, TNM stage and a poor survival rate of PDAC patients. Further study revealed that circ-PDE8A promotes the invasive growth of PDAC cells via upregulating MET. Circ-PDE8A acts as a ceRNA for miR-338 to regulate MACC1 and stimulates invasive growth via the MACC/MET/ERK or AKT pathways. We further imaged the exosome communication between tumor cells and identified the tumor secreted exosomes in blood circulation. Finally, we analyzed the circ-PDE8A expression in plasma exosomes of PDAC patients and found that exosomal circ-PDE8A was associated with progression and prognosis in PDAC patients. Thus, circ-PDE8A may play an important role in tumor invasion, and exosomal circ-PDE8A may be a useful marker of PDAC diagnosis or progression. PMID- 29709703 TI - Autophagy in glioma cells: An identity crisis with a clinical perspective. AB - Over the last decade, autophagy has emerged as one of the critical cellular systems that control homeostasis. Besides management of normal homeostatic processes, autophagy can also be induced by tissue damage stress or by rapidly progressing tumors. During tumor progression, autophagy mediates a cellular reaction to the changes inside and outside of cells, which leads to tumor adaptation. Even though the regulation of autophagy seems universal and is a well described process, its dysregulation and role in glioma progression remain an important topic of investigation. In this review, we summarize recent evidence of autophagy regulation in brain tumor tissues and possible interconnection between signaling pathways that govern cellular responses. This perspective may help to assess the qualitative differences and various outcomes in response to autophagy stimulation. PMID- 29709704 TI - A Photo-triggered and photo-calibrated nitric oxide donor: Rational design, spectral characterizations, and biological applications. AB - Nitric oxide (NO) donors are valuable tools to probe the profound implications of NO in health and disease. The elusive nature of NO bio-relevance has largely limited the use of spontaneous NO donors and promoted the development of next generation NO donors, whose NO release is not only stimulated by a trigger, but also readily monitored via a judiciously built-in self-calibration mechanism. Light is without a doubt the most sensitive, versatile and biocompatible method of choice for both triggering and monitoring, for applications in complex biological matrices. Herein, we designed and synthesized an N-nitroso rhodamine derivative (NOD560) as a photo-triggered and photo-calibrated NO donor to address this need. NOD560 is essentially non-fluorescent. Upon irradiation by green light (532 nm), it efficiently release NO and a rhodamine dye, the dramatic fluorescence turn-on from which could be harnessed to conveniently monitor the localization, flux, and dose of NO release. The potentials of NOD560 for in vitro biological applications were also exemplified in in vitro biological models, i.e. mesenchymal stem cell (MSC) migration suppression. NOD560 is expected to complement the existing NO donors and find widespread applications in chemical biological studies. PMID- 29709706 TI - Argirein alleviates vascular endothelial insulin resistance through suppressing the activation of Nox4-dependent O2- production in diabetic rats. AB - BACKGROUND: Insulin resistance in endothelial cells contributes to the development of cardiovascular disease in type 2 diabetes mellitus (T2DM). Therefore, there are great potential clinical implications in developing pharmacological interventions targeting endothelial insulin resistance. Our previous studies indicated that argirein which was developed by combining rhein with L-arginine by a hydrogen bond, could substantially relieved stress related exacerbation of cardiac failure and alleviated cardiac dysfunction in T2DM, which was associated with suppressing NADPH oxidase activity. However, it is unclear whether argirein treatment attenuates the vascular lesion and dysfunction in T2DM and its underlying mechanisms. METHODS AND RESULTS: The rat aortic endothelial cells (RAECs) were used to treat with palmitic acid (PA), a most common saturated free fatty acid, which could induce insulin resistance. It was showed that argirein increased glucose uptake and glucose transporter-4 (Glut4) expression and reversed the phosphorylation of IRS-1-ser307 and AKT-ser473, consequently resulting in the increase of the production of eNOS and NO in PA-induced RAECs. We further found that argirein blocked the Nox4-dependent superoxide (O2-.) generation, which regulated glucose metabolism in RAECs during PA stimulation. In vitro, argirein increased the release of endothelial NO to relieve the vasodilatory response to acetylcholine and insulin, and restored the expression of Nox4 and pIRS-1-ser307 in the aorta endothelium of high-fat diet (HFD)-fed rats following an injection of streptozocin (STZ). CONCLUSION: These results suggested that argirein could improve endothelial insulin resistance which was attributed to inhibiting Nox4-dependent redox signaling in RAECs. These studies thus revealed the novel effect of argirein to prevent the vascular complication in T2DM. PMID- 29709707 TI - Consequences of mutations and inborn errors of selenoprotein biosynthesis and functions. AB - In its 200 years of history, selenium has been defined first as a toxic element and finally as a micronutrient. Selenium is incorporated into selenoproteins as selenocysteine (Sec), the 21st proteinogenic amino acid codified by a stop codon. Specific biosynthetic factors recode UGA stop codon as Sec. The significance of selenoproteins in human health is manifested through the identification of patients with inborn errors in selenoproteins or their biosynthetic factors. Selenoprotein N-related myopathy was the first disease identified due to mutations in a selenoprotein gene. Mutations in GPX4 were linked to Sedaghatian disease, characterized by bone and brain anomalies and cardiorespiratory failure. Mutations in TXNRD2 produced familial glucocorticoid deficiency (FGD) and dilated cardiomyopathy (DCM). Genetic generalized epilepsy was associated with mutations in TXNRD1 gene. Mutations in biosynthetic factors as SEPSECS, SECISBP2 and even tRNA[Ser]Sec, have been also related to diseases. Thus, SEPSECS mutations produce a neurodegenerative disease called now pontocerebellar hypoplasia type 2D (PCH2D). SECISBP2 syndrome, caused by SECISBP2 mutations, is a multifactorial disease affecting mainly thyroid metabolism, bone, inner ear and muscle. Similar symptoms were reproduced in a patient carrying a mutation in tRNA[Ser]Sec gene, TRU-TCA1-1. This review describes human genetic disorders caused by selenoprotein deficiency. Human phenotypes will be compared with mouse models to explain the pathologic mechanisms of lack of selenoproteins. PMID- 29709705 TI - Aging attenuates redox adaptive homeostasis and proteostasis in female mice exposed to traffic-derived nanoparticles ('vehicular smog'). AB - Environmental toxicants are catalysts for protein damage, aggregation, and the aging process. Fortunately, evolution selected adaptive homeostasis as a system to mitigate such damage by expanding the normal capacity to cope with toxic stresses. Little is known about the subcellular degradative responses to proteins oxidatively damaged by air pollution. To better understand the impact of environmental toxicants upon the adaptive homeostatic response, female C57BL/6 mice were exposed for 10 weeks to filtered air or reaerosolized vehicular-derived nano-scale particulate matter (nPM), at which point tissues from young (6 month) and middle-aged (21 month) mice were studied. We found significant increases of proteolytic capacity in lung, liver, and heart. Up to two-fold increases were seen in the 20S Proteasome, the Immunoproteasome, the mitochondrial Lon protease, and NF-E2-related factor 2 (Nrf2), a major transcriptional factor for these and other stress-responsive genes. The responses were equivalent in all organs, despite the indirect input of inhaled particles to heart and liver which are downstream of lung. To our knowledge, this is the first exploration of proteostatic responses to oxidative damage by air pollution. Although, middle aged mice had higher basal levels, their Nrf2-responsive-genes exhibited no response to nanoparticulate exposure. We also found a parallel age-associated rise in the Nrf2 transcriptional inhibitors, Bach1 and c-Myc which appear to attenuate adaptive responses in older mammals, possibly explaining the 'age ceiling effect.' This report extends prior findings in male mice by demonstrating the involvement of proteolytic responses to traffic-related air pollution in lung, liver, and heart of female mice, with an age-dependent loss of adaptive homeostasis. PMID- 29709708 TI - Specific occlusal scheme for partially edentulous patients with TMD signs preliminary report. AB - BACKGROUND: The purpose of this study was to ascertain a specific occlusal scheme to reduce temporomandibular disorder signs and symptoms in the therapy of partially edentulous patients with removable partial acrylic dentures. METHODOLOGY: Thirty-four partially edentulous patients who had unilateral free end saddle in the mandible along with a history of TMD signs and symptoms were prosthodontically treated, fitting them with new removable acrylic partial dentures (NRAPD) for their lower jaws. The new and specific occlusal scheme was established with tendencies to restrict mandibular functional movements partly; this proved somewhat awkward, but had the benefit of allowing continued unrestricted occlusal contacts in grinding and functional movements. RDC-TMD clinical examinations and answers to questionnaires were provided for the old dentures, and nine weeks after delivery of NRAPD. RESULTS: After the NRAPD treatment, the patients' painful symptoms were reduced and their mandibular movements were corrected. Statistically significant changes were obtained for the opening pattern (Pearson Chi2=18.609; P=0001), the maximum unassisted opening (F=3.507; P=0.052), the maximum assisted opening (F=4.299; P=0.042), and the corrected position of midline (F=5.893; P=0.018) before and after the NRAPD treatment. Additionally, significant changes were seen for questions on changes in facial pain to ability to work (Pearson Chi2=26.921; P=0.00), jaws click or pop when they open, close, or chew (Pearson Chi2=6.227; P=0.013), jaws make a grating or grinding noise when they open, close, or chew (Pearson Chi2=9.273; P=0.002), and bites feel unusual (Pearson Chi2=13.170; P=0.000). Characteristic pain intensity (F=19.311; P=0.000), points for disability score (F=9.830; P=0.003), disability points (F=10.208; P=0.002), and chronic pain grade (F=7.961; P=0.006) were significantly different in terms of the effects of the NRAPD therapy. CONCLUSION: Specific occlusal scheme in NPARD promoted improvement in the therapy. PMID- 29709709 TI - Tissue-selective alteration of ethanolamine plasmalogen metabolism in dedifferentiated colon mucosa. AB - Human colon lipid analysis by imaging mass spectrometry (IMS) demonstrates that the lipid fingerprint is highly sensitive to a cell's pathophysiological state. Along the colon crypt axis, and concomitant to the differentiation process, certain lipid species tightly linked to signaling (phosphatidylinositols and arachidonic acid (AA)-containing diacylglycerophospholipids), change following a rather simple mathematical expression. We extend here our observations to ethanolamine plasmalogens (PlsEtn), a unique type of glycerophospholipid presenting a vinyl ether linkage at sn-1 position. PlsEtn distribution was studied in healthy, adenomatous, and carcinomatous colon mucosa sections by IMS. In epithelium, 75% of PlsEtn changed in a highly regular manner along the crypt axis, in clear contrast with diacyl species (67% of which remained constant). Consistently, AA-containing PlsEtn species were more abundant at the base, where stem cells reside, and decreased while ascending the crypt. In turn, mono /diunsaturated species experienced the opposite change. These gradients were accompanied by a gradual expression of ether lipid synthesis enzymes. In lamina propria, 90% of stromal PlsEtn remained unchanged despite the high content of AA and the gradient in AA-containing diacylglycerophospholipids. Finally, both lipid and protein gradients were severely affected in polyps and carcinoma. These results link PlsEtn species regulation to cell differentiation for the first time and confirm that diacyl and ether species are differently regulated. Furthermore, they reaffirm the observations on cell lipid fingerprint image sensitivity to predict cell pathophysiological status, reinforcing the translational impact both lipidome and IMS might have in clinical research. PMID- 29709710 TI - Are coresidence and nursing homes substitutes? Evidence from Medicaid spend-down provisions. AB - This paper measures the extent to which the price of nursing home care affects a potential substitute living arrangement: coresidence with adult children. Exploiting variation in state Medicaid income "spend-down" provisions over time, I find that living in a state with a spend-down provision decreases the prevalence of coresidence with adult children by 1-4 percentage points for single elderly individuals, with a corresponding increase in the use of nursing home care. These findings suggest that changes in Medicaid eligibility for long-term care benefits could have large impacts on living arrangements, care utilization patterns, and Medicaid expenditures. PMID- 29709711 TI - Compound heterozygous variants of the COG6 gene in a Chinese patient with deficiency of subunit 6 of the conserved oligomeric Golgi complex (COG6-CDG). AB - COG6-CDG is a rare autosomal recessive disease of congenital disorders of glycosylation (CDG) caused by deficiency of subunit 6 of the conserved oligomeric Golgi complex (COG6), which is characterized by growth retardation, developmental disability, microcephaly, liver and gastrointestinal disease, recurrent infections and hypohidrosis/hyperthermia. Only eight mutations causing COG6 deficiencies have been described since the first report in 2010. Here, we report the first Chinese patient with COG6-CDG. Utilizing targeted next generation sequencing and Sanger sequencing, we detected compound heterozygous variants (c.1A > G, p.? and c.388C > T, p.(Gln 130*)) of the COG6 gene, both of which were pathogenic. Our study therefore extended the genotype-phenotype relationship of the COG6 gene. PMID- 29709712 TI - Underdiagnoses resulting from variant misinterpretation: Time for systematic reanalysis of whole exome data? AB - BACKGROUND: Clinical whole exome sequencing (WES) yields a diagnosis in approximately 30% of patients evaluated for presumed genetic disorders. For unsolved cases, periodic reanalysis is usually predicated on the availability of improved bioinformatics tools or new gene discoveries. METHODS: Exome data reanalysis was independently performed on unsolved cases that had underwent trio analysis by an external service provider. The retrieved exome data was reannotated using wANNOVAR and reanalysed following standard filtering criteria. RESULTS: Independent reanalysis led to the identification of a disease-causing variation in two families segregating predominantly a neurological phenotype. As the causative genes were relatively well established at the time the WES referral was made, misinterpretation of the functional impact of the variant and/or underappreciation of the gene's associated phenotype are the most probable causes of the discrepancy in reporting. CONCLUSION: Non-diagnostic clinical exome resulting from variant misinterpretation is probably under appreciated. These results emphasise the relevance of implement a policy for the reanalysis of high throughput sequencing data, especially in a clinical context given the implications. PMID- 29709713 TI - Differential retention of pollen grains on clothing and the effectiveness of laboratory retrieval methods in forensic settings. AB - Forensic palynology has been important in criminal investigation since the 1950s and often provides evidence that is vital in identifying suspects and securing convictions. However, for such evidence to be used appropriately, it is necessary to understand the factors affecting taphonomic variability (i.e. the variability in the fate of pollen grains before they are found during forensic examination). Here, we test the relative amount of pollen retained on clothing after a period of simulated light or heavy wear based on pollen and fabric characteristics. We also test the efficiency of forensic laboratory protocols for retrieving pollen from fabrics for analysis. There was no statistically significant difference in retention of fresh or dried pollen on any fabric type. There was a substantial difference in pollen retention according to wear intensity, with considerably more pollen being retained after light wear than after heavy wear. Pollen from insect-pollinated species was retained at higher concentrations than pollen from wind-pollinated species. This pattern was consistent regardless of wear intensity but pollination type explained more of the variability in pollen retention after light wear. Fabric type was significantly related to pollen retention, but interacted strongly with plant species such that patterns were both complex and highly species-specific. The efficiency of removing pollen with the standard washing protocol differed substantially according to plant species, fabric type, and the interaction between these factors. The average efficiency was 67.7% but this ranged from 21% to 93%, demonstrating that previous assumptions on the reliability of the technique providing a representative sample for forensic use should be reviewed. This paper highlights the importance of understanding pollen and fabric characteristics when creating a pollen profile in criminal investigations and to ensure that evidence used in testimony is accurate and robust. PMID- 29709714 TI - Molecular analyses in the diagnosis and prediction of prognosis in non-GIST soft tissue sarcomas: A systematic review and meta-analysis. AB - BACKGROUND: The molecular pathogenesis of many forms of soft tissue sarcomas (STS) have been rigorously characterized in the medical literature, which may be particularly important for the diagnosis and prediction of prognosis in STS. METHODS: Electronic databases (2005 to October 2016) were searched. Gastrointestinal stromal tumor and pediatric sarcomas were excluded. The eligible individual study's risk of bias and the quality of aggregate evidence were assessed. Meta-analyses were performed. RESULTS: Of 6674 identified articles, 70 were eligible and analyzed, covering 13 types of STS. Meta-analyses showed that the test of detecting MDM2 amplification by fluorescence in situ hybridization was accurate in differentiating atypical lipomatous tumor/well-differentiated liposarcoma/dedifferentiated liposarcoma from benign tumors (N = 971; sensitivity = 95%, 95% confidence interval [CI] 89-98; specificity = 100%, CI 89-100) or from other STS (N = 347; sensitivity = 99%, CI 72-100; specificity = 90%, CI 78-95); that the test of detecting SS18-SSX fusion by reverse transcription polymerase chain reaction (PCR) was accurate in differentiating synovial sarcoma from other STS (N = 532; sensitivity = 93%, CI 85-96; specificity = 99%, CI 96-100). The presence of a CTNNB1 S45F mutation detected by PCR was a risk factor for decreased recurrence-free survival in desmoid tumors (N = 418; hazard ratio from 3.50 [CI 1.51-8.14] to 6.20 [CI 2.24-17.15]). CONCLUSIONS: Sarcomas are rare cancers whose molecular pathogenesis is becoming increasingly understood. The current evidence demonstrates that molecular analyses are useful in the diagnosis and prediction of prognosis in some STS. PMID- 29709715 TI - Automatic liver vessel segmentation using 3D region growing and hybrid active contour model. AB - This paper proposes a new automatic method for liver vessel segmentation by exploiting intensity and shape constraints of 3D vessels. The core of the proposed method is to apply two different strategies: 3D region growing facilitated by bi-Gaussian filter for thin vessel segmentation, and hybrid active contour model combined with K-means clustering for thick vessel segmentation. They are then integrated to generate final segmentation results. The proposed method is validated on abdominal computed tomography angiography (CTA) images, and obtains an average accuracy, sensitivity, specificity, Dice, Jaccard, and RMSD of 98.2%, 68.3%, 99.2%, 73.0%, 66.1%, and 2.56 mm, respectively. Experimental results show that our method is capable of segmenting complex liver vessels with more continuous and complete thin vessel details, and outperforms several existing 3D vessel segmentation algorithms. PMID- 29709716 TI - Eliminating artifacts in single-grid phase-contrast x-ray imaging for improving image quality. AB - In this study, we propose a modification to a single-grid phase-contrast x-ray imaging (PCXI) system using a Fourier domain analysis technique to extract absorption, scattering, and differential phase-contrast images. The proposed modification is to rotate the x-ray grid in the image plane to achieve spectral separation between the desired information and the moire artifact, which is introduced by the superposition of the periodic image of the grid shadow and the periodic sampling by the detector. In addition, we performed some system optimization by adjusting distances between source, object, grid, and detector to further improve image quality. This optimization aimed to increase the spectral spacing between the primary spectrum (lower frequency) and the harmonics of the spectrum (higher frequency) used to extract the various image contrasts. The table-top setup used in the experiment consisted of a focused-linear grid with a 200-lines/inch strip density, a microfocus x-ray tube with a 55-MUm focal spot size, and a CMOS flat-panel detector with a 49.5-MUm pixel size. The x-ray grid was rotated at 27.8 degrees with respect to the detector and the sample was placed as close as possible to the x-ray tube. Our results indicated that the proposed method effectively eliminated the PCXI artifacts, thus improving image quality. PMID- 29709717 TI - Nonlinear analysis is the most suitable method to detect changes in heart autonomic control after exercise of different durations. AB - This study aimed to compare the heart autonomic control (HAC) response during two time-limited physical workouts using linear and nonlinear methods. A total of 20 healthy volunteers performed two physical workouts lasting 5 (P5) and 10 min (P10). In both workouts, volunteers performed as many repetitions as possible within the time limit of sets of 10 repetitions of four different exercises in the order of pull-ups, push-ups, barbell power clean, and barbell shoulder to overhead press. Barbell exercises were performed using a load of 50% of each volunteer's personal record for the jerk lift. Successive RR intervals were recorded 1 h before, immediately after, and 1 h after each workout. HAC parameters were obtained using linear (e.g., time- and frequency-domain analysis) and nonlinear [e.g., recurrence plot (RP)] methods. The number of repetitions was recorded during each workout, and the cadence (e.g., repetitions per minute) was calculated. All HAC parameters showed a significant main effect with time; however, only some RP parameters (e.g., recurrence rate (REC), maximal length of lines (Lmax), and Shannon entropy) were significantly greater in P5. The number of repetitions was significantly greater in P10, but the cadence was higher in P5. Both workouts induced an acute increase in sympathetic activity and vagal withdrawal; however, P5 exhibited greater REC and Lmax, indicating a greater vagal withdrawal. This could be explained by a more intense performance in P5, as evidenced by the greater cadence. In addition, only the RP parameters (a nonlinear approach) were more suitable to detect acute exercise-induced changes in HAC. PMID- 29709718 TI - Commonly available activity tracker apps and wearables as a mental health outcome indicator: A prospective observational cohort study among young adults with psychological distress. AB - BACKGROUND: Monitoring is integral to adequately recognise and track mental health indicators of symptoms and functioning. Early identification of warning signs from digital footprints could facilitate adaptive and dynamic just in-time monitoring and care for individuals with common mental disorders. METHODS: Self report data on mental health and lifestyle behaviour from 120 male and female Australian young adults experiencing psychological distress were collected online. API software was used to download participant's daily activity duration measurements over eight months from linked commercial activity tracker apps and wearables in real time. An independent samples t-test was conducted to compare the differences in daily durations of recorded physical activity between wearable devises and smartphone apps. Entropy techniques using R interpol package were used to analyse volatility in daily activity duration. RESULTS: DASS-21 depression, stress and anxiety sub-scale scores indicated the study sample on average, had a moderate level of psychological distress. Daily activity duration was significantly greater from wearable devices when compared with smartphone apps (t-test = 25.4, p < 0.001). Entropy indices were not related with any of the DASS-21 measures. However, significant correlation between DASS-21 anxiety subscale scores and entropy of those with over 45 days measurements (r = 0.58, p = 0.02) was observed. LIMITATIONS: The observational nature of this study prohibits causal inference. As a convenience sample was used, the results may lack generalisability to the wider population. CONCLUSIONS: Continuous monitoring using commercial apps and wearables as a resource to help clinicians augment clinical care for common mental disorders appears viable. PMID- 29709719 TI - Cerebral processing of facial emotions in bipolar I and II disorders: An event related potential study. AB - BACKGROUND: Behavioral results have shown that bipolar disorder patients have impaired recognition of facial emotions, but the detailed information processing of facial emotions in patients with bipolar I (BD I) and II (BD II) disorders remain unknown. METHODS: We tested the cerebral event-related potentials to the static facial expressions of Neutral, Happiness, Anger and Sadness in 39 adult patients with BD I, 22 BD II, and 54 healthy volunteers. Participants' affective states were measured with the Mood Disorder Questionnaire, the Hypomania Checklist-32, and the Plutchik-van Praag Depression Inventory. RESULTS: Over processed right occipitotemporal cortex during N1 time window to Neutral and Happiness, and during P3b window to Sadness were found in BD I; prolonged N1 latencies to Neutral and Happiness, declined P3b amplitude to Sadness, negative correlation between P3b latency to Sadness and depression, and attenuated superior frontal activity during P3b window to Sadness were found in BD II; and the right-side dominance during facial emotion processing were found in both BD I and BD II. LIMITATIONS: We didn't record the personality traits or medication used in patients, nor included other facial emotions such as fear and disgust. CONCLUSIONS: When responding to facial emotions, both BD I and BD II showed a right-side processing dominance; BD I displayed enhanced processing in the right occipitotemporal cortex during structural encoding and categorical processing of facial emotions; while BD II displayed generalized impairments, less involvement of superior frontal cortex to negative emotions, and reduced ability to process negative emotions which was associated with depression. PMID- 29709720 TI - Outcome of patients with psychogenic nonepileptic seizures with limited resources: A longitudinal study. AB - PURPOSE: The aim of the current study was to investigate the long-term outcome of patients with psychogenic nonepileptic seizures (PNES) and factors potentially associated with their outcome in Iran. METHODS: We investigated all patients with PNES admitted to the epilepsy monitoring unit at the Shiraz Comprehensive Epilepsy Center from 2008 through 2013. Patients included in this study had a confirmed diagnosis of PNES. In a phone call interview to the patients in December 2017, we obtained the following information: seizure outcome (seizure free during the past 12 months or not), history of receiving any psychotherapy after confirming their diagnosis in the past, and number of psychotherapy sessions the patient had received. RESULTS: Eighty-six patients (54 females and 32 males) met the inclusion criteria. Seventy-four (86%) patients did not receive appropriate psychotherapy. Forty-seven (54.7%) patients were seizure-free during the past 12 months. Age at onset (P = 0.02), education (P = 0.01), and taking psychiatric drugs (P = 0.007) were associated with this outcome. CONCLUSIONS: Resources to treat patients with PNES are limited in Iran; however, more than half of the patients became free of seizures. Lower education, comorbid psychiatric problems, and a later age at the onset of seizures may affect the seizure outcome in patients with PNES. Well-designed multi-center cross-cultural long-term studies should address factors associated with outcome in patients with PNES, considering that seizure frequency should not be the only outcome measure. PMID- 29709721 TI - Dental age estimation using four Demirjian's, Chaillet's and Willems' methods in Kosovar children. AB - BACKGROUND: Tooth formation was recognized as useful body system to assess maturity and predict age. Tooth mineralization is much less affected by the endocrine and different nutritional status than bone mineralization, and teeth formation provides a more reliable indication of chronological age. Demirjian et al. in 1973 presented a scoring system and method for dental age estimation on a sample of French-Canadian children. Chaillet et al. and Willems et al. modified original Demirjian method. This study aimed to evaluate the accuracy of four Demirjian's, Chaillet and Willems methods for age estimation in the children of Kosovo. MATERIALS AND METHODS: The cross-sectional study was based on the evaluation of the sample of 1022 orthopantomograms (OPTs) of healthy Kosovar children, aged between 5 and 14 years. OPTs were taken from the Radiology unit of University Dentistry Clinical Center of Kosova, as part of random clinical treatment. We tested the accuracy of four methods based on seven mandibular teeth, Demirjian from 1973 (Dem73) and 1976 (Dem76), Chaillet from 2005 (Chaillet) and Willems from 2001 (Willems) and two Demirjian's methods based on different sets of four teeth (Dem76PM1 and Dem76IN2). RESULTS: For most tested methods, we found statistically significant differences between the chronological age (CA) and dental age (DA) (p < 0.05). In males, the most accurate method were those using four teeth, Dem76IN2 (0.03 years) following by Dem76PM1 (-0.05 years), following those using seven teeth, Willems (-0.14 years), Chaillet (-0.24 years) and Dem73 (0.43 years). In females, dental age was the most accurate for the Willems method (-0.24 years) following Chaillet (-0.35 years), Dem76 (0.43 years) and Dem73 (0.55 years), while Dem76PM1 and Dem76IN2 overestimated by 0.45 years and 0.46 years, respectively. The mean absolute difference between DA and CA were between 0.61 years for the Willems, to 0.78 years for the Dem73 in males, and 0.64 years for the Willems to 0.75 years for the Dem76IN2 in females. CONCLUSION: The Willems method was the most accurate for estimating a dental age if all seven mandibular teeth are available for analysis, and we found the similar accuracy of Dem76PM1 and Dem76IN2 methods. Therefore, we may encourage their use for age estimation on the Kosovar children. PMID- 29709722 TI - Transitioning from level surface to stairs in children with and without Down syndrome: Locomotor adjustments during stair ascent. AB - BACKGROUND: Children with Down syndrome (DS) often show underdeveloped motor ability and adaptation. Stair ascent is a common task to examine locomotor function and external ankle load is often used to perturb the stability of a system and observe the emergence of new patterns. RESEARCH QUESTION: How do stair height and external ankle load affect locomotor adjustments in 5-to-11-year-old children with typical development (TD) and with DS during stair ascent? METHODS: Fourteen children with DS and 14 age- and sex-matched children with TD participated in this study. They walked along a 5-m walkway and ascended 3-step staircases of different heights (low, moderate, and high) with or without ankle load. A 3D motion capture system was used for data collection. Dependent variables included stance time and toe-to-stair distance before stair ascent, and vertical toe clearance and horizontal toe velocity during stair ascent. Mixed ANOVAs with repeated measures were conducted for statistical analysis. RESULTS: The DS group presented a longer stance time and a shorter toe-to-stair distance than the TD group before stair ascent. External ankle load affected, to a greater extent, the DS group than the TD group in stance time and toe-to-stair distance. During stair ascent, while the TD group generally maintained toe clearance and decreased horizontal toe velocity with the increase of stair height, the DS group decreased toe clearance and maintained horizontal toe velocity. Particularly, the DS group displayed a greater toe clearance than the TD group in the LS condition but a smaller toe clearance in the HS condition. In addition, external ankle load increased toe clearance and decreased horizontal toe velocity in both groups. SIGNIFICANCE: Children with DS display underdeveloped locomotor adjustments during stair ascent. External ankle load appears to help the DS group regulate toe clearance and horizontal toe velocity for different stair heights. PMID- 29709723 TI - The effect of functional bracing on the arthrokinematics of anterior cruciate ligament injured knees during lunge exercise. AB - BACKGROUND: Functional knee braces are extensively used for partially and completely torn anterior cruciate ligament (ACL) patients and those who have undergone ACL graft reconstruction, in order to support the healing ACL, improve the joint's functional stability, and restore the normal joint kinematics. RESEARCH QUESTION: Does wearing braces alter the arthrokinematics of the ACL deficient knees during lung exercise? METHODS: For ten male unilateral ACL deficient subjects, 3D knee models were reconstructed from CT images, acquired in rest position. Sagittal plane fluoroscopy was then performed throughout a complete cycle of lunge in braced and non-braced conditions. The 3D kinematics of the knees were obtained using a 2D-3D registration method in which six anatomical bony landmarks on the fluoroscopic images were matched with those on the 3D models. RESULTS: No significant difference was found between the tibial anterior posterior translations and abduction-adduction motions of the braced and non braced knees. A significant decrease, however, was observed after bracing in the tibial internal rotation at 45 degrees flexion during eccentric (non-braced: 5.9 degrees (+/-6.7 degrees ) vs. braced: 2.4 degrees (+/-7.0 degrees ); p = 0.045), and at 30 degrees flexion during concentric (non-braced: 2.3 degrees (+/-6.9 degrees ) vs. braced: -1.6 degrees (+/-8.1 degrees ); p = 0.001) phases of the lunge cycle. SIGNIFICANCE: The immediate effect of knee bracing is limited to controlling the tibial rotation of the ACL deficient individuals during the lunge exercise. Hence, care should be taken in prescribing the lunge exercise for rehabilitation of ACL injured patients with high anterior-posterior knee instability, even when wearing knee braces. PMID- 29709724 TI - Despite the donor's age, human adipose-derived stem cells enhance the maturation and development rates of porcine oocytes in a co-culture system. AB - The paracrine interactions between cumulus-oocyte complexes (COCs) and follicular somatic cells during in vitro maturation (IVM) were investigated. To optimize IVM conditions, many studies have applied exogenous growth factors and cell feeding/co-culture systems using various cell types to replicate the natural follicular microenvironment during IVM. A potential candidate as cell feeders is adipose-derived stem cells (ASCs) which secrete high levels of growth factors that have roles in oocyte maturation. However, the cell donor's age should be considered because biological aging also occurs in stem cells. In the present study, the contributions of ASCs from young and old donors on an IVM co-culture system were analyzed by comparing the oocyte maturation rate, cumulus expansion index, preimplantation development after parthenogenetic activation (PA), and expression of growth factor signaling genes related to oocyte maturation in ASCs, oocytes and cumulus cells under the same culture conditions. Our study demonstrated that the confluence, viability and cell size of ASCs between young and old donors were not significantly different and only the Fibroblast Growth Factor 2 (FGF2) signaling gene showed higher expression in ASCs from young donors. The oocyte maturation rate in the young donor group (87.8 +/- 1.2%) was significantly higher than in the old donor (81.1 +/- 2.1%) and control (73.8 +/- 2.1%) groups. After IVM, most gene expression levels in oocytes and cumulus cells in the co-culture groups were higher than in the control but the apoptotic ratios were reduced. The blastocyst development rates were not different between the young and old donor groups (23.9 +/- 1.3% and 20.7 +/- 0.8%, respectively) but the percentages were higher in both groups compared to the control group (16.4 +/ 1.2%). A similar pattern was also found for blastocyst total cell numbers in that the young donor group (87.5 +/- 5.2 cells) was not different than the old donor group (77.5 +/- 3.4 cells) but both groups exhibited higher number of cells compared with the control group (57.9 +/- 6.0 cells, p < .05). Our study strongly suggested that the co-culture IVM system with ASCs greatly improved the maturation and development rates of porcine oocytes. Moreover, ASCs from young donors more effectively supported porcine oocyte maturation than those from old donors although this difference did not translate into improved developmental competence. PMID- 29709725 TI - Secrecy: Unshared Realities. AB - Much of the social psychological literature considers how people engage with their social worlds. Shared reality theory proposes that people do so for one of two reasons: to connect with others, and to obtain others' perspectives and insights to understand the world around them. Although the literature on shared reality has focused on the ways in which people develop and maintain shared realities with those around them as well as the consequences of achieving such shared realities, we propose that a critical future avenue for this work is to explore what happens when people choose to not share realities. People do not always seek to share their experiences with close others, but sometimes keep secrets. We propose that while shared reality theory is founded upon why and how people connect with others, it can also make predictions for the mechanisms of secrecy and how it relates to well-being. Secrecy could thwart both relational motives and epistemic motives with harm to well-being by making people feel less connected to others, and by preventing people from obtaining others' insights and perspectives with respect to the secret. New theoretical insights would be gained from integrating research on shared reality with research on secrecy, and future work should investigate the intersection of the two. PMID- 29709726 TI - RNA sequencing reveals significant miRNAs in Atypical endometrial hyperplasia. AB - PURPOSE: In this paper, we aimed to investigate the miRNAs that played a regulatory role in the development of atypical endometrial hyperplasia (AEH). METHODS: RNA sequencing was performed for endometrial tissues from 3 AEH patients and 3 endometrial normal hyperplasia patients. RNA sequencing data were processed and differentially expressed (DE) miRNAs were identified between AEH and controls. The target genes for DE miRNAs were identified and mapped to the protein-protein interaction (PPI) network. The miRNA related functions were predicted and miRNA-disease gene network was constructed. RESULTS: Total 18 DE miRNAs were overlapped in three sample groups, among which hsa-miR-577, hsa-miR 182-5p and hsa-miR-183-5p were top three miRNAs that targeting largest number of genes. Function analysis showed that the 18 overlapped miRNAs mainly related with cancer and signaling transduction related pathways. PPI network showed that total 12 genes were among top 20 genes based on three network topological features including BCL2, UMPS, MAPK13, PRKCB, CREB1, IGF1, SP1, SMAD3, IGF1R, NOTCH2, WNT5A, TK2. Top 10 miRNAs in miRNA-disease gene network were identified such as hsa-miR-577 (degree = 17), hsa-miR-182-5p (degree = 16) and hsa-miR-3609 (degree = 13). CONCLUSION: hsa-miR-577 and hsa-miR-182-5p may play regulatory role in AEH through AMPK signal pathway and Wnt signaling pathway. PMID- 29709727 TI - Clinical outcomes of a vitrified donor oocyte programme: A single UK centre experience. AB - OBJECTIVE: To assess the survival rate of vitrified oocytes used in an egg recipient programme and compare the clinical outcomes of pregnancy and live-birth rates per warmed oocyte with fresh autologous oocytes. The differences in the obstetrical outcomes between the two groups were also studied. DESIGN: A prospective case control study from a single in-vitro fertilisaton (IVF) Centre in UK SETTING: Centre of Reproductive and Genetic Health (CRGH), London POPULATION: Vitrified oocytes from egg donors and autologous fresh oocytes from patients attending for an IVF cycle METHODS: The study group consisted of 1490 vitrified oocytes, which were obtained from 145 egg donors who underwent a stimulation cycle at CRGH Centre. The control group included 145 age-matched women who underwent intra cytoplasmic sperm injection (ICSI) treatment with their own oocytes (n = 1528). The clinical outcomes clinical pregnancy rates (CPR) and live-birth rates (LBR) and obstetrical outcomes (gestational age and weight at delivery) were compared between the two groups. Statistical analysis of the summary data and logistic regression analysis was performed using statistical packages (SPSS Version 23 and Stata 2015). The percentages of all parameters in the cases and control groups were compared by Fisher's exact test. A statistical significance level of 5% was adopted throughout the study. MAIN OUTCOME MEASURES: Survival rate per thawed oocyte, clinical pregnancy rate and live-birth rate per embryo transfer was compared to the autologous oocyte group RESULTS: The survival rate of vitrified oocytes was 73.6% (95% CI: 71.3-75.8%). The clinical pregnancy rate (per embryo transfer) using vitrified oocytes was found to be 51.8% compared to 59.3% in the control group. The live birth rate per embryo transfer in the vitrified oocyte group was 46% (95% CI 37.4-54.7%) compared to 57.1% (95% CI 48.5 68.5%) in the control group. The live-birth rate per thawed oocyte was found to be 4.2%. The gestational ages of the fetus at delivery in both the groups were comparable 39.0 (95% CI 32.7-41.9%) and 39.1 (95% CI 25.6-42.0) (p = 0.38). There was no statistically significant difference in the birth weight between the study and the control group 3100 g (750-4337) and 3232 g (1616-4500) respectively (p = 0.28). CONCLUSIONS: This is the first study reporting on the efficacy of a vitrified donor oocyte programme from within the UK. There were no significant differences in the obstetrical outcomes between vitrified donor oocytes and autologous oocytes. The above data will be encouraging for women who are undertaking egg freezing for medical and or social reasons. PMID- 29709728 TI - Patterns of disease progression in patients with local and metastatic breast cancer as evaluated by whole-body magnetic resonance imaging. AB - BACKGROUND: Patterns of progressive disease (PD) in patients with local and metastatic sites of breast cancer are poorly described. Whole-body magnetic resonance imaging (WB-MRI) identifies PD earlier than CT. METHODS: Thirty-one patients receiving first-line systemic anti-cancer therapy (SACT) were studied. Data were obtained from original WB-MRI reports. RESULTS: First PD was reported at metastatic sites only in 77.4%, and at local and metastatic sites concurrently in 22.6%. None had first PD only in local disease, or clinical PD before PD on WB MRI. CONCLUSION: Clinical evidence of SACT benefit in local disease may give false reassurance about disease at metastatic sites. PMID- 29709730 TI - Understanding the psychological precursors of young drivers' willingness to speed and text while driving. AB - This study applied the Prototype Willingness Model (PWM) to investigate the factors that may predict young drivers' (non-intentional) willingness to text while driving, text while stopped, and engage in high and low levels of speeding. In addition, the study sought to assess whether general optimism bias would predict young drivers' willingness to text and speed over and above the PWM. Licenced drivers (N = 183) aged 17-25 years (M = 19.84, SD = 2.30) in Queensland, Australia completed an online survey. Hierarchical multiple regressions revealed that the PWM was effective in explaining the variance in willingness to perform all four illegal driving behaviours. Particularly, young drivers who possessed favourable attitudes and a positive prototype perception towards these behaviours were more willing to engage in texting and speeding. In contrast to the study's predictions, optimistically biased beliefs decreased young drivers' willingness to text while stopped and engage in high and low levels of speeding. The findings of the study may help inform policy and educational campaigns to better target risky driving behaviours by considering the influence of attitudes, prototypes and the non-intentional pathway that may lead to engagement in texting while driving and stopped and engagement in high and low levels of speeding. PMID- 29709729 TI - Smoking and FGFR2 rs2981582 variant independently modulate male breast cancer survival: A population-based study in Tuscany, Italy. AB - AIM: Male breast cancer (MBC) is a rare disease and recommendations for its clinical management are often extrapolated from those for female breast cancer, even if breast cancer (BC) has different characteristics in the two sexes. The purpose of this study was to assess the influence of several individual characteristics including clinico-pathological, lifestyle and genetic factors on overall survival (OS) of a relatively large and well characterized population based series of 166 MBCs enrolled in Tuscany. METHODS: We genotyped MBC cases at BRCA1/2 genes and at 9 candidate BC susceptibility SNPs. Kaplan-Meier method and multivariate Cox regression, adjusted for several individual characteristics were used. To reduce a possible selection bias related to the interval between diagnosis and enrolment of MBC cases into the study, we used the date of blood donation as the date of the start of observation for survival analysis. RESULTS: Only smoking habits had a significant effect on OS at 10 years (for current smokers, HR: 3.34; 95% CI 1.45-7.68; p = 0.004), while lymph node status fell short of reaching statistical significance (for pN positive, HR: 2.07; 95% CI 0.93-4.55; p = 0.07). In the same multivariate analysis we found a significantly higher OS in cases with FGFR2 rs2981582 variant in the dominant transmission model (HR: 0.29; 95% CI: 0.13-0.62; p = 0.028). A sensitivity analysis with left truncation showed similar results. CONCLUSIONS: Our results may contribute to shed light on factors influencing MBC survival suggesting an important role for cigarette smoking and FGFR2 rs2981582 variant, and provide clues for better patient management. PMID- 29709731 TI - Bidirectional juxtacrine ephrinB2/Ephs signaling promotes angiogenesis of ECs and maintains self-renewal of MSCs. AB - Co-transplantation of endothelial cells (ECs) and mesenchymal stem cells (MSCs) is an important strategy for repairing complex and large bone defects. However, the ways in which ECs and MSCs interact remain to be fully clarified. We found that forward ephrinB2/Ephs signaling from hBMSCs to hUVECs promoted the tube formation of hUVECs by activating the PI3K/AKT/mTOR pathway. Reverse ephrinB2/Ephs signaling from hUVECs to hBMSCs promoted the proliferation and maintenance of hBMSCs self-renewal via upregulation of OCT4, SOX2, and YAP1. Subcutaneous co-transplantation of ECs and MSCs in nude mice confirmed that forward ephrinB2/Ephs signaling could increase the cross-sectional area of blood vessels in the transplanted area, and reverse ephrinB2/Ephs signaling could maintain the self-renewal of transplanted hBMSCs in vivo. Based on these results, ephrinB2/Ephs bidirectional juxtacrine regulation between ECs and MSCs plays a pivotal role in improving the healing of bone defects by promoting angiogenesis and achieving a sufficient number of MSCs. PMID- 29709732 TI - Treatment initiation strategies for syringe exchange referrals to methadone maintenance: A randomized clinical trial. AB - This randomized clinical trial evaluated the efficacy of three treatment initiation strategies for improving retention to methadone maintenance for opioid dependent individuals referred from a syringe exchange program (SEP). New admissions (n = 212) were randomly assigned to one of three 3-month initiation strategies: 1) Low Threshold (LTI), 2) Voucher Reinforcement (VRI), or 3) Standard Care (SCI). LTI was modeled on interim methadone maintenance to transition SEP admissions to the structure of medication-assisted treatment while maximizing exposure to methadone pharmacotherapy. VRI used monetary incentives to reinforce adherence to pharmacotherapy and adaptive counseling. SCI participants received standard methadone dosing and adaptive counseling. All participants were stabilized on methadone pharmacotherapy with a target dose of 80 mg. Following the initiation phase, participants in each condition received standard adaptive counseling from months 4-6. Results showed that most participants failed to achieve the target methadone dose. While no condition differences were observed in retention rates over the 3-month and 6-month observation periods, participants across conditions exhibited reductions in objective and self-report measures of drug use. Results support the benefits of referring syringe exchangers to methadone maintenance, and demonstrate the challenge of retaining these individuals in treatment. PMID- 29709733 TI - A prospective study of newly incident cannabis use and cannabis risk perceptions: Results from the United States Monitoring the Future study, 1976-2013. AB - BACKGROUND: A prevailing epidemiological theory about drug use occurrence among secondary school students is that trends in perceived risk of drug-related harms can drive use. If so, cannabis risk perceptions during one school year should predict newly incident cannabis use in the same school the following year. We aimed to study trends in incidence and epidemiological clustering of cannabis use among United States (US) 12th-graders, and a novel prediction that incidence in school-year 't' is influenced by school-specific cannabis risk perceptions (CRP) of 12th-graders a year prior at 't-1'. METHODS: US schools sampled each year from 1976 to 2013 (~130 schools per year) yielded an annual nationally representative sample of ~15-16,000 12th-graders with questionnaire assessments. Analyses involved Alternating Logistic Regressions (ALR) to study trends in school-level clustering and slopes that estimate the degree to which CRP levels at 't-1' might predict newly incident cannabis use at 't'. RESULTS: School-level CRP levels at 't-1' predict newly incident cannabis use in the next year's 12th-grade class. For each unit CRP increment, the next year's class shows tangibly reduced incidence of starting to use cannabis (overall odds ratio, OR = 0.10; 95% CI: 0.03, 0.33). Within-school clustering of newly incident cannabis smoking also can be seen (e.g., pairwise odds ratio, PWOR = 1.11; 95% CI: 1.07, 1.15). CONCLUSIONS: Programmatic manipulation of perceived risk in one year's senior class via public health/school alliances might dampen the subsequent risk of newly incident cannabis use in the next year's class. PMID- 29709734 TI - Self-management assessment in multiple chronic conditions: A narrative review of literature. AB - OBJECTIVES: Effective self-management in individuals with multiple chronic conditions is necessary to optimize health outcomes. Self-management in multiple chronic conditions involves an iterative process prioritizing multiple changing needs/conditions. However, self-management in multiple chronic conditions has been assessed with instruments designed to assess self-management of a single chronic illness. The instruments may not address the complexity of self management in multiple chronic conditions. Thus, this review aimed to examine how self-management has been operationalized in the context of multiple chronic conditions. DESIGN: A narrative review method was used. DATA SOURCE: The online databases, Pubmed, CINAHL Plus, and PsycInfo, were searched. The search was conducted of the database from January 2006 through November 2017. REVIEW METHODS: Peer-reviewed research articles which operationalized self-management in adults with at least two or more chronic illnesses were selected for review. Two reviewers read full text of selected articles and extracted data regarding operational definitions of self-management and instruments used to assess self management. Operational definitions were categorized to conceptualize how self management has been assessed. RESULTS: A total of seven peer-reviewed research articles were selected for inclusion. This review found that self-management has been assessed through prerequisites of self-management and behaviors involved in self-management. Prerequisites of self-management included attitude, self efficacy, perceived ability, and knowledge. Behaviors included an individual's engagement in self-management such as health-related behaviors, health service use, and medication adherence. CONCLUSIONS: This review revealed that current literature does not operationalize self-management in multiple chronic conditions as a process, indicating incomplete assessments of self-management. To obtain a more comprehensive understanding of self-management in multiple chronic conditions, future studies should consider self-management as an iterative process in addition to prerequisites for self-management and behaviors. Such studies will inform the development of patient-centered self-management interventions for individuals with multiple chronic conditions. PMID- 29709735 TI - Safeness and Utility of Concomitant Intraoperative Monitoring with Intraoperative Magnetic Resonance Imaging in Children: A Pilot Study. AB - BACKGROUND: High-field intraoperative magnetic resonance imaging (MRI) has become increasingly available in neurosurgery centers. There is little experience with combined intraoperative MRI and intraoperative neurophysiologic monitoring (IONM). We report the first series, to our knowledge, of pediatric patients undergoing brain tumor surgery with 3T intraoperative MRI and IONM. METHODS: This pilot study included all consecutive children operated on for brain tumors between October 2013 and April 2016 in whom concomitant intraoperative MRI and somatosensory evoked potentials and motor evoked potentials were used. Neuromonitoring findings and related complications of all cases were retrospectively analyzed. RESULTS: During a 30-month period, 17 children (mean age 8.4 years; 3 girls) undergoing surgery met the study criteria. During intraoperative MRI, 483 IONM needles were left in place. Of these needles, 119 were located on the scalp, 94 were located above the chest, and 270 were located below the chest. Two complications with skin burns (first degree) were observed. In all patients, neuromonitoring was still reliable after MRI. In 1 case, a threshold increase for motor evoked potential stimulation (20 mA) was necessary after intraoperative MRI; in 2 cases, a reduction of 50% of the somatosensory evoked potential amplitude at the end of the surgery was observed compared with the values obtained before intraoperative MRI. CONCLUSIONS: The combination of intraoperative MRI and IONM can be safely used in pediatric patients. IONM data acquisition after intraoperative MRI was feasible and remained reliable. PMID- 29709736 TI - Wireless Phone Use and Risk of Adult Glioma: Evidence from a Meta-Analysis. AB - BACKGROUND: Wireless phone use has been increasing rapidly and is associated with the risk of glioma. Many studies have been conducted on this association without reaching agreement. The aim of this meta-analysis was to determine the possible association between wireless phone use and risk of adult glioma. METHODS: Eligible studies were identified by searching PubMed and Embase up to July 2017. Random-effects or fixed-effects model was used to combine the results depending on the heterogeneity of the analysis. Publication bias was evaluated using Begg's funnel plot and Egger's regression asymmetry test. Subgroup analysis was performed to evaluate possible influence of these variables. RESULTS: Ten studies on the association of wireless phone use and risk of glioma were included. The combined odds ratio of adult gliomas associated with ever use of wireless phones was 1.03 (95% confidence interval [CI], 0.92-1.16) with high heterogeneity (I2 = 54.2%, P = 0.013). In subgroup analyses, no significant association was found between tumor location in the temporal lobe and adult glioma risk, with odds ratios of 1.26 (95% CI, 0.87-1.84), 0.93 (95% CI, 0.69-1.24), and 1.61 (95% CI, 0.78-3.33). A significant association with risk of glioma was found in long-term users (>=10 years) with odds ratio of 1.33 (95% CI, 1.05-1.67). CONCLUSIONS: Ever use of wireless phones was not significantly associated with risk of adult glioma, but there could be increased risk in long-term users. PMID- 29709737 TI - A Rare Phantom Tentorial Lesion. AB - Spontaneous regression is a rare phenomenon. Here, we report a case of a 28-year old woman with a tentorial space-occupying lesion, which entirely disappeared 40 days after the onset of her symptoms. The patient did not have any relapse during 1-year follow-up. To our knowledge, the mechanism of this phenomenon is still unclear, and this case may provide a valuable addition to the current literature. PMID- 29709738 TI - Meta-Analysis of Predictive Significance of the Black Hole Sign for Hematoma Expansion in Intracerebral Hemorrhage. AB - OBJECTIVE: Hematoma expansion is related to unfavorable prognosis in intracerebral hemorrhage (ICH). The black hole sign is a novel marker on non contrast computed tomography for predicting hematoma expansion. However, its predictive values are different in previous studies. Thus, this meta-analysis was conducted to evaluate the predictive significance of the black hole sign for hematoma expansion in ICH. METHODS: A systematic literature search was performed. Original researches on the association between the black hole sign and hematoma expansion in ICH were included. Sensitivity and specificity were pooled to assess the predictive accuracy. Summary receiver operating characteristics curve (SROC) was developed. Deeks' funnel plot asymmetry test was used to assess the publication bias. RESULTS: Five studies with a total of 1495 patients were included in this study. The pooled sensitivity and specificity of the black hole sign for predicting hematoma expansion were 0.30 and 0.91, respectively. The area under the curve was 0.78 in SROC curve. There was no significant publication bias. CONCLUSIONS: This meta-analysis shows that the black hole sign is a helpful imaging marker for predicting hematoma expansion in ICH. Although the black hole sign has a relatively low sensitivity, its specificity is relatively high. PMID- 29709739 TI - Number of Fractured Calvarial Bones Predicts Outcome in Traumatic Brain Injury Patients After Early Craniotomy. AB - BACKGROUND: Prognostic markers are important for neurosurgeons to evaluate the indications for aggressive surgical management. The purpose of this study was to investigate whether the number of fractured calvarial bones could predict the outcome in patients with traumatic brain injury (TBI) after early craniotomy. METHODS: TBI patients who underwent early craniotomy were reviewed. The number of fractured calvarial bones was recorded by referring to preoperative computed tomographic (CT) images. Accordingly, patients were assigned to no calvarial fracture group, single calvarial fracture group, and multiple calvarial fractures group. Good outcome was defined as Glasgow Outcome Scale scores of 4 and 5 at discharge. Logistic regression analyses were used to assess the effect of calvarial fracture on outcome. A receiver operating characteristic curve was generated for the final model. RESULTS: In all, a total of 141 patients were enrolled. Patients with no calvarial fracture had a significantly lower rate of good outcome (12.5%) than did those with a single calvarial fracture (62.2%, P < 0.001) and those with multiple calvarial fractures (48.6%, P = 0.005). Binary logistic regression showed that the number of fractured calvarial bones was an independent imaging marker for predicting outcome (P = 0.003) after adjustment for age, Glasgow Coma Scale score on admission, and decompressive craniectomy. The area under the curve of the final model was 0.863. CONCLUSIONS: The number of fractured calvarial bones is an independent predictor of outcome in TBI patients after early craniotomy. No calvarial facture is associated with poor outcome in these patients. PMID- 29709740 TI - Retrospective Analysis of the Clinical Characteristics, Therapeutic Aspects, and Prognostic Factors of 18 Cases of Childhood Pineoblastoma. AB - BACKGROUND: Pineoblastoma is a rare malignant tumor of the pineal gland, which is more common in children. METHODS: We retrospectively reviewed 18 cases of pineoblastoma in children (10 girls), including general, clinical, and therapeutic information, and factors affecting prognosis. RESULTS: The median age of the children was 51.7 months (range, 19-156 months). Presenting symptoms included vomiting (64.70%), headache (47.06%), weak or unsteady walking (35.29%), and nausea (29.41%). Rarer symptoms (1 patient each) included limb rigidity, inability to speak, double vision, fever, and Parinaud syndrome. Five and 13 children, respectively, underwent subtotal and gross total resection; 5 and 13 children received adjuvant craniospinal irradiation therapy and chemotherapy. Two children received both craniospinal irradiation and chemotherapy. The 5-year overall survival of the patients was 27.8% (5/18). The survival rate of children older than 4 years (66.7%) was significantly higher than that of younger children (8.3%). The 5-year overall survival rate of boys (50.7%) was higher than that of girls (10.0%); that of children who underwent gross total resection (30.8%) was higher than that of children who underwent subtotal resection (20.0%); and that of children treated with adjuvant craniospinal irradiation (50.7%) was higher than that of those not given craniospinal irradiation (10.0%). However, in each of these 3 comparisons the differences were not significant. CONCLUSION: Pineoblastoma is rare but often fatal, especially in children younger than 4 years. Survival rates tend to be higher in boys, children undergoing gross total resection (rather than subtotal), and those given craniospinal irradiation. PMID- 29709741 TI - Long-Term Follow-Up of Patients with Metastatic Epidural Spinal Cord Compression from Solid Tumors Submitted for Surgery Followed by Radiation Therapy. AB - OBJECTIVE: To evaluate the outcome of patients with epidural spinal cord compression from different solid tumors treated with a combined approach, surgery plus radiotherapy (RT), with a follow-up longer than 10 years. METHODS: Ninety seven patients treated between 2002 and 2009 were included. Surgical treatment was performed in patients with good performance status, limited metastatic disease, life expectancy longer than 3 months, and progressive neurologic deficit and/or intractable pain. RT was performed delivering a median total dose of 30 Gy in 10 fractions. Clinical outcome was evaluated using the modified visual analog scale for pain, the Frankel scale for neurologic deficit, and magnetic resonance imaging before treatment, after treatment, and every 3 months thereafter. RESULTS: Palliative decompression was performed in 27% of patients, tumor curettage (debulking) was performed in 51%, and total vertebrectomy was performed in 22%, followed by RT in 78% of cases. Pain remission was obtained in 98% of patients, and recovery of neurologic function was obtained in 51%. The median follow-up time was 135 months (range, 96-209 months). The 5- and 10-year local control rates were 82.8% and 82.8%, respectively. The median and 5- and 10-year progression-free survival rates were 12 months, 16.9%, and 11.3%, respectively; the median and 5- and 10-year overall survival rates were 18 months, 21.3%, and 12%, respectively. On univariate and multivariate analysis, factors recorded as conditioning survival were the performance status and the presence of other metastases at the time of vertebral treatment (P < 0.01). CONCLUSIONS: Our update confirmed that surgery plus RT is a safe and feasible treatment with limited morbidity. In selected patients with favorable prognostic factors, the combined treatment may significantly impact on survival. PMID- 29709742 TI - Preoperative Assessment of Pathologic Subtypes of Meningioma and Solitary Fibrous Tumor/Hemangiopericytoma Using Dynamic Computed Tomography: A Clinical Research Study. AB - BACKGROUND: Solitary fibrous tumors (SFTs)/hemangiopericytomas (HPCs) are highly vascularized tumors well known for malignant, invasive, and highly vascular features. To date, several studies have reported the preoperative imaging findings of SFTs/HPCs. In this study, computed tomography (CT) tumor values acquired from dynamic CT scan were selected to determine the tumor pathology of highly vascular tumors, such as SFTs/HPCs. METHODS: We conducted a retrospective study on patients with pathologically diagnosed meningiomas and SFTs/HPCs who had undergone a dynamic contrast CT scan. We assessed and compared the CT values of these tumors according to the pathology. RESULTS: From a total of 34 patients, 30 patients with meningiomas and 4 patients with HPCs were included. The mean CT values of SFTs/HPCs and angiomatous meningioma were statistically significantly higher than those of the other meningioma subtypes (P = 0.003). We also performed receiver operating characteristic curve analyses to detect an appropriate cutoff point for the CT value to differentiate tumor pathology, and the calculated threshold was 161 Hounsfield units (HU) (sensitivity, 100%; specificity, 75%; area under the curve, 0.87; 95%, CI 0.75-0.99). CONCLUSIONS: This study showed that obtaining a CT value is useful in determining highly vascular tumor pathology preoperatively. When considering neurosurgical extra-axial tumor removal, and when the CT value of tumors is >161 HU, then highly vascular tumors such as SFTs/HPCs or angiomatous meningiomas are likely, and this should be considered prior to surgical intervention and for risk assessment. PMID- 29709743 TI - Case Report of Worth Syndrome and Chiari I Malformation: Unusual Association and Surgical Treatment. AB - BACKGROUND: Worth syndrome or autosomal dominant endosteal hyperostosis (ADEH) is an extremely rare genetic disease involving increased bone density. To the author's knowledge, this is the second case report of a family with neurologic involvement associated with this condition along with its surgical treatment. The most effective treatment for clinically significant neurologic symptoms in this scenario is currently unknown, and there is sparse experience on surgical treatment for this condition reported in the literature. Therefore we aim to make a contribution to the identification of a standard and consistently successful surgical management. CASE DESCRIPTION: Two patients, mother (Patient 1) and daughter (Patient 2), were diagnosed with Worth syndrome. Both presented with the typical facial characteristics described for ADEH. Interestingly, Patient 1 presented the novel mutation in the LRP5 gene that is associated with different conditions involving increased bone density. Although neurologic symptoms are infrequent in ADEH, both referred chronic headache, nausea, and vomiting. Neuroimaging showed an increased cranial bone density and Chiari I malformation. The patients underwent a midline suboccipital craniectomy with excision of the posterior arch of C1 and duroplasty. However, due to a symptomatic recurrence 5 years after surgery, Patient 1 was reoperated on. We extended the craniectomy and also carried out a C2 laminectomy. CONCLUSION: After surgical interventions, patients' neurologic symptoms were successfully resolved. This report shows that posterior fossa decompression including duroplasty may be a valid treatment option in case of neurologic involvement. PMID- 29709744 TI - Radiographic Fusion Grade Does Not Impact Health-Related Quality of Life in the Absence of Instrumentation Failure for Patients Undergoing Posterior Instrumented Fusion for Adult Spinal Deformity. AB - BACKGROUND: Pseudarthrosis and rod fracture (RF) remain significant concerns after fusion for adult spinal deformity (ASD). Although a radiographic system of fusion grade has been proposed, the correlation between fusion grade and health related quality of life measures (HRQoL) is not known. METHODS: In a retrospective review of a prospectively collected clinical database, patients that underwent >=5-level posterior instrumented arthrodesis for ASD were evaluated. Fusion grade was determined on plain films using the Lenke criteria. Patients were grouped as 1) complete fusion (grade I or II at all levels), 2) incomplete fusion (grade 3 or 4 at any level), 3) rod fracture without revision (RF), and 4) rod fracture with revision (RFR). Outcome measures were the Oswestry Disability Index, Medical Outcomes Study 36-Item Short-Form Health Survey Physical and Mental Component Summaries, Scoliosis Research Society-22r total, and Lumbar Stiffness and Disability Index. RESULTS: There were 205 (85%) patients who achieved the minimum 2-year follow-up and were included. Complete fusion was achieved in 115 patients (56.1%), 55% patients (26.8%) had incomplete fusion, and 35% patients (17.1%) had RF. Of the 35 patients with RF, 19 (17.1%; 19/205) underwent revision while 16 (7.8%; 16/205) had RF without revision. HRQoL measures were significantly worse in the RFR group, whereas no significant differences were found between groups 1, 2, and 3. CONCLUSIONS: Radiographic fusion grade after ASD surgery did not significantly impact HRQoL in the absence of RF. RFR was associated with significantly worse clinical outcomes. Fusion grade may be less predictive of clinical outcomes than the occurrence of RF. PMID- 29709745 TI - Intraoperative and Postoperative Segmental Lordosis Mismatch: Analysis of 3 Fusion Techniques. AB - OBJECTIVE: This study aimed to quantify the discrepancy between intraoperative and postoperative segmental lordosis in patients operated on for lumbar degenerative diseases, with 3 different fixation techniques: open posterolateral instrumentation alone (PLI) or in association with lumbar interbody cages (transforaminal lumbar interbody fusion [TLIF] or extreme lateral interbody fusion [XLIF]). METHODS: We retrospectively reviewed all adult patients affected by single-segment degenerative spondylotic disease who underwent PLI alone or percutaneous posterolateral instrumentation (pPLI) in association with TLIF or XLIF between April 2015 and December 2017 at our institution. Group I included patients who underwent PLI with transpedicular screws and rods, interlaminar bilateral decompression, and posterolateral fusion with autologous bone chips. Group II included patients treated with pPLI + TLIF using a complete unilateral arthrectomy. Group III included patients operated on with minimally invasive retroperitoneal pPLI + XLIF. RESULTS: No major complications were reported. The mean segmental loss of lordosis values ranged from 9.17% to 12.28% in Group I, from 6.31%-9.43% in Group II, and from 3.05%-4.71% in Group III. The statistical analysis revealed that pPLI + XLIF maintained a higher segmental lordosis than PLI and pPLI +TLIF in each operated segment (P < 0.05). pPLI + TLIF was more effective than PLI in reducing the loss of lordosis at L4-L5 and at L5-S1 (P < 0.05) but not at L3-L4 (P = 0.12). CONCLUSIONS: The documented mismatch between the preoperative and postoperative lumbar lordosis might affect the clinical outcome. Its relevance depends on the surgical technique used at the single level. PMID- 29709746 TI - Can K-Line Predict the Clinical Outcome of Anterior Controllable Antedisplacement and Fusion Surgery for Cervical Myelopathy Caused by Multisegmental Ossification of the Posterior Longitudinal Ligament? AB - OBJECTIVE: To analyze the correlation between the K-line-based classification of patients with ossification of the posterior longitudinal ligament (OPLL) and their outcome after anterior controllable antedisplacement and fusion (ACAF) surgery. METHODS: A series of 24 patients with multisegmental OPLL were enrolled. All patients underwent ACAF surgery. First, the patients were classified into 2 groups according to their K-line classification. Then, we separated the patients into subgroups according to their OPLL thickness. The Japanese Orthopaedic Association scores before and 6 months after surgery were studied, and the recovery rate (RR) was calculated. The preoperative and postoperative radiologic parameters were also investigated. RESULTS: Clinical and radiographic assessments showed no significant correlation between the K-line-based classification of patients with OPLL and their outcome of ACAF surgery (P > 0.05). When the OPLL was <=6 mm thick, K-line-based classification groups had a similar change of occupation ratio and RR (P > 0.05). However, when the OPLL was >6 mm thick, the mean RR was 61.8% +/- 14.0% in the K-line (+) group and 78.3% +/- 9.7% in the K line (-) group (P < 0.05), and the mean was 16.0% +/- 4.2% in the K-line (+) group and 28.0% +/- 7.1% in the K-line (-) group (P < 0.05). CONCLUSIONS: This study shows that K-line can predict the clinical outcome of ACAF surgery for multisegmental OPLL in a different way from posterior decompression surgery. When the OPLL was thin, the outcome was satisfactory and there was no correlation with K-line-based classification of patients with OPLL. When the OPLL was >6 mm thick, the K-line (-) group patients had a better outcome than did K-line (+) group patients. PMID- 29709747 TI - Factors Related to the Clinical Outcomes of Surgery for Extra-Temporal Lobe Epilepsy: Long-Term Follow-Up Results. AB - BACKGROUND: Compared with temporal lobe epilepsy, the surgical outcome in extra temporal lobe epilepsy (ETLE) is unsatisfactory. However, advances in diagnostic and surgical techniques have led to improved prognosis. This study investigated the outcomes and prognostic factors of ETLE based on long-term follow-up of patients undergoing surgical treatment for ETLE at a single institution. METHODS: We retrospectively reviewed medical records of 58 patients with refractory ETLE who underwent resection between 2003 and 2015. Clinical outcome was evaluated by Engel classification. Parameters analyzed as prognostic factors were clarity of the lesion on magnetic resonance imaging, completeness of resection, and histologic diagnoses. RESULTS: Of 58 patients (62.1%), 36 had a seizure-free state (Engel I) after surgery over a mean follow-up of 58 months. The most common pathology was cortical dysplasia (27 patients; 46.5%). In univariate analysis, only complete resection was a statistically significant prognostic factor (P = 0.001). CONCLUSIONS: Surgery is effective treatment for ETLE (79.4%, Engel I and II). Complete resection predicts more satisfactory results in patients with intractable ETLE. PMID- 29709748 TI - Correlation Between the Residual Tumor Volume, Extent of Tumor Resection, and O6 Methylguanine DNA Methyltransferase Status in Patients with Glioblastoma. AB - BACKGROUND: There is limited information on O6-methylguanine DNA methyltransferase (MGMT) status, extent of surgical resection, and its impact on overall outcomes in patients with glioblastoma (GBM). METHODS: After institutional review board approval, 233 newly diagnosed patients with GBM with known MGMT status (2009-2015) were included in our analysis. Clinical, imaging, and follow-up data were collected from the database. Overall survival (OS) and progression-free survival (PFS) were the primary and secondary end points, respectively. RESULTS: Of patients, 51.9% were younger than 65 years and 44.2% were noted to have promoter methylation of MGMT. Median residual tumor volume was 1.1 cm3 and extent of complete resection of enhancing tumor on imaging was 96%. Estimated median OS and PFS were 10.9 months and 5.4 months, respectively. MGMT status was an independent predictor of PFS (hazard ratio [HR], 0.52; P = 0.005) but only marginally associated with OS (P = 0.059). In MGMT methylated patients, extent of resection (>=86%) and good performance status (Karnofsky Performance Status >=70) were independently associated with PFS and OS, respectively (PFS: HR, 0.21; P = 0.015; OS: HR, 0.05; P = 0.002). In MGMT promoter unmethylated patients, extent of resection (>=86%) was independently associated with OS (P = 0.039). Concurrent chemoradiotherapy was associated with OS/PFS irrespective of age and MGMT status. CONCLUSIONS: Greater extent of resection of enhancing tumor was associated with improved PFS in MGMT promoter methylated patients, OS regardless of MGMT status. Elderly patients with methylated MGMT promoter were found to have improved PFS whereas younger patients had improved OS with MGMT promoter methylated status. PMID- 29709749 TI - Concurrent Validity and Comparative Responsiveness of PROMIS-SF Versus Legacy Measures in the Cervical and Lumbar Spine Population: Longitudinal Analysis from Baseline to Postsurgery. AB - BACKGROUND: The aim of our study was to evaluate the change in Patient-Reported Outcome Measurement Information System (PROMIS) scores at baseline, 3 months, and 12 months postprocedure and correlate with legacy measures. METHODS: We analyzed patients in 3 cohorts: lumbar, cervical, and the pooled cohort from our database, 2014-2017. Outcome variables were PROMIS items of pain interference, emotional distress and physical function, EuroQol 5 dimensions, visual analog scale, Oswestry Disability Index/Neck Disability Index, back, leg/neck and arm pain scales, and Patient Satisfaction Index. RESULTS: Patients with lumbar and cervical diseases constituted 55.3% (n = 52) and 44.7% (n = 42) of patients, respectively. There was a significant change in median PROMIS pain interference (65.5 to 57.6), anxiety (56.3 to 48.4), depression (51.2 to 37.1), and physical function (37.2 to 42.6) at baseline and 3 months, respectively. Similarly, change in these scores from baseline to 12 months was significant (n = 48). Compared with change in median Neck Disability Index and Oswestry Disability Index from baseline to 12 months (24.0 to 10.0; P = 0.0004 and 19.0 to 10.0; P < 0.0001), change in median PROMIS physical function score in the same cohort was 38.7 to 45.4 (P = 0.0025) and 37.2 to 41.8 (P < 0.0001), respectively. There was significant correlation between PROMIS pain interference/physical function and the legacy measures at 3 months. CONCLUSIONS: PROMIS items correlated with legacy measures at baseline and postsurgery. Patients undergoing spine surgery improved in their patient-reported outcomes from baseline to 3 months after surgery and the gain were maintained at 12 months. PMID- 29709751 TI - Safety of Running Two Rooms: A Systematic Review and Meta-Analysis of Overlapping Neurosurgical Procedures. AB - OBJECTIVE: Overlapping surgery, a long-standing practice within academic neurosurgery centers nationwide, has recently come under scrutiny from the government and media as potentially harmful to patients. Therefore, the objective of this systematic review and meta-analysis is to determine the safety of overlapping neurosurgical procedures. METHODS: The authors performed a systematic review and meta-analysis in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A review of PubMed and Medline databases was undertaken with the search phrase "overlapping surgery AND neurosurgery AND outcomes." Data regarding patient demographics, type of neurosurgical procedure, outcomes, and complications were extracted from each study. The principle summary measure was odds ratio (OR) of the association of overlapping versus non-overlapping surgery with outcomes. RESULTS: The literature search yielded a total of 36 studies, of which 5 studies met inclusion criteria and were included in this study. These studies included a total of 25,764 patients undergoing neurosurgical procedures. Overlapping surgery was associated with an increased likelihood of being discharged home (OR, 1.32; 95% confidence interval [CI], 1.20-1.44; P < 0.001) and a reduced 30-day unexpected return to the operating room (OR, 0.79; 95% CI, 0.72-0.87; P < 0.001). Overlapping surgery did not significantly affect OR of length of surgery, 30-day mortality, or 30-day readmission. CONCLUSIONS: Overlapping neurosurgical procedures were not associated with worse patient outcomes. In addition, prospective studies are needed to assess the safety overlapping procedures. PMID- 29709750 TI - Reliability and Agreement of Different Spine Fracture Classification Systems: An Independent Intraobserver and Interobserver Study. AB - OBJECTIVE: Currently, no spinal classification system has achieved universal acceptance. Therefore, it is important to choose a reliable classification within clinical practice. The objective of this study was to determine and compare the intraobserver and interobserver agreement of the Load Sharing Classification (LSC), the Thoracolumbar Injury Classification System (TLICS), and the AOSpine Thoracolumbar Spine Injury Classification System. METHODS: In this web-based intraobserver and interobserver study (www.spine.hostei.com), plain radiographs and computed tomographic scans of traumatic thoracolumbar fractures (T12-L2) were evaluated. By use of a questionnaire, fractures were classified according to the LSC, the TLICS, and the AOSpine classification. Data were analyzed with SPSS (Version 21, 76 Chicago, Illinois, USA). Intraobserver and interobserver agreement was determined by the Cohen kappa. Statistical significance was defined as P < 0.05. RESULTS: Data from 91 patients were classified twice by 7 board certified spine surgeons. The intraobserver and interobserver reliability considering the LSC total score was noted as fair (intraobserver/interobserver reliability: kappa = 0.26/0.22). Considering the resulting TLICS total score, a moderate intraobserver agreement (kappa = 0.41) was noted, whereas the interobserver results presented only fair reliability (kappa = 0.23). In contrast to the LSC and the TLICS, the AOSpine classification showed substantial agreement considering the fracture type (A;B;C) (intraobserver/interobserver reliability: kappa = 0.71/0.61) and moderate agreement considering the fracture subtype (e.g., A0;A1;...;B1;...) (intraobserver/interobserver reliability: kappa = 0.57/0.48). CONCLUSION: In conclusion, the reliability of the AOSpine fracture classification is superior to the TLICS and the LSC. Therefore, this classification system could best be applied within clinical practice. PMID- 29709752 TI - Hemodynamic Stress, Inflammation, and Intracranial Aneurysm Development and Rupture: A Systematic Review. AB - BACKGROUND: There seems to be a pathogenetic link between hemodynamics and inflammatory arterial wall alteration leading to the development and rupture of intracranial aneurysms (IAs). Noninvasive assessment of the inflammatory status of the aneurysm wall may guide the management of unruptured IAs by identifying reliable markers for increased rupture risk. METHODS: We conducted a qualitative systematic review following the ENTREQ (Enhancing Transparency in Reporting the Synthesis of Qualitative Research) framework. A search was made in MEDLINE/PubMed, Embase, and CINAHL from database inception to October 2017 using the terms "intracranial aneurysm" and "cerebral aneurysm" linked with the following key words: inflammation, hemodynamic(s), remodeling, macrophages, neutrophils, lymphocytes, complement system, vascular smooth muscle cells, mast cells, cytokines, and inflammatory biomarkers. RESULTS: One hundred and twenty three articles were included in the review. CONCLUSIONS: In this systematic review, we explore the relationship between hemodynamic stress, inflammation, vascular remodeling, and the formation and rupture of IAs to develop novel strategies to predict the individual risk of aneurysmal rupture. PMID- 29709753 TI - Endoscopic Endonasal Approach to the Anteromedial Temporal Fossa and Mobilization of the Lateral Wall of the Cavernous Sinus Through the Inferior Orbital Fissure and V1-V2 Corridor: An Anatomic Study and Clinical Considerations. AB - OBJECTIVE: The aim of this study was to identify key anatomic landmarks useful in gaining access to the anteromedial temporal region via the corridor formed by the inferior orbital fissure (IOF), the ophthalmic branch of the trigeminal nerve (V1), and the maxillary branch of the trigeminal nerve (V2) via an endoscopic endonasal approach (EEA). METHODS: An anatomic dissection of 6 cadaver heads was performed to confirm the feasibility and applicability of an EEA for accessing the anteromedial temporal region. RESULTS: After middle turbinectomy, the lateral recess of the sphenoid sinus was opened, the orbital apex was exposed, and the posterior wall of the maxillary sinus was removed, in sequence. The IOF and the pterygopalatine fossa (PPF) were then identified. After opening the foramen rotundum (FR) and removing the bony structure between the FR, V2 was transposed downward. The orbital muscle of Muller was removed. The PPF was mobilized downward exposing the greater wing of the sphenoid bone (GWS). The GWS between V1 and V2 was drilled, therefore exposing the temporal dura. With blunt dissection, the medial temporal dura was peeled away from the cavernous sinus to increase access to the anteromedial temporal region. CONCLUSIONS: The anteromedial temporal fossa was exposed by drilling the V1-V2 triangle corridor via an EEA. Endoscopic endonasal exposure of the anteromedial temporal fossa is feasible and requires limited endonasal work. This approach may be considered as an alternate surgical corridor to the temporomesial lobe that offers the advantages of a direct route with less temporal lobe retraction. PMID- 29709754 TI - Incidentally Found Double Aortic Arch While Treating Posterior Inferior Cerebellar Artery Aneurysm: Conversion from Femoral to Radial Artery Access. AB - BACKGROUND: Asymptomatic double aortic arches are a unique occurrence. CASE DESCRIPTION: An incidental finding of a double aortic arch in an elderly male was discovered during workup of a transient ischemic attack. The following case presentation details an effective treatment approach in cerebrovascular stenting in a patient with variant aortic arch anatomy. The initial diagnostic cerebral angiogram was performed via transfemoral approach and was quite challenging. CONCLUSIONS: Faced with challenging anatomy, the radial artery approach is a viable option when navigating into the cerebrovascular anatomy for stenting when proximal variants such as a double aortic arch are identified. PMID- 29709755 TI - The Outcomes of Pituitary Apoplexy with Conservative Treatment: Experiences at a Single Institution. AB - OBJECTIVE: Pituitary apoplexy is an unpredictable complication caused by hemorrhage or infarction in a pituitary adenoma. We retrospectively analyzed the radiologic and clinical outcomes of patients with conservatively managed pituitary apoplexy. METHODS: A total of 32 patients who had undergone conservative treatment with high-dose corticosteroid replacement were enrolled in this study. This cohort study consisted of 20 male and 12 female patients. The median patient age was 60 years. Five patients had a previously diagnosed pituitary tumor, and one third of the patients had a history of hypertension. RESULTS: The median follow-up duration was 50 months. The median tumor volumes at the initial and final assessments were 2.75 cm3 (range, 0.32-10.7 cm3) and 0.64 cm3 (range, 0-8.74 cm3), respectively. Complete radiographic regression occurred in 9 of the 32 patients, partial regression occurred in 14 patients, and no change in size or progression occurred in 9 patients. Eighteen of the 32 patients had visual disturbances at the initial presentation; in this subgroup, 17 patients showed improvement over the course of the study. One patient had newly developed diplopia related to tumor progression. Nineteen of the 32 patients had >=1 hormonal deficiency at the initial assessment, 8 of whom recovered to normal endocrine status. Three patients developed a new hormonal deficiency during the follow-up, and 3 patients experienced tumor recurrence. CONCLUSIONS: This study showed the regression of tumors related to pituitary apoplexy, with favorable ophthalmologic and endocrinologic recovery. Conservative management should be considered in patients without severe or progressive neuro-ophthalmic deficits. PMID- 29709756 TI - Deep Brain Stimulation for Parkinson Disease in the Philippines: Outcomes of the Philippine Movement Disorder Surgery Center. AB - OBJECTIVE: Deep brain stimulation (DBS) is an established treatment modality for Parkinson disease (PD). The first DBS for PD in the Philippines was performed at the Philippine Movement Disorder Surgery Center in 2006. There are no Philippine data on DBS for PD. We aim to determine the motor improvement and reduction in medication dosage of all patients with PD who underwent DBS at the Philippine Movement Disorder Surgery Center. METHODS: This is a retrospective study of all patients with PD (n = 17) who underwent DBS from 2006 to 2016. The change in the Unified Parkinson's Disease Rating Scale (UPDRS) motor and levodopa equivalent dose were determined. RESULTS: There was a statistically significant reduction in the UPDRS motor in all patients off medication at 3 months (48.2%; P = 0.004), 1 year (47.3%; P = 0.026), 2 years (48.4%; P = 0.021), and 3 years (66.0%; P = 0.032) after DBS and on medication at 3 months (43.3%; P = 0.023), 6 months (24.7%; P = 0.053), and 1 year (38.1%; P = 0.033). A significant reduction in the dosage of PD medications was also seen until the second year of follow-up (52.3%; P < 0.001). Adverse events included an attempted suicide and a device-related infection. CONCLUSIONS: DBS for PD improves the UPDRS motor score in the off medication and on-medication state, with the maximal benefit seen at 3 years after surgery and reduces PD medication dosage by half. Although the benefit from DBS is undeniable, the high cost of the procedure precludes more patients from benefitting from it. There is a need for government support to expand access to DBS. PMID- 29709757 TI - Rapid Recovery of Spontaneous Spinal Epidural Hematoma without Surgical Treatment: Case Report and Literature Review. AB - BACKGROUND: Spontaneous spinal epidural hematoma (SSEH) is a relatively uncommon yet potentially disabling neurologic emergency. The classical presentation includes a severe acute attack, sometimes radiating pain at the back, interscapular, or neck areas, followed by neurologic deficits. The main treatment is surgical, and self-healing cases are rare. CASE DESCRIPTION: A 17-year-old female was admitted to the neurosurgery department with neck pain, myasthenia of the limbs, and difficulty moving. Mild neck pain had developed 1 week prior with no obvious predisposing causes. The patient had suddenly suffered severe neck pain during normal walking and developed rapid paralysis of her limbs. There was no recent history of trauma, infection, or drug administration. Magnetic resonance imaging performed 1 hour after the onset of limb paralysis demonstrated a large spinal epidural hematoma that extended from C4 to C6. However, 9 hours after the initial onset of severe neck pain, her symptoms completely ceased. Magnetic resonance imaging demonstrated that the SSEH had nearly dissipated. CONCLUSIONS: Most cases of SSEH with spontaneous resolution are located on the upper thoracic and cervical spine. Surgery is the standard of care for these patients but can occasionally be deferred if the patient demonstrates significant rapid improvement. PMID- 29709758 TI - When couples' hearts beat together: Synchrony in heart rate variability during conflict predicts heightened inflammation throughout the day. AB - Hostile conflict in marriage can increase risks for disease and mortality. Physiological synchrony between partners-e.g., the linkage between their autonomic fluctuations-appears to capture engagement, or an inability to disengage from an exchange, and thus may amplify the health risks of noxious interactions such as marital conflict. Prior work has not examined the unique health correlates of this physiological signature. To test associations between couples' heart rate variability (HRV) synchrony during conflict and inflammation, 43 married couples engaged in a marital problem discussion while wearing heart monitors and provided four blood samples; they repeated this protocol at a second visit. When couples' moment-to-moment HRV changes tracked more closely together during conflict, they had higher levels of three inflammatory markers (i.e., IL 6, stimulated TNF-alpha, and sVCAM-1) across the day. Stronger HRV synchrony during conflict also predicted greater negative affect reactivity. Synchrony varied within couples, and was related to situational factors rather than global relationship traits. These data highlight partners' HRV linkage during conflict as a novel social-biological pathway to inflammation-related disease. PMID- 29709760 TI - Assessing the influence of humic acids on the weathering of galena and its environmental implications. AB - Galena weathering often occurs in nature and releases metal ions during the process. Humic acid (HA), a critical particle of natural organic matter, binds metal ions, thus affecting metal transfer and transformation. In this work, an electrochemical method combined with spectroscopic techniques was adopted to investigate the interfacial processes involved in galena weathering under acidic and alkaline conditions, as well as in the presence of HA. The results show that the initial step of galena weathering involved the transformation Pb2+ and S degrees , regardless of whether the solution was acidic or alkaline. Under acidic conditions, S degrees and Pb2+ further transform into anglesite, and HA adsorbs on the galena surface, inhibiting the transformation of sulfur. HA and Pb (II) ions form bridging complexes. Under alkaline conditions without HA, the sulfur produced undergoes no transformation, whereas Pb2+ will transform into PbO. The presence of HA changes the galena weathering mechanism via ionization effect, and Pb2+ is ultimately converted into anglesite. Higher acidity in acidic conditions or higher alkalinity in alkaline conditions causes galena corrosion when the electrolyte does not contain HA. Conversely, higher pH always accelerates galena corrosion when the electrolyte contains HA, whether the electrolyte is acidic or alkaline. At the same acidity/alkalinity, increasing the concentration of HA inhibits galena weathering. Galena will release 134.7 g m-2.y-1 Pb2+ to solution at pH 2.5, and the amount decreases to 28.09 g m-2.y-1 in the presence of 1000 mg/L HA. This study provides an in situ electrochemical method for the assessment of galena weathering. PMID- 29709759 TI - Gentrification and binge drinking in California neighborhoods: It matters how long you've lived there. AB - BACKGROUND: Neighborhood context plays a role in binge drinking, a behavior with major health and economic costs. Gentrification, the influx of capital and residents of higher socioeconomic status into historically-disinvested neighborhoods, is a growing trend with the potential to place urban communities under social and financial pressure. Hypothesizing that these pressures and other community changes resulting from gentrification could be tied to excessive alcohol consumption, we examined the relationship between gentrification and binge drinking in California neighborhoods. METHODS: California census tracts were categorized as non-gentrifiable, stable (gentrifiable), or gentrifying from 2006 to 2015. Outcomes and covariates were obtained from the California Health Interview Survey using combined 2013-2015 data (n = 60,196). Survey-weighted logistic regression tested for associations between gentrification and any binge drinking in the prior 12 months. Additional models tested interactions between gentrification and other variables of interest, including housing tenure, federal poverty level, race/ethnicity, sex, and duration of neighborhood residence. RESULTS: A third of respondents reported past-year binge drinking. Controlling for demographic covariates, gentrification was not associated with binge drinking in the population overall (AOR = 1.13, 95% CI = 0.95-1.34), but was associated with binge drinking among those living in the neighborhood <5 years (AOR = 1.49, 95% CI 1.15-1.93). No association was seen among those living in their neighborhood >=5 years. CONCLUSIONS: For those newer to their neighborhood, gentrification is associated with binge drinking. Further understanding the relationship between gentrification and high-risk alcohol use is important for policy and public health interventions mitigating the impact of this process. PMID- 29709761 TI - Degradation of bisphenol A through transition metals activating persulfate process. AB - In this study, the process of transition metals (Fe2+, Fe0, Ni2O3) activating persulfate was attempted to degrade aqueous bisphonel A (BPA). Compared with thermal activation mode, significant degradation can be achieved at normal atmospheric temperature in transition metal activation mode. BPA removal in the transition metal-PS system can be divided into rapid phase (0-5 min) and slow phase (5-60 min). In rapid phase, 87.71% and 90.60% removal efficiencies were obtained in the Fe2+-PS and Ni2O3-PS systems, and the contaminant was almost completely oxidized after 60 min. There are many similarities between the Fe2+-PS and Fe0-PS systems, in particular the optimal removal efficiencies were achieved at n0(Fe2+):n0(PS) = 1:2 and n0(Fe0):n0(PS) = 1:2 rather than with maximum metal dosage. The Ni2O3 dosage had positive correlation with BPA removal rate while the degradation efficiency of the Fe2+-PS system could be promoted by keeping n0(sodium citrate):n0(Fe2+) below 1:1. Intermediate products of the Fe2+-PS system were analyzed by LC-MS and were predominantly phenol, p hydroxyacetophenone, benzoquinone and propanedioic acid, therefore a possible oxidation degradation pathway was speculated. PMID- 29709762 TI - Non-toxic properties of TiO2 and STiO2 nanocomposite PES ultrafiltration membranes for application in membrane-based environmental biotechnology. AB - In membrane bioreactor (MBR) technology, nanocomposite membrane has a great potential to improve the filtration performance and antifouling. However, antibacterial activity of nanoparticles (NPs) is a significant disadvantage which can be impacted to bacterial growth and microbial community in MBRs. The modified polyethersulfone (PES) ultrafiltration (UF) membranes in the study were prepared by using TiO2 NPs and TiO2 NPs functionalized with sulfonation (STiO2). The antibacterial effect of NPs and non-toxic properties of nanocomposite membranes were examined by using three different Gram-negative bacterial species isolated from a local full scale membrane bioreactor treating municipal wastewater (Escherichia coli, Pantoea agglomerans, and Pseudomonas graminis). Results are revealed that the TiO2 and STiO2 NPs have 60% of antibacterial activity based on disc diffusion, viability tests, and TEM analysis. However, the PES-TiO2 and PES STiO2 nanocomposite UF membranes showed significantly lower antibacterial activity (<95%, significance at p < 0.0001), indicating innocuous to bacterial growth. This study highlights that the PES-TiO2 and PES-STiO2 nanocomposite membrane is more sustainable than PES membrane and promising materials for MBRs, by taking advantage of non-toxic properties to bacterial growth. PMID- 29709764 TI - Episodic traces and statistical regularities: Paired associate learning in typical and dyslexic readers. AB - Learning visual-phonological associations is a key skill underlying successful reading acquisition. However, we are yet to understand the cognitive mechanisms that enable efficient learning in good readers, and those which are aberrant in individuals with developmental dyslexia. Here, we use a repeated cued-recall task to examine how typical and reading-impaired adults acquire novel associations between visual and phonological stimuli, incorporating a looking-at-nothing paradigm to probe implicit memory for target locations. Cued recall accuracy revealed that typical readers' recall of novel phonological associates was better than dyslexic readers' recall, and it also improved more with repetition. Eye fixation-contingent error analyses suggest that typical readers' greater improvement from repetition reflects their more robust encoding and/or retrieval of each instance in which a given pair was presented: whereas dyslexic readers tended to recall a phonological target better when fixating its most recent location, typical readers showed this pattern more strongly when the target location was consistent across multiple trials. Thus, typical readers' greater success in reading acquisition may derive from their better use of statistical contingencies to identify consistent stimulus features across multiple exposures. We discuss these findings in relation to the role of implicit memory in forming new visual-phonological associations as a foundational skill in reading, and areas of weakness in developmental dyslexia. PMID- 29709763 TI - A detailed structural study of cytotoxicity effect of ionic liquids on the leukemia rat cell line IPC-81 by three dimensional quantitative structure toxicity relationship. AB - In the present study, a very thorough and in-depth three-dimensional quantitative structure-toxicity relationship (3D-QSTR) analysis has been implemented to make a correlation between the structural information of the ionic liquids (ILs) and their cytotoxicity towards Leukemia rat cell line IPC-81, as one of the ILs' toxicological consequences. To do this, alignment free GRid-INdependent Descriptors (GRINDs), which were derived from molecular interaction fields (MIFs), were correlated to the cytotoxicity values by partial least squares (PLS) and support vector regression (SVR). Genetic algorithm (GA), as a powerful linear tool, was used to select the best and interpretative subset of variables for the predictive model building. The selected variables with the capability to screen the effective structural features, showed direct and inverse contribution to the cytotoxicity. In silico modeling can reduce the amount of cellular testing necessary by predicting the toxicological functions of the chemical structures. Acceptable predictions of both internal and external validation sets made it possible to develop the predictive models for a large set of 269 diverse ILs containing 9 cationic cores and 44 types of anions. The constructed 3D-QSTR models use simple and interpretable descriptors to provide an in-depth and mechanistic interpretation of structural characteristics. This helps provide a clear understanding of the cytotoxicity effects of the understudy ILs. The effects of the nature of the cations, anions, and substituents on the cytotoxicities were evaluated and discussed. PMID- 29709765 TI - Pointing perception is precise. AB - The spontaneity and ease with which we point understates the gesture's significance to understanding cognition. Onset of pointing in infancy predicts early word acquisition and signals a capacity for shared intentionality. Yet, notwithstanding its importance, there is little research on the perception of pointing and its referents. Here we show that perceptual acuity for discerning where another person is pointing is remarkably accurate. Thresholds, as low as 0.5 degrees of visual angle across an interpersonal distance of ~2 m, are modulated by the referent's location in space and the hand used to point and remain constant when the pointer's eyes are occluded from view and when 'embodiment' cues are enhanced or minimized. Pointing with the index finger not only directs attention toward a general region of space but the morphology of arm, hand and finger can be used to discern the location of the pointer's attention with precision. PMID- 29709766 TI - Nitrogen transformation of 41 organic compounds during SCWO: A study on TN degradation rate, N-containing species distribution and molecular characteristics. AB - Supercritical water oxidation (SCWO) of 41 N-containing compounds was examined under a stable temperature and pressure of 450 degrees C and 24 MPa, respectively, reaction time ranged from 0.5 to 6 min with 500% excess oxygen, resulted in the degradation rate constants of total organic carbon (kTOC) and total nitrogen (kTN) were 0.162-3.693 and 0.065-0.416 min-1, respectively. The N containing products were primary N2, ammonium and nitrate. As for amino-group compounds, the main product was ammonia, while for nitro-group compounds, nitrate was the predominant. In terms of diazo and N-heterocyclic group compounds, the main products generally were nitrate and ammonium, respectively. Interestingly, 2 , 3- and 4-nitroaniline, containing both of nitro and amino group, would directly decompose into N2. The reaction pathways of acid orange 74 was proposed based on Fukui indices, which generally included denitrification, ring-open and mineralization. Density functional theory (DFT) method was applied to calculate the quantum properties of the 41 N-containing compounds in order to further examine the relationship between TN removal and molecular structural characteristics. The correlation result showed that among all the 17 molecular characteristics, F(+)n, F(-)n, F(0)n, and EHOMO achieved high correlation coefficients. PMID- 29709767 TI - High psychosocial burden in relatives of malignant brain tumor patients. AB - OBJECTIVE: Not only tumor patients suffer enormously from their disease, also the caregivers are massively affected by the disease of their relatives. In this study, we investigate the psychological burden in caregivers of outpatient malignant brain tumor patients. PATIENTS AND METHODS: Fifty caregivers of patients with primary malignant brain tumors were included in our study. Study participants filled in a form with demographic details, a self-established questionnaire concerning general well-being and three established psychological questionnaires to assess anxiety, depression, stress and social support: The "Hospital Anxiety and Depression Scale" (HADS), the "Perceived Stress Scale" (PSS 10) and the "Social Support Questionnaire" (F-SozU). RESULTS: Caregivers of patients with primary malignant brain tumors showed in the HADS clinically relevant anxiety in 49% and depression in 20% of the cases. The stress level of the caregivers was increased (mean: 18 points) compared to the general population mean: 13 points), although they felt well supported by their social environment (mean: 4.25 points; general population 3.99 points). There was a significant positive correlation between anxiety and depression (p < 0.001). Female caregivers suffered significantly more from anxiety (p = 0.017) and stress (p = 0.012) than their male counterparts. No correlation was found between tumor grade, age of relatives and patients or the state of living together with the patient and anxiety or depression. CONCLUSIONS: Although the caregivers felt well supported by their social environment, stress, anxiety and depression are common phenomena in caregivers of patients with malignant brain tumors. Especially female ones have an increased risk for developing these comorbidities. PMID- 29709768 TI - Marital Conflict, Cognitive Emotion Regulation, Maladaptive Schema and Sexual Satisfaction in spouse abused and non- abused women in Iran: A comparative study. PMID- 29709769 TI - The future of psychiatry and the story of two worlds. PMID- 29709770 TI - Regulatory T cells increase after treatment with poly (ADP-ribose) polymerase-1 inhibitor in ischemic stroke patients. AB - BACKGROUND: Regulatory T cells (Tregs) are thought to play a modulatory role in immune responses and to improve outcomes after ischemic stroke. Thus, various strategies for increasing Tregs in animal models of ischemic stroke have yielded successful results. The aim of this study was to examine the potential effect of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitor on Treg proportion in stroke patients. METHODS: Peripheral blood samples were collected from 12 ischemic stroke patients (within 72 h of stroke onset) and 5 healthy control subjects. Flow cytometry analyses and quantitative reverse transcription polymerase chain reactions (qRT-PCR) were performed on peripheral blood mononuclear cells (PBMCs) before and after treating them with PARP-1 inhibitor (3-AB; JPI-289 1 MUm, JPI 289 10 MUm) for 24 h. RESULTS: Treg proportions were significantly higher in healthy controls (median 2.8%, IQR 2.6-5.0%) than ischemic stroke patients (median 1.6%, IQR 1.25-2.2%) (p < 0.001). In the latter, Treg proportions were positively correlated with age (r = 0.595, p = 0.041), but not with infarct volume (r = 0.367, p = 0.241). After PARP-1 inhibitor treatment, Treg proportions among PBMCs increased in response to high dose (10 MUm) JPI-289 (median 2.3%, IQR 2.0-2.9%) as did Treg-associated transcription factors such as FoxP3 and CTLA-4 mRNA. PARP-1 inhibitor treatment also decreased pro-inflammatory cytokines (IFN gamma, TNF-alpha, and IL-17) and increased anti-inflammatory cytokines (IL-4, IL 10, and TGF-beta1). CONCLUSION: Treg proportions are reduced in ischemic stroke patients and increased by treatment with high-dose PARP-1 inhibitor JPI-289. The PARP-1 inhibitor also had a possible anti-inflammatory effect on cytokine levels, and may ameliorate the outcome of ischemic stroke by up-regulating Tregs. PMID- 29709771 TI - Sphingobactan, a new alpha-mannan exopolysaccharide from Arctic Sphingobacterium sp. IITKGP-BTPF3 capable of biological response modification. AB - An exopolysaccharide, from a new Arctic permafrost isolate, Sphingobacterium sp. IITKGP-BTPF3 was purified and characterized. Upon optimization of various parameters (pH, temperature, carbon and nitrogen source), the yield of EPS obtained was 1.42 g/L. Structural investigation through FT-IR, GC-MS/MS, HPLC and NMR (1D and 2D) revealed the molecule to be a mannan with alpha-(1 -> 2) and alpha-(1 -> 6) linkages. Anti-oxidant and macrophage immunomodulatory assays were employed for the assessment of bioactivity. Sphingobactan was found to be capable of scavenging superoxide anions, and reducing the nitric oxide production in LPS elicited murine macrophage (RAW 264.7) cell line. The in vitro findings indicate the potential of Sphingobactan as a biological response modification (BRM) agent, for containment and possible resolution of inflammatory response in vivo. PMID- 29709772 TI - Ginsenoside Rg1 protects against hind-limb ischemia reperfusion induced lung injury via NF-kappaB/COX-2 signaling pathway. AB - BACKGROUND/AIMS: Ginsenoside Rg1 is regarded as the primary bioactive ingredient in Panax notoginseng that has been well recognized for its protective effects against ischemia/reperfusion (IR) injury. However, the mechanisms still remain elusive. Our study aims to investigate the effects of Rg1 against lung injury induced by hind-limb IR in rats. METHODS: Twenty-four Sprague Dawley rats were randomly submitted to sham operation (SM group), hind-limb IR (IR group), hind limb IR + Rg1 (Rg1 group), and hind-limb IR + Pro-DTC group (PD group). All the rats except those in SM group were subjected to 3 h of ischemia followed by 6 h of reperfusion, and extra intravenous Rg1 and pyrrolidine dithiocarbamate (Pro DTC), a selective inhibitor of nuclear factor kappa B (NF-kappaB), was administered intravenously before ischemia in the Rg1 and PD group, respectively. The activities of myeloperoxidase (MPO), superoxide dismutase (SOD) and catalase (CAT), as well as protein expressions of NF-kappaB p65 and cyclooxygenases-2 (COX 2) in lung tissue, and thromboxane B2 (TXB2) and 6-keto-ProstaglandinF1alpha (6 keto-PGF1alpha) levels in bronchoalveolar lavage (BAL) fluid were detected. Morphological changes, index of quantitative assessment of histologic lung injury (IQA), apoptosis index (AI) and lung Wet/Dry ratio were also evaluated. RESULTS: The levels of Wet/Dry ratio, IQA, AI, activities of MPO and 6-keto-PGF1alpha/TXB2 ratio were increased, and NF-kappaB p65 and COX-2 protein expression were upregulated, while SOD and CAT levels were decreased in lung tissue in IR group as compared with SM group (p < 0.05), all the alterations could be significantly reversed by Rg1 or Pro-DTC pretreatment (p < 0.05). And Rg1 and Pro-DTC also significantly attenuated the pulmonary histological abnormalities induced by IR. CONCLUSION: Ginsenoside Rg1 potentially attenuated lung injury induced by hind limb IR by regulating NF-kappaB/COX-2 signaling pathway. PMID- 29709773 TI - Midwives' knowledge, attitudes and learning needs regarding antenatal vaccination. AB - OBJECTIVE: To determine the knowledge, attitudes and learning needs of midwives regarding antenatal vaccination. DESIGN AND SETTING: A cross-sectional, paper based survey of midwives employed at the only public tertiary maternity hospital in the Australian state of Western Australia between November 2015 and July 2016. PARTICIPANTS: 252 midwives providing care in antepartum, intrapartum, and/or postpartum settings. MEASUREMENTS: Self-reported responses to a 41-item survey. FINDINGS: The vast majority of midwives supported influenza and pertussis vaccination for pregnant women, with 90.0% and 71.7% reporting they would recommend pertussis and influenza vaccine, respectively, to a pregnant friend or family member, and almost all stating that midwives should administer vaccines to pregnant patients (94.8%). Seven out of ten midwives (68.1%) responded correctly to all knowledge items regarding vaccines recommended during pregnancy; 52.8% demonstrated correct knowledge regarding vaccine administration despite only 36.6% having attended an education session on antenatal vaccination in the previous two years. Nearly all midwives (97.3%) expressed a need for more education on vaccine administration. The most commonly reported barrier to administering influenza (61.3%) and pertussis (59.0%) vaccination was having staff available with the certification required to administer vaccines. KEY CONCLUSIONS: Midwives view antenatal vaccination as their responsibility and are interested and receptive to education. IMPLICATIONS FOR PRACTICE: There is an unmet need and demand among midwives for professional development that would enable them to recommend and administer vaccines to pregnant women in accordance with national immunisation guidelines and integrate vaccination into routine antenatal care. PMID- 29709774 TI - Allostatic load: A theoretical model for understanding the relationship between maternal posttraumatic stress disorder and adverse birth outcomes. AB - BACKGROUND: Adverse birth outcomes such as preterm birth and low birth weight are significant public health concerns and contribute to neonatal morbidity and mortality. Studies have increasingly been exploring the predictive effects of maternal posttraumatic stress disorder (PTSD) on adverse birth outcomes. However, the biological mechanisms by which maternal PTSD affects birth outcomes are not well understood. Allostatic load refers to the cumulative dysregulations of the multiple physiological systems as a response to multiple social-ecological levels of chronic stress. Allostatic load has been well documented in relation to both chronic stress and adverse health outcomes in non-pregnant populations. However, the mediating role of allostatic load is less understood when it comes to maternal PTSD and adverse birth outcomes. OBJECTIVE: To propose a theoretical model that depicts how allostatic load could mediate the impact of maternal PTSD on birth outcomes. METHOD: We followed the procedures for theory synthesis approach described by Walker and Avant (2011), including specifying focal concepts, identifying related factors and relationships, and constructing an integrated representation. We first present a theoretical overview of the allostatic load theory and the other 4 relevant theoretical models. Then we provide a brief narrative review of literature that empirically supports the propositions of the integrated model. Finally, we describe our theoretical model. FINDINGS/CONCLUSIONS: The theoretical model synthesized has the potential to advance perinatal research by delineating multiple biomarkers to be used in future. After it is well validated, it could be utilized as the theoretical basis for health care professionals to identify high-risk women by evaluating their experiences of psychosocial and traumatic stress and to develop and evaluate service delivery and clinical interventions that might modify maternal perceptions or experiences of stress and eliminate their impacts on adverse birth outcomes. PMID- 29709775 TI - Characterization of cathepsin D from Eriocheir sinensis involved in Spiroplasma eriocheiris infection. AB - Cathepsin D (catD) belongs to a lysosomal aspartic protease superfamily. The full length catD cDNA from the Chinese mitten crab Eriocheir sinensis (EscatD) was 2748 bp and contained a 1158-bp ORF encoding a protein of 385 amino acids, including a signal peptide and two N-glycosylation sites. Phylogenetic analysis showed that EscatD was clustered into a single group, together with other catD for crustaceans. Quantitative real-time PCR revealed that EscatD was expressed mainly in the eyes, hemocytes, intestine and nerve and was expressed weakly in heart, muscle and gills. After challenge with Spiroplasma eriocheiris, the expression of EscatD was significantly up-regulated from 1 d to 9 d. The copy number of S. eriocheiris in a silencing EscatD group was significantly higher than those in the control groups during S. eriocheiris infection. Meanwhile, the survival rate of crabs decreased in an EscatD-dsRNA group. We further found that knockdown of EscatD by RNA interference resulted in a downward trend of expression levels of JNK, ERK, relish and p38 during the early stage, as well as a reduction in the expression of five antimicrobial peptides genes, namely, crusrin1, crustin2, ALF1, ALF2 and ALF3. The subcellular localization experiment suggested that recombinant EscatD was mainly located in the cytoplasm. The over expression in Drosophila S2 cells indicated that EscatD could decrease the copy number of S. eriocheiris and increase cell viability. The above results demonstrated that EscatD plays an important immune role in E. sinensis to S. eriocheiris challenge. PMID- 29709776 TI - A cascade autocatalytic strand displacement amplification and hybridization chain reaction event for label-free and ultrasensitive electrochemical nucleic acid biosensing. AB - Herein, an autocatalytic strand displacement amplification (ASDA) strategy was proposed for the first time, which was further ingeniously coupled with hybridization chain reaction (HCR) event for the isothermal, label-free and multiple amplification toward nucleic acid detection. During the ASDA module, the target recognition opens the immobilized hairpin probe (IP) and initiates the annealing of the auxiliary DNA strand (AS) with the opened IP for the successive polymerization and nicking reaction in the presence of DNA polymerase and nicking endonuclease. This induces the target recycling and generation of a large amount of intermediate DNA sequences, which can be used as target analogy to execute the autocatalytic strand displacement amplification. Simultaneously, the introduced AS strand can propagate the HCR between two hairpins (H1 and H2) to form a linear DNA concatamer with cytosine (C)-rich loop region, which can facilitate the in situ synthesis of silver nanoclusters (AgNCs) as electrochemical tags for further amplification toward target responses. With current cascade ASDA and HCR strategy, the detection of target DNA could be achieved with a low detection limit of about 0.16 fM and a good selectivity. The developed biosensor also exhibits the distinct advantages of flexibility and simplicity in probe design and biosensor fabrication, and label-free electrochemical detection, thus opens a promising avenue for the detection of nucleic acid with low abundance in bioanalysis and clinical biomedicine. PMID- 29709777 TI - Bimetallic NiFe oxide structures derived from hollow NiFe Prussian blue nanobox for label-free electrochemical biosensing adenosine triphosphate. AB - We designed and constructed a novel aptasensor based on the porous nanostructured bimetallic NiFe-oxides embedded with the mesoporous carbon (represented by NiOxFeOy@mC) for sensitively detecting adenosine triphosphate (ATP), of which the porous NiOxFeOy@mC was derived from the hollow NiFe Prussian blue analogue (hollow NiFe PBA) by calcinating under high temperature. Owning to the excellent electrochemical activity originated from the metal oxides and mesoporous carbon and the strong binding interaction between the aptamer strands and the nanostructure hybrid, the formed porous NiOxFeOy@mC composite calcinated at 900 degrees C exhibited superior sensitivity toward ATP determination in comparison with other porous nanocubes obtained at 500 and 700 degrees C. The proposed aptasensor not only revealed a wide linear range from 5.0 fg.mL-1 to 5.0 ng mL-1 with a extremely low detection limit of 0.98 fg.mL-1 (1.62 fM) (S/N = 3), but also displayed high selectivity towards other interferences, good stability and reproducibility, and acceptable applicability. Therefore, this proposed approach provides a promising platform for ultra-sensitive detection of ATP, further having the potential applications on diagnosis of ATP-related diseases. PMID- 29709778 TI - Electrochemical immunosensor for differential diagnostic of Wuchereria bancrofti using a synthetic peptide. AB - Lymphatic filariasis (LF) is a neglected tropical disease transmitted by mosquitoes and the second cause of permanent disability leading to a significant morbidity and mortality rate. Previously, we have identified epitopes of the filarial abundant larval transcript-2 (ALT-2) protein using a microarray mapping. In this study, one of the epitopes (Wb/ALT2-A5) was used to construct an electrochemical immunosensor. Electrochemical technique of cyclic voltammetry was performed for detecting the signal generated by the interaction between the (Wb/ALT2-A5) peptide and circulating antibodies of serum human samples. (Wb/ALT2 A5) epitope antigens were successfully immobilized on the working electrode of a screen-printed carbon electrode (SPCE) by their amine groups via chitosan film by coupling with glutaraldehyde as crosslinker. After the sensor ready, a pool of human sera infected with Wuchereria bancrofti was added to its surface. Electrochemical responses were generated by applying a potential of - 0.6 to 0.6 V, scan rate of 0.025 V/s. A detection limit of 5.0 ug mL-1 for the synthetic peptides (Wb/ALT2-A5) and 0.002 ug mL-1 for human serum, with a sensitivity of 1.86 uA. The performance of this assay was successfully tested in human serum samples from infected and healthy patients. Thus, this proposed immunosensor, which is able to identify circulating antibodies, can be applied to the diagnosis of the W. bancrofti parasitic disease. PMID- 29709779 TI - Exploring the effects of climatic variables on monthly precipitation variation using a continuous wavelet-based multiscale entropy approach. AB - Understanding precipitation on a regional basis is an important component of water resources planning and management. The present study outlines a methodology based on continuous wavelet transform (CWT) and multiscale entropy (CWME), combined with self-organizing map (SOM) and k-means clustering techniques, to measure and analyze the complexity of precipitation. Historical monthly precipitation data from 1960 to 2010 at 31 rain gauges across Iran were preprocessed by CWT. The multi-resolution CWT approach segregated the major features of the original precipitation series by unfolding the structure of the time series which was often ambiguous. The entropy concept was then applied to components obtained from CWT to measure dispersion, uncertainty, disorder, and diversification of subcomponents. Based on different validity indices, k-means clustering captured homogenous areas more accurately, and additional analysis was performed based on the outcome of this approach. The 31 rain gauges in this study were clustered into 6 groups, each one having a unique CWME pattern across different time scales. The results of clustering showed that hydrologic similarity (multiscale variation of precipitation) was not based on geographic contiguity. According to the pattern of entropy across the scales, each cluster was assigned an entropy signature that provided an estimation of the entropy pattern of precipitation data in each cluster. Based on the pattern of mean CWME for each cluster, a characteristic signature was assigned, which provided an estimation of the CWME of a cluster across scales of 1-2, 3-8, and 9-13 months relative to other stations. The validity of the homogeneous clusters demonstrated the usefulness of the proposed approach to regionalize precipitation. Further analysis based on wavelet coherence (WTC) was performed by selecting central rain gauges in each cluster and analyzing against temperature, wind, Multivariate ENSO index (MEI), and East Atlantic (EA) and North Atlantic Oscillation (NAO), indeces. The results revealed that all climatic features except NAO influenced precipitation in Iran during the 1960-2010 period. PMID- 29709780 TI - Facile solvothermal fabrication of Pt47Ni53 nanopolyhedrons for greatly boosting electrocatalytic performances for oxygen reduction and hydrogen evolution. AB - Pt-based bimetallic nanostructures with low content of Pt were considered as one of the attractive nanocatalysts for their high Pt utilization efficiency, remarkable catalytic characters and cost-effectiveness in facilitating the sluggish cathodic reactions in fuel cells. Herein, three-dimensional Pt47Ni53 nanopolyhedrons (NPHs) with abundant active sites were constructed by a facile one-pot solvothermal strategy, in which cytosine and cetyltrimethylammonium chloride (CTAC) worked as the co-structure directing agents. The Pt47Ni53 NPHs were mainly characterized by a series of techniques, showing the high catalytic activity and stability towards oxygen reduction reaction (ORR) and hydrogen evolution reaction (HER) in comparison to Pt13Ni87 nanocrystals (NCs), Pt63Ni37 NCs, commercial Pt black and/or Pt/C catalysts. Impressively, the mass activity of Pt47Ni53 NPHs was about 215.80 mA mgPt-1 for ORR, approximately 4-time increase relative to Pt black (49.60 mA mgPt-1). These results demonstrate the promising applications of the synthesized nanocatalysts in energy storage and transformation. PMID- 29709781 TI - Hybrid pH-sensitive nanogels surface-functionalized with collagenase for enhanced tumor penetration. AB - Densely extracellular matrix (ECM) is one of the main barriers that hinder the penetration of drug into tumor parenchyma, compromising the therapeutic activity. In this work, alginic acid was copolymerized with an acid-labile monomer to give the acid-degradable nanogels (ALG NG), which was then immobilized with collagenase to obtain the surface-functionalized nanogels (Co@ALG NG). The introduction of collagenase would enhance the diffusion ability of nanogels in tumor parenchyma based on the hydrolytic activity to tumor ECM. The stability of these nanogels in various physiological environment and the pH-triggered degradation and drug release at different pH were then investigated. Monolayer cell and tumor-like spheroids were used to illustrate the penetration and drug delivery. In vivo drug distribution and antitumor efficiency of these nanogels were investigated using H22 tumor-bearing mice. The immobilization of collagenase significantly enhance the nanogels' penetration and diffusion ability in tumor area upon the digestion of tumor ECM, leading to higher drug concentration and superior antitumor effect. PMID- 29709782 TI - Violence prevention in special education schools - an integrated practice? AB - Research has shown that employees in special education settings are at high risk for work-related threats and violence. Previous research has not yet been able to identify the essential components of training programs that offer protection from work-related threats and violence. Therefore, the aim of this study was to explore how employees in special education schools deal with prevention of work related threats and violence. Group interviews were conducted with 14 employees working at 5 special education schools. Results show that employees use a wide range of prevention strategies drawing on specific violence prevention techniques as well as professional pedagogical approaches. We propose that the prevention of threats and violence in special education schools can be understood as an integrated pedagogical practice operating on three interrelated levels. PMID- 29709784 TI - Validation of an LC-MS/MS method for simultaneous quantitation of enzalutamide, N desmethylenzalutamide, apalutamide, darolutamide and ORM-15341 in mice plasma and its application to a mice pharmacokinetic study. AB - A sensitive and rapid LC-MS/MS method was developed and validated for the simultaneous quantitation of enzalutamide, N-desmethylenzalutamide (active metabolite of enzalutamide), apalutamide, darolutamide and ORM-15341 (active metabolite of darolutamide) in mice plasma as per regulatory guidelines. The analytes and the internal standard (I.S.: apalutamide-d3) were extracted from 50 MUL mice plasma by simple protein precipitation using acetonitrile, followed by chromatographic separation using an Atlantis C18 column with an isocratic mobile (0.2% formic acid:acetonitrile; 30:70, v/v) at a flow rate of 0.8 mL/min within 2.5 min. Detection and quantitation was done by multiple reaction monitoring on a triple quadrupole mass spectrometer following the transitions: m/z 465 -> 209, 451 -> 195, 478 -> 450, 399 -> 178, 397 -> 194 and 481 -> 453 for enzalutamide, N desmethylenzalutamide, apalutamide, darolutamide, ORM-15341 and the I.S. respectively. The calibration curves were linear from 1.07 to 2000 ng/mL with r2 >=0.99 for all the analytes. The intra- and inter-batch accuracy and precision (% CV) across quality controls varied from 88.5-111% and 1.13-13.1, 85.4-106% and 3.15-14.3, respectively for all the analytes. All the analytes were found to be stable under different conditions. The method was applied to an intravenous pharmacokinetic study in mice. PMID- 29709783 TI - Development and validation of an LC-MS/MS assay for tenofovir and tenofovir alafenamide in human plasma and cerebrospinal fluid. AB - A liquid chromatography with triple quadrupole mass spectrometry method was developed and validated for the determination of tenofovir and tenofovir alafenamide concentrations in human plasma and cerebrospinal fluid. Tenofovir and tenofovir alafenamide were extracted from matrix by solid phase extraction. The dried extraction eluents were dissolved in water for LC-MS/MS analysis. Separation was achieved with a Phenomenex Synergi 4 MUm Polar-RP 80A column (50 * 2 mm) with a gradient elution of 0.1% formic acid in water and acetonitrile. The total run time was 5 min. Detection of analytes was achieved using electrospray ionization (positive mode) and triple quadrupole selected reaction monitoring. Standard curve concentrations ranged from 0.5 to 500 ng/mL for the plasma assay and 0.1-50 ng/mL for the cerebrospinal fluid assay. The intra- and inter-day accuracy and precision were less than 12% in low, medium, and high quality control samples for both matrices. The validated methods were applied to the analysis of plasma and cerebrospinal fluid samples of a patient undergoing tenofovir therapy which involved the switch from Stribild(r) (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg) to Genvoya(r) (elvitegravir 150 mg/cobicistat 150 mg/emtricitabine 200 mg/tenofovir alafenamide 10 mg). PMID- 29709785 TI - High-performance liquid chromatography-based assay for glutathione transferase theta 2 activity: Application to characterize interindividual variability in human liver fractions. AB - Human glutathione transferase T2-2 (GSTT2-2) is one of the enzymes considered to play a role in inactivation of toxicants and carcinogens. The expression level of this enzyme is determined by genetic and environmental factors, which may lead to differences in susceptibility. As a specific assay for GSTT2-2 so far a spectroscopical assay based on GSH-conjugation of menaphthyl sulfate (MSu) was used. This spectrophotometric assay, however, appeared too insensitive to accurately quantify the GSTT2-2 activities in a panel of 20 human liver samples. More recently, expression levels of GSTT2-2 in biological samples are quantified by measuring mRNA levels. Since mRNA-levels do not always correlate well with enzyme activity, a specific and sensitive assay is required. In the present study a highly sensitive high-performance liquid chromatography (HPLC)-based method was developed. By applying the new method, firstly, the specificity of GSTT2-2 among 15 recombinant human GST isoforms in catalyzing GSH-conjugation of MSu was confirmed. In addition, a 65-fold inter-individual variation of GSTT2-2 activity was found from the individual liver fractions. By applying the method to individual liver fractions, a 65-fold inter-individual variation of GSTT2-2 activity was found. As a second application, the role of GSTT2-2 in GSH conjugation of the environmental carcinogen 1-methylpyrene sulfate (MPS) was studied by correlation analysis with GSTT2-2-catalyzed MSu conjugation. The relatively poor correlation suggested that other GSTs also contribute to MPS conjugation, as confirmed by incubations with recombinant GSTs. PMID- 29709787 TI - Voluntary muscle activation and evoked volitional-wave responses as a function of torque. AB - INTRODUCTION: This study employed a unique stimulation paradigm which allowed for the simultaneous assessment of voluntary activation levels (VA) via twitch interpolation, and the evoked V-wave responses of the plantar flexors during submaximal and maximal contractions. Test-retest reliability was also examined. METHODS: Fourteen participants repeated a stimulation protocol over four visits to assess VA and evoked V-wave amplitude across torque levels ranging from 20% to 100% MVC. MVC torque and EMG amplitude were also measured. RESULTS: VA increased nonlinearly with torque production and plateaued by 80% MVC. V-wave amplitude increased linearly from 20% to 100% MVC. There were no differences in any dependent variable across visits (p > 0.05). VA demonstrated moderate to substantial reliability across all torque levels (ICC = 0.76-0.91) while V-wave amplitude exhibited fair to moderate reliability from 40% to 100% (ICC = 0.48 0.74). DISCUSSION: We were able to reliably collect VA and the V-wave simultaneously in the plantar flexors. Collection of VA and V-wave during the same contraction provides distinct information regarding the contribution of motor-unit recruitment and descending cortico-spinal drive/excitability to force production. PMID- 29709786 TI - Discovery of coumarin-dihydroquinazolinone analogs as niacin receptor 1 agonist with in-vivo anti-obesity efficacy. AB - In this study, we presented rational designing and synthesis of coumarin dihydroquinazolinone conjugates to evaluate their agonist activity at GPR109a receptor. Among the synthesized small molecule library, compound 10c displayed robust agonist action at GPR109a with EC50 < 11 nM. Homology model of human GPR109a protein was generated to realize the binding interaction of the active molecule with the active site of GPR109a. Further, the efficacy of active compound 10c was supported by in-vivo experiments which showed reduced body weight in diet induced obese mice model. Interestingly, compound 10c reduced leptin in blood plasma and total serum cholesterol. These results suggest that the coumarin-dihydroquinazolinone conjugate is a suitable scaffold to further expand the chemical diversity and make them potential niacin receptor 1 agonist. PMID- 29709788 TI - Perceived effectiveness of NSSI in achieving functions on severity and suicide risk. AB - Nonsuicidal self-injury (NSSI) continues to be a psychiatric problem for youth and young adults, and is a robust risk factor for suicidal thoughts and behaviors. Research has established that NSSI is motivated by intrapersonal and interpersonal functions; however, research on the perceived effectiveness of NSSI for achieving the desired functions is lacking. In the current study, it was expected that using NSSI to achieve intrapersonal functions would be rated as more effective than interpersonal functions, and that perceived effectiveness of NSSI would be differentially related to NSSI severity and suicide risk outcomes. In a sample of 264 adults with lifetime NSSI history (over 70% past year), intrapersonal functions were endorsed more than interpersonal functions, and were rated as significantly more effective. Overall, perceived effectiveness of NSSI for intrapersonal functions was significantly and positively predictive of NSSI severity, while interpersonal functions were significantly and negatively related. Perceived effectiveness of NSSI for intrapersonal functions, but not interpersonal functions, were significantly predictive of more frequent and intense suicide ideation and greater likelihood of suicide plans and attempts. Results highlight the importance of assessing the perceived effectiveness of NSSI for specific functions in identifying individuals at risk for more severe NSSI and suicide. PMID- 29709789 TI - High-frequency repetitive transcranial magnetic stimulation of the left dorsolateral prefrontal cortex restores attention bias to negative information in methamphetamine addicts. AB - Methamphetamine (hereafter, meth) addiction results in various emotional problems linked to structural impairments in the prefrontal cortex (PFC). In this paper, we investigated whether high-frequency (10 Hz) repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral PFC (DLPFC) can improve emotional attention. Thirty-one meth addicts were randomly assigned to a 10 Hz or sham rTMS group; additionally, 31 healthy participants were enrolled, who were required to respond as correctly and quickly as possible to a yellow arrow embedded in an image depicting emotional content (neutral, fear, sadness, or disgust). Results showed that the healthy participants responded more rapidly to negative compared to neutral stimuli, while meth addicts responded indiscriminately to stimuli representing disgust, fear, and neutral content. The randomization check showed no significant differences in the pretest of emotional attention measures between the 10 Hz and sham groups. However, 10 Hz rTMS yielded faster response to negative pictures than to neutral pictures, which was similar to the performance of healthy participants but Sham not. However, this attention bias effect persisted in the 10 Hz group 2 weeks later. These results demonstrate that high frequency rTMS of the left DLPFC can improve the emotional attention of meth addicts. PMID- 29709790 TI - Associations between cognition and internalizing problems in young adults with early-onset schizophrenia: A 13-year follow-up study. AB - The present follow-up study examines the associations between cognition and parent-rated internalizing problems among adolescents with early-onset schizophrenia (EOS) at baseline (T1) and self-rated internalizing problems 13 years later (T2). Twelve individuals (8 male/4 female) with EOS and 30 healthy controls (16 male/14 female) were included in the study. All were between 12 and 18 years of age at T1. Internalizing problems were measured with the Achenbach System of Empirically Based Assessment Internalizing Scale. Cognition was examined with a neuropsychological test battery measuring auditory attention/working memory, visuomotor processing, cognitive flexibility and verbal memory. Compared to healthy controls, the EOS group had significant cognitive deficits and more internalizing problems both at T1 and T2. There was no correlation between parent-rated internalizing problems at T1 and self-rated internalizing problems at T2 in the EOS group. However, deficits in auditory attention/working memory at T1 were significantly associated with internalizing problems at T2. A focus on improving the treatment of cognitive impairments may be important in preventing the development of internalizing problems in young patients with schizophrenia. The small sample size of the study is a limitation and further research is recommended. PMID- 29709791 TI - Thwarted interpersonal needs mediate the relation between facets of mindfulness and suicide ideation among psychiatric inpatients. AB - Previous research suggests a negative association between mindfulness and suicide ideation, yet limited research has examined the specific role of mindfulness on suicide ideation or attempted to link this construct with theory-driven risk factors for suicide among high-risk individuals. The current study examined the mediating role of thwarted interpersonal needs (i.e., thwarted belongingness and perceived burdensomeness) in the relation between facets of mindfulness and suicide ideation among psychiatric inpatients. Participants were 118 psychiatric inpatients who completed self-report assessments of mindfulness, thwarted belongingness, perceived burdensomeness, and suicide ideation. Results indicated that the additive effect of thwarted belongingness and perceived burdensomeness mediated the relation between the act with awareness, non-judging, and non reactivity mindfulness facets, and suicide ideation. Facets of mindfulness appear to be differentially related to thwarted interpersonal needs and subsequent suicide ideation. Continued examination of specific facets of mindfulness, as they relate to suicide ideation, may highlight potentially important distinctions and better inform suicide risk assessment and treatment. PMID- 29709792 TI - An aptamer-based fluorescence bio-sensor for chiral recognition of arginine enantiomers. AB - In this study, a novel aptamer - based fluorescence bio-sensor (aptamer-AuNps) was developed for chiral recognition of arginine (Arg) enantiomers based on aptamer and gold nanoparticles (AuNps). Carboxyfluorescein (FAM) labeled aptamers (Apt) were absorbed on AuNps and their fluorescence intensity could be significantly quenched by AuNps based on fluorescence resonance energy transfer (FRET). Once d-Arg or l-Arg were added into the above solution, the aptamer specifically bind to Arg enantiomers and released from AuNps, so the fluorescence intensity of d-Arg system and l-Arg system were all enhanced. The affinity of Apt to l-Arg is tighter to d-Arg, so the enhanced fluorescence signals of l-Arg system was stronger than d-Arg system. What's more, the enhanced fluorescence were directly proportional to the concentration of d-Arg and l-Arg ranging from 0 300 nM and 0-400 nM with related coefficients of 0.9939 and 0.9952, respectively. Furthermore, the method was successfully applied to detection l-Arg in human urine samples with satisfactory results. Eventually, a simple "OR" logic gate with d-Arg &l-Arg as inputs and AuNps aggregation state as outputs was fabricated, which can help us understand the chiral recognition process deeply. PMID- 29709793 TI - Molecular orientation in aligned electrospun polyimide nanofibers by polarized FT IR spectroscopy. AB - Quantitative explanation on the improved mechanical properties of aligned electrospun polyimide (PI) nanofibers as the increased imidization temperatures is highly required. In this work, polarized FT-IR spectroscopy is applied to solve this problem. Based on the polarized FT-IR spectroscopy and the molecular model in the fibers, the length of the repeat unit of PI molecule, the angle between the fiber axis and the symmetric stretching direction of carbonyl group on the imide ring, and the angle between the PI molecular axis and fiber axis are all investigated. The Mark-Howink equation is used to calculate the number average molar mass of PI molecules. The orientation states of PI molecules in the electrospun nanofibers are studied from the number-average molar mass of PI molecules and the average fiber diameter. Quantitative analysis of the orientation factor of PI molecules in the electrospun nanofibers is performed by polarized FT-IR spectroscopy. PMID- 29709794 TI - Intramolecular hydrogen bonding promoted excited state double proton transfer mechanism based on a typical molecule: Porphycene. AB - The double excited state intramolecular proton transfer (ESIPT) mechanisms of porphycene, were theoretically studied. The primary bond lengths, IR vibrational spectra and hydrogen-bond energy indicate that the intramolecular hydrogen bonds were strengthened in the first excited state, which facilitate the ESIPT processes. To elucidate the proposed mechanism, the potential-energy surfaces of the ground state and first excited state were constructed as functions of NH bond lengths and its relative torsional angle rotation. The intramolecular proton transfer of prophycene is more likely to occur through lengthwise pathway and proceed in the concerted coordinated transfer manner. PMID- 29709795 TI - Analisis de los determinantes socioeconomicos del gasto de bolsillo en medicamentos en seis zonas geograficas de Panama. AB - OBJETIVO: Caracterizar el gasto de bolsillo privado en medicamentos en funcion de los determinantes sociodemograficos y socioeconomicos. MATERIALES Y MeTODOS: La fuente de datos es la Encuesta de Gasto de Bolsillo en Medicamentos de 2014. Se caracterizo el gasto de bolsillo privado mediante variables explicativas sociodemograficas (SOD) y socioeconomicas (SES). Se hizo analisis factorial por componentes principales, regresion logistica y lineal simple. RESULTADOS: Los Odds Ratio demuestran que la educacion y la zona geografica son determinantes fundamentales que inciden en el gasto de bolsillo. Los medicamentos son productos necesarios, en adicion a que el gasto de bolsillo aumenta a un promedio del 2% por cada ano de vida cronologica adicional. CONCLUSIONES: Existe mayor vulnerabilidad en las zonas mas pauperizadas respecto del acceso a medicamentos, en especial en las indigenas e implica un mayor riesgo de gasto catastrofico a menor ingreso ante la mayor prevalencia de enfermedades cronicas. PMID- 29709797 TI - Trident sign trumps Aquaporin-4-IgG ELISA in diagnostic value in a case of longitudinally extensive transverse myelitis. AB - Longitudinally-extensive T2-hyperintense spinal cord lesions (>=3 vertebral segments) are associated with neuromyelitis optical spectrum disorder but occur with other disorders including spinal cord sarcoidosis. When linear dorsal subpial enhancement is accompanied by central cord/canal enhancement the axial post-gadolinium sequences may reveal a "trident" pattern that has previously been shown to be strongly suggestive of spinal cord sarcoidosis. We report a case in which the patient was initially diagnosed with neuromyelitis optical spectrum disorder, but where the "trident" sign ultimately led to the correct diagnosis of spinal cord sarcoidosis. PMID- 29709796 TI - Pharmacodynamics and pharmacokinetics of insulin detemir and insulin glargine 300 U/mL in healthy dogs. AB - Insulin glargine 300 U/mL and insulin detemir are synthetic long-acting insulin analogs associated with minimal day-to-day variability or episodes of hypoglycemia in people. Here, 8 healthy purpose-bred dogs each received 2.4 nmol/kg subcutaneous injections of insulin detemir (0.1 U/kg) and insulin glargine 300 U/mL (0.4 U/kg) on 2 different days, >1 wk apart, in random order. Blood glucose (BG) was measured every 5 min, and glucose was administered intravenously at a variable rate with the goal of maintaining BG within 10% of baseline BG ("isoglycemic clamp"). Endogenous and exogenous insulin were measured for up to 24 h after insulin injection. The effect of exogenous insulin was defined by glucose infusion rate or a decline in endogenous insulin. Isoglycemic clamps were generated in all 8 dogs after detemir but only in 4 dogs after glargine. Median time to onset of action was delayed with glargine compared to detemir (4.0 h [3.3-5.8 h] vs 0.6 h [0.6-1.2 h], P = 0.002). There was no difference in time to peak (median [range] = 6.3 h [5.0-21.3 h] vs 4.3 h [2.9-7.4 h], P = 0.15) or duration of action (16.3 h [6.1-20.1 h] vs 10.8 h [8.8-14.8 h], P = 0.21) between glargine and detemir, respectively. Glargine demonstrated a peakless time-action profile in 4/8 dogs. The total metabolic effect and peak action of detemir was significantly greater than glargine. Significant concentrations of glargine were detected in all but 1 dog following administration. Glargine might be better suited than detemir as a once-daily insulin formulation in some dogs based on its long duration of action and peakless time-action profile. Day-to-day variability in insulin action should be further assessed for both formulations. PMID- 29709798 TI - Peripheral blood memory B cell frequency predicts conversion from clinically isolated syndrome to multiple sclerosis. AB - BACKGROUND: Starting from the first attack, activated B cells are found in multiple sclerosis (MS) patients and are associated with disease activity. METHODS: Peripheral blood cells of 17 clinically isolated syndrome (CIS) patients were collected during the first attack. CIS patients were divided as those converting to MS (CIS-MS+, n = 8) and not converting to MS (CIS-MS-, n = 9) in three years. Age-gender matched MS patients (n = 19) and healthy individuals (n = 20) were included as controls. Peripheral blood frequencies of total, immature, naive, unswitched and switched memory B cells, plasmablasts and plasma cells were measured by flow cytometry. RESULTS: CIS patients showed reduced unswitched memory B cell and plasma cell frequencies. CIS-MS- patients had significantly increased levels of total B cells and suppressed unswitched memory B cell and plasma cell frequencies. CONCLUSION: Our results suggest that conversion from CIS to MS occurs due to the inability of the immune system to suppress effector B cell production. PMID- 29709799 TI - Optimization of strong-base anion exchange O&M costs for hexavalent chromium treatment. AB - Hexavalent chromium [Cr(VI)] in drinking water is pending regulation in California and is being considered for regulation in other locations. While strong-base anion exchange (SBA-IX) can efficiently remove Cr(VI) to low-levels that may be required to comply with future MCLs, operational and maintenance (O&M) costs can be considerable if the spent brine is disposed of as hazardous waste. Through bench- and pilot-scale experiments and full-scale demonstrations, this study examined the ability of emerging and established brine treatment and reuse techniques as well as recently developed resins to decrease O&M costs. When profiling anion elution during regeneration with nanofiltration treated and untreated spent brine, it appeared that at least 1 and 3 reuse cycles were feasible, respectively. Stannous- and ferrous-based reductants were more efficient than sulfur-based reductants when treating spent brine. Bed volumes to 8 MUg/L chromium breakthrough with 7 resins varied by as much as a factor of 2 and correlated (R2 = 0.84) with resin total exchange capacities. Spent brine reuse, segmented regeneration (an optimized brine reuse method), ferrous reduction, and nanofiltration of spent brine were estimated to decrease O&M costs by 30, 70, 63, and 61%, respectively. Selection of high performing resins was the most simple way to decrease O&M costs (up to 70% savings). The sum of nitrate and sulfate raw water equivalent concentrations was found to be the principal water quality parameter that influenced the performance of 4 resins in 7 different groundwaters because nitrate and sulfate concentrations were orders of magnitude greater than chromium concentrations. Resins with higher chromium capacities eluted more co-contaminants including arsenic, selenium, uranium, and vanadium because they likely had higher co-contaminant capacities. Co-contaminant elution was found to be complex because associations can form between regenerant and co eluting anions. Sodium chloride was the most efficient regenerant, though other regenerants provided benefits such as enhanced uranium elution most likely by complexing with uranium to inhibit its precipitation. Nitrate peaking was found to be limited even when reusing untreated and nanofiltration treated spent brine. PMID- 29709800 TI - Evidences of extracellular abiotic degradation of hexadecane through free radical mechanism induced by the secreted phenazine compounds of P. aeruginosa NY3. AB - The aim of this work was to investigate the effects of secreted extracellular phenazine compounds (PHCs) on the degradation efficiency of alkanes by P. aeruginosa NY3. Under aerobic conditions, the PHCs secreted by P. aeruginosa NY3 initiate the oxidation of alkanes outside cells, in coupling with some reducing agents, such as beta-Nicotinamide adenine dinucleotide, reduced disodium salt (NADH) or reduced glutathione (GSH). This reaction might be via free radical reactions similar to Fenton Oxidation Reaction (FOR). P. aeruginosa NY3 secretes pyocyanin (Pyo), 1-hydroxyphenazine (HPE), phenazine-1-carboxylic acid (PCA), and phenazine-1-amide (PCN) simultaneously. The cell-free extracellular fluid containing these four PHCs degrades hexadecane effectively. The observation of Electron Spin Resonance (EPR) signals of superoxide anion radical (O2-), hydroxyl radical (OH) and/or carbon free radicals (R) both in vivo and in vitro suggested the degradation of hexadecane could be via a free radical pathway. Secretion of PHCs has been found to be characteristic of Pseudomonas which is often involved in or related to the degradation of organic pollutants. Our work suggested that certain organic contaminants may be oxidized through ubiquitously extracellular abiotic degradation by the free radicals produced during bio-remediation and bio treatment. PMID- 29709801 TI - Blue light decreases tanshinone IIA content in Salvia miltiorrhiza hairy roots via genes regulation. AB - The effect of light-emitting diodes (LEDs) on the production of secondary metabolites in medicinal plants and hairy roots is receiving much attention. The roots and rhizomes of the traditional Chinese medicinal plant Salvia miltiorrhiza Bunge are widely used for treating cardiovascular and cerebrovascular diseases. The main components are liposoluble tanshinones and hydrophilic phenolic acids. Moreover, hairy root culture of S. miltiorrhiza has been used in research of valuable plant-derived secondary metabolites. In this study, we examined the effect of LEDs with different combinations of wavelengths on the content of the main components in hairy roots of S. miltiorrhiza. Tanshinone IIA (TSIIA) content in hairy roots was significantly decreased with all light treatments containing blue light by >60% and was 9 times lower with LED treatment duration changed from 1 week to 3 weeks. HMGR, DXS2, DXR, GGPPS, CPS and CYP76AH1 genes involved in the tanshinone biosynthesis pathway were downregulated by blue light. Furthermore, light quality treatments have different effect on the accumulation of phenolic acids in hairy roots of S. miltiorrhiza. The light treatments 6R3B, 6B3IR, 7RGB and 2R6BUV for 3 weeks could increase rosmarinic acid (RA) content slightly but not salvianolic acid B (SAB) content. Different secondary metabolite contents could be regulated by different wavelength combinations of LEDs. Blue light could reduce TSIIA content in hairy roots of S. miltiorrhiza via gene regulation. PMID- 29709802 TI - Optimization of sample preparation and chromatography for the determination of perfluoroalkyl acids in sediments from the Yangtze Estuary and East China Sea. AB - Perfluoroalkyl acids (PFAAs) are ubiquitous pollutants present in various environmental media, including marine sediments. A method was proposed for the determination of 17 target PFAA analytes in marine sediment samples (n = 49) collected from the Yangtze Estuary and East China Sea. The proposed method involves the use of an optimized pretreatment procedure and ultrahigh-performance liquid chromatography electrospray ionization-tandem mass spectrometry in dynamic multiple reaction monitoring mode. The method relied on extraction cycles using methanol followed by concentration, filtration, and small volume injection to UHPLC-MS/MS. The recovery, time efficiency, and detection limit of the proposed method are improved relative to those of traditional methods. Limits of detection varied from 0.003 to 0.045 ng/g, and spike recoveries to sediment ranged from 90% to 110% with suitable precisions (1.7%-14.6%). PFAAs were widely present in the samples, and SigmaPFAAs ranged from 0.67 ng/g dw to 36.75 ng/g dw. Results indicated that terrigenous input strongly influences PFAA distribution in sediments from the study areas. Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS) were identified as the dominant perfluorocarboxylic acid (PFCA) and perfluoroalkylsulfonate (PFSA) in sediment samples from the Yangtze Estuary and the East China Sea. Preliminary environmental risk assessment indicated that PFOS may pose a higher environmental risk than PFOA. Furthermore, risk quotient values indicated that PFOS poses a significant risk to the aquatic ecosystem of the study areas. PMID- 29709803 TI - Variable-valence metals catalyzed solid NaBiO3 nanosheets for oxidative degradation of norfloxacin, ofloxacin and ciprofloxacin: Efficiency and mechanism. AB - In this work, we report metal ions catalyzed oxidative degradation of three typical fluoroquinolones norfloxacin (NOR), ofloxacin (OFL) and ciprofloxacin (CIP) by using NaBiO3 nanosheets. It was found that variable-valence metal ions such as Cu2+, Fe2+, Mn2+, Ce3+, Ag+ and Co2+ could obviously enhanced degradation of NOR, OFL and CIP by NaBiO3. The pseudo-first-order kinetic rate for the degradation of 20 MUmol L-1 NOR by NaBiO3 (2 mmol L-1) in the presence of 0.1 mmol L-1 Cu2+, Fe2+, Mn2+, Ce3+, Ag+ and Co2+ was 0.021, 0.084, 0.019, 0.23, 0.25 and 0.28 min-1, 2.1, 8.4, 19, 23, 25 and 28 times that by NaBiO3 without any metal ions. In comparison, Ca2+ and Fe3+ exhibited no obviously promotive or depressive effect for the degradation of NOR by NaBiO3. Singlet oxygen (1O2) was suggested as the main reactive species from NaBiO3 in the presence of metal ions by electron spin resonance technology and radicals scavenging experiments. The evolution of NaBiO3 was tracked with scanning electron microscope, energy dispersive spectrometer, X-ray diffraction, X-ray photoelectron spectroscopy and Raman spectroscopy. It was found that the metal ions were embedded into the crystal structure of NaBiO3 through ion-exchange between Na in NaBiO3 and metal ions. In the subsequent step, an electron transformation from lattice oxygen to Bi(V) sites was mediated by embedded variable-valence metal species, resulting in an enhanced generation of 1O2 from the crystal structure of NaBiO3. These results can shed light on the application of NaBiO3 for the organic pollutant decontamination. PMID- 29709804 TI - Mus musculus bone fluoride concentration as a useful biomarker for risk assessment of skeletal fluorosis in volcanic areas. AB - Fluoride is often found in elevated concentrations in volcanic areas due to the release of magmatic fluorine as hydrogen fluorine through volcanic degassing. The exposure to high levels of fluoride can affect the processes of bone formation and resorption causing skeletal fluorosis, a pathology that can easily be mistaken for other skeletal diseases. In this study, we aimed to determine if fluoride concentration in the femoral bone of wild populations of the house mouse (Mus musculus) is a good biomarker of exposure to active volcanic environments naturally enriched in fluoride, allowing their use in biomonitoring programs. The fluoride concentration of the whole femoral bone of 9 mice from Furnas (5 males and 4 females) and 33 mice from Rabo de Peixe (16 males and 17 females) was measured by the potentiometric method with a fluoride ion selective electrode. Fluoride in bones was significantly higher in the mice from Furnas when compared with the mice from Rabo de Peixe (616.5 +/- 129.3 MUg F/g vs. 253.8 +/- 10.5 MUg F/g). Accumulation rates were also significantly higher in the mice collected in Furnas when compared with Rabo de Peixe individuals (3.84 +/- 0.52 MUg F/day vs. 1.22 +/- 0.06 MUg F/day). The results demonstrate a significant association between exposure to fluoride in the active volcanic environment and fluoride content in bone, revealing that bone fluoride concentration is a suitable biomarker of chronic environmental exposure to fluoride. PMID- 29709805 TI - Performance and microbial community of anammox in presence of micro-molecule carbon source. AB - Because ammonium (NH4+-N) coexists with organic matter in some wastewaters, the possible adverse influences of organic matter become a major concern in the applications of anaerobic ammonium oxidation (anammox). In this study, the effects of acetate, as a representative of micro-molecule organic matter, on anammox were investigated. Efficient nitrogen removal was realized because denitrifying bacteria and anammox bacteria (AnAOB) had a better synergistic effect under the condition of chemical oxygen demand (COD) concentrations lower than 251 +/- 7 mg L-1. Furthermore, the nitrogen removal efficiency (NRE) decreased to 82.02 +/- 3.14% when COD was increased to 730 +/- 9 mg L-1, and effluent free ammonia (FA) reached 21.93 +/- 4.71 mg L-1 might be one of factors leading to inhibition. However, the nitrogen-removal contribution rate of anammox remained steady at 61.97 +/- 2.84% at COD of 730 +/- 9 mg L-1, which indicated that anammox was still dominant in the system. AnAOB, such as Ca. Kuenenia and Ca. Jettenia, and denitrifying bacteria, such as Denitratisoma and Thauera, were found to coexist in the reactor. Interestingly, Ca. Kuenenia presented in the trend of first decreased then increased with the increasing of organic matter concentration, which might be one of reasons that anammox played an important role in nitrogen removal at high COD concentration. PMID- 29709806 TI - Characterization of manganese oxidation by Brevibacillus at different ecological conditions. AB - Bacterial Mn(II) oxidation plays an important role in the biogeochemical cycling of manganese and many trace metals. This study describes Mn(II) oxidation by two isolated manganese (Mn)-oxidizing strains that were identified and assigned as Brevibacillus brevis MO1 and Brevibacillus parabrevis MO2 based on physiochemical and phylogenetic characterizations. The ecological conditions influenced Mn(II) oxidation by both strains. Mn(II) stimulated the growth of strain MO2 while slightly inhibiting strain MO1. Mn(II)-oxidizing activity of two strains was enhanced with increase of initial pH, and maximum Mn(II)-oxidizing activity occurred at pH 8 for both strains (93.5%-94.0%). Brevibacillus showed the capability of mesophilic and psychrophilic Mn(II) oxidation. X-ray photoelectron spectroscopy (XPS) analysis indicated that the biogenic manganese oxides had an intermediate valence between 3 and 4. These results demonstrated that Brevibacillus, which is capable of oxidizing dissolved Mn(II), will be a suitable strain for exploring the mechanism of manganese oxidation in engineered and natural environments. PMID- 29709807 TI - Metals geochemistry and mass export from the Mississippi-Atchafalaya River system to the Northern Gulf of Mexico. AB - Discharging 680 km3 of freshwater annually to the Northern Gulf of Mexico (NGOM), the Mississippi-Atchafalaya River System (MARS) plays a significant role in transporting major and trace elements to the ocean. In this study, we analyzed total recoverable concentrations of thirty-one metals from water samples collected at five locations along the MARS during 2013-2016 to quantify their seasonal mass exports. The Atchafalaya River flows through a large swamp floodplain, allowing us to also test the hypothesis that floodplains function as a sink for metals. We found that the seven major elements (Ca, Na, Mg, Si, K, Al, and Fe) constituted 99% of the total annual mass load of metals (7.38 * 107 tons) from the MARS. Higher concentrations of Al, Ba, B, Ca, Fe, Mg, Mn, Ag, and Ti were found in the Mississippi River, while significantly higher Si and Na concentrations were found in the Atchafalaya River. Significant relationships were found between daily discharge and daily loads of Ba, Ca, Fe, K, Sr, and Ti in both rivers, while significant relationships were also found for Al, Mg, Mn, V, and Zn in the Atchafalaya River and B in the Mississippi River. Overall, the Mississippi River contributed 64-76% of the total annual loading of metals from the MARS to the NGOM. Daily loads of Al, Ba, B, Fe, Li, Mn, P, K, Si, Ag, Ti, V, and Zn regularly decreased upstream to downstream in the Atchafalaya River, partially accepting the initial hypothesis on metals transport in river floodplains. PMID- 29709808 TI - Uptake of BDE-209 on zebrafish embryos as affected by SiO2 nanoparticles. AB - It was hypothesized that interactions between emerging contaminants such as decabromodiphenyl ether (BDE-209) and nanoparticles (NPs) such as nano-SiO2 (nSiO2), can affect contaminant transport in the aquatic environment and its ecotoxicity. This study assessed the influence of nSiO2 on the uptake of BDE-209 by zebrafish embryo. The distribution of BDE-209 and nSiO2 on the external chorion and the internal embryo mass (i.e., dechorionated embryo) was measured. For single exposure of nSiO2 to zebrafish embryo, separately, results showed that nSiO2 accumulation on the chorion surface was higher than that in the dechorionated embryo. The nSiO2 accumulation on the chorion surface was 129-200 mg-nSiO2/g-chorion at 48 h post fertilization, hpf, of exposure time, whereas the equilibrium adsorption of nSiO2 on the dechorionated embryo was ca. 0.42-0.54 mg nSiO2/g-embryo at 6 hpf. Results showed that the formation of nSiO2-BDE-209 associates promoted both extracellular and intracellular uptake of BDE-209 by zebrafish embryo, thereby increasing the bioconcentration of BDE-209 on the chorion surface and in embryo. The results also revealed that the accumulation of BDE-209 on the chorion was remarkably greater than that on the dechorionated embryo at 48 hpf. The uptake of BDE-209 was 17.2 +/- 0.45 mg/g-chorion (or 86 ng BDE-209/chorionated embryo) and 0.37 +/- 0.01 mg/g-embryo (or 18.6 ng-BDE 209/dechorionated embryo), respectively, when co-exposure of zebrafish embryos to BDE-209 and nSiO2. Results from the SEM and EDS analysis revealed that nSiO2 already passed through the chorion and adhered to the embryo surface/mass. PMID- 29709809 TI - Enrichment and physiological responses of dechlorane plus on juvenile marine macroalgae (Ulva pertusa). AB - Dechlorane Plus (DP), a chlorinated flame retardant, is increasingly reported in aquatic ecosystems worldwide. But little information is available regarding the toxicity of DP in marine organisms, especially in macroalgae. The objective of this study was to investigate effects of DP exposure on photosynthesis, oxidative stress and its enrichment in juvenile marine macroalgae (Ulva pertusa). Following 21- day uptake and 21- day depuration (10-8 mol/L), algae accumulated 1.18 times of DP compared to the initial concentration. Anti-DP was prone to accumulate in juvenile macroalgae. The enrichment of DP affected the physiological responses in algae. After 1, 7 and 14 days DP exposure (10-8, 10-7 and 10-6 mol/L), antioxidant enzymes (SOD and CAT) activities and MDA content changed in a dose and time depended manner. Chlorophyll fluorescence parameters, including Fv/Fm, PhiPSII and ETR decreased with the increasing DP concentration. It indicated that DP leads to a low rate of light energy utilization in algae which may ascribe to the oxidative damage induced by DP enrichment. Present study provides insight into the toxicological effects of DP on marine macroalgae, which is useful for risk assessment of DP in intertidal zone ecosystems. PMID- 29709810 TI - Effects of the aeration pattern, aeration rate, and turning frequency on municipal solid waste biodrying performance. AB - Interactive influences of the aeration pattern, aeration rate, and turning frequency on municipal solid waste biodrying performance were investigated. Energy and water mass balances were used to identify the main water-removal routes and determine the amount of energy used and efficiency. Changing the aeration pattern and turning frequency did not significantly affect biodrying performance when the other conditions and total aeration volume were constant. The total aeration volume controlled the pile temperature and evaporation, making it the main factor affecting water loss during biodrying. A continuous aeration rate of 0.5 L kg-1 dry matter.min-1 gave the best biodrying performance (the highest water-removal rate, biodrying index, and sorting efficiency, 0.5 kg kg-1, 4.12, and 86.87%, respectively, and the highest lower heat value (LHV) and heat utilization rate, 9440 kJ kg-1 and 68.3%, respectively). There was an optimum aeration rate, water loss reaching a maximum at an aeration rate of 0.5 L kg-1 DM.min-1 and not increasing further as the aeration rate increased further. Lower aeration rates gave higher volatile solid degradation rates. The effects of turning could be achieved by increasing the aeration rate. The recommended biodrying parameters are continuous aeration at an aeration rate of 0.5 L kg-1 dry matter min-1 and one turn every 3 d. PMID- 29709811 TI - Effect of long residence time and high temperature over anaerobic biodegradation of Scenedesmus microalgae grown in wastewater. AB - Anaerobic digestion of indigenous Scenedesmus spp. microalgae was studied in continuous lab-scale anaerobic reactors at different temperatures (35 degrees C and 55 degrees C), and sludge retention time - SRT (50 and 70 days). Mesophilic digestion was performed in a continuous stirred-tank reactor (CSTR) and in an anaerobic membrane bioreactor (AnMBR). Mesophilic CSTR operated at 50 days SRT only achieved 11.9% of anaerobic biodegradability whereas in the AnMBR at 70 days SRT and 50 days HRT reached 39.5%, which is even higher than the biodegradability achieved in the thermophilic CSTR at 50 days SRT (30.4%). Microbial analysis revealed a high abundance of cellulose-degraders in both reactors, AnMBR (mainly composed of 9.4% Bacteroidetes, 10.1% Chloroflexi, 8.0% Firmicutes and 13.2% Thermotogae) and thermophilic CSTR (dominated by 23.8% Chloroflexi and 12.9% Firmicutes). However, higher microbial diversity was found in the AnMBR compared to the thermophilic CSTR which is related to the SRT. since high SRT promoted low growth-rate microorganisms, increasing the hydrolytic potential of the system. These results present the membrane technology as a promising approach to revalue microalgal biomass, suggesting that microalgae biodegradability and consequently the methane production could be improved operating at higher SRT. PMID- 29709812 TI - A comparative experimental study of the anaerobic treatment of food wastes using an anaerobic digester with a polyamide stirring rake or a stainless-steel stirring rake. AB - A low treatment capacity and unstable operation are the main drawbacks of the anaerobic digestion of food wastes. The present work improved the efficiency and stabilization of the anaerobic digestion of food wastes using digesters with a polyamide stirring rake (DPSR) and compared it to a traditional digester with a stainless-steel stirring rake (DSSSR). The DPSR had a higher reliability and produced 3.97 times the methane yield of DSSSR in batch experiments at high loading rates (105 VS/L). Uniform design experiments were applied to investigate the relationship between methane yield and the stirring factors of the DPSR. A regression analysis of the uniform design indicated that stirring factors synergistically affect methane yield. The experiment verifying the optimal conditions showed that in the DPSR with 82 r/min stirring intensity and 10 min/d stirring time, the first 20 days of methane yield (392.1 mL/g VS) achieved to 85.26% of the theoretically derived methane yield. In brief, in the anaerobic digestion of food wastes for high methane production and stable operation, the DPSR was more beneficial for the anaerobic digestion of food wastes than the DSSSR. PMID- 29709813 TI - Biosynthesis of cobalt oxide nanoparticles using endophytic fungus Aspergillus nidulans. AB - Metallic oxide nanoparticles have profound applications in electrochemical devices, supercapacitors, biosensors and batteries. Though four fungi were isolated from Nothapodytes foetida, Aspergillus nidulans was found to be suitable for synthesis of cobalt oxide nanoparticles, as it has proficient tolerance towards metal under study. The broth containing precursor solution and organism Aspergillus nidulans had changed from pink to orange indicating the formation of nanoparticles. Characterization by x-ray diffraction analysis (XRD), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR) and energy dispersive x-ray analysis (EDX) confirmed the formation of spinel cobalt oxide nanoparticles at an average size of 20.29 nm in spherical shape with sulfur bearing proteins acting as a capping agent for the synthesized nanoparticles. The nanoparticles could be applied in energy storage, as a specific capacitance of 389 F/g showed competence. The study was a greener attempt to synthesize cobalt oxide nanoparticles using endophytic fungus. PMID- 29709814 TI - Reducing uncertainty of estimated nitrogen load reductions to aquatic systems through spatially targeting agricultural mitigation measures using groundwater nitrogen reduction. AB - The need to further abate agricultural nitrate (N)-loadings to coastal waters in Denmark represents the main driver for development of a new spatially targeted regulation that focus on locating N-mitigation measures in agricultural areas with high N-load. This targeting makes use of the spatial variation across the landscape in natural N-reduction (denitrification) of leached nitrate in the groundwater and surface water systems. A critical basis for including spatial targeting in regulation of N-load in Denmark is the uncertainty associated with the effect of spatially targeting measures, since the effect will be critically affected by uncertainty in the quantification of the spatial variation in N reduction. In this study, we used 30 equally plausible N-reduction maps, at 100 m grid and sub-catchment resolutions, for the 85-km2 groundwater dominated Norsminde catchment in Denmark, applying set-aside as the measure on high N-load areas to reach a N-load reduction target of 20%. The uncertainty on these N reduction maps resulted in uncertainty on the estimated N-load and on the required set-aside area. We tested several methods for spatially targeting set aside that took into account the uncertainty on set-aside area and developed methods to reduce uncertainty on the estimated N-load reductions. These methods includes application of set-aside based on each individual N-reduction map compared to a mean N-reduction map, using spatial frequency of high N-load and using spatial frequency of low N-reduction. The results revealed that increasing the ensemble size for averaging the N-reduction maps would decrease the uncertainty on the estimated set-aside area with a stable effect when using an ensemble of 15 or more maps. The spatial resolution of the groundwater N reduction map is essential for the effectiveness of set-aside, but uncertainty of the finer spatial resolution of N-reduction is greater compared to sub-catchment scale, and application of a spatially targeted strategy with uncertain N reduction maps will result in incorrect set-aside area and uncertain estimations of N-load reductions. To reduce the uncertainty on estimated N-load reductions, this study finds the method of set-aside application based on spatial frequency of high N-load to be more effective than other methods tested. PMID- 29709815 TI - Biochar, compost and biochar-compost blend as options to recover nutrients and sequester carbon. AB - This work assessed the potential environmental impact of recycling organic materials in agriculture via pyrolysis (biochar) and composting (compost), as well its combination (biochar-compost blend) versus business-as-usual represented by mineral fertiliser. Life cycle assessment methodology was applied using data sourced from experiments (FP7 project Fertiplus) in three countries (Spain, Italy and Belgium), and considering three environmental impact categories, (i) global warming; (ii) acidification and (iii) eutrophication. The novelty of this analysis is the inclusion of the biochar-compost blend with a focus on multiple European countries, and the inclusion of the acidification and eutrophication impact categories. Biochar, compost and biochar-compost blend all resulted in lower environmental impacts than mineral fertiliser from a systems perspective. Regional differences were found between biochar, compost and biochar-compost blend. The biochar-compost blend offered benefits related to available nutrients and sequestered C. It also produced yields of similar magnitude to mineral fertiliser, which makes its acceptance by farmers more likely whilst reducing environmental impacts. However, careful consideration of feedstock is required. PMID- 29709816 TI - Unbundling household preferences for improved sanitation: A choice experiment from an urban settlement in Nicaragua. AB - Many urban settlements in developing countries still lack access to sanitation services, which puts the environment and population health at risk. The lack of knowledge on household preferences for improved sanitation has been an impediment to extending conventional and onsite sanitation infrastructure. This study implemented a choice experiment to elicit households' willingness to pay for the disposal of different types of waste (i.e. wastewater, excreta, and rainwater) in an urban settlement in Nicaragua. Generalized multinomial logit models were estimated to account for heterogeneity among respondents in both choice behavior and preferences for specific attributes. Findings indicate that households are willing to pay a considerable amount of money for improved disposal of wastewater, excreta, and rainwater. However, households have stronger preferences for wastewater and excreta removal than for disposal of rainwater. PMID- 29709817 TI - Heavy metal removal from aqueous solution using sodium alginate immobilized sulfate reducing bacteria: Mechanism and process optimization. AB - Heavy metal removal was evaluated using sodium alginate immobilized sulfate reducing bacteria (SRB) under batch and continuous mode. Under batch conditions, more than 95% metal removal was achieved due to formation of insoluble metal sulfides exterior to the bead surface. Best heavy metal removal results were obtained at 48 h hydraulic retention time (HRT). Metal loading rate values upto 2.20 mg/L?h for Fe(III), Zn(II), Cd(II), Pb(II) and Ni(II) and upto 4.29 mg/L?h for Cu(II) were proved to be favorable for their removal using the continuous downflow column reactor packed with the immobilized SRB beads. Continuous metal removal from a mixture of the heavy metals showed that Cu(II) removal was maximum (99%), followed by Zn(II) (95.8%) and other metals at their respective low inlet concentrations. However, the removal values were reduced at a high inlet concentration of these metals, which matched well with low COD and sulfate reduction values. PMID- 29709818 TI - Comparative Life Cycle Assessment of possible methods for the treatment of contaminated soil at an environmentally degraded site. AB - This study reports on the assessment of the environmental sustainability of different management practices for an environmentally degraded site in Slovenia: the Old Zinc-Works in the town of Celje. Life Cycle Assessments (LCAs) were applied in order to evaluate possible trade-offs by comparing a proposed in situ remediation scenario with two other reclamation scenarios (scenario 2: incineration, metal extraction, underground disposal and reclamation of the site by refilling it with replacement material, and scenario 3: underground disposal and reclamation of the site by refilling it with replacement material) and with a no-action scenario. The results of the comparisons performed show that in the case of the in situ remediation scenario, the consumption of resources is smaller by a factor of 51 compared to that in the second scenario and by a factor of 7 compared to that in the third scenario. The impacts on human health and ecosystem quality are approximately 30 and 3.5 times less in the first scenario than in the second and third scenarios, respectively. Compared to the impact of the no-action scenario, the impact on human health of the in situ soil remediation scenario is approximately 6 times less, whereas its impact on the ecosystem is approximately 4 times less. The results confirmed that the in situ soil remediation scenario is the most sustainable practice from an environmental point of view. Its main advantage lies in the achieved conservation of natural resources. Despite the recovery of valuable metals (Zn, Pb, Cu, and Ni) from the bottom ash, the second scenario is significantly more environmentally burdensome compared to both the first and third scenarios. This outcome is due to the significantly high impacts related to the consumption of fuels needed to support the incineration of low calorific contaminated soil and to electricity consumption. The present study demonstrates that the results of LCA studies, in addition to technological, economic and social indicators, yield important information about the sustainability of different management practices and therefore should be an important part of decision-making when approaching the reclamation of environmentally degraded sites. PMID- 29709819 TI - Evaluation of simultaneous organic matters and nutrients removal from municipal wastewater using a novel bioreactor (D-A2O) system. AB - A novel bioreactor, the divisional influent dual-anaerobic-anoxic/oxic (D-A2O) system, was applied to treat municipal wastewater. This new system improved the removal efficiency of simultaneous organic matters and nutrients, and provided a reduction in the system's energy costs and sludge yield. Results from the reactor's 18 months of operation demonstrated the following optimal conditions for the 4 key parameters of the system: (1) a divisional ratio (DR) of 8:2 between the influent flow volumes fed into the anaerobic and anoxic tanks, (2) a hydraulic retention time (HRT) of 6 h, (3) a R:r ratio of 200%:100% between the mixed liquor return ratio (R) and the return activated sludge ratio (r), and (4) an alternative operating time (tA/B) of 1 h for the A/B anaerobic-anoxia series. Under optimal conditions, the system showed a high removal efficiency for the chemical oxygen demand (COD), total nitrogen (TN), ammonia nitrogen (NH3-N), and total phosphorus (TP) removals, with the average removal efficiencies (with a standard deviation of less than 3%) being 95.23%, 80.64%, 90.42%, and 90.03%, respectively. The final concentration ranges of COD, TN, NH3-N, and TP in the effluent were 26-48 mg L-1, 6.11-11.03 mg L-1, 2.93-4.04 mg L-1, and 0.21-0.45 mg L-1, respectively. The concentrations of the pollutants in the effluent from the D-A2O system were lower than those required for Level 1A (Chinese quality of wastewater discharge standard GB18918-2002). According to the results, we concluded that the divisional influent dual-anaerobic-anoxic system (which integrated the A2O and sequencing batch reactor (SBR) process) was successfully provided sufficient carbon sources for denitrification and phosphorus uptake without external carbon addition. Compared to the conventional anaerobic anoxic/oxic (A2O) process, the D-A2O system offers a high removal efficiency, simple operation, and significant energy saving of about 0.276 kWh m-3 based on the volume of the treated water. Therefore, the new D-A2O system has a strong potential for use in treatment plants. PMID- 29709820 TI - The long-run effects of economic, demographic, and political indices on actual and potential CO2 emissions. AB - This study examines the long-run drivers of potential and actual CO2 emissions in Ghana, a sub-Saharan Africa country. The use of the former helps address the reverse causality problem and capture the true long-run effects. The Stock-Watson dynamic OLS is used with data from 1970 to 2014. The result shows that potential CO2 emissions improve model efficiency. Income (except in "other sector") and financial development (except in manufacturing and construction sector) have compelling positive and negative effects on actual and potential CO2 emissions, respectively. A higher price (oil and electricity) reduces actual and potential CO2 emissions, but electricity price is more vital in residential, buildings and commercial and public services sector, while oil price is crucial in the transport sector. Democracy lowers actual and potential CO2 emissions in the aggregate (insignificant) and transport sectors but raises it in the manufacturing and construction sector. The effect is, however, inconsistent for the remaining sectors. Urbanization raises aggregate actual and potential CO2 emissions, but the effect is inconsistent for the transport sector. The findings have important implications for policy formulation. PMID- 29709821 TI - Managing the resilience space of the German energy system - A vector analysis. AB - The UN Sustainable Development Goals formulated in 2016 confirmed the sustainability concept of the Earth Summit of 1992 and supported UNEP's green economy transition concept. The transformation of the energy system (Energiewende) is the keystone of Germany's sustainability strategy and of the German green economy concept. We use ten updated energy-related indicators of the German sustainability strategy to analyse the German energy system. The development of the sustainable indicators is examined in the monitoring process by a vector analysis performed in two-dimensional Euclidean space (Euclidean plane). The aim of the novel vector analysis is to measure the current status of the Energiewende in Germany and thereby provide decision makers with information about the strains for the specific remaining pathway of the single indicators and of the total system in order to meet the sustainability targets of the Energiewende. Within this vector model, three vectors (the normative sustainable development vector, the real development vector, and the green economy vector) define the resilience space of our analysis. The resilience space encloses a number of vectors representing different pathways with different technological and socio-economic strains to achieve a sustainable development of the green economy. In this space, the decision will be made as to whether the government measures will lead to a resilient energy system or whether a readjustment of indicator targets or political measures is necessary. The vector analysis enables us to analyse both the government's ambitiousness, which is expressed in the sustainability target for the indicators at the start of the sustainability strategy representing the starting preference order of the German government (SPO) and, secondly, the current preference order of German society in order to bridge the remaining distance to reach the specific sustainability goals of the strategy summarized in the current preference order (CPO). PMID- 29709822 TI - Participative approach to elicit water quality monitoring needs from stakeholder groups - An application of integrated watershed management. AB - Water quality monitoring programs (WQMPs) must be based on monitoring objectives originating from the real knowledge needs of all stakeholders in a watershed and users of the resource. This paper proposes a participative approach to elicit knowledge needs and preferred modes of communication from citizens and representatives of organized stakeholders (ROS) on water quality and quantity issues. The participative approach includes six steps and is adaptable and transferable to different types of watersheds. These steps are: (1) perform a stakeholder analysis; (2) conduct an adaptable survey accompanied by a user friendly public participation geographical information system (PPGIS); (3) hold workshops to meet with ROS to inform them of the results of the survey and PPGIS; discuss attainment of past monitoring objectives; exchange views on new knowledge needs and concerns on water quality and quantity; (4) meet with citizens to obtain the same type of input (as from ROS); (5) analyze the data and information collected to identify new knowledge needs and modes of communication and (6) identify, in collaboration with the individuals in charge of the WQMPs, the short , medium- and long-term monitoring objectives and communication strategies to be pursued. The participative approach was tested on two distinct watersheds in the province of Quebec, Canada. It resulted in a series of optimization objectives of the existing WQMPs, new monitoring objectives and recommendations regarding communication strategies of the WQMPs' results. The results of this study show that the proposed methodology is appreciated by all parties and that the outcomes and monitoring objectives are acceptable. We also conclude that successful integrated watershed management is a question of scale, and that every aspect of integrated watershed management needs to be adapted to the surface watershed, the groundwater watershed (aquifers) and the human catchment area. PMID- 29709823 TI - Butanolysis: Comparison of potassium hydroxide and potassium tert-butoxide as catalyst for biodiesel preparing from rapeseed oil. AB - Biodiesel is a mixture of esters of fatty acids (most often palmitic, stearic and oleic) and lower alcohols (in our work butanol) produced by transesterification. It is a renewable source of energy, prepared from triacylglycerides, which are contained in vegetable oils and animal fats. This work focuses on alkaline catalyzed transesterification of rapeseed oil with butanol and comparison of two catalysts (potassium hydroxide and potassium tert-butoxide). In industry is usually transesterification of rapeseed oil carried out like reaction catalyzed by potassium hydroxide. Potassium hydroxide have high content of K2CO3, KHCO3 and water. Moreover water is formed by neutralization of potassium hydroxide with free fatty acids contained in oil. In cause of tert-butoxide catalyzed reaction, it is not possible because tert-butoxide have not a OH- aniont, which is needed for water forming. The influence of various conditions (addition of water, temperature of separation, intensity of stirring and type of catalyst) on butanolysis process was studied for both catalysts. For both catalysts dependence of conversions on time were plotted. When tert-butoxide was used, satisfactory phase separation was not achieved. The only way was separation of hot crude reaction mixture without adding water. Ester formed by this method had high content of free glycerol and soaps, but reached higher conversion. The best results were obtained with KOH and subsequent separation of cold crude reaction mixture with the addition of water and slow stirring. The difference between reactions catalyzed by potassium hydroxide and potassium tert-butoxide was described. PMID- 29709824 TI - Design and testing of a pilot scale magnetic separator for the treatment of textile dyeing wastewater. AB - Iron nanoparticles can be incorporated on the structure of natural clays to obtain magnetic clays, an adsorbent that be easily removed from a wastewater by magnetic means. Magnetic clays have high adsorption capacities of different contaminants such as heavy metals, fungicides, aromatic compounds and colorants and show rapid adsorption kinetics, but crucial data for achieving its full or pilot scale application is still lacking. In this work, magnetic bentonites with different amounts of magnetite (iron fractions on the clay of 0.55, 0.6 and 0.6) were used to remove color from a real textile wastewater. On a first stage the optimal conditions for the adsorption of the dye, including pH, temperature and clay dosage were determined. Also design parameters for the separation process such as residence time, distance from magnet to magnetic clay and magnet strength were obtained. Finally a pilot scale magnetic drum separator was constructed and tested. A removal of 60% of the dye from a wastewater that contained more than 250 ppm of azo dye was achieved with only 10 min of residence time inside the separator. PMID- 29709826 TI - Preliminary female cervical spine injury risk curves from PMHS tests. AB - The human cervical spine sustains compressive loading in automotive events and military operational activities, and the contact and noncontact loading are the two primary impact modes. Biomechanical and anatomical studies have shown differences between male and female cervical spines. Studies have been conducted to determine the human tolerance in terms of forces from postmortem human subject (PMHS) specimens from male and female spines; however, parametric risk curves specific to female spines are not available from contact loading to the head-neck complex under the axial mode. This study was conducted to develop female-spine based risk curves from PMHS tests. Data from experiments conducted by the authors using PMHS upright head-spines were combined with data from published studies using inverted head-spines. The ensemble consisted of 20 samples with ages ranging from 29 to 95 years. Except one, all specimens sustained neck injuries, consisting of fractures to cervical vertebrae, and disruptions to the intervertebral disc and facet joints, and ligaments. Parametric survival analysis was used to derive injury probability curves using the compressive force, uncensored for injury and right censored for noninjury data points. The specimen age was used as the covariate. Injury probability curves were derived using the best fit distribution, and the +/- 95% confidence interval limits were obtained. Results indicated that age is a significant covariate for injury for the entire ensemble. Peak forces were extracted for 35, 45, and 63 (mean) years of age, the former two representing the young (military) and the latter, the automobile occupant populations. The forces of 1.2 kN and 2.9 kN were associated with 5% and 50% probability of injury at 35 years. These values at 45 years were 1.0 kN and 2.4 kN, and at 63 years, they were 0.7 kN and 1.7 kN. The normalized widths of the confidence intervals at these probability levels for the mean age were 0.74 and 0.48. The preliminary injury risk curves presented should be used with appropriate caution. This is the first study to develop risk curves for females of different ages using parametric survival analysis, and can be used to advance human safety, and design and develop manikins for military and other environments. PMID- 29709825 TI - Improvement of carbon usage for phosphorus recovery in EBPR-r and the shift in microbial community. AB - Enhanced biological phosphorus removal and recovery (EBPR-r) is a biofilm process that makes use of polyphosphate accumulating organisms (PAOs) to remove and recover phosphorus (P) from wastewater. The original process was inefficient, as indicated by the low P-release to carbon (C)-uptake (Prel/Cupt) molar ratio of the biofilm. This study successfully validated a strategy to improve the Prel/Cupt ratio by at least 3-fold. With an unchanged supply of carbon in the recovery stream, an increase in the hydraulic loading in stages I, II and III (7.2, 14.4 and 21.6 L, respectively) resulted in a 43% increase in the Prel/Cupt ratio (0.069, 0.076 and 0.103, respectively). The ratio further increased by 150% (from 0.103 to 0.255) when the duration of the P uptake period was increased from 4 h (stage III) to 10 h (stage IV). Canonical correspondence analysis showed that, correlated to the 3-fold increase in the Prel/Cupt ratio, there was an increase in the abundance of PAOs ("Candidatus Accumulibacter" Clade IIA) and a decrease in the occurrence of glycogen accumulating organisms (GAOs) (family Sinobacteraceae). However, the four stage operation impaired denitrification, resulting in a 5-fold reduction in the Nden/Pupt ratio. The decline in denitrification was consistent with a decrease in the abundance of denitrifiers including denitrifying PAOs (family Comamonadaceae and "Candidatus Accumulibacter" Clade IA). Overall, a strategy to facilitate more efficient use of carbon was validated, enabling a 3-fold carbon saving for P recovery. The new process enabled up to 80% of the wastewater P to be captured in a P-enriched stream (>90 mg/L) with a single uptake/release cycle of recovery. PMID- 29709827 TI - A case of perampanel-induced delirium in a patient with symptomatic epilepsy. PMID- 29709828 TI - Effect of pH on the adsorption and interactions of Bovine Serum Albumin with functionalized silicon nitride surface. AB - Force-distance curves between atomic force microscopy (AFM) tip (Si3N4 non functionalized) and bovine serum Albumin (BSA) immobilized on Si3N4 substrates have been performed with the purpose to understand how multiple interactions between the protein and the tip were favored in different pHs (4, 6 and 10). In this work, 100 silicon wafer samples were used to deposit a layer of Si3N4. Protein immobilization consisted of the silanization of the substrates with 3 aminopropyltriethoxysilane (APTES) and crosslinking with glutaraldehyde (GA). All functionalization steps were evaluated by contact angle, X-Ray electron spectroscopy (XPS) and AFM. AFM images showed increase of roughness following functionalization. At pH 4, it was possible to note that small forces (49.1 +/- 2.4 pN) were needed to stretch BSA, with a contour length of CL = (30.0 +/- 1.1 nm). At pH 6, the force applied was higher (101.5 +/- 5.0 pN) with a higher molecule stretch CL = (75.6 +/- 3.8 nm) because the pH is close to the BSA isoelectric point where the folding of the protein is favored as surfaces charges are minimized leading to lower attractive intramolecular forces. Young's Modulus were also calculated and the lowest value (265 kPa) was observed at pH 10. PMID- 29709829 TI - Fabrication and characterization of collagen-based injectable and self crosslinkable hydrogels for cell encapsulation. AB - Injectable and self-crosslinkable hydrogels have drawn much attention for their potential application as cell delivery carriers to deliver cells to the injury site of arbitrary shape. In this study, injectable and self-crosslinkable hydrogels were designed and fabricated based on collagen type I (Col I) and activated chondroitin sulfate (CS-sNHS) by physical and chemical crosslinking without the addition of any catalysts. The physical properties of hydrogels, including mechanical properties, swelling and degradation properties, were investigated. The results demonstrated that the physical properties of hydrogels, especially the stiffness of hydrogels, were readily tuned by varying the degree of substitution (DS) of CS-sNHS without changing the concentration of collagen based precursor. Chondrocytes were encapsulated into hydrogels to investigate the effects of hydrogels on the survival, proliferation and extracellular matrix (ECM) secretion of cells by FDA/PI staining, CCK-8 test and histological staining. The results suggested that all of these hydrogels supported the survival and ECM secretion of chondrocytes, while there was more ECM secretion around chondrocytes encapsulated in hydrogel Col I/CS-sNHS56% in which the DS of CS-sNHS was 56%. When the neutral precursor solution for hydrogel of Col I or Col I/CS-sNHS56% was subcutaneously injected into SD rats, hydrogels both displayed acceptable biocompatibility in vivo. These results imply that these injectable and self-crosslinkable hydrogels are suitable candidates for applications in the fields of cell delivery and tissue engineering. PMID- 29709830 TI - Enzyme- and label-free electrochemical aptasensor for kanamycin detection based on double stir bar-assisted toehold-mediated strand displacement reaction for dual-signal amplification. AB - It is critically important to detect antibiotic residues for monitoring food safety. In this study, an enzyme- and label-free electrochemical aptasensor for antibiotics, with kanamycin (Kana) as a typical analyte, was developed based on a double stir bar-assisted toehold-mediated strand displacement reaction (dSB TMSDR) for dual-signal amplification. First, we modified two gold electrodes (E-1 and E-2) with different DNA probes (S1/S2 hybrid probe in E-1 and DNA fuel strand S3 in E-2). In the presence of Kana, an S1/S2 probe can be disassembled from E-1 to form an S2/Kana complex in supernatant. The S2/Kana could react with S3 on E-2 to form S2/S3 hybrid and release Kana through TMSDR. After then, the target recycling was triggered. Subsequently, the formed S2/S3 hybrid can also trigger a hybridization chain reaction (HCR). Consequently, the dual-signal amplification strategy was established, which resulted in many long dsDNA chains on E-2. The chains can associate with methylene blue (MB) as redox probes to produce a current response for the quantification of Kana. The assay exhibited high sensitivity and specificity with a detection limit at 16 fM Kana due to the dual signal amplification. The double stir bars system can both increase phase separation and prevent leakage of DNA fuel to reduce background interference. Moreover, it allows flexible sequence design of the TMSDR probes. The assay was successfully employed to detect Kana residues in food and showed potential application value in food safety detection. PMID- 29709832 TI - Effect of magnesium supplementation on endothelial function: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND AND AIMS: Findings of past studies are inconsistent regarding the effects of magnesium (Mg) supplementation on endothelial function (EF). We performed this meta-analysis to examine the effects of magnesium supplementation on flow-mediated dilation (FMD) and carotid intima media thickness (CIMT) as markers of EF. METHODS: Literature searches of English publications in MEDLINE and EMBASE databases were conducted up to November 2017. Results are reported as weighted mean difference (MD) with 95% confidence intervals (CI) using random effects model (DerSimonian-Laird method). Cochrane's Q test and I-squared (I2) were used to determine heterogeneity among included studies. To determine potential sources of heterogeneity, subgroup analysis was conducted for pre defined criteria. Funnel plot and Egger's regression test were used to assess publication bias. RESULTS: Seven RCTs with 306 participants were included. Mg supplementation significantly increased FMD (MD: 2.97; 95% CI: 0.23 to 5.70%, p = 0.033). Between studies heterogeneity was high and subgroup analysis could not identify the sources of heterogeneity. Magnesium supplementation had no significant effect on CIMT (MD: -0.13 mm; 95% CI: 0.27, 0.01; p = 0.077) with high heterogeneity. Mg dose, duration of treatment, healthy status, baseline CIMT and sample size were the potential sources of heterogeneity. Mg supplementation could decrease CIMT to a greater extent in hemodialysis (HD) patients; lower doses of Mg, higher sample size and follow up duration and subjects with higher baseline CIMT also reduced the heterogeneity to some degree (p < 0.001). CONCLUSIONS: Magnesium supplementation may improve endothelial function without affecting carotid intima media thickness. PMID- 29709831 TI - Rapid and background-free detection of avian influenza virus in opaque sample using NIR-to-NIR upconversion nanoparticle-based lateral flow immunoassay platform. AB - Rapid and sensitive on-site detection of avian influenza virus (AIV) is the key for achieving near real-time surveillance of AIV and reducing the risk of dissemination. However, unlike the laboratory-prepared transparent buffer solutions containing a single type of influenza virus, distinction between real- and false- positive outputs and detection of low concentrations of AIV in stool specimens or cloacal swabs are difficult. Here, we developed a rapid and background-free lateral flow immunoassay (LFA) platform that utilizes near infrared (NIR)-to-NIR upconversion nanoparticles (UCNPs) to yield a sensor that detects AIV nucleoproteins (NPs) from clinical samples within 20 min. Ca2+ as a heterogeneous dopant ion in the shell enhanced the NIR-to-NIR upconversion photoluminescence (PL) emission without inducing significant changes in the morphology of the UCNPs. In a mixture of opaque stool samples and gold nanoparticles (GNPs), which are components of commercial AIV LFA, the background signal of the stool samples masked the absorption peak of GNPs. However, UCNPs dispersed in the stool samples still show strong emission centered at 800 nm when excited at 980 nm, which enables the NIR-to-NIR upconversion nanoparticle-based lateral flow immunoassay (NNLFA) platform to detect 10-times lower viral load than a commercial GNP-based AIV LFA. The detection limit of NNLFA for LPAI H5N2 and HPAI H5N6 viruses was 102 and 103.5 EID50/mL, respectively. Moreover, the viruses were successfully detected within dark brown-colored samples using the NNLFA but not the commercial AIV LFA. Therefore, the rapid and background-free NNLFA platform can be used for sensitive on-site detection of AIV. PMID- 29709833 TI - Effect of incubation temperature and pH on the recovery of Bacillus weihenstephanensis spores after exposure to a peracetic acid-based disinfectant or to pulsed light. AB - The recovery at a range of incubation temperatures and pH of spores of Bacillus weihenstephanensis KBAB4 exposed to a peracetic acid-based disinfectant (PABD) or to pulsed light was estimated. Spores of B. weihenstephanensis were produced at 30 degrees C and pH 7.00, at 30 degrees C and pH 5.50, or at 12 degrees C and pH 7.00. The spores were treated with a commercial peracetic acid-based disinfectant at 80 mg.mL-1 for 0 to 200 min at 18 degrees C or by pulsed light at fluences ranging between 0.4 and 2.3 J.cm-2 for pulsed light treatment. After each treatment, the spores were incubated on nutrient agar at 12 degrees C, 30 degrees C or 37 degrees C, or at pH 5.10, 6.00 or 7.40. Incubation temperature during recovery had a significant impact only near the recovery limits, beyond which surviving spores previously exposed to a PABD or to pulsed light were not able to form colonies. In contrast, a decrease in pH of the recovery nutrient agar had a progressive impact on the ability of spores to form colonies. The time to first log reduction after PABD treatment was 29.5 +/- 0.7 min with recovery at pH 7.40, and was tremendously shortened 5.1 +/- 0.2 min with recovery at pH 5.10. Concerning the fluence necessary for the first log reduction, it was 1.5 times higher when the spores were recovered at pH 6.00 compared to a recovery at pH 5.10. The impact of recovery temperature and pH can be described with a mathematical model using cardinal temperature and pH as parameters. These effects of temperature and pH on recovery of Bacillus weihenstephanensis spores exposed to a disinfectant combining peracetic acid and hydrogen peroxide, or pulsed light are similar, although these treatments are of different natures. Sporulation temperature or pH did not impact resistance to the peracetic acid-based disinfectant or pulsed light. PMID- 29709834 TI - Vulnerability to the impact of temperature variability on mortality in 31 major Chinese cities. AB - Few studies have analyzed the health effects of temperature variability (TV) accounting for both interday and intraday variations in ambient temperature. In this study, TV was defined as the standard deviations of the daily minimum and maximum temperature during different exposure days. Distributed lag non-linear Poisson regression model was used to examine the city-specific effect of TV on mortality in 31 Chinese municipalities and provincial capital cities. The national estimate was pooled through a meta-analysis based on the restricted maximum likelihood estimation. To assess effect modification on TV-mortality association by individual characteristics, stratified analyses were further fitted. Potential effect modification by city characteristics was performed through a meta-regression analysis. In total, 259 million permanent residents and 4,481,090 non-accidental deaths were covered in this study. The effect estimates of TV on mortality were generally increased by longer exposure days. A 1 degrees C increase in TV at 0-7 days' exposure was associated with a 0.60% (95% CI: 0.25 0.94%), 0.65% (0.24-1.05%), 0.82% (0.29-1.36%), 0.86% (0.42-1.31%), 0.98% (0.57 1.39%) and 0.54% (-0.11-1.20%) increase in non-accidental, cardiovascular, IHD, stroke, respiratory and COPD mortalities, respectively. Those with lower levels of educational attainment were significantly susceptible to TV. Cities with dense population, higher mean temperatures, and relative humidity and lower diurnal temperature ranges also had higher mortality risks caused by TV. This study demonstrated that TV had considerable health effects. An early warning system to alert residents about large temperature variations is recommended, which may have a significant impact on the community awareness and public health. PMID- 29709835 TI - Sewer sediment-bound antibiotics as a potential environmental risk: Adsorption and desorption affinity of 14 antibiotics and one metabolite. AB - In this study, 14 antibiotics and one metabolite were determined in sewages and size-dependent sewer sediments at three sampling sites in the city of Dresden, Germany. Adsorption and desorption experiments were conducted with fractionated sediments. All antibiotics and the metabolite investigated were determined in the sewages; 9 of 14 antibiotics and the metabolite were adsorbed to sewer sediments. The adsorbed antibiotic loads in ng of antibiotic per g of sediment correlated with antibiotic concentrations in ng of antibiotic per litre of sewage. The size fractions <63 MUm, 63-100 MUm and 100-200 MUm had significantly higher loads of adsorbed antibiotics than bigger size fractions. In general, the adsorbed load decreased with an increasing size fraction, but size fractions >200 MUm had similar levels of adsorbed antibiotic loads. An antibiotic-specific adsorption coefficient, normalized to organic content, was calculated: four antibiotics exceeded 10.0 L g-1, three antibiotics fell below 1.0 L g-1 and all residual antibiotics and the metabolite were in the range of 1.0-10.0 L g-1. The adsorbed antibiotic load and the organic matter increased with time, generally. The mineral composition had a minor effect on the adsorption coefficients. Desorption dynamics of five antibiotics and the metabolite were quantified. Regardless of the size fraction, the predominant part of the equilibrium antibiotic concentration was desorbed after 10 min. The calculated desorption distribution coefficient indicated adsorption as irreversible at the pH investigated (7.5 +/- 0.5). PMID- 29709836 TI - Current and future hot-spots and hot-moments of nitrous oxide emission in a cold climate river basin. AB - An ecosystem in a cold climate river basin is vulnerable to the effects of climate change affecting permafrost thaw and glacier retreat. We currently lack sufficient data and information if and how hydrological processes such as glacier retreat, snowmelt and freezing-thawing affect sediment and nutrient runoff and transport, as well as N2O emissions in cold climate river basins. As such, we have implemented well-established, semi-empirical equations of nitrification and denitrification within the Soil and Water Assessment Tool (SWAT), which correlate the emissions with water, sediment and nutrients. We have tested this implementation to simulate emission dynamics at three sites on the Canadian prairies. We then regionalized the optimized parameters to a SWAT model of the Athabasca River Basin (ARB), Canada, calibrated and validated for streamflow, sediment and water quality. In the base period (1990-2005), agricultural areas (2662 gN/ha/yr) constituted emission hot-spots. The spring season in agricultural areas and summer season in forest areas, constituted emission hot-moments. We found that warmer conditions (+13% to +106%) would have a greater influence on emissions than wetter conditions (-19% to +13%), and that the combined effect of wetter and warmer conditions would be more offsetting than synergetic. Our results imply that the spatiotemporal variability of N2O emissions will depend strongly on soil water changes caused by permafrost thaw. Early snow freshet leads to spatial variability of soil erosion and nutrient runoff, as well as increases of emissions in winter and decreases in spring. Our simulations suggest crop residue management may reduce emissions by 34%, but with the mixed results reported in the literature and the soil and hydrology problems associated with stover removal more research is necessary. This modelling tool can be used to refine bottom-up emission estimations at river basin scale, test plausible management scenarios, and assess climate change impacts including climate feedback. PMID- 29709837 TI - Ultrafine particle emissions from modern Gasoline and Diesel vehicles: An electron microscopic perspective. AB - Ultrafine (<100 nm) particles related to traffic are of high environmental and human health concern, as they are supposed to be more toxic than larger particles. In the present study transmission electron microscopy (TEM) is applied to obtain a concrete picture on the nature, morphology and chemical composition of non-volatile ultrafine particles in the exhaust of state-of-the-art, Euro 6b, Gasoline and Diesel vehicles. The particles were collected directly on TEM grids, at the tailpipe, downstream of the after-treatment system, during the entire duration of typical driving cycles on the chassis dynamometer. Based on TEM imaging coupled with Energy Dispersive X-ray (EDX) analysis, numerous ultrafine particles could be identified, imaged and analyzed chemically. Particles <10 nm were rarely detected. The ultrafine particles can be distinguished into the following types: soot, ash-bearing soot and ash. Ash consists of Ca, P, Mg, Zn, Fe, S, and minor Sn compounds. Most elements originate from lubricating oil additives; Sn and at least part of Fe are products of engine wear; minor W +/- Si bearing nearly spherical particles in Diesel exhaust derive from catalytic coating material. Ultrafine ash particles predominate over ultrafine soot or are nearly equal in amount, in contrast to emissions of larger sizes where soot is by far the prevalent particle type. This is probably due to the low ash amount per volume fraction in the total emissions, which does not favor formation of large ash agglomerates, opposite to soot, which is abundant and thus easily forms agglomerates of sizes larger than those of the ultrafine range. No significant differences of ultrafine particle characteristics were identified among the tested Gasoline and Diesel vehicles and driving cycles. The present TEM study gives information also on the imaging and chemical composition of the solid fraction of the unregulated sub-23 nm size category particles. PMID- 29709838 TI - Major threats of pollution and climate change to global coastal ecosystems and enhanced management for sustainability. AB - Coastal zone is of great importance in the provision of various valuable ecosystem services. However, it is also sensitive and vulnerable to environmental changes due to high human populations and interactions between the land and ocean. Major threats of pollution from over enrichment of nutrients, increasing metals and persistent organic pollutants (POPs), and climate change have led to severe ecological degradation in the coastal zone, while few studies have focused on the combined impacts of pollution and climate change on the coastal ecosystems at the global level. A global overview of nutrients, metals, POPs, and major environmental changes due to climate change and their impacts on coastal ecosystems was carried out in this study. Coasts of the Eastern Atlantic and Western Pacific were hotspots of concentrations of several pollutants, and mostly affected by warming climate. These hotspots shared the same features of large populations, heavy industry and (semi-) closed sea. Estimation of coastal ocean capital, integrated management of land-ocean interaction in the coastal zone, enhancement of integrated global observation system, and coastal ecosystem-based management can play effective roles in promoting sustainable management of coastal marine ecosystems. Enhanced management from the perspective of mitigating pollution and climate change was proposed. PMID- 29709839 TI - Structural characterization of Chinese quince fruit lignin pretreated with enzymatic hydrolysis. AB - Lignin is an increasingly valuable raw material for industrial, pharmaceutical and the food industries; natural antioxidants are also being used more and more widely. The Chinese quince fruits have an abundance of lignins with antioxidant properties; however, the lignins cannot be isolated by the methods conventionally used on other sources (e.g., wood, straw). In this investigation, multi-enzymatic hydrolytic pretreatments were used to isolate lignins from Chinese quince fruit, and the structures of these multi-enzyme mixture lignin (EML) fractions were then analyzed and compared with conventional cellulolytic enzyme lignin (CEL). EML fractions are structurally similar to CEL fractions except for an increased S/G ratio, greater number of beta-O-4 linkages, higher average molecular weight and decreased thermal stability. The EML-2 fraction in particular seemed most representative of the lignins isolated, and it exhibited the highest antioxidant activity in comparison with CEL and other EML fractions. PMID- 29709840 TI - Transformation of organic nitrogen fractions with different molecular weights during different organic wastes composting. AB - This study aimed to investigate different transformation mechanisms of organic nitrogen (N) fractions during composting with different raw materials, and the contributions of bacterial communities and environmental factors to organic N fractions transformation. The results showed that high molecular weight organic N was first degraded to low molecular weight organic N and then turned into NH4+ during chicken manure composting. In comparison, organic N fractions were stored in composts rather than mineralization during garden waste and municipal solid waste composting. Meanwhile, bacterial communities, environmental factors and the combination of them were the main drivers of N transformation during chicken manure, municipal solid waste and garden waste composting, respectively. In conclusion, the proposed organic N transformation mechanisms in this study provided a theoretical basis for improving the quality of compost products. PMID- 29709841 TI - Biological acetate production from carbon dioxide by Acetobacterium woodii and Clostridium ljungdahlii: The effect of cell immobilization. AB - This study investigated the acetate production from gas mixture of hydrogen (H2) and carbon dioxide (CO2) in the ratio of 7:3 using two acetogens: Acetobacterium woodii and Clostridium ljungdahlii. Batch result shows A. woodii performed two phase degradation with the presence of glucose that lactate was produced from glucose and was reutilized for the production of butyrate and few acetate, while only acetate was detected when providing gas mixture. C. ljungdahlii produced butyrate and ethanol along with acetate when glucose was introduced, while only ethanol and acetate were found by feeding gas mixture. The acetate-to-ethanol (A/E) ratio can be enhanced by cell immobilization, while GAC immobilization produced only acetate and the production rate reached 0.072 mmol/d under fed batch operation. Acetate production rate increased from 18 to 28 mmol/L/d with GAC immobilization when gas flowrate increased from 100 to 300 mL/min in anaerobic fluidized membrane bioreactor (AFMBR), and a highest A/E ratio of 30 implies the possible application of acetate recovery from H2 and CO2. PMID- 29709842 TI - Two-steps gas double-dynamic solid-state fermentation enhances growth and spore production of Conithyrium minitans. AB - Gas double-dynamic solid-state fermentation (SSF) is a promising strategy with the potential in transforming open-pattern fermentation into closed-pattern fermentation. This paper investigated gas double-dynamic SSF performance in cultivating Coniothyrium minitans (C. minitans), as well as its effect on physiology of C. minitans. Results showed that gas double-dynamic increased biomass content by 48.6%. High temperature impeded pycnidia formation and increased glycine production. More pycnidia formed in solid matrix at 20 degrees C, which was responsible for higher conidia production (1.5 (+/-0.03) * 1010 spores/g dry mass), indicating decisive role of high temperature in pycnidia formation of C. minitans in solid-state fermentation. Higher glycine content may be the response of high temperature stress which has close relationship with pycnidia and conidia production. Based on the findings, a two-step strategy for gas double-dynamic SSF was proposed and an satisfactory conidia production was obtained while fermentation period shortened. PMID- 29709843 TI - Formation of microbial inhibitors in steam-explosion pretreatment of softwood impregnated with sulfuric acid and sulfur dioxide. AB - Wood chips of Norway spruce were pretreated by steam explosion at 195-215 degrees C after impregnation with either sulfuric acid (SA) or sulfur dioxide (SD). The effects of different pretreatment conditions on formation of microbial inhibitors were investigated, and the inhibitory effects on yeast of pretreatment liquids and of specific inhibitors that were found in the pretreatment liquids were elucidated. Whereas the concentrations of most inhibitors increased with increasing pretreatment temperatures, there were exceptions, such as formaldehyde and p-hydroxybenzaldehyde. The highest concentration of each inhibitor was typically found in SD-pretreated material, but formic acid was an exception. The toxic effects on yeast were studied using concentrations corresponding to loadings of 12 and 20% total solids (TS). Among individual inhibitors that were quantitated in pretreatment liquids, the concentrations of formaldehyde were by far most toxic. There was no or minimal yeast growth in the formaldehyde concentration range (5.8-7.7 mM) corresponding to 12% TS. PMID- 29709845 TI - Vitelline fistula associated with omphalocele: Diagnostic dilemma? AB - INTRODUCTION: Combination vitelline fistula (VF) and omphalocele at birth is a rare congenital anomaly as a result disturbance in organogenesis with failure of normal return of intestines into the abdominal cavity and failed obliteration of the vitelline duct. CASE PRESENTATION: A newborn presented with omphalocele sac with visible intestine, stoma like lesion with prolapsing mucosa just lateral to the umbilical cord and passage of meconium stool. Operative surgery was confirmed an intact omphalocele sac and vitelline fistula. Fistulectomy, using wedge resection of the small bowel and primary closure abdominal wall defect. DISCUSSION: In our review of literature, VF associated with omphalocele had not been reported. Combination of anomaly maybe misleading, however, can be easily diagnosed the location of VF opening on the omphalocele sac, which is adjacent to the umbilical cord and luminal passage of meconium stool after birth. A fistulogram may be the best initial diagnostic imaging approach for identifying and confirmation of a fistula tract. CONCLUSION: VF associated with omphalocele is rare. Post-natal diagnosis is easily by gross appearance stoma like lesion, which is located just lateral of the umbilical cord, an intact omphalocele sac and post-natal meconium stool passage. PMID- 29709844 TI - Lumbar pseudomeningocele presenting as decerebrate rigidity-A rare case entity. AB - INTRODUCTION: Spinal pseudomeningoceles are extradural collections of cerebrospinal fluid that result following a breach in the dural-arachnoid layer and is reported as one of the complications of lumbar disc surgery. Although they are often self subsiding and asymptomatic, they may occasionally cause low-back pain, headaches, and even nerve root entrapment. The purpose of this case report is to present an unreported presentation of pseudomeningocele PRESENTATION OF CASE: A 34 year obese male presented one month post lumbar discectomy with symptoms suggestive of raised intra cranial pressure presenting as repetitive decerebrate rigidity and altered sensorium lasting for few minutes when there is pressure on the pseudomeningocele sac and subsiding with change in position of the patient. He underwent surgical repair of the dural tear and was improved symptomatically with no recurrence of symptoms at five years follow up. DISCUSSION: Radiological investigation helped in ruling out the other causes of decerebrate rigidity and the possible mechanism of development of such symptom in pseudomeningocele is discussed. CONCLUSION: To the best of our knowledge, this is the first reported case of pseudomeningooele presenting as decerebrate rigidity. Spinal pseudomeningocele can present in varied ways and earliest detection is the key to avoid such complications. PMID- 29709846 TI - Osteogenesis of 3D printed porous Ti6Al4V implants with different pore sizes. AB - Selective laser melting (SLM) is one of the three-dimensional (3D) printing techniques that manufacturing versatile porous scaffolds with precise architectures for potential orthopedic application. To understand how the pore sizes of porous Ti6Al4V scaffolds affect their biological performances, we designed and fabricated porous Ti6Al4V implants with straightforward pore dimensions (500, 700, and 900 um) via SLM, termed as p500, p700, and p900 respectively. The morphological characteristics of Ti6Al4V scaffolds were assessed showing that the actual pore sizes of these scaffolds were 401 +/- 26 um, 607 +/- 24 um, 801 +/- 33 um, respectively. The mechanical properties of Ti6Al4V scaffolds were also evaluated showing that they were comparable to that of bone tissues. Meanwhile, the effect of pore size on biological responses was systematically investigated in vitro and in vivo. It was verified that 3D printing technique was able to fabricate porous Ti6Al4V implants with proper mechanical properties analogous to human bone. The in vitro results revealed that scaffolds with appropriate pore dimension were conducive to cell adhesion, proliferation and early differentiation. Furthermore, the porous Ti6Al4V scaffolds were implanted into the rabbit femur to investigate bone regeneration performance, the in vivo experiment showed the p700 sample was in favor of bone ingrowth into implant pores and bone-implant fixation stability. Taken together, the biological performance of p700 group with actual pore size of about 600 um was superior to other two groups. The obtained findings provide basis to individually design and fabricate suitable porous Ti6Al4V with specific geometries for orthopedic application. PMID- 29709847 TI - Big data on a big new market: Insights from Washington State's legal cannabis market. AB - INTRODUCTION: Voters in eight U.S. states have passed initiatives to legalize large-scale commercial production of cannabis for non-medical use. All plan or require some form of "seed-to-sale" tracking systems, which provide a view of cannabis market activity at a heretofore unimagined level of detail. Legal markets also create a range of new matters for policy makers to address. DATA: Publicly available data were obtained on approximately 45 million individually priced items purchased in the 35 million retail transactions that took place during the first two and a half years of Washington State's legal cannabis market. Records include product type (flower, extract, lotion, liquid edible, etc.), product name, price, and potency with respect to multiple cannabinoids, notably THC and CBD. Items sold can be traced back up the supply chain through the store to the processor and producer, to the level of identifying the specific production batch and mother plant, the firm that tested the product, and test results. METHOD: Data visualization methods are employed to describe spatial temporal patterns of multiple correlated attributes (e.g., price and potency) broken down by product. Text-analytic methods are used to subdivide the broad category of "extracts for inhalation" into more homogeneous sub-categories. To understand the competitiveness of the legal cannabis market in Washington we calculate the Herfindahl-Hirschman index (HHI) for processors and retailers. RESULTS: Cannabis prices fell steadily and proportionally at the processor and retailer levels. Retail and wholesale price maintained a roughly 3:1 ratio for multiple product types after some initial fluctuations. Although a wide range of edibles are sold, they account for a modest share of consumer spending; extracts for inhalation are a larger and heterogeneous market segment. The HHI indicates the cannabis market is highly competitive at the processor level, but less so for retail markets at the county level. CONCLUSIONS: Washington's state-legal cannabis market is diverse and rapidly evolving in terms of pricing, products, and organization. Post-legalization, researchers and policy makers may need to think in terms of a family of cannabis products, akin to how we think of new psychoactive substances and amphetamine-type stimulants, not a single drug "cannabis." PMID- 29709848 TI - Copper distribution in European topsoils: An assessment based on LUCAS soil survey. AB - Copper (Cu) distribution in soil is influenced by climatic, geological and pedological factors. Apart from geological sources and industrial pollution, other anthropogenic sources, related to the agricultural activity, may increase copper levels in soils, especially in permanent crops such as olive groves and vineyards. This study uses 21,682 soil samples from the LUCAS topsoil survey to investigate copper distribution in the soils of 25 European Union (EU) Member States. Generalized Linear Models (GLM) were used to investigate the factors driving copper distribution in EU soils. Regression analysis shows the importance of topsoil properties, land cover and climate in estimating Cu concentration. Meanwhile, a copper regression model confirms our hypothesis that different agricultural management practices have a relevant influence on Cu concentration. Besides the traditional use of copper as a fungicide for treatments in several permanent crops, the combined effect of soil properties such as high pH, soil organic carbon and clay, with humid and wet climatic conditions favours copper accumulation in soils of vineyards and tree crops. Compared to the overall average Cu concentration of 16.85 mg kg-1, vineyards have the highest mean soil Cu concentration (49.26 mg kg-1) of all land use categories, followed by olive groves and orchards. Gaussian Process Regression (GPR) combined with kriging were used to map copper concentration in topsoils and to evidence the presence of outliers. GPR proved to be performant in predicting Cu concentration, especially in combination with kriging, accounting for 66% of Cu deviance. The derived maps are novel as they include information about the importance of topsoil properties in the copper mapping process, thus improving its accuracy. Both models highlight the influence of land management practices in copper concentration and the strong correlation between topsoil copper and vineyards. PMID- 29709849 TI - Sources, behaviour, and environmental and human health risks of high-technology rare earth elements as emerging contaminants. AB - Recent studies show that high-technology rare earth elements (REEs) of anthropogenic origin occur in the environment including in aquatic systems, suggesting REEs are contaminants of emerging concern. However, compared to organic contaminants, there is a lack of comprehensive reviews on the anthropogenic sources, environmental behaviour, and public and ecological health risks of REEs. The current review aims to: (1) identify anthropogenic sources, transfer mechanisms, and environmental behaviour of REEs; (2) highlight the human and ecological health risks of REEs and propose mitigation measures; and (3) identify knowledge gaps and future research directions. Out of the 17 REEs, La, Gd, Ce and Eu are the most studied. The main sources of anthropogenic REE include; medical facilities, petroleum refining, mining and technology industries, fertilizers, livestock feeds, and electronic wastes and recycling plants. REEs are mobilized and transported in the environment by hydrological and wind-driven processes. Ecotoxicological effects include reduced plant growth, function and nutritional quality, genotoxicity and neurotoxicity in animals, trophic bioaccumulation, chronic and acute toxicities in soil organisms. Human exposure to REEs occurs via ingestion of contaminated water and food, inhalation, and direct intake during medical administration. REEs have been detected in human hair, nails, and biofluids. In humans, REEs cause nephrogenic systemic fibrosis and severe damage to nephrological systems associated with Gd-based contrast agents, dysfunctional neurological disorder, fibrotic tissue injury, oxidative stress, pneumoconiosis, cytotoxicity, anti-testicular effects, and male sterility. Barring REEs in medical devices, epidemiological evidence directly linking REEs in the environment to human health conditions remains weak. To minimize health risks, a conceptual framework and possible mitigation measures are highlighted. Future research is needed to better understand sources, environmental behaviour, ecotoxicology, and human epidemiology. Moreover, research on REEs in developing regions, including Africa, is needed given prevailing conditions predisposing humans to health risks (e.g., untreated drinking water). PMID- 29709850 TI - Integration of environmental aspects in modelling and optimisation of water supply chains. AB - Climate change becomes increasingly more relevant in the context of water systems planning. Tools are necessary to provide the most economic investment option considering the reliability of the infrastructure from technical and environmental perspectives. Accordingly, in this work, an optimisation approach, formulated as a spatially-explicit multi-period Mixed Integer Linear Programming (MILP) model, is proposed for the design of water supply chains at regional and national scales. The optimisation framework encompasses decisions such as installation of new purification plants, capacity expansion, and raw water trading schemes. The objective is to minimise the total cost incurring from capital and operating expenditures. Assessment of available resources for withdrawal is performed based on hydrological balances, governmental rules and sustainable limits. In the light of the increasing importance of reliability of water supply, a second objective, seeking to maximise the reliability of the supply chains, is introduced. The epsilon-constraint method is used as a solution procedure for the multi-objective formulation. Nash bargaining approach is applied to investigate the fair trade-offs between the two objectives and find the Pareto optimality. The models' capability is addressed through a case study based on Australia. The impact of variability in key input parameters is tackled through the implementation of a rigorous global sensitivity analysis (GSA). The findings suggest that variations in water demand can be more disruptive for the water supply chain than scenarios in which rainfalls are reduced. The frameworks can facilitate governmental multi-aspect decision making processes for the adequate and strategic investments of regional water supply infrastructure. PMID- 29709851 TI - Modelling the marine eutrophication: A review. AB - In the frame of a national, joint scientific appraisal, 45 scientific French speaking experts have been mandated in 2015-2016 by the French ministries of Environment and Agriculture to perform a global review of scientific literature dealing with the eutrophication phenomenon, in freshwater as well as in marine waters. This paper summarizes the main results of this review restricted to a sub domain, the modelling approach of the marine eutrophication. After recalling the different aims pursued, an overview is given on the historical time course of this modelling effort, its world distribution and the various tools used. Then, the main results obtained are examined, highlighting the specific strengths and weaknesses of the present models. Needs for future improvement are then listed. PMID- 29709852 TI - Defluorination of perfluoroalkyl acids is followed by production of monofluorinated fatty acids. AB - We investigated the capability of microorganisms isolated from environments polluted with perfluoroalkyl acids (PFAAs) to conduct biotransformation of these emerging pollutants. Two different microbial consortia (chemoorganoheterotrophic bacteria and total yeast and molds) were isolated from two river sediments in Saitama and Osaka, Japan, known for long term pollution with perfluorooctane sulfonic acid (PFOS) and perfluorooctanoic acid (PFOA). The microbial consortia were incubated in the presence of added PFOS and PFOA, and decreases in concentrations of these compounds were between 46-69% and 16-36%, respectively. Decreases in concentrations were, in part, due to sorption on biomass, but defluorinated PFOS and PFOA products were not detected. However, untargeted analysis suggested the presence of several metabolites found only in samples from consortia with PFOS and PFOA but not in the control samples. Molecular formula candidates were narrowed down to two options, C18H28O5F and C21H27O4. It was assumed that these formulas were associated with unsaturated monofluorinated fatty acids and hydrocarbons with multiple unsaturated bonds or ring structures. PMID- 29709853 TI - Mean annual precipitation predicts primary production resistance and resilience to extreme drought. AB - Extreme drought is increasing in frequency and intensity in many regions globally, with uncertain consequences for the resistance and resilience of ecosystem functions, including primary production. Primary production resistance, the capacity to withstand change during extreme drought, and resilience, the degree to which production recovers, vary among and within ecosystem types, obscuring generalized patterns of ecological stability. Theory and many observations suggest forest production is more resistant but less resilient than grassland production to extreme drought; however, studies of production sensitivity to precipitation variability indicate that the processes controlling resistance and resilience may be influenced more by mean annual precipitation (MAP) than ecosystem type. Here, we conducted a global meta-analysis to investigate primary production resistance and resilience to extreme drought in 64 forests and grasslands across a broad MAP gradient. We found resistance to extreme drought was predicted by MAP; however, grasslands (positive) and forests (negative) exhibited opposing resilience relationships with MAP. Our findings indicate that common plant physiological mechanisms may determine grassland and forest resistance to extreme drought, whereas differences among plant residents in turnover time, plant architecture, and drought adaptive strategies likely underlie divergent resilience patterns. The low resistance and resilience of dry grasslands suggests that these ecosystems are the most vulnerable to extreme drought - a vulnerability that is expected to compound as extreme drought frequency increases in the future. PMID- 29709854 TI - Geological setting control of flood dynamics in lowland rivers (Poland). AB - We aim to answer a question: how does the geological setting affect flood dynamics in lowland alluvial rivers? The study area covers three river reaches: not trained, relatively large on the European scale, flowing in broad valleys cut in the landscape of old glacial plains. We focus on the locations where levees [both: a) natural or b) artificial] were breached during flood. In these locations we identify (1) the erosional traces of flood (crevasse channels) on the floodplain displayed on DEM derived from ALS LIDAR. In the main river channel, we perform drillings in order to measure the depth of the suballuvial surface and to locate (2) the protrusions of bedrock resistant to erosion. We juxtapose on one map: (1) the floodplain geomorphology with (2) the geological data from the river channel. The results from each of the three study reaches are presented on maps prepared in the same manner in order to enable a comparison of the regularities of fluvial processes written in (1) the landscape and driven by (2) the geological setting. These processes act in different river reaches: (a) not embanked and dominated by ice jam floods, (b) embanked and dominated by rainfall and ice jam floods. We also analyse hydrological data to present hydrodynamic descriptions of the flood. Our principal results indicate similarity of (1) distinctive erosional patterns and (2) specific geological features in all three study reaches. We draw the conclusion: protrusions of suballuvial bedrock control the flood dynamics in alluvial rivers. It happens in both types of rivers. In areas where the floodplain remains natural, the river inundates freely during every flood. In other areas the floodplain has been reclaimed by humans who constructed an artificial levee system, which protects the flood-prone area from inundation, until levee breach occurs. PMID- 29709855 TI - Using hair, nail and urine samples for human exposure assessment of legacy and emerging per- and polyfluoroalkyl substances. AB - Non-invasive samples present ethical and practical benefits for investigating human exposure to hazardous contaminants, but analytical challenges and difficulties to interpret the results limit their application in biomonitoring. Here we investigated the potential for using hair, nail and urine samples as a measure of internal exposure to an array of legacy and emerging per- and polyfluoroalkyl substances (PFASs) in two populations with different exposure conditions. Paired urine-serum measurements of PFASs from a group of highly exposed fishery employees displayed strong correlations for PFASs with three to eight perfluorinated carbons (rho > 0.653; p < 0.01). Consistent statistical correlations and transfer ratios in nails and hair from both populations demonstrated that these non-invasive samples can be used as a measure of internal exposure to perfluorooctane sulfonic acid and C8 chlorinated polyfluoralkyl ether sulfonic acid (C8 Cl-PFESA). Contrastingly, the infrequent detections and/or lack of consistent transfer ratios for perfluorooctanoic acid, perfluorononanoic acid and short-chain PFASs in hair and nail samples indicate passive uptake from the external environment rather than uptake and internal distribution. Collectively, the study supports the use of urine samples as a valid measure of internal exposure for a range of short- and medium-chain PFASs, while the validity of nail and hair samples as a measure of internal exposure may vary for different PFASs and populations. The ubiquitous detection of C8 Cl-PFESA in all sample matrices from both populations indicates widespread exposure to this contaminant of emerging concern in China. PMID- 29709856 TI - Morphological and anatomical changes of Phragmites australis Cav. due to the uptake and accumulation of heavy metals from polluted soils. AB - The effect of strong chemical contamination of soils on the growth and structure of reed (Phragmites australis Cav.) roots and stems has been investigated. Soils and plants on monitoring plots in the zone of industrial sewage tanks and sludge reservoirs in the city of Kamensk-Shakhtinskii (southern Russia) were studied. Polyelement pollution of soils on the studied monitoring plots was revealed, with exceedances of Clarkes in hundreds of times for Zn and Cd, in tens of times for Pb, and in several times for Cu, Ni, Cr, and Mn. An ecological-geochemical estimation revealed an extremely hazardous level of soil contamination HMs in total. It is shown that the high level of soil contamination decelerates the ontogenetic development of plants and decreases their morphometric parameters. Electron-microscopic study of plants revealed changes in the ultrastructure of cell membranes, as well as the main cytoplasmic organelles of root and stem cells (mitochondria, plastids, etc.). It is suggested that the revealed structural changes in epidermis and mesoderm under the impact of metals hamper the radial migration of fluid in the root from the peripheral parts. These changes are one of the reasons for the decrease in the level of nutrient uptake and translocation from roots to shoots. PMID- 29709857 TI - Distribution, release and removal behaviors of tetrabromobisphenol A in water sediment systems under prolonged hydrodynamic disturbances. AB - Since tetrabromobisphenol A (TBBPA) has been increasingly used and found widely in the aquatic environment, it has attracted much attention due to its high toxicity to aquatic organisms. However, less work has been carried out for the TBBPA environmental fate in water-sediment systems. In this paper, the distribution, release and removal of TBBPA in different forms of the water sediment system were investigated under three typical hydrodynamic conditions using a specialized racetrack-style flume. Three water-sediment systems which are water, suspended particulate matter (SPM) and sediment were taken into account in this study. The results of 34 days experiments showed that the equilibrium of physicochemical parameters was reached under different disturbance conditions within a relatively short period. The distribution ratio of TBBPA in three water sediment systems will also reach a relatively equilibrium state over time under different disturbance conditions. The fluctuation range in each form was <1.26%. The TBBPA released to the water and SPM, increased remarkably with hydrodynamic enhancement due to adsorption and resuspension processes. Removal efficiency of TBBPA in each form was found to be observably accelerated with hydrodynamic disturbances. The half-lives (T1/2) in water, SPM and sediment ranged from 10.1 to 12.6 days in strong hydrodynamic condition, comparing to the static control, it ranges from 34.7 to 37.1 days. This phenomenon may result from the increase of dissolved oxygen (DO) and nutrient concentrations in overlying water affected by hydrodynamic force. The results of the experiment demonstrate that hydrodynamic disturbance may be an important driving factor which will influence the TBBPA environmental fate in aquatic environment. PMID- 29709858 TI - Eutrophication exacerbates the impact of climate warming on lake methane emission. AB - Net methane (CH4) emission from lakes depends on two antagonistic processes: CH4 production (methanogenesis) and CH4 oxidation (methanotrophy). It is unclear how climate warming will affect the balance between these processes, particularly among lakes of different trophic status. Here we show that methanogenesis is more sensitive to temperature than methanotrophy, and that eutrophication magnifies this temperature sensitivity. Using laboratory incubations of water and sediment from ten tropical, temperate and subarctic lakes with contrasting trophic states, ranging from oligotrophic to hypereutrophic, we explored the temperature sensitivity of methanogenesis and methanotrophy. We found that both processes presented a higher temperature sensitivity in tropical lakes, followed by temperate, and subarctic lakes; but more importantly, we found that eutrophication triggered a higher temperature sensitivity. A model fed by our empirical data revealed that increasing lake water temperature by 2 degrees C leads to a net increase in CH4 emissions by 101-183% in hypereutrophic lakes and 47-56% in oligotrophic lakes. We conclude that climate warming will tilt the CH4 balance towards higher lake emission and that this impact will be exacerbated by the eutrophication of the lakes. PMID- 29709859 TI - Gill bioenergetics dysfunction and oxidative damage induced by thiamethoxam exposure as relevant toxicological mechanisms in freshwater silver catfish Rhamdia quelen. AB - Thiamethoxam is a neonicotinoid pesticide utilized on a worldwide scale, it has been reported in freshwater ecosystems, and detected in fishery products. Nevertheless, there is a lack of information about thiamethoxam sublethal effects on the gills of freshwater fish, principally linked to energetic metabolism. In this context, creatine kinase (CK) is an enzyme of the phosphoryl transfer network that provides a temporal and spatial energy buffer to maintain cellular energy homeostasis in tissues with high energy requirements, such as gills. Based on this evidence, the aim of this study was to evaluate whether exposure to thiamethoxam impairs the cytosolic and mitochondrial CK activities in gills of Rhamdia quelen, and the involvement of oxidative stress in the energetic imbalance. Branchial CK (cytosolic and mitochondrial) activity and sodium potassium pump (Na+, K+-ATPase) were inhibited, and adenosine triphosphate (ATP) levels decreased after 96 h exposure to 1.125 and 3.75 MUg/L thiamethoxam compared to the control group. Moreover, levels of branchial thiobarbituric acid reactive substances (TBARS) and protein carbonylation increased at 3.75 MUg/L thiamethoxam after 96 h of exposure compared to the control group, while the non protein thiol (NPSH) content did not differ between groups. It is important to emphasize that all evaluated parameters did not recover after 48 h in clean water. To summarize, the data presented here clearly demonstrated that thiamethoxan exposure severely impairs cytosolic and mitochondrial CK activities, a key enzyme for gill energy buffering to maintain cellular energy homeostasis, and this effect appears to be mediated by oxidation of lipid and protein molecules, which consequently thereby induces oxidative stress. PMID- 29709860 TI - The effect of nitrification inhibitors on NH3 and N2O emissions in highly N fertilized irrigated Mediterranean cropping systems. AB - There is an increasing concern about the negative impacts associated to the release of reactive nitrogen (N) from highly fertilized agro-ecosystems. Ammonia (NH3) and nitrous oxide (N2O) are harmful N pollutants that may contribute both directly and indirectly to global warming. Surface applied manure, urea and ammonium (NH4+) based fertilizers are important anthropogenic sources of these emissions. Nitrification inhibitors (NIs) have been proposed as a useful technological approach to reduce N2O emission although they can lead to large NH3 losses due to increasing NH4+ pool in soils. In this context, a field experiment was carried out in a maize field with aiming to simultaneously quantify NH3 volatilization and N2O emission, assessing the effect of two NIs 3,4 dimethilpyrazol phosphate (DMPP) and 3,4-dimethylpyrazole succinic acid (DMPSA). The first treatment was pig slurry (PS) before seeding (50 kg N ha-1) and calcium ammonium nitrate (CAN) at top-dressing (150 kg N ha-1), and the second was DMPP diluted in PS (PS + DMPP) (50 kg N ha-1) and CAN + DMPSA (150 kg N ha-1) also before seeding and at top-dressing, respectively. Ammonia emissions were quantified by a micrometeorological method during 20 days after fertilization and N2O emissions were assessed using manual static chambers during all crop period. The treatment with NIs was effective in reducing c. 30% cumulative N2O losses. However, considering only direct N2O emissions after second fertilization event, a significant reduction was not observed using CAN+DMPSA, probably because high WFPS of soil, driven by irrigation, favored denitrification. Cumulative NH3 losses were not significantly affected by NIs. Indeed, NH3 volatilization accounted 14% and 10% of N applied in PS + DMPP and PS plots, respectively and c. 2% of total N applied in CAN+DMPSA and CAN plots. Since important NH3 losses still exist even although abating strategies are implemented, structural and political initiatives are needed to face this issue. PMID- 29709861 TI - Ambient air quality and exposure assessment study of the Gulf Cooperation Council countries: A critical review. AB - With rapid urbanization and economic growth, many developing countries have faced a greater share of air pollutants in recent years. An increasing number of exposure studies on air pollutants have been reported lately. However, due to lack of strict regulations and monitoring stations among developing countries, such as Gulf Cooperation Council (GCC) countries, limited air pollution and exposure assessment studies have been conducted in this region. Thus, the objective of this critical review was to identify the major sources of air pollutants in the region with hot and arid/semiarid climate for the main categories contributing to specific pollutants. Finally, a summary of the limitations and knowledge gaps were discussed. Additionally, the current available regulations, emission inventories and source apportionment studies in this region were discussed. In this study, the concentration levels of carbon dioxide (CO2), carbon monoxide (CO), particulate matter (PM), metal elements, nitrogen oxides (NOx), ozone (O3), sulfur dioxide (SO2), volatile organic compounds (VOCs), polycyclic aromatic hydrocarbons (PAHs), and persistent organic pollutants (POPs) were reviewed. Due to lack of scientific studies, various databases and indexed journals from early 2000 (sometimes prior that time) were considered. The review findings clearly indicated that the sand, dust (natural and anthropogenic, such as cement, metal, stone cutting industries), chemical industries (refinery, petrochemical, etc.) and transportation activities were the major contributors to the overall air pollution in the GCC countries. Besides, the study recommended that the difference between anthropogenic pollution and natural events in dust formation should be explored extensively. Furthermore, possible suggestions for future researches in the region were proposed. PMID- 29709862 TI - Supplementary feeding stations for conservation of vultures could be an important source of monophasic Salmonella typhimurium 1,4,[5],12:i:. AB - Vultures are nature's most successful scavengers, feeding on the carcasses of dead animals present in the field. Availability of domestic carrion has been unstable due to rapidly changing agro-grazing economies and increasing sanitary regulations that may require burial or burning of livestock carcasses. Thus, several griffon vulture (Gyps fulvus) recoveries are based on European legislation that guarantees the animals' welfare, avoids intense persecution of the vultures and allows the feeding of threatened wildlife in supplementary feeding stations (SFS). However, in recent years, many studies have speculated on the likelihood that avian scavengers may be infected by feeding on pig carcasses at SFS from intensive livestock. In this context, the present study evaluated whether free-living griffon vultures and pig farms share zoonotic Salmonella strains to test the hypothesis that vulture are infected during consumption of carcasses provided at SFS. Here, the occurrence, serotypes and genomic DNA fingerprinting (phage typing and pulsed-field gel electrophoresis) of isolated strains were carried out in griffon vultures and pig farms authorised to provided carcasses at SFS in Castellon province (eastern Spain). The bacteriological analyses revealed that 21.1% of vultures and 14.5% for pig farms samples tested were Salmonella-positive. Monophasic S. typhimurium 1,4,[5],12:i:- was the most frequently isolated serovar. Comparison of Salmonella strains isolated from vultures and pig farms revealed that monophasic S. typhimurium 1,4,[5],12:i:-, S. Derby and S. Rissen strains were highly genetically homogeneous (similar DNA fingerprint). In conclusion, the current study indicates that free-living griffon vultures and pig farms that provide the carcasses at SFS share several zoonotic Salmonella strains. On this basis, and although transmission could be bidirectional, our result seems to corroborate the pig carcasses-to-vulture transmission and cross-infection at SFS. As an immediate Salmonella control strategy in wild avian scavengers, we suggest the implementation of a programme to guarantee that solely pig carcasses from Salmonella-free farms arrive at SFS. PMID- 29709863 TI - Spatial and temporal distribution of platinum, palladium and rhodium in Zagreb air. AB - Platinum (Pt), palladium (Pd) and rhodium (Rh) are most widely used in the production of automotive catalytic converters that serve to reduce toxic emissions from motor vehicles. The aim of this study was to quantitatively determine the levels of platinum, palladium and rhodium in the PM10 and PM2.5 fraction of airborne particle matter and find their spatial and temporal distribution at different polluted areas of the city of Zagreb, Croatia. The method used in this paper included weekly sampling of airborne particle matter on quartz filters, microwave digestion in acid under high pressure and temperature, and analysis by inductively coupled plasma mass spectrometry (ICP MS). The results have shown that the highest mean values at all three sampling stations (North, Center, South) were obtained for palladium (3.856 pg m-3, 5.396 pg m-3, 5.600 pg m-3) and the lowest for rhodium (0.444 pg m-3, 0.643 pg m-3, 0.750 pg m 3). The average mass concentrations of platinum group elements (PGE) in PM10 increased for all three elements in the direction North < Center < South which had to do with the traffic load nearby the monitoring stations. The ratio of measured mass concentrations to all measuring stations was similar to platinum, palladium and rhodium content in automotive catalytic converters. Factor analysis grouped platinum, palladium and rhodium at all of the monitoring stations, and their relation to other metals together with the aforementioned results indicate that their main source of pollution is traffic or precisely automotive catalytic converters. At all three of the monitoring sites, higher values were measured during the colder part of the year. The results of measuring platinum, palladium and rhodium levels in the city of Zagreb are the first results of their kind for this area and will provide insights into the contribution of catalytic converters to the presence of these elements in the environment. PMID- 29709864 TI - Identification, contribution, and estrogenic activity of potential EDCs in a river receiving concentrated livestock effluent in Southern Taiwan. AB - We assessed 22 selected endocrine-disrupting compounds (EDCs) and other emerging, potentially endocrine-active compounds with estrogenic activity from the waters of the Wuluo River, southern Taiwan. This watershed receives high amounts of livestock and untreated household wastewaters. The river is surrounded by concentrated animal feedlot operations (CAFOs). River water samples were analyzed for selected compounds by liquid chromatography-tandem mass spectrometry (LC MS/MS), T47D-KBluc reporter gene assay, and E-screen cell proliferation in vitro bioassay. Total concentrations of ?alkylphenolic compounds (bisphenol A, 4 nonylphenol, t-nonylphenol, octylphenol, nonylphenol mono-ethoxylate, nonylphenol di-ethoxylate) were much higher than ?estrogens (estrone, 17 beta-estradiol, estriol, 17beta-ethynylestradiol, diethylstilbestrol), ?preservatives (methyl paraben, ethyl paraben, propyl paraben, butyl paraben), ?UV-filters (benzophenone, methyl benzylidene camphor, benzophenone-3), ?antimicrobials (triclocarben, triclosan, chloroxylenol), and an insect repellent (diethyltoluamide) over four seasonal sampling periods. The highest concentration was found for bisphenol A with a mean of 302 ng/L. However, its contribution to estrogenic activity was not significant due to its relatively low estrogenic potency. Lower detection rates were found for BP, EE2, TCS, and PCMX, while DES and EP were not detected. E1 and E2 levels in raw water samples were 50% higher than the predicted no-effect concentrations (PNEC) for aquatic organisms of 6 and 2 ng/L, respectively. The potency of estrogenic activity ranged from 11.7 to 190.1 ng/L E2T47D-Kbluc and 6.63 to 84.5 ng/L E2E-Screen for extracted samples. Importantly, estrone contributed 50% of the overall activity in 60% and 44% of the samples based on T47D-KBluc and MCF-7 bioassays, followed by 17 beta estradiol, highlighting the importance of total steroid estrogen loading. This study demonstrates that the estrogenic activity of target chemicals was comparable to levels found in different countries worldwide. More intense wastewater treatment is required in areas of intensive agriculture in order to prevent adverse impacts on the ambient environment and aquatic ecosystems. PMID- 29709865 TI - Uptake of pharmaceuticals by plants grown under hydroponic conditions and natural occurring plant species: A review. AB - Sizeable amount of research has been conducted on the possible uptake of pharmaceuticals by plants from contaminated soil and water used for irrigation of crops. In most cases, pharmaceuticals are taken by roots and translocated into various tissues by transpiration and diffusion. Due to the plant uptake, the occurrence of pharmaceuticals in food sources such as vegetables is a public concern. Few review papers focusing on the uptake of pharmaceuticals, in particular antibiotics, and their translocation in plant tissues have been published. In the current review paper, the work conducted on the uptake of pharmaceuticals belonging to different therapeutic groups such as antibiotics, non-steroidal anti-inflammatory drugs, beta-blockers and antiepileptics is reviewed. Such work includes the occurrence of pharmaceuticals in plants, translocation once taken by plants, toxicity studies as well as implications and future studies. Furthermore, the advantages and drawbacks associated with the detection and uptake of these pharmaceuticals by plants are discussed. In addition, the physico-chemical properties that could influence the plant uptake of pharmaceuticals are deliberated. PMID- 29709866 TI - Influential aspects of glacial resource for establishing Kuhl system (gravity flow irrigation) in the Hindu Kush, Karakoram and Himalaya ranges. AB - The meltwater components play an important role in the hydrological regime of the Hindu Kush, Karakorum and Himalaya (HKH) region, in terms of high demand of water for food and fiber from snow and glacial resource. The communities of Himalayan mountains are facing challenges of food security owing to lack of the resource information for meeting their water requirements. In this study, suitability index approach was adopted to assess glacier resource potential for establishing kuhl irrigation system in HKH ranges of Pakistan. The basis of indexing is glacier accessibility and water yield potential of the glacial resource for irrigation estimated in terms of number and ice reserve of the glaciers. The suitability index was found good for about 1.4% glaciers constituting about 80% of the total ice reserves of the HKH region. Medium suitability constitutes about 36.1% glaciers with 12.6% of the total ice reserves, while low suitability was assessed for about 60% glaciers containing 1.5% ice reserves only. Maximum unit glacial reserve was estimated for Shigar basin, i.e., 1.44 km3, and among HKH ranges, 0.46 km3 for the Karakoram range. A regular monitoring of the glacial resource would prove helpful in assessing vulnerability of this resource to climate change in the high Himalayan region in future. PMID- 29709867 TI - How weather conditions in non-breeding and breeding grounds affect the phenology and breeding abilities of white storks. AB - BACKGROUND: It has often been suggested that conditions in wintering grounds affect the breeding abilities of migratory birds. This is known as the carry-over effect. Heretofore, many studies have reported the relationship between conditions in wintering grounds, dates of departure from and arrival at breeding grounds, and breeding success. However, very few studies have shown how these conditions affect the capacity of females for egg production. AIMS: To describe how conditions in the remote non-breeding areas in Africa affect reproductory abilities of migratory birds breeding in Europe. METHODS: We recorded 863 arrival dates for 191 nests (in 2005-16), clutch sizes of 412 clutches, and egg dimensions of 1725 eggs (in 2003-16) of white storks in western Poland. We used generalised climatic indicators such as the Sahel precipitation index (SPI) and Indian Ocean Dipole (IOD) to assess conditions in wintering grounds prior to breeding and precipitation and temperature in breeding grounds during the breeding season. RESULTS: The white stork arrived significantly earlier in seasons preceded by a warmer and rainier March, while conditions in Africa did not affect arrival dates. Females laid more (and larger) eggs in seasons preceded by rainier winters in Africa. Breeding success was not affected by conditions in wintering grounds, but only by the weather during breeding season. CONCLUSIONS: Conditions in wintering grounds may affect migratory birds, not only in terms of their arrival dates, but rather with respect to females' egg production capacities. Studies on stable isotopes may yield more detailed findings as to how this process takes place. PMID- 29709868 TI - Legacy motivations & the psychology of intergenerational decisions. AB - Critical issues in society today involve long time horizons and multiple generations of people. A central challenge in intergenerational decisions is that the interests of present and future generations are not always aligned. The goals and focus of research on intergenerational decisions has been to (1) identify the key features of intergenerational decisions and use those insights to develop experiments that emulate those features, (2) identify the central barriers to intergenerational beneficence, and importantly, (3) identify variables that lead people to act on the behalf of future generations, void of any material or economic incentive to do so. Critically, intergenerational contexts are characterized by the intersection of intertemporal and interpersonal dimensions, which enables the enactment of legacy motivations-a key underlying force in overcoming the many barriers to intergenerational beneficence. PMID- 29709869 TI - A repeat offender: Recurrent extraintestinal Clostridium difficile infection following fecal microbiota transplantation. AB - Extraintestinal infection with Clostridium difficile has been reported but remains uncommon. Treatment of this unusual complication is complex given the limitations of current therapeutic options. Here we report a novel case of recurrent extraintestinal C. difficile infection that occurred following fecal microbiota transplantation. Using whole genome sequencing, we confirmed recrudescence rather than reinfection was responsible. The patient ultimately responded to prolonged, targeted antimicrobial therapy informed by susceptibility testing. PMID- 29709870 TI - Formation of iodinated trihalomethanes during breakpoint chlorination of iodide containing water. AB - This study investigated the formation of toxic iodinated trihalomethanes (I-THMs) during breakpoint chlorination of iodide-containing water. Impact factors including I- concentration, natural organic matter (NOM) concentration and type, pH as well as Br-/I- molar ratio were systematically investigated. Moreover, the incorporation of I- into I-THM formation was also calculated. The results showed that I-THM formation varied in different zones of the breakpoint curves. I-THMs increased with increasing chlorine dosage to breakpoint value and then dropped significantly beyond it. Iodoform (CHI3) and chlorodiiodomethane (CHClI2) were the major I-THMs in the pre-breakpoint zone, while dichloroiodomethane (CHCl2I) was the dominant one in the post-breakpoint zone. The formation of I-THMs increased remarkably with I- and dissolved organic carbon (DOC) concentrations. More bromine-containing species were formed as Br-/I- molar ratio increased from 0.5 to 5. In addition, the major I-THM compound shifted from CHCl2I to the more toxic CHClBrI. As pH increased from 6.0 to 8.0, I-THM formation kept increasing in the pre-breakpoint zone and the speciation of I-THMs changed alongside the breakpoint curves. The incorporation of I- during breakpoint chlorination was highly dependent on chlorine, I-, and NOM concentrations, NOM type, solution pH and Br-/I- molar ratio. PMID- 29709871 TI - Analysis of multiple vitamin D metabolites by ultra-performance supercritical fluid chromatography-tandem mass spectrometry (UPSFC-MS/MS). AB - In recent years, increased interest in the human health benefits of vitamin D has led to demand for improved analysis of patient vitamin D 'status'. Studies to date have focused primarily on a single vitamin D metabolite, 25-hydroxyvitamin D, despite the existence of a broad range of vitamin D metabolites, referred to as the vitamin D metabolome. This study reports on the development of a rapid UPSFC-MS/MS method for the analysis of nine vitamin D metabolites in human serum. Optimum separation was obtained with a Lux-Cellulose chiral column. We observed an orthogonal elution order when compared with ultra-high performance liquid chromatography (UHPLC). The order of elution was reversed based on hydroxyl- group number, however elution order did not differ between isomeric changes in hydroxyl- group position or epimers. Although UPSFC yielded superior resolution and selectivity over previously developed UHPLC-MS/MS methods, improvements in sensitivity could not be achieved owing to the lower injection volume required for UPSFC relative to UHPLC. Method validation was performed on the developed UPSFC-MS/MS method and found to be within acceptable limits. Applying the method to the analysis of human serum samples showed a significant correlation with serum concentrations of metabolites measured by UHPLC-MS/MS (25OHD3 r = 0.997, P=<0.001, and 3-epi-25OHD3 r = 0.996, P <=0.001). These data indicate that UPSFC provides an efficient analytical platform for rapid analysis of multiple vitamin D metabolites from serum. PMID- 29709874 TI - Parent-adolescent relationship and adolescent internet addiction: A moderated mediation model. AB - Substantial research has found that positive parent-adolescent relationship is associated with low levels of adolescent Internet addiction (IA). However, little is known about the mediating and moderating mechanisms underlying this relation. The present study examined a moderated mediation model that included the parent adolescent relationship (predictor variable), emotion regulation ability (mediator), stressful life events (moderator), and IA (outcome variable) simultaneously. A total of 998 (Mage = 15.15 years, SD = 1.57) Chinese adolescents completed the Parent-Adolescent Relationship Scale, Emotion Regulation Ability Scale, Adolescent Stressful Life Events Scale, and Internet Addiction Diagnostic Questionnaire. After controlling for adolescent gender, age, and family socioeconomic status, results revealed that good parent-adolescent relationship was positively associated with adolescent emotion regulation ability, which in turn was negatively associated with their IA. Moreover, stressful life events moderated the second part of the mediation process. In accordance with the reverse stress-buffering model, the relation between emotion regulation ability and adolescent IA was stronger for adolescents who experienced lower levels of stressful life events. The findings and their implications are discussed and a resilient contextual perspective proposed. PMID- 29709873 TI - Identification and evaluation of anti-inflammatory properties of aqueous components extracted from sesame (Sesamum indicum) oil. AB - We previously reported that sesame oil (SO) has anti-inflammatory, anti atherosclerotic and lipid lowering properties in vivo. Our recent studies have shown that, an aqueous extract of sesame oil (SOAE) has also anti-inflammatory and anti-atherosclerotic properties but with no lipid lowering effects. The extent of reduction in atherosclerosis led us to identify components of SOAE and evaluate their anti-inflammatory properties in vitro. Liquid chromatography mass spectrometric method was used to detect and identify components of SOAE. Methoxyphenol derivatives, short and long chain carboxylic acids, dicarboxylic acids, hydroxy and oxo- carboxylic acids were detected. To our surprise, sesamol and its derivatives (lignans), were not present in the SOAE. Among the identified, a combination of methoxy phenol compounds were selected and tested their ability to reduce LPS induced inflammatory gene expression. Monocyte derived macrophages/RAW 264.7 macrophages were pre-treated with these compounds for 2 h, followed by LPS stimulation for 24 h and pro-inflammatory gene expressions were analyzed. These methoxyphenol derivatives showed potent anti inflammatory properties. In conclusion, the anti-inflammatory molecules associated with SO may contribute the anti-inflammatory and anti-atherosclerotic properties. Also, our results shed light for the development of SOAE based non pharmacological therapeutics, nutritional supplements and health products for various inflammatory diseases in the future. PMID- 29709875 TI - A variable-frequency bidirectional shear horizontal (SH) wave transducer based on dual face-shear (d24) piezoelectric wafers. AB - Focusing the incident wave beam along a given direction is very useful in guided wave based structural health monitoring (SHM), as it will not only save input power but also simplify the interpretation of signals. Although the fundamental shear horizontal (SH0) wave is of practical importance in SHM due to its non dispersive characteristics so far there have been very limited transducers which can control the radiation patterns of SH0 wave. In this work, a variable frequency bidirectional SH0 wave piezoelectric transducer (BSH-PT) is proposed, which consists of two rectangular face-shear (d24) PZT wafers. The opposite face shear deformation of the two PZT wafers under applied electric fields makes the BSH-PT capable of exciting SH0 wave along two opposite directions (0 degrees and 180 degrees ). Both finite element simulations and experimental testings are conducted to examine the performance of the proposed BSH-PT. Results show that pure SH0 wave can be generated by this BSH-PT and its wave beam can be focused bi directionally. Moreover, the bidirectional characteristics of the BSH-PT can be kept over a wide frequency range from 150 kHz to 250 kHz. As the circumferential SH0 (CSH0) wave in a thin hollow cylindrical structure is essentially equivalent to the SH0 wave in a plate, the proposed BSH-PT may also be very useful to develop a CSH0-wave-based SHM system for hollow cylindrical structures. PMID- 29709876 TI - Chronic vagus nerve stimulation reverses heart rhythm complexity in patients with drug-resistant epilepsy: An assessment with multiscale entropy analysis. AB - OBJECTIVE: Vagus nerve stimulation (VNS) is an adjunctive treatment in drug resistant epilepsy. The alterations in heart rate dynamics through VNS are not well understood. This study aimed to determine changes in heart rhythm complexity in association with VNS and to relate the findings to the outcome of VNS treatment in patients with drug-resistant epilepsy. METHODS: We prospectively analyzed 32 patients with drug-resistant epilepsy, who underwent VNS implantation, and 32 age- and sex-matched healthy control subjects. The interictal heartbeat intervals were analyzed using the heart rhythm complexity with multiscale entropy (MSE) and traditional heart rate variability (HRV) analyses based on ambulatory 24-hour electrocardiograms (ECGs). RESULTS: Patients had significantly decreased complexity indices (Slope 5, Area 1-5, Area 6-15, Area 6-20) on MSE analysis and decreased HRV measurements (standard deviation of the heartbeat interval (SDNN), square root of the mean of sum of squares of the differences between adjacent RR intervals (RMSSD), pNN50, very low frequency (VLF), low frequency (LF), high frequency (HF), total power (TP)) in time and frequency domain analyses. After one year of VNS treatment in patients with drug resistant epilepsy, there was a trend in an elevated MSE profile with significant higher values between the scales 1 and 9. Vagus nerve stimulation induces a more significant increase of MSE in VNS responders than those in the nonresponders. The conventional HRV measurements did not change. CONCLUSION: Our results suggest that heart rhythm complexity is impaired in patients with drug-resistant epilepsy, and this is at least partially reversed by VNS treatment. Furthermore, VNS-induced effects on heart rate complexity may be associated with the therapeutic response to VNS in patients with drug-resistant epilepsy. PMID- 29709872 TI - Recent technical and biological development in the analysis of biomarker N deoxyguanosine-C8-4-aminobiphenyl. AB - 4-Aminobiphenyl (4-ABP) which is primarily formed during tobacco combustion and overheated meat is a major carcinogen responsible for various cancers. Its adducted form, N-deoxyguanosine-C8-4-aminobiphenyl (dG-C8-4-ABP), has long been employed as a biomarker for assessment of the risk for cancer. In this review, the metabolism and carcinogenisity of 4-ABP will be discussed, followed by a discussion of the current common approaches of analyzing dG-C8-4-ABP. The major part of this review will be on the history and recent development of key methods for detection and quantitation of dG-C8-4-ABP in complex biological samples and their biological applications, from the traditional 2P-postlabelling and immunoassay methods to modern liquid chromatography-mass spectrometry (LC-MS) with the latter as the focus. Many vital biological discoveries based on dG-C8-4 ABP have been published by using the nanoLC-MS with column switching platform in our laboratory, which has also been adopted and further improved by many other researchers. We hope this review can provide a perspective of the challenges that had to be addressed in reaching our present goals and possibly bring new ideas for those who are still working on the frontline of DNA adducts area. PMID- 29709877 TI - Affective and behavioral dysfunction under antiepileptic drugs in epilepsy: Development of a new drug-sensitive screening tool. AB - OBJECTIVE: Behavioral problems and psychiatric symptoms are common in patients with epilepsy and have a multifactorial origin, including adverse effects of antiepileptic drugs (AEDs). In order to develop a screening tool for behavioral AED effects, the aim of this study was to identify behavioral problems and symptoms particularly sensitive to AED drug load and the presence/absence of AEDs with known negative psychotropic profiles. METHODS: Four hundred ninety-four patients with epilepsy were evaluated who had been assessed with three self report questionnaires on mood, personality, and behavior (Beck Depression Inventory, BDI; Neurological Disorders Depression Inventory for Epilepsy extended, NDDI-E; and Fragebogen zur Personlichkeit bei zerebralen Erkrankungen, FPZ). Drug-sensitive items were determined via correlation analyses and entered into an exploratory factor analysis for scale construction. The resulting scales were then analyzed as a function of drug treatment. RESULTS: Analyses revealed 30 items, which could be allocated to six behavioral domains: Emotional Lability, Depression, Aggression/Irritability, Psychosis & Suicidality, Risk- & Sensation seeking, and Somatization. Subsequent analysis showed significant effects of the number of AEDs on behavior, as in Emotional Lability (F=2.54, p=.029), Aggression/Irritability (F=2.29, p=.046), Psychosis & Suicidality (F=2.98, p=.012), and Somatization (F=2.39, p=.038). Affective and behavioral difficulties were more prominent in those patients taking AEDs with supposedly negative psychotropic profiles. These effects were largely domain-unspecific and primarily manifested in polytherapy. CONCLUSION: Drug-sensitive behavioral domains and items were identified which qualify for a self-report screening tool. The tool indicates impairments with a higher drug load and when administering AEDs with negative psychotropic profiles. The next steps require normalization in healthy subjects and the clinical validation of the newly developed screening tool PsyTrack along with antiepileptic drug treatment. PMID- 29709878 TI - Genetic polymorphisms of the 5HT receptors are not related with depression in temporal lobe epilepsy caused by hippocampal sclerosis. AB - BACKGROUND: Temporal lobe epilepsy caused by hippocampal sclerosis (TLE-HS) is the most frequent form of drug-resistant epilepsy in adults. Mood disorders are the most frequent psychiatric comorbidities observed in these patients. Common pathophysiological mechanisms of epilepsy and psychiatric comorbidities include abnormalities in the serotonin pathway. The primary goal of this study was to determine the possible association between polymorphisms of genes encoding the serotonin receptors 5HT1A (rs6295), 5HT1B (rs6296), and 5HT2C (rs6318) and the presence of mood disorders in patients with TLE-HS. Our secondary goal was to evaluate the possible association between these variants and susceptibility to develop seizures in TLE-HS. METHODS: We assessed 119 patients with TLE-HS, with and without psychiatric comorbidities; 146 patients with major depressive disorder; and 113 healthy volunteers. Individuals were genotyped for the rs6295, rs6296, and rs6318 polymorphisms. RESULTS: No difference was observed between the group with TLE-HS, healthy controls, and the group with major depressive disorder without epilepsy regarding the polymorphisms that were evaluated. There was no correlation between rs6318, rs6295, rs6296, and epilepsy-related factors and history of psychiatric comorbidities. CONCLUSIONS: Our work suggests that the studied polymorphisms were not related to the presence of TLE, psychiatric comorbidities in TLE, and epilepsy-related factors. PMID- 29709879 TI - Change in illness perception is associated with short-term seizure burden outcome following video-EEG confirmation of psychogenic nonepileptic seizures. AB - OBJECTIVES: We aimed to evaluate whether potential changes in the patient's illness perception can significantly influence short-term seizure burden following video-electroencephalography (EEG) confirmation/explanation of psychogenic nonepileptic seizures (PNES). METHODS: Patients with PNES were dichotomized to two groups based on a five-point Symptom Attribution Scale: (a) those who prior to diagnosis perceived their seizures to be solely ("5") or mainly ("4") physical in origin (physical group) and (b) the remainder of patients with PNES (psychological group). The physical group (n=32), psychological group (n=40), and group with epilepsy (n=26) also completed the Brief Illness Perception Questionnaire (BIPQ) prior to diagnosis, and were followed up at 3months as well as at 6months postdiagnosis. RESULTS: At 3months postdiagnosis, the physical group experienced significantly greater improvement in seizure intensity (p=0.002) and seizure frequency (p=0.016) when compared with the psychological group. The physical group was significantly more likely to have modified their symptom attribution toward a greater psychological role to their seizures (p=0.002), and their endorsement on the BIPQ item addressing "consequences" (How much do your seizures affect your life?) was significantly less severe (p'=0.014) when compared with that of the psychological group and the group with epilepsy. At 6months postdiagnosis, the physical group continued to experience significantly greater improvement in seizure intensity (p=0.007) while their seizure frequency no longer reached significant difference (p=0.078) when compared with the psychological group. The physical group continued to be significantly more likely to have modified their symptom attribution toward a greater psychological role to their seizures (p=0.005), and their endorsement on the BIPQ item addressing "consequences" remained significantly less severe (p'=0.037) when compared with the psychological group and the group with epilepsy. CONCLUSIONS: Among patients with PNES, prediagnosis perception of seizures as "solely" or "mainly" physical in cause may be associated with greater likelihood of early postdiagnosis improvement in seizure burden. Within this physical group postdiagnosis, we uncovered preliminary evidence for significantly greater attribution toward psychological roles in seizures as well as reduction in cognitive distortion surrounding the adverse consequences of seizures. These findings portend particular impact of such changes in illness perception for this group. PMID- 29709881 TI - Preoperative MRI evaluation of meningioma consistency: A focus on detailed architectures. AB - OBJECTIVES: Meningioma is one of the most common primary intracranial tumors. Diagnosis by imaging is not difficult. However evaluation of tumor consistency is an important factor affecting the surgical outcomes. The purpose of our study is to discover the relationship of different findings on pre-operative MRI, with a focus on detailed architectures, and different degrees of intra-operative stiffness of meningioma. Consistency of meningioma is also analyzed in compression to semi-quantitative pathological grading of fibrosis. PATIENTS AND METHODS: Sixty patients who underwent pre-operative MRI and primary surgery at our hospital were included in prospective fashion. Pre-operative MRI parameters, including general data and detailed internal architectures, were recorded. Intra operative grading of tumor consistency was performed by the neurosurgeon. Pathological report according to WHO 2007 was performed with additional semi quantitative grading of fibrosis. This study is focused on correlation of operative grade and MRI findings. RESULTS: Meningioma with hard consistency shows significant correlation with several features including en plaque appearance (p = 0.0427), higher ADC value (p = 0.0046) and ratio (p = 0.0016), absent of prominent enhanced rim (p = 0.0306), absent of enostotic spur (p = 0.0040) and absent of vascular core (p = 0.0133) in univariate analysis but no significant correlation is found in multivariate analysis in all except ADC ratio. Higher ADC ratio increase relative risk of hard consistency of meningioma by a factor of 41.22 (ORs = 41.22; 95%CI = 1.19-1426.24, P = 0.04). Good to very good inter rater agreements are found. No significant correlation between tumor consistency and WHO grading was shown (p = 0.606). However, near significant p-value (p = 0.055) is found with increase degree of fibrosis in pathology as increase degree of tumor consistency. CONCLUSION: We found that en plaque appearance, higher ADC value and ADC ratio, absent of prominent capsular enhancement and absent of vascular core were suggestive of hard consistency in univariate analysis but not independent factors. Additionally, semi-quantitative pathological grading of fibrosis showed near significant correlation with tumor consistent. PMID- 29709880 TI - Seasonal changes in morphophysiological traits of two native Patagonian shrubs from Argentina with different drought resistance strategies. AB - In semi-arid regions, plants develop various biochemical and physiological strategies to adapt to dry periods. Understanding the resistance mechanisms to dry periods under field conditions is an important topic in ecology. Larrea divaricata and Lycium chilense provide various ecological services. The aim of this work is to elucidate new morpho-histological, biochemical and hormonal traits that contribute to the drought resistance strategies of two native shrubs. Green leaves and fine roots from L. divaricata and L. chilense were collected in each season for one year, and various traits were measured. The hormone (abscisic acid, ABA-glucose ester, gibberellins A1 and A3, and indole acetic acid) contents were determined by liquid chromatography coupled to mass spectrometry. Rainfall data and the soil water content were also measured. A multivariate analysis showed that green leaves from L. divaricata showed high values for the leaf dry weight, blade leaf thickness and ABA content in the summer compared with those from L. chilense. Fine roots from L. divaricata had high RWC and high IAA levels during the autumn-dry period compared with those from L. chilense, but both had similar levels during the winter and spring. Our results support the notion that species with different drought resistance mechanisms (avoidance or tolerance) display different responses to dry periods throughout the year. Larrea divaricata, which exhibits more xerophytic traits, modified its morphology and maintained its physiological parameters (high RWC in leaves and roots, high ABA levels in leaves during summer, high GA3 in leaves and high IAA in roots during autumn) to tolerate dry periods, whereas Lycium chilense, which displays more mesophytic traits, uses strategies to avoid dry periods (loss of leaves during autumn and winter, high RWC in leaves, high ABA-GE and GA3 in leaves during summer, high GA1 and GA3 in roots during summer, and high IAA in roots during autumn and summer) and thus has a metabolism that is more dependent on water availability for growth. PMID- 29709882 TI - The risk of developing seizures before and after primary brain surgery of low- and high-grade gliomas. AB - OBJECTIVE: To identify risk factors for developing seizures pre- and postoperatively in low- and high-grade gliomas. PATIENTS AND METHODS: 282 patients undergoing neurosurgical tumor resection between 2013-2015 were included in the present single-center retrospective cohort study. Seizure incidences according to various variables were described. Univariate and multivariate logistic regression analyses were performed to identify significant risk factors for both pre- and postoperative seizures. RESULTS: 37.6% of patients presented with seizures before surgery, 18.4% developed seizures in the postoperative course, and 55.0% had no record of seizures pre- or postoperatively. Focal, cognitive, and other symptoms, tumors located in a non-eloquent area, and tumors >= 40 mm in diameter were found to be associated with a reduced risk of preoperative seizures, whereas hypertension or no comorbidity posed an increased risk. The presence of seizures pre- or perioperatively (<= 24 h before and after surgery), and tumors located in the thalamus were associated with an increased risk of seizures in the postoperative course. CONCLUSION: Predictors for pre- and postoperative seizures identified in this study should be taken into account and integrated into the present knowledge, when determining patients at increased risk of developing seizures. Future prospective studies investigating the efficacy of prophylactic antiepileptic therapy in subgroups of glioma patients are needed before applied into clinical practice. PMID- 29709884 TI - Chronic moderate alcohol drinking alters insulin release without affecting cognitive and emotion-like behaviors in rats. AB - Because the consumption of alcoholic beverages prevails in society, its effects on diabetes risk is a subject of interest. Extant literature on this issue often disagrees. Here, we probed the effects of chronic moderate ethanol consumption on glucose metabolism in rats. The effect of chronic moderate alcohol drinking on depression- and anxiety-like behaviors and memory was also explored. Adolescent male and female Long-Evans rats consumed saccharin-sweetened 5% (1 week) and 10% ethanol (7 weeks) under a 7.5-h/day (Monday-Friday) access schedule. This exposure was followed by sucrose preference and elevated plus maze (EPM) tests during an intervening week, before a 6-week intermittent-access (Monday, Wednesday, Friday) to 20% unsweetened ethanol in a 2-bottle choice drinking paradigm was implemented (EtOH). A free-feeding control group received water (Water). Our prior work revealed that voluntary ethanol consumption decreases food intake in rats. Hence, a second control group that received water was mildly food-restricted (FR), and their average body weight was matched to that of the EtOH group. During the week following week 6 of intermittent-access to 20% ethanol, rats were submitted to sucrose preference, EPM, and novel object recognition (NOR) tests. Insulin response to a glucose load was subsequently assessed via an oral glucose tolerance test (OGTT). Rats attained and maintained blood ethanol concentrations of ~55 mg/dL that correlated with the dose of sweetened 10% ethanol ingested. Relative to intake by Water controls, EtOH rats consumed less chow. There was no body weight difference between both groups. Neither sex of EtOH rats showed increased depression- and anxiety-like behaviors, as respectively measured by sucrose preference and EPM, nor did they show deficit in object recognition memory during abstinence. Male EtOH rats, however, showed signs of reduced general activity on the EPM. During OGTT, male EtOH rats showed a time-dependent potentiation of insulin release for proper glucose clearance. Such an effect was not observed in females. This landmark study shows that chronic moderate alcohol consumption can have negative metabolic consequences in the absence of overt behavioral deficits, especially in males. PMID- 29709885 TI - Neural encoding of sensory and behavioral complexity in the auditory cortex. AB - Converging evidence now supports the idea that auditory cortex is an important step for the emergence of auditory percepts. Recent studies have extended the list of complex, nonlinear sound features coded by cortical neurons. Moreover, we are beginning to uncover general properties of cortical representations, such as invariance and discreteness, which reflect the structure of auditory perception. Complexity, however, emerges not only through nonlinear shaping of auditory information into perceptual bricks. Behavioral context and task-related information strongly influence cortical encoding of sounds via ascending neuromodulation and descending top-down frontal control. These effects appear to be mediated through local inhibitory networks. Thus, auditory cortex can be seen as a hub linking structured sensory representations with behavioral variables. PMID- 29709883 TI - Accumulation of polystyrene microplastics in juvenile Eriocheir sinensis and oxidative stress effects in the liver. AB - As a widespread and ubiquitous pollutant of marine ecosystems, microplastic has the potential to become an emerging global threat for aquatic organisms. The present study aims to elucidate the effects of microplastics on the growth, accumulation and oxidative stress response in the liver of Eriocheir sinensis. Fluorescent microplastic particles (diameter = 0.5 MUm) accumulated in the gill, liver and gut tissues of E. sinensis were investigated when crabs were exposed to a concentration of 40000 MUg/L for 7 days. A 21 day toxicity test suggested that the rate of weight gain, specific growth rate, and hepatosomatic index of E. sinensis decreased with increasing microplastic concentration (0 MUg/L, 40 MUg/L, 400 MUg/L, 4000 MUg/L and 40000 MUg/L). The activities of AChE and GPT in crabs exposed to microplastics were lower than those in control group. GOT activity increased significantly after exposure to a low concentration of microplastics and then decreased continuously with increasing microplastic concentrations. The activities of superoxide dismutase (SOD), aspartate transaminase (GOT), glutathione (GSH), and glutathione peroxidase (GPx) increased in specimens exposed to low concentrations of microplastics (40 and 400 MUg/L) compared to the control and decreased in organisms exposed to high concentrations (4000 and 40000 MUg/L). In contrast, the activities of acetylcholinesterase, catalase (CAT), and alanine aminotransferase were significantly lower in the organisms exposed to microplastics compared to control animals. Upon exposure to increasing microplastic concentrations, the expression of genes encoding the antioxidants SOD, CAT, GPx and glutathione S-transferase in the liver decreased after first increasing. Exposure to microplastics increased the expression of the gene encoding p38 in the MAPK signaling pathway and significantly decreased the expressions of genes encoding ERK, AKT, and MEK. The results of this study demonstrate that microplastics can accumulate in the tissues of E. sinensis and negatively affect growth. In addition, exposure to microplastics causes damage and induces oxidative stress in the hepatopancreas of E. sinensis. The findings provide basic biological data for environmental and human risk assessments of microplastics of high concern. PMID- 29709886 TI - Adult attachment and long-term singlehood. AB - Rates of singlehood are increasing rapidly in the Western World. In the current paper, we discuss the phenomenon of long-term singlehood from an attachment perspective, outline three distinct sub-groups of singles (anxious, avoidant, and secure), and demonstrate the utility of these groups by highlighting their unique characteristics and possible life outcomes, including factors that may moderate these outcomes. Finally, we offer suggestions for future research to enhance our understanding of this vastly under-researched population. PMID- 29709887 TI - Association Between Serum Folate Levels and Caffeinated Beverage Consumption in Pregnant Women in Chiba: The Japan Environment and Children's Study. AB - BACKGROUND: Several studies have reported the adverse effects of caffeine intake during pregnancy on fetal health. However, the effects of caffeine intake from green and oolong teas has not been investigated, despite the considerable consumption of these teas in Japan and the potential inhibitory effects of catechins-chemicals present at relatively high levels in green and oolong teas-on folic acid absorption. The potential associations of serum folate levels with caffeinated beverage consumption and catechin levels remain largely unstudied. The present study aimed to determine these associations in pregnant Japanese women. METHODS: Pregnant women (n = 2,701) not receiving folate supplementation were enrolled at the Chiba Unit Center, a regional site of the Japan Environment and Children's Study (JECS). Serum folate levels were measured using an Access folate assay kit, and nutrient and caffeine intakes were assessed using a self administered food frequency questionnaire that was previously evaluated in Japanese populations. RESULTS: The low and normal serum folate groups reported caffeine intakes of 42.3 mg/1,000 kcal and 34.4 mg/1,000 kcal, respectively, and tannin intakes of 40.8 mg/1,000 kcal and 36.3 mg/1,000 kcal, respectively. Multiple regression analyses revealed negative associations of serum folate levels with caffeine and tannin intakes and a positive association between serum folate levels and dietary folate intake. CONCLUSIONS: Considering the negative associations of caffeine and tannin levels with serum folate levels, pregnant women should consume caffeinated beverages, such as coffee and green/oolong teas, with caution. PMID- 29709888 TI - Simultaneous Validation of Seven Physical Activity Questionnaires Used in Japanese Cohorts for Estimating Energy Expenditure: A Doubly Labeled Water Study. AB - BACKGROUND: Physical activity questionnaires (PAQs) used in large-scale Japanese cohorts have rarely been simultaneously validated against the gold standard doubly labeled water (DLW) method. This study examined the validity of seven PAQs used in Japan for estimating energy expenditure against the DLW method. METHODS: Twenty healthy Japanese adults (9 men; mean age, 32.4 [standard deviation {SD}, 9.4] years, mainly researchers and students) participated in this study. Fifteen day daily total energy expenditure (TEE) and basal metabolic rate (BMR) were measured using the DLW method and a metabolic chamber, respectively. Activity energy expenditure (AEE) was calculated as TEE - BMR - 0.1 * TEE. Seven PAQs were self-administered to estimate TEE and AEE. RESULTS: The mean measured values of TEE and AEE were 2,294 (SD, 318) kcal/day and 721 (SD, 161) kcal/day, respectively. All of the PAQs indicated moderate-to-strong correlations with the DLW method in TEE (rho = 0.57-0.84). Two PAQs (Japan Public Health Center Study [JPHC]-PAQ Short and JPHC-PAQ Long) showed significant equivalence in TEE and moderate intra-class correlation coefficients (ICC). None of the PAQs showed significantly equivalent AEE estimates, with differences ranging from -547 to 77 kcal/day. Correlations and ICCs in AEE were mostly weak or fair (rho = 0.02-0.54, and ICC = 0.00-0.44). Only JPHC-PAQ Short provided significant and fair agreement with the DLW method. CONCLUSIONS: TEE estimated by the PAQs showed moderate or strong correlations with the results of DLW. Two PAQs showed equivalent TEE and moderate agreement. None of the PAQs showed equivalent AEE estimation to the gold standard, with weak-to-fair correlations and agreements. Further studies with larger sample sizes are needed to confirm these findings. PMID- 29709889 TI - Participation in Community Group Activities Among Older Adults: Is Diversity of Group Membership Associated With Better Self-rated Health? AB - BACKGROUND: Participation in community activities (eg, sports and hobby groups or volunteer organizations) is believed to be associated with better health status in the older population. We sought to (1) determine whether a greater diversity of group membership is associated with better self-rated health and (2) identify the key dimension of the membership diversity (eg, gender, residential area, or age). METHODS: We performed a cross-sectional study of 129,740 participants aged 65 years and older who were enrolled in the Japan Gerontological Evaluation Study in 2013. We assessed the diversity of group membership using (1) a continuous variable (range 0-4) accounting for the total degree of each diversity dimension or (2) dummy variables for each dimension. We estimated prevalence ratios (PRs) and 95% confidence intervals (CIs) for better self-rated health according to the diversity of group membership, using Poisson regression and robust variance with multiple imputation, adjusted for other covariates. RESULTS: The participants involved in social groups with greater diversity had better self-rated health: the PR per one point unit increase in diversity was 1.03 (95% CI, 1.02-1.04). Participation in gender-diverse groups was associated with the best profile of health (PR 1.07; 95% CI, 1.04-1.09). CONCLUSIONS: Among the older population in Japan, higher group diversity is associated with better self-rated health. Gender is the key dimension of diversity that is associated with better self-rated health. PMID- 29709890 TI - Solo and Keratin Filaments Regulate Epithelial Tubule Morphology. AB - Epithelial tubules, consisting of the epithelial cell sheet with a central lumen, are the basic structure of many organs. Mechanical forces play an important role in epithelial tubulogenesis; however, little is known about the mechanisms controlling the mechanical forces during epithelial tubule morphogenesis. Solo (also known as ARHGEF40) is a RhoA-targeting guanine-nucleotide exchange factor that is involved in mechanical force-induced RhoA activation and stress fiber formation. Solo binds to keratin-8/keratin-18 (K8/K18) filaments, and this interaction plays a crucial role in mechanotransduction. In this study, we examined the roles of Solo and K8/K18 filaments in epithelial tubulogenesis using MDCK cells cultured in 3D collagen gels. Knockdown of either Solo or K18 resulted in rounder tubules with increased lumen size, indicating that Solo and K8/K18 filaments play critical roles in forming the elongated morphology of epithelial tubules. Moreover, knockdown of Solo or K18 decreased the level of diphosphorylated myosin light chain (a marker of contractile force) at the luminal and outer surfaces of tubules, suggesting that Solo and K8/K18 filaments are involved in the generation of the myosin II-mediated contractile force during epithelial tubule morphogenesis. In addition, K18 filaments were normally oriented along the long axis of the tubule, but knockdown of Solo perturbed their orientation. These results suggest that Solo plays crucial roles in forming the elongated morphology of epithelial tubules and in regulating myosin II activity and K18 filament organization during epithelial tubule formation.Key words: epithelial tubulogenesis, Solo, keratin, Rho-GEF, myosin. PMID- 29709891 TI - Enzymatic and molecular characterization of an acidic and thermostable chitinase 1 from Streptomyces thermodiastaticus HF 3-3. AB - Chitinase 1 (Chi1) is an acidic and thermostable hydrolytic enzyme capable of the breakdown of chitin, a resilient biopolymer that is the primary building block of fungi cell walls and marine exoskeletons. In this study, Chi1 was purified from the bacterium Streptomyces thermodiastaticus HF 3-3, and its properties were carefully characterized. The molecular mass of Chi1 was estimated to be approximately 46 kDa and, through sequencing, its N-terminal amino acid sequence was identified as ADSGKVKL. Although the optimal operating temperature and pH for Chi1 were determined to be 65 degrees C and pH 5.5, respectively, the purified enzyme was stable over wide pH (1.5-9) and temperature ranges. Moreover, Chi1 retained 87% of its activity in the presence of 15% NaCl. While Chi1 activity was inhibited by Ag+ and Mn2+, other chemicals tested had no significant effect on its enzymatic activity. The Km and Vmax values of Chi1 for the substrate colloidal chitin were 1.23 +/- 0.7 mg/mL and 6.33 +/- 1.0 U/mg, respectively. Thin-layer chromatography analysis of the enzymatic reaction end products mainly detected diacetylchitobiose. We also cloned the Chi1 gene and purified the recombinant protein; the properties of the recombinant enzyme were nearly identical to those of the native enzyme. Therefore, Chi1 purified from S. thermodiastaticus HF 3-3 is unique, as it is highly stable under broad range of pH values, temperatures, and chemical exposures. Combined, these properties make this enzyme attractive for use in the industrial bioconversion of chitin. PMID- 29709892 TI - Comparing the Consistency and Performance of Various Coronary Heart Disease Prediction Models for Primary Prevention Using a National Representative Cohort in Taiwan. AB - BACKGROUND: Predicting future coronary artery disease (CAD) risk by model-based approaches can facilitate identification of high-risk individuals for prevention and management. Therefore, we compared the consistency and performance of various CAD models for primary prevention using 1 external validation dataset from a national representative cohort in Taiwan.Methods and Results:The 10 CAD prediction models were assessed in a validation cohort of 3559 participants (>=35 years old, 53.5% women) from a Taiwanese national representative cohort that was followed up for a median 9.70 (interquartile range, 9.63-9.74) years; 63 cases were documented as developing CAD events. The overall kappa value was 0.51 for all 10 models, with a higher value for women than for men (0.53 for women, 0.40 for men). In addition, the areas under the receiver operating characteristics curves ranged from 0.804 (95% confidence interval, 0.758-0.851) to 0.847 (95% confidence interval, 0.805-0.889). All non-significant chi-square values indicated good calibration ability. CONCLUSIONS: Our study demonstrated these 10 CAD prediction models for primary prevention were feasible and validated for use in Taiwanese subjects. Further studies of screening and management are warranted. PMID- 29709893 TI - Treatment Strategies for Atrial Fibrillation With Left Ventricular Systolic Dysfunction - Meta-Analysis. AB - BACKGROUND: Atrial fibrillation (AF) frequently coexists with heart failure (HF) with reduced ejection fraction (EF). This meta-analysis compared AF control strategies, that is, rhythm vs. rate, and catheter ablation (CA) vs. anti arrhythmic drugs (AAD) in patients with AF combined with HF.Methods and Results:The MEDLINE, EMBASE, and CENTRAL databases were searched, and 13 articles from 11 randomized controlled trials with 5,256 patients were included in this meta-analysis. The outcomes were echocardiographic parameters (left ventricular EF, LVEF), left atrial (LA) size, and left ventricular end-systolic volume, LVESV), clinical outcomes (mortality, hospitalization, and thromboembolism), exercise capacity, and quality of life (QOL). In a random effects model, rhythm control was associated with higher LVEF, better exercise capacity, and better QOL than the rate control. When the 2 different rhythm control strategies were compared (CA vs. AAD), the CA group had significantly decreased LA size and LVESV, and improved LVEF and 6-min walk distance, but mortality, hospitalization, and thromboembolism rates were not different between the rhythm and rate control groups. CONCLUSIONS: In AF combined with HF, even though mortality, hospitalization and thromboembolism rates were similar, a rhythm control strategy was superior to rate control in terms of improvement in LVEF, exercise capacity, and QOL. In particular, the CA group was superior to the AAD group for reversal of cardiac remodeling. PMID- 29709894 TI - Association Between Glycemic Control and Incident Stroke - Overview From an Epidemiologic Study. PMID- 29709895 TI - Importance of Soil Temperature for the Growth of Temperate Crops under a Tropical Climate and Functional Role of Soil Microbial Diversity. AB - A soil cooling system that prepares soil for temperate soil temperatures for the growth of temperate crops under a tropical climate is described herein. Temperate agriculture has been threatened by the negative impact of temperature increases caused by climate change. Soil temperature closely correlates with the growth of temperate crops, and affects plant processes and soil microbial diversity. The present study focuses on the effects of soil temperatures on lettuce growth and soil microbial diversity that maintains the growth of lettuce at low soil temperatures. A model temperate crop, loose leaf lettuce, was grown on eutrophic soil under soil cooling and a number of parameters, such as fresh weight, height, the number of leaves, and root length, were evaluated upon harvest. Under soil cooling, significant differences were observed in the average fresh weight (P<0.05) and positive development of the roots, shoots, and leaves of lettuce. Janthinobacterium (8.142%), Rhodoplanes (1.991%), Arthrospira (1.138%), Flavobacterium (0.857%), Sphingomonas (0.790%), Mycoplana (0.726%), and Pseudomonas (0.688%) were the dominant bacterial genera present in cooled soil. Key soil fungal communities, including Pseudaleuria (18.307%), Phoma (9.968%), Eocronartium (3.527%), Trichosporon (1.791%), and Pyrenochaeta (0.171%), were also recovered from cooled soil. The present results demonstrate that the growth of temperate crops is dependent on soil temperature, which subsequently affects the abundance and diversity of soil microbial communities that maintain the growth of temperate crops at low soil temperatures. PMID- 29709897 TI - AMPK-Mediated Regulation of Lipid Metabolism by Phosphorylation. AB - AMP-activated protein kinase (AMPK) is a metabolic sensor in mammals that is activated when ATP levels in the cell decrease. AMPK is a heterotrimeric protein that comprises 3 subunits, each of which has multiple phosphorylation sites that play critical roles in the regulation of either anabolism or catabolism by directly phosphorylating proteins or modulating gene transcription in multiple pathways, such as synthesis, oxidation and lipolysis of lipid. Research focused on the phosphorylation sites that are involved in lipid metabolism will lead to a better recognition of the role of AMPK in therapeutics for several common diseases. In this review, close attention is paid to the recent research on the structure, and multisite phosphorylation of AMPK subunits, as well as AMPK regulation of lipid metabolism via phosphorylation of related molecules. PMID- 29709896 TI - Ureolytic Prokaryotes in Soil: Community Abundance and Diversity. AB - Although the turnover of urea is a crucial process in nitrogen transformation in soil, limited information is currently available on the abundance and diversity of ureolytic prokaryotes. The abundance and diversity of the soil 16S rRNA gene and ureC (encoding a urease catalytic subunit) were examined in seven soil types using quantitative PCR and amplicon sequencing with Illumina MiSeq. The amplicon sequencing of ureC revealed that the ureolytic community was composed of phylogenetically varied prokaryotes, and we detected 363 to 1,685 species-level ureC operational taxonomic units (OTUs) per soil sample, whereas 5,984 OTUs were site-specific OTUs found in only one of the seven soil types. PMID- 29709898 TI - Angiotensin II aggravates lipopolysaccharide induced human pulmonary microvascular endothelial cells permeability in high glucose status. AB - Lung infection is one of the most common infections in diabetes mellitus and is characterized by increased pulmonary microvascular endothelial permeability. Local Angiotensin II (AngII) plays an important role in the pathogenesis of lung diseases. However, whether AngII can aggravate diabetic infectious lung injury is not clear. Therefore, we investigated the effects of AngII on the permeability of human pulmonary microvascular endothelial cells (HPMVECs) challenged by lipopolysaccharide (LPS) in high glucose states in vitro. HPMVECs were divided into five groups: a control group (CON), a high glucose group (HG), an LPS + high glucose group (LH), an LPS + high glucose + AngII group (LHA), and an LPS + high glucose + Losartan group (LHL). The HPMVECs permeability as well as the F-actin levels, cytoskeleton, apoptosis and TNF-alpha concentrations were evaluated. Compared to the CON group, the HG, LH and LHA groups had significantly higher cellular permeability, cellular apoptosis and TNF-alpha levels, with more extensive cytoskeletal damage and lower F-actin levels. Additionally, cells in the LHA group exhibited significantly elevated permeability, apoptosis and TNF alpha concentrations, lower F-actin levels and more extensive cytoskeletal damage than either the LH or HG group. However, compared to the HG or LH group, the LHL group showed significantly lower cellular permeability, cell apoptosis, cytoskeletal damage and TNF-alpha concentrations and higher F-actin levels. This study suggests that in a diabetic infectious lung injury cellular model, AngII could aggravate the permeability of HPMVEC via F-actin dynamics and cell apoptosis. Furthermore, blocking the Angiotension II Type 1 Receptor could significantly alleviate the hyperpermeability of HPMVECs. PMID- 29709899 TI - Testicular regulation of seasonal change in apocrine glands in the back skin of the brown bear (Ursus arctos). AB - Brown bears communicate with other individuals using marking behavior. Bipedal back rubbing has been identified as a common marking posture. Oily substances are secreted via enlarged sebaceous glands in the back skin of male bears during the breeding season. However, whether apocrine gland secretions are associated with seasonal changes remains unknown. The present study aimed to identify histological and histochemical changes in the secretory status and the glycocomposition of the apocrine glands in the back skin of male bears in response to changes in seasons and/or reproductive status. The apocrine glands of intact males during the breeding season were significantly larger and more active than those of castrated males during the breeding season and those of intact males during the non-breeding season. Lectin histochemical analyses revealed a more intense reaction to Vicia villosa agglutinin (VVA) in the cytoplasm, mainly Golgi zones of apocrine cells during the breeding season among castrated, compared with intact males. Positive staining for VVA was quite intense and weak in intact males during the non-breeding and breeding seasons, respectively. Ultrastructural analysis revealed VVA positivity in the Golgi zone, especially around secretory granules in apocrine cells. Changes in lectin binding might reflect a change in the secretory system in the apocrine cells. The present histological and histochemical findings of changes in the secretory status and glycocomposition of the apocrine glands according to the season and reproductive status suggest that these glands are important for chemical communication. PMID- 29709900 TI - Transcriptome analysis reveals differential gene expression in intramuscular adipose tissues of Jinhua and Landrace pigs. AB - Meat is a rich source of protein, fatty acids and carbohydrates for human needs. In addition to necessary nutrients, high fat contents in pork increase the tenderness and juiciness of the meat, featuring diverse application in various dishes. This study investigated the transcriptomic profiles of intramuscular adipose tissues in Jinhua and Landrace pigs by employing advanced RNA sequencing. Results showed significant interesting to note that there were significant differences in the expression of genes. 1,632 genes showed significant differential expression, 837 genes were up-regulated and 195 genes were down regulated. Variations in genes responsible for cell aggregation, extracellular matrix formation, cellular lipid catabolic process, and fatty acid binding strongly supported that both pig breeds feature variable fat and muscle metabolism. Certain differentially expressed genes are included in the pathway of mitogen-activated protein kinase signaling pathway, Ras signaling pathway and insulin pathway. Results from real-time quantitative polymerase chain reaction also validated the differential expression of 17 mRNAs between meats of the two pig breeds. Overall, these findings reveal significant differences in fat and protein metabolism of intramuscular adipose tissues of two pig breeds at the transcriptomic level and suggest diversification at the genetic level between breeds of the same species. PMID- 29709901 TI - Characterization of mycosporine-like amino acids in the cyanobacterium Nostoc verrucosum. AB - The aquatic cyanobacterium Nostoc verrucosum forms macroscopic colonies in streams, and its appearance is superficially similar to that of the terrestrial cyanobacterium Nostoc commune. N. verrucosum is sensitive to desiccation, unlike N. commune, although these Nostoc cyanobacterial species share physiological features, including massive extracellular polysaccharide production and trehalose accumulation capability. In this study, water-soluble sunscreen pigments of mycosporine-like amino acids (MAAs) were characterized in N. verrucosum, and the mysABCD genes responsible for MAA biosynthesis in N. verrucosum and N. commune were compared. N. verrucosum produced porphyra-334 and shinorine, with porphyra 334 accounting for >90% of the total MAAs. Interestingly, porphyra-334 is an atypical cyanobacteial MAA, whereas shinorine is known as a common and dominant MAA in cyanobacteria. Porphyra-334 from N. verrucosum showed little or no radical scavenging activity in vitro, although the glycosylated derivatives of porphyra 334 from N. commune are potent radical scavengers. The presence of the mysABCD gene cluster in N. commune strain KU002 (genotype A) supported its porphyra-334 producing capability via the Nostoc-type mechanism, although the genotype A of N. commune mainly produces the arabinose-bound porphyra-334. The mysABC gene cluster was conserved in N. verrucosum, but the mysD gene was not included in the cluster. These results suggest that the mysABCD gene products are involved in the biosynthesis of porphyra-334 commonly in these Nostoc species, and that the genotype A of N. commune additionally acquired the glycosylation of porphyra-334. PMID- 29709902 TI - Development of a quantitative real-time RT-PCR assay for detecting Taiwan ferret badger rabies virus in ear tissue of ferret badgers and mice. AB - In 2013, the first case of Taiwan ferret badger rabies virus (RABV-TWFB) infection was reported in Formosan ferret badgers, and two genetic groups of the virus were distinguished through phylogenetic analysis. To detect RABV-TWFB using a sensitive nucleic acid-based method, a quantitative real-time reverse transcription polymerase chain reaction targeting the conserved region of both genetic groups of RABV-TWFB was developed. This method had a limit of detection (LOD) of 40 RNA copies/reaction and detected viral RNA in brain and ear tissue specimens of infected and dead Formosan ferret badgers and mice with 100% sensitivity and specificity. The mean viral RNA load detected in the ear tissue specimens of ferret badgers ranged from 3.89 * 108 to 9.73 * 108 RNA copies/g organ, which was 111-fold to 2,220-fold lower than the concentration detected in the brain specimens, but 2,000-fold to 5,000-fold higher than the LOD of the assay. This highly sensitive technique does not require facilities or instruments complying with strict biosafety criteria. Furthermore, it is efficient, safe, and labor-saving as only ear specimens need be sampled. Therefore, it is a promising technique for epidemiological screening of Taiwan ferret badger rabies. PMID- 29709903 TI - Preventing the spread of norovirus-like infections by the airborne route using plasma assisted catalytic technology (PACT). AB - Zoonoses are frequently reported, and outbreaks of the highly pathogenic influenza virus, severe acute respiratory syndrome, and Middle East respiratory syndrome have occurred recently, in Africa, the Middle East, and Southeast Asia. Sterilization using a chemical reactor with plasma assisted catalytic technology (PACT) was investigated. Tests were carried out on the feline calicivirus (FCV) vaccine strain F9, which is a surrogate of airborne pathogen human norovirus. Results showed that the PACT device could inactivate FCV, which passed through the plasma chamber. Sterilization rate may be more than 99.99% (below the detection limit). These results indicate that PACT may be an effective mean to inactivate many viruses, including human norovirus, and potentially other airborne, infectious microorganisms. PMID- 29709904 TI - Development and Evaluation of Antibody Proteomics Technology for Rapid and Comprehensive Identification of Potential Biomarkers and Therapeutic Targets. AB - Proteomics-based analyses are powerful means of identifying potentially useful proteins in the initial stage of drug development. Technological developments in the field of proteomics, and increases in the sensitivity of MS analyses, now facilitate identification and examination of increasingly small amounts of proteins that are differentially expressed in diseased versus normal tissues and can be candidate biomarkers or therapeutic targets. However, the current approach is for candidate proteins to be prioritized by research interest and then validated one by one; this is very inefficient. To address this issue, we have developed what we refer to as "antibody proteomics technology," which uses a phage antibody library and tissue microarray analysis to rapidly and comprehensively isolate monoclonal antibodies against candidate proteins for the identification of potential biomarkers and therapeutic targets. In our validation of this technology, we successfully identified oxysterol binding protein-like 5 and calumenin as potential biomarkers related to metastasis in lung cancer, annexin A4 as a potential biomarker related to cisplatin resistance in malignant mesothelioma, and Eph receptor A10 as a potential therapeutic target in breast cancer, including refractory breast cancer. These findings suggest that antibody proteomics technology has the potential to become a fundamental technology in drug discovery for the development of novel biomarkers and therapeutic targets. PMID- 29709905 TI - Gastrodin Protects against Ethanol-Induced Liver Injury and Apoptosis in HepG2 Cells and Animal Models of Alcoholic Liver Disease. AB - This study aims to investigate the protective effects of gastrodin (GSTD), a natural compound isolated from the root of Gastrodia elata BL., on ethanol induced liver injury and apoptosis in HepG2 cells and animal models. For in vitro studies, GSTD was used to pre-treat the cells for 4 h followed by 600 mM of ethanol co-administration for 24 h. Alcoholic liver disease (ALD) of Sprague Dawley (SD) rats was induced by chronic ethanol-feeding plus a single dose (5 g/kg) of acute ethanol administration, GSTD at different doses were co administered for 8 weeks. For acute liver injury experiment of ICR mice, GSTD (100 mg/kg/d) was pre-treated for 3 d followed by ethanol administration (5 g/kg) for 3 times. The results showed that GSTD protects HepG2 cells from ethanol induced toxicity, injury, and apoptosis significantly. Co-administered with ethanol, GSTD prevented the loss of mitochondrial membrane potential, reduced the release cytochrome c from mitochondria, and inhibited the activation of caspase-3 in HepG2 cells. In SD rats induced by chronic ethanol-feeding, GSTD significantly restored liver function and ameliorated pathological changes of the liver. In rat liver, GSTD greatly suppressed the activation of caspase-3 and inhibited hepatocellular apoptosis. In ethanol-induced acute liver injury of ICR mice, GSTD reduced liver acetaldehyde and suppressed the up-regulation of alcohol dehydrogenase (ADH) and CYP2E1 significantly. Our results demonstrate that GSTD is efficacious in protecting liver cells from ethanol-induced injury and apoptosis; it may be useful for the development of novel agents for the treatment of ALD in the future. PMID- 29709907 TI - Development of a Caco-2 Cell Line Carrying the Human Intestine-Type CES Expression Profile as a Promising Tool for Ester-Containing Drug Permeability Studies. AB - Carboxylesterase 2 (CES2), which is a member of the serine hydrolase superfamily, is primarily expressed in the human small intestine, where it plays an important role in the metabolism of ester-containing drugs. Therefore, to facilitate continued progress in ester-containing drug development, it is crucial to evaluate how CES2-mediated hydrolysis influences its intestinal permeability characteristics. Human colon carcinoma Caco-2 cells have long been widely used in drug permeability studies as an enterocyte model. However, they are not suitable for ester-containing drug permeability studies due to the fact that Caco-2 cells express CES1 (which is not expressed in human enterocytes) but do not express CES2. To resolve this problem, we created a new Caco-2 cell line carrying the human small intestine-type CES expression profile. We began by introducing short hairpin RNA for CES1 mRNA knockdown into Caco-2 cells to generate CES1-decifient Caco-2 cells (Caco-2CES1KD cells). Then, we developed Caco-2CES1KD cells that stably express CES2 (CES2/Caco-2CES1KD cells) and their control Mock/Caco-2CES1KD cells. The results of a series of functional expression experiments confirmed that CES2-specific activity, along with CES2 mRNA and protein expression, were clearly detected in our CES2/Caco-2CES1KD cells. Furthermore, we also confirmed that CES2/Caco-2CES1KD cells retained their tight junction formation property as well as their drug efflux transporter functions. Collectively, based on our results clearly showing that CES2/Caco-2CES1KD cells carry the human intestinal type CES expression profile, while concomitantly retaining their barrier properties, it can be expected that this cell line will provide a promising in vitro model for ester-containing drug permeability studies. PMID- 29709906 TI - Dibenzoylmethane Suppresses Lipid Accumulation and Reactive Oxygen Species Production through Regulation of Nuclear Factor (Erythroid-Derived 2)-Like 2 and Insulin Signaling in Adipocytes. AB - The aim of this study was to investigate the effects of dibenzoylmethane (1,3 diphenyl-1,3-propanedione, DBM) from licorice roots on lipid accumulation and reactive oxygen species (ROS) production in 3T3-L1 cells. DBM effectively inhibited lipid accumulation during adipogenesis, and its inhibitory effect was shown to be due to the down-regulation of adipogenic factors such as CCAAT enhancer-binding protein-alpha (C/EBPalpha), peroxisome proliferator-activated receptor gamma (PPARgamma), and fatty acid-binding protein 4 (FABP4). DBM was observed to exert its inhibitory effect on lipid accumulation in the early adipogenic stage (days 0-2) by regulating early adipogenic factors including CCAAT-enhancer-binding protein-beta (C/EBPbeta) and Krueppel-like factor (KLF) 2. DBM significantly increased the translocation of nuclear factor (erythroid derived 2)-like 2(Nrf2) into the nucleus, promoting the protein expression of its target gene, heme oxygenase-1 (HO-1). DBM significantly suppressed the insulin mediated activation of phosphoinositide 3-kinase (PI3K) and protein kinase B (Akt), which are components of insulin signaling. In addition, intracellular ROS production was effectively reduced by DBM treatment, which upregulated antioxidant genes such as glutathione peroxidase (Gpx), catalase (CAT), and superoxide dismutase 1 (SOD1). Furthermore, DBM significantly regulated the expression of the adipokines, resistin and adiponectin. This DBM-mediated regulation of lipid accumulation, ROS production, and adipokine production was shown to be involved in the regulation of the Nrf2 and insulin signaling. PMID- 29709908 TI - Effects of Oridonin on Hepatic Cytochrome P450 Expression and Activities in PXR Humanized Mice. AB - Oridonin, the major terpene found in Rabdosia rubescens, is widely used as dietary supplement or therapeutic drug, while the effects of oridonin on CYP450 were still unclear. The pregnane X receptor (PXR) is an important regulatory factor for major drug metabolism enzyme CYPs, and it has been reported to have species-specific differences. Therefore, this study has employed more reliable models PXR-humanized mouse to investigate the influence of oridonin on PXR and downstream metabolism enzyme. Eight-week-old male PXR-humanized mice were treated with oridonin by orally (0, 25, 50, 100, 200 mg/kg) for 15 d. The effects of oridonin on major downstream CYPs of PXR were examined at both the mRNA and enzyme activity levels by RT-PCR and HPLC-MS/MS. In general, there was no significant toxic reaction in liver of PXR-humanized mice. The mRNA expression of CYPs and cytochrome P450 oxidoreductase (POR) were increased with oridonin treatment in a dose-dependent manner. CYP2c and CYP3a family catalytic activity were increased significantly in two higher doses groups. These results indicate that oridonin induced the expression and activation of CYP2c and CYP3a family, which might contribute to potential drug-drug interactions and appear to be a risk when co-administered with other clinical drugs. PMID- 29709909 TI - Induction of Apoptosis by Citrus unshiu Peel in Human Breast Cancer MCF-7 Cells: Involvement of ROS-Dependent Activation of AMPK. AB - The fruit of Citrus unshiu MARKOVICH used for various purposes in traditional medicine has various pharmacological properties including antioxidant, anti inflammatory, and antibacterial effects. Recently, the possibility of anti-cancer activity of the extracts or components of this fruit has been reported; however, the exact mechanism has not yet been fully understood. In this study, we evaluated the anti-proliferative effect of water extract of C. unshiu peel (WECU) on human breast cancer MCF-7 cells and investigated the underlying mechanism. Our results showed that reduction of MCF-7 cell survival by WECU was associated with the induction of apoptosis. WECU-induced apoptotic cell death was related to the activation of caspase-8 and -9, representative initiate caspases of extrinsic and intrinsic apoptosis pathways, respectively, and increase in the Bax : Bcl-2 ratio accompanied by cleavage of poly(ADP-ribose) polymerase (PARP). WECU also increased the mitochondrial dysfunction and cytosolic release of cytochrome c. In addition, AMP-activated protein kinase (AMPK) and its downstream target molecule, acetyl-CoA carboxylase, were activated in a concentration-dependent manner in WECU-treated cells. In contrast, compound C, an AMPK inhibitor, significantly inhibited WECU-induced apoptosis, while inhibiting increased expression of Bax and decreased expression of Bcl-2 by WECU and inhibition of WECU-induced PARP degradation. Furthermore, WECU provoked the production of reactive oxygen species (ROS); however, the activation of AMKP and apoptosis by WECU were prevented, when the ROS production was blocked by antioxidant N-acetyl cysteine. Therefore, our data indicate that WECU suppresses MCF-7 cell proliferation by activating the intrinsic and extrinsic apoptosis pathways through ROS-dependent AMPK pathway activation. PMID- 29709910 TI - A Novel Strategy to Increase the Yield of Exosomes (Extracellular Vesicles) for an Expansion of Basic Research. AB - Exosomes are tiny extracellular vesicles that are usually harvested in small quantities. Such small yield has been an obstacle for the expansion of the basic research regarding exosome analysis and applications in drug delivery. To increase exosome yield, we attempted to stimulate tumor cells via the addition of liposomes in vitro. Neutral, cationic-bare or PEGylated liposomes were incubated with four different tumor cell lines. The stimulatory effect of liposomal formulations on exosome secretion and cellular uptake propensity of the collected exosome by mother cells or different cells was evaluated. Both neutral and cationic-bare liposomes enhanced exosome secretion in a dose-dependent manner. Fluid cationic liposomes provided the strongest stimulation. Surprisingly, the PEGylation of bare liposomes diminished exosome secretion. Exosomes harvested in the presence of fluid cationic liposomes showed increased cellular uptake, but solid cationic liposomes did not. Our findings indicate that the physicochemical properties of liposomes determine whether they will act as a stimulant or as a depressant on exosome secretion from tumor cells. Liposomal stimulation may be a useful strategy to increase exosome yield, although further preparation to increase the purity of exosomes may be needed. In addition, fine-tuning of the biological properties of induced exosomes could be achieved via controlling the physicochemical properties of the stimulant liposomes. PMID- 29709911 TI - Sphingoid Base-Upregulated Caspase-14 Expression Involves MAPK. AB - Sphingolipids are putative intracellular signal mediators in cell differentiation, growth inhibition, and apoptosis. Especially, sphingoid base backbones of sphingolipids (sphingosine, sphinganine, and phytosphingosine) and their metabolites N-acyl-sphingoid bases (ceramides) are highly bioactive. In skin, one of the caspases, caspase-14, is expressed predominantly in cornifying epithelia, and caspase-14 plays an important role in keratinocyte differentiation. As ceramides were surrounding lipids in the keratinocytes and ceramides stimulate keratinocyte differentiation, we therefore examined the upregulation of caspase-14 by various sphingoid bases and ceramide. Sphingosine, sphinganine, phytosphingosine, and C2-ceramide treatment at the doses not damaging cells significantly increased caspase-14 mRNA and protein expression in dose-dependent manner on human keratinocyte HaCaT cells. These results indicated that sphingoid bases and ceramide upregulated caspase-14 mRNA to increase intracellular caspase-14 protein level. We next examined the caspase-14 upregulation mechanism by sphingoid bases. We used the most effective sphingoid base, phytosphingosine, and revealed that specific inhibitors of the mitogen activated protein kinase, p38 and c-jun N-terminal protein kinase (JNK), blocked caspase-14 expression. This indicates that phytosphingosine upregulation of caspase-14 is involved of p38 and JNK activation. Moreover, phytosphingosine induced caspase-14 upregulation in vivo, suggesting that sphingoid bases were involved in keratinocyte differentiation by affecting caspase-14. PMID- 29709912 TI - Influence of Polysorbate 60 on Formulation Properties and Bioavailability of Morin-Loaded Nanoemulsions with and without Low-Saponification-Degree Polyvinyl Alcohol. AB - The aim of the present study was to investigate the influence of polysorbate 60 (Tween 60) on the development of morin-loaded nanoemulsions to improve the oral bioavailability of morin. Nanoemulsions were prepared using Tween 60 and polyvinyl alcohol (PVA) as emulsifiers, and medium chain triglycerides (MCT) as the lipid base. Low-saponification-degree PVA (LL-810) was also added to stabilize dispersed droplets. MCT-LL810 nanoemulsion containing LL-810 was prepared with a reduced amount of Tween 60. However, the area under the blood concentration-time curve (AUC) of MCT-LL810 (0.18) nanoemulsion containing a small amount of Tween 60 did not increase because the absorption of morin was limited by P-glycoprotein (P-gp)-mediated efflux. MCT-LL810 (0.24) nanoemulsion containing a large amount of Tween 60 showed the highest AUC, dispersed droplets containing Tween 60 may have been transported into epithelial cells in the small intestine, and P-gp transport activity appeared to be suppressed by permeated Tween 60. Based on the plasma concentration profile, dispersed droplets in MCT LL810 (0.24) nanoemulsion permeated more rapidly through the mucus layer and the intestinal membrane than MCT (0.24) nanoemulsion without LL-810. In conclusion, a novel feature of Tween 60 incorporated into the dispersed droplets of a nanoemulsion interacting with P-gp was demonstrated herein. Dispersed droplets in MCT-LL810 (0.24) nanoemulsion containing LL-810 permeated rapidly through the mucus layer and intestinal membrane, and Tween 60 incorporated in dispersed droplets interacted with P-gp-mediated efflux, increasing the bioavailability of morin. PMID- 29709913 TI - Protective Effect of Ipragliflozin on Pancreatic Islet Cells in Obese Type 2 Diabetic db/db Mice. AB - Ipragliflozin is a selective sodium glucose cotransporter 2 (SGLT2) inhibitor that increases urinary glucose excretion and subsequently improves hyperglycemia in patients with type 2 diabetes mellitus (T2DM). To assess the beneficial effect of ipragliflozin on the mass and function of pancreatic beta-cells under diabetic conditions, obese T2DM db/db mice were treated with ipragliflozin for 5 weeks. Glucose and lipid metabolism parameters, pathological changes in pancreatic islet cells and insulin content were evaluated. Pathological examination of pancreatic islet cells comprised measuring the ratios of insulin- and glucagon-positive cells and levels of oxidative stress markers. Hemoglobin A1c, plasma glucose, non esterified fatty acid and triglyceride levels in ipragliflozin-treated groups were reduced compared to the diabetic control (DM-control) group. Histopathological examination of pancreatic islet cells revealed strong insulin staining and reduced glucagon staining in the ipragliflozin 10 mg/kg-treated group compared with the DM-control group. The ratio of alpha- to beta-cell mass was lower in the ipragliflozin 10 mg/kg-treated group than the DM-control group and was similar to that of the non-diabetic control group. The density of immunostaining for 4-hydroxy-2-nonenal, an oxidative stress marker, in pancreatic islets was significantly lower in the ipragliflozin 10 mg/kg-treated group than the DM-control group. Pancreatic insulin content tended to be higher in the ipragliflozin-treated groups than the DM-control group. Our findings demonstrate the benefit of ipragliflozin treatment in improving glucolipotoxicity and reducing oxidative stress in pancreatic islet cells. Treatment with ipragliflozin may protect against the progressive loss of islet beta-cells in patients with T2DM. PMID- 29709914 TI - Mansonone E from Mansonia gagei Inhibited alpha-MSH-Induced Melanogenesis in B16 Cells by Inhibiting CREB Expression and Phosphorylation in the PI3K/Akt Pathway. AB - Many natural products that inhibit melanogenesis, freckles, and hyperpigmentation have been selectively used in cosmetics because melanogenesis is linked to the multiple biogenesis cascades of melanin synthesis. However, some of these compounds have side effects that may result in their restriction in the future. We report here the isolation and structural elucidation of compounds extracted from Mansonia gagei and evaluate their activity on melanogenesis inhibition. We isolated five known compounds from M. gagei and identified them as mansonone E (1), mansorin I (2), populene F (3), mansonone G (4), and mansorin B (5). After evaluating the five compounds for cytotoxicity against B16 cells and inhibitory activity on alpha-melanocyte-stimulating hormone (alpha-MSH) induced melanogenesis, we determined that the cytotoxicity and melanogenesis-inhibitory effect of 1 were relatively low and high, respectively. Next, the effect of 1 on the expression of melanogenesis-related proteins was assessed; it was confirmed that 1 dose-dependently inhibited the expression levels of tyrosinase, tyrosinase related protein 1 (TRP-1), TRP-2, cAMP response element binding protein (CREB), and microphthalmia-associated transcription factor (MITF) which were increased after stimulation by alpha-MSH. Furthermore, the effects of 1 on the phosphorylation levels of intracellular signaling pathway-related proteins were evaluated, and it was found that 1 dose-dependently rescued the phosphorylation of Akt and p38 mitogen-activated protein kinases (MAPK), which were up- or down regulated after stimulation by alpha-MSH. In contrast, treatment with the phosphoinositide 3-kinase (PI3K)/Akt inhibitor wortmannin enhanced melanogenesis inhibition by mansonone E. Cumulatively, the data suggest that 1 suppresses alpha MSH-induced melanogenesis in B16 cells by inhibiting both phosphorylation in the PI3K/Akt pathway and the expression of melanogenesis-related proteins. PMID- 29709915 TI - Hydrogen Peroxide-Reducing Factor Released by PC12D Cells Increases Cell Tolerance against Oxidative Stress. AB - PC12D cells, a subline of rat adrenal pheochromocytoma PC12 cells, extend neurites rapidly in response to differentiation stimuli and are used to investigate the molecular mechanisms of neurite extension. In the present study, we found significant tolerance of PC12D cells against Parkinson's disease-related stimuli such as dopamine and 6-hydroxydopamine; this tolerance was significantly decreased by a change in the medium. Conditioned medium from PC12D cells induced tolerance against oxidative stress, which suggests that cytoprotective factor may be released by PC12D cells into the culture medium. Conditioned medium-induced tolerance was not found for PC12 cells or human neuroblastoma SH-SY5Y cells. A cytoprotective factor generated by PC12D cells exhibited hydrogen peroxide reducing activity. Chemical characterization showed that this cytoprotective factor is water soluble and has a molecular weight about 1000 Da, and that its activity is inhibited by sodium cyanide. Release of this cytoprotective factor was increased by differentiation stimuli and oxidative stress. Taken together, these results suggest that release of a hydrogen peroxide-reducing factor by PC12D cells increases cell tolerance against oxidative stress. This study provides new insights into the antioxidative properties of factors in extracellular fluid. PMID- 29709916 TI - Calcineurin B1 Deficiency in Glial Cells Induces Mucosal Degeneration and Inflammation in Mouse Small Intestine. AB - Although calcineurin is abundantly expressed in the nervous system and involved in neurite extension and synaptic plasticity in neurons, little is known about its roles in glial cells. To investigate the roles of calcineurin in glial cells, we generated glial calcineurin B1-conditional knockout (CKO) mice and analyzed the abnormalities in the small intestine. The CKO mice were generated by crossing floxed calcineurin B1 mice with glial fibrillary acidic protein (GFAP)-Cre mice. The CKO mice exhibited growth retardation approximately from the third postnatal week and died mostly within the fourth postnatal week. The small intestine of the CKO mice was thin and hemorrhagic. The mucosal layer was degenerated and GFAP expression was reduced in the CKO small intestine. These pathological changes were associated with inflammation and increased intestinal permeability. In contrast, no apparent abnormalities were observed in the large intestine of the CKO mice. Nuclear factor of activated T cells failed to translocate into the nucleus after stimulation in enteric glial cells of the CKO small intestine. In conclusion, the calcineurin B1 deficiency in glial cells impairs the small intestine and leads to malnutrition and eventual death in mice, suggesting that calcineurin plays a novel and important role in enteric glial cells. PMID- 29709917 TI - Knockout of Ceramide Kinase Aggravates Pathological and Lethal Responses in Mice with Experimental Colitis. AB - Sphingolipids and their metabolic enzymes are implicated in ulcerative colitis. Ceramide kinase (CerK) catalyzes the phosphorylation of ceramide to ceramide-1 phosphate (C1P). Previous studies showed the activation of CerK by the pro inflammatory cytokine interleukin-1beta, the C1P-induced up-regulation of prostanoids exerting protective effects against colitis, and the C1P-induced down regulation of the pro-inflammatory cytokine tumor necrosis factor-alpha. In order to elucidate CerK/C1P functions in colitis, we examined the severity of dextran sodium sulfate (DSS)-induced colitis in wild-type (WT) and CerK deletion (CerK(-/ )) mice. Lethal responses were observed in C57BL/6 mice treated with DSS in dose- and time-dependent manners. The depletion of CerK enhanced DSS-induced lethal responses without affecting the onset of these responses. In colons from mice treated with 2.5% DSS for 10 d, epithelial damage was significantly enhanced by the depletion of CerK by day 5, whereas decreases in occluding and E-cadherin levels were similar in both mice. On day 5, the DSS treatment increased spleen weights and colonic levels of cyclooxygenase-2, but not cytosolic phospholipase A2alpha, and induced a contractile dysfunction in the colons of both mice. The DSS-induced increase in the damage activity index score between days 5 and 10 was slightly enhanced and the decrease in this score from day 10 was slower in CerK( /-) mice than in WT mice. On day 7 after the DSS treatment, spleen weights slightly decreased and increased in WT and CerK(-/-) mice, respectively. These results indicate that the depletion of CerK enhances the pathology of colitis and lethal responses in DSS-treated mice. PMID- 29709918 TI - Biochemical Characterization of Ferulic Acid and Caffeic Acid Which Effectively Inhibit Melanin Synthesis via Different Mechanisms in B16 Melanoma Cells. AB - In this study, we examined the inhibitory effects of ferulic acid and caffeic acid on melanin production using a murine B16 melanoma cell line. The mechanisms by which the two acids inhibit melanin production were investigated by evaluating their effects on the activity of tyrosinase, which is involved is the first step of melanin biosynthesis. Ferulic acid showed no toxicity against the melanoma cells at any dose, whereas caffeic acid exerted cellular toxicity at concentrations higher than 0.35 mM. Both ferulic and caffeic acids effectively inhibited melanin production in the B16 melanoma cells. Ferulic acid reduced tyrosinase activity by directly binding to the enzyme, whereas no binding was observed between caffeic acid and tyrosinase. Both ferulic acid and caffeic acid inhibited casein kinase 2 (CK2)-induced phosphorylation of tyrosinase in a dose dependent manner in vitro. Ferulic acid was found to be a more effective inhibitor of melanin production than caffeic acid; this difference in the inhibitory efficacy between the two substances could be attributable to the difference in their tyrosine-binding activity. Our analysis revealed that both substances also inhibited the CK2-mediated phosphorylation of tyrosinase. PMID- 29709919 TI - Combination Strategy with Complexation Hydrogels and Cell-Penetrating Peptides for Oral Delivery of Insulin. AB - In previous studies we showed that the complexation hydrogels based in poly(methacrylic acid-g-ethylene glycol) [P(MAA-g-EG)] rapidly release insulin in the intestine owing to their pH-dependent complexation properties; they also exhibit a high insulin-loading efficiency, enzyme-inhibiting properties, and mucoadhesive characteristics. Cell-penetrating peptides (CPPs), such as oligoarginines [hexa-arginine (R6), comprising six arginine residues], have been employed as useful tools for the oral delivery of therapeutic macromolecules. The aim of our study was to investigate the combination strategy of using P(MAA-g-EG) hydrogels with R6-based CPPs to improve the intestinal absorption of insulin. A high efficiency of loading into crosslinked P(MAA-g-EG) hydrogels was observed for insulin (96.1+/-1.4%) and R6 (46.6+/-3.8%). In addition, immediate release of the loaded insulin and R6 from these hydrogels was observed at pH 7.4 (80% was released in approximately 30 min). Consequently, a strong hypoglycemic response was observed (approximately 18% reduction in blood glucose levels) accompanied by an improvement in insulin absorption after the co-administration of insulin loaded particles (ILP) and R6-loaded particles (ALP) into closed rat ileal segments compared with that after ILP administration alone. These results indicate that the combination of P(MAA-g-EG) hydrogels with CPPs may be a promising strategy for the oral delivery of various insulin preparations as an alternative to conventional parenteral routes. PMID- 29709920 TI - Impairment of Protease-Activated Receptor 2-Induced Relaxation of Aortas of Aged Spontaneously Hypertensive Rat. AB - Hypertension is one of the most prevalent diseases worldwide and can cause harmful complications within the vascular system. Further research on vascular responsiveness to different ligands and diverse receptors in various arteries is required to understand the mechanisms underlying the development of these vascular complications. Here, we investigated the vasorelaxant effect of the protease-activated receptor 2 (PAR2) agonist 2-furoyl-LIGRLO-amide (2-Fly) and two commonest agents, namely endothelium-dependent dilator acetylcholine (ACh) and endothelium-independent dilator sodium nitroprusside (SNP), on the thoracic aorta isolated from aged spontaneously hypertensive rats (SHR) (age, 52+/-1 weeks). The effects of these agents were compared between aortas isolated from SHR and age-matched normotensive Wistar Kyoto (WKY) rats. Compared with the WKY group, in the SHR group, 2-Fly-induced relaxation was impaired, ACh-induced relaxation was slightly decreased at low concentrations, and SNP-induced relaxation was similar. In addition, 2-Fly-induced aortic relaxation was largely decreased by a PAR2 antagonist (FSLLRY), endothelial denudation, and a nitric oxide (NO) synthase inhibitor NG-nitro-L-arginine (L-NNA) but not by an Akt inhibitor. These results suggested that PAR2-induced relaxations of aortas of aged SHR was impaired, and this impaired aortic relaxation may be attributed to decreased NO bioavailability rather than altered NO sensitivity unrelated to the Akt activity. PMID- 29709921 TI - 3-O-Glyceryl-2-O-hexyl Ascorbate Suppresses Melanogenesis through Activation of the Autophagy System. AB - The formation of skin pigmentation requires multiple steps, namely the activation of melanocytes, the synthesis of melanin, the transport of melanosomes to the tips of melanocyte dendrites and the transfer of melanosomes from melanocytes to surrounding keratinocytes. Recently, we reported that melanosomes accumulate in melanocytes when melanosome transport is disrupted and that they are then degraded by the autophagy system. In this study, we examined whether 3-O-glyceryl 2-O-hexyl ascorbate (VC-HG) suppresses melanogenesis through the activation of autophagy since VC-HG interferes with melanosome transport through the down regulated expression of MyosinVa and Kinesin. The results demonstrate that VC-HG treated B16 cells show an activation of autophagy through an increased expression level of Microtubule-associated protein 1 light chain 3 (LC3)-II and a decreased expression level of p62. Furthermore, the decrease of melanin content elicited by VC-HG was partially abolished by hydroxychloroquine or pepstatin A which are inhibitors of autophagy. Taken together, we conclude that VC-HG suppresses melanogenesis by activating the autophagy system. PMID- 29709922 TI - Comparison of Human Selenoprotein P Determinants in Serum between Our Original Methods and Commercially Available Kits. AB - Selenoprotein P (SeP) is a selenium (Se)-rich extracellular protein. SeP is identified as a hepatokine, causing insulin resistance in type 2 diabetes. Thus, the measurement of SeP in serum has received much attention, and several enzyme linked immunosorbent assay (ELISA) kits for SeP determination are now commercially available. In the present study, we determined the serum SeP levels by our original ELISA and sol particle homogeneous immunoassay (SPIA) methods and also by commercially available kits, and these determinants were compared. We found a kit-dependent correlation of the determinants with our methods. These results suggest that the selection of kit is critical for comparison with our previous reports and for discussing the relationship between the serum SeP levels and disease condition. PMID- 29709923 TI - Errata for Biological and Pharmaceutical Bulletin. PMID- 29709924 TI - Squamous Cell Carcinoma Appearing as a Multi-cystic Lesion. PMID- 29709925 TI - Relationship between Cytotoxicity in the Hippocampus and an Abnormal High Intensity Area on the Diffusion-weighted Images of Three Patients with Transient Global Amnesia. AB - Objective An abnormal high intensity area (HIA) on diffusion-weighted imaging (DWI) indicates the presence of cytotoxic edema and has been reported to be observed in the hippocampus of patients with transient global amnesia (TGA). The appearance of an HIA on DWI is usually delayed after the onset of patients with amnesia in TGA; thus, the significance of the HIA was evaluated in patients with TGA. Methods Three adult TGA patients who had a unilateral HIA on DWI (right, n=2; left, n=1) were enrolled. These patients were hospitalized due to acute onset amnesia. Amnesia subsided within 24 hours of hospitalization in all three patients. Results The HIA was confined to the upper lateral zone of the body in the unilateral hippocampus where the CA1 region exists. The lesions were confirmed after the improvement of amnesia in the three patients. The location of the lesions corresponded to the watershed area where the upper and lower hippocampal arteries were anastomosed. Conclusion Cytotoxicity caused by glutamate-mediated calcium influx in the neurons of the CA1 region was recently reported in the pathogenesis of TGA. Based on the pathogenesis, the cytotoxicity was considered to have been caused by calcium overload throughout the entire CA1 region, and amnesia occurred due to this cytotoxicity. The cytotoxicity was more marked in the lesions because of the lower blood flow in the watershed area and was prolonged after the function of the CA1 region (excluding the watershed area) improved, which led to cytotoxic edema in the lesions. PMID- 29709926 TI - A Unique Case of Renovascular Hypertension due to Fibromuscular Dysplasia in an Extra-renal Artery. AB - A 33-year-old man was admitted to our hospital to undergo an evaluation to determine the cause of secondary hypertension. Computerized tomography angiography (CTA) showed bilateral multiple renal arteries with significant stenosis of the right extra-renal artery due to fibromuscular dysplasia and segmental impairment of renal perfusion. Although the plasma aldosterone concentration and plasma renin activity were within the normal ranges, percutaneous balloon dilatation of the stenotic lesion resolved his hypertension, leading to a diagnosis of renovascular hypertension caused by segmental renal ischemia due to extra-renal artery stenosis. CTA should be considered during the examination of patients with early-age hypertension, even if the plasma renin activity is not sufficiently elevated. PMID- 29709927 TI - Effect of Eplerenone on the Glomerular Filtration Rate (GFR) in Primary Aldosteronism: Sequential Changes in the GFR During Preoperative Eplerenone Treatment to Subsequent Adrenalectomy. AB - Objective Eplerenone (EPL) is a mineralo-corticoid receptor antagonist that is highly selective and has few side effects. This study was conducted to examine whether or not EPL treatment was able to reverse glomerular hyperfiltration, as an indicator of aldosterone renal action, in primary aldosteronism (PA) patients. Methods Changes in the estimated glomerular filtration rate (DeltaGFR) were examined in 102 PA patients with EPL treatment. Furthermore, the sequential DeltaGFR in 40 patients initially treated with EPL followed by adrenalectomy was examined in order to evaluate the extent of the remaining glomerular hyperfiltration in the patients treated with EPL. Results EPL decreased the GFR at 1 month after treatment. The GFR at baseline was the sole significant predictor for the DeltaGFR. Patients initially treated by EPL followed by adrenalectomy showed three different DeltaGFR patterns during the treatment, despite having comparable doses of EPL and comparable control of blood pressure and serum potassium levels. The urinary aldosterone excretion was significantly different among these three groups, and the group with no decrease in the GFR after EPL treatment showed greater urinary aldosterone excretion. Glomerular hyperfiltration was completely restored only in 17.5% of our unilateral PA patients after EPL treatment. Conclusion The present study revealed that blockade of aldosterone action by EPL could, at least partially, reverse glomerular hyperfiltration in PA. Whether or not these differential effects on the GFR affect the long-term outcome needs to be investigated, especially in patients with unilateral PA who do not want adrenalectomy and choose the EPL treatment option. PMID- 29709928 TI - Longus Colli Tendinitis in a Patient Presenting with Neck Pain and Acute Systemic Inflammation. AB - The diagnosis of longus colli tendinitis (LCT) is sometimes challenging, especially when laboratory data show marked inflammation and neuroimaging studies do not indicate calcification within the tendon of the longus colli muscles. We herein report a case of LCT that presented with elevated inflammation parameters without calcification on imaging. Findings characteristic of LCT, such as prevertebral hyperintensity areas on T2-weighted images and no signs of purulent diseases, informed our diagnosis of LCT. Enhanced computed tomography and magnetic resonance imaging are useful procedures when diagnosing LCT after ruling out other critical purulent diseases. PMID- 29709929 TI - Photophobia in a Patient with Hashimoto's Thyroiditis. PMID- 29709930 TI - Dilated Cardiomyopathy with Eosinophilic Granulomatosis with Polyangiitis in Which Active Myocardial Inflammation Was Only Detected by Endomyocardial Biopsy. AB - Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare type of systemic vasculitis. Cardiac involvement is the main cause of death in patients with this disease. We herein report a case of congestive heart failure in a patient with EGPA. Neither 67Ga scintigraphy nor cardiac magnetic resonance imaging detected inflammation of the myocardium; however, myocardial biopsy revealed numerous infiltrating inflammatory cells, thereby fulfilling the criteria of inflammatory dilated cardiomyopathy. We improved the left ventricular systolic function by increasing the patient's prednisolone dosage. This case shows that in some cases the detection myocardial inflammation - which allows for appropriate therapy - may only be achieved by myocardial biopsy. PMID- 29709931 TI - The Antemortem Diagnosis of Primary Malignant Pericardial Mesothelioma: A Multidisciplinary Evaluation. AB - A 64-year-old woman complaining of progressive dyspnea was admitted with recurrence of massive pericardial effusion. The patient had been diagnosed with radiation pericarditis based on a previous case of pericardiocentesis. To make a diagnosis and improve her symptoms, imaging examinations and pericardial fenestration were performed. Because of difficulty making a diagnosis, after some months, pericardiotomy and incision of the epicardium were performed. The patient was ultimately diagnosed with primary malignant pericardial mesothelioma of the epithelioid type. Primary malignant pericardial mesothelioma is a rare tumor that is difficult to diagnose. An antemortem diagnosis can be made by a multidisciplinary evaluation. PMID- 29709932 TI - An Unusual Case of Inferior Vena Cava Thrombosis in a Healthy Male Bodybuilder. AB - Inferior vena cava (IVC) thrombosis is very rare, particularly in the absence of an apparent congenital caval abnormality or hypercoagulable state. We herein report an unusual case of a healthy and active 62-year-old male bodybuilder with a mass-like IVC thrombus. We placed an IVC filter and began treatment with rivaroxaban. The patient recovered successfully, and the IVC thrombus completely disappeared three months later. This case suggested that extrinsic compression of IVC by a tightened weightlifting belt around the abdomen is a triggering factor of IVC thrombosis, and rivaroxaban, a new oral anticoagulant, may be a useful option for treatment. PMID- 29709933 TI - Repetitive Discharge in a Case of Isaacs Syndrome with Burning Sensation. PMID- 29709934 TI - The Molar Ratio of N-terminal pro-B-type Natriuretic Peptide/B-type Natriuretic Peptide for Heart Failure-related Events in Stable Outpatients with Cardiovascular Risk Factors. AB - Objective B-type natriuretic peptide (BNP) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) should be secreted from cardiomyocytes in response to increased myocardial wall stress in a molar ratio of 1.00; however, the calculated molar blood levels of NT-proBNP are often greater than those of BNP in routine clinical practice. The purpose of this study was to investigate the hypothesis that the molar ratio of NT-proBNP/BNP provides useful clinical information in stable outpatients with cardiovascular risk factors. Methods We measured both the BNP and NT-proBNP levels simultaneously in 551 consecutive, stable outpatients with at least one cardiovascular risk factor and then calculated the molar ratio of NT-proBNP/BNP. All patients were prospectively followed-up for the occurrence of heart failure (HF)-related events. Results Of those patients, 38 patients had an HF-related event. A multivariate Cox hazards analysis showed that the log (molar ratio of NT-proBNP/BNP) was an independent predictor of future HF-related events (p=0.039). A Kaplan-Meier analysis showed a significantly higher probability of HF-related events in patients with a higher molar ratio of NT-proBNP/BNP (>=1.70) (p<0.001). The area under the curve (AUC) of the receiver operating characteristic curve (ROC) for the molar ratio of NT proBNP/BNP to predict HF-related events was 0.75 (p<0.001). The AUC of the ROC curve analysis with the molar ratio of NT-proBNP/BNP for the prediction of HF related events was not significantly greater than that of BNP or NT-proBNP. Conclusion The molar ratio of NT-proBNP/BNP may be a significant prognostic factor for HF-related events. PMID- 29709935 TI - Use of Nasopancreatic Drainage for Severe Post-endoscopic Retrograde Cholangiopancreatography Pancreatitis: A Case Series. AB - Five patients complaining of severe pain due to severe post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) underwent nasopancreatic drainage (NPD) placement. Pain relief was achieved on the second, fourth, and fifth day in three, one, and one patients, respectively. Four patients underwent pancreatic juice culture; all were positive. Our results suggest that NPD can relieve severe PEP with severe pain. Bacteria-induced protease-activated receptor-2 activation may be associated with PEP. PMID- 29709937 TI - The Surge in the Number of Circulating Tumor Cells Following Treatment with Sunitinib for Metastatic Renal Cell Carcinoma. AB - Circulating tumor cells (CTCs) are a promising biomarker for several cancers. We streamlined the experimental procedure of CTC immunofluorescent staining. We encountered a 72-year-old woman with metastatic right renal cell carcinoma (RCC) (clinical stage: T4N0M1), whose CTC number rapidly increased after the administration of sunitinib and then gradually decreased. The change in the CTC number appeared to coincide with laboratory data and hypertension, suggesting that a CTC analysis may be useful for promptly monitoring the treatment response. Our data provided the first evidence of an association between the CTC numbers and the treatment response in a metastatic RCC patient. PMID- 29709936 TI - Clinical Investigation of Adrenal Incidentalomas in Japanese Patients of the Fukuoka Region with Updated Diagnostic Criteria for Sub-clinical Cushing's Syndrome. AB - Objectives We retrospectively investigated the clinical and endocrinological characteristics of adrenal incidentalomas. Methods We studied 61 patients who had been diagnosed with adrenal incidentalomas and had undergone detailed clinical and endocrinological evaluations while hospitalized. We used common criteria to diagnose the functional tumors, but for sub-clinical Cushing's syndrome, we used an updated set of diagnosis criteria: serum cortisol >=1.8 MUg/dL after a positive response to a 1-mg dexamethasone suppression test if the patient has a low morning adrenocorticotropic hormone (ACTH) level (<10 pg/mL) and a loss of the diurnal serum cortisol rhythm. Results Of the 61 patients, none (0%) had malignant tumors, 8 (13.1%) had pheochromocytoma, and 15 (24.6%) had primary aldosteronism; when diagnosed by our revised criteria, 13 (21.3%) had cortisol secreting adenomas (Cushing's syndrome and sub-clinical Cushing's syndrome), and 25 (41.0%) had non-functional tumors. Compared with the non-functional tumor group, the primary aldosteronism group and the cortisol-secreting adenoma group were significantly younger and had significantly higher rates of hypokalemia, whereas the pheochromocytoma group had significantly larger tumors and a significantly lower body mass index. Conclusion Our study found a larger percentage of functional tumors among adrenal incidentalomas than past reports, partly because we used a lower serum cortisol level after a dexamethasone suppression test to diagnose sub-clinical Cushing's syndrome and because all of the patients were hospitalized and could therefore receive more detailed examinations. Young patients with hypokalemia or lean patients with large adrenal tumors warrant particularly careful investigation. PMID- 29709938 TI - Pulmonary Alveolar Proteinosis with Ulcerative Colitis. AB - A 65-year-old Japanese man was referred to our hospital for the further assessment of cough and dyspnea. He had a history of ulcerative colitis for which he was receiving treatment. Chest computed tomography showed a crazy-paving pattern. His bronchoalveolar lavage fluid had a milky appearance, and a transbronchial lung biopsy specimen revealed acellular periodic acid-Schiff stain positive bodies. The serum anti-granulocyte macrophage-colony stimulating factor (GM-CSF) antibody titer was elevated. The diagnosis was autoimmune pulmonary alveolar proteinosis (PAP). There are few reports of autoimmune PAP in patients with ulcerative colitis. Some reports suggest that PAP and inflammatory bowel disease might have a common pathogenesis involving the anti-GM-CSF antibody. PMID- 29709939 TI - Fatal Familial Insomnia Initially Developing Parkinsonism Mimicking Dementia with Lewy Bodies. AB - We report a rare case of fatal familial insomnia in a 58-year-old man who initially developed parkinsonism, secondary dementia, and visual hallucinations that were suspected to be due to dementia with Lewy bodies. We evaluated the function of the striatum via dopamine transporter single-photon emission computed tomography (DAT SPECT) using 123I-ioflupane and found marked presynaptic dopamine dysfunction in the bilateral striatum. This is the first reported case in which the initial symptom of fatal familial insomnia was parkinsonism and in which the dopamine transporter function was evaluated by DAT SPECT. PMID- 29709940 TI - Pyrexia-associated Relapse in Chronic Inflammatory Demyelinating Polyradiculoneuropathy. AB - Chronic inflammatory demyelinating polyradiculoneuropathy is a relapsing remitting or chronic progressive demyelinating polyradiculoneuropathy. We report the case of a patient with chronic inflammatory demyelinating polyradiculoneuropathy who experienced relapses on four occasions after experiencing pyrexia and flu-like symptoms. Our patient showed characteristic features, such as relapse after pyrexia and flu-like symptoms, remission after pyretolysis without treatment, and the absence of remarkable improvement in a nerve conduction study in the remission phase. The serum level of tumor necrosis factor-alpha was elevated in the relapse phase and reduced in the remission phase; thus, the induction of cytokine release by viral infection might have caused the relapses. PMID- 29709941 TI - Miller Fisher Syndrome Mimicking Tolosa-Hunt Syndrome. AB - We herein report a patient with Miller Fisher syndrome mimicking Tolosa-Hunt syndrome. A 47-year-old man presented with right orbital pain and diplopia. On a neurological examination, he had right oculomotor nerve palsy and diminished deep tendon reflexes. Brain magnetic resonance imaging failed to show any parenchymal lesions; however, the bilateral oculomotor nerves were gadolinium-enhanced. The presence of a triad of orbital pain, ipsilateral oculomotor nerve palsy, and a rapid response to steroid therapy met the diagnostic criteria for Tolosa-Hunt syndrome. After discharge, antibodies against GQ1b and GT1a were reported to be positive only with phosphatidic acid. The present case was ultimately diagnosed as an incomplete phenotype of Miller Fisher syndrome. PMID- 29709942 TI - Development of Autoimmune Hepatitis during Direct-acting Antiviral Therapy for Chronic Hepatitis C Virus Infection. AB - An 81-year-old woman developed liver dysfunction after two months' treatment with direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection. She was positive for serum anti-nuclear antibody, with an elevated immunoglobulin G level. A liver biopsy revealed high-grade interface hepatitis and infiltrate of lymphocytes and plasma cells. DAA-associated drug-induced autoimmune hepatitis (DI-AIH) was considered. Her liver dysfunction improved after discontinuing DAA therapy and starting prednisolone treatment. The differential diagnosis for AIH should include liver injury during DAA therapy for chronic HCV infection. PMID- 29709943 TI - Deep Sternal Wound Tuberculosis with Hypo-gamma-globulinemia. AB - A 44-year-old man was referred to our hospital for the treatment of a pulmonary and deep sternal wound tuberculosis infection, which is an extremely rare type of extrapulmonary tuberculosis. Laboratory testing revealed a serum immunoglobulin (Ig) G level of 286 mg/dL, IgA of 22 mg/dL and IgM of 13 mg/dL. We therefore diagnosed him with hypo-gamma-globulinemia. He was treated with anti-tuberculosis medications and intravenous immunoglobulin. At present, the tuberculosis has not relapsed in the past six years. It may be useful to assess the humoral immunity status in tuberculosis patients with a normal T cell function, and immunoglobulin therapy may be beneficial for protecting such patients from reactivation of tuberculosis. PMID- 29709944 TI - Interventional Treatment for Giant Hepatic Hemangioma Accompanied by Arterio portal Shunt with Ascites. AB - A 73-year-old woman with massive ascites associated with a giant hepatic mass accompanied by arterio-portal (AP) shunt was admitted to our hospital. Based on contrast-enhanced computed tomography (CT) and angiography findings, hepatic hemangioma with AP shunt and ascites due to portal hypertension was diagnosed. Transcatheter arterial embolization (TAE) by N-butyl-2-cyanoacrylate (NBCA) was performed without complications. The patient's ascites disappeared, and her liver function test results improved after the treatment. The patient has maintained a steady state for two years. This case indicates that TAE with NBCA is a safe and effective treatment for hepatic hemangioma accompanied by AP shunt. PMID- 29709945 TI - Fulminant Type 1 Diabetes Mellitus Complicated with a Life-threatening Electrolyte Abnormality and Abnormal Electrocardiogram Findings. AB - Fulminant type 1 diabetes mellitus (T1DM) is idiopathic T1DM with the rapid destruction of pancreatic beta-cells. We herein report a 48-year-old man who developed fulminant T1DM complicated with a life-threatening electrolyte abnormality and abnormal electrocardiogram findings. He had no remarkable medical history, but one day, he developed general fatigue. His blood glucose level and HbA1c were 806 mg/dL and 6.3%, and his insulin secretion was markedly suppressed. He had ketoacidosis, hyponatremia and hyperkalemia. Furthermore, a life threatening abnormality was noted on electrocardiogram. After fluid infusion and insulin therapy, the abnormality disappeared. In conclusion, we should bear in mind the possibility of fulminant T1DM in patients complaining of general malaise. PMID- 29709946 TI - A Refractory Case of Secondary Membranous Nephropathy Concurrent with IgG4 related Tubulointerstitial Nephritis. AB - A 58-year-old man with type 1 autoimmune pancreatitis was referred to nephrologists for severe proteinuria. Laboratory data revealed a high serum IgG4 level, hypoalbuminemia, and massive proteinuria, which were compatible with nephrotic syndrome. The renal pathological findings confirmed the diagnosis of secondary membranous nephropathy concurrent with IgG4-related tubulointerstitial nephritis. Despite the improvement of interstitial markers, the proteinuria was refractory to prednisolone, requiring cyclosporine to achieve complete remission. Membranous nephropathy is a rare manifestation of IgG4-related kidney disease. This case shows that the therapeutic response to prednisolone significantly differs between glomerular lesions and interstitial lesions of IgG4-related kidney disease. PMID- 29709948 TI - Sequential Symptomatic Arterial Dissections in Multiple Vascular Beds in a Patient with Fibromuscular Dysplasia. AB - A 60-year-old man was admitted to our hospital because of abdominal pain and disturbed consciousness. Head magnetic resonance imaging showed right vertebral artery dissection and abdominal enhanced computed tomography showed dissection of the superior mesenteric artery. The patient was diagnosed as having fibromuscular dysplasia (FMD) based on conventional angiography. Although multiple vascular bed involvement is observed in approximately 40% of FMD patients, reports of sequential symptomatic dissections in various vascular beds are rare. Patients with FMD and dissection require close observation, and hemodynamic stabilization may prevent not only the further development of dissection, but also subsequent dissection of other arteries. PMID- 29709947 TI - A Punctate Magnetic Resonance Imaging Pattern in a Patient with Systemic Lupus Erythematosus Is an Early Sign of Progressive Multifocal Leukoencephalopathy: A Clinicopathological Study. AB - A 37-year-old woman with systemic lupus erythematosus presented with gait disturbance and cognitive dysfunction. Brain magnetic resonance imaging (MRI) revealed small, punctate, T2-/fluid-attenuated inversion recovery-hyperintense and T1-hypointense lesions without gadolinium enhancement, which is atypical for progressive multifocal leukoencephalopathy (PML). On a pathological examination of biopsied brain tissues, JC virus-infected cells were hardly detected via immunohistochemistry but were certainly detected via in situ hybridization, conclusively verifying the PML diagnosis. After tapering off the immunosuppressant and mefloquine administration, the MRI findings revealed gradual improvement, and she has been stable for over 18 months. A punctate MRI pattern is not specific to natalizumab-associated PML but may be a ubiquitous early sign useful for the early diagnosis of PML. PMID- 29709949 TI - Myocardial Infarction Caused by Asymptomatic Spontaneous Coronary Dissection. PMID- 29709951 TI - Swyer-James-Macleod Syndrome: The Differential Diagnosis of Unilateral Hyperlucency. PMID- 29709950 TI - An Autopsy Case of Myeloperoxidase-anti-neutrophil Cytoplasmic Antibody (MPO ANCA)-associated Vasculitis Accompanied by Cryoglobulinemic Vasculitis Affecting the Kidneys, Skin, and Gastrointestinal Tract. AB - Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) and cryoglobulinemic vasculitis (CV) rarely coexist. An 83-year-old woman was admitted with rapidly progressive renal failure, gastrointestinal hemorrhage and purpura with myeloperoxidase (MPO)-ANCA positivity and cryoglobulinemia. Despite intensive immunosuppressive treatment, she died of aspergillus pneumonia. Autopsy revealed necrotizing crescentic glomerulitis in the majority of the glomeruli, accompanied by partially membranoproliferative-like glomerular changes. Immunofluorescence staining revealed the presence of neutrophil extracellular trap (NET) formation in the glomeruli and cutaneous arteries. These pathological findings suggested that MPO-AAV and/or CV caused NET formation, leading to lethal systemic vasculitis. PMID- 29709953 TI - Pulmonary Aspergilloma with Oxalosis. PMID- 29709952 TI - Pseudolipomatosis of the Colon and Cecum Followed by Pneumatosis Intestinalis. AB - A 74-year-old Japanese woman was diagnosed with pseudolipomatosis of the cecum and ascending colon. Colonoscopy was performed, which revealed the presence of slightly elevated white lesions, while a magnifying observation showed microbubbles within the mucosa. A month after colonoscopy, the patient was diagnosed with pneumatosis intestinalis. Although the exact pathogenesis is unclear, pneumatosis intestinalis may arise secondary to pseudolipomatosis. This case also indicates that a magnifying observation during colonoscopy may aid in the diagnosis of pseudolipomatosis of the large intestine, since it shows microbubbles within the mucosa, which may be a distinctive feature reflecting the pathology of this disease. PMID- 29709954 TI - Two Cases of Transiently Elevated Serum CEA Levels in Severe Hypothyroidism without Goiter. AB - Carcinoembryonic antigen (CEA), the level of which is known to increase in both patients with gastrointestinal cancers and those with non-neoplastic conditions, is one of the most widely-used tumor markers. Hypothyroidism is a common endocrinological disorder in which CEA levels can rise, and is sometimes overlooked as a diagnosis in the absence of typical symptoms or thyroid enlargement. We report the cases of two patients with non-goiterous severe hypothyroidism with markedly elevated CEA levels that effectively decreased with levothyroxine replacement therapy alone. Hypothyroidism should be considered as an important cause of unexplained high serum CEA levels in order to avoid unnecessary medical examination. PMID- 29709956 TI - Fibromuscular Dysplasia: Another Paradigm Shift in Renovascular Hypertension? PMID- 29709955 TI - Disease Exacerbation after the Cessation of Fingolimod Treatment in Japanese Patients with Multiple Sclerosis. AB - Objective In Japan, following the launch of dimethyl fumarate (DMF) after fingolimod as a disease-modifying drug in multiple sclerosis (MS), some patients switched from fingolimod to DMF. The aim of this study was to determine the follow-up status of MS patients who switched to DMF after fingolimod cessation. Methods Clinical and magnetic resonance imaging (MRI) data in 19 patients with MS who switched to DMF were collected for at least for 6 months after fingolimod cessation. Results Ten patients (52.6%) experienced clinical or MRI exacerbation after fingolimod cessation. The peripheral blood lymphocyte counts at the time of fingolimod cessation in those with disease exacerbation were significantly lower than in those without exacerbation. The patients with disease exacerbation were further classified into three groups based on MRI findings: those with some new T2-weighted lesions with or without gadolinium (Gd) enhancement (group I), those with more new and/or enlarged T2-weighted lesions with Gd enhancement compared to pre-fingolimod induction (group II), and those with multifocal tumefactive demyelinating lesions. In group II, the clinical disease activity, which was similar to that at fingolimod initiation in group I, was higher than the clinical disease activity observed before fingolimod initiation. Conversely, group III exhibited unexpected new MRI findings that were not evident before fingolimod initiation. Conclusion Cessation of fingolimod might precipitate rebound or reactivation of clinical disease in patients with MS, and careful follow-up is necessary for patients who discontinue fingolimod. PMID- 29709957 TI - Suffocation due to Acute Airway Edema in a Patient with Hereditary Angioedema Highlighted the Need for Urgent Improvements in Treatment Availability in Japan. AB - A 42-year-old Japanese man with hereditary angioedema suffered accidental trauma to his jaw in Shizuoka Prefecture, Japan, which gradually caused facial edema. Since plasma-derived human C1 inhibitor (pdh C1-INH) was unavailable, he had to be transferred to Juntendo University Hospital in Tokyo. Due to his severe edema, he suffered asphyxiation leading to cardiopulmonary arrest upon arrival. The patient was resuscitated and promptly treated with pdh C1-INH. In Japan, the self administration of pdh C1-INH is not allowed, and every prefecture does not always possess stocks of pdh C1-INH. This case emphasizes the need for urgent improvements in treatment availability in Japan. PMID- 29709958 TI - A Tuberculosis-associated Endobronchial Polyp That Was Negative for Acid-fast Bacillus. AB - The author reports the case of a patient with a tuberculosis-associated endobronchial inflammatory polyp. Acid-fast bacillus (AFB) staining and culturing of sputum and bronchial washing fluid specimens were negative on three occasions. Biopsy results twice showed chronic inflammation. The patient was finally diagnosed with Mycobacterium tuberculosis based on a polymerase chain reaction (PCR) of a biopsy tissue specimen, along with the finding of chronic granulomatous inflammation. The author herein reports a rare case of a tuberculosis-associated endobronchial inflammatory polyp that was AFB smear- and culture-negative and the patient's clinical course after treatment. PMID- 29709959 TI - Pulmonary Actinomyces graevenitzii Infection Diagnosed by Bronchoscopy using Endobronchial Ultrasonography with a Guide Sheath. AB - A 75-year-old man visited our hospital complaining of a low-grade fever, dry cough, and chest abnormal shadow. Chest computed tomography revealed a nodule with a cavity in the right upper lobe. Endobronchial ultrasonography (EBUS) of the lesion suggested that the lesion was benign. Actinomyces graevenitzii was cultured from the specimen obtained by bronchoscopy using endobronchial ultrasonography with a guide sheath technique and was identified by matrix assisted laser desorption/ionization time-of-flight mass spectrometry and 16S rRNA sequencing. The patient was treated with intravenous ampicillin; subsequently, his condition improved. We believe that careful observation of EBUS findings may be useful for the differential diagnosis. PMID- 29709960 TI - Multiple White and Flat Elevated Lesions Observed in the Stomach: A Prospective Study of Clinical Characteristics and Risk Factors. AB - Objective Multiple white and flat elevated lesions (MWFLs) observed in the stomach have only been presented in abstracts at academic conferences over the last decade; therefore, relatively little is known about these lesions. Our aim was to prospectively clarify the clinical characteristics of MWFLs, to identify their risk factors and to retrospectively evaluate the clinical progression of these lesions. Methods A prospective analysis of clinical characteristics and risk factors was conducted in participants who underwent esophagogastroduodenoscopic screening at our hospital. A retrospective analysis of the medical chart of patients identified as having MWFLs was conducted to describe the clinical progression of these lesions. Results The prevalence rate of MWFLs was 10.4% (80/767), with the following risk factors identified on a logistic regression analysis: use of proton pump inhibitors [odds ratio (OR), 3.51; 95% confidence interval (CI), 1.92-6.43], female sex (OR, 1.92; 95% CI, 1.19-3.12) and a 1-year increase in age (OR, 1.05; 95% CI, 1.02-1.08). Among the 70 cases with MWFLs observed over a mean duration of 2.3 years, no progression of MWFLs was detected in 67 cases (96%). Among the 3 remaining cases, progression was mild, with none of the lesions progressing to malignancy. Conclusion The use of proton pump inhibitors (PPIs), female sex, and age are risk factors for MWFLs. We believe that endoscopists should recognize these lesions. PMID- 29709961 TI - Aceruloplasminemia with Abnormal Compound Heterozygous Mutations Developed Neurological Dysfunction during Phlebotomy Therapy. AB - Aceruloplasminemia is an autosomal recessive inherited disorder caused by ceruloplasmin gene mutations. The loss of ferroxidase activity of ceruloplasmin due to gene mutations causes a disturbance in cellular iron transport. We herein describe a patient with aceruloplasminemia, who presented with diabetes mellitus that was treated by insulin injections, liver hemosiderosis treated by phlebotomy therapy, and neurological impairment. A genetic analysis of the ceruloplasmin gene revealed novel compound heterozygous mutations of c.1286_1290insTATAC in exon 7 and c.2185delC in exon 12. This abnormal compound heterozygote had typical clinical features similar to those observed in aceruloplasminemia patients with other gene mutations. PMID- 29709962 TI - Rat Bite Fever Caused by Streptobacillus moniliformis in a Cirrhotic Patient Initially Presenting with Various Systemic Features Resembling Henoch-Schonlein Purpura. AB - We herein report the case of a 61-year-old Japanese cirrhotic patient who developed rat bite fever (RBF) and whose first presentation was serious clinical features mimicking those of Henoch-Schonlein purpura (HSP). In addition to the critical clinical conditions, since the histopathology from purpuric skin eruptions was not inconsistent with that of HSP, therapy with prednisolone was promptly started in order to prevent his death. However, initial blood culture on admission yielded a small and slow-growing bacterial growth, which was gradually revealed by further subculture to be a peculiar bacterium, Streptobacillus moniliformis, leading to a definitive diagnosis of RBF. After the immediate cessation of prednisolone, the patient was treated with a more appropriate antibiotic and consequently made a full recovery. An immunocompromised condition with seriously decompensated liver cirrhosis together with moderately severe chronic kidney disease (CKD) in this patient probably exacerbated the severity of the disease. PMID- 29709964 TI - Bacterial-Culture-Negative Subclinical Intra-Amniotic Infection Can Be Detected by Bacterial 16S Ribosomal-DNA-Amplifying Polymerase Chain Reaction. AB - Comprehensive analysis of bacterial DNA has enhanced our understanding of the maternal microbiome and its disturbances in preterm birth although clinical utility of these techniques remains to be determined. We tested whether a broad range polymerase chain reaction (PCR) technique is useful for detection of culture-negative intra-amniotic infection (IAI). Pregnant women who underwent amniocentesis for the management of preterm birth with or without premature rupture of membranes. Bacterial 16S ribosomal DNA in the amniotic fluid was detected by PCR using primers for a sequence shared by Ureaplasma, Mycoplasma, and other bacteria. Sixty-four women were enrolled, 9 of whom were culture positive. Of the 55 culture-negative women, 13 were PCR-positive and exhibited significantly higher interleukin 6 and 8 levels and lower glucose levels in the amniotic fluid than the remaining 42 women did, who were PCR- and culture negative. C-reactive protein concentrations were elevated in cord and neonatal blood in the culture-negative, PCR-positive subgroup, whereas maternal C-reactive protein concentrations, white blood cell counts, and body temperatures were alike. The placental inflammation score (Blanc stage>=2) was significantly higher in the PCR-positive than in PCR-negative subgroup. This PCR-based method could be useful for identifying bacterial-culture-negative subclinical IAI and could help with predicting the severity of IAI. PMID- 29709963 TI - Evaluation of Diagnostic Assay for Rickettsioses Using Duplex Real-Time PCR in Multiple Laboratories in Japan. AB - Tsutsugamushi disease and Japanese spotted fever are representative rickettsioses in Japan, and are caused by infection with Orientia tsutsugamushi and Rickettsia japonica, respectively. For molecular-based diagnosis, conventional PCR assays, which independently amplify respective rickettsial DNA, are usually used; however, this approach is time-consuming. Here, we describe a new duplex real time PCR assay for the simultaneous detection of O. tsutsugamushi and spotted fever group rickettsiae, and its evaluation using several PCR conditions in 6 public health laboratories. The detection limit of the assay was estimated to be 102 copies and the sensitivity was almost identical to that of 3 conventional PCR methods. A total of 317 febrile patients were selected as clinically suspected or confirmed cases of rickettsioses. The detection efficiency of this assay for O. tsutsugamushi from blood or skin (eschar) specimens appeared to be almost the same as that of the conventional PCR method, even when performed in different laboratories, whereas the efficiency for spotted fever group rickettsiae tended to be higher than that of the 2 traditional double PCR assays. Our duplex real time PCR is thus a powerful tool for the rapid diagnosis of rickettsioses, especially at the acute stage of infection. PMID- 29709965 TI - A Multicenter Study of Clinical Presentations and Predictive Factors for Severe Manifestation of Dengue in Adults. AB - Severe dengue is more prevalent in adults than in children. Our objectives were to determine the clinical presentations of dengue in adults and to identify predictive factors for severe dengue. A retrospective cohort study was performed in adults with dengue, as confirmed by a positive NS1 antigen test result. Patients were classified as with non-severe or severe dengue. A total of 357 patients were enrolled; 45.4% were men, with a median (interquartile range [IQR]) age of 27.9 (21.8-43.5) years. Of all patients, 28.3% had warning signs and 10.6% had severe dengue. Patients with severe dengue were significantly older (35.1 [26.2-50.6] vs. 26.7 [21.7-43.3] years, P = 0.010), immunocompromised (7.9% vs. 0.9%, P = 0.018), and had cough (29% vs. 16%, P = 0.046), hepatomegaly (10.5% vs. 3.1%, P = 0.050), impaired consciousness (5.3% vs. 0%, P = 0.011) or higher (IQR) alanine aminotransferase (ALT) level (151 [57-295] vs. 66 [37-114] U/L, P = 0.008). By multivariate analysis, having cough (odds ratio [OR], 8.07; 95% confidence interval [CI], 2.51-30.16, P = 0.001) and ALT>120 U/L (OR, 3.51; 95% CI, 1.11-11.14, P = 0.033) were predictors of severe dengue. Early recognition of risk variables may be important for healthcare providers to appropriately manage dengue patients. PMID- 29709966 TI - Prevalence of Plasmid-Mediated Quinolone Resistance among Different Serotypes of Shigella flexneri Isolated from Jiangsu Province of China During 2001-2011. PMID- 29709967 TI - The Development of a Novel Diagnostic Assay That Utilizes a Pseudotyped Vesicular Stomatitis Virus for the Detection of Neutralizing Activity against Crimean-Congo Hemorrhagic Fever Virus. AB - Crimean-Congo hemorrhagic fever virus is a risk group 4 pathogen, which mandates the use of maximum containment facilities, often termed biosafety level 4 or containment level 4 when working with infectious materials. Diagnostic and research work involving live viruses in such laboratories is time-consuming and inconvenient, resulting in delays. Herein, we show that serum neutralizing activity against the virus can be measured in low-containment laboratories using a pseudotyped virus. PMID- 29709968 TI - A Novel System for Constructing a Recombinant Highly-Attenuated Vaccinia Virus Strain (LC16m8) Expressing Foreign Genes and Its Application for the Generation of LC16m8-Based Vaccines against Herpes Simplex Virus 2. AB - A novel system was developed for generating highly attenuated vaccinia virus LC16m8 (m8, third-generation smallpox vaccine) that expresses foreign genes. The innovations in this system are its excisable selection marker, specificity of the integration site of a gene of interest, and easy identification of clones with a fluorescent signal. Using this system, recombinant m8s, which expressed herpes simplex virus 2 (HSV-2) glycoprotein B (gB)-, gD-, or both gB and gD (gB + gD), were generated, and their efficacy was evaluated. First, the induction of a specific IgG against these HSV-2 glycoproteins in mice infected with one of these recombinant m8s was confirmed by an immunofluorescent assay. Next, mice preinfected with one of the recombinant m8s were infected with HSV-2 at a lethal dose to examine the vaccine efficacy. The fatality rate among the mice preinfected with either the recombinant gB + gD- or gD-expressing m8 significantly decreased in comparison with the control. The survival rate in male and female mice preinfected with either the recombinant gB + gD- or gD-expressing m8 increased to 100% and 60%, respectively, while most of the control mice died. In summary, this new system may be applicable to creation of a novel m8-based vaccine. PMID- 29709969 TI - First Identification of Human Adenovirus 57 (HAdV-57) in Japan. AB - Neutralization tests have been routinely used for the identification of human adenovirus C species (HAdV-C) in Japan until 2007. The aim of this study was to clarify the serological cross-reactivity of antiserum that has been used exclusively in Japan and to describe the first identification of HAdV type 57 (HAdV-57) in Japan. Anti-HAdV serum to HAdV-1, 2, 5, and 6 was quantitatively evaluated for cross-reactivity to the HAdV-57 isolates. Anti-HAdV-6 serum neutralized HAdV-57 with a concentration that was 32 to 64-fold higher than what was necessary to neutralize homologous HAdV-6. HAdV-1, 2, and 5 strains were not neutralized by anti HAdV-6 serum. Furthermore, 28 HAdV-6 strains isolated from 6,476 clinical samples were re-examined for HAdVs detected in the Shimane Prefecture of Japan from 2005 to 2014. These 28 strains were re-examined by PCR sequencing techniques using the penton, hexon, and fiber regions. 3 isolates were determined to be HAdV-57. These data show that HAdV-57 had already invaded Japan as early as 2005, and that HAdV-57 strains were misidentified as HAdV-6. PMID- 29709970 TI - Analysis of Human Parechovirus Genotypes in Yokohama District from 2000 to 2016. AB - Human parechovirus (HPeV) infections in Yokohama City, Japan, were surveyed from 2000 to 2016. The sequence of the VP1 region of HPeVs was used to construct a phylogenetic tree and to reveal the putative amino acid (aa) sequences. Phylogenetic analysis showed the presence of 3 genotypes in Yokohama City: HPeV1 (25 specimens), HPeV3 (86 specimens), and HPeV4 (2 specimens). HPeV1 was detected nearly every year, with the highest number detected in 2014. HPeV3 was not detected until 2005, but was detected over a 1- or 3-yr period thereafter. HPeV1 was most prevalent from July to November, whereas HPeV3 peaked in July and August each year. HPeV1 was mainly detected in patients with infectious gastroenteritis or respiratory tract infections. In contrast, 87% of HPeV3-positive cases were in patients less than 2 months of age with a viral-induced fever. An analysis of the aa sequence of VP1 revealed a divergence within the same HPeV genotype, which was useful in analyzing the emergence and re-emergence of HPeV infections during the survey period. These findings suggest that molecular analysis of HPeVs may contribute to a better understanding of its epidemiology. PMID- 29709971 TI - Prevalence of Fosfomycin Resistance in Methicillin-Resistant Staphylococcus aureus Isolated from Patients in a University Hospital in China from 2013 to 2015. AB - In this study, we investigated the fosfomycin susceptibility rates among different methicillin-resistant Staphylococcus aureus (MRSA) clones. A total of 293 MRSA isolates obtained from Sir Run Run Shaw hospital during 2013-2015 were tested for fosfomycin susceptibility. The overall fosfomycin resistance rate among these MRSA isolates was 53.2%. Although 91.9% of the ST5 MRSA isolates (MIC50>1,024 mg/L) were resistant to fosfomycin, no fosfomycin-resistant isolate was found among the 69 ST59 MRSA isolates (MIC50/90, 0.5/4 mg/L). The fosfomycin resistance rate among the MRSA isolates recovered from skin and soft tissue infections was 19.1%, which was lower than the rates detected among MRSA isolates from other types of invasive infections. The fosfomycin resistance rate in community-onset MRSA was 30.2%, which was lower than that detected in healthcare associated MRSA of 70.7%. One MRSA isolate had the fosB7 gene, whereas most (127/156) of the fosfomycin-resistant MRSA isolates had deletions in glpT genes. These findings highlight the importance of monitoring the fosfomycin susceptibility in MRSA isolates for epidemiological purposes. PMID- 29709973 TI - Short-Term Efficacy and Safety of Adding Ezetimibe to Current Regimen of Lipid Lowering Drugs in Human Immunodeficiency Virus-Infected Thai Patients Treated with Protease Inhibitors. AB - Long-term complications of protease inhibitor (PI) treatment includes increased cardiovascular risks due to dyslipidemia in patients infected with human immunodeficiency virus (HIV). Ezetimibe reduces low-density lipoprotein cholesterol (LDL-C) without drug interactions with PIs and statins. Furthermore, the addition of ezetimibe to statins is an optional treatment in HIV-infected patients with uncontrolled dyslipidemia. The objective of this study was to determine the short-term efficacy and safety of adding ezetimibe to the currently administered statin regimen. Thirty-two patients received ezetimibe (10 mg daily) in addition to their ongoing lipid-lowering therapy for 18 weeks. Serum LDL-C, total cholesterol (TC), triglycerides (TGs), TC/high-density lipoprotein cholesterol (HDL-C) ratio, and HDL-C were measured at baseline, and weeks 6, 12, and 18. Safety parameters were assessed by adverse event reports and laboratory assessments throughout the study. The mean percent change from baseline to endpoint in LDL-C, TC, TGs, and TC/HDL-C ratio were -23.3% (p<0.001), -15.0% (p=0.001), -22.1% (p=0.004), and -16.2% (p=0.018), respectively. No adverse event or other abnormal laboratory results occurred. Addition of ezetimibe to currently administered lipid-lowering drugs in HIV-infected patients receiving PIs with uncontrolled dyslipidemia demonstrated significantly improved efficacy in reducing their LDL-C, TC, TGs, and TC/HDL-C ratio levels. Moreover, this therapy was safe and well-tolerated. PMID- 29709972 TI - Comparative Analysis of Immune Responses to Outer Membrane Antigens OMP10, OMP19, and OMP28 of Brucella abortus. AB - Brucella infection is accompanied by cytokine production, which serves as an important factor to evaluate the innate and adaptive immune responses. Several researchers have been investigating the mechanisms involved in Brucella infection in the host. Here, we conducted an analytical study to define pathogenic pathways and immune mechanisms involved in Brucella infection by investigating the antigenic efficacy of recombinant outer membrane protein 10 (rOMP10), outer membrane protein 19 (rOMP19), and outer membrane protein 28 (rOMP28) in vitro and in vivo upon stimulation/immunization. Cytokine production was analyzed by nitric oxide (NO) assay and enzyme-linked immunosorbent assay (ELISA) after stimulation of RAW 264.7 cells and naive splenocytes with the recombinant proteins. Our results show that levels of NO, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 increased in RAW 264.7 cells in a time-dependent manner following recombinant protein stimulation. In contrast, levels of interferon (IFN)-gamma and IL-2 increased in naive splenocytes after stimulation with proteins. ELISA and ELISpot assays were performed after immunization of mice with recombinant proteins. rOMP28 greatly increased IFN-gamma, IL-2, and TNF-alpha levels than IL-4 and IL-6 levels in vitro. Of the recombinant proteins, rOMP19 elicited a mixed Th1/Th2 immune response by increasing the number of IgG secreting cells in vivo. PMID- 29709974 TI - Respiratory Syncytial Virus Surveillance System in Japan: Assessment of Recent Trends, 2008-2015. AB - Respiratory syncytial virus (RSV) is a major cause of lower respiratory tract illness in infants and young children. In Japan, surveillance for RSV infection started in 2003 based on approximately 3,000 pediatric sentinel sites. In recent years, RSV notifications have increased, but the interpretation of trends has been challenging due to a suspected increase in testing frequency and the expansion of the insurance coverage for RSV testing to include certain outpatients in late 2011. Therefore, we evaluated RSV surveillance data during 2008-2015, considering the number of sites that reported at least one RSV case during a surveillance year and restricting to sites that had continuous reporting status since 2008. While annual RSV notifications had increased, the number of sites reporting also increased. And the same magnitude of increase was not observed when the number of cases reported was restricted to the 1,372 sites that had continuous reporting status since 2008. Additionally, in the year following the insurance expansion, RSV notifications increased more remarkably for clinics than for hospitals. These results suggested that some of the recent increases in notifications might be due to an increase in testing frequency. PMID- 29709976 TI - Tuberculosis among Healthcare Workers at Chiang Mai University Hospital, Thailand: Clinical and Microbiological Characteristics and Treatment Outcomes. AB - Tuberculosis (TB) among healthcare workers (HCWs) highly affects morbidity and TB transmission in hospitals. A retrospective cohort study of TB among HCWs (HCW-TB) was conducted using a registered database from 2003 to 2016 at Chiang Mai University Hospital to determine clinical and microbiological characteristics and treatment outcomes of HCW-TB. A total of 76 patients comprising 54 nurses (71.1%), 12 physicians (15.8%), and 10 paramedics (13.2%) were diagnosed with TB disease. The men to women ratio was 25:51, with a mean age of 37.0+/-11.6 years, a median work duration of 12.0 years (5-20) and a body mass index of 19.4+/-2.5 kg/m2. Within the HCW-TB group, 28 (36.8%) worked in the Medical Department, 12 (15.8%) worked in the Outpatient Department/Emergency Room, and 9 (11.8%) worked in the Surgical Department. Pulmonary TB (PTB) was the most common manifestation of HCW-TB (92.1%). Sputum acid-fast stains were positive among 28 (40.0%) HCWs with PTB. Mycobacterium tuberculosis cultures were positive in 26 (34.2%) patients. Drug susceptibility testing showed sensitivity to all first-line drugs (75.0%), resistance to any one first-line drug (20.8%), and multidrug-resistant TB comprised 4.2%. The end-of-treatment success rate was 100%. Therefore, TB control guidelines should be strictly implemented to prevent TB transmission in healthcare settings. PMID- 29709975 TI - Isolation of an Egg-Adapted Influenza A(H3N2) Virus without Amino Acid Substitutions at the Antigenic Sites of Its Hemagglutinin. AB - Antigenic changes in the hemagglutinin protein of recent A(H3N2) viruses often arise when these viruses adapt to their egg host. By serial egg passages of a cell-propagated virus, we successfully isolated an egg-adapted influenza A(H3N2) virus, A/Saitama/103/2014, without amino acid substitutions at the antigenic sites of its hemagglutinin protein but with multiple substitutions in its neuraminidase protein. Antigenic analysis of this egg-adapted A/Saitama/103/2014 virus indicated that its antigenicity did not differ from that of the World Health Organization prototype cell-propagated vaccine virus: A/Hong Kong/4801/2014. Our results suggest that this strategy may facilitate egg-based vaccine production without antigenic alterations in hemagglutinin by egg adaptation. PMID- 29709977 TI - Report of Relapse Typhoid Fever Cases from Kolkata, India: Recrudescence or Reinfection? AB - Three relapse cases were reported out of 107 hospital-attending typhoid cases within a period of 2 years (2014-2016) from Apollo Gleneagles Hospital, Kolkata, India. During the first episode of typhoid fever, 2 of the 3 cases were treated with ceftriaxone (CRO) for 7 days, and 1 was treated for 14 days. Six Salmonella Typhi (S. Typhi) isolates, obtained from the 3 patients during both typhoid episodes, were subjected to antimicrobial susceptibility testing, detection of quinolone resistance-determining region (QRDR) mutation and molecular subtyping by pulsed-field gel electrophoresis (PFGE), multiple-locus variable number tandem repeat analysis (MLVA), multilocus sequence typing (MLST), clustered regularly interspaced short palindromic repeats (CRISPR), and H58 haplotyping. Pairs of the S. Typhi strains isolated from two of the patients during the 1st and 2nd episodes were similar with respect to the antimicrobial resistance (AMR) profiles, QRDR mutations, and molecular subtypes; whereas, the S. Typhi strain pair isolated from the 3rd patient were different in their AMR profiles, QRDR mutations, and MLVA profiles. From these observations, it may be concluded that in spite of treating typhoid cases with CRO for 7-14 days, relapse of typhoid fever might occur. The article also showed the advantage of MLVA typing over PFGE, MLST, and CRISPR typing for the discrimination of strains isolated from the same patient in case of relapse of typhoid fever. PMID- 29709978 TI - Epidemic Keratoconjunctivitis Cases Resulting from Adenovirus Types 8 and 54 Detected at Fukuoka University Hospital between 2014 and 2015. PMID- 29709979 TI - Molecular Evidence of Chandipura Virus from Sergentomyia species of Sandflies in Gujarat, India. AB - The spread and establishment of Chandipura virus (CHPV) infection in India has raised serious epidemiological concerns. The virus interface with the vertebrate hosts (including humans) and vector competence are the important parameters of disease prevalence. Interestingly, in the present study, a highly zoophilic species of the sandfly Sergentomyia was found to be a potential vector of CHPV in Gujarat. This is probably the first report from India of male sandflies testing positive for CHPV in RT-PCR analysis. These findings signify vertical transmission of the virus among sandflies and have epidemiological significance. Health Officers from Gujarat referred 9 pools comprising 277 adult sandflies from disease-affected and unaffected areas to the National Institute of Virology, Pune. The pools were subjected to RT-PCR analysis and sequencing. Of the 9, 2 female and one male pool tested positive for CHPV. Phylogenetic analysis showed similarity of the new sandfly-borne CHPV strains with the human strain from Andhra Pradesh (AP) 2003. The present study highlights the possible role of Sergentomyia spp. in the transmission of CHPV in India. PMID- 29709980 TI - On the Case Fatality Rate: H7N9 Influenza Resurgence in China in 2017. PMID- 29709981 TI - Plasmid-Mediated AmpC beta-Lactamase and Underestimation of Extended-Spectrum beta-Lactamase in Cefepime-Susceptible Elevated-Ceftazidime-MIC Enterobacteriaceae Isolates. AB - Phenotypic detection of extended-spectrum beta-lactamase (ESBL) is important for public health and infection control; however, plasmid-mediated AmpC beta lactamases (pAmpCs) can interfere with the ESBL phenotyping. We focused on Enterobacteriaceae strains that were susceptible to cefepime but had a mildly elevated minimum inhibitory concentration (MIC) of ceftazidime and studied the effect of pAmpC on the ESBL phenotyping in this population. Genotyping of ESBL and pAmpC was performed on 528 clinical isolates of Escherichia coli, Klebsiella spp., and Proteus spp. with a ceftazidime MIC of >=2 MUg/mL and cefepime MIC<=8 MUg/mL; these isolates were collected at Nagasaki University Hospital from January 2005 to March 2011. In this sample, 145 isolates (27.5%) tested positive for pAmpC (pAmpC group). The concordance rates of phenotypic and genotypic detection of ESBLs were 69.2% in the pAmpC group and 88.8% in the non-pAmpC group (P=0.04). pAmpC was more commonly detected in isolates with non-CTX-M genes (5/53, 9.4%) than in isolates with CTX-M genes (8/121, 6.6%). Our data suggest that the presence of pAmpC increases the false negative detection of ESBL. When ESBL phenotyping is used, the underestimation of the prevalence of ESBL producers should be taken into account. PMID- 29709982 TI - Performance Evaluation of a Genotypic Tropism Test Using HIV-1 CRF01_AE Isolates in Japan. AB - Geno2Pheno (coreceptor), a genotypic tropism test, demonstrates excellent agreement with the phenotypic tropism test for subtype B and some other subtypes. However, potential X4-overcalling for CRF01_AE might occur with the present version. To confirm X4 overcalling for AE and to optimize the algorithm for use with AE, we compared the tropism of 22 AE samples by both genotypic and phenotypic methods. The env V3 region was analyzed by bulk sequencing, and tropism was evaluated using the Geno2Pheno algorithm. PhenXR, a phenotypic tropism test, was performed in parallel to determine chemokine receptor preferences. A high X4-overcalling for select samples and a low rate of R5 concordant samples (9.1%) were observed for AE with the current version of Geno2Pheno (coreceptor). On the other hand, the new version, namely, Geno2Pheno (Sanger), showed a high concordance rate of 81.8%, with PhenXR. Because majority of the samples were selected based on discrepancies in the genotypic tropism calls between the present version Geno2Pheno (coreceptor) (FPR<10%) and the new version Geno2Pheno (Sanger) (X4-risk<36), it remains to be determined whether the new version provides improved R5-calls for the AE sequences in general or only in this setting. Further clinical validation studies are warranted. PMID- 29709983 TI - Low Seroprevalence of Severe Fever with Thrombocytopenia Syndrome Virus Antibodies in Individuals Living in an Endemic Area in Japan. AB - Severe fever with thrombocytopenia syndrome (SFTS) is a tick-borne infection with a high mortality rate. It is caused by the SFTS virus (SFTSV) and is endemic in some areas in western Japan, including the Kagoshima prefecture. In the present study, healthy individuals living in this prefecture were examined to assess for anti-SFTSV seroprevalence. An initial study was performed using the serum samples collected from a total of 646 individuals living in Kagoshima. At the same time, a questionnaire was used to collect information (such as occupation and a history of tick bite). Enzyme-linked immunosorbent assay and indirect immunofluorescence assay were used for the screening. Finally, the seroprevalence of anti-SFTSV antibodies was confirmed using a neutralization assay. Only 2 (0.3%) out of 646 study participants were positive for anti-SFTSV antibodies. No significant difference was observed between individuals who are at a high or low risk of tick bite in terms of seropositivity. Next, a total of 1,000 serum samples collected from general blood donors by the Japanese Red Cross Kyushu Block Blood Center were tested. None of these samples tested positive for anti-SFTSV antibodies. These results suggest a low seroprevalence of anti-SFTSV antibodies in healthy individuals living in an endemic area in Japan. PMID- 29709984 TI - The Protobothrops flavoviridis Hemorrhagic Metalloproteinase HR2 Is Inhibited by Human Alpha 2-Macroglobulin. AB - Vaccinations with habu (Protobothrops flavoviridis) venom toxoid were administered to individuals living in Amami Oshima from 1965 to 2002, and its effectiveness was investigated in 1991. The results raised the possibility that normal human serum inherently contains an inhibitor of the hemorrhagic metalloproteinase HR2, considered to be one of the major components of habu venom. In this study, we investigated the interaction between the hemorrhagic metalloproteinases HR1 and HR2 from habu-venom and human alpha 2-macroglobulin (alpha2M). Hemorrhagic activity of HR2 was completely inhibited by human alpha2M. However, the hemorrhagic activity of the large molecule HR1a was not inhibited. Size exclusion chromatography revealed that human alpha2M captured the HR2 molecule and formed a complex with it, thus inhibiting hemorrhagic activity. These results suggest that human alpha2M plays an important role in the inhibition of hemorrhage induced by HR2 from habu venom. PMID- 29709985 TI - The Use of Electric Toilet Seats with Water Spray Is Efficacious in Maintaining Hand Hygiene in Experimental Model. AB - A simulation experiment was conducted to examine hand contamination from wiping the buttocks after the use and non-use of an electric toilet seat with water spray. A model of the buttocks was smeared with artificial diarrheal feces containing Serratia marcescens, and wiped by the participants wearing disposable gloves with 4 sheets of toilet paper after the use and non-use of the water spray of an electric toilet seat. Subsequently, the presence of S. marcescens on the surface of the gloves was quantified. After using the water spray, the mean count+/-standard deviation of S. marcescens was 0.067+/-0.249 colony-forming units (cfu)/glove, and it was 4,275+/-6,069 cfu/glove when water spray was not used. The cfu of S. marcescens was significantly lower when the water spray was used (p<0.00001) prior to wiping the artificial diarrheal feces. This result supports the effectiveness of water spray to prevent defecation-related hand contamination. PMID- 29709986 TI - Emergence of New Recombinant Noroviruses GII.P16-GII.2 and GII.P16-GII.4 in Aichi, Japan, during the 2016/17 Season. PMID- 29709987 TI - Administrative Laboratory Findings for Highly Pathogenic Avian Influenza Virus A (H5N6) in Individuals Engaged in a Mass Culling of Poultry, Hokkaido, Japan, 2016. PMID- 29709988 TI - First Molecular Detection and Phylogenetic Analysis of Anaplasma phagocytophilum from a Clinical Case of Canine Granulocytic Anaplasmosis in Japan. AB - Anaplasma phagocytophilum DNA was detected from a dog with canine granulocytic anaplasmosis (CGA) in Japan. Phylogenetic analysis of the DNA using 16S rRNA, gltA, and groEL sequences revealed that the strain was nearly identical to A. phagocytophilum detected from Apodemus agrarius (black-striped field mouse) in China and Korea. To our knowledge, this is the first report of molecular detection and phylogenetic analysis of A. phagocytophilum from a clinical case of CGA in Japan. PMID- 29709989 TI - Congenital Cytomegalovirus Pneumonitis and Treatment Response Evaluation Using Viral Load during Ganciclovir Therapy: a Case Report. AB - Cytomegalovirus (CMV) is the most common cause of congenital infection. Pneumonitis is considered to be a rare manifestation although congenital CMV infection presents with various non-specific findings. Ganciclovir and valganciclovir are beneficial for improving neurodevelopmental sequelae and hearing outcomes of congenital CMV infection; however, treatment response evaluation is not well reported. We report a female case of congenital CMV infection presenting with pneumonitis, meningoencephalitis, and chorioretinitis. She was treated with intravenous ganciclovir for 6 weeks, and clinical features improved. Measurement of the CMV genome load by real-time polymerase chain reaction assay was performed during treatment. After the administration of ganciclovir, the CMV genome was not detected in the blood and levels decreased gradually in the urine. Physicians should consider the possibility of congenital CMV infection in neonates who present with respiratory distress. Furthermore, measurement of the CMV genome load in blood and urine may be useful for evaluating treatment response. PMID- 29709991 TI - Population Size Dependency of Measles Epidemic That Was Scalable from Japanese Prefectures to European Countries. AB - The relationship between the number of measles patients (y) and the population size (x) was expressed by the equation y=axs, where a is a constant and s the slope of the plot; s was 2.04-2.17 for prefectures in Japan, i.e., the number of patients was proportional to the square of the population size of the prefecture. For European countries that joined the European Union (EU) no later than 2009, the slope was 1.43-1.87. The population dependency of measles found among prefectures in Japan was thus scalable to European countries. This was surprising because, unlike Japan, the population densities of EU countries were not uniform and not proportional to the population size. The population size dependency was not observed among Western Pacific and South-East Asian countries probably due to confounding from interacting socioeconomic factors. The correlation between measles incidence and birth rate, infant mortality or gross domestic product per capita was almost insignificant. The size distribution of local infection clusters (LICs) of measles and rubella in Japan followed a power law. For measles, although the population dependency remained unchanged after "elimination," there were changes in the Zipf-type plots of LIC sizes. After "elimination," LICs linked to importation-related outbreaks in less populated prefectures emerged as the top-ranked LICs. PMID- 29709990 TI - Human Parechovirus Infection in Children in Taiwan: a Retrospective, Single Hospital Study. AB - To understand human parechovirus (HPeV) infections in Taiwanese children, we analyzed data for 112 children (age<=10 years) with HPeV infection diagnosed between July 2007 and June 2016 in a medical center in Kaohsiung, southern Taiwan. The patients were infected with HPeV1 (n=94), HPeV3 (n=3), HPeV4 (n=3), HPeV6 (n=1) and non-typeable HPeV (n=11). We compared the clinical implications for children younger than 3 months (n=56) and 3 months and older (n=31), excluding 25 children with concomitant infections. Fever was noted in almost half of the children younger than 3 months but was more frequent in older than in younger children (83.9% vs 46.4%). As compared with older children, children younger than 3 months had a lower incidence of respiratory symptoms (30.1% vs 83.9%), more frequently required intensive care unit admission (28.6% vs 3.2%), and had longer hospital stays (mean 10.95 vs 5.13 days). Importantly, about one third of the children were suspected to have hospital-acquired or cluster infections in the environment of medical institutions, with a significantly high proportion of 42.9% (24/56) in younger infants. Hospital-acquired infections might play a key role in the spread of HPeV, especially in children younger than 3 months. PMID- 29709992 TI - Characterization of Virucidal Activities of Chlorous Acid. AB - Virucidal effects of chlorous acid on enveloped and non-enveloped viruses were characterized. The virucidal activity was prominent in enveloped viruses. However, among non-enveloped viruses, viruses such as human rhinovirus and feline calicivirus showed a significant sensitivity to the reagent, whereas others such as poliovirus and coxsackievirus showed a weak sensitivity to the reagent, suggesting the presence of 2 classes of sensitivity to the reagent, among non enveloped viruses. In addition, characterization of the mode of inactivation by the reagent revealed that virus inactivation is strongly dependent on virus species, contaminated proteins, and solvent system composition. Comparison of the cytotoxic effects of chlorous acid with those of sodium hypochlorite or sodium dodecyl sulfate (SDS) revealed that chlorous acid was similar to SDS and remarkably weaker than sodium hypochlorite. These results indicate the unique nature of chlorous acid as a potent virucidal agent with tolerable tissue damage, and reveal the merits and limitations of chlorous acid as a disinfectant in food hygiene and sanitizer in healthcare. PMID- 29709993 TI - Comprehensive Assessment of Polyvascular Atherosclerosis. PMID- 29709994 TI - Prognostic Value of Frailty and Diastolic Dysfunction in Elderly Patients. AB - BACKGROUND: High prevalence of frailty and of diastolic dysfunction (DD) in heart failure and high mortality in frail adults have been noted. We characterized frailty by quantifying differences on echocardiography, and assessed the added prognostic utility of frailty and DD grade in an elderly population. METHODS AND RESULTS: One hundred and ninety-one patients >=65 years who had at least 1 cardiovascular risk factor were prospectively recruited for clinically indicated echocardiography at the present institute. Weight loss, exhaustion, and deficits in physical activity, gait speed, and handgrip strength were used to categorize patients as frail (>=3 features), intermediately frail (1 or 2 features), or non frail (0 features). DD grade >=2 was defined as severe. Frailty was associated with larger left atrial volume, smaller stroke volume, and worse DD grade after adjustment for age. In a period of 14 months, 29 patients (15%) had cardiovascular events. The addition of frailty score and severe DD significantly improved the prognostic power of a model containing male gender (model 1, male gender, chi2=6.4; model 2, model 1 plus frailty score, chi2=16.7, P=0.004; model 3, model 2 plus severe DD, chi2=25.5, P=0.015). CONCLUSIONS: Both frailty and DD grade were significantly associated with future cardiovascular events in an elderly population with preserved ejection fraction and >=1 risk factor of cardiovascular disease. PMID- 29709995 TI - Is Female Sex Always a Risk for Bleeding? PMID- 29709997 TI - Improving Progenitor Cell Selection to Promote Therapeutic Angiogenesis in Patients With Critical Limb Ischemia. PMID- 29709996 TI - Report of the Annual Scientific Session of the American College of Cardiology (ACC) 2018, Orlando. AB - The 67thAnnual Scientific Session and Expo of the American College of Cardiology (ACC) were held at the Orange County Convention Center, Orlando, from March 10 12, 2018. This meeting offered 2,700 accepted abstracts presented in oral and poster sessions by 2,100 experts and 37 Late-Breaking Clinical Trials and Featured Clinical Research presentations. This report introduces the key presentations and highlights from the ACC 2018 Scientific Session. PMID- 29709998 TI - [Development of a Novel Liposomal DDS by Manipulating Pharmacokinetics and Intracellular Trafficking for Drug Therapy and Nucleic Acid Medicine]. AB - Nucleic acid therapy is expected to be a next generation medicine. We recently developed a multifunctional envelope-type nano device (MEND) for use as a novel delivery system. The modification of polyethylene glycol (PEG), i.e., PEGylation, is useful for achieving the delivery of MENDs to tumors via an enhanced permeability and retention (EPR) effect. However, PEGylation strongly inhibits the cellular uptake and endosomal escape of MEND, which results in significant loss of action, and therefore lost effectiveness, of the cargo therapeutic. For successful nucleic acid delivery in cancer treatment, the crucial problem associated with the use of PEG, known as the "PEG dilemma", must be solved. In this review, we describe the development and application of MEND in overcoming the PEG dilemma based on manipulating both the pharmacokinetics and intracellular trafficking of cellular uptake and endosomal release using a cleavable PEG lipid, a pH-sensitive fusogenic peptide, and a pH-sensitive cationic lipid. We also developed dual-ligand liposomes with a controlled diameter of around 300 nm, then modified these with a specific ligand and a cell penetrating peptide designed to target the neovasculature of tumors. Dual-ligand liposomes could induce an anti tumor effect in drug resistant tumors by delivering drugs to tumor blood vessels, rather than to the cancer cells themselves. Here, we review our recent efforts to develop a novel liposomal drug delivery system (DDS) by manipulating pharmacokinetics and intracellular trafficking for drug therapy and nucleic acid medicine. PMID- 29709999 TI - [Improvement in the Quality of Regional Medical Care through the Cooperation of Doctors, Nurses, and Pharmacists: Cooperative Treatment of Undiagnosed Onychomycosis]. PMID- 29710000 TI - [Improvement in the Quality of Regional Medical Care through the Cooperation of Physicians, Nurses, and Pharmacists: Cooperative Treatment of Undiagnosed Onychomycosis]. PMID- 29710001 TI - [Current Status of Onychomycosis Topical Therapy Conducted at Home]. AB - Patients usually consult a dermatologist for the treatment of onychomycosis. However, in the case of home care, visiting nurses may assist with bathing, which offers the opportunity to observe patients' feet for possible signs of onychomycosis without causing anxiety. It is estimated that more than 30% of patients receiving home care have onychomycosis. Before the approval of efinaconazole, healthcare personnel hesitated to treat onychomycosis because of: 1) possible side effects, especially liver dysfunction and pain due to repeated blood collection, as a major goal of home care is to minimize pain; and 2) the questionable efficacy of previously available antifungal medications. In addition, many patients report fear of "transmitting athlete's foot to others" and "do not want to show my dirty toenails". On the other hand, caregivers reportedly worry about "athlete's foot being transmitted to them". PMID- 29710002 TI - [Study of Home-based Ringworm Treatment and Follow-up by Visiting Nurses and Physicians: Interventional Effects]. AB - The aim of this study was to assess the effects of cooperation by visiting nurses and physicians experienced in general patient care, dermatology, and podiatry for the treatment of ringworm. Questionnaires were delivered to 1184 patients receiving home-based care by one of 14 participating visiting nursing establishments with a combined capacity of 3273 patients throughout five wards of the Tokyo metropolitan area. Responses were obtained from 691 patients (participation rate, 60.2%; average age, 80.2 years). The onychomycosis morbidity rate among home care patients was 22.7%. The results showed a significant reduction in the incidence of ringworm in the intervention group, from 79.5% to 54.5% (p=0.022), and in the incidence of "foot skin infection", from 100.0% to 31.6% (p<0.001). Although the level of care deteriorated in the control group (p=0.008), there was no significant change in the intervention group. The incidence of leg pain also remained unchanged in the control group (p=0.285) but decreased in the intervention group (p=0.003). While the "degree of satisfaction with foot cleanliness" did not change significantly in the control group (p=0.260), patients in the intervention group were generally satisfied with foot cleanliness. It is necessary to take into account foot care and the effect of onychomycosis treatment vearsusu no treatment and to ensure that visiting nurses and caregivers master foot care-related treatment regimens. We suggest the need to improve the maintenance of foot care and ringworm intervention/treatment performed by physicians, nurses, and caregivers. PMID- 29710003 TI - [Role of Pharmacists in Topical Therapy for Onychomycosis in the Home-care Setting]. AB - There is an urgent need to promote home medical care in Japan because of the country's superaging society. Community pharmacists are expected to play an important role as part of home medical care teams. The prevalence of nail ringworm is high among home-care patients and can cause decreases in the quality of life, including difficulty in walking due to pain caused by nail deformation and inflammation around infected nails. Nail ringworm is typically treated with oral medication. However, the condition is left untreated in many elderly patients because of the risk of drug-drug interactions or concerns about severe liver damage. Efinaconazole, a novel triazole antifungal agent, has recently become available in Japan, enabling patients with nail ringworm to be treated with a topical medication. In topical treatment, the method of application is important because of its major impact on the therapeutic effect. Therefore, pharmacists should take special care to instruct patients and caregivers on the proper use of topical efinaconazole. Adherence to oral medication can be easily monitored by checking the number of tablets or capsules remaining, but adherence to topical medication regimens is more difficult to assess because the remaining amount cannot be determined precisely by checking the outer appearance of the container. The aim of this study was to determine and improve home-care patients' adherence to topical efinaconazole treatment regimens by measuring amounts remaining in the containers using a portable electronic scale. We found that this method is useful for determining the status of topical efinaconazole use. PMID- 29710005 TI - [Let's Challenge Practical Evidence-based Medicine Educational Program for Pharmacy Students and Pharmacists]. PMID- 29710004 TI - [Paradigm Shift in the Quality of Regional Medical Care: Cooperative Treatment of Onychomycosis]. AB - In a superaging society, the medical paradigm should include both less coverage of medical-care work flow by human resources and high-quality care for patients. Strategies such as establishing medical-care teams and community medicine systems mainly for home medical care should be implemented. However, a well-organized system for home-based medical treatment of elderly patients is not yet in place, as evidenced by the lack of care, problems with long-term polypharmacy resulting from visits to multiple healthcare providers, and declines in their physical strength. It is assumed that care might not be provided in association with treatment because planning based on the paradigm of "home medical care" has not been fully established. Therefore, in this study, we aimed to determine the "paradigm shift in home medical care" based on the treatment of onychomycosis. We also hoped to identify the types of medical support required to improve the general well-being of individuals and what needs to be done to ensure a high quality of life for patients. All those (including patients themselves) involved in patient care should together formulate a protocol for medical treatment and cooperate based on the role each can play. Although it may be difficult to maintain cooperation among healthcare workers, improvements in the medical quality of an entire region can be achieved by planning a life design including medical treatment for each patient. PMID- 29710006 TI - [Status of Evidence-based Medicine Education in Undergraduate Pharmacy Curricula]. AB - This research aimed to clarify the present status and challenges of evidence based medicine (EBM) education in schools of pharmacy. We sent a questionnaire to 268 faculty members in August 2015, and a total of 192 were completed. The educational contents by respondents differed considerably. Only about 30% of respondents self-assessed the current EBM courses they taught as "fulfilling". Challenges such as "time deficits", "lack of exercise lessons and practical training", "limited awareness and skills of teachers", "lack of appropriate educational tools", and "insufficient academic ability of students" were mentioned. PMID- 29710007 TI - [Approach to Practical Training in Basic Clinical Pharmacy for Third-Year Pharmacy Students: Literature Appraisal and Professional Writing]. AB - Training pharmacy students to become future clinical pharmacists is an important mission in the 6-year school of pharmacy curriculum in Japan. Since 2014, we have conducted an on-campus practical training program to develop basic skills in clinical pharmacy for third-year pharmacy students at Meiji Pharmaceutical University. This training program includes searching for and retrieving drug information; interpretation of laboratory findings, vital signs, and physical examinations; literature appraisal; and professional writing. These training sections are arranged in the above-mentioned order to facilitate effective understanding of each. In the literature appraisal section, each student group is assigned a report on a prospective controlled study of a given drug published in English and reads it critically according to the literature appraisal worksheet. Then the group writes a monograph on the drug described in the report based on the literature and other information. Thereafter, all students are reshuffled into new groups so that students who were assigned different drugs are placed together, in the so-called jigsaw learning method. Students then discuss which two or three drugs in a specific pharmacological class should be adopted in the hospital formulary according to the knowledge gained through this training program series. The themes were novel oral anticoagulants in the 2014 academic year, dipeptidyl peptidase 4 inhibitors in 2015, and 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors in 2016. Although there are some problems that need to be resolved in the future, this approach appears effective in helping students build drug information skills as a basic competence of clinical pharmacists. PMID- 29710008 TI - [Approach to Evidence-based Medicine Exercises Using Flipped Teaching: Introductory Education for Clinical Practice for 4th-Year Pharmacy Students]. AB - Osaka University of Pharmaceutical Sciences has included an evidence-based medicine (EBM) exercise in the introductory education for clinical practice for 4th-year pharmacy students since 2015. The purpose of this exercise is to learn the process of practice and basic concepts of EBM, especially to cultivate the practical ability to solve patients' problems and answer their questions. Additionally, in 2016, we have attempted flipped teaching. The students are instructed to review the basic knowledge necessary for active learning in this exercise by watching video teaching materials and to bring reports summarizing the contents on the flipped teaching days. The program includes short lectures [overview of EBM, document retrieval, randomized controlled trials (RCTs), and systematic review], exercises [patient, intervention, comparison, outcome (PICO) structuring, critical appraisal of papers in small groups with tutors], and presentations. The program includes: step 1, PICO structuring based on scenarios; step 2, critical appraisal of English-language papers on RCTs using evaluation worksheets; and step 3, reviewing the results of the PICO exercise with patients. The results of the review are shared among groups through general discussion. In this symposium, I discuss students' attitudes, the effectiveness of small group discussions using flipped teaching, and future challenges to be addressed in this program. PMID- 29710009 TI - [Training 5th-Year Clinical Pharmacy Students to Collect and Evaluate Information from Original Articles]. AB - Pharmacists are required to contribute to evidence-based medicine (EBM) by providing drug information, which can be collected from various sources such as books, websites, and original articles. In particular, information from original articles is needed in some situations. For example, original articles by international researchers are used to aid the management of novel in-hospital preparations on which little knowledge is available. We introduced an information evaluation program, the Okayama University Hospital EBM Model, into the clinical training of 5th-year pharmacy students. It aims to enable students to evaluate the validity of novel in-hospital preparations using original articles. This program has improved students' knowledge of EBM, and the satisfaction level of those enrolled was high. In addition, customer satisfaction analysis revealed that the overall degree of student satisfaction was related to their understanding of the necessity for EBM and the difficulty of practical training. In addition, students' achievements were evaluated using rubrics, and that method allowed the achievements of each student to be assessed appropriately. We hope to revise this program with the aim of improving students' understanding of EBM. PMID- 29710010 TI - [Evaluation of an Evidence-based Medicine Educational Program for Pharmacists and Pharmacy Students]. AB - Practicing evidence-based medicine (EBM) is likely to gain importance for clinical pharmacists in the relatively near future in Japan. An educational program including research and the critical appraisal of literature was required for pharmacy students as of 2015. We organized a six-month practical EBM course for pharmacy students at Hyogo University of Health Sciences. To evaluate its effectiveness, students took a 10-question test after completing the course. The mean score of six students was 8.33+/-1.79 points. We also conducted a 1-day practical EBM workshop for pharmacists. Changes in knowledge and skills related to EBM were evaluated based on the responses to 10 questions. Knowledge and skills related to several variables improved significantly after the workshop (6.36 points before versus 9.09 points after the workshop; p=0.023). The results suggested that our EBM educational course is effective in improving EBM-related knowledge and skills of pharmacists and pharmacy students. PMID- 29710011 TI - [The Cutting Edge of Retinal Circuit Research]. PMID- 29710013 TI - [Electrophysiological Analysis of Retinal Oscillation in Normal and Degenerated Retina]. AB - The vertebrate retina is one of the most sophisticated parts of the nervous system. It comprises five classes of neurons and one glial type cell. During development, but prior to a vertebrate's eyes opening, retinal circuits are refined by endogenous neural activity. Characteristic patterns of activity, including oscillatory activity, occur in the normal retina, whereas distinctive alternative patterns occur in abnormal retinas. In this paper, we first describe the electrophysiological and spike sorting methods used to study retinal oscillations. Next, we describe the mechanisms and functions of oscillation in the normal retina. Finally, we characterize the distinctive oscillations and abnormal spontaneous activities in the degenerative retina. PMID- 29710012 TI - [Viral and Electrophysiological Approaches for Elucidating the Structure and Function of Retinal Circuits]. AB - The mammalian retina consists of five classes of neurons: photoreceptor, horizontal, bipolar, amacrine, and ganglion cells. Based on cell morphology, electrophysiological properties, connectivity, and gene expression patterns, each class of retinal neurons is further subdivided into many distinct cell types. Each type of photoreceptor, bipolar, and ganglion cell tiles the retina, collectively providing a complete representation across the visual scene. Visual signals are processed by at least 80 distinct cell types and at least 20 separate circuits in the retina. These circuits comprise parallel pathways from the photoreceptor cells to ganglion cells, each forming a channel of visual information. Feed-forward and feedback inhibition of horizontal and amacrine cells shape these parallel pathways. However, the cell-type-specific roles of inhibitory circuits in retinal information processing remain unknown. Here we summarize parallel processing strategies in the retina, and then introduce our viral and electrophysiological approaches that reveal the roles of genetically defined subtypes of amacrine cells in retinal circuits. PMID- 29710014 TI - [A Potential Mechanism for Spontaneous Oscillation in the Abnormal Retina]. AB - Rhythmic neural activities are observed in many brain regions, and these are considered to play an important role in neural information processing. On the other hand, distinct rhythmic neural activities emerge under several pathological conditions, suggesting that rhythmic neural activity has a close relation to brain function and dysfunction. In many pathological cases, the intrinsic property of unusual rhythm generation in a neuron or a neuronal network is prevented under normal conditions, but released by the pathological condition. Therefore, it may be useful to explore which conditions determine rhythm generation in order to understand the mechanisms of brain function/dysfunction. The pathological retina in retinal degeneration exhibits rhythmic neural activity not observed in the healthy retina. In this review, we first provide a brief introduction to the possible mechanisms of rhythm generation in a neural system. Then we introduce experimental evidence of rhythm generation in the pathological retina, as well as two hypotheses regarding this mechanism. Finally, we raise several issues to be solved for the further understanding of pathological rhythm generation. PMID- 29710015 TI - [Effect of the Metabolic Modification of Environmental Chemicals on Endocrine disrupting Activity]. AB - The endocrine-disrupting activities of various environmental chemicals are metabolically activated. For example, diphenyls, styrene oligomers, chalcones, trans-stilbene and 2-nitrofluorene are not estrogens, but after incubation with liver microsomes, their metabolites show estrogenic activities. Thus, these chemicals are estrogenically activated by the cytochrome P450 system. In contrast, the antiandrogenic activity of fenthion, an organophosphorus insecticide, is abolished after metabolism to sulfoxide and sulfone derivatives. Structural requirements of twenty bisphenol A related compounds, as well as various benzophenones, for estrogenic and antiandrogenic activities have been investigated. The estrogenic and antiandrogenic activities of Benzophenone 3, a representative UV absorbant, are activated by oxidative metabolism. Parabens (used as antimicrobial agents) exhibit estrogenic activity, and their potency shows a bell-shaped curve between C1 (methylparaben) and C12 (dodecylparaben) parabens. The AhR ligand activity of indirubin is decreased by metabolism. Polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDE) are activated by hydroxylation to show estrogenic and thyroid hormone-disrupting activities. Halogen adjacent to a hydroxyl group is essential for thyroid hormone disrupting activity. Tetrabromobisphenol A, tetrachlorobisphenol A and tetramethylbisphenol A also exhibit thyroid hormone-disrupting activity. Amphibian metamorphosis of tadpoles to frogs is affected by hydroxylated PCB, hydroxylated PBDE and bisphenol A derivatives. These chemicals suppress thyroid hormone-dependent metamorphosis, acting as antagonists of thyroid hormone. Thus, metabolic modification can have a dramatic impact on the endocrine-disrupting activities of environmental chemicals. PMID- 29710016 TI - [Evaluation of a Two-day Hospital On-site Training Program for Community Pharmacists: Approach to Facilitate Collaboration among Community Healthcare Professionals]. AB - The importance of community-based care systems has increased due to the highly aging population and diversity of disease. To enhance the cooperation among healthcare professionals in community-based care systems, a two-day on-site training program for community pharmacists based on a multidisciplinary team approach was conducted at the Medical Science Hospital of Shiga University from April 2015 to March 2017. There were two professional courses in this training program: the palliative care course and nutrition support course. Both courses consisted of common pharmaceutical care training as follows: regional cooperation among healthcare professionals, pharmacist's clinical activities in the ward, pressure ulcer care, infection control, and aseptic technique for parenteral solutions. Each course was limited to 2 participants. A questionnaire was given to participants in the training program. Seventy-five pharmacists participated in the training and all of them answered the questionnaire. According to the questionnaire, 86% of participants felt that 2 days was an appropriate term for the training program. Positive answers regarding the content of each program and overall satisfaction were given by 100% and 99% of the participants, respectively. In the categorical classification of free comments regarding the expected change in pharmacy practice after the training, both "support for patients under nutritional treatment" and "cooperation with other medical staff" were answered by 24 participants. These results suggested that the 2-day on-site training for community pharmacists facilitated cooperation among healthcare professionals in the community. PMID- 29710017 TI - [Factors Related to the Awareness and Self-confidence of Pharmacists regarding "PRE-AVOID": Study Using VISTA Project Data]. AB - The objective of this survey is investigating pharmacists' recognition of and belief in the importance of doing PRE-AVOID using the drug profile book (DPB). The main survey items were: 1. Awareness and self-confidence concerning PRE-AVOID using DPB, 2.Status of educating patients of the merits of the DPB, 3. Status of educating patients of the utilities of the DPB, 4. Status of educating patients of the roles of the DPB, 5. Guidance provided on methods of DPB usage, and 6. Interactions with patients. A multiple regression analysis was performed using "Awareness and self-confidence concerning PRE-AVOID using DPB" as a dependent variable. A regression equation including three items ("Educating the roles", "Blood test", and "Not using multiple DPBs at same time") was derived for "Self confidence in PRE-AVOID work" (R2=0.20). The item most affecting "Self-confidence in PRE-AVOID work" was "Educating the roles" (R=0.28). A regression equation with "Awareness of PRE-AVOID work" as a dependent variable was not derived. The results of the study suggest that "Educating the roles" or "Not using multiple DPBs at same time" for patients, and asking the results of "Blood test" in a medication consultation may increase pharmacists belief in doing PRE-AVOID. PMID- 29710018 TI - Heat stress affects prostaglandin synthesis in bovine endometrial cells. AB - Heat stress (HS) negatively affects reproduction in cattle; however, its effect on endocrine function in bovine endometrial cells remains unclear. In this study, we examined the effects of HS on the production of prostaglandin (PG) E2 and PGF2alpha in the cultured bovine endometrial epithelial and stromal cells separately. To evaluate the effect of HS on endocrine function, the cells were cultured at 38.5 degrees C (control) or 40.5 degrees C (HS). After treatment, PGE2 and PGF2alpha levels were measured via enzyme immunoassay (EIA) and mRNA expressions of enzymes involved in PG synthesis were examined via quantitative reverse transcription polymerase chain reaction (RT-PCR). HS did not influence the production of PGE2 or PGF2alpha in the epithelial cells; however, HS significantly enhanced the production of both PGE2 and PGF2alpha in the stromal cells (P < 0.05). In addition, HS significantly increased phospholipase A2 (PLA2), cyclooxygenase 2 (COX2), prostaglandin F synthase (PGFS), prostaglandin E synthase (PGES), and carbonyl reductase 1 (CBR1) mRNA expression in the stromal cells (P < 0.05). The overall results suggest that HS induces mRNA expression of enzymes involved in PG synthesis, resulting in the upregulation of PGE2 and PGF2alpha production in the stromal cells, but not in the epithelial cells. The HS-induced increase of PGE2 and PGF2alpha secretion in bovine endometrial stromal cells may disrupt the normal estrous cycle and cause infertility in cows during summer. PMID- 29710019 TI - [Parkinson's disease associated with SAPHO syndrome: a case report]. AB - A 77-year-old woman with Parkinson's disease presented with left chest pain. Physical examination revealed tenderness at her second left sternocostal joint. There was no skin rash. Chest CT revealed hyperostosis of the sternocostal joint, and cervical MRI showed vertebral osteosclerosis and osteolysis. 99mTc-MDP bone scintigraphy showed an increased activity in the sternocostal joint and vertebral column. The patient was diagnosed with SAHPO syndrome according to the diagnostic criteria. Her chest pain was relieved after oral administration of nonsteroidal anti-inflammatory drugs. Although pain is a common non-motor symptom of Parkinson's disease, chest pain is relatively rare, according to a previous reports. When patients with Parkinson's disease complain of chest pain, physicians should make an appropriate differential diagnosis after excluding emergent cardiovascular disease. To the best of our knowledge, this is the first report of Parkinson's disease associated with SAPHO syndrome. The relationship between the two diseases is unclear. However, peripheral inflammation is known to exacerbate ongoing neuronal damage in neurodegenerative diseases, such as Parkinson's disease. Therefore, systemic inflammation of SAPHO syndrome may affect the disease course of Parkinson's disease. PMID- 29710021 TI - [Right parietal cerebral infarction with symptoms challenging to differentiate between alien hand sign and sensory ataxia: a case report]. AB - We report the case of a 73-year-old right-handed female with a right parietal cerebral infarction and presented symptoms that were challenging to differentiate between alien hand sign (AHS) and sensory ataxia. She presented to our emergency department with chief complaints of abnormal involuntary movements and a feeling of foreignness on her left upper limb. The first neurological examination revealed left spatial neglect, left-side sensory impairment that included superficial and deep sensations, left limb-kinetic apraxia, and left limb ataxia. Furthermore, her symptoms and complaints had characteristics of AHS that includes a sensation that her left upper limb dose not belong to herself and an abnormal behavior of left hand that is contrary to her own intent. Brain MRI revealed an acute cerebral infarction confined to the right postcentral gyrus. This case highlights that sensory ataxia due to the disturbance of deep sensation might present symptoms similar to AHS. Previous studies suggested the involvement of the disturbance of somatosensory pathway in posterior-variant AHS. Therefore, a precise distinction between AHS and sensory ataxia, especially in posterior variant AHS, is imperative to avoid confusion regarding the term "alien hand sign." PMID- 29710020 TI - [A 15-year-old girl with congenital cytomegalovirus infection presenting with sensorineural hearing impairment and cerebral while matter lesions but no intellectual disability]. AB - A 15-year-old girl presented with non-progressive sensorineural hearing impairment in her right ear since her early childhood. She had normal intellectual development. When she was 15 years old, small deep white matter lesions around the lateral ventricles were incidentally detected in brain MRI studies through further investigation of auditory organs. Laboratory data including cerebrospinal fluid analysis and antibodies to aquaporin-4 or myelin oligodendrocyte glycoprotein were normal. She was diagnosed as a congenital cytomegalovirus (CMV) infection based on the detection of CMV DNA from preserved umbilical cord tissue by real-time polymerase chain reaction. It should be kept in mind that a case of congenital CMV infection with normal intelligence may be underdiagnosed and that sensorineural hearing impairment from early childhood and deep white matter abnormalities can be key features giving rise to suspicion on congenital CMV infection. PMID- 29710022 TI - [A case of bilateral cervical internal carotid artery dissection following herpes zoster of the trigeminal nerve]. AB - A 62 year-old man, who was taking prednisolone for nephrotic syndrome, was diagnosed with herpes zoster of the trigeminal nerve and treated with oral valacyclovir. One month later, he reported pain from the right side of the head and vomiting. MRI revealed an acute infarction in the right frontal lobe and dissection of the internal carotid artery of the right cervix. Trauma or other potential triggers were not observed. In consideration of the preceding condition of varicella zoster virus infection, acyclovir was administered in addition to unfractionated heparin, but an intramural hematoma emerged in the left internal carotid artery. Furthermore, evidence showing progression of these lesions was found. On the fifth day, prednisolone was increased to 1 mg/kg/day, and progression of vascular lesions was not observed. This case may prove valuable because it suggests a relationship between cervical artery dissection and herpes zoster. PMID- 29710023 TI - [A case of acute disseminated encephalomyelitis concomitant with polyneuropathy associated with anti-lactosylceramide antibody]. AB - We report a case of acute disseminated encephalomyelitis (ADEM) concomitant with polyneuropathy associated with anti-lactosylceramide antibody. A 68-year-old man was admitted to our hospital with ophthalmoparesis, bulbar palsy, tetraplegia after suffering from upper respiratory infection and headache. Subsequently, he developed respiratory failure requiring mechanical ventilation. Fluid-attenuated inversion recovery (FLAIR) MRI showed high intensities in the pons and medulla, and a nerve conduction study revealed motor-dominant axonal polyneuropathy. Although the laboratory tests revealed the presence of anti-lactosylceramide antibody in his serum, he was diagnosed with acute disseminated encephalomyelitis concomitant with polyneuropathy. Whereas the intensive treatment with corticosteroids, plasmapharesis, and high-dose intravenous immunoglobulin (IVIg) brought a moderate improvement, his tetraparesis continued to exist. PMID- 29710024 TI - [Transient, recurrent, white matter lesions in X-linked Charcot-Marie-Tooth disease with heterozygote mutation of GJB1 gene: case report of a female patient]. AB - A 32-year-old woman showed transient central type facial nerve palsy and bulbar symptoms. Brain MRI revealed high intensity signals in the cerebral white matter, splenium of corpus callosum, and posterior limb of internal capsule. Two elder brothers of the patient had distal dominant peripheral neuropathies in four limbs. In this family, the point mutation of GJB1 gene, encoding connexin 32, was revealed and X-linked Charcot-Marie-Tooth disease (CMTX1) was diagnosed. The presented case was a heterozygote of this mutation. She showed severe transient central nervous system (CNS) symptoms and subclinical demyelinating peripheral neuropathy. The CNS symptoms and alterations of brain images were very similar among three siblings. There are many reports on male patients with CMTX1 who show associated CN symptoms, but female patients are very rare. There has been no previous report of a CMTX1 patient similar to the patient presented here. The trigger factors have been recognized at the onset of transient CN symptoms in these cases. The prevention of these factors is important for the management of such patients. PMID- 29710025 TI - [A survivor of Hodgkin lymphoma manifesting dropped head syndrome as a late-onset complication of radiotherapy: a case report]. AB - We report the case of a 50-year-old female survivor of Hodgkin lymphoma (HL), who developed dropped head syndrome (DHS). The patient was diagnosed with HL at 20 years of age, and underwent chemo-radiotherapy, which led to complete remission. Undergoing supplemental therapy for post-radiation hypothyroidism, she had twin babies. She noticed white stains on her neck at the age of 30, and the decolored area gradually expanded. Sixteen years after the radiotherapy (RT), her posterior neck muscle strength began to decline. She had to make considerable efforts to keep her neck straight, and came to experience a severe pain in the neck and shoulders. The patient visited our department due to DHS at the age of 50. She had leukoderma, muscle weakness, and muscle atrophy in the neck and para-spinal region, which were consistent with the area of RT. The strength was preserved in the other parts of the muscle, including the proximal upper limbs. Sensory nerve disorder was not detected. The serum creatine kinase level was slightly elevated. Cervical spine or cervical cord disease that can cause DHS was not detected by MRI examination. The MRI and CT images revealed marked atrophy in the posterior neck and para-spinal muscles. The electromyogram revealed myopathic changes, and the cause of her DHS was diagnosed as radiation-induced myopathy. DHS is a well known late-onset radiation injury, and Japanese cases have been reported in elderly persons with laryngeal or lung cancer. However, there have been no Japanese case reports of radiation-induced DHS due to RT against HL in younger persons. The patient had visited several clinics and hospitals before she came to our hospital, but RT-induced DHS had been overlooked. Greater recognition and consideration is required for DHS as one of the various issues arising after long passage of HL survivors. PMID- 29710026 TI - [Embolic stroke immediately after initial administration of intravitreal aflibercept]. AB - A 72-year-old man was admitted to our hospital because of right upper limb monoplegia 8 hours after the initial intravitreal injection of aflibercept, which is an inhibitor of vascular endothelial growth factor. Magnetic resonance diffusion-weighted images showed recent ischemic lesions in the left corona radiata and the right superior frontal gyrus. Laboratory findings showed mild hyperfibrinolysis. A patent foramen ovale was diagnosed on transesophageal echocardiography; however, lower-extremity ultrasonography did not detect deep vein thrombosis. The source of embolism remained unknown. A possible mechanism of cerebral emboli in the present case was a rapidly induced hypercoagulative state due to transfer of aflibercept from the vitreous body to the systemic circulation. PMID- 29710027 TI - [Two patients with progressive multifocal leukoencephalopathy with immune response against JC virus showing good long-term outcome by combination therapy of mefloquine, mirtazapine, and risperidone]. AB - Patient 1 was a 59-year-old woman receiving prednisolone for idiopathic hypereosinophilia. Brain MRI of patient 1 disclosed slight gadolinium enhancement at lesions, indicating inflammation. Patient 2 was a 32-year-old woman with systemic lupus erythematosus under immunosuppressive therapy. Brain biopsy of patient 2 showed balanced infiltration of CD8+ and CD4+ T lymphocytes at the sites of lesions. Both subjects were diagnosed as having progressive multifocal leukoencephalopathy (PML) shortly after the onset of neurological symptoms and were treated with a combination of mefloquine, mirtazapine, and risperidone. Both patients remain alive with improved neurological symptoms even after long-term follow-up (24 months in patient 1 and 45 months in patient 2). Although the prognosis of PML is very poor, our findings suggest that pharmacotherapy may be effective for patients with well-controlled immune reactions against the JC virus. PMID- 29710028 TI - Vitamin D Deficiency Increases Lipogenesis and Reduces Beta-Oxidation in the Liver of Diet-Induced Obese Mice. AB - The study was conducted to understand better the mechanisms involved in liver changes when there is a combination of diet-induced obesity (DIO) and vitamin D deficiency (VDD). After 8 wk of feeding a control diet (C group) or a high-fat diet (HF), both with vitamin D, and counterpart groups without vitamin D (VitD- groups), we found in plasma: higher alanine aminotransferase, and aspartate aminotransferase in the VitD- groups, and more elevated total cholesterol in the HF group. Compared to their counterparts, HF and HF/VitD- showed hyperinsulinemia and higher hepatic triglycerides and steatosis. The protein expressions of markers linked with the vitamin D action were altered by VDD (vitamin D receptor VDR, 25-hydroxyvitamin D-24-hydroxylase CYP24A1, CYP27B1, and CYP2R1). The hepatic lipogenesis and fatty acid synthesis were enhanced by VDD (peroxisome proliferator-activated receptor PPARgamma, sterol regulatory element-binding proteins SREBP1c, carbohydrate-responsive element-binding protein ChREBP, and fatty acid synthase FAS), but markers of beta-oxidation were reduced (PPARalpha and phosphoenolpyruvate carboxykinase PEPCK). In conclusion, the study provides convincing new evidence that there is an additive and adverse effect on the liver caused by the combination of VDD and DIO. The essence of these changes in the liver is in an increased lipogenesis and a reduced beta-oxidation, which predisposes to the accumulation of fat in the liver, accompanied by IR. The worsening of the pathogenesis of NAFLD may tilt to more severe stages of liver disease. PMID- 29710029 TI - Gender Difference and Dietary Supplemental Vitamin B6: Impact on Colon Luminal Environment. AB - Colon diseases can be affected by several factors such as gender difference and dietary supplemental vitamin B6 (B6). The nutritional status of B6 is affected by gender difference, leading us to hypothesize that gender difference affects colon luminal environment, which is dependent on B6 status. To investigate this hypothesis, we fed male and female rats a diet containing 1 mg, 7 mg, or 35 mg pyridoxine HCl/kg diet for 6 wk. We found significantly higher fecal mucin levels in female rats compared to those in male rats. Supplemental B6 significantly increased fecal mucins and was particularly profound in the female rats. The abundances of cecal and fecal Akkermansia muciniphila (mucin degrader) were unaffected. The fecal mucin levels were significantly correlated with colonic free threonine and serine and with gene expression of colon MUC16, implying that the combined effect of gender and dietary B6 on fecal mucins was mediated by the alteration in the levels of such amino acids and MUC16 expression. This study further showed the significant effects of gender difference on colonic free amino acids such as threonine, ornithine, asparagine/aspartate ratio, and glutamine/glutamate ratio, cecal and fecal Lactobacillus spp. levels, and colonic gene expressions of MUC16 and TLR8, the factors relating to colon health and diseases. Therefore, our findings suggest that gender difference and dietary B6 may have an impact on colon diseases by modulating these parameters. PMID- 29710030 TI - Characteristics of the Japanese Diet Described in Epidemiologic Publications: A Qualitative Systematic Review. AB - CONTEXT: International interest in the Japanese diet has grown in recent years. OBJECTIVE: The aim of this systematic review was to evaluate and organize the Japanese diet and dietary characteristics from an epidemiological perspective, mainly focusing on the nutritional and dietary elements. DATA SOURCES: PubMed, Web of Science, Japan Medical Abstracts Society, JDream III, and CiNii databases were searched. STUDY SELECTION: The eligibility criteria included research with an epidemiological study design that was either cross-sectional, cohort, or case control-based that defined the dietary patterns of the Japanese diet using dietary pattern analysis. A total of 39 research articles that described the Japanese diet were included. DATA EXTRACTION: The data that were extracted included the following: implementing country, location, study design, participant characteristics, key outcomes, methods used in the analysis of dietary patterns, and descriptions of the Japanese diet. DATA SYNTHESIS: As a result of the systematic review analyzing the descriptions of the Japanese diet from 39 selected articles, we were able to aggregate the descriptions into 16 categories from 33 factors. After performing a content analysis using a further aggregation of categories, we found that the top three applicable categories were soybeans/soybean-derived products, seafood, and vegetables; these were followed by rice and miso soup. CONCLUSION: The Japanese dietary content was found to be diverse based on an examination of epidemiological studies; however, we were able to aggregate the content into 16 categories. The Japanese diet is considered to be a dietary pattern that contains a combination of factors: the dietary staple, side dishes, and soup. PMID- 29710031 TI - Enzyme-Treated Asparagus Extract (ETAS) Facilitates the Turnover of UV-B Irradiated Keratinocytes. AB - Enzyme-treated asparagus extract (ETAS) is prepared from the lower, residual parts of asparagus, and some functionalities, such as anti-oxidative and neuroprotective activities, have been suggested. The purpose of the present study was to investigate the effects of ETAS on photoaging in the epidermal layer of the skin using cultured keratinocytes. Normal human epidermal keratinocytes were irradiated or left unirradiated with UV-B (10 mJ/cm2) and incubated with ETAS (0.5 or 2 mg/mL) or vehicle. After 3 or 13 h, molecular examinations were performed, and after 24 or 48 h, cell viabilities were determined by a CCK-8 assay. ETAS addition may induce keratinocyte migration and proliferation as well as apoptosis under molecular examination. These results suggest that ETAS might accelerate turnover of keratinocytes. PMID- 29710032 TI - Effects of Chronic Whey Protein Supplementation on Atherosclerosis in ApoE-/- Mice. AB - Whey protein is associated with improvement of metabolic syndrome. This study aimed to evaluate effects of whey protein on atherosclerosis in ApoE-/- mice. Male ApoE-/- mice were fed with a high-fat/cholesterol diet (HFCD), or HFCD supplemented with 10% or 20% whey protein for 18 wk. At the end of experiment, serum lipid profiles and inflammatory cytokines were assayed. Livers were examined using HE staining and Oil Red O staining. Aortas were used for en face and cryosection analyses to observe aortic lesions. Western blotting analysis was used to assess relative protein expression of cholesterol metabolism in the liver and aorta. No significant differences were observed in body weight or food intake among the three groups. Liver examination demonstrated decreased lipid droplets and cholesterol content in the whey-protein-supplemented groups. En face lesion of the aorta revealed a 21.51% and 31.78% lesion reduction in the HFCD supplemented with 10% and 20% whey groups, respectively. Decreased lesion was also observed in cryosection analysis. Whey protein significantly increased the serum high-density lipoprotein cholesterol level by 46.43% and 67.86%. The 20% whey protein significantly decreased serum IL-6 (a proinflammatory cytokine) by 70.99% and increased serum IL-10 (an anti-inflammatory cytokine) by 83.35%. Whey protein potently decreased lipogenic enzymes (ACC and FAS) in the liver and NF kappaB expression in the liver and aorta. Whey protein significantly increased protein expression of two major cholesterol transporters (ABCA1 and ABCG1) in the liver and aorta. Thus, chronic whey protein supplementation can improve HFCD induced atherosclerosis in ApoE null mice by regulating circulating lipid and inflammatory cytokines and increasing expressions of ABCA1 and ABCG1. PMID- 29710033 TI - Methylxanthine Derivative-Rich Cacao Extract Suppresses Differentiation of Adipocytes through Downregulation of PPARgamma and C/EBPs. AB - Cacao extract (CE) consumption has beneficial effects on human health, such as lowering the risk of obesity. However, the underlying molecular mechanism for the anti-obesity effect of CE remains incompletely understood. Here, we used a 50% aqueous alcohol extract of cacao mass, which is rich in methylxanthine derivatives (about 11%) and poor in flavan-3-ols (less than 1%), and assessed the suppression effects of this extract on adipocyte differentiation to investigate the anti-obesity mechanism. CE dose-dependently decreased fat accumulation in 3T3 L1 cells without affecting cell viability. CE also dose-dependently decreased the protein and gene expression levels of two adipogenesis-related transcription factors, peroxisome proliferator-activated receptor gamma (PPARgamma) and CCAAT/enhancer-binding proteins (C/EBPs). Moreover, CE decreased protein expression levels of sterol regulatory element-binding protein 1 (SREBP1) and its downstream fatty acid synthase (FAS), which was accompanied by the retained localization of SREBP1 in the cytoplasm of 3T3-L1 cells. After ICR mice were fed a diet containing 1% CE for 1 wk, their white adipose tissue weight was lower, whereas their brown adipose tissue weight was higher compared with those of control animals. Additionally, the protein expression levels of PPARgamma, C/EBPs, SREBP1, and FAS in the white adipose tissue of these mice were also lower than those in control animals. In contrast, diet supplementation with CE induced higher levels of phosphorylated AMP-activated protein kinase (AMPK) and its downstream acetyl-CoA carboxylase. In conclusion, methylxanthine derivative-rich CE decreases fat accumulation in adipocytes by downregulating the expression of the adipocyte differentiation master regulators through the activation of AMPK. PMID- 29710034 TI - The Relationship between Maternal Serum Vitamin D Levels and Infant Neurodevelopment and Anthropometry: A Prospective Observational Study. AB - This study was designed to determine whether there is a relationship between serum vitamin D levels and neurodevelopment and anthropometry in Chinese infants. A prospective cohort study with 160 women who gave birth to 160 healthy full-term infants and who were followed up for 6 mo was done. It included 80 pregnant women with vitamin D deficiency, and the other 80 pregnant women were enrolled matching the age and delivery method with a 25(OH)D level of more than 50 nmol/L. There was a signicant intergroup difference in length, weight or head circumference at birth (p<0.05). Meanwhile, there was a signicant intergroup difference in cognitive development and achievement at 6 mo (p<0.001). In multivariate analyses, maternal 25(OH)D levels less than 50 nmol/L were independently associated with a higher tendency for a low Bayley mental score (MDI) at 6 mo (OR=2.77, 95% CI: 1.44-5.35, p=0.002), as well as Bayley motor score (PDI) (OR=2.08, 95% CI: 1.07-4.04, p=0.032). Thus we observed that maternal vitamin D was associated with infant neurodevelopment and anthropometry. PMID- 29710035 TI - IUNS Workshop on Capacity and Leadership Development in Nutritional Sciences Held in Tokyo 2017. PMID- 29710037 TI - Organ Co-Relationship in Tryptophan Metabolism and Factors That Govern the Biosynthesis of Nicotinamide from Tryptophan. AB - The pathway of tryptophan (Trp)-nicotinamide is very important nutritionally because a vitamin nicotinamide is biosynthesized from an amino acid Trp. Until we started studying the factors that affect the Trp-nicotinamide conversion rate, little data existed. Data obtained from TDO (Trp 2,3-dioxygenase)-KO (knock-out) mice have revealed that mice can biosynthesize a necessary amount of nicotinamide from Trp by indoleamine 2,3-dioxygenase (IDO) even when TDO is lacking. It has also been shown that 3-hydroxyanthranilic acid is a key intermediate. Urine upper metabolites such as kynurenic acid and xanthurenic acid originate from non hepatic tissues but not from the liver. Data obtained from quinolinic acid phosphoribosyltransferase (QPRT)-KO mice indicated that the Trp->quinolinic acid conversion ratio was 6%. Urine quinolinic acid levels and the conversion ratio of Trp to nicotinamide were the same between hetero and wild mice. These findings indicate that QPRT is not the rate-limiting enzyme in the conversion. Thus, the limiting factors in the conversion of Trp to nicotinamide are the amounts of 3 hydroxyanthranilic acid and quinolinic acid in the liver and the activity of liver 3-hydroxyanthranilic acid 3,4-dioxygenase. Studies on factors have shown that conversion of Trp to nicotinamide is increased by adequate intake of good quality protein, and adequate intake of unsaturated fatty acids and starch. However, conversion was decreased by deficient niacin, vitamin B2, or vitamin B6, excessive intake of protein, saturated fatty acids, or glucose and fructose, or intake of protein with low Trp content, and insufficient mineral intake. PMID- 29710036 TI - Dietary Salt (Sodium Chloride) Requirement and Adverse Effects of Salt Restriction in Humans. AB - Inevitable sodium loss under sodium restriction must not be construed as evidence for the estimated average requirement (EAR) for sodium (Na) in humans. We conducted human mineral balance studies to determine the EAR for some minerals (Na, K, Ca, Mg, P, Zn, Fe, Cu and Mn). Na concentration in arm sweat was low while those of calcium (Ca) and magnesium (Mg) were high, during relatively heavy bicycle-ergometer exercise under relatively low Na intake (100 mmol/d). This suggests that Na was released from the bone, the sole pool of Na, with Ca and Mg. Additionally, the negative balances of Ca and Mg was observed under a relatively low sodium intake (100 mmol/d) even with the sufficient supply and intake of Ca and Mg into human body. Finally, we found no correlation between the Na intake and the Na balance, while the Na-intake was correlated significantly to the balances of K, Ca and Mg. The Na intake necessary to keep the balances of Ca and Mg positive was calculated to be 68 mg/kg body weight/d. To learn the signs and symptoms of low sodium intake, we compared the results of a metabolic study in which subjects consumed diets with 6 g and 12 g salt/d respectively. The blood pressure decreased only with the 6 g/d group. Fecal moisture contents of the 6 g/d group were lower than for the 12 g/d group, suggesting the fecal Na was strongly reabsorbed with water when the dietary Na was insufficienct. Indiscriminate Na restriction may have adverse effects on health. PMID- 29710038 TI - Current Vitamin D Status in Healthy Japanese Infants and Young Children. AB - This study aimed to characterize serum 25-hydroxyvitamin D (25OH-D) values among Japanese children aged <=48 mo. The study included 290 healthy infants and young children aged 0-48 mo (males/females=166/124) living in Shizuoka or Tokyo. The subjects were divided into three groups by age (Low Age: 0-5, Middle Age: 6-15, High Age: 16-48 mo). The vitamin D deficient state was defined as 25OH-D <12 ng/mL, the insufficient state as 12-20 ng/mL, and the sufficient state as >20 ng/mL. The seasonal variation of serum 25OH-D levels was also analyzed. The median serum 25OH-D levels in each group were: Low Age (n=50), 19 ng/mL; Middle Age (n=94), 30 ng/mL; and High Age (n=146), 30 ng/mL. The serum 25OH-D level was significantly lower in the Low Age group than in the other groups (p<0.01). Serum 25OH-D levels in summer and autumn (n=149) were significantly higher than in winter and spring (n=141) (33 vs. 25 ng/mL, p<0.01). In the Low Age group, there was a significant difference in serum 25OH-D levels between breast-fed infants (n=26) and formula-fed or mixed-fed infants (n=19) (12 vs. 32 ng/mL, p<0.01). However, there were no significant differences in 25OH-D levels between the two season classifications in either breast-fed or formula-fed and mixed-fed infants. Although clinical symptoms were not available, more than 75% of the breast-fed infants and 14.6% of infants and young children to whom food had been introduced were defined as having a vitamin D deficient or insufficient state. Breastfeeding seems one of the contributing factor to lower serum 25 OH-D levels among infants <=5 mo of age. PMID- 29710039 TI - Acrolein as a Major Volatile in the Early Stages of Fish Oil TAG Oxidation. AB - Fish oil rich in docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) is known to have an unpleasant smell, even at low oxidation levels. Therefore, it is highly important to know the major volatiles formed during the early stages of fish oil oxidation. Comparative study with solid-phase microextraction (SPME) and static headspace (SHS) methods showed that 2-propenal (acrolein) was formed as the major volatile from the beginning of fish oil triacylglycerol (TAG) oxidation. The effectiveness of SPME extraction on each volatile was different from each fiber. Among the three different SPME fibers used in the present study, carboxen/polydimethylsiloxane (CAR/PDMS) was determined to be a better fiber for measuring the volatiles, including acrolein. The present study also showed that the non-selective SHS method is useful for determining the characteristic volatile formation in the early stages of fish oil TAG oxidation. PMID- 29710040 TI - Development of New D,L-Methionine-based Gelators. AB - D,L-Methionine was chosen as a starting material for the preparation of a new gelator N-10-undecenoyl-D,L-methionylaminooctadecane (DL-Met-R18). Three oligo (dimethylsiloxane)-containing gelators, DL-Met-R18/Si3, DL-Met-R18/Si7-8, and DL Met-R18/Si14-15, were also prepared from DL-Met-R18 by hydrosilylation reactions. Their gelation abilities were evaluated on the basis of the minimum gel concentration using nine solvents. Compound DL-Met-R18 was able to gelate liquid paraffin and silicone oil, but it crystallized in most solvents. However, DL-Met R18/Si7-8 resulted to be the best gelator, gelling eight solvents at low concentrations. The results of gelation tests demonstrated that the ability to form stable gels decreases in the following order: DL-Met-R18/Si7-8 ~ DL-Met R18/Si14-15 > DL-Met-R18/Si3 >> DL-Met-R18. The aspects and thermal stabilities of the gels were investigated using three-component mixtures of solvents composed of hexadecyl 2-ethylhexanoate, liquid paraffin, and decamethylcyclopentasiloxane (66 combinations). DL-Met-R18/Si3, DL-Met-R18/Si7-8, and DL-Met-R18/Si14-15 could form gels with all these mixed solvent combinations; particularly, DL-Met-R18/Si7 8 gave rise to transparent or translucent gels. FT-IR spectra suggested that the formation of hydrogen bonds between the NH and C=O groups of the amides is one of driving forces involved in the gelation process. Aggregates comprising three dimensional networks were studied by transmission electron microscopy. Moreover, the viscoelastic behavior of the gels was investigated by rheology measurements. PMID- 29710041 TI - Synthesis, Surface Parameters, and Biodegradability of Water-soluble Surfactants for Various Applications. AB - The synthesis of water-soluble heterocyclic compounds was verified on the basis of nonionic surfactants for use as surface-active agents. Surface characteristics such as surface and interfacial tensions, cloud point, wetting time, emulsion stability, foaming height and foaming stability were measured for these surface factors in aqueous solutions. In addition, the critical micelle concentration (CMC), the surface pressure at CMC (picmc), the effectiveness of surface tension reduction (pC20), the maximum surface concentration (Gammama.) and the minimum area/molecule at the aqueous solution/air interface (Amin) were calculated. Moreover, the biodegradability for these nonionic surfactants has been investigated. Furthermore, the antimicrobial evaluation has been evaluated with some surfactants that have demonstrated a potent cytotoxicity as antibacterial, antifungal and anticancer. These surfactants have a good water solubility, low toxicity, environmentally friendly environment, high foam, good emulsifier and easy production that will be used them in various fields such as medical drugs, insecticides, detergents, emulsifiers, cosmetics, inks clothing, leather industry and oil recovery. PMID- 29710042 TI - The 1975 Type Japanese Diet Improves Lipid Metabolic Parameters in Younger Adults: A Randomized Controlled Trial. AB - In our previous study, the health benefits of the 1975 Japanese diet were shown to be the highest, since the diet suppressed visceral and liver fat accumulation, and hyperglycemia. In addition, the 1975 Japanese diet promoted maintenance of learning memory ability and a lengthened life span. However, the effect of the 1975 Japanese diet has not been ascertained in humans. In the current study, a diet with the characteristics of the 1975 Japanese diet was prepared to examine if this diet is beneficial for human health. The purpose of this randomized controlled trial was to determine effects of the 1975 Japanese diet (JD) in comparison with a modern Japanese diet (MD). Subjects aged 20~29 years old were randomly assigned to the MD (n=16) and JD (n=16) groups. Each subject consumed the diet three times a day for 28 days. Changes in physical conditions, including body composition and blood biochemistry, from before to after the study period were evaluated. As a result, body weight (p < 0.05), body fat percentage (p < 0.05), body fat mass (p < 0.05), serum triglyceride level (p < 0.05), and serum low-density lipoprotein cholesterol level (p < 0.05) were significantly decreased and serum high-density lipoprotein cholesterol (p < 0.05) and serum magnesium levels (p < 0.05) were significantly increased in JD group. These results showed that a diet with the characteristics of the 1975 Japanese diet has a beneficial effect on lipid metabolic parameters. PMID- 29710044 TI - Novel Bioactive Natural Products Isolated from Madagascar Plants and Marine Organisms (2009-2017). AB - Madagascar's rain forests and tropical dry forests are home to numerous endemic plant species and the island is considered a biodiversity hotspot. About 80% of the Madagascan (Malagasy) population relies on traditional medicines that have been proven to contain a variety of biologically active compounds. In the search for bioactive compounds from Madagascan biodiversity, we accessed and collected most of the literature dealing with the isolation, structure elucidation, and biological activities of organic small molecules originating from Madagascan plants and marine organisms. Since we published the first review of this work in 2009 (Curr. Med. Chem., 17, 2010, Hou and Harinantenaina), the present paper covers the isolation, structures, and bioactivity of 182 new secondary metabolites isolated from Malagasy higher plants and marine organisms in the last seven years (2009-2017). PMID- 29710045 TI - Antidiabetic Naphthoquinones and Their Plant Resources in Thailand. AB - Diabetes mellitus is the seventh leading cause of death globally. Ninety percent of the diabetic population suffers from type-2 diabetes, which still needs an effective, safe and economical oral hypoglycemic therapy. Plants are rich sources of various therapeutic molecules. More than 400 medicinal plants of interesting phytochemical diversity have been reported for their antidiabetic potential. Naphthoquinones are a group of phytochemicals, which have a wide range of pharmacological potential, including antidiabetic activity. Naphthoquinones exert their antidiabetic effects through various mechanisms such as the inhibition of alpha-glucosidase and protein tyrosine phosphatase 1B, increased glucose uptake in myocytes and adipocytes via glucose transporter type 4 (GLUT4) and GLUT2 translocations, enhanced peroxisome proliferator-activated receptor gamma (PPARgamma) ligand activity, and by normalizing carbohydrate metabolizing enzymes in the liver. Moreover, naphthoquinone inhibits adipogenesis by both upstream and downstream regulation to control obesity, which is one of the important risk factors for diabetes. Naturally occurring naphthoquinones, as well as their plant sources, are therefore of interest for exploring their antidiabetic potential. The present review aims to overview the antidiabetic potential of naphthoquinones and their plant resources in Thailand. PMID- 29710046 TI - New Compounds and Potential Candidates for Drug Discovery from Medicinal Plants of Vietnam. AB - The study of natural products introduces interesting new bioorganic structures and potential candidates for the drug discovery stage in the development of innovative drugs. Vietnam enjoys a broad biodiversity of native plant species, microorganisms, marine organisms, and a long tradition of using herbal remedies. Thus, the study of medicinal plants in determining the basis of their efficacy and safety is an important task for modern researchers in Vietnam. The present review covers literature on new compounds elucidated from the systematic study of medicinal plants within some popular genera in Vietnam, as well as their significant biological activities. PMID- 29710047 TI - Chemical Constituents and Bioactivities of Several Indonesian Plants Typically Used in Jamu. AB - This article reviews the chemical constituents and bioactivities of several Indonesian plants typically used in Jamu prescriptions in Indonesia. Jamu is Indonesia traditional medicine: it consists of either a single ingredient or a mixture of several medicinal plants. One plant family always used in Jamu is Zingiberaceae (ginger), such as Curcuma domestica/C. longa, C. xanthorrhizae, C. heyneana, C. zedoaria, C. aeruginosa, Zingiber aromaticum, Alpinia galanga. We also report other commonly used plant families such as Justicia gendarussa and Cassia siamea, whose activities have been extensively explored by our department. PMID- 29710048 TI - Okinawan Subtropical Plants as a Promising Resource for Novel Chemical Treasury. AB - The Okinawa Islands are a crescent-shaped archipelago and their natural forests hold a huge variety of unique subtropical plants with relatively high endemism. We have performed phytochemical study on Okinawan subtropical plants for many years. In this review, we describe our recent research progress on the isolation of new compounds and their various bioactivities. PMID- 29710049 TI - Determining the Influence of Granule Size on Simulation Parameters and Residual Shear Stress Distribution in Tablets by Combining the Finite Element Method into the Design of Experiments. AB - The influence of granule size on simulation parameters and residual shear stress in tablets was determined by combining the finite element method (FEM) into the design of experiments (DoE). Lactose granules were prepared using a wet granulation method with a high-shear mixer and sorted into small and large granules using sieves. To simulate the tableting process using the FEM, parameters simulating each granule were optimized using a DoE and a response surface method (RSM). The compaction behavior of each granule simulated by FEM was in reasonable agreement with the experimental findings. Higher coefficients of friction between powder and die/punch (MU) and lower by internal friction angle (alphay) were generated in the case of small granules, respectively. RSM revealed that die wall force was affected by alphay. On the other hand, the pressure transmissibility rate of punches value was affected not only by the alphay value, but also by MU. The FEM revealed that the residual shear stress was greater for small granules than for large granules. These results suggest that the inner structure of a tablet comprising small granules was less homogeneous than that comprising large granules. To evaluate the contribution of the simulation parameters to residual stress, these parameters were assigned to the fractional factorial design and an ANOVA was applied. The result indicated that MU was the critical factor influencing residual shear stress. This study demonstrates the importance of combining simulation and statistical analysis to gain a deeper understanding of the tableting process. PMID- 29710050 TI - Scale-Up of Lubricant Mixing Process by Using V-Type Blender Based on Discrete Element Method. AB - A method for scale-up of a lubricant mixing process in a V-type blender was proposed. Magnesium stearate was used for the lubricant, and the lubricant mixing experiment was conducted using three scales of V-type blenders (1.45, 21 and 130 L) under the same fill level and Froude (Fr) number. However, the properties of lubricated mixtures and tablets could not correspond with the mixing time or the total revolution number. To find the optimum scale-up factor, discrete element method (DEM) simulations of three scales of V-type blender mixing were conducted, and the total travel distance of particles under the different scales was calculated. The properties of the lubricated mixture and tablets obtained from the scale-up experiment were well correlated with the mixing time determined by the total travel distance. It was found that a scale-up simulation based on the travel distance of particles is valid for the lubricant mixing scale-up processes. PMID- 29710051 TI - Use of Mixer Torque Rheometer to Clarify the Relationship between the Kneading States of Wet Mass and the Dissolution of Final Product in High Shear Granulation. AB - The properties of wet mass, which indicate the progress of high shear granulation processes, usually have an effect on final product properties, such as tablet dissolution. The mixer torque rheometer (MTR) is a useful tool for quantitatively measuring the 'kneading state' of wet mass and detecting differences in granules. However, there have been no studies of the relationship between the MTR torque and the final product properties to date. In this study, we measured the MTR torque of wet granules at different kneading states, which were prepared by changing the granulation conditions. We then evaluated the relationship between the MTR torque and the dissolution rate of the final product properties. The amperage of the high shear granulator is usually monitored during granulation, but we could not detect a difference in the kneading state through the amperage. However, using MTR torque we were able to quantify the difference of the wet mass. Moreover, MTR torque showed a high correlation with dissolution, compared with the correlations with other intermediate properties, such as granules particle size and tablet hardness. These other properties are affected by following processes and are not properties that directly relate to the kneading state. Thus, MTR torque is a property of wet mass after granulation, and it can be used to directly evaluate differences of the kneading state, and as a result, dissolution. These results indicate the importance of controlling the kneading state, i.e., the progress of granulation, and the utility of MTR for detecting differences in wet mass. PMID- 29710052 TI - Synthesis of alpha-Methylene-gamma-lactone Structure by Cyclization of omega Formylallylsilane in Water. AB - Surfactant-type protonic acid-promoted intramolecular cyclization of functionalized allylsilanes was studied in water for the synthesis of alpha methylene-gamma-lactone compounds. omega-Formyl-beta-(acetoxymethyl)allylsilane afforded carbocyclic compounds in good yields, while the cyclization product was not obtained from the corresponding beta-ethoxycarbonyl derivative. It was found that (Z)-beta-(acetoxymethyl)allylsilane predominantly afforded the cis-product, while (E)-beta-(acetoxymethyl)allylsilane afforded both cis- and trans-products at a ratio of almost 1 : 1. The stereoselectivity of the cyclization reaction was almost the same as a protonic acid-promoted reaction in CH2Cl2 and was explained by an interaction between the C(Si)-C(alkene) bond and the carbonyl moiety. The cyclization products were converted to alpha-methylene-gamma-lactone compounds. PMID- 29710053 TI - Structural Development of Cell-Penetrating Peptides Containing Cationic Proline Derivatives. AB - We designed and synthesized a series of cell-penetrating peptides containing cationic proline derivatives (ProGu) that exhibited responsive changes in their secondary structures to the cellular environment. Effects of the peptide length and steric arrangement of the side chain in cationic proline derivatives [Pro4SGu and Pro4RGu] on their secondary structures and cell membrane permeability were investigated. Moreover, peptides 3 and 8 exhibited efficient intracellular delivery of plasmid DNA. PMID- 29710054 TI - Improvement of the Homogeneous Fenton Reaction for Degradation of Methylene Blue and Acid Orange II. AB - In this study, the degradation of methylene blue (MB) and acid orange II (ORII) by the Fenton reaction was improved by using HCl and HNO3. In addition, the effects of pH, temperature, concentration of Fenton's reagent, and adjustment reagent of solution pH on the decoloration were evaluated. The results showed that the optimal pH for decoloration of MB and ORII was 2.5 and that the decoloration of MB and ORII increased with higher temperature and concentration of Fenton's reagent. Moreover, the decoloration in the Fenton-reaction process with HCl and HNO3 was greater than the decoloration with H2SO4 by approximately 4.3-5.6 and 1.7-5.6 times for MB and 3.2-3.6 and 4.6-7.2 times for ORII compared to with H2SO4. These results indicated that Fenton-reaction with HCl and HNO3 could be useful for the degradation technology of dyes compared to generally Fenton-reactions. PMID- 29710055 TI - Tied Pipeline: A Case of Rare Complication. AB - A 48-year-old female with a symptomatic giant carotid cavernous aneurysm underwent endovascular treatment with multiple Pipeline Flex embolic devices (PED). The delivery catheter had to take a complicated course of multiple turns to cross the aneurysm, and its loop was tied in the aneurysm. When the catheter was to be withdrawn, it was apparent that the tied catheter had made a tight knot that bound the tail of the previous PED together. We successfully retrieved all of the system including the tied PED, and we used telescoping stents with five PEDs in the next operation. Although this is a rare complication, it is worth noting and checking to make sure that there is no knot before deploying the stent. PMID- 29710056 TI - Distribution Patterns of Spinal Epidural Fluid in Patients with Spontaneous Intracranial Hypotension Syndrome. AB - The aim of this study is to clarify the details of distribution patterns of spinal epidural fluid and to establish it as measure of spontaneous intracranial hypotension (SIH) syndrome diagnosis. Magnetic resonance imaging findings of the spine were analyzed in 37 patients, 24 women and 13 men (mean age 46.3 years), with SIH. Detection rate, thickness and patterns of the fluid collection were evaluated at every vertebral level. Follow-up spinal MRI findings were also analyzed for changes in epidural fluid collection and association with clinical symptoms. The MR images of the cervical spine were obtained in 30 patients, the thoracic spine in 36, and the lumbar spine in 17 patients. Epidural fluid collection was detected totally in 36 patients (97%) and was predominantly found at the mid-thoracic vertebrae. The fluid tended to locate dorsal to the dural sac at the thoracic spine and ventral at the cervical and lumbar spine. Patients with shorter duration of illness tended to have thicker fluid in the thoracic spine. In follow-up MRI, the findings of epidural fluid collection has disappeared in 32/36 cases within 3 months after treatment. Although residual fluid collection was found at the thoracic level in 4 cases, clinical symptoms were improved in all patients. This study suggested that the mid-thoracic spine should be chosen as the target of MRI in screening of SIH, and enlarged dorsal epidural space is strongly indicative of SIH. PMID- 29710057 TI - Efficacy of Dural Sealant System for Preventing Brain Shift and Improving Accuracy in Deep Brain Stimulation Surgery. AB - The success of deep brain stimulation (DBS) depends heavily on surgical accuracy, and brain shift is recognized as a significant factor influencing accuracy. We investigated the factors associated with surgical accuracy and showed the effectiveness of a dural sealant system for preventing brain shift in 32 consecutive cases receiving DBS. Thirty-two patients receiving DBS between March 2014 and May 2015 were included in this study. We employed conventional burr hole techniques for the first 18 cases (Group I) and a dural sealant system (DuraSeal) for the subsequent 14 cases (Group II). We measured gaps between the actual positions of electrodes and the predetermined target positions. We then retrospectively evaluated the factors involved in surgical accuracy. The average gap between an electrode's actual and target positions was 1.55 +/- 0.83 mm in all cases. Postoperative subdural air volume e, the only factor associated with surgical accuracy (r = 0.536, P < 0.0001), was significantly smaller in Group II (Group I: 43.9 +/- 27.7, Group II: 12.1 +/- 12.5 ml, P = 0.0006). The average electrode position gap was also significantly smaller in Group II (Group I: 1.77 +/- 0.91, Group II: 1.27 +/- 0.59 mm, P = 0.035). Use of a dural sealant system could significantly reduce intracranial air volume, which should improve surgical accuracy. PMID- 29710058 TI - Satisfaction of Patients With Spinal Cord Injury With Self-Care Teaching by Nurses: Is It Influenced by Learning Readiness? AB - PURPOSE: The aims of the study were to measure satisfaction of patients with a spinal cord injury (SCI) with discharge teaching by nurses and to examine the relationship between their stage of learning readiness and satisfaction. DESIGN: Quasi-experimental. METHOD: Ninety-seven patients were surveyed to determine satisfaction using the Modified Client Satisfaction Tool; nurses determined the stage of learning readiness for patients with SCI using the Olinzock Model. Satisfaction scores were analyzed with ANOVA F and chi-square tests and correlated with learning readiness stage using t tests. FINDINGS: Results showed no relationship between the stage of learning readiness and satisfaction. Patients indicated satisfaction regardless of the stage of learning readiness. Those commenting "nurses don't teach" were significantly less satisfied with self care teaching. CONCLUSION: The perception of patients with SCI of the role of the nurse as teacher influences satisfaction with discharge teaching by nurses. CLINICAL RELEVANCE: Nurses may need to consider changes in their practice to help patients realize their role as teacher. PMID- 29710059 TI - Tolerability and Product Properties of a Gum-Containing Thickener in Patients With Dysphagia. AB - PURPOSE: The aim of the study was to determine the gastrointestinal (GI) tolerability of drinks and foods thickened with a gum-containing thickener compared to a starch-based thickener in patients with dysphagia. DESIGN: A randomized, double-blind, controlled, parallel group study. METHODS: Subjects started with a 3-day run-in period on a starch-based thickener and continued with a 14-day intervention on either the starch-based or gum-containing thickener. GI tolerance parameters were recorded at baseline and for three consecutive days in both weeks. Product properties were studied using a feedback questionnaire from carers. FINDINGS: Incidence and intensity of GI symptoms was low and not significantly different between groups. Carers indicated that starch-thickened drinks became significantly thinner with time compared to gum-containing thickened drinks (p = .029). CONCLUSIONS AND CLINICAL RELEVANCE: No differences in GI tolerance parameters between groups were observed. We hypothesize that use of the gum-containing thickener is preferred to a starch-based thickener due to the stability of its viscosity during consumption. PMID- 29710060 TI - Effect of the 5A Model on Clinical Status Indexes of COPD Patients. AB - PURPOSE: This RCT study investigates the effects of a self-management program on clinical status indexes of COPD patients. DESIGN: In this study, 50 COPD patients referred to the respiratory clinic participated. METHODS: Patients were randomly assigned to control and intervention groups. The control group received standard care, and the intervention group received standard care plus the self-management program. Patients were assessed by spirometry, Modified Borg scale, and 6-minute walking test at the baseline and the end of 12-weeks. Paired t-test, independent t-test, and chi-square were used to analyze variables. FINDINGS: No significant difference was noted in the spirometry indexes mean in the two groups; however, significant differences were noted in dyspnea and exercise tolerance at the end. CONCLUSION/CLINICAL RELEVANCE: Using the 5A model can lead to increased exercise tolerance and decreased dyspnea in COPD patients. Therefore, this self-management program is recommended as an effective way to improve their functional status. PMID- 29710062 TI - Effects of a Home-Based Resistance Exercise in Chinese Individuals Living With Physical Disability: Resistance Exercise on PWPD. AB - PURPOSE: The purpose of this study was to explore the effect of a home-based resistance exercise program for people living with physical disability. DESIGN: A quasiexperimental study. METHOD: Forty participants enrolled, and 24 completed the 12-week study with 13 in the intervention group and 11 in the control group. Outcomes were measured by pretests and posttests, including Six-Minute Walk Test, Five Times Sit-to-Stand Test, 10-Meter Walk Test, Timed Up and Go, One Repetition Maximum, World Health Organization Disability Assessment Schedule 2.0, and Self administered Short Form Health Survey. FINDINGS: Outcomes of participants within intervention group improved significantly after the training. CONCLUSIONS: This home-based resistance exercise demonstrated impact on improving the functioning of the participants. CLINICAL RELEVANCE: A well-developed home-based resistance exercise for people with disability will improve their physical functioning. The trainers for the home-based program should have frequent interaction with the group to determine how to improve the outcome of physical abilities. Community health nurses could be taught how to conduct resistance exercise so that it will become routine care in the community health centers for people with disability. PMID- 29710061 TI - People Living With HIV: Implications for Rehabilitation Nurses. AB - PURPOSE: The aim of this study was to present a brief overview of challenges faced by people living with HIV (PLHIV) as they age, to discuss the relevance of HIV to rehabilitation nurses, and to provide evidence-based recommendations for rehabilitation professionals working with PLHIV. DESIGN: Current issues article. METHODS: Literature review related to age-related comorbidities in PLHIV with implications for rehabilitation nurses. FINDINGS: Rehabilitation nurses must be prepared to address issues specific to people living with HIV including sensitivity and privacy regarding HIV status and increased risk of delayed or complicated healing. Rehabilitation nurses should also promote self-management behavior to optimize health in people living with HIV. CONCLUSIONS: Understanding unique characteristics of PLHIV as well as applying focused assessment and tailored interventions in PLHIV will give rehabilitation nurses the tools to successfully guide PLHIV through the rehabilitation process and optimize clinical outcomes. CLINICAL RELEVANCE: As people with HIV age and experience acute and chronic comorbidities, they will require the clinical expertise of rehabilitation nurses in the process to successfully transition through acute and subacute health care and regain function. PMID- 29710064 TI - Announcing the Teachable Moment Editorial Fellowship. PMID- 29710063 TI - R Package for Pediatric Complex Chronic Condition Classification. PMID- 29710065 TI - The Need for Closed-Loop Systems for Management of Abnormal Test Results. PMID- 29710066 TI - Suggestions for Improving Conflict of Interest Processes in the US Food and Drug Administration Advisory Committees-Past Imperfect. PMID- 29710067 TI - The Power of Trust. PMID- 29710069 TI - Will Posting Nutritional Information on Menus Prod Diners to Make Healthier Choices? PMID- 29710068 TI - Association of Prehospital Advanced Life Support by Physician With Survival After Out-of-Hospital Cardiac Arrest With Blunt Trauma Following Traffic Collisions: Japanese Registry-Based Study. AB - Importance: Controversy remains as to whether advanced life support (ALS) or basic life support (BLS) is superior for critically ill and injured patients, including out-of-hospital cardiac arrest (OHCA) and major trauma, in the prehospital setting. Objective: To assess whether prehospital ALS should be provided for traumatic OHCA and who should perform it. Design, Setting, and Participants: Japanese government-managed nationwide population-based registry data of patients with OHCA transported to an emergency hospital were analyzed. Patients who experienced traumatic OHCA following a traffic collision from 2013 to 2014 were included. Patients provided prehospital ALS by a physician were compared with both patients provided ALS by emergency medical service (EMS) personnel and patients with only BLS. The data were analyzed on May 1, 2017. Exposures: Advanced life support by physician, ALS by EMS personnel, or BLS only. Main Outcomes and Measures: The primary outcome was 1-month survival. The secondary outcomes were prehospital return of spontaneous circulation and favorable neurologic outcomes with the Glasgow-Pittsburgh cerebral performance category score of 1 or 2. Results: A total of 4382 patients were included (mean [SD] age, 57.5 [22.2] years; 67.9% male); 828 (18.9%) received prehospital ALS by physician, 1591 (36.3%) received prehospital ALS by EMS personnel, and 1963 (44.8%) received BLS only. Among these patients, 96 (2.2%) survived 1 month after OHCA, including 26 of 828 (3.1%) for ALS by physician, 25 of 1591 (1.6%) for ALS by EMS personnel, and 45 of 1963 (2.3%) for BLS. After adjusting for potential confounders using multivariable logistic regression, ALS by physician was significantly associated with higher odds for 1-month survival compared with both ALS by EMS personnel and BLS (adjusted OR, 2.13; 95% CI, 1.20-3.78; and adjusted OR, 1.94; 95% CI, 1.14-3.25; respectively), whereas there was no significant difference between ALS by EMS personnel and BLS (adjusted OR, 0.91; 95% CI, 0.54 1.51). A propensity score-matched analysis in the ALS cohort showed that ALS by physician was associated with increased chance of 1-month survival compared with ALS by EMS personnel (risk ratio, 2.00; 95% CI, 1.01-3.97; P = .04). This association was consistent across a variety of sensitivity analyses. Conclusions and Relevance: In traumatic OHCA, ALS by physician was associated with increased chance of 1-month survival compared with both ALS by EMS personnel and BLS. PMID- 29710070 TI - Malignant Abnormalities in Male BRCA Mutation Carriers: Results From a Prospectively Screened Cohort. PMID- 29710072 TI - Treating Blood Pressure Correctly by Measuring It Correctly. PMID- 29710071 TI - Age Profile of Patients With Oropharyngeal Squamous Cell Carcinoma. PMID- 29710073 TI - Early Weight Gain in Pregnancy and Infant Birth Weight: May Early Blood Glucose Level Play a Role? PMID- 29710075 TI - Effect of Perioperative Gabapentin Use on Postsurgical Pain in Patients Undergoing Head and Neck Mucosal Surgery: A Randomized Clinical Trial. AB - Importance: Effective postoperative pain management increases patient satisfaction, reduces cost, reduces morbidity, and shortens hospitalizations. Previous studies investigating multimodal pain therapy in otolaryngology patients focused on homogenous patient groups with short postoperative follow-up times. Objective: To investigate the effect of perioperative gabapentin treatment on postsurgical pain in patients undergoing head and neck mucosal surgery. Design, Setting, and Participants: Adults undergoing head and neck mucosal surgery from July 25, 2016, through June 19, 2017, were included in this double-blinded, placebo-controlled randomized clinical trial and randomized to receive gabapentin, 300 mg twice daily, or placebo before surgery and up to 72 hours after surgery. Main Outcomes and Measures: Primary outcome was hourly narcotic use calculated in morphine equivalents. Secondary outcomes included subjective visual analog scale pain scores captured for resting, coughing, and swallowing using a 0- to 100-mm scale (a 100-mm line anchored with no pain on the left end and worst possible pain on the right end). A change of 10 mm or more was deemed to be clinically meaningful. Additional secondary outcome measures included degree of pain control, patient satisfaction, and adverse effects. Results: Of the 110 patients randomized to receive gabapentin or placebo, 11 and 10 withdrew from each group, respectively. Ninety patients were then analyzed: 44 in the gabapentin group (mean [SD] age, 61.1 [10.0] years; 33 [75%] male; 40 [91%] white) and 46 in the placebo group (mean [SD] age, 60.9 [11.3] years; 35 [78%] male; 43 [94%] white). Both groups had similar self-reported levels of preoperative pain and narcotic effectiveness. A median difference of 0.26 mg/h of morphine (95% CI, -0.27 to 0.94 mg/h) was found between groups. After controlling for comorbidity and self-reported baseline pain levels, mixed model analysis found the difference in marginal means of visual analog scale scores between groups to be lower in the gabapentin group compared with the placebo group for all categories (rest difference, 7.9 mm; 95% CI, -0.4 to 16.2 mm; cough difference, 8.9 mm; 95% CI, -0.5 to 18.3 mm; swallow difference, 9.4 mm; 95% CI, 1.2 to 20.0 mm). More patients in the gabapentin group reported that pain was always well controlled than in the placebo group (difference, 9.2%; 95% CI, -21% to 3%). Gabapentin and placebo groups reported similar levels of satisfaction with pain control (difference, 2%; 95% CI, -11% to 15%). There was no clinically meaningful difference in reported nausea between the 2 groups (difference, 6%; 95% CI, -14% to 26%). Conclusion and Relevance: Perioperative gabapentin given 300 mg twice daily did not result in reduced narcotic use, but results were compatible with clinically meaningful reductions in pain scores. Satisfaction with pain control and adverse effects were similar between groups. Trial Registration: ClinicalTrials.gov Identifier: NCT02926573. PMID- 29710076 TI - What's Next (Generation) for the Diagnosis of Chronic Meningitis? PMID- 29710074 TI - Association of Cannabis With Cognitive Functioning in Adolescents and Young Adults: A Systematic Review and Meta-analysis. AB - Importance: Substantial shifts in perception and policy regarding cannabis have recently occurred, with use of cannabis increasing while its perceived harm decreases. One possible risk of increased cannabis use is poorer cognitive functioning, especially in youth. Objective: To provide the first quantitative synthesis of the literature examining cannabis and cognitive functioning in adolescents and young adults (with a mean age of 26 years and younger). Data Sources: PubMed, PsycInfo, Academic Search Premier, Scopus, and bibliographies of relevant reviews were searched for peer-reviewed, English-language studies from the date the databases began through May 2017. Study Selection: Consensus criteria were used to determine study inclusion through abstract and manuscript review. Data Extraction and Synthesis: This study followed Meta-analysis of Observational Studies in Epidemiology guidelines. Effect size estimates were calculated using multivariate mixed-effects models for cognitive functioning outcomes classified into 10 domains. Main Outcomes and Measures: Results from neurocognitive tests administered in cross-sectional studies were primary outcomes, and we examined the influence of a priori explanatory variables on variability in effect size. Results: Sixty-nine studies of 2152 cannabis users (mean [SD] age, 20.6 [2.8] years; 1472 [68.4%] male) and 6575 comparison participants with minimal cannabis exposure were included (mean [SD] age, 20.8 [3.4]; 3669 [55.8%] male). Results indicated a small overall effect size (presented as mean d) for reduced cognitive functioning associated with frequent or heavy cannabis use (d, -0.25; 95% CI, -0.32 to -0.17; P < .001). The magnitude of effect sizes did not vary by sample age or age at cannabis use onset. However, studies requiring an abstinence period longer than 72 hours (15 studies; n = 928) had an overall effect size (d, -0.08; 95% CI, -0.22 to 0.07) that was not significantly different from 0 and smaller than studies with less stringent abstinence criteria (54 studies; n = 7799; d, -0.30; 95% CI, -0.37 to -0.22; P = .01). Conclusions and Relevance: Associations between cannabis use and cognitive functioning in cross-sectional studies of adolescents and young adults are small and may be of questionable clinical importance for most individuals. Furthermore, abstinence of longer than 72 hours diminishes cognitive deficits associated with cannabis use. Although other outcomes (eg, psychosis) were not examined in the included studies, results indicate that previous studies of cannabis in youth may have overstated the magnitude and persistence of cognitive deficits associated with use. Reported deficits may reflect residual effects from acute use or withdrawal. Future studies should examine individual differences in susceptibility to cannabis-associated cognitive dysfunction. PMID- 29710077 TI - Expression of Concern: "First Foods Most: After 18-Hour Fast, People Drawn to Starches First and Vegetables Last," "Hungry Grocery Shoppers Buy More Calories, Not More Food," and "Watch What You Eat: Action-Related Television Content Increases Food Intake" by Brian Wansink. PMID- 29710078 TI - Harry Potter, Magic, and Medicine. PMID- 29710079 TI - Neurobiology of Opioid Use Disorder and Comorbid Traumatic Brain Injury. AB - Importance: Treating patients with opioid use disorder (OUD) and traumatic brain injury illustrates 6 neurobiological principles about the actions of 2 contrasting opioid analgesics, morphine and fentanyl, as well as pharmacotherapies for OUD, methadone, naltrexone, and buprenorphine. Observations: This literature review focused on a patient with traumatic brain injury who developed OUD from chronic morphine analgesia. His treatment is described in a neurobiological framework of 6 opioid action principles. Conclusions and Relevance: The 6 principles are (1) coactivation of neuronal and inflammatory immune receptors (Toll-like receptor 4), (2) 1 receptor activating cyclic adenosine monophosphate and beta-arrestin second messenger systems, (3) convergence of opioid and adrenergic receptor types on 1 second messenger, (4) antagonist (eg, naltrexone)-induced receptor trafficking, (5) genetic MU-opioid receptor variants influencing analgesia and tolerance, and (6) cross-tolerance vs receptor antagonism as the basis of OUD pharmacotherapy with methadone or buprenorphine vs naltrexone. PMID- 29710080 TI - Gene Expression Profiling in HPV-Positive p16-Positive Oropharyngeal Squamous Cell Carcinomas: A Path to Deintensification? PMID- 29710081 TI - Spontaneous Hyphema in a Middle-aged Woman. PMID- 29710082 TI - Accuracy of Skin Cancer Diagnosis by Physician Assistants Compared With Dermatologists in a Large Health Care System. AB - Importance: Physician assistants (PAs) are increasingly used in dermatology practices to diagnose skin cancers, although, to date, their diagnostic accuracy compared with board-certified dermatologists has not been well studied. Objective: To compare diagnostic accuracy for skin cancer of PAs with that of dermatologists. Design, Setting, and Participants: Medical record review of 33 647 skin cancer screening examinations in 20 270 unique patients who underwent screening at University of Pittsburgh Medical Center-affiliated dermatology offices from January 1, 2011, to December 31, 2015. International Classification of Diseases, Ninth Revision code V76.43 and International Classification of Diseases and Related Health Problems, Tenth Revision code Z12.83 were used to identify pathology reports from skin cancer screening examinations by dermatologists and PAs. Exposure: Examination performed by a PA or dermatologist. Main Outcomes and Measures: Number needed to biopsy (NNB) to diagnose skin cancer (nonmelanoma, invasive melanoma, or in situ melanoma). Results: Of 20 270 unique patients, 12 722 (62.8%) were female, mean (SD) age at the first visit was 52.7 (17.4) years, and 19 515 patients (96.3%) self-reported their race/ethnicity as non-Hispanic white. To diagnose 1 case of skin cancer, the NNB was 3.9 for PAs and 3.3 for dermatologists (P < .001). Per diagnosed melanoma, the NNB was 39.4 for PAs and 25.4 for dermatologists (P = .007). Patients screened by a PA were significantly less likely than those screened by a dermatologist to be diagnosed with melanoma in situ (1.1% vs 1.8% of visits, P = .02), but differences were not significant for invasive melanoma (0.7% vs 0.8% of visits, P = .83) or nonmelanoma skin cancer (6.1% vs 6.1% of visits, P = .98). Conclusions and Relevance: Compared with dermatologists, PAs performed more skin biopsies per case of skin cancer diagnosed and diagnosed fewer melanomas in situ, suggesting that the diagnostic accuracy of PAs may be lower than that of dermatologists. Although the availability of PAs may help increase access to care and reduce waiting times for appointments, these findings have important implications for the training, appropriate scope of practice, and supervision of PAs and other nonphysician practitioners in dermatology. PMID- 29710083 TI - Publication and Dissemination of Results in Clinical Trials of Neurology. PMID- 29710084 TI - National Distribution of Cancer Genetic Testing in the United States: Evidence for a Gender Disparity in Hereditary Breast and Ovarian Cancer. PMID- 29710085 TI - The American College of Physicians Is Working Hard to Achieve Gender Equity, and Everyone Will Benefit. PMID- 29710086 TI - Physician Prescribing of Opioids to Patients at Increased Risk of Overdose From Benzodiazepine Use in the United States. AB - Importance: Recent increases in US opioid-related deaths underscore the need to understand drivers of fatal overdose. The initial prescription of opioids represents a critical juncture because it increases the risk of future opioid use disorder and is preventable. Objective: To examine new opioid prescribing patterns in US patients at increased risk of overdose from benzodiazepine use. Design, Setting, and Participants: This study used publicly available data from the National Ambulatory Medical Care Survey and National Hospital Ambulatory Medical Care Survey from January 1, 2005, through December 31, 2015, to identify adults 20 years or older receiving new opioid prescriptions and concurrently using a benzodiazepine. Main Outcomes and Measures: Population-based rates of new opioid prescriptions stratified by use of benzodiazepines. Results: This study analyzed 13 146 visits, representing 214 million visits nationally, with a new opioid prescription. Rates of new opioid prescriptions among adults using a benzodiazepine increased from 189 to 351 per 1000 persons between 2005 and 2010 (rate difference, 162; 95% CI, 29-295; P = .02) and decreased to 172 per 1000 persons by 2015 (rate difference, -179; 95% CI, -310 to -48; P = .008). New opioid prescriptions in the general population not using benzodiazepines increased nonsignificantly from 78 to 93 per 1000 US persons between 2005 and 2010 (rate difference, 15; 95% CI, -3 to 33; P = .10) and decreased nonsignificantly to 79 per 1000 persons by 2015 (rate difference, -14; 95% CI, 38 to 11; P = .28). The likelihood of receiving a new opioid prescription during an ambulatory visit remained higher for patients concurrently using benzodiazepines compared with the general population after adjusting for demographic characteristics, comorbidities, and diagnoses associated with pain (adjusted relative risk, 1.83; 95% CI, 1.56-2.15; P < .001). Naloxone was coprescribed in less than 1% of visits when a patient concurrently used a benzodiazepine. Conclusions and Relevance: In 2010, new opioid prescriptions for US adults stopped increasing and began to decrease among higher-risk patients who used benzodiazepines. These patterns suggest that the recent increase in opioid related deaths may be associated with factors other than physicians writing new opioid prescriptions. Nevertheless, prescribing among higher-risk patients still occurred at rates higher than rates in the general population, representing an important opportunity to improve quality of care for patients experiencing pain. PMID- 29710087 TI - Methods for Evaluating Natural Experiments in Obesity: A Systematic Review. AB - Background: Given the obesity pandemic, rigorous methodological approaches, including natural experiments, are needed. Purpose: To identify studies that report effects of programs, policies, or built environment changes on obesity prevention and control and to describe their methods. Data Sources: PubMed, CINAHL, PsycINFO, and EconLit (January 2000 to August 2017). Study Selection: Natural experiments and experimental studies evaluating a program, policy, or built environment change in U.S. or non-U.S. populations by using measures of obesity or obesity-related health behaviors. Data Extraction: 2 reviewers serially extracted data on study design, population characteristics, data sources and linkages, measures, and analytic methods and independently evaluated risk of bias. Data Synthesis: 294 studies (188 U.S., 106 non-U.S.) were identified, including 156 natural experiments (53%), 118 experimental studies (40%), and 20 (7%) with unclear study design. Studies used 106 (71 U.S., 35 non-U.S.) data systems; 37% of the U.S. data systems were linked to another data source. For outcomes, 112 studies reported childhood weight and 32 adult weight; 152 had physical activity and 148 had dietary measures. For analysis, natural experiments most commonly used cross-sectional comparisons of exposed and unexposed groups (n = 55 [35%]). Most natural experiments had a high risk of bias, and 63% had weak handling of withdrawals and dropouts. Limitation: Outcomes restricted to obesity measures and health behaviors; inconsistent or unclear descriptions of natural experiment designs; and imperfect methods for assessing risk of bias in natural experiments. Conclusion: Many methodologically diverse natural experiments and experimental studies were identified that reported effects of U.S. and non-U.S. programs, policies, or built environment changes on obesity prevention and control. The findings reinforce the need for methodological and analytic advances that would strengthen evaluations of obesity prevention and control initiatives. Primary Funding Source: National Institutes of Health, Office of Disease Prevention, and Agency for Healthcare Research and Quality. (PROSPERO: CRD42017055750). PMID- 29710088 TI - Safety of Osteopathic Cranial Manipulative Medicine as an Adjunct to Conventional Postconcussion Symptom Management: A Pilot Study. AB - Context: Osteopathic cranial manipulative medicine is not a well-established adjunct to conventional treatment for patients with postconcussion symptoms. Objective: To determine whether adjunctive osteopathic cranial manipulative medicine is safe for patients with concussion when accompanied by conventional treatments. Design: Prospective observational pilot study. Setting: Outpatient concussion clinic. Participants: Patients who sustained a concussion were prospectively recruited from an outpatient concussion clinic by a neuropsychologist specialized in concussion. All participants were identified to have a cranial dysfunction. Intervention: Each eligible participant received 1 session of the osteopathic cranial manipulative medicine vault hold technique. Main Outcome Measures: Self-reported adverse events during or after 1 session of the osteopathic cranial manipulative medicine procedure and improvement in concussion symptoms at return to follow-up. Results: None of the 9 participants reported adverse events during or immediately after receiving osteopathic cranial manipulative medicine. Five of the 7 participants who returned for follow-up demonstrated improvement in their overall concussion symptoms based on the Post Concussion Symptom Scale scores. Conclusions: Osteopathic cranial manipulative medicine was considered a safe adjunctive treatment option to improve concussion related symptoms and recovery. PMID- 29710089 TI - Making the Case for Importance of Health Literacy in the Surgical Population. PMID- 29710090 TI - Is There Validity in Propensity Score-Matched Estimates of Adjuvant Chemotherapy Effects for Patients With Rectal Cancer? PMID- 29710091 TI - Integrated Inpatient Medical and Psychiatric Care: Experiences of 5 Institutions. PMID- 29710092 TI - Evolution of Left Ventricular Assist Device Therapy for Advanced Heart Failure: A Review. AB - Importance: The mortality rate for the most advanced forms of heart failure with medical therapy alone remains unacceptably high at 30% to 80% at 1 year. In the past decade, left ventricular assist devices have assumed an increasingly prominent role in the management of these patients. This review included all English-language articles published over the past 15 years on left ventricular assist devices. Search topics focused on advanced heart failure and ventricular assist devices, including volume of implantations, patient selection, complications, cost, and recovery of function. The search also included all published clinical trials or reports of cohort studies as well as registry data. Observations: There has been significant progress in nearly all aspects of left ventricular assist device therapy, from patient selection to device design and postoperative management. Percutaneous devices have been developed to facilitate rapid deployment and provide short-term hemodynamic support. The devices have transitioned from pulsatile to continuous flow design and are now smaller, with enhanced durability more suited for long-term support. The mean survival following left ventricular assist device implantation is nearly 5 years. However, some complications, including bleeding, infection, pump thrombosis, and stroke, limit the potential of the therapy. There are many innovations now under investigation that promise to further improve outcomes and enhance patient satisfaction. Conclusions and Relevance: Advanced or end-stage heart failure remains a major health care problem in terms of both patient morbidity and mortality as well as cost. Physicians and health care professionals need to become aware of the significant progress in the field of mechanical support of circulation with the use of ventricular assist devices. PMID- 29710093 TI - Comparison of Rates of Firearm and Nonfirearm Homicide and Suicide in Black and White Non-Hispanic Men, by U.S. State. AB - Background: The extent to which differences in homicide and suicide rates in black versus white men vary by U.S. state is unknown. Objective: To compare the rates of firearm and nonfirearm homicide and suicide in black and white non Hispanic men by U.S. state and to examine whether these deaths are associated with state prevalence of gun ownership. Design: Surveillance study. Setting: 50 states and the District of Columbia, 2008 to 2016. Cause-of-death data were abstracted by using the Centers for Disease Control and Prevention's WONDER (Wide ranging Online Data for Epidemiologic Research) database. Participants: Non Hispanic black and non-Hispanic white males, all ages. Measurements: Absolute rates of and rate differences in firearm and nonfirearm homicide and suicide in black and white men. Results: During the 9-year study period, 84 113 homicides and 251 772 suicides occurred. Black-white differences in rates of firearm homicide and suicide varied widely across states. Relative to white men, black men had between 9 and 57 additional firearm homicides per 100 000 per year, with black men in Missouri, Michigan, Illinois, Indiana, and Pennsylvania having more than 40 additional firearm homicides per 100 000 per year. White men had between 2 fewer and 16 more firearm suicides per 100 000 per year, with the largest inequalities observed in southern and western states and the smallest in the District of Columbia and densely populated northeastern states. Limitations: Some homicides and suicides may have been misclassified as deaths due to unintentional injury. Survey data on state household gun ownership were collected in 2004 and may have shifted during the past decade. Conclusion: The large state-to-state variation in firearm homicide and suicide rates, as well as the racial inequalities in these numbers, highlights states where policies may be most beneficial in reducing homicide and suicide deaths and the racial disparities in their rates. Primary Funding Source: McGill University and the National Institutes of Health. PMID- 29710094 TI - Employment of Advanced Practice Clinicians in Physician Practices. PMID- 29710095 TI - Evolving Payer Coverage Policies on Genomic Sequencing Tests: Beginning of the End or End of the Beginning? PMID- 29710096 TI - Factors Contributing to Preschoolers' Communicative Participation Outcomes: Findings From a Population-Based Longitudinal Cohort Study in Ontario, Canada. AB - Purpose: The aim of this study was to identify predictors of communicative participation outcomes for a large cohort of preschoolers with speech and language impairments. Method: A secondary analysis of longitudinal program evaluation data from Ontario, Canada's Preschool Speech and Language Program was done. Data available for 46,872 children 18-67 months of age (M = 41.76 months, SD = 11.92; 68% boys, 32% girls) were previously used to predict children's communicative participation skill development in 5 levels of function. Demographic and intervention-based variables were added to the models to identify new predictors of growth. Results: Three demographic and 3 intervention-based variables were statistically significant predictors of children's communicative participation outcomes. Clinically significant predictors included participation in an early learning environment, receipt of speech-language interventions, and the amount of time spent in intervention. These variables impacted predicted outcomes differently, depending on a child's level of communicative function. Conclusions: This population-based study of preschoolers with speech and language impairments identified predictors of growth in communicative participation skills an outcome important and meaningful to families but not often explored. A broad picture emerged of factors that may influence the development of communicative participation skills and may be used to predict outcomes for preschoolers. Given the large sample size, these robust findings may be used to predict outcomes outside the Preschool Speech and Language Program as well. Supplemental Material: https://doi.org/10.23641/asha.6024422. PMID- 29710098 TI - Machine Learning and Evidence-Based Medicine. PMID- 29710097 TI - Effectiveness of Universal Self-regulation-Based Interventions in Children and Adolescents: A Systematic Review and Meta-analysis. AB - Importance: Childhood and adolescence self-regulation (SR) is gaining importance as a target of intervention because of mounting evidence of its positive associations with health, social and educational outcomes. Objective: To conduct a systematic review and meta-analysis of rigorously evaluated interventions to improve self-regulation in children and adolescents. Data Sources: Keyword searches of the PsycINFO, PubMed, EMBASE, CINAHL Plus, ERIC, British Education Index, Child Development and Adolescent Studies, and CENTRAL were used to identify all studies published through July 2016. Study Selection: To be eligible for this review, studies had to report cluster randomized trials or randomized clinical trials, evaluate universal interventions designed to improve self regulation in children and adolescents aged 0 to 19 years, include outcomes associated with self-regulation skills, and be published in a peer-reviewed journal with the full text available in English. Data Extraction and Synthesis: A total of 14 369 published records were screened, of which 147 were identified for full-text review and 49 studies reporting 50 interventions were included in the final review. Results were summarized by narrative review and meta-analysis. Main Outcomes and Measures: Self-regulation outcomes in children and adolescents. Results: This review identified 17 cluster randomized trials and 32 randomized clinical trials evaluating self-regulation interventions, which included a total of 23 098 participants ranging in age from 2 to 17 years (median age, 6.0 years). Consistent improvement in self-regulation was reported in 16 of 21 curriculum based interventions (76%), 4 of the 8 mindfulness and yoga interventions (50%), 5 of 9 family-based programs (56%), 4 of 6 exercise-based programs (67%), and 4 of 6 social and personal skills interventions (67%), or a total of 33 of 50 interventions (66%). A meta-analysis evaluating associations of interventions with self-regulation task performance scores showed a positive effect of such interventions with pooled effect size of 0.42 (95% CI, 0.32-0.53). Only 24 studies reported data on distal outcomes (29 outcomes). Positive associations were reported in 11 of 13 studies (85%) on academic achievement, 4 of 5 studies on substance abuse (80%), and in all studies reporting on conduct disorders (n = 3), studies on social skills (n = 2), studies on depression (n = 2), studies on behavioral problems (n = 2), and study on school suspensions (n = 1). No effect was seen on 2 studies reporting on academic achievement, 1 study reporting on substance abuse, and 1 additional study reporting on psychological well-being. Conclusions and Relevance: A wide range of interventions were successful in improving self-regulation in children and adolescents. There was improvement in distal academic, health, and behavioral outcomes in most intervention groups compared with controls. PMID- 29710100 TI - Achieving Gender Equity in Physician Compensation and Career Advancement: A Position Paper of the American College of Physicians. AB - Women comprise more than one third of the active physician workforce, an estimated 46% of all physicians-in-training, and more than half of all medical students in the United States. Although progress has been made toward gender diversity in the physician workforce, disparities in compensation exist and inequities have contributed to a disproportionately low number of female physicians achieving academic advancement and serving in leadership positions. Women in medicine face other challenges, including a lack of mentors, discrimination, gender bias, cultural environment of the workplace, imposter syndrome, and the need for better work-life integration. In this position paper, the American College of Physicians summarizes the unique challenges female physicians face over the course of their careers and provides recommendations to improve gender equity and ensure that the full potential of female physicians is realized. PMID- 29710099 TI - Effect of Pain Neuroscience Education Combined With Cognition-Targeted Motor Control Training on Chronic Spinal Pain: A Randomized Clinical Trial. AB - Importance: Effective treatments for chronic spinal pain are essential to reduce the related high personal and socioeconomic costs. Objective: To compare pain neuroscience education combined with cognition-targeted motor control training with current best-evidence physiotherapy for reducing pain and improving functionality, gray matter morphologic features, and pain cognitions in individuals with chronic spinal pain. Design, Setting, and Participants: Multicenter randomized clinical trial conducted from January 1, 2014, to January 30, 2017, among 120 patients with chronic nonspecific spinal pain in 2 outpatient hospitals with follow-up at 3, 6, and 12 months. Interventions: Participants were randomized into an experimental group (combined pain neuroscience education and cognition-targeted motor control training) and a control group (combining education on back and neck pain and general exercise therapy). Main Outcomes and Measures: Primary outcomes were pain (pressure pain thresholds, numeric rating scale, and central sensitization inventory) and function (pain disability index and mental health and physical health). Results: There were 22 men and 38 women in the experimental group (mean [SD] age, 39.9 [12.0] years) and 25 men and 35 women in the control group (mean [SD] age, 40.5 [12.9] years). Participants in the experimental group experienced reduced pain (small to medium effect sizes): higher pressure pain thresholds at primary test site at 3 months (estimated marginal [EM] mean, 0.971; 95% CI, -0.028 to 1.970) and reduced central sensitization inventory scores at 6 months (EM mean, -5.684; 95% CI, -10.589 to 0.780) and 12 months (EM mean, -6.053; 95% CI, -10.781 to -1.324). They also experienced improved function (small to medium effect sizes): significant and clinically relevant reduction of disability at 3 months (EM mean, -5.113; 95% CI, -9.994 to -0.232), 6 months (EM mean, -6.351; 95% CI, -11.153 to -1.550), and 12 months (EM mean, -5.779; 95% CI, -10.340 to -1.217); better mental health at 6 months (EM mean, 36.496; 95% CI, 7.998-64.995); and better physical health at 3 months (EM mean, 39.263; 95% CI, 9.644-66.882), 6 months (EM mean, 53.007; 95% CI, 23.805-82.209), and 12 months (EM mean, 32.208; 95% CI, 2.402-62.014). Conclusions and Relevance: Pain neuroscience education combined with cognition targeted motor control training appears to be more effective than current best evidence physiotherapy for improving pain, symptoms of central sensitization, disability, mental and physical functioning, and pain cognitions in individuals with chronic spinal pain. Significant clinical improvements without detectable changes in brain gray matter morphologic features calls into question the relevance of brain gray matter alterations in this population. Trial Registration: clinicaltrials.gov Identifier: NCT02098005. PMID- 29710101 TI - The Return of Duck and Cover and the Imminence of Death-What It Means for Physicians. PMID- 29710102 TI - Association of T and B Cells Infiltrating Orbital Tissues With Clinical Features of Graves Orbitopathy. AB - Importance: Graves orbitopathy (GO) responds to immunosuppressive treatments when clinically active but poorly when inactive. In other autoimmune diseases, response has been ascribed to a reduction in lymphocytes infiltrating the target organ. It is not known whether active vs inactive GO differs in this regard, which would help in understanding the link between GO immunologic features and clinical behavior. Objective: To investigate the association between orbital lymphocytic infiltrate and GO clinical features. Design, Setting, and Participants: A cohort study aimed at assessing the extent and immunohistochemical phenotype of orbital lymphocytes and associating it with the ophthalmologic features of GO, especially its clinical activity score (CAS), was conducted at a tertiary referral center. Twenty consecutive patients with GO who underwent orbital decompression were included. The study was conducted from January 1 to May 31, 2017. Exposures: Orbital tissue histology and immunohistochemistry testing as well as ophthalmologic evaluation. Main Outcomes and Measures: Association between CAS and orbital lymphocytes, analyzed as total number of lymphocytes and main lymphoid subsets. Results: The patient population included 8 men and 12 women, all of white race, with a mean (SD) age of 46 (13) years. With an established cutoff value of 300 lymphoid cells per tissue sample, lymphocytes above this value were found in orbital tissues of 9 of 20 patients (45%), often organized into distinct foci. The lymphocytes comprised a mixture of T (CD3-positive) and B (CD20-positive) cells, suggesting a mature, polyclonal autoimmune response. In a simple linear regression model, the total number of lymphocytes, as well as the number of CD3- and CD20-positive subsets, correlated with CAS (R = 0.63; 95% CI, 0.27-0.84; P = .003; R = 0.59; 95% CI, 0.20-0.82; P = .006; and R = 0.65; 95% CI, 0.30-0.85; P = .002, respectively). In a multiple linear regression model, lymphocytes maintained their effect on CAS when adjusted for 2 additional variables that were correlated with CAS-smoking and GO duration highlighting even more the important role of orbital lymphocytes in affecting CAS (total number: R = 0.58; 95% CI, 0.18-0.82; P = .01; CD3-positive: R = 0.58; 95% CI, 0.17-0.82; P = .01; and CD20-positive: R = 0.59; 95% CI, 0.19-0.83; P = .01). Conclusions and Relevance: This study shows a correlation between T and B lymphocytes infiltrating orbital tissues and the activity of GO, possibly enhancing our understanding of the association between GO immunologic features and clinical expression. PMID- 29710103 TI - Association of Mentor-to-Program Contact and Applicant Rank Disclosure With Vitreoretinal Fellowship Applicant's Final Match Outcome in 2016 and 2017. AB - Importance: Communication between applicants, mentors, and training programs is common before the residency and fellowship match. Few studies have examined the association of prematch communication on final match outcomes. Objectives: To report various characteristics of the vitreoretinal surgery fellowship match and to examine the association of mentor-to-program communication and applicant disclosure of their number 1 ranking with the probability of matching number 1. Design, Setting, and Participants: In this cross-sectional study of the 2016 and 2017 vitreoretinal surgery fellowship matches, an online survey examined (1) number of applications submitted, (2) number of programs ranked, (3) rank order of final match, (4) total application and interview-related costs, (5) mentor-to program contact, (6) applicant disclosure of number 1 ranking, and (7) mentor disclosure of number 1 ranking. A link to an anonymous online survey was sent to 198 matched fellows (105 fellows from the 2016 match and 93 from the 2017 match). Main Outcomes and Measures: Survey responses regarding the vitreoretinal surgery fellowship application process. Results: The survey was sent to 198 matched fellowship applicants, and 152 (77%) completed the survey. Of the 105 matched applicants in 2016, 21 (20%) were women. Of the 93 matched applicants in 2017, 24 (26%) were women. Matched applicants applied to a mean (SD) of 34 (17) programs (range, 1-85) and ranked a mean (SD) of 12 (4) programs (range, 1-27). Of 152 applicants, 66 (43%) matched at their number 1 ranked program, 23 (15%) matched number 2, and 21 (14%) matched number 3. The mean (SD) total cost was $5500 ($2776) (range, $500-$13 500). Two-sided chi2 testing found no association (odds ratio, 0.70; 95% CI, 0.34-1.4; P = .33) between mentor-to-program contact and the probability of applicants matching at their number 1 ranked program. Matched applicants who revealed their number 1 ranking either personally or via a mentor matched at a program ranked lower (more desirable) on their rank list (mean match ranking, 2.8) compared with those who did not reveal their number 1 ranking (mean match ranking, 4.2; 95% CI, 0.2-2.5; P = .01). Applicant disclosure of their intention to rank a program number 1, either personally or via a mentor, was associated with matching number 1 (odds ratio, 2.6; range, 1.1-6.0; P = .03). Conclusions and Relevance: Vitreoretinal fellowship applicants who disclosed their number 1 ranking, either personally or via a mentor, were associated with improved match outcomes compared with their cohorts who did not make such disclosures. PMID- 29710104 TI - Building a Stronger Care Loop Through mHealth Technology. PMID- 29710105 TI - Considering Whether the Dismissal of Vaccine-Refusing Families Is Fair to Other Clinicians. PMID- 29710106 TI - When You Hear Hoofbeats, Look for Horses, Not Zebras-Reply. PMID- 29710107 TI - Expression of Concern: Wansink B, Cheney MM. Super Bowls: Serving Bowl Size and Food Consumption. JAMA. 2005;293(14):1727-1728. PMID- 29710109 TI - A Closer Look at the Analgesic Regimen After Rhinoplasty-Reply. PMID- 29710108 TI - Association of a Proactive Swallowing Rehabilitation Program With Feeding Tube Placement in Patients Treated for Pharyngeal Cancer. AB - Importance: A proactive speech and language pathology (SLP) program is an important component of the multidisciplinary care of patients with head and neck squamous cell carcinoma (HNSCC). Swallowing rehabilitation can reduce the rate of feeding tube placement, thereby significantly improving quality of life. Objective: To evaluate the initiation of a proactive SLP rehabilitation program at a single institution and its association with rates of feeding tube placement and dietary intake in patients with HNSCC. Design, Setting, and Participants: Cohort study at a tertiary care and referral center for patients with HNSCC serving the northern Chicago region. Patients were treated for squamous cell carcinomas of the hypopharynx, oropharynx, and nasopharynx from 2004 to 2015 with radiation or chemoradiation therapy in the definitive or adjuvant setting. Patients who received less than 5000 cGy radiation or underwent reirradiation were excluded. Interventions: A proactive SLP program for patients with HNSCC was initiated in 2011. Study cohorts were divided into 2 groups: 2004 through 2010 and 2011 through 2015. Main Outcomes and Measures: Primary outcome variables were SLP referral placement and timing of the referral. Secondary outcomes were feeding tube placement and ability to tolerate any oral intake. Results: A total of 254 patients met inclusion criteria (135 before and 119 after implementation of SLP program; median age, 60 years [range, 14-94 years]; 77% male). With the initiation of a proactive SLP program, pretreatment evaluations increased from 29 (21.5%) to 70 (58.8%; risk ratio [RR], 2.74; 95% CI, 1.92-3.91), and rate of referral overall at any time increased from 60.0% to 79.8% (RR, 1.33; 95% CI, 1.13-1.57). Feeding tube placement rates decreased from 45.9% (n = 62) to 29.4% (n = 35; RR, 0.64; 95% CI, 0.46-0.89). Among patients receiving a swallow evaluation, feeding tube requirements were less frequent for those receiving a pretreatment evaluation (31 of 99 [31%]) than for those referred during (11 of 18 [61%]) or after (38 of 59 [64%]) treatment. The rate of tolerating any oral intake at the end of treatment improved from 71.1% (n = 96) in the preimplementation period to 82.4% (n = 98; RR, 1.16; 95% CI, 1.01-1.33). Conclusions and Relevance: A proactive SLP program can be successfully established as part of the multidisciplinary care of patients with HNSCC and improve patient quality of life. PMID- 29710110 TI - Limitations of the National Cancer Data Base to Evaluate Early-Stage Anal Cancer Treatment Outcomes. PMID- 29710112 TI - Erythematous Plaque on the Inferior Eyelid. PMID- 29710111 TI - Effect of Systematic Physician Cross-checking on Reducing Adverse Events in the Emergency Department: The CHARMED Cluster Randomized Trial. AB - Importance: Emergency departments (ED) are environments that are at high risk for medical errors. Previous studies suggested that the proportion of medical errors may decrease when more than 1 physician is involved. Objective: To reduce the proportion of medical errors by implementing systematic cross-checking between emergency physicians. Design, Setting, and Participants: This cluster randomized crossover trial includes a random sample of 14 adult patients (age >=18 years) per day during two 10-day period in 6 EDs (n = 1680 patients) in France. Interventions: Systematic cross-checking between emergency physicians, 3 times a day, which included a brief presentation of one physician's case to another, followed by the second physician's feedback to the first. Main Outcomes and Measures: Medical error in the ED, defined as an adverse event (either a near miss or a serious adverse event). The primary end point was identified using a 2 level error detection surveillance system, blinded to the strategy allocation. Results: Among the 1680 included patients (mean [SD] age, 57.5 [21.7] years), 144 (8.6%) had an adverse event. There were 54 adverse events among 840 patients (6.4%) in the cross-check group compared with 90 adverse events among 840 patients (10.7%) in the standard care group (relative risk reduction [RRR], 40% [95% CI, 12% to 59%]; absolute risk reduction [ARR], 4.3%; number needed to treat [NNT], 24). There was also a significant reduction rate of near misses (RRR, 47% [95% CI, 15% to 67%]; ARR, 2.7%; NNT, 37) but not of the rate of preventable serious adverse events (RRR, 29% [95% CI, -18% to 57%]; ARR, 1.2%; NNT, 83). Conclusions and Relevance: The implementation of systematic cross-checking between emergency physicians was associated with a significant reduction in adverse events, mainly driven by a reduction in near misses. Trial Registration: ClinicalTrials.gov Identifier: NCT02356926. PMID- 29710113 TI - Early Weight Gain in Pregnancy and Infant Birth Weight-Reply. PMID- 29710114 TI - Physical Inactivity and Mental Health in Late Adolescence. PMID- 29710115 TI - Effects of a Tablet-Based Home Practice Program With Telepractice on Treatment Outcomes in Chronic Aphasia. AB - Purpose: The aim of this study was to determine if a tablet-based home practice program with weekly telepractice support could enable long-term maintenance of recent treatment gains and foster new language gains in poststroke aphasia. Method: In a pre-post group study of home practice outcomes, 21 individuals with chronic aphasia were examined before and after a 6-month home practice phase and again at follow-up 4 months later. The main outcome measure studied was change in naming previously treated or untreated, practiced or unpracticed pictures of objects and actions. Individualized home practice programs were created in iBooks Author with semantic, phonemic, and orthographic cueing in pictures, words, and videos in order to facilitate naming of previously treated or untreated pictures. Results: Home practice was effective for all participants with severity moderating treatment effects, such that individuals with the most severe aphasia made and maintained fewer gains. There was a negative relationship between the amount of training required for iPad proficiency and improvements on practiced and unpracticed pictures and a positive relationship between practice compliance and same improvements. Conclusion: Unsupervised home practice with weekly video teleconferencing support is effective. This study demonstrates that even individuals with chronic severe aphasia, including those with no prior smart device or even computer experience, can attain independent proficiency to continue practicing and improving their language skills beyond therapy discharge. This could represent a low-cost therapy option for individuals without insurance coverage and/or those for whom mobility is an obstacle to obtaining traditional aphasia therapy. PMID- 29710116 TI - Baseline Cognition Assessment Among Patients With Oropharyngeal Cancer Using PROMIS and NIH Toolbox. AB - Importance: Cognitive dysfunction (CD) is recognized by the American Cancer Society as a treatment effect in head and neck cancer, but the extent of this problem at baseline in oropharyngeal cancer (OPC), the most common subsite in current practice, to our knowledge has never been studied. Objective: To assess the baseline cognition of patients with OPC using National Institutes of Health (NIH)-sponsored instruments of Patient-Reported Outcomes Measurement Information System (PROMIS) and NIH Toolbox Cognitive Battery (NIHTB-CB). Design, Setting, and Participants: This was a prospective cohort study conducted at a tertiary academic center. Of 83 consecutive patients, newly diagnosed as having OPC from September 2016 to May 2017, 16 were ineligible, 8 refused to participate, and 3 were lost to follow-up after screening, resulting in 56 study participants. Main Outcomes and Measures: Self-perceived and objective cognition with PROMIS and NIHTB-CB standardized T scores, respectively, were main outcomes. Impairment was defined as (1) T scores less than 0.5 SD for PROMIS; (2) T score less than 1.5 SD in at least 1 cognitive domain or less than 1 SD in 2 or more domains for NIHTB CB total cognition; and (3) T score per previously published criteria for NIHTB CB intelligence-stratified cognition. Results: Of the 56 study participants (52 men, 4 women; median age, 59 years [range, 42-77 years]), 19 (34%) had a college degree, and 20 (36%) had a professional or technical occupation. Thirty (about 53%) were never-smokers, 26 (46%) were never-drinkers, 29 (52%) were obese, 13 (23%) had a moderate to severe comorbidity, 3 (5%) used antidepressants, and 25 (52%) had hearing loss. Impaired self-reported, NIHTB-CB total, and intelligence stratified cognition scores were observed in 6 (11%), 18 (32%), and 12 (21%), respectively. Among all variables, objective impairment was more common in men (23% vs 0%) and those with p16-negative OPC (33% vs 20%), moderate to severe comorbidity (31% vs 18%), and hearing loss (31% vs 12%). Conclusions and Relevance: Impaired objective cognition was more common at baseline than self reported, and was more frequent in men, participants with p16-negative OPC, moderate to severe comorbidity, and hearing loss. NIHTB-CB allowed immediate scoring of demographically adjusted cognitive function. In clinical practice, these scores can be used to identify patients with impaired cognition at baseline who may be susceptible to developing further impairment after treatment. Identification of impairment at baseline will help to institute early cognitive interventions, which may lead to an improved posttreatment quality of life. PMID- 29710117 TI - Geriatric Dermatology-A Framework for Caring for Older Patients With Skin Disease. PMID- 29710118 TI - Disorganized Gyrification Network Properties During the Transition to Psychosis. AB - Importance: There is urgent need to improve the limited prognostic accuracy of clinical instruments to predict psychosis onset in individuals at clinical high risk (CHR) for psychosis. As yet, no reliable biological marker has been established to delineate CHR individuals who will develop psychosis from those who will not. Objectives: To investigate abnormalities in a graph-based gyrification connectome in the early stages of psychosis and to test the accuracy of this systems-based approach to predict a transition to psychosis among CHR individuals. Design, Setting, and Participants: This investigation was a cross sectional magnetic resonance imaging (MRI) study with follow-up assessment to determine the transition status of CHR individuals. Participants were recruited from a specialized clinic for the early detection of psychosis at the Department of Psychiatry (Universitare Psychiatrische Kliniken [UPK]), University of Basel, Basel, Switzerland. Participants included individuals in the following 4 study groups: 44 healthy controls (HC group), 63 at-risk mental state (ARMS) individuals without later transition to psychosis (ARMS-NT group), 16 ARMS individuals with later transition to psychosis (ARMS-T group), and 38 antipsychotic-free patients with first-episode psychosis (FEP group). The study dates were November 2008 to November 2014. The dates of analysis were March to November 2017. Main Outcomes and Measures: Gyrification-based structural covariance networks (connectomes) were constructed to quantify global integration, segregation, and small-worldness. Group differences in network measures were assessed using functional data analysis across a range of network densities. The extremely randomized trees algorithm with repeated 5-fold cross validation was used to delineate ARMS-T individuals from ARMS-NT individuals. Permutation tests were conducted to assess the significance of classification performance measures. Results: The 4 study groups comprised 161 participants with mean (SD) ages ranging from 24.0 (4.7) to 25.9 (5.7) years. Small-worldness was reduced in the ARMS-T and FEP groups and was associated with decreased integration and increased segregation in both groups (Hedges g range, 0.666 1.050). Using the connectome properties as features, a good classification performance was obtained (accuracy, 90.49%; balanced accuracy, 81.34%; positive predictive value, 84.47%; negative predictive value, 92.18%; sensitivity, 66.11%; specificity, 96.58%; and area under the curve, 88.30%). Conclusions and Relevance: These findings suggest that there is poor integration in the coordinated development of cortical folding in patients who develop psychosis. These results further suggest that gyrification-based connectomes might be a promising means to generate systems-based measures from anatomical data to improve individual prediction of a transition to psychosis in CHR individuals. PMID- 29710119 TI - Cerebral Microbleeds and the Effect of Intensive Blood Pressure Reduction on Hematoma Expansion and Functional Outcomes: A Secondary Analysis of the ATACH-2 Randomized Clinical Trial. AB - Importance: Response to intensive blood pressure (BP) lowering in acute intracerebral hemorrhage (ICH) might vary with the degree of underlying cerebral small vessel disease. Objectives: To characterize cerebral microbleeds (CMBs) in acute ICH and to assess the potential for interaction between underlying small vessel disease (as indicated by CMB number and location) and assignment to acute intensive BP targeting for functional outcomes and hematoma expansion. Design, Setting, and Participants: Preplanned subgroup analyses in the Antihypertensive Treatment of Acute Cerebral Hemorrhage 2 (ATACH-2) trial were performed. The ATACH-2 was an open-label international randomized clinical trial that investigated optimal acute BP lowering in 1000 patients with acute ICH. Analyses followed the intent-to-treat paradigm. Participants were enrolled between May 2011 and September 2015 and followed up for 3 months. Eligible participants were aged at least 18 years with ICH volumes less than 60 mL on computed tomography (CT) and a Glasgow Coma Scale score of at least 5 on initial assessment, in whom study drug could be initiated within 4.5 hours of symptom onset. Eight hundred thirty-three participants were excluded, leaving 167 who had an interpretable axial T2*-weighted gradient-recalled echo sequence on magnetic resonance imaging to assess CMBs for inclusion in these subgroup analyses. Main Outcomes and Measures: The primary outcome of interest was death or disability (modified Ranking Scale score, 4-6) at 3 months. The secondary outcome of interest was hematoma volume expansion of at least 33% on a CT scan obtained 24 hours after randomization compared with the entry scan. Results: A total of 167 patients were included; their mean (SD) age was 61.9 (13.2) years, and 98 (58.7%) were male. Cerebral microbleeds were present in 120 patients. Forty-six of 157 (29.3%) patients had poor outcome (modified Ranking Scale score, >=4), and hematoma expansion was observed in 29 of 144 (20.1%) patients. Risk of poor outcome was similar for those assigned to intensive vs standard acute BP lowering among patients with CMBs (relative risk, 1.19; 95% CI, 0.61-2.33; P = .61) and those without CMBs (relative risk, 1.42; 95% CI, 0.43-4.70; P = .57), and no significant interaction was observed (interaction coefficient, 0.18; 95% CI, 1.20 to 1.55; P = .80). Risk of hematoma expansion was also similar, and no significant interaction between treatment and CMBs was observed (interaction coefficient, 0.62; 95% CI, -1.08 to 2.31; P = .48). Conclusions and Relevance: Cerebral microbleeds are highly prevalent among patients with ICH but do not seem to influence response to acute intensive BP treatment. Trial Registration: ClinicalTrials.gov Identifier: NCT01176565. PMID- 29710120 TI - A Histologic Study of the Circadian System in Parkinson Disease, Multiple System Atrophy, and Progressive Supranuclear Palsy. AB - Importance: Circadian dysfunction may be associated with the symptoms and neurodegeneration in Parkinson disease (PD), multiple system atrophy (MSA), and progressive supranuclear palsy (PSP), although the underlying neuroanatomical site of disruption and pathophysiological mechanisms are not fully understood. Objective: To perform a neuropathological analysis of disease-specific inclusions in the key structures of the circadian system in patients with PD, MSA, and PSP. Design, Setting, and Participants: This investigation was a brain bank case control study assessing neuropathological inclusions in the suprachiasmatic nucleus (SCN) of the hypothalamus and pineal gland in healthy controls, PD (Lewy pathology), MSA (glial cytoplasmic inclusions), and PSP (tau inclusions). The study analyzed 12 healthy control, 28 PD, 11 MSA, and 21 PSP samples from consecutive brain donations (July 1, 2010, to June 30, 2016) to the Queen Square Brain Bank for Neurological Disorders and the Parkinson's UK Brain Bank, London, United Kingdom. Cases were excluded if neither SCN nor pineal tissue was available. Main Outcomes and Measures: Disease-specific neuropathological changes were graded using a standard semiquantitative scoring system (absent, mild, moderate, severe, or very severe) and compared between groups. Results: Because of limited tissue availability, the following total samples were examined in a semiquantitative histologic analysis: 5 SCNs and 7 pineal glands in the control group (6 male; median age at death, 83.8 years; interquartile range [IQR], 78.2 88.0 years), 13 SCNs and 17 pineal glands in the PD group (22 male; median age at death, 78.8 years; IQR, 75.5-83.8 years), 5 SCNs and 6 pineal glands in the MSA group (7 male; median age at death, 69.5 years; IQR, 61.6-77.7 years), and 5 SCNs and 19 pineal glands in the PSP group (13 male; median age at death, 74.3 years; IQR, 69.7-81.1 years). No neuropathological changes were found in either the SCN or pineal gland in healthy controls or MSA cases. Nine PD cases had Lewy pathology in the SCN, and only 2 PD cases had Lewy pathology in the pineal gland. All PSP cases showed inclusions in the SCN, but no PSP cases had pathology in the pineal gland. Conclusions and Relevance: Disease-related neuropathological changes were found in the SCN but not in the pineal gland in PD and PSP, while both structures were preserved in MSA, reflecting different pathophysiological mechanisms that may have important therapeutic implications. PMID- 29710123 TI - Making the Opioid Public Health Emergency Effective. PMID- 29710121 TI - Association of Retinal Ganglion Cell Layer Thickness With Future Disease Activity in Patients With Clinically Isolated Syndrome. AB - Importance: Clinically isolated syndrome (CIS) describes a first clinical incident suggestive of multiple sclerosis (MS). Identifying patients with CIS who have a high risk of future disease activity and subsequent MS diagnosis is crucial for patient monitoring and the initiation of disease-modifying therapy. Objective: To investigate the association of retinal optical coherence tomography (OCT) results with future disease activity in patients with CIS. Design, Setting, and Participants: This prospective, longitudinal cohort study took place between January 2011 and May 2017 at 2 German tertiary referral centers. A total of 179 patients with CIS were screened (80 in Berlin and 99 in Munich). Patients underwent neurological examination, magnetic resonance imaging (MRI), and OCT. Only eyes with no previous optic neuritis were considered for OCT analysis. Main Outcomes and Measures: The primary outcome was not meeting the no evidence of disease activity (NEDA-3) criteria; secondary outcomes were MS diagnosis (by the 2010 McDonald criteria) and worsening of disability. The primary measure was OCT derived ganglion cell and inner plexiform layer thickness; the secondary measures included peripapillary retinal nerve fiber layer thickness, inner nuclear layer thickness, and MRI-derived T2-weighted lesions. Results: A total of 97 of the 179 screened patients (54.2%) were enrolled in the study at a median of 93 (interquartile range [IQR], 62-161) days after a first demyelinating event. The median follow-up duration (Kaplan-Meier survival time) was 729 (IQR, 664-903) days. Of 97 patients with CIS (mean age 33.6 [7.9] years; 61 [62.9%] female), 58 (59%) did not meet NEDA-3 criteria during the follow-up period. A Kaplan-Meier analysis showed a significant probability difference in not meeting NEDA-3 criteria by ganglion cell and inner plexiform later thickness (thinnest vs thickest tertile: hazard ratio [HR], 3.33 [95% CI, 1.70-6.55; P < .001; log-rank P = .001). A follow-up diagnosis of MS was more likely for patients with low ganglion cell and inner plexiform layer thickness (thinnest vs thickest tertile: HR, 4.05 [95% CI, 1.93-8.50]; P < .001). Low peripapillary retinal nerve fiber layer thickness likewise indicated risk of not meeting NEDA-3 criteria (thinnest vs thickest tertile: HR, 2.46 [95% CI, 1.29-4.66]; P = .01; log-rank P = .02). Inner nuclear layer thickness and T2-weighted lesion count were not associated with not meeting NEDA-3 criteria. Conclusions and Relevance: Retinal ganglion cell and inner plexiform layer thickness might prove a valuable imaging marker for anticipating future disease activity and diagnosis of MS in patients with CIS, which can potentially support patient monitoring and initiation of disease modifying therapy. PMID- 29710122 TI - Association of Skin Examination Behaviors and Thinner Nodular vs Superficial Spreading Melanoma at Diagnosis. AB - Importance: Early melanoma detection strategies include skin self-examination (SSE), physician skin examination (PSE), and promotion of patient knowledge about skin cancer. Objective: To investigate the association of SSE, PSE, and patient attitudes with the detection of thinner superficial spreading melanoma (SSM) and nodular melanoma (NM), the latter of which tends to elude early detection. Design, Setting, and Participants: This cross-sectional, questionnaire-based, multicenter study identified patients with newly diagnosed cutaneous melanoma at 4 referral hospital centers in the United States, Greece, and Hungary. Among 920 patients with a primary invasive melanoma, 685 patients with SSM or NM subtype were included. Interventions: A standardized questionnaire was used to record sociodemographic information, SSE and PSE practices, and patient perceptions in the year prior to diagnosis. Main Outcomes and Measures: Data were analyzed according to histologic thickness, with a 2-mm cutoff for thinner SSM and NM. Results: Of 685 participants (mean [SD] age, 55.6 [15.1] years; 318 [46%] female), thinner melanoma was detected in 437 of 538 SSM (81%) and in 40 of 147 NM (27%). Patients who routinely performed SSE were more likely to be diagnosed with thinner SSM (odds ratio [OR], 2.61; 95% CI, 1.14-5.40) but not thinner NM (OR, 2.39; 95% CI, 0.84-6.80). Self-detected clinical warning signs (eg, elevation and onset of pain) were markers of thicker SSM and NM. Whole-body PSE was associated with a 2-fold increase in detection of thinner SSM (OR, 2.25; 95% CI, 1.16-4.35) and thinner NM (OR, 2.67; 95% CI, 1.05-6.82). Patient attitudes and perceptions focusing on increased interest in skin cancer were associated with the detection of thinner NM. Conclusions and Relevance: Our findings underscore the importance of complementary practices by patients and physicians for the early detection of melanoma, including regular whole-body PSE, SSE, and increased patient awareness. PMID- 29710124 TI - Automated and Clinical Breast Imaging Reporting and Data System Density Measures Predict Risk for Screen-Detected and Interval Cancers: A Case-Control Study. AB - Background: In 30 states, women who have had screening mammography are informed of their breast density on the basis of Breast Imaging Reporting and Data System (BI-RADS) density categories estimated subjectively by radiologists. Variation in these clinical categories across and within radiologists has led to discussion about whether automated BI-RADS density should be reported instead. Objective: To determine whether breast cancer risk and detection are similar for automated and clinical BI-RADS density measures. Design: Case-control. Setting: San Francisco Mammography Registry and Mayo Clinic. Participants: 1609 women with screen detected cancer, 351 women with interval invasive cancer, and 4409 matched control participants. Measurements: Automated and clinical BI-RADS density assessed on digital mammography at 2 time points from September 2006 to October 2014, interval and screen-detected breast cancer risk, and mammography sensitivity. Results: Of women whose breast density was categorized by automated BI-RADS more than 6 months to 5 years before diagnosis, those with extremely dense breasts had a 5.65-fold higher interval cancer risk (95% CI, 3.33 to 9.60) and a 1.43-fold higher screen-detected risk (CI, 1.14 to 1.79) than those with scattered fibroglandular densities. Associations of interval and screen-detected cancer with clinical BI-RADS density were similar to those with automated BI-RADS density, regardless of whether density was measured more than 6 months to less than 2 years or 2 to 5 years before diagnosis. Automated and clinical BI-RADS density measures had similar discriminatory accuracy, which was higher for interval than screen-detected cancer (c-statistics: 0.70 vs. 0.62 [P < 0.001] and 0.72 vs. 0.62 [P < 0.001], respectively). Mammography sensitivity was similar for automated and clinical BI-RADS categories: fatty, 93% versus 92%; scattered fibroglandular densities, 90% versus 90%; heterogeneously dense, 82% versus 78%; and extremely dense, 63% versus 64%, respectively. Limitation: Neither automated nor clinical BI-RADS density was assessed on tomosynthesis, an emerging breast screening method. Conclusion: Automated and clinical BI-RADS density similarly predict interval and screen-detected cancer risk, suggesting that either measure may be used to inform women of their breast density. Primary Funding Source: National Cancer Institute. PMID- 29710125 TI - Long-Term Effectiveness of Sigmoidoscopy Screening on Colorectal Cancer Incidence and Mortality in Women and Men: A Randomized Trial. AB - Background: The long-term effects of sigmoidoscopy screening on colorectal cancer (CRC) incidence and mortality in women and men are unclear. Objective: To determine the effectiveness of flexible sigmoidoscopy screening after 15 years of follow-up in women and men. Design: Randomized controlled trial. (ClinicalTrials.gov: NCT00119912). Setting: Oslo and Telemark County, Norway. Participants: Adults aged 50 to 64 years at baseline without prior CRC. Intervention: Screening (between 1999 and 2001) with flexible sigmoidoscopy with and without additional fecal blood testing versus no screening. Participants with positive screening results were offered colonoscopy. Measurements: Age-adjusted CRC incidence and mortality stratified by sex. Results: Of 98 678 persons, 20 552 were randomly assigned to screening and 78 126 to no screening. Adherence rates were 64.7% in women and 61.4% in men. Median follow-up was 14.8 years. The absolute risks for CRC in women were 1.86% in the screening group and 2.05% in the control group (risk difference, -0.19 percentage point [95% CI, -0.49 to 0.11 percentage point]; HR, 0.92 [CI, 0.79 to 1.07]). In men, the corresponding risks were 1.72% and 2.50%, respectively (risk difference, -0.78 percentage point [CI, 1.08 to -0.48 percentage points]; hazard ratio [HR], 0.66 [CI, 0.57 to 0.78]) (P for heterogeneity = 0.004). The absolute risks for death from CRC in women were 0.60% in the screening group and 0.59% in the control group (risk difference, 0.01 percentage point [CI, -0.16 to 0.18 percentage point]; HR, 1.01 [CI, 0.77 to 1.33]). The corresponding risks for death from CRC in men were 0.49% and 0.81%, respectively (risk difference, -0.33 percentage point [CI, -0.49 to -0.16 percentage point]; HR, 0.63 [CI, 0.47 to 0.83]) (P for heterogeneity = 0.014). Limitation: Follow-up through national registries. Conclusion: Offering sigmoidoscopy screening in Norway reduced CRC incidence and mortality in men but had little or no effect in women. Primary Funding Source: Norwegian government and Norwegian Cancer Society. PMID- 29710126 TI - Estimation of Future Cancer Burden Among Rescue and Recovery Workers Exposed to the World Trade Center Disaster. AB - Importance: Elevated rates of cancer have been reported in individuals exposed to the World Trade Center (WTC) disaster, including Fire Department of the City of New York (FDNY) rescue and recovery workers. Objective: To project the future burden of cancer in WTC-exposed FDNY rescue and recovery workers by estimating the 20-year cancer incidence. Design, Setting, and Participants: A total of 14 474 WTC-exposed FDNY employees who were cancer-free on January 1, 2012; subgroup analyses were conducted of the cohort's white male population (n = 12 374). In this closed-cohort study, we projected cancer incidence for the January 1, 2012, to December 31, 2031, period. Simulations were run using demographic-specific New York City (NYC) cancer and national mortality rates for each individual, summed for the whole cohort, and performed 1000 times to produce mean estimates. Additional analyses in the subgroup of white men compared case counts produced by using 2007-2011 FDNY WTC Health Program (FDNY-WTCHP) cancer rates vs NYC rates. Average and 20-year aggregate costs of first-year cancer care were estimated using claims data. Exposures: World Trade Center disaster exposure defined as rescue and recovery work at the WTC site at any time from September 11, 2001, to July 25, 2002. Main Outcomes and Measures: (1) Projected number of incident cancers in the full cohort, based on NYC cancer rates; (2) cancer incidence estimates in the subgroup projected using FDNY-WTCHP vs NYC rates; and (3) estimated first-year treatment costs of incident cancers. Results: On January 1, 2012, the cohort was 96.8% male, 87.1% white, and had a mean (SD) age of 50.2 (9.2) years. The projected number of incident cancer cases was 2960 (95% CI, 2883 3037). In our subgroup analyses using FDNY-WTCHP vs NYC cancer rates, the projected number of new cases in white men was elevated (2714 [95% CI, 2638-2786] vs 2596 [95% CI, 2524-2668]). Accordingly, we expect more prostate (1437 [95% CI, 1383-1495] vs 863 [95% CI, 816-910]), thyroid (73 [95% CI, 60-86] vs 57 [95% CI, 44-69]), and melanoma cases (201 [95% CI, 179-223] vs 131 [95% CI, 112-150), but fewer lung (237 [95% CI, 212-262] vs 373 [95% CI, 343-405]), colorectal (172 [95% CI, 152-191] vs 267 [95% CI, 241-292]), and kidney cancers (66 [95% CI, 54-80] vs 132 [95% CI, 114-152]) (P < .001 for all comparisons). The estimated 20-year cost of first-year treatment was $235 835 412 (95% CI, $187 582 227-$284 088 597). Conclusions and Relevance: We project that the FDNY-WTCHP cohort will experience a greater cancer burden than would be expected from a demographically similar population. This underscores the importance of cancer prevention efforts and routine screening in WTC-exposed rescue and recovery workers. PMID- 29710127 TI - Plus Disease in Retinopathy of Prematurity-Investigating Its Definition. PMID- 29710128 TI - Association of Timing of Aortic Valve Replacement Surgery After Stroke With Risk of Recurrent Stroke and Mortality. AB - Importance: Timing of surgical aortic valve replacement (SAVR) in patients with aortic valve stenosis and previous stroke for the risk of recurrent stroke is insufficiently investigated. Objective: To evaluate the association of time elapsed between previous stroke and SAVR with the risk of recurrent perioperative stroke, major adverse cardiovascular events (MACE), and mortality among patients with aortic valve stenosis. Design, Setting, and Participants: This cohort study using data from Danish administrative registries included all patients with aortic valve stenosis older than 18 years who underwent SAVR between 1996 and 2014 (n = 14 030). Patients who received simultaneous mitral, tricuspid, or pulmonary valve surgery and patients with endocarditis 1 year prior to surgery were excluded. Data were analyzed from March 2017 to January 2018. Exposures: Time elapsed between prior stroke and SAVR (<3 months, 3-<12 months, >=12 months, and no prior stroke). Main Outcomes and Measures: Thirty-day risks of MACE, ischemic stroke, and all-cause mortality reported as absolute events and multivariable adjusted odds ratios with 95% confidence intervals. Restricted cubic spline regression models were additionally applied on the subgroup with prior stroke. Results: Of the 14 030 included patients, 616 patients (190 [30.8%] women; mean [SD] age, 72.0 [9.1] years) with prior stroke underwent surgery, and 13 414 (4837 [36.1%] women; mean [SD] age, 69.8 [10.8] years) without prior stroke underwent surgery. The absolute risk of ischemic stroke was significantly increased in patients with stroke less than 3 months prior to surgery compared with patients with no prior stroke (18.4% [37 of 201] vs 1.2% [160 of 13 219]; odds ratio, 14.69; 95% CI, 9.69-22.27). Likewise, compared with patients without stroke, patients with stroke less than 3 months prior surgery were at significantly increased risk of MACE (23.3% [53 of 227] vs 5.7% [768 of 13 414]; odds ratio, 4.57; 95% CI, 3.24-6.44) but not all-cause mortality (6.8% [50 of 730] vs 3.6% [374 of 10 370]; odds ratio, 1.45; 95% CI, 0.83-2.54). Spline analyses supported a declining risk over time, reaching nadir after 2 to 4 months. Conclusions and Relevance: Previous stroke is a major risk factor of recurrent ischemic stroke and MACE in patients undergoing SAVR, especially if time elapsed between previous stroke and surgery is less than 3 months. PMID- 29710129 TI - Total Costs of Chimeric Antigen Receptor T-Cell Immunotherapy. PMID- 29710130 TI - In the Era of Precision Medicine and Big Data, Who Is Normal? PMID- 29710131 TI - In Blunt Traumatic Cardiac Arrest, Does It Really Matter Who Performs Prehospital Advanced Life Support? PMID- 29710133 TI - Extending the Ear-Kidney Association to Presbycusis. PMID- 29710134 TI - Erratum. PMID- 29710132 TI - Association of Behavior With Noise-Induced Hearing Loss Among Attendees of an Outdoor Music Festival: A Secondary Analysis of a Randomized Clinical Trial. AB - Importance: To date, factors associated with noise-induced hearing loss at music festivals have not yet been analyzed in a single comprehensive data set. In addition, little is known about the hearing loss-associated behavior of music festival attendees. Objectives: To assess which factors are associated with the occurrence of a temporary threshold shift (TTS) after music exposure and to investigate the behavior of music festival attendees. Design, Setting, and Participants: This prospective post hoc analysis gathered data from a randomized, single-blind clinical trial conducted on September 5, 2015, at an outdoor music festival in Amsterdam, the Netherlands. Adult volunteers with normal hearing were recruited via social media from August 26 through September 3, 2015. Intention to use earplugs was an exclusion criterion. Of 86 volunteers assessed, 51 were included. This post hoc analysis was performed from October 3, 2016, through February 27, 2017. Interventions: Music festival visit for 4.5 hours. Main Outcomes and Measures: The primary outcome was a TTS on a standard audiogram for the frequencies 3.0- and 4.0-kHz. Multivariable linear regression was performed to determine which factors are associated with a TTS. A questionnaire on behavior, hearing, and tinnitus was distributed to the participants before and after the festival visit. Results: A total of 51 participants were included (18 men [35%] and 33 women [65%]) with a mean (SD) age of 27 (6) years. Mean (SD) threshold change across 3.0 and 4.0 kHz was 5.4 (5.7) dB for the right ear and 4.0 (6.1) dB for the left ear. Earplug use (absolute difference in the left ear, 6.0 dB [95% CI, -8.7 to -3.2 dB]; in the right ear, -6.4 dB [95% CI, -8.8 to -4.1 dB]), quantity of alcohol use (absolute difference per unit in the left ear, 1.1 dB [95% CI, 0.5 to 1.7 dB]; in the right ear, 0.7 dB [95% CI, 0.1 to 1.4 dB]), drug use (absolute difference in the right ear, 6.0 dB [95% CI, 0.9 to 11.1 dB]), and male sex (absolute difference in the right ear, 4.1 dB [95% CI, 0.3 to 5.9 dB]) were independently associated with hearing loss, with earplug use being the most important factor. Unprotected participants reported significantly worse subjective hearing performance and tinnitus after the festival visit than did participants using earplugs (Cramer V, 0.62 [95% CI, 0.47-0.79] and 0.39 [95% CI, 0.16-0.62], respectively). In the earplug group, the perceived loudness (r = 0.72; 95% CI, -1.00 to -0.43) and appreciation (r = 0.53; 95% CI, 0.29 to 0.78) of music and speech perception (r = 0.21; 95% CI, 0.09 to 0.35) were correlated with the duration of earplug use. Conclusions and Relevance: The present study identified nonuse of earplugs, use of alcohol and drugs, and male sex as associated with a TTS at an outdoor music festival. Physicians should consider these factors to raise awareness about the combined risk of attending music festivals without using earplugs while consuming alcohol and/or drugs. The intention to use earplugs was correlated with the loudness and appreciation of music with earplugs, which may advocate for the use of personalized earplugs. Trial Registration: trialregister.nl Identifier: NTR5401. PMID- 29710136 TI - Physicians' Compassion, Communication Skills, and Professionalism With and Without Physicians' Use of an Examination Room Computer: A Randomized Clinical Trial. PMID- 29710135 TI - Association Between Muscular Strength and Cognition in People With Major Depression or Bipolar Disorder and Healthy Controls. AB - Importance: Objective physical fitness measures, such as handgrip strength, are associated with physical, mental, and cognitive outcomes in the general population. Although people with mental illness experience reduced physical fitness and cognitive impairment, the association between muscular strength and cognition has not been examined to date. Objective: To determine associations between maximal handgrip strength and cognitive performance in people with major depression or bipolar disorder and in healthy controls. Design, Setting, and Participants: In a multicenter, population-based study conducted between February 13, 2005, and October 1, 2010, in the United Kingdom, cross-sectional analysis was conducted of baseline data from 110 067 participants in the UK Biobank. Data analysis was performed between August 3 and August 18, 2017. Invitations were mailed to approximately 9.2 million UK homes, recruiting 502 664 adults, all aged 37 to 73 years. Clinically validated measures were used to identify individuals with major recurrent depression (moderate or severe) or bipolar disorder (type I or type II) and healthy controls (those with no indication of present or previous mood disorders). Main Outcomes and Measures: Handgrip dynamometry was used to measure muscular function. Cognitive functioning was assessed using computerized tasks of reaction time, visual memory, number memory, reasoning, and prospective memory. Generalized linear mixed models assessed the association between handgrip strength and cognitive performance, controlling for age, educational level, sex, body weight, and geographic region. Results: Of the 110 067 participants, analyses included 22 699 individuals with major depression (mean [95% range] age, 55.5 [41-68] years; 7936 [35.0%] men), 1475 with bipolar disorder (age, 54.4 [41 68] years; 748 [50.7%] men), and 85 893 healthy controls (age, 53.7 [41-69] years; 43 000 [50.0%] men). In those with major depression, significant positive associations (P < .001) between maximal handgrip strength and improved performance on all 5 cognitive tasks were found, including visual memory (coefficient, -0.146; SE, 0.014), reaction time (coefficient, -0.036; SE, 0.002), reasoning (coefficient, 0.213; SE, 0.02), number memory (coefficient, 0.160; SE, 0.023), and prospective memory (coefficient, 0.341; SE, 0.024). Similar results were found in healthy controls. Among participants with bipolar disorder, handgrip strength was positively associated with improved visual memory (coefficient, -0.129; SE, 0.052; P = .01), reaction time (coefficient, -0.047; SE, 0.007; P < .001), prospective memory (coefficient, 0.262; SE, 0.088; P = .003), and reasoning (coefficient, 0.354; SE, 0.08; P < .001). Conclusions and Relevance: Grip strength may provide a useful indicator of cognitive impairment in people with major depression and bipolar disorder. Future research should investigate causality, assess the functional implications of handgrip strength in psychiatric populations, and examine how interventions to improve muscular fitness affect neurocognitive status and socio-occupational functioning. PMID- 29710137 TI - The Role of Pediatricians in Reproductive Health Advocacy. PMID- 29710138 TI - Opioid Use Disorder After Self-medicating Pain From Traumatic Brain Injury. PMID- 29710139 TI - Errors in Title, Author Degrees, Key Points, and Abstract. PMID- 29710140 TI - Interventions to Prevent Falls in Older Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. AB - Importance: Falls are the most common cause of injury-related morbidity and mortality among older adults. Objective: To systematically review literature on the effectiveness and harms of fall prevention interventions in community dwelling older adults to inform the US Preventive Services Task Force. Data Sources: MEDLINE, PubMed, Cumulative Index for Nursing and Allied Health Literature, and Cochrane Central Register of Controlled Trials for relevant English-language literature published through August 2016, with ongoing surveillance through February 7, 2018. Study Selection: Randomized clinical trials of interventions to prevent falls in community-dwelling adults 65 years and older. Data Extraction and Synthesis: Independent critical appraisal and data abstraction by 2 reviewers. Random-effects meta-analyses using the method of DerSimonian and Laird. Main Outcomes and Measures: Number of falls (number of unexpected events in which a person comes to rest on the ground, floor, or lower level), people experiencing 1 or more falls, injurious falls, people experiencing injurious falls, fractures, people experiencing fractures, mortality, hospitalizations, institutionalizations, changes in disability, and treatment harms. Results: Sixty-two randomized clinical trials (N = 35 058) examining 7 fall prevention intervention types were identified. This article focused on the 3 most commonly studied intervention types: multifactorial (customized interventions based on initial comprehensive individualized falls risk assessment) (26 trials [n = 15 506]), exercise (21 trials [n = 7297]), and vitamin D supplementation (7 trials [n = 7531]). Multifactorial intervention trials were associated with a reduction in falls (incidence rate ratio [IRR], 0.79 [95% CI, 0.68-0.91]) but were not associated with a reduction in other fall related morbidity and mortality outcomes. Exercise trials were associated with statistically significant reductions in people experiencing a fall (relative risk, 0.89 [95% 13 CI, 0.81-0.97]) and injurious falls (IRR, 0.81 [95% CI, 0.73 0.90]) and with a statistically nonsignificant reduction in falls (IRR, 0.87 [95% CI, 0.75-1.00]) but showed no association with mortality. Few exercise trials reported fall-related fractures. Seven heterogeneous trials of vitamin D formulations (with or without calcium) showed mixed results. One trial of annual high-dose cholecalciferol (500 000 IU), which has not been replicated, showed an increase in falls, people experiencing a fall, and injuries, while 1 trial of calcitriol showed a reduction in falls and people experiencing a fall; the remaining 5 trials showed no significant difference in falls, people experiencing a fall, or injuries. Harms of multifactorial and exercise trials were rarely reported but generally included minor musculoskeletal injuries. Conclusions and Relevance: Multifactorial and exercise interventions were associated with fall related benefit, but evidence was most consistent across multiple fall-related outcomes for exercise. Vitamin D supplementation interventions had mixed results, with a high dose being associated with higher rates of fall-related outcomes. PMID- 29710141 TI - Interventions to Prevent Falls in Community-Dwelling Older Adults: US Preventive Services Task Force Recommendation Statement. AB - Importance: Falls are the leading cause of injury-related morbidity and mortality among older adults in the United States. In 2014, 28.7% of community-dwelling adults 65 years or older reported falling, resulting in 29 million falls (37.5% of which needed medical treatment or restricted activity for a day or longer) and an estimated 33 000 deaths in 2015. Objective: To update the 2012 US Preventive Services Task Force (USPSTF) recommendation on the prevention of falls in community-dwelling older adults. Evidence Review: The USPSTF reviewed the evidence on the effectiveness and harms of primary care-relevant interventions to prevent falls and fall-related morbidity and mortality in community-dwelling older adults 65 years or older who are not known to have osteoporosis or vitamin D deficiency. Findings: The USPSTF found adequate evidence that exercise interventions have a moderate benefit in preventing falls in older adults at increased risk for falls and that multifactorial interventions have a small benefit. The USPSTF found adequate evidence that vitamin D supplementation has no benefit in preventing falls in older adults. The USPSTF found adequate evidence to bound the harms of exercise and multifactorial interventions as no greater than small. The USPSTF found adequate evidence that the overall harms of vitamin D supplementation are small to moderate. Conclusions and Recommendation: The USPSTF recommends exercise interventions to prevent falls in community-dwelling adults 65 years or older who are at increased risk for falls. (B recommendation) The USPSTF recommends that clinicians selectively offer multifactorial interventions to prevent falls in community-dwelling adults 65 years or older who are at increased risk for falls. Existing evidence indicates that the overall net benefit of routinely offering multifactorial interventions to prevent falls is small. When determining whether this service is appropriate for an individual, patients and clinicians should consider the balance of benefits and harms based on the circumstances of prior falls, presence of comorbid medical conditions, and the patient's values and preferences. (C recommendation) The USPSTF recommends against vitamin D supplementation to prevent falls in community-dwelling adults 65 years or older. (D recommendation) These recommendations apply to community dwelling adults who are not known to have osteoporosis or vitamin D deficiency. PMID- 29710142 TI - When You Got the Yams-Kendrick Lamar and the Language of Power in Clinical Encounters. PMID- 29710143 TI - Data Errors in Table. PMID- 29710144 TI - Incorrect Funding/Support Section. PMID- 29710145 TI - Precision Medicine and Progress in the Treatment of Hutchinson-Gilford Progeria Syndrome. PMID- 29710146 TI - Ticagrelor Following Coronary Artery Bypass Grafting: For Better Vein Graft Patency or Better Patient Outcomes? PMID- 29710147 TI - Hydrolyzed Formula Compared With Standard Formula for Preterm Infants. AB - Clinical Question: For preterm infants, is hydrolyzed formula associated with lower rates of feeding intolerance, lower rates of necrotizing enterocolitis, and faster rates of growth compared with standard cow's milk formula? Bottom Line: Compared with standard formula, feeding preterm infants hydrolyzed formula is not associated with a lower rate of feeding intolerance, a lower rate of necrotizing enterocolitis, or with faster growth. PMID- 29710148 TI - Scientists Affirm Survey's Value for Impaired Driving Research. PMID- 29710149 TI - Just 4 Weeks of Antibiotics Prevents Active TB in People With HIV. PMID- 29710150 TI - VA Using Telemedicine to Provide Therapy to Rural Veterans With PTSD. PMID- 29710152 TI - Single-Payer Health Care: Opportunities and Vulnerabilities. PMID- 29710153 TI - Retrogression in New York City. PMID- 29710154 TI - Noncommercial Funders' Policies on Trial Registration, Access to Summary Results, and Individual Patient Data Availability. PMID- 29710155 TI - Medical Care for Undocumented Immigrants. PMID- 29710157 TI - Medical Care for Undocumented Immigrants-Reply. PMID- 29710156 TI - Machine Learning Compared With Pathologist Assessment. PMID- 29710159 TI - Better Communication Can Improve HPV Vaccine Rates. PMID- 29710158 TI - Machine Learning Compared With Pathologist Assessment-Reply. PMID- 29710160 TI - Vegetarian and Mediterranean Diets Effective for Weight Loss. PMID- 29710161 TI - Disadvantaged Pain Patients Benefit From Psychological Interventions. PMID- 29710162 TI - Virtual CBT Improves Social Functioning in Psychosis. PMID- 29710163 TI - Prazosin May Not Reduce Nightmares in Veterans With PTSD. PMID- 29710164 TI - Effect of Ticagrelor Plus Aspirin, Ticagrelor Alone, or Aspirin Alone on Saphenous Vein Graft Patency 1 Year After Coronary Artery Bypass Grafting: A Randomized Clinical Trial. AB - Importance: The effect of ticagrelor with or without aspirin on saphenous vein graft patency in patients undergoing coronary artery bypass grafting (CABG) is unknown. Objective: To compare the effect of ticagrelor + aspirin or ticagrelor alone vs aspirin alone on saphenous vein graft patency 1 year after CABG. Design, Setting, and Participants: Randomized, multicenter, open-label, clinical trial among 6 tertiary hospitals in China. Eligible patients were aged 18 to 80 years with indications for elective CABG. Patients requiring urgent revascularization, concomitant cardiac surgery, dual antiplatelet or vitamin K antagonist therapy post-CABG, and who were at risk of serious bleeding were excluded. From July 2014 until November 2015, 1256 patients were identified and 500 were enrolled. Follow up was completed in January 2017. Interventions: Patients were randomized (1:1:1) to start ticagrelor (90 mg twice daily) + aspirin (100 mg once daily) (n = 168), ticagrelor (90 mg twice daily) (n = 166), or aspirin (100 mg once daily) (n = 166) within 24 hours post-CABG. Neither patients nor treating physicians were blinded to allocation. Main Outcomes and Measures: Primary outcome was saphenous vein graft patency 1 year after CABG (FitzGibbon grade A) adjudicated independently by a committee blinded to allocation. Saphenous vein graft patency was assessed by multislice computed tomographic angiography or coronary angiography. Results: Among 500 randomized patients (mean age, 63.6 years; women, 91 [18.2%]), 461 (92.2%) completed the trial. Saphenous vein graft patency rates 1 year post-CABG were 88.7% (432 of 487 vein grafts) with ticagrelor + aspirin; 82.8% (404 of 488 vein grafts) with ticagrelor alone; and 76.5% (371 of 485 vein grafts) with aspirin alone. The difference between ticagrelor + aspirin vs aspirin alone was statistically significant (12.2% [95% CI, 5.2% to 19.2%]; P < .001), whereas the difference between ticagrelor alone vs aspirin alone was not statistically significant (6.3% [95% CI, -1.1% to 13.7%]; P = .10). Five major bleeding episodes occurred during 1 year of follow-up (3 with ticagrelor + aspirin; 2 with ticagrelor alone). Conclusions and Relevance: Among patients undergoing elective CABG with saphenous vein grafting, ticagrelor + aspirin significantly increased graft patency after 1 year vs aspirin alone; there was no significant difference between ticagrelor alone and aspirin alone. Further research with more patients is needed to assess comparative bleeding risks. Trial Registration: clinicaltrials.gov Identifier: NCT02201771. PMID- 29710167 TI - Prevention of Falls in Older Adults. PMID- 29710166 TI - Association of Lonafarnib Treatment vs No Treatment With Mortality Rate in Patients With Hutchinson-Gilford Progeria Syndrome. AB - Importance: Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare fatal premature aging disease. There is no approved treatment. Objective: To evaluate the association of monotherapy using the protein farnesyltransferase inhibitor lonafarnib with mortality rate in children with HGPS. Design, Setting, and Participants: Cohort study comparing contemporaneous (birth date >=1991) untreated patients with HGPS matched with treated patients by age, sex, and continent of residency using conditional Cox proportional hazards regression. Treatment cohorts included patients from 2 single-group, single-site clinical trials (ProLon1 [n = 27; completed] and ProLon2 [n = 36; ongoing]). Untreated patients originated from a separate natural history study (n = 103). The cutoff date for patient follow-up was January 1, 2018. Exposure: Treated patients received oral lonafarnib (150 mg/m2) twice daily. Untreated patients received no clinical trial medications. Main Outcomes and Measures: The primary outcome was mortality. The primary analysis compared treated patients from the first lonafarnib trial with matched untreated patients. A secondary analysis compared the combined cohorts from both lonafarnib trials with matched untreated patients. Results: Among untreated and treated patients (n = 258) from 6 continents, 123 (47.7%) were female; 141 (54.7%) had a known genotype, of which 125 (88.7%) were classic (c.1824C>T in LMNA). When identified (n = 73), the primary cause of death was heart failure (79.4%). The median treatment duration was 2.2 years. Median age at start of follow-up was 8.4 (interquartile range [IQR], 4.8-9.5) years in the first trial cohort and 6.5 (IQR, 3.7-9.0) years in the combined cohort. There was 1 death (3.7%) among 27 patients in the first trial group and there were 9 deaths (33.3%) among 27 patients in the matched untreated group. Treatment was associated with a lower mortality rate (hazard ratio, 0.12; 95% CI, 0.01-0.93; P = .04). In the combined cohort, there were 4 deaths (6.3%) among 63 patients in the treated group and 17 deaths (27.0%) among 63 patients in the matched untreated group (hazard ratio, 0.23; 95% CI, 0.06-0.90; P = .04). Conclusions and Relevance: Among patients with HGPS, lonafarnib monotherapy, compared with no treatment, was associated with a lower mortality rate after 2.2 years of follow up. Study interpretation is limited by its observational design. PMID- 29710169 TI - When Mind Deforms Body. PMID- 29710165 TI - Effect of a Home-Based Exercise Intervention of Wearable Technology and Telephone Coaching on Walking Performance in Peripheral Artery Disease: The HONOR Randomized Clinical Trial. AB - Importance: Clinical practice guidelines support home-based exercise for patients with peripheral artery disease (PAD), but no randomized trials have tested whether an exercise intervention without periodic medical center visits improves walking performance. Objective: To determine whether a home-based exercise intervention consisting of a wearable activity monitor and telephone coaching improves walking ability over 9 months in patients with PAD. Design, Setting, and Participants: Randomized clinical trial conducted at 3 US medical centers. Patients with PAD were randomized between June 18, 2015, and April 4, 2017, to home-based exercise vs usual care for 9 months. Final follow-up was on December 5, 2017. Interventions: The exercise intervention group (n = 99) received 4 weekly medical center visits during the first month followed by 8 months of a wearable activity monitor and telephone coaching. The usual care group (n = 101) received no onsite sessions, active exercise, or coaching intervention. Main Outcomes and Measures: The primary outcome was change in 6-minute walk distance at 9-month follow-up (minimal clinically important difference [MCID], 20 m). Secondary outcomes included 9-month change in subcomponents of the Walking Impairment Questionnaire (WIQ) (0-100 score; 100, best), SF-36 physical functioning score, Patient-Reported Outcomes Measurement Information System (PROMIS) mobility questionnaire (higher = better; MCID, 2 points), PROMIS satisfaction with social roles questionnaire, PROMIS pain interference questionnaire (lower = better; MCID range, 3.5-4.5 points), and objectively measured physical activity. Results: Among 200 randomized participants (mean [SD] age, 70.2 [10.4] years; 105 [52.5%] women), 182 (91%) completed 9-month follow up. The mean change from baseline to 9-month follow-up in the 6-minute walk distance was 5.5 m in the intervention group vs 14.4 m in the usual care group (difference, -8.9 m; 95% CI, -26.0 to 8.2 m; P = .31). The exercise intervention worsened the PROMIS pain interference score, mean change from baseline to 9 months was 0.7 in the intervention group vs -2.8 in the usual care group (difference, 3.5; 95% CI, 1.3 to 5.8; P = .002). There were no significant between-group differences in the WIQ score, the SF-36 physical functioning score, or the PROMIS mobility or satisfaction with social roles scores. Conclusions and Relevance: Among patients with PAD, a home-based exercise intervention consisting of a wearable activity monitor and telephone coaching, compared with usual care, did not improve walking performance at 9-month follow-up. These results do not support home-based exercise interventions of wearable devices and telephone counseling without periodic onsite visits to improve walking performance in patients with PAD. Trial Registration: clinicaltrials.gov Identifier: NCT02462824. PMID- 29710171 TI - ER Opioid Overdoses Increasing. PMID- 29710172 TI - Dentists at Risk of Lung Disease? PMID- 29710173 TI - Preventing Sudden Unexpected Death in Epilepsy. PMID- 29710175 TI - Study Limitations in HLA-Mismatched Microtransplant in Older Patients Newly Diagnosed With Acute Myeloid Leukemia-Reply. PMID- 29710174 TI - Association of Marital Status With T Stage at Presentation and Management of Early-Stage Melanoma. AB - Importance: Early detection of melanoma is associated with improved patient outcomes. Data suggest that spouses or partners may facilitate detection of melanoma before the onset of regional and distant metastases. Less well known is the influence of marital status on the detection of early clinically localized melanoma. Objective: To evaluate the association between marital status and T stage at the time of presentation with early-stage melanoma and the decision for sentinel lymph node biopsy (SLNB) in appropriate patients. Design, Setting, and Participants: This retrospective, population-based study used the Surveillance, Epidemiology, and End Results database of 18 population-based registered cancer institutes. Patients with cutaneous melanoma who were at least 18 years of age and without evidence of regional or distant metastases and presented from January 1, 2010, through December 31, 2014, were identified for the study. Data were analyzed from September 27 to December 5, 2017. Exposure: Marital status, categorized as married, never married, divorced, or widowed. Main Outcomes and Measures: Clinical T stage at presentation and performance of SLNB for lesions with Breslow thickness greater than 1 mm. Results: A total of 52 063 patients were identified (58.8% men and 41.2% women; median age, 64 years; interquartile range, 52-75 years). Among married patients, 16 603 (45.7%) presented with T1a disease, compared with 3253 never married patients (43.0%), 1422 divorced patients (39.0%), and 1461 widowed patients (32.2%) (P < .001). Conversely, 428 widowed patients (9.4%) presented with T4b disease compared with 1188 married patients (3.3%) (P < .001). The association between marital status and higher T stage at presentation remained significant among never married (odds ratio [OR], 1.32; 95% CI, 1.26-1.39; P < .001), divorced (OR, 1.38; 95% CI, 1.30-1.47; P < .001), and widowed (OR, 1.70; 95% CI, 1.60-1.81; P < .001) patients after adjustment for various socioeconomic and patient factors. Independent of T stage and other patient factors, married patients were more likely to undergo SLNB in lesions with Breslow thickness greater than 1 mm, for which SLNB is routinely recommended, compared with never married (OR, 0.59; 95% CI, 0.53-0.65; P < .001), divorced (OR, 0.87; 95% CI, 0.76-0.99; P = .03), and widowed (OR, 0.69; 95% CI, 0.62-0.76; P < .001) patients. Conclusions and Relevance: Marital status is associated with earlier presentation of localized melanoma. Moreover, never married, divorced, and widowed patients are less likely to undergo SLNB for appropriate lesions. Marital status should be considered when counseling patients for melanoma procedures and when recommending screening and follow-up to optimize patient care. PMID- 29710176 TI - Lymphocyte Expression in Graves Orbitopathy. PMID- 29710178 TI - Every Cloud Has a Silver Lining: Overdose-Death Donors in Organ Transplantation. PMID- 29710179 TI - Study Limitations in HLA-Mismatched Microtransplant in Older Patients Newly Diagnosed With Acute Myeloid Leukemia. PMID- 29710177 TI - Economics of Palliative Care for Hospitalized Adults With Serious Illness: A Meta analysis. AB - Importance: Economics of care for adults with serious illness is a policy priority worldwide. Palliative care may lower costs for hospitalized adults, but the evidence has important limitations. Objective: To estimate the association of palliative care consultation (PCC) with direct hospital costs for adults with serious illness. Data Sources: Systematic searches of the Embase, PsycINFO, CENTRAL, PubMed, CINAHL, and EconLit databases were performed for English language journal articles using keywords in the domains of palliative care (eg, palliative, terminal) and economics (eg, cost, utilization), with limiters for hospital and consultation. For Embase, PsycINFO, and CENTRAL, we searched without a time limitation. For PubMed, CINAHL, and EconLit, we searched for articles published after August 1, 2013. Data analysis was performed from April 8, 2017, to September 16, 2017. Study Selection: Economic evaluations of interdisciplinary PCC for hospitalized adults with at least 1 of 7 illnesses (cancer; heart, liver, or kidney failure; chronic obstructive pulmonary disease; AIDS/HIV; or selected neurodegenerative conditions) in the hospital inpatient setting vs usual care only, controlling for a minimum list of confounders. Data Extraction and Synthesis: Eight eligible studies were identified, all cohort studies, of which 6 provided sufficient information for inclusion. The study estimated the association of PCC within 3 days of admission with direct hospital costs for each sample and for subsamples defined by primary diagnoses and number of comorbidities at admission, controlling for confounding with an instrumental variable when available and otherwise propensity score weighting. Treatment effect estimates were pooled in the meta-analysis. Main Outcomes and Measures: Total direct hospital costs. Results: This study included 6 samples with a total 133 118 patients (range, 1020-82 273), of whom 93.2% were discharged alive (range, 89.0%-98.4%), 40.8% had a primary diagnosis of cancer (range, 15.7% 100.0%), and 3.6% received a PCC (range, 2.2%-22.3%). Mean Elixhauser index scores ranged from 2.2 to 3.5 among the studies. When patients were pooled irrespective of diagnosis, there was a statistically significant reduction in costs (-$3237; 95% CI, -$3581 to -$2893; P < .001). In the stratified analyses, there was a reduction in costs for the cancer (-$4251; 95% CI, -$4664 to -$3837; P < .001) and noncancer (-$2105; 95% CI, -$2698 to -$1511; P < .001) subsamples. The reduction in cost was greater in those with 4 or more comorbidities than for those with 2 or fewer. Conclusions and Relevance: The estimated association of early hospital PCC with hospital costs may vary according to baseline clinical factors. Estimates may be larger for primary diagnosis of cancer and more comorbidities compared with primary diagnosis of noncancer and fewer comorbidities. Increasing palliative care capacity to meet national guidelines may reduce costs for hospitalized adults with serious and complex illnesses. PMID- 29710180 TI - Estimation of the Percentage of US Patients With Cancer Who Benefit From Genome Driven Oncology. AB - Importance: To date, the benefit of genome-driven cancer therapy has not been quantified. Objective: We sought to estimate the annual percentage of patients in the United States with advanced or metastatic cancer who could be eligible for and benefit from US Food and Drug Administration (FDA)-approved genome-driven therapy from 2006 to 2018. Design, Setting, and Participants: Retrospective cross sectional study using publically available data of (1) demographic characteristics of patients with advanced or metastatic cancer; (2) FDA data on cancer drugs approved from January 2006 through January 2018; (3) measures of response and duration of response from drug labels; and (4) published reports estimating the frequency of various genomic aberrations used to estimate what percentage of patients would have been eligible for and would have benefited from genome-driven therapy during the studied period. Main Outcomes and Measures: Estimated percentage of US patients with cancer eligible for and benefiting from genome-targeted and genome-informed therapy by year, response rate of genome informed indications, and duration of response. Results: A total of 31 drugs with 38 FDA-approved indications met our inclusion criteria for genome-targeted or genome-informed therapy from January 1, 2006, through January 31, 2018. The estimated number of patients eligible for genome-targeted therapy in 2006 was 28 729 of a total 564 830 patients with metastatic cancer, or 5.09% (95% CI, 5.03% 5.14%). By 2018, this number had increased to 50 811 of 609 640, or 8.33% (95% CI, 8.26%-8.40%). For genome-informed therapy in 2006, the eligible number of patients was 59 301 of 564 830, or 10.50% (95% CI, 10.42%-10.58%). In 2018, genome-informed treatment could be offered to 94 157 of 609 640, or 15.44% (95% CI, 15.35%-15.53%) of patients with metastatic cancer. The percentage of patients with cancer estimated to benefit from genome-targeted therapy in 2006 was 0.70% (95% CI, 0.68%-0.72%), and in 2018, it had increased to 4.90% (95% CI, 4.85% 4.95%). For genome-informed treatment in 2006, the percentage estimated to benefit was 1.31% (95% CI, 1.28%-1.34%), and in 2018, it had increased to 6.62% (95% CI, 6.56%-6.68%). The median overall response rate for all genome-informed drugs through January 2018 was 54%, and the median duration of response was 29.5 months. Conclusions and Relevance: Although the number of patients eligible for genome-driven treatment has increased over time, these drugs have helped a minority of patients with advanced cancer. To accelerate progress in precision oncology, novel trial designs of genomic therapies should be developed, and broad portfolios of drug development, including immunotherapeutic and cytotoxic approaches, should be pursued. PMID- 29710181 TI - What Is the Prevalence of Childhood Hypertension?: It Depends on the Definition. PMID- 29710182 TI - Surveillance of Hypoglycemia-Limitations of Emergency Department and Hospital Utilization Data. PMID- 29710183 TI - An Update on the Management of Neonatal Brachial Plexus Palsy-Replacing Old Paradigms: A Review. AB - Importance: Neonatal brachial plexus palsy (NBPP) can result in persistent deficits for those who develop it. Advances in surgical technique have resulted in the availability of safe, reliable options for treatment. Prevailing paradigms include, "all neonatal brachial plexus palsy recovers," "wait a year to see if recovery occurs," and "don't move the arm." Practicing by these principles places these patients at a disadvantage. Thus, the importance of this review is to provide an update on the management of NBPP to replace old beliefs with new paradigms. Observations: Changes within denervated muscle begin at the moment of injury, but without reinnervation become irreversible 18 to 24 months following denervation. These time-sensitive, irreversible changes are the scientific basis for the recommendations herein for the early management of NBPP and put into question the old paradigms. Early referral has become increasingly important because improved outcomes can be achieved using new management algorithms that allow surgery to be offered to patients unlikely to recover sufficiently with conservative management. Mounting evidence supports improved outcomes for appropriately selected patients with surgical management compared with natural history. Primary nerve surgery options now include nerve graft repair and nerve transfer. Specific indications continue to be elucidated, but both techniques offer a significant chance of restoration of function. Conclusions and Relevance: Mounting data support both the safety and effectiveness of surgery for patients with persistent NBPP. Despite this support, primary nerve surgery for NBPP continues to be underused. Surgery is but one part of the multidisciplinary care of NBPP. Early referral and implementation of multidisciplinary strategies give these children the best chance of functional recovery. Primary care physicians, nerve surgeons, physiatrists, and occupational and physical therapists must partner to continue to modify current treatment paradigms to provide improved quality care to neonates and children affected by NBPP. PMID- 29710184 TI - Discovering New Benefits From Old Drugs With Big Data-Promise for Parkinson Disease. PMID- 29710185 TI - Accuracy and Reliability of Eye-Based vs Quadrant-Based Diagnosis of Plus Disease in Retinopathy of Prematurity. AB - Importance: Presence of plus disease in retinopathy of prematurity is the most critical element in identifying treatment-requiring disease. However, there is significant variability in plus disease diagnosis. In particular, plus disease has been defined as 2 or more quadrants of vascular abnormality, and it is not clear whether it is more reliably and accurately diagnosed by eye-based assessment of overall retinal appearance or by quadrant-based assessment combining grades of 4 individual quadrants. Objective: To compare eye-based vs quadrant-based diagnosis of plus disease and to provide insight for ophthalmologists about the diagnostic process. Design, Setting, and Participants: In this multicenter cohort study, we developed a database of 197 wide-angle retinal images from 141 preterm infants from neonatal intensive care units at 9 academic institutions (enrolled from July 2011 to December 2016). Each image was assigned a reference standard diagnosis based on consensus image-based and clinical diagnosis. Data analysis was performed from February 2017 to September 2017. Interventions: Six graders independently diagnosed each of the 4 quadrants (cropped images) of the 197 eyes (quadrant-based diagnosis) as well as the entire image (eye-based diagnosis). Images were displayed individually, in random order. Quadrant-based diagnosis of plus disease was made when 2 or more quadrants were diagnosed as indicating plus disease by combining grades of individual quadrants post hoc. Main Outcomes and Measures: Intragrader and intergrader reliability (absolute agreement and kappa statistic) and accuracy compared with the reference standard diagnosis. Results: Of the 141 included preterm infants, 65 (46.1%) were female and 116 (82.3%) white, and the mean (SD) gestational age was 27.0 (2.6) weeks. There was variable agreement between eye-based and quadrant-based diagnosis among the 6 graders (Cohen kappa range, 0.32-0.75). Four graders showed underdiagnosis of plus disease with quadrant-based diagnosis compared with eye based diagnosis (by McNemar test). Intergrader agreement of quadrant-based diagnosis was lower than that of eye-based diagnosis (Fleiss kappa, 0.75 [95% CI, 0.71-0.78] vs 0.55 [95% CI, 0.51-0.59]). The accuracy of eye-based diagnosis compared with the reference standard diagnosis was substantial to near-perfect, whereas that of quadrant-based plus disease diagnosis was only moderate to substantial for each grader. Conclusions and Relevance: Graders had lower reliability and accuracy using quadrant-based diagnosis combining grades of individual quadrants than with eye-based diagnosis, suggesting that eye-based diagnosis has advantages over quadrant-based diagnosis. This has implications for more precise definitions of plus disease regarding the criterion of 2 or more quadrants, clinical care, computer-based image analysis, and education for all ophthalmologists who manage retinopathy of prematurity. PMID- 29710186 TI - Association of Repeated Measurements With Blood Pressure Control in Primary Care. PMID- 29710188 TI - Electrocardiographic Changes in a Woman With Anorexia Nervosa. PMID- 29710187 TI - Prevalence and Severity of High Blood Pressure Among Children Based on the 2017 American Academy of Pediatrics Guidelines. AB - Importance: Based on the new 2017 blood pressure guidelines, the prevalence of high blood pressure (BP) among adults has increased from 32% to 46%. Based on new norms and diagnostic thresholds that better align with adult definitions, new clinical practice guidelines were also published for children. The American Academy of Pediatrics clinical practice guidelines for the management of elevated BP in children replace the 2004 fourth report from the National Heart, Lung, and Blood Institute. Objectives: To assess the consequences of the American Academy of Pediatrics clinical practice guidelines for the management of elevated BP in children on the prevalence and severity of elevated BP among children and to characterize risk factors for children with new-onset hypertension or a worsening in clinical stage ("reclassified upward"). Design, Setting, and Participants: This study applied both sets of guidelines to classify BP in 15 647 generally healthy, low-risk children aged 5 to 18 years from National Health and Nutrition Examination Surveys (from January 1, 1999, to December 31, 2014). In the case control portion of the study, children whose BP was reclassified upward (cases) were matched for sex, age, and height with controls with normal BP. Anthropometric and laboratory risk factors were compared, and age- and sex specific z scores for weight, waist circumference, and body mass index were calculated. Blood pressure was measured by auscultation by trained personnel. After the child rested quietly for 5 minutes, 3 to 4 consecutive BP readings were recorded. Main Outcomes and Measures: Blood pressure percentiles and clinical classification based on either the 2017 American Academy of Pediatrics guidelines or the 2004 National Heart, Lung, and Blood Institute report. Results: Among the 15 647 children in the study (7799 girls and 7848 boys; mean [SD] age, 13.4 [2.8] years), based on the American Academy of Pediatrics guidelines, the estimated (weighted) population prevalence of elevated BP increased from 11.8% (95% CI, 11.1%-13.0%) to 14.2% (95% CI, 13.4%-15.0%). Overall, 905 of 15 584 children (5.8%) had newly diagnosed hypertension (n = 381) or a worsening in clinical stage (n = 524), which represents a substantial increase in disease burden for the health care system. Children whose BP was reclassified upward were more likely to be overweight or obese, with higher z scores for weight, waist circumference, and body mass index. The prevalence of abnormal laboratory test results was also increased, with adverse lipid profiles and increased hemoglobin A1c levels (prediabetes). Conclusions and Relevance: Clustering of cardiovascular risk factors in otherwise healthy US children suggests that those whose BP was reclassified represent a high-risk population whose cardiovascular risk may previously have been underestimated. PMID- 29710189 TI - Aortic Valve Surgery After Recent Stroke: Patience Is a Virtue. PMID- 29710190 TI - Malignant Arrhythmia in a 40-Year-Old Man. PMID- 29710191 TI - Hearing Aid Use and Health Care Costs Among Older Adults. PMID- 29710192 TI - A Closer Look at the Analgesic Regimen After Rhinoplasty. PMID- 29710193 TI - A Systematic Review of Semantic Feature Analysis Therapy Studies for Aphasia. AB - Purpose: The purpose of this study was to review treatment studies of semantic feature analysis (SFA) for persons with aphasia. The review documents how SFA is used, appraises the quality of the included studies, and evaluates the efficacy of SFA. Method: The following electronic databases were systematically searched (last search February 2017): Academic Search Complete, CINAHL Plus, E-journals, Health Policy Reference Centre, MEDLINE, PsycARTICLES, PsycINFO, and SocINDEX. The quality of the included studies was rated. Clinical efficacy was determined by calculating effect sizes (Cohen's d) or percent of nonoverlapping data when d could not be calculated. Results: Twenty-one studies were reviewed reporting on 55 persons with aphasia. SFA was used in 6 different types of studies: confrontation naming of nouns, confrontation naming of verbs, connected speech/discourse, group, multilingual, and studies where SFA was compared with other approaches. The quality of included studies was high (Single Case Experimental Design Scale average [range] = 9.55 [8.0-11]). Naming of trained items improved for 45 participants (81.82%). Effect sizes indicated that there was a small treatment effect. Conclusions: SFA leads to positive outcomes despite the variability of treatment procedures, dosage, duration, and variations to the traditional SFA protocol. Further research is warranted to examine the efficacy of SFA and generalization effects in larger controlled studies. PMID- 29710194 TI - Unverifiable Publications on Residency Applications. PMID- 29710197 TI - Incremental Benefits and Harms of the 2017 American College of Cardiology/American Heart Association High Blood Pressure Guideline. PMID- 29710195 TI - Multiple Myeloma and Its Precursor Disease Among Firefighters Exposed to the World Trade Center Disaster. AB - Importance: The World Trade Center (WTC) attacks on September 11, 2001, created an unprecedented environmental exposure to known and suspected carcinogens suggested to increase the risk of multiple myeloma. Multiple myeloma is consistently preceded by the precursor states of monoclonal gammopathy of undetermined significance (MGUS) and light-chain MGUS, detectable in peripheral blood. Objective: To characterize WTC-exposed firefighters with a diagnosis of multiple myeloma and to conduct a screening study for MGUS and light-chain MGUS. Design, Setting, and Participants: Case series of multiple myeloma in firefighters diagnosed between September 11, 2001, and July 1, 2017, together with a seroprevalence study of MGUS in serum samples collected from Fire Department of the City of New York (FDNY) firefighters between December 2013 and October 2015. Participants included all WTC-exposed FDNY white, male firefighters with a confirmed physician diagnosis of multiple myeloma (n = 16) and WTC-exposed FDNY white male firefighters older than 50 years with available serum samples (n = 781). Exposures: WTC exposure defined as rescue and/or recovery work at the WTC site between September 11, 2001, and July 25, 2002. Main Outcomes and Measures: Multiple myeloma case information, and age-adjusted and age-specific prevalence rates for overall MGUS (ie, MGUS and light-chain MGUS), MGUS, and light-chain MGUS. Results: Sixteen WTC-exposed white male firefighters received a diagnosis of multiple myeloma after September 11, 2001; median age at diagnosis was 57 years (interquartile range, 50-68 years). Serum/urine monoclonal protein isotype/free light-chain data were available for 14 cases; 7 (50%) had light chain multiple myeloma. In a subset of 7 patients, myeloma cells were assessed for CD20 expression; 5 (71%) were CD20 positive. In the screening study, we assayed peripheral blood from 781 WTC-exposed firefighters. The age-standardized prevalence rate of MGUS and light-chain MGUS combined was 7.63 per 100 persons (95% CI, 5.45-9.81), 1.8-fold higher than rates from the Olmsted County, Minnesota, white male reference population (relative rate, 1.76; 95% CI, 1.34 2.29). The age-standardized prevalence rate of light-chain MGUS was more than 3 fold higher than in the same reference population (relative rate, 3.13; 95% CI, 1.99-4.93). Conclusions and Relevance: Environmental exposure to the WTC disaster site is associated with myeloma precursor disease (MGUS and light-chain MGUS) and may be a risk factor for the development of multiple myeloma at an earlier age, particularly the light-chain subtype. PMID- 29710196 TI - Long-term Outcomes of Pediatric-Onset Hypertrophic Cardiomyopathy and Age Specific Risk Factors for Lethal Arrhythmic Events. AB - Importance: Predictors of lethal arrhythmic events (LAEs) after a pediatric diagnosis of hypertrophic cardiomyopathy (HCM) are unresolved. Existing algorithms for risk stratification are limited to patients older than 16 years because of a lack of data on younger individuals. Objective: To describe the long term outcome of pediatric-onset HCM and identify age-specific arrhythmic risk factors. Design, Setting, and Participants: This study assessed patients with pediatric-onset hypertrophic cardiomyopathy diagnosed from 1974 to 2016 in 2 national referral centers for cardiomyopathies in Florence, Italy. Patients with metabolic and syndromic disease were excluded. Exposures: Patients were assessed at 1-year intervals, or more often, if their clinical condition required. Main Outcomes and Measures: Lethal arrhythmic events (LAEs) and death related to heart failure. Results: Of 1644 patients with HCM, 100 (6.1%) were 1 to 16 years old at diagnosis (median [interquartile range], 12.2 [7.3-14.1] years). Of these, 63 (63.0%) were boys. Forty-two of the 100 patients (42.0%) were symptomatic (defined as an New York Heart Association classification higher than 1 or a Ross score greater than 2). The yield of sarcomere gene testing was 55 of 70 patients (79%). During a median of 9.2 years during which a mean of 1229 patients were treated per year, 24 of 100 patients (24.0%) experienced cardiac events (1.9% per year), including 19 LAEs and 5 heart failure-related events (3 deaths and 2 heart transplants). Lethal arrhythmic events occurred at a mean (SD) age of 23.1 (11.5) years. Two survivors of LAEs with symptoms of heart failure experienced recurrent cardiac arrest despite an implantable cardioverter defibrillator. Risk of LAE was associated with symptoms at onset (hazard ratio [HR], 8.2; 95% CI, 1.5-68.4; P = .02) and Troponin I or Troponin T gene mutations (HR, 4.1; 95% CI, 0.9-36.5; P = .06). Adult HCM risk predictors performed poorly in this population. Data analysis occurred from December 2016 to October 2017. Conclusions and Relevance: Pediatric-onset HCM is rare and associated with adverse outcomes driven mainly by arrhythmic events. Risk extends well beyond adolescence, which calls for unchanged clinical surveillance into adulthood. In this study, predictors of adverse outcomes differ from those of adult populations with HCM. In secondary prevention, the implantable cardioverter defibrillator did not confer absolute protection in the presence of limiting symptoms of heart failure. PMID- 29710198 TI - Storing and Disposing of Opioid Analgesics: What Does Our Medicine Tell Us? PMID- 29710200 TI - The Role of Telehealth in the Medical Response to Disasters. PMID- 29710199 TI - Is Putting SUGAR (Sampling Utterances of Grammatical Analysis Revised) Into Language Sample Analysis a Good Thing? A Response to Pavelko and Owens (2017). AB - Purpose: In this letter, the authors respond to Pavelko and Owens' (2017) newly advanced set of procedures for language sample analysis: Sampling Utterances and Grammatical Analysis Revised (SUGAR). Method: The authors contrast some of the new guidelines for transcription, morpheme segmentation, and language sample elicitation in SUGAR with traditional conventions for language sample analysis (LSA). They address the potential impact of the new guidelines on some of the target measures in SUGAR-mean length of utterances in morphemes (MLUm), words per sentence (WPS), and clauses per sentence (CPS)-and provide their suggestions. Results: Inclusion of partially intelligible utterances in SUGAR may over- or underestimate children's MLUm and reduce the reliability of computing WPS. Counting derivational morphemes and the component morphemes of catenatives (e.g., gonna) may result in overestimation of children's morphosyntactic skills. Conclusion: Further data are needed to determine whether MLUm including derivational morphemes and the component morphemes of catenatives is a better measure of children's morphosyntactic skills than MLUm excluding those morphemes. Pending such data, the authors recommend maintaining traditional LSA conventions and measures. Furthermore, free, fast automated utilities already exist that reduce barriers for clinicians to conduct informative, in-depth LSA. PMID- 29710201 TI - Evaluating Treatment Effect Based on Duration of Response for a Comparative Oncology Study. PMID- 29710203 TI - Lack of Information on Surgical Care for Incarcerated Persons. PMID- 29710202 TI - The Neurobiology of Opioid Addiction and the Potential for Prevention Strategies. PMID- 29710204 TI - Limitations of the National Cancer Data Base to Evaluate Early-Stage Anal Cancer Treatment Outcomes-Reply. PMID- 29710206 TI - Sensory Impairments in Heart Failure-Are We Missing the Basics?: A Teachable Moment. PMID- 29710205 TI - Patterns of Early Mental Health Diagnosis and Medication Treatment in a Medicaid Insured Birth Cohort. AB - Importance: The increased use of psychiatric services in the US pediatric population raises concerns about the appropriate use of psychotropic medications for very young children. Objective: To assess the longitudinal patterns of psychotropic medication use in association with diagnosis and duration of use in a Medicaid-insured birth cohort. Design, Setting, and Participants: A cohort design was applied to computerized Medicaid administrative claims data for 35 244 children born in a mid-Atlantic state in 2007 and followed up for up to 96 months through December 31, 2014. Children were included in the birth cohort if they had an enrollment record at birth or within 3 months of birth and at least 6 months of continuous enrollment from birth. The cohort represents 92.2% of 38 225 Medicaid-insured newborns in 2007. Exposures: Mental health treatments from birth through age 7 years. Main Outcomes and Measures: Cumulative incidence of first psychiatric diagnosis and psychotropic medication use (monotherapy or concomitant use of psychotropic medications) from birth through age 7 years, total and by sex, and the cumulative incidence of the use of psychosocial services (age, 0-7 years) as well as the annual duration of medication use (ie, number of days of psychotropic medication use among children 3-7 years of age). Results: Of the 35 244 children in the cohort, 17 267 were girls and 17 977 were boys. By age 8 years, 4550 children in the birth cohort (19.7% [percentage adjusted for right censoring]) had received a psychiatric diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification codes 290-319); 2624 of these diagnoses (57.7%) were behavioral (codes 312, 313, or 314). Girls were more likely than boys to receive an incident psychiatric diagnosis of adjustment disorder (355 of 1598 [22.2%] vs 427 of 2952 [14.5%]; P < .001) or anxiety disorder (114 of 1598 [7.1%] vs 120 of 2952 [4.1%]; P < .001). By age 8 years, 2196 children in the cohort (10.2% [percentage adjusted for right censoring]) had received a psychotropic medication. Among medication users, 1763 of 2196 (80.5% [percentage adjusted for right censoring]) received monotherapy, 343 of 2196 (16.4% [percentage adjusted for right censoring]) received 2 medication classes concomitantly, and 90 of 2196 (4.3% [percentage adjusted for right censoring]) received 3 or more medication classes concomitantly for 60 days or more (range, 78-180 days). The annual median number of days of psychotropic medication use among medicated children increased with age, reaching 210 of 365 days for children 7 years of age. Among children 7 years of age, the median number of days of use of an antipsychotic (193 days [interquartile range, 60-266 days]), stimulant (183 days [interquartile range, 86-295 days]), or alpha-agonist (199 days [interquartile range, 85-305 days]) exceeded half of the year. Conclusions and Relevance: Medicaid-insured children received substantial mental health services and had prolonged exposure to psychotropic medications in the early years of life. These findings highlight the need for outcomes research in pediatric populations. PMID- 29710207 TI - Improving Reporting Quality in Ophthalmologic Observational Studies That Use Big Data: The Case of Retinal Detachment Associated With Fluoroquinolone Use. PMID- 29710209 TI - Multiple Liver Lesions in a Woman With Asthenia, Anorexia, and Fever. PMID- 29710208 TI - Comparison Between Patient-Perceived Voice Changes and Quantitative Voice Measures in the First Postoperative Year After Thyroidectomy: A Secondary Analysis of a Randomized Clinical Trial. AB - Importance: Voice changes after thyroidectomy are typically attributed to recurrent laryngeal nerve injury. However, most postoperative voice changes occur in the absence of clinically evident vocal fold paralysis. To date, no study has compared the prevalence, duration, and consequences of voice-related disability from the patient perspective with use of quantitative vocal measures. Objectives: To assess the quality-of-life consequences of postthyroidectomy voice change from the perspective of patients with thyroid cancer and to compare patient-perceived voice changes with changes in quantitative vocal variables at 5 time points in the first postoperative year. Design, Setting, and Participants: This prospective mixed methods observational study within a randomized clinical trial occurred at the University of Wisconsin Hospital and Clinics. Participants were 42 patients with clinically node-negative papillary thyroid cancer without a preexisting vocal cord paralysis who were recruited and enrolled from outpatient clinics between June 6, 2014, and March 6, 2017, as part of the ongoing randomized clinical trial. Intervention: Total thyroidectomy. Main Outcomes and Measures: Semistructured interviews, symptom prevalence, and instrumental voice evaluations (laryngoscopy, phonation threshold pressure, Dysphonia Severity Index, and Voice Handicap Index) occurred at baseline (n = 42) and 2-week (n = 42), 6-week (n = 39), 6-month (n = 35), and 1-year (n = 30) postoperative time points. Results: Participants had a mean age of 48 years (interquartile range, 38-58 years; age range, 22-70 years) and were mostly female (74% [31 of 42]) and of white race/ethnicity (98% [41 of 42]). Impaired communication was the primary theme derived from patient interviews from before thyroidectomy to after thyroidectomy. Voice changes were perceived by 24 participants at 2 weeks after thyroidectomy. After surgery, voice symptoms were prevalent and persisted for 50% (21 of 42) of participants out to at least 1 year of follow-up. Quantitative vocal perturbations were detected in the Dysphonia Severity Index and Voice Handicap Index at the 2-week follow-up but returned to baseline levels by the 6-week follow-up visit. Conclusions and Relevance: Voice changes are common after surgery for papillary thyroid cancer and affect quality of life for many patients out to 1 year of follow-up. Directly querying patients about postoperative voice changes and questioning whether commonly used aerodynamic and acoustic variables detect meaningful voice changes are important in identifying patients whose quality of life has been affected by postthyroidectomy dysphonia. Trial Registration: ClinicalTrials.gov Identifier: NCT02138214. PMID- 29710210 TI - If You Can't Beat It, Join It: Uncertainty and Trust in Medicine. PMID- 29710211 TI - Addressing Financial Barriers to Enrollment in Clinical Trials. PMID- 29710212 TI - Effectiveness of Low Doses of Hyaluronidase to Remove Hyaluronic Acid Filler Nodules: A Randomized Clinical Trial. AB - Importance: Although hyaluronidase is known to remove hyaluronic acid fillers, use of low doses has not been well studied. Objective: To assess the effectiveness and dose-related effect of small quantities of hyaluronidase to treat hyaluronic acid filler nodules. Design, Setting, and Participants: Split arm, parallel-group, randomized clinical trial at an urban academic center. Participants were 9 healthy women. Recruitment and follow-up occurred from February 2013 to March 2014; data analysis occurred from February to July 2016. Interventions: Each participant received aliquots (buttons) of either of 2 types of hyaluronic acid fillers into bilateral upper inner arms, respectively. At 1, 2, and 3 weeks each button was treated with a constant volume (0.1 mL) of variable-dose hyaluronidase (1.5, 3.0, or 9.0 U per 0.1 mL) or saline control. Main Outcomes and Measures: Both a blinded dermatologist and the participant independently assessed detectability. Results: Seventy-two treatment sites on 9 women (mean [SD] age, 45.8 [15.7] years) received all interventions and were analyzed. There was a significant difference in physician rater assessment between saline and hyaluronidase at 4 weeks (visual detection: mean difference = 1.15; 95% CI, 0.46-1.80; P < .001; palpability: mean difference = 1.22; 95% CI, 0.61-1.83; P < .001) and 4 months (visual detection: mean difference = 0.77; 95% CI, 0.33-1.26; P = .001; palpability: mean difference = 0.82; 95% CI, 0.38-1.25; P < .001) that was mirrored by participant self-assessment at 4 weeks (visual detection: mean difference = 0.87; 95% CI, 0.26-1.48; P = .006; palpability: mean difference = 1.59; 95% CI, 1.41-1.77; P < .001) and 4 months (visual detection: mean difference = 1.31; 95% CI, 1.09-1.53; P < .001; palpability: mean difference = 1.52; 95% CI, 1.03-2.01; P < .001), and hyaluronidase was associated with greater resolution of buttons compared with normal saline. The 9.0-unit hyaluronidase injection sites were significantly less palpable than the 1.5-unit sites at both 4 weeks (mean difference = 0.50; 95% CI, 0.01-.99; P = .045) and 4 months (mean difference = 0.47; 95% CI, 0.14-0.81; P = .007). Dose dependence was more notable for Restylane-L. Conclusions and Relevance: Although very small doses of hyaluronidase can remove hyaluronic acid fillers from patient skin, slightly higher doses often result in more rapid resolution. Trial Registration: clinicaltrials.gov Identifier: NCT01722916. PMID- 29710213 TI - Novel Glial Targets and Recurrent Longitudinally Extensive Transverse Myelitis. PMID- 29710214 TI - Association Between Hearing Aid Use and Health Care Use and Cost Among Older Adults With Hearing Loss. AB - Importance: Hearing loss (HL) is common among older adults and is associated with poorer health and impeded communication. Hearing aids (HAs), while helpful in addressing some of the outcomes of HL, are not covered by Medicare. Objective: To determine whether HA use is associated with health care costs and utilization in older adults. Design, Setting, and Participants: This retrospective cohort study used nationally representative 2013-2014 Medical Expenditure Panel Survey data to evaluate the use of HAs among 1336 adults aged 65 years or older with HL. An inverse propensity score weighting was applied to adjust for potential selection bias between older adults with and without HAs, all of whom reported having HL. The mean treatment outcomes of HA use on health care utilization and costs were estimated. Exposures: Encounter with the US health care system. Main Outcomes and Measures: (1) Total health care, Medicare, and out-of-pocket spending; (2) any emergency department (ED), inpatient, and office visit; and (3) number of ED visits, nights in hospital, and office visits. Results: Of the 1336 individuals included in the study, 574 (43.0%) were women; mean (SD) age was 77 (7) years. Adults without HAs (n = 734) were less educated, had lower income, and were more likely to be from minority subpopulations. The mean treatment outcomes of using HAs per participant were (1) higher total annual health care spending by $1125 (95% CI, $1114 to $1137) and higher out-of-pocket spending by $325 (95% CI, $322 to $326) but lower Medicare spending by $71 (95% CI, -$81 to -$62); (2) lower probability of any ED visit by 2 percentage points (PPs) (24% vs 26%; 95% CI, -2% to -2%) and lower probability of any hospitalization by 2 PPs (20% vs 22%; 95% CI, -3% to -1%) but higher probability of any office visit by 4 PPs (96% vs 92%; 95% CI, 4% to 4%); and (3) 1.40 more office visits (95% CI, 1.39 to 1.41) but 0.46 (5%) fewer number of hospital nights (95% CI, -0.47 to -0.44), with no association with the number of ED visits, if any (95% CI, 0.01 to 0). Conclusions and Relevance: This study demonstrates the beneficial outcomes of use of HAs in reducing the probability of any ED visits and any hospitalizations and in reducing the number of nights in the hospital. Although use of HAs reduced total Medicare costs, it significantly increased total and out-of-pocket health care spending. This information may have implications for Medicare regarding covering HAs for patients with HL. PMID- 29710215 TI - RNA Oncoimmune Phenotyping of HPV-Positive p16-Positive Oropharyngeal Squamous Cell Carcinomas by Nodal Status. AB - Importance: Clinical trials that deintensify treatment for patients with suspected human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) use p16 expression to identify HPV-mediated tumors and guide treatment. While p16 staining has a strong correlation with good outcomes, approximately 12% of p16-positive patients have recurrent disease. Biomarkers that reveal tumor-specific characteristics, such as nodal involvement, may change therapy decisions. Objective: To assess whether if a tumor-specific genetic signature exists for node-negative vs node-positive HPV 16-positive/p16-positive OPSCCs. Design, Setting, and Participants: This was a retrospective cohort study with randomized case selection for p16 OPSCCs undertaken at a university-based, tertiary care cancer center. Samples were collected from patients with p16 positive OPSCC. A total of 21 HPV 16/p16-positive tumors were used in this study. Main Outcomes and Measures: Gene expression profiles of node-negative vs node positive tumor samples were evaluated using a differential expression analysis approach and the sensitivity and specificity of a molecular signature was determined. Results: Among the 21 patients in the study (3 women, 18 men; mean [SD] age, 54.6 [9.6] years), 6 had node-negative disease and 15 had node-positive disease. Using differential expression analysis, we found 146 genes that were significantly different in patients with node-negative disease vs those with node positive disease, of which 15 genes were used to create a genetic signature that could distinguish node-negative-like from node-positive-like disease. The resultant molecular signature has a sensitivity of 88.2% (95% CI, 63.6%-98.5%) and specificity of 85.7% (95% CI, 42.1%-99.6%). The positive likelihood ratio of this signature was 6.1 (95% CI, 1.0-38.2) and the negative likelihood ratio was 0.1 (95% CI, 0.04-0.5). Given this population's prevalence of node-positive disease of 70.8%, the positive- and negative-predicative values for this gene signature were 93.7% (95% CI, 70.8%-98.9%) and 75.0% (95% CI, 44.1%-92.0%), respectively. In addition, we developed a gene signature using agnostic, machine learning software that identified a 40-gene profile that predicts node-negative disease from node-positive disease (area under the curve, 0.93; 95% CI, 0.63 1.00). Conclusions and Relevance: Many HPV-16 and p16-positive tumors are treated as "lower-risk," but they do not have similar genetic compositions at the biological level. The identification of subgroups with unique expression patterns, such as those with nodal metastases, may guide physicians toward alternative or more aggressive therapies. In our study, unguided clustering suggested that that the larger biological characteristics of a tumor could be a better prognostic biomarker. PMID- 29710216 TI - Association of Dasatinib With Progression-Free Survival Among Patients With Advanced Gastrointestinal Stromal Tumors Resistant to Imatinib. AB - Importance: Gastrointestinal stromal tumors (GISTs) are life-threatening when metastatic or not amenable to surgical removal. In a few patients with advanced GISTs refractory to imatinib mesylate, treatment with sunitinib malate followed by regorafenib provides tumor control; however, additional active treatments are needed for most patients. Objective: To evaluate the 6-month progression-free survival (PFS), tumor objective response, and overall survival rates in patients with GISTs treated with dasatinib. Design, Setting, and Participants: This single arm clinical trial used a Bayesian design to enroll patients 13 years or older with measurable imatinib-refractory metastatic GISTs treated at 14 sarcoma referral centers from June 1, 2008, through December 31, 2009. A control group was not included. Patients were followed up for survival for a minimum of 5 years from date of enrollment. Tumor imaging using computed tomography or magnetic resonance imaging was performed every 8 weeks for the first 24 weeks and every 12 weeks thereafter. Tumor response was assessed by local site using the Choi criteria. Treatment was continued until tumor progression, unacceptable toxic effects after reduction in drug dose, or patient or physician decision. Archival tumor tissue was evaluated for expression of the proto-oncogene tyrosine-protein kinase Src (SRC), phosphorylated SRC (pSRC), and succinate dehydrogenase complex iron sulfur subunit B (SDHB) proteins and for mutation in the V-Kit Hardy Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) and platelet-derived growth factor receptor alpha (PDGFRA) genes. Data analysis was performed from May 19, 2017, through December 20, 2017. Interventions: Dasatinib, 70 mg orally twice daily. Main Outcomes and Measures: The primary end point was the 6-month PFS estimate using greater than 30% as evidence of an active drug and less than 10% as evidence of inactive treatment. Results: In this study, 50 patients were enrolled (median age, 60 years; age range, 19-78 years; 31 [62%] male and 19 [38%] female; 41 [82%] white), and 48 were evaluable for response. The estimated 6-month PFS rate was 29% in the overall population and 50% in a subset of 14 patients with pSRC in GISTs. Objective tumor response was observed in 25%, including 1 patient with an imatinib-resistant mutation in PDGFRA exon 18. Conclusions and Relevance: Dasatinib may have activity in a subset of patients with imatinib-resistant GISTs. Further study is needed to determine whether pSRC is a prognostic biomarker. PMID- 29710217 TI - Association Between Hospice Length of Stay, Health Care Utilization, and Medicare Costs at the End of Life Among Patients Who Received Maintenance Hemodialysis. AB - Importance: Patients with end-stage renal disease are less likely to use hospice services than other patients with advanced chronic illness. Little is known about the timing of hospice referral in this population and its association with health care utilization and costs. Objective: To examine the association between hospice length of stay and health care utilization and costs at the end of life among Medicare beneficiaries who had received maintenance hemodialysis. Design, Setting, and Participants: This cross-sectional observational study was conducted via the United States Renal Data System registry. Participants were all 770 191 hemodialysis patients in the registry who were enrolled in fee-for-service Medicare and died between January 1, 2000, and December 31, 2014. The dates of analysis were April 2016 to December 2017. Main Outcomes and Measures: Hospital admission, intensive care unit (ICU) admission, and receipt of an intensive procedure during the last month of life; death in the hospital; and costs to the Medicare program in the last week of life. Results: Among 770 191 patients, the mean (SD) age was 74.8 (11.0) years, and 53.7% were male. Twenty percent of cohort members were receiving hospice services when they died. Of these, 41.5% received hospice for 3 days or fewer. In adjusted analyses, compared with patients who did not receive hospice, those enrolled in hospice for 3 days or fewer were less likely to die in the hospital (13.5% vs 55.1%; P < .001) or to undergo an intensive procedure in the last month of life (17.7% vs 31.6%; P < .001) but had higher rates of hospitalization (83.6% vs 74.4%; P < .001) and ICU admission (54.0% vs 51.0%; P < .001) and similar Medicare costs in the last week of life ($10 756 vs $10 871; P = .08). Longer lengths of stay in hospice beyond 3 days were associated with progressively lower rates of utilization and costs, especially for those referred more than 15 days before death (35.1% hospitalized and 16.7% admitted to an ICU in the last month of life; the mean Medicare costs in the last week of life were $3221). Conclusions and Relevance: Overall, 41.5% of hospice enrollees who had been treated with hemodialysis for their end-stage renal disease entered hospice within 3 days of death. Although less likely to die in the hospital and to receive an intensive procedure, these patients were more likely than those not enrolled in hospice to be hospitalized and admitted to the ICU, and they had similar Medicare costs. Without addressing barriers to more timely referral, greater use of hospice may not translate into meaningful changes in patterns of health care utilization, costs, and quality of care at the end of life in this population. PMID- 29710219 TI - Conflicts of Interest of Public Speakers at Meetings of the Anesthetic and Analgesic Drug Products Advisory Committee. PMID- 29710218 TI - Fertility and Birth Outcomes in Women With Epilepsy Seeking Pregnancy. AB - Importance: Prior studies report lower birth rates for women with epilepsy (WWE) but have been unable to differentiate between biological and social contributions. To our knowledge, we do not have data to inform WWE seeking pregnancy if their likelihood of achieving pregnancy is biologically reduced compared with their peers. Objective: To determine if WWE without a prior diagnosis of infertility or related disorders are as likely to achieve pregnancy within 12 months as their peers without epilepsy. Design, Setting, and Participants: The Women With Epilepsy: Pregnancy Outcomes and Deliveries study is an observational cohort study comparing fertility in WWE with fertility in control women (CW) without epilepsy. Participants were enrolled at 4 academic medical centers and observed up to 21 months from November 2010 to May 2015. Women seeking pregnancy aged 18 to 40 years were enrolled within 6 months of discontinuing contraception. Exclusion criteria included tobacco use and a prior diagnosis of infertility or disorders that lower fertility. Eighteen WWE and 47 CW declined the study, and 40 WWE and 170 CW did not meet study criteria. The Women With Epilepsy: Pregnancy Outcomes and Deliveries electronic diary app was used to capture data on medications, seizures, sexual activity, and menses. Data were analyzed from November 2015 to June 2017. Main Outcomes and Measures: The primary outcome was proportion of women who achieved pregnancy within 12 months after enrollment. Secondary outcomes were time to pregnancy using a proportional hazard model, pregnancy outcomes, sexual activity, ovulatory rates, and analysis of epilepsy factors in WWE. All outcomes were planned prior to data collection except for time to pregnancy. Results: Of the 197 women included in the study, 142 (72.1%) were white, and the mean (SD) age was 31.9 (3.5) years among the 89 WWE and 31.1 (4.2) among the 108 CW. Among 89 WWE, 54 (60.7%) achieved pregnancy vs 65 (60.2%) among 108 CW. Median time to pregnancy was no different between the groups after controlling for key covariates (WWE: median, 6.0 months; 95% CI, 3.8 10.1; CW: median, 9.0 months; 95% CI, 6.5-11.2; P = .30). Sexual activity and ovulatory rates were similar in WWE and CW. Forty-four of 54 pregnancies (81.5%) in WWE and 53 of 65 pregnancies (81.5%) in CW resulted in live births. No epilepsy factors were significant. Conclusions and Relevance: Women with epilepsy seeking pregnancy without prior known infertility or related disorders have similar likelihood of achieving pregnancy, time to pregnancy, and live birth rates compared with their peers without epilepsy. PMID- 29710220 TI - Rate of Unverifiable Publications Among Ophthalmology Residency Applicants Invited to Interview. AB - Importance: Unverifiable publications in applications for ophthalmology residencies could be a serious concern if they represent publication dishonesty. Objective: To determine the rate of unverifiable publications among applicants offered an interview. Design: Retrospective review of 322 ophthalmology residency applications for entering classes 2012 to 2017 at Vanderbilt University School of Medicine, Nashville, Tennessee. Interventions: Full-length publications reported in the applications were searched in PubMed, Google, Google Scholar, and directly on the journal's website. Applications were deemed unverifiable if there was no record of the publication by any of these means or if substantial discrepancies existed, such as incorrect authorship, incorrect journal, or a meaningful discrepancy in title or length (full-length article vs abstract). Main Outcomes and Measures: Inability to locate publication with search, incorrect author position, applicant not listed as an author, article being an abstract and not a published paper, substantial title discrepancy suggesting an alternative project, and incorrect journal. Results: Of the 322 applicants offered interviews during the 6-year study period, 22 (6.8%) had 24 unverifiable publications. Two hundred thirty-nine of these applicants (74.2%) reported at least 1 qualifying publication; of this group, 22 (9.2%) had an unverifiable publication. The applications with unverifiable publications were evenly distributed across the years of the study (range, 2-6 per cycle; Pearson chi25 = 3.65; P = .60). Two applicants had 2 unverifiable publications each. Two of the 22 applicants (9.1%) with unverifiable publications were graduates of medical schools outside the United States. Among the unverifiable publications, the most common reason was inability to locate the publication (13 [54%]). Additional issues included abstract rather than full-length publication (5 [20.8%]), incorrect author position (4 [16.7%]), applicant not listed as an author on the publication (1 [4.2%]), and substantial title discrepancy (1 [4.2%]). One listed publication had an incorrect author position and incorrect journal (1 [4.2%]). Conclusions and Relevance: Unverifiable publications among ophthalmology residency applicants is a persistent problem. Possible strategies to modify the review process include asking applicants to provide copies of their full-length works or the relevant PMCID (PubMed Central reference number) or DOI (digital object identifier) for their publications. PMID- 29710221 TI - What Surgeons Should Know About Non-Vitamin K Oral Anticoagulants: A Review. AB - Importance: Non-vitamin K oral anticoagulants (NOACs) are increasingly prescribed for patients to treat or prevent arterial or venous thromboembolism. The following 4 NOAC agents are approved by the US Food and Drug Administration for clinical use: dabigatran etexilate, apixaban, edoxaban tosylate, and rivaroxaban. A good understanding of these agents' pharmacologic properties is important for surgeons given their marked differences compared with warfarin sodium. This review highlights key practical issues surrounding the use of NOACs in the perioperative setting. Observations: The PubMed and Cochrane Library databases were searched for English-language studies from May 1, 2009, until May 1, 2017, for randomized clinical trials, meta-analyses, systematic reviews, observational studies, and clinical guidelines. From a systematic review of the published literature that included 70 articles and 166 404 patients, this study identified 5 key practical issues surrounding the use of NOACs in the perioperative setting. These include patient populations for which NOAC use is indicated and contraindicated, the timing of NOAC treatment cessation before invasive interventions, management of NOAC-treated patients requiring urgent interventions, the need for "bridging," and the timing of NOAC treatment's reinitiation after invasive interventions. Important findings are as follows: NOAC agents are not recommended for patients with mechanical heart valves or advanced kidney disease (creatinine clearance, <15 mL/min); minimal to no anticoagulant effect remains when therapy with a NOAC is withheld for 48 to 72 hours before surgery in the context of normal kidney function; a reversal agent is clinically available for dabigatran, while reversal agents for apixaban, edoxaban, and rivaroxaban are under regulatory review; and laboratory testing of the anticoagulant effects of NOACs are not routinely available. There is a paucity of high-quality data on the optimal timing of NOAC cessation and resumption in the perioperative period, particularly for patients who undergo procedures with high bleeding risk. Conclusions and Relevance: The anticoagulant effect of NOAC agents is predictable but not readily measurable in routine clinical practice. A number of uncertainties remain surrounding the use of these agents in the perioperative setting. Ongoing prospective studies and randomized clinical trials will provide greater clarity on these management issues in the near future. PMID- 29710223 TI - Have Laryngologists Found One More Disease to Treat With a Flexible Laryngoscope and a Needle? PMID- 29710222 TI - Erratum. PMID- 29710226 TI - Association Between Functional Health Literacy and Postoperative Recovery, Health Care Contacts, and Health-Related Quality of Life Among Patients Undergoing Day Surgery: Secondary Analysis of a Randomized Clinical Trial. AB - Importance: Day surgery puts demands on the patients to manage their own recovery at home according to given instructions. Low health literacy levels are shown to be associated with poorer health outcomes. Objective: To describe functional health literacy levels among patients in Sweden undergoing day surgery and to describe the association between functional health literacy (FHL) and health care contacts, quality of recovery (SwQoR), and health-related quality of life. Design, Setting, and Participants: This observational study was part of a secondary analysis of a randomized clinical trial of patients undergoing day surgery and was performed in multiple centers from October 2015 to July 2016 and included 704 patients. Main Outcomes and Measures: The primary end point was SwQoR in the FHL groups 14 days after surgery. Secondary end points were health care contacts, EuroQol-visual analog scales, and the Short Form (36) Health Survey in the FHL groups. Results: Of 704 patients (418 [59.4%] women; mean [SD] age with inadequate or problematic FHL levels, 47 [16] years and 49 [15.1], respectively), 427 (60.7%) reported sufficient FHL, 223 (31.7%) problematic FHL, and 54 (7.7%) inadequate FHL. The global score of SwQoR indicated poor recovery in both inadequate (37.4) and problematic (22.9) FHL. There was a statistically significant difference in the global score of SwQoR (SD) between inadequate (37.4 [34.7]) and sufficient FHL (17.7 [21.0]) (P < .001). The patients with inadequate or problematic FHL had a lower health-related quality of life than the patients with sufficient FHL in terms of EuroQol-visual analog scale scores (mean [SD], 73 [19.1], 73 [19.1], and 78 [17.4], respectively; P = .008), physical function (mean [SD], 72 [22.7], 75 [23.8], and 81 [21.9], respectively; P < .001), bodily pain (mean [SD], 51 [28.7], 53 [27.4], and 61 [27.0], respectively; P = .001), vitality (mean [SD], 50 [26.7], 56 [23.5], and 62 [25.4], respectively; P < .001), social functioning (mean [SD], 73 [28.2], 81 [21.8], and 84 [23.3], respectively; P = .004), mental health (mean [SD], 65 [25.4], 73 [21.2], and 77 [21.2], respectively; P < .001), and physical component summary (mean [SD], 41 [11.2], 42 [11.3], and 45 [10.1], respectively; P = .004). There were no differences between the FHL groups regarding health care contacts. Conclusions and Relevance: Inadequate FHL in patients undergoing day surgery was associated with poorer postoperative recovery and a lower health-related quality of life. Health literacy is a relevant factor to consider for optimizing the postoperative recovery in patients undergoing day surgery. Trial Registration: ClinicalTrials.gov Identifier: NCT02492191. PMID- 29710225 TI - Prevalence and Outcomes of Amyloid Positivity Among Persons Without Dementia in a Longitudinal, Population-Based Setting. AB - Importance: Brain amyloid deposition is a marker of Alzheimer disease (AD) pathology. The population-based prevalence and outcomes of amyloid positivity in a population without dementia are important for understanding the trajectory of amyloid positivity to clinically significant outcomes and for designing AD prevention trials. Objective: To determine prevalence and outcomes of amyloid positivity in a population without dementia. Design, Setting, and Participants: In the prospective, population-based Mayo Clinic Study of Aging in Olmsted County, Minnesota, participants without dementia were randomly selected from the county population and were clinically and cognitively evaluated at baseline and every 15 months from August 1, 2008, to September 18, 2018. They were also invited to undergo carbon11-Pittburgh compound B positron emission tomography (PET) imaging. Exposures: Amyloid positivity (defined as a standardized uptake value ratio >1.42 on PET). Main Outcomes and Measures: Prevalence of amyloid positivity in the Olmsted County population without dementia and risk of progression from no cognitive impairment (ie, normal cognition for age) to incident amnestic MCI (aMCI) and from MCI or aMCI to incident AD dementia. Results: Of 3894 participants, 1671 underwent PET imaging and were included in the study; 2198 did not undergo imaging, and 25 were excluded for other reasons. The mean (SD) age of participants was 71.3 (9.8) years; 892 (53.4%) were men, and 179 (10.7%) had prevalent MCI. The prevalence of amyloid positivity without cognitive impairment in the population without dementia increased from 2.7% (95% CI, 0.5% to 4.9%) in persons aged 50 to 59 years to 41.3% (95% CI, 33.4% to 49.2%) in those aged 80 to 89 years at baseline. Prevalence of amyloid-positive MCI in the population without dementia increased from 0% in persons aged 50 to 59 years to 16.4% (95% CI, 10.3% to 22.5%) in those aged 80 to 89 years. The incident aMCI risk increased more than 2-fold in participants without cognitive impairment who were amyloid positive vs those who were amyloid negative (hazard ratio [HR], 2.26; 95% CI, 1.52 to 3.35; P < .001). The risk of AD dementia was 1.86 (95% CI, 0.89 to 3.88; P = .10) for amyloid-positive participants with MCI vs amyloid-negative participants with MCI, 1.63 (95% CI, 0.78 to 3.41; P = .20) for participants with aMCI who were amyloid positive vs amyloid negative, and 2.56 (95% CI, 1.35 to 4.88; P = .004) for amyloid-positive participants who were either without cognitive impairment or had aMCI vs those who were amyloid negative. Global cognitive and memory domain z scores declined significantly in amyloid-positive individuals during follow-up. The mean (SD) follow-up time from baseline was 3.7 (1.9) years to incident aMCI and 3.8 (2.0) years to incident AD dementia. Conclusions and Relevance: Population-based prevalence of amyloid positive status and progression rates of amyloid positivity provide valid information for designing AD prevention trials and assessing the public health outcomes of AD prevention and interventions. PMID- 29710224 TI - Hormone Replacement Therapy After Oophorectomy and Breast Cancer Risk Among BRCA1 Mutation Carriers. AB - Importance: Prophylactic bilateral salpingo-oophorectomy is recommended for BRCA1 mutation carriers to prevent ovarian cancer. Whether or not hormone replacement therapy (HRT) initiated after oophorectomy is associated with an increased risk of breast cancer has not been evaluated in a prospective study. Objective: To determine the association between HRT use and BRCA1-associated breast cancer. Design, Setting, and Participants: A prospective, longitudinal cohort study of BRCA1 and BRCA2 mutation carriers from 80 participating centers in 17 countries was conducted between 1995 and 2017 with a mean follow-up of 7.6 years. Participants had sought genetic testing for a BRCA1 or BRCA2 mutation because of a personal or family history of breast and/or ovarian cancer. Carriers of BRCA1 mutation with no personal medical history of cancer who underwent bilateral oophorectomy following enrollment were eligible for the cohort study. Exposures: A follow-up questionnaire was administered every 2 years to obtain detailed information on HRT use. A left-truncated Cox proportional hazard analysis was used to estimate the hazard ratios (HRs) and 95% CIs associated with the initiation of HRT use postoophorectomy. Main Outcomes and Measures: Incident breast cancer. Results: A total of 872 BRCA1 mutation carriers with a mean postoophorectomy follow-up period of 7.6 years (range, 0.4-22.1) were included in this study. Mean (SD) age of participants was 43.4 (8.5) years. Among these, 92 (10.6%) incident breast cancers were diagnosed. Overall, HRT use after oophorectomy was not associated with an increased risk of breast cancer. The HR was 0.97 (95% CI, 0.62-1.52; P = .89) for ever use of any type of HRT vs no use; however, the effects of estrogen alone and combination hormonal therapy were different. After 10 years of follow-up, the cumulative incidence of breast cancer among women who used estrogen-alone HRT was 12% compared with 22% among women who used estrogen plus progesterone HRT (absolute difference, 10%; log rank P = .04). Conclusions and Relevance: These findings suggest that use of estrogen after oophorectomy does not increase the risk of breast cancer among women with a BRCA1 mutation and should reassure BRCA1 mutation carriers considering preventive surgery that HRT is safe. The possible adverse effect of progesterone-containing HRT warrants further study. PMID- 29710227 TI - Man Versus Machine: Does Automated Computer Density Measurement Add Value? PMID- 29710229 TI - Association of Celecoxib Use With Decreased Opioid Requirements After Head and Neck Cancer Surgery With Free Tissue Reconstruction. AB - Importance: Head and neck cancer (HNC) surgery with free tissue reconstruction is associated with considerable postoperative pain. Opioids are typically used but can have adverse effects, including respiratory depression and high rates of dependence and addiction. Safe alternative analgesics that minimize opioid requirements are beneficial in HNC surgery. Objective: To investigate the association of celecoxib use with opioid requirements in the postoperative setting after HNC surgery with free tissue reconstruction. Design, Setting, and Participants: A retrospective, matched-cohort study of 147 patients who had undergone HNC surgery with free tissue reconstruction between June 2015 and Sept 2017 in an academic cancer hospital. Patients were separated into groups based on whether celecoxib had been used perioperatively or not. These groups were then matched by stage and site resulting in 102 included participants (51 celecoxib, 51 control). Main Outcomes and Measures: Oral, intravenous (IV), and total morphine equivalents used in the postoperative setting per patient per day. Results: There were 51 patients in the celecoxib cohort (19 women and 32 men) and 51 patients in the control cohort (20 women and 31 men) who met inclusion criteria after clinicopathologic data were matched. The mean age of the celecoxib and control cohorts was 61.6 years and 66.1 years, respectively. Treatment with celecoxib in the postoperative setting was associated with decreased mean use of opioids in oral (mean difference, 9.9 mg/d; 95% CI, -1.2 to 21.1), IV (mean difference, 3.9 mg/d; 95% CI, 1.0-6.8), and total (mean difference, 14 mg/d; 95% CI, 2.6-25.4) amount of morphine equivalents per day. When patients were matched to surgical procedure, the effect was more significant. Patients who underwent composite oral resection and received celecoxib had decreased opioid use in oral (mean difference, 25 mg/d; 95% CI, 12.5-25.4), IV (mean difference, 3.4 mg/d; 95% CI, 1.5-5.5), and total (mean difference, 28.4 mg/d; 95% CI, 15.7-41.5) amounts compared with those in the control group. There was no significant difference in complication rates between the 2 cohorts. Conclusions and Relevance: Use of celecoxib after head and neck cancer surgery and reconstruction with free tissue transfer was associated with a decrease in oral, IV, and total opioid requirements without increasing surgical or flap-related complications. PMID- 29710228 TI - Immune Profiling of Premalignant Lesions in Patients With Lynch Syndrome. AB - Importance: Colorectal carcinomas in patients with Lynch syndrome (LS) arise in a background of mismatch repair (MMR) deficiency, display a unique immune profile with upregulation of immune checkpoints, and response to immunotherapy. However, there is still a gap in understanding the pathogenesis of MMR-deficient colorectal premalignant lesions, which is essential for the development of novel preventive strategies for LS. Objective: To characterize the immune profile of premalignant lesions from a cohort of patients with LS. Design, Setting, and Participants: Whole-genome transcriptomic analysis using next-generation sequencing was performed in colorectal polyps and carcinomas of patients with LS. As comparator and model of MMR-proficient colorectal carcinogenesis, we used samples from patients with familial adenomatous polyposis (FAP). In addition, a total of 47 colorectal carcinomas (6 hypermutants and 41 nonhypermutants) were obtained from The Cancer Genome Atlas (TCGA) for comparisons. Samples were obtained from the University of Texas MD Anderson Cancer Center and "Regina Elena" National Cancer Institute, Rome, Italy. All diagnoses were confirmed by genetic testing. Polyps were collected at the time of endoscopic surveillance and tumors were collected at the time of surgical resection. The data were analyzed from October 2016 to November 2017. Main Outcomes and Measures: Assessment of the immune profile, mutational signature, mutational and neoantigen rate, and pathway enrichment analysis of neoantigens in LS premalignant lesions and their comparison with FAP premalignant lesions, LS carcinoma, and sporadic colorectal cancers from TCGA. Results: The analysis was performed in a total of 28 polyps (26 tubular adenomas and 2 hyperplastic polyps) and 3 early-stage LS colorectal tumors from 24 patients (15 [62%] female; mean [SD] age, 48.12 [15.38] years) diagnosed with FAP (n = 10) and LS (n = 14). Overall, LS polyps presented with low mutational and neoantigen rates but displayed a striking immune activation profile characterized by CD4 T cells, proinflammatory (tumor necrosis factor, interleukin 12) and checkpoint molecules (LAG3 [lymphocyte activation gene 3] and PD-L1 [programmed cell death 1 ligand 1]). This immune profile was independent of mutational rate, neoantigen formation, and MMR status. In addition, we identified a small subset of LS polyps with high mutational and neoantigen rates that were comparable to hypermutant tumors and displayed additional checkpoint (CTLA4 [cytotoxic T-lymphocyte-associated protein 4]) and neoantigens involved in DNA damage response (ATM and BRCA1 signaling). Conclusions and Relevance: These findings challenge the canonical model, based on the observations made in carcinomas, that emphasizes a dependency of immune activation on the acquisition of high levels of mutations and neoantigens, thus opening the door to the implementation of immune checkpoint inhibitors and vaccines for cancer prevention in LS. PMID- 29710231 TI - Sulfur Ointment Treatment of Cutaneous Myiasis Caused by the Tumbu Fly. PMID- 29710230 TI - Long-term Outcomes of Temporal Hollowing Augmentation by Targeted Volume Restoration of Fat Compartments in Chinese Adults. AB - Importance: Previous anatomical and clinical studies have suggested that targeted restoration of the volume and distribution of fat compartments using appropriate cannula entry sites and injection planes is an excellent fat-grafting technique for facial contouring and hand rejuvenation. Objective: To perform subjective and objective evaluations of the safe and effective profile of the targeted fat grafting technique for temporal hollowing augmentation. Design, Setting, and Participations: In a retrospective cohort study, a total of 96 consecutive patients with temporal hollowing were treated at the Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai, China, with the targeted fat-grafting technique from January 1, 2009, to January 1, 2017. Main Outcomes and Measures: The safety and efficacy profile of this technique was evaluated by the following methods: (1) a quantitative measurement of fat-graft survival and temporal augmentation rates by using 3-dimensional laser scanning, (2) a subjective assessment using a satisfaction survey and the Hollowness Severity Rating Scale (grades range from 0-3, with higher grades representing more hollowness), and (3) the complication rate. Results: Of the 96 study patients, 94 (97.9%) were women and the mean (SD) age was 34.4 (7.4) years. Of the 142 autologous fat-grafting procedures performed, the mean (SD) total follow up time was 16.3 (3.2) months, with a mean (SD) of 1.5 (0.7) procedures performed. The mean (SD) baseline volume requirement per temple for each patient was 12.8 (4.8) mL, and the total volume of the fat graft per temple was 17.8 (7.5) mL. Quantitative analysis revealed that the mean (SD) total augmentation volume per temple was 11.7 (3.0) mL, the total survival rate of the fat grafts was 65.7% (12.6%), and total augmentation rate of hollowness was 91.4% (23.4%). Subjective analysis revealed that all patients showed an improved appearance after fat grafting, and 142 temples (74.0%) exhibited clinical improvement by more than 2 grades. In all, 88 patients (91.7%) were satisfied with the outcomes, with a low complication rate reported. Conclusions and Relevance: The targeted fat-grafting technique allows the transplant of fat tissue into 4 separate fat compartments in a double-plane manner through a unique cannula entry site that avoids severe neurovascular injury. The long-term results demonstrate that this technique is an effective, reproducible, and safe approach for temporal hollowing augmentation. Level of Evidence: 4. PMID- 29710232 TI - Choosing Wisely Campaigns: A Work in Progress. PMID- 29710233 TI - Misclassification of Upper Tract Urothelial Carcinoma in Patients With Lynch Syndrome. PMID- 29710235 TI - National Institutes of Health Pathways to Prevention Workshop: Methods for Evaluating Natural Experiments in Obesity. AB - On 5 and 6 December 2017, the National Institutes of Health (NIH) convened the Pathways to Prevention Workshop: Methods for Evaluating Natural Experiments in Obesity to identify the status of methods for assessing natural experiments to reduce obesity, areas in which these methods could be improved, and research needs for advancing the field. This article considers findings from a systematic evidence review on methods for evaluating natural experiments in obesity, workshop presentations by experts and stakeholders, and public comment. Research gaps are identified, and recommendations related to 4 key issues are provided. Recommendations on population-based data sources and data integration include maximizing use and sharing of existing surveillance and research databases and ensuring significant effort to integrate and link databases. Recommendations on measurement include use of standardized and validated measures of obesity-related outcomes and exposures, systematic measurement of co-benefits and unintended consequences, and expanded use of validated technologies for measurement. Study design recommendations include improving guidance, documentation, and communication about methods used; increasing use of designs that minimize bias in natural experiments; and more carefully selecting control groups. Cross-cutting recommendations target activities that the NIH and other funders might undertake to improve the rigor of natural experiments in obesity, including training and collaboration on modeling and causal inference, promoting the importance of community engagement in the conduct of natural experiments, ensuring maintenance of relevant surveillance systems, and supporting extended follow-up assessments for exemplar natural experiments. To combat the significant public health threat posed by obesity, researchers should continue to take advantage of natural experiments. The recommendations in this report aim to strengthen evidence from such studies. PMID- 29710234 TI - Association of Postoperative Readmissions With Surgical Quality Using a Delphi Consensus Process to Identify Relevant Diagnosis Codes. AB - Importance: Postoperative readmission data are used to measure hospital performance, yet the extent to which these readmissions reflect surgical quality is unknown. Objective: To establish expert consensus on whether reasons for postoperative readmission are associated with the quality of surgery in the index admission. Design, Setting, and Participants: In a modified Delphi process, a panel of 14 experts in medical and surgical readmissions comprising physicians and nonphysicians from Veterans Affairs (VA) and private-sector institutions reviewed 30-day postoperative readmissions from fiscal years 2008 through 2014 associated with inpatient surgical procedures performed at a VA medical center between October 1, 2007, and September 30, 2014. The consensus process was conducted from January through May 2017. Reasons for readmission were grouped into categories based on International Classification of Diseases, Ninth Revision (ICD-9) diagnosis codes. Panelists were given the proportion of readmissions coded by each reason and median (interquartile range) days to readmission. They answered the question, "Does the readmission reason reflect possible surgical quality of care problems in the index admission?" on a scale of 1 (never related) to 5 (directly related) in 3 rounds of consensus building. The consensus process was completed in May 2017 and data were analyzed in June 2017. Main Outcomes and Measures: Consensus on proportion of ICD-9-coded readmission reasons that reflected quality of surgical procedure. Results: In 3 Delphi rounds, the 14 panelists achieved consensus on 50 reasons for readmission; 12 panelists also completed group telephone calls between rounds 1 and 2. Readmissions with diagnoses of infection, sepsis, pneumonia, hemorrhage/hematoma, anemia, ostomy complications, acute renal failure, fluid/electrolyte disorders, or venous thromboembolism were considered associated with surgical quality and accounted for 25 521 of 39 664 readmissions (64% of readmissions; 7.5% of 340 858 index surgical procedures). The proportion of readmissions considered to be not associated with surgical quality varied by procedure, ranging from to 21% (613 of 2331) of readmissions after lower-extremity amputations to 47% (745 of 1598) of readmissions after cholecystectomy. Conclusions and Relevance: One-third of postoperative readmissions are unlikely to reflect problems with surgical quality. Future studies should test whether restricting readmissions to those with specific ICD-9 codes might yield a more useful quality measure. PMID- 29710236 TI - The Mediterranean Diet's Fight Against Frailty. PMID- 29710237 TI - A Modern Framework for Transfer of Simulation-Based Training to the Operating Room for Practicing Surgeons. PMID- 29710239 TI - Preoperative Photographing and Morphing for Predictable Profiles in Rhinoplasty: Precision Profileplasty. PMID- 29710238 TI - Insights Into Oropharyngeal Dysphagia From Administrative Data and Clinical Registries: A Literature Review. AB - Purpose: The call for data-driven health care has been bolstered by the digitization of medical records, quality initiatives, and payment reform. Administrative databases and clinical registries are increasingly being used to study oropharyngeal dysphagia and to facilitate data-driven decision making. The objective of this work was to summarize key findings, etiologies studied, data sources used, study objectives, and quality of evidence of all original research articles that have investigated oropharyngeal dysphagia or aspiration pneumonia using administrative or clinical registry data to date. Method: A literature search was completed in MEDLINE, Scopus, and Google Scholar (January 1, 1990, to February 1, 2017). Each study that met inclusion criteria was rated for quality of evidence on a 5-point scale. Results: Eighty-four research articles were included in the final analysis (n = 221-1,649,871). Over the past 20 years, the number of new publications in this area has quintupled. Most of the administrative database and clinical registry studies of dysphagia have been retrospective cohort studies and cross-sectional studies and limited to quality of evidence levels of 3-4. In these studies, much has been learned about risk factors for dysphagia and pneumonia in defined populations and health care costs and usage. Little has been gleaned from these studies regarding swallowing physiology or dysphagia management. Conclusions: Investigators are just beginning to develop the methods to study oropharyngeal dysphagia using administrative data and clinical registries. Future research is needed in all areas, from the fundamental issue of how to identify individuals with dysphagia with high sensitivity in these data sets to evaluating treatment effectiveness. Supplemental Material: https://doi.org/10.23641/asha.6066515. PMID- 29710241 TI - New Statistical Editor-February 2018. PMID- 29710240 TI - Three Steps Toward a More Sustainable Path for Targeted Cancer Drugs. PMID- 29710242 TI - Update on Emergency and Nonemergency Use of Hyaluronidase in Aesthetic Dermatology. PMID- 29710244 TI - Behavioral Phenotyping in Health Promotion: Embracing or Avoiding Failure. PMID- 29710245 TI - Warty Fingers and Toes in a Child With Congenital Lymphedema: Elephantiasis Nostras Verrucosa. PMID- 29710243 TI - Preventability of Early Versus Late Hospital Readmissions in a National Cohort of General Medicine Patients. AB - Background: Many experts believe that hospitals with more frequent readmissions provide lower-quality care, but little is known about how the preventability of readmissions might change over the postdischarge time frame. Objective: To determine whether readmissions within 7 days of discharge differ from those between 8 and 30 days after discharge with respect to preventability. Design: Prospective cohort study. Setting: 10 academic medical centers in the United States. Patients: 822 adults readmitted to a general medicine service. Measurements: For each readmission, 2 site-specific physician adjudicators used a structured survey instrument to determine whether it was preventable and measured other characteristics. Results: Overall, 36.2% of early readmissions versus 23.0% of late readmissions were preventable (median risk difference, 13.0 percentage points [interquartile range, 5.5 to 26.4 percentage points]). Hospitals were identified as better locations for preventing early readmissions (47.2% vs. 25.5%; median risk difference, 22.8 percentage points [interquartile range, 17.9 to 31.8 percentage points]), whereas outpatient clinics (15.2% vs. 6.6%; median risk difference, 10.0 percentage points [interquartile range, 4.6 to 12.2 percentage points]) and home (19.4% vs. 14.0%; median risk difference, 5.6 percentage points [interquartile range, -6.1 to 17.1 percentage points]) were better for preventing late readmissions. Limitation: Physician adjudicators were not blinded to readmission timing, community hospitals were not included in the study, and readmissions to nonstudy hospitals were not included in the results. Conclusion: Early readmissions were more likely to be preventable and amenable to hospital-based interventions. Late readmissions were less likely to be preventable and were more amenable to ambulatory and home-based interventions. Primary Funding Source: Association of American Medical Colleges. PMID- 29710246 TI - Blurry Vision and Eye Pain After Pterygium Surgery. PMID- 29710247 TI - Examining Acoustic and Kinematic Measures of Articulatory Working Space: Effects of Speech Intensity. AB - Purpose: The purpose of this study was to examine the effect of speech intensity on acoustic and kinematic vowel space measures and conduct a preliminary examination of the relationship between kinematic and acoustic vowel space metrics calculated from continuously sampled lingual marker and formant traces. Method: Young adult speakers produced 3 repetitions of 2 different sentences at 3 different loudness levels. Lingual kinematic and acoustic signals were collected and analyzed. Acoustic and kinematic variants of several vowel space metrics were calculated from the formant frequencies and the position of 2 lingual markers. Traditional metrics included triangular vowel space area and the vowel articulation index. Acoustic and kinematic variants of sentence-level metrics based on the articulatory-acoustic vowel space and the vowel space hull area were also calculated. Results: Both acoustic and kinematic variants of the sentence level metrics significantly increased with an increase in loudness, whereas no statistically significant differences in traditional vowel-point metrics were observed for either the kinematic or acoustic variants across the 3 loudness conditions. In addition, moderate-to-strong relationships between the acoustic and kinematic variants of the sentence-level vowel space metrics were observed for the majority of participants. Conclusions: These data suggest that both kinematic and acoustic vowel space metrics that reflect the dynamic contributions of both consonant and vowel segments are sensitive to within-speaker changes in articulation associated with manipulations of speech intensity. PMID- 29710248 TI - When Physicians Turn Into Patients-Becoming Kafka's Cockroach. PMID- 29710249 TI - Beyond "Pharyngocise" for Patients With Head and Neck Cancer: Does One Size Fit All? PMID- 29710250 TI - Controversies and Future Directions of Ocular Biomarkers in Alzheimer Disease. PMID- 29710251 TI - Growth and Growth Charts in Children. PMID- 29710252 TI - Setting Achievable Benchmarks for Value-Based Payments: No Perfect Solution. PMID- 29710253 TI - Web Exclusives. Annals Graphic Medicine - Finding the Funny: Diagnosis/Surgery. PMID- 29710254 TI - Accuracy of Cardiovascular Risk Prediction Varies by Neighborhood Socioeconomic Position. PMID- 29710256 TI - After Curing Hepatitis C Virus Infection. PMID- 29710255 TI - Accuracy of Cardiovascular Risk Prediction Varies by Neighborhood Socioeconomic Position. PMID- 29710257 TI - After Curing Hepatitis C Virus Infection. PMID- 29710258 TI - The Slippery Slope of Legalization of Physician-Assisted Suicide. PMID- 29710259 TI - The Slippery Slope of Legalization of Physician-Assisted Suicide. PMID- 29710260 TI - The Slippery Slope of Legalization of Physician-Assisted Suicide. PMID- 29710261 TI - Correction: Incorrect Photographer Name. PMID- 29710262 TI - Correction: Hot Tea Consumption and Its Interactions With Alcohol and Tobacco Use on the Risk for Esophageal Cancer: A Population-Based Cohort Study. PMID- 29710263 TI - Cirrhosis. PMID- 29710264 TI - A Physician's Place in the #MeToo Movement. PMID- 29710265 TI - Acute Colonic Diverticulitis. AB - Acute colonic diverticulitis is a gastrointestinal condition frequently encountered by primary care practitioners, hospitalists, surgeons, and gastroenterologists. Clinical presentation ranges from mild abdominal pain to peritonitis with sepsis. It can often be diagnosed on the basis of clinical features alone, but imaging is necessary in more severe presentations to rule out such complications as abscess and perforation. Treatment depends on the severity of the presentation, presence of complications, and underlying comorbid conditions. Medical and surgical treatment algorithms are evolving. This article provides an evidence-based, clinically relevant overview of the epidemiology, diagnosis, and treatment of acute diverticulitis. PMID- 29710266 TI - Annals for Educators - 1 May 2018. PMID- 29710268 TI - Insights on the Nationwide Project in Osteopathic Medical Education and Empathy (POMEE). AB - Initial data from the first phase of a nationwide study of cognitive empathy, the Project in Osteopathic Medical Education and Empathy (POMEE), have been gathered. At the beginning of their first year of medical school, more than 6000 osteopathic medical students filled out the Jefferson Scale of Empathy. The POMEE principal investigator and co-investigators-Mohammadreza Hojat, PhD; Leonard H. Calabrese, DO; and Stephen C. Shannon, DO-responded to a series of questions posed by the author pertaining to the importance of POMEE and the impact the findings will have on educating osteopathic medical students. Continued success of this large-scale study will depend on the deans of the 41 participating osteopathic medical schools to continue to encourage student involvement in the study as they progress through their 4 years of undergraduate medical education. Study results will be disseminated via national and international meetings and professional journals. PMID- 29710267 TI - Association Between Cystatin C and 20-Year Cumulative Incidence of Hearing Impairment in the Epidemiology of Hearing Loss Study. AB - Importance: Hearing impairment (HI) is one of the most common conditions affecting older adults. Identification of factors associated with the development of HI may lead to ways to reduce the incidence of this condition. Objective: To investigate the association between cystatin C, both as an independent biomarker and as a marker of kidney function, and the 20-year incidence of HI. Design, Setting, and Participants: Data were obtained from the Epidemiology of Hearing Loss Study (EHLS), a longitudinal, population-based study in Beaver Dam, Wisconsin. Baseline examinations began in 1993 and continued through 1995, and participants were examined approximately every 5 years, with the most recent examination phase completed in 2015. The EHLS participants with serum cystatin C concentration data and without HI at the baseline examination were included in this study. Main Outcomes and Measures: Participants without HI were followed up for incident HI (pure-tone average of hearing thresholds at 0.5, 1, 2, and 4 kHz >25 dB hearing level in either ear) for 20 years. Cystatin C was analyzed as a biomarker (concentration) and used to determine estimated glomerular filtration rate (eGFRCysC). Discrete-time Cox proportional hazards regression models were used to analyze the association between cystatin C concentration and eGFRCysC and the 20-year cumulative incidence of HI. Results: There were 863 participants aged 48 to 86 years with cystatin C data and without HI at baseline. Of these, 599 (69.4%) were women. In models adjusted for age and sex, cystatin C was associated with an increased risk of developing HI (hazard ratio [HR], 1.20; 95% CI, 1.07 1.34 per 0.2-mg/L increase in cystatin C concentration), but the estimate was attenuated after further adjusting for educational level, current smoking, waist circumference, and glycated hemoglobin (HR, 1.11; 95% CI, 0.98-1.27 per 0.2-mg/L increase in cystatin C concentration). Low eGFRCysC was significantly associated with the 20-year cumulative incidence of HI in both the age- and sex-adjusted model (HR, 1.70; 95% CI, 1.16-2.48; <60 vs >=60 mL/min/1.73 m2) and the multivariable-adjusted model (HR, 1.50; 95% CI, 1.02-2.22; <60 vs >=60 mL/min/1.73 m2). Conclusions and Relevance: Reduced kidney function as estimated using cystatin C, but not cystatin C alone, was associated with the 20-year cumulative incidence of HI, suggesting that some age-related HI may occur in conjunction with or as the result of reduced kidney function. PMID- 29710269 TI - Association of Sickle Cell Trait With Ischemic Stroke Among African Americans: A Meta-analysis. AB - Importance: African Americans and individuals of African ancestry have a higher risk of stroke compared with non-Hispanic white individuals. Identifying the source of this disparity could provide an opportunity for clinical stroke risk stratification and more targeted therapy. Whether sickle cell trait (SCT) is an indicator of increased risk of ischemic stroke among African Americans is still unclear. Objective: To examine whether SCT is associated with a higher risk of incident ischemic stroke among African Americans. Design, Setting, and Participants: This meta-analysis assessed the association of SCT with the risk of incident ischemic stroke. Four large, prospective, population-based studies with African American cohorts were assessed: Jackson Heart Study (September 1, 2005, through December 31, 2012), Multi-Ethnic Study of Atherosclerosis (July 1, 2002, through December 31, 2012), Reasons for Geographic and Racial Differences in Stroke (January 1, 2003, through December 31, 2014), and Women's Health Initiative (October 1, 1998, through December 31, 2012). Using a Cox proportional hazards regression model adjusted for major stroke risk factors, this study estimated the hazard ratio for incident ischemic stroke associated with SCT. Data analysis was performed from July 10, 2016, to February 2, 2017. Interventions or Exposures: Participants' SCT status determined by polymerase chain reaction assay genotyping or a combination of whole-exome sequencing and imputation. Main Outcomes and Measures: Incident ischemic stroke. Results: This meta-analysis included 19 464 African American individuals (1520 with SCT, 17 944 without SCT, and 620 with ischemic stroke) from 4 studies, with a mean (SD) age of 60.0 (13.0) years (5257 [27.0%] men and 14 207 [73.0%] women). No differences were found in the distribution of risk factors for ischemic stroke comparing participants with and those without SCT at study visit 1 in each cohort. The crude incidence of ischemic stroke was 2.9 per 1000 person-years (95% CI, 2.2-4.0 per 1000 person years) among those with SCT and 3.2 per 1000 person-years (95% CI, 2.7-3.8 per 1000 person-years) among those without SCT. After stroke risk factors were adjusted for, the hazard ratio of incident ischemic stroke independently associated with SCT in the meta-analysis of all 4 cohorts was 0.80 (95% CI, 0.47 1.35; P = .82). The results of the meta-analysis were similar to those of individual cohorts, in which the results were also similar. Conclusions and Relevance: Sickle cell trait may not be associated with incidence of ischemic stroke among African Americans. The results of this study suggest performing a more thorough clinical evaluation of a stroke patient with SCT rather than assuming that SCT is the etiologic factor for the stroke. PMID- 29710270 TI - Associations of Time-Related Deployment Variables With Risk of Suicide Attempt Among Soldiers: Results From the Army Study to Assess Risk and Resilience in Servicemembers (Army STARRS). AB - Importance: There has been limited systematic examination of whether risk of suicide attempt (SA) among US Army soldiers is associated with time-related deployment variables, such as time in service before first deployment, duration of first deployment, and dwell time (DT) (ie, length of time between deployments). Objective: To examine the associations of time-related deployment variables with subsequent SA among soldiers who had deployed twice. Design, Setting, and Participants: Using administrative data from January 1, 2004, through December 31, 2009, this longitudinal, retrospective cohort study identified person-month records of active-duty Regular Army enlisted soldiers who had served continuously in the US Army for at least 2 years and deployed exactly twice. The dates of analysis were March 1 to December 1, 2017. There were 593 soldiers with a medically documented SA during or after their second deployment. An equal-probability sample of control person-months was selected from other soldiers with exactly 2 deployments (n = 19 034). Logistic regression analyses examined the associations of time in service before first deployment, duration of first deployment, and DT with subsequent SA. Main Outcomes and Measures: Suicide attempts during or after second deployment were identified using US Department of Defense Suicide Event Report records and International Classification of Diseases, Ninth Revision, Clinical Modification E950 to E958 diagnostic codes. Independent variables were constructed from US Army personnel records. Results: Among 593 SA cases, most were male (513 [86.5%]), white non-Hispanic (392 [66.1%]), at least high school educated (477 [80.4%]), currently married (398 [67.1%]), and younger than 21 years when they entered the US Army (384 [64.8%]). In multivariable models adjusting for sociodemographics, service-related characteristics, and previous mental health diagnosis, odds of SA during or after second deployment were higher among soldiers whose first deployment occurred within the first 12 months of service vs after 12 months (odds ratio, 2.0; 95% CI, 1.6-2.4) and among those with a DT of 6 months or less vs longer than 6 months (odds ratio, 1.6; 95% CI, 1.2-2.0). Duration of first deployment was not associated with subsequent SA. Analysis of 2-way interactions indicated that the associations of early deployment and DT with SA risk were not modified by other characteristics. Multivariable population-attributable risk proportions were 14.2% for deployment within the first 12 months of service and 4.0% for DT of 6 months or less. Conclusions and Relevance: Time in service before first deployment and DT are modifiable risk factors for SA risk among soldiers. PMID- 29710271 TI - Children's Acoustic and Linguistic Adaptations to Peers With Hearing Impairment. AB - Purpose: This study aims to examine the clear speaking strategies used by older children when interacting with a peer with hearing loss, focusing on both acoustic and linguistic adaptations in speech. Method: The Grid task, a problem solving task developed to elicit spontaneous interactive speech, was used to obtain a range of global acoustic and linguistic measures. Eighteen 9- to 14-year old children with normal hearing (NH) performed the task in pairs, once with a friend with NH and once with a friend with a hearing impairment (HI). Results: In HI-directed speech, children increased their fundamental frequency range and midfrequency intensity, decreased the number of words per phrase, and expanded their vowel space area by increasing F1 and F2 range, relative to NH-directed speech. However, participants did not appear to make changes to their articulation rate, the lexical frequency of content words, or lexical diversity when talking to their friend with HI compared with their friend with NH. Conclusions: Older children show evidence of listener-oriented adaptations to their speech production; although their speech production systems are still developing, they are able to make speech adaptations to benefit the needs of a peer with HI, even without being given a specific instruction to do so. Supplemental Material: https://doi.org/10.23641/asha.6118817. PMID- 29710272 TI - Association of Adjuvant Chemotherapy With Overall Survival in Patients With Rectal Cancer and Pathologic Complete Response Following Neoadjuvant Chemotherapy and Resection. AB - Importance: Adjuvant chemotherapy (AC) in patients with rectal cancer with pathologic complete response following neoadjuvant chemoradiotherapy (nCRT) and resection is recommended by treatment guidelines. However, its role in this setting is equivocal because data supporting benefits are lacking. Objective: To compare the overall survival (OS) between AC and postoperative observation (OB) in patients with rectal cancer with pathologic complete response following nCRT and resection. Design, Setting, and Participants: We identified a cohort of patients with rectal cancer and a complete pathological response (ypT0N0) after nCRT in the National Cancer Database between 2006 and 2012. Patients who received AC were compared with OB patients by propensity score matching. Overall survival was compared using the stratified log-rank test and stratified Cox regression model. The outcomes after AC vs OB were also evaluated in patient subgroups. The data analysis was completed in June 2017. Exposures: Adjuvant chemotherapy and OB. Main Outcomes and Measures: Overall survival. Results: We identified 2764 patients (mean [SD] age, 60.0 [12.3] years; 40% female) with clinical stage II or III resected adenocarcinoma of the rectum who had received nCRT and were complete responders (ypT0N0M0). Of this cohort, 741 patients in the AC group were matched by propensity score to 741 patients who underwent OB. The AC cohort had better OS compared with the OB cohort (hazard ratio, 0.50; 95% CI, 0.32-0.79). The 1-, 3-, and 5-year OS rates were 99.7%, 97.1%, and 94.7% for the AC group and 99.2%, 93.6%, and 88.4% for the OB group (P = .005). In subgroup analysis, patients with clinical stage T3/T4 and node-positive disease benefited most from AC (hazard ratio, 0.47; 95% CI, 0.25-0.91). Conclusions and Relevance: Adjuvant chemotherapy was associated with improved OS in patients with pathologic complete response after nCRT for resected locally advanced rectal cancer. This study supports the use of AC in this setting where there is currently paucity of data. PMID- 29710273 TI - Nitrofurantoin vs Fosfomycin: Rendering a Verdict in a Trial of Acute Uncomplicated Cystitis. PMID- 29710275 TI - Expression of Concern: "Consequences of Belonging to the 'Clean Plate Club'" and "Preordering School Lunch Encourages Better Food Choices by Children" by Brian Wansink. PMID- 29710274 TI - Association Between Adjuvant Chemotherapy and Overall Survival in Patients With Rectal Cancer and Pathological Complete Response After Neoadjuvant Chemotherapy and Resection. AB - Importance: Although American guidelines recommend use of adjuvant chemotherapy in patients with locally advanced rectal cancer, individuals who achieve a pathological complete response (pCR) following neoadjuvant chemoradiotherapy are less likely to receive adjuvant treatment than incomplete responders. The association and resection of adjuvant chemotherapy with survival in patients with pCR is unclear. Objective: To determine whether patients with locally advanced rectal cancer who achieve pCR after neoadjuvant chemoradiation therapy and resection benefit from the administration of adjuvant chemotherapy. Design, Setting, and Participants: This retrospective propensity score-matched cohort study identified patients with locally advanced rectal cancer from the National Cancer Database from 2006 through 2012. We selected patients with nonmetastatic invasive rectal cancer who achieved pCR after neoadjuvant chemoradiation therapy and resection. Exposures: We matched patients who received adjuvant chemotherapy to patients who did not receive adjuvant treatment in a 1:1 ratio. We separately matched subgroups of patients with node-positive disease before treatment and node-negative disease before treatment to investigate for effect modification by pretreatment nodal status. Main Outcome and Measures: We compared overall survival between groups using Kaplan-Meier survival methods and Cox proportional hazards models. Results: We identified 2455 patients (mean age, 59.5 years; 59.8% men) with rectal cancer with pCR after neoadjuvant chemoradiation therapy and resection. We matched 667 patients with pCR who received adjuvant chemotherapy and at least 8 weeks of follow-up after surgery to patients with pCR who did not receive adjuvant treatment. Over a median follow-up of 3.1 years (interquartile range, 1.94-4.40 years), patients treated with adjuvant chemotherapy demonstrated better overall survival than those who did not receive adjuvant treatment (hazard ratio, 0.44; 95% CI, 0.28-0.70). When stratified by pretreatment nodal status, only those patients with pretreatment node-positive disease exhibited improved overall survival with administration of adjuvant chemotherapy (hazard ratio, 0.24; 95% CI, 0.10-0.58). Conclusions and Relevance: The administration of adjuvant chemotherapy in patients with rectal cancer with pCR is associated with improved overall survival, particularly in patients with pretreatment node positive disease. Although this study suggests a beneficial effect of adjuvant treatment on survival in patients with pCR, these results are limited by the presence of potential unmeasured confounding in this nonrandomized study. PMID- 29710276 TI - The Prevalence of Speech and Language Disorders in French-Speaking Preschool Children From Yaounde (Cameroon). AB - Purpose: The purpose of this study was to determine the prevalence of speech and language disorders in French-speaking preschool-age children in Yaounde, the capital city of Cameroon. Method: A total of 460 participants aged 3-5 years were recruited from the 7 communes of Yaounde using a 2-stage cluster sampling method. Speech and language assessment was undertaken using a standardized speech and language test, the Evaluation du Langage Oral (Khomsi, 2001), which was purposefully renormed on the sample. A predetermined cutoff of 2 SDs below the normative mean was applied to identify articulation, expressive language, and receptive language disorders. Fluency and voice disorders were identified using clinical judgment by a speech-language pathologist. Results: Overall prevalence was calculated as follows: speech disorders, 14.7%; language disorders, 4.3%; and speech and language disorders, 17.1%. In terms of disorders, prevalence findings were as follows: articulation disorders, 3.6%; expressive language disorders, 1.3%; receptive language disorders, 3%; fluency disorders, 8.4%; and voice disorders, 3.6%. Conclusion: Prevalence figures are higher than those reported for other countries and emphasize the urgent need to develop speech and language services for the Cameroonian population. PMID- 29710277 TI - Risk Adjustment for Quality Measures Is Neither Binary nor Mandatory. PMID- 29710278 TI - Association of Expectations of Training With Attrition in General Surgery Residents. AB - Importance: Attrition from general surgery training is highest during internship. Whether the expectations and attitudes of new trainees affect their subsequent risk of attrition is unknown. Objective: To identify the expectations of general surgery residency associated with attrition from training. Design, Setting, and Participants: This prospective observational cohort study included categorical general surgery interns entering training in the 2007-2008 academic year. Residents were surveyed regarding their expectations of training and of life as an attending at the start of their intern year (June 1 to August 31, 2007). Expectations were grouped into factors by principal component analysis, and a multivariable model was created using these factors in addition to known demographic and program characteristics associated with attrition. Follow-up was completed on December 31, 2016. Main Outcomes and Measures: Attrition from training was determined by linkage to American Board of Surgery resident files through 2016, allowing 8 additional years of follow-up. Results: Of 1048 categorical surgery interns in the study period, 870 took the survey (83.0% response rate), and 828 had complete information available for analysis (524 men [63.3%], 303 women [36.6%], and 1 missing information [0.1%]). Most were white (569 [69.1%]) and at academic programs (500 [60.4%]). Six hundred sixty-six residents (80.4%) completed training. Principal component analysis generated 6 factors. On adjusted analysis, 2 factors were associated with attrition. Interns who choose their residency based on program reputation (factor 2) were more likely to drop out (odds ratio, 1.08; 95% CI, 1.01-1.15). Interns who expected as an attending to work more than 80 hours per week, to have a stressful life, and to be the subject of malpractice litigation (career life expectation [factor 6]) were less likely to drop out (odds ratio, 0.90; 95% CI, 0.82-0.98). Conclusions and Relevance: Interns with realistic expectations of the demands of residency and life as an attending may be more likely to complete training. Medical students and residents entering training should be given clear guidance in what to expect as a surgery resident. PMID- 29710279 TI - Electric Cars and Electromagnetic Interference With Cardiac Implantable Electronic Devices: A Cross-sectional Evaluation. PMID- 29710280 TI - Reducing Surgical Resident Attrition. PMID- 29710281 TI - Have Laryngologists Found One More Disease to Treat With a Flexible Laryngoscope and a Needle?-Reply. PMID- 29710282 TI - Osteopenia and Multiple Fractures in an Infant With Harlequin Ichthyosis. PMID- 29710283 TI - Intervention Techniques Used With Autism Spectrum Disorder by Speech-Language Pathologists in the United States and Taiwan: A Descriptive Analysis of Practice in Clinical Settings. AB - Purpose: This study examined intervention techniques used with children with autism spectrum disorder (ASD) by speech-language pathologists (SLPs) in the United States and Taiwan working in clinic/hospital settings. The research questions addressed intervention techniques used with children with ASD, intervention techniques used with different age groups (under and above 8 years old), and training received before using the intervention techniques. Method: The survey was distributed through the American Speech-Language-Hearing Association to selected SLPs across the United States. In Taiwan, the survey (Chinese version) was distributed through the Taiwan Speech-Language Pathologist Union, 2018, to certified SLPs. Results: Results revealed that SLPs in the United States and Taiwan used 4 common intervention techniques: Social Skill Training, Augmentative and Alternative Communication, Picture Exchange Communication System, and Social Stories. Taiwanese SLPs reported SLP preparation program training across these common intervention strategies. In the United States, SLPs reported training via SLP preparation programs, peer therapists, and self-taught. Conclusions: Most SLPs reported using established or emerging evidence-based practices as defined by the National Professional Development Center (2014) and the National Standards Report (2015). Future research should address comparison of SLP preparation programs to examine the impact of preprofessional training on use of evidence-based practices to treat ASD. PMID- 29710285 TI - A Man With Infiltrated Plaques on the Pretibial Area. PMID- 29710284 TI - Association of Survival With Adherence to the American Cancer Society Nutrition and Physical Activity Guidelines for Cancer Survivors After Colon Cancer Diagnosis: The CALGB 89803/Alliance Trial. AB - Importance: The American Cancer Society Nutrition and Physical Activity Guidelines for Cancer Survivors (ACS guidelines) include maintaining (1) a healthy body weight; (2) physical activity; and (3) a diet that includes vegetables, fruits, and whole grains. It is not known whether patients with colon cancer who follow these guidelines have improved survival. Objective: To examine whether a lifestyle consistent with the ACS guidelines is associated with improved survival rates after colon cancer. Design, Setting, and Participants: This prospective cohort study included 992 patients with stage III colon cancer who were enrolled in the CALGB 89803 randomized adjuvant chemotherapy trial from 1999 through 2001. Data for the present study were analyzed between November 2016 and December 2017. Exposures: We assigned an ACS guidelines score for each included patient based on body mass index; physical activity; and intake of vegetables, fruits, whole grains, and red/processed meats (score range, 0-6, with higher score indicating healthier behaviors). Secondarily, we examined a score that also included alcohol intake in addition to the other factors (range, 0-8). Lifestyle was assessed during and 6 months after chemotherapy. Main Outcomes and Measures: Hazard ratios (HRs) and 95% confidence intervals (CIs) for disease free, recurrence-free, and overall survival. Results: Of the 992 patients enrolled in the study, 430 (43%) were women, and the mean (SD) age was 59.6 (11.2) years (range, 21-85 years). Over a 7-year median follow-up, we observed 335 recurrences and 299 deaths (43 deaths without recurrence). Compared with patients with a 0 to 1 ACS guidelines score (n = 262; 26%), patients with a 5 to 6 score (n = 91; 9%) had a 42% lower risk of death during the study period (HR, 0.58; 95% CI, 0.34-0.99; P = .01 for trend) and improved disease-free survival (HR, 0.69; 95% CI, 0.45-1.06; P = .03 for trend). When alcohol consumption was included in the score, the adjusted HRs comparing patients with scores of 6 to 8 (n = 162; 16%) vs those with scores of 0 to 2 (187; 91%) were 0.49 for overall survival (95% CI, 0.32-0.76; P = .002 for trend), 0.58 for disease-free survival (95% CI, 0.40, 0.84; P = .01 for trend), and 0.64 for recurrence-free survival (95% CI, 0.44-0.94; P = .05 for trend). Conclusions and Relevance: Having a healthy body weight, being physically active, and eating a diet rich in vegetables, fruits, and whole grains after diagnosis of stage III colon cancer was associated with a longer survival. Trial Registration: clinicaltrials.gov Identifier: NCT00003835. PMID- 29710286 TI - Carvedilol for Treatment of Red Vulva Syndrome. PMID- 29710287 TI - Misclassification of Upper Tract Urothelial Carcinoma in Patients With Lynch Syndrome-Reply. PMID- 29710288 TI - The Drug Overdose Epidemic and Deceased-Donor Transplantation in the United States: A National Registry Study. AB - Background: The epidemic of drug overdose deaths in the United States has led to an increase in organ donors. Objective: To characterize donors who died of overdose and to analyze outcomes among transplant recipients. Design: Prospective observational cohort study. Setting: Scientific Registry of Transplant Recipients, 1 January 2000 to 1 September 2017. Participants: 138 565 deceased donors; 337 934 transplant recipients at 297 transplant centers. Measurements: The primary exposure was donor mechanism of death (overdose-death donor [ODD], trauma-death donor [TDD], or medical-death donor [MDD]). Patient and graft survival and organ discard (organ recovered but not transplanted) were compared using propensity score-weighted standardized risk differences (sRDs). Results: A total of 7313 ODDs and 19 897 ODD transplants (10 347 kidneys, 5707 livers, 2471 hearts, and 1372 lungs) were identified. Overdose-death donors accounted for 1.1% of donors in 2000 and 13.4% in 2017. They were more likely to be white (85.1%), aged 21 to 40 years (66.3%), infected with hepatitis C virus (HCV) (18.3%), and increased-infectious risk donors (IRDs) (56.4%). Standardized 5-year patient survival was similar for ODD organ recipients compared with TDD organ recipients (sRDs ranged from 3.1% lower to 3.9% higher survival) and MDD organ recipients (sRDs ranged from 2.1% to 5.2% higher survival). Standardized 5-year graft survival was similar between ODD and TDD grafts (minimal difference for kidneys and lungs, marginally lower [sRD, -3.2%] for livers, and marginally higher [sRD, 1.9%] for hearts). Kidney discard was higher for ODDs than TDDs (sRD, 5.2%) or MDDs (sRD, 1.5%); standardization for HCV and IRD status attenuated this difference. Limitation: Inability to distinguish between opioid and nonopioid overdoses. Conclusion: In the United States, transplantation with ODD organs has increased dramatically, with noninferior outcomes in transplant recipients. Concerns about IRD behaviors and hepatitis C among donors lead to excess discard that should be minimized given the current organ shortage. Primary Funding Source: National Institutes of Health. PMID- 29710291 TI - Regulating Our Enthusiasm for Self-regulation Interventions. PMID- 29710289 TI - Association of a Smartphone Application With Medication Adherence and Blood Pressure Control: The MedISAFE-BP Randomized Clinical Trial. AB - Importance: Medication nonadherence accounts for up to half of uncontrolled hypertension. Smartphone applications (apps) that aim to improve adherence are widely available but have not been rigorously evaluated. Objective: To determine if the Medisafe smartphone app improves self-reported medication adherence and blood pressure control. Design, Setting, and Participants: This was a 2-arm, randomized clinical trial (Medication Adherence Improvement Support App For Engagement-Blood Pressure [MedISAFE-BP]). Participants were recruited through an online platform and were mailed a home blood pressure cuff to confirm eligibility and to provide follow-up measurements. Of 5577 participants who were screened, 412 completed consent, met inclusion criteria (confirmed uncontrolled hypertension, taking 1 to 3 antihypertensive medications), and were randomized in a ratio of 1:1 to intervention or control. Interventions: Intervention arm participants were instructed to download and use the Medisafe app, which includes reminder alerts, adherence reports, and optional peer support. Main Outcomes and Measures: Co-primary outcomes were change from baseline to 12 weeks in self reported medication adherence, measured by the Morisky medication adherence scale (MMAS) (range, 0-8, with lower scores indicating lower adherence), and change in systolic blood pressure. Results: Participants (n = 411; 209 in the intervention group and 202 controls) had a mean age of 52.0 years and mean body mass index, calculated as weight in kilograms divided by height in meters squared, of 35.5; 247 (60%) were female, and 103 (25%) were black. After 12 weeks, the mean (SD) score on the MMAS improved by 0.4 (1.5) among intervention participants and remained unchanged among controls (between-group difference: 0.4; 95% CI, 0.1 0.7; P = .01). The mean (SD) systolic blood pressure at baseline was 151.4 (9.0) mm Hg and 151.3 (9.4) mm Hg, among intervention and control participants, respectively. After 12 weeks, the mean (SD) systolic blood pressure decreased by 10.6 (16.0) mm Hg among intervention participants and 10.1 (15.4) mm Hg among controls (between-group difference: -0.5; 95% CI, -3.7 to 2.7; P = .78). Conclusions and Relevance: Among individuals with poorly controlled hypertension, patients randomized to use a smartphone app had a small improvement in self reported medication adherence but no change in systolic blood pressure compared with controls. Trial Registration: clinicaltrials.gov Identifier: NCT02727543. PMID- 29710292 TI - All Surgical Readmissions Are Not Created Equal. PMID- 29710290 TI - Comparison of Access to Eye Care Appointments Between Patients With Medicaid and Those With Private Health Care Insurance. AB - Importance: Although low-income populations have more eye problems, whether they face greater difficulty obtaining eye care appointments is unknown. Objective: To compare rates of obtaining eye care appointments and appointment wait times for those with Medicaid vs those with private insurance. Design, Setting, and Participants: In this prospective, cohort study conducted from January 1, 2017, to July 1, 2017, researchers made telephone calls to a randomly selected sample of vision care professionals in Michigan and Maryland stratified by neighborhood (urban vs rural) and professional type (ophthalmologist vs optometrist) to request the first available appointment. Appointments were sought for an adult needing a diabetic eye examination and a child requesting a routine eye examination for a failed vision screening. Researchers called each practice twice, once requesting an appointment for a patient with Medicaid and the other time for a patient with Blue Cross Blue Shield (BCBS) insurance, and asked whether the insurance was accepted and, if so, when the earliest available appointment could be scheduled. Main Outcomes and Measures: Rate of successfully made appointments and mean wait time for the first available appointment. Results: A total of 603 telephone calls were made to 330 eye care professionals (414 calls [68.7%] to male and 189 calls [31.3%] to female eye care professionals). The sample consisted of ophthalmologists (303 [50.2%]) and optometrists (300 [49.8%]) located in Maryland (322 [53.4%]) and Michigan (281 [46.6%]). The rates of successfully obtaining appointments among callers were 61.5% (95% CI, 56.0%-67.0%) for adults with Medicaid and 79.3% (95% CI, 74.7% 83.9%) for adults with BCBS (P < .001) and 45.4% (95% CI, 39.8%-51.0%) for children with Medicaid and 62.5% (95% CI, 57.1%-68.0%) for children with BCBS (P < .001). Mean wait time did not vary significantly between the BCBS and Medicaid groups for both adults and children. Adults with Medicaid had significantly decreased odds of receiving an appointment compared with those with BCBS (odds ratio [OR], 0.41; 95% CI, 0.28-0.59; P < .001) but had increased odds of obtaining an appointment if they were located in Michigan vs Maryland (OR, 2.40; 95% CI, 1.49-3.87; P < .001) or with an optometrist vs an ophthalmologist (OR, 1.91; 95% CI, 1.31-2.79; P < .001). Children with Medicaid had significantly decreased odds of receiving an appointment compared with those with BCBS (OR, 0.41; 95% CI, 0.28-0.60; P < .001) but had increased odds of obtaining an appointment if they were located in Michigan vs Maryland (OR, 1.68; 95% CI, 1.04 2.73; P = .03) or with an optometrist vs an ophthalmologist (OR, 8.00; 95% CI, 5.37-11.90; P < .001). Conclusions and Relevance: Callers were less successful in trying to obtain eye care appointments with Medicaid than with BCBS, suggesting a disparity in access to eye care based on insurance status, although confounding factors may have contributed to this finding. Improving access to eye care professionals for those with Medicaid may improve health outcomes and decrease health care spending in the long term. PMID- 29710293 TI - Use of Vitamins and Dietary Supplements by Patients With Multiple Sclerosis: A Review. AB - Importance: Surveys of patients with multiple sclerosis report that most are interested in modifying their diet and using supplements to potentially reduce the severity and symptoms of the disease. This review provides an updated overview of the current state of evidence for the role that vitamins and dietary supplements play in multiple sclerosis and its animal models, with an emphasis on recent studies, and addresses biological plausibility and safety issues. Observations: Several vitamins and dietary supplements have been recently explored both in animal models and by patients with multiple sclerosis. Most human trials have been small or nonblinded, limiting their generalizability. Biotin and vitamin D are currently being tested in large randomized clinical trials. Smaller trials are ongoing or planned for other supplements such as lipoic acid and probiotics. The results of these studies may help guide clinical recommendations. Conclusions and Relevance: At the present time, the only vitamin with sufficient evidence to support routine supplementation for patients with multiple sclerosis is vitamin D. Vitamin deficiencies should be avoided. It is important for clinicians to know which supplements their patients are taking and to educate patients on any known efficacy data, along with any potential medication interactions and adverse effects of individual supplements. Given that dietary supplements and vitamins are not subject to the same regulatory oversight as prescription pharmaceuticals in the United States, it is recommended that vitamins and supplements be purchased from reputable manufacturers with the United States Pharmacopeia designation. PMID- 29710294 TI - Another Nail in the Coffin for Fish Oil Supplements. PMID- 29710296 TI - Lateral Wall Insufficiency Severity and Patient-Reported Nasal Obstruction Measures. PMID- 29710297 TI - Pediatric Hypertrophy Cardiomyopathy-Another Case Where Children Are Not Small Adults. PMID- 29710298 TI - Recurrent Ischemic and Hemorrhagic Strokes in a Young Adult. PMID- 29710295 TI - Effect of 5-Day Nitrofurantoin vs Single-Dose Fosfomycin on Clinical Resolution of Uncomplicated Lower Urinary Tract Infection in Women: A Randomized Clinical Trial. AB - Importance: The use of nitrofurantoin and fosfomycin has increased since guidelines began recommending them as first-line therapy for lower urinary tract infection (UTI). Objective: To compare the clinical and microbiologic efficacy of nitrofurantoin and fosfomycin in women with uncomplicated cystitis. Design, Setting, and Participants: Multinational, open-label, analyst-blinded, randomized clinical trial including 513 nonpregnant women aged 18 years and older with symptoms of lower UTI (dysuria, urgency, frequency, or suprapubic tenderness), a positive urine dipstick result (with detection of nitrites or leukocyte esterase), and no known colonization or previous infection with uropathogens resistant to the study antibiotics. Recruitment took place from October 2013 through April 2017 at hospital units and outpatient clinics in Geneva, Switzerland; Lodz, Poland; and Petah-Tiqva, Israel. Interventions: Participants were randomized in a 1:1 ratio to oral nitrofurantoin, 100 mg 3 times a day for 5 days (n = 255), or a single 3-g dose of oral fosfomycin (n = 258). They returned 14 and 28 days after therapy completion for clinical evaluation and urine culture collection. Main Outcomes and Measures: The primary outcome was clinical response in the 28 days following therapy completion, defined as clinical resolution (complete resolution of symptoms and signs of UTI without prior failure), failure (need for additional or change in antibiotic treatment due to UTI or discontinuation due to lack of efficacy), or indeterminate (persistence of symptoms without objective evidence of infection). Secondary outcomes included bacteriologic response and incidence of adverse events. Results: Among 513 patients who were randomized (median age, 44 years [interquartile range, 31-64]), 475 (93%) completed the trial and 377 (73%) had a confirmed positive baseline culture. Clinical resolution through day 28 was achieved in 171 of 244 patients (70%) receiving nitrofurantoin vs 139 of 241 patients (58%) receiving fosfomycin (difference, 12% [95% CI, 4%-21%]; P = .004). Microbiologic resolution occurred in 129 of 175 (74%) vs 103 of 163 (63%), respectively (difference, 11% [95% CI, 1%-20%]; P = .04). Adverse events were few and primarily gastrointestinal; the most common were nausea and diarrhea (7/248 [3%] and 3/248 [1%] in the nitrofurantoin group vs 5/247 [2%] and 5/247 [1%] in the fosfomycin group, respectively). Conclusions and Relevance: Among women with uncomplicated UTI, 5 day nitrofurantoin, compared with single-dose fosfomycin, resulted in a significantly greater likelihood of clinical and microbiologic resolution at 28 days after therapy completion. Trial Registration: ClinicalTrials.gov Identifier: NCT01966653. PMID- 29710299 TI - Concerns About the Approval of Nusinersen Sodium by the US Food and Drug Administration. PMID- 29710301 TI - Eye gaze direction shows a positive serial dependency. AB - Recent work from several groups has shown that perception of various visual attributes in human observers at a given moment is biased towards what was recently seen. This positive serial dependency is a kind of temporal averaging which exploits short-term correlations in visual scenes to reduce noise and stabilize perception. Here we test for serial dependencies in perception of head and eye direction using a simple reproduction method to measure perceived head/eye gaze direction in rapid sequences of briefly presented face stimuli. In a series of three experiments, our results reveal that perceived eye gaze direction shows a positive serial dependency for changes in eye direction, along both the vertical and horizontal dimensions, although more strongly for horizontal gaze shifts. By contrast, we found no serial dependency at all for horizontal changes in head position. These findings show that a perception stabilizing 'continuity field' operates on eye position-well known to be quite variable over short timescales-while the more inherently stable signal from head position does not. PMID- 29710300 TI - Davida Teller Award Lecture 2017: What can be learned from natural behavior? AB - The essentially active nature of vision has long been acknowledged but has been difficult to investigate because of limitations in the available instrumentation, both for measuring eye and body movements and for presenting realistic stimuli in the context of active behavior. These limitations have been substantially reduced in recent years, opening up a wider range of contexts where experimental control is possible. Given this, it is important to examine just what the benefits are for exploring natural vision, with its attendant disadvantages. Work over the last two decades provides insights into these benefits. Natural behavior turns out to be a rich domain for investigation, as it is remarkably stable and opens up new questions, and the behavioral context helps specify the momentary visual computations and their temporal evolution. PMID- 29710302 TI - Contributions of monocular and binocular cues to distance discrimination in natural scenes. AB - Little is known about distance discrimination in real scenes, especially at long distances. This is not surprising given the logistical difficulties of making such measurements. To circumvent these difficulties, we collected 81 stereo images of outdoor scenes, together with precisely registered range images that provided the ground-truth distance at each pixel location. We then presented the stereo images in the correct viewing geometry and measured the ability of human subjects to discriminate the distance between locations in the scene, as a function of absolute distance (3 m to 30 m) and the angular spacing between the locations being compared (2 degrees , 5 degrees , and 10 degrees ). Measurements were made for binocular and monocular viewing. Thresholds for binocular viewing were quite small at all distances (Weber fractions less than 1% at 2 degrees spacing and less than 4% at 10 degrees spacing). Thresholds for monocular viewing were higher than those for binocular viewing out to distances of 15-20 m, beyond which they were the same. Using standard cue-combination analysis, we also estimated what the thresholds would be based on binocular-stereo cues alone. With two exceptions, we show that the entire pattern of results is consistent with what one would expect from classical studies of binocular disparity thresholds and separation/size discrimination thresholds measured with simple laboratory stimuli. The first exception is some deviation from the expected pattern at close distances (especially for monocular viewing). The second exception is that thresholds in natural scenes are lower, presumably because of the rich figural cues contained in natural images. PMID- 29710303 TI - Perceptual integration of kinematic components in the recognition of emotional facial expressions. AB - According to a long-standing hypothesis in motor control, complex body motion is organized in terms of movement primitives, reducing massively the dimensionality of the underlying control problems. For body movements, this low-dimensional organization has been convincingly demonstrated by the learning of low dimensional representations from kinematic and EMG data. In contrast, the effective dimensionality of dynamic facial expressions is unknown, and dominant analysis approaches have been based on heuristically defined facial "action units," which reflect contributions of individual face muscles. We determined the effective dimensionality of dynamic facial expressions by learning of a low dimensional model from 11 facial expressions. We found an amazingly low dimensionality with only two movement primitives being sufficient to simulate these dynamic expressions with high accuracy. This low dimensionality is confirmed statistically, by Bayesian model comparison of models with different numbers of primitives, and by a psychophysical experiment that demonstrates that expressions, simulated with only two primitives, are indistinguishable from natural ones. In addition, we find statistically optimal integration of the emotion information specified by these primitives in visual perception. Taken together, our results indicate that facial expressions might be controlled by a very small number of independent control units, permitting very low-dimensional parametrization of the associated facial expression. PMID- 29710304 TI - Optimal combination of illusory and luminance-defined 3-D surfaces: A role for ambiguity. AB - The shape of the illusory surface in stereoscopic Kanizsa figures is determined by the interpolation of depth from the luminance edges of adjacent inducing elements. Despite ambiguity in the position of illusory boundaries, observers reliably perceive a coherent three-dimensional (3-D) surface. However, this ambiguity may contribute additional uncertainty to the depth percept beyond what is expected from measurement noise alone. We evaluated the intrinsic ambiguity of illusory boundaries by using a cue-combination paradigm to measure the reliability of depth percepts elicited by stereoscopic illusory surfaces. We assessed the accuracy and precision of depth percepts using 3-D Kanizsa figures relative to luminance-defined surfaces. The location of the surface peak was defined by illusory boundaries, luminance-defined edges, or both. Accuracy and precision were assessed using a depth-discrimination paradigm. A maximum likelihood linear cue combination model was used to evaluate the relative contribution of illusory and luminance-defined signals to the perceived depth of the combined surface. Our analysis showed that the standard deviation of depth estimates was consistent with an optimal cue combination model, but the points of subjective equality indicated that observers consistently underweighted the contribution of illusory boundaries. This systematic underweighting may reflect a combination rule that attributes additional intrinsic ambiguity to the location of the illusory boundary. Although previous studies show that illusory and luminance-defined contours share many perceptual similarities, our model suggests that ambiguity plays a larger role in the perceptual representation of illusory contours than of luminance-defined contours. PMID- 29710305 TI - Corrections. PMID- 29710306 TI - Feature-location effects in the Thatcher illusion. AB - Face perception is impaired for inverted images, and a prominent example of this is the Thatcher illusion: "Thatcherized" (i.e., rotated) eyes and mouths make a face look grotesque, but only if the whole face is seen upright rather than inverted. Inversion effects are often interpreted as evidence for configural face processing. However, recent findings have led to the alternative proposal that the Thatcher illusion rests on orientation sensitivity for isolated facial regions. Here, we tested whether the Thatcher effect depends not only on the orientation of facial regions but also on their visual-field location. Using a match-to-sample task with isolated eye and mouth regions we found a significant Feature * Location interaction. Observers were better at discriminating Thatcherized from normal eyes in the upper compared to the lower visual field, and vice versa for mouths. These results show that inversion effects can at least partly be driven by nonconfigural factors and that one of these factors is a match between facial features and their typical visual-field location. This echoes recent results showing feature-location effects in face individuation. We discuss the role of these findings for the hypothesis that spatial and feature tuning in the ventral stream are linked. PMID- 29710307 TI - Visual search deficits in amblyopia. AB - Amblyopia is a neurodevelopmental disorder defined as a reduction in visual acuity that cannot be corrected by optical means. It has been associated with low level deficits. However, research has demonstrated a link between amblyopia and visual attention deficits in counting, tracking, and identifying objects. Visual search is a useful tool for assessing visual attention but has not been well studied in amblyopia. Here, we assessed the extent of visual search deficits in amblyopia using feature and conjunction search tasks. We compared the performance of participants with amblyopia (n = 10) to those of controls (n = 12) on both feature and conjunction search tasks using Gabor patch stimuli, varying spatial bandwidth and orientation. To account for the low-level deficits inherent in amblyopia, we measured individual contrast and crowding thresholds and monitored eye movements. The display elements were then presented at suprathreshold levels to ensure that visibility was equalized across groups. There was no performance difference between groups on feature search, indicating that our experimental design controlled successfully for low-level amblyopia deficits. In contrast, during conjunction search, median reaction times and reaction time slopes were significantly larger in participants with amblyopia compared with controls. Amblyopia differentially affects performance on conjunction visual search, a more difficult task that requires feature binding and possibly the involvement of higher-level attention processes. Deficits in visual search may affect day-to-day functioning in people with amblyopia. PMID- 29710308 TI - Eye movement training is most effective when it involves a task-relevant sensorimotor decision. AB - Eye and hand movements are closely linked when performing everyday actions. We conducted a perceptual-motor training study to investigate mutually beneficial effects of eye and hand movements, asking whether training in one modality benefits performance in the other. Observers had to predict the future trajectory of a briefly presented moving object, and intercept it at its assumed location as accurately as possible with their finger. Eye and hand movements were recorded simultaneously. Different training protocols either included eye movements or a combination of eye and hand movements with or without external performance feedback. Eye movement training did not transfer across modalities: Irrespective of feedback, finger interception accuracy and precision improved after training that involved the hand, but not after isolated eye movement training. Conversely, eye movements benefited from hand movement training or when external performance feedback was given, thus improving only when an active interceptive task component was involved. These findings indicate only limited transfer across modalities. However, they reveal the importance of creating a training task with an active sensorimotor decision to improve the accuracy and precision of eye and hand movements. PMID- 29710309 TI - No special treatment of independent object motion for heading perception. AB - How do we judge the direction of self-motion (i.e., heading) in the presence of independent object motion? Previous studies that examined this question confounded the effects of a moving object's speed and its position on heading judgments, and did not examine whether the visual system uses salient nonmotion visual cues (such as color contrast and binocular disparity) to segment a moving object from global optic flow prior to heading estimation. The current study addressed these issues with both behavioral testing and computational modeling. Our results show that the visual system does not treat independent object motion separately for the perception of heading during self-motion. This is surprising because we all can segment a moving object from global optic flow and perceive its scene-relative motion independent of self-motion. Our findings support the claim that the perception of self-motion with independent object motion and the perception of object motion during self-motion are performed by different neural mechanisms. PMID- 29710310 TI - Suprathreshold contrast summation over area using drifting gratings. AB - This study investigated contrast summation over area for moving targets applied to a fixed-size contrast pedestal-a technique originally developed by Meese and Summers (2007) to demonstrate strong spatial summation of contrast for static patterns at suprathreshold contrast levels. Target contrast increments (drifting gratings) were applied to either the entire 20% contrast pedestal (a full fixed size drifting grating), or in the configuration of a checkerboard pattern in which the target increment was applied to every alternate check region. These checked stimuli are known as "Battenberg patterns" and the sizes of the checks were varied (within a fixed overall area), across conditions, to measure summation behavior. Results showed that sensitivity to an increment covering the full pedestal was significantly higher than that for the Battenberg patterns (areal summation). Two observers showed strong summation across all check sizes (0.71 degrees -3.33 degrees ), and for two other observers the summation ratio dropped to levels consistent with probability summation once check size reached 2.00 degrees . Therefore, areal summation with moving targets does operate at high contrast, and is subserved by relatively large receptive fields covering a square area extending up to at least 3.33 degrees * 3.33 degrees for some observers. Previous studies in which the spatial structure of the pedestal and target covaried were unable to demonstrate spatial summation, potentially due to increasing amounts of suppression from gain-control mechanisms which increases as pedestal size increases. This study shows that when this is controlled, by keeping the pedestal the same across all conditions, extensive summation can be demonstrated. PMID- 29710311 TI - Perceptual coupling induces co-rotation and speeds up alternations in adjacent bi stable structure-from-motion objects. AB - When two bi-stable structure-from-motion (SFM) spheres are presented simultaneously, they tend to rotate in the same direction. This effect reflects a common state bias that is present for various multistable displays. However, it was also reported that when two spheres are positioned so that they touch each other, they tend to counterrotate instead. The latter effect is interpreted as a frictional interaction, indicating the influence of the embedded physics on our visual perception. Here, we examined the interplay between these two biases in two experiments using a wide range of conditions. Those included two SFM shapes, two types of disambiguation cues, the presence or absence of the disambiguation cues, different layout options, and two samples of observers from two different universities (in sum 26 participants). Contrary to the prior report, we observed a robust common state bias for all conditions, including those that were optimized for frictional and "gear meshing" interactions. We found that stronger coupling of perceptual states is accompanied by more frequent synchronous perceptual reversals of the two objects. However, we found that the simultaneity of the individual switches does not predict the duration of the following dominance phase. Finally, we report that stronger perceptual coupling speeds up perceptual alternations. PMID- 29710313 TI - Gaze Toward Naturalistic Social Scenes by Individuals With Intellectual and Developmental Disabilities: Implications for Augmentative and Alternative Communication Designs. AB - Purpose: A striking characteristic of the social communication deficits in individuals with autism is atypical patterns of eye contact during social interactions. We used eye-tracking technology to evaluate how the number of human figures depicted and the presence of sharing activity between the human figures in still photographs influenced visual attention by individuals with autism, typical development, or Down syndrome. We sought to examine visual attention to the contents of visual scene displays, a growing form of augmentative and alternative communication support. Method: Eye-tracking technology recorded point of-gaze while participants viewed 32 photographs in which either 2 or 3 human figures were depicted. Sharing activities between these human figures are either present or absent. The sampling rate was 60 Hz; that is, the technology gathered 60 samples of gaze behavior per second, per participant. Gaze behaviors, including latency to fixate and time spent fixating, were quantified. Results: The overall gaze behaviors were quite similar across groups, regardless of the social content depicted. However, individuals with autism were significantly slower than the other groups in latency to first view the human figures, especially when there were 3 people depicted in the photographs (as compared with 2 people). When participants' own viewing pace was considered, individuals with autism resembled those with Down syndrome. Conclusion: The current study supports the inclusion of social content with various numbers of human figures and sharing activities between human figures into visual scene displays, regardless of the population served. Study design and reporting practices in eye-tracking literature as it relates to autism and Down syndrome are discussed. Supplemental Material: https://doi.org/10.23641/asha.6066545. PMID- 29710312 TI - The role of gaze and prior knowledge on allocentric coding of reach targets. AB - In this study, we investigated the influence of gaze and prior knowledge about the reach target on the use of allocentric information for memory-guided reaching. Participants viewed a breakfast scene with five objects in the background and six objects on the table. Table objects served as potential reach targets. Participants first encoded the scene and, after a short delay, a test scene was presented with one table object missing and one, three, or five table objects horizontally shifted in the same direction. Participants performed a memory-guided reaching movement toward the position of the missing object on a blank screen. In order to examine the influence of gaze, participants either freely moved their gaze (free-view) or kept gaze at a fixation point (fixation) throughout the trial. The effect of prior knowledge was investigated by informing participants about the reach target either before (preview) or after (nonpreview) scene encoding. Our results demonstrate that humans use allocentric information for reaching even if a stable retinal reference is available. However, allocentric coding of reach targets is stronger when gaze is free and prior knowledge about the reach target is missing. PMID- 29710314 TI - Auditory-Perceptual Assessment of Fluency in Typical and Neurologically Disordered Speech. AB - Purpose: The aim of this study is to investigate how speech fluency in typical and atypical speech is perceptually assessed by speech-language pathologists (SLPs). Our research questions were as follows: (a) How do SLPs rate fluency in speakers with and without neurological communication disorders? (b) Do they differentiate the speaker groups? and (c) What features do they hear impairing speech fluency? Method: Ten SLPs specialized in neurological communication disorders volunteered as expert judges to rate 90 narrative speech samples on a Visual Analogue Scale (see Kempster, Gerratt, Verdolini Abbott, Barkmeier Kraemer, & Hillman, 2009; p. 127). The samples-randomly mixed-were from 70 neurologically healthy speakers (the control group) and 20 speakers with traumatic brain injury, 10 of whom had neurogenic stuttering (designated as Clinical Groups A and B). Results: The fluency rates were higher for typical speakers than for speakers with traumatic brain injury; however, the agreement among the judges was higher for atypical fluency. Auditory-perceptual assessment of fluency was significantly impaired by the features of stuttering and something else but not by speech rate. Stuttering was also perceived in speakers not diagnosed as stutterers. A borderline between typical and atypical fluency was found. Conclusions: Speech fluency is a multifaceted phenomenon, and on the basis of this study, we suggest a more general approach to fluency and its deviations that will take into account, in addition to the motor and linguistic aspects of fluency, the metalinguistic component of expression as well. The results of this study indicate a need for further studies on the precise nature of borderline fluency and its different disfluencies. PMID- 29710315 TI - Do Electric Cars Interfere With Pacemakers and Defibrillators? PMID- 29710316 TI - Hospice Use and End-of-Life Care for Patients With End-stage Renal Disease: Too Little, Too Late. PMID- 29710317 TI - Association of Substance Use Disorders With Conversion From Schizotypal Disorder to Schizophrenia. AB - Importance: Understanding the role of substance use disorders in conversion from schizotypal disorder to schizophrenia may provide physicians and psychiatrists with important tools for prevention or early detection of schizophrenia. Objective: To investigate whether substance use disorders, in particular cannabis use disorder, are associated with conversion to schizophrenia in individuals with schizotypal disorder. Design, Setting, and Participants: This prospective cohort study included a population-based sample of all individuals born in Denmark from January 1, 1981, through August 10, 2014, with an incident diagnosis of schizotypal disorder and without a previous diagnosis of schizophrenia. Follow-up was completed on August 10, 2014, and data were analyzed from March 10, 2017, through February 15, 2018. Exposures: Information on substance use disorders combined from 5 different registers. Main Outcomes and Measures: Cox proportional hazards regression using time-varying information on substance use disorders and receipt of antipsychotics and adjusted for parental history of mental disorders, sex, birth year, and calendar year were used to estimate hazard ratios (HRs) and 95% CIs for conversion to schizophrenia. Results: A total of 2539 participants with incident schizotypal disorder were identified (1448 men [57.0%] and 1091 women [43.0%]; mean [SD] age, 20.9 [4.4] years). After 2 years, 16.3% (95% CI, 14.8%-17.8%) experienced conversion to schizophrenia. After 20 years, the conversion rate was 33.1% (95% CI, 29.3%-37.3%) overall and 58.2% (95% CI, 44.8% 72.2%) among those with cannabis use disorders. In fully adjusted models, any substance use disorder was associated with conversion to schizophrenia (HR, 1.34; 95% CI, 1.11-1.63). When data were stratified by substance, cannabis use disorders (HR, 1.30; 95% CI, 1.01-1.68), amphetamine use disorders (HR, 1.90; 95% CI, 1.14-3.17), and opioid use disorders (HR, 2.74; 95% CI, 1.38-5.45) were associated with conversion to schizophrenia. These associations were not explained by concurrent use of antipsychotics, functional level before incident schizotypal disorder, or parental history of mental disorders. Conclusions and Relevance: Substance use disorders, in particular cannabis, amphetamines, and opioids, may be associated with conversion from schizotypal disorder to schizophrenia. However, conversion rates are high even in those without substance use disorders, indicating a need for universal and substance-targeted prevention in individuals with schizotypal disorder. PMID- 29710318 TI - A 3-Dimensional-Printed Short-Segment Template Prototype for Mandibular Fracture Repair. AB - Importance: After reduction of complex mandibular fractures, contouring of the fracture plates to fixate the reduced mandibular segments can be time-consuming. Objective: To explore the potential application of a 3-dimensional (3-D)-printed short-segment mandibular template in the management of complex mandibular fractures. Design, Setting, and Participants: A feasibility study was performed at a tertiary academic center using maxillofacial computed tomography data of 3 patients with comminuted mandibular fractures who required preoperative planning with a perfected complete mandible model. Interventions: Thresholding, segmentation, and realignment of the fractured mandible were performed based on computed tomography data. Each reduced mandible design was divided to create 3-D templates for 6 fracture sites: right and left angle, body, and symphyseal/parasymphyseal. Sessions were conducted with junior otolaryngology and plastic surgery residents, during which mandibular fracture plates were contoured in a "preoperative" setting against the 3-D-printed short-segment templates, and an "intraoperative" setting against the previously manufactured, complete mandible model. The previously manufactured, complete model served as a surrogate for the intraoperative mandible with the fracture site reduced. Main Outcomes and Measures: The time for 3-D template printing, the "preoperative" (measure of the time consumed preoperatively), and "intraoperative" (measure of the time saved intraoperatively) times were recorded. Comparisons were made for cost estimates between a complete model and the 3-D-printed short-segment template. The operating room charge equivalent of the intraoperative time was also calculated. Results: Of the 3 patients whose data were used, 1 was a teenager and 2 were young adults. The total time for 3-D modeling and printing per short-segment template was less than 3 hours. The median (range) intraoperative time saved by precontouring the fracture plates was 7 (1-14), 5 (1-30), and 7 (2-15) minutes, and the operating room charge equivalents were $350.35 ($50.05-$700.70), $250 ($50.05-$1501.50), and $350.35 ($100.10-$750.75) for the angle, body, and symphyseal/parasymphyseal segments, respectively. The total cost for a single 3-D printed template was less than $20, while that for a perfected complete model was approximately $2200. Conclusions and Relevance: We demonstrate that patient- and site-specific 3-D-printed short-segment templates can be created within the timeframe required for mandibular fracture repair. These novel 3-D-printed templates also demonstrate cost efficiency in the preoperative planning for complex mandibular fracture management compared with perfected models and facilitate plate contouring in a similar fashion. Estimation of reduced operative room cost and time with the application of these short-segment templates warrants studies in actual patient care. Level of Evidence: NA. PMID- 29710319 TI - Suprasegmental Features Are Not Acquired Early: Perception and Production of Monosyllabic Cantonese Lexical Tones in 4- to 6-Year-Old Preschool Children. AB - Purpose: Previous studies reported that children acquire Cantonese tones before 3 years of age, supporting the assumption in models of phonological development that suprasegmental features are acquired rapidly and early in children. Yet, recent research found a large disparity in the age of Cantonese tone acquisition. This study investigated Cantonese tone development in 4- to 6-year-old children. Method: Forty-eight 4- to 6-year-old Cantonese-speaking children and 28 mothers of the children labeled 30 pictures representing familiar words in the 6 tones in a picture-naming task and identified pictures representing words in different Cantonese tones in a picture-pointing task. To control for lexical biases in tone assessment, tone productions were low-pass filtered to eliminate lexical information. Five judges categorized the tones in filtered stimuli. Tone production accuracy, tone perception accuracy, and correlation between tone production and perception accuracy were examined. Results: Children did not start to produce adultlike tones until 5 and 6 years of age. Four-year-olds produced none of the tones with adultlike accuracy. Five- and 6-year-olds attained adultlike productions in 2 (T5 and T6) to 3 (T4, T5, and T6) tones, respectively. Children made better progress in tone perception and achieved higher accuracy in perception than in production. However, children in all age groups perceived none of the tones as accurately as adults, except that T1 was perceived with adultlike accuracy by 6-year-olds. Only weak association was found between children's tone perception and production accuracy. Conclusions: Contradicting to the long-held assumption that children acquire lexical tone rapidly and early before the mastery of segmentals, this study found that 4- to 6-year-old children have not mastered the perception or production of the full set of Cantonese tones in familiar monosyllabic words. Larger development was found in children's tone perception than tone production. The higher tone perception accuracy but weak correlation between tone perception and production abilities in children suggested that tone perception accuracy is not sufficient for children's tone production accuracy. The findings have clinical and theoretical implications. PMID- 29710320 TI - Value-Based Pricing for Drugs: Theme and Variations. PMID- 29710321 TI - Error in Data. PMID- 29710323 TI - New Prevention Guidelines for Falls and Fractures-Looking Beyond the Letters. PMID- 29710322 TI - Effects of Milk vs Dark Chocolate Consumption on Visual Acuity and Contrast Sensitivity Within 2 Hours: A Randomized Clinical Trial. AB - Importance: Consumption of dark chocolate can improve blood flow, mood, and cognition in the short term, but little is known about the possible effects of dark chocolate on visual performance. Objective: To compare the short-term effects of consumption of dark chocolate with those of milk chocolate on visual acuity and large- and small-letter contrast sensitivity. Design: A randomized, single-masked crossover design was used to assess short-term visual performance after consumption of a dark or a milk chocolate bar. Thirty participants without pathologic eye disease each consumed dark and milk chocolate in separate sessions, and within-participant paired comparisons were used to assess outcomes. Testing was conducted at the Rosenberg School of Optometry from June 25 to August 15, 2017. Main Outcomes and Measures: Visual acuity (in logMAR units) and large- and small-letter contrast sensitivity (in the log of the inverse of the minimum detectable contrast [logCS units]) were measured 1.75 hours after consumption of dark and milk chocolate bars. Results: Among the 30 participants (9 men and 21 women; mean [SD] age, 26 [5] years), small-letter contrast sensitivity was significantly higher after consumption of dark chocolate (mean [SE], 1.45 [0.04] logCS) vs milk chocolate (mean [SE], 1.30 [0.05] logCS; mean improvement, 0.15 logCS [95% CI, 0.08-0.22 logCS]; P < .001). Large-letter contrast sensitivity was slightly higher after consumption of dark chocolate (mean [SE], 2.05 [0.02] logCS) vs milk chocolate (mean [SE], 2.00 [0.02] logCS; mean improvement, 0.05 logCS [95% CI, 0.00-0.10 logCS]; P = .07). Visual acuity improved slightly after consumption of dark chocolate (mean [SE], -0.22 [0.01] logMAR; visual acuity, approximately 20/12) and milk chocolate (mean [SE], -0.18 [0.01] logMAR; visual acuity, approximately 20/15; mean improvement, 0.04 logMAR [95% CI, 0.02-0.06 logMAR]; P = .05). Composite scores combining results from all tests showed significant improvement after consumption of dark compared with milk chocolate (mean improvement, 0.20 log U [95% CI, 0.10-0.30 log U]; P < .001). Conclusions and Relevance: Contrast sensitivity and visual acuity were significantly higher 2 hours after consumption of a dark chocolate bar compared with a milk chocolate bar, but the duration of these effects and their influence in real-world performance await further testing. Trial Registration: clinicaltrials.gov Identifier: NCT03326934. PMID- 29710324 TI - Development and Validation of a Calculator for Estimating the Probability of Urinary Tract Infection in Young Febrile Children. AB - Importance: Accurately estimating the probability of urinary tract infection (UTI) in febrile preverbal children is necessary to appropriately target testing and treatment. Objective: To develop and test a calculator (UTICalc) that can first estimate the probability of UTI based on clinical variables and then update that probability based on laboratory results. Design, Setting, and Participants: Review of electronic medical records of febrile children aged 2 to 23 months who were brought to the emergency department of Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania. An independent training database comprising 1686 patients brought to the emergency department between January 1, 2007, and April 30, 2013, and a validation database of 384 patients were created. Five multivariable logistic regression models for predicting risk of UTI were trained and tested. The clinical model included only clinical variables; the remaining models incorporated laboratory results. Data analysis was performed between June 18, 2013, and January 12, 2018. Exposures: Documented temperature of 38 degrees C or higher in children aged 2 months to less than 2 years. Main Outcomes and Measures: With the use of culture-confirmed UTI as the main outcome, cutoffs for high and low UTI risk were identified for each model. The resultant models were incorporated into a calculation tool, UTICalc, which was used to evaluate medical records. Results: A total of 2070 children were included in the study. The training database comprised 1686 children, of whom 1216 (72.1%) were female and 1167 (69.2%) white. The validation database comprised 384 children, of whom 291 (75.8%) were female and 200 (52.1%) white. Compared with the American Academy of Pediatrics algorithm, the clinical model in UTICalc reduced testing by 8.1% (95% CI, 4.2%-12.0%) and decreased the number of UTIs that were missed from 3 cases to none. Compared with empirically treating all children with a leukocyte esterase test result of 1+ or higher, the dipstick model in UTICalc would have reduced the number of treatment delays by 10.6% (95% CI, 0.9%-20.4%). Conclusions and Relevance: UTICalc estimates the probability of UTI by evaluating the risk factors present in the individual child. As a result, testing and treatment can be tailored, thereby improving outcomes for children with UTI. PMID- 29710326 TI - Can Retail Clinics Transform Health Care? PMID- 29710325 TI - Delays in the Publication of Important Clinical Trial Findings in Oncology. AB - Importance: The complete and timely dissemination of clinical trial data is essential to all fields of medicine, with delayed or incomplete data release having potentially deleterious effects on both patient care and scientific inquiry. While prior analyses have noted a substantial lag in the reporting of final clinical study results, we sought to refine these observations through use of a novel starting point for the measurement of dissemination delays: the date of a corporate press release regarding a phase 3 study's results. Objective: To measure the length of time elapsed between when a sponsor had results of study findings they deemed important to announce, and when the medical community had access to them. Design and Setting: Covering the years 2011 through 2016, we measured the delay from when 8 large pharmaceutical companies issued a press release announcing completed analyses of phase 3 clinical trials in oncology, and the public sharing of those results either on ClinicalTrials.gov or in a peer reviewed biomedical journal as found via PubMed or Google Scholar. Press releases announcing regulatory steps and presentation schedules for conferences were excluded, as were those announcing results from preclinical trials, follow-up analyses, and studies of supportive care therapies or various modes of infusion for the same therapy. Main Outcomes and Measures: Time to public dissemination of clinical trial data. Results: Of the 100 press releases in our sample, 70 (70%) reported positive results, but only 31 (31%) included the magnitude of study findings. Through the end of follow-up, 99 (99%) of press releases had an associated peer-reviewed publication, complete data posting to ClinicalTrials.gov, or both, with a median time to reporting of 300 days (95% CI, 263-348 days). Positive findings were reported more quickly than negative ones (median of 272; 95% CI, 211-318 days vs 407; 95% CI, 298-705 days; log-rank P < .001). Conclusions and Relevance: Even for the most pressing study findings, median publication delays approach 1 year. As publication delays hinder research progress and advancements in clinical care, policies that enable early preprint release or public posting of completed data analysis should be pursued. PMID- 29710327 TI - Some Thoughts on Exposure to the World Trade Center Wreckage and Cancer. PMID- 29710328 TI - Heart and ____ or Give and ____? An Exploration of Variables That Influence Binomial Completion for Individuals With and Without Aphasia. AB - Purpose: The goal of this research was to institute an evidence base behind commonly used elicitation materials known as binomials (e.g., "day and night") that are commonly used for persons with aphasia (PWAs). The study explored a number of linguistic variables that could influence successful binomial completion in nonaphasic adults and PWAs. Method: Thirty nonaphasic adults and 11 PWAs were asked to verbally complete 128 binomials; responses were scored by accuracy and reaction time. Binomials were coded according to the following independent variables: frequency of usage, phonological (e.g., alliteration, rhyme) and semantic (i.e., antonymy) relationships, grammatical category of the response, and number of plausible binomial completions. Results: Regression analyses demonstrated that, for both groups, greater accuracy was predicted by presence of antonymy and absence of a phonological relationship. Though reaction time models differed between groups, items that elicited a greater number of response options led to longer latencies across participants. Conclusion: Findings suggest that clinicians consider antonymy as well as the number of plausible responses for a given prompt when adapting the level of difficulty for their clients. Results also contribute to broader interdisciplinary research on how automatic language is processed in adults with and without neurogenic communication disorder. Supplemental Material: https://doi.org/10.23641/asha.6030806. PMID- 29710330 TI - Saving a Death When We Cannot Save a Life in the Intensive Care Unit. PMID- 29710329 TI - Chronic Meningitis Investigated via Metagenomic Next-Generation Sequencing. AB - Importance: Identifying infectious causes of subacute or chronic meningitis can be challenging. Enhanced, unbiased diagnostic approaches are needed. Objective: To present a case series of patients with diagnostically challenging subacute or chronic meningitis using metagenomic next-generation sequencing (mNGS) of cerebrospinal fluid (CSF) supported by a statistical framework generated from mNGS of control samples from the environment and from patients who were noninfectious. Design, Setting, and Participants: In this case series, mNGS data obtained from the CSF of 94 patients with noninfectious neuroinflammatory disorders and from 24 water and reagent control samples were used to develop and implement a weighted scoring metric based on z scores at the species and genus levels for both nucleotide and protein alignments to prioritize and rank the mNGS results. Total RNA was extracted for mNGS from the CSF of 7 participants with subacute or chronic meningitis who were recruited between September 2013 and March 2017 as part of a multicenter study of mNGS pathogen discovery among patients with suspected neuroinflammatory conditions. The neurologic infections identified by mNGS in these 7 participants represented a diverse array of pathogens. The patients were referred from the University of California, San Francisco Medical Center (n = 2), Zuckerberg San Francisco General Hospital and Trauma Center (n = 2), Cleveland Clinic (n = 1), University of Washington (n = 1), and Kaiser Permanente (n = 1). A weighted z score was used to filter out environmental contaminants and facilitate efficient data triage and analysis. Main Outcomes and Measures: Pathogens identified by mNGS and the ability of a statistical model to prioritize, rank, and simplify mNGS results. Results: The 7 participants ranged in age from 10 to 55 years, and 3 (43%) were female. A parasitic worm (Taenia solium, in 2 participants), a virus (HIV-1), and 4 fungi (Cryptococcus neoformans, Aspergillus oryzae, Histoplasma capsulatum, and Candida dubliniensis) were identified among the 7 participants by using mNGS. Evaluating mNGS data with a weighted z score-based scoring algorithm reduced the reported microbial taxa by a mean of 87% (range, 41%-99%) when taxa with a combined score of 0 or less were removed, effectively separating bona fide pathogen sequences from spurious environmental sequences so that, in each case, the causative pathogen was found within the top 2 scoring microbes identified using the algorithm. Conclusions and Relevance: Diverse microbial pathogens were identified by mNGS in the CSF of patients with diagnostically challenging subacute or chronic meningitis, including a case of subarachnoid neurocysticercosis that defied diagnosis for 1 year, the first reported case of CNS vasculitis caused by Aspergillus oryzae, and the fourth reported case of C dubliniensis meningitis. Prioritizing metagenomic data with a scoring algorithm greatly clarified data interpretation and highlighted the problem of attributing biological significance to organisms present in control samples used for metagenomic sequencing studies. PMID- 29710332 TI - Morphosyntactic Production and Verbal Working Memory: Evidence From Greek Aphasia and Healthy Aging. AB - Purpose: The present work investigated whether verbal working memory (WM) affects morphosyntactic production in configurations that do not involve or favor similarity-based interference and whether WM interacts with verb-related morphosyntactic categories and/or cue-target distance (locality). It also explored whether the findings related to the questions above lend support to a recent account of agrammatic morphosyntactic production: Interpretable Features' Impairment Hypothesis (Fyndanis, Varlokosta, & Tsapkini, 2012). Method: A sentence completion task testing production of subject-verb agreement, tense/time reference, and aspect in local and nonlocal conditions and two verbal WM tasks were administered to 8 Greek-speaking persons with agrammatic aphasia (PWA) and 103 healthy participants. Results: The 3 morphosyntactic categories dissociated in both groups (agreement > tense > aspect). A significant interaction emerged in both groups between the 3 morphosyntactic categories and WM. There was no main effect of locality in either of the 2 groups. At the individual level, all 8 PWA exhibited dissociations between agreement, tense, and aspect, and effects of locality were contradictory. Conclusions: Results suggest that individuals with WM limitations (both PWA and healthy older speakers) show dissociations between the production of verb-related morphosyntactic categories. WM affects performance shaping the pattern of morphosyntactic production (in Greek: subject-verb agreement > tense > aspect). The absence of an effect of locality suggests that executive capacities tapped by WM tasks are involved in morphosyntactic processing of demanding categories even when the cue is adjacent to the target. Results are consistent with the Interpretable Features' Impairment Hypothesis (Fyndanis et al., 2012). Supplemental Material: https://doi.org/10.23641/asha.6024428. PMID- 29710331 TI - Anti-Tumor Necrosis Factor Therapy and Incidence of Parkinson Disease Among Patients With Inflammatory Bowel Disease. AB - Importance: Despite established genetic and pathophysiologic links between inflammatory bowel disease (IBD) and Parkinson disease (PD), clinical data supporting this association remain scarce. Although systemic inflammation is considered a potential biological mechanism shared between the 2 diseases, the role of reduced systemic inflammation through IBD-directed anti-tumor necrosis factor (anti-TNF) therapy in PD risk is largely unknown. Objective: To compare the incidence of PD among individuals with or without IBD and to assess whether PD risk among patients with IBD is altered by anti-TNF therapy. Design, Setting, and Participants: This is a retrospective cohort study analyzing information in the Truven Health MarketScan administrative claims database and the Medicare Supplemental Database between January 1, 2000, and March 31, 2016. Individuals were selected who had at least 2 claims for IBD diagnoses, at least 6 months of follow-up, and no prior diagnosis of PD on or before the IBD index date. Exposure to Anti-TNF therapy was measured from the anti-TNF index date to the last date of anti-TNF coverage or the end of enrollment or PD index date, whichever was earliest. Incidence rates per 1000 person-years were calculated, and crude and adjusted incidence rate ratios were estimated by Poisson regression models and presented with 95% CIs. Main Outcomes and Measures: Incidence of PD among patients with IBD with or without exposure to anti-TNF therapy. Results: In total, 144 018 individuals with IBD were matched on age, sex, and year of index date with 720 090 unaffected controls. Of them, 1796 individuals had at least 2 PD diagnoses and at least 1 filled PD-related prescription. The mean (SD) age of individuals with IBD was 51 (17) years, and 44% were men. The incidence of PD among patients with IBD was 28% higher than that among unaffected matched controls (adjusted incidence rate ratio, 1.28; 95% CI, 1.14-1.44; P < .001). A 78% reduction in the incidence rate of PD was detected among patients with IBD who were exposed to anti-TNF therapy compared with those who were not exposed (adjusted incidence rate ratio, 0.22; 95% CI, 0.05-0.88; P = .03). Conclusions and Relevance: A higher incidence of PD was observed among patients with IBD than among individuals without IBD. Early exposure to antiinflammatory anti-TNF therapy was associated with substantially reduced PD incidence. These findings support a role of systemic inflammation in the pathogenesis of both diseases. Further studies are required to determine whether anti-TNF treatment administered to high-risk individuals may mitigate PD risk. PMID- 29710333 TI - Creating Entrustable Professional Activities to Assess Internal Medicine Residents in Training: A Mixed-Methods Approach. AB - Background: Competency-based medical education has not advanced residency training as much as many observers expected. Some medical educators now advocate reorienting competency-based approaches to focus on a resident's ability to do authentic clinical work. Objective: To develop descriptions of clinical work for which internal medicine residents must gain proficiency to deliver meaningful patient care (for example, "Admit and manage a medical inpatient with a new acute problem"). Design: A modified Delphi process involving clinical experts followed by a conference of educational experts. Setting: The Royal College of Physicians and Surgeons of Canada. Participants: In phase 1 of the project, members of the Specialty Committee for Internal Medicine participated in a modified Delphi process to identify activities in internal medicine that represent the scope of the specialty. In phase 2 of the project, 5 experts who were scholars and leaders in competency-based medical education reviewed the results. Measurements: Phase 1 identified important activities, revised descriptions to improve accuracy and avoid overlap, and assigned activities to stages of training. Phase 2 compared proposed activity descriptions with published guidelines for their development and application in medical education. Results: The project identified 29 activities that qualify as entrustable professional activities. The project also produced a detailed description of each activity and guidelines for using them to assess residents. Limitation: These activities reflect the practice patterns of the developers and may not fully represent internal medicine practice in Canada. Conclusion: Identification of these activities is expected to facilitate modification of training and assessment programs for medical residents so that programs focus less on isolated skills and more on integrated tasks. Primary Funding Source: Southeastern Ontario Academic Medical Organization Endowed Scholarship and Education Fund and Queen's University Department of Medicine Innovation Fund. PMID- 29710334 TI - Remission of Nephrotic Syndrome After Therapy for Chronic Hepatitis C Virus Infection in a Patient With Systemic Lupus Erythematosus. PMID- 29710335 TI - Elderly Man With Left Iliac Fossa and Inguinal Pain. PMID- 29710336 TI - Association of Fibroblast Growth Factor 23 With Recurrent Cardiovascular Events in Patients After an Acute Coronary Syndrome: A Secondary Analysis of a Randomized Clinical Trial. AB - Importance: Elevated fibroblast growth factor 23 (FGF-23) concentrations are associated with myocardial fibrosis and renin-angiotensin system upregulation, potentially providing prognostic information distinct from standard cardiovascular (CV) biomarkers. Objective: To evaluate the association of FGF-23 with recurrent CV events in patients after an acute coronary syndrome (ACS). Design, Setting, and Participants: C-terminal FGF-23 was measured in plasma samples using an established enzyme-linked immunosorbent assay system for 4947 patients within 30 days of ACS (median, 14 days) and with 1 additional CV risk factor in the Stabilization of Plaques Using Darapladib-Thrombolysis in Myocardial Infarction 52 (SOLID-TIMI 52) trial of the lipoprotein-associated phospholipase A2 inhibitor darapladib vs placebo performed from December 1, 2009, to April 24, 2014 (median follow-up, 2.5 years). Analyses were adjusted for clinical risk factors, renal function, and established cardiorenal biomarkers. This secondary analysis was performed from September 25, 2014, to October 1, 2017. Exposure: The FGF-23 concentration at baseline. Main Outcomes and Measures: The primary end point for this post hoc analysis was the composite of CV death or hospitalization for heart failure. Results: In this study, baseline FGF-23 concentrations were available for 4947 patients (median age, 64.0 years; interquartile range, 59.0-71.0 years; 1276 [25.8%] female). Patients with higher FGF-23 concentrations were older and more likely female, with a greater proportion of hypertension, diabetes, and previous myocardial infarction. After multivariable adjustment for baseline clinical characteristics and established biomarkers (high-sensitivity troponin I, brain-type natriuretic peptide, and high sensitivity C-reactive protein), FGF-23 concentration in the top quartile was independently associated with an increased risk of CV death or heart failure hospitalization (adjusted hazard ratio [HR], 2.35; 95% CI, 1.82-3.02; P < .001) and its individual components. Elevated FGF-23 concentration was also associated with an increased risk of all-cause mortality (adjusted HR, 2.27; 95% CI, 1.73 2.97; P < .001) and CV death, myocardial infarction, or stroke (adjusted HR, 1.42; 95% CI, 1.17-1.71; P < .001). When analyses were stratified by patient sex, the association between FGF-23 and CV risk, including CV death or heart failure, appeared to be attenuated in women (adjusted HR, 1.11; 95% CI, 0.70-1.76; P = .67) compared with men (HR, 3.11; 95% CI, 2.29-4.22; P < .001; P < .001 for interaction). Conclusions and Relevance: In patients stabilized after ACS, elevated FGF-23 concentrations may be associated with recurrent major CV events and all-cause mortality, providing information independent of established clinical risk factors and cardiorenal biomarkers. A potential sex difference in these findings deserves further study. PMID- 29710337 TI - The Role of Language in Nonlinguistic Stimuli: Comparing Inhibition in Children With Language Impairment. AB - Purpose: There is conflicting evidence regarding if and how a deficit in executive function may be associated with developmental language impairment (LI). Nonlinguistic stimuli are now frequently used when testing executive function to avoid a language confound. However, it is possible that increased stimulus processing demands for nonlinguistic stimuli may also compound the complexity of the relationship between executive function and LI. The current study examined whether variability across nonlinguistic auditory stimuli might differentially affect inhibition and whether performance differs between children with and without language difficulties. Method: Sixty children, aged 8-14 years, took part in the study: 20 typically developing children, 20 children with autism spectrum disorder, and 20 children with specific LI. For the purposes of assessing the role of language, children were further categorized based on language ability: 33 children with normal-language (NL) ability and 27 children with LI. Children completed a go/no-go task with 2 conditions comparing nonlinguistic auditory stimuli: 2 abstract sounds and 2 familiar sounds (duck quack and dog bark). Results: There was no significant difference for diagnostic category. However, there was a significant interaction between language ability and condition. There was no significant difference in the NL group performance in the abstract and familiar sound conditions. In contrast, the group with LI made significantly more errors in the abstract condition compared with the familiar condition. There was no significant difference in inhibition between the NL group and the group with LI in the familiar condition; however, the group with LI made significantly more errors than the NL group in the abstract condition. Conclusions: Caution is needed in stimuli selection when examining executive function skills because, although stimuli may be selected on the basis of being "nonlinguistic and auditory," the type of stimuli chosen can differentially affect performance. The findings have implications for the interpretation of deficits in executive function as well as the selection of stimuli in future studies. PMID- 29710338 TI - Sigmoidoscopy Screening for Colorectal Cancer. PMID- 29710339 TI - Vision-Targeted Health-Related Quality of Life in Adult Survivors of Retinoblastoma. AB - Importance: Retinoblastoma survivors are at risk for adverse oculo-visual outcomes. Limited data are available regarding long-term vision-targeted health related quality of life (HRQoL) of adult retinoblastoma survivors. Objective: To examine vision-targeted HRQoL as reported on the 25-item National Eye Institute Visual Field Questionnaire for overall and specific scale scores among adult survivors of retinoblastoma. Design, Setting, and Participants: The Retinoblastoma Survivor Study is a retrospective cohort of adult retinoblastoma survivors treated at 3 academic medical centers in New York between 1932 and 1994. Participants completed a comprehensive questionnaire between April 2008 and June 2010. Items were scored in January 2013 and preliminary analyses were performed in July 2015. Models were finalized in May 2017. Main Outcomes and Measures: Self-reported vision-targeted HRQoL as reported on the 25-item National Eye Institute Visual Field Questionnaire. Items are scored from 0 to 100, with 100 representing the highest quality of life. Results: Among 470 adult retinoblastoma survivors (53.6% with bilateral disease; 52.1% female; 86.4% white and non-Hispanic; mean age at study, 43.3 years; range, 18.0-77.0 years), 86% had at least 1 eye removed (1 eye, 74.5%; both eyes, 11.5%); 56.5% were previously treated with radiotherapy; and 61.3% rated their eyesight as excellent/good while 16.2% reported complete blindness. The overall mean (SD) VFQ composite score for all survivors was 81.1 (17.2) (mean [SD] score for unilateral retinoblastoma survivors, 91.4 [7.7]; bilateral retinoblastoma survivors, 72.3 [18.2]; difference between survivors with unilateral and bilateral disease, 19.1 [95% CI, 16.5-21.7; P < .001]). Prior exposure to radiotherapy was not associated with decreased overall VFQ (beta = -0.08; 95% CI, -0.15 to 0.002; P = .06) but was related to a few specific subdomains of visual functioning. Conclusions and Relevance: These findings suggest retinoblastoma-related oculo-visual problems are associated with functional status and vision-targeted HRQoL of adult survivors, particularly among those with bilateral disease. PMID- 29710340 TI - Health Insurance for Asian Americans, Native Hawaiians, and Pacific Islanders Under the Affordable Care Act. PMID- 29710341 TI - Adding Cost-effectiveness to Define Low-Value Care. PMID- 29710342 TI - Population Health in Pediatric Speech and Language Disorders: Available Data Sources and a Research Agenda for the Field. AB - Purpose: The aim of the study was to provide an overview of population science as applied to speech and language disorders, illustrate data sources, and advance a research agenda on the epidemiology of these conditions. Method: Computer-aided database searches were performed to identify key national surveys and other sources of data necessary to establish the incidence, prevalence, and course and outcome of speech and language disorders. This article also summarizes a research agenda that could enhance our understanding of the epidemiology of these disorders. Results: Although the data yielded estimates of prevalence and incidence for speech and language disorders, existing sources of data are inadequate to establish reliable rates of incidence, prevalence, and outcomes for speech and language disorders at the population level. Conclusions: Greater support for inclusion of speech and language disorder-relevant questions is necessary in national health surveys to build the population science in the field. PMID- 29710343 TI - When You Hear Hoofbeats, Look for Horses, Not Zebras. PMID- 29710344 TI - Health Care Employment Growth and the Future of US Cost Containment. PMID- 29710345 TI - Limitations of the National Cancer Data Base to Evaluate Early-Stage Anal Cancer Treatment Outcomes. PMID- 29710346 TI - Use of Textured Thin Liquids in Patients With Dysphagia. AB - Purpose: The goals of this article are to explore the use of textured thin liquids for dysphagic patients who require thickened liquids and to illustrate their impact on hydration and patient satisfaction. Method: A retrospective evaluation of textured thin liquids was completed using patient data looking at laboratory values relevant to the detection of dehydration (blood urea nitrogen, creatinine, sodium) and patient satisfaction (using a clinician-generated questionnaire) on different modified liquid textures. In addition, the viscosity for all liquids was tested using a rheometer. Results: Measurements show that the viscosity of the textured thin liquids examined in this pilot study are significantly lower than the viscosity of nectar-thick liquids and fall within the "thin" category as defined by the National Dysphagia Diet guidelines. Patients on honey- and nectar-thick liquids had laboratory values signifying dehydration, whereas those receiving the textured thin liquid consistency were within the normal range for all laboratory values. Importantly, when consuming textured thin liquids, patients reported significant improvement in their satisfaction related to their thirst. Conclusion: The results of this pilot study highlight the consequences of common thickened liquid dietary recommendations and of the potentially beneficial clinical application of textured thin liquids for patients with dysphagia as well as the need for future prospective research. PMID- 29710347 TI - Why "More Research Is Needed," Despite Overall Certainty: Women and Colorectal Cancer Screening. PMID- 29710348 TI - Iatrogenic Infertility After Curative Stem Cell Transplantation in Patients With Sickle Cell Disease. PMID- 29710349 TI - Toward a Renewal of Patient Care: Insights From Viktor Frankl, MD, PhD. PMID- 29710351 TI - Proposed Amendments to the AOA Constitution, Bylaws, and Code of Ethics. PMID- 29710350 TI - Official Call: 2018 Annual Business Meeting of the American Osteopathic Association. PMID- 29710352 TI - Laboratory Tests and X-ray Imaging in a Surgical Intensive Care Unit: Checking the Checklist. AB - Context: Patients in the surgical intensive care unit (ICU) frequently undergo laboratory and imaging testing. These tests can lead to iatrogenic anemia and radiation exposure. Many of these tests may be unnecessary for the management of a patient's illness in the surgical ICU, and their ordering may be a reflex rather than in response to a clinical question. Checklists have been used in critical care to identify and address patient care strategies. Objective: To examine whether adding a "diagnostic testing" section to a daily checklist used for patient rounds in a surgical ICU would decrease the amount of laboratory tests and chest x-ray imaging ordered. Methods: An additional section was added to an established ICU daily checklist, which included the following 2 questions: "Is a [chest x-ray] needed for clinical management tomorrow?" and "What laboratory tests are medically necessary for tomorrow?" Comparison was made between 3-month preintervention (control group) and intervention (intervention group) periods. Medical records of hospitalized patients during the preintervention and intervention periods were compared to determine differences in the number of tests ordered per day during each period. Results: A total of 307 adult patients at a single institution were included in the analysis: 155 in the control group and 152 in the intervention group. The patients in each group were similar in terms of sex, age, Sequential Organ Failure scores, Charlson Comorbidity Index scores, elective admission status, surgical procedures, number of days of mechanical ventilation, ICU length of stay, and in-hospital death. No statistical reductions in laboratory tests or chest x-ray imaging ordered per day from the preintervention to intervention period were found. Conclusion: The addition of the diagnostic testing section to the daily checklist did not result in a reduction of the amount of tests ordered per day. Further research on test appropriateness and the possible addition of a clinician decision-making tool could be studied in the future to assist with reduction of tests ordered in the surgical ICU. PMID- 29710353 TI - Iatrogenic Hepatitis C Virus Transmission and Safe Injection Practices. AB - Hepatitis C virus (HCV) infection poses significant adverse health effects. Improper use of vials, needles, syringes, intravenous bags, tubing, and connectors for injections and infusions is a current preventable cause of iatrogenic HCV transmission. Numerous cases have demonstrated the need for continued vigilance and the widespread nature of this iatrogenic infection risk across a variety of medical practice settings in the United States. Failure to implement the evidence-based Centers for Disease Control and Prevention (CDC) infection prevention guidelines exposes patients to preventable harm. The guidelines establish the requirement to notify patients in cases of suspected virus transmission, as well as to screen those patients who would not otherwise have been at risk for HCV seroconversion and other bloodborne pathogens. Legal and regulatory ramifications, including state, criminal, and tort laws, hold physicians and other health care professionals accountable to use safe injection practices. This article reviews the major health risks of HCV infection, significant effects of iatrogenic infection transmission, CDC guidelines for safe injection practices, and legal regulations and ramifications designed to promote safe injection practices. PMID- 29710354 TI - Faculty Vitality in Osteopathic Medical Schools: A Pilot Study. AB - Context: Faculty vitality is defined as the synergy between high levels of satisfaction, productivity, and engagement that enables faculty members to maximize their professional success and achieve goals in concert with institutional goals. Many studies have examined faculty development efforts with regard to satisfaction, retention, or vitality, but, to the authors' knowledge, they have all been conducted in allopathic medical schools and academic health centers. Objective: To examine faculty vitality in osteopathic medical schools and address contributors to productivity, engagement, and career satisfaction. Methods: This multi-institutional exploratory survey-based study included faculty members from 4 osteopathic medical schools. Surveys with items related to productivity, engagement, career satisfaction, primary department climate and leadership, professional development, and career and life management were sent to faculty members at the 4 participating schools. Most item responses were ranked on Likert-type scales, ranging from 1 (low) to 5 (high). Open-ended questions that explored the participants' experience at their college, factors outside the institution that may affect vitality, and perceived faculty development needs were included at the end of the survey. The overall vitality index was calculated by taking the average of the 3 vitality indicator scores (ie, productivity, engagement, and career satisfaction). Results: Of 236 potential participants, 105 returned the survey for analysis. The mean overall faculty vitality index was 3.2 (range, 1-5). Regarding the 3 contributors to faculty vitality, the mean productivity score was 2.3; professional engagement, 3.5; and career satisfaction, 3.7. Primary department climate and leadership was a significant predictor of faculty vitality (P=.001). The influence of individual vitality factors did not differ between basic science and clinical faculty members. Open ended questions generated the following themes related to faculty vitality: leadership support, organizational climate, collegiality and value, workload, research funding climate, and family/home life. Participants listed a variety of faculty development needs in the areas of teaching, research, leadership, and professional development. Conclusions: The results of this study suggest that career satisfaction is a significant contributor to vitality in osteopathic medical school faculty members. Additionally, primary department climate and leadership is a significant predictor of faculty vitality. Responses to the open ended questions further elucidated extrinsic factors that positively and negatively affect vitality, including family and home life and dwindling funding from national medical research agencies. Faculty development efforts should be directed toward enhancing contributors to vitality. PMID- 29710355 TI - Women in Osteopathic and Allopathic Medical Schools: An Analysis of Applicants, Matriculants, Enrollment, and Chief Academic Officers. AB - In the 1993-1994 academic year, female enrollment was 34.7% in osteopathic medical schools and 40.2% in allopathic medical schools. To assess progress in female enrollment since that time, the authors examined admission data in the ensuing years, including female applicants, matriculants, and first-year students in osteopathic and allopathic medical schools, as well as female chief academic officers at these institutions. In the 2004-2005 academic year, 50.3% of first year students in osteopathic medical schools were women; however, by the 2013 2014 academic year, that figure dropped to 44.2%. The percentage rose slightly by the 2016-2017 academic year to 45.9%. Additionally, for the 2016-2017 academic year, allopathic medical schools had a significantly higher proportion of female matriculants than did osteopathic medical schools (49.8% vs 45.9%, respectively; P<.001). PMID- 29710356 TI - Atrial Flutter With Exercise-Induced 1:1 Atrioventricular Conduction. AB - Typical atrial flutter is a common atrial tachyarrhythmia. Symptoms are typically related to the rate of ventricular response. Although atrial flutter with 1:1 atrioventricular conduction is rare, it is important to recognize because it may precipitate rapid hemodynamic compromise. The authors present a case of exercise induced 1:1 atrioventricular conduction in a patient with typical atrial flutter. PMID- 29710357 TI - Biopsychosocial Effects of Osteopathic Interventions in Patients With Chronic Pain. PMID- 29710359 TI - Cervical Osteopathic Manipulation Shown to Affect Median Nerve Function. PMID- 29710358 TI - Cervical HVLA Used as Single Intervention Improves Motion and Strength. PMID- 29710360 TI - Osteopathic Manipulation Shown to Improve Upper Airway Stabilization. PMID- 29710361 TI - Fibromyalgia Symptoms Reduced by Osteopathic Manipulative Medicine and Gabapentin. PMID- 29710362 TI - Myofascial Release Therapy Beneficial for Patients With Chronic Low Back Pain. PMID- 29710363 TI - Posterior Leukoencephalopathy Syndrome. PMID- 29710364 TI - Psychogenic Dizziness: An Important but Overlooked Differential Diagnosis in the Workup of the Dizzy Patient. AB - Chronic dizziness can be challenging for both patients and physicians, as a variety of specialists may be consulted and tests ordered before a diagnosis is established. The various potential etiologic processes involved in chronic dizziness require an interdisciplinary approach to care. Common causes include neurologic, vestibular, and cardiac diseases. Psychiatric disorders, however, may be overlooked when establishing a differential diagnosis. This case report illustrates some of the complexities in diagnosing and effectively managing chronic dizziness and serves as a reminder that psychiatric disorders should be considered in the differential diagnosis. PMID- 29710365 TI - Letter to the Editor: A Functional MRI Exploration of Hamstring Activation During the Supine Bridge Exercise. PMID- 29710366 TI - Reply to Li et al. PMID- 29710367 TI - Spontaneous Intraventricular Hemorrhage Caused by Sphenoid Meningioma. AB - INTRODUCTION: Benign sphenoid meningioma presenting with an acute intraventricular hemorrhage is extremely uncommon. CASE REPORT: We report a case of a 61-year-old man who was admitted after sudden onset of a severe headache. Brain computed tomography revealed a sphenoid meningioma with acute intraventricular hemorrhage. DISCUSSION: Intraventricular hemorrhage caused by Meningiomas is infrequent. Several hypotheses have been proposed to explain the cause of hemorrhage. CONCLUSION: The benignity of meningiomas is relative because these tumors can cause exceptional complications such as bleeding. PMID- 29710368 TI - Optimized Screw Trajectory for Lumbar Cortical Bone Trajectory Pedicle Screws Based on Clinical Outcome: Evidence Favoring the Buttress Effect Theory. AB - BACKGROUND: Cortical bone trajectory (CBT) is a relatively new technique for pedicle screw insertion in the field of spine surgery. Previous studies have demonstrated the significantly better pullout and toggle characteristics the new method offers, and it appears to have certain advantages over the widely used traditional trajectory. The mechanism of the pullout and toggle characteristics still remains unknown. PURPOSE: To report the medium- to long-term follow-up findings of patients who underwent posterior lumbar interbody fusion or posterior lumbar fusion (PLIF/PLF) at our institution and to discuss the ideal screw trajectory when using this technique. STUDY DESIGN: Retrospective radiologic study. METHODS: Fifty-five patients who underwent PLIF/PLF for lumbar spondylosis using the new technique between January 2011 and January 2016 were included. Clinical outcome was assessed using the Japanese Orthopaedic Association scores for low back pain and visual analog scale scores. Screw loosening was evaluated via the presence of a translucent zone surrounding the pedicle screw using plain X-radiography (Xp). The screw trajectory was evaluated by measuring the rostral range (RR) and the lateral range score (LRS). The RR is the angle between the line drawn along the distal end plate of the vertebra and the line drawn along the screw on the lateral view. The LRS is the score given depending on the position of the tip of the screw seen on the Xp taken in the anteroposterior (AP) view. The pedicle ring is equally divided into the medial third (zone A), central third (zone B), and the lateral third (zone C) by four vertical lines. A score of 0 to 3 points is given depending on the position of the tip of the screw: 0, outside the pedicle ring; 1, zone A; 2, zone B; and 3, zone C. RESULTS: Bone fusion was recorded in 49 patients (49/55 patients). The total number of screws with a visible translucent zone on Xp was 26 (26/242 screws). When the screws are inserted at a more acute angle in the lateral view (low RR) or when the screws are directed more medially (low LRS), the risk of developing a translucent zone around the pedicle screw increased. CONCLUSION: With CBT, the pedicle screws are inserted from the pars interarticularis that is rich in cortical bone, strong enough to withstand the substantial forces usually encountered in the region. Our clinical data suggest that the optimal screw trajectory is one where the screw is inserted at an angle > 22.55 degrees (high RR) on the lateral view Xp and where the tip of the screw is directed toward the lateral third of the pedicle on the AP Xp. We believe the naturally occurring buttress effect that exists in the vertebra may give CBT a mechanical and anatomical advantage over the traditional screw trajectory. PMID- 29710369 TI - Arterial Stiffness Response to Regular Aerobic Training in Hypercholesterolemia Patients. AB - Physical exercise increase is confirmed as a fundamental treatment for hypercholesterolemia patients, but the effect on the arterial stiffness and oxidative stress is still unclear. 74 hypercholesterolemia patients were divided into 2 groups. The exercise group received dietary recommendations and a 3-month exercise program, prescribed according to their first cardiopulmonary exercise tests(CPET), while the control group only received dietary recommendations. All patients underwent blood tests, CPET and brachial-ankle pulse wave velocity (baPWV) studies at enrollment and at 3 months' follow-up. At the end of 3 months, there was no change in total cholesterol (TC) level in either group. However, in the exercise group, we found maximal exercise parameters increased and baPWV values declined. Meanwhile, there were significant changes in the level of malondialdehyde, 8-isoprostane-F2alpha and superoxide dismutase. Moreover, the change of baPWV was positively correlated with the change of 8-isoprostane F2alpha (r=0.36, P<0.01). In the control group, no change in baPWV or oxidative biomarker was observed. Our findings suggested that regular aerobic exercise could lessen arterial stiffness in hypercholesterolemia patients, even in the context of no obvious TC decrease. During this process, favorable adjustment in oxidative stress might be an important pathway, which remains to be further explored. PMID- 29710370 TI - Effects of Exercise Intensity on Microvascular Function in Obese Adolescents. AB - The optimal exercise modality for the improvement of health-related parameters and microvascular function in obese adolescents is not yet fully understood. Therefore, this study aimed to 1) compare the microvascular phenotype of obese and normal-weight adolescents; and 2) to determine the effects of a lifestyle intervention including three months of moderate continuous training (MCT) or high intensity interval training (HIIT) on health-related parameters and microvascular function in 29 obese adolescents. Body composition, metabolic profile, aerobic fitness and cutaneous blood flow, measured using laser Doppler flowmetry at rest and during post-occlusive reactive hyperemia, were assessed prior to and following lifestyle intervention. Sixteen normal-weight adolescents were included as reference controls for baseline microvascular parameters. At baseline, obese adolescents had higher peak blood flow, peak vascular conductance and area under the curve for post-occlusive reactive hyperemia than normal-weight adolescents. Conversely, peak blood flow, peak vascular conductance and area under the curve data remained unchanged after MCT and HIIT without intergroup differences. However, the peak/basal blood flow ratio decreased in both MCT and HIIT groups without any interaction between groups due to basal CBF increase (tendency p=0.074). Exercise training, whatever the modality, does not improve peak microcirculatory function. PMID- 29710371 TI - Reply to Colon cancer survival in the US Department of Veterans Affairs by race and stage: 2001 through 2009. PMID- 29710372 TI - A matter of phylogenetic scale: Distinguishing incomplete lineage sorting from lateral gene transfer as the cause of gene tree discord in recent versus deep diversification histories. AB - PREMISE OF THE STUDY: Discordant gene trees are commonly encountered when sequences from thousands of loci are applied to estimate phylogenetic relationships. Several processes contribute to this discord. Yet, we have no methods that jointly model different sources of conflict when estimating phylogenies. An alternative to analyzing entire genomes or all the sequenced loci is to identify a subset of loci for phylogenetic analysis. If we can identify data partitions that are most likely to reflect descent from a common ancestor (i.e., discordant loci that indeed reflect incomplete lineage sorting [ILS], as opposed to some other process, such as lateral gene transfer [LGT]), we can analyze this subset using powerful coalescent-based species-tree approaches. METHODS: Test data sets were simulated where discord among loci could arise from ILS and LGT. Data sets where analyzed using the newly developed program CLASSIPHY (Huang et al., ) to assess whether our ability to distinguish the cause of discord among loci varied when ILS and LGT occurred in the recent versus deep past and whether the accuracy of these inferences were affected by the mutational process. KEY RESULTS: We show that accuracy of probabilistic classification of individual loci by the cause of discord differed when ILS and LGT events occurred more recently compared with the distant past and that the signal-to-noise ratio arising from the mutational process contributes to difficulties in inferring LGT data partitions. CONCLUSIONS: We discuss our findings in terms of the promise and limitations of identifying subsets of loci for species-tree inference that will not violate the underlying coalescent model (i.e., data partitions in which ILS, and not LGT, contributes to discord). We also discuss the empirical implications of our work given the many recalcitrant nodes in the tree of life (e.g., origins of angiosperms, amniotes, or Neoaves), and recent arguments for concatenating loci. PMID- 29710373 TI - Transforming plant biology and breeding with CRISPR/Cas9, Cas12 and Cas13. AB - Currently, biology is revolutionized by ever growing applications of the CRISPR/Cas system. As discussed in this Review, new avenues have opened up for plant research and breeding by the use of the sequence-specific DNases Cas9 and Cas12 (formerly named Cpf1) and, more recently, the RNase Cas13 (formerly named C2c2). Although double strand break-induced gene editing based on error-prone nonhomologous end joining has been applied to obtain new traits, such as powdery mildew resistance in wheat or improved pathogen resistance and increased yield in tomato, improved technologies based on CRISPR/Cas for programmed change in plant genomes via homologous recombination have recently been developed. Cas9- and Cas12- mediated DNA binding is used to develop tools for many useful applications, such as transcriptional regulation or fluorescence-based imaging of specific chromosomal loci in plant genomes. Cas13 has recently been applied to degrade mRNAs and combat viral RNA replication. By the possibility to address multiple sequences with different guide RNAs and by the simultaneous use of different Cas proteins in a single cell, we should soon be able to achieve complex changes of plant metabolism in a controlled way. PMID- 29710374 TI - Peritumoral granulomatous reaction in endometrial carcinoma: association with DNA mismatch repair protein deficiency, particularly loss of PMS2 expression. AB - AIMS: The observation of peritumoral granulomatous reactions (PGRs) in two endometrial carcinomas (ECs) with a PMS2-deficient/MLH1-intact expression pattern led us to investigate whether PGRs in EC were specifically associated with DNA mismatch repair (MMR) protein deficiency, particularly PMS2 loss. METHODS AND RESULTS: Hysterectomy specimens from 22 MMR protein-intact and 54 MMR protein deficient ECs were reviewed with specific attention to the presence of a PGR and a tumour-associated lymphoid reaction [including tumour-infiltrating lymphocytes (TILs) and stromal lymphoid infiltrates]. The MMR protein-deficient ECs included 22 cases with combined MLH1/PMS2 loss, 11 with combined MSH2/MSH6 loss, 11 with isolated MSH6 loss, and 10 with PMS2 loss but intact MLH1 staining (including the two 'index' cases). Overall, PGRs were identified in seven of 54 (13%) MMR protein-deficient ECs, five of which showed a PMS2-deficient/MLH1-intact immunophenotype; three of these patients had germline PMS2 mutations and one additional patient had a germline MSH6 mutation. None of the MMR protein-intact tumours showed a PGR. Although five of the seven PGR-positive ECs had a high grade histological component, six were stage I. Most ECs with PGRs also showed TILs and stromal lymphoid reactions, similarly to MMR protein-deficient ECs in general. CONCLUSIONS: MMR protein-deficient ECs, particularly those with PMS2 loss, occasionally show PGRs in addition to stromal lymphoid infiltrates and TILs. Therefore, PGRs could be considered to constitute a histological prompt for consideration of Lynch syndrome. The potential prognostic significance of PGRs in EC requires further study. PMID- 29710376 TI - Ciguatoxin prevalence in 4 commercial fish species along an oceanic exposure gradient in the US Virgin Islands. AB - Ciguatera fish poisoning is a seafood-toxin illness resulting from consumption of fish contaminated with ciguatoxins. Managing ciguatera fish poisoning is complex. It is made easier, however, by local fishers from endemic areas reporting regional predictability for local fish species' ciguatera fish poisoning risk, which the present study then tested. We investigated the prevalence of ciguatoxins in 4 commonly marketed and consumed species (Balistes vetula, Haemulon plumierii, Ocyurus chrysurus, and Epinephelus guttatus) across an oceanic gradient (north, south, east, and west) from the US Virgin Islands. Fish muscle extracts were analyzed for Caribbean ciguatoxins using an in vitro mouse neuroblastoma (N2a) cytotoxicity assay and confirmed by liquid chromatography tandem mass spectrometry (LC-MS/MS). Fish collected from the north location had 0 fish with detectable ciguatoxins; this site also had the greatest wave energy. Caribbean ciguatoxins in fish ranged from 0.01 to 0.11, 0.004 to 0.10, and 0.005 to 0.18 ng Caribbean ciguatoxin-1 eq/g, from the west, east, and south respectively. Ciguatoxin-like activity was detectable by the N2a assay in 40, 41, 50, and 70% of H. plumierii, O. chrysurus, B. vetula, and E. guttatus, respectively. Of the fish collected, 4% had Caribbean ciguatoxin levels exceeding the US Food and Drug Administration guidance of 0.1 ng Caribbean ciguatoxin-1 eq/g fish. These findings concurred with spatial ciguatera fish poisoning prevalence information provided by local fishers in the US Virgin Islands and demonstrate how partnerships between researchers and fishers can aid the improvement of science-based ciguatera fish poisoning management. Environ Toxicol Chem 2018;39:1852-1863. Published 2018 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the United States of America. PMID- 29710375 TI - Review shows that parental reassurance and nutritional advice help to optimise the management of functional gastrointestinal disorders in infants. AB - AIM: Regurgitation, infantile colic and functional constipation are common functional gastrointestinal disorders (FGIDs) during infancy. Our aim was to carry out a concise review of the literature, evaluate the impact of these common FGIDs on infants and their families, and provide an overview of national and international guidelines and peer-reviewed expert recommendations on their management. METHODS: National and international guidelines and peer-reviewed expert recommendations on the management of regurgitation, infantile colic and functional constipation were examined and summarised. RESULTS: Regurgitation, infantile colic and functional constipation cause frequent parental concerns, lead to heavy personal and economic costs for families and impose a financial burden on public healthcare systems. Guidelines emphasise that the first-line management of these common FGIDs should focus on parental education, reassurance and nutritional advice. Nutritional advice should stress the benefits of continuing breastfeeding, while special infant formulas may be considered for non breastfed infants with common FGIDs. Drug treatment is seldom required, with the exception of functional constipation. CONCLUSION: By providing complete and updated parental education, reassurance and nutritional advice, healthcare professionals can optimise the management of FGIDs and related symptoms and reduce the inappropriate use of medication or dietary interventions. PMID- 29710377 TI - Theoretical Development of Near-Infrared Bioluminescent Systems. AB - The luciferin/luciferase system of the firefly has been used in bioluminescent imaging to monitor biological processes. In order to enhance the efficiency and expand the application range, some efforts have been made to tune the light emission, especially the effort to obtain NIR light. However, those case-by-case studies have not together revealed the nature and mechanism of the color tuning. In this paper, we theoretically investigated the fluorescence of all kinds of typical oxyluciferin analogues. The present systematical modifications of both oxyluciferin and luciferase indicate that the essential factor affecting the emission color is the charge distribution (or the electric dipole moment) on the oxyluciferin, which impacts on the charge transfer to form the light emitter and, subsequently, influence the strength and wavelength of the emission light. More negative charge distributed on the "thiazolone moiety" of the oxyluciferin or its analogues leads to a redshift. Based on this conclusion, we theoretically designed optimal pairs of luciferin analogue and luciferase for emitting NIR light, which could inspire new synthetic procedures and practical applications. PMID- 29710378 TI - Placental expression of asialoglycoprotein receptor associated with Hepatitis B virus transmission from mother to child. AB - BACKGROUND: Asialoglycoprotein receptor expression on hepatocytes has been associated with endocytosis, binding and uptake of hepatitis B virus. The role of asialoglycoprotein receptor in hepatitis B virus vertical transmission and its expression on placenta has not yet been studied. PATIENTS AND METHODS: Thirty four HBsAg+ve and 13 healthy pregnant mothers along with their newborns were enrolled. The former were categorized into transmitting and non-transmitting mothers based on their newborns being hepatitis B surface antigen and hepatitis B virus DNA positive. Expression of asialoglycoprotein receptor and hepatitis B surface antigen in placenta and isoform of asialoglycoprotein receptor on dendritic cell in peripheral and cord blood dendritic cells were analysed using flowcytometry, immune histochemistry, immune florescence and qRT-PCR. RESULTS: Twelve HBsAg+ve mothers transmitted hepatitis B virus to their newborns whereas the rest (n = 22) did not. Hepatitis B virus-transmitting mothers showed increased expression of asialoglycoprotein receptor in trophoblasts of placenta. Immunofluorescence microscopy revealed colocalization of hepatitis B surface antigen and asialoglycoprotein receptor in placenta as well as in DCs of transmitting mothers. There was no significant difference in the expression of asialoglycoprotein receptor on peripheral blood mononuclear cells or chord blood mononuclear cells between the 2 groups. However, hepatitis B virus-transmitting mothers and their HBsAg+ve newborns showed increased mRNA levels of isoform of asialoglycoprotein receptor on dendritic cell in peripheral blood mononuclear cells. Hepatitis B virus-transmitting mothers and their HBsAg+ve newborns showed an increased expression of isoform of asialoglycoprotein receptor on dendritic cell on circulating dendritic cells compared to hepatitis B virus non transmitting mothers and their negative newborns. CONCLUSIONS: This study revealed that increased expression of asialoglycoprotein receptor in placenta and colocalization with hepatitis B surface antigen strongly indicates its role in intrauterine transmission of hepatitis B virus. Asialoglycoprotein receptor blocking strategy can be used for therapeutic intervention of vertical transmission. PMID- 29710379 TI - An Integrated Proteomic Approach Uncovers Novel Substrates and Functions of the Lon Protease in Escherichia coli. AB - Controlling the cellular abundance and proper function of proteins by proteolysis is a universal process in all living organisms. In Escherichia coli, the ATP dependent Lon protease is crucial for protein quality control and regulatory processes. To understand how diverse substrates are selected and degraded, unbiased global approaches are needed. We employed a quantitative Super-SILAC (stable isotope labeling with amino acids in cell culture) mass spectrometry approach and compared the proteomes of a lon mutant and a strain producing the protease to discover Lon-dependent physiological functions. To identify Lon substrates, we took advantage of a Lon trapping variant, which is able to translocate substrates but unable to degrade them. Lon-associated proteins were identified by label-free LC-MS/MS. The combination of both approaches revealed a total of 14 novel Lon substrates. Besides the identification of known pathways affected by Lon, for example, the superoxide stress response, our cumulative data suggests previously unrecognized fundamental functions of Lon in sulfur assimilation, nucleotide biosynthesis, amino acid and central energy metabolism. PMID- 29710380 TI - Effects of Postoperative Parenteral Nutrition Enhanced by Multivitamin on Metabolic Phenotype in Postoperative Gastric Cancer Patients. AB - SCOPE: To investigate the effects of postoperative parenteral nutrition (PN) with multivitamins supplementation on oxidative stress and metabolism. METHODS AND RESULTS: The participants are randomly assigned in a 1:1 ratio to groups: total nutrient admixture (TNA) + multivitamin (n = 14, Group A) and TNA + normal saline (n = 16, Group B). The levels of blood vitamins, ILs, and MDA are assessed and the dysregulation of metabolism is analyzed using nontargeted metabolite profiling. The degree of postoperative stress in Group A is significantly lower than that in Group B by analyzing changes in the levels of IL-8 and MDA. A set of 43 features are qualified to have a variable importance parameter score of >1.5 of a partial least-squares discriminate analysis model and fold change of >1.5 at p-value <0.05 between Groups A and B. The principal metabolic alternations in Group A include increased tricarboxylic acid cycle and ketogenesis with reduced plasma-free amino acids. Backing the results of clinical biomarkers, increased levels of antioxidative molecules, together with decreased levels of inflammatory related polyunsaturated fatty acids, are observed. CONCLUSION: Postoperative PN enhanced by multivitamins can alleviate traumatic stress and improve metabolic transition from catabolism to anabolism in gastric cancer patients. PMID- 29710381 TI - Semantic segmentation of mFISH images using convolutional networks. AB - Multicolor in situ hybridization (mFISH) is a karyotyping technique used to detect major chromosomal alterations using fluorescent probes and imaging techniques. Manual interpretation of mFISH images is a time consuming step that can be automated using machine learning; in previous works, pixel or patch wise classification was employed, overlooking spatial information which can help identify chromosomes. In this work, we propose a fully convolutional semantic segmentation network for the interpretation of mFISH images, which uses both spatial and spectral information to classify each pixel in an end-to-end fashion. The semantic segmentation network developed was tested on samples extracted from a public dataset using cross validation. Despite having no labeling information of the image it was tested on, our algorithm yielded an average correct classification ratio (CCR) of 87.41%. Previously, this level of accuracy was only achieved with state of the art algorithms when classifying pixels from the same image in which the classifier has been trained. These results provide evidence that fully convolutional semantic segmentation networks may be employed in the computer aided diagnosis of genetic diseases with improved performance over the current image analysis methods. (c) 2018 International Society for Advancement of Cytometry. PMID- 29710382 TI - Charge and Potential Balancing for Optimized Capacitive Deionization Using Lignin Derived, Low-Cost Activated Carbon Electrodes. AB - Lignin-derived carbon is introduced as a promising electrode material for water desalination by using capacitive deionization (CDI). Lignin is a low-cost precursor that is obtained from the cellulose and ethanol industries, and we used carbonization and subsequent KOH activation to obtain highly porous carbon. CDI cells with a pair of lignin-derived carbon electrodes presented an initially high salt adsorption capacity but rapidly lost their beneficial desalination performance. To capitalize on the high porosity of lignin-derived carbon and to stabilize the CDI performance, we then used asymmetric electrode configurations. By using electrodes of the same material but with different thicknesses, the desalination performance was stabilized through reduction of the potential at the positive electrode. To enhance the desalination capacity further, we used cell configurations with different materials for the positive and negative electrodes. The best performance was achieved by a cell with lignin-derived carbon as a negative electrode and commercial activated carbon as a positive electrode. Thereby, a maximum desalination capacity of 18.5 mg g-1 was obtained with charge efficiency over 80 % and excellent performance retention over 100 cycles. The improvements were related to the difference in the potential of zero charge between the electrodes. Our work shows that an asymmetric cell configuration is a powerful tool to adapt otherwise inappropriate CDI electrode materials. PMID- 29710383 TI - A snapshot of the evolving epidemiology of oropharynx cancers. PMID- 29710384 TI - Resveratrol Prevents the Development of Hypertension Programmed by Maternal Plus Post-Weaning High-Fructose Consumption through Modulation of Oxidative Stress, Nutrient-Sensing Signals, and Gut Microbiota. AB - SCOPE: High-fructose (HF) intake, oxidative stress, nutrient-sensing signals, and gut microbiota dysbiosis are closely related to the development of hypertension. It was investigated whether resveratrol can prevent hypertension induced by maternal plus post-weaning HF diets in adult offspring via the above-mentioned mechanisms. METHODS AND RESULTS: Female Sprague-Dawley rats received either a normal (ND) or 60% high-fructose (HF) diet during gestation and lactation. Male offspring were assigned to five groups (maternal diet/post-weaning diet; n = 8 per group): ND/ND, ND/HF, HF/ND, HF/HF, and HF/HF+ Resveratrol. Resveratrol (50 mg L-1 ) was administered in drinking water from weaning to 3 months of age. It was found that HF/HF induced hypertension in adult offspring. Maternal HF diet altered gut microbiota composition in adult offspring, including decreasing the abundance of genera Bacteroides, Dysgonomonas, and Turicibacter, while increasing phylum Verrucomicrobia and Akkermansia muciniphila. Additionally, HF/HF diets increased oxidative stress and decreased renal mRNA expression of Prkaa2, Prkag2, Ppara, Pparb, Ppargc1a, and Sirt4. Resveratrol reduced renal oxidative stress, activated nutrient-sensing signals, modulated gut microbiota, and prevented associated HF/HF-induced programmed hypertension. CONCLUSION: Targeting oxidative stress, nutrient-sensing signals, and gut microbiota by resveratrol might be a useful therapeutic strategy for the treatment of hypertension induced by excessive consumption of fructose in the adult rat offspring. PMID- 29710385 TI - Histopathological Alterations in the Gonad of Megapitaria squalida (Mollusca: Bivalvia) Inhabiting a Heavy Metals Polluted Environment. AB - The gonadal health status of the chocolate clam Megapitaria squalida collected from the Santa Rosalia mining port and San Lucas beach (reference site), Gulf of California, Mexico, was assessed through histological analysis of the reproductive tissue, from which the histopathological alteration index (HAI) was determined. In addition, copper and iron accumulation in tissue was revealed using histochemical techniques. Our results showed a large presence of copper (30%) and iron (45%) only in the gonad tissue of clams from Santa Rosalia, in which histopathological alterations observed were inflammatory responses, degenerative-progressive processes, cell death, and response to infectious agents. The HAI was significantly higher in Santa Rosalia specimens (mean +/- SE, 72.18 +/- 6.12) than in San Lucas clams (4.60 +/- 1.07). At San Lucas beach, a higher prevalence of histopathological alterations occurred in clams in the spent stage (43.2%) and in autumn (18.4%) and winter (17.8%) in concordance with the normal reproductive rest period, whereas at Santa Rosalia a higher prevalence occurred in clams at the ripe stage (76.9%) and in spring (83.7%). In conclusion, our results showed the deteriorated health condition of gonads in M. squalida from the Santa Rosalia mining port, which suggests there is a relationship with chronic exposure to local high levels of heavy metals. The high prevalence and intensity of histopathological alterations in the gonad suggest a strong adverse effect on gametogenesis, gamete quality, and, ultimately, in the reproductive potential of M. squalida at this site. PMID- 29710386 TI - Proteolysis to Identify Protease Substrates: Cleave to Decipher. AB - Proteolysis is an irreversible post-translational modification process, characterized by highly precise yet stable cleavage of proteins. Downstream events in signaling processes are reliant on proteolysis triggered by the protease activity. Studies indicate that abnormal proteolytic activity may lead to the manifestation of diseased conditions. Therefore, characterization of proteases may provide clues to understand their role in fundamental cellular processes like cellular growth, differentiation, apoptosis, and survival. The relevance of proteases and their substrates as clinical targets are being studied. Understanding the mechanism of proteolytic activity, the identity, and the role of repertoire of its substrates in a physiological pathway has opened avenues for novel drug designing. However, only a limited knowledge of protease substrates is currently available. In this review, the authors recapitulate the library screening, proteomics, and bioinformatics based approaches that have been employed for the identification of protease substrates. PMID- 29710387 TI - Impact of a rare chronic genodermatosis on family daily life: the example of epidermolysis bullosa. PMID- 29710388 TI - Antitumor effect of sorafenib and mammalian target of rapamycin inhibitor in liver transplantation recipients with hepatocellular carcinoma recurrence. AB - Both sorafenib and mammalian target of rapamycin inhibitor (mTORi) have antitumor effects. This study aimed to evaluate their antitumor effects in liver transplantation (LT) recipients with hepatocellular carcinoma (HCC) recurrence. We performed a laboratory study using sorafenib and mTORi and subsequently validated their survival benefit in a clinical LT setting. In the laboratory study, the HepG2.2.15 liver tumor cell line and 5 patient-derived graft HCC cell lines were used for in vitro cytotoxic studies. After treatment with everolimus and sorafenib, cell viability and apoptosis assays revealed noticeable cytotoxic effects with individual agents and augmented effects by combination therapy. An in vivo mouse study also demonstrated similar cytotoxic outcomes. In the clinical study including 232 LT recipients with HCC recurrence, the 3-month medication drop-out rate was 35.6% for sorafenib administration and 23.5% for mTORi administration. Postrecurrence survival rates were not different according to sorafenib administration (P = 0.17) but were significantly improved following mTORi administration (P < 0.001). In mTORi subgroups with and without sorafenib, there was no difference in the overall postrecurrence patient survival period (P = 0.26), indicating an absence of synergistic or additional antitumor effect from sorafenib. The median progression-free and overall survival period was 6.4 and 11.8 months, respectively, after sorafenib administration. Time of tumor recurrence and use of mTORi were independent risk factors. In conclusion, our laboratory study demonstrated synergistic antitumor effects of sorafenib and mTORi, but this was not reproduced in our clinical LT study. Our clinical result of mTORi administration showed improved postrecurrence survival, thus administering mTORi in LT recipients with HCC recurrence appears worthwhile. However, the antitumor effect of sorafenib on posttransplant recurrence was not determined in this retrospective study, thus requiring further studies with early start of sorafenib administration. Liver Transplantation 24 932-945 2018. (c) 2018 AASLD. PMID- 29710389 TI - Terpenes associated with resistance against the gall wasp, Leptocybe invasa, in Eucalyptus grandis. AB - Leptocybe invasa is an insect pest causing gall formation on oviposited shoot tips and leaves of Eucalyptus trees leading to leaf deformation, stunting, and death in severe cases. We previously observed different constitutive and induced terpenes, plant specialized metabolites that may act as attractants or repellents to insects, in a resistant and susceptible clone of Eucalyptus challenged with L. invasa. We tested the hypothesis that specific terpenes are associated with pest resistance in a Eucalyptus grandis half-sib population. Insect damage was scored over 2 infestation cycles, and leaves were harvested for near-infrared reflectance (NIR) and terpene measurements. We used Bayesian model averaging for terpene selection and obtained partial least squares NIR models to predict terpene content and L. invasa infestation damage. In our optimal model, 29% of the phenotypic variation could be explained by 7 terpenes, and the monoterpene combination, limonene, alpha-terpineol, and 1,8-cineole, could be predicted with an NIR prediction ability of .67. Bayesian model averaging supported alpha pinene, gamma-terpinene, and iso-pinocarveol as important for predicting L. invasa infestation. Susceptibility was associated with increased gamma-terpinene and alpha-pinene, which may act as a pest attractant, whereas reduced susceptibility was associated with iso-pinocarveol, which may act to recruit parasitoids or have direct toxic effects. PMID- 29710390 TI - The Effect of Dispersion on the Structure of Diphenyl Ether Aggregates. AB - Dispersion interactions can play an important role in understanding unusual binding behaviors. This is illustrated by a systematic study of the structural preferences of diphenyl ether (DPE)-alcohol aggregates, for which OH???O-bound or OH???pi-bound isomers can be formed. The investigation was performed through a multi-spectroscopic approach including IR/UV and microwave methods, combined with a detailed theoretical analysis. The resulting solvent-size-dependent trend for the structural preference turns out to be counter-intuitive: the hydrogen-bonded OH???O structures become more stable for larger alcohols, which are expected to be stronger dispersion energy donors and thus should prefer an OH???pi arrangement. Dispersion interactions in combination with the twisting of the ether upon solvent aggregation are key for understanding this preference. PMID- 29710391 TI - The AAA protein spastin possesses two levels of basal ATPase activity. AB - The AAA ATPase spastin is a microtubule-severing enzyme that plays important roles in various cellular events including axon regeneration. Herein, we found that the basal ATPase activity of spastin is negatively regulated by spastin concentration. By determining a spastin crystal structure, we demonstrate the necessity of intersubunit interactions between spastin AAA domains. Neutralization of the positive charges in the microtubule-binding domain (MTBD) of spastin dramatically decreases the ATPase activity at low concentration, although the ATP-hydrolyzing potential is not affected. These results demonstrate that, in addition to the AAA domain, the MTBD region of spastin is also involved in regulating ATPase activity, making interactions between spastin protomers more complicated than expected. PMID- 29710392 TI - Kinetics of Ethylene Epoxidation on a Promoted Ag/alpha-Al2 O3 Catalyst-The Effects of Product and Chloride Co-Feeds on Rates and Selectivity. AB - The overall chloriding effectiveness factor (Z*), defined as the ratio of ethyl chloride concentration in parts per million to the sum of ethylene and ethane concentration in mole percent multiplied by a weighting factor to account for their efficacy in removing chlorine-adatoms from the surface, was used as a parameter to account for the effects of chlorine on the kinetics of ethylene epoxidation on a highly promoted 35 wt % Ag/alpha-Al2 O3 catalyst. An increase in O2 order (~0.7 to 1) and a decrease in C2 H4 order (~0.5 to <0) with increasing Z* (Z*=2.1, 3.4, 5.2, and 8.9) was observed implicating kinetic relevance of O2 activation on chloride-promoted silver catalysts. Carbon dioxide co-feed (1-5 mol %) was found to promote ethylene oxide selectivity as CO2 co-feed reversibly inhibits CO2 synthesis rates (-0.6 order) more than ethylene oxide synthesis rates (-0.49 order) at all Z* values. Ethylene oxide and CO2 rates were found to be invariant with ethylene oxide (0-0.5 mol %) and acetaldehyde (0-1.7 ppm) co feeds, suggesting that there is minimal product inhibition under reaction conditions. A model involving a common reaction intermediate for ethylene oxide and carbon dioxide synthesis and two types of atomically adsorbed oxygen species nucleophilic and electrophilic oxygen-is proposed to plausibly describe the observed reaction rate dependencies and selectivity trends as a function of the chloriding effectiveness. PMID- 29710394 TI - Adipose Derived Stem Cells Reduce Fibrosis and Promote Nerve Regeneration in Rats. AB - Peripheral nerve regeneration is critical and challenging in the adult humans. High level of collagen infiltration (i.e., scar tissue), in the niche of injury, impedes axonal regeneration and path finding. Unfortunately, studies focusing on the modulation of scar tissue in the nerves are scarce. To address part of this problem, we have evaluated the differentiated adipose derived stem cells (dASCs) for their antifibrotic and regenerative effects in a 10 mm nerve gap model in rats. Three different animal groups (N = 5) were treated with fibrin nerve conduits (empty), or seeded with dASCs (F + dASCs) and autograft, respectively. Histological analysis of regenerated nerves, at 12 weeks postoperatively, reveled the high levels of collagen infiltration (i.e., 21.5% +/- 6.1% and 24.1% +/- 2.9%) in the middle and distal segment of empty conduit groups in comparison with stem cells treated (16.6% +/- 2.1% and 12.1% +/- 2.9%) and autograft (15.0% +/- 1.7% and 12.8% +/- 1.0%) animals. Thus, the dASCs treatment resulted in significant reduction of fibrotic tissue formation. Consequently, enhanced axonal regeneration and remyelination was found in the animals treated with dASCs. Interestingly, these effects of dASCs appeared to be equivalent to that of autograft treatment. Thus, the dASCs hold great potential for preventing the scar tissue formation and for promoting nerve regeneration in the adult organisms. Future experiments will focus on the validation of these findings in a critical nerve injury model. Anat Rec, 301:1714-1721, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29710393 TI - Increasing prevalence of human papillomavirus-positive oropharyngeal cancers among older adults. AB - BACKGROUND: The incidence of oropharyngeal squamous cell carcinoma (OPSCC) is increasing among older adults. It is unknown whether these trends can be explained by human papillomavirus (HPV) and whether HPV-related tumors remain associated with an improved prognosis among older patients. METHODS: In a retrospective study of OPSCCs diagnosed from 1995 to 2013 at 2 National Comprehensive Cancer Network-designated cancer centers, p16 immunohistochemistry and in situ hybridization (ISH) for HPV-16, high-risk DNA, and/or E6/E7 RNA were performed. The median age at diagnosis was compared by p16 and ISH tumor status. Trends in age were analyzed with nonparametric trends. Survival was analyzed with the Kaplan-Meier method and Cox proportional hazards models. RESULTS: Among 239 patients, 144 (60%) were p16-positive. During 1998-2013, the median age increased among p16-positive patients (Ptrend = .01) but not among p16-negative patients (Ptrend = .71). The median age of p16-positive patients increased from 53 years (interquartile range [IQR] in 1995-2000, 45-65 years) to 58 years (IQR for 2001 2013, 53-64 years). Among patients >= 65 years old, the proportion of OPSCCs that were p16-positive increased from 41% during 1995-2000 to 75% during 2007-2013 (Ptrend = .04). Among all age groups, including older patients, a p16-positive tumor status conferred improved overall survival in comparison with a p16 negative status. CONCLUSIONS: The median age at diagnosis for HPV-related OPSCC is increasing as the proportion of OPSCCs caused by HPV rises among older adults. The favorable survival conferred by an HPV-positive tumor status persists in older adults. Cancer 2018;124:2993-9. (c) 2018 American Cancer Society. PMID- 29710395 TI - Age of first exposure to tackle football and chronic traumatic encephalopathy. AB - OBJECTIVE: To examine the effect of age of first exposure to tackle football on chronic traumatic encephalopathy (CTE) pathological severity and age of neurobehavioral symptom onset in tackle football players with neuropathologically confirmed CTE. METHODS: The sample included 246 tackle football players who donated their brains for neuropathological examination. Two hundred eleven were diagnosed with CTE (126 of 211 were without comorbid neurodegenerative diseases), and 35 were without CTE. Informant interviews ascertained age of first exposure and age of cognitive and behavioral/mood symptom onset. RESULTS: Analyses accounted for decade and duration of play. Age of exposure was not associated with CTE pathological severity, or Alzheimer's disease or Lewy body pathology. In the 211 participants with CTE, every 1 year younger participants began to play tackle football predicted earlier reported cognitive symptom onset by 2.44 years (p < 0.0001) and behavioral/mood symptoms by 2.50 years (p < 0.0001). Age of exposure before 12 predicted earlier cognitive (p < 0.0001) and behavioral/mood (p < 0.0001) symptom onset by 13.39 and 13.28 years, respectively. In participants with dementia, younger age of exposure corresponded to earlier functional impairment onset. Similar effects were observed in the 126 CTE-only participants. Effect sizes were comparable in participants without CTE. INTERPRETATION: In this sample of deceased tackle football players, younger age of exposure to tackle football was not associated with CTE pathological severity, but predicted earlier neurobehavioral symptom onset. Youth exposure to tackle football may reduce resiliency to late-life neuropathology. These findings may not generalize to the broader tackle football population, and informant-report may have affected the accuracy of the estimated effects. Ann Neurol 2018;83:886 901. PMID- 29710396 TI - Copper chelators promote nonamyloidogenic processing of AbetaPP via MT1/2 /CREB dependent signaling pathways in AbetaPP/PS1 transgenic mice. AB - Copper is essential for the generation of reactive oxygen species (ROS), which are induced by amyloid-beta (Abeta) aggregation; thus, the homeostasis of copper is believed to be a therapeutic target for Alzheimer's disease (AD). Although clinical trials of copper chelators show promise when applied in AD, the underlying mechanism is not fully understood. Here, we reported that copper chelators promoted nonamyloidogenic processing of AbetaPP through MT1/2 /CREB dependent signaling pathways. First, we found that the formation of Abeta plaques in the cortex was significantly reduced, and learning deficits were significantly improved in AbetaPP/PS1 transgenic mice by copper chelator tetrathiomolybdate (TM) administration. Second, TM and another copper chelator, bathocuproine sulfonate (BCS), promoted nonamyloidogenic processing of AbetaPP via inducing the expression of ADAM10 and the secretion of sAbetaPPalpha. Third, the inducible ADAM10 production caused by copper chelators can be blocked by a melatonin receptor (MT1/2 ) antagonist (luzindole) and a MT2 inhibitor (4-P-PDOT), suggesting that the expression of ADAM10 depends on the activation of MT1/2 signaling pathways. Fourth, three of the MT1/2 -downstream signaling pathways, Gq/PLC/MEK/ERK/CREB, Gs/cAMP/PKA/ERK/CREB and Gs/cAMP/PKA/CREB, were responsible for copper chelator-induced ADAM10 production. Based on these results, we conclude that copper chelators regulate the balance between amyloidogenic and nonamyloidogenic processing of AbetaPP via promoting ADAM10 expression through MT1/2 /CREB-dependent signaling pathways. PMID- 29710397 TI - Is Portal Venous Pressure Modulation Still Indicated for All Recipients in Living Donor Liver Transplantation? AB - There is a consensus that portal venous pressure (PVP) modulation prevents portal hypertension (PHT) and consequent complications after adult-to-adult living donor liver transplantation (ALDLT). However, PVP-modulation strategies need to be updated based on the most recent findings. We examined our 10-year experience of PVP modulation and reevaluated whether it was necessary for all recipients or for selected recipients in ALDLT. In this retrospective study, 319 patients who underwent ALDLT from 2007 to 2016 were divided into 3 groups according to the necessity and results of PVP modulation: not indicated (n = 189), indicated and succeeded (n = 92), and indicated but failed (n = 38). Graft survival and associations with various clinical factors were investigated. PVP modulation was performed mainly by splenectomy to lower final PVP to <=15 mm Hg. Successful PVP modulation improved prognosis to be equivalent to that of patients who did not need modulation, whereas failed modulation was associated with increased incidence of small-for-size syndrome (SFSS; P = 0.003) and early graft loss (EGL; P = 0.006). Among patients with failed modulation, donor age >= 45 years (hazard ratio [HR], 3.67; P = 0.02) and ABO incompatibility (HR, 3.90; P = 0.01) were independent risk factors for graft loss. Survival analysis showed that PVP > 15 mm Hg was related to poor prognosis in grafts from either ABO-incompatible or older donor age >= 45 years (P < 0.001), but it did not negatively affect grafts from ABO-compatible/identical and young donor age < 45 years (P = 0.27). In conclusion, intentional PVP modulation is not necessarily required in all recipients. Although grafts from both ABO-compatible/identical and young donors can tolerate PHT, lowering PVP to <=15 mm Hg is a key to preventing SFSS and consequent EGL with grafts from either ABO-incompatible or older donors. PMID- 29710399 TI - Patient-reported outcome assessment in acute leukemias: Moving beyond the barriers. PMID- 29710400 TI - First Report of Achlya oblongata Infection in Freshwater-Reared Asian Seabass Lates calcarifer. AB - In September 2014, a freshwater oomycete was first isolated from Asian Seabass Lates calcarifer fry that were reared in freshwater at a fish hatchery in Sabah, Malaysia. A fungal strain was isolated from infected fry by using glucose yeast extract (GY) agar. From morphological identification, the strain belonged to the genus Achlya based on the mode of zoospore release. Molecular phylogenetic analysis of the internal transcribed spacer region sequences from the strain showed high similarity (99-100%) to Achlya oblongata. The isolate was able to grow on GY agar incubated at 15-35 degrees C, in GY broth adjusted to pH 3.0 11.0, and in up to 1.0% NaCl. This is the first report of Achlya infection in freshwater-reared Asian Seabass in Malaysia. PMID- 29710398 TI - Phenethyl Isothiocyanate, a Dual Activator of Transcription Factors NRF2 and HSF1. AB - Cruciferous vegetables are rich sources of glucosinolates which are the biogenic precursor molecules of isothiocyanates (ITCs). The relationship between the consumption of cruciferous vegetables and chemoprotection has been widely documented in epidemiological studies. Phenethyl isothiocyanate (PEITC) occurs as its glucosinolate precursor gluconasturtiin in the cruciferous vegetable watercress (Nasturtium officinale). PEITC has multiple biological effects, including activation of cytoprotective pathways, such as those mediated by the transcription factor nuclear factor erythroid 2 p45-related factor 2 (NRF2) and the transcription factor heat shock factor 1 (HSF1), and can cause changes in the epigenome. However, at high concentrations, PEITC leads to accumulation of reactive oxygen species and cytoskeletal changes, resulting in cytotoxicity. Underlying these activities is the sulfhydryl reactivity of PEITC with cysteine residues in its protein targets. This chemical reactivity highlights the critical importance of the dose of PEITC for achieving on-target selectivity, which should be carefully considered in the design of future clinical trials. PMID- 29710401 TI - Infection by Nanophyetus salmincola and Toxic Contaminant Exposure in Out migrating Steelhead from Puget Sound, Washington: Implications for Early Marine Survival. AB - Out-migrating steelhead Oncorhynchus mykiss from four Puget Sound rivers and associated marine basins of Puget Sound in Washington State were examined for the parasite, Nanophyetus salmincola in 2014 to determine whether recent trends in reduced marine survival are associated with the presence of this pathogen. A subset of steelhead from three of these river-marine basin combinations was analyzed for the presence of persistent organic pollutants (POPs) to assess whether exposure to these contaminants is a contributing factor to their reduced marine survival. The prevalence and parasite load of N. salmincola were significantly higher in fish from central and southern Puget Sound than in fish from river systems in northern Puget Sound. The proportion of steelhead samples with concentrations of POPs higher than adverse effects thresholds (AETs) or concentrations known to cause adverse effects was also greater in fish from the central and southern regions of Puget Sound than in those from the northern region. Polybrominated diphenyl ether concentrations associated with increased disease susceptibility were observed in 10% and 40% of the steelhead sampled from central and southern Puget Sound regions, respectively, but in none of the fish sampled from the northern region. The AET for polychlorinated biphenyls was exceeded in steelhead collected from marine habitats: 25% of the samples from the marine basins in the central and southern regions of Puget Sound and 17% of samples from northern Puget Sound region. Both N. salmincola and POP levels suggest there are adverse health effects on out-migrating steelhead from one southern and one central Puget Sound river that have lower early marine survival than those from a river system in northern Puget Sound. PMID- 29710403 TI - Colon cancer survival in the US Department of Veterans Affairs by race and stage: 2001 through 2009. PMID- 29710402 TI - Chlamydial virulence factor TarP mimics talin to disrupt the talin-vinculin complex. AB - Vinculin is a central component of mechanosensitive adhesive complexes that form between cells and the extracellular matrix. A myriad of infectious agents mimic vinculin binding sites (VBS), enabling them to hijack the adhesion machinery and facilitate cellular entry. Here, we report the structural and biochemical characterisation of VBS from the chlamydial virulence factor TarP. Whilst the affinities of isolated VBS peptides from TarP and talin for vinculin are similar, their behaviour in larger fragments is markedly different. In talin, VBS are cryptic and require mechanical activation to bind vinculin, whereas the TarP VBS are located in disordered regions, and so are constitutively active. We demonstrate that the TarP VBS can uncouple talin:vinculin complexes, which may lead to adhesion destabilisation. PMID- 29710404 TI - Design, synthesis, and biological evaluation of structurally constrained hybrid analogues containing ropinirole moiety as a novel class of potent and selective dopamine D3 receptor ligands. AB - Two series of hybrid analogues were designed, synthesized, and evaluated as a novel class of selective ligands for the dopamine D3 receptor. Binding affinities of target compounds were determined (using the method of radioligand binding assay). Compared to comparator agent BP897, compounds 2a and 2c were found to demonstrate a considerable binding affinity and selectivity for D3 receptor, and especially compound 2h was similarly potent and more selective D3R ligand than BP897, a positive reference. Thus, they may provide valuable information for the discovery and development of highly potent dopamine D3 receptor ligands with outstanding selectivity. PMID- 29710405 TI - In Vitro Fermentation Behavior of Isomalto/Malto-Polysaccharides Using Human Fecal Inoculum Indicates Prebiotic Potential. AB - SCOPE: This study characterize intestinal fermentation of isomalto/malto polysaccharides (IMMPs), by monitoring degradation of IMMPs, production of short chain fatty acids (SCFAs), lactic acid, and succinic acid as well as enzyme activity and microbiota composition. METHODS AND RESULTS: IMMP-94 (94% alpha-(1 >6) glycosidic linkages), IMMP-96, IMMP-27, and IMMP-dig27 (IMMP-27 after removal of digestible starch segments) are fermented batchwise in vitro using human fecal inoculum. Fermentation digesta samples are taken for analysis in time up till 48 h. The fermentation of alpha-(1->6) glycosidic linkages in IMMP-94, IMMP-96, and IMMP-dig27 starts after 12 h and finishes within 48 h. IMMP-27 fermentation starts directly after inoculation utilizing alpha-(1->4) linked glucosyl residues; however, the utilization of alpha-(1->6) linked glucoses is delayed and start only after the depletion of alpha-(1->4) linked glucose moieties. SCFAs are produced in high amounts with acetic acid and succinic acid being the major products next to propionic acid and butyric acid. The polysaccharide fraction is degraded into isomalto-oligosaccharides (IMOs) mainly by extracellular enzymes. The smaller IMOs are further degraded by cell-associated enzymes. Overall microbial diversity and the relative abundance of Bifidobacterium and Lactobacillus, significantly increase during the fermentation of IMMPs. CONCLUSION: IMMP containing segments of alpha-(1->6) linked glucose units are slowly fermentable fibers with prebiotic potential. PMID- 29710406 TI - A Reversible Redox Reaction in a Keggin Polyoxometalate Crystal Driven by Visible Light: A Programmable Solid-State Photochromic Switch. AB - The colourless crystals of (PPh4 )3 [PW12 O40 ]?3 C3 H7 NO (1) are converted to the dark blue crystals of {(PPh4 )3 [PW12 O40 ]?3C3 H7 NO}0.85 {(PPh4 )3 (C3 H7 NO)+. [PWV WVI11 O40 ]- ?2C3 H7 NO)}0.15 (2) upon irradiation with visible light in an interesting single crystal to single crystal transformation. This photochromic conversion is accompanied by the reduction of concerned Keggin anion from {PWVI12 } to {PWV WVI11 }. This redox conversion is characterized by various spectroscopic techniques including single crystal X-ray diffraction studies. The photochromic properties of compound 1 can be controlled reversibly through the dimethylformamide (DMF) molecule as a function of temperature and proton exposure in a gas-solid reaction. The present work can be described as a new concept of programmable photochromism with the formation of photochromic pockets in crystalline 1 host (solid state), wherein a solvent can be plugged at a time to show light induced coloration. PMID- 29710407 TI - Distribution and Prevalence of Myxobolus cerebralis in Postfire Areas of Plumas National Forest: Utility of Environmental DNA Sampling. AB - Myxobolus cerebralis is a myxozoan parasite and the etiological agent of whirling disease in salmonids. The parasite's life cycle involves waterborne spores and requires both a salmonid fish and the benthic freshwater oligochaete worm Tubifex tubifex (Oligochaeta: Tubificidae). Wildfires can lead to the erosion of fine sediments into stream channels and have been implicated as promoting environmental conditions that are suitable for the survival and success of T. tubifex, whose presence in turn can affect the prevalence of M. cerebralis. Analysis of environmental DNA (eDNA) has the potential to be a powerful tool for evaluating the presence of microorganisms, for which direct observation is impossible. We investigated the presence of M. cerebraliseDNA in river water and river sediment samples collected from areas affected by recent fire activity in Plumas National Forest, California. We compared eDNA loads in the environment to M. cerebralis infection in T. tubifex and sentinel-exposed Rainbow Trout Oncorhynchus mykiss and the presence of T. tubifex lineages in the same environment. For the latter, we developed a multiplex quantitative PCR assay for detection of T. tubifex lineages I, III, and V. Lineage IIIT. tubifex and M. cerebralis (eDNA as well as DNA extracted from fish and worm tissues) were detected only in samples obtained from areas affected by the Moonlight wildfire. The association between M. cerebralis infection in sentinel-exposed fish and eDNA detection in environmental samples only approached significance at a P-value of 0.056. However, given the difference in relative effort between the two sampling methods (host versus nonhost environment), our data suggest that eDNA sampling of water and substrate is a promising approach for surveillance of myxozoan fish parasites. PMID- 29710408 TI - Preventing Atopic Dermatitis and ALLergies in Children-the PreventADALL study. PMID- 29710409 TI - Papillary Architecture and Functional Characterization of Mucosubstances in the Sheep Tongue. AB - This research aimed to reveal the general morphology and topographic distribution of lingual papillae, epithelial characteristics, mucosal structure, and glands with their mucin content in the sheep tongue, with consideration of species specific characteristics. The tongues of ten sheep were analyzed for this purpose. Filiform and fungiform papillae existed within the borders of the ventral surface of the lingual apex. The majority of the filiform papillae had multiple secondary projections. Fungiform papillae were also seen on the lingual torus among lenticular papillae, as well as 6 to 10 circumvallate papillae arranged on its caudal border. The species-specific details of the general anatomical structure of the tongue were determined and, in general, the papillary organization in the sheep was similar to goats, while the papillary organization also was similar to features with deer species, specifically the filiform papilla from the mechanical papillae and fungiform papilla from the gustatory papillae. Neutral and weak sulfated mucins and N-acetyl sialomucins were located in seromucous glands, salivary duct epithelium and von Ebner's glands. Carboxylated acid mucins and N-acetyl sialomucins were not present in seromucous and von Ebner's glands. In seromucous glands, MUC1, MUC5AC and MUC6 localized only in epithelial cells of ducts, whereas MUC2 localized in both glandular and ductal epithelial cells. All MUCs were present in both von Ebner's glands and salivary ducts. We showed that this mucin composition, may serve as a physical barrier in the initial section of the digestive system. This article is protected by copyright. All rights reserved. PMID- 29710410 TI - Comprehensive Peptide Analysis of Mouse Brain Striatum Identifies Novel sORF Encoded Polypeptides. AB - Bio-active peptides are involved in the regulation of most physiological processes in the body. Classical bio-active peptides (CBAPs) are cleaved from a larger precursor protein and stored in secretion vesicles from which they are released in the extracellular space. Recently, another non-classical type of bio active peptides (NCBAPs) has gained interest. These typically are not secreted but instead appear to be translated from short open reading frames (sORF) and released directly into the cytoplasm. In contrast to CBAPs, these peptides are involved in the regulation of intra-cellular processes such as transcriptional control, calcium handling and DNA repair. However, bio-chemical evidence for the translation of sORFs remains elusive. Comprehensive analysis of sORF-encoded polypeptides (SEPs) is hampered by a number of methodological and biological challenges: the low molecular mass (many 4-10 kDa), the low abundance, transient expression and complications in data analysis. We developed a strategy to address a number of these issues. Our strategy is to exclude false positive identifications. In total sample, we identified 926 peptides originated from 37 known (neuro)peptide precursors in mouse striatum. In addition, four SEPs were identified including NoBody, a SEP that was previously discovered in humans and three novel SEPS from 5' untranslated transcript regions (UTRs). PMID- 29710411 TI - Photobiomodulation with red light-emitting diodes accelerates hepatocyte proliferation through reactive oxygen species/extracellular signal-regulated kinase pathway. AB - AIM: Cell-based transplantation is an alternate method of liver transplantation to delay the onset of end-stage liver diseases. For successful treatment, cells need to be expended in vitro expeditiously. However, autogenetic hepatocytes as the ideal cell source for therapy remain in quiescence so proliferation is rare. Photobiomodulation therapy has been used to stimulate some kinds of cell proliferation, but is unknown whether red light-emitting diode (LED) irradiation can promote primary hepatocyte proliferation. The aim of this study was to evaluate the effect of red LED irradiation on hepatocytes in vitro. METHODS: Mouse primary hepatocytes were isolated and received red LED treatment. The cell viability, reactive oxygen species (ROS) levels, phosphorylated extracellular signal-regulated kinase1/2 (pERK1/2) and some cell cycle-related proteins were observed. Additionally, ROS inhibition and pERK1/2 inhibition were carried out to determine the effect of ROS and ERK1/2 in red LED irradiation. RESULTS: The red LED irradiation increased hepatocyte proliferation, elevated intracellular ROS levels, and stimulated ERK1/2 activation and cell cycle-related gene expression. The mitosis promoting effect of red LED irradiation could be disturbed by ROS or pERK inhibition. The red LED irradiation promoted hepatocyte proliferation through the ROS/pERK1/2 pathway. CONCLUSIONS: Red LED irradiation could accelerate hepatocyte proliferation through the ROS/pERK1/2 pathway. Red LED irradiation might be a potential method to increase hepatocyte cell numbers in vitro and support cell-based transplantation in clinical work. PMID- 29710412 TI - Post-translational modifications in priming the plant immune system: ripe for exploitation? AB - Microbes constantly challenge plants, and some can successfully infect their host and cause disease. Basal immunity against plant pathogens in many cases is not enough for survival and leads to disease and, ultimately, a premature death of the host plant. However, the plant immune system can be temporarily and even transgenerationally primed; this 'primed state' leads to changes in the plant involving transcriptional, post-translational, metabolic, physiological and epigenetic reprogramming, which enables fine-tuning defence mechanisms for a rapid and/or more robust response after abiotic and/or biotic stress. This can ultimately affect pathogen infection speed and, hence, decrease its ability to overcome host resistance and the final outcome of the host-pathogen interaction. The role of the three major post-translational modifications (PTMs) (protein ubiquitination, phosphorylation and SUMOylation) in plant immunity has been well established. However, the role of PTMs on defence priming, and how the PTM machinery is affected in primed plants and its connection to plant resistance against biotic/abiotic stress is not well understood. This Review highlights the current state of play of priming-mediated post-translational reprogramming and explores new areas for future research. PMID- 29710413 TI - Automated Pulmonary Embolism Risk Classification and Guideline Adherence for Computed Tomography Pulmonary Angiography Ordering. AB - BACKGROUND: The assessment of clinical guideline adherence for the evaluation of pulmonary embolism (PE) via computed tomography pulmonary angiography (CTPA) currently requires either labor-intensive, retrospective chart review or prospective collection of PE risk scores at the time of CTPA order. The recording of clinical data in a structured manner in the electronic health record (EHR) may make it possible to automate the calculation of a patient's PE risk classification and determine whether the CTPA order was guideline concordant. OBJECTIVES: The objective of this study was to measure the performance of automated, structured data-only versions of the Wells and revised Geneva risk scores in emergency department (ED) encounters during which a CTPA was ordered. The hypothesis was that such an automated method would classify a patient's PE risk with high accuracy compared to manual chart review. METHODS: We developed automated, structured data-only versions of the Wells and revised Geneva risk scores to classify 212 ED encounters during which a CTPA was performed as "PE likely" or "PE unlikely." We then combined these classifications with D-dimer ordering data to assess each encounter as guideline concordant or discordant. The accuracy of these automated classifications and assessments of guideline concordance were determined by comparing them to classifications and concordance based on the complete Wells and revised Geneva scores derived via abstractor manual chart review. RESULTS: The automatically derived Wells and revised Geneva risk classifications were 91.5 and 92% accurate compared to the manually determined classifications, respectively. There was no statistically significant difference between guideline adherence calculated by the automated scores compared to manual chart review (Wells, 70.8% vs. 75%, p = 0.33; revised Geneva, 65.6% vs. 66%, p = 0.92). CONCLUSION: The Wells and revised Geneva score risk classifications can be approximated with high accuracy using automated extraction of structured EHR data elements in patients who received a CTPA. Combining these automated scores with D-dimer ordering data allows for the automated assessment of clinical guideline adherence for CTPA ordering in the ED, without the burden of manual chart review. PMID- 29710414 TI - Combined Influence of Gelatin Fibre Topography and Growth Factors on Cultured Dorsal Root Ganglia Neurons. AB - Nerve guidance channels facilitate nerve regeneration and represent an attractive alternative to nerve graft. Actually, nano- and microstructured biomaterials for nerve reconstruction have gained much attention, thanks to recent discoveries about topography effects on cell behavior and morphology. Electrospun fibres have been proposed as filler or structural component for nerve guidance channels, principally due to their similarity with extracellular matrices which facilitate nerve regeneration. Among several tested biomaterials, gelatin has been used to prepare fibres able to support Schwann cell migration and neurite outgrowth. In this work, the effects of gelatin fibre size on axon elongation and Schwann cell migration have been tested using dorsal root ganglia cultures. Moreover, we analyzed how fibres might affect the expression of specific neuronal subtype markers in sensory neuron cultures and how the combined effect of substrate and biological cues affects neurite growth and gene expression. Data show that fibre topography differentially affects both neurite outgrowth and gene expression and suggest that fibre size and topography associated to specific growth factor exposure might be used to select neuron subpopulations and favor the axonal growth of specific neurons. Anat Rec, 301:1668-1677, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29710415 TI - Grazing disturbance increases transient but decreases persistent soil seed bank. AB - Very few studies have examined whether the impacts of grazing disturbance on soil seed banks occur directly or indirectly through aboveground vegetation and soil properties. The potential role of the seed bank in alpine wetland restoration is also unknown. We used SEM (structural equation modeling) to explore the direct effect of grazing disturbance on the seed bank and the indirect effect through aboveground vegetation and soil properties. We also studied the role of the seed bank on the restoration potential in wetlands with various grazing intensities: low (fenced, winter grazed only), medium (seasonally grazed), and high (whole year grazed). For the seed bank, species richness and density per plot showed no difference among grazing intensities for each depth (0-5, 5-10, 10-15 cm) and for the whole depth (0-15 cm) in spring and summer. There was no direct effect of grazing disturbance on seed bank richness and density both in spring and summer, and also no indirect effect on the seed bank through its direct effect on vegetation richness and abundance. Grazing disturbance indirectly increased spring seed bank density but decreased summer seed bank density through its direct effect (negative correlation) on soil moisture and total nitrogen and its indirect effect on vegetation abundance. Species composition of the vegetation changed with grazing regime, but that of the seed bank did not. An increased trend of similarity between the seed bank and aboveground vegetation with increased grazing disturbance was found in the shallow depth and in the whole depth only in spring. Although there was almost no change in seed bank size with grazing intensities, grazing disturbance increased the quantity of transient seeds but decreased persistent seeds. Persistent seeds stored in the soil could play a crucial role in vegetation regeneration and in restoration of degraded wetland ecosystems. The seed bank should be an integral part of alpine wetland restoration programs. PMID- 29710416 TI - Comprehensive in-hospital monitoring in acute heart failure: applications for clinical practice and future directions for research. A statement from the Acute Heart Failure Committee of the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). AB - This paper provides a practical clinical application of guideline recommendations relating to the inpatient monitoring of patients with acute heart failure, through the evaluation of various clinical, biomarker, imaging, invasive and non invasive approaches. Comprehensive inpatient monitoring is crucial to the optimal management of acute heart failure patients. The European Society of Cardiology heart failure guidelines provide recommendations for the inpatient monitoring of acute heart failure, but the level of evidence underpinning most recommendations is limited. Many tools are available for the in-hospital monitoring of patients with acute heart failure, and each plays a role at various points throughout the patient's treatment course, including the emergency department, intensive care or coronary care unit, and the general ward. Clinical judgment is the preeminent factor guiding application of inpatient monitoring tools, as the various techniques have different patient population targets. When applied appropriately, these techniques enable decision making. However, there is limited evidence demonstrating that implementation of these tools improves patient outcome. Research priorities are identified to address these gaps in evidence. Future research initiatives should aim to identify the optimal in-hospital monitoring strategies that decrease morbidity and prolong survival in patients with acute heart failure. PMID- 29710417 TI - Evaluation of Vascular Endothelial Growth Factor (VEGF) and Its Family Member Expression After Peripheral Nerve Regeneration and Denervation. AB - Vascular endothelial growth factor (VEGF) represents one of the main factors involved not only in angiogenesis and vasculogenesis but also in neuritogenesis. VEGF plays its function acting via different receptors: VEGF receptor1 (VEGFR-1), VEGF receptor2 (VEGFR-2), VEGF receptor3 (VEGFR-3), and co-receptors Neuropilin-1 (NRP1) and Neuropilin-2 (NRP2). This study reports on the first in vivo analysis of the expression of VEGF and VEGF family molecules in peripheral nerve degeneration and regeneration: for this purpose, different models of nerve lesion in rat were adopted, the median nerve crush injury and the median nerve transaction followed or not by end-to end microsurgical repair. Results obtained by real time polymerase chain reaction showed that VEGF and VEGF family molecules are differentially expressed under regenerating and degenerating condition, furthermore, in order to study the modulation and involvement of these factors in two different regenerative models, crush injury and end-to-end repair, protein expression analysis was evaluated. In addition, immunohistochemical analysis allowed to state a glial localization of VEGF and VEGFR-2 after peripheral nerve crush injury. Finally in vitro assay on primary Schwann cells culture show that VEGF165 stimulation increases Schwann cells migration, a major process in the promotion of neurite outgrowth. Anat Rec, 301:1646-1656, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29710418 TI - Synthesis of 5-Cyano-Tryptophan as a Two-Dimensional Infrared Spectroscopic Reporter of Structure. AB - A concise synthesis of protected 5-cyano-l-tryptophan (Trp5CN ) has been developed for 2D IR spectroscopic investigations within either peptides or proteins. To assess the potential of differently substituted cyano-tryptophans, several model cyano-indole systems were characterized using IR spectroscopy. Upon assessment of their spectroscopic properties, Trp5CN was integrated into a model peptide sequence, Trp5CN -Gly-Phe4CN , to elucidate its structure. This peptide demonstrates the capability of this probe to capture structural information by 2D IR spectroscopy. The 2D IR spectrum of the peptide in water was simulated to reveal a unique spectral signature resulting from the presence of dipolar coupling. The coupling strength between cyano labels was determined to be 1.4 cm 1 by matching the slopes along the max contour for the simulated and experimental spectrum. Using transition dipole coupling, a distance between the two probes of 13 A was calculated. PMID- 29710419 TI - IFN-gamma enhances the wound healing effect of late EPCs (LEPCs) via BST2 mediated adhesion to endothelial cells. AB - Circulating late endothelial progenitor cells (LEPCs) home to injured vessels, initiating blood vessel regeneration. This process requires the initial adhesion of LEPCs to endothelial cells within the wounded site. In this study, treating LEPCs with IFN-gamma enhanced wound healing through BST2-mediated adhesion to endothelial cells. We found that IFN-gamma significantly upregulated BST2 expression in both LEPCs and ECs and increased tube formation in LEPCs. Upregulated BST2 increased LEPC adhesion to ECs through a tight homophilic interaction of its extracellular domain. Finally, when the IFN-gamma-treated LEPCs were injected into the wounded mouse tail vein, superior therapeutic effects of wound closure were observed. This study provides a useful application to enhance the adhesion of LEPCs for vessel regeneration and wound closure. PMID- 29710420 TI - Partitioning of the net CO2 exchange using an automated chamber system reveals plant phenology as key control of production and respiration fluxes in a boreal peatland. AB - The net ecosystem CO2 exchange (NEE) drives the carbon (C) sink-source strength of northern peatlands. Since NEE represents a balance between various production and respiration fluxes, accurate predictions of its response to global changes require an in depth understanding of these underlying processes. Currently, however, detailed information of the temporal dynamics as well as the separate biotic and abiotic controls of the NEE component fluxes is lacking in peatland ecosystems. In this study, we address this knowledge gap by using an automated chamber system established across natural and trenching/vegetation removal plots to partition NEE into its production (i.e., gross and net primary production; GPP and NPP) and respiration (i.e., ecosystem, heterotrophic and autotrophic respiration; ER, Rh and Ra) fluxes in a boreal peatland in northern Sweden. Our results showed that daily NEE patterns were driven by GPP while variations in ER were governed by Ra rather than Rh. Moreover, we observed pronounced seasonal shifts in the Ra/Rh and above/belowground NPP ratios throughout the main phenological phases. Generalized linear model analysis revealed that the greenness index derived from digital images (as a proxy for plant phenology) was the strongest control of NEE, GPP and NPP while explaining considerable fractions also in the variations of ER and Ra. In addition, our data exposed greater temperature sensitivity of NPP compared to Rh resulting in enhanced C sequestration with increasing temperature. Overall, our study suggests that the temporal patterns in NEE and its component fluxes are tightly coupled to vegetation dynamics in boreal peatlands and thus challenges previous studies that commonly identify abiotic factors as key drivers. These findings further emphasize the need for integrating detailed information on plant phenology into process-based models to improve predictions of global change impacts on the peatland C cycle. PMID- 29710421 TI - Molecular Characterization of Cryptosporidium spp., Giardia duodenalis, and Enterocytozoon bieneusi in Rabbits in Xinjiang, China. AB - A total of 321 rabbit fecal samples were collected from 10 farms in the Xinjiang Uyghur Autonomous Region, China. The prevalence of Cryptosporidium spp., Giardia duodenalis, and Enterocytozoon bieneusi in the samples was 3.4% (11/321), 1.9% (6/321), and 2.8% (9/321), respectively. Small subunit ribosomal RNA (SSU rRNA) gene sequence analysis identified all 11 Cryptosporidium-positive samples as C. cuniculus. Further subtyping based on the 60-kDaglycoprotein locus (gp60) identified five of the C. cuniculus isolates as subtype VbA24. G. duodenalis genotypes were determined by multilocus sequence typing of the SSU rRNA, triosephosphate isomerase, beta-giardin and glutamate dehydrogenase loci, which confirmed that six G. duodenalis isolates belonged to subtype BIV of assemblage B. Analysis of the internal transcribed spacer region, showed that five, three, and one E. bieneusi isolates belonged to genotypes J, BEB8, and Type IV, respectively. These results suggest that Cryptosporidium spp., G. duodenalis, and E. bieneusi isolates from rabbits in China have zoonotic potential. PMID- 29710422 TI - Minocycline Does Not Reduce the Regenerative Capacity of Peripheral Motor and Sensory Neurons after a Conditioning Injury in Mice. AB - Minocycline has been reported to be both beneficial and detrimental for nerve regeneration after peripheral nerve injury. By reducing the inflammatory response, minocycline administration reduces pain and has neuroprotective effects, but it also inhibits Wallerian degeneration in the distal stump, and reduces microglia and macrophages activity on motor and sensory neurons, which could reduce their intrinsic regenerative capacity. The aim of this study was to determine if the administration of minocycline after nerve injury inhibits the regenerative capacity of motoneurons and sensory neurons after a conditioning lesion. We used two groups of mice: a control group and a group treated with minocycline (30 mg kg-1 ip twice daily). We labeled motor and sensory neurons that had regenerated to a distance of 3 mm in a predegenerated graft, after a conditioning lesion. Our results indicate that minocycline administration is not detrimental for nerve regeneration. Indeed, it even promoted a slight, no significant increase 7 days after the nerve graft. These results indicate that minocycline, given at a dose able to reduce pain after peripheral nerve injury, does not interfere with the intrinsic growth capacity of injured peripheral neurons. Anat Rec, 301:1638-1645, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29710423 TI - Patient-reported outcome instruments that evaluate adherence behaviours in adults with asthma: a systematic review of measurement properties. AB - AIM: The aim of the present study was to identify systematically the measurement properties of patient-reported outcome instruments (PROs) that evaluate adherence to inhaled maintenance medication in adults with asthma. METHODS: We conducted a systematic review of six databases. Two reviewers independently included studies on the measurement properties of PROs that evaluated adherence in asthmatic participants aged >=18 years. Based on the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN), the reviewers: (i) extracted data on internal consistency, reliability, measurement error, content validity, structural validity, hypotheses testing, cross-cultural validity, criterion validity and responsiveness; (ii) assessed the methodological quality of the included studies; (iii) assessed the quality of the measurement properties (positive or negative); and (iv) summarized the level of evidence (limited, moderate or strong). RESULTS: We screened 6068 records and included 15 studies (14 PROs). No studies evaluated measurement error or responsiveness. Based on methodological and measurement property quality assessments, we found limited positive evidence of: (i) internal consistency of the Adherence Questionnaire, Refined Medication Adherence Reason (MAR) scale, Medication Adherence Report Scale for Asthma (MARS-A) and Test of the Adherence to Inhalers (TAI); (ii) reliability of the TAI; and (iii) structural validity of the adherence questionnaire, MAR scale, MARS-A and TAI. We also found limited negative evidence of: (i) hypotheses testing of the Adherence Questionnaire; (ii) reliability of the MARS-A; and (iii) criterion validity of the MARS-A and TAI. CONCLUSIONS: Our results highlighted the need to conduct further high-quality studies to evaluate the reliability, validity and responsiveness of the available PROs. PMID- 29710424 TI - Inhibitors of elastase stimulate murine B lymphocyte differentiation into IgG- and IgA-producing cells. AB - It is well established that dendritic cells and macrophages play a role in antigen presentation to B and T cells and in shaping B and T cell responses via cytokines they produce. We have previously reported that depletion of neutrophils improves the production of mucosal IgA after sublingual immunization with Bacillus anthracis edema toxin as adjuvant. These past studies also demonstrated that an inverse correlation exists between the number of neutrophils and production of IgA by B cells. Using specific inhibitors of elastase, we addressed whether the elastase activity of neutrophil could be the factor that interferes with production of IgA and possibly other immunoglobulin isotypes. We found that murine splenocytes and mesenteric lymph node cells cultured for 5 days in the presence of neutrophil elastase inhibitors secreted higher levels of IgG and IgA than cells cultured in the absence of inhibitors. The effect of the inhibitors was dose-dependent and was consistent with increased frequency of CD138+ cells expressing IgG or IgA. Finally, neutrophil elastase inhibitors increased transcription of mRNA for AID, IL-10, BAFF and APRIL, factors involved in B cell differentiation. These findings identify inhibitors of elastase as potential adjuvants for increasing production of antibodies. PMID- 29710425 TI - Systemic inflammation and immune cell phenotypes are associated with neuro psychiatric symptoms in patients with chronic inflammatory liver diseases. AB - BACKGROUND & AIMS: Chronic inflammatory liver diseases are frequently associated with neuropsychiatric and cognitive dysfunctions. We hypothesized that symptomatic patients may show altered levels of soluble inflammatory mediators (SIMs) as well as changes in immune cell phenotypes. METHODS: A comprehensive immune-phenotyping including investigation of 50 SIMs as well as ex-vivo phenotypes of NK-cells, CD3+, CD4+, CD8+ and regulatory T cells in 40 patients with viral and autoimmune chronic liver diseases was performed. The patients' cognitive functions were assessed using an extensive battery of neuropsychological testing. RESULTS AND CONCLUSION: Overall, our data indicate that while SIMs are significantly up-regulated, NK- and T-cells are less activated in patients with neuropsychiatric symptoms accompanying chronic inflammatory liver diseases compared to patients without these symptoms. Moreover, HCV patients showed a unique pattern of immune alterations as compared to patients with HBV, autoimmune hepatitis and primary biliary cirrhosis. These findings hint towards potential mechanisms explaining these symptoms in patients with chronic liver diseases. PMID- 29710427 TI - IFI16 regulates HTLV-1 replication through promoting HTLV-1 RTI-induced innate immune responses. AB - Interferon (IFN)-inducible protein 16 (IFI16) regulates human immunodeficiency virus replication by inducing innate immune responses as a DNA sensor. Human T lymphotropic virus type 1 (HTLV-1), a delta retrovirus family member, has been linked to multiple diseases. Here, we report that IFI16 expression is induced by HTLV-1 infection or HTLV-1 reverse transcription intermediate (RTI) ssDNA90 transfection. IFI16 overexpression decreases HTLV-1 protein expression, whereas IFI16 knockdown increases it. Furthermore, the knockdown of IFI16 is followed by impaired innate immune responses upon HTLV-1 infection. In addition, IFI16 forms a complex with ssDNA90 and enhances ssDNA90-triggered innate immune responses. Collectively, our data suggest a critical role for IFI16 during HTLV-1 infection by interacting with HTLV-1 RTI ssDNA90 and restricting HTLV-1 replication. PMID- 29710426 TI - Resource reallocation patterns within Sagittaria trifolia inflorescences following differential pollination. AB - PREMISE OF THE STUDY: Understanding resource allocation to reproduction, a key factor in life history tradeoffs, has long intrigued plant ecologists. Despite the recognized importance of understanding the movement of resources among flowers following variable pollination, the patterns of resource reallocation to plant reproductive organs have not been thoroughly addressed. In this study, we aimed to empirically explore how resources redistribute within inflorescences in response to differential pollination intensities. METHODS: Using a common herb, Sagittaria trifolia, we conducted supplemental and controlled pollination for single, some, or all flowers in simple and complex inflorescences, and compared their resulting fruiting probabilities, seed production, and average seed masses. KEY RESULTS: Pollen supplementation of a single flower significantly increased its fruiting probability; however, the same manipulation of an inflorescence did not increase its overall reproduction. Single pollen-supplemented flowers had a higher percentage fruit set than inflorescences receiving supplemental pollination. In complex inflorescences, supplemental pollination had no effect on the reproductive success of flowers on the lateral or main branches. CONCLUSIONS: We provided evidence of resource reallocation from controlled to pollen supplemented flowers in simple inflorescences; however, resources were unlikely to be reallocated between the main and lateral branches in the complex inflorescences, suggesting that flowering branches represent integrated physiological units in S. trifolia. The results also demonstrated that single flower supplemental pollination would exaggerate pollen limitation and lead to a biased understanding of a plant's reproductive status. PMID- 29710428 TI - Horizons of Systems Biocatalysis and Renaissance of Metabolite Synthesis. AB - The small molecule domain of biological cellular systems is closely related to the synthesis and breakdown of larger molecules such as DNA, RNA, proteins, or polysaccharides. Although the analysis, identification, characterization and synthesis of metabolites has a long history of milestone discoveries, it continues to be of great interest in the search for novel biological activities, metabolic pathways, diagnostic and therapeutic applications. Biologically active metabolites benefit from advantages in diffusion and transport for various interactions with proteins and nucleic acids and regulatory events. Therefore, metabolism is receiving renewed interest and meets molecular biology in the context of a true molecular understanding of cellular systems in health and disease. The analysis of the spatial and temporal organization of biocatalysis in cellular and subcellular systems provides valuable clues for resource- and energy efficient synthetic routes to natural metabolites. At the same time metabolites are needed for these analyses and the synthesis of metabolites is experiencing a renaissance. A Systems Biocatalysis approach to the synthesis of metabolites aims at biocatalytic route designs with high molecular economy. Biocatalytic reaction platforms have been successfully developed as preferred synthetic methodology for a number of reaction classes, which can be assembled in the selection of routes to metabolites. PMID- 29710429 TI - Clinical Manifestation of Acute, Subacute, and Chronic Low Back Pain in Different Age Groups: Low Back Pain in 35,446 Patients. AB - BACKGROUND: Low back pain (LBP) is a major healthcare problem causing tremendous economic costs. METHODS: Clinical manifestation of LBP was characterized in 35,446 patients. We focused on the comparison of the acute, subacute, and chronic LBP stage with regard to patients' ages, based on epidemiologic and clinical questionnaires (eg, painDETECT Questionnaire, Pain Disability Index), pain intensity, pain descriptors, and functional impairment. RESULTS: We found that neuropathic components were most frequent in chronic LBP patients at the ages of 51 to 60 years. Elderly LBP patients showed a decrease in neuropathic and an increase in nociceptive pain. The most frequently reported pain descriptors were "pressure pain" and "pain attacks" through all stages of LBP, whereas "burning" and "prickling" were most frequent in the chronic stage. Patients after back surgery presented neuropathic pain symptoms most frequently and had the highest amount of pain medication intake. CONCLUSIONS: Burning and prickling were revealed as possible indicators for LBP chronicity. Combined with pain attacks and pressure pain, these 4 pain descriptors might be a promising adjunct to pain intensity in terms of outcome parameters for future LBP studies. The decrease of neuropathic pain syndromes in the elderly might be explained by degenerative processes. The presented work provides important insights on LBP management in the acute, subacute, and chronic stages. PMID- 29710431 TI - Dual efficacy of dupilumab in a patient with concomitant atopic dermatitis and alopecia areata. PMID- 29710430 TI - The Nasal Cavity of the Rat and Mouse-Source of Mesenchymal Stem Cells for Treatment of Peripheral Nerve Injury. AB - The nasal cavity performs several crucial functions in mammals, including rodents, being involved in respiration, behavior, reproduction, and olfaction. Its anatomical structure is complex and divided into several regions, including the olfactory recess where the olfactory mucosa (OM) is located and where the capture and interaction with the environmental odorants occurs. Among the cells of this region are the OM mesenchymal stem cells (MSCs), whose location raises the possibility that these cells could be involved in the peculiar ability of the olfactory nerve to regenerate continuously throughout life, although this relationship has not yet been confirmed. These cells, like all MSCs, present functional characteristics that make them candidates in new therapies associated with regenerative medicine, namely to promote the regeneration of the peripheral nerve after injury. The availability of stem cells to be therapeutically applied essentially depends on their collection in the tissue of origin. In the case of mice and rat's OM-MSCs, knowledge about the anatomy and histology of their nasal cavity is essential in establishing effective collection protocols. The present article describes the morphological characteristics of rodent's OM and establishes an alternative protocol for access to the olfactory recess and collection of the OM. Anat Rec, 301:1678-1689, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29710432 TI - A common polymorphic variant of UGT1A5 displays increased activity due to optimized cofactor binding. AB - Uridine diphosphate-glucuronosyltransferases (UGTs) are the most important phase II enzymes in human drug metabolism. Using permeabilized recombinant fission yeast cells (enzyme bags), we demonstrate that UGT1A5 can catalyze an N glucuronidation reaction. We characterized two new polymorphic UGT1A5 variants: a common ninefold mutant (UGT1A5*8) with double-fold activity and a much rarer sixfold mutant (UGT1A5*9), which has the same activity as the wild-type. Molecular modeling studies indicate that the minor effects of all mutations, except for Gly259Arg, are due to their distance to the substrate binding site. Extensive molecular dynamics simulations revealed that the Gly259Arg mutation stabilizes helix Q through a newly formed hydrogen bonding network, which places the cofactor in a much more favorable geometry in UGT1A5*8 as compared to the wild-type. PMID- 29710433 TI - Remnant vital tissue following locoregional therapy for hepatocellular carcinoma: another player in the game. AB - The applicability of liver transplantation (LT) as a curative option for patients with hepatocellular carcinoma (HCC) is limited by organ shortage. In addition to tumor size and number, other variables, particularly those that are surrogates of tumor biology should be incorporated into the allocation policies to improve the estimation of post-LT benefit. In this issue of Transplant International, Manzia et al. analyze the role of remnant vital tissue (RVT) of the target lesion after locoregional therapies (LRT) in predicting post-LT HCC recurrence This article is protected by copyright. All rights reserved. PMID- 29710434 TI - Improved HCP Reduction Using a New, All-Synthetic Depth Filtration Media Within an Antibody Purification Process. AB - Biologic manufacturing processes typically employ clarification technologies like depth filtration to remove insoluble and soluble impurities. Conventional depth filtration media used in these processes contain naturally-derived components like diatomaceous earth and cellulose. These components may introduce performance variability and contribute extractable/leachable components like beta-glucans that could interfere with limulus amebocyte lysate endotoxin assays. Recently a novel, all-synthetic depth filtration media is developed (Millistak+(r) HC Pro X0SP) that may improve process consistency, efficiency, and drug substance product quality by reducing soluble process impurities. This new media is evaluated against commercially available benchmark filters containing naturally derived components (Millistak+(r) HC X0HC and B1HC). Using model proteins, the synthetic media demonstrates increased binding capacity of positively charged proteins (72-126 mg g-1 media) compared to conventional media (0.3-8.6 mg g-1 media); and similar values for negatively charged species (1.3-5.6 mg g-1 media). Several CHO-derived monoclonal antibodies (mAbs) or mAb-like molecules are also evaluated. The X0SP filtration performance behaves similarly to benchmarks, and exhibits improved HCP reduction (at least 50% in 55% of cases tested). X0SP filtrates contained increased silicon extractables relative to benchmarks, but these were readily removed downstream. Finally, the X0SP devices demonstrates suitable lot-to-lot robustness when specific media components are altered intentionally to manufacturing specification limits. PMID- 29710435 TI - Bridging the Gap between the Direct and Hydrocarbon Pool Mechanisms of the Methanol-to-Hydrocarbons Process. AB - After a prolonged effort over many years, the route for the formation of a direct carbon-carbon (C-C) bond during the methanol-to-hydrocarbon (MTH) process has very recently been unveiled. However, the relevance of the "direct mechanism" derived molecules (that is, methyl acetate) during MTH, and subsequent transformation routes to the conventional hydrocarbon pool (HCP) species, are yet to be established. This important piece of the MTH chemistry puzzle is not only essential from a fundamental perspective, but is also important to maximize catalytic performance. The MTH process was probed over a commercially relevant H SAPO-34 catalyst, using a combination of advanced solid-state NMR spectroscopy and operando UV/Vis diffuse reflectance spectroscopy coupled to an on-line mass spectrometer. Spectroscopic evidence is provided for the formation of (olefinic and aromatic) HCP species, which are indeed derived exclusively from the direct C C bond-containing acetyl group of methyl acetate. New mechanistic insights have been obtained from the MTH process, including the identification of hydrocarbon based co-catalytic organic reaction centers. PMID- 29710436 TI - [Preface]. PMID- 29710437 TI - [Editorial]. PMID- 29710438 TI - [Next Generation Sequencing and ADPKD]. AB - Autosomal Dominant Polycistic Kidney Disease (ADPKD) is the most common inherited genetic disorder in the word, caused by mutations in PKD1 gene in 85% of cases and PKD 2 gene in the remaining 15%. Although diagnosis is usually based on ultrasound, MRI and CT scans, in some cases genetic testing is necessary, for example, in patients with atypical phenotype or with a negative family history, or in cases of donation from relatives. The presence of pseudogenes in PKD1, the size of the gene, the costs of the Sanger sequencing and genetic heterogeneity underlying kidney disease make genetic analysis particularly difficult to be performed. Next Generation Sequencing (NGS) represents the last frontier of innovation among diagnostic tools for molecular diagnosis of inherited cystic kidney disease thanks to the ability to analyze several genes at the same time. In this regard, we have developed a NGS platform, called Nephroplex, with the aim of identifying variations in 115 genes responsible for numerous kidney diseases, including cystic and polycystic disease, achieving, overall, a target region of 338.8 kbps. The technology used for the enrichment is HaloPlex system, based on the digestion of genomic DNA with restriction enzymes and the capture of the regions of interest with specific hybridization probes. With our platform, we have analyzed 9 patients with clinical diagnosis of ADPKD. We have obtained a depth coverage of 100x for 96.5% of the target, while the region not covered accounted for only 3% of the region of interest. In 6 patients, we found causative mutations in the genes PKD1 and PKD2, achieving a detection rate of 66%. In conclusion, the NephroPlex platform has proved to be an excellent device for molecular diagnosis of kidney disease and could clarify the mechanisms underlying genetic heterogeneity observed in kidney disease. PMID- 29710439 TI - [Nephrocalcinosis in children]. AB - Nephrocalcinosis (NC) is a renal disease characterized by deposition of calcium salts into the renal medulla. There are several causes, organic, iatrogenic, hereditary and sometimes related to extrarenal diseases. We studied 34 children affected by NC, 21 M and 13 F (average age at diagnosis 7.8 months), with the aim of analyzing the associated diseases, clinical manifestations, metabolic abnormalities, growth and renal function at onset and after follow-up. At onset 70% of patients were asymptomatic and diagnosis was occasional. Renal function was normal in 33 patients. The most frequent clinical symptoms were failure to thrive (9%), abdominal pain (6%), proteinuria/hematuria (7%). The associated diseases were: tubulopathies (8 pcs - tubular acidosis, Dent, Bartter and Lowe Syndromes), medullary sponge kidney, policalicosis (3 pcs ), Short bowel Syndrome (3 pcs), hyperparathyroidism, hypothyroidism (2 pcs), thalassemia (1pc), tyrosinemia (1 pc.). We recognized two forms of hypervitaminosis D. In a pc NC would be correlated with prematurity, another one with lipid necrosis. Among the metabolic abnormalities, observed in 25% of pcs, hyperoxaluria is the most frequent (47%), hypercalciuria (20%), hypercalcemia (15%). In some cases we found endocrine non pathogenic alterations: hypovitaminosis D (2 pcs) and hypoparathyroidism (6 pcs). During follow-up the growth was normal in 87% of cases and glomerular function was stable in 90% of pcs; IRC developed in 3 cases. From our analysis, it appears that the treatment of the underlying condition of NC is associated with catch-up growth and stabilization of renal function in most patients, but not with the reduction of the degree of the NC. PMID- 29710440 TI - [Atypical Hemolytic Uremic Syndrome: experience of a pediatric center]. AB - In the last two years we admitted in our Hospital 38 children with acute renal failure (ARF). Six of them were affected by hemolytic uremic syndrome (HUS) atypical. The aHUS is diagnosed in the presence of thrombotic microangiopathy (MAT), renal insufficiency (GFR 5%). The clinical presentation of our children has been varied and so also its evolution. Patients observed were all male, aged 2 to 12 years, and no one had a family history of kidney disease. In four patients we documented alterations of complement factors (MCP deficiency and factor H and presence of anti factor H). Repeated blood transfusions were required in 4 patients and in 3 patients the platelet count was slightly reduced. In 5 patients we did plasmapheresis and in 3 patients dialysis (hemodialysis and peritoneal dialysis). In three patients in whom the diagnosis was not clear, renal biopsy was performed to confirm the diagnosis. Eculizumab was administered in 3 patients resistant to plasma exchange. We obtain a rapid response on MAT with normalization of platelet count. The effect on renal function was variable (complete remission in a patient, partial improvement in another, and unresponsiveness in the last). The last had on Kidney biopsy signs of severe impairment and we documented the presence of antibodies to eculizumab. HUS is a rare condition, but probably much more common than reported. In children with ARF and microangiopathic anemia is necessary evaluated complement factors as early to obtain an improved clinical response to treatment with eculizumab. PMID- 29710441 TI - [Home Hemodialysis: Experience and Preliminary Results Of The First Center In Campania]. AB - The Home Hemodialysis (HHD) is an uncommon dialytic option that can offer better clinical outcomes and a more satisfactory quality of life. The Health Plan of the Region Campania 2011-2013 states that" the system of home care for regional planning is particularly important". From August 2014 to March 2015 two patients, on standard dialysis (HD) as inpatients at Dialysis Centre of the University "Federico II" of Naples, started Short Daily Home Hemodialysis (SDHD) (4-6 dialysis treatments%week, 2.5 hours per session) using the portable cycler NxStage System One). The data collected showed that the clinical benefits described in the literature were confirmed in patients enrolled in this HHD program. Shorter and more frequent hemodialysis sessions allowed a significant reduction in interdialytic weight gain and greater intradialytic hemodynamic stability. A significant reduction in blood pressure and anti-hypertensive drugs were obtained. The control of phosphorus appeared better and hemoglobin was to target with a lower dose of weekly erythropoetin. The patients reported a greater well-being and a reduction in post-dialytic asthenia. No problem has been reported in using the vascular access (CVC and FAV) by the patient%caregiver. The dialysis adequacy and efficiency were comparable between SDHD and HD. The experience with the HHD is encouraging as the patients achieved an adequate dialysis dose without any complications reporting an improving sense of well being and a better quality of life. PMID- 29710442 TI - [DPP-4 inhibitors in nephropatics]. AB - The use of glucose-lowering drugs in advanced stage diabetic nephropathic patients should be done very carefully. Some drugs are contraindicated or not recommended. The same insulin needs a dose reduction to avoid dangerous hypoglycemia. For some years the use of inhibitors of the DDP-4 has been approved in T2DM patients with CKD III and IV stage, proposing the use without limitations even in case of ESRD. We conducted a prospective observational study of a cohort of 60 patients with T2DM and CKD stage IV, selecting a sample of 15 patients taking an inhibitor of DPP-4 and comparing it with those who took therapy "old" drugs, despite having similar characteristics of CKD. In both groups, we found: 1) the effectiveness of therapy, through the assessment of glycated hemoglobin and glycemic profile; 2) the possible occurrence of "hypoglycemia", "side effects", accelerating the progression of CKD. No patients being treated with inhibitors of DPP-4 have experienced hypoglycemia, or adverse events, or adverse effects on the progression of CKD. The glycated hemoglobin, revealed more stability than the comparison group. Hypoglycaemic episodes were present only in the group receiving intensive insulin. Although kidneys and their dose, in case of high degree of CKD, primarily eliminate inhibitors of DPP-4, with some exceptions, should be reduced, in our experience they have proven beneficial drugs in diabetics with kidney disease, being effective and well tolerated in the case of ESRD, where the only treatment option was represented by insulin. PMID- 29710443 TI - [Technical- rganizational and Welfare Aspects Of The First Home Hemodialysis Program in Campania]. AB - To activate a program of home hemodialysis (HHD) and to ensure its sustainability and success, it is essential to provide a structured path with the realization of a programmatic document detailing the technological requirements and the type of organization and assistance in line with the regulations currently in force. The path must consider the following: (a) eligibility clinical criteria of the patient and the caregiver, (b) analysis of the most recent HHD literature and the reasons of the choice of the latest technology, (c) accurate information of the patient and the caregiver with their approval, (d) care coverage and hospital admission modalities (e) suitability of the rooms where the patient will perform the HHD treatment, (f) training program of the patient and the caregiver, home treatment start and patient follow-up. The implementation of this structured process has allowed us to launch a successful HHD program: this modus operandi has preventively defined the pathway care and analyzed the priorities of risk. We have analyzed the HHD process to identify the possible problems and predictable critical situations in home health care. The experience with the HHD is promising: the patients did not show any clinical problems and reported a better quality of life; this dialysis method can be considered as further treatment option to selected patients, according to the eligibility criteria. PMID- 29710444 TI - [PET with C-methionine and hyperparathyroidism]. AB - Scintigraphy 99mTc-sestamibi, in association ultrasound of the neck, is currently the technique of choice for the location of parathyroid adenomas in patients with hyperparathyroidism then undergo parathyroidectomy. After surgery, from 2% to 7% of patients continues to have a persistence of the disease. In this case, the sensitivity of scintigraphy with MIBI in locating ectopic parathyroid glands is limited and varies from 30% to 80%. Thanks to the introduction of a new method radiological, PET with 11C-methionine, it is now possible to detect the possible presence of parathyroid adenomas in patients with MIBI scintigraphy been examined and is also useful for false positives. PET with 11C-methionine is a diagnostic accurate in locating the parathyroid adenomas of the neck with a sensitivity of 91%, allowing you to run parathyroidectomy focused with a reduced invasiveness of surgery, with reduction of postoperative pain and better results aesthetic. In addition, a method is clinically useful in patients with secondary hyperparathyroidism and tertiary. The limits of this promising method are the poor availability of the tracer, the fact that it is executed in only four centers in Italy and the high cost. We present the cases of two patients who are diagnosed with hyperparathyroidism. They are submitted in the first instance to MIBI parathyroid scintigraphy parathyroidectomy and after removal of pathological glands. Persisting high values of PTH, patients are executed before a new scintigraphy with MIBI which is however negative and then a PET with 11C methionine which shows accumulation of tracer in a different place not detected by scintigraphy. PMID- 29710446 TI - [Enhanced adsorption dialysis on acute kidney injury in micromolecular myeloma]. AB - Acute kidney injury (AKI) is one of the mean causes of morbidity and mortality in patients with multiple myeloma. Approximately ten per cent of patients with diagnosis of multiple myeloma is in need of dialysis owing to AKI from accumulation of monoclonal free light chains (FLC) both K and lambda. In order to increasing their removal haemodialysis with protein-leaking dialyzers is necessary. It is clear that the series of filters with Polimetilmethacrylate (PMMA BK-F) is particularly able to absorb the FLC. The absorption has the greatest efficacy in the first hours of the dialysis, whereas it is almost lacking in the second part of dialysis, when the membrane is saturated. The Enhanced adsorption dialysis (EAD), trough the use of a second dialyzer, PMMA BK F and of a second haematic line, doubles the absorption capacity. We describe the case of a 70 years old patient, that comes to our examination owing to AKI in anuria. The positive serum immunofixation through K chains and osteological lesions, marked by RX, at the backbone and at the braincase, arouse suspicions of micromolecular myeloma, so the patient underwent dialytic treatment in EAD with halving of FLC lambda values and a 33 per cent decrease, following recovery of diuresis and partial betterment of renal function parameters. PMID- 29710445 TI - [Metformin and Diabetes: still has a sense of its use in patients CKD stage II or is an additional risk factor?] AB - : Pz woman of 62 years comes to P.S.G. for fatigue, low-grade fever, diuresis present. A history of hypertension refers to therapy for about five years, diabetes mellitus for about two years in therapy with Metformin 1gr x 3 gg / day. Blood tests: BUN 195 mg / dL, creatinine 8.0 mg / dl, Ph 6877, HCO3 5.1 mmol / L BE -29.1 mmol / l. Rapid clinical deterioration with occurrence of arterial hypotension - 85/60 mmHg, stupor. Start therapy Bicarbonates ev, is positioned in Urgency CVC and it undergoes AFB with infusion of bicarbonates 2000 ml / h for 4 hours, blood flow rate 250 ml / min., the hemodynamics has been supported with dopamine infusion 200 mg: 2 vials in 250 cc of physiological vel 30 - 40 ml / h, The pc after undergoing three AFB, interrupted the dialysis for resumption of diuresis spontaneous and progressive improvement of renal function and blood pressure. Monitored, after discharge, the parameters of renal function decreased to within normal limits, clearance compatible with IRC II - III stage. CONCLUSIONS: dehydration, fever, IRC II stadium, undiagnosed caused, in a very short time, an accumulation of metformin, which has been the cause of metabolic acidosis. The pc. saved thanks to the positioning of the CVC and to the AFB in the treatment with the infusion of large quantities of Bicarbonates e.v. The use of metformin in pcs. > 50 years and / or creatinine clearance <60 ml / min., must be subordinated to the preliminary study and periodic renal function. PMID- 29710447 TI - [Anxiety and depression in emodialysis]. AB - The patients in terminal uremia show anxiety and depression correlate with anagraphic and dialytic age, here evidenced trought the Hospital Anxiety and Depression Scale (HADS). In a cohort of 120 patients, only 100 have been selected, because of incompatibility (11.6%) or refusal (5%). The pool composed of 100 patients (59 men, 41 women; mean age of 70.8+/-12.07 years; 30% mean age of 74.27+/-3.12 and mean time on dialysis of 55.03+/-70.12 months, was treated with Bicarbonate High Flux, Hemodialysis Filtration(HDF), Hemofiltration Replacement (HFR), Acetate Free Hemofiltration (AFB), in Ultrapure, 40% in dialysis <24 months. Analyzing the data, the 58% (25% men, 33% women) presented level of anxiety and depression of IV degrees Likert, versus 16.6% of the general population. The correlation of variables indicates that among the patients under HD, the increase of anagraphyc age correlates with an increase at IV degrees of anxiety and depression, seen in 36% of patients with a mean age of 78.61+/- 5.95 (19% men, 17% women) and in 22% of patients with a mean age of 59.22+/- 8.43 (7% men, 15% women). Considering the dialytic time, the IV degrees itself correlates with patients under treatment <2 years, regardless for age. In fact 22% of these patients (8% man, 14% women - mean age of 69.31+/- 8.40) present a level of anxiety and depression worst than the population in longer treatment (87.36+/- 16.36 months), who instead represent 10% of the sample (3% men, 7% women -mean age 72.2+/- 11.24). This data can be read as a psychosomatic adaptation, but anymore as a consequence of the improvement of cenesthesy due to a personalized haemodialysis. PMID- 29710448 TI - FROM THE EDITOR. AB - No abstract available for this article. PMID- 29710449 TI - Effects of Cognitive Group Iterventions on Depression and Cognition Among Elderly Women in Long-Term Care. AB - The effects of cognitive-behavioral group therapy and focused visual imagery group therapy on cognition and depression in frail women residing in nursing homes were examined.' Twenty-four (24) women participated in a 24-week protocol of cognitive- behavioral group therapy and twenty-one (21) in a protocol of visual imagery group therapy of similar duration. Eleven (11) women in a comparison condition participated in a 24 week series of educational discussion group sessions. Data on cognition and depression are reported for four time points: 4 weeks before treatment initiation, 8 and 20 weeks after treatment initiation, and 4 weeks after treatment termination. Subjects in the cognitive behavioral and visual imagery groups experienced a significant improvement in cognition over the duration of the study, while subjects in the educational discussion groups did not. There was no effect for any of the interventions on depression. This lack of effect may indicate the tenacity of depression among female nursing home residents and. PMID- 29710450 TI - Social Work with the Osteoporotic Woman. AB - A chronic, progressive, and potentially debilitating condition, osteoporosis has a multitude of currently untapped implications for effective social work practice. A working knowledge of the medical framework of the disease process itself is a prerequisite to informed practice. This article presents such information, along with the psychological and social components, in order to provide the social worker with the comprehensive biopsyehosaial knowledge base necessary for effective practice with the osteoporotic woman and her family. PMID- 29710451 TI - Women's Retirement. AB - Women's work related issues such as retirement have not traditionally interested researchers. Social research has recently produced new information on women's work and retirement. However, such work has been quantitative, focusing on measurements of attitudes, satisfaction with retirement, and economic stability. This a proach has resulted in gaps in the record which we feel may be crosed through a case study approach. Pilot data from our research on women's retirement using such an approach suggests that women's decisions regarding retirement and its process may be more complex than previously reported in areas of family health problems, retirement planning and spouse's retirement. PMID- 29710452 TI - A Group Practice Strategy for Helping Unemployed Older Women Find Employment. AB - Unemployed older women face significant obstacles in the labor market when attempting to find employment. This article presents a grounded group practice strategy for assisting older women to regain employment. Previous research has shown that job search self-efficacy is a significant mediator of continued job search activity among older workers. Based on empirical research findings and Bandura's theory of self-efficacy, this practice approach focuses on helping older women to increase their job search self-efficacy and opportunities for securing employment. PMID- 29710453 TI - Aging Couples in Dual-Career/Earner Families. AB - The authors present results of an empirical study of 611 mature couples in a dual career or dual-earner famil where at least one spouse is a member of The National Retired Teacher's Association and is retired. We hypothesize that degree of role sharing will va among mature couples in this special population on the basis of sexcted personal and social characteristics. Through discriminant analysis we identify which personal and social variables best predict whether or not couples currently share roles. We also determine the change in role-sharing over time for these couples. Our hypothesis is confirmed. PMID- 29710454 TI - Sex, Intimacy and Self Esteem. AB - This is a pilot study exploring intimacy and self esteem in older black women. Twenty six married, urban, non-institutionalized African American women over the age of 60 were interviewed in this investigation. Information concerning their intimate relationships with their spouses and its relationship to their self esteem was gathered. Subjective passages are examhed to accent these relationships. These women were, generally, open about the quality of the relationship between themselves and their spouses. They reported relatively high levels of intimate relations. In particular they described the sub-factors of intimacy such as affection, friendship and a sense of empathy to be positively associated with self esteem. Interestingly, higher frequency of sexual intercourse was seen to be negatively associated with self esteem for these older women. Implications of these findings are discussed. PMID- 29710456 TI - Vitexin reverses the autophagy dysfunction to attenuate MCAO-induced cerebral ischemic stroke via mTOR/Ulk1 pathway. AB - Stroke, as a kind of acute cerebrovascular diseases, has greatly influenced the patients' quality of life and left a huge public health burden. Vitexin is a flavone C-glycoside (apigenin-8-C-?-D-glucopyranoside) present in several medicinal and other plants. This study aims to explore the role of vitexin in middle cerebral artery occlusion (MCAO)-induced cerebral ischemic stroke. The results showed that the MCAO-induced brain infarction was obviously decreased by vitexin. And the abnormal protein levels of Caspase-3, Bcl-2-associated X protein (Bax), antigen identified by monoclonal antibody (Ki-67) and B cell lymphoma 2 (Bcl-2) in MCAO model rats were reversed by vitexin. Further research indicated that vitexin alleviated MCAO-induced oxidative injury by reducing the levels of lactate dehydrogenase (LDH), malondialdehyde (MDA) and nitric Oxide (NO). In addition, vitexin attenuated the secretion of pro-inflammatory cytokine (interleukin (IL)-6 and tumor necrosis factor alpha (TNF-?)) and increased anti inflammatory cytokine (IL-10) production to ameliorate MCAO-induced inflammation. What's more, vitexin repressed the MCAO-induced autophagy through mechanistic target of rapamycin (mTOR)/Ulk1 pathway. Specifically, the MCAO-induced decreased expression of mTOR, peroxisome proliferator-activated receptor ? (PPAR?) and p62 were inhibited by vitexin. At the same time, MCAO-induced increased expression of Ulk1, Beclin1 and rate of LC3?/LC3? also were repressed by vitexin. But the inhibition of vitexin on the MCAO-induced oxidative injury, apoptosis and inflammation were reversed by rapamycin. These results implied that vitexin suppressed the autophagy dysfunction to attenuate MCAO-induced cerebral ischemic stroke via mTOR/Ulk1 pathway. PMID- 29710457 TI - Anti-inflammatory actions of herbal medicines in a model of chronic obstructive pulmonary disease induced by cigarette smoke. AB - The effects of four medicinal herbs (Arctium lappa, Plantago major, Mikania glomerata Spreng and Equisetum arvense) with anti-inflammatory properties were evaluated in a chronic obstructive pulmonary disease (COPD) model. Wistar rats were exposed to cigarette smoke during 8 weeks and one of the groups was orally given a solution containing 4% of each alcoholic herbal extracts during the exposure period. Control group was not exposed to smoke or treated. Histopathological, immunohistochemical and biochemical analyzes were performed. Normal blood plasma levels of gamma glutamyl transferase indicated no toxicity of the administered herbal extracts. The treatment reduced leukocytes influx in bronchoalveolar lavage, mast cell and macrophages numbers in lungs, as well as prevented pulmonary congestion and tracheal metaplasia. Herbal mixture also decreased plasma inflammatory mediator levels and pulmonary expression of annexin A1 and nuclear factor-k?. Our data indicate synergistic and protective effects of the used herbal medicines in animals exposed to cigarette smoke as a potential therapeutic strategy. PMID- 29710458 TI - Centaurea albonitens extract enhances the therapeutic effects of Vincristine in leukemic cells by inducing apoptosis. AB - Drug-induced toxicities and dose-related side effects are the major challenges in the conventional cancer therapy by the chemo drugs. On the other hand, herbal derivatives have obtained a great research interest in the field of therapeutic applications because of their more favorable specifications including less toxicity, cost-effective and more physiologically compatible than the chemical drugs. For this purpose, we evaluated methanolic extract prepared from Centaurea albonitens Turrill alone and in combination with Vincristine (VCR) for its potential cytotoxic effects in NALM-6, REH, NB4 and KMM-1 cell lines by using the various approaches. Centaurea genus is one of the current medicinal plants, which has used in traditional medicine, However, there are rare studies to examine its anticancer properties against hematologic malignant cells. In this study, we demonstrated Centaurea albonitens extract (CAE) induces cytotoxicity through G0/G1 phase arrest followed by apoptosis in a dose- and time- dependent manner, although with varying efficiency. Interestingly, normal cells didn't exhibit significant cytotoxicity after CAE treatment. Moreover, we found that low dose of CAE enhances anti-cancer effects of VCR in pre-B ALL cell lines (NALM-6 and REH). Further investigations validated synergistic anticancer activities of VCR and CAE through inducing apoptosis without significant cell cycle arrest. Taken together, our results demonstrated for the first time that the methanolic extract of Centaurea albonitens can be considered as a potential anticancer agent and/or an enhancer of chemotherapeutic sensitivity of VCR. PMID- 29710459 TI - Inhibitory effect of chidamide on the growth of human adenoid cystic carcinoma cells. AB - Adenoid cystic carcinoma (ACC) is a malignant epithelial neoplasm that limitedly responses to chemotherapy at the cost of significant toxicity. There is no single targeted drug approved by Food and Drug Administration (FDA) for ACC. Genomic landscape studies have revealed that frequently mutated pathways in ACC often involve in chromatin remodeling, which interfere multiple histone related proteins. Chidamide is a novel histone deacetylase inhibitor (HDACi) approved in clinical practice that was designed to increase the acetylation level of histone H3. It demonstrated anticancer effects in various cancers in preclinical study, but not in ACC. In this study, we aimed to investigate the anticancer effects of chidamide alone or in combination with cisplatin (cDDP) on ACC in vitro and in vivo. The results showed that chidamide alone or in combination with cDDP effectively inhibited the growth and proliferation of ACC cells in a dose- and time-dependent manner. Chidamide arrested cell cycle in G2/M phase by up regulating the acetylation of histone H3 and interfering phosphorylation of AKT protein. Chidamide alone or in combination with cDDP did not induce distinct apoptosis in ACC cells. In vivo experiments showed that chidamide combining cDDP exerted significant inhibitory effects on ACC. These suggest that chidamide may be a promising candidate drug for the treatment of patients with ACC. PMID- 29710460 TI - MiR-25 promotes proliferation, differentiation and migration of osteoblasts by up regulating Rac1 expression. AB - According to many studies, miRNAs are involved in the control of bone cell differentiation and function. Hence, an understanding of the pathways regulated by miRNAs involved in skeletal function is essential for the development of miRNA based therapeutic strategies for bone diseases. In this study we evaluated the role of miR-25 in osteoblast differentiation by examining the expressions of key osteoblast differentiation markers like Runx2 and Ocn and also evaluated the effects of miR-25-Rac1 axis on PI3K/AKT and JNK pathways. MC3T3-E1 osteoprogenitors were treated with osteogenic differentiation media which was refreshed every 48?h after the initial differentiation treatment and were then quantified for total miRNA content. The viability, migration as well as Runx2 and Ocn expressions in cells transfected with miR-25 mimic, miR-25 inhibitor, and si Rac1 were evaluated by CCK-8 assay, wound migration assay, qRT-PCR and Western blot. Finally, the effects of miR-25-Rac1 axis on PI3K/AKT and JNK pathways were studied. MiR-25 was found to significantly enhance cell viability and migration and up-regulate the expressions of Runx2 and Ocn. MiR-25 was also found to enhance the expression levels of Rac1, which contributed to the effects of miR-25 on osteoblastic cell lines. MiR-25 activated PI3K/AKT and JNK pathways possibly by up-regulation of Rac1. Enhanced expression of miR-25 led to the promotion of cell viability and migration, as well as up-regulation of Runx2 and Ocn markers by enhancing Rac1 expression. PMID- 29710461 TI - Overexpression of CRNDE promotes the progression of bladder cancer. AB - Accumulating evidences indicate that long non-coding RNAs (lncRNAs) are indispensable in cancer initiation and progression. Dysregulation of functional lncRNAs can promote the development of cancers. Previous research have revealed that augmented expression of CRNDE caused poor prognosis of cancer patients and facilitate the tumor progress in various cancers. Nevertheless, the underlying roles of CRNDE in bladder cancer progression are not entirely clear. To further identify the effects CRNDE in bladder cancer progression, we performed the gain and loss of function assay. In this work, we have presented evidence that CRNDE was significantly increased in bladder cancer, and overexpressed expression of CRNDE was positively related with advanced TNM stage of bladder cancer patients. In addition, in vitro experiments showed that CRNDE strengthened cell migration/proliferation and inhibited cell apoptosis in bladder cancer. To sum up, our results exhibited new understand into the role of lncRNA CRNDE in the development of bladder cancer. PMID- 29710462 TI - Thymelaea lythroides extract attenuates microglial activation and depressive-like behavior in LPS-induced inflammation in adult male rats. AB - Thymelaea lythroides extract is widely used as a traditional folk medicine in Morocco, especially for the treatment of diabetes, rheumatism and Inflammatory disease. The aim of the study is to evaluate the possible effect of methanolic extract of Thymelaea lythroides in repressing the inflammatory responses and long lasting depression-like behavior associated with neuroinflammation in adult rats after neonatal LPS exposure. Male rat pups were treated systemically with either LPS (250??g/kg) or vehicle (phosphate buffer saline) on postnatal day 14. Six hours later, the LPS groups were assigned to intraperitoneal (ip) injection of Minocycline (50?mg/kg) or Thymelaea lythroides (200?mg/kg). Thereafter, in adulthood (postnatal days 90-97), the spontaneous locomotor activity and depression-like behavior were assessed successively in open field and forced swim tests. The levels of proinflammatory cytokines, oxidative damage, and activation of microglia were determined in the hippocampus (HP) of male rats on (PND90-97). Our results showed that open field hypoactivity and increased immobility period in LPS-induced adult rats were normalized on treatment with Thymelaea lythroides and minocycline. Both treatments attenuate the overactivated microglial cells in the CA1 and CA3 of hippocampus (HP) and significantly reduced the oxidative nitrosative stress markers and cytokine (TNF ?) production in the HP. Thymelaea lythroides seems to have similar neuroprotective effects to Minocycline, and such protection may be due to: reduction of oxidative stress, upregulation of inflammatory mediators production, antidepressant behavior which all are associated with neuroinflammation. PMID- 29710463 TI - A comprehensive review on regulatory effects of crocin on ischemia/reperfusion injury in multiple organs. AB - Ischemia-reperfusion (I/R) injury affects o2-dependent organs including liver, kidneys, heart, brain, and intestine. I/R injury is described as the cellular injury in an organ caused by ischemia and then further aggravated during the reperfusion due to intracellular alterations. It is a process that happens in clinical settings such as organ transplantation, reperfusion after thrombolytic therapy, and coronary angioplasty. Crocus sativus L. known as saffron used in folk medicine for its beneficial effects. It contains multiple bioactive compounds including the crocin, crocetin, picrocrocin, and safranal. Crocin, a water-soluble carotenoid has antitumor, radical scavenging, anti hyperlipidemia and memory improving effects. Moreover, crocin has antioxidant, and protective effects on I/R models in rats at various organs such as heart, brain, kidney, stomach, liver, and kidney as described in detail in this review. PMID- 29710465 TI - The aqueous extract from Artemisia capillaris inhibits acute gastric mucosal injury by inhibition of ROS and NF-kB. AB - Artemisia capillaris, also called "InJin" in Korean, has been used as traditional oriental medicine in Korea because of its various pharmacological activities. These include hepatoprotective, analgesic, and antipyretic activities. The present study was designed to validate the beneficial effects of the aqueous extract of A. capillaris (AEAC) against acute gastric mucosal injury and investigate the underlying molecular mechanisms. The pharmacological efficacy of AEAC was evaluated using the gastric ulcer index and histological examination. AEAC decreased gastric mucosal lesions mediated by HCl/ethanol in vivo in a dose dependent manner. Interestingly, the mucosal damage was almost prevented by pretreatment with 200 or 400?mg/kg AEAC. However, AEAC did not have acid neutralizing activity in vitro and did not prevent histamine secretion in HMC-1 mast cells. In the gastric mucosa, AEAC also significantly inhibited lipid peroxide formation through superoxide dismutase (SOD) activation. Moreover, AEAC strongly reduced the generation of pro-inflammatory cytokines, such as interleukin-6 (IL-6) and interleukin-1? (IL-1?), through nuclear factor kappa B (NF-?B) downregulation. Taken together, our findings suggest that AEAC inhibits inflammation and maintains oxidant/antioxidant homeostasis, resulting in a gastro protective effect against HCl/ethanol-induced gastric damage. Therefore, AEAC might be a promising drug or useful neutraceutical for treatment of gastritis and gastric ulcer. PMID- 29710464 TI - Cistanche deserticola polysaccharides protects PC12 cells against OGD/RP-induced injury. AB - Ischemia stroke is a disease with high morbidity and mortality. Cistanche deserticola polysaccharides (CDP) possess a wide range of beneficial effects, including hepatoprotection and immune homeostasis. As far as we know, the protective effect of CDP on neurons injured by oxygen-glucose deprivation/reperfusion (OGD/RP) has not been investigated. In this study, OGD/RP injured a PC12 cell model. Briefly, CDP (0.05, 0.5 and 5??g/ml) was administered before reperfusion. The protective effect of CDP was then evaluated on the basis of cell viability, lactate dehydrogenase (LDH) leakage, [Ca2+]i, mitochondrial membrane potential (MMP)and cell apoptosis, and redox status after reperfusion was evaluated by assaying reactive oxygen species (ROS), catalase (CAT), glutathione peroxidase (GSH-Px) and total antioxidant capacity. Basing on the fact that Parkinson's disease-associated protein DJ-1 participates in endogenous antioxidation and performs neuroprotective effects after ischemia stroke, we investigated the interaction between CDP and DJ-1. DJ-1 expression was detected through ELISA and Western blot analysis, and the translocation of DJ-1 was evaluated through immunofluorescence. Result showed that CDP (0.05, 0.5 and 5??g/ml) attenuated PC12 cell death, preserved MMP and calcium homeostasis; inhibited oxidative stress and decreased cell apoptosis. Moreover, CDP (5??g/ml) markedly stimulated DJ-1 secretion and expression. Overall, the results suggested that CDP exerts neuroprotective effect against OGD/RP-induced injury by inhibiting oxidative stress and regulating the DJ-1 pathway. PMID- 29710466 TI - TGF-? regulates the ERK/MAPK pathway independent of the SMAD pathway by repressing miRNA-124 to increase MALAT1 expression in nasopharyngeal carcinoma. AB - Transforming growth factor beta (TGF-?), a pleiotropic cytokine, promotes cell proliferation and migration in multiple cancers, including nasopharyngeal carcinoma (NPC). microRNA-124 (miR-124) becomes downregulated in NPC and inhibits the tumorigenesis of this disease. However, the role of miR-124 in TGF-?-induced NPC development remains unknown. In this study, constant TGF-? stimulation repressed miR-124 expression, whereas miR-124 overexpression antagonized TGF-? promoted NPC cell growth and migration. miR-124 overexpression decreased p SMAD2/3, SMAD4, and p-ERK levels, indicating that ectopic miR-124 overexpression inhibited SMAD and non-SMAD pathways. Pro-oncogenic lncRNA MALAT1 was targeted by miR-124 that regulated ERK/MAPK by targeting MALAT1 independent of the SMAD signaling pathway. In conclusion, our work clarified the significant role of miR 124 in TGF-? signaling pathways independent of the SMAD signaling pathway and showed the potential of miR-124 as a new therapeutic target against NPC. PMID- 29710467 TI - Antioxidant and anti-inflammatory effect of plumieride in dextran sulfate sodium induced colitis in mice. AB - This study aimed to investigate the potential effect of plumieride, an iridoid glycoside isolated from Alamanda cathartica L. flowers, against dextran sulfate sodium (DSS)-induced colitis in mice. Colitis was induced in female swiss mice by adding DSS 3% to the drinking water. The animals were treated with vehicle (water), 5-aminosalicylic acid (100?mg/kg) or plumieride (10, 30 and 100?mg/kg) once a day, during 7 days. The body weight progression and the disease activity index was evaluated daily. On the eighth day, colons were collected for the measurement of the size, histological, histochemical, biochemical and inflammatory analysis. The cytotoxicity of plumieride on intestinal epithelial cell (IEC-6 cell line) was also evaluated. Plumieride, at dose of 100?mg/kg, significantly attenuated the mice weight loss, showed lower score in the disease activity index, diminished the colon shortening, improved the histological damage and avoided mucosa intestinal mucus depletion when compared with vehicle-treated only group. Moreover, plumieride was able to reduce the amount of colonic lipid hydroperoxides, while augmented reduced glutathione levels and superoxide dismutase activity. Although DSS intake stimulated an increase in myeloperoxidase activity and in tumor necrosis factor content on the colon tissue of the vehicle treated group, the colons obtained from mice treated with plumieride did not present any of these changes. Taking together, the results of the present study disclose that plumieride exhibited a significant efficacy in attenuating the parameters of experimental ulcerative colitis, which may be mediated by an antioxidant and anti-inflammatory effect. PMID- 29710468 TI - Bucindolol attenuates the vascular remodeling of pulmonary arteries by modulating the expression of the endothelin-1 A receptor in rats with pulmonary arterial hypertension. AB - The aim of this study was to investigate the role of the beta-adrenergic blocker bucindolol on endothelial dysfunction and pulmonary vascular remodeling in rats with pulmonary arterial hypertension (PAH). Male Wistar rats were divided into four groups: control, monocrotaline (MCT), control?+?bucindolol and monocrotaline?+?bucindolol (MCT?+?BCD). PAH was induced by an injection of monocrotaline (60?mg/kg i.p.). After two weeks, the animals were treated for seven days with bucindolol (2?mg/kg/day i.p.) or vehicle. Echocardiography was performed upon treatment completion to analyze pulmonary vascular resistance (PVR) and right ventricle (RV) myocardial performance index. Lungs were collected for oxidative stress and western blot analysis, and the pulmonary artery was analyzed for histological and immunohistochemical parameters. The MCT?+?BCD group showed a decrease (32%) in the protein expression of endothelin-1 type A receptor (ETAR) and in the ratio of ETA/endothelin-1 type B receptor (ETBR) (62%) as compared to the MCT group. Bucindolol treatment did not alter oxidative stress, as determined by lipid peroxidation analysis and antioxidant enzyme activities and expression, endothelial nitric oxide synthase immunocontent and decreased nitrotyrosine levels. Moreover, bucindolol improved vascular remodeling of the pulmonary artery in the MCT?+?BCD group by decreasing (21%) PVR and increasing RV workload in relation to MCT. PMID- 29710469 TI - Hydroxytyrosol nicotinate, a new multifunctional hypolipidemic and hypoglycemic agent. AB - Hydroxytyrosol (HT) is a natural polyphenol antioxidant that exists in olive oil. In the study of multifunctional hypolipidemic of nicotinic derivatives, we found that hydroxytyrosol nicotinate (HT-N) incorporation of niacin with HT displayed ? glucosidase inhibitory activities in vitro, such as yeast ?-glucosidase (IC50?=?117.72??M) and rat intestinal ?-glucosidases maltase (IC50?=?31.86??M) and sucrase (IC50?=?22.99??M), and had a good control of postprandial blood glucose (PBG). HT-N shown significantly hypoglycemic action by 16.9% and protection of pancreatic tissue in type 2 diabetic mellitus (T2DM) mouse model. HT-N also shown a potent antioxidant activity and property of anti-glycation in vitro, which were benefit for ameliorating diabetic complications. Moreover, HT-N exhibited much significant hypolipidemia, lowering plasma triglyceride (TG), total cholesterol (TC), and malonaldehyde (MDA) by 34.6%, 45.8% and 32.1% respectively, in hyperlipidemic mice induced by Triton WR 1339. The results indicated that HT-N has hypolipidemic, hypoglycemic and antioxidant actions. All these properties could be conducive to amelioration of oxidative stress, hyperlipidemia, and diabetes that HT-N may serve as a multifunctional potential therapeutic strategy in diabetic patients with hyperlipidemia. PMID- 29710470 TI - MiR-21 promotes ECM degradation through inhibiting autophagy via the PTEN/akt/mTOR signaling pathway in human degenerated NP cells. AB - Intervertebral disc degeneration (IDD) is the most common cause leading to low back pain, a highly prevalent, costly and crippling condition worldwide. Overexpression of miR-21 has been shown to promote proliferation of nucleus pulposus (NP) cells. However, it remains unclear whether miR-21 can promote the degradation of type II collagen (Col II) and aggrecan, two main extracellular matrix components within the disc. Here, the miRNA microassay assay identified 29 differentially expressed miRNAs in NP tissues from IDD patients compared with healthy controls. Following qRT-PCR validation, miR-21 expression was significantly upregulated in degenerated NP tissues, and showed a positive correlation with disc degeneration grade. Through gain-of-function and loss-of function studies in human NP cells, miR-21 was shown to inhibit autophagy and then upregulate the expression of matrix metalloproteinase (MMP)-3 and MMP-9, leading to increased degradation of Col II and aggrecan. Mechanistically, phosphatase and tensin homolog (PTEN) was identified as a direct target of miR 21, and activated PTEN/ Akt/mammalian target of rapamycin (mTOR) signaling pathway was involved in miR-21-induced autophagy inhibition and Col II and aggrecan breakdown. Taken together, these results suggest that miR-21 contributes to Col II and aggrecan catabolism by inhibiting autophagy via the PTEN/Akt/mTOR signaling pathway in human NP cells. PMID- 29710471 TI - Recent therapeutic approaches for the management of tuberculosis: Challenges and opportunities. AB - Tuberculosis is a highly contagious disease spread by Mycobacterium tuberculosis. It is responsible for highest numbers of death and soon will surpass the deaths caused by HIV. The pandemic disease causes, estimated 10.4 million new infections, among which 5.9 million were men, 3.5 million were women, 1.0 million were children and the HIV patients co-infected with tuberculosis accounted for 1.2 million of all new cases in 2015, alone. The increased number of drug resistant (MDR/XDR) strains and the failure of the conventional regimens against this strain are the challenges of the coming decades. The goals of new therapeutic approaches are to ensure cure without relapse, to inhibit deaths, contagions and the formation of drug-resistant strains. The main approaches of anti-tubercular therapy involves either development of new chemical entity with a novel mechanism of action or repurposing of old drugs which show significant activity on drug-resistant strains. Repurposing existing drugs is a promising alternative to the expensive and time-consuming process of drug discovery. A number of carrier-based drug delivery systems incorporating the principal anti tuberculosis drug has been developed to provide targeted action with reduced dosing frequency in order to improve the patient compliance which is a major reason for therapeutic treatment failure. This article reviews the recent approaches to the treatment of tuberculosis in terms of discovery of new chemical entity, repurposing of old drugs and the use of novel drug delivery technology such as liposomes, niosomes, liquid crystals, solid lipid nanoparticles, polymeric micelles, dendrimers, nanoemulsion, nanosuspension, silica nanoparticles, polymeric nanoparticles and microparticles for complete eradication of Mycobacterium tuberculosis. PMID- 29710472 TI - Diterpene ginkgolides meglumine injection protects against paraquat-induced lung injury and pulmonary fibrosis in rats. AB - In this study, we aimed to investigate the effects of diterpene ginkgolides meglumine injection (DGMI) on paraquat (PQ)-induced lung injury and pulmonary fibrosis in rats. Male SD rats were challenged by PQ (20?mg/kg, i.p.) with or without either DGMI (1.25, 2.5, 5?mg/kg, i.p.) or Edaravone (EDA, 6?mg/kg, i.p.) posttreatment 2?h after PQ administration. Lung tissues were removed for biochemical analyses and pathological examinations on day 1, day 3, day 7, day 14 and day 21. Results showed that the administration of DGMI significantly increased the survival of PQ-challenged rats. At the same time, DGMI reversed the increase of Malondialdehyde (MDA) level and the decrease of Super Oxide Dismutase (SOD) level in lung tissues. Moreover, lung to body weight ratio, Interleukin 1beta (IL-1?), Interleukin-6 (IL-6) and Tumor necrosis factor-alpha (TNF-?) levels in lung tissues were reduced compared with the model group. H&E and Masson staining revealed that DGMI (5?mg/kg) alleviated histological injury and pulmonary fibrosis, and EDA (6?mg/kg) exerted approximate effects. Immunohistochemistry staining presented that the benefit effects of DGMI were associated with its ability to activate Akt-Nrf-2 pathway. In conclusion, these results suggest that DGMI possesses potential role in future therapies for PQ induced lung injury and pulmonary fibrosis. PMID- 29710473 TI - Long non-coding RNAs: An essential emerging field in kidney pathogenesis. AB - Human Genome Project has made it clear that a majority of the genome is transcribed into the non-coding RNAs including microRNAs as well as long non coding RNAs (lncRNAs) which both can affect different features of cells. LncRNAs are long heterogenous RNAs that regulate gene expression and a variety of signaling pathways involved in cellular homeostasis and development. Studies over the past decade have shown that lncRNAs have a major role in the kidney pathogenesis. The effective roles of lncRNAs have been recognized in renal ischemia, injury, inflammation, fibrosis, glomerular diseases, renal transplantation, and renal cell carcinoma. The present review outlines the role and function of lncRNAs in kidney pathogenesis as novel essential regulators. Molecular mechanism insights into the functions of lncRNAs in kidney pathophysiological processes may contribute to effective future therapeutics. PMID- 29710474 TI - Resveratrol inhibits Interleukin-6 induced invasion of human gastric cancer cells. AB - Previous studies show that migration and invasion are the primary causes of death in patients with gastric carcinoma. Increasing evidences have been shown Interleukin-6 could stimulate cancer cells invasion and be associated with cancer development. However, its role in gastric cancer has never been investigated. As an anticancer drug isolated from Chinese medicine, resveratrol was reported to inhibit cancer cells growth and induce apoptosis, but its roles in gastric cancer have not been well understood. In this study, we found that Interleukin-6 was upregulated in blood of gastric cancer patients by enzyme-linked immunosorbent assay. In gastric cancer cell line model, we found that non-cytotoxic concentration of resveratrol inhibited the Interleukin-6 induced SGC7901 cell invasion and matrix metalloproteinases activation. Our studies showed that IL-6 induced SGC7901 cell invasion depends on the Raf/MAPK pathway activation, resveratrol could inhibit this pathway activation. We further showed that resveratrol inhibits the IL-6 induced metastasis by vein injection of luciferase labeled cancer cells. In conclusion, these results indicate that Interleukin-6 promotes tumor growth and metastasis in gastric cancer, resveratrol has the potential to prevent the Interleukin-6 induced gastric cancer metastasis by blocking the Raf/MAPK signaling activation. PMID- 29710475 TI - miR-200c targets nuclear factor IA to suppress HBV replication and gene expression via repressing HBV Enhancer I activity. AB - BACKGROUND: Hepatitis B virus (HBV) chronic infection is a health problem in the worldwide, with a underlying higher risk of liver cirrhosis and hepaticocellular carcinoma. A number of studies indicate that microRNAs (miRNAs) play vital roles in HBV replication. This study was designed to explore the potential molecular mechanism of miR-200c in HBV replication. METHODS: The expression of miR-200c, nuclear factor IA (NFIA) mRNA, HBV DNA, and HBV RNA (pregenomic RNA (pgRNA), and total RNA) were measured by qRCR. The levels of HBsAg and HBeAg were detected by ELISA. NFIA expression at protein level was measured by western blot. The direct interaction between miR-200c and NFIA were identified by Targetscan software and Dual-Luciferase reporter analysis. Enhance I activity were detected by Dual Luciferase reporter assay. RESULTS: miR-200c expression was prominently reduced in pHBV1.3-tranfected Huh7 and in stable HBV-producing cell line (HepG2.2.15). The enforced expression of miR-200c significantly suppressed HBV replication, as demonstrated by the reduced levels of HBV protein (HBsAg and HBeAg) and, DNA and RNA (pgRNA and total RNA) levels. NFIA was proved to be a target of miR-200c and NFIA overexpression notably stimulated HBV replication. In addition, the inhibitory effect of miR-200c on HBV Enhance I activity was abolished following restoration of NFIA. CONCLUSIONS: miR-200c repressed HBV replication by directly targeting NFIA, which might provide a novel therapeutic target for HBV infection. PMID- 29710476 TI - Acanthopanax senticosus reduces brain injury in mice exposed to low linear energy transfer radiation. AB - BACKGROUND: Compared with pharmaceuticals, natural medicines are gaining acceptance as countermeasures against radiation injury because of their distinct characteristics, specifically low toxicity and multi-target effects. METHODS: The ability of a traditional Chinese medicine, Acanthopanax senticosus (AS), to reduce radiation injury following exposure of the heads of mice to 4?Gy low linear energy transfer (LET) radiation was assessed histologically, behaviorally and metabolically''. RESULTS: Irradiated mice administered AS extract showed improved learning ability and central nervous system (CNS) function. AS extract effectively controlled nerve cell swelling, protein loss, and necrotic tissue liquefaction that was observed in the irradiated mouse brain. Metabolomics data demonstrated that treatment with AS extract resulted in significant quantitative changes of 16 classes of cerebral metabolites in the prefrontal cortex (PFC) of irradiated mice. Using a principal component analysis (PCA), three principal components, F1, F2 and F3, were identified as related to brain energy metabolism, brain tissue development, and brain glutamate cycle, respectively. In addition, the F2 and F3 scores of the AS-treated group of mice were higher compared to mice that were treated with Venlafaxine. Furthermore, the efficiency of balancing the glutamate cycle that the AS-treated group achieved was two times greater than that of the mice treated with Venlafaxine. CONCLUSIONS: AS is a promising approach to reduce radiation-induced brain injury. Further studies are warranted to examine the potential of AS to reduce the side effects caused by chemotherapeutics. PMID- 29710477 TI - miR-125b is downregulated in systemic lupus erythematosus patients and inhibits autophagy by targeting UVRAG. AB - Systemic lupus erythematosus (SLE) is a severe autoimmune disease and the pathogenesis remains incompletely understood. This study aimed to investigate the role of miR-125b in the pathogenesis of SLE and explore the underlying mechanism. Compared to healthy controls, the expression of miR-125b decreased in peripheral blood mononuclear cells (PBMCs) of SLE patients. In addition, PBMCs exposed to ultraviolet B had lower miR-125b level compared to those unexposed to radiation. We identified UV radiation resistance associated gene (UVRAG) as a target of miR 125b. Jurkat cells treated with miR-125b-5p agomir showed reduced levels of ATG7, Beclin-1 and LC3 II and decreased autophagy. In contrast, Jurkat cells treated with miR-125b-5p antagomir showed increased levels of ATG7, Beclin-1 and LC3 II and increased autophagy. Furthermore, Jurkat cells transfected with UVRAG expression vector showed higher expression of ATG7, Beclin-1 and LC3 II and increased autophagy. Conversely, cells transfected with UVRAG siRNA had lower expression of ATG7, Beclin-1 and LC3 II and decreased autophagy. Taken together, our data demonstrate that Ultraviolet B radiation can downregulate miR-125b-5p and increase UVRAG expression and autophagy activity in PBMCs of SLE patients. These findings help explain how ultraviolet B exacerbates SLE and suggest that UVRAG is a potential therapeutic target for SLE. PMID- 29710478 TI - Essential role of nuclear receptors for the evaluation of the benefits of bioactive herbal extracts on liver function. AB - Nuclear receptors (NRs), ligand-dependent transcription factors, play important regulatory roles in diverse metabolic processes including hepatic lipid, glucose and bile acids (BAs) metabolism involved in liver and metabolic disorders. Therefore, NRs are attractive targets for treatment or prevention of liver diseases. However, the cost-effectiveness and safety of currently available synthetic NRs agonists or antagonists are under question. Herbal extracts and their derivatives with superior cost-effectiveness and less toxicity have attracted much attention as the potential option for NRs agonists or antagonists. Several herbal extracts have been reported to regulate NRs level and exert hepatoprotective property through increasing fatty acid ?-oxidation, preventing hepatic BAs, cholesterol and lipid accumulation. Mechanistically, those herbal extracts have regulatory effect on NRs and subsequently alter their target gene cytochrome P450s (CYPs) level involved in the pathophysiology of liver diseases, which positively suggests that herbal extracts are valuable source of promising candidates for the prevention or treatment of liver diseases. This review highlights recent knowledge to discuss the benefits of bioactive herbal extracts on liver function through regulating NRs-dependent transcriptional activities of CYPs, collecting available studies on the herbal extracts with NRs-regulatory effect and the underlying mechanisms. PMID- 29710479 TI - Antigen-adjuvant effects of icariin in enhancing tumor-specific immunity in mastocytoma-bearing DBA/2J mice. AB - Cancer immunotherapy has attracted much attention in recent years because of the ability of immune system to identify tumor cells and limit their growth. Icariin (ICA) is a natural flavonoid glucoside isolated from Epimedium plants and has shown a variety of pharmacological activities such as anti-inflammatory effects, immunological regulation and anticancer potency. Furthermore, it has immunoadjuvant effects on enhancing Th1-immune response, suggesting that ICA may serve as an adjuvant for cancer immunotherapy. In this study, we used P815 mouse mastocytoma tumor model and immunized them with P815AB peptide and/or ICA. Our results demonstrated that ICA could increase the cytotoxic T lymphocytes (CTL) response for P815AB peptide on the tumor-bearing DBA/2J mice. In addition, the percentage of CD4+CD8+/CD3+CD69+/CD69+NKG2D+ positive cells in splenocytes of the tumor-bearing mice all significantly increased after combined immunization with ICA and P815AB peptide. This illustrated that ICA could enhance the immunogenicity of P815AB and improve the ability of T cells and CTLs in recognizing the tumor cells. Moreover, ICA improved the function of peritoneal macrophages with effects of inhibition on tumor growth. Besides, we discussed the possible mechanism of ICA to enhance body immunity by detecting the expression level of MHC-I and related genes in B16-F10 and RMA/S cells. The results suggested that ICA has the potential to up-regulate LMP/TAP related molecules and induce the expression of MHC-I, which increase the immune surveillance and keep cancer in remission. In conclusion, ICA showed an anti-tumor effect both in vitro and in vivo and may be an effective antigen adjuvant for cancer treatment by enhancing tumor-specific immunity. PMID- 29710480 TI - MicroRNA-542-3p functions as a tumor suppressor via directly targeting survivin in hepatocellular carcinoma. AB - MicroRNA-542-3p (miR-542-3p) functions as a tumor suppressor in many human cancers, but its biological roles in hepatocellular carcinoma (HCC) remains to be further explored. In our study, we revealed that miR-542-3p was frequently down expressed in HCC cell lines and tissues using real-time quantitative reverse transcription PCR (qRT-PCR). Overexpression of miR-542-3p inhibits the proliferation of HCC cells via induction of apoptosis and cell cycle arrest. Furthermore, we confirmed that survivin was a direct target of miR-542-3p in HCC cells, and overexpression of survivin attenuated the miR-542-3p-induced inhibition of HCC cell proliferation. A negative association between miR-542-3p and survivin mRNA levels was also found in HCC tissues. These findings showed that miR-542-3p inhibits the proliferation of HCC cells by targeting survivin, indicating that miR-542-3p/survivin signaling axis might serve as a potential therapeutic target in the treatment of HCC. PMID- 29710481 TI - Caffeic acid phenethyl ester inhibits the progression of ovarian cancer by regulating NF-?B signaling. AB - Ovarian cancer is one of the most common malignancies in women and characterized by a rapid progression to metastasis, which restricts effective treatment options. Caffeic acid phenethyl ester (CAPE), a natural honeybee product, exhibits a variety of biological activities, anti-tumor is included. Our study aims to explore whether CAPE could inhibit the progression of ovarian cancer and the underlying molecular mechanism. The establishment of ovarian cancer model was set up in mice through caudal vein injection of SKOV-3 cells. Results indicated that CAPE treatment remarkably decreased the viability, migration and invasion of SKOV-3 cells. Besides that, the apoptosis of SKOV-3 cells was significantly promoted by CAPE treatment. Moreover, the growth of ovarian cancer was tremendously inhibited by CAPE in vivo and its action was accompanied by the obstructed Ki67 and PCNA expression. Furthermore, nuclear factor kappa b (NF-?B) pathway was dramatically suppressed by CAPE through the inhibition of I?B phosphorylation, nuclear translocation of p65 and NF-?B p65 DNA binding activity. By contrast, cells transfected with p65 siRNA exhibited decreased cell viability, migration and invasion along with increased cell apoptosis in SKOV-3 cells. However, CAPE treatment could enhance these alters induced by p65 siRNA in KOV-3 cells. Taken together, these findings suggested that CAPE could restrain the progression of ovarian cancer via inactivating NF-?B signaling, and may provide novel therapeutic regimens for ovarian cancer. PMID- 29710482 TI - Long noncoding RNA BLACAT1 modulates ABCB1 to promote oxaliplatin resistance of gastric cancer via sponging miR-361. AB - Long non-coding RNAs (lncRNAs) have emerged as novel gene regulators in multiple tumorigenesis and chemoresistance. However, their potential roles and molecular mechanisms in gastric cancer chemoresistance remain unclear. In present study, our team investigated the role and potential regulatory mechanism of lncRNA s bladder cancer associated transcript-1 (BLACAT1) in the gastric cancer chemoresistance. Results showed that BLACAT1 expression was up-regulated in the oxaliplatin (OXA) resistant gastric cancer tissue and cells compared with OXA sensitive tissue and parental cell lines. In vitro, BLACAT1 knockdown decreased the expression levels of drug resistance related genes and ABCB1 protein. Besides, BLACAT1 knockdown significantly promoted apoptosis and down-regulated the invasion and the IC50 value of oxaliplatin. In vivo, BLACAT1 knockdown suppressed the tumor growth of gastric cancer cells. Bioinformatics tools and luciferase assay indicated that miR-361 both targeted 3?-UTR of BLACAT1 and ABCB1mRNA, suggesting the BLACAT1/miR-361/ABCB1 regulatory pathway. In summary, our results conclude that BLACAT1 accelerates the oxaliplatin-resistance of gastric cancer via promoting ABCB1 protein expression by targeting miR-361, providing a novel insight for the chemoresistance of gastric cancer. PMID- 29710483 TI - DNMT1/miR-200a/GOLM1 signaling pathway regulates lung adenocarcinoma cells proliferation. AB - OBJECTIVES: Lung adenocarcinoma (LAD) comprises about 80% of all diagnosed lung cancers. However, the underlying regulatory mechanism of LAD cell proliferation is largely unclear. The emergence of microRNAs and molecular-targeted therapies adds a new dimension in our efforts to combat this deadly disease. METHOD: In this work, the A549 and H1650 human lung cancer cell lines were used in this study. The proliferation was evaluated by the MTT and BrdU assay. The expression level of related proteins was detected by western blot. RESULT: We reported GOLM1 was highly expressed in LAD cells and associated with low survival ratio and higher grade malignancy. Knockdown of GOLM1 repressed the LAD cell proliferation. Overexpression of GOLM1 promoted the cell proliferation. Further we found that the level of microRNA-200a (miR-200a) expression was low in LAD cells. miR-200a repress GOLM1 expression by directly targeting its 3? UTR. Overexpression of miR 200a repressed the cell proliferation and blocked the increase of LAD cell proliferation caused by GOLM1 overexpression. Further, we found that miR-200 was downregulated by DNMT1.Overexpression of DNMT1 blocked the function of miR-200a on repressing proliferation. We then found that knockdown of DNMT1 repressed LAD cell proliferation, which could be rescued by GOLM1 overexpression. CONCLUSION: This work revealed the critical function of GOLM1/miR-200a/DNMT1 signaling pathway on regulating LAD cell proliferation, and might lay the foundation for further clinical treatment of LAD. PMID- 29710484 TI - Emerging roles of hsa_circ_0005075 targeting miR-431 in the progress of HCC. AB - Circular RNAs (circRNAs) are non-coding RNAs that play key roles in the pathogenesis of diseases and are associated with human hepatocellular carcinoma (HCC). Previous reports have shown the circRNA hsa_circ_0005075 is highly expressed in HCC tissues, but its function is unknown. In this study, we confirmed circ_0005075 is significantly increased in HCC tissues and cell lines. This overexpression was associated with increased numbers of proliferative, migrated and invasive SMMC-7721 cells. In addition, hsa_circ_0005075 inhibited the transcription activity of miR-431 measured by dual-luciferase reporter assays. In contrast, silencing hsa_circ_0005075 decreased cell number. Finally, effects after hsa_circ_0005075 silencing were rescued by co-transfection with miR 431 inhibitor. These results suggest hsa_circ_0005075 promotes HCC via miR-431 regulation. PMID- 29710485 TI - Stimulation of KLF14/PLK1 pathway by thrombin signaling potentiates endothelial dysfunction in Type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM) promotes a high oxidative stress and hypercoagulable state that drives microvascular injury and multiple-organ abnormality. Elevated thrombin activity underlies T2DM-linked endothelial dysfunction, but the mechanistic links between T2DM/oxidative stress axis and thrombin-associated endothelial pathologies are incompletely understood. In this work, immunohistochemical studies and quantitative analysis using isolated endothelial cells (ECs) identified accumulated Kruppel-like family of transcription factor 14 (KLF14) deposits in ECs from multiple organs as distinct features of T2DM mice. KLF14 upregulation in ECs, which was stimulated by thrombin treatment, was dependent on multiple pathways including calcium mobilization, activation of PKC and AMPK pathways. Functionally, inhibition of endogenous KLF14 expression significantly attenuated thrombin-induced endotheliocyte proliferation, endothelial cell migration and oxidative stress. Molecularly, by directly binding the promoter, KLF14 functions as a transcriptional activator of PLK1, a polo-like kinase whose overexpression induced excessive reactive oxygen species (ROS) production. Transient knockdown of PLK1 was sufficient to suppress KLF14 overexpression-potentiated endothelial dysfunction. Collectively, these data provide proof of concept that deregulation of KLF14/PLK1 cascade plays a key role in thrombin-induced endothelial dysfunction and targeting KLF14 or PLK1 may limit thrombin-associated pathologies in T2DM patients. PMID- 29710486 TI - Synergistic and non-synergistic effects of salmon calcitonin and omega - 3 fatty acids on antioxidant, anti-inflammatory, and haematological indices in diabetic rats. AB - The optimum therapy for the management of diabetes mellitus (DM) has been a controversial issue. Therefore, the study investigated the effects of salmon calcitonin (Sct) and/or omega-3 fatty acids {eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA); EPA/DHA ratio?=?3/2} relative to metformin in diabetic male Wistar rats. Forty rats were used for this study. They were randomly divided into 8 groups of five (5) rats each, which were treated with single or combined administration of salmon calcitonin, N-3 and metformin. DM was induced by the administration of streptozotocin (65?mg/kg b.w., i.p.), 15?min after the administration of nicotinamide (110?mg/kg b.w., i.p.). Nine days afterwards, treatments started, and they lasted for 28 days. Sct was administered at 2.5 and 5.0 IU/kg b.w./day (i.m.), while, N-3 and metformin were administered at 200 and 180?mg/kg b.w./day (p.o.) respectively. The results showed that the induced DM significantly increased pro-inflammatory markers, and significantly altered antioxidant and haematological indices. The combined administration of Sct and N-3 had synergistic effects on total bilirubin and total antioxidant capacity, but, non-synergistic actions on malondialdehyde, uric acid, interleukin 6, lactate dehydrogenase, superoxide dismutase, catalase, glutathione peroxidase, and the haematological parameters. These effects were comparable to that of metformin which showed a more or less therapeutic action than N-3. The study concluded that the antioxidant, anti-inflammatory, and haematological effects of the combined administration of Sct and N-3 is comparable to that of metformin. Nevertheless, the latter showed more or less therapeutic effects relative to N-3. PMID- 29710487 TI - Protective effect and mechanism of ginsenoside Rg1 in cerebral ischaemia reperfusion injury in mice. AB - BACKGROUND: Ginsenoside Rg1 is regarded as one of main bioactive compounds responsible for pharmaceutical actions of ginseng with little toxicity and has been shown to have possibly neuroprotective effects. However, the mechanism of its neuroprotection for acute ischemic stroke is still elusive. The purpose of present study is thus to assess the neuroprotective effects of the ginsenoside Rg1 against neurological injury in a mice model of cerebral ischemia/reperfusion (I/R), and then to explore the mechanisms for these neuroprotective effects. METHODS: Mices were pretreated with ginsenoside Rg1 20,40?mg?kg?1?d?1, ig, for 7d, respectively, then subjected to cerebral ischenmia (middle cerebral artery occlusion) for 2?h and reperfusion for 22?h. The infarct volume and the neurological deficit were determined by TTC staining and Longa?s scoring, respectively. The protein expression of brain-derived neurotrophic factor (BDNF) was analyzed by Immunohistochemistry and Western blot, respectively. Interleukin 1? (IL-1?), tumor necrosis factor alpha (TNF-?) and interleukin-6 (IL-6) expression in serum was measured by ELISA kit. High-performance liquid chromatography (HPLC) was used to explore the contents of Glu and Asp. RESULTS: Compared with the ischemia/reperfusion group, ginsenoside Rg1 40?mg/kg group has significantly reduced infarct volume, neurological deficit scores (P? 0.05). Among the selected PPCPs, DEET, the recalcitrant compound, was most effectively removed by the GAC sandwich filters. Combining the GAC layers with the slow sand filters significantly enhanced the removal of the target PPCP compounds (p < 0.05), demonstrating that both adsorption and biodegradation contributed to the removals. Furthermore, pseudo-second-order equation (Type 1) could best represent the adsorption kinetics of the four target PPCP compounds onto GAC. In relation to other quality parameters, sandwich filter with 20 cm of GAC also showed good average removals of chemical oxygen demand (COD) of 65.8% and total organic carbon (TOC) of 90.3%, but occurrence of ammonium up to 0.76 mg/L concentration indicated inapplicability of filtration rate of 5 cm/h. No significant difference was found between 10 cm/h and 20 cm/h filtration rates for nitrogen and phosphate removals (p > 0.05). Results of this lab-scale investigation show that GAC sandwich slow sand filter is potentially an effective process for removing PPCPs from tertiary wastewater. PMID- 29710574 TI - The nexus between climate change, ecosystem services and human health: Towards a conceptual framework. AB - This paper addresses the impact that changes in natural ecosystems can have on health and wellbeing focusing on the potential co-benefits that green spaces could provide when introduced as climate change adaptation measures. Ignoring such benefits could lead to sub-optimal planning and decision-making. A conceptual framework, building on the ecosystem-enriched Driver, Pressure, State, Exposure, Effect, Action model (eDPSEEA), is presented to aid in clarifying the relational structure between green spaces and human health, taking climate change as the key driver. The study has the double intention of (i) summarising the literature with a special emphasis on the ecosystem and health perspectives, as well as the main theories behind these impacts, and (ii) modelling these findings into a framework that allows for multidisciplinary approaches to the underlying relations between human health and green spaces. The paper shows that while the literature based on the ecosystem perspective presents a well-documented association between climate, health and green spaces, the literature using a health-based perspective presents mixed evidence in some cases. The role of contextual factors and the exposure mechanism are rarely addressed. The proposed framework could serve as a multidisciplinary knowledge platform for multi perspecitve analysis and discussion among experts and stakeholders, as well as to support the operationalization of quantitative assessment and modelling exercises. PMID- 29710575 TI - Canopy tree species determine herb layer biomass and species composition on a reclaimed mine spoil heap. AB - According facilitative models of succession, trees are great forest ecosystem engineers. The strength of tree stand influences on habitat were tested in rather homogenous conditions where heterogeneity of site condition was not an important influence. We hypothesized that canopy composition affects total aboveground vascular herb layer biomass (THB) and species composition of herb layer plant biomass (SCHB) more significantly than primary soil fertility or slope exposure. The study was conducted in 227 randomly selected research plots in seven types of forest stands: pure with Alnus glutinosa, Betula pendula, Pinus sylvestris, Quercus petraea and Robinia pseudoacacia, and mixed with dominance of Acer pseudoplatanus or Betula pendula located on hilltop and northern, eastern, western, and southern slopes on a reclaimed, afforested post-mining spoil heap of the Belchatow Brown Coal Mine (Poland). Generalized linear models (GLZ) showed that tree stand species were the best predictors of THB. Non-parametric variance tests showed significantly higher (nearly four times) THB under canopies of A. glutinosa, R. pseudoacacia, B. pendula and Q. petraea, compared to the lowest THB found under canopies of P. sylvestris and mixed with A. pseudoplatanus. Redundancy Analysis (RDA) showed that SCHB was significantly differentiated along gradients of light-nutrient herb layer species requirements. RDA and non parametric variance tests showed that SCHB under canopies of A. glutinosa, R. pseudoacacia and mixed with A. pseudoplatanus had large shares of nitrophilous ruderal species (32%, 31% and 11%, respectively), whereas SCHB under B. pendula, Q. petraea, mixed with B. pendula and P. sylvestris were dominated by light demanding meadow (49%, 51%, 51% and 36%, respectively) and Poaceae species. The results indicated the dominant role of tree stand composition in habitat-forming processes, and although primary site properties had minor importance, they were also modified by tree stand species. PMID- 29710576 TI - Modeling assisted evaluation of direct electricity generation from waste heat of wastewater via a thermoelectric generator. AB - The thermal energy represents a significant portion of energy potential in municipal wastewater and may be recovered as electricity by a thermoelectric generator (TEG). Converting heat to all-purpose electricity by TEG has been demonstrated with large heat gradients, but its application in waste heat recovery from wastewater has not been well evaluated. Herein, a bench-scale Bi2Te3-based waste heat recovery system was employed to generate electricity from a low temperature gradient through a combination of experiments and mathematical modeling. With an external resistance of 7.8 Omega and a water (hot side) flow rate of 75 mL min-1, a maximum normalized energy recovery of 4.5 * 10-4 kWh m-3 was achieved under a 2.8 degrees C temperature gradient (DeltaT). Model simulation indicated a boost in both power output and energy conversion efficiency from 0.76 mW and 0.13% at DeltaT = 2.8 degrees C to 61.83 mW and 1.15% at DeltaT = 25 degrees C. Based on the data of two-year water/air temperature obtained from the Christiansburg Wastewater Treatment Plant, an estimated energy generation of 1094 to 70,986 kWh could be expected annually with a saving of $163 to $6076. Those results have revealed a potential for TEG centered direct electricity generation from low-grade heat towards enhanced resource recovery from wastewater and encouraged further exploration of this approach. PMID- 29710577 TI - From global circulation to local flood loss: Coupling models across the scales. AB - Comprehensive flood risk modeling is crucial for understanding, assessing, and mitigating flood risk. Modeling extreme events is a well-established practice in the atmospheric and hydrological sciences and in the insurance industry. Several specialized models are used to research extreme events including atmospheric circulation models, hydrological models, hydrodynamic models, and damage and loss models. Although these model types are well established, and coupling two to three of these models has been successful, no assessment of a full and comprehensive model chain from the atmospheric to local scale flood loss models has been conducted. The present study introduces a model chain setup incorporating a GCM/RCM to model atmospheric processes, a hydrological model to estimate the catchment's runoff reaction to precipitation inputs, a hydrodynamic model to identify flood-affected areas, and a damage and loss model to estimate flood losses. Such coupling requires building interfaces between the individual models that are coherent in terms of spatial and temporal resolution and therefore calls for several pre- and post-processing steps for the individual models as well as for a computationally efficient strategy to identify and model extreme events. The results show that a coupled model chain allows for good representation of runoff for both long-term runoff characteristics and extreme events, provided a bias correction on precipitation input is applied. While the presented approach for deriving loss estimations for particular extreme events leads to reasonable results, two issues have been identified that need to be considered in further applications: (i) the identification of extreme events in long-term GCM simulations for downscaling and (ii) the representativeness of the vulnerability functions for local conditions. PMID- 29710578 TI - Influence of climate cycles on grapevine domestication and ancient migrations in Eurasia. AB - The objective of this work is to investigate the Holocenic climate cycles that may have influenced the domestication of grapevine in the Subcaucasian area and its subsequent spread in Eurasia. The analysis covered the longitudinal belt ranging from the Iberian Peninsula to Japan, seen as the preferential pathway for the Holocenic spread of grapevine and many other crops in Eurasia. Spectral analysis was considered as the criterion of investigation and the Holocenic cycles were analyzed considering different geochemical and biological proxies, of which seven are directly referred to vine. In this context the relation of the abovementioned proxies with spectral peaks of possible causal factors like Solar activity (SA), North Atlantic oceanic factors (Atlantic Multidecadal Oscillation AMO and North Atlantic Oscillation - NAO), and subtropical oceanic factors (El Nino Southern Oscillation - ENSO) was also analyzed. In order to acquire a sufficiently wide number of proxies sensitive to the causal factors, we referred to a latitudinal belt wider than the one colonized by vine, also acquiring proxy from the Scandinavian area, notoriously susceptible to North Atlantic forcings. The analysis of the proxy spectral peaks, considering 20 classes with a 50-years step in the 0-1000 years range, showed that the 50% of the classes have a higher frequency of peaks at East than West, the 20% a higher frequency at West than East and the 10% an equal frequency, showing the efficiency of the propagation of Western signals towards the center of Eurasia. The search of the causal factors spectral peaks in the proxy series showed that AMO, NAO and SA acted with a certain regularity on the entire belt investigated both latitudinally and longitudinally, while spectral peaks linked to ENSO underwent a considerable attenuation moving northward. Finally, the specific analysis on viticultural proxies showed common peaks with causal factors. PMID- 29710579 TI - How and to what extent does precipitation on multi-temporal scales and soil moisture at different depths determine carbon flux responses in a water-limited grassland ecosystem? AB - In water-limited ecosystems, hydrological processes significantly affect the carbon flux. The semi-arid grassland ecosystem is particularly sensitive to variations in precipitation (PRE) and soil moisture content (SMC), but to what extent is not fully understood. In this study, we estimated and analyzed how hydrological variables, especially PRE at multi-temporal scales (diurnal, monthly, phenological-related, and seasonal) and SMC at different soil depths (0 20 cm, 20-40 cm, 40-60 cm, 60-80 cm) affect the carbon flux. For these aims, eddy covariance data were combined with a Vegetation Photosynthesis and Respiration Model (VPRM) to simulate the regional gross primary productivity (GPP), ecosystem respiration (Reco), and net ecosystem exchange of CO2 (NEE). Interestingly, carbon flux showed no relationship with diurnal PRE or phenological-related PRE (precipitation in the growing season and non-growing season). However, carbon flux was significantly related to monthly PRE and to seasonal PRE (spring + summer, autumn). The GPP, Reco, and NEE increased in spring and summer but decreased in autumn with increasing precipitation due to the combined effect of salinization in autumn. The GPP, Reco, and NEE were more responsive to SMC at 0 20 cm depth than at deeper depths due to the shorter roots of herbaceous vegetation. The NEE increased with increasing monthly PRE because soil microbes responded more quickly than plants. The NEE significantly decreased with increasing SMC in shallow surface due to a hysteresis effect on water transport. The results of our study highlight the complex processes that determine how and to what extent PRE at multi-temporal scale and SMC at different depths affect the carbon flux response in a water-limited grassland. PMID- 29710580 TI - Development and validation of an environmental fragility index (EFI) for the neotropical savannah biome. AB - Augmented production and transport of fine sediments resulting from increased human activities are major threats to freshwater ecosystems, including reservoirs and their ecosystem services. To support large scale assessment of the likelihood of soil erosion and reservoir sedimentation, we developed and validated an environmental fragility index (EFI) for the Brazilian neotropical savannah. The EFI was derived from measured geoclimatic controls on sediment production (rainfall, variation of elevation and slope, geology) and anthropogenic pressures (natural cover, road density, distance from roads and urban centers) in 111 catchments upstream of four large hydroelectric reservoirs. We evaluated the effectiveness of the EFI by regressing it against a relative bed stability index (LRBS) that assesses the degree to which stream sites draining into the reservoirs are affected by excess fine sediments. We developed the EFI on 111 of these sites and validated our model on the remaining 37 independent sites. We also compared the effectiveness of the EFI in predicting LRBS with that of a multiple linear regression model (via best-subset procedure) using 7 independent variables. The EFI was significantly correlated with the LRBS, with regression R2 values of 0.32 and 0.40, respectively, in development and validation sites. Although the EFI and multiple regression explained similar amounts of variability (R2 = 0.32 vs 0.36), the EFI had a higher F-ratio (51.6 vs 8.5) and better AICc value (333 vs 338). Because the sites were randomly selected and well-distributed across geoclimatic controlling factors, we were able to calculate spatially explicit EFI values for all hydrologic units within the study area (~38,500 km2). This model-based inference showed that over 65% of those units had high or extreme fragility. This methodology has great potential for application in the management, recovery, and preservation of hydroelectric reservoirs and streams in tropical river basins. PMID- 29710581 TI - Interaction of carboxylated CdSe/ZnS quantum dots with fish embryos: Towards understanding of nanoparticles toxicity. AB - Due to colloidal instability even with protective coatings, nanoparticles tend to aggregate in complex environments and possibly interact with biota. In this study, visualization of quantum dots (QDs) interaction with rainbow trout (Oncorhynchus mykiss) embryos was performed. Studies on zebrafish (Danio rerio) and pearl gourami (Trichogaster leerii) embryos have shown that QDs interact with embryos in a general manner and their affects are independent on the type of the embryo. It was demonstrated that carboxylated CdSe/ZnS QDs (4 nM) were aggregating in accumulation media and formed agglomerates on the surface of fish embryos under 1-12 days incubation in deep-well water. Detailed analysis of QDs distribution on fish embryos surface and investigation of the penetration of QDs through embryo's membrane showed that the chorion protects embryos from the penetration through the chorion and the accumulation of nanoparticles inside the embryos. Confocal microscopy and spectroscopy studies on rainbow trout embryos demonstrated that QDs cause chorion damage, due to QDs aggregation on the surface of chorion, even the formation of the agglomerates at the outer part of the embryos and/or with the mucus were detected. Aggregation of QDs and formation of agglomerates on the outer part of the embryo's membrane caused the intervention of the aggregates to the chorion and even partially destroyed the embryo's chorion. The incorporation of QDs in chorion was confirmed by two methods: in living embryos from a 3D reconstruction view, and in slices of embryos from a histology view. The damage of chorion integrity might have adverse effects on embryonic development. Moreover, for the first time the toxic effect of QDs was separated from the heavy metal toxicity, which is most commonly discussed in the literature to the toxicity of the QDs. PMID- 29710582 TI - Insecticide exposure affects DNA and antioxidant enzymes activity in honey bee species Apis florea and A. dorsata: Evidence from Punjab, Pakistan. AB - Insecticide exposure can affect honey bees in agro-ecosystems, posing behavioral stresses that can lead to population decline. In this study, insecticide incidence, DNA damage, and antioxidant enzyme activity were studied in Apis florea and A. dorsata honey bee samples collected from insecticide-treated and insecticide-free areas of Punjab, Pakistan. Seven insecticides: chlorpyrifos, dimethoate, imidacloprid, phorate, emamectin, chlorfenapyr, and acetamiprid were detected in seven samples of A. florea and five samples of A. dorsata. In total, 12 samples (22.2%) of honey bees were found positive to insecticide presence out of 54 samples. The most frequently detected insecticide was chlorpyrifos, which was found in four samples (7.4%), with a concentration ranging from 0.01 to 0.05 MUg/g and an average concentration 0.03 MUg/g. The comet assay or single cell gel electrophoresis assay, a simple way to measure DNA strand breaks in eukaryotic cells, was used to microscopically find damage of DNA at the level of a single cell. Comet tail lengths of DNA in A. florea and A. dorsata samples from insecticide-treated areas were significantly higher (P < 0.05) than samples from insecticide-free areas. The highest comet tail length (19.28 +/- 2.67 MUm) was observed in DNA of A. dorsata from insecticide-treated areas, while the minimum one (3.18 +/- 1.46 MUm) was noted in A. dorsata from insecticide-free areas. Catalase (CAT) activity did not vary significantly between honey bee samples from insecticide-treated and insecticide-free areas, while glutathione S-transferase (GST) activity showed a significant reduction in response to insecticide exposure. Significant positive correlations were detected between enzyme activity and insecticide concentration in honey bee species from insecticide-treated areas compared with control groups. Toxicity from pesticide exposure at sub-lethal levels after application or from exposure to pesticide residues should not be underestimated in honey bees, as it may induce physiological impairment that can decline honey bees' health. PMID- 29710583 TI - Survey of selected personal care products in surface water of coral reefs in Kenting National Park, Taiwan. AB - Kenting National Park (KNP) located in the Hengchun Peninsula in southern Taiwan is a popular tourist spot, annually attracting millions of visitors, who engage in water sport and amusement activities. In this region, sewage is directly discharged into the marine environment. In this study, the concentrations of five organic UV filters [benzophenone (BP), 2,4-dihydroxy benzophenone (BP-1), 2 hydroxy-4-methoxy benzophenone (BP-3), 2,2'-dihydroxy-4-methoxy benzophenone (BP 8), and 4-methylbenzylidene camphor], five preservatives [methylparaben (MeP), ethylparaben, propylparaben (PrP), butylparaben, and benzylparaben], one disinfectant [triclosan (TCS)], and twenty-four detergent derivatives [nonylphenol (NP), nonylphenol ethoxylates (NP2EO-NP12EO), octylphenol (OP) and octylphenol ethoxylates OP2EO-OP12EO] were detected in seawater and river water samples collected from eight beaches in KNP and two major river estuaries in the Hengchun Peninsula. BP-3 was detected at all sampling sites and was higher in concentration than the other organic UV filters. The highest concentration of BP 3 was 1233 ng/L collected from Wanlitong Beach. MeP and PrP were the main preservative components in seawater. The highest total content of preservative agents was 164 ng/L collected from Houwan Beach. Moreover, NP was detected at all sampling sites, with the highest concentration found at Sail Rock Beach (26.5 ng/L). The highest concentration of OP was 113 ng/L in the Boli River estuary. The widespread use of personal care products (PCPs) has resulted in the release of their major ingredients into natural ecosystems. Therefore, the potential long term effects of multi-PCPs at low concentration exposure to on the coral reef ecosystem in KNP must be considered and monitored. PMID- 29710584 TI - Heavy metal and sulfate removal from sulfate-rich synthetic mine drainages using sulfate reducing bacteria. AB - The removals of heavy metals and sulfate in the synthetic acid mine drainages (AMDs) by Desulfovibrio desulfuricans, sulfate-reducing bacteria (SRB), and the indigenous bacteria isolated from the mine area soil sample were studied to compare the AMD treatment efficiencies. The AMD treatment by the D. desulfuricans grown in the Desulfovibrio medium was used to represent bioaugmentation, while the AMD treatment by the indigenous bacteria grown in the Desulfovibrio medium was used to represent biostimulation. The consumption of lactate and sulfate suggested that the zinc (Zn) removal in the Zn-spiked Desulfovibrio medium by D. desulfuricans involved chemical precipitation and biosorption. The complete Zn removal by D. desulfuricans took 24 h, while the indigenous bacteria took 360 h. The significantly lower rate can probably be attributed to the composition of the culture. The removal of Zn in the sulfate-rich synthetic AMD-containing Desulfovibrio medium (i.e., AMD) was adversely affected by the presence of other heavy metals. Also, the sulfate reduction by D. desulfuricans and the indigenous bacteria was reduced from 47% to 20% and from 36% to 6%, respectively. The inhibitive effects on the removal of heavy metals and sulfate were greater with the Zn/Cu-spiked AMD than the Zn-spiked AMD. Overall, the indigenous bacteria showed potential for removing heavy metals and sulfate in AMDs, while the removal efficiency was lower than D. desulfuricans. The continuous supply of carbon sources with an adaptation period may be required to enhance the AMD treatment efficiency by the indigenous bacteria. PMID- 29710585 TI - Bioavailability and bioaccumulation of heavy metals of several soils and sediments (from industrialized urban areas) for Eisenia fetida. AB - Soils and sediments are susceptible to anthropogenic contamination with Metallic Trace Elements (MTEs) and it can present some risks to ecosystems and human health. The levels of Cd, Cu, Fe, Ni, Pb and Zn were assessed in soils (C, G, K, L) from Estarreja (Portugal) and sediments from a stormwater basin in Lyon (DJG), a harbour (LDB) and a Rhone river site (TRS) (France). An ecotoxicological study was performed with Eisenia fetida (E. fetida) to infer about potential transfer risks to the soil invertebrates. To assess risks associated with MTEs contamination, it is important to know their total concentrations, fractionation and the potential available fractions. CaCl2, DTPA and NaOAc extractions were performed to assess the extractable and available MTEs fractions. The studied sediments were much more contaminated than the soils for all the MTEs analysed. The trace elements fraction linked with DTPA extraction shows higher values when compared with the NaOAc and the CaCl2 pools. Low mortality effects were recorded in the tests with E. fetida. The MTEs levels in soils and sediments and the concentrations bioaccumulated in adult earthworms contributed to a reduction in the number of juveniles produced. E. fetida adults and juveniles accumulated ETMs as follows: Cd > Cu = Zn > Ni > Pb > Fe. Determined BAFs were mostly lower than 1 with some higher values for Cd, Cu and Zn. Calculated SET and ERITME indexes allowed to classify the samples from the most to the less toxic for E. fetida as: LDB > DJG > L > G > C > K > TRS. Despite this order of toxicity, the earthworms exposed to the sediment TRS presented the lowest reproduction rate. The combination of "chemical" measurements with the calculation of BAFs, but especially SET and ERITME indexes can be a useful tool in risk assessment. PMID- 29710586 TI - Efficient removal of Cd2+ and Pb2+ from aqueous solution with amino- and thiol functionalized activated carbon: Isotherm and kinetics modeling. AB - In order to address the increasingly severe pollution issue caused by heavy metals, activated carbon-based absorbents have gained considerable attention. Herein, two novel adsorbents, amino-functionalized activated carbon (N-AC) and thiol-functionalized activated carbon (S-AC), were successfully synthesized by stepwise modification with tetraethylenepentamine (TEPA), cyanuric chloride (CC) and sodium sulfide. The pristine and synthesized materials were characterized by BET analysis, SEM, FTIR spectroscopy, elemental analysis and zeta-potential analyzer. Meanwhile, their adsorption properties for Cd2+ and Pb2+ and the effects of various variables on the adsorption processes were systematically investigated. The findings confirmed that amino-groups and thiol-groups endowed the AC with a strong affinity for metal ions and that the pH of solution affected the uptake efficiencies of the adsorbents by influencing their surface charges. Furthermore, six isotherm models (Langmuir, Freundlich, Temkin, Dubinin Radushkevich, Sips and Redlich-Peterson) and four kinetic models (pseudo-first order, pseudo-second-order, Intra-particle diffusion and Elovich) were applied to interpret the adsorption process at three different temperatures (288 K, 298 K and 308 K). The results indicated that temperature played an important role and that the rate-limiting step was chemosorption. A better fit for all adsorption systems was obtained with Langmuir model, with the maximum adsorption capacities at 298 K of 79.20 mg Cd2+/g and 142.03 mg Pb2+/g for N-AC, 130.05 mg Cd2+/g and 232.02 mg Pb2+/g for S-AC, respectively. Subsequently, the thermodynamic parameters revealed the nature of the adsorption was endothermic and spontaneous under the experimental condition. The possible adsorption procedures and the underlying mechanisms comprising physical and chemical interactions were proposed. Moreover, the as-synthesized adsorbents exhibited excellent regeneration performance after five adsorption/desorption cycles. The overall results demonstrated that both N-AC and S-AC could be the promising efficient candidates for removing Cd2+ and Pb2+ from contaminated water. PMID- 29710587 TI - Sorption of pharmaceuticals to soil organic matter in a constructed wetland by electrostatic interaction. AB - There is a growing interest in the removal of pharmaceuticals from wastewater because pharmaceuticals have potential ecotoxicological effects. Among several removal mechanisms, the sorption of pharmaceuticals to sediment organic matter is an important mechanism related to the mobility of pharmaceuticals. This study investigated the sorption of pharmaceuticals to soil organic matter (SOM) by electrostatic interactions. SOM located on the surface of soil/sediment generally has a negative charge because of the functional groups present (i.e., carboxylic and phenolic groups). Thus, the electrical characteristics of SOM can induce electrical attraction with positively charged chemical compounds. In this study, SOM was extracted from soils under different aquatic plants (Acorus and Typha) in a constructed wetland in Korea. Experiments were carried out with the following three pharmaceuticals with different electrical characteristics at pH 7: atenolol (positive charge; pKa 9.5), carbamazepine (neutral; no pKa), and ibuprofen (negative charge; pKa 4.9). The SOM in the Acorus pond had a higher hydrophobicity and electrical charge density than that in the Typha pond. Regarding the sorption efficiency between SOM and charged pharmaceuticals, atenolol showed highest sorption efficiency (~60%), followed by carbamazepine (~40%) and ibuprofen (<~30%). In addition, the removal efficiency of the targeted pharmaceuticals in the constructed wetland was estimated by comparing the concentrations of the pharmaceuticals at sampling points with flowing water. The results showed that the removal efficiency of atenolol and carbamazepine was almost 50%, whereas that of ibuprofen was only ~10%. A comparison of the results of lab-scale and field experiments showed that electrostatic interaction is one of the major pharmaceutical removal mechanisms in a constructed wetland. PMID- 29710588 TI - Measuring the sustainability of tin in China. AB - Tin is a component of many items used in daily activities, including solder in consumer electronics, tin can containing food and beverages, polyvinyl chloride stabilizers in construction products, catalysts in industrial processes, etc. China is the largest producer and consumer of refined tin, and more than 60% of this refined tin is applied in the electronics sector as solder. China is the leader in global economic growth; simultaneously, China is also a major producer and consumer of electrical and electronic equipment (EEE). Thus, future tin supply and demand in China are forecasted, based on the gross domestic product per capita and the average consumption of refined tin in past five years. Current tin reserves and identified resources in China can meet the future two decades of mine production, but import of tin will also be critical for China's future tin consumption. However, there will be a lot of uncertainty for import of tin from other countries. At the same time, virgin mining of geological ores is a process of high energy consumption and destruction of the natural environment. Hence recycling tin from Sn-bearing secondary resources like tailings and waste electrical and electronic equipment (WEEE) can not only address the shortage of tin mineral resources, but also save energy and protect the ecological environment. PMID- 29710589 TI - Effects of influent nitrogen loads on nitrogen and COD removal in horizontal subsurface flow constructed wetlands during different growth periods of Phragmites australis. AB - Horizontal subsurface constructed wetlands (HSSF-CWs) planted with Phragmites australis were established to examine the effect of influent nitrogen loads on the removal efficiencies of nitrogen and chemical oxygen demand (COD) during different plant growth periods of plants. Under low influent nitrogen loads, most of the dissolved oxygen was consumed during the oxidation of organic matter in the wetland systems, and a dissimilatory nitrate reduction to ammonium (DNRA) may have occurred in HSSF-CWs when excessive amounts of organic matter were present, which limited the nitrification of ammonium nitrogen (NH4-N) and hindered the NH4 N removal. An increase in the influent nitrogen loads resulted in an enhancement of the removal efficiencies of NH4-N, nitrate nitrogen (NO3-N) and total nitrogen (TN) during the same growth period, except for NO3-N under the highest influent nitrogen loads, whereas fluctuations occurred for the COD removal efficiency. Compared with the rapid growth period, the removal efficiency of NH4-N, NO3-N and TN increased during the mature period; however, the COD removal efficiency decreased. The change of COD: N (COD:TN in wastewater) ratios with retention times indicated the sufficiency or deficiency of organic matter as an electron donor in the wetland systems. The changes in the pH value and oxidation-reduction potential (ORP) indirectly demonstrated that many factors affected the effluent pH value and ORP, such as retention time, influent loads, plants and wetland substrate, and microorganisms. In this study, the changes of ORP also illustrated that the dissolved oxygen concentrations decreased with increasing retention time in the HSSF-CWs; however, no significant increase in the ORP was observed during the two growth periods. PMID- 29710590 TI - Temperature sensitivity of biodegradable dissolved organic carbon increases with elevating humification degree in subtropical rivers. AB - Biodegradable dissolved organic carbon (BDOC) plays a key role in C cycle in inland waters. However, the magnitude of temperature sensitivity (Q10 value) of BDOC is still unclear, and the effect of DOC quality on Q10 value of BDOC is not well verified in these aquatic systems. Here, we used a laboratory incubation experiment to determine the Q10 value of BDOC in 57 rivers in the Three Gorges Reservoir area, China, and then tested whether C quality-temperature hypothesis could be applied to BDOC in inland waters. We observed approximately twofold variations in Q10 values of BDOC (1.42-2.67) in these rivers. Moreover, the tight positive relationship between the Q10 values of BDOC and DOC humification index indicated the applicability of C quality-temperature hypothesis in subtropical rivers. In addition, the Q10 values of BDOC exhibited a negative relationship with pH. These findings suggest that DOC quality and pH are powerful predictors of temperature sensitivity of BDOC in subtropical rivers. In conclusion, our results would help to improve the C models and predict the feedback between climate warming and C dynamics in inland waters. PMID- 29710592 TI - Lateral spread affects nitrogen leaching from urine patches. AB - Nitrate leaching from urine deposited by grazing animals is a critical constraint for sustainable dairy farming in New Zealand. While considerable progress has been made to understand the fate of nitrogen (N) under urine patches, little consideration has been given to the spread of urinary N beyond the wetted area. In this study, we modelled the lateral spread of nitrogen from the wetted area of a urine patch to the soil outside the patch using a combination of two process based models (HYDRUS and APSIM). The simulations provided insights on the extent and temporal pattern for the redistribution of N in the soil following a urine deposition and enabled investigating the effect of lateral spread of urinary N on plant growth and N leaching. The APSIM simulation, using an implementation of a dispersion-diffusion function, was tested against experimental data from a field experiment conducted in spring on a well-drained soil. Depending on the geometry considered for the dispersion-diffusion function (plate or cylindrical) the area averaged N leaching decreased by 8 and 37% compared with simulations without lateral N spread; this was due to additional N uptake from pasture on the edge area. A sensitivity analysis showed that area-averaged pasture growth was not greatly affected by the value of the dispersion factor used in the model, whereas N leaching was very sensitive. Thus, the need to account for the edge effect may depend on the objective of the simulations. The modelling results also showed that considering lateral spread of urinary N was sufficient to describe the experimental data, but plant root uptake across urine patch zones may still be relevant in other conditions. Although further work is needed for improving accuracy, the simulated and experimental results demonstrate that accounting for the edge effect is important for determining N leaching from urine-affected areas. PMID- 29710591 TI - Deactivation of wastewater-derived N-nitrosodimethylamine precursors with chlorine dioxide oxidation and the effect of pH. AB - In this study, the effect of chlorine dioxide (ClO2) oxidation on the deactivation of wastewater (WW)-derived N-nitrosodimethylamine (NDMA) precursors was investigated under various conditions (i.e., ClO2 application pH, dose and contact time). At pH 6.0, decreases in NDMA formation potentials (FPs) or occurrences (under uniform formation conditions [UFC]) were relatively low (<25%) with ClO2 oxidation regardless of WW-impact. A negative removal was also observed after ClO2 oxidation in some of the non-impacted waters. However, NDMA FP removals were significant (up to ~85%) under the same oxidation conditions in WW impacted waters at pH 7.8. This indicates that the majority of WW-derived NDMA precursors can be deactivated with ClO2 oxidation above neutral pH. This was attributed to the better oxidative reaction of ClO2 with amines that have lone pair electrons to be shared at higher oxidation pH conditions. In addition, relatively short oxidation periods with ClO2 (i.e., <=10 min) or low Ct (concentration * time, ~10 mg * min/L) values were sufficient for the deactivation of WW-derived NDMA precursors. ClO2 oxidation was effective in freshly WW-impacted waters. Natural attenuation processes (e.g., sorption, biodegradation, etc.) can change the reactivity of WW-derived NDMA precursors for oxidation with ClO2. The effect of ClO2 on the removal of THM precursors was low (<25%) and independent of oxidation conditions. Given the low formation of regulated THMs and HAAs, ClO2 oxidation presents a viable option for the simultaneous control of NDMA and regulated DBP formation during water treatment, especially for utilities treating WW-impacted water sources. PMID- 29710593 TI - Understanding linkages between global climate indices and terrestrial water storage changes over Africa using GRACE products. AB - Africa, a continent endowed with huge water resources that sustain its agricultural activities is increasingly coming under threat from impacts of climate extremes (droughts and floods), which puts the very precious water resource into jeopardy. Understanding the relationship between climate variability and water storage over the continent, therefore, is paramount in order to inform future water management strategies. This study employs Gravity Recovery And Climate Experiment (GRACE) satellite data and the higher order (fourth order cumulant) statistical independent component analysis (ICA) method to study the relationship between terrestrial water storage (TWS) changes and five global climate-teleconnection indices; El Nino-Southern Oscillation (ENSO), North Atlantic Oscillation (NAO), Madden-Julian Oscillation (MJO), Quasi-Biennial Oscillation (QBO) and the Indian Ocean Dipole (IOD) over Africa for the period 2003-2014. Pearson correlation analysis is applied to extract the connections between these climate indices (CIs) and TWS, from which some known strong CI rainfall relationships (e.g., over equatorial eastern Africa) are found. Results indicate unique linear-relationships and regions that exhibit strong linkages between CIs and TWS. Moreover, unique regions having strong CI-TWS connections that are completely different from the typical ENSO-rainfall connections over eastern and southern Africa are also identified. Furthermore, the results indicate that the first dominant independent components (IC) of the CIs are linked to NAO, and are characterized by significant reductions of TWS over southern Africa. The second dominant ICs are associated with IOD and are characterized by significant increases in TWS over equatorial eastern Africa, while the combined ENSO and MJO are apparently linked to the third ICs, which are also associated with significant increase in TWS changes over both southern Africa, as well as equatorial eastern Africa. PMID- 29710594 TI - A CuNi bimetallic cathode with nanostructured copper array for enhanced hydrodechlorination of trichloroethylene (TCE). AB - To address the challenges of low hydrodechlorination efficiency by non-noble metals, a CuNi bimetallic cathode with nanostructured copper array film was fabricated for effective electrochemical dechlorination of trichloroethylene (TCE) in aqueous solution. The CuNi bimetallic cathodes were prepared by a simple one-step electrodeposition of copper onto the Ni foam substrate, with various electrodeposition time of 5/10/15/20 min. The optimum electrodeposition time was 10 min when copper was coated as a uniform nanosheet array on the nickel foam substrate surface. This cathode exhibited the highest TCE removal, which was twice higher compared to that of the nickel foam cathode. At the same passed charge of 1080C, TCE removal increased from 33.9 +/- 3.3% to 99.7 +/- 0.1% with the increasing operation current from 5 to 20 mA cm-2, while the normalized energy consumption decreased from 15.1 +/- 1.0 to 2.6 +/- 0.01 kWh log-1 m-3. The decreased normalized energy consumption at a higher current density was due to the much higher removal efficiency at a higher current. These results suggest that CuNi cathodes prepared by simple electrodeposition method represent a promising and cost-effective approach for enhanced electrochemical dechlorination. PMID- 29710595 TI - Explaining and modeling the concentration and loading of Escherichia coli in a stream-A case study. AB - Escherichia coli (E. coli) level in streams is a public health indicator. Therefore, being able to explain why E. coli levels are sometimes high and sometimes low is important. Using citizen science data from Fall Creek in central NY we found that complementarily using principal component analysis (PCA) and partial least squares (PLS) regression provided insights into the drivers of E. coli and a mechanism for predicting E. coli levels, respectively. We found that stormwater, temperature/season and shallow subsurface flow are the three dominant processes driving the fate and transport of E. coli. PLS regression modeling provided very good predictions under stormwater conditions (R2 = 0.85 for log (E. coli concentration) and R2 = 0.90 for log (E. coli loading)); predictions under baseflow conditions were less robust. But, in our case, both E. coli concentration and E. coli loading were significantly higher under stormwater condition, so it is probably more important to predict high-flow E. coli hazards than low-flow conditions. Besides previously reported good indicators of in stream E. coli level, nitrate-/nitrite-nitrogen and soluble reactive phosphorus were also found to be good indicators of in-stream E. coli levels. These findings suggest management practices to reduce E. coli concentrations and loads in streams and, eventually, reduce the risk of waterborne disease outbreak. PMID- 29710596 TI - Mixtures of macrophyte growth forms promote nitrogen cycling in wetlands. AB - The importance of aquatic plant diversity in regulating nutrient cycling in wetlands remains poorly understood. We investigated how variation in macrophyte growth form (emerging, submerged and bryophyte) combinations and species mixtures affect nitrogen (N) removal from the water and N accumulation in plant biomass. We conducted a wetland mesocosm experiment for 100 days during July-September 2015. Twelve species were grown in mono- and in two-species mixed cultures for a total of 32 single and two-growth form combinations. Nitrogen removal from the water was quantified on three occasions during the experiment, while N accumulation in plant biomass was determined following termination of the experiment. The number of species and growth forms present increased N removal and accumulation. The growth form combinations of emerging and bryophyte species showed the highest N accumulation and N removal from water, followed by combinations of emerging species. By contrast, submerged species growing in the presence of emerging or other submerged species showed the lowest levels of N accumulation and N removal. Temporal variation in N removal also differed among growth form combinations: N removal was highest for emerging-bryophyte combinations in July, but peaked for the emerging-submerged and emerging bryophyte combinations in August. Indeed, the occurrence of complementarity among macrophyte species, particularly in combinations of bryophyte and emerging species, enhanced N removal and uptake during the entire growing season. Our study highlights the importance of bryophytes, which have been neglected in research on nutrient cycling in wetlands, for aquatic N cycling, especially given their worldwide distribution across biomes. Overall, our findings point towards the potential important role of the diversity of macrophyte growth forms in regulating key ecosystem processes related to N cycling in wetlands. PMID- 29710597 TI - Impact of urbanization-related land use land cover changes and urban morphology changes on the urban heat island phenomenon. AB - Urban growth and development caused by urbanization influence the urban heat island (UHI) phenomenon. With the rapid development of urbanization, China's major cities are facing more serious climate change problems, especially the UHI phenomenon. Proper planning and urban design of compact cities may improve the ventilation of street canyons and change the heat balance in the urban canopy and thus mitigate the UHI phenomenon. The aim of this study is to evaluate and discuss the mitigation of UHI with different types of land-use and land-cover (LUCC), as well as different development patterns for compact cities. To this end, we applied the weather research and forecasting model (WRF) with urban canopy model (WRF/UCM) in this study. To evaluate the impact of LUCC changes on the UHI, we set 2 cases based on land use and land cover statistical data from 1965 and 2008 of Wuhan. Also, to evaluate the impact of urban morphology changes on the UHI, we designed 2 hypothetical cases based on 2 different urban developing patterns, one is high rise case and another is high density case, to simulate the impact of urban morphology on the UHI. As for the results of this study, with different LUCC of 1965 and 2008, UHI intensity of Wuhan increased by 0.2 degrees C-0.4 degrees C in average. Moreover, the critical wind speed which can mitigate UHI of case 1965 is much lower than case 2008. With different urban morphology, the high-rise case may lead to lower UHI intensity at the pedestrian level due to the shading effects of high-rise buildings. However, the critical value of wind speed in the high-rise case was almost 1.5-2 times greater than that of the high-density case, which illustrates the reduced possibility of mitigating the UHI phenomenon for high-rise buildings in Wuhan City. PMID- 29710598 TI - Tracking antibiotic resistance genes in soil irrigated with dairy wastewater. AB - The application of dairy wastewater to agricultural soils is a widely used practice to irrigate crops and recycle nutrients. In this study, small-scale field plots were irrigated monthly (6 times) with dairy wastewater (100%), wastewater diluted to 50% with irrigation (canal) water, and diluted wastewater spiked with copper sulfate (50 mg Cu L-1), while control plots were irrigated with canal water. In addition, half of all plots were either planted with wheat or were left as bare soil. Biweekly soil samples were collected during this period and processed to determine the occurrence and abundance of antibiotic resistance genes [blaCTX-M-1, erm(B), sul1, tet(B), tet(M), and tet(X)] and a class 1 integron-integrase gene (intI1) via quantitative real-time PCR (qPCR). Only sul1 and tet(X) were detected in soil (3 out of 32 samples) before the wastewater treatments were applied. However, the occurrence and relative abundance (normalized to 16S rRNA gene copies) of most genes [erm(B), intI1, sul1, and tet(M)] increased dramatically after wastewater irrigation and levels were maintained during the entire study period. blaCTX-M-1 was the only gene not detected in wastewater-treated soils, which is likely related to its absence in the dairy wastewater. Relative gene levels in soil were found to be statistically similar among the treatments in most cases, regardless of the wastewater percentage applied and presence or absence of plants. The key result from this study is that dairy wastewater irrigation significantly enlarges the reservoir of ARGs and intI1 in soils, while detection of these genes rarely occurred in soil irrigated only with canal water. In addition, elevated levels of Cu in the wastewater and treated soil did not produce a concomitant increase of the ARG levels. PMID- 29710599 TI - Modelling of THM formation potential and DOM removal based on drinking water catchment characteristics. AB - : Catchment properties influence the character and concentration of dissolved organic matter (DOM). Surface and subsurface runoff from discrete catchments were collected and DOM was measured and assessed in terms of its treatability by Enhanced Coagulation and potential for disinfection by-product (trihalomethane, THMFP) formation potential. Models were developed of [1] DOM character [i.e. SUVA and SpCoL] and concentration (measured as dissolved organic carbon), [2] treatability of DOM by coagulation/flocculation processes and [3] specific THMFP based on the catchment features including: (a) surface and sub-surface soil texture (% clay: 5-25%), (b) topography (% slope: 5-15%) and (c) vegetation cover [i.e. high photosynthetic vegetation, low photosynthetic vegetation and bare soil] extracted from RapidEye satellite imagery using spectral mixture analysis. From these models, a catchment management decision support tool was designed for application by catchment managers to support decision-making of land-use and expected water quality related to water resources for drinking water supply. SOFTWARE AND DATA AVAILABILITY: Data sets used for models developing presented in this paper have been published in Research Data Australia (RDA) under the title of "Impacts of catchment properties on DOM and nutrients in waters from drinking water catchments".1 These data sets are available in open access and published in June 2017. A catchment management decision support model (CMDSM) tool was developed. Macros created using Visual Basic for Applications in Excel 2010. Excel 2010 or higher is required to open the CMDSM tool. The tool is provided by the University of South Australia (UniSA) and is not currently available on-line so please contact the corresponding author for access or further information. PMID- 29710600 TI - Exposure inequality assessment for PM2.5 and the potential association with environmental health in Beijing. AB - Fine particulate matter (PM2.5) pollution exposure has an adverse impact on public health, and some vulnerable social groups suffer from unfair exposure. Few studies have been conducted to estimate and to compare the exposure and inequality of different residential demographics at multiple time scales. This study assessed the exposures level of age and education subgroups on the whole city and the exposure inequalities of these subgroups within a concentration interval area for PM2.5 pollution at multiple time scales in Beijing in 2015. The potential association of PM2.5 with cancer morbidity was also explored through spatial analysis. Comparing the model performance of the ordinary kriging (OK) interpolation method with that of the land use regression (LUR) model method, the OK method was applied to estimate the PM2.5 concentrations at 1 km resolution. The exposure and inequality assessments for PM2.5 pollution were conducted by calculating the population-weighted exposure level and the inequality index, respectively. The spatial correlation of PM2.5 with cancer morbidity was investigated by spatial autocorrelation and grey correlation degree analysis. Overall, for the highest 1-h concentration, older people (age >= 60) and residents with tertiary education were the most disproportionately exposed to PM2.5. For the higher PM2.5 concentration during the annual average, spring, autumn and winter periods, exposures to PM2.5 were disproportionately high for children (age <= 4) and residents with primary or secondary education. Moreover, exposures to PM2.5 were disproportionately low for the illiterate due to their geographical distribution characteristics. Additionally, the spatial distribution of cancer morbidity was similar to the spatial pattern of PM2.5, manifesting a potential spatial association between PM2.5 and cancer morbidity. These findings provide scientific support for air pollution exposure assessments and environmental epidemiology. PMID- 29710601 TI - Association between purity of drug seizures and illicit drug loads measured in wastewater in a South East Queensland catchment over a six year period. AB - This study aimed to examine associations between the annual average purity of seized illicit drugs and their corresponding load measured in wastewater. Daily loads (averaging 81 samples/year) and purity of seized methamphetamine (average 287 samples/year), cocaine (50/year) and MDMA (70/year) were collected from a catchment that serviced approximately 220,000 persons in Queensland, Australia during 2010-2015. Using regression models for mass load and purity data, we found a strong linear increase in the mass load of methamphetamine detected across study years (363-1126 mg/1000 people/day, R2 = 0.89). Strong linear increases in methamphetamine purity were also apparent (19-69%), and were closely correlated with detected mass load (r > 0.9). When differences in purity were controlled for, the linear trend in mass load over time was no longer significant (p > 0.27). For cocaine and MDMA there were no statistically significant trends in either mass load or drug purity over the study period. Our study demonstrates that purity changes may have accounted for a substantial proportion of increases of methamphetamine load measured in wastewater of the studied catchment. Wherever possible, when examining temporal trends in drug loads, or when making comparisons between geographic regions, purity trends should also be examined, as this can aid appropriate interpretation of findings by stakeholders and policy makers. PMID- 29710602 TI - Contrasting responses of bacterial and fungal communities to aggregate-size fractions and long-term fertilizations in soils of northeastern China. AB - Soils, with non-uniform distribution of nutrients across different aggregate-size fractions, provide spatially heterogeneous microhabitats for microorganisms. However, very limited information is available on microbial distributions and their response to fertilizations across aggregate-size fractions in agricultural soils. Here, we examined the structures of bacterial and fungal communities across different aggregate-size fractions (2000-250 MUm, 250-53 MUm and <53 MUm) in response to 35-years organic and/or chemical fertilization regimes in the soil of northeastern China by phospholipid fatty acid (PLFA) and high throughput sequencing (HTS) technology. Our results show that larger fractions (>53 MUm), especially 250-53 MUm aggregates, which contain more soil C and N, are associated with greater microbial biomass and higher fungi/bacteria ratio. We firstly reported the fungal community composition in different aggregate-size fractions by HTS technology and found more Ascomycota but less Zygomycota in larger fractions with higher C content across all fertilization regimes. Fertilization and aggregate-size fractions significantly affect the compositions of bacterial and fungal communities although their effects are different. The bacterial community is mainly driven by fertilization, especially chemical fertilizers, and is closely related to the shifts of soil P (phosphorus). The fungal community is preferentially impacted by different aggregate-size fractions and is more associated with the changes of soil C and N. The distinct responses of microbial communities suggest different mechanisms controlling the assembly of soil bacterial and fungal communities at aggregate scale. The investigations of both bacterial and fungal communities could provide a better understanding on nutrient cycling across aggregate-size fractions. PMID- 29710603 TI - Assessing the sustainability of acid mine drainage (AMD) treatment in South Africa. AB - The environmental sustainability of acid mine drainage (AMD) treatment at semi industrial scale is examined by means of the life cycle assessment (LCA) methodology. An integrated process which includes magnesite, lime, soda ash and CO2 bubbling treatment was employed to effectively treat, at semi-industrial scale, AMD originating from a coal mine in South Africa. Economic aspects are also discussed. AMD is a growing problem of emerging concern that cause detrimental effects to the environment and living organisms, including humans, and impose on development, health, access to clean water, thus also affect economic growth and cause social instability. Therefore, sustainable and cost effective treatment methods are required. A life cycle cost analysis (LCCA) revealed the viability of the system, since the levelized cost of AMD treatment can be as low as R112.78/m3 (?7.60/m3 or $9.35/m3). Moreover, due to its versatility, the system can be used both at remote locales, at stand-alone mode (e.g. using solar energy), or can treat AMD at industrial scale, thus substantially improving community resilience at local and national level. In terms of environmental sustainability, 29.6 kg CO2eq are emitted per treated m3 AMD or its environmental footprint amount to 2.96 Pt/m3. South Africa's fossil fuel depended energy mix and liquid CO2 consumption were the main environmental hotspots. The total environmental footprint is reduced by 45% and 36% by using solar energy and gaseous CO2, respectively. Finally, AMD sludge valorisation, i.e. mineral recovery, can reduce the total environmental footprint by up to 12%. PMID- 29710605 TI - Concentration and factors affecting the distribution of phthalates in the air and dust: A global scenario. AB - Phthalates are ubiquitously present environmental contaminants. Air and dust are the most important mediums of exposure to phthalates. The present study reviews the presence of phthalates in the air and dust reported from different countries in the last ten years (2007-2017). The phthalate concentrations revealed wide heterogeneity with a mean and median value 6 +/- 19 MUg/m3 and 0.5 MUg/m3 respectively in the air and 1.5 * 103 +/- 2.2 * 103 MUg/g and 7.8x102MUg/g respectively in the dust. The highest phthalates levels in the air were reported from India (1.1 * 102 MUg/m3) and in dust from Bulgaria (1.2 * 104 MUg/g). Overall higher levels were reported from developing countries as compared to developed countries. Di (2-ethylhexyl) phthalate (DEHP) and Di-n-butyl phthalate (DBP) were found to be predominant in both air and dust. Temperature, humidity, air exchange rate, building material and indoor maintenance were reported as the important factors influencing the levels of phthalates in the air and dust. In addition to policy level interventions, reducing the use of phthalate containing materials and controlling the factors which enhance the emission from existing sources can help in reducing human exposure to phthalates. PMID- 29710604 TI - Inputs, source apportionment, and transboundary transport of pesticides and other polar organic contaminants along the lower Red River, Manitoba, Canada. AB - The Red River originates in the U.S., drains into Lake Winnipeg, and is a significant pathway for nutrients. We investigate its role as a source for pesticides, pharmaceuticals, per- and polyfluoroalkyl substances (PFASs), and microbes bearing antibiotic resistance genes (ARGs). We delineate agricultural, urban, and rural land-use for organic contaminants to determine the extent of chemical transboundary riverine fluxes, and characterize levels and trends of organic contaminants and ARGs between spring and fall 2014 and 2015. The herbicide atrazine peaked at over 500 ng/L (14-day time-weighted average) near the border, indicating that the U.S. represents the major source into Canada from the Red River. Neonicotinoid insecticides had relatively constant concentrations, suggesting more widespread agricultural use in both countries. Pesticide concentrations were greatest post-application in June and July. Mass loadings of pesticides over the sampling periods, from the river to Lake Winnipeg, ranged from approximately 800 kg of atrazine, to 120 kg of thiamethoxam and clothianidin, to 40 kg of imidacloprid. Exposure distributions for atrazine exceeded benchmark water quality guidelines for protection of aquatic life (0.2% probability of exceeding chronic benchmark) with no exceedances for neonicotinoids. Seven pharmaceuticals were detected, mostly at low ng/L levels downstream of the City of Winnipeg wastewater treatment plant. Carbamazepine, the only pharmaceutical detected consistently at all sites, contributed on average 20 kg each year into Lake Winnipeg. While minor inputs were observed all along the river, city inputs represented the greatest source of pharmaceuticals to the river. Both PFASs and ARGs were observed consistently and ubiquitously, indicative of an anthropogenically-influenced system with no indications of any single point-source signature. While transboundary flux from the U.S. was an important source of pesticides to the Red River, especially for atrazine, observed concentrations of all measured contaminants suggest that known aquatic toxicological risk is minimal. PMID- 29710606 TI - Suspect screening and target quantification of human pharmaceutical residues in the surface water of Wuhan, China, using UHPLC-Q-Orbitrap HRMS. AB - In this study we developed a systematic method for suspect screening and target quantification of the human pharmaceutical residues in water, via solid phase extraction (SPE) followed by liquid chromatography-high resolution mass spectrometry (LC-HRMS). We then proceeded to study the occurrences and distribution of the pharmaceuticals in the surface waters of Wuhan, China, by analyzing water samples from lakes, rivers and municipal sewage. Initially, 33 human pharmaceuticals were identified from East Lake without using purchasing standards. Of these, 29 were later confirmed by using standards, and quantified using the aforementioned SPE pretreatment method and LC-HRMS analysis in full MS scan mode. The 29 compounds included 8 antibiotics, 9 metabolites, and 12 miscellaneous pharmaceuticals. The highest proportions of pharmaceutical residues were detected downstream of the Yangtze River and in the lakes close to the central city. Metformin, cotinine, and trans-3-hydroxy cotinine, were frequently encountered in all the surface water samples. High concentrations (>120 ng/l) of caffeine, metformin, theobromine, and valsartan were detected in the surface water samples; the removal rates of these compounds in the municipal sewage treatment plant were also high. In contrast, although the concentrations of 4-AAA and metoprolol acid in the surface water were high, the removal rates of these residues in the sewage treatment plant were low. PMID- 29710607 TI - Tracing catchment fine sediment sources using the new SIFT (SedIment Fingerprinting Tool) open source software. AB - The mitigation of diffuse sediment pollution requires reliable provenance information so that measures can be targeted. Sediment source fingerprinting represents one approach for supporting these needs, but recent methodological developments have resulted in an increasing complexity of data processing methods rendering the approach less accessible to non-specialists. A comprehensive new software programme (SIFT; SedIment Fingerprinting Tool) has therefore been developed which guides the user through critical data analysis decisions and automates all calculations. Multiple source group configurations and composite fingerprints are identified and tested using multiple methods of uncertainty analysis. This aims to explore the sediment provenance information provided by the tracers more comprehensively than a single model, and allows for model configurations with high uncertainties to be rejected. This paper provides an overview of its application to an agricultural catchment in the UK to determine if the approach used can provide a reduction in uncertainty and increase in precision. Five source group classifications were used; three formed using a k means cluster analysis containing 2, 3 and 4 clusters, and two a-priori groups based upon catchment geology. Three different composite fingerprints were used for each classification and bi-plots, range tests, tracer variability ratios and virtual mixtures tested the reliability of each model configuration. Some model configurations performed poorly when apportioning the composition of virtual mixtures, and different model configurations could produce different sediment provenance results despite using composite fingerprints able to discriminate robustly between the source groups. Despite this uncertainty, dominant sediment sources were identified, and those in close proximity to each sediment sampling location were found to be of greatest importance. This new software, by integrating recent methodological developments in tracer data processing, guides users through key steps. Critically, by applying multiple model configurations and uncertainty assessment, it delivers more robust solutions for informing catchment management of the sediment problem than many previously used approaches. PMID- 29710608 TI - Multi-surface modeling of Ni(II) and Cd(II) partitioning in soils: Effects of salts and solid/liquid ratios. AB - Metal partitioning in soils is a key process controlling metal bioavailability and mobility and is greatly influenced by the solid/liquid ratio. However, metal partitioning is difficult to describe either by a simple partition coefficient or by isotherm adsorption equations. This study investigated the solubility of Ni(II) and Cd(II) in 19 soils as a function of three extraction reagents (water, 0.01 M NaNO3, and 0.01 M CaCl2), five solid/liquid ratios (5-400 g/L) and field condition extracted by Rhizon samplers. Thermodynamically based multi-surface models (MSMs) that included generic parameters were used to describe metal partitioning under the studied conditions. The results showed that Ni/Cd solubility depended on the soil type, extraction reagent, and solid/liquid ratio. Soil major background cations (especially Ca2+, Mg2+, Fe3+ and Al3+) had a significant effect on the model's prediction ability. The MSM was able to predict the extractable metal in 0.01 M CaCl2 in various soils at different solid/liquid ratios when soil background cations were included in the calculation; without the background cations, the model was able to predict metal partitioning only at solid/liquid ratios of <100 g/L. In addition, the model failed to predict water extracted and 0.01 M-NaNO3-extracted Ni/Cd if background cations were not included, but could reasonably do so if they were included. More importantly, after the background cations were included, MSMs relatively well predicted the Ni/Cd content in soil pore water under 80% field capacity conditions with water as the solution matrix. PMID- 29710609 TI - Investigation of an early season river flood pulse: Carbon cycling in a subtropical estuary. AB - The January 2016 Bonnet Carre Spillway (BCS) opening resulted in a large-scale Mississippi River (MR) flood discharge that qualitatively and quantitatively impacted the dissolved organic matter (DOM) cycling in the Lake Pontchartrain Estuary (LPE) located in Louisiana, USA. This early season flood event was a result of the delay of snow formation caused by warmer than normal watershed temperatures. During the diversion period and the subsequent weeks, the LPE water temperature remained lower than pre-flood water temperatures, suppressing carbon cycling. Following that period, the water temperature increased, leading to an increase in the rate of abiotic and biological carbon processing (i.e., mineralization, degradation, and consumption). There were multiple and abnormally high discharges into LPE from the northern tributaries, totaling 43% of the MR flood discharge. As a secondary DOM source, the northern tributaries discharge was qualitatively and quantitatively different from the discharge originating from the river or estuarine sources. The dominant DOM source was determined using satellite images in conjunction with UV-Vis, fluorescence EEMs, and PARAFAC indicators. Overall, the three sources (MR, northern tributaries, and LPE) characteristics were identified by UV-Vis, fluorescence EEMs, and PARAFAC parameters, namely: i) spectral slope (S275), serving as an indicator of lignin like compounds' molecular weights, with a trend of MR > northern tributaries > LPE; ii) biological index (BIX), indicating freshness of DOM, with a trend of LPE > MR > northern tributaries; and iii) Fluorophore T intensity, serving as an indicator of the amount of terrestrial-like sourced DOM, with a trend of northern tributaries > LPE > MR. It was possible to identify DOM sources and monitor DOM transformation in the water column, increasing our understanding of DOM, carbon, and nitrogen ecological processing. PMID- 29710610 TI - Biomass decaying and elemental release of aquatic macrophyte detritus in waterways of the Indian River Lagoon basin, South Florida, USA. AB - Decaying experiments of four major aquatic macrophyte detritus, namely cattail (Typha orientalis), water lettuce (Pistia stratiotes), hydrilla (Hydrilla verticillata) and maidencane (Panicum hemitomon), were conducted using the litterbag technique in the stormwater detention pond of South Florida, USA. Dry weight and chemical composition of remaining biomass were dynamically determined during the 185-day decay experiment. The results showed that decomposition rates (k), and the derived turnover (t50% and t95%) were species specific. The k values decreased in the order of hydrilla (0.0123 g day-1) > water lettuce (0.0082 g day 1) > maidencane (0.0049 g day-1) > cattail (0.0031 g day-1), whereas t50% and t95% varied in the reverse way. Biomass properties including concentrations of C, N, P, lignin, cellulose, hemicellulose, and the ratios of C/N, C/P, N/P and lignin/N affected decaying rate of the studied aquatic plants. The dry mass loss and concentrations of C, N, P, lead (Pb), chromium (Cr), copper (Cu), manganese (Mn), zinc (Zn), lignin, cellulose, hemicellulose and ratios C/N, C/P, N/P and Lignin/N of plant detritus were significantly affected by species, decaying time, and their interactions. However, the influence of species differences was greater than that of decaying time on those indexes. The estimated amounts (kg) of nutrients and metals released based on k values for the waterways of the IRL basin (water surface area 15.6 km2) were N 126.85 * 103, P 8.89 * 103, Zn 408.20, Pb 97.95, Cr 128.99, Mn 313.03, and Cu 82.40. Water lettuce contributed most, accounting for 52.13% N, 56.81% P, 74.95% Zn, 59.58% Pb, and 74.65% Mn, followed by hydrilla, cattail and maidencane. For Cr and Cu, cattail had the greatest contribution of 65.77% and 54.15%, respectively, followed by water lettuce, hydrilla and maidencane. PMID- 29710611 TI - Halogenated flame retardants in stranded sperm whales (Physeter macrocephalus) from the Mediterranean Sea. AB - In recent years, decline of marine mammals' populations and increased frequency of strandings have arised the interest on the role that pollution may have in these events. The present work aimed at quantifying levels of brominated flame retardants (BFRs) and dechloranes (DECs) in tissues of 3 adult females and one foetus of sperm whales stranded in the Southern Adriatic Sea coasts (Italy). Results proved the presence of different flame retardants (FRs) in tissues of sperm whales, including various polybrominated diphenyl ethers (PBDE) congeners (47, 99, 100, 154, entering the composition of PentaBDE mixture), hexabromocyclodecanes (HBCDs), Dec 602 and methoxylated polibrominated diphenyl ethers (MeO-BDEs). In blubber, a target tissue for contaminant accumulation, SigmaPBDEs reached values of 160, 158 and 183 ng/g lw, alpha-HBCD of 5.75 ng/g lw, Dec 602 of 1632 ng/g lw and MeO-BDEs of 563 ng/g lw. The availability of foetal tissues allowed evaluating the potential maternal transfer on many of these compounds, and to discuss the potential adverse effects on foetal health. To the best of our knowledge, obtained data are the first reporting placental transfer of FRs in sperm whales. PBDE levels detected in foetus suggested a potentially long-term exposure to BFRs, which could cause severe damages to the developing organism, likely at the cerebral, endocrine and immunologic levels. Dec 602, which was detected at the highest concentrations among all FRs considered, could potentially cause dysfunctional effects on the immune system of adult females. PMID- 29710612 TI - An estimate of human and natural contributions to changes in water resources in the upper reaches of the Minjiang River. AB - Climate change and human activities have changed the spatial-temporal distribution of water resources, especially in a fragile ecological area such as the upper reaches of the Minjiang River (UMR) basin, where they have had a more profound effect. The average of double-mass curve (DMC) and Distributed Time Variant Gain Hydrological Model (DTVGM) are applied to distinguish between the impacts of climate change and human activities on water resources in this paper. Results indicated that water resources decreased over nearly 50 years in the UMR. At the annual scale, contributions of human activities and climate change to changes in discharge were -77% and 23%, respectively. In general, human activities decreased the availability of water resources, whereas climate change increased the availability of water resources. However, the impacts of human activities and climate change on water resources availability were distinctly different on annual versus seasonal scales, and they showed more inconsistency in summer and autumn. The main causes of decreasing water resources are reservoir regulation, and water use increases due to population growth. The results of this study can provide support for water resource management and sustainable development in the UMR basin. PMID- 29710613 TI - Heavy metal(loid)s and organic contaminants in groundwater in the Pearl River Delta that has undergone three decades of urbanization and industrialization: Distributions, sources, and driving forces. AB - Urbanization and industrialization have increased groundwater resource demands, and may drive the change of heavy metal(loid)s and organic chemicals in groundwater in the Pearl River Delta (PRD), southern China. Thus, a comprehensive understanding of the distributions, sources, and driving forces of heavy metal(loid)s and organic chemicals in groundwater in the PRD is vital for water resource management in this region. In this study, eight heavy metal(loid)s and fifty-five organic chemicals in groundwater across the PRD were investigated. The results show that undrinkable groundwater related to heavy metal(loid)s was mainly due to high concentrations of Fe (19.3%) and As (6.8%). Eighteen organic contaminants were detected in groundwater in the PRD, where the most frequently detected organic contaminant was naphthalene, and its detection rate was 2.51%. In 5.3% of all groundwater samples, one or more organic contaminants were found. All detected organic contaminants, except ones without allowable limits, in groundwater were at concentrations below allowable limits of China. The mean concentrations of heavy metal(loid)s in granular aquifers were higher than those in fissured and karst aquifers, especially for Fe and As. Except Se, the mean concentrations of other heavy metal(loid)s and the frequency of detection of organic contaminants in groundwater in urbanized and peri-urban areas were higher than those in non-urbanized areas, especially for Hg, Co, and organic contaminants. Fe, As, and Se in groundwater mainly originated from the release of Fe/As/Se rich sediments. The former two were driven by reduction reactions, while the latter was driven by oxidation resulting from the infiltration of NO3-. In contrast, other five heavy metal(loid)s and organic contaminants in groundwater mainly originated from the anthropogenic sources, such as the infiltration of industrial sewage. It is evident that urbanization and industrialization are two powerful driving forces for heavy metal(loid)s and organic contaminants in groundwater in the PRD. PMID- 29710615 TI - Dual removal of phosphate and ammonium from high concentrations of aquaculture wastewaters using an efficient two-stage infiltration system. AB - Nitrogen (N) and phosphorus (P) pollution from aquaculture has increased dramatically in recent years, and it is urgent to develop a cost-effective method to clean these polluted waters. The objective of this study is to investigate N and P removal using a two-stage infiltration system based on NaCl modified clinoptilolite (NCLP) and thermally-treated calcium-rich attapulgite (TCAP). Results from a batch study indicated that the maximum ammonium sorption capacity of NCLPs was in the range of 6.64 to 7.27 mg. N/g and decreased slightly among the three particle sizes studied (0.2-0.5 mm, 0.5 mm-1.0 mm and 1-2 mm). A 150 day column experiment indicated that the two-stage infiltration system achieved an average removal efficiency of 99.4% N and 99.0% P, and a removal rate of 50.3 g N/m3/d and 8.83 g P/m3/d for an influent concentration of 50 mg N/L and 10 mg P/L with a hydraulic retention time (HRT) of 16 h. When the influent concentration increased to 100 mg N/L and 20 mg P/L, the average ammonium removal efficiency decreased to 65.3%, while the system can still keep a high average P removal efficiency of 97.9% for 72 days of the experiment. Longer HRT favored N and P removal efficiency, but short HRTs can oxygenate ammonium sorbed in the NCLP filter and thereby refresh its sorption capacity. The results also indicated that longer wet and dry cycles can enhance the N removal efficiency of the system, but had minor influence on P removal. The sorbed clays contained high N and P content and might have use as a slow-release fertilizer. The results of this study indicate that a reactive clay-based treatment system can be used for dual removal of N and P from aquaculture wastewaters, making possible the development of a sustainable aquaculture model. PMID- 29710614 TI - Organic UV filters exposure induces the production of inflammatory cytokines in human macrophages. AB - Organic ultraviolet (UV) filters, found in many personal care products, are considered emerging contaminants due to growing concerns about potential long term deleterious effects. We investigated the immunomodulatory effects of four commonly used organic UV filters (2-hydroxy-4-methoxybenzophenone, BP-3; 4 methylbenzylidene camphor, 4-MBC; 2-ethylhexyl 4-methoxycinnamate, EHMC; and butyl-methoxydibenzoylmethane, BDM) on human macrophages. Our results indicated that exposure to these four UV filters significantly increased the production of various inflammatory cytokines in macrophages, particular tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6). After exposure to the UV filters, a significant 1.1-1.5 fold increase were found in TNF-alpha and IL-6 mRNA expression. In addition, both the p38 MAPK and the NF-kappaB signaling pathways were enhanced 2 to 10 times in terms of phosphorylation after exposure to the UV filters, suggesting that these pathways are involved in the release of TNF-alpha and IL-6. Molecular docking analysis predicted that all four UV filter molecules would efficiently bind transforming growth factor beta-activated kinase 1 (TAK1), which is responsible for the activation of the p38 MAPK and NF-kappaB pathways. Our results therefore demonstrate that exposure to the four organic UV filters investigated may alter human immune system function. It provides new clue for the development of asthma or allergic diseases in terms of the environmental pollutants. PMID- 29710616 TI - Reduced fecundity and cellular changes in Acheta domesticus after multigenerational exposure to graphene oxide nanoparticles in food. AB - Despite the fact that the demand for graphene and its derivatives in commercial applications is still growing, many aspects of its toxicity and biocompatibility are still poorly understood. Graphene oxide, which is released into the environment (air, soil and water) as so-called nanowaste or nanopollution, is able to penetrate living organisms. It is highly probable that, due to its specific nature, it can migrate along food chains thereby causing negative consequences. Our previous studies reported that short-term exposure to graphene oxide may increase the antioxidative defense parameters, level of DNA damage, which results in numerous degenerative changes in the gut and gonads. The presented research focuses on reproductive dysfunction and cellular changes in Acheta domesticus after exposure to GO nanoparticles in food (concentrations of 20 and 200 MUg.g-1 of food) throughout their entire life cycle. The results showed that long-term exposure to GO caused a significant decrease in the reproductive capabilities of the animals. Moreover, the next generation of A. domesticus had a lower cell vitality compared to their parental generation. It is possible that graphene oxide can cause multigenerational harmful effects. PMID- 29710617 TI - Illicit drugs and pharmaceuticals in swimming pool waters. AB - The occurrence of illicit drugs (cocaine, opioids, amphetamines and cannabis derivatives), some of their metabolites and 48 pharmaceuticals, was investigated in pool and source waters in ten Italian indoor swimming pools. The samples were analyzed by highperformance liquid chromatography-tandem mass spectrometry (HPLC MS/MS), after solid phase extraction (SPE). Cocaine and its metabolites were found in nine swimming pools, at concentrations from 0.3 to 4.2 ng/L for cocaine, 1.1 to 48.7 ng/L for norcocaine, 0.7 to 21.4 ng/L for benzoylecgonine and 0.1 to 7.3 ng/L for norbenzoylecgonine. Opioids, amphetamines and cannabis derivatives were never detected. The most frequent pharmaceuticals were anti-inflammatory drugs: ibuprofen was found in all the pool waters, with a maximum 197 ng/L and ketoprofen was detected in 9/10 samples (maximum 127 ng/L). Among anticonvulsants, carbamazepine and its metabolite, 10,11-dihydro 10,11dihydroxycarbamazepine, were frequent in swimming pool water (8/10 samples) at concentrations up to 62 ng/L. The cardiovascular drug valsartan was also found frequently (8/10 samples), but at lower concentrations (up to 9 ng/L). Other pharmaceuticals were detected occasionally and at lower concentrations (atenolol, enalapril, paracetamol, hydroclorothiazide, irbesartan and dehydro-erythromycin). Carbamazepine, irbesartan and dehydroerythromycin were detected at very low levels (up to 5 ng/L) in only one of the four source water samples. A quantitative risk assessment showed that the health risk for humans to these substance in swimming pool waters was generally negligible, even for vulnerable subpopulations such as children and adolescents. PMID- 29710618 TI - An integrated cell absorption process and quantitative PCR assay for the detection of the infectious virus in water. AB - Here we developed an integrated cell absorption process and quantitative (reverse transcription) polymerase chain reaction (ICAP-q(RT)PCR) assay to detect infectious viruses, which based on the detection of the viral nucleic acid (RNA or DNA) in the early stage of viral attachment and entry towards cells. The results showed that the poliovirus or adenovirus whose concentration was as low as 0.2 TCID50/mL could be detected by ICAP-q(RT)PCR after 4 h incubation. The ICAP-q(RT)PCR exhibited much higher sensitivity than the plaque assay. In parallel, it took shorter time to detect the viruses towards field samples compared with the integrated cell culture (ICC)-qPCR, but could still get the consistent detecting results with ICC-qPCR. This method is verified by detecting four different kinds of viruses including poliovirus, adenovirus, rotavirus, and astrovirus, which existed in the actual water samples. Among all the 24 Jinhe river samples, 50% (12/24) of river water samples were positive for poliovirus when detected by ICAP-q(RT)PCR, which was in accordance with the results detected by ICC-qPCR. However, 21% (5/24) and 68% (18/24) of the samples were detected to be positive for poliovirus by the plaque counting and the direct qPCR method, respectively. Compared with ICAP-q(PT)PCR and ICC-qPCR, the detecting results of qPCR or plaque assay displayed a marked expansion or decline, respectively, which lead to the evident deviations in the accuracy. The results demonstrated that our developed ICAP-q(RT)PCR method could dramatically reduce the test duration and quite improve the sensitivity towards infectious viruses. Therefore, the ICAP q(RT)PCR method could be an effective and quantitative tool for detecting infectious viruses in water environments. PMID- 29710619 TI - Evolutionary history and functional traits determine the spatial pattern of multifaceted plant diversity in a typical temperate desert disturbed by an expressway. AB - Temperate desert is one of the globally important biomes with unique and valuable biodiversity, which might be threatened by environmental stresses and human disturbance associated with rapid development. However, few studies have documented the spatial distribution of the multifaceted plant diversity of the temperate desert and their relationships with external impacting factors. We sampled multifaceted plant species diversity including taxonomic diversity, functional diversity and phylogenetic diversity in the Alashan Desert along Beijing-Xinjiang Expressway (G6) in Northern China to identify the key factors and process which regulate the multifaceted plant diversity of the temperate desert. We found that the dynamics of species richness, functional richness, and phylogenetic richness along the elevational gradient corresponded to the unimodal model. Species phylogenetic development shifted from aggregation to divergence, while species functional traits were the opposite along the elevational gradient. The sites at an elevation around 1200-1400 m were the key habitats for the occurrence of high plant diversity including species richness, functional richness and phylogenetic richness. There were no significant differences (p > 0.05) in plant diversity at different distances from the road (500 m, 1000 m and 1500 m) and human disturbances (the distance from the nearest human settlements). Temperature, temperature variability, precipitation, precipitation variability, soil physical and chemistry properties showed no significant effects on plant diversity. It was concluded that evolutionary history and functional traits, not environmental or anthropogenic factors were the key determinants of the pattern of multifaceted plant diversity. PMID- 29710620 TI - Comparison of different types of landfill leachate treatments by employment of nontarget screening to identify residual refractory organics and principal component analysis. AB - Three different chemical oxidation processes were investigated in terms of their capability to degrade organic chemical components of real mature landfill leachate in combination with biological treatment run in a Sequencing Batch Biofilter Granular Reactor (SBBGR). H2O2, H2O2 + UV and O3 were integrated with SBBGR and respective effluents were analyzed and compared with the effluent obtained from biological SBBGR treatment alone. In agreement with their respective oxidative power, conventional bulk parameters (residual COD, TOC, Ntot, TSS) determined from the resulting effluents evidenced the following efficacy ranking for degradation: SBBGR/O3 > SBBGR/UV + H2O2 > SBBGR/H2O2 > SBBGR. A more detailed characterization of the organic compounds was subsequently carried out for the four treated streams. For this, effluents were first subjected to a sample preparation step, allowing for a classification in terms of acidic, basic, strongly acidic and strongly basic compounds, and finally to analysis by liquid chromatography/high resolution mass spectrometry (LC/HR-MS). This classification, combined with further data post-processing (non-target screening, Venn Diagram, tri-dimensional plot and Principal Component Analysis), evidenced that the SBBGR/H2O2 process is comparable to the pure biological oxidation. In contrast, SBBGR/O3 and SBBGR/UV + H2O2 not only resulted in a very different residual composition as compared to SBBGR and SBBGR/H2O2, but also differ significantly from each other. In fact, and despite of the SBBGR/O3 being the most efficient process, this treatment remained chemically more similar to SBBGR/H2O2 than to SBBGR/UV + H2O2. This finding may be attributable to different mechanism of degradation involved with the use of UV radiation. Apart from these treatment differences, a series of recalcitrant compounds was determined in all of the four treatments and partly identified as hetero-poly-aromatic species (humic acids-like species). PMID- 29710621 TI - Increased occurrence of heavy metals, antibiotics and resistance genes in surface soil after long-term application of manure. AB - The purpose of this study was to investigate the impact of long-term application of pig manure on the accumulation of heavy metals, antibiotics and ARGs in surface soil sampled from the Jiaxing long-term field experimental site with three manure treatments, N-PM (0 kg/ha/y, dw), L-PM (7720 kg/ha/y, dw), and H-PM (11,580 kg/ha/y, dw), in 2013 and 2014. The results showed that most serious metal pollution of Zn and Cu was recorded in all manured samples in both years, and their contents exceeded the soil quality standards. Among the three tetracyclines, chlortetracycline was the predominant antibiotic detected with a range of 3.04-98.03 MUg.kg-1 in 2013 and 28.67-344.74 MUg.kg-1 in 2014 after long term pig manure application. Q-PCR results showed that the average accumulation of ribosomal protection protein genes (tetM, tetO, tetQ and tetW) was lower than most of the efflux pump genes (tetA and tetG). The abundance of tet and sul genes of those sites with manure application was significantly higher than that of sites without manure application in both years. Metagenomics analysis of ARGs revealed that the abundance of multidrug resistance genes was the most abundant subtype, followed by fluoroquinolone, bacitracin, sulfonamide and tetracycline. There was a positive correlation between the levels of ARGs; soil organic matter, antibiotics, Cu, As, and Zn levels in both years. These results may shed light on the mechanism underlining the effects of long-term manure application on the occurrence and dissemination of ARGs in surface soil. PMID- 29710622 TI - Zoning method for environmental engineering geological patterns in underground coal mining areas. AB - Environmental engineering geological patterns (EEGPs) are used to express the trend and intensity of eco-geological environment caused by mining in underground coal mining areas, a complex process controlled by multiple factors. A new zoning method for EEGPs was developed based on the variable-weight theory (VWT), where the weights of factors vary with their value. The method was applied to the Yushenfu mining area, Shaanxi, China. First, the mechanism of the EEGPs caused by mining was elucidated, and four types of EEGPs were proposed. Subsequently, 13 key control factors were selected from mining conditions, lithosphere, hydrosphere, ecosphere, and climatic conditions; their thematic maps were constructed using ArcGIS software and remote-sensing technologies. Then, a stimulation-punishment variable-weight model derived from the partition of basic evaluation unit of study area, construction of partition state-variable-weight vector, and determination of variable-weight interval was built to calculate the variable weights of each factor. On this basis, a zoning mathematical model of EEGPs was established, and the zoning results were analyzed. For comparison, the traditional constant-weight theory (CWT) was also applied to divide the EEGPs. Finally, the zoning results obtained using VWT and CWT were compared. The verification of field investigation indicates that VWT is more accurate and reliable than CWT. The zoning results are consistent with the actual situations and the key of planning design for the rational development of coal resources and protection of eco-geological environment. PMID- 29710623 TI - Seasonal and spatial dynamics of enteric viruses in wastewater and in riverine and estuarine receiving waters. AB - Enteric viruses represent a global public health threat and are implicated in numerous foodborne and waterborne disease outbreaks. Nonetheless, relatively little is known of their fate and stability in the environment. In this study we used carefully validated methods to monitor enteric viruses, namely adenovirus (AdV), JC polyomavirus (JCV), noroviruses (NoVs), sapovirus (SaV) and hepatitis A and E viruses (HAV and HEV) from wastewater source to beaches and shellfish beds. Wastewater influent and effluent, surface water, sediment and shellfish samples were collected in the Conwy catchment (North Wales, UK) once a month for one year. High concentrations of AdV and JCV were found in the majority of samples, and no seasonal patterns were observed. No HAV and HEV were detected and no related illnesses were reported in the area during the period of sampling. Noroviruses and SaV were also detected at high concentrations in wastewater and surface water, and their presence correlated with local gastroenteritis outbreaks during the spring and autumn seasons. Noroviruses were also found in estuarine sediment and in shellfish harvested for human consumption. As PCR-based methods were used for quantification, viral infectivity and degradation was estimated using a NoV capsid integrity assay. The assay revealed low-levels of viral decay in wastewater effluent compared to influent, and more significant decay in environmental waters and sediment. Results suggest that AdV and JCV may be suitable markers for the assessment of the spatial distribution of wastewater contamination in the environment; and pathogenic viruses can be directly monitored during and after reported outbreaks to prevent further environment derived illnesses. PMID- 29710624 TI - Extreme drought decouples silicon and carbon geochemical linkages in lakes. AB - Silicon and carbon geochemical linkages were usually regulated by chemical weathering and organism activity, but had not been investigated under the drought condition, and the magnitude and extent of drought effects remain poorly understood. We collected a comprehensive data set from a total of 13 sampling sites covering the main water body of the largest freshwater lake system in Australia, the Lower Lakes. Changes to water quality during drought (April 2008 September 2010) and post-drought (October 2010-October 2013) were compared to reveal the effects of drought on dissolved silica (DSi) and bicarbonate (HCO3-) and other environmental factors, including sodium (Na+), pH, electrical conductivity (EC), chlorophyll a (Chl-a), total dissolved solids (TDS), dissolved inorganic nitrogen (DIN), total nitrogen (TN), total phosphorus (TP) and water levels. Among the key observations, concentrations of DSi and DIN were markedly lower in drought than in post-drought period while pH, EC and concentrations of HCO3-, Na+, Chl-a, TDS, TN, TP and the ratio TN:TP had inverse trends. Stoichiometric ratios of DSi:HCO3-, DSi:Na+ and HCO3-:Na+ were significantly lower in the drought period. DSi exhibited significantly negative relationships with HCO3-, and DSi:Na+ was strongly correlated with HCO3-:Na+ in both drought and post-drought periods. The backward stepwise regression analysis that could avoid multicollinearity suggested that DSi:HCO3- ratio in drought period had significant relationships with fewer variables when compared to the post-drought, and was better predictable using nutrient variables during post-drought. Our results highlight the drought effects on variations of water constituents and point to the decoupling of silicon and carbon geochemical linkages in the Lower Lakes under drought conditions. PMID- 29710625 TI - Trends in heterogeneous aqueous reaction in continuous haze episodes in suburban Shanghai: An in-depth case study. AB - Heterogeneous aqueous reaction plays important roles in the enhanced formation of secondary aerosols during haze. However, its occurrence in haze episodes remains poorly understood. In this study, the trends in heterogeneous aqueous reaction in continuous haze episodes were investigated by an in-depth case analysis. The highly time-resolved measurements of water-soluble inorganic ions of PM2.5 were conducted in a suburban of Shanghai, China, and continuous haze episodes, which occurred from Feb. 18 to Feb. 28, were selected as studied cases. Results showed that fine particle pollution in Baoshan was serious. High concentrations of secondary inorganic aerosol ions and the higher sulfur oxidation ratio (SOR) and nitrogen oxidation ratio (NOR) on haze days indicated enhanced conversions from SO2 and NOx to their corresponding particulate phases. The high-nitrate haze episode and the high-sulfate haze episode were identified. Further simulations revealed that the PM2.5 particles had strong acidity during the high-nitrate and high-sulfate haze episodes whether they were calculated by E-AIM 4 or by ISORROPIA II. It was found that particulate liquid water was more sensitive to nitrate than sulfate, and played significant roles in the heterogeneous aqueous reactions of NO2 and secondary nitrate formation during haze episodes, especially in the high-sulfate haze episode. Further analysis indicated that the high nitrate haze episode favoured the occurrence of heterogeneous aqueous phase oxidation of SO2, and the more water was in the particles, the more SO2 was converted to sulfate aerosols. This work provides an important field measurement based evidence for understanding the important contributions of the heterogeneous aqueous reactions to secondary aerosol pollution and the tendencies of heterogeneous aqueous reactions in the formation of secondary sulfate and nitrate aerosols in suburban Shanghai. PMID- 29710626 TI - Source identification of PM2.5 at a port and an adjacent urban site in a coastal city of China: Impact of ship emissions and port activities. AB - Daily PM2.5 samples were collected simultaneously at an urban site (UB) and a nearby port-industrial site (PI) on the coast of southeastern China from April 2015 to January 2016. The PM2.5 mass concentration at the PI (51.9MUgm-3) was significantly higher than that at the UB. The V concentration at the PI was also significantly higher and well-correlated to the urban value, which suggests that shipping emissions had a significant impact on the PI and, to a lesser extent, on the urban area. A positive matrix factorization (PMF) analysis showed that secondary aerosols were the dominant contribution of PM2.5 at both sites (36.4% at the PI and 27.2% at the UB), while the contribution of industry and ship emissions identified by V, Mn, and Ba at the PI (26.1%) were double those at the UB. The difference in each source contribution among the trajectory clusters that included significant differences and insignificant differences from the UB to the PI provided insight into the role of local impacts. With regards to the UB, local potential sources play important roles in industry and ship emissions, traffic emissions, fugitive dust, and in their contributions to secondary aerosols. A conditional probability function further revealed that the ship emissions and port activities distributed in the NE, E, and SSE wind sectors were responsible for the source contributions of industry and ship emissions and secondary aerosols at the UB. This study provides an example of investigating the impact of ship emissions and port activities on the surrounding air environment using land based measurements. PMID- 29710627 TI - Effects of species biological traits and environmental heterogeneity on simulated tree species distribution shifts under climate change. AB - Demographic processes (fecundity, dispersal, colonization, growth, and mortality) and their interactions with environmental changes are not well represented in current climate-distribution models (e.g., niche and biophysical process models) and constitute a large uncertainty in projections of future tree species distribution shifts. We investigate how species biological traits and environmental heterogeneity affect species distribution shifts. We used a species specific, spatially explicit forest dynamic model LANDIS PRO, which incorporates site-scale tree species demography and competition, landscape-scale dispersal and disturbances, and regional-scale abiotic controls, to simulate the distribution shifts of four representative tree species with distinct biological traits in the central hardwood forest region of United States. Our results suggested that biological traits (e.g., dispersal capacity, maturation age) were important for determining tree species distribution shifts. Environmental heterogeneity, on average, reduced shift rates by 8% compared to perfect environmental conditions. The average distribution shift rates ranged from 24 to 200myear-1 under climate change scenarios, implying that many tree species may not able to keep up with climate change because of limited dispersal capacity, long generation time, and environmental heterogeneity. We suggest that climate-distribution models should include species demographic processes (e.g., fecundity, dispersal, colonization), biological traits (e.g., dispersal capacity, maturation age), and environmental heterogeneity (e.g., habitat fragmentation) to improve future predictions of species distribution shifts in response to changing climates. PMID- 29710628 TI - Spatiotemporal land use random forest model for estimating metropolitan NO2 exposure in Japan. AB - Adequate spatial and temporal estimates of NO2 concentrations are essential for proper prenatal exposure assessment. Here, we develop a spatiotemporal land use random forest (LURF) model of the monthly mean NO2 over four years in a metropolitan area of Japan. The overall objective is to obtain accurate NO2 estimates for use in prenatal exposure assessments. We use random forests to convey the non-linear relationship between NO2 concentrations and predictor variables, and compare the prediction accuracy with that of a linear regression. In addition, we include the distance decay effect of emission sources on NO2 concentrations for more efficient model construction. The prediction accuracy of the LURF model is evaluated through a leave-one-monitor-out cross validation. We obtain a high R2 value of 0.79, which is better than that of the conventional land use regression model using linear regression (R2 of 0.73). We also evaluate the LURF model via a temporal and overall cross validation and obtain R2 values of 0.84 and 0.92, respectively. We successfully integrate temporal and spatial components into our model, which exhibits higher accuracy than spatial models constructed individually for each month. Our findings illustrate the advantage of using a LURF to model the spatiotemporal variability of NO2 concentrations. PMID- 29710629 TI - Speciation of phosphorus in plant- and manure-derived biochars and its dissolution under various aqueous conditions. AB - Phosphorus (P) in biochar serves as both a P source for plant growth and a contributor to water eutrophication, thus prioritizing the efficient management of P in biochar. This study employed solid- and solution- state 31P-nuclear magnetic resonance and X-ray diffraction analyses to explore the impact of feedstock and heating treatment temperature (HTT) on P species of biochars. The effects of ambient temperature, coexisting anions, pH and nutrient solution on P release were also investigated to study the effect of various environmental factors on P release from biochars. P species in both plant- and manure- derived biochars were dominated by inorganic orthophosphate and pyrophosphate (mainly calcium-bound-phosphates). The HTT of biochar showed a negative impact upon its pyrophosphate content. Compared with plant biochars, manure biochars contained higher P but had a lower release degree. Release of P from biochars was controlled by diffusion-dissolution process and was enhanced by higher ambient temperature, co-existing anions, and both acidic and alkaline conditions but inhibited by coexisting Hoagland nutrients. Anion-induced increase in P release was more significant for plant biochars than manure biochars. These findings help to adjust favorable environmental conditions for the full utilization of P in biochars. PMID- 29710630 TI - Choice of pyrolysis parameters for urban wastes affects soil enzymes and plant germination in a Mediterranean soil. AB - The production of organic waste has steadily increased in recent years, with subsequent impact on the environment. The European Union committed to diminish the volume of biodegradable municipal waste disposed of in landfills by 2016 2020. The synthesis of biochar from urban waste and its application to improve soil quality can constitute a novel route for valorization. The aim of this paper was to study the effect of three biochars originated from pyrolysis of the organic fraction of urban waste at two different temperatures (300 degrees C and 500 degrees C) and two residence times (1h and 5h) on the biochemical properties of an agricultural soil. Soil was amended with biochars at a rate of 8% and incubated for 74days. A phytotoxicity assay, using garden cress as the test species, was conducted. CO2 emissions, microbial biomass C and the enzymes dehydrogenase, phosphomonoesterase and beta-glucosidase were measured in tested soils. Biochars prepared at 300 degrees C resulted in lower germination index values, which could partly be ascribed to a higher bioavailability of heavy metals and higher soluble organic matter, while the biochar prepared as 500 degrees C exhibited a phytostimulant effect. Biochars produced at 300 degrees C (B300-1h, B300-5h) augmented soil CO2 emissions while there was no effect on microbial respiration in the soil amended with the biochar prepared at 500 degrees C. Pyrolysis temperature and, for some enzymes, residence time, controlled soil enzymatic activity. PMID- 29710631 TI - Dynamic assessments of population exposure to urban greenspace using multi-source big data. AB - A growing body of evidence has proven that urban greenspace is beneficial to improve people's physical and mental health. However, knowledge of population exposure to urban greenspace across different spatiotemporal scales remains unclear. Moreover, the majority of existing environmental assessments are unable to quantify how residents enjoy their ambient greenspace during their daily life. To deal with this challenge, we proposed a dynamic method to assess urban greenspace exposure with the integration of mobile-phone locating-request (MPL) data and high-spatial-resolution remote sensing images. This method was further applied to 30 major cities in China by assessing cities' dynamic greenspace exposure levels based on residents' surrounding areas with different buffer scales (0.5km, 1km, and 1.5km). Results showed that regarding residents' 0.5-km surrounding environment, Wenzhou and Hangzhou were found to be with the greenest exposure experience, whereas Zhengzhou and Tangshan were the least ones. The obvious diurnal and daily variations of population exposure to their surrounding greenspace were also identified to be highly correlated with the distribution pattern of urban greenspace and the dynamics of human mobility. Compared with two common measurements of urban greenspace (green coverage rate and green area per capita), the developed method integrated the dynamics of population distribution and geographic locations of urban greenspace into the exposure assessment, thereby presenting a more reasonable way to assess population exposure to urban greenspace. Additionally, this dynamic framework could hold potential utilities in supporting urban planning studies and environmental health studies and advancing our understanding of the magnitude of population exposure to greenspace at different spatiotemporal scales. PMID- 29710632 TI - Maxent modeling for predicting the potential geographical distribution of two peony species under climate change. AB - Paeonia (Paeoniaceae), an economically important plant genus, includes many popular ornamentals and medicinal plant species used in traditional Chinese medicine. Little is known about the properties of the habitat distribution and the important eco-environmental factors shaping the suitability. Based on high resolution environmental data for current and future climate scenarios, we modeled the present and future suitable habitat for P. delavayi and P. rockii by Maxent, evaluated the importance of environmental factors in shaping their distribution, and identified distribution shifts under climate change scenarios. The results showed that the moderate and high suitable areas for P. delavayi and P. rockii encompassed ca. 4.46*105km2 and 1.89*105km2, respectively. Temperature seasonality and isothermality were identified as the most critical factors shaping P. delavayi distribution, and UVB-4 and annual precipitation were identified as the most critical for shaping P. rockii distribution. Under the scenario with a low concentration of greenhouse gas emissions (RCP2.6), the range of both species increased as global warming intensified; however, under the scenario with higher concentrations of emissions (RCP8.5), the suitable habitat range of P. delavayi decreased while P. rockii increased. Overall, our prediction showed that a shift in distribution of suitable habitat to higher elevations would gradually become more significant. The information gained from this study should provide a useful reference for implementing long-term conservation and management strategies for these species. PMID- 29710633 TI - Endocrine disruptors in breeding ponds and reproductive health of toads in agricultural, urban and natural landscapes. AB - Many chemical pollutants have endocrine disrupting effects which can cause lifelong reproductive abnormalities in animals. Amphibians are the most threatened group of vertebrates, but there is little information on the nature and quantity of pollutants occurring in typical amphibian breeding habitats and on the reproductive capacities of amphibian populations inhabiting polluted areas. In this study we investigated the occurrence and concentrations of endocrine disrupting chemicals in the water and sediment of under-studied amphibian breeding habitats in natural, agricultural and urbanized landscapes. Also, we captured reproductively active common toads (Bufo bufo) from these habitats and let them spawn in a 'common garden' to assess among-population differences in reproductive capacity. Across 12 ponds, we detected 41 out of the 133 contaminants we screened for, with unusually high concentrations of glyphosate and carbamazepine. Levels of polycyclic aromatic hydrocarbons, nonylphenol and bisphenol-A increased with urban land use, whereas levels of organochlorine and triazine pesticides and sex hormones increased with agricultural land use. Toads from all habitats had high fecundity, fertilization rate and offspring viability, but the F1 generation originating from agricultural and urban ponds had reduced development rates and lower body mass both as larvae and as juveniles. Females with small clutch mass produced thicker jelly coat around their eggs if they originated from agricultural and urban ponds compared with natural ponds. These results suggest that the observed pollution levels did not compromise reproductive potential in toads, but individual fitness and population viability may be reduced in anthropogenically influenced habitats, perhaps due to transgenerational effects and/or costs of tolerance to chemical contaminants. PMID- 29710634 TI - A highly reusable MANAE-agarose-immobilized Pleurotus ostreatus laccase for degradation of bisphenol A. AB - Bisphenol A (BPA) is an endocrine disruptor compound that is continuously released into the environment and is barely degraded in wastewater treatment plants. A previous study showed that free Pleurotus ostreatus laccase is efficient in degrading BPA producing less toxic metabolites. In the present study, this laccase was successfully immobilized onto MANAE-agarose, improving its efficiency in degrading BPA and its thermal and storage stabilities. In addition to this, the immobilized enzyme retained >90% of its initial capability to degrade BPA after 15cycles of reuse. P. ostreatus laccase immobilized onto MANAE-agarose could be an economical alternative for large scale degradation of BPA in aqueous systems. PMID- 29710635 TI - Dual role of DOM in a scenario of global change on photosynthesis and structure of coastal phytoplankton from the South Atlantic Ocean. AB - We evaluated the dual role of DOM (i.e., as a source of inorganic nutrients and as an absorber of solar radiation) on a phytoplankton community of the western South Atlantic Ocean. Using a combination of microcosms and a cluster approach, we simulated the future conditions of some variables that are highly influenced by global change in the region. We increased nutrients (i.e., anthropogenic input) and dissolved organic matter (DOM), and we decreased the pH, to assess their combined impact on growth rates (MU), species composition/abundance and size structure, and photosynthesis (considering in this later also the effects of light quality i.e., with and without ultraviolet radiation). We simulated two Future conditions (Fut) where nutrients and pH were similarly manipulated, but in one the physical role of DOM (Futout) was assessed whereas in the other (Futin) the physico-chemical role was evaluated; these conditions were compared with a control (Present condition, Pres). The MU significantly increased in both Fut conditions as compared to the Pres, probably due to the nutrient addition and acidification in the former. The highest MU were observed in the Futout, due to the growth of nanoplanktonic flagellates and diatoms. Cells in the Futin were photosynthetically less efficient as compared to those of the Futout and Pres, but these physiological differences, also between samples with or without solar UVR observed at the beginning of the experiment, decreased with time hinting for an acclimation process. The knowledge of the relative importance of both roles of DOM is especially important for coastal areas that are expected to receive higher inputs and will be more acidified in the future. PMID- 29710636 TI - Spatial pattern of urban change in two Chinese megaregions: Contrasting responses to national policy and economic mode. AB - Spatial pattern of urban change reflects the urbanization process. Previously, studies on the change of city more focused on the large cities and neglected the urban megaregion growth processes that may include changes in smaller cities. In this study, we investigated the spatial pattern of urban change in the megaregion development process. In addition, we discussed the megaregion responses to the national policy and economic growth mode. We chose the Beijing-Tianjin-Hebei (BTH) and Yangtze River Delta (YRD) urban megaregions as our study areas and comparatively quantified the urban expansion and change based on developed land at both the regional and city scales during 1984-2010. We found: 1) both the BTH and YRD experienced rapid urbanization, the magnitudes, rates, and spatial patterns of urban expansion, however, were very different between the two megaregions. In BTH, the magnitudes and rates of urban expansion were greater in larger cities than in medium- and small-sized cities through the entire period of 1984-2010. In contrast, the magnitudes and rates of urban expansion in YRD were greater in some medium- and small-sized cities than in larger cities from 1984 to 2000, and became similar from 2000 to 2010. 2) The BTH consistently followed a double-nucleated expansion pattern, while the spatial pattern of the YRD changed from single nucleated pattern to multi- nucleated pattern. A further analysis showed that while national policies on urbanization have to some extent guided the urbanization development in the two megaregions, economic growth modes seemed to play a more important role in affecting the urban growth patterns. PMID- 29710637 TI - Anticoagulant rodenticide use, non-target impacts and regulation: A case study from Australia. AB - The impacts of anticoagulant rodenticides (ARs) on non-target wildlife have been well documented in Europe and North America. While these studies are informative, patterns of non-target poisoning of wildlife elsewhere in the world may differ substantially from patterns occurring in Australia and other countries outside of cool temperate regions due to differences in the types of ARs used, patterns of use, legislation governing sales, and potential pathways of secondary exposure. Most of these differences suggest that the extent and severity of AR poisoning in wildlife may be greater in Australia than elsewhere in the world. While many anecdotal accounts of rodenticide toxicity were found - especially in conjunction with government control efforts and island eradications - no published studies have directly tested rodenticide exposure in non-target Australian wildlife in a comprehensive manner. The effects of private and agricultural use of rodenticides on wildlife have not been adequately assessed. Synthesis of reviewed literature suggests that anticoagulant rodenticides may pose previously unrecognised threats to wildlife and indigenous people in Australia and other nations with diverse and abundant reptile faunas relative to countries with cooler climates where most rodenticide ecotoxicology studies have been conducted. To address the identified knowledge gaps we suggest additional research into the role of reptiles as potential AR vectors, potential novel routes of human exposure, and comprehensive monitoring of rodenticide exposure in Australian wildlife, especially threatened and endangered omnivores and carnivores. Additionally, we recommend regulatory action to harmonise Australian management of ARs with existing and developing global norms. PMID- 29710638 TI - Sustainable Forest Operations (SFO): A new paradigm in a changing world and climate. AB - The effective implementation of sustainable forest management depends largely on carrying out forest operations in a sustainable manner. Climate change, as well as the increasing demand for forest products, requires a re-thinking of forest operations in terms of sustainability. In this context, it is important to understand the major driving factors for the future development of forest operations that promote economic, environmental and social well-being. The main objective of this paper is to identify important issues concerning forest operations and to propose a new paradigm towards sustainability in a changing climate, work and environmental conditions. Previously developed concepts of forest operations are reviewed, and a newly developed concept - Sustainable Forest Operations (SFO), is presented. Five key performance areas to ensure the sustainability of forest operations include: (i) environment; (ii) ergonomics; (iii) economics; (iv) quality optimization of products and production; and (v) people and society. Practical field examples are presented to demonstrate how these five interconnected principles are relevant to achieving sustainability, namely profit and wood quality maximization, ecological benefits, climate change mitigation, carbon sequestration, and forest workers' health and safety. The new concept of SFO provides integrated perspectives and approaches to effectively address ongoing and foreseeable challenges the global forest communities face, while balancing forest operations performance across economic, environmental and social sustainability. In this new concept, we emphasize the role of wood as a renewable and environmentally friendly material, and forest workers' safety and utilization efficiency and waste management as additional key elements of sustainability. PMID- 29710639 TI - Physical legacy of freshwater bivalves: Effects of habitat complexity on the taxonomical and functional diversity of invertebrates. AB - Bivalves may play a major role in structuring aquatic communities. This may be especially relevant in aquatic communities dominated by non-native invasive bivalves, which can contribute to the increase of habitat homogenization. In this study, we assess how habitat homogenization, through the reduction of empty bivalve shells identities, influences the macroinvertebrate assemblages. Towards this end, a manipulative experiment with the empty shells of two native (Potomida littoralis and Unio delphinus) and one non-native (Corbicula fluminea) species was performed. Seven treatments were prepared, three of them consisting of homogeneous substrates using shells of one species, and four of them consisting in heterogeneous substrates using more than one species. The associated fauna colonizing different treatments was analyzed through taxonomic and trait-based approaches. Our results showed that the substrate complexity influenced the density of macroinvertebrates, with the heterogeneous treatments significantly yielding more dense assemblages. Also, the trait patterns differed among the levels of habitat heterogeneity, influencing mainly organisms that feed on microphytes of both small and big sizes, that inhabit areas with slow to moderate water flow, and that have short and long live cycles. Further, the functional diversity was not influenced by the substrate heterogeneity. Therefore, the habitat homogenization, through the accumulation of non-native C. fluminea empty shells in the river bottom, did not affect the functional diversity of the macroinvertebrate assemblages. PMID- 29710640 TI - How to bring absolute sustainability into decision-making: An industry case study using a Planetary Boundary-based methodology. AB - The Planetary Boundaries concept has emerged as a framework for articulating environmental limits, gaining traction as a basis for considering sustainability in business settings, government policy and international guidelines. There is emerging interest in using the Planetary Boundaries concept as part of life cycle assessment (LCA) for gauging absolute environmental sustainability. We tested the applicability of a novel Planetary Boundaries-based life cycle impact assessment methodology on a hypothetical laundry washing case study at the EU level. We express the impacts corresponding to the control variables of the individual Planetary Boundaries together with a measure of their respective uncertainties. We tested four sharing principles for assigning a share of the safe operating space (SoSOS) to laundry washing and assessed if the impacts were within the assigned SoSOS. The choice of sharing principle had the greatest influence on the outcome. We therefore highlight the need for more research on the development and choice of sharing principles. Although further work is required to operationalize Planetary Boundaries in LCA, this study shows the potential to relate impacts of human activities to environmental boundaries using LCA, offering company and policy decision-makers information needed to promote environmental sustainability. PMID- 29710641 TI - Co-optimization of sponge-core bioreactors for removing total nitrogen and antibiotic resistance genes from domestic wastewater. AB - Inadequate sanitation can lead to the spread of infectious diseases and antimicrobial resistance (AMR) via contaminated water. Unfortunately, wastewater treatment is not universal in many developing and emerging countries, especially in rural and peri-urban locations that are remote from central sewers. As such, small-scale, more sustainable treatment options are needed, such as aerobic Denitrifying Downflow Hanging Sponge (DDHS) bioreactors. In this study, DDHS reactors were assessed for such applications, and achieved over 79% and 84% removal of Chemical Oxygen Demand and Ammonium, respectively, and up to 71% removal of Total Nitrogen (TN) from domestic wastes. Elevated TN removals were achieved via bypassing a fraction of raw wastewater around the top layer of the DDHS system to promote denitrification. However, it was not known how this bypass impacts AMR gene (ARG) and mobile genetic element (MGE) levels in treated effluents. High-throughput qPCR was used to quantify ARG and MGE levels in DDHS bioreactors as a function of percent bypass (0, 10, 20 and 30% by volume). All systems obtained over 90% ARG reduction, although effluent ARG and TN levels differed among bypass regimes, with co-optimal reductions occurring at ~20% bypass. ARG removal paralleled bacterial removal rate, although effluent bacteria tended to have greater genetic plasticity based on higher apparent MGE levels per cell. Overall, TN removal increased and ARG removal decreased with increasing bypass, therefore co-optimization is needed in each DDHS application to achieve locally targeted TN and AMR effluent levels. PMID- 29710642 TI - Legacy of legacies: Chlorinated naphthalenes in Lake Trout, Walleye, Herring Gull eggs and sediments from the Laurentian Great Lakes indicate possible resuspension during contaminated sediment remediation. AB - Polychlorinated naphthalenes (PCNs) are legacy contaminants, produced primarily as flame retardants and dielectrics until phased-out in Europe and North America in the 1970s. Spatial and temporal trends (1979-2013) of PCN concentrations were studied in whole fish and herring gull eggs throughout the Great Lakes and St. Lawrence River, whereas sediments were analyzed for 2011-2013 only. For both fish and gull eggs, concentrations of PCNs were highest in western Lake Erie (7660 & 3020pg/gww respectively), and declined downstream to St. Lawrence River (range: 34-2370pg/gww). For sediments, concentrations were highest in suspended sediments from the Detroit River (264,000pg/g), and were lower in surficial sediments downstream to the St. Lawrence River (range=440-19,300pg/g). PCNs declined at all sites from ~1980 to 1995, but in Lake Erie concentrations of PCNs increased in gulls fish from 1995 until 2005. The resurgence in PCNs in biota corresponded to the timing of remedial dredging of sediment highly contaminated with PCNs in the Detroit River, whose effects appear to manifest themselves downstream to Lake Ontario. Congener profiles of PCNs differed between Lake Erie and Lake Ontario until post-dredging, where PCN profiles of fish in both lakes became increasingly more similar. PCNs in gull eggs were mostly hepta-PCNs, whereas fish had higher concentrations of lower chlorinated PCNs. Patterns of PCNs in gulls and fish appear to be influenced by differences in not only routes of exposure and differential metabolic ability, but also resuspension of PCN contaminated sediments. PMID- 29710643 TI - PM2.5 induces male reproductive toxicity via mitochondrial dysfunction, DNA damage and RIPK1 mediated apoptotic signaling pathway. AB - Recent years, air pollution has been a serious problem, and PM2.5 is the main air particulate pollutant. Studies have investigated that PM2.5 is a risky factor to the deterioration of semen quality in males. But, the related mechanism is still unclear. To explore the effect of PM2.5, Sprague Dawley (SD) rats were exposed to PM2.5 (0, 1.8, 5.4 and 16.2mg/kg.bw.) through intratracheal instillation. The exposure was performed once every 3days and continued for 30days. In vitro, GC 2spd cells were treated using 0, 50, 100, 200MUg/mL PM2.5 for 24h. The data showed that sperm relative motility rates and density were remarkably decreased, while sperm malformation rates were significantly increased with exposure to the PM2.5. The expression of Fas/FasL/RIPK1/FADD/Caspase-8/Caspase-3 and the level of 8-OHdG expression in testes were significantly increased after exposure to PM2.5. Additionally, in vitro the results showed that PM2.5 inhibited cell viability, increased the release of lactate dehydrogenase (LDH) by increasing reactive oxygen species (ROS) level. And ROS induced-DNA damage led to cell cycle arrest at G0/G1 phases and proliferation inhibition. Similar to the vivo study, the expressions of Fas/FasL/RIPK1/FADD/Caspase-8/Caspase-3 in GC-2spd cells were significantly increased after exposure to PM2.5 for 24-h. In addition, PM2.5 decreased the levels of ATP by impairing mitochondria structures, which led to energy metabolism obstruction resulted in the decrease of sperm motility. The above three aspects together resulted in the decrease in sperm quantity and quality. PMID- 29710644 TI - Spatial heterogeneity of estuarine wetland ecosystem health influenced by complex natural and anthropogenic factors. AB - The evaluation of estuarine wetland ecosystem health (EWEH) is vital and difficult due to complex influencing factors and their spatial heterogeneities. An EWEH evaluation model was established in this study on the basis of the typical features of estuarine wetland ecosystems with focus on spatial heterogeneity. The index system comprises external factors, internal factors, and ecological state, and covers all aspects of the natural and anthropogenic factors, with each index possessing its own spatial heterogeneity. The Yellow River Delta, a typical estuarine wetland in China, was selected as the study area to demonstrate the model. Results indicated that the present EWEH in the entire study area was in good status with distinct spatial heterogeneity. Ecosystem productivity, seawater intrusion, human interference, and Yellow River input were the most relevant indexes of EWEH. The temporal variations of EWEH fluctuated from 1987 to 2016. The decrease in the Yellow River input and the increase in human activity intensity deteriorated EWEH, whereas the alongshore embankment and nature reserve construction improved EWEH in certain parts. The influence of natural factors continuously decreased, and human activity became the main driving factor of the EWEH spatial variation. Our model was proven to possess comprehensive reflections of estuarine wetland ecological characteristics, full exhibitions of spatial heterogeneity, and high applicability; therefore, it can be widely used to evaluate EWEH in different areas. PMID- 29710645 TI - Do we have to choose between feeding the human population and conserving nature? Modelling the global dependence of people on ecosystem services. AB - The ability of the human population to continue growing depends strongly on the ecosystem services provided by nature. Nature, however, is becoming more and more degraded as the number of individuals increases, which could potentially threaten the future well-being of the human population. We use a dynamic model to conceptualise links between the global proportion of natural habitats and human demography, through four categories of ecosystem services (provisioning, regulating, cultural recreational and informational) to investigate the common future of nature and humanity in terms of size and well-being. Our model shows that there is generally a trade-off between the quality of life and human population size and identifies four short-term scenarios, corresponding to three long-term steady states of the model. First, human population could experience declines if nature becomes too degraded and regulating services diminish; second the majority of the population could be in a famine state, where the population continues to grow with minimal food provision. Between these scenarios, a desirable future scenario emerges from the model. It occurs if humans convert enough land to feed all the population, while maintaining biodiversity and ecosystem services. Finally, we find a fourth scenario, which combines famine and a decline in the population because of an overexploitation of land leading to a decrease in food production. Human demography is embedded in natural dynamics; the two factors should be considered together if we are to identify a desirable future for both nature and humans. PMID- 29710646 TI - Review of brown carbon aerosols: Recent progress and perspectives. AB - Brown carbon (BrC), a carbonaceous aerosol which absorbs solar radiation over a broad range of wavelengths, is beginning to be seen as an important contributor to global warming. BrC absorbs both inorganic and organic pollutants, leading to serious effects on human health. We review the fundamental features of BrC, including its sources, chemical composition, optical properties and radiative forcing effects. We detail the importance of including photochemical processes related to BrC in the GEOS-Chem transport model for the estimation of aerosol radiative forcing. Calculation methods for BrC emission factors are examined, including the problems and limitations of current measurement methods. We provide some insight into existing publications and recommend areas for future research, such as further investigations into the reaction mechanisms of the aging of secondary BrC, calculations of the emission factors for BrC from different sources, the absorption of large and long-lived BrC molecules and the construction of an enhanced model for the simulation of radiative forcing. This review will improve our understanding of the climatic and environmental effects of BrC. PMID- 29710648 TI - Evaluation of the current contamination status of PFASs and OPFRs in South Korean tap water associated with its origin. AB - We investigated the concentrations of perfluoroalkyl substances (PFASs) and organophosphate flame retardants (OPFRs) in 44 tap water samples, collected from eight major cities in South Korea served by four representative watersheds, to evaluate the water contamination status. The total concentrations of PFASs and OPFRs ranged from 1.44 to 224ng/L (median=11.9ng/L), and 74.0 to 342ng/L (median=151ng/L), respectively. The predominant compounds in tap water were perfluorohexane sulfonate (PFHxS), perfluoropentanoic acid (PFPeA), perfluorohexanoic acid (PFHxA), perfluorooctanoic acid (PFOA), tris(2 chloroethyl) phosphate (TCEP), tris(chloroisopropyl) phosphate (TCIPP), and tris(2-butoxyethyl) phosphate (TBOEP). Tap water originating from the Nakdong River within an industrial complex showed a notably higher PFHxS proportion to total PFASs. In addition, significantly higher PFAS levels were found in river originating tap water than in lake/reservoir-originating tap water (Mann-Whitney U test, p<0.05). Meanwhile, major OPFRs showed no clear difference in distribution by region, and no significant difference in major OPFR levels was observed according to tap water origin. Finally, the average human exposure via tap water consumption was estimated for PFASs (46.8ng/person/day) and OPFRs (254ng/person/day). PMID- 29710647 TI - Impact of two centuries of intensive agriculture on soil carbon, nitrogen and phosphorus cycling in the UK. AB - This paper describes an agricultural model (Roth-CNP) that estimates carbon (C), nitrogen (N) and phosphorus (P) pools, pool changes, their balance and the nutrient fluxes exported from arable and grassland systems in the UK during 1800 2010. The Roth-CNP model was developed as part of an Integrated Model (IM) to simulate C, N and P cycling for the whole of UK, by loosely coupling terrestrial, hydrological and hydro-chemical models. The model was calibrated and tested using long term experiment (LTE) data from Broadbalk (1843) and Park Grass (1856) at Rothamsted. We estimated C, N and P balance and their fluxes exported from arable and grassland systems on a 5km*5km grid across the whole of UK by using the area of arable of crops and livestock numbers in each grid and their management. The model estimated crop and grass yields, soil organic carbon (SOC) stocks and nutrient fluxes in the form of NH4-N, NO3-N and PO4-P. The simulated crop yields were compared to that reported by national agricultural statistics for the historical to the current period. Overall, arable land in the UK have lost SOC by -0.18, -0.25 and -0.08MgCha-1y-1 whereas land under improved grassland SOC stock has increased by 0.20, 0.47 and 0.24MgCha-1y-1 during 1800-1950, 1950-1970 and 1970-2010 simulated in this study. Simulated N loss (by leaching, runoff, soil erosion and denitrification) increased both under arable (-15, -18 and -53kgNha 1y-1) and grass (-18, -22 and -36kgNha-1y-1) during different time periods. Simulated P surplus increased from 2.6, 10.8 and 18.1kgPha-1y-1 under arable and 2.8, 11.3 and 3.6kgPha-1y-1 under grass lands 1800-1950, 1950-1970 and 1970-2010. PMID- 29710649 TI - Culture- and molecular-based detection of swine-adapted Salmonella shed by avian scavengers. AB - Salmonella can play an important role as a disease agent in wildlife, which can then act as carriers and reservoirs of sanitary importance at the livestock-human interface. Transmission from livestock to avian scavengers can occur when these species consume contaminated carcasses and meat remains in supplementary feeding stations and rubbish dumps. We compared the performance of PCR-based detection with conventional culture-based methods to detect Salmonella in the faeces of red kites (Milvus milvus) and griffon vultures (Gyps fulvus) in central Spain. The occurrence of culturable Salmonella was intermediate in red kites (1.9%, n=52) and high in griffon vultures (26.3%, n=99). These proportions were clearly higher with PCR-based detection (13.5% and 40.4%, respectively). Confirmation cultures failed to grow Salmonella in all faecal samples positive by the molecular assay but negative by the initial conventional culture in both scavenger species, indicating the occurrence of false (non-culturable) positives by PCR-based detection. This suggests that the molecular assay is highly sensitive to detecting viable Salmonella in cultures, but also partial genomes and dead or unviable bacteria from past infections or contamination. Thus, the actual occurrence of Salmonella in a particular sampling time period can be underestimated when using only culture detection. The serovars found in the scavenger faeces were among the most frequently isolated in pigs from Spain and other EU countries, especially those generally recognized as swine-adapted monophasic variants of S. Typhimurium. Because the studied species obtain much of their food from pig carcasses, this livestock may be the primary source of Salmonella via direct ingestion of infected carcasses and indirectly via contamination due to the unsanitary conditions found in supplementary feeding stations established for scavenger conservation. Combining culture- and molecular based detection is encouraged to understand the epidemiology and impact of Salmonella in wildlife populations. PMID- 29710650 TI - Characterizing variable biogeochemical changes during the treatment of produced oilfield waste. AB - At the forefront of the discussions about climate change and energy independence has been the process of hydraulic fracturing, which utilizes large amounts of water, proppants, and chemical additives to stimulate sequestered hydrocarbons from impermeable subsurface strata. This process also produces large amounts of heterogeneous flowback and formation waters, the subsurface disposal of which has most recently been linked to the induction of anthropogenic earthquakes. As such, the management of these waste streams has provided a newfound impetus to explore recycling alternatives to reduce the reliance on subsurface disposal and fresh water resources. However, the biogeochemical characteristics of produced oilfield waste render its recycling and reutilization for production well stimulation a substantial challenge. Here we present a comprehensive analysis of produced waste from the Eagle Ford shale region before, during, and after treatment through adjustable separation, flocculation, and disinfection technologies. The collection of bulk measurements revealed significant reductions in suspended and dissolved constituents that could otherwise preclude untreated produced water from being utilized for production well stimulation. Additionally, a significant step-wise reduction in pertinent scaling and well-fouling elements was observed, in conjunction with notable fluctuations in the microbiomes of highly variable produced waters. Collectively, these data provide insight into the efficacies of available water treatment modalities within the shale energy sector, which is currently challenged with improving the environmental stewardship of produced water management. PMID- 29710651 TI - Considerations of nano-QSAR/QSPR models for nanopesticide risk assessment within the European legislative framework. AB - The European market for pesticides is currently legislated through the well developed Regulation (EC) No. 1107/2009. This regulation promotes the competitiveness of European agriculture, recognizing the necessity of safe pesticides for human and animal health and the environment to protect crops against pests, diseases and weeds. In this sense, nanotechnology can provide a tremendous opportunity to achieve a more rational use of pesticides. However, the lack of information regarding nanopesticides and their fate and behavior in the environment and their effects on human and animal health is inhibiting rapid nanopesticide incorporation into European Union agriculture. This review analyzes the recent state of knowledge on nanopesticide risk assessment, highlighting the challenges that need to be overcame to accelerate the arrival of these new tools for plant protection to European agricultural professionals. Novel nano Quantitative Structure-Activity/Structure-Property Relationship (nano-QSAR/QSPR) tools for risk assessment are analyzed, including modeling methods and validation procedures towards the potential of these computational instruments to meet the current requirements for authorization of nanoformulations. Future trends on these issues, of pressing importance within the context of the current European pesticide legislative framework, are also discussed. Standard protocols to make high-quality and well-described datasets for the series of related but differently sized nanoparticles/nanopesticides are required. PMID- 29710652 TI - Hydroelectric production from Brazil's Sao Francisco River could cease due to climate change and inter-annual variability. AB - By the end of this century higher temperatures and significantly reduced rainfall are projected for the Brazilian North and Northeast (NE) regions due to Global Warming. This study examines the impact of these long-term rainfall changes on the Brazilian Northeast's hydroelectric production. Various studies that use different IPCC models are examined in order to determine the average rainfall reduction by the year 2100 in comparison to baseline data from the end of the 20th century. It was found that average annual rainfall in the NE region could decrease by approximately 25-50% depending on the emissions scenario. Analysis of historical rainfall data in the Sao Francisco basin during the last 57years already shows a decline of more than 25% from the 1961-90 long-term average. Moreover, average annual rainfall in the basin has been below its long-term average every year bar one since 1992. If this declining trend continues, rainfall reduction in the basin could be even more severe than the most pessimistic model projections. That is, the marked drop in average rainfall projected for 2100, based on the IPCC high emissions scenario, could actually eventuate before 2050. Due to the elasticity factor between rainfall and streamflow and because of increased amounts of irrigation in the Sao Francisco basin, the reduction in the NE's average hydroelectric production in the coming decades could be double the predicted decline in rainfall. Conversely, it is estimated that wind power potential in the Brazilian NE will increase substantially by 2100. Therefore both wind and solar power will need to be significantly exploited in order for the NE region to sustainably replace lost hydroelectric production. PMID- 29710653 TI - Quantifying suspended solids in small rivers using satellite data. AB - The management of suspended solids and associated contaminants in rivers requires knowledge of sediment sources. In-situ sampling can only describe the integrated impact of the upstream sources. Empirical models that use surface reflectance from satellite images to estimate total suspended solid (TSS) concentrations can be used to supplement measurements and provide spatially continuous maps. However, there are few examples, especially in narrow, shallow and hydrologically dynamic rivers found in mountainous areas. A case study of the Didipio catchment in Philippines was used to address these issues. Four 5-m resolution RapidEye images, from between the years 2014 and 2016, and near-simultaneous ground measurements of TSS concentrations were used to develop a power law model that approximates the relationship between TSS and reflectance for each of four spectral bands. A second dataset using two 2-m resolution Pleiades-1A and a third using a 6-m resolution SPOT-6 image along with ground-based measurements, were consistent with the model when using the red band data. Using that model, encompassing data from all three datasets, gave an R2 value of 65% and a root mean square error of 519mgL-1. A linear relationship between reflectance and TSS exists from 1mgL-1 to approximately 500mgL-1. In contrast, for TSS measurements between 500mgL-1 and 3580mgL-1 reflectance increases at a generally lower and more variable rate. The results were not sensitive to changing the pixel location within the vicinity of the ground sampling location. The model was used to generate a continuous map of TSS concentration within the catchment. Further ground-based measurements including TSS concentrations that are higher than 3580mgL-1 would allow the model to be developed and applied more confidently over the full relevant range of TSS. PMID- 29710654 TI - Elevated mercury in blood and feathers of breeding marsh birds along the contaminated lower Penobscot River, Maine, USA. AB - Mercury (Hg) concentrations in the blood and feathers of five species of migratory marsh birds, Nelson's sparrow (Ammodramus nelson subvirgatus), song sparrow (Melospiiza melodia), swamp sparrow (Melospiza geogiana), red-winged blackbird (Agelaius phoeniceus), and Virginia rail (Rallus limicola), breeding in marshes along the lower Penobscot River, Maine, far exceeded reference concentrations, exceeded concentrations associated with reproductive health, and are the highest Hg concentrations reported to date for several species. Blood Hg concentrations in adult Nelson's sparrows were greatest in 2007, at 6.6MUg/gww (geometric mean) and in 2012, at 6.5MUg/gww and greatest in red-winged blackbirds in 2012, 8.0MUg/gww. Mercury in blood increased with residence time on the contaminated marshes at an estimated rate of 0.04 to 0.07MUg/gww per day. Feather mercury concentrations in specific primary, secondary and tail feathers (P1, S2, R6) were strongly associated with exposure location at the time of feather formation. Geometric mean Hg concentrations in primary feathers (P1) reached 39.6MUg/gfw in 2010 in Nelson's sparrows. The paper documents the dynamic nature of Hg concentrations in avian blood and feathers, an important consideration in contaminant study design, and the increased risk to marsh birds posed by Hg deposition from upstream sources. PMID- 29710655 TI - Demographics of the zooxanthellate coral Oculina patagonica along the Mediterranean Iberian coast in relation to environmental parameters. AB - Marine ecosystems are threatened by cumulative human-related impacts that cause structural and functional alterations. In the Mediterranean Sea, the zooxanthellate coral Oculina patagonica (Scleractinia, Oculinidae) can turn algal forests into coral-dominated ecosystems and provides a case study for examining how zooxanthellate corals can affect the structure of algal-dominated shallow water rocky ecosystems in temperate areas. Our goal was to provide a quantitative baseline assessment of O. patagonica demographics along ~1300km of the Mediterranean Iberian coast and relate them to environmental parameters. The highest coral success was in the South Balearic Sea zone, where the populations exhibited >6-fold higher mean living coral cover, lower partial colony mortality and colony size distributions indicating that the populations in this zone were growing faster than those in the peripheral south-west (North Alboran Sea) and north-east (Mid and North Balearic Sea, and West Gulf of Lyons) zones. The coral demographics (i.e., density, cover, and skewness and kurtosis coefficients of colony size distributions) were positively correlated with each other and the annual mean seawater temperature (ST), 10th-ST percentile (P10th-ST), 90th-ST percentile (P90th-ST) and photosynthetically active radiation at 3-m depth (PAR 3m), but they were negatively correlated with chlorophyll-a. Based on these results, we identified the following thresholds that may constrain the growth of O. patagonica colonies and populations: annual mean ST <19-20 degrees C, P10th-ST <14 degrees C, P90th-ST <25 degrees C and >27 degrees C, and PAR-3m <30molphotonsm-2day-1. The species abundance along the Iberian coast conforms to the abundant-center pattern of distribution. However, the coral demographics indicated that this pattern was not only related to the time of establishment but also to differences in coral population growth, which were correlated with key environmental parameters. Our results contribute understanding of the forces driving population growth of O. patagonica and support the hypothesis of an ongoing coral-mediated tropicalization of macroalgae-dominated temperate ecosystems. PMID- 29710656 TI - Analysis of environmental communication and its implication for sustainable development in Ethiopia. AB - BACKGROUND: Environmental issues have been causing debates around the globe. These issues have also got much attention in Ethiopia. Ethiopia has been adversely affected by the environmental crisis. Developing countries and the poor were depicted as unfortunate victims of climate change. The causes of climate change include deforestation, industries, mismanagement of the environment, and utilization of natural resources. One of the effects of climate change brought natural disaster what we call a drought. Drought affected many people, even recently, in Ethiopia. Concerning the environmental problems and issues in Ethiopia, there are beginnings at the policy level. However, the practical aspects of communicating and addressing these issues could not get much attention from the authority. OBJECTIVE: The aim of the research is to analyze environmental communication of Amhara National Regional State-Environmental Protection Authority. METHOD: Case study as a qualitative research method is used. The case design type is descriptive. The researcher selected two techniques of collecting data: in-depth interview and documents. RESULTS: The results show that the authority is unable to communicate environmental issues which were stated in the different conventions and policies. CONCLUSION: There are gaps that could be considered from the outcome of the research. The major gaps and challenges in addressing practical issues of environment are identified namely poor environmental information systems, lack of awareness creation through communications, and weak public dialogue and genuine participation consideration. PMID- 29710657 TI - Biogeochemistry of natural ponds in agricultural landscape: Lessons learned from modeling a kettle hole in Northeast Germany. AB - Kettle holes, small shallow ponds of glacial origin, represent hotspots for biodiversity and biogeochemical cycling. They abound in the young moraine landscape of Northeast Germany, potentially modulating element fluxes in a region where intensive agriculture prevails. The Rittgarten kettle hole, with semi permanent hydroperiod and a surrounding reed belt, can be considered as a representative case study for such systems. Aiming to provide insights into the biogeochemical processes driving nutrient and primary producer dynamics in the Rittgarten kettle hole, we developed a mechanistic model that simulates the carbon, nitrogen, phosphorus and oxygen, phytoplankton, and free-floating macrophyte biomass dynamics. After model calibration and sensitivity analysis, our modeling exercise quantified the simulated nutrient fluxes associated with all the major biogeochemical processes considered by the model. Seasonality of nutrient concentrations, magnitude of primary productivity rates, and biogeochemical process characterization in the pond were reasonably reproduced by the model from July 2013 to July 2014. Our results suggest that the establishment of a phytoplankton community well-adapted to low light availability, together with the differential use of N and P from free-floating macrophytes and phytoplankton can explain their coexistence in kettle holes. Sediment nutrient release along with decomposition of decaying submerged macrophyte are essential drivers of internal nutrient cycling in kettle holes. Our results also suggest that the Rittgarten kettle hole act as a net source of CO2 to the atmosphere on an annual scale, which offers a testable hypothesis for kettle holes with structural and functional similarities. We conclude by discussing the need to shed light on the effects of water level fluctuations on nutrient dynamics and biological succession patterns, as well as the relative importance of external sources and internal nutrient recycling mechanisms. PMID- 29710658 TI - Guava leaf inhibits hepatic gluconeogenesis and increases glycogen synthesis via AMPK/ACC signaling pathways in streptozotocin-induced diabetic rats. AB - Psidium guajava (PG) is a short shrub or tree cultivated in tropical and subtropical regions around the world. The leaf extract of PG (guava leaf) has been used historically to cure many ailments. However, mechanisms of action of guava leaf in treating diabetes are not fully understood. Effects and underlying mechanisms of guava leaf on gluconeogenesis and glycogenesis in hepatocytes, insulin signaling proteins, liver function markers, and lipid profile in streptozotocin (STZ) injected diabetic Wistar rats were investigated within the current study. PG was given orally at the dose of 100, 200, and 400 mg/kg b.w to diabetic rats for the period of 45 days. The results reveal that oral administration of PG (200 mg/kg b.w) has considerably raised the levels of insulin, glycogen, hexokinase, glucose-6-phosphatase dehydrogenase and significant (p < 0.05) belittled hepatic markers, gluconeogenic enzymes, and OGTT fasting blood glucose levels. OGTT has shown least statistical significance between the group 5 (200 mg/kg b.w) and group 6 and vital difference between group 5 and group 4 (400 mg/kg). PG has attenuated the triglycerides, total cholesterol, phospholipids, free fatty acid, and LDL levels and raised HDL levels. PG considerably (p < 0.05) activated IRS-1, IRS-2, Akt, p-Akt, PI3K, GLUT2, AMPK, p-AMPK, and p-ACC, which are the key effector molecules of the PI3K/Akt pathway in STZ rats. The results of our study specify that treatment with PG ameliorated glucose-metabolism and lipid profile in STZ evoked diabetic rats; the rationale ought to be the activation of PI3K/Akt, phosphorylation of AMPK pathway in liver and therefore has beneficial anti-diabetic activity. PMID- 29710659 TI - The promising future of nano-antioxidant therapy against environmental pollutants induced-toxicities. AB - Developmental toxicity caused by exposure to a mixture of environmental pollutants has become a major health concern. Human-made chemicals, including xenoestrogens, pesticides, heavy metals, polycyclic aromatic hydrocarbons (PAHs) are major factors that increase formation of Reactive Oxygen Species (ROS) and adversely influence endogen antioxidant defense. Humans have evolved complex antioxidants systems that protect cells from prooxidant conditions. Deficiency of any these components can cause destruction in the overall antioxidant status of an individual. Antioxidants agents can be endogenous or obtained exogenously, as a part of a diet or through dietary supplements. Although oxidative damage contributes to many pathologies the use of naturally occurring, small-molecule exogenous antioxidants as therapies for these disorders has not been successful. An ideal exogenous antioxidant should be readily absorbed, enough delivered to intracellular location required to decrease pathological oxidative damage, positively affecting gene expression. To develop effective antioxidant therapies the best strategy may be to create new nanoscale drug delivery systems. This review highlights the role of environmental induced oxidative stress factors and novel nanoparticle design techniques of antioxidants. PMID- 29710660 TI - Acute intraperitoneal administration of taurine decreases the glycemia and reduces food intake in type 1 diabetic rats. AB - Taurine, an amino acid with antioxidant and osmoregulatory properties, has been studied for its possible antidiabetic properties in type 1 and type 2 diabetic animals. In type 2 diabetic mice, taurine decreases blood glucose through increased insulin secretion and insulin receptor sensitization. However, insulin is absent in type 1 diabetic individuals. The aim of this study was to evaluate the effects of taurine on parameters related to the energy balance that could explain the metabolic action of this amino acid in type 1 diabetic rats. Control and streptozotocin-induced diabetic rats received saline or taurine (100 mg/kg/day), intraperitoneally, for 30 days. Parameters such as palatable food intake, gastrointestinal transit rate, serum glucose, insulin, leptin, and glucagon levels were measured 60 min after the last taurine administration. Liver, kidneys, heart, and retroperitoneal fat were dissected and weighted. Glycogen levels were measured in the liver and soleus muscle. Our results showed that acute taurine administration decreased glycemia. It also decreased food intake in diabetic rats, without affecting other metabolic parameters. Altogether, our results suggest that in type 1 diabetic rats, taurine decreases blood glucose by a non-insulin-dependent mechanism. Due to the safety profile of taurine, and its effect on glycemia, this amino acid may help to design new drugs to add benefit to insulin therapy in type 1 diabetic individuals. PMID- 29710661 TI - Grifolic acid causes osteosarcoma cell death in vitro and in tumor-bearing mice. AB - Grifolic acid is a natural compound isolated from the fungus Albatrellus confluens. In the present study, we assessed the effects of grifolic acid on human osteosarcoma cells. We found that grifolic acid dose- and time-dependently induced cell death in the U-2 OS, MG-63, Saos-2, and 143B human osteosarcoma cell lines. Grifolic acid decreased osteosarcoma cell mitochondrial membrane potential, ATP production, and cellular NADH levels, but did not impact mitochondrial membrane potential in isolated mitochondria from human osteosarcoma cells. Intratumoral injection of grifolic acid also promoted tumor cell death and prolonged survival in nude mice bearing human osteosarcoma xenografts. Grifolic acid had no obvious toxicity in mice, with no histological changes in liver, kidney, lung, or heart, and no changes in blood cell counts or levels of plasma total protein, alanine aminotransferase, or aspartate aminotransferase. These results show that grifolic acid induces osteosarcoma cell death by inhibiting NADH generation and ATP production without obvious toxicity. Intratumoral injection of grifolic acid may be a promising anti-osteosarcoma therapeutic option in patients. PMID- 29710662 TI - Antinociceptive effectiveness of Tithonia tubaeformis in a vincristine model of chemotherapy-induced painful neuropathy in mice. AB - BACKGROUND: Chemotherapy induced peripheral neuropathy (CIPN) is a painful side effect of commonly used chemotherapeutic agents that profoundly impair the quality of life of patients as the current pharmacotherapeutic strategies are inefficient in providing adequate pain relief. Complementary and alternative medicine (CAM) therapies are preferred by patients with neuropathic pain as they experience insufficient control of pain with conventional medications. This study describes the antinociceptive effect of Tithonia tubaeformis (Jacq.) Cass. in a vincristine mouse model of established CIPN. METHODS: Tithonia tubaeformis hydromethanolic extract was tested for preliminary qualitative phytochemical analysis and acute oral toxicity test in mice. The antinociceptive effect was investigated using the abdominal constriction (writhing) and tail immersion tests (25-200 mg/kg). The anti-neuropathic effect was determined in the vincristine mouse model, established by daily administration of vincristine (0.1 mg/kg/day, i.p) for consecutive 14 days. Acute treatment with Tithonia tubaeformis (100 and 200 mg/kg) and the positive control, gabapentin (75 mg/kg) was carried out on the 15th day of the last vincrsitine dose and the animals were tested for allodynia and thermal hyperalgesia at 30-120 min post extract/drug administration. RESULTS: Vincristine produced significant temporal tactile allodynia and thermal hyperalgesia (P < 0.01 and P < 0.001 on day 7 and 14) and was maintained for the subsequent day (P < 0.001 during 30-120 min). Tithonia tubaeformis was effective in attenuating the vincristine-induced allodynia and thermal hyperalgesia at 100 mg/kg (P < 0.05, P < 0.01) and 200 mg/kg (P < 0.01, P < 0.001). Similarly, gabapentin also showed a robust antinociceptive effect in counteracting the vincristine associated behavioral alterations. CONCLUSIONS: Tithonia tubaeformis can be an effective CAM therapeutic remedy for established CIPN due to its potential antinociceptive effect in attenuating vincristine-induced neuropathy. PMID- 29710663 TI - Effect of Zuoguiwan on osteoporosis in ovariectomized rats through RANKL/OPG pathway mediated by beta2AR. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The deficiency of kidney Yin is the main pathogenesis of postmenopausal osteoporosis (PMOP) according to traditional Chinese medicine (TCM). Zuoguiwan (ZGW) is among the classical prescriptions in TCM and has been applied to various diseases that are due to deficiency of kidney Yin, including osteoporosis, fractures, menopausal syndromes. However, the underlying mechanism of ZGW in treating PMOP remains poorly understood. AIM OF THE STUDY: ZGW, a traditional Chinese prescription, has been used to nourish Yin and reinforce the kidney since ancient times. The investigation aimed to explore the mechanism of ZGW via the receptor activator of nuclear factor kappa-B ligand (RANKL)/osteoprotegerin (OPG) signaling pathway as mediated by the beta2 adrenergic receptor (beta2AR) in an osteoporosis rat model. MATERIALS AND METHODS: An osteoporosis model induced by ovariectomy was established in rats. A total of 40 female Sprague-Dawley rats were randomly assigned into bilateral ovariectomy group (OVX), sham operated group (Sham), 17beta-estradiol-treated positive group (E2, 25 MUg/kg/d), ZGW low-dose group (ZGW-L, 2.3 g/kg/d lyophilized powder) and ZGW high-dose group (ZGW-H, 4.6 g/kg/d lyophilized powder). The serum markers of bone turnover were measured using enzyme-linked immunosorbent assay (ELISA). The morphological structure changes in bones were detected through H&E staining. Local bone mineral density (BMD) and trabecular bone microarchitecture of the right distal femur were measured and evaluated by using micro-CT. Furthermore, the mRNA and protein expressions levels of beta2AR, OPG and RANKL were measured by qPCR and Western blot analysis. RESULTS: Compared with the OVX group, ZGW groups showed significantly reduced levels of serum tartrate-resistant acid phosphatase 5b (TRACP-5b) and beta-cross-linked c telopeptide of type I collagen (beta-CTX) (P < 0.01), increased levels of serum bone-specific alkaline phosphatase (BALP) (P < 0.01) and OPG (P < 0.05), prevention of OVX-induced bone loss, and improved microarchitecture of the trabecular bone of distal femur. Moreover, ZGW mediated the osteoporosis syndrome by reducing the empty bone lacunae, promoting the ordered arrangement of trabeculae structure, and increasing the trabeculae structure thickness. Furthermore, in ZGW groups, the protein expression of OPG in the tibia was notably up-regulated (P < 0.01), whereas the mRNA and protein expression of beta2AR in the hippocampus (P < 0.01), and the protein expressions levels of beta2AR (P < 0.01) and RANKL (P < 0.05) in the tibia were down-regulated compared with OVX group. CONCLUSIONS: ZGW through its protective effects, stimulates bone formation and suppresses bone resorption. The underlying mechanism of ZGW in improving perimenopausal syndrome and increasing bone mass might be attributed to the regulation of RANKL/OPG, as mediated by beta2AR. Therefore, ZGW may be used as an alternative treatment for PMOP. PMID- 29710664 TI - MicroRNA-340 inhibits the growth and invasion of angiosarcoma cells by targeting SIRT7. AB - MicroRNAs (miRNAs) are emerging as critical regulators for the development and progression of various cancers, including angiosarcoma. Accumulating evidence suggests that miRNA-340 (miR-340) is an important cancer-associated miRNA. However, little is known about the role of miR-340 in angiosarcoma. In this study, we aimed to investigate the potential biological functions of miR-340 and its potential target gene in angiosarcoma. Our results showed that miR-340 expression was significantly decreased in angiosarcoma compared with normal controls. The overexpression of miR-340 inhibited the growth and invasion of angiosarcoma cells, while the inhibition of miR-340 showed the opposite effect. Bioinformatics analysis predicted that Sirtuin 7 (SIRT7) was a potential target gene of miR-340. The binding relationship between miR-340 and the SIRT7 3' untranslated region was verified by dual-luciferase reporter assay. Moreover, our results showed that miR-340 negatively regulated SIRT7 expression in angiosarcoma cells and an inverse correlation between miR-340 and SIRT7 expression was shown in clinical angiosarcoma tissues. We found that silencing SIRT7 significantly inhibited the proliferation and invasion of angiosarcoma cells. Notably, the overexpression of SIRT7 promoted the proliferation and invasion of angiosarcoma cells and also partially reversed the antitumor effect of miR-340 on angiosarcoma cell proliferation and invasion. Taken together, our results demonstrate that miR 340 inhibits the growth and invasion of angiosarcoma cells by targeting SIRT7. Our study provides evidence that the miR-340/SIRT7 axis may play an important role in the molecular pathogenesis of angiosarcoma and suggests that miR-340 and SIRT7 may be used as potential and novel therapeutic targets for the treatment of angiosarcoma. PMID- 29710665 TI - In vitro anti-leukemia activity of dual PI3K/mTOR inhibitor Voxtalisib on HL60 and K562 cells, as well as their multidrug resistance counterparts HL60/ADR and K562/A02 cells. AB - Current treatment strategies for leukemia still have some limitations such as severe side effects and drug resistance. Less toxic and more effective drugs for leukemia patients are therefore expected. In the present study, the efficacy of a dual PI3K/mTOR inhibitor, Voxtalisib, on acute myeloid leukemia (AML) cell line HL60 and chronic myeloid leukemia (CML) cell line K562, as well as their Adriamycin (ADR)-selected multi drug resistance (MDR) counterparts HL60/ADR and K562/A02, was investigated. Voxtalisib exhibited potent anti-proliferative activity on these four cell lines dose-dependently, with IC50 values as 2.23 MUM for HL60, 4.79 MUM for HL60/ADR, 4.20 MUM for K562 and 3.90 MUM for K562/A02 cells. Voxtalisib arrested cell cycle progression at G1 phase in all cell lines by upregulating p27, downregulating cyclin D1 and p-pRb. When combined with ADR, Voxtalisib reversed the ADR-resistance of HL60/ADR and K562/A02 cells, possibly by reducing MDR1 and MRP1 expression. In conclusion, Voxtalisib showed anti leukemia activity on AML and CML cell lines as well as their multidrug resistant ones, suggesting Voxtalisib might become a promising drug candidate for therapy of AML and CML in the future. PMID- 29710666 TI - Cytotoxic, analgesic and anti-inflammatory properties of Syzygium calophyllifolium bark. AB - The present study explores the effect of Syzygium calophyllifolium bark methanol (SCBM) extract on pain and inflammation as cancer associated symptoms. The anti proliferative and cell death-inducing ability of the extract was analysed using MCF-7 breast cancer cells. ATP and LDH levels, along with the cell morphology were noted. The anti-proliferative ability of the extract was examined in relation to pain and inflammation. Analgesic activity was determined using a hot plate, acetic acid and formalin-induced pain models in mice. Acute anti inflammatory activity was observed in carrageenan and egg albumin induced paw oedema in Wistar rats. Chronic inflammation was induced by placing a cotton pellet under the skin at the axial region of rats. Reduced ATP and increased LDH content indicated the cytotoxic effect of the extract. SCBM at 200 mg/kg dose depicted good activity in acetic acid (77.69%) and formalin (80.81%) induced pain models compared to the standard drug indomethacin. However, only a moderate activity was observed in the hot plate method (53.85%). The higher dose of SCBM was equally effective in anti-inflammatory models. The dose (200 mg/kg) significantly reduced the paw oedema in carrageenan (96.71%) and egg albumin models (54.24%) compared to the control. The chronic inflammation was also inhibited upto 70.46% by SCBM. These activities can be attributed to the phenolic compounds detected in HPLC. The outcome of the study states that the extract can reduce both acute and chronic inflammatory conditions and kill the cancer cells, proposing the dual role of SCBM in treating inflammatory pains in cancer. The result of these studies indicated that wild plants like Syzygium calophyllifolium could be taken forward for a detailed study to accomplish the demand for a better treatment against diseases. PMID- 29710667 TI - beta-Caryophyllene (BCP) ameliorates MPP+ induced cytotoxicity. AB - Parkinson's disease (PD) is one of the most common neurodegenerative diseases resulting from the continuous death of dopaminergic neurons in substantia nigra. MPP+ (1-methyl-4-phenylpyridinium) has been reported to be a major neurotoxin causing neurotoxic insults on dopaminergic neurons in humans. beta-Caryophyllene (BCP), an important cannabinoid derived from the essential oils of different species, has displayed pharmacological properties in different kinds of tissues and cells. However, neuroprotective effects of BCP in PD haven't been reported before. Our results indicate that treatment with MPP+ in SH-SY5Y cells led to a significant decrease in cell viability, which was restored by BCP. Additionally, BCP suppressed MPP+-induced release of lactic dehydrogenase (LDH) and the generation of reactive oxygen species (ROS). In contrast, BCP treatment restored the reduction in mitochondrial membrane potential (MMP) induced by MPP+. BCP treatment increased intracellular GSH and GPx activity. Also, we found that the antioxidant effects of BCP against MPP+- induced neurotoxicity are dependent on cannabinoid receptor type 2 (CB2R). Moreover, our results indicated that BCP prevented MPP+-induced apoptosis of SH-SY5Y through inhibiting the up-regulation of cleaved Caspase-3, Bax, and restoring the expression of Bcl-2. Besides, BCP markedly suppressed HO-1 activation and c-Jun N-terminal Kinase (JNK) phosphorylation. We conclude that BCP might act as a promising therapeutic agent against MPP+ toxicity in neuronal cells. PMID- 29710668 TI - Meta-analysis of no-tillage effect on wheat and maize water use efficiency in China. AB - No-tillage (NT) is a popular agricultural technique worldwide, but it remains unclear how NT affects the yield, evapotranspiration (ET), and water use efficiency (WUE) of maize and wheat. We performed a meta-analysis of the NT effects on the yield, ET and WUE for wheat and maize based on the literatures published during 1950-2018. Yield, ET, and WUE varied by species, region, and agronomic and environmental factors. Averaged across all the geographic locations NT had no effect on the yield, ET, or WUE of wheat in northwestern and northern China, and no effect on the yield or ET of maize, but significantly increased the maize WUE by 5.9%. NT increased the WUE and yield of wheat in regions with <=400 mm of mean annual precipitation, increased the yield in regions with 400-600 mm of precipitation, and decreased the yield and ET in regions with >=600 mm, but had no effects on maize. In the first 1-3 years of NT implementation, the wheat ET was reduced. However, a significant decrease in maize yield and ET occurred in 3-6 years of NT implementation. Meanwhile, yield and WUE in both wheat and maize were improved after >6 years. In general, NT effect on yield, ET, or WUE was not related to soil texture. However, NT increased maize WUE in a medium soil texture. Without crop rotation, NT increased wheat yield and ET but decreased maize yield. No NT effects were observed when crop residues retained and under crop rotation. Consequently, optimizing NT effects on yield, ET and WUE for wheat and maize in China was largely dependent on environmental conditions and management practices. PMID- 29710670 TI - Comprehensive method for the analysis of multi-class organic micropollutants in indoor dust. AB - In the last decades, there has been an increasing concern about the human exposure to indoor dust because it has been observed that its contact or ingestion represents an important exposure source to several contaminants. The principal aim of this study was to evaluate the presence of multi pollutants in indoor dust. Therefore, an efficient multi-residue analytical method based on gas chromatography-electron ionisation-tandem mass spectrometry (GC-EI-MS/MS) was developed for the quantitative determination of 59 pollutants in house dust. The studied compounds belong to different families which have been reported as dangerous due to their possible effects for human health (endocrine disruption, neurotoxicity, mucosa-irritating effects, etc.). They are plasticisers, pesticides, flame retardants or polycyclic aromatic hydrocarbons, and reflect compounds used in construction materials, domestic goods or coming from outdoor air accumulation in indoor environments. The optimised methodology was simple, reliable and sensitive and was tested to evaluate the presence of contaminants in house dust samples collected in the area of Barcelona (Spain). Among all compounds studied, 54 contaminants were detected, being phthalates the group of compounds encountered at the highest concentrations, followed by organophosphorus flame retardants and bisphenol A. PMID- 29710669 TI - Reducing marine eutrophication may require a paradigmatic change. AB - Marine eutrophication in the North-East Atlantic (NEA) strongly relies on nutrient enrichment at the river outlets, which is linked to human activities and land use in the watersheds. The question is whether human society can reduce its nutrient emissions by changing land use without compromising food security. A new version of Riverstrahler model (pyNuts-Riverstrahler) was designed to estimate the point and diffuse nutrient emissions (N, P, Si) to the rivers depending on land use in the watersheds across a large domain (Western Europe agro-food systems, waste water treatment). The loads from the river model have been used as inputs to three marine ecological models (PCOMS, ECO-MARS3D, MIRO&CO) covering together a large part of the NEA from the Iberian shelf to the Southern North Sea. The modelling of the land-ocean continuum allowed quantifying the impact of changes in land use on marine eutrophication. Pristine conditions were tested to scale the current eutrophication with respect to a "natural background" (sensu WFD), i.e. forested watersheds without any anthropogenic impact. Three scenarios representing potential management options were also tested to propose future perspectives in mitigating eutrophication. This study shows that a significant decrease in nitrogen fluxes from land to sea is possible by adapting human activities in the watersheds, preventing part of the eutrophication symptoms in the NEA rivers and adjacent coastal zones. It is also shown that any significant achievement in that direction would very likely require paradigmatic changes at social, economic and agricultural levels. This requires reshaping the connections between crop production and livestock farming, and between agriculture and local human food consumption. It also involves cultural changes such as less waste production and a shift towards lower-impact and healthier diets where half of the animal products consumption is replaced by vegetal proteins consumption, known as a demitarian diet (http://www.nine-esf.org/node/281/index.html). PMID- 29710671 TI - Characterizing fluvial heavy metal pollutions under different rainfall conditions: Implication for aquatic environment protection. AB - Globally, fluvial heavy metal (HM) pollution has recently become an increasingly severe problem. However, few studies have investigated the variational characteristics of fluvial HMs after rain over long periods (>=1 year). The Dakan River in Xili Reservoir watershed (China) was selected as a case study to investigate pollution levels, influencing factors, and sources of HMs under different rainfall conditions during 2015 and 2016. Fluvial HMs showed evident spatiotemporal variations attributable to the coupled effects of pollution generation and rainfall diffusion. Fluvial HM concentrations were significantly associated with rainfall characteristics (e.g., rainfall intensity, rainfall amount, and antecedent dry period) and river flow, which influenced the generation and the transmission of fluvial HMs in various ways. Moreover, this interrelationship depended considerably on the HM type and particle size distribution. Mn, Pb, Cr, and Ni were major contributors to high values of the comprehensive pollution index; therefore, they should be afforded special attention. Additionally, quantitative source apportionment of fluvial HMs was conducted by combining principal component analysis with multiple linear regression and chemical mass balance models to obtain comprehensive source profiles. Finally, an environment-friendly control strategy coupling "source elimination" and "transport barriers" was proposed for aquatic environment protection. PMID- 29710672 TI - Quantitative microbial risk assessment of Greywater on-site reuse. AB - Recycle domestic greywater for on-site non-potable uses can lessen the demand on potable water and the burden on wastewater treatment plants. However, lack of studies to assess health risk associated with such practices has hindered their popularity. A Quantitative Microbial Risk Assessment was conducted to estimate the public health risks for two greywater reuse scenarios: toilet flushing and food-crop irrigation. Household greywater quality from three sources (bathroom, laundry and kitchen) was analyzed. Mathematical exposure rates of different scenarios were established based on human behavior using Monte-Carlo simulation. The results showed that, greywater from all three household sources could be safely used for toilet flushing after a simple treatment of microfiltration. The median range of annual infection risk was 8.8 * 10-15-8.3 * 10-11 per-person-per year (pppy); and the median range of disease burden was 7.6 * 10-19-7.3 * 10-15 disability-adjusted life years (DALYs) pppy. In food-crop irrigation scenario, the annual infection risks and disease burdens of treated greywater from bathroom and laundry (2.8 * 10-8, 4.9 * 10-8 pppy; 2.3 * 10-12-4.2 * 10-12 DALYs pppy) were within the acceptable levels of U.S. EPA annual infection risk (<=10-4 pppy) and WHO disease burden (<=10-6 DALYs pppy) benchmarks, while kitchen greywater was not suitable for food-crop irrigation (4.9 * 10-6 pppy; 4.3 * 10-10 DALYs pppy) based on these benchmarks. The model uncertainties were discussed, which suggests that a more accurate risk estimation requires improvements on data collection and model refinement. PMID- 29710673 TI - Biotic and abiotic dissipation of tetracyclines using simulated sunlight and in the dark. AB - Veterinary antibiotics reaching soils and water bodies are considered emerging pollutants deserving special attention. In this work, dissipation of tetracycline (TC), oxytetracycline (OTC) and chlortetracycline (CTC) is investigated. Dissipation experiments in filtered water, using simulated sunlight, resulted in the following degradation sequence: TC < OTC ~ CTC, with half-life values of 229, 101 and 104 min, respectively; however, no dissipation took place in the dark. Dissipation of the three tetracyclines in culture medium and with simulated sunlight was much higher, giving the sequence TC ~ OTC < CTC, with half-lives of 9, 10 and 7 min, respectively; in the dark, TC and OTC did not suffer dissipation, but it was around 28% for CTC at the end of the experiment (480 min). The variable explaining a higher dissipation in culture medium and with light was pH, as this parameter caused changes in the distribution of species of tetracyclines, affecting degradation. Adding bacterial suspensions extracted from soil and poultry manure increased dissipation, giving the sequence: TC ~ OTC < CTC, which is attributed to the presence of humic acids, which adsorb these antibiotics. These results could facilitate understanding the fate of antibiotics reaching environmental compartments and causing public health hazards. PMID- 29710674 TI - Norcantharidin modulates the miR-30a/Metadherin/AKT signaling axis to suppress proliferation and metastasis of stromal tumor cells in giant cell tumor of bone. AB - Giant cell tumor of bone (GCTB) is a benign but locally aggressive tumor, which can cause significant bone destruction at the epiphysis of long bones. Recent studies have demonstrated that norcantharidin (NCTD) can inhibit the proliferation and migration of various human cancer cells, but the role of NCTD in GCTB has not previously been evaluated. The aim of this study was to explore the nature of the anti-cancer effects of NCTD in GCTB and to elucidate the biomolecular mechanisms responsible for these effects. Primary stromal cell cultures, representing the main neoplastic component of GCTB, were used for cell based experiments. Firstly, the anti-cancer effects of NCTD on GCTB stromal tumor cells were investigated by CCK-8 assay, flow cytometry and transwell invasion assay. Next, microRNA (miRNA) microarray and quantitative reverse transcription PCR (qRT-PCR) analyses were performed to examine and verify altered expression of miRNAs associated with NCTD treatment. Subsequently, the GCTB stromal cells were transfected with miR-30a inhibitor to confirm its involvement in the observed anti-cancer effects of NCTD. Luciferase reporter assays were carried out to identify the target gene of miR-30a. Moreover, changes in the expression of protein markers of AKT signaling were measured by Western Blot analysis. The results demonstrated that NCTD treatment could inhibit cell proliferation, block the cell cycle process and induce cell apoptosis in GCTB stromal cells. An inhibitory effect of NCTD on GCTB stromal cell invasion through inhibition of epithelial mesenchymal transition (EMT) was also observed. Expression of miR-30a was significantly upregulated by NCTD treatment and miR-30a knockdown significantly reversed the anti-tumor effects of NCTD against GCTB stromal cells. Of note, metadherin (MTDH), a novel oncogene which modulates the AKT pathway, was identified as a direct target of miR-30a in GCTB stromal cells. Further data showed that miR-30a could negatively regulate the expression of MTDH and the AKT pathway in GCTB stromal cells. Importantly, MTDH expression was found to be inversely correlated with miR-30a expression in clinical GCTB specimens. Moreover, NCTD treatment effectively suppressed the AKT signaling pathway as demonstrated by downregulation of phosphorylated-Akt S473 (p-Akt S473), p-Akt (T308), phosphorylated-glycogen synthase kinase (GSK)3beta (p-GSK3beta) and c Myc, whilst miR-30a inhibition re-activated the AKT signaling pathway in GCTB stromal cells. Our findings demonstrate that NCTD can inhibit cell proliferation and metastasis of GCTB stromal cells in vitro, via modulating the miR 30a/MTDH/AKT signaling axis. This suggests that NCTD has potential as a novel therapeutic treatment for GCTB. PMID- 29710675 TI - Analysis of Th22, Th17 and CD4+cells co-producing IL-17/IL-22 at different stages of human colon cancer. AB - T-helper (Th) 22 cells are involved in the immunopathogenesis of inflammatory diseases, but their specific role in the immunopathogenesis of cancer is unknown. In this study, we examined the profile of circulating and intratumoral Th17, Th22 and CD4+ cells co-producing IL-17/IL-22 in colon cancer (CC) patients in relation to tumor staging. Thirty newly diagnosed colon cancer (CC) patients participated in this study. The percentage of Th1 (CD4+IFN-gamma+IL-17-IL-22-), Th17 (CD4+IFN gamma-IL-17+IL-22-), Th22 (CD4+IFN-gamma-IL-17-IL-22+) and CD4+ cells co producing IL-17/IL-22 (CD4+IFN-gamma-IL-17+IL-22+) in the peripheral blood, tumor and paratumor tissues was assessed by multicolor flow cytometry. The percentage of circulating Th17 and Th22 cells was significantly increased in CC patients compared to that in healthy controls (HCs). In addition, the percentage of infiltrating Th1, Th17, Th22 and CD4+ cells co-producing IL-17/IL-22 was significantly increased in the tumor tissues compared to that in the parartumor tissues. Furthermore, we also found that the percentage of circulating and intratumoral Th17, Th22 and CD4+ cells co-producing IL-17/IL-22 was higher in advanced stages than in early stages. Our findings revealed that Th17, Th22 and CD4+ cells co-producing IL-17/IL-22 were accumulated in colon cancer tissues and may be involved in the tumor development and progression. A better comprehension of the immunopathogenesis of Th17, Th22 and CD4+ cells co-producing IL-17/IL-22 in colon cancer patients would help in the development of novel therapies. PMID- 29710676 TI - Single-dose intra-articular corticosteroid injection prior to platelet-rich plasma injection resulted in better clinical outcomes in patients with knee osteoarthritis: A pilot study. AB - BACKGROUND: The synergistic and protective effect of platelet-rich plasma (PRP) added to methlyprednisolone (MP) has been demonstrated via in-vitro studies. However, there is no report in the literature about this issue. OBJECTIVE: The aim of this study was to evaluate clinical outcomes of intra-articular (IA) MP injection prior to PRP injection in comparison with single-dose MP and PRP injections alone in patients with knee osteoarthritis (OA). METHODS: The treatment groups were "PRP group" (n= 37) who underwent single-dose IA PRP injection, "PRP + MP group" (n= 40) who underwent MP injection one week prior to single-dose PRP injection, and "MP group" (n= 38) who underwent single-dose MP injection. Visual Analog Scale (VAS) and The Western Ontario and McMaster Universities Arthritis Index (WOMAC) scores were applied at first admission and at 1st, 3rd, 6th, and 12th month follow-ups. RESULTS: At the end of the 1st month, WOMAC score in PRP + MP group was significantly lower than PRP group. At the 3rd month, WOMAC score in PRP + MP group was significantly lower than PRP and MP groups. At the 6th month, VAS and WOMAC score in PRP + MP group was significantly lower than MP group. At the end of the 12th month, no significant difference was observed among three groups in VAS and WOMAC scores. CONCLUSION: According to our results, IA MP injection prior to PRP injection resulted in significantly better clinical outcomes compared to PRP and MP injections alone in patients who had mild to moderate knee OA. PMID- 29710677 TI - Approaches to improve the predictive value of laser Doppler flowmetry in detection of microcirculation disorders in diabetes mellitus. AB - BACKGROUND: Laser Doppler flowmetry is widely used in scientific studies of blood microcirculation but constrained in clinical use due to the low diagnostic significance. OBJECTIVE: This research is aimed at creation of approaches to prognostic value increase in detection of microcirculation disorders in patients with type 2 diabetes mellitus. METHODS: The study included 10 volunteers and 10 patients with t2DM. Participants were observed using postural-heating test with LAKK-02 complex. We calculated median microcirculation for each period and then held a retroactive classification of the surveyed groups. RESULTS: Statistically significant differences between groups were found in the perfusion during the combination of postural and heating impacts. Conversion of this perfusion in the relative index (Irel) (relative to the baseline perfusion), allowed us to increase the significance of the differences. The value of AUC (95% CI) during the ROC-analysis in reverse classification was 0.81 (0,60-1,0) for the period of the impacts combination, and 0.93 (0,81-1,0) for Irel index. CONCLUSIONS: We demonstrated the possibility of using LDF method to achieve predictive value in the detection of microcirculatory disorders in an individual patient with diabetes. This extends the perspectives of the method beyond the purely scientific research. PMID- 29710678 TI - Diagnostic value of acoustic radiation force impulse for BI-RADS category 4 breast lesions of different sizes. AB - OBJECTIVE: To determine the diagnostic value of combined conventional ultrasound (US) and acoustic radiation force impulse (ARFI) imaging for the differential diagnosis of BI-RADS category 4 breast lesions of different sizes. MATERIALS AND METHODS: From April 2013 to January 2015, 283 patients (with a total of 292 breast lesions) who underwent US and ARFI examination were included in this retrospective study. The SWV for the lesion and adjacent normal breast tissue were measured and the SWV ratio was calculated. VTI grade was also assessed. The lesions were separated into three groups on the basis of size, and two combinations of ARFI parameters (SWV + VTI and SWV ratio + VTI) were applied to reassess the BI-RADS categories. Diagnoses were confirmed by pathological examination after biopsy or surgery. ROC analysis was performed to assess the diagnostic efficiency of each method. The Z test was used to compare the difference between AUC of the two methods. RESULTS: Significant improvement was seen in the diagnostic performance of US with the use of the ARFI parameters SWV + VTI (77/179 [43.0%] of BI-RADS category 4A breast lesions were downgraded) and SWV ratio + VTI (64/179 [35.8%] of BI-RADS category 4A breast lesions were downgraded, including two malignant cases that were misdiagnosed as benign) (P < 0.01). The difference between the performances of the two combinations-SWV + VTI and SWV ratio + VTI-was significant only in breast lesions <10 mm in size, where the AUC of SWV ratio + VTI was significantly greater than the AUC of SWV + VTI (0.929 vs. 0.874; P < 0.01). CONCLUSION: Combination of US with ARFI can improve diagnostic performance and help avoid unnecessary biopsy in BI-RADS category 4 breast lesions. The combination of SWV ratio + VTI can improve BI-RADS classification of small lesions (<10 mm size). PMID- 29710679 TI - Effects of polymer-coated boron nitrides with increased hemorheological compatibility on human erythrocytes and blood coagulation. AB - BACKGROUND: Boron nitride (BN) nanomaterials are promising in biomedical research owing to their large surface area, graphene-like structure, and chemical and thermal properties. However, the toxicological effects of BN on erythrocytes and blood coagulation remain uninvestigated. OBJECTIVE: The aims of our study were to synthesize glycol chitosan (GC)- and hyaluronic acid (HA)-coated BNs, and to investigate the effects of these BNs on human cancer cells, erythrocytes, and whole blood. METHODS: We prepared hemocompatible forms of BN coated with GC and HA, and evaluated them using cell uptake/viability tests, hemolysis analysis and FE-SEM, as well as through hemorheological evaluation methods such as RBC deformability and aggregation, and blood coagulation. RESULTS: GC/BN and HA/BN were both ~200 nm, were successfully taken into cells, and emitted blue fluorescence. Both BNs were less toxic than bare BN, even at higher concentrations. The aggregation index of human red blood cells (RBCs) after 2 h incubation with BN, GC/BN, and HA/BN was greatly influenced, whereas RBC deformability did not dramatically change. CONCLUSIONS: We found that GC/BN affected the intrinsic coagulation pathway, whereas both GC/BN and HA/BN affected the extrinsic pathway. Therefore, HA/BN is less detrimental to RBCs and blood coagulation dynamics than bare BN and GC/BN. PMID- 29710680 TI - Eryptosis in Haemochromatosis: Implications for rheology. AB - BACKGROUND: Haemochromatosis is an iron-storage disease with different genetic mutations, characterized by an increased intestinal absorption of iron, resulting in a deposition of excessive amounts of iron in parenchymal cells. When the iron is released in the blood, it is left in an unliganded form, where it can participate in Haber-Weiss and Fenton reactions, creating hydroxyl radicals. Erythrocytes (RBCs) are particularly vulnerable to hydroxyl radical damage, which can result in eryptosis (programmed cell death similar to apoptosis). STUDY DESIGN AND METHODS: Here, we used flow cytometry to study the presence of eryptosis in the main genotypic variations of HFE (heterozygous and homozygous C282Y; H63D; C282Y/H63D). We also viewed RBCs from the different mutations using super-resolution Airyscan confocal microscopy. RESULTS: Flow cytometry showed significant changes in membrane biochemistry, indicated by the presence of phosphatidylserine (PS) proteins on the outer leaflet of the membrane, as well as increased intracellular calpain. This was found in all of the studied mutations. Airyscan fluorescence revealed PS flip and also microparticles from RBCs. Such microparticles are known to be pro-inflammatory. CONCLUSION: We conclude that RBC pathology is present in all the studied HFE mutations, even in low penetrance mutations, and this might affect rheology in these individuals. PMID- 29710681 TI - Effects of ex vivo aging and storage temperature on blood viscosity. AB - BACKGROUND: Research on hemorheology is driven in part by its significance in blood diseases and the possible use of hemorheology as a diagnostic tool. However, existing data on blood rheology are limited largely to measurements of steady shear behavior often with varying measurement protocols and insufficient characterization of the physiology. OBJECTIVE: The effects of ex vivo aging and environmental conditions on blood viscosity are investigated to improve standards for hemorheology measurements. METHODS: Measurements on the viscosity of blood from nine healthy donors are obtained and the physiological state of the blood determined. Steady and transient shear measurements are reported as a function of time from withdrawal. The effect of transportation temperature is also assessed. RESULTS: Blood transported at 4 degrees C may exhibit anomalous viscosity variations for short to intermediate times, as opposed to blood transported at room temperature. A time of approximately 3.0 hours was identified as the maximum time after the initial test that accurate rheological tests can be conducted on blood samples. CONCLUSIONS: Measurement protocol and time limit guidelines are established for conducting accurate rheological measurements on blood. PMID- 29710682 TI - Comparative evaluation of Plateletworks, Multiplate analyzer and Platelet function analyzer-200 in cardiology patients. AB - The objective of this study was to comparatively evaluate three commercial whole blood platelet function analyzer systems: Platelet Function Analyzer-200 (PFA; Siemens Canada, Mississauga, Ontario, Canada), Multiplate analyzer (MP; Roche Diagnostics International Ltd., Rotkreuz, Switzerland), and Plateletworks Combo 25 kit (PLW; Helena Laboratories, Beaumont, TX, USA). Venipuncture was performed on 160 patients who visited a department of cardiology. Pairwise agreement among the three platelet function assays was assessed using Cohen's kappa coefficient and percent agreement within the reference limit. Kappa values with the same agonists were poor between PFA-collagen (COL; agonist)/adenosine diphosphate (ADP) and MP-ADP (-0.147), PFA-COL/ADP and PLW-ADP (0.089), MP-ADP and PLW-ADP (0.039), PFA-COL/ADP and MP-COL (-0.039), and between PFA-COL/ADP and PLW-COL ( 0.067). Nonetheless, kappa values for the same assay principle with a different agonist were slightly higher between PFA-COL/ADP and PFA-COL/EPI (0.352), MP-ADP and MP-COL (0.235), and between PLW-ADP and PLW-COL (0.247). The range of percent agreement values was 38.7% to 73.8%. Therefore, various measurements of platelet function by more than one method were needed to obtain a reliable interpretation of platelet function considering low kappa coefficient and modest percent agreement rates among 3 different platelet function tests. PMID- 29710683 TI - Aging decreases CO2 reactivity in the retinal artery, but not in the ocular choroidal vessels; a cross-sectional study. AB - BACKGROUND: The CO2 reactivity is often used to assess vascular function, but it is still unclear whether this reactivity is affected by aging. OBJECTIVE: To investigate the effects of aging on the CO2 reactivity in ocular and cerebral vessels, both of which are highly sensitive to hypercapnia, we compared the CO2 reactivity in the retinal artery (RA), retinal and choroidal vessels (RCV), optic nerve head (ONH), and middle cerebral artery (MCA) between young and middle-aged subjects. METHODS: We measured the CO2 reactivity in 14 young and 11 middle-aged males using laser-speckle flowgraphy during a 3-min inhalation of CO2-rich air. RESULTS: The CO2 reactivity in the RA and ONH were lower in the middle-aged group than in the young group, but no significant effect of age was observed in the RCV or MCA. The CO2 reactivity in the RA and ONH were correlated significantly with age, whereas those in the RCV or MCA were not. CONCLUSIONS: These findings suggest that there are regional differences in the effect of age on the CO2 reactivity among not only ocular and cerebral vessels, but also the retinal and choroidal vessels, even though these vessels are in neighboring areas. PMID- 29710684 TI - The utility and limitations of contrast-enhanced transrectal ultrasound scanning for the detection of prostate cancer in different area of prostate. AB - OBJECTIVE: To evaluate the ability of contrast-enhanced transrectal ultrasound (CETRUS) scanning for prostate cancer detection in different area, compared with conventional transrectal ultrasound (TRUS). METHODS: 228 patients underwent TRUS guided prostate biopsy after examinations of TRUS and CETRUS scanning. Cancer detection between CETRUS and TRUS were compared by patient and by site in different areas (right, left; base, mid-gland, apex). The receiver operating characteristic (ROC) curve was plotted to evaluate the diagnostic performance of CETRUS. RESULTS: 89 patients were malignant and 48 patients were significant cancer. Compared with TRUS, CETRUS could increase the detection rates of overall and significant cancer (P = 0.008; P = 0.031). CETRUS had higher sensitivity, specificity (except right lobe), accuracy, positive predictive value (PPV) and negative predictive value (NPV) in total, right and left lobe (P < 0.05). The sensitivity were greater for CETRUS in all areas except left base and right apex (P < 0.05). The accuracy were greater for CETRUS in all areas except left mid gland and right apex (P < 0.05). ROC analysis showed CETRUS totally got the AUC of 0.816. The AUC was higher in left lobe than right lobe (0.837 vs. 0.793). It was most accurate at the base (0.833), then mid-gland (0.826), and lowest in apex (0.772). CONCLUSIONS: CETRUS had a significant advantage over conventional TRUS for prostate cancer detection in different areas. CETRUS much more easily missed the cancer in apex, we must focus more on apex and may add other imaging modalities to improve the visualization and detection of prostate cancer. PMID- 29710686 TI - Capsular fibrosis in aesthetic and reconstructive-cancer patients: A retrospective analysis of 319 cases. AB - BACKGROUND: Implant-based breast augmentation is one of the most frequently performed operations in plastic surgery worldwide, for aesthetic and reconstructive reasons. Capsular fibrosis is the most common long-term foreign body response after breast implant augmentation. OBJECTIVE: To compare the occurrence of capsular contracture in aesthetic and reconstructive-cancer patients, including those patients who received radiotherapy prior to breast reconstruction with implants. METHODS: We conducted a retrospective evaluation of 319 patients who underwent breast implant revision between Jan 2000 and Oct 2016. The patient group was comprised of 175 reconstructive-cancer patients and 144 patients who underwent operation for aesthetic reasons. The occurrence of capsular fibrosis, other complications and the time-period between implantation of breast implants and revision surgery (TP) was analyzed. RESULTS: For all 319 patients the mean TP was 7.9 years (7.86+/-0.45). The most common complication in all revisions was capsular fibrosis (65.1% of all revisions). In aesthetic patients with capsular fibrosis the mean TP was 11.9 years (11.89+/-0.95, p < 0.001). This mean TP was significantly higher than the mean TP of 6.1 years (6.13+/-0.56, p < 0.001) in breast cancer patients with capsular fibrosis. Preoperatively irradiated cancer patients had a mean TP of 6.2 years (6.17+/ 0.95), compared to a mean TP of 5.1 years (5.07+/-0.19, p = 0.051) in non irradiated cancer patients, which was not significantly different. CONCLUSIONS: We found that aesthetic patients exhibit a significantly higher mean TP compared to breast cancer patients, suggesting that reconstructive-cancer patients in general develop capsular fibrosis earlier. Despite the literature, we did not find a significant influence of preoperative radiotherapy on the occurrence of capsular fibrosis in reconstructive-cancer patients. Further clinical studies need to be conducted to identify methods to decrease the risk of developing capsular fibrosis. PMID- 29710685 TI - Beneficial effects of remote organ ischemic preconditioning on micro-rheological parameters during liver ischemia-reperfusion in the rat. AB - BACKGROUND: Remote ischemic preconditioning (RIPC) can be protective against the damage. However, there is no consensus on the optimal amount of tissue, the number and duration of the ischemic cycles, and the timing of the preconditioning. The hemorheological background of the process is also unknown. OBJECTIVE: To investigate the effects of remote organ ischemic preconditioning on micro-rheological parameters during liver ischemia-reperfusion in rats. METHODS: In anesthetized rats 60-minute partial liver ischemia was induced with 120-minute reperfusion (Control, n = 7). In the preconditioned groups a tourniquet was applied on the left thigh for 3*10 minutes 1 hour (RIPC-1, n = 7) or 24 hours (RIPC-24, n = 7) prior to the liver ischemia. Blood samples were taken before the operation and during the reperfusion. Acid-base, hematological parameters, erythrocyte aggregation and deformability were tested. RESULTS: Lactate concentration significantly increased by the end of the reperfusion. Erythrocyte deformability was improved in the RIPC-1 group, erythrocyte aggregation increased during the reperfusion, particularly in the RIPC-24 group. CONCLUSIONS: RIPC alleviated several hemorheological changes caused by the liver I/R. However, the optimal timing of the RIPC cannot be defined based on these results. PMID- 29710687 TI - Analysis of human microcirculation in weightlessness: Study protocol and pre study experiments. AB - BACKGROUND: In weightlessness, alterations in organ systems have been reported. The microcirculation consists of a network of blood vessels with diameters of a few MUm. It is considered the largest part of the circulatory system of the human body and essential for exchange of gas, nutrients and waste products. An investigation of the microcirculation in weightlessness seems warranted but has not yet been performed. OBJECTIVE: In this paper, we outline a study in which we will investigate the possible interrelations between weightlessness and microcirculation. We will induce weightlessness in the course of parabolic flight maneuvers, which will be conducted during a parabolic flight campaign. In this study protocol also an evaluation of a possible influence of parabolic flight premedication on microcirculation will be described. METHODS: The microcirculation will be investigated by sublingual intravital measurements applying sidestream darkfield microscopy. Parameters of macrocirculation such as heart rate, blood pressure and blood oxygenation will also be investigated. RESULTS: In our pre-study experiments, neither dimenhydrinate nor scopolamine altered microcirculation. CONCLUSIONS: As the application of motion sickness therapy did not alter microcirculation, it will be applied during the parabolic flight maneuvers of the campaign. Our results might deepen the understanding of microcirculation on space missions and on earth. PMID- 29710688 TI - Application of contrast-enhanced ultrasound in the diagnosis of small breast lesions. AB - BACKGROUND: Breast cancer is the most common cancer in women worldwide. The purpose of the study was to observe the features of contrast-enhanced ultrasound (CEUS) and the combination with Breast Imaging-Reporting and Data System (BI RADS) of conventional ultrasound for assessing small breast lesions. OBJECTIVES: The study was to explore the small breast lesions' features of contrast-enhanced ultrasound (CEUS) and the combination with Breast Imaging-Reporting and Data System (BI-RADS) of conventional ultrasound, in order to improve the diagnostic accuracy of early breast cancer. METHODS: 105 lesions were subject to conventional US (ultrasound) and CEUS before operations or biopsies. Among 105 breast lesions, six patient diagnoses were established by thick core-needle biopsy, while the rest were all confirmed by surgery and pathology. RESULTS: Significant differences were found between benign and malignant lesions in qualitative and quantitative indexes (peak) of CEUS (P < 0.05). The qualitative features of malignant small breast lesions were as follows: (1) enhanced intensity within the lesion was not uniform (61/61,100%); (2) the speed of wash in was earlier than the surrounding tissue (58/61, 95.1%); (3) lesion interior and the surrounding tissues had contrast vessel performance (61/61,100%). Peak of malignant lesions (35.77+/-11.45) was higher than that of benign lesions (31.96+/ 10.76) (P < 0.05). The diagnostic performance of BI-RADS-US plus qualitative indexes (method one) in terms of area under receiver operating characteristic curve (AUROC) were the highest (i.e., AUROC = 0.817), in comparison with other combined diagnostic methods. The associated sensitivity, specificity and accuracy were 78.69%, 84.09% and 80.95%, respectively. With method one, however, was similar with US-BI-RADS in specificity, 11 malignant breast lesions were regarded as a higher classification of BI-RADS and classified into malignant group, which were identified as benign on US-BI-RADS originally. CONCLUSIONS: CEUS was useful to differentiate benign from malignant small breast lesions, and the combination of CEUS and BI-RADS-US can improve the early diagnosis of breast cancers. PMID- 29710689 TI - Pulmonary hemodynamic effects and pulmonary arterial compliance during hypovolemic shock and reinfusion with human relaxin-2 (serelaxin) treatment in a sheep model. AB - BACKGROUND: Previous studies on the recombinant form of human relaxin-2 (serelaxin) have shown a decrease of pulmonary hemodynamics after serelaxin injection. Currently, the effect of serelaxin treatment during hypovolemia in a large animal model remains mostly unknown. METHODS: 12 sheep were randomly assigned to a sham or serelaxin (30MUg/kg serelaxin) group and underwent right heart catheterization. 50% of the estimated total blood volume were removed to induce hypovolemia, and subsequently retransfused 20 min later (reinfusion). Blood gases, heart rate, peripheral and pulmonary arterial oxygen saturation, systolic, diastolic and mean values of both pulmonary artery pressure (PAP) and pulmonary capillary wedge pressure (PCW) were measured. Cardiac output (CO), pulmonary vascular resistance (PVR), pulmonary arterial compliance (PAcompl) and systemic vascular resistance (SVR) were calculated. RESULTS: Hypovolemia and shock led to a similar decrease of PAP and PCW in both groups (p<=0.001). CO, SV and PAcompl decreased only in the control group (p<=0.05) and remained higher in the serelaxin-treated group. The results of this study suggest that serelaxin treatment did not negatively influence hemodynamic parameters during hypovolemic shock. CONCLUSION: The main conclusion of this study is that cardiopulmonary adaption mechanisms are not critically altered by serelaxin administration during severe hypovolemia and retransfusion. PMID- 29710690 TI - The combined effects of the microcirculatory status and cardiopulmonary bypass on platelet count and function during cardiac surgery. AB - BACKGROUND: Cardiac surgery with cardiopulmonary bypass is associated with important changes in the microcirculation, usually attributed to endothelial dysfunction. Another common finding of cardiac surgery is postoperative thrombocytopenia and platelet loss of function. OBJECTIVE: To investigate the association between microvascular flow pattern and postoperative changes in platelet count and function in cardiac surgery patients. METHODS: Twelve adult cardiac surgery patients received microvascular circulation (sidestream darkfield sublingual mucosa analysis) and platelet count and function (multiple electrode aggregometry ADPtest and TRAPtest) assessment before and after cardiopulmonary bypass. RESULTS: After cardiopulmonary bypass, sublingual microcirculation showed a significantly (P = 0.001) decreased microvascular flow index and increased heterogeneity index (P = 0.006). Platelet function significantly decrease after cardiopulmonary bypass both at ADPtest (P = 0.011) and TRAPtest (P = 0.002). Preoperative patterns of poor microvascular perfusion (low perfused vessels density and total vessels density) were significantly associated with lower values of post-cardiopulmonary bypass platelet function (ADPtest, P = 0.009, TRAPtest, P = 0.031) and count (P = 0.048). CONCLUSIONS: A preoperative disturbance of the microcirculation is associated with a greater postoperative platelet dysfunction. Endothelial damage, chemical and mechanical stimuli are the possible link between the two patterns. PMID- 29710691 TI - Beta-estradiol and ethinylestradiol enhance RBC deformability dependent on their blood concentration. AB - BACKGROUND: Natural and synthetic estrogens seems to have opposite effects on thrombosis and female cardiovascular system, since natural estrogen was supposed to be protective against cardiovascular diseases and synthetic estrogen has been related to thrombosis and cardiovascular diseases. In this work we have investigated if these differences could be related with the effects on those hormones on some hemorheological parameters. OBJECTIVE: The objective of this work was to investigate the hemorheological changes of different concentrations of beta-estradiol and ethinylestradiol, on RBC aggregation and RBC deformability. METHODS: Samples of blood of healthy donors were added with different concentrations of natural beta-estradiol or synthetic ethinylestradiol and were analyzed for red blood cell (RBC) aggregation and RBC deformability. RESULTS: There were no significant changes in RBC aggregation. Both beta-estradiol and ethinylestradiol increase the RBC deformability in shear stresses above 3.0 Pa accordingly with the hormone's concentration. CONCLUSIONS: Beta-estradiol and ethinylestradiol enhance RBC deformability dependent of their concentration. These findings may explain the different patterns of thrombotic and cardiovascular effects in different phases of the menstrual cycle or different dosages of oral contraceptive or hormonal replacement therapy. PMID- 29710692 TI - Two-dimensional shear wave elastography for differential diagnosis between mastitis and breast malignancy. AB - OBJECTIVE: To determine the diagnostic performance of conventional ultrasound (US) and two-dimensional shear wave elastography (2D SWE) in the differential diagnosis between mastitis and breast malignancy. METHODS: Between January 2016 and March 2017, 105 patients with 105 pathologically proven breast lesions were enrolled. All the lesions were subject to conventional US and 2D SWE examinations. In 2D SWE, the qualitative parameter of stiff rim sign and quantitative parameter of maximal shear wave velocity (SWV) were obtained. The diagnosis performances of US and combination of US and 2D SWE were evaluated, including sensitivity, specificity and the area under the receiver operating characteristic curve (AUROC). The AUROC of US and the combined method were also evaluated in subgroups with different diameters. RESULTS: Pathologically, 26 breast lesions were confirmed to be mastitis and 79 were malignant. The cut-off value for maximal SWV was 6.75 m/sec. The AUROC of stiff rim sign and maximal SWV were 0.701 (95% CI: 0.587-0.815) and 0.753 (95% CI: 0.659-0.832) respectively. Compared with US, the specificity and AUROC of the combined method increased significantly (specificity: 11.5% vs. 96.1%, AUROC: 0.520 vs. 0.752; both P < 0.05). CONCLUSIONS: The combination of US and 2D SWE improved the diagnostic performance in the differential diagnosis between mastitis and breast malignancy in comparison with the conventional US alone. PMID- 29710693 TI - The ESCHM "1st Hemorheology Days", 19 - 21 July 2017 in Puchberg/Schneeberg, Austria. PMID- 29710694 TI - Seeking the optimal hematocrit: May hemorheological modelling provide a solution? AB - Hematocrit increases during exercise and is usually decreased after regular training. However the interpretation of these facts is ambiguous since hematocrit is both a determinant of oxygen supply and the major determinant of blood viscosity. Classically hematocrit was assumed to impair blood flow, but it has been evidenced to exert a biphasic effect on it. In order to cope with these two apparently opposite effects of hematocrit, hemorheologists have proposed the concept hematocrit/viscosity ratio (h/eta). This h/eta ratio is related to tissue oxygenation in vascular diseases (eg, POAD) but not in healthy subjects. h/eta displays a bell-shaped curve as a function of hematocrit and the hematocrit value corresponding to the maximal h/eta can be assumed to be a theoretically optimal hematocrit. We propose to analyse exercise-related alterations in hematocrit according to this theoretical approach, viscosity at high shear rate being reconstructed with Quemada's equation from actual plasma viscosity and red cell rigidity at various hematocrit levels. While theoretical and actual h/eta are fairly correlated in athletes both before and after exercise, actual hematocrit is lower at rest and higher after exercise compared to the theoretical one. The main statistic correlate of these discrepancies between actual and predicted hematocrit is red cell rigidity. Submaximal exercise acutely decreases the h/eta ratio (despite increasing both hematocrit and viscosity). This change is well predicted by the model and there is a strong correlation between predicted and actual h/eta ratio. Endurance training tends to increase h/eta and to reduce the discrepancy between predicted and actual hematocrit. Accordingly trained athletes have a higher h/eta (both model-predicted and actual) than sedentary subjects, and a lower hematocrit, this lowering being rather correlated to training volume than to fitness improvement. On the whole, this approach suggests that homeostatic "viscoregulation" in athletes results in a fine tuning of h/eta which seems to be a closely regulated parameter. Hematocrit alterations in this context are an adaptation involved in this regulation. PMID- 29710695 TI - Deformability of different red blood cell populations and viscosity of differently trained young men in response to intensive and moderate running. AB - BACKGROUND: Red blood cell (RBC) deformability and blood viscosity are essential to ensure optimal microcirculation and may contribute to athletic performance. OBJECTIVE: To investigate the acute responses of density fractionated young, middle old and old RBC, RBC viscosity (RBCV), plasma viscosity (PV) and hematological changes to two running modes (intensive and moderate). METHODS: 27 young and healthy men of different training status participated in this study and were grouped into three groups in accordance to their VO2peak and conducted an intensive and moderate running test, respectively (crossover design). Pre and Post exercise, RBC were fractionated via percoll density gradient centrifugation. RBC deformability of the entire RBC population and the fractionated RBC was determined. Viscosity, hematocrit and mean cellular volume were determined. RESULTS: Baseline results reveal that high trained subjects possess more young RBC and show increased deformability of un-fractioned RBC and middle aged RBC. Baseline PV, RBCV, hematocrit and mean cellular volume did not differ between groups. Applied running modes did not change RBC deformability of any sub fractions. Viscosity only increased after intensive running. Hematological changes were observed after both exercises. CONCLUSIONS: Acute effects of exercise on RBC are marginal, but chronic differences can be observed in RBC function. PMID- 29710696 TI - Viscoelasticity and structure of blood clots generated in-vitro by rheometry: A comparison between human, horse, rat, and camel. AB - BACKGROUND: Although the coagulation system is evolutionary well preserved, profound species differences exist in viscoelastic as well as in common laboratory tests of coagulation. OBJECTIVE: Evaluating differences in clot formation and material characterisation of clots of four mammalian species on macro-, micro- and nanoscales by the means of rheometry, scanning electron microscopy (SEM) and small angle x-ray scattering (SAXS). METHODS: Blood samples were collected from healthy human volunteers, laboratory rats (HL/LE inbred strain), warmblood horses and dromedary camels. Clot formation was observed by oscillating shear rheometry until plateau formation of the shear storage modulus G', at which point selected clots were prepared for scanning electron microscopy. SEM images were analysed for fibre diameter and fractal dimension. Additionally, scattering profiles for plasma and whole blood samples were obtained with SAXS. RESULTS: Viscoelasticity of clots showed great interspecies variation: clots of rats and horses exhibited shorter clotting times and higher G' plateau values, when compared to human clots. Camel clots showed unique clotting characteristics with no G' plateau formation in the timeframe observed. Less differentiating features were found with SEM and SAXS, although the rat fibre network appears to be more convoluted and dense, which resulted in a higher fractal dimension. CONCLUSION: Clotting kinetic differs between the species, which is not only of clinical interest, but could also be an important finding for animal models of blood coagulation. PMID- 29710697 TI - Temperature dependency of whole blood viscosity and red cell properties in desert ungulates: Studies on scimitar-horned oryx and dromedary camel. AB - Background: The dromedary camel and the oryx antelope are exposed to excessive heat and solar radiation in theirdesert habitat. Desertification of areas with by now little rainfall may occur eventually. Well-adapted large animal speciesshow us what is needed to survive in scorching regions. Methods: Four scimitar-horned oryx antelopes (Oryx dammah), 10 camels (Camelus dromedarius), nine South AfricanMerino sheep, and 17 Nguni cows were tested for RBC aggregation, RBC elongation, and plasma viscosity. The temperaturedependency of blood viscosity was tested in 10 camels and compared to human reference values. Results: Unlike sheep, Nguni cow, and dromedary camel, oryx RBCs aggregate in native plasma (M0:5.2 (3.3/6.7);M1:18.1 (16.7/27.9); Myrenne MA1). Elongation indices of oryx RBCs were intermediate to low (EImax: 22.6 (19.2/25.3);SS1/2 3.67 (2.52/4.95); Rheodyn SSD). Camel RBCs did not display the typical SS/EI curve by rotational ektacytometry.In-vitro blood viscosity (Physica MCR302) was lower in camels than in human blood at equal hematocrit. A decrease oftemperature had only little effect on camel blood. At 10 s-1, blood viscosity in camel increased from 2.18mPa*s (2.01/2.37)at 42?C to 4.39mPa*s (4.22/4.51) at 12?C. In human blood, viscosity ranged from 8.21mPa*s (6.95/8.25) at 37?C to15.52mPa*s (14.25/16.03) at 12?C. At 1000 s-1, blood viscosity in camel ranged from 2.00mPa*s (1.95/2.04) at 42?C to3.98mPa*s (3.88/4.08) at 12?C. In human blood, viscosity ranged from 5.35mPa*s (4.96/5.87) at 37?C to 11.24mPa*s(10.06/11.17) at 12?C. Conclusions: Desert ungulates may need RBC membranes, which are fortified to withstand changes in osmolalityduring dehydration-rehydration cycles. This reduces RBC deformability. Dromedary camel blood does not undergo starkchanges in viscosity with changes in temperature. Therefore, blood fluidity could be rather maintained during the day andnight cycle. This should reduce the need of the vascularity to rhythmically adapt to changing shear forces when camelsexperience heterothermy. PMID- 29710698 TI - Erythrocyte deformability and eryptosis during inflammation, and impaired blood rheology. AB - OBJECTIVE: This review focusses on the erythrocytes (RBCs) and their structural changes during inflammation and impaired blood rheology. We discuss systemic inflammation and the effects of dysregulated inflammatory molecules. These pro inflammatory molecules directly affect the haematological system, and particularly the RBCs, platelets and plasma proteins. We focus on the three main changes; increased RBC eryptosis (programmed cell death, similar to apoptosis) and pathological deformability, platelet hyperreactivity and anomalous blood clotting, due to pathological changes to fibrin(ogen) protein structure. This pro inflammatory haematological system directly affects blood rheology. In turn, hemorheological parameters such as RBC deformability are important parameters in hypercoagulation, which is a hallmark of inflammation. For RBC deformation to happen during blood flow, the RBC membrane needs to be elastic to elongate sufficiently to squeeze through small capillaries. However, of greater importance is that the cell must return to its original biconcave shape after exiting the small diameter capillaries. CONCLUSION: Hemorheological parameters such as RBC deformability are of great importance clinically, to both identify the presence and extent of inflammation, and to study these parameters during intervention therapies. RBC rheology and deformability may therefore be a useful cell model for pharmaceutical testing. PMID- 29710699 TI - The wavelet analysis for the assessment of microvascular function with the laser Doppler fluxmetry over the last 20 years. Looking for hidden informations. AB - The wavelet analysis has been applied to the Laser Doppler Fluxmetry for assessing the frequency spectrum of the flowmotion to study the microvascular function waves.Although the application of wavelet analysis has allowed a detailed evaluation of the microvascular function, its use does not seem to be yet widespread over the last two decades.Aiming to improve the diffusion of this methodology, we herein present a systematic review of the literature about the application of the wavelet analysis to the laser Doppler fluxmetry signal. A computer research has been performed on PubMed and Scopus databases from January 1990 to December 2017. The used terms for the investigation have been "wavelet analysis", "wavelet transform analysis", "Morlet wavelet transform" along with the terms "laser Doppler", "laserdoppler" and/or "flowmetry" or "fluxmetry". One hundred and eighteen studies have been found. After the scrutiny, 97 studies reporting data on humans have been selected. Fifty-three studies, 54.0% (95% CI 44.2-63.6) pooled rate, have been performed on 892 healthy subjects and 44, 45,9 % (95% CI 36.3-55.7%) pooled rate have been performed on 1679 patients. No significant difference has been found between the two groups (p 0,81). On average, the number of studies published each year was 4.8 (95% CI 3.4-6.2). The trend of studies production has increased significantly from 1998 to 2017, (p 0.0006). But only the studies on patients have shown a significant increase trend along the years (p 0.0003), than the studies on healthy subjects (p 0.09).In conclusion, this review highlights that despite being a promising and interesting methodology for the study of the microcirculatory function, the wavelet analysis has remained still neglected. PMID- 29710700 TI - Severity-Related Increase and Cognitive Correlates of Serum VEGF Levels in Alzheimer's Disease ApoE4 Carriers. AB - Vascular endothelial growth factor (VEGF) is an angioneurin involved in the regulation of vascular and neural functions relevant for the pathophysiology of Alzheimer's disease (AD), but the influence of AD severity and ApoE4 status on circulating VEGF and its relationship with cognition has not been investigated. We assessed serum VEGF levels and cognitive performance in AD, amnestic mild cognitive impairment (MCI), and control subjects. VEGF levels were higher in AD patients than in MCI cases and controls (p < 0.05) and showed a progressive increase with clinical severity in the whole study population (p < 0.01). Among AD patients, severity-related VEGF elevations were significant in ApoE4 carriers (p < 0.05), but not in non-carriers. Increased VEGF levels were associated with disease severity and showed mild correlations with cognitive impairment that were only consistent for the ADAS-cog+ items remembering test instructions (memory) and maze task (executive functions) in the group of AD patients (p < 0.05). On the other hand, higher VEGF values were related to better memory and language performance in ApoE4 carriers with moderately-severe AD. According to these results showing severity- and ApoE4-related differences in serum VEGF and its cognitive correlates, it is suggested that increases in VEGF levels might represent an endogenous response driven by pathological factors and could entail cognitive benefits in AD patients, particularly in ApoE4 carriers. Our findings support the notion that VEGF constitutes a relevant molecular target to be further explored in AD pathology and therapy. PMID- 29710703 TI - Inflammatory Cytokine, IL-1beta, Regulates Glial Glutamate Transporter via microRNA-181a in vitro. AB - Glutamate overload triggers synaptic and neuronal loss that potentially contributes to neurodegenerative diseases including Alzheimer's disease (AD). Glutamate clearance and regulation at synaptic clefts is primarily mediated by glial glutamate transporter 1 (GLT-1). We determined that inflammatory cytokines significantly upregulated GLT-1 through microRNA-181a-mediated post transcriptional modifications. Unveiling the key underlying mechanisms modulating GLT-1 helps better understand its physiological and pathological interactions with cytokines. Primary murine astrocyte and neuron co-culture received 20 ng/mL IL-1beta, TNF-alpha, or IL-6 for 48 h. Soluble proteins or total RNA were extracted after treatment for further analyses. Treatment with inflammatory cytokines, IL-1beta and TNF-alpha, but not IL-6, significantly increased GLT-1 steady-state levels (p<=0.05) without affecting mRNA levels, suggesting the cytokine-induced GLT-1 was regulated through post-transcriptional modifications. Among the candidate microRNAs predicted to modulate GLT-1, only microRNA-181a was significantly decreased following the IL-1beta treatment (p<=0.05). Co-treatment of microRNA-181a mimic in IL-1beta-treated primary astrocytes and neurons effectively blocked the IL-1beta-induced upregulation of GLT-1. Lastly, we attempted to determine the link between GLT-1 and microRNA-181a in human AD brains. A significant reduction of GLT-1 was found in AD hippocampus tissues, and the ratio of mature microRNA-181a over primary microRNA-181a had an increasing tendency in AD. MicroRNA-181a controls rapid modifications of GLT-1 levels in astrocytes. Cytokine-induced inhibition of microRNA-181a and subsequent upregulation of GLT-1 may have physiological implications in synaptic plasticity while aberrant maturation of microRNA-181a may be involved in pathological consequences in AD. PMID- 29710701 TI - Chinese Herbal Medicine Xueshuantong Enhances Cerebral Blood Flow and Improves Neural Functions in Alzheimer's Disease Mice. AB - Reduced cerebral blood flow in Alzheimer's disease (AD) may occur in early AD, which contributes to the pathogenesis and/or pathological progression of AD. Reversing this deficit may have therapeutic potential. Certain traditional Chinese herbal medicines (e.g., Saponin and its major component Xueshuantong [XST]) increase blood flow in humans, but whether they could be effective in treating AD patients has not been tested. We found that systemic XST injection elevated cerebral blood flow in APP/PS1 transgenic mice using two-photon time lapse imaging in the same microvessels before and after injection. Subchronic XST treatment led to improved spatial learning and memory and motor performance in the APP/PS1 mice, suggesting improved neural plasticity and functions. Two-photon time lapse imaging of the same plaques revealed a reduction in plaque size after XST treatment. In addition, western blots experiments showed that XST treatment led to reduced processing of amyloid-beta protein precursor (AbetaPP) and enhanced clearance of amyloid-beta (Abeta) without altering the total level of AbetaPP. We also found increased synapse density in the immediate vicinity of amyloid plaques, suggesting enhanced synaptic function. We conclude that targeting cerebral blood flow can be an effective strategy in treating AD. PMID- 29710702 TI - Sex-Dependent Differences in Spontaneous Autoimmunity in Adult 3xTg-AD Mice. AB - The triple-transgenic (3xTg-AD) mouse strain is a valuable model of Alzheimer's disease (AD) because it develops both amyloid-beta (Abeta) and tau brain pathology. However, 1-year-old 3xTg-AD males no longer show plaques and tangles, yet early in life they exhibit diverse signs of systemic autoimmunity. The current study aimed to address whether females, which exhibit more severe plaque/tangle pathology at 1 year of age, show similar autoimmune phenomena and if so, whether these immunological changes coincide with prodromal markers of AD pathology, markers of learning and memory formation, and epigenetic markers of neurodegenerative disease. Six-month-old 3xTg-AD and wild-type mice of both sexes were examined for T-cell phenotype (CD3+, CD8+, and CD4+ populations), serological measures (autoantibodies, hematocrit), soluble tau/phospho-tau and Abeta levels, brain-derived neurotrophic factor (BDNF) expression, and expression of histone H2A variants. Although no significant group differences were seen in tau/phospho-tau levels, 3xTg-AD mice had lower brain mass and showed increased levels of soluble Abeta and downregulation of BDNF expression in the cortex. Splenomegaly, depleted CD+ T-splenocytes, increased autoantibody levels and low hematocrit were more pronounced in 3xTg-AD males than in females. Diseased mice also failed to exhibit sex-specific changes in histone H2A variant expression shown by wild-type mice, implicating altered nucleosome composition in these immune differences. Our study reveals that the current 3xTg-AD model is characterized by systemic autoimmunity that is worse in males, as well as transcriptional changes in epigenetic factors of unknown origin. Given the previously observed lack of plaque/tangle pathology in 1-year-old males, an early, sex-dependent autoimmune mechanism that interferes with the formation and/or deposition of aggregated protein species is hypothesized. These results suggest that more attention should be given to studying sex-dependent differences in the immunological profiles of human patients. PMID- 29710704 TI - Assessment of the Mid-Life Demographic and Lifestyle Risk Factors of Dementia Using Data from the Framingham Heart Study Offspring Cohort. AB - BACKGROUND: Dementia is the leading cause of dependence and disability in the elderly population worldwide. However, currently there is no effective medication for dementia treatment. Therefore, identifying lifestyle-related risk factors including some that are modifiable may provide important strategies for reducing risk of dementia. OBJECTIVE: This study aims to highlight associations between easily obtainable lifestyle risk factors in mid-life and dementia in later adulthood. METHODS: Using data from the Framingham Heart Study Offspring cohort, we leveraged well-known classification models (decision tree classifier and random forests) to associate demographic and lifestyle behavioral data with dementia status. We then evaluated model performance by computing area under receiver operating characteristic (ROC) curve. RESULTS: As expected, age was strongly associated with dementia. The analysis also identified 'widowed' marital status, lower BMI, and less sleep at mid-life as risk factors of dementia. The areas under the ROC curves were 0.79 for the decision tree, and 0.89 for the random forest model. CONCLUSION: Demographic and lifestyle factors that are non invasive and inexpensive to implement can be assessed in midlife and used to potentially modify the risk of dementia in late adulthood. Classification models can help identify associations between dementia and midlife lifestyle risk factors. These findings inform further research, in order to help public health officials develop targeted programs for dementia prevention. PMID- 29710705 TI - Prevalence, Semiology, and Risk Factors of Epilepsy in Alzheimer's Disease: An Ambulatory EEG Study. AB - BACKGROUND: Alzheimer's disease (AD) is the primary cause of cognitive decline. A growing body of evidence suggests that AD patients have a higher risk to develop epileptic seizures; however, results are contradictory due to different methodological approaches of previous studies. OBJECTIVE: We aimed to identify the prevalence, semiology, and risk factors of epilepsy in AD using long-term EEG. METHODS: We selected forty-two AD patients and examined them using 24-hour ambulatory EEG. Neurological and epileptological data were collected with retro- and prospective methods. We analyzed the semiology of the identified seizures and the possible risk factors using logistic regression analysis. RESULTS: We identified seizures confirmed by EEG in 24%. The majority of the seizures were aware focal (72%) without any motor activity (55%). We found epileptiform discharges without seizures in 28%. Patients with seizures and only with epileptic EEG activity showed similar clinical and demographical features. Higher education (OR:1.8) and lower Addenbrooke Examination Score (OR: 0.9) were identified as risk factors of epilepsy. Increase of 0.1 point in the Verbal Language/Orientation-Memory ratio (VLOM) was associated with higher epilepsy risk as well (OR:2.9). CONCLUSION: Epilepsy is a frequent comorbidity of AD. Since most of the seizures are aware non-motor focal seizures, sensitive EEG techniques are required for precise diagnosis of epilepsy. Long-term ambulatory EEG is a safe and well-tolerated option. Epileptiform EEG in AD signals the presence of concomitant epilepsy. Clinicians have to pay attention to comorbid epilepsy in dementia patients with high education, with high VLOM ratio and severe stage. PMID- 29710706 TI - Utility of Amyloid and FDG-PET in Clinical Practice: Differences Between Secondary and Tertiary Care Memory Units. AB - The clinical utility of amyloid positron emission tomography (PET) has not been fully established. Our aim was to evaluate the effect of amyloid imaging on clinical decision making in a secondary care unit and compare our results with a previous study in a tertiary center following the same methods. We reviewed retrospectively 151 cognitively impaired patients who underwent amyloid (Pittsburgh compound B [PiB]) PET and were evaluated clinically before and after the scan in a secondary care unit. One hundred and fifty concurrently underwent fluorodeoxyglucose (FDG)-PET. We assessed changes between the pre- and post-PET clinical diagnosis and Alzheimer's disease treatment plan. The association between PiB/FDG results and changes in management was evaluated using chi2 and multivariate logistic regression. Concordance between classification based on scan readings and baseline diagnosis was 66% for PiB and 47% for FDG. The primary diagnosis changed after PET in 17.2% of cases. When examined independently, discordant PiB and discordant FDG were both associated with diagnostic change (p < 0.0001). However, when examined together in a multivariate logistic regression, only discordant PiB remained significant (p = 0.0002). Changes in treatment were associated with concordant PiB (p = 0.009) while FDG had no effect on treatment decisions. Based on our regression model, patients with diagnostic dilemmas, a suspected non-amyloid syndrome, and Clinical Dementia Rating <1 were more likely to benefit from amyloid PET due to a higher likelihood of diagnostic change. We found that changes in diagnosis after PET in our secondary center almost doubled those of our previous analysis of a tertiary unit (9% versus 17.2%). Our results offer some clues about the rational use of amyloid PET in a secondary care memory unit stressing its utility in mild cognitive impairment patients. PMID- 29710707 TI - Loss in PKC Epsilon Causes Downregulation of MnSOD and BDNF Expression in Neurons of Alzheimer's Disease Hippocampus. AB - Oxidative stress and amyloid-beta (Abeta) oligomers have been implicated in Alzheimer's disease (AD). The growth and maintenance of neuronal networks are influenced by brain derived neurotrophic factor (BDNF) expression, which is promoted by protein kinase C epsilon (PKCE). We investigated the reciprocal interaction among oxidative stress, Abeta, and PKCE levels and subsequent PKCE dependent MnSOD and BDNF expression in hippocampal pyramidal neurons. Reduced levels of PKCE, MnSOD, and BDNF and an increased level of Abeta were also found in hippocampal neurons from autopsy-confirmed AD patients. In cultured human primary hippocampal neurons, spherical aggregation of Abeta (amylospheroids) decreased PKCE and MnSOD. Treatment with t-butyl hydroperoxide (TBHP) increased superoxide, the oxidative DNA/RNA damage marker, 8-OHG, and Abeta levels, but reduced PKCE, MnSOD, BDNF, and cultured neuron density. These changes were reversed with the PKCE activators, bryostatin and DCPLA-ME. PKCE knockdown suppressed PKCE, MnSOD, and BDNF but increased Abeta. In cultured neurons, the increase in reactive oxygen species (ROS) associated with reduced PKCE during neurodegeneration was inhibited by the SOD mimetic MnTMPyP and the ROS scavenger NAc, indicating that strong oxidative stress suppresses PKCE level. Reduction of PKCE and MnSOD was prevented with the PKCE activator bryostatin in 5-6-month-old Tg2576 AD transgenic mice. In conclusion, oxidative stress and Abeta decrease PKCE expression. Reciprocally, a depression of PKCE reduces BDNF and MnSOD, resulting in oxidative stress. These changes can be prevented with the PKCE specific activators. PMID- 29710708 TI - Cerebral White Matter Lesions have Low Impact on Cognitive Function in a Large Elderly Memory Clinic Population. AB - BACKGROUND: Evidence suggests that cerebral white matter lesions (WML) play a role in cognitive decline. OBJECTIVE: To assess the impact of cerebral WML on cognitive function relative to absence or presence of medial temporal atrophy (MTA) in a large single-center memory clinic population. METHODS: Patients included had subjective cognitive impairment (SCI, n = 333), mild cognitive impairment (MCI, n = 492) and Alzheimer's disease (AD, n = 832). The relationships between visually rated WML (Fazekas scale, 0-3) on brain Computed Tomography and CAMCOG memory and non-memory function were investigated with regression analysis adjusted for age, gender and education in combined patient groups. We assessed possible interaction versus addition effects of these relationships with visually rated MTA (Scheltens scale). RESULTS: The highly statistical significant relationship between WML and memory function was no longer significant when MTA was taken into account. However, the strong significant relationship between WML and non-memory function remained significant after adjustment for MTA, but the explained variance attributed to WML was only 1.3%. There was no interaction between WML and MTA on CAMCOG test scores. In addition, shown by a 2*2 factorial model by presence versus absence of WML and MTA, WML affected non-memory function only in the presence of MTA. CONCLUSION: Our data suggest that presence of WML is associated with lower non-memory cognitive function but this effect is conditional on the presence of pre-existing MTA. The very small explained variance suggests little impact of WML to the clinical profile of a memory clinic patient. PMID- 29710709 TI - Diet Supplementation with Hydroxytyrosol Ameliorates Brain Pathology and Restores Cognitive Functions in a Mouse Model of Amyloid-beta Deposition. AB - Alzheimer's disease is the most common form of dementia affecting a large proportion of aged people. Plant polyphenols have been reported to be potentially useful in the prevention of AD due to their multiple pharmacological activities. The aim of the present study was to assess whether the previously reported neuroprotective and anti-inflammatory effects resulting from oleuropein aglycone administration were reproduced by diet supplementation with similar amounts of its metabolite hydoxytyrosol (HT). Four-month-old TgCRND8 and wild type mice were treated for 8 weeks with a low-fat diet (5%) supplemented with HT (50 mg/kg of diet). We found that HT supplementation significantly improved cognitive functions of TgCRND8 mice and significantly reduced Abeta42 and pE3-Abeta plaque area and number in the cortex; in the hippocampal areas of HT-fed TgCRND8 mice, we found a significant reduction in the pE3-Abeta plaque number together with a tendency toward a reduction in Abeta42 load and pE3-Abeta plaque area, associated with a marked reduction of TNF-alpha expression and astrocyte reaction. Macroautophagy induction and modulation of MAPKs signaling were found to underlie the beneficial effects of HT. Our findings indicate that HT administration reproduces substantially the beneficial effects on behavioral performance and neuropathology previously reported in TgCRND8 mice fed with oleuropein aglycone, resulting in comparable neuroprotection. PMID- 29710711 TI - Frequency and Correlates of Subjective Memory Complaints in Parkinson's Disease with and without Mild Cognitive Impairment: Data from the Parkinson's Disease Cognitive Impairment Study. AB - Subjective memory complaints (SMC) may represent the preclinical phase of mild cognitive impairment (MCI) due to Alzheimer's disease. Dementia/MCI have been described with a high prevalence in Parkinson's disease (PD), but whether SMC may predict the development of cognitive impairment has been barely explored. To evaluate the frequency and clinical correlates of isolated SMC (PD-SMC) or within the construct of MCI in subjects with PD, 147 PD patients from the PArkinson's disease COgnitive impairment Study (PACOS) were consecutively recruited for the study. This is a multicenter study involving two Movement Disorder Centers in south Italy. All subjects underwent comprehensive neuropsychological evaluation and PD-MCI was diagnosed according to Litvan's criteria. The Memory Assessment Clinics Questionnaire was used to assess SMC. Logistic regression analysis, adjusted for demographics and significant covariates, was used to evaluate clinical differences between groups. Forty-two (28.6%) individuals presented with PD without SMC and/or MCI (PDw), 40 (27,2%) with PD-SMC, 48 (32,6%) PD-SMC-MCI, and 17 (11,6%) PD-MCI without SMC (PD-MCI). When compared to PDw, PD-SMC was significantly associated with anxiety (OR = 3.93, 95% CI = 1.18-13.03), while PD SMC-MCI related to motor progression (OR = 5.29, 95% CI = 1.12-24.86), and instrumental disability (OR = 6.98, 95% CI = 2.08-23.38). About 60% of patients showed SMC, in isolation or within the MCI frame. The role of SMC in PD seems to have a different etiology depending on the presence/absence of MCI. In particular, PD-SMC would represent a subjective reaction to the disease, while PD SMC-MCI would depict motor progression and disability. PMID- 29710710 TI - Neural Correlates of Sleep Disturbance in Alzheimer's Disease: Role of the Precuneus in Sleep Disturbance. AB - BACKGROUND: Sleep disturbance may affect the development of Alzheimer's disease (AD), but the neural correlates of sleep disturbance in AD have not been fully clarified. OBJECTIVE: To examine the factors associated with sleep disturbance in AD. METHODS: A retrospective study was performed in 63 patients with AD. None of the patients had been prescribed antidementia or psychoactive drugs, and all underwent brain magnetic resonance imaging (MRI) before medication. Sleep disturbance was defined as a score of at least 1 point on the sleep disturbance subscale of the Neuropsychiatric Inventory (NPI). Whole brain image analysis was performed using SPM8 and VBM8. A two-sample t-test was used to compare patients with AD with (n = 19) and without (n = 44) sleep disturbance, with age and gender included as covariates. The statistical thresholds were set to an uncorrected p value of 0.001 at the voxel level and a corrected p-value of 0.05 at the cluster level. In addition, pineal gland volume (PGV) measured using MRI, and white matter hyperintensity (WMH) assessed with the modified Fazekas scale were compared between patients with AD with and without sleep disturbance using independent group t-tests. RESULTS: In whole brain analysis, the precuneus volume in patients with AD with sleep disturbance was significantly smaller than those without sleep disturbance. There were no significant differences in PGV and WMH between the two groups. CONCLUSION: Sleep disturbance in AD was associated with reduction of precuneus volume. This suggests that the precuneus might be an important region in sleep disturbance in AD. PMID- 29710712 TI - Melatonin in Synaptic Impairments of Alzheimer's Disease. AB - Alzheimer's disease (AD) underlies dementia for millions of people worldwide with no effective treatment. The dementia of AD is thought stem from the impairments of the synapses because of their critical roles in cognition. Melatonin is a neurohormone mainly released by the pineal gland in a circadian manner and it regulates brain functions in various manners. It is reported that both the melatonin deficit and synaptic impairments are present in the very early stage of AD and strongly contribute to the progress of AD. In the mammalian brains, the effects of melatonin are mainly relayed by two of its receptors, melatonin receptor type 1a (MT1) and 1b (MT2). To have a clear idea on the roles of melatonin in synaptic impairments of AD, this review discussed the actions of melatonin and its receptors in the stabilization of synapses, modulation of long term potentiation, as well as their contributions in the transmissions of glutamatergic, GABAergic and dopaminergic synapses, which are the three main types of synapses relevant to the synaptic strength. The synaptic protective roles of melatonin in AD treatment were also summarized. Regarding its protective roles against amyloid-beta neurotoxicity, tau hyperphosphorylation, oxygenation, inflammation as well as synaptic dysfunctions, melatonin may be an ideal therapeutic agent against AD at early stage. PMID- 29710713 TI - Rapidly Progressive Alzheimer's Disease: Contributions to Clinical-Pathological Definition and Diagnosis. AB - Rapidly progressive Alzheimer's disease (rpAD) has recently been recognized as a clinical disease subtype characterized by rapidly progressive cognitive decline and/or short disease duration, and the possible occurrence of early focal neurological signs. Consistently, rpAD represents a relatively frequent alternative diagnosis among cases referred as possible or probable Creutzfeldt Jakob disease (CJD) to surveillance centers for prion disease worldwide. Indeed, the early clinical differential diagnosis between the two disorders can be challenging given the partial overlap in clinical features and cerebrospinal fluid (CSF) levels of the protein surrogate markers 14-3-3 and total-tau. Although typical AD and rpAD seem to share the neuropathological core features, recent evidence suggests that a distinctive molecular signature involving the structure of amyloid-beta aggregates and the proteomic landscape of amyloid plaques may distinguish rpAD from typical AD. Here we review clinical, neuropathological, and molecular features and diagnostic findings, including CSF biomarker data, reported to date in rpAD. Furthermore, we summarize the main clinical, pathological and laboratory features of 27 autopsy confirmed cases of rpAD referred to our center. The results of this retrospective analysis, while largely confirming previously published genetic, clinical, and neuropathological data, suggest a higher prevalence of moderate to severe cerebral amyloid angiopathy in rpAD compared to typical AD, a finding to explore further and validate in a larger patient group. PMID- 29710714 TI - The End of the Beginning of the Alzheimer's Disease Nightmare: A Devil's Advocate's View. AB - Although there have been so many failures in Alzheimer's disease (AD) modifying trials, there are still many compounds in the pipeline and the hope still remains that the entrance of disease-modifying treatment (DMT) for AD will positively and dramatically change the whole situation of AD treatment. However, if DMT does enter the market, it will be the beginning of a great number of challenges and problems. The current infrastructure for diagnostics of early (pre-dementia) AD does not have the capacity to meet the demands and expectations of the population. Neither is there capacity for treatment monitoring and follow-ups. If screening is considered, there will be a great risk for false positive cases and a great number of people who will have to undergo diagnostics. There will be high costs for diagnostics and treatment initially, while potential benefits will occur much later in other sectors than where the payers for treatment are. Although there are great hopes that prevention of cardiovascular risk factors and changes in lifestyle might impact the risk for dementia, there is still no consensus that this is the case. Finally, the relevance of different AD paradigms such as amyloid and tau is still a matter of discussion, particularly regarding the oldest old. PMID- 29710715 TI - Targeting Insulin for Alzheimer's Disease: Mechanisms, Status and Potential Directions. AB - Insulin resistance can occur when the body is unable to respond to insulin even in excess. In the brain, insulin manages glucose metabolism in regions such as the hippocampus and plays a key role in directly regulating ERK, a kinase required for the type of memory compromised in early Alzheimer's disease (AD). Human imaging studies show that brain glucose utilization declines with age and is notably impaired in subjects with early AD. Likewise, animal models of AD or insulin resistance, or both, demonstrate that dysfunctional insulin signaling and insulin resistance in the brain have reciprocity with neuroinflammation and aberrant accumulation of amyloid-beta (Abeta), pathological hallmarks in AD. As such, the association between brain insulin activity and AD has led to clinical trials testing the efficacy of insulin and insulin-sensitizing drugs to intervene in AD. Based on recent inquiries to ClinicalTrials.gov, we evaluated thirty-three clinical studies related to AD and insulin. The search filtered for interventional clinical trials to test FDA-approved drugs or substances that impinge upon the insulin signaling pathway. Insulin, metformin, and thiazolidinediones were the three main interventions assessed. Overall, these strategies are expected to negate the effects of brain insulin resistance by targeting insulin signaling pathways involved in neuroinflammation, metabolic homeostasis, synaptic functional and structural integrity. The goal of this review is to provide an update on insulin and ERK signaling in relation to memory, its decline in early AD, and provide an overview of clinical trials related to insulin for early AD intervention. PMID- 29710716 TI - Brain Inflammation Connects Cognitive and Non-Cognitive Symptoms in Alzheimer's Disease. AB - Alzheimer's disease (AD) is the main form of dementia in the elderly and affects greater than 47 million people worldwide. Care for AD patients poses very significant personal and economic demands on individuals and society, and the situation is expected to get even more dramatic in the coming decades unless effective treatments are found to halt the progression of the disease. Although AD is most commonly regarded as a disease of the memory, the entire brain is eventually affected by neuronal dysfunction or neurodegeneration, which brings about a host of other behavioral disturbances. AD patients often present with apathy, depression, eating and sleeping disorders, aggressive behavior, and other non-cognitive symptoms, which deeply affect not only the patient but also the caregiver's health. These symptoms are usually associated with AD pathology but are often neglected as part of disease progression due to the early and profound impact of disease on memory centers such as the hippocampus and entorhinal cortex. Yet, a collection of findings offers biochemical insight into mechanisms underlying non-cognitive symptoms in AD, and indicate that, at the molecular level, such symptoms share common mechanisms. Here, we review evidence indicating mechanistic links between memory loss and non-cognitive symptoms of AD. We highlight the central role of the pro-inflammatory activity of microglia in behavioral alterations in AD patients and in experimental models of the disease. We suggest that a deeper understanding of non-cognitive symptoms of AD may illuminate a new beginning in AD research, offering a fresh approach to elucidate mechanisms involved in disease progression and potentially unveiling yet unexplored therapeutic targets. PMID- 29710717 TI - Behavioral and Neuropsychiatric Disorders in Alzheimer's Disease. AB - Alzheimer's disease (AD) is the most frequent type of dementia in the elderly, severely affecting functional and executive skills of subjects suffering from this disease. Moreover, the distress of caregivers as well as the social implications constitute a critical issue for families. Furthermore, cognitive impairment, along with behavioral disorders and neuropsychiatric symptoms are characteristics of AD. Although these are present with variations in prevalence, intensity, and progression, an important core of them is visible before cognitive impairment, especially depression and apathy, which affect at least 50% of patients. The most updated literature shows that depression and/or behavioral and neuropsychiatric symptoms (BNS) are part of the initial phase of the disease rather than just a risk factor. Thus, mood disorders are associated with anomalies in specific brain regions that disturb the normal balance of neurotransmission. This in turn is linked with an inflammatory pathway that leads to microglial activation and aggregated neurofibrillary tangle formation, finally triggering neuronal loss, according to our neuroimmunomodulation theory. Altogether, inflammation and tau aggregation are observed in preclinical stages, preceding the BNS of patients, which in turn are exhibited earlier than cognitive and functional impairment detected in AD. This review is focused on the latest insights of cellular and molecular processes associated with BNS in asymptomatic early-onset stages of AD. An important medical research focus is to improve quality of life of patients, through prevention and treatments of AD, and the study of behavioral disorders and early event in AD pathogenesis has a major impact. PMID- 29710718 TI - The Progressive Acalculia Presentation of Parietal Variant Alzheimer's Disease. AB - BACKGROUND: Many patients with early-onset Alzheimer's disease (EOAD; age of onset <65 years) have non-amnestic presentations involving language (logopenic primary progressive aphasia, lvPPA), visuospatial abilities (posterior cortical atrophy, PCA), and even asymmetric symptoms consistent with corticobasal syndrome (CBS). An inferior parietal lobule variant of EOAD commonly presents with progressive difficulty with calculations. METHODS: We reviewed 276 EOAD patients for presentations with predominant acalculia. These patients were diagnosed with clinically probable Alzheimer's disease (AD) verified by positron emission tomography (PET) or cerebrospinal fluid amyloid-beta or tau biomarkers. RESULTS: We identified 18 (9M/9F) (6.5%) EOAD patients with progressive acalculia that did not meet most criteria for lvPPA, visual PCA, or CBS. Their ages of onset and presentation were 56.6 (5.0) and 59.4 (6.5), respectively. Their acalculia was consistent with a primary acalculia ("anarithmetia") not explained by language or visuospatial impairments. Many also had anomia (14/18), ideomotor apraxia (13/18), and the complete Gerstmann's syndrome (7/18). Visual analysis of their diverse magnetic resonance imaging disclosed biparietal atrophy, disproportionately worse on the left. CONCLUSIONS: Primary acalculia may be the most common manifestation of an inferior parietal presentation of EOAD affecting the left intraparietal sulcus. This parietal variant also commonly involves progressive anomia, ideomotor apraxia, and other elements of Gerstmann's syndrome. The early recognition of patients with this variant, which is distinguishable from lvPPA, visual PCA, or CBS, would be facilitated by its recognition as a unique subtype of EOAD. PMID- 29710719 TI - Distinct Patterns of Rich Club Organization in Alzheimer's Disease and Subcortical Vascular Dementia: A White Matter Network Study. AB - Recent advances in neuroimaging technology have shown that rich club organization in human brain networks plays a crucial role in global communication and cognitive functionality. In this study, we investigated rich club organization within white matter structural brain networks in two common types of dementia, Alzheimer's disease (AD) and subcortical vascular dementia (SVaD). We recruited 30 AD patients ([11C] Pittsburgh compound-B (PiB) PET positive), 39 SVaD patients (PiB negative), and 72 age-, gender-, and education-matched cognitively normal (CN) subjects. Rich club organization was significantly disrupted in both dementia patient groups, which exhibited higher rich club coefficients than the CN group. Rich club organization in the patient groups was primarily disrupted over the left frontal and left middle temporal areas when compared to the CN group. The number of rich club nodes was significantly reduced in the dementia groups, which was more severe in SVaD (p = 0.0107, permutation-based t-test). Although rich club organization was disrupted both in the patient groups, its disruption pattern is different between them. The rich-club connections normalized by degree-and-strength preserved random networks were significantly increased in the dementia groups with SVaD more severely, and feeder connections were reduced more significantly than in AD. Furthermore, SVaD patients exhibited more sporadic disruption in white matter connectivity than AD patients, with local connections showing a more significant degree of deterioration. Combined with the distinct disruption in rich club nodes, these findings may imply a differing role for rich club organization in AD and SVaD, due to different pathological mechanisms. PMID- 29710720 TI - Integrating Sleep and Alzheimer's Disease Pathophysiology: Hints for Sleep Disorders Management. AB - Sleep represents an active phenomenon regulated by a highly integrated network of cortical and subcortical structures. This complex model results in disruptions at various levels during physiological aging and more deeply during neurodegenerative disorders, thus leading to different sleep alterations. In Alzheimer's disease (AD), sleep-wake abnormalities were described to occur even in the preclinical phase, thus suggesting they could be a possible AD biomarker. On the other hand, they also favor the progression of the disease. In this paper, we review current theories regarding sleep regulations and functions to highlight the pathophysiological mechanisms at the basis of the bidirectional relationship between sleep and AD. A better understanding of these complex interactions might also be useful to target both sleep disorder management and AD-related symptoms. PMID- 29710722 TI - Mitochondrial Dysfunction as a Predictor and Driver of Alzheimer's Disease-Like Pathology in OXYS Rats. AB - Growing evidence suggests that mitochondrial dysfunction is an early event in sporadic Alzheimer's disease (AD), but the impact of mitochondrial dysfunction on the transition from healthy aging to AD remains elusive. Here we estimated the influence of mitochondrial dysfunction on the initiation of AD signs in OXYS rats, which simulate key characteristics of sporadic AD. We assessed the mitochondrial ultrastructure of pyramidal neurons of the hippocampus at the age preceding the development (age 20 days), during manifestation (4-5 months), and at the well-pronounced stages (18-24 months) of the AD-like pathology in OXYS rats. Ultrastructural alterations were collated with the amounts of proteins mediating mitochondrial dynamics [mitofusins (MFN1 and MFN2) and dynamin-1-like protein (DRP1)]; with activity of respiratory chain complexes I, IV, and V in the hippocampal mitochondria; with reactive oxygen species (ROS) production; and with expression of uncoupling protein 2 (UCP2) regulating ROS production. Already at the preclinical stage, OXYS rats showed some characteristic changes in hippocampal mitochondria, which increased in size with the manifestation and progression of AD-like pathology, including decreased activity of respiratory complexes against the background of greater fusion and formation of larger mitochondria. Signs of AD developed simultaneously with increasing dysfunction of mitochondria, with a dramatic decrease in their number, and with increased fission but without upregulation of ROS production (observed only in 20-day-old OXYS rats). Summarizing the data from our present and previous studies, we conclude that mitochondrial dysfunction appears to mediate or possibly even initiate pathological molecular cascades of AD-like pathology in OXYS rats and can be considered a predictor of the early development of the late-onset form of AD in humans. PMID- 29710721 TI - Change of Amyloid-beta 1-42 Toxic Conformer Ratio After Cerebrospinal Fluid Diversion Predicts Long-Term Cognitive Outcome in Patients with Idiopathic Normal Pressure Hydrocephalus. AB - BACKGROUND: Alzheimer's disease (AD) pathology in idiopathic normal pressure hydrocephalus (iNPH) contributes to poor shunt responses. Amyloid-beta 1- 42 (Abeta42) toxic conformer was recently identified with features of rapid oligomerization, strong neurotoxicity and synaptotoxicity. OBJECTIVE: This observational study points to Abeta42 toxic conformer as a biomarker for AD pathology and for poor postoperative prognosis in patients with iNPH. METHODS: The first cohort consisted of patients with AD (n = 17) and iNPH (n = 17), and cognitively normal individuals (CN, n = 12). The second cohort, consisted of 51 patients with iNPH, was divided into two groups according to phosphorylated Tau (pTau) level (low- and high-pTau groups); the low-pTau group was further subdivided according to one-year postoperative change in Abeta42 toxic conformer ratio (%) [Abeta42 toxic conformer/Abeta42*100] (decreased- and increased conformer subgroups). Enzyme-linked immunosorbent assay was used to measure pTau, Abeta42, and Abeta42 toxic conformer in cerebrospinal fluid. Outcomes were evaluated using neuropsychological tests one- and two-years postoperatively. RESULTS: In the first cohort, Abeta42 toxic conformer ratio in the iNPH group (10.8%) was significantly higher than that in the CN group (6.3%) and significantly lower than that in the AD group (17.2%). In the second cohort, the high-pTau group showed cognitive decline two-years postoperatively compared to baseline. However, the low-pTau group showed favorable outcomes one-year postoperatively; furthermore, the increased-conformer subgroup showed cognitive decline two-years postoperatively while the decreased-conformer subgroup maintained the improvement. CONCLUSIONS: Change in Abeta42 toxic conformer ratio predicts long-term cognitive outcome in iNPH, even in the low-pTau group. PMID- 29710723 TI - Constructing a Local Potential Participant Registry to Improve Alzheimer's Disease Clinical Research Recruitment. AB - Potential participant registries are tools to address the challenge of slow recruitment to clinical research. In particular, registries may aid recruitment to secondary prevention clinical trials for Alzheimer's disease (AD), which enroll cognitively normal older individuals meeting specific genetic or biomarker criteria. Evidence of registry effectiveness is sparse, as is guidance on optimal designs or methods of conduct. We report our experiences of developing a novel local potential participant registry that implemented online enrollment and data collection. In the first year of operation, 957 individuals submitted email addresses to the registry, of whom 592 self-reported demographic, family history, and medical data. In addition, registrants provided information related to their interest and willingness to be contacted about studies. Local earned media and community education were the most effective methods of recruitment into the registry. Seventy-six (26%) of 298 registrants contacted about studies in the first year enrolled in those studies. One hundred twenty-nine registrants were invited to enroll in a preclinical AD trial, of whom 25 (18%) screened and 6 were randomized. These results indicate that registries can aid recruitment and provide needed guidance for investigators initiating new local registries. PMID- 29710725 TI - Prevalence of Dementia and Associated Risk Factors: A Population-Based Study in the Philippines. AB - BACKGROUND: The Philippines is experiencing rapid demographic aging and with it, the dementia epidemic. Prevalence of dementia and associated risk factors have not been studied in the Philippines. OBJECTIVES: The study aimed to provide a reliable estimate of dementia prevalence and identify associated risk factors in the Filipino population. METHODS: 1460 participants 60 years and older were randomly selected from the Marikina City's senior registry. A multidisciplinary team (nurse, psychologist, and neurologist) administered a comprehensive assessment to the study population: health history, neurological examination, Geriatric Depression Scale, Neuropsychiatric Inventory, Disability Assessment for Dementia, Alzheimer's Disease 8, and Clinical Dementia Rating Scale. The neurologist analyzed all clinical data to diagnose dementia based on the DSM-IV criteria, Alzheimer's Disease (AD) on the NINCDS-ADRDA criteria, vascular dementia (VaD) on the Hachinski Ischemic Scale, cognitive impairment no dementia (CIND) on a CDR score of 0.5 and not fulfilling DSM-IV criteria for dementia. Risk factors were correlated with dementia prevalence using multivariate binary logistic regression. RESULTS: 1460 persons were randomly selected. 1367 agreed to participate and underwent all assessments. The response rate was 93.6%. Dementia prevalence was found to be 10.6% (95% CI 9.0 to 12.4) with the breakdown 85.5% AD, 11.7% VaD, and 2.7% other dementias. In this population, 82.0% of men and 70.4% of women had at least one cardiovascular risk factor (hypertension, diabetes, dyslipidemia, smoking), which was associated with VaD prevalence but not AD. CONCLUSION: The prevalence of dementia, CIND, and cardiovascular risk factors are high in the Philippines. PMID- 29710726 TI - Effectiveness of Anti-Dementia Drugs in Extremely Severe Alzheimer's Disease: A 12-Week, Multicenter, Randomized, Single-Blind Study. AB - BACKGROUND/OBJECTIVE: There is insufficient evidence to guide decisions concerning how long anti-dementia drug (ADD) regimens should be maintained in severe Alzheimer's disease (AD). We investigated whether patients with extremely severe AD who were already receiving donepezil or memantine benefited from continuing treatment. METHODS: In this randomized and rater-blinded trial, 65 AD patients with a Mini-Mental State Examination score from 0 to 5 and a score of 6c or worse on Functional Assessment Staging were randomly assigned to an ADD continuation group (N = 30) or an ADD-discontinuation group (N = 35). The current use of donepezil or memantine was maintained for 12 weeks in the ADD-continuation group and was discontinued after baseline in the ADD-discontinuation group. Efficacy measures were obtained at baseline and 12 weeks. The primary efficacy variable was the change from baseline to the end of the study in Baylor Profound Mental State Examination (BPMSE) scores. RESULTS: The change in the BPMSE from baseline to the end of the study in the ADD-continuation group (a 0.4-point improvement) was not equivalent to that in the ADD-discontinuation group (a 0.5 point decline), as determined by two one-sided tests of equivalence. Study withdrawals due to adverse events (11.4% versus 6.7%) were more frequent in the ADD-discontinuation group than in the ADD-continuation group. CONCLUSION: Continued treatment with donepezil or memantine seems unequal and might be superior to withdrawal of the drugs in terms of the effects on global cognition in patients with extremely severe AD. Current Controlled Trials number: KCT0000874 (CRIS). PMID- 29710724 TI - Moringa Oleifera Alleviates Homocysteine-Induced Alzheimer's Disease-Like Pathology and Cognitive Impairments. AB - Alzheimer's disease (AD) is multifactorial with unclear etiopathology. Due to the complexity of AD, many attempted single therapy treatments, like Abeta immunization, have generally failed. Therefore, there is a need for drugs with multiple benefits. Naturally occurring phytochemicals with neuroprotective, anti amyloidogenic, antioxidative, and anti-inflammatory properties could be a possible way out. In this study, the effect of Moringa oleifera (MO), a naturally occurring plant with high antioxidative, anti-inflammatory, and neuroprotective effects, was evaluated on hyperhomocysteinemia (HHcy) induced AD-like pathology in rats. Homocysteine (Hcy) injection for 14 days was used to induce AD-like pathology. Simultaneous MO extract gavage followed the injection as a preventive treatment or, after injection completion, MO gavage was performed for another 14 days as a curative treatment. MO was found to not only prevent but also rescue the oxidative stress and cognitive impairments induced by Hcy treatment. Moreover, MO recovered the decreased synaptic proteins PSD93, PSD95, Synapsin 1 and Synaptophysin, and improved neurodegeneration. Interestingly, MO decreased the Hyc-induced tau hyperphosphorylation at different sites including S-199, T 231, S-396, and S-404, and at the same time decreased Abeta production through downregulation of BACE1. These effects in HHcy rats were accompanied by a decrease in calpain activity under MO treatment, supporting that calpain activation might be involved in AD pathogenesis in HHcy rats. Taken together, our data, for the first time, provided evidence that MO alleviates tau hyperphosphorylation and Abeta pathology in a HHcy AD rat model. This and previous other studies support MO as a good candidate for, and could provide new insights into, the treatment of AD and other tauopathies. PMID- 29710727 TI - Association between heart rhythm and cortical sound processing. AB - Sound signal processing signifies an important factor for human conscious communication and it may be assessed through cortical auditory evoked potentials (CAEP). Heart rate variability (HRV) provides information about heart rate autonomic regulation. We investigated the association between resting HRV and CAEP. We evaluated resting HRV in the time and frequency domain and the CAEP components. The subjects remained at rest for 10 minutes for HRV recording, then they performed the CAEP examinations through frequency and duration protocols in both ears. Linear regression indicated that the amplitude of the N2 wave of the CAEP in the left ear (not right ear) was significantly influenced by standard deviation of normal-to-normal RR-intervals (17.7%) and percentage of adjacent RR intervals with a difference of duration greater than 50 milliseconds (25.3%) time domain HRV indices in the frequency protocol. In the duration protocol and in the left ear the latency of the P2 wave was significantly influenced by low (LF) (20.8%) and high frequency (HF) bands in normalized units (21%) and LF/HF ratio (22.4%) indices of HRV spectral analysis. The latency of the N2 wave was significantly influenced by LF (25.8%), HF (25.9%) and LF/HF (28.8%). In conclusion, we promote the supposition that resting heart rhythm is associated with thalamo-cortical, cortical-cortical and auditory cortex pathways involved with auditory processing in the right hemisphere. PMID- 29710728 TI - An algebraic aspect of Pareto mixture parameter estimation using censored sample: A Bayesian approach. AB - Applications of Pareto distribution are common in reliability, survival and financial studies. In this paper, A Pareto mixture distribution is considered to model a heterogeneous population comprising of two subgroups. Each of two subgroups is characterized by the same functional form with unknown distinct shape and scale parameters. Bayes estimators have been derived using flat and conjugate priors using squared error loss function. Standard errors have also been derived for the Bayes estimators. An interesting feature of this study is the preparation of components of Fisher Information matrix. PMID- 29710729 TI - Carreau fluid over a radiated shrinking sheet in a suspension of dust and Titanium alloy nanoparticles with heat source. AB - This study explores the magneto hydrodynamic Carreau fluid in the interruption of titanium alloy nanoparticles with heat generation and porosity. The simulation is performed by combination of titanium alloy nanoparticles into base water. Titanium is strong and light in weight and sit is used in military and aerospace, in bio science it is used as anti-microbial, anti-biotic, and anti-fungal agents. The arising set of partial differential equations (P.D.E) are converted into set of ordinary differential equation (O.D.E) using suitable similarity transformation and then solved by the help of Runge-Kutta with shooting method technique. The computational results for non-dimensional temperature and velocity are presented with graphs. We analyzed the numerical values of physical quantities (friction factor and local Nusselt number) for various values physical parameters and they are presented in tables. We also compared the current result with existing result under some limited cases. At end of our analysis we notified that the temperature profiles are enriched with increasing values of heat generation and porosity parameter. PMID- 29710730 TI - Viral encephalitis in quantitative EEG. AB - OBJECTIVE: Our aim was to study the character of quantitative EEG of viral encephalitis. METHOD: Collect the EEG data of hospitalized children with viral encephalitis diagnosed by pediatricians from January 2013 to September 2016, and EEG data of normal cases at the same age were control group. Using quantitative EEG analysis technologies to obtain power spectrum value, power spectrum value, 1 power spectrum value, 12 power spectrum value, 21 power spectrum value, and 12 power spectrum value. Relative power spectrum values of 2 and were obtained by calculation. All the cases were divided into 5 groups according to the EEG character: age 3 group, age 4 group, age 5-6 group, age 7-9-year group, and age 10-14-year group. Viral encephalitis group and normal cases group were statistically compared to obtain characters of quantitative EEG with viral encephalitis. RESULTS: Power spectrum values and power spectrum values of 3-14 year-old cases with encephalitis increased. 1 power spectrum values existed in age 3 group with viral encephalitis and declined at the post-head lead, while 11 and 12 power spectrum values existed in age 4-14 group with viral encephalitis declined at the post-head lead. The value of 2 Power spectrum values of age 3-9 group was limited in diagnosing viral encephalitis. 1 and 12 power spectrum values decrease in age 10-14 group with viral encephalitis. Relative power spectrum values of 2 and increased in age 3-14 group with viral encephalitis; Relative power spectrum values of decreased in age 3-14 group with viral encephalitis, most lead of relative power spectrum decreased in age 3-14 group with viral encephalitis. CONCLUSION: The character of quantitative EEG of cases with viral encephalitis is similar to EEG, but more detailed, more precise, more intuitive and can be used for clinical diagnose of viral encephalitis. PMID- 29710731 TI - A comparative analysis for the solution of nonlinear Burgers' equation. AB - In this work, a comparative study of seven well-known mathematical techniques for the coupled Burgers' equations is reported. The techniques involve in this comparison are as follows: Laplace transform Adomian decomposition method, Laplace transform homotopy perturbation method, Variational iteration method, Variational iteration decomposition method, Variational iteration homotopy perturbation method, the optimal homotopy asymptotic method, and OHAM with Daftardar-Jafari polynomial. Here we considered a practical example which consists of coupled Burgers' equations with the kinematic viscosity epsilon=1. Convergence and stability analysis is a major part of this analysis. After a careful observation, it is found that the variational iteration method has faster convergence than all the remaining methods. Adomian decomposition method and Homotopy perturbation method show weaker stability in comparison with other involved techniques. PMID- 29710732 TI - The influence of cross diffusion on magnetohydrodynamic flow of Carreau liquid in the presence of buoyancy force. AB - The flow of magnetohydrodynamic Carreau liquid with the Brownian moment, thermophoresis and cross diffusion effects is investigated numerically. The buoyancy persuades on the flow is contemplated in such a way that the surface is neither perpendicular/horizontal nor wedge/cone. This is very helpful in the design of jet-engine. The equations govern the flow are transmuted using acceptable similarity variables and numerically solved by recruiting Runge-Kutta based Newtons method. The graphical results are obtained to discuss the stimulus of flow, thermal and concentration fields for different parameters of interest. The wall friction, local Nusselt and Sherwood numbers are examined with the assistance of tables. It is noticed that the parabolic flow is controlled by the buoyant forces developed by the temperature difference. Since the flow is laminar, the Reynolds number considered as <1000. This study has applicable in man-made products and various industries like pumps and oil purification, petroleum production, power engineering and chemical engineering processes. PMID- 29710733 TI - Stability of latent pathogen infection model with adaptive immunity and delays. AB - In this paper we propose and analyze a pathogen dynamics model with antibody and Cytotoxic T Lymphocyte (CTL) immune responses. We incorporate latently infected cells and three distributed time delays into the model. We show that the solutions of the proposed model are nonnegative and ultimately bounded. We derive four threshold parameters which fully determine the existence and stability of the five steady states of the model. Using Lyapunov functionals, we established the global stability of the steady states of the model. The theoretical results are confirmed by numerical simulations. PMID- 29710734 TI - Evidence of Neurobiological Changes in the Presymptomatic PINK1 Knockout Rat. AB - BACKGROUND: Genetic models of Parkinson's disease (PD) coupled with advanced imaging techniques can elucidate neurobiological disease progression, and can help identify early biomarkers before clinical signs emerge. PTEN-induced putative kinase 1 (PINK1) helps protect neurons from mitochondrial dysfunction, and a mutation in the associated gene is a risk factor for recessive familial PD. The PINK1 knockout (KO) rat is a novel model for familial PD that has not been neuroradiologically characterized for alterations in brain structure/function, alongside behavior, prior to 4 months of age. OBJECTIVE: To identify biomarkers of presymptomatic PD in the PINK1 -/- rat at 3 months using magnetic resonance imaging techniques. METHODS: At postnatal weeks 12-13; one month earlier than previously reported signs of motor and cognitive dysfunction, this study combined imaging modalities, including assessment of quantitative anisotropy across 171 individual brain areas using an annotated MRI rat brain atlas to identify sites of gray matter alteration between wild-type and PINK1 -/- rats. RESULTS: The olfactory system, hypothalamus, thalamus, nucleus accumbens, and cerebellum showed differences in anisotropy between experimental groups. Molecular analyses revealed reduced levels of glutathione, ATP, and elevated oxidative stress in the substantia nigra, striatum and deep cerebellar nuclei. Mitochondrial genes encoding proteins in Complex IV, along with mRNA levels associated with mitochondrial function and genes involved in glutathione synthesis were reduced. Differences in brain structure did not align with any cognitive or motor impairment. CONCLUSIONS: These data reveal early markers, and highlight novel brain regions involved in the pathology of PD in the PINK1 -/- rat before behavioral dysfunction occurs. PMID- 29710736 TI - Provoking Freezing of Gait in Clinical Practice: Turning in Place is More Effective than Stepping in Place. PMID- 29710737 TI - Cerebral glucose deficiency versus oxygen deficiency in neonatal encephalopathy. AB - Hypoxic-ischemic encephalopathy (HIE) in newborn infants is generally considered to result from decreased arterial oxygen content or cerebral blood flow. Cerebral injury similar to that of HIE has been noted with hypoglycemia. Studies in fetal lambs have shown that ventilation with 3% oxygen did not change cerebral blood flow, but ventilation with 100% oxygen resulted in marked reduction in cerebral blood flow, glucose delivery and glucose consumption. Blood glucose concentration falls markedly after birth; this, associated with the fall in cerebral blood flow, greatly reduces glucose supply to the brain. In preterm infants, blood glucose levels tend to be very low. Also persistent patency of the ductus arteriosus may reduce cerebral flow in diastole, thus exaggerating the decrease in glucose supply. I propose that glycopenic-ischemic encephalopathy is a more appropriate term for the cerebral insult. We should consider more aggressive management of the low blood glucose concentrations in the neonate, and particularly in preterm infants. Administration of high levels of oxygen in inspired air should be avoided to reduce the enhancement of cerebral vasoconstriction and decreased flow that normally occurs after birth. PMID- 29710738 TI - Medico-legal implications of hypothermic neuroprotection in the newborn. AB - Hypoxic-ischemic encephalopathy (HIE) continues to be a significant source of long term neurological sequelae in infants born at or near term. In the past decade, selective head or whole body cooling has shown promising benefit in ameliorating some of the brain injury from intrapartum asphyxial insults and has become standard care in most developed countries. A decision to offer neuroprotective hypothermia (NPH) may engender subsequent litigation because it presupposes an acute intrapartum injury. Conversely, failing to offer cooling may be interpreted as a violation in the standard of care. In this paper, we review the clinical aspects of NPH and the medico-legal scenarios often seen after acute birth injury. PMID- 29710739 TI - Have we made progress with educational services for students with TBI? PMID- 29710735 TI - Gene Therapy for Parkinson's Disease, An Update. AB - The current mainstay treatment of Parkinson's disease (PD) consists of dopamine replacement therapy which, in addition to causing several side effects, does not delay disease progression. The field of gene therapy offers a potential means to improve current therapy. The present review gives an update of the present status of gene therapy for PD. Both non-disease and disease modifying transgenes have been tested for PD gene therapy in animal and human studies. Non-disease modifying treatments targeting dopamine or GABA synthesis have been successful and promising at improving PD symptomatology in randomized clinical studies, but substantial testing remains before these can be implemented in the standard clinical treatment repertoire. As for disease modifying targets that theoretically offer the possibility of slowing the progression of disease, several neurotrophic factors show encouraging results in preclinical models (e.g., neurturin, GDNF, BDNF, CDNF, VEGF-A). However, so far, clinical trials have only tested neurturin, and, unfortunately, no trial has been able to meet its primary endpoint. Future clinical trials with neurotrophic factors clearly deserve to be conducted, considering the still enticing goal of actually slowing the disease process of PD. As alternative types of gene therapy, opto- and chemogenetics might also find future use in PD treatment and novel genome-editing technology could also potentially be applied as individualized gene therapy for genetic types of PD. PMID- 29710740 TI - A comparative study to determine the optimal intravitreal injection angle to the eye: A computational fluid-structure interaction model. AB - This study was aimed at investigating the role of IVI angle on the induced stresses and deformations among the components of the eye. Thereafter, the most optimal angle of IVI to minimize the complications of post IVI at the injection site on a basis of the computed stresses via a Fluid-Structure Interaction (FSI) computational model was proposed. IntraVitreal Injection (IVI) is broadly employed as a principal treatment of vascular vitro-retinal diseases. So far, there have been reports regarding the complications of post IVI and determine them as severe uveitis, tractional retinal detachment, IntraOcular Pressure (IOP) elevation as well as ocular haemorrhage. However, there is a lack of knowledge on how to reduce the subsequent ocular tissue damage and patient symptoms in the injection site. Seven different IVI angles were simulated, including 0?, 15?, 30?, 45?, 60?, 75?, and 90?, through the Finite Element (FE) code; and the term, 'post IVI complication' or 'injury', in the results was interpreted as the level of maximal principal stress in the eye components. The results revealed the lowest amount of stresses at the angle of 45? in respect to the horizontal line (acute to the surface of the sclera) for the lens, iris, vitreous body, aqueous body, ciliary body, sclera, retina, and choroid. The cornea illustrated the same amount of stress at the angles of 45?, 60?, 75?, and 90? with the highest one at the IVI angle of 30?. The lowest and the highest stresses among the eye components regardless of IVI angle were observed in the choroid and retina/sclera, respectively, which imply the importance of the IVI angle on the stresses of these eye components. The findings of the contemporary research revealed that the IVI angle of 45? would trigger less post IVI complications and, as a result, a more effective surgery outcome compared to the other angles, i.e., 0?, 15?, 30?, 60?, 75?, and 90?. PMID- 29710741 TI - The comparison of transfemoral amputees using mechanical and microprocessor- controlled prosthetic knee under different walking speeds: A randomized cross over trial. AB - BACKGROUND: The microprocessor-controlled prosthetic knees have been introduced to transfemoral amputees due to advances in biomedical engineering. A body of scientific literature has shown that the microprocessor-controlled prosthetic knees improve the gait and functional abilities of persons with transfemoral amputation. OBJECTIVE: The aim of this study was to propose a new microprocessor controlled prosthetic knee (MPK) and compare it with non-microprocessor controlled prosthetic knees (NMPKs) under different walking speeds. METHODS: The microprocessor-controlled prosthetic knee (i-KNEE) with hydraulic damper was developed. The comfortable self-selected walking speeds of 12 subjects with i KNEE and NMPK were obtained. The maximum swing flexion knee angle and gait symmetry were compared in i-KNEE and NMPK condition. RESULTS: The comfortable self-selected walking speeds of some subjects were higher with i-KNEE while some were not. There was no significant difference in comfortable self-selected walking speed between the i-KNEE and the NMPK condition (P= 0.138). The peak prosthetic knee flexion during swing in the i-KNEE condition was between sixty and seventy degree under any walking speed. In the NMPK condition, the maximum swing flexion knee angle changed significantly. And it increased with walking speed. There is no significant difference in knee kinematic symmetry when the subjects wear the i-KNEE or NMPK. CONCLUSIONS: The results of this study indicated that the new microprocessor-controlled prosthetic knee was suitable for transfemoral amputees. The maximum swing flexion knee angle under different walking speeds showed different properties in the NMPK and i-KNEE condition. The i-KNEE was more adaptive to speed changes. There was little difference of comfortable self-selected walking speed between i-KNEE and NMPK condition. PMID- 29710742 TI - A comprehensive prediction and evaluation method of pilot workload. AB - BACKGROUND: The prediction and evaluation of pilot workload is a key problem in human factor airworthiness of cockpit. OBJECTIVE: A pilot traffic pattern task was designed in a flight simulation environment in order to carry out the pilot workload prediction and improve the evaluation method. METHODS: The prediction of typical flight subtasks and dynamic workloads (cruise, approach, and landing) were built up based on multiple resource theory, and a favorable validity was achieved by the correlation analysis verification between sensitive physiological data and the predicted value. RESULTS: Statistical analysis indicated that eye movement indices (fixation frequency, mean fixation time, saccade frequency, mean saccade time, and mean pupil diameter), Electrocardiogram indices (mean normal-to normal interval and the ratio between low frequency and sum of low frequency and high frequency), and Electrodermal Activity indices (mean tonic and mean phasic) were all sensitive to typical workloads of subjects. CONCLUSION: A multinominal logistic regression model based on combination of physiological indices (fixation frequency, mean normal-to-normal interval, the ratio between low frequency and sum of low frequency and high frequency, and mean tonic) was constructed, and the discriminate accuracy was comparatively ideal with a rate of 84.85%. PMID- 29710743 TI - Study of altered functional connectivity in individuals at risk for Alzheimer's Disease. AB - BACKGROUND: Mild Cognitive Impairment (MCI) has been considered to have a high risk in converting into Alzheimer's Disease (AD). Previous studies showed that AD was associated with changes in resting-state networks (RSNs). However, few studies have evaluated the altered functional connectivity in early mild cognitive impairment (EMCI) and late mild cognitive impairment (LMCI). OBJECTIVE: The aim of this work was to evaluate the impaired network functional connectivity with the disease progression. METHODS: In this paper, we evaluated the impaired function connectivity with the progression of disease based on a priori defined 246 regions of interest based on Brainnetome Atlas. Connectivity analysis based on three levels (node integrity, intra-network, and inter-network) was conducted. RESULTS: Altered function connectivity was detected in several RSNs. These results provided insights into the dysfunction of more RSNs accompany the progression of AD. We also found that one brain region may belong to multiple RSNs and contribute to achieving different network function. CONCLUSIONS: The aberrant intra- and inter-network dysfunctions might be potential biomarkers or predictors of MCI and AD progression and provide new insight into the pathophysiology of these diseases. PMID- 29710744 TI - Changes in the bilateral pulse transit time difference with a moving arm. AB - BACKGROUND: Changes of pulse transit time (PTT) induced by arm position were studied for unilateral arm. However, consistency of the PTT changes was not validated for both arm sides. OBJECTIVE: We aimed to quantify the PTT changes between horizontal and non-horizontal positions from right arm and left arm in order to explore the consistency of both arms. METHODS: Twenty-four normal subjects aged between 21 and 50 (14 male and 10 female) years were enrolled. Left and right radial artery pulses were synchronously recorded from 24 healthy subjects with one arm (left or right) at five angles (90?, 45?, 0?, -45? and 90?) and the other arm at the horizontal level (0?) for reference. RESULTS: The overall mean PTT changes at the five angles (from 90? to -90?) in the left arm (right as reference) were 16.1, 12.3, -0.5, -2.5 and -2.6 ms, respectively, and in the right arm (left as reference) were 18.0, 12.6, 1.6, -1.6 and -2.0 ms, respectively. CONCLUSIONS: Obvious differences were not found in the PTT changes between the two arms (left arm moving or right arm moving) under each of the five different positions (all P> 0.05). PMID- 29710745 TI - Prediction of microRNA and gene target from an integrated network in chronic obstructive pulmonary disease based on canonical correlation analysis. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a complex disorder with a high mortality. The pathophysiology of COPD has not been characterized till date. OBJECTIVE: To identify COPD-related biomarkers by a bioinformatics analysis. METHODS: Here, we conducted the canonical correlation analysis to extract the potential COPD-related miRNAs and mRNAs based on the miRNA-mRNA dual expression profiling data. After identifying miRNAs and mRNAs related to COPD, we constructed an interaction network by integrating three validated miRNA-target sources. Then we expanded the network by adding miRNA-mRNA pairs, which were identified by Spearman rank correlation test. For miRNAs involved in the network, we further performed the Gene Ontology (GO) functional enrichment analysis of their targets. To validate COPD-related mRNAs involved in the network, we performed receiver operating characteristic (ROC) curve analysis and Support Vector Machine (SVM) classification on only those mRNAs that overlapped with COPD related mRNAs of Online Mendelian Inheritance in Man (OMIM) database. RESULTS: The results indicate that some identified miRNAs and their targets in the constructed network might be potential biomarkers of COPD. CONCLUSIONS: Our study helps us to predict the potential risk biomarkers of COPD, and it can certainly help in further elucidating the genetic etiology of COPD. PMID- 29710746 TI - Effect of 405 nm low intensity irradiation on the absorption spectrum of in-vitro hyperlipidemia blood. AB - BACKGROUND: Laser therapy is reported to be clinically effective for improving microcirculation, rheological properties and blood lipid profiles despite the lack of certainty on the mechanism. OBJECTIVE: This study intends to provide methods to drop blood lipid level of hyperlipidemia samples by low-intensity laser irradiation therapy and provide reasoning of mechanism. METHODS: Twenty whole blood samples of high level of lipids profile are irradiated by 405 nm low intensity laser at 12 J/cm2 twice a day for 3 days and compared with normal lipids profile group. Then whole blood sample are centrifuged to obtain result of erythrocyte for further interpretation. Multi-scan spectrum microplate reader is used to measure absorption spectrum and data is analyzed by software SPSS 14.0. RESULTS: Results show that after 405 nm low-intensity laser irradiation, whole blood samples of high lipid level statistically have higher absorbance peak value than normal samples while erythrocyte samples have lower absorbance peak value. CONCLUSIONS: From the divergence of absorption peak value change after low intensity laser irradiation for whole blood sample and erythrocyte, we suspect that low level laser irradiation affects the enzymes activity of lipid metabolism, improves the cholesterol balance of plasma and cytoplasm in erythrocyte, and decreases aggregation of the erythrocyte. PMID- 29710747 TI - Effect of rehabilitation on the somatosensory evoked potentials and gait performance of hemiparetic stroke patients. AB - BACKGROUND: Gait performance of stroke patients is affected by impaired sensory ability. The purpose of the present study was to determine the relationship between somatosensory-evoked potential (SSEP) parameters and gait performance in hemiparetic stroke patients. METHODS: A convenience sample of 17 hemiparetic stroke patients (mean age 60.11 +/- 8.83 years; 10 women; right hemiplegia: 10, left hemiplegia: 7) were recruited for the present study. The Electro Synergy system (Viasys Healthcare; San Diego, CA, USA) was used for SSEP evaluation. The 17 patients were assigned to two groups according to their SSEP results as follows: 8 patients to the normal response group and 9 patients to the abnormal group. All the participants underwent the same rehabilitation exercise programs during 4 weeks, followed by clinical evaluation. A mixed-design analysis of a variance model was used to test for differences in timed up-and-go (TUG) test and 10-meter walking test (10MWT) scores between the two independent groups while the participants were subjected to repeated measures (pretest and posttest). RESULTS: Analysis of variance revealed the main time effect (p< 0.05) and group by time interaction effect (p< 0.05). The post hoc test result confirmed that the normal sensory group showed greater improvement in TUG test and 10MWT scores than the abnormal sensory group (p< 0.05). The TUG test and 10MWT scores in the posttest were greater in the normal sensory group than in the abnormal sensory group. CONCLUSIONS: The present study demonstrated the importance of the clinical contribution of the baseline sensory function of individuals with hemiparetic stroke to their gait performance and recovery after stroke rehabilitation. As anticipated, the individuals who had intact or spared sensory function showed greater improvements in gait speed and performance measures than those who had impaired sensory function. PMID- 29710748 TI - Sparse feature learning for multi-class Parkinson's disease classification. AB - This paper solves the multi-class classification problem for Parkinson's disease (PD) analysis by a sparse discriminative feature selection framework. Specifically, we propose a framework to construct a least square regression model based on the Fisher's linear discriminant analysis (LDA) and locality preserving projection (LPP). This framework utilizes the global and local information to select the most relevant and discriminative features to boost classification performance. Differing in previous methods for binary classification, we perform a multi-class classification for PD diagnosis. Our proposed method is evaluated on the public available Parkinson's progression markers initiative (PPMI) datasets. Extensive experimental results indicate that our proposed method identifies highly suitable regions for further PD analysis and diagnosis and outperforms state-of-the-art methods. PMID- 29710749 TI - A novel hand gesture recognition method based on 2-channel sEMG. AB - Hand gesture recognition is getting more and more important in the area of rehabilitation and human machine interface (HMI). However, most current approaches are difficult to achieve practical application because of an excess of sensors. In this work, we proposed a method to recognize six common hand gestures and establish the optimal relationship between hand gesture and muscle by utilizing only two channels of surface electromyography (sEMG). We proposed an integrated approach to process the sEMG data including filtering, endpoint detection, feature extraction, and classifier. In this study, we used one-order digital lowpass infinite impulse response (IIR) filter with the cutoff frequency of 500 Hz to extract the envelope of the sEMG signals. The energy was utilized as a feature to detect the endpoint of motion. The short-time energy, zero-crossing rate and linear predictive coefficient (LPC) with 12 levels were chosen as the features and back propagation (BP) neural network was utilized to classify. In order to test the method, five subjects were involved in the experiment to test the hypothesis. With the proposed method, 96.41% to 99.70% recognition rate was obtained. The experimental results revealed that the proposed method is highly efficient both in sEMG data acquisition and hand motions recognition, and played a role in promoting hand rehabilitation and HMI. PMID- 29710750 TI - Multi-task fused sparse learning for mild cognitive impairment identification. AB - BACKGROUND: Brain functional connectivity network (BFCN) has been widely applied to identify biomarkers for the brain function understanding and brain diseases analysis. OBJECTIVE: Building a biologically meaningful brain network is a crucial work in these applications. For this task, sparse learning has been widely applied for the network construction. If multiple time-point data is added to the brain imaging application, the disease progression pattern in the longitudinal analysis can be better revealed. METHODS: A novel longitudinal analysis for MCI classification is devised based on resting-state functional magnetic resonating imaging (rs-fMRI). Specifically, this paper proposes a novel multi-task learning method to integrate fused penalty by regularization. In addition, a novel objective function is developed for fused sparse learning via smoothness constraint. RESULTS: The proposed method achieves the best classification performance with an accuracy of 95.74% for baseline and 93.64% for year 1 data. CONCLUSIONS: The experimental results show that our proposed method achieves quite promising classification performance. PMID- 29710751 TI - In vivo noninvasive blood glucose detection using near-infrared spectrum based on the PSO-2ANN model. AB - BACKGROUND: To improving the nursing level of diabetics, it is necessary to develop noninvasive blood glucose method. OBJECTIVE: In order to reduce the number of the near-infrared signal, consider the nonlinear relationship between the blood glucose concentration and near-infrared signal, and correct the individual difference and physiological glucose dynamic, 2 artificial neural networks (2ANN) combined with particle swarm optimization (PSO), named as PSO 2ANN, is proposed. METHOD: Two artificial neural networks (ANNs) are employed as the basic structure of the PSO-ANN model, and the weight coefficients of the two ANNs which represent the difference of individual and daily physiological rule are optimized by particle swarm optimization (PSO). RESULTS: Clarke error grid shows the blood glucose predictions are distributed in regions A and B, Bland Altman analysis show that the predictions and measurements are in good agreement. CONCLUSIONS: The PSO-2ANN model is a nonlinear calibration strategy with accuracy and robustness using 1550-nm spectroscopy, which can correct the individual difference and physiological glucose dynamics. PMID- 29710753 TI - Finger language recognition based on ensemble artificial neural network learning using armband EMG sensors. AB - BACKGROUND: Deaf people use sign or finger languages for communication, but these methods of communication are very specialized. For this reason, the deaf can suffer from social inequalities and financial losses due to their communication restrictions. OBJECTIVE: In this study, we developed a finger language recognition algorithm based on an ensemble artificial neural network (E-ANN) using an armband system with 8-channel electromyography (EMG) sensors. METHODS: The developed algorithm was composed of signal acquisition, filtering, segmentation, feature extraction and an E-ANN based classifier that was evaluated with the Korean finger language (14 consonants, 17 vowels and 7 numbers) in 17 subjects. E-ANN was categorized according to the number of classifiers (1 to 10) and size of training data (50 to 1500). The accuracy of the E-ANN-based classifier was obtained by 5-fold cross validation and compared with an artificial neural network (ANN)-based classifier. RESULTS AND CONCLUSIONS: As the number of classifiers (1 to 8) and size of training data (50 to 300) increased, the average accuracy of the E-ANN-based classifier increased and the standard deviation decreased. The optimal E-ANN was composed with eight classifiers and 300 size of training data, and the accuracy of the E-ANN was significantly higher than that of the general ANN. PMID- 29710752 TI - Effect of ventricular myocardium characteristics on the defibrillation threshold. AB - Myocardium characteristics differ markedly among individuals and play an important role in defibrillation threshold. The accuracy of simulation models used in most published studies are still have room to be improved and most of them only discussed the effect of myocardial anisotropy on defibrillation threshold. In our manuscript, a rabbit ventricular finite-element (FE) volume conductor model with high precision was constructed. Ventricular myocardium characteristics include cardiomyocyte coupling and the degree of myocardial anisotropy, which are represented as the value and the ratio of anisotropic conductivity, respectively. Quantitative analysis was performed simultaneously in terms of cardiomyocyte coupling and the degree of myocardial anisotropy. Based on this, the combined effects of these two factors were further discussed. The electric field distributions of shocks and the defibrillation thresholds under different myocardial characteristics were simulated on this model. The simulation results revealed that as the degree of myocardial anisotropy increases, defibrillation threshold increases, and cardiomyocyte decoupling (decrease in electrical conductivity) can considerably increase the defibrillation threshold. PMID- 29710754 TI - Structural analysis of a rehabilitative training system based on a ceiling rail for safety of hemiplegia patients. AB - The body-weight support (BWS) function, which helps to decrease load stresses on a user, is an effective tool for gait and balance rehabilitation training for elderly people with weakened lower-extremity muscular strength, hemiplegic patients, etc. This study conducts structural analysis to secure user safety in order to develop a rail-type gait and balance rehabilitation training system (RRTS). The RRTS comprises a rail, trolley, and brain-machine interface. The rail (platform) is connected to the ceiling structure, bearing the loads of the RRTS and of the user and allowing locomobility. The trolley consists of a smart drive unit (SDU) that assists the user with forward and backward mobility and a body weight support (BWS) unit that helps the user to control his/her body-weight load, depending on the severity of his/her hemiplegia. The brain-machine interface estimates and measures on a real-time basis the body-weight (load) of the user and the intended direction of his/her movement. Considering the weight of the system and the user, the mechanical safety performance of the system frame under an applied 250-kg static load is verified through structural analysis using ABAQUS (6.14-3) software. The maximum stresses applied on the rail and trolley under the given gravity load of 250 kg, respectively, are 18.52 MPa and 48.44 MPa. The respective safety factors are computed to be 7.83 and 5.26, confirming the RRTS's mechanical safety. An RRTS with verified structural safety could be utilized for gait movement and balance rehabilitation and training for patients with hemiplegia. PMID- 29710755 TI - Efficient use of mobile devices for quantification of pressure injury images. AB - Pressure Injuries are chronic wounds that are formed due to the constriction of the soft tissues against bone prominences. In order to assess these injuries, the medical personnel carry out the evaluation and diagnosis using visual methods and manual measurements, which can be inaccurate and may generate discomfort in the patients. By using segmentation techniques, the Pressure Injuries can be extracted from an image and accurately parameterized, leading to a correct diagnosis. In general, these techniques are based on the solution of differential equations and the involved numerical methods are demanding in terms of computational resources. In previous work, we proposed a technique developed using toroidal parametric equations for image decomposition and segmentation without solving differential equations. In this paper, we present the development of a mobile application useful for the non-contact assessment of Pressure Injuries based on the toroidal decomposition from images. The usage of this technique allows us to achieve an accurate segmentation almost 8 times faster than Active Contours without Edges (ACWE) and Dynamic Contours methods. We describe the techniques and the implementation for Android devices using Python and Kivy. This application allows for the segmentation and parameterization of injuries, obtain relevant information for the diagnosis and tracking the evolution of patient's injuries. PMID- 29710756 TI - Noise reduction algorithm with the soft thresholding based on the Shannon entropy and bone-conduction speech cross- correlation bands. AB - BACKGROUND: The conventional methods of speech enhancement, noise reduction, and voice activity detection are based on the suppression of noise or non-speech components of the target air-conduction signals. However, air-conduced speech is hard to differentiate from babble or white noise signals. OBJECTIVE: To overcome this problem, the proposed algorithm uses the bone-conduction speech signals and soft thresholding based on the Shannon entropy principle and cross-correlation of air- and bone-conduction signals. METHODS: A new algorithm for speech detection and noise reduction is proposed, which makes use of the Shannon entropy principle and cross-correlation with the bone-conduction speech signals to threshold the wavelet packet coefficients of the noisy speech. RESULTS: The proposed method can be get efficient result by objective quality measure that are PESQ, RMSE, Correlation, SNR. CONCLUSION: Each threshold is generated by the entropy and cross-correlation approaches in the decomposed bands using the wavelet packet decomposition. As a result, the noise is reduced by the proposed method using the MATLAB simulation. To verify the method feasibility, we compared the air- and bone-conduction speech signals and their spectra by the proposed method. As a result, high performance of the proposed method is confirmed, which makes it quite instrumental to future applications in communication devices, noisy environment, construction, and military operations. PMID- 29710757 TI - Safety evaluation and consideration of 4 Pin Multi-needle for meso-therapy. AB - This study was conducted according to the method presented in the Republic of Korea Pharmacopoeia 11th Revision, aseptic test method to evaluate the suitability of sterilization for a sterile needle (4 Pin Multi-needle). In this study, four tests were conducted: sterility test, cytotoxicity test, acute toxicity test, skin sensitization test. First, in the aseptic test, the microorganism was not proliferated in the aseptic test of the medium. As a result of the performance test of the medium, it was confirmed that the microorganism developed within 3 days and the fungus was evident within 5 days. Based on this, it was confirmed that the medium was suitable, and as a result of the aseptic test, the development of microorganisms was not observed during the total culture period. Based on these results, tests were conducted which were confirmed to be suitable for aseptic testing because the development of bacteria on the provided samples was not recognized. For cytotoxicity tests ISO10993-5; 2009 (Biological Evaluation of Medical Devices, Part 5: Test for in vitro Cytotoxicity). As a result, the MEM eluate of the test substance caused very slight cytotoxicity to the fibroblasts of the mouse and was judged to be Grade 1 (Slightly cytotoxic) according to the judgment standard of ISO 10993-5. On the other hand, solvent control, negative control and positive control showed the expected results on the test. Acute Toxicity Test Results: It was judged that there was no systemic toxicity change when ICR mice were treated with 50 mL/kg B.W. of the eluate of sterile injectable needle for 72 hours. Skin sensitization test result: The Hartley guinea pig was evaluated as a substance which is evaluated as a substance which does not induce any skin reaction when skin sensitization is applied to the dissected material of the sterile injectable needle and is weak in skin sensitivity. Based on the above tests, we will study the stability and efficacy of more reliable medical devices based on the verification and performance of medical devices. PMID- 29710758 TI - Soft tissue deformation estimation by spatio-temporal Kalman filter finite element method. AB - BACKGROUND: Soft tissue modeling plays an important role in the development of surgical training simulators as well as in robot-assisted minimally invasive surgeries. It has been known that while the traditional Finite Element Method (FEM) promises the accurate modeling of soft tissue deformation, it still suffers from a slow computational process. OBJECTIVE: This paper presents a Kalman filter finite element method to model soft tissue deformation in real time without sacrificing the traditional FEM accuracy. METHODS: The proposed method employs the FEM equilibrium equation and formulates it as a filtering process to estimate soft tissue behavior using real-time measurement data. The model is temporally discretized using the Newmark method and further formulated as the system state equation. RESULTS: Simulation results demonstrate that the computational time of KF-FEM is approximately 10 times shorter than the traditional FEM and it is still as accurate as the traditional FEM. The normalized root-mean-square error of the proposed KF-FEM in reference to the traditional FEM is computed as 0.0116. CONCLUSIONS: It is concluded that the proposed method significantly improves the computational performance of the traditional FEM without sacrificing FEM accuracy. The proposed method also filters noises involved in system state and measurement data. PMID- 29710759 TI - Classification of single-channel EEG signals for epileptic seizures detection based on hybrid features. AB - BACKGROUND: Epilepsy is a common chronic neurological disorder of the brain. Clinically, epileptic seizures are usually detected via the continuous monitoring of electroencephalogram (EEG) signals by experienced neurophysiologists. OBJECTIVE: In order to detect epileptic seizures automatically with a satisfactory precision, a new method is proposed which defines hybrid features that could characterize the epileptiform waves and classify single-channel EEG signals. METHODS: The hybrid features consist of both the ones usually used in EEG signal analysis and the Kraskov entropy based on Hilbert-Huang Transform which is proposed for the first time. With the hybrid features, EEG signals are classified and the epileptic seizures are detected. RESULTS: Three datasets are used for test on three binary-classification problems defined by clinical requirements for epileptic seizures detection. Experimental results show that the accuracy, sensitivity and specificity of the proposed methods outperform two state-of-the-art methods, especially on the databases containing signals from different sources. CONCLUSIONS: The proposed method provides a new avenue to assist neurophysiologists in diagnosing epileptic seizures automatically and accurately. PMID- 29710760 TI - Effects of live and video form action observation training on upper limb function in children with hemiparetic cerebral palsy. AB - PURPOSE: The purpose of this study was to investigate the effects of live and video form action observation training (AOT) on upper limb (UL) movement acceleration and function in children with cerebral palsy (CP). METHODS: In total, 12 children (7 boys, 5 girls) with CP participated in this study. The children were allocated randomly to live (experimental) and video (control) AOT groups. All children completed 20 treatment sessions, each 30 minutes in duration, 5 days per week for a month. Mediolateral (ML) and vertical (VT) acceleration data, Jebsen-Taylor Hand Function (JTHF) scores, and Box and Block Test (BBT) scores were obtained at baseline and at 4 weeks after the intervention. RESULTS: ML and VT movement acceleration and JTHF scores were significantly lower in the live group (p< 0.05). The BBT score was significantly higher in the live than in the video group (p< 0.05). CONCLUSIONS: Our findings suggest that live AOT is more effective than video AOT for improving UL movement acceleration and function. Clinically, our findings offer important insights for clinicians when planning AOT interventions to reduce UL movement acceleration and improve UL function. PMID- 29710761 TI - Performance of cardiopulmonary resuscitation feedback systems in a long-distance train with distributed traction. AB - BACKGROUND: Out-of-hospital cardiac arrest is common in public locations, including public transportation sites. Feedback devices are increasingly being used to improve chest-compression quality. However, their performance during public transportation has not been studied yet. OBJECTIVE: To test two CPR feedback devices representative of the current technologies (accelerometer and electromag- netic-field) in a long-distance train. METHODS: Volunteers applied compressions on a manikin during the train route using both feedback devices. Depth and rate measurements computed by the devices were compared to the gold standard values. RESULTS: Sixty-four 4-min records were acquired. The accelerometer-based device provided visual help in all experiments. Median absolute errors in depth and rate were 2.4 mm and 1.3 compressions per minute (cpm) during conventional speed, and 2.5 mm and 1.2 cpm during high speed. The electromagnetic-field-based device never provided CPR feedback; alert messages were shown instead. However, measurements were stored in its internal memory. Absolute errors for depth and rate were 2.6 mm and 0.7 cpm during conventional speed, and 2.6 mm and 0.7 cpm during high speed. CONCLUSIONS: Both devices were accurate despite the accelerations and the electromagnetic interferences induced by the train. However, the electromagnetic-field-based device would require modifications to avoid excessive alerts impeding feedback. PMID- 29710762 TI - Limitations of an automated embolism segmentation method in clinical practice. AB - PURPOSE: Automated pulmonary embolism (PE) segmentation is frequently used as a preprocessing step in the quantitative analysis of pulmonary embolism. Objective of this study is to analyze the potential limitation in automated PE segmentation using clinical cases. METHODS: A database of 304 computer tomography pulmonary angiography (CTPA) examinations was collected and confirmed to be PE. After processing using an automated scheme, two radiologists classified these cases into four groups of A, B, C and D, which represent 4 different segmentation results namely, (1) entire pulmonary artery identified without motivation artifacts, (2) entire pulmonary artery identified with motivation artifacts, (3) part of the pulmonary artery identified, and (4) none of the pulmonary artery identified. Then, the possible failed reasons in PE segmentation were analyzed and determined based on the image characterization of the diseases and the applied CTPA scanning protocols. RESULTS: In the study, 143 (47.0%., 30 (9.9%., 110 (36.2%. and 21 (6.9%. examinations were classified into groups A, B, C and D, respectively. Group C and D included the cases with failed segmentation. Fifteen failure reasons, including intrapulmonary abnormalities, extra-pulmonary abnormalities, diffuse pulmonary diseases, enlarged heart, absolute occluded vessels, embolism attached to artery wall, delayed scan time, skewed location, low scan dose, obvious artifact of superior vena cava, previous chest surgery, congenital deformities of the chest, incorrect positioning, missed images and other unknown reasons, were determined with corresponding case percentages ranging from 0.3%.o 9.2%. CONCLUSIONS: Automated segmentation failures were caused by specific lung diseases, anatomy varieties, improper scan time, improper scan dose, manual errors or other unknown reasons. Realization of those limitations is crucial for developing robust automated schemes to handle these issues in a single pass when a large number of CTPA examinations need to be analyzed. PMID- 29710764 TI - Liquid-Assisted Femtosecond Laser Precision-Machining of Silica. AB - We report a systematical study on the liquid assisted femtosecond laser machining of quartz plate in water and under different etching solutions. The ablation features in liquid showed a better structuring quality and improved resolution with 1/3~1/2 smaller features as compared with those made in air. It has been demonstrated that laser induced periodic structures are present to a lesser extent when laser processed in water solutions. The redistribution of oxygen revealed a strong surface modification, which is related to the etching selectivity of laser irradiated regions. Laser ablation in KOH and HF solution showed very different morphology, which relates to the evolution of laser induced plasma on the formation of micro/nano-features in liquid. This work extends laser precision fabrication of hard materials. The mechanism of strong absorption in the regions with permittivity (epsilon) near zero is discussed. PMID- 29710763 TI - Integration of 24 Feature Types to Accurately Detect and Predict Seizures Using Scalp EEG Signals. AB - The neurological disorder epilepsy causes substantial problems to the patients with uncontrolled seizures or even sudden deaths. Accurate detection and prediction of epileptic seizures will significantly improve the life quality of epileptic patients. Various feature extraction algorithms were proposed to describe the EEG signals in frequency or time domains. Both invasive intracranial and non-invasive scalp EEG signals have been screened for the epileptic seizure patterns. This study extracted a comprehensive list of 24 feature types from the scalp EEG signals and found 170 out of the 2794 features for an accurate classification of epileptic seizures. An accuracy (Acc) of 99.40% was optimized for detecting epileptic seizures from the scalp EEG signals. A balanced accuracy (bAcc) was calculated as the average of sensitivity and specificity and our seizure detection model achieved 99.61% in bAcc. The same experimental procedure was applied to predict epileptic seizures in advance, and the model achieved Acc = 99.17% for predicting epileptic seizures 10 s before happening. PMID- 29710765 TI - A Vitamin E-Enriched Antioxidant Diet Interferes with the Acute Adaptation of the Liver to Physical Exercise in Mice. AB - Physical exercise is beneficial for general health and is an effective treatment for metabolic disorders. Vitamin E is widely used as dietary supplement and is considered to improve non-alcoholic fatty liver disease by reducing inflammation and dyslipidemia. However, increased vitamin E intake may interfere with adaptation to exercise training. Here, we explored how vitamin E alters the acute exercise response of the liver, an organ that plays an essential metabolic role during physical activity. Mice fed a control or an α-tocopherol-enriched diet were subjected to a non-exhaustive treadmill run. We assessed the acute transcriptional response of the liver as well as glucocorticoid signalling and plasma free fatty acids (FFA) and performed indirect calorimetry. Vitamin E interfered with the exercise-induced increase in FFA and upregulation of hepatic metabolic regulators, and it shifted the transcriptional profile of exercised mice towards lipid and cholesterol synthesis while reducing inflammation. Energy utilization, as well as corticosterone levels and signalling were similar, arguing against acute differences in substrate oxidation or glucocorticoid action. Our results show that high-dose vitamin E alters the metabolic and inflammatory response of the liver to physical exercise. The interference with these processes may suggest a cautious use of vitamin E as dietary supplement. PMID- 29710766 TI - Solid-Phase Synthesis of Azole-Comprising Peptidomimetics and Coordination of a Designed Analog to Zn2. AB - Peptidomimetics that can coordinate transition metals have a variety of potential applications as catalysts, sensors, or materials. A new modular peptidomimetic scaffold, the “azole peptoid”, is introduced here. We report methods for the solid-phase synthesis of eleven examples of trimeric N-substituted oligoamides that include oxazole- or thiazole-functionalized backbones. The products prepared comprise a diversity of functionality, including a metal coordinating terpyridine group. The modular synthetic approach enables ready preparation of analogs for specific applications. To highlight a potential use of this new synthetic scaffold, a trimeric azole peptoid functionalized with a terpyridine residue was prepared and studied. The characteristic 2:1 ligand:metal binding of this terpyridine-functionalized azole peptoid to Zn2+ in aqueous solution was observed. These studies introduce azole peptoids as a useful class of biomimetic molecules for further study and application. PMID- 29710767 TI - Effects of Excitatory Repetitive Transcranial Magnetic Stimulation of the P3 Point in Chronic Stroke Patients-Case Reports. AB - OBJECTIVE: To evaluate the effects of excitatory repetitive transcranial magnetic stimulation (rTMS) of the international 10-20 system P3 point (intraparietal sulcus region) in chronic patients with a frontal lesion and parietal sparing due to stroke on the impaired upper (UL) and lower limb (LL) as measured by the Fugl Meyer Assessment (FMA). METHODS: Three patients (C1: 49.83/2.75, C2: 53.17/3.83, C3: 63.33/3.08-years-old at stroke/years post-stroke, respectively) received two weeks (five days/week) of rTMS at 10 Hz of P3. A patient was treated in similar conditions with a sham coil (S1: 56.58/4.33). Patients were evaluated before, after, and two months post-treatment (A1, A2, and A3, respectively). RESULTS: For LL, the scores of the motor function subsection of C1 and C3 as well as the sensory function of C2 increased by A2 and remained by A3. For UL, the score of the motor function of C2 and C3 also increased, but the score of C3 decreased by A3. The score of the range of motion subsection of C3 increased by the two follow up evaluations. CONCLUSION: This study suggests excitatory rTMS over P3 may be of use for some chronic stroke patients, but these findings need to be verified in a future clinical trial. PMID- 29710768 TI - Synthesis and Characterization of Silver-Doped Mesoporous Bioactive Glass and Its Applications in Conjunction with Electrospinning. AB - Since they were first developed in 2004, mesoporous bioactive glasses (MBGs) rapidly captured the interest of the scientific community thanks to their numerous beneficial properties. MBGs are synthesised by a combination of the sol gel method with the chemistry of surfactants to obtain highly mesoporous (pore size from 5 to 20 nm) materials that, owing to their high surface area and ordered structure, are optimal candidates for controlled drug-delivery systems. In this work, we synthesised and characterised a silver-containing mesoporous bioactive glass (Ag-MBG). It was found that Ag-MBG is a suitable candidate for controlled drug delivery, showing a perfectly ordered mesoporous structure ideal for the loading of drugs together with optimal bioactivity, sustained release of silver from the matrix, and fast and strong bacterial inhibition against both Gram-positive and Gram-negative bacteria. Silver-doped mesoporous glass particles were used in three electrospinning-based techniques to produce PCL/Ag-MBG composite fibres, to coat bioactive glass scaffolds (via electrospraying), and for direct sol electrospinning. The results obtained in this study highlight the versatility and efficacy of Ag-substituted mesoporous bioactive glass and encourage further studies to characterize the biological response to Ag-MBG-based antibacterial controlled-delivery systems for tissue-engineering applications. PMID- 29710769 TI - The Food-Specific Serum IgG Reactivity in Major Depressive Disorder Patients, Irritable Bowel Syndrome Patients and Healthy Controls. AB - There is an increasing amount of evidence which links the pathogenesis of irritable bowel syndrome (IBS) with food IgG hyperreactivity. Some authors have suggested that food IgG hyperreactivity could be also involved in the pathophysiology of major depressive disorder (MDD). The aim of this study was to compare levels of serum IgG against 39 selected food antigens between three groups of participants: patients with MDD (MDD group), patients with IBS (IBS group) and healthy controls (HC group). The study included 65 participants (22 in the MDD group, 22 in the IBS group and 21 in the HC group). Serum IgG levels were examined using enzyme-linked immunosorbent assay (ELISA). Medical records, clinical data and laboratory results were collected for the analysis. IgG food hyperreactivity (interpreted as an average of levels of IgG antibodies above 7.5 µg/mL) was detected in 28 (43%) participants, including 14 (64%) from the MDD group, ten (46%) from the IBS group and four (19%) from the HC group. We found differences between extreme IgG levels in MDD versus HC groups and in IBS versus HC groups. Patients with MDD had significantly higher serum levels of total IgG antibodies and IgG against celery, garlic and gluten compared with healthy controls. The MDD group also had higher serum IgG levels against gluten compared with the IBS group. Our results suggest dissimilarity in immune responses against food proteins between the examined groups, with the highest immunoreactivity in the MDD group. Further studies are needed to repeat and confirm these results in bigger cohorts and also examine clinical utility of IgG based elimination diet in patients with MDD and IBS. PMID- 29710771 TI - Dog Population & Dog Sheltering Trends in the United States of America. AB - Dog management in the United States has evolved considerably over the last 40 years. This review analyzes available data from the last 30 to 40 years to identify national and local trends. In 1973, The Humane Society of the US (The HSUS) estimated that about 13.5 million animals (64 dogs and cats per 1000 people) were euthanized in the US (about 20% of the pet population) and about 25% of the dog population was still roaming the streets. Intake and euthanasia numbers (national and state level) declined rapidly in the 1970s due to a number of factors, including the implementation of shelter sterilization policies, changes in sterilization practices by private veterinarians and the passage of local ordinances implementing differential licensing fees for intact and sterilized pets. By the mid-1980s, shelter intake had declined by about 50% (The HSUS estimated 7.6-10 million animals euthanized in 1985). Data collected by PetPoint over the past eight years indicate that adoptions increased in the last decade and may have become an additional driver affecting recent euthanasia declines across the US. We suspect that sterilizations, now part of the standard veterinary care, and the level of control of pet dogs exercised by pet owners (roaming dogs are now mostly absent in many US communities) played an important part in the cultural shift in the US, in which a larger proportion of families now regard their pet dogs as "family members". PMID- 29710772 TI - A Tensile Specimen of Tailor Rolled Blanks with Equal Probability in Yield and Its Mechanical Behavior Analysis. AB - In this paper, the microstructure and mechanical properties that distribute regulation along the rolling direction of tailor rolled blanks (TRB) were investigated. A tensile specimen with equal probability in yield (EYS) was first designed considering variation both in thickness and in material strength. The uniaxial tension test was carried out with a digital image correlation method to analyze the mechanical behaviors. The results showed that the strain distribution of EYS was homogeneous. From the results, it can be known that a new design philosophy for a TRB tensile specimen is reasonable and EYS is suitable to characterize the mechanical behavior of TRB. The true stress-strain curves of metal in different cross sections of TRB were calculated. On the basis of the true stress-strain curves, a material model of TRB was constructed and then implemented into finite element simulations of TRB uniaxial tensile tests. The strain distribution of numerical and experimental results was similar and the error between the elongation of the specimen after fracture obtained by experiment and FE ranged from 9.51% to 13.06%. Therefore, the simulation results match well with the experimental results and the material model has high accuracy and as well as practicability. PMID- 29710770 TI - Exercise Early and Often: Effects of Physical Activity and Exercise on Women's Bone Health. AB - In 2011 over 1.7 million people were hospitalized because of a fragility fracture, and direct costs associated with osteoporosis treatment exceeded 70 billion dollars in the United States. Failure to reach and maintain optimal peak bone mass during adulthood is a critical factor in determining fragility fracture risk later in life. Physical activity is a widely accessible, low cost, and highly modifiable contributor to bone health. Exercise is especially effective during adolescence, a time period when nearly 50% of peak adult bone mass is gained. Here, we review the evidence linking exercise and physical activity to bone health in women. Bone structure and quality will be discussed, especially in the context of clinical diagnosis of osteoporosis. We review the mechanisms governing bone metabolism in the context of physical activity and exercise. Questions such as, when during life is exercise most effective, and what specific types of exercises improve bone health, are addressed. Finally, we discuss some emerging areas of research on this topic, and summarize areas of need and opportunity. PMID- 29710773 TI - Recombinant Inga Laurina Trypsin Inhibitor (ILTI) Production in Komagataella Phaffii Confirms Its Potential Anti-Biofilm Effect and Reveals an Anti-Tumoral Activity. AB - Protease inhibitors have a broad biotechnological application ranging from medical drugs to anti-microbial agents. The Inga laurina trypsin inhibitor (ILTI) previously showed a great in vitro inhibitory effect under the adherence of Staphylococcus species, being a strong candidate for use as an anti-biofilm agent. Nevertheless, this is found in small quantities in its sources, which impairs its utilization at an industrial scale. Within this context, heterologous production using recombinant microorganisms is one of the best options to scale up the recombinant protein production. Thus, this work aimed at utilizing Komagataella phaffii to produce recombinant ILTI. For this, the vector pPIC9K+ILTI was constructed and inserted into the genome of the yeast K. phaffii, strain GS115. The protein expression was highest after 48 h using methanol 1%. A matrix-assisted laser desorption ionization-time-of-flight (MALDI-TOF) analysis was performed to confirm the production of the recombinant ILTI and its activity was investigated trough inhibitory assays using the synthetic substrate Nα Benzoyl-D,L-arginine p-nitroanilide hydrochloride (BAPNA). Finally, recombinant ILTI (rILTI) was used in assays, showing that there was no significant difference between native and recombinant ILTI in its inhibitory activity in biofilm formation. Anti-tumor assay against Ehrlich ascites tumor (EAT) cells showed that rILTI has a potential anti-tumoral effect, showing the same effect as Melittin when incubated for 48 h in concentrations above 25 µg/mL. All together the results suggests broad applications for rILTI. PMID- 29710774 TI - Discovery of Pyrazolo[4,3-c]quinolines Derivatives as Potential Anti-Inflammatory Agents through Inhibiting of NO Production. AB - The synthesis and anti-inflammatory effects of certain pyrazolo[4,3-c]quinoline derivatives 2a-2r are described. The anti-inflammatory activities of these derivatives were evaluated by means of inhibiting nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW 264.7 cells. Among them, 3-amino-4-(4 hydroxyphenylamino)-1H-pyrazolo[4,3-c]-quinoline (2i) and 4-(3-amino-1H pyrazolo[4,3-c]quinolin-4-ylamino)benzoic acid (2m) exhibited significant inhibition of LPS-stimulated NO production with a potency approximately equal to that of the positive control, 1400 W. Important structure features were analyzed by quantitative structure-activity relationship (QSAR) analysis to give better insights into the structure determinants for predicting the inhibitory effects on the accumulation of nitric oxide for RAW 264.7 cells in response to LPS. In addition, our results indicated that their anti-inflammatory effects involve the inhibition of inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) protein expression. Further studies on the structural optimization are ongoing. PMID- 29710775 TI - Novel Ex Vivo Human Osteochondral Explant Model of Knee and Spine Osteoarthritis Enables Assessment of Inflammatory and Drug Treatment Responses. AB - Osteoarthritis of the knee and spine is highly prevalent in modern society, yet a disease-modifying pharmacological treatment remains an unmet clinical need. A major challenge for drug development includes selection of appropriate preclinical models that accurately reflect clinical phenotypes of human disease. The aim of this study was to establish an ex vivo explant model of human knee and spine osteoarthritis that enables assessment of osteochondral tissue responses to inflammation and drug treatment. Equal-sized osteochondral fragments from knee and facet joints (both n = 6) were subjected to explant culture for 7 days in the presence of a toll-like receptor 4 (TLR4) agonist and an inhibitor of transforming growth factor-beta (TGF-β) receptor type I signaling. Markers of inflammation, interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP 1), but not bone metabolism (pro-collagen-I) were significantly increased by treatment with TLR4 agonist. Targeting of TGF-β signaling resulted in a strong reduction of pro-collagen-I and significantly decreased IL-6 levels. MCP-1 secretion was increased, revealing a regulatory feedback mechanism between TGF β and MCP-1 in joint tissues. These findings demonstrate proof-of-concept and feasibility of explant culture of human osteochondral specimens as a preclinical disease model, which might aid in definition and validation of disease-modifying drug targets. PMID- 29710776 TI - Circulating Tumor Cell Analysis in Preclinical Mouse Models of Metastasis. AB - The majority of cancer deaths occur because of metastasis since current therapies are largely non-curative in the metastatic setting. The use of in vivo preclinical mouse models for assessing metastasis is, therefore, critical for developing effective new cancer biomarkers and therapies. Although a number of quantitative tools have been previously developed to study in vivo metastasis, the detection and quantification of rare metastatic events has remained challenging. This review will discuss the use of circulating tumor cell (CTC) analysis as an effective means of tracking and characterizing metastatic disease progression in preclinical mouse models of breast and prostate cancer and the resulting lessons learned about CTC and metastasis biology. We will also discuss how the use of clinically-relevant CTC technologies such as the CellSearch® and Parsortix™ platforms for preclinical CTC studies can serve to enhance the study of cancer biology, new biomarkers, and novel therapies from the bench to the bedside. PMID- 29710777 TI - Egg and Soy-Derived Peptides and Hydrolysates: A Review of Their Physiological Actions against Diabetes and Obesity. AB - Type 2 diabetes and obesity are two chronic conditions associated with the metabolic syndrome and their prevalences are increasing worldwide. The investigation of food protein-derived bioactive peptides that can improve the pathophysiology of diabetes or obesity while causing minimal side effects is desired. Egg and soy proteins generate bioactive peptides with multiple biological effects, exerting nutritional and physiological benefits. This review focuses on the anti-diabetic and anti-obesity effects of egg- and soy-derived peptides and hydrolysates in vivo and in vitro relevant to these conditions. Studies using the intact protein were considered only when comparing the results with the hydrolysate or peptides. In vivo evidence suggests that bioactive peptides from egg and soy can potentially be used to manage elements of glucose homeostasis in metabolic syndrome; however, the mechanisms of action on glucose and insulin metabolism, and the interaction between peptides and their molecular targets remain unclear. Optimizing the production of egg- and soy-derived peptides and standardizing the physiological models to study their effects on diabetes and obesity could help to clarify the effects of these bioactive peptides in metabolic syndrome-related conditions. PMID- 29710778 TI - Occurrence of Aflatoxin M1 in Raw Milk from Manufacturers of Infant Milk Powder in China. AB - This survey was performed to investigate the occurrence of aflatoxin M1 (AFM1) contamination of raw milk from manufacturers of infant milk powder in China. A total of 1207 raw milk samples were collected overall from four seasons of 2016 in Northeast China, Northwest China, Northern China, and Central China (11 provinces and one municipality). Results showed that 56 of the 1207 raw milk samples (4.64%) were positive for AFM1, which were obtained from Heilongjiang (two samples), Gansu (one sample), Shaanxi (46 samples), Beijing (one sample), and Hunan (six samples) provinces. None of the raw milk samples from manufacturers of infant milk powder exceeded the Chinese limit (62.5 ng/L) in 2016. Only a few raw milk samples were not suitable for use in infant milk according to EU (European Union) or U.S. infant milk limits. Furthermore, based on this survey and previous studies, it is particularly important to avoid AFM1 contamination in raw milk during the winter. PMID- 29710779 TI - Long-Term Effectiveness, under a Mountain Environment, of a Novel Conservation Nanomaterial Applied on Limestone from a Roman Archaeological Site. AB - A novel alkoxysilane-based product was applied on limestone samples from a Roman archaeological site. The study consisted of an initial phase to evaluate site environmental conditions in order to choose the most suitable product type to be applied. The decay that was produced in the site is mainly caused by natural action, with water being the main vehicle for the decay agents. Thus, the effectiveness of an innovative product with hydrophobic/consolidant properties and two commercial products (consolidant and hydrophobic agent) were evaluated on limestone from Acinipo site, under laboratory conditions. Next, the long-term effectiveness of the three products under study was evaluated by the exposure of limestone samples in the archaeological site for a period of three years. Since the recognized incompatibility between alkoxysilanes and pure carbonate stones, the interaction between the products and the limestones was widely investigated. The results that were obtained allow for it to be concluded that the innovative product presents adequate compatibility and adherence to the limestone under study, producing a long-term effective, homogeneous, and continuous coating with a depth of penetration of up to 10 mm. However, the commercial products produced discontinuous aggregates on the limestone surface, did not penetrate into its porous structure and it did not produce long-lasting effects. PMID- 29710780 TI - High-Efficiency, Near-Diffraction Limited, Dielectric Metasurface Lenses Based on Crystalline Titanium Dioxide at Visible Wavelengths. AB - Metasurfaces are planar optical elements that hold promise for overcoming the limitations of refractive and conventional diffractive optics. Previous metasurfaces have been limited to transparency windows at infrared wavelengths because of significant optical absorption and loss at visible wavelengths. Here we report a polarization-insensitive, high-contrast transmissive metasurface composed of crystalline titanium dioxide pillars in the form of metalens at the wavelength of 633 nm. The focal spots are as small as 0.54 λ d , which is very close to the optical diffraction limit of 0.5 λ d . The simulation focusing efficiency is up to 88.5%. A rigorous method for metalens design, the phase realization mechanism and the trade-off between high efficiency and small spot size (or large numerical aperture) are discussed. Besides, the metalenses can work well with an imaging point source up to ±15° off axis. The proposed design is relatively systematic and can be applied to various applications such as visible imaging, ranging and sensing systems. PMID- 29710781 TI - Phenolic Composition and Bioactivity of Lavandula pedunculata (Mill.) Cav. Samples from Different Geographical Origin. AB - The aim of this study was to characterize the phenolic composition and evaluate the bioactivity of several samples of Lavandula pedunculata (Mill.) Cav, and to compare aqueous and hydroethanolic extracts. Plant materials were obtained by growing some accessions (seed samples) of various wild populations from different regions of Portugal conserved at the Portuguese Genebank in Braga. Phenolic compounds were analised by HPLC-DAD-ESI/MSn, antioxidant potential through in vitro assays (DPPH radical scavenging activity, reducing power and inhibition of lipid peroxidation), cytotoxicity on tumor cells (MCF-7, NCI-H460, HeLa and HepG2) and non-tumor (PLP2) cells, anti-inflammatory activity in rat RAW 264.7 macrophages, by the ability to inhibit NO production and antimicrobial potential by the microdilution method with INT dye (iodonitrotetrazolium chloride). Thirteen compounds were identified, being salvianolic acid B, rosmarinic acid and luteolin-7-O-glucuronide, the main compounds present, with values ranging between 44.3-582, 50.9-550, and 24.36-101.5 mg/g extract, respectively. L. pedunculata aqueous extract revealed a higher antioxidant potential (EC50 values between 14 to 530 μg/mL), which could be related to its higher concentration in phenolic compounds; however, the hydroethanolic extract showed a higher anti-inflammatory (lower EC50 values than 124 μg/mL) potential and antiproliferative capacity (lower GI50 values than 34 μg/mL). Thus, this study highlights the bioactive effects of this species and opens up possibilities of uses in food and pharmaceutical formulations. However, there are potential differences in such properties according to geographical origin of plant material, as in general, the samples from Alentejo presented higher results in all the bioactivities, compared with Trás-os-Montes samples. PMID- 29710782 TI - Different Effects of NSF and PCE Superplasticizer on Adsorption, Dynamic Yield Stress and Thixotropy of Cement Pastes. AB - This study compares the differences and similarities of two types of superplasticizers—NSF (Naphthalene Sulfonate Formaldehyde) and PCE (PolyCarboxylate Ester)—in fresh cement paste systems, in terms of adsorption, dynamic yield stress, and thixotropic index. Results show that with either NSF or PCE addition, the more superplasticizer is added, the more it is adsorbed and the more it remains in the interstitial pore solution. The dynamic yield stress and thixotropic index also decrease with increasing addition the amount of either superplasticizer. However, NSF is less efficient in decreasing the dynamic yield stress than PCE. More importantly, the decreasing patterns of dynamic yield stress and thixotropic index are different with NSF and PCE additions; this is tied to the adsorption and dispersing mechanisms of these two types of superplasticizers. PMID- 29710783 TI - Targeting Epigenetic Aberrations in Pancreatic Cancer, a New Path to Improve Patient Outcomes? AB - Pancreatic cancer has one of the highest mortality rates among all types of cancers. The disease is highly aggressive and typically diagnosed in late stage making it difficult to treat. Currently, the vast majority of therapeutic regimens have only modest curative effects, and most of them are in the surgical/neo-adjuvant setting. There is a great need for new and more effective treatment strategies in common clinical practice. Previously, pathogenesis of pancreatic cancer was attributed solely to genetic mutations; however, recent advancements in the field have demonstrated that aberrant activation of epigenetic pathways contributes significantly to the pathogenesis of the disease. The identification of these aberrant activated epigenetic pathways has revealed enticing targets for the use of epigenetic inhibitors to mitigate the phenotypic changes driven by these cascades. These pathways have been found to be responsible for overactivation of growth signaling pathways and silencing of tumor suppressors and other cell cycle checkpoints. Furthermore, new miRNA signatures have been uncovered in pancreatic ductal adenocarcinoma (PDAC) patients, further widening the window for therapeutic opportunity. There has been success in preclinical settings using both epigenetic inhibitors as well as miRNAs to slow disease progression and eliminate diseased tissues. In addition to their utility as anti-proliferative agents, the pharmacological inhibitors that target epigenetic regulators (referred to here as readers, writers, and erasers for their ability to recognize, deposit, and remove post-translational modifications) have the potential to reconfigure the epigenetic landscape of diseased cells and disrupt the cancerous phenotype. The potential to “reprogram” cancer cells to revert them to a healthy state presents great promise and merits further investigation. PMID- 29710785 TI - Employee Perceptions of Workplace Health Promotion Programs: Comparison of a Tailored, Semi-Tailored, and Standardized Approach. AB - In the design of workplace health promotion programs (WHPPs), employee perceptions represent an integral variable which is predicted to translate into rate of user engagement (i.e., participation) and program loyalty. This study evaluated employee perceptions of three workplace health programs promoting nutritional consumption and physical activity. Programs included: (1) an individually tailored consultation with an exercise physiologist and dietitian; (2) a semi-tailored 12-week SMS health message program; and (3) a standardized group workshop delivered by an expert. Participating employees from a transport company completed program evaluation surveys rating the overall program, affect, and utility of: consultations (n = 19); SMS program (n = 234); and workshops (n = 86). Overall, participants’ affect and utility evaluations were positive for all programs, with the greatest satisfaction being reported in the tailored individual consultation and standardized group workshop conditions. Furthermore, mode of delivery and the physical presence of an expert health practitioner was more influential than the degree to which the information was tailored to the individual. Thus, the synergy in ratings between individually tailored consultations and standardized group workshops indicates that low-cost delivery health programs may be as appealing to employees as tailored, and comparatively high-cost, program options. PMID- 29710784 TI - Evaluating Health Co-Benefits of Climate Change Mitigation in Urban Mobility. AB - There is growing recognition that implementation of low-carbon policies in urban passenger transport has near-term health co-benefits through increased physical activity and improved air quality. Nevertheless, co-benefits and related cost reductions are often not taken into account in decision processes, likely because they are not easy to capture. In an interdisciplinary multi-model approach we address this gap, investigating the co-benefits resulting from increased physical activity and improved air quality due to climate mitigation policies for three urban areas. Additionally we take a (macro-)economic perspective, since that is the ultimate interest of policy-makers. Methodologically, we link a transport modelling tool, a transport emission model, an emission dispersion model, a health model and a macroeconomic Computable General Equilibrium (CGE) model to analyze three climate change mitigation scenarios. We show that higher levels of physical exercise and reduced exposure to pollutants due to mitigation measures substantially decrease morbidity and mortality. Expenditures are mainly born by the public sector but are mostly offset by the emerging co-benefits. Our macroeconomic results indicate a strong positive welfare effect, yet with slightly negative GDP and employment effects. We conclude that considering economic co-benefits of climate change mitigation policies in urban mobility can be put forward as a forceful argument for policy makers to take action. PMID- 29710786 TI - Assessment of Sulfur Deficiency under Field Conditions by Single Measurements of Sulfur, Chloride and Phosphorus in Mature Leaves. AB - Determination of S status is very important to detect S deficiency and prevent losses of yield and seed quality. The aim of this study was to investigate the possibility of using the ([Cl−]+[NO3−]+[PO43−]):[SO42−] ratio as an indicator of S nutrition under field conditions in Brassica napus and whether this could be applied to other species. Different S and nitrogen (N) fertilizations were applied on a S deficient field of oilseed rape to harvest mature leaves and analyze their anion and element contents in order to evaluate a new S nutrition indicator and useful threshold values. Large sets of commercial varieties were then used to test S deficiency scenarios. As main results, this study shown that, under field conditions, leaf ([Cl−]+[NO3−]+[PO43−]):[SO42−] ratio was increased by lowering S fertilization, indicating S deficiency. The usefulness of this ratio was also found for other species grown under controlled conditions and it could be simplified by using the elemental ([Cl]+[P]):[S] ratio. Threshold values were determined and used for the clustering of commercial varieties within three groups: S deficient, at risk of S deficiency and S sufficient. The ([Cl]+[P]):[S] ratio quantified under field conditions, can be used as an early and accurate diagnostic tool to manage S fertilization. PMID- 29710787 TI - Is It Reliable to Take the Molecular Docking Top Scoring Position as the Best Solution without Considering Available Structural Data? AB - Molecular docking is the most frequently used computational method for studying the interactions between organic molecules and biological macromolecules. In this context, docking allows predicting the preferred pose of a ligand inside a receptor binding site. However, the selection of the “best” solution is not a trivial task, despite the widely accepted selection criterion that the best pose corresponds to the best energy score. Here, several rigid-target docking methods were evaluated on the same dataset with respect to their ability to reproduce crystallographic binding orientations, to test if the best energy score is a reliable criterion for selecting the best solution. For this, two experiments were performed: (A) to reconstruct the ligand-receptor complex by performing docking of the ligand in its own crystal structure receptor (defined as self-docking), and (B) to reconstruct the ligand-receptor complex by performing docking of the ligand in a crystal structure receptor that contains other ligand (defined as cross-docking). Root-mean square deviation (RMSD) was used to evaluate how different the obtained docking orientation is from the corresponding co-crystallized pose of the same ligand molecule. We found that docking score function is capable of predicting crystallographic binding orientations, but the best ranked solution according to the docking energy is not always the pose that reproduces the experimental binding orientation. This happened when self-docking was achieved, but it was critical in cross-docking. Taking into account that docking is typically used with predictive purposes, during cross-docking experiments, our results indicate that the best energy score is not a reliable criterion to select the best solution in common docking applications. It is strongly recommended to choose the best docking solution according to the scoring function along with additional structural criteria described for analogue ligands to assure the selection of a correct docking solution. PMID- 29710788 TI - Lifestyle Interventions for People with, and at Risk of Type 2 Diabetes in Polynesian Communities: A Systematic Review and Meta-Analysis. AB - There is evidence that lifestyle intervention among Polynesian people can reduce diabetes incidence and complications, but this evidence has not been systematically reviewed. The aim of this study was to systematically review the efficacy of lifestyle interventions, targeting the prevention and management of type 2 diabetes among Polynesian people. MEDLINE, Web of Science, Cochrane Library, and Embase were searched to find randomised controlled trials (RCTs) and pre-post studies. Eight studies (four RCTs and four pre-post studies) with 1590 participants met the inclusion criteria. The data on health outcomes that was reported in these studies included blood pressure, body mass index, waist circumference, weight, and glycated haemoglobin (HbA1c). The meta-analyses showed that the interventions had resulted in statistically significant reductions in systolic blood pressure (SBP) across four of the studies (WMD, −9.93 mmHg; 95% Cl, −10.77 to −9.09; and p < 0.00001). However, the effects on weight across five of the studies (WMD, −1.15 kg; 95% Cl, −2.80 to 0.51; p = 0.18) and the HbA1c levels across two of the studies (WMD, −0.38%; 95% Cl, −1.15 to 0.39; and p = 0.33) were not statistically significant. This review provides evidence that lifestyle interventions may be effective in achieving modest reductions in SBP in Polynesian people. Further research is needed to fully assess the effectiveness of these interventions in this population long-term. PMID- 29710790 TI - Hybrid Multi-Channel MAC Protocol for WBANs with Inter-WBAN Interference Mitigation. AB - Herein, we propose a hybrid multi-channel medium access control (HM-MAC) protocol for wireless body area networks (WBANs) that mitigates inter-WBAN interference significantly. In HM-MAC, a superframe consists of a random access phase and a scheduled access phase. That is, a carrier sensing multiple access with collision avoidance (CSMA/CA) phase and a time division multiple access (TDMA) phase are included in a superframe. The random access phase allows higher-priority users to transmit data packets with low latency and high reliability. The retransmission of data packets is also performed in the random access phase. The periodic data are transmitted in the scheduled phase, resulting in no contention and high reliability. A channel selection algorithm is also proposed to avoid collision between neighboring WBANs. The HM-MAC protocol allows multiple transmissions simultaneously on different channels, resulting in high throughput and low collision. The sensor nodes update idle channels by listening to the beacon signal; consequently, the sensor nodes can change the working channel to reduce inter-WBAN interference. According to our simulation results, HM-MAC achieves a higher packet delivery ratio and higher throughput with lower energy consumption than the conventional scheme in multi-WBAN scenarios. HM-MAC also causes lower end-to-end delays for higher-priority users. PMID- 29710789 TI - Daily Intake of Milk Powder and Risk of Celiac Disease in Early Childhood: A Nested Case-Control Study. AB - Milk powder and gluten are common components in Swedish infants' diets. Whereas large intakes of gluten early in life increases the risk of celiac disease in genetically at-risk Swedish children, no study has yet evaluated if intake of milk powder by 2 years of age is associated with celiac disease. A 1-to-3 nested case-control study, comprised of 207 celiac disease children and 621 controls matched for sex, birth year, and HLA genotype, was performed on a birth cohort of HLA-DR3-DQ2 and/or DR4-DQ8-positive children. Subjects were screened annually for celiac disease using tissue transglutaminase autoantibodies (tTGA). Three-day food records estimated the mean intake of milk powder at ages 6 months, 9 months, 12 months, 18 months, and 24 months. Conditional logistic regression calculated odds ratios (OR) at last intake prior to seroconversion of tTGA positivity, and for each time-point respectively and adjusted for having a first-degree relative with celiac disease and gluten intake. Intake of milk powder prior to seroconversion of tTGA positivity was not associated with celiac disease (OR = 1.00; 95% CI = 0.99, 1.03; p = 0.763). In conclusion, intake of milk powder in early childhood is not associated with celiac disease in genetically susceptible children. PMID- 29710791 TI - Using Sleep Time Data from Wearable Sensors for Early Detection of Migraine Attacks. AB - The migraine is a chronic, incapacitating neurovascular disorder, characterized by attacks of severe headache and autonomic nervous system dysfunction. Among the working age population, the costs of migraine are 111 billion euros in Europe alone. The early detection of migraine attacks would reduce these costs, as it would shorten the migraine attack by enabling correct timing when taking preventive medication. In this article, whether it is possible to detect migraine attacks beforehand using wearable sensors is studied, and t preliminary results about how accurate the recognition can be are provided. The data for the study were collected from seven study subjects using a wrist-worn Empatica E4 sensor, which measures acceleration, galvanic skin response, blood volume pulse, heart rate and heart rate variability, and temperature. Only sleep time data were used in this study. A novel method to increase the number of training samples is introduced, and the results show that, using personal recognition models and quadratic discriminant analysis as a classifier, balanced accuracy for detecting attacks one night prior is over 84%. While this detection rate is high, the results also show that balance accuracy varies greatly between study subjects, which shows how complicated the problem actually is. However, at this point, the results are preliminary as the data set contains only seven study subjects, so these do not cover all migraine types. If the findings of this article can be confirmed in a larger population, it may potentially contribute to early diagnosis of migraine attacks. PMID- 29710793 TI - Synthesis and Characterization of pH and Thermo Dual-Responsive Hydrogels with a Semi-IPN Structure Based on N-Isopropylacrylamide and Itaconamic Acid. AB - A series of semi-interpenetrating polymer network (semi-IPN) hydrogels were synthesized and investigated in this study. Linear copolymer poly(N isopropylacrylamide-co-itaconamic acid) p(NIPAM-co-IAM), which is formed by copolymerization of N-isopropylacrylamide (NIPAM) and itaconamic acid (IAM, 4 amino-2-ethylene-4-oxobutanoic acid), was introduced into a solution of NIPAM to form a series of pH and thermo dual-responsive p(NIPAM-co-IAM)/pNIPAM semi-IPN hydrogels by free radical polymerization. The structural, morphological, chemical, and physical properties of the linear copolymer and semi-IPN hydrogels were investigated. The semi-IPN hydrogel showed high thermal stability according to thermal gravimetric analyzer (TGA). Scanning electronic microscopy (SEM) images showed that the pore size was in the range of 119~297 µm and could be controlled by the addition ratio of the linear copolymer in the semi-IPN structure. The addition of linear copolymer increased the fracture strain from 57.5 ± 2.9% to 91.1 ± 4.9% depending on the added amount, while the compressive modulus decreased as the addition increased. Moreover, the pH and thermo dual-responsive properties were investigated using differential scanning calorimetry (DSC) and monitoring the swelling behavior of the hydrogels. In deionized (DI) water, the equilibrium swelling ratio of the hydrogels decreased as the temperature increased from 20 °C to 50 °C, while it varied in various pH buffer solutions. In addition, the swelling and deswelling rates of the hydrogels also significantly increased. The results indicate that the novel pH-thermo dual-responsive semi-IPN hydrogels were synthesized successfully and may be a potential material for biomedical, drug delivery, or absorption application. PMID- 29710792 TI - Epigenetic Modulation of CD8+ T Cell Function in Lentivirus Infections: A Review. AB - CD8+ T cells are critical for controlling viremia during human immunodeficiency virus (HIV) infection. These cells produce cytolytic factors and antiviral cytokines that eliminate virally- infected cells. During the chronic phase of HIV infection, CD8+ T cells progressively lose their proliferative capacity and antiviral functions. These dysfunctional cells are unable to clear the productively infected and reactivated cells, representing a roadblock in HIV cure. Therefore, mechanisms to understand CD8+ T cell dysfunction and strategies to boost CD8+ T cell function need to be investigated. Using the feline immunodeficiency virus (FIV) model for lentiviral persistence, we have demonstrated that CD8+ T cells exhibit epigenetic changes such as DNA demethylation during the course of infection as compared to uninfected cats. We have also demonstrated that lentivirus-activated CD4+CD25+ T regulatory cells induce forkhead box P3 (Foxp3) expression in virus-specific CD8+ T cell targets, which binds the interleukin (IL)-2, tumor necrosis factor (TNF)-α, and interferon (IFN)-γ promoters in these CD8+ T cells. Finally, we have reported that epigenetic modulation reduces Foxp3 binding to these promoter regions. This review compares and contrasts our current understanding of CD8+ T cell epigenetics and mechanisms of lymphocyte suppression during the course of lentiviral infection for two animal models, FIV and simian immunodeficiency virus (SIV). PMID- 29710794 TI - Organocatalyzed Synthesis of [3.2.1] Bicyclooctanes. AB - Organocatalysis constitutes one of the main research areas in organic chemistry from the last two decades. This chemistry has been applied to the synthesis of many natural products and structures in a manner that reduces the residues and so the ecological impact. In this review, we consider the work that has been done for the synthesis of bicyclo[3.2.1]octane framework. This structure is present in many natural products with very important biological activities. PMID- 29710795 TI - Au-Decorated Dragonfly Wing Bioscaffold Arrays as Flexible Surface-Enhanced Raman Scattering (SERS) Substrate for Simultaneous Determination of Pesticide Residues. AB - Rapid sampling and multicomponent analysis are vital in pesticide residue detection. In this work, we proposed a SERS platform to detect three kinds of pesticides on apple peels simultaneously by a straightforward “press and peel off” method. The flexible Au/dragonfly wing (Au/DW) substrate was obtained from sputtering Au nanoislands on DW bioscaffold arrays by a simple direct current (DC) magnetron sputtering system. The high-performance substrate exhibited a low limit of detection (LOD) to 4-aminothiophenol (4-ATP) (10−9 M), outstanding reproducibility (less than 12.15%), good stability and suitability in multifold pesticide residues detection. Considering its excellent sample collection efficiency, the Au/DW substrate was employed to solve critical pesticide residue problems for detection of acephate (APT), cypermethrin (CPT), tsumacide (MTMC) and their multiple components on apple peels. The results show that the LOD was 10−3 ng/cm2 for APT obtained on the apple surface with a calculation equation of y = 0.26x + 6.68 and a determination coefficient (R2) of 0.970. Additionally, the LOD values for CPT and MTMC were 10−3 ng/cm2 and 10−4 ng/cm2, respectively. The finding in this work may provide a promising biomimetic SERS platform for on-spot detection of other organic pollutants in the food industry and inenvironmental protection. PMID- 29710798 TI - Sensor Fault Detection and System Reconfiguration for DC-DC Boost Converter. AB - This paper presents a effective sensor fault detection and system reconfiguration approach for DC-DC Boost converter. We consider to design a Luenberger observer to solve the problem of the sensor fault detection of the DC-DC Boost converter. We establish mathematical model according to the state of the switch . Luenberger observer is designed to produce residual errors and analyse faults. We detect three types of sensor faults online and compare residuals with thresholds. The system is able to maintain stability by taking system reconfiguration approach. The effectiveness of this approach is demonstrated by simulations. PMID- 29710796 TI - DNA Methyltransferases, DNA Methylation, and Age-Associated Cognitive Function. AB - Ageing, a leading cause of the decline/deficits in human learning, memory, and cognitive abilities, is a major risk factor for age-associated neurodegenerative disorders such as Alzheimer’s disease. Emerging evidence suggests that epigenetics, an inheritable but reversible biochemical process, plays a crucial role in the pathogenesis of age-related neurological disorders. DNA methylation, the best-known epigenetic mark, has attracted most attention in this regard. DNA methyltransferases (DNMTs) are key enzymes in mediating the DNA methylation process, by which a methyl group is transferred, faithfully or anew, to genomic DNA sequences. Biologically, DNMTs are important for gene imprinting. Accumulating evidence suggests that DNMTs not only play critical roles, including gene imprinting and transcription regulation, in early development stages of the central nervous system (CNS), but also are indispensable in adult learning, memory, and cognition. Therefore, the impact of DNMTs and DNA methylation on age associated cognitive functions and neurodegenerative diseases has emerged as a pivotal topic in the field. In this review, the effects of each DNMT on CNS development and healthy and pathological ageing are discussed. PMID- 29710797 TI - Health Seeking Behavior among Rural Left-Behind Children: Evidence from Shaanxi and Gansu Provinces in China. AB - More than 60 million children in rural China are “left behind”—both parents live and work far from their rural homes and leave their children behind. This paper explores differences in how left-behind and non-left-behind children seek health remediation in China’s vast but understudied rural areas. This study examines this question in the context of a program to provide vision health care to myopic rural students. The data come from a randomized controlled trial of 13,100 students in Gansu and Shaanxi provinces in China. The results show that without a subsidy, uptake of health care services is low, even if individuals are provided with evidence of a potential problem (an eyeglasses prescription). Uptake rises two to three times when this information is paired with a subsidy voucher redeemable for a free pair of prescription eyeglasses. In fact, left-behind children who receive an eyeglasses voucher are not only more likely to redeem it, but also more likely to use the eyeglasses both in the short term and long term. In other words, in terms of uptake of care and compliance with treatment, the voucher program benefitted left-behind students more than non-left-behind students. The results provide a scientific understanding of differential impacts for guiding effective implementation of health policy to all groups in need in developing countries. PMID- 29710799 TI - Metal Free Graphene Oxide (GO) Nanosheets and Pristine-Single Wall Carbon Nanotubes (p-SWCNTs) Biocompatibility Investigation: A Comparative Study in Different Human Cell Lines. AB - The in vitro biocompatibility of Graphene Oxide (GO) nanosheets, which were obtained by the electrochemical exfoliation of graphite electrodes in an electrolytic bath containing salts, was compared with the pristine Single Wall Carbon Nanotubes (p-SWCNTs) under the same experimental conditions in different human cell lines. The cells were treated with different concentrations of GO and SWCNTs for up to 48 h. GO did not induce any significant morphological or functional modifications (demonstrating a high biocompatibility), while SWNCTs were toxic at any concentration used after a few hours of treatment. The cell viability or cytotoxicity were detected by the trypan blue assay and the lactate dehydrogenase LDH quantitative enzymatic test. The Confocal Laser Scanning Microscopy (CLSM) and transmission electron microscopy (TEM) analysis demonstrated the uptake and internalization of GO sheets into cells, which was localized mainly in the cytoplasm. Different results were observed in the same cell lines treated with p-SWCNTs. TEM and CLSM (Confocal Laser Scanning Microscopy) showed that the p-SWCNTs induced vacuolization in the cytoplasm, disruption of cellular architecture and damage to the nuclei. The most important result of this study is our finding of a higher GO biocompatibility compared to the p-SWCNTs in the same cell lines. This means that GO nanosheets, which are obtained by the electrochemical exfoliation of a graphite-based electrode (carried out in saline solutions or other physiological working media) could represent an eligible nanocarrier for drug delivery, gene transfection and molecular cell imaging tests. PMID- 29710802 TI - Investigation of the Behavior of Hardening Masonry Exposed to Variable Stresses. AB - This paper analyzes the behavior of masonry under variable loads during execution (construction stage). It specifies the creep coefficient for calcium silicate brick masonry, presenting the research data of masonry deformation under variable and constant long-term loads. The interaction of separate layers of composite material in masonry is introduced and the formulae for determining long-term deformations are offered. The research results of masonry’s compressive strength and deformation properties under variable and constant long-term loads are presented. These are then compared to calculated ones. According to the presented comparison, the calculated long-term deformations coincide quite well with those determined experimentally. PMID- 29710801 TI - Synthesis of a Novel Series of Amino Acid Prodrugs Based on Thienopyridine Scaffolds and Evaluation of Their Antiplatelet Activity. AB - The thienopyridines class of drugs used as P2Y12 receptor antagonists plays a vital role in antiplatelet therapy. To further optimized this compound class, we designed and synthesized a series of amino acid prodrugs of 2 hydroxytetrahydrothienopyridine. All compounds were then evaluated for their inhibitory effect on ADP-induced platelet aggregation in rats and then ED50 and bleeding time of the most potent compounds were compared with commercial drugs. The results showed compound 5c could be a potent and safe candidate for further research. PMID- 29710800 TI - Discovery of Potential Inhibitors of Squalene Synthase from Traditional Chinese Medicine Based on Virtual Screening and In Vitro Evaluation of Lipid-Lowering Effect. AB - Squalene synthase (SQS), a key downstream enzyme involved in the cholesterol biosynthetic pathway, plays an important role in treating hyperlipidemia. Compared to statins, SQS inhibitors have shown a very significant lipid-lowering effect and do not cause myotoxicity. Thus, the paper aims to discover potential SQS inhibitors from Traditional Chinese Medicine (TCM) by the combination of molecular modeling methods and biological assays. In this study, cynarin was selected as a potential SQS inhibitor candidate compound based on its pharmacophoric properties, molecular docking studies and molecular dynamics (MD) simulations. Cynarin could form hydrophobic interactions with PHE54, LEU211, LEU183 and PRO292, which are regarded as important interactions for the SQS inhibitors. In addition, the lipid-lowering effect of cynarin was tested in sodium oleate-induced HepG2 cells by decreasing the lipidemic parameter triglyceride (TG) level by 22.50%. Finally. cynarin was reversely screened against other anti-hyperlipidemia targets which existed in HepG2 cells and cynarin was unable to map with the pharmacophore of these targets, which indicated that the lipid-lowering effects of cynarin might be due to the inhibition of SQS. This study discovered cynarin is a potential SQS inhibitor from TCM, which could be further clinically explored for the treatment of hyperlipidemia. PMID- 29710803 TI - Understanding the Interaction between a Steel Microstructure and Hydrogen. AB - The present work provides an overview of the work on the interaction between hydrogen (H) and the steel’s microstructure. Different techniques are used to evaluate the H-induced damage phenomena. The impact of H charging on multiphase high-strength steels, i.e., high-strength low-alloy (HSLA), transformation-induced plasticity (TRIP) and dual phase (DP) is first studied. The highest hydrogen embrittlement resistance is obtained for HSLA steel due to the presence of Ti- and Nb-based precipitates. Generic Fe-C lab-cast alloys consisting of a single phase, i.e., ferrite, bainite, pearlite or martensite, and with carbon contents of approximately 0, 0.2 and 0.4 wt %, are further considered to simplify the microstructure. Finally, the addition of carbides is investigated in lab-cast Fe-C-X alloys by adding a ternary carbide forming element to the Fe-C alloys. To understand the H/material interaction, a comparison of the available H trapping sites, the H pick-up level and the H diffusivity with the H-induced mechanical degradation or H-induced cracking is correlated with a thorough microstructural analysis. PMID- 29710804 TI - Proteomic and Biochemical Changes during Senescence of Phalaenopsis 'Red Dragon' Petals. AB - Phalaenopsis flowers are some of the most popular ornamental flowers in the world. For most ornamental plants, petal longevity determines postharvest quality and garden performance. Therefore, it is important to have insight into the senescence mechanism of Phalaenopsis. In the present study, a proteomic approach combined with ultrastructural observation and activity analysis of antioxidant enzymes was used to profile the molecular and biochemical changes during pollination-induced petal senescence in Phalaenopsis “Red Dragon”. Petals appeared to be visibly wilting at 24 h after pollination, accompanied by the mass degradation of macromolecules and organelles during senescence. In addition, 48 protein spots with significant differences in abundance were found by two-dimensional electrophoresis (2-DE) and subjected to matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF/TOF-MS). There were 42 protein spots successfully identified and homologous to known functional protein species involved in key biological processes, including antioxidant pathways, stress response, protein metabolism, cell wall component metabolism, energy metabolism, cell structure, and signal transduction. The activity of all reactive oxygen species (ROS)-scavenging enzymes was increased, keeping the content of ROS at a low level at the early stage of senescence. These results suggest that two processes, a counteraction against increased levels of ROS and the degradation of cellular constituents for maintaining nutrient recycling, are activated during pollination-induced petal senescence in Phalaenopsis. The information provides a basis for understanding the mechanism regulating petal senescence and prolonging the florescence of Phalaenopsis. PMID- 29710805 TI - A Study of the Stability Mechanism of the Dispersed Particle Gel Three-Phase Foam Using the Interfacial Dilational Rheology Method. AB - The dispersed particle gel (DPG) three-phase foam is a novel profile control and flooding system. The stability mechanism of the DPG three-phase foam was studied using an interfacial dilational rheology method. The results show that the elastic modulus of the DPG three-phase foam is up to 14 mN/m, which is much higher than the traditional foam. The increase in interface elasticity produces significantly positive effects on foam stability. Emphasis is given to the influences of frequency, temperature, pressure, and concentration on the viscoelasticity and interfacial adsorption of DPG particles, which change the modules of the foam interface and have a significant effect on foam stability. In addition, the microstructure of the DPG three-phase foam was observed. A viscoelastic shell is formed by the aggregation of the DPG particles on the interface. The irreversible adsorption gives the interface high elasticity and mechanical strength. The electrostatic repulsion between particles increases the spacing between bubbles. The combined effects of these factors give the interface higher mechanical strength, slow down the film drainage, effectively prevent gas permeation, and significantly improve the foam stability. PMID- 29710806 TI - Self-Reference Refractive Index Sensor Based on Independently Controlled Double Resonances in Side-Coupled U-Shaped Resonators. AB - A plasmonic, refractive, index nanosensor is investigated theoretically and numerically in two U-shaped cavities side-coupled to a metal-dielectric-metal (MDM) waveguide. A transparency window between two transmission dips is observed. The physical origin of the transmission phenomenon is revealed by mapping the magnetic field distribution. Independent double resonances are realized through the proposed design. Double resonances showed diverse responses to the variations of the structural dimensions. In particular, they presented different dependences on a refraction index of the medium in an individual resonator. One resonance exhibited a remarkable shift with the increase of the refraction index; however, the other resonance remained unchanged. On the basis of this unique characteristic of differing sensitivities, self-reference sensing is discussed. The nanosensor yielded a high sensitivity of 917 nm/RIU and a figure of merit of 180 RIU−1. This work is helpful in terms of the design of on-chip optical sensors with high sensitivity and improved detection accuracy in complicated environments. PMID- 29710807 TI - Damage Detection of a Concrete Column Subject to Blast Loads Using Embedded Piezoceramic Transducers. AB - Some of the most severe structural loadings come in the form of blast loads, which may be caused by severe accidents or even terrorist activities. Most commonly after exposure to explosive forces, a structure will suffer from different degrees of damage, and even progress towards a state of collapse. Therefore, damage detection of a structure subject to explosive loads is of importance. This paper proposes a new approach to damage detection of a concrete column structure subjected to blast loads using embedded piezoceramic smart aggregates (SAs). Since the sensors are embedded in the structure, the proposed active-sensing based approach is more sensitive to internal or through cracks than surface damage. In the active sensing approach, the embedded SAs act as actuators and sensors, that can respectively generate and detect stress waves. If the stress wave propagates across a crack, the energy of the wave attenuates, and the reduction of the energy compared to the healthy baseline is indicative of a damage. With a damage index matrix constructed by signals obtained from an array of SAs, cracks caused by blast loads can be detected throughout the structure. Conventional sensing methods such as the measurement of dynamic strain and acceleration were included in the experiment. Since columns are critical elements needed to prevent structural collapse, knowledge of their integrity and damage conditions is essential for safety after exposure to blast loads. In this research, a concrete column with embedded SAs was chosen as the specimen, and a series of explosive tests were conducted on the column. Experimental results reveal that surface damages, though appear severe, cause minor changes in the damage index, and through cracks result in significant increase of the damage index, demonstrating the effectiveness of the active sensing, enabled by embedded SAs, in damage monitoring of the column under blast loads, and thus providing a reliable indication of structural integrity in the event of blast loads. PMID- 29710808 TI - Unsupervised Indoor Localization Based on Smartphone Sensors, iBeacon and Wi-Fi. AB - In this paper, we propose UILoc, an unsupervised indoor localization scheme that uses a combination of smartphone sensors, iBeacons and Wi-Fi fingerprints for reliable and accurate indoor localization with zero labor cost. Firstly, compared with the fingerprint-based method, the UILoc system can build a fingerprint database automatically without any site survey and the database will be applied in the fingerprint localization algorithm. Secondly, since the initial position is vital to the system, UILoc will provide the basic location estimation through the pedestrian dead reckoning (PDR) method. To provide accurate initial localization, this paper proposes an initial localization module, a weighted fusion algorithm combined with a k-nearest neighbors (KNN) algorithm and a least squares algorithm. In UILoc, we have also designed a reliable model to reduce the landmark correction error. Experimental results show that the UILoc can provide accurate positioning, the average localization error is about 1.1 m in the steady state, and the maximum error is 2.77 m. PMID- 29710810 TI - Exploring microRNA Biomarker for Amyotrophic Lateral Sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is among the severe neuro degenerative diseases that lack widely available effective treatments. As the disease progresses, patients lose the control of voluntary muscles. Although the neuronal degeneration is the cause of this disease, the failure mechanism is still unknown. In order to seek genetic mechanisms that initiate and progress ALS, the association of microRNA (miRNA) expression with this disease was considered. Serum miRNAs from healthy controls, sporadic ALS (sALS), familial ALS (fALS) and ALS mutation carriers were investigated. Principal component analysis (PCA)-based unsupervised feature extraction (FE) was applied to these serum miRNA profiles. As a result, we predict miRNAs that can discriminate patients from healthy controls with high accuracy. Thus, these miRNAs can be potential prognosis miRNA biomarkers for ALS. PMID- 29710809 TI - Anti-Oxidant and Anti-Inflammatory Activity of Ketogenic Diet: New Perspectives for Neuroprotection in Alzheimer's Disease. AB - The ketogenic diet, originally developed for the treatment of epilepsy in non responder children, is spreading to be used in the treatment of many diseases, including Alzheimer’s disease. The main activity of the ketogenic diet has been related to improved mitochondrial function and decreased oxidative stress. B Hydroxybutyrate, the most studied ketone body, has been shown to reduce the production of reactive oxygen species (ROS), improving mitochondrial respiration: it stimulates the cellular endogenous antioxidant system with the activation of nuclear factor erythroid-derived 2-related factor 2 (Nrf2), it modulates the ratio between the oxidized and reduced forms of nicotinamide adenine dinucleotide (NAD+/NADH) and it increases the efficiency of electron transport chain through the expression of uncoupling proteins. Furthermore, the ketogenic diet performs anti-inflammatory activity by inhibiting nuclear factor kappa-light-chain enhancer of activated B cells (NF-kB) activation and nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome as well as inhibiting histone deacetylases (HDACs), improving memory encoding. The underlying mechanisms and the perspectives for the treatment of Alzheimer’s disease are discussed. PMID- 29710811 TI - Type I Collagen and Strontium-Containing Mesoporous Glass Particles as Hybrid Material for 3D Printing of Bone-Like Materials. AB - Bone tissue engineering offers an alternative promising solution to treat a large number of bone injuries with special focus on pathological conditions, such as osteoporosis. In this scenario, the bone tissue regeneration may be promoted using bioactive and biomimetic materials able to direct cell response, while the desired scaffold architecture can be tailored by means of 3D printing technologies. In this context, our study aimed to develop a hybrid bioactive material suitable for 3D printing of scaffolds mimicking the natural composition and structure of healthy bone. Type I collagen and strontium-containing mesoporous bioactive glasses were combined to obtain suspensions able to perform a sol-gel transition under physiological conditions. Field emission scanning electron microscopy (FESEM) analyses confirmed the formation of fibrous nanostructures homogeneously embedding inorganic particles, whereas bioactivity studies demonstrated the large calcium phosphate deposition. The high-water content promoted the strontium ion release from the embedded glass particles, potentially enhancing the osteogenic behaviour of the composite. Furthermore, the suspension printability was assessed by means of rheological studies and preliminary extrusion tests, showing shear thinning and fast material recovery upon deposition. In conclusion, the reported results suggest that promising hybrid systems suitable for 3D printing of bioactive scaffolds for bone tissue engineering have been developed. PMID- 29710812 TI - Electrocardiographic and Electrooculographic Responses to External Emotions and Their Transitions in Bipolar I and II Disorders. AB - Bipolar disorder has two main types, bipolar I (BD I) and II (BD II), which present different affective states and personality characteristics, they might present different modes of emotional regulation. We hypothesized that the electrocardiogram and electrooculogram to external emotions are different in BD I and BD II. We asked 69 BD I and 54 BD II patients, and 139 healthy volunteers to undergo these tests in response to disgust, erotica, fear, happiness, neutral, and sadness, and their transitions. Their affective states were also measured. The heart rate in BD I was significantly higher under background fear after target neutral. The eyeball movement was quicker in BD I under target happiness after background disgust; in BD I under target sadness after background disgust; and in BD I under background disgust after target neutral. Some electrocardiographic and electrooculographic changes were correlated with affective states in patients. BD I and BD II had different physiological responses to external emotions and their transitions, indicating different pathophysiologies and suggesting different emotional-therapies for BD I and BD II. PMID- 29710813 TI - Decellularized Diaphragmatic Muscle Drives a Constructive Angiogenic Response In Vivo. AB - Skeletal muscle tissue engineering (TE) aims to efficiently repair large congenital and acquired defects. Biological acellular scaffolds are considered a good tool for TE, as decellularization allows structural preservation of tissue extracellular matrix (ECM) and conservation of its unique cytokine reservoir and the ability to support angiogenesis, cell viability, and proliferation. This represents a major advantage compared to synthetic scaffolds, which can acquire these features only after modification and show limited biocompatibility. In this work, we describe the ability of a skeletal muscle acellular scaffold to promote vascularization both ex vivo and in vivo. Specifically, chicken chorioallantoic membrane assay and protein array confirmed the presence of pro-angiogenic molecules in the decellularized tissue such as HGF, VEGF, and SDF-1α. The acellular muscle was implanted in BL6/J mice both subcutaneously and ortotopically. In the first condition, the ECM-derived scaffold appeared vascularized 7 days post-implantation. When the decellularized diaphragm was ortotopically applied, newly formed blood vessels containing CD31+, αSMA+, and vWF+ cells were visible inside the scaffold. Systemic injection of Evans Blue proved function and perfusion of the new vessels, underlying a tissue regenerative activation. On the contrary, the implantation of a synthetic matrix made of polytetrafluoroethylene used as control was only surrounded by vWF+ cells, with no cell migration inside the scaffold and clear foreign body reaction (giant cells were visible). The molecular profile and the analysis of macrophages confirmed the tendency of the synthetic scaffold to enhance inflammation instead of regeneration. In conclusion, we identified the angiogenic potential of a skeletal muscle-derived acellular scaffold and the pro-regenerative environment activated in vivo, showing clear evidence that the decellularized diaphragm is a suitable candidate for skeletal muscle tissue engineering and regeneration. PMID- 29710814 TI - A Feasible Strategy for Fabricating Surface Porous Network in Fe-Si Ribbons. AB - Porous materials have always attracted extensive attention owing to their low density, tunable porosity and high surface area. Generally, porosity is introduced in amorphous materials through dealloying or electrochemical dealloying processes. In this work, an iron-based surface porous network was successfully fabricated utilizing selective electrochemical dissolution of Fe-Si alloy ribbons based on the cellular structure prepared by melt-spinning technique. After 30 s, the surface of the ribbon gradually becomes flat and grains can be observed in the first stage of electrochemistry; after an extra 10 s, the pores spread throughout the surface of the ribbon in the second stage. The average size of pores is about 310 nm and the average size of the ligament is 150 nm. The associated dissolution mechanism has been proposed based on the inhomogeneous composition of the center and edge of the cell. The entire process of electrochemical dissolution has been divided into two stages and the entire duration of synthesis does not exceed one minute. This method is extremely feasible and provides a promising strategy for preparing surface porous materials for selective electrochemical dissolution of cellular structure. PMID- 29710815 TI - An Electrochemical Sensor of Poly(EDOT-pyridine-EDOT)/Graphitic Carbon Nitride Composite for Simultaneous Detection of Cd2+ and Pb2. AB - In this study, poly(2,5-bis(3,4-ethylenedioxythienyl)pyridine)/graphitic carbon nitride composites (poly(BPE)/g-C3N4) were prepared by an in situ chemical polymerization method. Composites were characterized by using Fourier transform infrared spectroscopy (FT-IR), ultraviolet-visible absorption spectra (UV-vis), X ray diffraction (XRD), energy-dispersive X-ray spectroscopy (EDS), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). Furthermore, electrochemical sensors were applied for the electrochemical determination of Cd2+ and Pb2+ using the differential pulse voltammetry (DPV) method. The results indicated that 10 wt % poly(BPE)/g-C3N4 composite-modified electrode exhibited linear detection ranging from 0.12 to 7.2 μM and 0.08 to 7.2 μM for Cd2+ and Pb2+, with detection limits (S/N = 3) of 0.018 μM and 0.00324 μM. Interference analysis suggested that the 10 wt % poly(BPE)/g-C3N4 modified electrode can be applied for the detection of the Cd2+ and Pb2+ in real samples. PMID- 29710816 TI - Natural Product Potential of the Genus Nocardiopsis. AB - Actinomycetes are a relevant source of novel bioactive compounds. One of the pharmaceutically and biotechnologically important genera that attract natural products research is the genus Nocardiopsis, mainly for its ability to produce a wide variety of secondary metabolites accounting for its wide range of biological activities. This review covers the literature from January 2015 until February 2018 making a complete survey of all the compounds that were isolated from the genus Nocardiopsis, their biological activities, and natural sources, whenever applicable. PMID- 29710818 TI - Microstructure and Mechanical Properties of the As-Cast and As-Homogenized Mg-Zn Sn-Mn-Ca Alloy Fabricated by Semicontinuous Casting. AB - In this paper, a new type of low-cost Mg-3.36Zn-1.06Sn-0.33Mn-0.27Ca (wt %) alloy ingot with a diameter of 130 mm and a length of 4800 mm was fabricated by semicontinuous casting. The microstructure and mechanical properties at different areas of the ingot were investigated. The microstructure and mechanical properties of the alloy under different one-step and two-step homogenization conditions were studied. For the as-cast alloy, the average grain size and the second phase size decrease from the center to the surface of the ingot, while the area fraction of the second phase increases gradually. At one-half of the radius of the ingot, the alloy presents the optimum comprehensive mechanical properties along the axial direction, which is attributed to the combined effect of relatively small grain size, low second-phase fraction, and uniform microstructure. For the as-homogenized alloy, the optimum two-step homogenization process parameters were determined as 340 °C × 10 h + 520 °C × 16 h. After the optimum homogenization, the proper size and morphology of CaMgSn phase are conducive to improve the microstructure uniformity and the mechanical properties of the alloy. Besides, the yield strength of the alloy is reduced by 20.7% and the elongation is increased by 56.3%, which is more favorable for the subsequent hot deformation processing. PMID- 29710817 TI - Transcriptional Profiling of Host Cell Responses to Virulent Haemophilus parasuis: New Insights into Pathogenesis. AB - Haemophilus parasuis is the causative agent of Glässer’s disease in pigs. H. parasuis can cause vascular damage, although the mechanism remains unclear. In this study, we investigated the host cell responses involved in the molecular pathway interactions in porcine aortic vascular endothelial cells (PAVECs) induced by H. parasuis using RNA-Seq. The transcriptome results showed that when PAVECs were infected with H. parasuis for 24 h, 281 differentially expressed genes (DEGs) were identified; of which, 236 were upregulated and 45 downregulated. The 281 DEGs were involved in 136 KEGG signaling pathways that were organismal systems, environmental information processing, metabolism, cellular processes, and genetic information processing. The main pathways were the Rap1, FoxO, and PI3K/Akt signaling pathways, and the overexpressed genes were determined and verified by quantitative reverse transcription polymerase chain reaction. In addition, 252 genes were clustered into biological processes, molecular processes, and cellular components. Our study provides new insights for understanding the interaction between bacterial and host cells, and analyzed, in detail, the possible mechanisms that lead to vascular damage induced by H. parasuis. This may lead to development of novel therapeutic targets to control H. parasuis infection. PMID- 29710819 TI - Carnosol Increases Skeletal Muscle Cell Glucose Uptake via AMPK-Dependent GLUT4 Glucose Transporter Translocation. AB - Skeletal muscle is a major insulin-target tissue and plays an important role in glucose homeostasis. Insulin action in muscle activates the phosphatidylinositol 3 kinase (PI3K)/Akt signaling pathway causing the translocation of intracellularly stored GLUT4 glucose transporters to the plasma membrane and increased glucose uptake. Impaired insulin action in muscle results in insulin resistance and type 2 diabetes mellitus (T2DM). Activation of the energy sensor AMP-activated kinase (AMPK) increases muscle glucose uptake and the use of AMPK activators is viewed as an effective strategy to combat insulin resistance. Rosemary extract (RE) has been shown to stimulate muscle AMPK and glucose uptake, but the exact components responsible for these effects are unknown. In the current study, we investigated the effect of carnosol, a RE polyphenol, in L6 rat muscle cells. Carnosol stimulated glucose uptake in L6 myotubes in a dose- and time-dependent manner, did not affect Akt, increased AMPK phosphorylation and plasma membrane GLUT4 levels. The carnosol-stimulated glucose uptake and GLUT4 translocation was significantly reduced by the AMPK inhibitor compound C (CC). Our study is the first to show an AMPK-dependent increase in muscle glucose uptake by carnosol. Carnosol has potential as a glucose homeostasis regulating agent and deserves further study. PMID- 29710820 TI - Comparison of Anorectic Potencies of Type A Trichothecenes T-2 Toxin, HT-2 Toxin, Diacetoxyscirpenol, and Neosolaniol. AB - Trichothecene mycotoxins are common contaminants in cereal grains and negatively impact human and animal health. Although anorexia is a common hallmark of type B trichothecenes-induced toxicity, less is known about the anorectic potencies of type A trichothecenes. The purpose of this study was to compare the anorectic potencies of four type A trichothecenes (T-2 toxin (T-2), HT-2 toxin (HT-2), diacetoxyscirpenol (DAS), and neosolaniol (NEO)) in mice. Following oral exposure to T-2, HT-2, DAS, and NEO, the no observed adverse effect levels (NOAELs) and lowest observed adverse effect levels (LOAELs) were 0.01, 0.01, 0.1, and 0.01 mg/kg body weight (BW), and 0.1, 0.1, 0.5, and 0.1 mg/kg BW, respectively. Following intraperitoneal (IP) exposure to T-2, HT-2, DAS, and NEO, the NOAELs were 0.01 mg/kg BW, except for DAS (less than 0.01 mg/kg BW), and the LOAELs were 0.1, 0.1, 0.01, and 0.1 mg/kg BW, respectively. Taken together, the results suggest that (1) type A trichothecenes could dose-dependently elicit anorectic responses following both oral gavage and IP exposure in mice; (2) the anorectic responses follow an approximate rank order of T-2 = HT-2 = NEO > DAS for oral exposure, and DAS > T-2 = HT-2 = NEO for IP administration; (3) IP exposure to T 2, HT-2, DAS, and NEO evoked stronger anorectic effects than oral exposure. From a public health perspective, comparative anorectic potency data should be useful for establishing toxic equivalency factors for type A trichothecenes. PMID- 29710821 TI - Frequency Analysis of Failure Scenarios from Shale Gas Development. AB - This study identified and prioritized potential failure scenarios for natural gas drilling operations through an elicitation of people who work in the industry. A list of twelve failure scenarios of concern was developed focusing on specific events that may occur during the shale gas extraction process involving an operational failure or a violation of regulations. Participants prioritized the twelve scenarios based on their potential impact on the health and welfare of the general public, potential impact on worker safety, how well safety guidelines protect against their occurrence, and how frequently they occur. Illegal dumping of flowback water, while rated as the least frequently occurring scenario, was considered the scenario least protected by safety controls and the one of most concern to the general public. In terms of worker safety, the highest concern came from improper or inadequate use of personal protective equipment (PPE). While safety guidelines appear to be highly protective regarding PPE usage, inadequate PPE is the most directly witnessed failure scenario. Spills of flowback water due to equipment failure are of concern both with regards to the welfare of the general public and worker safety as they occur more frequently than any other scenario examined in this study. PMID- 29710822 TI - Effect of Temperature and Growth Time on Vertically Aligned ZnO Nanorods by Simplified Hydrothermal Technique for Photoelectrochemical Cells. AB - Despite its large band gap, ZnO has wide applicability in many fields ranging from gas sensors to solar cells. ZnO was chosen over other materials because of its large exciton binding energy (60 meV) and its stability to high-energy radiation. In this study, ZnO nanorods were deposited on ITO glass via a simple dip coating followed by a hydrothermal growth. The morphological, structural and compositional characteristics of the prepared films were analyzed using X-ray diffractometry (XRD), field emission scanning electron microscopy (FESEM), and ultraviolet-visible spectroscopy (UV-Vis). Photoelectrochemical conversion efficiencies were evaluated via photocurrent measurements under calibrated halogen lamp illumination. Thin film prepared at 120 °C for 4 h of hydrothermal treatment possessed a hexagonal wurtzite structure with the crystallite size of 19.2 nm. The average diameter of the ZnO nanorods was 37.7 nm and the thickness was found to be 2680.2 nm. According to FESEM images, as the hydrothermal growth temperature increases, the nanorod diameter become smaller. Moreover, the thickness of the nanorods increase with the growth time. Therefore, the sample prepared at 120 °C for 4 h displayed an impressive photoresponse by achieving high current density of 0.1944 mA/cm2. PMID- 29710824 TI - Risk Analysis of Earth-Rock Dam Failures Based on Fuzzy Event Tree Method. AB - Earth-rock dams make up a large proportion of the dams in China, and their failures can induce great risks. In this paper, the risks associated with earth rock dam failure are analyzed from two aspects: the probability of a dam failure and the resulting life loss. An event tree analysis method based on fuzzy set theory is proposed to calculate the dam failure probability. The life loss associated with dam failure is summarized and refined to be suitable for Chinese dams from previous studies. The proposed method and model are applied to one reservoir dam in Jiangxi province. Both engineering and non-engineering measures are proposed to reduce the risk. The risk analysis of the dam failure has essential significance for reducing dam failure probability and improving dam risk management level. PMID- 29710823 TI - Nanobody Technology for Mycotoxin Detection in the Field of Food Safety: Current Status and Prospects. AB - Mycotoxins, which are toxic, carcinogenic, and/or teratogenic, have posed a threat to food safety and public health. Sensitive and effective determination technologies for mycotoxin surveillance are required. Immunoassays have been regarded as useful supplements to chromatographic techniques. However, conventional antibodies involved in immunoassays are difficult to be expressed recombinantly and are susceptible to harsh environments. Nanobodies (or VHH antibodies) are antigen-binding sites of the heavy-chain antibodies produced from Camelidae. They are found to be expressed easily in prokaryotic or eukaryotic expression systems, more robust in extreme conditions, and facile to be used as surrogates for artificial antigens. These properties make them the promising and environmentally friendly immunoreagents in the next generation of immunoassays. This review briefly describes the latest developments in the area of nanobodies used in mycotoxin detection. Moreover, by integrating the introduction of the principle of nanobodies production and the critical assessment of their performance, this paper also proposes the prospect of nanobodies in the field of food safety in the foreseeable future. PMID- 29710825 TI - Impact of a Specific Amino Acid Composition with Micronutrients on Well-Being in Subjects with Chronic Psychological Stress and Exhaustion Conditions: A Pilot Study. AB - Chronic work-life stress leads to dysfunction of the hypothalamus-pituitary adrenal axis, the autonomic nervous system, and the serotonergic system, with resultant impairment of overall well-being. Aim of the study was to improve perceived stress by a specific amino acid composition with micronutrients in the verum versus placebo group. A total of 59 participants (18-65 years) with self reported perceived chronic stress and exhaustion conditions participated in this randomized, double-blind, placebo-controlled study. The Perceived Stress Questionnaire (PSQ30), amino acid profile, anthropometric, clinical, blood, urine parameters, and dietary intake were assessed. After 12 weeks, the verum group achieved significantly greater improvements in the total PSQ30 score compared with the placebo group. In the verum group, serum taurine concentration, folic acid concentration, urinary magnesium excretion, and the ratio of l-tryptophan to the sum of competing amino acids rose significantly. In the placebo group, serum concentrations of serotonin, protein, and magnesium decreased significantly, whereas the cardiometabolic risk parameters body weight, body mass index, waist circumference, and waist-to-height ratio increased significantly. Compared with placebo, the verum supplementation resulted in a higher improvement in perceived stress. Beneficial effects on the serotonergic system and preventive effects on magnesium homeostasis and some cardiometabolic risk factors were supposed. Additional effects might be caused by the optimized food intake. PMID- 29710827 TI - The Effect of Different Porogens on Porous PMMA Microspheres by Seed Swelling Polymerization and Its Application in High-Performance Liquid Chromatography. AB - Monodisperse cross-linked porous poly (methyl methacrylate) (PMMA) microspheres (~2.5 μm in diameter) were prepared by using an improved two-step seed swelling polymerization method with monodisperse micron-grade PMMA microspheres seeds. The porous PMMA microspheres with diverse surface morphology and pore structure were obtained by tuning porogen systems. The monodisperse porous PMMA microspheres, which were prepared using toluene:dibutylphthalate (DBP) = 1:1 (v/v) as a porogen system, had the smallest pore size and the largest specific surface area. Then, the monodisperse porous PMMA microspheres were subjected to high-performance liquid chromatography. The liquid chromatographic column filler successfully realized complete separation of arginine, glycine and glutamic acid, and the separation effect was good. The porous PMMA microspheres provide a new material for the separation of amino acids by liquid chromatography. PMID- 29710826 TI - Comparison of Yeasts as Hosts for Recombinant Protein Production. AB - Recombinant protein production emerged in the early 1980s with the development of genetic engineering tools, which represented a compelling alternative to protein extraction from natural sources. Over the years, a high level of heterologous protein was made possible in a variety of hosts ranging from the bacteria Escherichia coli to mammalian cells. Recombinant protein importance is represented by its market size, which reached $1654 million in 2016 and is expected to reach $2850.5 million by 2022. Among the available hosts, yeasts have been used for producing a great variety of proteins applied to chemicals, fuels, food, and pharmaceuticals, being one of the most used hosts for recombinant production nowadays. Historically, Saccharomyces cerevisiae was the dominant yeast host for heterologous protein production. Lately, other yeasts such as Komagataella sp., Kluyveromyces lactis, and Yarrowia lipolytica have emerged as advantageous hosts. In this review, a comparative analysis is done listing the advantages and disadvantages of using each host regarding the availability of genetic tools, strategies for cultivation in bioreactors, and the main techniques utilized for protein purification. Finally, examples of each host will be discussed regarding the total amount of protein recovered and its bioactivity due to correct folding and glycosylation patterns. PMID- 29710828 TI - Molecular Mechanisms Governing "Hair-Trigger" Induction of Shiga Toxin-Encoding Prophages. AB - Shiga toxin (Stx)-encoding E. coli (STEC) strains are responsible for sporadic outbreaks of food poisoning dating to 1982, when the first STEC strain, E. coli O157:H7, was isolated. Regardless of STEC serotype, the primary symptoms of STEC infections are caused by Stx that is synthesized from genes resident on lambdoid prophage present in STEC. Despite similar etiology, the severity of STEC-mediated disease varies by outbreak. However, it is unclear what modulates the severity of STEC-mediated disease. Stx production and release is controlled by lytic growth of the Stx-encoding bacteriophage, which in turn, is controlled by the phage repressor. Here, we confirm our earlier suggestion that the higher spontaneous induction frequency of Stx-encoding prophage is a consequence, in part, of lower intracellular repressor levels in STEC strains versus non-STEC strains. We also show that this lowered intracellular repressor concentration is a consequence of the utilization of alternative binding/regulatory strategies by the phage repressor. We suggest that a higher spontaneous induction frequency would lead to increased virulence. PMID- 29710829 TI - Effect of Glutathione Bio-Molecule on Tooth Discoloration Associated with Silver Diammine Fluoride. AB - This study evaluated the effect of Glutathione (GSH) bio-molecule on the reduction of enamel and dentin discoloration after application of 38% silver diammine fluoride solution (SDF). One hundred and twenty bovine teeth specimens were used. The enamel and dentin specimens were divided into three groups: (1) SDF only (control); (2) SDF followed by application of a potassium iodide solution (KI); and (3) SDF mixed with 20% GSH. Half the specimens were exposed to light and the remainder kept in dark conditions (n = 10) Color changes were measured using a spectrophotometer at the following time intervals: before solution application (baseline) and immediately after application, then 3, 6, 24, 48, 72 h, and 7, 10 and 14 days. SEM/EDS analysis was performed on treated enamel and dentin. Statistical analysis was done using a repeated measures ANOVA test. The spectrophotometer results showed that the SDF group exhibited the greatest color changes under both light exposed and dark conditions, while SDF + GSH group was effective in decreasing the color changes in both light and dark conditions. The SDF + KI group showed an insignificant color changes over time. SEM/EDS analysis showed different patterns for the silver crystal formation in each group (SDF, SDF + GSH, and SDF + KI group). It was concluded GSH can effectively minimize color changes after application of SDF, especially on enamel and to a lesser extent on dentin. PMID- 29710830 TI - Zebrafish, a Novel Model System to Study Uremic Toxins: The Case for the Sulfur Amino Acid Lanthionine. AB - The non-proteinogenic amino acid lanthionine is a byproduct of hydrogen sulfide biosynthesis: the third endogenous vasodilator gas, after nitric oxide and carbon monoxide. While hydrogen sulfide is decreased in uremic patients on hemodialysis, lanthionine is increased and has been proposed as a new uremic toxin, since it is able to impair hydrogen sulfide production in hepatoma cells. To characterize lanthionine as a uremic toxin, we explored its effects during the early development of the zebrafish (Danio rerio), a widely used model to study the organ and tissue alterations induced by xenobiotics. Lanthionine was employed at concentrations reproducing those previously detected in uremia. Light-induced visual motor response was also studied by means of the DanioVision system. Treatment of zebrafish embryos with lanthionine determined acute phenotypical alterations, on heart organogenesis (disproportion in cardiac chambers), increased heart beating, and arrhythmia. Lanthionine also induced locomotor alterations in zebrafish embryos. Some of these effects could be counteracted by glutathione. Lanthionine exerted acute effects on transsulfuration enzymes and the expression of genes involved in inflammation and metabolic regulation, and modified microRNA expression in a way comparable with some alterations detected in uremia. Lanthionine meets the criteria for classification as a uremic toxin. Zebrafish can be successfully used to explore uremic toxin effects. PMID- 29710832 TI - Flight State Identification of a Self-Sensing Wing via an Improved Feature Selection Method and Machine Learning Approaches. AB - In this work, a data-driven approach for identifying the flight state of a self sensing wing structure with an embedded multi-functional sensing network is proposed. The flight state is characterized by the structural vibration signals recorded from a series of wind tunnel experiments under varying angles of attack and airspeeds. A large feature pool is created by extracting potential features from the signals covering the time domain, the frequency domain as well as the information domain. Special emphasis is given to feature selection in which a novel filter method is developed based on the combination of a modified distance evaluation algorithm and a variance inflation factor. Machine learning algorithms are then employed to establish the mapping relationship from the feature space to the practical state space. Results from two case studies demonstrate the high identification accuracy and the effectiveness of the model complexity reduction via the proposed method, thus providing new perspectives of self-awareness towards the next generation of intelligent air vehicles. PMID- 29710831 TI - Quantitative Changes in the Transcription of Phytohormone-Related Genes: Some Transcription Factors Are Major Causes of the Wheat Mutant dmc Not Tillering. AB - Tiller number is an important agronomic trait for grain yield of wheat (Triticum aestivum L.). A dwarf-monoculm wheat mutant (dmc) was obtained from cultivar Guomai 301 (wild type, WT). Here, we explored the molecular basis for the restrained tiller development of the mutant dmc. Two bulked samples of the mutant dmc (T1, T2 and T3) and WT (T4, T5 and T6) with three biological replicates were comparatively analyzed at the transcriptional level by bulked RNA sequencing (RNA Seq). In total, 68.8 Gb data and 463 million reads were generated, 80% of which were mapped to the wheat reference genome of Chinese Spring. A total of 4904 differentially expressed genes (DEGs) were identified between the mutant dmc and WT. DEGs and their related major biological functions were characterized based on GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) categories. These results were confirmed by quantitatively analyzing the expression profiles of twelve selected DEGs via real-time qRT-PCR. The down-regulated gene expressions related to phytohormone syntheses of auxin, zeatin, cytokinin and some transcription factor (TF) families of TALE, and WOX might be the major causes of the mutant dmc, not tillering. Our work provides a foundation for subsequent tiller development research in the future. PMID- 29710833 TI - Social Sentiment Sensor in Twitter for Predicting Cyber-Attacks Using l1 Regularization. AB - In recent years, online social media information has been the subject of study in several data science fields due to its impact on users as a communication and expression channel. Data gathered from online platforms such as Twitter has the potential to facilitate research over social phenomena based on sentiment analysis, which usually employs Natural Language Processing and Machine Learning techniques to interpret sentimental tendencies related to users’ opinions and make predictions about real events. Cyber-attacks are not isolated from opinion subjectivity on online social networks. Various security attacks are performed by hacker activists motivated by reactions from polemic social events. In this paper, a methodology for tracking social data that can trigger cyber attacks is developed. Our main contribution lies in the monthly prediction of tweets with content related to security attacks and the incidents detected based on l 1 regularization. PMID- 29710834 TI - Fish Oil Ameliorates High-Fat Diet Induced Male Mouse Reproductive Dysfunction via Modifying the Rhythmic Expression of Testosterone Synthesis Related Genes. AB - The present study aims to investigate the protective effects of omega-3 polyunsaturated fatty acids (omega-3PUFAs) against high-fat diet induced male mouse reproductive dysfunction and to explore circadian regulation mechanisms. Male C57BL/6 mice were randomly divided into three groups and fed a normal chow diet (control group, CON), a high-fat diet (HFD group) or a HFD supplemented with fish oil (FO group) for 12 weeks. After 12 weeks of feeding, the body weight and the ratio of perinephric and epididymal fat weight to body weight were significantly higher in the HFD group compared with the CON group. The supplement of fish oil rich in omega-3PUFAs only slightly reduced the HFD-induced obesity but remarkably ameliorated HFD-induced dyslipidemia, sexual hormones disorder, testicle lesions and germ cell apoptosis. Fish oil supplementation restored the expression of steroid synthesis associated genes in HFD fed mouse and flattened the HFD-induced oscillations in circadian genes' expression. Fish oil supplementation prevented HFD-induced male mouse reproductive dysfunction and modified the rhythmic expression of testosterone synthesis related genes. PMID- 29710835 TI - Eicosapentaenoic Acid (EPA) and Docosahexaenoic Acid (DHA) in Muscle Damage and Function. AB - Nutritional supplementation not only helps in improving and maintaining performance in sports and exercise, but also contributes in reducing exercise fatigue and in recovery from exhaustion. Fish oil contains large amounts of omega 3 fatty acids, eicosapentaenoic acid (EPA; 20:5 n-3) and docosahexaenoic acid (DHA; 22:6 n-3). It is widely known that omega-3 fatty acids are effective for improving cardiac function, depression, cognitive function, and blood as well as lowering blood pressure. In the relationship between omega-3 fatty acids and exercise performance, previous studies have been predicted improved endurance performance, antioxidant and anti-inflammatory responses, and effectivity against delayed-onset muscle soreness. However, the optimal dose, duration, and timing remain unclear. This review focuses on the effects of omega-3 fatty acid on muscle damage and function as evaluated by human and animal studies and summarizes its effects on muscle and nerve damage, and muscle mass and strength. PMID- 29710836 TI - Animal Models of the Neuromuscular Junction, Vitally Informative for Understanding Function and the Molecular Mechanisms of Congenital Myasthenic Syndromes. AB - The neuromuscular junction is the point of contact between motor nerve and skeletal muscle, its vital role in muscle function is reliant on the precise location and function of many proteins. Congenital myasthenic syndromes (CMS) are a heterogeneous group of disorders of neuromuscular transmission with 30 or more implicated proteins. The use of animal models has been instrumental in determining the specific role of many CMS-related proteins. The mouse neuromuscular junction (NMJ) has been extensively studied in animal models of CMS due to its amenability for detailed electrophysiological and histological investigations and relative similarity to human NMJ. As well as their use to determine the precise molecular mechanisms of CMS variants, where an animal model accurately reflects the human phenotype they become useful tools for study of therapeutic interventions. Many of the animal models that have been important in deconvolving the complexities of neuromuscular transmission and revealing the molecular mechanisms of disease are highlighted. PMID- 29710837 TI - Mechanism of the Dual Activities of Human CYP17A1 and Binding to Anti-Prostate Cancer Drug Abiraterone Revealed by a Novel V366M Mutation Causing 17,20 Lyase Deficiency. AB - The CYP17A1 gene regulates sex steroid biosynthesis in humans through 17α hydroxylase/17,20 lyase activities and is a target of anti-prostate cancer drug abiraterone. In a 46, XY patient with female external genitalia, together with a loss of function mutation S441P, we identified a novel missense mutation V366M at the catalytic center of CYP17A1 which preferentially impaired 17,20 lyase activity. Kinetic experiments with bacterially expressed proteins revealed that V366M mutant enzyme can bind and metabolize pregnenolone to 17OH-pregnenolone, but 17OH-pregnenolone binding and conversion to dehydroepiandrosterone (DHEA) was impaired, explaining the patient’s steroid profile. Abiraterone could not bind and inhibit the 17α-hydroxylase activity of the CYP17A1-V366M mutant. Molecular dynamics (MD) simulations showed that V366M creates a “one-way valve” and suggests a mechanism for dual activities of human CYP17A1 where, after the conversion of pregnenolone to 17OH-pregnenolone, the product exits the active site and re-enters for conversion to dehydroepiandrosterone. The V366M mutant also explained the effectiveness of the anti-prostate cancer drug abiraterone as a potent inhibitor of CYP17A1 by binding tightly at the active site in the WT enzyme. The V366M is the first human mutation to be described at the active site of CYP17A1 that causes isolated 17,20 lyase deficiency. Knowledge about the specificity of CYP17A1 activities is of importance for the development of treatments for polycystic ovary syndrome and inhibitors for prostate cancer therapy. PMID- 29710838 TI - Assessment of Genetic Diversity among Pleurotus spp. Isolates from Jordan. AB - Pleurotus is considered an important genus that belongs to the family Pleurotaceae and includes the edible King Oyster mushroom (Pleurotus eryngii). In the present study, 19 Pleurotus isolates were collected from two locations in the north of Jordan (Tell ar-Rumman and Um-Qais). The morphological characteristics among collected isolates revealed that there was a morphological similarity among the collected isolates. Nucleotide sequence analysis of the internal transcribed spacer (ITS1-5.8S rDNA-ITS4 region) and 28S nuclear large subunit (nLSU) in the ribosomal DNA gene of the isolated stains showed that all of them share over 98% sequence similarity with P. eryngii. Genetic diversity among the collected strains was assessed using inter simple sequence repeat (ISSR) analysis using 18 different primer pairs. Using this approach, 141 out of 196 bands obtained were considered polymorphic and the highest percentage of polymorphism was observed using primer UBC827 (92.3%) with an overall Polymorphism Information Content (PIC) value of 70.56%. Cluster analysis showed that the Jordanian Pleurotus isolates fall into two main clades with a coefficient of similarity values ranging from 0.59 to 0.74 with a clear clustering based on collection sites. The results of the present study reveal that molecular techniques of ISSR and rDNA sequencing can greatly aid in classification and identification of Pleurotus spp. in Jordan. PMID- 29710839 TI - Building-in-Briefcase: A Rapidly-Deployable Environmental Sensor Suite for the Smart Building. AB - A building’s environment has profound influence on occupant comfort and health. Continuous monitoring of building occupancy and environment is essential to fault detection, intelligent control, and building commissioning. Though many solutions for environmental measuring based on wireless sensor networks exist, they are not easily accessible to households and building owners who may lack time or technical expertise needed to set up a system and get quick and detailed overview of environmental conditions. Building-in-Briefcase (BiB) is a portable sensor network platform that is trivially easy to deploy in any building environment. Once the sensors are distributed, the environmental data is collected and communicated to the BiB router via the Transmission Control Protocol/Internet Protocol (TCP/IP) and WiFi technology, which then forwards the data to the central database securely over the internet through a 3G radio. The user, with minimal effort, can access the aggregated data and visualize the trends in real time on the BiB web portal. Paramount to the adoption and continued operation of an indoor sensing platform is battery lifetime. This design has achieved a multi-year lifespan by careful selection of components, an efficient binary communications protocol and data compression. Our BiB sensor is capable of collecting a rich set of environmental parameters, and is expandable to measure others, such as CO 2 . This paper describes the power characteristics of BiB sensors and their occupancy estimation and activity recognition functionality. We have demonstrated large-scale deployment of BiB throughout Singapore. Our vision is that, by monitoring thousands of buildings through BiB, it would provide ample research opportunities and opportunities to identify ways to improve the building environment and energy efficiency. PMID- 29710841 TI - Antidiabetic Effect of Cyclocarya paliurus Leaves Depends on the Contents of Antihyperglycemic Flavonoids and Antihyperlipidemic Triterpenoids. AB - Cyclocarya paliurus has been used commonly to treat diabetes in China. However, the effective components and the effect of plant origin remain unclear. In this study, C. paliurus leaves with different chemical compositions were selected from five geographical locations, and their effects on streptozotocin (STZ)-induced diabetic mice were evaluated with both ethanol and aqueous extracts. Glucose levels, lipid levels, and biomarkers of liver and kidney function were measured. The principal components of both C. paliurus ethanol and aqueous extracts from different geographical locations differed quantitatively and qualitatively. Results showed that C. paliurus extracts with better antihyperglycemic effects were characterized by higher contents of total flavonoids, especially quercetin-3 O-glucuronide and kaempferol-3-O-glucuronide. Furthermore, significantly negative correlations were found between triterpenoids contents and lipid levels. These results revealed the potential antihyperglycemic capacity of C. paliurus flavonoids and the antihyperlipidemic effect of C. paliurus triterpenoids. Thus, we suggest that the composition of C. paliurus compounds might help to design therapeutic alternatives for the treatment of diabetes mellitus. However, geographic origins and the extraction solvents can also affect the effectiveness of the treatment as these factors influence the chemical compositions and thereby the biological activities. PMID- 29710843 TI - Poly-L-lactic Acid (PLLA)-Chitosan-Collagen Electrospun Tube for Vascular Graft Application. AB - Poly-L-Lactic acid (PLLA) blended with chitosan and collagen was used to fabricate a conduit for blood vessel engineering through an electrospinning process. Various concentrations of chitosan were used in the blend in order to study its effect on the morphology, chemical bond, tensile strength, burst pressure, hemocompatibility, and cell viability (cytotoxicity) of the tube.In vitro assessments indicated that addition of chitosan-collagen could improve cell viability and hemocompatibility. Best results were demonstrated by the conduit with 10% PLLA, 0.5% chitosan, and 1% collagen. Tensile strength reached 2.13 MPa and burst pressure reached 2593 mmHg, both values that are within the range value of native blood vessel. A hemolysis percentage of 1.04% and a cell viability of 86.2% were obtained, meeting the standards of high hemocompatibility and low cytotoxicity for vascular graft material. The results are promising for further development toward vascular graft application. PMID- 29710840 TI - NADPH Oxidases and Mitochondria in Vascular Senescence. AB - Aging is the major risk factor in the development of cardiovascular diseases (CVDs), including hypertension, atherosclerosis, and myocardial infarction. Oxidative stress caused by overproduction of reactive oxygen species (ROS) and/or by reduced expression of antioxidant enzymes is a major contributor to the progression of vascular senescence, pathologic remodeling of the vascular wall, and disease. Both oxidative stress and inflammation promote the development of senescence, a process by which cells stop proliferating and become dysfunctional. This review focuses on the role of the mitochondria and the nicotinamide adenine dinucleotide phosphate (NADPH) oxidases Nox1 and Nox4 in vascular senescence, and their contribution to the development of atherosclerosis. Recent findings are reviewed, supporting a critical role of the mitochondrial regulator peroxisome proliferator-activated receptor gamma (PPARγ) coactivator-1α (PGC 1α), the inflammatory gene nuclear factor κB (NF-κB), zinc, the zinc transporters (ZnTs) ZnT3 and ZnT10, and angiotensin II (Ang II) in mitochondrial function, and their role in telomere stability, which provides new mechanistic insights into a previously proposed unified theory of aging. PMID- 29710842 TI - Synthesis, Spectroscopic Identification and Molecular Docking of Certain N-(2-{[2 (1H-Indol-2-ylcarbonyl) Hydrazinyl](oxo)Acetylphenyl)Acetamides and N-[2-(2-{[2 (Acetylamino)Phenyl](oxo)Acetylhydrazinyl)-2-Oxoethyl]-1H-Indole-2-Carboxamides: New Antimicrobial Agents. AB - N-(2-{[2-(1H-Indol-2-ylcarbonyl)hydrazinyl](oxo)acetyl}phenyl)acetamides (5a-h) and N-[2-(2-{[2-(acetylamino)phenyl](oxo)acetyl}hydrazinyl)-2-oxoethyl]-1H-indole 2-carboxamides (5i-l) were synthesized and characterized with different analytical tools. N-Acetylisatines 4a-d were subjected to ring opening at their C2 carbons with the aid of different indole-bearing hydrazides 3a,b and 7 to afford the respective glyoxylamides 5a-l. The antimicrobial activity of the target compounds 5a-l was assessed with the aid of Diameter of the Inhibition Zone (DIZ) and Minimum Inhibitory Concentration (MIC) assays against a panel of Gram-positive and Gram-negative bacteria and certain fungal strains. The antimicrobial screening revealed that Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans are the most sensitive microorganisms towards the synthesized compounds 5a-l. In addition, compounds 5c and 5h emerged as the most active congeners towards Staphylococcus aureus and Candida albicans, respectively. Molecular docking studies revealed the possible binding mode of compounds 5c and 5h to their target proteins. PMID- 29710844 TI - Synthesis and Characterization of Injectable Hydrogels with Varying Collagen Chitosan-Thymosin beta4 Composition for Myocardial Infarction Therapy. AB - Thirty percent of global mortalities are caused by cardiovascular disease, and 54% of the aforementioned amount is instigated by ischemic heart disease that triggered myocardial infarction. Myocardial infarction is due to blood flow cessation in certain coronary arteries that causes lack of oxygen (ischemia) and stimulates myocardial necrosis. One of the methods to treat myocardial infarction consists in injecting cells or active biomolecules and biomaterials into heart infarction locations. This study aimed to investigate the characteristics of a collagen-chitosan-based hydrogel with variations in its chitosan composition. The prepared hydrogels contained thymosin β4 (Tβ4), a 43-amino acid peptide with angiogenic and cardioprotective properties which can act as a bioactive molecule for the treatment of myocardial infarction. A morphological structure analysis showed that the hydrogels lacked interconnecting pores. All samples were not toxic on the basis of a cytotoxicity test. A histopathological anatomy test showed that the collagen-chitosan-thymosin β4 hydrogels could stimulate angiogenesis and epicardial heart cell migration, as demonstrated by the evaluation of the number of blood vessels and the infiltration extent of myofibroblasts. PMID- 29710845 TI - Evaluation of Residual Stress Distribution and Relaxation on In Situ TiB2/7050 Al Composites. AB - Interior residual stresses induced by quenching may cause distortion during subsequent machining processes. Hence, various strategies have been employed to relieve the interior residual stress, such as stretching, post treatment, and other techniques. In this study, the stress distribution inside TiB2/7050 Al composite extrusions was investigated and the effects of different methods on relieving the quenching-induced stress were compared. Firstly, three TiB2/7050 Al composite extrusions were treated by stretching, stretching and heat treatment, and stretching and cold treatment processes, respectively. Then, the multiple-cut contour method was employed to assess the residual stresses in the three workpieces. Experimental results indicate that the interior stress of TiB2/7050 Al composite extrusions after stretching ranges from −89 MPa to +55 MPa, which is larger than that in 7050 aluminum alloy, which ranges from −25 Pa to +25 MPa. The heat treatment performs better than the cold treatment to reduce the post-stretching residual stress, with a reduction of 23.2-46.4% compared to 11.3-40.8%, respectively. From the stress map, it is found that the stress distribution after the heat treatment is more uniform compared with that after the cold treatment. PMID- 29710846 TI - Anti-Proliferative Activity of HPOB against Multiple Myeloma Cells via p21 Transcriptional Activation. AB - Histone acetylation or deacetylation is closely associated with the progression of multiple myeloma (MM). Currently, many histone deacetylase (HDAC) inhibitors have been approved for being used in clinical trials, but theirtherapeutic effectsarestill not ideal. As a novel HDAC inhibitor, hydroxamicacid-based small moleculeN-hydroxy-4-(2-[(2-hydroxyethyl)(phenyl)amino]-2-oxoethyl)benzamide (HPOB)’s possible roles in MM have not been studied. In this present study, the effect of HPOB as a potential anti-tumor agent in preventingproliferation and inducing apoptosis of MM cells had been investigated in detail. Our results showed that HPOB decreased the survival of MM cells in dose- and time-dependent manner. In addition, HPOB caused the accumulation of MM cells in G1 phase compared with the dimethylsulfoxide (DMSO) control group. Interestingly, we found that HPOB could overcome bortezomib (BTZ) resistance inMM cells and combining HPOB with BTZ could further sensitize MM cells. Certainly, our data illuminated that HPOB-mediated cell death occurs via transcriptional activation of p21, which was associated with an elevated level of global histone 3 acetylation (H3Ac) modification. Therefore, HPOB could be a potential candidate for MM treatment and the combination of HPOB and bortezomibcould bea possible therapeutic strategy for relapsed and refractory MM. PMID- 29710847 TI - Groundwater Flow Processes and Human Impact along the Arid US-Mexican Border, Evidenced by Environmental Tracers: The Case of Tecate, Baja California. AB - With the increasing population, urbanization and industry in the arid area of Tecate, there is a concomitant increase in contaminants being introduced into the Tecate River and its aquifer. This contamination is damaging the usable groundwater supply and making local residents and commercial enterprises increasingly dependent on imported water from the Colorado River basin. In this study we apply a suite of chemical and isotopic tracers in order to evaluate groundwater flow and assess contamination trends. Groundwater recharge occurs through mountain-block and mountain-front recharge at higher elevations of the ranges. Groundwater from the unconfined, alluvial aquifer indicates recent recharge and little evolution. The increase in salinity along the flow path is due to interaction with weathering rock-forming silicate minerals and anthropogenic sources such as urban wastewater, residual solids and agricultural runoff from fertilizers, livestock manure and/or septic tanks and latrines. A spatial analysis shows local differences and the impact of the infiltration of imported waters from the Colorado River basin. The general trend of impaired water quality has scarcely been documented in the last decades, but it is expected to continue. Since the groundwater system is highly vulnerable, it is necessary to protect groundwater sources. PMID- 29710848 TI - Biofunctionalized Lysophosphatidic Acid/Silk Fibroin Film for Cornea Endothelial Cell Regeneration. AB - Cornea endothelial cells (CEnCs) tissue engineering is a great challenge to repair diseased or damaged CEnCs and require an appropriate biomaterial to support cell proliferation and differentiation. Biomaterials for CEnCs tissue engineering require biocompatibility, tunable biodegradability, transparency, and suitable mechanical properties. Silk fibroin-based film (SF) is known to meet these factors, but construction of functionalized graft for bioengineering of cornea is still a challenge. Herein, lysophosphatidic acid (LPA) is used to maintain and increase the specific function of CEnCs. The LPA and SF composite film (LPA/SF) was fabricated in this study. Mechanical properties and in vitro studies were performed using a rabbit model to demonstrate the characters of LPA/SF. ATR-FTIR was characterized to identify chemical composition of the films. The morphological and physical properties were performed by SEM, AFM, transparency, and contact angle. Initial cell density and MTT were performed for adhesion and cell viability in the SF and LPA/SF film. Reverse transcription polymerase chain reactions (RT-PCR) and immunofluorescence were performed to examine gene and protein expression. The results showed that films were designed appropriately for CEnCs delivery. Compared to pristine SF, LPA/SF showed higher biocompatibility, cell viability, and expression of CEnCs specific genes and proteins. These indicate that LPA/SF, a new biomaterial, offers potential benefits for CEnCs tissue engineering for regeneration. PMID- 29710849 TI - A Pooled Data Analysis to Determine the Relationship between Selected Metals and Arsenic Bioavailability in Soil. AB - Chronic exposure to arsenic (As) is a global concern due to worldwide exposure and adverse effects, and the importance of incorporating bioavailability in the exposure assessment and risk assessment of As is increasing acknowledged. The bioavailability of As is impacted by a number of soil properties, such as pH, clay and metal concentrations. By retrieving 485 data from 32 publications, the aim of this study was to determine the relationship between selected metals (Fe and Al) and As bioavailability. In present study, the bioaccessibility (BAC) data measured by in vitro approaches were converted into bioavailability data based on the previously determined relationship between BAC and bioavailability. The As relative bioavailability (RBA) was summarized to be 24.36 ± 18.49%, which is in the range previously reported. A significant association between Fe concentration and the bioavailability of As was observed while this association varied for different types of RBA data. This disparity may suggest a non-reliable association between Fe and As bioavailability. The correlations between logarithmically transformed total content of Fe + Al and As bioavailability is then outlined: RBA = (−8.40 ± 1.02) × Ln(Fe + Al) + (58.25 ± 4.09), R2 = 0.25, p < 0.001, n = 212. Jackknife resampling was also applied to validate the relation between total content of (Fe + Al) and As bioavailability, which suggested that the relation is robust. This is the first pooled study to address the relations between selected metal concentrations and As bioavailability, which may provide some implications to establish soil properties-based RBA prediction for As. PMID- 29710850 TI - Computational Characterization of Small Molecules Binding to the Human XPF Active Site and Virtual Screening to Identify Potential New DNA Repair Inhibitors Targeting the ERCC1-XPF Endonuclease. AB - The DNA excision repair protein ERCC-1-DNA repair endonuclease XPF (ERCC1-XPF) is a heterodimeric endonuclease essential for the nucleotide excision repair (NER) DNA repair pathway. Although its activity is required to maintain genome integrity in healthy cells, ERCC1-XPF can counteract the effect of DNA-damaging therapies such as platinum-based chemotherapy in cancer cells. Therefore, a promising approach to enhance the effect of these therapies is to combine their use with small molecules, which can inhibit the repair mechanisms in cancer cells. Currently, there are no structures available for the catalytic site of the human ERCC1-XPF, which performs the metal-mediated cleavage of a DNA damaged strand at 5′. We adopted a homology modeling strategy to build a structural model of the human XPF nuclease domain which contained the active site and to extract dominant conformations of the domain using molecular dynamics simulations followed by clustering of the trajectory. We investigated the binding modes of known small molecule inhibitors targeting the active site to build a pharmacophore model. We then performed a virtual screening of the ZINC Is Not Commercial 15 (ZINC15) database to identify new ERCC1-XPF endonuclease inhibitors. Our work provides structural insights regarding the binding mode of small molecules targeting the ERCC1-XPF active site that can be used to rationally optimize such compounds. We also propose a set of new potential DNA repair inhibitors to be considered for combination cancer therapy strategies. PMID- 29710851 TI - Diagnostic Accuracy of Protein Glycation Sites in Long-Term Controlled Patients with Type 2 Diabetes Mellitus and Their Prognostic Potential for Early Diagnosis. AB - Current screening tests for type 2 diabetes mellitus (T2DM) identify less than 50% of undiagnosed T2DM patients and provide no information about how the disease will develop in prediabetic patients. Here, twenty-nine protein glycation sites were quantified after tryptic digestion of plasma samples at the peptide level using tandem mass spectrometry and isotope-labelled peptides as internal standard. The glycation degrees were determined in three groups, i.e., 48 patients with a duration of T2DM exceeding ten years, 48 non-diabetic individuals matched for gender, BMI, and age, and 20 prediabetic men. In long-term controlled diabetic patients, 27 glycated peptides were detected at significantly higher levels, providing moderate diagnostic accuracies (ACCs) from 61 to 79%, allowing a subgrouping of patients in three distinct clusters. Moreover, a feature set of one glycated peptides and six established clinical parameters provided an ACC of 95%. The same number of clusters was identified in prediabetic males (ACC of 95%) using a set of eight glycation sites (mostly from serum albumin). All patients present in one cluster showed progression of prediabetic state or advanced towards diabetes in the following five years. Overall, the studied glycation sites appear to be promising biomarkers for subgrouping prediabetic patients to estimate their risk for the development of T2DM. PMID- 29710852 TI - Association of Insulin Resistance with Bone Strength and Bone Turnover in Menopausal Chinese-Singaporean Women without Diabetes. AB - Insulin resistance (IR) is accompanied by increased areal or volumetric bone mineral density (aBMD or vBMD), but also higher fracture risk. Meanwhile, imbalances in bone health biomarkers affect insulin production. This study investigates the effect of IR on proximal femur and lumbar spine BMD, femoral neck bending, compressive and impact strength indices (Composite Strength Indices) and circulating levels of parathyroid hormone (PTH), C-telopeptide of Type I collagen (CTx-1) and 25(OH) Vitamin D3, in a cohort of 97 healthy, non obese, menopausal Chinese-Singaporean women. Lumbar spine aBMD was inversely associated with IR and dependent on lean body mass (LBM) and age. No such associations were found for vBMD of the third lumbar vertebra, aBMD and vBMD of the proximal femur, or circulating levels of PTH, CTx-1 and 25(OH) Vitamin D3. Composite Strength Indices were inversely associated with IR and independent of LBM, but after adjusting for fat mass and age, this association remained valid only for the impact strength index. Composite Strength Indices were significantly lower in participants with a high degree of IR. Our findings on IR and Composite Strength Indices relationships were in agreement with previous studies on different cohorts, but those on IR and BMD associations were not. PMID- 29710853 TI - Comparison of the Hepatoprotective Effects of Four Endemic Cirsium Species Extracts from Taiwan on CCl4-Induced Acute Liver Damage in C57BL/6 Mice. AB - Species of Cirsium (Asteraceae family) have been used in folk hepatoprotective medicine in Taiwan. We collected four Cirsium species—including the aerial part of Cirsium arisanense (CAH), the aerial part of Cirsium kawakamii (CKH), the flower part of Cirsium japonicum DC. var. australe (CJF), and Cirsii Herba (CH)—and then made extractions from them with 70% methanol. We compared the antioxidant contents and activities of these four Cirsium species extracts by a spectrophotometric method and high-performance liquid chromatography-photodiode array detector (HPLC-DAD). We further evaluated the hepatoprotective effects of these extracts on CCl4-induced acute liver damage in C57BL/6 mice. The present study found CAH possesses the highest antioxidant activity among the four Cirsium species, and these antioxidant activities are closely related to phenylpropanoid glycoside (PPG) contents. The extracts decreased serum ALT and AST levels elevated by injection with 0.2% CCl4. However, only CJF and CH decreased hepatic necrosis. Silibinin decreased serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels and hepatic necrosis caused by CCl4. CJF and CH restored the activities of hepatic antioxidant enzymes and decreased hepatic malondialdehyde (MDA) levels. CJF further restored the expression of hepatic antioxidant enzymes including Cu/Zn-superoxide dismutase (Cu/Zn-SOD), Mn superoxide dismutase (Mn-SOD), and glutathione S-transferase (GST) proteins. HPLC chromatogram indicated that CKH, CJF, and CH contained silibinin diastereomers (α and β). Only CJF contained diosmetin. Hence, the hepatoprotective mechanism of CJF against CCl4-induced acute liver damage might be involved in restoring the activities and protein expression of the hepatic antioxidant defense system and inhibiting hepatic inflammation, and these hepatoprotective effects are related to the contents of silibinin diastereomers and diosmetin. PMID- 29710854 TI - Frondanol, a Nutraceutical Extract from Cucumaria frondosa, Attenuates Colonic Inflammation in a DSS-Induced Colitis Model in Mice. AB - Frondanol is a nutraceutical lipid extract of the intestine of the edible Atlantic sea cucumber, Cucumaria frondosa, with potent anti-inflammatory effects. In the current study, we investigated Frondanol as a putative anti-inflammatory compound in an experimental model of colonic inflammation. C57BL/6J male black mice (C57BL/6J) were given 3% dextran sodium sulfate (DSS) in drinking water for 7 days to induce colitis. The colitis group received oral Frondanol (100 mg/kg body weight/per day by gavage) and were compared with a control group and the DSS group. Disease activity index (DAI) and colon histology were scored for macroscopic and microscopic changes. Colonic tissue length, myeloperoxidase (MPO) concentration, neutrophil and macrophage marker mRNA, pro-inflammatory cytokine proteins, and their respective mRNAs were measured using ELISA and real-time RT PCR. The tissue content of leukotriene B4 (LTB4) was also measured using ELISA. Frondanol significantly decreased the DAI and reduced the inflammation-associated changes in colon length as well as macroscopic and microscopic architecture of the colon. Changes in tissue MPO concentrations, neutrophil and macrophage mRNA expression (F4/80 and MIP-2), and pro-inflammatory cytokine content (IL-1β, IL-6 and TNF-α) both at the protein and mRNA level were significantly reduced by Frondanol. The increase in content of the pro-inflammatory mediator leukotriene B4 (LTB4) induced by DSS was also significantly inhibited by Frondanol. It was thus found that Frondanol supplementation attenuates colon inflammation through its potent anti-inflammatory activity. PMID- 29710855 TI - Myoprotective Potential of Creatine Is Greater than Whey Protein after Chemically Induced Damage in Rat Skeletal Muscle. AB - The myoprotective effects of creatine monohydrate (CR) and whey protein (WP) are equivocal, with the use of proxy measures of muscle damage making interpretation of their effectiveness limited. The purpose of the study was to determine the effects of CR and WP supplementation on muscle damage and recovery following controlled, chemically-induced muscle damage. Degeneration of the extensor digitorum longus (EDL) muscle was induced by bupivacaine in rats supplemented with either CR, WP, or standard rat chow (CON). At day 7 and 14 post-myotoxic injury, injured EDL muscles were surgically removed and tested for isometric contractile properties, followed by the contralateral, non-injured EDL muscle. At the completion of testing, muscles were snap-frozen in liquid nitrogen and stored for later analysis. Data were analyzed using analysis of variance. Creatine supplemented muscles displayed a greater proportion of non-damaged (intact) fibers (p = 0.002) and larger cross-sectional areas of regenerating and non damaged fibers (p = 0.024) compared to CON muscles at day 7 post-injury. At day 14 post-injury, CR-supplemented muscles generated higher absolute forces concomitant with greater contractile protein levels compared to CON (p = 0.001, p = 0.008) and WP-supplemented muscles (p = 0.003, p = 0.006). Creatine supplementation appears to offer an element of myoprotection which was not observed following whey protein supplementation. PMID- 29710856 TI - Nicotine Alters Estrogen Receptor-Beta-Regulated Inflammasome Activity and Exacerbates Ischemic Brain Damage in Female Rats. AB - Smoking is a preventable risk factor for stroke and smoking-derived nicotine exacerbates post-ischemic damage via inhibition of estrogen receptor beta (ER β) signaling in the brain of female rats. ER-β regulates inflammasome activation in the brain. Therefore, we hypothesized that chronic nicotine exposure activates the inflammasome in the brain, thus exacerbating ischemic brain damage in female rats. To test this hypothesis, adult female Sprague-Dawley rats (6-7 months old) were exposed to nicotine (4.5 mg/kg/day) or saline for 16 days. Subsequently, brain tissue was collected for immunoblot analysis. In addition, another set of rats underwent transient middle cerebral artery occlusion (tMCAO; 90 min) with or without nicotine exposure. One month after tMCAO, histopathological analysis revealed a significant increase in infarct volume in the nicotine-treated group (64.24 ± 7.3 mm3; mean ± SEM; n = 6) compared to the saline-treated group (37.12 ± 7.37 mm3; n = 7, p < 0.05). Immunoblot analysis indicated that nicotine increased cortical protein levels of caspase-1, apoptosis-associated speck-like protein containing a CARD (ASC) and pro-inflammatory cytokines interleukin (IL)-1β by 88% (p < 0.05), 48% (p < 0.05) and 149% (p < 0.05), respectively, when compared to the saline treated group. Next, using an in vitro model of ischemia in organotypic slice cultures, we tested the hypothesis that inhibition of nicotine-induced inflammasome activation improves post-ischemic neuronal survival. Accordingly, slices were exposed to nicotine (100 ng/mL; 14-16 days) or saline, followed by treatment with the inflammasome inhibitor isoliquiritigenin (ILG; 24 h) prior to oxygen-glucose deprivation (OGD; 45 min). Quantification of neuronal death demonstrated that inflammasome inhibition significantly decreased nicotine induced ischemic neuronal death. Overall, this study shows that chronic nicotine exposure exacerbates ischemic brain damage via activation of the inflammasome in the brain of female rats. PMID- 29710857 TI - Anticancer Activity of Bacterial Proteins and Peptides. AB - Despite much progress in the diagnosis and treatment of cancer, tumour diseases constitute one of the main reasons of deaths worldwide. The side effects of chemotherapy and drug resistance of some cancer types belong to the significant current therapeutic problems. Hence, searching for new anticancer substances and medicines are very important. Among them, bacterial proteins and peptides are a promising group of bioactive compounds and potential anticancer drugs. Some of them, including anticancer antibiotics (actinomycin D, bleomycin, doxorubicin, mitomycin C) and diphtheria toxin, are already used in the cancer treatment, while other substances are in clinical trials (e.g., p28, arginine deiminase ADI) or tested in in vitro research. This review shows the current literature data regarding the anticancer activity of proteins and peptides originated from bacteria: antibiotics, bacteriocins, enzymes, nonribosomal peptides (NRPs), toxins and others such as azurin, p28, Entap and Pep27anal2. The special attention was paid to the still poorly understood active substances obtained from the marine sediment bacteria. In total, 37 chemical compounds or groups of compounds with antitumor properties have been described in the present article. PMID- 29710858 TI - Cancer Drug Development of Carbonic Anhydrase Inhibitors beyond the Active Site. AB - Carbonic anhydrases (CAs) catalyze the reversible hydration of carbon dioxide to produce bicarbonate and a proton. Multiple CA isoforms are implicated in a range of diseases, including cancer. In solid tumors, continuously dividing cells create hypoxic conditions that eventually lead to an acidic microenvironment. Hypoxic tumor cells have different mechanisms in place to regulate and adjust the surrounding microenvironment for survival. These mechanisms include expression of CA isoform IX (CA IX) and XII (CA XII). These enzymes help maintain a physiological intracellular pH while simultaneously contributing to an acidic extracellular pH, leading to tumor cell survival. Expression of CA IX and CA XII has also been shown to promote tumor cell invasion and metastasis. This review discusses the characteristics of CA IX and CA XII, their mechanism of action, and validates their prospective use as anticancer targets. We discuss the current status of small inhibitors that target these isoforms, both classical and non classical, and their future design in order to obtain isoform-specificity for CA IX and CA XII. Biologics, such as monoclonal antibodies, monoclonal-radionuclide conjugated chimeric antibodies, and antibody-small molecule conjugates are also discussed. PMID- 29710859 TI - The Vitamin D-Folate Hypothesis as an Evolutionary Model for Skin Pigmentation: An Update and Integration of Current Ideas. AB - Vitamin D is unique in being generated in our skin following ultraviolet radiation (UVR) exposure. Ongoing research into vitamin D must therefore always consider the influence of UVR on vitamin D processes. The close relationship between vitamin D and UVR forms the basis of the “vitamin D-folate hypothesis”, a popular theory for why human skin colour has evolved as an apparent adaption to UVR environments. Vitamin D and folate have disparate sensitivities to UVR; whilst vitamin D may be synthesised following UVR exposure, folate may be degraded. The vitamin D-folate hypothesis proposes that skin pigmentation has evolved as a balancing mechanism, maintaining levels of these vitamins. There are several alternative theories that counter the vitamin D folate hypothesis. However, there is significant overlap between these theories and the now known actions of vitamin D and folate in the skin. The focus of this review is to present an update on the vitamin D-folate hypothesis by integrating these current theories and discussing new evidence that supports associations between vitamin D and folate genetics, UVR, and skin pigmentation. In light of recent human migrations and seasonality in disease, the need for ongoing research into potential UVR-responsive processes within the body is also discussed. PMID- 29710861 TI - A CMOS Self-Contained Quadrature Signal Generator for SoC Impedance Spectroscopy. AB - This paper presents a low-power fully integrated quadrature signal generator for system-on-chip (SoC) impedance spectroscopy applications. It has been designed in a 0.18 μm-1.8 V CMOS technology as a self-contained oscillator, without the need for an external reference clock. The frequency can be digitally tuned from 10 to 345 kHz with 12-bit accuracy and a relative mean error below 1.7%, thus supporting a wide range of impedance sensing applications. The proposal is experimentally validated in two impedance spectrometry examples, achieving good magnitude and phase recovery results compared to the results obtained using a commercial LCR-meter. Besides the wide frequency tuning range, the proposed programmable oscillator features a total power consumption lower than 0.77 mW and an active area of 0.129 mm2, thus constituting a highly suitable choice as stimulation module for instrument-on-a-chip devices. PMID- 29710862 TI - Antimicrobial Activity of New Materials Based on Lavender and Basil Essential Oils and Hydroxyapatite. AB - This study presents, for the first-time, the results of a study on the hydrodynamic diameter of essential oils (EOs) of basil and lavender in water, and solutions of EOs of basil (B) and lavender (L) and hydroxyapatite (HAp). The possible influence of basil and lavender EOs on the size of hydroxyapatite nanoparticles was analyzed by Scanning Electron Microscopy (SEM). We also investigated the in vitro antimicrobial activity of plant EOs and plant EOs hydroxyapatite respectively, against Gram-positive bacteria (methicillin resistant Staphylococcus aureus1144 (MRSA 1144) and S. aureus 1426) and Gram negative bacteria (Escherichia coli ATCC 25922 and Escherichia coli ESBL 4493). From the autocorrelation function, obtained by Dynamic Light Scattering (DLS) measurements it was observed that basil yielded one peak at an average hydrodynamic diameter of 354.16 nm, while lavender yielded one peak at an average hydrodynamic diameter of 259.76 nm. In the case of HAp nanoparticles coated with basil (HApB) and lavender (HApL) essential oil, the aggregation was minimal. We found that the lavender EO exhibited a very good inhibitory growth activity (MIC values ranging from <0.1% for E. coli reference strain to 0.78% for S. aureus strains). The biological studies indicated that HapL material displayed an enhanced antimicrobial activity, indicating the potential use of HAp as vehicle for low concentrations of lavender EO with antibacterial properties. Flow cytometry analysis (FCM) allowed us to determine some of the potential mechanisms of the antimicrobial activities of EOs, suggesting that lavender EO was active against E. coli by interfering with membrane potential, the membrane depolarization effect being increased by incorporation of the EOs into the microporous structure of HAp. These findings could contribute to the development of new antimicrobial agents that are urgently needed for combating the antibiotic resistance phenomena. PMID- 29710860 TI - Nutritional Status and Nutritional Treatment Are Related to Outcomes and Mortality in Older Adults with Hip Fracture. AB - Malnutrition is very prevalent in geriatric patients with hip fracture. Nevertheless, its importance is not fully recognized. The objective of this paper is to review the impact of malnutrition and of nutritional treatment upon outcomes and mortality in older people with hip fracture. We searched the PubMed database for studies evaluating nutritional aspects in people aged 70 years and over with hip fracture. The total number of studies included in the review was 44, which analyzed 26,281 subjects (73.5% women, 83.6 ± 7.2 years old). Older people with hip fracture presented an inadequate nutrient intake for their requirements, which caused deterioration in their already compromised nutritional status. The prevalence of malnutrition was approximately 18.7% using the Mini Nutritional Assessment (MNA) (large or short form) as a diagnostic tool, but the prevalence was greater (45.7%) if different criteria were used (such as Body Mass Index (BMI), weight loss, or albumin concentration). Low scores in anthropometric indices were associated with a higher prevalence of complications during hospitalization and with a worse functional recovery. Despite improvements in the treatment of geriatric patients with hip fracture, mortality was still unacceptably high (30% within 1 year and up to 40% within 3 years). Malnutrition was associated with an increase in mortality. Nutritional intervention was cost effective and was associated with an improvement in nutritional status and a greater functional recovery. To conclude, in older people, the prevention of malnutrition and an early nutritional intervention can improve recovery following a hip fracture. PMID- 29710863 TI - Pilot Testing of an Intensive Cooking Course for New Zealand Adolescents: The Create-Our-Own Kai Study. AB - The role of cooking on health and wellbeing is a recent area of scientific interest. In order to investigate this role, a cooking program that is suitable for each target population is needed e.g., a program designed for American or Australian children might not be appropriate for teenagers in New Zealand. As there was no similar previously evaluated program already available, the study’s purpose was to test an intensive cooking intervention on cooking confidence and knowledge amongst a group of adolescents from Dunedin, New Zealand, and to assess its acceptability to participants. This five-day program comprised interactive cooking sessions and informal nutrition education and ran from 9 a.m. to 3:30 p.m., Monday to Friday during school holidays. Participants completed questionnaires on cooking skills and confidence at baseline and the end of intervention and took part in a group interview, which aimed to investigate the acceptability and outcome of the program. Twenty-one participants aged between 12 and 16 years old completed the program. At the end of the program, significant increases were seen in both skills and confidence levels, and feedback from the group interview indicated that the participants enjoyed the program and that it provided additional results other than those that were cooking related. PMID- 29710864 TI - Hypoglycemic Effects in Alloxan-Induced Diabetic Rats of the Phenolic Extract from Mongolian Oak Cups Enriched in Ellagic Acid, Kaempferol and Their Derivatives. AB - Our previous reports showed that crude extract prepared with 50% ethanol (ethanol crude extract, ECE) from Mongolian oak cups possessed excellent in vitro antioxidant capacities as well as inhibitory activities against α glucosidase, α-amylase and protein glycation caused by its enrichment in phenolics, including mainly ellagic acid, kaempferol and their derivatives. Nevertheless, few in vivo studies on antidiabetic activities of these phenolics were conducted. The present study investigated hypoglycemic effects with normal and diabetic rats being administrated orally without or with ECE at 200 and 800 mg/kg for 15 days. In normal rats, no significant differences were exhibited after ECE administration in body weight, fasting blood glucose level, levels of cholesterol, triglyceride, LDL and AST in serum, organ indexes, and levels of GSH and MDA in organs. In diabetic rats, the fasting blood glucose level, indexes of heart and liver, and levels of cholesterol and triglyceride in serum and MDA in heart tissue were significantly decreased. Moreover, HDL levels in serum and SOD activities in the four organs of diabetic rats were significantly improved after ECE administration at 800 mg/kg. Thus, in addition to inhibiting α glucosidase, α-amylase and protein glycation reported previously, oak cups might contain novel dietary phytonutrients in preventing abnormal changes in blood glucose and lipid profile and attenuating oxidant stress in vivo. The results also implied that it is ellagic acid, kaempferol and their derivatives enriched in ECE that might play vital roles in managing type 1 as well as type 2 diabetes. PMID- 29710865 TI - Screening and Identification for Immunological Active Components from Andrographis Herba Using Macrophage Biospecific Extraction Coupled with UPLC/Q TOF-MS. AB - The method of cell biospecific extraction coupled with UPLC/Q-TOF-MS has been developed as a tool for the screening and identification of potential immunological active components from Andrographis Herba (AH). In our study, a macrophage cell line (RAW264.7) was used to extract cell-combining compounds from the ethanol extract of AH. The cell binding system was then analyzed and identified by UPLC/Q-TOF-MS analysis. Finally, nine compounds, which could combine with macrophages, in an ethanol extract of AH were detected by comparing basic peak intensity (BPI) profiles of macrophages before and after treatment with AH. Then they were identified as Andrographidine E (1), Andrographidine D (2), Neoandrographolide (3), Dehydroandrographolide (4), 5, 7, 2′, 3′ tetramethoxyflavone (5), β-sitosterol (7), 5-hydroxy-7, 2′, 3′ trimethoxyflavone (8) and 5-hydroxy-7, 8, 2′, 3′-tetramethoxyflavone (9), which could classified into five flavonoids, three diterpene lactones, and one sterol. Their structures were recognized by their characteristic fragment ions and fragmentations pattern of diterpene lactones and flavonoids. Additionally, the activity of compounds 3, 4, and 7 was tested in vitro. Results showed that these three compounds could decrease the release of NO (p < 0.01) in macrophages remarkably. Moreover, 3, 4, and 7 showed satisfactory dose-effect relationships and their IC50 values were 9.03, 18.18, and 13.76 μg/mL, respectively. This study is the first reported work on the screening of immunological active components from AH. The potential immunological activity of flavonoids from AH has not been reported previously. PMID- 29710866 TI - Expressed Emotion, Shame, and Non-Suicidal Self-Injury. AB - A cross-sectional study examining relationships between perceived family Expressed Emotion and shame, emotional involvement, depression, anxiety, stress and non-suicidal self-injury, in 264 community and online adults (21.6% male). We compared self-injurers with non-self-injurers, and current with past self injurers. Self-injurers experienced more family Expressed Emotion (EE) than non injurers (t(254) = −3.24, p = 0.001), linear contrasts explaining 6% of between-groups variability (F(2, 254) = 7.36, p = 0.001, η2 = 0.06). Differences in EE between current and past self-injurers were not significant. Overall shame accounted for 33% of between-groups variance (F(2, 252) = 61.99, p < 0.001, η2 = 0.33), with linear contrasts indicating self-injurers experienced higher levels compared to non-injurers (t(252) = −8.23, p < 0.001). Current self-injurers reported higher overall shame than past self injurers (t(252) = 6.78, p < 0.001). In further logistic regression, emotional involvement and overall shame were the only significant predictors of self-injury status. With every one-unit increase in emotional involvement, odds of currently engaging in self-injury decreased by a factor of 0.860. Conversely, a one-unit increase in overall shame was associated with an increase in the odds of being a current self-injurer by a factor of 1.05. The findings have important treatment implications for engaging key family members in intervention and prevention efforts. PMID- 29710869 TI - Electroencephalography Based Fusion Two-Dimensional (2D)-Convolution Neural Networks (CNN) Model for Emotion Recognition System. AB - The purpose of this study is to improve human emotional classification accuracy using a convolution neural networks (CNN) model and to suggest an overall method to classify emotion based on multimodal data. We improved classification performance by combining electroencephalogram (EEG) and galvanic skin response (GSR) signals. GSR signals are preprocessed using by the zero-crossing rate. Sufficient EEG feature extraction can be obtained through CNN. Therefore, we propose a suitable CNN model for feature extraction by tuning hyper parameters in convolution filters. The EEG signal is preprocessed prior to convolution by a wavelet transform while considering time and frequency simultaneously. We use a database for emotion analysis using the physiological signals open dataset to verify the proposed process, achieving 73.4% accuracy, showing significant performance improvement over the current best practice models. PMID- 29710868 TI - Knockout of Pannexin-1 Induces Hearing Loss. AB - Mutations of gap junction connexin genes induce a high incidence of nonsyndromic hearing loss. Pannexin genes also encode gap junctional proteins in vertebrates. Recent studies demonstrated that Pannexin-1 (Panx1) deficiency in mice and mutation in humans are also associated with hearing loss. So far, several Panx1 knockout (KO) mouse lines were established. In general, these Panx1 KO mouse lines demonstrate consistent phenotypes in most aspects, including hearing loss. However, a recent study reported that a Panx1 KO mouse line, which was created by Genentech Inc., had no hearing loss as measured by the auditory brainstem response (ABR) threshold at low-frequency range (<24 kHz). Here, we used multiple auditory function tests and re-examined hearing function in the Genentech Panx1 (Gen-Panx1) KO mouse. We found that ABR thresholds in the Gen-Panx1 KO mouse were significantly increased, in particular, in the high-frequency region. Moreover, consistent with the increase in ABR threshold, distortion product otoacoustic emission (DPOAE) and cochlear microphonics (CM), which reflect active cochlear amplification and auditory receptor current, respectively, were significantly reduced. These data demonstrated that the Gen-Panx1 KO mouse has hearing loss and further confirmed that Panx1 deficiency can cause deafness. PMID- 29710867 TI - Towards Understanding Plant Calcium Signaling through Calmodulin-Like Proteins: A Biochemical and Structural Perspective. AB - Ca2+ ions play a key role in a wide variety of environmental responses and developmental processes in plants, and several protein families with Ca2+-binding domains have evolved to meet these needs, including calmodulin (CaM) and calmodulin-like proteins (CMLs). These proteins have no catalytic activity, but rather act as sensor relays that regulate downstream targets. While CaM is well studied, CMLs remain poorly characterized at both the structural and functional levels, even if they are the largest class of Ca2+ sensors in plants. The major structural theme in CMLs consists of EF-hands, and variations in these domains are predicted to significantly contribute to the functional versatility of CMLs. Herein, we focus on recent advances in understanding the features of CMLs from biochemical and structural points of view. The analysis of the metal binding and structural properties of CMLs can provide valuable insight into how such a vast array of CML proteins can coexist, with no apparent functional redundancy, and how these proteins contribute to cellular signaling while maintaining properties that are distinct from CaM and other Ca2+ sensors. An overview of the principal techniques used to study the biochemical properties of these interesting Ca2+ sensors is also presented. PMID- 29710870 TI - Effects of Providing High-Fat versus High-Carbohydrate Meals on Daily and Postprandial Physical Activity and Glucose Patterns: a Randomised Controlled Trial. AB - We determined the effects of altering meal timing and diet composition on temporal glucose homeostasis and physical activity measures. Eight sedentary, overweight/obese men (mean ± SD, age: 36 ± 4 years; BMI: 29.8 ± 1.8 kg/m2) completed two × 12-day (12-d) measurement periods, including a 7-d habitual period, and then 5 d of each diet (high-fat diet [HFD]: 67:15:18% fat:carbohydrate:protein versus high-carbohydrate diet [HCD]: 67:15:18% carbohydrate:fat:protein) of three meals/d at ±30 min of 0800 h, 1230 h, and 1800 h, in a randomised order with an 8-d washout. Energy intake (EI), the timing of meal consumption, blood glucose regulation (continuous glucose monitor system (CGMS)), and activity patterns (accelerometer and inclinometer) were assessed across each 12-d period. Meal provision did not alter the patterns of reduced physical activity, and increased sedentary behaviour following dinner, compared with following breakfast and lunch. The HCD increased peak (+1.6 mmol/L, p < 0.001), mean (+0.5 mmol/L, p = 0.001), and total area under the curve (+670 mmol/L/min, p = 0.001), as well as 3-h postprandial meal glucose concentrations (all p < 0.001) compared with the HFD. In overweight/obese males, the provision of meals did not alter physical activity patterns, but did affect glycaemic control. Greater emphasis on meal timing and composition is required in diet and/or behaviour intervention studies to ensure relevance to real-world behaviours. PMID- 29710872 TI - Facile Synthesis and Characterization of Ag3PO4 Microparticles for Degradation of Organic Dyestuffs under White-Light Light-Emitting-Diode Irradiation. AB - This study demonstrated facile synthesis of silver phosphate (Ag3PO4) photocatalysts for the degradation of organic contaminants. Ag3PO4 microparticles from different concentrations of precursor, AgNO3, were produced and characterized by scanning electron microscopy, powder X-ray diffraction, and UV visible diffuse reflectance spectroscopy. Degradation rates of methylene blue (MB) and phenol were measured in the presence of microparticles under low-power white-light light-emitting-diode (LED) irradiation and the reaction rate followed pseudo-first-order kinetics. The prepared Ag3PO4 microparticles displayed considerably high photocatalytic activity (>99.8% degradation within 10 min). This can be attributed to the microparticles' large surface area, the low recombination rate of electron-hole pairs and the higher charge separation efficiency. The practicality of the Ag3PO4 microparticles was validated by the degradation of MB, methyl red, acid blue 1 and rhodamine B under sunlight in environmental water samples, demonstrating the benefit of the high photocatalytic activity from Ag3PO4 microparticles. PMID- 29710873 TI - Deposition of Zinc Oxide on Different Polymer Textiles and Their Antibacterial Properties. AB - A surface modification of polyamide 6 (PA), polyethylene terephthalate (PET) and polypropylene (PP) textiles was performed using zinc oxide to obtain antibacterial layer. ZnO microrods were synthesized on ZnO nanoparticles (NPs) as a nucleus centers by chemical bath deposition (CBD) process. Scanning Electron Microscopy (SEM) and X-ray diffraction (XRD) indicated that wurzite ZnO microrods were obtained on every sample. Differential Scanning Calorimetry (DSC), Fourier Transform Infrared Spectroscopy (FTIR), Atomic Force Microscopy (AFM) and Liquid Absorption Capacity (LAC) analysis indicate that the amount and structure of antibacterial layer is dependent on roughness and wettability of textile surface. The rougher and more hydrophilic is the material, the more ZnO were deposited. All studied textiles show significant bactericidal activity against Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus). A possible mechanism and difference in sensitivity between Gram-negative and Gram-positive bacteria to ZnO is discussed. Considering that antibacterial activity of ZnO is caused by Reactive Oxygen Species (ROS) generation, an influence of surface to volume ratio and crystalline parameters is also discussed. PMID- 29710871 TI - Characteristics and Management of Community-Acquired Pneumonia in the Era of Global Aging. AB - Community-acquired pneumonia (CAP) can occur at any time of life, but its incidence and risk of death are linked to increasing age. CAP in the elderly is a major health problem associated with high rates of readmission, morbidity, and mortality. Since the clinical presentation of pneumonia in the elderly may be atypical, clinicians should suspect pneumonia in older patients presenting symptoms such as falls and altered mental status, fatigue, lethargy, delirium, anorexia, in order to avoid the complications associated with delayed diagnosis and therapy. Streptococcus pneumoniae remains the most frequently reported pathogen in this population. However, particular attention should be paid to patients with risk factors for multidrug resistant pathogens, because a large proportion of elderly persons present multimorbidity. Vaccination is one of the most important preventive approaches for CAP in the elderly. In addition, lifestyle-tailored interventions for different modifiable risk factors will help to reduce the risk of pneumonia in elderly persons. Surveillance of etiological pathogens may improve vaccination policies in this population. PMID- 29710875 TI - Optimization of Deep Neural Networks Using SoCs with OpenCL. AB - In the optimization of deep neural networks (DNNs) via evolutionary algorithms (EAs) and the implementation of the training necessary for the creation of the objective function, there is often a trade-off between efficiency and flexibility. Pure software solutions implemented on general-purpose processors tend to be slow because they do not take advantage of the inherent parallelism of these devices, whereas hardware realizations based on heterogeneous platforms (combining central processing units (CPUs), graphics processing units (GPUs) and/or field-programmable gate arrays (FPGAs)) are designed based on different solutions using methodologies supported by different languages and using very different implementation criteria. This paper first presents a study that demonstrates the need for a heterogeneous (CPU-GPU-FPGA) platform to accelerate the optimization of artificial neural networks (ANNs) using genetic algorithms. Second, the paper presents implementations of the calculations related to the individuals evaluated in such an algorithm on different (CPU- and FPGA-based) platforms, but with the same source files written in OpenCL. The implementation of individuals on remote, low-cost FPGA systems on a chip (SoCs) is found to enable the achievement of good efficiency in terms of performance per watt. PMID- 29710876 TI - Automated Bone Age Assessment of Older Children using the Radius. AB - The Digital Hand Atlas in Assessment of Skeletal Development is a large-scale Computer Aided Diagnosis (CAD) project for automating the process of grading Skeletal Development of children from 0-18 years of age. It includes a complete collection of 1,400 normal hand X-rays of children between the ages of 0-18 years of age. Bone Age Assessment is used as an index of skeletal development for detection of growth pathologies that can be related to endocrine, malnutrition and other disease types. Previous work at the Image Processing and Informatics Lab (IPILab) allowed the bone age CAD algorithm to accurately assess bone age of children from 1 to 16 (male) or 14 (female) years of age using the Phalanges as well as the Carpal Bones. At the older ages (16(male) or 14(female) -19 years of age) the Phalanges as well as the Carpal Bones are fully developed and do not provide well-defined features for accurate bone age assessment. Therefore integration of the Radius Bone as a region of interest (ROI) is greatly needed and will significantly improve the ability to accurately assess the bone age of older children. Preliminary studies show that an integrated Bone Age CAD that utilizes the Phalanges, Carpal Bones and Radius forms a robust method for automatic bone age assessment throughout the entire age range (1-19 years of age). PMID- 29710874 TI - Applicability of Precision Medicine Approaches to Managing Hypertension in Rural Populations. AB - As part of the Heart Healthy Lenoir Project, we developed a practice level intervention to improve blood pressure control. The goal of this study was: (i) to determine if single nucleotide polymorphisms (SNPs) that associate with blood pressure variation, identified in large studies, are applicable to blood pressure control in subjects from a rural population; (ii) to measure the association of these SNPs with subjects' responsiveness to the hypertension intervention; and (iii) to identify other SNPs that may help understand patient-specific responses to an intervention. We used a combination of candidate SNPs and genome-wide analyses to test associations with either baseline systolic blood pressure (SBP) or change in systolic blood pressure one year after the intervention in two genetically defined ancestral groups: African Americans (AA) and Caucasian Americans (CAU). Of the 48 candidate SNPs, 13 SNPs associated with baseline SBP in our study; however, one candidate SNP, rs592582, also associated with a change in SBP after one year. Using our study data, we identified 4 and 15 additional loci that associated with a change in SBP in the AA and CAU groups, respectively. Our analysis of gene-age interactions identified genotypes associated with SBP improvement within different age groups of our populations. Moreover, our integrative analysis identified AQP4-AS1 and PADI2 as genes whose expression levels may contribute to the pleiotropy of complex traits involved in cardiovascular health and blood pressure regulation in response to an intervention targeting hypertension. In conclusion, the identification of SNPs associated with the success of a hypertension treatment intervention suggests that genetic factors in combination with age may contribute to an individual's success in lowering SBP. If these findings prove to be applicable to other populations, the use of this genetic variation in making patient-specific interventions may help providers with making decisions to improve patient outcomes. Further investigation is required to determine the role of this genetic variance with respect to the management of hypertension such that more precise treatment recommendations may be made in the future as part of personalized medicine. PMID- 29710877 TI - Enhancing Self-Awareness: A Practical Strategy to Train Culturally Responsive Social Work Students. AB - A primary goal of social justice educators is to engage students in a process of self-discovery, with the goal of helping them recognize their own biases, develop empathy, and become better prepared for culturally responsive practice. While social work educators are mandated with the important task of training future social workers in culturally responsive practice with diverse populations, practical strategies on how to do so are scant. This article introduces a teaching exercise, the Ethnic Roots Assignment, which has been shown qualitatively to aid students in developing self-awareness, a key component of culturally competent social work practice. Practical suggestions for classroom utilization, common challenges, and past student responses to participating in the exercise are provided. The dissemination of such a teaching exercise can increase the field's resources for addressing the important goal of cultural competence training. PMID- 29710878 TI - "The Chain Has to Be Broken": A Qualitative Investigation of the Experiences of Young Women Following Juvenile Court Involvement. AB - Whereas the number of girls involved in the juvenile justice system is on the rise, little is known about female juvenile offenders after they reach adulthood. This study aims to explore the meaning that young adult women ascribe to their juvenile court experiences and assess their perceptions of facilitators and barriers to progress in their adult lives. Data on services and support are presented from nine semistructured interviews. Findings include the commonality of mental health issues, substance abuse, and problematic relationships with intimate partners. Implications for service provision and policy, as well as future research directions, are outlined. PMID- 29710880 TI - Sophie's story: writing missing journeys. AB - 'Sophie's story' is a creative rendition of an interview narrative gathered in a research project on missing people. The paper explains why Sophie's story was written and details the wider intention to provide new narrative resources for police officer training, families of missing people and returned missing people. We contextualize this cultural intervention with an argument about the transformative potential of writing trauma stories. It is suggested that trauma stories produce difficult and unknown affects, but ones that may provide new ways of talking about unspeakable events. Sophie's story is thus presented as a hopeful cultural geography in process, and one that seeks to help rewrite existing social scripts about missing people. PMID- 29710879 TI - A Statistical Approach to Correcting Cross-Annotations in a Metagenomic Functional Profile Generated by Short Reads. AB - Background: Categorizing protein coding sequences into one family, if the proteins they encode perform the same biochemical function, and then tabulating the relative abundances among all the families, is a widely-adopted practice for functional profiling of a metagenomic sample. By homology searching of metagenomic sequencing reads against a protein database, the relative abundance of a family can be represented by the number of reads aligned to its members. However, it has been observed that, for short reads generated by next-generation sequencing platforms, some may be erroneously assigned to the functional families they are not associated to. This commonly occurred phenomenon is termed as cross annotation. Current methods for functional profiling of a metagenomic sample use empirical cutoff values, to select the alignments and ignore such cross annotation problem, or employ summarized equation to do a simple adjustment. Result: By introducing latent variables, we use the Probabilistic Latent Semantic Analysis to model the proportions of reads assigned to functional families in a metagenomic sample. The approach can be applied on a metagenomic sample after the list of the true functional families being obtained or estimated. It was implemented in metagenomic samples functionally characterized by the database of Clusters of Orthologous Groups of proteins, and successfully addressed the cross annotation issue on both in vitro-simulated, bioinformatics tool simulated metagenomic samples, and a real-world data. Conclusions: Correcting cross annotation will increase the accuracy of the functional profiling of a metagenome generated by short reads. It will further benefit differential abundance analysis of metagenomic samples under different conditions. PMID- 29710881 TI - Spatial and temporal analysis of surface hardness across a third-generation artificial turf pitch over a year. AB - Despite the potentially negative effects on play performance and safety, little is currently known about the spatial and temporal variability in the properties of artificial turf pitches. The primary purpose of this study was to quantify the spatial and temporal variations in surface hardness across a 5-year-old third generation artificial turf pitch over full year cycle. The secondary purpose was to investigate the key variables that contributed to these variations in surface hardness using a correlation approach. Surface hardness (2.25 kg Clegg impact hammer, average of drops 2-5), ground temperature and infill depth were measured at 91 locations across the third-generation artificial turf pitch in 13-monthly test sessions from August 2011 to August 2012 inclusive. For each month, rainfall in the 24 h prior to testing and pitch usage statistics were also obtained. Shockpad thickness was obtained from measurements taken when the carpet was replaced in 2007. Spatial and temporal variations were assessed using robust statistical measures while Spearman correlation was used to assess the contributions of the secondary variables to surface hardness variability. The results indicated that spatial variation in surface hardness exceeded temporal variation; the former demonstrated a median absolute deviation of 12 +/- 1 G across the pitch in any test session while the median absolute deviation for the latter was only 4 +/- 2 G across the 13 test sessions. Spatial variation in surface hardness was moderately correlated with shockpad thickness and weakly correlated with infill depth (both negative). These results reinforce the importance of monitoring spatial and temporal variations in play performance variables for third-generation surfaces as well as providing support for the role of maintenance in minimising the spatial variation. PMID- 29710882 TI - Pragmatic failure, mind style and characterisation in fiction about autism. AB - This article presents an analysis of different types of pragmatic failure in the interactional behaviour of the 'autistic' protagonists of three recent novels. Three main types of pragmatic failure occur across all three novels: problems with informativeness and relevance in conversational contributions; problems with face management resulting in unintentional impolite behaviours; and problems with the interpretation of figurative language. These problems are salient and frequent enough to contribute to the projection of distinctive mind styles, and more generally to the characterisation of the protagonists as individuals with communication and socialisation difficulties that are likely to both reflect and reinforce general perceptions of autism-spectrum disorders. It is also argued that pragmatic failure contributes to the potential defamiliarisation of 'normal' communication, which is presented as being fraught with obscurity, ambiguity and insincerity. PMID- 29710883 TI - Methods Beyond Methods: A Model for Africana Graduate Methods Training. AB - A holistic graduate education can impart not just tools and knowledge, but critical positioning to fulfill many of the original missions of Africana Studies programs set forth in the 1960s and 1970s. As an interdisciplinary field with many approaches to examining the African Diaspora, the methodological training of graduate students can vary across graduate programs. Although taking qualitative methods courses are often required of graduate students in Africana Studies programs, and these programs offer such courses, rarely if ever are graduate students in these programs required to take quantitative methods courses, let alone have these courses offered in-house. These courses can offer Africana Studies graduate students new tools for their own research, but more importantly, improve their knowledge of quantitative research of diasporic communities. These tools and knowledge can assist with identifying flawed arguments about African descended communities and their members. This article explores the importance of requiring and offering critical quantitative methods courses in graduate programs in Africana Studies, and discusses the methods requirements of one graduate program in the field as an example of more rigorous training that other programs could offer graduate students. PMID- 29710884 TI - Biosynthesis of (+)- and (-)-Germacrene D in Solidago canadensis: Isolation and Characterization of Two Enantioselective Germacrene D Synthases. AB - Two different enantioselective sesquiterpene synthases catalyze the biosynthesis of the enantiomers (+)- and (-)-germacrene D (1 a and 1 b, respectively) in the plant Solidago canadensis, from which they were isolated and characterized for the first time. PMID- 29710885 TI - 3,5'-Anhydrosynadenol: A Polycyclic Anhydronucleoside Analogue. AB - Cyclization instead of O-phosphorylation is the result of the reaction of the antiviral nucleoside anologue 1 with highly reactive phosphorylating agents. The formation of the novel polycyclic compound 2 shows that 1 has the Z configuration, which is important for the antiviral activity of 1 and related compounds. PMID- 29710886 TI - Structural Diversity in the Solid-State Structures of the Rubidium and Cesium Salts of 2,6-Dimesitylphenylphosphane. AB - A coordination environment reminiscent of a paddle-wheel is exhibited by aryl groups about one of the two cesium ions in CsP(H)Dmp (Dmp=2,6-dimesitylphenyl; structure depicted on the right), which has now been synthesized and is found to exhibit Cs+ {Cs2 [P(H)Dmp]3 }- contact ion pairs in the solid state. In contrast, the analogous rubidium compound displays a Rb4 P4 cube as the central structural motif. PMID- 29710887 TI - Cationic Gold(I) Complexes: Highly Efficient Catalysts for the Addition of Alcohols to Alkynes. AB - Gold complexes are almost unknown in homogeneous catalysis, and for a long time gold was even thought of as "catalytically dead". This is clearly not the case for cationic phosphanegold(I) complexes (see reaction below), which can catalyze the addition of alcohols to alkynes with turnover frequencies up to 1.5 s-1 and total turnover numbers up to 105 ! R=H, alkyl, Ph, CH2 OH. PMID- 29710888 TI - Novel Bonding of Iodine: Crystal Structure of HIS2 O8. AB - Iodine bridges two sulfate tetrahedra in the title compound and therefore participates in unusual and novel bonding. The structure of the compound (section shown on the right) can be regarded as the result of a condensation reaction between the protonated form of the hypothetical iodic(III) acid, sulfuric acid, and hydrogensulfate. PMID- 29710889 TI - The Thioesterase of the Erythromycin-Producing Polyketide Synthase: Influence of Acyl Chain Structure on the Mode of Release of Substrate Analogues from the Acyl Enzyme Intermediates. AB - The production of genetically engineered polyketides depends critically on thioesterase activity for product release. In vitro studies with the thioesterase from the erythromycin polyketide synthase (PKS) have demonstrated that the ability of this enzyme to act as a universal decoupler is limited, but stereochemical variation is readily tolerated. Synthetic analogues with all four stereochemical configurations of the natural substrate's 2-methyl-3-hydroxy substitution pattern (1-4; X=p-nitrophenoxy) were substrates for the enzyme. PMID- 29710890 TI - Chemical Safety-An International Challenge. AB - The protection of health and environment need to be taken into account when chemicals leave the laboratory after development to be produced in large quantities and marketed as either end or intermediate products. Over the past 20 years this necessity has led to complex structures of national and international cooperation, which are characterized by both scientific findings and political targets. PMID- 29710891 TI - Catalysis of Organic Reactions by RNA. AB - From Diels-Alder reactions to peptide synthesis-the spectrum of reactions catalyzed by RNA keeps on growing. These developments became possible by new methods for the selection of catalysts from combinatorial libraries by using linker-coupled reactants. The formula on the right shows the product of a Diels Alder reaction. Biot-OH=biotin. PMID- 29710892 TI - Living and Controlled Anionic Polymerization of Methacrylates and Acrylates in the Presence of Tetraalkylammonium Halide-Alkylaluminum Complexes in Toluene. AB - The size of both the cation and the anion of added NR4 X influences the rate of living polymerization of acrylates and methacrylates with alkylaluminum compounds. This controlled reaction, which occurs near to room temperature, provides unimodal polymers with narrow molecular-weight distributions. The complex shown to the right is suggested as a possible active species. R=Me, Et, nBu; R'=Me, Et; X=Cl, Br, I. PMID- 29710893 TI - Biomimetic Oxidation of Aldehyde with NAD+ Models: Glycolysis-Type Hydrogen Transfer in an NAD+ /NADH Model System. AB - Just like in biological systems, the GAPDH-catalyzed oxidation of aldehyde to carboxylate proceeds in conjunction with 1,4-selective reduction of NAD+ to NADH model compounds [Eq. (1)]. The combination of GAPDH- and LDH-type transfer reactions is also described here as a system mimic for the NAD+ /NADH redox cycle in anaerobic glycolysis. GAPDH=D-glyceraldehyde-3-phosphate dehydrogenase, LDH=L lactate dehydrogenase. PMID- 29710894 TI - Cooperative Hairpin Dimers for Recognition of DNA by Pyrrole-Imidazole Polyamides. AB - A doubling of the length of binding site for the same size of ligand is achieved by the title compound by formation of a cooperative hairpin dimer on binding to DNA (depicted schematically below). The binding affinity and selectivity are unaffected by this new binding pattern. Circles represent heterocyclic rings, and diamonds and curved lines represent beta-alanine and (R)-2,4-diaminobutyric acid residues, respectively. PMID- 29710895 TI - Synthesis and Structure of (CH3 Si)6 (NH)9 : A Si-N Cage Made from Methyltrichlorosilane and Ammonia. AB - No bulky substituents are bonded to the silicon centers of the cagelike title compound 1, which is readily formed by reaction of methyltrichlorosilane with ammonia and sodium. According to X-ray structure analysis, 1 consists of two Si3 N3 rings in the chair conformation that are bridged through the silicon centers by NH groups. The result is a cage in which three bars are missing, as can be seen on the right. PMID- 29710896 TI - Polyhomologation: Synthesis of Novel Polymethylene Architectures by a Living Polymerization of Dimethylsulfoxonium Methylide. AB - Not conventional polymerization of ethylene, but rather the title reaction has allowed access to the omega-functionalized tertiary polymethylene alcohols 1. The ylide CH2 SOMe2 is the methylene source in this living polymerization, and the chain length can be set by the initial ratio of ylide to organoborane. PMID- 29710897 TI - Self-Assembly of Lamellar and Expanded Lamellar Coordination Networks. AB - Structural similarity with clay-type minerals is apparent in the self-assembled layered coordination network [{Ag(1)(MeCN)2 }infinity ][BF4 ]infinity , which is stabilized by a lamellar chelate effect (section of structure shown on the right). The interlayer region is expandable through the use of larger ligands such as PhCN. The void space is occupied by one PhCN molecule per repeat unit. PMID- 29710898 TI - Synthesis and Biological Activity of Sarcodictyins. AB - A new class of potential antitumor agents with a taxol-like mechanism of action is presented by the sarcodictyins 1. Modification of the reported syntheses of sarcodictyins permitted the preparation of additional derivatives, the biological properties of which are highly dependent upon the structure. PMID- 29710899 TI - Combinatorial Solid-Phase Synthesis of Structurally Complex Thiazolylhydantoines. AB - A nine-step (!) solid-phase synthesis and subsequent cleavage with cyclization from the polymeric support were the keys to preparing high-quality molecular libraries of thiazolylhydantoines 1 from modified amino acid building blocks. Each step in the synthesis is different. Because the final cyclization cleaves only molecules that have been successfully constructed, the products obtained are pure. R1 , R2 =alkyl; R3 =aryl, arylO; R4 =allyl. PMID- 29710900 TI - A Dodecagonal Quasicrystalline Chalcogenide. AB - Diffractograms with twelvefold rotational symmetry (depicted on the right) were obtained from the first quasicrystalline chalcogenide Ta1.6 Te. This compound was prepared on a preparative scale by the reduction of TaTe2 with tantalum below 1870 K. This tantalum-rich telluride, which is the first stable dodecagonal phase, has enabled an in-depth investigation of this unusual state of ordering. PMID- 29710901 TI - Reaction of Group 15 Trichlorides ECl3 with the Anion [Mo2 Cp2 (CO)4 (MU-PH2 )]- ; Synthesis and Characterization of the First Complexes Featuring a Hetero MU,eta2 -PE ligand (E=As, Sb). AB - An Me2 PE tetrahedrane framework is seen in complexes 2 a-c (E=P, As, Sb), which are prepared from the appropriate trichlorides and 1 in THF. The structures of the new antimony- and arsenic-containing compounds 2 b and 2 c have been determined-this is the first structural characterization of complexes with MU,eta2 -PE heteroligands from elements of Group 15. PMID- 29710902 TI - The Twin-Excited State as a Probe for the Transition State in Concerted Unimolecular Reactions: The Semibullvalene Rearrangement. AB - A twin of the transition state, which can be investigated spectroscopically and can thus supply information about the structure of the transition state, has now been characterized for the Cope rearrangement of semibullvalene (shown below). It involves an excited state with B2 symmetry and results from a linear combination of the ground-state wave functions of (mirror-image) reactant and product. PMID- 29710903 TI - KH(O2 )CO2 ?H2 O2 -An Oxygen-Rich Salt of Monoperoxocarbonic Acid. AB - The surprising accessibility of the title compound has enabled the first X-ray structural analysis of the hydrogen peroxocarbonate anion (shown on the right). PMID- 29710904 TI - Alkylidyne-Metal Templated Triboronate Condensation. AB - Under exceptionally mild conditions the alkylidyne metallatetraborane 1 undergoes an intriguing conversion into the dodecaboronate dianion in a rare example of metal-templated boronate condensation. PMID- 29710905 TI - Perchloropolysilane: X-Ray Structure, Solid-State 29 Si NMR Spectroscopy, and Reactions of [SiCl2 ]n. AB - The silicon backbone is all-trans in the crystal structure of perchloropolysilane [SiCl2 ]n (see structure on the right). The Cl atoms can be substituted by nucleophiles to form polymers such as peralkoxy- and peraminopolysilanes. PMID- 29710906 TI - A Surprising Adduct of a closo Cluster. AB - The geometry of the Si2 B10 framework remains nearly unchanged when the Si-Si edge is bridged by an electron-donating amido group. This finding is clearly evident from the single-crystal X-ray structure analysis and ab initio calculations of the uprecedented adduct that is formed by the addition of Et2 N- to o-silaborane (structure depicted bottom right). PMID- 29710908 TI - Liquid Crystalline Coronene Derivatives with Extraordinary Fluorescence Properties. AB - Tempering of polystyrene films containing the novel liquid crystalline coronenebis(dicarboximide)s 2, which are formed by an easy route from perylene 3,4;9,10-tetracarboxylic dianhydride (1), leads to a shift of the emission within a few seconds. This could be used for dot-by-dot coloring and thus optical displays. The photoluminescence properties of 2 in the solid matrix are dependent on the nature of the aggregates formed. PMID- 29710907 TI - A Monomeric d9 -Rhodium(0) Complex. AB - A pocket suitable for bonding transition metals is formed by the 5-phosphanyl group and the olefinic unit of the central seven-membered ring, which has a rigid boat conformation, of the ligand troppPh (1). This new ligand system allows the synthesis and isolation of stable d9 and d10 rhodium complexes 2 and 3, respectively. PMID- 29710909 TI - New Polyol Syntheses. AB - 1,3,5,...?-Polyol structures are characteristic components of polyene macrolide antibiotics such as filipin III (1). Iterative stereoselective alkylation of lithiated cyanohydrin acetonides and subsequent reductive decyanation is one possibility for the stepwise synthesis of this class of natural products characterized by a polyol framework of 1,3-diol units. PMID- 29710910 TI - Chemical Applications of Zero Kinetic Energy (ZEKE) Photoelectron Spectroscopy. PMID- 29710911 TI - An Artificial Regulatory System with Coupled Molecular Switches. AB - The availability of sodium ions can be regulated indirectly (through electron transfer reactions) and reversibly through the addition and removal of zinc ions. In this cyclic process (depicted on the right) a redox-responsive ferrocene substituted with two dipicolylamino ligands (Fcdpa) coordinates two Zn2+ ions, while a redox-switchable ferrocene cryptand (Fccrypt) only forms stable complexes with Na+ when the ligand is in its reduced form. L is a strong ligand such as 1,4,8,11-tetraazacyclotetradecane. PMID- 29710912 TI - Alkyl Polyglycosides-Properties and Applications of a new Class of Surfactants. AB - A new generation of nonionic surfactants that are widely applicable and simultaneously ecologically compatible has been developed in the alkyl polyglycosides. Their production from the renewable resources glucose and fatty alcohol and their ultimate biodegradation into carbon dioxide, water, and assimilated bacterial biomass is an example for a closed cycle. As a result of their physico-chemical properties and ecotoxicological evaluation, they have become very important as high-performance components of detergents and cosmetic preparations. PMID- 29710914 TI - Homoleptic Isocyanide Metalates. AB - Novelties and surprises in the chemistry of metal isocyanides: The synthesis and structure determination of homoleptic isocyanide metalates [M(CNXyl)m ]- (M=Co, m=4; M=Mn, m=5; Xyl=2,6-Me2 C6 H3 ) indicate that we need to revise our understanding of transition metal-isocyanide interactions. Further investigations will be required to determine whether these salts with isocyanide metalate ions display a chemistry as rich as that of the analogous carbonyl metalates. PMID- 29710913 TI - Two Novel Thermal Biradical Cyclizations of Enyne-Ketenimines: Theory, Experiment, and Synthetic Potential. AB - Both benzocarbazoles and quinolines can be synthesized from enyne ketenimines 1 generated in situ via biradical intermediates (see reaction below). Which of the heterocyclic ring systems is formed depends on the choice of the substituent R1 at the alkyne terminus. PMID- 29710915 TI - Ansa Macrolides as Molecular Workbenches: Stereocontrolled syn Additions to E olefins. AB - Fixed on an aromatic platform in a conformationally defined way, acyclic (E) alkenes can be considered gripped on a molecular workbench. The olefinic ansa macrolides formed in this way are shielded on one face. On epoxidation and dihydroxylation [Eq. (1)] the attack on the double bond takes place diastereoselectively from outside the ring, and the ansa chain can subsequently be cleaved from the workbench by mild hydrogenolysis. Bn=benzyl, NMO=N methylmorpholin-N-oxide. PMID- 29710916 TI - X-Ray Structural Analysis of a Novel Lithium Hydride/Lithium tert-Butoxide Superaggregate: Li33 H17 (OtBu)16. AB - Extraordinary solubility in hydrocarbons is exhibited by the novel superaggregate Li33 H17 (OtBu)16 , which crystallizes from photolyzed solutions of lithium tert butoxide and tert-butyllithium (ROLi:RLi>=7:3). The structure of the compound (the framework of Li, H, and O atoms without tBu groups is shown on the right) resembles a disrupted lithium hydride lattice with an inner hydride-rich core and an outer shell of lipophilic tert-butoxide groups. PMID- 29710917 TI - The First Specific TiIV -Protein Complex: Potential Relevance to Anticancer Activity of Titanocenes. AB - The transfer of titanium ions from titanium citrate and titanocene dichloride to the blood plasma protein transferrin was proven unequivocally by UV/Vis and NMR spectroscopy. The results may provide insight intoan important step in the mechanism of action of titanium anticancer drugs. PMID- 29710918 TI - Solid-Phase Synthesis of Oligosaccharides: Construction of a Dodecasaccharide. AB - Complicated oligosaccharides such as dodecasaccharide 1 can be constructed by a new solid-phase strategy. The attachment to the polymeric support (gray sphere) is through a photolabile linker (structure I), and thioglycosides serve as carbohydrate donors. Bn=benzyl, Bz=benzoyl. PMID- 29710919 TI - Parametrization of Substituents: Effects of Fluorine and Other Heteroatoms on OH, NH, and CH Acidities. AB - Fluorine, the heterosubstituent par excellence, which can have a stronger impact on the reactivity in its vicinity than any other element, may serve as a crucial test of any model of the origin and transmission of electronic effects. To what extent fluoro substituents in organic compounds (A-H) increase their kinetic proton mobility (H/D and H/metal (M) exchange) and thermodynamic acidity in aqueous media and in the gas phase (see below) depends on many factors such as induction, resonance, polarization, hyperconjugation, and dipolar interactions. PMID- 29710920 TI - Stabilization of p-Phenylenebis(N-tert-butylaminoxyl) Relative to p Benzoquinonediimine N,N'-Dioxide. AB - Steric interactions between methoxy and tert-butyl groups are the reason that 2 only exists as p-phenylenebis(N-tert-butylaminoxyl) B. The p-phenylenebis(N-tert butylaminoxyl) 1 has the p-quinonediimine N,N'-dioxide structure Q in solution as well as in the crystalline state. PMID- 29710921 TI - The Yellow Color of Silver-Containing Zeolite A. AB - Not the Ag clusters, but rather the O atoms are responsible for the yellow color of silver-containing zeolite A. The reason for this has remained unclear since 1962. It is now shown that a charge-transfer transition from the lattice oxygen atoms to the empty 5s orbital of the silver ions (shown schematically on the right) is responsible for the yellow coloring. PMID- 29710923 TI - X-Ray Structure of Bacteriorhodopsin at 2.5 A Resolution. AB - Microfocussed X-rays produced by an electron synchrotron were essential for the first structure elucidation of protein crystals having extremely small dimensions (5*20-40 MUm). A further prerequisite for the successful crystal structure analysis of bacteriorhodopsin was a novel crystallization method using a lipid matrix. These methodological breakthroughs pave the way for further advances in structure determinations of membrane proteins. PMID- 29710922 TI - 1,4-Addition of a Terminal Phosphinidene Complex to [5]Metacyclophane. AB - Three novel aspects emerge for the reaction of [5]metacyclophane (1) with the (intermediate) phenylphosphinidene complex 2 to give the 7-phosphanorbornadiene 3. It is the first 1,4-addition of a phosphinidene complex to an unsaturated system, the first addition of a phosphinidene complex to a benzene ring, and the first [4+1] cycloaddition to an aromatic compound. PMID- 29710924 TI - Homoleptic Lanthanide Amides as Homogeneous Catalysts for the Tishchenko Reaction. AB - Known for about 25 years, the bis(trimethylsilyl)amides of Group 3 metals and lanthanides, M[N(SiMe3 )2 ]3 , are well suited as highly efficient catalysts for the dimerization of aldehydes [Tishchenko reaction, Eq. (1)]. PMID- 29710925 TI - Electrostatic Assembly of Dendrimer Electrolytes: Negatively and Positively Charged Dendrimer Porphyrins. AB - Carboxylate and ammonium functionalities-32 of each-facilitate electrostatic interaction between oppositely charged dendrimer electrolytes and porphyrin cores, which leads in protic media to a supramolecular, fluorescence-active aggregate of two chromophores that communicate and have a predictable topology (see drawing on the right; A=acceptor, D=donor). In contrast to the complexation of linear polyelectrolytes, the contact area for the two dendrimer molecules is very limited, just as one would expect for an assembly of spherical molecules. PMID- 29710926 TI - NaSn5 : An Intermetallic Compound with Covalent alpha-Tin and Metallic beta-Tin Structure Motifs. AB - A novel and unusual three-dimensional network of tin atoms is present in NaSn5 , in which metallic layers analogous to those in beta-Sn alternate with tetravalent units analogous to alpha-Sn. The compound shows the emergence of pentagonal dodecahedral units from the metallic beta-Sn modification (see structure on the right; all unlabeled spheres are Sn atoms). Quantum-mechanical investigations indicate the simultaneous presence of structural regions with localized and delocalized bonds. PMID- 29710927 TI - Rhodium and Iridium Pyrazolato Blues. AB - The staggered arrangement of the two dimers in 1 facilitates the formation of an almost linear chain of four metal centers that is held together by a nonsupported metal-metal bond. The intense color of the compounds and the fractional oxidation states of the metal atoms can be explained by electron delocalization along the chain. M=Rh, Ir. PMID- 29710928 TI - The Hexanitridodimanganate(IV) Li6 Ca2 [Mn2 N6 ]: Preparation, Crystal Structure, and Chemical Bonding. AB - Unbridged Mn2 units are present in the hexanitridodimanganate(IV) ions of the title compound. This is the first example of a Mn-Mn single bond within a complex anion in which the manganese centers have the high oxidation state +4. According to ELF calculations, the Mn-Mn bond can be regarded as a two-electron, two-center bond. PMID- 29710930 TI - X-Ray Absorption Spectroscopy of Dimethylcuprates: Evidence for Solvent-Dependent Aggregation. AB - Dimeric in Et2 O and DMS, monomeric in THF-the degree of aggregation of dimethylcuprates depends on the solvent [Eq. (a)]. The Cu-Cu distance of 2.82 A was determined by EXAFS for a dimethylcuprate reagent derived from cuprous halide. In contrast, with cyanide as the counterion, no dimers are formed. PMID- 29710929 TI - A Lysoganglioside/Poly-L-glutamic Acid Conjugate as a Picomolar Inhibitor of Influenza Hemagglutinin. AB - Based on the principle of a multivalent interaction, the amphiphilic polymer 1, present in solution as an aggregate (see below right), is able to inhibit infection with the influenza virus. After recognition of a specific sialyllactose epitope through hemaglutinin (HA) on the virus surface, the sphingosine residues and the fluorescent tag form a stable complex with HA through hydrophobic interactions. Polymer 1 shows in vitro inhibitory activity 106 -fold greater than that of sialyllactose. PGA=polyglutamic acid. PMID- 29710931 TI - Small Potassium Clusters. AB - The molecules K2 , K3 , and K4 (structure shown on the right) have been isolated in krypton matrices at 15 K and characterized by Raman spectroscopy. Comparison of the experimental data with density functional calculations supports the prediction that potassium clusters are not only bonded by the valence electrons, but that there is also a contribution from the core electrons. PMID- 29710932 TI - Assembly of DNA/Fullerene Hybrid Materials. AB - Ordering of cationic fullerene derivatives on a DNA template by phosphate/fullerene complexation provides a rapid route to organic materials several hundred nanometers in length (shown on the right). Hydrophobic interactions between the fullerene units lead to DNA supercoiling that can be relieved by adding a nonionic surfactant. The products are easily imaged by transmission electron microscopy without the need for heavy-metal staining. PMID- 29710933 TI - Platinum(II) Complexes with Constructive and Destructive Interaction of Diphosphane and Binaphthol Ligands. AB - Eight molecules with different conformations are present in the unit cell of the PtII complex 1, which contains a mismatched arrangement of the chiral ligands Chiraphos and Binol (i.e., (S,S)-Chiraphos prefers the delta conformation, whereas (R)-Binol tends to induce the lambda conformation in the diphosphane). The observed flexibility of these bidentate ligands should not be disregarded in stereochemical models for explaining the selectivity in asymmetric catalysis. PMID- 29710934 TI - Adaptation of the Barton Reaction to Carborane Chemistry: The Synthesis and Reactivity of 2-Hydroxyimino-1-hydroxymethylnona-B-methyl-1,12-dicarba-closo dodecaborane(12). AB - Just one of the ten methyl groups of deca-B-methyl-1,12-dicarba-closo dodecarborane(12) (1) is selectively functionalized in a reaction sequence in which photolysis of a nitrite of 1 is the key step. Reduction of the resulting aldoxime with LiAlH4 generates, by way of the first Beckmann rearrangement of a boron-substituted oxime, the methylamino alcohol 2. PMID- 29710935 TI - A Synthetic Cation-Transporting Calix[4]arene Derivative Active in Phospholipid Bilayers. AB - One order of magnitude: The transport of Na+ and K+ ions through a phospholipid bilayer occurs with much higher conductance levels with 1 and 2 than with typical Na+ -transporting proteins or gramicidin. However, the cations do not appear to pass through the calix[4]arene ring, which has a rigid 1,3-alternate conformation. diazacrown=10-benyzl-1,10-diaza[18]crown-6 group. PMID- 29710936 TI - Interpenetrating Nets: Ordered, Periodic Entanglement. AB - Independent one-, two-, and even three-dimensional nets interpenetrate each other in many solid-state structures of polymeric, hydrogen-bonded nets and coordination polymers. For example, the interpenetration of the adamantane units of two diamondlike nets is shown on the right. A detailed and systematic examination of many interpenetrating nets of this kind is made, and implications for crystal engineering are discussed. PMID- 29710937 TI - Homoallyl-Substituted Vinylcyclopropanes from alpha,beta-Unsaturated Ketones and Allylindium Derivatives. AB - Simply reversing the order of addition of aqueous acid and Et2 O to the Barbier intermediate 1 of the known indium-mediated allylation leads to unprecedented deoxygenative rearrangements [Eq. (a)]. PMID- 29710938 TI - An Efficient Venus Flytrap for the Reversible Binding of Nitric Oxide. AB - Remarkably efficient reversible binding of nitric oxide (NO) by the stilbenoid derivative 1 is observed (K>3*106 M-1 ). This noncovalent interaction is readily controlled by simple oxidation and reduction. PMID- 29710939 TI - A Photoluminescent Copper(I) Complex with an Exceptionally High CuII /CuI Redox Potential: [Cu(bfp)2 ]+ (bfp=2,9-bis(trifluoromethyl)-1,10-phenanthroline). AB - Unprecedented stabilization of the copper(I) oxidation state is demonstrated for the complex cation [Cu(bfp)2 ]+ (1) due to the steric and electronic effects of the CF3 groups (E1/2 (CuII /CuI )=+1.55 V vs. SCE). The redox existence range of the copper(I) species is remarkably high at 2.77 V. It is emissive in solution at room temperature and shows great potential as a photocatalyst; in the excited state it is a very potent photooxidant. PMID- 29710940 TI - A Novel Copper Chelate Catalyzed Ring Closure Reaction of 1,2-Bisketenes with Alcohols To Give 5-Alkoxy-2,3-dihydrofuran-2-ones. AB - Copper complexes with distorted tetrahedral structure in solution catalyze regioselectively the cyclization of 1,2-bisketenes with alcohols to give 5-alkoxy 2,3-dihydrofuran-2-ones in very high yields (shown on the right). It seems remarkable that these new compounds could remain undiscovered despite having structural similarities with a great number of well-investigated and biologically active butenolides. PMID- 29710942 TI - Solution of the Crystal and Molecular Structure of Complex Low-Symmetry Organic Compounds with Powder Diffraction Techniques: Fluorescein Diacetate. AB - Without any prior knowledge of the molecular structure, all 31 carbon and oxygen atoms of fluorescein diacetate were accurately located based on a high-resolution powder diffraction experiment. Direct methods and Fourier recycling were used. This represents a considerable advance with respect to the size of an organic molecule whose structure can be solved by ab initio methods from measurements on a powder. PMID- 29710941 TI - The First Structural Characterization of an Azoaromatic Radical Anion Stabilized by Dicopper(I) Coordination. AB - Double chelate coordination of [Cu(Ph3 P)2 ]+ stabilizes the radical anion of 2,2'-azobis(5-chloropyrimidine), which exhibits a N-N bond length of 1.345(7) A in the complex (see picture). This is consistent with a one-electron reduced azo functionality. PMID- 29710943 TI - Diastereoface-Selective Epoxidations: Dependency on the Reagent Electrophilicity. AB - Substrate-imposed steric constraints can be overriden by the pronounced preference of strong peracids for epoxidation on the pi face, which has the highest electron density. For example, the syn:anti ratio for reaction (1) with CF3 CO3 H in CH2 Cl2 is 82:18, that with CH3 CO3 H in toluene is 3:97. PMID- 29710944 TI - Combinatorial Chemistry in Heterogeneous Catalysis: A New Scientific Approach or "the King's New Clothes"? AB - The spectacular success in materials science of the application of combinatorial chemistry has raised the hope that it may eventually lead to a new scientific approach to catalyst development. This method is, within the constraints of heterogeneous catalysis, merely a potentially efficient tool to be used in rational catalyst development and should not be considered an independent novel strategy towards rational catalyst design. PMID- 29710945 TI - Synthesis of Hyperbranched Aminopolysaccharides. AB - Sugar dihydroozaxole monomers with two free hydroxyl groups undergo acid catalyzed polymerization to hyperbranched aminopolysaccharides [Eq. (a)]. Their molecular weights were determined by the light-scattering method to be between 2.3*105 and 7.6*105 . The degree of branching determined by 1 H NMR spectroscopy after reaction with [iPr2 Si(Cl)]2 O is close to the ideal value. Ts=MeC6 H4 SO2 , CSA=10-camphorsulfonic acid. PMID- 29710947 TI - Monocyclic (CH)9+ -A Heilbronner Mobius Aromatic System Revealed. PMID- 29710946 TI - Porphyrin Tessellation by Design: Metal-Mediated Self-Assembly of Large Arrays and Tapes. AB - Twenty-one components self-assemble to form the large (ca. 25 nm2 ), planar porphyrin arrays of type 1: four dipyridylporphyrins, four tripyridylporphyrins, one tetrapyridylporphyrin, and twelve PdCl2 units. PMID- 29710948 TI - Spatially Resolved Immobilization of Peptides by Electrochemical Polymerization after Photolytic Cleavage of a Protecting Group. AB - Microstructuring of surfaces: Electrochemical polymerization after removal of a photolabile protecting group (nitrobenzyl group) represents a new method for spatially resolved immobilization of ligands or receptors. Thus, the electropolymerization of 3-hydroxyphenylacetyl peptides such as 1 on electrodes can be controlled by light. PMID- 29710949 TI - A New Allotrope of Elemental Sulfur: Convenient Preparation of cyclo-S14 from S8. AB - Three simple steps lead from S8 to cyclo-S14 , which is stable at 20 degrees C. The final synthetic step [Eq. (a)] provides the title compound, which was characterized spectroscopically and by X-ray structure analysis. Formally, the structure of S14 is derived by insertion of an S2 unit into S12 . tmeda=N,N,N',N' tetramethylethylenediamine. PMID- 29710950 TI - ATP Synthesis by Rotary Catalysis (Nobel lecture). AB - The cyclic modulation of nucleotide-binding properties of the three catalytic beta subunits by a series of conformational changes was an attractive explanation for the postulated binding change mechanism of ATP synthase. In the crystal structure of the catalytic F1 domain of this enzyme there is indeed a complex made up of three alpha subunits and three beta subunits arranged in alternation around a central alpha-helical segment of the gamma subunit. This complex is asymmetric owing to the different conformations of the beta subunits. The change in conformation is brought about by rotation of the rigid yet curved segment, which has meanwhile been proven experimentally. PMID- 29710951 TI - The Cluster Anion Si94. AB - Solely on the basis of Raman spectra and quantum chemical calculations, the previously unknown cluster anion Si94- (structure shown) was characterized and its structure determined. The anion is formed as a component of solid phases by the thermal decomposition of alkali metal monosilicides. PMID- 29710952 TI - Energy, Life, and ATP (Nobel Lecture). AB - The puzzling results of 18 O-exchange experiments churned in Paul Boyer's mind, and he realized that the proton-motive force generated upon oxidative phosphorylation is not used primarily for the synthesis of an ATP molecule, but instead its release. The concept of the binding change mechanism was born. For the formation of ATP from ADP and inorganic phosphate-one of the most important reactions in nature-catalysis by ATP synthase requires sequential conformational changes and a rotary mechanism that drives these changes; this enzyme is truly a remarkable molecular machine. PMID- 29710953 TI - Synthesis and Crystal Structure of a P-Hydridophosphoraniminato-Zirconium Complex and Reaction to the First Tris(hydrido)cyclotriphosphazene. AB - The first oligomeric phosphazene in which each phosphorus center features a PH functionality (3) was obtained from the amidophosphane 1 or its zirconium complex 2. PMID- 29710954 TI - Self-Organization of a Heteroditopic Molecule to Linear Polymolecular Arrays in Solution. AB - Like the proverbial monkey chain one heteroditopic self-complementary molecule, comprising a crown ether unit and a paraquat unit, catches a second such molecule in solution and thus by self-organization forms novel linear oligo- and polymolecular arrays (shown schematically; the crown ether unit is denoted by the ellipse, and the paraquat unit by the rectangle). PMID- 29710956 TI - Highly Efficient, Catalytic Meerwein-Ponndorf-Verley Reduction with a Novel Bidentate Aluminum Catalyst. AB - Double electrophilic activation of carbonyl groups allows a modern variant of the Meerwein-Ponndorf-Verley reduction to be carried out under mild conditions with bidentate catalyst 1 (see reaction). Various carbonyl substrates can be reduced efficiently at room temperature in CH2 Cl2 with 2-propanol or sec-phenethyl alcohol in the presence of a catalytic amount of 1. This system is also applicable to the Oppenauer oxidation of secondary alcohols to the corresponding ketones. PMID- 29710955 TI - Asymmetric Synthesis of Bryostatin 2. AB - The potent bryostatin antitumor agents are currently in phase II clinical trials for the treatment of a variety of forms of cancer. Aldol reactions and directed reductions are among the essential steps for the formation of fragments A-C in the total synthesis of the title compound. Coupling of these fragments by sulfone based olefination and alkylation reactions was followed by macrocyclization and introduction of the enoate moieties on rings B and C. PMID- 29710957 TI - An Efficient Nickel-Catalyzed Cross-Coupling Between sp3 Carbon Centers. AB - Since the pioneering work of Wurtz, cross-couplings between sp3 carbon centers have had the reputation of being difficult. In the presence of a catalytic amount of m-trifluoromethylstyrene, an efficient cross-coupling reaction takes place between polyfunctional primary alkyl iodides and diorganozinc compounds [Eq. (a)] to give a general catalytic cross-coupling between sp3 carbon centers. Piv=pivaloyl; Pent = pentyl; acac = acetalacetonate; NMP = N-methylpyrrolidone. PMID- 29710958 TI - The Crystal Structure of a Potassium Channel- A New Era in the Chemistry of Biological Signaling. AB - The similarity to crown ethers is apparent when the arrangement of the oxygen atoms of the carbonyl groups of the protein backbone in the structure of the potassium channel (see schematic drawing of a section of the structure) found in the bacterium Streptomyces lividans is considered. This particular part of the channel pore acts as the selectivity filter, with the permeability of the channel for K+ being as much as 10 000 times greater than for the Na+ ion. In fact, in this area of the structure two K+ ions are located, a feature that enables high flux through the channel. PMID- 29710959 TI - The Identification of the Sodium-Potassium Pump (Nobel Lecture). AB - Deemed too provocative, the word "pump" was omitted in the title of the 1957 publication "The Influence of Some Cations on an Adenosine Triphosphatase from Peripheral Nerves", in which J. C. Skou showed that an ATPase in the membrane of crab nerves had such characteristics from the point of view of substrate ATP and effect of Na and K that it was reasonable to suggest that it was involved in the active transport of Na across the cell membrane. PMID- 29710960 TI - Two Novel Thermal Biradical Cyclizations in Theory and Experiment: New Synthetic Routes to 6H-Indolo[2,3-b]quinolines and 2-Aminoquinolines from Enyne Carbodiimides. AB - The regioselectivity of the biradical cyclization of enyne-carbodiimides 1 can easily be controlled by variation of R1 at the alkyne terminus. Attachment of a hydrogen atom (R1 =H) leads to C2 -C7 cyclization and formation of biradical 2, whereas C2 -C6 cyclization to provide biradical 3 is observed with R1 =Me3 Si or Ph. PMID- 29710961 TI - Toposelective and Chiroselective Self-Assembly of [2*2] Grid-Type Inorganic Arrays Containing Different Octahedral Metallic Centers. AB - The introduction of different metal ions in specific positions is achieved in the synthesis of [2*2] grid-type heterometallic complexes (see schematic representation; the black bars symbolize the ditopic ligands, and the circles the different metals ions). This novel method for the construction of inorganic architectures opens the way to a number of developments. PMID- 29710963 TI - A Tethered Porphyrin Dimer with pi Overlap of a Single Pyrrole Ring. AB - The special pair of the bacterial photosystem has been modeled with a porphyrin dimer (the partial structure is shown). As with the natural system, only one pyrrole ring from each monomer subunit participates in pi overlap. PMID- 29710962 TI - Cp*3 Al5 I6 : An Intermediate in Reactions Leading to Elemental Aluminum and AlIII Species? AB - A first indication of the reaction mechanism for the disproportionation of an AlI species to an AlIII compound and metallic aluminum is provided by the isolation of [Cp*3 Al5 I6 ], an intermediate that is formed in the ready disproportionation of [Cp*Al] in the presence of Al2 I6 (see reaction sequence). This potentially key role of AlI compounds could be of great significance for large-scale industrial processes. X=I, Cl. PMID- 29710964 TI - Diastereoselective Ion Pairing of TRISPHAT Anions and Tris(4,4'-dimethyl-2,2' bipyridine)iron(II). AB - Two configurationally stable, chiral anions (TRISPHAT, 1) behave as efficient hosts that control the configuration of a configurationally labile iron(II) complex as the guest with high diastereoselectivity (>96 % de) upon ion pairing. The diastereoselectivity increases with decreasing solvent polarity. PMID- 29710965 TI - Average Octet Radical Polymer: A Stable Polyphenoxyl with Star-Shaped pi Conjugation. AB - An average spin quantum number of 7/2 is displayed by the star-shaped, pi conjugated polyradical 1, even with a spin concentration of 0.8 per monomer unit. Polymer 1 is stable at room temperature, and it is a powerful candidate for the synthesis of a feasible polymer with very high spin. PMID- 29710966 TI - Highly Enantioselective Catalytic Hetero-Diels-Alder Reaction with Inverse Electron Demand. AB - Valuable substrates for the synthesis of natural products, compounds 3 (R1 =alkyl, aryl, alkoxy; R2 , R3 =alkyl) are formed from beta,gamma-unsaturated alpha-keto esters 1 and vinyl ethers 2 by the title reaction [Eq. (1)]. Copper(II) bisoxazolines act as catalysts, and in many cases enantiomeric excesses higher than 99.5 % are achieved. PMID- 29710967 TI - Crystal Structures of Actinomycin D and Actinomycin Z3. AB - Untwinned single crystals of the actinomycins D and Z3 that diffracted to atomic resolution could be obtained for the first time. Low-temperature data collection and a new ab initio method for solving the structures led to precise crystal structures which showed, for example, that the unit cell of actinomycin D contains three molecules, two of which are present in the form of a hydrogen bridged dimer related by a pseudo-twofold axis (see picture). PMID- 29710968 TI - Catalytic Asymmetric Allenylation: Regulation of the Equilibrium between Propargyl- and Allenylstannanes during the Catalytic Process. AB - Achiral substrates 1 and 2 can be regioselectively converted into chiral allenyl alcohols 3 through the title reaction [Eq. (1)] with the synergetic reagent iPrSBEt2 and a chiral TiIV catalyst. The dramatic regioselectivity originates from the regulation of the equilibrium between propargyl- and allenylstannanes during the catalytic process. PMID- 29710969 TI - Dichlorodinickel(I) Complexes with MU2 -CO or MU2 -CS Bridges and Trimethylphosphane Ligands: Homologous Composition, but Different Frameworks. AB - High ligand mobility is shown by the coordinatively unsaturated nickel(I) compound 1 with a short Ni-Ni distance and an asymmetric CO bridge. The thio homologue 2 contains the novel (thiocarbonyl)trimethylphosphorane bridging ligand, which sits like a "stork's nest" on top of the roof-shaped dinuclear complex. In contrast to 1, complex 2 does not show fluctional behavior and can be methylated without decomposition. X=Cl, Me. PMID- 29710970 TI - The Family Approach to the Resolution of Racemates . AB - The resolution of racemates is revolutionized with the method presented here, in which mixtures ("families") of structurally and stereochemically related resolving agents are used to precipitate salts of acidic or basic racemates rapidly and dependably. The racemate is usually separated in a single operation into enantiomers-the enantiomeric excesses and yields are good to excellent. Reagent mixtures with racemic or achiral components have also been developed. PMID- 29710971 TI - Aerogels-Airy Materials: Chemistry, Structure, and Properties. AB - Air, air, air...? and some solid skeleton; this is the basis for an interesting class of materials-the aerogels (shown schematically on the right). Can one therefore speak of "simple" chemistry? The design of such a filigrane network requires the very careful control of chemical parameters. The reward is an assortment of different property profiles owing to the richness of possible variations. PMID- 29710972 TI - Tuning Dihydrogen Bonds: Enhanced Solid-State Reactivity in a Dihydrogen-Bonded System with Exceptionally Short H???H Distances. AB - Topochemical assembly of a covalent material can be achieved with the complex LiBH4 ?TEA (TEA=triethanolamine; section of structure shown), a dihydrogen-bonded system which has very short H???H contacts and high solid-state reactivity due to acidity enhancement in the OH groups by Li+ ion complexation. PMID- 29710973 TI - A FeIII /Oxo Cubane Contained in an Octanuclear Complex of T Symmetry That Is Stable Over Five Oxidation States. AB - Encapsulated in a protective [{Fe(pz)3 }4 ] outer layer, which provides the complex with structural stability, the octanuclear complex [Fe8 (MU4 -O)4 (MU pz)12 Cl4 ] contains a Fe4 O4 core (see drawing) that withstands four consecutive reversible one-electron reductions. Iron-oxygen clusters are shown to possess redox properties which rival those of their better studied iron-sulfur analogues. pz=pyrazolate anion. PMID- 29710974 TI - Total Synthesis of the CP Molecules CP-225,917 and CP-263,114- Part 2: Evolution of the Final Strategy. PMID- 29710975 TI - Lanthanide Nitrido Borates with Six-Membered B3 N6 Rings: Ln3 B3 N6. AB - Metal compounds with heteroatomic ring systems of main group elements are a domain of coordination chemistry. However, lanthanide nitrido borates Ln3 B3 N6 (Ln=La or Ce; see structure) are synthesized by the reaction of hexagonal boron nitride with LnN. The compounds contain the six-membered B3 N6 ring, which can be seen as a fragment from one layer of the hexagonal BN structure. PMID- 29710976 TI - Self-Assembly of Quinodimethanes through Covalent Bonds: A Novel Principle for the Synthesis of Functional Macrocycles. AB - A multiplication of functional units was accomplished in a simple fashion by the tetramerization of a quinodimethane. This principle is demonstrated by the convergent construction of a macrocyclic molecule with 16 ferrocenes and a macrocyclic molecule with 16 dendritic units at the periphery of the molecule (see scheme). FG=functional group. PMID- 29710977 TI - [RuCl2 {PPh2 (2,6-Me2 C6 H3 )}2 ]: A Neutral 14-Electron Ruthenium(II) Complex with Two Agostic Interactions. AB - "Bidentate" ligand behavior is shown by (2,6-dimethylphenyl)diphenylphosphane in the title compound: In the nearly octahedral environment of the ruthenium atom two coordination sites are occupied by methyl groups of the two xylyl substituents. NMR investigation and an X-ray analysis (see picture) reveal that the methyl groups act as weak donors to form two strong agostic Ru???C-H interactions. PMID- 29710978 TI - Total Synthesis of the CP Molecules CP-263,114 and CP-225,917- Part 1: Synthesis of Key Intermediates and Intelligence Gathering. PMID- 29710979 TI - Pleated Sheets and Turns of beta-Peptides with Proteinogenic Side Chains. AB - Components of a toolbox with predictable secondary structural elements: beta peptides. The beta-peptide shown here with proteinogenic side chains adopts a parallel pleated sheet structure in the solid state upon incorporation of suitably configured beta-amino acids. When a beta-dipeptide turn segment is incorporated in the center, a hairpin is formed in solution. PMID- 29710980 TI - Memory of Chirality in Electron Transfer Mediated Benzylic Umpolung Reactions of Arene-Cr(CO)3 Complexes. AB - As density functional calculations suggest, Cr(CO)3 -complexed benzylic radicals (such as 2) exhibit a significant degree of configurational stablility. This was exploited in an efficient method for the electron transfer mediated transformations of readily available 1-arylalkanol-Cr(CO)3 derivatives 1 to afford alkylated products 3 in good yields and with a high degree of stereochemical retention. PMID- 29710981 TI - Chemistry of C84 : Separation of Three Constitutional Isomers and Optical Resolution of D2 -C84 by Using the "Bingel-Retro-Bingel" Strategy. AB - The pure enantiomers of D2 -C84 as well as a third constitutional isomer of this higher fullerene were produced by a retro-Bingel reaction on the first organic derivatives of C84 (see scheme). These derivatives were synthesized by Bingel cyclopropenation of C84 , separated, and unambiguously structurally characterized. PMID- 29710982 TI - Sphingolipids-Their Metabolic Pathways and the Pathobiochemistry of Neurodegenerative Diseases. AB - Glycolipids such as ganglioside GM1 are involved in the building of carbohydrate layers on the surface of living cells. The investigation of the metabolism of this class of compounds gives insight into human diseases, novel signal transduction processes, and the epidermal water permeability barrier. PMID- 29710983 TI - eta5 -Phospholylgallium: The First Monomeric Polyhapto Compound between a Phospholyl Ligand and a Main Group Metal. AB - Monomeric polyhapto-bound phospholyl compounds were hitherto unknown for the main group elements. Use of a solution of metastable GaBr has allowed the synthesis of monomeric eta5 -phospholylgallium, which has been characterized by X-ray structure analysis as the Cr(CO)5 complex 1. PMID- 29710984 TI - A Polymer-Supported Phosphazine as a Stable and Practical Reagent in the Three Component Synthesis of Substituted (Cyclopentadienyl)tricarbonylrhenium Complexes. AB - A very stable heterogenized difunctional cyclopentadienyl-ring precursor, storable under ambient conditions, readily participates in the simultaneous formation of a eta5 bond with a [fac-Re(CO)3 ]+ species and a sigma bond with heteroatom (halides, carboxylates) or carbon nucleophiles (boronic acids) to produce halo-, acyloxy-, or carbon-substituted cyclopentadienyl-Re(CO)3 complexes in a one-pot reaction in yields of between 41 and 71 % [Eq. (1)]. No catalyst is required and unprotected (usually) sensitive functional groups are well tolerated. PMID- 29710985 TI - Asymmetric Phase-Transfer Catalysis. AB - Both in the laboratory and industrially, phase-transfer catalysis offers the potential to induce asymmetry into reactions with anionic intermediates. Equation (a) provides an example (conditions: a) 10 mol % phase-transfer catalyst, BnBr, CsOH?H2 O, PhMe, 15-24 h, -78 degrees C). PMID- 29710986 TI - Triple Helicate-Tetrahedral Cluster Interconversion Controlled by Host-Guest Interactions. AB - A unique ligand design allows the formation of both an M2 L3 triple helicate and an M4 L6 tetrahedron (M=Ti, Ga; L=ligand based on 2,6-diaminoanthracene). Although the tetrahedron is entropically disfavored, a strong host-guest interaction with Me4 N+ is enough to drive the equilibrium towards the tetrahedron. Remarkably, the helicate can be quantitatively converted into the tetrahedron simply by addition of Me4 N+ (shown schematically). PMID- 29710987 TI - Photoswitchable Hydrogen-Bonding in Self-Organized Cylindrical Peptide Systems. AB - The new photochromic supramolecular system 1 is based on the E->Z isomerization of an azobenzene substituted with cyclic peptides with alternating D- and L-alpha amino acids. This system allows reversible switching between inter- and intramolecularly assembled cylindrical beta-sheet structures in solution as well as in thin films at the air-water interface. Moreover, the system displays the rarely observed quantitative photoinduced E->Z isomerization. PMID- 29710988 TI - A Chiral Molecular Based Metamagnet Prepared from Manganese Ions and a Chiral Triplet Organic Radical as a Bridging Ligand. AB - Below 5.4 K the one-dimensional polymeric complex made up of manganese(II) hexafluoroacetylacetonate units and bridging bisaminooxylbenzene diradicals (shown in the picture) behaves as a metamagnet. The R-helical chain not only contains an S-configured chiral carbon center, but also an R-configured C2 symmetric chiral skeleton of the organic ligand. PMID- 29710989 TI - Total Synthesis of (-)-Bafilomycin A1 : Application of Diastereoselective Crotylboration and Methyl Ketone Aldol Reactions. AB - A careful orchestration of protecting groups is an essential requirement for the total synthesis of the macrolide antibiotic bafilomycin A1 (1). Key steps were the Suzuki cross-coupling reaction of two advanced, suitably protected intermediates prior to closure of the macrocycle, as well as a highly stereoselective methyl ketone aldol reaction. PMID- 29710990 TI - Very Stable Phosphiranes. AB - Zero-valent platinum complexes as precursors for hydrosilylation catalysts have been prepared for the first time with the new BABAR-Phos ligands (the structure of one such complex is depicted). These rather stable phosphiranes can be obtained when the three-membered PC2 ring is incorporated into a polycyclic cage. PMID- 29710991 TI - Contactless Electrodeposition of Palladium Catalysts. AB - Site-selective electrodeposition of catalytically active metals on electrically conducting support particles was achieved by polarization with an electric field in a nonconductive matrix in the presence of metal salt solutions. The transmission electron micrograph shows a graphite particle to which Pd and Au were applied sequentially to opposite ends by reversing the direction of the electric field. PMID- 29710992 TI - Organic Nitrates of Isoprene as Atmospheric Trace Compounds. AB - The occurrence in ambient air of organic nitrates of isoprene, which can form according to Equation (1), was established for the first time. The analytical method was a combination of NP-HPLC and capillary gas chromatography with mass selective detection by means of (methane)-NCI after high-volume sample collection (NCI=negative chemical ionization). PMID- 29710993 TI - Nucleophilic Addition of Telluroxides to a Cationic Ditelluroxane: Oligotelluroxanes. AB - Tellurane oligomers with oxo bridges, namely, the oligotelluroxanes 3, were prepared from the cationic ditelluroxane 1 and the telluroxide 2. The reactivity of 3 depends on the cationic character of the terminal telluronium group, and decreases with increasing chain length. Hence the degree of oligomerization can be selectively controlled by means of the ratio of the starting materials 1 and 2. PMID- 29710994 TI - Formation of Novel Dinuclear Mixed-Valence Rhodium Complexes by Intramolecular Migration of a Chelating Ligand. AB - Significantly different coordination spheres are displayed by the two central atoms of 2, the first representative of a novel type of mixed-valence dinuclear Rh0 -RhII compound, which was synthesized from the stibane-bridged complex 1. The Rh-Rh distance determined by an X-ray crystal structure analysis of 2 indicates a metal-metal interaction between the two metal centers. PMID- 29710995 TI - Design, Synthesis, and Evaluation of a Dye Library: Glass-Forming and Solid-State Luminescent Merocyanines for Functional Materials. AB - A highly efficient multicomponent reaction based on the little-known formylating agent dimethylformamide in acetic anhydride led to a multitude of dyes of the indoline (1) and of the thiazole type (2), whose systematic evaluation revealed desired and surprising solid-state properties. PMID- 29710996 TI - RNA and the Small Molecule World. AB - A key role in essential cellular processes is played by RNA molecules, and these are attractive targets for drug design. The functional diversity of RNA can be attributed to the sophisticated three-dimensional structures it assumes. These intricate folds create potential binding pockets for ions, low molecular weight ligands, and proteins. Recent experiments have demonstrated that small molecules such as tobramycin (1) can regulate gene expression in living cells through specific interactions with a messenger RNA (mRNA). PMID- 29710997 TI - Synthesis and Characterization of a Unimolecular Capsule. AB - There is more than one way to assemble the two halves of a tethered, urea substituted calix[4]arene dimer (shown schematically): formation of unimolecular capsules (far left), dimers, or oligomers. By combination of NMR spectroscopy and electrospray mass spectrometry, a hexamethylene spacer was shown to be exactly right to permit the preferential formation of a unimolecular capsule under inclusion of solvent or other guest molecules. PMID- 29710998 TI - 1,2-Dichalcogenins: Simple Syntheses of 1,2-Diselenins, 1,2-Dithiins, and 2 Selenathiin. AB - Ring opening of titanacyclopentadienes 1 with (SCN)2 or (SeCN)2 followed by bis(thiocyanate) or bis(selenocyanate) cyclization affords 1,2-dithiin (2 a) or 1,2-diselenin (2 b), respectively. Compound 1 gives 2 a directly on reaction with S2 Cl2 . Unsubstituted 1,2-diselenin is prepared by reaction of PhCH2 SeNa with 1,4-bis(trimethylsilyl)-1,3-butadiyne followed by reductive cleavage of the benzyl group and oxidation. The unsubstituted 2-selenathiin is prepared in an analogous manner, but from a mixture of PhCH2 SeNa and PhCH2 SNa. PMID- 29710999 TI - The Mechanism of 1,4- and 1,6-Cuprate Additions: The First Determination of Activation Parameters. AB - With a direct kinetic study, activation parameters for the 1,4-cuprate addition to enones (see the Arrhenius plot,?) and the 1,6-addition to acceptor-substituted enynes (?) were determined for the first time. Both reactions might involve sigma copper(III) species which are formed by oxidative addition of the respective substrate to the cuprate. PMID- 29711000 TI - Towards Perfect Asymmetric Catalysis: Additives and Cocatalysts. AB - Make your catalyst more enantioselective! The enantiomeric excess of a catalytic reaction system can sometimes be enhanced from below 10 to over 90 % by the use of suitable achiral additives. Since completely different mechanisms can influence the catalyst and reaction outcome, there is a range of additives that can be applied to improve the catalyst efficiency for a variety of organic reactions. PMID- 29711001 TI - Selective Hydrovinylation of Styrene in a Membrane Reactor: Use of Carbosilane Dendrimers with Hemilabile P,O Ligands. AB - A codimerization of styrene and ethene can be carried out continuously in a nanofiltration membrane reactor with dendritic Pd complexes such as 1. The selectivity of the reaction is increased considerably under continuous conditions. The activity and selectivity of monomeric model complexes and the dendritic catalysts were compared in batch reactions. PMID- 29711002 TI - Metals in Medicine. AB - Not only the 24 or so essential elements, but also nonessential and even radioactive elements have enormous potential for applications in medicine. In the fight against cancer cisplatin, one of the world's best selling anticancer drugs, is being joined by other platinum, titanium, and ruthenium complexes. Gadolinium(III) complexes can be safely injected as magnetic resonance imaging contrast agents, and ligand design allows targeting of paramagnetic ions as well as radiodiagnostic (e.g. 99m Tc) and radiotherapeutic isotopes (e.g. 186 Re). Manganese superoxide dismutase mimics, vanadium insulin mimics, ruthenium nitric oxide scavengers, lanthanide-based photosensitizers, and metal-targeted organic agents show exciting clinical potential. PMID- 29711003 TI - Study of the Interactions between Poly(vinyl pyrrolidone) and Sodium Dodecyl Sulfate by Fluorescence Correlation Spectroscopy. AB - Polymer-surfactant interactions are operative in a variety of industrial processes and important consumer products. Fluorescence correlation spectroscopy is a powerful method for investigating the complex formation and was used to study the well-known reference system involving the aggregation of sodium dodecyl sulfate (?) and poly(vinyl pyrrolidone) (?) in the presence of a fluorescence marked sodium decylsulfate probe (?, see picture). CT =surfactant concentration, dfl =hydrodynamic size of the probe. PMID- 29711004 TI - Blue Tetrakis(diisopropylamino)-cyclo-tetraborane and Yellow Tetrakis(tetramethylpiperidino)tetrabora-tetrahedrane. AB - The colored boranes closo-1 and cyclo-2 are obtained upon dehalogenation of sterically hindered diaminodichlorodiborane(4) 3. The TMP groups of 1 cause the formation of a tetrahedrane, whereas in 2 the diisopropylamino substituents stabilize the bent four-membered ring. TMP=2,2,6,6-tetramethylpiperidino. PMID- 29711005 TI - A Simple Lithographic Approach for Preparing Patterned, Micron-Scale Corrals for Controlling Cell Growth. AB - Hydrophobic n-alkanethiolate bottoms and walls consisting of hydrophilic three layer poly(acrylic acid)/poly(ethylene glycol) nanocomposite polymers are used for making patterned corrals having lateral dimensions of 63 MUm. Macrophage cells are confined within these corrals and are unable to grow over the corral walls (see picture). PMID- 29711006 TI - A Cationic, Macrocyclic, Six-Coordinate Phosphorus(V) Compound Containing a Mixed Valence PIII -PV -PIII Linear Chain. AB - In the highly symmetrical environment of the PV center in the cation [P{P(o-C6 H4 O)2 Ph}2 ]+ of 1 the two PV -PIII bonds are relatively short (2.2023(10) A) for compounds of this type. Compound 1 was obtained from the reaction of PCl5 with two equivalents of [(o-OSiMe3 )C6 H4 ]2 PPh. PMID- 29711007 TI - A Porphyrin as a Binucleating Ligand: Preparation and Crystal Structure of a Porphyrin Complex Containing a Coordinated B2 O2 Ring. AB - A new coordination mode for the porphyrin ligand is found in [B2 O2 (BCl3 )2 (tpClpp)] (tpClpp=dianion of 5,10,15,20-tetra-p-chlorophenylporphyrin; the p chlorophenyl groups are omitted for clarity in the picture shown on the right). This complex contains a four-membered B2 O2 ring in the cavity of the ligand. The two boron atoms are coplanar with the porphyrin molecule, which undergoes an elongation along the B???B axis to accomodate the unusual guest. PMID- 29711008 TI - Polysaccharide Derivatives for Chromatographic Separation of Enantiomers. AB - The first resolution of enantiomers was performed 150 years ago-mechanically. Today a powerful method for carrying out this task is HPLC on polysaccharide derivatives as chiral stationary phases. Most racemates, from an analytical to a preparative scale, now appear to be resolved by this technique. As an example, the chromatogram for the enantiomeric resolution of a fullerene derivative is shown on the right. PMID- 29711009 TI - Porphyrins Like Boron After All. AB - The central core and the macrocycle skeleton of porphyrins both offer room for boron, and a gap in the chemistry of nonmetal-containing porphyrins has now been filled. In one case a four-membered B2 O2 ring coordinates to a porphyrin cavity that has been distorted to a rectangle (A), and in the other case four boron atoms are located in the meso positions of a tetrathiaporphyrinogen (B). PMID- 29711010 TI - The Total Synthesis of Spirotryprostatin A. AB - Eight concise steps suffice for the first total synthesis of the title compound 1, which inhibits the transitions from the G2 and M phases into the next phases of the cell cycle. Key steps in the synthesis are a stereocontrolled oxidative rearrangement of an indole to form the chiral spiroindolinone nucleus and a regioselecitve sulfoxide elimination. PMID- 29711011 TI - Solution and Solid-State Studies of a Chiral Zinc-Sulfonamide Complex Relevant to Enantioselective Cyclopropanations. AB - A highly distorted tetrahedron formed by the four nitrogen atoms around zinc in the crystalline zinc-sulfonamide complex 1 may explain its catalytic activity in asymmetric cyclopropanations. The agent is formed by deprotonation of (R,R)-N,N' cyclohexane-1,2-diyl)bis(n-butanesulfonamide) with diethylzinc and addition of 2,2'-bipyridyl. PMID- 29711012 TI - Facile Synthesis of Cyclic Tetrapeptides from Nonactivated Peptide Esters on Metal Centers. AB - The cyclization of dipeptide esters of alpha-, beta-, gamma-, and delta-amino acids can be achieved by using NiII , PdII , or CuII templates. The structure of one of the complexes (1) obtained, which was determined by X-ray crystallography, reveals that the anions form layers and are linked to water molecules by hydrogen bonds. PMID- 29711013 TI - Highly Enantioselective Hydrogenation of Simple Ketones Catalyzed by a Rh PennPhos Complex. AB - Even alkyl methyl ketones undergo asymmetric hydrogenation with high enantioselectivity when a rhodium complex of the conformationally rigid chiral ligand 1 (Me-PennPhos; R=CH3 ) is used as the catalyst. Basic additives such as 2,6-lutidine contribute to the achievement of high enantiomeric excesses. PMID- 29711014 TI - Unusual Diastereoselection in the Synthesis of Nine-Membered Ring Lactams and Conformation-Controlled Transannular Reactions to Generate Optically Active Indolizidinones. AB - The aza-Claisen rearrangement of vinylpyrrolidines 1 yielded almost exclusively the trans-3,8-disubstituted nine-membered ring lactams 2 (TBS=tBuMe2 Si), independent of whether cis or trans isomers were used as starting materials. The conformation (which provided facial chirality) of the medium-sized ring controlled the regio- and diastereoselectivities of the transannular reactions that afforded indolizidinones 3. PMID- 29711015 TI - Stereocontrolled Routes to Bridged Ethers by Tandem Cyclizations. AB - Ring contraction of a 3,4-epoxyalcohol, then lactolization and electrophilic attack are the steps in the domino cyclization protocol for the formation of 8 oxabicyclo[3.2.1]octane systems [Eq. (a)]. PMID- 29711016 TI - A New Tetracycle from Dimerization of the N-Methylpyridazinium Ion in Aqueous Solution. AB - In a one-pot synthesis at room temperature the N-methylpyridazinium ion (1) dimerizes stereospecifically and with 100 % conversion in a series of OH- catalyzed processes to give a new tetraazafluorene (2). Four of the individual steps can be identified directly and monitored by 1 H NMR spectroscopy. PMID- 29711017 TI - Effect of Chain Length on the Adsorption Behavior of n-Alkanes in Ferrierite. AB - 13 C NMR spectroscopy and computer simulations have shown that the chain length of hydrocarbons has a surprising effect on where these molecules reside in the zeolite FER. Propane and butane can access the entire two-dimensional channel structure, while hexane only the one-dimensional substructure. This difference has important consequences for the catalytic activity and explains some of the experimental observations. PMID- 29711018 TI - Exceptionally Simple Enantioselective Syntheses of Chiral Hexa- and Tetracyclic Polyprenoids of Sedimentary Origin. AB - Coupling between a sulfone and an acylsilane fragment (see below) constitutes the first step in the exceptionally short total syntheses of two chiral hexacyclic hydrocarbons isolated from Eocene Messel shale (Germany). Like the first step, subsequent steps also employ a powerful synthetic tactic: polycyclization of a specially constructed chiral, multiply unsaturated oxirane. TBS=tBuMe2 Si. PMID- 29711019 TI - Silicon Phthalocyanines with Axial Dendritic Substituents. AB - Nonscattering glasses that are indefinitely stable with respect to crystallization can be prepared from the title compounds. In these solid solutions, the dendritic substituents effectively suppress interactions between the phthalocyanine units (see the structure depicted on the right). PMID- 29711020 TI - Binuclear Homoleptic Manganese(III,III) and Manganese(IV,III) Complexes with Deprotonated D-Mannose from Aqueous Solution. AB - Just a "reducing" sugar-namely, D-mannose-is a starting material in the synthesis of a mixed-valence complex of manganese in the oxidation states +III and +IV. Ba2 [MnIII MnIV (beta-D-ManfH-5 )2 ]Cl?14 H2 O (Manf=mannofuranose; the structure of the anion is shown on the right) is prepared in aqueous solution by oxidation of an analogous Mn2III complex with oxygen. In neutral solutions the MnIII MnIV binuclear complex is formed by disproportionation of the Mn2III precursor. PMID- 29711021 TI - The [Ag{Se2 C2 (CN)2 }(Se6 )]3- , [Sb{Se2 C2 (CN)2 }2 ]3- , and [As(Se)3 (CH2 CN)]2- Anions: Facile Formation of the Maleonitrilediselenolate (mns) Ligand, [Se2 C2 (CN)2 ]2. AB - An unusual route to the maleonitrilediselenolate (mns) ligand has been discovered with the isolation of compounds that contain this ligand bound to silver (structure shown on the right) or antimony. The formation of the [As(Se)3 (CH2 CN)]2- anion along with possible pathways to the mns ligands is discussed. PMID- 29711022 TI - The Paterno-Buchi Reaction of L-Ascorbic Acid. PMID- 29711023 TI - Amine Additives Greatly Expand the Scope of Asymmetric Hydrosilylation of Imines. AB - Slow addition of a primary amine to the reaction mixture greatly increases the scope of the titanium-catalyzed asymmetric reduction of imines 1. An important added feature of this method is that chiral secondary amines 2 can be obtained in much higher optical purity (up to 99 % ee) than would be predicted from the E:Z ratios of the starting imines 1. PMID- 29711024 TI - An Enzyme-Labile Linker Group for Organic Syntheses on Solid Supports. AB - Lipases and esterases can be used to fragment the 4-acetyloxybenzyloxy group used as a linker for organic synthesis on solid supports. (A support-bound compound is shown on the right; the enzyme-labile bond is marked with an arrow.) This enzyme initiated fragmentation proceeds under very mild conditions (pH 6-7, room temperature), and the compounds of interest (amines, alcohols, carboxylic acids; X=NH, O, CR2 ) constructed by combinatorial chemistry can be released with complete selectivity. PMID- 29711025 TI - Topochemical Conversion of a Hydrogen-Bonded Three-Dimensional Network into a Covalently Bonded Framework. AB - Thermal dehydration promotes the topochemical conversion of the hydrogen-bonded dimeric complex [{Zn(sala)(H2 O)2 }2 ]?2 H2 O (H2 (sala)=N-(2-hydroxybenzyl)-L alanine) to generate covalent [{Zn(sala)}n ]. X-ray crystallography reveals that hydrogen bonding plays a key role in this process (see the partial structure on the right). PMID- 29711026 TI - Extremely Facile and Selective Nickel-Catalyzed Allyl Ether Cleavage. AB - Child's play! Allyl ethers as protecting groups for hydroxyl functions can be removed readily with a combination of DIBAL and catalytic amounts of [NiCl2 (dppp)]. Propene is expelled in this remarkably selective reaction, and a nickel catalyzed hydroalumination-elimination pathway is proposed [Eq. (a)]. dppp=propane-1,3-diylbis(diphenylphosphane). PMID- 29711027 TI - Facile meso Functionalization of Porphyrins by Nucleophilic Substitution with Organolithium Reagents. AB - The ruffle of the porphyrin increases with the number of meso substituents. (Octaethylporphyrin)nickel(II) undergoes nucleophilic substitution reactions upon treatment with alkylating reagents such as butyllithium, hydrolysis with water, and oxidation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone [DDQ; Eq. (a)]. Alkylation can be achieved at all four meso positions, and access is provided to new nonplanar porphyrins and asymmetrically substituted systems. PMID- 29711028 TI - Light-Induced Structural Changes in the Primary Processes of Photosynthesis: Watching an Enzyme in Action. AB - Continuous illumination and subsequent freezing of the crystal enabled the structure of the light-induced charge-separated state in the reaction center of a photosynthetic bacterium to be obtained by X-ray crystallography. A comparison of the position of the secondary ubiquinone cofactor QB in this structure (shown in gray on the right) with that in the "dark" structure (shown in black) reveals substantial motions, which are required for the subsequent electron and proton transfer processes. PMID- 29711030 TI - 2,4,6,8-Tetracyanoazulene: A New Building Block for "Organic Metals". AB - Simply mixing solutions of the title compound 1 and tetrathiafulvene (TTF) in acetonitrile provides the charge-transfer complex 2. Here, 1 functions as a novel electron acceptor and is present in the complex as a radical anion. An electrical conductivity of up to 3 S cm-1 was determined for 2 with a two-point powder measurement. PMID- 29711029 TI - Modern Variants of the Mannich Reaction. AB - Important building blocks for the synthesis of drugs or natural products are found in Mannich bases and their derivatives. Modern variants of the Mannich reaction that expand the potential of the classical intermolecular reaction significantly and enable efficient control of the regioselectivity and stereoselectivity are therefore the topic of intensive research. Intramolecular reactions, in particular as part of domino reaction sequences, often afford astoundingly simple and elegant approaches to complex target compounds. PMID- 29711031 TI - Micelle-Bound Metalloporphyrins as Highly Selective Catalysts for the Epoxidation of Alkenes. AB - The porphyrin-surfactant interaction determines the activity of the title catalysts. Amphiphilic porphyrin derivatives (e.g. 1 with M=MnCl, R=CH2 CH2 (OCH2 CH2 )2 OH) are easy to prepare and can be included in micellar phases. PMID- 29711032 TI - Ruthenium Trichloride, Tricyclohexyl- phosphane, 1-Alkynes, Magnesium, Hydrogen, and Water-Ingredients of an Efficient One-Pot Synthesis of Ruthenium Catalysts for Olefin Metathesis. AB - An active role is played by MgCl2 during the conversion of the vinylidene precursor 2 into carbenes 3 (R=H, Ph; L=P(C6 H11 )3 ). These complexes can be prepared in a convenient and very efficient one-pot synthesis and have a catalytic activity in metathesis comparable to that of Grubbs compound (Ph instead of CH2 R). PMID- 29711033 TI - Novel Distorted Pentagonal-Pyramidal Coordination of Anionic Oxodiperoxo Molybdenum and Tungsten Complexes. AB - Model compounds for silica surfaces modified with metal complexes are provided by the mononuclear anionic diperoxo species 1 and the dinuclear complex anions 2 (M = Mo, W). They were obtained in fair to nearly quantitative yields by the reactions of Ph3 SiOH and [Ph2 Si(OH)]2 O, respectively, with an aqueous solution of [MO(O2 )2 (H2 O)2 ]. PMID- 29711034 TI - A New "Old" Sodium Boride: Linked Pentagonal Bipyramids and Octahedra in Na3 B20. AB - The title compound is not a hexaboride, as was believed for many years. It is therefore not surprising that its structure also contains a novelty: for the first time a pentagonal B7 bipyramid (shown on the right) has been identified as part of the framework of boron atoms in a solid-state compound. PMID- 29711035 TI - The First Delocalized Phosphole Containing a Planar Tricoordinate Phosphorus Atom: 1-[Bis(trimethylsilyl)methyl]-3,5-bis(trimethylsilyl)-1,2,4-triphosphole. AB - The sterically demanding groups on the tricoordinate phosphorus atom, the pi electron acceptors substituted on the ring, and the dicoordinate phosphorus atoms within the ring are the most significant factors contributing to the planarity and aromaticity of the 1,2,4-triphosphole ring in 1. The Bird aromaticity index for 1 shows that it has the most pronounced aromatic character of all known phospholes. PMID- 29711036 TI - A Short Synthesis of (+/-)-Matrine. AB - Three different radical reactions were used in a short total synthesis of (+/-) matrine (1). Two of the four six-membered rings and four new bonds were created in one radical cascade involving intermolecular addition followed by two successive cyclizations and transfer of a xanthate group. PMID- 29711037 TI - Determination of the Disordered Structure of Gd2 Ba2 CaCu2 Ti3 O14 with Multiple Edge EXAFS and Powder Diffractograms. AB - The overall structure and the local structural features of the superconductor related cuprate Gd2 Ba2 CaCu2 Ti3 O14 were determined by the simultaneous fitting of the data sets of five EXAFS spectra and a powder X-ray diffractogram with a single structural description. The method is particularly suitable for materials that do not exhibit perfect crystalline order. PMID- 29711038 TI - The First Homoleptic Metallabenzene Sandwich Complex. AB - Air-stable, yellow crystals are formed by the first bis(metallabenzene) sandwich complex 1. With regard to its properties, 1 shows many similarities to classical metallocenes, the syn-ecliptical arrangement of the metal atoms in the rings pointing to an additional interaction between the ring Ru atoms. PMID- 29711039 TI - Phosphanides of the Heavier Alkali Metals. AB - A variety of structures are shown in the solid state by the phosphanides MPHR of alkali metals. Whereas oligomeric and polymeric ladder or helical structures based on M-P bonds predominate for compounds of the lighter homologues (M=Li, Na, K), the 2,6-dimesitylphenylphosphanides of Rb and Cs are present as a Rb4 P4 cubane and a Cs+ {Cs2 (PHR)3 }- contact ion pair, respectively (the partial structures are shown above). These unexpected new structures show interactions between the metal center and pi electrons of the ligand. PMID- 29711040 TI - Radical Cyclization/beta-Elimination Tandem Reactions: Enantiopure Sulfoxides as Temporary Chiral Auxiliaries. AB - Alkylidene-substituted cyclopentane derivatives are formed in high enantiomeric purity by the reaction shown below. A highly diastereoselective radical cyclization is followed by elimination of a beta-sulfinyl radical. Interestingly, the addition of the Lewis acid methylaluminum bis(2,6-di-tert-butyl-4 methylphenoxide) (MAD) totally reverses the stereochemical outcome of the reaction. E=CO2 Me. PMID- 29711041 TI - Self-Assembly of Nanometer-Sized Macrotricyclic Complexes from Ten Small Component Molecules. AB - Nanometer-sized bowls: six metal centers and four tridentate ligands self assemble in aqueous solution to give the macrotricycle 1, which has approximate dimensions of 3*2*2 nm. Another macrocycle (not shown), obtained with a different ligand, is of similar size and topology but differs considerably from 1 in its host-guest behavior. PMID- 29711042 TI - Spectra, Structure, Ligand Exchange, and Decomposition of a Tungsten(II) Ether Complex. AB - Facile displacement of the ether ligand from complex 1 provides a convenient route to the reactive cation [WTp'(CO)(PhC=CMe)]+ (Tp'=hydridotris(3,5 dimethylpyrazol-1-yl)borate). In the absence of suitable ligands, 1 decomposes in dichloromethane and reacts with the solvent to form the metallacycle 2 [Eq. (a)]. PMID- 29711043 TI - Rearrangement of 5-Substituted 5-Aminopentadienals. AB - Strong nucleophiles are needed for inducing ring opening 3->4 since the pyrylium salt intermediates 3, formed from 5-X-substituted 5-aminopenta-2,4-dienals 2 upon treatment with acid, are quite unreactive due to "aromatic" stabilization. However, this allows an easy access to a variety of 2-aminopyrylium salts 3 from "push-pull" enynes 1. X=OAc, F, Cl, Br, I, OPh. PMID- 29711044 TI - Synthesis and Crystal Structure of delta-GeS2 , the First Germanium Sulfide with an Expanded Framework Structure. AB - Polycondensation of molecular adamantanoid [Ge4 S10 ]4- precursors at a remarkably low temperature (50 degrees C) affords the crystalline binary dichalcogenide delta-GeS2 . Its crystal structure contains two interpenetrating cristobalite-like frameworks composed of adamantanoid [Ge4 S6 S4/2 ] building blocks. Rings containing 24 atoms form the largest pores of each network (shown on the right). PMID- 29711045 TI - Transition Metal Catalyzed Synthesis of Arylamines and Aryl Ethers from Aryl Halides and Triflates: Scope and Mechanism. AB - Oxidative addition and reductive elimination are the central steps in new palladium-catalyzed chemistry that forms C-N and C-O bonds in arylamines and ethers. In the potential mechanism shown on the right the amine is formed by reductive elimination from a four-coordinate, 16-electron amido aryl complex. The use of a chelating ligand such as 1,1'-bis(diphenylphosphanyl)ferrocene (DPPF) reduces the occurrence of the competing beta-hydrogen elimination. X=Br, I; R, R'=alkyl, aryl. PMID- 29711046 TI - Metal--Metal "Communication" of Rh or Pd with Nd in Novel Heterobinuclear Complexes. AB - The reaction of a neodymium "ate" complex and an electron-rich transition metal chloride by salt elimination is an efficient method for synthesizing heterobinuclear compounds which contain a lanthanide and a Group 9 or 10 metal [Eq. (1), H2 Ap=2-amino-4-methylpyridine]. The use of bisaminopyridinato ligands allows extremely short distances between Rh or Pd and Nd. PMID- 29711047 TI - SSZ-23: An Odd Zeolite with Pore Openings of Seven and Nine Tetrahedral Atoms. AB - Single-crystal X-ray diffraction with synchrotron radiation enabled the structure of microcrystalline SSZ-23 (see drawing on the right), the first zeolite with channels bounded by seven- and nine-membered rings, to be solved. PMID- 29711048 TI - A Photochemical Switch for Controlling Protein-Protein Interactions. AB - Incorporation of an unnatural amino acid containing a photolabile group in the side chain allows specific interactions between two proteins to be prevented. The photocaged ras protein in which Asp 38 has been substituted by its beta nitrobenzyl ester (Nb) is unable to interact with its effector protein p120-GAP (see drawing below) although it has the same intrinsic GTPase activity. After photocleavage of the Nb group, 50% of the p120-GAP-dependent GTPase activity relative to the wild-type protein is restored. PMID- 29711049 TI - Formation of Isomeric Tetrathiotungstate Clusters [{Cp*Ru(CO)}2 (WS4 ){W(CO)4 }] by the Reaction of [Cp*2 Ru2 S4 ] with [W(CO)3 (MeCN)3 ]. AB - Thermal and photochemical interconversion occurs between the isomeric pair of tetrathiotungstate [WS4 ]2- clusters 1 and 2, which were formed by thermolysis of [Cp*2 Ru2 S4 ] and [W(CO)3 (MeCN)3 ] [Eq. (1)] and then structurally characterized. During synthesis, a dramatic redistribution of ligands between the Ru and W atoms takes place without the loss of any CO and S ligands. PMID- 29711050 TI - Total Synthesis of (+/-)-Halomon by a Johnson-Claisen Rearrangement. AB - The total synthesis of the polyhalogenated antitumour agent halomon (1) was accomplished with two novel transformations as key steps: a Johnson-Claisen rearrangement of a dichlorinated alkene for the preparation of the tertiary chlorinated C3 and a new rearrangement of bromohydrins for the regiospecific introduction of the bromine and chlorine atoms on C6 and C7, respectively. PMID- 29711051 TI - A Strong Positive Allosteric Effect in the Molecular Recognition of Dicarboxylic Acids by a Cerium(IV) Bis[tetrakis(4-pyridyl)porphyrinate] Double Decker. AB - With increasing number of bound dicarboxylic acid molecules, the binding of further molecules by the title compound becomes more favorable (a 1:4 complex is depicted schematically on the right). The association constant for binding of the first guest molecule is small, since the increase in Gibbs free energy due to binding is outweighed by the energy loss asssociated with the suppression of rotation of the porphyrin rings. Once rotation has been suppressed, further guest molecules can be more effectively bound (positive allosteric effect). PMID- 29711052 TI - Hexahelicenophanes and Their Racemization. AB - A drastic increase in the rate of racemization is found for the bridged hexahelicenophanes 1 (n=8, 10) relative to the unsubstituted parent [6]helicene. This unexpected result occurs from steric interactions between the polymethylenedioxy chains and the terminal rings, which causes the energy of the ground state to be raised and that of the transition state to be lowered. PMID- 29711053 TI - Mechanism of Reduction of Diphenylacetylene by Metallic Lithium. AB - A zero-order reaction converts cis-dilithiostilbene (1), formed upon reduction of diphenylacetylene by lithium, into the trans isomer 2. The cis-monolithiated adduct acts as a catalyst. PMID- 29711054 TI - One- and Two-Dimensional Electron Transfer Processes in Triarylamines with Multiple Redox Centers. PMID- 29711056 TI - Fast Oxidation of Organic Sulfides by Hydrogen Peroxide by In Situ Generated Peroxynitrous Acid. AB - A powerful oxidant and an unstable isomer of HNO3 , peroxynitrous acid ONOOH is generated by the fast reaction of H2 O2 with HNO2 in acidic medium [Eq. (1)]. If sulfides R2 S are present, ONOOH sulfoxidizes them in minutes. This reaction occurs faster than the decay of ONOOH to HNO3 and allows the fast preparation of sulfoxides with H2 O2 . (1). PMID- 29711055 TI - Regioselective Synthesis of trans-1 Fullerene Bis-Adducts Directed by a Crown Ether Tether: Alkali Metal Cation Modulated Redox Properties of Fullerene-Crown Ether Conjugates. AB - Regioselective Bingel macrocyclization of C60 with a bis-malonate containing a novel dibenzo[18] crown-6 tether provides a versatile access to trans-1 fullerene bis-adducts such as (+/-)-1. Complexation of a potassium ion by (+/-)-1 has a pronounced effect on the redox properties of the carbon sphere as a result of the close proximity of the fullerene surface to the crown ether bound cation, which is enforced by the double bridging. PMID- 29711057 TI - Unexpected cis-Selective 1,4-Addition Reaction of Lower Order Cyanocuprates to Optically Active 5-(tert-Butyldimethylsiloxy)-2-cyclohexenone. AB - A remarkable cis selectivity has been observed in the 1,4-addition of lower order primary and secondary alkylcyanocuprates to 5-silyloxy- and 5-benzyloxy substituted cyclohexenones. This enables the preparation of both enantiomers of the corresponding 5-alkyl-substituted cyclohexenones (S)- and (R)-3 by the reaction of the readily available 5-(tert-butyldimethylsiloxy)-2-cyclohexenone (1) with either the lower or higher order cyanocuprate. DBU=1,8 diazabicyclo[5.4.0]undec-7-ene. PMID- 29711058 TI - Photoluminescent Rigid Molecular Rods with Cumulenic Cn (n=3, 4) Spacers: Modulation of Electronic Interaction. AB - Varying the length of the carbon chain in the bridge of complexes of types 1 and 2 can influence the photophysical properties and redox potentials of the metal centers as well as the electronic communication between these metal centers (M=Ru, Os; bpy=2,2'-bipyridine). PMID- 29711059 TI - Synthesis, Structure, and Spectroscopic Properties of [Feiii (tnpa)(OH)(PhCOO)]ClO4 : A Model Complex for an Active Form of Soybean Lipoxygenase-1. AB - The cis configuration between the hydroxo and the carboxylato and the three amino groups of the tetradentate, tripodal ligand tris(6-neopentylamino-2 pyridylmethyl)amine favors the formation of hydrogen bonds which stabilize the hydroxo-Feiii complex 1. Thus, its structure closely resembles that of the active center of Feiii -soybean lipoxygenase-1, which also contains a six-coordinate Feiii atom. PMID- 29711060 TI - Nonclassical Metal Carbonyls: Appropriate Definitions with a Theoretical Justification. AB - MP2 calculations show that the Dinfinityh isoelectronic dicarbonyl complexes [M(CO)2 ]n (Mn =Rh- , Pd0 , Cu+ , Ag+ , Au+ , Zn2+ , Cd2+ , Hg2+ ) depicted in structure 1 can be classified as classical or nonclassical depending on whether the metal-carbon bond lengths decrease or increase when weak, anionic ligands approach the metal centers. PMID- 29711061 TI - Reduction of Carbonyl Compounds with Chiral Oxazaborolidine Catalysts: A New Paradigm for Enantioselective Catalysis and a Powerful New Synthetic Method. AB - High enantioselectivity can be achieved when chiral oxazaborolidines are used as catalysts in the reduction of ketones by borane. In the transition state on the way to the complex chiral compounds, the two reactants are activated and held in close proximity by the catalyst, as shown below. PMID- 29711062 TI - Synthesis, Structure, and Reactivity of a Palladium Hydrazonato Complex: A New Type of Reductive Elimination Reaction To Form C-N Bonds and Catalytic Arylation of Benzophenone Hydrazone. AB - A rare, structurally characterized MU1 ,eta1 -hydrazonato complex is a probable intermediate in the Pd-catalyzed N-arylation of hydrazones. Starting from aryl halides the reaction proceeds efficiently and under mild conditions with chelating phosphane ligands (L2 ); even Cs2 CO3 can be used as the base [Eq. (a)]. R=alkyl, aryl, MeCO, MeO; X=Br, I. PMID- 29711063 TI - Chemical Biology of Epothilones. AB - Only a few months after the disclosure of the absolute configuration of epothilones A (R=H, see picture on the right) and B (R=Me) the first total syntheses of these natural products were reported. Interest intensified with the realization of their potential as anticancer agents with a taxol-like mechanism of action. In addition to describing the most important total syntheses and biological properties of the naturally occurring epothilones A-E, this review also provides a systematic overview of numerous epothilone analogues that have been modified in the A-D regions in order to obtain information about structure activity relationships. PMID- 29711064 TI - [Re5 (MU-H)4 (CO)20 ]- and [Re5 (MU-H)5 (CO)20 ], Two Isolobal Analogues of Cyclopentane. AB - The first five-membered rings of metal atoms connected by M-M or M-H-M bonds only have been obtained by a Re2 +Re3 condensation in which a polyhydride acts as a bridging bidentate ligand toward a coordinatively unsaturated fragment (see scheme below). In spite of the octahedral coordination of the Re centers, the Re5 rings display conformations (twisted and envelope) comparable with those observed for organic five-membered rings of tetrahedral carbon atoms. PMID- 29711065 TI - Stereoselection at the Steady State: The Design of New Asymmetric Reactions. AB - Not a new principle, but a shrewd analysis of stereoconvergent reactions is leading to new and highly efficient asymmetric reactions. A prochiral compound can be converted through a clever combination of competing reactions, one of which must be stereoselective, into a sole chiral product (shown above). The strategy is reviewed by using a radical cyclization reaction as an example. PMID- 29711066 TI - A Fully Encapsulated Acetylenediide in Ag2 C2 ?8 AgF. AB - The reaction of Ag2 C2 with a concentrated aqueous solution of AgF leads to the title compound, in which the dianion C22- is completely enclosed in the Ag9 cage of a chandelierlike arrangement of ten silver atoms. PMID- 29711067 TI - A Boron-Bridged Tetrathiaporphyrinogen. AB - Lewis acid and Lewis base centers are simultaneously present in the boron-bridged thiophene-containing porphyrinogen 1 that has been synthesized in high yield. Its crystal structure reveals a nonplanar macrocycle; this and the colorless aspect suggest the absence of a delocalized pi-electron system. R = NiPr2 . PMID- 29711068 TI - Strain-Induced "Band Flips" in Cyclodecaamylose and Higher Homologues. AB - The cavity of the larger molecule has less space for guests! Unlike the structure of the smaller annular cyclodextrins, that of the higher homologues of cycloamyloses (CAs) with more than ten glucose units contains a 90 degrees kink between adjacent glucose residues within one half of the molecule and a 180 degrees band flip between adjacent units in different halves (see depicted section of the CA14 structure) to yield butterfly-shaped structures with narrow, groovelike cavities. PMID- 29711069 TI - Why Does the Active Form of Galactose Oxidase Possess a Diamagnetic Ground State? AB - The relative orientation of the two magnetic orbitals, the CuII d x 2-y 2 orbital and the half-occupied pi orbital of the tyrosyl radical, is the key to answering the question in the title. The arrangement shown (CuII -O-C bond angle of about 130 degrees and a dihedral angle of about 90 degrees between the x,y plane of the CuII polyhedron and the tyrosyl ring plane) leads to an overlap of the orbitals, which results in a singlet ground state. PMID- 29711070 TI - Polymers for 193-nm Microlithography: Regioregular 2-Alkoxycarbonylnortricyclene Polymers by Controlled Cyclopolymerization of Bulky Ester Derivatives of Norbornadiene. AB - Double duty for the tert-butyl residue: The bulky substituent in monomer 1 favors free-radical cyclopolymerization with maleic anhydride to give the regioregular nortricyclene copolymer 2. When the polymer is irradiated with a photoacid generator, the tert-butyl ester is cleaved and the polymer becomes soluble in aqueous base. This type of copolymer can be used in 193-nm microlithography; images with resolutions of less than 200 nm have been obtained. PMID- 29711071 TI - Cubic and Columnar Supramolecular Architectures of Rod-Coil Molecules in the Melt State. AB - The liquid crystalline behavior of compounds 1 (n = 7, 12, 15) differs significantly from that exhibited for conventional rodlike molecules. They organize into layered smectic, bicontinuous cubic or hexagonal columnar mesophases depending on the temperature or the volume fraction of coil segments. PMID- 29711072 TI - Combinatorial Approach to the Hydrothermal Synthesis of Zeolites. AB - One hundred or more solid-state syntheses can be conducted in parallel and employed for the combinatorial hydrothermal syntheses of zeolites by using a novel multiautoclave design. The operation of the multiautoclave was ascertained by the reinvestigation of the complete Na2 O-Al2 O3 -SiO2 ternary system in a single experiment. In the picture on the right, the shaded areas on the left show the crystallization fields of the different phases obtained. PMID- 29711073 TI - A Chemosensor for Citrate in Beverages. AB - Competitive binding like that in immunoassays is the principle behind the chemosensor based on receptor 1, which was used to measure the concentration of citrate (2) in a series of common beverages. Citrate displaces the fluorescent colorimetric probe 5-carboxylfluorescein (3) from 1, and the process can be monitored by UV or fluorescence spectroscopy. PMID- 29711074 TI - Superconductivity and Chemical Bonding in Mercury. AB - Band structure and Fermi surface calculations were performed for the metal mercury, for which superconductivity was discovered 87 years ago. The electronic properties of mercury were analyzed to find the origin of singlet electron pair formation and condensation which leads to superconductivity. PMID- 29711075 TI - [Mo12 S12 O12 (OH)12 (H2 O)6 ]: A Cyclic Molecular Cluster Based on the [Mo2 S2 O2 ]2+ Building Block. AB - The pH-dependent self-condensation of the [Mo2 S2 O2 ]2+ complex fragment gives the wheellike Mo12 cluster depicted on the right (ball-and-stick model; large balls: S, medium balls: O, small balls: Mo). Applying this synthetic strategy to other starting materials could provide access to other polyoxothiometalates with well-defined cavities. PMID- 29711076 TI - A Bifunctional Lewis Acidic Spacer in Self-Assembled Molecular Stairs and Ladders. AB - Depending on the stoichiometry, diindacycle 1 and pyrazine in THF reversibly form a stair- or a ladderlike self-organized coordination polymer. In both cases, the building blocks are assembled at angles close to 90 degrees . PMID- 29711077 TI - Heck Reactions without Salt Formation: Aromatic Carboxylic Anhydrides as Arylating Agents. AB - Environmentally benign and economical production of arylated olefins can be achieved by a new variant of the Heck reaction in which no halogen salts are formed. The trick is the use of aromatic carboxylic anhydrides 1 as arylating agents. With halide-activated palladium chloride as catalyst, which requires no phosphane ligands, the olefins 2 can be prepared according to Equation (a) in good yields. PMID- 29711078 TI - Synthesis of Unsaturated Nine-Membered Ring Ethers (Delta3 -Oxonenes) Containing a Z- or E-Configurated Double Bond: Thermodynamic versus Kinetic Control in Palladium-Catalyzed Allylic Cyclizations. AB - Double stereocontrol is achieved in the Pd-catalyzed cyclization of Delta3 oxonene precursors (see reactions outlined below). The configuration of the olefinic double bond and of the allylic carbon center alpha to the ether oxygen atom is dictated by the configuration of the double bond in the starting compound (E/Z), the Pd ligand (dppe = Ph2 PCH2 CH2 PPh2 ), and the reaction time. PMID- 29711079 TI - Synthesis and Characterization of the First Double-Bridged Tetraselenafulvalenophanes. AB - Recrystallization of the isomeric mixtures of 1 a and 1 b obtained by synthesis gave single crystals of the cis-trans and cis-cis isomers, respectively. The unique stacked structures of these compounds were elucidated by X-ray structure analysis. PMID- 29711080 TI - New Developments in Superacid Chemistry: Characterization of HC+ =O and FC+ =O Cations. AB - A high gas pressure and use of the superacid HF/SbF5 (1/1) were required for direct spectroscopic characterization of the HC+ =O cation, which was until recently discussed as the short-lived intermediate of carbonylation reactions. The fluorocarbonyl cation FC+ =O, which was equally difficult to characterize, was also directly observed with NMR spectroscopy as the product of protolytic cleavage of tert-butyl fluoroformate [Eq. (a)]. PMID- 29711081 TI - Stilbenoid Dendrimers. AB - A convergent synthesis in which all trans double bonds were constructed by Wittig Horner reactions produces dendrimers of the general structure 1. With long-chain alkoxy residues on the periphery of the benzene rings, the first two generations display liquid crystalline behavior. PMID- 29711082 TI - Carbohydrate-Arene Interactions Direct Conformational Equilibrium of a Flexible Glycophane in Water. AB - Water, the flexibility of the maltose molecule, and sugar/arene interactions are responsible for the equilibrium between a folded (I) and nonfolded (II) conformation in a glycophane (III is an intermediate). Glycophanes are cyclodextrin-cyclophane hybrids, which are of interest as models of receptors. PMID- 29711083 TI - Dioldehydratase Binds Coenzyme B12 in the "Base-On" Mode: ESR Investigations on Cob(II)alamin. AB - Even in the enzyme-bound state the dimethylbenzimidazole ligand in the dioldehydratase from Salmonella typhimurium remains bound to the cobalt ion in contrast to some coenzyme B12 -dependent enzymes. Direct, ESR spectroscopic proof for this "base-on" binding mode was obtained by using a coenzyme in which one of the nitrogen atoms of the dimethylbenzimidazole ligand was 15 N labeled (see schematic representation on the right). PMID- 29711084 TI - Fixation of Atmospheric Nitrogen: Synthesis of Heterocycles with Atmospheric Nitrogen as the Nitrogen Source. AB - Dry air is the source of molecular nitrogen for reactions with TiL4 , Li, and TMSCl (L = Cl, OiPr; TMS = trimethylsilyl). The nitrogen-titanium complexes thus prepared can be used to synthesize indoles, pyrroles, and lactams from carbonyl compounds. Applying this method to 1 provides access to 2, the key compound in the synthesis of (+/-)-lycopodine. PMID- 29711085 TI - "Self-Assembly" in Organolanthanide Chemistry: Formation of Rings and Clusters. AB - Highly symmetrical arrangements of the lanthanide metals Ln including the S6 symmetrical chair conformations of the [Sm(CN)]6 ring in 1 or an icosahedron as in 2 (see picture) are found in novel multinuclear cyclopentadienyl complexes. The formation of different structural motifs is directed by ionic bonding criteria such as the nature of the bridging heteroligands and the Cp/Ln ratio. [{(C5 Me5 )2 Sm(u-CN)}6 ] 1 [(C5 Me5 )12 Sm12 (u3 -Cl)24 ] 2. PMID- 29711086 TI - alpha-Silyl Ethers as Hydroxymethyl Anion Equivalents in Photoinduced Radical Electron Transfer Additions. AB - Nucleophilic alpha-hydroxymethyl radicals can be generated from alpha-silyl ethers by irradiation in the presence of 9,10-anthracenedicarbonitrile (ADC) and biphenyl (BP). Under these conditions the hydroxymethyl radicals are not oxidized further but add directly to electron-poor alkenes [Eq. (a); EWG=electron withdrawing group]. The radical adduct undergoes back electron transfer to form the carbanion, which is protonated. R=PhCH2 , tBuMe2 Si, Me; TMS=Me3 Si. PMID- 29711087 TI - Mesoporous Silica from Lyotropic Liquid Crystal Polymer Templates. AB - Amphiphilic block copolymer templates in sol-gel processes yield bicontinuous silicates with distorted hexagonal symmetry (see, for example, the transmission electron migrograph depicted on the right). The long Bragg distance of 8-13 nm combined with the high mechanical and thermal stability suggests some promising prospects for chemistry and materials science. PMID- 29711088 TI - Soft Lithography. AB - Elastomeric stamps and molds provide a great opportunity to eliminate some of the disadvantages of photolithograpy, which is currently the leading technology for fabricating small structures. In the case of "soft lithography" there is no need for complex laboratory facilities and high-energy radiation. Therefore, this process is simple, inexpensive, and accessible even to molecular chemists. The current state of development in this promising area of research is presented here. PMID- 29711089 TI - Synthesis of Microporous Transition Metal Oxide Molecular Sieves with Bifunctional Templating Molecules. AB - Systematic tuning of the micropore size in microporous transition metal oxide molecular sieves can be achieved by varying the length of the hydrocarbon chain of the diamine molecules used as templating agents. The large bifunctional molecules self-assemble with much smaller cross-sectional micellar dimensions than their monofunctional counterparts. The resulting family of porous materials offers exciting new flexibility in designing molecular sieves targeted for size selectivity and chemical functionality. PMID- 29711090 TI - Polariton-Induced Color Tuning of Thin Dye Layers. AB - A surprisingly broad variation of absorption wavelengths within almost the whole visible region was obtained in highly oriented, thin dye layers by variation of the molecule inclination relative to the layer plane (see sketch on the right). For the first time this phenomenon caused by polaritons was demonstrated for layers of a simple streptopolymethine dye. PMID- 29711091 TI - [MII (tcne)2 ]? x CH2 Cl2 (M=Mn, Fe, Co, Ni) Molecule-Based Magnets with Tc Values Above 100 K and Coercive Fields up to 6500 Oe. PMID- 29711092 TI - CIDNP Spectroscopic Observation of (S:.+ N) Radical Cations with a Two-Center Three-Electron Bond During the Photooxidation of Methionine. AB - Cyclic radical cations Met-(S...??+ N) of methionine could play an important role in processes such as long-range electron transfer across cell membranes and oxidative damage to cells. CIDNP spectroscopy (CIDNP = chemically induced dynamic nuclear polarization) furnishes direct structural proof and allows experimental investigation of the spin-density distribution in the two-center three-electron bonds. PMID- 29711093 TI - Bacterial Degradation of Quinoline and Derivatives-Pathways and Their Biocatalysts. AB - A series of interesting enzymes were discovered during investigations on the degradation of quinoline by microorganisms. These include the molybdenum containing hydroxylases that catalyze the transformation 1->2 and the unusual 2,4 dioxygenases that catalyze the reaction 3->4. The application of the hydroxylases may even be interesting in industry, because several quinoline derivatives are used as pharmaceuticals or agrochemicals. PMID- 29711094 TI - [Te6 N8 (TeCl4 )4 ]-Tellurium Nitride Stabilized by Tellurium Tetrachloride. AB - Shielding by four TeCl4 molecules is observed for the distorted rhombic dodecahedron core of the tellurium nitride Te6 N8 (see picture). With the characterization of this structure, the composition of the tellurium nitride discovered 100 years ago has now been determined. As a result of the shielding effect, the explosive character of the nitride is lost. PMID- 29711095 TI - Synthesis of Optically Active alpha-Amino- phosphinic Acids by Catalytic Asymmetric Hydrogenation in Organic Solvents and Aqueous Micellar Media. AB - Enantiomeric excesses of up to 99 % could be obtained in the synthesis of the biologically interesting acylated alpha-aminophosphinic acids 1 (R1 =Me, Ph; R2 =H, Me, Et; R3 =H, F, iPr) by asymmetric hydrogenation with rhodium complex catalysts and subsequent hydrolysis [Eq. (1)]. cod=1,5-cyclooctadiene. PMID- 29711096 TI - Metallosupramolecular Thin Polyelectrolyte Films. AB - Molecular recognition and electrostatic interaction of oppositely charged polyelectrolytes are combined in the fabrication of ultrathin metallosupramolecular multilayers [shown schematically in the picture, PEI=polyethyleneimine, PSS=poly(styrene sulfonate)]. The layers between the PSS layers are composed of an iron(II) bis(terpyridine) coordination polymer. PMID- 29711097 TI - Determination of End-to-End Distances in a Series of TEMPO Diradicals of up to 2.8 nm Length with a New Four-Pulse Double Electron Electron Resonance Experiment. AB - A four-pulse version of the pulsed double electron electron resonance (DEER) experiment has been applied to a series of TEMPO diradicals with well-defined interradical distances ranging from 1.4 to 2.8 nm (see picture). The new pulse sequence allows broad distributions of electron-electron distances to be measured without dead-time artifacts. PMID- 29711098 TI - Ca2 AuN: A Nitride Containing Infinite Zigzag Gold Chains. AB - The high-pressure reaction of solid Ca3 N2 with gold in a nitrogen atomsphere affords the ternary auride nitride Ca2 AuN. In the compound, gold forms infinite, planar zigzag chains with short Au-Au bond lengths of 2.857(1) A. The chains are sandwiched between corrugated layers of edge-sharing calcium nitride octahedra (Ca6 N; see picture). PMID- 29711099 TI - Nanomolar Inhibitors for Two Distinct Biological Target Families from a Single Synthetic Sequence: A Next Step in Combinatorial Library Design? AB - One common synthetic route creates small-molecule libraries directed toward two functionally distinct target families. The novel structural template 1 can independently display the necessary pharmacophore patterns for inhibition of members of two different biomolecular target families, the matrix metalloproteinases (MMPs) or the phosphodiesterases (PDEs). The incorporation of multiple target family directed design elements into combinatorial library design could help expedite the pharmaceutical lead discovery process. Z=OR' (PDE4), H (MMPs). PMID- 29711100 TI - Coupling of a Nucleoside with DNA by a Methyltransferase. AB - How to outwit a methyltransferase: Methyltransferases (Mtases) catalyze the transfer of the activated methyl group from the cofactor S-adenosyl-L-methionine (1) to acceptors R within a large variety of biomolecules. Through the use of the cofactor analogue 2 a whole nucleoside was coupled to DNA in a Mtase-catalyzed reaction. PMID- 29711101 TI - Sensitivity Enhancement in Transverse Relaxation Optimized NMR Spectroscopy. AB - Dramatically shortened transverse relaxation times in transverse relaxation optimized spectroscopy (TROSY) result from interference between dipole-dipole interactions and the anisotropy of the chemical shift. Thus NMR spectroscopy becomes a suitable method for studying large biomolecules, with optimal performance when 1-GHz spectrometers become available. By using new phase cycles and data-processing methods, the sensitivity of the TROSY experiment was increased by a factor of ?2, which is of considerable importance for applications in high-field NMR studies on large proteins. PMID- 29711102 TI - PNA: Synthetic Polyamide Nucleic Acids with Unusual Binding Properties. AB - The astonishing discovery that peptide nucleic acids (PNAs, B=nucleobase), in spite of their drastic structural difference to natural DNA, are better nucleic acid mimetics than many other oligonucleotides has resulted in an explosion of research into this class of compounds. The synthesis, physical properties, and biological interactions of PNAs as well as their chimeras with DNA and RNA are summarized here. PMID- 29711103 TI - Directed Positioning of Organometallic Fragments Inside a Calix[4]arene Cavity. AB - A hemispherical diphosphane based on a calixarene allows encapsulation of reactive M-R fragments (M=transition metal; R=H, alkyl, CO) inside the calixarene cavity. The ruthenium complex 1 has an unprecedented sandwich structure that contains a CO ligand confined between two phosphane-substituted phenyl rings. The separation between the CO segment and the two aromatic rings is only 2.75 A! PMID- 29711104 TI - Expanding the Potential of DNA for Binding and Catalysis: Highly Functionalized dUTP Derivatives That Are Substrates for Thermostable DNA Polymerases. AB - The discovery of a simple structural motif allows for the enzymatic synthesis by polymerase chain reactions (PCR) of modified DNA (see reaction scheme) bearing side chains similar or even identical to those of several amino acids. Libraries of DNA functionalized with both cationic and anionic groups may now be readily prepared. R=I, HgCl; X=functional group. PMID- 29711105 TI - Metalated 2-Alkenylsulfoximides in Asymmetric Synthesis: Diastereoselective Preparation of Highly Substituted Pyrrolidine Derivatives. AB - Thanks to a productive interaction between reagent and substrate control, 2 alkenylsulfoximides 1 react to provide highly substituted pyrrolidine derivatives 2 enantiomerically pure and with defined absolute configuration at the newly formed stereogenic centers. Tol=tolyl, BOC=tert-butoxycarbonyl. PMID- 29711106 TI - Explosions as a Synthetic Tool? Cycloalkynes as Precursors to Fullerenes, Buckytubes, and Buckyonions. AB - A provacative question is asked by the title. Explosions will probably not become a general synthetic method, but strained dehydrobenzoannulenes decompose explosively upon heating to give, inter alia, structured, fullerenoid carbon particles. The spectacular thermochemical behavior of these cycloalkynes has fueled hopes that acetylenic cyclophanes such as 1 can be prepared and brought to coalesce to spherical forms of carbon like the fullerenes. Promising progress in this area has recently been made and is highlighted in this contribution. PMID- 29711107 TI - Unusual Disordered Crystal Structure of a Racemate Exhibiting a Novel Enantiomeric Resolution: Preferential Enrichment. AB - Simple recrystallization of racemic (+/-)-NC leads to preferential enrichment of one enantiomer in the mother liquor, which allows the efficient resolution of the two enantiomers. In the unique disordered crystal structure of the racemate, the two enantiomers form centrosymmetric dimers as the major component. PMID- 29711108 TI - Diiodotetrasupersilylcyclotetrasilene (tBu3 Si)4 Si4 I2 -A Molecule Containing an Unsaturated Si4 Ring. AB - The red-orange tetrasilacyclobutene 1 (R*=SitBu3 ) is formed quantitatively by the reaction of tetrasilatetrahedrane 2 and iodine. Surprisingly, water and methanol do not react with 1 with addition to the Si-Si double bond, but instead with replacement of the silicon-bound iodine atoms with oxygen or the methoxy group, respectively. The substitutions possibly proceed by dissociative activation via intermediate 3. PMID- 29711109 TI - Langmuir-Blodgett Films of Single-Molecule Nanomagnets. AB - Magnetic Langmuir-Blodgett films containing well-organized monolayers of single molecule magnets are reported. The single-molecule magnets in question are high spin molecular clusters of the type [Mn12 O12 (carboxylate)16 ]. The structure of such multilayered inorganic-organic composites is depicted schematically in the figure. PMID- 29711110 TI - Transmembrane Transport of Adenosine 5'-Triphosphate Using a Lipophilic Cholesteryl Derivative. AB - The uptake of ATP in liposomes was achieved by using the lipophilic derivative cholesteryloxycarbonyl-ATP (1). Its hydrolysis leading to the release of ATP inside the vesicules (see scheme) was observed with the help of a pH gradient and monitored by 31 P NMR spectroscopy. This is the first successful transfer of a nucleoside 5'-triphosphate across a membrane. PMID- 29711111 TI - Efficient Sialyltransferase Inhibitors Based on Transition-State Analogues of the Sialyl Donor. AB - A 200- to 1000-fold higher affinity for sialyltransferase is shown by compounds 1 and 2 relative to the natural substrate. These inhibitors, which are derived from the transition state of SN 1-type sialyltransfer, contain a flat ring that is attached through a carbon atom with a phosphonate and a cytidine monophosphate group. PMID- 29711112 TI - A New Radical Allylation Reaction of Dithiocarbonates. AB - A radical allylation reaction without tin: The xanthate group in aliphatic xanthates can be replaced by an allyl unit [Eq. (a)]. This radical chain reaction is propagated by ethyl radicals generated by extrusion of sulfur dioxide from ethanesulfonyl radicals, which are themselves derived from allyl ethyl sulfone. PMID- 29711113 TI - Synthesis and Properties of Lanthanum- Pyrene Complexes-Structure of [(Cp*La)3 (MU-Cl)3 (thf)(MU-eta2 :eta6 :eta6 -C16 H10 )], the First Complex with a Pyrene Trianion. AB - Different bonding modes are characteristic for the lanthanum centers of the title compound, a trinuclear lanthanum-pyrene complex in which an arene trianion is present for the first time (see picture for the structure). Thus, La1 and La3 reside in a tetrahedral environment, the La2 center in a distorted trigonal bipyramidal one. PMID- 29711114 TI - Proof of Potassium Ions by Luminescence Signaling Based on Weak Gold-Gold Interactions in Dinuclear Gold(I) Complexes. AB - Two versatile luminescence ion probes for potassium ions have been designed based on the "switching on and off" of the gold-gold interaction. Addition of potassium ions to the gold(I) complexes [Au2 (R2 PCH2 PR2 )(S-benzo[15]crown-5)2 ] (see the picture; R=Ph, cyclohexyl; M+ =K+ ) give rise to an intense red luminescence. PMID- 29711115 TI - Enantioselective Hydrogenation of Olefins with Iridium-Phosphanodihydrooxazole Catalysts. AB - High turnover numbers and up to 98% ee were obtained in the catalytic hydrogenation of unfunctionalized aryl-substituted olefins with iridium phosphanyldihydrooxazole complexes 1 (see reaction scheme). The anion of the complex-for example, hexafluorophosphate or tetrakis[3,5 bis(trifluoromethyl)phenyl]borate (BARF- )-has a remarkable effect on the reactivity and longevity of the catalyst. PMID- 29711116 TI - Strategies for the Dynamic Integration of Combinatorial Synthesis and Screening. AB - Selection and amplification of only those components with the desired property the integration of combinatorial chemistry and screening makes this possible. If the components of a combinatorial library are in a reversible equilibrium, the desired components can be selected and amplified by shifting the equilibrium of the mixture (see schematic representation). PMID- 29711117 TI - Polyvalent Interactions in Biological Systems: Implications for Design and Use of Multivalent Ligands and Inhibitors. AB - Found throughout biology, polyvalent interactions are characterized by the simultaneous binding of multiple ligands on one biological entity to multiple receptors on another (top part of the illustration) and have a number of characteristics that monovalent interactions do not (bottom). In particular, polyvalent interactions can be collectively much stronger than corresponding monovalent interactions, and they can provide the basis for mechanisms of both agonizing and antagonizing biological interactions that are fundamentally different from those available in monovalent systems. PMID- 29711118 TI - Cyanoisocyanoacetylene, N=C-C=C-N=C. AB - Vacuum pyrolysis of the precursor complex [(CO)5 Cr(CN-CCl=CF-CN)] resulted in the isolation and structure elucidation by molecular spectroscopy of isomer 1. According to ab initio calculations 1 is 109 kJ mol-1 less stable than NC-C=C-CN, which has been known for some time. An accurate equilibrium structure for 1 has been determined with mixed experimental and theoretical methods. PMID- 29711119 TI - Efficient Suzuki-Type Cross-Coupling of Enantiomerically Pure Cyclopropylboronic Acids. AB - Optically active cyclopropanes (e.g. 1) can be prepared by the use of tartaric acid derivatives as chiral auxiliaries in the palladium-catalyzed cross-coupling of optically active cyclopropylboronic acids with electrophiles. The absolute configuration of the chiral carbon atom is retained, and the reaction proceeds with good yields and enantiomeric excesses. R=H, p-Ph, o-CO2 CH3 , p-CO2 CH3 , p NO2 , o-OCH3 , m-OCH3 . PMID- 29711120 TI - The First Anti-Markovnikov Hydration of Terminal Alkynes: Formation of Aldehydes Catalyzed by a Ruthenium(II)/Phosphane Mixture. AB - With the right auxiliary phosphane ligands-for example, pentafluorophenyldiphenylphosphane or the sodium salt of 3,3',3" phosphinidynetris(benzenesulfonic acid)-the ruthenium(II)-catalyzed hydration of terminal alkynes to aldehydes proceeds by the previously unknown anti-Markovnikov addition of water [Eq. (a)]. Complexes of the type [RuCl2 (PR2 R2' R")x ] (R=alkyl, Ph) are discussed as catalytically active species. PMID- 29711121 TI - A New Motif for the Self-Assembly of [2]Pseudorotaxanes; 1,2 Bis(pyridinium)ethane Axles and [24]Crown-8 Ether Wheels. AB - Multiple intramolecular interactions help to stabilize the novel [2]pseudorotaxanes formed from 1,2-bis(pyridinium)ethane dications (which act as axles) and 24-membered crown ethers (which act as wheels; see structure). This is the first successful sythesis of [2]pseudorotaxanes with [24]crown-8 as the macrocycle. PMID- 29711122 TI - New Protein Mimetics: The Zinc Finger Motif as a Locked-In Tertiary Fold. AB - The principle of a molecular kit is used for the covalent assembly of secondary structure forming peptide blocks to predetermined packing topologies. The resulting locked-in folds (LIFs; depicted schematically) are readily accessible and bypass the intriguing folding problem of linear peptide chains. This strategy allows, for example, mimicking of the essential structural and functional features of zinc finger proteins. PMID- 29711123 TI - [Bi2 (O2 CCF3 )4 ]?C6 Me6 -Arene Adduct of a Reduced Main Group Element Carboxylate with Paddle Wheel Structure. AB - The first main group dimetal complex with tetragonal-prismatic coordination is [Bi2 (O2 CCF3 )4 ] (structure depicted), which forms a component of a linear one dimensional coordination copolymer with hexamethylbenzene molecules. The "paddle wheel" motif well-known from chromium(II) acetate and hundreds of other transition metal complexes is thus introduced into the coordination chemistry of main group elements. PMID- 29711124 TI - On the Origin of the Low-Spin Character of Cytochrome P450cam in the Resting State-Investigations of Enzyme Models with Pulse EPR and ENDOR Spectroscopy. AB - The P450 enzyme model 1 is a high-spin system. EPR and ENDOR spectra reveal the coordination of water to the FeIII center. This is the first experimental proof that coordination of water is not the single determining factor in the stabilization of the low-spin character of the cytochrome P450 resting state. PMID- 29711125 TI - Crystallization of Calcite Spherules around Designer Nuclei. AB - Gold colloids modified with p-sulfanylphenol self-assembled monolayers provide novel nanoscopic seeds for the nucleation of calcium and strontium carbonate from aqueous solution. The morphologies of the crystalline precipitates are very different from what can normally be obtained through templated crystallization on flat surfaces. PMID- 29711126 TI - Gas Separation with Polymer Membranes. AB - Gas-selective polymer membranes have long been used in industrial applications. Studies of polymers with well-defined flexible phenyl ether segments such as 1 should contribute to the understanding of the selection mechanism and thus ultimately lead to the synthesis of optimized membrane materials. Various different bridging groups X were used in the studies. PMID- 29711127 TI - Studies in the Total Synthesis of Himastatin: A Revision of the Stereochemical Assignment. AB - A stereoisomer of the natural product and not himastatin, an unusual dimeric depsipeptide with promising antibiotic and antitumor properties, was obtained from pyrroloindoline anti-cis-1. This result led to a revision of the proposed stereostructure. The new stereostructure was confirmed by the total synthesis, which involves stereoselective access to the pyrroloindoline syn-cis-1 and the 5 hydroxypiperazic acid subunit and features a Stille coupling for the formation of the central carbon-carbon bond. PMID- 29711128 TI - Solvent-Free Organic Syntheses. AB - Ecological points of view must nowadays be taken into consideration in the development of new syntheses and apportioned due importance in assessing the viability of a new synthesis. A crucial factor here is the need to restrict the use of ecologically harmful organic solvents. Examples are presented which show that solvent-free reactions are not only of interest from an environmental viewpoint, but also offer considerable advantages in terms of yield, selectivity, and simplicity of the reaction procedures. PMID- 29711129 TI - Catalytic Copolymerization of Ethene and Carbon Monoxide on Nickel Complexes. AB - Can palladium be replaced by nickel? For the industrial copolymerization of carbon monoxide and ethene a palladium catalyst is used which cannot be recovered a cheaper procedure would be desirable. The presented complex 1 is the first structurally characterized nickel compound which does not polymerize ethene but a mixture from carbon monoxide and ethene unter mild conditions to give a perfectly alternating polyketone. PMID- 29711130 TI - New Chiral Ligands with Nonstereogenic Chirotopic Centers for Asymmetric Synthesis. AB - Pseudo-C2 -symmetrical ligands have been prepared efficiently: The attachment of the chiral alkyl group to the heteroatom (P or N) through a nonstereogenic, chirotopic carbon center facilitates their synthesis as the configuration at this carbon atom no longer needs to be controlled. Two such ligands were combined, for example, in the base 1, which is especially useful for asymmetric deprotonation of prochiral ketones [Eq. (a)]. PMID- 29711131 TI - Synthesis, Electrochemistry, and Spectroscopy of Blue Platinum(II) Polyynes and Diynes. AB - The smallest band gap observed so far (1.77 eV) for an organometallic polymer is exhibited by the blue, rigid-rod polymer 2, which is prepared by the reaction of trans-[PtCl2 (PnBu3 )2 ] with one equivalent of 1. PMID- 29711132 TI - A Novel Beryllium Thiolate Resulting from N-Si Bond Cleavage: Liberation of Ammonia in the Reaction of Be[N(SiMe3 )2 ]2 with HSPh. AB - A side reaction leads to the product. In the synthesis of [{Be(SPh)2 (py)(NH3 )}2 {[18]crown-6}] (1, py=pyridine) from [Be{N(SiMe3 )2 }2 ] and HSPh, the coordinated ammonia molecules (see the structure of 1 in the picture) are formed in a competing reaction between liberated hexamethyldisilazane and the thiol. PMID- 29711133 TI - Enantioselective Allylic Substitution of Cyclic Substrates by Catalysis with Palladium Complexes of P,N-Chelate Ligands with a Cymantrene Unit. AB - Mechanistic considerations made a decisive contribution to the development of new chiral P,N ligands L* containing tricarbonylcyclopentadienylmanganese (cymantrene). These ligands induce very high enantioselectivities (>99:1) in allylic substitutions of cyclic substrates 1 with formation of 2 (2-Bp=2 biphenylyl). PMID- 29711134 TI - Cooperative Hydrogen Bonding and Enzyme Catalysis. AB - An important contribution to enzyme catalysis may be made by cooperative effects which are induced by the interactions of a negatively charged ligand L with peptide hydrogen bond networks-through stabilization of charge formation along the reaction pathway. This has been found from density functional calculations on model systems for peptide hydrogen bond networks (an example is shown in the picture). PMID- 29711135 TI - Metalloporphyrin Dendrimers with Folding Arms. AB - Rigid and flexible linkers are combined in the new dendrimer shown schematically in the picture, which contains nine metalloporphyrin units (Porph). The construction is such that the four "arms" of the dendrimer can fold in a cooperative and predetermined manner in response to added 1,4 diazabicyclo[2.2.2]octane (DABCO). PMID- 29711136 TI - "Gelander" Helical Molecules. PMID- 29711137 TI - Pyrrole Denitrogenation and Fragmentation of Tetramethylethylenediamine Promoted by a NbII Cluster. AB - A nitrogen center was abstracted from a pyrrolyl ring to form the dinuclear nitrido- and dienyl-bridged complex 1 during the reaction of [{(tmeda)NbII Cl}2 (MU-Cl)3 Li(tmeda)] with the lithium salt of 2,5-dimethylpyrrole (tmeda=N,N,N',N' tetramethylethylenediamine). A second product from this reaction is the amido carbene-hydride niobium complex 2, which likewise forms under C-N bond cleavage. PMID- 29711138 TI - [Au(C6 F5 )3 (PPh2 H)]: A Precursor for the Synthesis of Gold(III) Phosphide Complexes. AB - The covalent radius of AuI is about 0.07 A smaller than that of AgI . This was determined from the crystal structures of the isostructural complexes [N(PPh3 )][{Au(C6 F5 )3 (MU-PPh2 )}2 M] (M=Au (structure shown in the picture), Ag). These mixed AuIII -M phosphides were synthesized from [Au(C6 F5 )3 (PPh2 H)], the first gold complex to contain a secondary phosphane. PMID- 29711139 TI - Amyloid Aggregates, Presenilins, and Alzheimer's Disease. AB - The cooperative action of three proteases is required to process the APP protein (695-770 amino acids) into small beta-amyloid peptides (Abeta, 40-42 amino acids). Abeta aggregates are found in the senile plaques of patients with Alzheimer's disease and play a major role in the onset of this disorder. The functional analysis of several factors that contribute to the production and aggregation of Abeta has enhanced our knowledge of the mechanism of amyloid formation and increased the potential for effective therapeutic treatment. PMID- 29711140 TI - Unprecedented Encapsulation of Carbonyl Guest with Designer Lewis Acid Receptor. AB - A reaction chamber is formed by a cage compound in which a dicarbonyl guest molecule is encapsulated by two bowl-shaped aluminum tris(2,6-diphenylphenoxide) molecules through Lewis acid-base interactions (structure of complex with 1,4 dimethylpiperazine-2,5-dione depicted). The carbonyl compound held inside the molecular capsule is effectively protected against the approach of external nucleophiles. On the other hand, the chamber is large enough to allow Diels-Alder cycloadditions to take place under mild conditions and with high selectivity. PMID- 29711141 TI - Nonlinear Effects in Asymmetric Synthesis and Stereoselective Reactions: Ten Years of Investigation. AB - Who would have thought before 1986 that an enantiomerically impure catalyst could give a product in an asymmetric synthesis with an enantiomeric excess higher than that of the catalyst? Until then it was assumed that the ee value of the product (eeprod ) from an asymmetric synthesis was linearly correlated to the ee value of the chiral auxiliary (eeaux )-in fact a large deviation is possible (see diagram). These nonlinear effects are not only of academic interest since they have a variety of practical uses, which are highlighted in this review. PMID- 29711142 TI - Total Synthesis of Himastatin: Confirmation of the Revised Stereostructure. AB - A stereoisomer of the natural product and not himastatin, an unusual dimeric depsipeptide with promising antibiotic and antitumor properties, was obtained from pyrroloindoline anti-cis-1. This result led to a revision of the proposed stereostructure. The new stereostructure was confirmed by the total synthesis, which involves stereoselective access to the pyrroloindoline syn-cis-1 and the 5 hydroxypiperazic acid subunit and features a Stille coupling for the formation of the central carbon-carbon bond. PMID- 29711143 TI - How Does the Intrinsic Barrier of Intermolecular Proton Transfer Depend on Molecular Parameters? AB - The question in the title is of fundamental importance, because the intrinsic barrier DeltaGint? is the key parameter connecting thermodynamics and kinetics. With a valence bond configuration mixing model for proton self-exchange (see picture), it is shown that DeltaGint? is a linear function of Iv -E(sigmaNH* ), where Iv is the ionization potential of the base and E(sigmaNH* ) the energy of the antibonding orbital of the N-H bond in the conjugated acid. With para substituted N,N'-dimethylanilines, this manifests itself by a linear relationship between DeltaGint? and the Hammett parameter sigma+ . PMID- 29711144 TI - Windmill-Like Porphyrin Arrays as Potent Light-Harvesting Antenna Complexes. AB - Up to 14 porphyrin rings are present in the title compounds 1, which are readily available with high regioselectivity from linear nickel-zinc porphyrins. Upon irradiation with light a rapid energy transfer from the peripheral porphyrin rings to the diporphyrin core takes place. PMID- 29711145 TI - Modified, Amorphous Titania-A Hybrid Semiconductor for Detoxification and Current Generation by Visible Light. AB - Amorphous, microporous TiO2 hybrid semiconductors modified with transition metals induce generation of a photocurrent and photocatalytic degradation of the water contaminant 4-chlorophenol through photoinduced charge separation (the postulated mechanism is shown in the picture, Ar=4-ClC6 H4 ). In contrast to the previously known crystalline titania photocatalysts, which are active only when excited with UV light, the amorphous semiconductors modified with platinum, rhodium, and gold chloride enable both processes also with visible light. PMID- 29711146 TI - Valence Tautomerism in a o-Benzoquinone Adduct of a Tetraazamacrocycle Complex of Manganese. AB - Two different charge distributions of the complex cation [MnIII (cth)(diox)]+ (cth=a tetraazamacrocycle, diox=3,5-di-tert-butyl-o-benzoquinone; structure shown in the picture) can be isolated by varying the counteranion: [MnIII (cth)(cat)]BPh4 and [MnII (cth)(sq)]ClO4 (cat and sq denote the catecholato and semiquinonato forms of the ligand). The complex undergoes noncooperative entropy driven valence tautomeric transitions. PMID- 29711147 TI - A New Strategy for the Destabilization of Double-Stranded Nucleic Acids by Phenylalkylamine Derivatives. AB - Drastic reduction in the melting points indicates considerable destabilization of double-stranded (ds) nucleic acids by stabilization of unfolded polymer parts with phenylalkylamine derivatives. These ligands cannot intercalate into ds duplex forms, but can stack with unfolded parts if the spacers separating the phenyl rings have the appropriate length. PMID- 29711148 TI - Supramolecular Assembly of Heterogeneous Multiporphyrin Arrays-Structures of [{ZnII (tpp)}2 (tpyp)] and the Coordination Polymer [{[MnIII (tpp)]2 (tpyp)(ClO4 )2 }infinity ]. AB - Channels make up 46% of the crystal volume: A two-dimensional coordination polymer of exceptional structural regularity (see schematic drawing; tpp=tetraphenylporphyrin, tpyp=tetrapyridylporphyrin) was assembled from [MnIII (tpp)]?ClO4 and tpyp. The crystal packing of these polymers yields an open bulk structure with networks of perpendicular channels filled with nitrobenzene solvent molecules. Only oligomeric entities are formed by the reaction of [ZnII (tpp)] with tpyp. PMID- 29711149 TI - First Synthetic Carbohydrates with the Full Anticoagulant Properties of Heparin. AB - A single disaccharide building block is required to obtain synthetic carbohydrates that reproduce the anticoagulant activity of heparin and inhibit thrombin (n>6) and/or factor Xa (n>=2; see reaction scheme). Thus, there is evidence that heparin fragments with at least 15 saccharide units are required for thrombin inhibition. Lev=levulinoyl. PMID- 29711150 TI - Ti2 Nb6 Cl14 O4 : A Unique 2D-1D Network Combination in Niobium Cluster Chemistry. AB - Layers of niobium clusters that are linked to each other through zigzag chains of edge-sharing [TiCl4 O2 ] ocatahedra are the central structural features of the title compound. Bridging of the chains by [(Nb6 Cl8i O4i )Cl6a ]6- clusters results in the formation of empty tunnels (a section of the structure is shown on the right). PMID- 29711151 TI - alpha-Heteroatom-Substituted 1-Alkenyllithium Reagents: Carbanions and Carbenoids for C-C Bond Formation. AB - Carbenoid, electrophilic and carbanionic, nucleophilic character is shown by compounds 1, which bear a lithium atom and an electronegative element X as leaving group at the vinyl carbon center. Now that structural investigations have contributed significantly to their understanding, these ambiphilic, thermally unstable compounds are increasingly being used as reagents for synthetic purposes. PMID- 29711152 TI - Actuating Cycloaromatization of a Bicyclo[7.3.1]enediyne by Annelation: An Example of Inverse Dependence on Bridge Atom Hybridization. AB - Although the acetylenic carbon atoms in 2 are closer together than those in 1, only the latter undergoes Bergman cyclization. In contrast, in analogous enediynes without an annelated cyclohexane ring a change in the hybridization of the bridging carbon atom from sp2 to sp3 leads to a dramatic increase in the cyclization rate. PMID- 29711153 TI - The Asymmetric Horner-Wadsworth-Emmons Reaction Mediated by An External Chiral Ligand. AB - The astonishingly simple chiral ligand 1 was used in the first asymmetric variant of the Horner-Wadsworth-Emmons reaction. The products of olefination of 4 substituted cyclohexanones with lithium phosphanates arise via the resulting hydroxyphosphonates, which are present in high enantiomeric excess (see scheme below). R=aryl, vinyl; R'=Me, tBu, Ph. PMID- 29711154 TI - A New Catalyst System for the Heck Reaction of Unreactive Aryl Halides. AB - A simple solution to the age-old problem of the Heck reaction of cheap but unreactive chloro- and bromoarenes [for example, reaction (1)] has been found in the catalyst [Pd(CH3 CN)2 Cl2 ]?6 Ph4 PCl in the presence of N,N-dimethylglycine as additive. The reaction then proceeds with exceptionally high efficiency. PMID- 29711155 TI - S4 NR (R=Methyl, n-Octyl) as Novel Chelating Ligands in Titanocene Complexes and First Synthesis of Small Sulfurimide Heterocycles Sn NR (n=5, 6). AB - Not the expected insertion into a S-S bond but rather substitution of one NR unit takes place in the reaction of [Cp2 Ti(CO)2 ] with cyclic tetrasulfurdiimides 1,4 S4 (NR)2 . The product obtained contains the novel ligand S4 NR and serves as precursor in the synthesis of small SN heterocycles not accessible before (see below). PMID- 29711156 TI - Direct Measurement of Dihedral Angles with High-Resolution NMR Spectroscopy. AB - Help in determining biomolecular structure by NMR spectroscopy is found in a new method recently proposed by Reif, Hennig, and Griesinger, which enables the direct measurement of angles between bond vectors (see picture; X, Y=13 C, 15 N). This work may be another milestone in the progress of NMR spectroscopy toward simpler and more generally applicable structure determination of biomolecules. PMID- 29711157 TI - Matrix Isolation and Characterization of a Reactive Intermediate in Olefin Oxidation with Chromyl Chloride. PMID- 29711158 TI - A Self-Replicating Peptide under Ionic Control. AB - The chemical coupling of two peptide fragments to give the peptide K1 K2 (shown in the helical wheel diagram on the right) is autocatalytic at high NaClO4 concentrations (1 M). Under these conditions K1 K2 assumes a coiled-coil conformation, which can function as a template for the coupling. Autocatalysis is not observed under conditions that prevent formation of the coiled-coil conformation. PMID- 29711159 TI - N-Functionalized 1-Alkynylamides: New Building Blocks for Transition Metal Mediated Inter- and Intramolecular [2+2+1] Cycloadditions. AB - A conceptually new, stereoselective approach to compounds such as 1 and 2 is expected from the so far unknown class of N-functionalized 1-alkynylamides. Building blocks of the type I and II can be applied to inter- and intramolecular, regio- and stereoselective [Co2 (CO)8 ]-mediated [2+2+1] cycloadditions. PMID- 29711160 TI - Functionalized Cross-Linked Copolymers: A "C2 -Symmetric" Solid-Phase Catalyst for Enantioselective Reactions. AB - Similar enantiomeric excesses as for analogous monomeric sulfonamides are provided by the chiral resin 1 (connections to the polymer are shown as circles) when it is used as catalyst for the reductive alkylation of aromatic aldehydes and for the cyclopropanation of cinnamyl alcohol. PMID- 29711161 TI - ortho-Diphenylphosphanylbenzoyl-Directed Cuprate Addition to Acyclic Enoates. AB - Killing two birds with one stone. The ortho-diphenylphosphanylbenzoyl group (o DPPB) acts as a catalyst-directing group in stereoselective Rh-catalyzed hydroformylation and as a reagent-directing group in stereoselective 1,4-addition of Gilman cuprates to acyclic enoates (see picture on the right; the o-DPPB group is represented by a sphere, D=donor). These two reactions could be efficiently used as part of a synthetic sequence. PMID- 29711162 TI - SH i Reactions at Silicon as Unimolecular Chain Transfer Steps in the Formation of Cyclic Alkoxysilanes. AB - A new radical approach to cyclic ethers 2 is offered by the intramolecular homolytic substitution (SH i) reaction at a silicon center. High diastereoselectivities can be obtained in this efficient unimolecular chain transfer reaction. Less suitable are radicals such as 1 in which an R3 Si group replaces the SnMe3 group. PMID- 29711163 TI - Activation of P4 and P2 by Transition Metal Complexes at Room Temperature. AB - The first complex with P2 as an eight-electron donor diphosphinidene ligand is 1, which forms at room temperature from [Cp*(OC)2 Re]2 and P4 (Cp*=C5 Me5 ). The by product of this reaction, which has a Re2 P2 butterfly structure, reacts with [W(CO)5 (thf)] at room temperature to give two multinuclear complexes-one with a ReWP2 tetrahedrane framework and 2, whose six atoms Re2 P2 W2 form a plane and in which the P2 ligand of the butterfly complex is converted into two u-P ligands. PMID- 29711164 TI - Tetrachloro-p-(o,p)-o-tribenzene: A Building Block for Diels-Alder Oligomers of Benzene and for a Laticyclic Conjugated Hexaene. AB - Intermolecular cycloaddition of the bifunctional tetrachlorotribenzene 1 results in higher Diels-Alder oligomers of benzene (2), of which the linear and an angular hexamer (n=1) were characterized. The oligomers decompose above 110 degrees C through stepwise extrusion of benzene and tetrachlorobenzene. PMID- 29711165 TI - A Novel Type of Liquid Crystals Based on Axially Fluorinated Cyclohexane Units. AB - Decidedly higher clearing temperatures and often also broader mesophases are exhibited by axially fluorinated cyclohexane derivatives 1 and 2 relative to their nonfluorinated analogues. A convenient method for the multigram synthesis of 1 and 2, which represent a promising new type of liquid crystals with positive or negative dielectric anisotropy, is presented. PMID- 29711166 TI - Si6 , Si14 , and Si22 Rings in Iodide Silicides of Rare Earth Metals. AB - A new class of compounds containing layers of Sin Zintl polyanions is represented by the silicides MISi (M=La, Ce, Pr), La4 I3 Si4 , and La5 I3 Si5 (a section of the structure is shown below). Their structures contain Si6 and the previously unknown Si14 and Si22 rings, which are condensed into layers. The Si atoms are coordinated in a trigonal-prismatic fashion by M atoms to give M-(SiSi)-M slabs that are bonded to one another through I atoms. An extensive chemistry of halide silicides similar to that of the carbide halides of the rare earth metals can be expected. PMID- 29711167 TI - Iterative Nucleophilic and Electrophilic Additions to Coordinated Cyclooctatetraene: An Efficient Route to cis-5,7-Disubstituted 1,3 Cyclooctadienes. AB - A great synthetic potential is shown by cis-5,7-disubstituted 1,3-cyclooctadienes 1 with regard to terpenoid cyclo-C8 compounds. Starting from the complexed cyclooctatetraene ligand, such compounds are readily available in good yields with the following procedure: nucleophilic addition, protonation, second nucleophilic addition, second protonation, and cleavage. PMID- 29711168 TI - Tris(tetramethylethylenediamine-sodium)-9,9-bianthryl-The Salt of a pi Hydrocarbon Radical Trianion with Three Na+ -Cpi Contacts to One Molecular Half. AB - Quite unexpectedly, all three electrons are taken up by the same anthryl moiety when 9,9'-bianthryl is reduced with an excess of sodium metal. Thanks to the "right" ligand/solvent mixture the first radical trianion salt (depicted on the right) could be isolated. It is a contact-ion quadruple of bianthryl in which all three Na+ counterions coordinate to the same half of the hydrocarbon molecule. PMID- 29711169 TI - Oxygenative Cleavage of Chlorocatechols with Molecular Oxygen Catalyzed by Non Heme Iron(III) Complexes and Its Relevance to Chlorocatechol Dioxygenases. AB - The degradation of halogenated arenes, which are considered as hazardous compounds from a toxicological and environmental point of view, can be effected by non-heme iron enzymes such as chlorocatechol dioxygenases. In principle, this process of biological oxygenation mimics the reaction of the iron complex shown below [Eq. (a); Py=2-pyridyl]. PMID- 29711170 TI - Methylalumoxane MCM-41 as Support in the Co-Oligomerization of Ethene and Propene with [{C2 H4 (1-indenyl)2 }Zr(CH3 )2 ]. AB - Superior to the homogeneous catalyst or physisorbed catalyst system is a system with the ansa-metallocene catalyst [{C2 H4 (1-ind)2 }Zr(CH3 )] on a support formed by covalently anchoring methylalumoxane (MAO) on the internal pore walls of MCM-41. This system is a highly active and shape-selective mesoporous host in the co-oligomerization [shown schematically in Equation (a)] of ethene and propene with ansa-metallocenes. TMA=trimethylaluminum, ind=indenyl. PMID- 29711171 TI - Formaldehyde in Super Acids: A Succession of Products from Carbenium through Oxonium Ion to Hydroxymethyl(methylidene)oxonium Salts. AB - An oxonium ion with hydroxymethyl and methylidene substituents is found in the salts 1-MF6 (M=As, Sb), which can be isolated from solutions of formaldehyde in superacids HF/MF5 . Their formation was at first surprising, since NMR spectroscopy indicates that protonated monofluoromethanol is present in solution. PMID- 29711172 TI - The Weak-Link Approach to the Synthesis of Inorganic Macrocycles. AB - Homobimetallic macrocycles are prepared from flexible ligands in high yield by means of a new and general synthetic strategy called the "weak-link approach" [Eq. (a)]. Small aromatic molecules can be aligned inside the cage based on their interactions with the two Rh centers of the macrocycle. PMID- 29711173 TI - Bioconjugation of Peptides by Palladium-Catalyzed C-C Cross-Coupling in Water. AB - The abiotic, regioselective conjugation of peptides and proteins with non proteinogenic structural elements requires mild and fast coupling reactions which are compatible with an aqueous reaction medium and orthogonal in their reactivity with all other functional groups in the protein. Sonogashira coupling with a palladium-guanidinophosphane catalyst that is prepared in situ (see reaction on the right) complies with these demands. PMID- 29711174 TI - The Catalytic Enantioselective Construction of Molecules with Quaternary Carbon Stereocenters. AB - A long-standing challenge to synthesis can now be met through the use of new and powerful catalytic asymmetric reactions for the assembly of complex chiral molecules with quaternary stereocenters from achiral building blocks. The reaction sequence shown below is just one example discussed in this review. PMID- 29711175 TI - Electron Transfer through DNA in the Course of Radical-Induced Strand Cleavage. AB - No benefit from base stacking is observed for rates of electron transfer in DNA. This conclusion was drawn from experiments with a new DNA assay in which a radical cationic site, generated by strand cleavage, can be reduced by the guanine bases in the same DNA (the electron transfer is indicated by arrows in the diagram). The distance dependence of this electron transfer step is determined by the chemical yield of the reduction product. PMID- 29711176 TI - Low-Temperature Photochemistry of Previtamin D: A Hula-Twist Isomerization of a Triene. AB - What is the standard course of the cis-trans isomerization of nonpolar polyenes? Many results support a pathway in which only a central CH group rotates out of the plane, while the remaining parts of the molecule reorient within the plane ("hula-twist" mechanism). The intermediate structure through which the molecule passes corresponds to the geometry predicted for the conical intersection of the S1 and S0 potential energy surfaces (see picture). PMID- 29711177 TI - Electroluminescent Conjugated Polymers-Seeing Polymers in a New Light. AB - A new exciting interdisciplinary research field has evolved following the discovery that conjugated polymers can emit light when put into light-emitting diodes. A myriad of light-emitting polymers (examples of which are shown below) shining in various colors have been developed through chemical intuition and structural design. PMID- 29711178 TI - Dithioacetals as an Entry to Titanium-Alkylidene Chemistry: A New and Efficient Carbonyl Olefination. AB - Wittig, Horner-Wadsworth-Emmons, Julia-Lythgoe, Tebbe, Grubbs, and Petasis-when it comes to carbonyl olefinations, these names are familiar to all chemistry students. In the future, the name Takeda will probably have to be added to this list. His recent work on the formation of titanium-alkylidene species from dithioacetals has provided organic chemists with a remarkable method for carbonyl olefination that is generally applicable under neutral to Lewis acidic conditions. PMID- 29711179 TI - Regio- and Enantioselective Prenyl Anion Transfer: Application to the Total Synthesis of (-)-Rosiridol. AB - At elevated temperature (refluxing THF) prenyl anion adds regio- and enantioselectively to aldehyde 1 when a chiral, borneol-derived ligand is present. This reaction is the key stepin the first total synthesis of the monoterpene (-)-rosiridol (retrosynthesis is shown on the right). In addition, the absolute configuration of this natural product has been assigned conclusively. M=Zn, R=tBuMe2 Si. PMID- 29711181 TI - Solid-Phase Synthesis of Thio-oligosaccharides. AB - No protecting groups are present in the highly reactive polymer-bound sugar 1 thiolates 1, which undergo reactions with sugar triflates 2 to give thio oligosaccharides 3 in high yield. Tr=trityl=triphenylmethyl, Tf=trifluoromethylsulfonyl, Bz=benzoyl. PMID- 29711180 TI - The Trivalent Neodymium Complex [(C5 Me5 )3 Nd] Is a One-Electron Reductant! AB - A Se22- complex, Ph3 P, and (C5 Me5 )2 are formed in the reduction of Se=PPh3 by the NdIII complex [(C5 Me5 )3 Nd] [Eq. (a)]. The latter is thus reminiscent of [(C5 Me5 )3 Sm], which, however, appears to be a stronger reductant than [(C5 Me5 )3 Nd]. This suggests that the reductive reactivity of [(C5 Me5 )3 Ln] complexes can be tuned by varying the size of the metal atom. PMID- 29711182 TI - Monitoring Chemical Warfare Agents: A New Method for the Detection of Methylphosphonic Acid. AB - Methylphosphonic acid (MPA) is the degradation product of many chemical warfare agents. The convenient detection of this substance would aid in field testing to confirm illicit manufacture and use of banned chemical weapons. Efficient functionalization of MPA with an aromatic diazo compound allowed binding by monoclonal antibodies elicited by using an analogous hapten (see scheme). An ELISA assay was rapid, sensitive, and specific. PMID- 29711183 TI - K6 Pb8 Cd: A Zintl Phase with Oligomers of Pb4 Tetrahedra Interconnected by Cd Atoms. AB - Unprecedented (Pb4 )Cd(Pb4 )Cd(Pb4 )Cd(Pb4 ) tetramers (see picture) are present in the structure of the title compound, in which they coexist with isolated Pb4 tetrahedra. Since Cs6 Ge8 Zn has the same stoichiometry as K6 Pb8 Cd but contains exclusively (Ge4 )2 Zn dimers, this can be viewed as a disproportionation reaction of the type (a). PMID- 29711184 TI - A Carbohydrate-Linked Cisplatin Analogue Having Antitumor Activity. AB - An unprotected and intact carbohydrate moiety has been observed for the first time in a transition metal complex. The carbohydrate-linked platinum(II) complex cis-dichloro[(2-beta-D-glucopyranosidyl)propane-1,3-diamine]platinum (see picture) is an analogue of cisplatin and exhibits comparable antitumor activity along with increased solubility in water. PMID- 29711185 TI - Al22 Br20 ?12 THF: The First Polyhedral Aluminum Subhalide-A Step on the Path to a New Modification of Aluminum? AB - The first polyhedral aluminum subhalide Al22 Br20 ?20 L forms in the disproportionation of aluminum(I) bromide solutions. The cluster is built up from an Al12 icosahedron with ten exohedrally bound (formally divalent) Al atoms (see structure). Such a homoatomic framework is unknown for molecular compounds. Even for the element boron this framework is only found as a section from the beta rhombohedral element modification. PMID- 29711186 TI - Transition Metal Catalyzed Coupling Reactions under C-H Activation. AB - C-C coupling by transition metal catalyzed C-H activation has developed into a diverse area of research. The applicable catalysts are manifold, and the variety of products obtained range from basic chemicals to pharmaceuticals and building blocks for carbon networks. One reaction, in which several C-C bonds are formed under C-H activation of a methyl group, is the conversion of ortho-iodoanisole according to Equation (1). PMID- 29711187 TI - A Versatile Route to Porous Solids: Organic-Inorganic Hybrid Materials Assembled through Hydrogen Bonds. AB - Square-planar and octahedral complexes of NiII and PtII link through head-to-head hydrogen bonds to form porous frameworks with large cavities that are suitable for inclusion of guest molecules. A series of four different complexes with pyridine-based ligands (in the center of the picture) are described, which contain either counterions or small molecules in channels. A=hydrogen-bond acceptor, D=hydrogen-bond donor, M=metal ion. PMID- 29711188 TI - ESI Fourier Transform Ion Cyclotron Resonance Mass Spectrometry (ESI-FT-ICR-MS): A Rapid High-Resolution Analytical Method for Combinatorial Compound Libraries. AB - The direct determination of the elemental compositions of the components of compound collections from combinatorial chemistry is achieved by ESI-FT-ICR mass spectrometry. Coupling with HPLC opens up a new dimension in high-resolution, informative analysis. The improved resolution of ESI-FT-ICR mass spectrometry in comparison to quadrupole mass spectrometry in the measurement of a compound obtained by solid-phase synthesis is illustrated. PMID- 29711189 TI - DNA-Based Assembly of Gold Nanocrystals. AB - Specific, designed, nonperiodic arrangements of gold nanocrystals that are 5 and 10 nm in diameter can be prepared with double-stranded DNA serving as a template (see drawing; A' and B' denote oligonucleotide sequences complementary to sequences A and B). The methods described should be applicable to nanocrystals composed of various materials. PMID- 29711190 TI - Photoionization and Electron Transfer of Biphenyl within the Channels of Al-ZSM-5 Zeolites. AB - Evidence of the photogenerated long-lived biphenyl radical and a trapped electron in the void space of aluminated nonacidic ZSM-5 zeolites has been obtained from the time-resolved UV/Vis absorption, Raman scattering, and EPR spectra. The restoration of the ground states implicates the existence of long-lived positive holes in the framework. PMID- 29711191 TI - Regio- and Stereoselective Synthesis of gamma-Alkylidenebutenolides by Cyclization of Dilithiated 1,3-Dicarbonyl Compounds with N,N'-Dimethoxy-N,N' dimethylethane- diamide. AB - The remarkably simple synthesis of gamma-alkylidenebutenolides 3 is achieved by cyclization of the dilithiated 1,3-dicarbonyl compounds 1 with N,N'-dimethoxy N,N'-dimethylethanediamide (2). This regio- and stereoselective cyclization provides a route to a wide range of butenolides, which are of pharmacological relevance and of importance for natural product synthesis. PMID- 29711192 TI - Manganese(III) Formate: A Three-Dimensional Framework That Traps Carbon Dioxide Molecules. AB - Carbon dioxide, formic acid, and water molecules are trapped in the crystal lattice of manganese(III) formate (see 1), which was obtained by reducing permanganate with formic acid. Each CO2 guest molecule exhibits four C-H???O-C-O interactions with the three-dimensional host framework of Mn(HCOO)3 units. Compound 1 undergoes an antiferromagnetic phase transition at 27 K. PMID- 29711193 TI - A New Route to Organic Intercalates Consisting of Vanadium Pentoxide and Pyridines: (4-H2 N-C5 H5 NH)V2 O5. AB - Light at the end of the tunnel! Intercalates of pyridine and layered inorganic compounds have intrigued chemists for at least two decades, but their structure determination has always been difficult owing to a lack of suitable single crystals. The intercalate (4-H2 N-C5 H5 NH)V2 O5 has now been characterized by X ray crystal structure analysis, and its electronic structure and magnetic properties have been studied in detail. PMID- 29711194 TI - A Triphenylamine Derivative with Three p-(N-tert-Butyl-N-oxylamino)phenyl Radical Units and Yet a Doublet Ground State. AB - A superexchange interaction through the lone pair of electrons on the central nitrogen atom in 1 is invoked to explain the existence of a doublet ground state; two spins on the aminoxyl radical centers couple antiferromagnetically, and one spin remains intact. This proposal is supported by EPR spectroscopic and magnetic measurements. PMID- 29711195 TI - Silicates and Perovskites: Two Themes with Variations. AB - An intermediate position between oxosilicates and nitridosilicates on one side and silicates and silicon oxo salts on the other is taken up by Ce16 Si15 O6 N32 . This compound is a perovskite derivative in which the octahedrally coordinated cations have been extensively replaced by tetrahedrally coordinated cations to give the formula Ce16 (Si[6] Si[4]14 ?)(O6 N32 ?10 ) ([n] =coordination number, ?=lattice vacancy). The presence of vacancies in both the cation and the anion sublattices leads to expectations of ionic conductivity. PMID- 29711196 TI - Characterization of Ligand Binding by Saturation Transfer Difference NMR Spectroscopy. AB - Fast identification of binding activity directly from mixtures of potential ligands is possible with the NMR method described, which is based on saturation transfer to molecules in direct contact to a protein. In addition, the ligand's binding epitope is easily identified. High sensitivity and ease of use are the principal advantages of this method. The picture shows the normal 1D NMR spectrum of a mixture and the spectrum obtained by applying the STD method, which exclusively shows signals from molecules with binding affinity. PMID- 29711197 TI - Measurement of Enantiomeric Excess by Kinetic Resolution and Mass Spectrometry. AB - New applications for your mass spectrometer-use it to measure enantiomeric excess! The enantiomeric content of very small quantities of chiral alcohols and amines has been determined by derivatization with chiral acylating agents in which mass is correlated to absolute configuration. The resultant esters and amides were then analyzed by electrospray ionization mass spectrometry (ESI-MS; shown schematically). The technique requires surprisingly low levels of diastereoselectivity in the acylation step, and is therefore generally applicable. PMID- 29711198 TI - [Mn(en)]3 [Cr(CN)6 ]2 ?4 H2 O: A Three-Dimensional Dimetallic Ferrimagnet (Tc =69 K) with a Defective Cubane Unit. AB - The first modified analogue of the AII3 [BIII (CN)6 ]2 ?x H2 O type of Prussian Blue, the title compound, has a three-dimensional network structure extended by CrIII -CN-MnII linkages, which is based on a defective cubane unit comprising three Cr and four Mn ions (see structure), and shows ferrimagnetic ordering below 69 K. PMID- 29711199 TI - Supramolecular Architecture and a New Mode of Pyrazolate Coordination (eta3 ) in the First Homoleptic Lanthanide Pyrazolate Complexes. AB - A linear supramoleculecular array of anions and cations is present in the solvent free potassium salt of the homoleptic erbium pyrazolate complex [K{Er(eta2 -tBu2 pz)4 }n ] (1). Treatment of 1 with [18]crown-6 in toluene/dimethoxyethane leads to formation of a charge-separated salt [Eq. (a)] in which the methyl group of a toluene molecule interacts with the potassium ion. tBu2 pz=3,5-di-tert butylpyrazolate. PMID- 29711200 TI - Isolation of Reduced Zirconium Chloride Clusters [(Zr6 CCl12 )Cl6 ]4- and [(Zr6 BCl12 )Cl6 ]5- from Acidic Aqueous Solution. AB - Crystallizable from concentrated hydrochloric acid: Compounds containing [(Zr6 BCl12 )Cl6 ]5- and [(Zr6 CCl12 )Cl6 ]4- clusters survive dissolution in deoxygenated water, and this enabled the study of reduced zirconium compounds in aqueous solution for the first time. In the solid state, the clusters are surrounded by novel hydrogen-bonded water networks that interact with the terminal chloride ligands (see graphic; black circles: Zr, smaller circle: B, gray circles: Cl, open circles: O of H2 O). PMID- 29711201 TI - A Solution-Phase Chemical Approach to a New Crystal Structure of Cobalt. AB - Kinetic control of crystal growth in the presence of a coordinating ligand is critical for the formation of a new structure of elemental cobalt (epsilon cobalt, the unit cell with the two different types of cobalt atoms is shown), which was discovered upon analyzing the metallic powder produced by the thermal decomposition of [Co2 (CO)8 ] in solution in the presence of trioctylphosphane oxide [TOPO, Eq. (1)]. PMID- 29711202 TI - Coordination Chemistry of Lanthanides at "High" pH: Synthesis and Structure of the Pentadecanuclear Complex of Europium(III) with Tyrosine. AB - A five-coordinate chloride ion is believed to template the assembly of a pentadecanuclear lanthanide complex of europium(III). This cluster (see picture) has been prepared by coordination of europium(III) perchlorate with tyrosine at about pH 6. Single crystal X-ray analysis established an unprecedented structure in which 15 constituent europium(III) ions are organized into three parallel pentagonal layers. PMID- 29711203 TI - [{[(eta7 -C2 B10 H12 )(eta6 -C2 B10 H12 )U][K2 (thf)5 ]}2 ]: A Metallacarborane Containing the Novel eta7 -C2 B10 H124- Ligand. AB - The tetranion ligand eta7 -C2 B10 H124- has been observed for the first time in 1, which was obtained from the reaction of o-C2 B10 H12 with excess K metal followed by treatment with UCl4 . As shown in the picture (without K cations and coordinated THF molecules), 1 is a centrosymmetric dimer with a bent sandwich structure. PMID- 29711204 TI - The Parent Hexacarbaborane arachno-C6 B6 H12 and a Methylated Pentacarbaborane arachno-CH3 C5 B7 H12 : Domains of Incipient Hydrocarbon Behavior within Borane Clusters. AB - Increasingly pronounced hydrocarbon character is exhibited by C6 H6 B12 , the first unsubstituted hexacarbaborane, and CH3 C5 B7 H12 , the first cluster pentacarbaborane. These compounds shed light on the structural dichotomy between open hydrocarbon skeletons and polyhedral borane frameworks for high-carbon carboranes. PMID- 29711205 TI - Axial and Equatorial Hydrogen Bonds in the Tetrahydropyran???HCl Dimer. AB - Two hydrogen-bond complexes formed between tetrahydropyran and hydrogen chloride have been observed by using a molecular beam Fourier transform microwave spectrometer. The rotation constants are consistent with Cs symmetry, with HCl pointing to the domain of the axial and equatorial lone pair at the oxygen atom (shown on the left and right, respectively). The axial form has been found to be the more stable one. PMID- 29711206 TI - Convergence of Catalytic Antibody and Terpene Cyclase Mechanisms: Polyene Cyclization Directed by Carbocation-pi Interactions. AB - A tandem cationic cyclization cascade similar to a terpenoid cyclase reaction is catalyzed by antibody HA5-19A4. The 2.7-A resolution crystal structure of the Fab hapten complex reveals convergence with the same catalytic strategy employed by a terpenoid cyclase: both serve as templates that enforce the productive conformation of a flexible polyene substrate, and both stabilize carbocation intermediates through cation-pi interactions with multiple aromatic residues in their active sites. PMID- 29711207 TI - Nitric Oxide: Chemical Puzzles Posed by a Biological Messenger. AB - Recent years have seen a massive growth of interest in the biological effects of nitric oxide (NO): It acts as a signaling molecule in blood vessels and the brain, and as a defense against pathogens in the immune system. Discussed are the chemical events underlying the physiology of this versatile little molecule. PMID- 29711208 TI - A Polycationic Metallodendrimer with 24 [Fe(eta5 -C5 Me5 )(eta6 -N Alkylaniline)]+ Termini That Recognizes Chloride and Bromide Anions. AB - Pronounced dendritic effects are shown by the title compound 1 in the recognition of Cl- and Br- -this is shown by the comparison with a mononuclear compound with one dendrimer arm and a trinuclear compound with a tripodal dendrimer branch. Thus, 1 differs distinctly from 24-ferrocene dendrimers of comparable topology. PMID- 29711209 TI - A Method for High-Throughput Screening of Enantioselective Catalysts. AB - About 1000 catalytic or stoichiometric asymmetric reactions of racemic compounds or prochiral substrates bearing enantiotopic groups can be analyzed per day. In this highly efficient method the enantioselectivity is determined by electrospray ionization mass spectrometry using isotopically labeled substrates. The picture shows the mass spectrum of the mixture obtained upon hydrolysis of 1 to afford the pseudo-enantiomeric products 2 and 3. PMID- 29711210 TI - The First Boron-Tethered Radical Cyclizations and Intramolecular Homolytic Substitutions at Boron. AB - 5-, 6-, and even 7-exo-trig radical cyclizations (1->2) are possible by applying a new boron-tethering approach with alkenylboronic esters. For certain substitution patterns, a subsequent intramolecular homolytic substitution (SH i) reaction at boron occurs (2->3) and leads to rearranged products. The C-B bond of the intermediate boracycles is readily oxidized to give diol products. PMID- 29711211 TI - Mixed Crossed Aldol Condensation between Conjugated Esters and Aldehydes Using Aluminum Tris(2,6-diphenylphenoxide). AB - The combined use of aluminum tris(2,6-diphenylphenoxide) (ATPH) and lithium 2,2,6,6-tetramethylpiperidide (LTMP) has proven to be effective for the mixed crossed aldol condensation between conjugated esters and various aldehydes. An example is shown in Equation (1). PMID- 29711212 TI - Two-Dimensional Nitroxide-Based Molecular Magnetic Materials. AB - Manganese(II) complexes of imidazolyl-substituted chelating nitronylnitroxides are characterized by a stereoselective arrangement of the metal centers and the ligands to give a honeycomblike layer structure (shown on the right). The magnetic properties at high temperature indicate the presence of a ferrimagnetic structure within the layers. At low temperatures, ferromagnetic ordering is observed. PMID- 29711213 TI - Solid-Phase Supported Synthesis of the Branched Pentasaccharide Moiety That Occurs in Most Complex Type N-Glycan Chains. AB - Repetitive glycosylation on a sulfanylalkyl-functionalized Merrifield resin leads to the branched, complex pentasaccharide 1 in 20% overall yield in ten steps when appropriately protected O-glycosyl trichloroacetimidates are used as glycosyl donors. A decisive factor here was the tuning of the reaction conditions for the solid-phase glycosylation and the conditions for selective removal of the protecting groups and for cleavage of the samples from the resin for characterization. The subsequent cleavage of the product was achieved with a thiophilic reagent that does not attack the O-glycosidic linkages. PMID- 29711214 TI - Expression of Chirality by Achiral Coadsorbed Molecules in Chiral Monolayers Observed by STM. AB - The supramolecular packing mode of physisorbed monolayers built up by chiral isophthalic acid derivatives and coadsorbed achiral solvent molecules was imaged at the liquid/graphite interface with scanning tunneling microscopy (STM). The picture on the right shows the submolecularly resolved STM image of an enantiomorphous domain composed of the R enantiomer of the isophthalic acid derivative studied and 1-heptanol molecules; the latter express the chirality of the monolayer. Upon adsorption a racemic mixture is separated into enantiomorphous domains. PMID- 29711215 TI - Redox-Active Nanotubes of Vanadium Oxide. AB - Unlike many small carbon nanotubes, VOx nanotubes (shown on the right) are obtained as the main product of a direct chemical synthesis at relatively low temperatures. The multiwalled material contains template molecules between the individual shells, which by a simple cation exchange can be removed without destruction of the tubes. PMID- 29711216 TI - Simultaneous Dual Living Polymerizations: A Novel One-Step Approach to Block and Graft Copolymers. AB - Just one step is required for the synthesis of block copolymers by simultaneous "living"/controlled ring-opening and radical polymerization initiated by a difunctional (A-B) compound (shown schematically on the right). PMID- 29711217 TI - A New Carborane Cage: Hexacarba-arachno-dodecaborane(12). AB - A drum-shaped cage built up from six carbon and six boron atoms is proposed for the structure of 2 based on the comparison of experimental and calculated NMR chemical shifts. The novel arachno carborane 2 was obtained upon treatment of bis(diethylboryl)ethyne (1) with an excess of tetraethyldiborane(6) [Eq. (a)]. PMID- 29711218 TI - Synthesis and Association Behavior of [4.4.4.4.4.4]Metacyclophanedodecayne Derivatives with Interior Binding Groups. AB - Intriguing association behavior in solution is exhibited by the rigid macrocycle 1. For instance, it reacts with organic cations to give ternary complexes of the composition (1?cation)?1, and with analogous macrocycles without cyano groups it forms heteroaggregates. R=CO2 C8 H17 . PMID- 29711219 TI - From Disymmetric Molecules to Chiral Polymers: A New Twist for Supramolecular Synthesis? AB - A new branch of crystal engineering appears to have borne fruit: A noncovalently bonded network consisting of the complex illustrated as a stick model on the right is converted directly into a coordination polymer with a similar molecular architecture. The implications of the new work extend beyond the boundaries of coordination chemistry since the same strategy should work equally well in organic and organometallic systems. PMID- 29711220 TI - Insertion of Imines into Palladium-Acyl Bonds: Towards Metal-Catalyzed Alternating Copolymerization of Imines with Carbon Monoxide To Form Polypeptides. AB - From a methyl ligand, CO, and an imine a chelating amide ligand is formed by insertion of the C=N bond into the metal-acyl bond in cationic palladium(II) complexes (see reaction below). The cationic acylpalladium complexes are obtained from CO and readily accessible palladium starting materials. LL=diphosphane ligand. PMID- 29711221 TI - New Iron-Mercury Clusters: [Hg7 {Fe(CO)4 }5 (StBu)3 Cl], [Hg14 Fe12 {Fe(CO)4 }6 S6 (StBu)8 Br18 ], and [Hg39 Fe8 {Fe(CO)4 }18 S8 (StBu)14 Br28 ]. AB - Three new chalcogen-bridged mercury-iron clusters with 7, 14, and 39 mercury centers were obtained from the reaction of tBuSSiMe3 with [Fe(CO)4 (HgX)2 ] (X= Cl, Br). The compounds were isolated in the form of orange crystals that were characterized by X-ray crystallography. The picture on the right shows the structure of the heavy-atom skeleton of [Hg14 Fe12 {Fe(CO)4 }6 S6 (StBu)8 Br18 ] (Hg, Fe, Br, and S are black, diagonally striped, white, and horizontally striped, respectively). PMID- 29711222 TI - Novel Reactions of Phosphaalkynes in the Coordination Sphere of tert-Butylimido- vanadium(V) Complexes: A Simple Synthesis of 3-Aza-1,2,4,6 tetraphosphaquadricyclanes and 1,3,5-Triphosphabenzenes. AB - A small variation in the vanadium reagent leads to a completely different product: The cyclooligomerization of phosphaalkynes 2 with tBuN=VCl3 ?DME (DME=1,2-dimethoxyethane) proceeds with incorporation of the imido fragment to give the azatetraphosphaquadricyclanes 1. In contrast, with the corresponding vanadium compound containing no Lewis base this fragment is not incorporated, and the 1,3,5-triphosphabenzenes 3 are obtained. PMID- 29711223 TI - pi-Stacked ortho-Palladated Bipyridine Complexes Exhibiting Unusual Liquid Crystalline Behavior. AB - A columnar structure with lamellar morphology in the liquid crystalline state is displayed by the palladium complex salt 1, which is synthesized from nonmesogenic ligands. PMID- 29711224 TI - Acetylenic Cyclophanes as Fullerene Precursors: Formation of C60 H6 and C60 by Laser Desorption Mass Spectrometry of C60 H6 (CO)12. AB - A logical precursor of macrocycle C60 H6 , cyclophane C60 H6 (CO)12 (1) represents a building block in a possible total synthesis of C60 . In Fourier transform ion cyclotron resonance laser desorption mass spectroscopic experiments in the negative-ion mode, 1 fragments to C60 H6 (2) under successive loss of CO. Further loss of six H atoms and rearrangement gives C60 ions with a fullerenic structure. PMID- 29711225 TI - Chiral Allyl Cations in Cycloadditions to Furan: Synthesis of 2-(1'-Phenylethoxy) 8-oxabicyclo[3.2.1]oct-6-en-3-one in High Enantiomeric Purity. AB - Efficient shielding of the pi face is offered by the phenyl group of the chiral auxiliary (TES=triethylsilyl) to the allyl cation generated at low temperature from 1. This protection induces high pi-facial selectivity and allows high chemical yield on the capture of the cation by furan to afford the title cycloadduct 2. PMID- 29711226 TI - Synthesis and Solid-State Structure of 2,6-Trip2 C6 H3 Tl (Trip=2,4,6-iPr3 C6 H2 ): A Monomeric Arylthallium(I) Compound with a Singly Coordinated Thallium Atom. AB - A "one-legged thallium" is observed in the arylthallium(I) compound 2,6-Trip2 C6 H3 Tl (Trip=2,4,6-iPr3 C6 H2 ), which was synthesized from the corresponding organolithium compound and thallium chloride. X-ray structure analysis reveals that 2,6-Trip2 C6 H3 Tl is monomeric in the solid state and contains a singly coordinated thallium atom (see space-filling model on the right). PMID- 29711227 TI - Strategy-Level Separations in Organic Synthesis: From Planning to Practice. AB - A dirty word in synthesis: separation! The normally unavoidable separation at the end of each reaction finds no friends among synthetic chemists and is often regarded as a technical procedure. However, the need to quickly and cheaply produce pure products is driving the development of new separation and purification techniques. Astonishingly, the modern concepts and techniques for coupling synthesis and separation are rooted in workup procedures that are as old as the art of synthesis itself. PMID- 29711228 TI - Dual Recognition of Double-Stranded DNA by 2'-Aminoethoxy-Modified Oligonucleotides. AB - Simultaneous interaction of the 2'-aminoethoxy-modified oligonucleotides with the phosphodiester backbone (shown on the right, A) and with the bases through Hoogsteen base contacts (B) is seen at each base-pair step of the duplex DNA target. The electrostatic interaction between the protonated amino group and the negatively charged phosphate group provides for a dramatic increase in the binding affinity and the association rate constant. PMID- 29711229 TI - Total Synthesis of Macrolactin A with Versatile Catalytic, Enantioselective Dienolate Aldol Addition Reactions. AB - A highly convergent total synthesis of macrolactin A (1) utilizes modern asymmetric catalytic C-C coupling methods. The longest linear sequence in the route is 16 steps with an average yield of 86% per step. This total synthesis is valuable, because 1, which has been shown to possess activity against HIV, is not readily accessible from its natural source, a taxonomically unclassified deep-sea bacterium. PMID- 29711230 TI - Methyl Transfer from Methanol to Co-cobyrinate: A model for the Coenzyme B12 Dependent Methyltransferase? AB - With CoI corrins as supernucleophiles, methylation by methanol is achieved when the leaving group is activated by Zn2+ ions at elevated temperatures (see reaction below). This methylation reaction is the first model for the Co dependent methyltransferase. PMID- 29711231 TI - Supramolecular Daisy Chains. AB - Our childhoods may be recalled when a self-complementary cation, endowed with both a dibenzo[24]crown-8 macroring and a secondary dialkylammonium sidearm, self assembles to form a two-component supramolecular architecture that is reminiscent of a daisy chain (depicted schematically on the right). This daisy-chain-like superarchitecture is stabilized by a combination of [N+ -H???O] hydrogen bonds and aryl-aryl stacking interactions. PMID- 29711232 TI - Synthesis and In Vitro Evaluation of the Ras Farnesyltransferase Inhibitor Pepticinnamin E. AB - A modularly built bisubstrate inhibitor, the natural product pepticinnamin E (shown on the right) was sythesized for the first time. In the case of in vitro assays it inhibits the enzyme farnesyltransferase with respect to both the peptide substrate and farnesylpyrophosphate (KI = 30 and 8 MUM, respectively). The inhibitory activity is decisively influenced by the central tripeptide unit and the absolute configuration of the non-proteinogenic amino acid incorporated therein. PMID- 29711233 TI - Characterization of Hydrogen-Bonded Supramolecular Assemblies by MALDI-TOF Mass Spectrometry after Ag+ Labeling. AB - The high affinity of Ag+ ions for aromatic pi donors and cyano groups is exploited in a novel MALDI-TOF mass spectrometric method for the identification of hydrogen-bonded assemblies. The interaction with the Ag+ ions-which, for example, can be complexed by two phenyl groups in a sandwich-type manner (see drawing on the right)-provides positively charged assemblies in a nondestructive way. PMID- 29711234 TI - Anion Control in the Self-Assembly of a Cage Coordination Complex. AB - An anion is encapsulated in the center of the new cage compound [Ni6 (atu)8 X]X3 (X=Cl-for the structure see picture-or Br; Hatu=amidinothiourea). A combination of Lewis acid-base and hydrogen-bonding interactions cause the square-planar [Ni(Hatu)2 ]2+ units, after deprotonation, to assemble to form this compound. A remarkable feature is the anion dependence of the cage formation; nitrate, acetate, and perchlorate are unsuitable as templates. PMID- 29711235 TI - A Dendritic Macrocyclic Organic Polyradical with a Very High Spin of S=10. AB - Designed as a ferromagnetically coupled spin pentamer, the macrocyclic polyradical 1 possesses an average spin of S=10 in the ground state. This is the highest spin quantum number that has yet been measured for an organic molecule. Ar=tBuC6 H4 . PMID- 29711236 TI - Formation of a Ring-Shaped Reduced "Metal Oxide" with the Simple Composition [(MoO3 )176 (H2 O)80 H32 ]. AB - The largest inorganic molecular system so far, [(MoO3 )176 (H2 O)80 H32 ] (1; the picture on the right shows the polyhedral representation), which has been characterized by X-ray structure analysis, possesses a cavity of diameter 2.3 nm and remarkably shows the stoichiometry of a (reduced) protonated and hydrated "molecular molybdenum trioxide". It is formed by reduction of an aqueous solution of lithium molybdate with tin(II) chloride at very high H+ concentrations. PMID- 29711237 TI - High-Resolution 14 N Solid-State NMR Spectroscopy. AB - Even without expensive isotope enrichment, it is possible to obtain nitrogen NMR parameters in the solid state. The isotropic chemical shifts in hexagonal and cubic boron nitride, and for the hexagonal modification also the quadrupole coupling, can thus be obtained for the first time. The recorded 14 N MAS NMR spectrum (28.809 MHz) of hexagonal boron nitride is shown on the right. PMID- 29711238 TI - Induced Chemical Defense in Plants. AB - Surprising parallels exist between the chemical defense mechanisms of plants and animals. The biosynthesis of defensive substances in plants can be induced by microbial or herbivoral attack. Recent results demonstrate that the chemical defense of plants is mediated by lipid-based signaling systems. Volicitin (1) acts as a chemical signal in a tritrophic interaction of plants and insects. Derivatives of jasmonic acid (2) play a key role in directing the chemical defense response. PMID- 29711239 TI - Maracin and Maracen: New Types of Ethynyl Vinyl Ether and alpha-Chloro Divinyl Ether Antibiotics from Sorangium cellulosum with Specific Activity Against Mycobacteria. AB - Like something originating from the chemistry laboratory rather than from Nature: However, the title compounds 1 and 2 are, in fact, synthesized by myxobacteria of the species Sorangium cellulosum according to the same assembly pattern from acetate and are excreted into the culture medium. Both compounds have remarkably good in vitro activity against the pathogen responsible for tuberculosis, Mycobacterium tuberculosis. PMID- 29711240 TI - The First Structure Determination of Nanosized Colloidal Particles of Pd3 P by High-Resolution Electron Microscopy. AB - The exact three-dimensional structure of a nanosized colloidal particle of Pd3 P was determined directly from high-resolution transmission electron microscopy (HRTEM) images that were recorded in several crystallographic directions. An HRTEM image recorded along [011] is shown on the right. The cores of the particles were excluded from the analysis because of severe multiple diffraction. PMID- 29711241 TI - Neutron Diffraction Study of [Nd(AlMe4 )3 ]?0.5 Al2 Me6 at 100 K: The First Detailed Look at a Bridging Methyl Group with a Trigonal-Bipyramidal Carbon Atom. AB - Weak agostic Nd???H interactions and Nd-C bonds are involved in the bonding of the bridging methyl groups in the title compound (see sketch on the right): Two of the three H atoms of the methyl group are directed at the Nd center. The C atoms have distorted trigonal-bipyramidal geometry with the Nd atom and one of the H atoms (HA ) as axial ligands, and the Al atom and the other two H atoms (HB and HC ) in equatorial positions. The Al2 Me6 "solvate" molecule is disordered. PMID- 29711242 TI - [Cp3 Ba]- : The First Structurally Characterized Barate Complex. AB - A [Cp3 Ba]infinity coordination polymer with a chain structure is present in the compound [Cp3 Ba]- [Bu4 P]+ . The barium center is tetrahedrally coordinated by four eta5 -Cp rings (a section of the chain is shown on the right). The Bu4 P cations bridge neighboring [Cp3 Ba]infinity chains through short hydrogen bonds, and the cocrystallized THF molecules do not coordinate to the barium centers but are instead involved in short CH???O hydrogen bonds with the Bu4 P cations. PMID- 29711243 TI - Anion-Templated Assembly of a Supramolecular Cage Complex. AB - The templating effect of the tetrafluoroborate ion leads to assembly of four CoII ions and six bridging ligands around this anion to give a tetrahedral complex with a bridging ligand along each edge and the anion trapped in the central cavity (shown below). Surprisingly under identical conditions but with NiII a simpler dinuclear complex forms. PMID- 29711244 TI - Transition Metal Catalysis in the Baeyer-Villiger Oxidation of Ketones. AB - Environmentally friendly oxidizing agents such as hydrogen peroxide or dioxygen can be used today in catalytic versions of the almost one century old Baeyer Villiger oxidation with transition metal complexes as catalysts. On the right is a sketch of a possible mechanism for this reaction with a platinum catalyst in homogeneous solution. PMID- 29711245 TI - Completely Stereospecific Self-Assembly of a Circular Helicate. AB - A nanoscale turbine wheel is an apt description of the structure of the enantiomerically pure helicate [Ag6 (L2)6 ]6+ (1), which precipitates as PF6 salt on mixing dissolved AgPF6 with the ligand L2 (a bis-bidentate ligand comprising two condensed alpha-pinene/bipyridine units linked by a xylylene bridge). The helicate has an outer diameter of about 3 nm and an inner diameter of 0.84 nm, and is a potential model for the study of stereospecific recognition processes. PMID- 29711246 TI - Self-Assembly of Novel Polyrotaxanes: Main-Chain Pseudopolyrotaxanes with Poly(ester crown ether) Backbones. AB - Not threading rings on chains, but chains through rings results in a new class of main-chain polyrotaxanes. The cations of bipyridinium salts thread through the crown ether units of a poly(ester crown ether) chain (shown below). The threading efficiency m/n of the polyrotaxane is controlled by stoichiometry and temperature. PMID- 29711247 TI - The Use of 15 N NMR Spectroscopy To Resolve the "Higher Order Cyanocuprate" Controversy: 15 N, 6 Li, and 13 C NMR Spectroscopic Investigations of CuCN Derived Butyl Cuprates. AB - Structure 1 is the major component obtained by the reaction of two equivalents of RLi and one equivalent of CuCN; other proposed structures can now be ruled out on the basis of 15 N NMR spectroscopic and theoretical studies. Thus, these useful synthetic reagents should be considered as cyano-Gilman reagents R2 CuLi?LiCN and not "higher order cyanocuprates" R2 Cu(CN)Li2 . PMID- 29711248 TI - Artificial Photosynthesis: Mimicking Redox Asymmetry. AB - Directional light-induced electron transfer takes place in the catenane shown schematically on the right. This catenane is similar to the photosynthetic reaction center: The two chemically identical electron acceptors (rectangles) bound to a ruthenium complex as donor have different reduction potentials because their environments are of different polarity. The electron transfer proceeds preferentially (85 %) to the external acceptor. PMID- 29711249 TI - Synthesis of a New Class of Solvent-Sensitive Fluorescent Labels. AB - Single biomolecules can be detected with the aid of new labels that absorb visible light and fluoresce by intramolecular charge transfer. The intensity of the fluorescence is highly dependent upon the environment of the fluorophore, and decreases greatly with increasing polarity. PMID- 29711250 TI - Isocyanate-Based Dendritic Building Blocks: Combinatorial Tier Construction and Macromolecular-Property Modification. AB - Used individually or combinatorially, unique isocyanate-based dendritic monomers generate homo- and heterofunctional materials (the sketch shows schematically a molecule with a heterofunctional surface). Tier construction by combinatorial monomer addition offers new avenues to macromolecular architectural design and the control of physical properties. PMID- 29711251 TI - Chemical Synthesis of a Circular Protein Domain: Evidence for Folding-Assisted Cyclization. AB - Extremely fast cyclization of the linear polypeptide precursor 1 takes place to form 2. The reaction appears to be assisted by the native fold of 1, which positions the reactive ends in close proximity. The circular topology has no influence on the folding or function of 2. PMID- 29711252 TI - A Biomimetic Synthesis of a Porphobilinogen Precursor Using a Mukaiyama Aldol Reaction. AB - Four steps suffice! A protected porphobilinogen was obtained in 25 % yield in a straightforward synthesis starting from a derivative of 5-aminolevulinate. The key was the use of a cyanide derivative instead of the azide. The synthesis imitates the mechanism proposed by Shemin for the biosynthesis of porphobilinogen. Phth = phthaloyl. PMID- 29711253 TI - C3 Symmetry in Asymmetric Catalysis and Chiral Recognition. AB - Rotational symmetry can be an important factor in the design of highly selective receptors for chiral recognition. This is well known for C2 -symmetric compounds, but the concept can be extended to chiral compounds of higher symmetry such as 1. PMID- 29711254 TI - Stereocontrolled Synthesis of (11Z)-Retinal and Its Analogues. AB - Suzuki coupling of stereochemically pure (Z)-bromotetraene 1-which is extremely unstable but can be kept in frozen benzene in the presence of a small amount of PPh3 at &sminus 01;20 degrees C-and (Z)-alkenylboronic acid 2 provides the stereocontrolled synthesis of (11Z)-retinal 3. The 11Z configuration, which is introduced by selective catalytic debromination of the corresponding dibromo precursor of 1, is retained in this step. TBDMS = tBuMe2 Si. PMID- 29711255 TI - First Isolation and Structural Characterization of a Nickel(III) Complex Containing Aliphatic Thiolate Donors. AB - Long overdue were syntheses of nickel(III) complexes containing aliphatic thiolate ligands. The complex anion [Ni(phmi)]- (phmi is the tetraanion of N,N' 1,2-phenylenebis(2-methyl-2-sulfanylpropionamide) has now been isolated-as PPh4 salt-and structurally characterized. The stability of the nickel(III) complex is attributed to the special properties of the ligand, which abolish or at least retard possible decomposition pathways. PMID- 29711256 TI - beta-Homoalanyl PNAs: Synthesis and Indication of Higher Ordered Structures. AB - Self-pairing complexes with extraordinarily high stability are formed by beta PNAs with four to six units of the nucleo-beta-amino acid 1. The key step in the synthesis is a Mitsunobu reaction between a beta-homoserine and a purine derivative. PMID- 29711257 TI - A Three-Dimensional Framework with Accessible Nanopores: RbCuSb2 Se4 ?H2 O. AB - Semiconductor properties are exhibited by the hydrothermally synthesized title compound, whose channels are occupied by Rb+ ions and water molecules. In topotactic reactions the exchange of the Rb+ ions for smaller alkali metal ions demonstrates the high mobility of the cations and may determine other interesting properties. PMID- 29711258 TI - Analysis of the Symmetry of Crystal Packing Forces by Methyl Proton Tunneling: A Strategy for the Unambiguous Assignment of the Magnetic Jahn - Teller Effect in Molecules. AB - Intrinsic and extrinsic forces behind the distortion in metal atom clusters can be readily distinguished provided that the clusters are embedded in a suitable ligand environment and that the tunneling of the protons in the peripheral ligands is then analyzed by inelastic neutron scattering. For the [Cr3 O(OOCCH3 )6 (H2 O)3 ]Cl?6 H2 O model system studied, the tunneling process is very sensitive to the local environment. Thus a tool is available to allow a better assessment of the cause of structural distortions. PMID- 29711259 TI - Copper-Catalyzed Enantioselective Michael Additions: Recent Progress with New Phosphorus Ligands. PMID- 29711260 TI - Crystal Structures of Chiral Diastereoisomers of a Carbon-Based High-Spin Molecule. AB - A chiral organic compound that displays magnetic properties has been synthesized for the first time. Two diastereomers of a molecule having an S=3/2 spin state have been characterized by X-ray crystal structure analysis (one of the diastereomers is shown in the space-filling model on the right). Optical resolution of one pair of stereoisomers was possible by chiral stationary phase HPLC. PMID- 29711261 TI - New Ligands for Regio- and Enantiocontrol in Pd-Catalyzed Allylic Alkylations. AB - The branched, chiral products 1 are formed preferentially in the allylic alkylations in Equation (1) when the Pd catalyst contains the P,N ligand L* or derivatives thereof. The ligands are readily synthesized from commercially available precursors. PMID- 29711262 TI - Redox-Switched Exciton-Coupled Circular Dichroism: A Novel Strategy for Binary Molecular Switching. AB - Intense chiroptical properties and efficient reversibility of the chemical redox cycle support the adaptability of the CuI /CuII complex system 1/2 for the development of a binary molecular device. Reduction proceeds with ascorbic acid, and oxidation with ammonium persulfate. PMID- 29711263 TI - Solid-Phase Immobilization of a New Epoxidation Catalyst. AB - The heterogenization of a titanium(IV) silsesquioxane complex in an MCM-41 molecular sieve, by tailoring the polarity of MCM-41, results in self-assembled materials (see the space-filling model on the right) that are active, truly heterogeneous, and recyclable catalysts for liquid-phase alkene epoxidation. PMID- 29711264 TI - Template Assembly of Polyiodide Networks at Complexed Metal Cations: Synthesis and Structures of [Pd2 Cl2 ([18]aneN2 S4 )]1.5 I5 (I3 )2 and [K([15]aneO5 )2 ]I9. AB - The cations [Pd2 Cl2 L]2+ and [KL2'+ (L = [18]aneN2 S4 , L' =[15]aneO5 ) have been used as templates for the synthesis of unique three-dimensional polyiodide networks. The metal cations in [Pd2 Cl2 L]1.5 I5 (I3 )2 are linked into infinite chains by pairwise hydrogen bonding; the resulting cationic polymers run through channels formed by the extended polyiodide network. [KL2' ]I9 shows a three dimensional network of puckered cubic cages of I9- ions whose cavities are occupied by the metal cations (section from the structure shown on the right). PMID- 29711265 TI - Triphenylphosphonioacetylide: A Species Isoelectronic with Isocyanides. AB - Stabilized only by triphenylphosphane, the title compound 1 was synthesized and investigated theoretically (the HOMO of 1 is depicted on the right). Both calculations and experimental NMR spectra show that no Lewis structure can describe the geometry and charge distribution accurately. Compound 1 undergoes an equivalent of the Passerini reaction. Ph3 P+ -C=C- : 1. PMID- 29711266 TI - A Symmetrically Bridging Triarylsilyl Ligand in a Dinuclear Rhodium Complex: Synthesis and Structure of [LRh(H)(u-Cl)(u-SiAr2 )(u-SiAr3 )Rh(H)L] (Ar=Ph, p-FC6 H4 ; L=PiPr3 ). AB - Simply warming solutions of the dinuclear complexes 1 provides novel complexes 2 [Eq. (a); Ar = Ph, p-FC6 H4 ; L = PiPr3 ], which contain a bridging triarylsilyl ligand and show unusual thermal stability. Compounds with this type of symmetric structure are of interest as models of the transition state for the migration of tertiary silyl groups in a bimetallic framework. PMID- 29711267 TI - Another Surprise from Pyrazolate Ligands. PMID- 29711268 TI - Single-Molecule Magnets: Different Rates of Resonant Magnetization Tunneling in Mn12 Complexes. AB - Two new molecular magnets, the dodecanuclear manganese complexes of the type [Mn12 O12 (O2 CR)16 (H2 O)4 ] (known for R = CH3 , new for R = o-ClC6 H4 , o-BrC6 H4 ) have contributed to a better quantum mechanical understanding of single molecule magnets. For instance, appreciable differences in the steps seen in the magnetization hysteresis loops of these high-spin clusters are attributed to changes in the rates of magnetization tunneling from one complex to another. PMID- 29711269 TI - A Glucose-Containing Ether Lipid (Glc-PAF) as an Antiproliferative Analogue of the Platelet-Activating Factor. AB - A new group of active substances, to which 1 belongs, inhibit cell proliferation and initiate programmed cell death (apoptosis) in keratinocytes. The glucosylated phospholipid 1 was synthesized from (S)-isopropylideneglycerol in nine steps with an overall yield of 25 %. PMID- 29711270 TI - A Chemically and Electrochemically Switchable [2]Catenane Incorporating a Tetrathiafulvalene Unit. AB - A mechanical switch in a [2]catenane, made up of a cyclobis(paraquat-p-phenylene) tetracation interlocked with a macrocyclic polyether containing a redox-active tetrathiafulvalene (TTF) unit and a 1,5-dioxynaphthalene ring system, can be thrown either chemically or electrochemically. The neutral TTF unit resides "inside" the tetracationic cyclophane in the reduced state and "alongside" it in the oxidized species (TTF+ / TTF2+ ). Switching between the reduced (I4+ ) and oxidized state (I5+ (I6+ )) is accompanied by a dramatic color change. PMID- 29711271 TI - Generation and Trapping Reactions of a Formal 1:1 Complex between Singlet Carbon and 2,2'-Bipyridine. AB - The structural element of a protonated imidazolium system was realized for the first time in the synthesis of 1 from 2,2'-bipyridine and a novel methylenating agent. Reversible deprotonations proceed via 2 to lead to carbene 3, a formal 1:1 complex between singlet carbon and 2,2'-bipyridine which is stable in solution and can be trapped. For 1 and 2, unusual hybridizations of the bridging C atom were found experimentally. PMID- 29711272 TI - Ylidic Four pi Electron Four-Membered lambda5 -Phosphorus Heterocycles: Electronical Isomers of Heterocyclobutadienes. PMID- 29711273 TI - Electrochemistry of Supramolecular Systems. AB - What is the role of electrochemistry in supramolecular chemistry? On one hand, it provides information on energy and kinetics that is not available with spectroscopic and mass spectrometric techniques; on the other, it can be used to alter the electronic states and thus the interactions between molecules, resulting in new compounds and materials. A typical cyclic voltammogram of the complex shown is depicted on the right; only the first three reductions are presented, although a total of six electrons can be transferred to the bipyridine units sequentially (E in V vs. ferrocene/ferrocenium). PMID- 29711274 TI - Breaking the Mold of Discotic Liquid Crystals. AB - Small molecules of the indene and pseudoazulene type like 1 and 2 form columnar mesophases! These compounds do not possess peripheral flexible chains like conventional columnar liquid crystals. Instead, polarizable chlorine and sulfur atoms, as well as the polar cyano group, function as unusual soft regions between the rigid columns. PMID- 29711275 TI - Detection of Specific Noncovalent Zinc Finger Peptide-Oligodeoxynucleotide Complexes by Matrix-Assisted Laser Desorption/Ionization Mass Spectrometry. AB - Faster than with conventional solution-phase methods, mass spectrometry can be used to recognize the formation of noncovalent complexes. This is shown by the detection of the specific triple complex between an 18-residue zinc finger peptide from the gag protein p55 of HIV-1, Zn2+ , and the oligodeoxynucleotide d(TTGTT) by MALDI-MS (see the spectrum). The results also indicate that MALDI mass spectra can qualitatively reflect solution-phase chemistry. PMID- 29711276 TI - Rapid Assembly of Oligosaccharides: Total Synthesis of a Glycosylphosphatidylinositol Anchor of Trypanosoma brucei. AB - Six building blocks, six reaction steps: The recently developed innovative methodology facilitated the convergent synthesis of the complex oligosaccharide core 1 (shown here with protecting groups) for the total synthesis of a glycosylphosphatidylinositol (GPI) anchor. The key factors are the tuning of the reactivity of the building blocks by using 1,2-diacetal protecting groups and the desymmetrization of glycerol and myo-inositol with a chiral bis(dihydropyran). PMID- 29711277 TI - Large Molecules from the Virtual Bakery- Filling a Gap in Structure Research. AB - Traditional direct methods alone are not potent enough to solve the crystal structures of mid-sized molecules (over 200 non-hydrogen atoms). Considerably more efficient are the new methods such as shake-and-bake and SHELXD. Even the 1000-atom barrier has now been overcome, so the gap between small and large molecules is closing. PMID- 29711278 TI - A Functional Model of Cytochrome c Oxidase: Thermodynamic Implications. AB - The environment of the CuI ion in the distal ligand group decides the fate of the reduction of O2 by the two analogues 1 and 2 of the heme a3 CuB center in cytochrome c oxidase. The fourfold coordination by N in 1 favors the CuII oxidation state and leads to a 4 e- -4 H+ reduction and the formation of H2 O under physiological conditions, while with 2 a 2 e- -2 H+ reduction occurs to form the cytotoxic H2 O2 . PMID- 29711279 TI - Unprecedented Facial Diastereoselectivity in the Paterno-Buchi Reaction of a Chiral Dihydropyrrole-A Short Total Synthesis of (+)-Preussin. PMID- 29711280 TI - Digitonin as a Chemical Trigger for the Selective Transformation of Giant Vesicles. AB - The rupture of cationic giant vesicles (see the picture) in the presence of anionic vesicles, or the reverse, on exposure to digitonin is dependent on the respective cholesterol levels (0-50 mol%). Thus a disparate giant vesicle population can be chemically induced to release the contents from only a portion of its members. PMID- 29711281 TI - Closure of the Cavity in Permethylated Cyclodextrins through Glucose Inversion, Flipping, and Kinking. AB - Glucose-flips in a small cycloamylose: the molecular structure of permethylated gamma-cyclodextrin, which crystallizes as the dihydrate, is characterized by 180 degrees flips of two diametrically opposed glucose residues. This leads to an elliptical distortion of the molecule and closure of the molecular cavity on one side so that it is no longer doughnut-shaped but is bowl-shaped. The hydrate water molecules are not located in the cavities! PMID- 29711282 TI - Quantitative Monitoring of Solid-Phase Synthesis Using Gated Decoupling 13 C NMR Spectroscopy with a 13 C-Enriched Protecting Group and an Internal Standard in the Synthesis of Sialyl LewisX Tetrasaccharide. AB - Just tagging along. For the nondestructive quantitative monitoring of solid-phase oligosaccharide synthesis a 13 C-enriched tag (*) was incorporated in the linker and a 13 C-enriched protecting group (?) was included in the growing molecule. By integration of the signals in a gated decoupling 13 C NMR experiment the reaction progress can be monitored. This method was demonstrated with the synthesis of sialyl Lewisx tetrasaccharide on a Tentagel support ((P)). Bn=benzyl, PEG=poly(ethylene glycol). PMID- 29711283 TI - Facile Oxidative Addition of O-H Bonds of Methanol and Water to IrI Complexes Having Peraryldiphosphane Ligands. AB - A new piece in the puzzle. Hydrido(alkoxo) complexes of late transition metals have often been postulated as intermediates or transition states in the catalytic hydrogenation of carbonyl compounds and catalytic hydrogen transfer reactions. Here the facile oxidative addition of the O-H bonds of alcohol and water to iridium(I) complexes of peraryldiphosphanes [Eq. (a)] is reported and the resulting complexes are described. R=H, Me. PMID- 29711284 TI - Novel Asymmetric and Stereospecific Aziridination of Alkenes with a Chiral Nitridomanganese Complex. AB - The addition of pyridine N-oxide is necessary to obtain high enantioselectivities in the asymmetric aziridination of styrene derivatives through transfer of a nitrogen atom from chiral, toluenesulfonic anhydride activated nitridomanganese complex 1 [Eq. (a)]. Remarkably, high stereospecificity was observed in all the aziridinations of trans- and cis-1,2-disubstituted alkenes. R1 =H, Me, nPr, iPr; R2 =H, Me; Ts=p-toluenesulfonyl. PMID- 29711285 TI - Novel Amidoniobium Complexes with a Functional Relationship to the [Cp2 ZrR]+ Ion. AB - Partial abstraction of apical methyl groups is observed in aminopyridinatoniobium alkyne complexes, as exemplified with the synthesis and characterization of 1. This results in cationic complex fragments, which facilitate the polymerization of ethylene and in the presence of methylalumoxane the selective dimerization of 1-butene. PMID- 29711286 TI - Diastereoselective Aldol Reaction with an Acetate Enolate: 2,6-Bis(2 isopropylphenyl)-3,5-dimethylphenol as an Extremely Effective Chiral Auxiliary. AB - A C2 -symmetrical phenol was used as a chiral auxiliary in the asymmetric aldol reaction of chiral acetates with various aldehydes [Eq. (a)]. The reaction proceeds readily under mild conditions to provide aldol adducts with high enantioselectivity. LDA=lithium diisopropylamide. PMID- 29711288 TI - Self-Assembling Sieves. AB - A modular strategy has been applied to synthesize large, porous, self-assembling capsules. The coupling of tricyclic building blocks incorporating glycoluril hydrogen-bonding units and derivatives of triethylbenzene produces monomers which readily form homo- and heterodimeric assemblies (calculated structure is shown). Large guests can be trapped while small solvent molecules flow freely through the pores of the capsules. PMID- 29711287 TI - Base-Catalyzed Synthesis of N-(2-Arylethyl)anilines and Base-Promoted Domino Synthesis of 2,3-Dihydroindoles. AB - The base is the key to the new one-pot reaction, which leads to pharmacologically interesting 2,3-dihydroindoles. The use of potassium tert-butylalcoholate enables the selective addition of primary anilines to substituted styrenes and a new domino reaction, consisting of a hydroamination and an aryne cyclization (see scheme). PMID- 29711289 TI - Carbynehydridoruthenium Complexes as Catalysts for the Selective, Ring-Opening Metathesis of Cyclopentene with Methyl Acrylate. AB - The first members of a homologous series of long-chain, multiply unsaturated esters were obtained upon selective ring-opening metathesis of cyclopentene with methyl acrylate [Eq. (a)]. The catalysts are cationic carbynehydridoruthenium complexes (e.g. L=OEt2 ), which were prepared for the first time by protonation of hydridovinylideneruthenium compounds in the presence of L. PMID- 29711290 TI - Dynamic Behavior of Organic Reactive Intermediates. AB - An unexpected yes is the answer the author gives to the following questions: If a reactive intermediate was faced with two equally high energy barriers to product formation, could the kinetic product ratio ever be anything other than 1:1? If the two barriers were of unequal height, could there ever be a preference to form the product that corresponds to the higher barrier pathway? The basis for this yes are the results from molecular dynamics simulations and experiments that suggest that the interpretation of reaction mechanisms by statistical models is not always correct. PMID- 29711291 TI - High Yields of Methanol from Methane by C-H Bond Activation at Low Temperatures. AB - Activation, oxidation, and functionalization are the essential steps in the direct selective conversion of methane into liquid chemicals such as methanol, formaldehyde, higher paraffins, and olefins. In the best process so far for the synthesis of methanol from methane, the reagent is converted with 90% conversion and 81% selectivity into methyl bisulfate in 102% sulfuric acid at 220 degrees C and in the presence of Pt complexes that contain very stable ligands. The desired product can be trapped by esterification and thus be protected from nonselective consecutive reactions. PMID- 29711292 TI - An Access to Glycoconjugate Libraries through Multicomponent Reactions. AB - Four-component reactions: The Ugi reaction of four suitably functionalized carbohydrate derivatives (as a per-O-benzylated amine, an aldehyde, a carboxylic acid, and an isocyanide) allow the effective assembly of diverse compound libraries. The complex glycoconjugates formed can be deprotected (see the picture for an example), and the resulting glycomimetics are of high interest for screening purposes. PMID- 29711293 TI - Ca5 Cl3 (C2 )(CBC): A Compound with a Layer Structure and an Unusual Anion Combination. AB - Allene homologous cumulenes are not always linear! The title compound, which has now been synthesized and structurally characterized, contains a BC2 unit that is isoelectronic with CO2 and that deviates by 16 degrees from linearity without losing the double-bond character of the B-C bonds. The BC2 unit is located in the center of a bicapped trigonal prism of calcium ions (see picture). PMID- 29711294 TI - Single-Step Construction of a Nine-Membered Carbocycle by a New [4+4+1] Cycloaddition. AB - A palladium catalyst serves as a template for the assembly of a nine-membered carbocycle from two molecules of vinylallene and one molecule of carbon monoxide [Eq. (a)]. This unprecedented [4+4+1] cycloaddition is in marked contrast to the [4+1] cycloaddition mediated by rhodium(I) catalysts. PMID- 29711295 TI - Unique Formation of a Crystal Phase Containing Cyclic Oligomers and Helical Polymers of the Same Monomeric Fragment. AB - The yellow, microcrystalline compound [Cu(pymo)] (Hpymo=2-hydroxypyrimidine) has been characterized with the newly emerging technique of ab initio X-ray powder diffraction. A unique and unprecedented crystal phase containing cyclic oligomers and infinite helical polymers (see picture) of the same monomeric fragment is selectively formed upon reaction of [Cu(CH3 CN)4 ][BF4 ] and Hpymo with NEt3 . PMID- 29711296 TI - Organizational Forms of Matter: An Inorganic Super Fullerene and Keplerate Based on Molybdenum Oxide. AB - Plato and Kepler would have been pleased. Despite the large number of atoms present the cluster anion 1 resembles an icosahedral-type structure. This represents definitively an unprecedented event in chemistry! The structure is made up of 12 {Mo11 } fragments such that the fivefold symmetry axes are retained in the resulting spherical object. As an inscribed icosahedron can be recognized in the spherical shell of 1 (see picture), similarities with Kepler's famous shell model of the cosmos can be seen. PMID- 29711297 TI - Ethenedithione (S=C=C=S): Does It Obey Hund's Rule? AB - Significantly higher in energy (24 kJ mol-1 ) than the triplet ground state (3 Sigmag- ) is the 1 Deltag state of ethenedithione (S=C=C=S), in agreement with Hund's rule. This result was obtained from high-level ab initio calculations. Thus, ethenedithione cannot, as had been proposed, be considered as the first example for the violation of Hund's rule in an equilibrium structure. PMID- 29711298 TI - A Surprising Solid-Phase Effect: Development of a Recyclable "Traceless" Linker System for Reactions on Solid Support. AB - Triazenes as "traceless" linkers for solid-phase synthesis have been utilized for the attachment of arenes to a solid support and yield the corresponding products after various organometallic reactions (Heck reaction and asymmetric dihydroxylation, see the reaction scheme) and cycloadditions (Diels-Alder reaction). The triazene linker is distinguished by its accessibility, thermal robustness, and capability to undergo regeneration. PMID- 29711299 TI - Chiral C2 -Symmetric CuII Complexes as Catalysts for Enantioselective Hetero Diels-Alder Reactions. AB - Air-stable and recyclable, the CuII -(bis)oxazoline complex 1 efficiently catalyzes diastereo- and enantioselective hetero-Diels-Alder reactions between beta,gamma-unsaturated alpha-keto acid derivatives 2 and vinyl ethers for the synthesis of substituted dihydropyrans 3 [Eq. (1)]. Results of the crystal structure analysis of 1 in combination with calculations on model compounds indicate the formation of a reactive intermediate through replacement of the two H2 O ligands with a chelating substrate. X=OEt, N(OMe)Me; R=alkyl, aryl, alkoxy, thiobenzyl. PMID- 29711300 TI - Micro-Scale Frontal Affinity Chromatography with Mass Spectrometric Detection: A New Method for the Screening of Compound Libraries. AB - In one run the binding constants Kd for all the active components of a ligand library at sub-microgram quantities can be determined. A mixture of ligands is continuously infused through a column of immobilized receptor, and the eluent analyzed by electrospray mass spectrometry. From the affinity chromatogram produced (see picture) the breakthrough volume of a single compound and hence its Kd value can be determined. PMID- 29711301 TI - Synthesis of Enantiopure alpha-Alkoxy-alpha-Trifluoromethyl Aldehydes and Carboxylic Acids from Trifluoromethyl Ketones. AB - Formaldehyde dialkylhydrazones behave as neutral d1 synthons in their uncatalyzed reaction with trifluoromethyl ketones (see reaction). Both racemic and optically pure 1,2-adducts were obtained in good yields. Efficient deprotection of the hydrazone moiety afforded interesting fluorinated quaternary compounds such as 1 and 2. PMID- 29711302 TI - Sapphyrin Supramolecules through C-H???S and C-H???Se Hydrogen Bonds-First Structural Characterization of meso- Arylsapphyrins Bearing Heteroatoms. AB - An unprecedented coupling reaction of heteroatom-containing tripyrranes leads to the formation of core-modified sapphyrins 1 and 2, which self-assemble in the solid state to form supramolecular ladders. Weak C-H???S and C-H???Se hydrogen bonding interactions in addition to C-H???N hydrogen bonds are responsible for the observed structures. PMID- 29711303 TI - Threefold and Fourfold [2+2] Cycloadditions of Cyclic Diynes as a Consequence of Steric Effects: En Route to Polymers. AB - The fine-tuning of the CpCo-mediated [2+2] cycloaddition of cyclic diynes with small bridges between the triple bonds (C2 H4 , Si2 Me4 ) yields nanosized beltlike cyclophanes 1 and 2. =SiMe2 ; R = H (1), CO2 Me (1, 2). PMID- 29711304 TI - A Convenient and General Method for Pd-Catalyzed Suzuki Cross-Couplings of Aryl Chlorides and Arylboronic Acids. AB - From only commercially available reagents a wide array of Suzuki cross-couplings of aryl chlorides with arylboronic acids can be effected in excellent yield [Eq. (a)]. This development provides a general solution to a long-standing limitation of this extremely powerful process-the poor reactivity of inexpensive and readily accessible aryl chlorides. dba=dibenzylideneacetone. PMID- 29711305 TI - Combinatorial Material Libraries on the Microgram Scale with an Example of Hydrothermal Synthesis. AB - In a 8-MUL multichambered microreactor (the photo shows the components) material libraries can be produced in a simple manner through combinatorial hydrothermal synthesis. In a model experiment the synthesis of the zeolite TS-1 has been varied combinatorially. The resulting library is characterized directly by automated microdiffraction. PMID- 29711306 TI - An Unprecedented Elimination-Driven Migration: The Reductive Dihalobornane Camphene Rearrangement. AB - An organometallic counterpart of the Wagner-Meerwein rearrangement, the incarnation of an carbocationic alkyl 1,2-migration, has now been discovered. However, the structural reorganization does not occur through carbanionic intermediates, but can only be brought about by a push-pull process via 1 a (see scheme). PMID- 29711307 TI - Nickel and Palladium Catalysis in the Stereoselective Synthesis of Functionalized Pyrrolidines: Enantioselective Formal Synthesis of (+)-alpha-Allokainic Acid. AB - Neuroexcitatory natural products are accessible from 1 via the intermediate 2, which is obtained by Ni-catalyzed cyclization, transposition of the protecting group, and Pd-catalyzed reduction with allylic transposition. This stepwise formation of stereocenters allows a highly direct and stereoselective synthesis of the excitatory amino acid (+)-alpha-allokainic acid, which displays an all trans arrangement of the substituents about the pyrrolidine ring. TBS=tert butyldimethylsilyl. PMID- 29711308 TI - Homogeneous Catalytic Hydrosilylation of Pyridines. AB - The color change from yellow to violet allows the formation of the intermediate [Cp2 Ti(SiHMePh)(pyridine)] to be monitored in the reaction of PhMeSiH2 with a pyridine in the presence of the precatalyst [Cp2 TiMe2 ] [Eq. (a)]; the hydride [Cp2 TiH] is postulated to be the key intermediate in the catalytic cycle. The regioselective hydrosilylation of pyridine and also substituted pyridines can be catalyzed by the titanocene [Cp2 TiMe2 ]. R=Me, CO2 Et. PMID- 29711309 TI - Synthesis of Immobilized CMP-Sialic Acids and Their Enzymatic Transfer with Sialyltransferase. AB - A novel immobilization procedure for glycoproteins is based on the reacion of immobilized CMP-NeuAc (CMP-sialic acids) with sialyltransferase (see scheme). The transfer ability was tested under various conditions; a corresponding oligosaccharide or asialoglycoprotein acted as sialyl acceptor. The solid-phase synthesis of CMP-NeuAc is also described. PMID- 29711310 TI - A New Intramolecular Reaction for the Regioselective Debenzylation or Protection of Alcohols. AB - Strained benzylidene acetals such as 1 can be prepared with a new intramolecular reaction that allows the selective removal of benzyl protecting groups neighboring free OH groups, without attacking other benzyl groups. The mechanism of this reaction, which is useful for carbohydrate synthesis, probably proceeds via ionic intermediates with neighboring group participation. PMID- 29711311 TI - Catalytic Enantioselective Aza Diels-Alder Reactions of Imino Dienophiles. AB - 1 mol% of catalyst is sufficient: The hetero Diels-Alder reaction of alpha-imino esters 1 with activated conjugated dienes 2 (R=H, Me) needs only 1 mol% of a 2,2' bis(diarylphosphanyl)-1,1'-binaphthyl (BINAP) copper(I) complex as the catalyst to generate the adducts 3 in good yields and with enantioselectivities up to 96%. The reaction can also be carried out on gram scale! Tos=H3 CC6 H4 SO2 ; TMS=Me3 Si. PMID- 29711312 TI - Two Coordination Modes of CO in Zeolites: A Temperature-Dependent Equilibrium. AB - CO interacts with exchangeable cations M+ (gray spheres in the picture) of zeolites to form M+ ???CO and M+ ???OC species (C: black; O: white) which are in a temperature-dependent equilibrium. For Na-ZSM-5 (M+ =Na+ ) the difference in interaction energy amounts to 3.8 kJ mol-1 , as determined by means of variable temperature FT-IR spectroscopy. PMID- 29711313 TI - Layered Dendritic Block Copolymers. AB - A star-shaped molecule and a layered structure are displayed by the title compound, where the layers consist of high molecular weight polymers. A core molecule that is functionalized by six hydroxyl groups acts as the initiator for the ring-opening polymerization of epsilon-caprolactone, leading to a six-arm star polymer. The second layer of the dendritic block copolymer with 12, 24, or 48 hydroxyl groups (depending on the dendron generation in use) is obtained by the linkage of chain ends with functionalized dendrons. These macromoleculse act as "macroinitiators" for the construction of a further layer of poly(epsilon caprolatone), the third generation of dendritic block copolymers. PMID- 29711314 TI - Novel Cyanide Coordination Models in Layer-Type Hydrated Double Salts of AgCN and AgF. AB - The edge-bridged triangular cluster [Ag3 (MU-CN)3 (H2 O)3 ] (left in picture) and the pseudo-cubane moiety [Ag3 F(H2 O)3 ] with an unoccupied Ag position (right in picture)-both hitherto unknown-are found in two new layer-type double salts of AgCN and AgF that display novel types of cyanide coordination modes. PMID- 29711315 TI - Supramolecular Aggregates of Dendritic Cyclophanes (Dendrophanes) Threaded on Molecular Rods with Steroid Termini. AB - Multinanometer-sized assemblies with molecular weights exceeding 14 000 are obtained by the threading of two dendritic cyclophanes (dendrophanes) onto molecular rods in which two testosterone termini are attached by rigid spacers to a central phenyl ring bearing two quaternary ammonium side chains. The formation of these structurally defined aggregates, in which the dendrophanes preferentially encapsulate the steroid termini (see picture), is driven by a combination of apolar interactions, hydrophobic desolvation, and ion pairing, and depends strongly on the length of the spacer. PMID- 29711316 TI - A Novel Domino Reaction: Cyclization of Alkynyl Sulfides by Reaction with IPy2 BF4. AB - Formation of polycyclic structures within a few minutes: The intramolecular cyclization of diynes, activated by a benzenesulfenyl substituent, upon reaction with IPy2 BF4 proceeds as an efficient exo-endo coupling. A subsequent novel Friedel-Crafts-like ring closure provides the product [Eq. (1)]. Thus, intra- and intermolecular cyclizations can be carried out. PMID- 29711317 TI - Mechanistic Implications of the Observation of Kinetic Resolution in a Palladium Catalyzed Enantioselective Allylic Alkylation. AB - Preferential rotation in substrate-palladium intermediates in a catalyzed asymmetric allylic alkylation is proposed to be responsible for both the observed kinetic resolution of the racemic allylic acetate starting material as well as the high selectivity found in the enantiodiscriminating product-forming step [Eq. (a)]. PMID- 29711318 TI - Desolvation of a Novel Microporous Hydrogen-Bonded Framework: Characterization by In Situ Single-Crystal and Powder X-ray Diffraction. AB - Despite significant structural rearrangement upon desolvation of a three dimensional molecular framework of hexaaquacobalt cations and redox-active functionalized tetrathiafulvalene anions (see the picture; the area filled with water molecules is shown in gray), monocrystallinity and microporosity are retained. X-ray analyses show that a unique combination of hydrogen bonds and pi???pi interactions within the framework gives this material a structural flexibility not seen in zeolites or their analogues. PMID- 29711319 TI - New Developments in the Field of Luminescent Materials for Lighting and Displays. AB - Owing to their use in fluorescent lamps and many display applications, luminescent materials affect our daily life. Improvement of already very mature as well as development of new materials demanded by a variety of new applications are the focus of research today. The latest advances in the field of electroluminescence enable new displays and light generation concepts that challenge the classical areas of application of luminescent materials. PMID- 29711320 TI - Synthesis of beta-Mannosides via Prearranged Glycosides. AB - The choice of activator is decisive for whether the alpha-(1->4)-linked disaccharide 2 alpha or the anomeric compound 2 beta is formed from the prearranged glycoside 1. Other beta-mannosylsaccharides can also be synthesized selectively by intramolecular glycosylation. Bn=benzyl, Bz=benzoyl, MeOTf= methyl trifluoromethanesulfonate, NIS=N-iodosuccinimide. PMID- 29711321 TI - Cationic Homoleptic Vanadium(II), (IV), and (V) Complexes Arising from Protonolysis of [V(NEt2 )4 ]. AB - At least three different cationic species arise in the classic protonolysis of [VIV (NEt2 )4 ] with a borate ammonium salt. The unexpected formation of the vanadium(V) species [V(NEt2 )4 ][B(C6 H5 )4 ] (shown in the picture without its counterion) underlines the problem of deducing the true oxidation state of vanadium species in Ziegler-Natta reactions. PMID- 29711322 TI - Encapsulation of Large, Neutral Molecules in a Self-Assembled Nanocage Incorporating Six Palladium(II) Ions. AB - What a large interior space in a molecule! Self-assembled cage compound 1 has a nanosized cavity (8 A in diameter) and can encapsulate as many as four molecules of o-carborane. A bulky guest, 1,3,5-tri-tert-butylbenzene, once encapsulated by means of thermally activated slippage, cannot escape from the cavity at room temperature since it is larger than the cavity entrance. PMID- 29711323 TI - Synthesis of Symmetric Metallocenes from Metallic Calcium, Strontium, or Barium and Pentaisopropylcyclopentadienyl Radicals. AB - The largest interplanar distance known to date between adjacent parallel rings of any sandwich compound (5.497(3) A) is displayed by decaisopropylbarocene, the first heavy alkaline earth metal sandwich compound to possess axial symmetry. A new efficient metallocene formation [Eq. (1)] utilizes the free cyclopentadienyl radical [C5 R5 ]. (R=CHMe2 ) as an oxidizing agent for elemental Ca, Sr, and Ba (M). PMID- 29711324 TI - Mechanistic Insights into Cu-Catalyzed Asymmetric Aldol Reactions: Chemical and Spectroscopic Evidence for a Metalloenolate Intermediate. AB - In situ IR spectroscopy and transmetalation experiments confirm a postulated catalytic cycle. The metalloenolate 1 describes the active intermediate in the aldol reaction catalyzed by [CuF2 {(S)-tol-binap}] (see reaction scheme). (S)-tol binap=(S)-(-)-2,2'-bis(di-p-tolylphosphanyl)-1,1'-binaphthyl. PMID- 29711325 TI - The First Organobismuth Rings: (RBi)3 and (RBi)4 , R=(Me3 Si)2 CH. AB - Surprisingly facile at low temperatures is the synthesis of the first cyclobismuthanes 1 and 2 [Eq. (1)]. In solution 1 and 2 are in equilibrium. The four-membered ring 2 forms black crystals, which were structurally analyzed. At room temperature the rings decompose to elemental bismuth and R3 Bi. R=(Me3 Si)2 CH. PMID- 29711326 TI - Acrylate-Assisted Arene-Chromium Bond Cleavage: Generation of a [Cr(CO)2 ] Fragment under Mild Conditions. AB - Displacement of the benzene ligand in 1 surprisingly occurs more readily than that of the methyl acrylate ligand. This paves the way for 1 to undergo arene exchange and arene substitution reactions, which may be triggered by a eta2 >eta4 haptotropic rearrangement of the acrylate. Complex 1 is thus a mild precursor of the highly unsaturated fragments [Cr(CO)2 ] (see scheme) and [Cr(CO)2 (eta2 -acrylate)]. PMID- 29711327 TI - Flight from the Tyranny of Tin: The Quest for Practical Radical Sources Free from Metal Encumbrances. AB - An urgent search is being made for generic reagents that promote free radical synthetic transformations as means of banishing the toxic threat of organotin hydrides. Although second-generation tin reagents are beguiling, organosilanes and a range of thiocarbonyl compounds are more intrinsically benign. Metal-free radical chain sequences based around cyclohexadiene derivatives are being developed (see reaction scheme), and tetrathiafulvalenes mimic metals and allow a crossover from homolytic to ionic chemistry. Z=alkene. PMID- 29711328 TI - Catalytic, Enantioselective Synthesis of alpha-Aminonitriles with a Novel Zirconium Catalyst. AB - Strecker reactions of aldimines with Bu3 SnCN in the presence of the novel chiral zirconium binuclear catalyst 1 provide alpha-aminonitriles in good yields and with high enantioselectivities. The reaction can be applied to a wide range of substrates. Since both enantiomers of the chiral sources are readily avaibable, both enantiomers of the alpha-aminonitriles are easily prepared according to this method. L=N-methylimidazole. PMID- 29711329 TI - Polycephalin B and C: Unusual Tetramic Acids from Plasmodia of the Slime Mold Physarum polycephalum (Myxomycetes). AB - Illumination results in increased formation of metabolites 1 and 2 in the plasmodia of the slime mold Physarum polycephalum. This was determined from HPLC studies undertaken in the search for the photoactive substances involved in the "blue-light phenomenon". The isolation and structure elucidation of 1 and 2 is described. PMID- 29711330 TI - Synthesis and Structure of the First Terminal Borylene Complexes. AB - A nearly linear arrangement is observed for the three atoms in the central W-B-N unit of the tungsten complex [(CO)5 WBN(SiMe3 )2 ] (1) in the crystal (W-B-N 177.9 degrees ; see picture). This compound along with its Cr analogue represent the first examples of terminal borylene complexes with a two-coordinate metal bound boron atom. The geometries of the axial and equatorial CO groups in 1 are similar, and thus indicate that there is no trans effect of the borylene ligand. PMID- 29711331 TI - Multiple Ga-Ga Bonding Character in Na2 [Ga(GaTrip2 )3 ], and a Comparison with Neutral Ga(GaTrip2 )3 (Trip=2,4,6-iPr3 C6 H2 ). AB - Delocalized over the Ga4 framework, the two electrons are lost in the oxidation of Na2 [Ga(GaTrip2 )3 ] to Ga(GaTrip2 )3 . This leads to a lengthening of the Ga Ga bond by about 0.08 A. Ar=Trip=2,4,6-iPr3 C6 H2 . PMID- 29711332 TI - Long-Range N->Si Interactions in Organosilicon Compounds with Hepta- and Octacoordinate Silicon Centers. AB - Coulomb-dominated donor-acceptor interactions are, according to results of density functional calculations, the rationale for the extremely long Si-N distances (about 300 pm) in unusual hypercoordinate organosilicon compounds with seven- and eight-coordinate Si centers. The picture shows an example with sevenfold coordination. PMID- 29711333 TI - Directed Evolution of Enzymes. AB - On the way to a combinatorial biotechnology? The directed evolution of enzymes promises a rapid access to effective biocatalysts. New molecular biology techniques for random mutagenesis in combination with high-throughput screening might revolutionize the creation of enzymes with new and improved properties. PMID- 29711334 TI - Versatile Ligands for Palladium-Catalyzed Asymmetric Allylic Alkylation. AB - Palladium complexes of the chiral diphosphanes 1 and 2 which possess a rigid backbone and a large bite angle catalyze the alkylation of allyl compounds with both high enantioselectivities and reaction rates, particularly with less sterically demanding substrates. 1: R=Me, X=S; 2: R=H, X=C(CH3 )2 . PMID- 29711335 TI - New Protecting Group Strategies for the Solid-Phase Synthesis and Modification of Peptides, Oligonucleotides, and Oligosaccharides. AB - Blocking and activation can be achieved with protecting groups such as the ortho nitrobenzenesulfonyl group (see picture). In solid-phase peptide synthesis, this group can be used for temporary protection (path A) as well as the activation and selective N-alkylation (path B) of an amino group. PMID- 29711336 TI - Synthesis of p-Phenylene Sulfide Molecular Asterisks. AB - "Megastars" with aromatic central cores, some of which fluoresce, were synthesized by the efficient connection of the side arms to the core by using the MacNicol reaction. Depending on the length of the side arm precursor, second-, third- (depicted), or fourth-generation molecular asterisks were obtained; a twelve-armed molecular asterisk was prepared when the benzene core was replaced by a coronene one. PMID- 29711337 TI - Remarkable Reaction of Hetero-S-Block-Metal Amides with Molecular Oxygen: Cationic (NMNMg)2 Ring Products (M=Li or Na) with Anionic Oxo or Peroxo Cores. AB - Deliberate treatment of solutions of amines with molecular oxygen has given rise to magnesium-substituted derivatives of classical alkali metal amide ring structures (NMNMg)2 (M=Li or Na), but with oxo or peroxo cores. The picture shows the structure of the sodium compound [{(Me3 Si)2 N}4 Na2 Mg2 (O2 )x (O)y ]. PMID- 29711338 TI - Three New Structural Types of Mo/Ag/S Polymeric Complexes. AB - Wavelike, zigzag, and helical polymers are formed by the reaction of [MoS4 ]2- , Ag2 S, and a complementary cation. The framework of the polymeric anions depends on the valence state of the latter. For example, the butterfly-type anionic chain shown in the picture is formed upon use of a divalent cation. There is a general tendency that a higher valence state of the cation will induce a more compact chain structure. PMID- 29711339 TI - Generation of a Silylene Complex by the 1,2-Migration of Hydrogen from Silicon to Platinum. AB - An extraordinary downfield-shifted 29 Si{1 H} NMR signal is seen at delta=338.5 for the platinum silylene complex [(dippe)(H)Pt=SiMes2 ][MeB(C6 F5 )3 ] (2). This remarkably stable metal silylene complex was obtained from 1 in the first intramolecular 1,2-hydride migration from silicon to a transition metal. dippe=iPr2 PCH2 CH2 PiPr2 , Mes=2,4,6-Me3 C6 H2 . PMID- 29711340 TI - A Novel Class of Ruthenium Catalysts for Olefin Metathesis. AB - The different nature of carbene ligands is clearly demonstrated by the first ruthenium-based complexes 1, which contain both alkylidene and N-heterocyclic carbene moieties. The latter exhibit a pronounced Lewis base behavior. Moreover, this difference forms the basis of the high catalytic activities of these compounds in olefin metathesis reactions. PMID- 29711341 TI - Magnesium Complexes Bearing eta2 -Pyrazolato Ligands. AB - Despite the small size of the magnesium ion, eta2 -bound pyrazolato ligands are found in complexes 1-3. These complexes provide new insight into the design of volatile Group 2 metal complexes for use in chemical vapor deposition processes. PMID- 29711342 TI - Efficient Synthesis of a Novel Estrone- Talaromycin Hybrid Natural Product. AB - Numerous pharmacologically interesting compounds are available by the synthesis of hybrid natural products. Thus, for instance, the estrone-talaromycin hybrid 2, which is synthesized in a few steps from the estrone derivative 1 by a sequence in which a hetero-Diels-Alder reaction is the key step, exhibits notable cytotoxic activity. PMID- 29711343 TI - Modeling of Benzene Adsorption in Metal-Exchanged Zeolites by Calculation of 7 Li Chemical Shifts. AB - A 1:1 complex between Li+ and benzene is formed when benzene is adsorbed into a Li-exchanged zeolite. This was the result of calculations of the 7 Li chemical shifts for several model complexes, including Li+ ?2 H2 O?C6 H6 (depicted). After 13 C and 2 H, 7 Li is a further nucleus that can be studied to determine the structure and dynamics of complexes formed between organic species and metal cations in zeolites. PMID- 29711344 TI - The First Six-Membered "True" Heterocycle - Hydrogen-Bond-Assisted Ladder Formation in a KOCNPS Ring System. AB - A ladder of alternating K2 S2 and K2 O2 rings exists in K[Ph2 P(S)NC(O)Ph]?MeOH, the first six-membered "true" heterocycle, in the solid state (see picture). A simple P-N bond-forming reaction between benzamide and Ph2 PCl gives the precursor Ph2 P(S)NHC(O)Ph, from which the potassium salt can be generated by reaction with KOtBu. PMID- 29711345 TI - Solid-Phase Synthesis of Macrocyclic Systems by a Cyclorelease Strategy: Application of the Stille Coupling to a Synthesis of (S)-Zearalenone. AB - No heteroatom required! In many solid-phase syntheses, after the release from the polymer support a heteroatom (e.g. O, S, N) remains in the substrate as a residue of a linking protecting group. With polymer-bound tin reagents cleavage and cyclization of the substrate with C-C bond formation (see picture) can now be achieved by intramolecular Stille coupling. S=substrate. PMID- 29711346 TI - Evidence for Selective Association of Tetrahedral BO4 Units with Na+ and of Trigonal BO3 Units with H+ in Dehydrated Zeolite B-ZSM-5 from Solid-State NMR Spectroscopy. AB - Conclusive proof has now been obtained for the selective association of trigonal BO3 and tetrahedral BO4 units with H+ and Na+ ions, respectively, in B-ZSM-5 zeolites (the interactions are depicted in the picture). This was achieved with a combination of 11 B{23 Na}, 11 B{1 H}, and 1 H{11 B} rotational echo double resonance (REDOR) NMR spectroscopic experiments. PMID- 29711347 TI - Novel Biocatalysts by Chemical Modification of Known Enzymes: Cross-Linked Microcrystals of the Semisynthetic Peroxidase Seleno-Subtilisin. AB - The linkage of lysine residues on the surfaces of subtilisin crystals (NH2 -Enz; see Scheme) with glutardialdehyde affords an immobilized biocatalyst of high stability and purity. The replacement of the serine OH group in the active site (Enz-OH) by SeO2 H leads to new activity as a peroxidase. Thus for the first time, chemical enzyme engineering has resulted in a biocatalyst with a modified peptide framework as well as a new catalytically active site. This methodology combines reasonable substrate selectivity of a semisynthetic enzyme with the exceptional stability of cross-linked enzyme crystals. PMID- 29711348 TI - Silicon Boron Nitrides: Hypothetical Polymorphs of Si3 B3 N7. AB - A simple construction principle is provided for the generation of Si-B-N structures. With this protocol, for example, starting from alpha-Si3 N4 (1) a nitrogen atom is removed (->2), three silicon atoms are replaced by boron (->3), and the structure is relaxed to give 4 (Si: large empty circles, N: small empty circles, B: small filled circles). For Si3 B3 N7 over 100 structures were derived in this way, whose geometries and energies were determined by density functional calculations. Two likely candidates for crystalline Si3 B3 N7 were found. PMID- 29711349 TI - How Does Nature Cleave Sulfuric Acid Esters? A Novel Posttranslational Modification of Sulfatases. AB - A rare inherited disease, multiple sulfatase deficiency, is attributed to a defect in a posttranslational protein modification which is essential for the catalytic activity of all known sulfatases. Structure analysis of arylsulfatase A, the enzyme that cleaves sulfatide 1, shows that the modification of a cysteine residue into a formylglycine residue is essential for catalytic activity. PMID- 29711350 TI - The Stability of the Oxidation State +4 in Group 14 Compounds from Carbon to Element 114. AB - The stability of the oxidation state +4 decreases from silicon to element 114, as shown by relativistic and nonrelativistic calculations on the hydrides, fluorides, and chlorides of the Group 14 elements (the energies of the decomposition reaction (1) are given in the plot). Thus it is unlikely that superheavy element 114, which may have stable isotopes due to its magic numbers of protons and neutrons, can be studied by atom-at-a-time chemistry in the oxidation state +4. PMID- 29711351 TI - A Coordination-Chemical Basis for the Biological Function of the Phytochelatins. AB - To fix toxic heavy-metal ions, plants synthesize the ligands (gamma-Glu-Cys)n Gly (PCn ), whose simplest representative is the pentapeptide PC2 . The knowledge of the composition and stabilities of the cadmium complexes of PC2 allow a better understanding of biological processes like the one outlined. PMID- 29711352 TI - Reactions of Selected Bismuth Oxide Cluster Cations with Propene. AB - Bismuth oxide cluster ions are reduced by propene in exactly the same way as solid bismuth oxide (Bi2 O3 ), which is used as a catalyst. Even in the case of the smallest bismuth oxide cluster ions, such as the Bi3 O4+ isomer shown in the picture, the supposedly unreactive bridging oxygen atom can participate in the alkene oxidation. PMID- 29711353 TI - Extended Calixpyrroles: meso-Substituted Calix[6]pyrroles. AB - A 1,3,5-alternate conformation of the pyrrole rings is adopted by the calix[6]pyrrole 1 in the crystal (see picture). Compound 1 was synthesized in a two-step process and although it crystallizes in the form of the adduct 1?3CH3 COCH3 ?H2 O?CHCl3 , there are no solvent molecules in the cavity (cross section ca. 60A2 ) of this macrocycle which possesses alternating dimethyl and diphenyl substitutents at the meso positions. PMID- 29711354 TI - Self-Organization and Formation of Liquid Crystal Phases by Molecular Templates Related to Membrane Components of Archaebacteria. AB - Tubular supramolecular aggregates are formed from glycolipids 1, which are closely related to natural components of membranes of archaebacteria. The glycolipids exhibit disordered columnar thermotropic and hexagonal lyotropic liquid crystal phases. Whereas formation of the mesophases is insensitive to stereochemical factors, formation of the tubules is dependent on the configuration of the stereocenters that are shown in the picture but not specified. PMID- 29711355 TI - Solid-State Structural Investigation of an Organolithium (-)-Sparteine Complex: eta3 -N-Boc-N-(p-methoxyphenyl)-3-phenylallyllithium?(-)-Sparteine. AB - A eta3 monomeric alkyllithium?(-)-sparteine complex has been isolated and characterized in the solid state (see picture). Determination of the absolute configuration of this key intermediate in asymmetric metalation/substitution sequences of N-tert-butoxycarbonyl-N-(p-methoxyphenyl)cinnamylamine allows definitive assignment of the stereochemical course of its electrophile-dependent substitution reactions. PMID- 29711356 TI - A Facile Generation of a Cyclopropylzinc Compound from an Alkenylzinc Derivative and Its Reaction with Electrophiles. AB - The one-pot synthesis of cyclopropyl compounds from 1-alkynes has been achieved by direct cyclopropanation of a 1-alkenylzinc species upon treatment with iodomethylzinc and trapping of the cyclopropylzinc intermediate with allyl bromide in the presence of CuCN?2 LiCl (see reaction scheme). This method proceeds under mild conditions and in good yield. PMID- 29711357 TI - Catalytic Enantioselective Retro-Aldol Reactions: Kinetic Resolution of beta Hydroxyketones with Aldolase Antibodies. AB - High enantiomeric enrichment after 50% conversion: Racemates of aldols can be resolved by the title reaction [Eq.(1)] by use of the aldolase antibody 38C2 or 33F12; the ee values of the unconverted aldols are greater than 95% in most cases. Since the antibodies also catalyze the aldol reaction-that is, the reverse reaction-it is possible to prepare both enantiomers using the same antibody catalysts. PMID- 29711358 TI - Fullerenes and Soot Formation- New Pathways to Large Particles in Flames. AB - For as long as man has known fire, he has also been aware of soot-but the fact that fullerenes can be formed in a flame has only been been known for eleven years (see diagram). The research into the mechanism of their formation has brought forth many other unexpected particles that can exist in flames, for example "aromers" (aromatic oligomers). PMID- 29711359 TI - Towards a Rational Synthesis of Large-Pore Zeolite-Type Materials? AB - A range of novel structures, such as the metalloaluminosilicate UCSB-8 (depicted schematically), are accessible by synthetic strategies that could provide the basis for the rational design of other large-pore zeolites and zeolite-type materials. The combination of experimental approaches with computational methods, for example host-guest shape analysis, may provide further breakthroughs in this field. PMID- 29711360 TI - Perhydroxylated 1,7-Dioxaspiro[5.5]undecanes ("Spiro Sugars"): Synthesis, Stereochemistry, and Structure. AB - As spiro sugars is an apt way of considering perhydroxylated 1,7 dioxaspiro[5.5]undecanes-a class of compounds which has not been found in nature up to now. The crystal structure of such a spiroacetal, in which the two pyran rings show the beta-D-manno configuration, is depicted. Note that the all-trans arrangement of C-6, C,-5, Opyr , Cspiro , Opyr' , C-5', and C-6' does not allow any of the stereoelectronic effects that are typical of carbohydrates. PMID- 29711361 TI - Mevalonate-Independent Biosynthesis of Terpenoid Volatiles in Plants: Induced and Constitutive Emission of Volatiles. AB - Terpenoids from flower and leaf volatiles are predominantly synthesized along the mevalonate-independent pathway, as shown by administration of [D2 ]deoxy-D xylulose and [D5 ]mevalolactone. The parallel use of two pathways for the biosynthesis of the sesquiterpenoid-derived 4,8-dimethylnona-1,3,7-triene (DMNT, see picture) may be important to ensure the synthesis of the volatile alarm codes of plants. PMID- 29711362 TI - Quadruple Decker [3.3][3.3][3.3]Orthocyclophane Acetal-An Orthocyclophane Ladder. AB - Through clever bridging of orthocyclophanes (in this case by acetalization), molecules such as 1 can be formed with four benzene rings in a stacked face-to face arrangement. UV/Vis spectroscopic and electrochemical properties of 1 are governed by pi-pi through-space interactions within the molecule. PMID- 29711363 TI - Carbohydrates as Multifunctional Chiral Scaffolds in Combinatorial Synthesis. AB - Four orthogonally stable protecting groups and a selectively cleavable anchor that are stable under basic conditions are required in order that carbohydrates can be employed as chiral polyfunctional scaffolds in combinatorial solid-phase syntheses of high diversity. The schematic representation shows the combinatorial synthesis with a carbohydrate scaffold (SG=protecting group, A=anchor, P=polymer carrier), which proceeds by sequential selective deprotection, functionalization, washing of the solid phase, and cleavage of the anchor. PMID- 29711364 TI - Photoactivated Preparation and Patterning of Self-Assembled Monolayers with 1 Alkenes and Aldehydes on Silicon Hydride Surfaces. AB - Direct lateral patterning in the formation of self-assembled monolayers (SAMs) on silicon was achieved by the photoinduced reaction of aldehydes with Si(111)-H surfaces by using the usual masking techniques (see the schematic illustration; on the right-hand side is a microscopy image of a patterned SAM formed from octadecanal). PMID- 29711365 TI - An Unexpected Layered Structure in Inorganic Cyanide Clusters: [Cu4 (MU3 -OH)4 ][Re4 (MU3 -Te)4 (CN)12 ]. AB - Diffusion of aqueous solutions of K4 [Re4 Te4 (CN)12 ] and CuCl2 in the opposite direction through silica gel gives rise to the new polymer-like compound 1. This complex has a layered structure built from the interconnected cubane-like cluster cations [Cu4 (MU3 -OH)4 ]4+ and the cluster anions [Re4 Te4 (CN)12 ]4- (see picture). PMID- 29711366 TI - Intermediate Product-Catalyst Complexes in the Homogeneous Hydrogenation of Styrene Derivatives with Parahydrogen and Cationic RhI Catalysts. AB - The catalyst-bound intermediate 1 is detected in the homogeneous hydrogenation of styrene derivatives in the presence of cationic RhI catalysts 2. The detachment from the catalyst of the ethylbenzene 3 formed turns out to be slow and possibly rate-determining in some cases. PMID- 29711368 TI - Colloid-Bound Catalysts for Ring-Opening Metathesis Polymerization: A Combination of Homogenous and Heterogeneous Properties. AB - Tailor-made thiols allow a ruthenium-based catalyst for ring-opening metathesis polymerization (ROMP) to be tethered to bulk gold surfaces and to gold colloids (see picture). The functionalized gold colloids combine the properties of homogeneous and heterogeneous catalyst systems. Tethering of the catalyst leads to a pronounced increase in its catalytic activity. PMID- 29711367 TI - The First Heterotriquinone and Dicyanoheterotriquinone Methide That Undergo a Five-Stage Amphoteric Redox Reaction. AB - The dicyanomethylene group and not the quinone oxygen atoms is the site of the first one-electron reduction for the dicyanohetereotriquinone methide 1, although the dicyanomethylene group is substituted at a cyclopentadienyl-like five membered ring! Compound 1 is amphoteric and undergoes a five-stage sequence of one-electron redox reactions. PMID- 29711369 TI - Electrochemical Synthesis of Polypyrrole Nanowires. AB - Through a hole in a poly(ethyl acrylate) (PEA) layer that is electrochemically grafted to the surface of a vitreous carbon electrode-that is the route that must be taken by a growing polypyrrole nanowire in the electropolymerization of pyrrole. Chain growth is controlled by diffusion of the monomer through the DMF swollen PEA layer, which acts as a template for the formation of nanowires (shown in the picture) with diameters of 400-1000 nm and lengths of up to 300 MUm. PMID- 29711370 TI - Stereoselective Allylic C-H Activation with Tertiary Alkylboranes: A New Method for Preparing Cycloalkyl Derivatives with Three Adjacent Stereocenters. AB - A regio- and stereoselective migration takes place under mild conditions for tertiary organoboranes obtained by hydroboration of tetrasubstituted cyclic alkenes. A subsequent amination proceeds with perfect control of the stereochemistry. The scheme shows an example of this for the reaction of bicyclo[4.3.0]non-1(6)-ene (1) to 2 via intermediates 3 and 4. Compound 2 is formed as the single diastereomer in 69% yield. PMID- 29711371 TI - Organic Synthesis and Biological Signal Transduction. AB - The understanding of cellular communication pathways in molecular detail is an important goal of bioorganic research. The synthesis of analogues of active substances (e.g. 1) to study the regulation of muscle contraction or the specific lipid modification of representative peptides (->2) to investigate their subcellular, targeted transfer to intracellular membranes are examples of the capability of organic synthesis is in the research of biological signal transduction mechanisms. PMID- 29711372 TI - A Naphthalene-Like Si1010- Unit in the Novel infinity2 [Si2030- ] Planar Anion of Sr13 Mg2 Si20. AB - Two interpenetrating 2infinity [Si2030- ] polyanions with naphthalene-like Si1010 building blocks (see picture) characterize the"nonclassical" Zintl phase Sr13 Mg2 Si20 , which is formed from the elements at 1230-1240 K. The ecliptical stacking of the Si1010- units leads to one-dimensional conductivity along the stacking direction. PMID- 29711373 TI - Silanediols: A New Class of Potent Protease Inhibitors. AB - Transition state analogues of the peptide hydrolysis intermediate can take the form of complex silanediols such as 1, which inhibits angiotensin-converting enzyme (ACE) at nanomolar concentrations. In contrast, earlier investigation of enzyme inhibition with simple silanediols and silanetriols showed them to be inactive. PMID- 29711374 TI - Amidoglycosylation of Polymer-Bound Glycals: A Complete Solid-Phase Synthesis of the Oligosaccharide Domain of the Lewisb Blood Group Determinant. AB - A new general method for the preparation of N-acetylglucosamine glycosidic linkages has been developed for solid-phase synthesis. The complete pentasaccharide domain of the Lewisb blood group antigen, which is a mediator in the formation of ulcers and gastric cancer, has now been synthesized on solid support (see 1; the shaded circle is the polystyrene support; TIPS=triisopropylsilyl). PMID- 29711375 TI - Controllable Intramolecular Motions That Generate Fluorescent Signals for a Metal Scorpionate Complex. AB - Simply by changing the pH value, the side chain of complex 1 can be reversibly moved between two positions. Coordination to the metal center through the nitrogen atom of the side chain at moderate pH values is accompanied by a decrease in fluorescence intensity (from IF =100% to IF =60%). A further decrease is observed upon deprotonation of the bound water molecule at higher pH (IF <=2%). Therefore, 1 can be seen as a molecular three-position switch. PMID- 29711376 TI - Influence of the trans Substituent on N2 Bonding in Iron(ii)-Phosphane Complexes: Structure, Synthesis, and Properties of the Monomeric Adducts trans-[FeXN2 (depe)2 ]BPh4 , X=Cl, Br. AB - Not a dimer but a monomer was found in the X-ray structure analysis of the complex "trans-[{FeCl(depe)2 }2 (u-N2 )](BPh4 )2 " (depe=Et2 PCH2 CH2 PEt2 ). The complexes [FeXN2 (depe)2 ]BPh4 (X=Cl, Br; structure of the cation for X=Cl shown on the right) are much less stable than the analogous hydride compounds and undergo N2 exchange at room temperature even in the solid state. PMID- 29711378 TI - Stabilities of Hydrogen-Bonded Supramolecular Complexes with Various Numbers of Single Bonds: Attempts To Quantify a Dogma in Host-Guest Chemistry. AB - The disadvantage of flexible bonds in supramolecular host-guest complexes is much smaller than usually assumed. In the association of dicarboxlic acids with diamides (shown on the right), freely rotatable single bonds have only a minor disadvantageous influence on the free energy of complexation DeltaGcplx . From the linear correlation between DeltaGcplx and the number of single bonds n, a decrease in the free energy of complexation of only 1.3 kJ mol-1 per single bond was determined. PMID- 29711377 TI - Structure and Properties of Tetracyanomanganate(II), [MnII (CN)4 ]2- , The First Paramagnetic Tetrahedral Cyanometalate Complex. AB - A place in the sun for solutions of [(Ph3 P)2 N]2 [Mn(CN)6 ] provides-by photochemical degradation-[MnII (CN)4 ]2- ions, the only homoleptic cyanide complex ion that is high spin (structure depicted on the right). Magnetic measurements indicate a high-spin 6 A1 ground state (S=5/2), and the cyanide ligands are virtually entirely sigma donors, without significant binding contributions from d-pi* back-bonding. PMID- 29711379 TI - Intermolecular Hydrogen Bonding between Water and Pyrazine. AB - Completely planar is the hydrogen-bonded complex of pyrazine and water (see sketch), which was obtained by supersonic expansion and investigated by rotational spectroscopy. The water molecule lies in the plane of the aromatic ring, and the lone pair of electrons on the nitrogen atom functions as the acceptor in the N???H-O hydrogen bond, not-as in the corresponding benzene complex-the pi electrons. PMID- 29711380 TI - Rhodium(I)-Catalyzed Regioselective Ring- Expanding Rearrangement of Allenylcyclopropanes into Methylenecyclopentenes. AB - A highly regioselective C-C bond cleavage of the cyclopropane rings occurs in substituted allenylcyclopropanes in the presence of cationic rhodium(I) complexes. Thus, ring expansion of readily accessible allenylcyclopropanes can be achieved to give 3-methylenecyclopentenes, which could have applications as multifunctional synthetic building blocks. PMID- 29711381 TI - From D-Arabinose to the Marine Natural Product Eleutherobin. AB - Two total syntheses of eleutherobin (1) were published within a short period of time by the research groups of K. C. Nicolaou and S. J. Danishefsky. The broad interest in this marine natural product from the soft coral Eleutherobia sp. is attributed to its ability to inhibit the depolymerization of the microtubuli and thereby prevent the division of cancer cells. PMID- 29711382 TI - The Most Twisted Amide: Structure and Reactions. AB - The title amide 1 behaves more like a ketone-up to a point! The crystal structure of this (90 degrees ) twisted amide shows a pyramidal nitrogen atom next to a planar carbonyl group. PMID- 29711383 TI - Alkaline Earth Diazapentadienyl Compounds: Structure of [Ba2 {(C6 H11 )NC(Me)CHC(Me)N(C6 H11 )}3 {(SiMe3 )2 N}]. AB - Three different bonding modes in one molecule! The diazapentadienyl ligands in the title compound 1 adopt eta1 ,eta1 -N,N-chelating plus eta5 -terminal, eta1 eta1 -N,N chelating plus eta5 -bridging, and novel eta1 -N plus eta3 -1-aza-allyl bonding modes. R=cyclohexyl. PMID- 29711384 TI - The Total Synthesis of Eleutherobin: A Surprise Ending. AB - An "sp2 -sp3 Stille coupling" of the vinyl triflate 1 and the stannyl compound 2 is a key step toward the completion of the total synthesis of eleutherobin, a natural product exhibiting taxol-like cytotoxic activity. PMID- 29711385 TI - A Spin-Frustrated System Composed of Organic Radicals and Magnetic Metal Ions. AB - Despite antiferromagnetic coupling between any two neighboring spins, parallel alignment of the 3d spins of the MnII ions and the 2p spins of the organic ligand is observed for the (degenerate) ground state of [{Mn(hfac)2 }2 (bnn)] (shown on the right). The "butterfly"-shaped arrangement of the spins contributes to this noteworthy spin configuration. hfac=hexafluoroacetylacetonate, bnn=2,2'-bis(1 oxyl-3-oxide-4,4,5,5-tetramethylimidazolinyl). PMID- 29711386 TI - In Situ X-Ray Diffraction Study of the Initial Stages of Formation of MCM-41 in a Tubular Reactor. AB - A continuous process for the synthesis of mesoporous silicates such as MCM-41 at room temperature has been achieved by employing a tubular reactor in which tetraethoxysilane was used as the silicate source (see schematic representation below). The formation of the hexagonal mesophase, which was monitored by using in situ XRD at different points of the tube, was completed in three minutes after mixing of the reactants. The product was stable to calcination, and N2 -sorption measurements confirmed the high surface area and narrow pore-size distribution. PMID- 29711387 TI - Yttrate-Mediated Ligand Transfer and Direct Synthesis as a Route to Amidopalladium Complexes. AB - A ligand transfer from yttrium to palladium and the regeneration of 1 are the crucial steps in the efficient synthesis of the very strained amidopallium complex 2 from [(cod)PdCl2 ] and 1 (cod=cyclooctadiene). In the light of the numerous "ate" complexes of early transition metals, this synthetic route should have enormous potential. PMID- 29711388 TI - Formation of Adamantane-Like Structures by Reaction of Titanocene Fluorides with an Iminoalane. AB - Fluorine-nitrogen metathesis in the reaction of a cyclic iminoalane with titanocene fluorides results in unexpected cage compounds. Treatment of one of these compounds with diethyl ether leads to 1, which contains a titanium-nitrogen double bond stabilized intramolecularly by fluorine. PMID- 29711389 TI - A Gas-Phase Model for the Pt+ -Catalyzed Coupling of Methane and Ammonia. AB - What exactly are the elementary steps in the Pt-catalyzed coupling of methane and ammonia (Degussa process) shown on the right? Mass spectrometry and ab initio theory have been used to probe the mechanistic details of this technically important synthesis of hydrogen cyanide. PMID- 29711391 TI - Direct Preparation of Trifluoromethyl Ketones from Carboxylic Esters: Trifluoromethylation with (Trifluoromethyl)trimethylsilane. AB - Previously difficult to prepare, aliphatic and alicyclic trifluoromethylketones (e.g. 1 and 2), which are of pharmacalogic interest as potential enzyme inhibitors, can now be synthesized easily and efficiently. The one-step reaction starting with carbonic esters and trimethyl(trifluoromethyl)silane is induced by tetrabutylammonium fluoride in nonpolar, aprotic solvents and proceeds without formation of double-addition products. PMID- 29711390 TI - Investigating the Selectivity of Triacontyl Interphases. AB - What causes the shape selectivity of C30 phases? This question can be answered by combining NMR and fluorescence spectroscopies with HPLC separations at various temperatures. The selectivities depend on the ratio of trans to gauche conformations of the alkyl chains, whose dynamic behavior was characterized with a two-dimensional solid-state NMR spectrum (shown on the right). PMID- 29711392 TI - SIAM, a Novel NMR Experiment for the Determination of Homonuclear Coupling Constants. AB - The simultaneous acquisition of in-phase and antiphase multiplets with high sensitivity and minimum overlap (see section of 2D spectra on the right) is possible in a novel NMR experiment. Based on this method, homonuclear coupling constants such as the 3 J(HN ,Halpha ) couplings in peptides and proteins can be determined quantitatively without isotope labeling. PMID- 29711393 TI - alpha-Iodoalkyl-Iodine-Ate Complexes as Observable Intermediates in the Iodine- Magnesium Exchange Reaction. AB - An intermediate with a half-life of 30 minutes has been observed in the iodine magnesium exchange reaction of 1,1-diiodoalkanes in THF at -78 degrees C. This intermediate is likely the ate complex 1. Its characteristic chemistry calls for a mechanistic reconsideration of several features of the halogen-metal exchange reaction. PMID- 29711394 TI - Mixed Ligands from Group 15/16 Elements: Interface of Solid-State and Molecular Chemistry. AB - A wide range of chemical compounds is spanned by heteroatomic ligands from Group 15/16 elements, which in Nature extend from AsS (in realgar) to [AsS2- ]infinity (in sulfosalt minerals). The stabilization of labile molecules or those that do not exist in the free state by incorporation into transition metal complexes like [Cp*2 Fe2 (AsSe)2 ] (1) and the oligomerization of molecular units under the influence of metal ions or complexes to form solids or hybrid clusters with inorganic cores and peripheral organometallic ligands are the main subjects of this article. Cp*=C5 Me5 . PMID- 29711395 TI - Rate Acceleration in Nucleophilic Alkylation of Carbonyl Compounds with a New Template Containing Two Metallic Centers. AB - Two aluminum centers aligned in the same direction capture carbonyl groups in such a way that efficient alkyl transfer becomes possible from aluminum to the carbon atom. This occurs via a favorable cyclic six-membered transition state (1). Carbonyl compounds can now be alkylated with otherwise less reactive alkylmetal species. PMID- 29711397 TI - Fluorescent Chemosensors for Cu2+ Ions: Fast, Selective, and Highly Sensitive. PMID- 29711396 TI - Catalytic Hydrogenolysis at Low Temperature and Pressure of Polyethylene and Polypropylene to Diesels or Lower Alkanes by a Zirconium Hydride Supported on Silica-Alumina: A Step Toward Polyolefin Degradation by the Microscopic Reverse of Ziegler-Natta Polymerization. AB - Cleavage and polymerization with the same catalyst: The catalyst system named in the title, which cleaves polyethylene and polypropylene under a hydrogen atmosphere, is also capable of polymerizing ethylene or propylene. This shows the close relationship between olefin insertion and beta-alkyl elimination [Eq. (a), (P)=polymer chain(P)]. PMID- 29711398 TI - A Kinetically Stabilized [1.1]Paracyclophane: Isolation and X-Ray Structural Analysis. AB - Benzene rings severely bent and closely stacked face-to-face are revealed in the crystal structure of the [1.1]paracyclophane derivative 1, which could be isolated thanks to the kinetic stabilization provided by the steric shielding of the bridgehead sites by the substituents. PMID- 29711399 TI - MnII [MnII (CN)4 ]-A Magnetic Interpenetrating Three-Dimensional Diamondlike Solid. AB - Three-dimensional extended diamondlike networks containing four-coordinate metal centers can be constructed from [MnII (CN)4 ]2- building blocks. Besides the title compound, which was prepared and its magnetic properties studied in detail, other novel magnetic solids might be able to be synthesized. PMID- 29711400 TI - Concise and Efficient Total Syntheses of Alkannin and Shikonin. AB - Two enantiomic natural products with wound-healing properties, alkannin (1) and shikonin (2), are accessible by a short and efficient total synthesis. The success was achieved by a novel protecting system for masking of 5,8-dihydroxy 1,4-naphthoquinones (naphthazarins) and a highly stereoselective ketone reduction. PMID- 29711401 TI - Structural and Spectroscopic Characterization of a Mononuclear Hydroperoxo Copper(II) Complex with Tripodal Pyridylamine Ligands. AB - A model for the key intermediate in copper oxygenase reactions, the Cu(II)-OOH complex, was prepared with the novel tripodal pyridylamine ligand, bis(6 pivalamide-2-pyridylmethyl)(2-pyridylmethyl)amine. The HOO- moiety is stabilized by hydrogen bonding to two amine H atoms (see structure on the right). PMID- 29711402 TI - Protein Mimicry: A New Dimension for Peptides as Lead Compounds? AB - A short peptide as mimic for the hemopoietic growth factor erythropoietin (containing 165 amino acids) could be identified with the aid of peptide libraries on phage surfaces (phage display). The crystal structure of a peptide dimer complexed with two erythropoietin receptors (shown on the right) provides an insight into the molecular basis of this protein mimicry. PMID- 29711403 TI - Chemical Recycling of Plastics to Useful Organic Compounds by Oxidative Degradation. AB - The degradation of plastic waste can be facilitated by a process in which polymers react with nitrogen oxides and dioxygen under relatively mild conditions. Polystyrene generates a mixture of benzoic and nitrobenzoic acids. Both high- and low-density polyethylene produce mixtures of short-chain alpha,omega-diacids (including adipic acid) in good yields. A mixture of acids is also formed from nylon-6,6. Other polymers that are degraded to oligomeric materials include polypropylene, polymethyl methacrylate, and polyacrylic acid. PMID- 29711404 TI - Solid-Phase Synthesis and Encoding Strategies for Olefin Polymerization Catalyst Libraries. AB - Active polymerization catalysts, novel resin-bound diimine complexes of nickel(II) and palladium(II) are obtained by combinatorial synthesis and combined in a catalyst library. By tagging with fluorescent markers, the catalysts can be coded. Therefore, after cleavage of the tag from the polymer-coated resin, HPLC can be used to determine the pathway along which the products were formed. PMID- 29711405 TI - Kinetic and Thermodynamic Control in Self-Assembly: Sequential Formation of Linear and Circular Helicates. AB - NMR and MS analysis as a function of time has shown that the self-assembly of a linear ligand with Fe2+ or Ni2+ , metal ions of octahedral coordination geometry, generates first a triple helicate and thereafter the circular helicate 1 as kinetic and thermodynamic products, respectively. The results provide insight into features of the energy hypersurface on which this self-assembly operates and point to the general role of kinetic and thermodynamic control in such processes. PMID- 29711406 TI - Ring-Closing Metathesis in Carbohydrate Annulation. AB - Even eight-membered rings (such as in 2) can be formed by ring-closing metathesis of glucose derivatives such as 1. Enantiomerically pure tricyclic spiro compounds can also be prepared. PMID- 29711407 TI - Nucleic Acid Nanostructures and Topology. AB - Knots, polyhedra, and Borromean rings with specific structural and topological features can be made from DNA. Biotechnologists have been exploiting the programmability of DNA intermolecular associations for a quarter of a century. These operations have now been applied successfully to branched DNA species to produce complex target structures (for example, the cube shown in the picture) and a nanomechanical device. The assembly of two-dimensional crystals with programmed topographic characteristics demonstrates the simplicity of translating design into surface structures. PMID- 29711408 TI - Cross-Section Molecular Imaging of Supramolecular Microtubes with Contact Atomic Force Microscopy. AB - Bent molecules, distorted layers, columnar domains, and tube membranes (shown schematically in the picture): These hierarchical layers were directly visualized by contact atomic force microscopy along the long axes of the molecules aligned within microtubes made up of bolaamphiphile 1 by self-assembly. PMID- 29711409 TI - Surface Reconstitution of a De Novo Synthesized Hemoprotein for Bioelectronic Applications. AB - A molecular rectifier and a bioelectrocatalytic assembly for the reduction of NO3 is provided by reconstitution of a de novo protein with two FeIII protoporphyrin IX units. The function of the de novo protein can be tuned and tailored within the synthetic protocol. PMID- 29711410 TI - Dendritic Pseudorotaxanes. AB - Self-organization is the key. A series of dendritic pseudorotaxanes were efficiently constructed from complementary building blocks-namely, a three-armed, triply charged ammonium salt and the first, second, and third generations of benzyl ether dendrons bearing the dibenzo[24]crown-8 moiety. The pseudorotaxane arising from the third-generation dendron is shown in the picture. PMID- 29711411 TI - An STM Study of Chemically Deposited Silver Nanoclusters on Mixed Self-Assembled Monolayers. AB - Small silver clusters Agn (primarily probably Ag4 clusters which aggregate to Agn (400kTBET ; TS=through-solvent, TB=through-bond). The ratio of the rates of charge separation to charge recombination is greater than 1400:1. PMID- 29711494 TI - p-Benzyne. AB - A noble gas matrix at low temperature was used to investigate the photochemical behavior of diacetyl terephthaloyl diperoxide and dipropionyl terephthaloyl diperoxide as well as 1,4-diiodobenzene. All three photoreactions formed small quantities of a compound with IR absorption bands at 725 and 980 cm-1 , which disappeared when the matrix was annealed. These bands correspond to the most intense of the calculated bands (B3LYP) for 1,4-didehydrobenzene (p-benzyne) (1). That decomposition of the peroxides in fact leads to 1 is confirmed by vapor phase pyrolysis experiments in which (Z)-2 was obtained in high yield. PMID- 29711495 TI - A Visual Tagging Process for Mix and Sort Combinatorial Chemistry. AB - Colored glass beads and caps provide a simple color-coding strategy adapted to porous plastic containers and allow visual identification of the individual constituents of combinatorial libraries. PMID- 29711496 TI - In Situ NMR Investigations of Heterogeneous Catalysis with Samples Prepared under Standard Reaction Conditions. AB - Only 170 milliseconds are required to cool the catalyst bed by 150 K in the catalytic reactor shown on the right. Thus, NMR spectroscopic investigations can be carried out on products that are formed after very short contact times and under real catalysis conditions. PMID- 29711497 TI - A Simple Preparative Route to Bis(imido)uranium(VI) Complexes by the Direct Reductions of Diazenes and Azides. AB - In clean, one-pot procedures, the uranium complex 1 reductively cleaves azides and azo compounds to generate bis(imido) derivatives [Eq. (a)]. This unusual reaction has not been observed previously in either the actinide series or with a metallocene complex. PMID- 29711498 TI - Models for the Carbonyl-ene Cyclization Reaction: Open and Closed Transition States. AB - Different cyclization products are formed with different Lewis acids in the ene cyclization of 5-hexenals (see scheme on the right; a: methylaluminum bisphenoxide, b: Me2 AlCl, c: Sc(OSO2 CF3 )3 ). This is not surprising, but it is gratifying that these result can be rationalized with an internally consistent model. PMID- 29711499 TI - Application of the 2-Azaallyl Anion Cycloaddition Method to an Enantioselective Total Synthesis of (+)-Coccinine. AB - A highly functionalized perhydroindole is formed by the intramolecular [pi4s+pi2s] cycloaddition of a 2-azaallyl anion with a vinyl sulfide [Eq. (a)]. This is the key step in the total synthesis of (+)-coccinine, the enantiomer of the Amaryllidaceae alkaloid (-)-coccinine. PMID- 29711500 TI - Synthesis and Characterization of the Dilithium Salt of the Octasilyl[4]radialene Dianion: Evidence for a Lithium Walk on the Eight-Center, Ten-Electron pi Electron System. AB - A highly symmetric structure is displayed in toluene by 1, which was obtained by reduction of octasilyl[4]radialene with lithium in THF. The two Li+ ions of 1 are not fixed to the pi-electron system in toluene, but are fluxional, giving rise to a bis-contact ion pair. In a solvating medium such as THF, one of the Li+ ions dissociates in such a way that 1 exists as a contact ion pair and a solvent separated ion pair. PMID- 29711501 TI - Fine-Tuning the Electronic Properties of Binuclear Bis(terpyridyl)ruthenium(II) Complexes. AB - Vastly improved photophysical properties of terminal RuII terpyridine-based chromophores is achieved by insertion of an ethynylene group between the terpyridine ligand and a covalently linked aromatic nucleus. In the case where the aromatic nucleus possesses vacant coordination sites, as shown in 1, complexation of certain cations (e. g., Zn2+ , Cd2+ , or Ba2+ ) at the central unit gives a further improvement in the photoproperties due to a better blending of the respective LUMO levels. PMID- 29711502 TI - Stepwise Assembly of [(C5 H5 )4 (C5 Me5 )4 Co4 Rh4 (CN)12 ]4+ , an "Organometallic Box" . AB - A volume of 132 A3 is enclosed by the title compound 1, which thus offers plenty of room for potential guest molecules. The synthesis from 2 [{Cp*RhCl2 }2 ] and 4 [CpCo(CN)3 ]- begins with the construction of a "molecular square" whose corners are alternately occupied by Co and Rh centers. Two squares react with one another to give a "molecular box" without cleavage of any M-C bonds. Cp=C5 H5 , Cp*=C5 Me5 . PMID- 29711503 TI - An Efficient and Concise Enantioselective Total Synthesis of Lactacystin. AB - A selective, irreversible inhibitor of proteasome function, lactacystin (1) is an important experimental tool in cell biology. An efficient and direct enantioselective synthesis of lactacystin proceeds via the intermediates shown below. This process allows for the first time easy access to analogues of lactacystin in which the isopropyl substituent is replaced by other lipophilic groups. PMB=p-methoxybenzyl. PMID- 29711504 TI - Transistors and Light Emitters from Single Nanoclusters. AB - The dream of molecular electronics and optics has recently been approached by several groups working on nanochemistry. They succeeded in building a transistor from a CdSe nanoparticle synthesized by wet-chemical methods (see diagram on the right) which can operate with single electrons. In the field of optics the luminescence of single CdS and CdSe nanoparticles could be studied, which allows important conclusions about the charge carrier dynamics. PMID- 29711505 TI - Highly Enantioselective One-Pot Synthesis of Chiral Tri- and Tetrasubstituted Ferrocenes from 1,1'-Ferrocenedicarbaldehyde. AB - Exclusively planar chirality is exhibited by the ferrocenes obtained in a highly enantioselective synthesis in which a chiral aminoamide acts as a temporary protecting/directing group. This method was used to obtain an enantiomerically pure tetrasubstituted ferrocene, which was transformed into the first C2 symmetric disubstituted ferrocenophane [Eq. (1)]. PMID- 29711506 TI - Preparation of Highly Functionalized Grignard Reagents by an Iodine-Magnesium Exchange Reaction and its Application in Solid-Phase Synthesis. AB - At -40 degrees C aryl iodides that contain other functional groups can be selectively converted into Grignard reagents, which react with electrophiles such as benzaldehyde in the usual manner [Eq. (a)]. Aryl bromides and iodides that are immobilized as esters on a Wang resin behave analogously. PMID- 29711507 TI - Ring-Closing Metathesis of Functionalized Acetylene Derivatives: A New Entry into Cycloalkynes. AB - A tungsten alkylidyne catalyst is the key to achieving ring-closing metatheses of diynes to form functionalized macrocycles [Eq. (a)]. Partial reduction of the cycloalkynes provides stereoselective Z-configured cycloalkenes, which are currently inaccessible by conventional alkene metathesis. PMID- 29711508 TI - [{(CO)5 Cr}6 Ge6 ]2- , A Molecular Organometallic Derivative of the Unknown Zintl Ion [Ge6 ]2. AB - Octahedral clusters from p-block elements are rare; however, the only known molecular aggregate of this kind, [{(CO)5 Cr}6 Sn6 ]2- , has now been supplemented by the isoelectronic cluster [{(CO)5 Cr}6 Ge6 ]2- (1). PMID- 29711509 TI - Unusual Five-Center, Four-Electron Bonding in a Rhodium-Bismuth Complex with Pentagonal-Bipyramidal Geometry. AB - A better understanding of the chemical bond in general is gained from the electronic structure of the molecular complex [{RhBi7 }Br8 ]. The interactions in the central Bi5 ring can be interpreted as an unusual five-center, four-electron bond based on ab initio calculations and group theory. Of the linear combinations of five Bi p orbitals two of the molecular orbitals are binding (depicted in the sketch). PMID- 29711510 TI - A Structural Model for [Fe]-Only Hydrogenases. PMID- 29711511 TI - Structure-Reactivity Relationship in the Reaction of Highly Reactive Zinc with Alkyl Bromides. AB - Zinc is different! Unlike with magnesium or lithium, the reactions of organic bromides with highly reactive zinc (Zn*) show sensitivity for the structure of the organic moiety. Selective insertions of Zn into tertiary C-Br bonds can be achieved [Eq. (a)]. Competitive kinetic techniques were used to quantify these findings. PMID- 29711512 TI - Complex Fluids Based on the Flexible One-Dimensional Mineral Polymers [K(MPS4 )]infinity (M=Ni, Pd): Autofragmentation to Concave, Cyclic (PPh4 )3 [(NiPS4 )3 ]. AB - A remarkable autofragmentation/rearrangement sequence results in the unprecedented formation of inorganic concave cyclic anion [(NiPS4 )3 ]3- (structure shown on the right) upon dissolving the potassium salt of the charged mineral polymer 1infinity [NiPS4 ]- in DMF; the initial complex fluid has a transient anisotropic texture that can be identified by optical microscopy under polarized light. In contrast, the complex fluid that results upon dissolving 1infinity [PdPS4 ]- is stable up to 323 K as persistent, flexible, charged chains. PMID- 29711513 TI - Differences Between Gas-Phase and Solid-State Molecular Structures of the Simplest Phosphonium Ylide, Me3 P=CH2. AB - Clearly different from local C3 symmetric is the heavy-atom core of Me3 P=CH2 , the simplest phosphonium ylide. The geometry obtained by reanalysis of gas electron-diffraction data from 1977 is now consistent with theoretical calculations, but different from the molecular structure in the solid state. The picture shows the structure of Me3 P=CH2 in the gas phase (a) and in the crystal (c) together with the calculated transition state (b) (viewed along the P=C bond). PMID- 29711514 TI - The Crystal Structures of Peroxonium Hexafluoroantimonate H3 O2 SbF6 and Bis(dihydrogenperoxo)hydrogen Hexafluoroantimonate H5 O4 SbF6. AB - Protonated hydrogen peroxide is produced from the reaction of antimony pentafluoride with bis(trimethylsilyl)peroxide in the presence of hydrogen fluoride. Depending on the stoichiometry of the reaction mixture, the compounds H3 O2 SbF6 and H5 O4 SbF6 are formed, which are stable up to room temperature and have been characterized by X-ray crystallography. The structure of the H3 O2+ ion is shown on the right. PMID- 29711515 TI - A New Base-Pairing Motif Based on Modified Guanosines. AB - Stable even in dimethyl sulfoxide, dimer I does not dissociate to monomers 1 in organic media. The unique base-pairing interaction involving four hydrogen bonds in the readily available compound 1 was characterized by NMR spectroscopy. PMID- 29711516 TI - Bioorganometallic Chemistry - Transition Metal Complexes with alpha-Amino Acids and Peptides. AB - A new, interdisciplinary research area has emerged known as bioorganometallic chemistry. It focuses on the introduction of organometallic fragments into biomolecules (see, for example, structure on the right). "Classical" alpha-amino acid and peptide ligands have proven particularly versatile, and provide access to compounds that display interesting stereochemistry. alpha-Amino acids and peptides can be synthesized, labeled, stabilized, or activated by organometallic fragments. PMID- 29711517 TI - Acylzirconocene Chloride as an "Unmasked" Acyl Anion. AB - Under mild conditions the acyl group of acylzirconocene chloride 1 formed from an alkene or alkyne and [(C5 H5 )2 ZrHCl] reacts as an "unmasked" acyl anion. The Lewis acid mediated reactions with aldehydes that yield alpha-ketol products in high yields demonstrate the versatility of this reagent for C-C coupling. PMID- 29711518 TI - Two-Step Synthesis of trans-2-Arylcyclopropane Carboxylates with 98-100 % ee by the Use of a Phosphazene Base. AB - Only the axial diastereomer of sulfonium salts 2 are formed upon alkylation of 1. Deprotonation of 2 results in ylides, which allow the highly enantioselective cyclopropanation of Michael systems. The chiral auxiliary 1 is recovered and can be reused. PMID- 29711519 TI - Carbocyclic Analogues of N-Acetyl-2,3-didehydro-2-deoxy-D-neuraminic Acid (Neu5Ac2en, DANA): Synthesis and Inhibition of Viral and Bacterial Neuraminidases. AB - Inhibition of neuraminidases from Influenza A and Salmonella typhimurium is shown by the carbocyclic compound 2, whereas its double-bond isomer 1 hardly binds to these enzymes. The cyclohexenes 1 and 2 were prepared from N-acetyl-D-mannosamine in 18 steps in 2.6 and 1.6 % yields, respectively. PMID- 29711520 TI - trans-[RuCl2 (phosphane)2 (1,2-diamine)] and Chiral trans-[RuCl2 (diphosphane)(1,2-diamine)]: Shelf-Stable Precatalysts for the Rapid, Productive, and Stereoselective Hydrogenation of Ketones. AB - A turnover number (TON) of 2 400 000 and a turnover frequency (TOF) of 63 s-1 are achieved with the chiral RuII complex 1 (R=p-CH3 C6 H4 ) in the asymmetric hydrogenation of acetophenone. Carbonyl-selective asymmetric hydrogenation of alpha,beta-unsaturated ketones proceeds in the presence of these RuII catalysts, and 4-substituted cyclohexanones are selectively converted into cis alcohols. PMID- 29711521 TI - Organometallic Triskelia: Novel Tris(vinylideneruthenium(II)), Tris(alkynylruthenium(II)), and Triruthenium-Triferrocenyl Complexes. AB - Incorporation of a redox-passive bridge affords three identical redox systems in the triskelion-shaped, carbon-rich, polyvinylidenemetal complex 1. The complex was isolated from the activation of the tripodal polyyne 1,3,5-(HC=CC6 H4 C=C)3 C6 H3 with [RuCl2 ({(Ph2 P)2 C2 H4 }2 ] and further converted into polyynylmetal complexes and a triple ferrocenyl-substituted ruthenium complex. PMID- 29711522 TI - Multiple Coordination of Metal Atoms to Arenes: The Coordination of Six Ruthenium Atoms to Naphthalene-1,8-diyl in [Ru6 (MU6 -C10 H6 )(MU3 -PPh)(CO)14 ]. AB - Six ruthenium atoms are coordinated to the naphthalene-1,8-diyl ligand in the cluster [Ru6 (CO)14 (C10 H6 )(PPh)] through two Ru-C sigma bonds, two eta2 , and two eta3 interactions (section of structure depicted on the right). The complex could, therefore, serve as a model for the chemisorption of naphthalene on a step site on a (111) metal surface. PMID- 29711523 TI - Methoxide Coordination at the Pocket of [CuII TpCum, Me] and a Simple Model for the Cu Center of Galactose Oxidase. AB - An unusually negative oxidation potential is found for the tyrosine residue in the center of fungal galactose oxidase. The complex [Cu(TpCum,Me ){O(MeS)C6 H4 }] (see picture on the right; TpCum,Me =hydrotris(pyrazolyl)borate) offers insight into the mode of (cysteinyl-tyrosine) coordination to the copper center, and the reason for the low oxidation potential. PMID- 29711524 TI - Parallel Synthesis of Sialyl Lewis X Mimetics on a Solid Phase: Access to a Library of Fucopeptides. AB - A novel anchoring group p-(acyloxymethyl)benzylidene acetal (p-AMBA) enables the bidirectional functionalization of glycosylated amino acid derivatives and thus the rapid parallel synthesis of fucopeptides as sialyl Lewis X mimetics on a solid phase [Eq. (a), PEG-PS=poly(ethylene glycol) graft copolymer]. This led to the discovery of new mimetics against P-selectin with IC50 values in the low MUM range. PMID- 29711525 TI - Diastereoselective Synthesis of Highly Substituted Five-Membered-Ring Oxygen Heterocycles by Zirconocene-Mediated C-C Coupling Reactions. AB - As homoenolate equivalents, zirconocene-1-aza-1,3-diene complexes were used for the first time in stereoselective synthesis. By insertion of an unsymmetrical ketone in the Zr-C sigma bond, sterically demanding trisubstituted dihydro- and tetrahydrofuran derivatives were prepared in good overall yields and with high diastereoselectivities (see below). PMID- 29711526 TI - The Crystal Structures of a Lower Order and a "Higher Order" Cyanocuprate: [tBuCu(CN)Li(OEt2 )2 ]infinity and [tBuCutBu{Li(thf)(pmdeta)}2 CN]. AB - Different types of bonding are present in cyanocuprates 1 and 2, whose crystal structures could be determined (the drawings below show the important structural characteristics). Accordingly, 1 is a lower order cyanocuprate of the type RCu(CN)Li, whereas 2, which is of the type R2 Cu(CN)Li2 , does not exist as a "higher order" cyanocuprate with Cu-CN bonds, but rather as a cyano-Gilman cuprate. PMID- 29711527 TI - Tethered Bis-Amidinates as Supporting Ligands: A Concerted Elimination/sigma-pi Rearrangement Reaction Forming an Unusual Titanium Arene Complex. AB - A 1,4-cyclohexadiene dianion resonance structure makes a significant contribution to the structure of the (arene)Ti complex [LTi(eta6 -PhCH3 )] (see picture on the right). Labeling experiments have demonstrated that the structure forms through an unusual elimination/sigma-pi rearrangement reaction in which [LTi(CH2 Ph)2 ] reacts readily with hydrogen; the use of the cyclohexane-linked bis-amidinate ligand L with constrained geometry makes the transformation possible. PMID- 29711528 TI - Selectivity of DNA Replication: The Importance of Base-Pair Geometry over Hydrogen Bonding. AB - The polymerase enzyme hardly differentiates between thymine and difluorotoluene nucleotides with respect to the replication selectivity. X-ray structure analysis show the importance of the Watson-Crick geometry for the replication fidelity; base selection is determined by the spatial prerequisite of the substrate pocket and directed protein interactions in the minor groove (schematically shown on the right). PMID- 29711529 TI - Partially Oxidized Zintl Ions? The Characterization of [(MU3 -OH)(MU3 -O)3 (OEt)3 {(CO)5 W}7 Sn7 ]2. AB - A formally isoelectronic (MU3 -Sn)2- ion replaces the MU3 -O building block in the subvalent anion 1, which is a derivative of the known cage compound [(MU3 OR)4 (MU3 -O)4 Sn6 ]. Thus, compound 1 forms a link between oxo metal clusters and Zintl ions. [(MU3 -OH)(MU3 -O)3 (OEt)3 {(CO)5 W}7 Sn7 ]2- 1. PMID- 29711530 TI - Lipases: Interfacial Enzymes with Attractive Applications. AB - Unusually versatile substrate specificity is shown by lipases. Not only do they hydrolyze triacylglycerols-for example, in the stomach and intestine during digestion of dietary fat-and various synthetic esters and amides, but their high stability in organic solvents permits their use in transesterification reactions and ester synthesis as well. Reactions based on lipase catalysis usually proceed with high regio- and enantioselectivity. Thus, the Ca2+ antagonist diltiazem (1) was obtained with lipase from Serratia marcescens. Over 30 lipases have been cloned in the last few years. Since the tertiary structure of 12 lipases is known, there are presently significant efforts to improve this class of enzymes by protein engineering techniques, in view of their use in detergents and other fields of industrial application. PMID- 29711531 TI - Macrocyclic Cyclopropenes by Highly Enantioselective Intramolecular Addition of Metal Carbenes to Alkynes. AB - The intramolecular addition of a diazo ester group to a triple bond in the presence of chiral dirhodium(II) carboxamidate catalysts gives macrocyclic lactones with a fused cycloproprene ring [Eq. (a)]. This efficient reaction is characterized by high enantiocontrol (up to 98% ee) and chemoselectivity. PMID- 29711532 TI - A Novel, Highly Enantioselective Ketone Alkynylation Reaction Mediated by Chiral Zinc Aminoalkoxides. AB - Kilogram-scale synthesis of the HIV reverse transcriptase inhibitor efavirenz was achieved by means of a highly enantioselective alkynylation of prochiral ketones 1 with alkynyllithium or alkynylmagnesium reagents in the presence of chiral zinc aminoalkoxides as mediators. With the achiral auxiliary 2,2,2-trifluoroethanol (R3 =CF3 CH2 ), the efavirenz precursor 2 (R1 =H, R2 =cyclopropyl) was obtained with an ee of 99.2%. PMID- 29711533 TI - Shape-Induced, Hexagonal, Open Frameworks: Rubidium Ion Complexed Cucurbituril. AB - A honeycomb structure is shown by the one-dimensional coordination polymer comprising D6h -symmetric cucurbituril molecules and rubidium ions (see picture). The cucurbituril molecules stack atop one another and show coordination of their carbonyl groups to the rubidium ions in between. The shape and symmetry of the building blocks encourage the coordination polymer chains to be arranged in such a way as to produce an open-framework structure with large, linear, hexagonal channels. PMID- 29711534 TI - "Base Flipping": Photodamaged DNA-RNA Duplexes Are Poor Substrates for Photoreactivating DNA-Repair Enzymes. AB - What is damaged cannot always be readily repaired. This is observed for particular areas in the genome (mutation hot spots), which are repaired with low efficiency. DNA-DNA duplexes that exist in the B-conformation are repaired relatively efficiently by photolyases. DNA-RNA duplexes, which prefer an A-type conformation are only moderately destabilized by DNA photolesions and are slowly repaired. This suggests that the DNA conformation modulates the necessary "flipping" process for the repair of DNA lesions. PMID- 29711535 TI - Total Syntheses of Vancomycin. AB - A total synthesis of the vancomycin aglycon 1 has eluded synthetic chemists for so many years that the preparation of this molecule has become a vendetta for some groups. Finally, and almost simultaneously, research teams led by Evans and by Nicolaou have succeeded. Similarities and differences in their synthetic approaches are highlighted herein. PMID- 29711536 TI - A Novel Three-Way Chromophoric Molecular Switch: pH and Light Controllable Switching Cycles. AB - Programmed with an unusual number of functions, the tetraethynylethene derivative 1 exhibits three addressable switching subunits, which can undergo individual reversible switching cycles that are controllable by pH and light. Three "write/erase" processes and one "AND" logic gate process can be separately addressed, and in each case an efficient nondestructive readout is possible. PMID- 29711538 TI - What Can We Learn from Nature about the Reactivity of Coordinated Phenoxyl Radicals?-A Bioinorganic Success Story. PMID- 29711537 TI - Functional Molecular Thin Films: Topological Templates for the Chemoselective Ligation of Antigenic Peptides to Self-Assembled Monolayers. AB - The combination of self-assembly and regioselective surface chemistry has made it possible to immobilize peptide recognition sites 1 on a template attached to a gold surface. Each of the seven individual reaction steps, including the final functional biomolecular recognition, was controlled in situ with surface sensitive detection techniques. The presented strategy is of general importance for the formation of complex supramolecular structures with biologically interesting functionalities at the interfaces. PMID- 29711539 TI - Synthetic Utility of Stable Phosphanylcarbenes: Synthesis and Crystal Structure of an alpha-(Lithiomethylene)phosphorane. AB - The first crystallographically characterized phosphonium yldiide 2 was obtained in a simple reaction by addition of n-butyllithium to the stable phosphanyl(silyl)carbene 1. R=cHex2 N. PMID- 29711540 TI - Convergent Route to Organometallic Dendrimers Composed of Platinum-Acetylide Units. AB - The third-generation dendrimer with 45 platinum atoms (shown schematically) was synthesized efficiently by a convergent methodology in which two different trialkylsilyl groups (symbolized by the nodal points) are used to protect the bridging triethynylbenzene derivatives. PT=[Pt(PEt3 )2 ]. PMID- 29711541 TI - Valence Bond Diagrams and Chemical Reactivity. AB - A unified description of chemical reactivity is made possible with valence bond (VB) diagrams, such as those shown for the a simple case (only reactants and products must be considered) and a more complex system (an intermediate state also plays an important role; RC = reaction coordinate). Analysis of reactivity and mechanistic problems in organic and organometallic chemistry exemplifies the generality of the VB paradigm: in situ DNA repair, C-F and C-H bond activation, SRN 2c mechanism, stepwise versus concerted cycloaddition, and a lot more. PMID- 29711542 TI - Trihydroxycarbenium Hexafluorometalates: Salts of Protonated Carbonic Acid. AB - Stabilization by salt formation: carbonic acid, which is not available as a pure substance, was isolated in the form of its trihydroxycarbenium salts, C(OH)3+ MF6- (M=As, Sb), from the reaction of carbonic acid bis(trimethylsilyl) ester in the superacids HF/MF5 . The structure of the cation is shown in the picture. The ion was also characterized by vibrational spectroscopic studies. PMID- 29711544 TI - Induced Color Change of Conjugated Polymeric Vesicles by Interfacial Catalysis of Phospholipase A2. AB - A blue to red color change is induced on addition of phospholipase A2 to modified PDA vesicles 1 (PDA=polydiacetylene). This bathochromic transition results from chemical modification of the vesicles by hydrolysis of the enzyme substrate embedded in the PDA matrix. Addition of a known phospholipase inhibitor or removal of Ca2+ ions suppresses the color change, which suggests the potential for applications in high-throughput screening assays. PMID- 29711543 TI - Opposite Orientation of Backbone Inclination in Pyranosyl-RNA and Homo-DNA Correlates with Opposite Directionality of Duplex Properties. AB - Backbone inclination is a parameter which can be used for the classification of the structure type of oligonucleotide duplexes. Its significance for the interpretation of the sequence dependence of duplex stability is illustrated based on examples of the p-RNA and homo-DNA series. PMID- 29711545 TI - Hydrogen-Bonding Cavities about Metal Ions: A Redox Pair of Coordinatively Unsaturated Paramagnetic Co-OH Complexes. AB - Nature uses hydrogen bonds to regulate a variety of metal-based reactions. These effects are emulated in the stabilization of trigonal-bipyramidal, paramagnetic Co-OH complexes such as the mono- or dianionic redox-active complex 1 by use of a new hydrogen-bonding ligand. PMID- 29711547 TI - Practically Perfect Asymmetric Autocatalysis with (2-Alkynyl-5 pyrimidyl)alkanols. AB - Extremely high enantioselectivity (>99.5% ee) and chemical yield (>99%) are achieved in an asymmetric autocatalytic reaction. A (5-pyrimidyl)alkanol with a tert-butylethynyl group at its 2-position (1) is a very efficient asymmetric autocatalyst in the enantioselective alkylation in Equation (1). PMID- 29711546 TI - Synthesis of a Five-Membered Molecular Necklace: A 2+2 Approach. AB - Like with a string of pearls, four molecular "beads" are threaded on a molecular rectangle to form a molecular necklace. This rectangular species is synthesized from two L-shaped, preorganized pseudorotaxanes with two molecular beads each (cucurbituril, schematically symbolized by the barrels), held together by Cu2+ ions [Eq. (1)]. PMID- 29711548 TI - A Novel Method for the Demetalation of Tricarbonyliron-Diene Complexes by a Photolytically Induced Ligand Exchange Reaction with Acetonitrile. AB - The photochemical exchange of all three carbonyl ligands with acetonitrile converts tricarbonyliron-diene complexes into the very labile triacetonitrile iron-diene complexes. These easily demetalate in high yields to the corresponding free ligands on injection of air at -30 degrees C [Eq. (1)]. The novel demetalation procedure is applied to the tricarbonyliron complexes of cyclopentadienones, cyclohexa-1,3-dienes, and buta-1,3-dienes. PMID- 29711549 TI - Sequence-Specific DNA Alkylation by Hybrid Molecules between Segment A of Duocarmycin A and Pyrrole/Imidazole Diamide. AB - In the absence of distamycin A (Dist), hybrids 1 (X=N, CH) selectively alkylate the 3' end of adenine in AT-rich DNA sequences. However, these hybrids can form a heterodimer with Dist to alkylate G residues of predetermined DNA sequences efficiently and with high selectivity. PMID- 29711550 TI - A Functionalized Heterocubane with Extensive Intermolecular Hydrogen Bonds. AB - A unique three-dimensional assembly is evident in the crystal structure of the cage compound 1: each molecule participates in the formation of eight O-H???O hydrogen bonds with neighboring molecules to form cavities with approximate dimensions of 3*3*8 A3 . In contrast, compound 2, which contains the same framework structure, does not show this behavior in the crystal. PMID- 29711551 TI - Biphasic Synthesis of Hydrogen Peroxide from Carbon Monoxide, Water, and Oxygen Catalyzed by Palladium Complexes with Bidentate Nitrogen Ligands. AB - Effective and stable Pd catalysts for the biphasic synthesis of hydrogen peroxide from carbon monoxide, oxygen, and water [Eq. (a)] can be obtained by the right choice of bidentate nitrogen ligand. The best turnover numbers (578) for this reaction have been achieved with palladium complexes with 2,9-dimethyl-4,7 diphenyl-1,10-phenanthroline ligands. PMID- 29711552 TI - Statistical Investigation into the Structural Complementarity of Natural Products and Synthetic Compounds. AB - The potential of new natural products as an important source for the exploration and development of new drugs and crop protection products is a long way from being exhausted. The statistical analysis of the structures of the natural and synthetically derived compounds has shown conspicuous variations in structural types in the natural products derived from different natural sources, which can be utilized in the search for individual active substances. The occasionally voiced prepossession that natural products have already been sufficiently examined and therefore no more innovations are to be expected can definitely be rejected. PMID- 29711553 TI - Asymmetric Total Synthesis of Fredericamycin A. AB - Seventeen years after the isolation of the promising antitumor antibiotic fredericamycin A, the first asymmetric total synthesis of this compound has been accomplished and thereby its absolute configuration established. The key feature is the regiocontrolled [4+2] cycloaddition of 3 to 2, which was obtained by the stereospecific rearrangement of 1. Cp = (-)-camphanoyl. PMID- 29711554 TI - Surface-Initiated Polymerization for Amplification of Self-Assembled Monolayers Patterned by Microcontact Printing. AB - Patterned polymer brushes can be prepared by a novel strategy that combines surface-initiated polymerization and microcontact printing (see picture; MUCP SAM indicates the self-assembled monolayer formed by microcontact printing). The living nature of the polymerization process permits the thickness of the polymer brush and its physical properties to be accurately controlled. PMID- 29711555 TI - Self-Assembly of Predesigned Trimetallic Macrocycles Based on Benzimidazole as Nonlinear Bridging Motifs: Crystal Structure of a Luminescent Platinum(II) Cyclic Trimer. AB - A trimetallic macrocycle: Starting from nonlinear N-deprotonated benzimidazole and square-planar cyclometalated platinum(II) precursors, cyclic trimers with three metal vertices can be obtained by a general and rational strategy (shown schematically, M=Pt). A complex is formed with 2-(2-thienyl)pyridine as chelating ligand which photoluminesces in solution at room temperature. PMID- 29711556 TI - Nonsteroidal Antiinflammatory Drugs: A New Generation of Cyclooxygenase Inhibitors. AB - The multitalented therapeutic agent that is used to relieve a variety of ailments, acetylsalicylic acid (Aspirin(r) ) is facing new competition. The goal is to use tailor-made inhibitors of cyclooxygenase-2 to selectively reduce pain while minimizing side effects. Do these new drugs represent a new generation of nonsteroidal pain relievers? PMID- 29711557 TI - A New Type of Glycosidic Linkage: An Open-Chain Acetal-Linked N Acetylgalactosamine in the Core Part of the Lipopolysaccharides from Proteus Microorganisms. AB - Chemical stability similar to that of a normal glycosidic linkage is displayed by the novel acetal linkage between monosaccharides through the structural element shown. This survives hydrolysis with dilute acetic acid, but is cleaved under the hydrolytic conditions normally used in monosaccharide analysis (2 M HCl)-a possible reason why the structural element has only now been identified. PMID- 29711558 TI - An Open-Framework Germanate with Polycubane-Like Topology. AB - Body-centered Ge9 parallelepiped building blocks form the basis of the structure of [Ge9 O18 (OH)4 ]?2 (H2 ppz)?0.5 (H2 O) (ASU-14, ppz=piperazine). In this new structure type for an open-framework germanate (see picture for a section of the structure) the building blocks are linked together at each of their eight vertices to give the rare polycubane topology with an intersecting channel system of ten- and eight-membered rings (pore sizes 5*6 and 4*4 A2 , respectively) in which the piperazinium cations and water molecules reside. PMID- 29711559 TI - Ln2 Al3 Si2 (Ln=Ho, Er, Tm): New Silicides from Molten Aluminum-Determination of the Al/Si Distribution with Neutron Crystallography and Metamagnetic Transitions. AB - Highly metallic compounds with a quasi-one-dimensional structure, the new ternary compounds Ln2 Al3 Si2 (Ln=Ho, Er, Tm) are synthesized in molten aluminum from lanthanoid and silicon as reagents. Their structures show a formally [Al3 Si2 ]6- framework that contains infinite Al zigzag chains and Si-Si dimers and accommodates rows of Ln3+ ions in parallel tunnels. The compounds exhibit metamagnetic transitions at high magnetic fields. PMID- 29711560 TI - [Zn2 (thf)2 (EtZn)6 Zn4 (MU4 -O)(tBuPO3 )8 ]: A Dodecanuclear Zincophosphonate Aggregate with a Zn4 (MU4 -O) Core. AB - The largest multinuclear zinc framework synthesized is in the title compound (see picture), which contains structural features closely related to the motifs found in layered and three-dimensional zincophosphates and zincophosphonates. The reactive centers make this zincophosphonate a viable precursor for the synthesis of porous zincophosphonate materials. PMID- 29711561 TI - Regioselective Lactonization of alpha-(2->8)-Trisialic Acid. AB - A simple and selective method has been developed to obtain both monolactones of the title compound, a model compound for biologically important polyneuraminic acid derivatives: acidic lactonization and alkaline hydrolysis of dilactone 1. The two monolactonized trimers can be separated by capillary electrophoresis, and then distinguished by enzymatic hydrolysis with neuraminidase; only the 2 monolactone undergoes reaction. PMID- 29711562 TI - Zinc Silicates: Very Efficient Heterogeneous Catalysts for the Addition of Primary Alcohols to Alkynes and Allenes. AB - There is an astonishing parallel between the mechanism generally accepted for the addition of water to CO2 catalyzed by the enzyme carbonic anhydrase and the mechanism calculated for the addition of methanol to allene catalyzed by the naturally occurring zinc silicate hemimorphite. The latter reaction was investigated in detail following the observation that hemimorphite as well as an amorphous zinc silicate prepared in situ are excellent heterogeneous catalysts for the addition of primary alcohols to alkynes and allenes [Eq. (1)]. PMID- 29711564 TI - Two New Modes of Pd-Catalyzed Domino-Tetracyclization of Bromodienynes-5-exo-trig Cyclization Wins over beta-Hydride Elimination. AB - Remarkable increases of molecular complexity in a single procedural step are achieved with the title reaction. Only a slight modification in the substitution pattern on the acyclic precursor 2 can change the mode of tetracyclization to either yield skeletons of type 1 or 3 exclusively. PMID- 29711563 TI - Synthesis and Conformational Properties of the Sterically Crowded D3d -Symmetric all-trans Hexa(spirotetrahydrofuranyl)cyclohexane System. AB - An unprecedented high barrier to ring inversion [Eq. (1)] prevents 1 from engaging in bifacial complexation with lithium ions. The X-ray crystal structure analysis of this hexaspiro compound corroborates the adoption of a cyclohexane chair with all six C-O bonds projected equatorially (1-eq). PMID- 29711565 TI - Cesium Hydroxide: A Superior Base for the Catalytic Alkynylation of Aldehydes and Ketones and Catalytic Alkenylation of Nitriles. AB - The efficient addition of terminal alkynes to aldehydes or ketones to give propargyl alcohols in yields of 66-96 % can be achieved by activation with catalytic amounts of CsOH?H2 O [Eq. (a)]. A CsOH-catalyzed addition of acetonitrile derivatives to terminal alkynes is also possible. PMID- 29711566 TI - Self-Assembly of a Molecular Floral Lace with One-Dimensional Channels and Inclusion of Glucose. AB - A three-dimensional network with one-dimensional channels (see picture) has been self-assembled from the nickel(II) complex of cyclam and 1,3,5 benzenetricarboxylate in water through hydrogen-bond formation. The channels have an appropriate diameter (10.3 A) to include D-glucose with a formation constant of Kf =(1.38+/-0.01)*104 M-1 . Under similar conditions maltose is not included. PMID- 29711567 TI - Stereospecific Sulfur-Mediated Cleavage of a Spirocyclobutanone: Synthesis of a Fully Functional Precursor to the CP Compounds. AB - A reaction sequence made up of a Sakurai reaction, ketene cyclization, sulfur directed Baeyer-Villiger reaction, and tandem lactone cleavage/isomerization provided the fully functionalized core of the CP compounds. Key steps were the methanolysis of 1, which leads via 2 to the CP precursor 3. PMID- 29711568 TI - The First Direct Synthesis of Corroles from Pyrrole. AB - The solvent-free, catalyst-free condensation of pyrrole and aldehydes provides an extremely facile synthetic pathway to novel corroles [Eq. (1); Ar=C6 F5 , 2,6-F2 C6 H3 , 2,6-Cl2 C6 H3 ]. The product containing pentafluorophenyl groups is an excellent precursor of other derivatives, including an ionic, water-soluble corrole. PMID- 29711569 TI - Efficient Intermolecular Charge Transport in Self-Assembled Fibers of Mono- and Bithiophene Bisurea Compounds. AB - Hydrogen bonds between urea units allow self-organization of pi systems in mono- and bithiophenes into fibers as shown schematically. In these fibers there is a surprisingly high mobility of charge carriers as determined by pulse-radiolysis time-resolved microwave conductivity measurements. PMID- 29711570 TI - Biodegradable Polymeric Materials-Not the Origin but the Chemical Structure Determines Biodegradability. AB - It is completely plausible that unmodified materials of natural origin, such as the native macromolecules cellulose or starch, are biodegradable. If these materials are modified then degradation may, depending on the degree of modification, be more difficult or even impossible. In the same manner synthesized macromolecules, whether from renewable or petrochemical sources, could be inert or completey biodegradable, depending on their chemical structure. PMID- 29711571 TI - A Belted Monofacial Ionophore Featuring High Selectivity for Lithium Ion Complexation. AB - Despite its preferred equatorial conformation in the solid state and in solution, the cis,cis-trispiro ether 1 binds readily and strongly to lithium ions. The 2:1 sandwich complex 2 is initially formed and transformed progressively into the 1:1 species 3 upon the addition of more LiClO4 . PMID- 29711572 TI - Direct Synthesis of N-Arylquinone Imine Acetals and Quinol Imines from Acetals. AB - In the absence of any added acidic catalyst quinone acetals as well as simple ketone and aldehyde acetals react with a variety of substituted anilines to form imines [Eq. (a)]. Contrary to what is expected from arguments based on their nucleophilicity, the most reactive anilines are those bearing electron withdrawing groups. PMID- 29711573 TI - Fast Experiments for Charge-Density Determination: Topological Analysis and Electrostatic Potential of the Amino Acids L-Asn, dl-Glu, dl-Ser, and L-Thr. AB - Synchrotron radiation and CCD detection give the possibility for fast diffraction experiments, which were employed to deduce the exact charge-density distributions of some amino acids. Their topological analysis (the figure shows the negative Laplacian function of dl-serine in the plane of the carboxylate group) yields not only comparable information about intramolecular but also about weak intermolecular interactions. PMID- 29711574 TI - Strobilurins: Evolution of a New Class of Active Substances. AB - A fungus that grows on pinecones yields a compound with antifungal activity that has become the natural model for a significant innovation in crop protection. Variation and optimization of the lead structure of strobilurin A (1) and selection of derivatives which fulfill all practical requirements, for example, kresoxim-methyl (2), led to an exciting and pan-industrial competition for the development of the strobilurines as a new, highly active, and broadly applicable class of fungicides-a fascinating success story. PMID- 29711575 TI - From Substrate to Transition State Analogues: The First Potent Inhibitor of Sialyltransferases. PMID- 29711576 TI - Light Harvesting and Energy Transfer in Novel Convergently Constructed Dendrimers. AB - By the attachment of interacting laser dyes to the chain ends and focal point of a dendritic macromolecule it is possible to funnel energy harvested by the large peripheral antenna of the dendrimer (see picture on the left) efficiently and directly to the central fluorescent core (picture in the middle) by a process that does not involve the dendrimer inner backbone. The energy is then emitted as a narrow band of fluorescent radiation from the core (picture on the right). PMID- 29711577 TI - Fullerene Pipes, Tube-in-Tube Membranes, and Carbon-Nanotube Tips: Adding New Dimensions to Molecular Technology. AB - Gold fever currently dominates scientists who work on the chemistry and physics of carbon nanotubes. Better ways of preparing and manipulating these fascinating materials have been found. Potential applications extend from catalysis to the construction of flat screens and to the imaging of sensitive biological structures. This article gives an overview of current results and future trends. PMID- 29711578 TI - Carbohydrate-Carbohydrate Recognition between LewisX Glycoconjugates. AB - The strong dependence of the NOE on the molecular mobility rendered the weak bond of a homotypical carbohydrate-carbohydrate recognition detectable in a simplified model system. The membrane-bound LeX trisaccharide 1, which functions as a receptor, transiently binds the dissolved LeX trisaccharide 2, thus slowing down its rotational diffusion. This kind of molecular recognition plays an important part in cell adhesion. PMID- 29711579 TI - Pentacarba-arachno-tridecaalane (AlMe)8 (CCH2 Ph)5 H with an Al8 C5 Skeleton-The First Polyhedral Carbaalane. AB - Hydroalumination of an aluminum alkynide led to the formation of a polyhedral carbaalane as the first example of a new class of aluminum derivatives analogous to carbaboranes. A pentacarbatridecaalane was obtained, which has an Al8 C5 skeleton and which, owing to the number of electrons in the cluster, belongs to the arachno-type group of compounds (see structure). PMID- 29711580 TI - Ferromagnetism in Transition Metals: A Chemical Bonding Approach. AB - Band structure calculations from first principles provide the basis of a simple explanation for the appearance of ferromagnetism in iron, cobalt, and nickel that is founded upon a uniquely chemical concept: bonding. It is shown that the onset of ferromagnetism strengthens the metal-metal bonds in these transition metals by reducing the antibonding nearest neighbor interactions that would otherwise appear at the Fermi level. PMID- 29711581 TI - Reversible Fixation of Ethylene on a SmII Calix-Pyrrole Complex. AB - Reversible ethylene fixation in lanthanide chemistry is demonstrated by the SmII derivatives [R8 -calix-pyrrole)(Et2 O)Sm{Li(thf)2 }{Li(MU3 -OCH=CH2 )}] (R=Et, { (CH2 )5 -}0.5 ), which react with ethylene to afford the corresponding dinuclear complexes (see picture). PMID- 29711582 TI - [Ph2 P(NSiMe3 )]2 CLi2 : A Dilithium Dianionic Methanide Salt with an Unusual Li4 C2 Cluster Structure. AB - Four lithium atoms in a square-planar arrangement are capped by two carbon atoms and encapsulated by NSiMe3 chelation in the dilithium methanide salt 1. This air- and moisture-sensitive complex is formed by the reaction of CH2 (Ph2 P=NSiMe3 )2 with alkyl- or aryllithium reagents. PMID- 29711583 TI - A New Approach to Glycopeptides. AB - In only three or four steps glycosylated dipeptide and tripeptide fragments, respectively (see scheme), can be obtained from hydroxy amino acids by using a novel protecting group/activation concept. The method presented is even superior to the pentafluorophenyl ester method. PMID- 29711584 TI - Palladium-Catalyzed Synthesis of Substituted Hydantoins-A New Carbonylation Reaction for the Synthesis of Amino Acid Derivatives. AB - One-step synthesis of substituted hydantoins can be achieved by the palladium catalyzed "ureidocarbonylation" of aldehydes with urea derivatives and carbon monoxide [Eq. (1)]. This surprisingly selective protocol converts substituted ureas into 1,5- and 1,3,5-substituted hydantoins in yields of up to 93 %. PMID- 29711585 TI - Regioselective Reduction of NAD+ Models with [Cp*Rh(bpy)H]+ : Structure-Activity Relationships and Mechanistic Aspects in the Formation of the 1,4-NADH Derivatives. AB - The hydride transfer mechanism of the NAD+ model compound 1 to its 1,4-NADH derivative 3 [Eq. (1)] is proposed to be a consequence of the critical role of the carbonyl group of the amide to coordinate to the ring-slipped eta5 - to eta3 Cp*Rh metal center of the catalyst [Cp*Rh(bpy)H]+ , prepared in situ from 2, while a steric effect of a substituent in the 3 position, for example, C(O)NEt2 , was found to totally inhibit this regioselective reduction. bpy=2,2'-bipyridine, Cp*=C5 Me5 , OTf=trifluoromethanesulfanate. PMID- 29711586 TI - A Novel Layered Silicate with a Helical Morphology. AB - Helices composed of stacked layers are present in the novel silicate obtained from a silica sol and NaOH by hydrothermal synthesis in the presence of tetramethylammonium (TMA) hydroxide and 1,4-dioxane. The helical morphology is evident in scanning electron micrographs (see picture). The TMA and sodium ions of the silicate are readily replaced by protons, and on heating to 200 degrees C a reversible phase transition occurs in which water molecules are lost from between the layers. PMID- 29711587 TI - Nucleotide Platination Induced by Visible Light. AB - A two-step photoreaction is induced by irradiation of the PtIV complex trans,cis [Pt(OCOCH3 )2 I2 (en)] with visible light in the presence of guanosine 5' monophosphate (5'-GMP; see scheme): A photoinduced ligand exchange followed by photoreduction gives the bis-GMP adduct of [Pt(en)]2+ . Although the dihydroxodiiodo complex also undergoes a photoinduced ligand exchange, no reaction with the nucleotide was observed. PMID- 29711588 TI - Phase Changes and Electronic Properties in Toroidal Mesoporous Molybdenum Oxides. AB - Toroidal mesostructured molybdenum bronzes and blues (shown schematically) have been synthesized. The effect of phase changes on the electrical conductivity of these materials is explored in depth. A unique shape-evolution reaction is also discussed. PMID- 29711589 TI - Radical Dimerization of 5,5'-Diphenyl-3,3',4,4'-tetramethoxy-2,2'-bipyrrole: pi Dimer in the Crystal, sigma Dimer in Solution. AB - The crystalline, spinless pi dimer (1.+ ?PF6 )2 was obtained by the oxidation of bipyrrole 1 with ferrocenium hexafluorophosphate. The diamagnetic species generated electrochemically in solution was identified as the sigma dimer by NMR spectroscopy. PMID- 29711590 TI - Linear Monodisperse pi-Conjugated Oligomers: Model Compounds for Polymers and More. AB - The development of structure-property relationships for monodisperse oligomers has been extremely useful to rationalize the properties of high molecular weight linear pi-conjugated polymers. A great variety of spectacular molecular architecture has been generated, culminating in the recent preparation of molecular wires such as 1 with lengths exceeding 10 nm that have potential applications in molecular electronics. PMID- 29711591 TI - Directed Metalation Linked to Transition Metal Catalyzed Cascade Reactions: Two Total Syntheses of Plicadin, the Alleged Coumestan from Psoralea plicata. AB - The oxygen-rich heterocyclic compound 1-which was proposed to be the structure of plicadin, the alleged naturally occurring coumestan from the herb Psoralea plicata-was synthesized by the rational combinations of directed ortho and remote metalation reactions with cascades of Negishi, Sonogashira, Castro-Stephens, and carbamoyl Baker-Venkataraman reactions. PMID- 29711592 TI - Ni(tpt)(NO3 )2 -A Three-Dimensional Network with the Exceptional (12,3) Topology: A Self-Entangled Single Net. AB - The shortest circuits in the three-dimensional network with (12,3) topology of solvated Ni(tpt)(NO3 )2 pass through one another (see picture). This network based upon interlinked double helices occupies a unique position in the set of (n,3) nets. tpt=tri-4-pyridyl-1,3,5-triazine. PMID- 29711593 TI - Topological Links between Duplex DNA and a Circular DNA Single Strand. AB - DNA nanostructures of building blocks topologically linked at a precise position can be assembled from DNA duplexes and circularized oligonucleotides with the aid of peptide nucleic acids (PNAs). Shown schematically is a linked catenane yielding an earring topological DNA label. PMID- 29711594 TI - Tetrathiafulvalene Belts with Large Cavities. AB - The latest member of the cyclophane family, the macrotricyclic tetrathiafulvalene (TTF) "belt", is now available. A general synthetic strategy for the construction of tetraconnected belt-type TTFs (shown schematically) has been developed, made possible by the use of a TTF with two different protecting groups. In the solid state structure of one of the three TTF-belts prepared two chloroform molecules reside inside the spacious cavity. PMID- 29711595 TI - Synthesis and Stereoselective Reactions of New Stable alpha-Ferrocenyllithium Derivatives. An Umpolung of the Ferrocene Reactivity. AB - The reductive lithiation of various alpha-ferrocenylcarbinol derivatives yields stable alpha-ferrocenyllithium species (see scheme). These can be quenched with different electrophiles with complete retention of configuration. PMID- 29711596 TI - Chelated Enolates of Amino Acid Esters-Efficient Nucleophiles in Palladium Catalyzed Allylic Substitutions. AB - Complementary to the Claisen rearrangement, the title reaction-which when carried out with chelated enolates of amino acid esters as nucleophiles gives rise to unsaturated amino acids-preferentially provides anti instead of syn products. This palladium-catalyzed reaction proceeds under very mild conditions and is suitable for the synthesis of enantiomerically pure amino acids (see reaction scheme). Tfa=trifluoroacetyl. PMID- 29711597 TI - Stereospecific Migration of P from N to C sp 2: Ring-Expansion Reaction of Chiral Diazaphospholidine Oxides. AB - An addition-pseudorotation-elimination pathway is proposed for the first stereospecific ring-expansion reaction of chiral diazaphospholidine oxides by a 1,3-migration of P from N to C sp 2 [Eq. (1)]. R=H, Ph; LDA=lithium diisopropylamide. PMID- 29711598 TI - A Novel Aldol Condensation with 2-Methyl-4-pentenal and Its Application to an Improved Total Synthesis of Epothilone B. AB - The stabilization of the transition state through a favorable interaction between the double bond of 1 and the carbonyl group of 2 appears to be responsible for the high diastereoface selectivity of the aldol reaction. This key step in the highly concise total synthesis of epothilone B is followed by a Suzuki coupling to introduce the thiazole domain, a Noyori reduction to control the stereochemistry at C3, and a final macrolactonization (see reaction scheme). X=protecting group. PMID- 29711599 TI - Two New Isopolyoxotungstates(VI) with the Empirical Composition Cs2 W2 O7 ?2 H2 O and Na2 W2 O7 ?H2 O: An Icosatetratungstate and a Polymeric Compound. AB - The largest isopolyoxotunstate ion known to date, W24 O8424- (structure shown in the picture), isolated as the cesium salt, and a chainlike polyoxotungstate ion made up of planar W4 O16 units, isolated as the sodium salt, hide behind the simple empirical formulas of the title compounds. PMID- 29711600 TI - Synthesis and Structure of New Ag-Se Clusters: [Ag30 Se8 (SetBu)14 (PnPr3 )8 ], [Ag90 Se38 (SetBu)14 (PEt3 )22 ], [Ag114 Se34 (SenBu)46 (PtBu3 )14 ], [Ag112 Se32 (SenBu)48 (PtBu3 )12 ], and [Ag172 Se40 (SenBu)92 (dppp)4 ]. PMID- 29711601 TI - Total Syntheses of Vancomycin and Eremomycin Aglycons. AB - Controlling the elements of planar and axial chirality are the principal challenges in the synthesis of the aglycon of vancomycin. Vancomycin is the prototypical member of the glycopeptide family of antibiotics which are effective for the treatment of infections by methicillin-resistant Staphylococcus aureus. The first total syntheses of the vancomycin and eremomycin aglycons provide insight into the influence of structure on kinetic and thermodynamic control of atropselective macrocyclizations. PMID- 29711602 TI - Nonconventional Stereochemical Issues in the Design of the Synthesis of the Vancomycin Antibiotics: Challenges Imposed by Axial and Nonplanar Chiral Elements in the Heptapeptide Aglycons. AB - Controlling the elements of planar and axial chirality are the principal challenges in the synthesis of the aglycon of vancomycin. Vancomycin is the prototypical member of the glycopeptide family of antibiotics which are effective for the treatment of infections by methicillin-resistant Staphylococcus aureus. The first total syntheses of the vancomycin and eremomycin aglycons provide insight into the influence of structure on kinetic and thermodynamic control of atropselective macrocyclizations. PMID- 29711603 TI - A Coordination-Induced 1,4->1,2-Quinonediimine Isomerization. AB - Hitherto unused in coordination compounds, the para-quinonoid azophenine (p-ap) has now been applied for the synthesis of [Cu(PPh3 )2 (o-ap)](BF4 ) (1), in which the ligand exists as its ortho-quinonoid tautomer. Additional stabilization of this metal-pi donor/ligand-pi acceptor arrangement occurs through chelate-like hydrogen bonding between the NH functionalities, which are both now ortho positioned, and the BF4- counterion. PMID- 29711604 TI - A New Route to Heterosilsesquioxane Frameworks. AB - The substitution of an O atom in the Cy8 Si8 O12 framework by a heteroatom or a heteroatom-containing group (Z) provides a simple route to discrete heterosilsesquioxane frameworks 1. In this reaction the Cy8 Si8 O12 framework is initially opened with triflic acid and then treated with different nucleophiles (Cy=cyclohexyl; Z=NPh, SO4 , nBuBO2 , CrO4 ). PMID- 29711605 TI - Total Synthesis of Vancomycin Aglycon-Part 1: Synthesis of Amino Acids 4-7 and Construction of the AB-COD Ring Skeleton. AB - A triazene-based synthetic strategy for the construction of the complex biaryl ethers and a Suzuki coupling reaction were the key steps in the synthesis of precursor 1 of the aglycon of vancomycin, which already contains the complete skeleton of the target compound. The cleavage of the triazene unit from the D ring and the removal of the other protecting groups led to the aglycon of vancomycin. These strategies should be particularly valuable for the synthesis of other naturally occurring glycopeptide antibiotics and offer opportunities for the synthesis of combinatorial libraries of compounds of the vancomycin family for chemical biology studies. PMID- 29711607 TI - Olefin Metathesis of a Ruthenium Carbene Complex by Electrospray Ionization in the Gas Phase. AB - Surprisingly similar reactions in the gas phase and in solution [Eq. (a)]: The ion 1 obtained by electrospray ionization behaves in the gas phase analogously to the corresponding complex [RuCl2 (=CHPh)(PCy3 )2 ] in solution. Measured relative rates for ring-opening metathesis are interpreted under the assumption of an intramolecular pi complex, which leads to an estimation of the equilibrium constant for pi complexation. PMID- 29711606 TI - Site-Directed Surface Derivatization of MCM-41: Use of High-Resolution Transmission Electron Microscopy and Molecular Recognition for Determining the Position of Functionality within Mesoporous Materials. AB - The "staining" cluster-crown compound [Ru6 C(CO)14 (eta6 -C6 H4 C10 H20 O6 )] verifies that the internal walls of mesoporous silica MCM-41 may be selectively functionalized with propylammonium groups (see picture). By the use of high resolution transmission electron microscopy the presence and position of the cluster and also of the functional groups may be directly determined. PMID- 29711608 TI - A Robust (10,3)-a Network Containing Chiral Micropores in the AgI Coordination Polymer of a Bridging Ligand that Provides Three Bidentate Metal-Binding Sites. AB - Framework integrity is retained when water molecules replace the nitromethane molecules in the coordination polymer [Ag(hat)ClO4 ]?2 CH3 NO2 (see picture for structure), which are arranged in a helical fashion within the chiral micropores of the three-dimensional [Ag(hat)+ ]n network with a (10,3)-a topology. Remarkably, this is also the case after subsequent displacement of the water by nitromethane molecules. hat=1,4,5,8,9,12-hexaazatriphenylene. PMID- 29711609 TI - A Soluble C60 Graphite Segment. AB - At the limits of analytical investigation one finds the nanodimensional C60 graphite segment 1, which, thanks to its long-chain alkyl substituents, is soluble. Monolayers of 1 on graphite can be characterized by scanning tunneling microscopy. PMID- 29711610 TI - Structures of Solvent-Free, Monomeric LiCCH, NaCCH, and KCCH. AB - The simplest alkali metal acetylides MCCH were made in the gas phase for the first time (see drawing), and their bond lengths were determined by millimeter/submillimeter spectroscopy of their isotopomers. The M-C bond lengths rCM are the shortest known for organoalkali metal compounds. In the case of LiCCH, the experimentally determined Li-C distance of 1.888 A has an estimated accuracy of +/-0.0005 A, which should allow a rigorous test of theoretical methods. PMID- 29711611 TI - Gemini Surfactants as New, Low Molecular Weight Gelators of Organic Solvents and Water. AB - As many as 1200 solvent molecules can be entrapped by one molecule of the cationic dimeric surfactants 1 to form a gel in CHCl3 . These new gelators contain chiral counterions and form gels with both organic solvents and water upon their assembly into helical aggregates, which have similar structures in both media. PMID- 29711612 TI - Calixarene-Based Copper(I) Complexes as Models for Monocopper Sites in Enzymes. AB - A cavity that acts as a molecular funnel is formed from calix[6]arene 1 and [CuI (NCCH3 )4 ]PF6 [Eq. (a)]. An exchange of the well-protected acetonitrile ligand for other nitriles RCN is only possible with small R groups. The protection of the copper ions precludes oxidative dimerization; thus, the complexes mimic the mononuclear site of copper enzymes. PMID- 29711613 TI - Total Synthesis of Vancomycin Aglycon-Part 2: Synthesis of Amino Acids 1-3 and Construction of the AB-COD-DOE Ring Skeleton. AB - A triazene-based synthetic strategy for the construction of the complex biaryl ethers and a Suzuki coupling reaction were the key steps in the synthesis of precursor 1 of the aglycon of vancomycin, which already contains the complete skeleton of the target compound. The cleavage of the triazene unit from the D ring and the removal of the other protecting groups led to the aglycon of vancomycin. These strategies should be particularly valuable for the synthesis of other naturally occurring glycopeptide antibiotics and offer opportunities for the synthesis of combinatorial libraries of compounds of the vancomycin family for chemical biology studies. PMID- 29711614 TI - 2-Nitrobenzylarsonium Compounds That Photorelease Heavy-Atom Cholinergic Ligands for Time-Resolved Crystallographic Studies on Cholinesterases. AB - As heavy-atom analogues of caged cholinergic ligands, the arsonium compounds 1-3 were synthesized for potential time-resolved crystallographic studies on cholinesterases. Compounds 1 and 3 possess the desired properties for dynamic studies on the catalytic mechanism of cholinesterases: structural similarity with the N-homologue, strong X-ray diffracting effect of arsenic, inhibitory effects on cholinesterases, and excellent photofragmentation kinetics. PMID- 29711615 TI - Direct NMR Spectroscopic Observation of a Lanthanide-Coordinated Water Molecule whose Exchange Rate Is Dependent on the Conformation of the Complexes. AB - A large difference in the exchange rate of the coordinated water molecule is seen in solution for the diastereoisomers M and m of a europium(III) complex with an octadentate, neutral macrocyclic ligand (kex (M)90 % ee by Sulfoxide/Magnesium Exchange. AB - Not only for ligand exchange at sulfoxides can the sulfoxide/magnesium exchange reaction be used, but it also provides a possibility to generate Grignard reagents in way that avoids metallic magnesium and thus radical processes. Therefore, enantiomerically pure Grignard reagents can be obtained from the corresponding sulfoxides [Eq. (a)]. PMID- 29711668 TI - Ion-Channel Gating in Transmembrane Receptor Proteins: Functional Activity in Tethered Lipid Membranes. AB - Through thiolipids a planar lipid bilayer (1) was immobilized on a gold support (2) for use as an electrode. This allows the detection of the ligand-gating function of the natural transmembrane channel protein OmpF (3) reconstituted in the artificial membrane: the binding of a domain (4) of the toxin colicin N, observed by surface plasmon resonance, induces the blocking of the OmpF channel protein, as shown by impedance spectroscopy. PMID- 29711669 TI - [{Ag(tBuNH2 )2 }4 ][{Ag(tBuNH2 )(tBuN=CHCH3 )}2 ][Ag12 (CF3 CO2 )14 ]: A Compound with an Ag128+ Cluster Core. PMID- 29711670 TI - The High-Valent Compound of Cytochrome P450: The Nature of the Fe-S Bond and the Role of the Thiolate Ligand as an Internal Electron Donor. PMID- 29711671 TI - Super-High-Throughput Screening of Enantioselective Catalysts by Using Capillary Array Electrophoresis. PMID- 29711672 TI - Self-Assembled Organometallic Block Copolymer Nanotubes. PMID- 29711673 TI - Enzymatic Glycosylation in Plasticized Glass Phases: A Novel and Efficient Route to O-Glycosides. PMID- 29711674 TI - Self-Repairing DNA Based on a Reductive Electron Transfer through the Base Stack. PMID- 29711675 TI - Direct Bromination of Keggin Fragments To Give [PW9 O28 Br6 ]3- : A Polyoxotungstate with a Hexabrominated Face. PMID- 29711676 TI - Synthesis, Crystal Structure, and Binding Properties of the Mixed Valence Clusters [Cu32 As30 (dppm)8 ] and [Cu26 Te12 (PEt2 Ph)12 ]. PMID- 29711677 TI - Formation of Novel Ordered Mesoporous Silicas with Square Channels and Their Direct Observation by Transmission Electron Microscopy. PMID- 29711678 TI - A Three-Step Entry to the Aspirochlorine Family of Antifungal Agents. PMID- 29711679 TI - (CN3 H6 )4 [Zn3 (SeO3 )5 ]: The First Organically Templated Selenite. PMID- 29711680 TI - Molecular Topology: Easy Self-Assembly of an Organometallic Doubly Braided [2]Catenane. PMID- 29711681 TI - Second-Order Nonlinear Optical Properties of Functionalized Ionophores: Cation Steered Modulation of the First Hyperpolarizability. PMID- 29711682 TI - Correlation of the Topology of the Electron Density of Pyrite-Type Transition Metal Sulfides with Their Catalytic Activity in Hydrodesulfurization. PMID- 29711683 TI - [{Ir(eta5 -C5 Me5 )(CO)}6 Hg8 ][CF3 CO2 ]6 , a Mixed-Metal Cluster with an Ir6 Hg6 Twelve-Membered Ring and Additional Hg Centers and Metal-Metal Bonds. PMID- 29711684 TI - Open Square-Grid Coordination Polymers of the Dimensions 20*20 A: Remarkably Stable and Crystalline Solids Even after Guest Removal. PMID- 29711685 TI - Novel Nickel(II) Complexes for the Catalytic Copolymerization of Ethylene and Carbon Monoxide: Polyketone Synthesis in Supercritical Carbon Dioxide. PMID- 29711686 TI - On Closed-Shell Interactions, Polar Covalences, d Shell Holes, and Direct Images of Orbitals: The Case of Cuprite. PMID- 29711687 TI - A Concise Stereoselective Route to the Pentacyclic Frameworks of Arisugacin A and Territrem B. PMID- 29711688 TI - Synthesis and Application of a Permanently Immobilized Olefin-Metathesis Catalyst. PMID- 29711689 TI - Photoinduced Electron Transfer from a Porphyrin to an Electron Acceptor in an Antibody-Combining Site. PMID- 29711690 TI - Speciation in Solution: Silicate Oligomers in Aqueous Solutions Detected by Mass Spectrometry. PMID- 29711691 TI - Cisplatin Changes the Mechanics of Single DNA Molecules. PMID- 29711692 TI - The Cl4+ Ion. PMID- 29711693 TI - Stepwise Assembled Photoactive Films Containing Donor-Linked Fullerenes. PMID- 29711694 TI - Hexagonal Layered Materials Composed of [M2 (O2 CCF3 )4 ] (M=Ru and Rh) Donors and TCNQ Acceptors. PMID- 29711695 TI - Higher Adducts of C60 by Tether-Directed Remote Functionalization: X-Ray Crystal Structure and Reactivity of a Chiral Hexakis-Cyclopropanated Fullerene with all Addends Located along an Equatorial Belt. PMID- 29711697 TI - Breaking the Rule: Synthesis and Molecular Structure of Dinuclear Rhodium Complexes with Bridging and Semibridging Trialkylphosphane Ligands. PMID- 29711698 TI - Supramolecular Chemistry of Anionic Cobalt(III) Bis(dicarbollide) and Cyclotriveratrylene in the Solid State and the Gas Phase. PMID- 29711699 TI - Control of Xanthine Oxidase Activity by Light. PMID- 29711700 TI - Ion-Specific Aggregation in Conjugated Polymers: Highly Sensitive and Selective Fluorescent Ion Chemosensors. PMID- 29711701 TI - Final Comment on the Discussions of "The Case of Cuprite". PMID- 29711702 TI - Novel Oligosaccharide Binding to the Cerium(IV) Bis(porphyrinate) Double Decker: Effective Amplification of a Binding Signal through Positive Homotropic Allosterism. PMID- 29711703 TI - Formation of the Unprecedented Trilithio-Capped Heteroadamantanyl Iminoalane Anion [(HAl)4 (NPh)6 {Li(OEt2 )}3 ]- : An Open Cage Derived from a Rhombododecahedron. PMID- 29711704 TI - A Blue Luminescent Starburst Molecule and Its Orange Luminescent Trinuclear PdII Complex: 1,3,5-tris(7-azaindol-1-yl)benzene (tabH) and [Pd II3(tab)2 Cl4 ]. PMID- 29711705 TI - Monosaccharide-Alkyl Glycoside Glass Phases: Plasticization with Hydrophilic and Hydrophobic Molecules. PMID- 29711706 TI - Spherical Aromaticity in Ih Symmetrical Fullerenes: The 2(N+1)2 Rule. PMID- 29711707 TI - New Fused Bicyclic Cyclotrigermanes from Cycloaddition Reactions of Cyclotrigermene. PMID- 29711708 TI - Target-Accelerated Combinatorial Synthesis and Discovery of Highly Potent Antibiotics Effective Against Vancomycin-Resistant Bacteria. PMID- 29711709 TI - Synthesis of Thymine Glycol Containing Oligonucleotides from a Building Block with the Oxidized Base. PMID- 29711710 TI - The Electrical Properties of Gold Nanoparticle Assemblies Linked by DNA. PMID- 29711711 TI - High-Throughput Structure Verification of a Substituted 4-Phenylbenzopyran Library by Using 2D NMR Techniques. PMID- 29711712 TI - A Soluble Polymer-Bound Ruthenium Carbene Complex: A Robust and Reusable Catalyst for Ring-Closing Olefin Metathesis. PMID- 29711713 TI - Rapid, Reversible Oxygen Atom Transfer between an Oxomanganese(V) Porphyrin and Bromide: A Haloperoxidase Mimic with Enzymatic Rates. PMID- 29711714 TI - Highly Enantioselective Rh-Catalyzed Hydrogenation Reactions Based on Chiral Monophosphite Ligands. PMID- 29711715 TI - Stable Systems with a Triple Bond to Silicon or Its Homologues: Another Challenge. PMID- 29711716 TI - Room Temperature Oxidation of Carbon Monoxide Catalyzed by Hydrous Ruthenium Dioxide. PMID- 29711717 TI - Pentamethylcyclopentadienylrhodium(III) and -iridium(III) Complexes Showing P,O Coordination: Unprecedented Insertion of tcne and tcnq into a C-H Bond. AB - Strongly electron withdrawing cyanoolefins tetracyanoethylene (tcne) and 7,7,8,8 tetracyano-p-quinodimethane (tcnq) react with [(eta5 -C5 Me5 )MCl(MDMPP-P,O)] (M=Rh, Ir; MDMPP-P,O=PPh2 (2-O-6-MeO-C6 H3 ), a P,O chelating phosphane) by insertion into the C-H bond adjacent to the M-O sigma bond. The crystal structure of the iridium complex formed upon insertion of tcne is shown. PMID- 29711718 TI - Imprint Coating: A Novel Synthesis of Selective Functionalized Ordered Mesoporous Sorbents. AB - Molecular imprinting of surfaces of mesoporous sorbents is a novel method for introducing template-selective recognition sites. This method makes use of the unique surface environment of hexagonally packed mesopore surfaces of selected pore sizes (see the schematic representation) and coats such surfaces with functional ligands by binding to a metal ion template. PMID- 29711719 TI - The Vancomycin Group of Antibiotics and the Fight against Resistant Bacteria. AB - A last line of defence against "superbugs" are the vancomycin group antibiotics. This review describes the determination of their mode of action, and a mechanism of resistance to them. Remarkably, this mechanism of resistance can be overcome without directly modifying the binding site of the antibiotics for the cell-wall precursors of pathogenic bacteria. PMID- 29711720 TI - Functional Monolayers with Coordinatively Embedded Metalloporphyrins. AB - Perpendicularly oriented iron porphyrins are absorbed onto a gold surface when interconnected long-chain diimidazolyl groups coordinate axially to the metal center from either side of the ring plane (see schematic representation). The stacking of the rings is simultaneously prevented. The monolayers have been characterized structurally and electrochemically. PMID- 29711721 TI - Covalent Surface Functionalization and Self-Organization of Silica Nanoparticles. PMID- 29711722 TI - Optically Active Organometallic Compounds of Transition Elements with Chiral Metal Atoms. AB - Chiral transition metal atoms are not only present in tris-chelate complexes [M(LL)3 ]n+ , which were already resolved into the enantiomers by Alfred Werner, but also in organometallic half-sandwich complexes such as 1 with three- or four legged piano-stool structure. These complexes have been tools in the elucidation of the spatial course of reactions and in organic syntheses. Applications in enantioselective catalysis are beginning to show up. PMID- 29711723 TI - Strong N-H???O Hydrogen Bonding in a Model Compound of the Catalytic Triad in Serine Proteases. AB - Low-barrier hydrogen bond (LBHB) involvement in enzyme catalysis is examined by analysis of experimental nuclear and electron densities of a model compound for the catalytic triad in serine proteases (shown schematically), which is based on a cocrystal of betaine, imidazole, and picric acid. The three short, strong N H???O hydrogen bonds in the structure have varying degrees of covalent bonding contributions suggesting a gradual transition to the LBHB situation. PMID- 29711724 TI - Determination of the Electron Density Distribution in the Bonds of a Fullerene Derivative by High-Resolution X-Ray Structure Analysis. AB - Bent bonds in the strained fullerene system, restricted to the [5,6] bonds, were detected by high-resolution X-ray structure analysis of the 1,2 dihydro[60]fullerene derivative 1. In addition the maxima of electron densities are higher in the [6,6] bonds than in the [5,6] bonds-an important finding with respect to the question of the extent of electron delocalization in fullerenes. PMID- 29711725 TI - Real-Time Characterization of Ribozymes by Fluorecence Resonance Energy Transfer (FRET). AB - More rapid than with conventional methods is the analysis of ribozyme kinetics upon use of FRET substrates. In these substrates a fluorophore and a fluorescence quenching molecule lie in close spatial proximity. The intramolecular fluorescence quenching is neutralized upon cleavage, and the fluorescence intensity is a measure of the ribozyme activity. By automation and computer assistance the activity of ribozymes can be monitored under high-throughput conditions. PMID- 29711726 TI - 2,3,5-Tri-tert-butyl-1-carba-nido-tetraborane. AB - The missing link in the series of tert-butyl derivatives of the isoelectronic nido clusters B4 H8 , CB3 H7 , and NB3 H6 with a bicyclobutane-type structure is represented by the title compound CB3 H4 tBu3 (1), the clusters B4 H4 tBu4 and NB3 H3 tBu3 being well known. Compound 1 may also be considered to be a derivative of the nido-triborane B3 H7 , which has hitherto not been isolated, formed by replacing three H atoms by tBu groups and two H atoms by a CH2 bridge, as expressed by the formula B3 H2 tBu3 (CH2 ). PMID- 29711727 TI - [(TeMe2 )Mn(CO)4 (MU5 -Te)(MU4 -Te)Mn4 (CO)12 ]- : A Pentacoordinate Bridging Tellurido Ligand in a Square-Pyramidal Geometry. AB - The first Te-Mn-CO clusters were obtained by the thermal reaction of K2 TeO3 with [Mn2 (CO)10 ] in MeOH. The basicity of the MU4 -Te ligand in the octahedral cluster anion [(MU4 -Te)2 Mn4 (CO)12 ]2- is demonstrated by its binding to the fragment [(TeMe2 )Mn(CO)4 ]+ in an axial fashion to afford the novel cluster 1. PMID- 29711728 TI - [M3 V18 O42 (H2 O)12 (XO4 )]?24 H2 O (M=Fe, Co; X=V, S): Metal Oxide Based Framework Materials Composed of Polyoxovanadate Clusters. AB - New framework materials composed of well-defined vanadium oxide clusters were prepared by low-temperature reactions and characterized by X-ray crystal structure analysis. The structures of these solids contain {V18 O42 } cages linked into two interpenetrating three-dimensional networks by bridging {M(H2 O)4 } groups (M=FeII , CoII ; see picture). PMID- 29711729 TI - Synthesis and Biological Evaluation of a Cyclo-beta-tetrapeptide as a Somatostatin Analogue. AB - Short beta-peptides can mimic natural peptide hormones, as has been shown with a cyclo-beta-tetrapeptide (1) that displays micromolar affinity to human somatostatin receptors. beta-Peptides are thus a promising new class of peptidomimetics with potential high bioavailability due to their excellent resistance against proteases. PMID- 29711730 TI - Total Synthesis of (-)-Mucocin. AB - A highly convergent, modular strategy for the total synthesis of the annonaceous acetogenin (-)-mucocin is reported. The remarkable features are the endo selective formation of the tetrahydropyran ring from an activated epoxide and the stability of the butenolide in the coupling with an organomagnesium compound. PMID- 29711731 TI - Highly Substituted Spiro[4.4]nonatrienes from a beta-Amino-Substituted alpha,beta Unsaturated Fischer Carbene Complex and Three Molecules of an Arylalkyne. AB - A novel mode of reaction towards arylethynes is shown by the beta-trimethylsilyl substituted alpha,beta-unsaturated Fischer carbene complexes 1. A mixture of the isomeric, highly substituted spiro[4.4]nonatrienes 2 and 3 is formed by the formal insertion of three alkyne molecules and subsequent cyclization (see scheme). Such selective triple insertions of alkynes into ethenylcarbene complexes have not been previously observed. PMID- 29711732 TI - Combinatorial Chemistry-Challenge and Chance for the Development of New Catalysts and Materials. AB - One should not underestimate the capability of the combinatorial method in solid state chemistry; this is the opinion of the author. Combinatorial chemistry can provide a large number of new compounds, but once the components that are interesting for a certain application have been successfully selected, the techniques of conventional catalysis and materials research are required. The strengths of conventional chemistry lie in the optimization, systematic modification, and improvement of new lead structures. In contrast, discovery is the potential strength of combinatorial chemistry. Careful design is most important for the synthesis of useful libraries, since the diversity of the periodic table is much too large to be accessed comprehensively or systematically by such large libraries. PMID- 29711733 TI - Photochemical Cycloaromatization of Non-Benzenoid Enediynes. AB - An efficient photo-Bergman reaction of aliphatic enediynes has been realized. Photolysis of 1 results in the formation of 4 in good yields along with [D2 ]3. Enediyne 4, which has never been isolated in the thermal reaction of 1, arises here by a retro-Bergman reaction of the diradical intermediate 2. PMID- 29711734 TI - The Biosynthesis of Barbamide-A Radical Pathway for "Biohalogenation"? AB - A stereoselective chlorination of a methyl group and the preference of cleavage of nonactivated primary C-H bonds in one of the methyl groups with respect to a weaker tertiary C-H bond in the course of the biosynthesis of barbamide point to a surprising, new mechanism of "biohalogenation" (see schematic diagram). PMID- 29711735 TI - Exploiting Incommensurate Symmetry Numbers: Rational Design and Assembly of M2 M3 'L6 Supramolecular Clusters with C3h Symmetry. AB - Mixed-metal mesocates [M2 Pd3 Br6 L6 ]4- (M=TiIV , SnIV ; L=4-diphenylphosphanyl catecholate) have been synthesized, in which the two incommensurate symmetry elements generated by the different metal ions are linked by a rigid, bifunctional ligand to generate a C3h -symmetrical cluster (see picture). PMID- 29711736 TI - Monovalent Group 13 Organometallic Compounds: Weak Association to Monomeric, Versatile Two-Electron Donors. AB - A weakly associated hexamer is formed for [GaCp*] (Cp*=C5 Me5 ) in the solid state (see picture). The recent X-ray crystal structure analyses of [GaCp*] as well as the monomeric InI and TlI compounds [M(2,4,6-Trip3 C6 H2 )] (Trip=2,4,6 iPr3 C6 H2 ) throw new light on the association and aggregation of monovalent Group 13 elements in the solid state. The synthesis of [Ni0 {In[C(SiMe3 )3 ]}4 ], a complex with terminally bonded InI R ligands, offers alternative sigma-donor/pi acceptor ligands to organometallic chemists. The newest results in this area are likely to open up new and intriguing possibilities in the preparation of main group-transition metal clusters. PMID- 29711737 TI - A New Class of Ruthenium Carbene Complexes: Synthesis and Structures of Highly Efficient Catalysts for Olefin Metathesis. AB - Cationic RuII carbene complexes with tBu2 PCH2 PtBu2 (dtbpm) as a chelating ligand, which are accessible by chloride abstraction from neutral precursors [(kappa2 -dtbpm)Cl2 Ru=CHR] with trimethylsilyl triflate, are established as highly efficient ring opening metathesis polymerization catalysts (see scheme). Solv=solvent. PMID- 29711738 TI - New Tripodal, "Supercharged" Analogues of Adenosine Nucleotides: Inhibitors for the Fhit Ap3 A Hydrolase. AB - Methanetrisphosphonic acids provide a branch point for synthetic nucleotide analogues which can be exploited either to generate novel tripodal nucleotides or to incorporate additional negative charge into linear analogues relative to the parent nucleotide, as exemplified in the picture for ATP and diadenosine tetraphosphate (Ap4 A). These compounds show valuable discriminatory behavior as competitive inhibitors for the tumor suppressor protein Fhit and a second Apn A pyrophosphohydrolase. X=H, Cl, F. PMID- 29711739 TI - A New CoII Complex as a Bulge-Specific Probe for DNA. AB - Bulge cleavage of two or three bases occurs when a DNA substrate is specifically cleaved oxidatively by [CoII (tfa)2 (happ)] (see picture). Hydrogen peroxide is necessary for the activation of this octahedral complex, which suggests that hydroxyl radicals are the reactive species. The complex has no significant reactivity towards the corresponding sequence in a single-stranded DNA region, and it exhibits only a low affinity towards double-stranded DNA. happ=macrocyclic ligand based on 1,10-phenanthroline, tfa=trifluoroacetate. PMID- 29711740 TI - Structure and Magnetic Properties of a Dodecanuclear Twisted-Ring Iron(III) Cluster. AB - An unprecedented nonplanar structure characterizes the complex [Fe(OCH3 )2 (dbm)]12 (on the left in the picture), which contains the largest cyclic ferric cluster yet reported with chemically equivalent bridging units. It is made up of twelve high-spin, antiferromagnetically coupled iron(III) centers and neatly reacts with NaI or LiI templates in organic solution to give hexairon(III) coronates (right). Fe=*, O=?, NaI or LiI=* Hdbm=dibenzoylmethane. PMID- 29711741 TI - From Axial Chirality to Central Chiralities: Pinacol Cyclization of 2,2' Biaryldicarbaldehyde to trans-9,10-Dihydrophenanthrene-9,10-diol. AB - Two salient features-the stereoselectivity to give only the trans-diol, and the stereospecificity to transmit the axial chirality (in case the starting biphenyl is configurationally stable) onto two stereogenic centers of the product characterize the pinacol cyclization of 2,2'-biaryldicarbaldehydes (see reaction). The accessibility of trans-9,10-dihydrophenanthrene-9,10-diols provides the new enantiopure C2 -symmetric diol 1, which shows potential utility in asymmetric synthesis. PMID- 29711742 TI - Spacer Control of Directionality in Supramolecular Helicates Using an Inexpensive Approach. AB - Careful selection of the spacer group used to separate the metal-binding domains allows control of the directionality in a helix; self-assembly leads uniquely to a double-helical cation with a head-to-tail (HT) configuration (shown schematically) in both the solid state and solution. PMID- 29711743 TI - Catalytic Diastereoselective Imidation of Diaryl Sulfides Bearing a Chiral Oxazolinyl Moiety with Chloramine T Trihydrate. AB - Up to 99 % de is obtained in the imidation of diaryl sulfides bearing a chiral oxazolinyl moiety at the ortho position. The corresponding N-p-tosylsulfimides are produced upon use of chloramine T trihydrate in the presence of Cu(OTf)2 as catalyst [Eq. (1)]. OTf=trifluoromethanesulfonate; Ts=toluenesulfonyl. PMID- 29711744 TI - A Stable and Recoverable Chiral Ru Lewis Acid: Synthesis, Asymmetric Diels-Alder Catalysis and Structure of the Lewis Acid Methacrolein Complex. AB - Ease of generation, stablity in solution at ambient temperature, high enantioselectivity in Diels-Alder reactions, efficient catalyst recovery, and large rate differences on variation of the anion are all characteristics of the new Ru Lewis acid [CpRu((S,S)-biphop-F)]+ (biphop-F=(C6 F5 )2 POCH2 (Ph)CH2 (Ph)OP(C6 F5 )2 ). The structure of complex 1 (L=methacrolein, Y=SbF6 ) provides evidence for a cooperative binding of the dienophile by both the Lewis acid and the anion. PMID- 29711745 TI - Chemoenzymatic Synthesis of a Characteristic Glycophosphopeptide from the Transactivation Domain of the Serum Response Factor. AB - Glycopeptides, phosphopeptides, and glycophosphopeptides can be synthesized efficiently by a strategy based on a combination of suitable enzyme-labile protecting groups. Thus, probes for biological studies can be accessed. An example is the glycosylated and phosphorylated heptapeptide 1 from the transactivation domain of the human serum response factor, which contains an additional biotin label for detection with streptavidin. PMID- 29711746 TI - Large Circular Dichroism Ellipticities for N-Templated Helical Polypeptides Are Inconsistent with Currently Accepted Helicity Algorithms. AB - An unprecedented, high degree of helicity as judged by CD spectroscopy is observed in N-templated model peptides of the type AcHel-(Ala4 Lys)n Ala2 -NH2 (AcHel-Ala peptide pictured; AcHel is an N-terminal helix-inducing template for polypeptides). These results raise concern over the current methods for determining 100 % helicity. PMID- 29711747 TI - [(Ph)2 (NMe2 )C(OLi)?THF]2 : Crystal Structure of the Tetrahedral Intermediate Formed in the Reaction of N,N-Dimethylbenzamide and Phenyllithium. AB - Information on the reaction path for the 1,2-eliminiation of LiNMe2 to form benzophenone is provided by the X-ray crystal structure analysis of the tetrahedral adduct [(Ph)2 (NMe2 )C(OLi)?THF]2 (a portion of the structure is shown schematically), which is prepared from N,N-dimethylbenzamide and phenyllithium. A N1-Li1 interaction, which is not observed, would lead to loss of the anomeric effect (nN ->sigma*C-O ) as well as high conformational strain along the C1-N1 bond. PMID- 29711748 TI - Enantiomerically Pure Cyclic trans-1,2-Diols, Diamines, and Amino Alcohols by Intramolecular Pinacol Coupling of Planar Chiral Mono-Cr(CO)3 Complexes of Biaryls. AB - Without any formation of stereoisomers, the intramolecular pinacol cyclization of 1-planar chiral mono-Cr(CO)3 complexes of 1,1'-biphenyls with carbonyl functionalities at the 2- and 2'-positions-with samarium diiodide gives cyclic trans-1,2-diols 2. Upon exposure to sunlight, the chromium-complexed diols 2 produce optically pure chromium-free trans-diols 3. Similarly, the corresponding enantiomerically pure trans-1,2-diamines and amino alcohols are obtained from the planar chiral chromium complexes of biphenyls with diimino or keto-imino functionalities. R1 =H, OMe; R2 =H, Me; R3 =H, Me. PMID- 29711749 TI - A New In Vitro Model of Lignin Biosynthesis. AB - A strictly coordinate sequence of radical and ionic steps appears to be the mechanism by which oligolignols are generated. A synthetic lignin was produced under micellar conditions [Eq. (1)], and the beginning of the polymerization process was studied by electrospray ionization mass spectrometry. CTA=cetyltrimethylammonium ion. PMID- 29711750 TI - Highly Regio- and Stereoselective Synthesis of Mannose-Containing Oligosaccharides with Acetobromo Sugars as the Donors and Partially Protected Mannose Derivatives as the Acceptors via Sugar Orthoester Intermediates. AB - An orthoester formation/rearrangement sequence, in which 1,2-O-ethylidenated mannose or partially protected mannosides function as the glycosyl acceptors and simple acetobromo sugars as the glycosyl donors (see reaction scheme), provides an efficient and highly regio- and stereoselective route to mannose-containing 1 >6, 1->3, and 3,6-branched oligosaccharides with exclusive 1,2-trans linkage. PMID- 29711751 TI - Total Synthesis of Pradimicinone, the Common Aglycon of the Pradimicin Benanomicin Antibiotics. AB - A benzo[a]naphthacenequinone core, an amino acid, and a disaccharide are the constituents of pradimicin-benanomicin antibiotics 1 (R1 =disaccharide), a class of natural products with significant antifungal and anti-HIV activities. The first total synthesis of pradimicinone (benanomicinone, 1; R1 =H), the common aglycon of this class of natural products, has now been achieved based on the transmission of chirality during the pinacol cyclization of 2,2' biaryldicarbaldehydes. PMID- 29711752 TI - SSZ-35 and SSZ-44: Two Related Zeolites Containing Pores Circumscribed by Ten- and Eighteen-Membered Rings. AB - Unusual one-dimensional pores circumscribed by 10- and 18-membered rings are a feature of the structures of two high-silica molecular sieves, SSZ-44 and SSZ-35. Structure solution and Rietveld refinement from synchrotron powder X-ray data reveal that the two materials are the pure end-member polymorphs of a new fault series and contain similar layerlike units (see picture). The SSZ-44 structure is formed by an AB stacking of the layers, whereas the SSZ-35 structure is formed through an ABC stacking of the layer units. PMID- 29711753 TI - Modeling the Selectivity of Potassium Channels with Synthetic, Ligand-Assembled pi Slides. AB - A supramolecular ion channel model mediates transmembrane ion transport (shown schematically) with a selectivity topology similar to that of K+ channels. This supports the biological significance of flexible arene arrays as selective cation binding sites. PMID- 29711754 TI - Reaction of RGeBr3 (R=iPr2 C6 H3 NSiMe3 ) with Ammonia To Give (RGe)2 (NH2 )4 (NH): A Compound Containing Terminal NH2 Groups. AB - The surprisingly facile preparation of (RGe)2 (NH2 )4 (NH) (1; R=iPr2 C6 H3 NSiMe3 ), which contains one NH and four NH2 groups, is achieved by the introduction of gaseous ammonia into a solution of iPr2 C6 H3 NSiMe3 GeBr3 in diethyl ether. PMID- 29711755 TI - A Chelate with Conformational Memory? AB - Coordinated out, pendant in! Exchange of coordinated for pendant amino groups is achieved by the complex cation 1. The incoming group attacks the concave and convex positions with the same rate and always adopts the same conformation as the leaving group. However, this "conformational memory" is an inexorable consequence of well-known and dependable concepts: the principle of microscopic reversibility and the induction of chirality in prochiral reagents. PMID- 29711756 TI - Selective Vesicle Formation from Calixarenes by Self-Assembly. AB - Amphiphilic polyhydroxy macrocycles self-assemble in water to form vesicles selectively. These vesicles are uniform in size (50-200 nm; see representation) and stable both in aqueous solution and in dried form. The selective mode of aggregation can be correlated with structural characteristics of the phenolic amphiphiles, in particular, the macrocyclic moiety and intra- and intermolecular hydrogen bonds between the phenolic OH groups. PMID- 29711757 TI - Phenylene-Bridged Cyclic Siloxanes as Precursors to Nonshrinking Sol-Gel Systems and Their Use as Encapsulants. AB - A new class of thermally robust sol-gel polymers have been prepared from the disilaoxacyclopentane derivative 1 by ring-opening polymerization to form nonshrinking polysiloxanes. This reaction, which does not need solvent or water, can be used for, amongst other things, the encapsulation of an electronic microchip. PMID- 29711758 TI - Helical Coordination Polymers with Large Chiral Cavities. AB - A quarter of the unit cell volume of [{Ni(4,4'-dipy)(3-nitrobenzoate)2 (MeOH)2 }n ], which crystallizes in the form of helices, is occupied by large chiral cavities (400-500 A3 ). The cavities are capable of encapsulating not only single molecules, but also face-to-face dimers of nitrobenzene (see stick model). 4,4' dipy=4,4'-bipyridine. PMID- 29711759 TI - Alkyne Metathesis as a New Synthetic Tool: Ring-Closing, Ring-Opening, and Acyclic. AB - Conceptually and mechanistically (!) the metathesis of disubstituted alkynes in the presence of molybdenum or tungsten catalysts (see scheme) is related to alkene metathesis. With skillful experimentation and careful selection of substrate, alkyne metathesis can result in both ring opening/ring closing and the formation of high molecular weight polymers. PMID- 29711760 TI - Easy Access to Soluble Polyanions-Stabilization of the One-Dimensional Chain 1infinity [K4 Sn9 ] by [18]Crown-6 in [K4 Sn9 ([18]crown-6)3 ]?ethylenediamine. AB - Well-characterized Group 14 Zintl anions were accessible by solution methods only in low yields up to now. An easy and inexpensive reaction route to polyanions, which starts from the elements, is admissible through the usage of [18]crown-6 as reaction medium at 40 degrees C. The [K([18]crown-6)] unit proves to be an advantageous connecting device between intermetallic and organic networks. The title compound can be regarded as a supramolecular aggregate of a one-dimensional substructure of the composition K4 Sn9 (see picture) and an organic component. PMID- 29711761 TI - Hydrolysis of Amides Catalyzed by 4-Heterocyclohexanones: Small Molecule Mimics of Serine Proteases. AB - The base-promoted hydrolysis of amide substrates that contain a thiol substituent in the position alpha to the amide carbonyl group is effectively catalyzed by 4 heterocyclohexanones [Eq. (1)]. The proposed mechanism of the hydrolysis reaction mimics that employed by serine proteases, and involves equilibrium binding of the substrate to the catalyst, formation of an acyl-catalyst intermediate, and deacylation of the intermediate to release the product and regenerate the catalyst. PMID- 29711762 TI - A Self-Assembled Calix[4]arene Dimer Linked through Hydrogen-Bonded 2 Ureidopyrimidin-4(1H)-one Groups. AB - Tightly linked! A linear array of complementary hydrogen bonds forms between two 2-ureidopyrimidin-4(1H)-one rings attached to the upper rims of facing 1,3 alternate calix[4]arenes (shown schematically). The strength of the binding (Kass >106 M-1 in chloroform) and the efficiency of the self-assembly open up interesting perspectives in the design of highly ordered multicomponent cages. PMID- 29711763 TI - Crystal Engineering of Acentric Diamondoid Metal-Organic Coordination Networks. AB - Acentric three-dimensional coordination polymers bis(isonicotinato)zinc (1) and bis(4-pyridylacrylato)cadmium?H2 O (2) were synthesized under hydro(solvo)thermal conditions; they exhibit a threefold (see picture) and fivefold diamondoid structure, respectively. Both 1 and 2 are active for second harmonic generation and exhibit remarkable thermal stability. PMID- 29711764 TI - Reactions of a Transient Carbonyl(chloro)(hydrido)ruthenium(II) Complex with Ethylene, Alkynes, and CO; Chemistry of the New Anion [Ru2 (CO)4 Cl5 ]. AB - A 97% yield of [Ru3 (CO)12 ] (2) in 20 minutes is obtained simply by treating [Ru(CO)3 Cl2 (thf)] with KOH under CO (1 atm). The reduction to Ru0 can be explained in terms of the facile reductive elimination of HCl from the transient hydrido complex 1. Though elusive, the latter can be intercepted by olefins or alkynes to produce trappable alkyl or alkenyl complexes such as 3 and 4.? denotes a vacant coordination site. PMID- 29711765 TI - Conformationally Flexible Biphenyl-phosphane Ligands for Ru-Catalyzed Enantioselective Hydrogenation. AB - Stereomutation of a BIPHEP/RuCl2 /diamine complex (shown schematically) is possible because of the conformational flexibilty of BIPHEP ligands. The result is an asymmetric activation in the Ru-catalyzed hydrogenation of carbonyl compounds to optically active alcohols. Whereas a racemic BINAP/RuCl2 complex with a chiral diamine activator gives a 1:1 mixture of two diastereomers, unequal amounts of the diastereomers can be produced from a BIPHEP/RuCl2 complex and a chiral diamine. Ar=3,5-dimethylphenyl, BINAP=2,2'-bis(diphenylphosphanyl)-1,1' binaphthyl, BIPHEP=2,2'-bis(diarylphosphanyl)biphenyl. PMID- 29711766 TI - New Insight into the Source of Biomolecular Homochirality: An Extraterrestrial Origin for Molecules of Life? AB - Circular polarized light in space might be responsible for the fact that amino acids isolated from meteorites are not racemic. For example, 1 has been found with an enantiomeric excess of up to 10.4%. Such radiation has now been observed for the first time. PMID- 29711767 TI - Bleomycin: Synthetic and Mechanistic Studies. AB - The subtleties of the structure and function of bleomycin A2 (1), a clinically employed antitumor agent that derives its biological properties through the sequence-selective cleavage of DNA in a process that is dependent on the metal ion and O2 , have been unraveled in a stepwise manner. Systematic modifications in the structure of 1 enabled many of the subtle functional roles of the individual subunits and their substituents in the efficiency, selectivity, and preference (double strand versus single strand) of DNA cleavage to be elucidated. PMID- 29711769 TI - Selective RGD-Mediated Adhesion of Osteoblasts at Surfaces of Implants. AB - Osteoblasts: yes, platelets: no! Bone implants have to be integrated with the surrounding tissue to allow a smooth and stable connection. A new procedure is shown which is based on covalent linking of a highly selective RGD peptide to a poly(methyl methacrylate) (PMMA) material (see picture). Osteoblasts very effectively bind to the treated surface and are stimulated to proliferate. PMID- 29711768 TI - The Hume-Rothery Compound Mn8 Ga27.4 Zn13.6 : Separated Zn13 -Clusters Interspersed in a Primitive Cubic Host Lattice. AB - Separated Zn13 cluster entities unexpectedly occur in the solid-state structure of Mn8 Ga27.4 Zn13.6 (the central building block is shown). They correspond to centered cuboctahedra, that is, small volumes of face-centered cubic metal. The intriguing segregation of Ga and Zn atoms in Mn8 Ga27.4 Zn13.6 was verfied by Rietveld refinement of neutron powder diffraction data. PMID- 29711770 TI - New Ni-Pt Carbonyl Clusters with a Tetrahedron of Platinum Atoms Encapsulated in an Incomplete Tetrahedron of Nickel Atoms: [Ni36 Pt4 (CO)45 ]6- and [Ni37 Pt4 (CO)46 ]6- . AB - A fully encapsulated Pt4 tetrahedron in an incomplete tetrahedron of 36 nickel atoms is present in [Ni36 Pt4 (CO)45 ]6- (1; see picture for the metal framework), which is obtained as an inseparable mixture with [Ni37 Pt4 (CO)46 ]6- (2) by reaction of [Ni6 (CO)12 ]2- with K2 [PtCl4 ]. The trimethylbenzylammonium salts of 1 and 2 cocrystallize in a 1:1 ratio. The additional Ni atom of 2 caps the truncated vertex of 1. PMID- 29711771 TI - Ag2 Cu2 O3 : The First Silver Copper Oxide. AB - An efficient low-temperature route provides the first mixed oxide of silver and copper. Ag2 Cu2 O3 represents an important precedent in the search for silver containing superconductors. It has an open structure with three-dimensional tunnels displaying square-planar CuO4 units, linerly coordinated silver ions, and vacant oxygen sites (see picture; Ag, Cu, and O are represented by white, large black, and small black spheres, respectively). The last feature allows for a rich solid-state redox chemistry. PMID- 29711772 TI - Adsorption of Acetone onto MgO: Experimental and Theoretical Evidence for the Presence of a Surface Enolate. AB - A new band at 1640 cm-1 is revealed by diffuse reflectance FT-IR spectroscopy of acetone adsorbed on a MgO surface (shown schematically). On the grounds of ab initio quantum-mechanical calculations, this band is assigned to an adsorbed enolate species. This evidence proves the catalytic role of the metal oxide surface in the condensation reaction mechanism. PMID- 29711773 TI - Chiral Induction by Elimination-Coupled Lithium-Ene Reaction: Synthesis of (+) (3R,4R)-1,2-Dihydromultifidene. AB - Cyclization of the alkadienyl carbamates 1 to the cis-divinylcyclopentanes 2 with high enantioselectivity and diastereoselectivity has been successfully achieved by (-)-sparteine-induced asymmetric deprotonation. The conversion may be described as a hybrid of a lithium-ene reaction and an Sn ' reaction. PMID- 29711774 TI - Template-Directed Self-Recognition of Alkyl-Bridged Bis(catechol) Ligands in the Formation of Helicate-Type Complexes. AB - A controlling influence on the self-assembly in the complexation reaction of a mixture of methylene- and ethylene-bridged bis(catechol) ligands (1-H4 and 2-H4 , respectively) with titanium(IV) ions is exerted by alkali metal cations (see scheme). Thus, not a complicated mixture of complexes, but as a result of a self recognition of the ligands only well-defined products are formed. PMID- 29711776 TI - [Cu12 (NPEt3 )8 ]4+ and [Ag12 (NPEt3 )8 ]4+ : Cubane Structures. AB - Unusual, highly symmetrical cubes are formed by the dodecameric cationic phosphoraneiminato complexes of copper(I) and silver(I) [M12 (NPEt3 )8 ]4+ , in which the metal atoms occupy the edges and the N atoms of NPEt 3-3 groups the corners of the cube (see figure). The structures can be understood as molecular sections of the Cu3 N structure, which is inverse to the ReO3 -type structure. PMID- 29711775 TI - High-Throughput Synthesis and Screening of Combinatorial Heterogeneous Catalyst Libraries. AB - In less than one minute the catalytic activity and selectivity of a single catalyst was measured in combinatorial libraries of ternary Rh-Pd-Pt-Cu alloys. Only slightly more than two hours were needed to complete a library with 136 elements. The elements of the libraries (ca. 2-4 MUg of material) are contained in a two-dimensional array synthesized by a thin-film technique. The analysis was performed by a scanning mass spectrometer (see picture). PMID- 29711777 TI - A 1-Aza-2-silacyclobut-3-ene and an Alkyne from [Li{Si(SiMe3 )3 }(thf)3 ] and the Isocyanide 2,6-Me2 C6 H3 NC. AB - The novel zwitterionic heterocycle 1 was unexpectedly obtained from the reaction between [Li(SiR3 )(thf)3 ] and ArNC. Upon heating 1 underwent an interesting ring opening to give the alkyne 2. Hence the C=C bond effectively arises from the C-C coupling of two ArNC moieties. R=SiMe3 , Ar=2,6-Me2 C6 H3 , tmeda=N,N,N',N' tetramethylethylenediamine. PMID- 29711778 TI - Tetravalent Tellurium Ligands. AB - Oxidative addition of TeCl4 to Vaska's complex gave the trichlorotelluronium complex [IrCl2 (TeCl3 )(CO)(PPh3 )2 ] (structure depicted), which contains a rare example of a structurally characterized tetravalent tellurium ligand. The coordination at the TeIV center is-in full agreement with the VSEPR model distorted trigonal bipyramidal. PMID- 29711779 TI - Structure and Reactivity of a Cobalt(I) Phthalaldehyde Complex with Both sigma- and pi-Bonded Aldehyde Groups. AB - A bidentate phthalaldehyde ligand with both sigma and pi coordination of the aldehyde groups is found in [(C5 Me5 )Co{(C(O)H)2 C6 H4 }] (structure depicted). This complex is the "resting state" of the catalyst in the ring closure of the dialdehyde to give the lactone. Interchange of coordination modes occurs with a barrier of 70 kJ mol-1 at 35 degrees C. Investigation of other CoI chelate complexes with a single aldehyde group shows that the coordination mode of the aldehyde is dictated by the nature of the bonding of the other ligating group. PMID- 29711780 TI - A Fully Synthetic Globo H Carbohydrate Vaccine Induces a Focused Humoral Response in Prostate Cancer Patients: A Proof of Principle. AB - Human trials on the globo H carbohydrate vaccine (see picture, KLH=the carrier protein keyhole limpet hemocyanin) show that it produces strong IgM, and in some cases IgG, responses in patients with progressive and recurrent prostate cancer. Furthermore, these antibodies not only recognize synthetic antigens, but also globo H-positive tumors in biopsy extracts and tumor tissues. PMID- 29711781 TI - Highly Enantioselective Hydrogenation of Cyclic Enol Acetates Catalyzed by a Rh PennPhos Complex. AB - The electron-rich and conformationally rigid (R,S,R,S)-Me-PennPhos ligand (shown schematically) appears to chelate rhodium and form well-defined chiral pockets. This allows, for example, efficient differentiation between the two enantiotopic approaches available to a substrate in a hydrogenation reaction. The Rh-Me PennPhos complex is the first catalyst for the highly enantioselective asymmetric hydrogenation of cyclic enol acetates. For example, 3,4-dihydronaphth-1-yl acetate can be hydrogenated with up to 99% ee. PMID- 29711782 TI - Highly Efficient Ruthenium-Based Catalytic Systems for the Controlled Free Radical Polymerization of Vinyl Monomers. AB - A new set of ruthenium complexes such as 1 and 2 (the Grubbs ruthenium-carbene complex) has been shown to mediate the controlled atom-transfer radical polymerization (ATRP) of vinyl monomers with exceptional efficiency. Furthermore, there is a striking parallelism between the catalytic activity of these compounds in olefin metathesis and in ATRP. PMID- 29711783 TI - Chemo-Enzymatic Synthesis of Fluorescent Rab 7 Proteins: Tools to Study Vesicular Trafficking in Cells. AB - The N-methylanthraniloylisoprenoid diphosphate derivatives 1 and 2 bind to RabGGTase II and are enzymatically transferred to Rab 7 (the Rab proteins are small G-proteins that control events of docking and fusion of intracellular vesicles). The fluorescent Rab 7 proteins thus obtained may become important tools for further biological studies on vesicular trafficking in cells. PMID- 29711784 TI - A Novel Route to the Fused Maleic Anhydride Moiety of CP Molecules. AB - A seven-step cascade reaction-in which selective mesylation, epoxide formation, epoxide lysis, cyclization, reiterative oxidation, and nitrogen-oxygen exchange occur sequentially-facilitates the construction of the maleic anhydride moiety of CP molecules 1 and 2 (>93% yield per step). Unstable intermediates of this reaction sequence were detected, providing evidence for the proposed mechanism and resulting in the discovery of a new chemical entity. PMID- 29711785 TI - Super High Throughput Screening (SHTS) of Chiral Ligands and Activators: Asymmetric Activation of Chiral Diol-Zinc Catalysts by Chiral Nitrogen Activators for the Enantioselective Addition of Diethylzinc to Aldehydes. AB - The most effective catalyst system for the enantioselective alkylation of an aldehyde on the basis of "asymmetric activation" can be found by super high throughput screening of chiral ligands (L*) and activators (A*) for the diethylzinc complex. The product, an optically active alcohol, could be obtained with 99% ee and in up to 100% yield (see reaction scheme). R=benzylidene. PMID- 29711786 TI - The Search for New-Generation Olefin Polymerization Catalysts: Life beyond Metallocenes. AB - Even late transition metal complexes function as active and selective catalysts for alpha-olefin polymerization. The discovery of a highly active family of catalysts 1 based on iron, a metal that had no previous track record in this field, has highlighted the possibilities for further new catalyst discoveries. As a result, an intense search has developed for new-generation catalysts, in both academic and industrial research laboratories. R1 =H, Me; R2 =Me, iPr; R3 =H, Me, iPr; R4 =H, Me; X=halide. PMID- 29711787 TI - Evolving Opportunities in Structure Solution from Powder Diffraction Data-Crystal Structure Determination of a Molecular System with Twelve Variable Torsion Angles. AB - The genetic algorithm approach, in which a population of trial structures is allowed to evolve subject to well-defined procedures for mating, mutation, and natural selection, was employed to solve the complex molecular crystal structure of Ph2 P(O)(CH2 )7 P(O)Ph2 directly from powder diffraction data. The structure solution reveals an interesting (perhaps unexpected) molecular conformation (see picture), which emphasizes the importance of allowing complete conformational flexibility of the molecule in the structure solution calculation. PMID- 29711788 TI - [{MeAl(MU2 -F)}2 N(2,6-iPr2 C6 H3 )]4 - A Molecular Al-F-N Cage Compound. AB - In a two-step elimination reaction the molecular Al-F-N cage compound 1 is synthesized from (2,6-iPr2 C6 H3 )NH2 (ArNH2 ) and Me2 AlF under methane evolution. Compound 1 was characterized by means of X-ray structure analysis and can be regarded as a precursor for ternary Al-F-N systems. PMID- 29711789 TI - Recent Insights into Inhibition, Structure, and Mechanism of Configuration Retaining Glycosidases. AB - Not "from above", but "from the side": Configuration-retaining beta-glycosidases protonate their substrate either anti or syn to the endocyclic C1-O bond as the first step in the enzymic cleavage of the glycosidic bond (see schematic drawing). Insights into the mechanism of action of glycosidases have been gained by a combination of the synthesis of inhibitors, the study of the kinetics of their inhibition, and the analysis of the crystal structures of glycosidases and glycosidase-ligand complexes. PMID- 29711790 TI - Preparation and Properties of Nanoporous Triblock Copolymer Membranes. AB - "Unplug those pores!" could be a slogan common to cosmetologists and polymer chemists. Membranes with nanochannels can be obtained by first forming a film by casting a solution of a triblock and homopolymer mixture, then selectively cross linking domains in the film by photolysis, and finally forming nanochannels through removal of the homopolymer by solvent extraction. Such membranes are not liquid permeable but have gas-permeability constants about six orders of magnitude higher than that of low-density polyethylene films. PMID- 29711791 TI - Monodisperse Poly(triacetylene) Rods: Synthesis of a 11.9 nm Long Molecular Wire and Direct Determination of the Effective Conjugation Length by UV/Vis and Raman Spectroscopies. AB - With 16 C-C double and 32 C-C triple bonds and a length of 11.9 nm, the hexadecameric poly(triacetylene) (PTA) of type 1 is currently the longest linear fully pi-conjugated molecular wire that does not contain aromatic repeat units. A series of PTA oligomers 1 extending from monomer to hexadecamer was prepared by a rapid and efficient statistical deprotection-oligomerization sequence; the effective conjugation length at which saturation of molecular properties occurs was determined as n=10 (n=number of monomeric units) by both UV/Vis and Raman spectroscopies. PMID- 29711792 TI - Dodecaindane (tBu3 Si)8 In12 -A Compound with an In12 Deltapolyhedron Framework. AB - A unique feature among polyhedron frameworks of boron group elements is exhibited by the In12 framework of the black-violet dodecaindane R*8 In12 (R*=SitBu3 ), which can be obtained by the thermolysis of R*2 In-InR*2 . The molecular structure of R*8 In12 (tBu groups omitted in picture shown) can be described as a combination of two R*4 In6 octahedral building blocks and can thus be classified as a conjuncto dodecaindane. PMID- 29711793 TI - Hydrogen Bonding, Hydrophobic Interactions, and Failure of the Rigid Receptor Hypothesis. AB - Why does experimental determination of the structure of drug-receptor complexes so often result in surprises? The importance of hydrogen bonding and hydrophobic interactions in drug receptor binding is discussed. Hydrophobic interactions receive too little consideration from most molecular modeling packages. Their role in the failure of the rigid receptor hypothesis and the implications for drug design are considered. PMID- 29711794 TI - Strong Hydrogen Bonding to the Amide Nitrogen Atom in an "Amide Proton Sponge": Consequences for Structure and Reactivity. AB - N-Protonated amides have been proposed as intermediates in several biologically important reactions, but they have yet to be identified spectroscopically. The first step toward this goal is now reported in the form of spectroscopic and crystallographic proof of a strong intramolecular hydrogen bond between a charged proton donor and an amide nitrogen atom in the "proton sponge" derivative 1; novel reactivity results from this interaction. TfO-= trifluoromethanesulfonate. PMID- 29711795 TI - The Carbonyl Chlorine(I) Cation [ClCO]+ . AB - The first carbonyl halogen cation in the condensed phase, the superelectrophilic [ClCO]+ ion, has been clearly and unambiguously established by its complete, fully assigned vibrational spectrum. The cation is obtained by the reaction of COCl2 with SbF5 at room temperature in the form of a suspension, in which it is stabilized by oligomeric fluoroantimonate ions. PMID- 29711796 TI - Metal Complexes Bearing Terminal Borylene Ligands. AB - More and more metal complexes with terminal borylene ligands will be synthesized. Although these ligands in metal complexes must be stabilized either by integration of the boron atom into a polyhedral skeleton (1) or by B-N pi interactions with a bulky amino group (2), the route to new complexes with terminal RB ligands (R=alkyl, aryl) is clearly indicated. PMID- 29711797 TI - The Role of Ligand Density in the Enzymatic Glycosylation of Carbohydrates Presented on Self-Assembled Monolayers of Alkanethiolates on Gold. AB - The biological activity of immobilized carbohydrates can show a dramatic dependence on the density of carbohydrate. This is the result of investigations with self-assembled monolayers that present N-acetylglucosamine groups as a model substrate for glycosylation by bovine beta-1,4-galactosyltransferase (GalTase; see picture). Surface plasmon resonance spectroscopy and carbohydrate-binding lectins were used to characterize the reaction at the interface. UDP-Gal=uridine diphosphogalactose. PMID- 29711798 TI - The Heyns Rearrangement Revisited: An Exceptionally Simple Two-Step Chemical Synthesis of D-Lactosamine from Lactulose. AB - Disaccharides containing D-glucosamine at the reducing end can be conveniently synthesized in good yields from O-glycosylated D-fructoses by the title reaction [Eq. (a)]. With all the disaccharides investigated, the method proceeded presumably because of the pronounced destabilizing interactions of the glycosyl residue at O-4 with the other polar groups-considerably more efficiently than with unsubstituted D-fructose, whose reaction with ammonia to give D-glucosamine was described by Heyns and Koch in the 1950s. PMID- 29711799 TI - Reverse versus Normal Prenyl Transferases in Paraherquamide Biosynthesis Exhibit Distinct Facial Selectivities. AB - Both a face-selective and a non-face-selective mode of formation of quaternary centers of isoprene-derived structural moieties of the natural alkaloid paraherquamide A (1) have been discovered by feeding experiments on Penicillium fellutanum with [U-13 C6 ]-glucose and [13 C2 ]-acetate. The labeling patterns suggest that the methyl groups (C22, C23) are introduced in a non-face-selective manner by a reverse prenyl transferase. The C5 unit comprising the dioxepin moiety retains stereochemical integrity indicative of a single, face-selective addition of the phenolic group to the dimethylallyl group. PMID- 29711800 TI - Efficient Catalysis of Polysiloxane Synthesis by Silicatein alpha Requires Specific Hydroxy and Imidazole Functionalities. AB - A protein isolated from a biosilica (shown schematically) catalyzes alkoxysilane polycondensation at neutral pH values and low temperatures. Replacement of either of two specific side chain functionalities (Ser-26 and His-165) significantly diminishes catalysis, supporting a reaction mechanism analogous to that of a well known enzyme that is highly homologous to the silica protein. These results may be useful in the development of synthetic catalysts for environmentally benign synthesis of polysiloxanes. PMID- 29711801 TI - A Novel Phenylene Topology: Total Syntheses of Zigzag [4]- and [5]Phenylene. AB - In agreement with theory, the title compounds 1 and 2, which were prepared by CpCo-catalyzed cycloisomerizations of appropriate oligoalkynylbenzenes, display physical properties that are in contrast with those of the corresponding linear isomers, but that are very similar to those of the angular topomers. PMID- 29711802 TI - Coordinative Approach to Mediated Electron Transfer: Ruthenium Complexed to Native Glucose Oxidase. AB - Catalytically and electrocatalytically very active and stable are the complexes Ru(LL)-GO, which are extremely readily accessible from glucose oxidase (GO) and the RuII complexes cis-[Ru(LL)2 Cl2 ] (LL=bpy, phen). These provide an unprecedentedly high amplification coefficient I/Io (see cyclic voltammograms) even at high scan rates and, correspondingly, very high rates of intramolecular electron transfer. PMID- 29711803 TI - Energetics of Molecular Complexes in a Supersonic Beam: A Novel Spectroscopic Tool for Enantiomeric Discrimination. PMID- 29711804 TI - A New Samarium Diiodide Induced Reaction: Intramolecular Attack of Ketyl Radical Anions on Aryl Substituents with Formation of 1,4-Cyclohexadiene Derivatives. AB - Beware of samarium diiodide and aryl ketones! If the ketyl radical anion which is formed by electron transfer finds a properly placed aryl group, a highly diastereoselective cyclization may occur. After the transfer of a second electron and protonation bi- and polycyclic products with a common 1,4-cyclohexadiene moiety may be isolated [Eq. (a)]. X=CHCO2 R, NCH2 Ph; HMPA=(Me2 N)3 PO. PMID- 29711805 TI - BDH-TTP as a Structural Isomer of BEDT-TTF, and Its Two-Dimensional Hexafluorophosphate Salt. AB - Metallic behavior down to low temperature is shown by charge transfer salts of BDH-TTP (1), a structural isomer of bis(ethylenedithio)tetrathiafulvalene (BEDT TTF). In the case of (BDH-TTP)2 PF6 this behavior is attributed to the structure, which is made up of kappa-type sheets of BDH-TTP donor molecules and sheets of PF6- anions. PMID- 29711806 TI - Separation of a Racemic Mixture of Two-Dimensional Molecular Clusters by Scanning Tunneling Microscopy. AB - Adsorption of sub-monolayer amounts of 1-nitronaphthalene (NN) onto Au(111) leads to the aggregation of NN decamers, which exhibit two-dimensional chirality and represent a racemic mixture. In analogy to Pasteur's experiment of 1848 a scanning tunneling microscope can be used to discriminate and separate the enantiomers on a molecular scale. PMID- 29711807 TI - The Critical Importance of Water in the Asymmetric Allylboration of N Trimethylsilylbenzaldimines with B-Allyldiisopinocampheylborane. AB - The free aldimine is probably the intermediate in the asymmetric allylboration of N-trimethylsilylaldimines in the presence of water (see scheme), which is critical for the reaction. The aldimine is rapidly captured by the allylborating agent. Ipc2 BAll=B-allyldiisopinocampheylborane. PMID- 29711808 TI - Discovery and Optimization of Heterogeneous Catalysts by Using Combinatorial Chemistry. AB - A novel ceramic array microreactor system has been designed and, in conjunction with resonance-enhanced multiphoton ionization (REMPI), used for the discovery of an optimum ternary catalyst composition for the dehydrogenation of cyclohexane to benzene. The catalyst library consisted of 66 ternary combinations of Pt, Pd, and In loaded on gamma-Al2 O3 pellets. The optimum catalyst for the production of benzene had the composition 0.8 % Pt, 0.1 % Pd, and 0.1 % In (see diagram). The preparation and screening of the library of 66 catalysts took about 2.5 days to complete-with conventional methods this would have taken several months! PMID- 29711809 TI - Neutral, Cationic, and Anionic Alkyl Derivatives of Tungsten Bonded to a Calix[4]arene Oxo Surface. AB - The chemically reversible reduction of [(Me)2 W(calix)] to the diamagnetic [(Me)2 W(calix)Na2 ] [Eq. (1)], without major changes in the connectivity of the molecule, illustrates the flexibility of the calixarene ligand and stresses its potential as a molecular functional model of heterogeneous oxo surfaces. PMID- 29711810 TI - Recent Advances in the Conversion of Carbohydrate Furanosides and Pyranosides into Carbocycles. AB - Replacing the oxygen atom of the sugar ring with carbon is easy on paper, but it is more difficult to carry out this transformation and form five- and six membered carbon rings (see scheme) in the flask. Nature has found a way to perform this tandem fragmentation/cyclization reaction in a stereospecific way at neutral pH values. Human creativity and good luck have uncovered synthetic strategies which can compete efficiently with nature. PMID- 29711811 TI - Cyclotrimethylenetriphosphinic Acid. AB - The cyclotrimethylenetriphosphinic acid (1), isoelectronic to the cyclotriphosphoric acid, is formed in the hydrolysis of 1,1,3,3,5,5 hexakis(dimethylamino)-1lambda5 ,3lambda5 ,5lambda5 -[1,3,5]triphosphinine. Compound 1 is stable to acids and bases. On heating for a longer period of time in D2 O each of the three methylene groups is monodeuterated. PMID- 29711812 TI - The Structural Characterization of Amavadin. AB - Fly agaric accumulate vanadium in the form of amavadin, whose structure has been elucidated (see picture for the crystal structure). Amavadin contains one VIV center coordinated to two (S,S)-hidpa3- ligands (H3 hidpa=2,2' (hydroxyimino)dipropionic acid) through one eta2 -NO- group and two unidentate carboxylato groups from each ligand. The arrangement of the two eta2 -NO- groups leads to a chiral vanadium center, which has been characterized in both the Lambda and Delta forms. The carboxylato groups of the amavadin anions bind cations, for example, Ca2+ ions, and/or become involved in hydrogen bonding. PMID- 29711813 TI - Beneficial Effect of ortho-Methoxy Groups in the Asymmetric Ring Opening of meso Epoxides with Silicon Tetrachloride Catalyzed by Chiral ortho Methoxyphenyldiazaphosphonamide Lewis Bases Response to the Communication by G. Buono et al. AB - The reported ability of chiral phosphonamide 1 to effect the enantioselective opening of meso epoxides with silicon tetrachloride has not withstood experimental verification by Denmark's group. Having reexamined the ring-opening of cyclooctene oxide, Denmark and co-workers found a serious discrepancy between their results (81-83 % recovery of the epoxide and an essentially racemic product) and those reported by Buono et al. (77 % yield and >99 % ee). PMID- 29711814 TI - Matrix Isolation of Perfluorinated p-Benzyne. AB - As the first isolated derivative of 1,4-didehydrobenzene, 1,4-didehydro-2,3,5,6 tetrafluorobenzene (1) was generated from 1,4-diiodotetrafluorobenzene (2) by photolysis at 254 nm in a neon matrix at 3 K. The 4-iodo-2,3,5,6 tetrafluorophenyl radical 3 is formed as an intermediate in this reaction. Both 1 and 3 were characterized by their IR spectra. Compound 1 is photolabile and undergoes a photochemical retro-Bergman reaction to 1,3,4,6-tetrafluorohex-3-ene 1,5-diyne (4) upon broad-band UV irradiation (260-320 nm). PMID- 29711815 TI - Pure Polymorph C of Zeolite Beta Synthesized by Using Framework Isomorphous Substitution as a Structure-Directing Mechanism. AB - Subsitution of germanium for silicon in the preparation of the zeolite Beta allows the synthesis and characterization of a third, heretofore predicted, polymorph "C"; a [001] view is shown in the picture. Germanium preferentially occupies positions in double four-membered ring cages, the secondary building units of polymorph C, and favors the formation of polymorph C regardless of which of the eight organic structure-directing agents were used. PMID- 29711817 TI - Quantitative Studies of Binding between Synthetic Galactosyl Ceramide Analogues and HIV-1 Gp120 at Planar Membrane Surfaces. AB - A critical spacer arm length necessary to promote efficient binding of the HIV-1 surface glycoprotein rgp120 to several synthetic galactosyl-conjugated lipids, reconstituted into planar lipid bilayers, was identified. This should aid the design of anti-HIV-1 agents based on membrane-tethered, carbohydrate-based receptors for gp120. PMID- 29711818 TI - sigma-Bond Metathesis of Alkanes on a Silica-Supported Tantalum(V) Alkyl Alkylidene Complex: First Evidence for Alkane Cross-Metathesis. AB - C-C activation of unactivated alkanes on a silica-supported neopentyl neopentylidene TaV complex [Eq. (1)] affords the alkane cross-metathesis products tBuCH2 R and an alkane-metathesis catalyst. Since the activity and product distributions are similar to those obtained with a silica-supported TaIII hydride, these results are a first step in understanding alkane sigma-bond metathesis on metal hydrides. PMID- 29711819 TI - Inversion of Enantioselectivity during the Platinum-Catalyzed Hydrogenation of an Activated Ketone. AB - Two competing reaction pathways, which lead to opposite enantiomers, occur in the hydrogenation of 1 over chirally modified platinum, as revealed by catalytic and NMR spectroscopic experiments: the fast reduction of the ketoform 1 a (minor species) and the slow hydrogenolysis of the hydrate 3 (major species). PMID- 29711820 TI - [Cu12 (P2 Se6 ){Se2 P(OR)2 }8 ]: Discrete Copper Clusters Containing an Ethane Like Hexaselenodiphosphate(IV). AB - The coexistence of P4+ and P5+ in one complex and the presence of an ethane-like hexaselenodiphosphato ligand, P2 Se64- , are the novel features of the title compounds (see structure, in which R=Et or iPr; OR groups omitted for clarity). The coordination mode of P2 Se64- in these dodecanuclear copper species is unprecedented and has not even been identified in any mixed ligands containing Group 15/16 elements. PMID- 29711821 TI - Constructing Tricyclic Compounds Containing a Seven-Membered Ring by Ruthenium Catalyzed Intramolecular [5+2] Cycloaddition. AB - Efficient access to tricyclic compounds such as 2 and 3, which contain a seven membered ring, is provided by the ruthenium-catalyzed intramolecular [5+2] cycloaddition of a 1,2,3-trisubstituted cyclopropyl enyne such as 1. Improved regioselectivity is observed when In(OTf)3 is used as the cocatalyst. (No cocatalyst: 2:3 6:1; cat. In(OTf)3 (10 %): 2:3 >20:1; Tf=trifluoromethanesulfonyl). PMID- 29711822 TI - The Hg32+ Group as a Framework Unit in a Host-Guest Compound: [Hg11 As4 ](GaBr4 )4. AB - Pyramids in a mercury tunnel: Hg32+ and Hg22+ units form the tunnel walls of the novel inorganic supramolecular compound [Hg11 As4 ](GaBr4 )4 . This is the first three-dimensional framework that incorporates the subvalent mercury cluster Hg32+ as a structural unit. Each of the two types of tunnel that extend along the b axis of the unit cell contains two columns of GaBr4- ions. PMID- 29711824 TI - Electronic Transduction of Polymerase or Reverse Transcriptase Induced Replication Processes on Surfaces: Highly Sensitive and Specific Detection of Viral Genomes. AB - Replication, precipitation, and amplification: Polymerase or reverse transcriptase induced replication of DNA/RNA on a transducer (electrode or piezoelectric crystal) leads to the ultrasensitive specific electronic transduction of viral genomes. Biotin tags (B) on the double-stranded assembly provide docking sites for a conjugate between avidin (A) and an alkaline phosphatase (AP). Enzyme biocatalysis of substrate (S) to the insoluble product (P), which precipitates onto the transducer (yellow surface), provides amplification in the analysis of the target DNA. PMID- 29711823 TI - Hybrid Molecular Materials Based on Covalently Linked Inorganic Polyoxometalates and Organic Conjugated Systems. AB - The Mo=N bond is conjugated with the organic segment in the novel molecular organic-inorganic hybrid materials that have been obtained by Pd-catalyzed coupling of an iodo-functionalized hexamolybdate anion and an alkyne (see scheme; Ar=4-methylphenyl,3-5-di(tert-butyl)phenyl). The interaction between the polyoxometalate cluster and the organic conjugated system is particularly apparent from the strong red-shifted absorption in the UV/Vis spectrum. PMID- 29711825 TI - A Schizophrenic Water-Soluble Diblock Copolymer. AB - Two micellar states are possible for a novel PPO-PDEA diblock copolymer synthesized by atom-transfer radical polymerization. Subtle variation of the solution pH value and temperature is all that is needed to form both conventional micelles (with the PDEA block in the core) and reverse micelles (with the PPO block in the core) in aqueous media (shown schematically). DEA=2 (diethylamino)ethyl methacrylate, PO=propylene oxide. PMID- 29711826 TI - Pentacoordination of Silicon by Four Covalent Si-S Bonds and One Covalent Si-C Bond. AB - The zwitterionic compounds 1 and 2 are the first pentacoordinate silicates with covalent SiS4 C skeletons. They were characterized by crystal-structure analyses and NMR spectroscopic studies. Although pentacoordination of silicon is usually favored by ligand atoms of high electronegativity, the structural data of both 1 and 2 are consistent with the presence of five covalent bonds to the silicon atom. PMID- 29711827 TI - Cesium- and Rubidium-Selective Redox-Active Bis(calix[4]diquinone) Ionophores. AB - The length of the bridging alkylene chain between two calix[4]diquinone moieties determines the selectivity of the receptors for Group 1 metal ions. These redox active receptors exhibit remarkable selectivity preferences and substantial electrochemical recognition effects towards Cs+ and Rb+ ions. The solid-state crystal structure of the Cs+ complex of a bis(calix[4]diquinone) derivative is shown (green: Cs+ , red: oxygen). PMID- 29711828 TI - Bi4 Te44+ -A Cube-Shaped, Polycationic Main Group Element Cluster. AB - Two valence electrons more than in square-antiprismatic 38-electron clusters such as Bi82+ or Sn86- : This is the reason for the unusual cube-shaped structure of the cation Bi4 Te44+ , which is obtained as the chloroaluminate salt from acidic AlCl3 /Na[AlCl4 ] melts. PMID- 29711829 TI - Metal Complexes of an N-Confused Calix[4]phyrin Derivative-The First X-ray Structure of an Organometallic Compound of Divalent Copper. AB - Rare organometallic complexes can be stabilized by using an N-confused system as a carbon ligand. A stable organocopper(II) compound of N-confused calix[4]phyrin has been characterized by X-ray crystallography. Complete pi conjugation was found not to be a prerequisite for the formation of the metal-carbon bond. PMID- 29711830 TI - 1,3-Diethynylallenes: New Modules for Three-Dimensional Acetylenic Scaffolding. AB - Regioselective Pd0 -catalyzed cross-coupling of bispropargylic precursors 1 with silyl-protected alkynes gave rise to the first 1,3-diethynylallenes 2 [Eq. (1), LG=leaving group]. In enantiomerically pure form, these novel carbon-rich modules could provide access-by oxidative oligomerization-to a fascinating new class of helical oligomers and polymers. PMID- 29711831 TI - The Mechanism of the [Cp2 TiMe2 ]-Catalyzed Intermolecular Hydroamination of Alkynes. AB - A complex interplay between the catalyst concentration and the reaction rate exists, as shown by kinetic studies, for the [Cp2 TiMe2 ]-catalyzed intermolecular hydroamination of alkynes. The reason for this is a reversible dimerization of the catalytically active species [Eq. (1)]. L1 , L2 =Cp (cyclopentadienyl), Tol-NH (Tol=4-MeC6 H4 , tolyl). PMID- 29711832 TI - Active Site Design in a Chemzyme: Development of a Highly Asymmetric and Remarkably Temperature-Independent Catalyst for the Imino Aldol Reaction. AB - Unusually robust: A remarkably temperature-independent catalyst has been developed for the imino aldol reaction of imines derived from ortho-aminophenols. This catalyst is prepared from two equivalents of the VAPOL ligand and a zirconium tetraalkoxide. From a consideration of likely intermediates in the catalytic cycle it was deduced that a methyl substituent ortho to the phenol (R1 ) should enhance induction. This resulted in asymmetric inductions in excess of 98 % ee at room temperature as well as at 100 degrees C. TMS=trimethylsilyl. PMID- 29711833 TI - Correlating Electron Transport and Molecular Structure in Organic Thin Films. AB - A convenient experimental system is described, with which electron transport through structurally well-defined, 2-5 nm-thick, organic films can be examined. Two types of junction J have been studied in which self-assembled monolayers (SAMs, for example, SAM(1) formed on Ag from aliphatic and aromatic thiols, and SAM(2), formed on Hg from hexadecanethiol) are in contact through either van der Waals interactions or through covalent, hydrogen, or ionic bonds. PMID- 29711834 TI - Gold Glyconanoparticles as Water-Soluble Polyvalent Models To Study Carbohydrate Interactions. AB - Glycosphingolipid clustering and interactions at the cell membrane can be modeled by gold glyconanoparticles prepared with biologically significant oligosaccharides. Such water-soluble gold glyconanoparticles with highly polyvalent carbohydrate displays (see picture, gray hemisphere: gold nanoparticle) have been obtained by a simple and versatile strategy. PMID- 29711835 TI - Cyclic Hexamer with a Cubic Cavity: Crystal Structure of [{Rh(6-Purinethione Ribosido)(Cp*)}6 ](CF3 SO3 )6. AB - The stereoselective formation of a pseudo-S6 hexamer resulted from the self assembling reaction between [Rh(Cp*)(H2 O)3 ]2+ and 6-purinethione riboside (see left structure; Cp*=C5 Me5 ). The schematic representation (right) shows the direction of the coordination to the S6 and N(7) donor atoms. C (clockwise) and A (anticlockwise) indicate the chirality of each unit complex. PMID- 29711836 TI - The [(eta-C6 H5 Me)NbSn6 Nb(eta-C6 H5 Me)]2- Ion: A Complex Containing a Metal Stabilized Sn612- Cyclohexane-Like Zintl Ion. AB - Sitting in a tin chair: the compound [Nb(eta-C6 H5 Me)2 ] reacts with the Sn94- ion in ethylenediamine to give the [(eta-C6 H5 Me)NbSn6 Nb(eta-C6 H5 Me)]2- ion, 1. The complex contains a new Zintl ion, Sn612- , with a chair cyclohexane-like structure and 2c-2e bonds. PMID- 29711837 TI - Diastereocontrol in the Synthesis of Models of Rings C and D of Phorbol: Directing Effect of an Ether Substituent on Lithium Carbenoid Mediated Cyclopropanation. AB - The diastereocomplementarity of halo- and alkylcarbenes (paths a and b, respectively) was shown in the cyclopropanation reaction of 1. The conversion of 1 into 7,7-dimethylbicyclo[4.1.0]heptan-1,2-diols (+/-)-2 and (+/-)-3 represents an important transformation in a synthetic strategy towards phorbol derivatives. TBDMS=tert-butyldimethylsilyl. PMID- 29711838 TI - [ReH(SH)2 (PMe3 )4 ]: A Catalyst for Fundamental Transformations Involving H2 and H2 S. AB - Not a poison! In contrast to the high reactivity of 1, the corresponding trihydride [ReH3 (PMe3 )4 ] is kinetically inert. Thus, the usual view that sulfur poisons catalysts is clearly inappropriate in this case. The catalytic properties of 1 result from its difunctional nature with both protic (SH) and hydridic (ReH) sites; these sites communicate by an intramolecular exchange process (see scheme; X=OMe, SH). PMID- 29711839 TI - A Superoxovanadium(V) Complex Linking the Peroxide and Dioxygen Chemistry of Vanadium. AB - A missing link: A superoxovanadium(V) complex is the first reaction intermediate in the oxidative conversion of a peroxovanadium(V) complex into a vanadyl(IV) complex and molecular oxygen. The superoxo species appears also to play an essential role in the formation of the peroxovanadium(V) complex from the vanadyl(IV) complex and molecular oxygen. PMID- 29711840 TI - Hydrophobic Pockets in a Nonpolymeric Aqueous Gel: Observation of such a Gelation Process by Color Change. AB - Efficient gelation of aqueous fluids by a novel tripodal trischolamide generates chiral hydrophobic pockets in the gel network. A yellow to green color change (see absorbance spectra) in the presence of bromophenol blue (BPBH) indicates the formation of the gel. The bound (anionic) dye (BPB- ) shows induced circular dichroism, which is indicative of a chiral environment. PMID- 29711841 TI - Fragmentation of Carbohydrate Anomeric Alkoxy Radicals: A New Synthesis of Chiral 1-Halo-1-iodo Compounds. AB - One less carbon atom is found in 1-halo-1-iodo compounds obtained by C1-C2 radical fragmentation of carbohydrate 1,2-halohydrins. This fragmentation is achieved via the anomeric alkoxy radicals of the halohydrins, formed upon reaction with (diacetoxyiodo)benzene and iodine [Eq. (1); X=Cl, Br, I]. PMID- 29711842 TI - Chemoenzymatic-Chemical Synthesis of a (2-3)-Sialyl T Threonine Building Block and Its Application to the Synthesis of the N-Terminal Sequence of Leukemia Associated Leukosialin (CD 43). AB - Protection of all functional groups of the carbohydrate portion of the chemoenzymatically synthesized sialyl T threonine ester 1 (R=R1 =H, R2 =tBu, Fmoc=9-fluorenylmethoxycarbonyl) and subsequent acidolysis of the tert-butyl ester afforded the building block 2 (R=Ac, R1 =Me, R2 =H). The latter is a useful tool in the solid-phase synthesis of the N-terminal sequence 3 of the leukemia associated leukosialin. PMID- 29711843 TI - Directed Intermolecular Carbomagnesation across Vinylsilanes: 2-PyMe2 Si Group as a Removable Directing Group. AB - Facile addition of primary alkyl Grignard reagents to vinylsilanes has been realized for the first time by exploiting the directing effect of a 2-pyridyl group on silicon [Eq. (1)]. Three-component coupling reactions of a Grignard reagent, the vinylsilane, and an electrophile, followed by oxidative removal of the 2-pyridyldimethylsilyl group with H2 O2 furnishes various secondary alcohols in excellent overall yields. PMID- 29711844 TI - E(SiMe3 )4+ Ions (E=P, As): Persilylated Phosphonium and Arsonium Ions. AB - Only strong Lewis acidic, arene-solvated Me3 Si+ ions react with E(SiMe3 )3 compounds (E=P, As) to give the crystallographically characterized E(SiMe3 )4+ onium ions 1 (left hand picture), which contain highly negative polarized P and As atoms, respectively. The masked Me3 Si+ ions in 1 can be easily transferred to Et2 O, to give the first structurally characterized planar silyloxonium ion [Et2 (Me3 Si)O]+ 2 (right hand picture). PMID- 29711845 TI - Self-Assembly and Manipulation of Crown Ether Phthalocyanines at the Gel-Graphite Interface. AB - Two "face-on" phases and one "edge-on" lamellar phase comprised of self-assembled structures of phthalocyanines have been visualized by scanning tunneling microscopy (STM) at the gel-graphite interface. The switching between the phases can be stimulated with the microscope tip with a resolution on the molecular scale. The STM image shows the manipulated area consisting of pi-pi stacked phthalocyanines forming the lamellar phase, which is embedded in a hexagonally packed "face-on" phase. PMID- 29711846 TI - Cu2+ Inhibits the Aggregation of Amyloid beta-Peptide(1-42) in vitro. AB - A distinct biochemical role of Cu2+ as an inhibitor in the aggregation of the peptide Abeta(42) in vitro was revealed by thioflavin T fluorescence assay and atomic force microscopy. The Cu2+ -Abeta(42) complex is responsible for the inhibition because it stabilizes the soluble form of Abeta(42) and controls the conformational transition ([Eq. (1)]; ki =[Abeta(42)][Cu2+ ]/[Cu2+ -Abeta(42)]). PMID- 29711847 TI - Two Isomers of C60 F48 : An Indented Fullerene. AB - Deflated buckyballs: The single-crystal structure of C60 F48 ?2 (mesitylene) revealed the presence of both D3 and S6 isomers in the same crystal. C(sp2 ) C(sp2 ) bonds (1.30 A) are much shorter than C(sp3 )-C(sp3 ) bonds (1.54-1.63 A). The C60 cage is characterized by concave areas in the regions of six double bonds. Each double bond is effectively shielded by four F atoms, which accounts for the low reactivity of C60 F48 . PMID- 29711848 TI - Novel Aluminum-Containing Ring Systems: An Octanuclear Structural Analogue of a Calix[4]pyrrole. AB - Depending on the hydrazine reagent, Me3 Al reacts to afford novel aluminum containing macrocyclic ring structures. The reaction of Me3 Al with Me2 NNH2 provides the octanuclear calix[4]pyrrole-like 1, while under analogous conditions the reaction with MePhNNH2 gives a tetranuclear complex. Both complexes are formed by incorporation of acetonitrile. PMID- 29711850 TI - The Search for New Environmentally Friendly Chemical Processes. AB - Minimization of the hazards in chemical industry processes and the avoidance of the production of toxic substances-these are the goals of environmentally friendly processes. These technologies can also be economically advantageous. This approach is exemplified by a new, almost ideal atom-efficient oxidative route to adipic acid (1, see scheme), which offers several environmentally improved features compared to the traditional manufacture. [W]=tungsten catalyst. PMID- 29711849 TI - The gem-Diol Form of (py)2 CO as a Ligand in Cobalt(II) Carboxylate Clusters: A Cubane Complex and a Novel Nonanuclear Species with a Vertex-Sharing Double Square Pyramidal Structure. AB - A vertex-sharing double square pyramid of cobalt(II) ions (see picture) is present in the nonanuclear complex 1, obtained by treating cobalt acetate with 0.5 equivalents of (py2 )CO. The corresponding 1:1 reaction gave 2, which has a central core with a cubane structure. py=pyridine. PMID- 29711851 TI - Dendrimers: From Design to Application-A Progress Report. AB - A unique combination of a clearly defined particle structure and a very highly functionalized surface is offered by the topical dendrimers. Many groups work on this unusual molecular architecture to develop new applications. The most advanced progress in this respect is an MRI contrast agent based on dendrimers (see schematic representation) that facilitate the visualization of bloodstreams. PMID- 29711852 TI - Domino Hydroformylation-Wittig Reactions. AB - Methallyl and homomethallyl alcohols can undergo stereoselective hydroformylation Wittig and hydroformylation-Wittig-hydrogenation reactions in one-pot domino processes. This sequential transformation allows the formation of C-C bonds and the generation of a new stereogenic center, and gives preparatively interesting compounds [Eq. (a)]. The reaction products are obtained in satisfactory to good yields and in diastereoselectivities of 90:10 to >98:2. CDG=catalyst-directing group; R'=H; R"=OEt, Me. PMID- 29711853 TI - A New Anion-Trapping Radical Host, [(Cu-dppe)3 {hat-(CN)6 }]2+ . AB - Anions PF6- and CF3 SO3- are trapped by the new radical host [(Cu-dppe)3 {hat (CN)6 }]2+ , which was synthesized in a one-pot reaction from a copper(I) source, hat-(CN)6 , and dppe in acetone. The trapped salts have been characterized both in solution and in the solid state (see picture: A- : PF6- , CF3 SO3- ). hat (CN)6 =hexaazatriphenylene hexacarbonitrile; dppe=1,2 bis(diphenylphosphanyl)ethane. PMID- 29711854 TI - A Concise Synthesis of Fumagillol. AB - A 13-step synthesis of (+/-)-fumagillol (1), the direct precursor of the potent angiogenesis inhibitors TNP-470 and fumagillin, from crotonaldehyde, diethylamine, and acrolein (see the scheme) has been achieved. The synthesis features a remarkable hetero-Claisen rearrangement. Small-molecule inhibitors of angiogenesis are promising chemotherapeutic agents for the treatment of cancer and inflammatory diseases. PMID- 29711855 TI - The pi Complexation of Calcium inside the meso-Octaethylporphyrinogen Tetraanion Cavity. AB - A possible binding cavity for alkali and alkaline earth metal ions: The synthesis and structural characterization of the complex shown, which was obtained from meso-octaethylporphyrinogen and calcium metal, shows that the porphyrinogen functions as a binucleating ligand with four eta3 -azaallyl binding sites for two calcium cations. PMID- 29711856 TI - Decreased Electron Transfer Rates of Manganese Porphyrins with Conformational Distortion of the Macrocycle. AB - Slow electron transfer to manganese(iii) porphyrins results when the macrocycle deviates from planarity. This was demonstrated by measuring the kinetics of homogeneous electron transfer from a series of semiquinone radical anions to synthetic manganese porphyrins (shown schematically; R1 =H, Cl, F; R2 =H, F). Three of the four porphyrins studied have nonplanar macrocycles. These results could have implications for the role of manganese in biological electron transfer processes. PMID- 29711857 TI - Covalently Cross-Linked Watson-Crick Base Pair Models. AB - Structural characteristics of Watson-Crick hydrogen-bonded base pairs are displayed by methylene-bridged base pairs of type A. The shown superposition of the X-ray structure obtained for the base pair A (Rib1 =Et; Rib2 =Me) over that of a C-G base pair illustrates that A occupies an area similar to that occupied by a traditional Watson-Crick hydrogen-bonded base pair. Temperature-dependent 1 H NMR studies indicate that the energy barrier for rotation along its CH2 bridge is about 10 kcal mol-1 , and that it exists predominantly in one conformer at -70 degrees C. PMID- 29711858 TI - Long-Range Electron Transfer through DNA Films. AB - Regardless of its position within the DNA film, cross-linked daunomycin (DM) is efficiently reduced electrochemically, indicating that the electron transfer exhibits a shallow distance dependence. Upon the introduction of an intervening cytosine-adenine (CA) mismatch, the electrochemical response is dramatically attenuated (shown schematically). Therefore, the DNA double helix can facilitate long-range electron transfer, but only in the presence of a well-stacked pathway. PMID- 29711859 TI - Sodium Salts of the Bipyridine Dianion: Polymer [(bpy)2- {Na+ (dme)}2 ]infinity , Cluster [(Na8 O)6+ Na+6 (bpy)62- (tmeda)6 ], and Monomer [(bpy)2- {Na+ (pmdta)}2 ]. AB - Bipyridine, a workhorse among the ligands of complex chemistry, can be reduced with sodium to its dianion. Depending on the solvent different sodium salts crystallize: from dimethoxyethane/toluene a polymer, from tetramethylethylenediamine/benzene a lipophilically wrapped [Na14 O]12+ cluster, and from pure pentamethyldiethylenetriamine a normal Na2 -bpy salt (see picture) are obtained. PMID- 29711860 TI - Coordination-Ionspray-MS (CIS-MS), a Universal Detection and Characterization Method for Direct Coupling with Separation Techniques. AB - By on-line addition of a central atom (for example, AgI , BIII , PdII , LiI ) positively or negatively charged complexes of analytes can be formed for CIS-MS. This technique is applicable to both polar and nonpolar compounds-for example, for alcohols, ethers, and a large number of olefins, polyolefins, and arenes as well as steroids, vitamins of the D and E families, carotinoids, polystyrols, terpenes, and unsaturated fatty acids-and can be readily coupled with separation techniques. PMID- 29711861 TI - Total Synthesis of the Proposed Structure of (+)-Tolyporphin A O,O-Diacetate. AB - Four monocyclic precursors were assembled in the total synthesis of the proposed structure 1-A of (+)-tolyporphin A O,O-diacetate (X=Ac). Comparison of the spectroscopic data demonstrated that synthetic tolyporphin O,O-diacetate did not match the O,O-diacetate prepared from natural (+)-tolyporphin A (X=H), calling for a structural revision of this class of natural products. On the basis of a series of NMR experiments including synthetic intermediates, the structure of tolyporphin A is concluded to be 1-B, in which the configurations of quaternary centers C7 and C17 are opposite to those in the originally proposed structure. PMID- 29711862 TI - Dynamic Light Scattering Evidence for a Ligand-Induced Motion between the Two Domains of Glucoamylase G1 of Aspergillus niger with Heterobivalent Substrate Analogues. AB - Heterobifunctional ligands that bind at the same time to the catalytic domain and to the starch-binding domain of glucoamylase induce a conformational change of the protein, as shown by dynamic light scattering. The ligands consist of acarbose and beta-cyclodextrin linked together by oligoethylene glycols of variable length (see the schematic diagram). PMID- 29711863 TI - Electron Tunneling in DNA. AB - The reorganization energy that accompanies interfacial or through-strand electron tunneling in DNA is remarkably similar to that of a protein, and the attenuation factor for electron transfer between intercalated reagents also remains protein like. These factors ensure rapid, but short-range electron tunneling through the duplex (shown schematically). PMID- 29711864 TI - Isomerism and Blue Electroluminescence of a Novel Organoboron Compound: BIII2 (O)(7-azain)2 Ph2. AB - Bright blue light with a maximum at 450 nm is emitted by both structural isomers of the novel, stable BIII2 (O)(7-azain)2 Ph2 (7-azain=7-azaindole anion) on irradiation with UV light. The isomer shown in the picture has approximate C2 symmetry (the other isomer approximate Cs symmetry) and electroluminesces when used as the emitting layer in an electroluminescent device. PMID- 29711865 TI - Formation of Giant Liposomes from Crystalline Complexes of Monoalkylammonium Surfactants and 4-Hydroxybiphenyl. AB - A parallel rather than a perpendicular alignment of aromatic compounds with respect to surfactant molecules (see schematic representation) is preferred for the formation of a liposome structure, because the perpendicular alignment would reduce the hydrophilicity of the aggregate. This is the result of studies on crystalline complexes of monoalkylammonium halides and various aromatic compounds. PMID- 29711866 TI - The Proton Cryptate of Hexaethylenetetramine. AB - The next higher homologue of hexamethylenetetramine was synthesized as the proton cryptate H+ @1?Br- (shown schematically), and its X-ray structure determined. The proton trapped by the lone pairs accumulated at the center of the T-symmetric tetraaza cage could not be exchanged or removed, even after heating for three days in 3 M NaOD. PMID- 29711867 TI - On the Mechanism of Long-Range Electron Transfer through DNA. AB - Hopping between bases of similar redox potentials is the mechanism by which charge transport occurs through DNA. This was shown by rate measurements performed with double strands 1-3. This mechanism explains why hole transfer displays a strong sequence dependence, and postulates that electron transfer in unperturbed DNA should not be dependent on the sequence. PMID- 29711868 TI - [Me2 AlBi(SiMe3 )2 ]3 -The First Structurally Characterized Organometallic Compound Containing a Bond between an Element of Group 13 and Bi. AB - Dehydrosilylation of Bi(SiMe3 )3 with Me2 AlH gave the title compound. This has a trimeric structure, the central unit of which is a six-membered Al3 Bi3 ring (see structure). In agreement with the VSEPR model the angles are greater at the Al centers and smaller at the Bi centers. PMID- 29711869 TI - Phosphate and Vanadate in Biological Systems: Chemical Relatives or More? AB - Structural and functional analogies between acid phosphatases and vanadium haloperoxidases are reflected in the conservation of the amino acid residues contributing to the active sites of these enzymes. This has interesting consequences for the research on both enzyme systems. A first example is the newly proposed structure for the active site of human glucose-6-phosphatase: The picture shows parts of six of the nine transmembrane helices as well as the amino acids (black ovals) that presumably participate in the formation of the active site. PMID- 29711870 TI - Inter- or Intramolecular Carbometalation of Nonactivated Alkynes by Zirconacyclopentanes in the Presence of Copper Chloride. AB - Five- and six-membered carbocyles 2 and 3 can be obtained from zirconacyclopentanes of type 1 by a novel carbometalation with nonactivated alkynes in the presence of CuCl (see reaction scheme). PMID- 29711871 TI - Selective Alkene Oxidation with H2 O2 and a Heterogenized Mn Catalyst: Epoxidation and a New Entry to Vicinal cis-Diols. AB - Covalent anchoring of 1,4-dimethyl-1,4,7-triazacyclononane on silica gel is the first step in the preparation of a heterogenized Mn catalyst. When H2 O2 is used as the oxidant, this material can catalyze the vicinal cis-dihydroxylation of disubstituted olefins, as shown schematically here. Both enantiomers of the product are obtained. PMID- 29711872 TI - Noncovalent Assembly of a Fifteen-Component Hydrogen-Bonded Nanostructure. AB - A total of 72 hydrogen bonds are formed in the spontaneous association of calix[4]arene tetramelamine and barbituric acid derivatives to give nanosized assemblies of the type represented in the picture. These consist of 15 components that assemble in a completely diastereoselective sense: of the eight possible diastereomers only the all-staggered diastereoisomer is obtained. PMID- 29711873 TI - Metal Insertion into C-C Bonds in Solution. AB - What kind of ligated metal center is necessary for insertion into the "hidden" C C bond? How can one tune the metal center for C-C bond activation by variation of the steric and electronic properties of ligands? What are the possible mechanisms of C-C bond activation in various reaction systems? A systematic look at the available data on C-C bond activation in solution provides some answers to these questions. PMID- 29711874 TI - Revised Structure of Tolyporphin A. AB - Four monocyclic precursors were assembled in the total synthesis of the proposed structure 1-A of (+)-tolyporphin A O,O-diacetate (X=Ac). Comparison of the spectroscopic data demonstrated that synthetic tolyporphin O,O-diacetate did not match the O,O-diacetate prepared from natural (+)-tolyporphin A (X=H), calling for a structural revision of this class of natural products. On the basis of a series of NMR experiments including synthetic intermediates, the structure of tolyporphin A is concluded to be 1-B, in which the configurations of quaternary centers C7 and C17 are opposite to those in the originally proposed structure. PMID- 29711875 TI - Discovery of Novel Catalysts for Alkene Epoxidation from Metal-Binding Combinatorial Libraries. AB - New lead structures for olefin oxidation catalysts have been obtained from a combinatorial library of 5760 metal-ligand complexes (see the microscopy picture). Iron complexes led to clean epoxide product formation using H2 O2 as the terminal oxidant. Parallel libraries were used to determine ligand features important for high catalytic activity and to identify enantioselective catalyst structures (see the Equation). PMID- 29711876 TI - Metal-Free Haloperoxidases: Fact or Artifact? AB - Lipases can catalyze halogenations (see scheme for an example) under the same experimental conditions as "metal-free haloperoxidases". This activity should, therefore, not be attributed to a new unique class of enzymes, or even to metal free haloperoxidases, but should rather be regarded as a side activity of well known hydrolases. PMID- 29711877 TI - The Melting Point Alternation in the Short-Chain n-Alkanes: Single-Crystal X-Ray Analyses of Propane at 30 K and of n-Butane to n-Nonane at 90 K. AB - A less dense packing is observed in the odd-numbered n-alkanes compared to the even-numbered members, which consequently lowers melting temperatures. The reason for this is that the even-numbered n-alkanes have optimal intermolecular interactions at both ends (see the picture on the left), while the odd-numbered ones possess these only at one end-at the other end the intermolecular distances are longer (right). PMID- 29711878 TI - Tribenzotriquinacenes with Sixfold Peripheral Functionalization-Potential Building Blocks for Novel Organic Networks. AB - Hatlike tribenzotriquinacenes 1 that bear six identical functional groups at the peripheral positions of the benzene nuclei were synthesized as starting materials for the construction of convex-concave organic networks and other three dimensional molecular frameworks. X=NO2 , NH2 , Br, I, SnBu, Ph, CCPh. PMID- 29711879 TI - A Potassium Complex of a Fluorine-Containing Macrocyclic Cage Compound: Interactions between Fluorine Atoms and Metal Ions. AB - A new donor, the C-F unit, can be added to the field of host-guest chemistry. The interaction between fluorine atoms and a potassium ion was proven with the fluorine-containing cage compound 1 as a host. The six fluorine atoms of K+ ?1 are coordinated to K+ in a distorted octahedral fashion. PMID- 29711880 TI - Alumoxane Hydride and Aluminum Chalcogenide Hydride Compounds with Pyrazolato Ligands. PMID- 29711882 TI - An Unusually Shallow Distance-Dependence for Triplet-Energy Transfer. PMID- 29711883 TI - First Generation Light-Harvesting Dendrimers with a [Ru(bpy)3 ]2+ Core and Aryl Ether Ligands Functionalized with Coumarin 450. PMID- 29711884 TI - Analysis of the Silkworm Moth Pheromone Binding Protein-Pheromone Complex by Electrospray-Ionization Mass Spectrometry. PMID- 29711885 TI - Wound-Activated Chemical Defense in Unicellular Planktonic Algae. PMID- 29711886 TI - Complexation of Antimony(III) by Trypanothione. PMID- 29711887 TI - [Cu(2-pyrazinecarboxylato)2 HgI2 ]?HgI2 : An Open Noninterpenetrating CuII -HgII Mixed-Metal Cuboidal Framework Encapsulating Nearly Linear HgI2 Guest Molecules. PMID- 29711889 TI - Single Fullerene Molecules and the Wave-Particle Dualism. PMID- 29711888 TI - A Tandem Sulfur Transfer/Reduction/Michael Addition Mediated by Benzyltriethylammonium Tetrathiomolybdate. PMID- 29711890 TI - Stereochemical Assignment of the C21-C38 Portion of the Desertomycin/Oasomycin Class of Natural Products by Using Universal NMR Databases: Proof. PMID- 29711891 TI - Selective Enhancement of the One-Electron Oxidation of Guanine by Base Pairing with Cytosine. PMID- 29711892 TI - Combinatorial Testing of Supported Catalysts for the Heterogeneous Polymerization of Olefins. PMID- 29711893 TI - Ternary Complexes Between DNA, Polyamine, and Cucurbituril: A Modular Approach to DNA-Binding Molecules. PMID- 29711894 TI - Catalyst Screening Using an Array of Thermistors. PMID- 29711895 TI - Stereochemical Assignment of the C21-C38 Portion of the Desertomycin/Oasomycin Class of Natural Products by Using Universal NMR Databases: Prediction. AB - Stereochemistry can be predicted: The stereoselective synthesis of the C21-C38 degradation product derived from oasomycins A and B has confirmed the stereochemistry predicted from a comparitive study of the NMR chemical shifts of the C21-C38 portion of the natural products with those obtained for its diastereomers. PMID- 29711896 TI - Octahedral SeO66- and Square-Pyramidal SeO54- , Two New Oxoselenate Anions. PMID- 29711897 TI - The Hexaazidogermanate(IV) Ion: Syntheses, Structures, and Reactions. PMID- 29711898 TI - Homoleptic Phosphoraneiminato Complexes of Rare Earth Elements as Initiators for Ring-Opening Polymerization of Lactones. PMID- 29711899 TI - "Remote Stereocontrol" in Organocopper Chemistry: Highly Enantioselective Synthesis of Vinylallenes by 1,5-Substitution of Enyne Acetates. PMID- 29711900 TI - Remote Enantioselection Transmitted by an Achiral Peptide Nucleic Acid Backbone. PMID- 29711901 TI - Selective Trimerization of alpha-Olefins with Triazacyclohexane Complexes of Chromium as Catalysts. PMID- 29711902 TI - Revision of the Absolute Configuration of Salicylihalamide A through Asymmetric Total Synthesis. PMID- 29711903 TI - Combinatorial Solid-Phase Synthesis of Multivalent Cyclic Neoglycopeptides. PMID- 29711904 TI - Synthesis and Structure of a Monomeric Aluminum(I) Compound [{HC(CMeNAr)2 }Al] (Ar=2,6-iPr2 C6 H3 ): A Stable Aluminum Analogue of a Carbene. PMID- 29711905 TI - Transition Metal Complexes as Photosensitizers for Near-Infrared Lanthanide Luminescence. PMID- 29711906 TI - Reexamination of the Evidence for Solvent-Induced Intramolecular Electrophilic Catalysis by a cis Vicinal Hydroxyl Group in Ribonucleoside Phosphorylation Reactions. PMID- 29711907 TI - Catalytic Enantioselective Fluorination of beta-Ketoesters. PMID- 29711908 TI - Nematic Liquid Crystals for Active Matrix Displays: Molecular Design and Synthesis. AB - Substances forming calamitic mesophases have been known for more than 100 years but only the recent, rapid advance in active matrix liquid crystal display (AM LCD) technology helped these materials to achieve the crucial position in flat panel display technology they hold today. Due to their high contrast, large viewing angle, and rapid switching times, modern AM-LCDs offer a superior picture quality even compared to conventional cathode ray tubes. Their flatness, low weight, and low energy consumption render them the technology of choice for all kinds of portable devices. Some of the future promises of AM-LCD technology are centered around the development of liquid crystalline materials for the different subtypes of active matrix applications. This development is aimed, on the one hand, towards improved electrooptical and viscoelastic properties; on the other hand, the increasing performance of LCDs leads to extremely stringent reliability demands on the liquid crystals. Responding to these high standards of performance and quality, most liquid crystals for contemporary AM-LCD applications are multiply fluorinated compounds with very high purities, as is typical for materials used in the electronics industry. The synthesis of these superfluorinated materials (SFMs) often requires specialized methods, which, in several cases, had to be introduced for the first time into the canon of industrial production. The immense market pressure, as well as the rapid advance of AM-LCD technology on the side of the display manufacturers, urges an increasing pace of the materials development. This demand for new materials can no longer be fulfilled by conventional trial-and-error approaches. As in the pharmaceutical industry, in the search for new, superior liquid crystals, the purely empirical methods are increasingly supported by a rational design based on computational methods. PMID- 29711909 TI - New Mesotextured Hybrid Materials Made from Assemblies of Dendrimers and Titanium(IV)-Oxo-Organo Clusters. PMID- 29711910 TI - Clean and Efficient Catalytic Reduction of Perchlorate. PMID- 29711911 TI - A Novel Iron-Based Catalyst for the Biphasic Oxidation of Benzene to Phenol with Hydrogen Peroxide. PMID- 29711912 TI - Chemo-, Regio-, and Stereoselective Cyclization of 1,3-Bis(trimethylsilyloxy)-1,3 butadienes with Functionalized Epoxides. PMID- 29711913 TI - The First Entry to Complex Bakkanes: A Highly Effective Retroaldol-Aldol-Based Approach to (-)-Bakkenolides III, B, C, and H. PMID- 29711914 TI - Molecular Gold-Multinuclear Gold(I) Complexes. PMID- 29711915 TI - Supramolecular Modification of the Periphery of Dendrimers Resulting in Rigidity and Functionality. PMID- 29711916 TI - Tailored Alkene Oligomerization with H-ZSM-57 Zeolite. PMID- 29711917 TI - Tuning the Regiospecificity of Cleavage in FeIII Catecholate Complexes: Tridentate Facial versus Meridional Ligands. PMID- 29711918 TI - An Allosteric Ribozyme Regulated by Doxycyline. PMID- 29711919 TI - ZnBr2 -Catalyzed Insertions of Carbonyl Compounds into Silacyclopropanes: Regiochemical Reversal Dependent on Metal Salt. PMID- 29711920 TI - Charge-Transfer Diamondoid Lattices: An Unprecedentedly Huge and Highly Catenating Diamondoid Network Arising from a Tetraphenol as a Tetrahedral Node and Benzoquinone as a Linear Spacer. PMID- 29711921 TI - Ras-A Molecular Switch Involved in Tumor Formation. AB - Ras, a GTP-hydrolyzing protein, is the product of a proto-oncogene found mutated in about 20-30 % of human tumors. It binds GDP/GTP with high affinity and in the presence of a GTPase-activating protein (GAP) has high GTP-hydrolyzing activity. The proto-oncogenic "normal" Ras functions as a regulated molecular switch cycling between a GDP-bound OFF and a GTP-bound ON state and is involved in signal transduction pathways controling cell growth, differentiation, apoptosis, and other events. The oncogenic versions of Ras contain point mutations which block the GTPase activity in the presence and absence of GAP. This process in turn inhibits the cycling of the switch and leads to the accumulation of Ras in the active form and contributes to tumor formation. Substantial effort has been devoted towards understanding the molecular basis for the switch function of Ras proteins and developing Ras-directed antitumor drugs. PMID- 29711922 TI - An Eldorado for Homogeneous Catalysis? PMID- 29711923 TI - A Linker Scaffold to Present Dimers of Pharmacophores Prepared by Solid-Phase Syntheses. PMID- 29711924 TI - First Synthesis of the Dendralene Family of Fundamental Hydrocarbons. PMID- 29711925 TI - Cyclodextrin Bilayer Vesicles. PMID- 29711926 TI - Total Synthesis of (+)-Ratjadone. PMID- 29711927 TI - The Distinct Effect of the o-Carboranyl Fragment: Its Influence on the I-I Distance in R3 PI2 Complexes. PMID- 29711928 TI - Highly Regio- and Enantioselective Reduction of 3,5-Dioxocarboxylates. PMID- 29711929 TI - Eight-Membered Carbocycles from a Dotz-Like Reaction. PMID- 29711930 TI - A New Class of Easily Obtained Carbonate-Related MU3 -Ligands and a Protein-Sized Doughnut-Shaped Coordination Oligomer. PMID- 29711931 TI - Functionalized Fullerene as an Artificial Vector for Transfection. PMID- 29711932 TI - Identification of a New Sex Pheromone from the Silk Dragline of the Tropical Wandering Spider Cupiennius salei. PMID- 29711933 TI - Tribochemical Activation of Iron Oxide for the Reduction of NO with CO: How Lattice Defects Can Influence the Catalytic Activity. PMID- 29711934 TI - Kinetic Resolution of Amines by a Nonenzymatic Acylation Catalyst. PMID- 29711935 TI - Catalytic Asymmetric Friedel-Crafts Alkylation of beta,gamma-Unsaturated alpha Ketoesters: Enantioselective Addition of Aromatic C-H Bonds to Alkenes. PMID- 29711936 TI - A Mass Spectrometric Labeling Strategy for High-Throughput Reaction Evaluation and Optimization: Exploring C-H Activation. PMID- 29711937 TI - Highly Enantioselective Palladium-Catalyzed Ene-Type Cyclization of a 1,6-Enyne. PMID- 29711938 TI - The Unusual Photochemistry of Dendrimers with an Anthracene Core. PMID- 29711939 TI - Resolution and Kinetic Stability of a Chiral Supramolecular Assembly Made of Labile Components. PMID- 29711940 TI - Efficient Catalytic Alkane Nitration with NO2 under Air Assisted by N Hydroxyphthalimide. PMID- 29711941 TI - Singly and Doubly Oxidized Phthalocyanine (pc) Rings: [Cu(pc)(ReO4 )] and [Cu(pc)(ReO4 )2 ]. PMID- 29711942 TI - Synthesis of 1,4-Diazidobuta-1,3-dienes by Electrocyclic Ring Opening: Precursors for Bi-2H-azirin-2-yls and Their Valence Isomerization to Diazabenzenes. PMID- 29711943 TI - The Spongistatins: Architecturally Complex Natural Products-Part Two: Synthesis of the C(29-51) Subunit, Fragment Assembly, and Final Elaboration to (+) Spongistatin 2. PMID- 29711945 TI - Structure and Base Catalysis of Supercritical Water in the Noncatalytic Benzaldehyde Disproportionation Using Water at High Temperatures and Pressures. PMID- 29711946 TI - Tetracyclopropylmethane: A Unique Hydrocarbon with S4 Symmetry. PMID- 29711947 TI - Synthesis, Structure, and Preliminary Magnetic Studies of a Ni24 Wheel. PMID- 29711948 TI - The Spongistatins: Architecturally Complex Natural Products-Part One: A Formal Synthesis of (+)-Spongistatin 1 by Construction of an Advanced ABCD Fragment. PMID- 29711949 TI - High-Nuclearity Chromium-Nickel-Cyanide Clusters: An Open Cr8 Ni5 (CN)24 Cage and a C3 -Symmetric Cr10 Ni9 (CN)42 Cluster Incorporating Three Forms of Cyanonickelate. PMID- 29711950 TI - New Synthetic Technology for the Construction of N-Containing Quinones and Derivatives Thereof: Total Synthesis of Epoxyquinomycin B. PMID- 29711951 TI - Highly Active Metathesis Catalysts Generated In Situ from Inexpensive and Air Stable Precursors. PMID- 29711952 TI - Highly Enantioselective Isomerization of 4,7-Dihydro-1,3-dioxepins Catalyzed by Me-DuPHOS-Modified Dihalogenonickel Complexes and Determination of the Absolute Configuration of the Isomerization Products. PMID- 29711953 TI - A Chemical Model of Homeostasis. PMID- 29711954 TI - Reversible S-S Bond Breaking and Bond Formation in Disulfide-Containing Dinuclear Complexes of MnI. PMID- 29711955 TI - Asymmetric Total Synthesis of Rhizoxin D. PMID- 29711957 TI - Coordinatively Unsaturated Metal Centers as Building Blocks for High Coordination Number Metallomesogens. PMID- 29711956 TI - Mechanistic Studies of Periodinane-Mediated Reactions of Anilides and Related Systems. PMID- 29711958 TI - Isolation of Dinuclear (MU-Silylene)(silyl)nickel Complexes and Si-Si Bond Formation on a Dinuclear Nickel Framework. PMID- 29711959 TI - Immobilization of Redox-Active Ligands on an Electrode: The Dendrimer Route. PMID- 29711960 TI - Patterning Solid-Supported Lipid Bilayer Membranes by Lithographic Polymerization of a Diacetylene Lipid. PMID- 29711961 TI - Cyclopentadienyl-Free Calcium Alkyls with Heteroelement-Substituted Anionic Phosphane Ligands: Synthesis and Structure of a Trialkyl Calcate(II) and of an Organocalcium Heterocubane. PMID- 29711962 TI - A Rare Phosphane Coordination Mode: A Symmetrically MU2 -Bridging Phosphole in a Dinuclear Palladium(I) Complex. PMID- 29711963 TI - Off-the-Shelf Colorimetric Anion Sensors. PMID- 29711964 TI - Chelate Formation around a Hexarhenium Cluster Core by the Diphosphane Ligand Ph2 P(CH2 )6 PPh2. PMID- 29711965 TI - Nonpeptidic alphav beta3 Integrin Antagonist Libraries: On-Bead Screening and Mass Spectrometric Identification without Tagging. PMID- 29711967 TI - Editorial: 40 Years of Angewandte Chemie International Edition. PMID- 29711966 TI - The First Synthetic Application of a Monooxygenase Employing Indirect Electrochemical NADH Regeneration. PMID- 29711968 TI - Evidence for sigma Dimerization During Anodic Redox Switching of 1,3,5 Tripyrrolidinobenzene: A New Molecular Switch. AB - 1,3,5-tripyrrolidinobenzene is the first example of an aromatic amine that forms sigma dimers during oxidation/reduction cycles [Eq. (1); X- =ClO4- ], and thus turns out to be an efficient molecular switch. Surprisingly, such sigma dimers are relatively stable intermediates during the formation of conjugated oligomers and polymers. PMID- 29711969 TI - Butane-2,3-Diacetal-Desymmetrized Glycolic Acid-A New Building Block for the Stereoselective Synthesis of Enantiopure alpha-Hydroxy Acids. AB - According to a chiral memory protocol, a chiral glycolic acid equivalent, the butane-2,3-diacetal-desymmetrized glycolate 2, is obtained from chiral 3 halopropane-1,2-diols 1. Compound 2 is a new and effective building block for the synthesis of mono- and dialkylated alpha-hydroxy acids 3, which constitute a biologically and pharmacologically important structural motif. PMID- 29711970 TI - [(MU4 -H)Rh4 (PNNP)2 (CO)4 ]+ : A Novel Hydride Bridging Mode. AB - Metal-metal bonds are not essential for multiply bridging hydride ligands. A tetranuclear MU4 -hydride complex [(MU4 -H)Rh4 (PNNP)2 (CO)4 ]+ (PNNP=3,5 bis(diphenylphosphanylmethyl)pyrazolate), in which the quadruply bridging hydrido ligand holds the four isolated metal centers together to form a tetrahedral metal array, has been prepared and characterized by spectroscopic methods and single crystal X-ray diffraction. PMID- 29711971 TI - Methylenation of Aldehydes: Transition Metal Catalyzed Formation of Salt-Free Phosphorus Ylides. AB - A variety of terminal alkenes are produced in excellent yields by the rhodium(I) catalyzed methylenation of aldehydes using TMSCHN2 and PPh3 [Eq. (1)]. These mild reaction conditions allowed the conversion of enolizable substrates and the chemoselective methylenation of aldehydes over ketones. TMS=trimethylsilyl. PMID- 29711972 TI - CH/pi Attraction: The Origin of Enantioselectivity in Transfer Hydrogenation of Aromatic Carbonyl Compounds Catalyzed by Chiral eta6 -Arene-Ruthenium(II) Complexes. AB - The through-space CH/pi attraction between the eta6 -arene ligand on Ru and the carbonyl aryl substituent (see transition states in picture) plays a key role in the enantioselective transfer hydrogenation of aromatic carbonyl compounds with 2 propanol or formic acid, catalyzed by chiral eta6 -arene-RuII complexes. PMID- 29711973 TI - Synthesis of Tri- and Tetracoordinate Phosphorus Compounds Containing a PCF3 Group by Nucleophilic Trifluoromethylation of the Corresponding PF Compounds. AB - A new way of forming P-C bonds: Catalytic amounts of F- ions facilitate the reaction of PIII -F compounds with CF3 SiMe3 to give PIII -CF3 compounds. These compounds can also be obtained in a one-pot procedure from PIII -OAr precursors (also shown). PMID- 29711974 TI - Ruthenium-Catalyzed One-Step Transformation of Propargylic Alcohols into Alkylidene Cyclobutenes: X-ray Characterization of an Ru(eta3 -cyclobutenyl) Intermediate. AB - The precatalyst [Cp*RuCl(cod)] promotes the head-to-head cyclodimerization of propargylic alcohols and the formation of novel alkylidene cyclobutenes (see scheme; Cp*=C5 Me5 , cod=1,5-cyclooctadiene) by addition of carboxylic acid to the Ru(eta4 -cyclobutadiene) intermediate and dehydration. PMID- 29711975 TI - Synthesis, Structure, and Properties of a Novel Heterooctametallic Complex Containing a Cyclic Ru4 Ni4 Core. AB - From two to five: A mononuclear Ru complex of salicylaldehyde thiosemicarbazone (H3 saltsc, 1), in which only two of the coordination sites of 1 participate in bonding ([Ru(bpy)2 (H2 saltsc)]ClO4 ), could be used to synthesize the cyclic complex cation [{Ru(bpy)2 (saltsc)}4 Ni4 ]4+ (bpy=2,2'-bipyridine). Its formation demonstrates that the Ru complex can act as an N,N,O donor ligand for the construction of polynuclear complexes. PMID- 29711977 TI - How Does Ethene Inactivate Cytochrome P450 En Route to Its Epoxidation? A Density Functional Study. AB - The suicidal complex 4 2, which inactivates cytochrome P450 during olefin epoxidation, was shown by density functional calculations to be formed from the same high-spin intermediate (4 1-III) that leads to stereochemical scrambling. PMID- 29711976 TI - Nickel(II) Phosphate VSB-5: A Magnetic Nanoporous Hydrogenation Catalyst with 24 Ring Tunnels. AB - Nanoporosity, good thermal stability, antiferromagnetic ordering, and hydrogenation with basic catalytic character are four important properties of the large-pore (24MR), zeolitic nickel(II) phosphate, VSB-5 (Ni20 [(OH)12 (H2 O)6 ][(HPO4 )8 (PO4 )4 ]?12 H2 O), which has been prepared under alkaline hydrothermal conditions. The structure of VSB-5 is depicted: NiO6 octahedra: green; PO4 tetrahedra: red. PMID- 29711978 TI - A Fully Characterized Complex Ion with Unreduced TCNQ as Fourfold Bridging Ligand: [(MU4 -TCNQ){fac-Re(CO)3 (bpy)}4 ]4+ . AB - Innocent behavior of a typical non-innocent ligand has been observed for the first structurally characterized discrete metal complex with tetranucleating TCNQ. The coordination of four [Re(CO)3 (bpy)]+ units (see picture: C: black, N: green, O: blue, Re: red) facilitates the reduction of the already excellent pi acceptor molecule TCNQ by a further 0.74 V! TCNQ=7,7,8,8-tetracyano-p quinodimethane, bpy=2,2'-bipyridine. PMID- 29711979 TI - Hydrolysis/Polycondensation in the Solid State: Access to Crystalline Silica Based Hybrid Materials. AB - Mild solid/gas or solid/liquid reactions can be used to prepare crystalline organosilicates, a class of silica-based hybrid materials, from the corresponding solid chlorosilanes. Hydrolysis and polycondensation in the solid state lead to the formation of the highly anisotropic organosilicates. PMID- 29711980 TI - Chemical Involvement of Solvent Water Molecules in Elementary Steps of the Fenton Oxidation Reaction. AB - The spontaneous formation of the contested ferryl ion is evident in ab initio molecular dynamics calculations on the FeII /H2 O2 system in aqueous solution (Fenton reagents). Not only is the ferryl ion preferred over the hydroxyl radical as the active oxidative species, but the solvent water molecules play a crucial role in the mechanism. The picture shows the unit cell containing the iron complex surrounded by solvent water molecules 1.8 ps after the start of the simulation, when the ferryl ion is being formed (blue: iron, red: oxygen, white: hydrogen). PMID- 29711981 TI - Incorporation of Peptide Isosteres into Enantioselective Peptide-Based Catalysts as Mechanistic Probes. AB - Olefinic analogues of effective peptide-based catalysts for the kinetic resolution of functionalized racemic secondary alcohols have been synthesized. The isosteric replacement of the peptide amide bond in 1 with an (E)-alkene to form 2 has enabled the evaluation of the kinetic role of particular amides within these catalysts. PMID- 29711982 TI - Directed Assembly of Periodic Materials from Protein and Oligonucleotide-Modified Nanoparticle Building Blocks. AB - DNA hybridization enables the three-dimensional assembly of Au nanoparticles and streptavidin. The high-density DNA-modified Au nanoparticles were stable to nonspecific binding of streptavidin. Structural and melting investigations on the assemblies showed their formation was reversible. PMID- 29711984 TI - Time- and Space-Resolved Luminescence of a Photonic Dye-Zeolite Antenna. AB - In a radiationless process, electronic excitation energy can be transported in the photonic antennae presented herein from the borders to the center of cylindrical zeolite L crystals (ca. 2 MUm). These antennae are formed by supramolecular organization of a cationic and a neutral dye in the parallel channels of the crystal. The rectangles symbolize adsorption sites, for which the red ones are filled with red-emitting dyes and blue ones with blue-emitting dyes. PMID- 29711985 TI - The First Organically Templated Open-Framework Niobium Silicate and Germanate Phases: Low-Temperature Hydrothermal Syntheses of [(C4 N2 H11 )Nb3 SiO10 ] (NSH 1) and [(C4 N2 H11 )Nb3 GeO10 ] (NGH-1). AB - Eight- and six-ring channels built from NbO6 octahedra and SiO4 or GeO4 tetrahedra, respectively, are contained in the structures of the first organically templated niobium silicate and germanate open-framework structures. The organic template (piperazine) occupies a well-defined position at the intersection of the channels. PMID- 29711986 TI - The Thioglycoside and Glycosyl Phosphite of 5-Azido Sialic Acid: Excellent Donors for the alpha-Glycosylation of Primary Hydroxy Groups. AB - 5-Azido sialyl donors with O-acetyl protecting groups are useful alpha-selective glycosylation reagents, especially for primary hydroxyl groups as acceptors. This is shown with a variety of reactions using 1 as a sialyl donor. It was also possible to synthesize NeuAcalpha(2->9)NeuAc as a thioglycoside donor for use in subsequent glycosylations. PMID- 29711987 TI - Tandem Intramolecular Alkyne Silylformylation-Allylsilylation: A Case of Remote 1,5-Asymmetric Induction. AB - Two new C-C bonds as well as a remote stereocenter are formed in the title reaction. With remarkable efficiency, this new reaction provides, through remote 1,5-asymmetric induction, anti-1,5 diols that are useful synthons for polyol synthesis (see scheme; Hacac=acetylacetone). PMID- 29711988 TI - A Lewis Acid Catalyst Anchored on Silica Grafted with Quaternary Alkylammonium Chloride Moieties. AB - Resistance to leaching and re-usability are characteristic of the novel heterogeneous Lewis acid catalyst that was prepared by anchoring tin(IV) chloride on silica grafted with tetraalkylammonium or pyridinium chloride groups. The catalyst displays high activity and selectivity in the synthesis of 3-methyl-3 buten-1-ol by the Prins condensation of isobutene with formaldehyde [Eq. (1)]. PMID- 29711989 TI - Spherical Aromaticity of Inorganic Cage Molecules. AB - Not only fullerenes but also inorganic cage molecules can be highly spherical aromatic. The molecular allotropes 1 (E=N, P, As, Sb, Bi) of the Group V elements and a variety of Zintl anions are even double spherical aromatic and obey the 2(N+1)2 rule, since both their sigma and pi shells are completely filled. This is reflected by a pronounced diatropic character. PMID- 29711990 TI - Chameleon States: High-Valent Metal-Oxo Species of Cytochrome P450 and Its Ruthenium Analogue. AB - Chameleon states: the ruthenium and iron metalloporphyrin analogues of compound I of cytochrome P450 (1; L = thiolate) possess low-lying states that change their electronic structure with solvent polarization. The ground state of the ruthenium complex is a low-spin electrophilic state, whereas the ground state of the iron complex is triradicaloid. PMID- 29711991 TI - Real and Hypothetical Intermediate-Valence AgII /AgIII and AgII /AgI Fluoride Systems as Potential Superconductors. AB - With the aim of gauging their potential as conducting or superconducting materials, we examine the crystal structures and magnetic properties of the roughly one hundred binary, ternary, and quaternary AgII and AgIII fluorides in the solid state reported up to date. The AgII cation appears in these species usually in a distorted octahedral environment, either in an [AgF]+ infinite chain or as [AgF2 ] sheets. Sometimes one finds discrete square-planar [AgF4 ]2- ions. The AgIII cation occurs usually in the form of isolated square-planar [AgF4 ]- ions. Systems containing AgIII (d8 ) centers are typically diamagnetic. On the other hand, the rich spectrum of AgII (d9 ) environments in binary and ternary fluorides leads to most diverse magnetic properties, ranging from paramagnetism, through temperature-independent paramagnetism (characteristic for half-filled band and metallic behavior) and antiferromagnetism, to weak ferromagnetism. AgII and AgIII have the same d-electron count as CuII (d9 ) and CuIII (d8 ), respectively. F- and O2- ions are isoelectronic, closed-shell (s2 p6 ) species; both are weak-field ligands. Led by these similarities, and by some experimental evidence, we examine analogies between the superconducting cuprates (CuII /CuIII O2- and CuII /CuI -O2- systems) and the formally mixed-valence AgII /AgIII -F- and AgII /AgI -F- phases. For this purpose we perform electronic-structure computations for a number of structurally characterized binary and ternary AgI , AgII , and AgIII fluorides and compare the results with similar calculations for oxocuprate superconductors. Electronic levels in the vicinity of the Fermi level (x2 -y2 or z2 ) have usually strongly mixed Ag(d)/F(p) character and are Ag-F antibonding, thus providing the potential of efficient vibronic coupling (typical for d9 systems with substantially covalent bonds). According to our computations this is the result not only of a coincidence in orbital energies; surprisingly the Ag-F bonding is substantially covalent in AgII and AgIII fluorides. The electron density of state at the Fermi level (DOSF ) for silver fluoride materials and frequencies of the metal-ligand stretching modes have values close to those for copper oxides. The above features suggest that properly hole- or electron-doped AgII fluorides might be good BCS-type superconductors. We analyze a comproportionation/disproportionation equilibrium in the hole-doped AgII fluorides, and the possible appearance of holes in the F(p) band. It seems that there is a chance of generating an AgIII -F- /AgII -F0 "ionic/covalent" curve crossing in the hole-doped AgII -F- fluorides, significantly increasing vibronic coupling. PMID- 29711992 TI - A More Efficient Catalyst for the Carbonylation of Chloroarenes. AB - The right ligand enables the efficient carbonylation of unactivated chloroarenes. A general synthesis of benzoic acid derivatives is possible with the palladium ferrocenylphosphane catalysts. PMID- 29711993 TI - Dioxygen Activation and Methane Hydroxylation by Soluble Methane Monooxygenase: A Tale of Two Irons and Three Proteins. AB - Methanotrophic bacteria are capable of using methane as their sole source of carbon and energy. The first step in methane metabolism, the oxidation of methane to methanol, is catalyzed by a fascinating enzyme system called methane monooxygenase (MMO). The selective oxidation of the very stable C-H bond in methane under ambient conditions is a remarkable feat that has not yet been repeated by synthetic catalysts and has attracted considerable scientific and commercial interest. The best studied MMO is a complex enzyme system that consists of three soluble protein components, all of which are required for efficient catalysis. Dioxygen activation and subsequent methane hydroxylation are catalyzed by a hydroxylase enzyme that contains a non-heme diiron site. A reductase protein accepts electrons from NADH and transfers them to the hydroxylase where they are used for the reductive activation of O2 . The third protein component couples electron and dioxygen consumption with methane oxidation. In this review we examine different aspects of catalysis by the MMO proteins, including the mechanisms of dioxygen activation at the diiron site and substrate hydroxylation by the activated oxygen species. We also discuss the role of complex formation between the different protein components in regulating various aspects of catalysis. PMID- 29711994 TI - Ion-Pair Recognition by Nucleoside Self-Assembly: Guanosine Hexadecamers Bind Cations and Anions. AB - G-Quartets can bind anions as well as cations: Solid-state and solution data indicate that self-assembled ion-pair receptors are formed from 16 guanosine monomers, 2 divalent cations, and 4 picrate anions. Hydrogen-bonding, ion-dipole, and base-stacking interactions combine to give a tubular complex with a cation loaded interior. An array of hydrogen-bond donors on the receptor's surface then enables anion coordination (see schematic representation, shaded rectangles=G quartets, shaded circles=cations). PMID- 29711995 TI - Double Photoionization of Dimethylaminobenzonitrile in Solution: A Three-Quantum Process with Intervening Chemical Step. AB - Startling facts are often revealed by the quantitative investigation of a reaction thought to be understood. The photoionization of dimethylaminobenzonitrile, which was previously regarded as biphotonic, was found to occur by the successive absorption of three photons, and to produce two electrons per starting molecule [Eq. (1)]. The explanation is an intervening rapid chemical reaction: deprotonation followed by intramolecular charge transfer. PMID- 29711996 TI - The Structure of [Fe(CO)4 ]-An Important New Chapter in a Long-Running Story. AB - The structure of the singlet state (1 A1 ) of [Fe(CO)4 ] in the gas phase has been determined by a combination of laser photochemistry of [Fe(CO)5 ] and electron diffraction imaging. The ground state of [Fe(CO)4 ] is known to be a triplet species (3 B2 ), and this is the species detected in picosecond time resolved IR experiments with [Fe(CO)5 ] in solution. This is an appropriate moment to survey the state of knowledge on [Fe(CO)4 ], beginning from the first low-temperature matrix experiments. PMID- 29711997 TI - The First In(OTf)3 -Catalyzed Conversion of Kinetically Formed Homoallylic Alcohols into the Thermodynamically Preferred Regioisomers: Application to the Synthesis of 22alpha-Sterols. AB - A retro-ene reaction that generates the parent aldehyde and a sigmatropic rearrangement are involved in the In(OTf)3 -catalyzed conversion of homoallylic alcohols 1 into the thermodynamically favored regioisomers 2. This method can be used for the stereocontrolled synthesis of linear homoallylic 22alpha-sterols from their readily accessible branched 22beta isomers. PMID- 29711998 TI - Enzyme-Activated Gd3+ Magnetic Resonance Imaging Contrast Agents with a Prominent Receptor-Induced Magnetization Enhancement. AB - Clinically relevant relaxivity enhancement of a magnetic resonance imaging (MRI) contrast agent has been achieved by using prodrug Gd3+ complexes (see picture, DTPA=diethylenetriaminepentaaceto). Enzymatic cleavage of lysine residues from the prodrug exposes a group that has a high affinity to human serum albumin and promotes enhanced relaxivity, thus enabling the detection of targets at submicromolar concentrations. PMID- 29711999 TI - Selective Photoproduction of O2 from the Mn4 O4 Cubane Core: A Structural and Functional Model for the Photosynthetic Water-Oxidizing Complex. AB - Cores for thought! A new [Mn4 O4 ]6+ "cubane" core complex (L6 Mn4 O4 ) with six facially bridging phosphinate chelate ligands (L- =(MePh)2 PO2- ) was synthesized. Photo-excitation releases molecular O2 by intramolecular coupling of two core oxygen atoms and selective rearrangement to a [Mn4 O2 ]6+ "butterfly" core ([L5 Mn4 O2 ]+ ; see scheme). Thus the Mn4 O4 cubane core exhibits unique reactivity in O2 evolution which may account for its presence in the photosynthetic enzyme. PMID- 29712000 TI - By Overexpression in the Yeast Pichia pastoris to Enhanced Enantioselectivity: New Aspects in the Application of Pig Liver Esterase. AB - Stable product quality without the interfering influences of other isoenzymes and hydrolases is possible through the application of recombinant pig liver esterase (rPLE), for which functional expression has now been achieved for the first time. In the hydrolysis of 1-phenyl-2-butyl acetate rPLE leads to substantially higher enantioselectivity than commercial PLE preparations. PMID- 29712001 TI - Targeting Molecular Recognition: Exploring the Dual Role of Functional Pseudoprolines in the Design of SH3 Ligands. AB - Pseudoprolines (PsiPro) have been developed as tools for inducing bioactive conformations that allow for optimal spatial complementation in protein-protein interactions. This dual function of PsiPro was explored for tuning proline-rich peptides as potent ligands for SH3 domains. PMID- 29712002 TI - Molecular Models of Titania-Silica Systems and a Late Transition Metal Complex Grafted Thereon. AB - Rhodium supported on titania-silica is modeled by 1, which was obtained from [{Cp*TiMe(MU-O2 SiPh2 )}2 ] (2) and [{Rh(OH)(cod)}2 ]. Complex 2 and its triply bridged derivative [Cp*Ti(MU-O2 SiPh2 )3 TiCp*] (3) can be envisaged as molecular models of titania-silica systems. Compounds 1-3 could potentially provide insights into the nature of the catalytically active sites in these systems; cod=1,5-cycloctadiene, Cp*=eta5 -C5 Me5 . PMID- 29712003 TI - Catalytic Use of a Boron Source for Boron Enolate Mediated Stereoselective Aldol Reactions in Water. AB - Use of boron enolates in water! Boron enolates can be generated and used for aldol reactions in water by using a catalytic amount of Ph2 BOH. This is the first example of a catalytic use of a boron source in stereoselective aldol reactions mediated by boron enolates. The mechanism of the reaction is discussed. PMID- 29712004 TI - Insights into the Aryl-Aryl Exchange between Palladium and Phosphane Ligands in PdII Complexes: Preparation of Phthalocyanine-Containing Phosphonium Salts. AB - At least three phthalocyanine units can be incorporated into phosphonium salts to give compounds such as 1, following unprecedented exchange reactions between phthalocyanine moieties bound to a palladium center and phenyl groups bound to the coordinated phosphane. Preliminary second-order nonlinear optics studies of the phthalocyanine-phosphonium salts have been carried out. PMID- 29712005 TI - Designed Molecules for Self-Assembly: The Controlled Formation of Two Chiral Self Assembled Polynuclear Species with Predetermined Configuration. AB - Squaring the cycle: Ligand L1 has been developed for the fabrication of chiral molecular squares, which can also be considered as circular helicates. By using a chirally modified ligand, one of the two forms of the complex can be generated selectively. bpy=2,2'-bipyridin-6-yl. PMID- 29712006 TI - Synthesis, Structure, and Reactivity of a Diphosphadiferratetrahedrane with a Fe Fe Double Bond. AB - The short thermolysis of the butterfly molecule [{Cp'''(OC)2 Fe}2 P4 ] affords, besides [Cp'''FeP5 ] and [{Cp'''Fe}2 P4 ], the diphosphadiferratetrahedrane [{Cp'''Fe}2 (MU-CO)(MU-eta2 :eta2 -P2 )] with a Fe-Fe double bond in 18 % yield. The P2 building block was split photochemically into two MU-P ligands with elimination of CO. In the resulting dinuclear complex 1, the 31 P NMR signal is shifted to extremely low field (delta=1406.9), and the rhombic Fe2 P2 four membered ring is almost orthogonal to the eclipsed Cp''' five-membered rings; Cp'''=tBu3 C5 H2 . PMID- 29712007 TI - First Catalytic Asymmetric Aldol-Tishchenko Reaction-Insight into the Catalyst Structure and Reaction Mechanism. AB - Unmodified carbonyl compounds are converted in an enantioselective aldol Tishchenko reaction directly into the chiral adduct by using catalytic amounts of a chiral base prepared in situ [Eq. (1)]. The catalyst was developed through the combination of arrayed catalyst evaluation and informed ligand design. Ad=adamantyl. PMID- 29712008 TI - Radical Azidonation of Benzylic Positions with Iodonium Azide. AB - Introduction of an azido substituent at the alpha position of benzyl ethers can be achieved by treating them with IN3 in refluxing acetonitrile. Some of the products obtained after 20 min-5 h are given. PMID- 29712009 TI - Palladium-Catalyzed Domino Reaction of 4-Methoxycarbonyloxy-2-butyn-1-ols with Phenols: A Novel Synthetic Method for Cyclic Carbonates with Recycling of CO2. AB - Refixation of the CO2 from a decarboxylation occurs in the palladium-catalyzed domino reaction of 4-methoxycarbonyloxy-2-butyn-1-ols with phenols. The reaction enables the construction of various cyclic carbonates [Eq. (1)] by efficient reincorporation of the CO2 molecule under mild conditions, and is thus a convenient and environmentally friendly method. PMID- 29712010 TI - A Heterogeneous cis-Dihydroxylation Catalyst with Stable, Site-Isolated Osmium Diolate Reaction Centers. AB - Involatile OsO4 ! A tetrasubstituted olefin is immobilized on SiO2 and reacts with OsO4 to form a stable osmate(IV) ester, which is a leak-proof heterogeneous catalyst for the cis-dihydroxylation of olefins. PMID- 29712011 TI - On the Aromatic Character of Electrocyclic and Pseudopericyclic Reactions: Thermal Cyclization of (2Z)-Hexa-2,4-5-trienals and Their Schiff Bases. AB - Pericyclic or pseudopericyclic? Although both mechanisms lead to the same product, they are deeply different in nature. The ring-current model proves to be a useful tool to define different kinds of aromaticity and to distinguish between pericyclic and pseudopericyclic reactions. PMID- 29712012 TI - Stereoselective Multiple Functionalization of Pyrylium Salts by Domino Reactions with 2-Silyloxybuta-1,3-dienes. AB - Six at a time! Up to six stereogenic centers can be diastereoselectively formed in one step in three-component domino reactions of 4-silyloxypyrylium triflates with 2-silyloxybuta-1,3-dienes. Annulated or bridged ring systems such as 1 and 2, respectively, can be formed with high selectivity. R1 =silyl group; R2 , R3 =organyl group. PMID- 29712014 TI - Mass Spectrometry of an Intact Virus. AB - The simultaneous measurement of the time-of-flight and the number of charges on each electrosprayed ion provides a new way to determine the mass of a whole intact virus. The weights of an icosahedral virus (rice yellow mottle virus) consisting of a single-stranded RNA surrounded by a homogeneous protein shell with a mass of 6.5*106 Da, and a rod-shaped RNA virus (tobacco mosaic virus) with a mass of 40.5*106 Da were measured with this technique. PMID- 29712015 TI - Alkylene-bridged N,N,N'N'-Tetrasubstituted Bis(2-amino-5-thiazolyl)methinium Salts-A New Class of Strongly Fluorescent Dyes. AB - The fluorescence-enhancing effect of the oxygen bridge in pyronine and rhodamine di- or triphenylmethane dyes, is connected to a significant hypsochrome shift of the absorption bands. This shift is absent when the bridge is an alkylene unit. While the preparation of such compounds is difficult, that of the heterocyclic analogues 1 is relatively simple and gives rise to intensely fluorescent dyes with absorptions at long wavelength. PMID- 29712016 TI - Fabrication and Properties of Gold Single-Crystal Ultramicroelectrodes. AB - Areas of 80-3500 MUm2 are displayed by gold single-crystal ultramicroelectrodes, which were fabricated from gold single crystals grown electrolytically in silicate gels. According to their cyclic voltammograms in 0.01 M HCl, these ultramicroelectrodes behave similarly to electrodes of more normal dimensions with the same crystallographic orientation of the surface. PMID- 29712017 TI - Dendron-Controlled Nucleation and Growth of Gold Nanoparticles. AB - Passivation of the metal surface by dendrons bearing a focal 4-pyridone functionality (the second-generation dendron is shown; C: gray, N: blue, O: red) allows controlled nucleation and growth of gold nanoclusters. The particle size is a direct function of the generation number of the dendritic ligands, with higher generation dendron producing larger particles. PMID- 29712018 TI - Stereoselective Nucleophilic Trifluoromethylation of N-(tert-Butylsulfinyl)imines by Using Trimethyl(trifluoromethyl)silane. AB - A very general reaction is presented to achieve the nucleophilic transfer of "CF3 " to chiral N-(tert-butylsulfinyl)imines in high yield and high stereoselectivity. Tetrabutylammonium difluorotriphenylsilicate (TBAT) functions as a fluoride source, and aromatic, heterocyclic, and aliphatic sulfinylimines react smoothly. The high stereoselectivity suggests that the reaction proceeds through an open transition state. TMS=trimethylsilyl. PMID- 29712019 TI - Oxathiaphospholane Approach to the Synthesis of P-Chiral, Isotopomeric Deoxy(ribonucleoside phosphorothioate)s and Phosphates Labeled with an Oxygen Isotope. AB - Diastereomerically pure and isotopically labeled 5'-O-DMT-nucleoside-3'-O-(2-thio and -oxo-4,4-"spiro"-pentamethylene-1,3,2-[18 O]oxathiaphospholane)s were used for stereocontrolled synthesis of P-chiral, isotopically labeled oligonucleotide phosphorothioates and phosphates, as well as "chimeric" PS18 O/P18 O oligomers without loss of isotope enrichment. DBU=1,8-diazabicyclo[5.4.0]undec-7-ene, DMT=4,4'-dimethoxytrityl, ROH=3'-O-acetylthymidine, Bz=benzoyl. PMID- 29712020 TI - Iron-Catalyzed Regio- and Stereoselective Carbolithiation of Alkynes. AB - Butylation problems ironed out: 3-Pentynyl ethers react with butyllithium at -20 degrees C in toluene, upon addition of a catalytic amount of a cheap iron(III) salt, to afford (E)-4-methyl-3-octenyl ethers in high yields. Stereochemically defined tetrasubstituted alkenes were also obtained by the subsequent addition of electrophiles (E+ , see scheme; acac = acetylacetonate, Bn=benzyl). PMID- 29712021 TI - Total Synthesis of the Callipeltoside Aglycon. AB - Following macrolactonization, a Sonogashira coupling leads efficiently from 1 and 2 to the aglycon of the structurally unique cytotoxic macrolide callipeltoside A, isolated in tiny quantities from the lithistid sponge Callipelta sp. Key steps in the preparation of macrolide precursor 1 include a boron-mediated anti-aldol coupling (A) in tandem with Yamamoto's vinylogous aldol reaction (B). TES=triethylsilyl. PMID- 29712022 TI - EPR and Density Functional Studies of Light-Induced Radical Pairs in a Single Crystal of a Hexaarylbiimidazolyl Derivative. AB - The intermolecular exchange coupling 2J for the light-induced radical pair in a crystal of 2,2'-di(ortho-chlorophenyl)-4,4',5,5'-tetraphenylbiimidazole (o-Cl HABI) was measured for the first time on the basis of Curie analyses of the EPR spectral intensities. The coupling constant evaluated from density functional theory calculations compares well with the experimental value. The picture shows the distribution of spin density for the radical pair. PMID- 29712024 TI - Insights into the Branched-Chain Formation of Mycarose: Methylation Catalyzed by an (S)-Adenosylmethionine-Dependent Methyltransferase. AB - A C-methyltransferase involved in methyl-branch formation in sugars has been characterized for the first time. TylC3, an (S)-adenosylmethylthionine(AdoMet) dependent enzyme, catalyzes the attachment of a methyl branch [Eq. (1)] in the biosynthesis of L-mycarose, an unusual sugar found in tylosin and as its O-3 methyl derivative in erythromycin. The C-3 methylation proceeds with inversion of configuration and does not require the assistance of any cofactors. The turnover rate is 1.4+/-0.1 min-1 . TDP=thymidine-5'-dihydrogenphosphate. PMID- 29712023 TI - Hexaphyrin(1.0.1.0.0.0): An Expanded Porphyrin Ligand for the Actinide Cations Uranyl (UO22+ ) and Neptunyl (NpO2+ ). AB - Applications of actinide chemistry, whether for energy or defense purposes, have left a legacy of potential waste hazards. The new expanded porphyrin ligand 1 forms stable complexes with both uranyl (UO22+ ) and neptunyl (NpO2+ ) ions and presents a potential new avenue for waste remediation. PMID- 29712025 TI - Liquid-Phase Synthesis of Colloids and Redispersible Powders of Strongly Luminescing LaPO4 :Ce,Tb Nanocrystals. AB - Nanoparticles with high photoluminescence quantum yield have been recently considered as possible biolabels and as emitters in optoelectronic devices. Now gram amounts of nontoxic, chemically stable LaPO4 :Ce,Tb nanocrystals have been obtained in a coordinating solvent. These nanoparticles can be easily redispersed in polar solvents to give scatter-free colloids that exhibit quantum yields of up to 61 %. PMID- 29712026 TI - Engineering Catalysts for Enantioselective Addition of Diethylzinc to Aldehydes with Racemic Amino Alcohols: Nonlinear Effects in Asymmetric Deactivation of Racemic Catalysts. AB - Correct additions make a difference: Asymmetric deactivation and asymmetric amplification concepts coupled with a high-throughput screening technique provided a successful strategy for designing a highly enantioselective catalytic system by simple combination of a racemic amino alcohol (rac-DB) and a nonracemic additive (AA). The example in the scheme shows the conversion of 1 into 2 with up to 92.7 % ee. PMID- 29712027 TI - Synthesis of Functionalized Cyclohexadiene-trans-Diols with Recombinant Cells of Escherichia coli. AB - As valuable chiral building blocks for the syntheses of natural products and pharmacologically active substances, especially of carbohydrate mimetics, functionalized cyclohexadiene-trans-diols such as (2S,3S)-dihydroxy-2,3 dihydrobenzoic acid (1) can be prepared easily in 17 % yield starting from glucose by using metabolically deregulated, recombinant microorganisms such as the Escherichia coli strain AN193. PMID- 29712028 TI - Ga9 (CMe3 )9 , an Important New Building Block in the Structural Chemistry of the Alkylelement(I) Compounds En Rn (E=B-In). AB - A simple preparative method has been employed for the synthesis of the novel cluster compound Ga9 (CMe3 )9 , which contains a tricapped trigonal prism of monovalent gallium atoms. Electron transfer processes were observed similar to those of polyboranes, leading to the the reversible formation of the corresponding radical anion. PMID- 29712029 TI - Diastereo- and Enantioselective Synthesis of Pyrrolo[1,4]benzodiazepines through Decarboxylative Photocyclization. AB - Memory of chirality in triplet 1,7-diradicals was detected for the first time and to a remarkably high degree in the decarboxylative photocyclization of the proline derivative of N-phthaloyl anthranilic acid 1 into 2 (X=H: 45 % yield, 86 % ee; X=Cl: 50 % yield, 79 % ee). PMID- 29712030 TI - Chiral Recognition in Bis-Urea-Based Aggregates and Organogels through Cooperative Interactions. AB - Chiral recognition in organogels occurs in the coassembly of the chiral gelator 1 with the chiral guest molecule 2. The diastereomeric aggregates formed from (R,R) 2 with (R,R)-1 or (S,S)-1 were found to be truly different in structure and strength. Cooperativity makes a major contribution to the chiral recognition in this system. PMID- 29712031 TI - Stereoselective Formation of C2 -Symmetric ansa-Lanthanocenes by Reductive Coupling of Acenaphthylene with Activated Ytterbium or Samarium. AB - A fulvene-type coupling results from the reduction of acenaphthylene by activated samarium or ytterbium in THF. This leads exclusively to the formation of the respective C2 -symmetric trans-rac-ansa-lanthanocene complexes [(eta5 -C12 H8 )2 Ln(thf)2 ] [Eq. (1); Ln=Sm, Yb]. PMID- 29712032 TI - Narrow Molecular Weight Distribution Precursors for Polymer-Drug Conjugates. AB - Atom transfer polymerization has been used to prepare a narrow molecular weight distribution (MWD), active ester homopolymer that acted as a precursor to prepare families of narrow MWD polymer-drug conjugates during preclinical studies. PMID- 29712033 TI - SrN and SrN2 : Diazenides by Synthesis under High N2 -Pressure. AB - Nitride and/or diazenide ions in the octahedral holes of nearly close-packed arrangements of Sr2+ ions characterize the new compounds described herein. They were obtained as single-phase products by oxidation of Sr2 N with molecular nitrogen under high pressure. PMID- 29712034 TI - CO2 Technology Platform: An Important Tool for Environmental Problem Solving. AB - CO2 is a good solvent for many substances when compressed into its liquid or supercritical fluid state. Above the critical temperature and critical pressure (Tc =31 degrees C, Pc =73.8 bar, see Figure 1 for the phase diagram for CO2 ), CO2 has both gaslike viscosities and liquidlike densities. These moderate critical conditions allow CO2 to be used within safe commercial and laboratory operating conditions. Small changes in temperature and pressure cause dramatic changes in the density, viscosity, and dielectric properties of CO2 , making it a tunable solvent that can be tailored for various applications. Combined, these unique properties make CO2 a "solvent of choice" for the new millennium. PMID- 29712035 TI - A Rh-Catalyzed C-H Insertion Reaction for the Oxidative Conversion of Carbamates to Oxazolidinones. AB - Selective intramolecular alkane oxidations: an RhII carboxylate catalyzed C-H amination reaction facilitates the preparation of 1,2-amino alcohols from primary carbamates. The reaction is stereospecific, providing access to chiral alpha branched amines from optically pure starting materials with no loss in enantiomeric excess. PMID- 29712036 TI - Total Synthesis of Dermostatin A. AB - An oxo-hexaene macrolide antibiotic, dermostatin A has been synthesized. Key features of the synthesis include the application of cyanohydrin acetonide couplings for the synthesis of the polyol portion, and the convergent introduction of the polyene segment by means of a Stille coupling. PMID- 29712037 TI - Do More Electrophilic Aldehydes/Ketones Exhibit Higher Reactivity toward Nucleophiles in the Presence of Lewis Acids? AB - A crucial role in the chemoselective synthesis of primary, secondary, and homoallylic alcohols and of Diels-Alder adducts is played by Lewis acids (LA) in the addition of nucleophiles (Nu) to carbonyl compounds (see scheme; EWG = electron-withdrawing group, EDG = electron-donating group). PMID- 29712038 TI - Homo- and Heterochiral Supramolecular Tapes from Achiral, Enantiopure, and Racemic Promesogenic Formamides: Expression of Molecular Chirality in Two and Three Dimensions. AB - Enantiomorphous monolayers of enantiopure formamides form on a graphite surface, while the racemic compound does not undergo a spontaneous resolution under similar conditions. This difference in the two-dimensional behavior has been studied by scanning tunneling microscopy (see image of the racemate adsorbed on graphite). A study of the three-dimensional crystallization of the racemic formamide by X-ray crystallographic analysis also shows that it forms racemic tapes. PMID- 29712039 TI - The Use of Carbon Monoxide and Imines as Peptide Derivative Synthons: A Facile Palladium-Catalyzed Synthesis of alpha-Amino Acid Derived Imidazolines. AB - One of the most facile routes to prepare carboxylate-substituted imidazolines is by the palladium-catalyzed coupling of an imine, carbon monoxide, and an acid chloride. In this reaction, a peptide unit is constructed and directly incorporated into the heterocyclic core. PMID- 29712040 TI - A Large Dendritic Multiporphyrin Array as a Mimic of the Bacterial Light Harvesting Antenna Complex: Molecular Design of an Efficient Energy Funnel for Visible Photons. AB - pi-Electronic conjugation is not necessary to facilitate long-range energy migration and transfer: A rapid (kENT =1.04*109 s-1 ) and efficient (PhiEXT =71 %) energy transfer from the 28 photoexcited zinc porphyrin units to the focal free-base porphyrin unit occurs in a large, star-shaped dendritic multiporphyrin array in which the chromophore units are linked through flexible ether groups. PMID- 29712041 TI - [NdI2 (thf)5 ], the First Crystallographically Authenticated Neodymium(II) Complex. AB - Two new starting materials for a new chemistry of low-valent lanthanide compounds are the first crystallographically characterized molecular complexes of the rare Nd2+ ion, [NdI2 (thf)5 ] (1), and [TmI2 (thf)(dme)2 ] (2; dme=1,2 dimethoxyethane). These have a pentagonal-bipyramidal structure in which the two iodine atoms are in axial positions. PMID- 29712042 TI - Sensing A Paradigm Shift in the Field of Molecular Recognition: From Selective to Differential Receptors. AB - Molecular recognition has evolved from a science designed to understand biological systems into a much more diverse area of research. While work continues to elucidate "nature's tricks" with respect to intermolecular interactions, much attention has turned to the perspective that molecular recognition, by design, can lead to new technologies. Applications ranging from molecular sensing to information storage and even working molecular machines have been envisioned. This review will highlight a few historical hallmarks of molecular recognition oriented at studying the basic science of intermolecular interactions, but then detail recent advances in molecular recognition aimed towards applications in the field of molecular sensing. Rational design can be used to create synthetic receptors with a good deal of predictability and selectivity, and many signal transduction mechanisms exist for converting these receptors into sensors. This is the first topic discussed. The concept of "differential" or "generalized" sensing is then presented, where one uses an array of sensors that do not necessarily conform to the "lock and key" principle. This approach to sensing is inspired by the mammalian senses of taste and smell, which we briefly describe. To mimic senses of taste and smell, one is naturally led to the use of combinatorial libraries, a direction of research that has seen continued growth over the past few years. We summarize the current state of the art in synthetic combinatorial receptors/sensors, and then predict a future direction that the field of molecular recognition will possibly take. The review is not meant for the specialist, but instead for a general audience. It does not present a highly detailed analysis of each individual topic: synthetic receptors, sensors, olfaction/gustation, and combinatorial receptors/sensors. Instead, this review shows how all these fields complement each other and fit together to create sensing devices. Our conclusion is that specific analyte sensing, differential sensing, and combinatorial chemistry can and will be combined to create sensor arrays, and give the subfield of molecular recognition that uses synthetic systems a bright future in this type of sensing scenario. PMID- 29712043 TI - Color Indicators of Molecular Chirality Based on Doped Liquid Crystals. AB - A simple color test for enantiomeric excess requires no chiral auxiliaries and only microgram quantities of chiral products. The method is based on a chirality dependent color generation in doped LC films on formation of an imine or ester from an amine and carbaldehyde or alcohol and acid chloride, respectively, and will enable the rapid screening of libraries of nonracemic compounds. PMID- 29712044 TI - Hapten-Functionalized DNA-Streptavidin Nanocircles as Supramolecular Reagents in a Competitive Immuno-PCR Assay. AB - Analysis with nanorings: The endogeneous proteins of supramolecular DNA nanocircles, obtained in high yields from oligomeric precursors containing bisbiotinylated DNA and streptavidin, are conveniently functionalized with biotinylated hapten moieties. These modular conjugates can be used as reagents in a novel competitive immunoassay for the high-sensitivity detection of low molecular weight analytes. PMID- 29712045 TI - Synthesis of a Trisaccharide Library by Using a Phenylsulfonate Traceless Linker on Synphase Crowns. AB - 44 members are in the trisaccharide library synthesized by the method described here. Six differently protected glucoside building blocks were sulfonylated with 1, coupled to the solid support 2 (a crown compound) by Pd0 -catalyzed carbonylative amidation, glycosylated twice, and cleaved from the sulfonate linker with four nucleophiles. PMID- 29712046 TI - Flexible meso-Bis(sulfinyl) Ligands as Building Blocks for Copper(II) Coordination Polymers: Cavity Control by Varying the Chain Length of Ligands. AB - Fillings and cavities: Three novel pseudo-octahedral metal-organic frameworks, 1 3, consisting of macrometallacyclic noninterpenetrating meso networks and exhibiting weak antiferromagnetic interactions, have been constructed from CuII centers and structurally flexible R,S-bis(sulfinyl) ligands. Varying the chain length of ligands is found to control the cavity sizes of the networks. PMID- 29712047 TI - Direct Observation of a Distant Ion Pair Generated in a Photoconductive Poly(N vinylcarbazole) Film with Dopant. AB - Photoconduction in charge transfer materials apparently occurs through a distant geminate ion pair with an interionic separation of about 8 A, as demonstrated by time-resolved EPR spectroscopy of a doped poly(N-vinylcarbazole) film. PMID- 29712048 TI - Combinatorial Discovery of New Photocatalysts for Water Purification with Visible Light. PMID- 29712049 TI - Catalysis of the Asymmetric Desymmetrization of Cyclic Anhydrides by Nucleophilic Ring-Opening with Alcohols. AB - The single symmetry-breaking transformation of a relatively simple meso compound can provide highly expedient access to a wide variety of usefully functionalized chiral building blocks. Recent advances in asymmetric desymmetrization, through the development of tertiary amines as nonenzymatic catalysts for the ring opening of meso cyclic anhydrides with alcohols [for example, see Eq. (1)], are discussed here. PMID- 29712050 TI - Landmark Crystal Structure of an Experimentally Utilized Tetralithium Tetrapotassium Amide-Alkoxide Superbase. AB - At long last an experimentally utilized superbase has been crystallographically characterized. Isolated from a lithium amide-potassium alkoxide-arene mixture, this landmark compound adopts a novel sixteen-vertex "carousel" arrangement stabilized by two distinct types of benzene ligation. PMID- 29712051 TI - Transition Metal Complexes with the Proton Sponge 4,9-Dichloroquino[7,8 h]quinoline: Highly Twisted Aromatic Systems and an Extreme "Out-of-Plane" Position of the Coordinated Transition Metal Atom. AB - An extremely high thermal and chemical stability as well as a unique "out-of plane" position of the metal atom is shown by the first stable transition metal complexes formed with the proton sponge 1 as the ligand. The properties of these complexes await wide application in catalysis and medicine. PMID- 29712052 TI - Rational Design of Low Molecular Mass Organogelators: Toward a Library of Functional N-Acyl-1,omega-Amino Acid Derivatives. AB - N-Acyl amino acids RCONH(CH2 )n COOR1 represent a new family of organogelators that can be obtained in a combinatorial approach from libraries of activated acids and amino acids. The amounts required for gel formation in solvents such as DMF are less than 1 mg mL-1 and the gels formed are very stable. n=5, 7, 10, 12; R=aromatic or aliphatic group; R1 =H or alkali metal (Na). PMID- 29712053 TI - Homoleptic Azidometalates. AB - Azidometalates are not explosive if the solid salts contain sufficiently large cations. Structure determinations on single crystals of such compounds elucidate how the azide ions act as covalently bound ligands and have several different bridging modes. PMID- 29712054 TI - Synthesis of the C1-C13 Fragment of Kendomycin: Atropisomerism around a C-Aryl Glycosidic Bond. AB - The left-hand fragment 2 of the novel antibiotic kendomycin (1) has been synthesized by an aldol addition and a Michael-type 1,4-addition of a C5 alcohol with a C9-C11 enone. Compound 2 shows an interesting atropisomerism around the C4a-C5-sp2 -sp3 bond. The atropisomers can be separated in pure forms by low temperature high-pressure liquid chromatography. PMID- 29712056 TI - "Total Synthesis" Supramolecular Style: Design and Hydrogen-Bond-Directed Assembly of Ternary Supermolecules. AB - Getting the right balance between intermolecular interactions is crucial for the synthesis of supermolecules in a preconceived manner. The three-component supermolecule in the ternary cocrystal of 3,5-dinitrobenzoic acid, isonicotinamide, and 4-(dimethylamino)benzoic acid (1:1:1) assembles through a "primary" (between the stronger acid and pyridine) and a "secondary" hydrogen bonding interaction (between the weaker acid and amide). PMID- 29712058 TI - A Redox Switch Based on Dihydro[5]helicene: Drastic Chiroptical Response Induced by Reversible C-C Bond Making/Breaking upon Electron Transfer. AB - Helicity and axial chirality are reversibly interconverted in the novel redox pair 1 and 22+ ; the compounds exhibit drastic UV/Vis and circular dichroism spectral changes as well as dynamic structural changes upon electron transfer, thus furnishing an unprecedented multi-output response system with high bistability. X=S or O. PMID- 29712057 TI - High Nuclearity ZnII /MeCO2- /(C5 NH4 )2 CO22- Clusters by "Depolymerization": Conversion of a Three-Dimensional Coordination Polymer Containing Hexameric Units into Its Constituent Hexanuclear Complex. AB - The controlled cleavage of coordination polymers consisting of well-defined large units can be employed for the rational synthesis of high nuclearity clusters. This synthetic concept is demonstrated by the conversion (schematically shown) of a three-dimensional ZnII coordination polymer containing repeating hexameric units with a "twin-anchor" arrangement of the metal ions into the corresponding hexanuclear cluster by reaction with a donor solvent. PMID- 29712059 TI - Magnetic Nanosensors for the Detection of Oligonucleotide Sequences. AB - Superparamagnetic nanoparticles conjugated to oligonucleotides exert sensitive and reversible effects on the spin-spin relaxation rates of adjacent water protons when the conjugates hybridize to target oligonucleotides (see temperature cycle in the picture). The fluid-phase magnetic sensors provide the basis for detecting specific nucleic acid sequences in turbid media and potentially in tissues in vivo. PMID- 29712060 TI - From Structure to Function: A New Approach to Detect Functional Similarity among Proteins Independent from Sequence and Fold Homology. AB - Protein function is almost invariably linked with the specific recognition of substrates or endogenous ligands in particular binding pockets; proteins of related function should, therefore, share comparable recognition pockets. On the basis of this idea a new computer method has been developed to detect functional relationships among proteins, independent of a particular sequence or fold homology, in which the functionality of the residues is translated into simple physicochemical descriptors. By this method novel ligands in drug design can be suggested. PMID- 29712061 TI - From Split-Pool Libraries to Spatially Addressable Microarrays and Its Application to Functional Proteomic Profiling. AB - Small molecules encoded with peptidonucleic acid (PNA) were used to probe protein function in a microarray format. The PNA tag served to encode the synthetic history of the small molecule and to positionally encode the identity of the small molecule by its location upon hybridization to an oligonucleotide microarray. PMID- 29712062 TI - The Fate of Bis(eta3 -allyl)palladium Complexes in the Presence of Aldehydes (or Imines) and Allylic Chlorides: Stille Coupling versus Allylation of Aldehydes (or Imines). AB - The mere presence or absence of PPh3 suffices to control the reactivity of bis(eta3 -allyl)palladium complexes. In the absence of PPh3 they undergo chemoselective allylic addition to aldehydes or imines, even in the presence of allylic chlorides, whereas in the presence of PPh3 the Stille coupling reaction takes place chemoselectively, even when aldehydes or imines are also present. PMID- 29712063 TI - Large-Pore Mesoporous Materials with Semi-Crystalline Zeolitic Frameworks. AB - Crystallizing walls: Following the templated solid-state secondary crystallization of an amorphous mesoporous material the amorphous pore walls of the mesoporous precursor are partially reorganized into a crystalline material, the zeolite ZSM-5, as indicated by the dark-field transmission electron micrograph image shown. The bright spots correspond to the ZSM-5 nanocrystals. PMID- 29712064 TI - Mass-Spectrometric Monitoring of a PNA-Based Ligation Reaction for the Multiplex Detection of DNA Single-Nucleotide Polymorphisms. AB - An abasic-site-forming ligation reaction might allow multiplex analysis of single base mutations to be performed in homogeneous solution. The ligation strategy capitalizes upon the use of the non-ionic DNA-analogue peptide nucleic acids (PNAs) and combines the highly sequence-selective base pairing of short-length PNA with its ease and accuracy of detection by MALDI-TOF mass spectrometry. PMID- 29712065 TI - Nonempirical Calculation of Polymethine Excited States. AB - Sometimes the simplest systems need the most sophisticated treatment! Only with multiconfigurational SCF methodology including second-order correction (CASPT2) is it possible to quantitatively reproduce the position of the high-intensity methine band of streptocyanine dyes such as the one shown. PMID- 29712066 TI - Mononuclear eta2 (4e)-Bonded Phosphaalkyne Complexes; Selective Formation of a 1,2-Diphosphacyclobutadiene Tantalum Complex. AB - Only the 1,2-diphosphacyclobutadiene and none of its 1,3 isomer was obtained in the reaction of 1 with tBuC=P to give 2. In complex 1, which was prepared from [TaCl2 (eta5 -C5 Me5 )(CO)2 (thf)] and tBuC=P, the phosphaalkyne adopts an eta2 (4e) bonding mode according to NMR data, crystal structure analysis, and theoretical calculations. PMID- 29712067 TI - Application of Chemical Shift Imaging for Simultaneous and Fast Acquisition of NMR Spectra on Multiple Samples. AB - A reduction of a factor of 10 in the time needed to measure highly resolved NMR spectra of multiple samples can be achieved with any NMR spectrometer by using a combination of chemical shift imaging and a compartmented detection volume consisting of a bundle of capillaries. The picture shows the cross-sectional image of a bundle of nine 1-mm capillaries after Fourier transformation along the spatial dimensions only. PMID- 29712068 TI - Ligand-Gated Ion Channels. AB - Ion channels are at the heart of many biological processes such as nerve activity and muscle contraction. How are their impressive ion selectivity and highly specialized gating brought about? In recent years, X-ray crystallography and high resolution electron microscopy, as well as photo-affinity labeling and site specific mutagenesis techniques in combination with patch-clamp electrophysiology have provided a detailed picture of some channel proteins. Herein we summarize the main structural and functional properties of channel proteins based on the advances made mainly within the last decade. We integrate these novel insights into a comprehensive description of the class of ligand-gated ion channels. PMID- 29712069 TI - Core-Shell-Corona Micelles with a Responsive Shell. AB - A reactor for the synthesis of gold nanoparticles is one of the uses of a poly(styrene)-block-poly(2-vinylpyridine)-block-poly(ethylene oxide) triblock copolymer (PS-b-P2VP-b-PEO) which forms core-shell-corona micelles in water. Very low polydispersity spherical micelles are observed that consist of a PS core surrounded by a pH-sensitive P2VP shell and a corona of PEO chains end-capped by a hydroxyl group. The corona can act as a site for attaching responsive or sensing molecules. PMID- 29712070 TI - Metal-Mediated Self-Assembly of pi-Bonded Benzoquinone Complexes into Polymers with Tunable Geometries. AB - Coordination of Mn(CO)3+ to the pi system in hydroquinone facilitates proton loss to afford benzoquinone complexes. Subsequent sigma coordination of the benzoquinone oxygen atoms to added metal ions results in neutral one-, two-, or three-dimensional quinoid polymers. The geometrical requirements of the metal ion and the presence of added "spacer" ligands dictate the type of polymer formed. PMID- 29712071 TI - C-S Bond Cleavage and C-C Coupling in Cyclopentadienylchromium Complexes To Give the First Dithiooxamide-Bridged and Doubly Dithiocarbamate-Bridged Double Cubanes: [Cp6 Cr8 S8 {(C(S)NEt2 )2 }] and [Cp6 Cr8 S8 (S2 CNEt2 )2 ]. AB - Thermolysis of the dithiocarbamate complex 1 led to the formation of the thiocarbenoid complex 2 and two double cubanes: 3, which has an intercubane Cr-Cr bond and a dithiooxamide ligand in the MU-eta2 ,eta4 bonding mode, and 4, which contains two dithiocarbamate ligands in the MU-eta1 ,eta2 bonding mode. PMID- 29712073 TI - Unusual Formation of an Azaphospholene from 1,3,4,5-Tetramethylimidazol-2-ylidene and Di(isopropyl)aminophosphaalkyne. AB - Intramolecular C-H insertion into the methyl group of the amino substituent of 1 is shown by density functional theory calculations to stabilize this intermediate in the formation of the novel 1:1 carbene-phosphaalkyne adduct 2. Compound 2 is formed in near quantitative yield by reaction of 1,3,4,5-tetramethylimidazol-2 ylidene with P=CNiPr2 . PMID- 29712072 TI - S2 N3+ : An Aromatic SN Cation with an N3 Unit. AB - Surprisingly stable is the first example of a binary six pi electron aromatic SN cation with an N3 unit, S2 N3+ . It can be isolated on a macroscopic scale when a large counter anion is present. The structure determined by X-ray investigations is in good agreement with theoretical data. The unequivocal identification was supported by Raman and infrared studies. The structure and bonding are discussed on the basis of MO (molecular orbital) and AIM (atoms-in-molecules) analysis. PMID- 29712074 TI - Regioselective Cross-Coupling Reactions as an Entry into Biologically Relevant Bithiazoles: First Total Synthesis of Cystothiazole E. AB - No problems have been encountered while using bithiazoles in Pd-catalyzed cross coupling reactions. It was thus possible to achieve the first synthesis of cystothiazole E (1) with a Suzuki coupling of the building blocks 2 and 3 as the pivotal C-C bond-formation step (94 % yield, TBDMS=tBuMe2 Si). The bithiazole 3 could be prepared very conveniently from 2,4-dibromothiazole by regioselective cross-coupling reactions. PMID- 29712075 TI - Two Mechanisms of Slow Host-Guest Complexation between Cucurbit[6]uril and Cyclohexylmethylamine: pH-Responsive Supramolecular Kinetics. AB - 20 times more rapid is the complexation of the organic ammonium ion receptor cucurbit[6]uril (CB6) with cyclohexylmethylamine than with the cyclohexylmethylammonium species. Within the narrow pH region around the pKa value of the amine, the complexation kinetics are accelerated but the binding constant remains essentially unaffected. In this region, the ammonium complex is formed through binding of the amine form followed by fast protonation and not through direct complexation of the ammonium form. Molecular dynamics calculations suggest that the amine form undergoes a direct inclusion into CB6 while the ingression of the ammonium form is retarded by the formation of an association complex, which reacts through a different, higher lying transition state to the inclusion complex. PMID- 29712076 TI - A New Method toward Microengineered Surfaces Based on Reactive Coating. AB - By using chemical vapor deposition (CVD) a range of substrates can be coated with a highly reactive polymer containing pentafluorophenol ester groups. A biotin modified pattern is generated on the substrate by microcontact printing; such a pattern interacts specifically with fluorescein-conjugated streptavidin and thereby the pattern becomes observable with fluorescence microscopy. PMID- 29712077 TI - Coil-Ring-Coil Block Copolymers as Building Blocks for Supramolecular Hollow Cylindrical Brushes. AB - Solvent-induced self-assembly of oligomer-substituted shape-persistent macrocycles leads to the formation of cylindrical aggregates, which have been fully characterized in solution. These aggregates, bound by nonspecific interactions, can be described as supramolecular hollow polymer brushes. PMID- 29712078 TI - Towards Synthetic Adrenaline Receptors-Shape-Selective Adrenaline Recognition in Water. AB - A new rationally designed receptor molecule binds adrenaline derivatives in water. Its binding pattern imitates the interplay of noncovalent interactions operating in the natural receptor. High shape selectivity is achieved for the slim dopamine skeleton, and leads to rejection of substrates with an alpha substituent, such as amino acid derivatives. PMID- 29712080 TI - Molecular Recognition of UDP-Gal by beta-1,4-Galactosyltransferase T1. AB - Saturation transfer difference (STD) NMR experiments reveal the binding epitopes of UDP-Gal and UDP-Glc bound to the glycosyltransferase beta4Gal-T1. Whereas the enzyme recognizes the galactose residue in UDP-Gal, it does not make any close contacts with the glucose residue in UDP-Glc. This observation explains why beta4Gal-T1 binds to UDP-Glc but is unable to transfer glucose to an acceptor substrate. PMID- 29712081 TI - A Transition Metal Complex of D-Glucose. AB - The most important monosaccharide-and not a single structurally characterized transition metal complex. That is the actual situation regarding basis data for understanding or designing metal-catalyzed reactions of D-glucose. This oversight is remedied with a palladium(II) complex and a structural analysis (see picture, en=ethylenediamine). PMID- 29712082 TI - Novel Calcium Half-Sandwich Complexes for the Living and Stereoselective Polymerization of Styrene. AB - Tackling tacticity: The first well-defined heteroleptic benzylcalcium complex initiates the living polymerization of styrene. Chain-end control results in a polymer enriched in syndiotactic sequences. Stereo errors arise from fast inversion of the chiral carbanionic chain end. Increasing the styrene concentration accelerates the insertion and leads to a considerable reduction of the stereo errors. PMID- 29712083 TI - 1-Silyl-1-boryl-2-alkenes: Reagents for Stereodivergent Allylation Leading to 4 Oxy-(E)-1-alkenylboronates and 4-Oxy-(Z)-1-alkenylsilanes. AB - Silylboryl reagents for organic synthesis: 1-silyl-1-boryl-2-alkenes (2) were prepared efficiently by gem-silylborylation of alpha-chloroallyllithium compounds from (dimethylphenylsilyl)(pinacolato)borane (1; see scheme, LDA=lithium diisopropylamide) and were demonstrated to allylate acetals and aldehydes in the presence of a Lewis acid to produce (E)-4-alkoxy-alkenylboronates. Heating the reagents with aldehydes in the absence of Lewis acid afforded (Z)-4-hydroxy alkenylsilanes stereospecifically. PMID- 29712084 TI - Electrophilic Fluorination Mediated by Cinchona Alkaloids: Highly Enantioselective Synthesis of alpha-Fluoro-alpha-phenylglycine Derivatives. AB - A decisive step forward: A one-step fluorination on modified cinchona alkaloids produced a new range of enantiopure fluorinating agents that display high enantioselectivities in electrophilic fluorination. The first enantioselective synthesis of N-protected alpha-fluorophenylglycine derivatives was achieved with an enantiomeric excess up to 94 % [Eq. (a); R=Et, CN; HMDS=hexamethyldisilazanide]. PMID- 29712085 TI - The XeCl+ Ion: [XeCl]+ [Sb2 F11 ]. AB - Chlorine-fluorine exchange in XeF+ leads to the orange crystalline salt [XeCl]+ [Sb2 F11 ]- , which is stable below -10 degrees C. Thus, the number of known noble gas monohalogen cations is now three and, as calculations show, is approaching the theoretically possible limit. The synthesis of other such compounds-with the exception of ArF+ , which remains a formidable task-seems unlikely. PMID- 29712086 TI - Magnetic Interactions as Supramolecular Function: Structure and Magnetic Properties of Hydrogen-Bridged Dinuclear Copper(II) Complexes. AB - The self-complementary coordination unit [Cu(H2 sabhea)]+ with a pentadentate amino alcohol as ligand enables the synthesis of the first triply hydrogen bridged dinuclear copper(II) complex. Proton transfer allows the reversible transformation between this triply and the corresponding doubly hydrogen-bridged form. Despite the very short hydrogen bond found for the triply bridged complex, its exchange coupling constant is much smaller than that for the doubly bridged complex. H3 sabhea=N-salicylidene-2-(bis(2-hydroxyethyl)amino)ethyl amine. PMID- 29712087 TI - 1,2-Bis(3-methyl-imidazolin-2-ylium iodobromoselenanide)ethane: Oxidative Addition of IBr at the Se Atom of a >C=Se Group. AB - Almost linear I-Se-Br groups with d(Se-Br)>d(Se-I) occur in 1?2 IBr, the first "T shaped" Se adduct with IBr, which was synthesized by the oxidative addition of IBr to 1,2-bis(3-methylimidazoline-2-selonyl)ethane (1) in MeCN. Density functional theory calculations indicate the intramolecular Br???H interactions as being responsible for the peculiar structural features of the I-Se-Br groups. PMID- 29712088 TI - First Example of Coexistence of Thermal Spin Transition and Liquid-Crystal Properties. AB - The rodlike FeIII complex of an N-alkyloxysalicylidenyl-N'-ethyl-N ethylenediamine ligand, shown as a computer model in the picture, is the first compound in which spin-crossover (SC) and liquid-crystalline (LC) properties coexist. This synergy should allow the magnetic and optical properties of SC compounds to be combined with the sensitivity of the LC state to electromagnetic fields. PMID- 29712089 TI - Parity Violation Dominates the Dynamics of Chirality in Dichlorodisulfane. AB - Meaninglessly small would be the effects from parity violation according to the traditional point of view on the structure and dynamics of chiral molecules; enantiomers would thus exist as symmetry-related structures, which are de facto stable because of very long tunneling times. With ClSSCl as the first example, electroweak and tunneling dynamics calculations demonstrate that the de lege asymmetry arising from the parity-violating energy difference DeltaEpv between the two enantiomers ((P)- and (M)-ClSSCl, the figure shows the torsional potentials) dominates by far over the tunneling splitting in the symmetrical case. These results are of fundamental interest for our concept of molecular chirality. PMID- 29712090 TI - NaBa2 O: A Fresh Perspective in Suboxide Chemistry. AB - Linear $?rm{^{1}_{?infty }}$[Ba4/2 O] chains of edge-sharing Ba4 O tetrahedra are separated by sodium atoms in the crystal structure of the new sodium barium suboxide NaBa2 O. The metal-rich compound is held together by a combination of ionic and metallic bonding according to the formulation Na+ (Ba2+ )2 O2- ?3 e- . PMID- 29712091 TI - Assembly of Encapsulated Transition Metal Catalysts. AB - Enforced ligand dissociation as a result of steric interactions between ZnII porphyrin units and the N atoms of pyridylphosphane ligands determines the catalytic properties of the encapsulated transition metal complexes. These assemblies show increased catalytic activity in the palladium-catalyzed Heck reaction and rhodium-catalyzed hydroformylation. M=transition metal catalyst. PMID- 29712092 TI - A Three-Dimensional Ferrimagnet with a High Magnetic Transition Temperature (TC ) of 53 K Based on a Chiral Molecule. AB - The transparent, double bridged-(R)-spiral three-dimensional polymeric complex K0.4 [Cr(CN)6 ][Mn(S)-pn](S)-pnH0.6 ((S)-pn=(S)-1,2-diaminopropane) has been synthesized and characterized (see X-ray structure; Cr: brown, Mn: red, C: gray, N: blue, K: green). Magnetic measurements on the complex show that the MnII and CrIII ions interact ferrimagnetically and magnetic transition occurs at 53 K (Curie temperature). PMID- 29712093 TI - "Biomimetic" Cascade Reactions in Organic Synthesis: Construction of 4 Oxatricyclo[4.3.1.0]decan-2-one Systems and Total Synthesis of 1-O Methylforbesione via Tandem Claisen Rearrangement/Diels-Alder Reactions. AB - A further demonstration of the value of "biomimetically" inspired synthetic strategies toward natural products is provided by the title reactions that were developed for the construction of 4-oxatricyclo[4.3.1.0]decan-2-one systems from prochiral aromatic precursors. This biomimetic cascade was applied to the synthesis of 1-O-methylforbesione (2) from the prenylated xanthone 1 in one pot. PMID- 29712094 TI - Self-Assembly of a Mixed-Valence Copper(II)/Copper(III) Dithiocarbamate Catenane. AB - Chemical oxidation of two preformed dinuclear copper(II) dithiocarbamate macrocycles leads to the formation of a novel mixed-valence tetranuclear copper(II)/copper(III) dithiocarbamate [2]catenane in near quantitative yield. Structural (see X-ray crystal structure), magnetic susceptibility, electrospray mass spectrometry, and electrochemical studies all support the formation of a CuII CuIII CuII CuIII tetranuclear catenane dication. PMID- 29712095 TI - Homoatomic Polyhedra as Structural Modules in Chemistry: What Binds Fullerenes and Homonuclear Zintl Ions? AB - Ligand-free homoatomic polyhedra are fascinating, not only because of their aesthetic simplicity but also because of their physical and chemical properties. They serve as electron reservoirs, show structural changes that depend upon the electron count, and can be used as "superatomic" building blocks for the targeted assembly of complex structures. Herein, the increasingly pronounced relationship between the fullerides and the nine-atom Zintl ions, the terels, is considered, even though one class of the compounds can be described as large polyhedra with classical bonds and the other as small clusters with nonclassical bonds (Wade rules). In both classes soluble salts with isolated ions, polymer chains, and binary phases with strong interactions between the ions occur. PMID- 29712096 TI - Organoclay Derivatives in the Synthesis of Macrocycles. AB - As an alternative to the rotaxane method, an organoclay can be used as a template for the efficient formation of macrocycles (ring in schematic representation) which are easily extracted from the clay interlayer space. The four-step synthesis involved preparation of a pillared clay from the dihydrochloride salt of p-xylylenediamine, insertion of neutral p-xylylenediamine into the pillared structure, reaction of the neutral p-xylylenediamine in the layers with isophthaloyl chloride and formation of the tetramide macrocycle, and extraction of the product from the clay. PMID- 29712097 TI - Sodium Tetra-tert-butylcyclopentaphosphanide: Synthesis, Structure, and Unexpected Formation of a Nickel(0) Tri-tert-butylcyclopentaphosphene Complex. AB - Forming a phosphorus envelope: The first structurally characterized cyclooligophosphanide ion [cyclo-(P5 tBu4 )]- to be obtained by a targeted synthesis reacts with [NiCl2 (PEt3 )2 ] by loss of a tBu group to give (eta2 3,4,5-tri-tert-butylcyclopentaphosphene)bis(triethylphosphane)nickel(0) (1). The previously unknown cyclopentaphosphene ring in 1 has an envelope conformation in solution and in the solid state, and the tBu groups adopt an all-trans configuration. PMID- 29712098 TI - Artificial Enzymes Formed through Directed Assembly of Molecular Square Encapsulated Epoxidation Catalysts. AB - Supramolecular complex formation imparts stability and substrate selectivity to a simple manganese-porphyrin-based epoxidation catalyst. Lewis acid/Lewis base directed assembly was used to encapsulate the epoxidation catalyst within a supramolecular square structure to form an enzyme-like catalyst system. The "molecular square" takes on the functions of the protein superstructure in an enzyme: it spatially protects the catalytic core from decomposition and induces reaction selectivity. PMID- 29712100 TI - A High-Throughput-Screening Method for the Identification of Active and Enantioselective Hydrolases. AB - A rapid and reliable test for the determination of hydrolase activity and enantioselectivity comprises the conversion of acetic acid released from acetates to NADH by using a commercially available enzymatic test-kit. The NADH is spectrophotometrically quantified in a microtiter plate format. PMID- 29712099 TI - [(OC)5 Cr=BSi(SiMe3 )3 ]: A Terminal Borylene Complex with an Electronically Unsaturated Boron Atom. AB - An extremely low-field shifted 11 B NMR signal at delta=204.3 and a very short Cr B distance of 187.8 pm characterize the title compound [(OC)5 Cr=B-Si(SiMe3 )3 ], which is the first borylene complex in which the boron atom is both coordinatively and electronically unsaturated. PMID- 29712102 TI - Preview. PMID- 29712101 TI - Heterocycles through Domino Reactions with Trimethyl Aconitate, a Versatile Synthetic Building Block. AB - The multitalented synthetic reagent trimethyl aconitate (1) is a renewable raw material with a high density of functional groups that up to now has only been scarcely used as a C6 building block. Domino reactions with 1 consisting of imine additions and intramolecular acylations provide simple access to heteropolycycles in one-pot reactions. For example, 1 reacts with N-methylbenzylidenamine (2) to give the spiro[pyrrolidinone-3,3'-dihydropyrrolinone] 3 in 40 % yield. PMID- 29712103 TI - Siloxyalkyne-Alkene Metathesis: Rapid Access to Highly Functionalized Enones. AB - Mechanistically intriguing participation of siloxyalkynes occurs in the intramolecular Ru-catalyzed metathesis with terminal alkenes (see scheme; Ms=methanesulfonyl). Combined with efficient protodesilylation, this process resulted in the development of a new method for the synthesis of highly functionalized enones starting from readily accessible acyclic precursors. Heterocyclic and polycyclic compounds were prepared efficiently, which illustrates the generality of this novel method. PMID- 29712104 TI - Calixarene-Porphyrin Supramolecular Complexes: pH-Tuning of the Complex Stoichiometry. AB - Self-aggregation of water-soluble pyridinium-substituted porphyrins with functionalized calixarenes leads to well-defined pH-tunable stoichiometries. Two assemblies with different porphyrin:calixarene ratios that crystallized at pH 2 and 6 have been structurally characterized. The Job plots of Soret band broadenings indicate that these structures are also preserved in solution. PMID- 29712105 TI - Host-Guest Chemistry Aids and Abets a Stereospecific Photodimerization in the Solid State. AB - A bis(dialkylammonium ion)-substituted stilbene derivative cocrystallizes with bisparaphenylene[34]crown-10 to form, in the solid state, a 2:2 host-guest complex wherein the stilbene double bonds are aligned with a relative geometry suitable for a stereospecific photochemical [2+2] cycloaddition. When irradiated with white light, this crystalline complex forms a single diastereoisomer of the corresponding cyclobutane derivative, the stereochemistry of which has been determined unambiguously in the solid state by X-ray crystallography to be syn anti-syn. PMID- 29712106 TI - Coordinated B2 Bridges in Porphyrins-Unexpected Formation of a Diborane(4)- from a Diborylporphyrin. AB - Fitting B2 bridges in porphyrins can be achieved by reaction of dilithiated porphyrins with B2 Cl4 as well as by reductive elimination from diborylporphyrins. Coordination takes place under rectangular distortion of the porphyrin framework. PMID- 29712107 TI - Computational Methods Facilitate the Assignment of Protein Functions. AB - From genome data to a successful drug: Many companies are eager to make this journey in the future, though roadmaps are still scarce. We comment on a novel method that promises to make the trip from gene to drug shorter and more effective by predicting protein functions from their three-dimensional structure. PMID- 29712108 TI - Testing Racemic Chiral Catalysts for Kinetic Resolution Potential. AB - An even-handed approach: by use of an enantiomerically enriched substrate and study of the changes in enantiomer ratio of substrate under pseudo zero-order conditions, racemic catalysts may be employed to determine whether the enantiomerically pure catalyst would be effective for kinetic resolution of the racemic substrate (see scheme; E=CO2 Me). PMID- 29712109 TI - Nanoparticles, Proteins, and Nucleic Acids: Biotechnology Meets Materials Science. AB - Based on fundamental chemistry, biotechnology and materials science have developed over the past three decades into today's powerful disciplines which allow the engineering of advanced technical devices and the industrial production of active substances for pharmaceutical and biomedical applications. This review is focused on current approaches emerging at the intersection of materials research, nanosciences, and molecular biotechnology. This novel and highly interdisciplinary field of chemistry is closely associated with both the physical and chemical properties of organic and inorganic nanoparticles, as well as to the various aspects of molecular cloning, recombinant DNA and protein technology, and immunology. Evolutionary optimized biomolecules such as nucleic acids, proteins, and supramolecular complexes of these components, are utilized in the production of nanostructured and mesoscopic architectures from organic and inorganic materials. The highly developed instruments and techniques of today's materials research are used for basic and applied studies of fundamental biological processes. PMID- 29712110 TI - T-Symmetrical Icosahedra: A New Type of Chirality in Metal Complexes. AB - A homoleptic metal complex with four tripodal tridentate ligands can have chiral tetrahedral T symmetry. An example of such a complex has been prepared, and the proposed highly symmetric, but chiral structure (see schematic representation, MP=mirror plane, R=NHCH2 PH) has been confirmed. PMID- 29712111 TI - Efficient, Catalytic, Aerobic Oxidation of Alcohols with Octahedral Molecular Sieves. AB - Mixed-valent manganese octahedral molecular sieves K-OMS-2 and H-K-OMS-2 are used to oxidize a wide range of alcohols with 100 % selectivity and 90-100 % conversion in most cases. The reaction is aerobic, catalytic, mild, efficient, stable, inexpensive, selective, and environmentally friendly. PMID- 29712112 TI - Immobilization of Olefin Metathesis Catalysts on Monolithic Sol-Gel: Practical, Efficient, and Easily Recyclable Catalysts for Organic and Combinatorial Synthesis. AB - Glass-bound Ru-based catalysts! Ru-containing glass pellets efficiently promote olefin metathesis reactions and are easily employed in syntheses of compound libraries. These robust catalysts are active in air and commercially available solvents, can be recycled up to 16 times, and removed from reaction mixtures with a simple pair of tweezers (minimal solvent waste). PMID- 29712113 TI - Reactions of Et4 Bi2 with tBu3 M (M=Al, Ga)-Synthesis of Complexes with a Bidentate Dibismuthane Ligand. AB - Functioning as a bidentate ligand toward Lewis acids, dibismuthane forms bisadducts of the type [R3 M]2 [Bi2 R$?rm{^{?prime }_{4}}$] with R3 M=tBu3 Al (1) and tBu3 Ga (2; structure depicted; R'=Et), which were characterized by single crystal X-ray diffraction. PMID- 29712114 TI - Cucurbit[n]uril Derivatives Soluble in Water and Organic Solvents. AB - Reminiscent of the ringed planet Saturn, new cucurbit[n]uril (CB[n]) derivatives CB*[5] and CB*[6] have rings decorating the "equator". The rings in this case are five- and six-fused cyclohexane rings, respectively (the structure of CB*[6] is shown). The remarkable solubility of the new CB[n] derivatives in water and organic solvents allows not only their unusual binding properties toward metal and organic ions in neutral water but also their applications in ion-selective electrodes to be studied. PMID- 29712115 TI - Pore-Size Engineering of Silicon Imido Nitride for Catalytic Applications. AB - High specific surface areas and adjustable pore sizes are outstanding characteristics of nanoporous silicon nitride based materials prepared by using oxygen-free molecular precursors in a novel template-assisted sol-gel approach. The nitrides represent a new class of shape-selective superbase catalysts (see, for example, the schematic representation of alkene isomerization). PMID- 29712116 TI - Watching the Photo-Oxidation of a Single Aromatic Hydrocarbon Molecule. AB - The photooxidation of single dye molecules can be followed by confocal fluorescence microscopy. The self-sensitized reaction with singlet oxygen leads to a suite of products, which may be differentiated spectrally. Tentative structures for certain photoproducts have been obtained from quantum-chemical calculations. PMID- 29712117 TI - A Novel Electrophilic Diamination Reaction of Alkenes. AB - A three-component electrophilic reaction transforms olefins into imidazoline and diamine derivatives. Rhodium(II) heptafluorobutyrate dimer (2 mol %) was utilized as the catalyst and N,N-dichloro-p-toluenesulfonamide (TsNCl2 ) and acetonitrile as the nitrogen sources. Modest to good yields (45-82 %) and high regio- and stereoselectivity were achieved. PMID- 29712118 TI - Millisecond Time Resolved Photo-CIDNP NMR Reveals a Non-Native Folding Intermediate on the Ion-Induced Refolding Pathway of Bovine alpha-Lactalbumin. AB - Aspects of the structure of the intermediate populated after 200 ms in the Ca2+ induced refolding of alpha-lactalbumin have been derived by time-resolved photo CIDNP NMR methods. Refolding at constant denaturant concentration was initiated by laser-induced ion release from photolabile chelators. The NMR data demonstrated that part of the polypeptide chain in the beta-domain of alpha lactalbumin samples adopt non-native conformations while a hydrophobic core of the alpha-domain is already formed. PMID- 29712119 TI - Fluorescence Quenching by Sequential Hydrogen, Electron, and Proton Transfer in the Proximity of a Conical Intersection. AB - Radical-pair disproportionation through sequential electron-proton transfer (Polanyi's harpoon) is one efficient mechanism leading to quenching fluorescence of n,pi*-excited states by hydrogen donors. This mechanism is demonstrated by ab initio MS-CASPT2 calculations and experimental investigations (photoproduct studies and EPR spin-trapping experiments) on the quenching of singlet-excited azoalkanes by chlorinated hydrocarbons. PMID- 29712120 TI - Pauling's Left-Handed alpha-Helix. PMID- 29712121 TI - Total Synthesis of Apoptolidin: Part 1. Retrosynthetic Analysis and Construction of Building Blocks. AB - No less than 30 stereogenic elements, a highly unsaturated 20-membered macrocyclic system, four carbohydrate units, and unique biological activity, make the natural occurring apoptolidin (1) a challenging synthetic target. The retrosynthetic analysis revealed five key building blocks-three for the construction of the macrolide ring B and two prospective pendant saccharide units which were synthesized in a highly convergent manner and then connected. Apoptolidin's rather labile nature proved particularly challenging in the final deprotection, purification, and characterization procedures. PMID- 29712122 TI - Synthesis of Exceptionally Stable Iron and Ruthenium eta1 -tetrahedro Tetraphosphorus Complexes: Evidence for a Strong Temperature Dependence of M-P4 pi Back Donation. AB - At variance with white phosphorus, the most reactive allotrope of the element, which is unstable and ignites spontaneously in air, the new eta1 -tetrahedro tetraphosphorus complexes [Cp*M(PR3 )2 (eta1 -P4 )]Y (M=Fe, Ru; Y=Cl, PF6 , BPh4 , BAr$?rm{^{?prime }_{4}}$; Cp*=C5 Me3 the structure of the [Cp*Fe(Ph2 PCH2 CH2 PPh2 )(eta1 -P4 )]+ ion is depicted) exhibit a surprising and unprecedented thermal stability and an astonishing reluctance to react with oxygen and other oxidants. PMID- 29712123 TI - Grafted Metal Oxide/Polymer/Carbon Nanostructures Exhibiting Fast Transport Properties. AB - A "grafting" method for creating new polymer/V2 O5 /carbon structures with nanodimensions results in materials that are chemically tailored to exhibit fast ion/electron transport. The rate responses are high enough to be of interest in applications such as lithium batteries and supercapacitors, and the concept is applicable to a variety of materials. The picture shows the atomic force microscopy image of V2 O5 /C-PEG nanoparticles on a mica surface. C PEG=polyethylene glycol functionalized carbon. PMID- 29712124 TI - Immobilization of pi-Assembled Metallo-Supramolecular Arrays in Thin Films: From Crystal-Engineered Structures to Processable Materials. AB - Layer-by-layer deposition of pi-assembled arrays of discrete metallo units with aryl tails and polystyrenesulfonate gives structurally well-defined thin films. The formation of these films, which is controlled by pi-pi interactions, metal ion coordination, and electrostatic interactions, bridges the gap between supramolecular crystal engineering and design of layered materials. PMID- 29712125 TI - Photochemical Activation of the N=N Bond in a Dimolybdenum-Dinitrogen Complex: Formation of a Molybdenum Nitride. AB - Photoinduced cleavage of the residual N-N bond in the dimetallahydrazone 1 (Mes=2,4,6-Me3 C6 H2 ) led to a transient monomeric nitrido complex, which reacts further with 1 to form 2. Compound 1 was synthesized by the reductive arylation of MoCl4 ?DME by MesMgBr under an N2 atmosphere. PMID- 29712126 TI - Which Structural Elements Are Relevant for the Efficacy of Neocarzinostatin? AB - While the general course of the mode of action of the antitumor agent neocarzinostatin (NCS) is clarified, it is still unclear which structural elements are relevant for the high efficacy of NCS. This question and the role of alternatively possible biradicals are addressed. PMID- 29712127 TI - Combined Effects of Metal and Ligand Capable of Accepting a Proton or Hydrogen Bond Catalyze Anti-Markovnikov Hydration of Terminal Alkynes. AB - A binding pocket for water is created in 1 by the imidazolyl phosphane ligands and the RuII center. Compound 1 proves to be an excellent catalyst for a highly selective anti-Markovnikov hydration of terminal alkynes to give aldehydes rather than isomeric ketones under near-neutral conditions (aldehyde-to-ketone ratio up to 1000:1). PMID- 29712128 TI - Serial [5+2]/[4+2] Cycloadditions: Facile, Preparative, Multi-Component Syntheses of Polycyclic Compounds from Simple, Readily Available Starting Materials. AB - Four new bonds and up to four new stereocenters are formed in the title reactions which allow the conversion of readily available starting materials into complex bicyclo[5.4.0]undecane derivatives. The reactions are performed in a single, simple operation that can be conducted on a preparative scale (100 mmol thus far). PMID- 29712129 TI - Samarium-Catalyzed Tandem Semipinacol Rearrangement/Tishchenko Reaction of alpha Hydroxy Epoxides: A Novel Approach to Highly Stereoselective Construction of 2 Quaternary 1,3-Diol Units. AB - Three contiguous stereocenters are constructed with high diastereoselectivity in a novel samarium-catalyzed tandem reaction of alpha-hydroxy epoxides 1 to give exclusively the C1,C2-anti isomers of 2 and 2'. This could lead to the development of a general procedure for the diastereoselective construction of 2 quaternary 1,3-diol units. PMID- 29712130 TI - Chaotropic Anions Strongly Stabilize Short, N-Capped Uncharged Peptide Helicies: A New Look at the Perchlorate Effect. AB - Regiospecific binding of perchlorate ions to the N-terminus of short-chained template-substituted polyalanine sequences in water dramatically increases helicity. PMID- 29712131 TI - Effects of a Side Chain Aromatic Ring on the Reactivity of Copper(I) Complexes with Dioxygen. AB - Stabilization of the bis(MU-oxo)dicopper(III) intermediate is achieved by using a bidentate N-donor ligand with pendent indole rings: N,N-bis[(3-indolyl)methyl]-N [(2'-pyridyl)methyl]amine (BIP). The intermediate decomposes to give products arising from N-dealkylation and a product with a spiro ring composed of two indole rings. This latter product probably results from a radical-coupling reaction. PMID- 29712132 TI - Allosteric Regulation of an HIV-1 Protease Inhibitor by ZnII Ions. AB - A sevenfold increase in the ability to bind to the dimerization interface of HIV 1 protease is observed by adding a ZnII ion to a tris(aminoethyl)amine (TREN) templating unit, which bears two peptides with similar sequences as those at the C and N termini of each monomer of the dimeric enzyme. It is suggested that the metal ion changes the conformation of the putative inhibitor. PMID- 29712133 TI - Regioselective Tetrametalation of Ferrocene in a Single Reaction: Extension of s Block Inverse Crown Chemistry to the d-Block. AB - Remarkably, four hydrogen atoms have been regioselectively removed from the 1,1',3,3'-positions of ferrocene in a single reaction leading to the formation of the new macrocyclic host-guest complex [{Fe(C5 H3 )2 }Na4 Mg4 {iPr2 N}8 ]. This novel addition to the s-block metal inverse crown family possesses a tetrasodium tetramagnesium amido (Na4 Mg4 N8 )4+ ring to complete a series of 8, 12, 16, and 24-membered rings. PMID- 29712134 TI - Highly Diastereoselective Intramolecular [1,2]-Stevens Rearrangements-Asymmetric Syntheses of Functionalized Isopavines as Morphinomimetics. AB - The power of visual imagery can reach Daliesque proportions in the mind's eye of the synthetic chemist. The topologically interesting isopavine nucleus, with an orthogonal orientation of two aryl groups, can be obtained as two diastereomeric structures, depending on the course of a [1,2]-Stevens rearrangement. When viewed as a constrained piperidine, a close spatial relationship with morphine (1) becomes apparent. Indeed, tetracyclic isopavine 2 exhibits morphine-like activity toward the human MU-opioid receptor. PMID- 29712135 TI - Photoluminescent Silicate Microsticks Containing Aligned Nanodomains of Conjugated Polymers by Sol-Gel-Based In Situ Polymerization. AB - Sticklike silicate materials containing aligned nanodomains of conjugated polymers were synthesized by sol-gel-based in situ polymerization of ammonium ion terminated diacetylenic surfactant monomers. Upon photoexcitation at 450 nm, the silicate microsticks emit a yellowish green luminescence centered at 550 nm. PMID- 29712136 TI - Total Synthesis of Apoptolidin: Part 2. Coupling of Key Building Blocks and Completion of the Synthesis. AB - No less than 30 stereogenic elements, a highly unsaturated 20-membered macrocyclic system, four carbohydrate units, and unique biological activity, make the natural occurring apoptolidin (1) a challenging synthetic target. The retrosynthetic analysis revealed five key building blocks-three for the construction of the macrolide ring B and two prospective pendant saccharide units which were synthesized in a highly convergent manner and then connected. Apoptolidin's rather labile nature proved particularly challenging in the final deprotection, purification, and characterization procedures. PMID- 29712137 TI - Electronic Semiconductor-Support Interaction-A Novel Effect in Semiconductor Photocatalysis. AB - The bandgap of CdS increases with decreasing coverage when CdS is supported on silica (see plot of Ebg against CdS concentration c). Likewise the photocatalytic activity of these heterogeneous photocatalysts increases, as illustrated by the relative rate (vrel ) of an organic addition reaction. CdS (A, vrel =1), CdS 50/SiO2 (B), CdS-30/SiO2 (C), and CdS-12/SiO2 (D). PMID- 29712138 TI - Synthetic Inhibitors of Cell Adhesion: A Glycopeptide from E-Selectin Ligand 1 (ESL-1) with the Arabino Sialyl Lewisx Structure. AB - Particularly selective methods are required for the synthesis of arabino sialyl Lewisx glycopeptides owing to the acid-labile beta-arabinopyranoside bond. It is important for the inhibition of cell adhesion that the arabino sialyl Lewisx glycopeptide 1, which contains the Gly 672 -Asp 681 sequence of the E-selectin Ligand 1 (ESL-1), binds ten times more strongly than sialyl Lewisx to E-selectin, although it is monovalent and does not contain L-fucose, which is considered essential. PMID- 29712139 TI - Metal-Catalyzed Selective Deoxygenation of Diols to Alcohols. AB - The internal OH group of 1,2-propanediol is selectively removed in the deoxygenation catalyzed by [{Cp*Ru(CO)2 }2 (MU-H)]+ OTf- (1, Cp*=C3 Me5 , OTf=trifluoromethanesulfonate; see scheme). This reaction provides a model for deoxygenation of polyols derived from carbohydrates, for use in alternative, biomass-based feedstock applications. An ionic mechanism is proposed that involves the dihydrogen complex [Cp*Ru(CO)2 (eta2 -H2 )]+ . PMID- 29712140 TI - A New Lyotropic Liquid Crystalline System: Oligo(ethylene oxide) Surfactants with [M(H2 O)n ]Xm Transition Metal Complexes. AB - Coordinated water molecules induce the aggregation and self-assembly of the lyotropic liquid crystalline phase formed from non-ionic surfactants Cn H2n+1 (CH2 CH2 O)m OH and transition metal aqua complexes ([Ni(H2 O)6 ](NO3 )2 , [Co(H2 O)6 ](NO3 )2 , [Zn(H2 O)6 ](NO3 )2 , [Cd(H2 O)4 ](NO3 )2 , and [Co(H2 O)6 ]Cl2 ) into hexagonal and/or cubic structures. While the NiII and CoII complexes undergo recrystallization and phase separation at high complex concentrations, the ZnII and CdII complexes form cubic phases above metal/surfactant molar ratios of 3.2/1 at room temperature. PMID- 29712141 TI - A Dual Channel Fluorescence Chemosensor for Anions Involving Intermolecular Excited State Proton Transfer. AB - A macrocycle containing an aminocoumarin fluorophore showed two different fluorescence emission bands on binding with certain anions. Proton transfer from the fluorophore excited state occurred depending on the basicity of the bound anion (see scheme, A- : anion) and this new pathway makes more-sensitive anion sensing possible. PMID- 29712142 TI - Chemical Reaction between Colliding Vesicles. AB - An organic reaction between two populations of vesicles, one containing a nucleophile (blue) and the other an electrophile (red), was examined kinetically. By comparing the rates with those of suitable controls, it was demonstrated that the electrophile is transferred during vesicle collisions, and a fast intra vesicular reaction ensues. PMID- 29712143 TI - An Intramolecular Case of Sharpless Kinetic Resolution: Total Synthesis of Laulimalide. AB - The microtubule-stabilizing antitumor agent laulimalide (1) has been obtained in by new synthetic route. The carbon skeleton was assembled by means of Julia Kocienski (C16-C17) and Horner-Wadsworth-Emmons (C21-C22) olefinations. Still Gennari olefination was used for the C2-C3 ring closure. The key step of the synthesis was a regioselective C16-C17 matched Sharpless asymmetric epoxidation. PMID- 29712144 TI - A New Screen for Combinatorial Catalysis; On-Bead Testing in Agarose Gel. AB - Catalytic beads are readily distinguished from inactive controls in a method which exploits the localizing potential of a gel. A useful variant employs an acid/base indicator to detect the pH change on ester hydrolysis. Precipitation of the acidified indicator (red) creates an especially strong contrast between active and inactive beads. PMID- 29712145 TI - Platinum Group Organometallics Based on "Pincer" Complexes: Sensors, Switches, and Catalysts. AB - Since the first reports in the late 1970s on transition metal complexes containing pincer-type ligands-named after the particular coordination mode of these ligands-these systems have attracted increasing interest owing to the unusual properties of the metal centers imparted by the pincer ligand. Typically, such a ligand comprises an anionic aryl ring which is ortho,ortho-disubstituted with heteroatom substituents, for example, CH2 NR2 , CH2 PR2 or CH2 SR, which generally coordinate to the metal center, and therefore support the M-C sigma bond. This commonly results in a terdentate and meridional coordination mode consisting of two metallacycles which share the M-C bond. Detailed studies of the formation and the properties of a large variety of pincers containing platinum group metal complexes have provided direct access to both a fundamental understanding of a variety of reactions in organometallic chemistry and to a range of new applications of these complexes. The discovery of alkane dehydrogenation catalysts, the mechanistic elucidation of fundamental transformations (for example, C-C bond activation), the construction of the first metallodendrimers for sustainable homogeneous catalysis, and the engineering of crystalline switches for materials processing represent only a few of the many highlights which have emanated from these numerous investigations. This review discusses the synthetic methodologies that are currently available for the preparation of platinum group metal complexes containing pincer ligands and especially emphasizes different applications that have been realized in materials science such as the development and engineering of sensors, switches, and catalysts. PMID- 29712146 TI - Design and Evolution of a Miniature Bcl-2 Binding Protein. AB - A major challenge for chemical biologists lies in the design of potent and selective ligands for protein surfaces. Here a protein grafting and evolution strategy is used to discover highly potent and specific miniature protein ligands for human Bcl-2 and Bcl-XL . Miniature proteins could be used to dissect, modulate, or analyze a single protein function, irrespective of the other functions the protein may regulate within the proteome. PMID- 29712147 TI - Methylenetriimidosulfate H2 CS(NtBu)32- -The First Dianionic Sulfur(VI) Ylide. AB - Through isoelectronic replacement of the oxygen atoms in SO42- ions by one CH2 and three NtBu groups one arrives formally at the dianion H2 CS(NtBu)32- , which has been isolated for the first time in the form of the sulfur(VI) ylide complex [(tmeda)2 Li2 {CH2 S(NtBu)3 }]. Deprotonation of the S-bonded methyl group in the triimidosulfonate MeS(NtBu)3- ion provides facile access in good yields. Hydrolysis favors the formation of the triimidosulfate [{(tmeda)Li2 [OS(NtBu)3 ]}3 ] and methane, and not, as one might expect, diimidomethylenesulfate and the amine. tmeda=Me2 NCH2 CH2 NMe2 . PMID- 29712148 TI - A New Class of Cyclic Hexamer: [Co6 L6 ]24- (H6 L=hexaazatriphenylene hexacarboxylic acid). AB - The construction of nanostructured polynuclear metal complexes with cyclic topologies, particularly those containing multifunctional ligands containing pi electronic structures, is of great interest since they can potentially lead to compounds with unusual electrochemical properties. A novel cyclic module with a hexacarboxylate derivative is described. The results show that the peripheral substituents not only control the electronic structure, but also influence its mode of coordination. PMID- 29712149 TI - Jacobus Henricus van 't Hoff; Hundred Years of Impact on Stereochemistry in the Netherlands. AB - The first Nobel Prize in Chemistry was awarded to the Dutch physical chemist Jacobus Henricus van 't Hoff in 1901, exactly hundred years ago. His impact on the chemical sciences is unparalleled with concepts ranging from tetrahedra to thermodynamics. He reshaped the discipline of chemistry at a very young age. Through the years, Van 't Hoff has inspired many Dutch scientists to perform research on novel stereochemical concepts. The picture shows stereochemical models, which Van 't Hoff produced himself. PMID- 29712150 TI - Synthesis of Isotopically Labeled (E)-beta,gamma-Unsaturated Esters with Total or High Diastereoselectivity by Using Samarium Diiodide. AB - A simple, efficient, highly diastereoselective method for preparing (E) alpha,delta-dideuterio-beta,gamma-unsaturated esters: SmI2 -promoted reduction/elimination of alpha-halo-beta-hydroxy-gamma,delta-unsaturated esters in the presence of D2 O. This provides the desired products in which the C-C double bond is generated with total or high diastereoselectivity. PMID- 29712151 TI - On-Line Liquid Chromatography Mass Spectrometry: A Useful Tool for the Detection of DNA Sequence Variation. AB - Indications of the occurrence of mutations can be gained from accurate mass measurements by electrospray ionization mass spectrometry. On-line coupling to liquid chromatography is essential for the application to real samples. By utilizing the coupled method, insertions, deletions, and point mutations are rapidly discovered in DNA restriction fragments and PCR products. PMID- 29712152 TI - Unusual Fluorenylidene-philic Interactions for Effective Conformational Induction. AB - Control of the conformation of the fluorenylidene moiety is achieved through an intramolecular interaction between the fluorenylidene moiety and the axial ligand during the oxidative addition and successive substitution of [PtII (fm)] to give [PtIV (X)(X')(fm)] (fm=9-fluorenylidenemalonate; see scheme). The conformation of the fm moiety can be effectively induced by the fluorenylidene-philicity of the axial X/X' ligands, OOCCH3 >OCH3 >OH. PMID- 29712154 TI - Design, Synthesis, and Biological Evaluation of alpha4 beta1 Integrin Antagonists Based on beta-D-Mannose as Rigid Scaffold. AB - A cyclic peptide role model was used for the design and synthesis of a new class of biologically active and alpha4 -selective integrin antagonists (e.g. 1) based on beta-D-mannose. These carbohydrate-based peptidomimetics were synthesized to include the functional groups of their cyclic peptide precursors without the redundant amide backbone. PMID- 29712155 TI - Chlorophyll Catabolism Leading to the Skeleton of Dinoflagellate and Krill Luciferins: Hypothesis and Model Studies. AB - Remarkable selectivity is exhibited in the photooxidation of 20-methoxychlorin methyl ester (1) to exclusively yield the C1-C20 bond cleaved product 2. This selectivity lends strong support to the hypothesis that a hydroxy or equivalent group at C20 directs the C1-C20 bond cleavage that transforms chlorophylls into krill and dinoflagellate luciferins. PMID- 29712156 TI - Direct Comparison of Hydrogenation Catalysis by Intact versus Fragmented Triruthenium Clusters. PMID- 29712157 TI - From Oligomers to Conducting Polymers of the Metal-Dinitrogen Functionality. AB - A new avenue is opened up in the potential use of dinitrogen. Oligomerization of the metalla-dinitrogen functionality leads to the formation of polymers based on a [-(Mes)3 W-N2 -] nq moiety. PMID- 29712158 TI - A Novel Concept in Combinatorial Chemistry in Solution with the Advantages of Solid-Phase Synthesis: Formation of N-Betaines by Multicomponent Domino Reactions. AB - Advantages of solid-phase and liquid-phase synthesis are combined in a new concept of combinatorial chemistry: a domino sequence comprising Knoevenagel and hetero-Diels-Alder reactions with subsequent hydrogenation starting from protected aminoaldehydes, 1,3-dicarbonyl compounds, and enol ethers leads to N heterocycles of high diversity with a betaine structure, which are isolated in highly pure form by precipitation with diethyl ether. Cbz=benzyloxycarbonyl, Bn=benzyl. PMID- 29712159 TI - A Versatile and High-Yield Route to Active and Well-Defined Catalysts [Ru(bisphosphane)(H)(solvent)3 ](BF4 ). AB - Simple and efficient: Protonation of [Ru(1,2:5,6-eta-cod)(eta6 -cot)] (cod=1,5 cyclooctadiene, cot=1,3,5-cyclooctatriene) with HBF4 ?Et2 O and then reaction with chiral bisphosphane ligands ($_{?rm PP}^{?frown }$=Me-DuPHOS, BINAP, Tol BINAP, JOSIPHOS) affords the corresponding [Ru($_{?rm PP}^{?frown }$)(H)(eta6 cot)]+ or [Ru($_{?rm PP}^{?frown }$)(1,2,3,4,5-eta-C8 H11 ')]+ (C8 H11 '=2,4 cyclooctadienyl; see scheme). Exposure of these cations to H2 in solvents (sol) such as acetone, methanol, and THF affords [Ru($_{?rm PP}^{?frown }$)(H)(sol)3 ]+ , which are catalysts for (amongst other things) enantioselective hydrogenations of alkenes. PMID- 29712160 TI - Multilayer Formation on a Curved Drop Surface. AB - Folded drops: A skinlike folded drop surface is formed by the coadsorption of two components from different phases at the chloroform/water interface. Both pure beta-lactoglobulin and mixtures of alpha-dipalmitoylphosphatidylcholine (DPPC) and beta-lactoglobulin can form the skinlike film; the lipid accelerates this process by coadsorption with the protein. Atomic force microscopy provided information on the morphology of the complex film and confirmed the formation of a multilayer film at the liquid/liquid interface. PMID- 29712161 TI - Ruthenium-Catalyzed Regioselective alpha-Alkylation of Ketones: The First Alkyl Group Transfer from Trialkylamines to the alpha-C Atom of Ketones. AB - A new reaction: A ruthenium-catalyzed transfer of an alkyl group from a trialkylamine to the alpha-carbon atom of a ketone leads in good yields to alpha alkylated ketones [Eq. (1)]. The reaction is applicable to a wide range of alkyl(alkyl), alkyl(aryl), and cyclic ketones, and in the case of unsymmetrical ketones it takes place regioselectively at the less hindered alpha-position. PMID- 29712163 TI - Half-Metallocene Tantalum Complexes Bearing Methyl Methacrylate (MMA) and 1,4 Diaza-1,3-diene Ligands as MMA Polymerization Catalysts. AB - Activation with AlMe3 at low temperature converts half-metallocene complexes of tantalum with methyl methacrylate (MMA) and diazadiene ligands such as [Cp*Ta(eta2 -Cy-DAD)(eta4 -MMA)] (structure shown) into effective catalysts for the polymerization of MMA. Polymerization is complete after 10 min at -20 degrees C and gives a poly(methyl methacrylate) of narrow polydispersity. Cp*=eta5 -C5 H5 , Cy-DAD=1,4-dicyclohexyl-1,4-diaza-1,3-butadiene. PMID- 29712162 TI - Unique Single-Atom Binding of Pseudohalogeno Ligands to Four Metal Ions Induced by Their Trapping into High-Nuclearity Cages. AB - MU4 end-on coordination (through the N atom) of the pseudohalogeno ligands X- =N3 and NCO- has been observed in the isostructural nonanuclear CoII cages with the general formula [Co9 {(2-C5 H4 N)2 CO2 }4 (O2 CMe)8 X2 ]; this mode is imposed by the trapping of anions X- into cavities formed inside the cage. The change of X- modulates the magnetic behavior of the cage from antiferromagnetic coupling to a ferrimagnetic high-spin ground state. PMID- 29712164 TI - Fronts, Waves, and Stationary Patterns in Electrochemical Systems. AB - Oscillatory behavior has been observed for almost all electrochemical reactions in a certain, although sometimes small, range of external parameters. Only in the past ten years has it been possible, however, to find a common explanation for the occurrence of these temporal self-organization phenomena of chemically completely different electrochemical reactions. The breakthrough was achieved because new methods and concepts, which had been developed in nonlinear dynamics to describe the spontaneous formation of order in various disciplines, could be applied. This development in turn was only possible because the underlying laws are universal at a certain abstract level. Oscillations are only one possible manifestation of nonlinear behavior. Examples of other features that are often closely associated with temporal instabilities are spatial structures and waves. Initiated by the theoretical progress and the development of new experimental techniques, spatial pattern formation in electrochemical systems has been targeted for investigations in the past few years. Based on these investigations, it can be predicted under which conditions temporal or spatial pattern formation can be expected. Furthermore, the possibility of predicting the occurrence of instabilities indicates that it might be feasible to exploit nonlinear effects to increase, for example, the yield of electrocatalytic reactions. Here we discuss physicochemical mechanisms that lead to pattern formation in electrochemical systems. At the same time, we stress the generic principles that are responsible for self-structuring processes in many chemical and biological systems. PMID- 29712165 TI - Hydrogen Bond in Molecules with Large-Amplitude Motions: A Rotational Study of Trimethylene Sulfide???HCl. AB - Two different conformers (axial (in the left picture) and equatorial (right)) are formed in a supersonic jet stream when trimethylene sulfide, a floppy molecule with a large-amplitude ring-puckering motion, is complexed to hydrogen chloride. The axial conformer is the most stable. The relaxation from the equatorial to the axial conformational has been observed using different carrier gases. PMID- 29712166 TI - A Direct and Efficient alpha-Selective Glycosylation Protocol for the Kedarcidin Sugar, L-Mycarose: AgPF6 as a Remarkable Activator of 2-Deoxythioglycosides. AB - The alpha-selective effect and potency of AgPF6 on readily prepared 2 deoxythioglycosides allows the direct attachment of a partially protected allo sugar, such as L-mycarose, to an advanced and hindered aglycon unit of kedarcidin. This method also permits access to other 2-deoxyglycosides in an expedient and mild manner. PMBM=p-methoxybenzyloxymethyl, Alloc=allyloxycarbonyl, TES=triethylsilyl. PMID- 29712167 TI - Chiral Molecular Recognition on Formation of a Metalloanthocyanin: A Supramolecular Metal Complex Pigment from Blue Flowers of Salvia patens. AB - The chirality of the sugar moiety is responsible for the chiral molecular recognition on formation of a metalloanthocyanin from Salvia patens. This mechanism was revealed by using the synthetic apigenin 7,4'-diglucosides derived from D- or L-glucose. The supermolecule consists of six malonylawobanin molecules (blue) coordinated to two Mg2+ ions (red) with an M-helical arrangement of six 7,4'-diglucoside molecules (yellow) intercalated. PMID- 29712168 TI - Evidence for the Existence of the McMillan Phase in a Binary System of a Metallomesogen and 2,4,7-Trinitrofluorenone. AB - Molecular self-organization, driven by attractive face-to-face interactions between 1 and 2,4,7-trinitrofluorenone, leads to the formation of an optically biaxial smectic A liquid crystalline phase-a long-predicted new state of ordered soft matter. PMID- 29712169 TI - Highly Enantioselective Regiodivergent and Catalytic Parallel Kinetic Resolution. AB - Chiral recognition leads to enantio- and regiodivergent reactivity: An unusual regiodivergent catalytic kinetic resolution has been accomplished for the first time in an organometallic reaction in which a C-C bond is formed. Chiral copper complexes of the non-racemic phosphoramidite ligand L* discriminate the enantiomers of semirigid vinyloxiranes (having a blocked s-cis or s-trans conformation) to give separable regioisomeric products with very high stereocontrol in a two-step process. PMID- 29712170 TI - Total Synthesis of the Macrolide Antibiotic 5,6-Dihydrocineromycin B. AB - Three building blocks are coupled convergently in the first total synthesis of the macrolide antibiotic 5,6-tetrahydrocineromycin B (1); the facial selective allylation of a methyl ketone is the key step of the synthesis. TBDMS=tert butyldimethylsilyl, PMB=p-methoxybenzyl. PMID- 29712171 TI - Adsorption-Mediated Electrochemical Sensing of Halides. AB - A new strategy for detecting halides is presented that employs gold electrodes plated to expose a monolayer of silver atoms. Cl- , Br- , and I- ions each adsorb onto this surface and stochastically produce electrochemical changes (see picture; upd=underpotentially deposited) in the stripping characteristic of the silver layer that reflect the identity and surface coverage of these halides. The latter provides measurements that relate to the solution concentrations of the halides. PMID- 29712172 TI - A Route to a Germanium-Carbon Triple Bond: First Chemical Evidence for a Germyne. AB - Photolysis of a diazogermylene generates a germylene-carbene species, a resonance form of a germyne. Support for the intermediacy of the triply bonded form in the trapping reaction with an alcohol is provided by the fact that the diazo precursor does not behave as a germylene and that its photolysis product does not react with carbene traps such as 2,3-dimethylbutadiene. Hence, this is the first chemical evidence for a germyne. Ar=2,6-(iPr2 NCH2 )2 C6 H3 ; R=Me, tBu. PMID- 29712173 TI - Fluoroprolines as Tools for Protein Design and Engineering. AB - The preference of the peptidyl-fluoroproline amide bond for the cis or trans conformation in the model compounds N-acetyl-4-fluoroproline methyl esters fully correlates with the thermostability of the related mutants of the model protein barstar. Thus, the (4S)-L-FPro mutants show a higher and the(4R)-L-FPro mutants a lower thermal stability than barstar. PMID- 29712174 TI - In Vivo Protein-Protein Interaction Assays: Beyond Proteins. AB - The scope of cell-based assays is being expanded to allow the detection of interactions between proteins and DNA, RNA, or small molecules. The yeast two hybrid assay, which normally detects protein-protein interactions, can be modified to detect interactions between ligands (the two dark yellow shapes in the diagram) and receptors (DHFR or GR). A small bridging molecule (made up of the ligands joined together) is used to join two fusion proteins (DHFR-DBD and AD GR), thereby activating the reporter gene. PMID- 29712175 TI - Highly Enantioselective Copper-Phosphoramidite Catalyzed Kinetic Resolution of Chiral 2-Cyclohexenones. AB - A variety of substituted 2-cyclohexenones, such as (R)-1, is obtained enantiomerically pure by employing the chiral copper-phosphoramidite complex [Cu(OTf)2 L*] as a highly efficient catalyst for their kinetic resolution (>99 % ee at 52 % conversion, selectivity S>200). These important building blocks can be obtained on a synthetically interesting scale, as was demonstrated by the successful multigram resolution of 5-methyl-2-cyclohexenone. Tf=trifluoromethanesulfonyl. PMID- 29712176 TI - H2 O2 -Dependent Fe-Catalyzed Oxidations: Control of the Active Species. AB - Manipulation of the coordination sphere of an FeII ion can be used to tune the balance between different catalytic pathways for oxidation (OH. versus iron-based oxidant; see scheme). This reinvestigation of Fenton chemistry uses the iron complex shown as a mechanistic probe. PMID- 29712177 TI - Synthesis of an Array Comprising 837 Variants of the hYAP WW Protein Domain. AB - Comprehensive structure-function analyses are possible with an array comprising more than 800 synthetic variants of a protein domain composed of 44 amino acids. This array was produced by SPOT synthesis on a cellulose membrane and successfully employed for a parallel ligand-binding assay. PMID- 29712178 TI - Intramolecular DNA Coiling Mediated by a Metallo-Supramolecular Cylinder. AB - In the groove! A tetracationic supramolecular cylinder, [Fe2 L3 ]4+ (L=C25 H20 N4 ), with a triple-helical architecture is just the right size to fit into the major groove of DNA and too big to fit into the minor groove. NMR spectroscopic data confirm that the cylinder binds in the major groove. Linear dichroism shows that very low loadings of [Fe2 L3 ]4+ have a dramatic bending effect on the DNA and atomic force microscopy images show that this is an intramolecular effect resulting in coils of DNA. PMID- 29712179 TI - sigma-Bishomoconjugation (sigma-Bishomoaromaticity) in 4C/3(2)e Cations-Scope and Limitations. AB - For the seco-dodecahedradiene 1, in which the distance dpipi between the carbon atoms of the two double bonds ranges from 2.90 to 3.20 A and pyramidalization angles Phi range from 14.9 to 35.5 degrees , the geometrical prerequisites for in plane (sigma)-homoconjugative (sigma-bishomoaromatic) electron delocalization in 4C/3(2)e cations could be better defined. Whilst the 4C/3e radical cation is persistent in a matrix, the 4C/2e dication in superacid medium is, at best, an intermediate en route to the stable bisallylic dication. PMID- 29712180 TI - Mid-Membrane Photolabeling of the Transmembrane Domain of Glycophorin A in Phospholipid Vesicles. AB - The tandem use of the photosensitive bola-amphiphile 1 (X=3 H) and cholesterol enabled the determination of the center of the transmembrane domain of glycophorin A (131 amino acid residues) in a membrane by selective functionalization of the protein within a phospholipid bilayer. PMID- 29712181 TI - Heterogeneous Dinuclear Rhodium(II) Hydroformylation Catalysts-Performance Evaluation and Silsesquioxane-Based Chemical Modeling. AB - Supported, air stable, and reusable hydroformylation catalysts have been prepared by immobilizing dinuclear rhodium(II) complexes bearing ortho-metalated arylphosphane ligands on amorphous silica and mesoporous MCM-41 supports by phosphane tethers. The oligosilsesquioxane model complex of the catalytic site 1 has been prepared analogously and characterized by single-crystal X-ray diffraction analysis. PMID- 29712182 TI - "Supramolecular" Solid-State Chemistry: Interpenetrating Diamond-Type Frameworks of U4+ Ions Linked by S,S'-Bidentate P2 S62- Molecular Rods in UP4 S12. AB - Inseparably interwoven are three independent polymeric diamond-type U(P2 S6 )2 frameworks in the structure of the title compound. The linear P2 S6 units act as molecular rods linking the pseudotetrahedral U4+ centers. U(P2 S6 )2 may be viewed as a coordination polymer which is formed from U/P/S melts by the solid state equivalent of the self-assembly reactions in solution. PMID- 29712184 TI - A New Photomagnetic Molecular System Based on Photoinduced Self-Assembly of Radicals. AB - An irreversible trans->cis isomerization of the imino group occurs during the irradiation of the new ferrocenyl Schiff-base polychlorotriphenylmethyl radical 1 by light. Low-temperature ESR investigations of frozen solutions revealed that the cis isomer exists as the (cis-1)2 dimer with strong antiferromagnetic interactions. The radical 1 constitutes an example of a one-way photoswitchable magnetic system in which a conversion between a doublet and a singlet ground state species is promoted by a photoinduced self-assembly process driven by the formation of hydrogen bonds. PMID- 29712185 TI - Remote Stereocontrol in Carbonyl Additions Promoted by Vinylstannanes. AB - syn to tin is the preferred mode of addition of organolithium reagents to the carbonyl group of cyclic ketones with a beta-stannylvinyl group. This remarkable remote control is a consequence of the anchoring of the organolithium reagent by the tin and carbonyl groups. PMID- 29712186 TI - Self-Assembling Cyclic Peptide Cylinders as Nuclei for Crystal Engineering. AB - A supramolecular recognition interface is formed through the self-assembly of cyclic D,L-peptides. Phenyl-phenyl interactions direct the solid-state organization of dimeric peptide cyclo[(-L-Phe-D-Me N-Ala-L-hPhe-D-Me N-Ala)2 ] (1) by forming clusters of edge-to-face contacts between dimers (shown left), which suggests that these peptide scaffolds may be useful subunits for crystal engineering. PMID- 29712187 TI - Color-Tuned Electroluminescence from Columnar Liquid Crystalline Alkyl Arenecarboxylates. AB - Simple ester derivatives of polycyclic arenes offer access to light-emitting diodes of nearly any visible color by making use of the good charge-transport properties of the columnar liquid crystals of these derivatives. The picture shows the orange-red electroluminescence of a light-emitting diode containing the perylene 3,4,9,10-tetracarboxylic acid ethyl ester (structure shown, R=Et). Through use of multiple layers of different esters light-emitting diodes with almost white luminescence can be obtained. PMID- 29712188 TI - The Novel Open-Framework Vanadium Silicates K2 (VO)(Si4 O10 )?H2 O (VSH-1) and Cs2 (VO)(Si6 O14 )?3 H2 O (VSH-2). AB - Silicate layers cross-linked by interlayer VO5 square pyramids form the basis of the three-dimensional frameworks of the structures of the title compounds (the structure of K2 (VO)(Si4 O10 )?H2 O is depicted). Alkali metal cations (*) and water molecules (?) occupy nonframework sites in these structures, which were synthesized hydrothermally. PMID- 29712189 TI - Rapid Access to Complex Molecular Architectures via o-Azaquinones. AB - A multitude of natural product like molecules such as 2 and 3 can be readily obtained from hydroxyketoamide 1. The versatile 1 is derived, via the intermediate o-azaquinone 4, from the Dess-Martin periodinane oxidation of the corresponding anilide. PMID- 29712190 TI - Orthogonal Photolysis of Protecting Groups. AB - The selective activation of photolabile protecting groups was made possible by the use of monochromatic light of suitable wavelength. This new approach allowed the orthogonal deprotection of a substrate containing several photosensitive groups. PMID- 29712191 TI - A Rationally Designed NH4+ Receptor Based on Cation-pi Interaction and Hydrogen Bonding. AB - A cage-type receptor binds an NH4+ ion by cation-pi interactions and hydrogen bonding with high sensitivity and selectivity, comparable or even superior to those of the natural antibiotic nonactin over a wide pH range. The high performance, low cost, and easy synthesis may offer practical applications for this receptor as an ammonium ion sensor. PMID- 29712192 TI - Base-Assisted Formation of Organozirconium Oxides with the [Zr6 (MU6 -O)(MU3 -O)8 ] Core Structure. AB - KH and the two-phase system liquid ammonia/toluene provide the basis for a new method for the synthesis of organozirconium oxides such as [{(EtMe4 C5 )Zr}6 (MU6 -O)(MU3 - O)8 ]?C7 H8 (the central inorganic core of the cluster is shown). Altering the solvent to mesitylene has no influence on the core structure of the resulting organozirconium oxide. PMID- 29712193 TI - A General Solution to the Modular Synthesis of Polyketide Building Blocks by Kanemasa Hydroxy-Directed Nitrile Oxide Cycloadditions. AB - A single, convenient reaction protocol and the same set of readily available starting materials suffice for the modular synthesis of all possible polypropionate diastereomers. This general method for the diastereoselective synthesis of syn, anti, and methyl ketone aldol adducts utilizes a powerful MgII mediated, hydroxy-directed nitrile oxide cycloaddition. The free hydroxy group provides an ideal synthetic handle enabling the rapid assembly of complex polyketide structures. TBS=tBuMe2 Si. PMID- 29712194 TI - Dehydrogenative Dimerization of Tin Hydrides Catalyzed by Ruthenium-Allenylidene Complexes. AB - Conjuring with conjugation: catalysis by ruthenium-allenylidene complexes has been observed for the conversion of tin hydrides into distannanes and dihydrogen. Alkyne or alkene groups (R) in conjugation with an aromatic ring are required for catalytic activity, providing an unusual example of control of metal-centered reactivity by a remote substituent. PMID- 29712195 TI - Separation of Spliceosome Assembly from Catalysis with Caged pre-mRNA Substrates. AB - Getting spliced? Pre-mRNA splicing is catalyzed by the spliceosome, a complex assembly of proteins and RNA, which forms in an ordered fashion on the substrate. If one of the residues of the substrate is caged with a photolabile o-nitrobenzyl group, the splicing reaction can be transiently blocked, until subsequent initiation by photolysis of the complexes. This RNA-caging approach effectively separates the spliceosome assembly from the catalytic reaction and allows the two processes to be studied independently. PMID- 29712196 TI - A 2',4'-Bridged Nucleic Acid Containing 2-Pyridone as a Nucleobase: Efficient Recognition of a C?G Interruption by Triplex Formation with a Pyrimidine Motif. AB - Significantly enhanced binding affinity to C?G base pairs without loss of sequence selectivity is achieved by using a nucleotide containing a 2-pyridone and a 2'-O,4'-C-methylene-bridged nucleic acid analogue (PB , see picture). The degree of stabilization of the triplex formed enables C?G interruptions in a homopurine?homopyrimidine double-stranded DNA to be detected. PMID- 29712197 TI - Self-Assembly of Nanometer-Scale Secondary Building Units into an Undulating Two Dimensional Network with Two Types of Hydrophobic Cavity. AB - A series of bowls separated by hour-glass-shaped channels characterizes the structure of the undulating two-dimensional coordination polymer that is prepared from a nanoscale secondary building unit (nSBU), which is formed by four square metal(II)carboxylate SBUs that have 1,3-benzenedicarboxylate units as 120 degrees spacers. PMID- 29712198 TI - Detection of TNT and Picric Acid on Surfaces and in Seawater by Using Photoluminescent Polysiloles. AB - Nitroaromatic explosives can be detected in a simple and rapid method by the quenching of the photoluminescence of fluorescent polysiloles. Quenching is achieved by electron transfer from the conduction band of the polysiloles to electron-poor molecules such as picric acid, nitrobenzene, 2,4-dinitrotoluene (DNT), and 2,4,6-trinitrotoluene (TNT). Dilute polymer solutions can also be employed as a forensic spray-on reagent to visualize TNT or picric acid residues under a UV lamp (see picture of the print of a nitrile-gloved hand that had been in contact with TNT). PMID- 29712199 TI - A Large 24-Membered-Ring Germanate Zeolite-Type Open-Framework Structure with Three-Dimensional Intersecting Channels. AB - Pores for thought: A new extra large germanate zeolite-type structure has been synthesized by using high-charge multiamine as a template in a pseudo-aqueous system (DMF/H2 O). The novel zeolite-type germanate with low framework density (11.1) has a 24- and 12-membered ring honeycomb array with three-dimensional intersecting channels. PMID- 29712200 TI - Synthesis of Apoptolidinone. AB - A CuI -mediated coupling of the northern and southern units and a ring-size selective macrolactonization are the key steps in the convergent, first total synthesis of apoptolidinone, the aglycon of the potential antitumor compound apoptolidin. (The wavey lines in the picture are the retrosynthetic disconnections.). PMID- 29712201 TI - A Striking, Multifaceted, Decalithium Aggregate with Carbanion, Organoamide, and Alkoxide Functionalities. AB - The three most important "superbase" anionic building blocks are contained in the striking decalithium aggregate in the structure of which a single lithium atom is surrounded solely by an amide, an alkoxide, and a carbanion. PMID- 29712202 TI - Macrocycles within Macrocycles: Cyclen, Cyclam, and Their Transition Metal Complexes Encapsulated in Cucurbit[8]uril. AB - Reminiscent of Russian Matrioshka dolls, tetraazamacrocycles (1,4,7,10 tetraazacyclododecane (cyclen) and 1 , 4 , 8 , 11 - tetraazacyclotetradecane (cyclam)) and their transition metal complexes are encapsulated in the cavity of cucurbit[8]uril (CB[8]). The X-ray crystal structure of the [Cu(cyclen)] in CB[8] complex (see picture; copper: green, oxygen: red, nitrogen: blue, carbon: gray) reveals a five-coordinate CuII center in a square-pyramidal environment with a water molecule bound to the axial position. PMID- 29712203 TI - Recent Advances in High-Resolution Solid-State NMR Spectroscopy. AB - Diverse complex systems may be studied by the new methods in solid-state NMR spectroscopy described herein. These methods use magic-angle spinning (MAS) on samples in oriented bilayers (right picture) and in orientationally disordered samples (left picture). Systems as diverse as uniformly 13 C,15 N-labeled proteins, model membrane systems, and silk, as produced by the silkworm, can be structurally characterized. PMID- 29712204 TI - A Luminescent Gold Ring That Flips Like Cyclohexane. AB - A chair of gold: Analogous to cyclohexane, the trinuclear gold ring [Au3 (PAnP)3 ][ClO4 ]3 (PAnP=9,10-bis(diphenylphosphino)anthracene) shows a chair conformation and diastereotopic axial and equatorial phenyl rings. Variable temperature and 2D EXSY NMR studies reveal that the gold ring undergoes cyclohexane-like ring inversion (enantiomerization) in solution. In addition, the gold ring exhibits intense excimeric emission at room temperature. - = anthracene ring system in PAnP, ? = ClO4- . PMID- 29712205 TI - Alkylative Preparation of alpha-Silylalkylmagnesium from R3 SiCHBr2 Using a Magnesate Reagent. AB - Magnesium-bromine exchange to provide the 1-bromo-1-silylmethylmagnesium species is mediated by treatment of dibromomethylsilane with an trialkylmagnesate reagent. The addition of a copper catalyst induces facile migration of an alkyl group to afford an alpha-silylalkylmagnesium compound, which furnishes alpha silyl ketones in good yield upon treatment with acyl chloride. PMID- 29712206 TI - A Novel Route to Fulvene Complexes of Titanium-Diastereoselective Complexation of Pentafulvenes to Cyclopentadienyltitanium Fragments. AB - An alternative to the known thermally induced syntheses of fulvene complexes of early transition metals is now provided by the direct reductive complexation of pentafulvenes to [CpTiCl] fragments. These generally highly diastereoselective reactions enable a broad variation of substitution patterns and establish an extensive subsequent chemistry. PMID- 29712207 TI - A Perfluorinated Nanosphere: Synthesis and Structure of Perfluoro-deca-B-methyl para-carborane. AB - Exhaustive fluorination of deca-B-methyl-para-carborane (1) furnishes perfluoro deca-B-methyl-para-carborane (2) almost quantitatively [Eq. (1)]. Compound 2 represents the first neutral perfluorinated sphere mimicking a "Teflon ball". The properties of 2 as well as its X-ray structure are discussed. PMID- 29712209 TI - High-Valent Manganese Corroles and the First Perhalogenated Metallocorrole Catalyst. AB - On pyrrole! The pyrrole-based corrole ligands can offer an alternative to porphyrin systems. The manganese corroles 1-4 are readily synthesized, undergo metal- not ligand-based redox chemistry, and 4 in particular shows impressive catalytic activity in the oxygenation of styrene with iodosylbenzene. PMID- 29712210 TI - Stable, Monomeric Imides of Aluminum and Gallium: Synthesis and Characterization of [{HC(MeCDippN)2 }MN-2,6-Trip2 C6 H3 ] (M=Al or Ga; Dipp=2,6-iPr2 C6 H3 ; Trip=2,4,6-iPr3 C6 H2 ). AB - A short Ga-N bond with double-bond character is displayed by the first monomeric imide of gallium, which was obtained by the reaction of [{HC(MeCDippN)2 }M:] (Dipp=2,6-iPr2 C6 H3 , M=Ga; see picture) with N3 -2,6-Trip2 C6 H3 (Trip=2,4,6 iPr3 C6 H2 ). The analogous aluminum (M=Al) compound is also readily available. PMID- 29712211 TI - Turning a Transition State into a Minimum-The Nature of the Bonding in Diplumbylene Compounds RPbPbR (R=H, Ar). AB - Quantum-chemical calculations at the B3LYP level show that the bulky ligands Ar*=2,6-Ph2 C6 H3 in Ar*PbPbAr* yield the trans-bent equilibrium structure shown as the lowest lying energy minimum form. There is no Pb-Pb pi bond in Ar*PbPbAr*. The parent compounds PhPbPbPh and HPbPbH have doubly bridged energy minima structures. PMID- 29712212 TI - Classification of Terpenoids according to the Methylerythritolphosphate or the Mevalonate Pathway with Natural 12 C/13 C Isotope Ratios: Dynamic Allocation of Resources in Induced Plants. AB - Plants utilize two different pathways for the biosynthesis of isopentenyl diphosphate, the universal building block of all terpenes. Application of compound-specific isotope-ratio mass spectrometry (GC-C-IRMS) to volatile terpenoids allows distinction between the pathways on the basis of natural 12 C/13 C ratios. PMID- 29712213 TI - Rate Enhancement and Enantioselectivity of the Jacobsen-Katsuki Epoxidation: The Significance of the Sixth Coordination Site. AB - New light on the origin of the high enantioselectivities achieved in the Jacobsen Katsuki epoxidation is shed by the results of density functional calculations. Axial ligation to the metal center not only enhances the epoxidation rate, but in addition leads to highly nonplanar, bent conformations of the active catalyst. PMID- 29712214 TI - Titanocene-Catalyzed Coupling of Amides in the Presence of Organosilanes To Form Vicinal Diamines. AB - A sequence of reduction, deoxygenation, and coupling steps results in a remarkable reaction, which represents an important new method for the synthesis of 1,2-diamines. The vicinal diamines are formed by the facile coupling of aromatic amides in the presence of titanocene catalysts and PhMeSiH2 . PMID- 29712215 TI - New Transmembrane Polyene Bolaamphiphiles as Fluorescent Probes in Lipid Bilayers. AB - Inspired by Archaebacterial lipids, transmembrane probes anchor a sensing fluorescent polyene with Angstrom resolution deep within a lipid layer. These new bolaamphiphiles are obtained in good yields from a double cross-coupling between esters with a terminal acetylene group and conjugated 1,omega-dihalopolyenes, followed by partial reduction of the triple bond. PMID- 29712216 TI - Carbon Nanofilaments in Heterogeneous Catalysis: An Industrial Application for New Carbon Materials? AB - Special carbon! Carbon nanofilaments differ from graphite and soot catalysts in their high stability during the oxidative dehydrogenation of ethylbenzene to styrene. The high yields of styrene achieved suggest that a first industrial application of carbon nanofilaments in catalysis is possible. PMID- 29712217 TI - Fabrication of Micro-Chain Mail by Simultaneous, Patterned Electrodeposition on a Plane and Multiple Cylinders. AB - Modeling with paper clips? No, a general method for the fabrication of complex three-dimensional (3D) microstructures is reported. The 3D structure is decomposed into substructures that can be patterned onto separate substrates and then these substrustures are joined to form the desired microstructure. The picture shows an optical micrograph of a free-linked nickel chain mail. PMID- 29712218 TI - Novel Templating Effect in the Macrocyclization of Functionalized Diynes by Zirconocene Coupling. AB - A zirconocene double act: The course of zirconocene-mediated macrocyclization is controlled by templating effects. In macrocyclizations of bipyridine-containing diynes, the zirconocene reagent [Cp2 Zr(py)(Me3 SiC=SiMe3 )] (1; py=pyridine) acts as both coupling and templating agent. Thus, by controlling the stoichiometry, dimeric or trimeric macrocycles are obtained. PMID- 29712219 TI - Polygons and Faceted Polyhedra and Nanoporous Networks. AB - Small rhombihexahedra and small cubicuboctahedra, namely faceted polyhedra, form the basis of two novel low-density framework solids that are afforded by the self assembly of molecular squares only or molecular squares and triangles, respectively. PMID- 29712220 TI - Polymerization of Ureidopyrimidinone-Functionalized Olefins by Using Late Transition Metal Ziegler-Natta Catalysts: Synthesis of Thermoplastic Elastomeric Polyolefins. AB - Mimicking nature: The central mechanisms of living organisms depend on the formation of specific hydrogen bonds. Advances in the areas of catalysis and supramolecular chemistry have been applied here for the synthesis of a novel class of elastomeric polyolefins with properties dependent upon strong intermolecular hydrogen bonding. PMID- 29712221 TI - Modular Self-Assembly of a Microporous Solid Based upon Mercuracarborand-4 and a New Bonding Motif. AB - Modular units of Li2 [B-octaiodo-12-mercuracarborand-4?I2 ] (Li2 [(HgC2 B10 H8 I2 )4 ?I2 ]) self-assemble forming infinite one-dimensional chains and microporous channels in the solid state. Self-assembly is directed by a unique B-I???Li???I-B intermolecular interaction involving electron-rich B-I vertices and electron deficient lithium cations. PMID- 29712222 TI - Self-Assembly of Uniform Spherical Aggregates of Magnetic Nanoparticles through pi-pi Interactions. AB - Nanoparticles of Fe3 O4 coated with 2-carboxyterthiophene (TTP-COOH) self assemble through pi-pi interactions to form uniform transparent microspheres. The interaction between individual particles is relatively weak and the spherical aggregates can be destroyed by sonication to leave the monodispersed nanoparticles. PMID- 29712223 TI - 3-Rhoda-1,2-dioxolanes through Dioxygenation of a Rhodium-Ethene Complex by Air. AB - Proposed as intermediates in the catalytic oxidation of olefins to ketones, 3 rhoda-1,2-dioxolanes (kappa2 C1 ,O2 -2-peroxyethyl rhodium complexes) have now been prepared by oxygenation of solid [(N4 -ligand)RhI (ethene)]PF6 with air. This process leads to stable isomeric 3-rhoda-1,2-dioxolanes A and B. Upon substitution of PF6- by BPh4- only isomer B is obtained. The X-ray structure of isomer B is presented. PMID- 29712224 TI - Formation of Aryl- and Benzylboronate Esters by Rhodium-Catalyzed C-H Bond Functionalization with Pinacolborane. AB - Direct borylation of C-H bonds in aromatic compounds can be achieved by using the efficient homogeneous catalyst precursor [RhCl(PiPr3 )2 (N2 )] and pinacolborane (HBpin; see scheme). High selectivity for the benzyl positions, observed for toluene, p-xylene, and mesitylene, was attributed to the formation of eta3 benzyl intermediates. PMID- 29712225 TI - Cyclohexylether delta-Amino Acids: New Leads for Selectivity Filters in Ion Channels. AB - Synthetic ion channels containing delta-amino acids can become cation selective! delta-Amino acids with a cyclohexylether unit were combined with structural motives from gramicidin A and led to channels with a NH4+ /K+ permeability ratio of >10/1. (The current trace for an NH4+ channel is shown.). PMID- 29712226 TI - Fluorinated Bis(enyl) Ligands by Metal-Induced Dimerization of Fluorinated Allenes. AB - Cobalt and manganese complexes provide access to novel fluoroallyl ligands: Fluorinated bis(enyl) ligands can be easily synthesized by metal-induced dimerization of 1,1-difluoroallene and tetrafluoroallene. By using octacarbonyldicobalt the coupling reaction occurs at the central carbon atom of the allene leading to the formation of fluorinated MU-(eta3 :eta3 -2,3 dimethylenebuta-1,4-diyl) ligands such as those in complex 1. Additional products arise from fluoride abstraction and CO insertion reactions. Decacarbonyldimanganese reacts with 1,1-difluoroallene under C-C coupling of the methylene group to give decacarbonyl-MU-(eta1 :eta1 -1,1,6,6-tetrafluoro-1,5 hexadiene-2,5-diyl)dimanganese. PMID- 29712227 TI - Nanoscale Push-Push Dihydrophenanthrene Derivatives as Novel Fluorophores for Two Photon-Excited Fluorescence. AB - Outperforming fluorescein by far, elongated fluorophores (e.g. 1) give rise to large two-photon absorption cross-sections sigma2 in the visible-red or NIR region and high quantum fluorescence yields Phi (see figure; GM = 10-50 cm4 s photon-1 ). This opens interesting prospects in the field of two-photon microscopy imaging of cell membranes. PMID- 29712228 TI - Linear Polymeric C702- Ions. AB - Under mild conditions, a linear polymeric (C702- )n fulleride was synthesized as single crystals which allow, for the first time, a complete structural analysis of a polymeric fulleride. Starting from the strongest "disturbance" of the cage geometry at the linkage sites, the pronounced alternation of the bond lengths decreases towards the middle of the C70 units (see Schlegel diagram of the C702- building block; color coding of the bond lengths [A]: blue <1.39, black 1.39 1.47, red 1.47-1.52 A, green >1.52). PMID- 29712229 TI - PASSflow Syntheses Using Functionalized Monolithic Polymer/Glass Composites in Flow-Through Microreactors. AB - A chemistapos;s wish finally becomes reality: microreactors for every synthetic laboratory! By precipitation polymerization various polymers are introduced into the irregular pore system of a porous glass rod. By embedding these rods into a housing, followed by functionalization and immobilization of reagents onto the polymer phase, versatile microreactors are obtained. With this apparatus, chemical transformations in solution can be performed, for example, a steroid derivatization. PMID- 29712230 TI - About the Antiaromaticity of Planar Cyclooctatetraene. AB - A negligible antiaromatic destabilization is found in planar D4h 1,3,5,7 cyclooctatetraene with alternating bond lengths. The same is also true for the delocalized D8h structure, which has a stabilization energy of only 3-4 kcal mol 1 . According to quantum-chemical calculations, the ground state of 1 is expected to be the planar C2v -symmetric (1,1) singlet diradical 1'. PMID- 29712231 TI - Helical Chiral Polyisocyanides Possessing Porphyrin Pendants: Determination of Helicity by Exciton-Coupled Circular Dichroism. AB - Exciton-coupled circular dichroism of the porphyrin Soret band of triblock copolymers prepared from chiral isocyanide monomers and an achiral tetraphenylporphyrin derivative (TPP) provides a novel method for determining the helical sense of poly(aryl isocyanide)s (see the schematic representation of the structure). PMID- 29712232 TI - Silynes (RC=SiR') and Disilynes (RSi=SiR'): Why Are Less Bonds Worth Energetically More? AB - Bond stabilization through bending! Valence bond analysis shows that the sigma frames of 1-3 (1: E = Si, E' = C; 2: E = E' = Si; 3: E = E' = C) are stabilized by trans bending (B), while pi bonding is weakened. In acetylene (3) pi bonding overrides the sigma frame and establishes a linear molecule (3 L). In contrast, the sigma frames dominate in silyne (1) and disilyne (2) and lead to trans-bent structures (1 B and 2 B). PMID- 29712233 TI - "Nanoobjects" by Self-Assembly Concomitant with Modifications under Alterable Boundary Conditions: Incorporation of Paramagnetic Metal Centers (Cu2+ ) in Ring Shaped Molybdenum-Oxide Based Clusters. AB - Are adaptations in the nanocosmos observable? Or in other words, can formation or self-assembly of nanoparticles be achieved with a variety of characteristic modifications of a parent structure based solely on the variation of boundary conditions? This possibility exists for the ring-shaped nanostructured giant molybdenum clusters-known as "big wheels"-in which well-defined transformations and reactions can be observed at various well-defined positions on the surface and even internally. The integration of magnetic copper centers into cavities (violet tetrahedra) of exactly the right size is described. PMID- 29712234 TI - The Zipper-Mode Domino Intramolecular Diels-Alder Reaction: A New 0->ABCD Strategy for Steroids and Related Compounds. AB - Four C-C bonds, four rings, and eight contiguous stereocenters in one go! Tetracyclic product 2, which results on warming simple acyclic precursor 1 with a mild Lewis acid, is formed through an efficient and highly stereoselective domino sequence of two intramolecular Diels-Alder reactions. Pharmacologically important norsteroids are just one potential application of this extremely effective approach to fused polycyclic systems. PMID- 29712235 TI - Lamellae-Nanotube Isomerism in Hydrogen-Bonded Host Frameworks. AB - Inclusion compounds based on a flexible hydrogen-bonded sheet of guanidinium ions and sulfonate moieties display lamellar and tubular architectures, depending on the guest and the organic substituent attached to the sulfonate. The observed single-crystal architectures resemble lamellar and hexagonal microstructures in block copolymers and surfactant assemblies. PMID- 29712236 TI - Gold Nanoparticles with Covalently Attached Polymer Chains. AB - "Living"/controlled radical polymerization according to the atom transfer radical polymerization mechanism is a suitable method for the graft-polymerization of nanoparticles. With this method, in which the core nanoparticles remain unchanged, the chain length and therefore the thickness of the polymer shell can be adjusted. PMID- 29712237 TI - Intrinsic Bond Strengths of Multiple C-C, Si-Si, and C-Si Bonds. AB - Really a triple bond? According to quantum-chemical calculations of inverted Hessian matrices (compliance matrices), the strength of the C=Si bond in I is only marginally stronger than the C=Si bond in silaethylene (II). Real-space force constants overestimate the C=Si bond in I and should therefore be abandoned as bond strength descriptors. PMID- 29712238 TI - Isolation and Characterization of the Osmium(V)-Imido Complex [OsV (Tp)(Cl)2 (NH)]. AB - Trapped by a proton: In the formation of OsII -N2 -OsII dimers, an OsV =N complex has been invoked as a transient intermediate but not isolated. Herein conditions are reported that allow OsV =N species to be trapped either in acidic, aqueous solutions as a neutral osmium(V) imido complex (OsV =NH, see structure) or in non aqueous solvents, with high concentrations of added reductant, by N- ion transfer before coupling can occur. PMID- 29712239 TI - Yttrate Metathesis: Ligand Design for the Controlled Synthesis of f-Block Heterobimetallic Compounds. AB - The use of a Me2 Si-bridged amido-cyclopentadienyl ligand containing pendant pyridine functionality allows clean "yttrate metathesis" to occur and the synthesis of the unusual C2 -symmetric Y/Cu bimetallic compound 1. PMID- 29712240 TI - Functionalized DNA: A New Replicable Biopolymer. AB - New DNA: By enzymatic polymerization of base-modified nucleoside triphosphates, a functionalized DNA (fDNA; see picture) was generated in which every base bears an additional amino acid like residue, thus mimicking the functional group repertoire of peptides on a nucleic acid backbone. These modified oligonucleotides can in turn serve as templates for polymerase chain reaction amplification, thus utilizing fDNA as a novel class of biopolymers for in vitro selection techniques. PMID- 29712241 TI - X-ray Crystal Structure of a Bisubstrate Inhibitor Bound to the Enzyme Catechol-O methyltransferase: A Dramatic Effect of Inhibitor Preorganization on Binding Affinity. AB - With an IC50 value of 9 nM, 1 is the most potent known disubstrate inhibitor for catechol-O-methyltransferase (COMT). Inhibition of COMT is of significant interest in the therapy of Parkinsonapos;s disease since it ensures that a larger percentage of orally administered L-dopa reaches-in the form of dopamine-its target in the brain. The X-ray crystal structure of a complex formed by COMT and 1 has been solved at 2.6-A resolution. PMID- 29712242 TI - Steric Turnoff of Vibrationally Mediated Negative Differential Resistance in a Single Molecule. AB - Negative differential resistance (NDR), mediated by vibrational excitation, is strongly dependent on molecular structure and dynamics, according to scanning tunneling microscopy on Cu(001)-bound pyrrolidine and N-methylpyrrolidine at 9 K. Tunneling electrons cause the former to switch between conformations I and II, so that NDR is observed. The methyl group of of the latter compound restricts it to a single conformation, and a linear current-voltage characteristic results. PMID- 29712243 TI - Polyphenylene Dendrimers as Sensitive and Selective Sensor Layers. AB - Rigid, dendritic poly(paraphenylene)s are excellently suited as sensitive and selective coatings for gravimetric sensors (quartz microbalances), since they incorporate guest molecules reversibly into their interior voids. The variety of their potential designs allows an optimal match of these multitalented hosts to the guests (analytes) to be monitored. PMID- 29712244 TI - Chiral Recognition of O-Phosphoserine by Mass Spectrometry. AB - Identification and quantification of the enantiomeric excess of O-phosphoserine (OP Ser) residues from post-translational modified proteins is now possible by the application of a very reproducible and sensitive mass spectrometric method. This technique is based on the different mass-spectral fragmentation patterns of the diastereomeric cluster ions generated in water/methanol solutions of the analyte (OP SerD/L ) with a suitable chiral compound (OP ThrL ) by collision induced dissociation (CID; see mass spectra). PMID- 29712245 TI - Carbon Dioxide Fixation by Binuclear Complexes with Hydrophobic Binding Pockets. AB - The unusual reactivity of binuclear complexes of the macrocyclic ligand (LR )2- can be attributed to the hydrophobic microenvironment about the free coordination site. The new compounds can be used for the stabilization of reactive intermediates or for the activation of small molecules such as carbon dioxide. PMID- 29712246 TI - Experimental Detection of Tetraoxygen. AB - Although suggested by Lewis in 1924 and theoretically predicted, O4 has so far proved extremely elusive, defying all attempts at the positive experimental detection of a bound, intact O4 species. The search has now been brought to an end by the conclusive proof, achieved by neutralization-re-ionization mass spectrometry, of the existence of intact O4 as a gas-phase species with a lifetime in excess of 1 MUs, whose dissociation requires overcoming a barrier of the order of 10 kcal mol-1 . PMID- 29712247 TI - An Analytical Approach for a Comprehensive Study of Organic Aerosols. AB - Unknown products identified precisely: The coupling of liquid chromatography to NMR spectroscopy, mass spectrometry, and infrared spectroscopy and the use of high-resolution mass spectrometry is utilized to investigate the formation of atmospheric-relevant organic aerosols. The investigation focussed on the gas phase reaction of alpha-pinene with ozone and the subsequent identification of the reaction products by the coupled analytical techniques. PMID- 29712248 TI - Discrete Mixed-Valence Metal Chains: Iridium Pyridonate Blues. AB - Binuclear complexes with head-to-tail (HT) configurations are appropriate for building tetrametallic chains, contrary to previous speculations. Moreover, the isolated HT,HH tetrametallic species are converted into the thermodynamically more stable HH,HH compounds. PMID- 29712249 TI - Stereocontrolled Total Synthesis of (+)-Altohyrtin A/Spongistatin 1. AB - As an exceptionally potent antimitotic macrolide, altohyrtin A/spongistatin 1 shows great promise in cancer chemotherapy but its extreme scarcity in the natural sponges has halted its further preclinical development. A highly stereocontrolled total synthesis, which exploits boron-mediated aldol bond constructions, has been realized to provide, for the first time, a useful amount of synthetic material. PMID- 29712250 TI - Redox Activation of a Polyaniline-Coated Cantilever: An Electro-Driven Microdevice. AB - Bent by oxidation! A polyaniline (PAn, blue) coated cantilever acts as an electro driven microdevice. Reversible oxidation/reduction of the PAn results in reversible deflection of the cantilever originating from the electrostatic repulsion of the charged polymer chains of PAn2+ (green). PMID- 29712251 TI - Structure of Ca13 Cd76 : A Novel Approximant to the MCd5.7 Quasicrystals (M=Ca, Yb). AB - The closest cubic approximant to the MCd5.7 (M = Ca, Yb) quasicrystals known so far, namely Ca13 Cd76 , was obtained by high-temperature reaction of the elements. It exhibits a new type of structure for intermetallic compounds with an unprecedented arrangement of triacontahedral clusters, which could prove useful in modeling the structures of the MCd5.7 quasicrystals. PMID- 29712252 TI - Polystyrene-Bound Tetrafluorophenylbis(triflyl)methane as an Organic-Solvent Swellable and Strong Bronsted Acid Catalyst. AB - Several advantages over inorganic solid acids such as zeolites and perfluororesinsulfonic acids such as Nafion are offered by the new reusable polystyrene-bound catalyst 1: a broader range of applications, improved yields, improved selectivity, and milder reaction conditions. Tf = F3 CSO2 . PMID- 29712253 TI - Nitrogen Photofixation at Nanostructured Iron Titanate Films. AB - Mild reducing agents such as ethanol, sodium formate, and humic acids effect the photofixation of nitrogen to ammonia and nitrate at thin films of nanostructured iron titanates. The reaction occurs in the presence of air and light, but is inhibited by the presence of carbon monoxide. PMID- 29712254 TI - [12.12]Paracyclophanedodecaynes C36 H8 and C36 Cl8 : The Smallest Paracyclophynes and Their Transformation into the Carbon Cluster Ion C36. AB - The smallest [n.n]cyclophyne known, [12.12]paracyclophanedodecaynes C36 H8 and C36 Cl8 , were generated by [2+2] cycloreversion of its precursor under photolytic and mass spectrometric conditions. The stepwise loss of chlorine atoms from the anion of the octachloro derivative C36 Cl8- produced a carbon cluster anion C36- in the gas phase. PMID- 29712255 TI - Fundamental Zeolite Crystal Growth Rates from Simulation of Atomic Force Micrographs. AB - An accurate model of the surface growth of one of the most important industrial zeolites, zeolite A, has been created. Comparison of the simulation with experimental data in the form of atomic force micrographs highlights the non diffusion-limited nature of zeolite growth and provides the first ever quantification of fundamental crystal growth processes in zeolites. PMID- 29712256 TI - alpha(1-3)-Galactosyltransferase Inhibition Based on a New Type of Disubstrate Analogue. AB - How do retaining glycosyltransferases function? To answer this question, UDP-Gal and galactose were covalently linked to form disubstrate analogues 1, of which surprisingly 1beta and not 1alpha inhibited alpha(1-3)-galactosyltransferases very well. An understanding of this inhibition is a key to the pharmacological prevention of hyperacute rejection in pig to primate xenotransplantation. PMID- 29712257 TI - Solvothermal Synthesis of a 24-Nuclear, Cube-Shaped Squarato-oxovanadium(IV) Framework: [N(nBu)4 ]8 [V24 O24 (C4 O4 )12 (OCH3 )32 ]. AB - Polydentate bridging ligands can be used to link small polyoxo-alkoxo-metalate units to form supramolecular clusters. In the title compound, twelve MU4 bridging squarato groups connect eight trinuclear methoxo-oxo-vanadate units to form a tetradodecanuclear cubic framework, in whose cavity six n-butyl groups of the tetra-n-butylammonium cations are anchored. PMID- 29712258 TI - 1,6-Methano[10]annulene has a Delocalized Structure in S0 and S1 : High Resolution Spectroscopy in a Supersonic Jet. AB - For the ground state of the Huckel aromatic ring 1,6-methano[10]annulene (MA) both a localized and a delocalized structure have been proposed in the past, depending on the theoretical methods used. A high-resolution electronic spectrum in a supersonic jet unambiguously shows that isolated, ultracold MA has a delocalized structure in its S0 ground state as well as in its S1 excited state. PMID- 29712259 TI - Synthesis of a 10-Membered Carbocycle By Olefin Metathesis. AB - Even 10-membered rings can be obtained by ring-closing metathesis (RCM). The synthesis of carbocycle B by RCM, which is the key step in the synthesis of the pine-resin sesquiterpene 1,6-germacradien-5-ol, was improved by protecting the hydroxy group of the precursor bisolefin A as a bulky tert-butyldimethylsilyl ether and by complexing its carbonyl group with Ti(OiPr)4 . PMID- 29712261 TI - A New Type of Heteropolyoxometalates formed from Lacunary Polyoxotungstate Ions and Europium or Yttrium Cations. AB - Four lacunary PW9 O349- ions (blue polyhedra) are held together by eight MIII (M = Y, Eu) ions and seven W atoms that form a [M8 W7 O30 ]6+ network (center) in the novel heteropolyoxometalates [(PM2 W10 O38 )4 (W3 O14 )]30- . In the solid state, the anions interact strongly with K+ countercations, which thus play a role in the formation of this particular structure. PMID- 29712262 TI - Sidewall Functionalization of Carbon Nanotubes. AB - The addition of nitrenes, nucleophilic carbenes, and radicals affords soluble, individual single-walled nanotubes (shown here is a carbene-functionalized adduct) by covalent sidewall functionalization. The characterization, a fundamental problem in nanotube chemistry, is simple to carry out. PMID- 29712263 TI - A Blue Luminescent Star-Shaped ZnII Complex that Can Detect Benzene. AB - Binding benzene: A novel blue luminescent star-shaped ZnII complex has been found to be able to detect benzene selectively by fluorescent quenching. This is attributed to the compoundapos;s high affinity to benzene, as demonstrated in the crystal structure (see picture; yellow: benzene, red: zinc). PMID- 29712264 TI - First Desymmetrization of a Centrosymmetric Molecule in Natural Product Synthesis: Preparation of a Key Fragment in the Synthesis of Hemibrevetoxin B. AB - Exploitation of molecular symmetry can greatly improve the efficiency of syntheses. The symmetry embedded in the centrosymmetric AB dioxepane fragment of hemibrevetoxin B was exploited for the first time in the preparation of an established intermediate in its total synthesis. Desymmetrization of the centrosymmetric diepoxide 1 by enantioselective epoxide hydrolysis followed by acetonization gave the known synthetic intermediate 2. PMID- 29712265 TI - No Polymerization with Metallocenes in Water?-A Prejudice is Refuted. AB - Water-sensitive catalysts work in water! Metallocene catalysts that normally have to be handled under the strict exclusion of air and moisture, for example [TiCp*(OMe)3 ] (1, Cp*=pentamethylcyclopentadienyl), are successfully employed in the aqueous emulsion polymerization of styrene to syndiotactic polystyrene. The catalyst is encapsulated inside the monomer droplets and thus protected against attack by water. PMID- 29712266 TI - Enantiomeric Discrimination in a Reiterative Domino Coupling Process: CuI mediated Syn Cyclotrimerization of Racemic Polycyclic Trimethylstannyl Bromonorbornadienes. AB - The challenge to generate all-syn architecture has prompted the synthesis of syn cyclotrimers 2 from racemic bromotrimethylstannyl polycyclic alkenes 1. The syn selective CuI -catalyzed cyclotrimerization process is both regio- and chemoselective. PMID- 29712267 TI - Synthesis of the ABCD Ring System of Azaspiracid. AB - Previously attempted spirocyclizations to form the ABCD ring system of azaspiracid (1) have proven unsuccessful owing to the anomeric effects that favor the formation of the undesired 13S diastereomer. By the use of a hydrogen bond donor as an auxiliary group, such anomeric effects were successfully overcome. Thus, the first synthesis of the ABCD ring system of azaspiracid with the proper 13R configuration of the C13 stereocenter was achieved. PMID- 29712268 TI - A Very Rigid Bis-bispidine Tetraazamacrocycle and Its Unusual Copper(II) Complex. AB - The absorption maximum of the orange-colored copper(II) complex of the cyclam derivative L, which has two 3,7-diazabicyclo[3.3.1]nonane units, occurs at 390 nm. This is the lowest value for a copper(II) tetraamine known so far, and indicates an extremely strong ligand field. This maximum is shifted by 110 nm (5740 cm-1 , 68 kJ mol-1 ) to lower wavelengths than that of the parent compound [Cu(cyclam)]2+ ; cyclam=1,4,8,11-tetraazacyclotetradecane. PMID- 29712269 TI - Working Supramolecular Machines Trapped in Glass and Mounted on a Film Surface. AB - Two surface-tethered nanomachines have been constructed at a supramolecular level by employing cylinders of the pi-electron deficient tetracationic cyclophane, cyclobis(paraquat-p-phenylene) (blue), inside which polyether pistons incorporating pi-electron rich dioxynaphthalene units (red and pink) can be induced to move when reductants are supplied either by chemicals or from a light source with 9-anthracenecarboxylic acid (yellow) as the photosensitizer and ethylenediaminetetraacetate (green) as a sacrificial reagent. PMID- 29712270 TI - The First Inorganic "Tennis Ball" Encapsulating an Anion. AB - New balls please! Reaction of Cu(BF4 )2 with [(dach)PtII ] (dach=trans (+/-)-1,2 diaminocyclohexane) and bis(ethylthio)methylenepropanedioate (BETMP) gave [{(dach)Pt(BETMP)}2 Cu(BF4 )2 ] (1; shown schematically). Dimerization of 1 in methanol leads to the first inorganic "tennis ball" 2 [Eq. (1)]. A BF4- ion is encapsulated in the cavity of 2. PMID- 29712271 TI - Bis(germavinylidene) [(Me3 SiN=PPh2 )2 C=Ge->Ge=C(Ph2 P=NSiMe3 )] and 1,3 Dimetallacyclobutanes [M{MU2 -C(Ph2 P=NSiMe3 )2 }]2 (M=Sn, Pb). AB - Low-valent metallavinylidenes :M=C/? are scarce owing to the low stability of such species. Compound 1, prepared from [CH(Ph2 P=NSiMe3 )2 Li(thf)] and GeCl2 ?dioxane, represents the first stable bis(germavinylidene). The dimetallacyclobutanes 2 (M=Pb, Sn) were also prepared-they are believed to form by dimerization of the intermediate metallavinylidenes. PMID- 29712272 TI - IR-UV Double-Resonance Photodissociation of Nitric Acid (HONO2 ) Viewed as Molecular Information Processing. PMID- 29712273 TI - Synthesis of the First 1,3,4-Triphosphole Complex. AB - Surprisingly selective is the preparation of the novel 1,3,4-triphosphole complex 1 by insertion of a phosphaalkyne into a 1H-diphosphirene complex. NMR spectroscopic experiments and quantum-mechanical calculations indicate a small P inversion barrier for the sigma3 -phosphorus center in 1 as well as new possibilities of "pi-tuning". PMID- 29712274 TI - Switching a Catalyst System from Ethene Polymerization to Ethene Trimerization with a Hemilabile Ancillary Ligand. AB - A drastic ligand effect was observed in the catalytic ethene conversion by the substituted mono(cyclopentadienyl)titaniumtrichloride/methylalumoxane (MAO) catalysts shown. The catalyst with R=Me produces polyethene, whereas the catalyst with R=Ph selectively trimerizes ethene to 1-hexene. This switch in catalyst performance appears to be the result of a hemilabile behavior of the cyclopentadienyl ligand with the pendant arene group, involving reversible coordination of the arene moiety. PMID- 29712275 TI - Total Synthesis of Colombiasin A. AB - Colombian corals of the species Pseudopterogorgia elisabethae produce the title compound, colombiasin A (1). This structurally novel, biologically active tetracyclic compound has now been synthesized for the first time in racemic form. Preliminary studies toward the asymmetric total synthesis of both enantiomers indicate that the determination of the absolute stereochemistry can be expected soon. PMID- 29712276 TI - Synthesis of a Remarkably Stable Dehydro[14]annulene. AB - The substituents at the peri positions of dehydro[14]annulenes 1 have a dramatic effect on the stability of these macrocycles, and lead to derivatives that are stable even at elevated temperatures (up to 190 degrees C). PMID- 29712277 TI - Reactions of Organoselenenyl Iodides with Thiouracil Drugs: An Enzyme Mimetic Study on the Inhibition of Iodothyronine Deiodinase. AB - The proposed mechanism of iodothyronine deiodinase inhibition by the thiourea derived drugs 6-n-propylthiouracil (PTU) and 6-methylthiouracil is supported by experimental evidence. Model reactions with sterically or coordinatively stabilized organoselenyl iodides as enzyme-mimetic substrates (E-SeI; see scheme) support the proposal that PTU reacts not with the enzyme but with the enzyme-SeI intermediate containing a covalent Se-I bond, and suggest that the Se-I bond is kinetically activated by basic amino acid groups such as histidine. PMID- 29712278 TI - Tetrathiafulvaleno-Annelated Porphyrins. AB - Two efficient synthetic routes to the first tetrathiafulvaleno-annelated porphyrins are reported. These novel porphyrin systems (see picture; Pe=pentyl) have been characterized by using a variety of techniques including EPR spectroscopy, cyclic voltammetry, and mass spectrometry. Langmuir-Blodgett films obtained from the porphyrins were used to carry out structural studies by using X ray diffraction and atomic force microscopy. PMID- 29712279 TI - Novel Amide-Based Molecular Knots: Complete Enantiomeric Separation, Chiroptical Properties, and Absolute Configuration. AB - By comparison of experimental and theoretical CD curves the absolute configurations of chromatographically baseline-separated enantiomers of new trefoil molecular knots could be determined. From the results of syntheses with differently substituted starting materials, conclusions can be drawn about the knot-formation mechanism. PMID- 29712280 TI - Editorial: Minireviews, Referees, Journals, and the Future. PMID- 29712281 TI - Low-Temperature Selective Catalytic Reduction (SCR) of NO with NH3 by Using Mn, Cr, and Cu Oxides Supported on Hombikat TiO2. AB - A Highly active, time stable, and water resistant, Hombikat TiO2 supported Mn catalyst has been developed for the selective reduction of NO by NH3 [Eq. (1)]. The analogous Cu and Cr supported catalysts also provide 100 % N2 selectivity at <=120 degrees C. Lewis acidity, redox properties, and a high surface metal oxide concentration are essential for good catalytic performance. PMID- 29712282 TI - Exceptionally Long (>=2.9 A) C-C Bonds between [TCNE]- Ions: Two-Electron, Four Center pi*-pi* C-C Bonding in pi-[TCNE]22. AB - Attractive interaction with the cation overcomes the electrostatic repulsion between two tetracyanoethylene radical anions, [TCNE].- , and leads to the formation of a diamagnetic dimer [TCNE]22- , for example, in [K(glyme)]2 [TCNE]2 . The bonding is described as two-electron, four-center bonding arising from pi* pi* overlap. Crystallographic as well as spectroscopic (IR and UV/Vis) features of this bonding are observed. PMID- 29712283 TI - Oxide Addition to a Reactive Polysulfide Flux: Synthesis of K4 Ba[Ti6 OS20 ] Containing Isolated [Ti6 OS8 (S2 )6 ]6- Clusters. AB - The zero-dimensional cluster compound K4 Ba[Ti6 OS8 (S2 )6 ] has been synthesized from a reactive flux similar to that of K2 Sn and Ti used in the synthesis of the one-dimensional compound K4 Ti3 S14 , but augmented by the deliberate introduction of TiO2 . The picture shows the structure of the [Ti6 OS8 (S2 )6 ]6- ion. PMID- 29712284 TI - Separation of Enantiomers by Extraction Based on Lipase-Catalyzed Enantiomer Selective Fluorous-Phase Labeling. AB - No chromatography is necessary to separate a racemic alcohol into its enantiomers. A highly fluorinated acyl residue was tranferred in an enantiomer selective manner onto a racemic alcohol in the presence of a lipase [Eq. (1)]. The labeled enantiomer was separated from the unlabeled one by a simple but very efficient partition between fluorous and organic phases. PMID- 29712285 TI - [{(tBuC5 H4 )2 Nb(CO)}3 Co9 (CO)8 Te6 ?3 Cr(CO)5 ]: Unusual Stabilization of a Cubic Body-Centered Metal Telluride Cluster by Peripheral Complex Fragments. AB - The Te bridges of the [Co9 (CO)8 Te6 ] cube of 1 serve as anchors for three Cp$?rm{^{?prime }_{2}}$Nb(CO) (Cp'=tBuC5 H4 ) and three Cr(CO)5 fragments. This new principle allows the synthesis and structural comparison of clusters with 122 124 metal valence electrons. PMID- 29712286 TI - Unexpected Splitting of ansa-Ytterboacene and ansa-Calcoacene: Formation of [(eta2 -C12 H8 )ZrCl2 (thf)3 ] and (Me3 Si)2 C12 H8. AB - A ligand-splitting transmetalation: The ansa-metalloacenes [(eta5 -C12 H8 )2 M(thf)2 ] (M=Yb, Ca) react with ZrCl4 or Me3 SiCl unexpectedly by splitting the ansa-bisacenyl ligand, leading to the formation of the zirconacycle [(eta2 -C12 H8 )ZrCl2 (thf)3 ] (1) [Eq. (1)] and the 1,2-bistrimethylsilylacenaphthene (Me3 Si)C12 H8 , respectively. PMID- 29712287 TI - An Insoluble Polymer-Bound Bis-Oxazoline Copper(II) Complex: A Highly Efficient Heterogeneous Catalyst for the Enantioselective Mukaiyama Aldol Reaction. AB - The polystyrene-supported bis-oxazoline 1 forms a complex with copper(II)triflate that is a highly effective catalyst for the heterogeneously catalyzed enantioselective Mukaiyama aldol reaction of silylthioketene acetals with methyl pyruvate (ca. 90 % yield, ca. 90 % ee). The catalyst can be recovered by simple filtration and reused several times without a decline in enantioselectivity. PMID- 29712288 TI - Tuning the Electronic Structure of Halidobis(o-imino-benzosemiquinonato)iron(III) Complexes. AB - The halide ligand determines the ground state for the complexes 1. The chloride complex has a pure St =3/2 state, the iodide complex a pure St =1/2 state, and the bromide complex contains both spin-state isomers (St =3/2 and 1/2) in a 1:1 ratio. Strong intramolecular antiferromagnetic exchange coupling between the FeIII ion, which in the chloride complex has a high-spin (SFe = 5/2) state and in the iodide complex an intermediate-spin (SFe =3/2) state, and the two pi radicals leads to observed ground states, St . PMID- 29712289 TI - Self-Assembly of Pyramidal Tetrapalladium Complexes with a Halide at the Apex. AB - Halide ions act as the template for the self-assembly of tetrapalladium macrocyclic pyramidal structures. These undergo easy inversion in which the halide ion apparently jumps across the macrocycle. PMID- 29712290 TI - DFT Calculation of Intermolecular Nuclear Spin-Spin Coupling in van der Waals Dimers. AB - A small but detectable intermolecular spin-spin coupling (JC,H ) is predicted by density functional calculations on van der Waals bonded dimers like methane benzene and benzene-benzene, as shown in the picture. PMID- 29712291 TI - A Synthetic Pore-Mediated Transmembrane Transport of Glutamic Acid. AB - Transported to the other side: Cyclic D,L-alpha-peptides self-assemble in lipid bilayers into transmembrane ion channels that may allow efficient transport of glutamic acid. The molecular transport is size/shape selective, as evidenced by the high transport rates observed with cyclodecapeptide-based transmembrane pores but not with the smaller cyclooctapeptide analogue. PMID- 29712292 TI - Helical Superstructures of a C2 -Symmetric Molecule Exhibiting Strong Second Harmonic Generation in the Solid-State. AB - The crystallization solvent exerts a critical control of the nonlinear optical properties of helical superstructures in molecular crystals based on N,N'-bis(4 nitrophenyl)-(1R,2R)-diaminocyclohexane. While crystallization from ethyl acetate resulted in mutually orthogonal helices with different handedness, crystallization from ethyl acetate/hexane or acetyl acetone/hexane resulted in the formation of helical motifs of a single-handedness oriented in one direction. The latter showed a strong solid-state second harmonic generation capability. PMID- 29712293 TI - Unprecedented Detection of Distinct Barriers Involving Formally Enantiotopic Substituents: Phenyl Rotation in Solid Diphenyl Sulfoxide. AB - The formally enantiotopic phenyl rings of Ph2 SO (Cs symmetry) display different rotation rates about the Ph-S bonds in the crystalline state. For example, at 0 degrees C one phenyl ring rotates (see picture; cylinder represents rotating phenyl ring), whereas the other does not. Two distinct barriers (13.0 and 14.0 kcal mol-1 ) were determined by solid-state NMR spectroscopy. PMID- 29712294 TI - Stereoselective Hydrocyanation of Alkenyl Sulfoxides as a Method to Highly Enantiomerically Enriched Compounds with Tertiary and Quaternary Chiral Carbon Atoms. AB - Terminal alkynes are easily transformed into enantiomerically enriched compounds containing tertiary and quaternary carbon atoms. Sulfinylation followed by reduction (or alkylation) and hydrocyanation of the resulting vinyl sulfoxides with Et2 AlCN provides nitriles bearing the chiral center, which can in turn undergo reaction to form the desired products. Tol=4-tolyl. PMID- 29712295 TI - Ruthenium Nitrides: Redox Chemistry and Photolability of the Ru-Nitrido Group. AB - Tunable electrophilicity/nucleophilicity by means of the redox properties of the Ru=N group and reversible interconversion of mononuclear and dinuclear species as a result of the photolability of the Ru=N=Ru group are characteristic of the nitrido derivatives of Ru porphyrinogens. For example, 2, the product of reversible reduction of a Ru=N precusor, reacts with 1 in the dark to form 3, which undergoes photocleavage to 1 and 2. PMID- 29712296 TI - A New Family of Layered Molybdenum(V) Cobalto-Phosphates Built up of [H14 (Mo16 O32 )Co16 (PO4 )24 (H2 O)20 ]10- Wheels. AB - Four tetramers of MoV centers and four tetramers of CoII centers, linked by phosphate groups around a central isolated [Co(H2 O)6 ]2+ octahedron form the key structural unit in the molybdenum(V) cobaltophosphates 1 and 2, which were prepared by hydrothermal synthesis. These units are connected to produce two dimensional structures in which the cobalt atoms are antiferromagnetically coupled. PMID- 29712297 TI - A New Type of Doubly Silylamido-Bridged Cyclopentadienyl Group 4 Metal Complexes. AB - Doubly bridged di(silyl-eta-amido)cyclopentadienyltitanium and -zirconium complexes and their related cations as the [(PhCH2 )B(C6 F5 )3 ]- salts have been isolated (see structure of the Ti derivative). The neutral benzylzirconium complex was a very efficient catalyst in the presence of methylaluminoxane for producing high molecular weight polyethylene and ethylene-1-hexene copolymers. PMID- 29712299 TI - A New Strategy for Synthesizing Endohedral Metallocenophanes. AB - The template-controlled synthesis of pi ligands offers new methods for synthesizing endohedral metallocenophanes. This strategy allows the assembly of previously inaccessible bridged metallocenes, for example, the doubly bridged cobaltocenes 2, prepared from 1, n = 3, 4, 5. PMID- 29712300 TI - Tin-Free Radical Acylation Reactions with Methanesulfonyl Oxime Ether. AB - A simple strategy involving thermal decomposition of the methanesulfonyl radical into the methyl radical and the subsequent transfer of an iodine atom or phenyl telluride group was used to develop a tin-free radical acylation reaction (see scheme; V-40=1,1'-azobis(cyclohexane-1-carbonitrile). The key was finding reaction conditions under which the I or PhTe transfer is faster than the direct addition of the alkyl radical to the methanesulfonyl oxime ether. PMID- 29712301 TI - Unprecedented Seven- and Eight-Connected Lanthanide Coordination Networks. AB - Eight-coordinate metal-ion nodes are linked through 4,4-bipyridine-N,N'-dioxide (L) ligands to form the first examples of eight- and seven-connected coordination networks. Thus, whereas [La(L)4 ](CF3 SO3 )3 adopts an eight-connected body centered hypercubic CsCl-like lattice, [La(L)4 ](BPh4 )(ClO4 )2 shows eight coordinate, but seven-connected, nodes linked in an unprecedented 417 62 topology. PMID- 29712302 TI - Photochemical Carbonylation of Ethane under Supercritical Conditions. AB - Feasible photocatalysis: The rhodium catalyst [Rh(CO)(PMe3 )2 Cl] photochemically transforms ethane to propionaldehyde in single-phase mixtures of ethane and in carbon dioxide/ethane single phases [Eq. (1)]. A side reaction of carbon dioxide with the catalyst to give OPMe3 and [Rh(CO)2 (PMe3 )Cl] or [Rh2 (CO)2 (PMe3 )2 (MU-Cl)2 ] has also been observed. PMID- 29712304 TI - Inherent Asymmetry of Constitutionally Equivalent Methyl Groups in the H/D Equilibration of n- and i-C3 H7 Fe(OH)+ Complexes. AB - Transiently formed, constitutionally identical methyl groups remain inequivalent in the course of an n-propyl?isopropyl isomerization operative in Fe+ -mediated dehydration of propanols. The reversibility of the beta-hydrogen transfer steps is addressed by examination of the H/D equilibration in metastable complexes of Fe+ with a set of selectively deuterated propanols by using tandem mass spectrometry. PMID- 29712303 TI - A Chiral Metal Surface. AB - Pronounced surface restructuring leads to the formation of chiral kink sites when a chiral molecular overlayer (2,5,8,11,14,17-hexa-(tert-butyl)decacyclene) is adsorbed onto an extended, flat metal surface (Cu{110}). The process is proposed to happen as a result of the adsorbed molecule inducing chirality in the achiral surface. PMID- 29712305 TI - Cleavage of Tellurium-Carbon Bonds of Hexavalent Organotellurium Compounds by Potassium Graphite. AB - The potassium ion intercalated in graphite results in unique reactivity of Ar5 Te K+ C8 (1), formed by cleavage of one of the Te-C(Ar) bonds of Ar6 Te by KC8 . Thus, 1 reacted quantitatively with CH3 I to give Ar5 TeCH3 , which was not obtainable from Ar5 Te- Li+ . The Te-CH3 bond of Ar5 TeCH3 is cleaved in preference to the Te-C(Ar) bonds, and formation of Ar4 Te(CD3 )2 suggests the intermediacy of the hypervalent dianion Ar4 Te2- . PMID- 29712306 TI - Physically Cross-Linked Ultrathin Elastomeric Membranes. AB - Spreading a hydrophobic liquid star polymer with ionic head groups and transferring the resulting monomolecular layers to solid substrates with holes provides access to ultrathin, freely suspended elastomeric membranes, which are stable for at least several months. PMID- 29712307 TI - Ring-Opening Polymerization of 1-Methylene-2-phenylcyclopropane Catalyzed by a Pd Complex To Afford Regioregulated Polymers. AB - Selective 2,1-insertion of the monomer and subsequent elimination of the beta carbon atom of the growing polymer end is proposed as a new mechanism for polymer synthesis that involves ring opening of the monomer. A palladium complex promotes the ring-opening polymerization of 1-methylene-2-arylcyclopropanes to afford polymers with a vinylidene group in each monomer unit. PMID- 29712308 TI - Noncovalent Assembly of [2]Rotaxane Architectures. AB - Reversible zinc-pyridine coordination and hydrogen-bonding interactions have been used to assemble a [2]rotaxane from three components. Cooperativity in the macrocyclization process that results in the porphyrin dimer makes the system exceptionally stable. However, the kinetic lability of the zinc-porphyrin interaction means the dimer is in dynamic equilibrium with its monomer, and this has been exploited in the construction of a [2]rotaxane. PMID- 29712310 TI - A Novel Hemiporphyrazine Comprising Three Isoindolediimine and Three Thiadiazole Units. AB - Incorporation of three metal ions (Ni or Cu) in the macrocyclic ring and the formation of hexamers following a 3+3 approach are novel features of the hemiporphyrazines (one example shown) formed by the condensation of 2,5-diamino 1,3,4-triazole with isoindolediimines. This is in contrast to the corresponding reactions with diaminotriazoles, which afford 2+2 products. PMID- 29712311 TI - Remote Communication between Charge Centers and Hydrogen-Bonding Sites: Possibility for a Signal Transducer? AB - Signal enhancement from a reaction center to a hydogen-bonding site occurs when they are separated by an azo linker. A computational study has shown that the binding of ammonia to a pyrrole unit in an iminium compound increases as the length of the azo group between the two sites increases. This surprising result is explained in terms of resonance effects and the larger electron-withdrawing power of longer azo linkers. PMID- 29712312 TI - A Colorimetric ATP Sensor Based on 1,3,5-Triarylpent-2-en-1,5-diones. AB - A new family of chromogenic ionophores for anion sensing has been developed with 1,3,5-triarylpent-2-en-1,5-diones. These species form yellow solutions that undergo a color change to magenta in the presence of certain inorganic ions or nucleotides, depending on the derivative. The reaction with ATP is particulary remarkable and therefore these compounds are chromogenic reagents for "naked-eye" sensing of ATP. The picture shows the color changes induced on one derivative in the presence of GMP, ADP, and ATP (from left to right). PMID- 29712313 TI - First O-H-N Hydrogen Bond with a Centered Proton Obtained by Thermally Induced Proton Migration. AB - Within a range of 0.1 A, the H atom in the O-H-N hydrogen bond of the adduct 4 methylpyridine?pentachlorophenol could be shifted by a simple adjustment of temperature. At approximately 90 K the H atom is exactly centered between the O and the N atoms, as could be shown by stepwise monitoring by using variable temperature single-crystal neutron diffraction. PMID- 29712314 TI - Nonorthogonal Dilithium-1,3-biborataallenes Containing Planar-Tetracoordinate Carbon Atoms. AB - Deviations of up to 36 degrees from the orthogonality of the planes of the terminal B atoms of the allene skeleton and their neighbors (ipso-C atoms) are observed in tetraaryl-1,3-diborataallenes of contact-ion triples 1. The unusual geometries are caused by steric hindrance between ortho-methyl groups, which is induced by interactions of the lithium counterions with the pi electrons of the aryl substituents, as well as by small barriers to planarization of 1,3 diborataallenes. Ar=for example, 2,3,5,6-tetramethylphenyl. PMID- 29712315 TI - "Synthetic Metals": A Novel Role for Organic Polymers (Nobel Lecture). AB - Since the initial discovery in 1977, that polyacetylene (CH)x , now commonly known as the prototype conducting polymer, could be p- or n-doped either chemically or electrochemically to the metallic state, the development of the field of conducting polymers has continued to accelerate at an unexpectedly rapid rate and a variety of other conducting polymers and their derivatives have been discovered. Other types of doping are also possible, such as "photo-doping" and "charge-injection doping" in which no counter dopant ion is involved. One exciting challenge is the development of low-cost disposable plastic/paper electronic devices. Conventional inorganic conductors, such as metals, and semiconductors, such as silicon, commonly require multiple etching and lithographic steps in fabricating them for use in electronic devices. The number of processing and etching steps involved limits the minimum price. On the other hand, conducting polymers combine many advantages of plastics, for example, flexibility and processing from solution, with the additional advantage of conductivity in the metallic or semiconducting regimes; however, the lack of simple methods to obtain inexpensive conductive polymer shapes/patterns limit many applications. Herein is described a novel, simple, and cheap method to prepare patterns of conducting polymers by a process which we term, "Line Patterning". PMID- 29712316 TI - Synthesis and Structure of a Dimeric Alkyldibariumtriszincate with a Tetraanionic Triszincate Ligand and a Unique Central Ba4 Zn2 C6 Moiety. AB - Transmetalations of zincates succeed only after activation of the barium metal. Dialkylbarium, the initial product, metalates the zincate anions which are still present in solution and leads to the formation of tetraanionic tris(zincate) ligands, which sterically shield the Ba-C bonds of a Ba4 Zn2 C6 cage. PMID- 29712317 TI - Zeosil Nanoslabs: Building Blocks in nPr4 N+ -Mediated Synthesis of MFI Zeolite. AB - Tetrapropylammonium (TPA)-containing precursors are the building blocks in the crystallization of silica. In the first steps slab-shaped silicalite nanoparticles are formed by ordered combination of the precursors. These nanoslabs have MFI-type zeolite framework topology and play a key role in TPA-ion mediated zeolite crystallization from monomeric and polymeric silica sources. PMID- 29712318 TI - A Cyclic Hexapeptide Containing L-Proline and 6-Aminopicolinic Acid Subunits Binds Anions in Water. AB - A neutral receptor that binds anions by hydrogen bonds even in water is the cyclopeptide reported in this article. This property results from the particular structure of the complex in which the anions are effectively shielded from the surrounding solvent, as can be seen in the iodide complex shown. PMID- 29712319 TI - The Discovery of Polyacetylene Film: The Dawning of an Era of Conducting Polymers (Nobel Lecture). AB - This lecture is not directly related to our discovery and development of conducting polymers to which the Nobel Prize in Chemistry 2000 was awarded. However, I would like to present my previous work that I had carried out just before we reached the discovery of chemical doping. I hope that this will be of use and deepen your understandings by learning what had happened before and how we reached the idea of chemical doping. PMID- 29712320 TI - Nematic Dendrimers Based on Carbosilazane Cores. AB - The controlled synthesis of nematic nanophase-separated materials poses an attractive synthetic challenge. The use of carbosilazane multipodes and dendrimers (such as 1) in conjunction with laterally attached mesogens allows the systematic investigation of the structure-property relationships of room temperature nematic liquid crystals. PMID- 29712322 TI - Nitroglycal Concatenation: A Broadly Applicable and Efficient Approach to the Synthesis of Complex O-Glycans. AB - Base-catalyzed glycosylations provide the basis for a new and general entry to the synthesis of mucin-type O-glycans. The desired alpha-linked 2 acetamidoglycosyl amino acids B are accessible selectively starting from glycals of type A. Fmoc=9-fluorenylmethoxycarbonyl. PMID- 29712321 TI - High-Pressure Synthesis of gamma-P3 N5 at 11 GPa and 1500 degrees C in a Multianvil Assembly: A Binary Phosphorus(V) Nitride with a Three-Dimensional Network Structure from PN4 Tetrahedra and Tetragonal PN5 Pyramids. AB - Extreme reaction conditions lead to the synthesis of gamma-P3 N5 . Its crystal structure, unlike that of the normal pressure modification alpha-P3 N5 , is not exclusively built from PN4 tetrahedra, but from both PN4 tetrahedra (blue) and tetragonal PN5 pyramids (red). A tetragonal PN5 pyramid structure element has not been observed previously. PMID- 29712323 TI - Rearrangement of a Tricyclic 2,5-Cyclohexadienone: Towards a General Synthetic Route to the Daphnanes and (+)-Resiniferatoxin. AB - Light as a reagent: A highly functionalized structure that serves as a daphnane template can be formed by the photorearrangement of a 2,5-cyclohexadienone subunit within a complex tricyclic ring system. The chemistry we describe should not only find use in the total synthesis of resiniferatoxin and related daphnanes, but should also provide useful templates for access to complex analogues. PMID- 29712324 TI - Semiconducting and Metallic Polymers: The Fourth Generation of Polymeric Materials (Nobel Lecture). AB - When asked to explain the importance of the discovery of conducting polymers, I offer two basic answers: first they did not (could not?) exist, and second, that they offer a unique combination of properties not available from any other known materials. The first expresses an intellectual challenge; the second expresses a promise for utility in a wide variety of applications. PMID- 29712325 TI - Highly Sensitive Novel Biosensor Based on an Immobilized lac Repressor. AB - Sensitive repressors: The conformational change that occurs in the lac repressor protein when it binds to an inducer molecule has been used to develop a biosensor that permits the detection of the corresponding operator sequence or specific inducer molecules. A capacitive signal transducer was used to translate the conformational change of the lac repressor protein, covalently immobilized on a gold electrode (see schematic representation, A=bound inducer molecule or DNA), into a measurable signal. PMID- 29712326 TI - Barium Triphenylmethanide: An Examination of Anion Basicity. AB - Differences in anion basicity seem to be key for the formation of the first charge-separated barium triphenylmethanide versus a novel heteroleptic vinyl ether which results from cleavage of the attendant [18]crown-6. Ba: green; O: red; P: yellow; N: blue. PMID- 29712327 TI - trans-[Fe(CN)4 (CO)2 ]2- , a 21st Century [Fe(CN)(CO)] Compound. AB - In 1887, more than a century after the synthesis of [FeII (CN)6 ]4- , the complex [FeII (CN)5 (CO)]3- , in which a CN- ligand is replaced by CO, was reported. It has taken an additional century for the synthesis of the complex in which a second CN- ligand is substituted by CO: trans-[FeII (CN)4 (CO)2 ]2- (structure shown). Remarkably, this anion is prepared by the simple reaction of FeCl2 with NaCN and CO in water. [Fe(CN)x (CO)y ] complexes are of interest as models for the active site of hydrogenase enzymes. PMID- 29712328 TI - Synthesis of a Nanoporous Polymer with Hexagonal Channels from Supramolecular Discotic Liquid Crystals. AB - Hydrogen-bonding interactions between a benzotri(imidazole) derivative and a polymerizable alkoxybenzoic acid result in the formation of a supramolecular hexagonal columnar liquid crystal. Light-induced polymerization followed by removal of the benzotri(imidazole) core produces a porous polymer with hexagonal channels. PMID- 29712329 TI - New Paradigms for Organic Catalysts: The First Organocatalytic Living Polymerization. AB - A metal-free approach to the living ring-opening polymerization (ROP, shown schematically) of lactide has been developed using strongly basic amines such as 4-(dimethylamino)pyridine as transesterification catalysts. These organic catalysts must be used in combination with a nucleophile such as an alcohol, which is the actual initiating species. PMID- 29712330 TI - Molecular Paneling by Coordination: An M15 L6 Hexahedral Molecular Capsule having Clefts for Reversible Guest Inclusion. AB - Only one positional isomer is obtained from the assembly of 21 small components. A triangular molecular panel with five coordination sites is assembled upon complexation with [PdII (en)] (en=ethylenediamine) into a unique M15 L6 hexahedral coordination capsule (see X-ray structure). The capsule can encapsulate/exchange organic guests reversibly through the clefts at the nonbinding sites of the capsule. PMID- 29712331 TI - Dicyclopenta[a,d]cyclooctene: A [14]Annulene Containing Two Zero-Atom Cross Links. AB - 14pi-Electrocyclization across the two pentafulvenoid moieties of pentafulvene 1 occurs upon heating to provide dicyclopenta[a,d]cyclooctene 2 [Eq. (1)]. The nonalternant hydrocarbon 2 shows diatropic character and a distinctive absorption spectrum with the longest wavelength maximum at 767 nm. PMID- 29712332 TI - nido<->closo Interconversion of Six-Vertex Metallacarboranes: Access to CoC2 B3 and CoC2 B4 Clusters with Nonadjacent Carbon Atoms. AB - Replacement of B-H hydrogen atoms with Cl or Br facilitates the previously unknown oxidative conversion of a nido- to a closo-6-vertex metallacarborane [Eq. (1); X=Cl, Br]. Oxidative cage closure, separation of carbon atoms upon thermal rearrangement, reductive cage opening, and cage expansion by boron insertion have all been applied to a single system, to afford synthetic access to new cluster types. PMID- 29712333 TI - Synthesis, Biological, and Immunological Properties of Cyclic Peptides from Plasmodium Falciparum Merozoite Surface Protein-1. AB - Effective structural mimics of a functionally important epitope from the malarial Merozoite Surface Protein-1 (MSP-1) include N-backbone cyclic peptides such as 1. They mimic the interaction of MSP-1 with human erythrocytes and can be used to induce parasite-specific monoclonal antibodies. PMID- 29712334 TI - Enantioselective Incorporation of Azobenzenes into Oligodeoxyribonucleotide for Effective Photoregulation of Duplex Formation. AB - A drop in melting point of 21.5 degrees C is induced by the UV-photolytic trans >cis isomerization of the duplex formed between an oligonucleotide bearing two D threoninol-tethered azobenzene moieties in the side chain and its complementary counterpart. On irradiation with visible light, the dissociated single-stranded oligonucleotides regenerate the duplex. PMID- 29712335 TI - Synthetic seco Forms of (-)-Diazonamide A. AB - One bond and a water molecule separate title compound 1 from the potently bioactive peptide metabolite diazonamide A. Compositionally similar, yet topographically distinct, diazonamide A and 1 are both toxic towards cultured human cancer cells although the mechanisms underlying their actions likely differ. The quest towards completely synthetic diazonamides continues. PMID- 29712336 TI - The Reaction Mechanism of the Enzyme-Catalyzed Central Cleavage of beta-Carotene to Retinal. AB - Seeing things as they really are: The enzyme catalyzing the central cleavage of beta-carotene (1) to retinal (2) is not, as previously thought, a dioxygenase. Incubation of the substrate analogue alpha-carotene in the presence of highly enriched 17 O2 and H218 O revealed a monooxygenase mechanism. PMID- 29712338 TI - Activation, Tuning, and Immobilization of Homogeneous Catalysts in an Ionic Liquid/Compressed CO2 Continuous-Flow System. AB - A new immobilization scheme for enantioselective catalysts was developed by using a combination of ionic liquids and compressed CO2 . Under continuous flow conditions, stable conversion and asymmetric induction was achieved over more than 60 h in the enantioselective Ni-catalyzed hydrovinylation of styrene. While the ionic liquid dissolves and activates the organometallic catalyst in a tuneable manner, the presence of compressed CO2 greatly facilitates mass transfer and gives easy access to continuous processes. PMID- 29712337 TI - Saddle-Shaped Six-Coordinate Iron(III) Porphyrin Complexes Showing a Novel Spin Crossover between S=1/2 and S=3/2 Spin States. AB - The field strength of the axial ligands determines the spin state of saddled iron(III) porphyrin complexes. Strong axial ligands (L), such as imidazole and 4 dimethylaminopyridine, lead to the formation of complexes with a pure S=1/2 state, while weak ligands, such as THF, give complexes with a pure S=3/2 state. Intermediate strength ligands, such as pyridine and 4-cyanopyridine, give complexes that show a novel spin crossover between the S=1/2 and S=3/2 states. PMID- 29712339 TI - Polymetallic Cobalt and Manganese Cages with Phosphinate and Phosphonate Ligands. AB - Addition of a coligand in reactions of phosphonates with salts of late 3d metals can lead to more soluble and tractable materials, such as the {Co13 } cage shown (Co: green; P: purple). The structure contains two central PhPO32- ligands, surrounded by a hexanuclear cobalt helix, capped by seven further cobalt sites. PMID- 29712340 TI - First Example of the MU3 -eta1 ,eta2 ,eta1 -C60 Bonding Mode: Ligand-Induced Conversion of pi to sigma C60 -Metal Complexes. AB - A boat-shaped 1,4-cyclohexadiene-like ring is present in the C60 molecule with a novel sigma-type MU3 -eta1 ,eta2 ,eta1 bonding mode in the clusters 2 a and 2 b. The change in coordination mode was induced by insertion of an RNC ligand into an Os-Os bond of the pi-type C60 complex 1. R=CH2 C6 H5 . PMID- 29712341 TI - Catalytic Asymmetric Synthesis of Epoxides from Aldehydes Using Sulfur Ylides with In Situ Generation of Diazocompounds. AB - A practical, general, and convergent route to epoxides with control of the relative and absolute stereochemistry has been achieved by generating the reactive intermediate (the diazo compound) in situ from tosylhydrazone salts (see scheme, PTC=phase-transfer catalyst, Ts=toluene-4-sulfonyl). High yields (58-82 %), high d.r. (88:12-98:2), and high ee values (87-94 %) have been obtained using a new class of stable chiral sulfides at low catalyst loading (5 mol %) and [Rh2 (OAc)4 ] (0.5 mol %). PMID- 29712342 TI - Selective Inclusion of a Hetero-Guest Pair in a Molecular Host: Formation of Stable Charge-Transfer Complexes in Cucurbit[8]uril. AB - Two different molecules are selectively included in cucurbit[8]uril to form a stable 1:1:1 ternary complex, which has been characterized by X-ray crystallography. The inclusion of a hetero-guest pair (a pyridinium derivative (blue) and 2,6-dihydroxynaphthalene (magenta)) in the molecular host is driven and stabilized by a charge-transfer interaction between the electron-rich and electron-deficient guests. PMID- 29712343 TI - A Readily Available and User-Friendly Chiral Catalyst for Efficient Enantioselective Olefin Metathesis. AB - No glove box required! A new chiral catalyst for olefin metathesis is prepared from commercially available materials and is equally or more effective and selective than the previous systems. The new user-friendly catalyst can be prepared in situ (see scheme, Ar=aryl, Tf=trifluoromethanesulfonyl), isolation not needed, outside of a glove box, and delivers reactivity and enantioselectivity levels formerly available only through multiple catalysts. PMID- 29712344 TI - [{Fe(C5 H4 )2 }3 {Ga(C5 H5 N)}2 ]: A Trinuclear Gallium-Bridged Ferrocenophane with a Carousel Structure. AB - A molecular carousel, that is the appearance of the structure of the title compound [1?2 py], the first complex of a new structure type prepared by a highly selective condensation reaction from the equally new complex [Fe(C5 H4 GaMe2 )2 ]. The first gallium bridged [m.m]ferrocenophane [{Fe(C5 H4 )2 }2 {GaMe(C5 H5 N)} 2 ] is formed as an intermediate; this compound can also be prepared in a planned synthesis and can be converted into [1?2 py] by warming. The complex [1?2 py] as well as [1?2 Et2 O] and [1?2 DMSO], which were formed by donor exchange, offers various interesting properties, for example, [1?2 DMSO] can be reversibly oxidized to the mono-, di-, and trication. PMID- 29712345 TI - Total Synthesis of (-)-Tetrazomine and Determination of Its Stereochemistry. AB - A new method for the formation of the allylic amine precursor to an azomethine ylide 1 has been developed and exploited in an efficient 1,3-dipolar cycloaddition to afford the key tetracyclic intermediate used in the synthesis of (-)-tetrazomine (2). Bn=benzyl. PMID- 29712346 TI - NaV3 (OH)6 (SO4 )2 : A Kagome-Type Vanadium(III) Compound with Strong Intralayer Ferromagnetic Interactions. AB - A dominant ferromagnetic exchange interaction propagates about the magnetic sites of the Kagome lattice of the title compound through the bridging hydroxy groups (see section of the structure). This is at variance with the antiferromagnetic exchange observed for jarosite and its derivatives. The ferromagnetism probably arises from the d2 electron count of the VIII centers. PMID- 29712347 TI - Crystal Structures from a Building Set: The First Boridecarbides of Niobium. PMID- 29712348 TI - Modular Pyridinyl Peptide Ligands in Asymmetric Catalysis: Enantioselective Synthesis of Quaternary Carbon Atoms Through Copper-Catalyzed Allylic Substitutions. AB - Highest enantioselectivities so far with dialkylzinc reagents! Quaternary carbon centers are formed enantioselectively through a Cu-catalyzed allylic substitution reaction that is promoted by pyridinyl peptide-based ligands in the presence of dialkylzinc reagents. The modularity of this new class of chiral ligands is exploited for reactivity and selectivity optimization. PMID- 29712349 TI - High-Density Labeling of DNA: Preparation and Characterization of the Target Material for Single-Molecule Sequencing. PMID- 29712351 TI - Controlled Synthesis of Cross-Linked Ultrathin Polymer Films by Using Surface Initiated Atom Transfer Radical Polymerization. AB - Ambient-temperature atom transfer radical polymerization of ethyleneglycol dimethacrylate from a surface yields homogeneous, cross-linked polymer films. The absence of polymerization in solution in this "living" procedure avoids physisorption and gives uniform, cross-linked films with controlled thicknesses from 3 to 300 nm. PMID- 29712350 TI - Acetylenes Rearranging on Ruthenium-Porphyrinogen and Leading to Vinylidene and Carbene Functionalities. AB - Through a proton-transfer reaction a porphyrinogen assists the transformation of terminal acetylenes into Ru-vinylidenes, which are the entry point to a variety of Ru-carbenes and Ru-cumulenes. The scheme (in which the porphyrinogen is stylized) shows the reversible interconversion of an acetylide into a divinylidene unit. PMID- 29712352 TI - Neutral Cyclooctasulfur as a Polydentate Ligand: Supramolecular Structures of [Rh2 (O2 CCF3 )4 ]n (S8 )m (n:m=1:1, 3:2). AB - Coordination of neutral S8 molecules by transition metal centers has been structurally confirmed for the first time. The monoadduct [Rh2 (O2 CCF3 )4 ](S8 ) is a one-dimensional polymer with an alternating chain of dirhodium(II) tetra(trifluoroacetate) and bidentate S8 rings, whereas [Rh2 (O2 CCF3 )4 ]3 (S8 )2 is a pseudo-two-dimensional ribbon in which all cyclo-S8 ligands act in a tridentate fashion. PMID- 29712353 TI - Ultrafast Electron Diffraction of Transient [Fe(CO)4 ]: Determination of Molecular Structure and Reaction Pathway. AB - The temporal diffraction-difference approach of the ultrafast electron diffraction (UED) technique was used to determine the molecular structure of the transient [Fe(CO)4 ] formed during the elimination of CO ligands from [Fe(CO)5 ]. The results clearly show that the major product, up to 200 ps, is the transient [Fe(CO)4 ] which is formed in the 1 A1 state, rather than the ground 3 B2 state. PMID- 29712355 TI - Difluorooxymethylene-Bridged Liquid Crystals: A Novel Synthesis Based on the Oxidative Alkoxydifluorodesulfuration of Dithianylium Salts. AB - Insertion of a difluorooxymethylene bridge into the mesogenic core structure of phenylcyclohexane-based liquid crystals results in a class of materials that exhibits a surprising and unprecedented improvement of essentially all application-relevant properties. A novel synthetic procedure allows the convenient large-scale preparation of a variety of compounds based on alpha,alpha difluoroalkyl ether structures. PMID- 29712354 TI - Insertion of Helium and Molecular Hydrogen Through the Orifice of an Open Fullerene. AB - A "molecular surgery" approach has been used to create an opening within a fullerene cage that is large enough to allow atoms and small molecules to pass through. The thermodynamics for the insertion of He and H2 into the open fullerene (left and right pictures, respectively) as well as their escape have been studied by NMR spectroscopy and theoretical methods. PMID- 29712356 TI - Wittig and His Accomplishments: Still Relevant Beyond His 100th Birthday. PMID- 29712357 TI - Dual-Signaling Fluorescent Chemosensors Based on Conformational Restriction and Induced Charge Transfer. AB - Twist and shout! By restricting conformation, 2,6-biarylpyridines can be induced to "speak" to us through increased fluorescence emission. In combination with induced charge transfer, this allows these simple fluorophores to reveal otherwise silent binding events to alkali metal and alkaline earth cations through brightening and color change (see picture; from left to right: no metal, Li+ , Mg2+ , and Ca2+ ). PMID- 29712358 TI - Synthesis and Characterization of RbLi7 Ge8 with Isolated closo-[Li4 Ge12 ]8- Ions, Lithium-Capped Truncated Tetrahedra of Ge1212. AB - The largest isolated clusters of Group 14 elements, giant truncated tetrahedra of Ge1212- , are found in the title compound. RbLi7 Ge8 , which is an electronically balanced, saltlike Zintl phase, was synthesized by heating the corresponding stoichiometric mixture of elements. PMID- 29712359 TI - Application of Chiral Sulfides to Catalytic Asymmetric Aziridination and Cyclopropanation with In Situ Generation of the Diazo Compound. AB - Imines and alkenes can be converted into the corresponding aziridines and cyclopropanes (see scheme, PTC=phase-transfer catalyst, Ts=toluene-4-sulfonyl) in good yield with moderate to high d.r. and high ee values using tosylhydrazone salts with catalytic quantities of chiral sulfide (5-20 mol %) and metal catalyst (1 mol %). The process is particularly suited to the synthesis of conformationally locked cyclopropyl amino acids, which can now be prepared in only three steps from commercially available material in 100 % ee. PMID- 29712360 TI - A Short Copper-Copper Distance in a (MU-1,2-Peroxo)dicopper(II) Complex Having a 1,8-Naphthyridine Unit as an Additional Bridge. AB - A copper-copper separation of about 2.84 A is determined by extended X-ray absorption fine structure studies for the (MU-1,2-peroxo)dicopper(II) species 1, which has only a 1,8-naphthyridine unit as an additional bridge. Complex 1 was prepared by the reaction of O2 with a dicopper(I) complex formed from BPMAN. PMID- 29712361 TI - Template and Guest Effects on the Self-Assembly of a Neutral and Homochiral Helix. AB - Coordination-driven assembly based on manganese(II) centers and flexible 1,3 bis(4-pyridyl)propane leads to the solid-state formation of electronically neutral, self-templated homochiral helices, closed ring structures, and racemic mixtures of helices depending upon the presence or absence of guests such as benzene and 1,2-diphenylethane. PMID- 29712362 TI - Intrinsically Competitive Photoinduced Polycyclization and Double-Bond Shift through a Boatlike Conical Intersection. AB - A mechanistic view of the deactivation of photoexcited cycloocta-1,3,5,7-tetraene (COT*) through a novel type of conical intersection is provided by ab initio studies. As a consequence of this deactivation, the formation of semibullvalene (SBV) and of the double-bond-shifted isomer of COT are intrinsically bound. Both gas-phase and solution-phase experimental data are explained. PMID- 29712363 TI - Application of a Planar Chiral eta5 -Cyclopentadienylrhenium(I)tricarbonyl Complex in Asymmetric Catalysis: Highly Enantioselective Phenyl Transfer to Aldehydes. AB - A novel planar chiral cyrhetrene 1 has been identified as an efficient catalyst precursor for the asymmetric synthesis of diarylmethanol compounds 2 by phenylation of aldehydes. Compared to the corresponding ferrocene derivative, the performance of the cyrhetrene is superior or at least equally as good and gives excellent enantioselectivities even with catalyst loadings as low as 2 mol %. PMID- 29712364 TI - Expanding the Pyrimidine Diphosphosugar Repertoire: The Chemoenzymatic Synthesis of Amino- and Acetamidoglucopyranosyl Derivatives. AB - The exploitation of a unique thymidylyltransferase (Ep ) allows the rapid syntheses of thymidine and uridine 5'-(aminodeoxy-alpha-D-hexopyranosyl diphosphates), 5'-(acetamidodeoxy-alpha-D-hexopyranosyl diphosphates), and even 5'-(aminodideoxy-alpha-D-hexopyranosyl diphosphates), which are amino analogues of the products from the native reaction of Ep . PMID- 29712365 TI - Individual Alumina Nanotubes. AB - Anodization of aluminum with H2 SO4 on an Si substrate results in the formation of individual alumina nanotubes (ANTs). The picture shows an ANT with a length of 650 nm and internal and external diameters of 12 and 35 nm, respectively. Detailed studies by transmission electron microscopy revealed that the ANTs are completely detached cells of the porous anodized aluminum film. PMID- 29712366 TI - Complex Chemical Stabilization of Dichlorodiphosphene. AB - In contrast to the cis configuration of N2 F2 , the analogous phosphorus subhalogenides, P2 X2 (X=F, Cl) adopt a trans configuration according to density functional theory calculations. Now for the first time dichlorodiphosphene has been stabilized in the coordination sphere of transition metals in the form of complex 1. PMID- 29712367 TI - Fluorinated Coiled-Coil Proteins Prepared In Vivo Display Enhanced Thermal and Chemical Stability. AB - Fluorination of the hydrophobic core of a coiled-coil protein significantly improved its stability toward thermal and chemical denaturation. 5',5',5' Trifluoroleucine (2) was efficiently incorporated into a leucine-zipper protein in place of leucine (1) during E. coli biosynthesis. The fluorinated variant maintained stable secondary and tertiary structures under conditions that caused denaturation of the "wild-type" protein. PMID- 29712368 TI - Oxoammonium Resins as Metal-Free, Highly Reactive, Versatile Polymeric Oxidation Reagents. AB - Polymer-supported oxidation of alcohols was conducted very efficiently by employing oxoammonium salts, the reactive intermediates in TEMPO oxidations (TEMPO=2,2,6,6-tetramethylpiperidinoxyl). These highly reactive salts (see scheme; X=Br, Cl) could be prepared and isolated on the polymeric support, and were used for the conversion of single compounds as well as of complex mixtures of alcohols. PMID- 29712369 TI - A Ligand-Modulated Padlock Oligonucleotide for Supercoiled Plasmids. AB - Catenation of a circular oligonucleotide to a supercoiled plasmid can be achieved in high yields by means of ligand-induced triple-helix formation. The noncovalent interactions in this supramolecular structure can be modulated by a triplex stabilizing agent (TSA; see picture). The circular oligonucleotide represents a noncovalent anchor for plasmid functionalization. PMID- 29712370 TI - Concave Butterfly-Shaped Organometallic Hydrocarbons? AB - A metamorphosis of the tetraethynyl precursor 1 through double Cu-catalyzed ring closure leads to the corresponding butterfly-shaped cyclobutadiene complexes 2 in high yield (94 %). Single-crystal X-ray diffraction shows that the large organic ligand is distinctly nonplanar with a concave topology. Cp=cyclopentadiene. PMID- 29712371 TI - [Ru(N2 )(PiPr3 )('N2 Me2 S2 ')]: Coordination of Molecular N2 to Metal Thiolate Cores under Mild Conditions. AB - N2 coordination to the nitrogenase Fe7 MoS9 cofactor is considered a key step of biological N2 fixation, however, modeling this step with metal-sulfur complex fragments under mild conditions has remained a long-standing challenge. The title complex 2 represents a first example, forming from N2 and the precursor CH3 CN complex 1 under standard conditions [Eq. (1)]. PMID- 29712372 TI - Synthesis of DNA Oligomers Possessing a Covalently Cross-Linked Watson-Crick Base Pair Model. AB - Building bridges: A feasible solid-phase synthesis of antiparallel n-, h-, and H type DNA oligomers has been demonstrated. The oligomers possess a CH2 -bridged base-pair model that should be conformationally flexible, even after base pairing. PMID- 29712373 TI - A Novel and Highly Stereoselective Intramolecular Formal [3+3] Cycloaddition Reaction of Vinylogous Amides Tethered with alpha,beta-Unsaturated Aldehydes: A Formal Total Synthesis of (+)-Gephyrotoxin. AB - Complex piperidinyl heterocycles (for example, 2) were accessed by using a novel intramolecular formal [3+3] cycloaddition reaction of vinylogous amides tethered with enals (for example, 1). This method has been applied to a formal total synthesis of (+)-gephyrotoxin (3). PMID- 29712374 TI - Benzylic Imine Catenates: Readily Accessible Octahedral Analogues of the Sauvage Catenates. AB - The shape of rings to come: The first members of a new family of simple-to prepare octahedral analogues of the tetrahedral Sauvage catenates are described. M=Mn2+ , Fe2+ , Co2+ , Ni2+ , Cu2+ , Zn2+ , Cd2+ , Hg2+ . PMID- 29712377 TI - Unique Chemistry at Ice Surfaces: Incomplete Proton Transfer in the H3 O+ -NH3 System. PMID- 29712376 TI - First Total Synthesis of the Re-Type Lipopolysaccharide. AB - Three sequential efficient glycosylation reactions starting from D-glucosamine were used in the first total synthesis of Escherichia coli Re lipopolysaccharide, which is one of the most simple lipopolysaccharides found on the surface of living bacteria. PMID- 29712378 TI - An Atom-Economic Three-Carbon Chain Extension to Give Enamides. AB - Di- or trisubstituted alkenes of defined geometry, with terminal enamide groups, are formed in an atom-economic three-carbon chain extension of alkynes with allyl amides catalyzed by ruthenium (see, for example, Equation (1); Boc=tert butoxycarbonyl, TMS=trimethylsilyl). PMID- 29712379 TI - Thwarting beta-Hydride Elimination: Capture of the Alkylpalladium Intermediate of an Asymmetric Intramolecular Heck Reaction. AB - In spite of containing three conformationally accessible beta-H atoms, palladacycle 1 a is an isolable intermediate in the asymmetric Heck cyclization of 2 a. Although 1 a is stable in the presence of the hydrotriflate salt of 1,2,2,6,6-pentamethylpiperidine, it is converted into the oxindole Heck product when exposed to the more acidic hydrotriflate salt of 2,6-di-tert-butylpyridine. Heck cyclization of 2 b is also believed to proceed by way of a palladacyclic intermediate 1 b, which in this case undergoes beta-methoxide elimination. Bn=benzyl. PMID- 29712380 TI - Identification and Isolation of a Receptor for N-Methyl Alkylammonium Salts: Molecular Amplification in a Pseudo-peptide Dynamic Combinatorial Library. AB - A cyclic pseudo-peptide receptor for acetylcholine has been amplified and isolated from a dynamic combinatorial library by virtue of templated stabilization under thermodynamic control (see scheme, TFA=trifluoroacetic acid). This is a demonstration of significant molecular amplification in dynamic systems to evolve a novel receptor. PMID- 29712381 TI - Cyano-Bridged 4f-3d Coordination Polymers with a Unique Two-Dimensional Topological Architecture and Unusual Magnetic Behavior. AB - Rings of 24 atoms form part of the two-dimensional structure of the novel compounds [NdM(bpym)(H2 O)4 (CN)6 ]?3 H2 O (M = Fe (1), Co (2); bpym = 2,2' bipyrimidine). These compounds are the first two-dimensional cyano-bridged species containing lanthanide and transition metal centers. The structures and magnetic properties are investigated. PMID- 29712383 TI - Wilhelm Schlenk: The Man Behind the Flask. PMID- 29712382 TI - An Exceptionally Stable Ti Superoxide Radical Ion: A Novel Heterogeneous Catalyst for the Direct Conversion of Aromatic Primary Amines to Nitro Compounds. AB - A matrix-bound superoxide radical anion, generated by treating Ti(OR)4 (R=iPr, nBu) with H2 O2 , is a selective heterogeneous catalyst for the oxidation of anilines to the corresponding nitroarenes with 50 % aqueous H2 O2 [Eq. (1)]. Yields of 82-98 % are obtained, even with anilines bearing electron-withdrawing substituents (R=NO2 , COOH). PMID- 29712384 TI - Thioformaldehyde S-sulfide (Thiosulfine). AB - Matrix isolation spectroscopy allows the direct identification of ylide 1 and its cyclic isomer 2. They were obtained by pyrolysis of 1,2,4-trithiolane under high vacuum; the cyclic compound forms from 1 by thermal ring closure in a kinetically controlled reaction. PMID- 29712385 TI - Chemically Modified Amino Acids in Copper Proteins That Bind or Activate Dioxygen. AB - Changing mechanisms: More than half of the known classes of copper oxidase contain a chemically modified amino acid within their active site. Recent experiments by Klinman et al. on the biogenesis of one of these, topaquinone (TPQ; see scheme), have shown that this occurs by a different mechanism from that observed for the aqueous aerobic synthesis of hydroxybenzoquinones in vitro. PMID- 29712386 TI - A Scandium Carbide Endohedral Metallofullerene: (Sc2 C2 )@C84. AB - Not Sc2 @C86 but Sc2 C2 @C84 : that is the conclusion of 13 C NMR spectroscopic and synchrotron X-ray powder diffraction studies on a new metallofullerene obtained by arc discharge of Sc2 O3 /graphite rods. The picture shows a schematic representation of the deduced structure, in which the novel scandium carbide cluster Sc2 C2 is encaged in D2d -C84 . PMID- 29712387 TI - Diversity-Based Organic Synthesis in the Era of Genomics and Proteomics. PMID- 29712390 TI - Bowl-Shaped Tris(2,6-diphenylbenzyl)tin Hydride: A Unique Reducing Agent for Radical and Ionic Chemistry. AB - Unique selectivity, hitherto not observable in ordinary radical and ionic reactions, is achieved with the bowl-shaped tris(2,6-diphenylbenzyl)tin hydride (TDTH; see structure), which has been successfully utilized as a new reducing agent. PMID- 29712389 TI - Catalytic Enantioselective Protonation of Lithium Ester Enolates Generated by Conjugate Addition of Arylthiolate to Enoates. AB - A chiral ligand, a catalytic amount of lithium cation, and no chiral proton source: These are features of the present asymmetric addition-protonation of propenoates with 2-trimethylsilylbenzenethiol. The reaction is catalyzed by a combination of lithium 2-trimethylsilylbenzenethiolate and the chiral ligand 1. Desulfurization of the product affords 2-substituted propanoates with high ee values and without racemization. Furthermore, 1 can be recovered quantitatively for reuse. PMID- 29712391 TI - Induction of a Preferred Twist in a Biphenyl Core by Stereogenic Centers: A Novel Approach to the Absolute Configuration of 1,2- and 1,3-Diols. AB - A quick, simple, and reliable method to assign the absolute configuration of 1,2- and 1,3-diols: all that is needed is to measure the CD sign of the A band (250 nm) of their biphenyldioxolanes 1 (n=0, 1). The chirality of the diol induces a preferred sense of twist in the biphenyl moiety (R,R->M and S,S->P), and a positive A band (a probe of M twist) reveals an R or R,R configuration of the diol. PMID- 29712392 TI - Fullerene Anions: Unusual Charge Distribution in C706. AB - The full NMR assignment by the INADEQUATE method clarifies the reduced aromaticity of the C706- ion (see picture; a-e indicate the five different carbon environments) relative to the neutral system, as well as the charge delocalization pattern. The reduction process was carried out with lithium in the presence of corannulene, which acts as an "electron shuttle". PMID- 29712393 TI - Alkylating Polymers: Resin-Released Carbenium Ions as Versatile Reactive Intermediates in Polymer-Assisted Solution-Phase Synthesis. AB - Solid-supported diazoalkane analogues for the smooth and clean esterifications of carboxylic acids [Eq. (1)] as well as of complex compound mixtures: the alkylating polymers presented here were synthesized as solid-supported 3-alkyl-1 aryltriazenes and are capable of releasing carbenium ions following acidic activation. PMID- 29712394 TI - Immobilization of Homogeneous Palladium(II) Complex Catalysts on Novel Polysiloxanes with Controllable Solubility: Important Implications for the Study of Heterogeneous Catalysis on Silica Surfaces. AB - Supported catalysts with controllable solubility were obtained by partial hydrolysis and derivatization of (MeO)3 Si(CH2 )11 N3 . The soluble Pd complex 1 thus obtained undergoes further hydrolysis to give an insoluble supported complex. Both materials are effective catalysts for the cyclotrimerization of alkynes. Hence, this methodology allows the soluble analogue of a heterogeneous catalyst to be studied by high-resolution solution NMR spectroscopy. TMS=SiMe3 , py=2-pyridyl. PMID- 29712395 TI - Parallel Synthesis of ZSM-5 Zeolite Films from Clear Organic-Free Solutions. AB - Twenty-one zeolite films were grown on a 2.5 cm alumina disk using a multiwell reactor. This parallel synthesis from clear organic-free solutions offers an interesting approach to the preparation of catalytic libraries. The morphologies of the films produced were found to be similar to those synthesized under conventional conditions but their X-ray diffraction patterns indicated a lower degree of orientation of crystallites. PMID- 29712396 TI - Synthesis and Self-Assembly of Monodisperse Indium Nanoparticles Prepared from the Organometallic Precursor [In(eta5 -C5 H5 )]. AB - Spontaneous decomposition of [In(eta5 -C5 H5 )] in the presence of poly(vinyl pyrrolidone) or trioctylphosphane oxide (TOPO) as a stabilizer gave monodisperse indium nanoparticles with a mean diameter of about 5-6 nm. In the case of TOPO, self-organization of the nanoparticles in two- and three-dimensional superlattices is observed. PMID- 29712397 TI - Molecular Switching in the Near Infrared (NIR) with a Functionalized Boron Dipyrromethene Dye. AB - The highly fluorescent, unsymmetrically substituted boron-dipyrromethene dye 1 shows emission features that are strongly dependent on the solvent polarity. Thus, 1 can be used for highly sensitive fluorometric probing of solvent polarity and acidity and furthermore can be switched chemically or electrochemically in the near infrared. PMID- 29712398 TI - About the Chemistry of Phosphorus Suboxides. AB - A terra incognita of chemistry is represented by the phosphorus suboxides owing to their high reactivity. The present computational study provides the first insights into this interesting class of compound. The picture shows the most stable isomer of P4 O2 (the smaller, darker centers denote oxygen atoms). PMID- 29712399 TI - Chemoselective Iterative Dehydrative Glycosylation. AB - The inherent difference in nucleophilicity between alkyl alcohols and free hemiacetals is capitalized upon in a new approach to chemoselective glycosylation. The strategy employs a controlled dehydrative coupling reaction for the rapid assembly of complex oligosaccharides and obviates the need for the extensive protective group and anomeric leaving group differentiation that is traditionally required. PMID- 29712400 TI - The Key to Solving the Protein-Folding Problem Lies in an Accurate Description of the Denatured State. AB - Accurate simulation at the atomic level of the folding process of a variety of peptides into different native folds can be achieved with a general purpose force field and Newton's equations of motion. The key to understanding this peptide folding lies in the unexpectedly small size of the denatured state and an accurate description thereof. PMID- 29712401 TI - Counter-Rotating Ring Currents in Coronene and Corannulene. AB - Explicit ab initio current-density maps contradict the annulene-within-an annulene model of [n]circulenes: in both coronene and corannulene the expected diamagnetic current on the perimeter is opposed by the central, paramagnetic ring current. PMID- 29712402 TI - First Use of a Mineral Liquid Crystal for Measurement of Residual Dipolar Couplings of a Nonlabeled Biomolecule. AB - Superimposing the two 13 C,1 H correlation maps of an unlabeled pentasaccharide acquired in D2 O (upper doublet) and in a magnetically aligned mineral liquid crystal, a colloidal suspension of V2 O5 (lower doublet), reveals that, in the second case, D components appear in addition to the usual splittings J. This is a result of the partial alignment of the biomolecule, and provides long-range structural NMR data. PMID- 29712403 TI - Electronic Insight into an Antithrombotic Agent by High-Resolution X-Ray Crystallography. AB - Five instead of 200 days measurement time are sufficient (thanks to area detection rather than conventional scintillation detection) to obtain the accurate charge density distribution of an antithrombotic agent with more than 50 atoms by a high-resolution X-ray diffraction experiment. The preferred sites of intermolecular interactions were identified from various topological properties, such as the reactive surface (zero Laplacian function, see picture) and the electrostatic potential. PMID- 29712404 TI - Towards the Development of Antitumor Vaccines: A Synthetic Conjugate of a Tumor Associated MUC1 Glycopeptide Antigen and a Tetanus Toxin Epitope. AB - Proliferation of cytotoxic T-cells, a prerequisite for the development of antitumor vaccines, was induced by 1, but not by its partial structures A and B. The conjugate 1 containing a tumor-associated Sialyl-TN -MUC-1 glycopeptide antigen A and a T-cell epitope B of tetanus toxin was synthesized by fragment condensation on a solid phase. PMID- 29712405 TI - Polyol-Mediated Preparation of Nanoscale Oxide Particles. AB - Largely monodisperse, crystalline nanoscale oxide particles (for example, Cu2 O, TiO2 , Nb2 O5 ) are preparatively accessible with the polyol method. The colloidal suspensions of the particles thus obtained can be employed readily for the homogeneous coating of various substrates (for example, glass plates, Al2 O3 powder). PMID- 29712406 TI - A Two-Dimensional Polyrotaxane with Large Cavities and Channels: A Novel Approach to Metal-Organic Open-Frameworks by Using Supramolecular Building Blocks. AB - A seven-membered molecular necklace composed of six copper ions and six pseudorotaxane units behaves as a secondary building block in the formation of a two-dimensional polyrotaxane network with large voids. This novel metal-organic framework allows size-selective anion exchange as well as the exchange of coordinated ligands. Thus a new synthetic strategy has been identified for modular porous solids which utilizes large, rigid, interlocked supermolecules as primary or secondary building blocks. PMID- 29712407 TI - 6-Aminofulvene-1-aldimine: A Model Molecule for the Study of Intramolecular Hydrogen Bonds. AB - An unusually substantial coupling is observed across the hydrogen bond of fully 15 N-labeled compound 1 when it is studied by 1 H and 15 N NMR spectroscopy. The structure was determined by X-ray diffraction and shown to correspond to tautomer 1 a (both in the solid state and in solution). These results open up a new field of hydrogen-bond research by NMR spectroscopic methods. PMID- 29712408 TI - X-Ray Photoelectron Spectroscopy of Porphycenes: Charge Asymmetry Across Low Barrier Hydrogen Bonds. AB - It is ironic that although it is typically a technique that "sees" all elements other than hydrogen atoms, X-ray photoelectron spectroscopy (XPS) acts as a sensitive probe of low-barrier hydrogen bonds, as seen in a study of free-base tetrapyrroles. The nitrogen 1s XPS peaks never quite coalesce, even when the N???H???N hydrogen bonds are almost perfectly symmetrical, as is the case for dibenzo[cde,mno]porphycenes. PMID- 29712409 TI - Design of a Molecular Beacon DNA Probe with Two Fluorophores. AB - Fluorescence resonance energy transfer between two fluorophores (F1 and F2 ) attached to the two ends of a molecular beacon DNA probe containing a hairpin structure can be used for quantitative DNA/RNA studies. Concentrations of target DNA as low as 1.7*10-10 M could be determined with a commercial spectrometer by using coumarin and 6-carboxyfluorescein as the fluorophores. Measurements on the Forster energy transfer distance for the donor/acceptor pair can also be carried out using these DNA probes. PMID- 29712410 TI - Synthesis of Nanophase Iron Oxide in Lumazine Synthase Capsids. AB - An enzyme-based bio-nanoreactor: By acting as a mineralization template, lumazine synthase, a 60-subunit enzyme complex which has a hollow porous shell, can fabricate nanocrystalline iron oxide. Fe ions can permeate the capsid through hydrophilic funnel-shaped channels lined with glutamic acid residues and become encapsulated in the cavity as FeIII oxide. The capsid increases in size from 15 to 30 nm in diameter through formation of a higher order structure as the concentration of FeIII increases. PMID- 29712411 TI - beta-Cyclodextrin-Assisted Intervalence Charge Transfer in Mixed-Valent [2]Rotaxane Complexes Having Metal Centers Linked by an Interrupted pi-Electron System. AB - FeII to RuIII electron transfer is initiated by the inclusion of saturated bridging ligands into the beta-cyclodextrin (CD) cavity of [2]rotaxane complexes and is observed as an intervalence charge transfer (IVCT) band in the electronic spectra. The rotaxanes are synthesized by using RuIII and FeII complexes as stoppers, beta-CD as the cyclic molecular head, and 4,4'-bipyridine derivatives with interrupted pi-electron system as the bridging ligand between the metal centers. PMID- 29712412 TI - beta-Mannosynthase: Synthesis of beta-Mannosides with a Mutant beta-Mannosidase. AB - Engineering enzymes: The glutamic acid nucleophile of a retaining beta mannosidase has been replaced with a serine residue to form a beta-mannosynthase. When the new enzyme is provided with an alpha-mannosyl fluoride donor and an appropriate acceptor, beta-mannoside linkages are synthesized. Remarkably, alpha mannosyl fluoride can be generated in situ by providing the mannosynthase with excess fluoride ion. PMID- 29712413 TI - An Artificial Ion Channel Formed by a Macrocyclic Resorcin[4]arene with Amphiphilic Cholic Acid Ether Groups. AB - Tail-to-tail assembly of two molecules of a resorcin[4]arene resulted in a bilayer membrane with an intramembrane ion channel. The steroidal tails introduced here have the advantages of giving a long-lived open state of the pore (2.5-4.5 s, as opposed to tens of milliseconds for alkyl tails) and of allowing the hydrophilic pore to be modified without changing the overall structural features. PMID- 29712414 TI - Synthesis of a Conjugated Macromolecular Initiator for Nitroxide-Mediated Free Radical Polymerization. AB - Controlled synthesis of rod-coil block copolymers is possible with a new macroinitiator for "living" nitroxide-mediated radical polymerization (NMRP). The synthesis of the new macroinitiator which contains a rodlike, conjugated poly(p phenylene vinylene) block is described. Electron microscopy imaging indicates microphase separation of the resulting block copolymer when cast from chloroform. PMID- 29712415 TI - Novel Approach to Mixed Group 15/16 Element Ligands-Formation of Unusual Trichalcogenophosphonato Ligands in Mixed Fe/Cr Clusters. AB - Trithiophosphonato and triselenophosphonato ligands containing mixed Fe/Cr clusters have been synthesized from the reaction of [Fe3 (CO)9 (MU3 -Y)2 ] (Y=S or Se) with [CpCr(CO)2 (eta3 -P3 ] in the presence of trimethylamine oxide. This novel approach leads to new clusters containing the first examples of P(S)S2 and P(Se)Se2 ligands in complexed forms. PMID- 29712416 TI - An Efficient Cobalt(I) Catalyst System for the Selective 1,4-Hydrovinylation of 1,3-Dienes. AB - Not a Diels-Alder reaction but a 1,4-hydrovinylation takes place on treatment of 1,3-dienes with functionalized alkenes in the presence of the catalyst system [CoBr2 (dppe)]/ZnI2 /Bu4 NBH4 (dppe = 1,2-bis(diphenylphosphanyl)ethane). With this reaction the 1,4-dienes with different substituents R1 -R4 can be obtained in high selectivity and good to excellent yields. PMID- 29712417 TI - Synthesis and Membrane-Binding Properties of a Characteristic Lipopeptide from the Membrane-Anchoring Domain of Influenza Virus A Hemagglutinin. AB - On the trail of the influenza virus! Fluorescent-labeled lipopeptides, such as the characteristic S-palmitoylated partial structure from influenza virus hemagglutinin A, can be synthesized efficiently by employing a new enzymatic protecting-group technique in the key steps. Their binding to model membranes was determined in a kinetic assay, so leading to a first approximation of the membrane-anchoring ability of the corresponding lipopeptide motif in the parent protein. PMID- 29712418 TI - SWATH Tandem Mass Spectrometry Workflow for Quantification of Mass Isotopologue Distribution of Intracellular Metabolites and Fragments Labeled with Isotopic 13C Carbon. AB - Accurate quantification of mass isotopologue distribution (MID) of metabolites is a prerequisite for 13C-metabolic flux analysis. Currently used mass spectrometric (MS) techniques based on multiple reaction monitoring (MRM) place limitations on the number of MIDs that can be analyzed in a single run. Moreover, the deconvolution step results in amplification of error. Here, we demonstrate that SWATH MS/MS, a data independent acquisition (DIA) technique allows quantification of a large number of precursor and product MIDs in a single run. SWATH sequentially fragments all precursor ions in stacked mass isolation windows. Co fragmentation of all precursor isotopologues in a single SWATH window yields higher sensitivity enabling quantification of MIDs of fragments with low abundance and lower systematic and random errors. We quantify the MIDs of 53 precursor and product ions corresponding to 19 intracellular metabolites from a dynamic 13C-labeling of a model cyanobacterium, Synechococcus sp. PCC 7002. The use of product MIDs resulted in an improved precision of many measured fluxes compared to when only precursor MIDs were used for flux analysis. The approach is truly untargeted and allows additional metabolites to be quantified from the same data. PMID- 29712419 TI - Correlation of Cell Surface Biomarker Expression Levels with Adhesion Contact Angle Measured by Lateral Microscopy. AB - Immunophenotyping is typically achieved using flow cytometry, but any influence a biomarker may have on adhesion or surface recognition cannot be determined concurrently. In this manuscript, we demonstrate the utility of lateral microscopy for correlating cell surface biomarker expression levels with quantitative descriptions of cell morphology. With our imaging system, we observed single cells from two T cell lines and two B cell lines adhere to antibody-coated substrates and quantified this adhesion using contact angle measurements. We found that SUP-T1 and CEM CD4+ cells, both of which express similar levels of CD4, experienced average changes in contact angle that were not statistically different from one another on surfaces coated in anti-CD4. However, MAVER-1 and BJAB K20 cells, both of which express different levels of CD20, underwent average changes in contact angle that were significantly different from one another on surfaces coated in anti-CD20. Our results indicate that changes in cell contact angles on antibody-coated substrates reflect the expression levels of corresponding antigens on the surfaces of cells as determined by flow cytometry. Our lateral microscopy approach offers a more reproducible and quantitative alternative to evaluate adhesion compared to commonly used wash assays and can be extended to many additional immunophenotyping applications to identify cells of interest within heterogeneous populations. PMID- 29712421 TI - Fuel-Driven Dissipative Self-Assembly of a Supra-Amphiphile in Batch Reactor. AB - Dissipative self-assembly is an intriguing but challenging research topic in chemistry, materials science, physics, and biology because most functional self assembly in nature, such as the organization and operation of cells, is actually an out-of-equilibrium system driven by energy dissipation. In this article, we successfully fabricated an I2-responsive supra-amphiphile by a PEGylated poly(amino acid) and realize its dissipative self-assembly in batch reactor by coupling it with the redox reaction between NaIO3 and thiourea, in which I2 is an intermediate product. The formation and dissipative self-assembly of the supra amphiphile can be repeatedly initiated by adding the mixture of NaIO3 and thiourea, which herein acts as "chemical fuel", while the lifetime of the transient nanostructures formed by the dissipative self-assembly is easily tuned by altering thiourea concentration in the "chemical fuel". Furthermore, as an application demo, the dissipative self-assembly of the supra-amphiphile is examined to control dispersion of multiwalled carbon nanotubes in water, exhibiting a good performance of organic pollutant removal. PMID- 29712420 TI - Directed Evolution Mimics Allosteric Activation by Stepwise Tuning of the Conformational Ensemble. AB - Allosteric enzymes contain a wealth of catalytic diversity that remains distinctly underutilized for biocatalysis. Tryptophan synthase is a model allosteric system and a valuable enzyme for the synthesis of noncanonical amino acids (ncAA). Previously, we evolved the beta-subunit from Pyrococcus furiosus, PfTrpB, for ncAA synthase activity in the absence of its native partner protein PfTrpA. However, the precise mechanism by which mutation activated TrpB to afford a stand-alone catalyst remained enigmatic. Here, we show that directed evolution caused a gradual change in the rate-limiting step of the catalytic cycle. Concomitantly, the steady-state distribution of the intermediates shifts to favor covalently bound Trp adducts, which have increased thermodynamic stability. The biochemical properties of these evolved, stand-alone TrpBs converge on those induced in the native system by allosteric activation. High-resolution crystal structures of the wild-type enzyme, an intermediate in the lineage, and the final variant, encompassing five distinct chemical states, show that activating mutations have only minor structural effects on their immediate environment. Instead, mutation stabilizes the large-scale motion of a subdomain to favor an otherwise transiently populated closed conformational state. This increase in stability enabled the first structural description of Trp covalently bound in a catalytically active TrpB, confirming key features of catalysis. These data combine to show that sophisticated models of allostery are not a prerequisite to recapitulating its complex effects via directed evolution, opening the way to engineering stand-alone versions of diverse allosteric enzymes. PMID- 29712423 TI - Readily Accessible Ambiphilic Cyclopentadienes for Bioorthogonal Labeling. AB - A new class of bioorthogonal reagents based on the cyclopentadiene scaffold is described. The diene 6,7,8,9-tetrachloro-1,4-dioxospiro[4,4]nona-6,8-diene (a tetrachlorocyclopentadiene ketal, TCK) is ambiphilic and self-orthogonal with remarkable stability. The diene reacts rapidly with a trans-cyclooctene and an endo-bicyclononyne, but slowly with dibenzoazacyclooctyne (DIBAC), allowing for tandem labeling studies with mutually orthogonal azides that react rapidly with DIBAC. TCK analogues are synthesized in three steps from inexpensive, commercially available starting materials. PMID- 29712422 TI - [11C]Para-Aminobenzoic Acid: A Positron Emission Tomography Tracer Targeting Bacteria-Specific Metabolism. AB - Imaging studies are frequently used to support the clinical diagnosis of infection. These techniques include computed tomography (CT) and magnetic resonance imaging (MRI) for structural information and single photon emission computed tomography (SPECT) or positron emission tomography (PET) for metabolic data. However, frequently, there is significant overlap in the imaging appearance of infectious and noninfectious entities using these tools. To address this concern, recent approaches have targeted bacteria-specific metabolic pathways. For example, radiolabeled sugars derived from sorbitol and maltose have been investigated as PET radiotracers, since these are efficiently incorporated into bacteria but are poor substrates for mammalian cells. We have previously shown that para-aminobenzoic acid (PABA) is an excellent candidate for development as a bacteria-specific imaging tracer as it is rapidly accumulated by a wide range of pathogenic bacteria, including metabolically quiescent bacteria and clinical strains, but not by mammalian cells. Therefore, in this study, we developed an efficient radiosynthesis for [11C]PABA, investigated its accumulation into Escherichia coli and Staphylococcus aureus laboratory strains in vitro, and showed that it can distinguish between infection and sterile inflammation in a murine model of acute bacterial infection. PMID- 29712424 TI - In Situ Surface-Enhanced Infrared Absorption Spectroscopy of Aqueous Molecules with Facile-Prepared Large-Area Reduced Graphene Oxide Island Film. AB - Midinfrared plasmons in patterned graphene could advance the development of surface-enhanced infrared absorption spectroscopy (SEIRAS). However, limitation in measuring the extinction spectra with transmission and external reflection configurations greatly restricts the analyses of aqueous samples. In addition, complicated, time- and cost-consuming preparation of patterned graphene also limits its progress. Here we demonstrate a facile-prepared large-scale reduced graphene oxide island film on a total internal reflection silicon prism, which not only shows a prominent enhancement effect in mid-infrared region but also effectively eliminates the contribution of bulk solution by optical near-field effect. As a result, the entire vibrational fingerprints of methylene blue monolayer in aqueous solution can be acquired with high sensitivity in real time. Our work extends the application of graphene-based SEIRAS to aqueous environment, breaking through previously unattainable technology. PMID- 29712425 TI - Interface Engineering of Colloidal CdSe Quantum Dot Thin Films as Acid-Stable Photocathodes for Solar-Driven Hydrogen Evolution. AB - Colloidal semiconductor quantum dot (CQD)-based photocathodes for solar-driven hydrogen evolution have attracted significant attention because of their tunable size, nanostructured morphology, crystalline orientation, and band gap. Here, we report a thin film heterojunction photocathode composed of organic PEDOT:PSS as a hole transport layer, CdSe CQDs as a semiconductor light absorber, and conformal Pt layer deposited by atomic layer deposition (ALD) serving as both a passivation layer and cocatalyst for hydrogen evolution. In neutral aqueous solution, a PEDOT:PSS/CdSe/Pt heterogeneous photocathode with 200 cycles of ALD Pt produces a photocurrent density of -1.08 mA/cm2 (AM-1.5G, 100 mW/cm2) at a potential of 0 V versus reversible hydrogen electrode (RHE) ( j0) in neutral aqueous solution, which is nearly 12 times that of the pristine CdSe photocathode. This composite photocathode shows an onset potential for water reduction at +0.46 V versus RHE and long-term stability with negligible degradation. In the acidic electrolyte (pH = 1), where the hydrogen evolution reaction is more favorable but stability is limited because of photocorrosion, a thicker Pt film (300 cycles) is shown to greatly improve the device stability and a j0 of -2.14 mA/cm2 is obtained with only 8.3% activity degradation after 6 h, compared with 80% degradation under the same conditions when the less conformal electrodeposition method is used to deposit the Pt layer. Electrochemical impedance spectroscopy and time-resolved photoluminescence results indicate that these enhancements stem from a lower bulk charge recombination rate, higher interfacial charge-transfer rate, and faster reaction kinetics. We believe that these interface engineering strategies can be extended to other colloidal semiconductors to construct more efficient and stable heterogeneous photoelectrodes for solar fuel production. PMID- 29712427 TI - Beyond Gene Transfection with Methacrylate-Based Polyplexes-The Influence of the Amino Substitution Pattern. AB - Methacrylate-based polymers represent promising nonviral gene delivery vectors, since they offer a large variety of polymer architectures and functionalities, which are beneficial for specific demands in gene delivery. In combination with controlled radical polymerization techniques, such as the reversible addition fragmentation chain transfer polymerization, the synthesis of well-defined polymers is possible. In this study we prepared a library of defined linear polymers based on (2-aminoethyl)-methacrylate (AEMA), N-methyl-(2-aminoethyl) methacrylate (MAEMA), and N,N-dimethyl-(2-aminoethyl)-methacrylate (DMAEMA) monomers, bearing pendant primary, secondary, and tertiary amino groups, and investigated the influence of the substitution pattern on their gene delivery capability. The polymers and the corresponding plasmid DNA complexes were investigated regarding their physicochemical characteristics, cytocompatibility, and transfection performance. The nonviral transfection by methacrylate-based polyplexes differs significantly from poly(ethylene imine)-based polyplexes, as a successful transfection is not affected by the buffer capacity. We observed that polyplexes containing a high content of primary amino groups (AEMA) offered the highest transfection efficiency, whereas polyplexes bearing tertiary amino groups (DMAEMA) exhibited the lowest transfection efficiency. Further insights into the uptake and release mechanisms could be identified by fluorescence and transmission electron microscopy, emphasizing the theory of membrane-pore formation for the time-efficient endosomal release of methacrylate-based vectors. PMID- 29712426 TI - Hydrogen Sulfide Sensing through Reactive Sulfur Species (RSS) and Nitroxyl (HNO) in Enterococcus faecalis. AB - Recent studies of hydrogen sulfide (H2S) signaling implicate low molecular weight (LMW) thiol persulfides and other reactive sulfur species (RSS) as signaling effectors. Here, we show that a CstR protein from the human pathogen Enterococcus faecalis ( E. faecalis), previously identified in Staphylococcus aureus ( S. aureus), is an RSS-sensing repressor that transcriptionally regulates a cst-like operon in response to both exogenous sulfide stress and Angeli's salt, a precursor of nitroxyl (HNO). E. faecalis CstR reacts with coenzyme A persulfide (CoASSH) to form interprotomer disulfide and trisulfide bridges between C32 and C61', which negatively regulate DNA binding to a consensus CstR DNA operator. A Delta cstR strain exhibits deficiency in catheter colonization in a catheter associated urinary tract infection (CAUTI) mouse model, suggesting sulfide regulation and homeostasis is critical for pathogenicity. Cellular polysulfide metabolite profiling of sodium sulfide-stressed E. faecalis confirms an increase in both inorganic polysulfides and LMW thiols and persulfides sensed by CstR. The cst-like operon encodes two authentic thiosulfate sulfurtransferases and an enzyme we characterize here as an NADH and FAD-dependent coenzyme A (CoA) persulfide reductase (CoAPR) that harbors an N-terminal CoA disulfide reductase (CDR) domain and a C-terminal rhodanese homology domain (RHD). Both cysteines in the CDR (C42) and RHD (C508) domains are required for CoAPR activity and complementation of a sulfide-induced growth phenotype of a S. aureus strain lacking cstB, encoding a nonheme FeII persulfide dioxygenase. We propose that S. aureus CstB and E. faecalis CoAPR employ orthogonal chemistries to lower CoASSH that accumulates under conditions of cellular sulfide toxicity and signaling. PMID- 29712428 TI - NAD(P)H:Quinone Oxidoreductase 1 (NQO1) as a Therapeutic and Diagnostic Target in Cancer. AB - NAD(P)H:quinone oxidoreductase 1 (NQO1) is a two-electron reductase responsible for detoxification of quinones and also bioactivation of certain quinones. It is abnormally overexpressed in many tumors and intimately linked with multiple carcinogenic processes. NQO1 is considered to be a cancer-specific target for therapy but currently available NQO1 inhibitors have not yet led to chemotherapeutic success. Utilization of NOQ1's ability to bioactivate chemotherapeutic quinones, however, has emerged as a promising selective anticancer therapy. On the basis of the different levels of NQO1 between cancer and normal cells, the catalytic property of NQO1 has recently been exploited to develop effective probes for cancer detection. This article summarizes the most significant advances concerning the discovery and development of NQO1 inhibitors, NQO1-directed chemotherapeutic quinones, and NQO1-activated optical probes, along with the prospects and potential obstacles in this research area. PMID- 29712430 TI - Angle-Dependent Atomic Force Microscopy Single-Chain Pulling of Adsorbed Macromolecules from Planar Surfaces Unveils the Signature of an Adsorption Desorption Transition. AB - The adsorption-desorption behavior of polymer chains is at the heart of macromolecular surface science and technology. With the current developments in atomic force microscopy (AFM), it has now become possible to address the desorption problem from the perspective of a single macromolecule. Here, we report on desorption of single polymer chains on planar surfaces by AFM-based single molecule force spectroscopy (SMFS) as a function of the pulling angle with respect to the surface-normal direction. SMFS experiments were performed in water with various substrates using different polymers covalently attached to the AFM probe tip. End-grafting at the AFM tip was achieved by surface-initiated polymerization using initiator functionalized tips. We found that the desorption force increases with a decreasing pulling angle, i.e., an enhanced adhesion of the polymer chain was observed. The magnitude of the desorption force shows a weak angular dependence at pulling angles close to the surface normal. A significant increase of the force is observed at shallower pulling from a certain pulling angle. This behavior carries the signature of an adsorption-desorption transition. The angular dependence of the normalized desorption force exhibits a universal behavior. We compared and interpreted our results using theoretical predictions for single-chain adsorption-desorption transitions. PMID- 29712431 TI - Asparagine Deamidation in a Complementarity Determining Region of a Recombinant Monoclonal Antibody in Complex with Antigen. AB - Asparagine deamidation in the complementarity determining regions of recombinant monoclonal antibodies has been extensively studied and shown to have a negative impact on antigen binding. Those asparagine residues are typically exposed and thus have a higher tendency toward deamidation, depending also on local structure and environmental factors such as temperature and pH. Deamidation rates and products of a susceptible asparagine residue in the complementarity determining regions of a recombinant monoclonal antibody free in solution or in the antibody antigen complex were studied. The results demonstrated that incubation of the antibody or its antigen complex generated a similar amount of aspartate. The expected amount of isoaspartate product was detected in free antibody, but it was completely lacking in the antibody-antigen complex. PMID- 29712429 TI - In Silico Pharmacoepidemiologic Evaluation of Drug-Induced Cardiovascular Complications Using Combined Classifiers. AB - Drug-induced cardiovascular complications are the most common adverse drug events and account for the withdrawal or severe restrictions on the use of multitudinous postmarketed drugs. In this study, we developed new in silico models for systematic identification of drug-induced cardiovascular complications in drug discovery and postmarketing surveillance. Specifically, we collected drug-induced cardiovascular complications covering the five most common types of cardiovascular outcomes (hypertension, heart block, arrhythmia, cardiac failure, and myocardial infarction) from four publicly available data resources: Comparative Toxicogenomics Database, SIDER, Offsides, and MetaADEDB. Using these databases, we developed a combined classifier framework through integration of five machine-learning algorithms: logistic regression, random forest, k-nearest neighbors, support vector machine, and neural network. The totality of models included 180 single classifiers with area under receiver operating characteristic curves (AUC) ranging from 0.647 to 0.809 on 5-fold cross-validations. To develop the combined classifiers, we then utilized a neural network algorithm to integrate the best four single classifiers for each cardiovascular outcome. The combined classifiers had higher performance with an AUC range from 0.784 to 0.842 compared to single classifiers. Furthermore, we validated our predicted cardiovascular complications for 63 anticancer agents using experimental data from clinical studies, human pluripotent stem cell-derived cardiomyocyte assays, and literature. The success rate of our combined classifiers reached 87%. In conclusion, this study presents powerful in silico tools for systematic risk assessment of drug-induced cardiovascular complications. This tool is relevant not only in early stages of drug discovery but also throughout the life of a drug including clinical trials and postmarketing surveillance. PMID- 29712432 TI - Toward Accurate Solvation Free Energy Calculation with the Reference Interaction Site Model Self-Consistent Field: Introduction of a New Bridge Function. AB - The reference interaction site model self-consistent field (RISM-SCF) has the potential to become a powerful tool for studying solution chemistry because of its low computational cost and the capability of calculating local solvation structures accurately, such as hydrogen bonding. However, RISM-SCF has a critical weakness: it is not possible to accurately reproduce the experimental data for solvation free energy. In this study, we proposed a new bridge function and combined it with the repulsive bridge correction (RBC) proposed by Kovalenko and Hirata. To verify the effectiveness of our approach, we computed the hydration free energies of 70 organic molecules. Our method successfully improved the overestimation of the cavitation free energy inherent in the original RISM-SCF. PMID- 29712433 TI - Bilirubin Nanoparticle-Assisted Delivery of a Small Molecule-Drug Conjugate for Targeted Cancer Therapy. AB - Despite growing interest in targeted cancer therapy with small molecule drug conjugates (SMDCs), the short half-life of these conjugates in blood associated with their small size has limited their efficacy in cancer therapy. In this report, we propose a new approach for improving the antitumor efficacy of SMDCs based on nanoparticle-assisted delivery. Ideally, a nanoparticle-based delivery vehicle would prolong the half-life of an SMDC in blood and then release it in response to stimuli in the tumor microenvironment (TME). In this study, PEGylated bilirubin-based nanoparticles (BRNPs) were chosen as an appropriate delivery carrier because of their ability to release drugs in response to TME-associated reactive oxygen species (ROS) through rapid particle disruption. As a model SMDC, ACUPA-SN38 was synthesized by linking the prostate-specific membrane antigen (PSMA)-targeting ligand, ACUPA, to the chemotherapeutic agent, SN38. ACUPA-SN38 was loaded into BRNPs using a film-formation and rehydration method. The resulting ACUPA-SN38@BRNPs exhibited ROS-mediated particle disruption and rapid release of the SMDC, resulting in greater cytotoxicity toward PSMA-overexpressing prostate cancer cells (LNCaP) than toward ROS-unresponsive ACUPA-SN38@Liposomes. In a pharmacokinetic study, the circulation time of ACUPA-SN38@BRNPs in blood was prolonged by approximately 2-fold compared with that of the SMDC-based micellar nanoparticles. Finally, ACUPA-SN38@BRNPs showed greater antitumor efficacy in a PSMA-overexpressing human prostate xenograft tumor model than SN38@BRNPs or the SMDC alone. Collectively, these findings suggest that BRNPs are a viable delivery carrier option for various cancer-targeting SMDCs that suffer from short circulation half-life and limited therapeutic efficacy. PMID- 29712434 TI - Estimating Atomic Contributions to Hydration and Binding Using Free Energy Perturbation. AB - We present a general method called atom-wise free energy perturbation (AFEP), which extends a conventional molecular dynamics free energy perturbation (FEP) simulation to give the contribution to a free energy change from each atom. AFEP is derived from an expansion of the Zwanzig equation used in the exponential averaging method by defining that the system total energy can be partitioned into contributions from each atom. A partitioning method is assumed and used to group terms in the expansion to correspond to individual atoms. AFEP is applied to six example free energy changes to demonstrate the method. Firstly, the hydration free energies of methane, methanol, methylamine, methanethiol, and caffeine in water. AFEP highlights the atoms in the molecules that interact favorably or unfavorably with water. Finally AFEP is applied to the binding free energy of human immunodeficiency virus type 1 protease to lopinavir, and AFEP reveals the contribution of each atom to the binding free energy, indicating candidate areas of the molecule to improve to produce a more strongly binding inhibitor. FEP gives a single value for the free energy change and is already a very useful method. AFEP gives a free energy change for each "part" of the system being simulated, where part can mean individual atoms, chemical groups, amino acids, or larger partitions depending on what the user is trying to measure. This method should have various applications in molecular dynamics studies of physical, chemical, or biochemical phenomena, specifically in the field of computational drug discovery. PMID- 29712435 TI - Prolyl Hydroxylase Inhibitors: A Breakthrough in the Therapy of Anemia Associated with Chronic Diseases. AB - Chronic kidney disease, cancer, chronic inflammatory disorders, nutritional, and genetic deficiency can cause anemia. Hypoxia causes induction of hypoxia inducible factor (HIF), which stimulates erythropoietin (EPO) synthesis. Prolyl hydroxylase domain (PHD) enzyme inhibition can stabilize hypoxia-inducible factor (HIF). HIF stabilization also decreases hepcidin, a hormone of hepatic origin, which regulates iron homeostasis. PHD inhibitors represent a novel pharmacological treatment of anemia associated with chronic diseases. Many orally active PHD inhibitors like roxadustat, molidustat, vadadustat, and desidustat are in late phase clinical trials. This review discusses the role of PHD inhibitors in the treatment of anemia associated with chronic diseases. PMID- 29712436 TI - Special Issue on Membraneless Organelles. PMID- 29712438 TI - Design and Fabrication of Far-Ultraviolet Reflective Broadband Filter Based on Dielectric Materials. AB - In the far-ultraviolet (UV) region, optical materials are dispersive and absorbing. The previous successful design method utilized in the visible band should be re-examined. We report on the design and fabrication of a far-UV reflective broadband filter based on dielectric materials lanthanum fluoride (LaF3) and magnesium fluoride (MgF2). Extended bandwidth technology is utilized in designing this filter. The obtained filter has a high reflectance in the working wavelength range of 140-180 nm, meanwhile, with good suppression in shorter and longer wavelength regions. In 2016, this filter was employed in a wide-angle aurora imager (WAAI) installed in the Feng Yun III satellite that will be launched in China. PMID- 29712437 TI - Near-Infrared Diffuse Reflectance Measurement Method Based on Temperature Insensitive Radial Distance. AB - The variation of temperature is one of the main interference factors that affect the detection accuracy of near-infrared (NIR) diffuse reflectance. In this paper, a measurement method based on temperature-insensitive radial distance was proposed, and its feasibility and effectiveness were verified in Intralipid solutions. First, the possibility of temperature-insensitive radial distance was deduced based on the analytic solution of the steady-state diffusion equation in an infinite media, and the temperature-insensitive radial distances of 3% Intralipid solution in the wavelength range of 1000-1600 nm was calculated. Second, a detection system was designed to measure the diffuse reflectance of 3% Intralipid solutions at multiple radial distances with different glucose concentration (0-100 mM) and different temperatures (35-40 C). Both theoretical calculations and experimental results demonstrated the existence of temperature insensitive radial distances in the range of 1000-1340 nm and 1440-1600 nm, and the distances were hardly affected by glucose variations. Finally, the glucose information extracted from the diffuse reflectance of Intralipid solutions at different radial distances under random temperature variations and constant temperature were compared. The result showed that the correlation between the glucose concentration and the diffuse reflectance obtained at the temperature insensitive radial distance was significantly better than that of other radial distances, which was almost close to the situation of constant temperature. Therefore, the measurement method based on temperature-insensitive radial distance can effectively reduce the influence of temperature variations on NIR diffuse reflectance, and it is expected to improve the accuracy of diffuse reflectance in human body components detection and industrial field analysis. PMID- 29712439 TI - Blood-based novel biomarkers for nonalcoholic steatohepatitis. AB - Nonalcoholic fatty liver disease has become a social health challenge of global concern. The term nonalcoholic steatohepatitis (NASH) is a more severe condition than simple steatosis and distinguishing NASH from nonalcoholic fatty liver disease is particularly important. Liver biopsy remains a gold standard in diagnosing NASH. Meanwhile, radiological techniques such as ultrasonography and MRI are also applied widely. However, the invasive and expensive examination is not suitable for screening, and there is a great need for reliable and appropriate biomarkers to screen patients for NASH. Based on the current studies of blood-based novel biomarkers, we attempt to summarize the latest findings on biomarkers for NASH, including blood biomarkers encompassing proteins, lipids and miRNAs; the correlation between extracellular vesicles and NASH; and treatment strategies for NASH. PMID- 29712440 TI - On the Widths of Bands in the Infrared Spectra of Oxyanions. AB - It is well known that the antisymmetric stretching (nu3) band in the mid-infrared spectra of oxyanion salts is usually very broad, whereas all the other fundamental bands are narrow. In this paper, we propose that the underlying cause of the increased width is the effect of the very high absorption index of this band for samples prepared with a range of particle sizes. When oxyanion salts are ground, the diameter of the resulting particles usually varies from less than 100 nm to about 2 um. While the peak absorbance of the nu3 band of the smaller particles (diameter < 200 nm) is less than 1, that of the larger particles can be as high as 6. We show that the average transmittance of these particles leads to a significant band broadening, especially when there are small voids in the resulting sample. Although the effect is always seen in the spectra of alkali halide disks and mineral oil mulls, it is also seen in diffuse reflection and attenuated total reflection (ATR) spectra. Because the depth of penetration of infrared radiation below 1500 cm-1 is less than 1 um for ATR spectra measured with a germanium internal reflection element (IRE), the width of the nu3 band is lower than that of ATR spectra measured with an IRE of lower refractive index such as diamond on zinc selenide. PMID- 29712441 TI - Construction of pSPI12-cured Salmonella enterica serovar Pullorum and identification of IpaJ as an immune response modulator. AB - In Salmonella, plasmids participate in many pathways involved in virulence, metabolism, and antibiotic resistance. To investigate the function of the ipaJ gene in a multi-copy plasmid pSPI12 prevalent in Salmonella enterica serovar Pullorum (S. Pullorum), we established a method to eliminate the plasmid and constructed the plasmid-cured bacteria C79-13-DeltapSPI12 by using the suicide vector pDM4. Briefly, a 500 bp fragment ipaJU from pSPI12 was cloned into pDM4 and transformed into S. Pullorum C79-13 by conjugative transfer. After homologous recombination, the suicide vector was inserted into pSPI12 to produce pSPI12-pDM4 ipaJU. Induction of the expression of the sacB gene in the suicide vector killed the bacteria harbouring plasmid, while the progeny losing the plasmid survived in the plate with sucrose. The plasmid-cured strain showed extremely decreased ability to infect chicken macrophage HD11 cells and LMH hepatic epithelial cells compared to wild type strain and complementary strain carrying ipaJ. Additionally, IFN-gamma mRNA levels were up-regulated in HD11 cells or chicken spleens infected by plasmid-cured strain, but no difference was detected in IL-4 among the three strains. Transforming ipaJ into S. Enteritidis also decreased expression of proinflammatory cytokines in infected macrophages or chicken spleens compared to wild type strain. These results suggest that the ipaJ gene in pSPI12 is involved in S. Pullorum infection and that IpaJ protein modulates immune response. PMID- 29712442 TI - Validation of Fluorescence Spectroscopy to Detect Adulteration of Edible Oil in Extra Virgin Olive Oil (EVOO) by Applying Chemometrics. AB - Due to high price and nutritional values of extra virgin olive oil (EVOO), it is vulnerable to adulteration internationally. Refined oil or other vegetable oils are commonly blended with EVOO and to unmask such fraud, quick, and reliable technique needs to be standardized and developed. Therefore, in this study, adulteration of edible oil (sunflower oil) is made with pure EVOO and analyzed using fluorescence spectroscopy (excitation wavelength at 350 nm) in conjunction with principal component analysis (PCA) and partial least squares (PLS) regression. Fluorescent spectra contain fingerprints of chlorophyll and carotenoids that are characteristics of EVOO and differentiated it from sunflower oil. A broad intense hump corresponding to conjugated hydroperoxides is seen in sunflower oil in the range of 441-489 nm with the maximum at 469 nm whereas pure EVOO has low intensity doublet peaks in this region at 441 nm and 469 nm. Visible changes in spectra are observed in adulterated EVOO by increasing the concentration of sunflower oil, with an increase in doublet peak and correspondingly decrease in chlorophyll peak intensity. Principal component analysis showed a distinct clustering of adulterated samples of different concentrations. Subsequently, the PLS regression model was best fitted over the complete data set on the basis of coefficient of determination (R2), standard error of calibration (SEC), and standard error of prediction (SEP) of values 0.99, 0.617, and 0.623 respectively. In addition to adulterant, test samples and imported commercial brands of EVOO were also used for prediction and validation of the models. Fluorescence spectroscopy combined with chemometrics showed its robustness to identify and quantify the specified adulterant in pure EVOO. PMID- 29712444 TI - Survival: A Medical Memoir: From Drug Discovery to Clinical Cancer Trials by Lorne J. Brandes Survival: A Medical Memoir: From Drug Discovery to Clinical Cancer Trials Lorne J. Brandes Victoria, BC : FriesenPress , 2016 , xv+ 583 p., $34.99. PMID- 29712445 TI - ? PMID- 29712443 TI - Evaluation of full S1 gene sequencing of classical and variant infectious bronchitis viruses extracted from allantoic fluid and FTA cards. AB - : Sequence variability in the S1 gene determines the genotype of infectious bronchitis virus (IBV) strains. A single RT-PCR assay was developed to amplify and sequence the full S1 gene for six classical and variant IBVs (M41, D274, 793B, IS/885/00, IS/1494/06 and Q1) enriched in allantoic fluid (AF) or the same AF inoculated onto Flinders Technology Association (FTA) cards. Representative strains from each genotype were grown in specific-pathogen-free eggs and RNA was extracted from AF. Full S1 gene amplification was achieved using primer A and primer 22.51. Products were sequenced using primers A, 1050+, 1380+ and SX3+ to obtain short sequences covering the full gene. Following serial dilutions of AF, detection limits of the partial assay were higher than those of the full S1 gene. Partial S1 sequences exhibited higher-than-average nucleotide similarity percentages (79%; 352 bp) compared to full S1 sequences (77%; 1756 bp), suggesting that full S1 analysis allows greater strain differentiation. For IBV detection from AF-inoculated FTA cards, four serotypes were incubated for up to 21 days at three temperatures, 4 degrees C, room temperature (approximately 24 degrees C) and 40 degrees C. RNA was extracted and tested with partial and full S1 protocols. Through partial sequencing, all IBVs were successfully detected at all sampling points and storage temperatures. In contrast, using full S1 sequencing it was not possible to amplify the gene beyond 14 days or when stored at 40 degrees C. Data presented show that for full S1 sequencing, a substantial amount of RNA is needed. Field samples collected onto FTA cards are unlikely to yield such quantity or quality. ABBREVIATIONS: AF: allantoic fluid; CD50: ciliostatic dose 50; FTA: Flinders Technology Association; IB: infectious bronchitis; IBV: infectious bronchitis virus. PMID- 29712447 TI - ? PMID- 29712448 TI - ? PMID- 29712450 TI - ? PMID- 29712453 TI - ? PMID- 29712454 TI - ? PMID- 29712455 TI - ? PMID- 29712456 TI - ? PMID- 29712457 TI - ? PMID- 29712459 TI - ? PMID- 29712462 TI - ? PMID- 29712461 TI - ? PMID- 29712464 TI - ? PMID- 29712465 TI - Concerns Regarding the Proposed New Diagnosis of "Modern-Type Depression" in Japan. PMID- 29712466 TI - Eradicating Traumatic Memories: Implications for PTSD Treatment. PMID- 29712467 TI - Toward Dissemination of Secondary Prevention for Psychosis. PMID- 29712468 TI - Failure to Identify a Human Trafficking Victim. PMID- 29712469 TI - Comment on Late-Onset ADHD Reconsidered With Comprehensive Repeated Assessments Between Ages 10 and 25. PMID- 29712470 TI - A Role for Placental CRH in Cortical Thinning and Neuropsychiatric Outcomes. PMID- 29712471 TI - Addressing Incomplete Psychiatric Histories in Adult ADHD: Response to Agnew Blais and Arseneault. PMID- 29712474 TI - CORRECTION. PMID- 29712476 TI - Addressing the Homeless Mentally Ill in San Francisco. PMID- 29712475 TI - Developmental Delay, Treatment-Resistant Psychosis, and Early-Onset Dementia in a Man With 22q11 Deletion Syndrome and Huntington's Disease. PMID- 29712477 TI - The Importance of Scrutinizing Emergent ADHD Symptoms in Adults: Response to Chamberlain and Muller. PMID- 29712478 TI - Mindful Pharmacogenetics: Drug Dosing for Mental Health. PMID- 29712479 TI - Is a Socio-Cultural Analysis of Depressive Disorders a Matter of Concern? Response to Kaiya. PMID- 29712480 TI - Late-Onset ADHD: Case Closed or Open Question? PMID- 29712481 TI - Quantifying and reducing powder shear sensitivity when manufacturing capsules with lubricants. AB - The purpose of this work was to develop a methodology that quantifies the extent of shear induced during an encapsulation process and show how formulation composition and manufacturing process designs can be changed to reduce the negative impact on drug product quality attributes. The powder feed system used in a dosing disc type pharmaceutical capsule filling machine induced additional shear of the powder prior to slug formation. The shear occurred both in the hopper portion, via the rotation of the feed auger and impeller, and in the powder bowl via the tamping pin agitation and/or shear against the stationary surfaces such as the powder level scraper. The extent of shear was quantified to assess the impact of further dispersing the hydrophobic lubricant, magnesium stearate, in both active and placebo formulations. Stratified samples over the course of the encapsulation run showed suppression in the drug dissolution profiles and decrease in the interparticulate tensile strength of the encapsulated product. The amount of shear (duration and rate) induced during the encapsulation unit operation can be much greater than that from typical bin blending operations and therefore requires consideration during product design and scale-up to ensure product robustness. PMID- 29712482 TI - Does pregnancy interval after laparoscopic sleeve gastrectomy affect maternal and perinatal outcomes? AB - BACKGROUND: Obesity is a global health epidemic and is associated with many maternal and neonatal complications. Laparoscopic sleeve gastrectomy (LSG) is among the surgical treatments for obesity. The appropriate timing of pregnancy following LSG remains controversial and few studies have evaluated this public health issue. OBJECTIVE: To evaluate the effect of pregnancy timing after LSG on maternal and perinatal outcomes. STUDY DESIGN: We performed a retrospective observational study of 23 pregnant women who underwent LSG at a tertiary hospital in Turkey. Women who became pregnant within 18 months of undergoing LSG were included in the early pregnancy after LSG group, and those who became pregnant after 18 months were included the late pregnancy after LSG group. Maternal and perinatal outcomes were evaluated, including gestational diabetes mellitus (GDM), pregnancy-associated hypertensive disorders, preterm birth, mode of delivery, small and large for gestational age births (small for gestational age (SGA), large for gestational age (LGA)), birth injury, and congenital malformations. RESULTS: Body mass index (BMI) at conception was higher in the early pregnancy after LSG group than in the late pregnancy after LSG group (30.48 versus 27.25, respectively; p = .03). Pregnancy interval after LSG did not impact maternal fetal complications or mode of delivery. After a 75 g oral glucose tolerance test (OGTT) for GDM, 75% (n = 6) of the early pregnancy group presented with early dumping syndrome, compared to only 13.3% (n = 2) of the late pregnancy after LSG group (p = .009). CONCLUSIONS: LSG may reduce obesity-related gestational complications, such as GDM and LGA. The interval between LSG and conception did not impact maternal or neonatal outcomes. Screening for GDM can result in dumping syndrome in pregnancies after LSG. PMID- 29712483 TI - Evaluation the relationship between serum progesterone level and pain perception after cesarean delivery. AB - INTRODUCTION: Cesarean delivery is the most common surgery in obstetrics, and pain relief after cesarean section is an important concern for obstetricians and their patients. OBJECTIVE: The aim of this study was to evaluate the relationship between serum progesterone level and pain perception after cesarean delivery. METHOD: The study was performed as a prospective cohort study on 166 pregnant women who were candidates for elective cesarean delivery due to previous cesarean section. Before surgery, serum progesterone level was measured. Pain score of women was evaluated 4, 8, 12, and 24 h after surgery using visual analog scale (VAS) score, and correlation between progesterone level and pain was evaluated. RESULTS: The median value of serum progesterone was 119.45 ng/ml. Mean pain score in hours 4, 8, 12, and 24 were 6.80 +/- 2.11, 5.31 +/- 1.48, 3.89 +/- 1.68, and 2.30 +/- 1.26, respectively. The women were divided according to mean progesterone level of 119.45 ng/ml into two groups of high progesterone level (>=119.45) and low progesterone level (<119.45), and the pain score was evaluated in different times (hour 4, 8, 12, and 24) for both levels of progesterone. The mean pain score in the 4, 8, 12, and 24 h were significantly lower in high progesterone group (progesterone level >=119.45). The number of women with low pain score (less than five) in hours 12 and 24 was significantly higher in high progesterone level group. With increasing BMI, progesterone level was lower and women with higher BMI, had a higher pain score in hours 4, 8, 12, and 24, while women with lower BMI had a lower pain score during the same hours. (p = .004, r = 0.223; p = .004, r = 0.223; p = .039, r = 0.160; and p = .007, r = 0.207). Progesterone level and BMI (p = .025, r = - 0.174), and progesterone level and pain score in hours 4, 8, 12, and 24 (p = .000, r = - 0.324; p = .000, r = - 0.474; p = .000, r = - 0.329; and p = .000, r = - 0.417, respectively) showed a negative significant correlation. Putting three variables of age, gestational age, and BMI in a multiple regression model, progesterone level showed significant negative correlation with the pain score in hour 4 (p = .000, r = - 0.305), hour 8 (p = .000, r = - 0.461), hour 12 (p = .000, r = - 0.328), and hour 24 (p = .000, r = - 0.409). CONCLUSIONS: Serum progesterone level showed a negative correlation with the pain score after cesarean section. PMID- 29712484 TI - Does prenatal diagnosis of critical congenital heart diseases influence the prereferral mortality in a center without surgical intervention? AB - BACKGROUND: Prenatal diagnosis ameliorates some preoperative and postoperative outcomes in critical congenital heart disease (CHD). Despite large variability among anatomical defect types, nearly half of them are diagnosed antenatally. We aimed to investigate the effect of the antenatal diagnosis on prereferral mortality of infants with critical CHD in a center without cardiovascular surgery clinic. METHODS: Medical records of the neonates who were diagnosed with critical CHD between the years 2010 and 2016 in Zekai Tahir Burak Women's health Education and Research Hospital were retrospectively reviewed for the study. Patients were divided in two groups as prenatal and postnatal regarding the time of diagnosis. Groups were compared in terms of demographical, clinical characteristics, and prereferral mortality rates. RESULTS: Seventy seven neonates were included in the study. Of those, 39 (50%) infants had prenatal diagnosis. Most common types of CHD were tetralogy of Fallot (TOF) with pulmonary atresia, hypoplastic left heart syndrome (HLHS), and transposition of the great arteries (TGA), respectively. Demographical and clinical characteristics were similar between the groups. Minor congenital anomalies were more common in the patients with prenatal diagnosis (41 versus 18%, p = .021). Blood gas parameters were similar except pCO2 levels, which were slightly lower in the postnatal diagnosis group (p = .048). There was no difference with regard to prereferral mortality between prenatal and postnatal diagnosed infants. CONCLUSIONS: Prenatal diagnosis may not be always associated with improved survival in critical CHD in a center without immediate surgical intervention opportunity. PMID- 29712485 TI - Reply to letter to the editor regarding the article: Measurement of the fetal occiput-spine angle during the first stage of labor as predictor of the progress and outcome of labor. PMID- 29712486 TI - Hypoxia and tumor angiogenesis in the era of hepatocellular carcinoma transarterial loco-regional treatments. AB - This review focuses upon interactions and potential therapeutic targets in the 'vicious cycle' between hypoxia and neoangiogenesis following treatment of hepatocellular carcinoma with transarterial loco-regional therapies. Biomarkers correlated with angiogenesis have been studied by many authors as prognostic determinants following transarterial intrahepatic therapy. According to these results future therapies directed toward specific factors related to angiogenesis could play a significant role in preventing local tumor recurrence and remote metastasis. PMID- 29712487 TI - Prospective study of myelin water fraction changes after mild traumatic brain injury in collegiate contact sports. AB - OBJECTIVE Mild traumatic brain injury (mTBI) in athletes, including concussion, is increasingly being found to have long-term sequelae. Current imaging techniques have not been able to identify early damage caused by mTBI that is predictive of long-term symptoms or chronic traumatic encephalopathy. In this preliminary feasibility study, the authors investigated the use of an emerging magnetic resonance imaging (MRI) technique, multicomponent driven equilibrium single pulse observation of T1 and T2 (mcDESPOT), in visualizing acute and chronic white matter changes after mTBI in collegiate football and rugby players. METHODS This study was a nonrandomized, nonblinded prospective trial designed to quantify changes in the myelin water fraction (MWF), used as a surrogate MRI measure of myelin content, in a group of male collegiate football and rugby players, classified here as a contact sport player (CSP) cohort, at the time of mTBI diagnosis and 3 months after injury when the acute symptoms of the injury had resolved. In addition, differences in the MWF between the CSP cohort and a control cohort of noncontact sport players (NCSPs) were quantified. T-tests and a threshold-free cluster enhancement (TFCE) statistical analysis technique were used to identify brain structures with significant changes in the MWF between the CSP and NCSP cohorts and between immediately postinjury and follow-up images obtained in the CSP cohort. RESULTS Brain MR images of 12 right-handed male CSPs were analyzed and compared with brain images of 10 right-handed male NCSPs from the same institution. A comparison of CSP and NCSP baseline images using TFCE showed significantly higher MWFs in the bilateral basal ganglia, anterior and posterior corpora callosa, left corticospinal tract, and left anterior and superior temporal lobe (p < 0.05). At the 3-month follow-up examination, images from the CSP cohort still showed significantly higher MWFs than those identified on baseline images from the NCSP cohort in the bilateral basal ganglia, anterior and posterior corpora callosa, and left anterior temporal lobe, and also in the bilateral corticospinal tracts, parahippocampal gyrus, and bilateral juxtapositional (previously known as supplemental motor) areas (p < 0.05). In the CSP cohort, a t-test comparing the MWF at the time of injury and 3 months later showed a significant increase in the overall MWF at follow-up (p < 0.005). These increases were greatest in the bilateral basal ganglia and deep white matter. MWF decreases were seen in more superficial white matter (p < 0.005). CONCLUSIONS In this preliminary study, MWF was found to be increased in the brains of CSPs compared with the brains of controls, suggesting acute/chronic MWF alterations in CSPs from previous injuries. Increases in the MWF were also demonstrated in the brains of CSPs 3 months after the players sustained an mTBI. The full clinical significance of an increased MWF and whether this reflects axon neuropathology or disorderly remyelination leading to hypermyelination has yet to be determined. PMID- 29712488 TI - Noninvasive detection of PD-L1 on circulating tumor cells in patient blood samples. PMID- 29712489 TI - Sensitivity of prenatal ultrasound for detection of trisomy 18. AB - OBJECTIVES: To evaluate the sensitivity of prenatal ultrasound (US) for trisomy (T18) diagnosis and describe US findings in a large tertiary care institution in the USA. MATERIALS AND METHODS: This was a retrospective cohort of all T18 cases diagnosed at our institution from October 2004 to October 2014 based on prenatal or postnatal genetic diagnostic testing. We included all women with a fetus affected by T18 who had a comprehensive US by a maternal-fetal medicine specialist performed at our institution. US findings were reviewed, classified by organ system, and categorized as an anomaly or soft marker. Chi-square or t-test was used for statistical analysis. RESULTS: We included 128 cases of T18 with confirmed cytogenetic analysis -110 (86%) of which were diagnosed prenatally or suspected by cell-free DNA and confirmed postnatally, and 18 of which underwent neonatal blood sampling alone. One hundred and twenty-one (95%) had at least one abnormal US finding. Anomalies were more frequently identified on US at >=20 weeks as compared with <20 weeks (93% versus 76%; p = .004). The mean number of findings detected per fetus was 5.1 +/- 3.0. Fetuses diagnosed by postnatal sampling alone had a similar number of US exams performed and number of abnormal findings compared to those diagnosed prenatally. CONCLUSION: Ninety-five percent of fetuses with T18 had at least one abnormal US finding. This sensitivity of is higher than reported in most prior studies, but is not 100%, and should be considered when counseling women regarding prenatal diagnosis of T18. RATIONALE: Historical detection rates for abnormal sonographic findings in trisomy 18 fetuses range from 70% to 100%. These studies are limited by small sample sizes. This is a contemporary study of ultrasound findings in a large group of women with confirmed trisomy 18 by prenatal or postnatal genetic diagnosis. We provide expansive detail on soft markers and anomalies broken down by organ-system and gestational age. PMID- 29712490 TI - Random urine uric acid to creatinine and prediction of perinatal asphyxia: a meta analysis. AB - OBJECTIVE: The purpose of the present review is to evaluate whether urine uric acid to creatinine ratio is increased in perinatal asphyxia and hypoxic-ischemic encephalopathy (HIE), as well as to assess its predictive accuracy in the disease. METHODS: We used the Medline (1966-2017), Scopus (2004-2017), Clinicaltrials.gov (2008-2017), Embase (1980-2017), Cochrane Central Register of Controlled Trials CENTRAL (1999-2017), and Google Scholar (2004-2017) databases in our primary search along with the reference lists of electronically retrieved full-text papers. The hierarchical summary receiver operating characteristic (HSROC) model was used for the meta-analysis of diagnostic accuracy. RESULTS: Fourteen studies were finally included in the present review, that investigated 1226 neonates. Urinary uric acid to creatinine ratio was significantly higher in neonates with perinatal asphyxia than in healthy controls (mean differences (MD): 1.43 95%CI [1.17, 1.69]). Specifically, the mean difference for Sarnat stage 1 was 0.70 (95%CI [0.28, 1.13]), for stage 2 1.41 (95%CI [0.99, 1.84]), and for stage 3 2.71 (95%CI [2.08, 3.35]). The estimated sensitivity for the summary point was 0.90 (95%CI (0.82-0.95)), the specificity was 0.88 (95%CI (0.73-0.95)) and the diagnostic odds ratio was calculated at 63.62 (95%CI (17.08-236.96)). CONCLUSIONS: Urinary uric acid to creatinine ratio is a rapid and an easily detected biomarker that may help physicians identify neonates at risk of developing perinatal asphyxia and HIE. However, large-scale prospective studies are still needed to determine its value in predicting mortality, as well as short and long-term adverse neurological outcomes. PMID- 29712491 TI - Factors associated with receipt of hematopoietic cell transplantation for acute lymphoblastic leukemia. AB - AIM: To evaluate practice patterns of hematopoietic cell transplantation (HCT) for acute lymphoblastic leukemia. MATERIALS & METHODS: We utilized the National Cancer Database to extract patient-level data of adults (aged 18-80 years) diagnosed with acute lymbhoblastic leukemia between 2003 and 2012. We performed multivariable logistic regression to determine variables associated with the use of HCT. RESULTS: Out of a total of 11,871 patients, 12.7% received HCT. In a multivariate analysis, older age, male sex, higher Charlson co-morbidity score, nonacademic treatment center, poor education and Medicare/Medicaid or no insurance were associated with lower likelihood of receiving HCT. CONCLUSION: Our study demonstrates variations in the utilization of HCT based on socioeconomic and health system factors. PMID- 29712492 TI - A Critical Review on the Concept of Avapeedaka Snehapana, a Special Mode of Lipid Administration. AB - Avapeedaka Snehapana is a unique and special method of internal administration of Sneha dravya (unctuous medicine) mentioned in the classical ayurveda texts. It is mainly indicated in mutravegarodha janya vikara (diseases due to the suppression of urge of micturition). Because of the lack of adequate review and analysis, this method of administration of snehapana (internal administration of lipid) is losing its significance from the practices and the concept remains unexplored. The reasons for not being practiced like other snehana (oleation therapy) procedures are because of the less understanding of the concept of administration, scattered and minimal textual references. Through this review, we intend to have a detailed analysis on the concept of avapeedaka snehapana mentioned in the Brihatrayees (Caraka Samhita, Sushruta Samhita, and Ashtanga Hridaya-the 3 main texts of ayurveda) with its possible practical methods of administration. The role of ghrita (ghee) in inducing the ketogenesis is also analyzed. Being a ketogenic diet, the benefits of ghrita are interpreted. These efforts may help bring down avapeedaka snehapana into the mainstream of practice. PMID- 29712493 TI - McDonald versus Shirodkar cervical cerclage for the prevention of preterm birth: impact of body mass index. AB - OBJECTIVE: To compare obstetrical outcomes on women undergoing a McDonald or Shirodkar cerclage and to estimate the impact of maternal body mass index (BMI) on these outcomes. METHODS: We conducted a retrospective review of the medical records of all women with singleton pregnancies who underwent placement of a McDonald or Shirodkar cerclage at St. Francis Hospital from January 2008 to October 2013. The subjects were categorized based on BMI groups (normal: less than 25 kg/m2, overweight: 25-29 kg/m2, obese: 30 kg/m2 or more). The primary outcome was gestational age at delivery. Statistical analyses included chi square, Student's t-test, and multivariable regression analysis. RESULTS: Of 95 women, 47 (49.5%) received a Shirodkar, and 48 (50.5%) a McDonald cerclage. 16 women (16.8%) were categorized as normal weight, 35 (36.8%) as overweight, and 44 (46.3%) as obese. Gestational age at delivery differed significantly by group, decreasing with each categorical increase in BMI (normal: 39.0 +/- 0.3 weeks; overweight: 36.6 +/- 0.7 weeks; obese: 33.0 +/- 1.1 weeks; p < .01). Overall, women receiving a Shirodkar cerclage had significantly longer pregnancies than women with a McDonald cerclage (36.7 +/- 0.6 weeks versus 33.9 +/- 1.0 weeks; p = .02). However, analysis showed a significant interaction between weight status and gestational age at delivery. Obese women had significantly longer pregnancies when they received a Shirodkar cerclage versus a McDonald cerclage (32.6 +/- 1.0 weeks versus 28.8 +/- 0.9 weeks; p < .01). However, there was no significant difference in gestational age at delivery between women categorized as normal/overweight (Shirodkar: 33.5 +/- 0.9 weeks; McDonald: 32.9 +/- 0.9 weeks; p = .63). CONCLUSIONS: Compared to obese women receiving a McDonald cerclage, obese women receiving a Shirodkar cerclage had significantly longer pregnancies. No significant differences in pregnancy duration were found in normal/overweight women regardless of cerclage technique. Pregnancy duration in obese women receiving a Shirodkar cerclage was similar to the pregnancy duration of normal/overweight women. PMID- 29712494 TI - Chromogranin A as a biomarker for prostate cancer: is it actually relevant for clinical practice? PMID- 29712495 TI - Development of a novel diagnostic algorithm to predict NASH in HCV-positive patients. AB - Non-alcoholic steato-hepatitis (NASH) is a severe disease characterised by liver inflammation and progressive hepatic fibrosis, which may progress to cirrhosis and hepatocellular carcinoma. Clinical evidence suggests that in hepatitis C virus patients steatosis and NASH are associated with faster fibrosis progression and hepatocellular carcinoma. A safe and reliable non-invasive diagnostic method to detect NASH at its early stages is still needed to prevent progression of the disease. We prospectively enrolled 91 hepatitis C virus-positive patients with histologically proven chronic liver disease: 77 patients were included in our study; of these, 10 had NASH. For each patient, various clinical and serological variables were collected. Different algorithms combining squamous cell carcinoma antigen-immunoglobulin-M (SCCA-IgM) levels with other common clinical data were created to provide the probability of having NASH. Our analysis revealed a statistically significant correlation between the histological presence of NASH and SCCA-IgM, insulin, homeostasis model assessment, haemoglobin, high-density lipoprotein and ferritin levels, and smoke. Compared to the use of a single marker, algorithms that combined four, six or seven variables identified NASH with higher accuracy. The best diagnostic performance was obtained with the logistic regression combination, which included all seven variables correlated with NASH. The combination of SCCA-IgM with common clinical data shows promising diagnostic performance for the detection of NASH in hepatitis C virus patients. PMID- 29712496 TI - Circulating tumor DNA as prognostic markers for late stage NSCLC with bone metastasis. AB - PURPOSE: Bone metastases from non-small cell lung cancer (NSCLC) are common, and current prognostic stratification methods are challenging to predict outcomes. The aim of the study is to examine circulating tumor DNA as a potential biomarker to gauge overall survival. METHODS: Late stage NSCLC patients associated with bone metastasis were recruited for the study. Circulating tumor DNA was quantified using droplet digital polymerase chain reaction, a sensitive assay that is capable to pick up low mutant DNA frequencies. KRAS and EGFR genes were serially profiled at monthly intervals to ascertain their variations in different patients during monitoring. These were correlated to overall survival as an endpoint measure. RESULTS: Analysis of circulating tumor DNA and tumor tissues samples yielded a 94.7% overall agreement for KRAS and EGFR mutations. Higher circulating tumor DNA quantities of more than 1.4-fold were also detected in patients with bone metastases. To gauge the prognostic utility of circulating tumor DNA for these patient groups, circulating tumor DNA quantities as well as the patients' genotypes were used to stratify patients in the survival analysis. Hazard ratios for patient groups with and without bone metastasis was 1.63. Patients groups separated by circulating tumor DNA quantity and molecular profile were 1.51 and 1.58, respectively. The results showed that circulating tumor DNA was a useful marker to identify patients with better survival outcomes. CONCLUSION: The good overall concordance in genetic profiling and circulating tumor DNA measurements associated with NSCLC patients with bone metastases supports plasma-based testing. This study presents exploratory evidence of the prognostic role of circulating tumor DNA that can be of value in the management of the disease. PMID- 29712498 TI - Evaluation of the PROMIS pediatric global health scale (PGH-7) in children with asthma. AB - OBJECTIVE: To evaluate the reliability and validity of the PROMIS Pediatric Global Health scale, a 7-item measure of perceived physical, mental, and social health, in children with asthma. METHODS: From February 2014 to February 2015, convenience samples of 8-17 year-old children (n = 182) and parents of 5-17 year old children (n = 328) visiting an emergency department for treatment of asthma were enrolled. The Asthma Control Test was used to characterize children as controlled versus not controlled, and the PROMIS Asthma Impact Scale was used to assess asthma symptoms' impact on functional status. We conducted longitudinal analyses among 92 children and 218 parents at 3 weeks, and 74 children and 171 parents at 8 weeks after enrollment. RESULTS: The PGH-7 reliability ranged from 0.66 to 0.81 for child-report and 0.76 to 0.82 for parent-proxy. In cross sectional analyses, children with controlled asthma had PGH-7 scores 0.40-0.95 standard deviation units higher than those who were uncontrolled. The PGH-7 was responsive to changes in overall general health between time points, with moderate effect sizes (0.5-0.6 standard deviation units). In longitudinal analyses, PGH-7 scores were no different between those who stayed uncontrolled versus became controlled at 3 weeks of follow-up; however, by 8 weeks of follow up, the differences between these groups were 0.7-0.8 standard deviation units, indicative of large effects. CONCLUSIONS: The PGH-7 is a reliable and valid patient-reported outcome for assessing general health among children with asthma. It is a useful complement to other asthma-specific outcome measures. PMID- 29712497 TI - First-trimester metabolomic prediction of stillbirth. AB - BACKGROUND: Stillbirth remains a major problem in both developing and developed countries. Omics evaluation of stillbirth has been highlighted as a top research priority. OBJECTIVE: To identify new putative first-trimester biomarkers in maternal serum for stillbirth prediction using metabolomics-based approach. METHODS: Targeted, nuclear magnetic resonance (NMR) and mass spectrometry (MS), and untargeted liquid chromatography-MS (LC-MS) metabolomic analyses were performed on first-trimester maternal serum obtained from 60 cases that subsequently had a stillbirth and 120 matched controls. Metabolites by themselves or in combination with clinical factors were used to develop logistic regression models for stillbirth prediction. Prediction of stillbirths overall, early (<28 weeks and <32 weeks), those related to growth restriction/placental disorder, and unexplained stillbirths were evaluated. RESULTS: Targeted metabolites including glycine, acetic acid, L-carnitine, creatine, lysoPCaC18:1, PCaeC34:3, and PCaeC44:4 predicted stillbirth overall with an area under the curve [AUC, 95% confidence interval (CI)] = 0.707 (0.628-0.785). When combined with clinical predictors the AUC value increased to 0.740 (0.667-0.812). First-trimester targeted metabolites also significantly predicted early, unexplained, and placental-related stillbirths. Untargeted LC-MS features combined with other clinical predictors achieved an AUC (95%CI) = 0.860 (0.793-0.927) for the prediction of stillbirths overall. We found novel preliminary evidence that, verruculotoxin, a toxin produced by common household molds, might be linked to stillbirth. CONCLUSIONS: We have identified novel biomarkers for stillbirth using metabolomics and demonstrated the feasibility of first-trimester prediction. PMID- 29712499 TI - Lightning may pose a danger to patients receiving deep brain stimulation: case report. AB - Deep brain stimulation (DBS) is an established treatment option for advanced stages of Parkinson's disease and other movement disorders. It is known that DBS is susceptible to strong electromagnetic fields (EMFs) that can be generated by various electrical devices at work, home, and in medical environments. EMFs can interfere with the proper functioning of implantable pulse generators (IPGs). Very strong EMFs can generate induction currents in implanted electrodes and even damage the brain. Manufacturers of DBS devices have issued a list of warnings on how to avoid this danger. Strong EMFs can result from natural forces as well. The authors present the case of a 66-year-old woman who was being treated with a rechargeable DBS system for neck dystonia when her apartment was struck by lightning. Domestic electronic devices that were operating during the event were burned and destroyed. The woman's IPG switched off but remained undamaged, and she suffered no neurological consequences. PMID- 29712500 TI - Effects of fentanyl for pain control and neuroprotection in very preterm newborns on mechanical ventilation. AB - OBJECTIVE: This study aimed to evaluate the cerebral protection effect of fentanyl infusion in very preterm infants in the first 72 h of mechanical ventilation. METHODS: In this double-blind, randomized, controlled trial, mechanically ventilated newborns (<32 weeks' gestational age) were randomized to fentanyl (continuous infusion of fentanyl) or placebo (continuous infusion of glucose, controls) in the first 72 h of the mechanical ventilation period. The premature infant pain profile (PIPP), cerebral blood flow velocity, neuron specific enolase (NSE) concentrations in plasma samples, and cerebral function monitoring (CFM) recordings were evaluated. RESULTS: Twenty-seven infants were allocated to the fentanyl group and 26 to the control group. The fentanyl group had significantly lower PIPP scores than did the control group at 12, 24, 48, and 72 h after the start of infusion (all p < .05). No significant changes in hemodynamic parameters were observed during the observation period using transcranial Doppler flow measurements (p > .05). The fentanyl group had lower NSE levels and higher total CFM scores compared with the control group (both p < .05). CONCLUSION: In very preterm infants on mechanical ventilation, continuous fentanyl infusion might protect the developing brain by relieving pain during the first 72 h of mechanical ventilation. PMID- 29712501 TI - The feasibility and accuracy of ultrasound assessment in the labor room. AB - OBJECTIVE: Vaginal examination is widely used to assess the progress of labor; however, it is subjective and poorly reproducible. We aim to assess the feasibility and accuracy of transabdominal and transperineal ultrasound compared to vaginal examination in the assessment of labor and its progress. METHODS: Women were recruited as they presented for assessment of labor to a tertiary inner city maternity service. Paired vaginal and ultrasound assessments were performed in 192 women at 24-42 weeks. Fetal head position was assessed by transabdominal ultrasound defined in relation to the occiput position transformed to a 12-hour clock face; fetal head station defined as head-perineum distance by transperineal ultrasound; cervical dilatation by anterior to posterior cervical rim measurement and caput succedaneum by skin-skull distance on transperineal ultrasound. RESULTS: Fetal head position was recorded in 99.7% (298/299) of US and 51.5% (154/299) on vaginal examination (p < .0001 1 ). Bland-Altman analysis showed 95% limits of agreement, -5.31 to 4.84 clock hours. Head station was recorded in 96.3% (308/320) on vaginal examination (VE) and 95.9% (307/320) on US (p = .79 1 ). Head station and head perineum distance were negatively correlated (Spearman's r = -.57, p < .0001). 54.4% (178/327) of cervical dilatation measurements were determined using US and 100% on VE/speculum (p < .0001). Bland Altman analysis showed 95% limits of agreement -2.51-2.16 cm. The presence of caput could be assessed in 98.4% (315/320) of US and was commented in 95.3% (305/320) of VEs, with agreement for the presence of caput of 76% (p < .05). Fetuses with caput greater than 10 mm had significantly lower head station (p < .0001). CONCLUSIONS: We describe comprehensive ultrasound assessments in the labor room that could be translated to the assessment of women in labor. Fetal head position is unreliably determined by vaginal examination and agrees poorly with US. Head perineum distance has a moderate correlation with fetal head station in relation to the ischial spines based on vaginal examination. Cervical dilatation is not reliably assessed by ultrasound except at dilatations of less than 4 cm. Caput is readily quantifiable by ultrasound and its presence is associated with lower fetal head station. Transabdominal and transperineal ultrasound is feasible in the labor room with an accuracy that is generally greater than vaginal examinations. PMID- 29712502 TI - A new approach for assessing executive functions in everyday life, among adolescents with Genetic Generalised Epilepsies. AB - Studies have characterised relationships between cognitive status and a variety of clinical epilepsy factors. The aim of this study was to describe a new approach for assessing executive functions in everyday life and its unique expression in adolescents with Genetic Generalised Epilepsies (GGEs) compared with typical peers. Twenty adolescents with a diagnosis of GGEs and 20 typical healthy peers, matched by age and gender, were studied. Assessment of everyday executive function was carried out using: (1) the Weekly Calendar Planning Activity (WCPA), a direct performance based and outcome measure of strategy use and cognitive performance; and (2) Behavior Rating Inventory of Executive Function (BRIEF) parental report. Adolescents with GGEs demonstrated significantly less accuracy, less efficiency and fewer strategies used, as measured by the WCPA. Parents of adolescents with GGEs rated their child's daily performance as less efficient compared with typical peers. Better ratings of executive function (low BRIEF score) were associated with greater WCPA accuracy in the entered appointments. The WCPA provides a useful evaluation of cognitive performance for adolescents with GGEs and a functionally relevant information on task efficiency, self-monitoring and effective strategy use. Direct observation of performance supplements parental ratings and has strong potential to guide intervention and measure outcomes. PMID- 29712503 TI - Disparities in Screening for Head and Neck Cancer: Evidence from the NHANES, 2011 2014. AB - Objective To measure the association between race and head and neck cancer screening and education. Study Design Nationally representative survey. Setting US National Center for Health Statistics. Subjects and Methods Pooled data from the 2011-2014 National Health and Nutrition Examination Survey were used to examine disparities in head and neck cancer education and screening among US citizens aged >=18 years. We measured the association between race and head and neck cancer education and screening, adjusting for age, sex, education, income, and health insurance. Subtype analyses were performed on ever smokers, a lifetime consumption of >=100 cigarettes, and nonsmokers, a lifetime consumption of <100 cigarettes. Results Among smokers, only 20.2% were educated about the benefits of giving up cigarette smoking; 27.7% had ever received an oral cancer screening examination in which a doctor or dentist pulls on the tongue; and 24.8% had ever had a screening examination in which a doctor or dentist feels the neck. As compared with white smokers, nonwhite smokers were significantly less likely to receive an oral cancer screening examination in which the tongue was pulled (black smokers: odds ratio, 0.44; 95% CI, 0.31-0.63). Although 72.2% of screenings of white participants were performed by dentists, black participants were more often screened by a physician (36.4%) as compared with any other race. Conclusion This study highlights socioeconomic disparities in head and neck cancer screening and education. We advocate increased patient screening and education by primary care physicians, especially for nonwhite patients and patients with relevant risk factors. PMID- 29712504 TI - Preliminary Assessment of Dynamic Voice CT in Post-Airway Reconstruction Patients. AB - Objectives To compare the ability of the dynamic voice computed tomography (CT) scan to characterize laryngeal function in airway reconstruction patients vs bedside endoscopic nasopharyngolaryngoscopy and videolaryngostroboscopy. Study Design Case series with chart review. Settings Pediatric tertiary care center. Subjects and Methods Retrospective case series of children and young adults with a history of complex airway surgeries with subsequent dysphonia. We analyzed clinical data for all patients who underwent an airway reconstruction procedure between January 1, 2010, and April 30, 2016, and also had a dynamic voice CT and bedside endoscopic exam during the same period. Results Twenty-four patients were analyzed (4 male, 20 female) with a mean age of 15.1 years (95% confidence interval [CI], 12.9-17.22). Patients had a mean of 2.2 airway surgeries (95% CI, 1.8-2.6), with 62.5% of them being open procedures. Laryngotracheoplasty with a cartilage graft was the most common procedure (40.0%). The pattern of laryngeal closure could be detected in all cases with the dynamic CT scan (n = 24/24, 100%) compared to 87.5% (21/24) with the standard endoscopic examination ( P = .04). The location of gap closure could be detected in all cases (24/24) with the dynamic voice CT while 20.8% (5/24 patients) could not be rated with standard endoscopy/stroboscopy ( P = .02). Dynamic voice CT was able to assess the vertical closure pattern of the glottis 100% (24/24) while it could be detected in 83.3% (20/24) cases with endoscopic study ( P = .04). Conclusion Dynamic voice CT shows promise as an additional tool for evaluation of patients with a history of complex airway procedures by providing complementary information. PMID- 29712505 TI - The weight of fatherhood: identifying mechanisms to explain paternal perinatal weight gain. AB - Men appear to gain weight during the transition to parenthood, and fathers are heavier than non-fathers. Paternal perinatal weight gain may set weight trajectories in midlife and have long-term health implications. Since men do not undergo the physical demands of pregnancy and breastfeeding, the specific mechanisms underlying weight gain in new fathers warrant investigation. This review aims to stimulate research on paternal perinatal weight gain by suggesting testable potential mechanisms that (1) show change across the transition to parenthood and (2) play a role in weight and body composition. We identify seven mechanisms, within three categories: behavioural mechanisms (sleep, physical activity, and diet), hormonal mechanisms (testosterone and cortisol), and psychological mechanisms (depression and stress). We also discuss direct effects of partner pregnancy influences (e.g., 'couvade syndrome') on men's body weight. In presenting each mechanism, we discuss how it may be affected by the transition to parenthood, and then review its role in body composition and weight. Next, we describe bidirectional and interactive effects, discuss timing, and present three broad research questions to propel theoretical development. PMID- 29712507 TI - Sulodexide Monotherapy in Chronic Idiopathic Subjective Tinnitus: A Randomized Controlled Trial. AB - Objective To report the therapeutic value of sulodexide monotherapy in the management of patients with chronic subjective idiopathic tinnitus. Study Design Randomized double-blinded controlled trial. Setting Single tertiary care institution. Subjects and Methods Observations from 124 patients who received either sulodexide or placebo were collected from the patients' medical records. Computer-generated tables were used to allocate treatments. Patients took 1 tablet of the drug or placebo each morning and evening for 40 consecutive days. The response was assessed by the Tinnitus Handicap Inventory and the Mini Tinnitus Questionnaire. Results Between 2014 and 2017, 124 patients were divided into 2 treatment arms. The sulodexide group encompassed 63 patients, whereas the placebo arm contained 61 patients. Tinnitus Handicap Inventory and Mini-Tinnitus Questionnaire scores were more decreased in the sulodexide arm compared to the placebo group ( P = .03 and P < .01, respectively). Conclusions Sulodexide monotherapy decreases chronic subjective idiopathic tinnitus. PMID- 29712508 TI - A qualitative investigation of masculine identity after traumatic brain injury. AB - Men are twice as likely as women to experience a traumatic brain injury (TBI), suggesting that aspects of masculine identity contribute to how people acquire their brain injuries. Research also suggests that masculine identity impacts on how people manage their health experiences. The current study aimed to explore the experience of masculine identity following TBI. Individual interviews were conducted with 10 men aged 21-67 years who had experienced a TBI. All were living in the community. Interpretative phenomenological analysis was used to consider lived experiences and to explore the meaning of the TBI experience in relation to masculine identity. Three superordinate themes emerged from the analysis: doing life and relationships differently, self-perceptions and the perceived view of others, and managing the impact of TBI as a man. These themes are considered in relation to how participants' experiences interacted with dominant social ideals of masculine identity. The findings highlighted how masculine identity may be a valuable aspect of self in considering threats to and reconstruction of self identity after TBI. Aspects of gender identity should be considered in order to promote engagement, support adjustment and achieve meaningful outcomes in rehabilitation. PMID- 29712506 TI - Spinal CXCL9 and CXCL11 are not involved in neuropathic pain despite an upregulation in the spinal cord following spinal nerve injury. AB - Chemokines-mediated neuroinflammation in the spinal cord plays a critical role in the pathogenesis of neuropathic pain. Chemokine CXCL9, CXCL10, and CXCL11 have been identified as a same subfamily chemokine which bind to CXC chemokine receptor 3 to exert functions. Our recent work found that CXCL10 is upregulated in spinal astrocytes after spinal nerve ligation (SNL) and acts on chemokine receptor CXCR3 on neurons to contribute to central sensitization and neuropathic pain, but less is known about CXCL9 and CXCL11 in the maintenance of neuropathic pain. Here, we report that CXCL9 and CXCL11, same as CXCL10, were increased in spinal astrocytes after SNL. Surprisingly, inhibition of CXCL9 or CXCL11 by spinal injection of shRNA lentivirus did not attenuate SNL-induced neuropathic pain. In addition, intrathecal injection of CXCL9 and CXCL11 did not produce hyperalgesia or allodynia behaviors, and neither of them induced ERK activation, a marker of central sensitization. Whole-cell patch clamp recording on spinal neurons showed that CXCL9 and CXCL11 enhanced both excitatory synaptic transmission and inhibitory synaptic transmission, whereas CXCL10 only produced an increase in excitatory synaptic transmission. These results suggest that, although the expression of CXCL9 and CXCL11 are increased after SNL, they may not contribute to the maintenance of neuropathic pain. PMID- 29712509 TI - Systematic Review and Meta-analysis of SNOT-22 Outcomes after Surgery for Chronic Rhinosinusitis with Nasal Polyposis. AB - Objective Wide variation exists regarding reported outcomes after endoscopic sinus surgery (ESS) for chronic rhinosinusitis with nasal polyps (CRSwNP). This study seeks to combine data across studies to generate a summary measure and explore factors that might lead to variation. Data Sources OVID Medline, Scopus, EbscoHost, Database of Abstracts and Reviews of Effects, Health Technology Assessment, and National Health Service Economic Evaluation Database. Review Methods A search was performed following the PRISMA guidelines. Two independent researchers conducted a search using the mentioned data sources. Studies published before August 29, 2016, that involved ESS to treat CRSwNP were included. Mean changes in Sinonasal Outcome Test-22 (SNOT-22) scores were determined through metaregression of the following independent variables: publication year, sex, age, allergy status, asthma, tobacco use, prior surgery, follow-up length, and preoperative SNOT-22. Results Fifteen articles with 3048 patients treated with ESS met inclusion criteria. Pooled analyses of SNOT-22 scores revealed a mean change of 23.0 points (95% CI, 20.2-25.8; P < .001). A metaregression of patient factor effects on the mean change of SNOT-22 scores demonstrated that age ( r = 0.71, P = .01), asthma ( r = 0.21, P = .01), prior ESS ( r = 0.29, P = .01), and preoperative SNOT-22 score ( r = 0.4, P < .01) correlated with greater improvement in SNOT-22 scores. Tobacco use ( r = -0.91, P = .01) and longer lengths of follow-up ( r = -0.45, P < .01) were associated with less improvement in SNOT-22 scores. Conclusions Quality-of-life outcomes are significantly improved after ESS among patients with CRSwNP. Patient-specific factors may affect the degree of SNOT-22 change after surgery. PMID- 29712510 TI - Modulation of brain insulin signaling in Alzheimer's disease: New insight on the protective role of green coffee bean extract. AB - OBJECTIVE: Alzheimer's disease (AD), a neurodegenerative disorder, involves brain insulin signaling cascades and insulin resistance (IR). Because of limited treatment options, new treatment strategies are mandatory. Green coffee bean extract (GCBE) was reported to attenuate IR and improve brain energy metabolism. We aimed to investigate the possible use of GCBE as a prophylactic strategy to delay the onset of AD or combined with pioglitazone (PIO) as a strategy to retard the progression of AD. METHODS: Rats received 10% fructose in drinking water for 18 weeks to induce AD. GCBE-prophylactic group received GCBE for 22 weeks started 4 weeks prior to fructose administration. The PIO group treated with PIO for 6 weeks started on week 12 of fructose administration. The GCBE+PIO group received GCBE for 22 weeks started 4 weeks prior to fructose administration and treated with PIO for the last 6 weeks of fructose administration. RESULTS: Pretreatment with GCBE, either alone or combined with PIO, alleviated IR-induced AD changes. GCBE improved cognition, decreased serine phosphorylation of insulin receptor substrate, increased phosphoinositol-3 kinase (PI3K) activity and protein kinase B (Akt) gene expression, decreased glycogen synthase kinase-3beta (GS3Kbeta) gene expression and Tau hyperphosphorylation. DISCUSSION: GCBE exerted neuroprotective effects against IR-induced AD mediated by alleviating IR and modulating brain insulin signaling cascade. PMID- 29712511 TI - The Production of Corporate Research to Manufacture Doubt About the Health Hazards of Products: An Overview of the Exponent Bakelite(r) Simulation Study. AB - Although corporate sponsorship of research does not necessarily lead to biased results, in some industries, it has resulted in the publication of inaccurate and misleading data. Some companies have hired scientific consulting firms to retrospectively calculate exposures to hazardous products during use that are no longer manufactured or sold. As an example, this paper reviews one such study-a litigation-generated study of Union Carbide Corporation's asbestos-containing product, Bakelite(r). This analysis is based on previously secret documents, produced as a result of litigation. The study generated asbestos fiber exposure measurements which resulted in underestimates of actual exposures to create doubt about the hazards associated with manufacture and manipulation of Bakelite(r). PMID- 29712512 TI - Incidence of Vestibular Schwannoma over the Past Half-Century: A Population-Based Study of Olmsted County, Minnesota. AB - Objective The absence of a centralized health system has limited epidemiologic research surrounding vestibular schwannoma (VS) in the United States. The Rochester Epidemiology Project (REP) comprises a unique medical consortium that covers a complete population of all ages in a well-defined geographic region over the past half-century. The objective of this study was to characterize the incidence of sporadic VS over this extended period. Study Design Population-based study. Setting Olmsted County, Minnesota. Subjects and Methods Review of all VSs diagnosed between January 1, 1966, and December 31, 2016, was conducted with the REP medical records linkage system. Results A total of 153 incident cases of VS were identified. The incidence of VS significantly increased over the past half century from 1.5 per 100,000 person-years during the first decade to 4.2 in the last decade ( P < .001). Incidence increased with age ( P < .001): those aged >=70 years exhibited the highest incidence rate at 18.3 per 100,000 person-years in the last decade. Age at diagnosis significantly increased from a median of 52 years in the first decade to 62 years in the last ( P < .001). Despite presenting with fewer symptoms and smaller tumors, the time delay between symptom onset and diagnosis significantly decreased over the past 5 decades (all P < .05). Almost 1 in 4 patients was diagnosed incidentally in the last decade. Conclusion The incidence of VS increased significantly over the past half-century to a rate greater than previously reported. Patients' ease of access to medical care in Olmsted County and the comprehensive REP system likely contributed to this elevated detection rate of VS. PMID- 29712514 TI - Prenatal diagnosis of suprarenal mass by magnetic resonance imaging: a case series. AB - OBJECTIVE: The aim of this study was to evaluate the perinatal outcomes and postnatal follow-up of prenatally diagnosed suprarenal masses (SRMs) evaluated by magnetic resonance imaging (MRI). METHODS: Thirteen fetuses with SRMs detected during routine prenatal ultrasound screening were evaluated by MRI between February 2007 and May 2015. The prenatal characteristics of the masses, complications of the pregnancies, and related malformations were collected as the postnatal clinical, radiological, and pathological data. RESULTS: The median gestational age at MRI was 30 weeks (18-41), and birth weight was 3285 (1700 3750) g. The mean follow-up period was 6 years (1.3-10). We observed 69.2% of the masses, which were predominantly cystic (69.2%), located on the left side. Associated malformations were found in 23% of the fetuses, with congenital heart defects being more prevalent. During the pregnancy, 15.4% of the fetuses had involution of the SRM, and one fetus had surgical treatment and different ultrasound and MRI diagnoses. Of the 69.2% of the cases, spontaneous resolution occurred in 30.7% during the first year of life and 38.4% the masses presented without modifications or signs of regression since the neonatal period. CONCLUSIONS: Prenatal SRMs were associated with congenital heart defects. Spontaneous regression and absence of modifications in the masses were commonly observed in the long-term follow-up of the SRMs. PMID- 29712515 TI - The effect of initiating intravenous oxytocin infusion before uterine incision on the blood loss during elective cesarean section: a randomized clinical trial. AB - OBJECTIVE: This study compares the effect of starting intravenous oxytocin infusion early before uterine incision versus late after umbilical cord clamping on the blood loss during elective cesarean section (CS). METHODS: A single blinded randomized clinical trial conducted on 200 pregnant women at term (>37 weeks) gestation scheduled for elective CS were assigned to either IV infusion of 30 IU of oxytocin started before uterine incision (Group I) or started immediately after clamping the umbilical cord (Group II). The primary outcome was the mean volume of blood loss during CS. The secondary outcomes included the mean volume of postoperative blood loss, the mean reduction in the hemoglobin and hematocrit levels, the need for additional uterotonics, blood transfusion and additional surgical procedures. RESULTS: The baseline characteristics of both groups are quiet similar. No statistical significant difference between both groups as regard to pre- and postpartum hemoglobin levels (p = .06 and 0.24 respectively) and hematocrit values (p = .12 and .51 respectively). There was a significant reduction in the intraoperative blood loss in group I compared with group II (432.7 +/- 90.6 versus 588.9 +/- 96.3 mL respectively, p = .001). The need for additional uterotonics was more frequent in the group II (19 women) than in group I (seven women) with statistical significance (p = .002). No differences between both groups regarding the need for blood transfusion or additional surgical procedures. CONCLUSIONS: Initiating intravenous oxytocin infusion before uterine incision during elective CS could be associated with reduction in the intraoperative blood loss and the need for additional uterotonics. PMID- 29712516 TI - Assessment of cost drivers and cost variation for lumbar interbody fusion procedures using the Value Driven Outcomes database. AB - OBJECTIVE Efforts to examine the value of care-combining both costs and quality are gaining importance in the current health care climate. This thrust is particularly evident in treating common spinal disease where both incidences and costs are generally high and practice patterns are variable. It is often challenging to obtain direct surgical costs for these analyses, which hinders the understanding of cost drivers and cost variation. Using a novel tool, the authors sought to understand the costs of posterior lumbar arthrodesis with interbody devices. METHODS The Value Driven Outcomes (VDO) database at the University of Utah was used to evaluate the care of patients who underwent open or minimally invasive surgery (MIS), 1- and 2-level lumbar spine fusion (Current Procedural Terminology code 22263). Patients treated from January 2012 through June 2017 were included. RESULTS A total of 276 patients (mean age 58.9 +/- 12.4 years) were identified; 46.7% of patients were men. Most patients (82.2%) underwent 1 level fusion. Thirteen patients (4.7%) had major complications and 11 (4.1%) had minor complications. MIS (beta = 0.16, p = 0.002), length of stay (beta = 0.47, p = 0.0001), and number of operated levels (beta = 0.37, p = 0.0001) predicted costs in a multivariable analysis. Supplies and implants (55%) and facility cost (36%) accounted for most of the expenditure. Other costs included pharmacy (7%), laboratory (1%), and imaging (1%). CONCLUSIONS These results provide direct cost accounting for lumbar fusion procedures using the VDO database. Efforts to improve the value of lumbar surgery should focus on high cost areas, i.e., facility and supplies/implant. PMID- 29712513 TI - Prenatal maternal stress induces visceral hypersensitivity of adult rat offspring through activation of cystathionine-beta-synthase signaling in primary sensory neurons. AB - Irritable bowel syndrome is a disorder of unknown etiology characterized by widespread, chronic abdominal pain associated with altered bowel movements. Increasing amounts of evidence indicate that stressors presented during gestational periods could have long-term effects on the offspring's tissue structure and function, which may predispose to gastrointestinal diseases. The aim of the present study is to determine whether prenatal maternal stressis a adverse factor affecting gastrointestinal sensitivity and to investigate possible mechanisms underlying prenatal maternal stress-induced visceral hypersensitivity in adult offspring. Prenatal maternal stress was induced in pregnant Sprague Dawley rats by exposure to heterotypic intermitent stress from gestational day 7 to delivery. Prenatal maternal stress significantly increased visceromotor response to colorectal distention in adult offspring from the age of 6 weeks to 10 weeks. Prenatal maternal stress also enhanced neuronal excitability including depolarization of resting membrane potentials, reduction in rheobase, and an increase in the number of action potentials evoked by 2* and 3* rheobase current stimultion of colon-specific dorsal root ganglion neurons. Prenatal maternal stress remarkably enhanced expression of cystathionine-beta-synthase and Nav1.7 in T13-L2 thoracolumbar dorsal root ganglions both at protein and mRNA levels. Intraperitoneal injection of aminooxyacetic acid, an inhibitor of cystathionine beta-synthase, attenuated prenatal maternal stress-induced visceral hypersensitivity in a dose-dependent manner. A consecutive seven-day administration of aminooxyacetic acid reversed the hyperexcitability of colon specific dorsal root ganglion neurons and markedly reduced Nav1.7 expression. These results indicate that the presence of multiple psychophysical stressors during pregnancy is associated with visceral hypersensitivity in offspring, which is likely mediated by an upregualtion of cystathionine-beta-synthase and Nav1.7 expression. Prenatal maternal stress might be a significant contributor to irritable bowel syndrome, and cystathionine-beta-synthase might be a potential target for treatment for chronic visceral hypersensitivity in patients with irritable bowel syndrome. PMID- 29712517 TI - Economic benefit of carpal tunnel release in the Medicare patient population. AB - OBJECTIVE The epidemiology of carpal tunnel syndrome (CTS) has been extensively researched. However, data describing the economic burden of CTS is limited. The purpose of this study was to quantify the disease burden of CTS and determine the economic benefit of its surgical management. METHODS The authors utilized the PearlDiver database to identify the number of individuals with CTS in the Medicare patient population, and then utilized CPT codes to identify which individuals underwent surgical management. These data were used to calculate the total number of disability-adjusted life years (DALYs) associated with CTS. A human capital approach was employed and gross national income per capita was used to calculate the economic burden. RESULTS From 2005 to 2012 there were 1,500,603 individuals identified in the Medicare patient population with the diagnosis of CTS. Without conservative or surgical management, this results in 804,113 DALYs without age weighting and discounting, and 450,235 DALYs with age weighting and a discount rate of 3%. This amounts to between $21.8 and $39 billion in total economic burden, or $2.7-$4.8 billion per year. Surgical management of CTS has resulted in the aversion of 173,000-309,000 DALYs. This has yielded between $780 million and $1.6 billion in economic benefit per year. Endoscopic carpal tunnel release provided between $11,683 and $23,186 per patient at 100% success while open carpal tunnel release provided between $10,711 and $22,132 per patient at 100% success. The benefit-cost ratio at its most conservative is 2.7:1, yet could be as high as 6.9:1. CONCLUSIONS CTS is prevalent in the Medicare patient population, and is associated with a large amount of economic burden. The surgical management of CTS leads to a large reduction in this burden, yielding extraordinary economic benefit. PMID- 29712518 TI - Unruptured aneurysms in the elderly: perioperative outcomes and cost analysis of endovascular coiling and surgical clipping. AB - OBJECTIVE Observation and neurosurgical intervention for unruptured intracranial aneurysms (UIAs) in the elderly population is rapidly increasing. Cerebral aneurysm coiling (CACo) is favored over cerebral aneurysm clipping (CAC) in elderly patients, yet some elderly individuals still undergo CAC. The cost effectiveness of treating UIAs requires further exploration. Understanding the effect of intervention on hospital charges and length of stay (LOS) as well as perioperative mortality and complications can further shed light on its economic impact. The purpose of this study was to analyze the cost and perioperative outcomes of UIAs in elderly patients (>= 65 years of age) after CACo or CAC intervention. METHODS Retrospective cohorts of CACo and CAC admissions were extracted from National (Nationwide) Inpatient Sample data obtained between 2002 and 2013, forming parallel intervention groups to compare the following outcomes between elderly and nonelderly patients: average LOS and mean hospital admission costs, in-hospital mortality, and complications. Covariates included sex, race or ethnicity, and comorbidities. RESULTS Elderly patients undergoing CAC experienced an average LOS of 8.0 days, whereas elderly patients undergoing CACo stayed an average of 3.2 days. The mean hospital charges incurred during admission totaled $95,960 in the elderly patients who underwent CAC versus $87,960 in the ones who underwent CACo. Elderly patients in whom CAC was performed had a 2.2% rate of in hospital mortality, with a 2.6 greater adjusted odds of in-hospital mortality than nonelderly patients treated with CAC. In contrast, elderly patients who underwent CACo had a 1.36 greater adjusted odds of in-hospital mortality than their nonelderly counterparts. Compared to nonelderly patients receiving both interventions, elderly individuals had a significantly higher prevalence of various comorbidities and incidence of complications. Elderly patients who received CAC experienced a 10.3% incidence rate of perioperative stroke, whereas their CACo counterparts experienced this complication at a rate of 3.5%. Elderly patients treated with CAC had greater odds of perioperative acute renal failure, whereas their CACo counterparts had greater odds of perioperative deep venous thrombosis and pulmonary embolism. CONCLUSIONS Intervention with CAC and CACo in the elderly is resource intensive and is associated with higher risk than in the nonelderly. Those deciding between intervention and conservative management should consider these risks and costs, especially the 2.2% postoperative mortality rate associated with CAC in the elderly population. Further comparative cost-effectiveness research is needed to weigh these costs and outcomes against those of conservative management. PMID- 29712519 TI - Systematic review of health economic studies in cranial neurosurgery. AB - OBJECTIVE As the cost of health care continues to increase, there is a growing emphasis on evaluating the relative economic value of treatment options to guide resource allocation. The objective of this systematic review was to evaluate the current evidence regarding the cost-effectiveness of cranial neurosurgery procedures. METHODS The authors performed a systematic review of the literature using PubMed, EMBASE, and the Cochrane Library, focusing on themes of economic evaluation and cranial neurosurgery following the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Included studies were publications of cost-effectiveness analysis or cost-utility analysis between 1995 and 2017 in which health utility outcomes in life years (LYs), quality-adjusted life years (QALYs), or disability-adjusted life years (DALYs) were used. Three independent reviewers conducted the study appraisal, data abstraction, and quality assessment, with differences resolved by consensus discussion. RESULTS In total, 3485 citations were reviewed, with 53 studies meeting the inclusion criteria. Of those, 34 studies were published in the last 5 years. The most common subspecialty focus was cerebrovascular (32%), followed by neurooncology (26%) and functional neurosurgery (24%). Twenty-eight (53%) studies, using a willingness to pay threshold of US$50,000 per QALY or LY, found a specific surgical treatment to be cost-effective. In addition, there were 11 (21%) studies that found a specific surgical option to be economically dominant (both cost saving and having superior outcome), including endovascular thrombectomy for acute ischemic stroke, epilepsy surgery for drug-refractory epilepsy, and endoscopic pituitary tumor resection. CONCLUSIONS There is an increasing number of cost-effectiveness studies in cranial neurosurgery, especially within the last 5 years. Although there are numerous procedures, such as endovascular thrombectomy for acute ischemic stroke, that have been conclusively proven to be cost-effective, there remain promising interventions in current practice that have yet to meet cost-effectiveness thresholds. PMID- 29712520 TI - Outpatient spine surgery: defining the outcomes, value, and barriers to implementation. AB - Spine surgery is a key target for cost reduction within the United States health care system. One possible strategy involves the transition of inpatient surgeries to the ambulatory setting. Lumbar laminectomy with or without discectomy, lumbar fusion, anterior cervical discectomy and fusion, and cervical disc arthroplasty all represent promising candidates for outpatient surgeries in select populations. In this focused review, the authors clarify the different definitions used in studies describing outpatient spine surgery. They also discuss the body of evidence supporting each of these procedures and summarize the proposed cost savings. Finally, they examine several patient- and surgeon specific considerations to highlight the barriers in translating outpatient spine surgery into actual practice. PMID- 29712521 TI - The unreimbursed costs of preventing revision surgery in adult spinal deformity: analysis of cost-effectiveness of proximal junctional failure prevention with ligament augmentation. AB - OBJECTIVE Proximal junctional kyphosis (PJK) is a well-recognized complication of surgery for adult spinal deformity and is characterized by increased kyphosis at the upper instrumented vertebra (UIV). PJK prevention strategies have the potential to decrease morbidity and cost by reducing rates of proximal junctional failure (PJF), which the authors define as radiographic PJK plus clinical sequelae requiring revision surgery. METHODS The authors performed an analysis of 195 consecutive patients with adult spinal deformity. Age, sex, levels fused, upper instrumented vertebra (UIV), use of 3-column osteotomy, pelvic fixation, and mean time to follow-up were collected. The authors also reviewed operative reports to assess for the use of surgical adjuncts targeted toward PJK prevention, including ligament augmentation, hook fixation, and vertebroplasty. The cost of surgery, including direct and total costs, was also assessed at index surgery and revision surgery. Only revision surgery for PJF was included. RESULTS The mean age of the cohort was 64 years (range 25-84 years); 135 (69%) patients were female. The mean number of levels fused was 10 (range 2-18) with the UIV as follows: 2 cervical (1%), 73 upper thoracic (37%), 108 lower thoracic (55%), and 12 lumbar (6%). Ligament augmentation was used in 99 cases (51%), hook fixation in 60 cases (31%), and vertebroplasty in 71 cases (36%). PJF occurred in 18 cases (9%). Univariate analysis found that ligament augmentation and hook fixation were associated with decreased rates of PJF. However, in a multivariate model that also incorporated age, sex, and UIV, only ligament augmentation maintained a significant association with PJF reduction (OR 0.196, 95% CI 0.050-0.774; p = 0.020). Patients with ligament augmentation, compared with those without, had a higher cost of index surgery, but ligament augmentation was overall cost effective and produced significant cost savings. In sensitivity analyses in which we independently varied the reduction in PJF, cost of ligament augmentation, and cost of reoperation by +/- 50%, ligament augmentation remained a cost-effective strategy for PJF prevention. CONCLUSIONS Prevention strategies for PJK/PJF are limited, and their cost-effectiveness has yet to be established. The authors present the results of 195 patients with adult spinal deformity and show that ligament augmentation is associated with significant reductions in PJF in both univariate and multivariate analyses, and that this intervention is cost effective. Future studies will need to determine if these clinical results are reproducible, but for high-risk cases, these data suggest an important role of ligament augmentation for PJF prevention and cost savings. PMID- 29712522 TI - Editorial. Unruptured aneurysms in the elderly: handle with care. PMID- 29712523 TI - Strategic hospital partnerships: improved access to care and increased epilepsy surgical volume. AB - OBJECTIVE Surgical treatment of patients with medically refractory focal epilepsy is underutilized. Patients may lack access to surgically proficient centers. The University of California, Irvine (UCI) entered strategic partnerships with 2 epilepsy centers with limited surgical capabilities. A formal memorandum of understanding (MOU) was created to provide epilepsy surgery to patients from these centers. METHODS The authors analyzed UCI surgical and financial data associated with patients undergoing epilepsy surgery between September 2012 and June 2016, before and after institution of the MOU. Variables collected included the length of stay, patient age, seizure semiology, use of invasive monitoring, and site of surgery as well as the monthly number of single-surgery cases, complex cases (i.e., staged surgeries), and overall number of surgery cases. RESULTS Over the 46 months of the study, a total of 104 patients underwent a total of 200 operations; 71 operations were performed in 39 patients during the pre-MOU period (28 months) and 129 operations were performed in 200 patients during the post-MOU period (18 months). There was a significant difference in the use of invasive monitoring, the site of surgery, the final therapy, and the type of insurance. The number of single-surgery cases, complex-surgery cases, and the overall number of cases increased significantly. CONCLUSIONS Partnerships with outside epilepsy centers are a means to increase access to surgical care. These partnerships are likely reproducible, can be mutually beneficial to all centers involved, and ultimately improve patient access to care. PMID- 29712524 TI - Patient out-of-pocket spending in cranial neurosurgery: single-institution analysis of 6569 consecutive cases and literature review. AB - OBJECTIVE With drastic changes to the health insurance market, patient cost sharing has significantly increased in recent years. However, the patient financial burden, or out-of-pocket (OOP) costs, for surgical procedures is poorly understood. The goal of this study was to analyze patient OOP spending in cranial neurosurgery and identify drivers of OOP spending growth. METHODS For 6569 consecutive patients who underwent cranial neurosurgery from 2013 to 2016 at the authors' institution, the authors created univariate and multivariate mixed effects models to investigate the effect of patient demographic and clinical factors on patient OOP spending. The authors examined OOP payments stratified into 10 subsets of case categories and created a generalized linear model to study the growth of OOP spending over time. RESULTS In the multivariate model, case categories (craniotomy for pain, tumor, and vascular lesions), commercial insurance, and out-of-network plans were significant predictors of higher OOP payments for patients (all p < 0.05). Patient spending varied substantially across procedure types, with patients undergoing craniotomy for pain ($1151 +/- $209) having the highest mean OOP payments. On average, commercially insured patients spent nearly twice as much in OOP payments as the overall population. From 2013 to 2016, the mean patient OOP spending increased 17%, from $598 to $698 per patient encounter. Commercially insured patients experienced more significant growth in OOP spending, with a cumulative rate of growth of 42% ($991 in 2013 to $1403 in 2016). CONCLUSIONS Even after controlling for inflation, case-mix differences, and partial fiscal periods, OOP spending for cranial neurosurgery patients significantly increased from 2013 to 2016. The mean OOP spending for commercially insured neurosurgical patients exceeded $1400 in 2016, with an average annual growth rate of 13%. As patient cost sharing in health insurance plans becomes more prevalent, patients and providers must consider the potential financial burden for patients receiving specialized neurosurgical care. PMID- 29712525 TI - Analysis of cerebrovascular aneurysm treatment cost: retrospective cohort comparison of clipping, coiling, and flow diversion. AB - OBJECTIVE With the continuous rise of health care costs, hospitals and health care providers must find ways to reduce costs while maintaining high-quality care. Comparing surgical and endovascular treatment of intracranial aneurysms may offer direction in reducing health care costs. The Value-Driven Outcomes (VDO) database at the University of Utah identifies cost drivers and tracks changes over time. In this study, the authors evaluate specific cost drivers for surgical clipping and endovascular management (i.e., coil embolization and flow diversion) of both ruptured and unruptured intracranial aneurysms using the VDO system. METHODS The authors retrospectively reviewed surgical and endovascular treatment of ruptured and unruptured intracranial aneurysms from July 2011 to January 2017. Total cost (as a percentage of each patient's cost to the system), subcategory costs, and potential cost drivers were evaluated and analyzed. RESULTS A total of 514 aneurysms in 469 patients were treated; 273 aneurysms were surgically clipped, 102 were repaired with coiling, and 139 were addressed with flow diverter placements. Middle cerebral artery aneurysms accounted for the largest portion of cases in the clipping group (29.7%), whereas anterior communicating artery aneurysms were most frequently involved in the coiling group (30.4%) and internal carotid artery aneurysms were the majority in the flow diverter group (63.3%). Coiling (mean total cost 0.25% +/- 0.20%) had a higher cost than flow diversion (mean 0.20% +/- 0.16%) and clipping (mean 0.17 +/- 0.14%; p = 0.0001, 1 way ANOVA). Coiling cases cost 1.5 times as much as clipping and flow diversion costs 1.2 times as much as clipping. Facility costs were the most significant contributor to intracranial clipping costs (60.2%), followed by supplies (18.3%). Supplies were the greatest cost contributor to coiling costs (43.2%), followed by facility (40.0%); similarly, supplies were the greatest portion of costs in flow diversion (57.5%), followed by facility (28.5%). Cost differences for aneurysm location, rupture status, American Society of Anesthesiologists (ASA) grade, and discharge disposition could be identified, with variability depending on surgical procedure. A multivariate analysis showed that rupture status, surgical procedure type, ASA status, discharge disposition, and year of surgery all significantly affected cost (p < 0.0001). CONCLUSIONS Facility utilization and supplies constitute the majority of total costs in aneurysm treatment strategies, but significant variation exists depending on surgical approach, rupture status, and patient discharge disposition. Developing and implementing approaches and protocols to improve resource utilization are important in reducing costs while maintaining high-quality patient care. PMID- 29712526 TI - The estimated cost of surgically managed isolated traumatic head injury secondary to road traffic accidents. AB - OBJECTIVE Traumatic brain injury due to road traffic accidents occurs mainly in the younger age group in which injury-related disability leads to long-term impact on employment and economic and social consequences across the lifespan. This study was designed to assign a monetary cost (in Malaysian ringgits [RM]) to the treatment of patients with surgically treated isolated traumatic head injury as determined up to 1 year after injury. METHODS Relevant resource items used were identified and valued using the direct measurement of costs method, cost accounting methods, standard unit costs method, fees, charges and/or market prices method. These values were then tabulated to generate the total costs for each patient, via a combination of macro-costing and micro-costing methods. Malaysian currency values were converted to US dollars according to the average conversion rate for the period from January to May 2016: RM1 = US$0.2452. RESULTS This costing study analyzed data from 49 patients. The estimated cost for the 1st year of care for all patients was RM1,471,919.80 (US$360,914.735), with a mean (+/- SD) cost per case of RM30,039.18 +/- 22,986.25 or $7365.61 +/- $5636.23. The mean cost of care per case was RM11,041.35 +/- 10,936.88 or $2707.34 +/- $2681.72 for mild head injury, RM32,550.00 +/- 20,998.76 or $7981.26 +/- $5148.90 for moderate head injury, and RM36,917.86 +/- 23,697.34 or $9052.26 +/- $5810.59 for severe head injury. Severe head injury (p = 0.001), sustaining 2 or more intracranial pathologies (p = 0.01), having a poor Glasgow Outcome Scale (GOS) score (GOS score 1-3) (p = 0.02), requiring a tracheostomy (p < 0.001), and contracting pneumonia (p < 0.001) were significantly associated with higher cost. Logistic regression analysis revealed that cost of care increased by RM591.60 or $145.06 per year increment of age (beta = RM591.60, p = 0.05). CONCLUSIONS The mean cost of treatment for traumatic head injury is high compared to the per capita income of RM37,900 in 2016. The cost values generated in this study provide baseline cost estimates that the authors hope will be used as a guide to determine where adequate funding should be allocated to provide timely and appropriate delivery of care. PMID- 29712527 TI - Propensity-matched comparison of outcomes and cost after macroscopic and microscopic lumbar discectomy using a national longitudinal database. AB - OBJECTIVE There has been considerable debate about the utility of the operating microscope in lumbar discectomy and its effect on outcomes and cost. METHODS A commercially available longitudinal database was used to identify patients undergoing discectomy with or without use of a microscope between 2007 and 2015. Propensity matching was performed to normalize differences between demographics and comorbidities in the 2 cohorts. Outcomes, complications, and cost were subsequently analyzed using bivariate analysis. RESULTS A total of 42,025 patients were identified for the "macroscopic" group, while 11,172 patients were identified for the "microscopic" group. For the propensity-matched analysis, the 11,172 patients in the microscopic discectomy group were compared with a group of 22,340 matched patients who underwent macroscopic discectomy. There were no significant differences in postoperative complications between the groups other than a higher proportion of deep vein thrombosis (DVT) in the macroscopic discectomy cohort versus the microscopic discectomy group (0.4% vs 0.2%, matched OR 0.48 [95% CI 0.26-0.82], p = 0.0045). Length of stay was significantly longer in the macroscopic group compared to the microscopic group (mean 2.13 vs 1.83 days, p < 0.0001). Macroscopic discectomy patients had a higher rate of revision surgery when compared to microscopic discectomy patients (OR 0.92 [95% CI 0.84 1.00], p = 0.0366). Hospital charges were higher in the macroscopic discectomy group (mean $19,490 vs $14,921, p < 0.0001). CONCLUSIONS The present study suggests that the use of the operating microscope in lumbar discectomy is associated with decreased length of stay, lower DVT rate, lower reoperation rate, and decreased overall hospital costs. PMID- 29712528 TI - Markov modeling for the neurosurgeon: a review of the literature and an introduction to cost-effectiveness research. AB - OBJECTIVE Markov modeling is a clinical research technique that allows competing medical strategies to be mathematically assessed in order to identify the optimal allocation of health care resources. The authors present a review of the recently published neurosurgical literature that employs Markov modeling and provide a conceptual framework with which to evaluate, critique, and apply the findings generated from health economics research. METHODS The PubMed online database was searched to identify neurosurgical literature published from January 2010 to December 2017 that had utilized Markov modeling for neurosurgical cost effectiveness studies. Included articles were then assessed with regard to year of publication, subspecialty of neurosurgery, decision analytical techniques utilized, and source information for model inputs. RESULTS A total of 55 articles utilizing Markov models were identified across a broad range of neurosurgical subspecialties. Sixty-five percent of the papers were published within the past 3 years alone. The majority of models derived health transition probabilities, health utilities, and cost information from previously published studies or publicly available information. Only 62% of the studies incorporated indirect costs. Ninety-three percent of the studies performed a 1-way or 2-way sensitivity analysis, and 67% performed a probabilistic sensitivity analysis. A review of the conceptual framework of Markov modeling and an explanation of the different terminology and methodology are provided. CONCLUSIONS As neurosurgeons continue to innovate and identify novel treatment strategies for patients, Markov modeling will allow for better characterization of the impact of these interventions on a patient and societal level. The aim of this work is to equip the neurosurgical readership with the tools to better understand, critique, and apply findings produced from cost-effectiveness research. PMID- 29712529 TI - Cost-effectiveness development for the postoperative care of craniotomy patients: a safe transitions pathway in neurological surgery. AB - OBJECTIVE The authors' institution is in the top 5th percentile for hospital cost in the nation, and the neurointensive care unit (NICU) is one of the costliest units. The NICU is more expensive than other units because of lower staff/patient ratio and because of the equipment necessary to monitor patient care. The cost differential between the NICU and Neuro transitional care unit (NTCU) is $1504 per day. The goal of this study was to evaluate and to pilot a program to improve efficiency and lower cost by modifying the postoperative care of patients who have undergone a craniotomy, sending them to the NTCU as opposed to the NICU. Implementation of the pilot will expand and utilize neurosurgery beds available on the NTCU and reduce the burden on NICU beds for critically ill patient admissions. METHODS Ten patients who underwent craniotomy to treat supratentorial brain tumors were included. Prior to implementation of the pilot, inclusion criteria were designed for patient selection. Patients included were less than 65 years of age, had no comorbid conditions requiring postoperative intensive care unit (ICU) care, had a supratentorial meningioma less than 3 cm in size, had no intraoperative events, had routine extubation, and underwent surgery lasting fewer than 5 hours and had blood loss less than 500 ml. The Safe Transitions Pathway (STP) was started in August 2016. RESULTS Ten tumor patients have utilized the STP (5 convexity meningiomas, 2 metastatic tumors, 3 gliomas). Patients' ages ranged from 29 to 75 years (median 49 years; an exception to the age limit of 65 years was made for one 75-year-old patient). Discharge from the hospital averaged 2.2 days postoperative, with 1 discharged on postoperative day (POD) 1, 7 discharged on POD 2, 1 discharged on POD 3, and 1 discharged on POD 4. Preliminary data indicate that quality and safety for patients following the STP (moving from the operating room [OR] to the neuro transitional care unit [OR NTCU]) are no different from those of patients following the traditional OR-NICU pathway. No patients required escalation in level of nursing care, and there were no readmissions. This group has been followed for greater than 1 month, and there were no morbidities. CONCLUSIONS The STP is a new and efficient pathway for the postoperative care of neurosurgery patients. The STP has reduced hospital cost by $22,560 for the first 10 patients, and there were no morbidities. Since this pilot, the authors have expanded the pathway to include other surgical cases and now routinely schedule craniotomy patients for the (OR-NTCU) pathway. The potential cost reduction in one year could reach $500,000 if we reach our potential of 20 patients per month. PMID- 29712530 TI - Editorial. Telemedicine for elective neurosurgical routine follow-up care: a promising patient-centered and cost-effective alternative to in-person clinic visits. PMID- 29712531 TI - Editorial. The challenges of estimating the cost of traumatic brain injury worldwide. PMID- 29712532 TI - Comparison of telemedicine with in-person care for follow-up after elective neurosurgery: results of a cost-effectiveness analysis of 1200 patients using patient-perceived utility scores. AB - OBJECTIVE The utility of telemedicine (TM) in neurosurgery is underexplored, with most of the studies relating to teletrauma or telestroke programs. In this study, the authors evaluate the cost-effectiveness of TM consultations for follow-up care of a large population of patients who underwent neurosurgical procedures. METHODS A decision-analytical model was used to assess the cost-effectiveness of TM for elective post-neurosurgical care patients from a predominantly nonurban cohort in West Bengal, India. The model compared TM care via a nodal center in West Bengal to routine, in-person, per-episode care at the provider site in Bangalore, India. Cost and effectiveness data relating to 1200 patients were collected for a 52-month period. The effectiveness of TM care was calculated using efficiency in terms of the percentage of successful TM consultations, as well as patient-perceived utility values for overall experience of the type of health care access that they received. Incremental cost-effectiveness ratio (ICER) analysis was done using the 4-quadrant charting of the cost-effectiveness plane. One-way sensitivity and tornado analyses were performed to identify thresholds where the care strategy would change. RESULTS The overall utility for the 3 TM scenarios was found to be higher (89%) than for the utility of routine care (80%). TM was found to be more cost-effective (Indian rupee [INR] 2630 per patient) compared to routine care (INR 6848 per patient). The TM strategy "dominates" that of routine care by being more effective and less expensive (ICER value of -39,400 INR/unit of effectiveness). Sensitivity analysis revealed that cost-effectiveness of TM was most sensitive to changes in the number of TM patients, utility and success rate of TM, and travel distance to the TM center. CONCLUSIONS TM care dominates the in-person care strategy by providing more effective and less expensive follow-up care for a remote post-neurosurgical care population in India. In the authors' setting, this benefit of TM is sustainable even if half the TM consultations turn out to be unsuccessful. The viability of TM as a cost-effective care protocol is attributed to a combination of factors, like an adequate patient volume utilizing TM, patient utility, success rate of TM, and the patient travel distance. PMID- 29712533 TI - Introduction. Neurosurgical economics and cost-effectiveness. PMID- 29712534 TI - A scoping review on health economics in neurosurgery for acute spine trauma. AB - OBJECTIVE Acute spine trauma (AST) has a relatively low incidence, but it often results in substantial individual impairments and societal economic burden resulting from the associated disability. Given the key role of neurosurgeons in the decision-making regarding operative management of individuals with AST, the authors performed a systematic search with scoping synthesis of relevant literature to review current knowledge regarding the economic burden of AST. METHODS This systematic review with scoping synthesis included original articles reporting cost-effectiveness, cost-utility, cost-benefit, cost-minimization, cost comparison, and economic analyses related to surgical management of AST, whereby AST is defined as trauma to the spine that may result in spinal cord injury with motor, sensory, and/or autonomic impairment. The initial literature search was carried out using MEDLINE, EMBASE, CINAHL, CCTR, and PubMed. All original articles captured in the literature search and published from 1946 to September 27, 2017, were included. Search terms used were the following: (cost analysis, cost effectiveness, cost benefit, economic evaluation or economic impact) AND (spine or spinal cord) AND (surgery or surgical). RESULTS The literature search captured 5770 titles, of which 11 original studies met the inclusion/exclusion criteria. These 11 studies included 4 cost-utility analyses, 5 cost analyses that compared the cost of intervention with a comparator, and 2 studies examining direct costs without a comparator. There are a few potentially cost-saving strategies in the neurosurgical management of individuals with AST, including 1) early surgical spinal cord decompression for acute traumatic cervical spinal cord injury (or traumatic thoracolumbar fractures, traumatic cervical fractures); 2) surgical treatment of the elderly with type-II odontoid fractures, which is more costly but more effective than the nonoperative approach among individuals with age at AST between 65 and 84 years; 3) surgical treatment of traumatic thoracolumbar spine fractures, which is implicated in greater direct costs but lower general-practitioner visit costs, private expenditures, and absenteeism costs than nonsurgical management; and 4) removal of pedicle screws 1-2 years after posterior instrumented fusion for individuals with thoracolumbar burst fractures, which is more cost-effective than retaining the pedicle screws. CONCLUSIONS This scoping synthesis underscores a number of potentially cost saving opportunities for neurosurgeons when managing patients with AST. There are significant knowledge gaps regarding the potential economic impact of therapeutic choices for AST that are commonly used by neurosurgeons. PMID- 29712535 TI - Health care utilization and overall costs based on opioid dependence in patients undergoing surgery for degenerative spondylolisthesis. AB - OBJECTIVE Opioid abuse is highly prevalent in patients with back pain. The aim of this study was to identify health care utilization and overall costs associated with opioid dependence in patients undergoing surgery for degenerative spondylolisthesis (DS). METHODS The authors queried the MarketScan database using ICD-9 and CPT-4 codes from 2000 to 2012. Opioid dependency was defined as having a diagnosis of opioid use disorder, having a prescription for opioid use disorder, or having 10 or more opioid prescriptions. Opioid dependency was evaluated in 12-month period leading to surgery and in the period 3-15 months following the procedure. Patients were segregated into 4 groups based on opioid dependence before and after surgery: group NDND (prior nondependent who remain nondependent), group NDD (prior nondependent who become dependent), group DND (prior dependent who become nondependent), and group DD (prior dependent who remain dependent). The outcomes of interest were discharge disposition, hospital length of stay (LOS), complications, and health care resource costs. The 4 groups were compared using the Kruskal-Wallis test and linear contrasts built from generalized regression models. RESULTS A total of 10,708 patients were identified, with 81.57%, 3.58%, 8.54%, and 6.32% of patients in groups NDND, NDD, DND, and DD, respectively. In group DD, 96.31% of patients had decompression with fusion, compared with 93.59% in group NDND. Patients in group NDD, DND, and DD had longer hospital LOS compared with those in group NDND. Patients in group DD were less likely to be discharged home compared with those in group NDND (odds ratio 0.639, 95% confidence interval 0.52-0.785). At 3-15 months postdischarge, patients in group DD incurred 21% higher hospital readmission costs compared with those in group NDND. However, patients in groups NDD and DD were likely to incur 2.8 times the overall costs compared with patients in group NDND (p < 0.001) at 3 15 months after surgery (median overall payments: group NDD $20,033 and group DD $19,654, vs group NDND $7994). CONCLUSIONS Patients who continued to be opioid dependent or became opioid dependent following surgery for DS incurred significantly higher health care utilization and costs within 3 months and in the period 3-15 months after discharge from surgery. PMID- 29712536 TI - QSOX1 regulates trophoblastic apoptosis in preeclampsia through hydrogen peroxide production. AB - OBJECTIVE: Oxidative stress plays a significant role in the pathogenesis of preeclampsia (PE), by inducing trophoblast cell death and consequent placental dysfunction. Quiescin sulfhydryl oxidase 1 (QSOX1) is upregulated in many types of cancer cells; it promotes disulfide bond formation as well as hydrogen peroxide (H2O2) production. The aims of present study are to investigate the expression pattern of QSOX1 in placentae of pregnancies complicated by PE and the role of QSOX1 in the regulation of trophoblastic function, thus providing in depth understanding of the putative involvement of QSOX1 in the development of PE. METHODS: Human term placenta from normal pregnancies and from pregnancies complicated by PE was collected to measure QSOX1 expression and H2O2 levels. Down regulation of QSOX1 in HTR-8/SVneo cells was achieved by siRNA interference. An in vitro cellular PE model was generated by hypoxic incubation. Protein expression levels were assessed by Western blotting, and H2O2 levels were determined in the cell culture medium as well as in the cell lysate. Trophoblast apoptosis was evaluated by TUNEL staining. RESULTS: QSOX1 was overexpressed in the PE placenta. Inhibition of QSOX1 expression in HTR-8/SVneo cells attenuated cell apoptosis and intracellular H2O2 levels. Hypoxia-induced QSOX1 expression in HTR-8/SVneo cells and led to apoptosis of HTR-8/SVneo cells, and knock-down of QSOX1 rescued hypoxia-induced trophoblast apoptosis. CONCLUSIONS: Hypoxia-induced upregulation of QSOX1 and a consequent elevation in intracellular H2O2 increased apoptosis in placentae of pregnancies complicated by PE. PMID- 29712538 TI - The relationship between early post-stroke cognition and longer term activities and participation: A systematic review. AB - This systematic review examined whether early cognitive impairment after stroke is predictive of outcome within the "activity" and "participation" domains of the International Classification of Functioning, Disability and Health (ICF) at 6-12 months post-injury. Studies were included if cognitive functioning was assessed within 6 weeks of injury and outcome was measured at least 6 months post-injury. PsycINFO, MEDLINE, CINAHL and EMBASE databases were searched and 14 studies were identified. Studies were categorised according to whether "domain-general" or "domain-specific" cognitive assessment was undertaken and whether outcomes measured the ICF activities or participation domains, as determined by three independent raters using previous established linking rules. Quality of studies was assessed using a modified version of Downs and Black's Quality Index. Overall, early cognitive impairment predicted activities and participation 6-12 months post-stroke. This relationship was more consistent when domain-specific cognitive assessment was used. For the domain of activities, visuospatial perception/construction, visual memory, visual neglect, and attention/executive functioning predicted functioning 6-12 months post-stroke. Early domain-specific cognitive assessment may be clinically informative of longer term activities. For the domain of participation, further well-controlled studies are needed to determine the relationship with early post-stroke cognitive impairments. PMID- 29712539 TI - The ethanolic extract obtained from Campomanesia pubescens (D.C.) O.BERG fruits exerts anxiolytic and antidepressant effects on chronic mild stress model and on anxiety models in Wistar rats: Behavioral evidences. AB - OBJECTIVES: Campomanesia pubescens (DC) O.BERG (Myrtaceae) fruits contain high levels of flavonoids and are widely consumed by the South American population. In the central nervous system (CNS), some flavonoids act as modulators of GABA-A receptors and monoamine oxidase inhibitors, resulting in anxiolytic antidepressants effects, respectively. The objective of the present study was to evaluate the anxiolytic and antidepressant effects of ethanolic extract of C. pubescens fruits (EEFCP) in rats. METHODS: In order to prove the antidepressant effect of the EEFCP, rats were submitted to the chronic mild stress model, to the sucrose preference test (SPT), and the forced swimming test. To test the anxiolytic effects, the Elevated plus-maze (EPM), open field (OF), and Marble Burying models were used. RESULTS: After 2 weeks of treatment, imipramine 25 mg/kg, EEFCP 250 mg/kg, and EEFCP 500 mg/kg reversed the anhedonic behavior measured by SPT and significantly reduced the immobility time of animals under stress. In addition, treatment with diazepam 2 mg/kg, EEFCP 250 mg/kg, and EEFCP 500 mg/kg increased the percentage of entries and time spent on the open arms of the EPM, increased locomotion, rearing, and reduced the grooming time in OF. DISCUSSION: The chemical analysis of the EEFCP indicated high content of flavonoids and the behavioral analysis revealed an antidepressant and anxiolytic effect, suggesting that these phytochemicals may be involved with these actions in the CNS. PMID- 29712540 TI - The Role of Peers in Health Interventions for Serious Mental Illness. PMID- 29712541 TI - Refractory Ulnar Nerve Symptoms in an Adolescent Pitcher With Medial Apophysitis. AB - A 16-year-old high school baseball pitcher with a 3-week history of acute-onset pain in his medial elbow during throwing presented to physical therapy. Following examination, physical therapy was initiated and the patient was referred for imaging, with suspicion of ulnar collateral ligament (UCL) injury. Radiographs were noncontributory. Ultrasound imaging, however, was performed by a physiatrist and was suggestive of a partial-thickness tear of the UCL and ulnar nerve enlargement. The physiatrist ordered magnetic resonance imaging, which confirmed a medial apophyseal stress reaction, a mild UCL sprain, and reactive ulnar nerve edema. J Orthop Sports Phys Ther 2018;48(5):419. doi:10.2519/jospt.2018.7359. PMID- 29712537 TI - Global expression profiling and pathway analysis of mouse mammary tumor reveals strain and stage specific dysregulated pathways in breast cancer progression. AB - It is believed that the alteration of tissue microenvironment would affect cancer initiation and progression. However, little is known in terms of the underlying molecular mechanisms that would affect the initiation and progression of breast cancer. In the present study, we use two murine mammary tumor models with different speeds of tumor initiation and progression for whole genome expression profiling to reveal the involved genes and signaling pathways. The pathways regulating PI3K-Akt signaling and Ras signaling were activated in Fvb mice and promoted tumor progression. Contrastingly, the pathways regulating apoptosis and cellular senescence were activated in Fvb.B6 mice and suppressed tumor progression. We identified distinct patterns of oncogenic pathways activation at different stages of breast cancer, and uncovered five oncogenic pathways that were activated in both human and mouse breast cancers. The genes and pathways discovered in our study would be useful information for other researchers and drug development. PMID- 29712542 TI - 2017 JOSPT Award Recipients. AB - During the American Physical Therapy Association's Combined Sections Meeting in New Orleans, LA in February 2018, JOSPT recognized the authors of the most outstanding research and clinical practice manuscripts published in JOSPT during 2017. The 2017 George J. Davies-James A. Gould Excellence in Clinical Inquiry Award was presented to Noa Ben-Ami, PT, PhD; Gabriel Chodick, MHA, PhD; Yigal Mirovsky, MD; Tamar Pincus, MPhil, MSc, PhD; and Yair Shapiro, MD, PhD, for their February 2017 article "Increasing Recreational Physical Activity in Patients With Chronic Low Back Pain: A Pragmatic Controlled Clinical Trial." The 2017 JOSPT Excellence in Research Award was presented to Sanneke Don, PT, MPT; Margot de Kooning, PT, PhD; Lennard Voogt, PT, MT, PhD; Kelly Ickmans, PT, PhD; Liesbeth Daenen, PT, PhD; and Jo Nijs, PT, MT, PhD, for their March 2017 article "The Effect of Visual Feedback of the Neck During Movement in People With Chronic Whiplash-Associated Disorders: An Experimental Study." J Orthop Sports Phys Ther 2018;48(5):348. doi:10.2519/jospt.2018.0104. PMID- 29712543 TI - Achilles Pain, Stiffness, and Muscle Power Deficits: Midportion Achilles Tendinopathy Revision 2018. AB - The Orthopaedic Section of the American Physical Therapy Association (APTA) has an ongoing effort to create evidence-based practice guidelines for orthopaedic physical therapy management of patients with musculoskeletal impairments described in the World Health Organization's International Classification of Functioning, Disability, and Health (ICF). The purpose of these revised clinical practice guidelines is to review recent peer-reviewed literature and make recommendations related to midportion Achilles tendinopathy. J Orthop Sports Phys Ther 2018;48(5):A1-A38. doi:10.2519/jospt.2018.0302. PMID- 29712544 TI - May 2018 Letters to the Editor-in-Chief. AB - Letters to the Editor-in-Chief of JOSPT as follows: "Regarding 'Unraveling the Mechanisms of Manual Therapy'" with Authors' Response "The Use of a Broad or Narrow Definition of Injury in Dance Surveillance" with Authors' Response J Orthop Sports Phys Ther 2018;48(5):421-424. doi:10.2519/jospt.2018.0201. PMID- 29712545 TI - Myositis Ossificans: Delayed Complication of Severe Muscle Contusion. AB - A 39-year-old male nonprofessional cyclist presented to physical therapy reporting deep, stabbing, anterolateral left thigh pain. Clinical findings led the physical therapist to request radiographs, which revealed myositis ossificans in the left thigh. J Orthop Sports Phys Ther 2018;48(5):420. doi:10.2519/jospt.2018.7567. PMID- 29712546 TI - Can We Reduce the Epidemic of Elbow Injuries in Youth Throwers? AB - As participation in youth sports continues to increase across the nation, more adolescents are participating in Little League baseball in the United States than ever before. Accompanying this increased participation is an epidemic of upper extremity injuries in young throwers. In this Viewpoint, the authors discuss the impetus behind the youth thrower elbow injury epidemic and how to best evaluate these patients. J Orthop Sports Phys Ther 2018;48(5):354-357. doi:10.2519/jospt.2018.0607. PMID- 29712547 TI - Physical Therapists' Role in Solving the Opioid Epidemic. AB - An estimated 116 million Americans suffer from chronic pain, at a cost of over $600 billion per year, or roughly $2000 per person per year. In this Viewpoint, the authors highlight the challenges of the current opioid epidemic and outline strategies that the physical therapy profession may adopt to be part of the solution. These strategies include facilitating and providing patient education, early access to physical therapy services, and the promotion of health, wellness, and prevention. J Orthop Sports Phys Ther 2018;48(5):349-353. doi:10.2519/jospt.2018.0606. PMID- 29712548 TI - Optimizing Recovery After Achilles Tendon Pain: Guidelines Help Deliver Quality Care. AB - Achilles tendinopathy can temporarily stop many active people, and particularly those who participate in sports. Pain in the Achilles tendon often occurs in the middle of this fibrous tissue that connects the muscles at the back of the lower leg to the heel bone. Physical therapists can help ensure that patients with Achilles tendinopathy receive the best quality care to optimize their recovery. Guidelines published in the May 2018 issue of JOSPT recommend best practices from the published literature for evaluating, diagnosing, and treating Achilles tendon pain. These guidelines also suggest how physical therapists can determine when their patients are ready to return to activities after this injury. For patients, these guidelines outline the best rehabilitation treatment options based on scientific research. J Orthop Sports Phys Ther 2018;48(5):427. doi:10.2519/jospt.2018.0506. PMID- 29712549 TI - Achilles Pain, Stiffness, and Muscle Power Deficits: Midportion Achilles Tendinopathy Revision 2018: Using the Evidence to Guide Physical Therapist Practice. AB - Midportion Achilles tendinopathy is a relatively common, overuse, lower extremity soft tissue injury for individuals who are active and participate in sports. The clinical practice guideline published in the May 2018 issue of JOSPT, titled "Achilles Pain, Stiffness, and Muscle Power Deficits: Midportion Achilles Tendinopathy Revision 2018," can help physical therapists engage in evidence informed practice and reduce unnecessary clinical variation. J Orthop Sports Phys Ther 2018;48(5):425-426. doi:10.2519/jospt.2018.0505. PMID- 29712550 TI - Sound pressure levels generated at risk volume steps of portable listening devices: types of smartphone and genres of music. AB - BACKGROUND: The present study estimated the sound pressure levels of various music genres at the volume steps that contemporary smartphones deliver, because these levels put the listener at potential risk for hearing loss. METHODS: Using six different smartphones (Galaxy S6, Galaxy Note 3, iPhone 5S, iPhone 6, LG G2, and LG G3), the sound pressure levels for three genres of K-pop music (dance-pop, hip-hop, and pop-ballad) and a Billboard pop chart of assorted genres were measured through an earbud for the first risk volume that was at the risk sign proposed by the smartphones, as well as consecutive higher volumes using a sound level meter and artificial mastoid. RESULTS: The first risk volume step of the Galaxy S6 and the LG G2, among the six smartphones, had the significantly lowest (84.1 dBA) and highest output levels (92.4 dBA), respectively. As the volume step increased, so did the sound pressure levels. The iPhone 6 was loudest (113.1 dBA) at the maximum volume step. Of the music genres, dance-pop showed the highest output level (91.1 dBA) for all smartphones. Within the frequency range of 20~ 20,000 Hz, the sound pressure level peaked at 2000 Hz for all the smartphones. CONCLUSIONS: The results showed that the sound pressure levels of either the first volume step or the maximum volume step were not the same for the different smartphone models and genres of music, which means that the risk volume sign and its output levels should be unified across the devices for their users. In addition, the risk volume steps proposed by the latest smartphone models are high enough to cause noise-induced hearing loss if their users habitually listen to music at those levels. PMID- 29712551 TI - Barriers to mental health care utilization among internally displaced persons in the republic of Georgia: a rapid appraisal study. AB - BACKGROUND: There is a paucity of evidence on access to services for mental health and psychosocial support for conflict-affected populations in low- and middle-income countries. In the Republic of Georgia, rates of utilization of mental health services among internally displaced people with mental disorders are low. We set out to identify the health system barriers leading to this treatment gap. METHODS: We used rapid appraisal methods (collection and triangulation of multiple data sources) to investigate barriers to accessing mental health care services among adult IDPs in Georgia. Data collection included review of existing policy documents and other published data, as well as semi structured interviews with 29 key informants including policy makers, NGO staff, health professionals and patients. RESULTS: The following factors emerged as important barriers affecting access to mental health care services among IDPs in Georgia: inadequate insurance coverage of mental disorders and poor identification and referral systems, underfunding, shortage of human resources, poor information systems, patient out-of-pocket payments and stigmatization. CONCLUSION: While rapid appraisal methods cannot control for potential biases or achieve representativeness, triangulation supports internal validity and reliability of the data collected, allowing data to be used to inform health care interventions. The appropriateness and potential effectiveness of policy interventions such as insurance coverage of a wider range of mental disorders, integration of services for these at the primary health care level, and community based approaches in this context should be explored. PMID- 29712552 TI - Are one-stop centres an appropriate model to deliver services to sexually abused children in urban Malawi? AB - BACKGROUND: The Republic of Malawi is creating a country-wide system of 28 One Stop Centres (known as 'Chikwanekwanes' - 'everything under one roof') to provide medical, legal and psychosocial services for survivors of child maltreatment and adult intimate partner violence. No formal evaluation of the utility of such services has ever been undertaken. This study focused on the experiences of the families served at the country's first Chikwanekwane in the large, urban city of Blantyre. METHODS: One hundred seven families were surveyed in their home three months after their initial evaluation for sexual abuse at the Blantyre One Stop Centre, and 25 families received a longer interview. The survey was designed to inquire what types of initial evaluation and follow-up services the children received from the medical, legal and social welfare services. RESULTS: All 107 received an initial medical exam and HIV testing, and 83% received a follow-up HIV test by 3 months; 80.2% were seen by a social welfare worker on the initial visit, and 29% had a home visit by 3 months; 84% were seen by a therapist at the initial visit, and 12% returned for further treatment; 95.3% had an initial police report and 27.1% ended in a criminal conviction for child sexual abuse. Most of the families were satisfied with the service they received, but a quarter of the families were not satisfied with the law enforcement response, and 2% were not happy with the medical assessment. CONCLUSIONS: Although a perception of corruption or negligence by police may discourage use of service, we believe that the One-Stop model is an appropriate means to deliver high quality care to survivors of abuse in Malawi. PMID- 29712553 TI - Correction to: Psychosocial issues discovered through reflective group dialogue between medical students. AB - Following publication of the original article [1], the authors reported that they had had mistakenly put the wrong IRB number in the last paragraph of the Methods section (as IRB NO.: IRB101-80 instead of IRB102-20 as given in the Ethics approval and consent to participate in Declarations). The corrected last paragraph on the Method section should read as follows. PMID- 29712554 TI - Correction to: Improving implementation of health promotion interventions for maternal and newborn health. AB - Following publication of the original article [1], it was noted that the formatting of the authors' manes was inconsistent with that of the other articles in the series. PMID- 29712556 TI - Correction to: Updated clinical guidelines experience major reporting limitations. AB - After publication of the original article [1] it was brought to our attention that author Laura Hidalgo Armas was incorrectly included as Laura Hildago Armas. PMID- 29712555 TI - Prognostic value of the Stanniocalcin-2/PAPP-A/IGFBP-4 axis in ST-segment elevation myocardial infarction. AB - OBJECTIVE: The aim of the present study was to evaluate the prognostic value of the Stanniocalcin-2/PAPP-A/IGFBP-4 axis in patients with ST-segment elevation myocardial infarction (STEMI). METHODS: Observational cohort study performed in 1085 consecutive STEMI patients treated with early reperfusion between February 2011 and August 2014. Stanniocalcin-2, PAPP-A, and IGFBP-4 were measured using state-of-the art immunoassays. The primary outcome was the composite endpoint of all-cause mortality and readmission due to heart failure (HF). RESULTS: Median follow-up was 3.3 years (IQR 1.0-3.7), during which 176 patients (16.2%) presented a composite endpoint. Multivariable cox regression analysis revealed that Stanniocalcin-2 (HR 2.06; 95% CI 1.13-3.75; p = 0.018), IGFBP-4 (HR 1.73; 95% CI 1.14-2.64; p = 0.010), Killip-Kimball class III-IV (HR 1.40; 95% CI 1.13 1.74; p = 0.002), NT-ProBNP (HR 1.21; 95% CI 1.07-1.37; p = 0.002), age (HR 1.06; 95% CI 1.04-1.08; p < 0.001) and left ventricular ejection fraction (HR 0.97; 95% CI 0.95-0.98; p < 0.001) were independent predictors of the composite endpoint. A model containing Stanniocalcin-2 and IGFBP-4 on top of clinical variables significantly improved C-index discrimination (p = 0.036). Stanniocalcin-2 was also identified as independent predictor of all-cause mortality (HR 2.23; 95% CI 1.16-4.29; p = 0.017) and readmission due to HF (HR 3.42; 95% CI 1.22-9.60; p = 0.020). CONCLUSIONS: In STEMI patients, Stanniocalcin-2 and IGFBP-4 emerged as independent predictors of all-cause death and readmission due to HF. The Stanniocalcin-2/PAPP-A/IGFBP-4 axis exhibits a significant role in STEMI risk stratification. PMID- 29712557 TI - Association of apolipoprotein E gene polymorphisms with blood lipids and their interaction with dietary factors. AB - BACKGROUND: Several candidate genes have been identified in relation to lipid metabolism, and among these, lipoprotein lipase (LPL) and apolipoprotein E (APOE) gene polymorphisms are major sources of genetically determined variation in lipid concentrations. This study investigated the association of two single nucleotide polymorphisms (SNPs) at LPL, seven tagging SNPs at the APOE gene, and a common APOE haplotype (two SNPs) with blood lipids, and examined the interaction of these SNPs with dietary factors. METHODS: The population studied for this investigation included 660 individuals from the Prevention of Cancer by Intervention with Selenium (PRECISE) study who supplied baseline data. The findings of the PRECISE study were further replicated using 1238 individuals from the Caerphilly Prospective cohort (CaPS). Dietary intake was assessed using a validated food-frequency questionnaire (FFQ) in PRECISE and a validated semi quantitative FFQ in the CaPS. Interaction analyses were performed by including the interaction term in the linear regression model adjusted for age, body mass index, sex and country. RESULTS: There was no association between dietary factors and blood lipids after Bonferroni correction and adjustment for confounding factors in either cohort. In the PRECISE study, after correction for multiple testing, there was a statistically significant association of the APOE haplotype (rs7412 and rs429358; E2, E3, and E4) and APOE tagSNP rs445925 with total cholesterol (P = 4 * 10- 4 and P = 0.003, respectively). Carriers of the E2 allele had lower total cholesterol concentration (5.54 +/- 0.97 mmol/L) than those with the E3 (5.98 +/- 1.05 mmol/L) (P = 0.001) and E4 (6.09 +/- 1.06 mmol/L) (P = 2 * 10- 4) alleles. The association of APOE haplotype (E2, E3, and E4) and APOE SNP rs445925 with total cholesterol (P = 2 * 10- 6 and P = 3 * 10- 4, respectively) was further replicated in the CaPS. Additionally, significant association was found between APOE haplotype and APOE SNP rs445925 with low density lipoprotein cholesterol in CaPS (P = 4 * 10- 4 and P = 0.001, respectively). After Bonferroni correction, none of the cohorts showed a statistically significant SNP-diet interaction on lipid outcomes. CONCLUSION: In summary, our findings from the two cohorts confirm that genetic variations at the APOE locus influence plasma total cholesterol concentrations, however, the gene diet interactions on lipids require further investigation in larger cohorts. PMID- 29712558 TI - Enhancement of the catalytic activity of Isopentenyl diphosphate isomerase (IDI) from Saccharomyces cerevisiae through random and site-directed mutagenesis. AB - BACKGROUND: Lycopene is a terpenoid pigment that has diverse applications in the food and medicine industries. A prospective approach for lycopene production is by metabolic engineering in microbial hosts, such as Escherichia coli. Isopentenyl diphosphate isomerase (IDI, E.C. 5.3.3.2) is one of the rate-limiting enzymes in the lycopene biosynthetic pathway and one major target during metabolic engineering. The properties of IDIs differ depending on the sources, but under physiological conditions, IDIs are limited by low enzyme activity, short half-life and weak substrate affinity. Therefore, it is important to prepare an excellent IDI by protein engineering. RESULTS: Directed evolution strategy (error-prone PCR) was utilized to optimize the activity of Saccharomyces cerevisiae IDI. Using three rounds of error-prone PCR; screening the development of a lycopene-dependent color reaction; and combinatorial site-specific saturation mutagenesis, three activity-enhancing mutations were identified: L141H, Y195F, and W256C. L141H, located near the active pocket inside the tertiary structure of IDI, formed a hydrogen bond with nearby beta-phosphates of isopentenylpyrophosphate (IPP). Phe-195 and Cys-256 were nonpolar amino acids and located near the hydrophobic group of IPP, enlarging the hydrophobic scope, and the active pocket indirectly. Purified IDI was characterized and the result showed that the Km of mutant IDI decreased by 10% compared with Km of the parent IDI, and Kcat was 28% fold improved compared to that of the original IDI. Results of a fermentation experiment revealed that mutant IDI had a 1.8-fold increased lycopene production and a 2.1-fold increased yield capacity compared to wild-type IDI. CONCLUSION: We prepared an engineered variant of IDI with improved catalytic activity by combining random and site directed mutagenesis. The best mutants produced by this approach enhanced catalytic activity while also displaying improved stability in pH, enhanced thermostability and longer half-life. Importantly, the mutant IDI could play an important role in fed-batch fermentation, being an effective and attractive biocatalyst for the production of biochemicals. PMID- 29712559 TI - Heterologous expression of Spathaspora passalidarum xylose reductase and xylitol dehydrogenase genes improved xylose fermentation ability of Aureobasidium pullulans. AB - BACKGROUND: Aureobasidium pullulans is a yeast-like fungus that can ferment xylose to generate high-value-added products, such as pullulan, heavy oil, and melanin. The combinatorial expression of two xylose reductase (XR) genes and two xylitol dehydrogenase (XDH) genes from Spathaspora passalidarum and the heterologous expression of the Piromyces sp. xylose isomerase (XI) gene were induced in A. pullulans to increase the consumption capability of A. pullulans on xylose. RESULTS: The overexpression of XYL1.2 (encoding XR) and XYL2.2 (encoding XDH) was the most beneficial for xylose utilization, resulting in a 17.76% increase in consumed xylose compared with the parent strain, whereas the introduction of the Piromyces sp. XI pathway failed to enhance xylose utilization efficiency. Mutants with superior xylose fermentation performance exhibited increased intracellular reducing equivalents. The fermentation performance of all recombinant strains was not affected when glucose or sucrose was utilized as the carbon source. The strain with overexpression of XYL1.2 and XYL2.2 exhibited excellent fermentation performance with mimicked hydrolysate, and pullulan production increased by 97.72% compared with that of the parent strain. CONCLUSIONS: The present work indicates that the P4 mutant (using the XR/XDH pathway) with overexpressed XYL1.2 and XYL2.2 exhibited the best xylose fermentation performance. The P4 strain showed the highest intracellular reducing equivalents and XR and XDH activity, with consequently improved pullulan productivity and reduced melanin production. This valuable development in aerobic fermentation by the P4 strain may provide guidance for the biotransformation of xylose to high-value products by A. pullulans through genetic approach. PMID- 29712561 TI - Systematic review of interventions to increase the provision of care for chronic disease risk behaviours in mental health settings: review protocol. AB - BACKGROUND: People with a mental illness experience a higher morbidity and mortality from chronic diseases relative to the general population. A higher prevalence of risk behaviours, including tobacco smoking, poor nutrition, harmful alcohol consumption and physical inactivity, is a substantial contributor to this health inequity. Clinical practice guidelines recommend that mental health services routinely provide care to their clients to address these risk behaviours. Such care may include the following elements: ask, assess, advise, assist and arrange (the '5As'), which has been demonstrated to be effective in reducing risk behaviours. Despite this potential, the provision of such care is reported to be low internationally and in Australia, and there is a need to identify effective strategies to increase care provision. The proposed review will examine the effectiveness of interventions which aimed to increase care provision (i.e. increase the proportion of clients receiving or clinicians providing the 5As) for the chronic disease risk behaviours of clients within the context of mental health service delivery. METHODS: Eligible studies will be any quantitative study designs with a comparison group and which report on the effectiveness of an intervention strategy (including delivery arrangements, financial arrangements, governance arrangements and implementation strategies) to increase care provision specifically for chronic disease risk behaviours (tobacco smoking, poor nutrition, harmful alcohol consumption and physical inactivity). Screening for studies will be conducted across seven electronic databases: PsycINFO, MEDLINE, Excerpta Medica database (EMBASE), Psychology and Behavioural Sciences Collection, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL) and Cumulative Index to Nursing and Allied Health Literature (CINAHL). Two authors will independently screen studies for eligibility and extract data from included studies. Where studies are sufficiently homogenous, meta-analysis will be performed. Where considerable heterogeneity exists (I2 >= 75), narrative synthesis will be used. DISCUSSION: This review will be the first to synthesise evidence for the effectiveness of intervention approaches to facilitate care provision for chronic disease risk behaviours in the context of mental health service delivery. The results have the potential to inform the development of evidenced-based approaches to address the health inequities experienced by this population group. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017074360 . PMID- 29712560 TI - Cardiovascular disease risk factor responses to a type 2 diabetes care model including nutritional ketosis induced by sustained carbohydrate restriction at 1 year: an open label, non-randomized, controlled study. AB - BACKGROUND: Cardiovascular disease (CVD) is a leading cause of death among adults with type 2 diabetes mellitus (T2D). We recently reported that glycemic control in patients with T2D can be significantly improved through a continuous care intervention (CCI) including nutritional ketosis. The purpose of this study was to examine CVD risk factors in this cohort. METHODS: We investigated CVD risk factors in patients with T2D who participated in a 1 year open label, non randomized, controlled study. The CCI group (n = 262) received treatment from a health coach and medical provider. A usual care (UC) group (n = 87) was independently recruited to track customary T2D progression. Circulating biomarkers of cholesterol metabolism and inflammation, blood pressure (BP), carotid intima media thickness (cIMT), multi-factorial risk scores and medication use were examined. A significance level of P < 0.0019 ensured two-tailed significance at the 5% level when Bonferroni adjusted for multiple comparisons. RESULTS: The CCI group consisted of 262 participants (baseline mean (SD): age 54 (8) year, BMI 40.4 (8.8) kg m-2). Intention-to-treat analysis (% change) revealed the following at 1-year: total LDL-particles (LDL-P) (- 4.9%, P = 0.02), small LDL-P (- 20.8%, P = 1.2 * 10-12), LDL-P size (+ 1.1%, P = 6.0 * 10-10), ApoB (- 1.6%, P = 0.37), ApoA1 (+ 9.8%, P < 10-16), ApoB/ApoA1 ratio (- 9.5%, P = 1.9 * 10-7), triglyceride/HDL-C ratio (- 29.1%, P < 10-16), large VLDL-P (- 38.9%, P = 4.2 * 10-15), and LDL-C (+ 9.9%, P = 4.9 * 10-5). Additional effects were reductions in blood pressure, high sensitivity C-reactive protein, and white blood cell count (all P < 1 * 10-7) while cIMT was unchanged. The 10-year atherosclerotic cardiovascular disease (ASCVD) risk score decreased - 11.9% (P = 4.9 * 10-5). Antihypertensive medication use was discontinued in 11.4% of CCI participants (P = 5.3 * 10-5). The UC group of 87 participants [baseline mean (SD): age 52 (10) year, BMI 36.7 (7.2) kg m-2] showed no significant changes. After adjusting for baseline differences when comparing CCI and UC groups, significant improvements for the CCI group included small LDL-P, ApoA1, triglyceride/HDL-C ratio, HDL-C, hsCRP, and LP-IR score in addition to other biomarkers that were previously reported. The CCI group showed a greater rise in LDL-C. CONCLUSIONS: A continuous care treatment including nutritional ketosis in patients with T2D improved most biomarkers of CVD risk after 1 year. The increase in LDL-cholesterol appeared limited to the large LDL subfraction. LDL particle size increased, total LDL-P and ApoB were unchanged, and inflammation and blood pressure decreased. Trial registration Clinicaltrials.gov: NCT02519309. Registered 10 August 2015. PMID- 29712563 TI - Correction to: Comparative analysis of COPD associated with tobacco smoking, biomass smoke exposure or both. AB - In the original publication [1] is an error in table 1. The correct version can be found in this Erratum. PMID- 29712562 TI - Endometrium metabolomic profiling reveals potential biomarkers for diagnosis of endometriosis at minimal-mild stages. AB - BACKGROUND: The sensitivity and specificity of non-invasive diagnostic methods for endometriosis, especially at early stages, are not optimal. The clinical diagnostic indicator cancer antigen 125 (CA125) performs poorly in the diagnosis of minimal endometriosis, with a sensitivity of 24%. Therefore, it is urgent to explore novel diagnostic biomarkers. We evaluated the metabolomic profile variation of the eutopic endometrium between minimal-mild endometriosis patients and healthy women by ultra-high-performance liquid chromatography coupled with electrospray ionization high-resolution mass spectrometry (UHPLC-ESI-HRMS). METHODS: Our study comprised 29 patients with laparoscopically confirmed endometriosis at stages I-II and 37 infertile women who underwent diagnostic laparoscopy combined with hysteroscopy from January 2014 to January 2015. Eutopic endometrium samples were collected by pipelle endometrial biopsy. The metabolites were quantified by UHPLC-ESI-HRMS. The best combination of biomarkers was then selected by performing step-wise logistic regression analysis with backward elimination. RESULTS: Twelve metabolites were identified as endometriosis associated biomarkers. The eutopic endometrium metabolomic profile of the endometriosis patients was characterized by a significant increase in the concentration of hypoxanthine, L-arginine, L-tyrosine, leucine, lysine, inosine, omega-3 arachidonic acid, guanosine, xanthosine, lysophosphatidylethanolamine and asparagine. In contrast, the concentration of uric acid was decreased. Metabolites were filtered by step-wise logistic regression with backward elimination, and a model containing uric acid, hypoxanthine, and lysophosphatidylethanolamine was constructed. Receiver-operating characteristic (ROC) analysis confirmed the prognostic value of these parameters for the diagnosis of minimal/mild endometriosis with a sensitivity of 66.7% and a specificity of 90.0%. CONCLUSIONS: Metabolomics analysis of the eutopic endometrium in endometriosis was effectively characterized by UHPLC-ESI-HRMS based metabolomics. Our study supports the importance of purine and amino acid metabolites in the pathophysiology of endometriosis and provides potential biomarkers for semi-invasive diagnosis of early-stage endometriosis. PMID- 29712565 TI - Correction to: Contrasting transcriptional responses of PYR1/PYL/RCAR ABA receptors to ABA or dehydration stress between maize seedling leaves and roots. AB - Following publication of the original article [1], a reader spotted that the article appears to have some misplaced/duplicated figures. In particular, Fig. 5a and Fig. 6a appear to be identical, and do not match what is written in the text. The authors apologized for this oversight and supplied the original pictures, which are reproduced below. PMID- 29712564 TI - Effectiveness of a new model of primary care management on knee pain and function in patients with knee osteoarthritis: Protocol for THE PARTNER STUDY. AB - BACKGROUND: To increase the uptake of key clinical recommendations for non surgical management of knee osteoarthritis (OA) and improve patient outcomes, we developed a new model of service delivery (PARTNER model) and an intervention to implement the model in the Australian primary care setting. We will evaluate the effectiveness and cost-effectiveness of this model compared to usual general practice care. METHODS: We will conduct a mixed-methods study, including a two arm, cluster randomised controlled trial, with quantitative, qualitative and economic evaluations. We will recruit 44 general practices and 572 patients with knee OA in urban and regional practices in Victoria and New South Wales. The interventions will target both general practitioners (GPs) and their patients at the practice level. Practices will be randomised at a 1:1 ratio. Patients will be recruited if they are aged >=45 years and have experienced knee pain >=4/10 on a numerical rating scale for more than three months. Outcomes are self-reported, patient-level validated measures with the primary outcomes being change in pain and function at 12 months. Secondary outcomes will be assessed at 6 and 12 months. The implementation intervention will support and provide education to intervention group GPs to deliver effective management for patients with knee OA using tailored online training and electronic medical record support. Participants with knee OA will have an initial GP visit to confirm their diagnosis and receive management according to GP intervention or control group allocation. As part of the intervention group GP management, participants with knee OA will be referred to a centralised multidisciplinary service: the PARTNER Care Support Team (CST). The CST will be trained in behaviour change support and evidence-based knee OA management. They will work with patients to develop a collaborative action plan focussed on key self-management behaviours, and communicate with the patients' GPs. Patients receiving care by intervention group GPs will receive tailored OA educational materials, a leg muscle strengthening program, and access to a weight-loss program as appropriate and agreed. GPs in the control group will receive no additional training and their patients will receive usual care. DISCUSSION: This project aims to address a major evidence-to practice gap in primary care management of OA by evaluating a new service delivery model implemented with an intervention targeting GP practice behaviours to improve the health of people with knee OA. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12617001595303 , date of registration 1/12/2017. PMID- 29712566 TI - POWIFF- Prospective study of wrist internal fixation of fracture: A protocol for a single centre, superiority, randomised controlled trial to study the efficacy of the VRP (2.0) distal radius plate (Austofix) versus the VA-LCP (Depuy-Synthes) for distal radius fractures. AB - BACKGROUND: Distal radial fractures are one of the most common orthopaedic cases that present to the A&E department. Surgical intervention is warranted in displaced intraarticular fractures and fractures with more than the recommended angulation or shortening, and is most commonly treated with volarly placed fixed angle locking plates. The aim of this study is to determine and compare the efficacy of two different plates for surgical treatment of distal radius fractures. The VRP 2.0 is a new plate produced by the Austofix company and this system will be compared against the VA-LP (Variable angle-locking plate) produced by Depuy-Synthes which has been used as the standard treatment device. METHODS AND DESIGN: Patients between the ages of 18 and 80 presenting to the Royal Adelaide Hospital with isolated closed distal radial fractures will be invited to participate in this study. A total of 200 patients are required to provide 90% statistical power at a 5% alpha level to detect a difference of 11.5 points on the PRWE (Patient rated Wrist evaluation) score. The primary outcome measure will be the PRWE score while the secondary outcome measures will include the DASH score, EQ5D score, clinical range of movements, grip strength as well as patient perceived return of function at the wrist and time to resumption to work. These will be measured at 6 weeks, 3 months and 12 months. Radiographic indices including the radial tilt, length, volar inclination and plate prominence will also be measured. Complications will be recorded up to 12 months. Post hoc comparisons will be done using paired t tests. An intention to treat and a per protocol analysis will be done to compare the 2 groups. DISCUSSION: Distal radial fractures are increasingly being treated by internal fixation using volar locking plates. However, there is no prospective study to date comparing one plate against another in terms of outcome and complications. This study could provide more information about the best way to treat these injuries surgically. TRIAL REGISTRATION: The trial is registered with the Australia New Zealand Clinical Trials Registry (ANZCTR). Trial registration date-17/11/2016. Trial registration number- ACTRN12616001590459 . PMID- 29712567 TI - Wernekink commissure syndrome with palatal myoclonus at onset: a case report and review of the literature. AB - BACKGROUND: Wernekink commissure syndrome causes a peculiar combination of internuclear ophthalmoplegia, dysarthria, and delayed-onset palatal myoclonus. Palatal myoclonus is thought to be secondary to delayed hypertrophic degeneration of the bilateral inferior olivary nuclei secondary to involvement of bilateral dentatoolivary tract. We describe a case of a patient with early-onset palatal myoclonus. CASE PRESENTATION: A 53-year-old Caucasian man with several vascular risk factors presented to our emergency room with slurred speech, double vision, difficulty with swallowing and walking, and rhythmic contractions of the soft palate. Brain magnetic resonance imaging showed an acute infarct of the right caudal midbrain and an old infarct of the right medulla. We hypothesize that the cause of early palatal myoclonus in our patient was a two-hit mechanism with degeneration of the right olivary nucleus resulting from prior right medullary lacunar stroke with the new infarct affecting the dentato-rubro-olivary tract on the left side, causing bilateral dysfunction initiating palatal myoclonus. CONCLUSIONS: Wernekink commissure syndrome with palatal myoclonus at onset suggests the presence of a prior ischemic insult in the medulla. Careful examination is important to identification of this presentation. PMID- 29712568 TI - Discovery and preclinical characterization of the antagonist anti-PD-L1 monoclonal antibody LY3300054. AB - BACKGROUND: Modulation of the PD-1/PD-L1 axis through antagonist antibodies that block either receptor or ligand has been shown to reinvigorate the function of tumor-specific T cells and unleash potent anti-tumor immunity, leading to durable objective responses in a subset of patients across multiple tumor types. RESULTS: Here we describe the discovery and preclinical characterization of LY3300054, a fully human IgG1lambda monoclonal antibody that binds to human PD-L1 with high affinity and inhibits interactions of PD-L1 with its two cognate receptors PD-1 and CD80. The functional activity of LY3300054 on primary human T cells is evaluated using a series of in vitro T cell functional assays and in vivo models using human-immune reconstituted mice. LY3300054 is shown to induce primary T cell activation in vitro, increase T cell activation in combination with anti CTLA4 antibody, and to potently enhance anti-tumor alloreactivity in several xenograft mouse tumor models with reconstituted human immune cells. High-content molecular analysis of tumor and peripheral tissues from animals treated with LY3300054 reveals distinct adaptive immune activation signatures, and also previously not described modulation of innate immune pathways. CONCLUSIONS: LY3300054 is currently being evaluated in phase I clinical trials for oncology indications. PMID- 29712569 TI - The dual blockade of MET and VEGFR2 signaling demonstrates pronounced inhibition on tumor growth and metastasis of hepatocellular carcinoma. AB - BACKGROUND: The application of VEGF signaling inhibitors have been associated with more invasive or metastatic behavior of cancers including hepatocellular carcinoma (HCC). We explored the contribution of MET pathway to the enhanced HCC invasion and metastasis by VEGF signaling inhibition, and investigated the antitumor effects of NZ001, a novel dual inhibitor of MET and VEGFR2, in HCC. METHODS: Immunocompetent orthotopic mice model of hepal-6 was established to investigate the effects of either VEGF antibody alone or in combination with the selective MET inhibitor on tumor aggressiveness. The antitumor effects of NZ001 were examined in cultured HCC cells as well as in vivo models. MET gene amplification was determined by SNP 6.0 assay. MET/P-MET expression was detected by IHC. RESULTS: Selective VEGF signaling inhibition by VEGF antibody significantly reduced in vivo tumor growth of the orthotopic mice models, simultaneously also enhanced tumor invasion and metastasis, but inhibiting MET signaling attenuated this side-effect. Further study revealed that hypoxia caused by VEGF signaling inhibition induced HIF-1alpha nuclear accumulation, subsequently leading to elevated total-MET expression, and synergized with HGF in inducing invasion. NZ001, a novel dual inhibitor of MET and VEGFR2, markedly inhibited both tumor growth and metastasis of HCC, which showed obvious advantages over sorafenib in not inducing more invasive and metastatic behaviors. This effect is more pronounced in HCC with MET amplification and overexpression. CONCLUSIONS: The activation of MET is responsible for the metastasis-promoting effects induced by VEGF inhibition. MET and VEGFR2 dual blockade, NZ001, has advantages over sorafenib in not inducing more invasive and metastatic behaviors; MET amplification and overexpression can be used to identify the subgroup of patients most likely to get the optimal benefit from NZ001 treatment. PMID- 29712571 TI - Correction to: Outcomes of oblique lateral interbody fusion for degenerative lumbar disease in patients under or over 65 years of age. AB - In the original publication of this article [1] is an error in the Results section in the first paragraph in regards to a patient value introduced. PMID- 29712570 TI - IL-1beta suppresses cLTP-induced surface expression of GluA1 and actin polymerization via ceramide-mediated Src activation. AB - BACKGROUND: Brain inflammation including increases in inflammatory cytokines such as IL-1beta is widely believed to contribute to the pathophysiology of Alzheimer's disease. Although IL-1beta-induced impairments in long-term potentiation (LTP) in acute hippocampal slices and memory functions in vivo have been well documented, the neuron-specific molecular mechanisms of IL-1beta mediated impairments of LTP and memory remain unclear. METHODS: This study uses an in vitro approach in primary hippocampal neurons to evaluate the effect of IL 1beta on chemical LTP (cLTP)-induced structural plasticity and signaling. RESULTS: We found that IL-1beta reduces both the surface expression of alpha amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor subunit GluA1 and the spine growth following cLTP. These effects of IL-1beta were mediated by impairing actin polymerization during cLTP, as IL-1beta decreased the cLTP induced formation of F-actin, and the effect of IL-1beta on cLTP-induced surface expression of GluA1 can be mimicked by latrunculin, a toxin that disrupts dynamics of actin filaments, and can be prevented by jasplakinolide, a cell permeable peptide that stabilizes F-actin. Moreover, live-cell imaging demonstrated that IL-1beta decreased the stability of the actin cytoskeleton in spines, which is required for LTP consolidation. We further examined the role of sphingolipid signaling in the IL-1beta-mediated impairment of spine plasticity and found that both the neutral sphingomyelinase inhibitor GW4869 and the inhibitor of Src kinase PP2 attenuated the IL-1beta-mediated suppression of cLTP induced surface expression of GluA1 and actin polymerization. CONCLUSIONS: These findings support a mechanism by which IL-1beta, via the sphingomyelinase/ceramide/Src pathway, impairs structural spine remodeling essential for LTP consolidation and memory. PMID- 29712573 TI - Green monomeric photosensitizing fluorescent protein for photo-inducible protein inactivation and cell ablation. AB - BACKGROUND: Photosensitizing fluorescent proteins, which generate reactive oxygen species (ROS) upon light irradiation, are useful for spatiotemporal protein inactivation and cell ablation. They give us clues about protein function, intracellular signaling pathways and intercellular interactions. Since ROS generation of a photosensitizer is specifically controlled by certain excitation wavelengths, utilizing colour variants of photosensitizing protein would allow multi-spatiotemporal control of inactivation. To expand the colour palette of photosensitizing protein, here we developed SuperNova Green from its red predecessor, SuperNova. RESULTS: SuperNova Green is able to produce ROS spatiotemporally upon blue light irradiation. Based on protein characterization, SuperNova Green produces insignificant amounts of singlet oxygen and predominantly produces superoxide and its derivatives. We utilized SuperNova Green to specifically inactivate the pleckstrin homology domain of phospholipase C-delta1 and to ablate cancer cells in vitro. As a proof of concept for multi spatiotemporal control of inactivation, we demonstrate that SuperNova Green can be used with its red variant, SuperNova, to perform independent protein inactivation or cell ablation studies in a spatiotemporal manner by selective light irradiation. CONCLUSION: Development of SuperNova Green has expanded the photosensitizing protein toolbox to optogenetically control protein inactivation and cell ablation. PMID- 29712575 TI - Doctors, suicide and mental illness. AB - This article focuses on doctors and suicide. It provides real examples to illustrate why doctors die by their own hand. These reasons are replicated in the general population, but also include a host of additional risk factors related to being a doctor. In each case, information about the doctor is in the public domain or, as in one case, consent from the next of kin has been obtained for a detail not in the public domain. The author is a doctors' doctor, heading up a confidential health service for doctors with mental illness or addiction, the National Health Service Practitioner Health Programme. Mortality data from the programme (January 2008-January 2017) will also be included. For the sake of confidentiality, data is collated and details regarding age and gender have been approximated.Declaration of interestNone. PMID- 29712572 TI - Astrocytes, neurons, synapses: a tripartite view on cortical circuit development. AB - In the mammalian cerebral cortex neurons are arranged in specific layers and form connections both within the cortex and with other brain regions, thus forming a complex mesh of specialized synaptic connections comprising distinct circuits. The correct establishment of these connections during development is crucial for the proper function of the brain. Astrocytes, a major type of glial cell, are important regulators of synapse formation and function during development. While neurogenesis precedes astrogenesis in the cortex, neuronal synapses only begin to form after astrocytes have been generated, concurrent with neuronal branching and process elaboration. Here we provide a combined overview of the developmental processes of synapse and circuit formation in the rodent cortex, emphasizing the timeline of both neuronal and astrocytic development and maturation. We further discuss the role of astrocytes at the synapse, focusing on astrocyte-synapse contact and the role of synapse-related proteins in promoting formation of distinct cortical circuits. PMID- 29712574 TI - Durable regression of Medulloblastoma after regional and intravenous delivery of anti-HER2 chimeric antigen receptor T cells. AB - BACKGROUND: Standard-of-care therapies for treating pediatric medulloblastoma have long-term side effects, even in children who are cured. One emerging modality of cancer therapy that could be equally effective without such side effects would be chimeric antigen receptor (CAR) T cells. Knowing that human epidermal growth factor receptor 2 (HER2) is overexpressed in many medulloblastomas and has been used as a CAR T target before, we sought to evaluate the efficacy of more sophisticated anti-HER2 CAR T cells, as well as the feasibility and efficacy of different routes of delivering these cells, for the treatment of pediatric medulloblastoma. METHODS: Daoy, D283 and D425 medulloblastoma cell lines were characterized by flow cytometry to evaluate HER2 expression. Anti-tumor efficacy of HER2-BBz-CAR T cells in vitro was performed using cytokine release and immune cytotoxicity assays compared to control CD19 CAR T cells. In vivo, Daoy and D283 tumor cells were orthotopically implanted in the posterior fossa of NOD.Cg-Prkdc scid Il2rg tm1Wjl /SzJ (NSG) mice and treated with regional or intravenous HER2-BBz-CAR T cells or control CD19 CAR T cells. Non-human primates (NHPs) bearing ventricular and lumbar reservoirs were treated with target autologous cells bearing extracellular HER2 followed by autologous HER2-CAR T cells intraventricularly. Cerebrospinal fluid and blood were collected serially to measure the persistence of delivered cells and cytokines. RESULTS: HER2-BBz-CAR T cells effectively clear medulloblastoma orthotopically implanted in the posterior fossa of NSG mice via both regional and intravenous delivery in xenograft models. Intravenous delivery requires a log higher dose compared to regional delivery. NHPs tolerated intraventricular delivery of autologous cells bearing extracellular HER2 followed by HER2-BBz-CAR T cells without experiencing any systemic toxicity. CONCLUSIONS: HER2-BBz-CAR T cells show excellent pre clinical efficacy in vitro and in mouse medulloblastoma models, and their intraventricular delivery is feasible and safe in NHPs. A clinical trial of HER2 BBz-CAR T cells directly delivered into cerebrospinal fluid should be designed for patients with relapsed medulloblastoma. PMID- 29712581 TI - Common Iliac Arterial-Rectal Fistula Managed with Endovascular Stenting in a Patient with History of Pelvic External Beam Radiation. PMID- 29712590 TI - Esophageal Achalasia: Pathophysiology, Clinical Presentation, and Diagnostic Evaluation. AB - Esophageal achalasia is a primary esophageal motility disorder characterized by the absence of esophageal peristalsis and failure of the lower esophageal sphincter to relax in response to swallowing. These abnormalities lead to impaired emptying of food from the esophagus into the stomach with resulting food stasis. Most patients experience severe dysphagia, and regurgitation can lead to aspiration and respiratory problems. Consequently, the quality of life of patients affected by achalasia is severely impacted. A thorough evaluation with upper endoscopy, barium swallow, and esophageal manometry is mandatory to establish the diagnosis and plan the optimal treatment. In selected patients, an ambulatory pH monitoring is recommended to distinguish between gastroesophageal reflux disease and achalasia. PMID- 29712591 TI - Endoscopic Pneumatic Dilation for Esophageal Achalasia. AB - Pneumatic dilation is a well-established treatment modality that has withstood the test of time. Prospective and randomized trials have shown that in expert hands, it provides results similar to a laparoscopic Heller myotomy with fundoplication. In addition, it should be considered the primary form of treatment in patients who experience recurrence of symptoms after a surgical myotomy. PMID- 29712592 TI - Laparoscopic Heller Myotomy for Achalasia Technical Aspects. AB - Esophageal achalasia is a primary esophageal motility disorder defined by the lack of esophageal peristalsis, and by a lower esophageal sphincter that fails to relax in response to swallowing. Patients' symptoms include dysphagia, regurgitation, aspiration, heartburn, and chest pain. Achalasia is a chronic condition without cure, and treatment options are aimed at providing symptomatic relief, improving esophageal emptying, and preventing the development of megaesophagus. Presently, a laparoscopic Heller myotomy with a partial fundoplication is considered the best treatment modality. A properly executed operation is key for the success of a laparoscopic Heller myotomy. PMID- 29712593 TI - Laparoscopic Heller Myotomy and Fundoplication: What Is the Evidence? AB - There is no agreement about the best type of fundoplication to add in patients undergoing laparoscopic Heller myotomy (LHM) for achalasia to reduce the risk of postoperative gastroesophageal reflux. This article reviews the current evidence about the outcomes in achalasia patients undergoing LHM with a partial anterior, a partial posterior, or a total fundoplication. We performed a review of the literature in PubMed/Medline electronic databases, which was evaluated according to the GRADE system. The results of the published randomized controlled trials show with a high level of evidence that the addition of a fundoplication reduces the risk of postoperative abnormal reflux, without impairing the food emptying of the esophagus. LHM with partial fundoplication is considered in most centers worldwide the standard of care for the treatment of patients with achalasia. The current evidence fails to show any significant difference between partial anterior and posterior fundoplication. In the absence of further large randomized controlled trial, the decision of performing an anterior or a posterior wrap is based on the surgeon's experience and preference. The addition of a partial fundoplication to LHM leads to a significantly lower rate of postoperative pathological reflux without impairing the esophageal emptying. PMID- 29712594 TI - POEM for Achalasia. AB - In 2008, a new treatment modality for esophageal achalasia was introduced-peroral endoscopic myotomy (POEM). POEM is a procedure performed endoscopically, which allows transection of the muscular fibers of the distal esophagus and of the lower esophageal sphincter. The procedure is therefore similar to a laparoscopic Heller myotomy without a fundoplication. Short-term studies have shown that POEM is very effective in relieving dysphagia and regurgitation, but concerns have been raised about the incidence of post-POEM gastroesophageal reflux. Prospective and randomized trials will be needed to determine the role of this new procedure in the treatment algorithm of esophageal achalasia. PMID- 29712595 TI - Laparoscopic Heller Myotomy versus Per Oral Endoscopic Myotomy: Evidence-Based Approach to the Treatment of Esophageal Achalasia. AB - Esophageal achalasia is a rare disorder characterized by a failure of the lower esophageal sphincter to relax during swallowing, combined with aperistalsis of the esophageal body. Treatment is not curative, but aims to eliminate the outflow resistance caused by the nonrelaxing lower esophageal sphincter. Current evidence suggests that both laparoscopic Heller myotomy and per oral endoscopic myotomy (POEM) are very effective in the relief of symptoms in patients with achalasia. Specifically, for type III achalasia, POEM may achieve higher success rates. However, POEM is associated to a very high incidence of pathologic reflux, with the risk of exchanging one disease-achalasia-with another-gastroesophageal reflux. PMID- 29712596 TI - The Treatment of Achalasia in Obese Patients. AB - : Epidemiological studies have demonstrated that obesity is frequently associated with esophageal motility disorders. Morbid obesity and achalasia may coexist in the same patient. The management of the morbidly obese patient with achalasia is complex and the most effective treatment remains controversial. The aim of this study is to review the pathophysiology, clinical presentation, diagnostic evaluation, and treatment of achalasia in morbidly obese patients. EVIDENCE REVIEW: PubMed search from January 1990 to July 2017, including the following terms: achalasia, morbid obesity, bariatric, and treatment. Achalasia in the setting of morbid obesity may be successfully treated by endoscopic or surgical methods. Surgeons may choose to add a bariatric procedure, with various strategies present in the literature. A review of the present literature suggests that the preferred approach to achalasia in the morbidly obese patient is to address both disease processes simultaneously with a laparoscopic Heller myotomy and a Roux-en-Y gastric bypass. Roux-en-Y gastric bypass is cited by most experts as the bariatric procedure of choice, given its antireflux benefits. A well powered study, comparing the various approaches to the treatment of achalasia in the setting of morbid obesity, is required to establish a consensus. PMID- 29712597 TI - Esophageal Resection for End-Stage Achalasia. AB - Achalasia is a rare disease characterized by impaired lower esophageal sphincter relaxation loss and of peristalsis in the esophageal body. Endoscopic balloon dilation and laparoscopic surgical myotomy have been established as initial treatment modalities. Indications and outcomes of esophagectomy in the management of end-stage achalasia are less defined. A literature search was conducted to identify all reports on esophagectomy for end-stage achalasia between 1987 and 2017. MEDLINE, Embase, and Cochrane databases were consulted matching the terms "achalasia," "end-stage achalasia," "esophagectomy," and "esophageal resection." Seventeen articles met the inclusion criteria and 1422 patients were included in this narrative review. Most of the patients had previous multiple endoscopic and/or surgical treatments. Esophagectomy was performed through a transthoracic (74%) or a transhiatal (26%) approach. A thoracoscopic approach was used in a minority of patients and seemed to be safe and effective. In 95 per cent of patients, the stomach was used as an esophageal substitute. The mean postoperative morbidity rate was 27.1 per cent and the mortality rate 2.1 per cent. Symptom resolution was reported in 75 to 100 per cent of patients over a mean follow-up of 43 months. Only five series including 195 patients assessed the long-term follow-up (>5 years) after reconstruction with gastric or colon conduits, and the results seem similar. Esophagectomy for end-stage achalasia is safe and effective in tertiary referral centers. A thoracoscopic approach is a feasible and safe alternative to thoracotomy and may replace the transhiatal route in the future. PMID- 29712598 TI - Association of Increasing Frailty with Detrimental Outcomes after Pancreatic Resection. AB - An association between detrimental outcomes and frailty has been documented; however, the impact specific to pancreatic surgery is unknown. Using NSQIP data, patients were classified as non-, mildly, moderately, or severely frail. A total of 16,028 patients were included in the study; most of the patients were white (78.5%) and underwent pancreaticoduodenectomy (PD) (67%). Complications occurred in 17.6 per cent cases, and the median length of stay (LOS) was 11.89 days. Prolonged LOS and mortality occurred in 9.1 and 2.3 per cent of the cases. In the PD group, most of the patients were mildly frail (40.6%), followed by nonfrail (39.83%), whereas in the distal pancreatectomy (DP) group, the majority were nonfrail (43.82%), followed by mildly frail (39.37%) (P < 0.0001). The 30-day complications, mortality, and LOS were significantly higher in patients undergoing PD compared with DP (19.5 vs 14.3%, 2.8 vs 1.2%, and 13.4 vs 8.7 days, respectively; P < 0.0001). PD conferred a significantly higher risk of death in all frailty groups compared with DP [nonfrail: odds ratio (OR) 1.76, mildly frail: OR 1.03, moderately frail: OR 2.03, P < 0.05], with the exception of severely frail patients. Compared with DP, PD conferred a significant risk of complication in all the frailty groups. Increases in frailty are associated with poorer outcomes after pancreatectomy. PMID- 29712599 TI - Biomechanical and Histologic Evaluation of LifeMeshTM: A Novel Self-Fixating Mesh Adhesive. AB - Mesh fixation with the use of adhesives results in an immediate and total surface area adhesion of the mesh, removing the need for penetrating fixation points. The purpose of this study was to evaluate LifeMeshTM, a prototype mesh adhesive technology which coats polypropylene mesh. The strength of the interface between mesh and tissue, inflammatory responses, and histology were measured at varying time points in a swine model, and these results were compared with sutures. Twenty Mongrel swine underwent implantation of LifeMeshTM and one piece of bare polypropylene mesh secured with suture (control). One additional piece of either LifeMeshTM or control was used for histopathologic evaluation. The implants were retrieved at 3, 7, and 14 days. Only 3- and 7-day specimens underwent lap shear testing. On Day 3, LifeMeshTM samples showed considerably less contraction than sutured samples. The interfacial strength of Day 3 LifeMeshTM samples was similar to that of sutured samples. At seven days, LifeMeshTM samples continued to show significantly less contraction than sutured samples. The strength of fixation at seven days was greater in the control samples. The histologic findings were similar in LifeMeshTM and control samples. LifeMeshTM showed significantly less contraction than sutured samples at all measured time points. Although fixation strength was similar at three days, the interfacial strength of LifeMeshTM remained unchanged, whereas sutured controls increased by day 7. With histologic equivalence, considerably less contraction, and similar early fixation strength, LifeMeshTM is a viable mesh fixation technology. PMID- 29712600 TI - Redefining the Surgical Council of Resident Education (SCORE) Curriculum: A Comparison with the Operative Experiences of Graduated General Surgical Residents. AB - Our objective was to investigate the number and classify surgical operations performed by general surgery residents and compare these with the updated Surgical Council on Resident Education (SCORE) curriculum. We performed a retrospective review of logged surgical cases from general surgical residents who completed training at a single center from 2011 to 2015. The logged cases were correlated with the operations extracted from the SCORE curriculum. Hundred and fifty-one procedures were examined; there were 98 "core" and 53 "advanced" cases as determined by the SCORE. Twenty-eight residents graduated with an average of 1017 major cases. Each resident completed 66 (67%) core cases and 17 (32%) advanced cases an average of one or more times with 39 (40%) core cases and 6 (11%) advanced cases completed five or more times. Core procedures that are infrequently or not performed by residents should be identified in each program to focus on resident education. PMID- 29712601 TI - Central Lymph Node Dissection Improves Lymph Node Clearance in Papillary Thyroid Cancer Patients with Lateral Neck Metastases, Even after Prior Total Thyroidectomy. AB - The oncologic benefit of a central lymph node dissection (CLND) at the time of modified radical neck dissection (MRND) in patients with papillary thyroid cancer who have previously undergone a total thyroidectomy (TT) has not been studied. Patients with lateral cervical metastases were divided into two treatment groups: the concurrent cohort (TT with CLND and MRND), and the interval cohort (CLND and MRND after prior TT). Primary outcomes were lymph node metastases, skip metastases, level VI cancer recurrence, hypoparathyroidism and recurrent laryngeal nerve injury. Treatment groups consisted of 63 and 16 patients in the concurrent and interval groups, respectively. More central lymph nodes were removed (15.4 +/- 8.4 to 10.1 +/- 5.2 (P = 0.02)), but similar level VI lymph node metastasis occurred (92.0-93.8% (P = 0.99)) in the concurrent group compared with the interval group, respectively. Skip metastases were identified in only 7.6 per cent of patients. The incidence of level VI recurrence and recurrent laryngeal nerve injury was 1.2 per cent. Three patients developed hypoparathyroidism (3.7%). All permanent morbidities occurred in the concurrent group. CLND at the time of MRND for metastatic papillary thyroid cancer frequently identifies level VI metastases and can be done with low operative morbidity by experienced endocrine surgeons, even in patients who have undergone a prior TT. PMID- 29712602 TI - Ability of Intraoperative Pathologic Analysis of Ductal Carcinoma In Situ to Guide Selective Use of Sentinel Lymph Node Surgery. AB - For patients with ductal carcinoma In Situ (DCIS), sentinel lymph node (SLN) surgery is generally reserved for patients at high risk of being upstaged to invasive disease. The use of frozen section (FS) pathologic analysis of the primary tumor may allow for selective surgical nodal staging within one procedure. We sought to define the reliability of FS for detection of upstaging. Eight hundred and twenty-seven patients were identified with DCIS on core needle biopsy that underwent 834 operations at our institution between January 2004 and October 2014. We calculated the rate of upstage from DCIS to invasive cancer on both intraoperative FS and final pathology to determine the performance of FS. Upstage rate on final pathology was 118/834 (14.1%) 95 per cent confidence interval 11.8 to 16.7 per cent. FS identified 88/118 (74.6%) of the upstages. Specificity was 99.3 per cent (711/716). Overall accuracy was 95.8 per cent (799/834) and the positive predictive value was 96.0 per cent (711/741 patients). Mean size of invasive cancers identified on FS was 5.6 mm, versus 3.5 mm for those identified only on permanent section, P = 0.11. Intraoperative FS analysis of DCIS is useful for identification of upstage to invasive disease. This may facilitate a selective approach to SLN surgery that both decreases unnecessary SLN surgery and the need for a second operation. PMID- 29712603 TI - Effectiveness of an Early Ultrasound Training Curriculum for General Surgery Residents. AB - Ultrasound (US) is fast becoming an extension of the physical examination in most surgical settings. Unfortunately, few residency programs offer a formal US training curriculum to their general surgical residents. This study aimed to assess the efficacy of a formal US training module for general surgery residents. We studied the degree of improvement observed between junior and senior residents. A training-based study was conducted to evaluate baseline knowledge and skills. Subsequently, a formal didactic and practical training program for our surgery residents was instituted. Residents were then scored in various categories. A total of 18 surgical residents comprising 10 junior and 8 senior residents completed our US training module. There was no significant improvement in the scores of the senior resident group. In the junior group, the written test, image detection, optimization, and interpretation categories improved significantly after completion of the training module. Comparison of improvement in scores between junior and senior residents revealed a significantly better improvement in the junior group than in the senior group. Early training of surgical residents can significantly improve US performance in junior residents. This early training has the benefit of increased utilization of bedside US for diagnostic and procedural purposes. Interestingly, even without formal training, skill acquisition of senior residents is noted to occur during modern surgical training. PMID- 29712604 TI - A New Approach to an Old Technique-The S.U.T.R. First Technique. AB - Ventral and incisional hernias of the abdominal wall are common problems treated by surgeons around the globe. Incisional hernias are common postoperative complications of abdominal laparotomies with a reported incidence of up to 20 per cent. The increasing use of prosthetic mesh in open ventral hernia repairs necessitated the development of different operative techniques used in the repairs. It also required that surgeons become facile with placement of the mesh in different anatomical positions on the abdominal wall. One of the most common locations is placement of the mesh in the underlay position. Many surgeons who use the underlay technique have expressed significant concerns. Among these are fear of an inadvertent bowel injury while placing the mesh, poor visualization during mesh placement, and the inability to use the underlay technique for difficult hernias. We present a very useful, if not, novel technique of open hernia repair using mesh in the underlay position that helps to 1) prevent complications, 2) facilitate easier mesh fixation, 3) simplify open repair of atypical ventral hernias, and 4) reduce total operative time while still adhering to the important fundamental principles of a tension-free hernia repair. This technique as we describe it has been compared with the old parachute technique, but we think this is a significant improvement of that seldom used technique. We believe the use of this technique for the underlay position makes open ventral hernia repair safer, faster, and easier; however, our goal for this article is to describe the procedure in detail. In addition, we recently have started using this technique to fix the mesh when doing the retrorectus approach as well. PMID- 29712605 TI - Long-Term Functional Outcomes after Blunt Cerebrovascular Injury: A 20-Year Experience. AB - Since blunt cerebrovascular injury (BCVI) became increasingly recognized more than 20 years ago, significant improvements have been made in both diagnosis and treatment. Little is known regarding long-term functional outcomes in BCVI. The purpose of this study was to evaluate the impact of BCVI on those long-term outcomes. All patients with BCVI from 1996 to 2014 were identified from the trauma registry. Functional outcome was measured using the Boston University Activity Measure for Post-Acute Care. Multiple regression analysis was performed to identify potential predictors of outcomes. A total of 509 patients were identified. Overall mortality was 18 per cent (BCVI-related = 1%). Of the 415 survivors, follow-up was obtained in 77 (19%). Mean follow-up was five years, with a maximum of 19 years. Mean age and injury severity score were 47 and 25, respectively. Six (8%) patients suffered strokes. Mean Activity Measure for Post Acute Care scores were 59 (mobility), 58 (activity), and 44 (cognitive function), each indicating significant impairment compared with normal. Multiple regression models identified 1) age as a predictor of decreased mobility, 2) injury severity score as a predictor of decreased mobility, activity, and cognitive function, and 3) stroke as a predictor of decreased activity, cognitive function, and likely mobility. Development of stroke and increased injury severity resulted in worse long-term functional outcomes after BCVI. Thus, stroke prevention with optimal diagnostic and treatment algorithms remains critical in the successful treatment of BCVI because it has significant impact on long-term functional outcomes and is the only modifiable predictor of outcomes in patients after BCVI. PMID- 29712606 TI - Level I Trauma Centers: More Is Not Necessarily Better. AB - The optimal number of level I trauma centers (L1TCs) in a region has not been elucidated. To begin addressing this, we compared mortalities for patients treated in counties or regions with 1 L1TC to those with >1 L1TC across Ohio. Ohio Trauma Registry data from 2010 to 2012 were analyzed. Patients with age >=15 from counties/regions with L1TC were included. Region was defined as a L1TC containing county and its neighboring counties. Two analyses were performed. In the county analysis, counties containing 1 L1TC were compared with counties with multiple L1TCs. This comparison is repeated on a regional level for the regional analysis. Subgroup analyses were performed. 38,661 and 55,064 patients were in the county and regional analysis, respectively. Patients treated in counties or regions with multiple L1TCs were significantly younger (P < 0.001). Despite this, the mortality was similar for the two groups in the county analysis and significantly higher for regions with multiple L1TCs (P < 0.001). Multivariate logistic regression demonstrated that having multiple L1TC coverage in a region was an independent predictor for death (odds ratios: 1.17; 1.07-1.28; P = 0.001). Subgroup analyses showed that mortality in counties and regions with multiple L1TCs was not lower in any subgroups but was higher in patients with age >=65 and patients with blunt injuries (P < 0.05). Having multiple L1TCs in a county was associated with increased mortality in certain patient subgroups. Having multiple L1TCs in a region was an independent predictor for death. These results should be considered carefully when designing future regionalized trauma networks. More L1TCs is not necessarily better. PMID- 29712607 TI - Single-Incision Laparoscopic Colectomy for Colon Cancer: Experiences with 308 Consecutive Cases. AB - Single-incision laparoscopic surgery (SILS) has been developed with the aim to further reduce the invasiveness of conventional laparoscopy. Our experiences with more than 300 consecutive patients with SILS for colon cancer are reviewed, and its outcomes are evaluated to determine the midterm clinical and oncologic safety of SILS for colon cancer in a community hospital. A single surgeon's consecutive experience of SILS for colon cancer is presented. Three hundred and eight patients were treated with the SILS procedure for colon cancer between December 2010 and March 2015. Data were analyzed according to intention to treat. Of these 308 patients, 19 (6.2%) were converted to laparotomy. Intraoperative injury occurred in five patients. Postoperative complications occurred in 19 patients (6.2%). The 2-year relapse-free survival rates of patients with Stage I, Stage II, and Stage III were 97.8, 92.2, and 80.4 per cent, respectively, and the 2 year overall survival rates of patients with Stage I, Stage II, Stage III, and Stage IV were 100, 95.7, 93.0, and 74.4 per cent, respectively. Our initial experiences showed that SILS colectomy for cancer can be performed safely and with good short-term oncologic outcomes by a skilled surgeon. PMID- 29712608 TI - Nongastrointestinal Stromal Tumor Spindle Cell Sarcomas of the Colon or Rectum. AB - Because of the low incidence of nongastrointestinal stromal tumor (non-GIST) spindle cell sarcomas of the colon or rectum, the clinical behavior and ideal surgical treatment of these tumors and patient outcomes are poorly defined. The purpose of this study was to characterize these tumors and to determine the best surgical approach. We identified 1056 patients with non-GIST spindle cell sarcomas of the colon or rectum (1998-2010) in the National Cancer Database and collected data for each patient that included patient and tumor characteristics, tumor site (colon vs rectum), surgery type, and outcomes. The median overall survival was significantly longer in patients with rectal tumors than in those with colon tumors (P < 0.01). Patients with colon tumors who underwent anatomic surgical resection showed a trend toward longer median survival than those with no surgical treatment [hazard ratio (HR), 1.94; P = 0.09] or who underwent local excision (HR, 1.74; P = 0.09). Patients with rectal tumors did not benefit from anatomic surgical resection, but there was a trend favoring local excision (HR, 0.55; P = 0.06). Local sphincter-sparing procedures should be considered for rectal non-GIST tumors whenever technically feasible. PMID- 29712610 TI - Fatal Agricultural Accidents in Kansas: A Thirty-One-Year Study. AB - Agricultural work results in numerous injuries and deaths. Efficacy of farm equipment safety interventions remains unclear. This study evaluated agricultural mortality pre- and postimplementation of safety initiatives. A 31-year retrospective review of mortality data from agriculture-related injuries was conducted. Demographics and injury patterns were evaluated by mechanism of injury. There were 660 deaths (mean age 48.6 years). Female deaths increased from 5.2 to 11.7 per cent (P = 0.032). Mortality associated with tractors decreased (75.6% vs 53.9%; P < 0.001) and with all-terrain vehicles increased (3.5% vs 22.0%; P < 0.001) from Period I to III. However, tractors remain the primary cause of mortality. For mechanical equipment-associated mortality, there was a decrease (83.3% vs 50.0%) in "caught in equipment," and an increase (6.7% vs 38.9%) in those killed by "crush injury" from Period I to III. Application of safety devices to enclose and stabilize machinery has led to an overall decrease in mortality associated with tractors and "caught in equipment." Expanded rural education, as well as further development and use of safety devices, is warranted to curtail farm-related injuries and deaths. PMID- 29712609 TI - Prophylactic Antibiotics for Elective Laparoscopic Cholecystectomy. AB - Surgical site infections with elective laparoscopic cholecystectomy are less frequent and less severe, leading some to suggest that prophylactic antibiotics (PA) are no longer indicated. We compared the incidence of surgical site infections before and after an institutional practice change of withholding PA for elective laparoscopic cholecystectomy. Between May 7, 2013, and March 11, 2015, no PA were given to patients selected for elective cholecystectomy by two surgeons at a single center. The only patients excluded were those who received antibiotics before surgery for any reason. All others, including those at high risk for infection, were included. The incidence and severity of infections were compared with historical controls treated with prophylaxis by the same two surgeons from November 6, 2011, to January 13, 2013. There were 268 patients in the study group and 119 patients in the control group. Infection occurred in 3.0 per cent in the study group compared with 0.9 per cent in the controls (P = 0.29). All infections were mild except one. Based on these data, the routine use of PA for elective laparoscopic cholecystectomy is not supported. PMID- 29712611 TI - The Development of Extracorporeal Membrane Oxygenation. AB - Evolving from the development of heart-lung machines for open-heart surgery, extracorporeal membrane oxygenation has reemerged as a rescue modality for patients with acute respiratory failure that cannot be supported by conventional modes of ventilation. The history of extracorporeal membrane oxygenation begins with the discovery of heparin, fundamental to the success of extracorporeal circulation and membrane lungs. Engineers and scientists created suitable artificial membranes that allowed gas exchange while keeping gas and blood phases separate. Special pumps circulated blood through the devices and into patients without damage to delicate red cells and denaturing plasma. Initial attempts in adults ended in failure, but Robert Bartlett, first at Loma Linda, CA, then at Ann Arbor, MI, succeeded in applying the technology in newborn infants with persistent pulmonary hypertension. Preserved in the critical care of infants, the technology in time could be reapplied in the life support of older children and adults. PMID- 29712612 TI - Determination of Proper Timing for the Placement of Intra-Abdominal Mesh after Incidental Enterotomy in a Rodent Model (Rattus norvegicus). AB - Controversy exists regarding the appropriate timing for placement of permanent intra-abdominal mesh after inadvertent enterotomy during elective hernia repair. The aim of this study was to examine mesh placement at variable postoperative periods and the subsequent risk of infection. Fifty rodents were divided into five groups. Groups one to four underwent laparotomy, enterotomy, and repair. Physiomesh(r) was placed at the index operation one, three, or seven days postoperatively in Groups 1, 2, 3, and 4. Group 5 underwent mesh placement only. Necropsy with mesh harvest was performed seven days after placement. Cultures of mesh were obtained and Fisher's exact test was used to compare groups. Bacterial growth postsonication was identified in 30, 30, 50, and 90 per cent versus 20 per cent in controls. Compared with controls, there was significantly increased risk of mesh infection when it was placed seven days after enterotomy (P = 0.006). There was no significant difference in bacterial growth when mesh was placed at the time of enterotomy, one or three days later. The risk of bacterial contamination of permanent mesh placed immediately after inadvertent enterotomy during elective hernia repair is as safe as placing mesh at one or three days. Placing mesh at seven days significantly increased the risk of mesh contamination. PMID- 29712613 TI - Bacteriology and Comorbidities in Patients Requiring Surgical Management of Empyema. AB - Concern over the changing bacteriology of empyema has led to numerous attempts to characterize the most common locoregional bacterial isolates. The purpose of this study is to better characterize the bacteriology and demographics in patients with community-acquired pneumonia (CAP) and hospital-acquired pneumonia requiring surgery for empyema. All patients diagnosed with empyema preoperatively and had either a video-assisted thoracoscopic or open decortication surgery from January 2010 to September 2015 were reviewed. Forty-seven patients were identified with a mean age of 54.7 +/- 16.8 years (X +/- SD). Sixty per cent of patients had CAP. Anaerobes were the most common isolate at 21 per cent, followed by Streptococcus species and Staphylococcus aureus (50% Methicillin Resistant). Coagulase-negative Staphylococcus species were the next most frequent at 13 per cent. Hospital acquired pneumonia patients had a higher incidence of S. aureus infections (P = 0.047). Cancer history had higher rates of both fungal (P = 0.004) and gram negative infections (P = 0.03). Older patients had increased incidence of gram negative infections (P = 0.05). The median length of stay for CAP patient who were intravenous drug abusers (n = 3) were 31 days (95% confidence interval (CI) [15, NA]), which was significantly longer than the others (median 12 days, 95% CI: [9, 18], P = 0.014). Streptococcus pneumoniae was not found in any of the isolates. Our data reveal that anaerobes and Staphylococcus species have replaced S. pneumoniae as the major regional pathogens in surgically treated empyema. In addition, anaerobic isolates were found in higher incidence in CAP than previously reported. PMID- 29712614 TI - The Impact of Price Transparency for Surgical Services. AB - Increasing insurance deductibles have prompted some medical centers to initiate transparent pricing. However, the impact of price transparency (PT) on surgical volume, revenue, and patient satisfaction is unknown, along with the barriers to achieving PT. We identified ambulatory surgical centers in the Free Market Medical Association database that publicly list prices for surgical services online. Six of eight centers (75%) responded to our data collection inquiry. Among five centers that reported their patient volume and revenue after adopting PT, patient volume increased by a median of 50 per cent (range 10-200%) at one year. Four centers (80%) reported an increase in revenue by a median of 30 per cent (range 4-75%), whereas three centers (60%) experienced an increase in third party administrator contracts with the average increase being seven new third party administrator contracts (range = 2-12 contracts). Three centers (50%) reported a reduction in their administrative burden and five centers (83%) reported an increase in patient satisfaction and patient engagement after PT. The leading barrier reported to making prices transparent was discouragement from another practice, hospital, or insurance company. The findings of this preliminary study may help guide medical practices in designing and implementing PT strategies. PMID- 29712616 TI - What is the added value of ultrasound joint examination for monitoring synovitis in rheumatoid arthritis and can it be used to guide treatment decisions? A systematic review and cost-effectiveness analysis. AB - BACKGROUND: Synovitis (inflamed joint synovial lining) in rheumatoid arthritis (RA) can be assessed by clinical examination (CE) or ultrasound (US). OBJECTIVE: To investigate the added value of US, compared with CE alone, in RA synovitis in terms of clinical effectiveness and cost-effectiveness. DATA SOURCES: Electronic databases including MEDLINE, EMBASE and the Cochrane databases were searched from inception to October 2015. REVIEW METHODS: A systematic review sought RA studies that compared additional US with CE. Heterogeneity of the studies with regard to interventions, comparators and outcomes precluded meta-analyses. Systematic searches for studies of cost-effectiveness and US and treatment-tapering studies (not necessarily including US) were undertaken. MATHEMATICAL MODEL: A model was constructed that estimated, for patients in whom drug tapering was considered, the reduction in costs of disease-modifying anti-rheumatic drugs (DMARDs) and serious infections at which the addition of US had a cost per quality-adjusted life-year (QALY) gained of L20,000 and L30,000. Furthermore, the reduction in the costs of DMARDs at which US becomes cost neutral was also estimated. For patients in whom dose escalation was being considered, the reduction in number of patients escalating treatment and in serious infections at which the addition of US had a cost per QALY gained of L20,000 and L30,000 was estimated. The reduction in number of patients escalating treatment for US to become cost neutral was also estimated. RESULTS: Fifty-eight studies were included. Two randomised controlled trials compared adding US to a Disease Activity Score (DAS)-based treat-to-target strategy for early RA patients. The addition of power Doppler ultrasound (PDUS) to a Disease Activity Score 28 joints-based treat-to-target strategy in the Targeting Synovitis in Early Rheumatoid Arthritis (TaSER) trial resulted in no significant between-group difference for change in Disease Activity Score 44 joints (DAS44). This study found that significantly more patients in the PDUS group attained DAS44 remission (p = 0.03). The Aiming for Remission in Rheumatoid Arthritis (ARCTIC) trial found that the addition of PDUS and grey-scale ultrasound (GSUS) to a DAS-based strategy did not produce a significant between group difference in the primary end point: composite DAS of < 1.6, no swollen joints and no progression in van der Heijde-modified total Sharp score (vdHSS). The ARCTIC trial did find that the erosion score of the vdHS had a significant advantage for the US group (p = 0.04). In the TaSER trial there was no significant group difference for erosion. Other studies suggested that PDUS was significantly associated with radiographic progression and that US had added value for wrist and hand joints rather than foot and ankle joints. Heterogeneity between trials made conclusions uncertain. No studies were identified that reported the cost-effectiveness of US in monitoring synovitis. The model estimated that an average reduction of 2.5% in the costs of biological DMARDs would be sufficient to offset the costs of 3-monthly US. The money could not be recouped if oral methotrexate was the only drug used. LIMITATIONS: Heterogeneity of the trials precluded meta-analysis. Therefore, no summary estimates of effect were available. Additional costs and health-related quality of life decrements, relating to a flare following tapering or disease progression, have not been included. The feasibility of increased US monitoring has not been assessed. CONCLUSION: Limited evidence suggests that US monitoring of synovitis could provide a cost-effective approach to selecting RA patients for treatment tapering or escalation avoidance. Considerable uncertainty exists for all conclusions. Future research priorities include evaluating US monitoring of RA synovitis in longitudinal clinical studies. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015017216. FUNDING: The National Institute for Health Research Health Technology Assessment programme. PMID- 29712617 TI - Negative effects of oxidative stress in bovine spermatozoa on in vitro development and DNA integrity of embryos. AB - Oxidative stress in spermatozoa has effects on subsequent embryo development. The aim of the present study was to elucidate whether sperm oxidative stress results in increased DNA damage in the embryo. To this end, bovine spermatozoa were incubated for 1h at 37 degrees C without or with 100uM H2O2, resulting in non oxidised (NOX-S) and oxidised (OX-S) spermatozoa respectively. Non-incubated spermatozoa served as the control group (CON-S). After IVF, developmental rates 30, 46 and 60h and 7 days after IVF were assessed. DNA damage was analysed in embryos using the comet assay and a DNA damage marker (gammaH2AX immunostaining); the apoptotic index was determined in blastocysts. Exposure of spermatozoa to H2O2 induced a significant amount of sperm chromatin damage. The use of OX-S in IVF resulted in significantly reduced cleavage and blastocyst rates compared with the use of CON-S and NOX-S. Furthermore, in embryos resulting from the use of OX S, a developmental delay was evident 30 and 46h after IVF. gammaH2AX immunostaining was lower in blastocysts than in early embryos. In blastocysts, the comet and apoptotic indices were significantly higher in embryos resulting from the use of OX-S than CON-S and NOX-S. In conclusion, oxidative stress in spermatozoa induces developmental abnormalities and is a source of DNA damage in the resulting embryos. PMID- 29712618 TI - Lymphatic endothelium stimulates melanoma metastasis and invasion via MMP14 dependent Notch3 and beta1-integrin activation. AB - Lymphatic invasion and lymph node metastasis correlate with poor clinical outcome in melanoma. However, the mechanisms of lymphatic dissemination in distant metastasis remain incompletely understood. We show here that exposure of expansively growing human WM852 melanoma cells, but not singly invasive Bowes cells, to lymphatic endothelial cells (LEC) in 3D co-culture facilitates melanoma distant organ metastasis in mice. To dissect the underlying molecular mechanisms, we established LEC co-cultures with different melanoma cells originating from primary tumors or metastases. Notably, the expansively growing metastatic melanoma cells adopted an invasively sprouting phenotype in 3D matrix that was dependent on MMP14, Notch3 and beta1-integrin. Unexpectedly, MMP14 was necessary for LEC-induced Notch3 induction and coincident beta1-integrin activation. Moreover, MMP14 and Notch3 were required for LEC-mediated metastasis of zebrafish xenografts. This study uncovers a unique mechanism whereby LEC contact promotes melanoma metastasis by inducing a reversible switch from 3D growth to invasively sprouting cell phenotype. PMID- 29712620 TI - A Web-Based Treatment Decision Support Tool for Patients With Advanced Knee Arthritis: Evaluation of User Interface and Content Design. AB - BACKGROUND: Data-driven surgical decisions will ensure proper use and timing of surgical care. We developed a Web-based patient-centered treatment decision and assessment tool to guide treatment decisions among patients with advanced knee osteoarthritis who are considering total knee replacement surgery. OBJECTIVE: The aim of this study was to examine user experience and acceptance of the Web-based treatment decision support tool among older adults. METHODS: User-centered formative and summative evaluations were conducted for the tool. A sample of 28 patients who were considering total knee replacement participated in the study. Participants' responses to the user interface design, the clarity of information, as well as usefulness, satisfaction, and acceptance of the tool were collected through qualitative (ie, individual patient interviews) and quantitative (ie, standardized Computer System Usability Questionnaire) methods. RESULTS: Participants were older adults with a mean age of 63 (SD 11) years. Three quarters of them had no technical questions using the tool. User interface design recommendations included larger fonts, bigger buttons, less colors, simpler navigation without extra "next page" click, less mouse movement, and clearer illustrations with simple graphs. Color-coded bar charts and outcome-specific graphs with positive action were easiest for them to understand the outcomes data. Questionnaire data revealed high satisfaction with the tool usefulness and interface quality, and also showed ease of use of the tool, regardless of age or educational status. CONCLUSIONS: We evaluated the usability of a patient-centered decision support tool designed for advanced knee arthritis patients to facilitate their knee osteoarthritis treatment decision making. The lessons learned can inform other decision support tools to improve interface and content design for older patients' use. PMID- 29712619 TI - Inhibitor-induced HER2-HER3 heterodimerisation promotes proliferation through a novel dimer interface. AB - While targeted therapy against HER2 is an effective first-line treatment in HER2+ breast cancer, acquired resistance remains a clinical challenge. The pseudokinase HER3, heterodimerisation partner of HER2, is widely implicated in the resistance to HER2-mediated therapy. Here, we show that lapatinib, an ATP-competitive inhibitor of HER2, is able to induce proliferation cooperatively with the HER3 ligand neuregulin. This counterintuitive synergy between inhibitor and growth factor depends on their ability to promote atypical HER2-HER3 heterodimerisation. By stabilising a particular HER2 conformer, lapatinib drives HER2-HER3 kinase domain heterocomplex formation. This dimer exists in a head-to-head orientation distinct from the canonical asymmetric active dimer. The associated clustering observed for these dimers predisposes to neuregulin responses, affording a proliferative outcome. Our findings provide mechanistic insights into the liabilities involved in targeting kinases with ATP-competitive inhibitors and highlight the complex role of protein conformation in acquired resistance. PMID- 29712621 TI - Incidence of Lower Respiratory Tract Infections and Atopic Conditions in Boys and Young Male Adults: Royal College of General Practitioners Research and Surveillance Centre Annual Report 2015-2016. AB - BACKGROUND: The Royal College of General Practitioners Research and Surveillance Centre comprises more than 150 general practices, with a combined population of more than 1.5 million, contributing to UK and European public health surveillance and research. OBJECTIVE: The aim of this paper was to report gender differences in the presentation of infectious and respiratory conditions in children and young adults. METHODS: Disease incidence data were used to test the hypothesis that boys up to puberty present more with lower respiratory tract infection (LRTI) and asthma. Incidence rates were reported for infectious conditions in children and young adults by gender. We controlled for ethnicity, deprivation, and consultation rates. We report odds ratios (OR) with 95% CI, P values, and probability of presenting. RESULTS: Boys presented more with LRTI, largely due to acute bronchitis. The OR of males consulting was greater across the youngest 3 age bands (OR 1.59, 95% CI 1.35-1.87; OR 1.13, 95% CI 1.05-1.21; OR 1.20, 95% CI 1.09-1.32). Allergic rhinitis and asthma had a higher OR of presenting in boys aged 5 to 14 years (OR 1.52, 95% CI 1.37-1.68; OR 1.31, 95% CI 1.17-1.48). Upper respiratory tract infection (URTI) and urinary tract infection (UTI) had lower odds of presenting in boys, especially those older than 15 years. The probability of presenting showed different patterns for LRTI, URTI, and atopic conditions. CONCLUSIONS: Boys younger than 15 years have greater odds of presenting with LRTI and atopic conditions, whereas girls may present more with URTI and UTI. These differences may provide insights into disease mechanisms and for health service planning. PMID- 29712622 TI - Mobile Breast Cancer e-Support Program for Chinese Women With Breast Cancer Undergoing Chemotherapy (Part 2): Multicenter Randomized Controlled Trial. AB - BACKGROUND: Women undergoing chemotherapy for the treatment of breast cancer have frequently reported unmet supportive care needs. Moreover, easily accessible and innovative support is lacking. OBJECTIVE: The purpose of this trial was to determine the effectiveness of an app-based breast cancer e-support program to address women's self-efficacy (primary outcome), social support, symptom distress, quality of life, anxiety, and depression. Secondary objectives included exploring the association between women's health outcomes and the breast cancer e support usage data. METHODS: A multicenter, single-blinded, randomized controlled trial was conducted. A total of 114 women with breast cancer, who were commencing chemotherapy and were able to access internet through a mobile phone, were recruited in the clinics from 2 university-affiliated hospitals in China. Women were randomized either to the intervention group (n=57) receiving breast cancer e support plus care as usual or the control group (n=57) receiving care as usual alone. The health care team and research assistants collecting data were blinded to the women's group allocation. Bandura's self-efficacy theory and the social exchange theory guided the development of the breast cancer e-support program, which has 4 components: (1) a Learning forum, (2) a Discussion forum, (3) an Ask the-Expert forum, and (4) a Personal Stories forum. Moderated by an experienced health care professional, the breast cancer e-support program supported women for 12 weeks covering 4 cycles of chemotherapy. Health outcomes were self-assessed through paper questionnaires in clinics at baseline before randomization (T0), after 3 (T1), and 6 months (T2) of follow-ups. RESULTS: Fifty-five participants in the intervention group and 49 in the control group completed the follow-up assessments (response rate: 91.2%). During the 12-week intervention, the log-in frequency ranged from 0 to 774 times (mean 54.7; SD 131.4; median 11; interquartile range, IQR 5-27), and the total usage duration ranged from 0 to 9371 min (mean 1072.3; SD 2359.5; median 100; IQR 27-279). Repeated measures multivariate analysis of covariance (intention-to-treat) found that breast cancer e-support + care as usual participants had significant better health outcomes at 3 months regarding self-efficacy (21.05; 95% CI 1.87-40.22; P=.03; d=0.53), symptom interference (-0.73; 95% CI -1.35 to -.11; P=.02; d=-0.51), and quality of life (6.64; 95% CI 0.77-12.50; P=.03, d=0.46) but not regarding social support, symptom severity, anxiety, and depression compared with care as usual participants. These beneficial effects were not sustained at 6 months. Spearman rank-order correlation showed that the breast cancer e-support usage duration was positively correlated with self-efficacy (r=.290, P=.03), social support (r=.320, P=.02), and quality of life (r=.273, P=.04) at 3 months. CONCLUSIONS: The breast cancer e-support program demonstrated its potential as an effective and easily accessible intervention to promote women's self-efficacy, symptom interference, and quality of life during chemotherapy. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12616000639426; www.ANZCTR.org.au/ACTRN12616000639426.aspx (Archived by Webcite at http://www.webcitation.org/6v1n9hGZq). PMID- 29712623 TI - An Early Model for Value and Sustainability in Health Information Exchanges: Qualitative Study. AB - BACKGROUND: The primary value relative to health information exchange has been seen in terms of cost savings relative to laboratory and radiology testing, emergency department expenditures, and admissions. However, models are needed to statistically quantify value and sustainability and better understand the dependent and mediating factors that contribute to value and sustainability. OBJECTIVE: The purpose of this study was to provide a basis for early model development for health information exchange value and sustainability. METHODS: A qualitative study was conducted with 21 interviews of eHealth Exchange participants across 10 organizations. Using a grounded theory approach and 3.0 as a relative frequency threshold, 5 main categories and 16 subcategories emerged. RESULTS: This study identifies 3 core current perceived value factors and 5 potential perceived value factors-how interviewees predict health information exchanges may evolve as there are more participants. These value factors were used as the foundation for early model development for sustainability of health information exchange. CONCLUSIONS: Using the value factors from the interviews, the study provides the basis for early model development for health information exchange value and sustainability. This basis includes factors from the research: fostering consumer engagement; establishing a provider directory; quantifying use, cost, and clinical outcomes; ensuring data integrity through patient matching; and increasing awareness, usefulness, interoperability, and sustainability of eHealth Exchange. PMID- 29712624 TI - The Unanticipated Challenges Associated With Implementing an Observational Study Protocol in a Large-Scale Physical Activity and Global Positioning System Data Collection. AB - BACKGROUND: Large-scale primary data collections are complex, costly, and time consuming. Study protocols for trial-based research are now commonplace, with a growing number of similar pieces of work being published on observational research. However, useful additions to the literature base are publications that describe the issues and challenges faced while conducting observational studies. These can provide researchers with insightful knowledge that can inform funding proposals or project development work. OBJECTIVES: In this study, we identify and reflectively discuss the unforeseen or often unpublished issues associated with organizing and implementing a large-scale objectively measured physical activity and global positioning system (GPS) data collection. METHODS: The SPACES (Studying Physical Activity in Children's Environments across Scotland) study was designed to collect objectively measured physical activity and GPS data from 10- to 11-year-old children across Scotland, using a postal delivery method. The 3 main phases of the project (recruitment, delivery of project materials, and data collection and processing) are described within a 2-stage framework: (1) intended design and (2) implementation of the intended design. RESULTS: Unanticipated challenges arose, which influenced the data collection process; these encompass four main impact categories: (1) cost, budget, and funding; (2) project timeline; (3) participation and engagement; and (4) data challenges. The main unforeseen issues that impacted our timeline included the informed consent process for children under the age of 18 years; the use of, and coordination with, the postal service to deliver study information and equipment; and the variability associated with when participants began data collection and the time taken to send devices and consent forms back (1-12 months). Unanticipated budgetary issues included the identification of some study materials (AC power adapter) not fitting through letterboxes, as well as the employment of fieldworkers to increase recruitment and the return of consent forms. Finally, we encountered data issues when processing physical activity and GPS data that had been initiated across daylight saving time. CONCLUSIONS: We present learning points and recommendations that may benefit future studies of similar methodology in their early stages of development. PMID- 29712625 TI - Intervention to Increase HIV Testing Among Substance-Using Young Men Who Have Sex With Men: Protocol for a Randomized Controlled Trial. AB - BACKGROUND: Young men who have sex with men (YMSM) and transgender people in the Detroit Metro Area are the only risk group for whom the incidence of HIV and sexually transmitted infections (STI) has increased since 2000, with HIV incidence nearly doubling among youth. Substance use (including alcohol), which is relatively frequent among YMSM and transgender people, creates barriers to the optimal delivery of HIV prevention and care services. Standard HIV counseling, testing, and referral (CTR) is limited in providing strategies to identify and address substance use. Hence, in its current form, CTR may not be serving the prevention needs of substance-using YMSM and transgender people. Brief counseling interventions, grounded in principles of motivational interviewing, may offer a mechanism to meet the HIV prevention and care needs of substance-using YMSM and transgender people. OBJECTIVE: This prospective, 4-arm, factorial randomized controlled trial aims to examine the efficacy of an motivational interviewing based substance use brief intervention (SUBI) on participants' substance use and engagement in HIV prevention. METHODS: The research implements a prospective randomized controlled trial (Project Swerve) of 600 YMSM and transgender people recruited both online and in person. Eligibility criteria include participants who (1) are between the ages of 15 to 29 years, (2) live in the Detroit Metro Area, (3) self-identify as a man or transgender man or woman, (4) have had sexual contact with a man in the 6 months before enrollment, (5) self-report binge drinking or any substance use in the 3 months before enrollment, and (6) self report an unknown or negative HIV status upon enrollment. Participants are randomized to receive, 3-months apart starting at baseline, 2 individual sessions. Sessions are CTR-only, SUBI-only, CTR followed by SUBI, or SUBI followed by CTR. RESULTS: Project Swerve was launched in April 2017 and enrollment is ongoing. CONCLUSIONS: Incorporating a SUBI that utilizes the principles of motivational interviewing into HIV CTR provides an opportunity to tailor counseling services for YMSM and transgender people to address additional client barriers to HIV and STI testing. TRIAL REGISTRATION: ClinicalTrials.gov NCT02945436; http://clinicaltrials.gov/ct2/show/NCT02945436 (Archived by WebCite at http://www.webcitation.org/6yFyOK57w). PMID- 29712627 TI - A Remote Collaborative Care Program for Patients with Depression Living in Rural Areas: Open-Label Trial. AB - BACKGROUND: In the treatment of depression, primary care teams have an essential role, but they are most effective when inserted into a collaborative care model for disease management. In rural areas, the shortage of specialized mental health resources may hamper management of depressed patients. OBJECTIVE: The aim was to test the feasibility, acceptability, and effectiveness of a remote collaborative care program for patients with depression living in rural areas. METHODS: In a nonrandomized, open-label (blinded outcome assessor), two-arm clinical trial, physicians from 15 rural community hospitals recruited 250 patients aged 18 to 70 years with a major depressive episode (DSM-IV criteria). Patients were assigned to the remote collaborative care program (n=111) or to usual care (n=139). The remote collaborative care program used Web-based shared clinical records between rural primary care teams and a specialized/centralized mental health team, telephone monitoring of patients, and remote supervision by psychiatrists through the Web-based shared clinical records and/or telephone. Depressive symptoms, health-related quality of life, service use, and patient satisfaction were measured 3 and 6 months after baseline assessment. RESULTS: Six-month follow-up assessments were completed by 84.4% (221/250) of patients. The remote collaborative care program achieved higher user satisfaction (odds ratio [OR] 1.94, 95% CI 1.25-3.00) and better treatment adherence rates (OR 1.81, 95% CI 1.02-3.19) at 6 months compared to usual care. There were no statically significant differences in depressive symptoms between the remote collaborative care program and usual care. Significant differences between groups in favor of remote collaborative care program were observed at 3 months for mental health related quality of life (beta 3.11, 95% CI 0.19-6.02). CONCLUSIONS: Higher rates of treatment adherence in the remote collaborative care program suggest that technology-assisted interventions may help rural primary care teams in the management of depressive patients. Future cost-effectiveness studies are needed. TRIAL REGISTRATION: Clinicaltrials.gov NCT02200367; https://clinicaltrials.gov/ct2/show/NCT02200367 (Archived by WebCite at http://www.webcitation.org/6xtZ7OijZ). PMID- 29712626 TI - A Gamified Smartphone App to Support Engagement in Care and Medication Adherence for HIV-Positive Young Men Who Have Sex With Men (AllyQuest): Development and Pilot Study. AB - BACKGROUND: HIV disproportionately impacts young men who have sex with men (YMSM) who experience disparities across the HIV care continuum. Addressing antiretroviral therapy (ART) adherence among YMSM is an urgent public health priority. Technology-based interventions-particularly mobile health platforms-can provide tailored adherence interventions and allow YMSM to engage and connect with others. OBJECTIVE: The objective of this study was to describe the development of AllyQuest, a novel, theoretically-based, smartphone app designed to improve engagement in care and ART adherence and social support among HIV positive YMSM. METHODS: AllyQuest was built on an established platform for patient engagement that embeds social networking and fundamental game mechanics, such as challenges, points, and rewards. A medication tracker provides reminders to promote ART adherence via personalized adherence strategies that are user and context specific; a calendar allows for reflection on adherence over time. After iterative development with input from two youth advisory boards, usability testing was conducted to assess app functionality, comprehension of the educational content, use of intervention features, and overall impressions of app relevance and appeal. A 28-day pilot trial was conducted with 20 HIV+ YMSM to evaluate intervention feasibility and acceptability. RESULTS: Mean age of participants was 21.8 years (range 19-24), and 95% (19/20) of the participants were nonwhite. The mean time of app use was 158.4 min (SD 114.1), with a range of 13 to 441 min. There was a mean of 21.2 days of use (out of a total possible 28 days). There were 222 posts to the daily discussion social wall. Feasibility and acceptability ratings were high. Overall, participants found the app easy to use and navigate, not intrusive, and had few reported technical issues. Higher levels of app usage were positively correlated with HIV self-management outcomes, and there was a statistically significant (P<.05) positive association between the number of days logged into the app and knowledge and confidence in ability to reliably take HIV medications. CONCLUSIONS: AllyQuest represents a new, highly scalable solution that is well-suited to meet the specific prevention and care needs of HIV+ YMSM. The development of this intervention is both timely and vital, given the urgency of the ongoing HIV epidemic among YMSM. PMID- 29712628 TI - A Web-Based Intervention to Reduce Distress After Prostate Cancer Treatment: Development and Feasibility of the Getting Down to Coping Program in Two Different Clinical Settings. AB - BACKGROUND: Distress after prostate cancer treatment is a substantial burden for up to one-third of men diagnosed. Physical and emotional symptoms and health service use can intensify, yet men are reticent to accept support. To provide accessible support that can be cost effectively integrated into care pathways, we developed a unique, Web-based, self-guided, cognitive-behavior program incorporating filmed and interactive peer support. OBJECTIVE: To assess feasibility of the intervention among men experiencing distress after prostate cancer treatment. Demand, acceptability, change in distress and self-efficacy, and challenges for implementation in clinical practice were measured. METHODS: A pre-post, within-participant comparison, mixed-methods research design was followed. Phase I and II were conducted in primary care psychological service and secondary care cancer service, respectively. Men received clinician-generated postal invitations: phase I, 432 men diagnosed <5 years; phase II, 606 men diagnosed <3.5 years. Consent was Web-based. Men with mild and moderate distress were enrolled. Web-based assessment included demographic, disease, treatment characteristics; distress (General Health Questionnaire-28); depression (Patient Health Questionnaire-9); anxiety (General Anxiety Disorder Scale-7); self efficacy (Self-Efficacy for Symptom Control Inventory); satisfaction (author generated, Likert-type questionnaire). Uptake and adherence were assessed with reference to the persuasive systems design model. Telephone interviews explored participant experience (phase II, n=10); interviews with health care professionals (n=3) explored implementation issues. RESULTS: A total of 135 men consented (phase I, 61/432, 14.1%; phase II, 74/606, 12.2%); from 96 eligible men screened for distress, 32% (30/96) entered the intervention (phase I, n=10; phase II, n=20). Twenty-four completed the Web-based program and assessments (phase I, n=8; phase II, n=16). Adherence for phase I and II was module completion rate 63% (mean 2.5, SD 1.9) versus 92% (mean 3.7, SD 1.0); rate of completing cognitive behavior therapy exercises 77% (mean 16.1, SD 6.2) versus 88% (mean 18.6, SD 3.9). Chat room activity occurred among 63% (5/8) and 75% (12/16) of men, respectively. In phase I, 75% (6/8) of men viewed all the films; in phase II, the total number of unique views weekly was 16, 11, 11, and 10, respectively. The phase II mood diary was completed by 100% (16/16) of men. Satisfaction was high for the program and films. Limited efficacy testing indicated improvement in distress baseline to post intervention: phase I, P=.03, r=-.55; phase II, P=.001, r=-.59. Self-efficacy improved for coping P=.02, r=-.41. Service assessment confirmed ease of assimilation into clinical practice and clarified health care practitioner roles. CONCLUSIONS: The Web-based program is acceptable and innovative in clinical practice. It was endorsed by patients and has potential to positively impact the experience of men with distress after prostate cancer treatment. It can potentially be delivered in a stepped model of psychological support in primary or secondary care. Feasibility evidence is compelling, supporting further evaluative research to determine clinical and cost effectiveness. PMID- 29712629 TI - Recommendations for Assessment of the Reliability, Sensitivity, and Validity of Data Provided by Wearable Sensors Designed for Monitoring Physical Activity. AB - Although it is becoming increasingly popular to monitor parameters related to training, recovery, and health with wearable sensor technology (wearables), scientific evaluation of the reliability, sensitivity, and validity of such data is limited and, where available, has involved a wide variety of approaches. To improve the trustworthiness of data collected by wearables and facilitate comparisons, we have outlined recommendations for standardized evaluation. We discuss the wearable devices themselves, as well as experimental and statistical considerations. Adherence to these recommendations should be beneficial not only for the individual, but also for regulatory organizations and insurance companies. PMID- 29712631 TI - Social Media as a New Vital Sign: Commentary. AB - Mobile technologies, such as wireless glucometers and mobile health apps, are increasingly being integrated into health and medical care. Because patients openly share real-time information about their health behaviors and outcomes on social media, social media data may also be used as a tool for monitoring patient care. This commentary describes how recent advances in computer science, psychology, and medicine enable social media data to become a new health "vital sign," as well as actionable steps that public health officials, health systems, and clinics can take to integrate social data into both public and population health as well as into individual patient care. Barriers that first need to be addressed, including privacy concerns, legal and ethical responsibilities, and infrastructure support, are discussed. PMID- 29712630 TI - Efficacy of a Community-Based Technology-Enabled Physical Activity Counseling Program for People With Knee Osteoarthritis: Proof-of-Concept Study. AB - BACKGROUND: Current practice guidelines emphasize the use of physical activity as the first-line treatment of knee osteoarthritis; however, up to 90% of people with osteoarthritis are inactive. OBJECTIVE: We aimed to assess the efficacy of a technology-enabled counseling intervention for improving physical activity in people with either a physician-confirmed diagnosis of knee osteoarthritis or having passed two validated criteria for early osteoarthritis. METHODS: We conducted a proof-of-concept randomized controlled trial. The immediate group received a brief education session by a physical therapist, a Fitbit Flex, and four biweekly phone calls for activity counseling. The delayed group received the same intervention 2 months later. Participants were assessed at baseline (T0) and at the end of 2 months (T1), 4 months (T2), and 6 months (T3). Outcomes included (1) mean time on moderate-to-vigorous physical activity (MVPA >=3 metabolic equivalents [METs], primary outcome), (2) mean time on MVPA >=4 METs, (3) mean daily steps, (4) mean time on sedentary activities, (5) Knee Injury and Osteoarthritis Outcome Score (KOOS), and (6) Partners in Health scale. Mixed effects repeated measures analysis of variance was used to assess five planned contrasts of changes in outcome measures over measurement periods. The five contrasts were (1) immediate T1-T0 vs delayed T1-T0, (2) delayed T2-T1 vs delayed T1-T0, (3) mean of contrast 1 and contrast 2, (4) immediate T1-T0 vs delayed T2 T1, and (5) mean of immediate T2-T1 and delayed T3-T2. The first three contrasts estimate the between-group effects. The latter two contrasts estimate the effect of the 2-month intervention delay on outcomes. RESULTS: We recruited 61 participants (immediate: n=30; delayed: n=31). Both groups were similar in age (immediate: mean 61.3, SD 9.4 years; delayed: mean 62.1, SD 8.5 years) and body mass index (immediate: mean 29.2, SD 5.5 kg/m2; delayed: mean 29.2, SD 4.8 kg/m2). Contrast analyses revealed significant between-group effects in MVPA >=3 METs (contrast 1 coefficient: 26.6, 95% CI 4.0-49.1, P=.02; contrast 3 coefficient: 26.0, 95% CI 3.1-49.0, P=.03), daily steps (contrast 1 coefficient: 1699.2, 95% CI 349.0-3049.4, P=.02; contrast 2 coefficient: 1601.8, 95% CI 38.7 3164.9, P=.045; contrast 3 coefficient: 1650.5, 95% CI 332.3-2968.7; P=.02), KOOS activity of daily living subscale (contrast 1 coefficient: 6.9, 95% CI 0.1-13.7, P=.047; contrast 3 coefficient: 7.2, 95% CI 0.8-13.6, P=.03), and KOOS quality of life subscale (contrast 1 coefficient: 7.4, 95% CI 0.0-14.7, P=.049; contrast 3 coefficient: 7.3, 95% CI 0.1-14.6, P=.048). We found no significant effect in any outcome measures due to the 2-month delay of the intervention. CONCLUSIONS: Our counseling program improved MVPA >=3 METs, daily steps, activity of daily living, and quality of life in people with knee osteoarthritis. These findings are important because an active lifestyle is an important component of successful self-management. TRIAL REGISTRATION: ClinicalTrials.gov NCT02315664; https://clinicaltrials.gov/ct2/show/NCT02315664 (Archived by WebCite at http://www.webcitation.org/6ynSgUyUC). PMID- 29712632 TI - Shining a light on "hidden patients". PMID- 29712633 TI - How I treat T-cell chronic active Epstein-Barr virus disease. AB - T-cell chronic active Epstein-Barr virus (CAEBV) is a rare disease in which EBV is present predominantly in T cells that infiltrate the tissues; patients have high levels of EBV in the blood. If untreated, patients often develop liver failure, hemophagocytic lymphohistiocytosis, coronary artery aneurysms, EBV infiltrating T cells impairing organ function, or T-cell lymphomas refractory to treatment. At present, hematopoietic stem-cell transplantation is the only curative therapy, and it is critical to make a proper diagnosis and initiate transplantation before the disease progresses to an irreversible stage. Specific medications such as high-dose systemic corticosteroids or ganciclovir combined with either histone deacetylase inhibitors or bortezomib may temporarily reduce systemic toxicity associated with T-cell CAEBV and allow the patient time to receive a transplant. Relapses of the disease after transplantation have also occurred, and the use of donor-derived virus-specific T cells may help to treat these relapses. PMID- 29712634 TI - Enhanced phosphocholine metabolism is essential for terminal erythropoiesis. AB - Red cells contain a unique constellation of membrane lipids. Although much is known about regulated protein expression, the regulation of lipid metabolism during erythropoiesis is poorly studied. Here, we show that transcription of PHOSPHO1, a phosphoethanolamine and phosphocholine phosphatase that mediates the hydrolysis of phosphocholine to choline, is strongly upregulated during the terminal stages of erythropoiesis of both human and mouse erythropoiesis, concomitant with increased catabolism of phosphatidylcholine (PC) and phosphocholine as shown by global lipidomic analyses of mouse and human terminal erythropoiesis. Depletion of PHOSPHO1 impaired differentiation of fetal mouse and human erythroblasts, and, in adult mice, depletion impaired phenylhydrazine induced stress erythropoiesis. Loss of PHOSPHO1 also impaired phosphocholine catabolism in mouse fetal liver progenitors and resulted in accumulation of several lipids; adenosine triphosphate (ATP) production was reduced as a result of decreased oxidative phosphorylation. Glycolysis replaced oxidative phosphorylation in PHOSPHO1-knockout erythroblasts and the increased glycolysis was used for the production of serine or glycine. Our study elucidates the dynamic changes in lipid metabolism during terminal erythropoiesis and reveals the key roles of PC and phosphocholine metabolism in energy balance and amino acid supply. PMID- 29712635 TI - Indian paediatrician arrested over deaths of dozens of children gets bail after campaign to free him. PMID- 29712636 TI - Cheap alcohol disappears from shelves in Scotland as minimum unit price starts. PMID- 29712637 TI - Efficacy of non-fovea-sparing ILM peeling for symptomatic myopic foveoschisis with and without macular hole. AB - AIM: To study anatomical and visual outcomes of pars plana vitrectomy (PPV) with non-fovea-sparing (entire) internal limiting membrane (ILM) peeling in eyes with myopic foveoschisis (MF). METHODS: Prospective interventional case series of eyes undergoing PPV with entire ILM peeling for symptomatic MF. MAIN OUTCOME MEASURES: Preoperative spectral domain optical coherence tomography (SD-OCT) epiretinal membrane, anomalous posterior vitreous detachment, vitreoschisis and postoperative changes in SD-OCT central foveal thickness (CFT), ellipsoid zone defect, foveal detachment (FD), macular hole (MH) diameter (if present) and best corrected visual acuity (BCVA) in logarithm of the minimum angle of resolution (logMAR). RESULTS: This study included 21 eyes (21 patients) with mean age 60.4+/ 13.1, 15 females (71.4%). All patients achieved complete postoperative reattachment by SD-OCT (no FD) 6 months post vitrectomy, with no iatrogenic intraoperative or postoperative MH, and with significant improvement in final BCVA from 1.6+/-0.30 to1.0+/-0.2 logMAR, and in CFT from 918.2+/-311.4 to182.3+/ 33.1 um. Patients were subdivided into subgroup A: 11 eyes without MH; and subgroup B: 10 eyes with MH, the latter had significant improvement in MH diameter (p=0.005). Preoperative BCVA was a significant risk factor for visual gain, while preoperative FD and CFT were significant for CFT change. CONCLUSION: Vitrectomy with non-fovea-sparing (entire) ILM peeling resulted in a significant functional and anatomical improvement in eyes with MF with/without MH with no reported complications. Results are comparable to fovea-sparing ILM peeling. PMID- 29712638 TI - High-throughput live-imaging of embryos in microwell arrays using a modular specimen mounting system. AB - High-throughput live-imaging of embryos is an essential technique in developmental biology, but it is difficult and costly to mount and image embryos in consistent conditions. Here, we present OMMAwell, a simple, reusable device to easily mount dozens of embryos in arrays of agarose microwells with customizable dimensions and spacing. OMMAwell can be configured to mount specimens for upright or inverted microscopes, and includes a reservoir to hold live-imaging medium to maintain constant moisture and osmolarity of specimens during time-lapse imaging. All device components can be fabricated by cutting pieces from a sheet of acrylic using a laser cutter or by making them with a 3D printer. We demonstrate how to design a custom mold and use it to live-image dozens of embryos at a time. We include descriptions, schematics, and design files for 13 additional molds for nine animal species, including most major traditional laboratory models and a number of emerging model systems. Finally, we provide instructions for researchers to customize OMMAwell inserts for embryos or tissues not described herein. PMID- 29712639 TI - A generalized model for communicating individuality through teleost swim bladder modulation. AB - Arguments have been made for and against the traditional swim bladder model as a primary component of fish vocalization. This paper presents arguments for decoupled forced and resonant responses being extractable features within a variable air volume. As such, a mechanical analog is used to show how envelope modulation may be used by some species to identify air volume and consequently size in conspecifics. These arguments consider how an arbitrary fish may apply a genetic strategy of forcing vocalization through slow, fast, or both slow and fast sonic musculature while amplitude modulating via swim bladder. The classic resonant bubble model is revised to account for a hypothetical carrier signal resonance associated with static or varying volume. In the absence of live specimens, a test is conducted in different cylindrical structures with equally sized air volumes. First, a proposed method for extraction of swim bladder volume features through blind amplitude demodulated signals in the time and frequency domain is applied. Second, a proposed method for extraction of swim bladder volume features through cyclostationary analysis of the cross-spectral coherent spectra of the modulated and demodulated signal is applied. Both methods take average frequency content as derived by the prescribed signal processing techniques as the input to the correlator functions used to identify air volumes. Vocalizations of Epinephelus guttatus, or more commonly known as the red hind grouper, are used as test signals. PMID- 29712640 TI - Patient found in contempt of court for trying to claim L837 000 from hospital trust. PMID- 29712642 TI - Spatial regulation of microtubule disruption during dendrite pruning in Drosophila. AB - Large-scale neurite pruning is an important specificity mechanism during neuronal morphogenesis. Drosophila sensory neurons prune their larval dendrites during metamorphosis. Pruning dendrites are severed in their proximal regions, but how this spatial information is encoded is not clear. Dendrite severing is preceded by local breakdown of dendritic microtubules through PAR-1-mediated inhibition of Tau. Here, we investigated spatial aspects of microtubule breakdown during dendrite pruning. Live imaging of fluorescently tagged tubulin shows that microtubule breakdown first occurs at proximal dendritic branchpoints, followed by breakdown at more distal branchpoints, suggesting that the process is triggered by a signal emanating from the soma. In fly dendrites, microtubules are arranged in uniformly oriented arrays where all plus ends face towards the soma. Mutants in kinesin-1 and -2, which are required for uniform microtubule orientation, show defects in microtubule breakdown and dendrite pruning. Our data suggest that the local microtubule organization at branchpoints determines where microtubule breakdown occurs. Local microtubule organization may therefore contribute spatial information for severing sites during dendrite pruning. PMID- 29712643 TI - The lesser of two evils: a qualitative study of quetiapine prescribing by family physicians. AB - BACKGROUND: Quetiapine is an antipsychotic that is widely prescribed off-label by family physicians despite evidence that safer alternatives exist. The aim of this research was to explore, in-depth, family physicians' reasons for this behaviour. METHODS: We conducted qualitative interviews with 15 urban family physicians in Alberta between October 2015 and April 2016. Participants were purposively selected based on sex, years of experience and practice type. Interviews explored participants' experiences prescribing quetiapine. Interviews were recorded, transcribed verbatim and coded with the use of thematic analysis. RESULTS: A wish to support day-to-day function of patients with complex psychosocial needs without causing benzodiazepine addiction motivated participants to prescribe quetiapine. The indications were varied and included incomplete symptom resolution, unclear or multiple mental health diagnoses, and complicated psychosocial problems. Family physicians benchmarked their prescribing against peers and were reluctant to stop medication started by colleagues. Limited knowledge of quetiapine's adverse effects led prescribers to choose low dosages. INTERPRETATION: Quetiapine helped family physicians treat patients with complex mental health problems without prescribing benzodiazepines, but awareness of quetiapine's adverse effects was poor. Education about quetiapine should combine psychopharmacology with multidisciplinary educational initiatives that focus on symptom resolution, comorbidity and nondrug options to promote more appropriate prescribing. PMID- 29712641 TI - Histone deacetylases 1 and 2 regulate the transcriptional programs of nephron progenitors and renal vesicles. AB - Nephron progenitor cells (NPCs) are Six2-positive metanephric mesenchyme cells, which undergo self-renewal and differentiation to give rise to nephrons until the end of nephrogenesis. Histone deacetylases (HDACs) are a group of epigenetic regulators that control cell fate, but their role in balancing NPC renewal and differentiation is unknown. Here, we report that NPC-specific deletion of Hdac1 and Hdac2 genes in mice results in early postnatal lethality owing to renal hypodysplasia and loss of NPCs. HDAC1/2 interact with the NPC renewal regulators Six2, Osr1 and Sall1, and are co-bound along with Six2 on the Six2 enhancer. Although the mutant NPCs differentiate into renal vesicles (RVs), Hdac1/2 mutant kidneys lack nascent nephrons or mature glomeruli, a phenocopy of Lhx1 mutants. Transcriptional profiling and network analysis identified disrupted expression of Lhx1 and its downstream genes, Dll1 and Hnf1a/4a, as key mediators of the renal phenotype. Finally, although HDAC1/2-deficient NPCs and RVs overexpress hyperacetylated p53, Trp53 deletion failed to rescue the renal dysgenesis. We conclude that the epigenetic regulators HDAC1 and HDAC2 control nephrogenesis via interactions with the transcriptional programs of nephron progenitors and renal vesicles. PMID- 29712644 TI - Ethical drug marketing criteria for the 21st century. PMID- 29712645 TI - Bawa-Garba campaign group reports progress in Scotland. PMID- 29712646 TI - Trump administration could reject decades of landmark health studies under "transparency" rule. PMID- 29712647 TI - European Commission moves to boost vaccination cover across the continent. PMID- 29712648 TI - Biases in electronic health record data due to processes within the healthcare system: retrospective observational study. AB - OBJECTIVE: To evaluate on a large scale, across 272 common types of laboratory tests, the impact of healthcare processes on the predictive value of electronic health record (EHR) data. DESIGN: Retrospective observational study. SETTING: Two large hospitals in Boston, Massachusetts, with inpatient, emergency, and ambulatory care. PARTICIPANTS: All 669 452 patients treated at the two hospitals over one year between 2005 and 2006. MAIN OUTCOME MEASURES: The relative predictive accuracy of each laboratory test for three year survival, using the time of the day, day of the week, and ordering frequency of the test, compared to the value of the test result. RESULTS: The presence of a laboratory test order, regardless of any other information about the test result, has a significant association (P<0.001) with the odds of survival in 233 of 272 (86%) tests. Data about the timing of when laboratory tests were ordered were more accurate than the test results in predicting survival in 118 of 174 tests (68%). CONCLUSIONS: Healthcare processes must be addressed and accounted for in analysis of observational health data. Without careful consideration to context, EHR data are unsuitable for many research questions. However, if explicitly modeled, the same processes that make EHR data complex can be leveraged to gain insight into patients' state of health. PMID- 29712649 TI - Tolerance to paternal genotoxic damage promotes survival during embryo development in zebrafish (Danio rerio). AB - Spermatozoa carry DNA damage that must be repaired by the oocyte machinery upon fertilization. Different strategies could be adopted by different vertebrates to face the paternal genotoxic damage. Mammals have strong sperm selection mechanisms and activate a zygotic DNA damage response (DDR) (including cell cycle arrest, DNA repair and alternative apoptosis) in order to guarantee the genomic conformity of the reduced progeny. However, external fertilizers, with different reproductive strategies, seem to proceed distinctively. Previous results from our group showed a downregulation of apoptotic activity in trout embryos with a defective DNA repairing ability, suggesting that mechanisms of tolerance to damaged DNA could be activated in fish to maintain cell survival and to progress with development. In this work, zebrafish embryos were obtained from control or UV-irradiated sperm (carrying more than 10% of fragmented DNA but still preserving fertilization ability). DNA repair (gammaH2AX and 53BP1 foci), apoptotic activity, expression of genes related to DDR and malformation rates were analyzed throughout development. Results showed in the progeny from damaged sperm, an enhanced repairing activity at the mid-blastula transition stage that returned to its basal level at later stages, rendering at hatching a very high rate of multimalformed larvae. The study of transcriptional and post translational activity of tp53 (ZDF-GENE-990415-270) revealed the activation of an intense DDR in those progenies. However, the downstream pro-apoptotic factor noxa (ZDF-GENE-070119-3) showed a significant downregulation, whereas the anti apoptotic gene bcl2 (ZDF-GENE-051015-1) was upregulated, triggering a repressive apoptotic scenario in spite of a clear genomic instability. This repression can be explained by the observed upregulation of p53 isoform Delta113p53, which is known to inhibit bcl2 transcription. Our results showed that tp53 is involved in DNA damage tolerance (DDT) pathways, allowing the embryo survival regardless of the paternal DNA damage. DDT could be an evolutionary mechanism in fish: tolerance to unrepaired sperm DNA could introduce new mutations, some of them potentially advantageous to face a changing environment. PMID- 29712650 TI - Activities of Combinations of Antistaphylococcal Antibiotics with Fusidic Acid against Staphylococcal Biofilms in In Vitro Static and Dynamic Models. AB - Staphylococcal biofilms are a major cause of therapeutic failure, especially when caused by multiresistant strains. Oral fusidic acid is currently being redeveloped in the United States for skin, skin structure, and orthopedic infections, in which biofilms play a major role. The aim of this study was to examine the activity of fusidic acid alone or combined with other antistaphylococcal drugs against biofilms made by a reference strain and five clinical isolates of Staphylococcus aureus or Staphylococcus epidermidis in in vitro static and dynamic models (microtiter plates and a CDC reactor) exposed to clinically relevant concentrations. In microtiter plates, antibiotics alone were poorly active, with marked differences among strains. At concentrations mimicking the free-drug human maximum concentration of drug in serum (Cmax), the combination of fusidic acid with linezolid, daptomycin, or vancomycin resulted in increased activity against 4 to 5 strains, while the combination with doxycycline, rifampin, or moxifloxacin increased activity against 1 to 3 strains only. In the CDC reactor, biofilms were grown under constant flow and antibiotic concentrations decreased over time according to human elimination rates. A bactericidal effect was obtained when fusidic acid was combined with daptomycin or linezolid, but not with vancomycin. The higher tolerance of biofilms to antibiotics in the CDC reactor is probably attributable to the more complex architecture they adopt when growing under constant flow. Because biofilms grown in the CDC reactor are considered more similar to those developing in vivo, the data support further testing of combinations of fusidic acid with daptomycin or linezolid in models pertinent to chronic skin, skin structure, or orthopedic infections. PMID- 29712651 TI - Resistance to Echinocandins in Candida Can Be Detected by Performing the Etest Directly on Blood Culture Samples. AB - We examined the rapid evaluation of susceptibility to echinocandins in Candida spp. using the Etest performed directly on positive blood cultures and anidulafungin-containing agar plates. We prospectively collected 80 positive blood cultures (Bactec-FX system, Becton-Dickinson, Cockeysville, MD, USA) with echinocandin-susceptible Candida spp. (n = 60) and echinocandin-intermediate Candida parapsilosis (n = 20) from patients with candidemia. Additionally, blood culture bottles of nonfungemic/bacteremic patients were spiked with 35 echinocandin-resistant Candida species isolates. A total of 2 to 4 drops of medium from each bottle were stroked directly onto both RPMI 1640 agar plates with micafungin and anidulafungin Etest strips (ETDIR) and Sabouraud agar plates containing 2 mg/liter of anidulafungin. The isolates were tested according to the EUCAST method and Etest standard (ETSD). Essential and categorical agreement between the methods was calculated. The essential agreement and categorical agreement between the EUCAST method and ETDIR and ETSD were both >97.4%. The essential agreement between ETDIR and the EUCAST method for both echinocandins was >97%. The categorical agreement between the FKS sequence and ETDIR was 97.4%. The ETDIR MICs of anidulafungin and micafungin (>=0.19 mg/liter and >=0.064 mg/liter, respectively) effectively separated all susceptible FKS wild-type isolates from the resistant FKS mutant isolates. The categorical agreement (62.6%) between the EUCAST method and growth on anidulafungin-containing plates was poor, with the best agreement observed for Candida glabrata (94.2%). When performed directly on positive blood cultures from patients with candidemia, the Etest with micafungin and anidulafungin is a reliable procedure for the rapid testing of susceptibility to echinocandins in Candida species isolates. PMID- 29712652 TI - First Penicillin-Binding Protein Occupancy Patterns of beta-Lactams and beta Lactamase Inhibitors in Klebsiella pneumoniae. AB - Penicillin-binding proteins (PBPs) are the high-affinity target sites of all beta lactam antibiotics in bacteria. It is well known that each beta-lactam covalently binds to and thereby inactivates different PBPs with various affinities. Despite beta-lactams serving as the cornerstone of our therapeutic armamentarium against Klebsiella pneumoniae, PBP binding data are missing for this pathogen. We aimed to generate the first PBP binding data on 13 chemically diverse and clinically relevant beta-lactams and beta-lactamase inhibitors in K. pneumoniae PBP binding was determined using isolated membrane fractions from K. pneumoniae strains ATCC 43816 and ATCC 13883. Binding reactions were conducted using beta-lactam concentrations from 0.0075 to 256 mg/liter (or 128 mg/liter). After beta-lactam exposure, unbound PBPs were labeled by Bocillin FL. Binding affinities (50% inhibitory concentrations [IC50]) were reported as the beta-lactam concentrations that half-maximally inhibited Bocillin FL binding. PBP occupancy patterns by beta lactams were consistent across both strains. Carbapenems bound to all PBPs, with PBP2 and PBP4 as the highest-affinity targets (IC50, <0.0075 mg/liter). Preferential PBP2 binding was observed by mecillinam (amdinocillin; IC50, <0.0075 mg/liter) and avibactam (IC50, 2 mg/liter). Aztreonam showed high affinity for PBP3 (IC50, 0.06 to 0.12 mg/liter). Ceftazidime bound PBP3 at low concentrations (IC50, 0.06 to 0.25 mg/liter) and PBP1a/b at higher concentrations (4 mg/liter), whereas cefepime bound PBPs 1 to 4 at more even concentrations (IC50, 0.015 to 2 mg/liter). These PBP binding data on a comprehensive set of 13 clinically relevant beta-lactams and beta-lactamase inhibitors in K. pneumoniae enable, for the first time, the rational design and optimization of double beta-lactam and beta-lactam-beta-lactamase inhibitor combinations. PMID- 29712653 TI - Direct Activation of Adenosine Monophosphate-Activated Protein Kinase (AMPK) by PF-06409577 Inhibits Flavivirus Infection through Modification of Host Cell Lipid Metabolism. AB - Mosquito-borne flaviviruses are a group of RNA viruses that constitute global threats for human and animal health. Replication of these pathogens is strictly dependent on cellular lipid metabolism. We have evaluated the effect of the pharmacological activation of AMP-activated protein kinase (AMPK), a master regulator of lipid metabolism, on the infection of three medically relevant flaviviruses, namely, West Nile virus (WNV), Zika virus (ZIKV), and dengue virus (DENV). WNV is responsible for recurrent outbreaks of meningitis and encephalitis, affecting humans and horses worldwide. ZIKV has caused a recent pandemic associated with birth defects (microcephaly), reproductive disorders, and severe neurological complications (Guillain-Barre syndrome). DENV is the etiological agent of the most prevalent mosquito-borne viral disease, which can induce a potentially lethal complication called severe dengue. Our results showed, for the first time, that activation of AMPK using the specific small molecule activator PF-06409577 reduced WNV, ZIKV, and DENV infection. This antiviral effect was associated with an impairment of viral replication due to the modulation of host cell lipid metabolism exerted by the compound. These results support that the pharmacological activation of AMPK, which currently constitutes an important pharmacological target for human diseases, could also provide a feasible approach for broad-spectrum host-directed antiviral discovery. PMID- 29712654 TI - Pharmacokinetics, Pharmacodynamics, and Tolerability of Single-Dose Oral LCB01 0371, a Novel Oxazolidinone with Broad-Spectrum Activity, in Healthy Volunteers. AB - LCB01-0371 is a novel oxazolidinone with broad-spectrum activity against Gram positive pathogens in both in vitro studies and animal infection models. The objectives of this study were to evaluate its safety, tolerability, pharmacokinetics, and pharmacodynamics following single ascending doses. Single oral doses of 600 mg linezolid, a placebo, or LCB01-0371 of between 50 mg and 3,200 mg were tested in 69 healthy male subjects. Blood and urine were sampled, LCB01-0371 concentrations were measured, and the serum inhibitory and bactericidal titers of LCB01-0371 and linezolid were determined. LCB01-0371 was well tolerated up to 2,400 mg. The most common drug-related clinical and laboratory adverse events were nausea with or without vomiting, decreased neutrophil counts, and increased total bilirubin levels. The frequency of adverse events and drug-related adverse events was similar among the treatment groups. The systemic exposure was approximately dose proportional over the range of 50 mg to 800 mg, which includes the anticipated clinical dose. The mean clearance, renal clearance, and volume of distribution were significantly decreased at higher doses (above 800 mg). LCB01-0371 exhibited early bacteriostatic activity against all tested strains except for Streptococcus pneumoniae strains, and the potency of LCB01-0371 at 800 mg was similar to that of linezolid at the therapeutic dose (600 mg). However, LCB01-0371 had less bactericidal activity than linezolid. Taken together, LCB01-0371 was well tolerated, exhibited approximate dose proportionality within the anticipated clinically relevant dose range, and showed bacteriostatic and bactericidal activity comparable to that of linezolid. These results support the further clinical development of LCB01-0371. (This study has been registered at ClinicalTrials.gov under registration no. NCT01554995.). PMID- 29712655 TI - Genetic and Functional Characterization of an MCR-3-Like Enzyme-Producing Escherichia coli Isolate Recovered from Swine in Brazil. AB - A collection of 126 pigs was screened for carriage of colistin-resistant Enterobacteriaceae in a farm in Minas Gerais, Brazil. Out of this collection, eight colistin-resistant Escherichia coli isolates were recovered, including one from Minas Gerais State producing a new MCR-3 variant (MCR-3.12). Analysis of the lipopolysaccharide revealed that MCR-3.12 had a function similar to that of MCR-1 and MCR-2 as a result of the addition of a phosphoethanolamine group to the lipid A moiety. Genetic analysis showed that the mcr-3.12 gene was carried by an IncA/C2 plasmid and was embedded in an original genetic environment. This study reports the occurrence of the MCR-3-like determinant in South America and is the first to demonstrate the functionality of this group of enzymes as a phosphoethanolamine transferase. PMID- 29712656 TI - The Artemisinin Derivative Artemisone Is a Potent Inhibitor of Human Cytomegalovirus Replication. AB - Human cytomegalovirus (HCMV) is a major cause of disease in immunocompromised individuals and the most common cause of congenital infection and neurosensorial disease. The expanding target populations for HCMV antiviral treatment along with the limitations of the currently available HCMV DNA polymerase inhibitors underscore the need for new antiviral agents with alternative modes of action. The antimalarial artemisinin derivative artesunate was shown to inhibit HCMV in vitro yet has demonstrated limited antiviral efficacy in vivo, prompting our search for more potent anti-HCMV artemisinin derivatives. Here we show that the innovative artemisinin derivative artemisone, which has been screened for its activity against malaria parasites in human clinical studies, is a potent and noncytotoxic inhibitor of HCMV. Artemisone exhibited an antiviral efficacy comparable to that of ganciclovir (50% effective concentration, 1.20 +/- 0.46 MUM) in human foreskin fibroblasts, with enhanced relative potency in lung fibroblasts and epithelial cells. Significantly, the antiviral efficacy of artemisone was consistently >=10-fold superior to that of artesunate in all cells. Artemisone effectively inhibited both laboratory-adapted and low-passage number clinical strains, as well as drug-resistant HCMV strains. By using quantitative viral kinetics and gene expression studies, we show that artemisone is a reversible inhibitor targeting an earlier phase of the viral replication cycle than ganciclovir. Importantly, artemisone most effectively inhibited HCMV infection ex vivo in a clinically relevant multicellular model of integral human placental tissues maintained in organ culture. Our promising findings encourage preclinical and clinical studies of artemisone as a new inhibitor against HCMV. PMID- 29712657 TI - Commonly Used Oncology Drugs Decrease Antifungal Effectiveness against Candida and Aspergillus Species. AB - The incidence of invasive fungal infections has risen significantly in recent decades as medical interventions have become increasingly aggressive. These infections are extremely difficult to treat due to the extremely limited repertoire of systemic antifungals, the development of drug resistance, and the extent to which the patient's immune function is compromised. Even when the appropriate antifungal therapies are administered in a timely fashion, treatment failure is common, even in the absence of in vitro microbial resistance. In this study, we screened a small collection of FDA-approved oncolytic agents for compounds that impact the efficacy of the two most widely used classes of systemic antifungals against Candida albicans, Candida glabrata, and Aspergillus fumigatus We have identified several drugs that enhance fungal growth in the presence of azole antifungals and examine the potential that these drugs directly affect fungal fitness, specifically antifungal susceptibility, and may be contributing to clinical treatment failure. PMID- 29712658 TI - Determination of MIC Distribution and Mechanisms of Decreased Susceptibility to Bedaquiline among Clinical Isolates of Mycobacterium abscessus. AB - Chemotherapeutic options against Mycobacterium abscessus infections are very limited. Bedaquiline, a new antituberculosis (anti-TB) drug, is effective for the treatment of multidrug-resistant TB. However, few data are available on bedaquiline for treatment of M. abscessus infections. In this study, we determined the profile for in vitro susceptibility of M. abscessus clinical isolates to bedaquiline and investigated the potential molecular mechanisms of decreased susceptibility. A total of 197 M. abscessus clinical isolates were collected from sputum and bronchoalveolar fluid of patients with lung infections. Standard broth microdilution test revealed that bedaquiline exhibited high in vitro killing activity against M. abscessus isolates, with a MIC50 of 0.062 and a MIC90 of 0.125 mg/liter. Whole-genome sequencing data showed that no nonsynonymous mutation occurred in atpE, the gene encoding the bedaquiline targeted protein. However, of 6 strains with decreased susceptibility of bedaquiline (MIC = 0.5 to 1 mg/liter), 3 strains had nonsynonymous mutations in mab_4384, the gene encoding the repressor of efflux pump MmpS5/MmpL5. Quantitative reverse transcription-PCR (qRT-PCR) analysis showed that the expression of MmpS5/MmpL5 in the group with decreased susceptibility to bedaquiline was significantly higher than in those with medium MICs (MIC = 0.125 to 0.5 mg/liter) or in the low-MIC group (MIC <= 0.062 mg/liter). Two isolates with increased MICs did not show overexpression of MmpS5/MmpL5, which could not be explained by known molecular mechanisms. This is the first report showing the association of MmpS5/MmpL5 with decreased bedaquiline susceptibility in M. abscessus clinical isolates and suggesting the presence of other, yet-to-be identified mechanisms for decreased bedaquiline susceptibility in M. abscessus. PMID- 29712659 TI - Carbapenem-Resistant Hypervirulent Klebsiella pneumoniae of Sequence Type 36. AB - Sequence type 36 (ST36) Klebsiella pneumoniae is distributed worldwide. We found an ST36 K. pneumoniae clinical isolate that was carbapenem resistant, carried blaKPC-2, had mucoid regulator gene rmpA, and exhibited high virulence. The finding suggests the emergence of carbapenem-resistant hypervirulent K. pneumoniae of ST36, and surveillance of carbapenem-resistant hypervirulent K. pneumoniae is required. PMID- 29712660 TI - Novel Mutations Associated with Clofazimine Resistance in Mycobacterium abscessus. AB - Mycobacterium abscessus is a major nontuberculous mycobacterial (NTM) pathogen and is responsible for about 80% of all pulmonary infections caused by rapidly growing mycobacteria. Clofazimine is an effective drug active against M. abscessus, but the mechanism of resistance to clofazimine in M. abscessus is unknown. To investigate the molecular basis of clofazimine resistance in M. abscessus, we isolated 29 M. abscessus mutants resistant to clofazimine and subjected them to whole-genome sequencing to identify possible mutations associated with clofazimine resistance. We found that mutations in the MAB_2299c gene (which encodes a possible transcriptional regulatory protein), MAB_1483, and MAB_0540 are most commonly associated with clofazimine resistance. In addition, mutations in MAB_0416c, MAB_4099c, MAB_2613, MAB_0409, and MAB_1426 were also associated with clofazimine resistance but less frequently. Two identical mutations which are likely to be polymorphisms unrelated to clofazimine resistance were found in MAB_4605c and MAB_4323 in 13 mutants. We conclude that mutations in MAB_2299c, MAB_1483, and MAB_0540 are the major mechanisms of clofazimine resistance in M. abscessus Future studies are needed to address the role of the identified mutations in clofazimine resistance in M. abscessus Our findings have implications for understanding mechanisms of resistance to clofazimine and for rapid detection of clofazimine resistance in this organism. PMID- 29712661 TI - Incidence of Acute Kidney Injury among Patients Treated with Piperacillin Tazobactam or Meropenem in Combination with Vancomycin. AB - Acute kidney injury (AKI) increases during empirical antimicrobial therapy with the combination of piperacillin-tazobactam (TZP) and vancomycin (VAN) compared to the number of incidences with monotherapy or the combination of cefepime and VAN. Limited data regarding the impact of meropenem (MEM) combined with VAN exist. This study examined the AKI incidence among patients treated with MEM plus VAN (MEM+VAN) or TZP+VAN. Data were collected from the University of Kentucky Center for Clinical and Translational Science Enterprise Data Trust from September 2007 through October 2015. Adults without previous renal disease who received MEM+VAN or TZP+VAN for at least 2 days were included. AKI was assessed using risk, injury, failure, loss, and end-stage (RIFLE) criteria. Inverse probability of treatment weighting was utilized to control for differences between groups. In total, 10,236 patients met inclusion criteria, with 9,898 receiving TZP+VAN and 338 receiving MEM+VAN. AKI occurred in 15.4% of MEM+VAN patients and in 27.4% of TZP+VAN patients (P < 0.001). TZP+VAN was associated with increased AKI compared to the level with MEM+VAN (odds ratio [OR], 2.53; 95% confidence interval [CI], 1.82 to 3.52), after controlling for confounders. Use of MEM+VAN should be considered an appropriate alternative therapy to TZP+VAN if nephrotoxicity is a major concern. The results of this study demonstrate that judicial use of TZP+VAN for empirical coverage of infection is needed. PMID- 29712662 TI - Emergence of High-Level Colistin Resistance in an Acinetobacter baumannii Clinical Isolate Mediated by Inactivation of the Global Regulator H-NS. AB - Colistin is a crucial last-line drug used for the treatment of life-threatening infections caused by multidrug-resistant strains of the Gram-negative bacterium Acinetobacter baumannii However, colistin-resistant A. baumannii isolates can still be isolated following failed colistin therapy. Resistance is most often mediated by the addition of phosphoethanolamine (pEtN) to lipid A by PmrC, following missense mutations in the pmrCAB operon encoding PmrC and the two component signal transduction system PmrA/PmrB. We recovered a pair of A. baumannii isolates from a single patient before (6009-1) and after (6009-2) failed colistin treatment. These strains displayed low and very high levels of colistin resistance (MICs, 8 to 16 MUg/ml and 128 MUg/ml), respectively. To understand how increased colistin resistance arose, we sequenced the genome of each isolate, which revealed that 6009-2 had an extra copy of the insertion sequence element ISAba125 within a gene encoding an H-NS family transcriptional regulator. To confirm the role of H-NS in colistin resistance, we generated an hns deletion mutant in 6009-1 and showed that colistin resistance increased upon the deletion of hns We also provided 6009-2 with an intact copy of hns and showed that the strain was no longer resistant to high concentrations of colistin. Transcriptomic analysis of the clinical isolates identified more than 150 genes as being differentially expressed in the colistin-resistant hns mutant 6009-2. Importantly, the expression of eptA, encoding a second lipid A-specific pEtN transferase but not pmrC, was increased in the hns mutant. This is the first time an H-NS family transcriptional regulator has been associated with a pEtN transferase and colistin resistance. PMID- 29712663 TI - A Population Pharmacokinetic Model for a Solid Oral Tablet Formulation of Posaconazole. AB - A delayed-release solid tablet formulation that releases posaconazole in the small intestine was developed to maximize systemic absorption. This study aimed to characterize the pharmacokinetics of the posaconazole solid tablet formulation in adult subjects and to investigate the potential impact of demographic and clinical factors on posaconazole exposure through a population pharmacokinetic approach. Nonlinear mixed-effects modeling was performed using data from several studies conducted in healthy volunteers and patients. The influence of demographic and clinical factors on pharmacokinetic parameters was evaluated using a stepwise forward inclusion/backward exclusion procedure. The final pharmacokinetic model was used to simulate posaconazole exposure in patients at high risk for invasive fungal diseases treated with the proposed posaconazole dose of 300 mg twice daily on day 1, followed by 300 mg daily for 27 days. A one compartment pharmacokinetic model with sequential zero-order and first-order absorption and a first-order disposition from the central compartment adequately described the pharmacokinetic profile of the posaconazole solid tablet formulation. Significant covariates included disease state (acute myeloid leukemia/myelodysplasia versus allogeneic hematopoietic stem cell transplantation), body weight, and formulation on bioavailability; food status on first-order absorption rate; and dosing regimen (a single dose versus multiple doses) on clearance. Except for body weight, the impact of these covariates on posaconazole exposure was considered clinically irrelevant. This population pharmacokinetic analysis confirmed that the proposed dose of the posaconazole solid tablet formulation provides adequate target therapeutic exposure (>0.5 mg/liter) to a broad range of patients at high risk for invasive fungal disease. PMID- 29712664 TI - Pharmacokinetics of Anidulafungin in Obese and Normal-Weight Adults. AB - In 2025, approximately one out of five adults will be obese. Physiological changes associated with obesity have been shown to influence the pharmacokinetics of drugs. Anidulafungin is frequently used in critically ill patients, and to achieve optimal efficacy, it is essential that its dose is appropriate for each patient's characteristics. We combined data from obese subjects with data from normal-weight subjects and determined an optimal dosing regimen for obese patients by population pharmacokinetic modeling. Twenty adults, 12 of which were normal-weight healthy subjects (median weight, 67.7 kg; range, 61.5 to 93.6 kg) and 8 of which were morbidly obese subjects (median weight, 149.7 kg; range, 124.1 to 166.5 kg) were included in the analysis. Subjects received a single dose of 100 mg anidulafungin intravenously over 90 min, upon which blood samples were obtained. Monte Carlo simulations were performed to optimize dosing in obesity. A three-compartment model and equal volumes of distribution described the data best. Total body weight was identified as a descriptor for both clearance and the volume of distribution, but the effect of weight on these parameters was limited. Simulations showed that with the licensed 100-mg dose, more than 97% of subjects with a weight above 140 kg will have an area under the concentration-time curve from 0 to 24 h of less than 99 mg . h/liter (the reference value for normal weight individuals). We found that in obese and normal-weight subjects, weight influenced both of the anidulafungin pharmacokinetic parameters clearance and volume of distribution, implying a lower exposure to anidulafungin in (morbidly) obese individuals. Consequently, a 25% increase in the loading and maintenance doses could be considered in patients weighing more than 140 kg. PMID- 29712665 TI - Alfie Evans case: Proposed law aims to prevent conflicts between parents and doctors. PMID- 29712666 TI - Randomized phase 2 trial of monthly vitamin D to prevent respiratory complications in children with sickle cell disease. AB - In sickle cell disease, respiratory infection and asthma may lead to respiratory complications that are a leading cause of morbidity and mortality. Vitamin D has anti-infective and immunomodulatory effects that may decrease the risk for respiratory infections, asthma, and acute chest syndrome. We conducted a randomized double-blind active-controlled clinical trial to determine whether monthly oral vitamin D3 can reduce the rate of respiratory events in children with sickle cell disease. Seventy sickle cell subjects, ages 3-20 years, with baseline records of respiratory events over 1 year before randomization, underwent screening. Sixty-two subjects with 25-hydroxyvitamin D levels of 5-60 ng/mL were randomly assigned to oral vitamin D3 (100 000 IU or 12 000 IU, n = 31 each) under observed administration once monthly for 2 years. The primary outcome was the annual rate of respiratory events (respiratory infection, asthma exacerbation, or acute chest syndrome) ascertained by the use of a validated questionnaire administered biweekly. Analysis included 62 children (mean age of 9.9 years, 52% female, and predominantly with homozygous HbS disease [87%]) with mean baseline 25-hydroxyvitamin D of 14.3 ng/mL. The annual rates of respiratory events at baseline and intervention years 1 and 2 were 4.34 +/- 0.35, 4.28 +/- 0.36, and 1.49 +/- 0.37 (high dose) and 3.91 +/- 0.35, 3.34 +/- 0.37, and 1.54 +/ 0.37 (standard dose), respectively. In pediatric patients with sickle cell disease, 2-year monthly oral vitamin D3 was associated with a >50% reduction in the rate of respiratory illness during the second year (P = .0005), with similar decreases associated with high- and standard-dose treatment. This trial was registered at www.clinicaltrials.gov as #NCT01443728. PMID- 29712668 TI - TCPTP Regulates Insulin Signaling in AgRP Neurons to Coordinate Glucose Metabolism With Feeding. AB - Insulin regulates glucose metabolism by eliciting effects on peripheral tissues as well as the brain. Insulin receptor (IR) signaling inhibits AgRP-expressing neurons in the hypothalamus to contribute to the suppression of hepatic glucose production (HGP) by insulin, whereas AgRP neuronal activation attenuates brown adipose tissue (BAT) glucose uptake. The tyrosine phosphatase TCPTP suppresses IR signaling in AgRP neurons. Hypothalamic TCPTP is induced by fasting and degraded after feeding. Here we assessed the influence of TCPTP in AgRP neurons in the control of glucose metabolism. TCPTP deletion in AgRP neurons (Agrp Cre;Ptpn2fl/fl ) enhanced insulin sensitivity, as assessed by the increased glucose infusion rates, and reduced HGP during hyperinsulinemic-euglycemic clamps, accompanied by increased [14C]-2-deoxy-d-glucose uptake in BAT and browned white adipose tissue. TCPTP deficiency in AgRP neurons promoted the intracerebroventricular insulin-induced repression of hepatic gluconeogenesis in otherwise unresponsive food-restricted mice, yet had no effect in fed/satiated mice where hypothalamic TCPTP levels are reduced. The improvement in glucose homeostasis in Agrp-Cre;Ptpn2fl/fl mice was corrected by IR heterozygosity (Agrp Cre;Ptpn2fl/fl ;Insrfl/+ ), causally linking the effects on glucose metabolism with the IR signaling in AgRP neurons. Our findings demonstrate that TCPTP controls IR signaling in AgRP neurons to coordinate HGP and brown/beige adipocyte glucose uptake in response to feeding/fasting. PMID- 29712669 TI - Proliferation-independent role of NF2 (merlin) in limiting biliary morphogenesis. AB - The architecture of individual cells and cell collectives enables functional specification, a prominent example being the formation of epithelial tubes that transport fluid or gas in many organs. The intrahepatic bile ducts (IHBDs) form a tubular network within the liver parenchyma that transports bile to the intestine. Aberrant biliary 'neoductulogenesis' is also a feature of several liver pathologies including tumorigenesis. However, the mechanism of biliary tube morphogenesis in development or disease is not known. Elimination of the neurofibromatosis type 2 protein (NF2; also known as merlin or neurofibromin 2) causes hepatomegaly due to massive biliary neoductulogenesis in the mouse liver. We show that this phenotype reflects unlimited biliary morphogenesis rather than proliferative expansion. Our studies suggest that NF2 normally limits biliary morphogenesis by coordinating lumen expansion and cell architecture. This work provides fundamental insight into how biliary fate and tubulogenesis are coordinated during development and will guide analyses of disease-associated and experimentally induced biliary pathologies. PMID- 29712670 TI - Failure to cope. PMID- 29712667 TI - Restructuring of the Gut Microbiome by Intermittent Fasting Prevents Retinopathy and Prolongs Survival in db/db Mice. AB - Intermittent fasting (IF) protects against the development of metabolic diseases and cancer, but whether it can prevent diabetic microvascular complications is not known. In db/db mice, we examined the impact of long-term IF on diabetic retinopathy (DR). Despite no change in glycated hemoglobin, db/db mice on the IF regimen displayed significantly longer survival and a reduction in DR end points, including acellular capillaries and leukocyte infiltration. We hypothesized that IF-mediated changes in the gut microbiota would produce beneficial metabolites and prevent the development of DR. Microbiome analysis revealed increased levels of Firmicutes and decreased Bacteroidetes and Verrucomicrobia. Compared with db/db mice on ad libitum feeding, changes in the microbiome of the db/db mice on IF were associated with increases in gut mucin, goblet cell number, villi length, and reductions in plasma peptidoglycan. Consistent with the known modulatory effects of Firmicutes on bile acid (BA) metabolism, measurement of BAs demonstrated a significant increase of tauroursodeoxycholate (TUDCA), a neuroprotective BA, in db/db on IF but not in db/db on AL feeding. TGR5, the TUDCA receptor, was found in the retinal primary ganglion cells. Expression of TGR5 did not change with IF or diabetes. However, IF reduced retinal TNF-alpha mRNA, which is a downstream target of TGR5 activation. Pharmacological activation of TGR5 using INT-767 prevented DR in a second diabetic mouse model. These findings support the concept that IF prevents DR by restructuring the microbiota toward species producing TUDCA and subsequent retinal protection by TGR5 activation. PMID- 29712671 TI - The association between home care visits and same-day emergency department use: a case-crossover study. AB - BACKGROUND: The extent to which home care visits contribute to the delay or avoidance of emergency department use is poorly characterized. We examined the association between home care visits and same-day emergency department use among patients receiving publicly funded home care. METHODS: We conducted a population based case-crossover study among patients receiving publicly funded home care in the Hamilton-Niagara-Haldimand-Brant region of Ontario between January and December 2015. Within individuals, all days with emergency department visits after 5 pm were selected as cases and matched with control days from the previous week. The cohort was stratified according to whether patients had ongoing home care needs ("long stay") or short-term home care needs ("short stay"). We used conditional logistical regression to estimate the association between receiving a home care visit during the day and visiting the emergency department after 5 pm on the same day. RESULTS: A total of 4429 long-stay patients contributed 5893 emergency department visits, and 2836 short-stay patients contributed 3476 visits. Receiving a home care nursing visit was associated with an increased likelihood of visiting the emergency department after 5 pm on the same day in both long-stay (odds ratio [OR] 1.32, 95% confidence interval [CI] 1.17-1.48) and short-stay patients (OR 1.22, 95% CI 1.07-1.39). Stronger associations were observed for less acute visits to the emergency department. No associations were observed for other types of home care visits. INTERPRETATION: Patients receiving home care were more likely to visit the emergency department during the evening on days they received a nursing visit. The mechanism of the association between home care visits and same-day emergency department use and the extent to which same-day emergency department visits could be prevented or diverted require additional investigation. PMID- 29712672 TI - Diagnosing and managing drug allergy. PMID- 29712673 TI - A 52-year-old man with fentanyl-induced muscle rigidity. PMID- 29712674 TI - Eosinophilic esophagitis. PMID- 29712675 TI - Treatment of subclinical hypothyroidism in pregnant women. PMID- 29712676 TI - The authors respond to "Treatment of subclinical hypothyroidism in pregnant women". PMID- 29712677 TI - Exercise-induced vasculitis. PMID- 29712678 TI - That's "not medicine" - when doctors advocate for safer roads, gun bans or reducing poverty. PMID- 29712679 TI - Recognition of family physicians as experts rather than gatekeepers requires "cultural shift". PMID- 29712680 TI - Waits increasing for some priority surgeries. PMID- 29712681 TI - The Genomics of Prostate Cancer: A Historic Perspective. AB - The genomics of prostate cancer (PCA) has been difficult to study compared with some other cancer types for a multitude of reasons, despite significant efforts since the early 1980s. Overcoming some of these obstacles has paved the way for greater insight into the genomics of PCA. The advent of high-throughput technologies coming from the initial use of microsatellite and oligonucleotide probes gave rise to techniques like comparative genomic hybridization (CGH). With the introduction of massively parallel genomic sequencing, referred to as next generation sequencing (NGS), a deeper understanding of cancer genomics in general has occurred. Along with these technologic advances, there has been the development of computational biology and statistical approaches to address novel large data sets characterized by single base resolution. This review will provide a historic perspective of PCA genomics with an emphasis on the cardinal mutations and alterations observed to be consistently seen in PCA for both hormone-naive localized PCA and castration-resistant prostate cancer (CRPC). There will be a focus on alterations that have the greatest potential to play a role in disease progression and therapy management. PMID- 29712682 TI - History of the Discovery of Hepatitis A Virus. AB - Disease outbreaks resembling hepatitis A have been known since antiquity. However, it was not until World War II when two forms of viral hepatitis were clearly differentiated. After the discovery of Australia antigen and its association with hepatitis B, similar methodologies were used to find the hepatitis A virus. The virus was ultimately identified when investigators changed the focus of their search from serum to feces and applied appropriate technology. PMID- 29712683 TI - Comparative Pathology of Hepatitis A Virus and Hepatitis E Virus Infection. AB - Hepatitis A virus (HAV) and hepatitis E virus (HEV) cause acute, self-limiting hepatic infections that are usually spread by the fecal-oral route in humans. Naturally occurring and experimental infections are possible in a variety of nonhuman primates and, in the case of HEV, a number of other species. Many advances in understanding the pathogenesis of these viruses have come from studies in experimental animals. In general, animals infected with these viruses recapitulate the histologic lesions seen in infected humans, but typically with less severe clinical and histopathological manifestations. This review describes the histopathologic changes associated with HAV and HEV infection in humans and experimental animals. PMID- 29712684 TI - Epidemiology and Transmission of Hepatitis A Virus and Hepatitis E Virus Infections in the United States. AB - There are many similarities in the epidemiology and transmission of hepatitis A virus (HAV) and hepatitis E virus (HEV) genotype (gt)3 infections in the United States. Both viruses are enterically transmitted, although specific routes of transmission are more clearly established for HAV than for HEV: HAV is restricted to humans and primarily spread through the fecal-oral route, while HEV is zoonotic with poorly understood modes of transmission in the United States. New cases of HAV infection have decreased dramatically in the United States since infant vaccination was recommended in 1996. In recent years, however, outbreaks have occurred among an increasingly susceptible adult population. Although HEV is the most common cause of acute viral hepatitis in developing countries, it is rarely diagnosed in the United States. PMID- 29712686 TI - CDK9 Inhibitor FIT-039 Suppresses Viral Oncogenes E6 and E7 and Has a Therapeutic Effect on HPV-Induced Neoplasia. AB - Purpose: Cervical cancer is one of the leading causes of cancer-related deaths among women worldwide. The purpose of this study is to assess the therapeutic effect of the newly developed cyclin-dependent kinase 9 (CDK9) inhibitor FIT-039 on cervical neoplasia induced by human papillomavirus (HPV) infection.Experimental Design: We examined FIT-039 for its effect on HPV gene expression in HPV+ cervical cancer cells. Primary keratinocytes monolayer and organotypic raft culture models were used to evaluate HPV viral replication and cervical intraepithelial neoplasia (CIN) phenotypes. Preclinical pharmacokinetics and toxicity tests for FIT-039 were also conducted. Finally, the anti-HPV effect of FIT-039 was further examined in vivo, using HPV+ cervical cancer xenografts.Results: FIT-039 inhibits HPV replication and expression of E6 and E7 viral oncogenes, restoring tumor suppressors p53 and pRb in HPV+ cervical cancer cells. The therapeutic effect of FIT-039 was demonstrated in CIN model of an organotypic raft culture, where FIT-039 suppressed HPV18-induced dysplasia/hyperproliferation with reduction in viral load. FIT-039 also repressed growth of HPV16+, but not HPV- cervical cancer xenografts without any significant adverse effects. Safety and pharmacokinetics of FIT-039 were confirmed for systemic and topical routes.Conclusions: The CDK9 inhibitor FIT-039 showed potent anti-HPV activity without significant toxicity in preclinical studies. Thus, FIT 039 is expected to be a novel therapeutic for CIN to prevent cervical cancer. Clin Cancer Res; 24(18); 4518-28. (c)2018 AACR. PMID- 29712685 TI - Novel Effector Phenotype of Tim-3+ Regulatory T Cells Leads to Enhanced Suppressive Function in Head and Neck Cancer Patients. AB - Purpose: Regulatory T (Treg) cells are important suppressive cells among tumor infiltrating lymphocytes (TIL). Treg cells express the well-known immune checkpoint receptor PD-1, which is reported to mark "exhausted" Treg with lower suppressive function. T-cell immunoglobulin mucin (Tim)-3, a negative regulator of Th1 immunity, is expressed by a sizeable fraction of TIL Tregs, but the functional status of Tim-3+ Tregs remains unclear.Experimental Design: CD4+CTLA 4+CD25high Treg cells were sorted from freshly excised head and neck squamous cell carcinoma (HNSCC) TIL based on Tim-3 expression. Functional and phenotypic features of these Tim-3+ and Tim-3- TIL Tregs were tested by in vitro suppression assays and multi-color flow cytometry. Gene-expression profiling and NanoString analysis of Tim-3+ TIL Treg were performed. A murine HNSCC tumor model was used to test the effect of anti-PD-1 immunotherapy on Tim-3+ Treg.Results: Despite high PD-1 expression, Tim-3+ TIL Treg displayed a greater capacity to inhibit naive T-cell proliferation than Tim-3- Treg. Tim-3+ Treg from human HNSCC TIL also displayed an effector-like phenotype, with more robust expression of CTLA-4, PD-1, CD39, and IFN-gamma receptor. Exogenous IFN-gamma treatment could partially reverse the suppressive function of Tim-3+ TIL Treg. Anti-PD-1 immunotherapy downregulated Tim-3 expression on Tregs isolated from murine HNSCC tumors, and this treatment reversed the suppressive function of HNSCC TIL Tregs.Conclusions: Tim-3+ Treg are functionally and phenotypically distinct in HNSCC TIL, and are highly effective at inhibiting T-cell proliferation despite high PD-1 expression. IFN-gamma induced by anti-PD-1 immunotherapy may be beneficial by reversing Tim 3+ Treg suppression. Clin Cancer Res; 24(18); 4529-38. (c)2018 AACR. PMID- 29712687 TI - Cross-talk between T Cells and Hematopoietic Stem Cells during Adoptive Cellular Therapy for Malignant Glioma. AB - Purpose: Adoptive T-cell immunotherapy (ACT) has emerged as a viable therapeutic for peripheral and central nervous system (CNS) tumors. In peripheral cancers, optimal efficacy of ACT is reliant on dendritic cells (DCs) in the tumor microenvironment. However, the CNS is largely devoid of resident migratory DCs to function as antigen-presenting cells during immunotherapy. Herein, we demonstrate that cellular interactions between adoptively transferred tumor-reactive T cells and bone marrow-derived hematopoietic stem and progenitor cells (HSPCs) lead to the generation of potent intratumoral DCs within the CNS compartment.Experimental Design: We evaluated HSPC differentiation during ACT in vivo in glioma-bearing hosts and HSPC proliferation and differentiation in vitro using a T-cell coculture system. We utilized FACS, ELISAs, and gene expression profiling to study the phenotype and function of HSPC-derived cells ex vivo and in vivo To demonstrate the impact of HSPC differentiation and function on antitumor efficacy, we performed survival experiments.Results: Transfer of HSPCs with concomitant ACT led to the production of activated CD86+CD11c+MHCII+ cells consistent with DC phenotype and function within the brain tumor microenvironment. These intratumoral DCs largely supplanted abundant host myeloid derived suppressor cells. We determined that during ACT, HSPC-derived cells in gliomas rely on T-cell-released IFNgamma to differentiate into DCs, activate T cells, and reject intracranial tumors.Conclusions: Our data support the use of HSPCs as a novel cellular therapy. Although DC vaccines induce robust immune responses in the periphery, our data demonstrate that HSPC transfer uniquely generates intratumoral DCs that potentiate T-cell responses and promote glioma rejection in situClin Cancer Res; 24(16); 3955-66. (c)2018 AACR. PMID- 29712688 TI - Intraoperative Resection Guidance with Photoacoustic and Fluorescence Molecular Imaging Using an Anti-B7-H3 Antibody-Indocyanine Green Dual Contrast Agent. AB - Purpose: Breast cancer often requires surgical treatment including breast conserving surgical resection. However, with current postsurgical histologic margin analysis, one quarter of breast cancer patients undergo reexcision to achieve negative margins corresponding to decreased local recurrence and better outcomes. Therefore, a method with high resolution and specificity for intraoperative margin assessment is needed.Experimental Design: First, quantitative immunofluorescence staining of B7-H3 expression was assessed in four pathologic stages of breast cancer progression of the MMTV-PyMT transgenic murine model. Next, an antibody-dye contrast agent, B7-H3-ICG, was injected into mice prior to surgical resection of breast cancer. Anatomic ultrasound, spectroscopic photoacoustic (sPA), and fluorescence imaging were used to guide resection of mammary glands suspected of containing cancer. Resected tissues were processed for H&E staining and pathologic assessment and compared with sPA and fluorescence imaging signals.Results: Tissue containing DCIS (46.0 +/- 4.8 a.u.) or invasive carcinoma (91.7 +/- 21.4 a.u.) showed significantly higher (P < 0.05) B7-H3 expression than normal and hyperplastic tissues (1.3 +/- 0.8 a.u.). During image guided surgical resection, tissue pieces assessed as normal or hyperplastic (n = 17) showed lower average sPA (3.17 +/- 0.48 a.u.) and fluorescence signal [6.83E07 +/- 2.00E06 (p/s)/(MUW/cm2)] than DCIS and invasive carcinoma tissue (n = 63) with an average sPA signal of 23.98 +/- 4.88 a.u. and an average fluorescence signal of 7.56E07 +/- 1.44E06 (p/s)/(MUW/cm2) with AUCs of 0.93 [95% confidence interval (CI), 0.87-0.99] and 0.71 (95% CI, 0.57-0.85), respectively.Conclusions: It was demonstrated that sPA and fluorescence molecular imaging combined with B7-H3-ICG agent can assess the disease status of tissues with high diagnostic accuracy, intraoperatively, with high resolution, sensitivity, and specificity. Clin Cancer Res; 24(15); 3572-82. (c)2018 AACR. PMID- 29712689 TI - A systematic analysis of UK cancer research funding by gender of primary investigator. AB - OBJECTIVES: To categorically describe cancer research funding in the UK by gender of primary investigator (PIs). DESIGN: Systematic analysis of all open-access data. METHODS: Data about public and philanthropic cancer research funding awarded to UK institutions between 2000 and 2013 were obtained from several sources. Fold differences were used to compare total investment, award number, mean and median award value between male and female PIs. Mann-Whitney U tests were performed to determine statistically significant associations between PI gender and median grant value. RESULTS: Of the studies included in our analysis, 2890 (69%) grants with a total value of L1.82 billion (78%) were awarded to male PIs compared with 1296 (31%) grants with a total value of L512 million (22%) awarded to female PIs. Male PIs received 1.3 times the median award value of their female counterparts (P<0.001). These apparent absolute and relative differences largely persisted regardless of subanalyses. CONCLUSIONS: We demonstrate substantial differences in cancer research investment awarded by gender. Female PIs clearly and consistently receive less funding than their male counterparts in terms of total investment, the number of funded awards, mean funding awarded and median funding awarded. PMID- 29712690 TI - Support for midlife anxiety diagnosis as an independent risk factor for dementia: a systematic review. AB - OBJECTIVES: Anxiety is an increasingly recognised predictor of cognitive deterioration in older adults and in those with mild cognitive impairment. Often believed to be a prodromal feature of neurodegenerative disease, anxiety may also be an independent risk factor for dementia, operationally defined here as preceding dementia diagnosis by >=10 years. DESIGN: A systematic review of the literature on anxiety diagnosis and long-term risk for dementia was performed following published guidelines. SETTING AND PARTICIPANTS: Medline, PsycINFO and Embase were searched for peer-reviewed journals until 8 March 2017. Publications reporting HR/OR for all-cause dementia based on clinical criteria from prospective cohort or case-control studies were selected. Included studies measured clinically significant anxiety in isolation or after controlling for symptoms of depression, and reported a mean interval between anxiety assessment and dementia diagnosis of at least 10 years. Methodological quality assessments were performed using the Newcastle-Ottawa Scale. OUTCOME MEASURE: HR/OR for all cause dementia. RESULTS: Searches yielded 3510 articles, of which 4 (0.02%) were eligible. The studies had a combined sample size of 29 819, and all studies found a positive association between clinically significant anxiety and future dementia. Due to the heterogeneity between studies, a meta-analysis was not conducted. CONCLUSIONS: Clinically significant anxiety in midlife was associated with an increased risk of dementia over an interval of at least 10 years. These findings indicate that anxiety may be a risk factor for late-life dementia, excluding anxiety that is related to prodromal cognitive decline. With increasing focus on identifying modifiable risk factors for dementia, more high-quality prospective studies are required to clarify whether clinical anxiety is a risk factor for dementia, separate from a prodromal symptom. PMID- 29712691 TI - What proportion of patients at the end of life contact out-of-hours primary care? A data linkage study in Oxfordshire. AB - OBJECTIVES: Out-of-hours (OOH) primary care services are a key element of community care at the end of life, yet there have been no previous attempts to describe the scope of this activity. We aimed to establish the proportion of Oxfordshire patients who were seen by the OOH service within the last 30 days of life, whether they were documented in a palliative phase of care and the demographic and clinical features of these groups. DESIGN: Population-based study linking a database of patient contacts with OOH primary care with the register of all deaths within Oxfordshire (600 000 population) during 13 months. SETTING: Oxfordshire. PARTICIPANTS: Between 1 December 2014 and 30 November 2015 there were 102 877 OOH contacts made by 67 943 patients with the OOH service. MAIN OUTCOME MEASURES: Proportion of patients dying in the Oxfordshire population who were seen by the OOH service within the last 30 days of life. Demographic and clinical features of these contacts. RESULTS: 29.5% of all population deaths were seen by the OOH service in the last 30 days of life. Among the 1530 patients seen, patients whose palliative phase was documented (n=577, 36.4%) were slightly younger (median age=83.5 vs 85.2 years, P<0.001) and were seen closer to death (median days to death=2 vs 8, P<0.001). More were assessed at home (59.8% vs 51.9%, P<0.001) and less were admitted to hospital (2.7% vs 18.0%, P<0.001). CONCLUSIONS: OOH services see around one-third of all patients who die in a population. Most patients at the end of life are not documented as palliative by OOH services and are less likely to receive ongoing care at home. PMID- 29712692 TI - Identification of a Small Molecule That Selectively Inhibits ERG-Positive Cancer Cell Growth. AB - Oncogenic activation of the ETS-related gene (ERG) by recurrent gene fusions (predominantly TMPRSS2-ERG) is one of the most validated and prevalent genomic alterations present in early stages of prostate cancer. In this study, we screened small-molecule libraries for inhibition of ERG protein in TMPRSS2-ERG harboring VCaP prostate cancer cells using an In-Cell Western Assay with the highly specific ERG-MAb (9FY). Among a subset of promising candidates, 1-[2 Thiazolylazo]-2-naphthol (NSC139021, hereafter ERGi-USU) was identified and further characterized. ERGi-USU selectively inhibited growth of ERG-positive cancer cell lines with minimal effect on normal prostate or endothelial cells or ERG-negative tumor cell lines. Combination of ERGi-USU with enzalutamide showed additive effects in inhibiting growth of VCaP cells. A screen of kinases revealed that ERGi-USU directly bound the ribosomal biogenesis regulator atypical kinase RIOK2 and induced ribosomal stress signature. In vivo, ERGi-USU treatment inhibited growth of ERG-positive VCaP tumor xenografts with no apparent toxicity. Structure-activity-based derivatives of ERGi-USU recapitulated the ERG-selective activity of the parental compound. Taken together, ERGi-USU acts as a highly selective inhibitor for the growth of ERG-positive cancer cells and has potential for further development of ERG-targeted therapy of prostate cancer and other malignancies.Significance: A highly selective small-molecule inhibitor of ERG, a critical driver of early stages of prostate cancer, will be imperative for prostate cancer therapy. Cancer Res; 78(13); 3659-71. (c)2018 AACR. PMID- 29712693 TI - Ventricular Tachycardia Ablation in Patients With Implantable Cardioverter Defibrillators Should No Longer Be a Therapy of Last Resort. PMID- 29712694 TI - Fitness, Exercise, and Coronary Calcification. PMID- 29712695 TI - Geographic Variations in Cardiac Rehabilitation Use: Regional Variations in Medical Care or in Patient Behaviors? PMID- 29712697 TI - Precision Obesity Care on the Horizon. PMID- 29712698 TI - Highlights From the Circulation Family of Journals. PMID- 29712699 TI - Association Between Race and Clinical Profile of Patients Referred for Hypertrophic Cardiomyopathy. PMID- 29712700 TI - Letter by Jin-shan and Xue-bin Regarding Article, "Chronic Myocardial Infarction: Where Is It Located?" PMID- 29712701 TI - Response by Goldwasser et al to Letter Regarding Article, "Chronic Myocardial Infarction: Where Is It Located?" PMID- 29712702 TI - Letter by Gazmuri and Karmazyn Regarding Article, "Activation and Inhibition of Sodium-Hydrogen Exchanger Is a Mechanism That Links the Pathophysiology and Treatment of Diabetes Mellitus With That of Heart Failure". PMID- 29712703 TI - Response by Packer to Letter Regarding Article, "Activation and Inhibition of Sodium-Hydrogen Exchange Is a Mechanism That Links the Pathophysiology and Treatment of Diabetes Mellitus With That of Heart Failure". PMID- 29712696 TI - Cardiovascular Magnetic Resonance in Acute ST-Segment-Elevation Myocardial Infarction: Recent Advances, Controversies, and Future Directions. AB - Although mortality after ST-segment elevation myocardial infarction (MI) is on the decline, the number of patients developing heart failure as a result of MI is on the rise. Apart from timely reperfusion by primary percutaneous coronary intervention, there is currently no established therapy for reducing MI size. Thus, new cardioprotective therapies are required to improve clinical outcomes after ST-segment-elevation MI. Cardiovascular magnetic resonance has emerged as an important imaging modality for assessing the efficacy of novel therapies for reducing MI size and preventing subsequent adverse left ventricular remodeling. The recent availability of multiparametric mapping cardiovascular magnetic resonance imaging has provided new insights into the pathophysiology underlying myocardial edema, microvascular obstruction, intramyocardial hemorrhage, and changes in the remote myocardial interstitial space after ST-segment-elevation MI. In this article, we provide an overview of the recent advances in cardiovascular magnetic resonance imaging in reperfused patients with ST-segment elevation MI, discuss the controversies surrounding its use, and explore future applications of cardiovascular magnetic resonance in this setting. PMID- 29712704 TI - Letter by Grocott Regarding Article, "Sodium Glucose Cotransporter-2 Inhibition in Heart Failure: Potential Mechanisms, Clinical Applications, and Summary of Clinical Trials". PMID- 29712705 TI - Response by Lytvyn et al to Letter Regarding Article, "Sodium Glucose Cotransporter-2 Inhibition in Heart Failure: Potential Mechanisms, Clinical Applications, and Summary of Clinical Trials". PMID- 29712706 TI - Letter by d'Aloja et al Regarding Article, "Competitive Sport Participation Among Athletes With Heart Disease: A Call for a Paradigm Shift in Decision Making". PMID- 29712707 TI - Response by Baggish et al to Letter Regarding Article, "Competitive Sport Participation Among Athletes With Heart Disease: A Call for a Paradigm Shift in Decision Making". PMID- 29712708 TI - Home devices deliver data for dementia care. PMID- 29712709 TI - Hormone disrupting chemicals: slow progress to regulation. PMID- 29712710 TI - Austrian doctors secure potential reprieve for scrapped smoking ban. PMID- 29712711 TI - Medical Nutrition Education, Training, and Competencies to Advance Guideline Based Diet Counseling by Physicians: A Science Advisory From the American Heart Association. AB - Growing scientific evidence of the benefits of heart-healthy dietary patterns and of the massive public health and economic burdens attributed to obesity and poor diet quality have triggered national calls to increase diet counseling in outpatients with atherosclerotic cardiovascular disease or risk factors. However, despite evidence that physicians are willing to undertake this task and are viewed as credible sources of diet information, they engage patients in diet counseling at less than desirable rates and cite insufficient knowledge and training as barriers. These data align with evidence of large and persistent gaps in medical nutrition education and training in the United States. Now, major reforms in undergraduate and graduate medical education designed to incorporate advances in the science of learning and to better prepare physicians for 21st century healthcare delivery are providing a new impetus and novel ways to expand medical nutrition education and training. This science advisory reviews gaps in undergraduate and graduate medical education in nutrition in the United States, summarizes reforms that support and facilitate more robust nutrition education and training, and outlines new opportunities for accomplishing this goal via multidimensional curricula, pedagogies, technologies, and competency-based assessments. Real-world examples of efforts to improve undergraduate and graduate medical education in nutrition by integrating formal learning with practical, experiential, inquiry-driven, interprofessional, and population health management activities are provided. The authors conclude that enhancing physician education and training in nutrition, as well as increasing collaborative nutrition care delivery by 21st century health systems, will reduce the health and economic burdens from atherosclerotic cardiovascular disease to a degree not previously realized. PMID- 29712713 TI - Prevalence of Masked Hypertension in Untreated and Treated Patients With Office Blood Pressure Below 130/80 mm Hg. PMID- 29712712 TI - Impact of Healthy Lifestyle Factors on Life Expectancies in the US Population. AB - Background -Americans have a shorter life expectancy compared with residents of almost all other high-income countries. We aim to estimate the impact of lifestyle factors on premature mortality and life expectancy in the US population. Methods -Using data from the Nurses' Health Study (1980-2014; n=78 865) and the Health Professionals Follow-up Study (1986-2014, n=44 354), we defined 5 low-risk lifestyle factors as never smoking, body mass index of 18.5 to 24.9 kg/m2, >=30 min/d of moderate to vigorous physical activity, moderate alcohol intake, and a high diet quality score (upper 40%), and estimated hazard ratios for the association of total lifestyle score (0-5 scale) with mortality. We used data from the NHANES (National Health and Nutrition Examination Surveys; 2013-2014) to estimate the distribution of the lifestyle score and the US Centers for Disease Control and Prevention WONDER database to derive the agespecific death rates of Americans. We applied the life table method to estimate life expectancy by levels of the lifestyle score. Results -During up to 34 years of follow-up, we documented 42 167 deaths. The multivariable-adjusted hazard ratios for mortality in adults with 5 compared with zero low-risk factors were 0.26 (95% confidence interval [CI], 0.22-0.31) for all-cause mortality, 0.35 (95% CI, 0.27 0.45) for cancer mortality, and 0.18 (95% CI, 0.12-0.26) for cardiovascular disease mortality. The population-attributable risk of nonadherence to 5 low-risk factors was 60.7% (95% CI, 53.6-66.7) for all-cause mortality, 51.7% (95% CI, 37.1-62.9) for cancer mortality, and 71.7% (95% CI, 58.1-81.0) for cardiovascular disease mortality. We estimated that the life expectancy at age 50 years was 29.0 years (95% CI, 28.3-29.8) for women and 25.5 years (95% CI, 24.7-26.2) for men who adopted zero low-risk lifestyle factors. In contrast, for those who adopted all 5 low-risk factors, we projected a life expectancy at age 50 years of 43.1 years (95% CI, 41.3-44.9) for women and 37.6 years (95% CI, 35.8-39.4) for men. The projected life expectancy at age 50 years was on average 14.0 years (95% CI, 11.8-16.2) longer among female Americans with 5 lowrisk factors compared with those with zero low-risk factors; for men, the difference was 12.2 years (95% CI, 10.1-14.2). Conclusions -Adopting a healthy lifestyle could substantially reduce premature mortality and prolong life expectancy in US adults. PMID- 29712714 TI - State of Behavioral Health Integration in U.S. Diabetes Care: How Close Are We to ADA Recommendations? PMID- 29712715 TI - NMDAR-dependent Argonaute 2 phosphorylation regulates miRNA activity and dendritic spine plasticity. AB - MicroRNAs (miRNAs) repress translation of target mRNAs by associating with Argonaute (Ago) proteins to form the RNA-induced silencing complex (RISC), underpinning a powerful mechanism for fine-tuning protein expression. Specific miRNAs are required for NMDA receptor (NMDAR)-dependent synaptic plasticity by modulating the translation of proteins involved in dendritic spine morphogenesis or synaptic transmission. However, it is unknown how NMDAR stimulation stimulates RISC activity to rapidly repress translation of synaptic proteins. We show that NMDAR stimulation transiently increases Akt-dependent phosphorylation of Ago2 at S387, which causes an increase in binding to GW182 and a rapid increase in translational repression of LIMK1 via miR-134. Furthermore, NMDAR-dependent down regulation of endogenous LIMK1 translation in dendrites and dendritic spine shrinkage requires phospho-regulation of Ago2 at S387. AMPAR trafficking and hippocampal LTD do not involve S387 phosphorylation, defining this mechanism as a specific pathway for structural plasticity. This work defines a novel mechanism for the rapid transduction of NMDAR stimulation into miRNA-mediated translational repression to control dendritic spine morphology. PMID- 29712716 TI - Regulation of the metabolism of apolipoprotein M and sphingosine 1-phosphate by hepatic PPARgamma activity. AB - Apolipoprotein M (apoM) is a carrier and a modulator of sphingosine 1-phosphate (S1P), an important multifunctional bioactive lipid. Since peroxisome proliferator-activated receptor gamma (PPARgamma) is reportedly associated with the function and metabolism of S1P, we investigated the modulation of apoM/S1P homeostasis by PPARgamma. First, we investigated the modulation of apoM and S1P homeostasis by the overexpression or knockdown of PPARgamma in HepG2 cells and found that both the overexpression and the knockdown of PPARgamma decreased apoM expression and S1P synthesis. When we activated or suppressed the PPARgamma more mildly with pioglitazone or GW9662, we found that pioglitazone suppressed apoM expression and S1P synthesis, while GW9662 increased them. Next, we overexpressed PPARgamma in mouse liver through adenoviral gene transfer and observed that both the plasma and hepatic apoM levels and the plasma S1P levels decreased, while the hepatic S1P levels increased, in the presence of enhanced sphingosine kinase activity. Treatment with pioglitazone decreased both the plasma and hepatic apoM and S1P levels only in diet-induced obese mice. Moreover, the overexpression of apoM increased, while the knockdown of apoM suppressed PPARgamma activities in HepG2 cells. These results suggested that PPARgamma regulates the S1P levels by modulating apoM in a bell-shaped manner, with the greatest levels of apoM/S1P observed when PPARgamma was mildly expressed and that hepatic apoM/PPARgamma axis might maintain the homeostasis of S1P metabolism. PMID- 29712717 TI - Long-term Mortality After Acute Kidney Injury in the Pediatric ICU. AB - OBJECTIVES: (1) To evaluate the association between acute kidney injury (AKI) in the PICU and long-term mortality and (2) to determine the extent to which adding the urine output (UO)-defined AKI alters the association. METHODS: A 2-center retrospective cohort study of children (<=18 years old) admitted to the PICU between 2003 and 2005 for noncardiac surgery, with follow-up until 2010. Patients with end stage renal disease, no provincial health insurance number, who died during hospitalization, or could not be linked to administrative data were excluded. One hospitalization per patient was included. AKI was defined by using serum creatinine criteria and/or UO criteria. Mortality was ascertained by using administrative data. Cox regression analysis was performed to evaluate the association between AKI and long-term mortality. RESULTS: The study population included 2041 patients (55.7% male, mean admission age 6.5 +/- 5.8 years). Of 2041 hospital survivors, 9 (0.4%) died within 30 days, 51 (2.5%) died within 1 year, and 118 (5.8%) died within 5 to 7 years postdischarge. AKI was independently associated with 5- to 7-year mortality (adjusted hazard ratio [95% confidence interval]: 3.10 [1.46-6.57] and 3.38 [1.63-7.02], respectively). Including UO did not strengthen the association. CONCLUSIONS: AKI is associated with 5- to 7-year mortality. Because this is an observational study we cannot determine if AKI is causative of mortality or of the pathophysiology. However, patients with AKI represent a high-risk group. It is reasonable that these patients be considered for targeted follow-up until future researchers better elucidate these relationships. PMID- 29712718 TI - Persisting adverse body composition changes 2 years after cessation of androgen deprivation therapy for localised prostate cancer. AB - OBJECTIVE: Hypogonadism from androgen deprivation therapy (ADT) for prostate cancer causes adverse body composition changes associated with insulin resistance and decreased quality of life (QoL). Our objective was to assess whether adverse body composition changes improve after cessation of ADT. DESIGN: Prospective case control study in a tertiary referral hospital. Thirty-four men newly commencing ADT (cases, median age: 67.6 years (interquartile range: 64.6-72.0)) and 29 age matched (70.6 years (65.3-72.9)) prostate cancer controls not on ADT were assessed 2 years after cessation of ADT (median: 4.4 years). METHODS: Serum testosterone, body composition, handgrip strength, frailty and QoL were measured. Using a mixed model, the mean adjusted differences (MADs (95% CI)) between groups from baseline to study end are reported. RESULTS: Twenty-seven cases and 19 controls completed the study. Median duration of ADT was 2.3 years (interquartile range: 1.8-3.1). Two years after cessation of ADT, total testosterone remained lower (MAD: -3.4 nmol/L (-6.3 to -0.5), P < 0.022), fat mass (2214 g (490-3933), P = 0.025) and insulin resistance (homeostasis model assessment of insulin resistance: 0.69 (0.31-1.07), P < 0.001) remained higher in cases, whereas lean mass (-1450 g (-2259 to -640), P < 0.001) and physical component of QoL remained lower than controls (-11.9 (-16.4 to -7.4), P < 0.001). CONCLUSION: Two years after ADT cessation, metabolically adverse changes in body composition, increased insulin resistance and reduced QoL persisted. This may be related to incomplete testosterone recovery. Persisting adverse effects need to be considered in the risk to benefit assessment of ADT and proactive mitigation should continue after cessation of treatment. PMID- 29712719 TI - Dietary intake and age at natural menopause: results from the UK Women's Cohort Study. AB - BACKGROUND: Age at natural menopause is a matter of concern for women of reproductive age as both an early or late menopause may have implications for health outcomes. METHODS: Study participants were women aged 40-65 years who had experienced a natural menopause from the UK Women's Cohort Study between baseline and first follow-up. Natural menopause was defined as the permanent cessation of menstrual periods for at least 12 consecutive months. A food frequency questionnaire was used to estimate diet at baseline. Reproductive history of participants was also recorded. Regression modelling, adjusting for confounders, was used to assess associations between diet and age at natural menopause. RESULTS: During the 4-year follow-up period, 914 women experienced a natural menopause. A high intake of oily fish and fresh legumes were associated with delayed onset of natural menopause by 3.3 years per portion/day (99% CI 0.8 to 5.8) and 0.9 years per portion/day (99% CI 0.0 to 1.8), respectively. Refined pasta and rice was associated with earlier menopause (per portion/day: -1.5 years, 99% CI -2.8 to -0.2). A higher intake of vitamin B6 (per mg/day: 0.6 years, 99% CI 0.1 to 1.2) and zinc (per mg/day: 0.3 years, 99% CI -0.0 to 0.6) was also associated with later age at menopause. Stratification by age at baseline led to attenuated results. CONCLUSION: Our results suggest that some food groups (oily fish, fresh legumes, refined pasta and rice) and specific nutrients are individually predictive of age at natural menopause. PMID- 29712720 TI - Metabolic disorders during pregnancy and postpartum cardiometabolic risk. AB - Hormonal changes during pregnancy can trigger gestational diabetes (GDM), which is constantly increasing. Its main characteristic is pronounced insulin resistance, but it appears to be a multifactorial process involving several metabolic factors; taken together, the latter leads to silent or clinically evident cardiovascular (CV) events. Insulin resistance and central adiposity are of crucial importance in the development of metabolic syndrome, and they appear to correlate with CV risk factors, including hypertension and atherogenic dyslipidaemia. Hypertensive disease of pregnancy (HDP) is more likely to be an accompanying co-morbidity in pregnancies complicated with GDM. There is still inconsistent evidence as to whether or not co-existent GDM and HDP have a synergistic effects on postpartum risk of cardiometabolic disease; however, this synergism is becoming more accepted since both these conditions may promote endothelial inflammation and early atherosclerosis. Regardless of the presence or absence of the synergism between GDM and HDP, these conditions need to be dealt early enough, in order to reduce CV morbidity and to improve health outcomes for both women and their offspring. PMID- 29712721 TI - A comparative, population-based analysis of pituitary incidentalomas vs clinically manifesting sellar masses. AB - PURPOSE: Sellar masses may present either with clinical manifestations of mass effect/hormonal dysfunction (CMSM) or incidentally on imaging (pituitary incidentaloma (PI)). This novel population-based study compares these two entities. METHODS: Retrospective analysis of all patients within a provincial pituitary registry between January 2006 and June 2014. RESULTS: Nine hundred and three patients were included (681 CMSM, 222 PI). CMSM mainly presented with secondary hormone deficiencies (SHDs) or stalk compression (29.7%), whereas PIs were found in association with neurological complaints (34.2%) (P < 0.0001). PIs were more likely to be macroadenomas (70.7 vs 49.9%; P < 0.0001). The commonest pathologies among CMSM were prolactinomas (39.8%) and non-functioning adenomas (NFAs) (50%) in PI (P < 0.0001). SHDs were present in 41.3% CMSM and 31.1% PI patients (P < 0.0001) and visual field deficit in 24.2 and 29.3%, respectively (P = 0.16). CMSM were more likely to require surgery (62.9%) than PI (35.8%) (P < 0.0005). The commonest surgical indications were impaired vision and radiological evidence of optic nerve compression. Over a follow-up period of 5.7 years for CMSM and 5.0 years for PI, tumour growth/recurrence occurred in 7.8% of surgically treated CMSM and 2.6% without surgery and PI, 0 and 4.9%, respectively (P = 1.0). There were no significant differences in the risk of new-onset SHD in CMSM vs PI in those who underwent surgery (P = 0.7) and those who were followed without surgery (P = 0.58). CONCLUSIONS: This novel study compares the long-term trends of PI with CMSM, highlighting the need for comprehensive baseline and long term radiological and hormonal evaluations in both entities. PMID- 29712722 TI - Melanopsin (Opn4) utilizes Galphai and Gbetagamma as major signal transducers. AB - Melanopsin (Opn4), a ubiquitously expressed photoreceptor in all classes of vertebrates, is crucial for both visual and non-visual signaling. Opn4 supports visual functions of the eye by sensing radiance levels and discriminating contrast and brightness. Non-image-forming functions of Opn4 not only regulate circadian behavior, but also control growth and development processes of the retina. It is unclear how a single photoreceptor could govern such a diverse range of physiological functions; a role in genetic hardwiring could be one explanation, but molecular and mechanistic evidence is lacking. In addition to its role in canonical Gq pathway activation, here we demonstrate that Opn4 efficiently activates Gi heterotrimers and signals through the G protein betagamma. Compared with the low levels of Gi pathway activation observed for several Gq-coupled receptors, the robust Galphai and Gbetagamma signaling of Opn4 led to both generation of PIP3 and directional migration of RAW264.7 macrophages. We propose that the ability of Opn4 to signal through Galphai and Gbetagamma subunits is a major contributor to its functional diversity. PMID- 29712724 TI - Residential proximity to livestock farms is associated with a lower prevalence of atopy. AB - OBJECTIVES: Exposure to farm environments during childhood and adult life seems to reduce the risk of atopic sensitisation. Most studies have been conducted among farmers, but people living in rural areas may have similar protective effects for atopy. This study aims to investigate the association between residential proximity to livestock farms and atopy among non-farming adults living in a rural area in the Netherlands. METHODS: We conducted a cross sectional study among 2443 adults (20-72 years). Atopy was defined as specific IgE to common allergens and/or total IgE >=100 IU/mL. Residential proximity to livestock farms was assessed as 1) distance to the nearest pig, poultry, cattle or any farm, 2) number of farms within 500 m and 1000 m, and 3) modelled annual average fine dust emissions from farms within 500 m and 1000 m. Data were analysed with multiple logistic regression and generalised additive models. RESULTS: The prevalence of atopy was 29.8%. Subjects living at short distances from farms (<327 m, first tertile) had a lower odds for atopy compared with subjects living further away (>527 m, third tertile) (OR 0.79, 95% CI 0.63 to 0.98). Significant associations in the same direction were found with distance to the nearest pig or cattle farm. The associations between atopy and livestock farm exposure were somewhat stronger in subjects who grew up on a farm. CONCLUSIONS: Living in close proximity to livestock farms seems to protect against atopy. This study provides evidence that protective effects of early-life and adult farm exposures may extend beyond farming populations. PMID- 29712723 TI - Modification by isolevuglandins, highly reactive gamma-ketoaldehydes, deleteriously alters high-density lipoprotein structure and function. AB - Cardiovascular disease risk depends on high-density lipoprotein (HDL) function, not HDL-cholesterol. Isolevuglandins (IsoLGs) are lipid dicarbonyls that react with lysine residues of proteins and phosphatidylethanolamine. IsoLG adducts are elevated in atherosclerosis. The consequences of IsoLG modification of HDL have not been studied. We hypothesized that IsoLG modification of apoA-I deleteriously alters HDL function. We determined the effect of IsoLG on HDL structure-function and whether pentylpyridoxamine (PPM), a dicarbonyl scavenger, can preserve HDL function. IsoLG adducts in HDL derived from patients with familial hypercholesterolemia (n = 10, 233.4 +/- 158.3 ng/mg) were found to be significantly higher than in healthy controls (n = 7, 90.1 +/- 33.4 pg/mg protein). Further, HDL exposed to myeloperoxidase had elevated IsoLG-lysine adducts (5.7 ng/mg protein) compared with unexposed HDL (0.5 ng/mg protein). Preincubation with PPM reduced IsoLG-lysine adducts by 67%, whereas its inactive analogue pentylpyridoxine did not. The addition of IsoLG produced apoA-I and apoA II cross-links beginning at 0.3 molar eq of IsoLG/mol of apoA-I (0.3 eq), whereas succinylaldehyde and 4-hydroxynonenal required 10 and 30 eq. IsoLG increased HDL size, generating a subpopulation of 16-23 nm. 1 eq of IsoLG decreased HDL mediated [3H]cholesterol efflux from macrophages via ABCA1, which corresponded to a decrease in HDL-apoA-I exchange from 47.4% to only 24.8%. This suggests that IsoLG inhibits apoA-I from disassociating from HDL to interact with ABCA1. The addition of 0.3 eq of IsoLG ablated HDL's ability to inhibit LPS-stimulated cytokine expression by macrophages and increased IL-1beta expression by 3.5-fold. The structural-functional effects were partially rescued with PPM scavenging. PMID- 29712725 TI - Quantitative Analysis of Complex Drug-Drug Interactions between Cerivastatin and Metabolism/Transport Inhibitors Using Physiologically Based Pharmacokinetic Modeling. AB - Cerivastatin (CER) was withdrawn from the world market because of lethal rhabdomyolysis. Coadministrations of CER and cyclosporine A (CsA) or gemfibrozil (GEM) have been reported to increase the CER blood concentration. CsA is an inhibitor of organic anion transporting polypeptide (OATP)1B1 and CYP3A4, and GEM and its glucuronide (GEM-glu) inhibit OATP1B1 and CYP2C8. The purpose of this study was to describe the transporter-/enzyme-mediated drug-drug interactions (DDIs) of CER with CsA or GEM based on unified physiologically based pharmacokinetic (PBPK) models and to investigate whether the DDIs can be quantitatively analyzed by a bottom-up approach. Initially, the PBPK models for CER and GEM/GEM-glu were constructed based on the previously reported standard protocols. Next, the drug-dependent parameters were optimized by Cluster Newton Method. Thus, described concentration-time profiles for CER and GEM/GEM-glu agreed well with the clinically observed data. The DDIs were then simulated using the established PBPK models with previously obtained in vitro inhibition constants of CsA or GEM/GEM-glu against the OATP1B1 and cytochrome P450s. DDIs with the inhibitors were underestimated compared with observed data using the geometric means of reported values. To search for better described parameters within the range of in vitro values, sensitivity analyses were performed for DDIs of CER. Using the in vitro parameter sets selected by sensitivity analyses, these DDIs were well reproduced, indicating that the present PBPK models were able to describe adequately the clinical DDIs based on a bottom-up approach. The approaches in this study would be applicable to the prediction of other DDIs involving both transporters and metabolic enzymes. PMID- 29712726 TI - Assembly of the small ribosomal subunit in yeast: mechanism and regulation. AB - The eukaryotic ribosome is made of four intricately folded ribosomal RNAs and 79 proteins. During rapid growth, yeast cells produce an incredible 2000 ribosomes every minute. Ribosome assembly involves more than 200 trans-acting factors, intervening from the transcription of the preribosomal RNA in the nucleolus to late maturation events in the cytoplasm. The biogenesis of the small ribosomal subunit, or 40S, is especially intricate, requiring more than four times the mass of the small subunit in assembly factors for its full maturation. Recent studies have provided new insights into the complex assembly of the 40S subunit. These data from cryo-electron microscopy, X-ray crystallography, and other biochemical and molecular biology methods, have elucidated the role of many factors required in small subunit maturation. Mechanisms of the regulation of ribosome assembly have also emerged from this body of work. This review aims to integrate these new results into an updated view of small subunit biogenesis and its regulation, in yeast, from transcription to the formation of the mature small subunit. PMID- 29712727 TI - The human cathelicidin antimicrobial peptide LL-37 promotes the growth of the pulmonary pathogen Aspergillus fumigatus. AB - The pulmonary mucus of cystic fibrosis (CF) patients displays elevated levels of the cathelicidin antimicrobial peptide LL-37 and the aim of this work was to assess the effect of LL-37 on the growth of Aspergillus fumigatus, a common pathogen of CF patients. Exposure of A. fumigatus to LL-37 and its derived fragment RK-31 (1.95 MUg/ml) for 24 hours had a positive effect on growth (199.94 +/- 6.172%, p < 0.05) and (218.20 +/- 4.63%, p < 0.05) respectively, whereas scrambled LL-37 peptide did not (85.12 +/- 2.92%). Exposure of 24 hour pre-formed mycelium to 5 MUg/ml intact LL-37 for 48 hours increased hyphal wet weight (4.37 +/- 0.23 g, p < 0.001) compared to the control (2.67 +/- 0.05 g) and scrambled LL 37 (2.23 +/- 0.09 g) treatments. Gliotoxin secretion was increased at 24 hours from LL-37 exposed hyphae (169.1 +/- 6.36 ng/mg hyphae, p < 0.05) compared to the control (102 +/- 18.81 ng/mg hyphae) and scrambled LL-37 (96.09 +/- 15.15 ng/mg hyphae) treatments. Shotgun proteomic analysis of 24 hour LL-37 treated hyphae revealed an increase in the abundance of proteins associated with growth (eIF-5A (16.3 fold increased), tissue degradation (aspartic endopeptidase (4.7 fold increased)) and allergic reactions (Asp F13 (10 fold increased)). By 48 hour there was an increase in proteins indicative of cellular stress (glutathione peroxidase (9 fold increased)), growth (eIF-5A (6 fold increased)), and virulence (ribonuclease mitogillin (3.7 fold increased)). These results indicate that LL-37 stimulates A. fumigatus growth and this may result in increased fungal growth and secretion of toxins in the lungs of CF patients. PMID- 29712728 TI - Acidic Mammalian Chitinase Negatively Affects Immune Responses during Acute and Chronic Aspergillus fumigatus Exposure. AB - Chitin is a polysaccharide that provides structure and rigidity to the cell walls of fungi and insects. Mammals possess multiple chitinases, which function to degrade chitin, thereby supporting a role for chitinases in immune defense. However, chitin degradation has been implicated in the pathogenesis of asthma. Here, we determined the impact of acidic mammalian chitinase (AMCase) (Chia) deficiency on host defense during acute exposure to the fungal pathogen Aspergillus fumigatus as well as its contribution to A. fumigatus-associated allergic asthma. We demonstrate that chitin in the fungal cell wall was detected at low levels in A. fumigatus conidia, which emerged at the highest level during hyphal transition. In response to acute A. fumigatus challenge, Chia-/- mice unexpectedly demonstrated lower A. fumigatus lung burdens at 2 days postchallenge. The lower fungal burden correlated with decreased lung interleukin 33 (IL-33) levels yet increased IL-1beta and prostaglandin E2 (PGE2) production, a phenotype that we reported previously to promote the induction of IL-17A and IL 22. During chronic A. fumigatus exposure, AMCase deficiency resulted in lower dynamic and airway lung resistance than in wild-type mice. Improved lung physiology correlated with attenuated levels of the proallergic chemokines CCL17 and CCL22. Surprisingly, examination of inflammatory responses during chronic exposure revealed attenuated IL-17A and IL-22 responses, but not type 2 responses, in the absence of AMCase. Collectively, these data suggest that AMCase functions as a negative regulator of immune responses during acute fungal exposure and is a contributor to fungal asthma severity, putatively via the induction of proinflammatory responses. PMID- 29712729 TI - Conservation of Intracellular Pathogenic Strategy among Distantly Related Cryptococcal Species. AB - The genus Cryptococcus includes several species pathogenic for humans. Until recently, the two major pathogenic species were recognized to be Cryptococcus neoformans and Cryptococcus gattii We compared the interaction of murine macrophages with three C. gattii species complex strains (WM179, R265, and WM161, representing molecular types VGI, VGIIa, and VGIII, respectively) and one C. neoformans species complex strain (H99, molecular type VNI) to ascertain similarities and differences in the yeast intracellular pathogenic strategy. The parameters analyzed included nonlytic exocytosis frequency, phagolysosomal pH, intracellular capsular growth, phagolysosomal membrane permeabilization, and macrophage transcriptional response, assessed using time-lapse microscopy, fluorescence microscopy, flow cytometry, and gene expression microarray analysis. The most striking result was that the intracellular pathogenic strategies of C. neoformans and C. gattii species complex strains were qualitatively similar, despite the species having separated an estimated 100 million years ago. Macrophages exhibited a leaky phagolysosomal membrane phenotype and nonlytic exocytosis when infected with either C. gattii or C. neoformans Conservation of the intracellular strategy among species that separated long ago suggests that it is ancient and possibly maintained by similar selection pressures through eons. PMID- 29712730 TI - Pulmonary Surfactant Promotes Virulence Gene Expression and Biofilm Formation in Klebsiella pneumoniae. AB - The interactions between Klebsiella pneumoniae and the host environment at the site of infection are largely unknown. Pulmonary surfactant serves as an initial point of contact for inhaled bacteria entering the lung and is thought to contain molecular cues that aid colonization and pathogenesis. To gain insight into this ecological transition, we characterized the transcriptional response of K. pneumoniae MGH 78578 to purified pulmonary surfactant. This work revealed changes within the K. pneumoniae transcriptome that likely contribute to host colonization, adaptation, and virulence in vivo Notable transcripts expressed under these conditions include genes involved in capsule synthesis, lipopolysaccharide modification, antibiotic resistance, biofilm formation, and metabolism. In addition, we tested the contributions of other surfactant-induced transcripts to K. pneumoniae survival using engineered isogenic KPPR1 deletion strains in a murine model of acute pneumonia. In these infection studies, we identified the MdtJI polyamine efflux pump and the ProU glycine betaine ABC transporter to be significant mediators of K. pneumoniae survival within the lung and confirmed previous evidence for the importance of de novo leucine synthesis to bacterial survival during infection. Finally, we determined that pulmonary surfactant promoted type 3 fimbria-mediated biofilm formation in K. pneumoniae and identified two surfactant constituents, phosphatidylcholine and cholesterol, that drive this response. This study provides novel insight into the interactions occurring between K. pneumoniae and the host at an important infection site and demonstrates the utility of purified lung surfactant preparations for dissecting host-lung pathogen interactions in vitro. PMID- 29712731 TI - Characterization of Chlamydial Rho and the Role of Rho-Mediated Transcriptional Polarity during Interferon Gamma-Mediated Tryptophan Limitation. AB - As an obligate intracellular, developmentally regulated bacterium, Chlamydia is sensitive to amino acid fluctuations within its host cell. When human epithelial cells are treated with the cytokine interferon gamma (IFN-gamma), the tryptophan (Trp)-degrading enzyme, indoleamine-2,3-dioxygenase, is induced. Chlamydiae within such cells are starved for Trp and enter a state of so-called persistence. Chlamydia lacks the stringent response used by many eubacteria to respond to this stress. Unusually, chlamydial transcription is globally elevated during Trp starvation with transcripts for Trp codon-containing genes disproportionately increased. Yet, the presence of Trp codons destabilized 3' ends of transcripts in operons or large genes. We initially hypothesized that ribosome stalling on Trp codons rendered the 3' ends sensitive to RNase activity. The half-life of chlamydial transcripts containing different numbers of Trp codons was thus measured in untreated and IFN-gamma-treated infected cells to determine whether Trp codons influenced the stability of transcripts. However, no effect of Trp codon content was detected. Therefore, we investigated whether Rho-dependent transcription termination could play a role in mediating transcript instability. Rho is expressed as a midcycle gene product, interacts with itself as predicted, and is present in all chlamydial species. Inhibition of Rho via the Rho-specific antibiotic, bicyclomycin, and overexpression of Rho are detrimental to chlamydiae. Finally, when we measured transcript abundance 3' to Trp codons in the presence of bicyclomycin, we observed that transcript abundance increased. These data are the first to demonstrate the importance of Rho in Chlamydia and the role of Rho-dependent transcription polarity during persistence. PMID- 29712733 TI - Condensins under the microscope. AB - Condensins are key players in mitotic chromosome condensation. Using an elegant combination of state-of-the-art imaging techniques, Walther et al. (2018. J. Cell Biol. https://doi.org/10.1083/jcb.201801048) counted the number of Condensins, examined their behaviors on human mitotic chromosomes, and integrated the quantitative data to propose a new mechanistic model for chromosome condensation. PMID- 29712734 TI - Centrobin is essential for C-tubule assembly and flagellum development in Drosophila melanogaster spermatogenesis. AB - Centrobin homologues identified in different species localize on daughter centrioles. In Drosophila melanogaster sensory neurons, Centrobin (referred to as CNB in Drosophila) inhibits basal body function. These data open the question of CNB's role in spermatocytes, where daughter and mother centrioles become basal bodies. In this study, we report that in these cells, CNB localizes equally to mother and daughter centrioles and is essential for C-tubules to attain the right position and remain attached to B-tubules as well as for centrioles to grow in length. CNB appears to be dispensable for meiosis, but flagellum development is severely compromised in Cnb mutant males. Remarkably, three N-terminal POLO phosphorylation sites that are critical for CNB function in neuroblasts are dispensable for spermatogenesis. Our results underpin the multifunctional nature of CNB that plays different roles in different cell types in Drosophila, and they identify CNB as an essential component for C-tubule assembly and flagellum development in Drosophila spermatogenesis. PMID- 29712732 TI - Sirtuins in Renal Health and Disease. AB - Sirtuins belong to an evolutionarily conserved family of NAD+-dependent deacetylases that share multiple cellular functions related to proliferation, DNA repair, mitochondrial energy homeostasis, and antioxidant activity. Mammalians express seven sirtuins (SIRT1-7) that are localized in different subcellular compartments. Changes in sirtuin expression are critical in several diseases, including metabolic syndrome, diabetes, cancer, and aging. In the kidney, the most widely studied sirtuin is SIRT1, which exerts cytoprotective effects by inhibiting cell apoptosis, inflammation, and fibrosis together with SIRT3, a crucial metabolic sensor that regulates ATP generation and mitochondrial adaptive response to stress. Here, we provide an overview of the biologic effects of sirtuins and the molecular targets thereof regulating renal physiology. This review also details progress made in understanding the effect of sirtuins in the pathophysiology of chronic and acute kidney diseases, highlighting the key role of SIRT1, SIRT3, and now SIRT6 as potential therapeutic targets. In this context, the current pharmacologic approaches to enhancing the activity of SIRT1 and SIRT3 will be discussed. PMID- 29712735 TI - Uncoordinated centrosome cycle underlies the instability of non-diploid somatic cells in mammals. AB - In animals, somatic cells are usually diploid and are unstable when haploid for unknown reasons. In this study, by comparing isogenic human cell lines with different ploidies, we found frequent centrosome loss specifically in the haploid state, which profoundly contributed to haploid instability through subsequent mitotic defects. We also found that the efficiency of centriole licensing and duplication changes proportionally to ploidy level, whereas that of DNA replication stays constant. This caused gradual loss or frequent overduplication of centrioles in haploid and tetraploid cells, respectively. Centriole licensing efficiency seemed to be modulated by astral microtubules, whose development scaled with ploidy level, and artificial enhancement of aster formation in haploid cells restored centriole licensing efficiency to diploid levels. The ploidy-centrosome link was observed in different mammalian cell types. We propose that incompatibility between the centrosome duplication and DNA replication cycles arising from different scaling properties of these bioprocesses upon ploidy changes underlies the instability of non-diploid somatic cells in mammals. PMID- 29712736 TI - Association of Pulse Wave Velocity With Chronic Kidney Disease Progression and Mortality: Findings From the CRIC Study (Chronic Renal Insufficiency Cohort). AB - Patients with chronic kidney diseases (CKDs) are at risk for further loss of kidney function and death, which occur despite reasonable blood pressure treatment. To determine whether arterial stiffness influences CKD progression and death, independent of blood pressure, we conducted a prospective cohort study of CKD patients enrolled in the CRIC study (Chronic Renal Insufficiency Cohort). Using carotid-femoral pulse wave velocity (PWV), we examined the relationship between PWV and end-stage kidney disease (ESRD), ESRD or halving of estimated glomerular filtration rate, or death from any cause. The 2795 participants we enrolled had a mean age of 60 years, 56.4% were men, 47.3% had diabetes mellitus, and the average estimated glomerular filtration rate at entry was 44.4 mL/min per 1.73 m2 During follow-up, there were 504 ESRD events, 628 ESRD or halving of estimated glomerular filtration rate events, and 394 deaths. Patients with the highest tertile of PWV (>10.3 m/s) were at higher risk for ESRD (hazard ratio [95% confidence interval], 1.37 [1.05-1.80]), ESRD or 50% decline in estimated glomerular filtration rate (hazard ratio [95% confidence interval], 1.25 [0.98 1.58]), or death (hazard ratio [95% confidence interval], 1.72 [1.24-2.38]). PWV is a significant predictor of CKD progression and death in people with impaired kidney function. Incorporation of PWV measurements may help define better the risks for these important health outcomes in patients with CKDs. Interventions that reduce aortic stiffness deserve study in people with CKD. PMID- 29712737 TI - FGF23 (Fibroblast Growth Factor-23) and Incident Hypertension in Young and Middle Aged Adults: The CARDIA Study. AB - Blacks have the highest prevalence of hypertension in the United States. Higher levels of FGF23 (fibroblast growth factor-23) have been associated with worse cardiovascular outcomes. Whether FGF23 is associated with rising blood pressure (BP) and racial differences in incident hypertension is unclear. We studied 1758 adults (45.0+/-3.7 years; 57.8% female; 36.9% black) without hypertension or cardiovascular disease who participated in the year 20 (2005-2006) follow-up examination of the CARDIA study (Coronary Artery Risk Development in Young Adults). We investigated the associations of baseline (year 20) cFGF23 (C terminal FGF23) levels with longitudinal BP patterns and incident hypertension (defined as being on antihypertensive medication, systolic BP >=130 or diastolic BP >=80 mm Hg) during 2 follow-up visits (years 25 and 30). During follow-up, 35.2% of participants developed hypertension. In multivariable linear mixed models, there were greater increases in systolic BP from year 20 to 25 and year 25 to 30 in the highest FGF23 quartile relative to the lowest quartile (+2.1 mm Hg, P=0.0057 and +2.2 mm Hg, P=0.0108, respectively for each time period), whereas there were greater increases in diastolic BP from year 20 to 25 in the highest quartile relative to the lowest (+1.6 mm Hg; P=0.0024). In multivariable modified Poisson regression analyses, the highest FGF23 quartile was associated with a 45% greater risk of developing hypertension during follow-up compared with the lowest quartile (relative risk, 1.45 [1.18-1.77]). Results did not vary by race (Pinteraction=0.1523). Higher FGF23 levels are independently associated with rising BP over time and an increased risk of incident hypertension but not racial differences in hypertension. PMID- 29712739 TI - Pulse Wave Velocity and Prognosis in End-Stage Kidney Disease. AB - High pulse wave velocity (PWV) is a hallmark of end-stage kidney disease (ESKD) where it is considered useful for risk stratification. We investigated whether PWV adds meaningful prognostic information to 2 simple, well-validated, clinical risk scores specific to ESKD (the Annualized Rate of Occurrence scores) for predicting all-cause and cardiovascular mortality by applying state-of-the-art prognostic tests including discrimination (Harrell C-index), risk reclassification (integrated discrimination improvement), and calibration. We performed these analyses in the 2 largest ESKD cohorts with available PWV data, the Manhes-Hospital cohort in Paris (n=287 patients) and the Quebec Research Center cohort in Canada (n=246 patients). The Harrell C-index of the 2 clinical risk scores was consistently higher than that by PWV both for all-cause (Manhes cohort, 77.5% versus 73.7%; Quebec cohort, 61.5% versus 58.9%) and cardiovascular mortality (Manhes cohort, 77.9% versus 77.2%; Quebec cohort, 63.8% versus 60.3%). Furthermore, PWV provided a very modest increase in discriminatory power over and above clinical risk scores by Harrell C-index (from 0.5% to 1.8%) and in risk reclassification by Integrated Discrimination Improvement (from 0.9% to 5.1%) and actually worsened models calibration. In patients with ESKD, PWV has a prognostic power for all-cause and cardiovascular mortality inferior to that by simple clinical risk scores and only modestly improves the risk discrimination and reclassification by the same risk scores and worsens models calibration. Clinicians may better rely on available clinical risk scores rather than on PWV for risk stratification in the ESKD population. PMID- 29712738 TI - Involvement of Neuroinflammation in the Pathogenesis of Monocrotaline-Induced Pulmonary Hypertension. AB - Pulmonary hypertension (PH) is a devastating disease and its successful treatment remains to be accomplished despite recent advances in pharmacotherapy. It has been proposed that PH be considered as a systemic disease, rather than primarily a disease of the pulmonary vasculature. Consequently, an investigation of the intricate interplay between multiple organs such as brain, vasculature, and lung in PH could lead to the identification of new targets for its therapy. However, little is known about this interplay. This study was undertaken to examine the concept that altered autonomic-pulmonary communication is important in PH pathophysiology. Therefore, we hypothesize that activation of microglial cells in the paraventricular nucleus of hypothalamus and neuroinflammation is associated with increased sympathetic drive and pulmonary pathophysiology contributing to PH. We utilized the monocrotaline rat model for PH and intracerebroventricular administration of minocycline for inhibition of microglial cells activation to investigate this hypothesis. Hemodynamic, echocardiographic, histological, immunohistochemical, and confocal microscopic techniques assessed cardiac and pulmonary function and microglial cells. Monocrotaline treatment caused cardiac and pulmonary pathophysiology associated with PH. There were also increased activated microglial cells and mRNA for proinflammatory cytokines (IL [interleukin]-1beta, IL-6, and TNF [tumor necrosis factor]-alpha) in the paraventricular nucleus. Furthermore, increased sympathetic drive and plasma norepinephrine were observed in rats with PH. Intracerebroventricular infusion of minocycline inhibited all these parameters and significantly attenuated PH. These observations implicate a dysfunctional autonomic-lung communication in the development and progression of PH providing new therapeutic targets, such as neuroinflammation, for PH therapy. PMID- 29712740 TI - Beneficial Effects of High Potassium: Contribution of Renal Basolateral K+ Channels. PMID- 29712741 TI - Cystathionine gamma-Lyase-Produced Hydrogen Sulfide Controls Endothelial NO Bioavailability and Blood Pressure. AB - Hydrogen sulfide (H2S) and NO are important gasotransmitters, but how endogenous H2S affects the circulatory system has remained incompletely understood. Here, we show that CTH or CSE (cystathionine gamma-lyase)-produced H2S scavenges vascular NO and controls its endogenous levels in peripheral arteries, which contribute to blood pressure regulation. Furthermore, eNOS (endothelial NO synthase) and phospho-eNOS protein levels were unaffected, but levels of nitroxyl were low in CTH-deficient arteries, demonstrating reduced direct chemical interaction between H2S and NO. Pretreatment of arterial rings from CTH-deficient mice with exogenous H2S donor rescued the endothelial vasorelaxant response and decreased tissue NO levels. Our discovery that CTH-produced H2S inhibits endogenous endothelial NO bioavailability and vascular tone is novel and fundamentally important for understanding how regulation of vascular tone is tailored for endogenous H2S to contribute to systemic blood pressure function. PMID- 29712742 TI - Persistent Organochlorine Pollutants in Plasma, Blood Pressure, and Hypertension in a Longitudinal Study. AB - Persistent organochlorine pollutants (POPs) have shown to be involved in the atherosclerotic process and to cause endothelial cell dysfunction. To assess longitudinally whether plasma concentrations of different POPs were associated with blood pressure and risk of hypertension in middle-aged women and men. Study subjects were 850 participants in the VIP (Vasterbotten Intervention Programme) with 2 blood samples and blood pressure measurements, 10 years apart, during 1990 to 2003 (baseline) and during 2000 to 2013 (follow-up). Dioxin-like and nondioxin like polychlorinated biphenyls (DL-PCBs, NDL-PCBs) and p,p' dichlorodiphenyldichloroethylene (DDE) were measured. Associations were assessed using generalized estimating equations. At baseline sampling 49% and at follow-up 64% had hypertension. DL-PCBs and DDE, but not NDL-PCBs or hexachlorobenzene, were associated with hypertension. Only the association for DL-PCBs remained statistically significant after lipid-standardization and adjustment for body mass index and total serum lipids. The multivariable-adjusted odds ratio of hypertension based on repeated measurements were 1.52 (95% confidence interval, 1.08-2.13) for DL-PCBs (third versus first tertile of lipid-standardized POPs). In stratified adjusted analyses, odds ratio for those born after 1950 increased to 3.99 (95% confidence interval, 2.15-7.43), whereas no association was observed among those born earlier. Based on repeated measurements, the accumulated exposure to DL-PCBs and DDE, although less clear for the latter, may disrupt the normal blood pressure levels and increase the odds of hypertension. Moreover, individuals experiencing early-life POP exposure may be at elevated risk of vascular POP effects. PMID- 29712743 TI - Impact of Pituitary-Gonadal Axis Hormones on Pulmonary Arterial Hypertension in Men. AB - The association of sex hormone (estradiol, testosterone, and progesterone) with cardiopulmonary disease has already attracted great attention, especially in pulmonary arterial hypertension (PAH). However, the impact of sex hormones and their pituitary stimulators (follicle-stimulating hormone and luteinizing hormone) on PAH in men remains unclear. We conducted a prospective cohort study recruiting 95 patients with idiopathic PAH from 2008 to 2014 and following up for a median of 65 months for death. Compared with control, abnormal plasma levels of sex hormones were more common in patients with PAH. Higher estradiol and estradiol/testosterone levels were associated with risk of PAH diagnosis (odds ratio per ln estradiol, 3.55; P<0.001; odds ratio per ln estradiol/testosterone, 4.30; P<0.001), whereas higher testosterone and progesterone were associated with a reduced risk (odds ratio per ln testosterone, 0.48; P=0.003; odds ratio per ln progesterone, 0.09; P<0.001). Fifty patients died during follow-up. Men with higher estradiol had increased mortality (hazard ratio per ln estradiol, 2.02; P=0.007), even after adjustment for baseline characteristics and PAH treatment. According to receiver operating characteristic analysis, patients with PAH with higher estradiol level (>=145.55 pmol/L) had worse 5-year survival rate compared with those with lower estradiol (38.6% versus 68.2%; log-rank test P=0.001). Therefore, our data show higher estradiol, estradiol/testosterone ratio, lower testosterone, and progesterone were associated with increased risk of PAH. Meanwhile, higher estradiol was independently associated with higher mortality in men with PAH. Further studies are needed to explain the origin of these hormonal derangements and their potential pathophysiological implications in PAH. PMID- 29712744 TI - Vascular Cell Glycocalyx-Mediated Vascular Remodeling Induced by Hemodynamic Environmental Alteration. AB - Vascular remodeling induced by hemodynamic stimuli contributes to the pathophysiology of cardiovascular diseases. The importance of vascular cells (endothelial cells and smooth muscle cells) glycocalyx in the mechanotransduction of flow-induced shear stress at the cellular and molecular levels has been demonstrated over the past decade. However, its potential mechanotransduction role in vascular remodeling has triggered little attention. In the present study, a home-made apparatus was used to expose the rat abdominal aorta to sterile, flow or no flow, normal-pressure or high-pressure conditions for 4 days. The histomophometric, cellular, and molecular analysis of vessels were performed. The results showed that after exposing the vessels in the flow and high-pressure condition, the apoptotic rate, the cell number, and the RNA level of contractile marker gene smooth muscle 22 of smooth muscle cells were significantly increased, whereas the expression of nitric oxide synthase, alpha-smooth muscle actin, smoothelin, and calponion showed no significant differences compared with the flow and normal-pressure groups. Moreover, the histomophometric analysis of vascular walls suggested a remodeling induced by flow and high-pressure loading consistent with the classic hypertensive aortic phenotype, which is characterized by a thicker and more rigid vascular wall as well as increased aortic diameter. However, those phenomena were totally abolished after compromising the integrity of glycocalyx by the treatment of vessels with hyaluronidase, which provided evidence of the important mechanotransduction role of the vascular cells glycocalyx in vascular remodeling induced by hemodynamic stimuli. PMID- 29712746 TI - Nocturnal Hypertension: New Technology and Evidence. PMID- 29712745 TI - Impact of Intensive Versus Standard Blood Pressure Management by Tertiles of Blood Pressure in SPRINT (Systolic Blood Pressure Intervention Trial). AB - Intensive systolic blood pressure (SBP) control improved outcomes in SPRINT (Systolic Blood Pressure Intervention Trial). Our objective was to expand on reported findings by analysis of baseline characteristics, primary outcomes, adverse events, follow-up blood pressure, and medication use differences by baseline SBP (tertile 1 [T1], <132; tertile 2 [T2], 132-145; and tertile 3 [T3], >145 mm Hg). Participants with higher baseline SBP tertile were more often women and older, had higher cardiovascular risk, and lower utilization of antihypertensive medications, statins, and aspirin. Achieved SBP in both treatment arms was slightly higher in T2 and T3 compared with T1 and fewer in the T3 groups achieved SBP targets compared with T1 and T2 groups. The primary composite outcome with intensive versus standard SBP treatment was reduced by 30% in T1, 23% in T2, and 17% in T3 with no evidence of an interaction (P=0.77). Event rates were lower in the intensive arm, and there was no evidence that this benefit differed by SBP tertile. There was no difference in the hazard for serious adverse events in any of the 3 tertiles. Medication utilization differed across the SBP tertiles at baseline with a lesser percentage of diuretics and angiotensin-converting enzyme inhibitors/angiotensin receptor blocker drugs in the higher tertiles-a finding that reversed during the trial. The beneficial effects of intensive SBP lowering were not modified by the level of baseline SBP. Within the parameters of this population, these findings add support for clinicians to treat blood pressure to goal irrespective of baseline SBP. PMID- 29712747 TI - Holding tight to feathers - structural specializations and attachment properties of the avian ectoparasite Crataerina pallida (Diptera, Hippoboscidae). AB - The louse fly Crataerina pallida is an obligate blood-sucking ectoparasite of the common swift Apus apus As a result of reduction of the wings, C. pallida is unable to fly; thus, an effective and reliable attachment to their host's plumage is of utmost importance. The attachment system of C. pallida shows several modifications in comparison to that of other calyptrate flies, notably the large tridentate claws and the dichotomously shaped setae located on the pulvilli. Based on data from morphological analysis, confocal laser scanning microscopy, cryo-scanning electron microscopy and attachment force experiments performed on native (feathers) as well as artificial substrates (glass, epoxy resin and silicone rubber), we showed that the entire attachment system is highly adapted to the fly's lifestyle as an ectoparasite. The claws in particular are the main contributor to strong attachment to the host. Resulting attachment forces on feathers make it impossible to detach C. pallida without damage to the feathers or to the legs of the louse fly itself. Well-developed pulvilli are responsible for the attachment to smooth surfaces. Both dichotomously shaped setae and high setal density explain high attachment forces observed on smooth substrates. For the first time, we demonstrate a material gradient within the setae, with soft, resilin-dominated apical tips and stiff, more sclerotized bases in Diptera. The empodium seems not to be directly involved in the attachment process, but it might operate as a cleaning device and may be essential to maintain the functionality of the entire attachment system. PMID- 29712748 TI - Kleptoplast photoacclimation state modulates the photobehaviour of the solar powered sea slug Elysia viridis. AB - Some sacoglossan sea slugs incorporate intracellular functional algal chloroplasts (kleptoplasty) for periods ranging from a few days to several months. Whether this association modulates the photobehaviour of solar-powered sea slugs is unknown. In this study, the long-term kleptoplast retention species Elysia viridis showed avoidance of dark independently of light acclimation state. In contrast, Placida dendritica, which shows non-functional retention of kleptoplasts, showed no preference over dark, low or high light. High light acclimated (HLac) E. viridis showed a higher preference for high light than low light-acclimated (LLac) conspecifics. The position of the lateral folds (parapodia) was modulated by irradiance, with increasing light levels leading to a closure of parapodia and protection of kleptoplasts from high light exposure. Furthermore, closure of parapodia occurred at higher irradiance in HLacE. viridis Our results strongly indicate that kleptoplast photoacclimation state modulates the photobehaviour of the solar-powered sea slug E. viridis. PMID- 29712749 TI - Non-linear amplification of graded voltage signals in the first-order visual interneurons of the butterfly Papilio xuthus. AB - Lamina monopolar cells (LMCs) are the first-order visual interneurons of insects and crustacea, primarily involved in achromatic vision. Here, we investigated morphological and electrophysiological properties of LMCs in the butterfly Papilio xuthus Using intracellular recording coupled with dye injection, we found two types of LMCs. Cells with roundish terminals near the distal surface of the medulla demonstrating no or small depolarizing spikes were classified as L1/2. Cells with elongated terminals deep in the medulla that showed prominent spiking were classified as L3/4. The majority of LMCs of both types had broad spectral sensitivities, peaking between 480 and 570 nm. Depending on the experimental conditions, spikes varied from small to action potential-like events, with their amplitudes and rates decreasing as stimulus brightness increased. When the eye was stimulated with naturalistic contrast-modulated time series, spikes were reliably triggered by high-contrast components of the stimulus. Spike-triggered average functions showed that spikes emphasize rapid membrane depolarizations. Our results suggest that spikes are mediated by voltage-activated Na+ channels, which are mainly inactivated at rest. Strong local minima in the coherence functions of spiking LMCs indicate that the depolarizing conductance contributes to the amplification of graded responses even when detectable spikes are not evoked. We propose that the information transfer strategies of spiking LMCs change with light intensity. In dim light, both graded voltage signals and large spikes are used together without mutual interference, as a result of separate transmission bandwidths. In bright light, signals are non-linearly amplified by the depolarizing conductance in the absence of detectable spikes. PMID- 29712750 TI - X-ray computed tomography study of the flight-adapted tracheal system in the blowfly Calliphora vicina, analysing the ventilation mechanism and flow-directing valves. AB - Following the discovery of flight motor-driven unidirectional gas exchange with rising PO2 in the blowfly, X-ray computed tomography (CT) was used to visualize the organization of the tracheal system in the anterior body with emphasis on the arrangement of the pathways for airflow. The fly's head is preferentially supplied by cephalic tracheae originating from the ventral orifice of the mesothoracic spiracle (Sp1). The respiratory airflow during flight is a by product of cyclic deformations of the thoracic box by the flight muscles. The air sacs below the tergal integument (scutum and scutellum) facilitate the respiratory airflow: the shortening of the thorax turns the scutellum and the wings downward and the scutum upward with a volume increase in the scutal air sacs. The resulting negative pressure sucks air from Sp1 through special tracheae towards the scutal air sacs. The airflow is directed by two valves that open alternately: (1) the hinged filter flaps of the metathoracic spiracles (Sp2) are passively pushed open during the upstroke by the increased tracheal pressure, thereby enabling expiration; (2) a newly described tracheal valve-like septum behind the regular spiracular valve lids of Sp1 opens passively and air is sucked in through Sp1 during the downstroke and prevents expiration by closing during the upstroke. This stabilizes the unidirectional airflow. The tracheal volume of the head, thorax and abdomen and their mass were determined. Despite the different anatomy of birds and flies, the unidirectional airflow reveals a comparable efficiency of the temporal throughput in flies and hummingbirds. PMID- 29712752 TI - Molecular dissection of a natural transposable element invasion. AB - The first tracking of the dynamics of a natural invasion by a transposable element (TE) provides unprecedented details on the establishment of host defense mechanisms against TEs. We captured a D. simulans population at an early stage of a P-element invasion and studied the spread of the TE in replicated experimentally evolving populations kept under hot and cold conditions. We analyzed the factors controlling the invasion by NGS, RNA-FISH, and gonadal dysgenesis assays. Under hot conditions, the P-element spread rapidly for 20 generations, but no further spread was noted later on. This plateauing of the invasion was mediated by the rapid emergence of P-element-specific piRNAs. Under cold conditions, we observed a lower expression of the P-element and a slower emergence of the piRNA defense, resulting in a three times slower invasion that continued beyond 40 generations. We conclude that the environment is a major factor determining the evolution of TEs in their host. PMID- 29712753 TI - Birth, evolution, and transmission of satellite-free mammalian centromeric domains. AB - Mammalian centromeres are associated with highly repetitive DNA (satellite DNA), which has so far hindered molecular analysis of this chromatin domain. Centromeres are epigenetically specified, and binding of the CENPA protein is their main determinant. In previous work, we described the first example of a natural satellite-free centromere on Equus caballus Chromosome 11. Here, we investigated the satellite-free centromeres of Equus asinus by using ChIP-seq with anti-CENPA antibodies. We identified an extraordinarily high number of centromeres lacking satellite DNA (16 of 31). All of them lay in LINE- and AT rich regions. A subset of these centromeres is associated with DNA amplification. The location of CENPA binding domains can vary in different individuals, giving rise to epialleles. The analysis of epiallele transmission in hybrids (three mules and one hinny) showed that centromeric domains are inherited as Mendelian traits, but their position can slide in one generation. Conversely, centromere location is stable during mitotic propagation of cultured cells. Our results demonstrate that the presence of more than half of centromeres void of satellite DNA is compatible with genome stability and species survival. The presence of amplified DNA at some centromeres suggests that these arrays may represent an intermediate stage toward satellite DNA formation during evolution. The fact that CENPA binding domains can move within relatively restricted regions (a few hundred kilobases) suggests that the centromeric function is physically limited by epigenetic boundaries. PMID- 29712754 TI - Arrayed CRISPR screen with image-based assay reliably uncovers host genes required for coxsackievirus infection. AB - Pooled CRISPR screens based on lentiviral systems have been widely applied to identify the effect of gene knockout on cellular phenotype. Although many screens were successful, they also have the limitation that genes conferring mild phenotypes or those essential for growth can be overlooked, as every genetic perturbation is incorporated in the same population. Arrayed screens, on the other hand, incorporate a single genetic perturbation in each well and could overcome these limitations. However, arrayed screens based on siRNA-mediated knockdown were recently criticized for low reproducibility caused by incomplete inhibition of gene expression. To overcome these limitations, we developed a novel arrayed CRISPR screen based on a plasmid library expressing a single guide RNA (sgRNA) and disrupted 1514 genes, encoding kinases, proteins related to endocytosis, and Golgi-localized proteins, individually using 4542 sgRNAs (three sgRNAs per gene). This screen revealed host factors required for infection by coxsackievirus B3 (CVB3) from Picornaviridae, which includes human pathogens causing diverse diseases. Many host factors that had been overlooked in a conventional pooled screen were identified for CVB3 infection, including entry related factors, translational initiation factors, and several replication factors with different functions, demonstrating the advantage of the arrayed screen. This screen was quite reliable and reproducible, as most genes identified in the primary screen were confirmed in secondary screens. Moreover, ACBD3, whose phenotype was not affected by siRNA-mediated knockdown, was reliably identified. We propose that arrayed CRISPR screens based on sgRNA plasmid libraries are powerful tools for arrayed genetic screening and applicable to larger-scale screens. PMID- 29712755 TI - A comparative transcriptional landscape of maize and sorghum obtained by single molecule sequencing. AB - Maize and sorghum are both important crops with similar overall plant architectures, but they have key differences, especially in regard to their inflorescences. To better understand these two organisms at the molecular level, we compared expression profiles of both protein-coding and noncoding transcripts in 11 matched tissues using single-molecule, long-read, deep RNA sequencing. This comparative analysis revealed large numbers of novel isoforms in both species. Evolutionarily young genes were likely to be generated in reproductive tissues and usually had fewer isoforms than old genes. We also observed similarities and differences in alternative splicing patterns and activities, both among tissues and between species. The maize subgenomes exhibited no bias in isoform generation; however, genes in the B genome were more highly expressed in pollen tissue, whereas genes in the A genome were more highly expressed in endosperm. We also identified a number of splicing events conserved between maize and sorghum. In addition, we generated comprehensive and high-resolution maps of poly(A) sites, revealing similarities and differences in mRNA cleavage between the two species. Overall, our results reveal considerable splicing and expression diversity between sorghum and maize, well beyond what was reported in previous studies, likely reflecting the differences in architecture between these two species. PMID- 29712756 TI - TOR Facilitates the Targeting of the 19S Proteasome Subcomplex To Enhance Transcription Complex Assembly at the Promoters of the Ribosomal Protein Genes. AB - TOR (target of rapamycin) has been previously implicated in transcriptional stimulation of the ribosomal protein (RP) genes via enhanced recruitment of NuA4 (nucleosome acetyltransferase of H4) to the promoters. However, it is not clearly understood how TOR enhances NuA4 recruitment to the promoters of the RP genes. Here we show that TOR facilitates the recruitment of the 19S proteasome subcomplex to the activator to enhance the targeting of NuA4 to the promoters of the RP genes. NuA4, in turn, promotes the recruitment of TFIID (transcription factor IID, composed of TATA box-binding protein [TBP] and a set of TBP associated factors [TAFs]) and RNA polymerase II to the promoters of the RP genes to enhance transcriptional initiation. Therefore, our results demonstrate that TOR facilitates the recruitment of the 19S proteasome subcomplex to the promoters of the RP genes to promote the targeting of NuA4 for enhanced preinitiation complex (PIC) formation and consequently transcriptional initiation, hence illuminating TOR regulation of RP gene activation. Further, our results reveal that TOR differentially regulates PIC formation (and hence transcription) at the non-RP genes, thus demonstrating a complex regulation of gene activation by TOR. PMID- 29712757 TI - Defective Flux of Thrombospondin-4 through the Secretory Pathway Impairs Cardiomyocyte Membrane Stability and Causes Cardiomyopathy. AB - Thrombospondins are stress-inducible secreted glycoproteins with critical functions in tissue injury and healing. Thrombospondin-4 (Thbs4) is protective in cardiac and skeletal muscle where it activates an adaptive endoplasmic reticulum (ER) stress-response, induces expansion of the ER, and enhances sarcolemmal stability. However, it is unclear if Thbs4 has these protective functions from within the cell, from the extracellular matrix, or from the secretion process itself. Here we generated transgenic mice with cardiac-specific overexpression of a secretion-defective mutant of Thbs4 to evaluate its exclusive intracellular and secretion-dependent functions. Like wild-type Thbs4, the secretion-defective mutant upregulates the adaptive ER stress response and expands the ER and intracellular vesicles in cardiomyocytes. However, only the secretion-defective Thbs4 mutant produces cardiomyopathy with sarcolemmal weakness and rupture that is associated with reduced adhesion-forming glycoproteins in the membrane. Similarly, deletion of Thbs4 in the mdx mouse model of Duchenne muscular dystrophy enhances cardiomyocyte membrane instability and cardiomyopathy. Finally, overexpression of the secretion-defective Thbs4 mutant in Drosophila, but not wild-type Thbs4, impaired muscle function and sarcomere alignment. These results suggest that transit through the secretory pathway is required for Thbs4 to augment sarcolemmal stability, while ER stress induction and vesicular expansion mediated by Thbs4 is an exclusively intracellular process. PMID- 29712759 TI - Authors' Response Sedation Safety Has Many Perspectives, and the Discussion is Ongoing. PMID- 29712758 TI - MicroRNA 33 Regulates the Population of Peripheral Inflammatory Ly6Chigh Monocytes through Dual Pathways. AB - MicroRNA 33 (miR-33) targets ATP-binding cassette transporter A1 (ABCA1), and its deficiency increases serum high-density lipoprotein (HDL)-cholesterol (HDL-C) and ameliorates atherosclerosis. Although we previously reported that miR-33 deficiency increased peripheral Ly6Chigh monocytes on an ApoE-deficient background, the effect of miR-33 on the monocyte population has not been fully elucidated, especially in a wild-type (WT) background. We found that Ly6Chigh monocytes in miR-33-/- mice were decreased in peripheral blood and increased in bone marrow (BM). Expansion of myeloid progenitors and decreased apoptosis in Lin Sca1+ c-Kit+ (LSK) cells were observed in miR-33-/- mice. A BM transplantation study and competitive repopulation assay revealed that hematopoietic miR-33 deficiency caused myeloid expansion and increased peripheral Ly6Chigh monocytes and that nonhematopoietic miR-33 deficiency caused reduced peripheral Ly6Chigh monocytes. Expression of high-mobility group AT-hook 2 (HMGA2) targeted by miR-33 increased in miR-33-deficient LSK cells, and its knockdown abolished the reduction of apoptosis. Transduction of human apolipoprotein A1 and ABCA1 in WT mouse liver increased HDL-C and reduced peripheral Ly6Chigh monocytes. These data indicate that miR-33 deficiency affects distribution of inflammatory monocytes through dual pathways. One pathway involves the enhancement of Hmga2 expression in hematopoietic stem cells to increase Ly6Chigh monocytes, and the other involves the elevation of HDL-C to decrease peripheral Ly6Chigh monocytes. PMID- 29712760 TI - Author Response. PMID- 29712761 TI - Concerns About the Study "Congenital Heart Surgery on In-Hospital Mortality in Trisomy 13 and 18". PMID- 29712762 TI - The Tobacco Industry and Children's Rights. AB - The manufacture, use, and marketing of tobacco present a serious threat to children's right to health. This makes the Convention on the Rights of the Child a potentially powerful tobacco-control tool and the United Nations Children's Fund (UNICEF), which oversees the convention's implementation, a potential leader in tobacco control. UNICEF actively supported tobacco control initiatives in the late 1990s, but since the early 2000s UNICEF's role in tobacco control has been minimal. Using the Truth Tobacco Industry Documents library, an online collection of previously secret tobacco industry documents, we sought to uncover information on the tobacco industry's ties with UNICEF. We found that from 1997 to 2000, when UNICEF was actively promoting tobacco control to support children's rights, the tobacco industry saw children's rights and UNICEF as potentially powerful threats to business that needed to be closely monitored and neutralized. The industry then positioned itself as a partner with UNICEF on youth smoking prevention initiatives as a way to avoid meaningful tobacco control measures that could save children's lives. After UNICEF's corporate engagement guidelines were loosened in 2003, tobacco companies successfully engaged with UNICEF directly and via front groups, including the Eliminating Child Labour in Tobacco Growing Foundation. This was part of an overall tobacco industry strategy to improve its corporate image, infiltrate the United Nations, and weaken global tobacco-control efforts. As part of its mission to protect children's rights, UNICEF should end all partnerships with the tobacco industry and its front groups. PMID- 29712763 TI - School Bus Transportation of Children With Special Health Care Needs. AB - School systems are responsible for ensuring that children with special needs are safely transported on all forms of federally approved transportation provided by the school system. A plan to provide the most current and proper support to children with special transportation needs should be developed by the Individualized Education Program team, including the parent, school transportation director, and school nurse, in conjunction with physician orders and recommendations. With this statement, we provide current guidance for the protection of child passengers with specific health care needs. Guidance that applies to general school transportation should be followed, inclusive of staff training, provision of nurses or aides if needed, and establishment of a written emergency evacuation plan as well as a comprehensive infection control program. Researchers provide the basis for recommendations concerning occupant securement for children in wheelchairs and children with other special needs who are transported on a school bus. Pediatricians can help their patients by being aware of guidance for restraint systems for children with special needs and by remaining informed of new resources. Pediatricians can also play an important role at the state and local level in the development of school bus specifications. PMID- 29712766 TI - The Whole Story on Sedation. PMID- 29712764 TI - The Grief of Mothers After the Sudden Unexpected Death of Their Infants. AB - : : media-1vid110.1542/5741323271001PEDS-VA_2017-3651Video Abstract BACKGROUND: The loss of a child is associated with elevated grief severity, and sudden infant death syndrome (SIDS) is the leading cause of postneonatal mortality in the United States. The diagnosis of prolonged grief disorder (PGD) has gained broader acceptance and use. Little is known about PGD in mothers after SIDS. METHODS: Between May 2013 and July 2016, we assessed 49 SIDS-bereaved mothers living in informal settlements near Cape Town, South Africa, and on the Pine Ridge Indian Reservation and 359 SIDS-bereaved mothers affiliated with SIDS parent-support organizations in the United States, United Kingdom, Australia, New Zealand, and the Netherlands. We examined PGD symptom severity and diagnostic prevalence rates between the samples and other significant grief indicators during the period 2 to 48 months after the deaths of their infants. RESULTS: Extremely high, persistent, and similar rates of PGD were found in both samples at every time interval. The prevalence of PGD was 50.0% in either sample (mean months from loss: 20.5 vs 24.9). Daily, intrusive emotional pain or yearning was found in 68.1% of subjects; yearning was significantly associated with emotional pain (P < .0001). Role confusion and anger were the most prevalent symptoms, reported by the majority at every time interval. Rates of role confusion, anger, and diminished trust in others remained constant. Acceptance was less prevalent than other grief indicators at every interval. CONCLUSIONS: Severe symptoms and heightened risk for PGD was seen in mothers after their infants died of SIDS, with discernible symptom profiles. Given their involvement with families after SIDS, pediatricians may have a unique role in identifying this problem and helping address its consequences. PMID- 29712767 TI - Sharara-Chami et al. Combination Analgesia for Neonatal Circumcision: A Randomized Controlled Trial. Pediatrics. 2017;140(6):e20171935. PMID- 29712768 TI - Correction for Han et al., "Biochemical and Structural Properties of Mouse Kynurenine Aminotransferase III". PMID- 29712769 TI - Correction for Ghoshal et al., "5-Aza-Deoxycytidine Induces Selective Degradation of DNA Methyltransferase 1 by a Proteasomal Pathway That Requires the KEN Box, Bromo-Adjacent Homology Domain, and Nuclear Localization Signal". PMID- 29712770 TI - REDD1/Autophagy Pathway Is Associated with Neutrophil-Driven IL-1beta Inflammatory Response in Active Ulcerative Colitis. AB - Infiltration of neutrophils into colonic mucosa has been associated with the severity of ulcerative colitis (UC). We investigated the effect of disease microenvironment on the release of neutrophil extracellular traps (NETs) as well as the involved mechanisms in NETosis and whether certain NET proteins are correlated with disease phenotype. Peripheral blood neutrophils, sera, and colonic tissue were collected from treatment-naive and mesalazine-treated patients with active UC, treatment-naive patients with active Crohn's disease, patients suffering from infectious colitis, or healthy individuals (controls). Analysis of colonic biopsy specimens and peripheral blood neutrophils for the presence of NET-related markers using immunofluorescence confocal microscopy, ELISA, immunoblotting, flow cytometry, and quantitative PCR were performed. In vitro cell and tissue culture systems were further deployed. The local inflammatory response in colon in UC, but not Crohn's disease, is characterized by the presence of NETs carrying bioactive IL-1beta and thrombogenic tissue factor. The inflammatory environment of UC is able to induce neutrophil activation, IL-1beta expression, and NET release, as shown both ex vivo and in vitro. REDD1 expression, as a mediator linking inflammation, autophagy, and NET release, was also specifically associated with the inflammatory response of UC. We show that neutrophil expression of REDD1 in colon tissue and the presence of IL-1beta in neutrophils/NETs provide candidate biomarkers for the differential diagnosis of inflammatory colitis and possible targets for the treatment of UC, suggesting that UC shares common features with autoinflammatory disorders. PMID- 29712771 TI - IgG Immunocomplexes Sensitize Human Monocytes for Inflammatory Hyperactivity via Transcriptomic and Epigenetic Reprogramming in Rheumatoid Arthritis. AB - Prevalence of circulating immunocomplexes (ICs) strongly correlates with rheumatoid arthritis (RA) in humans. Deposits of IgG-ICs are abundant in affected joints of patients, yet molecular mechanisms for the pathogenic roles of such ICs are not fully understood. In this study, we present evidence that IgG-ICs precipitated from RA sera sensitized human monocytes for a long-lasting inflammatory functional state, characterized by a strong TNF-alpha response to cellular proteins representing damage-associated molecular patterns and microbe derived pathogen-associated molecular patterns. Importantly, plate-coated human IgG (a mimic of deposited IC without Ag restriction) exhibited a similarly robust ability of monocyte sensitization in vitro. The plate-coated human IgG-induced functional programming is accompanied by transcriptomic and epigenetic modification of various inflammatory cytokines and negative regulator genes. Moreover, macrophages freshly isolated from synovia of patients with RA, but not sera-negative arthropathy, displayed a signature gene expression profile highly similar to that of IC-sensitized human monocytes, indicative of historical priming events by IgG-ICs in vivo. Thus, the ability of IgG-ICs to drive sustainable functional sensitization/reprogramming of monocytes and macrophages toward inflammation may render them key players in the development of RA. PMID- 29712772 TI - SOCS1 and SOCS3 Target IRF7 Degradation To Suppress TLR7-Mediated Type I IFN Production of Human Plasmacytoid Dendritic Cells. AB - Type I IFN production of plasmacytoid dendritic cells (pDCs) triggered by TLR signaling is an essential part of antiviral responses and autoimmune reactions. Although it was well-documented that members of the cytokine signaling (SOCS) family regulate TLR-signaling, the mechanism of how SOCS proteins regulate TLR7 mediated type I IFN production has not been elucidated yet. In this article, we show that TLR7 activation in human pDCs induced the expression of SOCS1 and SOCS3. SOCS1 and SOCS3 strongly suppressed TLR7-mediated type I IFN production. Furthermore, we demonstrated that SOCS1- and SOCS3-bound IFN regulatory factor 7, a pivotal transcription factor of the TLR7 pathway, through the SH2 domain to promote its proteasomal degradation by lysine 48-linked polyubiquitination. Together, our results demonstrate that SOCS1/3-mediated degradation of IFN regulatory factor 7 directly regulates TLR7 signaling and type I IFN production in pDCs. This mechanism might be targeted by therapeutic approaches to either enhance type I IFN production in antiviral treatment or decrease type I IFN production in the treatment of autoimmune diseases. PMID- 29712773 TI - Chronic Lymphocytic Leukemia-Derived IL-10 Suppresses Antitumor Immunity. AB - Chronic lymphocytic leukemia (CLL) patients progressively develop an immunosuppressive state. CLL patients have more plasma IL-10, an anti inflammatory cytokine, than healthy controls. In vitro human CLL cells produce IL 10 in response to BCR cross-linking. We used the transgenic EMU-T cell leukemia oncogene-1 (TCL1) mouse CLL model to study the role of IL-10 in CLL associated immunosuppression. EMU-TCL mice spontaneously develop CLL because of a B cell specific expression of the oncogene, TCL1. EMU-TCL1 mouse CLL cells constitutively produce IL-10, which is further enhanced by BCR cross-linking, CLL derived IL-10 did not directly affect survival of murine or human CLL cells in vitro. We tested the hypothesis that the CLL-derived IL-10 has a critical role in CLL disease in part by suppressing the host immune response to the CLL cells. In IL-10R-/- mice, wherein the host immune cells are unresponsive to IL-10-mediated suppressive effects, there was a significant reduction in CLL cell growth compared with wild type mice. IL-10 reduced the generation of effector CD4 and CD8 T cells. We also found that activation of BCR signaling regulated the production of IL-10 by both murine and human CLL cells. We identified the transcription factor, Sp1, as a novel regulator of IL-10 production by CLL cells and that it is regulated by BCR signaling via the Syk/MAPK pathway. Our results suggest that incorporation of IL-10 blocking agents may enhance current therapeutic regimens for CLL by potentiating host antitumor immune response. PMID- 29712775 TI - The ITIM Domain-Containing NK Receptor Ly49Q Impacts Pulmonary Infection by Mediating Neutrophil Functions. AB - Pulmonary infection is a frequent pathology associated with excessive neutrophil infiltration. Ly49Q, an ITIM domain-bearing receptor expressed on different leukocytes, has been recently reported to impact neutrophil migration and polarization. Utilizing a murine model of Klebsiella pneumoniae-induced pulmonary infection in combination with additional in vivo and in vitro assays, we show that Ly49Q is critically involved in different steps of the leukocyte adhesion cascade. Ly49Q deficiency is associated with a reduced rolling velocity, impaired crawling capacity, and diminished transmigration. We show that overactivation of the neutrophil beta2 integrins Mac-1 and LFA-1 is responsible for increased adhesion and reduced neutrophil transmigration, resulting in a strongly impaired immune defense against pulmonary infection. Structure function analysis in vitro and in vivo demonstrated that different domains of Ly49Q are important for its function. In summary, Ly49Q regulates integrin activation and neutrophil recruitment and is required for an adequate immune response in pulmonary infection. PMID- 29712774 TI - eIF4E-Binding Proteins 1 and 2 Limit Macrophage Anti-Inflammatory Responses through Translational Repression of IL-10 and Cyclooxygenase-2. AB - Macrophages represent one of the first lines of defense during infections and are essential for resolution of inflammation following pathogen clearance. Rapid activation or suppression of protein synthesis via changes in translational efficiency allows cells of the immune system, including macrophages, to quickly respond to external triggers or cues without de novo mRNA synthesis. The translational repressors eIF4E-binding proteins 4E-BP1 and 4E-BP2 (4E-BP1/2) are central regulators of proinflammatory cytokine synthesis during viral and parasitic infections. However, it remains to be established whether 4E-BP1/2 play a role in translational control of anti-inflammatory responses. By comparing translational efficiencies of immune-related transcripts in macrophages from wild type and 4E-BP1/2 double-knockout mice, we found that translation of mRNAs encoding two major regulators of inflammation, IL-10 and PG-endoperoxide synthase 2/cyclooxygenase-2, is controlled by 4E-BP1/2. Genetic deletion of 4E-BP1/2 in macrophages increased endogenous IL-10 and PGE2 protein synthesis in response to TLR4 stimulation and reduced their bactericidal capacity. The molecular mechanism involves enhanced anti-inflammatory gene expression (sIl1ra, Nfil3, Arg1, Serpinb2) owing to upregulation of IL-10-STAT3 and PGE2-C/EBPbeta signaling. These data provide evidence that 4E-BP1/2 limit anti-inflammatory responses in macrophages and suggest that dysregulated activity of 4E-BP1/2 might be involved in reprogramming of the translational and downstream transcriptional landscape of macrophages during pathological conditions, such as infections and cancer. PMID- 29712776 TI - eIF5A is required for autophagy by mediating ATG3 translation. AB - Autophagy is an essential catabolic process responsible for recycling of intracellular material and preserving cellular fidelity. Key to the autophagy pathway is the ubiquitin-like conjugation system mediating lipidation of Atg8 proteins and their anchoring to autophagosomal membranes. While regulation of autophagy has been characterized at the level of transcription, protein interactions and post-translational modifications, its translational regulation remains elusive. Here we describe a role for the conserved eukaryotic translation initiation factor 5A (eIF5A) in autophagy. Identified from a high-throughput screen, we find that eIF5A is required for lipidation of LC3B and its paralogs and promotes autophagosome formation. This feature is evolutionarily conserved and results from the translation of the E2-like ATG3 protein. Mechanistically, we identify an amino acid motif in ATG3 causing eIF5A dependency for its efficient translation. Our study identifies eIF5A as a key requirement for autophagosome formation and demonstrates the importance of translation in mediating efficient autophagy. PMID- 29712777 TI - Palladin Is a Neuron-Specific Translational Target of mTOR Signaling That Regulates Axon Morphogenesis. AB - The mTOR signaling pathway regulates protein synthesis and diverse aspects of neuronal morphology that are important for brain development and function. To identify proteins controlled translationally by mTOR signaling, we performed ribosome profiling analyses in mouse cortical neurons and embryonic stem cells upon acute mTOR inhibition. Among proteins whose translation was significantly affected by mTOR inhibition selectively in neurons, we identified the cytoskeletal regulator protein palladin, which is localized within the cell body and axons in hippocampal neurons. Knockdown of palladin eliminated supernumerary axons induced by suppression of the tuberous sclerosis complex protein TSC1 in neurons, demonstrating that palladin regulates neuronal morphogenesis downstream of mTOR signaling. Our findings provide novel insights into an mTOR-dependent mechanism that controls neuronal morphogenesis through translational regulation.SIGNIFICANCE STATEMENT This study reports the discovery of neuron specific protein translational responses to alterations of mTOR activity. By using ribosome profiling analysis, which can reveal the location and quantity of translating ribosomes on mRNAs, multiple aspects of protein translation were quantitatively analyzed in mouse embryonic stem cells and cortical neurons upon acute mTOR inhibition. Neurons displayed distinct patterns of ribosome occupancy for each codon and ribosome stalling during translation at specific positions of mRNAs. Importantly, the cytoskeletal regulator palladin was identified as a translational target protein of mTOR signaling in neurons. Palladin operates downstream of mTOR to modulate axon morphogenesis. This study identifies a novel mechanism of neuronal morphogenesis regulated by mTOR signaling through control of translation of the key protein palladin. PMID- 29712778 TI - GDNF, Neurturin, and Artemin Activate and Sensitize Bone Afferent Neurons and Contribute to Inflammatory Bone Pain. AB - Pain associated with skeletal pathology or disease is a significant clinical problem, but the mechanisms that generate and/or maintain it remain poorly understood. In this study, we explored roles for GDNF, neurturin, and artemin signaling in bone pain using male Sprague Dawley rats. We have shown that inflammatory bone pain involves activation and sensitization of peptidergic, NGF sensitive neurons via artemin/GDNF family receptor alpha-3 (GFRalpha3) signaling pathways, and that sequestering artemin might be useful to prevent inflammatory bone pain derived from activation of NGF-sensitive bone afferent neurons. In addition, we have shown that inflammatory bone pain also involves activation and sensitization of nonpeptidergic neurons via GDNF/GFRalpha1 and neurturin/GFRalpha2 signaling pathways, and that sequestration of neurturin, but not GDNF, might be useful to treat inflammatory bone pain derived from activation of nonpeptidergic bone afferent neurons. Our findings suggest that GDNF family ligand signaling pathways are involved in the pathogenesis of bone pain and could be targets for pharmacological manipulations to treat it.SIGNIFICANCE STATEMENT Pain associated with skeletal pathology, including bone cancer, bone marrow edema syndromes, osteomyelitis, osteoarthritis, and fractures causes a major burden (both in terms of quality of life and cost) on individuals and health care systems worldwide. We have shown the first evidence of a role for GDNF, neurturin, and artemin in the activation and sensitization of bone afferent neurons, and that sequestering these ligands reduces pain behavior in a model of inflammatory bone pain. Thus, GDNF family ligand signaling pathways are involved in the pathogenesis of bone pain and could be targets for pharmacological manipulations to treat it. PMID- 29712780 TI - The Neural Correlates of Hierarchical Predictions for Perceptual Decisions. AB - Sensory information is inherently noisy, sparse, and ambiguous. In contrast, visual experience is usually clear, detailed, and stable. Bayesian theories of perception resolve this discrepancy by assuming that prior knowledge about the causes underlying sensory stimulation actively shapes perceptual decisions. The CNS is believed to entertain a generative model aligned to dynamic changes in the hierarchical states of our volatile sensory environment. Here, we used model based fMRI to study the neural correlates of the dynamic updating of hierarchically structured predictions in male and female human observers. We devised a crossmodal associative learning task with covertly interspersed ambiguous trials in which participants engaged in hierarchical learning based on changing contingencies between auditory cues and visual targets. By inverting a Bayesian model of perceptual inference, we estimated individual hierarchical predictions, which significantly biased perceptual decisions under ambiguity. Although "high-level" predictions about the cue-target contingency correlated with activity in supramodal regions such as orbitofrontal cortex and hippocampus, dynamic "low-level" predictions about the conditional target probabilities were associated with activity in retinotopic visual cortex. Our results suggest that our CNS updates distinct representations of hierarchical predictions that continuously affect perceptual decisions in a dynamically changing environment.SIGNIFICANCE STATEMENT Bayesian theories posit that our brain entertains a generative model to provide hierarchical predictions regarding the causes of sensory information. Here, we use behavioral modeling and fMRI to study the neural underpinnings of such hierarchical predictions. We show that "high level" predictions about the strength of dynamic cue-target contingencies during crossmodal associative learning correlate with activity in orbitofrontal cortex and the hippocampus, whereas "low-level" conditional target probabilities were reflected in retinotopic visual cortex. Our findings empirically corroborate theorizations on the role of hierarchical predictions in visual perception and contribute substantially to a longstanding debate on the link between sensory predictions and orbitofrontal or hippocampal activity. Our work fundamentally advances the mechanistic understanding of perceptual inference in the human brain. PMID- 29712781 TI - Mapping Frequency-Specific Tone Predictions in the Human Auditory Cortex at High Spatial Resolution. AB - Auditory inputs reaching our ears are often incomplete, but our brains nevertheless transform them into rich and complete perceptual phenomena such as meaningful conversations or pleasurable music. It has been hypothesized that our brains extract regularities in inputs, which enables us to predict the upcoming stimuli, leading to efficient sensory processing. However, it is unclear whether tone predictions are encoded with similar specificity as perceived signals. Here, we used high-field fMRI to investigate whether human auditory regions encode one of the most defining characteristics of auditory perception: the frequency of predicted tones. Two pairs of tone sequences were presented in ascending or descending directions, with the last tone omitted in half of the trials. Every pair of incomplete sequences contained identical sounds, but was associated with different expectations about the last tone (a high- or low-frequency target). This allowed us to disambiguate predictive signaling from sensory-driven processing. We recorded fMRI responses from eight female participants during passive listening to complete and incomplete sequences. Inspection of specificity and spatial patterns of responses revealed that target frequencies were encoded similarly during their presentations, as well as during omissions, suggesting frequency-specific encoding of predicted tones in the auditory cortex (AC). Importantly, frequency specificity of predictive signaling was observed already at the earliest levels of auditory cortical hierarchy: in the primary AC. Our findings provide evidence for content-specific predictive processing starting at the earliest cortical levels.SIGNIFICANCE STATEMENT Given the abundance of sensory information around us in any given moment, it has been proposed that our brain uses contextual information to prioritize and form predictions about incoming signals. However, there remains a surprising lack of understanding of the specificity and content of such prediction signaling; for example, whether a predicted tone is encoded with similar specificity as a perceived tone. Here, we show that early auditory regions encode the frequency of a tone that is predicted yet omitted. Our findings contribute to the understanding of how expectations shape sound processing in the human auditory cortex and provide further insights into how contextual information influences computations in neuronal circuits. PMID- 29712779 TI - Dopamine Triggers CTCF-Dependent Morphological and Genomic Remodeling of Astrocytes. AB - Dopamine is critical for processing of reward and etiology of drug addiction. Astrocytes throughout the brain express dopamine receptors, but consequences of astrocytic dopamine receptor signaling are not well established. We found that extracellular dopamine triggered rapid concentration-dependent stellation of astrocytic processes that was not a result of dopamine oxidation but instead relied on both cAMP-dependent and cAMP-independent dopamine receptor signaling. This was accompanied by reduced duration and increased frequency of astrocytic Ca2+ transients, but little effect on astrocytic voltage-gated potassium channel currents. To isolate possible mechanisms underlying these structural and functional changes, we used whole-genome RNA sequencing and found prominent dopamine-induced enrichment of genes containing the CCCTC-binding factor (CTCF) motif, suggesting involvement of chromatin restructuring in the nucleus. CTCF binding to promoter sites bidirectionally regulates gene transcription and depends on activation of poly-ADP-ribose polymerase 1 (PARP1). Accordingly, antagonism of PARP1 occluded dopamine-induced changes, whereas a PARP1 agonist facilitated dopamine-induced changes on its own. These results indicate that astrocyte response to elevated dopamine involves PARP1-mediated CTCF genomic restructuring and concerted expression of gene networks. Our findings propose epigenetic regulation of chromatin landscape as a critical factor in the rapid astrocyte response to dopamine.SIGNIFICANCE STATEMENT Although dopamine is widely recognized for its role in modulating neuronal responses both in healthy and disease states, little is known about dopamine effects at non-neuronal cells in the brain. To address this gap, we performed whole-genome sequencing of astrocytes exposed to elevated extracellular dopamine and combined it with evaluation of effects on astrocyte morphology and function. We demonstrate a temporally dynamic pattern of genomic plasticity that triggers pronounced changes in astrocyte morphology and function. We further show that this plasticity depends on activation of genes sensitive to DNA-binding protein CTCF. Our results propose that a broad pattern of astrocyte responses to dopamine specifically relies on CTCF-dependent gene networks. PMID- 29712782 TI - Activity in Human Auditory Cortex Represents Spatial Separation Between Concurrent Sounds. AB - The primary and posterior auditory cortex (AC) are known for their sensitivity to spatial information, but how this information is processed is not yet understood. AC that is sensitive to spatial manipulations is also modulated by the number of auditory streams present in a scene (Smith et al., 2010), suggesting that spatial and nonspatial cues are integrated for stream segregation. We reasoned that, if this is the case, then it is the distance between sounds rather than their absolute positions that is essential. To test this hypothesis, we measured human brain activity in response to spatially separated concurrent sounds with fMRI at 7 tesla in five men and five women. Stimuli were spatialized amplitude-modulated broadband noises recorded for each participant via in-ear microphones before scanning. Using a linear support vector machine classifier, we investigated whether sound location and/or location plus spatial separation between sounds could be decoded from the activity in Heschl's gyrus and the planum temporale. The classifier was successful only when comparing patterns associated with the conditions that had the largest difference in perceptual spatial separation. Our pattern of results suggests that the representation of spatial separation is not merely the combination of single locations, but rather is an independent feature of the auditory scene.SIGNIFICANCE STATEMENT Often, when we think of auditory spatial information, we think of where sounds are coming from-that is, the process of localization. However, this information can also be used in scene analysis, the process of grouping and segregating features of a soundwave into objects. Essentially, when sounds are further apart, they are more likely to be segregated into separate streams. Here, we provide evidence that activity in the human auditory cortex represents the spatial separation between sounds rather than their absolute locations, indicating that scene analysis and localization processes may be independent. PMID- 29712783 TI - Conditional Bistability, a Generic Cellular Mnemonic Mechanism for Robust and Flexible Working Memory Computations. AB - Persistent neural activity, the substrate of working memory, is thought to emerge from synaptic reverberation within recurrent networks. However, reverberation models do not robustly explain the fundamental dynamics of persistent activity, including high-spiking irregularity, large intertrial variability, and state transitions. While cellular bistability may contribute to persistent activity, its rigidity appears incompatible with persistent activity labile characteristics. Here, we unravel in a cellular model a form of spike-mediated conditional bistability that is robust and generic. and provides a rich repertoire of mnemonic computations. Under asynchronous synaptic inputs of the awakened state, conditional bistability generates spiking/bursting episodes, accounting for the irregularity, variability, and state transitions characterizing persistent activity. This mechanism has likely been overlooked because of the subthreshold input it requires, and we predict how to assess it experimentally. Our results suggest a reexamination of the role of intrinsic properties in the collective network dynamics responsible for flexible working memory.SIGNIFICANCE STATEMENT This study unravels a novel form of intrinsic neuronal property: conditional bistability. We show that, thanks to its conditional character, conditional bistability favors the emergence of flexible and robust forms of persistent activity in PFC neural networks, in opposition to previously studied classical forms of absolute bistability. Specifically, we demonstrate for the first time that conditional bistability (1) is a generic biophysical spike-dependent mechanism of layer V pyramidal neurons in the PFC and that (2) it accounts for essential neurodynamical features for the organization and flexibility of PFC persistent activity (the large irregularity and intertrial variability of the discharge and its organization under discrete stable states), which remain unexplained in a robust fashion by current models. PMID- 29712784 TI - Temporal Response Properties of Accessory Olfactory Bulb Neurons: Limitations and Opportunities for Decoding. AB - The vomeronasal system (VNS) is a major vertebrate chemosensory system that functions in parallel to the main olfactory system (MOS). Despite many similarities, the two systems dramatically differ in the temporal domain. While MOS responses are governed by breathing and follow a subsecond temporal scale, VNS responses are uncoupled from breathing and evolve over seconds. This suggests that the contribution of response dynamics to stimulus information will differ between these systems. While temporal dynamics in the MOS are widely investigated, similar analyses in the accessory olfactory bulb (AOB) are lacking. Here, we have addressed this issue using controlled stimulus delivery to the vomeronasal organ of male and female mice. We first analyzed the temporal properties of AOB projection neurons and demonstrated that neurons display prolonged, variable, and neuron-specific characteristics. We then analyzed various decoding schemes using AOB population responses. We showed that compared with the simplest scheme (i.e., integration of spike counts over the entire response period), the division of this period into smaller temporal bins actually yields poorer decoding accuracy. However, optimal classification accuracy can be achieved well before the end of the response period by integrating spike counts within temporally defined windows. Since VNS stimulus uptake is variable, we analyzed decoding using limited information about stimulus uptake time, and showed that with enough neurons, such time-invariant decoding is feasible. Finally, we conducted simulations that demonstrated that, unlike the main olfactory bulb, the temporal features of AOB neurons disfavor decoding with high temporal accuracy, and, rather, support decoding without precise knowledge of stimulus uptake time.SIGNIFICANCE STATEMENT A key goal in sensory system research is to identify which metrics of neuronal activity are relevant for decoding stimulus features. Here, we describe the first systematic analysis of temporal coding in the vomeronasal system (VNS), a chemosensory system devoted to socially relevant cues. Compared with the main olfactory system, timescales of VNS function are inherently slower and variable. Using various analyses of real and simulated data, we show that the consideration of response times relative to stimulus uptake can aid the decoding of stimulus information from neuronal activity. However, response properties of accessory olfactory bulb neurons favor decoding schemes that do not rely on the precise timing of stimulus uptake. Such schemes are consistent with the variable nature of VNS stimulus uptake. PMID- 29712785 TI - Remote Memory and Cortical Synaptic Plasticity Require Neuronal CCCTC-Binding Factor (CTCF). AB - The molecular mechanism of long-term memory has been extensively studied in the context of the hippocampus-dependent recent memory examined within several days. However, months-old remote memory maintained in the cortex for long-term has not been investigated much at the molecular level yet. Various epigenetic mechanisms are known to be important for long-term memory, but how the 3D chromatin architecture and its regulator molecules contribute to neuronal plasticity and systems consolidation is still largely unknown. CCCTC-binding factor (CTCF) is an 11-zinc finger protein well known for its role as a genome architecture molecule. Male conditional knock-out mice in which CTCF is lost in excitatory neurons during adulthood showed normal recent memory in the contextual fear conditioning and spatial water maze tasks. However, they showed remarkable impairments in remote memory in both tasks. Underlying the remote memory-specific phenotypes, we observed that female CTCF conditional knock-out mice exhibit disrupted cortical LTP, but not hippocampal LTP. Similarly, we observed that CTCF deletion in inhibitory neurons caused partial impairment of remote memory. Through RNA sequencing, we observed that CTCF knockdown in cortical neuron culture caused altered expression of genes that are highly involved in cell adhesion, synaptic plasticity, and memory. These results suggest that remote memory storage in the cortex requires CTCF-mediated gene regulation in neurons, whereas recent memory formation in the hippocampus does not.SIGNIFICANCE STATEMENT CCCTC-binding factor (CTCF) is a well-known 3D genome architectural protein that regulates gene expression. Here, we use two different CTCF conditional knock-out mouse lines and reveal, for the first time, that CTCF is critically involved in the regulation of remote memory. We also show that CTCF is necessary for appropriate expression of genes, many of which we found to be involved in the learning- and memory-related processes. Our study provides behavioral and physiological evidence for the involvement of CTCF-mediated gene regulation in the remote long-term memory and elucidates our understanding of systems consolidation mechanisms. PMID- 29712786 TI - Encoding of Serial Order in Working Memory: Neuronal Activity in Motor, Premotor, and Prefrontal Cortex during a Memory Scanning Task. AB - We have adapted Sternberg's context-recall task to investigate the neural mechanisms of encoding serial order information in working memory, in 2 male rhesus monkeys. We recorded from primary motor, premotor, and dorsolateral prefrontal cortex while the monkeys performed the task. In each cortical area, most neurons displayed marked modulation of activity during the list presentation period of the task, whereas the serial order of the stimuli needed to be encoded in working memory. The activity of many neurons changed in a consistent manner over the course of the list presentation period, without regard to the location of the stimuli presented. Remarkably, these neurons encoded serial position information in a relative (rather than absolute) manner across different list lengths. In addition, many neurons showed activity related to both location and serial position, in the form of an interaction effect. Surprisingly, the activity of these neurons was often modulated by the location of stimuli presented before the epoch in which the activity changes occurred. In motor and premotor areas, a large proportion of neurons with list presentation activity also showed direction related activity during the response phase, whereas in prefrontal cortex most cells showed only list presentation effects. These results show that many neurons had a heterogeneous functionality by representing distinct task variables at different periods of the task. Finally, potential confounds could not account for the effects observed. For these reasons, we conclude that these neurons were indeed participating in sequence encoding in working memory.SIGNIFICANCE STATEMENT Traditionally, primary motor, premotor, and prefrontal areas have been considered to be mainly engaged in motor output, visuomotor transformation, and higher cognitive functions, respectively. Here we show that neurons in all three cortical regions participate in the encoding of a sequence of spatial stimuli in working memory. Furthermore, a central question in cognitive neuroscience has been the manner in which the position of an item within a sequence is encoded in the brain. Our findings provide direct neurophysiological support for a specific hypothesis from cognitive psychology: that of relative coding of serial order. PMID- 29712789 TI - Macrophage Depletion Ameliorates Peripheral Neuropathy in Aging Mice. AB - Aging is known as a major risk factor for the structure and function of the nervous system. There is urgent need to overcome such deleterious effects of age related neurodegeneration. Here we show that peripheral nerves of 24-month-old aging C57BL/6 mice of either sex show similar pathological alterations as nerves from aging human individuals, whereas 12-month-old adult mice lack such alterations. Specifically, nerve fibers showed demyelination, remyelination and axonal lesion. Moreover, in the aging mice, neuromuscular junctions showed features typical for dying-back neuropathies, as revealed by a decline of presynaptic markers, associated with alpha-bungarotoxin-positive postsynapses. In line with these observations were reduced muscle strengths. These alterations were accompanied by elevated numbers of endoneurial macrophages, partially comprising the features of phagocytosing macrophages. Comparable profiles of macrophages could be identified in peripheral nerve biopsies of aging persons. To determine the pathological impact of macrophages in aging mice, we selectively targeted the cells by applying an orally administered CSF-1R specific kinase (c FMS) inhibitor. The 6-month-lasting treatment started before development of degenerative changes at 18 months and reduced macrophage numbers in mice by ~70%, without side effects. Strikingly, nerve structure was ameliorated and muscle strength preserved. We show, for the first time, that age-related degenerative changes in peripheral nerves are driven by macrophages. These findings may pave the way for treating degeneration in the aging peripheral nervous system by targeting macrophages, leading to reduced weakness, improved mobility, and eventually increased quality of life in the elderly.SIGNIFICANCE STATEMENT Aging is a major risk factor for the structure and function of the nervous system. Here we show that peripheral nerves of 24-month-old aging mice show similar degenerative alterations as nerves from aging human individuals. Both in mice and humans, these alterations were accompanied by endoneurial macrophages. To determine the pathological impact of macrophages in aging mice, we selectively targeted the cells by blocking a cytokine receptor, essential for macrophage survival. The treatment strongly reduced macrophage numbers and substantially improved nerve structure and muscle strength. We show, for the first time, that age-related degenerative changes in peripheral nerves are driven by macrophages. These findings may be helpful for treatment weakness and reduced mobility in the elderly. PMID- 29712787 TI - FLP-18 Functions through the G-Protein-Coupled Receptors NPR-1 and NPR-4 to Modulate Reversal Length in Caenorhabditis elegans. AB - Animal behavior is critically dependent on the activity of neuropeptides. Reversals, one of the most conspicuous behaviors in Caenorhabditis elegans, plays an important role in determining the navigation strategy of the animal. Our experiments on hermaphrodite C. elegans show the involvement of a neuropeptide FLP-18 in modulating reversal length in these hermaphrodites. We show that FLP-18 controls the reversal length by regulating the activity of AVA interneurons through the G-protein-coupled neuropeptide receptors, NPR-4 and NPR-1. We go on to show that the site of action of these receptors is the AVA interneuron for NPR 4 and the ASE sensory neurons for NPR-1. We further show that mutants in the neuropeptide, flp-18, and its receptors show increased reversal lengths. Consistent with the behavioral data, calcium levels in the AVA neuron of freely reversing C. elegans were significantly higher and persisted for longer durations in flp-18, npr-1, npr-4, and npr-1 npr-4 genetic backgrounds compared with wild type control animals. Finally, we show that increasing FLP-18 levels through genetic and physiological manipulations causes shorter reversal lengths. Together, our analysis suggests that the FLP-18/NPR-1/NPR-4 signaling is a pivotal point in the regulation of reversal length under varied genetic and environmental conditions.SIGNIFICANCE STATEMENT In this study, we elucidate the circuit and molecular machinery required for normal reversal behavior in hermaphrodite Caenorhabditis elegans We delineate the circuit and the neuropeptide receptors required for maintaining reversal length in C. elegans Our work sheds light on the importance of a single neuropeptide, FLP-18, and how change in levels in this one peptide could allow the animal to change the length of its reversal, thereby modulating how the C. elegans explores its environment. We also go on to show that FLP-18 functions to maintain reversal length through the neuropeptide receptors NPR-4 and NPR-1. Our study will allow for a better understanding of the complete repertoire of behaviors shown by freely moving animals as they explore their environment. PMID- 29712788 TI - Mesocorticolimbic Connectivity and Volumetric Alterations in DCC Mutation Carriers. AB - The axon guidance cue receptor DCC (deleted in colorectal cancer) plays a critical role in the organization of mesocorticolimbic pathways in rodents. To investigate whether this occurs in humans, we measured (1) anatomical connectivity between the substantia nigra/ventral tegmental area (SN/VTA) and forebrain targets, (2) striatal and cortical volumes, and (3) putatively associated traits and behaviors. To assess translatability, morphometric data were also collected in Dcc-haploinsufficient mice. The human volunteers were 20 DCC+/- mutation carriers, 16 DCC+/+ relatives, and 20 DCC+/+ unrelated healthy volunteers (UHVs; 28 females). The mice were 11 Dcc+/- and 16 wild-type C57BL/6J animals assessed during adolescence and adulthood. Compared with both control groups, the human DCC+/- carriers exhibited the following: (1) reduced anatomical connectivity from the SN/VTA to the ventral striatum [DCC+/+: p = 0.0005, r(effect size) = 0.60; UHV: p = 0.0029, r = 0.48] and ventral medial prefrontal cortex (DCC+/+: p = 0.0031, r = 0.53; UHV: p = 0.034, r = 0.35); (2) lower novelty-seeking scores (DCC+/+: p = 0.034, d = 0.82; UHV: p = 0.019, d = 0.84); and (3) reduced striatal volume (DCC+/+: p = 0.0009, d = 1.37; UHV: p = 0.0054, d = 0.93). Striatal volumetric reductions were also present in Dcc+/- mice, and these were seen during adolescence (p = 0.0058, d = 1.09) and adulthood (p = 0.003, d = 1.26). Together these findings provide the first evidence in humans that an axon guidance gene is involved in the formation of mesocorticolimbic circuitry and related behavioral traits, providing mechanisms through which DCC mutations might affect susceptibility to diverse neuropsychiatric disorders.SIGNIFICANCE STATEMENT Opportunities to study the effects of axon guidance molecules on human brain development have been rare. Here, the identification of a large four-generational family that carries a mutation to the axon guidance molecule receptor gene, DCC, enabled us to demonstrate effects on mesocorticolimbic anatomical connectivity, striatal volumes, and personality traits. Reductions in striatal volumes were replicated in DCC-haploinsufficient mice. Together, these processes might influence mesocorticolimbic function and susceptibility to diverse neuropsychiatric disorders. PMID- 29712790 TI - NMDA Receptor Signaling Is Important for Neural Tube Formation and for Preventing Antiepileptic Drug-Induced Neural Tube Defects. AB - Failure of neural tube closure leads to neural tube defects (NTDs), which can have serious neurological consequences or be lethal. Use of antiepileptic drugs (AEDs) during pregnancy increases the incidence of NTDs in offspring by unknown mechanisms. Here we show that during Xenopus laevis neural tube formation, neural plate cells exhibit spontaneous calcium dynamics that are partially mediated by glutamate signaling. We demonstrate that NMDA receptors are important for the formation of the neural tube and that the loss of their function induces an increase in neural plate cell proliferation and impairs neural cell migration, which result in NTDs. We present evidence that the AED valproic acid perturbs glutamate signaling, leading to NTDs that are rescued with varied efficacy by preventing DNA synthesis, activating NMDA receptors, or recruiting the NMDA receptor target ERK1/2. These findings may prompt mechanistic identification of AEDs that do not interfere with neural tube formation.SIGNIFICANCE STATEMENT Neural tube defects are one of the most common birth defects. Clinical investigations have determined that the use of antiepileptic drugs during pregnancy increases the incidence of these defects in the offspring by unknown mechanisms. This study discovers that glutamate signaling regulates neural plate cell proliferation and oriented migration and is necessary for neural tube formation. We demonstrate that the widely used antiepileptic drug valproic acid interferes with glutamate signaling and consequently induces neural tube defects, challenging the current hypotheses arguing that they are side effects of this antiepileptic drug that cause the increased incidence of these defects. Understanding the mechanisms of neurotransmitter signaling during neural tube formation may contribute to the identification and development of antiepileptic drugs that are safer during pregnancy. PMID- 29712791 TI - Advancing national climate change risk assessment to deliver national adaptation plans. AB - A wide range of climate vulnerability and risk assessments have been implemented using different approaches at different scales, some with a broad multi-sectoral scope and others focused on single risks or sectors. This paper describes the novel approach to vulnerability and risk assessment which was designed and put into practice in the United Kingdom's Second Climate Change Risk Assessment (CCRA2) so as to build upon its earlier assessment (CCRA1). First, we summarize and critique the CCRA1 approach, and second describe the steps taken in the CCRA2 approach in detail, providing examples of how each was applied in practice. Novel elements of the approach include assessment of both present day and future vulnerability, a focus on the urgency of adaptation action, and a structure focused around systems of receptors rather than conventional sectors. Both stakeholders and reviewers generally regarded the approach as successful in providing advice on current risks and future opportunities to the UK from climate change, and the fulfilment of statutory duty. The need for a well-supported and open suite of impact indicators going forward is highlighted.This article is part of the theme issue 'Advances in risk assessment for climate change adaptation policy'. PMID- 29712792 TI - Assessing climate change risks to the natural environment to facilitate cross sectoral adaptation policy. AB - Climate change policy requires prioritization of adaptation actions across many diverse issues. The policy agenda for the natural environment includes not only biodiversity, soils and water, but also associated human benefits through agriculture, forestry, water resources, hazard alleviation, climate regulation and amenity value. To address this broad agenda, the use of comparative risk assessment is investigated with reference to statutory requirements of the UK Climate Change Risk Assessment. Risk prioritization was defined by current adaptation progress relative to risk magnitude and implementation lead times. Use of an ecosystem approach provided insights into risk interactions, but challenges remain in quantifying ecosystem services. For all risks, indirect effects and potential systemic risks were identified from land-use change, responding to both climate and socio-economic drivers, and causing increased competition for land and water resources. Adaptation strategies enhancing natural ecosystem resilience can buffer risks and sustain ecosystem services but require improved cross sectoral coordination and recognition of dynamic change. To facilitate this, risk assessments need to be reflexive and explicitly assess decision outcomes contingent on their riskiness and adaptability, including required levels of human intervention, influence of uncertainty and ethical dimensions. More national-scale information is also required on adaptation occurring in practice and its efficacy in moderating risks.This article is part of the theme issue 'Advances in risk assessment for climate change adaptation policy'. PMID- 29712793 TI - A systems framework for national assessment of climate risks to infrastructure. AB - Extreme weather causes substantial adverse socio-economic impacts by damaging and disrupting the infrastructure services that underpin modern society. Globally, $2.5tn a year is spent on infrastructure which is typically designed to last decades, over which period projected changes in the climate will modify infrastructure performance. A systems approach has been developed to assess risks across all infrastructure sectors to guide national policy making and adaptation investment. The method analyses diverse evidence of climate risks and adaptation actions, to assess the urgency and extent of adaptation required. Application to the UK shows that despite recent adaptation efforts, risks to infrastructure outweigh opportunities. Flooding is the greatest risk to all infrastructure sectors: even if the Paris Agreement to limit global warming to 2 degrees C is achieved, the number of users reliant on electricity infrastructure at risk of flooding would double, while a 4 degrees C rise could triple UK flood damage. Other risks are significant, for example 5% and 20% of river catchments would be unable to meet water demand with 2 degrees C and 4 degrees C global warming respectively. Increased interdependence between infrastructure systems, especially from energy and information and communication technology (ICT), are amplifying risks, but adaptation action is limited by lack of clear responsibilities. A programme to build national capability is urgently required to improve infrastructure risk assessment.This article is part of the theme issue 'Advances in risk assessment for climate change adaptation policy'. PMID- 29712794 TI - How normative interpretations of climate risk assessment affect local decision making: an exploratory study at the city scale in Cork, Ireland. AB - Urban areas already suffer substantial losses in both economic and human terms from climate-related disasters. These losses are anticipated to grow substantially, in part as a result of the impacts of climate change. In this paper, we investigate the process of translating climate risk data into action for the city level. We apply a commonly used decision-framework as our backdrop and explore where in this process climate risk assessment and normative political judgements intersect. We use the case of flood risk management in Cork city in Ireland to investigate what is needed for translating risk assessment into action at the local city level. Evidence presented is based on focus group discussions at two stakeholder workshops, and a series of individual meetings and phone discussions with stakeholders involved in local decision-making related to flood risk management and adaptation to climate change, in Ireland. Respondents were chosen on the basis of their expertise or involvement in the decision-making processes locally and nationally. Representatives of groups affected by flood risk and flood risk management and climate adaptation efforts were also included. The Cork example highlights that, despite ever more accurate data and an increasing range of theoretical approaches available to local decision-makers, it is the normative interpretation of this information that determines what action is taken. The use of risk assessments for decision-making is a process that requires normative decisions, such as setting 'acceptable risk levels' and identifying 'adequate' protection levels, which will not succeed without broader buy-in and stakeholder participation. Identifying and embracing those normative views up-front could strengthen the urban adaptation process-this may, in fact, turn out to be the biggest advantage of climate risk assessment: it offers an opportunity to create a shared understanding of the problem and enables an informed evaluation and discussion of remedial action.This article is part of the theme issue 'Advances in risk assessment for climate change adaptation policy'. PMID- 29712795 TI - Transmission of climate risks across sectors and borders. AB - Systemic climate risks, which result from the potential for cascading impacts through inter-related systems, pose particular challenges to risk assessment, especially when risks are transmitted across sectors and international boundaries. Most impacts of climate variability and change affect regions and jurisdictions in complex ways, and techniques for assessing this transmission of risk are still somewhat limited. Here, we begin to define new approaches to risk assessment that can account for transboundary and trans-sector risk transmission, by presenting: (i) a typology of risk transmission that distinguishes clearly the role of climate versus the role of the social and economic systems that distribute resources; (ii) a review of existing modelling, qualitative and systems-based methods of assessing risk and risk transmission; and (iii) case studies that examine risk transmission in human displacement, food, water and energy security. The case studies show that policies and institutions can attenuate risks significantly through cooperation that can be mutually beneficial to all parties. We conclude with some suggestions for assessment of complex risk transmission mechanisms: use of expert judgement; interactive scenario building; global systems science and big data; innovative use of climate and integrated assessment models; and methods to understand societal responses to climate risk. These approaches aim to inform both research and national-level risk assessment. PMID- 29712796 TI - Turning risk assessment and adaptation policy priorities into meaningful interventions and governance processes. AB - The UK is one of the first countries in the world to have set up a statutory system of national climate risk assessments followed by a national adaptation programme. Having this legal framework has been essential for enabling adaptation at the government level in a challenging political environment. However, using this framework to create an improvement in resilience to climate change across the country requires more than publishing a set of documents; it requires careful thought about what interventions work, how they can be enabled and what level of risk acceptability individuals, organizations and the country should be aiming for.This article is part of the theme issue 'Advances in risk assessment for climate change adaptation policy'. PMID- 29712797 TI - Climate risk index for Italy. AB - We describe a climate risk index that has been developed to inform national climate adaptation planning in Italy and that is further elaborated in this paper. The index supports national authorities in designing adaptation policies and plans, guides the initial problem formulation phase, and identifies administrative areas with higher propensity to being adversely affected by climate change. The index combines (i) climate change-amplified hazards; (ii) high-resolution indicators of exposure of chosen economic, social, natural and built- or manufactured capital (MC) assets and (iii) vulnerability, which comprises both present sensitivity to climate-induced hazards and adaptive capacity. We use standardized anomalies of selected extreme climate indices derived from high-resolution regional climate model simulations of the EURO CORDEX initiative as proxies of climate change-altered weather and climate related hazards. The exposure and sensitivity assessment is based on indicators of manufactured, natural, social and economic capital assets exposed to and adversely affected by climate-related hazards. The MC refers to material goods or fixed assets which support the production process (e.g. industrial machines and buildings); Natural Capital comprises natural resources and processes (renewable and non-renewable) producing goods and services for well-being; Social Capital (SC) addressed factors at the individual (people's health, knowledge, skills) and collective (institutional) level (e.g. families, communities, organizations and schools); and Economic Capital (EC) includes owned and traded goods and services. The results of the climate risk analysis are used to rank the subnational administrative and statistical units according to the climate risk challenges, and possibly for financial resource allocation for climate adaptation.This article is part of the theme issue 'Advances in risk assessment for climate change adaptation policy'. PMID- 29712798 TI - Assessing climate risks across different business sectors and industries: an investigation of methodological challenges at national scale for the UK. AB - Climate change poses severe risks for businesses, which companies as well as governments need to understand in order to take appropriate steps to manage those. This, however, represents a significant challenge as climate change risk assessment is itself a complex, dynamic and geographically diverse process. A wide range of factors including the nature of production processes and value chains, the location of business sites as well as relationships and interdependencies with customers and suppliers play a role in determining if and how companies are impacted by climate risks. This research explores the methodological challenges for a national-scale assessment of climate risks through the lens of the UK Climate Change Risk Assessment (UKCCRA) process and compares the approaches adopted in the first and second UKCCRA (2011, 2016), while also reflecting on international experiences elsewhere. A review of these issues is presented, drawing on a wide body of contemporary evidence from a range of sources including the research disciplines, grey literature and government policy. The study reveals the methodological challenges and highlights six broad themes, namely scale, evidence base, adaptation responses, scope, interdependencies and public policy. The paper concludes by identifying suitable lessons for future national climate risk assessments, which should guide the next phase of research in preparation for UKCCRA3 and those of national-level risk assessments elsewhere.This article is part of the theme issue 'Advances in risk assessment for climate change adaptation policy'. PMID- 29712799 TI - Coastal and river flood risk analyses for guiding economically optimal flood adaptation policies: a country-scale study for Mexico. AB - Many countries around the world face increasing impacts from flooding due to socio-economic development in flood-prone areas, which may be enhanced in intensity and frequency as a result of climate change. With increasing flood risk, it is becoming more important to be able to assess the costs and benefits of adaptation strategies. To guide the design of such strategies, policy makers need tools to prioritize where adaptation is needed and how much adaptation funds are required. In this country-scale study, we show how flood risk analyses can be used in cost-benefit analyses to prioritize investments in flood adaptation strategies in Mexico under future climate scenarios. Moreover, given the often limited availability of detailed local data for such analyses, we show how state of-the-art global data and flood risk assessment models can be applied for a detailed assessment of optimal flood-protection strategies. Our results show that especially states along the Gulf of Mexico have considerable economic benefits from investments in adaptation that limit risks from both river and coastal floods, and that increased flood-protection standards are economically beneficial for many Mexican states. We discuss the sensitivity of our results to modelling uncertainties, the transferability of our modelling approach and policy implications.This article is part of the theme issue 'Advances in risk assessment for climate change adaptation policy'. PMID- 29712801 TI - What's happening in Neurology(r). PMID- 29712802 TI - What's happening in Neurology(r)Clinical Practice. PMID- 29712800 TI - Advances in risk assessment for climate change adaptation policy. AB - Climate change risk assessment involves formal analysis of the consequences, likelihoods and responses to the impacts of climate change and the options for addressing these under societal constraints. Conventional approaches to risk assessment are challenged by the significant temporal and spatial dynamics of climate change; by the amplification of risks through societal preferences and values; and through the interaction of multiple risk factors. This paper introduces the theme issue by reviewing the current practice and frontiers of climate change risk assessment, with specific emphasis on the development of adaptation policy that aims to manage those risks. These frontiers include integrated assessments, dealing with climate risks across borders and scales, addressing systemic risks, and innovative co-production methods to prioritize solutions to climate challenges with decision-makers. By reviewing recent developments in the use of large-scale risk assessment for adaptation policy making, we suggest a forward-looking research agenda to meet ongoing strategic policy requirements in local, national and international contexts.This article is part of the theme issue 'Advances in risk assessment for climate change adaptation policy'. PMID- 29712803 TI - What's happening in Neurology(r)Genetics. PMID- 29712804 TI - What's happening in Neurology(r)Neuroimmunology & Neuroinflammation. PMID- 29712805 TI - What's happening in Innovations in Care Delivery. PMID- 29712806 TI - Whirled world (can't face self). PMID- 29712807 TI - Right Brain: Withholding treatment from a child with an epileptic encephalomyopathy. AB - The case of Charlie Gard, an infant who was hospitalized in England due to a mitochondrial DNA depletion syndrome that led to an epileptic encephalomyopathy, was highly publicized. Though Charlie's parents lobbied for him to receive experimental nucleoside replacement therapy as a desperate effort to save him, this request was denied, and after a lengthy legal battle, he died in late July 2017. We discuss the ethical considerations and consequences of this case. PMID- 29712808 TI - Editors' note: Smoking cessation and secondary stroke prevention. PMID- 29712809 TI - Reader response: Smoking cessation and secondary stroke prevention. PMID- 29712810 TI - Author response: Smoking cessation and secondary stroke prevention. PMID- 29712811 TI - Editors' note: Teaching NeuroImages: RCVS causing simultaneous convexity subarachnoid hemorrhage and hemimedullary infarction. PMID- 29712812 TI - Reader response: Teaching NeuroImages: RCVS causing simultaneous convexity subarachnoid hemorrhage and hemimedullary infarction. PMID- 29712813 TI - Author response: Teaching NeuroImages: RCVS causing simultaneous convexity subarachnoid hemorrhage and hemimedullary infarction. PMID- 29712814 TI - Clinical Reasoning: A 60-year-old woman with ataxia. PMID- 29712815 TI - Clinical Reasoning: A 22-year-old postpartum woman with new-onset seizures and headache. PMID- 29712816 TI - Teaching Video NeuroImages: Acquired focal neuromyotonia in LGI-1 autoimmunity. PMID- 29712817 TI - (Auto-)immune signature in aplastic anemia. PMID- 29712818 TI - Hematopoietic stem cell mobilization with plerixafor in sickle cell disease. PMID- 29712819 TI - Age-related clonal hematopoiesis and monoclonal B-cell lymphocytosis/chronic lymphocytic leukemia: a new association? PMID- 29712820 TI - Denosumab for bone lesions in multiple myeloma - what is its value? PMID- 29712821 TI - Osteoprotective medication in the era of novel agents: a European perspective on values, risks and future solutions. PMID- 29712822 TI - Unexpected slowdown of US pollutant emission reduction in the past decade. AB - Ground and satellite observations show that air pollution regulations in the United States (US) have resulted in substantial reductions in emissions and corresponding improvements in air quality over the last several decades. However, large uncertainties remain in evaluating how recent regulations affect different emission sectors and pollutant trends. Here we show a significant slowdown in decreasing US emissions of nitrogen oxides (NO x ) and carbon monoxide (CO) for 2011-2015 using satellite and surface measurements. This observed slowdown in emission reductions is significantly different from the trend expected using US Environmental Protection Agency (EPA) bottom-up inventories and impedes compliance with local and federal agency air-quality goals. We find that the difference between observations and EPA's NO x emission estimates could be explained by: (i) growing relative contributions of industrial, area, and off road sources, (ii) decreasing relative contributions of on-road gasoline, and (iii) slower than expected decreases in on-road diesel emissions. PMID- 29712823 TI - Comparative terrestrial feed and land use of an aquaculture-dominant world. AB - Reducing food production pressures on the environment while feeding an ever growing human population is one of the grand challenges facing humanity. The magnitude of environmental impacts from food production, largely around land use, has motivated evaluation of the environmental and health benefits of shifting diets, typically away from meat toward other sources, including seafood. However, total global catch of wild seafood has remained relatively unchanged for the last two decades, suggesting increased demand for seafood will mostly have to rely on aquaculture (i.e., aquatic farming). Increasingly, cultivated aquatic species depend on feed inputs from agricultural sources, raising concerns around further straining crops and land use for feed. However, the relative impact and potential of aquaculture remains unclear. Here we simulate how different forms of aquaculture contribute and compare with feed and land use of terrestrial meat production and how spatial patterns might change by midcentury if diets move toward more cultured seafood and less meat. Using country-level aquatic and terrestrial data, we show that aquaculture requires less feed crops and land, even if over one-third of protein production comes from aquaculture by 2050. However, feed and land-sparing benefits are spatially heterogeneous, driven by differing patterns of production, trade, and feed composition. Ultimately, our study highlights the future potential and uncertainties of considering aquaculture in the portfolio of sustainability solutions around one of the largest anthropogenic impacts on the planet. PMID- 29712824 TI - Green function of correlated genes in a minimal mechanical model of protein evolution. AB - The function of proteins arises from cooperative interactions and rearrangements of their amino acids, which exhibit large-scale dynamical modes. Long-range correlations have also been revealed in protein sequences, and this has motivated the search for physical links between the observed genetic and dynamic cooperativity. We outline here a simplified theory of protein, which relates sequence correlations to physical interactions and to the emergence of mechanical function. Our protein is modeled as a strongly coupled amino acid network with interactions and motions that are captured by the mechanical propagator, the Green function. The propagator describes how the gene determines the connectivity of the amino acids and thereby, the transmission of forces. Mutations introduce localized perturbations to the propagator that scatter the force field. The emergence of function is manifested by a topological transition when a band of such perturbations divides the protein into subdomains. We find that epistasis the interaction among mutations in the gene-is related to the nonlinearity of the Green function, which can be interpreted as a sum over multiple scattering paths. We apply this mechanical framework to simulations of protein evolution and observe long-range epistasis, which facilitates collective functional modes. PMID- 29712825 TI - Molecular rotary motors: Unidirectional motion around double bonds. AB - The field of synthetic molecular machines has quickly evolved in recent years, growing from a fundamental curiosity to a highly active field of chemistry. Many different applications are being explored in areas such as catalysis, self assembled and nanostructured materials, and molecular electronics. Rotary molecular motors hold great promise for achieving dynamic control of molecular functions as well as for powering nanoscale devices. However, for these motors to reach their full potential, many challenges still need to be addressed. In this paper we focus on the design principles of rotary motors featuring a double-bond axle and discuss the major challenges that are ahead of us. Although great progress has been made, further design improvements, for example in terms of efficiency, energy input, and environmental adaptability, will be crucial to fully exploit the opportunities that these rotary motors offer. PMID- 29712827 TI - Retrospective of Charles Pence Slichter (NAS 1967). PMID- 29712826 TI - Catalytic amino acid production from biomass-derived intermediates. AB - Amino acids are the building blocks for protein biosynthesis and find use in myriad industrial applications including in food for humans, in animal feed, and as precursors for bio-based plastics, among others. However, the development of efficient chemical methods to convert abundant and renewable feedstocks into amino acids has been largely unsuccessful to date. To that end, here we report a heterogeneous catalyst that directly transforms lignocellulosic biomass-derived alpha-hydroxyl acids into alpha-amino acids, including alanine, leucine, valine, aspartic acid, and phenylalanine in high yields. The reaction follows a dehydrogenation-reductive amination pathway, with dehydrogenation as the rate determining step. Ruthenium nanoparticles supported on carbon nanotubes (Ru/CNT) exhibit exceptional efficiency compared with catalysts based on other metals, due to the unique, reversible enhancement effect of NH3 on Ru in dehydrogenation. Based on the catalytic system, a two-step chemical process was designed to convert glucose into alanine in 43% yield, comparable with the well-established microbial cultivation process, and therefore, the present strategy enables a route for the production of amino acids from renewable feedstocks. Moreover, a conceptual process design employing membrane distillation to facilitate product purification is proposed and validated. Overall, this study offers a rapid and potentially more efficient chemical method to produce amino acids from woody biomass components. PMID- 29712829 TI - Correction for Sheehan et al., Coevolution of landesque capital intensive agriculture and sociopolitical hierarchy. PMID- 29712828 TI - Earth's magnetic field is probably not reversing. AB - The geomagnetic field has been decaying at a rate of ~5% per century from at least 1840, with indirect observations suggesting a decay since 1600 or even earlier. This has led to the assertion that the geomagnetic field may be undergoing a reversal or an excursion. We have derived a model of the geomagnetic field spanning 30-50 ka, constructed to study the behavior of the two most recent excursions: the Laschamp and Mono Lake, centered at 41 and 34 ka, respectively. Here, we show that neither excursion demonstrates field evolution similar to current changes in the geomagnetic field. At earlier times, centered at 49 and 46 ka, the field is comparable to today's field, with an intensity structure similar to today's South Atlantic Anomaly (SAA); however, neither of these SAA-like fields develop into an excursion or reversal. This suggests that the current weakened field will also recover without an extreme event such as an excursion or reversal. The SAA-like field structure at 46 ka appears to be coeval with published increases in geomagnetically modulated beryllium and chlorine nuclide production, despite the global dipole field not weakening significantly in our model during this time. This agreement suggests a greater complexity in the relationship between cosmogenic nuclide production and the geomagnetic field than is commonly assumed. PMID- 29712830 TI - Tertiary structure of apolipoprotein A-I in nascent high-density lipoproteins. AB - Understanding the function of high-density lipoprotein (HDL) requires detailed knowledge of the structure of its primary protein, apolipoprotein A-I (APOA1). However, APOA1 flexibility and HDL heterogeneity have confounded decades of efforts to determine high-resolution structures and consistent models. Here, molecular dynamics simulations totaling 30 MUs on two nascent HDLs, each with 2 APOA1 and either 160 phospholipids and 24 cholesterols or 200 phospholipids and 20 cholesterols, show that residues 1-21 of the N-terminal domains of APOA1 interact via strong salt bridges. Residues 26-43 of one APOA1 in the smaller particle form a hinge on the disc edge, which displaces the C-terminal domain of the other APOA1 to the phospholipid surface. The proposed structures are supported by chemical cross-linking, Rosetta modeling of the N-terminal domain, and analysis of the lipid-free ?185APOA1 crystal structure. These structures provide a framework for understanding HDL maturation and revise all previous models of nascent HDL. PMID- 29712831 TI - Structured networks support sparse traveling waves in rodent somatosensory cortex. AB - Neurons responding to different whiskers are spatially intermixed in the superficial layer 2/3 (L2/3) of the rodent barrel cortex, where a single whisker deflection activates a sparse, distributed neuronal population that spans multiple cortical columns. How the superficial layer of the rodent barrel cortex is organized to support such distributed sensory representations is not clear. In a computer model, we tested the hypothesis that sensory representations in L2/3 of the rodent barrel cortex are formed by activity propagation horizontally within L2/3 from a site of initial activation. The model explained the observed properties of L2/3 neurons, including the low average response probability in the majority of responding L2/3 neurons, and the existence of a small subset of reliably responding L2/3 neurons. Sparsely propagating traveling waves similar to those observed in L2/3 of the rodent barrel cortex occurred in the model only when a subnetwork of strongly connected neurons was immersed in a much larger network of weakly connected neurons. PMID- 29712832 TI - Hidden collapse is driven by fire and logging in a socioecological forest ecosystem. AB - Increasing numbers of ecosystems globally are at risk of collapse. However, most descriptions of terrestrial ecosystem collapse are post hoc with few empirically based examples of ecosystems in the process of collapse. This limits learning about collapse and impedes development of effective early-warning indicators. Based on multidecadal and multifaceted monitoring, we present evidence that the Australian mainland Mountain Ash ecosystem is collapsing. Collapse is indicated by marked changes in ecosystem condition, particularly the rapid decline in populations of keystone ecosystem structures. There also has been significant decline in biodiversity strongly associated with these structures and disruptions of key ecosystem processes. In documenting the decline of the Mountain Ash ecosystem, we uncovered evidence of hidden collapse. This is where an ecosystem superficially appears to be relatively intact, but a prolonged period of decline coupled with long lag times for recovery of dominant ecosystem components mean that collapse is almost inevitable. In ecosystems susceptible to hidden collapse, management interventions will be required decades earlier than currently perceived by policy makers. Responding to hidden collapse is further complicated by our finding that different drivers produce different pathways to collapse, but these drivers can interact in ways that exacerbate and perpetuate collapse. Management must focus not only on reducing the number of critical stressors influencing an ecosystem but also on breaking feedbacks between stressors. We demonstrate the importance of multidecadal monitoring programs in measuring state variables that can inform quantitative predictions of collapse as well as help identify management responses that can avert system-wide collapse. PMID- 29712833 TI - Genomic adaptation to drought in wild barley is driven by edaphic natural selection at the Tabigha Evolution Slope. AB - Ecological divergence at a microsite suggests adaptive evolution, and this study examined two abutting wild barley populations, each 100 m across, differentially adapted to drought tolerance on two contrasting soil types, Terra Rossa and basalt at the Tabigha Evolution Slope, Israel. We resequenced the genomes of seven and six wild barley genotypes inhabiting the Terra Rossa and basalt soils, respectively, and identified a total of 69,192,653 single-nucleotide variants (SNVs) and insertions/deletions in comparison with a reference barley genome. Comparative genomic analysis between these abutting wild barley populations involved 19,615,087 high-quality SNVs. The results revealed dramatically different selection sweep regions relevant to drought tolerance driven by edaphic natural selection within 2,577 selected genes in these regions, including key drought-responsive genes associated with ABA synthesis and degradation (such as Cytochrome P450 protein) and ABA receptor complex (such as PYL2, SNF1-related kinase). The genetic diversity of the wild barley population inhabiting Terra Rossa soil is much higher than that from the basalt soil. Additionally, we identified different sets of genes for drought adaptation in the wild barley populations from Terra Rossa soil and from wild barley populations from Evolution Canyon I at Mount Carmel. These genes are associated with abscisic acid signaling, signaling and metabolism of reactive oxygen species, detoxification and antioxidative systems, rapid osmotic adjustment, and deep root morphology. The unique mechanisms for drought adaptation of the wild barley from the Tabigha Evolution Slope may be useful for crop improvement, particularly for breeding of barley cultivars with high drought tolerance. PMID- 29712834 TI - Revisiting the role of IRF3 in inflammation and immunity by conditional and specifically targeted gene ablation in mice. AB - IFN regulatory factor 3 (IRF3) is a transcription regulator of cellular responses in many cell types that is known to be essential for innate immunity. To confirm IRF3's broad role in immunity and to more fully discern its role in various cellular subsets, we engineered Irf3-floxed mice to allow for the cell type specific ablation of Irf3 Analysis of these mice confirmed the general requirement of IRF3 for the evocation of type I IFN responses in vitro and in vivo. Furthermore, immune cell ontogeny and frequencies of immune cell types were unaffected when Irf3 was selectively inactivated in either T cells or B cells in the mice. Interestingly, in a model of lipopolysaccharide-induced septic shock, selective Irf3 deficiency in myeloid cells led to reduced levels of type I IFN in the sera and increased survival of these mice, indicating the myeloid-specific, pathogenic role of the Toll-like receptor 4-IRF3 type I IFN axis in this model of sepsis. Thus, Irf3-floxed mice can serve as useful tool for further exploring the cell type-specific functions of this transcription factor. PMID- 29712835 TI - Histone demethylase JMJD1A promotes alternative splicing of AR variant 7 (AR-V7) in prostate cancer cells. AB - Formation of the androgen receptor splicing variant 7 (AR-V7) is one of the major mechanisms by which resistance of prostate cancer to androgen deprivation therapy occurs. The histone demethylase JMJD1A (Jumonji domain containing 1A) functions as a key coactivator for AR by epigenetic regulation of H3K9 methylation marks. Here, we describe a role for JMJD1A in AR-V7 expression. While JMJD1A knockdown had no effect on full-length AR (AR-FL), it reduced AR-V7 levels in prostate cancer cells. Reexpression of AR-V7 in the JMJD1A-knockdown cells elevated expression of select AR targets and partially rescued prostate cancer cell growth in vitro and in vivo. The AR-V7 protein level correlated positively with JMJD1A in a subset of human prostate cancer specimens. Mechanistically, we found that JMJD1A promoted alternative splicing of AR-V7 through heterogeneous nuclear ribonucleoprotein F (HNRNPF), a splicing factor known to regulate exon inclusion. Knockdown of JMJD1A or HNRNPF inhibited splicing of AR-V7, but not AR-FL, in a minigene reporter assay. JMJD1A was found to interact with and promote the recruitment of HNRNPF to a cryptic exon 3b on AR pre-mRNA for the generation of AR-V7. Taken together, the role of JMJD1A in AR-FL coactivation and AR-V7 alternative splicing highlights JMJD1A as a potentially promising target for prostate cancer therapy. PMID- 29712836 TI - Local initiation conditions for water autoionization. AB - The pH of liquid water is determined by the infrequent process in which water molecules split into short-lived hydroxide and hydronium ions. This reaction is difficult to probe experimentally and challenging to simulate. One of the open questions is whether the local water structure around a slightly stretched OH bond is actually initiating the eventual breakage of this bond or whether this event is driven by a global ordering that involves many water molecules far away from the reaction center. Here, we investigated the self-ionization of water at room temperature by rare-event ab initio molecular dynamics and obtained autoionization rates and activation energies in good agreement with experiments. Based on the analysis of thousands of molecular trajectories, we identified a couple of local order parameters and show that if a bond stretch occurs when all these parameters are around their ideal range, the chance for the first dissociation step (double-proton jump) increases from [Formula: see text] to 0.4. Understanding these initiation triggers might ultimately allow the steering of chemical reactions. PMID- 29712838 TI - Butane dihedral angle dynamics in water is dominated by internal friction. AB - The dihedral dynamics of butane in water is known to be rather insensitive to the water viscosity; possible explanations for this involve inertial effects or Kramers' turnover, the finite memory time of friction, and the presence of so called internal friction. To disentangle these factors, we introduce a method to directly extract the friction memory function from unconstrained simulations in the presence of an arbitrary free-energy landscape. By analysis of the dihedral friction in butane for varying water viscosity, we demonstrate the existence of an internal friction contribution that does not scale linearly with water viscosity. At normal water viscosity, the internal friction turns out to be eight times larger than the solvent friction and thus completely dominates the effective friction. By comparison with simulations of a constrained butane molecule that has the dihedral as the only degree of freedom, we show that internal friction comes from the six additional degrees of freedom in unconstrained butane that are orthogonal to the dihedral angle reaction coordinate. While the insensitivity of butane's dihedral dynamics to water viscosity is solely due to the presence of internal friction, inertial effects nevertheless crucially influence the resultant transition rates. In contrast, non Markovian effects due to the finite memory time are present but do not significantly influence the dihedral barrier-crossing rate of butane. These results not only settle the character of dihedral dynamics in small solvated molecular systems such as butane, they also have important implications for the folding of polymers and proteins. PMID- 29712837 TI - Mechanistic studies of a small-molecule modulator of SMN2 splicing. AB - RG-7916 is a first-in-class drug candidate for the treatment of spinal muscular atrophy (SMA) that functions by modulating pre-mRNA splicing of the SMN2 gene, resulting in a 2.5-fold increase in survival of motor neuron (SMN) protein level, a key protein lacking in SMA patients. RG-7916 is currently in three interventional phase 2 clinical trials for various types of SMA. In this report, we show that SMN-C2 and -C3, close analogs of RG-7916, act as selective RNA binding ligands that modulate pre-mRNA splicing. Chemical proteomic and genomic techniques reveal that SMN-C2 directly binds to the AGGAAG motif on exon 7 of the SMN2 pre-mRNA, and promotes a conformational change in two to three unpaired nucleotides at the junction of intron 6 and exon 7 in both in vitro and in-cell models. This change creates a new functional binding surface that increases binding of the splicing modulators, far upstream element binding protein 1 (FUBP1) and its homolog, KH-type splicing regulatory protein (KHSRP), to the SMN C2/C3-SMN2 pre-mRNA complex and enhances SMN2 splicing. These findings underscore the potential of small-molecule drugs to selectively bind RNA and modulate pre mRNA splicing as an approach to the treatment of human disease. PMID- 29712839 TI - Habitat degradation negatively affects auditory settlement behavior of coral reef fishes. AB - Coral reefs are increasingly degraded by climate-induced bleaching and storm damage. Reef recovery relies on recruitment of young fishes for the replenishment of functionally important taxa. Acoustic cues guide the orientation, habitat selection, and settlement of many fishes, but these processes may be impaired if degradation alters reef soundscapes. Here, we report spatiotemporally matched evidence of soundscapes altered by degradation from recordings taken before and after recent severe damage on Australia's Great Barrier Reef. Postdegradation soundscapes were an average of 15 dB re 1 uPa quieter and had significantly reduced acoustic complexity, richness, and rates of invertebrate snaps compared with their predegradation equivalents. We then used these matched recordings in complementary light-trap and patch-reef experiments to assess responses of wild fish larvae under natural conditions. We show that postdegradation soundscapes were 8% less attractive to presettlement larvae and resulted in 40% less settlement of juvenile fishes than predegradation soundscapes; postdegradation soundscapes were no more attractive than open-ocean sound. However, our experimental design does not allow an estimate of how much attraction and settlement to isolated postdegradation soundscapes might change compared with isolated predegradation soundscapes. Reductions in attraction and settlement were qualitatively similar across and within all trophic guilds and taxonomic groups analyzed. These patterns may lead to declines in fish populations, exacerbating degradation. Acoustic changes might therefore trigger a feedback loop that could impair reef resilience. To understand fully the recovery potential of coral reefs, we must learn to listen. PMID- 29712840 TI - MYB30 links ROS signaling, root cell elongation, and plant immune responses. AB - Reactive oxygen species (ROS) are known to be important signal molecules that are involved in biotic and abiotic stress responses as well as in growth regulation. However, the molecular mechanisms by which ROS act as a growth regulator, as well as how ROS-dependent growth regulation relates to its roles in stress responses, are not well understood. We performed a time-course microarray analysis of Arabidopsis root tips upon treatment with hydrogen peroxide, which we named "ROS map." Using the ROS-map, we identified an MYB transcription factor, MYB30, which showed a strong response to ROS treatment and is the key regulator of a gene network that leads to the hydrogen peroxide-dependent inhibition of root cell elongation. Intriguingly, this network contained multiple genes involved in very long-chain fatty acid (VLCFA) transport. Finally, we showed that MYB30 is necessary for root growth regulation during defense responses, thus providing a molecular link between these two ROS-associated processes. PMID- 29712841 TI - Symbiotic polydnavirus and venom reveal parasitoid to its hyperparasitoids. AB - Symbiotic relationships may provide organisms with key innovations that aid in the establishment of new niches. For example, during oviposition, some species of parasitoid wasps, whose larvae develop inside the bodies of other insects, inject polydnaviruses into their hosts. These symbiotic viruses disrupt host immune responses, allowing the parasitoid's progeny to survive. Here we show that symbiotic polydnaviruses also have a downside to the parasitoid's progeny by initiating a multitrophic chain of interactions that reveals the parasitoid larvae to their enemies. These enemies are hyperparasitoids that use the parasitoid progeny as host for their own offspring. We found that the virus and venom injected by the parasitoid during oviposition, but not the parasitoid progeny itself, affected hyperparasitoid attraction toward plant volatiles induced by feeding of parasitized caterpillars. We identified activity of virus related genes in the caterpillar salivary gland. Moreover, the virus affected the activity of elicitors of salivary origin that induce plant responses to caterpillar feeding. The changes in caterpillar saliva were critical in inducing plant volatiles that are used by hyperparasitoids to locate parasitized caterpillars. Our results show that symbiotic organisms may be key drivers of multitrophic ecological interactions. We anticipate that this phenomenon is widespread in nature, because of the abundance of symbiotic microorganisms across trophic levels in ecological communities. Their role should be more prominently integrated in community ecology to understand organization of natural and managed ecosystems, as well as adaptations of individual organisms that are part of these communities. PMID- 29712843 TI - Correction for Gao et al., Chronic stress promotes colitis by disturbing the gut microbiota and triggering immune system response. PMID- 29712842 TI - Less immune activation following social stress in rural vs. urban participants raised with regular or no animal contact, respectively. AB - Urbanization is on the rise, and environments offering a narrow range of microbial exposures are linked to an increased prevalence of both physical and mental disorders. Human and animal studies suggest that an overreactive immune system not only accompanies stress-associated disorders but might even be causally involved in their pathogenesis. Here, we show in young [mean age, years (SD): rural, 25.1 (0.78); urban, 24.5 (0.88)] healthy human volunteers that urban upbringing in the absence of pets (n = 20), relative to rural upbringing in the presence of farm animals (n = 20), was associated with a more pronounced increase in the number of peripheral blood mononuclear cells (PBMCs) and plasma interleukin 6 (IL-6) concentrations following acute psychosocial stress induced by the Trier social stress test (TSST). Moreover, ex vivo-cultured PBMCs from urban participants raised in the absence of animals secreted more IL-6 in response to the T cell-specific mitogen Con A. In turn, antiinflammatory IL-10 secretion was suppressed following TSST in urban participants raised in the absence of animals, suggesting immunoregulatory deficits, relative to rural participants raised in the presence of animals. Questionnaires, plasma cortisol, and salivary alpha-amylase, however, indicated the experimental protocol was more stressful and anxiogenic for rural participants raised in the presence of animals. Together, our findings support the hypothesis that urban vs. rural upbringing in the absence or presence of animals, respectively, increases vulnerability to stress-associated physical and mental disorders by compromising adequate resolution of systemic immune activation following social stress and, in turn, aggravating stress-associated systemic immune activation. PMID- 29712844 TI - Escherichia coli cultures maintain stable subpopulation structure during long term evolution. AB - How genetic variation is generated and maintained remains a central question in evolutionary biology. When presented with a complex environment, microbes can take advantage of genetic variation to exploit new niches. Here we present a massively parallel experiment where WT and repair-deficient (?mutL) Escherichia coli populations have evolved over 3 y in a spatially heterogeneous and nutritionally complex environment. Metagenomic sequencing revealed that these initially isogenic populations evolved and maintained stable subpopulation structure in just 10 mL of medium for up to 10,000 generations, consisting of up to five major haplotypes with many minor haplotypes. We characterized the genomic, transcriptomic, exometabolomic, and phenotypic differences between clonal isolates, revealing subpopulation structure driven primarily by spatial segregation followed by differential utilization of nutrients. In addition to genes regulating the import and catabolism of nutrients, major polymorphisms of note included insertion elements transposing into fimE (regulator of the type I fimbriae) and upstream of hns (global regulator of environmental-change and stress-response genes), both known to regulate biofilm formation. Interestingly, these genes have also been identified as critical to colonization in uropathogenic E. coli infections. Our findings illustrate the complexity that can arise and persist even in small cultures, raising the possibility that infections may often be promoted by an evolving and complex pathogen population. PMID- 29712845 TI - Systematic analysis of copy number variation associated with congenital diaphragmatic hernia. AB - Congenital diaphragmatic hernia (CDH), characterized by malformation of the diaphragm and hypoplasia of the lungs, is one of the most common and severe birth defects, and is associated with high morbidity and mortality rates. There is growing evidence demonstrating that genetic factors contribute to CDH, although the pathogenesis remains largely elusive. Single-nucleotide polymorphisms have been studied in recent whole-exome sequencing efforts, but larger copy number variants (CNVs) have not yet been studied on a large scale in a case control study. To capture CNVs within CDH candidate regions, we developed and tested a targeted array comparative genomic hybridization platform to identify CNVs within 140 regions in 196 patients and 987 healthy controls, and identified six significant CNVs that were either unique to patients or enriched in patients compared with controls. These CDH-associated CNVs reveal high-priority candidate genes including HLX, LHX1, and HNF1B We also discuss CNVs that are present in only one patient in the cohort but have additional evidence of pathogenicity, including extremely rare large and/or de novo CNVs. The candidate genes within these predicted disease-causing CNVs form functional networks with other known CDH genes and play putative roles in DNA binding/transcription regulation and embryonic development. These data substantiate the importance of CNVs in the etiology of CDH, identify CDH candidate genes and pathways, and highlight the importance of ongoing analysis of CNVs in the study of CDH and other structural birth defects. PMID- 29712848 TI - Rational application of macrophage-specific LXR agonists avoids the pitfalls of SREBP-induced lipogenesis. PMID- 29712847 TI - An endogenous dAMP ligand in Bacillus subtilis class Ib RNR promotes assembly of a noncanonical dimer for regulation by dATP. AB - The high fidelity of DNA replication and repair is attributable, in part, to the allosteric regulation of ribonucleotide reductases (RNRs) that maintains proper deoxynucleotide pool sizes and ratios in vivo. In class Ia RNRs, ATP (stimulatory) and dATP (inhibitory) regulate activity by binding to the ATP-cone domain at the N terminus of the large alpha subunit and altering the enzyme's quaternary structure. Class Ib RNRs, in contrast, have a partial cone domain and have generally been found to be insensitive to dATP inhibition. An exception is the Bacillus subtilis Ib RNR, which we recently reported to be inhibited by physiological concentrations of dATP. Here, we demonstrate that the alpha subunit of this RNR contains tightly bound deoxyadenosine 5'-monophosphate (dAMP) in its N-terminal domain and that dATP inhibition of CDP reduction is enhanced by its presence. X-ray crystallography reveals a previously unobserved (noncanonical) alpha2 dimer with its entire interface composed of the partial N-terminal cone domains, each binding a dAMP molecule. Using small-angle X-ray scattering (SAXS), we show that this noncanonical alpha2 dimer is the predominant form of the dAMP bound alpha in solution and further show that addition of dATP leads to the formation of larger oligomers. Based on this information, we propose a model to describe the mechanism by which the noncanonical alpha2 inhibits the activity of the B. subtilis Ib RNR in a dATP- and dAMP-dependent manner. PMID- 29712846 TI - Ribosome protection by antibiotic resistance ATP-binding cassette protein. AB - The ribosome is one of the richest targets for antibiotics. Unfortunately, antibiotic resistance is an urgent issue in clinical practice. Several ATP binding cassette family proteins confer resistance to ribosome-targeting antibiotics through a yet unknown mechanism. Among them, MsrE has been implicated in macrolide resistance. Here, we report the cryo-EM structure of ATP form MsrE bound to the ribosome. Unlike previously characterized ribosomal protection proteins, MsrE is shown to bind to ribosomal exit site. Our structure reveals that the domain linker forms a unique needle-like arrangement with two crossed helices connected by an extended loop projecting into the peptidyl-transferase center and the nascent peptide exit tunnel, where numerous antibiotics bind. In combination with biochemical assays, our structure provides insight into how MsrE binding leads to conformational changes, which results in the release of the drug. This mechanism appears to be universal for the ABC-F type ribosome protection proteins. PMID- 29712849 TI - Symbiotic root infections in Medicago truncatula require remorin-mediated receptor stabilization in membrane nanodomains. AB - Plant cell infection is tightly controlled by cell surface receptor-like kinases (RLKs). Like other RLKs, the Medicago truncatula entry receptor LYK3 laterally segregates into membrane nanodomains in a stimulus-dependent manner. Although nanodomain localization arises as a generic feature of plant membrane proteins, the molecular mechanisms underlying such dynamic transitions and their functional relevance have remained poorly understood. Here we demonstrate that actin and the flotillin protein FLOT4 form the primary and indispensable core of a specific nanodomain. Infection-dependent induction of the remorin protein and secondary molecular scaffold SYMREM1 results in subsequent recruitment of ligand-activated LYK3 and its stabilization within these membrane subcompartments. Reciprocally, the majority of this LYK3 receptor pool is destabilized at the plasma membrane and undergoes rapid endocytosis in symrem1 mutants on rhizobial inoculation, resulting in premature abortion of host cell infections. These data reveal that receptor recruitment into nanodomains is indispensable for their function during host cell infection. PMID- 29712851 TI - Incorporating light atoms into synthetic analogues of FeMoco. PMID- 29712850 TI - Distinct gating mechanism of SOC channel involving STIM-Orai coupling and an intramolecular interaction of Orai in Caenorhabditis elegans. AB - Store-operated calcium entry (SOCE), an important mechanism of Ca2+ signaling in a wide range of cell types, is mediated by stromal interaction molecule (STIM), which senses the depletion of endoplasmic reticulum Ca2+ stores and binds and activates Orai channels in the plasma membrane. This inside-out mechanism of Ca2+ signaling raises an interesting question about the evolution of SOCE: How did these two proteins existing in different cellular compartments evolve to interact with each other? We investigated the gating mechanism of Caenorhabditis elegans Orai channels. Our analysis revealed a mechanism of Orai gating by STIM binding to the intracellular 2-3 loop of Orai in C. elegans that is radically different from Orai gating by STIM binding to the N and C termini of Orai in mammals. In addition, we found that the conserved hydrophobic amino acids in the 2-3 loop of Orai1 are important for the oligomerization and gating of channels and are regulated via an intramolecular interaction mechanism mediated by the N and C termini of Orai1. This study identifies a previously unknown SOCE mechanism in C. elegans and suggests that, while the STIM-Orai interaction is conserved between invertebrates and mammals, the gating mechanism for Orai channels differs considerably. PMID- 29712853 TI - Tunneling explains efficient electron transport via protein junctions. AB - Metalloproteins, proteins containing a transition metal ion cofactor, are electron transfer agents that perform key functions in cells. Inspired by this fact, electron transport across these proteins has been widely studied in solid state settings, triggering the interest in examining potential use of proteins as building blocks in bioelectronic devices. Here, we report results of low temperature (10 K) electron transport measurements via monolayer junctions based on the blue copper protein azurin (Az), which strongly suggest quantum tunneling of electrons as the dominant charge transport mechanism. Specifically, we show that, weakening the protein-electrode coupling by introducing a spacer, one can switch the electron transport from off-resonant to resonant tunneling. This is a consequence of reducing the electrode's perturbation of the Cu(II)-localized electronic state, a pattern that has not been observed before in protein-based junctions. Moreover, we identify vibronic features of the Cu(II) coordination sphere in transport characteristics that show directly the active role of the metal ion in resonance tunneling. Our results illustrate how quantum mechanical effects may dominate electron transport via protein-based junctions. PMID- 29712854 TI - Adaptive and nonadaptive changes in phenological synchrony. PMID- 29712852 TI - Revealing the specificity of regulatory T cells in murine autoimmune diabetes. AB - Regulatory T cells (Tregs) control organ-specific autoimmunity in a tissue antigen-specific manner, yet little is known about their specificity in a natural repertoire. In this study, we used the nonobese diabetic (NOD) mouse model of autoimmune diabetes to investigate the antigen specificity of Tregs present in the inflamed tissue, the islets of Langerhans. Compared with Tregs present in spleen and lymph node, Tregs in the islets showed evidence of antigen stimulation that correlated with higher proliferation and expression of activation markers CD103, ICOS, and TIGIT. T cell receptor (TCR) repertoire profiling demonstrated that islet Treg clonotypes are expanded in the islets, suggesting localized antigen-driven expansion in inflamed islets. To determine their specificity, we captured TCRalphabeta pairs from islet Tregs using single-cell TCR sequencing and found direct evidence that some of these TCRs were specific for islet-derived antigens including insulin B:9-23 and proinsulin. Consistently, insulin B:9-23 tetramers readily detected insulin-specific Tregs in the islets of NOD mice. Lastly, islet Tregs from prediabetic NOD mice were effective at preventing diabetes in Treg-deficient NOD.CD28-/- recipients. These results provide a glimpse into the specificities of Tregs in a natural repertoire that are crucial for opposing the progression of autoimmune diabetes. PMID- 29712855 TI - FACT complex is required for DNA demethylation at heterochromatin during reproduction in Arabidopsis. AB - The DEMETER (DME) DNA glycosylase catalyzes genome-wide DNA demethylation and is required for endosperm genomic imprinting and embryo viability. Targets of DME mediated DNA demethylation reside in small, euchromatic, AT-rich transposons and at the boundaries of large transposons, but how DME interacts with these diverse chromatin states is unknown. The STRUCTURE SPECIFIC RECOGNITION PROTEIN 1 (SSRP1) subunit of the chromatin remodeler FACT (facilitates chromatin transactions), was previously shown to be involved in the DME-dependent regulation of genomic imprinting in Arabidopsis endosperm. Therefore, to investigate the interaction between DME and chromatin, we focused on the activity of the two FACT subunits, SSRP1 and SUPPRESSOR of TY16 (SPT16), during reproduction in Arabidopsis We found that FACT colocalizes with nuclear DME in vivo, and that DME has two classes of target sites, the first being euchromatic and accessible to DME, but the second, representing over half of DME targets, requiring the action of FACT for DME mediated DNA demethylation genome-wide. Our results show that the FACT-dependent DME targets are GC-rich heterochromatin domains with high nucleosome occupancy enriched with H3K9me2 and H3K27me1. Further, we demonstrate that heterochromatin associated linker histone H1 specifically mediates the requirement for FACT at a subset of DME-target loci. Overall, our results demonstrate that FACT is required for DME targeting by facilitating its access to heterochromatin. PMID- 29712856 TI - Loss of a highly conserved sterile alpha motif domain gene (WEEP) results in pendulous branch growth in peach trees. AB - Plant shoots typically grow upward in opposition to the pull of gravity. However, exceptions exist throughout the plant kingdom. Most conspicuous are trees with weeping or pendulous branches. While such trees have long been cultivated and appreciated for their ornamental value, the molecular basis behind the weeping habit is not known. Here, we characterized a weeping tree phenotype in Prunus persica (peach) and identified the underlying genetic mutation using a genomic sequencing approach. Weeping peach tree shoots exhibited a downward elliptical growth pattern and did not exhibit an upward bending in response to 90 degrees reorientation. The causative allele was found to be an uncharacterized gene, Ppa013325, having a 1.8-Kb deletion spanning the 5' end. This gene, dubbed WEEP, was predominantly expressed in phloem tissues and encodes a highly conserved 129 amino acid protein containing a sterile alpha motif (SAM) domain. Silencing WEEP in the related tree species Prunus domestica (plum) resulted in more outward, downward, and wandering shoot orientations compared to standard trees, supporting a role for WEEP in directing lateral shoot growth in trees. This previously unknown regulator of branch orientation, which may also be a regulator of gravity perception or response, provides insights into our understanding of how tree branches grow in opposition to gravity and could serve as a critical target for manipulating tree architecture for improved tree shape in agricultural and horticulture applications. PMID- 29712857 TI - Symbiont switching and alternative resource acquisition strategies drive mutualism breakdown. AB - Cooperative interactions among species, termed mutualisms, have played a crucial role in the evolution of life on Earth. However, despite key potential benefits to partners, there are many cases in which two species cease to cooperate and mutualisms break down. What factors drive the evolutionary breakdown of mutualism? We examined the pathways toward breakdowns of the mutualism between plants and arbuscular mycorrhizal fungi. By using a comparative approach, we identify ~25 independent cases of complete mutualism breakdown across global seed plants. We found that breakdown of cooperation was only stable when host plants (i) partner with other root symbionts or (ii) evolve alternative resource acquisition strategies. Our results suggest that key mutualistic services are only permanently lost if hosts evolve alternative symbioses or adaptations. PMID- 29712859 TI - Doped Kondo chain, a heavy Luttinger liquid. AB - The doped 1D Kondo Lattice describes complex competition between itinerant and magnetic ordering. The numerically computed wave vector-dependent charge and spin susceptibilities give insights into its low-energy properties. Similar to the prediction of the large N approximation, gapless spin and charge modes appear at the large Fermi wave vector. The highly suppressed spin velocity is a manifestation of "heavy" Luttinger liquid quasiparticles. A low-energy hybridization gap is detected at the small (conduction band) Fermi wave vector. In contrast to the exponential suppression of the Fermi velocity in the large-N approximation, we fit the spin velocity by a density-dependent power law of the Kondo coupling. The differences between the large-N theory and our numerical results are associated with the emergent magnetic Ruderman-Kittel-Kasuya-Yosida interactions. PMID- 29712858 TI - Distinct roles of resident and nonresident macrophages in nonischemic cardiomyopathy. AB - Nonischemic cardiomyopathy (NICM) resulting from long-standing hypertension, valvular disease, and genetic mutations is a major cause of heart failure worldwide. Recent observations suggest that myeloid cells can impact cardiac function, but the role of tissue-intrinsic vs. tissue-extrinsic myeloid cells in NICM remains poorly understood. Here, we show that cardiac resident macrophage proliferation occurs within the first week following pressure overload hypertrophy (POH; a model of heart failure) and is requisite for the heart's adaptive response. Mechanistically, we identify Kruppel-like factor 4 (KLF4) as a key transcription factor that regulates cardiac resident macrophage proliferation and angiogenic activities. Finally, we show that blood-borne macrophages recruited in late-phase POH are detrimental, and that blockade of their infiltration improves myocardial angiogenesis and preserves cardiac function. These observations demonstrate previously unappreciated temporal and spatial roles for resident and nonresident macrophages in the development of heart failure. PMID- 29712860 TI - The C-terminal extension landscape of naturally presented HLA-I ligands. AB - HLA-I molecules play a central role in antigen presentation. They typically bind 9- to 12-mer peptides, and their canonical binding mode involves anchor residues at the second and last positions of their ligands. To investigate potential noncanonical binding modes, we collected in-depth and accurate HLA peptidomics datasets covering 54 HLA-I alleles and developed algorithms to analyze these data. Our results reveal frequent (442 unique peptides) and statistically significant C-terminal extensions for at least eight alleles, including the common HLA-A03:01, HLA-A31:01, and HLA-A68:01. High resolution crystal structure of HLA-A68:01 with such a ligand uncovers structural changes taking place to accommodate C-terminal extensions and helps unraveling sequence and structural properties predictive of the presence of these extensions. Scanning viral proteomes with the C-terminal extension motifs identifies many putative epitopes and we demonstrate direct recognition by human CD8+ T cells of a 10-mer epitope from cytomegalovirus predicted to follow the C-terminal extension binding mode. PMID- 29712861 TI - HCMV glycoprotein B subunit vaccine efficacy mediated by nonneutralizing antibody effector functions. AB - Human cytomegalovirus (HCMV) is the most common congenital infection worldwide, frequently causing hearing loss and brain damage in afflicted infants. A vaccine to prevent maternal acquisition of HCMV during pregnancy is necessary to reduce the incidence of infant disease. The glycoprotein B (gB) + MF59 adjuvant subunit vaccine platform is the most successful HCMV vaccine tested to date, demonstrating ~50% efficacy in preventing HCMV acquisition in multiple phase 2 trials. However, the mechanism of vaccine protection remains unknown. Plasma from 33 postpartum women gB/MF59 vaccinees at peak immunogenicity was tested for gB epitope specificity as well as neutralizing and nonneutralizing anti-HCMV effector functions and compared with an HCMV-seropositive cohort. gB/MF59 vaccination elicited IgG responses with gB-binding magnitude and avidity comparable to natural infection. Additionally, IgG subclass distribution was similar with predominant IgG1 and IgG3 responses induced by gB vaccination and HCMV infection. However, vaccine-elicited antibodies exhibited limited neutralization of the autologous virus, negligible neutralization of multiple heterologous strains, and limited binding responses against gB structural motifs targeted by neutralizing antibodies including AD-1, AD-2, and domain I. Vaccinees had high-magnitude IgG responses against AD-3 linear epitopes, demonstrating immunodominance against this nonneutralizing, cytosolic region. Finally, vaccine elicited IgG robustly bound membrane-associated gB on the surface of transfected or HCMV-infected cells and mediated virion phagocytosis, although were poor mediators of NK cell activation. Altogether, these data suggest that nonneutralizing antibody functions, including virion phagocytosis, likely played a role in the observed 50% vaccine-mediated protection against HCMV acquisition. PMID- 29712862 TI - Symbiotic polydnavirus of a parasite manipulates caterpillar and plant immunity. AB - Obligate symbioses occur when organisms require symbiotic relationships to survive. Some parasitic wasps of caterpillars possess obligate mutualistic viruses called "polydnaviruses." Along with eggs, wasps inject polydnavirus inside their caterpillar hosts where the hatching larvae develop inside the caterpillar. Polydnaviruses suppress the immune systems of their caterpillar hosts, which enables egg hatch and wasp larval development. It is unknown whether polydnaviruses also manipulate the salivary proteins of the caterpillar, which may affect the elicitation of plant defenses during feeding by the caterpillar. Here, we show that a polydnavirus of the parasitoid Microplitis croceipes, and not the parasitoid larva itself, drives the regulation of salivary enzymes of the caterpillar Helicoverpa zea that are known to elicit tomato plant-defense responses to herbivores. The polydnavirus suppresses glucose oxidase, which is a primary plant-defense elicitor in the saliva of the H. zea caterpillar. By suppressing plant defenses, the polydnavirus allows the caterpillar to grow at a faster rate, thus improving the host suitability for the parasitoid. Remarkably, polydnaviruses manipulate the phenotypes of the wasp, caterpillar, and host plant, demonstrating that polydnaviruses play far more prominent roles in shaping plant-herbivore interactions than ever considered. PMID- 29712863 TI - Gravisensors in plant cells behave like an active granular liquid. AB - Plants are able to sense and respond to minute tilt from the vertical direction of the gravity, which is key to maintain their upright posture during development. However, gravisensing in plants relies on a peculiar sensor made of microsize starch-filled grains (statoliths) that sediment and form tiny granular piles at the bottom of the cell. How such a sensor can detect inclination is unclear, as granular materials like sand are known to display flow threshold and finite avalanche angle due to friction and interparticle jamming. Here, we address this issue by combining direct visualization of statolith avalanches in plant cells and experiments in biomimetic cells made of microfluidic cavities filled with a suspension of heavy Brownian particles. We show that, despite their granular nature, statoliths move and respond to the weakest angle, as a liquid clinometer would do. Comparison between the biological and biomimetic systems reveals that this liquid-like behavior comes from the cell activity, which agitates statoliths with an apparent temperature one order of magnitude larger than actual temperature. Our results shed light on the key role of active fluctuations of statoliths for explaining the remarkable sensitivity of plants to inclination. Our study also provides support to a recent scenario of gravity perception in plants, by bridging the active granular rheology of statoliths at the microscopic level to the macroscopic gravitropic response of the plant. PMID- 29712864 TI - Quantum indistinguishability in chemical reactions. AB - Quantum indistinguishability plays a crucial role in many low-energy physical phenomena, from quantum fluids to molecular spectroscopy. It is, however, typically ignored in most high-temperature processes, particularly for ionic coordinates, implicitly assumed to be distinguishable, incoherent, and thus well approximated classically. We explore enzymatic chemical reactions involving small symmetric molecules and argue that in many situations a full quantum treatment of collective nuclear degrees of freedom is essential. Supported by several physical arguments, we conjecture a "quantum dynamical selection" (QDS) rule for small symmetric molecules that precludes chemical processes that involve direct transitions from orbitally nonsymmetric molecular states. As we propose and discuss, the implications of the QDS rule include (i) a differential chemical reactivity of para- and orthohydrogen, (ii) a mechanism for inducing intermolecular quantum entanglement of nuclear spins, (iii) a mass-independent isotope fractionation mechanism, (iv) an explanation of the enhanced chemical activity of "reactive oxygen species", (v) illuminating the importance of ortho water molecules in modulating the quantum dynamics of liquid water, and (vi) providing the critical quantum-to-biochemical linkage in the nuclear spin model of the (putative) quantum brain, among others. PMID- 29712865 TI - Mechanism for survival of homozygous nonsense mutations in the tumor suppressor gene BRCA1. AB - BRCA1 is essential for repair of DNA double-strand breaks by homologous recombination, and hence for survival. Complete loss of its function is lethal during early embryonic development. Patients who are compound heterozygous for BRCA1 truncating mutations and missense alleles that retain some DNA repair capacity may survive, albeit with very high risk of early onset breast or ovarian cancer and features of Fanconi anemia. However, a mechanism enabling survival of patients homozygous for BRCA1 truncating mutations has not been described. We studied two unrelated families in which four children presented with multiple congenital anomalies and severe chromosomal fragility. One child developed T cell acute lymphocytic leukemia (ALL), and a second child developed neuroblastoma. Each of the four children was homozygous for a nonsense mutation in BRCA1 exon 11. Homozygosity for the nonsense mutations was viable thanks to the presence of a naturally occurring alternative splice donor in BRCA1 exon 11 that lies 5' of the mutations. The mutations did not affect the alternative splice site, but transcription from it produced an in-frame BRCA1 message with deletion of 3,309 bp. The translated BRCA1 protein was only 40% of normal length, but with intact N and C-terminal sequences. These patients extend the range of BRCA1-related phenotypes and illustrate how naturally occurring alternative splicing can enable survival, albeit with severe consequences, of otherwise lethal genotypes of an essential gene. PMID- 29712866 TI - Optimizing the impact of low-efficacy influenza vaccines. AB - The efficacy of influenza vaccines varies from one year to the next, with efficacy during the 2017-2018 season anticipated to be lower than usual. However, the impact of low-efficacy vaccines at the population level and their optimal age specific distribution have yet to be ascertained. Applying an optimization algorithm to a mathematical model of influenza transmission and vaccination in the United States, we determined the optimal age-specific uptake of low-efficacy vaccine that would minimize incidence, hospitalization, mortality, and disability adjusted life-years (DALYs), respectively. We found that even relatively low efficacy influenza vaccines can be highly impactful, particularly when vaccine uptake is optimally distributed across age groups. As vaccine efficacy declines, the optimal distribution of vaccine uptake shifts toward the elderly to minimize mortality and DALYs. Health practitioner encouragement and concerted recruitment efforts are required to achieve optimal coverage among target age groups, thereby minimizing influenza morbidity and mortality for the population overall. PMID- 29712867 TI - Symbolic emblems of the Levantine Aurignacians as a regional entity identifier (Hayonim Cave, Lower Galilee, Israel). AB - The Levantine Aurignacian is a unique phenomenon in the local Upper Paleolithic sequence, showing greater similarity to the West European classic Aurignacian than to the local Levantine archaeological entities preceding and following it. Herewith we highlight another unique characteristic of this entity, namely, the presence of symbolic objects in the form of notched bones (mostly gazelle scapulae) from the Aurignacian levels of Hayonim Cave, Lower Galilee, Israel. Through both macroscopic and microscopic analyses of the items, we suggest that they are not mere cut marks but rather are intentional (decorative?) human-made markings. The significance of this evidence for symbolic behavior is discussed in its chrono-cultural and geographical contexts. Notched bones are among the oldest symbolic expressions of anatomically modern humans. However, unlike other Paleolithic sites where such findings were reported in single numbers, the number of these items recovered at Hayonim Cave is sufficient to assume they possibly served as an emblem of the Levantine Aurignacian. PMID- 29712868 TI - Insulin promoter in human pancreatic beta cells contacts diabetes susceptibility loci and regulates genes affecting insulin metabolism. AB - Both type 1 and type 2 diabetes involve a complex interplay between genetic, epigenetic, and environmental factors. Our laboratory has been interested in the physical interactions, in nuclei of human pancreatic beta cells, between the insulin (INS) gene and other genes that are involved in insulin metabolism. We have identified, using Circularized Chromosome Conformation Capture (4C), many physical contacts in a human pancreatic beta cell line between the INS promoter on chromosome 11 and sites on most other chromosomes. Many of these contacts are associated with type 1 or type 2 diabetes susceptibility loci. To determine whether physical contact is correlated with an ability of the INS locus to affect expression of these genes, we knock down INS expression by targeting the promoter; 259 genes are either up or down-regulated. Of these, 46 make physical contact with INS We analyze a subset of the contacted genes and show that all are associated with acetylation of histone H3 lysine 27, a marker of actively expressed genes. To demonstrate the usefulness of this approach in revealing regulatory pathways, we identify from among the contacted sites the previously uncharacterized gene SSTR5-AS1 and show that it plays an important role in controlling the effect of somatostatin-28 on insulin secretion. These results are consistent with models in which clustering of genes supports transcriptional activity. This may be a particularly important mechanism in pancreatic beta cells and in other cells where a small subset of genes is expressed at high levels. PMID- 29712869 TI - Quantifying flow and stress in ice melange, the world's largest granular material. AB - Tidewater glacier fjords are often filled with a collection of calved icebergs, brash ice, and sea ice. For glaciers with high calving rates, this "melange" of ice can be jam-packed, so that the flow of ice fragments is mostly determined by granular interactions. In the jammed state, ice melange has been hypothesized to influence iceberg calving and capsize, dispersion and attenuation of ocean waves, injection of freshwater into fjords, and fjord circulation. However, detailed measurements of ice melange are lacking due to difficulties in instrumenting remote, ice-choked fjords. Here we characterize the flow and associated stress in ice melange, using a combination of terrestrial radar data, laboratory experiments, and numerical simulations. We find that, during periods of terminus quiescence, ice melange experiences laminar flow over timescales of hours to days. The uniform flow fields are bounded by shear margins along fjord walls where force chains between granular icebergs terminate. In addition, the average force per unit width that is transmitted to the glacier terminus, which can exceed 107 N/m, increases exponentially with the melange length-to-width ratio. These "buttressing" forces are sufficiently high to inhibit the initiation of large-scale calving events, supporting the notion that ice melange can be viewed as a weak granular ice shelf that transmits stresses from fjord walls back to glacier termini. PMID- 29712870 TI - High-order fractal states in graphene superlattices. AB - Graphene superlattices were shown to exhibit high-temperature quantum oscillations due to periodic emergence of delocalized Bloch states in high magnetic fields such that unit fractions of the flux quantum pierce a superlattice unit cell. Under these conditions, semiclassical electron trajectories become straight again, similar to the case of zero magnetic field. Here, we report magnetotransport measurements that reveal second-, third-, and fourth-order magnetic Bloch states at high electron densities and temperatures above 100 K. The recurrence of these states creates a fractal pattern intimately related to the origin of Hofstadter butterflies. The hierarchy of the fractal states is determined by the width of magnetic minibands, in qualitative agreement with our band-structure calculations. PMID- 29712871 TI - Structural homo- and heterosynaptic plasticity in mature and adult newborn rat hippocampal granule cells. AB - Adult newborn hippocampal granule cells (abGCs) contribute to spatial learning and memory. abGCs are thought to play a specific role in pattern separation, distinct from developmentally born mature GCs (mGCs). Here we examine at which exact cell age abGCs are synaptically integrated into the adult network and which forms of synaptic plasticity are expressed in abGCs and mGCs. We used virus mediated labeling of abGCs and mGCs to analyze changes in spine morphology as an indicator of plasticity in rats in vivo. High-frequency stimulation of the medial perforant path induced long-term potentiation in the middle molecular layer (MML) and long-term depression in the nonstimulated outer molecular layer (OML). This stimulation protocol elicited NMDA receptor-dependent homosynaptic spine enlargement in the MML and heterosynaptic spine shrinkage in the inner molecular layer and OML. Both processes were concurrently present on individual dendritic trees of abGCs and mGCs. Spine shrinkage counteracted spine enlargement and thus could play a homeostatic role, normalizing synaptic weights. Structural homosynaptic spine plasticity had a clear onset, appearing in abGCs by 28 d postinjection (dpi), followed by heterosynaptic spine plasticity at 35 dpi, and at 77 dpi was equally as present in mature abGCs as in mGCs. From 35 dpi on, about 60% of abGCs and mGCs showed significant homo- and heterosynaptic plasticity on the single-cell level. This demonstration of structural homo- and heterosynaptic plasticity in abGCs and mGCs defines the time course of the appearance of synaptic plasticity and integration for abGCs. PMID- 29712872 TI - A comprehensive omics analysis and functional survey of cuticular proteins in the brown planthopper. AB - Cuticle, mainly composed of chitin and cuticular proteins (CPs), is a multifunctional structure of arthropods. CPs usually account for >1% of the total insect proteins. Why does an insect encode so many different CP genes in the genome? In this study, we use comprehensive large-scale technologies to study the full complement of CPs (i.e., the CP-ome) of the brown planthopper (BPH), Nilaparvata lugens, a major rice plant pest. Eight CP families (CPR, CPF, TWDL, CPLCP, CPG, CPAP1, CPAP3, and CPAPn) including 140 proteins in BPH, in which CPAPn is a CP family that we discovered. The CPG family that was considered to be restricted to the Lepidoptera has also been identified in BPH. As reported here, CPLCP family members are characterized by three conserved sequence motifs. In addition, we identified a testis protein family with a peritrophin A domain that we named TPAP. We authenticated the real existence of 106 proteins among the 140 CPs. RNA interference (RNAi) experiments were conducted against 135 CP genes in early- and late-instar nymphs and newly emerged female adults, demonstrating that 32 CPs were essential for BPH normal development or egg production. Combined RNAi experiments suggested redundant and complementary functions of the large number of CPs. Transcriptomic data revealed that the CP genes were expressed in a tissue specific manner, and there were four clusters of developmental expression patterns. This study gives a comprehensive understanding of the roles of CPs in an insect cuticle. PMID- 29712873 TI - Autoregulation of SafA Assembly through Recruitment of a Protein Cross-Linking Enzyme. AB - The coat of Bacillus subtilis spores is a multiprotein protective structure that also arbitrates many of the environmental interactions of the spore. The coat assembles around the cortex peptidoglycan layer and is differentiated into an inner and an outer layer and a crust. SafA governs assembly of the inner coat, whereas CotE drives outer coat assembly. SafA localizes to the cortex-coat interface. Both SafA and its short form C30 are substrates for Tgl, a coat associated transglutaminase that cross-links proteins through epsilon-(gamma glutamyl)lysyl isopeptide bonds. We show that SafA and C30 are distributed between the coat and cortex layers. The deletion of tgl increases the extractability of SafA, mainly from the cortex. Tgl itself is mostly located in the inner coat and cortex. The localization of Tgl-cyan fluorescent protein (Tgl CFP) is strongly, but not exclusively, dependent on safA However, the association of Tgl with the cortex requires safA Together, our results suggest an assembly pathway in which Tgl is first recruited to the forming spore in a manner that is only partially dependent on SafA and then is drafted to the cortex by SafA. Tgl, in turn, promotes the conversion of coat- and cortex-associated SafA into forms that resist extraction, possibly by catalyzing the cross-linking of SafA to other coat proteins, to the cortex, and/or to cortex-associated proteins. Therefore, the final assembly state of SafA relies on an autoregulatory pathway that requires the subcellular localization of a protein cross-linking enzyme. Tgl most likely exerts a "spotwelding" activity, cross-linking preformed complexes in the cortex and inner coat layers of spores.IMPORTANCE In this work, we show how two proteins work together to determine their subcellular location within the coat of bacterial endospores. Bacillus subtilis endospores are surrounded by a multilayer protein coat composed of over 80 proteins, which surrounds an underlying peptidoglycan layer (the spore cortex) protecting it from lytic enzymes. How specific coat proteins are targeted to specific layers of the coat is not well understood. We found that the protein SafA recruits a protein-cross-linking enzyme (a transglutaminase) to the cortex and inner layers of the coat, where both are cemented, by cross-linking, into macromolecular complexes. PMID- 29712874 TI - Arginine and Citrulline Catabolic Pathways Encoded by the arc Gene Cluster of Lactobacillus brevis ATCC 367. AB - High concentrations of l-arginine or l-citrulline in the growth medium provided the wine bacterium Lactobacillus brevis with a significant growth advantage. The arginine deiminase pathway (ADI) arc gene cluster of Lactobacillus brevis contains three genes-arcD, arcE1, and arcE2-encoding putative l-arginine/l ornithine exchangers. Uptake experiments with Lactococcus lactis cells expressing the genes showed that all three transported l-ornithine with affinities in the micromolar range. Similarly, ArcD and ArcE2 transported l-arginine, while ArcE1 transported l-citrulline, an intermediate of the ADI pathway. Chase experiments showed very efficient exchange of l-arginine and l-ornithine by ArcD and ArcE2 and of l-citrulline and l-ornithine by ArcE1. Low affinities (millimolar range) combined with low translocation rates were found for ArcD and ArcE2 with l citrulline and for ArcE1 with l-arginine. Resting cells of Lactobacillus brevis grown in the presence of l-arginine and l-citrulline rapidly consumed l-arginine and l-citrulline, respectively, while producing ammonia and l-ornithine. About 10% of l-arginine degraded was excreted by the cells as l-citrulline. Degradation of l-arginine and l-citrulline was not subject to carbon catabolite repression by glucose in the medium. At a high medium pH, l-citrulline in the medium was required for induction of the l-citrulline degradation pathway. Pathways are proposed for the catabolic breakdown of l-arginine and l-citrulline that merge at the level of ornithine transcarbamylase in the ADI pathway. l-Arginine uptake is catalyzed by ArcD and/or ArcE2, l-citrulline by ArcE1. l-Citrulline excretion during l-arginine breakdown is proposed to be catalyzed by ArcD and/or ArcE2 through l-arginine/l-citrulline exchange.IMPORTANCELactobacillus brevis, a bacterium isolated from wine, as well as other food environments, expresses a catabolic pathway for the breakdown of l-citrulline in the medium that consists of the l-citrulline/l-ornithine exchanger ArcE1 and part of the catabolic arginine deiminase (ADI) pathway enzymes. The proposed pathways for l-arginine and l-citrulline breakdown provide a mechanism for l-citrulline accumulation in fermented food products that is the precursor of the carcinogen ethyl carbamate. PMID- 29712875 TI - Roles of Alanine Dehydrogenase and Induction of Its Gene in Mycobacterium smegmatis under Respiration-Inhibitory Conditions. AB - Here we demonstrated that the inhibition of electron flux through the respiratory electron transport chain (ETC) by either the disruption of the gene for the major terminal oxidase (aa3 cytochrome c oxidase) or treatment with KCN resulted in the induction of ald encoding alanine dehydrogenase in Mycobacterium smegmatis A decrease in functionality of the ETC shifts the redox state of the NADH/NAD+ pool toward a more reduced state, which in turn leads to an increase in cellular levels of alanine by Ald catalyzing the conversion of pyruvate to alanine with the concomitant oxidation of NADH to NAD+ The induction of ald expression under respiration-inhibitory conditions in M. smegmatis is mediated by the alanine responsive AldR transcriptional regulator. The growth defect of M. smegmatis by respiration inhibition was exacerbated by inactivation of the ald gene, suggesting that Ald is beneficial to M. smegmatis in its adaptation and survival under respiration-inhibitory conditions by maintaining NADH/NAD+ homeostasis. The low susceptibility of M. smegmatis to bcc1 complex inhibitors appears to be, at least in part, attributable to the high expression level of the bd quinol oxidase in M. smegmatis when the bcc1-aa3 branch of the ETC is inactivated.IMPORTANCE We demonstrated that the functionality of the respiratory electron transport chain is inversely related to the expression level of the ald gene encoding alanine dehydrogenase in Mycobacterium smegmatis Furthermore, the importance of Ald in NADH/NAD+ homeostasis during the adaptation of M. smegmatis to severe respiration inhibitory conditions was demonstrated in this study. On the basis of these results, we propose that combinatory regimens including both an Ald-specific inhibitor and respiration-inhibitory antitubercular drugs such as Q203 and bedaquiline are likely to enable a more efficient therapy for tuberculosis. PMID- 29712876 TI - Guanine limitation results in CodY-dependent and -independent alteration of Staphylococcus aureus physiology and gene expression. AB - In Staphylococcus aureus, the global transcriptional regulator CodY modulates the expression of hundreds of genes in response to the availability of GTP and the branched-chain amino acids isoleucine, leucine, and valine (ILV). CodY DNA binding activity is high when GTP and ILV are abundant. When GTP and ILV are limited, CodY's affinity for DNA drops, altering expression of CodY regulated targets. In this work, we investigated the impact of guanine nucleotides on S. aureus physiology and CodY activity by constructing a guaA null mutant (DeltaguaA). De novo biosynthesis of guanine monophosphate is abolished due to the guaA mutation; thus, the mutant cells require exogenous guanosine for growth. We also found that CodY activity was reduced when we knocked out guaA, activating the Agr two-component system and increasing secreted protease activity. Notably, in a rich, complex medium, we detected an increase in alternative sigma factor B activity in the DeltaguaA mutant, which results in a 5-fold increase in production of the antioxidant pigment staphyloxanthin. Under biologically relevant flow conditions, DeltaguaA cells failed to form robust biofilms when limited for guanine or guanosine. RNA-seq analysis of S. aureus transcriptome during growth in guanosine-limited chemostats revealed substantial CodY-dependent and -independent alteration of gene expression profiles. Importantly, these changes increase production of proteases and delta-toxin, suggesting that S. aureus exhibits a more invasive lifestyle when limited for guanosine. Further, gene-products upregulated under GN limitation, including those necessary for lipoic acid biosynthesis and sugar transport, may prove to be useful drug targets for treating Gram-positive infections.ImportanceStaphylococcus aureus infections impose a serious economic burden on healthcare facilities and patients because of the emergence of strains resistant to last-line antibiotics. Understanding the physiological processes governing fitness and virulence of S. aureus in response to environmental cues is critical for developing efficient diagnostics and treatments. De novo purine biosynthesis is essential for both fitness and virulence in S. aureus, since inhibiting production cripples S. aureus's ability to cause infection. Here, we corroborate these findings and show that blocking guanine nucleotide synthesis severely affects S. aureus fitness by altering metabolic and virulence gene expression. Characterizing pathways and gene products upregulated in response to guanine limitation can aid in the development of novel adjuvant strategies to combat S. aureus infections. PMID- 29712878 TI - Joint statement on EPA proposed rule and public availability of data. PMID- 29712877 TI - Characterization of the collagen microstructural organization of human cervical tissue. AB - The cervix shortens and softens as its collagen microstructure remodels in preparation for birth. Altered cervical tissue collagen microstructure can contribute to a mechanically weak cervix and premature cervical dilation and delivery. To investigate the local microstructural changes associated with anatomic location and pregnancy, we used second-harmonic generation microscopy to quantify the orientation and spatial distribution of collagen throughout cervical tissue from 4 pregnant and 14 non-pregnant women. Across patients, the alignment and concentration of collagen within the cervix was more variable near the internal os and less variable near the external os. Across anatomic locations, the spatial distribution of collagen within a radial zone adjacent to the inner canal of the cervix was more homogeneous than that of a region comprising the middle and outer radial zones. Two regions with different collagen distribution characteristics were found. The anterior and posterior sections in the outer radial zone were characterized by greater spatial heterogeneity of collagen than that of the rest of the sections. Our findings suggest that the microstructural alignment and distribution of collagen varies with anatomic location within the human cervix. These observed differences in collagen microstructural alignment may reflect local anatomic differences in cervical mechanical loading and function. Our study deepens the understanding of specific microstructural cervical changes in pregnancy and informs investigations of potential mechanisms for normal and premature cervical remodeling. PMID- 29712879 TI - Low Levels of Caveolin-1 Predict Symptomatic Bleeding After Thrombolytic Therapy in Patients With Acute Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Experimental models of cerebral ischemia demonstrate that the decrease in the caveolin-1 membrane protein results in an increase in endothelial permeability. Because this phenomenon is responsible for hemorrhagic transformation (HT) after cerebral ischemia, we aimed to determine whether caveolin-1 levels may predict bleeding after recombinant tissue-type plasminogen activator (r-tPA) administration in patients with acute stroke. METHODS: We studied 133 patients with a first hemispheric stroke treated with r-tPA within 4.5 hours of symptom onset. HT was evaluated and classified on cranial computed tomography at 24 hours and was considered as symptomatic HT (sHT) if associated with neurological deterioration. Serum caveolin-1 levels were analyzed before and at 2, 24, and 72 hours post-r-tPA administration in patients and in 40 healthy controls. RESULTS: Baseline caveolin-1 levels were higher in patients than controls (0.24 [0.17-0.40] versus 0.07 [0.0-0.20] ng/mL; P<0.000). Twenty six (19.5%) patients had HT, which was symptomatic in 7 (5.3%). Patients with parenchymal hemorrhage-2 and sHT had lower baseline caveolin-1 levels than the rest of patients (0.08 [0.04-0.19] versus 0.26 [0.14-0.40]; P=0.019 and 0.08 [0.02-0.17] versus 0.26 [0.13-0.41]; P=0.019, respectively). The levels remained stable in the first 72 hours in patients with parenchymal hemorrhage-2 and sHT, whereas in the rest of patients levels decreased in this time. Caveolin-1 levels <=0.17 ng/mL had the highest predictive capacity of sHT (86% sensitivity, 65% specificity, 99% negative predictive value, 12% positive predictive value). After adjustment for confounders, caveolin-1 levels <=0.17 ng/mL independently predicted sHT (odds ratio, 11.6; 95% confidence interval, 11.3-102.8; P=0.027). CONCLUSIONS: Low serum levels of caveolin-1 are an independent predictor of sHT after r-tPA administration. Because of the small sample size, further research is needed to validate these data. PMID- 29712880 TI - Different Effects of Normobaric Oxygen in Normotensive Versus Hypertensive Rats After Focal Cerebral Ischemia. AB - BACKGROUND AND PURPOSE: The efficacy of neuroprotective approaches in stroke may be influenced by existing comorbidities. Here, we compared the effects of normobaric hyperoxia (NBO) in normotensive versus hypertensive rats subjected to transient focal cerebral ischemia. METHODS: Male Sprague-Dawley and spontaneously hypertensive rats were subjected to transient focal ischemia via intraluminal filament occlusions of the middle cerebral artery. NBO was started 15 minutes after ischemic onset and stopped at the time of reperfusion. Acute neurological deficits and tetrazolium-stained infarct volumes were quantified at 24 hours. RESULTS: NBO reduced mean infarct volumes by ~50% (P=0.0064) in normotensive Sprague-Dawley rats subjected to 100 minutes transient ischemia. No effects of NBO were observed in hypertensive spontaneously hypertensive rats subjected to either 100 minutes or 75 minutes of transient ischemia. No significant changes in neurological outcomes were detectable in any group. CONCLUSIONS: NBO reduced infarction in Sprague-Dawley but not in spontaneously hypertensive rats. These findings suggest that comorbidities may influence responses to potential treatments after stroke. PMID- 29712881 TI - Delays in the Air or Ground Transfer of Patients for Endovascular Thrombectomy. AB - BACKGROUND AND PURPOSE: For suspected large vessel occlusion patients efficient transfer to centers that provide endovascular therapy (ET) is critical to maximizing treatment opportunity. Our objective was to examine associations between transfer time, modes of transfer, ET, and outcomes within a hub-and-spoke telestroke network. METHODS: Patients with ischemic stroke were included if transferred to a single hub hospital between January 2011 and October 2015 with National Institutes of Health Stroke Scale>6, onset<12 hours from hub arrival with complete clinical, imaging, and transfer data. Transfer time was the interval between initiation of telestroke consult and arrival at the hub. Algorithms were created for ideal transfer times; ideal time was subtracted from actual time to calculate delay. We examined bivariate relationships between transfer time and several clinical outcomes and used multivariable regression modeling to explore possible predictors of delay. RESULTS: Of 234 patients that met inclusion criteria, 51% were transferred by ambulance and 49% by helicopter; 27% underwent ET (36% achieved modified Rankin Scale score of 0-2 at 90 days). Median actual transfer time was 132 minutes (interquartile range, 103-165), compared with median ideal transfer time at 102 minutes (interquartile range, 96 123). Longer transfer time was associated with decreased likelihood of undergoing ET (odds ratio, 0.990; P=0.003). Nocturnal transfer (18:00 to 06:00 hours) was associated with significantly longer delay (beta=20.5; P<0.0005), whereas intravenous tissue-type plasminogen activator (tPA) delivery at spoke hospital was not. The median delay for nocturnal transfer was 31 minutes (interquartile range, 11-51), compared with daytime at 14 minutes (interquartile range, -9 to 36). CONCLUSIONS: Within a large telestroke network, there was an association between longer transfer time and decreased likelihood of undergoing ET. Nocturnal transfers were associated with a substantial delay relative to daytime transfers. In contrast, delivery of tPA was not associated with delays, underscoring the impact of effective protocols at spoke hospitals. More efficient transfer may enable higher ET treatment rates. Metrics and protocols for transfer, especially at night, may improve transfer times. PMID- 29712882 TI - Angiotensin generation in the brain: a re-evaluation. AB - The existence of a so-called brain renin-angiotensin system (RAS) is controversial. Given the presence of the blood-brain barrier, angiotensin generation in the brain, if occurring, should depend on local synthesis of renin and angiotensinogen. Yet, although initially brain-selective expression of intracellular renin was reported, data in intracellular renin knockout animals argue against a role for this renin in angiotensin generation. Moreover, renin levels in brain tissue at most represented renin in trapped blood. Additionally, in neurogenic hypertension brain prorenin up-regulation has been claimed, which would generate angiotensin following its binding to the (pro)renin receptor. However, recent studies reported no evidence for prorenin expression in the brain, nor for its selective up-regulation in neurogenic hypertension, and the (pro)renin receptor rather displays RAS-unrelated functions. Finally, although angiotensinogen mRNA is detectable in the brain, brain angiotensinogen protein levels are low, and even these low levels might be an overestimation due to assay artefacts. Taken together, independent angiotensin generation in the brain is unlikely. Indeed, brain angiotensin levels are extremely low, with angiotensin (Ang) I levels corresponding to the small amounts of Ang I in trapped blood plasma, and Ang II levels at most representing Ang II bound to (vascular) brain Ang II type 1 receptors. This review concludes with a unifying concept proposing the blood origin of angiotensin in the brain, possibly resulting in increased levels following blood-brain barrier disruption (e.g. due to hypertension), and suggesting that interfering with either intracellular renin or the (pro)renin receptor has consequences in an RAS-independent manner. PMID- 29712884 TI - Imbalance of gut microbiome and intestinal epithelial barrier dysfunction in cardiovascular disease. AB - The main function of the intestinal barrier is to regulate the absorption of nutrients, electrolytes, and water from the lumen into circulation and to prevent the entry of pathogenic microorganisms and toxic luminal substances. To maintain this function, an ideal microbiota balance is required and gut microbiota are critical for the intestinal epithelial barrier dysfunction and for the maintenance of physiological homeostasis. There is a demonstrable link between dysbiosis and intestinal dysfunction and diseases such as diabetes, obesity, and cardiovascular disease. However, links amongst gut pathology, microbial ecology, and blood pressure remain elusive. In a recent issue of Clinical Science (vol. 132, issue 6, 701-718), Kim et al. demonstrate a crucial link between gut microbiota and bacterial metabolites such as butyrate, gut leakiness, and hypertension. PMID- 29712883 TI - Small vessels, dementia and chronic diseases - molecular mechanisms and pathophysiology. AB - Cerebral small vessel disease (SVD) is a major contributor to stroke, cognitive impairment and dementia with limited therapeutic interventions. There is a critical need to provide mechanistic insight and improve translation between pre clinical research and the clinic. A 2-day workshop was held which brought together experts from several disciplines in cerebrovascular disease, dementia and cardiovascular biology, to highlight current advances in these fields, explore synergies and scope for development. These proceedings provide a summary of key talks at the workshop with a particular focus on animal models of cerebral vascular disease and dementia, mechanisms and approaches to improve translation. The outcomes of discussion groups on related themes to identify the gaps in knowledge and requirements to advance knowledge are summarized. PMID- 29712885 TI - Leishmania in a Patient with Small Lymphocytic Lymphoma/Chronic Lymphocytic Leukemia. AB - BACKGROUND Leishmaniasis is a parasitic infection spread by the bite of infected sand flies that are usually present in the Middle East, Africa, and some parts of Asia and Europe. Leishmaniasis manifests in 3 different forms: Visceral (also known as Kala Azar), which is the most serious type; cutaneous, which is the most common type; and mucocutaneous. The symptoms of this infection range from a silent infection to fever, enlargement of the liver and spleen, weight loss, and pancytopenia. CASE REPORT In this case report, we discuss a 73-year-old man known to have chronic lymphocytic leukemia (CLL), presenting with unremitting fever and who to our surprise was found to have Kala Azar. CONCLUSIONS Early diagnosis and treatment are very important in treating visceral leishmaniasis. While the conventional treatment in immunocompromised patients is liposomal amphotericin B, our patient responded to corticosteroids. PMID- 29712886 TI - Outcomes of Adult Liver Transplantation from Donation After Brain Death Followed by Circulatory Death in China. AB - BACKGROUND Organ donation from a deceased donor, which is donation after brain death followed by circulatory death, is a unique transplantation practice in China. Pathological features of grafts help guide the utilization of grafts. MATERIAL AND METHODS We retrospectively reviewed our experiences in 188 DBCD allografts from May 2014 to April 2017. We divided 183 transplanted allografts into 3 groups according to pretransplant histology: the good quality graft group (n=62), the preservation injury group (n=27), and the steatotic graft group (n=94). Univariate and multivariate analyses were performed to identify factors in the steatotic graft group predicting the prognoses. RESULTS The prevalence rates of allografts in the good quality, steatotic liver, and preservation injury groups were 33.0% (62/188), 50.0% (94/188), and 14.4%(27/188), respectively, and the discarded rate was 2.7% (5/188). The 1- and 3-year overall survival rates were 92.1% and 88.1%, respectively. There were no differences in 1- and 3-year patient survival among the 3 groups (p=0.615). Some complications occurred: acute rejection in 7 cases, lung infection in 11 recipients, biliary stricture and bile leak in 9 patients, and portal thrombosis in 1 recipient; 17 recipients died of various causes. Cox multivariate analysis revealed that longer cold storage time was associated with worse outcome in the steatotic graft group. CONCLUSIONS Clinical outcomes of adult liver transplantation from deceased donation in China are acceptable. PMID- 29712887 TI - Short-Course Versus Long-Course Chemoradiotherapy for Stage IE-IIE Extranodal Natural Killer/T cell Lymphoma, Nasal Type: A Multicenter Retrospective Study. AB - BACKGROUND This study compared clinical outcomes and adverse events between L asparaginase/pegaspargase-based short-course and long-course chemoradiotherapy in newly diagnosed stage IE-IIE extranodal natural killer/T cell lymphoma, nasal type (ENKTL). MATERIAL AND METHODS Patients were categorized into a short-course (2-4 chemotherapy cycles, median: 4, n=153) and long-course group (5-6 cycles, median: 6, n=83). The chemotherapy regimens included GELOX, SMILE, and VLP. The radiotherapy dose was 40-63 Gy (median: 55 Gy). Adverse events, treatment responses, and survival outcomes between the 2 groups were compared. RESULTS Ann Arbor stage IIE and short-course chemotherapy adversely affected overall survival (OS). Ann Arbor stage IE favorably affected progression-free survival (PFS). Grade 3-4 hematological toxicities were higher in the long-course group (25.3% vs. 14.4%, p=0.038). Ann Arbor stage was the single different clinical feature between the 2 groups, and independently affected survival outcomes. In subgroup analysis of stage IE, there was no difference in response rates and survival outcomes between the 2 groups. In subgroup analysis of stage IIE, the recurrence and death rates were significantly lower in the long-course group (6.1% vs. 23.2%, p=0.015; 12.2% vs. 39.3%, p=0.002; respectively), and the 3-year OS and PFS rates were much longer in the long-course group (87.8% vs. 62.5%, p<0.001; 83.7% vs. 57.1%, p=0.001; respectively). CONCLUSIONS When radiotherapy was combined with L-asparaginase/pegaspargase-based chemotherapy to treat early-stage ENKTL patients, 2-4 cycles of chemotherapy might be sufficient for stage IE patients, while stage IIE patients might require 5+ cycles. PMID- 29712888 TI - Regulation of DNA damage repair and lipid uptake by CX3CR1 in epithelial ovarian carcinoma. AB - Failure of currently used cytotoxic chemotherapy is one of the main reasons behind high mortality from metastatic high grade serous ovarian carcinoma. We found that high expression of a receptor for fractalkine (CX3CR1) significantly correlated with shorter survival of patients with serous ovarian carcinoma treated with cytotoxic DNA damage chemotherapies, and reduction of CX3CR1 expression resulted in sensitization to several DNA damaging modalities, including x-ray radiation and cisplatin. Here, we show that CX3CR1 plays a role in double-strand DNA break response and repair by regulating expression of RAD50 by a MYC-dependent mechanism. We demonstrate that downregulation of CX3CR1 alone and in a combination with irradiation affects peritoneal metastasis in an organ specific manner; we show that CX3CR1 regulates lipid uptake which could control omental metastasis. This study identifies CX3CR1 as a novel potential target for sensitization of ovarian carcinoma to DNA damage therapies and reduction of peritoneal carcinomatosis. PMID- 29712889 TI - Native mass spectrometry combined with enzymatic dissection unravels glycoform heterogeneity of biopharmaceuticals. AB - Robust manufacturing processes resulting in consistent glycosylation are critical for the efficacy and safety of biopharmaceuticals. Information on glycosylation can be obtained by conventional bottom-up methods but is often limited to the glycan or glycopeptide level. Here, we apply high-resolution native mass spectrometry (MS) for the characterization of the therapeutic fusion protein Etanercept to unravel glycoform heterogeneity in conditions of hitherto unmatched mass spectral complexity. Higher spatial resolution at lower charge states, an inherent characteristic of native MS, represents a key component for the successful revelation of glycan heterogeneity. Combined with enzymatic dissection using a set of proteases and glycosidases, assignment of specific glycoforms is achieved by transferring information from subunit to whole protein level. The application of native mass spectrometric analysis of intact Etanercept as a fingerprinting tool for the assessment of batch-to-batch variability is exemplified and may be extended to demonstrate comparability after changes in the biologic manufacturing process. PMID- 29712890 TI - Increasing occurrence of cold and warm extremes during the recent global warming slowdown. AB - The recent levelling of global mean temperatures after the late 1990s, the so called global warming hiatus or slowdown, ignited a surge of scientific interest into natural global mean surface temperature variability, observed temperature biases, and climate communication, but many questions remain about how these findings relate to variations in more societally relevant temperature extremes. Here we show that both summertime warm and wintertime cold extreme occurrences increased over land during the so-called hiatus period, and that these increases occurred for distinct reasons. The increase in cold extremes is associated with an atmospheric circulation pattern resembling the warm Arctic-cold continents pattern, whereas the increase in warm extremes is tied to a pattern of sea surface temperatures resembling the Atlantic Multidecadal Oscillation. These findings indicate that large-scale factors responsible for the most societally relevant temperature variations over continents are distinct from those of global mean surface temperature. PMID- 29712891 TI - Large thermoelectric power factor from crystal symmetry-protected non-bonding orbital in half-Heuslers. AB - Modern society relies on high charge mobility for efficient energy production and fast information technologies. The power factor of a material-the combination of electrical conductivity and Seebeck coefficient-measures its ability to extract electrical power from temperature differences. Recent advancements in thermoelectric materials have achieved enhanced Seebeck coefficient by manipulating the electronic band structure. However, this approach generally applies at relatively low conductivities, preventing the realization of exceptionally high-power factors. In contrast, half-Heusler semiconductors have been shown to break through that barrier in a way that could not be explained. Here, we show that symmetry-protected orbital interactions can steer electron acoustic phonon interactions towards high mobility. This high-mobility regime enables large power factors in half-Heuslers, well above the maximum measured values. We anticipate that our understanding will spark new routes to search for better thermoelectric materials, and to discover high electron mobility semiconductors for electronic and photonic applications. PMID- 29712892 TI - Sequencing of intraductal biopsies is feasible and potentially impacts clinical management of patients with indeterminate biliary stricture and cholangiocarcinoma. AB - BACKGROUND: Definite diagnosis and therapeutic management of cholangiocarcinoma (CCA) remains a challenge. The aim of the current study was to investigate feasibility and potential impact on clinical management of targeted sequencing of intraductal biopsies. METHODS: Intraductal biopsies with suspicious findings from 16 patients with CCA in later clinical course were analyzed with targeted sequencing including tumor and control benign tissue (n = 55 samples). A CCA specific sequencing panel containing 41 genes was designed and a dual strand targeted enrichment was applied. RESULTS: Sequencing was successfully performed for all samples. In total, 79 mutations were identified and a mean of 1.7 mutations per tumor sample (range 0-4) as well as 2.3 per biopsy (0-6) were detected and potentially therapeutically relevant genes were identified in 6/16 cases. In 14/18 (78%) biopsies with dysplasia or inconclusive findings at least one mutation was detected. The majority of mutations were found in both surgical specimen and biopsy (68%), while 28% were only present in biopsies in contrast to 4% being only present in the surgical tumor specimen. CONCLUSION: Targeted sequencing from intraductal biopsies is feasible and potentially improves the diagnostic yield. A profound genetic heterogeneity in biliary dysplasia needs to be considered in clinical management and warrants further investigation. TRANSLATIONAL IMPACT: The current study is the first to demonstrate the feasibility of sequencing of intraductal biopsies which holds the potential to impact diagnostic and therapeutical management of patients with biliary dysplasia and neoplasia. PMID- 29712893 TI - Linear mitochondrial DNA is rapidly degraded by components of the replication machinery. AB - Emerging gene therapy approaches that aim to eliminate pathogenic mutations of mitochondrial DNA (mtDNA) rely on efficient degradation of linearized mtDNA, but the enzymatic machinery performing this task is presently unknown. Here, we show that, in cellular models of restriction endonuclease-induced mtDNA double-strand breaks, linear mtDNA is eliminated within hours by exonucleolytic activities. Inactivation of the mitochondrial 5'-3'exonuclease MGME1, elimination of the 3' 5'exonuclease activity of the mitochondrial DNA polymerase POLG by introducing the p.D274A mutation, or knockdown of the mitochondrial DNA helicase TWNK leads to severe impediment of mtDNA degradation. We do not observe similar effects when inactivating other known mitochondrial nucleases (EXOG, APEX2, ENDOG, FEN1, DNA2, MRE11, or RBBP8). Our data suggest that rapid degradation of linearized mtDNA is performed by the same machinery that is responsible for mtDNA replication, thus proposing novel roles for the participating enzymes POLG, TWNK, and MGME1. PMID- 29712894 TI - Increased proteasomal activity supports photoreceptor survival in inherited retinal degeneration. AB - Inherited retinal degenerations, affecting more than 2 million people worldwide, are caused by mutations in over 200 genes. This suggests that the most efficient therapeutic strategies would be mutation independent, i.e., targeting common pathological conditions arising from many disease-causing mutations. Previous studies revealed that one such condition is an insufficiency of the ubiquitin proteasome system to process misfolded or mistargeted proteins in affected photoreceptor cells. We now report that retinal degeneration in mice can be significantly delayed by increasing photoreceptor proteasomal activity. The largest effect is observed upon overexpression of the 11S proteasome cap subunit, PA28alpha, which enhanced ubiquitin-independent protein degradation in photoreceptors. Applying this strategy to mice bearing one copy of the P23H rhodopsin mutant, a mutation frequently encountered in human patients, quadruples the number of surviving photoreceptors in the inferior retina of 6-month-old mice. This striking therapeutic effect demonstrates that proteasomes are an attractive target for fighting inherited blindness. PMID- 29712895 TI - Waldenstrom macroglobulinemia treatment algorithm 2018. AB - Waldenstrom macroglobulinemia is often an indolent disorder, and many patients are candidates for observation with careful monitoring. For symptomatic patients, one must distinguish between those patients whose symptoms are related to immunologic manifestations associated with the IgM monoclonal protein and those that have symptoms related to progressive marrow and nodal infiltration with lymphoplasmacytic lymphoma. In Waldenstrom macroglobulinemia, the driver for therapy in the majority of patients is progressive anemia, secondary to bone marrow replacement by lymphoplasmacytic lymphoma. Recent introduction of MYD88 mutational analysis has been very useful for diagnostic purposes but is unclear what effect it might have on the prognosis or response rate to therapy. An algorithm is provided on the management of asymptomatic individuals and the sequence used for chemotherapeutic intervention of symptomatic patients. PMID- 29712896 TI - Daratumumab, lenalidomide, and dexamethasone in East Asian patients with relapsed or refractory multiple myeloma: subgroup analyses of the phase 3 POLLUX study. AB - In the phase 3 POLLUX study, daratumumab plus lenalidomide and dexamethasone (DRd) significantly reduced the risk of progression/death and induced deeper responses vs. lenalidomide and dexamethasone alone (Rd) in patients with relapsed/refractory multiple myeloma (RRMM). We report a subgroup analysis of East Asian (Japanese, Korean, and Taiwanese) patients from POLLUX based on a longer follow-up of 24.7 months. Median progression-free survival was not reached (NR) for DRd vs. 13.8 months for Rd (hazard ratio [HR], 0.42; 95% confidence interval [CI], 0.23-0.76), and overall response rates were higher for DRd vs. Rd (90.2 vs. 72.1%). DRd extended the median duration of response vs. Rd (NR vs. 20.2 months), and minimal residual disease-negative rates at the 10-5 sensitivity threshold were 21.2 vs. 9.1% for DRd vs. Rd. No new safety signals were observed. Similar efficacy and safety were observed in the smaller subgroup of Japanese patients treated with DRd vs. Rd. These results demonstrate favorable efficacy and safety of DRd vs. Rd in East Asian patients and also in the Japanese-only patient subgroup that are consistent with findings in the overall patient population of POLLUX. PMID- 29712897 TI - Optical detection of field cancerization in the buccal mucosa of patients with esophageal cancer. AB - INTRODUCTION: Esophageal cancer is an increasingly common type of neoplasm with a very poor prognosis. This prognosis could improve with more early tumor detection. We have previously shown that we can use an optical spectroscopy to detect field cancerization in the buccal mucosa of patients with laryngeal cancer. The aim of this prospective study was to investigate whether we could detect field cancerization of buccal mucosa of patients with esophageal squamous cell carcinoma (ESCC) and esophageal adenocarcinoma (EAC). METHODS: Optical measurements were performed in vivo using a novel optical technique: multidiameter single-fiber reflectance (MDSFR) spectroscopy. MDSFR spectra were acquired by a handheld probe incorporating three fiber diameters. Multiple absorption and scattering parameters that are related to the physiological and ultrastructural properties of the buccal mucosa were derived from these spectra. A linear discriminant analysis of the parameters was performed to create a combined biomarker sigma to discriminate oncologic from non-oncologic patients. RESULTS: Twelve ESCC, 12 EAC, and 24 control patients were included in the study. The median value of our biomarker sigma was significantly higher in patients with ESCC (2.07 [1.93-2.10]) than control patients (1.86 [1.73-1.95], p = 0.022). After cross-validation sigma was able to identify ESCC patients with a sensitivity of 66.7% and a specificity of 70.8%. There were no significant differences between the EAC group and the control group. CONCLUSION: Field cancerization in the buccal mucosa can be detected using optical spectroscopy in ESCC patients. This may be the first step towards non-invasive ESCC cancer screening. PMID- 29712899 TI - Porous polycarbene-bearing membrane actuator for ultrasensitive weak-acid detection and real-time chemical reaction monitoring. AB - Soft actuators with integration of ultrasensitivity and capability of simultaneous interaction with multiple stimuli through an entire event ask for a high level of structure complexity, adaptability, and/or multi-responsiveness, which is a great challenge. Here, we develop a porous polycarbene-bearing membrane actuator built up from ionic complexation between a poly(ionic liquid) and trimesic acid (TA). The actuator features two concurrent structure gradients, i.e., an electrostatic complexation (EC) degree and a density distribution of a carbene-NH3 adduct (CNA) along the membrane cross-section. The membrane actuator performs the highest sensitivity among the state-of-the-art soft proton actuators toward acetic acid at 10-6 mol L-1 (M) level in aqueous media. Through competing actuation of the two gradients, it is capable of monitoring an entire process of proton-involved chemical reactions that comprise multiple stimuli and operational steps. The present achievement constitutes a significant step toward real-life application of soft actuators in chemical sensing and reaction technology. PMID- 29712898 TI - C/EBPbeta enhances platinum resistance of ovarian cancer cells by reprogramming H3K79 methylation. AB - Chemoresistance is a major unmet clinical obstacle in ovarian cancer treatment. Epigenetics plays a pivotal role in regulating the malignant phenotype, and has the potential in developing therapeutically valuable targets that improve the dismal outcome of this disease. Here we show that a series of transcription factors, including C/EBPbeta, GCM1, and GATA1, could act as potential modulators of histone methylation in tumor cells. Of note, C/EBPbeta, an independent prognostic factor for patients with ovarian cancer, mediates an important mechanism through which epigenetic enzyme modifies groups of functionally related genes in a context-dependent manner. By recruiting the methyltransferase DOT1L, C/EBPbeta can maintain an open chromatin state by H3K79 methylation of multiple drug-resistance genes, thereby augmenting the chemoresistance of tumor cells. Therefore, we propose a new path against cancer epigenetics in which identifying and targeting the key regulators of epigenetics such as C/EBPbeta may provide more precise therapeutic options in ovarian cancer. PMID- 29712900 TI - Environmental fluctuations accelerate molecular evolution of thermal tolerance in a marine diatom. AB - Diatoms contribute roughly 20% of global primary production, but the factors determining their ability to adapt to global warming are unknown. Here we quantify the capacity for adaptation to warming in the marine diatom Thalassiosira pseudonana. We find that evolutionary rescue under severe (32 degrees C) warming is slow, but adaptation to more realistic scenarios where temperature increases are moderate (26 degrees C) or fluctuate between benign and severe conditions is rapid and linked to phenotypic changes in metabolic traits and elemental composition. Whole-genome re-sequencing identifies genetic divergence among populations selected in the different warming regimes and between the evolved and ancestral lineages. Consistent with the phenotypic changes, the most rapidly evolving genes are associated with transcriptional regulation, cellular responses to oxidative stress and redox homeostasis. These results demonstrate that the evolution of thermal tolerance in marine diatoms can be rapid, particularly in fluctuating environments, and is underpinned by major genomic and phenotypic change. PMID- 29712901 TI - Warm/cool-tone switchable thermochromic material for smart windows by orthogonally integrating properties of pillar[6]arene and ferrocene. AB - Functional materials play a vital role in the fabrication of smart windows, which can provide a more comfortable indoor environment for humans to enjoy a better lifestyle. Traditional materials for smart windows tend to possess only a single functionality with the purpose of regulating the input of solar energy. However, different color tones also have great influences on human emotions. Herein, a strategy for orthogonal integration of different properties is proposed, namely the thermo-responsiveness of ethylene glycol-modified pillar[6]arene (EGP6) and the redox-induced reversible color switching of ferrocene/ferrocenium groups are orthogonally integrated into one system. This gives rise to a material with cooperative and non-interfering dual functions, featuring both thermochromism and warm/cool tone-switchability. Consequently, the obtained bifunctional material for fabricating smart windows can not only regulate the input of solar energy but also can provide a more comfortable color tone to improve the feelings and emotions of people in indoor environments. PMID- 29712902 TI - High spatial resolution nanoslit SERS for single-molecule nucleobase sensing. AB - Solid-state nanopores promise a scalable platform for single-molecule DNA analysis. Direct, real-time identification of nucleobases in DNA strands is still limited by the sensitivity and the spatial resolution of established ionic sensing strategies. Here, we study a different but promising strategy based on optical spectroscopy. We use an optically engineered elongated nanopore structure, a plasmonic nanoslit, to locally enable single-molecule surface enhanced Raman spectroscopy (SERS). Combining SERS with nanopore fluidics facilitates both the electrokinetic capture of DNA analytes and their local identification through direct Raman spectroscopic fingerprinting of four nucleobases. By studying the stochastic fluctuation process of DNA analytes that are temporarily adsorbed inside the pores, we have observed asynchronous spectroscopic behavior of different nucleobases, both individual and incorporated in DNA strands. These results provide evidences for the single-molecule sensitivity and the sub-nanometer spatial resolution of plasmonic nanoslit SERS. PMID- 29712903 TI - Oxygen minimum zone cryptic sulfur cycling sustained by offshore transport of key sulfur oxidizing bacteria. AB - Members of the gammaproteobacterial clade SUP05 couple water column sulfide oxidation to nitrate reduction in sulfidic oxygen minimum zones (OMZs). Their abundance in offshore OMZ waters devoid of detectable sulfide has led to the suggestion that local sulfate reduction fuels SUP05-mediated sulfide oxidation in a so-called "cryptic sulfur cycle". We examined the distribution and metabolic capacity of SUP05 in Peru Upwelling waters, using a combination of oceanographic, molecular, biogeochemical and single-cell techniques. A single SUP05 species, U Thioglobus perditus, was found to be abundant and active in both sulfidic shelf and sulfide-free offshore OMZ waters. Our combined data indicated that mesoscale eddy-driven transport led to the dispersal of U T. perditus and elemental sulfur from the sulfidic shelf waters into the offshore OMZ region. This offshore transport of shelf waters provides an alternative explanation for the abundance and activity of sulfide-oxidizing denitrifying bacteria in sulfide-poor offshore OMZ waters. PMID- 29712904 TI - The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1. AB - The senescence-associated secretory phenotype (SASP) can be provoked by side effects of therapeutic agents, fueling advanced complications including cancer resistance. However, the intracellular signal network supporting initiation and development of the SASP driven by treatment-induced damage remains unclear. Here we report that the transcription factor Zscan4 is elevated for expression by an ATM-TRAF6-TAK1 axis during the acute DNA damage response and enables a long term SASP in human stromal cells. Further, TAK1 activates p38 and PI3K/Akt/mTOR to support the persistent SASP signaling. As TAK1 is implicated in dual feedforward mechanisms to orchestrate the SASP development, pharmacologically targeting TAK1 deprives cancer cells of resistance acquired from treatment-damaged stromal cells in vitro and substantially promotes tumour regression in vivo. Together, our study reveals a novel network that links functionally critical molecules associated with the SASP development in therapeutic settings, thus opening new avenues to improve clinical outcomes and advance precision medicine. PMID- 29712905 TI - Spatiotemporal manipulation of ciliary glutamylation reveals its roles in intraciliary trafficking and Hedgehog signaling. AB - Tubulin post-translational modifications (PTMs) occur spatiotemporally throughout cells and are suggested to be involved in a wide range of cellular activities. However, the complexity and dynamic distribution of tubulin PTMs within cells have hindered the understanding of their physiological roles in specific subcellular compartments. Here, we develop a method to rapidly deplete tubulin glutamylation inside the primary cilia, a microtubule-based sensory organelle protruding on the cell surface, by targeting an engineered deglutamylase to the cilia in minutes. This rapid deglutamylation quickly leads to altered ciliary functions such as kinesin-2-mediated anterograde intraflagellar transport and Hedgehog signaling, along with no apparent crosstalk to other PTMs such as acetylation and detyrosination. Our study offers a feasible approach to spatiotemporally manipulate tubulin PTMs in living cells. Future expansion of the repertoire of actuators that regulate PTMs may facilitate a comprehensive understanding of how diverse tubulin PTMs encode ciliary as well as cellular functions. PMID- 29712907 TI - Theoretical principles of transcription factor traffic on folded chromatin. AB - All organisms regulate transcription of their genes. To understand this process, a complete understanding of how transcription factors find their targets in cellular nuclei is essential. The DNA sequence and other variables are known to influence this binding, but the distribution of transcription factor binding patterns remains mostly unexplained in metazoan genomes. Here, we investigate the role of chromosome conformation in the trajectories of transcription factors. Using molecular dynamics simulations, we uncover the principles of their diffusion on chromatin. Chromosome contacts play a conflicting role: at low density they enhance transcription factor traffic, but at high density they lower it by volume exclusion. Consistently, we observe that in human cells, highly occupied targets, where protein binding is promiscuous, are found at sites engaged in chromosome loops within uncompacted chromatin. In summary, we provide a framework for understanding the search trajectories of transcription factors, highlighting the key contribution of genome conformation. PMID- 29712906 TI - Promotion of virus assembly and organization by the measles virus matrix protein. AB - Measles virus (MeV) remains a major human pathogen, but there are presently no licensed antivirals to treat MeV or other paramyxoviruses. Here, we use cryo electron tomography (cryo-ET) to elucidate the principles governing paramyxovirus assembly in MeV-infected human cells. The three-dimensional (3D) arrangement of the MeV structural proteins including the surface glycoproteins (F and H), matrix protein (M), and the ribonucleoprotein complex (RNP) are characterized at stages of virus assembly and budding, and in released virus particles. The M protein is observed as an organized two-dimensional (2D) paracrystalline array associated with the membrane. A two-layered F-M lattice is revealed suggesting that interactions between F and M may coordinate processes essential for MeV assembly. The RNP complex remains associated with and in close proximity to the M lattice. In this model, the M lattice facilitates the well-ordered incorporation and concentration of the surface glycoproteins and the RNP at sites of virus assembly. PMID- 29712908 TI - The novel hsa-miR-12528 regulates tumourigenesis and metastasis through hypo phosphorylation of AKT cascade by targeting IGF-1R in human lung cancer. AB - Lung cancer cases are increasing yearly; however, few novel therapeutic strategies for treating this disease have been developed. Here the dysregulation between microRNAs and oncogenes or tumour-suppressor genes forms a close connection-loop to the development or progression in human lung carcinogenesis. That is, the relationship between microRNAs and carcinogenic mechanism may find the critical clue to improve the treatment efficacy. Accordingly, we identified and characterised a novel microRNA, hsa-miR-12528, in A549 cells. The miR-12528 expression was aberrantly downregulated in cancer cell lines and in the patient tissues derived from human non-small cell lung cancer. In addition, we found that miR-12528 post-transcriptionally controls the translation of the insulin-like growth factor 1 receptor (IGF-1R) gene by directly targeting the 3'-untranslated region of IGF-1R mRNA. Notably, the IGF-1R gene is elevated in the majority of cancers and may be an attractive therapeutic target for anticancer therapy because elevated IGF-1R mediates the signalling amplification of a major oncogenic pathway in neoplasia. In A549 cells, miR-12528 overexpression epigenetically altered the downstream phosphorylation of the primary IGF-1R networks, negatively regulated proliferation, apoptosis and migratory activity, and consequently inhibited tumourigenesis and metastasis in vivo. Therefore, our discovery of hsa-miR-12528 may be able to be applied to the development of molecular-target therapeutic strategies and diagnosis-specific biomarkers for human lung cancer. PMID- 29712909 TI - Widespread intronic polyadenylation diversifies immune cell transcriptomes. AB - Alternative cleavage and polyadenylation (ApA) is known to alter untranslated region (3'UTR) length but can also recognize intronic polyadenylation (IpA) signals to generate transcripts that lose part or all of the coding region. We analyzed 46 3'-seq and RNA-seq profiles from normal human tissues, primary immune cells, and multiple myeloma (MM) samples and created an atlas of 4927 high confidence IpA events represented in these cell types. IpA isoforms are widely expressed in immune cells, differentially used during B-cell development or in different cellular environments, and can generate truncated proteins lacking C terminal functional domains. This can mimic ectodomain shedding through loss of transmembrane domains or alter the binding specificity of proteins with DNA binding or protein-protein interaction domains. MM cells display a striking loss of IpA isoforms expressed in plasma cells, associated with shorter progression free survival and impacting key genes in MM biology and response to lenalidomide. PMID- 29712910 TI - Direct binding of CEP85 to STIL ensures robust PLK4 activation and efficient centriole assembly. AB - Centrosomes are required for faithful chromosome segregation during mitosis. They are composed of a centriole pair that recruits and organizes the microtubule nucleating pericentriolar material. Centriole duplication is tightly controlled in vivo and aberrations in this process are associated with several human diseases, including cancer and microcephaly. Although factors essential for centriole assembly, such as STIL and PLK4, have been identified, the underlying molecular mechanisms that drive this process are incompletely understood. Combining protein proximity mapping with high-resolution structural methods, we identify CEP85 as a centriole duplication factor that directly interacts with STIL through a highly conserved interaction interface involving a previously uncharacterised domain of STIL. Structure-guided mutational analyses in vivo demonstrate that this interaction is essential for efficient centriolar targeting of STIL, PLK4 activation and faithful daughter centriole assembly. Taken together, our results illuminate a molecular mechanism underpinning the spatiotemporal regulation of the early stages of centriole duplication. PMID- 29712911 TI - Reconstruction of the ancestral metazoan genome reveals an increase in genomic novelty. AB - Understanding the emergence of the Animal Kingdom is one of the major challenges of modern evolutionary biology. Many genomic changes took place along the evolutionary lineage that gave rise to the Metazoa. Recent research has revealed the role that co-option of old genes played during this transition, but the contribution of genomic novelty has not been fully assessed. Here, using extensive genome comparisons between metazoans and multiple outgroups, we infer the minimal protein-coding genome of the first animal, in addition to other eukaryotic ancestors, and estimate the proportion of novelties in these ancient genomes. Contrary to the prevailing view, this uncovers an unprecedented increase in the extent of genomic novelty during the origin of metazoans, and identifies 25 groups of metazoan-specific genes that are essential across the Animal Kingdom. We argue that internal genomic changes were as important as external factors in the emergence of animals. PMID- 29712912 TI - The LetA/S two-component system regulates transcriptomic changes that are essential for the culturability of Legionella pneumophila in water. AB - Surviving the nutrient-poor aquatic environment for extended periods of time is important for the transmission of various water-borne pathogens, including Legionella pneumophila (Lp). Previous work concluded that the stringent response and the sigma factor RpoS are essential for the survival of Lp in water. In the present study, we investigated the role of the LetA/S two-component signal transduction system in the successful survival of Lp in water. In addition to cell size reduction in the post-exponential phase, LetS also contributes to cell size reduction when Lp is exposed to water. Importantly, absence of the sensor kinase results in a significantly lower survival as measured by CFUs in water at various temperatures and an increased sensitivity to heat shock. According to the transcriptomic analysis, LetA/S orchestrates a general transcriptomic downshift of major metabolic pathways upon exposure to water leading to better culturability, and likely survival, suggesting a potential link with the stringent response. However, the expression of the LetA/S regulated small regulatory RNAs, RsmY and RsmZ, is not changed in a relAspoT mutant, which indicates that the stringent response and the LetA/S response are two distinct regulatory systems contributing to the survival of Lp in water. PMID- 29712913 TI - Piezo1 is a mechanically activated ion channel and mediates pressure induced pancreatitis. AB - Merely touching the pancreas can lead to premature zymogen activation and pancreatitis but the mechanism is not completely understood. Here we demonstrate that pancreatic acinar cells express the mechanoreceptor Piezo1 and application of pressure within the gland produces pancreatitis. To determine if this effect is through Piezo1 activation, we induce pancreatitis by intrapancreatic duct instillation of the Piezo1 agonist Yoda1. Pancreatitis induced by pressure within the gland is prevented by a Piezo1 antagonist. In pancreatic acinar cells, Yoda1 stimulates calcium influx and induces calcium-dependent pancreatic injury. Finally, selective acinar cell-specific genetic deletion of Piezo1 protects mice against pressure-induced pancreatitis. Thus, activation of Piezo1 in pancreatic acinar cells is a mechanism for pancreatitis and may explain why pancreatitis develops following pressure on the gland as in abdominal trauma, pancreatic duct obstruction, pancreatography, or pancreatic surgery. Piezo1 blockade may prevent pancreatitis when manipulation of the gland is anticipated. PMID- 29712914 TI - Structural basis for energy transduction by respiratory alternative complex III. AB - Electron transfer in respiratory chains generates the electrochemical potential that serves as energy source for the cell. Prokaryotes can use a wide range of electron donors and acceptors and may have alternative complexes performing the same catalytic reactions as the mitochondrial complexes. This is the case for the alternative complex III (ACIII), a quinol:cytochrome c/HiPIP oxidoreductase. In order to understand the catalytic mechanism of this respiratory enzyme, we determined the structure of ACIII from Rhodothermus marinus at 3.9 A resolution by single-particle cryo-electron microscopy. ACIII presents a so-far unique structure, for which we establish the arrangement of the cofactors (four iron sulfur clusters and six c-type hemes) and propose the location of the quinol binding site and the presence of two putative proton pathways in the membrane. Altogether, this structure provides insights into a mechanism for energy transduction and introduces ACIII as a redox-driven proton pump. PMID- 29712915 TI - An effector from the Huanglongbing-associated pathogen targets citrus proteases. AB - The citrus industry is facing an unprecedented challenge from Huanglongbing (HLB). All cultivars can be affected by the HLB-associated bacterium 'Candidatus Liberibacter asiaticus' (CLas) and there is no known resistance. Insight into HLB pathogenesis is urgently needed in order to develop effective management strategies. Here, we use Sec-delivered effector 1 (SDE1), which is conserved in all CLas isolates, as a molecular probe to understand CLas virulence. We show that SDE1 directly interacts with citrus papain-like cysteine proteases (PLCPs) and inhibits protease activity. PLCPs are defense-inducible and exhibit increased protein accumulation in CLas-infected trees, suggesting a role in citrus defense responses. We analyzed PLCP activity in field samples, revealing specific members that increase in abundance but remain unchanged in activity during infection. SDE1-expressing transgenic citrus also exhibit reduced PLCP activity. These data demonstrate that SDE1 inhibits citrus PLCPs, which are immune-related proteases that enhance defense responses in plants. PMID- 29712916 TI - Tailoring supercurrent confinement in graphene bilayer weak links. AB - The Josephson effect is one of the most studied macroscopic quantum phenomena in condensed matter physics and has been an essential part of the quantum technologies development over the last decades. It is already used in many applications such as magnetometry, metrology, quantum computing, detectors or electronic refrigeration. However, developing devices in which the induced superconductivity can be monitored, both spatially and in its magnitude, remains a serious challenge. In this work, we have used local gates to control confinement, amplitude and density profile of the supercurrent induced in one dimensional nanoscale constrictions, defined in bilayer graphene-hexagonal boron nitride van der Waals heterostructures. The combination of resistance gate maps, out-of-equilibrium transport, magnetic interferometry measurements, analytical and numerical modelling enables us to explore highly tunable superconducting weak links. Our study opens the path way to design more complex superconducting circuits based on this principle, such as electronic interferometers or transition-edge sensors. PMID- 29712917 TI - Being right, but losing money: the role of striatum in joint decision making. AB - Joint decision-making entails that you sometimes have to go along with the other's choice even though you disagree. In this situation, a resulting negative outcome may, however, elicit a feeling of satisfaction and an impulse to say "I told you so". Using fMRI, we investigated the neural correlates of this complex process comprised of both positive and negative outcomes. During a social visual search task, 19 participants gave their advice to a co-actor who then made the decision resulting in a mutual loss or gain. This design allowed direct comparisons of situations that resulted in the same monetary outcome but that differed with respect to the correctness of the initial advice of the participant. Increased striatal activations were found for gains compared to losses and for correct compared to incorrect advice. Importantly, ROI analyses also showed enhanced striatum activation for monetary losses that were preceded by correct compared to incorrect advices. The current study therefore suggests that reward-related neural mechanisms may be involved when being right even in situations that end in monetary losses. PMID- 29712918 TI - High-density lipoprotein suppresses tumor necrosis factor alpha production by mycobacteria-infected human macrophages. AB - Immune responses to parasitic pathogens are affected by the host physiological condition. High-density lipoprotein (HDL) and low-density lipoprotein (LDL) are transporters of lipids between the liver and peripheral tissues, and modulate pro inflammatory immune responses. Pathogenic mycobacteria are parasitic intracellular bacteria that can survive within macrophages for a long period. Macrophage function is thus key for host defense against mycobacteria. These basic facts suggest possible effects of HDL and LDL on mycobacterial diseases, which have not been elucidated so far. In this study, we found that HDL and not LDL enhanced mycobacterial infections in human macrophages. Nevertheless, we observed that HDL remarkably suppressed production of tumor necrosis factor alpha (TNF-alpha) upon mycobacterial infections. TNF-alpha is a critical host protective cytokine against mycobacterial diseases. We proved that toll-like receptor (TLR)-2 is responsible for TNF-alpha production by human macrophages infected with mycobacteria. Subsequent analysis showed that HDL downregulates TLR2 expression and suppresses its intracellular signaling pathways. This report demonstrates for the first time the substantial action of HDL in mycobacterial infections to human macrophages. PMID- 29712919 TI - On Anderson Localization and Chiral Anomaly in Disordered Time-Reversal Invariant Weyl Semimetals: Nonperturbative and Berry Phase Effects. AB - Weyl semimetal, a three-dimensional electronic system with relativistic linear energy dispersion around gapless points carrying nontrivial Berry charge, is predicted to exhibit a wealth of unique response and transport properties. A crucial question is whether those properties are robust against disorder and whether Anderson localization occurs. In this work, the effects of nonperturbative topological (vortex loop) excitations and Berry phase in disordered time-reversal invariant 3d Weyl semimetal are studied. It is shown that the chiral symmetry is restored in the nonlinear sigma model describing the diffusons upon disorder average as any net topological term and its delocalization result do not take effect at sufficiently short length scales. Anderson localization occurs at sufficiently strong disorder and we predict that chirality and related phenomena disappear at such transition. Nevertheless, we uncover a mechanism that originates from Berry phase that impedes such localization effect. We show the occurrence of destructive interference between the vortex loops and between scattering paths due to the the vortex loops' Berry phase which resists the Anderson localization. We emphasize the applicability of our theory to the candidate Weyl materials where we point out the consistency of our theory with a recent experimental finding of the absent chiral anomaly in a noncentrosymmetric Weyl semimetal. PMID- 29712922 TI - Highly nitrogen doped carbon nanofibers with superior rate capability and cyclability for potassium ion batteries. AB - Potassium-ion batteries are a promising alternative to lithium-ion batteries. However, it is challenging to achieve fast charging/discharging and long cycle life with the current electrode materials because of the sluggish potassiation kinetics. Here we report a soft carbon anode, namely highly nitrogen-doped carbon nanofibers, with superior rate capability and cyclability. The anode delivers reversible capacities of 248 mAh g-1 at 25 mA g-1 and 101 mAh g-1 at 20 A g-1, and retains 146 mAh g-1 at 2 A g-1 after 4000 cycles. Surface-dominated K-storage is verified by quantitative kinetics analysis and theoretical investigation. A full cell coupling the anode and Prussian blue cathode delivers a reversible capacity of 195 mAh g-1 at 0.2 A g-1. Considering the cost-effectiveness and material sustainability, our work may shed some light on searching for K-storage materials with high performance. PMID- 29712921 TI - On-surface synthesis of a nitrogen-embedded buckybowl with inverse Stone-Thrower Wales topology. AB - Curved pi-conjugated polycyclic aromatic hydrocarbons, buckybowls, constitute an important class of materials with wide applications in materials science. Heteroatom doping of buckybowls is a viable route to tune their intrinsic physicochemical properties. However, synthesis of heteroatom-doped buckybowls is a challenging task. We report on a combined in-solution and on-surface synthetic strategy toward the fabrication of a buckybowl containing two fused nitrogen doped pentagonal rings. We employ ultra-high-resolution scanning tunneling microscopy and spectroscopy, in combination with density functional theory calculations to characterize the final compound. The buckybowl contains a unique combination of non-hexagonal rings at its core, identified as the inverse Stone Thrower-Wales topology, resulting in a distinctive bowl-opening-down conformation of the buckybowl on the surface. Our controlled design of non-alternant, heteroatom-doped polycyclic aromatic frameworks with established bottom-up fabrication techniques opens new opportunities in the synthesis of carbon nanostructures with the perspective of engineering properties of graphene-based devices. PMID- 29712920 TI - Development of an optogenetic toolkit for neural circuit dissection in squirrel monkeys. AB - Optogenetic tools have opened a rich experimental landscape for understanding neural function and disease. Here, we present the first validation of eight optogenetic constructs driven by recombinant adeno-associated virus (AAV) vectors and a WGA-Cre based dual injection strategy for projection targeting in a widely used New World primate model, the common squirrel monkey Saimiri sciureus. We observed opsin expression around the local injection site and in axonal projections to downstream regions, as well as transduction to thalamic neurons, resembling expression patterns observed in macaques. Optical stimulation drove strong, reliable excitatory responses in local neural populations for two depolarizing opsins in anesthetized monkeys. Finally, we observed continued, healthy opsin expression for at least one year. These data suggest that optogenetic tools can be readily applied in squirrel monkeys, an important first step in enabling precise, targeted manipulation of neural circuits in these highly trainable, cognitively sophisticated animals. In conjunction with similar approaches in macaques and marmosets, optogenetic manipulation of neural circuits in squirrel monkeys will provide functional, comparative insights into neural circuits which subserve dextrous motor control as well as other adaptive behaviors across the primate lineage. Additionally, development of these tools in squirrel monkeys, a well-established model system for several human neurological diseases, can aid in identifying novel treatment strategies. PMID- 29712923 TI - Activity dependent LoNA regulates translation by coordinating rRNA transcription and methylation. AB - The ribosome is indispensable for precisely controlling the capacity of protein synthesis. However, how translational machinery is coordinated to meet the translational demands remains elusive. Here, we identify a nucleolar-specific lncRNA (LoNA), its 5' portion binds and sequesters nucleolin to suppress rRNA transcription, and its snoRNA like 3' end recruits and diminishes fibrillarin activity to reduce rRNA methylation. Activity-dependent decrease of LoNA leads to elevated rRNA and ribosome levels, an increased proportion of polysomes, mRNA polysome loading, and protein translation. In addition, transport of ribosomes to synapses is particularly promoted, resulting in increased levels of AMPA/NMDA receptor, enhanced synaptic plasticity, long-term potentiation and consolidated memory. Strikingly, hippocampal LoNA deficiency not only enhances long-term memory in WT mice, but also restores impaired memory function in APP/PS1 transgenic mice. Together, these findings reveal the multifaceted role of LoNA in modulating ribosome biogenesis to meet the translational demands of long-term memory. PMID- 29712924 TI - Transcriptional landscape of Mycobacterium tuberculosis infection in macrophages. AB - Mycobacterium tuberculosis (Mtb) infection reveals complex and dynamic host pathogen interactions, leading to host protection or pathogenesis. Using a unique transcriptome technology (CAGE), we investigated the promoter-based transcriptional landscape of IFNgamma (M1) or IL-4/IL-13 (M2) stimulated macrophages during Mtb infection in a time-kinetic manner. Mtb infection widely and drastically altered macrophage-specific gene expression, which is far larger than that of M1 or M2 activations. Gene Ontology enrichment analysis for Mtb induced differentially expressed genes revealed various terms, related to host protection and inflammation, enriched in up-regulated genes. On the other hand, terms related to dis-regulation of cellular functions were enriched in down regulated genes. Differential expression analysis revealed known as well as novel transcription factor genes in Mtb infection, many of them significantly down regulated. IFNgamma or IL-4/IL-13 pre-stimulation induce additional differentially expressed genes in Mtb-infected macrophages. Cluster analysis uncovered significant numbers, prolonging their expressional changes. Furthermore, Mtb infection augmented cytokine-mediated M1 and M2 pre-activations. In addition, we identified unique transcriptional features of Mtb-mediated differentially expressed lncRNAs. In summary we provide a comprehensive in depth gene expression/regulation profile in Mtb-infected macrophages, an important step forward for a better understanding of host-pathogen interaction dynamics in Mtb infection. PMID- 29712926 TI - Author Correction: The characterization of the circadian clock in the olive fly Bactrocera oleae (Diptera: Tephritidae) reveals a Drosophila-like organization. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29712925 TI - The RNA-binding protein YBX1 regulates epidermal progenitors at a posttranscriptional level. AB - The integrity of stratified epithelia depends on the ability of progenitor cells to maintain a balance between proliferation and differentiation. While much is known about the transcriptional pathways underlying progenitor cells' behavior in the epidermis, the role of posttranscriptional regulation by mRNA binding proteins-a rate-limiting step in sculpting the proteome-remains poorly understood. Here we report that the RNA binding protein YBX1 (Y-box binding protein-1) is a critical effector of progenitors' function in the epidermis. YBX1 expression is restricted to the cycling keratinocyte progenitors in vivo and its genetic ablation leads to defects in the architecture of the skin. We further demonstrate that YBX1 negatively controls epidermal progenitor senescence by regulating the translation of a senescence-associated subset of cytokine mRNAs via their 3' untranslated regions. Our study establishes YBX1 as a posttranscriptional effector required for maintenance of epidermal homeostasis. PMID- 29712927 TI - Decolorization of recalcitrant dyes by a multicopper oxidase produced by Iodidimonas sp. Q-1 with iodide as a novel inorganic natural redox mediator. AB - A multicopper oxidase (IOX) produced by Iodidimonas sp. Q-1 has high catalytic efficiency for iodide (I-) oxidation to form molecular iodine (I2). In this study, the potential capacity of IOX for decolorization of recalcitrant dyes was determined. Although IOX did not decolorize any dyes in the absence of redox mediator, significant decolorization of Orange G, Indigo Carmine, Amido Black, and Remazol Brilliant Blue R (RBBR) was observed in the presence of iodide. Addition of 0.1 mM iodide was sufficient to decolorize a total of 3 mM Indigo Carmine, suggesting that iodide functions as a mediator. Such mediator-like function of iodide was not observed in commercially available fungal laccases. The IOX-iodide decolorization system showed much alkaline pH optima of 5.5-6.5 and stronger salt tolerance than fungal laccases did. In addition, actual wastewater discharged from a dyeing factory could be decolorized more than 50% by the system. Since iodide is naturally occurring, non-toxic, and cheaper than common synthetic mediators, the IOX-iodide system is potentially more advantageous than fungal laccase-mediator systems for decolorization of recalcitrant dyes. PMID- 29712928 TI - Ocular higher-order aberrations and axial eye growth in young Hong Kong children. AB - This retrospective longitudinal analysis aimed to investigate the association between ocular higher-order aberrations (HOAs) and axial eye growth in Hong Kong children. Measures of axial length and ocular HOAs under cycloplegia were obtained annually over a two-year period from 137 subjects aged 8.8 +/- 1.4 years with mean spherical equivalent refraction of -2.04 +/- 2.38 D. A significant negative association was observed between the RMS of total HOAs and axial eye growth (P = 0.03), after adjusting for other significant predictors of axial length including age, sex and refractive error. Similar negative associations with axial elongation were found for the RMS of spherical aberrations ([Formula: see text] and [Formula: see text] combined) (P = 0.037). Another linear mixed model also showed that greater levels of vertical trefoil [Formula: see text], primary spherical aberration [Formula: see text] and negative oblique trefoil [Formula: see text] were associated with slower axial elongation and longer axial length (all P < 0.05). These findings support the potential role of HOAs, image quality and a vision-dependent mechanism in childhood eye growth. PMID- 29712929 TI - Author Correction: Decentralized dynamic understanding of hidden relations in complex networks. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29712930 TI - Mycobacterium marinum infections in Denmark from 2004 to 2017: A retrospective study of incidence, patient characteristics, treatment regimens and outcome. AB - Mycobacterium marinum (M. marinum) is a slowly growing nontuberculous mycobacterium. The incidence of M. marinum infections in Denmark is unknown. We conducted a retrospective nationwide study including all culture confirmed cases of M. marinum from 2004 to 2017 in Denmark. All available medical records were reviewed. Demographics, clinical characteristics, and treatment regiments were analyzed. Fifty-five patients were identified, 40 (72.7%) were men with a median age of 50 years. Aquatic exposure was reported by 48 (90.6%) of the patients. Site of infection was upper extremities in 49 (92.5%) patients and 49 (92.5%) had superficial infection. The median time from symptom presentation to diagnosis was 194 days. All patients received antibiotics. Median time of treatment duration among all patients was 112 days. Treatment outcome was classified as improved in 40 (75%), improved with sequela in 4 (7.6%) patients and only 3 patients (3.8%) were classified as failed. Infection with M. marinum is rare and there is a long delay from symptom manifestation to diagnosis. The infection is predominantly related to aquatic exposure. M. marinum should be a differential diagnose in patients with slow-developing cutaneous elements and relevant exposure. Treatment outcomes are overall good and severe sequela are rare. PMID- 29712932 TI - Author Correction: Functional Detection of TNF Receptor Family Members by Affinity-Labeled Ligands. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29712931 TI - Evolution of Metastable Defects and Its Effect on the Electronic Properties of MoS2 Films. AB - We report on structural and electronic properties of defects in chemical vapor deposited monolayer and few-layer MoS2 films. Scanning tunneling microscopy, Kelvin probe force microscopy, and transmission electron microscopy were used to obtain high resolution images and quantitative measurements of the local density of states, work function and nature of defects in MoS2 films. We track the evolution of defects that are formed under heating and electron beam irradiation. We observe formation of metastable domains with different work function values after annealing the material in ultra-high vacuum to moderate temperatures. We attribute these metastable values of the work function to evolution of crystal defects forming during the annealing. The experiments show that sulfur vacancies formed after exposure to elevated temperatures diffuse, coalesce, and migrate bringing the system from a metastable to equilibrium ground state. The process could be thermally or e-beam activated with estimated energy barrier for sulfur vacancy migration of 0.6 eV in single unit cell MoS2. Even at equilibrium conditions, the work function and local density of states values are strongly affected near grain boundaries and edges. The results provide initial estimates of the thermal budgets available for reliable fabrication of MoS2-based integrated electronics and indicate the importance of defect control and layer passivation. PMID- 29712933 TI - Effect of Electroacupuncture on 99mTc-Sodium Pertechnetate Uptake and Extracellular Fluid Free Molecules in the Stomach in Acupoint ST36 and ST39. AB - Electroacupuncture (EA) is a therapeutic modality in which the electrical stimulation is integrated with concepts of acupuncture to treat diseases. This study was designed to evaluate the connection between the electro-acupuncture induced increase in Na99mTcO4 uptake in the stomach wall, and the ionic molecule levels in the extracellular fluid in the acupoints. Wistar rats were treated by 2 or 100 Hz EA at Zusanli (ST 36) and Xiajuxu (ST 39) bilaterally for 60 minutes. The accumulation of Na99mTcO4 in the gastric wall and the free ions, including Ca2+, K+, Na+, and Cl-, in the acupoints were measured every 60 minutes. The radioactivity uptake in the stomach was significantly increased during EA, reaching peak at 180 minutes after the EA. The concentration of extracellular ions was also significantly increased during EA. The Ca2+ level continued to rise until 60 minutes after EA, then started to decrease at 120 minutes post-EA. The results suggest this up-regulatory effect of EA on gastric activity might be triggered by the increase of the extracellular ion levels, this effect lasts longer than stimulating the release of transmembrane Ca2+ flow alone. This might aid in providing a better understanding of the long-lasting effect claimed in acupuncture treatment. PMID- 29712934 TI - Elevated urinary N-acetyl-beta-D-glucosaminidase is associated with high glycoalbumin-to-hemoglobin A1c ratio in type 1 diabetes patients with early diabetic kidney disease. AB - Urinary N-acetyl-beta-D-glucosaminidase (uNAG) predicted the progression of diabetic kidney disease (DKD) prior to development of albuminuria in diabetes patients. We sought whether uNAG level is associated with glycoalbumin-to hemoglobin A1c ratio (G/A ratio), a marker of postprandial hyperglycemia and glycemic excursion, independent of albuminuria and kidney function. The association between uNAG excretion and G/A ratio was assessed in 204 consecutive subjects with type 1 diabetes (T1D) (mean age 43.9 years; 49.0% men). uNAG excretion level increased along with older age, hyperglycemia, and degree of albuminuria, but was not correlated with body mass index or estimated glomerular filtration rate (eGFR). Elevated uNAG showed robust association with higher G/A ratio (adjusted beta = 0.103, P = 0.020) after adjustment for age, sex, body mass index, duration of diabetes, uACR, angiotensin blockers use, fasting plasma glucose, and hemoglobin level. uNAG showed better discriminatory performance for individuals with high G/A ratio than albuminuria (AUC 0.613 vs. 0.518, P = 0.038). Measurement of uNAG improved AUC for high G/A ratio from 0.699 to 0.748 (P = 0.043) when added to conventional risk factors (cutoff 5.24 U/g creatinine; sensitivity 62.5% and specificity 58.0%). In conclusion, Elevated uNAG was found to be associated with high G/A ratio in patients with T1D with early stage DKD, independent of age and albuminuria. PMID- 29712936 TI - Author Correction: Dimerization: a structural feature for the protection of hepatitis E virus capsid protein against trypsinization. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29712935 TI - A low voltage nanopipette dielectrophoretic device for rapid entrapment of nanoparticles and exosomes extracted from plasma of healthy donors. AB - An insulator-based dielectrophoresis (iDEP) is a label-free method that has been extensively utilized for manipulation of nanoparticles, cells, and biomolecules. Here, we present a new iDEP approach that can rapidly trap nanoparticles at the close proximity of a glass nanopipette's tip by applying 10 V/cm direct current (DC) across the pipette's length. The trapping mechanism was systemically studied using both numerical modeling and experimental observations. The results showed that the particle trapping was determined to be controlled by three dominant electrokinetic forces including dielectrophoretic, electrophoretic and electroosmotic force. Furthermore, the effect of the ionic strength, the pipette's geometry, and the applied electric field on the entrapment efficiency was investigated. To show the application of our device in biomedical sciences, we demonstrated the successful entrapment of fluorescently tagged liposomes and unlabeled plasma-driven exosomes from the PBS solution. Also, to illustrate the selective entrapment capability of our device, 100 nm liposomes were extracted from the PBS solution containing 500 nm polystyrene particles at the tip of the pipette as the voltage polarity was reversed. PMID- 29712938 TI - Sauchinone controls hepatic cholesterol homeostasis by the negative regulation of PCSK9 transcriptional network. AB - Whole-transcriptome analysis and western blotting of sauchinone-treated HepG2 cells demonstrated that sauchinone regulated genes relevant to cholesterol metabolism and synthesis. In particular, it was found that the expression of proprotein convertase subtilisin/kexin type 9 (PCSK9) was downregulated, and the expression of low density lipoprotein receptor (LDLR) was upregulated in sauchinone-treated HepG2 cells. Consequently, LDL-cholesterol (LDL-C) uptake was increased. As a transcriptional regulator of PCSK9 expression, sterol regulatory elements binding protein-2 (SREBP-2) was proposed by transcriptome analysis and western blotting. Oral administration of sauchinone increased hepatic LDLR through PCSK9 inhibition in obese mice and showed the reduced serum LDL-C levels and downstream targets of SREBP-2. Thus, it is evident that sauchinone reduces hepatic steatosis by downregulating the expression of hepatic PCSK9 via SREBP-2. PMID- 29712937 TI - Galactic Cosmic Radiation Induces Persistent Epigenome Alterations Relevant to Human Lung Cancer. AB - Human deep space and planetary travel is limited by uncertainties regarding the health risks associated with exposure to galactic cosmic radiation (GCR), and in particular the high linear energy transfer (LET), heavy ion component. Here we assessed the impact of two high-LET ions 56Fe and 28Si, and low-LET X rays on genome-wide methylation patterns in human bronchial epithelial cells. We found that all three radiation types induced rapid and stable changes in DNA methylation but at distinct subsets of CpG sites affecting different chromatin compartments. The 56Fe ions induced mostly hypermethylation, and primarily affected sites in open chromatin regions including enhancers, promoters and the edges ("shores") of CpG islands. The 28Si ion-exposure had mixed effects, inducing both hyper and hypomethylation and affecting sites in more repressed heterochromatic environments, whereas X rays induced mostly hypomethylation, primarily at sites in gene bodies and intergenic regions. Significantly, the methylation status of 56Fe ion sensitive sites, but not those affected by X ray or 28Si ions, discriminated tumor from normal tissue for human lung adenocarcinomas and squamous cell carcinomas. Thus, high-LET radiation exposure leaves a lasting imprint on the epigenome, and affects sites relevant to human lung cancer. These methylation signatures may prove useful in monitoring the cumulative biological impact and associated cancer risks encountered by astronauts in deep space. PMID- 29712939 TI - Essential Role of the a3 Isoform of V-ATPase in Secretory Lysosome Trafficking via Rab7 Recruitment. AB - Secretory lysosomes are required for the specialised functions of various types of differentiated cells. In osteoclasts, the lysosomal proton pump V-ATPase (vacuolar-type ATPase) is targeted to the plasma membrane via secretory lysosomes and subsequently acidifies the extracellular compartment, providing optimal conditions for bone resorption. However, little is known about the mechanism underlying this trafficking of secretory lysosomes. Here, we demonstrate that the lysosome-specific a3 isoform of the V-ATPase a subunit plays an indispensable role in secretory lysosome trafficking, together with Rab7, a small GTPase involved in organelle trafficking. In osteoclasts lacking a3, lysosomes were not transported to the cell periphery, and Rab7 was not localised to lysosomes but diffused throughout the cytoplasm. Expression of dominant-negative (GDP-bound form) Rab7 inhibited lysosome trafficking in wild-type cells. Furthermore, a3 directly interacted with the GDP-bound forms of Rab7 and Rab27A. These findings reveal a novel role for the proton pump V-ATPase in secretory lysosome trafficking and an unexpected mechanistic link with Rab GTPases. PMID- 29712940 TI - Disequilibrium of fire-prone forests sets the stage for a rapid decline in conifer dominance during the 21st century. AB - The impacts of climatic changes on forests may appear gradually on time scales of years to centuries due to the long generation times of trees. Consequently, current forest extent may not reflect current climatic patterns. In contrast with these lagged responses, abrupt transitions in forests under climate change may occur in environments where alternative vegetation states are influenced by disturbances, such as fire. The Klamath forest landscape (northern California and southwest Oregon, USA) is currently dominated by high biomass, biodiverse temperate coniferous forests, but climate change could disrupt the mechanisms promoting forest stability (e.g. growth, regeneration and fire tolerance). Using a landscape simulation model, we estimate that about one-third of the Klamath forest landscape (500,000 ha) could transition from conifer-dominated forest to shrub/hardwood chaparral, triggered by increased fire activity coupled with lower post-fire conifer establishment. Such shifts were widespread under the warmer climate change scenarios (RCP 8.5) but were surprisingly prevalent under the climate of 1949-2010, reflecting the joint influences of recent warming trends and the legacy of fire suppression that may have enhanced conifer dominance. Our results demonstrate that major forest ecosystem shifts should be expected when climate change disrupts key stabilizing feedbacks that maintain the dominance of long-lived, slowly regenerating trees. PMID- 29712941 TI - Additive and interactive effects of spatial attention and expectation on perceptual decisions. AB - Spatial attention and expectation are two critical top-down mechanisms controlling perceptual inference. Based on previous research it remains unclear whether their influence on perceptual decisions is additive or interactive. We developed a novel multisensory approach that orthogonally manipulated spatial attention (i.e. task-relevance) and expectation (i.e. signal probability) selectively in audition and evaluated their effects on observers' responses in vision. Critically, while experiment 1 manipulated expectation directly via the probability of task-relevant auditory targets across hemifields, experiment 2 manipulated it indirectly via task-irrelevant auditory non-targets. Surprisingly, our results demonstrate that spatial attention and signal probability influence perceptual decisions either additively or interactively. These seemingly contradictory results can be explained parsimoniously by a model that combines spatial attention, general and spatially selective response probabilities as predictors with no direct influence of signal probability. Our model provides a novel perspective on how spatial attention and expectation facilitate effective interactions with the environment. PMID- 29712942 TI - Higher physical fitness levels are associated with less language decline in healthy ageing. AB - Healthy ageing is associated with decline in cognitive abilities such as language. Aerobic fitness has been shown to ameliorate decline in some cognitive domains, but the potential benefits for language have not been examined. In a cross-sectional sample, we investigated the relationship between aerobic fitness and tip-of-the-tongue states. These are among the most frequent cognitive failures in healthy older adults and occur when a speaker knows a word but is unable to produce it. We found that healthy older adults indeed experience more tip-of-the-tongue states than young adults. Importantly, higher aerobic fitness levels decrease the probability of experiencing tip-of-the-tongue states in healthy older adults. Fitness-related differences in word finding abilities are observed over and above effects of age. This is the first demonstration of a link between aerobic fitness and language functioning in healthy older adults. PMID- 29712943 TI - Potential Protective Effect of Osteocalcin in Middle-Aged Men with Erectile Dysfunction: Evidence from the FAMHES Project. AB - In a similar manner to erectile dysfunction (ED), osteocalcin (OC) is also said to be associated with cardiovascular disease (CVD); however, the effect of OC in ED is unclear. This study was conducted based on the Fangchenggang Area Male Health and Examination Survey (FAMHES) project that ran between September and December 2009. ED was evaluated using the International Index of Erectile Function (IIEF-5). OC was shown to be associated with mild (unadjusted: OR = 0.647; P = 0.016) or moderate (unadjusted: OR = 0.453; P = 0.007) ED. Meanwhile, higher OC levels were more prominently associated with ED (unadjusted: OR = 0.702; P = 0.014). When subdividing the groups by age, the correlation between OC and ED presented in those aged 40-49 years, even in the multi-adjusted model, for those with moderate (OR = 0.255, P = 0.044) and severe (OR = 0.065, P = 0.005) ED. The relationship between OC and ED was also associated with a high level of testosterone, non-obesity, drinking, and non-metabolic syndrome. In summary, OC may play a protective role in middle-aged (40-49 years) men with moderate-severe ED, especially those with a high level of testosterone, non-obesity, drinking, and non-metabolic syndrome. PMID- 29712944 TI - Appetitive and reactive aggression are differentially associated with the STin2 genetic variant in the serotonin transporter gene. AB - Appetitive aggression is a sub-category of instrumental aggression, characterised by the primary intrinsic enjoyment of aggressive activity. Aggression is heritable, and serotonergic and monoaminergic neurotransmitter systems have been found to contribute to the underlying molecular mechanisms. The aim of this study was to investigate the role that genetic variants in the serotonin transporter (SLC6A4) and monoamine oxidase A (MAOA) genes play in the aetiology of appetitive aggression in South African Xhosa males (n = 290). SLC6A4 5-HTTLPR, rs25531, and STin2 variants, as well as MAOA-uVNTR were investigated for their association with levels of appetitive aggression using Poisson regression analysis. The STin2 VNTR12 allele was found to be associated with increased levels of appetitive aggression (p = 0.003), but with decreased levels of reactive aggression (p = 7 * 10-5). This study is the first to investigate genetic underpinnings of appetitive aggression in a South African population, with preliminary evidence suggesting that SCL6A4 STin2 variants play a role in its aetiology, and may also be important in differentiating between appetitive and reactive aggression. Although the results require replication, they shed some preliminary light on the molecular dichotomy that may underlie the two forms of aggression. PMID- 29712946 TI - Publisher Correction: Experimental identification of non-classicality of noisy twin beams and other related two-mode states. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29712945 TI - Preliminary evidence of altered neural response during intertemporal choice of losses in adult attention-deficit hyperactivity disorder. AB - Impulsive behaviours are common symptoms of attention-deficit hyperactivity disorder (ADHD). Although previous studies have suggested functional models of impulsive behaviour, a full explanation of impulsivity in ADHD remains elusive. To investigate the detailed mechanisms behind impulsive behaviour in ADHD, we applied an economic intertemporal choice task involving gains and losses to adults with ADHD and healthy controls and measured brain activity by functional magnetic resonance imaging. In the intertemporal choice of future gains, we observed no behavioural or neural difference between the two groups. In the intertemporal choice of future losses, adults with ADHD exhibited higher discount rates than the control participants. Furthermore, a comparison of brain activity representing the sensitivity of future loss in the two groups revealed significantly lower activity in the striatum and higher activity in the amygdala in adults with ADHD than in controls. Our preliminary findings suggest that an altered size sensitivity to future loss is involved in apparent impulsive choice behaviour in adults with ADHD and shed light on the multifaceted impulsivity underlying ADHD. PMID- 29712947 TI - Resting-state fMRI study of brain activation using low-intensity repetitive transcranial magnetic stimulation in rats. AB - Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique used to treat many neuropsychiatric conditions. However, the mechanisms underlying its mode of action are still unclear. This is the first rodent study using resting-state functional MRI (rs-fMRI) to examine low-intensity (LI) rTMS effects, in an effort to provide a direct means of comparison between rodent and human studies. Using anaesthetised Sprague-Dawley rats, rs-fMRI data were acquired before and after control or LI-rTMS at 1 Hz, 10 Hz, continuous theta burst stimulation (cTBS) or biomimetic high-frequency stimulation (BHFS). Independent component analysis revealed LI-rTMS-induced changes in the resting-state networks (RSN): (i) in the somatosensory cortex, the synchrony of resting activity decreased ipsilaterally following 10 Hz and bilaterally following 1 Hz stimulation and BHFS, and increased ipsilaterally following cTBS; (ii) the motor cortex showed bilateral changes following 1 Hz and 10 Hz stimulation, a contralateral decrease in synchrony following BHFS, and an ipsilateral increase following cTBS; and (iii) hippocampal synchrony decreased ipsilaterally following 10 Hz, and bilaterally following 1 Hz stimulation and BHFS. The present findings demonstrate that LI-rTMS modulates functional links within the rat RSN with frequency-specific outcomes, and the observed changes are similar to those described in humans following rTMS. PMID- 29712948 TI - G-395A polymorphism in the promoter region of the KLOTHO gene associates with frailty among the oldest-old. AB - Frailty is characterized by a decline in physiological reserve and increased vulnerability. Previous studies have shown that KLOTHO (KL) plays a protective role in several age-related diseases. We hypothesize a probable protective effect of KL on frailty in the elderly population and included a cohort of Chinese nonagenarians and centenarians for our study. This study is part of a cross sectional study and secondary analysis of the Project of Longevity and Aging in Dujiangyan (PLAD) study, which was conducted in Southwest China. Community dwelling Chinese residents aged 90 years or older were included in this study. Frailty was determined using the FRAIL scale as proposed by the International Association of Nutrition and Aging. On the FRAIL scale, frailty was defined by a score of >=3. G-395A (rs1207568) genotyping of the promoter region of the KL gene was performed using TaqMan allelic discrimination assay. A total of 632 participants (68.4% females; mean age: 93.5 +/- 3.2 years) were included. KL G 395A polymorphism genotype frequencies were 1.7% AA, 25.6% GA, and 72.7% GG in our sample. GG genotype frequencies for the frailty and control groups were 83.6% and 71.2%, respectively. Frailty prevalence was significantly lower in the GA+AA group when compared to the GG genotype group (6.9% vs. 13.3%, P = 0.026). In addition, subjects with a GA+AA genotype had a significantly lower risk of frailty (odds ratio (OR): 0.47, 95% confidence interval (CI) 0.23 to 0.97, P = 0.040) compared to the GG genotype after adjusting for age, gender, education level, smoking, alcohol consumption, exercise, body mass index (BMI), cognitive impairment, and other potential factors. KL-395A allele carrying genotypes (GA and AA) is associated with a lower risk of frailty relative to GG genotypes in a sample of Chinese nonagenarians and centenarians. PMID- 29712949 TI - Association between maternal exposure to phthalates and lower language ability in offspring derived from hair metabolome analysis. AB - The fetus undergoes a crucial period of neurodevelopment in utero. The maternal hair metabolome provides an integrated record of the metabolic state of the mother prior to, and during pregnancy. We investigated whether variation in the maternal hair metabolome was associated with neurodevelopmental differences across infants. Maternal hair samples and infant neurocognitive assessments (using the Bayley III Scales of Infant Development at 24 months) were obtained for 373 infant-mother dyads between 26-28 weeks' gestation from the Growing Up in Singapore Towards Healthy Outcomes cohort. The hair metabolome was analysed using gas chromatography-mass spectrometry. Intensity measurements were obtained for 276 compounds. After controlling for maternal education, ethnicity, and infant sex, associations between metabolites and expressive language skills were detected, but not for receptive language, cognitive or motor skills. The results confirm previous research associating higher levels of phthalates with lower language ability. In addition, scores were positively associated with a cluster of compounds, including adipic acid and medium-chain fatty acids. The data support associations between the maternal hair metabolome and neurodevelopmental processes of the fetus. The association between phthalates and lower language ability highlights a modifiable risk factor that warrants further investigation. PMID- 29712951 TI - Publisher Correction: Small-angle neutron scattering modeling of spin disorder in nanoparticles. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29712950 TI - Hsp90 inhibition as a means to inhibit activation of the NLRP3 inflammasome. AB - Once activated, the intracellular receptor NLRP3 assembles an inflammasome protein complex that facilitates the caspase-1-mediated maturation of IL-1beta and IL-18. Inactive NLRP3 is guarded by a protein complex containing Hsp90. In response to stress stimuli, Hsp90 is released, and NLRP3 can be activated to promote inflammation. In this study, we blocked Hsp90 with geldanamycin and studied the fate of NLRP3 in human retinal pigment epithelial (RPE) cells. RPE cells play a central role in the development of age-related macular degeneration (AMD), a progressive eye disease causing severe vision loss in the elderly. IL 1alpha-primed ARPE-19 cells, human embryonal stem cell (hESC)-derived RPE cells, and primary human RPE cells were exposed to MG-132 and bafilomycin A to activate NLRP3 via the inhibition of proteasomes and autophagy, respectively. Additionally, RPE cells were treated with geldanamycin at different time points and the levels of NLRP3 and IL-1beta were determined. Caspase-1 activity was measured using a commercial assay. Geldanamycin prevented the activation of the inflammasome in human RPE cells. NLRP3 released from its protective complex became degraded by autophagy or secreted from the cells. Controlled destruction of NLRP3 is a potential way to regulate the inflammation associated with chronic diseases, such as AMD. PMID- 29712952 TI - Mercury transport and human exposure from global marine fisheries. AB - Human activities have increased the global circulation of mercury, a potent neurotoxin. Mercury can be converted into methylmercury, which biomagnifies along aquatic food chains and leads to high exposure in fish-eating populations. Here we quantify temporal trends in the ocean-to-land transport of total mercury and methylmercury from fisheries and we estimate potential human mercury intake through fish consumption in 175 countries. Mercury export from the ocean increased over time as a function of fishing pressure, especially on upper trophic-level organisms. In 2014, over 13 metric tonnes of mercury were exported from the ocean. Asian countries were important contributors of mercury export in the last decades and the western Pacific Ocean was identified as the main source. Estimates of per capita mercury exposure through fish consumption showed that populations in 38% of the 175 countries assessed, mainly insular and developing nations, were exposed to doses of methylmercury above governmental thresholds. Our study shows temporal trends and spatial patterns of Hg transport by fisheries. Given the high mercury intake through seafood consumption observed in several understudied yet vulnerable coastal communities, we recommend a comprehensive assessment of the health exposure risk of those populations. PMID- 29712953 TI - Toxicity evaluation of Wanzhou watershed of Yangtze Three Gorges Reservior in the flood season in Caenorhabditis elegans. AB - Three Gorges Reservoir (TGR) in the upper stream of Yangtze River in China is a reservoir with the largest and the longest yearly water-level drop. Considering the fact that most of safety assessments of water samples collected from TGR region were based on chemical analysis, we here employed Caenorhabditis elegans to perform in vivo safety assessment of original surface water samples collected from TGR region in the flood season in Wanzhou, Chongqing. Among the examined five original surface water samples, only exposure to original surface water sample collected from backwater area could induce the significant intestinal ROS production, enhance the intestinal permeability, and decrease the locomotion behavior. Additionally, exposure to original surface water sample collected from backwater area altered the expressions of sod-2, sod-5, clk-1, and mev-1. Moreover, mutation of sod-2 or sod-5 was susceptible to the potential toxicity of original surface water sample collected from backwater area on nematodes. Together, our results imply that exposure to surface water sample from the backwater area may at least cause the adverse effects on intestinal function and locomotion behavior in nematodes. PMID- 29712954 TI - Impact of surface adhesion and sample heterogeneity on the multiscale mechanical characterisation of soft biomaterials. AB - The mechanical properties of soft materials used in the biomedical field play an important role on their performance. In the field of tissue engineering, it is known that cells sense the mechanical properties of their environment, however some materials, such as Sylard 184 PDMS (poly(dimethylsiloxane)), have failed to elicit such response. It was proposed that differences in the mechanical properties of such soft materials, at different scales, could account for these discrepancies. Indeed, the variation in the elastic moduli obtained for soft materials characterised at different scales can span several orders of magnitude. This called for a side-by-side comparison of the mechanical behaviour of soft materials at different scales. Here we use indentation, rheology and atomic force microscopy nanoidentation (using different tip geometries) to characterise the mechanical properties of PDMS, poly(acrylamide) (PAAm) and carboxymethyl cellulose (CMC) hydrogels at different length scales. Our results highlight the importance of surface adhesion and the resulting changes in contact area, and sample microstructural heterogeneity, in particular for the mechanical characterisation of ultra-soft substrates at the nano- to micro-scale. PMID- 29712955 TI - Scale Effects on the Ballistic Penetration of Graphene Sheets. AB - Carbon nanostructures are promising ballistic protection materials, due to their low density and excellent mechanical properties. Recent experimental and computational investigations on the behavior of graphene under impact conditions revealed exceptional energy absorption properties as well. However, the reported numerical and experimental values differ by an order of magnitude. In this work, we combined numerical and analytical modeling to address this issue. In the numerical part, we employed reactive molecular dynamics to carry out ballistic tests on single, double, and triple-layered graphene sheets. We used velocity values within the range tested in experiments. Our numerical and the experimental results were used to determine parameters for a scaling law. We find that the specific penetration energy decreases as the number of layers (N) increases, from ~15 MJ/kg for N = 1 to ~0.9 MJ/kg for N = 350, for an impact velocity of 900 m/s. These values are in good agreement with simulations and experiments, within the entire range of N values for which data is presently available. Scale effects explain the apparent discrepancy between simulations and experiments. PMID- 29712956 TI - Parallel evolution of vgsc mutations at domains IS6, IIS6 and IIIS6 in pyrethroid resistant Aedes aegypti from Mexico. AB - Aedes aegypti is the primary urban mosquito vector of viruses causing dengue, Zika and chikungunya fevers -for which vaccines and effective pharmaceuticals are still lacking. Current strategies to suppress arbovirus outbreaks include removal of larval-breeding sites and insecticide treatment of larval and adult populations. Insecticidal control of Ae. aegypti is challenging, due to a recent rapid global increase in knockdown-resistance (kdr) to pyrethroid insecticides. Widespread, heavy use of pyrethroid space-sprays has created an immense selection pressure for kdr, which is primarily under the control of the voltage-gated sodium channel gene (vgsc). To date, eleven replacements in vgsc have been discovered, published and shown to be associated with pyrethroid resistance to varying degrees. In Mexico, F1,534C and V1,016I have co-evolved in the last 16 years across Ae. aegypti populations. Recently, a novel replacement V410L was identified in Brazil and its effect on vgsc was confirmed by electrophysiology. Herein, we screened V410L in 25 Ae. aegypti historical collections from Mexico, the first heterozygote appeared in 2002 and frequencies have increased in the last 16 years alongside V1,016I and F1,534C. Knowledge of the specific vgsc replacements and their interaction to confer resistance is essential to predict and to develop strategies for resistance management. PMID- 29712957 TI - Author Correction: Lateral attachment of kinetochores to microtubules is enriched in prometaphase rosette and facilitates chromosome alignment and bi-orientation establishment. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29712959 TI - Transition from poor ductility to room-temperature superplasticity in a nanostructured aluminum alloy. AB - Recent developments of nanostructured materials with grain sizes in the nanometer to submicrometer range have provided ground for numerous functional properties and new applications. However, in terms of mechanical properties, bulk nanostructured materials typically show poor ductility despite their high strength, which limits their use for structural applications. The present article shows that the poor ductility of nanostructured alloys can be changed to room temperature superplastisity by a transition in the deformation mechanism from dislocation activity to grain-boundary sliding. We report the first observation of room-temperature superplasticity (over 400% tensile elongations) in a nanostructured Al alloy by enhanced grain-boundary sliding. The room-temperature grain-boundary sliding and superplasticity was realized by engineering the Zn segregation along the Al/Al boundaries through severe plastic deformation. This work introduces a new boundary-based strategy to improve the mechanical properties of nanostructured materials for structural applications, where high deformability is a requirement. PMID- 29712958 TI - Structural characteristics and membrane interactions of tandem alpha-synuclein oligomers. AB - Pre-fibrillar oligomers of alpha-synuclein are thought to be pathogenic molecules leading to neurotoxicity associated with Parkinson's disease and other neurodegenerative disorders. However, small oligomers are difficult to isolate for study. To gain better insight into the properties of small alpha-synuclein oligomers, we investigated engineered oligomers of specific size (dimers, tetramers, and octamers) linked head-to-tail in tandem, comparing the behavior of the oligomers to monomeric alpha-synuclein. All oligomeric constructs remained largely disordered in solution, as determined from dynamic light scattering and size-exclusion chromatography. Electron microscopy revealed that each construct could aggregate to form fibrils similar to those formed by monomeric alpha synuclein. The interactions with large unilamellar vesicles (LUVs) composed of negatively-charged lipids differed depending on size, with smaller oligomers forming more extensive helical structure as determined by CD spectroscopy. Monitoring the influx of a fluorescence bleaching agent into vesicles showed that larger oligomers were somewhat more effective at degrading vesicular integrity and inducing membrane permeabilization. PMID- 29712960 TI - Association patterns of urinary sodium, potassium, and their ratio with blood pressure across various levels of salt-diet regions in China. AB - We aim to evaluate the association of systolic and diastolic blood pressure (SBP and DBP) with estimated urinary sodium (Na) and potassium(K) excretions, and their gram-to-gram Na/K ratio across various salt-diet regions during 2005-2009 in China. A prospective cohort study was conducted to recruit 46,285 participants in China. A single fasting morning urine specimen was collected to estimate 24 hour urinary Na and K excretion using Kawasaki formula. Means of estimated Na and K were 5.7 +/- 1.7 and 2.1 +/- 0.5 grams/day, respectively, and mean estimated Na/K ratio was 2.8 +/- 0.8. Adjusted analyses showed 1.70 mmHg SBP and 0.49 mmHg DBP increase per 1-g increment of estimated Na, while 1.10 mmHg SBP and 0.91 mmHg DBP decrease for one-gram increase of K. A significant increase in SBP (4.33 mmHg) and DBP (1.54 mmHg) per 1 unit increase in Na/K ratio was observed. More changes of SBP (4.39 mmHg) and DBP (1.67 mmHg) per one-unit increase of Na/K ratio were observed in low-salt regions, though significant changes were also found in moderate- and heavy-salt regions (P for heterogeneity < 0.01). Conclusively, decreasing sodium combined with increasing potassium is likely to have a more beneficial effect than decreasing sodium alone, even if those were living in low-salt regions. PMID- 29712961 TI - Liquid-Liquid Phase Separation of Patchy Particles Illuminates Diverse Effects of Regulatory Components on Protein Droplet Formation. AB - Recently many cellular functions have been associated with membraneless organelles, or protein droplets, formed by liquid-liquid phase separation (LLPS). Proteins in these droplets often contain RNA-binding domains, but the effects of RNA on LLPS have been controversial. To gain better understanding on the roles of RNA and other macromolecular regulators, here we used Gibbs-ensemble simulations to determine phase diagrams of two-component patchy particles, as models for mixtures of proteins with regulatory components. Protein-like particles have four patches, with attraction strength epsilonPP; regulatory particles experience mutual steric repulsion but have two attractive patches toward proteins, with the strength epsilonPR tunable. At low epsilonPR, the regulator, due to steric repulsion, preferentially partitions in the dispersed phase, thereby displacing the protein into the droplet phase and promoting LLPS. At moderate epsilonPR, the regulator starts to partition and displace the protein in the droplet phase, but only to weaken bonding networks and thereby suppress LLPS. At epsilonPR > epsilonPP, the enhanced bonding ability of the regulator initially promotes LLPS, but at higher amounts, the resulting displacement of the protein suppresses LLPS. These results illustrate how RNA can have disparate effects on LLPS, thus able to perform diverse functions in different organelles. PMID- 29712962 TI - Annexin A5 reduces infarct size and improves cardiac function after myocardial ischemia-reperfusion injury by suppression of the cardiac inflammatory response. AB - Annexin A5 (AnxA5) is known to have anti-inflammatory and anti-apoptotic properties. Inflammation and apoptosis are key processes in post-ischemic cardiac remodeling. In this study, we investigated the effect of AnxA5 on left ventricular (LV) function and remodeling three weeks after myocardial ischemia reperfusion (MI-R) injury in hypercholesterolemic ApoE*3-Leiden mice. Using a mouse model for MI-R injury, we demonstrate AnxA5 treatment resulted in a 27% reduction of contrast-enhanced MRI assessed infarct size (IS). End-diastolic and end-systolic volumes were decreased by 22% and 38%, respectively. LV ejection fraction was increased by 29% in the AnxA5 group compared to vehicle. Following AnxA5 treatment LV fibrous content after three weeks was reduced by 42%, which was accompanied by an increase in LV wall thickness of the infarcted area by 17%. Two days and three weeks after MI-R injury the number of cardiac macrophages was significantly reduced in both the infarct area and border zones following AnxA5 treatment compared to vehicle treatment. Finally, we found that AnxA5 stimulation leads to a reduction of IL-6 production in bone-marrow derived macrophages in vitro. AnxA5 treatment attenuates the post-ischemic inflammatory response and ameliorates LV remodeling which improves cardiac function three weeks after MI-R injury in hypercholesterolemic ApoE*3-Leiden mice. PMID- 29712963 TI - Publisher Correction: Functional interaction between FUS and SMN underlies SMA like splicing changes in wild-type hFUS mice. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29712964 TI - An in vitro transepithelial migration assay to evaluate the role of neutrophils in Respiratory Syncytial Virus (RSV) induced epithelial damage. AB - Large numbers of neutrophils migrate into the lungs of children with severe Respiratory Syncytial Virus (RSV) disease. It is unclear how these cells contribute to viral clearance and recovery from infection or whether they contribute to disease pathology. We have developed a novel in vitro model to study neutrophil migration through airway epithelial cells (AECs), the main cellular target of RSV infection. Our model reproduces a physiologically relevant cell polarity and directionality of neutrophil migration. Using this model, we found that RSV infected AECs induced rapid neutrophil transepithelial migration. We also detected increased AEC damage associated with RSV infection, with a further increase in epithelial cells shedding from the Transwell membrane following neutrophil migration. This was not observed in the mock infected controls. Neutrophils that migrated through the RSV infected AECs showed increased cell surface expression of CD11B and MPO compared to neutrophils that had not migrated. In conclusion, our in vitro co-culture assay can be used to identify critical mechanisms that mediate epithelial cell damage and promote inflammation in children with severe RSV disease. PMID- 29712965 TI - Head-to-head comparison of two engineered cardiac grafts for myocardial repair: From scaffold characterization to pre-clinical testing. AB - Cardiac tissue engineering, which combines cells and supportive scaffolds, is an emerging treatment for restoring cardiac function after myocardial infarction (MI), although, the optimal construct remains a challenge. We developed two engineered cardiac grafts, based on decellularized scaffolds from myocardial and pericardial tissues and repopulated them with adipose tissue mesenchymal stem cells (ATMSCs). The structure, macromechanical and micromechanical scaffold properties were preserved upon the decellularization and recellularization processes, except for recellularized myocardium micromechanics that was ~2-fold stiffer than native tissue and decellularized scaffolds. Proteome characterization of the two acellular matrices showed enrichment of matrisome proteins and major cardiac extracellular matrix components, considerably higher for the recellularized pericardium. Moreover, the pericardial scaffold demonstrated better cell penetrance and retention, as well as a bigger pore size. Both engineered cardiac grafts were further evaluated in pre-clinical MI swine models. Forty days after graft implantation, swine treated with the engineered cardiac grafts showed significant ventricular function recovery. Irrespective of the scaffold origin or cell recolonization, all scaffolds integrated with the underlying myocardium and showed signs of neovascularization and nerve sprouting. Collectively, engineered cardiac grafts -with pericardial or myocardial scaffolds were effective in restoring cardiac function post-MI, and pericardial scaffolds showed better structural integrity and recolonization capability. PMID- 29712966 TI - Localization and Functional Characterization of an Occipital Visual Word form Sensitive Area. AB - In human occipitotemporal cortex, category-specific processing for visual objects seems to involve pairs of cortical regions, often with one located in the occipital cortex and another more anteriorly. We investigated whether such an arrangement might be the case for visual word processing. In addition to the Visual Word Form Area (VWFA) located in the occipitotemporal sulcus, we observed that another region in occipital lobe with robust responses to written words (Chinese characters). The current fMRI study investigated this area's precise location and its functional selectivity using Chinese characters and other categories of visual images (cars, chairs and insects). In all the 13 subjects we could identify a cluster of voxels near the inferior occipital gyrus or middle occipital gyrus with stronger responses to Chinese characters than scrambled objects. We tentatively label this area as the Occipital Word Form Sensitive Area (OWA). The OWA's response amplitudes showed similar preference to written words as the VWFA, with the VWFA showing a higher degree of word selectivity, which was confirmed by the result from spatial patterns of response. These results indicate that the OWA, together with the VWFA, are critical parts of the network for processing and representing the category information for word. PMID- 29712967 TI - Place preference and vocal learning rely on distinct reinforcers in songbirds. AB - In reinforcement learning (RL) agents are typically tasked with maximizing a single objective function such as reward. But it remains poorly understood how agents might pursue distinct objectives at once. In machines, multiobjective RL can be achieved by dividing a single agent into multiple sub-agents, each of which is shaped by agent-specific reinforcement, but it remains unknown if animals adopt this strategy. Here we use songbirds to test if navigation and singing, two behaviors with distinct objectives, can be differentially reinforced. We demonstrate that strobe flashes aversively condition place preference but not song syllables. Brief noise bursts aversively condition song syllables but positively reinforce place preference. Thus distinct behavior generating systems, or agencies, within a single animal can be shaped by correspondingly distinct reinforcement signals. Our findings suggest that spatially segregated vocal circuits can solve a credit assignment problem associated with multiobjective learning. PMID- 29712968 TI - Lignite coal burning seam in the remote Altai Mountains harbors a hydrogen-driven thermophilic microbial community. AB - Thermal ecosystems associated with underground coal combustion sites are rare and less studied than geothermal features. Here we analysed microbial communities of near-surface ground layer and bituminous substance in an open quarry heated by subsurface coal fire by metagenomic DNA sequencing. Taxonomic classification revealed dominance of only a few groups of Firmicutes. Near-complete genomes of three most abundant species, 'Candidatus Carbobacillus altaicus' AL32, Brockia lithotrophica AL31, and Hydrogenibacillus schlegelii AL33, were assembled. According to the genomic data, Ca. Carbobacillus altaicus AL32 is an aerobic heterotroph, while B. lithotrophica AL31 is a chemolithotrophic anaerobe assimilating CO2 via the Calvin cycle. H. schlegelii AL33 is an aerobe capable of both growth on organic compounds and carrying out CO2 fixation via the Calvin cycle. Phylogenetic analysis of the large subunit of RuBisCO of B. lithotrophica AL31 and H. schlegelii AL33 showed that it belongs to the type 1-E. All three Firmicutes species can gain energy from aerobic or anaerobic oxidation of molecular hydrogen, produced as a result of underground coal combustion along with other coal gases. We propose that thermophilic Firmicutes, whose spores can spread from their original geothermal habitats over long distances, are the first colonizers of this recently formed thermal ecosystem. PMID- 29712970 TI - Gaining new insights into nanoporous gold by mining and analysis of published images. AB - One way of expediting materials development is to decrease the need for new experiments by making greater use of published literature. Here, we use data mining and automated image analysis to gather new insights on nanoporous gold (NPG) without conducting additional experiments or simulations. NPG is a three dimensional porous network that has found applications in catalysis, sensing, and actuation. We assemble and analyze published images from among thousands of publications on NPG. These images allow us to infer a quantitative description of NPG coarsening as a function of time and temperature, including the coarsening exponent and activation energy. They also demonstrate that relative density and ligament size in NPG are not correlated, indicating that these microstructure features are independently tunable. Our investigation leads us to propose improved reporting guidelines that will enhance the utility of future publications in the field of dealloyed materials. PMID- 29712971 TI - Author Correction: Grain Yield, Starch Content and Activities of Key Enzymes of Waxy and Non-waxy Wheat (Triticum aestivum L.). AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has not been fixed in the paper. PMID- 29712969 TI - Nucleolar-nucleoplasmic shuttling of TARG1 and its control by DNA damage-induced poly-ADP-ribosylation and by nucleolar transcription. AB - Macrodomains are conserved protein folds associated with ADP-ribose binding and turnover. ADP-ribosylation is a posttranslational modification catalyzed primarily by ARTD (aka PARP) enzymes in cells. ARTDs transfer either single or multiple ADP-ribose units to substrates, resulting in mono- or poly-ADP ribosylation. TARG1/C6orf130 is a macrodomain protein that hydrolyzes mono-ADP ribosylation and interacts with poly-ADP-ribose chains. Interactome analyses revealed that TARG1 binds strongly to ribosomes and proteins associated with rRNA processing and ribosomal assembly factors. TARG1 localized to transcriptionally active nucleoli, which occurred independently of ADP-ribose binding. TARG1 shuttled continuously between nucleoli and nucleoplasm. In response to DNA damage, which activates ARTD1/2 (PARP1/2) and promotes synthesis of poly-ADP ribose chains, TARG1 re-localized to the nucleoplasm. This was dependent on the ability of TARG1 to bind to poly-ADP-ribose. These findings are consistent with the observed ability of TARG1 to competitively interact with RNA and PAR chains. We propose a nucleolar role of TARG1 in ribosome assembly or quality control that is stalled when TARG1 is re-located to sites of DNA damage. PMID- 29712972 TI - First long-term detection of paleo-oceanic signature of dust aerosol at the southern marginal area of the Taklimakan Desert. AB - We firstly conducted a long-term in-situ field measurement at a marginal area (Hotan) of the southern Taklimakan Desert covering all four seasons. Detailed chemical characterization of dust aerosol over Hotan showed several unconventional features, including (1) ubiquity of high Na+ and Cl- abundances in the Taklimakan dust aerosol and its Cl-/Na+ ratio close to seawater; (2) high Ca content in the Taklimakan dust (7.4~8.0%) which was about two times of that in the natural crust; (3) high abundance of soluble sulfate concentrations and strong correlations between sulfate and Na+ and Cl- as well as typical mineral tracers such as Al and Ca. Our results collectively indicated that the dust aerosol from the Taklimakan Desert was characterized of evident paelo-oceanic signature as the Taklimakan Desert was found as an ocean in the ancient times from the perspective of paleogeology. It was estimated that primary sources dominated the total abundances of sulfate during the dust seasons while previous climate modeling works had seldom considered the cooling effects of sulfate from the Taklimakan Desert. PMID- 29712974 TI - Author Correction: Sensorimotor adaptation as a behavioural biomarker of early spinocerebellar ataxia type 6. AB - A correction has been published and is appended to both the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29712975 TI - Author Correction: Alleviation of drought stress in pulse crops with ACC deaminase producing rhizobacteria isolated from acidic soil of Northeast India. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29712973 TI - Functional and structural characterization of osteocytic MLO-Y4 cell proteins encoded by genes differentially expressed in response to mechanical signals in vitro. AB - The anabolic response of bone to mechanical load is partially the result of osteocyte response to fluid flow-induced shear stress. Understanding signaling pathways activated in osteocytes exposed to fluid flow could identify novel signaling pathways involved in the response of bone to mechanical load. Bioinformatics allows for a unique perspective and provides key first steps in understanding these signaling pathways. We examined proteins encoded by genes differentially expressed in response to fluid flow in murine osteocytic MLO-Y4 cells. We considered structural and functional characteristics including putative intrinsic disorder, evolutionary conservation, interconnectedness in protein protein interaction networks, and cellular localization. Our analysis suggests that proteins encoded by fluid flow activated genes have lower than expected conservation, are depleted in intrinsic disorder, maintain typical levels of connectivity for the murine proteome, and are found in the cytoplasm and extracellular space. Pathway analyses reveal that these proteins are associated with cellular response to stress, chemokine and cytokine activity, enzyme binding, and osteoclast differentiation. The lower than expected disorder of proteins encoded by flow activated genes suggests they are relatively specialized. PMID- 29712976 TI - Impact of HIV and Type 2 diabetes on Gut Microbiota Diversity, Tryptophan Catabolism and Endothelial Dysfunction. AB - HIV infection and type 2 diabetes are associated with altered gut microbiota, chronic inflammation, and increased cardiovascular risk. We aimed to investigate the combined effect of these diseases on gut microbiota composition and related metabolites, and a potential relation to endothelial dysfunction in individuals with HIV-infection only (n = 23), diabetes only (n = 16) or both conditions (n = 21), as well as controls (n = 24). Fecal microbiota was analyzed by Illumina sequencing of the 16 S rRNA gene. Markers of endothelial dysfunction (asymmetric dimethylarginine [ADMA]), tryptophan catabolism (kynurenine/tryptophan [KT] ratio), and inflammation (neopterin) were measured by liquid chromatography tandem mass spectrometry. The combination of HIV and type 2 diabetes was associated with reduced gut microbiota diversity, increased plasma KT-ratio and neopterin. Microbial genes related to tryptophan metabolism correlated with KT ratio and low alpha diversity, in particular in HIV-infected with T2D. In multivariate analyses, KT-ratio associated with ADMA (beta = 4.58 [95% CI 2.53 6.63], p < 0.001), whereas microbiota composition per se was not associated with endothelial dysfunction. Our results indicate that tryptophan catabolism may be related to endothelial dysfunction, with a potentially detrimental interaction between HIV and diabetes. The potential contribution of gut microbiota and the impact for cardiovascular risk should be further explored in prospective studies powered for clinical end points. PMID- 29712977 TI - Concordant association validates MGMT methylation and protein expression as favorable prognostic factors in glioma patients on alkylating chemotherapy (Temozolomide). AB - O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation and its subsequent loss of protein expression has been identified to have a variable impact on clinical outcome of glioma patients indicated for chemotherapy with alkylating agents (Temozolomide). This study investigated methylation status of MGMT gene along with in situ protein expression in malignant glioma patients of different histological types to evaluate the associated clinical outcome vis-a vis use of alkylating drugs and radiotherapy. Sixty three cases of glioma were evaluated for MGMT promoter methylation by methylation-specific PCR (MS-PCR) and protein expression by immunostaining (IHC). Methylation status of MGMT and loss of protein expression showed a very high concordant association with better survival and progression free survival (PFS) (p < 0.0001). Multivariate Cox regression analysis showed both MGMT methylation and loss of protein as significant independent prognostic factors in glioma patients with respect to lower Hazard Ratio (HR) for better OS and PFS) [p < 0.05]. Interestingly concordant MGMT methylation and lack of protein showed better response in TMZ therapy treated patient subgroups with HR of 2.02 and 0.76 (p < 0.05). We found the merits of prognostication of MGMT parameters, methylation as well as loss of its protein as predictive factors for favorable outcome in terms of better survival for TMZ therapy. PMID- 29712978 TI - Artifact Removal using Improved GoogLeNet for Sparse-view CT Reconstruction. AB - Sparse-view Reconstruction can be used to provide accelerated low dose CT imaging with both accelerated scan and reduced projection/back-projection calculation. Despite the rapid developments, image noise and artifacts still remain a major issue in the low dose protocol. In this paper, a deep learning based method named Improved GoogLeNet is proposed to remove streak artifacts due to projection missing in sparse-view CT reconstruction. Residual learning is used in GoogLeNet to study the artifacts of sparse-view CT reconstruction, and then subtracts the artifacts obtained by learning from the sparse reconstructed images, finally recovers a clear correction image. The intensity of reconstruction using the proposed method is very close to the full-view projective reconstructed image. The results indicate that the proposed method is practical and effective for reducing the artifacts and preserving the quality of the reconstructed image. PMID- 29712979 TI - Three-dimensional computational model simulating the fracture healing process with both biphasic poroelastic finite element analysis and fuzzy logic control. AB - A dynamic model regulated by both biphasic poroelastic finite element analysis and fuzzy logic control was established. Fuzzy logic control was an easy and comprehensive way to simulate the tissue differentiation process, and it is convenient for researchers and medical experts to communicate with one another to change the fuzzy logic rules and improve the simulation of the tissue differentiation process. In this study, a three-dimensional fracture healing model with two different interfragmentary movements (case A: 0.25 mm and case B: 1.25 mm) was analysed with the new set-up computational model. As the healing process proceeded, both simulated interfragmentary movements predicted a decrease and the time that the decrease started for case B was later than that for case A. Compared with experimental results, both cases corresponded with experimental data well. The newly established dynamic model can simulate the healing process under different mechanical environments and has the potential to extend to the multiscale healing model, which is essential for reducing the animal experiments and helping to characterise the complex dynamic interaction between tissue differentiations within the callus region. PMID- 29712980 TI - A Comparison of the Antibacterial and Antifungal Activities of Thiosulfinate Analogues of Allicin. AB - Allicin (diallylthiosulfinate) is a defence molecule from garlic (Allium sativum L.) with broad antimicrobial activities in the low uM range against Gram-positive and -negative bacteria, including antibiotic resistant strains, and fungi. Allicin reacts with thiol groups and can inactivate essential enzymes. However, allicin is unstable at room temperature and antimicrobial activity is lost within minutes upon heating to >80 degrees C. Allicin's antimicrobial activity is due to the thiosulfinate group, so we synthesized a series of allicin analogues and tested their antimicrobial properties and thermal stability. Dimethyl-, diethyl-, diallyl-, dipropyl- and dibenzyl-thiosulfinates were synthesized and tested in vitro against bacteria and the model fungus Saccharomyces cerevisiae, human and plant cells in culture and Arabidopsis root growth. The more volatile compounds showed significant antimicrobial properties via the gas phase. A chemogenetic screen with selected yeast mutants showed that the mode of action of the analogues was similar to that of allicin and that the glutathione pool and glutathione metabolism were of central importance for resistance against them. Thiosulfinates differed in their effectivity against specific organisms and some were thermally more stable than allicin. These analogues could be suitable for applications in medicine and agriculture either singly or in combination with other antimicrobials. PMID- 29712981 TI - TMS Over the Cerebellum Interferes with Short-term Memory of Visual Sequences. AB - Growing evidence suggests that the cerebellum is not only involved in motor functions, but it significantly contributes to sensory and cognitive processing as well. In particular, it has been hypothesized that the cerebellum identifies recurrent serial events and recognizes their violations. Here we used transcranial magnetic stimulation (TMS) to shed light on the role of the cerebellum in short-term memory of visual sequences. In two experiments, we found that TMS over the right cerebellar hemisphere impaired participants' ability to recognize the correct order of appearance of geometrical stimuli varying in shape and/or size. In turn, cerebellar TMS did not affect recognition of highly familiar short sequences of letters or numbers. Overall, our data suggest that the cerebellum is involved in memorizing the order in which (concatenated) stimuli appear, this process being important for sequence learning. PMID- 29712982 TI - Defects and lithium migration in Li2CuO2. AB - Li2CuO2 is an important candidate material as a cathode in lithium ion batteries. Atomistic simulation methods are used to investigate the defect processes, electronic structure and lithium migration mechanisms in Li2CuO2. Here we show that the lithium energy of migration via the vacancy mechanism is very low, at 0.11 eV. The high lithium Frenkel energy (1.88 eV/defect) prompted the consideration of defect engineering strategies in order to increase the concentration of lithium vacancies that act as vehicles for the vacancy mediated lithium self-diffusion in Li2CuO2. It is shown that aluminium doping will significantly reduce the energy required to form a lithium vacancy from 1.88 eV to 0.97 eV for every aluminium introduced, however, it will also increase the migration energy barrier of lithium in the vicinity of the aluminium dopant to 0.22 eV. Still, the introduction of aluminium is favourable compared to the lithium Frenkel process. Other trivalent dopants considered herein require significantly higher solution energies, whereas their impact on the migration energy barrier was more pronounced. When considering the electronic structure of defective Li2CuO2, the presence of aluminium dopants results in the introduction of electronic states into the energy band gap. Therefore, doping with aluminium is an effective doping strategy to increase the concentration of lithium vacancies, with a minimal impact on the kinetics. PMID- 29712983 TI - Stable isotope compositions (delta2H, delta18O and delta17O) of rainfall and snowfall in the central United States. AB - Stable isotopes of hydrogen and oxygen (delta2H, delta18O and delta17O) can be used as natural tracers to improve our understanding of hydrological and meteorological processes. Studies of precipitation isotopes, especially 17O excess observations, are extremely limited in the mid-latitudes. To fill this knowledge gap, we measured delta2H, delta18O and delta17O of event-based precipitation samples collected from Indianapolis, Indiana, USA over two years and investigated the influence of meteorological factors on precipitation isotope variations. The results showed that the daily temperature played a major role in controlling the isotope variations. Precipitation experienced kinetic fractionation associated with evaporation at the moisture source in the spring and summer and for rainfall, while snowfall, as well as precipitation in the fall and winter, were mainly affected by equilibrium fractionation. The 17O-excess of both rainfall and snowfall were not affected by local meteorological factors over the whole study period. At the seasonal scale, it was the case only for the spring. Therefore, 17O-excess of rainfall, snowfall and the spring precipitation could be considered as tracers of evaporative conditions at the moisture source. This study provides a unique precipitation isotope dataset for mid-latitudes and provides a more mechanistic understanding of precipitation formation mechanisms in this region. PMID- 29712984 TI - An inside view on pesticide policy. PMID- 29712986 TI - Are patients with poorer vision more polite? A study examining door closing tendencies in patients with poor vision. PMID- 29712985 TI - Identification and pathogenomic analysis of an Escherichia coli strain producing a novel Shiga toxin 2 subtype. AB - Shiga toxin (Stx) is the key virulent factor in Shiga toxin-producing Escherichia coli (STEC). To date, three Stx1 subtypes and seven Stx2 subtypes have been described in E. coli, which differed in receptor preference and toxin potency. Here, we identified a novel Stx2 subtype designated Stx2h in E. coli strains isolated from wild marmots in the Qinghai-Tibetan plateau, China. Stx2h shares 91.9% nucleic acid sequence identity and 92.9% amino acid identity to the nearest Stx2 subtype. The expression of Stx2h in type strain STEC299 was inducible by mitomycin C, and culture supernatant from STEC299 was cytotoxic to Vero cells. The Stx2h converting prophage was unique in terms of insertion site and genetic composition. Whole genome-based phylo- and patho-genomic analysis revealed STEC299 was closer to other pathotypes of E. coli than STEC, and possesses virulence factors from other pathotypes. Our finding enlarges the pool of Stx2 subtypes and highlights the extraordinary genomic plasticity of E. coli strains. As the emergence of new Shiga toxin genotypes and new Stx-producing pathotypes pose a great threat to the public health, Stx2h should be further included in E. coli molecular typing, and in epidemiological surveillance of E. coli infections. PMID- 29712987 TI - Author Correction: Role of iRhom2 in intestinal ischemia-reperfusion-mediated acute lung injury. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29712988 TI - Author Correction: Critical Shear Stress is Associated with Diabetic Kidney Disease in Patients with Type 2 Diabetes. AB - A correction to this article has been published and is linked from the HTML version of this paper. The error has not been fixed in the paper. PMID- 29712989 TI - A comparison of clinical and molecular characteristics of patients with systemic mastocytosis with chronic myelomonocytic leukemia to CMML alone. PMID- 29712990 TI - What calls for service tell us about suicide: A 7-year spatio-temporal analysis of neighborhood correlates of suicide-related calls. AB - Previous research has shown that neighborhood-level variables such as social deprivation, social fragmentation or rurality are related to suicide risk, but most of these studies have been conducted in the U.S. or northern European countries. The aim of this study was to analyze the spatio-temporal distribution of suicide in a southern European city (Valencia, Spain), and determine whether this distribution was related to a set of neighborhood-level characteristics. We used suicide-related calls for service as an indicator of suicide cases (n = 6,537), and analyzed the relationship of the outcome variable with several neighborhood-level variables: economic status, education level, population density, residential instability, one-person households, immigrant concentration, and population aging. A Bayesian autoregressive model was used to study the spatio-temporal distribution at the census block group level for a 7-year period (2010-2016). Results showed that neighborhoods with lower levels of education and population density, and higher levels of residential instability, one-person households, and an aging population had higher levels of suicide-related calls for service. Immigrant concentration and economic status did not make a relevant contribution to the model. These results could help to develop better-targeted community-level suicide prevention strategies. PMID- 29712991 TI - Author Correction: Implementation, coverage and equity of large-scale door-to door delivery of Seasonal Malaria Chemoprevention (SMC) to children under 10 in Senegal. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29712992 TI - A protocol for culturing environmental strains of the Buruli ulcer agent, Mycobacterium ulcerans. AB - Contaminations and fastidiousness of M. ulcerans may have both hamper isolation of strains from environmental sources. We aimed to optimize decontamination and culture of environmental samples to circumvent both limitations. Three strains of M. ulcerans cultured onto Middlebrook 7H10 at 30 degrees C for 20 days yielded a significantly higher number of colonies in micro-aerophilic atmosphere compared to ambient atmosphere, 5% CO2 and anaerobic atmosphere. In a second step, we observed that M. ulcerans genome uniquely encoded chitinase, fucosidase and A-D GlcNAc-diphosphoryl polyprenol A-3-L-rhamnosyl transferase giving M. ulcerans the potential to metabolize chitine, fucose and N-acetyl galactosamine (NAG), respectively. A significant growth-promoting effect of 0.2 mg/mL chitin (p < 0.05), 0.01 mg/mL N-acetyl galactosamine (p < 0.05), 0.01 mg/mL fucose (p < 0.05) was observed with M. ulcerans indicating that NAG alone or combined with fucose and chitin could complement Middlebrook 7H10. Finally, the protocol combining 1% chlorhexidine decontamination with micro-aerophilic incubation on Middlebrook 7H10 medium containing chitin (0.2%), NAG (0.01%) and fucose (0.01%) medium and auto-fluorescence detection of colonies allowed for the isolation of one mycolactone-encoding strain from Thryonomys swinderianus (aulacode) feces specimens collected near the Kossou Dam, Cote d'Ivoire. We propose that incubation of chlorhexidine-decontaminated environmental specimens on Middlebrook 7H10-enriched medium under micro-aerophilic atmosphere at 30 degrees C may be used for the tentative isolation of M. ulcerans strains from potential environmental sources. PMID- 29712993 TI - Development of a quantitative PCR detecting Cunninghamella bertholletiae to help in diagnosing this rare and aggressive mucormycosis. AB - Mucormycosis is an invasive mold infection, frequently fatal in immunocompromised patients. We report the case of a patient with chronic lymphocytic leukemia admitted to the hematology unit for febrile aplasia. Pulmonary lesions suggesting a fungal infection expanded/increased despite a combination of posaconazole and liposomal amphotericin B. The fungal biomarkers performed repeatedly were negative. At D65 after chemotherapy a bronchial biopsy was positive for Cunninghamella bertholletiae. The patient died despite appropriate antifungal management. A qPCR targeting Cunninghamella was developed a posteriori, and a retrospective analysis showed that a sample was positive more than 30 days before culture-based identification could be made. PMID- 29712994 TI - Allogeneic hematopoietic stem cell transplantation should be in preference to conventional chemotherapy as post-remission treatment for adults with lymphoblastic lymphoma. PMID- 29712997 TI - Purinergic system and suicidal behavior: exploring the link between adenosine A2A receptors and depressive/impulsive features. PMID- 29712995 TI - Postoperative Rehabilitation May Reduce the Risk of Readmission After Groin Hernia Repair. AB - Thirty-day readmission after surgery has been proposed as a quality-of-care indicator. We explored the effect of postoperative rehabilitation on readmission risk after groin hernia repair. We used the French National Discharge Database to identify all index hospitalizations for groin hernia repair in 2011. Readmissions within 30 days of discharge were clinically classified in terms of their relationship to the index stay. We used logistic regression to adjust the risk of readmission for patient, procedure and hospital factors. Among 122,952 index hospitalizations for inguinal hernia repair, 3,357 (2.7%) related 30-day readmissions were recorded. Reiterated analyses indicated that readmission risk was consistently associated with patient complexity: age (per year after 60 years, OR 1.03, 95% CI 1.02-1.03, P < 0.001), hospitalization within the previous year (OR 1.56, 95% CI 1.44-1.69, P < 0.001), and increasing severity and combination of co-morbidities. Postoperative rehabilitation was identified as a protective factor (OR 0.56, 95% CI 0.46-0.69, P < 0.001). Older patients and those with greater comorbidity are at elevated risk of readmission after inguinal hernia repair. Postoperative rehabilitation may reduce this risk. Further studies are warranted to confirm the protective effect of postoperative rehabilitation. PMID- 29712996 TI - Properties of the ternary complex formed by yeast eIF4E, p20 and mRNA. AB - Yeast p20 is a small, acidic protein that binds eIF4E, the cap-binding protein. It has been proposed to affect mRNA translation and degradation, however p20's function as an eIF4E-binding protein (4E-BP) and its physiological significance has not been clearly established. In this paper we present data demonstrating that p20 is capable of binding directly to mRNA due to electrostatic interaction of a stretch of arginine and histidine residues in the protein with negatively charged phosphates in the mRNA backbone. This interaction contributes to formation of a ternary eIF4E/p20/capped mRNA complex that is more stable than complexes composed of capped mRNA bound to eIF4E in the absence of p20. eIF4E/p20 complex was found to have a more pronounced stimulatory effect on capped mRNA translation than purified eIF4E alone. Addition of peptides containing the eIF4E binding domains present in p20 (motif YTIDELF), in eIF4G (motif YGPTFLL) or Eap1 (motif YSMNELY) completely inhibited eIF4E-dependent capped mRNA translation (in vitro), but had a greatly reduced inhibitory effect when eIF4E/p20 complex was present. We propose that the eIF4E/p20/mRNA complex serves as a stable depository of mRNAs existing in a dynamic equilibrium with other complexes such as eIF4E/eIF4G (required for translation) and eIF4E/Eap1 (required for mRNA degradation). PMID- 29712999 TI - Author Correction: Sulfate Reduction in Sediments Produces High Levels of Chromophoric Dissolved Organic Matter. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29713001 TI - Attention: Direct-To-Consumer patrons: Proceed with caution. PMID- 29712998 TI - A novel role for CAMKIIbeta in the regulation of cortical neuron migration: implications for neurodevelopmental disorders. AB - Perturbation of CaMKIIbeta expression has been associated with multiple neuropsychiatric diseases, highlighting CaMKIIbeta as a gene of interest. Yet, in contrast to CaMKIIalpha, the specific functions of CaMKIIbeta in the brain remain poorly explored. Here, we reveal a novel function for this CaMKII isoform in vivo during neuronal development. By using in utero electroporation, we show that CaMKIIbeta is an important regulator of radial migration of projection neurons during cerebral cortex development. Knockdown of CaMKIIbeta causes accelerated migration of nascent pyramidal neurons, whereas overexpression of CaMKIIbeta inhibits migration, demonstrating that precise regulation of CaMKIIbeta expression is required for correct neuronal migration. More precisely, CaMKIIbeta controls the multipolar-bipolar transition in the intermediate zone and locomotion in the cortical plate through its actin-binding and -bundling activities. In addition, our data indicate that a fine-tuned balance between CaMKIIbeta and cofilin activities is necessary to ensure proper migration of cortical neurons. Thus, our findings define a novel isoform-specific function for CaMKIIbeta, demonstrating that CaMKIIbeta has a major biological function in the developing brain. PMID- 29713000 TI - Effects of inhaled nitric oxide on outcome after prolonged cardiac arrest in mild therapeutic hypothermia treated rats. AB - Guidelines endorse targeted temperature management to reduce neurological sequelae and mortality after cardiac arrest (CA). Additional therapeutic approaches are lacking. Inhaled nitric oxide (iNO) given post systemic ischemia/reperfusion injury improves outcomes. Attenuated inflammation by iNO might be crucial in brain protection. iNO augmented mild therapeutic hypothermia (MTH) may improve outcome after CA exceeding the effect of MTH alone. Following ten minutes of CA and three minutes of cardiopulmonary resuscitation, 20 male Sprague-Dawley rats were randomized to receive MTH at 33 degrees C for 6hrs or MTH + 20ppm iNO for 5hrs; one group served as normothermic control. During the experiment blood was taken for biochemical evaluation. A neurological deficit score was calculated daily for seven days post CA. On day seven, brains and hearts were harvested for histological evaluation. Treatment groups showed a significant decrease in lactate levels six hours post resuscitation in comparison to controls. TNF-alpha release was significantly lower in MTH + iNO treated animals only at four hours post ROSC. While only the combination of MTH and iNO improved neurological function in a statistically significant manner in comparison to controls on days 4-7 after CA, there was no significant difference between groups treated with MTH and MTH + iNO. PMID- 29713002 TI - Smooth translation to maintain a healthy skin. PMID- 29713003 TI - Multi-omics profiling of younger Asian breast cancers reveals distinctive molecular signatures. AB - Breast cancer (BC) in the Asia Pacific regions is enriched in younger patients and rapidly rising in incidence yet its molecular bases remain poorly characterized. Here we analyze the whole exomes and transcriptomes of 187 primary tumors from a Korean BC cohort (SMC) enriched in pre-menopausal patients and perform systematic comparison with a primarily Caucasian and post-menopausal BC cohort (TCGA). SMC harbors higher proportions of HER2+ and Luminal B subtypes, lower proportion of Luminal A with decreased ESR1 expression compared to TCGA. We also observe increased mutation prevalence affecting BRCA1, BRCA2, and TP53 in SMC with an enrichment of a mutation signature linked to homologous recombination repair deficiency in TNBC. Finally, virtual microdissection and multivariate analyses reveal that Korean BC status is independently associated with increased TIL and decreased TGF-beta signaling expression signatures, suggesting that younger Asian BCs harbor more immune-active microenvironment than western BCs. PMID- 29713006 TI - Macropinocytosis for proliferation. PMID- 29713004 TI - Obese Subjects With Specific Gustatory Papillae Microbiota and Salivary Cues Display an Impairment to Sense Lipids. AB - Some obese subjects overeat lipid-rich foods. The origin of this eating behavior is unknown. We have here tested the hypothesis that these subjects could be characterized by an impaired fatty taste sensitivity linked to a change in the gustatory papillae microbial and salivary environment. The composition of microbiota and saliva surrounding the circumvallate papillae was analyzed in combination with the orosensory lipid detection threshold in normal weight (NW) and obese (O) adults. Microbial architecture was similar to what was known in feces, but with an increased frequency of Proteobacteria. No difference in the orosensory sensitivity to lipids and composition of oral microbiota and saliva was observed between NW and O subjects. By contrast, specific bacterial and salivary signatures were found in lipid non-tasters, irrespectively of BMI. A multivariate approach highlighted that the salivary flow, lysozyme activity, total antioxidant capacity and TM7 bacterial family discriminated between tasters and non-tasters. Subgroup analysis of obese tasters (OT) versus obese non-tasters (ONT) identified specific bacterial metabolic pathways (i.e. phosphotransferase and simple sugar transport systems) as being higher in ONT. Altogether with the identification of a set of significant salivary variables, our study suggests that an "obese tongue" phenotype is associated with decreased orosensory sensitivity to lipids in some obese subjects. PMID- 29713005 TI - Genetic structure of pharmacogenetic biomarkers in Brazil inferred from a systematic review and population-based cohorts: a RIBEF/EPIGEN-Brazil initiative. AB - We present allele frequencies involving 39 pharmacogenetic biomarkers studied in Brazil, and their distribution on self-reported race/color categories that: (1) involve a mix of perceptions about ancestry, morphological traits, and cultural/identity issues, being social constructs pervasively used in Brazilian society and medical studies; (2) are associated with disparities in access to health services, as well as in their representation in genetic studies, and (3), as we report here, explain a larger portion of the variance of pharmaco-allele frequencies than geography. We integrated a systematic review of studies on healthy volunteers (years 1968-2017) and the analysis of allele frequencies on three population-based cohorts from northeast, southeast, and south, the most populated regions of Brazil. Cross-validation of results from these both approaches suggest that, despite methodological heterogeneity of the 120 studies conducted on 51,747 healthy volunteers, allele frequencies estimates from systematic review are reliable. We report differences in allele frequencies between color categories that persist despite the homogenizing effect of >500 years of admixture. Among clinically relevant variants: CYP2C9*2 (null), CYP3A5*3 (defective), SLCO1B1-rs4149056(C), and VKORC1-rs9923231(A) are more frequent in Whites than in Blacks. Brazilian Native Americans show lower frequencies of CYP2C9*2, CYP2C19*17 (increased activity), and higher of SLCO1B1-rs4149056(C) than other Brazilian populations. We present the most current and informative database of pharmaco-allele frequencies in Brazilian healthy volunteers. PMID- 29713007 TI - Historical and contemporary perspectives on cribriform morphology in prostate cancer. AB - The Gleason scoring system is widely used for the grading and prognostication of prostate cancer. A Gleason pattern 4 subtype known as cribriform morphology has now been recognized as an aggressive and often lethal pattern of prostate cancer. The vast majority of published and ongoing prostate cancer studies still do not acknowledge the prognostic differences between various Gleason pattern 4 morphologies. As a result, current treatment recommendations are likely to be imprecise and not tailored towards patients who are most likely to die from the disease. Use of active surveillance for patients with Gleason score 3 + 4 prostate cancer has been suggested. However, the success of such paradigms would require cribriform morphology to be reported at the time of prostate biopsy, as patients harbouring such a pattern are poor candidates for surveillance. To date, only a limited number of studies have described the molecular alterations that occur in the cribriform morphological pattern. Further refinement of prostate cancer grading paradigms to distinguish cribriform from noncribriform Gleason pattern 4 is essential. PMID- 29713008 TI - Author Correction: Dynamic cellular phenotyping defines specific mobilization mechanisms of human hematopoietic stem and progenitor cells induced by SDF1alpha versus synthetic agents. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29713010 TI - Dynamics of fibroblast activation in the infarcted heart. PMID- 29713009 TI - Role of salt intake in prevention of cardiovascular disease: controversies and challenges. AB - Strong evidence indicates that reduction of salt intake lowers blood pressure and reduces the risk of cardiovascular disease (CVD). The WHO has set a global target of reducing the population salt intake from the current level of approximately 10 g daily to <5 g daily. This recommendation has been challenged by several studies, including cohort studies, which have suggested a J-shaped relationship between salt intake and CVD risk. However, these studies had severe methodological problems, such as reverse causality and measurement error due to assessment of salt intake by spot urine. Consequently, findings from such studies should not be used to derail vital public health policy. Gradual, stepwise salt reduction as recommended by the WHO remains an achievable, affordable, effective, and important strategy to prevent CVD worldwide. The question now is how to reduce population salt intake. In most developed countries, salt reduction can be achieved by a gradual and sustained reduction in the amount of salt added to food by the food industry. The UK has pioneered a successful salt-reduction programme by setting incremental targets for >85 categories of food; many other developed countries are following the UK's lead. In developing countries where most of the salt is added by consumers, public health campaigns have a major role. Every country should adopt a coherent, workable strategy. Even a modest reduction in salt intake across the whole population can lead to a major improvement in public health and cost savings. PMID- 29713011 TI - Pathophysiological coronary and microcirculatory flow alterations in aortic stenosis. AB - Regulation of coronary blood flow is maintained through a delicate balance of ventriculoarterial and neurohumoral mechanisms. The aortic valve is integral to the functions of these systems, and disease states that compromise aortic valve integrity have the potential to seriously disrupt coronary blood flow. Aortic stenosis (AS) is the most common cause of valvular heart disease requiring medical intervention, and the prevalence and associated socio-economic burden of AS are set to increase with population ageing. Valvular stenosis precipitates a cascade of structural, microcirculatory, and neurohumoral changes, which all lead to impairment of coronary flow reserve and myocardial ischaemia even in the absence of notable coronary stenosis. Coronary physiology can potentially be normalized through interventions that relieve severe AS, but normality is often not immediately achievable and probably requires continued adaptation. Finally, the physiological assessment of coronary artery disease in patients with AS represents an ongoing challenge, as the invasive physiological measures used in current cardiology practice are yet to be validated in this population. This Review discusses the key concepts of coronary pathophysiology in patients with AS through presentation of contemporary basic science and data from animal and human studies. PMID- 29713012 TI - Prions, prionoids and protein misfolding disorders. AB - Prion diseases are progressive, incurable and fatal neurodegenerative conditions. The term 'prion' was first nominated to express the revolutionary concept that a protein could be infectious. We now know that prions consist of PrPSc, the pathological aggregated form of the cellular prion protein PrPC. Over the years, the term has been semantically broadened to describe aggregates irrespective of their infectivity, and the prion concept is now being applied, perhaps overenthusiastically, to all neurodegenerative diseases that involve protein aggregation. Indeed, recent studies suggest that prion diseases (PrDs) and protein misfolding disorders (PMDs) share some common disease mechanisms, which could have implications for potential treatments. Nevertheless, the transmissibility of bona fide prions is unique, and PrDs should be considered as distinct from other PMDs. PMID- 29713013 TI - Tracing cell-lineage histories. PMID- 29713015 TI - Atherogenic dyslipidemia promotes autoimmune follicular helper T cell responses via IL-27. AB - The incidence of atherosclerosis is higher among patients with systemic lupus erythematosus (SLE); however, the mechanism by which an atherogenic environment affects autoimmunity remains unclear. We found that reconstitution of atherosclerosis-prone Apoe-/- and Ldlr-/- mice with bone marrow from lupus-prone BXD2 mice resulted in increased autoantibody production and glomerulonephritis. This enhanced disease was associated with an increase in CXCR3+ follicular helper T cells (TFH cells). TFH cells isolated from Apoe-/- mice had higher expression of genes associated with inflammatory responses and SLE and were more potent in inducing production of the immunoglobulin IgG2c. Mechanistically, the atherogenic environment induced the cytokine IL-27 from dendritic cells in a Toll-like receptor 4 (TLR4)-dependent manner, which in turn triggered the differentiation of CXCR3+ TFH cells while inhibiting the differentiation of follicular regulatory T cells. Blockade of IL-27 signals diminished the increased TFH cell responses in atherogenic mice. Thus, atherogenic dyslipidemia augments autoimmune TFH cell responses and subsequent IgG2c production in a TLR4- and IL-27-dependent manner. PMID- 29713016 TI - Amyloid-beta - a reflection of risk or a preclinical marker? PMID- 29713017 TI - Microglial memory. PMID- 29713014 TI - The Rosa genome provides new insights into the domestication of modern roses. AB - Roses have high cultural and economic importance as ornamental plants and in the perfume industry. We report the rose whole-genome sequencing and assembly and resequencing of major genotypes that contributed to rose domestication. We generated a homozygous genotype from a heterozygous diploid modern rose progenitor, Rosa chinensis 'Old Blush'. Using single-molecule real-time sequencing and a meta-assembly approach, we obtained one of the most comprehensive plant genomes to date. Diversity analyses highlighted the mosaic origin of 'La France', one of the first hybrids combining the growth vigor of European species and the recurrent blooming of Chinese species. Genomic segments of Chinese ancestry identified new candidate genes for recurrent blooming. Reconstructing regulatory and secondary metabolism pathways allowed us to propose a model of interconnected regulation of scent and flower color. This genome provides a foundation for understanding the mechanisms governing rose traits and should accelerate improvement in roses, Rosaceae and ornamentals. PMID- 29713018 TI - A PAX5-OCT4-PRDM1 developmental switch specifies human primordial germ cells. AB - Dysregulation of genetic pathways during human germ cell development leads to infertility. Here, we analysed bona fide human primordial germ cells (hPGCs) to probe the developmental genetics of human germ cell specification and differentiation. We examined the distribution of OCT4 occupancy in hPGCs relative to human embryonic stem cells (hESCs). We demonstrated that development, from pluripotent stem cells to germ cells, is driven by switching partners with OCT4 from SOX2 to PAX5 and PRDM1. Gain- and loss-of-function studies revealed that PAX5 encodes a critical regulator of hPGC development. Moreover, an epistasis analysis indicated that PAX5 acts upstream of OCT4 and PRDM1. The PAX5-OCT4-PRDM1 proteins form a core transcriptional network that activates germline and represses somatic programmes during human germ cell differentiation. These findings illustrate the power of combined genome editing, cell differentiation and engraftment for probing human developmental genetics that have historically been difficult to study. PMID- 29713019 TI - Imaging of angiogenesis of human umbilical vein endothelial cells by uptake of exosomes secreted from hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is a typical hyper-vascular tumor, so the understanding the mechanisms of angiogenesis in HCC is very important for its treatment. However, the influence of the exosomes secreted from HCC cells (HCC exosomes) on angiogenesis remains poorly understood. We herein examined the effects of the exosomes secreted from HepG2 cells (HepG2-exosomes) on the lumen formation of human umbilical vein endothelial cells (HUVECs) by the imaging of angiogenesis. The degree of lumen formation of HUVECs was dependent on the number of HepG2-exosomes. The HepG2-exosomes expressed NKG2D, an activating receptor for immune cells, and HSP70, a stress-induced heat shock protein associated with angiogenesis through the vascular endothelial growth factor (VEGF) receptor. In addition, the HepG2-exosomes contained several microRNAs (miRNAs) reported to exist in the serum of HCC patients. These results suggest that the HCC-exosomes play an important role in angiogenesis. Further studies on the function of HCC exosomes may provide a new target for HCC treatment. PMID- 29713021 TI - Risk of cardiomyopathy and cardiac arrhythmias in patients with nonalcoholic fatty liver disease. AB - Nonalcoholic fatty liver disease (NAFLD) is a common, progressive liver disease that affects up to one-quarter of the adult population worldwide. The clinical and economic burden of NAFLD is mainly due to liver-related morbidity and mortality (nonalcoholic steatohepatitis, cirrhosis or hepatocellular carcinoma) and an increased risk of developing fatal and nonfatal cardiovascular disease, chronic kidney disease and certain types of extrahepatic cancers (for example, colorectal cancer and breast cancer). Additionally, there is now accumulating evidence that NAFLD adversely affects not only the coronary arteries (promoting accelerated coronary atherosclerosis) but also all other anatomical structures of the heart, conferring an increased risk of cardiomyopathy (mainly left ventricular diastolic dysfunction and hypertrophy, leading to the development of congestive heart failure), cardiac valvular calcification (mainly aortic-valve sclerosis), cardiac arrhythmias (mainly atrial fibrillation) and some cardiac conduction defects. This Review focuses on the association between NAFLD and non ischaemia-related cardiac disease, discusses the putative pathophysiological mechanisms and briefly summarizes current treatment options for NAFLD that might also beneficially affect cardiac disease. PMID- 29713020 TI - Pathway-based dissection of the genomic heterogeneity of cancer hallmarks' acquisition with SLAPenrich. AB - Cancer hallmarks are evolutionary traits required by a tumour to develop. While extensively characterised, the way these traits are achieved through the accumulation of somatic mutations in key biological pathways is not fully understood. To shed light on this subject, we characterised the landscape of pathway alterations associated with somatic mutations observed in 4,415 patients across ten cancer types, using 374 orthogonal pathway gene-sets mapped onto canonical cancer hallmarks. Towards this end, we developed SLAPenrich: a computational method based on population-level statistics, freely available as an open source R package. Assembling the identified pathway alterations into sets of hallmark signatures allowed us to connect somatic mutations to clinically interpretable cancer mechanisms. Further, we explored the heterogeneity of these signatures, in terms of ratio of altered pathways associated with each individual hallmark, assuming that this is reflective of the extent of selective advantage provided to the cancer type under consideration. Our analysis revealed the predominance of certain hallmarks in specific cancer types, thus suggesting different evolutionary trajectories across cancer lineages. Finally, although many pathway alteration enrichments are guided by somatic mutations in frequently altered high-confidence cancer genes, excluding these driver mutations preserves the hallmark heterogeneity signatures, thus the detected hallmarks' predominance across cancer types. As a consequence, we propose the hallmark signatures as a ground truth to characterise tails of infrequent genomic alterations and identify potential novel cancer driver genes and networks. PMID- 29713022 TI - Preserving the liver for transplantation. PMID- 29713023 TI - Personalized screening for colorectal cancer. PMID- 29713024 TI - Gastric cancer: evidence boosts Helicobacter pylori eradication. PMID- 29713025 TI - Genome-wide Identification and characterization of circular RNAs in the rice blast fungus Magnaporthe oryzae. AB - Numerous circRNAs have been identified in different organisms, but little attention has been addressed on fungal circRNAs. Here, we identified a total of 8,848 circRNAs from the model plant pathogenic fungus M. oryzae. 5,840 circRNAs were identified from mycelium, 2,721 circRNAs from conidium, while only 287 circRNAs from both tissues. This indicated that most of the M. oryzae circRNAs were specifically expressed in mycelium or in conidium. Parental genes of circRNAs in mycelium were enriched in basic metabolisms required for normal growth, while in conidium, they were enriched in biogenesis of storages potentially used for infection. M. oryzae circRNAs could also bind to miRNAs, suggesting they may also function as sponges in fungi. This study suggested M. oryzae circRNAs could play important roles in regulation of growth and development. PMID- 29713026 TI - Low mean platelet volume is associated with critical limb ischemia in peripheral arterial occlusive disease. AB - Mean platelet volume (MPV) was recently published as a possible marker of coronary artery disease in patients at high risk for major adverse cardiac events. Because platelets play an important role in atherosclerosis, we examined the relationship between critical limb ischemia (CLI) and MPV in patients with peripheral arterial occlusive disease (PAOD). Our study comprised 2124 PAOD patients. Univariate logistic regression was performed to analyze potential predictors for CLI. Nagelkerke's R2 is reported. Cross validation was performed using the leave-one-out principle. ROC analyses were performed to identify the best cut off value for MPV predicting CLI; to this end, Youden's index was calculated. For CLI diabetes (p < 0.001, OR 2.44, 95% CI 1.97-3.02), hsCRP (p < 0.001, OR 1.01, 95% CI 1.01-1.01), age (p < 0.001, OR 1.05, 95% CI 1.04-1.06), thrombocytosis (p = 0.025, OR 1.84, 95%CI 1.08-3.14), and MPV (p = 0.003, OR 0.84, 95% CI 0.75-0.94) were significant independent predictors for CLI. ROC analysis (AUC: 0.55, 95% CI 0.52-0.58, p < 0.001) showed <=10.2 as the best cut off value for MPV to predict CLI. As there is a significant relationship between low MPV and a high risk for CLI in PAOD patients, MPV can be used to identify patients who are likely to develop CLI. PMID- 29713027 TI - Evaluation of chronic diarrhea and irritable bowel syndrome with diarrhea in adults in the era of precision medicine. AB - Chronic diarrhea is a common clinical problem, affecting roughly 5% of the population in any given year. Evaluation and management of these patients can be difficult due to the extensive differential diagnosis of this symptom. Many patients with chronic diarrhea have structural problems, such as inflammatory bowel disease or celiac disease, that can be readily identified. Others do not, and often are given a diagnosis of irritable bowel syndrome with diarrhea (IBS D). When based on generally accepted clinical criteria, a diagnosis of IBS-D identifies a group of patients who are unlikely to have disorders producing anatomical changes in the gut. It is less clear that a diagnosis of IBS-D identifies a specific pathophysiology or leads to better management of symptoms. Disorders such as small intestinal bacterial overgrowth, bile acid malabsorption, food intolerance, and motility disorders may account for symptoms in patients with IBS-D. More effective tests are being developed to identify the clinical problems underlying IBS-D and may lead to more specific diagnoses that may improve the results of therapy. Application of the principles of precision medicine (identifying a specific mechanism for disease and applying treatments that work on that mechanism) should lead to more expeditious diagnosis and treatment for patients with chronic diarrhea including IBS-D, but currently is limited by the availability of sufficiently sensitive and specific tests for underlying mechanisms that can predict response to treatment. PMID- 29713028 TI - Post-operative morbidity and mortality of a cohort of steroid refractory acute severe ulcerative colitis: Nationwide multicenter study of the GETECCU ENEIDA Registry. AB - BACKGROUND: Despite the increased use of rescue medical therapies for steroid refractory acute severe ulcerative colitis, mortality related to this entity still remains high. We aimed to assess the mortality and morbidity related to colectomy and their predictive factors in steroid refractory acute severe ulcerative colitis, and to evaluate the changes in mortality rates, complications, indications of colectomy, and the use of rescue therapy over time. METHODS: We performed a multicenter observational study of patients with steroid refractory acute severe ulcerative colitis requiring colectomy, admitted to 23 Spanish hospitals included in the ENEIDA registry (GETECCU) from 1989 to 2014. Independent predictive factors of mortality were assessed by binary logistic regression analysis. Mortality along the study was calculated using the age standardized rate. RESULTS: During the study period, 429 patients underwent colectomy, presenting an overall mortality rate of 6.3% (range, 0-30%). The main causes of death were infections and post-operative complications. Independent predictive factors of mortality were: age >=50 years (OR 23.34; 95% CI: 6.46 84.311; p < 0.0001), undergoing surgery in a secondary care hospital (OR 3.07; 95% CI: 1.01-9.35; p = 0.047), and in an emergency setting (OR 10.47; 95% CI: 1.26-86.55; p = 0.029). Neither the use of rescue medical treatment nor the type of surgical technique used (laparoscopy vs. open laparotomy) influenced mortality. The proportion of patients undergoing surgery in an emergency setting decreased over time (p < 0.0001), whereas the use of rescue medical therapy prior to colectomy progressively increased (p > 0.001). CONCLUSIONS: The mortality rate related to colectomy in steroid refractory acute severe ulcerative colitis varies greatly among hospitals, reinforcing the need for a continuous audit to achieve quality standards. The increasing use of rescue therapy is not associated with a worse outcome and may contribute to reducing emergency surgical interventions and improve outcomes. PMID- 29713029 TI - How we approach it: treatment options for hepatocellular carcinoma. PMID- 29713030 TI - Ring-through-ring molecular shuttling in a saturated [3]rotaxane. AB - Mechanically interlocked molecules such as rotaxanes and catenanes comprise two or more components whose motion relative to each other can be controlled. A [2]rotaxane molecular shuttle, for example, consists of an axle bearing two recognition sites and a single macrocyclic wheel that can undergo a to-and-fro motion along the axle-shuttling between the recognition sites. The ability of mechanically interlocked molecules to undergo this type of large-amplitude change is the core mechanism behind almost every interlocked molecular switch or machine, including sophisticated mechanical systems such as a molecular elevator and a peptide synthesizer. Here, as a way to expand the scope of dynamics possible at the molecular level, we have developed a molecular shuttling mechanism involving the exchange of rings between two recognition sites in a saturated [3]rotaxane (one with no empty recognition sites). This was accomplished by passing a smaller ring through a larger one, thus achieving ring through-ring molecular shuttling. PMID- 29713031 TI - Amino-acid-encoded biocatalytic self-assembly enables the formation of transient conducting nanostructures. AB - Aqueous compatible supramolecular materials hold promise for applications in environmental remediation, energy harvesting and biomedicine. One remaining challenge is to actively select a target structure from a multitude of possible options, in response to chemical signals, while maintaining constant, physiological conditions. Here, we demonstrate the use of amino acids to actively decorate a self-assembling core molecule in situ, thereby controlling its amphiphilicity and consequent mode of assembly. The core molecule is the organic semiconductor naphthalene diimide, functionalized with D- and L- tyrosine methyl esters as competing reactive sites. In the presence of alpha-chymotrypsin and a selected encoding amino acid, kinetic competition between ester hydrolysis and amidation results in covalent or non-covalent amino acid incorporation, and variable supramolecular self-assembly pathways. Taking advantage of the semiconducting nature of the naphthalene diimide core, electronic wires could be formed and subsequently degraded, giving rise to temporally regulated electro conductivity. PMID- 29713032 TI - A molecular multi-gene classifier for disease diagnostics. AB - Despite its early promise as a diagnostic and prognostic tool, gene expression profiling remains cost-prohibitive and challenging to implement in a clinical setting. Here, we introduce a molecular computation strategy for analysing the information contained in complex gene expression signatures without the need for costly instrumentation. Our workflow begins by training a computational classifier on labelled gene expression data. This in silico classifier is then realized at the molecular level to enable expression analysis and classification of previously uncharacterized samples. Classification occurs through a series of molecular interactions between RNA inputs and engineered DNA probes designed to differentially weigh each input according to its importance. We validate our technology with two applications: a classifier for early cancer diagnostics and a classifier for differentiating viral and bacterial respiratory infections based on host gene expression. Together, our results demonstrate a general and modular framework for low-cost gene expression analysis. PMID- 29713034 TI - Dynamic actuation of glassy polymersomes through isomerization of a single azobenzene unit at the block copolymer interface. AB - Nature has engineered exquisitely responsive systems where molecular-scale information is transferred across an interface and propagated over long length scales. Such systems rely on multiple interacting, signalling and adaptable molecular and supramolecular networks that are built on dynamic, non-equilibrium structures. Comparable synthetic systems are still in their infancy. Here, we demonstrate that the light-induced actuation of a molecularly thin interfacial layer, assembled from a hydrophilic- azobenzene -hydrophobic diblock copolymer, can result in a reversible, long-lived perturbation of a robust glassy membrane across a range of over 500 chemical bonds. We show that the out-of-equilibrium actuation is caused by the photochemical trans-cis isomerization of the azo group, a single chemical functionality, in the middle of the interfacial layer. The principles proposed here are implemented in water-dispersed nanocapsules, and have implications for on-demand release of embedded cargo molecules. PMID- 29713033 TI - Rapid phenolic O-glycosylation of small molecules and complex unprotected peptides in aqueous solvent. AB - Glycosylated natural products and synthetic glycopeptides represent a significant and growing source of biochemical probes and therapeutic agents. However, methods that enable the aqueous glycosylation of endogenous amino acid functionality in peptides without the use of protecting groups are scarce. Here, we report a transformation that facilitates the efficient aqueous O-glycosylation of phenolic functionality in a wide range of small molecules, unprotected tyrosine, and tyrosine residues embedded within a range of complex, fully unprotected peptides. The transformation, which uses glycosyl fluoride donors and is promoted by Ca(OH)2, proceeds rapidly at room temperature in water, with good yields and selective formation of unique anomeric products depending on the stereochemistry of the glycosyl donor. High functional group tolerance is observed, and the phenol glycosylation occurs selectively in the presence of virtually all side chains of the proteinogenic amino acids with the singular exception of Cys. This method offers a highly selective, efficient, and operationally simple approach for the protecting-group-free synthesis of O-aryl glycosides and Tyr-O glycosylated peptides in water. PMID- 29713035 TI - Cyclization of peptides with two chemical bridges affords large scaffold diversities. AB - Successful screening campaigns depend on large and structurally diverse collections of compounds. In macrocycle screening, variation of the molecular scaffold is important for structural diversity, but so far it has been challenging to diversify this aspect in large combinatorial libraries. Here, we report the cyclization of peptides with two chemical bridges to provide rapid access to thousands of different macrocyclic scaffolds in libraries that are easy to synthesize, screen and decode. Application of this strategy to phage-encoded libraries allowed for the screening of an unprecedented structural diversity of macrocycles against plasma kallikrein, which is important in the swelling disorder hereditary angioedema. These libraries yielded inhibitors with remarkable binding properties (subnanomolar Ki, >1,000-fold selectivity) despite the small molecular mass (~1,200 Da). An interlaced bridge format characteristic of this strategy provided high proteolytic stability (t1/2 in plasma of >3 days), making double-bridged peptides potentially amenable to topical or oral delivery. PMID- 29713037 TI - Manganese-catalysed benzylic C(sp3)-H amination for late-stage functionalization. AB - Reactions that directly install nitrogen into C-H bonds of complex molecules are significant because of their potential to change the chemical and biological properties of a given compound. Although selective intramolecular C-H amination reactions are known, achieving high levels of reactivity while maintaining excellent site selectivity and functional-group tolerance remains a challenge for intermolecular C-H amination. Here, we report a manganese perchlorophthalocyanine catalyst [MnIII(ClPc)] for intermolecular benzylic C-H amination of bioactive molecules and natural products that proceeds with unprecedented levels of reactivity and site selectivity. In the presence of a Bronsted or Lewis acid, the [MnIII(ClPc)]-catalysed C-H amination demonstrates unique tolerance for tertiary amine, pyridine and benzimidazole functionalities. Mechanistic studies suggest that C-H amination likely proceeds through an electrophilic metallonitrene intermediate via a stepwise pathway where C-H cleavage is the rate-determining step of the reaction. Collectively, these mechanistic features contrast with previous base-metal-catalysed C-H aminations and provide new opportunities for tunable selectivities. PMID- 29713038 TI - Motorizing fibres with geometric zero-energy modes. AB - Responsive materials1-3 have been used to generate structures with built-in complex geometries4-6, linear actuators7-9 and microswimmers10-12. These results suggest that complex, fully functional machines composed solely from shape changing materials might be possible 13 . Nonetheless, to accomplish rotary motion in these materials still relies on the classical wheel and axle motifs. Here we explore geometric zero-energy modes to elicit rotary motion in elastic materials in the absence of a rigid wheel travelling around an axle. We show that prestrained polymer fibres closed into rings exhibit self-actuation and continuous motion when placed between two heat baths due to elastic deformations that arise from rotational-symmetry breaking around the rod's axis. Our findings illustrate a simple but robust model to create active motion in mechanically prestrained objects. PMID- 29713036 TI - Engineering the entropy-driven free-energy landscape of a dynamic nanoporous protein assembly. AB - De novo design and construction of stimuli-responsive protein assemblies that predictably switch between discrete conformational states remains an essential but highly challenging goal in biomolecular design. We previously reported synthetic, two-dimensional protein lattices self-assembled via disulfide bonding interactions, which endows them with a unique capacity to undergo coherent conformational changes without losing crystalline order. Here, we carried out all atom molecular dynamics simulations to map the free-energy landscape of these lattices, validated this landscape through extensive structural characterization by electron microscopy and established that it is predominantly governed by solvent reorganization entropy. Subsequent redesign of the protein surface with conditionally repulsive electrostatic interactions enabled us to predictably perturb the free-energy landscape and obtain a new protein lattice whose conformational dynamics can be chemically and mechanically toggled between three different states with varying porosities and molecular densities. PMID- 29713039 TI - An unusual continuous paramagnetic-limited superconducting phase transition in 2D NbSe 2. AB - Time reversal and spatial inversion are two key symmetries for conventional Bardeen-Cooper-Schrieffer (BCS) superconductivity 1 . Breaking inversion symmetry can lead to mixed-parity Cooper pairing and unconventional superconducting properties1-5. Two-dimensional (2D) NbSe2 has emerged as a new non centrosymmetric superconductor with the unique out-of-plane or Ising spin-orbit coupling (SOC)6-9. Here we report the observation of an unusual continuous paramagnetic-limited superconductor-normal metal transition in 2D NbSe2. Using tunelling spectroscopy under high in-plane magnetic fields, we observe a continuous closing of the superconducting gap at the upper critical field at low temperatures, in stark contrast to the abrupt first-order transition observed in BCS thin-film superconductors10-12. The paramagnetic-limited continuous transition arises from a large spin susceptibility of the superconducting phase due to the Ising SOC. The result is further supported by self-consistent mean field calculations based on the ab initio band structure of 2D NbSe2. Our findings establish 2D NbSe2 as a promising platform to explore novel spin dependent superconducting phenomena and device concepts 1 , such as equal-spin Andreev reflection 13 and topological superconductivity14-16. PMID- 29713041 TI - RNA sequencing of Xp11 translocation-associated cancers reveals novel gene fusions and distinctive clinicopathologic correlations. AB - Both Xp11 translocation renal cell carcinomas and the corresponding mesenchymal neoplasms are characterized by a variety of gene fusions involving TFE3. It has been known that tumors with different gene fusions may have different clinicopathologic features; however, further in-depth investigations of subtyping Xp11 translocation-associated cancers are needed in order to explore more meaningful clinicopathologic correlations. A total of 22 unusual cases of Xp11 translocation-associated cancers were selected for the current study; 20 cases were further analyzed by RNA sequencing to explore their TFE3 gene fusion partners. RNA sequencing identified 17 of 20 cases (85%) with TFE3-associated gene fusions, including 4 ASPSCR1/ASPL-TFE3, 3 PRCC-TFE3, 3 SFPQ/PSF-TFE3, 1 NONO TFE3, 4 MED15-TFE3, 1 MATR3-TFE3, and 1 FUBP1-TFE3. The results have been verified by fusion fluorescence in situ hybridization (FISH) assays or reverse transcriptase polymerase chain reaction (RT-PCR). The remaining 2 cases with specific pathologic features highly suggestive of MED15-TFE3 renal cell carcinoma were identified by fusion FISH assay. We provide the detailed morphologic and immunophenotypic description of the MED15-TFE3 renal cell carcinomas, which frequently demonstrate extensively cystic architecture, similar to multilocular cystic renal neoplasm of low malignant potential, and expressed cathepsin K and melanotic biomarker Melan A. This is the first time to correlate the MED15-TFE3 renal cell carcinoma with specific clinicopathologic features. We also report the first case of the corresponding mesenchymal neoplasm with MED15-TFE3 gene fusion. Additional novel TFE3 gene fusion partners, MATR3 and FUBP1, were identified. Cases with ASPSCR1-TFE3, SFPQ-TFE3, PRCC-TFE3, and NONO-TFE3 gene fusion showed a wide variability in morphologic features, including invasive tubulopapillary pattern simulating collecting duct carcinoma, extensive calcification and ossification, and overlapping and high columnar cells with nuclear grooves mimicking tall cell variant of papillary thyroid carcinoma. Furthermore, we respectively evaluated the ability of TFE3 immunohistochemistry, TFE3 FISH, RT PCR, and RNA sequencing to subclassify Xp11 translocation-associated cancers. In summary, our study expands the list of TFE3 gene fusion partners and the clinicopathologic features of Xp11 translocation-associated cancers, and highlights the importance of subtyping Xp11 translocation-associated cancers combining morphology, immunohistochemistry, and multiple molecular techniques. PMID- 29713040 TI - Assessment of programmed cell death ligand-1 expression by 4 diagnostic assays and its clinicopathological correlation in a large cohort of surgical resected non-small cell lung carcinoma. AB - Immune checkpoint blockade targeting the PD-1/PD-L1 axis has recently demonstrated efficacy and promise in cancer treatment. Appropriate biomarker selection is therefore essential for improving treatment efficacy. However, the establishment of PD-L1 assay in pathology laboratories is complicated by the presence of multiple testing platforms using different scoring systems. Here we assessed the PD-L1 expression in 713 consecutive non-small cell lung carcinomas by four commercially available PD-L1 immunohistochemical assays, namely, 22C3, 28 8, SP142 and SP263. The analytical performances of the four assays and diagnostic performances across clinically relevant cutoffs were evaluated. The prevalence of PD-L1 (22C3) expression was 21% with a >=50% cutoff and 56% with a >=1% cutoff. High PD-L1 expression (using a >=50% cutoff) was significantly associated with male sex (P = 0.001), ever smoking history (P < 0.001), squamous cell carcinoma (P = 0.001), large cell carcinoma (P < 0.001), lymphoepithelioma-like carcinoma (P = 0.006), sarcomatoid carcinoma (P < 0.001), mutant KRAS (P = 0.005) and wild type EGFR (P = 0.003). Elevated PD-L1 expression was also significantly associated with shorter survival in patients with adenocarcinoma (log-rank P = 0.026) and remained an independent prognostic factor by multivariable analysis. Among the four assays, 22C3, 28-8 and SP263 were highly concordant for tumor cell scoring. With a cutoff of >=50% (i.e., the threshold for first-line patient selection), inter-rater agreement was high among the three assays with percentage agreement >97%. In conclusion, three PD-L1 assays showed good analytical performance and a high agreement with each other, but not all cases were correctly classified using the same clinical cutoff. Further studies comparing the predictive value of these assays are required to address the interchangeability of these assays for clinical use. PMID- 29713042 TI - Endothelial trans-differentiation in glioblastoma recurring after radiotherapy. AB - We hypothesized that in glioblastoma recurring after radiotherapy, a condition whereby the brain endothelium undergoes radiation-induced senescence, tumor cells with endothelial phenotype may be relevant for tumor neovascularization. Matched glioblastoma samples obtained at primary surgery and at surgery for tumor recurrence after radiotherapy, all expressing epidermal growth factor receptor variant III (EGFRvIII), were assessed by a technique that combines fluorescent in situ hybridization (FISH) for the EGFR/CEP7 chromosomal probe with immunostaining for endothelial cells (CD31) and activated pericytes (alpha Smooth Muscle Actin). Five EGFRvIII-expressing paired primary/recurrent glioblastoma samples, in which the tumor cells showed EGFR/CEP7 amplification, were then assessed by CD31 and alpha Smooth Muscle Actin immunofluorescence. In glomeruloid bodies, the ratio between CD31+ cells with amplified EGFR/CEP7 signal and the total CD31+ cells was 0.23 +/- 0.09 (mean +/- sem) and 0.63 +/- 0.07 in primary tumors and in recurrent ones, respectively (p < 0.002, Student-t test). In capillaries, the ratio of CD31+ cells with amplified EGFR/CEP7 over the total CD31+ cells lining the capillary lumen was 0.21 +/- 0.06 (mean +/- sem) and 0.42 +/- 0.07 at primary surgery and at recurrence, respectively (p < 0.005, Student-t test). Expression of alpha Smooth Muscle Actin by cells with EGFR/CEP7 amplification was not observed. Then, in glioblastoma recurring after radiotherapy, where the brain endothelium suffers from radiation-induced cell senescence, tumor-derived endothelium plays a role in neo-vascularization. PMID- 29713043 TI - Epigenome-wide association study of adiposity and future risk of obesity-related diseases. AB - BACKGROUND: Obesity is an established risk factor for several common chronic diseases such as breast and colorectal cancer, metabolic and cardiovascular diseases; however, the biological basis for these relationships is not fully understood. To explore the association of obesity with these conditions, we investigated peripheral blood leucocyte (PBL) DNA methylation markers for adiposity and their contribution to risk of incident breast and colorectal cancer and myocardial infarction. METHODS: DNA methylation profiles (Illumina Infinium(r) HumanMethylation450 BeadChip) from 1941 individuals from four population-based European cohorts were analysed in relation to body mass index, waist circumference, waist-hip and waist-height ratio within a meta-analytical framework. In a subset of these individuals, data on genome-wide gene expression level, biomarkers of glucose and lipid metabolism were also available. Validation of methylation markers associated with all adiposity measures was performed in 358 individuals. Finally, we investigated the association of obesity-related methylation marks with breast, colorectal cancer and myocardial infarction within relevant subsets of the discovery population. RESULTS: We identified 40 CpG loci with methylation levels associated with at least one adiposity measure. Of these, one CpG locus (cg06500161) in ABCG1 was associated with all four adiposity measures (P = 9.07*10-8 to 3.27*10-18) and lower transcriptional activity of the full-length isoform of ABCG1 (P = 6.00*10-7), higher triglyceride levels (P = 5.37*10-9) and higher triglycerides-to-HDL cholesterol ratio (P = 1.03*10-10). Of the 40 informative and obesity-related CpG loci, two (in IL2RB and FGF18) were significantly associated with colorectal cancer (inversely, P < 1.6*10-3) and one intergenic locus on chromosome 1 was inversely associated with myocardial infarction (P < 1.25*10-3), independently of obesity and established risk factors. CONCLUSION: Our results suggest that epigenetic changes, in particular altered DNA methylation patterns, may be an intermediate biomarker at the intersection of obesity and obesity-related diseases, and could offer clues as to underlying biological mechanisms. PMID- 29713044 TI - Probing the Structural and Electronic Properties of Dirhenium Halide Clusters: A Density Functional Theory Study. AB - Dirhenium halide dianions received considerable attention in past decades due to the unusual metal-metal quadruple bond. The systematic structural evolution of dirhenium halide clusters has not been sufficiently studied and hence is not well understood. In this work, we report an in-depth investigation on the structures and electronic properties of doubly charged dirhenium halide clusters Re2X82- (X = F, Cl, Br, I). Our computational efforts rely on the well-tested unbiased CALYPSO (Crystal structure AnaLYsis by Particle Swarm Optimization) method combined with density functional theory calculations. We find that all ground state Re2X82- clusters have cube-like structures of D4h symmetry with two Re atoms encapsulated in halogen framework. The reasonable agreement between the simulated and experimental photoelectron spectrum of the Re2Cl82- cluster supports strongly the reliability of our computational strategy. The chemical bonding analysis reveals that the delta bond is the pivotal factor for the ground state Re2X82- (X = F, Cl, Br, I) clusters to maintain D4h symmetric cube-like structures, and the enhanced stability of Re2Cl82- is mainly attributed to the chemical bonding of 5d orbital of Re atoms and 3p orbital of Cl atoms. PMID- 29713045 TI - Author Correction: Analysis of DNA methylation in cancer: location revisited. AB - The originally published article contained an error in the acknowledgements section in which the Universiteitsfonds Limburg/SWOL is incorrectly presented as awarding an SU2C- DCS International Translational Cancer Research Dream Team Grant (Stand Up To Cancer (SU2C)-AACR- DT1415, MEDOCC). This has been corrected in the HTML and PDF versions of the manuscript to reflect that Universiteitsfonds Limburg/SWOL is not the funding body that awarded this grant. PMID- 29713046 TI - Doctor is my blood pressure OK? PMID- 29713047 TI - Cardiovascular morbidity of severe resistant hypertension among treated uncontrolled hypertensives: a 4-year follow-up study. AB - Data regarding the prognosis of resistant hypertension (RHTN) with respect to its severity is limited. We investigated the cardiovascular risk of severe RHTN in a prospective observational study. A cohort of 1700 hypertensive patient with treated uncontrolled HTN was followed for a mean period of 3.6 +/- 1.8 years. At baseline, standard clinical and laboratory workup was performed, including testing for secondary causes of RHT where applicable. Three groups were identified depending on presence of RHTN (office-based uncontrolled HTN under at least three drugs including a diuretic) and levels of office systolic blood pressure (BP): 1187 patients (70%) without RHTN, 313 (18%) with not-severe RHTN (systolic BP < 160 mmHg) and 200 (12%) with severe RHTN (systolic BP >= 160 mmHg). Endpoint of interest was cardiovascular morbidity set as the composite of coronary heart disease and stroke. During follow-up, incidence rates of cardiovascular events per 1000 person-years were 7.1 cases in the non-RHTN group, 12.4 cases in the not-severe RHTN group and 18 cases in the severe RHTN group. Unadjusted analysis showed that compared to uncontrolled patients without RHTN, patients with not-severe RHTN exhibited a similar risk but patients with severe RHTN had a significantly higher risk, by 2.5 times (CI: 1.28-4.73, p = 0.007). Even after multivariate adjustment for established risk factors including BP levels and isolated systolic HTN, severe RHTN remained as an independent predictor of the cardiovascular outcome (OR: 2.30, CI: 1.00-5.29, p = 0.05). In conclusion, among treated yet uncontrolled hypertensive patients, severe RHTN exhibits a significantly higher cardiovascular risk indicating the need for prompt management. PMID- 29713048 TI - Could self-measured office blood pressure be a hypertension screening tool for limited-resources settings? AB - Blood pressure (BP) was assessed by patients themselves in recently published trials. Self-measured office blood pressure (SMOBP) seems particularly interesting for limited health resources regions. The aim of our study was to evaluate the relationship between SMOBP values and those estimated by ambulatory blood pressure monitoring (ABPM). Six hundred seventy-seven patients were evaluated using both, SMOBP and ABPM. The differences between SMOBP and daytime ABPM were evaluated with paired "t" test. The correlations among SMOBP and ABPM were estimated using Pearson's r. The accuracy of SMOBP to identify abnormal ABPM was determined using area under ROC curve (AUC). Sensitivity, specificity, and positive and negative predictive values were calculated for different SMOBP cut points. Using the average of three readings, systolic SMOBP was higher (3.7 (14.2) mmHg, p < 0.001) and diastolic SMOBP lower (1.5 (8.1) mmHg, p < 0.001) than ABPM. Both BP estimates had a significant correlation, r = 0.67 and r = 0.75 (p < 0.01) for systolic and diastolic BP, respectively. Systolic SMOBP predicted systolic abnormal ABPM; the AUC were 0.80 (0.77-0.84) and 0.78 (0.74-0.81) for daytime and 24 h hypertension, respectively. Diastolic SMOBP predicted diastolic hypertension, AUC 0.86 (0.83-0.88) for both daytime and 24 h hypertension. Neither correlations nor AUCs improved significantly using the average of five readings. SMOBP >= 160/90 mmHg was highly specific (>95%) to identify individuals with hypertension in the ABPM; SMOBP < 130/80 mmHg reasonably discarded abnormal ABPM. In conclusion, a high proportion of individuals could be classified adequately using SMOBP, reducing the necessity of healthcare resources and supporting its utility for screening purposes. PMID- 29713049 TI - Maximum home blood pressure readings are associated with left atrial diameter in essential hypertensives. AB - We tested the hypothesis that the maximum value of home systolic BP (MSBP) is a marker of hypertensive target organ damage (TOD). We conducted a cross-sectional study of 220 hypertensives. The subjects performed HBP monitoring using a telemonitoring system and measured their HBP for 7 days. Mean, maximum, standard deviation, and coefficient of variation of SBPs were used as independent variables. Brachial-ankle pulse wave velocity, left ventricular mass index (LVMI), mean carotid intima-media thickness, and left atrial diameter index (LADI) were used as dependent variables. Mean and maximum SBPs were significantly associated with each TOD marker. MSBP showed a significantly stronger association with LADI compared to mean SBP (p = 0.0012) and a significant relationship with LADI independent of LVMI (p = 0.024). Our findings suggest that MSBP is associated with TOD measures, similar to mean SBP. These results may indicate that MSBP could be a target of intervention for patients with atrial fibrillation. PMID- 29713050 TI - Gaps in awareness and control of hypertension: a cross-sectional study in Chinese urban adults. AB - Hypertension is a serious public health threat worldwide. This study sought to explore gaps in urban Chinese adults' awareness and control of hypertension. A cross-sectional study was carried out in eight Chinese cities in 2016. Participants were organized into four groups on the basis of blood pressure (BP) and self-reported disease history: healthy group (63.0%), well-controlled BP group (9.1%), unaware hypertension group (14.0%), and poorly controlled BP group (13.9%). Multinomial logistic regression with the healthy group as the reference group showed that younger age and body mass index <24 kg/m2 were negatively associated with lack of awareness of hypertension and poor control of BP. Lower salt intake, but not sodium intake, was associated with poor control of BP. Other factors associated with lack of awareness of hypertension included low fish and seafood intake. Low sodium intake contributed to good control of BP. In conclusion, there are gaps in urban Chinese adults' awareness and control of hypertension. A comprehensive strategy for enhancing awareness of hypertension and changing behaviors associated with the condition should be developed and implemented. PMID- 29713051 TI - Difficult-to-control hypertension: identification of clinical predictors and use of ICT-based integrated care to facilitate blood pressure control. AB - Difficult-to-control (DTC) hypertension represents a burden in real life that can be partially solved through identification of the characteristics of clinical patterns and tailoring antihypertensive strategies, including ICT-enabled integrated care (ICT-IC). In the quest for clinical predictors of DTC hypertension, we screened 482 hypertensive patients who were consecutively referred to the departmental hypertension clinic. Following a data quality check, patients were divided into controlled (C, 49.37%) and uncontrolled (UC, 50.63%) groups based on their systolic blood pressure (BP) at follow-up. We then performed statistical analysis on the demographic, clinical, laboratory, and ultrasound data and observed that older age, female sex, higher BP levels, and a family history of hypertension were predictors of DTC hypertension. We then developed a pilot service of ICT-IC, including weekly home visits by nurses and patient education on self-monitoring of BP, heart rate, body weight, and oxygen saturation using 3G-connected devices. Self-monitored data were transmitted to the hospital servers on the electronic chart of the patient for remote assessment by the hospital hypertension specialists. A total of 20 UC patients (M/F = 10/10; age: 72.04 +/- 2.17 years) were enrolled to verify the efficacy of BP control without changes in medical treatment. After 1 month of the ICT-IC program, BP was reduced both at the office assessment (systolic BP (SBP): 162.40 +/- 2.23 mm Hg, beginning of the program vs. 138.20 +/- 4.26 mm Hg at 1 month, p < 0.01) and at home (SBP: 149.83 +/- 3.44, beginning of the program vs. 134.16 +/- 1.67 mm Hg at 1 month, p < 0.01). We concluded that DTC hypertension can be predicted based on the clinical characteristics at the first visit. For these patients, ICT-IC is a feasible therapeutic strategy to achieve BP control. PMID- 29713052 TI - Predictors of diastolic dysfunction in ethnic groups: observations from the Hypertensive Cohort of The Ethnic-Echocardiographic Heart of England Screening Study (E-ECHOES). AB - The study aimed to establish a relationship of ethnicity to diastolic dysfunction in subjects of African-Caribbean and South Asian origins and the impact of diastolic dysfunction and ethnicity on all-cause and cardiovascular mortality. Hypertensive subjects with ejection fraction >=55% and no history of ischaemic heart disease/valve pathology (n = 1546, 830 South Asians and 716 African Caribbeans) were identified from the Ethnic-Echocardiographic Heart of England Screening Study (E-ECHOES). Diastolic function and cardiac remodelling were measured by echocardiography. African-Caribbean ethnicity was associated with lower prevalence of having diastolic dysfunction (odds ratio 0.67, 95% confidence interval 0.51-0.87, p = 0.003) and increased left ventricular filling pressure (odds ratio 0.48, 95% confidence interval 0.34-0.69, p < 0.001) as well as lower left atrial index (p < 0.001). This was the case despite the fact that African Caribbean ethnicity was independently associated with higher left ventricular mass index (p < 0.001). Ninety-two deaths (6%) occurred during 68 +/- 21 months follow-up. On Cox regression analysis, South Asian ethnicity (p = 0.024) was predictive of all-cause death before adjustment for parameters of diastolic dysfunction, but it was no longer predictive of death after accounting for these variables. South Asian ethnicity is independently associated with worse parameters of diastolic function in hypertension, despite African-Caribbeans having more prominent hypertrophy. PMID- 29713053 TI - First-line renin-angiotensin system inhibitors vs. other first-line antihypertensive drug classes in hypertensive patients with type 2 diabetes mellitus. AB - First-line renin-angiotensin system (RAS) inhibitors are recommended for diabetic patients because of their potential nephron-protective properties. For hypertensive patients with type 2 diabetes mellitus, little is known about first line RAS inhibitors vs. other first-line antihypertensive agents in terms of cardiovascular outcomes. We performed a meta-analysis of randomized controlled trials (RCTs) to assess the comparative efficacy of first-line RAS inhibitors vs. other first-line antihypertensive drug classes in hypertensive patients with type 2 diabetes mellitus. We identified RCTs by searching the Cochrane Central Register of Controlled Trials, MEDLINE and EMBASE up to December 15, 2015. Eighteen RCTs involving 18,862 participants were included. First-line RAS inhibitors were not different from first-line diuretics for all the primary outcomes. First-line RAS inhibitors reduced major cardiovascular events (2 RCTs, relative risk [RR] 0.78, 95% confidence interval [CI] 0.66, 0.91) and heart failure (4 RCTs, RR 0.72, 95% CI 0.61, 0.83) compared to first-line calcium channel blockers. Compared to beta-blockers, RAS inhibitors reduced the risk of all-cause mortality (1 RCT, RR 0.63, 95% CI 0.47, 0.84), major cardiovascular events (1 RCT, RR 0.76, 95% CI 0.62, 0.93) and heart failure (1 RCT, RR 0.60, 95% CI 0.40, 0.92). Our meta-analysis indicates that, in patients with type 2 diabetes mellitus and hypertension, first-line RAS inhibitors reduced adverse cardiovascular events to the same degree as first-line diuretics but to a greater degree than first-line calcium channel blockers and first-line beta blockers. PMID- 29713054 TI - Structures of Angptl3 and Angptl4, modulators of triglyceride levels and coronary artery disease. AB - Coronary artery disease is the most common cause of death globally and is linked to a number of risk factors including serum low density lipoprotein, high density lipoprotein, triglycerides and lipoprotein(a). Recently two proteins, angiopoietin-like protein 3 and 4, have emerged from genetic studies as being factors that significantly modulate plasma triglyceride levels and coronary artery disease. The exact function and mechanism of action of both proteins remains to be elucidated, however, mutations in these proteins results in up to 34% reduction in coronary artery disease and inhibition of function results in reduced plasma triglyceride levels. Here we report the crystal structures of the fibrinogen-like domains of both proteins. These structures offer new insights into the reported loss of function mutations, the mechanisms of action of the proteins and open up the possibility for the rational design of low molecular weight inhibitors for intervention in coronary artery disease. PMID- 29713055 TI - A kinome-wide high-content siRNA screen identifies MEK5-ERK5 signaling as critical for breast cancer cell EMT and metastasis. AB - An epithelial to mesenchymal transition (EMT) has been correlated to malignant tumor progression and metastasis by promoting cancer cell migration and invasion and chemoresistance. Hence, finding druggable EMT effectors is critical to efficiently interfere with metastasis formation and to overcome therapy resistance. We have employed a high-content microscopy screen in combination with a kinome and phosphatome-wide siRNA library to identify signaling pathways underlying an EMT of murine mammary epithelial cells and breast cancer cells. This screen identified the MEK5-ERK5 axis as a critical player in TGFbeta mediated EMT. Suppression of MEK5-ERK5 signaling completely prevented the morphological and molecular changes occurring during a TGFbeta-induced EMT and, conversely, forced highly metastatic breast cancer cells into a differentiated epithelial state. Inhibition of MEK5-ERK5 signaling also repressed breast cancer cell migration and invasion and substantially reduced lung metastasis without affecting primary tumor growth. The results suggest that the MEK5-ERK5 signaling axis via activation of MEF2B and other transcription factors plays an important role in the induction and maintenance of breast cancer cell migration and invasion and thus represents an exploitable target for the pharmacological inhibition of cancer cell metastasis. PMID- 29713056 TI - Immunosuppressive effects of hypoxia-induced glioma exosomes through myeloid derived suppressor cells via the miR-10a/Rora and miR-21/Pten Pathways. AB - While immunosuppressive environments mediated by myeloid-derived suppressor cells (MDSCs) have been well documented in glioma patients, the mechanisms of MDSC development and activation have not been clearly defined. Here, we elucidated a role for glioma-derived exosomes (GDEs) in potentiating an MDSC pathway. We isolated normoxia-stimulated and hypoxia-stimulated GDEs and studied their MDSC induction abilities in vivo and in vitro. Analyses of spleen and bone marrow MDSC proportions (flow cytometry) and reactive oxygen species (ROS), arginase activity, nitric oxide (NO), T-cell proliferation and immunosuppressive cytokine (IL-10 and TGF-beta, ELISA) levels were used to assess MDSC expansion and functional capacity. We also performed microRNA (miRNA) sequencing analysis of two types of GDEs to find miRNAs that potentially mediate the development and activation of MDSCs. GDE miRNA intracellular signaling in MDSCs was also studied. Hypoxia promoted the secretion of GDEs, and mouse MDSCs could uptake GDEs. Hypoxia-stimulated GDEs had a stronger ability to induce MDSCs than N-GDEs. The hypoxia-inducible expression of miR-10a and miR-21 in GDEs mediated GDE-induced MDSC expansion and activation by targeting RAR-related orphan receptor alpha (RORA) and phosphatase and tensin homolog (PTEN). Mice inoculated with miR-10a or miR-21 knockout glioma cells generated fewer MDSCs than those inoculated with normal glioma cells. These data elucidated a mechanism by which glioma cells influence the differentiation and activation of MDSCs via exosomes and demonstrated how local glioma hypoxia affects the entirety of tumor immune environments. PMID- 29713057 TI - Intermittent hypoxia induces a metastatic phenotype in breast cancer. AB - Hypoxia arises frequently in solid tumors and is a poor prognostic factor as it promotes tumor cell proliferation, invasion, angiogenesis, therapy resistance, and metastasis. Notably, there are two described forms of hypoxia present in a growing tumor: chronic hypoxia, caused by abnormal tumor vasculature, and intermittent hypoxia, caused by transient perfusion facilitated by tumor supplying blood vessels. Here, we demonstrate that intermittent hypoxia, but not chronic hypoxia, endows breast cancer cells with greater metastatic potential. Using an immunocompetent and syngeneic murine model of breast cancer, we show that intermittent hypoxia enhances metastatic seeding and outgrowth in lungs in vivo. Furthermore, exposing mammary tumor cells to intermittent hypoxia promoted clonal diversity, upregulated metastasis-associated gene expression, induced a pro-tumorigenic secretory profile, increased stem-like cell marker expression, and gave rise to tumor-initiating cells at a relatively higher frequency. This work demonstrates that intermittent hypoxia, but not chronic hypoxia, induces a number of genetic, molecular, biochemical, and cellular changes that facilitate tumor cell survival, colonization, and the creation of a permissive microenvironment and thus enhances metastatic growth. PMID- 29713059 TI - Inactivation of the serine protease HTRA1 inhibits tumor growth by deregulating angiogenesis. AB - The serine protease HTRA1 is involved in several vascular diseases and its expression is often deregulated in cancer. We aimed at identifying how HTRA1 in the vasculature affects tumor growth. Here we report that silencing of HTRA1 in cultured endothelial cells increased migration rate and tube formation, whereas forced HTRA1 expression impaired sprouting angiogenesis. Mechanistically, endothelial HTRA1 expression enhanced Delta/Notch signaling by reducing the amount of the weak Notch ligand JAG1. HTRA1 physically interacted with JAG1 and cleaved it within the intracellular domain, leading to protein degradation. Expression of a constitutive active Notch1 prevented the hypersprouting phenotype upon silencing of HTRA1. In HtrA1-deficient mice, endothelial Notch signaling was diminished and isolated endothelial cells had increased expression of VEGF receptor-2. Growth of syngeneic tumors was strongly impaired in HtrA1-/- mice. The tumor vasculature was much denser in HtrA1-/- mice and less covered with mural cells. This chaotic and immature vascular network was poorly functional as indicated by large hypoxic tumor areas and low tumor cell proliferation rates. In summary, inhibition of HTRA1 in the tumor stroma impaired tumor progression by deregulating angiogenesis. PMID- 29713058 TI - Ubiquitylation and degradation of adenomatous polyposis coli by MKRN1 enhances Wnt/beta-catenin signaling. AB - The adenomatous polyposis coli (APC) protein has a tumor-suppressor function by acting as a negative regulator of the Wnt signaling pathway. While its role as a tumor suppressor is well-defined, the post-translational modifications that regulate APC stability are not fully understood. Here we showed that MKRN1, an E3 ligase, could directly interact with and ubiquitylate APC, promoting its proteasomal degradation. In contrast, an E3 ligase-defective MKRN1 mutant was no longer capable of regulating APC, indicating that its E3 ligase activity is required for APC regulation by MKRN1. Strengthening these results, MKRN1 ablation resulted in reduced beta-catenin activity and decreased expression of Wnt target genes. The ability of the Wnt-dependent pathway to induce cancer cell proliferation, migration, and invasion was impaired by MKRN1 depletion, but restored by simultaneous APC knockdown. Taken together, these results demonstrate that MKRN1 functions as a novel E3 ligase of APC that positively regulates Wnt/beta-catenin-mediated biological processes. PMID- 29713060 TI - Pre-neoplastic pancreas cells enter a partially mesenchymal state following transient TGF-beta exposure. AB - Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease and a major health problem in the United States. While the cytokine TGF-beta has been implicated in PDAC development, it can exert both pro-tumorigenic and anti-tumorigenic effects that are highly context dependent and incompletely understood. Using three dimensional (3D) cultures of KrasG12D-expressing mouse pancreatic epithelial cells we demonstrated that while exposure to exogenous TGF-beta induced growth arrest of the KrasG12D cells, its subsequent removal allowed the cells to enter a hyper-proliferative, partially mesenchymal (PM), and progenitor-like state. This state was highly stable and was maintained by autocrine TGF-beta signaling. While untreated KrasG12D cells formed cystic lesions in vivo, PM cells formed ductal structures resembling human PanINs, suggesting that they had attained increased oncogenic potential. Supporting this hypothesis, we determined that the PM cells share salient molecular and phenotypic features with the quasi mesenchymal/squamous subtype of human PDAC, which has the worst prognosis of any of the recently identified subtypes. Transient pulses of TGF-beta have been observed during pancreatitis, a major risk factor for PDAC. Our data suggest that transient TGF-beta exposure is sufficient to induce the acquisition of stable PDAC-associated phenotypes in pre-neoplastic KrasG12D cells, providing novel molecular insight into the complex role of TGF-beta in tumorigenesis. PMID- 29713063 TI - Life of a liver awaiting transplantation. PMID- 29713061 TI - Shared strategies for beta-lactam catabolism in the soil microbiome. AB - The soil microbiome can produce, resist, or degrade antibiotics and even catabolize them. While resistance genes are widely distributed in the soil, there is a dearth of knowledge concerning antibiotic catabolism. Here we describe a pathway for penicillin catabolism in four isolates. Genomic and transcriptomic sequencing revealed beta-lactamase, amidase, and phenylacetic acid catabolon upregulation. Knocking out part of the phenylacetic acid catabolon or an apparent penicillin utilization operon (put) resulted in loss of penicillin catabolism in one isolate. A hydrolase from the put operon was found to degrade in vitro benzylpenicilloic acid, the beta-lactamase penicillin product. To test the generality of this strategy, an Escherichia coli strain was engineered to co express a beta-lactamase and a penicillin amidase or the put operon, enabling it to grow using penicillin or benzylpenicilloic acid, respectively. Elucidation of additional pathways may allow bioremediation of antibiotic-contaminated soils and discovery of antibiotic-remodeling enzymes with industrial utility. PMID- 29713064 TI - Faulty replication can sting. PMID- 29713062 TI - Thymidine catabolism promotes NADPH oxidase-derived reactive oxygen species (ROS) signalling in KB and yumoto cells. AB - Thymidine phosphorylase (TP) is a rate-limiting enzyme in the thymidine catabolic pathway. TP is identical to platelet-derived endothelial cell growth factor and contributes to tumour angiogenesis. TP induces the generation of reactive oxygen species (ROS) and enhances the expression of oxidative stress-responsive genes, such as interleukin (IL)-8. However, the mechanism underlying ROS induction by TP remains unclear. In the present study, we demonstrated that TP promotes NADPH oxidase-derived ROS signalling in cancer cells. NADPH oxidase inhibition using apocynin or small interfering RNAs (siRNAs) abrogated the induction of IL-8 and ROS in TP-expressing cancer cells. Meanwhile, thymidine catabolism induced by TP increased the levels of NADPH and intermediates of the pentose phosphate pathway (PPP). Both siRNA knockdown of glucose 6-phosphate dehydrogenase (G6PD), a rate limiting enzyme in PPP, and a G6PD inhibitor, dihydroepiandrosterone, reduced TP induced ROS production. siRNA downregulation of 2-deoxy-D-ribose 5-phosphate (DR5P) aldolase, which is needed for DR5P to enter glycolysis, also suppressed the induction of NADPH and IL-8 in TP-expressing cells. These results suggested that TP-mediated thymidine catabolism increases the intracellular NADPH level via the PPP, which enhances the production of ROS by NADPH oxidase and activates its downstream signalling. PMID- 29713065 TI - Nobel prize lagged my undergraduate lectures by 20 years. PMID- 29713066 TI - Sea-bed mining - count the true costs. PMID- 29713067 TI - AI surveillance studies need ethics review. PMID- 29713068 TI - Shore up support for climate action using SDGs. PMID- 29713069 TI - Data reviews quick to produce but open to abuse. PMID- 29713071 TI - Virtual-reality applications give science a new dimension. PMID- 29713072 TI - Molecular machines swap rings. PMID- 29713073 TI - Calcium-dependent molecular fMRI using a magnetic nanosensor. AB - Calcium ions are ubiquitous signalling molecules in all multicellular organisms, where they mediate diverse aspects of intracellular and extracellular communication over widely varying temporal and spatial scales 1 . Though techniques to map calcium-related activity at a high resolution by optical means are well established, there is currently no reliable method to measure calcium dynamics over large volumes in intact tissue 2 . Here, we address this need by introducing a family of magnetic calcium-responsive nanoparticles (MaCaReNas) that can be detected by magnetic resonance imaging (MRI). MaCaReNas respond within seconds to [Ca2+] changes in the 0.1-1.0 mM range, suitable for monitoring extracellular calcium signalling processes in the brain. We show that the probes permit the repeated detection of brain activation in response to diverse stimuli in vivo. MaCaReNas thus provide a tool for calcium-activity mapping in deep tissue and offer a precedent for the development of further nanoparticle-based sensors for dynamic molecular imaging with MRI. PMID- 29713074 TI - Multifunctional biophotonic nanostructures inspired by the longtail glasswing butterfly for medical devices. AB - Numerous living organisms possess biophotonic nanostructures that provide colouration and other diverse functions for survival. While such structures have been actively studied and replicated in the laboratory, it remains unclear whether they can be used for biomedical applications. Here, we show a transparent photonic nanostructure inspired by the longtail glasswing butterfly (Chorinea faunus) and demonstrate its use in intraocular pressure (IOP) sensors in vivo. We exploit the phase separation between two immiscible polymers (poly(methyl methacrylate) and polystyrene) to form nanostructured features on top of a Si3N4 substrate. The membrane thus formed shows good angle-independent white-light transmission, strong hydrophilicity and anti-biofouling properties, which prevent adhesion of proteins, bacteria and eukaryotic cells. We then developed a microscale implantable IOP sensor using our photonic membrane as an optomechanical sensing element. Finally, we performed in vivo testing on New Zealand white rabbits, which showed that our device reduces the mean IOP measurement variation compared with conventional rebound tonometry without signs of inflammation. PMID- 29713075 TI - Full control of ligand positioning reveals spatial thresholds for T cell receptor triggering. AB - Elucidating the rules for receptor triggering in cell-cell and cell-matrix contacts requires precise control of ligand positioning in three dimensions. Here, we use the T cell receptor (TCR) as a model and subject T cells to different geometric arrangements of ligands, using a nanofabricated single molecule array platform. This comprises monovalent TCR ligands anchored to lithographically patterned nanoparticle clusters surrounded by mobile adhesion molecules on a supported lipid bilayer. The TCR ligand could be co-planar with the supported lipid bilayer (2D), excluding the CD45 transmembrane tyrosine phosphatase, or elevated by 10 nm on solid nanopedestals (3D), allowing closer access of CD45 to engaged TCR. The two configurations resulted in different T cell responses, depending on the lateral spacing between the ligands. These results identify the important contributions of lateral and axial components of ligand positioning and create a more complete foundation for receptor engineering for immunotherapy. PMID- 29713076 TI - A framework for sustainable nanomaterial selection and design based on performance, hazard, and economic considerations. AB - Engineered nanomaterials (ENMs) and ENM-enabled products have emerged as potentially high-performance replacements to conventional materials and chemicals. As such, there is an urgent need to incorporate environmental and human health objectives into ENM selection and design processes. Here, an adapted framework based on the Ashby material selection strategy is presented as an enhanced selection and design process, which includes functional performance as well as environmental and human health considerations. The utility of this framework is demonstrated through two case studies, the design and selection of antimicrobial substances and conductive polymers, including ENMs, ENM-enabled products and their alternatives. Further, these case studies consider both the comparative efficacy and impacts at two scales: (i) a broad scale, where chemical/material classes are readily compared for primary decision-making, and (ii) within a chemical/material class, where physicochemical properties are manipulated to tailor the desired performance and environmental impact profile. Development and implementation of this framework can inform decision-making for the implementation of ENMs to facilitate promising applications and prevent unintended consequences. PMID- 29713077 TI - Tunnelling spectroscopy of gate-induced superconductivity in MoS2. AB - The ability to gate-induce superconductivity by electrostatic charge accumulation is a recent breakthrough in physics and nanoelectronics. With the exception of LaAlO3/SrTiO3 interfaces, experiments on gate-induced superconductors have been largely confined to resistance measurements, which provide very limited information about the superconducting state. Here, we explore gate-induced superconductivity in MoS2 by performing tunnelling spectroscopy to determine the energy-dependent density of states (DOS) for different levels of electron density n. In the superconducting state, the DOS is strongly suppressed at energy smaller than the gap Delta, which is maximum (Delta ~2 meV) for n of ~1 * 1014 cm-2 and decreases monotonously for larger n. A perpendicular magnetic field B generates states at E < Delta that fill the gap, but a 20% DOS suppression of superconducting origin unexpectedly persists much above the transport critical field. Conversely, an in-plane field up to 10 T leaves the DOS entirely unchanged. Our measurements exclude that the superconducting state in MoS2 is fully gapped and reveal the presence of a DOS that vanishes linearly with energy, the explanation of which requires going beyond a conventional, purely phonon driven Bardeen-Cooper-Schrieffer mechanism. PMID- 29713078 TI - Parallel mapping of optical near-field interactions by molecular motor-driven quantum dots. AB - In the vicinity of metallic nanostructures, absorption and emission rates of optical emitters can be modulated by several orders of magnitude1,2. Control of such near-field light-matter interaction is essential for applications in biosensing3, light harvesting4 and quantum communication5,6 and requires precise mapping of optical near-field interactions, for which single-emitter probes are promising candidates7-11. However, currently available techniques are limited in terms of throughput, resolution and/or non-invasiveness. Here, we present an approach for the parallel mapping of optical near-field interactions with a resolution of <5 nm using surface-bound motor proteins to transport microtubules carrying single emitters (quantum dots). The deterministic motion of the quantum dots allows for the interpolation of their tracked positions, resulting in an increased spatial resolution and a suppression of localization artefacts. We apply this method to map the near-field distribution of nanoslits engraved into gold layers and find an excellent agreement with finite-difference time-domain simulations. Our technique can be readily applied to a variety of surfaces for scalable, nanometre-resolved and artefact-free near-field mapping using conventional wide-field microscopes. PMID- 29713079 TI - Precise multimodal optical control of neural ensemble activity. AB - Understanding brain function requires technologies that can control the activity of large populations of neurons with high fidelity in space and time. We developed a multiphoton holographic approach to activate or suppress the activity of ensembles of cortical neurons with cellular resolution and sub-millisecond precision. Since existing opsins were inadequate, we engineered new soma-targeted (ST) optogenetic tools, ST-ChroME and IRES-ST-eGtACR1, optimized for multiphoton activation and suppression. Employing a three-dimensional all-optical read-write interface, we demonstrate the ability to simultaneously photostimulate up to 50 neurons distributed in three dimensions in a 550 * 550 * 100-um3 volume of brain tissue. This approach allows the synthesis and editing of complex neural activity patterns needed to gain insight into the principles of neural codes. PMID- 29713080 TI - Complex formation between the vasopressin 1b receptor, beta-arrestin-2, and the MU-opioid receptor underlies morphine tolerance. AB - Chronic morphine exposure upregulates adenylate cyclase signaling and reduces analgesic efficacy, a condition known as opioid tolerance. Nonopioid neurotransmitters can enhance morphine tolerance, but the mechanism for this is poorly understood. We show that morphine tolerance was delayed in mice lacking vasopressin 1b receptors (V1bRs) or after administration of V1bR antagonist into the rostral ventromedial medulla, where transcripts for V1bRs and MU-opioid receptors are co-localized. Vasopressin increased morphine-binding affinity in cells expressing both V1bR and MU-opioid receptors. Complex formation among V1bR, beta-arrestin-2, and MU-opioid receptor resulted in vasopressin-mediated upregulation of ERK phosphorylation and adenylate cyclase sensitization. A leucine-rich segment in the V1bR C-terminus was necessary for the association with beta-arrestin-2. Deletion of this leucine-rich segment increased morphine analgesia and reduced vasopressin-mediated adenylate cyclase sensitization. These findings indicate that inhibition of MU-opioid-receptor-associated V1bR provides an approach for enhancing morphine analgesia without increasing analgesic tolerance. PMID- 29713081 TI - Picky comprehensively detects high-resolution structural variants in nanopore long reads. AB - Acquired genomic structural variants (SVs) are major hallmarks of cancer genomes, but they are challenging to reconstruct from short-read sequencing data. Here we exploited the long reads of the nanopore platform using our customized pipeline, Picky ( https://github.com/TheJacksonLaboratory/Picky ), to reveal SVs of diverse architecture in a breast cancer model. We identified the full spectrum of SVs with superior specificity and sensitivity relative to short-read analyses, and uncovered repetitive DNA as the major source of variation. Examination of genome wide breakpoints at nucleotide resolution uncovered micro-insertions as the common structural features associated with SVs. Breakpoint density across the genome is associated with the propensity for interchromosomal connectivity and was found to be enriched in promoters and transcribed regions of the genome. Furthermore, we observed an over-representation of reciprocal translocations from chromosomal double-crossovers through phased SVs. We demonstrate that Picky analysis is an effective tool for comprehensive detection of SVs in cancer genomes from long-read data. PMID- 29713082 TI - Self-interference 3D super-resolution microscopy for deep tissue investigations. AB - Fluorescence localization microscopy has achieved near-molecular resolution capable of revealing ultra-structures, with a broad range of applications, especially in cellular biology. However, it remains challenging to attain such resolution in three dimensions and inside biological tissues beyond the first cell layer. Here we introduce SELFI, a framework for 3D single-molecule localization within multicellular specimens and tissues. The approach relies on self-interference generated within the microscope's point spread function (PSF) to simultaneously encode equiphase and intensity fluorescence signals, which together provide the 3D position of an emitter. We combined SELFI with conventional localization microscopy to visualize F-actin 3D filament networks and reveal the spatial distribution of the transcription factor OCT4 in human induced pluripotent stem cells at depths up to 50 um inside uncleared tissue spheroids. SELFI paves the way to nanoscale investigations of native cellular processes in intact tissues. PMID- 29713084 TI - On the cutting edge. PMID- 29713083 TI - Accurate detection of complex structural variations using single-molecule sequencing. AB - Structural variations are the greatest source of genetic variation, but they remain poorly understood because of technological limitations. Single-molecule long-read sequencing has the potential to dramatically advance the field, although high error rates are a challenge with existing methods. Addressing this need, we introduce open-source methods for long-read alignment (NGMLR; https://github.com/philres/ngmlr ) and structural variant identification (Sniffles; https://github.com/fritzsedlazeck/Sniffles ) that provide unprecedented sensitivity and precision for variant detection, even in repeat rich regions and for complex nested events that can have substantial effects on human health. In several long-read datasets, including healthy and cancerous human genomes, we discovered thousands of novel variants and categorized systematic errors in short-read approaches. NGMLR and Sniffles can automatically filter false events and operate on low-coverage data, thereby reducing the high costs that have hindered the application of long reads in clinical and research settings. PMID- 29713085 TI - Determinants of response and resistance to CD19 chimeric antigen receptor (CAR) T cell therapy of chronic lymphocytic leukemia. AB - Tolerance to self-antigens prevents the elimination of cancer by the immune system1,2. We used synthetic chimeric antigen receptors (CARs) to overcome immunological tolerance and mediate tumor rejection in patients with chronic lymphocytic leukemia (CLL). Remission was induced in a subset of subjects, but most did not respond. Comprehensive assessment of patient-derived CAR T cells to identify mechanisms of therapeutic success and failure has not been explored. We performed genomic, phenotypic and functional evaluations to identify determinants of response. Transcriptomic profiling revealed that CAR T cells from complete responding patients with CLL were enriched in memory-related genes, including IL 6/STAT3 signatures, whereas T cells from nonresponders upregulated programs involved in effector differentiation, glycolysis, exhaustion and apoptosis. Sustained remission was associated with an elevated frequency of CD27+CD45RO-CD8+ T cells before CAR T cell generation, and these lymphocytes possessed memory-like characteristics. Highly functional CAR T cells from patients produced STAT3 related cytokines, and serum IL-6 correlated with CAR T cell expansion. IL 6/STAT3 blockade diminished CAR T cell proliferation. Furthermore, a mechanistically relevant population of CD27+PD-1-CD8+ CAR T cells expressing high levels of the IL-6 receptor predicts therapeutic response and is responsible for tumor control. These findings uncover new features of CAR T cell biology and underscore the potential of using pretreatment biomarkers of response to advance immunotherapies. PMID- 29713086 TI - Carboplatin in BRCA1/2-mutated and triple-negative breast cancer BRCAness subgroups: the TNT Trial. AB - Germline mutations in BRCA1/2 predispose individuals to breast cancer (termed germline-mutated BRCA1/2 breast cancer, gBRCA-BC) by impairing homologous recombination (HR) and causing genomic instability. HR also repairs DNA lesions caused by platinum agents and PARP inhibitors. Triple-negative breast cancers (TNBCs) harbor subpopulations with BRCA1/2 mutations, hypothesized to be especially platinum-sensitive. Cancers in putative 'BRCAness' subgroups-tumors with BRCA1 methylation; low levels of BRCA1 mRNA (BRCA1 mRNA-low); or mutational signatures for HR deficiency and those with basal phenotypes-may also be sensitive to platinum. We assessed the efficacy of carboplatin and another mechanistically distinct therapy, docetaxel, in a phase 3 trial in subjects with unselected advanced TNBC. A prespecified protocol enabled biomarker-treatment interaction analyses in gBRCA-BC and BRCAness subgroups. The primary endpoint was objective response rate (ORR). In the unselected population (376 subjects; 188 carboplatin, 188 docetaxel), carboplatin was not more active than docetaxel (ORR, 31.4% versus 34.0%, respectively; P = 0.66). In contrast, in subjects with gBRCA BC, carboplatin had double the ORR of docetaxel (68% versus 33%, respectively; biomarker, treatment interaction P = 0.01). Such benefit was not observed for subjects with BRCA1 methylation, BRCA1 mRNA-low tumors or a high score in a Myriad HRD assay. Significant interaction between treatment and the basal-like subtype was driven by high docetaxel response in the nonbasal subgroup. We conclude that patients with advanced TNBC benefit from characterization of BRCA1/2 mutations, but not BRCA1 methylation or Myriad HRD analyses, to inform choices on platinum-based chemotherapy. Additionally, gene expression analysis of basal-like cancers may also influence treatment selection. PMID- 29713087 TI - Molecular subtypes of diffuse large B cell lymphoma are associated with distinct pathogenic mechanisms and outcomes. AB - Diffuse large B cell lymphoma (DLBCL), the most common lymphoid malignancy in adults, is a clinically and genetically heterogeneous disease that is further classified into transcriptionally defined activated B cell (ABC) and germinal center B cell (GCB) subtypes. We carried out a comprehensive genetic analysis of 304 primary DLBCLs and identified low-frequency alterations, captured recurrent mutations, somatic copy number alterations, and structural variants, and defined coordinate signatures in patients with available outcome data. We integrated these genetic drivers using consensus clustering and identified five robust DLBCL subsets, including a previously unrecognized group of low-risk ABC-DLBCLs of extrafollicular/marginal zone origin; two distinct subsets of GCB-DLBCLs with different outcomes and targetable alterations; and an ABC/GCB-independent group with biallelic inactivation of TP53, CDKN2A loss, and associated genomic instability. The genetic features of the newly characterized subsets, their mutational signatures, and the temporal ordering of identified alterations provide new insights into DLBCL pathogenesis. The coordinate genetic signatures also predict outcome independent of the clinical International Prognostic Index and suggest new combination treatment strategies. More broadly, our results provide a roadmap for an actionable DLBCL classification. PMID- 29713088 TI - Genomic and geographic footprints of differential introgression between two divergent fish species (Solea spp.). AB - Investigating gene flow between closely related species and its variation across the genome is important to understand how reproductive barriers shape genome divergence before speciation is complete. An efficient way to characterize differential gene flow is to study how the genetic interactions that take place in hybrid zones selectively filter gene exchange between species, leading to heterogeneous genome divergence. In the present study, genome-wide divergence and introgression patterns were investigated between two sole species, Solea senegalensis and Solea aegyptiaca, using restriction-associated DNA sequencing (RAD-Seq) to analyze samples taken from a transect spanning the hybrid zone. An integrative approach combining geographic and genomic clines methods with an analysis of individual locus introgression accounting for the demographic history of divergence was conducted. Our results showed that the two sole species have come into secondary contact postglacially, after experiencing a prolonged period (ca. 1.1 to 1.8 Myrs) of allopatric separation. Secondary contact resulted in the formation of a tension zone characterized by strong reproductive isolation, which only allowed introgression in a limited fraction of the genome. We found multiple evidence for a preferential direction of introgression in the S. aegyptiaca genetic background, indicating a possible recent or ongoing movement of the hybrid zone. Deviant introgression signals found in the opposite direction suggested that S. senegalensis could have possibly undergone adaptive introgression that has not yet spread throughout the entire species range. Our study thus illustrates the varied outcomes of genetic interactions between divergent gene pools that recently met after a long history of divergence. PMID- 29713090 TI - Candidate genes associated with color morphs of female-limited polymorphisms of the damselfly Ischnura senegalensis. AB - Many Odonata species exhibit female-limited polymorphisms, where one morph is similar to the conspecific male in body color and other traits (andromorph), whereas one or more other morphs differ from the male (gynomorphs). Here we investigated the differentially expressed transcripts (DETs) among males and two female morph groups (gynomorphs and andromorphs) using RNA-seq to identify candidate transcripts encoding female-limited polymorphisms in the damselfly Ischnura senegalensis. Seven DETs that had significantly different expression levels between males and gynomorphs, but not between males and andromorphs, were identified. The expression levels of four of these candidate genes, doublesex (dsx), black, ebony, and chaoptin (chp), were selected for further analysis using qRT-PCR. Sequence analysis of the dsx amplicons revealed that this gene produced at least three transcripts. Two short transcripts were mainly expressed in males and andromorphs, whereas the long transcript was specifically expressed in both morph female groups; that is, the expression pattern of the dsx splice variants in andromorphs was an intermediate between that of males and gynomorphs. Because the dsx gene functions as a transcription factor that regulates the sex-specific expression of multiple genes, its splice variants in I. senegalensis may explain why the andromorph is female but exhibits some masculinized traits. Because we did not detect different coding sequences of the candidate genes among the different morphs, a diallelic genomic region controlling alternative splicing of dsx, thus determining female-limited polymorphism in I. senegalensis most likely lies in a non-coding region of the dsx gene or in a gene upstream of it. PMID- 29713089 TI - Genomic selection using principal component regression. AB - Many statistical methods are available for genomic selection (GS) through which genetic values of quantitative traits are predicted for plants and animals using whole-genome SNP data. A large number of predictors with much fewer subjects become a major computational challenge in GS. Principal components regression (PCR) and its derivative, i.e., partial least squares regression (PLSR), provide a solution through dimensionality reduction. In this study, we show that PCR can perform better than PLSR in cross validation. PCR often requires extracting more components to achieve the maximum predictive ability than PLSR and thus may be associated with a higher computational cost. However, application of the HAT method (a strategy of describing the relationship between the fitted and observed response variables with a hat matrix) to PCR circumvents conventional cross validation in testing predictive ability, resulting in substantially improved computational efficiency over PLSR where cross validation is mandatory. Advantages of PCR over PLSR are illustrated with a simulated trait of a hypothetical population and four agronomical traits of a rice population. The benefit of using PCR in genomic selection is further demonstrated in an effort to predict 1000 metabolomic traits and 24,973 transcriptomic traits in the same rice population. PMID- 29713091 TI - Brillouin micro-spectroscopy through aberrations via sensorless adaptive optics. AB - Brillouin spectroscopy is a powerful optical technique for non-contact viscoelastic characterizations which has recently found applications in three dimensional mapping of biological samples. Brillouin spectroscopy performances are rapidly degraded by optical aberrations and have therefore been limited to homogenous transparent samples. In this work, we developed an adaptive optics (AO) configuration designed for Brillouin scattering spectroscopy to engineer the incident wavefront and correct for aberrations. Our configuration does not require direct wavefront sensing and the injection of a "guide-star"; hence, it can be implemented without the need for sample pre-treatment. We used our AO Brillouin spectrometer in aberrated phantoms and biological samples and obtained improved precision and resolution of Brillouin spectral analysis; we demonstrated 2.5-fold enhancement in Brillouin signal strength and 1.4-fold improvement in axial resolution because of the correction of optical aberrations. PMID- 29713092 TI - LOW-TEMPERATURE AQUEOUS ALTERATION ON THE CR CHONDRITE PARENT BODY: IMPLICATIONS FROM IN SITU OXYGEN-ISOTOPE ANALYSES. AB - The presence of hydrated minerals in chondrites indicates that water played an important role in the geologic evolution of the early Solar System; however, the process of aqueous alteration is still poorly understood. Renazzo-like carbonaceous (CR) chondrites are particularly well-suited for the study of aqueous alteration. Samples range from being nearly anhydrous to fully altered, essentially representing snapshots of the alteration process through time. We studied oxygen isotopes in secondary-minerals from six CR chondrites of varying hydration states to determine how aqueous fluid conditions (including composition and temperature) evolved on the parent body. Secondary minerals analyzed included calcite, dolomite, and magnetite. The O-isotope composition of calcites ranged from delta18O ~ 9 to 35 0/00, dolomites from delta18O ~ 23 to 27 0/00, and magnetites from delta18O ~ -18 to 5 0/00. Calcite in less-altered samples showed more evidence of fluid evolution compared to heavily altered samples, likely reflecting lower water/rock ratios. Most magnetite plotted on a single trend, with the exception of grains from the extensively hydrated chondrite MIL 090292. The MIL 090292 magnetite diverges from this trend, possibly indicating an anomalous origin for the meteorite. If magnetite and calcite formed in equilibrium, then the relative 18O fractionation between them can be used to extract the temperature of co-precipitation. Isotopic fractionation in Al Rais carbonate-magnetite assemblages revealed low precipitation temperatures (~60 degrees C). Assuming that the CR parent body experienced closed-system alteration, a similar exercise for parallel calcite and magnetite O-isotope arrays yields "global" alteration temperatures of ~55 to 88 degrees C. These secondary mineral arrays indicate that the O-isotopic composition of the altering fluid evolved upon progressive alteration, beginning near the Al Rais water composition of Delta17O ~ 1 0/00 and delta18O ~ 10 0/00, and becoming increasingly 16O-enriched toward a final fluid composition of Delta17O ~ -1.2 0/00 and delta18O ~ -15 0/00. PMID- 29713093 TI - "Big data" in economic history. AB - Big data is an exciting prospect for the field of economic history, which has long depended on the acquisition, keying, and cleaning of scarce numerical information about the past. This article examines two areas in which economic historians are already using big data - population and environment - discussing ways in which increased frequency of observation, denser samples, and smaller geographic units allow us to analyze the past with greater precision and often to track individuals, places, and phenomena across time. We also explore promising new sources of big data: organically created economic data, high resolution images, and textual corpora. PMID- 29713094 TI - Language Acculturation, Acculturation-Related Stress, and Marital Quality in Chinese American Couples. AB - The current study examines the longitudinal indirect pathways linking language acculturation to marital quality. Three waves of data were collected from 416 Chinese American couples over eight years (Mage.wave1 = 48 for husbands, 44 for wives). Actor-partner interdependence model analyses revealed that for both husbands and wives, lower levels of language acculturation were associated with higher levels of stress over being stereotyped as a perpetual foreigner. Individuals' foreigner stress, in turn, was directly related to greater levels of their own and their partners' marital warmth, suggesting that foreigner stress may have some positive relational effects. However, individuals' foreigner stress also was associated with increases in their own depressive symptoms, which predicted higher levels of marital hostility in the partner. Overall, these results underscore the complexity of how language acculturation and foreigner stress relate to marital quality and the importance of considering the interdependence of the marital system. PMID- 29713095 TI - Vibration of Mechanically-Assembled 3D Microstructures Formed by Compressive Buckling. AB - Micro-electromechanical systems (MEMS) that rely on structural vibrations have many important applications, ranging from oscillators and actuators, to energy harvesters and vehicles for measurement of mechanical properties. Conventional MEMS, however, mostly utilize two-dimensional (2D) vibrational modes, thereby imposing certain limitations that are not present in 3D designs (e.g., multi directional energy harvesting). 3D vibrational microplatforms assembled through the techniques of controlled compressive buckling are promising because of their complex 3D architectures and the ability to tune their vibrational behaviour (e.g., natural frequencies and modes) by reversibly changing their dimensions by deforming their soft, elastomeric substrates. A clear understanding of such strain-dependent vibration behaviour is essential for their practical applications. Here, we present a study on the linear and nonlinear vibration of such 3D mesostructures through analytical modeling, finite element analysis (FEA) and experiment. An analytical solution is obtained for the vibration mode and linear natural frequency of a buckled ribbon, indicating a mode change as the static deflection amplitude increases. The model also yields a scaling law for linear natural frequency that can be extended to general, complex 3D geometries, as validated by FEA and experiment. In the regime of nonlinear vibration, FEA suggests that an increase of amplitude of external loading represents an effective means to enhance the bandwidth. The results also uncover a reduced nonlinearity of vibration as the static deflection amplitude of the 3D structures increases. The developed analytical model can be used in the development of new 3D vibrational microplatforms, for example, to enable simultaneous measurement of diverse mechanical properties (density, modulus, viscosity etc.) of thin films and biomaterials. PMID- 29713096 TI - Characterizing the Effects of Quetiapine in Military Post-Traumatic Stress Disorder. AB - Objectives: A previous randomized placebo-controlled trial in military veterans posttraumatic stress disorder (PTSD) found that quetiapine improved global PTSD symptoms severity, depression and anxiety as well as the re-experiencing and hypearousal clusters. However, it is not known if individual symptoms had a preferential response to this medication. The goal of this study was to analyze the individual symptom response in this group of patients. Methods: Data from a previous trial was re-analyzed. Each of the of the scale items was analyzed individually using Repeated Measures Analysis of Variance. Results: Compared to placebo, there was a significant decline in the Clinician-Administered PTSD Scale intrusive memories and insomnia questions. In the Davidson Trauma Scale, greater improvements were observed on irritability, difficulty concentrating, hyperstartle and a trend was observed on avoiding thoughts or feelings about the event. Greater improvements compared with placebo were noted on the Hamilton Depression (HAM-D) middle and late insomnia items. On the Hamilton Anxiety scale (HAM-A), the insomnia item was significantly improved. Conclusions: Quetiapine demonstrated greater effect than placebo on several symptoms. The strongest response was seen on insomnia, which the highest significance level on the CAPS. The insomnia items of both the HAM-D and HAM-A also demonstrated improvement with quetiapine. These finding indicate quetiapine improved sleep measure. Insomnia can be a difficult problem to treat in PTSD patients, therefore quetiapine should be considered in difficult cases. PMID- 29713097 TI - A Pilot Evaluating Clinical Pharmacy Services in an Ambulatory Psychiatry Setting. AB - Objectives: A pilot of clinical services provided by psychiatric clinical pharmacists in an outpatient clinic are described and evaluated. The primary objective was to evaluate the difference in change of Patient Health Questionnaire (PHQ)-9 and/or Generalized Anxiety Disorder (GAD) Questionnaire scores between the two groups. Secondary objectives were to assess time patients spent in clinic, time to target psychotropic medication dose, and patient self reported medication adherence. Experimental Design: Data were collected from January 2014 to November 2015 for patients with depression and/or anxiety who had an appointment within an outpatient psychiatric clinic with either a provider (control) or both a provider and clinical pharmacist (case). Principle Observations: A total of 217 patients were included in the study; 117 patients served as controls and 100 patients received clinical pharmacist intervention. No statistical difference was detected in the primary outcome. However, patients in the case group had higher baseline PHQ-9/GAD scores, and the frequency of measured values was lower than anticipated, limiting power to detect a difference. All secondary outcomes achieved statistical significance. Both time in clinic and time to reach a stabilized psychotropic medication regimen were shorter in the control group. Patient self-reported adherence favored a higher adherence rate in the intervention group. Conclusion: While this study found no significant difference in the change in PHQ-9/GAD scores between groups, it demonstrated the need for enhanced utilization of measurement-based outcomes in the psychiatric setting. Pharmacists provide a range of services to patients and providers and can serve as key partners to enhance measurement-based care. PMID- 29713098 TI - Successful Management of Psychotropics Induced Stuttering Priapism with Pseudoephedrine in a Patient with Schizophrenia. AB - Stuttering Priapism is a recurrent, persistent penile erection in the absence of sexual desire due to altered genital hemodynamics, affecting the arterial component (high flow, non-ischemic) or the veno-occlusive mechanism (low flow, ischemic). Both typical and atypical antipsychotics increase the risk for priapism with greater implications in typicals than atypicals. Prompt recognition and treatment are important as 40% to 50% of patients with stuttering priapism may develop an erectile dysfunction if left untreated. There are several case reports in the literature about the association between psychotropic agents and priapism. However, there are no reports of successfully treating stuttering priapism using pseudoephedrine (sudafed) in the adult population. Here we present successful management of psychotropics induced stuttering priapism with pseudoephedrine in a male patient with schizophrenia. PMID- 29713100 TI - Do Long-Acting Injectable Antipsychotics Prevent or Delay Hospital Readmission? AB - Introduction: Long-acting injectable (LAI) antipsychotics were developed as a way to decrease pill burden and simplify medication regimens by allowing less frequent administration to assist with medication adherence. Methods: The purpose of this study was to determine whether LAI antipsychotics prevent or delay hospital readmission in patients with a known history of medication non adherence. The study is a retrospective evaluation of 240 men and women 18-65 years of age diagnosed with bipolar disorder, schizophrenia, or schizoaffective disorder discharged from an inpatient state hospital over a 2 year period of time on a LAI antipsychotic (fluphenazine LAI, haloperidol LAI, risperidone LAI or paliperidone LAI) or oral antipsychotic. Patients on LAIs were matched to patients on an equivalent oral dose, psychiatric diagnosis, number of prior hospital admissions, and length of stay. Results: Those who received a LAI (N = 120) had a significantly longer survival time (mean 278.0 days) without readmission compared to those who did not (N = 120; mean 243.6 days). There was no statistically significant difference in the frequency of one-year readmission between those who did receive a LAI (43.1%) and those who did not (56.9%). Those who received a LAI with administration frequency of a month or longer had a significantly longer survival time without readmission (mean 307.9 days) when compared to those with a shorter administration frequency (mean 245.0 days). Conclusion: This study revealed the use of LAI antipsychotics in those with a history of medication non-adherence, particularly those with longer administration frequency, have potentially promising outcomes. PMID- 29713099 TI - Dosing and Monitoring: Children and Adolescents. PMID- 29713101 TI - An Interesting Presentation About Cyclical Menstrual Psychosis with an Updated Review of Literature. AB - Cyclical menstrual psychosis is an uncommon, generally a self-limiting mental illness that occurs only in females. It is associated with other menstruation related disorders and stressful psychogenic factors. Nonetheless, many cases remain unrecognized due to poor awareness of its presence. A young female who presented with psychotic and mood symptoms during each cycle of menstruation was admitted to the psychiatric inpatient unit. There was severe disruption in her activities of daily living and socio-occupational functioning. Treatment involved bio-psycho-social approach in collaboration with Ob-Gyn team with symptoms responding well to a combination of valproic acid and risperidone. Severe affective instability with evident psychosis during menstrual cycle should be evaluated for cyclical menstrual psychosis. PMID- 29713102 TI - Major Depressive Disorder Following Dermatomyositis: A Case Linking Depression with Inflammation. AB - Major depressive disorder (MDD) is one of the most common psychiatric disorders. Recent studies have shown a strong association between MDD and peripheral inflammation, shown by a higher incidence of depression in patients with inflammatory diseases including rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis and systemic lupus erythematosus. Dermatomyositis (DM), an idiopathic inflammatory connective tissue disease that is associated with inflammation, predominantly affects the skin and skeletal muscle. The association between DM and MDD in the context of inflammation has seldom been reported. Here we report a 30- year- old Caucasian female with symptoms of depression dating back to 2 years. These symptoms started after cutaneous manifestations of DM. In the past two years, her DM symptoms have worsened that paralleled an increase of depressive symptoms. Also, during the course of the patient's DM, we tracked elevated inflammatory markers including creatine kinase and aldolase, whereas C reactive protein, C3, and C4 were in a high normal range which correlated with worsening of depression. Hence, a temporal relationship between the onset of MDD and DM symptoms suggests that inflammation may be a common mechanism linking these two conditions. PMID- 29713103 TI - A Case of Concomitant Pseudocyesis and Couvade Syndrome Variant. AB - Per DSM-V, pseudocyesis is included under the category "other specified somatic symptom and related disorder" and is defined as a false belief of being pregnant that is associated with objective signs and reported symptoms of pregnancy. The male counterpart of pseudocyesis is Couvade syndrome, also called "sympathetic pregnancy" where a man experiences symptoms of pregnancy when his female partner is pregnant. There are extensive reports on pseudocyesis and Couvade syndrome in psychiatric literature but none with features of both, in a single case. Here we present a unique case of a fifty-eight-year-old mother who presented with symptoms of concomitant pseudocyesis and Couvade syndrome concurrently when her daughter was pregnant. This case report discusses the epidemiology, course of symptoms and common comorbidities associated with this interesting diagnosis. PMID- 29713104 TI - Efficacy and Tolerability of Two Different Kinds of Titration of Paroxetine Hydrocloride Solution: an Observational Study. AB - Background: Depressive disorders are expected to be the second highest cause of morbidity in the world until few years. Moreover, patients with depression frequently show many side effects and low compliance to therapy. To find a more tolerated and more efficacy therapy is a growing need. Objective: This observational study investigates the efficacy, safety and tolerability of paroxetine hydrochloride comparing slow versus standard titration in a population affected by Depressive Disoders (according to DSM 5). Methods: 186 outpatients were assessed throught the following scales: Hamilton Depression Rating Scale (HDRS) for depression and World Health Organization Quality of Life Scale Bref for the perceived quality of life (WHOQOL BREF). Treatment-emerged Adverse Events (TEAEs) were recorded throught self-reports. Statystical analysys was performed by GraphPad Prism Version 5.1. Results: The efficacy of paroxetine was confirmed in both titrations by the number of clinical remitters (HDRS <= 7 at 12 weeks for 53% of the standard titration group and 58% of the slow titration group), without differences. About safety and tolerability there were more frequent TEAEs among the standard titration group (p < 0.01). Comparing WHOQOL BREF between the two groups at the recruitment and at the twelth week emerged a statistically significant difference (p = 0.003), with highest scores reached in slow titration group. Conclusions: Although the short observation period is an evident limit, this study is consistent to the literature about the efficacy of both titrations of paroxetine to improve depression and shows promising results about the increased tolerability of paroxetine slow titration. PMID- 29713105 TI - Progressive Non-familial Adult onset Cerebellar Degeneration: An Unusual Occurrence with Hashimoto's Thyroiditis. AB - Progressive non-familial adult onset cerebellar degeneration has been rarely associated with hypothyroidism and is known to be reversible after therapy. We report a case of cerebellar atrophy in a 31 year old female whose detailed evaluation had revealed sub-clinical hypothyroidism secondary to autoimmune thyroiditis with a very high anti-TPO (anti-thyroid peroxidase) antibody levels. MRI (Magnetic Resonanace Imaging) of brain showed diffuse bilateral cerebellar atrophy. She was treated with thyroid hormone supplementation and after one year of follow up, cerebellar signs had disappeared completely with significant reduction in anti-TPO antibody levels. Imaging of the brain post one year of follow-up revealed normal cerebellum. Hence, we opine that thyroid dysfunction should always be kept in mind while evaluating patients presenting with acute onset cerebellar ataxia as it can be easily reversed with thyroid hormone replacement therapy. PMID- 29713106 TI - Risperidone Induced Isolated Thrombocytopenia: A Rare Adverse Event. PMID- 29713108 TI - Volcano and ship tracks indicate excessive aerosol-induced cloud water increases in a climate model. AB - Aerosol-cloud interaction is the most uncertain mechanism of anthropogenic radiative forcing of Earth's climate, and aerosol-induced cloud water changes are particularly poorly constrained in climate models. By combining satellite retrievals of volcano and ship tracks in stratocumulus clouds, we compile a unique observational dataset and confirm that liquid water path (LWP) responses to aerosols are bidirectional, and on average the increases in LWP are closely compensated by the decreases. Moreover, the meteorological parameters controlling the LWP responses are strikingly similar between the volcano and ship tracks. In stark contrast to observations, there are substantial unidirectional increases in LWP in the Hadley Centre climate model, because the model accounts only for the decreased precipitation efficiency and not for the enhanced entrainment drying. If the LWP increases in the model were compensated by the decreases as the observations suggest, its indirect aerosol radiative forcing in stratocumulus regions would decrease by 45%. PMID- 29713107 TI - Lymphatic System Flows. AB - The supply of oxygen and nutrients to tissues is performed by the blood system, and involves a net leakage of fluid outward at the capillary level. One of the principal functions of the lymphatic system is to gather this fluid and return it to the blood system to maintain overall fluid balance. Fluid in the interstitial spaces is often at subatmospheric pressure, and the return points into the venous system are at pressures of approximately 20 cmH2O. This adverse pressure difference is overcome by the active pumping of collecting lymphatic vessels, which feature closely spaced one-way valves and contractile muscle cells in their walls. Passive vessel squeezing causes further pumping. The dynamics of lymphatic pumping have been investigated experimentally and mathematically, revealing complex behaviours indicating that the system performance is robust against minor perturbations in pressure and flow. More serious disruptions can lead to incurable swelling of tissues called lymphoedema. PMID- 29713109 TI - LOCAL POPULATION CHANGE AND VARIATIONS IN RACIAL INTEGRATION IN THE UNITED STATES, 2000-2010. AB - While population growth has been consistently tied to decreasing racial segregation at the metropolitan level in the United States, little work has been done to relate small-scale changes in population size to integration. We address this question through a novel technique that tracks population changes by race and ethnicity for comparable geographies in both 2000 and 2010. Using the Theil Index, we analyze the fifty most populous Metropolitan Statistical Areas in 2010 for changes in multigroup segregation. We classify local areas by their net population change between 2000 and 2010 using a novel unit of analysis based on aggregating census blocks. We find strong evidence that growing parts of rapidly growing metropolitan areas of the United States are crucial to understanding regional differences in segregation that have emerged in past decades. Multigroup segregation declined the most in growing parts of growing metropolitan areas. Comparatively, growing parts of shrinking or stagnant metropolitan areas were less diverse and had smaller declines in segregation. We also find that local areas with shrinking populations had disproportionately high minority representation in 2000 before population loss took place. We conclude that the regional context of population growth or decline has important consequences for the residential mixing of racial groups. PMID- 29713110 TI - Joint reconstruction of the initial pressure and speed of sound distributions from combined photoacoustic and ultrasound tomography measurements. AB - The initial pressure and speed of sound (SOS) distributions cannot both be stably recovered from photoacoustic computed tomography (PACT) measurements alone. Adjunct ultrasound computed tomography (USCT) measurements can be employed to estimate the SOS distribution. Under the conventional image reconstruction approach for combined PACT/USCT systems, the SOS is estimated from the USCT measurements alone and the initial pressure is estimated from the PACT measurements by use of the previously estimated SOS. This approach ignores the acoustic information in the PACT measurements and may require many USCT measurements to accurately reconstruct the SOS. In this work, a joint reconstruction method where the SOS and initial pressure distributions are simultaneously estimated from combined PACT/USCT measurements is proposed. This approach allows accurate estimation of both the initial pressure distribution and the SOS distribution while requiring few USCT measurements. PMID- 29713111 TI - Estimating environmental co-benefits of U.S. low-carbon pathways using an integrated assessment model with state-level resolution. AB - There are many technological pathways that can lead to reduced carbon dioxide emissions. However, these pathways can have substantially different impacts on other environmental endpoints, such as air quality and energy-related water demand. This study uses an integrated assessment model with state-level resolution of the energy system to compare environmental impacts of alternative low-carbon pathways for the United States. One set of pathways emphasizes nuclear energy and carbon capture and storage, while another set emphasizes renewable energy, including wind, solar, geothermal power, and bioenergy. These are compared with pathways in which all technologies are available. Air pollutant emissions, mortality costs attributable to particulate matter smaller than 2.5 MUm in diameter, and energy-related water demands are evaluated for 50% and 80% carbon dioxide reduction targets in 2050. The renewable low-carbon pathways require less water withdrawal and consumption than the nuclear and carbon capture pathways. However, the renewable low-carbon pathways modeled in this study produce higher particulate matter-related mortality costs due to greater use of biomass in residential heating. Environmental co-benefits differ among states because of factors such as existing technology stock, resource availability, and environmental and energy policies. PMID- 29713112 TI - Bayesian Modeling of NMR Data: Quantifying Longitudinal Relaxation in Vivo, and in Vitro with a Tissue-Water-Relaxation Mimic (Crosslinked Bovine Serum Albumin). AB - Recently, a number of MRI protocols have been reported that seek to exploit the effect of dissolved oxygen (O2, paramagnetic) on the longitudinal 1H relaxation of tissue water, thus providing image contrast related to tissue oxygen content. However, tissue water relaxation is dependent on a number of mechanisms, and this raises the issue of how best to model the relaxation data. This problem, the model selection problem, occurs in many branches of science and is optimally addressed by Bayesian probability theory. High signal-to-noise, densely sampled, longitudinal 1H relaxation data were acquired from rat brain in vivo and from a cross-linked bovine serum albumin (xBSA) phantom, a sample that recapitulates the relaxation characteristics of tissue water in vivo. Bayesian-based model selection was applied to a cohort of five competing relaxation models: (i) monoexponential, (ii) stretched-exponential, (iii) biexponential, (iv) Gaussian (normal) R1-distribution, and (v) gamma R1-distribution. Bayesian joint analysis of multiple replicate datasets revealed that water relaxation of both the xBSA phantom and in vivo rat brain was best described by a biexponential model, while xBSA relaxation datasets truncated to remove evidence of the fast relaxation component were best modeled as a stretched exponential. In all cases, estimated model parameters were compared to the commonly used monoexponential model. Reducing the sampling density of the relaxation data and adding Gaussian distributed noise served to simulate cases in which the data are acquisition-time or signal-to-noise restricted, respectively. As expected, reducing either the number of data points or the signal-to-noise increases the uncertainty in estimated parameters and, ultimately, reduces support for more complex relaxation models. PMID- 29713113 TI - The creation, management, and use of data quality information for life cycle assessment. AB - Purpose: Despite growing access to data, questions of "best fit" data and the appropriate use of results in supporting decision making still plague the life cycle assessment (LCA) community. This discussion paper addresses revisions to assessing data quality captured in a new US Environmental Protection Agency guidance document as well as additional recommendations on data quality creation, management, and use in LCA databases and studies. Approach: Existing data quality systems and approaches in LCA were reviewed and tested. The evaluations resulted in a revision to a commonly used pedigree matrix, for which flow and process level data quality indicators are described, more clarity for scoring criteria, and further guidance on interpretation are given. Discussion: Increased training for practitioners on data quality application and its limits are recommended. A multi-faceted approach to data quality assessment utilizing the pedigree method alongside uncertainty analysis in result interpretation is recommended. A method of data quality score aggregation is proposed and recommendations for usage of data quality scores in existing data are made to enable improved use of data quality scores in LCA results interpretation. Roles for data generators, data repositories, and data users are described in LCA data quality management. Guidance is provided on using data with data quality scores from other systems alongside data with scores from the new system. The new pedigree matrix and recommended data quality aggregation procedure can now be implemented in openLCA software. Future work: Additional ways in which data quality assessment might be improved and expanded are described. Interoperability efforts in LCA data should focus on descriptors to enable user scoring of data quality rather than translation of existing scores. Developing and using data quality indicators for additional dimensions of LCA data, and automation of data quality scoring through metadata extraction and comparison to goal and scope are needed. PMID- 29713114 TI - 'I am not very well I feel nearly mad when I think of you': Male Jealousy, Murder and Broadmoor in Late-Victorian Britain. AB - This article compares the representations of jealousy in popular culture, medical and legal literature, and in the trials and diagnoses of men who murdered or attempted to murder their wives or sweethearts before being found insane and committed into Broadmoor Criminal Lunatic Asylum between 1864 and 1900. It is shown that jealousy was entrenched in Victorian culture, but marginalised in medical and legal discourse and in the courtroom until the end of the period, and was seemingly cast aside at Broadmoor. As well as providing a detailed examination of varied representations of male jealousy in late-Victorian Britain, the article contributes to understandings of the emotional lives of the working class, and the causes and representations of working-class male madness. PMID- 29713115 TI - 'If experts differ, what are we to do in the matter?' The Medico-legal Investigation of Gunshot Wounds in a 1927 Scottish Murder Trial. AB - This article uses a notorious criminal trial, that of John Donald Merrett for the murder of his mother, as a case study to explore forensic medicine's treatment of gunshot wounding in pre-war Scotland. This topic, which has hitherto received little attention from historians, provides insight into two issues facing the discipline at this time. First, the competing attempts by prosecution and defence expert witnesses to recreate the wound in a laboratory setting, in order to determine the distance from which the shot had been fired, exposed the uncertainties surrounding the application of a well-known laboratory technique for which no fully agreed-upon protocol existed. Secondly, the case allows the examination of the working relationship of a medical expert and a gunsmith, in which disciplinary boundaries became indistinct and the wound a shared site of analysis, in a period before the separate profession of forensic science became institutionally grounded in Scotland. PMID- 29713116 TI - Hiding in the Pub to Cutting the Cord? Men's Presence at Childbirth in Britain c.1940s-2000s. AB - Since the 1940s, men's presence at childbirth has changed from being out of the question to not only very common but often presented as highly valuable. This article examines this shift, charting how many men were present at their children's births over recent decades, considering how medical practitioners influenced men's participation, and analysing what meanings parents gave to this experience. It suggests a number of factors led to the relatively rapid move towards the acceptance of men's presence in the delivery room, but highlights this was not a simple transformation as a first glance at the figures would suggest. It argues that men's involvement in home births became more usual before hospitals changed their policies about men's presence, and considers how the role of fathers related to the increasingly medicalised nature of childbirth as this period progressed. It also considers whether men's involvement is always positive or welcome for those involved. PMID- 29713117 TI - 'A Change of Heart': Racial Politics, Scientific Metaphor and Coverage of 1968 Interracial Heart Transplants in the African American Press. AB - This paper explores the African American response to an interracial heart transplant in 1968 through a close reading of the black newspaper press. This methodological approach provides a window into African American perceptions of physiological difference between the races, or lack thereof, as it pertained to both personal identity and race politics. Coverage of the first interracial heart transplant, which occurred in apartheid South Africa, was multifaceted. Newspapers lauded the transplant as evidence of physiological race equality while simultaneously mobilising the language of differing 'black' and 'white' hearts to critique racist politics through the metaphor of a 'change of heart'. While interracial transplant created the opportunity for such political commentary, its material reality-potential exploitation of black bodies for white gain-was increasingly a cause for concern, especially after a contentious heart transplant from a black to a white man in May 1968 in the American South. PMID- 29713118 TI - Being Well, Looking Ill: Childbirth and the Return to Health in Seventeenth century England. AB - For a month after childbirth, the authors of medical and religious prescriptive literature instructed new mothers to keep to their beds. During this time they were expected to bleed away the bodily remnants of pregnancy. At the end of this month writers considered women 'well'. Bleeding, in this definition, was commensurate with recovery. This article shows that although in prescriptive material, maternal health was measured according to this process of purging, for early modern middling and upper sort women and their families, the bodily effects of childbearing continued to impede their ability to return to normal household tasks and behaviours long after the ritual month of 'lying-in' had ended. Using life-writing, casebooks and vernacular medical literature, this article challenges prevailing notions of what it meant to recover in early modern England, arguing that women's 'childing' or 'childebed' narratives only ended when they perceived their bodies to be unaffected by pregnancy and labour. PMID- 29713119 TI - John Wickham's New Surgery: 'Minimally Invasive Therapy', Innovation, and Approaches to Medical Practice in Twentieth-century Britain. AB - The term 'minimally invasive' was coined in 1986 to describe a range of procedures that involved making very small incisions or no incision at all for diseases traditionally treated by open surgery. We examine this major shift in British medical practice as a means of probing the nature of surgical innovation in the twentieth century. We first consider how concerns regarding surgical invasiveness had long been present in surgery, before examining how changing notions of post-operative care formed a foundation for change. We then go on to focus on a professional network involved in the promotion of minimally invasive therapy led by the urologist John Wickham. The minimally invasive movement, we contend, brought into focus tensions between surgical innovation and the evidence based model of medical practice. Premised upon professional collaborations beyond surgery and a re-positioning of the patient role, we show how the movement elucidated changing notions of surgical authority. PMID- 29713120 TI - Concepts, Diagnosis and the History of Medicine: Historicising Ian Hacking and Munchausen Syndrome. AB - Concepts used by historians are as historical as the diagnoses or categories that are studied. The example of Munchausen syndrome (deceptive presentation of illness in order to adopt the 'sick role') is used to explore this. Like most psychiatric diagnoses, Munchausen syndrome is not thought applicable across time by social historians of medicine. It is historically specific, drawing upon twentieth-century anthropology and sociology to explain motivation through desire for the 'sick role'. Ian Hacking's concepts of 'making up people' and 'looping effects' are regularly utilised outside of the context in which they are formed. However, this context is precisely the same anthropological and sociological insight used to explain Munchausen syndrome. It remains correct to resist the projection of Munchausen syndrome into the past. However, it seems inconsistent to use Hacking's concepts to describe identity formation before the twentieth century as they are given meaning by an identical context. PMID- 29713121 TI - 'His Whole Nature requires Development': Education, School Life and Deafness in Wales, 1850-1914. AB - The history of deaf education has focused heavily on one major issue: the role of sign language and the rise of oralism as a means of suppressing the use of signs. This was a crucial debate which affected the lives of deaf children, informed social and cultural attitudes towards deafness and in many cases spurred resistance from deaf communities. However, other aspects of daily school life and the curriculum of Victorian and Edwardian deaf schools have rarely been commented upon. Focusing on the Cambrian Institution for the Deaf and Dumb, Wales' first deaf institution, this article will examine the teaching of writing and moral, religious and industrial education, all of which constructed an image of the intellectual and moral capabilities of the deaf child. The article will argue that deaf children were prescribed a moral and religious identity, and played an active role in wider Victorian and Edwardian discourses of education and childhood. PMID- 29713122 TI - Russia and the Medical Drug Trade in the Seventeenth Century. AB - This article deals with the trade in medicines into Russia in the seventeenth century. Both the early modern medical drug trade, and Russian medicine, have previously received substantial attention, but no work has thus far been undertaken on the Russian angle of the drug trade. Drawing on previously unused documents, this article traces the kinds of drugs acquired by the Moscow court. In contrast to the dominant view of official Russian medicine as divorced from native healing practices and fundamentally reliant upon Western European trends, these documents reveal that drugs were sourced as locally as Moscow markets, and from as far afield as East Asia and the Americas, but that not all drugs were accepted. As many of these imports came through Western European markets, this article also sheds further light on what drugs were available there, demonstrating the great diversity of drugs traded in early modern Europe. PMID- 29713123 TI - The Sounds and Sights of Natural Childbirth: Films and Records in Antenatal Preparation Classes, 1950s-1980s. AB - Film and sound recordings are a ubiquitous part of the antenatal preparation courses that serve as a rite of passage to parenthood in Western Europe and North America. This article analyses a sample of these didactic tools used in classes from the 1950s to the 1980s, the heyday of the natural childbirth movement. These audio-visual artefacts both reflected and conditioned expectations for women's behaviour during labour and birth through their representation of pain. They demonstrate changing norms in the role of the father, but show how physician authority-and male authority more broadly-remained largely unchallenged. Two phases are discernable in these sources. From the 1950s through the mid-1960s, natural childbirth was presented as essentially painless. From the late 1960s through the 1980s, pain and effort in labour and birth found graphic representation on the screen, reflecting a shift in what was considered a desirable birth experience and what natural childbirth preparation could accomplish. PMID- 29713124 TI - Not Noble Savages after all: Limits to early altruism. AB - Many scholars draw on evidence from evolutionary biology, behavioral economics, and infant research to argue that humans are "noble savages", endowed with indiscriminate kindness. We believe this is mistaken. While there is evidence for an early-emerging moral sense - even infants recognize and favor instances of fairness and kindness amongst third parties - altruistic behaviors are selective from the start. Babies and young children favor those who have been kind to them in the past, and favor familiar individuals over strangers. They hold strong biases for ingroup over outgroup and for self over other, and indeed are more unequivocally selfish than older children and adults. Much of what is most impressive about adult morality arises not through inborn capacities, but a fraught developmental process that involves exposure to culture and the exercise of rationality. PMID- 29713125 TI - Beneficial effects of naringenin in liver diseases: Molecular mechanisms. AB - Liver diseases are caused by different etiological agents, mainly alcohol consumption, viruses, drug intoxication or malnutrition. Frequently, liver diseases are initiated by oxidative stress and inflammation that lead to the excessive production of extracellular matrix (ECM), followed by a progression to fibrosis, cirrhosis and hepatocellular carcinoma (HCC). It has been reported that some natural products display hepatoprotective properties. Naringenin is a flavonoid with antioxidant, antifibrogenic, anti-inflammatory and anticancer properties that is capable of preventing liver damage caused by different agents. The main protective effects of naringenin in liver diseases are the inhibition of oxidative stress, transforming growth factor (TGF-beta) pathway and the prevention of the transdifferentiation of hepatic stellate cells (HSC), leading to decreased collagen synthesis. Other effects include the inhibition of the mitogen activated protein kinase (MAPK), toll-like receptor (TLR) and TGF-beta non-canonical pathways, the inhibition of which further results in a strong reduction in ECM synthesis and deposition. In addition, naringenin has shown beneficial effects on nonalcoholic fatty liver disease (NAFLD) through the regulation of lipid metabolism, modulating the synthesis and oxidation of lipids and cholesterol. Moreover, naringenin protects from HCC, since it inhibits growth factors such as TGF-beta and vascular endothelial growth factor (VEGF), inducing apoptosis and regulating MAPK pathways. Naringenin is safe and acts by targeting multiple proteins. However, it possesses low bioavailability and high intestinal metabolism. In this regard, formulations, such as nanoparticles or liposomes, have been developed to improve naringenin bioavailability. We conclude that naringenin should be considered in the future as an important candidate in the treatment of different liver diseases. PMID- 29713126 TI - Naturally occurring hepatitis B virus reverse transcriptase mutations related to potential antiviral drug resistance and liver disease progression. AB - The annual number of deaths caused by hepatitis B virus (HBV)-related disease, including cirrhosis and hepatocellular carcinoma (HCC), is estimated as 887000. The reported prevalence of HBV reverse transcriptase (RT) mutation prior to treatment is varied and the impact of preexisting mutations on the treatment of naive patients remains controversial, and primarily depends on geographic factors, HBV genotypes, HBeAg serostatus, HBV viral loads, disease progression, intergenotypic recombination and co-infection with HIV. Different sensitivity of detection methodology used could also affect their prevalence results. Several genotype-dependent HBV RT positions that can affect the emergence of drug resistance have also been reported. Eight mutations in RT (rtL80I, rtD134N, rtN139K/T/H, rtY141F, rtM204I/V, rtF221Y, rtI224V, and rtM309K) are significantly associated with HCC progression. HBeAg-negative status, low viral load, and genotype C infection are significantly related to a higher frequency and prevalence of preexisting RT mutations. Preexisting mutations are most frequently found in the A-B interdomain of RT which overlaps with the HBsAg "a" determinant region, mutations of which can lead to simultaneous viral immune escape. In conclusion, the presence of baseline RT mutations can affect drug treatment outcomes and disease progression in HBV-infected populations via modulation of viral fitness and host-immune responses. PMID- 29713127 TI - Nucleotide-binding oligomerization domain 1 and Helicobacter pylori infection: A review. AB - Nucleotide-binding oligomerization domain 1 (NOD1) is an intracellular innate immune sensor for small molecules derived from bacterial cell components. NOD1 activation by its ligands leads to robust production of pro-inflammatory cytokines and chemokines by innate immune cells, thereby mediating mucosal host defense systems against microbes. Chronic gastric infection due to Helicobacter pylori (H. pylori) causes various upper gastrointestinal diseases, including atrophic gastritis, peptic ulcers, and gastric cancer. It is now generally accepted that detection of H. pylori by NOD1 expressed in gastric epithelial cells plays an indispensable role in mucosal host defense systems against this organism. Recent studies have revealed the molecular mechanism by which NOD1 activation caused by H. pylori infection is involved in the development of chronic gastritis and gastric cancer. In this review, we have discussed and summarized how sensing of H. pylori by NOD1 mediates the prevention of chronic gastritis and gastric cancer. PMID- 29713128 TI - Diversion colitis and pouchitis: A mini-review. AB - Diversion colitis is characterized by inflammation of the mucosa in the defunctioned segment of the colon after colostomy or ileostomy. Similar to diversion colitis, diversion pouchitis is an inflammatory disorder occurring in the ileal pouch, resulting from the exclusion of the fecal stream and a subsequent lack of nutrients from luminal bacteria. Although the vast majority of patients with surgically-diverted gastrointestinal tracts remain asymptomatic, it has been reported that diversion colitis and pouchitis might occur in almost all patients with diversion. Surgical closure of the stoma, with reestablishment of gut continuity, is the only curative intervention available for patients with diversion disease. Pharmacologic treatments using short-chain fatty acids, mesalamine, or corticosteroids are reportedly effective for those who are not candidates for surgical reestablishment; however, there are no established assessment criteria for determining the severity of diversion colitis, and no management strategies to date. Therefore, in this mini-review, we summarize and review various recently-reported treatments for diversion disease. We are hopeful that the information summarized here will assist physicians who treat patients with diversion colitis and pouchitis, leading to better case management. PMID- 29713129 TI - Nonalcoholic steatohepatitis severity is defined by a failure in compensatory antioxidant capacity in the setting of mitochondrial dysfunction. AB - AIM: To comprehensively evaluate mitochondrial (dys) function in preclinical models of nonalcoholic steatohepatitis (NASH). METHODS: We utilized two readily available mouse models of nonalcoholic fatty liver disease (NAFLD) with or without progressive fibrosis: Lepob/Lepob (ob/ob) and FATZO mice on high trans fat, high fructose and high cholesterol (AMLN) diet. Presence of NASH was assessed using immunohistochemical and pathological techniques, and gene expression profiling. Morphological features of mitochondria were assessed via transmission electron microscopy and immunofluorescence, and function was assessed by measuring oxidative capacity in primary hepatocytes, and respiratory control and proton leak in isolated mitochondria. Oxidative stress was measured by assessing activity and/or expression levels of Nrf1, Sod1, Sod2, catalase and 8-OHdG. RESULTS: When challenged with AMLN diet for 12 wk, ob/ob and FATZO mice developed steatohepatitis in the presence of obesity and hyperinsulinemia. NASH development was associated with hepatic mitochondrial abnormalities, similar to those previously observed in humans, including mitochondrial accumulation and increased proton leak. AMLN diet also resulted in increased numbers of fragmented mitochondria in both strains of mice. Despite similar mitochondrial phenotypes, we found that ob/ob mice developed more advanced hepatic fibrosis. Activity of superoxide dismutase (SOD) was increased in ob/ob AMLN mice, whereas FATZO mice displayed increased catalase activity, irrespective of diet. Furthermore, 8-OHdG, a marker of oxidative DNA damage, was significantly increased in ob/ob AMLN mice compared to FATZO AMLN mice. Therefore, antioxidant capacity reflected as the ratio of catalase:SOD activity was similar between FATZO and C57BL6J control mice, but significantly perturbed in ob/ob mice. CONCLUSION: Oxidative stress, and/or the capacity to compensate for increased oxidative stress, in the setting of mitochondrial dysfunction, is a key factor for development of hepatic injury and fibrosis in these mouse models. PMID- 29713130 TI - Mucosa repair mechanisms of Tong-Xie-Yao-Fang mediated by CRH-R2 in murine, dextran sulfate sodium-induced colitis. AB - AIM: To explore the significance of corticotropin-releasing hormone (CRH) receptor (R)2 in mucosal healing of dextran sulfate sodium (DSS)-induced colitis and the effect of Tong-Xie-Yao-Fang (TXYF) on CRH-R2 expression and regulation. METHODS: Ulcerative colitis was induced in mice by administration of 3% (w/v) DSS for 7 d. Once the model was established, mice were administered urocortin-2 (30 MUg/kg), a peptide which binds exclusively to CRH-R2, or various doses of aqueous TXYF extracts (2.8-11.2 g/kg), a CRH-R2 antagonist Astressin (Ast)2B (20 MUg/kg), Ast2B + Ucn2, or Ast2B with various doses of aqueous TXYF extracts for 9 d. Colonic mucosal permeability was then evaluated by measuring the fluorescence intensity in serum. The colitis disease activity index (DAI), histology, body weight loss and colon length were assessed to evaluate the condition of colitis. Terminal deoxynucleotidyl transferase dUTP nick-end labeling was used to detect apoptosis of the intestinal epithelial cells. The expression level of Ki-67 represented the proliferation of colonic epithelial cells and was detected by immunohistochemistry. The expression levels of inflammation cytokines IL-6, TNF alpha and CXCL-1 were examined in colon tissues using real-time PCR and ELISA kits. RESULTS: Compared with the DSS group, mice treated with the CRH-R2 antagonist Ast2B showed greater loss of body weight, shorter colon lengths (4.90 +/- 0.32 vs 6.21 +/- 0.34 cm, P < 0.05), and higher DAI (3.61 +/- 0.53 vs 2.42 +/ 0.32, P < 0.05) and histological scores (11.50 +/- 1.05 vs 8.33 +/- 1.03, P < 0.05). Additionally, the Ast2B group showed increased intestinal permeability (2.76 +/- 0.11 MUg/mL vs 1.47 +/- 0.11 MUg/mL, P < 0.001), improved secretion of inflammatory cytokines in colon tissue, and reduced colonic epithelial cell proliferation (4.97 +/- 4.25 vs 22.51 +/- 8.22, P < 0.05). Increased apoptosis (1422.39 +/- 90.71 vs 983.01 +/- 98.17, P < 0.001) was also demonstrated. The Ucn2 group demonstrated lower DAI (0.87 +/- 0.55 vs 2.42 +/- 0.32, P < 0.001) and histological scores (4.33 +/- 1.50 vs 8.33 +/- 1.03, P < 0.05). Diminished weight loss, longer colon length (9.58 +/- 0.62 vs 6.21 +/- 0.34 cm, P < 0.001), reduced intestinal permeability (0.75 +/- 0.07 vs 1.47 +/- 0.11 MUg/mL, P < 0.001), inhibited secretion of inflammatory cytokines in colon tissue and increased colonic epithelial cell proliferation (90.04 +/- 15.50 vs 22.51 +/- 8.22, P < 0.01) were all observed. Reduced apoptosis (149.55 +/- 21.68 vs 983.01 +/- 98.17, P < 0.05) was also observed. However, significant statistical differences in the results of the Ast2B group and Ast2B + Ucn2 group were observed. TXYF was also found to ameliorate symptoms of DSS-induced colitis in mice and to promote mucosal repair like Ucn2. There were significant differences between the Ast2B + TXYF groups and the TXYF groups. CONCLUSION: CRH-R2 activates the intestinal mucosal antiinflammatory response by regulating migration, proliferation and apoptosis of intestinal epithelial cells in colitis-induced mice, and plays an important antiinflammatory role. TXYF promotes mucosal repair in colitis mice by regulating CRH-R2. PMID- 29713131 TI - Sodium chloride exacerbates dextran sulfate sodium-induced colitis by tuning proinflammatory and antiinflammatory lamina propria mononuclear cells through p38/MAPK pathway in mice. AB - AIM: To investigate the influence of high salt on dextran sulfate sodium (DSS) induced colitis in mice and explore the underlying mechanisms of this effect. METHODS: DSS and NaCl were used to establish the proinflammatory animal model. We evaluated the colitis severity. Flow cytometry was employed for detecting the frequencies of Th1, macrophages and Tregs in spleen, mesenteric lymph node and lamina propria. The important role of macrophages in the promotion of DSS-induced colitis by NaCl was evaluated by depleting macrophages with clodronate liposomes. Activated peritoneal macrophages and lamina propria mononuclear cells (LPMCs) were stimulated with NaCl, and proteins were detected by western blotting. Cytokines and inflammation genes were analyzed by enzyme-linked immunosorbent assay and RT-PCR, respectively. RESULTS: The study findings indicate that NaCl up regulates the frequencies of CD11b+ macrophages and CD4+IFN-gamma+IL-17+ T cells in lamina propria in DSS-treated mice. CD3+CD4+CD25+Foxp3+ T cells, which can secrete high levels of IL-10 and TGF-beta, increase through feedback in NaCl- and DSS-treated mice. Furthermore, clodronate liposomes pretreatment significantly alleviated DSS-induced colitis, indicating that macrophages play a vital role in NaCl proinflammatory activity. NaCl aggravates peritoneal macrophage inflammation by promoting the expressions of interleukin (IL)-1, IL-6 and mouse inducible nitric oxide synthase. Specifically, high NaCl concentrations promote p38 phosphorylation in lipopolysaccharide- and IFN-gamma-activated LPMCs mediated by SGK1. CONCLUSION: Proinflammatory macrophages may play an essential role in the onset and development of NaCl-promoted inflammation in DSS-induced colitis. The underlining mechanism involves up-regulation of the p38/MAPK axis. PMID- 29713132 TI - High tacrolimus intra-patient variability is associated with graft rejection, and de novo donor-specific antibodies occurrence after liver transplantation. AB - AIM: To investigate the role of tacrolimus intra-patient variability (IPV) in adult liver-transplant recipients. METHODS: We retrospectively assessed tacrolimus variability in a cohort of liver-transplant recipients and analyzed its effect on the occurrence of graft rejection and de novo donor-specific antibodies (dnDSAs), as well as graft survival during the first 2 years posttransplantation. Between 02/08 and 06/2015, 116 patients that received tacrolimus plus mycophenolate mofetil (with or without steroids) were included. RESULTS: Twenty-two patients (18.5%) experienced at least one acute-rejection episode (BPAR). Predictive factors for a BPAR were a tacrolimus IPV of > 35% [OR = 3.07 95%CI (1.14-8.24), P = 0.03] or > 40% [OR = 4.16 (1.38-12.50), P = 0.01), and a tacrolimus trough level of < 5 ng/mL [OR=3.68 (1.3-10.4), P =0.014]. Thirteen patients (11.2%) developed at least one dnDSA during the follow-up. Tacrolimus IPV [coded as a continuous variable: OR = 1.1, 95%CI (1.0-1.12), P = 0.006] of > 35% [OR = 4.83, 95%CI (1.39-16.72), P = 0.01] and > 40% [OR = 9.73, 95%CI (2.65-35.76), P = 0.001] were identified as predictors to detect dnDSAs. IPV did not impact on patient- or graft-survival rates during the follow-up. CONCLUSION: Tacrolimus-IPV could be a useful tool to identify patients with a greater risk of graft rejection and of developing a de novo DSA after liver transplantation. PMID- 29713133 TI - Papillary fistulotomy vs conventional cannulation for endoscopic biliary access: A prospective randomized trial. AB - AIM: To compare the cannulation success, biochemical profile, and complications of the papillary fistulotomy technique vs catheter and guidewire standard access. METHODS: From July 2010 to May 2017, patients were prospectively randomized into two groups: Cannulation with a catheter and guidewire (Group I) and papillary fistulotomy (Group II). Amylase, lipase and C-reactive protein at T0, as well as 12 h and 24 h after endoscopic retrograde cholangiopancreatography, and complications (pancreatitis, bleeding, perforation) were recorded. RESULTS: We included 102 patients (66 females and 36 males, mean age 59.11 +/- 18.7 years). Group I and Group II had 51 patients each. The successful cannulation rates were 76.5% and 100%, respectively (P = 0.0002). Twelve patients (23.5%) in Group I had a difficult cannulation and underwent fistulotomy, which led to successful secondary biliary access (Failure Group). The complication rate was 13.7% (2 perforations and 5 mild pancreatitis) vs 2.0% (1 patient with perforation and pancreatitis) in Groups I and II, respectively (P = 0.0597). CONCLUSION: Papillary fistulotomy was more effective than guidewire cannulation, and it was associated with a lower profile of amylase and lipase. Complications were similar in both groups. PMID- 29713135 TI - Longitudinal Evaluation of the Role of Academic and Social Impairment and Parent Adolescent Conflict in the Development of Depression in Adolescents with ADHD. AB - Older adolescents with attention-deficit/hyperactivity disorder (ADHD) have a significantly increased likelihood of developing comorbid depression. It is important to evaluate factors during the early adolescent period that may contribute to this risk. A predominant theory is that impairment and failure experiences lead to the development of low-self efficacy and depression, and that parent and family factors also play a role. In a sample of 326 young adolescents with ADHD (Mage = 12), the present study evaluated whether parent-adolescent conflict mediated the association between social and academic impairment and the development of depression. This study builds upon prior work by evaluating these associations longitudinally and by using a multi-rater approach, including the parent, adolescent, and teacher perspectives. Social and academic impairment directly predicted depression controlling for baseline levels of depression and change in ADHD symptoms. The association between social impairment and depression was partially mediated by parent-adolescent conflict. Mediation through conflict was not found for academic impairment, and the association between academic impairment and depression was no longer significant when accounting for conflict. These findings highlight the importance of social impairment in the development of depression in adolescents with ADHD. Caregivers may play an important role in determining whether adolescents with ADHD internalize social impairment and failure experiences and develop depressive symptoms. Implications of these findings in terms of the importance of interventions focused on parent-adolescent conflict are discussed. PMID- 29713134 TI - Compared efficacy of preservation solutions on the outcome of liver transplantation: Meta-analysis. AB - AIM: To compare the effects of the four most commonly used preservation solutions on the outcome of liver transplantations. METHODS: A systematic literature search was performed using MEDLINE, Scopus, EMBASE and the Cochrane Library databases up to January 31st, 2017. The inclusion criteria were comparative, randomized controlled trials (RCTs) for deceased donor liver (DDL) allografts with adult and pediatric donors using the gold standard University of Wisconsin (UW) solution or histidine-tryptophan-ketoglutarate (HTK), Celsior (CS) and Institut Georges Lopez (IGL-1) solutions. Fifteen RCTs (1830 livers) were included; the primary outcomes were primary non-function (PNF) and one-year post-transplant graft survival (OGS 1). RESULTS: All trials were homogenous with respect to donor and recipient characteristics. There was no statistical difference in the incidence of PNF with the use of UW, HTK, CS and IGL-1 (RR = 0.02, 95%CI: 0.01-0.03, P = 0.356). Comparing OGS-1 also failed to reveal any difference between UW, HTK, CS and IGL 1 (RR = 0.80, 95%CI: 0.80-0.80, P = 0.369). Two trials demonstrated higher PNF levels for UW in comparison with the HTK group, and individual studies described higher rates of biliary complications where HTK and CS were used compared to the UW and IGL-1 solutions. However, the meta-analysis of the data did not prove a statistically significant difference: the UW, CS, HTK and IGL-1 solutions were associated with nearly equivalent outcomes. CONCLUSION: Alternative solutions for UW yield the same degree of safety and effectiveness for the preservation of DDLs, but further well-designed clinical trials are warranted. PMID- 29713136 TI - Parental Problem Drinking and Emerging Adult Problem Behavior: The Moderating Role of Parental Support. AB - This study examined the relationship between parental problem drinking (maternal and paternal) and emerging adult problem behaviors (alcohol use, drug use, and antisocial behavior). In addition, the moderating role of parental support (maternal and paternal) was explored. Data were drawn from a nationally representative sample of emerging adults (N = 600; Mage = 20.00, SD = 1.42; 50% women; 62% White). Results from regression analyses of survey data indicated that both maternal problem drinking and maternal support moderated the relationship between paternal problem drinking and emerging adult alcohol use. For drug use, there was a three-way interaction between paternal problem drinking, maternal problem drinking, and maternal support. The relationship between paternal problem drinking and drug use only was significant for those who reported high maternal problem drinking and low maternal support. For antisocial behavior, there were positive relationships between paternal problem drinking and antisocial behavior and between maternal problem drinking and antisocial behavior in contexts of varying levels of parental support. Findings highlight the potential for parental support to both buffer and enhance the adverse influence of parental problem drinking across varied contexts. PMID- 29713137 TI - Does Parent Training Format Affect Treatment Engagement? A Randomized Study of Families at Social Risk? AB - We examined whether parent engagement in parent training (PT) differed based on PT format (parent group-based with video versus mastery-based individual coaching with child) in an economically disadvantaged sample of families seeking behavioral treatment for their preschool children in an urban mental health clinic. Parents (N=159; 76.1% mothers, 69.8% African American, 73% low-income) were randomized to one of two interventions, Chicago Parent Program (parent group + video; CPP) or Parent Child Interaction Therapy (individualized mastery-based coaching; PCIT). Parent engagement indicators compared were PT attendance and completion rates, participation quality, and parent satisfaction. Risk factors predictive of PT attrition (parent depression, psychosocial adversity, child behavior problem severity, length of wait time to start PT) were also compared to determine whether they were more likely to affect engagement in one PT format versus the other. No significant differences were found in PT attendance or completion rates by format. Clinicians rated parents' engagement higher in PCIT than in CPP while satisfaction with PT was rated higher by parents in CPP compared to PCIT. Never attending PT was associated with more psychosocial adversity and externalizing behavior problems for CPP and with higher baseline depression for PCIT. Parents with more psychosocial adversities and higher baseline depression were less likely to complete PCIT. None of the risk factors differentiated CPP completers from non-completers. Delay to treatment start was longer for PCIT than CPP. Strengths and limitations of each PT format are discussed as they relate to the needs and realities of families living in urban poverty. PMID- 29713138 TI - Glaucoma therapy: preservative-free for all? AB - Preservatives used in topical glaucoma medications have a plethora of well described toxic effects on the ocular surface. Such ocular toxicity is manifest clinically as ocular surface disease (OSD) and has been confirmed in epidemiologic, prospective clinical trials and studies in which patients are switched from preservative-added to preservative-free topical therapy. Such toxicity has implications not only for tolerability, but also for adherence and persistence with therapy that is known to be poor in glaucoma. Glaucoma medication is now widely available in preservative-free formulations, and the question arises as to which patients should receive preservative-free glaucoma therapy in preference to preservative-added medication. A case can be made for several subpopulations of patients who might particularly benefit from preservative-free medication: patients with existing OSD, older patients, younger adult patients, female patients, pediatric and juvenile patients, patients who work in air-conditioned environments or who use electronic screens frequently, patients with medical risk factors for OSD, patients in whom trabecular surgery may become indicated in the future, contact lens users, perhaps patients with Asian ethnicity and patients with severe or treatment-refractory glaucoma. Whilst arguments could be made for selecting patients for preservative-free medication on the basis of their existing risk of OSD, collectively, these patients form a significant proportion of the glaucoma patient population as a whole and, in the absence of any cost premium or positive indication for preservative-added medication, preservative-free glaucoma medication for all patients seems an appropriate strategy. PMID- 29713139 TI - Foveal threshold and photoreceptor integrity for prediction of visual acuity after intravitreal aflibercept on age-related macular degeneration. AB - Purpose: To determine whether baseline foveal threshold and photoreceptor integrity can predict best-corrected visual acuity (BCVA) at 12 months after intravitreal aflibercept (IVA) therapy in eyes with neovascular age-related macular degeneration (AMD). Patients and methods: We evaluated 25 eyes of 25 patients with treatment-naive neovascular AMD who received IVA once a month for 3 months, followed by once every 2 months for 8 months. BCVA, integrity of the external limiting membrane (ELM) or the ellipsoid zone (EZ) of the photoreceptors, and retinal sensitivity were determined before (baseline) and at 6 and 12 months after initial IVA. The average threshold foveal sensitivity and mean deviation within the central 10 degrees were determined by Humphrey central 10-2 perimetry. Correlations between BCVA at 12 months and integrity of the ELM or EZ, foveal threshold, and mean deviation at each visit were determined. Results: At 12 months, BCVA improved significantly from 0.20+/-0.23 to 0.10+/ 0.22 logMAR (logarithm of the minimum angle of resolution) units, and foveal threshold and mean deviation improved significantly from 29.0+/-5.1 and -3.38+/ 3.10 dB to 32.6+/-3.2 and -1.64+/-2.10 dB, respectively (P=0.0009 and P=0.0021). At baseline, both foveal threshold and integrity of the ELM were significantly correlated with BCVA at 12 months (P=0.0428 and P=0.0275). Conclusion: These results indicate that both integrity of the ELM and foveal threshold at baseline can predict BCVA after treatment for neovascular AMD. There is a possibility that these parameters can predict the efficacy of IVA in each case. PMID- 29713140 TI - Better detection of Demodex mites by Loffler's alkaline methylene blue staining in patients with blepharitis. AB - Purpose: To determine whether the Loffler's alkaline methylene blue staining method is better than no staining in detecting Demodex mites in the eyelashes of patients with blepharitis. Materials and methods: Eyelashes were collected from 22 patients with blepharitis. The mean age of the patients was 82.5+/-6.2 years (+/- SD) with a range from 71 to 93 years. Eyelashes were epilated by forceps and placed individually on microscope slides. The number of Demodex mites was determined by conventional optical microscopy before and immediately after the addition of the methylene blue staining solution. Results: The mean Demodex count before the addition of the methylene blue solution was 2.9+/-2.9, and it was 4.4+/-3.9 after the addition of the methylene blue solution (P<0.01, Wilcoxon test). Conclusion: The methylene blue staining method is a simple and useful method in detecting the presence and quantifying the number of Demodex mites. We recommend the methylene blue staining method not only for the diagnosis of the presence of Demodex mites but also to evaluate the therapeutic effects of medications to eliminate the mite infestation. PMID- 29713141 TI - Risk factors for requirement of filtration surgery after vitrectomy in patients with proliferative diabetic retinopathy. AB - Purpose: We retrospectively reviewed patients with postoperative neovascular glaucoma (NVG) after vitrectomy for proliferative diabetic retinopathy to investigate how variables assessed before, during, and after vitrectomy are associated with the requirement for filtration surgery. Patients and methods: The subjects in this retrospective, observational, comparative study were 55 consecutive patients (61 eyes) who underwent vitrectomy for proliferative diabetic retinopathy at Toho University Sakura Medical Center between December 2011 and November 2016, were followed up for at least 6 months after surgery, and developed NVG within 2 years after surgery. They comprised 44 men and 11 women of mean age 52.4+/-9.1 years, who were followed up for a mean 7.1+/-6.1 months. We collected data on the following 16 variables: sex, age, history of panretinal photocoagulation completed within 3 months before vitrectomy, presence/absence of a lens, obvious iris/angle neovascularization, tractional retinal detachment, diabetic macular edema, vitreous hemorrhage, visual acuity and intraocular pressure before vitrectomy and at the onset of NVG, glycated hemoglobin, fasting blood glucose, estimated glomerular filtration rate, and use of intraoperative gas tamponade. Results: Logistic regression analysis with the backward elimination method identified preoperative fasting hyperglycemia (P=0.08), high intraocular pressure at the onset of NVG (P=0.04), and use of gas tamponade during vitrectomy (P=0.008) to be significant risk factors for requirement of filtration surgery. Conclusion: Preoperative fasting hyperglycemia, high intraocular pressure at the onset of NVG, and use of gas tamponade during vitrectomy predispose patients to require filtration surgery in the event of postoperative NVG. PMID- 29713142 TI - Ketamine ameliorates oxidative stress-induced apoptosis in experimental traumatic brain injury via the Nrf2 pathway. AB - Background: Ketamine can act as a multifunctional neuroprotective agent by inhibiting oxidative stress, cellular dysfunction, and apoptosis. Although it has been proven to be effective in various neurologic disorders, the mechanism of the treatment of traumatic brain injury (TBI) is not fully understood. The aim of this study was to investigate the neuroprotective function of ketamine in models of TBI and the potential role of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway in this putative protective effect. Materials and methods: Wild type male mice were randomly assigned to five groups: Sham group, Sham + ketamine group, TBI group, TBI + vehicle group, and TBI + ketamine group. Marmarou's weight drop model in mice was used to induce TBI, after which either ketamine or vehicle was administered via intraperitoneal injection. After 24 h, the brain samples were collected for analysis. Results: Ketamine significantly ameliorated secondary brain injury induced by TBI, including neurological deficits, brain water content, and neuronal apoptosis. In addition, the levels of malondialdehyde (MDA), glutathione peroxidase (GPx), and superoxide dismutase (SOD) were restored by the ketamine treatment. Western blotting and immunohistochemistry showed that ketamine significantly increased the level of Nrf2. Furthermore, administration of ketamine also induced the expression of Nrf2 pathway-related downstream factors, including hemeoxygenase-1 and quinine oxidoreductase-1, at the pre- and post-transcriptional levels. Conclusion: Ketamine exhibits neuroprotective effects by attenuating oxidative stress and apoptosis after TBI. Therefore, ketamine could be an effective therapeutic agent for the treatment of TBI. PMID- 29713143 TI - Population pharmacokinetics and dosing optimization of cefathiamidine in children with hematologic infection. AB - Purpose: Cefathiamidine, a first-generation cephalosporin, has approval from the China Food and Drug Administration for the treatment of infections caused by susceptible bacteria in both adults and children. As pharmacokinetic data are limited in the pediatric population, we aimed to evaluate the population pharmacokinetics of cefathiamidine in children and to define the appropriate dose in order to optimize cefathiamidine treatment. Methods: Blood samples were collected from children treated with cefathiamidine, and concentrations were quantified by high-performance liquid chromatography and tandem mass spectrometry. Population pharmacokinetic analysis was conducted using NONMEM software. Results: Fifty-four children (age range: 2.0-11.8 years) were included. Sparse pharmacokinetic samples (n=120) were available for analysis. A two compartment model with first-order elimination showed the best fit with the data. A covariate analysis identified that bodyweight had a significant impact on cefathiamidine pharmacokinetics. Monte Carlo simulation demonstrated that the currently used dosing regimen of 100 mg/kg/day q12h was associated with a high risk of underdosing in pediatric patients. To reach the target 70% fT>MIC, a dose of 100 mg/kg/day cefathiamidine q6h is required for effective treatment against Haemophilus influenzae. Conclusion: A population pharmacokinetics model of cefathiamidine in children with hematologic disease was established. A dosing regimen of 100 mg/kg/day cefathiamidine q6h should be used in clinical practice against H. influenza infections. PMID- 29713144 TI - Lymphoma-targeted treatment using a folic acid-decorated vincristine-loaded drug delivery system. AB - Purpose: B-cell lymphoma is the most frequently diagnosed lymphoid tumor. Folic acid (FA)-decorated systems were found to be preferentially internalized on the B cell lymphoma cell line which is reported to express the folate receptor. This study was designed to develop an FA-decorated vincristine (VCR)-loaded system for targeted lymphoma treatment. Methods: FA-decorated lipid was synthesized. VCR loaded lipid-polymer hybrid nanoparticles (LPNs) were fabricated. In vitro cell lines and an in vivo lymphoma animal model was used to evaluate the anti B-cell lymphoma effect. Results: FA-decorated, VCR-loaded LPNs (FA-VCR/LPNs) have shown a targeted effect in delivery to B-cell lymphoma cells. FA-VCR/LPNs also showed the highest anti-tumor effect in murine-bearing lymphoma xenografts. Conclusion: FA-VCR/LPNs can achieve targeted delivery of VCR, bring about an outstanding therapeutic effect to treat lymphoma, and also reduce the systemic toxicity. FA VCR/LPNs could be an excellent system for lymphoma therapy. PMID- 29713145 TI - Inhibition of ghrelin o-acyltransferase attenuated lipotoxicity by inducing autophagy via AMPK-mTOR pathway. AB - Background: Nonalcoholic fatty liver disease (NAFLD) has been considered the most commonly occurring chronic hepatopathy in the world. Ghrelin o-acyltransferase (GOAT) is an acylation enzyme which has an acylated position 3 serine on ghrelin. Recent investigation revealed that activated autophagy could attenuate liver steatosis. The aim of this study was to explore therapeutic roles that inhibit GOAT exerted in NAFLD, and its potential association with autophagy. Materials and methods: Human LO2 cells were pretreated with siRNA-GOAT to induce liver steatosis using free fatty acids (FFAs). A chronic NAFLD model was established by feeding male mice C57bl/6 with high-fat diet (HFD) for 56 days with GO-CoA-Tat administrated subcutaneously. Lipid droplets were identified by Oil Red O stains. Body weight (BW) of mice was measured every week. Autophagy, tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), serum biochemical indicators (glucose [Glu], total cholesterol [TC], triglyceride [TG], aspartate aminotransferase [AST], alanine aminotransferase [ALT]) and signaling pathway proteins of phosphorylated AMPK-mTOR were measured. Results: The TG contents of the FFA and HFD groups were decreased by the inhibition of GOAT. Among mice treated with GO-CoA-Tat and siRNA-GOAT, IL-6 and TNF-alpha concentrations were remarkably decreased. Indicators of liver injury such as ALT and AST were also remarkably decreased among mice treated with GO-CoA-Tat. Likewise, GO-CoA-Tat significantly reduced the BW of mice and serum TG, TC and Glu. Autophagy was induced along with reduced lipids in the cells of the FFA and HFD groups. The inhibition of GOAT upregulated autophagy via AMPK-mTOR restoration. Conclusion: These results indicate that the inhibition of GOAT attenuates lipotoxicity by autophagy stimulation via AMPK-mTOR restoration and offers innovative evidence for using GO-CoA-Tat or siRNA-GOAT in NAFLD clinically. PMID- 29713146 TI - Prehospital Index provides prognosis for hospitalized patients with acute trauma. AB - Objective: To evaluate the prognostic value of the Prehospital Index (PHI) for hospitalized patients with acute trauma. Materials and methods: PHI score and the Injury Severity Score (ISS) were determined in 1,802 hospitalized patients with acute trauma. Receiver-operator characteristic (ROC) curves were used to compare the PHI and ISS in subgroups, and corresponding prediction indicators were calculated. Results: There were significant differences in PHI score and ISS between the survival group and the death group (Z=2.674, P=0.007). The area under the ROC curve was 0.871 (95% CI 0.855-0.886) for PHI score and 0.792 (95% CI 0.773-0.811) for ISS. Optimal cutoff points to determine the risk of critical illness were PHI >=4 and ISS >=22. The sensitivity of the PHI was superior to the ISS (chi2=6.975, P=0.008), but the specificity and the accuracy of the PHI and ISS showed no significant difference (P>0.05). Conclusion: The PHI is valuable in prognostic prediction of hospitalized patients with acute trauma, and it is superior to the ISS. The PHI has such advantages as being simple in operation, easy to learn, capable of reflecting conditions timely and reliably, and suitable for dynamic evaluation and screening for critical patients with trauma. PMID- 29713147 TI - Effects of oral amino acid supplementation on Multidimensional Prognostic Index in hospitalized older patients: a multicenter randomized, double-blind, placebo controlled pilot study. AB - Background: It is not known whether amino acid supplementations may influence health status in hospitalized older acutely ill patients. Aim: The aim of this study was to determine whether nutritional supplementation with amino acids (Aminoglutam(r)) is associated with multidimensional improvement assessed with the Multidimensional Prognostic Index (MPI). Methods: In this randomized, double blind, placebo-controlled pilot clinical trial, 126 patients aged >=65 years were enrolled from 6 Italian geriatric wards. A multidimensional assessment to calculate the MPI was performed at baseline and after 4 weeks of treatment with nutritional supplementation (96 kcal, 12 g amino acids, 0.18 g fat, 11.6 g carbohydrate, and vitamins B1, B6, and C) or placebo administered twice a day. Logistic regression modeling was applied to determine the effect of treatment on the improvement of MPI (vs no-change/worsening), adjusting for gender, age, and MPI at baseline. Treatment's interactions with age, gender, and MPI at baseline were tested adding the appropriate interaction parameter in the regression models. Results: Of the 126 patients included, 117 patients (93%) completed the study. A significant improvement in the MPI score was detected in the overall population (mean difference post-pretreatment: -0.03, p=0.001), with no differences between active and placebo arms. Men in the amino acid supplementation group had a significantly higher rate of improvement in MPI (81%) compared to the placebo group (46%) (Fisher's exact test p=0.03). Adjusting for age, diagnosis, and MPI at baseline, amino acid treatment was shown to be associated with an improvement in MPI in men (OR=4.82, 95% confidence interval [CI]: 0.87-26.7) and not in women (OR=0.70, 95% CI: 0.27-1.81). The interaction effect between active treatment and gender was significant (p=0.04). Conclusion: A 4-week amino acid supplementation improved the MPI significantly in hospitalized older male patients but not in female patients. Further studies are needed to confirm the gender effect of amino acid supplementation on MPI in older patients. PMID- 29713148 TI - Association of prealbumin levels with contrast-induced acute kidney injury in elderly patients with elective percutaneous coronary intervention. AB - Purpose: Inflammatory factors play a critical role in contrast-induced acute kidney injury (CI-AKI). Prealbumin, a nutritional and inflammatory indicator, is a well-established predictor of short- and long-term outcomes in numerous clinical conditions. The current study investigated the association of pre procedural prealbumin levels with CI-AKI and long-term outcomes in geriatric patients after elective percutaneous coronary intervention (PCI). Patients and methods: A total of 558 patients aged>=75 years, who underwent elective PCI between January 2012 and December 2015, were selected for the current study. Pre procedural prealbumin levels were measured before PCI. Multivariable logistic regression and Cox proportional hazard regression analyses were performed to identify the independent risk factors for CI-AKI and long-term mortality. Results: Out of 558 patients, 54 developed CI-AKI. The optimal cutoff value of prealbumin for detecting CI-AKI was 185.5 mg/L with 62.7% sensitivity and 70.4% specificity based on the receiver operating characteristic analysis (C statistic=0.710; 95% confidence interval [CI] 0.673-0.751). Multivariable analysis demonstrated that prealbumin<=185.5 mg/L was significantly associated with CI-AKI (odds ratio [OR] 0.397; 95% CI 0.195-0.808; P=0.011). Cox regression analysis demonstrated that prealbumin<=185.5 mg/L was associated with long-term mortality (adjusted hazard ratio [HR] 0.525; 95% CI 0.289-0.952; P=0.034) during the follow-up. Conclusion: Pre-procedural levels of prealbumin were independently associated with an increased risk of CI-AKI and long-term mortality in elderly patients undergoing elective PCI. PMID- 29713149 TI - Reduced ejection fraction heart failure - new data from multicenter studies and national registries regarding general and elderly populations: hopes and disappointments. AB - The evaluation of patients diagnosed with impaired systolic function heart failure represents a great challenge, in both the general and elderly population. We consider that elderly patients are the most severely affected by this disease that represents the final impact of cardiovascular disease continuum. Cardiovascular diseases are associated with serious morbidity and mortality, and considerable health care costs related to diagnosis and treatment. In this report we discuss some controversies regarding methods of heart failure evaluation as well as therapeutic steps and devices, including: reparatory therapeutic steps and initiation of therapy with loop diuretics, inconsistent dose titration for angiotensin-converting enzyme inhibitors/angiotensin receptor blocker and beta blockers, as well as novel therapies, such as angiotensin receptor neprilysin inhibitor and treatments that directly improve cardiomyocyte function. We conclude that, beyond technical progress, which is raising the cost of therapy for patients with heart failure, more careful monitoring of patient progress through clinical and paraclinical control visits, both at medical facilities and at home, would have greater impact and be more cost-effective. Physical therapy and promoting emotional and psychological wellbeing, to maintain a positive state of mind, contribute substantially to the quality of life and life expectancy, and are most important in elderly people who are most affected by dramatic reductions in wellbeing. Unfortunately, for many patients with severe impairment of left ventricular ejection fraction, these goals and therapeutic procedures are often lacking in current health care systems. PMID- 29713151 TI - Design and implementation of an empowerment model to prevent elder abuse: a randomized controlled trial. AB - Background: Older adults are more vulnerable to health risks than younger people and may get exposed to various dangers, including elder abuse. This study aimed to design and implement an empowerment educational intervention to prevent elder abuse. Methods: This parallel randomized controlled trial was conducted in 2014 2016 for 18 months on 464 older adults aged above 60 years who visited health houses of 22 municipalities in Tehran. Data were collected using standard questionnaires, including the Elder Abuse-Knowledge Questionnaire, Health Promoting Behavior Questionnaire, Health-Promoting Lifestyle Profile II, Barriers to Healthy Lifestyle, Perceived Social Support, Perceived Self-Efficacy, Loneliness Scale, Geriatric Depression Scale, Multidimensional Health Locus of Control Scale, and the SCARED (stress, coping, argument, resources, events, and dependence) tool. The intervention was done in twenty 45- to 60-minute training sessions over 6 months. Data analysis were performed using chi2 tests, multiple linear and logistic regression, and structural equation modeling (SEM). Results: The frequency of knowledge of elder abuse, self-efficacy, social support and health promoting lifestyle before the intervention was similar in the two groups. However, the frequency of high knowledge of elder abuse (94.8% in the intervention group and 46.6% in the control group), high self-efficacy (82.8% and 7.8%, respectively), high social support (97.0% and 10.3%, respectively) and high health promoting lifestyle (97.0% and 10.3%, respectively) was significantly higher (P<0.001) and the frequency of elder abuse risk (28.0% and 49.6%, respectively) was significantly less in the intervention group after the intervention. SEM standardized beta (Sbeta) showed that the intervention had the highest impact on increase social support (Sbeta=0.80, beta=48.64, SE=1.70, P<0.05), self-efficacy (Sbeta=0.76, beta=13.32, SE=0.52, P<0.05) and health promoting behaviors (Sbeta=0.48, beta=33.08, SE=2.26, P<0.05), respectively. The effect of the intervention on decrease of elder abuse risk was indirect and significant (Sbeta=-0.406, beta=-0.340, SE=0.03, P<0.05), and through social support, self-efficacy, and health promoting behaviors. Conclusion: Educational interventions can be effective in preventing elder abuse. PMID- 29713150 TI - Review of antimicrobial use and considerations in the elderly population. AB - Pharmacologic management of infections in elderly patients presents multiple challenges to health care professionals due to variable pharmacokinetics, pharmacodynamics, and immune function. Age is a well-established risk factor for infection, but furthermore is a risk factor for prolonged length of hospital stay, increased incidence of complications, and significant and sustained decline in baseline functional status. In 2014, 46.2 million Americans were aged >=65 years, accounting for 14.5% of the total population. By 2033, for the first time, the population of persons aged >=65 years is projected to outnumber the people <18 years of age. According to the National Ambulatory Medical Care Survey and the National Hospital Ambulatory Medical Care Survey, 154 million prescriptions for antimicrobials were estimated to have been written in doctors' offices and emergency departments during a 1-year time period. In 2014, 266.1 million courses of antimicrobials were dispensed to outpatients by US community pharmacies. A study that evaluated 2007-2009 Medicare Part D data found that patients aged >=65 years used more antimicrobials, at 1.10 per person per year, compared to 0.88 antimicrobials used per person per year in patients aged 0-64 years. With the abundance of antimicrobial prescriptions and the current growth in the number and proportion of older adults in the US, it is essential that health care providers understand appropriate antimicrobial pharmacotherapy in the elderly patient. This review focuses on the use and implications of antimicrobial agents in the elderly population. PMID- 29713152 TI - Deep vein thrombosis in bilateral lower extremities after hip fracture: a retrospective study of 463 patients. AB - Objective: To investigate the incidences of deep vein thrombosis (DVT) before and after operation in inpatients with hip fractures in both lower extremities. Patients and methods: We collected the clinical data of 463 patients with lower extremities fractures who presented at Xi'an Honghui Hospital between July 1, 2014, and October 31, 2016 and met all the inclusion criteria. Doppler ultrasonography was used to diagnose DVT. The patients were examined preoperatively and postoperatively and divided into the thrombosis and non thrombosis group according to the ultrasonographic findings. We divided the DVT cases into central, peripheral, and mixed thromboses. Results: The incidence of preoperative DVT was 34.98%, and the prevalence of DVT on the uninjured side was 13.60%. This composition ratio increased to 57.23% postoperatively, and the prevalence of DVT on the uninjured side was 25.05%. Age (odds ratio [OR], 1.03; 95% CI: 1.01-1.04; P=0.002), venous thrombosis at admission (OR, 4.05; 95% CI, 2.30-7.13; P=0.000), and the days between the fracture and the operation (OR, 1.10; 95% CI, 1.02-1.20; P=0.020) were the independent risk factors of preoperative DVT. Coronary heart disease (OR, 1.85; 95% CI: 1.18-2.89; P=0.007), venous thrombosis at admission (OR, 22.35; 95% CI: 6.78-73.60; P=0.000), days between fracture and operation (OR, 1.06; 95% CI: 1.01-1.11; P=0.021), and blood loss (OR, 1.002; 95% CI: 1.000-1.003; P=0.014) were independent risk factors of postoperative DVT. Conclusion: The actual incidence of DVT after hip fracture may be underestimated. The incidences of preoperative and postoperative DVTs and the incidence of DVT on the uninjured limb were high. PMID- 29713153 TI - Long-term effects of oxygen-enriched high-flow nasal cannula treatment in COPD patients with chronic hypoxemic respiratory failure. AB - Background: This study investigated the long-term effects of humidified high-flow nasal cannula (HFNC) in COPD patients with chronic hypoxemic respiratory failure treated with long-term oxygen therapy (LTOT). Patients and methods: A total of 200 patients were randomized into usual care +/- HFNC. At inclusion, acute exacerbation of COPD (AECOPD) and hospital admissions 1 year before inclusion, modified Medical Research Council (mMRC) score, St George's Respiratory Questionnaire (SGRQ), forced expiratory volume in 1 second (FEV1), 6-minute walk test (6MWT) and arterial carbon dioxide (PaCO2) were recorded. Patients completed phone interviews at 1, 3 and 9 months assessing mMRC score and AECOPD since the last contact. At on-site visits (6 and 12 months), mMRC, number of AECOPD since last contact and SGRQ were registered and FEV1, FEV1%, PaCO2 and, at 12 months, 6MWT were reassessed. Hospital admissions during the study period were obtained from hospital records. Hours of the use of HFNC were retrieved from the high-flow device. Results: The average daily use of HFNC was 6 hours/day. The HFNC group had a lower AECOPD rate (3.12 versus 4.95/patient/year, p<0.001). Modeled hospital admission rates were 0.79 versus 1.39/patient/year for 12- versus 1 month use of HFNC, respectively (p<0.001). The HFNC group had improved mMRC scores from 3 months onward (p<0.001) and improved SGRQ at 6 and 12 months (p=0.002, p=0.033) and PaCO2 (p=0.005) and 6MWT (p=0.005) at 12 months. There was no difference in all-cause mortality. Conclusion: HFNC treatment reduced AECOPD, hospital admissions and symptoms in COPD patients with hypoxic failure. PMID- 29713154 TI - Prevalence of osteoarthritis in individuals with COPD: a systematic review. AB - The objective of this review was to examine the prevalence of osteoarthritis (OA) in individuals with COPD. A computer-based literature search of CINAHL, Medline, PsycINFO and Embase databases was performed. Studies reporting the prevalence of OA among a cohort of individuals with COPD were included. The sample size varied across the studies from 27 to 52,643 with a total number of 101,399 individuals with COPD recruited from different countries. The mean age ranged from 59 to 76 years. The prevalence rates of OA among individuals with COPD were calculated as weighted means. A total of 14 studies met the inclusion criteria with a prevalence ranging from 12% to 74% and an overall weighted mean of 35.5%. Our findings suggest that the prevalence of OA is high among individuals with COPD and should be considered when developing and applying interventions in this population. PMID- 29713155 TI - Bioinformatics-based identification of potential microRNA biomarkers in frequent and non-frequent exacerbators of COPD. AB - Objectives: MicroRNAs (miRNAs) play essential roles in the development of COPD. In this study, we aimed to identify and validate potential miRNA biomarkers in frequent and non-frequent exacerbators of COPD patients using bioinformatic analysis. Materials and methods: The candidate miRNA biomarkers in COPD were screened from Gene Expression Omnibus (GEO) dataset and identified using GEO2R online tool. Then, we performed bioinformatic analyses including target prediction, gene ontology (GO), pathway enrichment analysis and construction of protein-protein interaction (PPI) network. Furthermore, the expression of the identified miRNAs in peripheral blood monocular cells (PBMCs) of COPD patients was validated using quantitative real-time polymerase chain reaction (qRT-PCR). Results: MiR-23a, miR-25, miR-145 and miR-224 were identified to be significantly downregulated in COPD patients compared with healthy controls. GO analysis showed the four miRNAs involved in apoptotic, cell differentiation, cell proliferation and innate immune response. Pathway analysis showed that the targets of these miRNAs were associated with p53, TGF-beta, Wnt, VEGF and MAPK signal pathway. In healthy controls, the miR-25 and miR-224 levels were significantly decreased in smokers compared with nonsmokers (P<0.001 and P<0.05, respectively). In COPD patients, the levels of miR-23a, miR-25, miR-145 and miR-224 were associated with Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages. Notably, miR-23a and miR-145 were significantly elevated in non-frequent exacerbators compared with frequent exacerbators (P<0.05), and miR-23a showed higher area under the receiver-operator characteristic curve (AUROC) than miR-145 (0.707 vs 0.665, P<0.05). Conclusion: MiR-23a, miR-25, miR-145 and miR-224 were associated with the development of COPD, and miR-23a might be a potential biomarker for discriminating the frequent exacerbators from non-frequent exacerbators. PMID- 29713156 TI - Indacaterol/glycopyrronium reduces the risk of clinically important deterioration after direct switch from baseline therapies in patients with moderate COPD: a post hoc analysis of the CRYSTAL study. AB - Purpose: COPD is a progressive disease characterized by exacerbations and a decline in health status and lung function. Clinically important deterioration (CID) is a composite endpoint used to evaluate treatment efficacy. This analysis evaluated the impact of a direct switch to once-daily indacaterol/glycopyrronium 110/50 ug (IND/GLY) from previous monotherapy with a long-acting beta2-agonist (LABA) or long-acting muscarinic antagonist (LAMA) or with an LABA and an inhaled corticosteroid (LABA + ICS) on reducing CID. Methods: CRYSTAL was a 12-week, prospective, multicenter, randomized, open-label study conducted in clinical practice settings. Three definitions of CID (D1-D3) were used, including: 1) >=100 mL decrease in trough forced expiratory volume in 1 second (FEV1), 2) >=1 point decrease in transition dyspnea index (TDI) and/or >=0.4 points increase in clinical COPD questionnaire score (CCQ), or 3) an acute moderate/severe exacerbation (AECOPD). In D1 and D2, either TDI or CCQ was evaluated along with FEV1 and AECOPD, whereas in D3, all 4 parameters were included. ClinicalTrials.gov number: NCT01985334. Results: Of the 2,159 patients analyzed, 1,622 switched to IND/GLY and 537 continued their baseline treatments. The percentage of patients with a CID was significantly lower after a direct switch to IND/GLY versus LABA or LAMA using all 3 CID definitions (D1: odds ratio [OR] 0.41 [95% CI: 0.30-0.55]; D2: OR 0.41 [95% CI: 0.31-0.55]; D3: OR 0.39 [95% CI: 0.29-0.52]). Compared with LABA + ICS, IND/GLY also reduced the risk of CID (D1: OR 0.76 [95% CI: 0.56-1.02]; D2: OR 0.75 [95% CI: 0.56-1.00]; D3: OR 0.67 [95% CI: 0.51-0.89]). Conclusion: In this analysis, IND/GLY reduced the risk of a CID in moderate COPD patients after direct switch from LABA + ICS or LABA or LAMA in real-life clinical practice. PMID- 29713157 TI - Effectiveness of meditative movement on COPD: a systematic review and meta analysis. AB - Background: The effectiveness of meditative movement (tai chi, yoga, and qigong) on COPD remained unclear. We undertook a systematic review and meta-analysis to determine the effectiveness of meditative movement on COPD patients. Methods: We searched PubMed, Web of Science, EMBASE, and the Cochrane Center Register of Controlled Trials for relevant studies. The methods of standard meta-analysis were utilized for identifying relevant researches (until August 2017), quality appraisal, and synthesis. The primary outcomes were the 6-minute walking distance (6MWD), lung function, and dyspnea levels. Results: Sixteen studies involving 1,176 COPD patients were included. When comparing with the control group, the 6MWD was significantly enhanced in the treatment group (3 months: mean difference [MD]=25.40 m, 95% CI: 16.25 to 34.54; 6 months: MD=35.75 m, 95% CI: 22.23 to 49.27), as well as functions on forced expiratory volume in 1 s (FEV1) (3 months: MD=0.1L, 95% CI: 0.02 to 0.18; 6 months: MD=0.18L, 95% CI: 0.1 to 0.26), and FEV1 % predicted (3 months: 4L, 95% CI: 2.7 to 5.31; 6 months: MD=4.8L, 95% CI: 2.56 to 7.07). Quality of life for the group doing meditative movement was better than the control group based on the Chronic Respiratory Disease Questionnaire dyspnea score (MD=0.9 units, 95% CI: 0.51 to 1.29) and fatigue score (MD=0.75 units, 95% CI: 0.42 to 1.09) and the total score (MD=1.92 units, 95% CI: 0.54 to 3.31). Conclusion: Meditative movement may have the potential to enhance lung function and physical activity in COPD patients. More large-scale, well-designed, multicenter, randomized controlled trials should be launched to evaluate the long range effects of meditative movement. PMID- 29713158 TI - Heterogeneity of asthma and COPD overlap. AB - Background: Asthma and COPD are heterogeneous diseases. Patients with both disease features (asthma-COPD overlap [ACO]) are common. However, clinical characteristics and socio-economic burden of ACO are still controversial. The aim of this study was to identify the heterogeneity of ACO and to find out the subtypes with clinical impact among ACO subtypes. Methods: In the Korean National Health and Nutrition Examination Survey (KNHANES) conducted between 2007 and 2012, subjects who were >=40 years and had prebronchodilator FEV1/FVC <0.7 and FEV1 >=50% predicted were included. The presence or absence of self-reported wheezing was indicated by W+ or W- and used as an index of airway hyper responsiveness. S+/S- was defined as subjects who were smokers/never smokers. The subjects were divided into the following four groups: W-S-, W-S+, W+S-, and W+S+. W+S- and W+S+ were asthma-predominant ACO and COPD-predominant ACO, respectively. KNHANES and linked National Health Insurance data were analyzed. Results: The asthma-predominant ACO group showed the lowest socioeconomic status, FEV1, FVC% predicted, and quality of life (QoL) levels. The COPD-predominant ACO group showed the highest hospitalization rate, outpatient medical cost, and total and outpatient health care utilization. COPD-predominant ACO was associated with exacerbations compared to the W-S- group (adjusted odds ratio [aOR], 1.79; 95% confidence interval [CI], 1.12-2.85; P=0.015) and W-S+ group (OR 2.11; 95% CI 1.43-3.10; P<0.001). COPD-predominant ACO was associated with increased medical cost. Conclusion: Asthma-predominant ACO individuals displayed poorer socioeconomic status and QoL compared to the COPD-predominant ACO group. The COPD predominant ACO group displayed more frequent exacerbations and greater medical costs. Considering the heterogeneity of ACO, it is desirable to identify subtypes of ACO patients and appropriately allocate limited medical resources. PMID- 29713160 TI - Static and dynamic hyperinflation during severe acute exacerbations of chronic obstructive pulmonary disease. AB - Background: Static hyperinflation is known to be increased during moderate acute exacerbations of chronic obstructive pulmonary disease (COPD) (AECOPD), but few data exist in patients with severe exacerbations of COPD. The role of dynamic hyperinflation during exacerbations is unclear. Methods: In a prospective, observational cohort study, we recruited patients admitted to hospital for AECOPD. The following measurements were performed upon admission and again after resolution (stable state) at least 42 days later: inspiratory capacity (IC), body plethysmography, dynamic hyperinflation by metronome-paced IC measurement, health related quality of life and dyspnea. Results: Forty COPD patients were included of whom 28 attended follow-up. The IC was low at admission (2.05+/-0.11 L) and increased again during resolution by 15.6%+/-23.1% or 0.28+/-0.08 L (mean +/- standard error of the mean, p<0.01). Testing of metronome-paced changes in IC was feasible, and it decreased by 0.74+/-0.06 L at admission, similarly to at stable state. Clinical COPD Questionnaire score was 3.7+/-0.2 at admission and improved by 1.7+/-0.2 points (p<0.01), and the Borg dyspnea score improved by 2.2+/-0.5 points from 4.4+/-0.4 at admission (p<0.01). Conclusion: Static hyperinflation is increased during severe AECOPD requiring hospitalization compared with stable state. We could measure metronome-paced dynamic hyperinflation during severe AECOPD but found no increase. PMID- 29713159 TI - The impact of exposure to biomass smoke versus cigarette smoke on inflammatory markers and pulmonary function parameters in patients with chronic respiratory failure. AB - Purpose: The aim of this study was to evaluate the impact of exposure to biomass smoke vs cigarette smoke on serum inflammatory markers and pulmonary function parameters in patients with chronic respiratory failure (CRF). Patients and methods: A total of 106 patients with CRF divided into age and gender-matched groups of cigarette-smoke exposure (n=55, mean [SD] age: 71.0 [12.0] years, 92.7% were females) and biomass smoke exposure (n=51, mean [SD] age: 73.0 [11.0] years, 94.1% were females) were included in this retrospective study. Data on patient demographics (age and gender), inflammatory markers, including neutrophil-to lymphocyte ratio, C-reactive protein, platelet/mean platelet volume ratio, arterial blood gas analysis, and pulmonary function test findings, including forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV1/FVC were obtained from medical records. Results: Carbon dioxide partial pressure levels were significantly higher in the biomass smoke exposure than in the cigarette smoke exposure group (mean [SD] 51.0 [8.0] vs 47.0 [8.0] mmHg, p=0.026, respectively). Spirometry revealed similarly low levels for FEV1 (%) (38.0 [16.0] vs 40.0 [12.0]%) and FVC (%) (45.0 [19.0] vs 39.0 [19.0]%) in cigarette-smoke and biomass smoke exposure groups, whereas biomass smoke exposure was associated with significantly higher FEV1/FVC (75.0 [14.0] vs 58.0 [12.0]%, p=0.001), lower FVC (mL) (mean [SD] 744.0 [410.0] vs 1,063.0 [592.0] mL, p=0.035) and lower percentage of patients with FEV1/FVC <70% (36.8% vs 82.0%, p<0.001) than cigarette smoke exposure. Conclusion: Our findings indicate similarly increased inflammatory markers and abnormally low pulmonary function test findings in both biomass smoke exposure and cigarette smoke exposure groups, emphasizing the adverse effects of biomass smoke exposure on lungs to be as significant as cigarette smoke exposure. Association of biomass smoke exposure with higher likelihood of FEV1/FVC ratio of >70% and more prominent loss of vital capacity than cigarette smoke exposure seems to indicate the likelihood of at least 18 years of biomass exposure to be sufficiently high to be responsible for both obstructive and restrictive pulmonary diseases. PMID- 29713161 TI - Role of Au(NPs) in the enhanced response of Au(NPs)-decorated MWCNT electrochemical biosensor. AB - Background: The combination of Au-metallic-NPs and CNTs are a new class of hybrid nanomaterials for the development of electrochemical biosensor. Concentration of Au(nanoparticles [NPs]) in the electrochemical biosensor is crucial for the efficient charge transfer between the Au-NPs-MWCNTs modified electrode and electrolytic solution. Methods: In this work, the charge transfer kinetics in the glassy carbon electrode (GCE) modified with Au(NPs)-multiwalled carbon nanotube (MWCNT) nanohybrid with varied concentrations of Au(NPs) in the range 40-100 nM was studied using electrochemical impedance spectroscopy (EIS). Field emission scanning electron microscopy and transmission electron microscopy confirmed the attachment of Au(NPs) on the surface of MWCNTs. Results: The cyclic voltammetry and EIS results showed that the charge transfer mechanism was diffusion controlled and the rate of charge transfer was dependent on the concentration of Au(NPs) in the nanohybrid. The formation of spherical diffusion zone, which was dependent on the concentration of Au(NPs) in nanohybrids, was attributed to result in 3 times the increase in the charge transfer rate ks, 5 times increase in mass transfer, and 5% (9%) increase in Ipa (Ipc) observed in cyclic voltammetry in 80 nM Au(NP) nanohybrid-modified GCE from MWCNT-modified GCE. The work was extended to probe the effect of charge transfer rates at various concentrations of Au(NPs) in the nanohybrid-modified electrodes in the presence of Escherichia coli. The cyclic voltammetry results clearly showed the best results for 80 nM Au(NPs) in nanohybrid electrode. Conclusion: The present study suggested that the formation of spherical diffusion zone in nanohybrid-modified electrodes is critical for the enhanced electrochemical biosensing applications. PMID- 29713162 TI - miR-221 suppression through nanoparticle-based miRNA delivery system for hepatocellular carcinoma therapy and its diagnosis as a potential biomarker. AB - Background: MicroRNA-221(miR-221) is frequently dysregulated in cancer. The purpose of this study was to explore whether miR-221 can be used as a potential diagnostic marker or therapeutic target for hepatocellular carcinoma (HCC). Methods: In this study, we investigated whether miR-221 expression was associated with clini-copathological characteristics and prognosis in HCC patients, and we developed a nanoparticle-based miRNA delivery system and detected its therapeutic efficacy in vitro and in vivo. Results: We found that miR-221 was upregulated in HCC tissues, cell lines and blood of HCC patients. Upregulated miR-221 was associated with clinical TNM stage and tumor capsular infiltration, and showed poor prognosis, suggesting that its suppression could serve as an effective approach for hepatocellular carcinoma therapy. Treatment of HCC cells with nanoparticle/miR-221 inhibitor complexes suppressed their growth, colony formation ability, migration and invasion. In vivo, the growth of the tumors treated by the nanoparticle/miR-221 inhibitor complexes were significantly less than those treated by the nanoparticle/miRNA scramble complexes. In addition, circulating miR-221 may act as a potential tumor biomarker for early diagnosis of HCC, and combined serum miR-221 and AFP detection gave a better performance than individual detection in early diagnosis of HCC. Conclusion: These findings suggest that a nanoparticle-based miRNA delivery system could potentially serve as a safe and effective treatment and miR-221 could also be a potential diagnostic marker for HCC. PMID- 29713163 TI - Efficient gene transfection to the brain with ultrasound irradiation in mice using stabilized bubble lipopolyplexes prepared by the surface charge regulation method. AB - Introduction: We previously developed anionic ternary bubble lipopolyplexes, an ultrasound-responsive carrier, expecting safe and efficient gene transfection. However, bubble lipopolyplexes have a low capacity for echo gas (C3F8) encapsulation (EGE) in nonionic solution such as 5% glucose. On the other hand, we were able to prepare bubble lipopolyplexes by inserting phosphate-buffered saline before C3F8 encapsulation. Surface charge regulation (SCR) by electrolytes stabilizes liposome/plasmid DNA (pDNA) complexes by accelerated membrane fusion. Considering these facts, we hypothesized that SCR by electrolytes such as NaCl would promote C3F8 encapsulation in bubble lipopolyplexes mediated by accelerated membrane fusion. We defined this hypothesis as SCR-based EGE (SCR-EGE). Bubble lipopolyplexes prepared by the SCR-EGE method (SCR-EGE bubble lipopolyplexes) are expected to facilitate the gene transfection because of the high amount of C3F8. Therefore, we applied these methods for gene delivery to the brain and evaluated the characteristics of transgene expression in the brain. Methods: First, we measured the encapsulation efficiency of C3F8 in SCR-EGE bubble lipopolyplexes. Next, we applied these bubble lipopolyplexes to the mouse brain; then, we evaluated the transfection efficiency. Furthermore, three-dimensional transgene distribution was observed using multicolor deep imaging. Results: SCR-EGE bubble lipopolyplexes had a higher C3F8 content than conventional bubble lipopolyplexes. In terms of safety, SCR-EGE bubble lipopolyplexes possessed an anionic potential and showed no aggregation with erythrocytes. After applying SCR-EGE bubble lipopolyplexes to the brain, high transgene expression was observed by combining with ultrasound irradiation. As a result, transgene expression mediated by SCR EGE bubble lipopolyplexes was observed mainly on blood vessels and partially outside of blood vessels. Conclusion: The SCR-EGE method may promote C3F8 encapsulation in bubble lipopolyplexes, and SCR-EGE bubble lipopolyplexes may be potent carriers for efficient and safe gene transfection in the brain, especially to the blood vessels. PMID- 29713164 TI - Global trends in nanomedicine research on triple negative breast cancer: a bibliometric analysis. AB - Nanotechnology has emerged as a promising tool in the clinic to combat several difficult-to-manage diseases, such as cancer, which is the second leading cause of death worldwide. Chemotherapeutic drugs present several limitations such as undesired side effects, low specificity, resistance, and high relapse rates. Triple negative breast cancer (TNBC) is caused by cells that lack specific receptors in their membrane, such as estrogen (ER+) and progesterone (PR+) receptors, or by cells that do not express the amplification of human epidermal growth factor receptor-2 (HER-2+). This cancer type has poor prognosis, high relapse rates, and no targeted therapies. Thus, this study aimed to investigate the trends of nanotechnology research in TNBC and compare the contribution of research from different regions, institutions, and authors. A search of the studies published between 2012 and 2017, related to nanotechnology and TNBC, with different keyword combinations, was performed in the Scopus database. The keywords found in this search were grouped into four clusters, in which "breast cancer" was the most mentioned (1,133 times) and the word "MCF-7 cell line" is one of the latest hotspots that appeared in the year 2016. A total of 1,932 articles, which were cited 26,450 times, were identified. The USA accounted for 28.36% of the articles and 27.61% of the citations; however, none of its centers appeared in the list of 10 most productive ones in terms of publications. The journals Biomaterials and International Journal of Nanomedicine had the highest number of publications. The USA and China had the highest number of articles produced and cited; however, the highest average citation per article was from Singapore. The studies focused on the research of antineoplastic agents in animal models and cell culture, and these were the most used topics in research with nanotechnology and TNBC. PMID- 29713165 TI - Sensitive determination of dopamine levels via surface-enhanced Raman scattering of Ag nanoparticle dimers. AB - Background: Dopamine (DA) is an important neurotransmitter in the hypothalamus and pituitary gland, which can produce a direct influence on mammals' emotions in midbrain. Additionally, the level of DA is highly related with some important neurologic diseases such as schizophrenia, Parkinson, and Huntington's diseases, etc. In light of the important roles that DA plays in the disease modulation, it is of considerable significance to develop a sensitive and reproducible approach for monitoring DA. Purpose: The objective of this study was to develop an efficient approach to quantitatively monitor the level of DA using Ag nanoparticle (NP) dimers and enhanced Raman spectroscopy. Methods: Ag NP dimers were synthesized for the sensitive detection of DA via surface-enhanced Raman scattering (SERS). Citrate was used as both the capping agent of NPs and sensing agent to DA, which is self-assembled on the surface of Ag NP dimers by reacting with the surface carboxyl group to form a stable amide bond. To improve accuracy and precision, the multiplicative effects model for surface-enhanced Raman spectroscopy was utilized to analyze the SERS assays. Results: A low limits of detection (LOD) of 20 pM and a wide linear response range from 30 pM to 300 nM were obtained for DA quantitative detection. The SERS enhancement factor was theoretically valued at approximately 107 by discrete dipole approximation. DA was self-assembled on the citrate capped surface of Ag NPs dimers through the amide bond. The adsorption energy was estimated to be 256 KJ/mol using the Langmuir isotherm model. The density functional theory was used to simulate the spectral characteristics of SERS during the adsorption of DA on the surface of the Ag dimers. Furthermore, to improve the accuracy and precision of quantitative analysis of SERS assays with a multiplicative effects model for surface-enhanced Raman spectroscopy. Conclusion: A LOD of 20 pM DA-level was obtained, and the linear response ranged from 30 pM to 300 nM for quantitative DA detection. The absolute relative percentage error was 4.22% between the real and predicted DA concentrations. This detection scheme is expected to have good applications in the prevention and diagnosis of certain diseases caused by disorders in the DA level. PMID- 29713166 TI - In vivo antimicrobial activity of silver nanoparticles produced via a green chemistry synthesis using Acacia rigidula as a reducing and capping agent. AB - Introduction: One of the main issues in the medical field and clinical practice is the development of novel and effective treatments against infections caused by antibiotic-resistant bacteria. One avenue that has been approached to develop effective antimicrobials is the use of silver nanoparticles (Ag-NPs), since they have been found to exhibit an efficient and wide spectrum of antimicrobial properties. Among the main drawbacks of using Ag-NPs are their potential cytotoxicity against eukaryotic cells and the latent environmental toxicity of their synthesis methods. Therefore, diverse green synthesis methods, which involve the use of environmentally friendly plant extracts as reductive and capping agents, have become attractive to synthesize Ag-NPs that exhibit antimicrobial effects against resistant bacteria at concentrations below toxicity thresholds for eukaryotic cells. Purpose: In this study, we report a green one pot synthesis method that uses Acacia rigidula extract as a reducing and capping agent, to produce Ag-NPs with applications as therapeutic agents to treat infections in vivo. Materials and methods: The Ag-NPs were characterized using transmission electron microscopy (TEM), high-resolution TEM, selected area electron diffraction, energy-dispersive spectroscopy, ultraviolet-visible, and Fourier transform infrared. Results: We show that Ag-NPs are spherical with a narrow size distribution. The Ag-NPs show antimicrobial activities in vitro against Gram-negative (Escherichia coli, Pseudomonas aeruginosa, and a clinical multidrug-resistant strain of P. aeruginosa) and Gram-positive (Bacillus subtilis) bacteria. Moreover, antimicrobial effects of the Ag-NPs, against a resistant P. aeruginosa clinical strain, were tested in a murine skin infection model. The results demonstrate that the Ag-NPs reported in this work are capable of eradicating pathogenic resistant bacteria in an infection in vivo. In addition, skin, liver, and kidney damage profiles were monitored in the murine infection model, and the results demonstrate that Ag-NPs can be used safely as therapeutic agents in animal models. Conclusion: Together, these results suggest the potential use of Ag-NPs, synthesized by green chemistry methods, as therapeutic agents against infections caused by resistant and nonresistant strains. PMID- 29713167 TI - Characterization and evaluation of graphene oxide scaffold for periodontal wound healing of class II furcation defects in dog. AB - Introduction: The 3-dimensional scaffold plays a key role in volume and quality of repair tissue in periodontal tissue engineering therapy. We fabricated a novel 3D collagen scaffold containing carbon-based 2-dimensional layered material, named graphene oxide (GO). The aim of this study was to characterize and assess GO scaffold for periodontal tissue healing of class II furcation defects in dog. Materials and methods: GO scaffolds were prepared by coating the surface of a 3D collagen sponge scaffold with GO dispersion. Scaffolds were characterized using cytotoxicity and tissue reactivity tests. In addition, GO scaffold was implanted into dog class II furcation defects and periodontal healing was investigated at 4 weeks postsurgery. Results: GO scaffold exhibited low cytotoxicity and enhanced cellular ingrowth behavior and rat bone forming ability. In addition, GO scaffold stimulated healing of dog class II furcation defects. Periodontal attachment formation, including alveolar bone, periodontal ligament-like tissue, and cementum-like tissue, was significantly increased by GO scaffold implantation, compared with untreated scaffold. Conclusion: The results suggest that GO scaffold is biocompatible and possesses excellent bone and periodontal tissue formation ability. Therefore, GO scaffold would be beneficial for periodontal tissue engineering therapy. PMID- 29713168 TI - Curdlan sulfate-O-linked quaternized chitosan nanoparticles: potential adjuvants to improve the immunogenicity of exogenous antigens via intranasal vaccination. AB - Introduction: The development of ideal vaccine adjuvants for intranasal vaccination can provide convenience for many vaccinations. As an ideal intranasal vaccine adjuvant, it should have the properties of assisting soluble antigens to pass the mucosal barrier and potentiating both systemic and mucosal immunity via nasal administration. Methods: By using the advantages of polysaccharides, which can promote both T-helper 1 and 2 responses, curdlan sulfate (CS)-O-(2 hydroxyl)propyl-3-trimethyl ammonium chitosan chloride (O-HTCC) nanoparticles were prepared by interacting CS with O-HTCC, and the adjuvancy of the nanoparticles was investigated. Results: The results showed that the polysaccharide-based nanoparticles induced the proliferation and activation of antigen-presenting cells. High protein-loading efficiency was obtained by testing with the model antigen ovalbumin (Ova), and the Ova adsorbed onto the cationic CS/O-HTCC complexes was taken up easily by the epithelium. To evaluate the capacity of the Ova/CS/O-HTCC nanoparticles for immune enhancement in vivo, we collected and analyzed immunocytes, serum, and mucosal lavage fluid from intranasally vaccinated mice. The results showed that Ova/CS/O-HTCC nanoparticles induced activation and maturation of antigen-presenting cells and provoked the proliferation and differentiation of lymphocytes more significantly compared to the immunization of Ova mixed with aluminum hydroxide gel. Furthermore, CS/O-HTCC evoked a significantly higher level of Ova-specific antibodies. Conclusion: Therefore, these results suggest that CS/O-HTCC nanoparticles are ideal vaccine adjuvants for soluble antigens used in intranasal or mucosal vaccination. PMID- 29713169 TI - Colon-specific pulsatile drug release provided by electrospun shellac nanocoating on hydrophilic amorphous composites. AB - Background: Colon-specific pulsatile drug release, as a combined drug controlled release model, is a useful drug delivery manner for a series of diseases. New nanomedicines and related preparation methods are highly desired. Methods: With diclofenac sodium (DS) as a model drug, a new type of structural nanocomposite (SC), in which composite polyvinylpyrrolidone (PVP)-DS core was coated by shellac, was fabricated via modified coaxial electrospinning. For comparison, traditional PVP-DS monolithic hydrophilic nanocomposites (HCs) were generated using a traditional blending process. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), attenuated total reflectance-Fourier transform infrared (ATR-FTIR), water contact angle (WCA), and in vitro dissolution and ex vivo permeation tests were conducted to characterize the composites. Results: SEM images demonstrated that both composites were linear nanofibers with smooth surface morphology and cross sections. TEM disclosed that the SCs had a thin shellac sheath layer of approximately 12 nm. XRD and ATR-FTIR results demonstrated that the crystalline DS was converted into amorphous composites with PVP because of favorable secondary interactions. WCA and in vitro dissolution tests demonstrated that the sheath shellac layers in SC could resist acid conditions and provide typical colon-specific pulsatile release, rather than a pulsatile release of HC under acid conditions. Ex vivo permeation results demonstrated that the SCs were able to furnish a tenfold drug permeation rate than the DS particles on the colon membrane. Conclusion: A new SC with a shellac coating on hydrophilic amorphous nanocomposites could furnish a colon-specific pulsatile drug release profile. The modified coaxial process can be exploited as a useful tool to create nanocoatings. PMID- 29713170 TI - Metabolite-related antidepressant action of diterpene ginkgolides in the prefrontal cortex. AB - Purpose: Ginkgo biloba extract (GBE) contains diterpene ginkgolides (DGs), which have been shown to have neuroprotective effects by a number of previous studies. We previously demonstrated part of the action of DG. However, the impact of DG on the prefrontal cortex (PFC) remains unclear. Here, we evaluated the effects of DG and venlafaxine (for comparison) on behavioral and metabolite changes in the PFC using mice models and gas chromatography-mass spectrometry-based metabolomics. Materials and methods: Mice were randomly divided into control (saline), DG (12.18 mg/kg) and venlafaxine (16 mg/kg) groups. After 2 weeks of treatment, depression and anxiety-related behavioral tests were performed. Metabolic profiles of the PFC were detected by gas chromatography-mass spectrometry. Results: The DG group exhibited positive effects in the sucrose preference test. The differential metabolites were mainly related to amino acid metabolism, energy metabolism and lipid metabolism. The results indicated that the DG group exhibited perturbed lipid metabolism, molecular transport and small-molecule biochemistry in the PFC. Compared with the control group, pathway analysis indicated that venlafaxine and DG had similar effects on alanine, aspartate and glutamate metabolism. Conclusion: These findings demonstrate that DG has antidepressant-like, but not anxiolytic-like, effects in mice, suggesting that it might have therapeutic potential for the treatment of major depressive disorder. PMID- 29713171 TI - Does higher severity really correlate with a worse quality of life in obsessive compulsive disorder? A meta-regression. AB - Background: Obsessive-compulsive disorder (OCD) is one of the leading causes of disability and reduced quality of life (QOL), with impairment in a number of domains. However, there is a paucity of literature on the association between severity of OCD symptoms and QOL, and the data that do exist are inconsistent. In addition, the role of severity in QOL has not been summarized as yet from a cross generational perspective (ie, across childhood/adolescence and adulthood). Through meta-regression techniques, the current study summarized evidence about the moderator role of severity of OCD symptoms on differences in global QOL between individuals with OCD and controls. Methods: Online databases were searched, and cross-sectional case-control studies comparing participants of all ages with OCD with controls on self-report QOL measures were included. Random effect meta-regression techniques were used to comment on the role of illness severity in global QOL in individuals with OCD. Results: Thirteen studies were included. A positive significant association emerged between OCD severity and effect sizes on global QOL: in samples with higher severity, there were narrower differences in QOL between patients with OCD and controls than in samples with lower severity. Such positive association was confirmed by a sensitivity analysis conducted on studies including only adults, where the difference in QOL ratings between patients and controls was significantly narrower when OCD severity was higher. Conversely, a negative association between severity and QOL was found in those studies including only children/adolescents, where the difference in QOL was significantly larger between patients and controls when OCD severity was higher. Conclusion: QOL remains an important issue to address in the management of OCD in all age groups, irrespective of illness severity. Even in those with lower severity ratings, QOL may be considered as an important marker of treatment response. PMID- 29713172 TI - Gender-specific association of functional prodynorphin 68 bp repeats with cannabis exposure in an African American cohort. AB - Background: Cannabis use disorders (CUDs) cause substantial neuropsychiatric morbidity and comorbidity. There is evidence for gender-based differences in CUDs, for instance, a greater prevalence in males than in females. The main active component of cannabis is delta 9-tetrahydrocannabinol (delta 9-THC), a partial agonist of the cannabinoid type 1 receptor. Preclinical studies show that genetic or pharmacological manipulation of the kappa opioid receptor/dynorphin system modulates the effects of delta 9-THC. Methods: In this case-control study of adult African Americans (n=476; 206 females, 270 males), we examined the association of the functional prodynorphin 68 bp (PDYN 68 bp) promoter repeats with categorical diagnoses of cannabis dependence (Diagnostic and Statistical Manual of Mental Disorders-IV criteria), as well as with a rapid dimensional measure of maximum lifetime cannabis exposure (the Kreek-McHugh-Schluger-Kellogg cannabis scale). Results: The PDYN 68 bp genotype (examined as short-short [SS], short-long [SL], or long-long [LL], based on the number of repeats) was not significantly associated with categorical cannabis-dependence diagnoses, either in males or in females. However, in males, the PDYN 68 bp SS+SL genotype was associated with both greater odds of any use of cannabis (p<0.05) and earlier age of first cannabis use, compared to the LL genotype (ie, 15 versus 16.5 years of age; p<0.045). Males in the SS+SL group also had greater odds of high lifetime exposure to cannabis, compared to the LL group (p<0.045). Of interest, none of the aforementioned genetic associations were significant in females. Conclusion: This study provides the first data on how the PDYN 68 bp genotype is associated with gender-specific patterns of exposure to cannabis. Overall, this study shows that PDYN 68 bp polymorphisms affect behaviors involved in early stages of nonmedical cannabis use and potentially lead to increasing self-exposure. These data may eventually lead to improvements in personalized medicine for the prevention and treatment of highly prevalent CUDs and neuropsychiatric comorbidities. PMID- 29713173 TI - Significant association of BDNF rs6265 G>A polymorphism with susceptibility to epilepsy: a meta-analysis. AB - Introduction: Previously published articles have suggested that BDNF rs6265 G>A polymorphism is a potential risk factor for epilepsy. However, the results were not consistent. Methods: We conducted a meta-analysis to explore the association between BDNF rs6265 G>A polymorphism and epilepsy risk. Four online databases were searched, and related studies were reviewed from their inception up to June 20, 2017. ORs and corresponding 95% CIs were used to calculate the associations of each genetic model. Overall, 10 case-control publications involving 9,512 subjects were included in this meta-analysis. Results: Significant associations were found between BDNF rs6265 G>A polymorphism and epilepsy (A vs G: OR=0.88, 95% CI=0.83-0.94, P<0.01, I2=0%; GA vs GG: OR=0.88, 95% CI=0.79-0.97, P=0.01, I2=0%; AA vs GG: OR=0.79, 95% CI=0.70-0.90, P<0.01, I2=0%; GA+AA vs GG: OR=0.85, 95% CI=0.77-0.94, P<0.01, I2=0%; AA vs GG+GA: OR=0.85, 95% CI=0.76-0.95, P=0.01, I2=0%). Subgroup analysis also showed similar results in an Asian population. Conclusion: Our meta-analysis indicated that BDNF rs6265 G>A polymorphism might be involved in epilepsy susceptibility, especially in the Asian population. PMID- 29713174 TI - REAC neuromodulation treatments in subjects with severe socioeconomic and cultural hardship in the Brazilian state of Para: a family observational pilot study. AB - Purpose: The purpose of this preliminary observational study was to evaluate the usefulness of a humanitarian initiative, aimed at improving the neuropsychological and behavioral attitude of children with severe socioeconomic and cultural hardship, in the Brazilian state of Para. This humanitarian initiative was realized through the administration of two neuromodulation protocols, with radioelectric asymmetric conveyor (REAC) technology. During several years of clinical use, the REAC neuromodulation protocols have already proved to be effective in countering the effects of environmental stress on neuropsycho-physical functions. Patients and methods: After the preliminary medical examination, all subjects were investigated with the Strengths and Difficulties Questionnaire (SDQ), including the impact supplement with teacher's report. After the SDQ, they received the neuromodulation treatment with REAC technology named neuro postural optimization (NPO), to evaluate their responsiveness. Subsequently, every 3 months all subjects underwent a treatment cycle of neuropsycho-physical optimization (NPPO) with REAC technology, for a total of three cycles. At the end of the last REAC-NPPO treatment cycle, all subjects were investigated once again with the SDQ. For the adequacy of the data, the Wilcoxon and the Signs tests were used. For the subdivision into clusters, the Kruskal-Wallis test was applied for the adequacy of the procedure. For all the applied tests, a statistical significance of p<0.5 was found. Results: The results showed that the REAC-NPO and REAC-NPPO neuromodulation protocols are able to improve the quality of life, the scholastic and socialization skills, and the overall state of physical and mental health in children of a family with severe socioeconomic and cultural hardship. Conclusion: The REAC-NPO and REAC-NPPO neuromodulation protocols, due to their non-invasive characteristics, painlessness, and speed of administration, can be hypothesized as a treatment to improve the overall state of physical and mental health in a large number of people with socioeconomic and cultural discomfort. PMID- 29713175 TI - Electroconvulsive therapy in 77-year-old patient with pacemaker: a case report. AB - The treatment of a 77-year-old patient suffering from severe psychotic depression with a cardiac pacemaker is described. Because of treatment-resistant depression, electroconvulsive therapy (ECT) was introduced. In the course of ECT, there was a great improvement in his mental state without any cardiac complications. This case may be evidence for the safety and effectiveness of ECT in the elderly, even with cardiac comorbidities. Some recommendations for ECT in patients with pacemakers are discussed. PMID- 29713176 TI - Aberrant brain functional connectome in patients with obstructive sleep apnea. AB - Objective: Obstructive sleep apnea (OSA) is accompanied by widespread abnormal spontaneous regional activity related to cognitive deficits. However, little is known about the topological properties of the functional brain connectome of patients with OSA. This study aimed to use the graph theory approaches to investigate the topological properties and functional connectivity (FC) of the functional connectome in patients with OSA, based on resting-state functional magnetic resonance imaging (rs-fMRI). Methods: Forty-five male patients with newly diagnosed untreated severe OSA and 45 male good sleepers (GSs) underwent a polysomnography (PSG), clinical evaluations, and rs-fMRI scans. The automated anatomical labeling (AAL) atlas was used to construct the functional brain connectome. The topological organization and FC of brain functional networks in patients with OSA were characterized using graph theory methods and investigated the relationship between functional network topology and clinical variables. Results: Both the patients with OSA and the GSs exhibited high-efficiency "small world" network attributes. However, the patients with OSA exhibited decreased sigma, gamma, Eglob; increased Lp, lambda; and abnormal nodal centralities in several default-mode network (DMN), salience network (SN), and central executive network (CEN) regions. However, the patients with OSA exhibited abnormal functional connections between the DMN, SN, and CEN. The disrupted FC was significantly positive correlations with the global network metrics gamma and sigma. The global network metrics were significantly correlated with the Epworth Sleepiness Scale (ESS) score, Montreal Cognitive Assessment (MoCA) score, and oxygen desaturation index. Conclusion: The findings suggest that the functional connectome of patients with OSA exhibited disrupted functional integration and segregation, and functional disconnections of the DMN, SN, and CEN. The aberrant topological attributes may be associated with disrupted FC and cognitive functions. These topological abnormalities and disconnections might be potential biomarkers of cognitive impairments in patients with OSA. PMID- 29713177 TI - Total hip arthroplasty and cardiovascular complications: a review. AB - Most adverse events following total hip arthroplasty (THA) are uncommon and preventable or treated easily as expected. Adverse effects related to any major surgical procedure, including anesthesia, performing with other medical problems, drugs, and allergic reactions, might also occur. Potential cardiovascular complications are known to occur during or following THA and will be reviewed here. Complications can be categorized as myocardial infarction, cardiac arrest, thromboembolism, and so on. Special considerations in cardiovascular procedures are also reviewed in this paper. PMID- 29713178 TI - Safety study: is there a pathologic IGF-1, PDGF and TGF-beta cytokine expression caused by adjunct BMP-7 in tibial and femoral non-union therapy? AB - Background: In this prospective safety study, we investigated if the characteristic cytokine expression during bone regeneration is manipulated by the local application of bone morphogenetic protein-7 (BMP-7) in non-union surgery. Therefore, the levels of insulin like growth factor 1 (IGF-1), platelet-derived growth factor AB (PDGF-AB) and transforming growth factor beta (TGF-beta) were compared between patients with the gold standard use of autologous bone graft (ABG) and those with additional application of BMP-7 as part of the diamond concept. Patients and methods: Between 2009 and 2014, of the 153 patients with tibial and femoral non-unions, a matched pair analysis was performed to compare the serological cytokine expressions. Blood samples were collected preoperatively, 1, 2 and 6 weeks as well as 3 and 6 months after non-union surgery. Matching criteria were smoking status, fracture location, gender, age and body mass index (BMI). Patients in G1 (n=10) were treated with ABG and local BMP-7 while their matching partners in G2 (n=10) received ABG only. The routine clinical and radiologic follow-up was 1 year. Results: Although the IGF-1 quantification in G2 showed higher pre- and postoperative values compared to G1 (p<0.05), the courses of both groups were similar. Likewise, PDGF-AB and TGF-beta expressions appeared similar in G1 and G2 with peaks in both groups at 2 weeks follow-up. Osseous consolidation was assessed in all operated non-unions. The adjunct application of BMP-7 did not cause any pathologic cytokine expression. Conclusion: Similar expressions of the serum cytokines IGF-1, PDGF-AB and TGF beta were demonstrated in non-union patients treated with ABG and additional application of BMP-7 according to the diamond concept. Our findings indicate that the local application of BMP-7, which imitates the physiologic secretion of growth factors during bone regeneration, is safe and without the risk of abnormal systemic cytokine expression. Studies with higher patient numbers will have to validate these assumptions. PMID- 29713179 TI - Levodopa/carbidopa/entacapone versus levodopa/dopa-decarboxyiase inhibitor for the treatment of Parkinson's disease: systematic review, meta-analysis, and economic evaluation. AB - Aims: To review the evidence for efficacy, safety, and cost-effectiveness of levodopa/carbidopa/entacapone (LCE) compared with levodopa/dopa-decarboxyiase inhibitor (DDCI) for Parkinson's disease (PD). Methods: PubMed, Embase, the Cochrane Library, and Chinese databases WangFang Data, Chinese Sci-tech Journals Database and China National Knowledge Infrastructure, as well as ClinicalTrials.gov, were searched for randomized controlled trials with "levodopa/carbidopa/entacapone" as keywords. The search period was from inception to August 2017. We conducted meta-analyses to synthesize the evidence quantitatively. Results: A total of 5,693 records were obtained. We included seven randomized controlled trials and one cost-effectiveness study after the screening process. Compared with levodopa-DDCI, LCE improved patient Unified Parkinson's Disease Rating Scale (UPDRS) II score (mean difference [MD] -1.17, 95% CI -1.64 to -0.71), UPDRS III score (MD -1.55, 95% CI -2.29 to -0.81), and Schwab and England daily activity rating (MD 2.05, 95% CI 0.85-3.26). There was no statistically significant difference in the risk of serious adverse events (AEs) or discontinuation due to AEs in patients with LCE, and the risk of total AEs was higher in the LCE group (risk ratio [RR] 1.33, 95% CI 1.05-1.70). The incremental cost-effectiveness ratio of LCE was L3,105 per quality-adjusted life year (QALY) gained in the UK. Conclusion: LCE can improve PD patients' motor symptoms and daily living functioning when compared with levodopa/DDCI. PMID- 29713180 TI - Calcification score versus arterial stenosis grading: comparison of two CT-based methods for risk assessment of anastomotic leakage after esophagectomy and gastric pull-up. AB - Purpose: Anastomotic leakage is a major surgical complication following esophagectomy and gastric pull-up. Specific risk factors such as celiac trunk (TC) stenosis and high calcification score of the aorta have been identified, but no data are available on their relative prognostic values. This retrospective study aimed to compare and evaluate calcification score versus stenosis quantification with regards to prognostic impact on anastomotic leakage. Patients and methods: Preoperative contrast-enhanced computed tomography scans of 164 consecutive patients with primary esophageal cancer were evaluated by two radiologists to apply a calcification score (0-3 scale) assessing the aorta, the celiac axis and the right and left postceliac arteries. Concurrently, the presence and degree of stenosis of TC and superior mesenteric artery were recorded for stenosis quantification. Results: Anastomotic leakage was noted in 14/164 patients and 12/14 showed stenosis of TC (n=11). The presence of TC stenosis was found to have a significant impact on anastomotic healing (p=0.004). The odds ratio for the prediction of anastomotic leakage by the degree of stenosis was 1.04 (95% CI, 1.02-1.07). Ten of 14 patients had aortic calcification scores of 1 or 2, but calcification scores of the aorta, the celiac axis and the right and left postceliac arteries did not correlate with the corresponding TC stenosis values and showed no influence on patient outcome as defined by the occurrence of anastomotic insufficiency (p=0.565, 0.855, 0.518 and 1.000, respectively). Inter-reader reliability of computed tomography analysis and absolute agreement on calcium scoring was mostly over 90%. No significant differences in preoperative comorbidities and patient characteristics were found between those with and without anastomotic leakage. Conclusion: Measurement of TC stenosis in preoperative contrast-enhanced computed tomography scans proved to be more reliable than calcification scores in predicting anastomotic leakage and should, therefore, be used in the risk assessment of patients undergoing esophagectomy and gastric pull-up. PMID- 29713181 TI - Minodronate for the treatment of osteoporosis. AB - Minodronate is a third-generation bisphosphonate that was developed and approved for clinical use in osteoporosis therapy in Japan. The mechanism of action for suppressing bone resorption is the inhibition of farnesyl pyrophosphate synthase, a key enzyme in the mevalonic acid metabolic pathway of osteoclasts, to induce apoptosis of the cells. Minodronate is the strongest inhibitor of bone resorption among the currently available oral bisphosphonates. Large randomized, placebo controlled, double-blind clinical trials have revealed an increase in bone mineral density of both the lumbar spine and femoral neck over 3 years of daily minodronate therapy and risk reduction in vertebral fractures over 2 years of therapy. The increase in bone mass and the prevention of vertebral fractures are similar to those with alendronate or risedronate. The incidence of adverse events, especially gastrointestinal disturbance, is the same as or less than that with weekly or daily alendronate or risedronate. The unique mechanism of action of minodronate via the inhibition of the P2X(2/3) receptor compared with other bisphosphonates may be an advantage in reducing low back pain in patients with osteoporosis. The monthly regimen of minodronate, introduced in 2011, is expected to have better patient adherence and longer persistence. In experimental animal models, minodronate preserved, or even ameliorated, bone microarchitectures, including microcracks and perforation of the trabeculae in the short term. The lowest incidence of bisphosphonate-related osteonecrosis of the jaw among all bisphosphonates and the lack of atypical femoral fractures attributed to its use to date, however, are partly because only a smaller population used minodronate than those using other bisphosphonates. To date, minodronate is available only in Japan. Hip fracture risk reduction has not been verified yet. More clinical studies on minodronate and its use in osteoporosis treatment, with a large number of subjects, should be conducted to verify hip fracture risk reduction and long term results. PMID- 29713182 TI - Small ubiquitin-like modifier 1 modification of pyruvate kinase M2 promotes aerobic glycolysis and cell proliferation in A549 human lung cancer cells. AB - Objective: Lung cancer is the leading cause of cancer-related death worldwide. Aerobic glycolysis is considered the seventh hallmark of cancer. The M2 isoform of pyruvate kinase (PKM2) is an important rate-limiting enzyme in glycolytic pathway, and is strongly expressed in several types of cancer. Thus, understanding the underlying mechanisms of regulation of PKM2 is of great value for targeted therapy for lung cancer. Patients and methods: Seventy-three lung adenocarcinoma patients were analyzed in our study. The expression levels of PKM2 were analyzed by immunohistochemistry on tissues. The effect of small ubiquitin like modifier 1 (SUMO1) on PKM2 expression was investigated using Western blot assay and quantitative polymerase chain reaction. PKM2 SUMO1 modification was determined by in vitro and in vivo SUMOylation assays. 18F-deoxyglucose uptake and lactate production measurements were conducted to research the levels of glycolysis. The level of oxidative phosphorylation in cells was determined by cellular oxygen consumption rate measurements. Cell proliferation assays were carried out to confirm the growth ability of tumor cells. Results: PKM2 was overexpressed in lung adenocarcinoma patients based on immunohistochemical staining. Patients with high PKM2 expression had reduced overall survival rate (P=0.017) and disease-free survival rate (P=0.027) compared with those with low PKM2 expression. SUMO1 promoted PKM2-dependent glycolysis. Western blotting analysis showed that SUMO1 knockdown in A549 cells led to a significant decrease in PKM2 protein expression. PKM2 could be covalently modified by SUMO1 at K336 (Lys336) site. SUMO1 modification of PKM2 at Lys-336 site increased glycolysis and promoted its cofactor functions. Moreover, PKM2 SUMO1 modification promoted the proliferation of A549 cells in vitro. Conclusion: This information is important in elucidating a new mechanism of regulation of PKM2, and suggested that SUMO1 modification of PKM2 could be a potential therapeutic target in lung cancer. PMID- 29713183 TI - Multiple treatment modalities for brain metastasis in patients with EGFR-mutant non-small-cell lung cancer. AB - Background: There are many controversies concerning the best management of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer (NSCLC) patients with brain metastases (BMs). The use of upfront EGFR tyrosine kinase inhibitors (TKIs) and the withholding of local therapies or upfront radiation therapies (RTs) remain controversial. Available treatment options include local therapies such as whole-brain radiation therapy (WBRT), stereotactic radiosurgery (SRS) and surgery, EGFR-TKIs, and chemotherapy. However, the optimal management of combination therapies is still under consideration. Patients and methods: A total of 45 EGFR-mutated NSCLC patients with BMs were included. All patients successively received EGFR-TKIs, RT (WBRT or SRS), and chemotherapy between 2010 and 2015 at Zhejiang Cancer Hospital. Patient follow-up was conducted by telephone until February 2017. The treatment response was evaluated, and survival data were collected and analyzed by Kaplan-Meier analysis and the Cox regression method. Results: The median overall survival (OS) was 28 months. Patients with the exon 19 deletion showed the strongest trend toward a longer median OS compared to patients with the exon 21 L858R mutation (not reached vs 26.5 months, P=0.0969). There was no difference in OS between the upfront RT group and the deferral group (26.5 vs 28 months, P=0.57), and similar results were found between the first-line chemotherapy group and the EGFR-TKI group (28 vs 23.2 months, P=0.499). In multivariate analysis, the prognosis correlated with EGFR mutation type (P=0.017). Conclusion: EGFR-mutant NSCLC patients with BM benefited from the combination and sequential therapies of EGFR-TKIs, chemotherapy, and RTs. Patients with the EGFR exon 19 deletion may have a better OS. However, the optimal timing of RT interval remains to be explored. PMID- 29713184 TI - Prognostic and clinicopathological value of SIRT3 expression in various cancers: a systematic review and meta-analysis. AB - Background: Several studies have explored the prognostic value of sirtuin 3 (SIRT3) in various cancers, but obtained inconsistent results. The current systematic review and meta-analysis was conducted to investigate the association between SIRT3 expression and prognosis in various cancers. Methods: PubMed, Embase, Web of Science and the Cochrane Library were comprehensively retrieved by the end of September 29, 2017. All the relevant studies were checked and included in the meta-analysis if they met the inclusion criteria. Results: A total of 17 studies involving 2,865 patients were included in the systematic review and meta analysis. The results indicated that SIRT3 expression was not significantly associated with overall survival (OS) (hazard ratio [HR]=0.87, 95% CI=0.59-1.29, P=0.50) and disease-free survival (HR=0.87, 95% CI=0.57-1.31, P=0.50) in total various cancers. However, significant relationship between SIRT3 expression and OS in specific cancers was detected, including chronic lymphocytic leukemia (CLL) (HR=0.48, 95% CI=0.26-0.89, P=0.019), hepatocellular carcinoma (HCC) (HR=0.56, 95% CI=0.42-0.74, P<0.001), pancreatic carcinoma (PC) (HR=0.55, 95% CI=0.30-1.00, P=0.049), renal cell carcinoma (RCC) (HR=0.13, 95% CI=0.02-0.98, P=0.048), breast cancer (BC) (HR=2.53, 95% CI=1.83-3.67, P<0.001), colon cancer (CC) (HR=1.87, 95% CI=1.12-3.26, P=0.022) and non-small-cell lung cancer (NSCLC) (HR=2.20, 95% CI=1.38-3.50, P=0.001). Moreover, SIRT3 expression was obviously associated with tumor size (odds ratio [OR]=1.41, 95% CI=1.02-1.94, P=0.04), tumor differentiation (OR=1.52, 95% CI=1.08-2.16, P=0.02) and clinical stage (OR=2.07, 95% CI=1.23-3.46, P=0.01) in HCC. Conclusion: SIRT3 was distinctly related to the OS in specific cancers. SIRT3 was an unfavorable prognostic factor in BC, CC and NSCLC; however, it was also a favorable prognostic factor in CLL, HCC, PC and RCC, especially in HCC. PMID- 29713185 TI - Preoperative apolipoprotein B/apolipoprotein A1 ratio: a novel prognostic factor for gastric cancer. AB - Background: The correlations between lipid profile (lipid molecules and their derivative indexes) and clinical outcome have been widely testified in many carcinomas, but its prognostic value remains unknown in gastric cancer (GC). Our purpose in the study was to comprehensively evaluate the clinical significance of lipid profile in GC. Methods: We retrospectively collected clinical information of 1,201 GC patients who received surgery at Sun Yat-sen University Cancer Center from 2005 to 2010. Kaplan-Meier analysis and Cox proportional hazards regression model were performed to determine its prognostic significance. Results: Lipid profile including cholesterol, triglyceride, high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C), apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), LDL-C/HDL-C ratio, and ApoB/ApoA1 ratio were analyzed. For the first time, we found ApoB/ApoA1 ratio showed the biggest prognostic potency among all lipid-related variables and could act as an independent prognostic factor in GC. Patients with a high ApoB/ApoA1 ratio (>=1) had a shorter overall survival (hazard ratio: 1.373, 95% confidence interval: 1.123 1.68; P=0.002). Conclusion: Preoperative serum ApoB/ApoA1 ratio might be used as a novel prognostic indicator of GC. PMID- 29713186 TI - Overexpression of HDAC9 is associated with poor prognosis and tumor progression of breast cancer in Chinese females. AB - Background: Breast cancer represents a serious health issue among females. HDAC9 has been identified as an oncogene in human cancers. This study sought to assess the prognostic value and the biologic function of HDAC9 in breast cancer patients. Methods: Expression of HDAC9 in breast cancer tissues and cells was evaluated by quantitative real-time polymerase chain reaction. Kaplan-Meier survival analysis and Cox regression assay were conducted to explore the prognostic significance of HDAC9. Cell experiments were performed to investigate the effects of HDAC9 on the biologic behaviors of breast cancer cells. Results: Expression of HDAC9 was significantly upregulated in both cancerous tissues and cells compared with the normal controls (all P<0.05). Overexpression of HDAC9 was correlated with lymph node metastasis (P=0.021) and TNM stage (P=0.004). Patients with high HDAC9 had poor overall survival compared to those with low levels of HDAC9 (log-rank P<0.05). Elevated HDAC9 was found to be an independent prognostic factor for the patients (hazard ratio=2.996, 95% CI=1.611-5.572, P=0.001). According to the cell experiments, tumor cell proliferation, migration and invasion were suppressed by knockdown of HDAC9. Conclusion: All data demonstrated that overexpression of HDAC9 serves as a prognostic biomarker and may be involved in the tumor progression of breast cancer. PMID- 29713187 TI - The role of Hippo signal pathway in breast cancer metastasis. AB - The Hippo pathway is a novel and highly conserved mammalian signaling pathway. Mutations and altered expression of core Hippo pathway components promote the migration, invasion, malignancy, and chemotherapy resistance of breast cancer cells. In cancer metastasis, tumor cells must detach from the primary tumor, invade surrounding tissue, and enter and survive in a foreign microenvironment. The metastatic potential of breast cancer is closely related to individual patient genetic profile. Nevertheless, the exact molecular mechanism that regulates the Hippo pathway in breast cancer metastasis is yet to be fully elucidated. This article discusses the function and regulation of the Hippo pathway, with focus given to its role in the context of breast cancer metastasis. PMID- 29713188 TI - miR-30a suppresses osteosarcoma proliferation and metastasis by downregulating MEF2D expression. AB - Many studies have revealed that microRNAs (miRNAs) play crucial roles in cancer development and progression. miRNA-30a (miR-30a), as a member of the miR-30 family, has been implicated in various cancers. However, the role of miR-30a in osteosarcoma remains unclear. In the current study, we found that miR-30a was significantly downregulated in osteosarcoma tissues and cell lines by using quantitative real-time polymerase chain reaction (qRT-PCR). In addition, miR-30a could inhibit cancer cell growth, migration, and invasion in vitro. Furthermore, bioinformatics of miRNA target prediction and luciferase reporter assay indicated that MEF2D is a direct target of miR-30a. miR-30a was able to reduce the mRNA and protein expression of MEF2D as assessed using RT-PCR and Western blotting assay. Interestingly, overexpression of MEF2D partially reversed the miR-30a-reduced cell proliferation, migration, and invasion of osteosarcoma cell, indicating that miR-30a suppresses osteosarcoma cell proliferation and metastasis partially mediated by inhibition of MEF2D. Overall, our study demonstrated that miR-30a functions as a tumor suppressor by targeting MEF2D in osteosarcoma, providing a promising prognostic biomarker and a therapeutic strategy for osteosarcoma. PMID- 29713189 TI - miR-488 inhibits cell growth and metastasis in renal cell carcinoma by targeting HMGN5. AB - Purpose: microRNAs are thought to play crucial roles in tumorigenesis. Dysregulation of miR-488 has been implicated to be involved in several cancer progressions. However, the biological functions of miR-488 in renal cell carcinoma (RCC) remain unclear. This study aimed to explore the molecular mechanism underlying the role of miR-488 in RCC development. Materials and methods: The expression levels of miR-488 were detected in 38 paired RCC tumor samples and cell lines by quantitative real-time polymerase chain reaction method. miR-488 was upregulated by mimics transfection in RCC cell lines. MTT, colony formation, transwell assay, flow cytometry assay, and a xenograft model were performed to determine cell proliferation, invasion, migration, epithelial to-mesenchymal transition, and apoptosis in vitro and in vivo. Moreover, the potential target of miR-488 was verified by dual-luciferase reporter assay, quantitative real-time polymerase chain reaction, and Western blot. The correlation between miR-488 expression and its target gene expression was confirmed by Spearman's correlation analysis in 38 selected RCC tissue samples. Results: We found that miR-488 was remarkably downregulated in human RCC samples and cell lines compared with paired normal tissues and cell lines. Functional investigations revealed that overexpression of miR-488 significantly suppressed cell proliferation, invasion, and migration, and promoted cell apoptosis in RCC cells. Nucleosome binding protein 1 (high-mobility group nucleosome binding domain 5 [HMGN5]) was identified as a direct target of miR-488, and an inverse relationship was found between miR-488 expression and HMGN5 mRNA levels in RCC specimens. Rescue experiments suggested that restoration of HMGN5 partially abolished miR-488-mediated cell proliferation and invasion inhibition in RCC cells through regulating phosphatidylinositol 3-kinase/protein kinase B/the mammalian target of rapamycin and epithelial-to-mesenchymal transition signaling pathways. Conclusion: These data indicated that miR-488 acted as a tumor suppressor in RCC proliferation and invasion by targeting HMGN5, which might provide potential therapeutic biomarker for RCC patients. PMID- 29713190 TI - Recurrent candidal intertrigo: challenges and solutions. AB - Intertrigo is a common inflammatory dermatosis of opposing skin surfaces that can be caused by a variety of infectious agents, most notably candida, under the effect of mechanical and environmental factors. Symptoms such as pain and itching significantly decrease quality of life, leading to high morbidity. A multitude of predisposing factors, particularly obesity, diabetes mellitus, and immunosuppressive conditions facilitate both the occurrence and recurrence of the disease. The diagnosis of candidal intertrigo is usually based on clinical appearance. However, a range of laboratory studies from simple tests to advanced methods can be carried out to confirm the diagnosis. Such tests are especially useful in treatment-resistant or recurrent cases for establishing a differential diagnosis. The first and key step of management is identification and correction of predisposing factors. Patients should be encouraged to lose weight, followed up properly after endocrinologic treatment and intestinal colonization or periorificial infections should be medically managed, especially in recurrent and resistant cases. Medical treatment of candidal intertrigo usually requires topical administration of nystatin and azole group antifungals. In this context, it is also possible to use magistral remedies safely and effectively. In case of predisposing immunosuppressive conditions or generalized infections, novel systemic agents with higher potency may be required. PMID- 29713191 TI - Endoscopic comparison of gastroduodenal injury with over-the-counter doses of new fast-dissolving ibuprofen and paracetamol formulations: a randomized, placebo controlled, 4-way crossover clinical trial. AB - Background: While gastrointestinal (GI) effects of standard ibuprofen and N acetyl-p-aminophenol (APAP) have been reported, upper GI injury following treatment with fast-dissolving (FD) formulations of these analgesics has not been investigated. We evaluated upper GI effects of over-the-counter doses of 2 FD ibuprofen products and 1 FD-APAP product. Methods: In a randomized, placebo controlled, endoscopist-blinded, 4-way crossover study, 28 healthy subjects received FD ibuprofen 2*200 mg liquid capsules 3 times daily (TID), ibuprofen 2*200 mg tablets TID, FD-APAP 2*500 mg tablets 4 times daily (QID), and placebo 2*500 mg tablets QID for 7 days. The primary end point was gastric mucosal damage assessed by endoscopy using the Lanza scale: 0=normal stomach or proximal duodenum, 1=mucosal hemorrhages only, 2=1 or 2 erosions, 3=numerous (3-10) erosions, and 4=large number of erosions (>10) or ulcer. Secondary end points included duodenal mucosal damage (Lanza scale); gastroduodenal mucosal injury, classified as present (gastric and/or duodenal endoscopy score >=2) or absent (gastric and/or duodenal endoscopy score <2); and number of hemorrhages, erosions, and ulcers counted separately in the stomach and duodenum. Results: Significantly greater gastric mucosal injury was observed after treatment with both ibuprofen products vs FD-APAP (p<0.0001 and p=0.0095, respectively). FD-APAP showed no difference from placebo (p=0.4794). The odds of having an incidence of gastroduodenal mucosal injury were over 6 times greater from FD ibuprofen liquid capsule treatment (odds ratio [OR]=6.19, 95% confidence interval [CI]: 1.60, 23.97) and over 3 times greater from ibuprofen tablet treatment (OR=3.19, 95% CI: 0.8, 12.74) vs FD-APAP. Conclusion: Treatment with 2 ibuprofen products was associated with significant gastric mucosal injury. Of the 4 treatments studied, FD ibuprofen liquid capsules had the highest risk of incidence of gastroduodenal mucosal injury. Treatment with FD-APAP did not induce any clinically or statistically significant gastroduodenal mucosal injury. PMID- 29713193 TI - Supracondylar process syndrome: two cases of median nerve neuropathy due to compression by the ligament of Struthers. AB - The supracondylar process is a beak-shaped bony process on the anteromedial aspect of the distal humerus. The ligament of Struthers is a fibrous band extending from the tip of the process to the medial epicondyle. The median nerve and brachial artery pass under the ligament of Struthers and consequently can be compressed, causing supracondylar process syndrome. As a rare cause of proximal median nerve entrapment, supracondylar process syndrome is triggered when the median nerve is located in the superficial or deep layer of the ligament of Struthers as a result of anatomical variation. The supracondylar process can be easily detected on X-ray images obtained in oblique views but may not be identified in only anteroposterior or lateral views. In this article, we present 2 cases of supracondylar process syndrome and describe the process of diagnosis and treatment and results of a literature review. PMID- 29713192 TI - Reliability and validity of the Athens Insomnia Scale in chronic pain patients. AB - Purpose: To confirm the psychometric properties of the Athens Insomnia Scale (AIS) among Japanese chronic pain patients. Patients and methods: In total, 144 outpatients were asked to complete questionnaires comprising the AIS and other study measures. According to the original article, the AIS has 2 versions: the AIS-8 (full version) and the AIS-5 (brief version). To validate the AIS-8 and AIS 5 among chronic pain patients, we confirmed: 1) factor structure by confirmatory factor analysis; 2) internal consistency by Cronbach's a; 3) test-retest reliability using with interclass correlation coefficients; 4) known-group validity; 5) concurrent validity; and 6) cut-off values by receiver operating characteristic analysis. In addition, semi-structured interviews were conducted to assess the participants' sleep disturbance. If the participants had any sleep complaints, including difficulty in initiating sleep, difficulty in maintaining sleep, and early morning awakening, they were defined as insomnia symptoms. Results: A 2-factor model of the AIS-8 and 1-factor model of the AIS-5 demonstrated good fit. The AIS had adequate internal consistency and test-retest reliability. Patients with insomnia had a higher AIS score than those without insomnia. The sleep disturbance measured by the AIS was positively associated with pain intensity, disability, depression, anxiety, and pain catastrophizing, and negatively associated with pain-related self-efficacy. The cut-off values for detecting insomnia were estimated at 8 points in the AIS-8 and 4 points in the AIS-5. Conclusion: The AIS-8 and AIS-5 had adequate reliability and validity in chronic pain patients. PMID- 29713194 TI - A randomized, double-blind, placebo-controlled Phase III trial of duloxetine in Japanese patients with knee pain due to osteoarthritis. AB - Purpose: To examine the efficacy and safety of duloxetine in Japanese patients with knee pain due to osteoarthritis. Patients and methods: Patients were randomized to receive duloxetine 60 mg/day or placebo for 14 weeks in a double blind manner (ClinicalTrials.gov Identifier: NCT02248480). The primary efficacy endpoint was mean change in Brief Pain Inventory pain severity (BPI-Severity) average pain. Secondary endpoints included improvement in other BPI-Severity scales, Patient Global Impression of Improvement, Clinical Global Impressions of Severity, health-related quality of life (HRQoL) scales, range of motion of the knee joint, safety and tolerability, and structural changes on X-ray images. Results: Of the 354 randomized patients, 161 in the duloxetine group and 162 in the placebo group completed the study. BPI-Severity average pain improved significantly with duloxetine vs. placebo (-2.57 vs. -1.80; adjusted mean difference: -0.77; 95% CI: -1.11 to -0.43; P<0.0001). Secondary efficacy endpoints and most HRQoL scales showed greater improvements in the duloxetine group than the placebo group. Adverse events observed in >=5% of patients that were more frequent in the duloxetine than placebo group were somnolence, constipation, dry mouth, nausea, malaise, and decreased appetite. There were no marked changes in range of motion of the knee joint (efficacy), X-ray images, or Kellgren-Lawrence grade (safety) in either group. Conclusion: Duloxetine reduced pain and improved function in patients with knee osteoarthritis, without causing X-ray abnormalities or altered knee joint mobility. Reduced pain was associated with improved HRQoL. Adverse events were consistent with duloxetine's known safety profile. PMID- 29713195 TI - An integrated program with home blood-pressure monitoring and village health volunteers for treating poorly controlled hypertension at the primary care level in an urban community of Thailand. AB - Purpose: Hypertension (HT) is accountable for death in half of the patients suffering from heart disease and stroke. Many treatment strategies have been used, but little research exists on an integrated program with home blood pressure monitoring (HBPM) and village health volunteers (VHVs) in an urban area of Thailand. The present study aims to determine the effectiveness of the integrated program, HBPM, and VHVs in supporting the target population. Patients and methods: This quasi-experiment was conducted from July to November 2017. Patients with poorly controlled HT were randomly selected from each of the two primary care units in Nakhon Ratchasima, Thailand. The participants were separated into an experiment (n=63) and control group (n=65). The experiment group participated in the integrated program, which was based on the 20-item Health Literate Care Model. A valid and reliable questionnaire was used to collect data from participant interviews. Blood-pressure monitoring was used to measure systolic home blood pressure and diastolic home blood pressure. Descriptive statistics, chi-squared tests, Fisher's exact test, the independent t test, and the Wilcoxon-Mann-Whitney test were used to compare the baseline data. Multiple logistic regression was used to compare the differences between the mean changes in the outcomes. Results: At the end of the 3-month follow-up appointment, significant statistical changes were found. Systolic home blood pressure, diastolic home blood pressure, and body mass index changed -4.61 (95% CI -8.32, -0.90) mmHg (P-value=0.015), -3.5 (95% CI -5.31, -1.72) mmHg (P-value <0.001), and -0.86 (95% CI -1.29, -042) (P-value <0.001) respectively. Participant scores in lifestyle and management knowledge, and self-management behaviors significantly increased by 0.76 (95% CI 0.15-1.38) point (P value=0.016) and 0.15 (95% CI 0.06, 0.24) point (P-value=0.001), respectively. Conclusion: The integrated program, HBPM, and VHVs were effective in decreasing blood pressure and body mass index, and increasing knowledge and self-management behaviors among urban patients with poorly controlled HT. PMID- 29713197 TI - Effective prevention of sorafenib-induced hand-foot syndrome by dried-bonito broth. AB - Background: Sorafenib (SOR) is a molecular medicine that prolongs the survival of patients with hepatocellular carcinoma (HCC). Therefore, the management of side effects is essential for the longer period of continuous medication. Among the various side effects, hand-foot syndrome (HFS) is the most common, occurring in 30%-50% of patients, and often results in discontinuation of the SOR medication. However, its mechanism has not been clarified, and no effective prevention method has been reported for the symptoms. Therefore, this study aimed to analyze its mechanism and to develop an effective prevention regimen for the symptoms. Materials and methods: To assess the mechanism of SOR-induced HFS, the peripheral blood flow in the hand and foot was carefully monitored by Doppler ultrasound, thermography, and laser speckle flowgraphy in the cases treated with SOR and its contribution was assessed. Then, the effect of dried-bonito broth (DBB), which was reported to improve peripheral blood flow, on the prevention of the symptom was examined by monitoring its occurrence and the peripheral blood flow. Results: A total of 25 patients were enrolled in this study. In all, eight patients developed HFS, and all cases showed a significant decrease in the peripheral blood flow. DBB contributed to an increase in the flow (p = 0.009) and significantly decreased occurrence of HFS (p = 0.005) than control. Multivariable analysis showed that the ingestion of DBB is a significant independent contributor to HFS-free survival period (p = 0.035). Conclusion: The mechanism of SOR-induced HFS involves a decrease in the peripheral blood flow, and the ingestion of DBB effectively prevents the development of the syndrome by maintaining the flow. PMID- 29713196 TI - Identification of potential prognostic microRNA biomarkers for predicting survival in patients with hepatocellular carcinoma. AB - Background: The aim of the present study was to identify potential prognostic microRNA (miRNA) biomarkers for hepatocellular carcinoma (HCC) prognosis prediction based on a dataset from The Cancer Genome Atlas (TCGA). Materials and methods: A miRNA sequencing dataset and corresponding clinical parameters of HCC were obtained from TCGA. Genome-wide univariate Cox regression analysis was used to screen prognostic differentially expressed miRNAs (DEMs), and multivariable Cox regression analysis was used for prognostic signature construction. Comprehensive survival analysis was performed to evaluate the prognostic value of the prognostic signature. Results: Five miRNAs were regarded as prognostic DEMs and used for prognostic signature construction. The five-DEM prognostic signature performed well in prognosis prediction (adjusted P < 0.0001, adjusted hazard ratio = 2.249, 95% confidence interval =1.491-3.394), and time-dependent receiver operating characteristic (ROC) analysis showed an area under the curve (AUC) of 0.765, 0.745, 0.725, and 0.687 for 1-, 2-, 3-, and 5-year HCC overall survival (OS) prediction, respectively. Comprehensive survival analysis of the prognostic signature suggests that the risk score model could serve as an independent factor of HCC and perform better in prognosis prediction than other traditional clinical indicators. Functional assessment of the target genes of hsa-mir-139 and hsa-mir 5003 indicates that they were significantly enriched in multiple biological processes and pathways, including cell proliferation and cell migration regulation, pathways in cancer, and the cyclic adenosine monophosphate (cAMP) signaling pathway. Conclusion: Our study indicates that the novel miRNA expression signature may be a potential prognostic biomarker for HCC patients. PMID- 29713198 TI - Prognostic significance of preoperative serum albumin in epithelial ovarian cancer patients: a systematic review and dose-response meta-analysis of observational studies. AB - Purpose: To comprehensively assess the impact of preoperative serum albumin levels on survival of patients with epithelial ovarian cancer (EOC). Materials and methods: Two independent researchers searched the PubMed, Embase, and Web of Science databases to identify relevant studies from inception to October 20, 2017. The studies were independently reviewed and those deemed eligible were selected based on predetermined selection criteria. Summarized HRs and 95% CIs were calculated for overall survival (OS) with a profile likelihood random effects model. Results: Twelve cohort studies comprising 3884 EOC patients were included for analysis. Comparison of the highest vs the lowest categories of preoperative serum albumin yielded a summarized HR of 0.63 (95% CI=0.45-0.88, I2=88.8%). Although the results were robust in all subgroup analyses stratified by International Federation of Gynecology and Obstetrics (FIGO) stage, cutoff definition, geographical location, quality of study, number of EOC cases, followup time, and adjustments made for potential confounders, not all were statistically significant. Of note, dose-response analysis showed that for each 10 g/L increment in preoperative serum albumin level, the summary HR was 0.56 (95% CI=0.35-0.92, I2=78.6%). No evidence of publication bias was detected by funnel plot analysis and formal statistical tests. Sensitivity analyses showed no important differences in the estimates of effects. Conclusion: The present meta analysis suggests that preoperative serum albumin can be used as an independent prognostic predictor of OS in EOC patients. Since the included studies had high heterogeneity and retrospective designs, these results require further validation with prospective cohort trials enrolling larger patient populations with longer follow-up examinations. PMID- 29713199 TI - Severe mental illness and chronic kidney disease: a cross-sectional study in the United Kingdom. AB - Objective: We investigated the burden of chronic kidney disease (CKD) among patients with severe mental illness (SMI). Methods: We identified patients with SMI among all those aged 25-74 registered in the UK Clinical Practice Research Datalink as on March 31, 2014. We compared the prevalence of CKD (two measurements of estimated glomerular filtration rate <60 mL/min/1.73 m2 for >=3 months) and renal replacement therapy between patients with and without SMI. For patients with and without a history of lithium prescription separately, we used logistic regression to examine the association between SMI and CKD, adjusting for demographics, lifestyle characteristics, and known CKD risk factors. Results: The CKD prevalence was 14.6% among patients with SMI and a history of lithium prescription (n = 4,295), 3.3% among patients with SMI and no history of lithium prescription (n = 24,101), and 2.1% among patients without SMI (n = 2,387,988; P < 0.001). The prevalence of renal replacement therapy was 0.23%, 0.15%, and 0.11%, respectively (P = 0.012). Compared to patients without SMI, the fully adjusted odds ratio for CKD was 6.49 (95% CI 5.84-7.21) for patients with SMI and a history of lithium prescription and 1.45 (95% CI 1.34-1.58) for patients with SMI and no history of lithium prescription. The higher prevalence of CKD in patients with SMI may, in part, be explained by more frequent blood testing as compared to the general population. Conclusion: CKD is identified more commonly among patients with SMI than in the general population. PMID- 29713201 TI - Use of risk-adjusted CUSUM charts to monitor 30-day mortality in Danish hospitals. AB - Background: Monitoring hospital outcomes and clinical processes as a measure of clinical performance is an integral part of modern health care. The risk-adjusted cumulative sum (CUSUM) chart is a frequently used sequential analysis technique that can be implemented to monitor a wide range of different types of outcomes. Objective: The aim of this study was to describe how risk-adjusted CUSUM charts based on population-based nationwide medical registers were used to monitor 30 day mortality in Danish hospitals and to give an example on how alarms of increased hospital mortality from the charts can guide further in-depth analyses. Materials and methods: We used routinely collected administrative data from the Danish National Patient Registry and the Danish Civil Registration System to create risk-adjusted CUSUM charts. We monitored 30-day mortality after hospital admission with one of 77 selected diagnoses in 24 hospital units in Denmark in 2015. The charts were set to detect a 50% increase in 30-day mortality, and control limits were determined by simulations. Results: Among 1,085,576 hospital admissions, 441,352 admissions had one of the 77 selected diagnoses as their primary diagnosis and were included in the risk-adjusted CUSUM charts. The charts yielded a total of eight alarms of increased mortality. The median of the hospitals' estimated average time to detect a 50% increase in 30-day mortality was 50 days (interquartile interval, 43;54). In the selected example of an alarm, descriptive analyses indicated performance problems with 30-day mortality following hip fracture surgery and diagnosis of chronic obstructive pulmonary disease. Conclusion: The presented implementation of risk-adjusted CUSUM charts can detect significant increases in 30-day mortality within 2 months, on average, in most Danish hospitals. Together with descriptive analyses, it was possible to use an alarm from a risk-adjusted CUSUM chart to identify potential performance problems. PMID- 29713200 TI - The impact of moderate wine consumption on the risk of developing prostate cancer. AB - Objective: To investigate the impact of moderate wine consumption on the risk of prostate cancer (PCa). We focused on the differential effect of moderate consumption of red versus white wine. Design: This study was a meta-analysis that includes data from case-control and cohort studies. Materials and methods: A systematic search of Web of Science, Medline/PubMed, and Cochrane library was performed on December 1, 2017. Studies were deemed eligible if they assessed the risk of PCa due to red, white, or any wine using multivariable logistic regression analysis. We performed a formal meta-analysis for the risk of PCa according to moderate wine and wine type consumption (white or red). Heterogeneity between studies was assessed using Cochrane's Q test and I2 statistics. Publication bias was assessed using Egger's regression test. Results: A total of 930 abstracts and titles were initially identified. After removal of duplicates, reviews, and conference abstracts, 83 full-text original articles were screened. Seventeen studies (611,169 subjects) were included for final evaluation and fulfilled the inclusion criteria. In the case of moderate wine consumption: the pooled risk ratio (RR) for the risk of PCa was 0.98 (95% CI 0.92 1.05, p=0.57) in the multivariable analysis. Moderate white wine consumption increased the risk of PCa with a pooled RR of 1.26 (95% CI 1.10-1.43, p=0.001) in the multi-variable analysis. Meanwhile, moderate red wine consumption had a protective role reducing the risk by 12% (RR 0.88, 95% CI 0.78-0.999, p=0.047) in the multivariable analysis that comprised 222,447 subjects. Conclusions: In this meta-analysis, moderate wine consumption did not impact the risk of PCa. Interestingly, regarding the type of wine, moderate consumption of white wine increased the risk of PCa, whereas moderate consumption of red wine had a protective effect. Further analyses are needed to assess the differential molecular effect of white and red wine conferring their impact on PCa risk. PMID- 29713202 TI - Derivation and validation of a multivariable model to predict when primary care physicians prescribe antidepressants for indications other than depression. AB - Objective: Physicians commonly prescribe antidepressants for indications other than depression that are not evidence-based and need further evaluation. However, lack of routinely documented treatment indications for medications in administrative and medical databases creates a major barrier to evaluating antidepressant use for indications besides depression. Thus, the aim of this study was to derive a model to predict when primary care physicians prescribe antidepressants for indications other than depression and to identify important determinants of this prescribing practice. Methods: Prediction study using antidepressant prescriptions from January 2003-December 2012 in an indication based electronic prescribing system in Quebec, Canada. Patients were linked to demographic files, medical billings data, and hospital discharge summary data to create over 370 candidate predictors. The final prediction model was derived on a random 75% sample of the data using 3-fold cross-validation integrated within a score-based forward stepwise selection procedure. The performance of the final model was assessed in the remaining 25% of the data. Results: Among 73,576 antidepressant prescriptions, 32,405 (44.0%) were written for indications other than depression. Among 40 predictors in the final model, the most important covariates included the molecule name, the patient's education level, the physician's workload, the prescribed dose, and diagnostic codes for plausible indications recorded in the past year. The final model had good discrimination (concordance (c) statistic 0.815; 95% CI, 0.787-0.847) and good calibration (ratio of observed to expected events 0.986; 95% CI, 0.842-1.136). Conclusion: In the absence of documented treatment indications, researchers may be able to use health services data to accurately predict when primary care physicians prescribe antidepressants for indications other than depression. Our prediction model represents a valuable tool for enabling researchers to differentiate between antidepressant use for depression versus other indications, thus addressing a major barrier to performing pharmacovigilance research on antidepressants. PMID- 29713203 TI - Evaluating cardiac risk: exposure response analysis in early clinical drug development. AB - The assessment of a drug's cardiac liability has undergone considerable metamorphosis by regulators since International Council for Harmonization of Technical Requirement for Pharmaceuticals for Human Use E14 guideline was introduced in 2005. Drug developers now have a choice in how proarrhythmia risk can be evaluated; the options include a dedicated thorough QT (TQT) study or exposure response (ER) modeling of intensive electrocardiogram (ECG) captured in early clinical development. The alternative approach of ER modeling was incorporated into a guidance document in 2015 as a primary analysis tool which could be utilized in early phase dose escalation studies as an option to perform a dedicated TQT trial. This review will describe the current state of ER modeling of intensive ECG data collected during early clinical drug development; the requirements with regard to the use of a positive control; and address the challenges and opportunities of this alternative approach to assessing QT liability. PMID- 29713204 TI - Efficacy and patient satisfaction after NovaSure and Minerva endometrial ablation for treating abnormal uterine bleeding: a retrospective comparative study. AB - Objective: Compare amenorrhea rate, menstrual symptoms, patient satisfaction, and adverse events in women who underwent endometrial ablation with the NovaSure versus the Minerva radiofrequency ablation systems. Methods: We surveyed 189 premenopausal women (mean 40.8+/-6.2 years old) who underwent endometrial ablation for abnormal uterine bleeding using the NovaSure (n=97) or Minerva (n=92) systems, at four private US gynecology clinics, and whose procedure date was after July 2015 with follow-up >=3 months. Women were surveyed an average of 11.3+/-3.9 months (range 137-532 days) after ablation. Results: The subject reported amenorrhea rate was 52% higher in NovaSure subjects than Minerva subjects (64% and 42%, respectively; p=0.004). Age and bleeding cyclicity did not affect amenorrhea rate in either group. Normal-to-no bleeding was reported by >90% of subjects after either treatment. NovaSure was significantly more effective than Minerva at reducing pad/tampon use in women with any residual bleeding (2.4+/-5.2 items/day versus 4.7+/-5.5 items/day, p=0.049). NovaSure was significantly more effective than Minerva at reducing premenstrual syndrome (PMS) symptoms (p=0.019) and menstrual pain (p=0.003), and more NovaSure subjects (94%) than Minerva subjects (78%) were satisfied with clinical outcomes (p=0.003). Adverse events did not differ by treatment; three women in each group progressed to hysterectomy. Conclusion: While overall bleeding reduction in premenopausal women with abnormal uterine bleeding was excellent with either endometrial ablation system, NovaSure treatment resulted in a higher patient-reported 1-year amenorrhea rate, and women with residual bleeding used fewer pads and tampons than Minerva-treated women. Additionally, NovaSure subjects reported better menstrual-related life quality and PMS symptom alleviation, and greater satisfaction with outcomes than Minerva-treated women. PMID- 29713205 TI - Pessary use in stress urinary incontinence: a review of advantages, complications, patient satisfaction, and quality of life. AB - Stress urinary incontinnce (SUI) is a common condition among women. The usual approach to treatment of SUI is a stepwise plan from conservative to surgical procedures. A vaginal pessary is one of the commonly used conservative treatments that offer symptomatic improvement for women with incontinence. This review provides a critical analysis of the benefits and shortcomings offered by vaginal pessaries to patients affected by SUI, with a particular focus on indications, advantages, quality of life, patient satisfaction, and potential complications. To obtain the required information, an extensive search of PubMed and Cochrane databases was performed, covering the time frame from January 2000 to December 2016. We also surveyed the published guidelines of American Urological Association, Canadian Urological Association, American Urogynecological Society, National Institutes of Health (USA), and National Institute for Health and Care Excellence (UK). A total of 192 original research papers, review articles, and clinical trials were identified. The analysis of retrieved data provides evidence that vaginal pessaries constitute an effective nonsurgical option for SUI. The satisfaction rate with pessary use is high and only minor complications, if any, occur, vaginal discharge being the most common. The reviewed studies document that vaginal pessaries provide an adequate control of SUI if they are fit properly and managed by frequent replacements and regular checkups. They should be considered among the first line of treatment for SUI associated with exercise and increased intra-abdominal pressure. PMID- 29713206 TI - Antibacterial and antibiofouling clay nanotube-silicone composite. AB - Introduction: Invasive medical devices are used in treating millions of patients each day. Bacterial adherence to their surface is an early step in biofilm formation that may lead to infection, health complications, longer hospital stays, and death. Prevention of bacterial adherence and biofilm development continues to be a major healthcare challenge. Accordingly, there is a pressing need to improve the anti-microbial properties of medical devices. Materials and Methods: Polydimethylsiloxane (PDMS) was doped with halloysite nanotubes (HNTs), and the PDMS-HNT composite surfaces were coated with PDMS-b-polyethylene oxide (PEO) and antibacterials. The composite material properties were examined using SEM, energy dispersive spectroscopy, water contact angle measurements, tensile testing, UV-Vis spectroscopy, and thermal gravimetric analysis. The antibacterial potential of the PDMS-HNT composites was compared to commercial urinary catheters using cultures of E. coli and S. aureus. Fibrinogen adsorption studies were also performed on the PDMS-HNT-PEO composites. Results: HNT addition increased drug load during solvent swelling without reducing material strength. The hydrophilic properties provided by PEO were maintained after HNT addition, and the composites displayed protein-repelling properties. Additionally, composites showed superiority over commercial catheters at inhibiting bacterial growth. Conclusion: PDMS-HNT composites showed superiority regarding their efficacy at inhibiting bacterial growth, in comparison to commercial antibacterial catheters. Our data suggest that PDMS-HNT composites have potential as a coating material for anti bacterial invasive devices and in the prevention of institutional-acquired infections. PMID- 29713207 TI - Knowledge and practice of parents and guardians about childhood asthma at King Abdulaziz Medical City for National Guard, Riyadh, Saudi Arabia. AB - Background: Family management of asthmatic children is affected by several factors, primarily the parent's knowledge and attitude toward asthma. Objective: The aim of this study was to explore the knowledge and practice of parents and guardians about asthma in their children. Methods: Two hundred and thirty-one self-administered questionnaires were distributed to parents and guardians attending, with their children, general pediatric and pediatric pulmonology outpatient clinics at King Abdullah Specialist Children's Hospital, King Abdulaziz Medical City for National Guard, Riyadh, Saudi Arabia, during the period from August 2016 to March 2017. Results: Most of the participants (79.6%) have moderate knowledge. The mean of total knowledge was found to be higher among mothers compared with other groups (p=0.019). Most participants (88.3%) reported providing asthma treatment regularly and 61.9% visited the clinic regularly. Almost half of the participants have misconceptions about asthma medications. During acute asthma attacks, more than half of the participants (54.5%) massaged their child's chest or back, and 52.4% provided the child homemade or herbal remedies. Conclusion: This study revealed a moderate level of knowledge about asthma among the parents and guardians of asthmatic children, but poor knowledge about asthma medications. For better control of asthma, more effort is needed to educate caregivers and to enhance their awareness about asthma and highlight the misconceptions about asthma medications at both hospital level and community level. PMID- 29713208 TI - Educational needs of hematologists and laboratory professionals regarding factor activity assays. AB - Introduction: Diagnosis and management of hemophilia require accurate and precise measurements of factor activity levels. Activity is traditionally measured via one-stage (OS) clot-based assay; however, chromogenic substrate (CS) assays may be needed for certain cases. A survey was performed to understand assay-related knowledge gaps among hematologists and laboratory professionals. Methods: Separate web-based surveys were administered to hematologists who manage hemophilia and to laboratory professionals and queried practice patterns, knowledge of/attitudes toward CS assays, and interest in continuing education. Results: A total of 51 hematologists participated in this study; 67% managed hemophilia patients for >=10 years and 24% were affiliated with a hemophilia treatment center (HTC). Most (80%) stated familiarity with general assay interpretation. Majorities of non-HTC and HTC respondents agreed that CS assays are more accurate than OS assays (62%/67%), although non-HTC hematologists indicated less understanding of when to order a CS assay (49%/67%). Fewer non-HTC respondents expressed concerns regarding the reliability of OS assays for diagnosis (38%/67%) and monitoring (38%/75%). Most (80%) expressed an interest in factor assay education, especially on available assays, efficacy, and best practices (39%). A total of 57 laboratory professionals participated, averaging 10 years in their current position; most (88%) were hospital based. More performed OS (72%) than CS (10%) or both (17%) assays; only 11% reported confidence with the interpretation of CS results. Few expressed concerns regarding the reliability of OS for diagnosis (9%) or monitoring (12%). Reported barriers to CS use included infrequent need (68%), lack of US Food and Drug Administration (FDA) approval (61%), and need for validation work (56%). Most (70%) were interested in CS assay education; top interests included advantages over traditional assays, general information on CS assays, and indications for testing (each 18%). Conclusion: Future educational efforts may focus on limitations of OS assays, indications for CS assay diagnosis/monitoring, and support for clinic-laboratory dialog. PMID- 29713209 TI - Adoption of the American Academy of Pediatrics' neonatal hyperbilirubinemia guidelines and its effect on blood exchange transfusion rate in a tertiary care center in Amman, Jordan. AB - Introduction: Severe neonatal hyperbilirubinemia can cause mortality and serious morbidities. When phototherapy fails, neonates with severe hyperbilirubinemia should undergo double volume blood exchange transfusion (BET). As this procedure carries a significant risk of mortality and morbidity, adopting guidelines for the treatment of neonatal hyperbilirubinemia is critical to avoid hyperbilirubinemia toxicity and also the complication of an unindicated procedure. Methods: This study investigated the causes, complications, and trend of BET rate in our unit over a 13-year period. The medical charts and laboratory databases of all infants who underwent BET in Jordan University Hospital between 2003 and 2015 were retrospectively reviewed. Results: The rate of exchange cases decreased significantly after adopting the guidelines of American Academy of Pediatrics (P<0.0001). Most neonates were term newborns (69%). Average birth weight was 2,800 g. The most common causes of exchange transfusion were non hemolytic conditions. Late prematurity alone accounted for 20% of the cases. Thrombocytopenia was the most commonly encountered complication (33%). Chronic neurological complications were seen in 12% of those who were followed for >12 months of age. Conclusions: This study showed a clear decline in the rate of BET after implementing the guidelines of American Academy of Pediatrics. In addition to improving the strategies for the identification and follow-up of at-risk newborns, we should intensify our efforts to prevent the progression of neonatal hyperbilirubinemia to the exchange level by enhancing parents' awareness of this potentially harmful neonatal condition. PMID- 29713210 TI - Inotuzumab ozogamicin in the treatment of relapsed/refractory acute B cell lymphoblastic leukemia. AB - The improvement in outcomes of adult patients with acute lymphoblastic leukemia (ALL) has been modest, with the exception of Philadelphia chromosome-positive disease, despite advances in supportive care and stem cell transplantation. The recent approvals of novel agents, including the bispecific T-cell engager blinatumomab, the antibody-drug conjugate inotuzumab ozogamicin, and chimeric antigen receptor T-cell products are changing the management of B-ALL, which traditionally relied on chemotherapy-based approaches. Inotuzumab ozogamicin is a humanized CD22 monoclonal antibody linked to the cytotoxic agent calicheamicin. CD22 is expressed on leukemic blasts in >90% of ALL patients, and inotuzumab ozogamicin has shown excellent clinical activity even among heavily pretreated relapsed/refractory (R/R) B-ALL patients and elderly B-ALL patients. Clinical trials have shown superior survival with the drug over chemotherapy-based approaches in the first- or second-line salvage therapy for relapsed B-ALL as monotherapy. Currently, new trials are evaluating inotuzumab ozogamicin in the frontline setting in combination-based approaches. In this review, we summarize the preclinical and clinical data of inotuzumab ozogamicin in R/R B-ALL and foresee the future use of this drug in the clinic. PMID- 29713211 TI - Medical students' logbook case loads do not predict final exam scores in surgery clerkship. AB - Purpose: To investigate the reliability of medical student logbook data in assessing student performance and predicting outcomes in an objective standardized clinical exam and a multiplechoice exam during surgery rotation. In addition, we examined the relationship between exam performance and the number of clinical tutors per student. Materials and methods: A retrospective review of the logbooks of first and third clinical year medical students at the Faculty of Medicine, Kuwait University, was undertaken during their surgery rotation during the academic year 2012-2013. Results: Logbooks of 184 students were reviewed and analyzed. There were 92 and 93 students in the first and third clinical years, respectively. We did not identify any correlation between the number of clinical encounters and clinical exam or multiple-choice exam scores; however, there was an inverse relationship between the number of clinical tutors encountered during a rotation and clinical exam scores. Conclusion: Overall, there was no correlation between the volume of self-reported clinical encounters and exam scores. Furthermore, an inverse correlation between the number of clinical tutors encountered and clinical exam scores was detected. These findings indicate a need for reevaluation of the way logbook data are entered and used as an assessment tool. PMID- 29713212 TI - The impact of critical appraisal workshops on residents' evidence based medicine skills and knowledge. AB - Objective: To assess the impact of four evidence based medicine (EBM) critical appraisal education workshops in improving residents' EBM knowledge and skills. Methods: The eligible participants in the workshops were 88 residents-in training, postgraduate years one through four, rotating through the outpatient internal medicine clinic. Four EBM workshops, consisting of 3 days each (30 minutes daily), were taught by our faculty. Topics covered included critical appraisal of randomized controlled trials, case-control and cohort studies, diagnosis studies, and systematic reviews. Results: As a program evaluation, anonymous pre-workshop and post-workshop tests were administered. Each of the four sets of tests showed improvement in scores: therapy from 58% to 77% (42% response rate), harm from 65% to 73% (38% response rate), diagnosis from 49% to 68% (49% response rate), and systematic review from 57% to 72% (30% response rate). Conclusion: We found that teaching EBM in four short workshops improved EBM knowledge and critical appraisal skills related to the four topics. PMID- 29713213 TI - Announcement of New Section Editors. PMID- 29713214 TI - Single-Dose Gadoterate Meglumine for 3T Late Gadolinium Enhancement MRI for the Assessment of Chronic Myocardial Infarction: Intra-Individual Comparison with Conventional Double-Dose 1.5T MRI. AB - Objective: To intra-individually compare 3T magnetic resonance (MR) images obtained with one dose gadoterate meglumine to 1.5T MR using conventional double dose for assessment of chronic myocardial infarction. Materials and Methods: Sixteen patients diagnosed with chronic myocardial infarctions were examined on single-dose 3T MR within two weeks after undergoing double-dose 1.5T MR. Representative short-axis images were acquired at three points after administration of gadoterate meglumine. Contrast-to-noise ratios between infarcted and normal myocardium (CNRinfarct-normal) and between infarct and left ventricular cavity (CNRinfarct-LVC) were calculated and compared intra individually at each temporal scan. Additionally, two independent readers assessed relative infarct size semi-automatically and inter-observer reproducibility was evaluated using intraclass correlation coefficient. Results: While higher CNRinfarct-normal was revealed at single-dose 3T at only 10 minutes scan (p = 0.047), the CNRinfarct-LVC was higher at single-dose 3T MR at each temporal scan (all, p < 0.05). Measurement of relative infarct size was not significantly different between both examinations for both observers (all, p > 0.05). However, inter-observer reproducibility was higher at single-dose 3T MR (all, p < 0.05). Conclusion: Single-dose 3T MR is as effective as double-dose 1.5T MR for delineation of infarcted myocardium while being superior in detection of infarcted myocardium from the blood cavity, and provides better reproducibility for infarct size quantification. PMID- 29713215 TI - Magnetic Resonance Venography Findings of Obstructed Hepatic Veins and the Inferior Vena Cava in Patients with Budd-Chiari Syndrome. AB - Objective: This study aimed to illustrate the magnetic resonance venography (MRV) manifestations of obstructed hepatic veins (HVs), the inferior vena cava (IVC), and accessory hepatic veins (AHVs) in patients with Budd-Chiari syndrome (BCS) and to evaluate the visualization capacity of MRV in the diagnosis of BCS. Materials and Methods: Fifty-two patients with chronic BCS were included in this study. All patients were examined via MRV performed with a 3T system following injections of gadolinium-diethylene triamine pentaacetic acid (Gd-DTPA) or Gd ethoxibenzyl-DTPA. HV and IVC lesions were classified, and their characteristics were described. HV cord-like occlusions detected via MRV were compared using ultrasonography (US). Digital subtraction angiography (DSA) was performed as a contrast in the MRV detection of IVC lesions. The HVs draining collaterals, mainly AHVs, were carefully observed. HV lesions were classified as segmental stenosis, segmental occlusion, membranous stenosis, membranous occlusion, cord like occlusion, or non-visualized. Except for patent IVCs, IVC lesions were classified as segmental occlusion, segmental stenosis, membranous occlusion, membranous stenosis, and hepatomegaly-induced stenosis. Results: All patients (52/52, 100%) showed HV lesions of different degrees. MRV was inferior to US in detecting cord-like occlusions (6 vs. 19, chi2 = 11.077, p < 0.001). Dilated AHVs, including 50 (50/52, 96.2%) caudate lobe veins and 37 (37/52, 71.2%) inferior HV and AHV lesions, were well-detected. There were no significant differences in detecting segmental lesions and thrombosis between MRV and DSA (chi2 = 0.000, p1 = 1.000, p2 = 1.000). The capacity of MRV to detect membranous lesions was inferior to that of DSA (7 vs. 15, chi2 = 6.125, p = 0.013). Conclusion: In patients with BCS, MRV can clearly display the lesions in HVs and the IVC, as well as in AHVs, and it has diagnostic and therapeutic value. PMID- 29713216 TI - Diffusion-Weighted Imaging of Upper Abdominal Organs Acquired with Multiple B Value Combinations: Value of Normalization Using Spleen as the Reference Organ. AB - Objective: To compare apparent diffusion coefficient (ADC) of the upper abdominal organs acquired with multiple b-value combinations and to investigate usefulness of normalization. Materials and Methods: We retrospectively analyzed data, including 3T diffusion-weighted images, of 100 patients (56 men, 44 women; mean age, 63.9) that underwent liver magnetic resonance imaging. An ADC map was derived with the following six b-value combinations: b1 = 0, 50, 400, 800; b2 = 0, 800; b3 = 0, 50, 800; b4 = 0, 400, 800; b5 = 50, 800; and b6 = 50, 400, 800 s/mm2. ADC values of the right liver lobe, left liver lobe, spleen, pancreas, right kidney, and left kidney were measured. ADC values of the spleen were used for normalization. Intraclass correlation coefficients (ICCs), comparison of dependent ICCs, and repeated-measures analysis of variance were used for statistical analysis. Results: Intraclass correlation coefficients of the original ADC revealed moderate to substantial agreement (0.5145-0.6509), while normalized ADCs revealed almost perfect agreement (0.8014-0.8569). ICC of normalized ADC for all anatomical regions revealed significantly less variability than that of the original ADC (p < 0.05). Coefficient of variance for normalized ADC was significantly lower than that for the original ADC (3.0.3.8% vs. 4.8.8.8%, p < 0.05). Conclusion: Normalization of the ADC values of the upper abdominal organs using the spleen as the reference organ significantly decreased variability in ADC measurement acquired with multiple b-value combinations. PMID- 29713217 TI - Pelvic MRI: Is Endovaginal or Rectal Filling Needed? AB - Magnetic resonance imaging is the optimal modality for pelvic imaging. It is based on T2-weighted magnetic resonance (MR) sequences allowing uterine and vaginal cavity assessment as well as rectal evaluation. Anatomical depiction of these structures may benefit from distension, and conditions either developing inside the lumen of cavities or coming from the outside may then be better delineated and localized. The need for distension, either rectal or vaginal, and the way to conduct it are matters of debate, depending on indication for which the MR examination is being conducted. In this review, we discuss advantages and potential drawbacks of this technique, based on literature and our experience, in the evaluation of various gynecological and rectal diseases. PMID- 29713218 TI - Paclitaxel-Coated Balloon Angioplasty for Early Restenosis of Central Veins in Hemodialysis Patients: A Single Center Initial Experience. AB - Objective: To report the results of angioplasty with paclitaxel-coated balloons for the treatment of early restenosis of central veins in hemodialysis patients. Materials and Methods: Sixteen patients (9 men and 7 women; mean age 65.8 +/- 14.4 years; range, 40-82 years) with 16 episodes of early restenoses of central veins within 3 months (median patency duration 2.5 months) were enrolled from January 2014 to June 2015. Ten native central veins and 6 intra-stent central veins were treated with double paclitaxel-coated balloons (diameter 6-7 mm) plus a high pressure balloon (diameter 12-14 mm). The study outcomes included procedural success (< 30% residual stenosis) and primary patency of the treated lesion (< 50% angiographic stenosis without re-intervention). Results: Procedural success was achieved in all 16 cases of central vein stenoses. The mean diameter of the central vein was 3.7 +/- 2.4 mm before the procedure vs. 11.4 +/- 1.8 mm after the initial procedure. There were no procedure-related complications. The mean diameters of the central veins at 6 months and 12 months were 7.8 +/- 1.3 mm and 6.9 +/- 2.7 mm, respectively. The primary patency rates at 6 months and 12 months were 93.8% and 31.2%, respectively. One patient had significant restenosis of the central vein at 3 months. The median primary patency period was 9 months for paclitaxel-coated balloons and 2.5 months for the last previous procedure with conventional balloons (p < 0.001). Conclusion: In our limited study, paclitaxel-coated balloons seem to improve the patency rate in cases of early restenosis of central veins. However, a further randomized control trial is necessary. PMID- 29713219 TI - The Diagnostic Reproducibility of Tomosynthesis for the Correlation between Acromiohumeral Distance and Rotator Cuff Size or Type. AB - Objective: To correlate the acromiohumeral distance (AHD) using tomosynthesis and rotator cuff (RC) pathology and various anatomical indices and to assess the diagnostic reproducibility of tomosynthesis for the evaluation of subacromial impingement. Materials and Methods: A retrospective review of 63 patients with clinically suspected subacromial impingement was conducted. Two musculoskeletal radiologists independently measured the following quantitative data: the AHD on plain radiographs and the AHD at three compartments (anterior, middle, and posterior) using tomosynthesis, computed tomography (CT) arthrography, or magnetic resonance (MR) arthrography. To investigate the association between the AHD and RC pathology and various anatomical indices, we reviewed the arthroscopic operation record as the referenced standard. Results: The size of rotator cuff tear (RCT) in full-thickness tears displayed a significant inverse correlation with the middle and the posterior tomosynthetic AHDs (p < 0.05). The results of an ANOVA revealed that the middle tomosynthetic AHD retained a significant association with the type of RCT (p = 0.042), and the posterior tomosynthetic AHD retained significance for the size of RCT in a full-thickness tear (p = 0.024). The inter-modality correlation exhibited significant agreement especially among the plain radiography, tomosynthesis, and CT or MR arthrography (p < 0.05). The intraobserver and interobserver correlation coefficients (ICCs) displayed excellent agreement (ICC = 0.896-0.983). The humeral head diameter and glenoid height were significantly correlated with patient height and weight. Conclusion: Acromiohumeral distance measurement using tomosynthesis is reproducible compared with other modalities. PMID- 29713220 TI - Ultrasonographic Findings of Scleredema Adultorum of Buschke Involving the Posterior Neck. AB - Objective: To describe the clinical and ultrasonographic (US) findings in patients with scleredema adultorum of Buschke, who presented with sclerotic skin on their posterior neck. Materials and Methods: After obtaining IRB approval, eight patients with scleredema adultorum of Buschke were enrolled. They underwent US examination of their posterior neck. The diagnoses were confirmed pathologically. The clinical history and US images were evaluated retrospectively. Dermal thickness was compared between the patient group and the age- and sex-matched control group. Results: The patients included seven males and one female with a mean age of 51.5 years. All patients presented with thickening of the skin and/or a palpable mass on the posterior neck. Five (62.5%) of the eight patients showed erythematous discoloration. Six patients (75.0%) had a history of diabetes. The Hemoglobin A1c level was found to be increased in all patients. US images did not show any evidence of a soft tissue mass or infection. The mean dermal thickness in patients (7.01 +/- 1.95 mm) was significantly greater than that in the control group (3.08 +/- 0.87 mm) (p = 0.001). Multiple strong echogenic spots in the dermis were seen in all patients. Seven patients (87.5%) showed posterior shadowing in the lower dermis. Conclusion: When a patient with a history of diabetes presents with a palpable mass or erythematous discoloration of the posterior neck and US shows the following imaging features: 1) no evidence of a soft tissue mass or infection, 2) thickening of the dermis, 3) multiple strong echogenic spots and/or posterior shadowing in the dermis, scleredema adultorum of Buschke should be considered in the differential diagnosis. PMID- 29713221 TI - Altered White Matter Integrity in Human Immunodeficiency Virus-Associated Neurocognitive Disorder: A Tract-Based Spatial Statistics Study. AB - Objective: Human immunodeficiency virus (HIV) infection has been known to damage the microstructural integrity of white matter (WM). However, only a few studies have assessed the brain regions in HIV-associated neurocognitive disorders (HAND) with diffusion tensor imaging (DTI). Therefore, we sought to compare the DTI data between HIV patients with and without HAND using tract-based spatial statistics (TBSS). Materials and Methods: Twenty-two HIV-infected patients (10 with HAND and 12 without HAND) and 11 healthy controls (HC) were enrolled in this study. A whole-brain analysis of fractional anisotropy (FA), mean diffusivity (MD), radial diffusivity (RD), and axial diffusivity was performed with TBSS and a subsequent 20 tract-specific region-of-interest (ROI)-based analysis to localize and compare altered WM integrity in all group contrasts. Results: Compared with HC, patients with HAND showed decreased FA in the right frontoparietal WM including the upper corticospinal tract (CST) and increased MD and RD in the bilateral frontoparietal WM, corpus callosum, bilateral CSTs and bilateral cerebellar peduncles. The DTI values did not significantly differ between HIV patients with and without HAND or between HIV patients without HAND and HC. In the ROI-based analysis, decreased FA was observed in the right superior longitudinal fasciculus and was significantly correlated with decreased information processing speed, memory, executive function, and fine motor function in HIV patients. Conclusion: These results suggest that altered integrity of the frontoparietal WM contributes to cognitive dysfunction in HIV patients. PMID- 29713222 TI - Utility of Readout-Segmented Echo-Planar Imaging-Based Diffusion Kurtosis Imaging for Differentiating Malignant from Benign Masses in Head and Neck Region. AB - Objective: To compare the diagnostic performance of readout-segmented echo-planar imaging (RS-EPI)-based diffusion kurtosis imaging (DKI) and that of diffusion weighted imaging (DWI) for differentiating malignant from benign masses in head and neck region. Materials and Methods: Between December 2014 and April 2016, we retrospectively enrolled 72 consecutive patients with head and neck masses who had undergone RS-EPI-based DKI scan (b value of 0, 500, 1000, and 1500 s/mm2) for pretreatment evaluation. Imaging data were post-processed by using monoexponential and diffusion kurtosis (DK) model for quantitation of apparent diffusion coefficient (ADC), apparent diffusion for Gaussian distribution (Dapp), and apparent kurtosis coefficient (Kapp). Unpaired t test and Mann-Whitney U test were used to compare differences of quantitative parameters between malignant and benign groups. Receiver operating characteristic curve analyses were performed to determine and compare the diagnostic ability of quantitative parameters in predicting malignancy. Results: Malignant group demonstrated significantly lower ADC (0.754 +/- 0.167 vs. 1.222 +/- 0.420, p < 0.001) and Dapp (1.029 +/- 0.226 vs. 1.640 +/- 0.445, p < 0.001) while higher Kapp (1.344 +/- 0.309 vs. 0.715 +/- 0.249, p < 0.001) than benign group. Using a combination of Dapp and Kapp as diagnostic index, significantly better differentiating performance was achieved than using ADC alone (area under curve: 0.956 vs. 0.876, p = 0.042). Conclusion: Compared to DWI, DKI could provide additional data related to tumor heterogeneity with significantly better differentiating performance. Its derived quantitative metrics could serve as a promising imaging biomarker for differentiating malignant from benign masses in head and neck region. PMID- 29713223 TI - Brain Regional Homogeneity Changes in Cirrhotic Patients with or without Hepatic Encephalopathy Revealed by Multi-Frequency Bands Analysis Based on Resting-State Functional MRI. AB - Objective: To investigate brain regional homogeneity (ReHo) changes of multiple sub-frequency bands in cirrhotic patients with or without hepatic encephalopathy using resting-state functional MRI. Materials and Methods: This study recruited 46 cirrhotic patients without clinical hepatic encephalopathy (noHE), 38 cirrhotic patients with clinical hepatic encephalopathy (HE), and 37 healthy volunteers. ReHo differences were analyzed in slow-5 (0.010-0.027 Hz), slow-4 (0.027-0.073 Hz), and slow-3 (0.073-0.198 Hz) bands. Routine analysis of (0.010 0.080 Hz) band was used as a benchmark. Associations of abnormal ReHo values in each frequency band with neuropsychological scores and blood ammonia level were analyzed. Pattern classification analyses were conducted to determine whether ReHo differences in each band could differentiate the three groups of subjects (patients with or without hepatic encephalopathy and healthy controls). Results: Compared to routine analysis, more differences between HE and noHE were observed in slow-5 and slow-4 bands (p < 0.005, cluster > 12, overall corrected p < 0.05). Sub-frequency band analysis also showed that ReHo abnormalities were frequency dependent (overall corrected p < 0.05). In addition, ReHo abnormalities in each sub-band were correlated with blood ammonia level and neuropsychological scores, especially in the left inferior parietal lobe (overall corrected p < 0.05 for all frequency bands). Pattern classification analysis demonstrated that ReHo differences in lower slow-5 and slow-4 bands (both p < 0.05) and higher slow-3 band could differentiate the three groups (p < 0.05). Compared to routine analysis, ReHo features in slow-4 band obtained better classification accuracy (89%). Conclusion: Cirrhotic patients showed frequency-dependent changes in ReHo. Sub-frequency band analysis is important for understanding HE and clinical monitoring. PMID- 29713224 TI - Falcine Sinus: Incidence and Imaging Characteristics of Three-Dimensional Contrast-Enhanced Thin-Section Magnetic Resonance Imaging. AB - Objective: To evaluate the incidence, characteristics, and variations of the falcine sinus with contrast-enhanced three-dimentional (3D) thin-section magnetic resonance (MR) images. Materials and Methods: A retrospective review identified 1531 patients (745 males and 786 females, 2 months to 85 years) who underwent cranial MR imaging including T1-weighted imaging, T2-weighted imaging, T2 weighted fluid-attenuated inversion recovery, contrast-enhanced 3D thin-section sagittal scans, and MR venography, from June 2014 to January 2016. The incidence, characteristics of the falcine sinus, and coexisted intracranial lesions were confirmed by two neuroradiologists. Results: Falcine sinuses were identified in 81 (38 males and 43 females) cases (5.3%, 81/1531, 5 months to 76 years of age) with calibers ranging from 2.3 mm to 17.0 mm. Three major forms of falcine sinuses were defined: arch-like (n = 47), stick-like (n = 22), and bifurcated (n = 12). Persistent falcine sinuses were found in 57 cases, among which 3 cases showed complicated cerebral anomalies, and 2 cases showed smaller straight sinuses. Recanalization of falcine sinuses were found in 24 cases, including 17 cases with tumor compression, 6 cases with cerebral venous sinus thrombosis, and one case with hypertrophic meningitis. Conclusion: Falcine sinus is not as rare as has been reported previously. Most falcine sinuses are not associated with congenital cerebral abnormalities. Diseases that cause increased pressure in the venous sinus may lead to recanalization of falcine sinus. Illustrating the characteristics of falcine sinus may prompt a more comprehensive understanding and diagnosis of associated diseases, and avoid potential surgical damage in the future. PMID- 29713226 TI - Prognostic Value of Baseline 18F-Fluorodeoxyglucose PET/CT in Patients with Multiple Myeloma: A Multicenter Cohort Study. AB - Objective: We investigated the prognostic value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in patients with multiple myeloma (MM). Materials and Methods: Subjects were 76 patients with newly diagnosed myeloma and pretreatment with 18F-FDG PET/CT from four hospitals. The PET/CT features were evaluated and the clinical characteristics were reviewed. Prognostic factors related to poor progression-free survival (PFS) and overall survival (OS) were identified using a Cox proportional hazards regression model and a prediction scale was developed based on the identified factors. Results: Multivariate analysis showed that the presence of 18F-FDG-avid focal bone lesions (>= 3) was a significant and independent predictor of PFS (hazard ratio [HR] = 3.28, p = 0.007) and OS (HR = 11.78, p = 0.001). The presence of extramedullary disease on PET/CT scan was also a significant predictor of poor PFS (HR = 2.79, p = 0.006) and OS (HR = 3.89, p = 0.003). A prognostic scale was developed using these two predictors. An increase in score on the scale corresponded to a significantly increased risk of poor OS (p = 0.005). In addition, Kaplan-Meier analysis demonstrated that patient survival varied significantly according to the scale (p < 0.001 for OS and p = 0.001 for PFS). Conclusion: 18F-FDG-avid focal lesions and the presence of extramedullary disease on PET/CT scan are significantly associated with poor OS in MM patients. The scale developed according to these predictors represents a potential prognostic tool for evaluation of patients with MM. PMID- 29713225 TI - Utility of Quantitative Parameters from Single-Photon Emission Computed Tomography/Computed Tomography in Patients with Destructive Thyroiditis. AB - Objective: Quantitative parameters from Tc-99m pertechnetate single-photon emission computed tomography/computed tomography (SPECT/CT) are emerging as novel diagnostic markers for functional thyroid diseases. We intended to assess the utility of SPECT/CT parameters in patients with destructive thyroiditis. Materials and Methods: Thirty-five destructive thyroiditis patients (7 males and 28 females; mean age, 47.3 +/- 13.0 years) and 20 euthyroid patients (6 males and 14 females; mean age, 45.0 +/- 14.8 years) who underwent Tc-99m pertechnetate quantitative SPECT/CT were retrospectively enrolled. Quantitative parameters from the SPECT/CT (%uptake, standardized uptake value [SUV], thyroid volume, and functional thyroid mass [SUVmean * thyroid volume]) and thyroid hormone levels were investigated to assess correlations and predict the prognosis for destructive thyroiditis. The occurrence of hypothyroidism was the outcome for prognosis. Results: All the SPECT/CT quantitative parameters were significantly lower in the 35 destructive thyroiditis patients compared to the 20 euthyroid patients using the same SPECT/CT scanner and protocol (p < 0.001 for all parameters). T3 and free T4 did not correlate with any SPECT/CT parameters, but thyroid-stimulating hormone (TSH) significantly correlated with %uptake (p = 0.004), SUVmean (p < 0.001), SUVmax (p = 0.002), and functional thyroid mass (p < 0.001). Of the 35 destructive thyroiditis patients, 16 progressed to hypothyroidism. On univariate and multivariate analyses, only T3 levels were associated with the later occurrence of hypothyroidism (p = 0.002, exp(beta) = 1.022, 95% confidence interval: 1.008 - 1.035). Conclusion: Novel quantitative SPECT/CT parameters could discriminate patients with destructive thyroiditis from euthyroid patients, suggesting the robustness of the quantitative SPECT/CT approach. However, disease progression of destructive thyroiditis could not be predicted using the parameters, as these only correlated with TSH, but not with T3, the sole predictor of the later occurrence of hypothyroidism. PMID- 29713227 TI - Two Small Intravenous Catheters for High-Rate Contrast Medium Injection for Computed Tomography in Patients Lacking Superficial Veins to Accommodate a Large Catheter. AB - Objective: To prospectively investigate the feasibility of using 2 small intravenous catheters for high-rate computed tomography (CT) contrast injection in patients lacking superficial veins capable of accommodating <= 20-gauge catheters. Materials and Methods: Sixty-eight consecutive eligible adults referred for dynamic liver CT were enrolled; 58 had previously undergone liver CT, including 8 that experienced extravasation. Two 22- or 24-gauge catheters were placed in all patients after 2-5 venipunctures, and 2 mL/kg of contrast agent (370 mg I/mL) was split-administered through both catheters to achieve total flow rate of 4 mL/s. Patients' experience and examination success rate, defined as uneventful scans completed at 4 mL/s or at < 4 mL/s achieving standard image quality in all phases, were analyzed. Quantitative hepatic signal-to-noise and hepatic vascular contrast-to-noise ratios (CNRs) were compared with 30 control examinations scanned at 4 mL/s using an 18-gauge catheter. Results: One case each of extravasation and severe injection pain caused the examination to be aborted. Success rate was 88.2% (60/68; 54 patients scanned at 4 mL/s, 6 at 3.5 3.9 mL/s). Fifty-five of 58 patients (94.8%) that had past CT regarded the venipuncture as more tolerable than (n = 36) or similar to (n = 19) past experiences; 45 of 58 patients (77.6%) found contrast injection less painful than (n = 35) or similar to (n = 10) past experiences. When compared with control examinations, signal-to-noise ratio was similar in all phases (p >= 0.502), but the hepatic arterial CNR in arterial phase was slightly inferior (p <= 0.047). Conclusion: Using 2 small intravenous catheters can effectively achieve high-rate CT contrast injection in patients lacking adequate superficial veins. PMID- 29713228 TI - Blood-Brain Barrier Disruption and Perivascular Beta-Amyloid Accumulation in the Brain of Aged Rats with Spontaneous Hypertension: Evaluation with Dynamic Contrast-Enhanced Magnetic Resonance Imaging. AB - Objective: Whether blood-brain barrier (BBB) disruption induced by chronic spontaneous hypertension is associated with beta-amyloid (Abeta) accumulation in the brain remains poorly understood. The purpose of this study was to investigate the relationship between BBB disruption and Abeta influx and accumulation in the brain of aged rats with chronic spontaneous hypertension. Materials and Methods: Five aged spontaneously hypertensive rats (SHRs) and five age-matched normotensive Wistar-Kyoto (WKY) rats were studied. The volume transfer constant (Ktrans) obtained from dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) was used to evaluate BBB permeability in the hippocampus and cortex in vivo. The BBB tight junctions, immunoglobulin G (IgG), Abeta, and amyloid precursor protein (APP) in the hippocampus and cortex were examined with immunohistochemistry. Results: As compared with WKY rats, the Ktrans values in the hippocampus and cortex of the SHRs increased remarkably (0.316 +/- 0.027 min 1 vs. 0.084 +/- 0.017 min-1, p < 0.001 for hippocampus; 0.302 +/- 0.072 min-1 vs. 0.052 +/- 0.047 min-1, p < 0.001 for cortex). Dramatic occludin and zonula occludens-1 losses were detected in the hippocampus and cortex of SHRs, and obvious IgG exudation was found there. Dramatic Abeta accumulation was found and limited to the area surrounding the BBB, without extension to other parenchyma regions in the hippocampus and cortex of aged SHRs. Alternatively, differences in APP expression in the hippocampus and cortex were not significant. Conclusion: Blood-brain barrier disruption is associated with Abeta influx and accumulation in the brain of aged rats with chronic spontaneous hypertension. DCE-MRI can be used as an effective method to investigated BBB damage. PMID- 29713229 TI - Diameter of the Solid Component in Subsolid Nodules on Low-Dose Unenhanced Chest Computed Tomography: Measurement Accuracy for the Prediction of Invasive Component in Lung Adenocarcinoma. AB - Objective: To determine if measurement of the diameter of the solid component in subsolid nodules (SSNs) on low-dose unenhanced chest computed tomography (CT) is as accurate as on standard-dose enhanced CT in prediction of pathological size of invasive component of lung adenocarcinoma. Materials and Methods: From February 2012 to October 2015, 114 SSNs were identified in 105 patients that underwent low dose unenhanced and standard-dose enhanced CT pre-operatively. Three radiologists independently measured the largest diameter of the solid component. Intraclass correlation coefficients (ICCs) were used to assess inter-reader agreement. We estimated measurement differences between the size of solid component and that of invasive component. We measured diagnostic accuracy of the prediction of invasive adenocarcinoma using a size criterion of a solid component >= 6 mm, and compared them using a generalized linear mixed model. Results: Inter-reader agreement was excellent (ICC, 0.84.0.89). The mean +/- standard deviation of absolute measurement differences between the solid component and invasive component was 4 +/- 4 mm in low-dose unenhanced CT and 5 +/- 4 mm in standard-dose enhanced CT. Diagnostic accuracy was 81.3% (95% confidence interval, 76.7.85.3%) in low-dose unenhanced CT and 76.6% (71.8.81.0%) in standard-dose enhanced CT, with no statistically significant difference (p = 0.130). Conclusion: Measurement of the diameter of the solid component of SSNs on low-dose unenhanced chest CT was as accurate as on standard-dose enhanced CT for predicting the invasive component. Thus, low-dose unenhanced CT may be used safely in the evaluation of patients with SSNs. PMID- 29713231 TI - The Potential Role of Grid-Like Software in Bedside Chest Radiography in Improving Image Quality and Dose Reduction: An Observer Preference Study. AB - Objective: To compare the observer preference of image quality and radiation dose between non-grid, grid-like, and grid images. Materials and Methods: Each of the 38 patients underwent bedside chest radiography with and without a grid. A grid like image was generated from a non-grid image using SimGrid software (Samsung Electronics Co. Ltd.) employing deep-learning-based scatter correction technology. Two readers recorded the preference for 10 anatomic landmarks and the overall appearance on a five-point scale for a pair of non-grid and grid-like images, and a pair of grid-like and grid images, respectively, which were randomly presented. The dose area product (DAP) was also recorded. Wilcoxon's rank sum test was used to assess the significance of preference. Results: Both readers preferred grid-like images to non-grid images significantly (p < 0.001); with a significant difference in terms of the preference for grid images to grid like images (p = 0.317, 0.034, respectively). In terms of anatomic landmarks, both readers preferred grid-like images to non-grid images (p < 0.05). No significant differences existed between grid-like and grid images except for the preference for grid images in proximal airways by two readers, and in retrocardiac lung and thoracic spine by one reader. The median DAP were 1.48 (range, 1.37-2.17) dGy*cm2 in grid images and 1.22 (range, 1.11-1.78) dGy*cm2 in grid-like images with a significant difference (p < 0.001). Conclusion: The SimGrid software significantly improved the image quality of non-grid images to a level comparable to that of grid images with a relatively lower level of radiation exposure. PMID- 29713230 TI - Nodule Classification on Low-Dose Unenhanced CT and Standard-Dose Enhanced CT: Inter-Protocol Agreement and Analysis of Interchangeability. AB - Objective: To measure inter-protocol agreement and analyze interchangeability on nodule classification between low-dose unenhanced CT and standard-dose enhanced CT. Materials and Methods: From nodule libraries containing both low-dose unenhanced and standard-dose enhanced CT, 80 solid and 80 subsolid (40 part solid, 40 non-solid) nodules of 135 patients were selected. Five thoracic radiologists categorized each nodule into solid, part-solid or non-solid. Inter protocol agreement between low-dose unenhanced and standard-dose enhanced images was measured by pooling kappa values for classification into two (solid, subsolid) and three (solid, part-solid, non-solid) categories. Interchangeability between low-dose unenhanced and standard-dose enhanced CT for the classification into two categories was assessed using a pre-defined equivalence limit of 8 percent. Results: Inter-protocol agreement for the classification into two categories {kappa, 0.96 (95% confidence interval [CI], 0.94-0.98)} and that into three categories (kappa, 0.88 [95% CI, 0.85-0.92]) was considerably high. The probability of agreement between readers with standard-dose enhanced CT was 95.6% (95% CI, 94.5-96.6%), and that between low-dose unenhanced and standard-dose enhanced CT was 95.4% (95% CI, 94.7-96.0%). The difference between the two proportions was 0.25% (95% CI, -0.85-1.5%), wherein the upper bound CI was markedly below 8 percent. Conclusion: Inter-protocol agreement for nodule classification was considerably high. Low-dose unenhanced CT can be used interchangeably with standard-dose enhanced CT for nodule classification. PMID- 29713232 TI - Impact of Nodule Size on Malignancy Risk Differs according to the Ultrasonography Pattern of Thyroid Nodules. AB - Objective: To test whether the impact of thyroid-nodule size on the malignancy risk differs according to the ultrasonography (US) patterns of nodules. Materials and Methods: This study is a post hoc analysis using data from the Thyroid Imaging Reporting and Data System (TIRADS) multicenter retrospective study which included 2000 consecutive thyroid nodules (>= 1 cm) with final diagnoses. A total of 2000 consecutive thyroid nodules from 1802 patients (1387 women and 613 men; mean age, 51.2 +/- 12.2 years) were enrolled in this study. The malignancy risk of the nodules was assessed according to the nodule size and US patterns (Korean TIRADS). Results: Overall, the malignancy risk did not increase as nodules enlarged. In high-suspicion nodules, the malignancy rate had no association with nodule size (p = 0.467), whereas in intermediate- or low-suspicion nodules there was a trend toward an increasing malignancy risk as the nodule size increased (p = 0.004 and 0.002, respectively). The malignancy rate of large nodules (>= 3 cm) was higher than that of small nodules (< 3 cm) in intermediate-suspicion nodules (40.3% vs. 22.6%, respectively; p = 0.001) and low-suspicion nodules (11.3% vs. 7.0%, respectively; p = 0.035). There was a trend toward a decreasing risk and proportion of papillary carcinoma and an increasing risk and proportion of follicular carcinoma or other malignant tumors as nodule size increased (p < 0.001, respectively). Conclusion: The impact of nodule size on the malignancy risk differed according to the US pattern. A large nodule size (>= 3 cm) showed a higher malignancy risk than smaller nodules in intermediate- and low-suspicion nodules. PMID- 29713233 TI - A new species of Pristimantis (Anura, Craugastoridae) from the Cajas Massif, southern Ecuador. AB - A new species of Pristimantis is described from the highland paramos on the eastern slopes of the Cajas Massif, southern Andes of Ecuador, at 3400 m. This new species is characterized by having a distinctive reddish color, cutaneous macroglands in suprascapular region and surfaces of arm and legs, and by lacking dentigerous processes of vomers. The cutaneous macroglands are similar to those exhibited by several species of the Pristimantis orcesi group, and may suggest a close phylogenetic relationship. The new species could be a latitudinal substitution of Pristimantis orcesi in the southern Andes of Ecuador. PMID- 29713234 TI - An audit of some processing effects in aggregated occurrence records. AB - A total of ca 800,000 occurrence records from the Australian Museum (AM), Museums Victoria (MV) and the New Zealand Arthropod Collection (NZAC) were audited for changes in selected Darwin Core fields after processing by the Atlas of Living Australia (ALA; for AM and MV records) and the Global Biodiversity Information Facility (GBIF; for AM, MV and NZAC records). Formal taxon names in the genus- and species-groups were changed in 13-21% of AM and MV records, depending on dataset and aggregator. There was little agreement between the two aggregators on processed names, with names changed in two to three times as many records by one aggregator alone compared to records with names changed by both aggregators. The type status of specimen records did not change with name changes, resulting in confusion as to the name with which a type was associated. Data losses of up to 100% were found after processing in some fields, apparently due to programming errors. The taxonomic usefulness of occurrence records could be improved if aggregators included both original and the processed taxonomic data items for each record. It is recommended that end-users check original and processed records for data loss and name replacements after processing by aggregators. PMID- 29713235 TI - Antimalarial drug prescribing by healthcare workers when malaria testing is negative: a qualitative study in Madagascar. AB - Background: Despite the World Health Organization and the National Malaria Program of Madagascar recommending that antimalarial drugs only be prescribed for patients with positive results on malaria rapid diagnostic tests, healthcare workers continue to prescribe these drugs for cases with negative test results. We explored why and how primary healthcare workers in Madagascar continue to prescribe antimalarial drugs despite this guidance. Methods: We purposively selected 14 medical doctors and 2 nurses from 11 primary health facilities (6 public, 5 private) in Toliara, Madagascar, and interviewed them regarding their antimalarial prescribing behaviors. Semi-structured interviews were conducted, focusing on why and how antimalarials were prescribed for clients with negative rapid diagnostic test results. Interviews were audio-recorded and transcribed verbatim, and the responses were manually coded until consistent themes emerged. Results: The narrative of healthcare workers regarding their continued prescribing of antimalarials despite negative test results revealed the following: (1) they prescribe antimalarials without positive test results due to their faith to give top priority to clients including the ethical value of beneficence, hope to maintain clinician's independence, and belief in drug effectiveness; (2) they use antimalarials despite negative test results due to the availability of alternative ways to procure antimalarials; and (3) they carefully select cases to prescribe and determine specific antimalarials despite negative test results by considering the client's physical condition, preference, and economic status. Our results indicate that healthcare workers prioritized clinician autonomy to give the best care they believed for each client they received, which led to conflict with policy administrators that urged clinicians to follow the national policy and guidelines. Moreover, healthcare workers had access to multiple sources of antimalarial drugs, and there was a lack of consistency in the program provisions that allowed alternative routes for prescribing outside of official policy. Conclusions: We have shown how a national malarial treatment policy was translated into practice in Madagascar and have highlighted the barriers that may prevent policy success. We must attend to each of these barriers if we are to promote optimal use of antimalarial drugs. PMID- 29713236 TI - Accuracy and practicality of a portable ozone monitor for personal exposure estimates. AB - Accurate measurements of personal exposure to atmospheric pollutants such as ozone are important for understanding health risks. We tested a new personal ozone monitor (POM; 2B Technologies) for accuracy, precision, and ease of use. The POM's measurements were compared to simultaneous ozone measurements from a 2B Model 205 monitor and a ThermoScientific 49i monitor, and multiple POMs were placed side-by-side to check precision. Tests were undertaken in a controlled environmental facility, outdoors, and in a private residence. Additionally, ten volunteers wore a POM for five days and answered a questionnaire about its ease of use. The POM measured ozone accurately compared to the 49i ozone monitor, with average relative differences of less than 8%. In the controlled environment tests, the POM's ozone measurements did not change in the presence of additional atmospheric constituents with similar absorption lines to ozone, though there may have been a small decrease in precision and accuracy. Precision between POMs varied by environment (r2 = 0.98 outdoors; r2 = 0.3 to 0.9 in controlled lab conditions). Volunteers reported that the POM was reasonably comfortable to wear, although all reported that they felt that it was too noisy. Overall, the POM is a viable option for personal ozone monitoring. PMID- 29713237 TI - Effective Instruction for Persisting Dyslexia in Upper Grades: Adding Hope Stories and Computer Coding to Explicit Literacy Instruction. AB - Children in grades 4 to 6 (N=14) who despite early intervention had persisting dyslexia (impaired word reading and spelling) were assessed before and after computerized reading and writing instruction aimed at subword, word, and syntax skills shown in four prior studies to be effective for treating dyslexia. During the 12 two-hour sessions once a week after school they first completed HAWK Letters in Motion(c) for manuscript and cursive handwriting, HAWK Words in Motion(c) for phonological, orthographic, and morphological coding for word reading and spelling, and HAWK Minds in Motion(c) for sentence reading comprehension and written sentence composing. A reading comprehension activity in which sentences were presented one word at a time or one added word at a time was introduced. Next, to instill hope they could overcome their struggles with reading and spelling, they read and discussed stories about struggles of Buckminister Fuller who overcame early disabilities to make important contributions to society. Finally, they engaged in the new Kokopelli's World (KW)(c), blocks-based online lessons, to learn computer coding in introductory programming by creating stories in sentence blocks (Tanimoto and Thompson 2016). Participants improved significantly in hallmark word decoding and spelling deficits of dyslexia, three syntax skills (oral construction, listening comprehension, and written composing), reading comprehension (with decoding as covariate), handwriting, orthographic and morphological coding, orthographic loop, and inhibition (focused attention). They answered more reading comprehension questions correctly when they had read sentences presented one word at a time (eliminating both regressions out and regressions in during saccades) than when presented one added word at a time (eliminating only regressions out during saccades). Indicators of improved self-efficacy that they could learn to read and write were observed. Reminders to pay attention and stay on task needed before adding computer coding were not needed after computer coding was added. PMID- 29713238 TI - Methylene Blue Attenuates Lung Injury Induced by Hindlimb Ischemia Reperfusion in Rats. AB - Objective: This study was aimed to investigate the protective effect of methylene blue against lung injury induced by reperfusion of ischemic hindlimb in a rat model. Methods: Twenty-four healthy adult male Sprague-Dawley rats were equally randomized into three groups: sham (SM) group, ischemia reperfusion (IR) group, and methylene blue (MB) group. Rats in both IR and MB groups were subjected to 4 h of ischemia by clamping the left femoral artery and then followed by 4 h of reperfusion. Treatment with 1% methylene blue (50 mg/kg) was administrated intraperitoneally at 10 min prior to reperfusion in the MB group. After 4 h of reperfusion, malondialdehyde (MDA) level, myeloperoxidase (MPO), and superoxide dismutase (SOD) activities in lung tissue were detected; inflammatory cytokines, including IL-1beta and IL-6, were measured in bronchoalveolar lavage fluid (BALF); correspondingly, the morphological changes and water content in both gastrocnemius muscle and lung samples were evaluated. Results: Hindlimb IR caused remarkable morphological abnormalities and edema in both muscle and lung tissues. SOD activity was decreased, both the MPO activity and MDA level in lung tissue, as well as IL-1beta and IL-6 levels in BALF, were increased in the IR group (p < 0.05). Compared with the IR group, SOD activity was increased, whereas MPO activity and MDA level in lung tissue and IL-1beta and IL-6 levels in BALF were decreased in the MB group (p < 0.05). Also, the histological damage and edema in both lung and muscle tissues were significantly attenuated by the treatment of methylene blue. Conclusion: Methylene blue attenuates lung injury induced by hindlimb IR in rats, at least in part, by inhibiting oxidative stress. PMID- 29713239 TI - Oxysterols Increase Inflammation, Lipid Marker Levels and Reflect Accelerated Endothelial Dysfunction in Experimental Animals. AB - Objective: Oxidized cholesterol derivatives are thought to exert atherogenic effect thus adversely affecting vascular endothelium. The aim of the study was to assess the effect of 5alpha,6alpha-epoxycholesterol on experimentally induced hypercholesterolemia in rabbits, and the levels of homocysteine (HCY), asymmetric dimethylarginine (ADMA), paraoxonase-1 (PON-1), and inflammatory parameters (IL 6, TNF-alpha, CRP). Material and methods: The rabbits were divided into 3 groups, 8 animals each, and fed with basic fodder (C), basic fodder plus cholesterol (Ch) or basic fodder plus 5alpha,6alpha-epoxycholesterol, and unoxidized cholesterol (ECh). Serum concentrations of studied parameters were determined at 45-day intervals. The study was continued for six months. Results: We demonstrated that adding 5alpha,6alpha-epoxycholesterol to basic fodder significantly affected lipid status of the experimental animals, increasing total cholesterol and LDL cholesterol levels, as well as HCY and ADMA levels, whilst leaving the PON-1 activity unaffected. Additionally, the ECh group presented with significantly higher concentrations of inflammatory biomarkers (IL-6, TNF-alpha, and CRP). In the Ch group, lower yet significant (as compared to the C group) changes of levels of studied parameters were observed. Conclusion: Exposure of animals with experimentally induced hypercholesterolemia to 5alpha,6alpha-epoxycholesterol increases dyslipidaemia, endothelial dysfunction, and inflammatory response. PMID- 29713240 TI - IL-33/IL-31 Axis: A Potential Inflammatory Pathway. AB - Cytokines play an important role in the regulation of the immune system (adaptive and innate). Given their importance in proinflammatory processes, cytokines have been used for understanding the pathogenesis and as biomarkers in many diseases. IL-31 and IL-33 are still considered novel cytokines. IL-31 controls signalling and regulates a huge amount of biological functions: it induces proinflammatory cytokines, regulates cell proliferation, and is involved also in tissue remodelling. On the other hand, IL-33 has been identified as an "alarmin" released from the epithelial cells and from different human tissues and organs after a damage following, that is, an inflammatory process. The aim of this literature review is to strengthen the hypothesis about an IL-31/IL-33 axis by evaluating the most recent studies linking these two cytokines. Literature data showed that, in many cases, IL-31 and IL-33 are linked to each other and that their expression is correlated with disease severity. The presence of one interleukin might stimulate the induction of the other, amplifying inflammation and the consequent detrimental processes. In a near future, influencing their balance could be helpful in modulating the first responses of the immune system in order to prevent the development of many inflammation-related diseases. PMID- 29713242 TI - Caring for late preterm infants: public health nurses' experiences. AB - Background: Public health nurses (PHNs) care for and support late preterm infants (LPIs) and their families when they go home from the hospital. PHNs require evidence-informed guidelines to ensure appropriate and consistent care. The objective of this research study is to capture the lived experience of PHNs caring for LPIs in the community as a first step to improving the quality of care for LPIs and support for their parents. Methods: To meet our objectives we chose a descriptive phenomenology approach as a method of inquiry. We conducted semi structured interviews with PHNs (n = 10) to understand PHN perceptions of caring for LPIs and challenges in meeting the needs of families within the community. Interpretative thematic analysis revealed PHN perceptions of caring for LPIs and challenges in meeting the needs of families within the community. Results: Four themes emerged from the data. First, PHNs expressed challenges with meeting the physiological needs of LPIs and gave voice to the resulting strain this causes for parents. Second, nurses conveyed that parents require more anticipatory guidance about the special demands associated with feeding LPIs. Third, PHNs relayed that parents sometimes receive inconsistent advice from different providers. Lastly, PHNs acknowledged that due to lack of resources, families sometimes did not receive the full scope of evidence informed care required by fragile, immature infants. Conclusion: The care of LPIs by PHNs would benefit from more research about the needs of these infants and their families. Efforts to improve quality of care should focus on: evidence-informed guidelines, consistent care pathways, coordination of follow up care and financial resources, to provide physical, emotional, informational support that families require once they leave the hospital. More research on meeting the challenges of caring for LPIs and their families would provide direction for the competencies PHNs require to improve the quality of care in the community. PMID- 29713241 TI - Intestinal Immunomodulatory Cells (T Lymphocytes): A Bridge between Gut Microbiota and Diabetes. AB - Diabetes mellitus (DM) is one of the most familiar chronic diseases threatening human health. Recent studies have shown that the development of diabetes is closely related to an imbalance of the gut microbiota. Accordingly, there is increasing interest in how changes in the gut microbiota affect diabetes and its underlying mechanisms. Immunomodulatory cells play important roles in maintaining the normal functioning of the human immune system and in maintaining homeostasis. Intestinal immunomodulatory cells (IICs) are located in the intestinal mucosa and are regarded as an intermediary by which the gut microbiota affects physiological and pathological properties. Diabetes can be regulated by IICs, which act as a bridge linking the gut microbiota and DM. Understanding this bridge role of IICs may clarify the mechanisms by which the gut microbiota contributes to DM. Based on recent research, we summarize this process, thereby providing a basis for further studies of diabetes and other similar immune-related diseases. PMID- 29713243 TI - Identification of four differentially methylated genes as prognostic signatures for stage I lung adenocarcinoma. AB - Background: Lung adenocarcinoma (LUAD) is the main subtype of non-small cell lung cancer with a low survival prognosis. We aimed to generate a prognostic model for the postoperative recurrence of LUAD. Methods: The methylated DNA data of LUAD patients were downloaded from the Cancer Genome Atlas (TCGA). The differentially methylated genes were identified and protein-protein interacting network was constructed, with which prognostic signature of this cancer was generated. Survival and functional pathways analysis w used to evaluate the clustering ability of the prognostic signature. Results: We identified 151 differentially methylated genes related to relapse-free survival of patients with LUAD. Nine hub genes were identified in PPI network, with which 4 gene pair signature was selected as prognostic signature. The potential functions of 6 genes (JDP2, SERPINA5, PLG, SEMG2, RFX5, and POLR3B) in the 4-gene pair signature were enriched in intracellular protein synthesis and transportation. Conclusion: The four gene pair signature can predict the prognosis of patients with stage I LUAD. Our study provides a reference for patients with postoperative adjuvant therapy. PMID- 29713244 TI - Prognostic role of RDW in hematological malignancies: a systematic review and meta-analysis. AB - Background: Red blood cell distribution width (RDW), a biomarker for discrimination of anemia, has been recently identified as a prognostic factor in various types of cancer. Here we performed a meta-analysis in order to assess the correlation between RDW and the survival outcomes in patients with hematologic malignances. Patients/methods: We systematically searched PubMed, Embase, and ISI Web of Science for relevant studies, to investigate the prognostic significance of RDW in hematological malignancies. Odds ratios or hazards ratios (HRs) with corresponding 95% confidence intervals (CIs) are pooled to estimate the association between RDW and clinicopathological parameters of patients with hematologic malignances. Results: Seven trials with 1031 patients suffering from hematological malignancies were included in the meta-analysis, and the results indicated that increased pretreatment RDW predicted poor overall survival (HR = 2.35, 95% CI 1.70-3.24), poor progress-free survival (HR = 2.44, 95% CI 1.70 3.49) and poor event-free survival (EFS) (HR = 3.15, 95% CI 1.59-6.25). Furthermore, the similar results were observed in subgroup analysis stratified by cancer type, such as multiple myeloma, and diffuse large B cell lymphoma, etc. Conclusions: As for hematologic malignances, patients with higher RDW are more likely to have poorer prognosis than those with lower RDW. PMID- 29713246 TI - Autophagy inhibition improves the cytotoxic effects of receptor tyrosine kinase inhibitors. AB - Background: A growing field of evidence suggests the involvement of oncogenic receptor tyrosine kinases (RTKs) in cell transformation. Deregulated activity of RTKs in tumors can determine disease progression and therapeutic responses in several types of cancer, including neuroblastoma (NB). Therefore, RTKs targeting is a worthwhile challenge for the oncologists. Nevertheless, acquired resistance to RTK inhibitors (RTKi) remains a serious problem. Autophagy activation is among the possible obstacles for good efficacy of the therapy with RTKi. Methods: Under different treatment conditions we measured autophagic flux using immunoblot and immunofluorescence assays. Death induction was validated by trypan blue exclusion assay and FACS analysis (calcein-AM/propidium iodide). The NB cell lines SH-SY5Y and Kelly were used for the in vitro study. Results: In order to define whether autophagy might be a limiting factor for the efficacy of RTKi in NB cells, we firstly checked its activation following the treatment with several RTKi. Next, we investigated the possibility to increase their therapeutic efficiency by combining RTKi with autophagy blocking agents in vitro. We exploited the effectiveness of three RTKi either alone or in combination with autophagy inhibitors (Chloroquine-CQ and Spautin-1). We demonstrated that autophagy induction was drug-dependent, and that its inhibition increased the anti-tumor activity of a single RTKi unevenly. We observed that the combined use of blocking agents which impair late autophagy events, such as CQ, and RTKi can be more effective with respect to the use of RTKi alone. Conclusions: In the present report, we assessed the conditions under which autophagy is activated during the use of different RTKi currently in the pre-clinical evaluation for NB. We summarized the achievements of combined RTK/autophagy inhibitors treatment as a promising approach to enhance the efficacy of RTKi in impairing tumor cells viability. PMID- 29713245 TI - Allogeneic stem-cell transplantation for multiple myeloma: a systematic review and meta-analysis from 2007 to 2017. AB - Background: Despite recent advances, multiple myeloma (MM) remains incurable. However, the appearance of allogeneic stem cell transplantation (allo-SCT) through graft-versus-myeloma effect provides a potential way to cure MM to some degree. This systematic review aimed to evaluate the outcome of patients receiving allo-SCT and identified a series of prognostic factors that may affect the outcome of allo-SCT. Patients/methods: We systematically searched PubMed, Embase, and the Cochrane Library from 2007.01.01 to 2017.05.03 using the keywords 'allogeneic' and 'myeloma'. Results: A total of 61 clinical trials involving 8698 adult patients were included. The pooled estimates (95% CI) for overall survival (OS) at 1, 2, 3 and 5 years were 70 (95% CI 56-84%), 62 (95% CI 53-71%), 52 (95% CI 44-61%), and 46 (95% CI 40-52%), respectively; for progression-free survival were 51 (95% CI 38-64%), 40 (95% CI 32-48%), 34 (95% CI 27-41%), and 27 (95% CI 23-31%), respectively; and for treatment-related mortality (TRM) were 18 (95% CI 14-21%), 21 (95% CI 17-25%), 20 (95% CI 13-26%), and 27 (95% CI 21-33%), respectively. Additionally, the pooled 100-day TRM was 12 (95% CI 5-18%). The incidences of grades II-IV acute graft-versus-host disease (GVHD) and chronic GVHD were 34 (95% CI 30-37%) and 51 (95% CI 46-56%), respectively. The incidences of relapse rate (RR) and death rate were 50 (95% CI 45-55%) and 51 (95% CI 45 57%), respectively. Importantly, disease progression was the most major cause of death (48%), followed by TRM (44%). The results failed to show an apparent benefit of allo-SCT for standard risk patients, compared with tandem auto-SCT. In contrast, all 14 trials in our study showed that patients with high cytogenetic risk after allo-SCT had similar OS and PFS compared to those with standard risk, suggesting that allo-SCT may overcome the adverse prognosis of high cytogenetic risk. Conclusion: Due to the lack of consistent survival benefit, allo-SCT should not be considered as a standard of care for newly diagnosed and relapsed standard risk MM patients. However, for patients with high-risk MM who have a poor long term prognosis, allo-SCT may be a strong consideration in their initial course of therapy or in first relapse after chemotherapy, when the risk of disease progression may outweigh the transplant-related risks. A large number of prospective randomized controlled trials were needed to prove the benefits of these therapeutic options. PMID- 29713247 TI - Are men's misogynistic attitudes associated with poor mental health and substance use behaviors? An exploratory study of men in Tijuana, Mexico. AB - Men's misogynistic attitudes (i.e., dislike or contempt for women) have been shown to be associated with men's perpetration of physical/sexual violence against women and poor health outcomes for women. However, these attitudes have rarely been examined for their influence on men's own health. This paper examines the socio-demographic, substance use, and mental health correlates of misogynistic attitudes among a binational sample of men (n=400) in Tijuana, Mexico with high-risk substance use and sexual behaviors. We used a 6-item scale to measure misogynistic attitudes (alpha = .72), which was developed specifically for this context. We used descriptive statistics to describe our sample population and the extent to which they hold misogynistic attitudes. Then, using misogynistic attitudes as our dependent variable, we conducted bivariate linear regression and multivariable linear regression to examine the relationship between these attitudes and socio-demographic characteristics, substance use behaviors (i.e., use of alcohol, marijuana, heroin, methamphetamines, cocaine), and mental health (i.e., depression, self-esteem). In the multivariable model, we found significant relationships between misogynistic attitudes and education level (t = -4.34, p < 0.01), heroin use in the past 4 months (t = 2.50, p = 0.01), and depressive symptoms (t = 3.37, p < 0.01). These findings suggest that misogynistic attitudes are linked to poor health outcomes for men and future research needs to further explore the temporality of these relationships and identify strategies for reducing men's misogynistic attitudes with the ultimate aim of improving the health and well-being of both women and men. PMID- 29713248 TI - Development and validation of a brief general and sports nutrition knowledge questionnaire and assessment of athletes' nutrition knowledge. AB - Background: The Nutrition for Sport Knowledge Questionnaire (NSKQ) is an 89-item, valid and reliable measure of sports nutrition knowledge (SNK). It takes 25 min to complete and has been subject to low completion and response rates. The aim of this study was to develop an abridged version of the NSKQ (A-NSKQ) and compare response rates, completion rates and NK scores of the NSKQ and A-NSKQ. Methods: Rasch analysis was used for the questionnaire validation. The sample (n = 181) was the same sample that was used in the validation of the full-length NSKQ. Construct validity was assessed using the known-group comparisons method. Temporal stability was assessed using the test-retest reliability method. NK assessment was cross-sectional; responses were collected electronically from members of one non-elite Australian football (AF) and netball club, using Qualtrics Software (Qualtrics, Provo, UT). Results: Validation - The A-NSKQ has 37 items that assess general (n = 17) and sports (n = 20) nutrition knowledge (NK). Both sections are unidimensional (Perc5% = 2.84% [general] and 3.41% [sport]). Both sections fit the Rasch Model (overall-interaction statistic mean (SD) = - 0.15 +/- 0.96 [general] and 0.22 +/- 1.11 [sport]; overall-person interaction statistic mean (SD) = - 0.11 +/- 0.61 [general] and 0.08 +/- 0.73 [sport]; Chi-Square probability = 0.308 [general] and 0.283 [sport]). Test-retest reliability was confirmed (r = 0.8, P < 0.001 [general] and r = 0.7, P < 0.001 [sport]). Construct validity was demonstrated (nutrition students = 77% versus non-nutrition students = 60%, P < 0.001 [general] and nutrition students = 60% versus non-nutrition students = 40%, P < 0.001 [sport]. Assessment of NK - 177 usable survey responses from were returned. Response rates were low (7%) but completion rates were high (85%). NK scores on the A-NSKQ (46%) are comparable to results obtained in similar cohorts on the NSKQ (49%). The A-NSKQ took on average 12 min to complete, which is around half the time taken to complete the NSKQ (25 min). Conclusions: The A-NSKQ is a valid and reliable, brief questionnaire designed to assess general NK (GNK) and SNK. PMID- 29713249 TI - Effects of n-3 fatty acids and exercise on oxidative stress parameters in type 2 diabetic: a randomized clinical trial. AB - Background: The relationship between diabetes and oxidative stress has been previously reported. Exercise represents a useful non-pharmacological strategy for the treatment in type 2 diabetic (T2DM) patients, but high intensity exercise can induce a transient inflammatory state and increase oxidative stress. Nutritional strategies that may contribute to the reduction of oxidative stress induced by acute exercise are necessary. The aim of this study was to examine if n-3 PUFA supplementation intervention can attenuate the inflammatory response and oxidative stress associated with high intensity exercise in this population. As a primary outcome, lipoperoxidation measurements (TBARS and F2-isoprostanes) were selected. Methods: Thirty T2DM patients, without chronic complications, were randomly allocated into two groups: placebo (gelatin capsules) or n-3 PUFA (capsules containing 180 mg of eicosapentaenoic acid and 120 mg of docosahexaenoic acid). Blood samples were collected fasting before and after 8 weeks supplementation. In the beginning and at the end of protocol, an acute exercise was performed (treadmill), and new blood samples were collected before and immediately after the exercise for measurements of oxidative stress and high sensitivity C-reactive protein (hs-CRP). Results: After the supplementation period, a decrease in triglycerides levels was observed only in n-3 PUFA supplementation group (mean difference and 95% CI of 0.002 (0.000-0.004), p = 0.005). Supplementation also significantly reduced TRAP levels after exercise (mean difference and 95% CI to 9641 (- 20,068-39,351) for - 33,884 (- 56,976 - 10,793), p = 0.004, Cohen's d effect size = 1.12), but no significant difference was observed in n-3 PUFA supplementation group in lipoperoxidation parameters as TBARS (mean difference and 95% CI to - 3.8 (- 10-2.4) for - 2.9 (- 1.6-7.4) or F2 isoprostanes (mean difference and 95% CI -0.05 (- 0.19-0.10) for - 0.02 (- 0.19 0.16), p > 0.05 for both. Conclusion: PUFA n-3 supplementation reduced triglycerides as well as TRAP levels after exercise, without a significant effect on inflammatory and oxidative stress markers.This study is registered at ClinicalTrials.gov with the registration number of NCT03182712. PMID- 29713250 TI - Effects of beta-alanine supplementation during a 5-week strength training program: a randomized, controlled study. AB - Background: beta-Alanine (BA) is a non-essential amino acid that has been shown to enhance exercise performance. The purpose of this investigation was to determine if BA supplementation improved the adaptive response to five weeks of a resistance training program. Methods: Thirty healthy, strength-trained individuals were randomly assigned to the experimental groups placebo (PLA) or BA. Over 5 weeks of strength training, subjects in BA took 6.4 g/day of BA as 8 * 800 mg doses each at least 1.5 h apart. The training program consisted of 3 sessions per week in which three different leg exercises were conducted as a circuit (back squat, barbell step ups and loaded jumping lunges). The program started with 3 sets of 40 s of work per exercise and rest periods between sets of 120 s in the first week. This training volume was then gradually built up to 5 sets of 20 s work/60 s rest in the fifth week. The work load during the program was set by one of the authors according to the individual's perceived effort the previous week. The variables measured were average velocity, peak velocity, average power, peak power, and load in kg in a back squat, incremental load, one repetition maximum (1RM) test. In addition, during the rest period, jump ability (jump height and power) was assessed on a force platform. To compare data, a general linear model with repeated measures two-way analysis of variance was used. Results: Significantly greater training improvements were observed in the BA group versus PLA group (p = 0.045) in the variables average power at 1RM (BA: 42.65%, 95% CI, 432.33, 522.52 VS. PLA: 21.07%, 95% CI, 384.77, 482.19) and average power at maximum power output (p = 0.037) (BA: 20.17%, 95% CI, 637.82, 751.90 VS. PLA; 10.74%, 95% CI, 628.31, 751.53). The pre- to post training average power gain produced at 1RM in BA could be explained by a greater maximal strength gain, or load lifted at 1RM (p = 0.014) (24 kg, 95% CI, 19.45, 28.41 VS. 16 kg, 95% CI, 10.58, 20.25) and in the number of sets executed (p = 0.025) in the incremental load test (BA: 2.79 sets, 95% CI, 2.08, 3.49 VS. PLA: 1.58 sets, 95% CI, 0.82, 2.34). Conclusions: beta-Alanine supplementation was effective at increasing power output when lifting loads equivalent to the individual's maximal strength or when working at maximum power output. The improvement observed at 1RM was explained by a greater load lifted, or strength gain, in response to training in the participants who took this supplement. PMID- 29713251 TI - Assessment of Liver Function Using Pharmacokinetic Parameters of Gd-EOB-DTPA: Experimental Study in Rat Hepatectomy Model. AB - Objectives: To determine whether the pharmacokinetic parameters of Gd-EOB-DTPA can identify the difference in liver function in a rat hepatectomy model. Methods: A total of 56 eight-week-old male Sprague-Dawley rats were divided into the following groups: control group without hepatectomy (n = 16), 70% hepatectomy group (n = 14), and 90% hepatectomy group (n = 26). On postoperative day 2, Gd EOB-DTPA (0.1 mmol/kg) was injected intravenously and serial blood samples were obtained. Pharmacokinetic analysis was performed using a noncompartmental method. Statistical analysis was performed using one-way analysis of variance and post hoc pairwise group comparisons. Results: After excluding 6 rats that died unexpectedly, blood samples were obtained from 16, 14, and 20 rats in the control group, 70% hepatectomy group, and 90% hepatectomy group. There was a significant increase in area under the concentration-time curve from time zero to the time of the last measurable concentration between the 70% and 90% hepatectomy group (P < 0.001). The volume of distribution at steady state was significantly decreased between the control and 70% hepatectomy group (P < 0.001). The clearance was significantly different in all pairwise group comparisons (P < 0.001). Conclusions: The vascular clearance of Gd-EOB-DTPA can identify the difference in liver function in a rat hepatectomy model. PMID- 29713253 TI - Characteristics and Incidence Trends for Pediatric Inflammatory Bowel Disease in Daegu-Kyungpook Province in Korea: a Multi-Center Study. AB - Background: Inflammatory bowel disease (IBD) is a heterogeneous chronic disease of unknown etiology. Although it is an important disease that shows a rapid increase in pediatric population, there are no pediatric studies that represent a specific region in Korea. Therefore, we studied the epidemiological and phenotypic characteristics of pediatric IBD in Daegu-Kyungpook province, Korea. Methods: We included 122 children with pediatric IBD initially diagnosed at one of four university hospitals in Daegu-Kyungpook province between July 2010 and June 2016. We investigated the incidence trends, and the clinical characteristics at diagnosis were compared by Paris classification. Results: We included 122 children: 98 with Crohn's disease (CD) and 24 with ulcerative colitis (UC). The average age at diagnosis was 13.6 years for IBD. The incidence shows an increasing trend. CD showed a significant increase, whereas UC appears to be increasing slowly. In CD, there was a significant male predominance. For disease activity sites, the most common location was L3 (77.6%), indicating ileocolonic involvement as the major type. B1 (88.8%) was the most common disease behaviors type. Perianal disease was noted in 43 patients (43.9%) and weight loss in 60 (61.2%). In UC, E4 (58.4%) was the most common disease activity site, indicating pancolonic involvement as the major type. Conclusion: We found that the number of pediatric patients with IBD is increasing rapidly in Daegu-Kyungpook province in Korea. Our study also revealed that the characteristics of pediatric IBD in our province differ somewhat from those of pediatric IBD in Western countries. PMID- 29713252 TI - Quantitative proteomic analysis of pancreatic cyst fluid proteins associated with malignancy in intraductal papillary mucinous neoplasms. AB - Background: The application of advanced imaging technologies for identifying pancreatic cysts has become widespread. However, accurately differentiating between low-grade dysplasia (LGD), high-grade dysplasia (HGD), and invasive intraductal papillary mucinous neoplasms (IPMNs) remains a diagnostic challenge with current biomarkers, necessitating the development of novel biomarkers that can distinguish IPMN malignancy. Methods: Cyst fluid samples were collected from nine IPMN patients (3 LGD, 3 HGD, and 3 invasive IPMN) during their pancreatectomies. An integrated proteomics approach that combines filter-aided sample preparation, stage tip-based high-pH fractionation, and high-resolution MS was applied to acquire in-depth proteomic data of pancreatic cyst fluid and discover marker candidates for IPMN malignancy. Biological processes of differentially expressed proteins that are related to pancreatic cysts and aggressive malignancy were analyzed using bioinformatics tools such as gene ontology analysis and Ingenuity pathway analysis. In order to confirm the validity of the marker candidates, 19 cyst fluid samples were analyzed by western blot. Results: A dataset of 2992 proteins was constructed from pancreatic cyst fluid samples. A subsequent analysis found 2963 identified proteins in individual samples, 2837 of which were quantifiable. Differentially expressed proteins between histological grades of IPMN were associated with pancreatic diseases and malignancy according to ingenuity pathway analysis. Eighteen biomarker candidates that were differentially expressed across IPMN histological grades were discovered-7 DEPs that were upregulated and 11 that were downregulated in more malignant grades. HOOK1 and PTPN6 were validated by western blot in an independent cohort, the results of which were consistent with our proteomic data. Conclusions: This study demonstrates that novel biomarker candidates for IPMN malignancy can be discovered through proteomic analysis of pancreatic cyst fluid. PMID- 29713254 TI - Long-term Survival Benefit of Statin in Patients with Coronary Chronic Total Occlusion without Revascularization. AB - Background: Limited data are available on the efficacy of statin therapy in stable ischemic heart disease with chronic total occlusion (CTO) without revascularization. We investigated whether statin therapy could be beneficial in stable patients with CTO without revascularization. Methods: From March 2003 to February 2012, 2,024 patients with at least one CTO were enrolled in a retrospective, single-center registry; 664 of these patients were managed conservatively without an initial revascularization strategy. Among them, we excluded CTO cases involving acute coronary syndrome, in-hospital death or incomplete data and classified 551 patients into statin (n = 369) and non-statin (n = 182) groups according to use of statin at discharge. Propensity score matching analysis was also performed in 148 pairs. The primary outcome was cardiac death. Results: The median overall follow-up duration was 45.7 months (interquartile range: 19.9-70.5 months). Cardiac death occurred in 22 patients (6.0%) in the statin group vs. 24 patients (13.2%) in the non-statin group (P < 0.001). In propensity score matching analysis, statin therapy was associated with a low risk of cardiac death (adjusted hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.18-0.85; P = 0.022) and major adverse cardiac events (adjusted HR, 0.66; 95% CI, 0.43-0.98; P = 0.043). On multivariate analysis, independent predictors for cardiac death were age > 70 years, renal insufficiency, prior myocardial infarction, left ventricular ejection fraction < 40%, proximal-to-mid CTO location, and no use of statin in CTO patients. Conclusion: Statin therapy at discharge may be associated with a reduction in long-term cardiac mortality in stable CTO patients without revascularization. PMID- 29713256 TI - Primary Glomerulonephritis with Unique C4d Deposition and Concurrent Non infectious Intermediate Uveitis: a Case Report and Literature Review. AB - C4 glomerulopathy is a recently introduced entity that presents with bright C4d staining and minimal or absent immunoglobulin and C3 staining. We report a case of a 62-year-old man with C4 glomerulonephritis (GN) and uveitis. He presented to the nephrology department with proteinuria and hematuria. The patient also had intermediate uveitis along with proteinuria and hematuria. A kidney biopsy that was performed in light of continuing proteinuria and hematuria showed a focal proliferative, focal sclerotic glomerulopathy pattern on light microscopy, absent staining for immunoglobulin or C3 by immunofluorescence microscopy, with bright staining for C4d on immunohistochemistry, and electron-dense deposits on electron microscopy. Consequently, C4 GN was suggested as the pathologic diagnosis. Although laser microdissection and mass spectrometry for glomerular deposit and pathologic evaluation of the retinal tissue were not performed, this is the first report of C4 GN in Korea and the first case of coexisting C4 GN and uveitis in the English literature. PMID- 29713255 TI - Who Really Benefits from 3D-Based Planning of Brachytherapy for Cervical Cancer? AB - Background: Although intracavitary radiotherapy (ICR) is essential for the radiation therapy of cervical cancer, few institutions in Korea perform 3 dimensional (3D)-based ICR. To identify patients who would benefit from 3D-based ICR, dosimetric parameters for tumor targets and organs at risk (OARs) were compared between 2-dimensional (2D)- and 3D-based ICR. Methods: Twenty patients with locally advanced cervical cancer who underwent external beam radiation therapy (EBRT) following 3D-based ICR were retrospectively evaluated. New 2D based plans based on the Manchester system were developed. Tumor size was measured by magnetic resonance imaging. Results: The mean high risk clinical target volume (HR-CTV) D90 value was about 10% lower for 2D- than for 3D-based plans (88.4% vs. 97.7%; P = 0.068). Tumor coverage did not differ between 2D- and 3D-based plans in patients with tumors <= 4 cm at the time of brachytherapy, but the mean HR-CTV D90 values in patients with tumors > 4 cm were significantly higher for 3D-based plans than for 2D-based plans (96.0% vs. 78.1%; P = 0.017). Similar results were found for patients with tumors > 5 cm initially. Other dosimetric parameters for OARs were similar between 2D- and 3D-based plans, except that mean sigmoid D2cc was higher for 2D- than for 3D-based plans (67.5% vs. 58.8%; P = 0.043). Conclusion: These findings indicate that 3D-based ICR plans improve tumor coverage while satisfying the dose constraints for OARs. 3D based ICR should be considered in patients with tumors > 4 cm size at the time of brachytherapy or > 5 cm initially. PMID- 29713257 TI - Measuring Individual Performance with Comprehensive Bibliometric Reports as an Alternative to h-Index Values. AB - The h-index is frequently used to measure the performance of single scientists in Korea (and beyond). No single indicator alone, however, is able to provide a stable and complete assessment of performance. The Stata command bibrep.ado is introduced which automatically produces bibliometric reports for single researchers (senior researchers working in the natural or life sciences). The user of the command receives a comprehensive bibliometric report which can be used in research evaluation instead of the h-index. PMID- 29713259 TI - Prognostic Impact of Statins in Patients with Chronic Total Occlusion. PMID- 29713258 TI - Researcher and Author Impact Metrics: Variety, Value, and Context. AB - Numerous quantitative indicators are currently available for evaluating research productivity. No single metric is suitable for comprehensive evaluation of the author-level impact. The choice of particular metrics depends on the purpose and context of the evaluation. The aim of this article is to overview some of the widely employed author impact metrics and highlight perspectives of their optimal use. The h-index is one of the most popular metrics for research evaluation, which is easy to calculate and understandable for non-experts. It is automatically displayed on researcher and author profiles on citation databases such as Scopus and Web of Science. Its main advantage relates to the combined approach to the quantification of publication and citation counts. This index is increasingly cited globally. Being an appropriate indicator of publication and citation activity of highly productive and successfully promoted authors, the h index has been criticized primarily for disadvantaging early career researchers and authors with a few indexed publications. Numerous variants of the index have been proposed to overcome its limitations. Alternative metrics have also emerged to highlight 'societal impact.' However, each of these traditional and alternative metrics has its own drawbacks, necessitating careful analyses of the context of social attention and value of publication and citation sets. Perspectives of the optimal use of researcher and author metrics is dependent on evaluation purposes and compounded by information sourced from various global, national, and specialist bibliographic databases. PMID- 29713260 TI - High reduction of ozone and particulate matter during the 2016 G-20 summit in Hangzhou by forced emission controls of industry and traffic. AB - Many regions in China experience air pollution episodes because of the rapid urbanization and industrialization over the past decades. Here we analyzed the effect of emission controls implemented during the G-20 2016 Hangzhou summit on air quality. Emission controls included a forced closure of highly polluting industries, and limiting traffic and construction emissions in the cities and surroundings. Particles with aerodynamic diameter lower than 2.5 um (PM2.5) and ozone (O3) were measured. We also simulated air quality using a forecast system consisting of the two-way coupled Weather Research and Forecast and Community Multi-scale Air Quality (WRF-CMAQ) model. Results show PM2.5 and ozone levels in Hangzhou during the G-20 Summit were considerably lower than previous to the G-20 Summit. The predicted concentrations of ozone were reduced by 25.4%, whereas the predicted concentrations of PM2.5 were reduced by 56%. PMID- 29713261 TI - Transcranial Direct Current Stimulation (tDCS) Can Modulate EEG Complexity of Children With Autism Spectrum Disorder. AB - Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental disorder which affects the developmental trajectory in several behavioral domains, including impairments of social communication, cognitive and language abilities. Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique, and it was used for modulating the brain disorders. In this paper, we enrolled 13 ASD children (11 males and 2 females; mean +/- SD age: 6.5 +/- 1.7 years) to participate in our trial. Each patient received 10 treatments over the dorsolateral prefrontal cortex (DLPFC) once every 2 days. Also, we enrolled 13 ASD children (11 males and 2 females; mean +/- SD age: 6.3 +/- 1.7 years) waiting to receive therapy as controls. A maximum entropy ratio (MER) method was adapted to measure the change of complexity of EEG series. It was found that the MER value significantly increased after tDCS. This study suggests that tDCS may be a helpful tool for the rehabilitation of children with ASD. PMID- 29713262 TI - A Fast, Open EEG Classification Framework Based on Feature Compression and Channel Ranking. AB - Superior feature extraction, channel selection and classification methods are essential for designing electroencephalography (EEG) classification frameworks. However, the performance of most frameworks is limited by their improper channel selection methods and too specifical design, leading to high computational complexity, non-convergent procedure and narrow expansibility. In this paper, to remedy these drawbacks, we propose a fast, open EEG classification framework centralized by EEG feature compression, low-dimensional representation, and convergent iterative channel ranking. First, to reduce the complexity, we use data clustering to compress the EEG features channel-wise, packing the high dimensional EEG signal, and endowing them with numerical signatures. Second, to provide easy access to alternative superior methods, we structurally represent each EEG trial in a feature vector with its corresponding numerical signature. Thus, the recorded signals of many trials shrink to a low-dimensional structural matrix compatible with most pattern recognition methods. Third, a series of effective iterative feature selection approaches with theoretical convergence is introduced to rank the EEG channels and remove redundant ones, further accelerating the EEG classification process and ensuring its stability. Finally, a classical linear discriminant analysis (LDA) model is employed to classify a single EEG trial with selected channels. Experimental results on two real world brain-computer interface (BCI) competition datasets demonstrate the promising performance of the proposed framework over state-of-the-art methods. PMID- 29713263 TI - Music Evolution in the Laboratory: Cultural Transmission Meets Neurophysiology. AB - In recent years, there has been renewed interest in the biological and cultural evolution of music, and specifically in the role played by perceptual and cognitive factors in shaping core features of musical systems, such as melody, harmony, and rhythm. One proposal originates in the language sciences. It holds that aspects of musical systems evolve by adapting gradually, in the course of successive generations, to the structural and functional characteristics of the sensory and memory systems of learners and "users" of music. This hypothesis has found initial support in laboratory experiments on music transmission. In this article, we first review some of the most important theoretical and empirical contributions to the field of music evolution. Next, we identify a major current limitation of these studies, i.e., the lack of direct neural support for the hypothesis of cognitive adaptation. Finally, we discuss a recent experiment in which this issue was addressed by using event-related potentials (ERPs). We suggest that the introduction of neurophysiology in cultural transmission research may provide novel insights on the micro-evolutionary origins of forms of variation observed in cultural systems. PMID- 29713265 TI - Septal and Hippocampal Neurons Contribute to Auditory Relay and Fear Conditioning. AB - The hippocampus has been thought to process auditory information. However, the properties, pathway, and role of hippocampal auditory responses are unclear. With loose-patch recordings, we found that hippocampal neurons are mainly responsive to noise and are not tonotopically organized. Their latencies are shorter than those of primary auditory cortical (A1) neurons but longer than those of medial septal (MS) neurons, suggesting that hippocampal auditory information comes from MS neurons rather than from A1 neurons. Silencing the MS blocks both hippocampal auditory responses and memory of auditory fear conditioning trained with noise and tone. Auditory fear conditioning was associated with some cues but not with a specific frequency of sound, as demonstrated by animals trained with noise, 2.5-, 5-, 10-, 15-, or 30-kHz tones, and tested with these sounds. Therefore, the noise responses of hippocampal neurons have identified a population of neurons that can be associated with auditory fear conditioning. PMID- 29713266 TI - The Effect of Single Pyramidal Neuron Firing Within Layer 2/3 and Layer 4 in Mouse V1. AB - : The influence of cortical cell spiking activity on nearby cells has been studied extensively in vitro. Less is known, however, about the impact of single cell firing on local cortical networks in vivo. In a pioneering study, Kwan and Dan (Kwan and Dan, 2012) reported that in mouse layer 2/3 (L2/3), under anesthesia, stimulating a single pyramidal cell recruits ~2.1% of neighboring units. Here we employ two-photon calcium imaging in layer 2/3 of mouse V1, in conjunction with single-cell patch clamp stimulation in layer 2/3 or layer 4, to probe, in both the awake and lightly anesthetized states, how (i) activating single L2/3 pyramidal neurons recruits neighboring units within L2/3 and from layer 4 (L4) to L2/3, and whether (ii) activating single pyramidal neurons changes population activity in local circuit. To do this, it was essential to develop an algorithm capable of quantifying how sensitive the calcium signal is at detecting effectively recruited units ("followers"). This algorithm allowed us to estimate the chance of detecting a follower as a function of the probability that an epoch of stimulation elicits one extra action potential (AP) in the follower cell. Using this approach, we found only a small fraction (<0.75%) of L2/3 cells to be significantly activated within a radius of ~200 MUm from a stimulated neighboring L2/3 pyramidal cell. This fraction did not change significantly in the awake vs. the lightly anesthetized state, nor when stimulating L2/3 vs. underlying L4 pyramidal neurons. These numbers are in general agreement with, though lower than, the percentage of neighboring cells (2.1% pyramidal cells and interneurons combined) reported by Kwan and Dan to be activated upon stimulating single L2/3 pyramidal neurons under anesthesia (Kwan and Dan, 2012). Interestingly, despite the small number of individual units found to be reliably driven, we did observe a modest but significant elevation in aggregate population responses compared to sham stimulation. This underscores the distributed impact that single cell stimulation has on neighboring microcircuit responses, revealing only a small minority of relatively strongly connected partners. One sentence summary: Patch-clamp stimulation in conjunction with 2 photon imaging shows that activating single layer-2/3 or layer-4 pyramidal neurons produces few (<1% of local units) reliable single-cell followers in L2/3 of mouse area V1, either under light anesthesia or in quiet wakefulness: instead, single cell stimulation was found to elevate aggregate population activity in a weak but highly distributed fashion. PMID- 29713264 TI - Modeling Fragile X Syndrome in Drosophila. AB - Intellectual disability (ID) and autism are hallmarks of Fragile X Syndrome (FXS), a hereditary neurodevelopmental disorder. The gene responsible for FXS is Fragile X Mental Retardation gene 1 (FMR1) encoding the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein involved in RNA metabolism and modulating the expression level of many targets. Most cases of FXS are caused by silencing of FMR1 due to CGG expansions in the 5'-UTR of the gene. Humans also carry the FXR1 and FXR2 paralogs of FMR1 while flies have only one FMR1 gene, here called dFMR1, sharing the same level of sequence homology with all three human genes, but functionally most similar to FMR1. This enables a much easier approach for FMR1 genetic studies. Drosophila has been widely used to investigate FMR1 functions at genetic, cellular, and molecular levels since dFMR1 mutants have many phenotypes in common with the wide spectrum of FMR1 functions that underlay the disease. In this review, we present very recent Drosophila studies investigating FMRP functions at genetic, cellular, molecular, and electrophysiological levels in addition to research on pharmacological treatments in the fly model. These studies have the potential to aid the discovery of pharmacological therapies for FXS. PMID- 29713267 TI - Callosal Influence on Visual Receptive Fields Has an Ocular, an Orientation-and Direction Bias. AB - One leading hypothesis on the nature of visual callosal connections (CC) is that they replicate features of intrahemispheric lateral connections. However, CC act also in the central part of the binocular visual field. In agreement, early experiments in cats indicated that they provide the ipsilateral eye part of binocular receptive fields (RFs) at the vertical midline (Berlucchi and Rizzolatti, 1968), and play a key role in stereoscopic function. But until today callosal inputs to receptive fields activated by one or both eyes were never compared simultaneously, because callosal function has been often studied by cutting or lesioning either corpus callosum or optic chiasm not allowing such a comparison. To investigate the functional contribution of CC in the intact cat visual system we recorded both monocular and binocular neuronal spiking responses and receptive fields in the 17/18 transition zone during reversible deactivation of the contralateral hemisphere. Unexpectedly from many of the previous reports, we observe no change in ocular dominance during CC deactivation. Throughout the transition zone, a majority of RFs shrink, but several also increase in size. RFs are significantly more affected for ipsi- as opposed to contralateral stimulation, but changes are also observed with binocular stimulation. Noteworthy, RF shrinkages are tiny and not correlated to the profound decreases of monocular and binocular firing rates. They depend more on orientation and direction preference than on eccentricity or ocular dominance of the receiving neuron's RF. Our findings confirm that in binocularly viewing mammals, binocular RFs near the midline are constructed via the direct geniculo-cortical pathway. They also support the idea that input from the two eyes complement each other through CC: Rather than linking parts of RFs separated by the vertical meridian, CC convey a modulatory influence, reflecting the feature selectivity of lateral circuits, with a strong cardinal bias. PMID- 29713268 TI - Lateral Hypothalamus as a Motivation-Cognition Interface in the Control of Feeding Behavior. AB - Converging evidence for an essential function of the lateral hypothalamus (LHA) in the control of feeding behavior has been accumulating since the classic work conducted almost 80 years ago. The LHA is also important in reward and reinforcement processes and behavioral state control. A unifying function for the LHA across these processes has not been fully established. Nonetheless, it is considered to integrate motivation with behavior. More recent work has demonstrated that the LHA is also required when cognitive processes, such as associative learning and memory control feeding behavior, suggesting it may serve as a motivation-cognition interface. Structurally, the LHA is well positioned within the cerebral hemisphere, with its extensive connectional network across the forebrain-brainstem axis, to link motivational and behavioral systems with cognitive processes. Studies that examined how learned cues control food seeking and consumption have implicated the LHA, but due to methodological limitations could not determine whether it underlies motivation, learning, or the integration of these processes. Furthermore, the identification of specific substrates has been limited by the LHA's extraordinary complexity and heterogeneity. Recent methodological advancements with chemo-and opto-genetic approaches have enabled unprecedented specificity in interrogations of distinct neurons and their pathways in behaving animals, including manipulations during temporally distinct events. These approaches have revealed novel insights about the LHA structure and function. Recent findings that the GABA LHA neurons control feeding and food reward learning and memory will be reviewed together with past work within the context of the LHA function as an interface between cognition and motivation. PMID- 29713270 TI - Eye Movements During Everyday Behavior Predict Personality Traits. AB - Besides allowing us to perceive our surroundings, eye movements are also a window into our mind and a rich source of information on who we are, how we feel, and what we do. Here we show that eye movements during an everyday task predict aspects of our personality. We tracked eye movements of 42 participants while they ran an errand on a university campus and subsequently assessed their personality traits using well-established questionnaires. Using a state-of-the art machine learning method and a rich set of features encoding different eye movement characteristics, we were able to reliably predict four of the Big Five personality traits (neuroticism, extraversion, agreeableness, conscientiousness) as well as perceptual curiosity only from eye movements. Further analysis revealed new relations between previously neglected eye movement characteristics and personality. Our findings demonstrate a considerable influence of personality on everyday eye movement control, thereby complementing earlier studies in laboratory settings. Improving automatic recognition and interpretation of human social signals is an important endeavor, enabling innovative design of human computer systems capable of sensing spontaneous natural user behavior to facilitate efficient interaction and personalization. PMID- 29713269 TI - Effects of Subanesthetic Ketamine Administration on Visual and Auditory Event Related Potentials (ERP) in Humans: A Systematic Review. AB - Ketamine is a non-competitive N-Methyl-D-Aspartate (NMDA) receptor antagonist whose effect in subanesthetic doses has been studied for chronic pain and mood disorders treatment. It has been proposed that ketamine could change the perception of nociceptive stimuli by modulating the cortical connectivity and altering the top-down mechanisms that control conscious pain perception. As this is a strictly central effect, it would be relevant to provide fresh insight into ketamine's effect on cortical response to external stimuli. Event-related potentials (ERPs) reflect the combined synchronic activity of postsynaptic potentials of many cortical pyramidal neurons similarly oriented, being a well established technique to study cortical responses to sensory input. Therefore, the aim of this study was to examine the current evidence of subanesthetic ketamine doses on patterns of cortical activity based on ERPs in healthy subjects. To answer the question whether ERPs could be potential markers of the cortical effects of ketamine, we conducted a systematic review of ketamine's effect on ERPs after single and repeated doses. We have searched PubMed, EMBASE and Cochrane Databases and pre-selected 141 articles, 18 of which met the inclusion criteria. Our findings suggest that after ketamine administration some ERP parameters are reduced (reduced N2, P2, and P3 amplitudes, PN and MMN) while others remain stable or are even increased (P50 reduction, PPI, P1, and N1 amplitudes). The current understanding of these effects is that ketamine alters the perceived contrast between distinct visual and auditory stimuli. The analgesic effect of ketamine might also be influenced by a decreased affective discrimination of sensorial information, a finding from studies using ketamine as a model for schizophrenia, but that can give an important hint not only for the treatment of mood disorders, but also to treat pain and ketamine abuse. PMID- 29713271 TI - Commentary: Evaluation of Phase-Amplitude Coupling in Resting State Magnetoencephalographic Signals: Effect of Surrogates and Evaluation Approach. PMID- 29713272 TI - Credibility, Replicability, and Reproducibility in Simulation for Biomedicine and Clinical Applications in Neuroscience. AB - Modeling and simulation in computational neuroscience is currently a research enterprise to better understand neural systems. It is not yet directly applicable to the problems of patients with brain disease. To be used for clinical applications, there must not only be considerable progress in the field but also a concerted effort to use best practices in order to demonstrate model credibility to regulatory bodies, to clinics and hospitals, to doctors, and to patients. In doing this for neuroscience, we can learn lessons from long-standing practices in other areas of simulation (aircraft, computer chips), from software engineering, and from other biomedical disciplines. In this manuscript, we introduce some basic concepts that will be important in the development of credible clinical neuroscience models: reproducibility and replicability; verification and validation; model configuration; and procedures and processes for credible mechanistic multiscale modeling. We also discuss how garnering strong community involvement can promote model credibility. Finally, in addition to direct usage with patients, we note the potential for simulation usage in the area of Simulation-Based Medical Education, an area which to date has been primarily reliant on physical models (mannequins) and scenario-based simulations rather than on numerical simulations. PMID- 29713273 TI - Targeting Beta-Amyloid at the CSF: A New Therapeutic Strategy in Alzheimer's Disease. AB - Although immunotherapies against the amyloid-beta (Abeta) peptide tried so date failed to prove sufficient clinical benefit, Abeta still remains the main target in Alzheimer's disease (AD). This article aims to show the rationale of a new therapeutic strategy: clearing Abeta from the CSF continuously (the "CSF-sink" therapeutic strategy). First, we describe the physiologic mechanisms of Abeta clearance and the resulting AD pathology when these mechanisms are altered. Then, we review the experiences with peripheral Abeta-immunotherapy and discuss the related hypothesis of the mechanism of action of "peripheral sink." We also present Abeta-immunotherapies acting on the CNS directly. Finally, we introduce alternative methods of removing Abeta including the "CSF-sink" therapeutic strategy. As soluble peptides are in constant equilibrium between the ISF and the CSF, altering the levels of Abeta oligomers in the CSF would also alter the levels of such proteins in the brain parenchyma. We conclude that interventions based in a "CSF-sink" of Abeta will probably produce a steady clearance of Abeta in the ISF and therefore it may represent a new therapeutic strategy in AD. PMID- 29713274 TI - Theta-Gamma Coupling and Working Memory in Alzheimer's Dementia and Mild Cognitive Impairment. AB - Working memory deficits are common among individuals with Alzheimer's dementia (AD) or mild cognitive impairment (MCI). Yet, little is known about the mechanisms underlying these deficits. Theta-gamma coupling-the modulation of high frequency gamma oscillations by low-frequency theta oscillations-is a neurophysiologic process underlying working memory. We assessed the relationship between theta-gamma coupling and working memory deficits in AD and MCI. We hypothesized that: (1) individuals with AD would display the most significant working memory impairments followed by MCI and finally healthy control (HC) participants; and (2) there would be a significant association between working memory performance and theta-gamma coupling across all participants. Ninety-eight participants completed the N-back working memory task during an electroencephalography (EEG) recording: 33 with AD (mean +/- SD age: 76.5 +/- 6.2), 34 with MCI (mean +/- SD age: 74.8 +/- 5.9) and 31 HCs (mean +/- SD age: 73.5 +/- 5.2). AD participants performed significantly worse than control and MCI participants on the 1- and 2-back conditions. Regarding theta-gamma coupling, AD participants demonstrated the lowest level of coupling followed by the MCI and finally control participants on the 2-back condition. Finally, a linear regression analysis demonstrated that theta-gamma coupling (beta = 0.69, p < 0.001) was the most significant predictor of 2-back performance. Our results provide evidence for a relationship between altered theta-gamma coupling and working memory deficits in individuals with AD and MCI. They also provide insight into a potential mechanism underlying working memory impairments in these individuals. PMID- 29713275 TI - The Novel Small Molecule STK899704 Promotes Senescence of the Human A549 NSCLC Cells by Inducing DNA Damage Responses and Cell Cycle Arrest. AB - The novel synthetic compound designated STK899704 (PubChem CID: 5455708) suppresses the proliferation of a broad range of cancer cell types. However, the details of its effect on lung cancer cells are unclear. We investigated the precise anticancer effect of STK899704 on senescence and growth arrest of A549 human non-small cell lung cancer (NSCLC) cells. STK899704 affected NSCLC cell cycle progression and decreased cell viability in a dose-dependent manner. Immunofluorescence staining revealed that STK899704 destabilized microtubules. Cell cycle analysis showed an increase in the population of NSCLC cells in the sub-G1 and G2/M phases, indicating that STK899704 might cause DNA damage via tubulin aggregation. Furthermore, we observed increased mitotic catastrophe in STK899704-treated cells. As STK899704 led to elevated levels of the p53 pathway associated proteins, it would likely affect the core DNA damage response pathway. Moreover, STK899704 promoted senescence of NSCLC cells by inducing the p53 associated DNA damage response pathways. These findings suggest that the novel anti-proliferative small molecule STK899704 promotes cell death by inducing DNA damage response pathways and senescence after cell cycle arrest, being a potential drug for treating human lung cancers. PMID- 29713276 TI - Amyotrophic Lateral Sclerosis (ALS) and Adenosine Receptors. AB - In the present review we discuss the potential involvement of adenosinergic signaling, in particular the role of adenosine receptors, in amyotrophic lateral sclerosis (ALS). Though the literature on this topic is not abundant, the information so far available on adenosine receptors in animal models of ALS highlights the interest to continue to explore the role of these receptors in this neurodegenerative disease. Indeed, all motor neurons affected in ALS are responsive to adenosine receptor ligands but interestingly, there are alterations in pre-symptomatic or early symptomatic stages that mirror those in advanced disease stages. Information starts to emerge pointing toward a beneficial role of A2A receptors (A2AR), most probably at early disease states, and a detrimental role of caffeine, in clear contrast with what occurs in other neurodegenerative diseases. However, some evidence also exists on a beneficial action of A2AR antagonists. It may happen that there are time windows where A2AR prove beneficial and others where their blockade is required. Furthermore, the same changes may not occur simultaneously at the different synapses. In line with this, it is not fully understood if ALS is a dying back disease or if it propagates in a centrifugal way. It thus seems crucial to understand how motor neuron dysfunction occurs, how adenosine receptors are involved in those dysfunctions and whether the early changes in purinergic signaling are compensatory or triggers for the disease. Getting this information is crucial before starting the design of purinergic based strategies to halt or delay disease progression. PMID- 29713277 TI - Greater Celandine's Ups and Downs-21 Centuries of Medicinal Uses of Chelidonium majus From the Viewpoint of Today's Pharmacology. AB - As antique as Dioscorides era are the first records on using Chelidonium as a remedy to several sicknesses. Inspired by the "signatura rerum" principle and an apparent ancient folk tradition, various indications were given, such as anti jaundice and cholagogue, pain-relieving, and quite often mentioned ophthalmological problems. Central and Eastern European folk medicine has always been using this herb extensively. In this region, the plant is known under many unique vernacular names, especially in Slavonic languages, associated or not with old Greek relation to "chelidon"-the swallow. Typically for Papaveroidae subfamily, yellow-colored latex is produced in abundance and leaks intensely upon injury. Major pharmacologically relevant components, most of which were first isolated over a century ago, are isoquinoline alkaloids-berberine, chelerythrine, chelidonine, coptisine, sanguinarine. Modern pharmacology took interest in this herb but it has not ended up in gaining an officially approved and evidence-based herbal medicine status. On the contrary, the number of relevant studies and publications tended to drop. Recently, some controversial reports and sometimes insufficiently proven studies appeared, suggesting anticancer properties. Anticancer potential was in line with anecdotical knowledge spread in East European countries, however, in the absence of directly-acting cytostatic compounds, some other mechanisms might be involved. Other properties that could boost the interest in this herb are antimicrobial and antiviral activities. Being a common synanthropic weed or ruderal plant, C. majus spreads in all temperate Eurasia and acclimates well to North America. Little is known about the natural variation of bioactive metabolites, including several aforementioned isoquinoline alkaloids. In this review, we put together older and recent literature data on phytochemistry, pharmacology, and clinical studies on C. majus aiming at a critical evaluation of state-of-the-art from the viewpoint of historical and folk indications. The controversies around this herb, the safety and drug quality issues and a prospective role in phytotherapy are discussed as well. PMID- 29713278 TI - Dehydroepiandrosterone Antagonizes Pain Stress-Induced Suppression of Testosterone Production in Male Rats. AB - Background: Leydig cells secrete the steroid hormone, testosterone, which is essential for male fertility and reproductive health. Stress increases the secretion of glucocorticoid [corticosterone, (CORT) in rats] that decreases circulating testosterone levels in part through a direct action on its receptors in Leydig cells. Intratesticular CORT level is dependent on oxidative inactivation of CORT by 11beta-hydroxysteroid dehydrogenase 1 (HSD11B1) in rat Leydig cells. Pain may cause the stress, thus affecting testosterone production in Leydig cells. Methods: Adult male Sprague-Dawley rats orally received vehicle control or 5 or 10 mg/kg dehydroepiandrosterone (DHEA) 0.5 h before being subjected to pain stimulation for 1, 3, and 6 h. In the present study, we investigated the time-course changes of steroidogenic gene expression levels after acute pain-induced stress in rats and the possible mechanism of DHEA that prevented it. Plasma CORT, luteinizing hormone (LH), and testosterone (T) levels were measured, and Leydig cell gene expression levels were determined. The direct regulation of HSD11B1 catalytic direction by DHEA was detected in purified rat Leydig, liver, and rat Hsd11b1-transfected COS1 cells. Results: Plasma CORT levels were significantly increased at hour 1, 3, and 6 during the pain stimulation, while plasma T levels were significantly decreased starting at hour 3 and 6. Pain-induced stress also decreased Star, Hsd3b1, and Cyp17a1 expression levels at hour 3. When 5 and 10 mg/kg DHEA were orally administered to rats 0.5 h before starting pain stimulation, DHEA prevented pain-mediated decrease in plasma T levels and the expression of Star, Hsd3b1, and Cyp17a1 without affecting plasma CORT levels. DHEA was found to modulate HSD11B1 activities by increasing its oxidative activity and decreasing its reductive activity, thus decreasing the intracellular CORT levels in Leydig cells. Conclusion: Stress induced by acute pain can inhibit Leydig cell T production by upregulation of corticosterone. DHEA can prevent the negative effects of excessive corticosterone by modulating HSD11B1 activity. PMID- 29713279 TI - Astragaloside IV Inhibits Triglyceride Accumulation in Insulin-Resistant HepG2 Cells via AMPK-Induced SREBP-1c Phosphorylation. AB - Objective: Insulin resistance (IR) is a risk factor for non-alcoholic fatty liver disease (NAFLD), which is characterized by lipid accumulation in hepatocytes. AMP activated protein kinase (AMPK)-induced sterol regulatory element binding protein 1c (SREBP-1c) phosphorylation is crucial for proper regulation of lipid metabolism in the liver. Astragaloside IV (AST-IV) was found to decrease lipid accumulation in hepatocytes by activating AMPK, which is required to regulate lipid metabolism in liver tissue by inducing SREBP-1c phosphorylation. Method: To evaluate the direct effect of AST on lipid accumulation in hepatocytes with IR and elucidate the underlying mechanisms, we induced IR in HepG2 cells, and used compound C and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR) (an AMPK inhibitor and agonist, respectively) as control substances. We evaluated glucose, triglyceride (TG), and non-esterified fatty acid (NEFA) production, as well as SREBP-1c transcription, SREBP-1c protein expression, and downstream gene expression with or without the presence of AST. We also investigated whether phosphorylation of SREBP-1c at Ser372 was required for AST function. Results: We found that AST attenuated IR and lipid accumulation in HepG2 cells. As an AMPK activator, AST promoted gene expression and activation of AMPK by increasing phosphorylation of AMPKa. AST also inhibited translocation of SREBP-1c into the nucleus of insulin-resistant HepG2 cells by inducing phosphorylation of SREBP-1c at Ser372. Conclusion: This study demonstrated that AST attenuates IR and lipid accumulation in HepG2 cells by regulating AMPK-dependent phosphorylation of SREBP 1c at Ser372, suggesting AST as a promising drug for treating hepatic steatosis. PMID- 29713280 TI - Oridonin Targets Multiple Drug-Resistant Tumor Cells as Determined by in Silico and in Vitro Analyses. AB - Drug resistance is one of the main reasons of chemotherapy failure. Therefore, overcoming drug resistance is an invaluable approach to identify novel anticancer drugs that have the potential to bypass or overcome resistance to established drugs and to substantially increase life span of cancer patients for effective chemotherapy. Oridonin is a cytotoxic diterpenoid isolated from Rabdosia rubescens with in vivo anticancer activity. In the present study, we evaluated the cytotoxicity of oridonin toward a panel of drug-resistant cancer cells overexpressing ABCB1, ABCG2, or DeltaEGFR or with a knockout deletion of TP53. Interestingly, oridonin revealed lower degree of resistance than the control drug, doxorubicin. Molecular docking analyses pointed out that oridonin can interact with Akt/EGFR pathway proteins with comparable binding energies and similar docking poses as the known inhibitors. Molecular dynamics results validated the stable conformation of oridonin docking pose on Akt kinase domain. Western blot experiments clearly revealed dose-dependent downregulation of Akt and STAT3. Pharmacogenomics analyses pointed to a mRNA signature that predicted sensitivity and resistance to oridonin. In conclusion, oridonin bypasses major drug resistance mechanisms and targets Akt pathway and might be effective toward drug refractory tumors. The identification of oridonin-specific gene expressions may be useful for the development of personalized treatment approaches. PMID- 29713281 TI - The Effectiveness and Safety of Tripterygium wilfordii Hook. F Extracts in Rheumatoid Arthritis: A Systematic Review and Meta-Analysis. AB - Objective: To conduct a meta-analysis of the effectiveness and safety of Tripterygium wilfordii Hook. F (TwHF) extracts for the treatment of rheumatoid arthritis (RA). Methods: A systematic literature search was conducted in PubMed, EMBASE, Cochrane, Medline, CNKI, SinoMed and WanFang Library till 12 July 2017. All included studies were analyzed with the use of the Review Manager 5.2 software according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement protocol. Results: Fourteen randomized controlled trials (RCTs) were identified. TwHF extracts provided a statistically significant improvement in grip strength (GS), swelling joint count (SJC) and morning stiffness (MS) compared with placebo (P < 0.001). The meta-analysis showed significant differences between TwHF extract-treated group and the DMARDs group in GS, MS, C-reactive protein (CRP), and tender joint count (TJC) (P < 0.05), aside from ESR and SJC (P > 0.05). The pooled results also displayed significant differences between the combination of TwHF extracts with DMARDs and the DMARDs alone group in ESR, CRP, SJC, and TJC (P <= 0.05). For the safety analysis, two trials favored TwHF extract-treatment and one trial favored non TWHF extract-treatment in AEs (P < 0.05). Eleven trials showed no statistically significant differences between TwHF extract-treated group and the DMARDs group (P > 0.05). Conclusions: The findings of this systematic review with meta analysis indicate that TwHF extracts provides statistically significant and clinically important improvement in RA symptoms and has an acceptable safety profile. PMID- 29713282 TI - Synergistic Killing of Polymyxin B in Combination With the Antineoplastic Drug Mitotane Against Polymyxin-Susceptible and -Resistant Acinetobacter baumannii: A Metabolomic Study. AB - Polymyxins are currently used as the last-resort antibiotics against multidrug resistant Acinetobacter baumannii. As resistance to polymyxins emerges in A. baumannii with monotherapy, combination therapy is often the only remaining treatment option. A novel approach is to employ the combination of polymyxin B with non-antibiotic drugs. In the present study, we employed metabolomics to investigate the synergistic mechanism of polymyxin B in combination with the antineoplastic drug mitotane against polymyxin-susceptible and -resistant A. baumannii. The metabolomes of four A. baumannii strains were analyzed following treatment with polymyxin B, mitotane and the combination. Polymyxin B monotherapy induced significant perturbation in glycerophospholipid (GPL) metabolism and histidine degradation pathways in polymyxin-susceptible strains, and minimal perturbation in polymyxin-resistant strains. Mitotane monotherapy induced minimal perturbation in the polymyxin-susceptible strains, but caused significant perturbation in GPL metabolism, pentose phosphate pathway and histidine degradation in the LPS-deficient polymyxin-resistant strain (FADDI-AB065). The polymyxin B - mitotane combination induced significant perturbation in all strains except the lipid A modified polymyxin-resistant FADDI-AB225 strain. For the polymyxin-susceptible strains, the combination therapy significantly perturbed GPL metabolism, pentose phosphate pathway, citric acid cycle, pyrimidine ribonucleotide biogenesis, guanine ribonucleotide biogenesis, and histidine degradation. Against FADDI-AB065, the combination significantly perturbed GPL metabolism, pentose phosphate pathway, citric acid cycle, and pyrimidine ribonucleotide biogenesis. Overall, these novel findings demonstrate that the disruption of the citric acid cycle and inhibition of nucleotide biogenesis are the key metabolic features associated with synergistic bacterial killing by the combination against polymyxin-susceptible and -resistant A. baumannii. PMID- 29713284 TI - An Integrated Proteomics and Bioinformatics Approach Reveals the Anti inflammatory Mechanism of Carnosic Acid. AB - Drastic macrophages activation triggered by exogenous infection or endogenous stresses is thought to be implicated in the pathogenesis of various inflammatory diseases. Carnosic acid (CA), a natural phenolic diterpene extracted from Salvia officinalis plant, has been reported to possess anti-inflammatory activity. However, its role in macrophages activation as well as potential molecular mechanism is largely unexplored. In the current study, we sought to elucidate the anti-inflammatory property of CA using an integrated approach based on unbiased proteomics and bioinformatics analysis. CA significantly inhibited the robust increase of nitric oxide and TNF-alpha, downregulated COX2 protein expression, and lowered the transcriptional level of inflammatory genes including Nos2, Tnfalpha, Cox2, and Mcp1 in LPS-stimulated RAW264.7 cells, a murine model of peritoneal macrophage cell line. The LC-MS/MS-based shotgun proteomics analysis showed CA negatively regulated 217 LPS-elicited proteins which were involved in multiple inflammatory processes including MAPK, nuclear factor (NF)-kappaB, and FoxO signaling pathways. A further molecular biology analysis revealed that CA effectually inactivated IKKbeta/IkappaB-alpha/NF-kappaB, ERK/JNK/p38 MAPKs, and FoxO1/3 signaling pathways. Collectively, our findings demonstrated the role of CA in regulating inflammation response and provide some insights into the proteomics-guided pharmacological mechanism study of natural products. PMID- 29713283 TI - Polygonum multiflorum Thunb.: A Review on Chemical Analysis, Processing Mechanism, Quality Evaluation, and Hepatotoxicity. AB - Polygonum multiflorum Thunb. and its processed products have been used in China for centuries due to their multiple beneficial effects to human body. Currently, liver injuries caused by taking P. multiflorum have been reported worldwide, but the potential toxic components and possible mechanism that caused hepatotoxicity remain unclear. It is worth noting that the processing procedure could significantly decrease the toxicity of raw P. multiflorum and the processed products of P. multiflorum are considered to be relatively safe. However, the processing mechanism is still ambiguous, and there is the lack of a scientific approach to control the quality of P. multiflorum praeparata. This study is the first review that summarizes the recently advances (from 2007 to 2017) in the chemical analysis of P. multiflorum, and provides comprehensive information on the quantitative and qualitative analysis of P. multiflorum as well as its related species. In addition, the processing mechanism and quality evaluation of processed P. multiflorum are discussed. Moreover, the toxicity of P. multiflorum is analyzed from the perspectives of exploration of the proposed toxic ingredients, metabolite identification, metabolomics studies, and exogenous contaminant determination. Furthermore, trends and perspectives for future research of this medicine are discussed. PMID- 29713285 TI - Inhibition of Streptococcus suis Adhesion and Biofilm Formation in Vitro by Water Extracts of Rhizoma Coptidis. AB - Streptococcus suis is difficult to treat and responsible for various infections in humans and pigs. It can also form biofilms and induce persistent infections. Rhizoma Coptidis is a medicinal plant widely used in Traditional Chinese Medicine. Although the inhibitory effects of Rhizoma Coptidis on biofilm formation have been investigated in several studies, the ability of Rhizoma Coptidis to inhibit S. suis biofilm formation and the underlying mechanisms have not yet been reported. In this study, we showed that sub-minimal inhibitory concentrations (25 and 50 MUg mL-1) of water extracts of Rhizoma Coptidis (Coptis deltoidea C.Y.Cheng & P.K.Hsiao, obtained from Sichuan Province) were sufficient to inhibit biofilm formation, as shown in the tissue culture plate (TCP) method and scanning electron microscopy. Real-time PCR and iTRAQ were used to measure gene and protein expression in S. suis. Sub-minimum inhibitory concentrations (25 and 50 MUg mL-1) of Rhizoma Coptidis water extracts inhibited S. suis adhesion significantly in an anti-adherence assay. Some genes, such as gapdh, sly, and mrp, and proteins, such as antigen-like protein, CPS16V, and methyltransferase H, involved in adhesion were significantly modulated in cells treated with 50 MUg mL 1 of Rhizoma Coptidis water extracts compared to untreated cells. The results from this study suggest that compounds in Rhizoma Coptidis water extracts play an important role in inhibiting adhesion of S. suis cells and, therefore, biofilm formation. PMID- 29713286 TI - The Wnt Signaling Pathway Effector TCF7L2 Mediates Olanzapine-Induced Weight Gain and Insulin Resistance. AB - Olanzapine is a widely used atypical antipsychotic medication for treatment of schizophrenia and is often associated with serious metabolic abnormalities including weight gain and impaired glucose tolerance. These metabolic side effects are severe clinical problems but the underpinning mechanism remains poorly understood. Recently, growing evidence suggests that Wnt signaling pathway has a critical role in the pathogenesis of schizophrenia and molecular cascades of antipsychotics action, of which Wnt signaling pathway key effector TCF7L2 is strongly associated with glucose homeostasis. In this study, we aim to explore the characteristics of metabolic disturbance induced by olanzapine and to elucidate the role of TCF7L2 in this process. C57BL/6 mice were subject to olanzapine (4 mg/kg/day), or olanzapine plus metformin (150 mg/kg/day), or saline, respectively, for 8 weeks. Metabolic indices and TCF7L2 expression levels in liver, skeletal muscle, adipose, and pancreatic tissues were closely monitored. Olanzapine challenge induced remarkably increased body weight, fasting insulin, homeostasis model assessment-insulin resistance index, and TCF7L2 protein expression in liver, skeletal muscle, and adipose tissues. Notably, these effects could be effectively ameliorated by metformin. In addition, we found that olanzapine-induced body weight gain and insulin resistance actively influence the expression of TCF7L2 in liver and skeletal muscle, and elevated level of insulin determines the increased expression of TCF7L2 in adipose tissue. Our results demonstrate that TCF7L2 participates in olanzapine-induced metabolic disturbance, which presents a novel mechanism for olanzapine-induced metabolic disturbance and a potential therapeutic target to prevent the associated metabolic side effects. PMID- 29713287 TI - Transcriptional Repression and Protein Degradation of the Ca2+-Activated K+ Channel KCa1.1 by Androgen Receptor Inhibition in Human Breast Cancer Cells. AB - The large-conductance Ca2+-activated K+ channel KCa1.1 plays an important role in the promotion of breast cancer cell proliferation and metastasis. The androgen receptor (AR) is proposed as a therapeutic target for AR-positive advanced triple negative breast cancer. We herein investigated the effects of a treatment with antiandrogens on the functional activity, activation kinetics, transcriptional expression, and protein degradation of KCa1.1 in human breast cancer MDA-MB-453 cells using real-time PCR, Western blotting, voltage-sensitive dye imaging, and whole-cell patch clamp recording. A treatment with the antiandrogen bicalutamide or enzalutamide for 48 h significantly suppressed (1) depolarization responses induced by paxilline (PAX), a specific KCa1.1 blocker and (2) PAX-sensitive outward currents induced by the depolarizing voltage step. The expression levels of KCa1.1 transcripts and proteins were significantly decreased in MDA-MB-453 cells, and the protein degradation of KCa1.1 mainly contributed to reductions in KCa1.1 activity. Among the eight regulatory beta and gamma subunits, LRRC26 alone was expressed at high levels in MDA-MB-453 cells and primary and metastatic breast cancer tissues, whereas no significant changes were observed in the expression levels of LRRC26 and activation kinetics of PAX-sensitive outward currents in MDA-MB-453 cells by the treatment with antiandrogens. The treatment with antiandrogens up-regulated the expression of the ubiquitin E3 ligases, FBW7, MDM2, and MDM4 in MDA-MB-453 cells, and the protein degradation of KCa1.1 was significantly inhibited by the respective siRNA-mediated blockade of FBW7 and MDM2. Based on these results, we concluded that KCa1.1 is an androgen-responsive gene in AR-positive breast cancer cells, and its down-regulation through enhancements in its protein degradation by FBW7 and/or MDM2 may contribute, at least in part, to the antiproliferative and antimetastatic effects of antiandrogens in breast cancer cells. PMID- 29713288 TI - 3D Fluid-Structure Interaction Simulation of Aortic Valves Using a Unified Continuum ALE FEM Model. AB - Due to advances in medical imaging, computational fluid dynamics algorithms and high performance computing, computer simulation is developing into an important tool for understanding the relationship between cardiovascular diseases and intraventricular blood flow. The field of cardiac flow simulation is challenging and highly interdisciplinary. We apply a computational framework for automated solutions of partial differential equations using Finite Element Methods where any mathematical description directly can be translated to code. This allows us to develop a cardiac model where specific properties of the heart such as fluid structure interaction of the aortic valve can be added in a modular way without extensive efforts. In previous work, we simulated the blood flow in the left ventricle of the heart. In this paper, we extend this model by placing prototypes of both a native and a mechanical aortic valve in the outflow region of the left ventricle. Numerical simulation of the blood flow in the vicinity of the valve offers the possibility to improve the treatment of aortic valve diseases as aortic stenosis (narrowing of the valve opening) or regurgitation (leaking) and to optimize the design of prosthetic heart valves in a controlled and specific way. The fluid-structure interaction and contact problem are formulated in a unified continuum model using the conservation laws for mass and momentum and a phase function. The discretization is based on an Arbitrary Lagrangian-Eulerian space-time finite element method with streamline diffusion stabilization, and it is implemented in the open source software Unicorn which shows near optimal scaling up to thousands of cores. Computational results are presented to demonstrate the capability of our framework. PMID- 29713290 TI - High Altitude Affects Nocturnal Non-linear Heart Rate Variability: PATCH-HA Study. AB - Background: High altitude (HA) exposure can lead to changes in resting heart rate variability (HRV), which may be linked to acute mountain sickness (AMS) development. Compared with traditional HRV measures, non-linear HRV appears to offer incremental and prognostic data, yet its utility and relationship to AMS have been barely examined at HA. This study sought to examine this relationship at terrestrial HA. Methods: Sixteen healthy British military servicemen were studied at baseline (800 m, first night) and over eight consecutive nights, at a sleeping altitude of up to 3600 m. A disposable cardiac patch monitor was used, to record the nocturnal cardiac inter-beat interval data, over 1 h (0200-0300 h), for offline HRV assessment. Non-linear HRV measures included Sample entropy (SampEn), the short (alpha1, 4-12 beats) and long-term (alpha2, 13-64 beats) detrend fluctuation analysis slope and the correlation dimension (D2). The maximal rating of perceived exertion (RPE), during daily exercise, was assessed using the Borg 6-20 RPE scale. Results: All subjects completed the HA exposure. The average age of included subjects was 31.4 +/- 8.1 years. HA led to a significant fall in SpO2 and increase in heart rate, LLS and RPE. There were no significant changes in the ECG-derived respiratory rate or in any of the time domain measures of HRV during sleep. The only notable changes in frequency domain measures of HRV were an increase in LF and fall in HFnu power at the highest altitude. Conversely, SampEn, SD1/SD2 and D2 all fell, whereas alpha1 and alpha2 increased (p < 0.05). RPE inversely correlated with SD1/SD2 (r = -0.31; p = 0.002), SampEn (r = -0.22; p = 0.03), HFnu (r = -0.27; p = 0.007) and positively correlated with LF (r = 0.24; p = 0.02), LF/HF (r = 0.24; p = 0.02), alpha1 (r = 0.32; p = 0.002) and alpha2 (r = 0.21; p = 0.04). AMS occurred in 7/16 subjects (43.8%) and was very mild in 85.7% of cases. HRV failed to predict AMS. Conclusion: Non-linear HRV is more sensitive to the effects of HA than time and frequency domain indices. HA leads to a compensatory decrease in nocturnal HRV and complexity, which is influenced by the RPE measured at the end of the previous day. HRV failed to predict AMS development. PMID- 29713289 TI - The Molecular Basis for Altered Cation Permeability in Hereditary Stomatocytic Human Red Blood Cells. AB - Normal human RBCs have a very low basal permeability (leak) to cations, which is continuously corrected by the Na,K-ATPase. The leak is temperature-dependent, and this temperature dependence has been evaluated in the presence of inhibitors to exclude the activity of the Na,K-ATPase and NaK2Cl transporter. The severity of the RBC cation leak is altered in various conditions, most notably the hereditary stomatocytosis group of conditions. Pedigrees within this group have been classified into distinct phenotypes according to various factors, including the severity and temperature-dependence of the cation leak. As recent breakthroughs have provided more information regarding the molecular basis of hereditary stomatocytosis, it has become clear that these phenotypes elegantly segregate with distinct genetic backgrounds. The cryohydrocytosis phenotype, including South-east Asian Ovalocytosis, results from mutations in SLC4A1, and the very rare condition, stomatin-deficient cryohydrocytosis, is caused by mutations in SLC2A1. Mutations in RHAG cause the very leaky condition over-hydrated stomatocytosis, and mutations in ABCB6 result in familial pseudohyperkalemia. All of the above are large multi-spanning membrane proteins and the mutations may either modify the structure of these proteins, resulting in formation of a cation pore, or otherwise disrupt the membrane to allow unregulated cation movement across the membrane. More recently mutations have been found in two RBC cation channels, PIEZO1 and KCNN4, which result in dehydrated stomatocytosis. These mutations alter the activation and deactivation kinetics of these channels, leading to increased opening and allowing greater cation fluxes than in wild type. PMID- 29713291 TI - Byssus Structure and Protein Composition in the Highly Invasive Fouling Mussel Limnoperna fortunei. AB - Biofouling mediated by byssus adhesion in invasive bivalves has become a global environmental problem in aquatic ecosystems, resulting in negative ecological and economic consequences. Previous studies suggested that mechanisms responsible for byssus adhesion largely vary among bivalves, but it is poorly understood in freshwater species. Understanding of byssus structure and protein composition is the prerequisite for revealing these mechanisms. Here, we used multiple methods, including scanning electron microscope, liquid chromatography-tandem mass spectrometry, transcriptome sequencing, real-time quantitative PCR, inductively coupled plasma mass spectrometry, to investigate structure, and protein composition of byssus in the highly invasive freshwater mussel Limnoperna fortunei. The results indicated that the structure characteristics of adhesive plaque, proximal and distal threads were conducive to byssus adhesion, contributing to the high biofouling capacity of this species. The 3,4 dihydroxyphenyl-alpha-alanine (Dopa) is a major post-transnationally modification in L. fortunei byssus. We identified 16 representative foot proteins with typical repetitive motifs and conserved domains by integrating transcriptomic and proteomic approaches. In these proteins, Lfbp-1, Lffp-2, and Lfbp-3 were specially located in foot tissue and highly expressed in the rapid byssus formation period, suggesting the involvement of these foot proteins in byssus production and adhesion. Multiple metal irons, including Ca2+, Mg2+, Zn2+, Al3+, and Fe3+, were abundant in both foot tissue and byssal thread. The heavy metals in these irons may be directly accumulated by L. fortunei from surrounding environments. Nevertheless, some metal ions (e.g., Ca2+) corresponded well with amino acid preferences of L. fortunei foot proteins, suggesting functional roles of these metal ions by interacting with foot proteins in byssus adhesion. Overall, this study provides structural and molecular bases of adhesive mechanisms of byssus in L. fortunei, and findings here are expected to develop strategies against biofouling by freshwater organisms. PMID- 29713292 TI - Avatar Therapy for Persistent Auditory Verbal Hallucinations in an Ultra Resistant Schizophrenia Patient: A Case Report. AB - Effective treatment strategies for schizophrenia remain very challenging and many treatment-resistant patients will suffer from persistent auditory verbal hallucinations (AVH). While clozapine is the gold-standard medication for this complex population, many will not respond to this molecule. For these ultra resistant patients, limited options are available. Cognitive-behavioral therapy (CBT) is the most widely used psychological intervention, though it offers modest effects. With the interpersonal dimension of AVH being recognized, Avatar Therapy (AT), a novel experiential treatment enabling patients to create an avatar of their persecutor and allowing them to gain control over their symptoms, was developed and tested. Results have shown significant improvements in AVH symptomatology. This paper details a case report showcasing the beneficial results of AT for even the most severe and symptomatic cases of schizophrenia. Mr. Smith has been afflicted with the persistency of all his voices for almost 20 years. To our knowledge, this patient tried almost all possible treatments with little efficacy. This case highlights the difficulty of finding an adequate treatment for ultra-resistant patients. Mr. Smith first followed CBT before initiating AT. With AT, he significantly improved in a way that was not observed with any other intervention and these improvements remained afterward. The severity of his positive symptoms as well as his depressive symptoms diminished, and his most distressing persecutory voice disappeared. He was able to regain a life. The effects of AT went well beyond the patient, the morale of the entire family improved. This ultra-resistant case suggests that AT may be a promising intervention for refractory AVH in schizophrenia. PMID- 29713293 TI - Neurocognitive Impairments Are More Severe in the Binge-Eating/Purging Anorexia Nervosa Subtype Than in the Restricting Subtype. AB - Objective: To evaluate cognitive function impairment in patients with anorexia nervosa (AN) of either the restricting (ANR) or binge-eating/purging (ANBP) subtype. Method: We administered the Japanese version of the MATRICS Consensus Cognitive Battery to 22 patients with ANR, 18 patients with ANBP, and 69 healthy control subjects. Our participants were selected from among the patients at the Kobe University Hospital and community residents. Results: Compared to the healthy controls, the ANR group had significantly lower visual learning and social cognition scores, and the ANBP group had significantly lower processing speed, attention/vigilance, visual learning, reasoning/problem-solving, and social cognition scores. Compared to the ANR group, the ANBP group had significantly lower attention/vigilance scores. Discussion: The AN subtypes differed in cognitive function impairments. Participants with ANBP, which is associated with higher mortality rates than ANR, exhibited greater impairment severities, especially in the attention/vigilance domain, confirming the presence of impairments in continuous concentration. This may relate to the impulsivity, an ANBP characteristic reported in the personality research. Future studies can further clarify the cognitive impairments of each subtype by addressing the subtype cognitive functions and personality characteristics. PMID- 29713294 TI - Characteristics and Pathways of Long-Stay Patients in High and Medium Secure Settings in England; A Secondary Publication From a Large Mixed-Methods Study. AB - Background: Many patients experience extended stays within forensic care, but the characteristics of long-stay patients are poorly understood. Aims: To describe the characteristics of long-stay patients in high and medium secure settings in England. Method: Detailed file reviews provided clinical, offending and risk data for a large representative sample of 401 forensic patients from 2 of the 3 high secure settings and from 23 of the 57 medium secure settings in England on 1 April 2013. The threshold for long-stay status was defined as 5 years in medium secure care or 10 years in high secure care, or 15 years in a combination of high and medium secure settings. Results: 22% of patients in high security and 18% in medium security met the definition for "long-stay," with 20% staying longer than 20 years. Of the long-stay sample, 58% were violent offenders (22% both sexual and violent), 27% had been convicted for violent or sexual offences whilst in an institutional setting, and 26% had committed a serious assault on staff in the last 5 years. The most prevalent diagnosis was schizophrenia (60%) followed by personality disorder (47%, predominantly antisocial and borderline types); 16% were categorised as having an intellectual disability. Overall, 7% of the long stay sample had never been convicted of any offence, and 16.5% had no index offence prompting admission. Although some significant differences were found between the high and medium secure samples, there were more similarities than contrasts between these two levels of security. The treatment pathways of these long-stay patients involved multiple moves between settings. An unsuccessful referral to a setting of lower security was recorded over the last 5 years for 33% of the sample. Conclusions: Long-stay patients accounted for one fifth of the forensic inpatient population in England in this representative sample. A significant proportion of this group remain unsettled. High levels of personality pathology and the risk of assaults on staff and others within the care setting are likely to impact on treatment and management. Further research into the treatment pathways of longer stay patients is warranted to understand the complex trajectories of this group. PMID- 29713296 TI - Statistical Models for Predicting Threat Detection From Human Behavior. AB - Users must regularly distinguish between secure and insecure cyber platforms in order to preserve their privacy and safety. Mouse tracking is an accessible, high resolution measure that can be leveraged to understand the dynamics of perception, categorization, and decision-making in threat detection. Researchers have begun to utilize measures like mouse tracking in cyber security research, including in the study of risky online behavior. However, it remains an empirical question to what extent real-time information about user behavior is predictive of user outcomes and demonstrates added value compared to traditional self-report questionnaires. Participants navigated through six simulated websites, which resembled either secure "non-spoof" or insecure "spoof" versions of popular websites. Websites also varied in terms of authentication level (i.e., extended validation, standard validation, or partial encryption). Spoof websites had modified Uniform Resource Locator (URL) and authentication level. Participants chose to "login" to or "back" out of each website based on perceived website security. Mouse tracking information was recorded throughout the task, along with task performance. After completing the website identification task, participants completed a questionnaire assessing their security knowledge and degree of familiarity with the websites simulated during the experiment. Despite being primed to the possibility of website phishing attacks, participants generally showed a bias for logging in to websites versus backing out of potentially dangerous sites. Along these lines, participant ability to identify spoof websites was around the level of chance. Hierarchical Bayesian logistic models were used to compare the accuracy of two-factor (i.e., website security and encryption level), survey-based (i.e., security knowledge and website familiarity), and real-time measures (i.e., mouse tracking) in predicting risky online behavior during phishing attacks. Participant accuracy in identifying spoof and non-spoof websites was best captured using a model that included real time indicators of decision-making behavior, as compared to two-factor and survey based models. Findings validate three widely applicable measures of user behavior derived from mouse tracking recordings, which can be utilized in cyber security and user intervention research. Survey data alone are not as strong at predicting risky Internet behavior as models that incorporate real-time measures of user behavior, such as mouse tracking. PMID- 29713295 TI - The Relationship Between Alexithymia and Emotional Awareness: A Meta-Analytic Review of the Correlation Between TAS-20 and LEAS. AB - Background: Alexithymia and emotional awareness may be considered overlapping constructs and both have been shown to be related to psychological and emotional well-being. However, it is not clear how the constructs relate to each other empirically or if they may overlap more or less in different populations. The aim of this review was therefore to conduct a meta-analysis of correlations between the most commonly used measures of alexithymia (i.e., the self-report instrument Toronto Alexithymia Scale; TAS-20) and emotional awareness (i.e., the observer rated instrument Level of Emotional Awareness Scale; LEAS) and to explore potential moderators of their relationship. Methods: Electronic databases were searched for studies published until the end of February 2018. Study samples were coded as medical conditions, psychiatric disorders and/or healthy controls and sample mean age and gender distribution were extracted. Correlations between the TAS-20 and the LEAS were subjected to a random effect of meta-analysis and moderators were explored in subgroup analyses and meta-regressions. Publication bias was considered. Results: 21 studies reporting on 28 independent samples on correlation analysis were included, encompassing a total of 2857 subjects (57% women). The aggregated correlation between TAS-20 and LEAS was r = -0.122 (95% CI [-0.180, -0.064]; Z = -4.092; p < 0.001), indicating a significant, but weak, negative relationship between the measures. Heterogeneity was moderate, but we found no indication of significant differences between patients with medical conditions, psychiatric disorders or healthy controls, nor that mean age or percentage of female subjects moderated the relationship. The overall estimate became somewhat weaker after adjusting for possible publication bias. Conclusions: Our results indicate that TAS-20 and LEAS measure different aspects of emotional functioning. The small overlap suggests that alexithymia and emotional awareness are distinct constructs of emotional well-being. Clinicians need to assess both aspects when considering treatment options for individual patients. Moreover, from the clinical standpoint, an easy reliable and valid way of measuring emotional awareness is still needed. More research should be focus on the differences between alexithymia and emotional awareness in specific conditions, but also how to integrate self-report instrument and observed based measures in a clinical situation. PMID- 29713298 TI - Modeling Linguistic Variables With Regression Models: Addressing Non-Gaussian Distributions, Non-independent Observations, and Non-linear Predictors With Random Effects and Generalized Additive Models for Location, Scale, and Shape. AB - As statistical approaches are getting increasingly used in linguistics, attention must be paid to the choice of methods and algorithms used. This is especially true since they require assumptions to be satisfied to provide valid results, and because scientific articles still often fall short of reporting whether such assumptions are met. Progress is being, however, made in various directions, one of them being the introduction of techniques able to model data that cannot be properly analyzed with simpler linear regression models. We report recent advances in statistical modeling in linguistics. We first describe linear mixed effects regression models (LMM), which address grouping of observations, and generalized linear mixed-effects models (GLMM), which offer a family of distributions for the dependent variable. Generalized additive models (GAM) are then introduced, which allow modeling non-linear parametric or non-parametric relationships between the dependent variable and the predictors. We then highlight the possibilities offered by generalized additive models for location, scale, and shape (GAMLSS). We explain how they make it possible to go beyond common distributions, such as Gaussian or Poisson, and offer the appropriate inferential framework to account for 'difficult' variables such as count data with strong overdispersion. We also demonstrate how they offer interesting perspectives on data when not only the mean of the dependent variable is modeled, but also its variance, skewness, and kurtosis. As an illustration, the case of phonemic inventory size is analyzed throughout the article. For over 1,500 languages, we consider as predictors the number of speakers, the distance from Africa, an estimation of the intensity of language contact, and linguistic relationships. We discuss the use of random effects to account for genealogical relationships, the choice of appropriate distributions to model count data, and non-linear relationships. Relying on GAMLSS, we assess a range of candidate distributions, including the Sichel, Delaporte, Box-Cox Green and Cole, and Box Cox t distributions. We find that the Box-Cox t distribution, with appropriate modeling of its parameters, best fits the conditional distribution of phonemic inventory size. We finally discuss the specificities of phoneme counts, weak effects, and how GAMLSS should be considered for other linguistic variables. PMID- 29713297 TI - Metabolic and Electrophysiological Changes Associated to Clinical Improvement in Two Severely Traumatized Subjects Treated With EMDR-A Pilot Study. AB - Neuroimaging represents a powerful tool to investigate the neurobiological correlates of Eye Movements Desensitization and Reprocessing (EMDR). The impact of EMDR on cortical and sub-cortical brain regions has been proven by several investigations demonstrating a clear association between symptoms disappearance and changes in cortical structure and functionality. The aim of this study was to assess by electroencephalography (EEG) and for the first time by positron emission tomography (PET) the changes occurring after EMDR therapy in two cases of psychological trauma following brain concussion and comatose state due to traffic accident. A 28 and a 29 years old men underwent extensive neuropsychological examination, which investigated: (i) categorical and phonological verbal fluency; (ii) episodic verbal memory; (iii) executive functions; (iv) visuospatial abilities; (v) attention and working memory as well as clinical assessment by means of psychopathological tests (CAPS, IES, BDI, SCL90R, and DES). They were then treated by eight sessions of EMDR. During the first session EEG monitoring was continuously performed and 18F-FDG PET scans, depicting brain metabolism, were acquired at rest within a week (T0). After the last session, in which the two clients were considered to be symptoms-free, neuropsychological, clinical, and PET assessment were repeated (T1). PET data were semi-quantitatively compared to a group of 18 normal controls, as for EEG the preferential cortical activations were disclosed by thresholding the individual z-score to a p < 0.05. There was a significant improvement in clinical condition for both clients associated with a significant decrease in CAPS scores. IES and BDI were found to be pathological at T0 and improved at T1 in only one subject. Visuo-constructive abilities and abstract reasoning improved after EMDR in both subjects. As for EEG, the most striking changes occurred in fronto temporal-parietal cortex in subject 1 while subject 2 showed only minor changes. PET showed more pronounced metabolism in orbito-frontal and prefrontal cortex at T1 as compared to T0 in both subjects. In conclusion both clients had a clear clinical improvement in PTSD symptoms associated with metabolic and electrophysiological changes in limbic and associative cortex, respectively, highlighting the value of EMDR also in such extreme pathological conditions. PMID- 29713299 TI - Regional Cultures and the Psychological Geography of Switzerland: Person Environment-Fit in Personality Predicts Subjective Wellbeing. AB - The present study extended traditional nation-based research on person-culture fit to the regional level. First, we examined the geographical distribution of Big Five personality traits in Switzerland. Across the 26 Swiss cantons, unique patterns were observed for all traits. For Extraversion and Neuroticism clear language divides emerged between the French- and Italian-speaking South-West vs. the German-speaking North-East. Second, multilevel modeling demonstrated that person-environment-fit in Big Five, composed of elevation (i.e., mean differences between individual profile and cantonal profile), scatter (differences in mean variances) and shape (Pearson correlations between individual and cantonal profiles across all traits; Furr, 2008, 2010), predicted the development of subjective wellbeing (i.e., life satisfaction, satisfaction with personal relationships, positive affect, negative affect) over a period of 4 years. Unexpectedly, while the effects of shape were in line with the person-environment fit hypothesis (better fit predicted higher subjective wellbeing), the effects of scatter showed the opposite pattern, while null findings were observed for elevation. Across a series of robustness checks, the patterns for shape and elevation were consistently replicated. While that was mostly the case for scatter as well, the effects of scatter appeared to be somewhat less robust and more sensitive to the specific way fit was modeled when predicting certain outcomes (negative affect, positive affect). Distinguishing between supplementary and complementary fit may help to reconcile these findings and future research should explore whether and if so under which conditions these concepts may be applicable to the respective facets of person-culture-fit. PMID- 29713300 TI - Illustration of Step-Wise Latent Class Modeling With Covariates and Taxometric Analysis in Research Probing Children's Mental Models in Learning Sciences. AB - This paper illustrates two psychometric methods, latent class analysis (LCA) and taxometric analysis (TA) using empirical data from research probing children's mental representation in science learning. LCA is used to obtain a typology based on observed variables and to further investigate how the encountered classes might be related to external variables, where the effectiveness of classification process and the unbiased estimations of parameters become the main concern. In the step-wise LCA, the class membership is assigned and subsequently its relationship with covariates is established. This leading-edge modeling approach suffers from severe downward-biased estimations. The illustration of LCA is focused on alternative bias correction approaches and demonstrates the effect of modal and proportional class-membership assignment along with BCH and ML correction procedures. The illustration of LCA is presented with three covariates, which are psychometric variables operationalizing formal reasoning, divergent thinking and field dependence-independence, respectively. Moreover, taxometric analysis, a method designed to detect the type of the latent structural model, categorical or dimensional, is introduced, along with the relevant basic concepts and tools. TA was applied complementarily in the same data sets to answer the fundamental hypothesis about children's naive knowledge on the matters under study and it comprises an additional asset in building theory which is fundamental for educational practices. Taxometric analysis provided results that were ambiguous as far as the type of the latent structure. This finding initiates further discussion and sets a problematization within this framework rethinking fundamental assumptions and epistemological issues. PMID- 29713302 TI - Alleviation of Psychological Distress and the Improvement of Quality of Life in Patients With Amyotrophic Lateral Sclerosis: Adaptation of a Short-Term Psychotherapeutic Intervention. AB - Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease that is inevitably fatal. To be diagnosed with a terminal illness such as ALS deeply affects one's personal existence and goes along with significant changes regarding the physical, emotional, and social domains of the patients' life. ALS patients have to face a rapidly debilitating physical decline which restrains mobility and impairs all activities of daily living. This progressive loss of autonomy may lead to a sense of hopelessness and loss of quality of life, which in turn may even result in thoughts about physician-assisted suicide. Here, we would like to propose a psychotherapeutic manualized, individual, semi-structured intervention to relieve distress and promote psychological well-being in ALS patients. This short-term intervention was originally developed for advanced cancer patients. "Managing Cancer and Living Meaningfully (CALM)" focuses on the four dimensions: (i) symptom management and communication with healthcare providers, (ii) changes in self and relations with close others, (iii) spirituality, sense of meaning and purpose and (iv) thinking of the future, hope, and mortality. We suggest to supplement the concept by two additional dimensions which take into account specific issues of ALS patients: (v) communication skills, and (vi) emotional expression and control. This therapeutic concept named "ManagIng Burden in ALS and Living Meaningfully (mi-BALM)" may be a further treatment option to help improving quality of life of ALS patients. PMID- 29713301 TI - The Senses of Agency and Ownership: A Review. AB - Usually, we do not question that we possess a body and act upon the world. This pre-reflective awareness of being a bodily and agentive self can, however, be disrupted by different clinical conditions. Whereas sense of ownership (SoO) describes the feeling of mineness toward one's own body parts, feelings or thoughts, sense of agency (SoA) refers to the experience of initiating and controlling an action. Although SoA and SoO naturally coincide, both experiences can also be made in isolation. By using many different experimental paradigms, both experiences have been extensively studied over the last years. This review introduces both concepts, with a special focus also onto their interplay. First, current experimental paradigms, results and neurocognitive theories about both concepts will be presented and then their clinical and therapeutic relevance is discussed. PMID- 29713303 TI - Association Between Peripheral Inflammation and DATSCAN Data of the Striatal Nuclei in Different Motor Subtypes of Parkinson Disease. AB - The interplay between peripheral and central inflammation has a significant role in dopaminergic neural death in nigrostriatal pathway, although no direct assessment of inflammation has been performed in relation to dopaminergic neuronal loss in striatal nuclei. In this study, the correlation of neutrophil to lymphocyte ratio (NLR) as a marker of peripheral inflammation to striatal binding ratios (SBRs) of DAT SPECT images in bilateral caudate and putamen nuclei was calculated in 388 drug-naive early PD patients [288 tremor dominant (TD), 73 postural instability and gait difficulty (PIGD), and 27 indeterminate] and 148 controls. NLR was significantly higher in PD patients than in age- and sex matched healthy controls, and showed a negative correlation to SBR in bilateral putamen and ipsilateral caudate in all PD subjects. Among our three subgroups, only TD patients showed remarkable results. A positive association between NLR and motor severity was observed in TD subgroup. Besides, NLR could negatively predict the SBR in ipsilateral and contralateral putamen and caudate nuclei in tremulous phenotype. Nonetheless, we found no significant association between NLR and other clinical and imaging findings in PIGD and indeterminate subgroups, supporting the presence of distinct underlying pathologic mechanisms between tremor and non-tremor predominant PD at early stages of the disease. PMID- 29713305 TI - Periprocedural Antithrombotic Treatment During Acute Mechanical Thrombectomy for Ischemic Stroke: A Systematic Review. AB - Background: More than one-third of the patients with ischemic stroke caused by an intracranial large vessel occlusion do not recover to functional independence despite fast and successful recanalization by acute mechanical thrombectomy (MT). This may partially be explained by incomplete microvascular reperfusion. Some antithrombotics, e.g., antiplatelet agents and heparin, may be able to restore microvascular reperfusion. However, antithrombotics may also increase the risk of symptomatic intracranial hemorrhage (sICH). The aim of this review was to assess the potential safety and functional outcome of periprocedural antiplatelet or heparin use during acute MT for ischemic stroke. Methods: We systematically searched PubMed, Embase, Medline, Web of Science, and Cochrane for studies investigating the safety and functional outcome of periprocedural antiplatelet or heparin treatment during acute MT for ischemic stroke. The primary outcome was the risk for sICH. Secondary outcomes were functional independence after 3-6 months (modified Rankin Scale 0-2) and mortality within 6 months. Results: 837 studies were identified through the search, of which 19 studies were included. The sICH risks of the periprocedural use of antiplatelets ranged from 6 to 17%, and for heparin from 5 to 12%. Two of four studies reporting relative effects of the use of antithrombotics are pointing toward an increased risk of sICH. Among patients treated with antiplatelet agents, functional independence varied from 23 to 60% and mortality from 18 to 33%. For heparin, this was, respectively, 19-54% and 19-33%. The three studies presenting relative effects of antiplatelets on functional independence showed neutral effects. Both studies reporting relative effects of heparin on functional independence found it to increase this chance. Conclusion: Randomized controlled trials investigating the effect of periprocedural antithrombotic treatment in MT are lacking. Some observational studies report a slight increase in sICH risk, which may be acceptable because they also suggest a beneficial effect on functional outcome. Therefore, randomized controlled trials are warranted to address the question whether the potentially higher risk of sICH could be outweighed by improved functional outcome. PMID- 29713306 TI - Association Between Carotid Artery Function and Structure in the Northern Manhattan Study. AB - Background and purpose: Carotid plaque (CP), carotid intima media thickness (cIMT), and stiffness (STIFF) are pre-clinical markers of atherosclerosis and predictors of cerebrovascular disease (CVD). We sought to investigate whether STIFF is a significant determinant of cIMT and CP, which may provide an insight into the mechanism by which STIFF adds to the risk of CVD. Methods: We analyzed 876 stroke-free subjects from the Northern Manhattan Study with available ultrasound measures. To obtain the associations with STIFF, we performed multivariable-adjusted regression, negative binomial regression (for CP number), and multinomial logistic regression (for plaque area). Results: The mean age was 64 +/- 9 years; 63% women and 65% Caribbean Hispanics. The mean cIMT was 0.93 +/- 0.9 mm, the mean diastolic diameter 6.24 +/- 0.94 mm, and STIFF 8.6 +/- 6.2 ln mmHg. Prevalence of CP was 57%, and the mean total plaque area was 22.6 +/- 23.0 mm2. STIFF was positively associated with cIMT but not with CP. There was an association between diastolic diameter and thick plaque. For each millimeter increase in diastolic diameter, there was about a 20% increased risk of having thick plaque (vs. no plaque). In longitudinal analyses, each millimeter increase in diastolic diameter was associated with a 37% increased risk of incident plaque. Conclusion: Increased STIFF was associated with increased cIMT and carotid artery dilatation with greater plaque burden. Increased cIMT and plaque burden represent vascular remodeling likely resulting from the two different age related mechanisms, one that includes diffuse wall thickening (cIMT) with STIFF and another that incorporates focal atherosclerosis (plaque) with luminal dilatation. PMID- 29713304 TI - Uncovering True Cellular Phenotypes: Using Induced Pluripotent Stem Cell-Derived Neurons to Study Early Insults in Neurodevelopmental Disorders. AB - Animal models of neurodevelopmental disorders have provided invaluable insights into the molecular-, cellular-, and circuit-level defects associated with a plethora of genetic disruptions. In many cases, these deficits have been linked to changes in disease-relevant behaviors, but very few of these findings have been translated to treatments for human disease. This may be due to significant species differences and the difficulty in modeling disorders that involve deletion or duplication of multiple genes. The identification of primary underlying pathophysiology in these models is confounded by the accumulation of secondary disease phenotypes in the mature nervous system, as well as potential compensatory mechanisms. The discovery of induced pluripotent stem cell technology now provides a tool to accurately model complex genetic neurogenetic disorders. Using this technique, patient-specific cell lines can be generated and differentiated into specific subtypes of neurons that can be used to identify primary cellular and molecular phenotypes. It is clear that impairments in synaptic structure and function are a common pathophysiology across neurodevelopmental disorders, and electrophysiological analysis at the earliest stages of neuronal development is critical for identifying changes in activity and excitability that can contribute to synaptic dysfunction and identify targets for disease-modifying therapies. PMID- 29713307 TI - Fetal Neuroprotection by Magnesium Sulfate: From Translational Research to Clinical Application. AB - Despite improvements in perinatal care, preterm birth still occurs regularly and the associated brain injury and adverse neurological outcomes remain a persistent challenge. Antenatal magnesium sulfate administration is an intervention with demonstrated neuroprotective effects for preterm births before 32 weeks of gestation (WG). Owing to its biological properties, including its action as an N methyl-d-aspartate receptor blocker and its anti-inflammatory effects, magnesium is a good candidate for neuroprotection. In hypoxia models, including hypoxia ischemia, inflammation, and excitotoxicity in various species (mice, rats, pigs), magnesium sulfate preconditioning decreased the induced lesions' sizes and inflammatory cytokine levels, prevented cell death, and improved long-term behavior. In humans, some observational studies have demonstrated reduced risks of cerebral palsy after antenatal magnesium sulfate therapy. Meta-analyses of five randomized controlled trials using magnesium sulfate as a neuroprotectant showed amelioration of cerebral palsy at 2 years. A meta-analysis of individual participant data from these trials showed an equally strong decrease in cerebral palsy and the combined risk of fetal/infant death and cerebral palsy at 2 years. The benefit remained similar regardless of gestational age, cause of prematurity, and total dose received. These data support the use of a minimal dose (e.g., 4 g loading dose +/- 1 g/h maintenance dose over 12 h) to avoid potential deleterious effects. Antenatal magnesium sulfate is now recommended by the World Health Organization and many pediatric and obstetrical societies, and it is requisite to maximize its administration among women at risk of preterm delivery before 32 WG. PMID- 29713308 TI - In Vivo Multimodal Magnetic Resonance Imaging Changes After N-Methyl-d-Aspartate Triggered Spasms in Infant Rats. AB - Objective: Despite the serious neurodevelopmental sequelae of epileptic encephalopathy during infancy, the pathomechanisms involved remain unclear. To find potential biomarkers that can reflect the pathogenesis of epileptic encephalopathy, we explored the neurometabolic and microstructural sequelae after infantile spasms using a rat model of infantile spasms and in vivo magnetic resonance imaging techniques. Methods: Rats prenatally exposed to betamethasone were subjected to three rounds of intraperitoneal N-methyl-d-aspartate (NMDA) triggering of spasms or received saline injections (controls) on postnatal days (P) 12, 13, and 15. Chemical exchange saturation transfer imaging of glutamate (GluCEST) were performed at P15 and 22 and diffusion tensor imaging and additional spectroscopy (1H-MRI/MRS) of the cingulate cortex were serially done at P16, 23, and 30 and analyzed. Pathological analysis and western blotting were performed with rats sacrificed on P35. Results: Within 24 h of the three rounds of NMDA-induced spasms, there was an acute increase in the GluCEST (%) in the cortex, hippocampus, and striatum. When focused on the cingulate cortex, mean diffusivity (MD) was significantly decreased during the acute period after multiple spasms with an increase in gamma-aminobutyric acid (GABA), glutamate, and glutamine N-acetylaspartate-plus-N-acetylaspartylglutamate (tNAA), total choline, and total creatine. The juvenile rats also showed decreased MD on diffusion tensor imaging and significant decreases in taurine, tNAA, and macromolecules-plus-lipids in the cingulate cortex. Pathologically, there was a significant reduction in glial fibrillary acidic protein, myelin basic protein, and neuronal nuclei expression in the cingulate cortex of rats with NMDA-induced spasms. Significance: These neurometabolic and microstructural alterations after NMDA-triggered spasms might be potential imaging biomarkers of epileptic encephalopathy. PMID- 29713309 TI - Nontoxic Goiter (NTG) and Radioiodine: What Do Patients Think About It? Quality of Life in Patients with NTG Before and After 131-I Therapy. AB - Objective: Despite numerous publications regarding nontoxic goiter (NTG) treatment and an increasing interest in patients' quality of life, few studies present the outcome of 131-I treatment from the patients' perspective. Our study's main aim was to verify whether there is any improvement in life quality following 131-I treatment. Materials and methods: Thirty-five patients with NTG qualified to participate in the study. All patients completed a Thyroid-Related Health-Related Quality of Life (Thy-R-HRQoL) questionnaire created by us and the Medical Outcomes Study 36-item Short Form (SF-36), right before and 1 year after 131-I. Results: We observed an improvement in six out of eight SF-36 and three out of seven Thy-R-HRQoL domains. In comparison with the control group, we observed worse results in two out of eight, prior to treatment, and one out of eight SF-36 afterward, as well as in all Thy-R-HRQoL domains. We did not find any correlation between improvement of Thy-R-HRQoL and SF-36 and goiter size reduction, except for Bodily Pain. There was also no correlation between improvement of SF-36 and Thy-R-HRQoL domains, and goiter size before treatment. The older the patient, the less noticeable improvement was observed in Physical and Social Functioning, and Vitality in SF-36, but age had no influence on the assessment by Thy-R-HRQoL. Conclusion: Radioiodine treatment improves life quality in patients with NTG. Use of the Health-Related Quality of Life questionnaire should be taken into consideration when evaluating life quality of patients with NTG. Relentless pursuit of maximal goiter size reduction in 131-I treatment is worth consideration. In our study, life quality improvement did not depend directly on the goiter size reduction. Life quality improvement after 131 I might not depend on initial goiter size, and for certain domains of SF-36 might be less clearly expressed in older patients. PMID- 29713310 TI - Kisspeptin and Metabolism: The Brain and Beyond. AB - Apart from the well-established role of kisspeptin (Kp) in the regulation of reproductive functions, recent data described its action in the control of metabolism. Of particular interest for the review is the population of Kp neurons localized in the arcuate nucleus (ARC) of the hypothalamus, the site of the brain where reproductive and metabolic cross talk occurs. However, within the hypothalamus Kp does not work alone, but rather interacts with other neuropeptides, e.g., neurokinin B, dynorphin A, proopiomelanocortin, the cocaine- and amphetamine-regulated transcript, agouti-related peptide, and neuropeptide Y. Beyond the brain, Kp is expressed in peripheral tissues involved in metabolic functions. In this review, we will mainly focus on the local action of this peptide in peripheral organs such as the pancreas, liver, and the adipose tissue. We will concentrate on dysregulation of the Kp system in cases of metabolic imbalance, e.g., obesity and diabetes. Importantly, these patients besides metabolic health problems often suffer from disruptions of the reproductive system, manifested by abnormalities in menstrual cycles, premature child birth, miscarriages in women, decreased testosterone levels and spermatogenesis in men, hypogonadism, and infertility. We will review the evidence from animal models and clinical data indicating that Kp could serve as a promising agent with clinical applications in regulation of reproductive problems in individuals with obesity and diabetes. Finally, emerging data indicate a role of Kp in regulation of insulin secretion, potentially leading to development of further therapeutic uses of this peptide to treat metabolic problems in patients with these lifestyle diseases. PMID- 29713311 TI - Cryptorchidism in Boys With Cerebral Palsy Is Associated With the Severity of Disease and With Co-Occurrence of Other Congenital Anomalies. AB - Background: Cryptorchidism is reported in 40-50% of small case series of cerebral palsy (CP) and attributed to hypothalamic-pituitary-gonadal axis abnormalities, intellectual disability (ID), or cremaster spasticity. We collected demographic and clinical data to define the frequency of cryptorchidism and clinical comorbidities in a large CP population. Methods: Electronic health record data were collected for all male patients >=7 years of age seen in a large, multidisciplinary CP clinic between 2000 and 2016. Variables including age, testicular position, surgical findings, CP severity, birth history, and comorbidities were tested for association using univariable and stepwise backward logistic regression analyses. Results: Of 839 established patients, testis position was scrotal in 553, undescended in 185 (24%), retractile in 38 (5%), and undocumented in 63 cases. Cryptorchidism were diagnosed at a mean age of 5.8 years, with 20% documented as acquired, and testes were most commonly in the superficial inguinal pouch (41%) and associated with an inguinal hernia (56%). Severity was bilateral in 114/166 (69%) undescended and 24/36 (66%) retractile cases, respectively. Mean birth weight and the frequency of prematurity (55, 58, and 54%) and multiple birth (14, 13, and 9%) were not significantly different among the three groups. We observed a strong ordinal trend in the frequency of comorbidities, including quadriplegia, syndromic features/known genetic disease, intrauterine growth restriction (IUGR), death, brain malformations, seizures, gastrostomy, absent continence, ID and hearing, speech or visual impairment, with the retractile group holding the intermediate position for the majority. The stepwise multivariable analysis showed independent positive associations of cryptorchidism with quadriplegia, syndromic features/known genetic disease, hearing loss, and absent continence, and inverse associations with gestational age and multiple birth. Conclusion: These data suggest that cryptorchidism is less common than previously reported in CP cases, but most strongly associated with quadriplegia. Delayed diagnosis may be related to an acquired condition or to the multiple additional functional deficits that occur in this population. Our data suggest that UDT and CP may both be components of malformation syndromes occurring in singleton births whose clinical features are more likely to include earlier delivery, IUGR, hearing loss, and/or global spasticity. PMID- 29713312 TI - Integrated Characterization of MicroRNA and mRNA Transcriptome in Papillary Thyroid Carcinoma. AB - The incidence rate of papillary thyroid carcinoma (PTC) has rapidly increased in the recent decades, and the microRNA (miRNA) is one of the potential biomarkers in this cancer. Despite good prognosis, certain features such as lymph node metastasis (LNM) and BRAF V600E mutation are associated with a poor outcome. More than 50% of PTC patients present with LNM and BRAF V600E is the most common mutation identified in this cancer. The molecular mechanisms underlying these features are yet to be elucidated. This study aims to elucidate miRNA-genes interaction networks in PTC with or without LNM and to determine the association of BRAF V600E mutation with miRNAs and genes expression profiles. Next generation sequencing was performed to characterize miRNA and gene expression profiles in 20 fresh frozen tumor and the normal adjacent tissues of PTC with LNM positive (PTC LNM-P) and PTC without LNM (PTC LNN). BRAF V600E was genotyped using Sanger sequencing. Bioinformatics integration and pathway analysis were performed to determine the regulatory networks involved. Based on network analysis, we then investigated the association between miRNA and gene biomarkers, and pathway enrichment analysis was performed to study the role of candidate biomarkers. We identified 138 and 43 significantly deregulated miRNAs (adjusted p value < 0.05; log2 fold change <= -1.0 or >=1.0) in PTC LNM-P and PTC LNN compared to adjacent normal tissues, respectively. Ninety-six miRNAs had significant expression ratios of 3p-to-5p in PTC LNM-P as compared to PTC LNN. In addition, ribosomal RNA reduced RNA sequencing analysis revealed 699 significantly deregulated genes in PTC LNM-P versus normal adjacent tissues, 1,362 genes in PTC LNN versus normal adjacent tissue, and 1,576 genes in PTC LNM-P versus PTC LNN. We provide the evidence of miRNA and gene interactions, which are involved in LNM of papillary thyroid cancer. These findings may lead to better understanding of carcinogenesis and metastasis processes. This study also complements the existing knowledge about deregulated miRNAs in papillary thyroid carcinoma development. PMID- 29713314 TI - Background Adjusted Alignment-Free Dissimilarity Measures Improve the Detection of Horizontal Gene Transfer. AB - Horizontal gene transfer (HGT) plays an important role in the evolution of microbial organisms including bacteria. Alignment-free methods based on single genome compositional information have been used to detect HGT. Currently, Manhattan and Euclidean distances based on tetranucleotide frequencies are the most commonly used alignment-free dissimilarity measures to detect HGT. By testing on simulated bacterial sequences and real data sets with known horizontal transferred genomic regions, we found that more advanced alignment-free dissimilarity measures such as CVTree and [Formula: see text] that take into account the background Markov sequences can solve HGT detection problems with significantly improved performance. We also studied the influence of different factors such as evolutionary distance between host and donor sequences, size of sliding window, and host genome composition on the performances of alignment-free methods to detect HGT. Our study showed that alignment-free methods can predict HGT accurately when host and donor genomes are in different order levels. Among all methods, CVTree with word length of 3, [Formula: see text] with word length 3, Markov order 1 and [Formula: see text] with word length 4, Markov order 1 outperform others in terms of their highest F1-score and their robustness under the influence of different factors. PMID- 29713313 TI - Amino-Terminal Processing of Helicobacter pylori Serine Protease HtrA: Role in Oligomerization and Activity Regulation. AB - The HtrA family of serine proteases is found in most bacteria, and plays an essential role in the virulence of the gastric pathogen Helicobacter pylori. Secreted H. pylori HtrA (HtrA Hp ) cleaves various junctional proteins such as E cadherin disrupting the epithelial barrier, which is crucial for bacterial transmigration across the polarized epithelium. Recent studies indicated the presence of two characteristic HtrA Hp forms of 55 and 52 kDa (termed p55 and p52, respectively), in worldwide strains. In addition, p55 and p52 were produced by recombinant HtrA Hp , indicating auto-cleavage. However, the cleavage sites and their functional importance are yet unclear. Here, we determined the amino terminal ends of p55 and p52 by Edman sequencing. Two proteolytic cleavage sites were identified (H46/D47 and K50/D51). Remarkably, the cleavage site sequences are conserved in HtrA Hp from worldwide isolates, but not in other Gram-negative pathogens, suggesting a highly specific assignment in H. pylori. We analyzed the role of the amino-terminal cleavage sites on activity, secretion and function of HtrA Hp . Three-dimensional modeling suggested a trimeric structure and a role of amino-terminal processing in oligomerization and regulation of proteolytic activity of HtrA Hp . Furthermore, point and deletion mutants of these processing sites were generated in the recently reported Campylobacter jejuni DeltahtrA/htrAHp genetic complementation system and the minimal sequence requirements for processing were determined. Polarized Caco-2 epithelial cells were infected with these strains and analyzed by immunofluorescence microscopy. The results indicated that HtrA Hp processing strongly affected the ability of the protease to disrupt the E-cadherin-based cell-to-cell junctions. Casein zymography confirmed that the amino-terminal region is required for maintaining the proteolytic activity of HtrA Hp . Furthermore, we demonstrated that this cleavage influences the secretion of HtrA Hp in the extracellular space as an important prerequisite for its virulence activity. Taken together, our data demonstrate that amino-terminal cleavage of HtrA Hp is conserved in this pathogen and affects oligomerization and thus, secretion and regulatory activities, suggesting an important role in the pathogenesis of H. pylori. PMID- 29713315 TI - Oral Administration of Probiotics Increases Paneth Cells and Intestinal Antimicrobial Activity. AB - The huge amount of intestinal bacteria represents a continuing threat to the intestinal barrier. To meet this challenge, gut epithelial cells produce antimicrobial peptides (AMP) that act at the forefront of innate immunity. We explore whether this antimicrobial activity and Paneth cells, the main intestinal cell responsible of AMP production, are influenced by probiotics administration, to avoid the imbalance of intestinal microbiota and preserve intestinal barrier. Administration of Lactobacillus casei CRL 431 (Lc 431) and L. paracasei CNCM I 1518 (Lp 1518) to 42 days old mice, increases the number of Paneth cells on small intestine, and the antimicrobial activity against the pathogens Staphylococcus aureus and Salmonella Typhimurium in the intestinal fluids. Specifically, strong damage of the bacterial cell with leakage of cytoplasmic content, and cellular fragmentation were observed in S. Typhimurium and S. aureus. Even more important, probiotics increase the antimicrobial activity of the intestinal fluids at the different ages, from weaning (21 days old) to old age (180 days old). Intestinal antimicrobial activity stimulated by oral probiotics, do not influence significantly the composition of total anaerobic bacteria, lactobacilli and enterobacteria in the large intestine, at any age analyzed. This result, together with the antimicrobial activity observed against the same probiotic bacteria; endorse the regular consumption of probiotics without adverse effect on the intestinal homeostasis in healthy individuals. We demonstrate that oral probiotics increase intestinal antimicrobial activity and Paneth cells in order to strengthen epithelial barrier against pathogens. This effect would be another important mechanism by which probiotics protect the host mainly against infectious diseases. PMID- 29713316 TI - Comparative Genomic Analysis of Holospora spp., Intranuclear Symbionts of Paramecia. AB - While most endosymbiotic bacteria are transmitted only vertically, Holospora spp., an alphaproteobacterium from the Rickettsiales order, can desert its host and invade a new one. All bacteria from the genus Holospora are intranuclear symbionts of ciliates Paramecium spp. with strict species and nuclear specificity. Comparative metabolic reconstruction based on the newly sequenced genome of Holospora curviuscula, a macronuclear symbiont of Paramecium bursaria, and known genomes of other Holospora species shows that even though all Holospora spp. can persist outside the host, they cannot synthesize most of the essential small molecules, such as amino acids, and lack some central energy metabolic pathways, including glycolysis and the citric acid cycle. As the main energy source, Holospora spp. likely rely on nucleotides pirated from the host. Holospora-specific genes absent from other Rickettsiales are possibly involved in the lifestyle switch from the infectious to the reproductive form and in cell invasion. PMID- 29713317 TI - Building a Geochemical View of Microbial Salt Tolerance: Halophilic Adaptation of Marinococcus in a Natural Magnesium Sulfate Brine. AB - Current knowledge of life in hypersaline habitats is mostly limited to sodium and chloride-dominated environments. This narrow compositional window does not reflect the diversity of brine environments that exist naturally on Earth and other planetary bodies. Understanding the limits of the microbial biosphere and predicting extraterrestrial habitability demands a systematic effort to characterize ionic specificities of organisms from a representative range of saline habitats. Here, we investigated a strain of Marinococcus isolated from the magnesium and sulfate-dominated Basque Lakes (British Columbia, Canada). This organism was the sole isolate obtained after exposure to exceptionally high levels of Mg2+ and SO42- ions (2.369 and 2.840 M, respectively), and grew at extremes of ionic strength not normally encountered in Na+/Cl- brines (12.141 mol liter-1). Its association at the 16S rDNA level with bacterial halophiles suggests that ancestral halophily has allowed it to adapt to a different saline habitat. Growth was demonstrated in media dominated by NaCl, Na2SO4, MgCl2, and MgSO4, yet despite this plasticity the strain was still restricted; requiring either Na+ or Cl- to maintain short doubling times. Water activity could not explain growth rate differences between media, demonstrating the importance of ionic composition for dictating microbial growth windows. A new framework for understanding growth in brines is required, that accounts for the geochemical history of brines as well as the various stresses that ions impose on microbes. Studies such as this are required to gain a truly universal understanding of the limits of biological ion tolerance. PMID- 29713318 TI - Complement Activation in Inflammatory Skin Diseases. AB - The complement system is a fundamental part of the innate immune system, playing a crucial role in host defense against various pathogens, such as bacteria, viruses, and fungi. Activation of complement results in production of several molecules mediating chemotaxis, opsonization, and mast cell degranulation, which can contribute to the elimination of pathogenic organisms and inflammation. Furthermore, the complement system also has regulating properties in inflammatory and immune responses. Complement activity in diseases is rather complex and may involve both aberrant expression of complement and genetic deficiencies of complement components or regulators. The skin represents an active immune organ with complex interactions between cellular components and various mediators. Complement involvement has been associated with several skin diseases, such as psoriasis, lupus erythematosus, cutaneous vasculitis, urticaria, and bullous dermatoses. Several triggers including auto-antibodies and micro-organisms can activate complement, while on the other hand complement deficiencies can contribute to impaired immune complex clearance, leading to disease. This review provides an overview of the role of complement in inflammatory skin diseases and discusses complement factors as potential new targets for therapeutic intervention. PMID- 29713320 TI - A Conformational Change in C-Reactive Protein Enhances Leukocyte Recruitment and Reactive Oxygen Species Generation in Ischemia/Reperfusion Injury. AB - Introduction: C-reactive protein circulates as a pentameric protein (pCRP). pCRP is a well-established diagnostic marker as plasma levels rise in response to tissue injury and inflammation. We recently described pro-inflammatory properties of CRP, which are mediated by conformational changes from pCRP to bioactive isoforms expressing pro-inflammatory neo-epitopes [pCRP* and monomeric C-reactive protein (mCRP)]. Here, we investigate the role of CRP isoforms in renal ischemia/reperfusion injury (IRI). Methods: Rat kidneys in animals with and without intraperitoneally injected pCRP were subjected to IRI by the time of pCRP exposure and were subsequently analyzed for monocyte infiltration, caspase-3 expression, and tubular damage. Blood urea nitrogen (BUN) was analyzed pre ischemia and post-reperfusion. CRP effects on leukocyte recruitment were investigated via intravital imaging of rat-striated muscle IRI. Localized conformational CRP changes were analyzed by immunohistochemistry using conformation specific antibodies. 1,6-bis(phosphocholine)-hexane (1,6-bisPC), which stabilizes CRP in its native pentameric form was used to validate CRP effects. Leukocyte activation was assessed by quantification of reactive oxygen species (ROS) induction by CRP isoforms ex vivo and in vitro through electron spin resonance spectroscopy. Signaling pathways were analyzed by disrupting lipid rafts with nystatin and subsequent ROS detection. In order to confirm the translational relevance of our findings, biopsies of microsurgical human free tissue transfers before and after IRI were examined by immunofluorescence for CRP deposition and co-localization of CD68+ leukocytes. Results: The application of pCRP aggravates tissue damage in renal IRI. 1,6-bisPC reverses these effects via inhibition of the conformational change that leads to exposure of pro inflammatory epitopes in CRP (pCRP* and mCRP). Structurally altered CRP induces leukocyte-endothelial interaction and induces ROS formation in leukocytes, the latter can be abrogated by blocking lipid raft-dependent signaling pathways with Nystatin. Stabilizing pCRP in its native pentameric state abrogates these pro inflammatory effects. Importantly, these findings are confirmed in human IRI challenged muscle tissue. Conclusion: These results suggest that CRP is a potent modulator of IRI. Stabilizing the native pCRP conformation represents a promising anti-inflammatory therapeutic strategy by attenuation of leukocyte recruitment and ROS formation, the primary pathomechanisms of IRI. PMID- 29713321 TI - Clec9a-Mediated Ablation of Conventional Dendritic Cells Suggests a Lymphoid Path to Generating Dendritic Cells In Vivo. AB - Conventional dendritic cells (cDCs) are versatile activators of immune responses that develop as part of the myeloid lineage downstream of hematopoietic stem cells. We have recently shown that in mice precursors of cDCs, but not of other leukocytes, are marked by expression of DNGR-1/CLEC9A. To genetically deplete DNGR-1-expressing cDC precursors and their progeny, we crossed Clec9a-Cre mice to Rosa-lox-STOP-lox-diphtheria toxin (DTA) mice. These mice develop signs of age dependent myeloproliferative disease, as has been observed in other DC-deficient mouse models. However, despite efficient depletion of cDC progenitors in these mice, cells with phenotypic characteristics of cDCs populate the spleen. These cells are functionally and transcriptionally similar to cDCs in wild type control mice but show somatic rearrangements of Ig-heavy chain genes, characteristic of lymphoid origin cells. Our studies reveal a previously unappreciated developmental heterogeneity of cDCs and suggest that the lymphoid lineage can generate cells with features of cDCs when myeloid cDC progenitors are impaired. PMID- 29713319 TI - Debunking the Myth of Exercise-Induced Immune Suppression: Redefining the Impact of Exercise on Immunological Health Across the Lifespan. AB - Epidemiological evidence indicates that regular physical activity and/or frequent structured exercise reduces the incidence of many chronic diseases in older age, including communicable diseases such as viral and bacterial infections, as well as non-communicable diseases such as cancer and chronic inflammatory disorders. Despite the apparent health benefits achieved by leading an active lifestyle, which imply that regular physical activity and frequent exercise enhance immune competency and regulation, the effect of a single bout of exercise on immune function remains a controversial topic. Indeed, to this day, it is perceived by many that a vigorous bout of exercise can temporarily suppress immune function. In the first part of this review, we deconstruct the key pillars which lay the foundation to this theory-referred to as the "open window" hypothesis-and highlight that: (i) limited reliable evidence exists to support the claim that vigorous exercise heightens risk of opportunistic infections; (ii) purported changes to mucosal immunity, namely salivary IgA levels, after exercise do not signpost a period of immune suppression; and (iii) the dramatic reductions to lymphocyte numbers and function 1-2 h after exercise reflects a transient and time-dependent redistribution of immune cells to peripheral tissues, resulting in a heightened state of immune surveillance and immune regulation, as opposed to immune suppression. In the second part of this review, we provide evidence that frequent exercise enhances-rather than suppresses-immune competency, and highlight key findings from human vaccination studies which show heightened responses to bacterial and viral antigens following bouts of exercise. Finally, in the third part of this review, we highlight that regular physical activity and frequent exercise might limit or delay aging of the immune system, providing further evidence that exercise is beneficial for immunological health. In summary, the over-arching aim of this review is to rebalance opinion over the perceived relationships between exercise and immune function. We emphasize that it is a misconception to label any form of acute exercise as immunosuppressive, and, instead, exercise most likely improves immune competency across the lifespan. PMID- 29713322 TI - TCR Signaling Abnormalities in Human Th2-Associated Atopic Disease. AB - Stimulation of naive CD4 T cells with weak T cell receptor agonists even in the absence of T helper-skewing cytokines can result in IL-4 production which can drive a Th2 response. Evidence for the in vivo consequences of such a phenomenon can be found in a number of mouse models and, importantly, a series of monogenic human diseases associated with significant atopy which are caused by mutations in the T cell receptor signaling cascade. Such diseases can help understand how Th2 responses evolve in humans, and potentially provide insight into therapeutic interventions. PMID- 29713324 TI - Antibodies Reactive to Commensal Streptococcus mitis Show Cross-Reactivity With Virulent Streptococcus pneumoniae Serotypes. AB - Current vaccines against Streptococcus pneumoniae, a bacterial species that afflicts people by causing a wide spectrum of diseases, do not protect against all pneumococcal serotypes. Thus, alternative vaccines to fight pneumococcal infections that target common proteins are under investigation. One promising strategy is to take advantage of immune cross-reactivity between commensal and pathogenic microbes for cross-protection. In this study, we examined the antibody mediated cross-reactivity between S. pneumoniae and Streptococcus mitis, a commensal species closely related to S. pneumoniae. Western blot analysis showed that rabbit antisera raised against S. mitis reacted with multiple proteins of virulent S. pneumoniae strains (6B, TIGR4, and D39). Rabbit anti-S. pneumoniae IgG antibodies also showed binding to S. mitis antigens. Incubation of rabbit antisera raised against S. mitis with heterologous or homologous bacterial lysates resulted in marked inhibition of the developments of bands in the Western blots. Furthermore, plasma IgG antibodies from adult human volunteers intranasally inoculated with S. pneumoniae 6B revealed enhanced S. mitis-specific IgG titers compared with the pre-inoculation samples. Using an on-chip protein microarray representing a number of selected membrane and extracellular S. pneumoniae proteins, we identified choline-binding protein D (CbpD), cell division protein (FtsH), and manganese ABC transporter or manganese-binding adhesion lipoprotein (PsaA) as common targets of the rabbit IgG antibodies raised against S. mitis or S. pneumoniae. Cumulatively, these findings provide evidence on the antibody-mediated cross-reactivity of proteins from S. mitis and S. pneumoniae, which may have implications for development of effective and wide range pneumococcal vaccines. PMID- 29713323 TI - Implication of Interleukin-12/15/18 and Ruxolitinib in the Phenotype, Proliferation, and Polyfunctionality of Human Cytokine-Preactivated Natural Killer Cells. AB - A brief in vitro stimulation of natural killer (NK) cells with interleukin (IL) 12, IL-15, and IL-18 endow them a memory-like behavior, characterized by higher effector responses when they are restimulated after a resting period of time. These preactivated NK cells, also known as cytokine-induced memory-like (CIML) NK cells, have several properties that make them a promising tool in cancer immunotherapy. In the present study, we have described the effect that different combinations of IL-12, IL-15, and IL-18 have on the generation of human CIML NK cells. Our data points to a major contribution of IL-15 to CIML NK cell-mediated cytotoxicity against target cells. However, the synergistic effect of the three cytokines grant them the best polyfunctional profile, that is, cells that simultaneously degranulate (CD107a) and produce multiple cytokines and chemokines such as interferon gamma, tumor necrosis factor alpha, and C-C motif chemokine ligand 3. We have also analyzed the involvement of each cytokine and their combinations in the expression of homing receptors CXCR4 and CD62L, as well as the expression of CD25 and IL-2-induced proliferation. Furthermore, we have tested the effects of the Jak1/2 inhibitor ruxolitinib in the generation of CIML NK cells. We found that ruxolitinib-treated CIML NK cells expressed lower levels of CD25 than non-treated CIML NK cells, but exhibited similar proliferation in response to IL-2. In addition, we have also found that ruxolitinib-treated NK cells displayed reduced effector functions after the preactivation, which can be recovered after a 4 days expansion phase in the presence of low doses of IL-2. Altogether, our results describe the impact that each cytokine and the Jak1/2 pathway have in the phenotype, IL-2-induced proliferation, and effector functions of human CIML NK cells. PMID- 29713326 TI - Editorial: Neuro-Immune Interactions in Inflammation and Autoimmunity. PMID- 29713325 TI - Are Anti-Retinal Autoantibodies a Cause or a Consequence of Retinal Degeneration in Autoimmune Retinopathies? AB - Autoantibodies (AAbs) against various retinal proteins have been associated with vision loss in paraneoplastic and non-paraneoplastic autoimmune retinopathies (AR). There are two major paraneoplastic syndromes associated anti-retinal AAbs, cancer-associated retinopathy (CAR), and melanoma-associated retinopathy. Some people without a cancer diagnosis may present symptoms of CAR and have anti retinal AAbs. The etiology and pathogenesis of those entities are not fully understood. In this review, we provide evidence for the role of AAbs in retinal death and degeneration. Studies of epitope mapping for anti-recoverin, anti enolase, and anti-carbonic anhydrase II revealed that although patients' AAbs may recognize the same retinal protein as normal individuals they bind to different molecular domains, which allows distinguishing between normal and diseased AAbs. Given the great diversity of anti-retinal AAbs, it is likely some antibodies have greater pathogenic potential than others. Pathogenic, but not normal antibodies penetrate the target cell, reach their specific antigen, induce apoptosis, and impact retinal pathophysiology. Photoreceptors, dying by apoptosis, induced by other than immunologic mechanisms produce substantial amounts of metabolic debris, which consequently leads to autoimmunization and enhanced permeability of the blood-retinal barrier. AAbs that were made as a part of anti-cancer response are likely to be the cause of retinal degeneration, whereas others, generated against released antigens from damaged retina, contribute to the progression of retinopathy. Altogether, AAbs may trigger retinal degeneration and may also exacerbate the degenerative process in response to the release of sequestered antigens and influence disease progression. PMID- 29713327 TI - Impact of Interferon-alpha Receptor-1 Promoter Polymorphisms on the Transcriptome of the Hepatitis B Virus-Associated Hepatocellular Carcinoma. AB - Background and aims: Genetic polymorphisms within the promoter of interferon alpha receptor type-1 (IFNAR1) have been associated with the susceptibility to and the outcome of chronic hepatitis B virus (HBV) infection. However, the impact of these polymorphisms in the transcriptome of the HBV-associated hepatocellular carcinoma (HCC) remains largely unexplored. Methods: Using whole-genome and exome sequencing data from The Cancer Genome Atlas project, we characterized three single-nucleotide polymorphisms (SNPs: -568G/C, -408C/T, -3C/T) and one variable number tandem repeat [VNTR: -77(GT)n] within the IFNAR1 promoter sequence in 49 HCC patients. RNAseq data from 10 genotyped HCC samples were grouped according to their -77VNTR or -3SNP genotype to evaluate the impact of these polymorphisms on the differential expression on the HCC transcriptome. Results: There is a fourfold higher impact of the -77VNTR on the HCC transcriptome compared to the 3SNP (q < 0.1, p < 0.001). The expression of the primary IFNAR1 transcript is not affected by these polymorphisms but a secondary, HCC-specific transcript is expressed only in homozygous -77VNTR <=8/<=8(GT)n samples (p < 0.05). At the same time, patients carrying at least one -77VNTR >8(GT) allele, presented a strong upregulation of the fibronectin-1 (FN-1) gene, which has been associated with the development of HCC. Gene Ontology and pathway enrichment analysis of the differentially expressed genes revealed a strong disruption of the PI3K-AKT signaling pathway, which can be partially triggered by the extracellular matrix FN-1. Conclusion: The IFNAR-1 promoter polymorphisms are not involved in the expression levels of the main IFNAR-1 transcript. The -77VNTR has a regulatory role on the expression of a secondary, truncated, HCC-specific transcript, which in turn coincides with disruptions in cancer-associated pathways and in FN-1 expression modifications. PMID- 29713328 TI - High Incidence of Severe Combined Immunodeficiency Disease in Saudi Arabia Detected Through Combined T Cell Receptor Excision Circle and Next Generation Sequencing of Newborn Dried Blood Spots. AB - Severe combined immunodeficiency disease (SCID) is the most severe form of primary immunodeficiency disorders (PID). T-cell receptor excision circle (TREC) copy number analysis is an efficient tool for population-based newborn screening (NBS) for SCID and other T cell lymphopenias. We sought to assess the incidence of SCID among Saudi newborn population and examine the feasibility of using targeted next generation sequencing PID gene panel (T-NGS PID) on DNA isolated from dried blood spots (DBSs) in routine NBS programs as a mutation screening tool for samples with low TREC count. Punches from 8,718 DBS collected on Guthrie cards were processed anonymously for the TREC assay. DNA was extracted from samples with confirmed low TREC count, then screened for 22q11.2 deletion syndrome by real-time polymerase chain reaction and for mutations in PID-related genes by T-NGS PID panel. Detected mutations were confirmed by Sanger sequencing. Sixteen out of the 8,718 samples were confirmed to have low TREC copy number. Autosomal recessive mutations in AK2, JAK3, and MTHFD1 were confirmed in three samples. Two additional samples were positive for the 22q11.2 deletion syndrome. In this study, we provide evidence for high incidence of SCID among Saudi population (1/2,906 live births) and demonstrate the feasibility of using T-NGS PID panel on DNA extracted from DBSs as a new reliable, rapid, and cost-effective mutation screening method for newborns with low TREC assay, which can be implemented as part of NBS programs for SCID. PMID- 29713329 TI - Corrigendum: Functional Mechanisms of Treg in the Context of HIV Infection and the Janus Face of Immune Suppression. AB - [This corrects the article on p. 192 in vol. 7, PMID: 27242797.]. PMID- 29713330 TI - Climate Is Not All: Evidence From Phylogeography of Rhodiola fastigiata (Crassulaceae) and Comparison to Its Closest Relatives. AB - How geological events and climate oscillations in the Pleistocene glaciation shaped the geographic distribution of genetic variation of species on the Qinghai Tibetan Plateau (QTP) and its adjacent areas has been extensively studied. However, little studies have investigated whether closely related species in the same genus with similar physiological and life history traits responded similarly to the glacial climatic oscillations. If this is not the case, we would expect that the population histories of studied species were not driven by extrinsic environmental changes alone. Here we conducted a phylogeographic study of a succulent alpine plant Rhodiola fastigiata, using sequences from chloroplast genome and nrITS region, as well as ecological niche modeling. The results of R. fastigiata were compared to other congeneric species that have been studied, especially to R. alsia and R. crenulata. We found that for both markers, two geographic groups could be revealed, corresponding to the QTP plateau and the Hengduan Mountains, respectively, indicating isolated refugia in those two areas. The two groups diverged 1.23 Mya during the Pleistocene. We detected no significant population expansion by mismatch distribution analysis and Bayesian Skyline Plot. We found that even these similar species with similar physiological and life history traits have had different demographic histories in the Quaternary glacial periods. Our comparative phylogeographic study sheds new lights into phylogeographic research that extrinsic environmental changes are not the only factor that can drive population demography, and other factors, such as coevolved interactions between plants and their specialized pathogens, that probably played a role need to be examined with more case studies. PMID- 29713331 TI - Optimization of Nitrogen, Phosphorus, and Potassium Fertilization Rates for Overseeded Perennial Ryegrass Turf on Dormant Bermudagrass in a Transitional Climate. AB - Bermudagrass [Cynodon dactylon (L.) Pers.] turf loss due to severe cold in transitional climates is a major concern. To overcome this problem, warm-season grass is often overseeded with a cool-season turfgrass. In this study, modeling and efficient nutrient management were used to evaluate this problem. A three factor and five-level central composite rotatable design (CCRD) with a simulation of a regression model was used to optimize fertilization rates. The study investigated the combined effects of fertilization with nitrogen (N), phosphorus (P), and potassium (K) on both the morphological and physiological attributes and on the integrated turf performance (ITP) of overseeded perennial ryegrass (Lolium perenne). Fertilization with N and P significantly increased turf height, density, color, fresh and dry weights, while N, P, and K significantly affected turf cover, quality and winter-kill. The Spring transition was delayed by fertilization with N and P, and accelerated by fertilization with K. Photosynthesis (Pn), transpiration (Tr), and stomatal conductance (Gs) were considerably enhanced by fertilization with N, P, and K. Protein levels and total chlorophyll levels were substantially increased by fertilization with N and P and with N, P, and K, respectively, during a 2-year period. During two separate experiments conducted during 2 consecutive years, the optimal combinations of N, P, and K were N: 30, P: 24, K: 9, and N: 30, P: 27, K: 6 g m-2. The major conclusion of this study is that a balanced nutrient application utilizing N, P, and K is key to enhancing the winter performance of perennial ryegrass. PMID- 29713332 TI - Coordination Between ROS Regulatory Systems and Other Pathways Under Heat Stress and Pathogen Attack. AB - Regulatory systems of reactive oxygen species (ROS) are known to be integrated with other pathways involving Ca2+ signaling, protein kinases, hormones and programmed cell death (PCD) pathways to regulate defense mechanisms in plants. Coordination between ROS regulatory systems and other pathways needs to be flexibly modulated to finely tune the mechanisms underlying responses of different types of tissues to heat stress, biotic stresses and their combinations during different growth stages. Especially, modulation of the delicate balance between ROS-scavenging and producing systems in reproductive tissues could be essential, because ROS-dependent PCD is required for the proper fertilization, despite the necessity of ROS scavenging to prevent the damage on cells under heat stress and biotic stresses. In this review, we will update the recent findings associated with coordination between multiple pathways under heat stress, pathogen attack and their combinations. In addition, possible integrations between different signals function in different tissues via ROS-dependent long distance signals will be proposed. PMID- 29713333 TI - Responses to Sedimentation in Ramet Populations of the Clonal Plant Carex brevicuspis. AB - In aquatic ecosystems, sedimentation is an important factor that affects plant growth, mainly due to sediment depth. Clonal morphological plasticity is an effective strategy in clonal plants for acclimatization to sediment burial. To date, few studies have examined growth responses to sedimentation on the clonal plants at the ramet population level. This study aimed to explore the interactive effects of population size and burial depth on growth and clonal morphology of Carex brevicuspis. Three population sizes (2, 8, and 32 ramets) and 3 burial depths (0 cm, 5 cm, and 10 cm) were used in this experiment. Under shallow (5 cm) and deep (10 cm) burial conditions, biomass accumulation and relative growth rate (RGR) were lower than in the no burial treatment (P < 0.05). RGR of the small and medium populations was especially high compared to the large populations (P < 0.05). Biomass allocation was higher to belowground parts than aboveground parts, except for the small populations in the 5 cm burial treatments. Both shallow burial and smaller populations led to more biomass being allocated to aboveground parts. Deep burial elongated the first order spacer more than shallow burial, and sedimentation had negative effects on the second order spacer length. The number of new ramets did not decrease in the 5 or 10 cm burial treatments compared to the unburial treatment, and larger populations usually had more ramets than smaller ones; the proportion of clumping ramets was higher than the proportion of spreading ramets, and deeper burial and smaller populations led to higher proportions of spreading ramets. These results indicated that the growth of C. brevicuspis was limited by sediment burial at the ramet population level. Smaller populations enable C. brevicuspis to adjust its escape response to burial stress, may allow this species to effectively survive and widely distribute in Dongting Lake wetland. PMID- 29713334 TI - Bayesian Hierarchical Random Effects Models in Forensic Science. AB - Statistical modeling of the evaluation of evidence with the use of the likelihood ratio has a long history. It dates from the Dreyfus case at the end of the nineteenth century through the work at Bletchley Park in the Second World War to the present day. The development received a significant boost in 1977 with a seminal work by Dennis Lindley which introduced a Bayesian hierarchical random effects model for the evaluation of evidence with an example of refractive index measurements on fragments of glass. Many models have been developed since then. The methods have now been sufficiently well-developed and have become so widespread that it is timely to try and provide a software package to assist in their implementation. With that in mind, a project (SAILR: Software for the Analysis and Implementation of Likelihood Ratios) was funded by the European Network of Forensic Science Institutes through their Monopoly programme to develop a software package for use by forensic scientists world-wide that would assist in the statistical analysis and implementation of the approach based on likelihood ratios. It is the purpose of this document to provide a short review of a small part of this history. The review also provides a background, or landscape, for the development of some of the models within the SAILR package and references to SAILR as made as appropriate. PMID- 29713335 TI - Trends in Karyotype Evolution in Astyanax (Teleostei, Characiformes, Characidae): Insights From Molecular Data. AB - The study of patterns and evolutionary processes in neotropical fish is not always an easy task due the wide distribution of major fish groups in large and extensive river basins. Thus, it is not always possible to detect or correlate possible effects of chromosome rearrangements in the evolution of biodiversity. In the Astyanax genus, chromosome data obtained since the 1970s have shown evidence of cryptic species, karyotypic plasticity, supernumerary chromosomes, triploidies, and minor chromosomal rearrangements. In the present work, we map and discuss the main chromosomal events compatible with the molecular evolution of the genus Astyanax (Characiformes, Characidae) using mitochondrial DNA sequence data, in the search for major chromosome evolutionary trends within this taxon. PMID- 29713336 TI - Molecular Characterization, Evolution, and Expression Profiling of the Dirigent (DIR) Family Genes in Chinese White Pear (Pyrus bretschneideri). AB - Stone cells content and size are the key factors determining the internal quality of the pear fruit. Synthesis of lignin and thickening of secondary cell wall are the keys to the development of stone cells. The polymerization of monolignols and secondary cell wall formation requires the participation of dirigent proteins (DIRs). In recent years, DIR family have been studied in higher plants, but lack of comprehensive study in the pear DIR (PbDIR) family. This study focuses on the identification and analysis of PbDIR family for the first time. We identified 35 PbDIRs from the pear genome, 89% of which are intronless genes. Phylogenetic tree and chromosome localization analysis showed that 35 PbDIRs were divided into four subfamilies (DIR-a, -b/d, -e, and -g) and irregularly distributed among 10 chromosomes. In addition, we identified 29, 26, and 14 DIRs from the other three Rosids (peach, Mei, and grape), respectively. Interspecies microsynteny analysis revealed the collinear gene pairs between pear and peach are the most. Temporal expression analysis showed that the expression changes of seven PbDIRs (DIR-a subfamily: PbDIR4 and PbDIR5; DIR-b/d subfamily: PbDIR11; DIR-g subfamily: PbDIR19; DIR-e subfamily: PbDIR23, 25 and 26) in fruits were consistent with the changes of fruit lignin and stone cells contents. In addition, the subfamily of PbDIRs in fruits showed significant responses after treatment with ABA, SA, and MeJA. According to the protein tertiary structure, key amino acid residues and expression patterns analysis found that PbDIR4 might be involved in the metabolism of lignin and related to stone cells contents in pear fruits. In this study, we systematically analyzed the structure, evolution, function and expression of PbDIR family, which not only confirmed the characteristics of PbDIR family, but also laid the foundation for revealing the role of DIR in pear stone cell development and lignin polymerization. PMID- 29713337 TI - Alternagin-C binding to alpha2beta1 integrin controls matrix metalloprotease-9 and matrix metalloprotease-2 in breast tumor cells and endothelial cells. AB - Background: Matrix metalloproteinases (MMPs) are key players in tumor progression, helping tumor cells to modify their microenvironment, which allows cell migration to secondary sites. The role of integrins, adhesion receptors that connect cells to the extracellular matrix, in MMP expression and activity has been previously suggested. However, the mechanisms by which integrins control MMP expression are not completely understood. Particularly, the role of alpha2beta1 integrin, one of the major collagen I receptors, in MMP activity and expression has not been studied. Alternagin-C (ALT-C), a glutamate-cysteine-aspartate disintegrin from Bothrops alternatus venom, has high affinity for an alpha2beta1 integrin. Herein, we used ALT-C as a alpha2beta1 integrin ligand to study the effect of ALT-C on MMP-9 and MMP-2 expression as well as on tumor cells, fibroblats and endothelial cell migration. Methods: ALT-C was purified by two steps of gel filtration followed by anion exchange chromatography. The alpha2beta1 integrin binding properties of ALT-C, its dissociation constant (Kd ) relative to this integrin and to collagen I (Col I) were determined by surface plasmon resonance. The effects of ALT-C (10, 40, 100 and 1000 nM) in migration assays were studied using three human cell lines: human fibroblasts, breast tumor cell line MDA-MB-231, and microvascular endothelial cells HMEC-1, considering cells found in the tumor microenvironment. ALT-C effects on MMP-9 and MMP-2 expression and activity were analyzed by quantitative PCR and gelatin zymography, respectively. Focal adhesion kinase activation was determined by western blotting. Results: Our data demonstrate that ALT-C, after binding to alpha2beta1 integrin, acts by two distinct mechanisms against tumor progression, depending on the cell type: in tumor cells, ALT-C decreases MMP-9 and MMP-2 contents and activity, but increases focal adhesion kinase phosphorylation and transmigration; and in endothelial cells, ALT-C inhibits MMP-2, which is necessary for tumor angiogenesis. ALT-C also upregulates c-Myc mRNA level, which is related to tumor suppression. Conclusion: These results demonstrate that alpha2beta1 integrin controls MMP expression and reveal this integrin as a target for the development of antiangiogenic and antimetastatic therapies. PMID- 29713340 TI - Supine Percutaneous Nephrolithotripsy in Double-S Position. AB - Background: At present, the percutaneous nephrolithotripsy (PCNL) is performed both in supine and in prone position. The aim of this paper is to describe an innovative position during PCNL. Methods: We describe a supine position. The patient's legs are slightly abducted at the hips. The thorax is laterally tilted (inclination 30 degrees -35 degrees ) and kept in the right position by one or two gel pads placed between the scapula and the vertebrae. External genitalia can be accessed at any time, so that it is always possible to use flexible instruments in the upper urinary tract. We used this position for a period of 12 months to treat with PCNL 45 patients with renal lithiasis. Results: All the procedures were successfully completed without complications, using the position we are describing. The following are some of its benefits: an easier positioning of the patient; a better exposure of the flank for an easier access to the posterior renal calyces of the kidney; a lower risk of pressure injuries compared to positions foreseeing the use of knee crutches; the possibility of combined procedures (ECIRS) through the use of flexible instruments; and a good fluoroscopic visualization of the kidney not overlapped by the vertebrae. Conclusions: This position is effective, safe, easy, and quick to prepare and allows for combined anterograde/retrograde operations. PMID- 29713338 TI - How Visual Body Perception Influences Somatosensory Plasticity. AB - The study of somatosensory plasticity offers unique insights into the neuronal mechanisms that underlie human adaptive and maladaptive plasticity. So far, little attention has been paid on the specific influence of visual body perception on somatosensory plasticity and learning in humans. Here, we review evidence on how visual body perception induces changes in the functional architecture of the somatosensory system and discuss the specific influence the social environment has on tactile plasticity and learning. We focus on studies that have been published in the areas of human cognitive and clinical neuroscience and refer to animal studies when appropriate. We discuss the therapeutic potential of socially mediated modulations of somatosensory plasticity and introduce specific paradigms to induce plastic changes under controlled conditions. This review offers a contribution to understanding the complex interactions between social perception and somatosensory learning by focusing on a novel research field: socially mediated sensory plasticity. PMID- 29713339 TI - Exercise Intervention Associated with Cognitive Improvement in Alzheimer's Disease. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disease with the syndrome of cognitive and functional decline. Pharmacotherapy has always been in a dominant position for the treatment of AD. However, in most cases, drug therapy is accompanied with clinical delays when older adults have suffered from cognitive decline in episodic memory, working memory, and executive function. On the other hand, accumulating evidence suggests that exercise intervention may ameliorate the progression of cognitive impairment in aging ones while the standard strategy is lacking based on different levels of cognitive decline especially in mild cognitive impairment (MCI) and AD. MCI is the preclinical stage of AD in which neurodegeneration may be reversed via neuroplasticity. Therefore, taking exercise intervention in the early stage of MCI and healthy aging at the risk of AD could slow down the process of cognitive impairment and provide a promising cost-effective nonpharmacological therapy to dementia. PMID- 29713341 TI - Use of Telemedicine in Addiction Treatment: Current Practices and Organizational Implementation Characteristics. AB - Telemedicine applications offer innovative approaches for treating and reducing the effects of substance use disorders (SUDs). This analysis assessed the interest in and use of 11 telemedicine applications in a sample of 363 SUD organizations in the United States of America. Fifty percent of the organizations expressed high rates of interest in seven of the telemedicine applications, demonstrating the appeal of telemedicine within this field. The top three self reported telemedicine applications being used were (1) computerized screening/assessments (44.6%), (2) telephone-based recovery supports (29.5%), and (3) telephone-based therapy (28.37%). The greatest gaps between interest and use were for (1) texting appointment reminders (55.2% differential), (2) mobile apps for posttreatment recovery (46.6% differential), and (3) recovery support chats (46.6% differential). A Latent Class Analysis (LCA) of the organizations' telemedicine use behavior identified three groupings: "Innovators" that were using a range of technologies (n = 27, 7.4%); "Technology Traditionalists" that limited their use to telephone, video, and web portal technologies (n = 101, 27.8%); and "Low Tech" that had low overall technology use (n = 235, 64.7%). Future studies should build on how telemedicine could be applied in SUD settings, organizational behaviors towards its adoption, and telemedicine's effect on treatment adherence and clinical outcomes. PMID- 29713342 TI - Copy Number Variation of Immune-Related Genes and Their Association with Iodine in Adults with Autoimmune Thyroid Diseases. AB - Background: Autoimmune thyroid diseases (AITD) are complex conditions that are caused by an interaction between genetic susceptibility and environmental triggers. Iodine is already known to be an environmental trigger for AITD, but genes associated with susceptibility need to be further assessed. Therefore, the aims of this study were to assess the association between copy number variations (CNVs) and AITD, to identify genes related with susceptibility to AITD, and to investigate the interaction between iodine status and CNVs in the occurrence of AITD. Methods: Blood samples from 15 patients with AITD and 15 controls were assessed by chromosome microarray to identify candidate genes. The copy number of candidate genes and urinary iodine level was determined in adults from areas of different iodine statuses including 158 patients and 181 controls. Results: The immune-related genes, SIRPB1 and TMEM91, were selected as candidate genes. The distribution of SIRPB1 CNV in AITD patients and controls was significantly different and was considered a risk factor for AITD. There was no significant association between urinary iodine level and candidate gene CNVs. Conclusion: SIRPB1 CNV and an excess of iodine were risk factors for AITD, but an association with the occurrence of AITD was not found. PMID- 29713344 TI - Gender-Specific Risk of Central Compartment Lymph Node Metastasis in Papillary Thyroid Carcinoma. AB - Our aim was to evaluate the impact of gender on the predictive factors of central compartment lymph node metastasis (CLNM) in papillary thyroid carcinoma (PTC). A retrospective study of 590 patients treated for PTC was performed. Univariate and multivariate analyses showed that gender (female; P = 0.001), age (>=45 y; P < 0.001), tumor size (>1 cm; P < 0.001), and multifocality (P = 0.004) were independent predictive factors of CLNM in PTC patients. Patients were divided into male group (n = 152) and female group (n = 438). Age (>=45 y; P = 0.001), T4 (P = 0.006) and multifocality (P = 0.024) were independent predictive risk factors of CLNM in male patients. As for female patients, age (>=45 y; P < 0.001), tumor size (>1 cm; P < 0.001), multifocality (P = 0.002), and microcalcification (P = 0.027) were independently correlated with CLNM. The sensitivity of the multivariate model for predicting CLNM in male patients was 64.9%, specificity was 82.9%, and area under the ROC curve (AUC) was 0.764. As for female patients, the sensitivity was 55.7%, specificity was 77.9%, and AUC was 0.73. This study showed that the predictive factors of CLNM indeed varied according to gender. To have a more accurate evaluation of CLNM, different predictive systems should be used for male and female patients. PMID- 29713343 TI - Elevated Serum IL-17 Expression at Cessation Associated with Graves' Disease Relapse. AB - Background: Antithyroid drug (ATD) treatment occupies the cornerstone therapeutic modality of Graves' disease (GD) with a high relapse rate after discontinuation. This study aimed to assess potential risk factors for GD relapse especially serum interleukin-17 (IL-17) expression. Methods: Consecutive newly diagnosed GD patients who were scheduled to undergo ATD therapy from May 2011 to May 2014 were prospectively enrolled. Risk factors for GD relapse were analyzed by univariate and multivariate Cox proportional hazard analyses. The association between serum IL-17 expression at cessation and GD relapse was analyzed with relapse-free survival (RFS) by the Kaplan-Meier survival analysis and log-rank test. Results: Of the 117 patients, 72 (61.5%) maintained a remission for 12 months after ATD withdrawal and 45 (38.5%) demonstrated GD relapse. The final multivariate Cox analysis indicated elevated IL-17 expression at cessation to be an independent risk factor for GD relapse within 12 months after ATD withdrawal (HR: 3.04, 95% CI: 1.14-7.67, p = 0.021). Patients with higher expressions of IL-17 (>=median value) at cessation demonstrated a significantly higher RFS than those with lower levels by the Kaplan-Meier analysis and log-rank test (p = 0.028). Conclusions: This present study indicated elevated serum IL-17 expression at cessation to be a predictor for GD relapse within 12 months. PMID- 29713345 TI - ElectromyoFigureic Evaluation of Functional Adaptation of Patients with New Complete Dentures. AB - Objective: The objective of this study was to evaluate the level of adaptation of patients to newly fitted complete dentures in their dominant and nondominant sides, by means of ElectromyoFigureic signals. Materials and Methods: Eighty eight patients with complete dentures were evaluated in the study. Masticatory muscle (masseter and temporal) bioelectric activity of the patients with complete dentures was recorded at maximum intercuspal relation. Parametric statistical data were analyzed with one-way repeated measures ANOVA test. Results: Measurement time was significantly different for both dominant (DS) and nondominant (NDS) sides: FSigmas-DS = 21.51, p=0.0001; FSigmas-NDS = 13.25, p=0.0001. Gender was also significantly different: FSigmas-DS-gender = 41.53, p=0.001; FSigmas-NDS-gender = 85.76, p=0.0001. The average surface area values showed significant difference in females. Prior experience with dentures showed no significant difference for both sides of mastication: FSigmas-DS-experiences = 1.83, p=0.1772; F Sigmas-NDS-experiences = 3.30, p=0.0697. Conclusion: The planimetric indicators of bioelectric activity of masseter and temporalis muscles at maximum physiological loading conditions are significant discriminators of the level of functional adaptation of patients with new complete dentures. PMID- 29713346 TI - Preferred Source and Perceived Need of More Information about Dental Implants by the Undergraduate Dental Students of Nepal: All Nepal Survey. AB - Objectives: This study was conducted to know the preferred source and perceived need of more information about dental implants by the undergraduate students of Nepal and their association with academic levels and gender. Materials and Methods: It was conducted in all the dental colleges of Nepal from June 2016 to June 2017 after taking ethical clearance and approval from the research committee of BPKIHS. It included all those who were present at the time of survey. Data collection was done through a cross-sectional questionnaire survey during the academic schedule of the colleges, supervised and monitored by the investigators themselves. The collected data were coded and entered in Microsoft excel 2013, and statistical analysis was done by SPSS 20 version. Result: A majority of the respondents agreed that they were not provided with sufficient information about implant treatment procedures during their BDS program (65.3%), would like more to be provided in the curriculum (95.1%), and would like to get additional reliable information from dental consultants and specialists (40.7%) and training on it from fellowship programs conducted by universities (39.2%). Significant association was seen between the responses and academic levels. Conclusion: Undergraduate dental students of Nepal want more information about dental implants through various means. PMID- 29713347 TI - Integration of Family Planning Counselling to Mass Screening Campaign for Cervical Cancer: Experience from Guinea. AB - Aim: To assess feasibility of integrating family planning counselling into mass screening for cervical cancer in Guinea. Methodology: This was a descriptive cross-sectional study conducted over a month in Guinea regional capital cities. The targeted population comprised women aged 15 to 49 years. Nearly 4000 women were expected for the screening campaigns that utilized VIA and VIL methods with confirmation of positive tests through biopsy. A local treatment was immediately performed when the patient was eligible. Results: Overall 5673 women aged 15 to 60 years were received, a surplus of 42% of the expected population. 92.3% of women were aged 15-49 years and 90.1% were 25-49 years. Long-acting methods were the most utilized (89.2% of family planning users). 154 precancerous and cancerous lesions were screened, a global positivity rate of 2.7%. Conclusion: Integration of counselling and family planning services provision during cervical cancer mass screening is a feasible strategy. A cost-effective analysis of this approach would help a better planning of future campaigns and its replication in other contexts. PMID- 29713348 TI - A Case of Nongerminomatous Germ Cell Tumor of the Pineal Region: Risks and Advantages of Biopsy by Endoscopic Approach. AB - A 21-year-old male was admitted to our department with headache and drowsiness. CT scan and MRI revealed acute obstructive hydrocephalus caused by a pineal region mass. The serum and CSF levels of beta-human chorionic gonadotropin (beta hCG) were 215 IU/L and 447 IU/L, respectively, while levels of alpha-fetoprotein (AFP) were normal. A germ cell tumor (GCT) was suspected, and the patient underwent endoscopic third ventriculostomy (ETV) with biopsy. After four days from surgery, the tumor bled with mass expansion and ETV stoma occlusion; thus, a ventriculoperitoneal shunt was positioned. After ten months, the tumor metastasized to the thorax and abdomen with progression of intracerebral tumor mass. Despite the aggressive nature of this tumor, ETV remains a valid approach for a pineal region mass, but in case of GCT, the risk of bleeding should be taken into account, during and after the surgical procedure. PMID- 29713349 TI - The Dynamic DNA Demethylation during Postnatal Neuronal Development and Neural Stem Cell Differentiation. AB - Background: DNA demethylation, the conversion of 5-methylcytosine (5mC) to 5 hydroxymethylcytosine (5hmC), 5-formylcytosine (5fC), and 5-carboxylcytosine (5caC), plays important roles in diverse biological processes and multiple diseases by regulating gene expression. Methods: In this study, utilizing DNA dot blot, immunofluorescence staining, and qRT-PCR, we studied the expression pattern of Tets, the enzymes governing DNA demethylation, and the levels of 5hmC, 5fC, and 5caC during the postnatal neuronal development of mice. Results: It was found that 5hmC, 5fC, and 5caC were highly enriched in multiple brain regions and aNSCs and displayed temporal and spatial patterns during postnatal neuronal development and the differentiation of aNSCs. Consistently, the expression of Tets also exhibited temporal and spatial patterns. Conclusion: DNA demethylation displayed dynamic features during postnatal neuronal development and the differentiation of aNSCs of mice, which could contribute to appropriate gene expression. PMID- 29713350 TI - Sphingosine 1-Phosphate Receptor 1 Is Required for MMP-2 Function in Bone Marrow Mesenchymal Stromal Cells: Implications for Cytoskeleton Assembly and Proliferation. AB - Bone marrow-derived mesenchymal stromal cell- (BM-MSC-) based therapy is a promising option for regenerative medicine. An important role in the control of the processes influencing the BM-MSC therapeutic efficacy, namely, extracellular matrix remodelling and proliferation and secretion ability, is played by matrix metalloproteinase- (MMP-) 2. Therefore, the identification of paracrine/autocrine regulators of MMP-2 function may be of great relevance for improving BM-MSC therapeutic potential. We recently reported that BM-MSCs release the bioactive lipid sphingosine 1-phosphate (S1P) and, here, we demonstrated an impairment of MMP-2 expression/release when the S1P receptor subtype S1PR1 is blocked. Notably, active S1PR1/MMP-2 signalling is required for F-actin structure assembly (lamellipodia, microspikes, and stress fibers) and, in turn, cell proliferation. Moreover, in experimental conditions resembling the damaged/regenerating tissue microenvironment (hypoxia), S1P/S1PR1 system is also required for HIF-1alpha expression and vinculin reduction. Our findings demonstrate for the first time the trophic role of S1P/S1PR1 signalling in maintaining BM-MSCs' ability to modulate MMP-2 function, necessary for cytoskeleton reorganization and cell proliferation in both normoxia and hypoxia. Altogether, these data provide new perspectives for considering S1P/S1PR1 signalling a pharmacological target to preserve BM-MSC properties and to potentiate their beneficial potential in tissue repair. PMID- 29713352 TI - Chemical Activation of the Hypoxia-Inducible Factor Reversibly Reduces Tendon Stem Cell Proliferation, Inhibits Their Differentiation, and Maintains Cell Undifferentiation. AB - Adult stem cell-based therapeutic approaches for tissue regeneration have been proposed for several years. However, adult stem cells are usually limited in number and difficult to be expanded in vitro, and they usually tend to quickly lose their potency with passages, as they differentiate and become senescent. Culturing stem cells under reduced oxygen tensions (below 21%) has been proposed as a tool to increase cell proliferation, but many studies reported opposite effects. In particular, cell response to hypoxia seems to be very stem cell type specific. Nonetheless, it is clear that a major role in this process is played by the hypoxia inducible factor (HIF), the master regulator of cell response to oxygen deprivation, which affects cell metabolism and differentiation. Herein, we report that a chemical activation of HIF in human tendon stem cells reduces their proliferation and inhibits their differentiation in a reversible and dose dependent manner. These results support the notion that hypoxia, by activating HIF, plays a crucial role in preserving stem cells in an undifferentiated state in the "hypoxic niches" present in the tissue in which they reside before migrating in more oxygenated areas to heal a damaged tissue. PMID- 29713351 TI - The Role of Fibroblast Growth Factors in Tooth Development and Incisor Renewal. AB - The mineralized tissue of the tooth is composed of enamel, dentin, cementum, and alveolar bone; enamel is a calcified tissue with no living cells that originates from oral ectoderm, while the three other tissues derive from the cranial neural crest. The fibroblast growth factors (FGFs) are critical during the tooth development. Accumulating evidence has shown that the formation of dental tissues, that is, enamel, dentin, and supporting alveolar bone, as well as the development and homeostasis of the stem cells in the continuously growing mouse incisor is mediated by multiple FGF family members. This review discusses the role of FGF signaling in these mineralized tissues, trying to separate its different functions and highlighting the crosstalk between FGFs and other signaling pathways. PMID- 29713354 TI - Severe, eosinophilic asthma in primary care in Canada: a longitudinal study of the clinical burden and economic impact based on linked electronic medical record data. AB - Background: Stratification of patients with severe asthma by blood eosinophil counts predicts responders to anti-interleukin (IL)-5 (mepolizumab and reslizumab) and anti-IL-5 receptor alpha (benralizumab) therapies. This study characterized patients with severe asthma who could qualify for these biologics in a primary care setting. Methods: We retrospectively selected patients from July 1, 2010, to June 30, 2014, using a linked electronic medical records (EMR) database (IMS Evidence 360 EMR Canada) for > 950,000 patients in primary care in Ontario, Canada. Patients aged >= 12 years with >= 2 documented asthma diagnoses were identified as having severe asthma based on prescriptions for high-dosage inhaled corticosteroids (ICS) plus either a leukotriene receptor antagonist, long acting beta2-agonist (LABA), or theophylline filled on the same day. Patients' asthma was considered severe also if they received a prescription for ICS with oral corticosteroids (OCS) or an additional prescription for omalizumab. Patient characteristics, asthma-related medications, and blood eosinophil counts were captured using observed care patterns for the year prior to ICS/LABA and/or OCS prescription. Health care resource use (HCRU) and costs were captured throughout the 1-year follow-up period. Results: We identified 212 patients who met the criteria for severe asthma. These patients required an average of 6.5 physician visits during the 1-year follow-up period (95% confidence interval 5.7-7.3), and 20 (9%) were referred to respiratory specialists. Overall, 56 patients (26%) with severe asthma had complete blood counts, of whom 23 (41%) had blood eosinophil counts >= 300 cells/MUL and might be considered for anti-eosinophil therapies. Patients with severe asthma and blood eosinophil counts >= 300 cells/MUL had more respiratory specialist referrals (17% vs. 12%) than patients with blood eosinophils < 300 cells/MUL. Conclusions: Our data suggest that during 2010-2014, Ontario primary care patients with severe asthma and high blood eosinophil counts had greater HRCU than those with lower counts. Approximately 41% of patients with severe asthma could qualify for anti-eosinophil drugs based on blood eosinophil counts. However, the eosinophilic status of most patients was unknown. It is appropriate to increase awareness of the use of blood eosinophil counts to identify patients who could be considered for anti-eosinophil therapies. PMID- 29713353 TI - The norpurpureine alkaloid from Annona purpurea inhibits human platelet activation in vitro. AB - Background: The leaves of Annona purpurea have yielded several alkaloids with anti-aggregation activities against rabbit platelets. This is promising in the search for agents that might act against platelets and reduce the incidence of cardiovascular diseases. Since significant differences in platelet function have been reported between human and animal platelets, a study focusing on the effect of A. purpurea extracts against human platelet activation is necessary. Methods: The compounds in an A. purpurea ethanolic extract underwent bio-guided fractionation and were used for in vitro human platelet aggregation assays to isolate the compounds with anti-platelet activity. The bioactive compounds were identified by spectroscopic analysis. Additional platelet studies were performed to characterize their action as inhibitors of human platelet activation. Results: The benzylisoquinoline alkaloid norpurpureine was identified as the major anti platelet compound. The IC50 for norpurpureine was 80 MUM against platelets when stimulated with adenosine 5'-diphosphate (ADP), collagen and thrombin. It was pharmacologically effective from 20 to 220 MUM. Norpurpureine (220 MUM) exhibited its in vitro effectiveness in samples from 30 healthy human donors who did not take any drugs during the 2 weeks prior to the collection. Norpurpureine also gradually inhibited granule secretion and adhesion of activated platelets to immobilized fibrinogen. At the intra-platelet level, norpurpureine prevented agonist-stimulated calcium mobilization and cAMP reduction. Structure-activity relationship analysis indicates that the lack of a methyl group at the nitrogen seems to be key in the ability of the compound to interact with its molecular target. Conclusion: Norpurpureine displays a promising in vitro pharmacological profile as an inhibitor of human platelet activation. Its molecular target could be a common effector between Ca2+ and cAMP signaling, such as the PLC-PKC-Ca2+ pathway and PDEs. This needs further evaluation at the protein isoform level. PMID- 29713355 TI - Epilepsy syndromes during the first year of life and the usefulness of an epilepsy gene panel. AB - Recent advances in genetics have determined that a number of epilepsy syndromes that occur in the first year of life are associated with genetic etiologies. These syndromes range from benign familial epilepsy syndromes to early-onset epileptic encephalopathies that lead to poor prognoses and severe psychomotor retardation. An early genetic diagnosis can save time and overall cost by reducing the amount of time and resources expended to reach a diagnosis. Furthermore, a genetic diagnosis can provide accurate prognostic information and, in certain cases, enable targeted therapy. Here, several early infantile epilepsy syndromes with strong genetic associations are briefly reviewed, and their genotype-phenotype correlations are summarized. Because the clinical presentations of these disorders frequently overlap and have heterogeneous genetic causes, next-generation sequencing (NGS)-based gene panel testing represents a more powerful diagnostic tool than single gene testing. As genetic information accumulates, genetic testing will likely play an increasingly important role in diagnosing pediatric epilepsy. However, the efforts of clinicians to classify phenotypes in nondiagnosed patients and improve their ability to interpret genetic variants remain important in the NGS era. PMID- 29713356 TI - Sudden unexpected cardio-respiratory arrest after venipuncture in children. AB - Purpose: This study aimed to investigate the clinical and socioenvironmental characteristics of sudden cardiorespiratory arrest after venipuncture in children. Methods: We conducted a retrospective email-based survey of all members of the Korean Pediatric Society. The questionnaire included items on patient demographics, socioenvironmental circumstances of the venipuncture, type of cardiorespiratory arrest, symptoms and signs, treatment, prognosis, and presumed cause of the arrest. Results: Fourteen patients were identified. Of these, 13 were young children (<2 years old), and 1 was 14 years old. All patients had been previously healthy and had no specific risk factors for sudden cardiorespiratory arrest. Most cases (n=11, 79%) were defined as cardiac or cardiorespiratory arrest, while the remaining cases (n=3, 21%) were defined as respiratory arrest. Aspiration (n=3), acute myocarditis (n=2), and laryngeal chemoreflex (n=1) were presumed as the causes; however, the exact causes were unclear. The overall prognosis was poor (death, n=7; morbidity, n=5; full recovery, n=2). The medical institutions faced severe backlash because of these incidents (out-of-court settlement, n=5; medical lawsuit, n=5; continuous harassment, n=3). Conclusion: Cardiorespiratory arrest after venipuncture is unpredictable and the probable cause of most cases is a vasovagal reaction. Medical personnel must be aware of the risk of unexpected cardiorespiratory arrest during routine intravenous procedures. PMID- 29713357 TI - TORCH (toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus) screening of small for gestational age and intrauterine growth restricted neonates: efficacy study in a single institute in Korea. AB - Purpose: Routine screening for toxoplasmosis, rubella, cytomegalovirus (CMV), and herpes simplex virus (TORCH) in intrauterine growth restriction (IUGR) and small for gestational age (SGA) neonates has become a common practice. However, the incidence of TORCH varies across countries, and the cost of TORCH testing may be disadvantageous compared to disease-specific screening. To evaluate the efficacy of TORCH screening, the medical charts of IUGR or SGA neonates born in a single institution in Bucheon, Korea from 2011 to 2015 were reviewed. Methods: The clinical data of the 126 IUGR or SGA neonates were gathered, including gestational age, Apgar scores, neonatal sonographic findings, chromosome study, morbidities, developmental follow-up, and growth catch-up. Maternal factors including underlying maternal disease and fetal sonography were collected, and placental findings were recorded when available. TORCH screening was done using serum IgM, CMV urine culture, quantification of CMV DNA with real-time polymerase chain reaction, and rapid plasma reagin qualitative test for syphilis. Tests were repeated only for those with positive results. Results: Of the 119 TORCH screenings, only one was positive for toxoplasmosis IgM. This result was deemed false positive due to negative IgM on repeated testing and the absence of clinical symptoms. Conclusion: Considering the incidence and risk of TORCH in Korea, the financial burden of TORCH screening, and the single positive TORCH finding in our study, we suggest disease-specific screening based on maternal history and the clinical symptoms of the neonate. Regarding CMV, which may present asymptomatically, universal screening may be appropriate upon cost benefit analysis. PMID- 29713358 TI - The association of total blood mercury levels and overweight among Korean adolescents: analysis of the Korean National Health and Nutrition Examination Survey (KNHANES) 2010-2013. AB - Purpose: Obesity has been associated with higher total blood mercury levels, based on animal studies; however, studies that focus on children and adolescents are lacking. We aimed to assess the association between total blood mercury levels and the incidence of overweight and abdominal obesity in Korean adolescents. Methods: The study population comprised 1,567 adolescents (793 boys and 774 girls; aged 10-19 years), who participated in the Korea National Health and Nutrition Examination Survey 2010-2013. We analyzed total blood mercury levels according to obesity status in all participants. Results: The geometric mean of total blood mercury levels was 1.93 ug/L. Participants with overweight (2.20 ug/L) and obesity (2.17 ug/L) had higher levels than those with normal weight (1.86 ug/L, P<0.0001). The prevalence of overweight significantly increased with elevation of the total blood mercury quartile in both sexes. Increased incidence of abdominal obesity corresponding to increased total blood mercury level was observed in boys. After adjusting for covariates, those in the highest total blood mercury quartile were found to be at higher risk of overweight/obesity than those in the lowest quartile in both sexes (odds ratio [95% confidence interval]: boys, 3.27 [1.66-6.41]; girls, 1.90 [1.03-3.49]). The association between total blood mercury quartile and abdominal obesity was significant after controlling for covariates in boys (2.35 [1.05-5.24]). Conclusion: Our results suggest an association between total blood mercury levels and overweight in Korean adolescents. PMID- 29713359 TI - Hypercalciuria and febrile convulsion in children under 5 years old. AB - Purpose: The association between hypercalciuria and febrile convulsion is controversial. The present study aimed to investigate the statistical association between hypercalciuria and childhood febrile convulsions. Methods: Overall, 160 children aged 6 months to 5 years, including 80 children with febrile convulsion and 80 febrile children without convulsion (comparison group), were recruited. All laboratory tests, including 24-hour urine calcium, were undertaken in an academic clinical laboratory. Results: Forty-five children of the febrile convulsion group (60%) and 30 of the comparison group (40%) had hypercalciuria. There was a significant difference between the 2 groups (P=0.02). Conclusion: Our results indicated that there is a statistical association between convulsion and hypercalciuria in children. Since we found this association with a cross sectional assessment, further studies, especially prospective and controlled designs, are needed. PMID- 29713360 TI - Intestinal duplication revealed by posterior reversible encephalopathy syndrome. AB - We report a unique case of intestinal duplication detected on posterior reversible encephalopathy syndrome (PRES) in a 13-year-old girl. She was admitted to the pediatric Emergency Department because of generalized seizures. Radiological assessment revealed a large, well-defined, thick-walled cystic lesion in the mid abdomen, suggestive of duplication cyst associated to a PRES. Exploration confirmed the diagnosis of ileal duplication cyst, and the mass was resected. The postoperative course was uneventful. Both hypertension and neurological dysfunction resolved after the mass resection. A followup brain magnetic resonance imaging was performed 9 months later and showed complete resolution of the cerebellar changes. Although extrinsic compression of the retroperitoneal structures has not been reported in the literature as a complication of duplication cyst, we strongly believe that this is the most logical and plausible hypothesis that would explain the pathogenesis of PRES in our patient. PMID- 29713361 TI - Effects of Angelica gigas Nakai as an Anti-Inflammatory Agent in In Vitro and In Vivo Atopic Dermatitis Models. AB - We investigated the cellular and molecular mechanisms mediating the effects of Angelica gigas Nakai extract (AGNE) through the mitogen-activated protein kinases (MAPKs)/NF-kappaB pathway using in vitro and in vivo atopic dermatitis (AD) models. We examined the effects of AGNE on the expression of proinflammatory cytokines and chemokines in human mast cell line-1 (HMC-1) cells. Compound 48/80 induced pruritus and 2,4-dinitrochlorobenzene- (DNCB-) induced AD-like skin lesion mouse models were also used to investigate the antiallergic effects of AGNE. AGNE reduced histamine secretion, production of proinflammatory cytokines including interleukin- (IL-) 1beta, IL-4, IL-6, IL-8, and IL-10, and expression of cyclooxygenase- (COX-) 2 in HMC-1 cells. Scratching behavior and DNCB-induced AD-like skin lesions were also attenuated by AGNE administration through the reduction of serum IgE, histamine, tumor necrosis factor-alpha (TNF-alpha), IL-6 levels, and COX-2 expression in skin tissue from mouse models. Furthermore, these inhibitory effects were mediated by the blockade of the MAPKs and NF-kappaB pathway. The findings of this study proved that AGNE improves the scratching behavior and atopy symptoms and reduces the activity of various atopy-related mediators in HMC-1 cells and mice model. These results suggest the AGNE has a therapeutic potential in anti-AD. PMID- 29713362 TI - Tanshinone IIA Attenuates Diabetic Peripheral Neuropathic Pain in Experimental Rats via Inhibiting Inflammation. AB - Diabetic peripheral neuropathic pain (DPNP) is a common and intractable complication of diabetes. Conventional therapies are always not ideal; development of novel drugs is still needed to achieve better pain relief. Recent evidences have demonstrated that inflammation is involved in the onset and maintenance of DPNP. The anti-inflammatory property of Tanshinone IIA (TIIA) makes it a promising candidate to block or alter the pain perception. This study was conducted to investigate whether TIIA could attenuate DPNP in streptozotocin- (STZ-) induced rats model and its potential mechanisms. TIIA was administered to STZ-induced diabetic rats at the dose of 40 mg/kg once a day for 3 weeks. The effects of TIIA on thermal hyperalgesia and mechanical allodynia were investigated using behavioral tests. The mRNA level and expression of interleukin (IL-) 1beta, interleukin- (IL-) 6, tumor necrosis factor- (TNF-) alpha, and interleukin- (IL-) 10 in the fourth to sixth segments of the dorsal root ganglion (L4-6 DRG) were detected by quantitative real-time PCR (qPCR) and Western blot. TIIA treatment significantly attenuated mechanical allodynia and thermal hyperalgesia in diabetic rats. In addition, the expression of the proinflammatory cytokines IL-1beta, IL-6, and TNF-alpha was inhibited, and the level of the anti inflammatory cytokine IL-10 was increased by TIIA. This study demonstrated that TIIA has significant antiallodynic and antihyperalgesic effects in a rat model of STZ-induced DPNP, and the effect may be associated with its anti-inflammation property. PMID- 29713363 TI - Hypoglycaemic and Antioxidant Effects of Propolis of Chihuahua in a Model of Experimental Diabetes. AB - Propolis is a bee-collected natural product that has been proven to have various bioactivities. This study tested the effects of a Mexican propolis on streptozotocin-induced diabetes mellitus in a murine model. The results showed that an ethanolic extract of propolis of Chihuahua (EEPCh) significantly inhibited increases in blood glucose and the loss of body weight in diabetic mice. EEPCh increased plasma insulin levels in STZ-diabetic mice, whereas, in untreated diabetic mice, there was no detection of insulin. EEPCh had a high antioxidant capacity (SA50 = 15.75 MUg/mL), which was directly related to the concentrations of total phenols (314 mg GAE/g of extract) and flavonoids (6.25 mg QE/g of extract). In addition, increased activities of the enzymes superoxide dismutase, catalase, and glutathione peroxidase were observed in diabetic mice treated with EEPCh. Compounds such as pinocembrin, quercetin, naringin, naringenin, kaempferol, acacetin, luteolin, and chrysin were identified by HPLC MS analysis. This investigation demonstrated that propolis of Chihuahua possesses hypoglycaemic and antioxidant activities and can alleviate symptoms of diabetes mellitus in mice. These effects may be directly related to the chemical composition of propolis, as most of the compounds identified in propolis are reportedly active in terms of the different parameters evaluated in this work. PMID- 29713364 TI - Potential Hypoglycaemic and Antiobesity Effects of Senna italica Leaf Acetone Extract. AB - Background: Type II diabetes is on the rise while obesity is one of the strongest risk factors of type II diabetes. The search for a drug for type II that can equally mitigate obesity related complication is desired. Methods: The acetone leaf extract of Senna italica was evaluated for its cytotoxic, antiglycation, and lipolytic effect, glucose uptake, and GLUT4 translocation and expression using published methods, while that for adipogenesis and protein expression levels of obesity related adipokines was assessed using adipogenesis assay and mouse adipokine proteome profiler kit, respectively. The possible mechanism of glucose uptake was assessed through the inhibition of PI3K pathway. Results: The extract had no adverse effect on 3T3-L1 cell viability (CC50 > 1000 MUg/ml). High antiglycation effect was attained at 10 mg/ml, while at 25-200 MUg/ml it showed no significant increase in adipogenesis and lipolysis. The extract at 100 MUg/ml was shown to decrease the expression levels of various adipokines and minimal glucose uptake at 50-100 MUg/ml with a nonsignificant antagonistic effect when used in combination with insulin. GLUT4 translocation and expression were attained at 50-100 MUg/ml with an increase in GLUT4 expression when in combination with insulin. Conclusion: The acetone leaf extract of S. italica stimulates glucose uptake through the PI3K-dependent pathway and can serve as a source of therapeutic agent for the downregulation of obesity-associated adipokines in obesity and antiglycation agents. PMID- 29713365 TI - Shape variation and modularity of skull and teeth in domesticated horses and wild equids. AB - Background: In horses, the morphological changes induced by the process of domestication are reportedly less pronounced than in other species, such as dogs or pigs - although the horses' disparity has rarely been empirically tested. We investigated shape differences and modularity of domesticated horses, Przewalski's horses, donkeys and zebras. Mandibular and tooth shape have been shown to be valuable features for differentiating wild and domesticated forms in some mammals. Results: Both mandible and teeth, show a pattern of shape space occupation analogous to that of the cranium, with domesticated horses occupying a similar extension in shape space to that of wild equids. Only cranial shape data exhibit a tendency to separate domesticated horses and Przewalski's horses from donkeys and zebras. Maximum likelihood model-based tests confirm the horse cranium is composed of six developmental modules, as reported for placental mammals in general. The magnitude of integration in domesticated horse skull was lower than in wild equids across all six cranial modules, and lower values of integration were associated with higher disparity values across all modules. Conclusion: This is the first study that combines different skeletal features for the description and comparison of shape changes in all living equid groups using geometric morphometrics. We support Darwin's hypothesis that the shape variation in the skull of domesticated horses is similar to the shape variation of all wild equid species existing today. Lower magnitudes of module integration are recovered in domesticated horses compared to their wild relatives. PMID- 29713366 TI - Accurate and easy method for systemin quantification and examining metabolic changes under different endogenous levels. AB - Background: Systemin has been extensively studied since it was discovered and is described as a peptidic hormone in tomato plants and other Solanaceae. Jasmonic acid and systemin are proposed to act through a positive feed-back loop with jasmonic acid, playing synergistic roles in response to both wounding and insect attack. Despite its biological relevance, most studies regarding the function of systemin in defence have been studied via PROSYSTEMIN (PROSYS) gene expression, which encodes the propeptide prosystemin that is later cleaved to systemin (SYS). Interestingly, hardly any studies have been based on quantification of the peptide. Results: In this study, a simple and accurate method for systemin quantification was developed to understand its impact on plant metabolism. The basal levels of systemin were found to be extremely low. To study the role of endogenous systemin on plant metabolism, systemin was quantified in a transgenic line overexpressing the PROSYS gene (PS+) and in a silenced antisense line (PS-). We evaluated the relevance of systemin in plant metabolism by analysing the metabolomic profiles of both lines compared to wildtype plants through untargeted metabolomic profiling. Compounds within the lignan biosynthesis and tyrosine metabolism pathways strongly accumulated in PS+ compared to wild-type plants and to plants from the PS- line. The exogenous treatments with SYS enhanced accumulation of lignans, which confirms the role of SYS in cell wall reinforcement. Unexpectedly, PS+ plants displayed wild-type levels of jasmonic acid (JA) but elevated accumulation of 12-oxo-phytodienoic acid (OPDA), suggesting that PS+ should not be used as an over-accumulator of JA in experimental setups. Conclusions: A simple method, requiring notably little sample manipulation to quantify the peptide SYS, is described. Previous studies were based on genetic changes. In our study, SYS accumulated at extremely low levels in wild-type tomato leaves, showed slightly higher levels in the PROSYSTEMIN-overexpressing plants and was absent in the silenced lines. These small changes have a significant impact on plant metabolism. SA and OPDA, but not JA, were higher in the PROSYS-overexpressing plants. PMID- 29713367 TI - Wentong decoction cures allergic bronchial asthma by regulating the apoptosis imbalance of EOS. AB - Background: Eosinophils (EOS) is one of the most important cells involved in the pathogenesis of chronic airway inflammation in asthma, and its apoptosis is part of the mechanisms of asthma. Therefore, this study aimed to observe the effect of Chinese medicine Wentong decoction (WTD) in EOS apoptosis in asthmatic rats. This work also explored the mechanism of WTD regulation in EOS apoptosis and provided a new target for clinical treatment of asthma. Methods: Asthmatic rats induced by ovalbumin were treated with WTD. Lung function of rats in each group was detected, and lung tissue pathology, EOS counts in blood and bronchoalveolar lavage fluid were observed. The degree of the EOS apoptosis in rats was detected. The expression content of interleukin (IL)-5, IL-10, chemokine (C-C motif) ligand 5 (CCL5), granulocyte-macrophage colony-stimulating factor (GM-CSF), transforming growth factor beta 1 (TGF-beta1), interferon (IFN)-gamma, and other cytokines in rat serum and the genes of Eotaxin mRNA, Fas mRNA, FasL mRNA, Fas/FasL and Bcl-2 mRNA in the lung tissues were determined. Results: WTD can reduced airway resistance in rat models and improved airway compliance. The pathological changes of lung tissue in WTD group were significantly alleviated, at the same time, WTD could reduce the EOS count in the blood and BALF smears of the asthmatic model rats. Compared with the model group, the apoptosis degree of EOS significantly increased in rats in the WTD group. The expression of IL-5, CCL5, and GM-CSF in the serum and the expression of Eotaxin mRNA, Bcl-2 mRNA in the lung tissues in rats in the WTD group rats decreased. Moreover, the expression of IL-10, TGF beta1, and IFN-gamma in the serum and the expression of Fas mRNA, FasL mRNA in the lung tissues in rats in the WTD group rats increased compared with that in rats in the model group. Conclusions: Wentong decoction may accelerate EOS apoptosis, reduce asthma inflammation, and alleviate the disease through regulating and controlling the factors related to the anti-apoptosis and pro apoptosis. PMID- 29713368 TI - Comparative study of the polyphenol content-related anti-inflammatory and antioxidant activities of two Urera aurantiaca specimens from different geographical areas. AB - Background: Urera aurantiaca is an Argentinean species that has been traditionally used to treat symptoms of inflammation. The aim of this study was to determine and compare the anti-inflammatory and antioxidant effects of two specimens of Urera aurantiaca obtained in the provinces of Salta and Misiones, which are two different geographical areas of Argentina. Methods: The anti inflammatory activity of the extracts was tested in LPS-stimulated macrophages through the DPPH radical scavenging activity, the SOD-like activity, the reducing power and the inhibition of lipid peroxidation. The anti-inflammatory activity was also evaluated by the inhibition of albumin denaturation and proteinase inhibitory action tests. The total polyphenols, flavonoids and tannins content were quantified. Results: Both extracts were able to reduce the augmented NO release in LPS-activated macrophages and showed antioxidant and in vitro anti inflammatory activities. The polyphenols content was higher in the extract obtained from the specimen from Salta than in that obtained in Misiones. This finding accounts for the higher anti-inflammatory and antioxidant properties obtained with the former. Conclusion: The differences in chemical composition and the biological activities observed between the extracts are probably related to the different environmental conditions found in both provinces. PMID- 29713369 TI - Extrahepatic cytochrome P450s play an insignificant role in triptolide-induced toxicity. AB - Background: Triptolide, an active ingredient of Chinese medicine plant Tripterygium wilfordii Hook.f., has been shown to exert anti-tumor, immunosuppressive, anti-inflammatory, and anti-fertility pharmacological effects. However, triptolide also causes severe side effects, which are manifested as toxicities in multiple organs. The aim of this study was to analyze the role of extrahepatic cytochrome P450 enzymes in triptolide-induced toxicity. Methods: Xh CL mouse model with normal liver, but low extrahepatic P450 expression levels was used in this study. Xh-CL mice and C57BL/6 (wildtype, WT) mice were treated with 200 MUg/kg triptolide intraperitoneally every other day for 30 days. The serum levels of alanine aminotransferase (ALT), aspartate transaminase (AST), creatine (Cre), and blood urea nitrogen (BUN) were detected by kits. The changes of tissue were observed with H&E staining. Two groups of mice (Xh-CL and WT animals), were received a single dose of 1 mg/kg TP by oral gavage for pharmacokinetic analysis. Results: Xh-CL mice displayed higher serum levels of ALT, AST, Cre, and BUN compared to untreated Xh-CL mice. The organ-to-body weight ratio for spleen was high, while that for testes was low. Histopathological changes were observed in multiple organs. However, compared with triptolide-treated WT mice, no significant differences in either blood chemistry or histopathology were recorded. Furthermore, pharmacokinetic studies showed no significant differences between triptolide-treated Xh-CL and WT mice. Conclusions: Our findings suggest that sub-chronic triptolide treatment can induce toxicities in mouse kidney, spleen, and testis with or without normal local P450 functions. Therefore, extrahepatic P450s play an insignificant role in triptolide-induced toxicity. PMID- 29713370 TI - SOV_refine: A further refined definition of segment overlap score and its significance for protein structure similarity. AB - Background: The segment overlap score (SOV) has been used to evaluate the predicted protein secondary structures, a sequence composed of helix (H), strand (E), and coil (C), by comparing it with the native or reference secondary structures, another sequence of H, E, and C. SOV's advantage is that it can consider the size of continuous overlapping segments and assign extra allowance to longer continuous overlapping segments instead of only judging from the percentage of overlapping individual positions as Q3 score does. However, we have found a drawback from its previous definition, that is, it cannot ensure increasing allowance assignment when more residues in a segment are further predicted accurately. Results: A new way of assigning allowance has been designed, which keeps all the advantages of the previous SOV score definitions and ensures that the amount of allowance assigned is incremental when more elements in a segment are predicted accurately. Furthermore, our improved SOV has achieved a higher correlation with the quality of protein models measured by GDT TS score and TM-score, indicating its better abilities to evaluate tertiary structure quality at the secondary structure level. We analyzed the statistical significance of SOV scores and found the threshold values for distinguishing two protein structures (SOV_refine > 0.19) and indicating whether two proteins are under the same CATH fold (SOV_refine > 0.94 and > 0.90 for three- and eight-state secondary structures respectively). We provided another two example applications, which are when used as a machine learning feature for protein model quality assessment and comparing different definitions of topologically associating domains. We proved that our newly defined SOV score resulted in better performance. Conclusions: The SOV score can be widely used in bioinformatics research and other fields that need to compare two sequences of letters in which continuous segments have important meanings. We also generalized the previous SOV definitions so that it can work for sequences composed of more than three states (e.g., it can work for the eight-state definition of protein secondary structures). A standalone software package has been implemented in Perl with source code released. The software can be downloaded from http://dna.cs.miami.edu/SOV/. PMID- 29713372 TI - Water, sanitation, and hygiene access in southern Syria: analysis of survey data and recommendations for response. AB - Background: Water, sanitation, and hygiene (WASH) are immediate priorities for human survival and dignity in emergencies. In 2010, > 90% of Syrians had access to improved drinking water. In 2011, armed conflict began and currently 12 million people need WASH services. We analyzed data collected in southern Syria to identify effective WASH response activities for this context. Methods: Cross sectional household surveys were conducted in 2016 and 2017 in 17 sub-districts of two governorates in opposition controlled southern Syria. During the survey, household water was tested for free chlorine residual (FCR). Descriptive statistics were calculated, and mixed effect logistic regressions were completed to determine associations between demographic and WASH variables with outcomes of FCR > 0.1 mg/L in household water and reported diarrhea in children < 5 years old. Results: In 2016 and 2017, 1281 and 1360 surveys were conducted. Piped water as the main water source declined from 22.0% to 15.3% over this time. Households accessed 50-60 l per capita daily (primarily from private water trucking networks). Households spent ~ 20% of income on water and reported market available hygiene items were unaffordable. FCR > 0.1 mg/L increased from 4.1% to 27.9% over this time, with Water Safety Plan (WSP) programming strongly associated with FCR (mOR: 24.16; 95% CI: 5.93-98.5). The proportion of households with childhood diarrhea declined from 32.8% to 20.4% over this time; sanitation and hygiene access were protective against childhood diarrhea. Conclusions: The private sector has effectively replaced decaying infrastructure in Syria, although at high cost and uncertain quality. Allowing market forces to manage WASH services and quantity, and targeting emergency response activities on increasing affordability with well-targeted subsidies and improving water quality and regulation via WSPs can be an effective, scalable, and cost-effective strategy to guarantee water and sanitation access in protracted emergencies with local markets. PMID- 29713371 TI - Association between uncooperativeness and the glucose metabolism of patients with chronic behavioral disorders after severe traumatic brain injury: a cross sectional retrospective study. AB - Bakground: Patients with behavioral disorders following severe traumatic brain injury (sTBI) often have disorders of consciousness that make expressing their emotional distress difficult. However, no standard method for assessing the unsettled and unforeseen responses that are associated with behavioral disorders has yet to be established. Because the thalamus is known to play a role in maintaining consciousness and cognition, we used 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG-PET/CT) to examine the association between brain glucose metabolism in the thalamus and behavioral disorders. Methods: We retrospectively analyzed 70 consecutive patients with sTBI who had been involved in motor vehicle accidents. To assess behavioral disorders, we evaluated 18 symptoms using the Brief Psychiatric Rating Scale (BPRS): Emotional Withdrawal, Conceptual Disorganization, Tension, Mannerisms and Posturing, Motor Retardation, Uncooperativeness, Blunted Affect, Excitement, Somatic Concern, Anxiety, Feeling of Guilt, Grandiosity, Depressive Mood, Hostility, Suspiciousness, Hallucinatory Behavior, Unusual Thought Content, and Disorientation. First, we identified clinical characteristics of sTBI patients with behavioral disorders. Next, we retrospectively analyzed 18F-FDG-PET/CT data to assess how thalamic activity was related with abnormal behaviors. Results: Twenty-six patients possessed the minimum communicatory ability required for psychiatric interview. Among them, 15 patients (57.7%) were diagnosed with behavioral disorder, 14 of whom had reached a stable psychiatric state after about 426.6 days of treatment. Excitement (13 patients) and uncooperativeness (10 patients) were the most frequently observed symptoms. Available 18F-FDG-PET/CT data indicated that thalamic glucose metabolism was imbalanced and lateralized (p = 0.04) in 6 patients who exhibited uncooperativeness. Conclusions: Behavioral symptoms of excitement and uncooperativeness were common in patients with sTBI, although most symptoms improved as the chronic stage continued. Our data support the idea that imbalanced laterality of glucose metabolism in the thalamus might be related to behavioral disorders characterized by uncooperativeness. Trial registration: UMIN 000029531. Registered 27 March 2017, retrospectively registered. PMID- 29713373 TI - Enhancing the functional output of transplanted islets in diabetic mice using a drug-eluting scaffold. AB - Background: Islet transplantation is increasingly used in the diabetic patients to control the blood glucose level. However, the functional output of transplanted islets remains hampered due to the local inflammation, loss of islets, etc. To that end, in this study we explored to enhance the functional output of transplanted islets in diabetic mice by employing a drug-eluting scaffold with a payload of interleukin 4 (IL-4). Results: According to the in vitro studies, the scaffold showed no cytotoxicity, a rapid release of IL-4 within a week and the IL-4 retained its bioactivity. During the 4-week time window after the islet transplantation, in vivo studies showed that the levels of blood insulin and C-peptide 2 in diabetic mice in the drug-eluting scaffold group significantly increased since week 2, which effectively reduced the blood glucose level. In addition, these mice demonstrated a stronger capability to withstand a rapid glucose spike as evidenced by the tolerance of sudden oral glucose challenge test result. A further mechanistic study suggested that the enhanced functional output could be attributed to the M2 polarization of macrophages as evidenced by the increase of CD163+/CD68+ macrophages in the islet tissues. A M2 polarization of macrophages is widely believed to exert an anti-inflammatory influence on local tissues, which could accelerate the resolution of local inflammation following the islet transplantation. Conclusion: Our study shed a new light on the hyperglycemia management of diabetic patients following the islet transplantation. PMID- 29713374 TI - Mannanase hydrolysis of spruce galactoglucomannan focusing on the influence of acetylation on enzymatic mannan degradation. AB - Background: Galactoglucomannan (GGM) is the most abundant hemicellulose in softwood, and consists of a backbone of mannose and glucose units, decorated with galactose and acetyl moieties. GGM can be hydrolyzed into fermentable sugars, or used as a polymer in films, gels, and food additives. Endo-beta-mannanases, which can be found in the glycoside hydrolase families 5 and 26, specifically cleave the mannan backbone of GGM into shorter oligosaccharides. Information on the activity and specificity of different mannanases on complex and acetylated substrates is still lacking. The aim of this work was to evaluate and compare the modes of action of two mannanases from Cellvibrio japonicus (CjMan5A and CjMan26A) on a variety of mannan substrates, naturally and chemically acetylated to varying degrees, including naturally acetylated spruce GGM. Both enzymes were evaluated in terms of cleavage patterns and their ability to accommodate acetyl substitutions. Results: CjMan5A and CjMan26A demonstrated different substrate preferences on mannan substrates with distinct backbone and decoration structures. CjMan5A action resulted in higher amounts of mannotriose and mannotetraose than that of CjMan26A, which mainly generated mannose and mannobiose as end products. Mass spectrometric analysis of products from the enzymatic hydrolysis of spruce GGM revealed that an acetylated hexotriose was the shortest acetylated oligosaccharide produced by CjMan5A, whereas CjMan26A generated acetylated hexobiose as well as diacetylated oligosaccharides. A low degree of native acetylation did not significantly inhibit the enzymatic action. However, a high degree of chemical acetylation resulted in decreased hydrolyzability of mannan substrates, where reduced substrate solubility seemed to reduce enzyme activity. Conclusions: Our findings demonstrate that the two mannanases from C. japonicus have different cleavage patterns on linear and decorated mannan polysaccharides, including the abundant and industrially important resource spruce GGM. CjMan26A released higher amounts of fermentable sugars suitable for biofuel production, while CjMan5A, producing higher amounts of oligosaccharides, could be a good candidate for the production of oligomeric platform chemicals and food additives. Furthermore, chemical acetylation of mannan polymers was found to be a potential strategy for limiting the biodegradation of mannan-containing materials. PMID- 29713375 TI - Engineering global transcription to tune lipophilic properties in Yarrowia lipolytica. AB - Background: Evolution of complex phenotypes in cells requires simultaneously tuning expression of large amounts of genes, which can be achieved by reprograming global transcription. Lipophilicity is an important complex trait in oleaginous yeast Yarrowia lipolytica. It is necessary to explore the changes of which genes' expression levels will tune cellular lipophilic properties via the strategy of global transcription engineering. Results: We achieved a strategy of global transcription engineering in Y. lipolytica by modifying the sequences of a key transcriptional factor (TF), SPT15-like (Yl-SPT15). The combinatorial mutagenesis of this gene was achieved by DNA assembly of up to five expression cassettes of its error-prone PCR libraries. A heterologous beta-carotene biosynthetic pathway was constructed to research the effects of combined Yl-SPT15 mutants on carotene and lipid production. As a result, we obtained both an "enhanced" strain with 4.7-fold carotene production and a "weakened" strain with 0.13-fold carotene production relative to the initial strain, nearly 40-fold changing range. Genotype verification, comparative transcriptome analysis, and detection of the amounts of total and free fatty acids were made for the selected strains, indicating effective tuning of cells' lipophilic properties. We exploited the key pathways including RNA polymerase, ketone body metabolism, fatty acid synthesis, and degradation that drastically determined cells' variable lipophilicity. Conclusions: We have examined the effects of combinatorial mutagenesis of Yl-SPT15 on cells' capacity of producing beta-carotene and lipids. The lipophilic properties in Y. lipolytica could be effectively tuned by simultaneously regulating genome-wide multi-gene expression levels. The exploited gene targets and pathways could guide design and reconstruction of yeast cells for tunable and optimal production of other lipophilic products. PMID- 29713376 TI - Genome-centric metatranscriptomes and ecological roles of the active microbial populations during cellulosic biomass anaerobic digestion. AB - Background: Although anaerobic digestion for biogas production is used worldwide in treatment processes to recover energy from carbon-rich waste such as cellulosic biomass, the activities and interactions among the microbial populations that perform anaerobic digestion deserve further investigations, especially at the population genome level. To understand the cellulosic biomass degrading potentials in two full-scale digesters, this study examined five methanogenic enrichment cultures derived from the digesters that anaerobically digested cellulose or xylan for more than 2 years under 35 or 55 degrees C conditions. Results: Metagenomics and metatranscriptomics were used to capture the active microbial populations in each enrichment culture and reconstruct their meta-metabolic network and ecological roles. 107 population genomes were reconstructed from the five enrichment cultures using a differential coverage binning approach, of which only a subset was highly transcribed in the metatranscriptomes. Phylogenetic and functional convergence of communities by enrichment condition and phase of fermentation was observed for the highly transcribed populations in the metatranscriptomes. In the 35 degrees C cultures grown on cellulose, Clostridium cellulolyticum-related and Ruminococcus-related bacteria were identified as major hydrolyzers and primary fermenters in the early growth phase, while Clostridium leptum-related bacteria were major secondary fermenters and potential fatty acid scavengers in the late growth phase. While the meta-metabolism and trophic roles of the cultures were similar, the bacterial populations performing each function were distinct between the enrichment conditions. Conclusions: Overall, a population genome-centric view of the meta metabolism and functional roles of key active players in anaerobic digestion of cellulosic biomass was obtained. This study represents a major step forward towards understanding the microbial functions and interactions at population genome level during the microbial conversion of lignocellulosic biomass to methane. The knowledge of this study can facilitate development of potential biomarkers and rational design of the microbiome in anaerobic digesters. PMID- 29713378 TI - Enhanced extraction of butyric acid under high-pressure CO2 conditions to integrate chemical catalysis for value-added chemicals and biofuels. AB - Background: Extractive fermentation with the removal of carboxylic acid requires low pH conditions because acids are better partitioned into the solvent phase at low pH values. However, this requirement conflicts with the optimal near-neutral pH conditions for microbial growth. Results: CO2 pressurization was used, instead of the addition of chemicals, to decrease pH for the extraction of butyric acid, a fermentation product of Clostridium tyrobutyricum, and butyl butyrate was selected as an extractant. CO2 pressurization (50 bar) improved the extraction efficiency of butyric acid from a solution at pH 6, yielding a distribution coefficient (D) 0.42. In situ removal of butyric acid during fermentation increased the production of butyric acid by up to 4.10 g/L h, an almost twofold increase over control without the use of an extraction process. Conclusion: In situ extraction of butyric acid using temporal CO2 pressurization may be applied to an integrated downstream catalytic process for upgrading butyric acid to value added chemicals in an organic solvent. PMID- 29713377 TI - Process analysis and optimization of simultaneous saccharification and co fermentation of ethylenediamine-pretreated corn stover for ethanol production. AB - Background: Improving ethanol concentration and reducing enzyme dosage are main challenges in bioethanol refinery from lignocellulosic biomass. Ethylenediamine (EDA) pretreatment is a novel method to improve enzymatic digestibility of lignocellulose. In this study, simultaneous saccharification and co-fermentation (SSCF) process using EDA-pretreated corn stover was analyzed and optimized to verify the constraint factors on ethanol production. Results: Highest ethanol concentration was achieved with the following optimized SSCF conditions at 6% glucan loading: 12-h pre-hydrolysis, 34 degrees C, pH 5.4, and inoculum size of 5 g dry cell/L. As glucan loading increased from 6 to 9%, ethanol concentration increased from 33.8 to 48.0 g/L, while ethanol yield reduced by 7%. Mass balance of SSCF showed that the reduction of ethanol yield with the increasing solid loading was mainly due to the decrease of glucan enzymatic conversion and xylose metabolism of the strain. Tween 20 and BSA increased ethanol concentration through enhancing enzymatic efficiency. The solid-recycled SSCF process reduced enzyme dosage by 40% (from 20 to 12 mg protein/g glucan) to achieve the similar ethanol concentration (~ 40 g/L) comparing to conventional SSCF. Conclusions: Here, we established an efficient SSCF procedure using EDA-pretreated biomass. Glucose enzymatic yield and yeast viability were regarded as the key factors affecting ethanol production at high solid loading. The extensive analysis of SSCF would be constructive to overcome the bottlenecks and improve ethanol production in cellulosic ethanol refinery. PMID- 29713379 TI - AC-202, a highly effective fluorophore for the visualization of lipid droplets in green algae and diatoms. AB - Background: Lipid-specific live cell dyes are an important tool for the study of algal lipid metabolism, the monitoring of lipid production, and the identification of algal strains with high lipid yields. Nile Red and BODIPY have emerged as the principal dyes for these purposes. However, they suffer from a number of shortcomings including for specificity, penetration, interference from chlorophyll autofluorescence, and incompatibility with widely used genetically encoded reporters in the green and blue regions of the spectrum such as the green fluorescent protein and the red fluorescent protein. Results: We tested a new blue fluorescent dye, AC-202, in both the green algae Chlamydomonas reinhardtii and the pennate diatom Phaeodactylum tricornutum. We show that AC-202 is effective in both algae and that after minimal sample preparation, it can label lipid droplets induced by nitrogen starvation or by inhibitors of the TOR (target of rapamycin) kinase. We found that AC-202 benefits from a low background signal and is therefore more sensitive than BODIPY for semiquantitative in vivo fluorescence measurements. Finally, a co-staining experiment indicated that AC 202 can be used for multicolor imaging in combination with both red and green fluorophores. Conclusions: AC-202 is an alternative and highly effective fluorophore for algal research that resolves drawbacks encountered with other neutral lipid dyes. AC-202 can be used to rapidly and sensitively visualize lipid droplets, and will contribute to the identification of metabolic and signaling pathways involved in lipid droplet formation, monitoring lipid production, and in the development of screens for algal strains suitable for biofuel production. PMID- 29713380 TI - Meta-proteomic analysis of protein expression distinctive to electricity generating biofilm communities in air-cathode microbial fuel cells. AB - Background: Bioelectrochemical systems (BESs) harness electrons from microbial respiration to generate power or chemical products from a variety of organic feedstocks, including lignocellulosic biomass, fermentation byproducts, and wastewater sludge. In some BESs, such as microbial fuel cells (MFCs), bacteria living in a biofilm use the anode as an electron acceptor for electrons harvested from organic materials such as lignocellulosic biomass or waste byproducts, generating energy that may be used by humans. Many BES applications use bacterial biofilm communities, but no studies have investigated protein expression by the anode biofilm community as a whole. Results: To discover functional protein expression during current generation that may be useful for MFC optimization, a label-free meta-proteomics approach was used to compare protein expression in acetate-fed anode biofilms before and after the onset of robust electricity generation. Meta-proteomic comparisons were integrated with 16S rRNA gene-based community analysis at four developmental stages. The community composition shifted from dominance by aerobic Gammaproteobacteria (90.9 +/- 3.3%) during initial biofilm formation to dominance by Deltaproteobacteria, particularly Geobacter (68.7 +/- 3.6%) in mature, electricity-generating anodes. Community diversity in the intermediate stage, just after robust current generation began, was double that at the early stage and nearly double that of mature anode communities. Maximum current densities at the intermediate stage, however, were relatively similar (~ 83%) to those achieved by mature-stage biofilms. Meta proteomic analysis, correlated with population changes, revealed significant enrichment of categories specific to membrane and transport functions among proteins from electricity-producing biofilms. Proteins detected only in electricity-producing biofilms were associated with gluconeogenesis, the glyoxylate cycle, and fatty acid beta-oxidation, as well as with denitrification and competitive inhibition. Conclusions: The results demonstrate that it is possible for an MFC microbial community to generate robust current densities while exhibiting high taxonomic diversity. Moreover, these data provide evidence to suggest that startup growth of air-cathode MFCs under conditions that promote the establishment of aerobic-anaerobic syntrophy may decrease startup times. This study represents the first investigation into protein expression of a complex BES anode biofilm community as a whole. The findings contribute to understanding of the molecular mechanisms at work during BES startup and suggest options for improvement of BES generation of bioelectricity from renewable biomass. PMID- 29713382 TI - Self-assessment of surgical ward crisis management using video replay augmented with stress biofeedback. AB - Background: We aimed to explore the feasibility and attitudes towards using video replay augmented with real time stress quantification for the self-assessment of clinical skills during simulated surgical ward crisis management. Methods: Twenty two clinicians participated in 3 different simulated ward based scenarios of deteriorating post-operative patients. Continuous ECG recordings were made for all participants to monitor stress levels using heart rate variability (HRV) indices. Video recordings of simulated scenarios augmented with real time stress biofeedback were replayed to participants. They were then asked to self-assess their performance using an objective assessment tool. Participants attitudes were explored using a post study questionnaire. Results: Using HRV stress indices, we demonstrated higher stress levels in novice participants. Self-assessment scores were significantly higher in more experienced participants. Overall, participants felt that video replay and augmented stress biofeedback were useful in self assessment. Conclusion: Self-assessment using an objective self-assessment tool alongside video replay augmented with stress biofeedback is feasible in a simulated setting and well liked by participants. PMID- 29713381 TI - Switchgrass (Panicum virgatum L.) promoters for green tissue-specific expression of the MYB4 transcription factor for reduced-recalcitrance transgenic switchgrass. AB - Background: Genetic engineering of switchgrass (Panicum virgatum L.) for reduced cell wall recalcitrance and improved biofuel production has been a long pursued goal. Up to now, constitutive promoters have been used to direct the expression of cell wall biosynthesis genes toward attaining that goal. While generally sufficient to gauge a transgene's effects in the heterologous host, constitutive overexpression often leads to undesirable plant phenotypic effects. Green tissue specific promoters from switchgrass are potentially valuable to directly alter cell wall traits exclusively in harvestable aboveground biomass while not changing root phenotypes. Results: We identified and functionally characterized three switchgrass green tissue-specific promoters and assessed marker gene expression patterns and intensity in stably transformed rice (Oryza sativa L.), and then used them to direct the expression of the switchgrass MYB4 (PvMYB4) transcription factor gene in transgenic switchgrass to endow reduced recalcitrance in aboveground biomass. These promoters correspond to photosynthesis-related light-harvesting complex II chlorophyll-a/b binding gene (PvLhcb), phosphoenolpyruvate carboxylase (PvPEPC), and the photosystem II 10 kDa R subunit (PvPsbR). Real-time RT-PCR analysis detected their strong expression in the aboveground tissues including leaf blades, leaf sheaths, internodes, inflorescences, and nodes of switchgrass, which was tightly up-regulated by light. Stable transgenic rice expressing the GUS reporter under the control of each promoter (756-2005 bp in length) further confirmed their strong expression patterns in leaves and stems. With the exception of the serial promoter deletions of PvLhcb, all GUS marker patterns under the control of each 5'-end serial promoter deletion were not different from that conveyed by their respective promoters. All of the shortest promoter fragments (199-275 bp in length) conveyed strong green tissue-specific GUS expression in transgenic rice. PvMYB4 is a master repressor of lignin biosynthesis. The green tissue-specific expression of PvMYB4 via each promoter in transgenic switchgrass led to significant gains in saccharification efficiency, decreased lignin, and decreased S/G lignin ratios. In contrast to constitutive overexpression of PvMYB4, which negatively impacts switchgrass root growth, plant growth was not compromised in green tissue expressed PvMYB4 switchgrass plants in the current study. Conclusions: Each of the newly described green tissue-specific promoters from switchgrass has utility to change cell wall biosynthesis exclusively in aboveground harvestable biomass without altering root systems. The truncated green tissue promoters are very short and should be useful for targeted expression in a number of monocots to improve shoot traits while restricting gene expression from roots. Green tissue specific expression of PvMYB4 is an effective strategy for improvement of transgenic feedstocks. PMID- 29713384 TI - Improving machine learning reproducibility in genetic association studies with proportional instance cross validation (PICV). AB - Background: Machine learning methods and conventions are increasingly employed for the analysis of large, complex biomedical data sets, including genome-wide association studies (GWAS). Reproducibility of machine learning analyses of GWAS can be hampered by biological and statistical factors, particularly so for the investigation of non-additive genetic interactions. Application of traditional cross validation to a GWAS data set may result in poor consistency between the training and testing data set splits due to an imbalance of the interaction genotypes relative to the data as a whole. We propose a new cross validation method, proportional instance cross validation (PICV), that preserves the original distribution of an independent variable when splitting the data set into training and testing partitions. Results: We apply PICV to simulated GWAS data with epistatic interactions of varying minor allele frequencies and prevalences and compare performance to that of a traditional cross validation procedure in which individuals are randomly allocated to training and testing partitions. Sensitivity and positive predictive value are significantly improved across all tested scenarios for PICV compared to traditional cross validation. We also apply PICV to GWAS data from a study of primary open-angle glaucoma to investigate a previously-reported interaction, which fails to significantly replicate; PICV however improves the consistency of testing and training results. Conclusions: Application of traditional machine learning procedures to biomedical data may require modifications to better suit intrinsic characteristics of the data, such as the potential for highly imbalanced genotype distributions in the case of epistasis detection. The reproducibility of genetic interaction findings can be improved by considering this variable imbalance in cross validation implementation, such as with PICV. This approach may be extended to problems in other domains in which imbalanced variable distributions are a concern. PMID- 29713383 TI - Collective feature selection to identify crucial epistatic variants. AB - Background: Machine learning methods have gained popularity and practicality in identifying linear and non-linear effects of variants associated with complex disease/traits. Detection of epistatic interactions still remains a challenge due to the large number of features and relatively small sample size as input, thus leading to the so-called "short fat data" problem. The efficiency of machine learning methods can be increased by limiting the number of input features. Thus, it is very important to perform variable selection before searching for epistasis. Many methods have been evaluated and proposed to perform feature selection, but no single method works best in all scenarios. We demonstrate this by conducting two separate simulation analyses to evaluate the proposed collective feature selection approach. Results: Through our simulation study we propose a collective feature selection approach to select features that are in the "union" of the best performing methods. We explored various parametric, non parametric, and data mining approaches to perform feature selection. We choose our top performing methods to select the union of the resulting variables based on a user-defined percentage of variants selected from each method to take to downstream analysis. Our simulation analysis shows that non-parametric data mining approaches, such as MDR, may work best under one simulation criteria for the high effect size (penetrance) datasets, while non-parametric methods designed for feature selection, such as Ranger and Gradient boosting, work best under other simulation criteria. Thus, using a collective approach proves to be more beneficial for selecting variables with epistatic effects also in low effect size datasets and different genetic architectures. Following this, we applied our proposed collective feature selection approach to select the top 1% of variables to identify potential interacting variables associated with Body Mass Index (BMI) in ~ 44,000 samples obtained from Geisinger's MyCode Community Health Initiative (on behalf of DiscovEHR collaboration). Conclusions: In this study, we were able to show that selecting variables using a collective feature selection approach could help in selecting true positive epistatic variables more frequently than applying any single method for feature selection via simulation studies. We were able to demonstrate the effectiveness of collective feature selection along with a comparison of many methods in our simulation analysis. We also applied our method to identify non-linear networks associated with obesity. PMID- 29713386 TI - Hookah smoking is strongly associated with diabetes mellitus, metabolic syndrome and obesity: a population-based study. AB - Objectives: The adverse effects of cigarette smoking have been widely studied before, whilst the effects of hookah smoking has received less attention, although it is a common habit in the Middle East. Here we have investigated the effects of cigarette and hookah smoking on biochemical characteristics in a representative population sample derived from the Mashhad stroke and heart atherosclerotic disorder (MASHAD) cohort study, from Northeastern Iran. Study design: A total of 9840 subjects from the MASHAD population study were allocated to five groups; non-smokers (6742), ex-smokers (976), cigarette smokers (864), hookah smokers (1067), concomitant cigarette and hookah smokers (41). Methods: Baseline characteristics were recorded in a questionnaire. Biochemical characteristics were measured by routine methods. Data were analyzed using SPSS software and p < 0.05 was considered significant. Results: After adjustment for age and sex; the presence of CVD, obesity, metabolic syndrome, DM and dyslipidemia were significantly (p < 0.001) related to smoking status. After multivariate analysis, HDL (p < 0.001), WBC (p < 0.001), MCV (p < 0.05), PLT (p < 0.01) and RDW (p < 0.001), and the presence of CVD (p < 0.01), obesity (p < 0.001), metabolic syndrome (p < 0.05) and DM (p < 0.01) remained significant between cigarette smokers and non-smokers. Between hookah smokers and non smokers; uric acid (p < 0.001), PLT (p < 0.05) and RDW (p < 0.05), and the presence of obesity (p < 0.01), metabolic syndrome (p < 0.001), diabetes (p < 0.01) and dyslipidemia (p < 0.01) remained significant after logistic regression. Conclusion: There was a positive association between hookah smoking and metabolic syndrome, diabetes, obesity and dyslipidemia which was not established in cigarette smoking. PMID- 29713385 TI - A minimal markerset for three-dimensional foot function assessment: measuring navicular drop and drift under dynamic conditions. AB - Background: The validity of predicting foot pronation occurring mainly at the midfoot by surrogate measures from the rearfoot, like eversion excursion, is limited. The dynamic navicular mobility in terms of vertical navicular drop (dNDrop) and medial navicular drift (dNDrift) may be regarded as meaningful clinical indicators to represent overall foot function. This study aimed to develop a minimal approach to measure the two parameters and to examine their intra- and interday reliability during walking. Methods: The minimal markerset uses markers at the lateral and medial caput of the 1st and 5th metatarsals, respectively, at the dorsal calcaneus and at the tuberosity of the navicular bone. Dynamic navicular drop and drift were assessed with three-dimensional motion capture in 21 healthy individuals using a single-examiner test-retest study design. Results: Intra- and interday repeatability were 1.1 mm (ICC21 0.97) and 2.3 mm (ICC21 0.87) for dynamic navicular drop and 1.5 mm (ICC21 0.96) and 5.3 mm (ICC21 0.46) for dynamic navicular drift. The contribution of instrumental errors was estimated to 0.25 mm for dynamic navicular drop and 0.86 mm for dynamic navicular drift. Conclusions: Interday reliability was generally worse than intraday reliability primary due to day-to-day variations in movement patterns and the contribution of instrumental errors was below 23% for dynamic navicular drop but reached 57% for dynamic navicular drift. The minimal markerset allows to simply transfer the known concepts of navicular drop and drift from quasi-static clinical test conditions to functional tasks, which is recommended to more closely relate assessments to the functional behavior of the foot. PMID- 29713387 TI - Metabolic syndrome among overweight and obese adults in Palestinian refugee camps. AB - Background: Metabolic syndrome (MetS) is one of the main reasons for elevated cardiovascular morbidity and mortality worldwide. Obese and overweight individuals are at high risk of developing these chronic diseases. The aim of this study was to characterize and establish sex-adjusted prevalence of metabolic syndrome and its components. Methods: A cross-sectional study was conducted in 2015, 689 (329 men and 360 women) aged 18-65 years from three refugee camps in the West Bank. International Diabetes Federation and modified National Cholesterol Education Program-Third Adult Treatment Panel definitions were used to identify MetS. Results: The overall prevalence of obesity and overweight was high, 63.1%; Obesity (42 and 29.2% in women men; respectively and overweight 25.8 and 28.9% in women and men; respectively. The prevalence of MetS among obese and overweight was significantly higher (69.4%) according to IDF than NCEP definition (52%) (p < 0.002) with no significant differences between men and women using both definitions; (IDF; 71.8% men vs. 67.6% women, and (NCEP/ATP III; 51.9% men vs. 52.2% women). The prevalence of MetS increased significantly with increasing obesity and age when NCEP criterion is applied but not IDF. The prevalence of individual MetS components was: high waist circumference 81.3% according to IDF and 56.5% according to NCEP, elevated FBS 65.3% according to IDF and 56% according to NCEP, elevated blood pressure 48%, decreased HDL 65.8%, and elevated triglycerides 31.7%. Based on gender differences, waist circumferences were significantly higher in women according to both criteria and only elevated FBS was higher in women according to IDF criteria. Physical activity was inversely associated with MetS prevalence according to NCEP but not IDF. No significant associations were found with gender, smoking, TV watching, and family history of hypertension or diabetes mellitus. Conclusion: In this study, irrespective of the definition used, metabolic syndrome is highly prevalent in obese and overweight Palestinian adults with no gender-based differences. The contribution of the metabolic components to the metabolic syndrome is different in men and women. With the increase of age and obesity, the clustering of metabolic syndrome components increased remarkably. More attention through health care providers should, therefore, be given to the adult population at risk to reduce adulthood obesity and subsequent cardiovascular diseases. PMID- 29713388 TI - Post-operative stress hyperglycemia is a predictor of mortality in liver transplantation. AB - Background: A significant association is known between increased glycaemic variability and mortality in critical patients. To ascertain whether glycaemic profiles during the first week after liver transplantation might be associated with long-term mortality in these patients, by analysing whether diabetic status modified this relationship. Method: Observational long-term survival study includes 642 subjects undergoing liver transplantation from July 1994 to July 2011. Glucose profiles, units of insulin and all variables with influence on mortality are analysed using joint modelling techniques. Results: Patients registered a survival rate of 85% at 1 year and 65% at 10 years, without differences in mortality between patients with and without diabetes. In glucose profiles, however, differences were observed between patients with and without diabetes: patients with diabetes registered lower baseline glucose values, which gradually rose until reaching a peak on days 2-3 and then subsequently declined, diabetic subjects started from higher values which gradually decreased across the first week. Patients with diabetes showed an association between mortality and age, Model for End-Stage Liver Disease score (MELD) score and hepatitis C virus; among non-diabetic patients, mortality was associated with age, body mass index, malignant aetiology, red blood cell requirements and parenteral nutrition. Glucose profiles were observed to be statistically associated with mortality among patients without diabetes (P = 0.022) but not among patients who presented with diabetes prior to transplantation (P = 0.689). Conclusions: Glucose profiles during the first week after liver transplantation are different in patients with and without diabetes. While glucose profiles are associated with long-term mortality in patients without diabetes, after adjusting for potential confounding variables such as age, cause of transplantation, MELD, nutrition, immunosuppressive drugs, and units of insulin administered, this does not occur among patients with diabetes. PMID- 29713389 TI - Establishing post mortem criteria for the metabolic syndrome: an autopsy based cross-sectional study. AB - Background: Individuals who suffer from mental illness are more prone to obesity and related co-morbidities, including the metabolic syndrome. Autopsies provide an outstanding platform for the macroscopic, microscopic and molecular-biological investigation of diseases. Autopsy-based findings may assist in the investigation of the metabolic syndrome. To utilise the vast information that an autopsy encompasses to elucidate the pathophysiology behind the syndrome further, we aimed to both develop and evaluate a method for the post mortem definition of the metabolic syndrome. Methods: Based on the nationwide Danish SURVIVE study of deceased mentally ill, we established a set of post mortem criteria for each of the harmonized criteria of the metabolic syndrome. We based the post mortem (PM) evaluation on information from the police reports and the data collected at autopsy, such as anthropometric measurements and biochemical and toxicological analyses (PM information). We compared our PM evaluation with the data from the Danish health registries [ante mortem (AM) information, considered the gold standard] from each individual. Results: The study included 443 deceased individuals (272 male and 171 female) with a mean age of 50.4 (+/- 15.5) years and a median (interquartile range) post mortem interval of 114 (84-156) hours. We found no significant difference when defining the metabolic syndrome from the PM information in comparison to the AM information (P = 0.175). The PM evaluation yielded a high specificity (0.93) and a moderate sensitivity (0.63) with a moderate level of agreement compared to the AM evaluation (Cohen's kappa = 0.51). Neither age nor post mortem interval affected the final results. Conclusions: Our model of a PM definition of the metabolic syndrome proved reliable when compared to the AM information. We believe that an appropriate estimate of the prevalence of the metabolic syndrome can be established post mortem. However, while neither the PM nor the AM information is exhaustive in terms of defining an individual's health status, a superlative estimate may be obtained by combining the PM and the AM information. With this model, we open up the possibility of utilising autopsy data for future studies of the metabolic syndrome. PMID- 29713391 TI - Metabolic and inflammatory biomarkers are associated with epigenetic aging acceleration estimates in the GOLDN study. AB - Background: Recently, epigenetic age acceleration-or older epigenetic age in comparison to chronological age-has been robustly associated with mortality and various morbidities. However, accelerated epigenetic aging has not been widely investigated in relation to inflammatory or metabolic markers, including postprandial lipids. Methods: We estimated measures of epigenetic age acceleration in 830 Caucasian participants from the Genetics Of Lipid Lowering Drugs and diet Network (GOLDN) considering two epigenetic age calculations based on differing sets of 5'-Cytosine-phosphate-guanine-3' genomic site, derived from the Horvath and Hannum DNA methylation age calculators, respectively. GOLDN participants underwent a standardized high-fat meal challenge after fasting for at least 8 h followed by timed blood draws, the last being 6 h postmeal. We used adjusted linear mixed models to examine the association of the epigenetic age acceleration estimate with fasting and postprandial (0- and 6-h time points) low density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride (TG) levels as well as five fasting inflammatory markers plus adiponectin. Results: Both DNA methylation age estimates were highly correlated with chronological age (r > 0.90). We found that the Horvath and Hannum measures of epigenetic age acceleration were moderately correlated (r = 0.50). The regression models revealed that the Horvath age acceleration measure exhibited marginal associations with increased postprandial HDL (p = 0.05), increased postprandial total cholesterol (p = 0.06), and decreased soluble interleukin 2 receptor subunit alpha (IL2sRalpha, p = 0.02). The Hannum measure of epigenetic age acceleration was inversely associated with fasting HDL (p = 0.02) and positively associated with postprandial TG (p = 0.02), interleukin-6 (IL6, p = 0.007), C reactive protein (C-reactive protein, p = 0.0001), and tumor necrosis factor alpha (TNFalpha, p = 0.0001). Overall, the observed effect sizes were small and the association of the Hannum residual with inflammatory markers was attenuated by adjustment for estimated T cell type percentages. Conclusions: Our study demonstrates that epigenetic age acceleration in blood relates to inflammatory biomarkers and certain lipid classes in Caucasian individuals of the GOLDN study. Future studies should consider epigenetic age acceleration in other tissues and extend the analysis to other ethnic groups. PMID- 29713390 TI - Retrotransposon targeting to RNA polymerase III-transcribed genes. AB - Retrotransposons are genetic elements that are similar in structure and life cycle to retroviruses by replicating via an RNA intermediate and inserting into a host genome. The Saccharomyces cerevisiae (S. cerevisiae) Ty1-5 elements are long terminal repeat (LTR) retrotransposons that are members of the Ty1-copia (Pseudoviridae) or Ty3-gypsy (Metaviridae) families. Four of the five S. cerevisiae Ty elements are inserted into the genome upstream of RNA Polymerase (Pol) III-transcribed genes such as transfer RNA (tRNA) genes. This particular genomic locus provides a safe environment for Ty element insertion without disruption of the host genome and is a targeting strategy used by retrotransposons that insert into compact genomes of hosts such as S. cerevisiae and the social amoeba Dictyostelium. The mechanism by which Ty1 targeting is achieved has been recently solved due to the discovery of an interaction between Ty1 Integrase (IN) and RNA Pol III subunits. We describe the methods used to identify the Ty1-IN interaction with Pol III and the Ty1 targeting consequences if the interaction is perturbed. The details of Ty1 targeting are just beginning to emerge and many unexplored areas remain including consideration of the 3 dimensional shape of genome. We present a variety of other retrotransposon families that insert adjacent to Pol III-transcribed genes and the mechanism by which the host machinery has been hijacked to accomplish this targeting strategy. Finally, we discuss why retrotransposons selected Pol III-transcribed genes as a target during evolution and how retrotransposons have shaped genome architecture. PMID- 29713392 TI - Fetal growth is associated with the CpG methylation of the P2 promoter of the IGF1 gene. AB - Background: There are many reasons to think that epigenetics is a key determinant of fetal growth variability across the normal population. Since IGF1 and INS genes are major determinants of intrauterine growth, we examined the methylation of selected CpGs located in the regulatory region of these two genes. Methods: Cord blood was sampled in 159 newborns born to mothers prospectively followed during their pregnancy. A 142-item questionnaire was filled by mothers at inclusion, during the last trimester of the pregnancy and at the delivery. The methylation of selected CpGs located in the promoters of the IGF1 and INS genes was measured in cord blood mononuclear cells collected at birth using bisulfite PCR-pyrosequencing. Results: Methylation at IGF1 CpG-137 correlated negatively with birth length (r = 0.27, P = 3.5 * 10-4). The same effect size was found after adjustment for maternal age, parity, and smoking: a 10% increase in CpG-137 methylation was associated with a decrease of length by 0.23 SDS. Conclusion: The current results suggest that the methylation of IGF1 CpG-137 contributes to the individual variation of fetal growth by regulating IGF1 expression in fetal tissues. PMID- 29713393 TI - Circulating microRNAs as potential cancer biomarkers: the advantage and disadvantage. AB - MicroRNAs are endogenous single-stranded non-coding small RNA molecules that can be secreted into the circulation and exist stably. They usually exhibit aberrant expression under different physiological and pathological conditions. Recently, differentially expressed circulating microRNAs were focused on as potential biomarkers for cancer screening. We herein review the role of circulating microRNAs for cancer diagnosis, tumor subtype classification, chemo- or radio resistance monitoring, and outcome prognosis. Moreover, circulating microRNAs still have several issues hindering their reliability for the practical clinical application. Future studies need to elucidate further potential application of circulating microRNAs as specific and sensitive markers for clinical diagnosis or prognosis in cancers. PMID- 29713394 TI - Who counts as family? Family typologies, family support, and family undermining among young adult gay and bisexual men. AB - Gay and bisexual men may form chosen families in addition to or in place of families of origin. However, the characteristics of these diverse families remain largely unexamined in the quantitative literature. The purpose of this study was to develop a family typology based on responses from a racially and ethnically diverse sample of young adult gay and bisexual men (YGBM) recruited from the Detroit Metropolitan Area (N=350; 18-29 years old). To explore the role of family, we then examined family social support and social undermining in relation to YGBM psychological distress within different family types. A series of multivariate regressions were used to examine associations between family social support and social undermining with depression and anxiety outcomes. The majority (88%) of YGBM included family of origin in their definitions of family and 63% indicated having chosen families. Associations between family social processes and psychological outcomes varied by type of family, suggesting that family composition shapes how perceptions of support and undermining relate to experiencing symptoms of depression and anxiety. Chosen families play a prominent role in the lives of YGBM and should not be overlooked in family research. Findings also highlight the importance of examining co-occurring family social support and social stress processes to further address psychological distress symptoms among YGBM. PMID- 29713395 TI - Electrokinetic ion transport in nanofluidics and membranes with applications in bioanalysis and beyond. AB - Electrokinetic transport of ions between electrolyte solutions and ion permselective solid media governs a variety of applications, such as molecular separation, biological detection, and bioelectronics. These applications rely on a unique class of materials and devices to interface the ionic and electronic systems. The devices built on ion permselective materials or micro-/nanofluidic channels are arranged to work with aqueous environments capable of either manipulating charged species through applied electric fields or transducing biological responses into electronic signals. In this review, we focus on recent advances in the application of electrokinetic ion transport using nanofluidic and membrane technologies. We start with an introduction into the theoretical basis of ion transport kinetics and their analogy to the charge transport in electronic systems. We continue with discussions of the materials and nanofabrication technologies developed to create ion permselective membranes and nanofluidic devices. Accomplishments from various applications are highlighted, including biosensing, molecular separation, energy conversion, and bio-electronic interfaces. We also briefly outline potential applications and challenges in this field. PMID- 29713396 TI - A high-performance polydimethylsiloxane electrospun membrane for cell culture in lab-on-a-chip. AB - Thin porous membranes are important components in a microfluidic device, serving as separators, filters, and scaffolds for cell culture. However, the fabrication and the integration of these membranes possess many challenges, which restrict their widespread applications. This paper reports a facile technique to fabricate robust membrane-embedded microfluidic devices. We integrated an electrospun membrane into a polydimethylsiloxane (PDMS) device using the simple plasma activated bonding technique. To increase the flexibility of the membrane and to address the leakage problem, the electrospun membrane was fabricated with the highest weight ratio of PDMS to polymethylmethacrylate (i.e., 6:1 w/w). The membrane-integrated microfluidic device could withstand a flow rate of up to 50 MUl/min. As a proof of concept, we demonstrated that such a compartmentalized microfluidic platform could be successfully used for cell culture with the capability of providing a more realistic in vivo-like condition. Human lung cancer epithelial cells (A549) were seeded on the membrane from the top microchannel, while the continuous flow of the culture medium through the bottom microchannel provided a shear-free cell culture condition. The tortuous micro /nanofibers of the membrane immobilized the cells within the hydrophobic micropores and with no need of extracellular matrix for cell adhesion and cell growth. The hydrophobic surface conditions of the membrane were suitable for anchorage-independent cell types. To further extend the application of the device, we qualitatively showed that rinsing the membrane with ethanol prior to cell seeding could temporarily render the membrane hydrophilic and the platform could also be used for anchorage-dependent cells. Due to the three-dimensional (3D) topography of the membranes, three different configurations were observed, including individual single cells, monolayer cells, and 3D cell clusters. This cost-effective and robust compartmentalized microfluidic device may open up new avenues in translational medicine and pharmacodynamics research. PMID- 29713397 TI - A Single-Center Review of Facial Fractures as the Result of High-Speed Projectile Injuries. AB - Purpose: Gunshot injuries to the face that result in fractures of the underlying skeleton present a challenge in management. The goal of this study was to evaluate patterns of facial fractures as a result of gunshot injuries and strategies for management. Methods: A retrospective review of facial fractures resulting from gunshot injuries in a level 1 trauma center was performed for the years 2000 to 2012. Data were collected for patient demographics, fracture distribution, concomitant injuries, and surgical management strategies. Results: A total of 190 patients sustained facial fractures from a gunshot injury. The average age was 29.9 years, and 90% were male. Sixteen injuries were self inflicted. The most common fractures were of the mandible and the orbit. Uncontrolled hemorrhage was noted on presentation in 68 patients; 100 patients were intubated on arrival. The average Glasgow Coma Scale score on arrival was 11.9. Concomitant injuries included skull fracture, intracranial hemorrhage, and intrathoracic injury. Surgical management was required in 89 patients. Nine patients required soft-tissue coverage. Thirty patients expired. Conclusion: Gunshot injuries to the face resulting in fractures of the underlying skeleton have high instances of morbidity and mortality. Life-threatening concomitant injuries can complicate management of facial fractures in this population. PMID- 29713398 TI - Review of the literature laparoscopic surgery for metastatic hepatic leiomyosarcoma associated with smooth muscle tumor of uncertain malignant potential: Case report. AB - Metastatic hepatic leiomyosarcoma is a rare malignant smooth muscle tumor. We report a case of metastatic hepatic leiomyosarcoma associated with smooth muscle tumor of uncertain malignant potential (STUMP). A 68-year-old female presented with a liver mass (60 mm * 40 mm, Segment 4). She underwent left salpingo oophorectomy for an ovary tumor with STUMP in a broad ligament 6 years ago. Though FDG-PET showed obvious metabolically active foci, abnormal metabolically active foci other than the lesion were not detected. A malignant liver tumor was strongly suspected and laparoscopic partial liver resection was performed with vessel-sealing devices using the crush clamping method and Pringle maneuver. Immunohistochemical findings revealed metastatic liver leiomyosarcoma associated with STUMP in a broad ligament. This case is an extremely rare case of malignant transformation from primary STUMP to metastatic hepatic leiomyosarcoma. It provides important evidence regarding the treatment for metastatic hepatic leiomyosarcoma associated with STUMP. PMID- 29713399 TI - Chitosan Pad, Cellulose Membrane, or Gelatin Sponge for Peridural Bleeding: An Efficacy Study on a Lumbar Laminectomized Rat Model. AB - Study Design: Experimental study in an animal model. Purpose: This study aims to evaluate the hemostatic properties of four common hemostatic materials including the chitosan clot pad, absorbable gelatin sponge, cellulose membrane, and gauze on peridural bleeding using a rat model. Overview of Literature: Intraoperative bleeding during spinal surgery can lead to morbidities. Hemostatic materials have been developed, but the efficacy of these materials on peridural bleeding remains unclear. Methods: Forty 8-week-old Sprague-Dawley rats were used in this study. Under adequate anesthesia, each rat was posteriorly dissected to their L5 and L6 spinous processes. Bleeding from muscles and soft tissue dissections was stopped before lumbar bone cutting. Immediately after the L5-L6 laminae were cut and removed, the rats were randomly allocated to receive one of the abovementioned hemostatic materials. All hemostatic materials were placed over the raw surface of cut bone and dura and changed every 60 seconds. The procedure was stopped when there was no further bleeding. Time to staunching and amount of bleeding were recorded for statistical analysis. Results: The respective mean+/-standard deviation hemorrhage volume and time for the cellulose membrane, gelatin sponge, chitosan pad, and gauze were 1.19+/-0.44, 1.03+/-0.72, 0.96+/-0.57, and 1.98+/ 0.62 mL, respectively, and 2.9+/-0.6, 2.1+/-0.6, 1.7+/-0.5, and 2.9+/-1.0 minutes, respectively. The overall bleeding volumes for the cellulose membrane, gelatin sponge, and chitosan pad were significantly lower than the overall bleeding volume for gauze. Conclusions: Chitosan clot pads, gelatin sponges, and cellulose membranes have better hemostatic properties than gauze. The chitosan pad had the lowest average bleeding volume, followed by gelatin sponge and cellulose membrane. PMID- 29713400 TI - APSS-ASJ Best Clinical Research Award: Predictability of Curve Progression in Adolescent Idiopathic Scoliosis Using the Distal Radius and Ulna Classification. AB - Study Design: Prospective study. Purpose: To determine the risk of clinically significant curve progression in adolescent idiopathic scoliosis (AIS) based on the initial Cobb angle and to test the utility of the distal radius and ulna (DRU) classification in predicting these outcomes. Overview of Literature: Determining the remaining growth potential in AIS patients is necessary for predicting prognosis and initiating treatment. Limiting the maturity Cobb angle to <40 degrees and <50 degrees reduces the risk of adulthood progression and need for surgery, respectively. The risk of curve progression is the greatest with skeletally immature patients and thus warrants close monitoring or early intervention. Many parameters exist for measuring the skeletal maturity status in AIS patients, but the DRU classification has been shown to be superior in predicting peak growth and growth cessation. However, its predictive capabilities for curve progression are unknown. Methods: Totally, 513 AIS patients who presented with Risser 0-3 were followed until either skeletal maturity or the need for surgery, with a minimum 2-year follow-up period. Outcomes of 40 degrees and 50 degrees were used for probability analysis based on the cut-offs of adulthood progression risk and surgical threshold, respectively. Results: At the R6/U5 grade, most curves (probability of >=48.1%-55.5%) beyond a Cobb angle of 25 degrees progressed to the 40 degrees threshold. For curves of >=35 degrees , there was a high risk of unfavorable outcomes, regardless of skeletal maturity. Most patients with the R9 grade did not progress, regardless of the initial curve magnitude (probability of 0% to reach the 50 degrees threshold for an initial Cobb angle of >=35 degrees ). Conclusions: This large-scale study illustrates the utility of the DRU classification for predicting curve progression and how it may effectively guide the timing of surgery. Bracing may be indicated for skeletally immature patients at an initial Cobb angle of 25 degrees , and those with a scoliosis >=35 degrees are at an increased risk of an unfavorable outcome, despite being near skeletal maturity. PMID- 29713401 TI - Morphometric Evaluation of Occipital Condyles: Defining Optimal Trajectories and Safe Screw Lengths for Occipital Condyle-Based Occipitocervical Fixation in Indian Population. AB - Study Design: Computed tomographic (CT) morphometric analysis. Purpose: To assess the feasibility and safety of occipital condyle (OC)-based occipitocervical fixation (OCF) in Indians and to define anatomical zones and screw lengths for safe screw placement. Overview of Literature: Limitations of occipital squama based OCF has led to development of two novel OC-based OCF techniques. Methods: Morphometric analysis was performed on the OCs of 70 Indian adults. The feasibility of placing a 3.5-mm-diameter screw into OCs was investigated. Safe trajectories and screw lengths for OC screws and C0-C1 transarticular screws without hypoglossal canal or atlantooccipital joint compromise were estimated. Results: The average screw length and safe sagittal and medial angulations for OC screws were 19.9+/-2.3 mm, <=6.4 degrees +/-2.4 degrees cranially, and 31.1 degrees +/-3 degrees medially, respectively. An OC screw could not be accommodated by 27% of the population. The safe sagittal angles and screw lengths for C0-C1 transarticular screw insertion (48.9 degrees +/-5.7 degrees cranial, 26.7+/-2.9 mm for junctional entry technique; 36.7 degrees +/-4.6 degrees cranial, 31.6+/-2.7 mm for caudal C1 arch entry technique, respectively) were significantly different than those in other populations. The risk of vertebral artery injury was high for the caudal C1 arch entry technique. Screw placement was uncertain in 48% of Indians due to the presence of aberrant anatomy. Conclusions: There were significant differences in the metrics of OC-based OCF between Indian and other populations. Because of the smaller occipital squama dimensions in Indians, OC-based OCF techniques may have a higher application rate and could be a viable alternative/salvage option in selected cases. Preoperative CT, including three-dimensional-CT-angiography (to delineate vertebral artery course), is imperative to avoid complications resulting from aberrant bony and vascular anatomy. Our data can serve as a valuable reference guide in placing these screws safely under fluoroscopic guidance. PMID- 29713402 TI - Pathophysiology and Grading of the Ventral Displacement of Dorsal Spinal Cord Spectrum. AB - Study Design: A retrospective study of the ventral displacement of dorsal spinal cord (VDDSC) spectrum pathophysiology and grading. Purpose: This study aimed at examining the pathophysiology of VDDSC between D3 and D7, using magnetic resonance imaging (MRI) correlation and severity grading. Overview of Literature: The pathologies that lead to VDDSC were previously discussed in various articles. We attempted to group these pathological conditions under a single spectrum, and grade them according to their severity. Methods: We reviewed the MRI images of the dorsal spines of 1,350 patients over a period of 4 years (February 2013 February 2017); all MRI images were analyzed by two experienced radiologists. Results: Of the 1,350 patients, 28 exhibited VDDSC between D3 and D7. Additional findings included ventral transdural herniation of the spinal cord (n=10), anterior spinal cord adhesion (n=7), arachnoid web (n=6), and arachnoid cyst (n=5). Conclusions: We grouped the pathologies that lead to VDDSC at the thoracic level into a single spectrum of varying severity and graded VDDSC, from mild to severe. PMID- 29713403 TI - Efficacy of Trigger Point Injections in Patients with Lumbar Disc Hernia without Indication for Surgery. AB - Study Design: Prospective comparative study. Purpose: To investigate the efficacy of gluteal trigger point (TP) injections with prilocaine in patients with lumbosacral radiculopathy complaining of gluteal pain. Overview of Literature: TP injections can be performed using several anesthetic agents, primarily lidocaine and prilocaine. While several studies have used lidocaine, few have used prilocaine. Methods: A total of 65 patients who presented at the polyclinic with complaints of lower back pain with lumbar disc herniation (based on physical examination and magnetic resonance imaging) and TPs in the gluteal region were included in this prospective comparative study. Group 1 comprised 30 patients who were given TP injections, a home exercise program, and oral medications, and group 2 comprised 35 patients who were only treated with a home exercise program and oral medications. The patients' demographic data, Oswestry Disability Index (ODI) scores, and Visual Analog Scale (VAS) scores were recorded, and these data were evaluated at 1- and 3-month follow-ups. Results: The ODI and VAS scores of both groups significantly decreased initially and at the follow-up examinations, but the decreases were more marked in group 1. Conclusions: We obtained better results with TP injections than only a home exercise program and oral medications in patients with radiculopathy and TPs in the gluteal region. PMID- 29713404 TI - Accuracy and Safety of Percutaneous Lumbosacral Pedicle Screw Placement Using Dual-Planar Intraoperative Fluoroscopy. AB - Study Design: Retrospective case series with prospective arm. Purpose: To assess the safety and accuracy of percutaneous lumbosacral pedicle screw placement (PLPSP) in the lumbosacral spine using intraoperative dual-planar fluoroscopy (DPF). Overview of Literature: There are several techniques available for achieving consistent, safe, and accurate results with PLPSP. There is a paucity of literature describing the beneficial operative, economic, and clinical outcomes of DPF, the most readily accessible image guidance system. Methods: From 2004 to 2014, 451 consecutive patients underwent PLPSP using DPF, for a total of 2,345 screw placement. The results of prospectively obtained postoperative computed tomography (CT) examinations of an additional 41 consecutive patients were compared with the results of 104 CT examinations obtained postoperatively due to clinical symptomatology; these results were interpreted by three reviewers. The rates of revision indicated by misplaced screws with consistent clinical symptomatology were compared between groups. Pedicle screw placement was graded according to 2-mm increments in medial pedicle wall breach and measurement of screw axis placement. Results: Seven of the 2,345 pedicle screws placed percutaneously with the use of the dual-planar fluoroscopic technique required revision because of a symptomatic misplaced screw, for a screw revision rate of 0.3%. There were no statistically significant demographic differences between patients who had screws revised and those who did not. All screws registered greater than 10 mA on electromyographic stimulation. In the 41 prospectively obtained CT examinations, one out of 141 screws (0.7%) was revised due to pedicle wall breach; whereas among the 104 patients with 352 screws, three screws were revised (0.9%). Conclusions: DPF is an extremely accurate, safe, and reproducible technique for placement of percutaneous pedicle screws and is a readily available and cost-effective alternative to CT-guided pedicle screw placement techniques. Postoperative CT evaluation is not necessary with PLPSP unless the patient is symptomatic. Acceptable electromyographic thresholds may need to be reevaluated. PMID- 29713405 TI - Minimally Invasive Transtubular Endoscopic Decompression for L5 Radiculopathy Induced by Lumbosacral Extraforaminal Lesions. AB - Study Design: Retrospective study. Purpose: This study aimed to evaluate the efficacy of minimally invasive transtubular endoscopic decompression for the treatment of lumbosacral extraforaminal lesion (LSEFL). Overview of Literature: Conventional procedures for surgical decompression for the treatment of LSEFL involve certain technical challenges because the lumbosacral extraforaminal region has unique anatomical features. Moreover, the efficacy of minimally invasive procedures performed via the posterolateral approach for LSEFL has been reported. Methods: Twenty-five patients who had undergone minimally invasive transtubular endoscopic decompression for the treatment of LSEFL and could be followed up for at least 1 year postoperatively were enrolled. Five of these patients had a history of lumbar surgery, and seven had concomitant adjacent level spinal stenosis. The clinical outcomes were evaluated using the Japanese Orthopaedic Association (JOA) lumbar score, numeric rating scale (NRS), and the JOA Back Pain Evaluation Questionnaire (JOABPEQ). The mean postoperative follow up (FU) duration was 3.8 years. Results: All procedures could be completed without any severe surgical complications, and all patients could resume their previous activity level within 1 month postoperatively. The JOA score significantly increased from 14.1+/-4.0 at baseline to 23.1+/-3.7 at the 1-year FU and 22.1+/-3.8 at the last FU. Similarly, there were significant improvements in the postoperative NRS and JOABPEQ scores. An additional surgery was performed in two patients (8%) during the FU period. Patients with degenerative scoliosis exhibited significantly poorer outcomes compared with those without this condition. Conclusions: Transtubular endoscopic decompression can overcome certain technical challenges involved in the conventional procedures for LSEFL treatment; therefore, it can be recommended as a useful procedure for treating LSEFL. This procedure can provide some benefits to LSEFL patients and offer a well-illuminated surgical field and high surgical safety for the surgeon. However, the procedure should be carefully adapted for LSEFL patients with concomitant degenerative scoliosis. PMID- 29713406 TI - Assessment of Paraspinal Muscle Atrophy Percentage after Minimally Invasive Transforaminal Lumbar Interbody Fusion and Unilateral Instrumentation Using a Novel Contralateral Intact Muscle-Controlled Model. AB - Study Design: Retrospective comparative clinical study. Purpose: This study aimed to assess paraspinal muscle atrophy in patients who underwent minimally invasive transforaminal lumbar interbody fusion (MI-TLIF) and unilateral pedicle screw fixation using a novel contralateral intact muscle-controlled model. Overview of Literature: The increased incidence of paravertebral lumbar muscle injuries after open techniques has raised the importance of implementing minimally invasive spine surgical techniques using tubular retractors and minimally invasive screw placement. The functional cross-sectional area (FCSA) represents the lean muscle mass; furthermore, FCSA is a useful marker of the contractile ability of a muscle following a spine surgery. However, the benefits of unilateral fixation and MI TLIF on paraspinal muscles have not been defined. Methods: We performed a retrospective imagenological review on eleven patients who underwent unilateral MI-TLIF and unilateral transpedicular screw lumbar placement. FCSAs of the multifidus and erector spinae were measured 1 year after surgery at adjacent levels and were compared to the contralateral intact muscles. Measurement differences between the surgical and nonsurgical sites were compared. The interobserver reliability was calculated using an intraclass correlation coefficient. Results: The mean FCSA at the surgical site was 20.97+/-5.07 cm2 at the superior level and 8.89+/-2.87 cm2 at the inferior level. The mean FCSA at the contralateral nonsurgical site was 20.15+/-5.95 cm2 at the superior level and 9.20+/-2.66 cm2 at the inferior level was. The superior and inferior FCSA measurements showed no significant difference between the surgical and nonsurgical sites (p=0.5, p=0.922, respectively). Conclusions: Using a mini-open tubular approach through the sulcus between the longissimus and iliocostalis, MI TLIF and unilateral pedicle screw instrumentation produced minimal paraspinal muscle damage at the superior and inferior adjacent levels. PMID- 29713407 TI - The Incidence of Adjacent Segment Degeneration after the Use of a Versatile Dynamic Hybrid Stabilization Device in Lumbar Stenosis: Results of a 5-8-Year Follow-up. AB - Study Design: Retrospective study with long-term follow-up. Purpose: To evaluate the long-term incidence of adjacent segment degeneration (ASD) and clinical outcomes in a consecutive series of patients who underwent spinal decompression associated with dynamic or hybrid stabilization with a Flex+TM stabilization system (SpineVision, Antony, France) for lumbar spinal stenosis. Overview of Literature: The incidence of ASD and clinical outcomes following dynamic or hybrid stabilization with the Flex+TM system used for lumbar spinal stenosis have not been well investigated. Methods: Twenty-one patients with lumbar stenosis and probable post-decompressive spinal instability underwent decompressive laminectomy followed by spinal stabilization using the Flex+TM stabilization system. The indication for a mono-level dynamic stabilization was a preoperative magnetic resonance imaging (MRI) demonstrating evidence of severe disc disease associated with severe spinal stenosis. The hybrid stabilization (rigid-dynamic) system was used for multilevel laminectomies with associated initial degenerative scoliosis, first-grade spondylolisthesis, or rostral pathology. Results: The improvement in Visual Analog Scale and Oswestry Disability Index scores at follow up were statistically significant (p<0.0001 and p<0.0001, respectively). At the 5 8-year follow-up, clinical examination, MRI, and X-ray findings showed an ASD complication with pain and disability in one of 21 patients. The clinical outcomes were similar in patients treated with dynamic or hybrid fixation. Conclusions: Patients treated with laminectomy and Flex+TM stabilization presented a satisfactory clinical outcome after 5-8 years of follow-up, and ASD incidence in our series was 4.76% (one patient out of 21). We are aware that this is a small series, but our long-term follow-up may be sufficient to contribute to the expanding body of literature on the development of symptomatic ASD associated with dynamic or hybrid fixation. PMID- 29713408 TI - Vertebral Lateral Notch as Optimal Entry Point for Lateral Mass Screwing Using Modified Roy-Camille Technique. AB - Study Design: Retrospective study of 37 consecutive female patients with cervical spondylotic myelopathy who underwent reconstructed computed tomography (CT) scanning of the cervical spine. Purpose: The purpose of this study was to investigate whether the vertebral lateral notch of the cervical spine is an effective landmark to determine the entry point for lateral mass screwing. A modified Roy-Camille technique was used to determine the entry point associated with the lateral notch of the cervical spine. Overview of Literature: The Roy Camille technique has been a popular technique for the posterior fixation of the cervical spine. A problem with this technique is determining the entry point on the lateral mass via visual inspection, such as in cases with degenerative or destructive cervical facet joints. Methods: Thirty-three female patients with cervical spondylotic myelopathy underwent reconstructed CT scanning of the cervical spine. Overall, 132 vertebrae from C3 to C6 were reviewed using reconstructed CT. The probable trajectory using a modified Roy-Camille technique was determined using reconstructed CT scans, and the optimal entry point was identified. Horizontal and vertical distances from the vertebral lateral notch were measured. Results: The entry point determined using the modified Roy-Camille technique was significantly superior and medial compared with that determined using the conventional Roy-Camille technique. At C3 and C4 levels, the entry point using the modified technique was 1.4 mm below and 4.4 mm medial to the lateral notch, and at C5 and C6 levels, it was 2.3 mm below and 4.9 mm medial to the lateral notch. Conclusions: The vertebral lateral notch of the cervical spine was an effective landmark to determine the entry point for lateral mass screwing. The modified Roy-Camille technique proposed here may prevent surgical complications and poor outcomes. PMID- 29713409 TI - Prognostic Importance of Spinopelvic Parameters in the Assessment of Conservative Treatment in Patients with Spondylolisthesis. AB - Study Design: This was a prospective, two-group comparative study. Purpose: The present study aimed to determine the importance of the spinopelvic parameters in the causation and progression of spondylolisthesis. Overview of Literature: Spondylolisthesis is slippage of one vertebra over the vertebra below. Since the discovery of pelvic incidence (PI) in 1998 in addition to documentation of other parameters in spinopelvic balance, slippage in spondylolisthesis has been attributed to these parameters. Many studies on the Caucasian population have implicated high PI as a causative factor of spondylolisthesis. To the best of our knowledge, no study has described the role of these parameters in the progression of spondylolisthesis. Methods: The study was conducted in Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India. Seventy-nine patients with spondylolisthesis consented to participate in the study. All patients were advised to undergo conservative treatment and were regularly followed up according to the protocol. Seventy-five asymptomatic volunteers were recruited as a control group. Of the total of 79 patients, 54 were followed up for 6 months, during which 46 improved, eight showed no improvement, and 25 were lost to follow-up. Sagittal spinopelvic parameters were measured by a single observer using the Surgimap spine software ver. 2.1.2 (Nemaris, New York, NY, USA). Parameters measured were PI, pelvic tilt (PT), sacral slope (SS), thoracic kyphosis, and lumbar lordosis. The results from patients and controls were compared using appropriate statistical methods. Results: The normal and spondylolisthesis groups significantly differed with respect to PI, SS, and PT (p<0.001). There were no significant differences in the measured spinopelvic parameters between patients with high- and low-grade spondylolisthesis or between those whose condition improved and those whose condition worsened. Conclusions: PI, the most important of all spinopelvic parameters, is responsible for the slip in spondylolisthesis, but not for its progression. PMID- 29713410 TI - Minimally Invasive Lumbar Spinal Decompression in Elderly Patients with Magnetic Resonance Imaging Morphological Analysis. AB - Study Design: Case-control study. Purpose: In this study, we aimed to investigate clinical outcomes and morphological features in elderly patients with lumbar spinal stenosis (LSS) who were treated by minimally invasive surgery (MIS) unilateral laminectomy for bilateral decompression (ULBD) using a tubular retractor. Overview of Literature: Numerous methods using imaging have been attempted to describe the severity of spinal stenosis. But the relationship between clinical symptoms and radiological features remains debatable. Objective: In this study, we aimed to investigate clinical outcomes and morphological features in elderly patients with LSS who were treated by MIS-ULBD. Methods: We methodically assessed 85 consecutive patients aged >65 years who were treated for LSS. The patients were retrospectively analyzed in two age groups: 66-75 years (group 1) and >75 years (group 2). Clinical outcomes were assessed using the Visual Analog Scale (VAS), Oswestry Disability Index (ODI), and the modified MacNab criteria. Outcome parameters were compared between the groups at the 1 year follow-up. Core radiologic parameters for central and lateral stenosis were analyzed and clinical findings of the groups were compared. Results: At the 1 year follow-up, patients in both groups 1 and 2 demonstrated significant improvement in their VAS and ODI scores. All clinical outcomes, except postoperative ODI, were not significantly difference between the groups. In addition, no significant difference was noted in the preoperative radiological parameters between the groups. There was no statistically significant correlation between radiological parameters and clinical symptoms or their outcomes. Moreover, no differences were noted in perioperative adverse events and in the need for repeat surgery at follow-ups between the groups. Conclusions: MIS-ULBD by tubular approach is a safe and effective treatment option for elderly patients with LSS. Clinical outcomes in patients with LSS and aged >75 years were comparable with those in patients with LSS and aged 66-75 years. Moreover, we did not find any correlation between radiological parameters and clinical outcomes in either of the two patient groups. PMID- 29713411 TI - Percutaneous Endoscopic Cervical Discectomy: Surgical Approaches and Postoperative Imaging Changes. AB - Study Design: Retrospective clinical study. Purpose: This study investigated the relationship between surgical approaches and surgical outcomes in patients undergoing percutaneous endoscopic cervical discectomy (PECD), including the reduction in intervertebral disc height and the incidence of Modic changes. Overview of Literature: The anterior approach involves partial invasion of the intervertebral disc, with a reported reduction in intervertebral disc height after PECD. Methods: Forty-two patients with cervical disk hernia who underwent PECD and magnetic resonance imaging at least 3 months postoperatively were divided into four groups according to the hernia sites and the surgical approach used: unilateral hernia treated using the contralateral approach (group C, n=18), unilateral hernia treated using the ipsilateral approach (group I, n=15), midline hernia (group M, n=4), and broad and bilateral hernia (group B, n=5). Modic changes and intervertebral disc height were evaluated. Results: The overall incidence of Modic changes was 52.4%: 72.2% in group C, 26.7% in group I, 25.0% in group M, and 80.0% in group B. The reduction in intervertebral disc height was 21.8% across all the patients: 24.5% in group C, 11.0% in group I, 22.8% in group M, and 23.9% in group B. Conclusions: The incidence of Modic changes and the reduction in intervertebral disc height were lower in the patients treated using the ipsilateral approach than in those treated using the contralateral approach. Traditionally, a contralateral approach has been used for PECD; however, the ipsilateral approach is more appropriate and is therefore recommended. PMID- 29713412 TI - Reciprocal Changes in Sagittal Alignment in Adolescent Idiopathic Scoliosis Patients Following Strategic Pedicle Screw Fixation. AB - Study Design: Retrospective observational study. Purpose: To analyze the effect of low-density (LD) strategic pedicle screw fixation on the correction of coronal and sagittal parameters in adolescent idiopathic scoliosis (AIS) patients. Overview of Literature: LD screw fixation achieves favorable coronal correction, but its effect on sagittal parameters is not well established. AIS is often associated with decreased thoracic kyphosis (TK), and the use of multi-level pedicle screws may result in further flattening of the sagittal profile. Methods: A retrospective analysis was performed on 92 patients with AIS to compare coronal and sagittal parameters preoperatively and at 2-year follow-up. All patients underwent posterior correction via LD strategic pedicle screw fixation. Radiographs were analyzed for primary Cobb angle (PCA), coronal imbalance, cervical sagittal angle (CSA), TK, lumbar lordosis (LL), pelvic incidence, pelvic tilt (PT), sacral slope (SS), C7 plumb line, spino-sacral angle, curve flexibility, and screw density. Results: PCA changed significantly from 57.6 degrees +/-13.9 degrees to 19 degrees +/-8.4 degrees (p <0.0001) with 67% correction, where the mean curve flexibility was 41% and screw density was 68%. Regional sagittal parameters did not change significantly, including CSA (from 10.76 degrees to 10.56 degrees , p =0.893), TK (from 24.4 degrees to 22.8 degrees , p =0.145), and LL (from 50.3 degrees to 51.1 degrees , p =0.415). However, subgroup analysis of the hypokyphosis group (<10 degrees ) and the hyperkyphosis group (>40 degrees ) showed significant correction of TK (p <0.0001 in both). Sacro-pelvic parameters showed a significant decrease of PT and increase of SS, suggesting a reduction in pelvic retroversion SS (from 37 degrees to 40 degrees , p =0.0001) and PT (from 15 degrees to 14 degrees , p =0.025). Conclusions: LD strategic pedicle screw fixation provides favorable coronal correction and improves overall sagittal sacro-pelvic parameters. This technique does not cause significant flattening of TK and results in a favorable restoration of TK in patients with hypokyphosis or hyperkyphosis. PMID- 29713413 TI - Comparative Prospective Study Reporting Intraoperative Parameters, Pedicle Screw Perforation, and Radiation Exposure in Navigation-Guided versus Non-navigated Fluoroscopy-Assisted Minimal Invasive Transforaminal Lumbar Interbody Fusion. AB - Study Design: Prospective cohort study. Purpose: To compare intraoperative parameters, radiation exposure, and pedicle screw perforation rate in navigation guided versus non-navigated fluoroscopy-assisted minimal invasive transforaminal lumbar interbody fusion (MIS TLIF). Overview of Literature: The poor reliability of fluoroscopy-guided instrumentation and growing concerns about radiation exposure have led to the development of navigation-guided instrumentation techniques in MIS TLIF. The literature evaluating the efficacy of navigation guided MIS TLIF is scant. Methods: Eighty-seven patients underwent navigation- or fluoroscopy-guided MIS TLIF for symptomatic lumbar/lumbosacral spondylolisthesis. Demographics, intraoperative parameters (surgical time, blood loss), and radiation exposure (sec/mGy/Gy.cm2 noted from C-arm for comparison only) were recorded. Computed tomography was performed in patients in the navigation and non navigation groups at postoperative 12 months and reviewed by an independent observer to assess the accuracy of screw placement, perforation incidence, location, grade (Mirza), and critical versus non-critical neurological implications. Results: Twenty-seven patients (male/female, 11/16; L4-L5/L5-S1, 9/18) were operated with navigation-guided MIS TLIF, whereas 60 (male/female, 25/35; L4-L5/L5-S1, 26/34) with conventional fluoroscopy-guided MIS TILF. The use of navigation resulted in reduced fluoroscopy usage (dose area product, 0.47 Gy.cm2 versus 2.93 Gy.cm2), radiation exposure (1.68 mGy versus 10.97 mGy), and fluoroscopy time (46.5 seconds versus 119.08 seconds), with p-values of <0.001. Furthermore, 96.29% (104/108) of pedicle screws in the navigation group were accurately placed (grade 0) (4 breaches, all grade I) compared with 91.67% (220/240) in the non-navigation group (20 breaches, 16 grade I+4 grade II; p=0.114). None of the breaches resulted in a corresponding neurological deficit or required revision. Conclusions: Navigation guidance in MIS TLIF reduced radiation exposure, but the perforation status was not statistically different than that for the fluoroscopy-based technique. Thus, navigation in nondeformity cases is useful for significantly reducing the radiation exposure, but its ability to reduce pedicle screw perforation in nondeformity cases remains to be proven. PMID- 29713414 TI - Evaluation of Lumbar Intervertebral Disc Degeneration Using T1rho and T2 Magnetic Resonance Imaging in a Rabbit Disc Injury Model. AB - Study Design: An in vivo histologic and magnetic resonance imaging (MRI) study of lumbar intervertebral disc (IVD) degeneration was conducted. Purpose: To clarify the sensitivity and efficacy of T1rho/T2 mapping for IVD degeneration, the correlation between T1rho/T2 mapping and degenerative grades and histological findings in the lumbar IVD were investigated. Overview of Literature: The early signs of IVD degeneration are proteoglycan loss, dehydration, and collagen degradation. Recently, several quantitative MRI techniques have been developed; T2 mapping can be used to evaluate hydration and collagen fiber integrity within cartilaginous tissue, and T1rho mapping can be used to evaluate hydration and proteoglycan content. Methods: Using New Zealand White rabbits, annular punctures of the IVD were made 10 times at L2/3, 5 times at L3/4, and one time at L4/5 using an 18-gauge needle (n=6) or a 21-gauge needle (n=6). At 4 and 8 weeks post surgery, MRI was performed including T1rho and T2 mapping. The degree of IVD degeneration was macroscopically assessed using the Thompson grading system. All specimens were cut for hematoxylin and eosin, safranin-O, and toluidine blue staining. Results: Disc degeneration became more severe as the number of punctures increased and when the larger needle was used. T1rho and T2 values were significantly different between grade 1 and grade 3 IVDs, grade 1 and grade 4 IVDs, grade 2 and grade 3 IVDs, and grade 2 and grade 4 IVDs (p<0.05). There was a significant difference between grade 1 and grade 2 IVDs only in terms of T1rho values (p<0.05). Conclusions: T1rho and T2 quantitative MRI could detect these small differences. Our results suggest that T1rho and T2 mapping are sensitive to degenerative changes of lumbar IVDs and that T1rho mapping can be used as a clinical tool to identify early IVD degeneration. PMID- 29713415 TI - Spinopelvic Alignment and Low Back Pain after Total Hip Replacement Arthroplasty in Patients with Severe Hip Osteoarthritis. AB - Study Design: Retrospective observational study. Purpose: We examined change in lumbrosacral spine alignment and low back pain (LBP) following total hip arthroplasty (THA) in patients with severe hip osteoarthritis (OA). Overview of Literature: Severe hip osteoarthritis has been reported to cause spine alignment abnormalities and low back pain, and it has been reported that low back pain is improved following THA. Methods: Our target population included 30 patients (29 female, mean age 63.5 years) with hip OA who underwent direct anterior approach THA. There were 12 cases with bilateral hip disease and 18 cases with unilateral osteoarthritis. Visual analogue scale (VAS) scores for LBP and coxalgia, the Roland-Morris Disability Questionnaire (RDQ), and the Japanese Orthopaedic Association Back Pain Evaluation Questionnaire (JOABPEQ) were assessed before and after surgery. Spinal alignment metrics were measured before and after surgery. Results: VAS for LBP change from preoperative to final postoperative observation was significantly improved (p <0.05), as was VAS for hip pain (p<0.001). RDQ improved significantly (p<0.01). All five domains of JOABPEQ were significantly improved (p<0.05). In terms of coronal alignment, lumbar scoliosis change from preoperative to last observation was significantly reduced (p<0.05). There were no significant changes in the sagittal alignment metrics. In addition, there was a correlation between before and after RDQ difference and before and after lumbar scoliosis difference (p<0.05). VAS for LBP (p<0.05) as well as RDQ (p<0.05) were significantly improved only in unilateral OA. Lumbar scoliosis was significantly improved in cases of unilateral OA (p<0.05), but alignment did not improve in cases of bilateral OA (p=0.29). Conclusions: The present study demonstrates improvements in VAS for LBP, RDQ, and all domains of JOABPEQ. There were also significant reductions in lumbar scoliosis and an observed correlation of RDQ improvement with lumbar scoliosis improvement. We were able to observe improvements in lumbar scoliosis and low back pain only in cases of unilateral OA. It has been suggested that the mechanism of low back pain improvement following THA is related to compensatory lumbar scoliosis improvement. PMID- 29713416 TI - Relationship between Displacement of the Psoas Major Muscle and Spinal Alignment in Patients with Adult Spinal Deformity. AB - Study Design: Cross sectional study. Purpose: To clarify the difference in position of the psoas muscle between adult spinal deformity (ASD) and lumbar spinal stenosis (LSS). Overview of Literature: Although it is known that the psoas major muscle deviates in ASD patients, no report is available regarding the difference in comparison with LSS patients. Methods: This study investigates 39 patients. For evaluating spinal alignment, pelvic tilt (PT), pelvic incidence (PI), sacral slope, lumbar lordosis (LL), PI-LL, Cobb angle, and the convex side, the lumbar curves were measured. For measuring the position of the psoas major at the L4/5 disk level, magnetic resonance imaging was used. The displacements of psoas major muscle were measured separately in the anterior-posterior and lateral directions. We examined the relationship between the radiographic parameters and anterior displacement (AD) and lateral displacement (LD) of the psoas major muscle. Results: AD was demonstrated in 15 cases with ASD and nine cases with LSS (p>0.05). LD was observed in 13 cases with ASD and no cases with LSS (p<0.01). The Cobb angle was significantly greater in cases with AD than in those without AD (p=0.04). PT, LL, PI-LL, and Cobb angle were significantly greater in cases with LD (p<0.05). All cases with LD had AD, but no case without AD had LD (p<0.001). The side of greater displacement at L4/5 and the convex side of the lumbar curve were consistent in all cases. Conclusions: Despite AD being observed in LSS as well, LD was observed only in the ASD group. Radiographic parameters were worse when LD was seen, rather than AD. PMID- 29713417 TI - Clinical Relationship of Degenerative Changes between the Cervical and Lumbar Spine. AB - Study Design: Retrospective, observational, case series. Purpose: To elucidate the prevalence of degenerative changes in the cervical and lumbar spine and estimate the degenerative changes in the cervical spine based on the degeneration of lumbar disc through a retrospective review of magnetic resonance (MR) images. Overview of Literature: Over 50% of middle-aged adults show evidence of spinal degeneration. However, the relationship between degenerative changes in the cervical and lumbar spine has yet to be elucidated. Methods: A retrospective review of positional MR images of 152 patients with symptoms related to cervical and lumbar spondylosis with or without a neurogenic component was conducted. The degree of intervertebral disc degeneration (IDD) was assessed on a grade of 1-5 for each segment of the cervical and lumbar spine using MR T2-weighted sagittal images. The grades across all segments were summed to produce the degenerative disc score (DDS) for the cervical and lumbar spine. The patients were divided into two groups based on the IDD grade for each lumbar segment: normal (grades 1 and 2) and degenerative (grades 3-5). Results: DDSs for the cervical and lumbar spine were positively correlated. Significant differences in cervical DDSs between the groups were observed in all lumbar segments. Although there were no significant differences in cervical DDSs among the degenerative lumbar segment, cervical DDSs at the L1-2 and L2-3 segments tended to be higher than those at the L3-4, L4-5, and L5-S degenerative segments. Conclusions: Our study shows that participants with degenerative changes in the upper lumbar segments are more likely to have a certain amount of cervical spondylosis. This information could be used to lower the incidence of a missed diagnosis of cervical spine disorders in patients presenting with lumbar spine symptomology. PMID- 29713418 TI - Does Vertical Ground Reaction Force of the Hip, Knee, and Ankle Joints Change in Patients with Adolescent Idiopathic Scoliosis after Spinal Fusion? AB - Study Design: Comparative cross-sectional study. Purpose: We measured the vertical ground reaction force (vGRF) of the hip, knee, and ankle joints during normal gait in normal patients, adolescent idiopathic scoliosis (AIS) patients with a Cobb angle <40 degrees and in AIS patients with spinal fusion. We aimed to investigate whether vGRF in the aforementioned joints is altered in these three groups of patients. Overview of Literature: vGRF of the lower limb joints may be altered in these groups of patients. Although it is known that excessive force in the joints may induce early arthritis, there is limited relevant information in the literatures. Methods: We measured vGRF of the hip, knee, and ankle joints during heel strike, early stance, mid stance, and toe-off phases in normal subjects (group 1, n=14), AIS patients with Cobb angle <40 degrees (group 2, n=14), and AIS patients with spinal fusion (group 3, n=13) using a gait analysis platform. Fifteen auto-reflective tracking markers were attached to standard anatomical landmarks in both the lower limbs. The captured motion images were used to define the orientations of the body segments and force exerted on the force plate using computer software. Statistical analysis was performed using independent t-test and analysis of variance to examine differences between the right and left sides as well as those among the different subject groups. Results: The measurements during the four gait phases in all the groups did not show any significant difference (p>0.05). In addition, no significant difference was found in the vGRF measurements of all the joints among the three groups (p>0.05). Conclusions: A Cobb angle <40 degrees and spinal fusion did not significantly create imbalance or alter vGRF of the lower limb joints in AIS patients. PMID- 29713419 TI - Comparison of Clinical and Radiologic Results of Mini-Open Transforaminal Lumbar Interbody Fusion and Extreme Lateral Interbody Fusion Indirect Decompression for Degenerative Lumbar Spondylolisthesis. AB - Study Design: Retrospective study. Purpose: In this study, we compared the postoperative outcomes of extreme lateral interbody fusion (XLIF) indirect decompression with that of mini-open transforaminal lumbar interbody fusion (TLIF) in patients with lumbar degenerative spondylolisthesis. Overview of Literature: There are very few reports examining postoperative results of XLIF and minimally invasive TLIF for degenerative lumbar spondylolisthesis, and no reports comparing XLIF and mini-open TLIF. Methods: Forty patients who underwent 1-level spinal fusion, either by XLIF indirect decompression (X group, 20 patients) or by mini-open TLIF (T group, 20 patients), for treatment of lumbar degenerative spondylolisthesis were included in this study. Invasiveness of surgery was evaluated on the basis of surgery time, blood loss, hospitalization period, and perioperative complications. The Japanese Orthopedic Association Back Pain Evaluation Questionnaire (JOABPEQ), disc angle (DA), disc height (DH), and slipping length (SL) were evaluated before surgery, immediately after surgery, and at 12 months after surgery. Cross-sectional spinal canal area (CSA) was also measured before surgery and at 1 month after surgery. Results: There was no significant difference between the groups in terms of surgery time or hospitalization period; however, X group showed a significant decrease in blood loss (p<0.001). Serious complications were not observed in either group. In clinical assessment, no significant differences were observed between the groups with regard to the JOABPEQ results. The change in DH at 12 months after surgery increased significantly in the X group (p<0.05), and the changes in DA and SL were not significantly different between the two groups. The change in CSA was significantly greater in the T group (p<0.001). Conclusions: Postoperative clinical results were equally favorable for both procedures; however, in comparison with mini-open TLIF, less blood loss and greater correction of DH were observed in XLIF. PMID- 29713420 TI - Emergence of Three-Dimensional Printing Technology and Its Utility in Spine Surgery. AB - In the last decade, spine surgery has advanced tremendously. Tissue engineering and three-dimensional (3D) printing/additive manufacturing have provided promising new research avenues in the fields of medicine and orthopedics in recent literature, and their emergent role in spine surgery is encouraging. We reviewed recent articles that highlighted the role of 3D printing in medicine, orthopedics, and spine surgery and summarized the utility of 3D printing. 3D printing has shown promising results in various aspects of spine surgery and can be a useful tool for spine surgeons. The growing research on tissue bioengineering and its application in conjunction with additive manufacturing has revealed great potential for tissue bioengineering in the treatment of spinal ailments. PMID- 29713421 TI - Failed Back Surgery Syndrome: A Review Article. AB - Postsurgical spine syndrome is becoming an increasingly common challenge for clinicians who deal with spinal disorders owing to the expanding indications for spinal surgery and the aging world population. A multidisciplinary approach is most appropriate for patients who are unlikely to benefit from further formal surgical intervention. Anticonvulsant medications are effective in managing neuropathic pain after surgery, whereas opioids are rarely beneficial. Neuromodulation via a surgically implanted dorsal column neurostimulator is gaining popularity owing to its substantial superiority over conventional medical management and/or further surgical intervention. However, considering that prevention is always better than cure, spinal surgeons need to be well aware of the many poor prognostic indicators for spinal surgery, particularly psychosocial overlay. PMID- 29713422 TI - Pulmonary Embolism from Cement Augmentation of the Vertebral Body. AB - Pulmonary cement embolism (PCE) can follow cement augmentation procedures for spine fractures due to osteoporosis, traumatic injuries, and painful metastatic lesions. PCE is underreported and it is likely that many cases remain undiagnosed. Risk factors for PCE have been identified, which can help alert clinicians to patients likely to develop the condition, and there are recommended techniques to reduce its incidence. Most patients with PCE are asymptomatic or only develop transient symptoms, although a few may exhibit florid cardiorespiratory manifestations which can ultimately be fatal. Diagnosis is mainly by radiographic means, commonly using simple radiographs and computed tomography scans of the chest with ancillary tests that assess the patient's cardiorespiratory condition. Management depends on the location and size of the emboli as well as the patient's symptomatology. The aim of this review is to raise awareness of the not uncommon complications of PCE following vertebral cement augmentation and the possibility of serious sequelae. Recommendations for the diagnosis and management of PCE are presented, based on the most recent literature. PMID- 29713423 TI - Quantitative Histological Analysis of Ligamentum Flavum. PMID- 29713424 TI - Response to: "Quantitative Histological Analysis of Ligamentum Flavum". PMID- 29713425 TI - Follow up of MRI bone marrow edema in the treated diabetic Charcot foot - a review of patient charts. AB - Background: Ill-defined areas of water-like signal on bone magnetic resonance imaging (MRI), characterized as bone marrow edema or edema-equivalent signal changes (EESC), is a hallmark of active-stage pedal neuro-osteoarthropathy (Charcot foot) in painless diabetic neuropathy, and is accompanied by local soft tissue edema and hyperthermia. The longitudinal effects on EESC of treating the foot in a walking cast were elucidated by reviewing consecutive cases of a diabetic foot clinic. Study design: Retrospective observational study, chart review Material and methods: Cases with active-stage Charcot foot were considered, in whom written reports on baseline and follow-up MRI studies were available for assessment. Only cases without concomitant infection or skin ulcer were chosen, in whom both was documented, onset of symptomatic foot swelling and patient compliance with cast treatment. Results: From 1994 to 2017, 45 consecutive cases in 37 patients were retrieved, with 95 MRI follow-up studies (1 6 per case, average interval between studies 13 weeks). Decreasing EESC was documented in 66/95 (69%) follow-up studies. However, 29/95 (31%) studies revealed temporarily increasing, migrating or stagnating EESC. Conclusion: EESC on MRI disappear in response to prolonged offloading and immobilizing treatment; however, physiologic as well as pathologic fluctuations of posttraumatic EESC have to be considered when interpreting the MR images. Conventional MRI is useful for surveillance of active-stage Charcot foot recovery. PMID- 29713426 TI - Extracellular vesicles from bone marrow-derived mesenchymal stromal cells support ex vivo survival of human antibody secreting cells. AB - Extracellular vesicles (EVs) from bone marrow (BM)-derived mesenchymal stromal cells (BM-MSC) are novel mechanisms of cell-cell communication over short and long distances. BM-MSC have been shown to support human antibody secreting cells (ASC) survival ex vivo, but whether the crosstalk between the MSC-ASC interaction can occur via EVs is not known. Thus, we evaluated the role of EVs in ASC survival and IgG secretion. EVs were isolated from irradiated and non-irradiated primary BM-MSC and were quantified. They were further characterized by electron microscopy (EM) and CD63 and CD81 immuno-gold EM staining. Human ASC were isolated via fluorescence-activated cell sorting (FACS) and cultured ex vivo with the EV fractions, the EV-reduced fractions, or conventional media. IgG Elispots were used to measure the survival and functionality of the ASC. Contents of the EV fractions were evaluated by proteomics. We saw that both irradiated and non irradiated MSC secretome preparations afforded vesicles of a size consistent with EVs. Both preparations appeared comparable in EM morphology and CD63 and CD81 immuno-gold EM. Both irradiated and non-irradiated EV fractions supported ASC function, at 88% and 90%, respectively, by day 3. In contrast, conventional media maintained only 4% ASC survival by day 3. To identify the specific factors that provided in vitro ASC support, we compared proteomes of the irradiated and non irradiated EV fractions with conventional media. Pathway analysis of these proteins identified factors involved in the vesicle-mediated delivery of integrin signalling proteins. These findings indicate that BM-MSC EVs provide an effective support system for ASC survival and IgG secretion. PMID- 29713427 TI - In-vitro performance and fracture strength of thin monolithic zirconia crowns. AB - PURPOSE: All-ceramic restorations required extensive tooth preparation. The purpose of this in vitro study was to investigate a minimally invasive preparation and thickness of monolithic zirconia crowns, which would provide sufficient mechanical endurance and strength. MATERIALS AND METHODS: Crowns with thickness of 0.2 mm (group 0.2, n=32) or of 0.5 mm (group 0.5, n=32) were milled from zirconia and fixed with resin-based adhesives (groups 0.2A, 0.5A) or zinc phosphate cements (groups 0.2C, 0.5C). Half of the samples in each subgroup (n=8) underwent thermal cycling and mechanical loading (TCML)(TC: 5C and 55C, 2*3,000 cycles, 2 min/cycle; ML: 50 N, 1.2*106 cycles), while the other samples were stored in water (37C/24 h). Survival rates were compared (Kaplan-Maier). The specimens surviving TCML were loaded to fracture and the maximal fracture force was determined (ANOVA; Bonferroni; alpha=.05). The fracture mode was analyzed. RESULTS: In both 0.5 groups, all crowns survived TCML, and the comparison of fracture strength among crowns with and without TCML showed no significant difference (P=.628). Four crowns in group 0.2A and all of the crowns in group 0.2C failed during TCML. The fracture strength after 24 hours of the cemented 0.2 mm-thick crowns was significantly lower than that of adhesive bonded crowns. All cemented crowns provided fracture in the crown, while about 80% of the adhesively bonded crowns fractured through crown and die. CONCLUSION: 0.5 mm thick monolithic crowns possessed sufficient strength to endure physiologic performance, regardless of the type of cementation. Fracture strength of the 0.2 mm cemented crowns was too low for clinical application. PMID- 29713428 TI - Hydroxyapatite-coated implant: Clinical prognosis assessment via a retrospective follow-up study for the average of 3 years. AB - PURPOSE: This research evaluated clinical outcomes of two types of hydroxyapatite (HA)-coated implants: OT (Osstem TS III-HA, Osstem implant Co., Busan, Korea) and ZM (Zimmer TSV-HA, Zimmer dental, Carlsbad, USA). MATERIALS AND METHODS: The research was conducted on 303 implants (89 of OT, 214 of ZM), which were placed from January 16, 2010 to December 20, 2012. The prognosis was evaluated in terms of success rates, survival rates, annual marginal bone loss, and implant stability quotients (ISQ). The samples were classified into immediate, early, conventional, and delayed groups according to the loading time. RESULTS: Overall, there were no significant differences between OT and ZM in success rates, survival rates, and annual marginal bone loss, except for the result of secondary stability. OT showed 77.83 +/- 8.23 ISQ, which was marginally higher than 76.09 +/- 6.90 ISQ of ZM (P<.05). In terms of healing periods, only immediate loading showed statistically significant differences (P<.05). Differences between OT and ZM were observed in terms of two indices, the annual marginal bone loss (0.17 +/- 0.58 mm/year < 0.45 +/- 0.80 mm/year) and secondary stability (84.36 +/- 3.80 ISQ > 82.48 +/- 3.69 ISQ) (P<.05). OT and ZM did not have any statistically significant differences in early, conventional, and delayed loading (P>.05). CONCLUSION: OT (97.75%) and ZM (98.50%) showed relatively good outcomes in terms of survival rates. In general, OT and ZM did not show statistically significant differences in most indices (P>.05), although OT performed marginally better than ZM in the immediate loading and 1-stage surgery (P<.05). PMID- 29713429 TI - What is the changing frequency of diamond burs? AB - PURPOSE: The purpose of this study was to determine the changing frequency of a diamond bur after multiple usages on 3 different surfaces. MATERIALS AND METHODS: Human premolar teeth (N = 26), disc shaped direct metal laser sintered CoCr (N = 3) and zirconia specimens (N = 3) were used in this study. Groups named basically as Group T for teeth, Group M for CoCr, and Group Z for zirconia. Round tapered black-band diamond bur was used. The specimens were randomly divided into three groups and placed with a special assembly onto the surveyor. 1, 5, and 10 preparation protocols were performed to the first, second, and third sub-groups, respectively. The subgroups were named according to preparation numbers (1, 5, 10). The mentioned bur of each group was then used at another horizontal preparation on a new tooth sample. The same procedure was used for CoCr and zirconia disc specimens. All of the bur surfaces were evaluated using roughness analysis. Then, horizontal tooth preparation surfaces were examined under both stereomicroscope and SEM. The depth maps of tooth surfaces were also obtained from digital stereomicroscopic images. The results were statistically analyzed using One-Way ANOVA, and the Tukey HSD post-hoc tests (alpha=.05). RESULTS: All of the groups were significantly different from the control group (P<.001). There was no significant difference between groups Z5 and Z10 (P=.928). Significant differences were found among groups T5, M5, and Z5 (P<.001). CONCLUSION: Diamond burs wear after multiple use and they should be changed after 5 teeth preparations at most. A diamond bur should not be used for teeth preparation after try-in procedures of metal or zirconia substructures. PMID- 29713430 TI - Repair bond strength of resin composite to bilayer dental ceramics. AB - PURPOSE: The purpose of this study was to investigate the effect of various surface treatments (ST) on the shear bond strength of resin composite to three bilayer dental ceramics made by CAD/CAM and two veneering ceramics. MATERIALS AND METHODS: Three different bilayer dental ceramics and two different veneering ceramics were used (Group A: IPS e.max CAD+IPS e.max Ceram; Group B: IPS e.max ZirCAD+IPS e.max Ceram, Group C: Vita Suprinity+Vita VM11; Group D: IPS e.max Ceram; Group E: Vita VM11). All groups were divided into eight subgroups according to the ST. Then, all test specimens were repaired with a nano hybrid resin composite. Half of the test specimens were subjected to thermocycling procedure and the other half was stored in distilled water at 37C. Shear bond strength tests for all test specimens were carried out with a universal testing machine. RESULTS: There were statistically significant differences among the tested surface treatments within the all tested fracture types (P<.005). HF etching showed higher bond strength values in Groups A, C, D, and E than the other tested ST. However, bonding durability of all the surface-treated groups were similar after thermocycling (P>.00125). CONCLUSION: This study revealed that HF etching for glass ceramics and sandblasting for zirconia ceramics were adequate for repair of all ceramic restorations. The effect of ceramic type exposed on the fracture area was not significant on the repair bond strength of resin composites to different ceramic types. PMID- 29713431 TI - Effects of incorporation of 2.5 and 5 wt% TiO2 nanotubes on fracture toughness, flexural strength, and microhardness of denture base poly methyl methacrylate (PMMA). AB - PURPOSE: The aim of this preliminary study was to investigate, for the first time, the effects of addition of titania nanotubes (n-TiO2) to poly methyl methacrylate (PMMA) on mechanical properties of PMMA denture base. MATERIALS AND METHODS: TiO2 nanotubes were prepared using alkaline hydrothermal process. Obtained nanotubes were assessed using FESEM-EDX, XRD, and FT-IR. For 3 experiments of this study (fracture toughness, three-point bending flexural strength, and Vickers microhardness), 135 specimens were prepared according to ISO 20795-1:2013 (n of each experiment=45). For each experiment, PMMA was mixed with 0% (control), 2.5 wt%, and 5 wt% nanotubes. From each TiO2:PMMA ratio, 15 specimens were fabricated for each experiment. Effects of n-TiO2 addition on 3 mechanical properties were assessed using Pearson, ANOVA, and Tukey tests. RESULTS: SEM images of n-TiO2 exhibited the presence of elongated tubular structures. The XRD pattern of synthesized n-TiO2 represented the anatase crystal phase of TiO2. Moderate to very strong significant positive correlations were observed between the concentration of n-TiO2 and each of the 3 physicomechanical properties of PMMA (Pearson's P value <=.001, correlation coefficient ranging between 0.5 and 0.9). Flexural strength and hardness values of specimens modified with both 2.5 and 5 wt% n-TiO2 were significantly higher than those of control (P<=.001). Fracture toughness of samples reinforced with 5 wt% n-TiO2 (but not those of 2.5% n-TiO2) was higher than control (P=.002). CONCLUSION: Titania nanotubes were successfully introduced for the first time as a means of enhancing the hardness, flexural strength, and fracture toughness of denture base PMMA. PMID- 29713432 TI - Effect of polymerization method and fabrication method on occlusal vertical dimension and occlusal contacts of complete-arch prosthesis. AB - PURPOSE: This study evaluated the dimensional stability of a complete-arch prosthesis processed by conventional method in water bath or microwave energy and polymerized by two different curing cycles. MATERIALS AND METHODS: Forty maxillary complete-arch prostheses were randomly divided into four groups (n = 10): MW1 - acrylic resin cured by one microwave cycle; MW2 - acrylic resin cured by two microwave cycles: WB1 - conventional acrylic resin polymerized using one curing cycle in a water bath; WB2 - conventional acrylic resin polymerized using two curing cycles in a water bath. For evaluation of dimensional stability, occlusal vertical dimension (OVD) and area of contact points were measured in two different measurement times: before and after the polymerization method. A digital caliper was used for OVD measurement. Occlusal contact registration strips were used between maxillary and mandibular dentures to measure the contact points. The images were measured using the software IpWin32, and the differences before and after the polymerization methods were calculated. The data were statistically analyzed using the one-way ANOVA and Tukey test (alpha = .05). RESULTS: he results demonstrated significant statistical differences for OVD between different measurement times for all groups. MW1 presented the highest OVD values, while WB2 had the lowest OVD values (P<.05). No statistical differences were found for area of contact points among the groups (P=.7150). CONCLUSION: The conventional acrylic resin polymerized using two curing cycles in a water bath led to less difference in OVD of complete-arch prosthesis. PMID- 29713433 TI - Precision of the milled full-arch framework fabricated using pre-sintered soft alloy: A pilot study. AB - PURPOSE: This study aimed to evaluate the marginal discrepancy of full-arch frameworks in implant-supported prostheses fabricated using pre-sintered soft alloy (PSA). MATERIALS AND METHODS: Full-arch metal frameworks were fabricated on the edentulous implant model using casting alloy (CA), fully-sintered hard alloy (FHA), and PSA (n = 4 in each group). To evaluate the misfit of the framework to the abutments, the absolute marginal discrepancy (AMD) values of the frameworks were measured in cross-sectional images that had been drawn as part of the triple scan protocol. The AMD values were compared among the tested alloy groups using the Kruskal-Wallis test, with a post hoc Mann-Whitney U test (alpha=.05). RESULTS: The FHA and PSA groups showed lower marginal discrepancies than the CA group (P<.001). However, the FHA group did not differ significantly from the PSA group. CONCLUSION: Soft alloy milling is comparable to hard alloy milling, and it is more precise than casting in terms of the marginal fit of implant-supported, full-arch prostheses. PMID- 29713434 TI - The effect of various polishing systems on surface roughness and phase transformation of monolithic zirconia. AB - PURPOSE: The purpose of this study was to evaluate and compare three polishing systems on the surface roughness and phase transformation of monolithic zirconia. MATERIALS AND METHODS: 100 disk shaped specimens (10 mm diameter, 3 mm thickness) were fabricated from monolithic zirconia blocks. 20 specimens were left as a control group and remaining specimens were grinded by diamond bur to simulate the occlusal adjustments. Grinded specimens were randomly divided into 4 groups: group G (no polishing), group M (Meisinger, zirconia polishing kit), group E (EVE Diacera, zirconia polishing kit), and group P (EVE Diapol, porcelain polishing kit). Surface roughness was measured with profilometer and surface topography was observed with SEM. XRD analysis was performed to investigate the phase transformation. Statistical analysis was performed with one-way ANOVA and Tukey's post hoc tests at a significance level of P=.05. RESULTS: All polishing groups showed a smoother surface than group G. Among 3 polishing systems, group M and group E exhibited a smoother surface than the group P. However, no significant differences were observed between group M and group E (P>.05). Grinding and polishing did not cause phase transformations in zirconia specimens. CONCLUSION: Zirconia polishing systems created a smoother surface on zirconia than the porcelain polishing system. Phase transformation did not occur during the polishing procedure. PMID- 29713435 TI - Three-dimensional finite element analysis of the splinted implant prosthesis in a reconstructed mandible. AB - PURPOSE: The purpose of this study was to analyze the effects of the splinted implant prosthesis in a reconstructed mandible using three-dimensional finite element analysis. MATERIALS AND METHODS: Three-dimensional finite element models were generated from a patient's computed tomography data. The patient had undergone partial resection of the mandible that covered the area from the left canine to the right condyle. The mandible was reconstructed using a fibula bone graft and dental implants. The left mandibular premolars and molars remained intact. Three types of models were created. The implant-supported prosthesis was splinted and segmented into two or three pieces. Each of these models was further subcategorized into two situations to compare the stress distribution around normal teeth and implants. Oblique loading of 300 N was applied on both sides of the mandible unilaterally. The maximum von Mises stress and displacement of the models were analyzed. RESULTS: The stress distribution of the natural mandible was more uniform than that of the reconstructed fibula. When the loading was applied to the implant prosthesis of reconstructed fibula, stress was concentrated at the cortical bone around the neck of the implants. The three piece prosthesis model showed less uniform stress distribution compared to the others. Displacement of the components was positively correlated with the distance from areas of muscle attachment. The three-piece prosthesis model showed the greatest displacement. CONCLUSION: The splinted implant prosthesis showed a more favorable stress distribution and less displacement than the separated models in the reconstructed mandible. PMID- 29713436 TI - Analysis of osteogenic potential on 3mol% yttria-stabilized tetragonal zirconia polycrystals and two different niobium oxide containing zirconia ceramics. AB - PURPOSE: This study was performed to evaluate the osteogenic potential of 3mol% yttria-stabilized tetragonal zirconia polycrystals (3Y-TZP) and niobium oxide containing Y-TZPs with specific ratios, new (Y,Nb)-TZPs, namely YN4533 and YN4533/Al20 discs. MATERIALS AND METHODS: 3Y-TZP, YN4533 and YN4533/Al20 discs (15 mm diameter and 1 mm thickness) were prepared and their average surface roughness (Ra) and surface topography were analyzed using 3-D confocal laser microscope (CLSM) and scanning electron microscope (SEM). Mouse pre-osteoblast MC3T3-E1 cells were seeded onto all zirconia discs and evaluated with regard to cell attachment and morphology by (CLSM), cell proliferation by PicoGreen assay, and cell differentiation by Reverse-Transcription PCR and Quantitative Real-Time PCR, and alkaline phosphatase (Alp) staining. RESULTS: The cellular morphology of MC3T3-E1 pre-osteoblasts was more stretched on a smooth surface than on a rough surface, regardless of the material. Cellular proliferation was higher on smooth surfaces, but there were no significant differences between 3Y-TZP, YN4533, and YN4533/Al20. Osteoblast differentiation patterns on YN4533 and YN4533/Al20 were similar to or slightly higher than seen in 3Y-TZP. Although there were no significant differences in bone marker gene expression (alkaline phosphatase and osteocalcin), Alp staining indicated better osteoblast differentiation on YN4533 and YN4533/Al20 compared to 3Y-TZP. CONCLUSION: Based on these results, niobium oxide containing Y-TZPs have comparable osteogenic potential to 3Y-TZP and are expected to be suitable alternative ceramics dental implant materials to titanium for aesthetically important areas. PMID- 29713437 TI - Comparison of implant component fractures in external and internal type: A 12 year retrospective study. AB - PURPOSE: The aim of this study was to compare the fracture of implant component behavior of external and internal type of implants to suggest directions for successful implant treatment. MATERIALS AND METHODS: Data were collected from the clinical records of all patients who received WARANTEC implants at Seoul National University Dental Hospital from February 2002 to January 2014 for 12 years. Total number of implants was 1,289 and an average of 3.2 implants was installed per patient. Information about abutment connection type, implant locations, platform sizes was collected with presence of implant component fractures and their managements. SPSS statistics software (version 24.0, IBM) was used for the statistical analysis. RESULTS: Overall fracture was significantly more frequent in internal type. The most frequently fractured component was abutment in internal type implants, and screw fracture occurred most frequently in external type. Analyzing by fractured components, screw fracture was the most frequent in the maxillary anterior region and the most abutment fracture occurred in the maxillary posterior region and screw fractures occurred more frequently in NP (narrow platform) and abutment fractures occurred more frequently in RP (regular platform). CONCLUSION: In external type, screw fracture occurred most frequently, especially in the maxillary anterior region, and in internal type, abutment fracture occurred frequently in the posterior region. placement of an external type implant rather than an internal type is recommended for the posterior region where abutment fractures frequently occur. PMID- 29713438 TI - Clinical outcome of immediately and early loaded implants with laser treated surface: a 3-year retrospective study. AB - PURPOSE: The marginal bone loss of implants with laser treated surface was investigated after six weeks of loading after implant installation to the mandible molar area. MATERIALS AND METHODS: A total of 23 implants were placed in the edentulous molar area of the mandible: 13 implants were immediately loaded and 10 implants were early loaded. The implants used were made of titanium grade 23, screw shaped, 4.2 mm in diameter, and 10 mm in length. Patients were evaluated with resonance frequency analysis at implant fixture installation and 1, 2 (final prosthesis installation), 3, 5, 8, and 14 months later. X-rays were taken at 2 months after fixture installation and 1, 2, 3 years after to measure the marginal bone loss. RESULTS: The mean ISQ value measured at the implant installation was over 70 at all-time points. The average of marginal bone loss was average 0.33 mm. CONCLUSION: Immediate implant loading for laser treated implants would be possible. PMID- 29713439 TI - ANN and Fuzzy Logic Based Model to Evaluate Huntington Disease Symptoms. AB - We introduce an approach to predict deterioration of reaction state for people having neurological movement disorders such as hand tremors and nonvoluntary movements. These involuntary motor features are closely related to the symptoms occurring in patients suffering from Huntington's disease (HD). We propose a hybrid (neurofuzzy) model that combines an artificial neural network (ANN) to predict the functional capacity level (FCL) of a person and a fuzzy logic system (FLS) to determine a stage of reaction. We analyzed our own dataset of 3032 records collected from 20 test subjects (both healthy and HD patients) using smart phones or tablets by asking a patient to locate circular objects on the device's screen. We describe the preparation and labelling of data for the neural network, selection of training algorithms, modelling of the fuzzy logic controller, and construction and implementation of the hybrid model. The feed forward backpropagation (FFBP) neural network achieved the regression R value of 0.98 and mean squared error (MSE) values of 0.08, while the FLS provides a final evaluation of subject's reaction condition in terms of FCL. PMID- 29713440 TI - Social Robotics in Therapy of Apraxia of Speech. AB - Apraxia of speech is a motor speech disorder in which messages from the brain to the mouth are disrupted, resulting in an inability for moving lips or tongue to the right place to pronounce sounds correctly. Current therapies for this condition involve a therapist that in one-on-one sessions conducts the exercises. Our aim is to work in the line of robotic therapies in which a robot is able to perform partially or autonomously a therapy session, endowing a social robot with the ability of assisting therapists in apraxia of speech rehabilitation exercises. Therefore, we integrate computer vision and machine learning techniques to detect the mouth pose of the user and, on top of that, our social robot performs autonomously the different steps of the therapy using multimodal interaction. PMID- 29713441 TI - Did Hans Asperger actively assist the Nazi euthanasia program? PMID- 29713442 TI - Hans Asperger, National Socialism, and "race hygiene" in Nazi-era Vienna. AB - Background: Hans Asperger (1906-1980) first designated a group of children with distinct psychological characteristics as 'autistic psychopaths' in 1938, several years before Leo Kanner's famous 1943 paper on autism. In 1944, Asperger published a comprehensive study on the topic (submitted to Vienna University in 1942 as his postdoctoral thesis), which would only find international acknowledgement in the 1980s. From then on, the eponym 'Asperger's syndrome' increasingly gained currency in recognition of his outstanding contribution to the conceptualization of the condition. At the time, the fact that Asperger had spent pivotal years of his career in Nazi Vienna caused some controversy regarding his potential ties to National Socialism and its race hygiene policies. Documentary evidence was scarce, however, and over time a narrative of Asperger as an active opponent of National Socialism took hold. The main goal of this paper is to re-evaluate this narrative, which is based to a large extent on statements made by Asperger himself and on a small segment of his published work. Methods: Drawing on a vast array of contemporary publications and previously unexplored archival documents (including Asperger's personnel files and the clinical assessments he wrote on his patients), this paper offers a critical examination of Asperger's life, politics, and career before and during the Nazi period in Austria. Results: Asperger managed to accommodate himself to the Nazi regime and was rewarded for his affirmations of loyalty with career opportunities. He joined several organizations affiliated with the NSDAP (although not the Nazi party itself), publicly legitimized race hygiene policies including forced sterilizations and, on several occasions, actively cooperated with the child 'euthanasia' program. The language he employed to diagnose his patients was often remarkably harsh (even in comparison with assessments written by the staff at Vienna's notorious Spiegelgrund 'euthanasia' institution), belying the notion that he tried to protect the children under his care by embellishing their diagnoses. Conclusion: The narrative of Asperger as a principled opponent of National Socialism and a courageous defender of his patients against Nazi 'euthanasia' and other race hygiene measures does not hold up in the face of the historical evidence. What emerges is a much more problematic role played by this pioneer of autism research. Future use of the eponym should reflect the troubling context of its origins in Nazi-era Vienna. PMID- 29713443 TI - Prenatal mercury exposure and features of autism: a prospective population study. AB - Background: Mercury (Hg) has been suspected of causing autism in the past, especially a suspected link with vaccinations containing thiomersal, but a review of the literature shows that has been largely repudiated. Of more significant burden is the total quantity of Hg in the environment. Here, we have used the Avon Longitudinal Study of Parents and Children (ALSPAC) to test whether prenatal exposure from total maternal blood Hg in the first half of pregnancy is associated with the risk of autism or of extreme levels of autistic traits. This is the largest longitudinal study to date to have tested this hypothesis and the only one to have considered early pregnancy. Methods: We have used three strategies: (1) direct comparison of 45 pregnancies resulting in children with diagnosed autism from a population of 3840, (2) comparison of high scores on each of the four autistic traits within the population at risk (n~2800), and (3) indirect measures of association of these outcomes with proxies for increased Hg levels such as frequency of fish consumption and exposure to dental amalgam (n > 8000). Logistic regression adjusted for social conditions including maternal age, housing circumstances, maternal education, and parity. Interactions were tested between risks to offspring of fish and non-fish eaters. Results: There was no suggestion of an adverse effect of total prenatal blood Hg levels on diagnosed autism (AOR 0.89; 95% CI 0.65, 1.22) per SD of Hg (P = 0.485). The only indication of adverse effects concerned a measure of poor social cognition when the mother ate no fish, where the AOR was 1.63 [95% CI 1.02, 2.62] per SD of Hg (P = 0.041), significantly different from the association among the offspring of fish-eaters (AOR = 0.74 [95% CI 0.41, 1.35]). Conclusion: In conclusion, our study identifies no adverse effect of prenatal total blood Hg on autism or autistic traits provided the mother ate fish. Although these results should be confirmed in other populations, accumulating evidence substantiates the recommendation to eat fish during pregnancy. PMID- 29713444 TI - Personalizing initial therapy in acute myeloid leukemia: incorporating novel agents into clinical practice. AB - While the past decade has seen a revolution in understanding of the genetic and molecular etiology of the disease, in clinical practice, initial therapy for acute myeloid leukemia (AML) patients has been a relatively straightforward choice between intensive combination cytotoxic induction therapy as used for decades or less-intensive hypomethylating therapy. The year 2017, however, witnessed US Food and Drug Administration approvals of midostaurin, enasidenib, gemtuzumab ozogamicin and CPX-351 for AML patients, with many other promising agents currently in clinical trials. This review discusses these options, highlights unanswered questions regarding optimal combinations and proposes some suggested approaches for the personalization of initial therapy for AML patients. PMID- 29713445 TI - The evolution of stem-cell transplantation in multiple myeloma. AB - Autologous stem-cell transplantation (ASCT) remains an integral part of treatment for previously untreated, and may have value in the treatment of relapsed patients with, multiple myeloma (MM). The addition of novel agents like immunomodulators and proteasome inhibitors as induction therapy before and as consolidation/maintenance therapy after ASCT has led to an improvement in complete response (CR) rates, progression-free survival (PFS) and overall survival (OS). With advances in supportive care, older patients and patients with renal insufficiency are now able to safely undergo the procedure. The data concerning the timing of ASCT (early in the disease course or at first relapse), single versus tandem (double) ASCT and the role and duration of consolidation and maintenance therapy post ASCT remain conflicting. This review aims to discuss the evolution of stem-cell transplant over the past 3 decades and its current role in the context of newer, safer and more effective therapeutic agents. PMID- 29713446 TI - Evidence of Oropharyngeal Dysfunction in Feeding in the Rat Rotenone Model of Parkinson's Disease. AB - Swallowing disorders in Parkinson's disease are not responsive to dopamine depletion therapy and contribute to morbidity. They are poorly understood owing to a lack of adequate models. We present the first evidence of oropharyngeal changes in a rotenone toxicity model of Parkinson's disease. Rats were recorded while feeding before and after daily rotenone injections at two different doses (2.75 mg/kg and 3 mg/kg). The higher dose had a much more severe parkinsonian phenotype than the low dose. Timing and amplitude of chewing changed, as did the coordination of chewing and swallowing. Dose-dependent effects were evident. These preliminary results indicate that future research in toxicological models of Parkinson's disease should incorporate the study of oropharyngeal dysfunction. A better understanding of nongenetic models of Parkinson's disease in feeding may open new avenues for research into the neurological and behavioral bases for swallowing dysfunction in Parkinson's disease. PMID- 29713447 TI - Over-the-scope clip (OTSC(r)) closure of a recto-acetabular fistula. AB - A 25-year-old male Syrian refugee presented in our hospital with recurrent hip infections after having undergone hip arthroplasty abroad following destruction of his right hip joint by shell splinters in the Syrian civil war. The patient underwent hip arthroplasty revision with implantation of a cement spacer. CT-scan with rectal contrast media filling revealed a recto-acetabular fistula. Consecutively, the patient underwent ileostomy formation. The fistula was then successfully closed by endoscopic over-the-scope clipping (OTSC(r)). Fistulas between intestines and joints rarely develop and in the few cases published mostly extensive abdominal rescue surgery has been performed. Here, we present a case of a traumatic recto-acetabular fistula that was successfully closed by OTSC. This innovative method could represent a safe and suitable option to effectively close fistulas between joints and intestines thereby avoiding extensive rescue surgery with bowel resection or permanent ostomy. PMID- 29713449 TI - Sclerosing encapsulating peritonitis presenting as acute-on-chronic small-bowel obstruction in a patient with history of peritoneal carcinomatosis. AB - Sclerosing encapsulating peritonitis (SEP) is a whitish fibrous envelope that encapsulates intra-abdominal peritonealized organs. Although it pathophysiology is not well understood, several possible causes have been reported in the literature, including peritoneal dialysis, past abdominal surgeries, peritonitis, beta-blockers and peritoneal carcinomatosis (PC). Some idiopathic cases, with no apparent causes, were described. We present a SEP case in a 43-year-old woman with a surgical history of pancreatic and liver resection for metastatic pseudopapillary pancreatic tumor, followed by several peritonectomies for PC. She was admitted for acute-on-chronic small-bowel obstruction that did not resolve with conservative management. Surgical exploration revealed a fibrous sheath covering the small-bowel. Extensive dissection, along with small-bowel segmental resection and anastomosis, was performed. The specimen was cancer-free. The mechanism through which SEP develops in certain surgical patients is still unknown. This report presents a case of successful surgical management and a review of the literature. PMID- 29713448 TI - Pseudoaneurysm of the internal maxillary artery secondary to subcondylar fracture: case report and literature review. AB - Pseudoaneurysms are an uncommon complication of mandibular condylar-subcondylar fractures; however, if present, their recognition and management is mandatory to avoid life-threatening situations. The authors report a case of internal maxillary artery pseudoaneurysm rupture that occurred after an open reduction and internal fixation of a mandibular subcondylar fracture, along with a review of the literature. PMID- 29713450 TI - Alkanethiolate-capped palladium nanoparticles for selective catalytic hydrogenation of dienes and trienes. AB - Selective hydrogenation of dienes and trienes is an important process in the pharmaceutical and chemical industries. Our group previously reported that the thiosulfate protocol using a sodium S-alkylthiosulfate ligand could generate catalytically active Pd nanoparticles (PdNP) capped with a lower density of alkanethio-late ligands. This homogeneously soluble PdNP catalyst offers several advantages such as little contamination via Pd leaching and easy separation and recycling. In addition, the high activity of PdNP allows the reactions to be completed under mild conditions, at room temperature and atmospheric pressure. Herein, a PdNP catalyst capped with octanethiolate ligands (C8 PdNP) is investigated for the selective hydrogenation of conjugated dienes into monoenes. The strong influence of the thiolate ligands on the chemical and electronic properties of the Pd surface is confirmed by mechanistic studies and highly selective catalysis results. The studies also suggest two major routes for the conjugated diene hydrogenation: the 1,2-addition and 1,4-addition of hydrogen. The selectivity between two mono-hydrogenation products is controlled by the steric interaction of substrates and the thermodynamic stability of products. The catalytic hydrogenation of trienes also results in the almost quantitative formation of mono-hydrogenation products, the isolated dienes, from both ocimene and myrcene. PMID- 29713451 TI - Effectiveness of paliperidone long-acting injection in clinical practice. AB - Background: The efficacy of the long-acting injectable formulation of the antipsychotic paliperidone (paliperidone palmitate) has been investigated in randomized controlled trials. Due to the nature of study designs, these may not be representative of usual clinical practice. The aim of this study was to assess the clinical effectiveness of the long-acting injectable antipsychotic paliperidone palmitate using treatment continuation at 1 year as an outcome. Methods: Patients were initiated on paliperidone palmitate prior to December 2014 in a single health board in Wales (UK). Demographic factors that may have influenced outcome, including diagnosis, age at initiation, sex, inpatient or outpatient status on initiation, were analysed to assess whether they influenced patient outcome. For patients completing 1 year of treatment, inpatient stay in the 12 months prior to and following paliperidone palmitate initiation was compared. Results: Data were available for 64 patients; 41 had a diagnosis of schizophrenia and 7 had previously received clozapine. Continuation rates at 6 and 12 months were 69% and 63% respectively. Treatment continuation was not associated with demographic factors. For continuers, mean inpatient stay pre- and post-initiation was 83.2 +/- 105.3 and 73.5 +/- 103.3 days respectively (p = 0.61). The most common reason for discontinuation was lack of effect (n = 9). Conclusions: The proportion of patients remaining on treatment was comparable to that reported in other naturalistic studies. Prescribing for indications outside the product licence was relatively common, but did not appear to influence outcome, although the number of patients in each group was small. Treatment continuation at 6 months appeared to be a predictor of longer-term outcome. PMID- 29713453 TI - Anti-CTLA-4 antibodies in cancer immunotherapy: selective depletion of intratumoral regulatory T cells or checkpoint blockade? AB - Antibodies to human CTLA-4 have been shown to induce long-lasting protection against melanoma. It is assumed that these antibodies cause tumor rejection by blocking negative signaling from the B7-CTLA-4 interactions to enhance priming of naive T cells in the lymphoid organs. Recently, we reported that anti-CTLA-4 antibody Ipilimumab effectively induces tumor rejection in vivo although it blocks neither B7 transendocytosis by CTLA-4 nor CTLA-4 binding to immobilized or cell-associated B7. Using genetic model in which the anti-CTLA-4 antibodies are unable to engage more than 50% of CTLA-4, we demonstrated that saturating binding of CTLA-4 is not necessary for tumor rejection. Our results argue against B7-CTLA 4 blockade as the mechanism of action for the clinically effective Ipilimumab. Moreover, Ipilimumab induces tumor rejection even in the absence of de novo T cell priming in the lymphoid organs. Thus, our data are inconsistent with key provisions of the prevailing hypothesis on mechanism of action by anti-CTLA-4 antibodies. Furthermore, anti-CTLA-4 antibodies effectively induce depletion of regulatory T (Treg) cells in tumor microenvironment but not in the peripheral lymphoid organs, which is strictly dependent on Fc receptor on host cells. Based on these data and other recent publications on the subject, we propose that anti human CTLA-4 antibodies induce tumor rejection by selective depletion of Tregs in the tumors rather than blockade of B7-CTLA-4 interaction in lymphoid organs. PMID- 29713452 TI - Challenges of the pharmacological management of benzodiazepine withdrawal, dependence, and discontinuation. AB - Background: Benzodiazepines (BZDs) are among the most prescribed sedative hypnotics and among the most misused and abused medications by patients, in parallel with opioids. It is estimated that more than 100 million Benzodiazepine (BZD) prescriptions were written in the United States in 2009. While medically useful, BZDs are potentially dangerous. The co-occurring abuse of opioids and BZD, as well as increases in BZD abuse, tolerance, dependence, and short- and long-term side effects, have prompted a worldwide discussion about the challenging aspects of medically managing the discontinuation of BZDs. Abrupt cessation can cause death. This paper addresses the challenges of medications suggested for the management of BZD discontinuation, their efficacy, the risks of abuse and associated medical complications. The focus of this review is on the challenges of several medications suggested for the management of BZD discontinuation, their efficacy, the risks of abuse, and associated medical complications. Methods: An electronic search was performed of Medline, Worldwide Science, Directory of Open Access Journals, Embase, Cochrane Library, Google Scholar, PubMed Central, and PubMed from 1990 to 2017. The review includes double blind, placebo-controlled studies for the most part, open-label pilot studies, and animal studies, in addition to observational research. We expand the search to review articles, naturalistic studies, and to a lesser extent, letters to the editor/case reports. We exclude abstract and poster presentations, books, and book chapters. Results: The efficacy of these medications is not robust. While some of these medicines are relatively safe to use, some of them have a narrow therapeutic index, with severe, life-threatening side effects. Randomized studies have been limited. There is a paucity of comparative research. The review has several limitations. The quality of the documents varies according to whether they are randomized studies, nonrandomized studies, naturalistic studies, pilot studies, letters to the editors, or case reports. Conclusions: The use of medications for the discontinuation of BZDs seems appropriate. It is a challenge that requires further investigation through randomized clinical trials to maximize efficacy and to minimize additional risks and side effects. PMID- 29713454 TI - Is adult cardiac regeneration absent in Xenopus laevis yet present in Xenopus tropicalis? AB - We recently used an endoscopy-based resection method to explore the consequences of cardiac injury in adult Xenopus laevis, obtaining the result that the adult Xenopus heart is unable to regenerate. At 11 months post-amputation, cellular and biological marks of scarring persisted. We thus concluded that, contrary to urodeles and teleosts, adult anurans share a cardiac injury outcome similar to adult mammals. However, in their work published in this journal on the 13 December 2017, Liao et al. showed that the adult Xenopus tropicalis heart is capable of efficient, almost scar free regeneration, a result at odds with our previous observation. These findings contrast with and challenge the outcome of adult heart repair following injury in Xenopus species. Here we discuss the question of the intrinsic cardiac regenerative properties of an adult heart in anuran amphibians. PMID- 29713455 TI - Cardiac regeneration in Xenopus tropicalis and Xenopus laevis: discrepancies and problems. AB - Two studies have recently focused on adult heart regeneration in Xenopus. While we reported on cardiac myogenic regeneration in Xenopus tropicalis after injury, Marshall and colleagues found no regeneration in an injured heart in Xenopus laevis. Here, we would like to join the discussion initiated by Marshall et al. who debated the methods and species differences in both studies. We agree with their view that the species difference in cardiac regenerative capacity could lead to different results in both of these studies. Moreover, we suggest that the age of the animals used in these studies could lead to differences in regeneration. A 5-year old X. laevis is much more advanced in age than a 1-year old X. tropicalis. The other reason for the discrepancies could be the size of the clot. Due to different resection protocols, the clot formed after the endoscopic resection performed by Marshall et al. was much larger than that after a conventional resection, as used in our study. Furthermore, the difference in the site of injury could influence the healing and regeneration differences. The influence of the organismal age, techniques used to induce injury and site of injury on regeneration need to be examined in detail to assess the regenerative potential of the amphibian heart. PMID- 29713456 TI - Diverse expression of TNF-alpha and CCL27 in serum and blister of Stevens-Johnson syndrome/toxic epidermal necrolysis. AB - Background: The pathogenesis of Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) is not fully understood. Our previous study reported that chemokine CCL27 was overexpressed in serum of SJS/TEN patients. The objective of this study was to investigate the levels of CCL27 and TNF-alpha in serum and blister fluid from patients with SJS/TEN during the acute stage or resolution phase. Methods: A total of 27 patients with SJS/TEN and 39 healthy donors were recruited to the study. Serum and vesicular levels of CCL27 and TNF-alpha were determined by enzyme-linked immunosorbent assays. Results: Serum levels of CCL27 and TNF-alpha were significantly elevated in patients with SJS/TEN during the acute stage as compared to the resolution phase and also compared with levels observed in normal controls (P = 0.001/< 0.001; P = 0.012/< 0.001). Serum TNF alpha levels were significantly higher in patients with SJS/TEN during the resolution phase compared with normal controls (P < 0.001). Serum CCL27 levels were positively correlated with TNF-alpha levels during the acute stage (rs = 0.660; P < 0.001). Blister fluid exhibited much lower CCL27 levels than serum did during the acute stage (P = 0.008). TNF-alpha levels were much higher in vesicles in contrast to serum from acute stage (P = 0.040) as well as serum from resolution phase (P = 0.029). Conclusions: Our study demonstrated roles of CCL27 and TNF-alpha in promoting the course of SJS/TEN. CCL27 may act early in the course of disease, via the circulation, whereas TNF-alpha acts throughout the course of disease, in skin lesions. PMID- 29713457 TI - The regional effect of spinal manipulation on the pressure pain threshold in asymptomatic subjects: a systematic literature review. AB - Background: Spinal manipulation (SM) has been shown to have an effect on pain perception. More knowledge is needed on this phenomenon and it would be relevant to study its effect in asymptomatic subjects. Objectives: To compare regional effect of SM on pressure pain threshold (PPT) vs. sham, inactive control, mobilisation, another SM, and some type of physical therapy. In addition, we reported the results for the three different spinal regions. Method: A systematic search of literature was done using PubMed, Embase and Cochrane. Search terms were ((spinal manipulation) AND (experimental pain)); ((spinal manipulative therapy OR spinal manipulation) AND ((experimental pain OR quantitative sensory testing OR pressure pain threshold OR pain threshold)) (Final search: June 13th 2017). The inclusion criteria were SM performed anywhere in the spine; the use of PPT, PPT tested in an asymptomatic region and on the same day as the SM. Studies had to be experimental with at least one external or internal control group. Studies on only spinal motion or tenderness, other reviews, case reports, and less than 15 invited participants in each group were excluded. Evidence tables were constructed with information relevant to each research question and by spinal region. Results were reported in relation to statistical significance and were interpreted taking into account their quality. Results: Only 12 articles of 946 were accepted. The quality of studies was generally good. In 8 sham controlled studies, a psychologically and physiologically "credible" sham was found in only 2 studies. A significant difference was noted between SM vs. Sham, and between SM and an inactive control. No significant difference in PPT was found between SM and another SM, mobilisation or some type of physical therapy. The cervical region more often obtained significant findings as compared to studies in the thoracic or lumbar regions. Conclusion: SM has an effect regionally on pressure pain threshold in asymptomatic subjects. The clinical significance of this must be quantified. More knowledge is needed in relation to the comparison of different spinal regions and different types of interventions. PMID- 29713458 TI - Can chiropractors contribute to work disability prevention through sickness absence management for musculoskeletal disorders? - a comparative qualitative case study in the Scandinavian context. AB - Background: Despite extensive publication of clinical guidelines on how to manage musculoskeletal pain and back pain in particular, these efforts have not significantly translated into decreases in work disability due to musculoskeletal pain. Previous studies have indicated a potential for better outcomes by formalized, early referral to allied healthcare providers familiar with occupational health issues. Instances where allied healthcare providers of comparable professional characteristics, but with differing practice parameters, can highlight important social and organisational strategies useful for informing policy and practice. Currently, Norwegian chiropractors have legislated sickness certification rights, whereas their Danish and Swedish counterparts do not. Against the backdrop of legislative variation, we described, compared and contrasted the views and experiences of Scandinavian chiropractors engaging in work disability prevention and sickness absence management. Methods: This study was embedded in a two-phased, sequential exploratory mixed-methods design. In a comparative qualitative case study design, we explored the experience of chiropractors regarding sickness absence management drawn from face-to-face, semi structured interviews. We subsequently coded and thematically restructured their experiences and perceptions. Results: Twelve interviews were conducted. Thematically, chiropractors' capacity to support patients in sickness absence management revolved around four key issues: issues of legislation and politics; the rationale for being a sickness absence management partner; whether an integrated sickness absence management pathway existed/could be created; and finally, the barriers to service provision for sickness absence management. Conclusion: Allied health providers, in this instance chiropractors, with patient management expertise can fulfil a key role in sickness absence management and by extension work disability prevention when these practices are legislatively supported. In cases where these practices occur informally, however, practitioners face systemic-related issues and professional self-image challenges that tend to hamper them in fulfilling a more integrated role as providers of work disability prevention practices. PMID- 29713459 TI - Effect of pre-milking teat disinfection on new mastitis infection rates of dairy cows. AB - Background: The practise of teat disinfection prior to cluster attachment for milking is being adopted by farmers in Ireland, particularly where there are herd issues with new infection rates. Pre-milking teat disinfection has been shown to reduce bacterial numbers on teat skin and to be most effective against environmental bacteria such as Escherichia coli and Streptococcus uberis. A split udder design experiment was undertaken on two research herds (A = 96 cows: B = 168 cows) to test the benefit of pre-milking teat disinfection on new mastitis infection levels. The disinfectant was applied to the left front and right hind teats of all cows in each herd and the right front and left hind teats received no disinfectant treatment prior to milking over a complete lactation. Individual quarter foremilk samples were taken on 5 occasions during the lactation and all clinical cases were recorded. The presence and number of staphylococcus and streptococcus bacteria on teat skin of a random sample of experimental cows (n = 20) was measured on 3 occasions during lactation (April, June, and October). Results: Pre-milking teat disinfection had no significant impact on quarter SCC and new infection rates (P > 0.05). The median SCC was 169 (95% CI = 144-198) * 103 cells/mL and 170 (95% CI = 145-199) * 103 cells/mL for disinfected teats and non-disinfected teats, respectively. There were no differences in SCC observed between herds (A = 161 (95% CI = 127-205) * 103 cells/mL; B = 169 (95% CI = 144 198) * 103 cells/mL) over the complete lactation. Bacterial levels on teat skin were reduced significantly with pre-milking teat disinfection compared to teats receiving no disinfectant (P < 0.001). Total infections (clinical and sub clinical) were similar for disinfected teats (n = 36) and not disinfected teats (n = 40), respectively. Staphylococcus aureus (n = 47) and Strep. uberis (n = 9) were identified as the predominant bacteria in quarter foremilk samples with both clinical and sub-clinical infections. Conclusion: SCC and new infection rates were similar in non-disinfected teats and disinfected (pre-milking) teats. The routine application of pre-milking teat disinfectant in pasture-grazed herds is unlikely to be of benefit where herd SCC is below 200 * 103 cells/mL. PMID- 29713461 TI - Investigation on uric acid biosensor model for enzyme layer thickness for the application of arthritis disease diagnosis. AB - Uric acid biosensors for arthritis disease has been developed for the specific selection of uricase enzyme film thickness coated over the TiO2-CeO2 nano composite matrix is modelled mathematically. This model is purely based on R diffusion conditions with irreversible first-order catalytic reactions. By arithmetical method, the impact of the thickness of enzyme layer on the current response of the biosensor was explored. This article displays a structure for choice of the enzyme layer thickness, guaranteeing the adequately stable sensitivity of a biosensor in a required extent of the maximal enzymatic rate. The numerical outcomes showed subjective and sensible quantitative information for oxidation current due to uric acid also shows the maximum change in the biosensor current response due to the change in membrane thickness, which will be more suitable for uric acid biosensor for the application of arthritis disease diagnosis. PMID- 29713460 TI - Sensing the cilium, digital capture of ciliary data for comparative genomics investigations. AB - Background: Cilia are specialized, hair-like structures that project from the cell bodies of eukaryotic cells. With increased understanding of the distribution and functions of various types of cilia, interest in these organelles is accelerating. To effectively use this great expansion in knowledge, this information must be made digitally accessible and available for large-scale analytical and computational investigation. Capture and integration of knowledge about cilia into existing knowledge bases, thus providing the ability to improve comparative genomic data analysis, is the objective of this work. Methods: We focused on the capture of information about cilia as studied in the laboratory mouse, a primary model of human biology. The workflow developed establishes a standard for capture of comparative functional data relevant to human biology. We established the 310 closest mouse orthologs of the 302 human genes defined in the SYSCILIA Gold Standard set of ciliary genes. For the mouse genes, we identified biomedical literature for curation and used Gene Ontology (GO) curation paradigms to provide functional annotations from these publications. Results: Employing a methodology for comprehensive capture of experimental data about cilia genes in structured, digital form, we established a workflow for curation of experimental literature detailing molecular function and roles of cilia proteins starting with the mouse orthologs of the human SYSCILIA gene set. We worked closely with the GO Consortium ontology development editors and the SYSCILIA Consortium to improve the representation of ciliary biology within the GO. During the time frame of the ontology improvement project, we have fully curated 134 of these 310 mouse genes, resulting in an increase in the number of ciliary and other experimental annotations. Conclusions: We have improved the GO annotations available for mouse genes orthologous to the human genes in the SYSCILIA Consortium's Gold Standard set. In addition, ciliary terminology in the GO itself was improved in collaboration with GO ontology developers and the SYSCILIA Consortium. These improvements to the GO terms for the functions and roles of ciliary proteins, along with the increase in annotations of the corresponding genes, enhance the representation of ciliary processes and localizations and improve access to these data during large-scale bioinformatic analyses. PMID- 29713462 TI - Immigration: analysis, trends and outlook on the global research activity. AB - Background: Immigration has a strong impact on the development of health systems, medicine and science worldwide. Therefore, this article provides a descriptive study on the overall research output. Methods: Utilizing the scientific database Web of Science, data research was performed. The gathered bibliometric data was analyzed using the established platform NewQIS, a benchmarking system to visualize research quantity and quality indices. Findings: Between 1900 and 2016 a total of 6763 articles on immigration were retrieved and analyzed. 86 different countries participated in the publications. Quantitatively the United States followed by Canada and Spain were prominent regarding the article numbers. On comparing by additionally taking the population size into account, Israel followed by Sweden and Norway showed the highest performance. The main releasing journals are the Public Health Reports, the Journal of Immigrant and Minority Health and Social Science & Medicine. Over the decades, an increasing number of Public, Environmental & Occupational Health articles can be recognized which finally forms the mainly used subject area. Conclusion: Considerably increasing scientific work on immigration cannot only be explained by the general increase of scientific work but is also owed to the latest development with increased mobility, worldwide crises and the need of flight and migration. Especially countries with a good economic situation are highly affected by immigrants and prominent in their publication output on immigration, since the countries' publication effort is connected with the appointed expenditures for research and development. Remarkable numbers of immigrants throughout Europe compel medical professionals to consider neglected diseases, requires the public health system to restructure itself and finally promotes science. PMID- 29713463 TI - Zinc as an adjunct therapy in the management of severe pneumonia among Gambian children: randomized controlled trial. AB - Background: The benefit of zinc as an adjunct therapy for severe pneumonia is not established. We assessed the benefit of adjunct zinc therapy for severe pneumonia in children and determined whether the study children were zinc deficient. Methods: This was a randomized, parallel group, double-blind, placebo-controlled trial with an allocation ratio of 1:1 conducted in children with severe pneumonia to evaluate the efficacy of daily zinc as an adjunct treatment in preventing 'treatment failure' (presence of any sign of severe pneumonia) on day-5 and day 10 and in reducing the time to resolution of signs of severe pneumonia. Six hundred and four children 2-59 months of age presenting with severe pneumonia at six urban and rural health care facilities in The Gambia were individually randomised to receive placebo (n = 301) or zinc (n = 303) for seven days. To determine if the study children were zinc deficient, supplementation was continued in a randomly selected subgroup of 121 children from each arm for six months post-enrolment, and height-gain, nutritional status, plasma zinc concentrations, and immune competence were compared. Results: Percentage of treatment failure were similar in placebo and zinc arms both on day 5 (14.0% vs 14.1%) and day 10 (5.2% vs 5.9%). The time to recovery from lower chest wall indrawing and sternal retraction was longer in the placebo compared to zinc arm (24.4 vs 23.0 hours; P = 0.011 and 18.7 vs 11.0 hours; P = 0.006 respectively). The time to resolution for all respiratory symptoms of severity was not significantly different between placebo and zinc arms (42.3 vs 30.9 hours respectively; P = 0.242). In the six months follow-up sub-group, there was no significant difference in height gain, height-for-age and weight-for-height Z scores, mid upper arm circumference, plasma zinc concentrations, and anergy at six months post-enrolment. Conclusions: In this population, zinc given as an adjunct treatment for severe pneumonia showed no benefit in treatment failure rates, or clinically important benefit in time to recovery from respiratory symptoms and showed marginal benefit in rapidity of resolution of some signs of severity. This finding does not support routine use of zinc as an adjunct treatment in severe pneumonia in generally zinc replete children. Trial registration: ISRCTN33548493. PMID- 29713464 TI - An observational case study of hospital associated infections in a critical care unit in Astana, Kazakhstan. AB - Background: Hospital Associated infections (HAI) are very common in Intensive Care Units (ICU) and are usually associated with use of invasive devices in the patients. This study was conducted to determine the prevalence and etiological agents of HAI in a Surgical ICU in Kazakhstan, and to assess the impact of these infections on ICU stay and mortality. Objective: To assess the rate of device associated infections and causative HAI etiological agents in an ICU at the National Research Center for Oncology and Transplantation (NRCOT) in Astana, Kazakhstan. Methods: This retrospective, observational study was conducted in a 12-bed ICU at the NRCOT, Astana, Kazakhstan. We enrolled all patients who were admitted to the ICU from January, 2014 through November 2015, aged 18 to 90 years of age who developed an HAI. Results: The most common type of HAI was surgical site infection (SSI), followed by ventilator-associated pneumonia (VAP), catheter related blood stream infection (BSI) and catheter-associated urinary tract infection (UTI). The most common HAI was SSI with Pseudomonas aeruginosa as the most common etiological agent. The second most common HAI was VAP also with P. aeruginosa followed by BSI which was also associated with P. aeruginosa (in 2014) and Enterococcus faecalis, and Klebsiella pneumoniae (in 2015) as the most common etiological agents causing these infections. Conclusion: We found that HAI among our study population were predominantly caused by gram-negative pathogens, including P. aeruginosa, K. pneumoniae, and E. coli. To our knowledge, this is the only study that describes ICU-related HAI situation from a country within the Central Asian region. Many developing countries such as Kazakhstan lack surveillance systems which could effectively decrease incidence of HAIs and healthcare costs for their treatment. The epidemiological data on HAI in Kazakhstan currently is underrepresented and poorly reported in the literature. Based on this and previous studies, we propose that the most important interventions to prevent HAI at the NRCOT and similar Healthcare Institutions in Kazakhstan are active surveillance, regular infection control audits, rational and effective antibacterial therapy, and general hygiene measures. PMID- 29713465 TI - Estimating the burden of antimicrobial resistance: a systematic literature review. AB - Background: Accurate estimates of the burden of antimicrobial resistance (AMR) are needed to establish the magnitude of this global threat in terms of both health and cost, and to paramaterise cost-effectiveness evaluations of interventions aiming to tackle the problem. This review aimed to establish the alternative methodologies used in estimating AMR burden in order to appraise the current evidence base. Methods: MEDLINE, EMBASE, Scopus, EconLit, PubMed and grey literature were searched. English language studies evaluating the impact of AMR (from any microbe) on patient, payer/provider and economic burden published between January 2013 and December 2015 were included. Independent screening of title/abstracts followed by full texts was performed using pre-specified criteria. A study quality score (from zero to one) was derived using Newcastle Ottawa and Philips checklists. Extracted study data were used to compare study method and resulting burden estimate, according to perspective. Monetary costs were converted into 2013 USD. Results: Out of 5187 unique retrievals, 214 studies were included. One hundred eighty-seven studies estimated patient health, 75 studies estimated payer/provider and 11 studies estimated economic burden. 64% of included studies were single centre. The majority of studies estimating patient or provider/payer burden used regression techniques. 48% of studies estimating mortality burden found a significant impact from resistance, excess healthcare system costs ranged from non-significance to $1 billion per year, whilst economic burden ranged from $21,832 per case to over $3 trillion in GDP loss. Median quality scores (interquartile range) for patient, payer/provider and economic burden studies were 0.67 (0.56-0.67), 0.56 (0.46-0.67) and 0.53 (0.44-0.60) respectively. Conclusions: This study highlights what methodological assumptions and biases can occur dependent on chosen outcome and perspective. Currently, there is considerable variability in burden estimates, which can lead in-turn to inaccurate intervention evaluations and poor policy/investment decisions. Future research should utilise the recommendations presented in this review. Trial registration: This systematic review is registered with PROSPERO (PROSPERO CRD42016037510). PMID- 29713466 TI - Dissemination of blaNDM-5 gene via an IncX3-type plasmid among non-clonal Escherichia coli in China. AB - Background: The emergence and spread of New Delhi metallo-beta-lactamase producing Enterobacteriaceae has been a serious challenge to manage in the clinic due to its rapid dissemination of multi-drug resistance worldwide. As one main type of carbapenemases, New Delhi metallo-beta-lactamase (NDM)is able to confer resistance to almost all beta-lactams, including carbapenems, in Enterobacteriaceae. Recently, New Delhi metallo-beta-lactamase-5 attracted extensive attention because of increased resistance to carbapenems and widespread dissemination. However, the dissemination mechanism of blaNDM-5 gene remains unclear. Methods: A total of 224 carbapenem-resistant Enterobacteriaceae isolates (CRE) were collected from different hospitals in Zhejiang province. NDM-5 positive isolates were identified and subjected to genotyping, susceptibility testing, and clinical data analysis. We established the genetic location of blaNDM-5 with southern blot hybridisation, and analysed plasmids containing blaNDM-5 with filter mating and DNA sequencing. Results: Eleven New Delhi metallo beta-lactamase-5 (NDM-5)-producing strains were identified, including 9 Escherichia coli strains, 1 Klebsiella pneumoniae strain, and 1 Citrobacter freundii strain. No epidemiological links for E. coli isolates were identified by multilocus sequence typing (MLST) and pulsed-field gel electrophoresis (PFGE). S1 PFGE and southern blot suggested that the blaNDM-5 gene was located on a 46-kb IncX3-type plasmid in all isolates. Nine of the 11 isolates (81.8%) tested could successfully transfer their carbapenem-resistant phenotype to E. coli strain C600. Moreover, sequence analysis further showed that this plasmid possessed high sequence similarity to most of previously reported blaNDM-5-habouring plasmids in China. Conclusion: The present data in this study showed the IncX3 type plasmid played an important role in the dissemination of blaNDM-5 in Enterobacteriaceae. In addition, to the best of our knowledge, this report is the first to isolate both E. coli and C. freundii strains carrying blaNDM-5 from one single patient, which further indicated the possibility of blaNDM-5 transmission among diverse species. Close surveillance is urgently needed to monitor the further dissemination of NDM-5-producing isolates. PMID- 29713467 TI - Cerebral glucose metabolic prediction from amnestic mild cognitive impairment to Alzheimer's dementia: a meta-analysis. AB - Brain 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has been utilized to monitor disease conversion from amnestic mild cognitive impairment (aMCI) to Alzheimer's dementia (AD). However, the conversion patterns of FDG-PET metabolism across studies are not conclusive. We conducted a voxel-wise meta analysis using Seed-based d Mapping that included 10 baseline voxel-wise FDG-PET comparisons between 93 aMCI converters and 129 aMCI non-converters from nine longitudinal studies. The most robust and reliable metabolic alterations that predicted conversion from aMCI to AD were localized in the left posterior cingulate cortex (PCC)/precuneus. Furthermore, meta-regression analyses indicated that baseline mean age and severity of cognitive impairment, and follow-up duration were significant moderators for metabolic alterations in aMCI converters. Our study revealed hypometabolism in the left PCC/precuneus as an early feature in the development of AD. This finding has important implications in understanding the neural substrates for AD conversion and could serve as a potential imaging biomarker for early detection of AD as well as for tracking disease progression at the predementia stage. PMID- 29713468 TI - Dietary resveratrol improves antioxidant status of sows and piglets and regulates antioxidant gene expression in placenta by Keap1-Nrf2 pathway and Sirt1. AB - Background: Resveratrol, a plant phenol, affords protection against inflammation and oxidative stress. The objective of this study was to investigate the effects of dietary resveratrol supplementation during pregnancy and lactation on the antioxidant status of sows and piglets and on antioxidant gene expression and pathway in placenta. Methods: Forty sows were allotted to 2 dietary treatments 20 d after breeding. Sows were fed a control diet and a control diet with 300 mg/kg resveratrol. Oxidative stress biomarkers and antioxidant enzymes were measured in the placenta, milk, and plasma of sows and piglets. Antioxidant gene expression and protein expression of Kelch-like ECH-associated protein 1-Nuclear factor E2 related factor 2 (Keap1-Nrf2), nuclear factor kappa B-p65 (NFkappaB-p65) and sirtuin1 (Sirt1) were quantified in the placenta. Results: Dietary resveratrol increased the litter and piglets weaning weights. Antioxidant status in the milk, placenta and plasma of sows and piglets was partially improved by dietary resveratrol. In placenta, Nrf2 protein expression was increased and Keap1 protein expression was decreased by dietary resveratrol. The mRNA expression of antioxidant genes including catalase (CAT), glutathione peroxidase 1 (GPX1), GPX4, superoxide dismutase 1 (SOD1) and heme oxygenase 1 (HO1), and phase 2 detoxification genes, including glutamate-cysteine ligase modifier (GCLM), microsomal glutathione S-transferase 1(MGST1) and UDP glucuronosyltransferase family 1 member A1 (UGT1A1), was increased by dietary resveratrol. Dietary resveratrol also increased Sirt1 and phosphorylated NFkappaB-p65 protein expression in the placenta. We failed to observe any influences of dietary resveratrol on pro-inflammatory cytokine levels, including those of interleukin 1beta (IL-1beta), IL-6, IL-8 and tumor necrosis factor alpha (TNF-alpha). However, we observed that the mRNA expression of IL-8 in placenta was reduced by maternal resveratrol. In addition, dietary resveratrol showed interactive effects with day of lactation on activities of SOD and CAT and levels of malonaldehyde (MDA) and hydrogen peroxide (H2O2) in milk. Conclusions: Dietary resveratrol supplementation during pregnancy and lactation improves the antioxidant status of sows and piglets, which is beneficial to the reproductive performance of sows. Dietary resveratrol regulates placental antioxidant gene expression by the Keap1 Nrf2 pathway and Sirt1 in placenta. PMID- 29713469 TI - Metabolomic analysis of longissimus from underperforming piglets relative to piglets with normal preweaning growth. AB - Background: Recent increases in intra-litter variability in weaning weight have raised swine production costs. A contributor to this variability is the normal birth weight pig that grows at a slower rate than littermates of similar birth weight. The goal of this study was to interrogate biochemical profiles manifested in skeletal muscle originating from slow growing (SG) and faster growing littermates (control), with the aim of identifying differences in metabolic pathway utilization between skeletal muscle of the SG pig relative to its littermates. Samples of longissimus muscle from littermate pairs of pigs were collected at 21 d of age for metabolomic analysis (Metabolon, Inc., Durham, NC). Results: Birth weights did not differ between littermate pairs of SG and Control pigs (P > 0.05). Weaning weights differed by 1.51 +/- 0.19 kg (P < 0.001). Random forest (RF) analysis was effective at segregating the metabolome of muscle samples by growth rate, resulting in a predictive accuracy of 81% versus random segregation (50%). Decreases in sugars in the pentose phosphate pathway (PPP) in the longissimus of SG pigs were detected (P < 0.05). Decreases were also apparent in glycolytic intermediates (glycerol-3-phosphate and lactate) and key glycolysis derived intermediates (glucose-6-phosphate and fructose-6-phosphate; P < 0.05). SG pigs had increased levels of phospholipids, lysolipids, diacylglycerols, and sphingolipids (P < 0.05). Pathway analysis identified a cluster of molecules associated with muscle and collagen/extracellular matrix breakdown that are increased in the SG pig (glutamate, 3-methylhistidine and hydroxylated proline moieties; P < 0.05). Nicotinate metabolism was altered in SG pigs, resulting in a 78% decrease in the nicotinamide adenine dinucleotide pool (P < 0.05). Conclusions: These metabolomic data provide the first evidence for biochemical mechanisms that should be investigated to determine if they have a potential role in the slow growth in some normal birth weight piglets that contribute to increased intra-litter variability in weaning weights and provides essential information and potential targets for the development of nutritional intervention strategies. PMID- 29713470 TI - HIV-related knowledge in Nigeria: a 2003-2013 trend analysis. AB - Background: Given Nigeria's status as the country with the second highest number of people living with HIV globally, and 9% of the total global burden of HIV being attributable to Nigeria alone in 2013, improving our understanding of the nature of the HIV epidemic in Nigeria is crucial. As HIV-related knowledge may be an important contributor to engagement in preventive behaviours, it is of interest to investigate trends in HIV-related knowledge in Nigeria with the purpose of informing future HIV prevention and education efforts. This study therefore aims to investigate trends in HIV-related knowledge in Nigeria between 2003 and 2013. Methods: Data were derived from the 2003-2013 Nigerian Demographic and Health Surveys, and HIV-related knowledge scores were computed based on answers to HIV-related knowledge questions in the surveys. The significance of the difference between HIV-related knowledge across the time points was determined via the Kruskal-Wallis test, and changes in HIV-related knowledge were displayed graphically, stratified by relevant socio-demographic characteristics. ARIMA models were fit to the 2003 to 2013 trend data. Results: Although there was generally a decrease in HIV-related knowledge across most knowledge domains in 2008, an overall increase was observed between 2003 and 2013. Unfortunately however, this was not the case for knowledge of mother-to-child transmission, which decreased between 2003 and 2013. The disparity in knowledge of HIV risk reduction between states also increased over time. Conclusion: These findings suggest that although HIV-related knowledge appears to be increasing overall, future HIV prevention and education programs should focus on specific knowledge domains such as mother-to-child transmission, and on specific states in which HIV related knowledge remains low. PMID- 29713471 TI - Recent novel approaches to limit oxidative stress and inflammation in diabetic complications. AB - Diabetes is considered a major burden on the healthcare system of Western and non Western societies with the disease reaching epidemic proportions globally. Diabetic patients are highly susceptible to developing micro- and macrovascular complications, which contribute significantly to morbidity and mortality rates. Over the past decade, a plethora of research has demonstrated that oxidative stress and inflammation are intricately linked and significant drivers of these diabetic complications. Thus, the focus now has been towards specific mechanism based strategies that can target both oxidative stress and inflammatory pathways to improve the outcome of disease burden. This review will focus on the mechanisms that drive these diabetic complications and the feasibility of emerging new therapies to combat oxidative stress and inflammation in the diabetic milieu. PMID- 29713473 TI - NKX2.2, PDX-1 and CDX-2 as potential biomarkers to differentiate well differentiated neuroendocrine tumors. AB - Background: Well-differentiated neuroendocrine tumors (NET) most frequently arise from the gastrointestinal tract (GI), pancreas, and lung. Patients often present as metastasis with an unknown primary, and the clinical management and outcome depend on multiple factors, including the accurate diagnosis with the tumor primary site. Determining the site of the NET with unknown primary remains challenging. Many biomarkers have been investigated in primary NETs and metastatic NETs, with heterogeneous sensitivity and specificity observed. Methods: We used high-throughput tissue microarray (TMA) and immunohistochemistry (IHC) with antibodies against a panel of transcriptional factors including NKX2.2, PDX-1, PTF1A, and CDX-2 on archived formalin-fixed paraffin-embedded NETs, and investigated the protein expression pattern of these transcription factors in 109 primary GI (N = 81), pancreatic (N = 17), and lung (N = 11) NETs. Results: Differential expression pattern of these markers was observed. In the GI and pancreatic NETs (N = 98), NKX2.2, PDX-1, and CDX-2 were immunoreactive in 82 (84%), 14 (14%), and 52 (52%) cases, respectively. PDX-1 was expressed mainly in the small intestinal and appendiceal NETs, occasionally in the pancreatic NETs, and not in the colorectal NETs. All three biomarkers including NKX2.2, PDX-1, and CDX-2 were completely negative in lung NETs. PTF1A was expressed in all normal and neuroendocrine tumor cells. Conclusions: Our findings suggest that NKX2.2 was a sensitive and specific biomarker for the GI and pancreatic neuroendocrine tumors. We proposed that a panel of immunostains including NKX2.2, PDX-1, and CDX 2 may show diagnostic utility for the most common NETs. PMID- 29713472 TI - The role of IL-22 in the resolution of sterile and nonsterile inflammation. AB - In a broad sense, inflammation can be conveniently characterised by two phases: the first phase, which is a pro-inflammatory, has evolved to clear infection and/or injured tissue; and the second phase concerns regeneration of normal tissue and restitution of normal physiology. Innate immune cell-derived pro inflammatory cytokines and chemokines activate and recruit nonresident immune cells to the site of infection, thereby amplifying the inflammatory responses to clear infection or injury. This phase is followed by a cytokine milieu that promotes tissue regeneration. There is no absolute temporal distinction between these two phases, and cytokines may have dual pleiotropic effects depending on the timing of release, inflammatory microenvironment or concentrations. IL-22 is a cytokine with reported pro- and anti-inflammatory roles; in this review, we contend that this protein has primarily a function in restitution of normal tissue and physiology. PMID- 29713474 TI - The Belgian commitment to pharmaceutical quality: a model policy to improve quality assurance of medicines available through humanitarian and development programs. AB - : Today, a combination of globalization of pharmaceutical production, lack of regulatory harmonization, and weakness of Medicines Regulatory Authorities, creates the "perfect conditions" for poor-quality medicine to circulate in the global market and to penetrate the less-regulated countries. Medicines regulation is the responsibility of the national regulatory authorities in the recipient country, but in the poorer countries, in practice, the responsibility of supply of quality-assured medicines is often taken by Non-Governmental Organizations and other implementers. But with some notable exceptions, many donors lack a pharmaceutical procurement policy with adequate quality requirements; and many implementers lack the skills and expertise needed to orient themselves in the complex web of global pharmaceutical supply. Thus, patients served by humanitarian or development programs may remain exposed to the risk of poor quality medicines. When public money is used to purchase medicines for medical programs to be carried out overseas, adequate policies should be in place to assure that the same quality requirements are set that would be required for medicines marketed in the "donor" country. We will describe here a policy recently adopted in Belgium, i.e. the "Commitment to Quality Assurance for Pharmaceutical Products", signed in October 2017 by the Vice Prime Minister and Minister for Development Cooperation and 19 Belgian implementing agencies. By signing the new policy, the counterparts committed to ensure quality of medicines in the programs funded by Belgium's Official Development Assistance, and to build quality-assurance capacity in the recipient countries. Implementers are requested to integrate in their financing applications a section for pharmaceutical quality assurance, with a justified budget. They are also invited to consider how costs could be rationalized and mutualized by aligning the strengths of the various implementers. This model policy has the potential to be considered for adoption by other donors, to help to reduce the current multiple standards in pharmaceutical quality, and to contribute to protect vulnerable communities from the plague of poor-quality medicines. Electronic additional files: The online version of this article (10.1186/s40545-018-0136-z) contains an additional file, which is available to authorized users. PMID- 29713476 TI - Relationship between residence characteristics and polycyclic aromatic hydrocarbon exposure in housewives: second Korean National Environmental Health Survey (2012-2014). AB - Background: Polycyclic aromatic hydrocarbons (PAHs) produced by incomplete combustion have negative effects on human health due to their carcinogenicity and teratogenicity. Indoor sources of PAHs include tobacco smoke, heating sources, and cooking. This study evaluated the relationship between human PAH exposure and residence characteristics. Method: This study was based on the second Korean National Environmental Health Survey (2012-2014). Non-smoking housewives were included in the analyses (n = 1269). The concentrations of urinary PAH metabolites (2-naphthol, 2-hydroxyfluorene, 1-hydroxyphenanthrene, and 1 hydroxypyrene) were adjusted by urine creatinine level. The geometric mean concentrations of urinary PAH metabolites by residential factors were examined. Logistic regression models were used to evaluate associations between residential variables and PAH exposures. Results: The adjusted geometric mean concentrations of urinary 2-hydroxyfluorene and 1-hydroxyphenanthrene were significantly higher in the group residing within 100 m of a major road (p < 0.05) than in those residing > 100 m from a major road. In logistic regression analyses, the odds ratio (OR) for exceeding the third quartile of urinary 1-hydroxypyrene concentration was significantly higher in the group using coal or wood fuel for residential heating than in the group using gas (OR = 2.745, 95% confidence interval [CI] = 1.295-5.819). The detached house group had a significantly higher OR for 1-hydroxyphenanthrene compared with the apartment group (OR = 1.515, 95% CI = 1.023-2.243). Conclusion: Our study shows the evidence of associations between some urinary PAH metabolite levels (1-hydroxyphenanthrene and 1 hydroxypyrene) and residence characteristics. Additional studies are needed to clarify these associations. PMID- 29713477 TI - Female non-smokers' environmental tobacco smoking exposure by public transportation mode. AB - Background: This study aimed to analyze environmental tobacco smoking exposure in female nonsmokers by public transportation mode using representative data of Koreans. Methods: Data from the Second Korean National Environmental Health Survey (2012-2014) were analyzed. Urine cotinine was analyzed by public transport behavior, secondhand smoke exposure, socioeconomic factors, and health-related factors. Participants were 1322 adult females; those with the top 75% urine cotinine concentrations were assigned to the high exposure group. A logistic regression analysis was performed considering appropriate weights and stratification according to the sample design of the Second Korean National Environmental Health Survey. Results: The geometric mean of urine cotinine concentrations differed according to public transportation modes: subway (1.66 MUg/g creatinine) bus (1.77 MUg/g creatinine), and taxi (1.94 MUg/g creatinine). The odds ratio [OR] was calculated for the high exposure group. The OR of the taxi (2.39; 95% confidence interval, 1.00-5.69) was statistically significantly higher than the subway value (reference), and marginally significant after adjusted with life style, sociodemographic factors and involuntary smoking frequency (2.42, 95% confidence interval, 0.97-6.04). Conclusions: The odds ratio of passengers who mainly used taxis was marginally significantly higher than those of passengers who used subways and buses after adjusted with life style and sociodemographic factors. Implementation of supplementary measures and further studies on exposure to environmental tobacco smoking in taxis are warranted. PMID- 29713475 TI - Exercise for Toxicity Management in Cancer-A Narrative Review. AB - Although the treatment of cancer is more effective now than ever, patients with cancer still face acute and chronic toxicities such as fatigue, cardiotoxicity, pain, cognitive impairment, and neurotoxicity. In this narrative review, we briefly discuss the use of exercise for toxicity management in patients with cancer, biological mechanisms underlying the toxicities and the effects of exercise, barriers that patients- especially underserved patients-face in adopting and adhering to exercise programs, and new technologies to overcome barriers to exercise. Our conclusions and clinical suggestions are: (1) exercise is safe and effective for treating many toxicities; (2) patients can benefit from a variety of exercise modalities (e.g., walking, cycling, resistance bands, yoga); (3) exercise should be started as soon as possible, even before treatments begin; (4) exercise should be continued as long as possible, as a lifestyle; and (5) barriers to exercise should be identified and addressed, (e.g., continually encouraging patients to exercise, using mobile technology, advocating for safe communities that encourage active lifestyles). Future research should inform definitive clinical guidelines for the use of exercise to ameliorate toxicities from cancer and its treatment. PMID- 29713478 TI - Reliability and validity of the Korean version of organizational justice questionnaire. AB - Background: Many studies show that organizational justice (OJ) is related to psychological determinants of employee health. To prevent health problems related to OJ in Korean workplaces and to accurately measure OJ, we developed the Korean version of the Organizational Justice Questionnaire (K-OJQ) and assessed its validity and reliability. Methods: A questionnaire draft of the K-OJQ was developed using back-translation methods, which was preliminary tested by 32 employees in Korea. Feedback was received and the K-OJQ was finalized. This study used data from 303 workers (172 males, 131 females) in Korea using the K-OJQ, job stress, and lifestyle questionnaires. Results: Cronbach's alpha coefficients of the internal consistency reliability was 0.92 for procedural justice and 0.94 for interactional justice. Factor analyses using SPSS 24 and Amos 23 extracted two expected factors, named procedural justice (7 items; range, 1.0-5.0) and interactional justice (6 items; range, 1.0-5.0) and showed a reliable fit (chi2 = 182; p = .000; GFI = .912; AGFI = .877; CFI = .965; RMSEA = .077). Furthermore, higher procedural justice and interactional justice levels were correlated with lower job demand (- 0.33; - 0.36), insufficient job control (- 0.36; - 0.41), interpersonal conflict (- 0.45; - 0.51), job insecurity (- 0.33; - 0.34), organizational system (- 0.64; - 0.64), and lack of reward (- 0.55; - 0.63). Conclusions: The K-OJQ was objectively validated through statistical methods. PMID- 29713479 TI - Pulmonary involvement in Fabry disease: effect of plasma globotriaosylsphingosine and time to initiation of enzyme replacement therapy. AB - Introduction: Anderson-Fabry disease (AFD) is an X-linked lysosomal storage disorder caused by mutations of GLA gene leading to reduced alpha-galactosidase activity and resulting in a progressive accumulation of globotriaosylceramide (Gb3) and its deacylated derivative, globotriaosyl-sphingosine (Lyso-Gb3). Plasma Lyso-Gb3 levels serve as a disease severity and treatment monitoring marker during enzyme replacement therapy (ERT). Methods: Adult patients with AFD who had yearly pulmonary function tests between 1999 and 2015 were eligible for this observational study. Primary outcome measures were the change in z-score of forced expiratory volume in the first second (FEV1) and FEV1/FVC over time. Plasma Lyso-Gb3 levels and the age of ERT initiation were investigated for their association with lung function decline. Results: Fifty-three patients (42% male, median (range) age at diagnosis of AFD 34 (6-61) years in men, 34 (13-67) in women) were included. The greatest decrease of FEV1/FVC z-scores was observed in Classic men (-0.048 per year, 95% CI -0.081 to -0.014), compared with the Later Onset men (+0.013,95% CI -0.055 to 0.082), Classic women (-0.008, 95% CI -0.035 to +0.020) and Later-Onset women (-0.013, 95% CI -0.084 to +0.058). Cigarette smoking (P=0.022) and late ERT initiation (P=0.041) were independently associated with faster FEV1 decline. FEV1/FVC z-score decrease was significantly reduced after initiation of ERT initiation (-0.045 compared with -0.015, P=0.014). Furthermore, there was a trend towards a relevant influence of Lyso-Gb3 (P=0.098) on airflow limitation with age. Conclusion: Early ERT initiation seems to preserve pulmonary function. Plasma Lyso-Gb3 is maybe a useful predictor for airflow limitation. Classic men need a closer monitoring of the lung function. PMID- 29713480 TI - Real-world crude incidence of hypoglycemia in adults with diabetes: Results of the InHypo-DM Study, Canada. AB - Objective: Very few real-world studies have been conducted to assess the incidence of diabetes-related hypoglycemia. Moreover, there is a paucity of studies that have investigated hypoglycemia among people taking secretagogues as a monotherapy or in combination with insulin. Accordingly, our research team developed and validated the InHypo-DM Person with Diabetes Mellitus Questionnaire (InHypo-DMPQ) with the aim of capturing the real-world incidence of self reported, symptomatic hypoglycemia. The questionnaire was administered online to a national sample of Canadians (>=18 years old) with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) treated with insulin and/or insulin secretagogues. Research design and methods: Self-report data obtained from the InHypo-DMPQ were descriptively analyzed to ascertain the crude incidence proportions and annualized incidence densities (rates) of 30-day retrospective non-severe and 1-year retrospective severe hypoglycemia, including daytime and nocturnal events. Results: A total of 552 people (T2DM: 83%; T1DM: 17%) completed the questionnaire. Over half (65.2%) of the total respondents reported experiencing at least one event (non-severe or severe) at an annualized crude incidence density of 35.1 events per person-year. The incidence proportion and rate of non-severe events were higher among people with T1DM versus T2DM (77% and 55.7 events per person-year vs 54% and 28.0 events per person-year). Severe hypoglycemia was reported by 41.8% of all respondents, at an average rate of 2.5 events per person-year. Conclusions: The results of the InHypo-DMPQ, the largest real-world investigation of hypoglycemia epidemiology in Canada, suggest that the incidence of hypoglycemia among adults with diabetes taking insulin and/or insulin secretagogues is higher than previously thought. PMID- 29713481 TI - Intent-to-treat analysis of a simultaneous multisite telehealth diabetes prevention program. AB - Objective: Determine the effectiveness of a 16-week modified diabetes prevention program (DPP) administered simultaneously to multiple rural communities from a single urban site, as compared with a similar face-to-face intervention. A 12 week intervention was evaluated to consider minimization of staff costs in communities where resources are limited. Research design and methods: A prospective cohort study compared DPP interventions implemented in rural (via telehealth technology) and urban (face-to-face) communities using an intent-to treat analysis. Primary outcome measures included 5% and 7% body weight loss. Logistic regression analyses were used to determine predictors of intervention success and included a variable for treatment effect. Results: Between 2010 and 2015, up to 667 participants were enrolled in the study representing one urban and 15 rural communities across Montana. The 16-week urban and rural interventions were comparable; 33.5% and 34.6% of participants lost 7% body weight, respectively; 50% and 47% lost 5% (p=0.22). Participants who were male (OR=2.41; 95% CI 1.32 to 4.40), had lower baseline body mass index (OR=1.03; 95% CI 1.01 to 1.07), attended more sessions (OR=1.33; 95% CI 1.11 to 1.58), and more frequently reported (OR=3.84; 95% CI 1.05 to 14.13) and met daily fat gram (OR=4.26; 95% CI 1.7 to 10.6) and weekly activity goals (OR=2.46; 95% CI 1.06 to 5.71) were more likely to meet their 7% weight loss goal. Predictors of meeting weight loss goals were similar for participants enrolled in the 12-week intervention. Conclusions: Using telehealth technology to administer a modified DPP to multiple rural communities simultaneously demonstrated weight loss results comparable to those in a face-to-face intervention. Given the limitation of resources, linking rural areas to urban centers using telemedicine may increase access to much needed services to prevent or delay progression to diabetes. PMID- 29713482 TI - Impact of periodontitis as representative of chronic inflammation on long-term clinical outcomes in patients with atrial fibrillation. AB - Objectives: Relationship between atrial fibrillation (AF) and inflammation was shown in previous studies. However, there was limited data about the association between the periodontitis and AF in the long-term follow-up. The aim of this study was to evaluate the impact of periodontitis on long-term clinical outcomes in patients with AF. Methods: The Kosin University echocardiography, ECG and periodontitis database were reviewed from 2013 to 2015 to identify patients with AF. Those patients were divided into two groups according to the presence of periodontitis and clinical events including any arrhythmic attack, thromboembolic and bleeding and death were collected during a median of 18 months. Results: Among 227 patients with AF, 47 (20.7%) patients had periodontitis. Major adverse cardiac events (MACE) were significantly higher in patients with periodontitis compared with those without periodontitis (p<0.001). Arrhythmias including AF, atrial tachycardia, atrial premature beat, ventricular tachycardia and ventricular premature beat also occurred in 44 (93.6%) patients, which was higher significantly higher incidence in patients with periodontitis than in those without periodontitis (p<0.001). In univariate analysis, age, CHA2DS2-VASc, left atrial volume index (LAVi) and periodontitis were significantly associated with arrhythmic events and MACE including bleeding events, thromboembolic events, arrhythmic events and mortality. In multivariate analysis, LAVi (p=0.005) and periodontitis (p<0.001) were independent risk factors for arrhythmic events and periodontitis (p<0.001) for MACE at the long-term follow-up. Conclusions: The periodontitis as representative of chronic inflammation was an independent predictor of arrhythmic events and MACE in patients with AF. PMID- 29713483 TI - Risk prediction in stable cardiovascular disease using a high-sensitivity cardiac troponin T single biomarker strategy compared to the ESC-SCORE. AB - Objective: To evaluate the prognostic performance of high-sensitivity cardiac troponin T (hs-cTnT) compared with the ESC-SCORE. Methods: We included low-risk outpatients with stable cardiovascular (CV) disease categorised into need for non secondary and secondary prevention. The prognostication of hs-cTnT at index visit was compared with the European Society of Cardiology-Systematic COronary Risk Evaluation (ESC-SCORE) with respect to all-cause mortality (ACM) and two composite endpoints (ACM, acute myocardial infarction (AMI) and stroke and ACM, AMI, stroke and rehospitalisation for acute coronary syndrome (ACS) and decompensated heart failure (DHF)). Results: Within a median follow-up of 796 days, a total of 16 deaths, 32 composite endpoints of ACM, AMI and stroke and 83 composite endpoints of ACM, AMI, stroke, rehospitalisation for ACS and DHF were observed among 693 stable low-risk outpatients. Using C-statistics, measurement of hs-cTnT alone outperformed the ESC-SCORE for the prediction of ACM in the entire study population (Deltaarea under the curve (AUC) 0.221, p=0.0039) and both prevention groups (non-secondary: DeltaAUC 0.164, p=0.0208; secondary: DeltaAUC 0.264, p=0.0134). For the prediction of all other secondary endpoints, hs-cTnT was at least as effective as the ESC-SCORE, both in secondary and non secondary prevention. Using continuous and categorical net reclassification improvement and integrated discrimination improvement, hs-cTnT significantly improved reclassification regarding all endpoints in the entire population and in the secondary prevention cohort. In non-secondary prevention, hs-cTnT improved reclassification only for ACM. The results were confirmed in an independent external cohort on 2046 patients. Conclusions: Hs-cTnT is superior to the multivariable ESC-SCORE for the prediction of ACM and a composite endpoint in stable outpatients with and without relevant CV disease. Trial registration number: NCT01954303; Pre-results. PMID- 29713484 TI - Impact of transcatheter aortic valve implantation on the risk of mortality in patients with severe aortic valve diseases: a health insurance-based analysis. AB - Background: Transcatheter aortic valve implantation (TAVI) is a minimally invasive treatment for aortic valve patients who are inoperable or have a prohibitively high surgical risk for surgical aortic valve replacement (SAVR). Most studies compare the efficacy of TAVI and SAVR, yet the assessment of TAVI for this group of patients requires more study. Methods: This quasiexperimental study compares TAVI cases (ages of 75-90 years, n=187) ex-post with a control group without implantation (n=728, 4:1 ratio intended). The control group was drawn randomly on the condition that it matches the TAVI cases based on age at aortic valve disease incidence, gender and comorbidity index. The mortality risk is analysed from incident diagnosis. Data were taken from three random samples of health claims data in Germany's largest public health insurance (Allgemeine Ortskrankenkassen) and cover the years 2004-2013 (n=750 000). Results: Compared with the medically treated control group with 6+ comorbidities, medically treated patients with fewer comorbidities have half the mortality risk (HR 0.48, 95% CI 0.34 to 0.69, p<0.001). TAVI patients with fewer than six comorbidities show a mortality risk half that (HR 0.23, 95% CI 0.09 to 0.63, p=0.004). TAVI patients with 6+ comorbidities do not benefit from TAVI compared with the control group with 6+ comorbidities (HR 0.99, 95% CI 0.71 to 1.36, p=0.93). Conclusion: TAVI is an effective therapy for aortic valve disease patients with few comorbidities; it is not effective for patients with a high comorbidity burden. Careful assessment of the individual patient in terms of comorbidities is important for a beneficial outcome. PMID- 29713485 TI - Strengths and weaknesses of 'real-world' studies involving non-vitamin K antagonist oral anticoagulants. AB - Randomised controlled trials (RCTs) provide the reference standard for comparing the efficacy of one therapy or intervention with another. However, RCTs have restrictive inclusion and exclusion criteria; thus, they are not fully representative of an unselected real-world population. Real-world evidence (RWE) studies encompass a wide range of research methodologies and data sources and can be broadly categorised as non-interventional studies, patient registries, claims database studies, patient surveys and electronic health record studies. If appropriately designed, RWE studies include a patient population that is far more representative of unselected patient populations than those of RCTs, but they do not provide a robust basis for comparing treatment strategies. RWE studies can have very large sample sizes, can provide information on treatments in patient groups that are usually excluded from RCTs, are generally less expensive and quicker than RCTs, and can assess a broad range of outcomes. Limitations of RWE studies can include low internal validity, lack of quality control surrounding data collection and susceptibility to multiple sources of bias for comparing outcomes. RWE studies can complement the findings from RCTs by providing valuable information on treatment practices and patient characteristics among unselected patients. This information is necessary to guide treatment decisions and for reimbursement and payment decisions. RWE studies have been extensively applied in the postmarketing approval assessment of non-vitamin K antagonist oral anticoagulants since 2010. However, the benefits, costs, limitations and methodological challenges associated with the different types of RWE must be considered carefully when interpreting the findings. PMID- 29713486 TI - Plasma cytokines and risk of coronary heart disease in the PROCARDIS study. AB - Objective: The aims of the study were to examine the associations of plasma levels of five cytokines (interleukin (IL)-6, IL-5, interferon-gamma (IFN-gamma), tumour necrosis factor-alpha (TNF-alpha) and IL-6 receptor (IL-6R)) and C reactive protein (CRP) with risk of coronary heart disease (CHD). Methods: In a case-control study of 931 CHD cases and 974 controls, logistic regression was used to estimate the OR and 95% CI of CHD for extreme thirds of biomarkers after adjustment for established risk factors. Sensitivity analyses were conducted in non-statin and in non-aspirin users. Results: Plasma levels of CRP were moderately correlated with IL-6 (r=0.45) in controls, but more weakly correlated with other cytokines. Likewise, all other cytokines were only weakly correlated with each other. After adjustment for established risk factors, the ORs (95% CI) for CHD comparing extreme thirds of cytokine levels (defined in controls) were 2.53 (1.86 to 3.43) for IL-6, 1.46 (1.11 to 1.93) for IL-5 and 1.46 (1.09 to 1.95) for IFN-gamma, respectively. However, neither TNF-alpha, IL-6R nor CRP was significantly associated with CHD. After further adjustment for the associated cytokines, only IL-5 (1.34; 1.00 to 1.80) and IL-6 (2.39; 1.73 to 3.30) remained significantly associated with CHD. The risk associations of cytokines in non users of statins or aspirin were comparable with the overall population. Conclusions: This study confirmed the importance of IL-6 as the most strongly associated cytokine with CHD risk, but also demonstrated novel and independent associations of IL-5 with CHD that warrant further investigation using larger panels of cytokines. PMID- 29713487 TI - Everolimus induced pneumonitis in a lung transplant recipient. AB - Everolimus is a mechanistic target of rapamycin inhibitor used for the treatment of various cancers and prevention of allograft rejection in solid organ transplantation. We present a case of a lung transplant recipient on everolimus who was admitted with generalized weakness, hypoxia and new onset bilateral pulmonary infiltrates on imaging. Extensive workup revealed no infectious etiology and high levels of serum everolimus levels. Her condition deteriorated over the hospital course with symptoms and signs of systemic everolimus toxicity. She was treated with high-dose steroids with significant improvement. Follow-up imaging showed resolution of infiltrates. Everolimus induced pneumonitis is seldom reported in the lung transplant literature. It is important to recognize early signs of toxicity to intervene and preserve the lung allograft. PMID- 29713488 TI - Progressive renal insufficiency related to ALK inhibitor, alectinib. AB - Alectinib is a second generation anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor and is generally effective and tolerated in patients who have demonstrated disease progression or adverse effects while on the first generation inhibitor, crizotinib. ALK inhibitors can cause a reversible chronic increase of serum creatinine concentration; however, they rarely induce progressive renal insufficiency. We herein report a case of a 68-year-old woman diagnosed with ALK positive advanced non-small cell lung cancer and who received ALK inhibitors. Due to dysgeusia and transaminitis, her medication was switched from crizotinib to alectinib. Rapid progressive glomerulonephritis developed 1 year after the initiation of alectinib treatment. A renal biopsy revealed unique kidney lesions in both tubules and glomeruli. Glucocorticoid therapy partially reversed kidney impairment. However, re-administration of alectinib caused kidney dysfunction, which was improved by the cessation of alectinib. Our case suggests that much attention should be paid to kidney function when using ALK inhibitors. PMID- 29713490 TI - Clinical characteristics and comorbidities of elderly asthmatics who attend allergy clinics. AB - Background: To date, few studies have focused on the clinical and allergic characteristics of asthma in the elderly, defined as asthma in people aged 60 or over. Thus, we propose to identify and study the clinical and allergic characteristics and comorbidities of patients with asthma among the elderly. Methods: A retrospective, observational, descriptive study was developed in five clinics and hospitals in Argentina. Allergy Physicians analyzed their patients' medical records in 2014 and included those adults over the age of 60, who had been diagnosed with asthma according to the GINA guidelines. Clinical and allergic characteristics were analyzed. Results: A total of 152 patients diagnosed with asthma, of whom 73% were women and 11% ex-smokers, were included in this study, with a mean age of 66 years. Only 10.5% of the participants had onset asthma past the age of 60. Regarding asthma severity, 74.3% were diagnosed with moderate persistent asthma, and 7.2% with severe persistent asthma. Eighty four percent of the patients were treated with an inhaled corticosteroid (ICS) along with a long-acting beta 2-adrenergic agent (LABA). More than half of the patients had two or more comorbidities simultaneously. Allergic comorbidities were the most frequent comorbidities, followed by arterial hypertension. Among allergic comorbidities, most patients presented allergies at the nasal level. There were no significant differences between the subpopulations of patients with late-onset asthma (LOA) and asthma with onset before the age of 60, i.e. early onset asthma (EOA) in most of their clinical characteristics. However, it was observed that EOA accounted for a higher percentage of patients with nasal allergies as compared to LOA (71% vs 46%, p < 0.05).It is worth mentioning that almost half of the patients with LOA had allergies at the nasal level. Conclusion: These results may provide a better understanding of the clinical characteristics of asthma in the elderly in Argentina, thus, enabling the development of future therapeutic strategies and a better quality of life for our elderly asthma patients. PMID- 29713489 TI - Regulation of plant cell wall degradation by light in Trichoderma. AB - Trichoderma reesei (syn. Hypocrea jecorina) is the model organism for industrial production of plant cell wall degradating enzymes. The integration of light and nutrient signals for adaptation of enzyme production in T. reesei emerged as an important regulatory mechanism to be tackled for strain improvement. Gene regulation specific for cellulase inducing conditions is different in light and darkness with substantial regulation by photoreceptors. Genes regulated by light are clustered in the genome, with several of the clusters overlapping with CAZyme clusters. Major cellulase transcription factor genes and at least 75% of glycoside hydrolase encoding genes show the potential of light dependent regulation. Accordingly, light dependent protein complex formation occurs within the promoters of cellulases and their regulators. Additionally growth on diverse carbon sources is different between light and darkness and dependent on the presence of photoreceptors in several cases. Thereby, also light intensity plays a regulatory role, with cellulase levels dropping at higher light intensities dependent in the strain background. The heterotrimeric G-protein pathway is the most important nutrient signaling pathway in the connection with light response and triggers posttranscriptional regulation of cellulase expression. All G protein alpha subunits impact cellulase regulation in a light dependent manner. The downstream cAMP pathway is involved in light dependent regulation as well. Connections between the regulatory pathways are mainly established via the photoreceptor ENV1. The effect of photoreceptors on plant cell wall degradation also occurs in the model filamentous fungus Neurospora crassa. In the currently proposed model, T. reesei senses the presence of plant biomass in its environment by detection of building blocks of cellulose and hemicellulose. Interpretation of the respective signals is subsequently adjusted to the requirements in light and darkness (or on the surface versus within the substrate) by an interconnection of nutrient signaling with light response. This review provides an overview on the importance of light, photoreceptors and related signaling pathways for formation of plant cell wall degrading enzymes in T. reesei. Additionally, the relevance of light dependent gene regulation for industrial fermentations with Trichoderma as well as strategies for exploitation of the observed effects are discussed. PMID- 29713491 TI - Simplified antibiotic regimens for treating neonates and young infants with severe infections in the Democratic Republic of Congo: a comparative efficacy trial. AB - Background: One-quarter of neonatal and infant deaths are due to infection, and the majority of these deaths occur in developing countries. Standard treatment for infection, which includes parenteral treatment only, is often not available in low-resource settings. Infant mortality will not be reduced in developing countries without a reduction in deaths due to infection. We participated in a multi-site trial that demonstrated the effectiveness of three simplified antibiotic regimens compared to standard treatment (The AFRINEST Trial: parent study). For this report, we examined the site-specific data for the Democratic Republic Congo (DRC), the most impoverished of the countries that participated in the study, to determine if outcomes in the DRC were similar to outcomes across all sites. Methods: The parent study was an individually randomized, open-label, equivalence trial. Infants with clinical signs of severe infection were randomized to receive one of four regimens: 1) injectable penicillin-gentamicin for 7 days (standard therapy; regimen A), 2) injectable gentamicin and oral amoxicillin for 7 days (regimen B), 3) injectable penicillin-gentamicin for 2 days then oral amoxicillin for 5 days (regimen C), or 4) injectable gentamicin for 2 days and oral amoxicillin for 5 days (regimen D). In the DRC, we enrolled 574 infants, of whom 560 met the per-protocol criteria for analysis of treatment effect. The main outcome was treatment failure within the first week of enrollment. Results: Treatment failure occurred in 52 (9.3%) infants: 17 (11.6%) with the referent treatment regimen, 13 (9.6%) with regimen B (risk difference [RD] -2.0%; CI -9.2% to 5.2%), 13 (9.0%) with regimen C (RD -2.6%; CI -9.6% to 4.4%), and 9 (6.7%) with regimen D (RD -5.0%; CI -11.7% to 1.7%). Conclusion: As in the parent study, the risk difference between each of the experimental treatments and the reference treatment suggests equivalence. These findings suggest that the conclusion from the parent study, that a simplified antibiotic regimen can be used for the community-based management of possible severe infection in young infants where referral to a hospital for standard care is often not possible, is true in the DRC. We speculate that the widespread use of a simplified, community-based treatment could result in increased coverage with treatment and improved survival in poor areas. Trial registration: ACTRN12610000286044 on April 9, 2010. PMID- 29713492 TI - Effect of cold stress on infanticide by female Swiss albino mice Mus musculus: a pilot study. AB - Background: Mice are widely accepted research models of great clinical significance. Maintenance of laboratory mice breed is an essential aspect for performing research activities in various fields of science. Infanticide is one of the prominent causes of litter loss during maintenance of laboratory mice stock. The present study is an effort to monitor the effect of change in ambient temperature of female mice below the normal range on cannibalism and infanticide during early postparturition phase. Adult female Swiss albino mice have been divided into two groups of control and treatment. On the day of litter group one was maintained under controlled temperature conditions (minimum 20 degrees C to maximum 23 degrees C) throughout, while female mice belong to group two have been exposed to variation of room temperature (maximum 15 degrees C to minimum 10 degrees C for two nights and one day) until 36 h postparturition. Results: The effects of temperature changes were observed on the infanticide behaviour of dams along with the survival of pups in early postparturition phase till 36 h after delivery. The significant statistical difference (P < 0.05) was reported in infanticide behaviour of dams when control and treatment group was compared. It is observed that decrement in surrounding temperature promotes decrement in the ambient body temperature of dams during early postparturition. It is proposed that alteration of hypothalamic homeostasis due to temperature change induces cannibalism and infanticide behaviour. Lack of thermoregulation during early postparturition creates the sense of insecurity, in-satiety, anxiety and stress. Conclusions: Authors strongly recommend the maintenance of body and surrounding temperature to prevent infanticidal behaviour and cannibalism within Swiss albino mice population. Further investigations are advisable to authenticate the active behavioural and biochemical pathway behind the phenomena. PMID- 29713493 TI - Prophylaxis of acute respiratory infections via improving the immune system in late preterm newborns with E. coli strain Nissle 1917: a controlled pilot trial. AB - Background: Acute respiratory infections (ARIs), caused by the high level of immaturity of the immune system, are a major cause of morbidity in preterm newborns. The probiotic Escherichia coli strain Nissle 1917 (EcN) is well known for its immuno-modulatory properties and may therefore enhance the immune competence. Thus, EcN administration may provide a promising possibility to decrease the risk of ARIs in this vulnerable group of children. However, clinical data supporting or refuting this hypothesis are, to our knowledge, not available. Therefore, the aim of the presented pilot trial was to collect first data on the efficacy and safety of EcN treatment to prevent ARIs in late preterm newborns. Methods: Right after birth, 62 late preterm newborns were included into an open labeled, controlled 4-week trial with two parallel groups and a follow-up phase until the age of 1 year. All children of the treatment group received an EcN suspension orally for 3 weeks, whereas the control group was only observed. Primary efficacy variable was the number of participants with at least one ARI during the first 28 days of life. Secondary efficacy variables were the number of ARIs and the number and duration of hospitalizations caused by ARIs during the first year of life. Results: The number of participants with at least one ARI during the first 28 days of life was significantly lower in the group treated with EcN compared to that in the control group. Although only of exploratory nature, analyses of secondary efficacy variables suggest that EcN treatment may also reduce the average number of ARIs, the average number of hospitalizations caused by ARIs, and the mean duration of such hospitalizations. There is also some evidence that early EcN treatment may have long-term benefits on newborns' health status. Conclusion: The present pilot trial provides first evidence that EcN is able to reduce the incidence of ARIs in the neonatal period of late preterm newborns. Additionally, EcN is characterized by an excellent individual biocompatibility in the absence of adverse drug reactions. Limitations of the current trial are discussed and recommendations for future confirmatory studies are made. Trial registration: ClinicalTrials.gov identifier: NCT01540162; retrospectively registered on 16 February 2012. PMID- 29713494 TI - Developing and feasibility testing of data collection methods for an economic evaluation of a supported selfmanagement programme for adults with a learning disability and type 2 diabetes. AB - Background: The challenges of conducting research with hard to reach vulnerable groups are particularly pertinent for people with learning disabilities. Data collection methods for previous cost and cost-effectiveness analyses of health and social care interventions targeting people with learning disabilities have relied on health care/health insurance records or data collection forms completed by the service provider rather than by people with learning disabilities themselves. This paper reports on the development and testing of data collection methods for an economic evaluation within a randomised controlled trial (RCT) for a supported self-management programme for people with mild/moderate learning disabilities and type 2 diabetes. Methods: A case finding study was conducted to identify types of health and social care use and data collection methods employed in previous studies with this population. Based on this evidence, resource use questionnaires for completion by GP staff and interviewer-administered participant questionnaires (covering a wider cost perspective and health-related quality of life) were tested within a feasibility RCT. Interviewer-administered questionnaires included the EQ-5D-3L (the NICE recommended measure for use in economic evaluation). Participants were adults > 18 years with a mild or moderate learning disability and type 2 diabetes, with mental capacity to give consent to research participation. Results: Data collection for questionnaires completed by GP staff requesting data for the last 12 months proved time intensive and difficult. Whilst 82.3% (121/147) of questionnaires were returned, up to 17% of service use items were recorded as unknown. Subsequently, a shorter recall period (4 months) led to a higher return rate but with a higher rate of missing data. Missing data for interviewer-administered participant questionnaires was > 8% but the interviewers reported difficulty with participant recall. Almost 60% (48/80) of participants had difficulty completing the EQ-5D-3L. Conclusions: Further investigation as to how service use can be recorded is recommended. Concerns about the reliability of identifying service use data directly from participants with a learning disability due to challenges in completion, specifically around recall, remain. The degree of difficulty to complete EQ-5D-3L indicates concerns regarding the appropriateness of using this measure in its current form in research with this population. Trial registration: Current Controlled Trials ISRCTN41897033 (registered 21 January 2013). PMID- 29713495 TI - High out-of-clinic blood pressure is associated with adiposity indicators in leisure physical activity practitioners in Midwest Brazil. AB - Background: Several diseases, such as obesity, hypertension and type 2 diabetes are frequently associated with metabolic abnormalities, high costs of healthcare and morbi-mortality; thus the aim of this study was to investigate the relationship between out-of-clinic high blood pressure and chronic disease associated adiposity indicators in practitioners of leisure physical activity. Methods: A cross-sectional study with 414 subjects of both genders aged 24-65 years. Data were collected by trained interviewers in five public parks. Body Mass Index (BMI), triceps skinfold and waist circumference (WC) were evaluated. Exercise training, smoking status, alcohol consumption and hypertension diagnosis were self-reported. Casual glycemia concentrations were collected and blood pressure was measured out-of-clinic once during the study. Participants with systolic >=140 mmHg and diastolic >=90 mmHg blood pressures were classified as high blood pressure. All analyses were adjusted for age and sex. Results: High blood pressure was diagnosed in 31.4% (n = 130), but 34 (8.3%) from patients took medication anti-hypertensive and were previously hypertension diagnosed. Participants with high blood pressure had a higher BMI (25.66 vs. 26.87 kg/m2; p = 0.012), WC (90.92 vs. 95.02 cm; p = 0.001), and systolic and diastolic blood pressure (p < 0.0001) when compared to subjects with normal blood pressure. Logistic regression analysis revealed that overweight status assessed by BMI, triceps skinfold and WC increases the high blood pressure probability by approximately 1.61 (95 CI%: 1.06-2.45), 1.02 (95%CI: 1.01-1.05) and 1.61 (95%CI: 1.06-2.45), respectively. Conclusions: Adiposity indicators are associated with high out-of-clinic blood pressure measured in practitioners of leisure physical activity. PMID- 29713496 TI - Choroidal thickness changes measured by enhanced depth imaging optical coherence tomography in third trimester pregnant women. AB - The aim of this article is to underline the effect of pregnancy on the variations of choroidal thickness caused by hormonal and haemodynamic changes. PMID- 29713497 TI - Patient-derived orthotopic xenograft models for cancer of unknown primary precisely distinguish chemotherapy, and tumor-targeting S. typhimurium A1-R is superior to first-line chemotherapy. AB - Cancer of unknown primary (CUP) is a recalcitrant disease with poor prognosis because it lacks standard first-line therapy. CUP consists of diverse malignancy groups, making personalized precision therapy essential. The present study aimed to identify an effective therapy for a CUP patient using a patient-derived orthotopic xenograft (PDOX) model. This paper reports the usefulness of the PDOX model to precisely identify effective and ineffective chemotherapy and to compare the efficacy of S. typhimurium A1-R with first-line chemotherapy using the CUP PDOX model. The present study is the first to use a CUP PDOX model, which was able to precisely distinguish the chemotherapeutic course. We found that a carboplatinum (CAR)-based regimen was effective for this CUP patient. We also demonstrated that S. typhimurium A1-R was more effective against the CUP tumor than first-line chemotherapy. Our results indicate that S. typhimurium A1-R has clinical potential for CUP, a resistant disease that requires effective therapy. PMID- 29713498 TI - Association of baseline absolute neutrophil counts and survival in patients with metastatic colorectal cancer treated with second-line antiangiogenic therapies: exploratory analyses of the RAISE trial and validation in an electronic medical record data set. AB - Background: In the RAISE trial, ramucirumab+leucovorin/fluorouracil/irinotecan (FOLFIRI) improved the median overall survival (mOS) of patients with previously treated metastatic colorectal cancer versus patients treated with placebo+FOLFIRI but had a higher incidence of neutropaenia, leading to more chemotherapy dose modifications and discontinuations. Thus, we conducted an exploratory post-hoc analysis of RAISE and a retrospective, observational analysis of electronic medical record (EMR) data to determine and verify the association of neutropaenia, baseline absolute neutrophil count (ANC) and survival. Methods: The RAISE analysis used the study safety population (n=1057). IMS Health Oncology Database (IMS EMR) was the source for the real-world data set (n=617). Results: RAISE patients with treatment-emergent neutropaenia had improved mOS compared with those without (ramucirumab arm: 16.1 vs 10.7 months, HR=0.57, p<0.0001; placebo arm: 12.7 vs 10.7 months, HR=0.76, p=0.0065). RAISE patients with low ANC versus high baseline ANC also had longer mOS (ramucirumab arm: 15.2 vs 8.9 months, HR=0.49, p<0.0001; placebo arm: 13.2 vs 7.3 months, HR=0.50, p<0.0001). The results were similar for IMS EMR low versus high baseline ANC (bevacizumab+FOLFIRI patients: 14.9 vs 7.7 months, HR=0.59, p<0.0001; FOLFIRI alone: 14.6 vs 5.4 months, HR=0.37, p<0.0001). Patients in the RAISE trial with low baseline ANC were more likely to develop neutropaenia (OR: ramucirumab arm=2.62, p<0.0001; placebo arm=2.16, p=0.0003). Conclusion: Neutropaenia during treatment, and subsequent dose modifications or discontinuations, do not compromise treatment efficacy. Baseline ANC is a strong prognostic factor for survival and is associated with treatment-emergent neutropaenia in the analysed population. Trial registration number: NCT01183780, Results. PMID- 29713499 TI - Safety data from the phase III Japanese ACHIEVE trial: part of an international, prospective, planned pooled analysis of six phase III trials comparing 3 versus 6 months of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer. AB - Background: The International Duration Evaluation of Adjuvant chemotherapy project investigated whether a shorter duration of oxaliplatin-based adjuvant chemotherapy was as effective as 6 months of identical chemotherapy for resected stage III colon cancer. As part of this project, we report safety data from the Japanese ACHIEVE study (JFMC47-1202-C3). Patients and methods: ACHIEVE was an open-label, multicentre trial randomising patients with stage III colon cancer to receive 3 m or 6 m of mFOLFOX6/CAPOX after surgery. Choice of regimen was declared before randomisation by a site investigator. Results: Between August 2012 and June 2014, 1313 patients were enrolled and, of those, 1277 were analysed for the safety analysis, with 635 in arm 6 (mFOLFOX6, n=158; CAPOX, n=477) and 642 in arm 3 (mFOLFOX6, n=161; CAPOX, n=481). Grade 3 or worse peripheral sensory neuropathy (PSN) developed in 5%/0.6% of patients receiving mFOLFOX6 in arm 6/3 (p=0.019) and 6%/1% of those receiving CAPOX in arm 6/3 (p<0.001). Similarly, grade 2 or worse PSN developed in 36%/11% of patients receiving mFOLFOX6 in arm 6/3 (p<0.001) and 37%/14% of those receiving CAPOX in arm 6/3 (p<0.001). An association between baseline creatinine clearance (CCr) and adverse events (AEs) was found that patients with CAPOX were significantly more likely to develop AEs >=grade 3 when they had a CCr <=50 (OR 1.67; p=0.048). Conclusions: We confirmed in the Japanese population that the shorter duration of adjuvant chemotherapy resulted in a significant reduction of PSN. In patients with CAPOX, renal function was significantly related to severe AEs. Trial registration number: UMIN000008543, Results. PMID- 29713500 TI - New data: new options for front-line therapy in NSCLC? PMID- 29713501 TI - Management of recurrent or metastatic thyroid cancer. AB - Recently, vascular endothelial growth factor receptor (VEGFR)-targeted tyrosine kinase inhibitors (TKIs) have become available for the treatment of recurrent or metastatic thyroid cancer. However, a number of clinical challenges that impact the use of VEGFR-targeted TKI in daily clinical practice have arisen. Toxicity is considerable, to the extent that most physicians hesitate to start VEGFR-targeted TKI and prefer to continue a watch-and-wait approach until the patient's disease markedly worsens. This delayed use of VEGFR-targeted TKI leads to a higher incidence of serious adverse events than was reported in clinical trials. Moreover, the watch-and-wait approach has several demerits, including a worsening of quality of life, worsening of outcomes in patients of older age or with follicular thyroid cancer and increased risk of brain metastasis or bleeding. Thus, optimal timing for the start of VEGFR-targeted TKI requires careful consideration. Moreover, management of VEGFR-targeted TKI toxicities requires appropriate supportive care, well-organised infrastructure in the outpatient clinic and patient education. Future treatment will progress to precision medicine based on molecular testing. Promotion of precision medicine requires the establishment of a system of easy access to molecular testing and the promotion of translational research for the development of new drugs. PMID- 29713503 TI - Mobile health messaging service and helpdesk for South African mothers (MomConnect): history, successes and challenges. AB - MomConnect is a flagship programme of the South African National Department of Health that has reached over 1.5 million pregnant women. Using mobile technology, MomConnect provides pregnant and postpartum women with twice-weekly health information text messages as well as access to a helpdesk for patient queries and feedback. In just 3 years, MomConnect has been taken to scale to reach over 95% of public health facilities and has reached 63% of all pregnant women attending their first antenatal appointment. The helpdesk has received over 300 000 queries at an average of 250 per day from 6% of MomConnect users. The service is entirely free to its users. The rapid deployment of MomConnect has been facilitated by strong government leadership, and an ecosystem of mobile health implementers who had experience of much of the content and technology required. An early decision to design MomConnect for universal coverage has required the use of text-based technologies (short messaging service and Unstructured Supplementary Service Data) that are accessible via even the most basic mobile phones, but cumbersome to use and costly at scale. Unlike previous mobile messaging services in South Africa, MomConnect collects the user's identification number and facility code during registration, enabling future linkages with other health and population databases and geolocated feedback. MomConnect has catalysed additional efforts to strengthen South Africa's digital health architecture. The rapid growth in smartphone penetration presents new opportunities to reduce costs, increase real time data collection and expand the reach and scope of MomConnect to serve health workers and other patient groups. PMID- 29713502 TI - Prevalence and determinants of terminated and unintended pregnancies among married women: analysis of pooled cross-sectional surveys in Nigeria. AB - Background: Induced pregnancy termination and unintended pregnancy are two commonly occurring phenomena in the discipline of women's reproductive health. In the present study, we explored cross-sectional data pooled from three rounds of Nigeria Demographic and Health Survey (NDHS) to understand the trends of prevalence of pregnancy termination and unintended pregnancy as well as the interplay of various sociodemographic and economic factors whereby these health issues occur. Methods: Study participants were 79 825 currently married women aged 15-49 years. Data were collected from NDHS conducted in 2003, 2008 and 2013. Outcome variables were self-reported history of pregnancy termination and unintended pregnancy for the last birth. Data were analysed using descriptive and multivariable logistic regression methods. Results: Mean (+/-SD) age of the respondents was 28.7 years (+/-9.6). The overall prevalence of pregnancy termination and unintended pregnancy were about 11%. Older women had increase in the odds of terminated pregnancies, compared with women aged 15-19 years, while the converse was true for unintended pregnancy in the adjusted model. Educated women had significant higher odds of terminated and unintended pregnancies compared with women with no formal education. Women with higher wealth index were more likely to have unintended and terminated pregnancies after adjusting for other covariates. Remarkably, women who had unintended pregnancy were 1.47 times as likely to have terminated pregnancy compared with those who had no unintended pregnancy (OR=1.47; 95% CI 1.30 to 1.65). Experience of intimate partner violence had significant association with terminated and unintended pregnancies. Conclusion: The findings of this study showed that unintended and terminated pregnancies remain part of the issues to be addressed if the goal of ensuring healthy lives and promoting the well-being for all at all ages must be met. Stakeholders in Nigerian healthcare system should protect the lives of women who are vulnerable to the fatal consequences of unsafe abortion, especially in cases of rape, sexual assault, incest and where continuing a pregnancy would endanger the lives of women. PMID- 29713504 TI - User assessments and the use of information from MomConnect, a mobile phone text based information service, by pregnant women and new mothers in South Africa. AB - MomConnect was designed to provide crucial health information to mothers during pregnancy and in the early years of child rearing in South Africa. The design drew on the success of the Mobile Alliance for Maternal Action's programme in South Africa, as well as a growing list of mobile health (mHealth) interventions implemented internationally. Services such as MomConnect are dependent on user acceptability as all engagements are voluntary, meaning that tools have to be easy to use and useful to be successful. This paper describes the evaluation of the tool by pregnant women and new mothers using the tool. A purposive sample of 32 individual semistructured interviews and 7 focus groups were conducted, across five provinces in South Africa. All the sessions were transcribed and then analysed using a contextualised interpretative approach, with the assistance of Atlas.ti. The women were consistently positive about MomConnect, attaching high value to the content of the messages and the medium in which they were delivered. The system was found to work well, with minor problems in some language translations. Respondents were enthusiastic about the messages, stating that the information was of great use and made them feel empowered in their role as a mother, with some saving the messages to use as a resource or to share with others. The most significant problems related to network coverage. There was strong support for this intervention to continue. Given the user acceptability of mHealth interventions, MomConnect appeared to meet the target of identifying and responding to the recipient's needs. PMID- 29713505 TI - Achieving scale, sustainability and impact: a donor perspective on a mobile health messaging service and help desk (MomConnect) for South African mothers. PMID- 29713506 TI - Designing for scale: optimising the health information system architecture for mobile maternal health messaging in South Africa (MomConnect). AB - MomConnect is a national initiative coordinated by the South African National Department of Health that sends text-based mobile phone messages free of charge to pregnant women who voluntarily register at any public healthcare facility in South Africa. We describe the system design and architecture of the MomConnect technical platform, planned as a nationally scalable and extensible initiative. It uses a health information exchange that can connect any standards-compliant electronic front-end application to any standards-compliant electronic back-end database. The implementation of the MomConnect technical platform, in turn, is a national reference application for electronic interoperability in line with the South African National Health Normative Standards Framework. The use of open content and messaging standards enables the architecture to include any application adhering to the selected standards. Its national implementation at scale demonstrates both the use of this technology and a key objective of global health information systems, which is to achieve implementation scale. The system's limited clinical information, initially, allowed the architecture to focus on the base standards and profiles for interoperability in a resource constrained environment with limited connectivity and infrastructural capacity. Maintenance of the system requires mobilisation of national resources. Future work aims to use the standard interfaces to include data from additional applications as well as to extend and interface the framework with other public health information systems in South Africa. The development of this platform has also shown the benefits of interoperability at both an organisational and technical level in South Africa. PMID- 29713507 TI - Self-enrolment antenatal health promotion data as an adjunct to maternal clinical information systems in the Western Cape Province of South Africa. AB - Information systems designed to support health promotion in pregnancy, such as the MomConnect programme, are potential sources of clinical information which can be used to identify pregnancies prospectively and early on. In this paper we demonstrate the feasibility and value of linking records collected through the MomConnect programme, to an emergent province-wide health information exchange in the Western Cape Province of South Africa, which already enumerates pregnancies from a range of other clinical data sources. MomConnect registrations were linked to pregnant women known to the public health services using the limited identifiers collected by MomConnect. Three-quarters of MomConnect registrations could be linked to existing pregnant women, decreasing over time as recording of the national identifier decreased. The MomConnect records were usually the first evidence of pregnancy in pregnancies which were subsequently confirmed by other sources. Those at lower risk of adverse pregnancy outcomes were more likely to register. In some cases, MomConnect was the only evidence of pregnancy for a patient. In addition, the MomConnect records provided gestational age information and new and more recently updated contact numbers to the existing contact registry. The pilot integration of the data in the Western Cape Province of South Africa demonstrates how a client-facing system can augment clinical information systems, especially in contexts where electronic medical records are not widely available. PMID- 29713508 TI - Optimising mHealth helpdesk responsiveness in South Africa: towards automated message triage. AB - In South Africa, a national-level helpdesk was established in August 2014 as a social accountability mechanism for improving governance, allowing recipients of public sector services to send complaints, compliments and questions directly to a team of National Department of Health (NDoH) staff members via text message. As demand increases, mechanisms to streamline and improve the helpdesk must be explored. This work aims to evaluate the need for and feasibility of automated message triage to improve helpdesk responsiveness to high-priority messages. Drawing from 65 768 messages submitted between October 2016 and July 2017, the quality of helpdesk message handling was evaluated via detailed inspection of (1) a random sample of 481 messages and (2) messages reporting mistreatment of women, as identified using expert-curated keywords. Automated triage was explored by training a naive Bayes classifier to replicate message labels assigned by NDoH staff. Classifier performance was evaluated on 12 526 messages withheld from the training set. 90 of 481 (18.7%) NDoH responses were scored as suboptimal or incorrect, with median response time of 4.0 hours. 32 reports of facility-based mistreatment and 39 of partner and family violence were identified; NDoH response time and appropriateness for these messages were not superior to the random sample (P>0.05). The naive Bayes classifier had average accuracy of 85.4%, with >=98% specificity for infrequently appearing (<50%) labels. These results show that helpdesk handling of mistreatment of women could be improved. Keyword matching and naive Bayes effectively identified uncommon messages of interest and could support automated triage to improve handling of high-priority messages. PMID- 29713509 TI - The MomConnect helpdesk: how an interactive mobile messaging programme is used by mothers in South Africa. AB - South Africa's MomConnect mobile messaging programme, which aims to promote safe motherhood and improve pregnancy outcomes for South African women, includes a helpdesk feature which allows women registered on the system to ask maternal and child health (MCH)-related questions and to provide feedback on health services received at public health clinics. Messages sent to the helpdesk are answered by staff located at the National Department of Health. We examined event data from the MomConnect helpdesk database to identify any patterns in messages received, such as correlation of frequency or types of messages with location. We also explored what these data could tell us about the helpdesk's effectiveness in improving health service delivery at public health clinics. We found that approximately 8% of registered MomConnect users used the helpdesk, and that usage was generally proportional to the use of antenatal care (ANC) services in provinces (as indicated by number of ANC first visits and number of MomConnect registrations), except in two provinces. Language, category and key topics of helpdesk messages were correlated with provinces. Most users accessed the helpdesk to seek maternal information, and where feedback about health services was provided, there were significantly more compliments than complaints. The MomConnect helpdesk is an important resource providing expectant mothers and mothers of infants with an interactive option for accessing MCH-related information-above that included in the standard MomConnect messages-and advances achievement of the health goals of the MomConnect programme. PMID- 29713510 TI - Unpacking the performance of a mobile health information messaging program for mothers (MomConnect) in South Africa: evidence on program reach and messaging exposure. AB - Despite calls to address broader evidence gaps in linking digital technologies to outcome and impact level health indicators, limited attention has been paid to measuring processes pertaining to the performance of programs. In this paper, we assess the program reach and message exposure of a mobile health information messaging program for mothers (MomConnect) in South Africa. In this descriptive study, we draw from system generated data to measure exposure to the program through registration attempts and conversions, message delivery, opt-outs and drop-outs. Using a logit model, we additionally explore determinants for early registration, opt-outs and drop-outs. From August 2014 to April 2017, 1 159 431 women were registered to MomConnect; corresponding to half of women attending antenatal care 1 (ANC1) and nearly 60% of those attending ANC1 estimated to own a mobile phone. In 2016, 26% of registrations started to get women onto MomConnect did not succeed. If registration attempts were converted to successful registrations, coverage of ANC1 attendees would have been 74% in 2016 and 86% in 2017. When considered as percentage of ANC1 attendees with access to a mobile phone, addressing conversion challenges bring registration coverage to an estimated 83%-89% in 2016 and 97%-100% in 2017. Among women registered, nearly 80% of expected short messaging service messages were received. While registration coverage and message delivery success rates exceed those observed for mobile messaging programs elsewhere, study findings highlight opportunities for program improvement and reinforce the need for rigorous and continuous monitoring of delivery systems. PMID- 29713511 TI - Taking digital health innovation to scale in South Africa: ten lessons from MomConnect. PMID- 29713512 TI - Digital health vision: could MomConnect provide a pragmatic starting point for achieving universal health coverage in South Africa and elsewhere? PMID- 29713513 TI - Digital health in South Africa: innovating to improve health. PMID- 29713515 TI - The Role of TAL1 in Hematopoiesis and Leukemogenesis. AB - TAL1 (SCL/TAL1, T-cell acute leukemia protein 1) is a transcription factor that is involved in the process of hematopoiesis and leukemogenesis. It participates in blood cell formation, forms mesoderm in early embryogenesis, and regulates hematopoiesis in adult organisms. TAL1 is essential in maintaining the multipotency of hematopoietic stem cells (HSC) and keeping them in quiescence (stage G0). TAL1 forms complexes with various transcription factors, regulating hematopoiesis (E2A/HEB, GATA1-3, LMO1-2, Ldb1, ETO2, RUNX1, ERG, FLI1). In these complexes, TAL1 regulates normal myeloid differentiation, controls the proliferation of erythroid progenitors, and determines the choice of the direction of HSC differentiation. The transcription factors TAL1, E2A, GATA1 (or GATA2), LMO2, and Ldb1 are the major components of the SCL complex. In addition to normal hematopoiesis, this complex may also be involved in the process of blood cell malignant transformation. Upregulation of C-KIT expression is one of the main roles played by the SCL complex. Today, TAL1 and its partners are considered promising therapeutic targets in the treatment of T-cell acute lymphoblastic leukemia. PMID- 29713514 TI - "Social Life" of Senescent Cells: What Is SASP and Why Study It? AB - Cellular senescence was first described as a failure of normal human cells to divide indefinitely in culture. Until recently, the emphasis in the study of cell senescence has been focused on the accompanying intracellular processes. The focus of the attention has been on the irreversible growth arrest and two important physiological functions that rely on it: suppression of carcinogenesis due to the proliferation loss of damaged cells, and the acceleration of organism aging due to the deterioration of the tissue repair mechanism with age. However, the advances of the past years have revealed that senescent cells can impact the surrounding tissue microenvironment, and, thus, that the main consequences of senescence are not solely mediated by intracellular alterations. Recent studies have provided evidence that a pool of molecules secreted by senescent cells, including cytokines, chemokines, proteases and growth factors, termed the senescence-associated secretory phenotype (SASP), via autocrine/paracrine pathways can affect neighboring cells. Today it is clear that SASP functionally links cell senescence to various biological processes, such as tissue regeneration and remodeling, embryonic development, inflammation, and tumorigenesis. The present article aims to describe the "social" life of senescent cells: basically, SASP constitution, molecular mechanisms of its regulation, and its functional role. PMID- 29713516 TI - Pathogenesis of Type 1 Diabetes Mellitus and Rodent Experimental Models. AB - The global prevalence of diabetes mellitus and its severe complications is on the rise. The study of the pathogenesis of the onset and the progression of complications related to the disease, as well as the search for new therapeutic agents and methods of treatment, remains relevant. Experimental models are extremely important in the study of diabetes. This survey contains a synthesis of the most commonly used experimental animal models described in scientific literature. The mechanisms of the streptozotocin model are also analyzed and discussed, as it is considered as the most adequate and easily reproducible diabetes model. A review of the significant advantages and disadvantages of the described models has also been conducted. PMID- 29713517 TI - The Effect of TNF and VEGF on the Properties of Ea.hy926 Endothelial Cells in a Model of Multi-Cellular Spheroids. AB - Endothelial cells play a major role in the development of inflammation and neoangiogenesis in cancer and chronic inflammatory diseases. In 3D cultures, cells are under conditions that closely resemble those existing in healthy and disease-stricken human organs and tissues. Therefore, the development of a 3D model based on the Ea.hy926 endothelial cell line is an urgent need in molecular and cellular biology. Cell cultivation on an anti-adhesive substrate under static conditions was shown to lead to the formation of spheroids (3D cultures). Expression of ICAM-1 and VEGFR-2 and production of cytokines were screened in 2D and 3D cultures in the presence of TNF and VEGF. According to flow cytometry and confocal microscopy data, TNF significantly increased the expression of the cell adhesion molecule ICAM-1 in both 2D and 3D cultures but did not affect the expression level of VEGFR-2. Increased production of pro-inflammatory (IL-8, IL 6, IP-10) and anti-inflammatory (IL-10, TGF-beta 1-3) factors was observed in spontaneous 3D cultures but not in 2D cultures, which was confirmed by flow cytometry and qPCR. TNF-induced secretion of IL-10, GM-CSF, and IL-6 was 11-, 4.7 , and 1.6-fold higher, respectively, in 3D cultures compared to 2D cultures. Thus, the use of a Ea.hy926 3D cell culture is a promising approach in studying the effects of anti- and pro-inflammatory agents on endothelial cells. PMID- 29713518 TI - The PTENP1 Pseudogene, Unlike the PTEN Gene, Is Methylated in Normal Endometrium, As Well As in Endometrial Hyperplasias and Carcinomas in Middle-Aged and Elderly Females. AB - The tumor suppressor PTEN controls multiple cellular functions, including cell cycle, apoptosis, senescence, transcription, and mRNA translation of numerous genes. In tumor cells, PTEN is frequently inactivated by genetic mutations and epimutations. The aim of this study was to investigate the methylation patterns of the PTEN gene and its pseudogene PTENP1 as potential genetic markers of endometrial hyperplasia (EH) and endometrial carcinoma (EC). Methylation of the 5'-terminal regions of the PTEN and PTENP1 sequences was studied using methyl sensitive PCR of genomic DNA isolated from 57 cancer, 43 endometrial hyperplasia, and normal tissue samples of 24 females aged 17-34 years and 19 females aged 45 65 years, as well as 20 peripheral venous blood samples of EC patients. None of the analyzed DNA samples carried a methylated PTEN gene. On the contrary, the PTENP1 pseudogene was methylated in all analyzed tissues, except for the peripheral blood. Comparison of PTENP1 methylation rates revealed no differences between the EC and EH groups (0.80 < p < 0.50). In all these groups, the methylation level was high (71-77% in patients vs. 58% in controls). Differences in PTENP1 methylation rates between normal endometrium in young (4%) and middle aged and elderly (58%) females were significant (p < 0.001). These findings suggest that PTENP1 pseudogene methylation may reflect age-related changes in the body and is not directly related to the endometrium pathology under study. It is assumed that, depending on the influence of a methylated PTENP1 pseudogene on PTEN gene expression, the pseudogene methylation may protect against the development of EC and/or serve as a marker of a precancerous condition of endometrial cells. PMID- 29713519 TI - A Highly Productive CHO Cell Line Secreting Human Blood Clotting Factor IX. AB - Hemophilia B patients suffer from an inherited blood-clotting defect and require regular administration of blood-clotting factor IX replacement therapy. Recombinant human factor IX produced in cultured CHO cells is nearly identical to natural, plasma-derived factor IX and is widely used in clinical practice. Development of a biosimilar recombinant human factor IX for medical applications requires the generation of a clonal cell line with the highest specific productivity possible and a high level of specific procoagulant activity of the secreted factor IX. We previously developed plasmid vectors, p1.1 and p1.2, based on the untranslated regions of the translation elongation factor 1 alpha gene from Chinese hamster. These vectors allow one to perform the methotrexate- driven amplification of the genome-integrated target genes and co-transfect auxiliary genes linked to various resistance markers. The natural open reading frame region of the factor IX gene was cloned in the p1.1 vector plasmid and transfected to CHO DG44 cells. Three consecutive amplification rounds and subsequent cell cloning yielded a producer cell line with a specific productivity of 10.7 +/- 0.4 pg/cell/day. The procoagulant activity of the secreted factor IX was restored nearly completely by co-transfection of the producer cells by p1.2 plasmids bearing genes of the soluble truncated variant of human PACE/furin signal protease and vitamin K oxidoreductase from Chinese hamster. The resulting clonal cell line 3B12-86 was able to secrete factor IX in a protein-free medium up to a 6 IU/ml titer under plain batch culturing conditions. The copy number of the genome- integrated factor IX gene for the 3B12-86 cell line was only 20 copies/genome; the copy numbers of the genome-integrated genes of PACE/furin and vitamin K oxidoreductase were 3 and 2 copies/genome, respectively. Factor IX protein secreted by the 3B12-86 cell line was purified by three consecutive chromatography rounds to a specific activity of up to 230 IU/mg, with the overall yield > 30%. The developed clonal producer cell line and the purification process employed in this work allow for economically sound industrial-scale production of biosimilar factor IX for hemophilia B therapy. PMID- 29713520 TI - Gene Expression in the Three-Spined Stickleback (Gasterosteus aculeatus) of Marine and Freshwater Ecotypes. AB - Three-spine stickleback (Gasterosteus aculeatus) is a well-known model organism that is routinely used to explore microevolution processes and speciation, and the number of studies related to this fish has been growing recently. The main reason for the increased interest is the processes of freshwater adaptation taking place in natural populations of this species. Freshwater three-spined stickleback populations form when marine water three-spined sticklebacks fish start spending their entire lifecycle in freshwater lakes and streams. To boot, these freshwater populations acquire novel biological traits during their adaptation to a freshwater environment. The processes taking place in these populations are of great interest to evolutionary biologists. Here, we present differential gene expression profiling in G. aculeatus gills, which was performed in marine and freshwater populations of sticklebacks. In total, 2,982 differentially expressed genes between marine and freshwater populations were discovered. We assumed that differentially expressed genes were distributed not randomly along stickleback chromosomes and that they are regularly observed in the "divergence islands" that are responsible for stickleback freshwater adaptation. PMID- 29713521 TI - New Experimental Models of Retinal Degeneration for Screening Molecular Photochromic Ion Channel Blockers. AB - Application of molecular photochromic ion channel blockers to recover the visual function of a degenerated retina is one of the promising trends in photopharmacology. To this day, several photochromic azobenzene-based compounds have been proposed and their functionality has been demonstrated on cell lines and knockout mouse models. Further advance necessitates testing of the physiological activity of a great number of new compounds. The goal of this study is to propose animal models of photoreceptor degeneration that are easier to obtain than knockout mouse models but include the main features required for testing the physiological activity of molecular photoswitches. Two amphibian based models were proposed. The first model was obtained by mechanical deletion of the photoreceptor outer segments. The second model was obtained by intraocular injection of tunicamycin to induce the degeneration of rods and cones. To test our models, we used 2-[(4-{(E)-[4-(acryloylaminophenyl]diazenyl}phenyl)amino] N,N,N-triethyl-2-oxoethanammonium chloride (AAQ), one of the compounds that have been studied in other physiological models. The electroretinograms recorded from our models before and after AAQ treatment are in agreement with the results obtained on knockout mouse models and reported in other studies. Hence, the proposed models can be used for primary screening of molecular photochromic ion channel blockers. PMID- 29713522 TI - Influence of the Linking Order of Fragments of HA2 and M2e of the influenza A Virus to Flagellin on the Properties of Recombinant Proteins. AB - The ectodomain of the M2 protein (M2e) and the conserved fragment of the second subunit of hemagglutinin (HA2) are promising candidates for broadly protective vaccines. In this paper, we report on the design of chimeric constructs with differing orders of linkage of four tandem copies of M2e and the conserved fragment of HA2 (76-130) from phylogenetic group II influenza A viruses to the C terminus of flagellin. The 3D-structure of two chimeric proteins showed that interior location of the M2e tandem copies (Flg-4M2e-HA2) provides partial alpha helix formation nontypical of native M2e on the virion surface. The C-terminal position of the M2e tandem copies (Flg-HA2-4M2e) largely retained its native M2e conformation. These conformational differences in the structure of the two chimeric proteins were shown to affect their immunogenic properties. Different antibody levels induced by the chimeric proteins were detected. The protein Flg HA2-4M2e was more immunogenic as compared to Flg-4M2e-HA2, with the former offering full protection to mice against a lethal challenge. We obtained evidence suggesting that the order of linkage of target antigens in a fusion protein may influence the 3D conformation of the chimeric construct, which leads to changes in immunogenicity and protective potency. PMID- 29713523 TI - Clinical Analysis of 42 Cases of Ocular Ischemic Syndrome. AB - Ocular ischemic syndrome (OIS) is a severe ocular disease caused by ocular hypoperfusion due to stenosis or occlusion of the common or internal carotid arteries. OIS is easily misdiagnosed or undiagnosed given its asymptomatic onset and complicated ocular manifestations. The present study reviewed 42 patients with OIS, including 30 males (71.43%), 29 older patients (69.05%, >61 yrs), and 35 patients (83.33%) with two or more systemic diseases. Only 6 patients had ocular symptoms as the initial signs upon visiting the Department of Ophthalmology of three hospitals (the First Affiliated Hospital, Sun Yat-sen University; Zhongshan Ophthalmic Center, Sun Yat-sen University; and the Second Affiliated Hospital, Guangzhou Medical University). The ocular symptoms varied from visual deterioration to periorbital pain. Thirty-seven patients (88.10%) complained of constitutional symptoms. Ocular manifestations were diverse and involved both anterior and posterior segments. We reported a case of corneal edema and corneal epithelium erosion in the ipsilateral eye due to internal carotid artery stenosis. As the clinical manifestations of OIS are complex, ophthalmologists must carefully examine patients to avoid a misdiagnosis or a failure to diagnose. The management of OIS requires cooperation with cardiologists and neurologists. PMID- 29713524 TI - Refractive and Biometric Outcomes in Patients with Retinopathy of Prematurity Treated with Intravitreal Injection of Ranibizumab as Compared with Bevacizumab: A Clinical Study of Correction at Three Years of Age. AB - Purpose: To compare refractive and biometric outcomes in patients with type 1 retinopathy of prematurity (ROP) treated with intravitreal injection of ranibizumab (IVR) versus bevacizumab (IVB), at a corrected age of 3 years. Methods: A retrospective case series compared cycloplegic refractive statuses and biometric statuses in patients who received either IVR or IVB for type 1 ROP, from April 2011 to April 2014. Results: A total of 62 eyes (33 patients) with type 1 ROP were evaluated (26 eyes in 13 IVR patients and 36 eyes in 20 IVB patients). There were no differences in birth statuses including gestational age and birth body weight between the two groups. The prevalence of refractive error greater than 1 D was higher in the IVB group (p = 0.03), and there was a higher prevalence of high myopia (<-5.0 D, p = 0.03) in the IVB group. Comparisons in biometric finding showed that IVB patients had shallower anterior chamber depth (p = 0.01). Conclusion: Both IVR and IVB showed low refractive errors, even followed at the corrected age of 3 years. No difference was noted between the two groups in refractive statuses. However, IVB was associated with shallower anterior chamber and higher prevalence of refractive error at the corrected age of 3 years. This trial is registered with NCT03334513. PMID- 29713525 TI - Efficacy of Osthole in Management of Hypoperfused Retina. AB - Purpose: To determine the effect of osthole on the retina in a chronic cerebral hypoperfusion (CCH) rat model and to investigate its therapeutic activity. Methods: Seventy-two rats were randomly allocated into 6 groups. CCH was induced by permanent bilateral common carotid artery occlusion (BCCAO) in five groups. Sham surgery was performed without occlusion of the artery in the sixth group (control group). Animals were administered with saline (model group), osthole (osthole-IG group), aspirin (aspirin group), or ginaton (ginaton group); the osthole-PI group was performed with peribulbar injection of osthole. Four rats in each group were sacrificed every 5 days after drug administration, and histopathology along with morphology of retina were observed. Fundus fluorescein angiography was performed before the animals were sacrificed at day 15. Retinal Akt, NF-kappaB, Bax, and Bcl-2 levels were assessed using immunohistochemistry, immunofluorescence, and reverse-transcription PCR; retinal injury was assessed using TUNEL in situ; retinal levels of superoxide dismutase (SOD) and malondialdehyde (MDA) were measured. Results: Fundus fluorescein angiography revealed the retinal vascular diameter in the osthole-IG group rats to be wider than that in the model, osthole-PI, aspirin, or ginaton group rats. Histological analysis of retinal tissue revealed an increase in retinal thickness in all treatment groups, and significant improvement was noticed in the osthole-IG group. TUNEL staining revealed fewer apoptotic cells in the osthole-IG and osthole-PI groups than in the other groups. For immunohistochemistry results, in the osthole-IG group, levels of NF-kappaB and Akt were lower than those in the other treated groups, while levels of the ratio Bcl-2/Bax were higher. Levels of MDA were lower and levels of SOD were higher in the osthole-IG group than in the other groups. Conclusions: Osthole protects the retina from ischemia injury secondary to CCH induced by BCCAO, mainly through anti-inflammatory, antioxidant, and antiapoptotic effects. PMID- 29713526 TI - Long-Term Functional and Anatomical Outcome after Descemet Stripping Automated Endothelial Keratoplasty: A Prospective Single-Center Study. AB - Purpose: To investigate the long-term anatomical and functional outcomes of Descemet stripping automated endothelial keratoplasty (DSAEK). Methods: Prospective follow-up of 114 eyes (95 subjects) after DSAEK for endothelial dysfunction. Measurements included best spectacle-corrected visual acuity (BSCVA), straylight, endothelial cell density (ECD), and graft thickness. Results: The mean follow-up time was 5.1 +/- 1.5 years. Four grafts ultimately failed (after 5 to 7 years). From baseline up to 1 year after DSAEK, mean BSCVA improved by 0.30 logMAR. This beneficial effect remained until the last follow-up (LFU). After DSAEK, straylight was reduced. ECD sharply dropped by 900 cells/mm2 (33%) immediately after surgery and, thereafter, steadily decreased at a rate of 11 cells/mm2 per month. No significant correlation was observed between graft thickness at 3 years and BSCVA. Conclusions: We observed a low graft failure rate and a normalization of graft thickness. Postoperative straylight remained elevated relative to the normal population. The sharp initial and the subsequent more gradual ECD decline are consistent with other studies. A significant and prolonged functional gain can be achieved by posterior lamellar grafting for endothelial dysfunction. PMID- 29713528 TI - Training Nursing Skills: A Quantitative Study of Nursing Students' Experiences before and after Clinical Practice. AB - Introduction: Requirements for Patient Safety suggest that students encounter patients well prepared. In clinical laboratory practice (CLP), the students simulate patient situations as a preparation for internship. Various CLP models have been tried out to meet the students' prerequisites and learning strategies. Objectives: The purpose of this study was to try out two different learning sessions related to the bed bath procedure. Design and Methods: The study has a descriptive, quantitative design with elements from clinically controlled trials. Sample: The population of 160 first-year students was randomly divided into two classes. Questionnaires: Two questionnaires were answered with six-month intervals: Form 1 immediately after the first training session and Form 2 a short time after clinical practice. Findings: A majority of the nursing students reported that the exercises in the clinical lab were a good way to prepare for the practice, although most of them did not perceive that the procedure conducted at the university resembled how it is conducted in clinical practice. Age or level of discomfort related to organization of the skills training did not have impact on the students' confidence in mastering bed bath in clinical practice. Students without previous experience were less confident to master the procedure in clinical practice, but the results evened out during the internship. Conclusions: The results from this study could indicate that the students' age to a larger extent should be considered in the universities' facilitation of nursing students' clinical preparations, to improve the transition to "real life" as smoothly and meaningfully as possible to nursing students. PMID- 29713527 TI - Characterization of the Catalytic Structure of Plant Phytase, Protein Tyrosine Phosphatase-Like Phytase, and Histidine Acid Phytases and Their Biotechnological Applications. AB - Phytase plays a prominent role in monogastric animal nutrition due to its ability to improve phytic acid digestion in the gastrointestinal tract, releasing phosphorus and other micronutrients that are important for animal development. Moreover, phytase decreases the amounts of phytic acid and phosphate excreted in feces. Bioinformatics approaches can contribute to the understanding of the catalytic structure of phytase. Analysis of the catalytic structure can reveal enzymatic stability and the polarization and hydrophobicity of amino acids. One important aspect of this type of analysis is the estimation of the number of beta sheets and alpha-helices in the enzymatic structure. Fermentative processes or genetic engineering methods are employed for phytase production in transgenic plants or microorganisms. To this end, phytase genes are inserted in transgenic crops to improve the bioavailability of phosphorus. This promising technology aims to improve agricultural efficiency and productivity. Thus, the aim of this review is to present the characterization of the catalytic structure of plant and microbial phytases, phytase genes used in transgenic plants and microorganisms, and their biotechnological applications in animal nutrition, which do not impact negatively on environmental degradation. PMID- 29713529 TI - An Objective Study of Anatomic Shifts in Intracranial Hypotension Using Four Anatomic Planes. AB - Purpose: Intracranial hypotension (IH) often remains undetected using current MR diagnostic criteria. This project aims to demonstrate that central incisural herniation is highly effective in helping to make this diagnosis. Materials and Methods: Magnetic resonance imaging (MRI) was analyzed in 200 normal and 81 clinically known IH patients. MRI reference lines approximating the plane of the incisura, the plane of the diaphragma sella, the plane of the foramen magnum, and the plane of the visual pathway were utilized to measure the position of selected brain structures relative to these reference lines. Results: All IH patients had highly statistically significant (p < 0.0001) measurable evidence of downward central incisural herniation when compared to normal controls. The first of the important observations was a downward shift of the mammillary bodies, which shortened the midsagittal width of the interpeduncular fossa cistern. A concurrent downward shift and deformity of the tuber cinereum accompanied the mammillary body shift. The second essential observation was an abnormal clockwise rotation of the long axis of the visual pathway. A severity grading system is proposed based on the extent of these shifts as well as secondary shifts of the brain stem, splenium, and cerebellar tonsils. Conclusion: This study objectively delineates the anatomic shifts of brain structures adjacent to the incisura and foramen magnum. This methodology is sufficient to recognize the features of IH and to stratify the spectrum of IH findings into a functional grading system for quantifying the results of interventional therapy. PMID- 29713530 TI - Arab J Urol. PMID- 29713531 TI - Geographical differences in semen characteristics of 13 892 infertile men. AB - Objective: To assess the relationship between geographical differences and all semen parameters, across 13,892 infertile men of 84 diverse nationalities, recruited at a specialised tertiary hospital that represents the main healthcare provider in Qatar. Male infertility is an important and global public health problem. Despite this, there is a significant scarcity of epidemiological male infertility and semen analysis research in the Middle East and North Africa (MENA) region, as well as geographical comparisons with other parts of the world. Patients and methods: Retrospective study of semen findings of 13 892 infertile men assessed at the Male Infertility Unit at Hamad Medical Corporation, in Qatar between January 2012 and August 2015. Based on country of origin, patients were categorised into those from the MENA region (n = 8799) and non-MENA patients (n = 5093). The two groups were compared across demographic features and semen characteristics: age, sperm volume, sperm total motility, sperm progressive motility (PMot), abnormal sperm forms (ABF), and sperm DNA fragmentation (SDF). Results: The whole sample's mean (SD) age was 35.7 (0.7) years, sperm concentration was 32.3 (0.25) * 106 sperm/mL, total motility was 45.4 (0.2)%, sperm PMot was 25.1 (0.2)%, and ABF was 79.9 (0.2)%. Overall, 841 patients had azoospermia (6.05%), 3231 had oligospermia (23.3%), 4239 had asthenospermia (30.5%) and 6772 had teratospermia (48.7%). SDF (1050 patients) was abnormal in 333 patients (31.7%). MENA patients were significantly younger than their non MENA counterparts and had a greater semen volume. Non-MENA patients had significantly higher sperm counts, total motility and PMot, and lower ABF. SDF showed no statistical difference between the two groups. MENA patients had significantly higher prevalence of oligospermia, asthenospermia, and teratospermia; and lower prevalence of normal sperm concentration, normal motility, and normal morphology. Throughout the 4 years of the study, MENA patients constantly had significantly lower sperm counts; generally lower sperm total motility percentage and generally lower quality sperm morphology. We compared patients by age (<=40 and >40 years): in the patients aged <=40 years, the same results as for the overall study were reproduced; in the >40-years group, the same results were reproduced with the exception of morphology, which was not significantly different between the MENA and non-MENA patients. Conclusion: Semen quality is generally lower in male infertility patients from the MENA region compared to non-MENA regions. PMID- 29713532 TI - Lifestyle causes of male infertility. AB - Objective: To examine the potential effects of lifestyle factors on male reproductive health. Evidence of a global decline in human sperm quality over recent decades has been accumulating. Environmental, occupational, and modifiable lifestyle factors may contribute to this decline. This review focuses on key lifestyle factors that are associated with male infertility such as smoking cigarettes, alcohol intake, use of illicit drugs, obesity, psychological stress, advanced paternal age, dietary practices, and coffee consumption. Other factors such as testicular heat stress, intense cycling training, lack of sleep and exposure to electromagnetic radiation from mobile phone use are briefly discussed. Materials and method: A comprehensive literature search was performed to identify and synthesise all relevant information, mainly from within the last decade, on the major lifestyle factors associated with male infertility and semen quality. Database searches were limited to reports published in English only. A manual search of bibliographies of the reports retrieved was conducted to identify additional relevant articles. Results: In all, 1012 articles were identified from the database search and after reviewing the titles and abstract of the reports, 104 articles met the inclusion criteria. Of these, 30 reports were excluded as the full-text could not be retrieved and the abstract did not have relevant data. The remaining 74 reports were reviewed for data on association between a particular lifestyle factor and male infertility and were included in the present review. Conclusion: The major lifestyle factors discussed in the present review are amongst the multiple potential risk factors that could impair male fertility. However, their negative impact may well be mostly overcome by behaviour modification and better lifestyle choices. Greater awareness and recognition of the possible impact of these lifestyle factors are important amongst couples seeking conception. PMID- 29713533 TI - Role of sperm DNA fragmentation in male factor infertility: A systematic review. AB - Objective: To summarise the latest evidence on the role of sperm DNA fragmentation (SDF) in male factor infertility, as SDF has been emerging as a valuable tool for male infertility evaluation. Methods: A search of PubMed was conducted using the keywords 'sperm DNA fragmentation' and 'male infertility'. Studies in languages other than English were excluded. All identified studies were screened and clinical studies in humans were included. Results: In all, 150 articles were included for analysis. Current evidence supports the association between high SDF and poor reproductive outcomes for natural conception and intrauterine insemination. Although the relationship between high SDF and in vitro fertilisation and intracytoplasmic sperm injection is less clear, the negative implication of high SDF on pregnancy loss is evident. Various treatment strategies have been attempted with varying success. The predictive value of SDF testing on outcomes of natural pregnancy and assisted reproduction illustrates its value in clinical practice. Conclusion: The significant role of SDF in male factor infertility is supported by current evidence. The beneficial role of SDF testing in selection of varicocelectomy candidates, evaluation of patients with unexplained infertility and recurrent pregnancy loss, selection of the most appropriate assisted reproductive technique with highest success rate for infertile couples, and assessment of infertile men with modifiable lifestyle factors or gonadotoxin exposure has been recently proposed. PMID- 29713534 TI - Role of reactive oxygen species in male infertility: An updated review of literature. AB - Objectives: To review the literature and provide an updated summary on the role of reactive oxygen species (ROS) in male infertility. Methods: A review of PubMed, Cochrane review, and Web of Science databases for full-text English language articles published between 1943 and 2017 was performed, focusing on the aetiology of ROS, physiological role of ROS on spermatic function, pathological role of ROS in infertility, evaluation of ROS, and role of antioxidants in oxidative stress. Results: ROS play a role in spermatic function and fertilisation. The literature describes both a physiological and a pathological role of ROS in fertility. A delicate balance between ROS necessary for physiological activity and antioxidants to protect from cellular oxidative injury is essential for fertility. Conclusion: Although elevated levels of ROS are implicated as a cause of infertility, there is no consensus on selecting patients to test for ROS, which test to perform, or if treatment for ROS can have a positive impact on infertility rates and pregnancy. PMID- 29713535 TI - Hyperprolactinaemia in male infertility: Clinical case scenarios. AB - Objective: To explore the evaluation, treatment and impact of hyperprolactinaemia on male infertility and testicular function, as hyperprolactinaemia is commonly detected during the evaluation of infertile men. Methods: A literature search was performed using MEDLINE/PubMed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify all studies exploring hyperprolactinaemia in male infertility. Results: Elevated levels of serum prolactin have a detrimental effect on male reproduction through inhibition of the pulsatile release of gonadotrophins from the anterior pituitary gland, and a direct effect on spermatogenesis. Treatment of confirmed hyperprolactinaemia with dopamine agonists leads to significant improvements in both semen parameters and hormone levels. Conclusion: Hyperprolactinaemia, both directly and indirectly, has a negative effect on sperm production, and its detection and management in men seeking fertility is mandatory. PMID- 29713536 TI - A systematic review on the genetics of male infertility in the era of next generation sequencing. AB - Objectives: To identify the role of next-generation sequencing (NGS) in male infertility, as advances in NGS technologies have contributed to the identification of novel genes responsible for a wide variety of human conditions and recently has been applied to male infertility, allowing new genetic factors to be discovered. Materials and methods: PubMed was searched for combinations of the following terms: 'exome', 'genome', 'panel', 'sequencing', 'whole-exome sequencing', 'whole-genome sequencing', 'next-generation sequencing', 'azoospermia', 'oligospermia', 'asthenospermia', 'teratospermia', 'spermatogenesis', and 'male infertility', to identify studies in which NGS technologies were used to discover variants causing male infertility. Results: Altogether, 23 studies were found in which the primary mode of variant discovery was an NGS-based technology. These studies were mostly focused on patients with quantitative sperm abnormalities (non-obstructive azoospermia and oligospermia), followed by morphological and motility defects. Combined, these studies uncover variants in 28 genes causing male infertility discovered by NGS methods. Conclusions: Male infertility is a condition that is genetically heterogeneous, and therefore remarkably amenable to study by NGS. Although some headway has been made, given the high incidence of this condition despite its detrimental effect on reproductive fitness, there is significant potential for further discoveries. PMID- 29713538 TI - Laboratory assessment of oxidative stress in semen. AB - Objectives: To evaluate different laboratory assessments of oxidative stress (OS) in semen and identify a cost-efficient and highly sensitive instrument capable of providing a comprehensive measure of OS in a clinical setting, as early intervention and an accurate diagnostic test are important because they help maintain a balance of free radicals and antioxidants; otherwise, excessive OS could lead to sperm damage and result in male infertility. Materials and methods: A systematic literature search was performed through a MedLine database search using the keywords 'semen' AND 'oxygen reduction potential'. We also reviewed the references of retrieved articles to search for other potentially relevant research articles and additional book chapters discussing laboratory assessments for OS, ranging from 1994 to 2017. A total of 29 articles and book chapters involving OS-related laboratory assays were included. We excluded animal studies and articles written in languages other than English. Results: Direct laboratory techniques include: chemiluminescence, nitro blue tetrazolium, cytochrome C reduction test, fluorescein probe, electron spin resonance and oxidation reduction potential (ORP). Indirect laboratory techniques include: measurement of Endtz test, lipid peroxidation, chemokines, antioxidants/micronutrients/vitamins, ascorbate, total antioxidant capacity, or DNA damage. Each of these laboratory techniques has its advantages and disadvantages. Conclusion: Traditional OS laboratory assessments have their limitations. Amongst the prevalent laboratory techniques, ORP is novel and better option as it can be easily used in a clinical setting to provide a comprehensive review of OS. However, more studies are needed to evaluate its reproducibility across various laboratory centres. PMID- 29713537 TI - A systematic review on sperm DNA fragmentation in male factor infertility: Laboratory assessment. AB - Objective: To review sperm DNA fragmentation (SDF) testing as an important sperm function test in addition to conventional semen analysis. High SDF is negatively associated with semen quality, the fertilisation process, embryo quality, and pregnancy outcome. Over recent decades, different SDF assays have been developed and reviewed extensively to assess their applicability and accuracy as advanced sperm function tests. Amongst them, the standardisation of the terminal deoxynucleotidyl transferased UTP nick-end labelling (TUNEL) assay with a bench top flow cytometer in clinical practice deserves special mention with a threshold value of 16.8% to differentiate infertile men with DNA damage from fertile men. Materials and methods: A systematic literature search was performed through the PubMed, Medline, and ScienceDirect databases using the keywords 'sperm DNA fragmentation' and 'laboratory assessment'. Non-English articles were excluded and studies related to humans were only included. Results: Of the 618 identified, 87 studies (original research and reviews) and in addition eight book chapters meeting the selection criteria were included in this review. In all, 366 articles were rejected in the preliminary screening and a further 165 articles related to non-human subjects were excluded. Conclusion: There are pros and cons to all the available SDF assays. TUNEL is a reliable technique with greater accuracy and as an additional diagnostic test in Andrology laboratories along with basic semen analysis can predict fertility outcome, and thus direct the choice of an assisted reproductive technology procedure for infertile couples. Also, the TUNEL assay can be used as a prognostic test and results are beneficial in deciding personalised treatment for infertile men. PMID- 29713539 TI - Oxidation-reduction potential and sperm DNA fragmentation, and their associations with sperm morphological anomalies amongst fertile and infertile men. AB - Objective: To assess seminal oxidation-reduction potential (ORP) and sperm DNA fragmentation (SDF) in male infertility and their relationships with sperm morphology in fertile and infertile men. Patients and methods: Prospective case control study comparing the findings of infertile men (n = 1168) to those of men with confirmed fertility (n = 100) regarding demographics and semen characteristics (conventional and advanced semen tests). Spearman rank correlation assessed the correlation between ORP, SDF, and different morphological indices. Means of ORP and SDF were assessed in variable levels of normal sperm morphology amongst all participants. Results: Infertile patients had a significantly lower mean sperm count (32.7 vs 58.7 * 106 sperm/mL), total motility (50.1% vs 60.4%), and normal morphology (5.7% vs 9.9%). Conversely, infertile patients had significantly higher mean head defects (54% vs 48%), and higher ORP and SDF values than fertile controls. ORP and SDF showed significant positive correlations and significant negative correlations with sperm head defects and normal morphology in infertile patients, respectively. ORP and SDF were significantly inversely associated with the level of normal sperm morphology. Using receiver operating characteristic curve analysis, ORP and SDF threshold values of 1.73 mV/106 sperm/mL and 25.5%, respectively, were associated with 76% and 56% sensitivity and 72% and 72.2% specificity, respectively, in differentiating <4% from >=4% normal morphology. Conclusion: A direct inverse relationship exists between seminal ORP and SDF with various levels of normal sperm morphology. Using ORP and SDF measures in conjunction with standard semen morphology analysis could validate the result of the fertility status of patients. PMID- 29713540 TI - Prediction of male infertility by the World Health Organization laboratory manual for assessment of semen analysis: A systematic review. AB - Objective: To discuss the role, reliability and limitations of the semen analysis in the evaluation of fertility with reference to the World Health Organization (WHO) fifth edition guidelines, with semen analysis reference values published in 2010. We also discuss the limitations of using a single threshold value to distinguish 'abnormal' and 'normal' parameters. Methods: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used to search the MEDLINE, EMBASE, and the Cochrane electronic database for articles discussing the effectiveness of semen analysis. Results: Limitations affecting the reliability of semen analysis as a predictor of fertility were found. These include: the lack of consideration of the female factor, the vaguely defined threshold values, and the intra-individual variation in semen parameters. Conclusions: Impaired semen parameters alone cannot be used to predict fertility as these men still have a chance of being fertile, except when a man has azoospermia, necrospermia or globozoospermia. PMID- 29713541 TI - Update on the proteomics of male infertility: A systematic review. AB - Objective: To assess the role of differentially expressed proteins as a resource for potential biomarker identification of infertility, as male infertility is of rising concern in reproductive medicine and evidence pertaining to its aetiology at a molecular level particularly proteomic as spermatozoa lack transcription and translation. Proteomics is considered as a major field in molecular biology to validate the target proteins in a pathophysiological state. Differential expression analysis of sperm proteins in infertile men and bioinformatics analysis offer information about their involvement in biological pathways. Materials and methods: Literature search was performed on PubMed, Medline, and Science Direct databases using the keywords 'sperm proteomics' and 'male infertility'. We also reviewed the relevant cross references of retrieved articles and included them in the review process. Articles written in any language other than English were excluded. Results: Of 575 articles identified, preliminary screening for relevant studies eliminated 293 articles. At the next level of selection, from 282 studies only 80 articles related to male infertility condition met the selection criteria and were included in this review. Conclusion: In this molecular era, sperm proteomics has created a platform for enhanced understanding of male reproductive physiology as a potential tool for identification of novel protein biomarkers related to sperm function in infertile men. Therefore, it is believed that proteomic biomarkers can overcome the gaps in information from conventional semen analysis that are of limited clinical utility. PMID- 29713542 TI - Systematic review of antioxidant types and doses in male infertility: Benefits on semen parameters, advanced sperm function, assisted reproduction and live-birth rate. AB - Objective: To explore the current evidence concerning the effect of oral antioxidant supplementation on various male fertility outcomes, as antioxidants are widely available compounds that are commonly used for the treatment of male infertility. Materials and methods: PubMed, Medline and Cochrane electronic databases were searched according to a modified Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines looking for studies investigating the effect of antioxidant therapy on infertile men. The studies were explored looking for antioxidants: (i) types and doses; (ii) mechanism of action and rationale for use; and (iii) effect on the different outcome measures reported. Results: In all, 26 studies reported a significant positive effect of antioxidant therapy on basic semen parameters, advanced sperm function, outcomes of assisted reproductive therapy, and live-birth rate. Vitamin E, vitamin C, carnitines, N-acetyl cysteine, co-enzyme Q10, zinc, selenium, folic acid and lycopene were most commonly used. The vitamins' mechanism of action and reported doses is presented in Table 1, Table 2. Conclusion: Antioxidants generally have a favourable effect on male fertility. Further studies are needed to identify the optimal antioxidant regimen that can be used safely and efficiently in clinical practice. PMID- 29713543 TI - Advances in sperm retrieval techniques in azoospermic men: A systematic review. AB - Objective: To evaluate various methods of operative sperm retrieval in men with non-obstructive azoospermia (NOA) and to determine the optimal surgical approach in terms of effectiveness, morbidity, and complications. Materials and methods: PubMed and Cochrane databases were searched to identify five recent reviews and meta-analyses evaluating outcomes for sperm retrieval in men with NOA. Results and Conclusion: Micro-TESE is the most efficient method for retrieving sperm but requires special expertise and can be traumatic for the testes. Conventional biopsies are twice more likely to retrieve sperm than fine-needle aspiration. Testicular aspiration performed by multiple passes into the testis is traumatic and is not efficient for sperm retrieval. Needle-aspiration biopsy and open real time testicular mapping by the single seminiferous tubule technique can offer less traumatic methods for sperm retrieval, which can be tried before proceeding to micro-TESE. The first attempt at sperm retrieval is the best chance the patient has and should combine various techniques sequentially to give the highest chance of success with the least morbidity. PMID- 29713544 TI - Chromosomal abnormalities in infertile men with azoospermia and severe oligozoospermia in Qatar and their association with sperm retrieval intracytoplasmic sperm injection outcomes. AB - Objective: To study the types and incidence of chromosomal abnormalities in infertile men with azoospermia and severe oligozoospermia in Qatar, and to compare the hormonal changes, testicular sperm retrieval rate, and intracytoplasmic sperm injection (ICSI) outcome between patients with chromosomal abnormalities and patients with idiopathic infertility. Patients and methods: This study involved the retrospective chart review of 625 infertile male patients attending an academic tertiary medical centre in Qatar. Retrieved information included data on medical history, family history, clinical examination, semen analysis, initial hormonal profiles, and genetic studies, ICSI, and sperm retrieval results. Results: The incidence of chromosomal abnormalities was 9.59% (10.6% amongst Qatari patients, 9.04% amongst non-Qataris). About 63.6% of the sample had azoospermia, of whom 10.8% had chromosomal abnormalities. Roughly 36.4% of the sample had oligozoospermia, of whom 7.5% had chromosomal abnormalities. There were no differences between patients with chromosomal abnormalities and those with idiopathic infertility for demographic and infertility features; but for the hormonal profiles, patients with idiopathic infertility had significantly lower luteinising hormone and follicle-stimulating hormone values. For ICSI outcomes, patients with chromosomal abnormalities had a significantly lower total sperm retrieval rate (47.4% vs 65.8%), surgical sperm retrieval rate (41.2% vs 58.1%), and lower clinical pregnancy rate (16.7% vs 26.6%) when compared to the idiopathic infertility group. Conclusion: The incidence of chromosomal abnormalities in Qatar as a cause of severe male infertility is within a similar range as their prevalence internationally. PMID- 29713546 TI - Review of the role of robotic surgery in male infertility. AB - Objectives: To present the current state of the art in various robot-assisted microsurgical procedures in male infertility and review the latest literature, as the technology in infertility procedures has substantially developed since the incorporation of the Vinci(r) robotic platform (Intuitive Surgical, Inc., Sunnyvale, CA, USA). Materials and methods: The search strategy in this review was conducted in accordance with Cochrane guidelines and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). A search strategy was conducted in MEDLINE, PubMed and the Cochrane electronic databases (from 2000 to present) to identify studies that included both robotic and male infertility. Results: In all, 23 studies were found, 12 of which met our inclusion criteria. Articles were excluded if the study did not include both male infertility and robotics. Conclusions: Robotic assistance for microsurgical procedures in male infertility appears to be safe and feasible. It has several advantages including elimination of tremor, multi-view magnification, additional instrument arms, and enhanced dexterity with articulating instrument arms. It also has a short learning curve with a small skin incision. However, larger, prospective studies are needed to establish the clinical benefits over standard microsurgery. PMID- 29713545 TI - Systematic review of hormone replacement therapy in the infertile man. AB - Objectives: To highlight alternative treatment options other than exogenous testosterone administration for hypogonadal men with concomitant infertility or who wish to preserve their fertility potential, as testosterone replacement therapy (TRT) inhibits spermatogenesis, representing a problem for hypogonadal men of reproductive age. Materials and methods: We performed a comprehensive literature review for the years 1978-2017 via PubMed. Also abstracts from major urological/surgical conferences were reviewed. Review was consistent with the Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) criteria. We used Medical Subject Heading terms for the search including 'testosterone replacement therapy' or 'TRT' and 'male infertility'. Results: In all, 91 manuscripts were screened and the final number used for the review was 56. All studies included were performed in adults, were written in English and had an abstract available. Conclusions: Exogenous testosterone inhibits spermatogenesis. Hypogonadal men wanting to preserve their fertility and at the same time benefiting from TRT effects can be prescribed selective oestrogen receptor modulators or testosterone plus low-dose human chorionic gonadotrophin (hCG). Patients treated for infertility with hypogonadotrophic hypogonadism can be prescribed hCG alone at first followed by or in combination from the start with follicle-stimulating hormone preparations. PMID- 29713548 TI - Spermatogonial stem cell transplantation and male infertility: Current status and future directions. AB - Objective: To summarise the current state of research into spermatogonial stem cell (SSC) therapies with a focus on future directions, as SSCs show promise as a source for preserving or initiating fertility in otherwise infertile men. Materials and methods: We performed a search for publications addressing spermatogonial stem cell transplantation in the treatment of male infertility. The search engines PubMed and Google Scholar were used from 1990 to 2017. Search terms were relevant for spermatogonial stem cell therapies. Titles of publications were screened for relevance; abstracts were read, if related and full papers were reviewed for directly pertinent original research. Results: In all, 58 papers were found to be relevant to this review, and were included in appropriate subheadings. This review discusses the various techniques that SSCs are being investigated to treat forms of male infertility. Conclusions: Evidence does not yet support clinical application of SSCs in humans. However, significant progress in the in vitro and in vivo development of SSCs, including differentiation into functional germ cells, gives reason for cautious optimism for future research. PMID- 29713547 TI - Varicocele management for infertility and pain: A systematic review. AB - Despite being first described two thousand years ago, the varicocele remains a controversial multifaceted disease process with numerous biological consequences including infertility, hypogonadism, and chronic orchidalgia. The underlying mechanisms remain poorly understood and likely include hypoxia, oxidative stress, hyperthermia, anatomical aberrations, and genetics as primary components. Despite a high prevalence amongst asymptomatic fertile men, varicoceles paradoxically also represent the most common correctable cause for male infertility. In this systematic review we discuss the rich historical aspects of the varicocele and the contemporary data regarding its clinical manifestations. We performed a systematic literature review with the goal of comparing outcomes and complication rates of each of the major surgical approaches as they relate to infertility and pain. We performed a Preferred Reporting Items for Systematic Reviews and Meta Analysis (PRISMA)-compliant systematic literature review for manuscripts focused on varicocele and its biological consequences. We identified 112 studies suitable for qualitative analysis and included 56 of these for quantitative analysis, with an emphasis on infertility and chronic pain outcomes. Taken together, the clinical work to date suggests that the highest fertility rates and the lowest complication rates are associated with the microsurgical subinguinal surgical approach to varicocelectomy. In all, 26-40% of patients undergoing varicocelectomy will successfully achieve short-term spontaneous pregnancy, and up to 90% of all patients undergoing varicocelectomy for pain will have improvement and/or resolution of their symptoms. Taken together, the data support an ongoing role for varicocelectomy in both of these clinical arenas. PMID- 29713549 TI - Microscopic subinguinal varicocelectomy in 100 consecutive cases: Spermatic cord vascular anatomy, recurrence and hydrocele outcome analysis. AB - Objective: To evaluate the detailed vascular anatomy of the spermatic cord during subinguinal microscopic varicocelectomy and to assess the outcome of the cases with regard to varicocele recurrence and hydrocele formation. Patients and methods: In all, 100 varicocele cases including 74 left-sided and 26 bilateral, comprising 126 spermatic cord units with clinically palpable varicoceles underwent microscopic subinguinal varicocelectomy. Detailed description of vascular anatomy of the spermatic cords was reported. The number of spermatic, cremasteric, and inguinal veins was recorded. A record of testicular arteries and lymphatics was noted. Testicular delivery was done in all the cases and assessment of the gubernacular veins was reported. The patients underwent clinical evaluation, as well as scrotal Doppler ultrasonography, to detect varicocele recurrence and hydrocele formation. The mean (range) postoperative evaluation period was 6 (3-12) months. Results: The mean number of spermatic veins was 14 on both sides. The mean number of spermatic arteries on both sides was 1.3. For lymphatics, the mean number was around three on both sides. The gubernacular veins were noted in 75% of the cases on the left side (mean number of 1.2) and in 85% on the right-side, (mean number of 1). The mean number of cremasteric veins on the left and right sides was 1.4 and 1.2, respectively. Finally, inguinal floor vessels were noted in 9% on the left-side and were not seen in the right-side cases. The incidence of varicocele recurrence was 2% and for hydrocele that was not clinically significant was 0.07%. Conclusion: Microscopic subinguinal varicocelectomy accurately evaluated the detailed vascular anatomy of the spermatic cord, achieving excellent surgical outcome with minimal varicocele recurrence and hydrocele formation. Microscopic subinguinal varicocelectomy should be the 'gold standard' for varicocelectomy. PMID- 29713550 TI - Role of varicocele treatment in assisted reproductive technologies. AB - Objective: In this review, we investigate the advantage of varicocele repair prior to assisted reproductive technologies (ART) for infertile couples and provide cost analysis information. Materials and methods: We searched the following electronic databases: PubMed, Medline, Excerpta Medica Database (Embase), Cumulative Index to Nursing and Allied Health Literature (CINAHL). The following search strategy was modified for the various databases and search engines: 'varicocele', 'varicocelectomy', 'varicocele repair', 'ART', 'in vitro fertilisation (IVF)', 'intracytoplasmic sperm injection (ICSI)'. Results: A total of 49 articles, including six meta-analyses, 32 systematic reviews, and 11 original articles, were included in the analysis. Bypassing potentially reversible male subfertility factors using ART is currently common practice. However, varicocele may be present in 35% of men with primary infertility and 80% of men with secondary infertility. Varicocele repair has been shown to be an effective treatment for infertile men with clinical varicocele, thus should play an important role in the treatment of such patients due to the foetal/genetic risks and high costs that are associated with increased ART use. Conclusion: Varicocele repair is a cost-effective treatment method that can improve semen parameters, pregnancy rates, and live-birth rates in most infertile men with clinical varicocele. By improving semen parameters and sperm structure, varicocele repair can decrease or even eliminate ART requirement. PMID- 29713551 TI - A Combination of Tachycardia-Mediated Heart Failure and Coronary Artery Vasospasm Induced Silent Myocardial Infarction in a Patient with Severe Thyrotoxicosis. AB - Severe thyrotoxicosis can present with a myriad of cardiovascular complications. It may be mild features such as palpitations, tachycardia, and exertional dyspnea or may progress to life-threatening consequences such as atrial fibrillation, tachyarrhythmias, heart failure, myocardial infarction, and shock. In rare cases, they may present with myocardial ischemia secondary to coronary artery vasospasm. We report a case of a 59-year-old Malay gentleman who presented with fast atrial fibrillation and tachycardia-mediated heart failure that evolved to a silent myocardial infarction secondary to severe coronary artery vasospasm with undiagnosed severe thyrotoxicosis. He had complete resolution of heart failure and no further recurrence of coronary artery vasospasm once treatment for thyrotoxicosis was initiated and euthyroidism achieved. This life-threatening consequence has an excellent prognosis if recognised early and treated promptly. PMID- 29713552 TI - Persistent Hiccups as the Only Presenting Symptom of ST Elevation Myocardial Infarction. AB - Clinical manifestations of acute myocardial infarction can be more than just chest pain. Patients can present with dyspnea, fatigue, heart burn, diaphoresis, syncope, and abdominal pain to name a few. Our patient was a 74-year-old male with a past medical history of type 2 diabetes mellitus, hypertension, hyperlipidemia, and COPD due to chronic tobacco use, who presented with persistent hiccups for 4 days and no other complaints. Coincidently, he was found to have a diabetic foot ulcer with sepsis and acute kidney injury and hence was admitted to the hospital. A routine 12-lead EKG was done, and he was found to have an inferior wall ST elevation myocardial infarction. He underwent diagnostic catheterization which demonstrated 100% right coronary artery occlusion and a thallium viability study which confirmed nonviable myocardium; hence, he did not undergo percutaneous coronary intervention. Elderly patients who present with persistent hiccups should be investigated for an underlying cardiac etiology. PMID- 29713553 TI - Acquired Amegakaryocytic Thrombocytopenia and Pure Red Cell Aplasia in Thymoma. AB - Association of thymoma with myasthenia gravis, pure red cell aplasia, and aplastic anemia is well documented. However, thymoma complicated by acquired amegakaryocytic thrombocytopenia (AAMT) is rarely reported. Here, we present a case of a 60-year-old male with past medical history of recurrent invasive thymoma who presented with cough and blood in sputum. He was found to have severe normocytic normochromic anemia and thrombocytopenia that did not improve with intravenous steroids or multiple transfusions of red cells and platelets. Subsequent bone marrow biopsy showed severely depleted megakaryocytes and erythroid precursor cells with relative myeloid hyperplasia suggestive of amegakaryocytic thrombocytopenia and red cell aplasia. He was started on oral cyclosporine but subsequently developed leukopenia and refused any further treatment or diagnostic procedures and left the hospital against medical advice. AAMT, thus, may be a very early presentation of impending aplastic anemia, and treating physicians need to be aware of this entity. PMID- 29713554 TI - Postinfantile Giant Cell Hepatitis with Features of Acute Severe Autoimmune Hepatitis Probably Triggered by Diclofenac in a Patient with Primary Myelofibrosis. AB - Giant cell hepatitis (GCH) is commonly reported in neonatal and infantile liver diseases but rarely in adults where the term postinfantile GCH (PIGCH) is used. PIGCH is associated with many diseases, including drugs toxicity, viruses, and autoimmune liver diseases, with autoimmune hepatitis (AIH) being the most prevalent. We present a case of PIGCH in a 76-year-old female without known history of liver disease who suffered from an acute severe episode of hepatitis. After careful exclusion of other hepatitis causes by imaging, virological, immunological, and microbiological investigations, a diagnosis of acute severe AIH (AS-AIH) was established. The patient was started on corticosteroids but she did not respond and died 3 days later because of advanced acute liver failure. Postmortem liver biopsy showed typical PIGCH lesions. Physicians must keep this catastrophic entity in mind in cases of unexplained acute liver injury as, contrary to our case, prompt rescue therapy with corticosteroids may be life saving. PMID- 29713555 TI - Bacillus cereus Typhlitis in a Patient with Acute Myelogenous Leukemia: A Case Report and Review of the Literature. AB - Bacillus cereus is a Gram-positive rod that is now recognized as a rare cause of frank disease in the neutropenic hematologic malignancy patient. Because this pathogen is rarely isolated in clinical specimens, no large studies exist to guide the management of these acutely ill patients. Individual case reports and case series exist in the literature describing various clinical manifestations of B. cereus in the neutropenic patient including bacteremia/septicemia, pneumonia, meningitis/encephalitis, hepatic abscesses, and gastritis. In this report, we describe a case of typhlitis caused by B. cereus in a 74-year-old female with recently diagnosed acute myelogenous leukemia (AML), and we summarize the available English language literature to draw tentative conclusions regarding the clinical manifestations of this organism. PMID- 29713556 TI - Relapsing Malaria: A Case Report of Primaquine Resistance. AB - Primaquine (an 8-aminoquinoline malarial therapy) is the only FDA-approved therapy to treat the hypnozoite stage of P. vivax. We think of relapse occurring because of parasitic resistance or poor compliance secondary to drug toxicities. However, in patients with repeated treatment failure, we must consider CYP-450 mutations affecting drug metabolism as an important cause of relapse. A 47-year old man who travelled to a jungle in Venezuela was diagnosed with P. falciparum and P. vivax in July 2015. He was treated with seven rounds of primaquine-based therapy in the following year, all resulted in relapse without further exposure to endemic areas. On his eighth presentation, he was found to have CYP-4502D6 mutation that affected the metabolism and activation of primaquine. Thereafter, he was treated without relapse. Primaquine efficacy depends on many factors. Understanding the mechanism responsible for malaria relapse is paramount for successful treatment and reduction in morbidity and mortality. This case illustrates the importance of considering cytochrome mutations that affect drug efficacy in cases of relapsing malaria. PMID- 29713557 TI - A Novel CACNA1A Nonsense Variant [c.4054C>T (p.Arg1352*)] Causing Episodic Ataxia Type 2. AB - Episodic ataxia is a heterogenous group of uncommon neurological disorders characterised by recurrent episodes of vertigo, dysarthria, and ataxia for which a variety of different genetic variations have been implicated. Episodic ataxia type two (EA2) is the most common and also has the largest number of identified causative genetic variants. Treatment with acetazolamide is effective in improving symptoms, so accurate diagnosis is essential. However, a large proportion of patients with EA2 have negative genetic testing. We present a patient with a typical history of EA2 who had a novel variant in the CACNA1A gene not previously described. Report of such variations is important in learning more about the disease and improving diagnostic yield for the patient. PMID- 29713558 TI - Effect of 4DryField(r) PH, a Novel Adhesion Barrier, on Recurrence of Intestinal Adhesions after Extensive Visceral Adhesiolysis. AB - Background: Adhesions occur after up to 97% of abdominal interventions causing chronic pain, infertility, and intestinal obstruction. Various concepts to prevent adhesions have been presented but mostly either have low efficacy or are not applicable in resective intestinal surgery or incomplete hemostasis. In this retrospective one-center clinical trial, the course of patients with extensive abdominal adhesiolysis and application of a recent starch-based formulation, 4DryField PH (4DF), is analyzed. Case Report: Five female patients (age 65-83 years) underwent extensive open adhesiolysis with application of 4DF gel for adhesion prevention, premixed extracorporeally with saline or Ringer's solution (60-70 mL per 5 g 4DF) for homogeneous gel distribution on intestinal loops and in the peritoneal cavity. In addition, dry 4DF powder was dispersed on the greater omentum and subsequently transformed into a gel by dripping with saline or Ringer's solution directly before abdominal closure. Patients were followed up for more than two years, except for one patient who died after nine months due to metastases. One patient with complex situation due to Gore-Tex mesh in the lower abdomen showed no adhesions at scheduled second-look operation but after six months had relaparotomy for adhesiolysis. All other patients have remained free of adhesions or adhesion-related symptoms during follow-up. Conclusion: Considering the extent and complexity of adhesions, treatment with 4DF gel for adhesion prevention after open adhesiolysis appears promising. Prospective randomized trials should further elaborate on this clinical concept. PMID- 29713559 TI - Substance Use, Criminal Recidivism, and Mortality in Criminal Justice Clients: A Comparison between Men and Women. AB - Background. This study aimed to map differences between male and female offenders with substance abuse, with respect to descriptive characteristics and risk factors for mortality and criminal recidivism. Methods. Criminal justice clients with substance abuse problems (n = 7085) were interviewed with the Addiction Severity Index. Mortality and data on return to criminal justice were retrieved from national registers. Results. Female offenders reported heavier substance use patterns, more psychiatric symptoms, and more often a partner with substance abuse, but had lower mortality (2% versus 4%) and criminal recidivism (62% versus 71%) during follow-up. Having a substance-abusing partner was associated with criminal recidivism among females. Conclusions. Female offenders with substance abuse differ from their male counterparts. Males and females had different risk factors for criminal recidivism. PMID- 29713560 TI - Rapid Screening and Quantitative Determination of Active Components in Qing-Hua Yu-Re-Formula Using UHPLC-Q-TOF/MS and HPLC-UV. AB - Qing-Hua-Yu-Re-Formula (QHYRF), a new herbal preparation, has been extensively used for treating diabetic cardiomyopathy. However, the chemical constituents of QHYRF remain uninvestigated. In the present study, rapid ultrahigh-performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) was used to qualitatively analyze the components of QHYRF. Qualitative detection was performed on a Kromasil C18 column through the gradient elution mode, using acetonitrile-water containing 0.1% formic acid. Twenty-seven compounds were identified or tentatively characterized, including 12 phenolic acids, nine monoterpene glycosides, two flavonoids, three iridoids, and one unknown compound. Among these, six compounds were confirmed by comparing with standards. A high-performance liquid chromatography (HPLC) method was developed to simultaneously determine the following six active components in QHYRF: danshensu, paeoniflorin, acteoside, lithospermic acid, salvianolic acid B, and salvianolic acid C. These HPLC chromatograms were monitored at 254, 280, and 320 nm. The method was well validated with respect to specificity, linearity, limit of detection, limit of quantification, precision, stability, and recovery. The HPLC-UV method was successfully applied to 10 batches of QHYRF. PMID- 29713561 TI - Sialidase-catalyzed one-pot multienzyme (OPME) synthesis of sialidase transition state analogue inhibitors. AB - Sialidase transition state analog inhibitor 2,3-dehydro-2-deoxy-N acetylneuraminic acid (Neu5Ac2en, DANA) has played a leading role in developing clinically used anti-influenza virus drugs. Taking advantage of the Neu5Ac2en forming catalytic property of Streptococcus pneumoniae sialidase SpNanC, an effective one-pot multienzyme (OPME) strategy has been developed to directly access Neu5Ac2en and its C-5, C-9, and C-7-analogs from N-acetylmannosamine (ManNAc) and analogs. The obtained Neu5Ac2en analogs can be further derivatized at various positions to generate a larger inhibitor library. Inhibition studies demonstrated improved selectivity of several C-5- or C-9-modified Neu5Ac2en derivatives against several bacterial sialidases. The study provides an efficient enzymatic method to access sialidase inhibitors with improved selectivity. PMID- 29713562 TI - Changing Face: A Key Residue for the Addition of Water by Sclareol Synthase. AB - Sclareol synthase from Salvia sclarea (SsSS) naturally acts on 8alpha-hydroxy copalyl diphosphate (1), stereoselectively adding water to produce (13R)-sclareol (2a), and similarly yields hydroxylated products with manifold other such bicyclic diterpene precursors. Here a key residue for this addition of water was identified. Strikingly, substitution with glutamine switches stereochemical outcome with 1, leading to selective production of (13S)-sclareol (2b). Moreover, changes to the stereospecificity of water addition with the structurally closely related substrate copalyl diphosphate (4) could be accomplished with alternative substitutions. Thus, this approach is expected to provide biosynthetic access to both epimers of 13-hydroxylated derivatives of manifold labdane-related diterpenes. PMID- 29713563 TI - Comparison of pathological characteristics between self-detected and screen detected invasive breast cancers in Chinese women: a retrospective study. AB - Background: In China, there is insufficient evidence to support that screening programs can detect breast cancer earlier and improve outcomes compared with patient self-reporting. Therefore, we compared the pathological characteristics at diagnosis between self-detected and screen-detected cases of invasive breast cancer at our institution and determined whether these characteristics were different after the program's introduction (vs. prior to). Methods: Three databases were selected (breast cancer diagnosed in 1995-2000, 2010, and 2015), which provided a total of 3,014 female patients with invasive breast cancer. The cases were divided into self-detected and screen-detected groups. The pathological characteristics were compared between the two groups and multiple imputation and complete randomized imputation were used to deal with missing data. Results: Compared with patient self-reporting, screening was associated with the following factors: a higher percentage of stage T1 tumors (75.0% vs 17.1%, P = 0.109 in 1995-2000; 66.7% vs 40.4%, P < 0.001 in 2010; 67.8% vs 35.7%, P < 0.001 in 2015); a higher percentage of tumors with stage N0 lymph node status (67.3% vs. 48.4%, P = 0.007 in 2010); and a higher percentage of histologic grade I tumors (22.9% vs 13.9%, P = 0.017 in 2010). Conclusion: Screen-detected breast cancer was associated with a greater number of favorable pathological characteristics. However, although screening had a beneficial role in early detection in China, we found fewer patients were detected by screening in this study compared with those in Western and Asian developed countries. PMID- 29713564 TI - Study of interaction of antimutagenic 1,4-dihydropyridine AV-153-Na with DNA damaging molecules and its impact on DNA repair activity. AB - Background: 1,4-dihydropyridines (1,4-DHP) possesses important biochemical and pharmacological properties, including antioxidant and antimutagenic activities. It was shown that the antimutagenic 1,4-dihydropyridine AV-153-Na interacts with DNA. The aim of the current study was to test the capability of the compound to scavenge peroxynitrite and hydroxyl radical, to test intracellular distribution of the compound, and to assess the ability of the compound to modify the activity of DNA repair enzymes and to protect the DNA in living cells against peroxynitrite-induced damage. Methods: Peroxynitrite decomposition was assayed by UV spectroscopy, hydroxyl radical scavenging-by EPR spectroscopy. DNA breakage was determined by the "comet method", activity of DNA repair enzymes-using Glyco SPOT and ExSy-SPOT assays. Intracellular distribution of the compound was studied by laser confocal scanning fluorescence microscopy. Fluorescence spectroscopy titration and circular dichroism spectroscopy were used to study interactions of the compound with human serum albumin. Results: Some ability to scavenge hydroxyl radical by AV-153-Na was detected by the EPR method, but it turned out to be incapable of reacting chemically with peroxynitrite. However, AV-153-Na effectively decreased DNA damage produced by peroxynitrite in cultured HeLa cells. The Glyco-SPOT test essentially revealed an inhibition by AV-153-Na of the enzymes involved thymine glycol repair. Results with ExSy-SPOT chip indicate that AV-153-Na significantly stimulates excision/synthesis repair of 8-oxoguanine (8 oxoG), abasic sites (AP sites) and alkylated bases. Laser confocal scanning fluorescence microscopy demonstrated that within the cells AV-153-Na was found mostly in the cytoplasm; however, a stain in nucleolus was also detected. Binding to cytoplasmic structures might occur due to high affinity of the compound to proteins revealed by spectroscopical methods. Discussion: Activation of DNA repair enzymes after binding to DNA appears to be the basis for the antimutagenic effects of AV-153-Na. PMID- 29713565 TI - Increased chemical acetylation of peptides and proteins in rats after daily ingestion of diacetyl analyzed by Nano-LC-MS/MS. AB - Background: Acetylation alters several protein properties including molecular weight, stability, enzymatic activity, protein-protein interactions, and other biological functions. Our previous findings demonstrating that diacetyl/peroxynitrite can acetylate L-lysine, L-histidine, and albumin in vitro led us to investigate whether diacetyl-treated rats suffer protein acetylation as well. Methods: Wistar rats were administered diacetyl daily for four weeks, after which they were sacrificed, and their lung proteins were extracted to be analysed by Nano-LC-MS/MS (Q-TOF). A C18 reversed-phase column and gradient elution with formic acid/acetonitrile solutions from 2 to 50% over 150 min were used to separate the proteins. Protein detection was performed using a microTOF-Q II (QTOF) equipped with captive source and an electrospray-ionization source. The data from mass spectrometry were processed using a Compass 1.7 and analyzed using Protein Scape, software that uses Mascot algorithms to perform protein searches. Results: A set of 3,162 acetylated peptides derived from 351 acetylated proteins in the diacetyl-treated group was identified. Among them, 23 targeted proteins were significantly more acetylated in the diacetyl-treated group than in the PBS control. Protein acetylation of the group treated with 540 mg/kg/day of diacetyl was corroborated by Western blotting analysis. Conclusions: These data support our hypothesis that diacetyl exposure in animals may lead to the generation of acetyl radicals, compounds that attach to proteins, affecting their functions and triggering adverse health problems. PMID- 29713566 TI - Proanthocyanidins in seed coat tegmen and endospermic cap inhibit seed germination in Sapium sebiferum. AB - Sapium sebiferum, an ornamental and bio-energetic plant, is propagated by seed. Its seed coat contains germination inhibitors and takes a long time to stratify for germination. In this study, we discovered that the S. sebiferum seed coat (especially the tegmen) and endospermic cap (ESC) contained high levels of proanthocyanidins (PAs). Seed coat and ESC removal induced seed germination, whereas exogenous application with seed coat extract (SCE) or PAs significantly inhibited this process, suggesting that PAs in the seed coat played a major role in regulating seed germination in S. sebiferum. We further investigated how SCE affected the expression of the seed-germination-related genes. The results showed that treatment with SCE upregulated the transcription level of the dormancy related gene, gibberellins (GAs) suppressing genes, abscisic acid (ABA) biosynthesis and signalling genes. SCE decreased the transcript levels of ABA catabolic genes, GAs biosynthesis genes, reactive oxygen species genes and nitrates-signalling genes. Exogenous application of nordihydroguaiaretic acid, gibberellic acid, hydrogen peroxide and potassium nitrate recovered seed germination in seed-coat-extract supplemented medium. In this study, we highlighted the role of PAs, and their interactions with the other germination regulators, in the regulation of seed dormancy in S. sebiferum. PMID- 29713568 TI - phylopath: Easy phylogenetic path analysis in R. AB - Confirmatory path analysis allows researchers to evaluate and compare causal models using observational data. This tool has great value for comparative biologists since they are often unable to gather experimental data on macro evolutionary hypotheses, but is cumbersome and error-prone to perform. I introduce phylopath, an R package that implements phylogenetic path analysis (PPA) as described by von Hardenberg & Gonzalez-Voyer (2013). In addition to the published method, I provide support for the inclusion of binary variables. I illustrate PPA and phylopath by recreating part of a study on the relationship between brain size and vulnerability to extinction. The package aims to make the analysis straight-forward, providing convenience functions, and several plotting methods, which I hope will encourage the spread of the method. PMID- 29713567 TI - Palmitic acid induces neurotoxicity and gliatoxicity in SH-SY5Y human neuroblastoma and T98G human glioblastoma cells. AB - Background: Obesity-related central nervous system (CNS) pathologies like neuroinflammation and reactive gliosis are associated with high-fat diet (HFD) related elevation of saturated fatty acids like palmitic acid (PA) in neurons and astrocytes of the brain. Methods: Human neuroblastoma cells SH-SY5Y (as a neuronal model) and human glioblastoma cells T98G (as an astrocytic model), were treated with 100-500 uM PA, oleic acid (OA) or lauric acid (LA) for 24 h or 48 h, and their cell viability was assessed by 3-(4,5-dimetylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay. The effects of stable overexpression of gamma-synuclein (gamma-syn), a neuronal protein recently recognized as a novel regulator of lipid handling in adipocytes, and transient overexpression of Parkinson's disease (PD) alpha-synuclein [alpha-syn; wild-type (wt) and its pathogenic mutants A53T, A30P and E46K] in SH-SY5Y and T98G cells, were also evaluated. The effects of co-treatment of PA with paraquat (PQ), a Parkinsonian pesticide, and leptin, a hormone involved in the brain-adipose axis, were also assessed. Cell death mode and cell cycle were analyzed by Annexin V/PI flow cytometry. Reactive oxygen species (ROS) level was determined using 2',7' dichlorofluorescien diacetate (DCFH-DA) assay and lipid peroxidation level was determined using thiobarbituric acid reactive substances (TBARS) assay. Results: MTT assay revealed dose- and time-dependent PA cytotoxicity on SH-SY5Y and T98G cells, but not OA and LA. The cytotoxicity was significantly lower in SH-SY5Y gamma-syn cells, while transient overexpression of wt alpha-syn or its PD mutants (A30P and E46K, but not A53T) modestly (but still significantly) rescued the cytotoxicity of PA in SH-SY5Y and T98G cells. Co-treatment of increasing concentrations of PQ exacerbated PA's neurotoxicity. Pre-treatment of leptin, an anti-apoptotic adipokine, did not successfully rescue SH-SY5Y cells from PA induced cytotoxicity-suggesting a mechanism of PA-induced leptin resistance. Annexin V/PI flow cytometry analysis revealed PA-induced increase in percentages of cells in annexin V-positive/PI-negative quadrant (early apoptosis) and subG0 G1 fraction, accompanied by a decrease in G2-M phase cells. The PA-induced ROS production and lipid peroxidation was at greater extent in T98G as compared to that in SH-SY5Y. Discussion: In conclusion, PA induces apoptosis by increasing oxidative stress in neurons and astrocytes. Taken together, the results suggest that HFD may cause neuronal and astrocytic damage, which indirectly proposes that CNS pathologies involving neuroinflammation and reactive gliosis could be prevented via the diet regimen. PMID- 29713569 TI - Haimormus shimojiensis, a new genus and species of Pseudozeuxidae (Crustacea: Tanaidacea) from a submarine limestone cave in Northwestern Pacific. AB - We establish a new pseudozeuxid genus Haimormus gen. nov. based on a new species Haimormus shimojiensis sp. nov. which was collected from a submarine limestone cave with the entrance at 35 m depth, in the Northwestern Pacific Ocean. H. shimojiensis differs from the other confamilial members, Pseudozeuxo belizensis Sieg, 1982 and Charbeitanais spongicola Bamber & Bird, 1997, in having the pleonite 1 without the pleopod, the pereopods 2 and 3 propodus with a ventral spiniform seta, and the pereopods 4-6 propodus with one long and two short dorsodistal setae. A key to females of species of Pseudozeuxidae is presented. This is the first tanaidacean report from submarine caves around Japan. PMID- 29713570 TI - Hepatitis C Infection Patterns at a Tertiary Care Center in New York: A Cross Sectional Study. AB - Introduction In the United States, 2.7 to 3.9 million patients are infected with the hepatitis C virus (HCV) with 3,500 new cases reported yearly. According to the Centers for Disease Control and Prevention, HCV was the underlying or contributing cause of death of 19,659 patients in 2014. These facts underscore the need for a better understanding of the scope of this disease. Our epidemiologic study aimed at analyzing the pattern of occurrence of HCV infection at Staten Island University Hospital (SIUH) by evaluating the characteristics of newly infected patients with hepatitis C in 2014. The identified features served to better distinguish the targets for preventive health care in our particular population. Methodology A cross-sectional study of all newly diagnosed patients with HCV infections in the year 2014 presenting to SIUH was conducted using International Classification of Disease-9 codes (ICD-9) for hepatitis C. We included all patients with a positive HCV antibody confirmed by polymerase chain reaction testing. Patients were divided into groups according to age to simulate the age groups in the 2013 - 2014 Hepatitis B and C Annual Report of the New York City (NYC) Department of Health and Mental Hygiene published in 2016 (abbreviated to 2014 NYCDOH Report, hereafter). Gender and HCV genotypes were also collected. We compared disease frequency between age groups, gender, and genotype with the results of the 2014 NYCDOH Report. Results A total of 378 newly diagnosed HCV cases were identified; 60.05% were men, and 39.95% were women. The rate of infection with genotype 1a was the highest (36. 5%) followed by 1b (25.9%). In women, genotype 1b was predominant (13.76%) versus genotype 1a as the most common in men. The mean age was 54 years for men and 57 years for women. Most cases fell into the 60 to 69-year age group (32.28%), followed by the 50 to 59-year age group (31.48%). More so, all patients 80 years and older were exclusively women. Conclusions We found most new HCV infections at SIUH were diagnosed in patients aged 60 to 69 years, and the 2014 NYC DOH Report indicates most new HCV infections occur in patients aged 40 to 59 years. Also, all HCV infections detected in patients older than 80 years of age were found in women. These findings provide a better understanding of the patient demographics for appropriate HCV screening policies. Increased awareness and strict adherence to screening policies in baby boomers and high-risk populations are paramount in order to diagnose HCV infection early, offer therapy, and prevent HCV-related mortality and morbidity. PMID- 29713571 TI - Superior Vena Cava Obstruction: A Rare Cause of Recurrent Esophageal Variceal Bleeding. AB - "Downhill" esophageal varices are formed in upper two-thirds of the esophagus as a consequence of a superior vena cava obstruction. We present a case of 55-year old African-American female with a medical history of multiple comorbidities, including end-stage renal disease, who presented with an upper gastrointestinal bleed and was found to have distended neck veins on physical examination. She gave a history of the insertion of an intravenous central line in her neck area for hemodialysis purposes about six years previously. An endoscopy showed the presence of esophageal varices and computed tomography (CT) of the abdomen showed the presence of a superior vena cava (SVC) obstruction. The patient was managed supportively. This case represents a rare cause of acute upper gastrointestinal bleeding in an individual with a central line for dialysis leading to SVC thrombosis. PMID- 29713572 TI - Langerhans Cell Histiocytosis of the Gastrointestinal Tract - A Rare Entity. AB - Langerhans cell histiocytosis (LCH) is an idiopathic and rare disease that ranges in clinical severity based on location and organ involvement. LCH most commonly affects the skin and bones. The involvement of the gastrointestinal tract (GI) in adults is exceedingly rare and only 10 cases have been reported in the literature. We present the case of a 60-year-old male who was referred for a routine screening colonoscopy. Numerous 3-5 mm nodular lesions were present throughout the colon. A histopathological examination revealed diffuse aggregates of histiocytes within the lamina propria of the mucosa and immunohistochemical staining further confirmed the presence of Langerhans cells with a positive CD1-a stain. Although extremely rare, LCH involving the GI tract should be considered as a differential diagnosis when polyps or nodular lesions are witnessed on screening colonoscopies. In addition, the lesions must be biopsied to confirm the diagnosis of LCH and additional follow-up is essential to rule out systemic disease. PMID- 29713573 TI - Percutaneous Management of Biliary Enteric Anastomotic Strictures: An Institutional Review. AB - Purpose Stricture formation at the biliary enteric anastomotic site is a common complication due to fibrotic healing. Few therapeutic options are available for biliary-enteric anastomotic site stricture (BES) including new surgical reconstruction or percutaneous transhepatic biliary drainage followed by balloon dilation of BES or stent placement. The purpose of this study is to assess the technical success, complications and reintervention rate of percutaneous transhepatic balloon dilatation (PTBD) of BES after iatrogenic bile duct injuries (BDI). Methods A retrospective review of patients who underwent PTBD for benign resistant BES, previously treated for iatrogenic BDI, from December 2004 to January 2016 was performed. Diagnostic transhepatic cholangiogram was performed to assess the level of obstruction. BES was dilated using 8-12 mm diameter balloons followed by placement of eight to ten Fr internal-external drainage catheters, which were removed after three to six weeks post-PTBD cholangiogram. Follow-up by clinical assessment, liver function tests, and ultrasound was done. Fischer exact test was used to determine if there was a significant association between PTBD sessions and recurrent strictures. Results In total, 37 patients underwent 66 sessions of PTBD, including 10 (27%) males and 27 (73%) females. The mean age was 41.3 years (range 23-70 years). Out of these, 29 (78%) were treated with choledochojejunostomy and eight (22%) with hepaticojejunostomy. 100% technical success was achieved in all the PTBD sessions. Nineteen (51.3%) patients were treated with a single PTBD session. Mean follow-up time was 36 months (range 1-75 months). Eighteen (48.7%) patients needed reintervention, out of these, 11 (29.7%) were symptom-free after second session on three-year follow up, three (8%) were symptom-free after the third session of PTBD. No significant difference was observed in risk of recurrent strictures after first and second PTBD sessions [18 (48%) vs. 7 (39%); p-value 0.495]. In four (11%) patients, the symptoms persisted and BES recurred even after third session and those were treated by placing metallic stent. In total, three (8.1%) patients got complicated with the stone formation; in two (5%) patients stone was successfully removed percutaneously and in one (3%) patient percutaneous attempt failed so it was followed by surgical removal. Conclusion PTBD is a safe and useful treatment option for benign BES for long-term symptom-free time-period. However, there is no significant difference in developing recurrent BES after PTBD sessions. Few patients with resistant strictures might require stent placement. PMID- 29713574 TI - Idiopathic Peroneal Tenosynovitis Caused by a Previously Undiagnosed Auto-immune Condition. AB - In this case report, we present a unique case of idiopathic peroneal tenosynovitis in an otherwise healthy patient, presenting with a three-month history of pain over the lateral aspect of the right foot. Imaging revealed that fluid distention and synovial thickening distend the common peroneal tendon sheath and peroneus longus and brevis tendon sheaths. The patient was managed operatively with excision of the peroneus longus tendon, a side-to-side tenodesis, and Brostrom-Gould lateral ankle ligament repair. Histologic examination was suggestive of a chronic inflammatory process possibly due to underlying autoimmune etiology. At three-month follow-up, the patient reported complete resolution of pain and is resuming normal activities without difficulty. PMID- 29713575 TI - An Evaluation of Complications in Femoral Arterial Sheaths Maintained Post Neuroangiographic Procedures. AB - BACKGROUND: Digital subtraction angiography (DSA) is a frequently used technique in the neuro-diagnosis and treatment of cerebrovascular diseases. The routine use of femoral arterial sheaths (FAS) peri-procedurally has become standard. The maintenance of a FAS post-procedure may be warranted while awaiting the normalization of coagulopathy or to reaccess emergently. We retrospectively reviewed our stroke dataset to evaluate for complications associated with the prolonged use of FAS post-procedure. METHODS: A retrospective chart review was performed over a five-month period, including adult patients admitted to the neuroscience intensive care unit (NSICU) following a neuro-endovascular procedure at a tertiary healthcare facility. The patients' age and sex along with catheter size, duration of sheath placement, coagulation status, usage of heparinized saline, reuse of FAS for angiographic interventions, and closure technique employed when sheath was removed were recorded. FAS were maintained and evaluated by the neurocritical care team for vascular complications according to protocols. Furthermore, patients were categorized as delayed extubation when they remained intubated post-procedure. A spontaneous breathing trial was performed once FAS could be removed following evaluation. Data were expressed with descriptive statistics. RESULTS: One hundred and seventy-eight neuro-endovascular procedures were reviewed. Fourteen patients in which the sheaths were left in place for a prolonged period of time after the procedure were identified with seven (50%) having complications. The most common complication was delayed extubation, which was noted in all seven of the patients with complications. Bleeding complications were noted in four (28.6%). None had thromboembolic complications. Only one FAS was reaccessed for the evaluation of vasospasm and the introduction of intra arterial verapamil. There was a linear increase in complications with the duration the catheter remained in place after the procedure. CONCLUSION: The practice of keeping FAS in for a prolonged period of time following procedures should be evaluated given the association with direct and indirect complications and minimal need to reaccess the catheter after the procedure. PMID- 29713576 TI - Meningomyelocele Simulation Model: Pre-surgical Management-Technical Report. AB - This technical report describes the creation of a myelomeningocele model of a newborn baby. This is a simple, low-cost, and easy-to-assemble model that allows the medical team to practice the delivery room management of a newborn with myelomeningocele. The report includes scenarios and a suggested checklist with which the model can be employed. PMID- 29713578 TI - A Surgical Conundrum in Feeding Jejunostomy-Jejunojejunal Intussusception: A Case Series. AB - Intussusception is a common cause of intestinal obstruction in the pediatric population. Usually, it is primary and benign and can be managed by nonoperative interventions in 80% of the cases. Adult intussusception accounts for only 5% of all cases of intussusception and 1%-5% of all cases of intestinal obstruction. Unlike in the pediatric population, intussusception in adults is usually caused by a pathologic lead point. The initial investigation to diagnose it is an ultrasound abdomen followed by contrast-enhanced computed tomography (CECT) of the abdomen. The placement of an intestinal tube for feeding purposes has been rarely reported as a cause of intussusception. Here, we present a case series of four patients who had jejunojejunal intussusception following the placement of feeding tubes into the jejunum. Three patients were operatively managed and one was managed conservatively. PMID- 29713577 TI - Subthalamic and Pallidal Deep Brain Stimulation for Parkinson's Disease. AB - Deep brain stimulation (DBS) is a surgical treatment in which stimulation electrodes are permanently implanted in basal ganglia to treat motor fluctuations and symptoms of Parkinson's disease (PD). Subthalamic nucleus (STN) and globus pallidus internus (GPi) are the commonly used targets for DBS in PD. Many studies have compared motor and non-motor outcomes of DBS in both targets. However, the selection of PD patients for DBS targets is still poorly studied. Therefore, we performed this narrative review to summarize published studies comparing STN DBS and GPi DBS. GPi DBS is better for patients with problems in speech, mood, or cognition while STN DBS is better from an economic point of view as it allows much reduction in antiparkinson medications and less battery consumption. PMID- 29713579 TI - Laryngeal Squamous Cell Carcinoma Survival in the Context of Human Papillomavirus: A Systematic Review and Meta-analysis. AB - BACKGROUND: Head and neck (H&N) squamous cell carcinoma (SCC) is a significant contributor to worldwide mortality and morbidity. Human papillomavirus (HPV) has been linked with H&N cancer and HPV-positive H&N SCC have been shown to have better survival outcomes. OBJECTIVE: To evaluate the effect of human papillomavirus (HPV) on laryngeal carcinoma (LSCC) survival outcomes and prognosis. METHOD: A systematic review and meta-analysis were performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. LSCC was confirmed based on histopathology, and HPV status was confirmed by either polymerase chain reaction, immunohistochemistry, and/or in situ hybridization. RESULTS: There were 1214 studies which were identified, of which 14 studies were eligible for our review. A total of 2,578 cases of LSCC were included in analysis with 413 (16.0%) HPV-positive. Overall survival (OS) was not significant for HPV-positive LSCC in first five years (year one: OR 1.44 p=0.13; year two: OR 1.24 p=0.30; year three: OR 1.01 p=0.97; year four: OR 1.13 p=0.63; year five: OR 1.01 p=0.98). Disease-free survival (DFS) was similarly not significant for HPV-positive LSCC (year one: OR 1.08 p=0.68; year two: OR 1.22, p=0.31; year three: OR 1.13, p=0.69; year four: OR 0.93, p=0.80 and year five: OR 1.42, p=0.30). When studies are sub-divided into global regions, Chinese studies had better HPV-positive survival compared to North American studies in year five (OR 1.84 vs OR 0.46, p=0.04). CONCLUSION: This is the first study of its kind to evaluate the survival impact of HPV-positive LSCC patients. Unlike oropharyngeal cancer, HPV status does not make a difference to OS or DFS in LSCC. This supports data that HPV is not a prognostic factor in squamous carcinoma of the larynx. PMID- 29713580 TI - Breast Cancer Incidence and Risk Reduction in the Hispanic Population. AB - Breast cancer is the most common non-skin cancer amongst women worldwide and is the fifth leading cause of cancer-related mortality overall. It is also the foremost reason for cancer-related mortality in Hispanic females in the United States (US). Although the current incidence of breast cancer is significantly lower in Hispanics compared to that of non-Hispanic Whites (NHW) and Blacks, (91.9, 128.1, and 124.3 per 100,000, respectively, annually), this may increase if Hispanics develop similar lifestyle behaviors to other American women, in categories such as weight management, age at first birth, number of children, and breastfeeding habits. Stage-for-stage mortality for Hispanics is similar to NHWs, but the mortality rate is not declining as rapidly in this ethnic group. Hispanic women share many of the same risk factors for developing breast cancer as NHWs and Blacks. This suggests that many of the risk reduction strategies used in other racial populations may also benefit this group. Providing education about breast cancer and implementing risk reduction strategies in culturally-aware environments could help keep incidence low and reduce cancer-related mortality. Since Hispanics are the largest minority group in the US, this could have a significant impact on the incidence and mortality nationally. PMID- 29713581 TI - Bioconversion of acrylonitrile using nitrile hydratase activity of Bacillus sp. APB-6. AB - Bacillus sp. APB-6 harboring nitrile hydratase was used in the production of acrylamide from acrylonitrile. Bacillus sp. APB-6, for maximum production of Co++ containing nitrile hydratase, was cultured in the medium containing lactose (18.0 g l-1), peptone (1.0 g l-1), yeast extract (2.0 g l-1), MgSO4 (0. 5 g l-1), K2HPO4 (0.6 g l-1), urea (9.0 g l-1), and CoCl2 (0.01 g l-1), pH 7.0, and incubated at 35 degrees C for 24 h in an incubator shaker (160 rpm). Nitrile hydratase exhibited relatively high specificity for aliphatic nitriles. Free cells were immobilized using 2% (w/v) agar solution to enhance enzyme stability and reusability in repetitive cycles of acrylamide production. Under optimized conditions, nearly complete bioconversion of acrylonitrile was achieved with a fair recovery of 85% using free and immobilized cells equivalent to 500 mg dcw l 1. An efficient nitrile hydratase-mediated bioconversion of acrylonitrile to acrylamide at 1-l scale was achieved with time and space productivity of 426 g h 1 g-1 dcw using free cells. PMID- 29713582 TI - Association analysis of drought tolerance in cut chrysanthemum (Chrysanthemum morifolium Ramat.) at seedling stage. AB - Understanding the genetic architecture is a prerequisite for crop improvement. The current research aimed to characterize the extent of genetic variation of drought tolerance harbored in a global collection of 159 chrysanthemum cultivars over 2 years. An average subordinate function value (ASFV), integrating the wilting index, the fresh weight retention rate, and the survival rate after re watering under two drought-stressed trials, was used to quantify the level of drought tolerance. The performance of ASFV was generally correlated between the 2 years; and a high magnitude (0.95) of broad-sense heritability, coupled with the moderate genetic advance, was estimated for the ASFV. By applying MLM model with both population structure and kinship matrix as covariates association mapping identified 16 markers linked to drought tolerance, with the proportion of the phenotypic variation explained by an individual marker ranging from 4.4 to 7.6%. Of the eight markers predictive across the 2 years, four (E11M24-9, E3M2-8, E1M5 5, and EST-SSR34-3) were identified as favorable alleles for drought tolerance. Several cultivars that carry at least three of the four favorable alleles were identified as potential donor parents for future improvement of the drought tolerance. The findings provide an insight into the genetic basis of the drought tolerance in chrysanthemum and will, therefore, aid in developing new cultivars with enhanced tolerance against drought stress. PMID- 29713583 TI - Identification of Malignancy-Associated Changes in Histologically Normal Tumor Adjacent Epithelium of Patients with HPV-Positive Oropharyngeal Cancer. AB - The incidence of HPV-positive oropharyngeal cancer (HPV+ OPC) is increasing, thus presenting new challenges for disease detection and management. Noninvasive methods involving brush biopsies of diseased tissues were recently reported as insufficient for tumor detection in HPV+ OPC patients, likely due to differences between the site of tumor initiation at the base of involuted crypts and the site of brush biopsy at the crypt surface. We hypothesized that histologically normal surface epithelial cells in the oropharynx contain changes in nuclear morphology that arise due to tumor proximity. We analyzed the nuclear phenotype of matched tumor, tumor-adjacent normal, and contralateral normal tissues from biopsies of nine HPV+ OPC patients. Measurements of 89 nuclear features were used to train a random forest-based classifier to discriminate between normal and tumor nuclei. We then extracted voting scores from the trained classifier, which classify nuclei on a continuous scale from zero ("normal-like") to one ("tumor-like"). In each case, the average score of the adjacent normal nuclei was intermediate between the tumor and contralateral normal nuclei. These results provide evidence for the existence of phenotypic changes in histologically normal, tumor-adjacent surface epithelial cells, which could be used as brush biopsy-based biomarkers for HPV+ OPC detection. PMID- 29713585 TI - To reach elimination one needs to think and act locally, to support the global vision. PMID- 29713584 TI - PD-L1 testing using the clone 22C3 pharmDx kit for selection of patients with non small cell lung cancer to receive immune checkpoint inhibitor therapy: are cytology cell blocks a viable option? AB - Introduction: Programmed death ligand 1 (PD-L1) testing of non-small cell lung cancer (NSCLC) specimens helps select patients most likely to respond to immune checkpoint inhibitors. PD-L1 immunohistochemical testing is approved for formalin fixed, paraffin-embedded (FFPE) surgical pathology specimens; however, the testing performance on FFPE cytology cell block specimens is unknown. Materials and Methods: The study is a retrospective cohort analysis of advanced stage NSCLC patients treated at our institution where tumor PD-L1 expression using the clone 22C3 pharmDx kit on the Dako Automated Link 48 platform was performed on either cytology cell block or surgical pathology specimens. Concomitant tumor mutation biomarkers were also collected, as well as tumor clinicopathologic characteristics and clinical outcome data following pembrolizumab treatment. Results: 232 patient tumor specimens were tested for PD-L1 expression (94 on cytology cell block and 138 on surgical pathology specimens). No significant differences in PD-L1 tumor proportion score (TPS) were observed between cytology and surgical pathology groups, with both patient cohorts containing ~35% of tumors showing TPS >=50%. Although few in number, patients with PD-L1 TPS >=50% based on cytology vs. surgical pathology who received treatment with pembrolizumab demonstrated similar response and disease control rates. Conclusions: In this cohort of advanced NSCLC patients with standard of care PD L1 testing performed on either FFPE cytology cell blocks or FFPE surgical pathology specimens, similar patterns were observed in population tumor PD-L1 expression patterns, concomitant driver mutations, and clinical response to palliative pembrolizumab in selected patients with TPS >=50%. PMID- 29713586 TI - Case management of malaria in Swaziland, 2011-2015: on track for elimination? AB - Objective: To assess adherence to malaria diagnosis and treatment guidelines (2010 and 2014) in all health care facilities in Swaziland between 2011 and 2015. Methods: This was a cross-sectional descriptive study involving all health care facilities that diagnosed and managed malaria cases in Swaziland. Patients' age, sex, diagnosis method and type of treatment were analysed. Results: Of 1981 records for severe and uncomplicated malaria analysed, 56% of cases were uncomplicated and 14% had severe malaria. The type of malaria was not recorded for 30% of cases. Approximately 71% of cases were confirmed by rapid diagnostic tests (RDT) alone, 3% by microscopy alone and 26% by both RDT and microscopy. Of the uncomplicated cases, 93% were treated with artemether-lumefantrine (AL) alone, 5% with quinine alone and 2% with AL and quinine. Amongst the severe cases, 11% were treated with AL alone, 44% with quinine alone and 45% with AL and quinine. For severe malaria, clinics and health centres prescribed AL alone more often than hospitals (respectively 13%, 12% and 4%, P = 0.03). Conclusion: RDTs and/or microscopy results are used at all facilities to inform treatment. Poor recording of malaria type causes difficulties in assessing the prescription of antimalarial drugs. PMID- 29713587 TI - From diagnosis to case investigation for malaria elimination in Swaziland: is reporting and response timely? AB - Background: Swaziland is one of the southern African countries that aim to eliminate malaria by 2020. In 2010, the country introduced an Immediate Disease Notification System (IDNS) for immediate reporting of notifiable diseases, including malaria. Health facilities are to report malaria cases within 24 h through a toll-free telephone number (977), triggering an alert for case investigation at the patient's household within 48 h. We assessed the completeness of reporting in the IDNS, the subsequent case investigation, and whether it was done within the stipulated timelines. Methods: A cross-sectional study using routine country-wide data. Results: Of 1991 malaria cases notified between July 2011 and June 2015, 76% were reported in the IDNS, of which 68% were investigated-a shortfall of 24% in reporting and 32% in case investigations. Of the 76% of cases reported through the IDNS, 62% were reported within 24 h and 20% were investigated within 48 h. These shortcomings were most pronounced in hospitals and private facilities. Investigated cases (n = 1346) were classified as follows: 60% imported, 35% local and 5% undetermined. Conclusion: The utilisation of the IDNS for case reporting to trigger investigation is crucial for active surveillance. There is a need to address the reporting and investigation gaps identified to ensure that malaria cases receive appropriate interventions. PMID- 29713588 TI - Three parallel information systems for malaria elimination in Swaziland, 2010 2015: are the numbers the same? AB - Background: To be able to eliminate malaria, accurate, timely reporting and tracking of all confirmed malaria cases is crucial. Swaziland, a country in the process of eliminating malaria, has three parallel health information systems. Design: This was a cross-sectional study using country-wide programme data from 2010 to 2015. Methods: The Malaria Surveillance Database System (MSDS) is a comprehensive malaria database, the Immediate Disease Notification System (IDNS) is meant to provide early warning and trigger case investigations to prevent onward malaria transmission and potential epidemics, and the Health Management Information Systems (HMIS) reports on all morbidity at health facility level. Discrepancies were stratified by health facility level and type. Results: Consistent over-reporting of 9-85% was noticed in the HMIS, principally at the primary health care level (clinic and/or health centre). In the IDNS, the discrepancy went from under-reporting (12%) to over-reporting (32%); this was also seen at the primary care level. At the hospital level, there was under reporting in both the HMIS and IDNS. Conclusions: There are considerable discrepancies in the numbers of confirmed malaria cases in the HMIS and IDNS in Swaziland. This may misrepresent the malaria burden and delay case investigation, predisposing the population to potential epidemics. There is an urgent need to improve data integrity in order to guide and evaluate efforts toward elimination. PMID- 29713589 TI - Moving towards malaria elimination: trends and attributes of cases in Kavango region, Namibia, 2010-2014. AB - Setting: Kavango, a 'moderate' transmission risk region located in north-eastern Namibia, borders Angola, a country with higher malaria transmission levels. Objective: To determine 1) the trends in malaria incidence between 2010 and 2014 in Kavango, 2) the socio-demographic and clinical characteristics of confirmed cases in 2014, and 3) associated risk factors of cases classified as imported. Design: This was a retrospective study of malaria case investigation forms conducted in all 52 public health facilities in 2014. Incidence was derived from aggregate routine surveillance data from the Health Information System (HIS). Results: During the 5-year study, incidence fell from 53.6 to 3.6 cases per 1000 population, then increased again to 47.3/1000. Fifty-five per cent of cases were males, and 49% were aged between 5 and 17 years. Of the 2014 cases, 23% were imported, and were associated with higher odds of severe malaria (adjusted odds ratio [aOR] 1.8; 95%CI 1.01-3.29), not having long-lasting insecticide treated nets (aOR 2.1, 95%CI, 1.3-3.4) and not receiving insecticide residual spraying (aOR 3.2, 95%CI, 2.1-5.1). Conclusion: Sporadic outbreaks in the 5-year period posed a threat to malaria elimination. Better targeting of vector control interventions, strong cross-border collaboration and robust health promotion will be key to achieving malaria elimination. PMID- 29713590 TI - Driving towards malaria elimination in Botswana by 2018: progress on case-based surveillance, 2013-2014. AB - Background: Reliable information reporting systems ensure that all malaria cases are tested, treated and tracked to avoid further transmission. Botswana aimed to eliminate malaria by 2018, and surveillance is key. This study focused on assessing the uptake of the new malaria case-based surveillance (CBS) system introduced in 2012, which captures information on malaria cases reported in the Integrated Disease Surveillance and Response (IDSR) system. Methods: This was a retrospective descriptive study based on routine data focusing on Ngami, Chobe and Okavango, three high-risk districts in Botswana. Aggregated data variables were extracted from the IDSR and compared with data from the CBS. Results: The IDSR reported 456 malaria cases in 2013 and 1346 in 2014, of which respectively only 305 and 884 were reported by the CBS. The CBS reported 34% fewer cases than the IDSR system, indicating substantial differences between the two systems. The key malaria indicators with the greatest variability among the districts included in the study were case identification number and date of diagnosis. Conclusion: The IDSR and CBS systems are essential for malaria elimination, as shown by the significant gaps in reporting between the two systems. These findings highlight the need for further investigation into these discrepancies. Strengthening the CBS system will help to reach the objective of malaria elimination in Botswana. PMID- 29713591 TI - Low uptake of preventive interventions among malaria cases in Swaziland: towards malaria elimination. AB - Settings: Swaziland is striving to achieve sustainable malaria elimination. Three preventive interventions are vital for reaching this goal: 1) effective household utilisation of long-lasting insecticide nets (LLINs), 2) indoor residual spraying (IRS), and 3) provision of chemoprophylaxis for those travelling to malaria endemic areas. Objectives: To assess the uptake of preventive intervention among confirmed malaria cases. Design: A longitudinal study using nation-wide programme data from 2010 to 2015. Data on malaria cases from health facilities were sourced from the Malaria Surveillance Database System. Results: Of a total 2568 confirmed malaria cases in Swaziland, 2034 (79%) had complete data on case investigations and were included in the analysis. Of 341 (17%) individuals who owned LLINs, 169 (8%) used them; 338 (17%) had IRS and 314 (15%) slept in sprayed structures. Of 1403 travellers to areas at high malaria risk, 59 (4%) used any form of malaria prevention, including chemoprophylaxis. Conclusion: The uptake of all three key malaria prevention interventions is low, and could threaten the progress made thus far toward malaria elimination. Efforts to improve this situation, including qualitative research to understand the reasons for low uptake, are urgently needed. PMID- 29713592 TI - Advances in malaria elimination in Botswana: a dramatic shift to parasitological diagnosis, 2008-2014. AB - Background: Malaria elimination requires infection detection using quality assured diagnostics and appropriate treatment regimens. Although Botswana is moving towards malaria elimination, reports of unconfirmed cases may jeopardise this effort. This study aimed to determine the proportion of cases treated for malaria that were confirmed by rapid diagnostic testing (RDT) and/or microscopy. Methods: This was a retrospective descriptive study using routine national data from the integrated disease surveillance and case-based surveillance systems from 2008 to 2014. The data were categorised into clinical and confirmed cases each year. An analysis of the data on cases registered in three districts that reported approximately 70% of all malaria cases was performed, stratified by year, type of reporting health facilities and diagnostic method. Results: During 2008-2014, 50 487 cases of malaria were reported in Botswana, and the proportion of RDT and/or blood microscopy confirmed cases improved from 6% in 2008 to 89% in 2013. The total number of malaria cases decreased by 97% in the same period, then increased by 41% in 2013. Conclusion: This study shows that malaria diagnostic tests dramatically improved malaria diagnosis and consequently reduced the malaria burden in Botswana. The study identified a need to build capacity on microscopy for species identification, parasite quantification and guiding treatment choices. PMID- 29713593 TI - Changing distribution and abundance of the malaria vector Anopheles merus in Mpumalanga Province, South Africa. AB - Background: The malaria vector Anopheles merus occurs in the Mpumalanga Province of South Africa. As its contribution to malaria transmission in South Africa has yet to be ascertained, an intensification of surveillance is necessary to provide baseline information on this species. The aim of this study was therefore to map An. merus breeding sites in the Ehlanzeni District of Mpumalanga Province and to assess qualitative trends in the distribution and relative abundance of this species over a 9-year period. Methods: The study was carried out during the period 2005-2014 in the four high-risk municipalities of Ehlanzeni District. Fifty-two breeding sites were chosen from all water bodies that produced anopheline mosquitoes. The study data were extracted from historical entomological records that are captured monthly. Results: Of the 15 058 Anopheles mosquitoes collected, 64% were An. merus. The abundance and distribution of An. merus increased throughout the four municipalities in Ehlanzeni District during the study period. Conclusion: The expanded distribution and increased abundance of An. merus in the Ehlanzeni District may contribute significantly to locally acquired malaria in Mpumalanga Province, likely necessitating the incorporation of additional vector control methods specifically directed against populations of this species. PMID- 29713594 TI - Is there a correlation between malaria incidence and IRS coverage in western Zambezi region, Namibia? AB - Setting: A comparison of routine Namibia National Malaria Programme data (reported) vs. household survey data (administrative) on indoor residual spraying (IRS) in western Zambezi region, Namibia, for the 2014-2015 malaria season. Objectives: To determine 1) IRS coverage (administrative and reported), 2) its effect on malaria incidence, and 3) reasons for non-uptake of IRS in western Zambezi region, Namibia, for the 2014-2015 malaria season. Design: This was a descriptive study. Results: IRS coverage in western Zambezi region was low, ranging from 42.3% to 52.2% for administrative coverage vs. 45.9-66.7% for reported coverage. There was no significant correlation between IRS coverage and malaria incidence for this region (r = -0.45, P = 0.22). The main reasons for households not being sprayed were that residents were not at home during spraying times or that spray operators did not visit the households. Conclusions: IRS coverage in western Zambezi region, Namibia, was low during the 2014-2015 malaria season because of poor community engagement and awareness of times for spray operations within communities. Higher IRS coverage could be achieved through improved community engagement. Better targeting of the highest risk areas by the use of malaria surveillance will be required to mitigate malaria transmission. PMID- 29713596 TI - Bacterial NanoCellulose: what future? AB - Acetic acid bacteria (AAB) have been used in various fermentation processes. Of several ABB, the bacterial nanocellulose (BNC) producers, notably Komagataeibacter xylinus, appears as an interesting species, in large part because of their ability in the secretion of cellulose as nano/microfibrils. In fact, BNC is characterized by a native nanofibrillar structure, which may outperform the currently used celluloses in the food industry as a promising novel hydrocolloid additive. During the last couple of years, a number of companies worldwide have introduced some BNC-based products to the market. The main aim of this editorial is to underline the BNC potentials. PMID- 29713595 TI - Did microbial larviciding contribute to a reduction in malaria cases in eastern Botswana in 2012-2013? AB - Setting: Larviciding has potential as a component of integrated vector management for the reduction of malaria transmission in Botswana by complementing long lasting insecticide nets and indoor residual sprays. Objective: To evaluate the susceptibility of local Anopheles to commonly used larvicides. Design: This field test of the efficacy of Bacillus thuringiensis subsp. israliensis vs. Anopheles was performed by measuring larval density before treatment and 24 h and 48 h after treatment in seven sites of Bobirwa district, eastern Botswana, in 2012 and 2013. Vector density and malaria cases were compared between Bobirwa and Ngami (northwestern Botswana), with no larviciding in the control arm. Results: Larviciding reduced larval density by 95% in Bobirwa in 2012, with two cases of malaria, while in 2013 larval density reduction was 81%, with 11 cases. Adult mosquito density was zero for both years in Robelela village (Bobirwa), compared to respectively four and 26 adult mosquitoes per room in Shorobe village (Ngami) in 2012 and 2013. There were no cases of malaria in Robelela in either year, but in Shorobe there were 20 and 70 cases, respectively, in 2012 and 2013. Conclusion: Larviciding can reduce the larval density of mosquitoes and reduce malaria transmission in Botswana. Large-scale, targeted implementation of larviciding in districts at high risk for malaria is recommended. PMID- 29713597 TI - The role of PRP and adipose tissue-derived keratinocytes on burn wound healing in diabetic rats. AB - Introduction: Diabetic burn wounds and ulcers are significant complications of diabetic patients. The aim of this study is to investigate the use of platelet rich-plasma (PRP) and/or keratinocyte-like cells (KLCs) in diabetic thermal wound rat model and to evaluate EGF, FGF-2, TGF-beta1, COL1alpha2, MCP-1 and VEGF-alpha as wound healing markers at gene expression level. Method: In this study, we used adipose tissue as the source of mesenchymal stem cells (MSCs) and differentiated MSCs into KLCs. KLCs were characterized and transferred to the burn areas on the dorsum of streptozotocine (STZ)-induced diabetic rats. We prepared PRP from rat blood and evaluated its effect alone or in combination with KLCs. On 3rd, 7th, 10th and 14th days after treatment, wound areas were measured and biopsy samples were excised from the wound areas of the KLCs and/or PRP-treated and untreated diabetic rats to analyze gene expression levels of wound healing markers by qPCR. Results: We observed that, wound contraction started earlier in the PRP and/or KLCs-treated groups in comparison to the control group. However, PRP and KLCs when applied in combination showed additive affect in wound healing. In all groups treated with KLCs and/or PRP, the gene expression levels of evaluated growth factors and COL1alpha2 increased, while MCP-1 levels decreased when compared to the untreated diabetic rats. In addition, the most prominent difference in qPCR results belongs to combined PRP and KLCs-treated group. Conclusion: We demonstrated that applying PRP and KLCs in combination has a greater potential for treatment of diabetic burn wounds. PMID- 29713598 TI - Development of a new sequential block finding strategy for detection of conserved sequences in riboswitches. AB - Introduction: Some non-coding RNAs have an important role in the regulation of gene expression and consequently cellular function. Riboswitches are examples of these regulatory RNAs. Riboswitches are classified into various families according to sequential and structural similarities. Methods: In this study, a block finder algorithm for identification of frequently appearing sequential blocks in five families of riboswitches from Rfam 12.0 database, without the use of alignment methods, was developed. Results: The developed program identified 21 frequently appearing blocks in five families of riboswitches. Conclusion: Comparison of the results of the proposed algorithm with those of sequential alignment methods revealed that our method can recognize most of the patterns present in conserved areas of individual riboswitch families and determine them as specific blocks, implying potential of the developed program as a platform for further studies and developments. PMID- 29713599 TI - Caralluma umbellata Haw. protects liver against paracetamol toxicity and inhibits CYP2E1. AB - Introduction: Paracetamol is a potent hepatotoxin and may cause severe acute hepatocellular injury. The present study was intended to assess the hepatoprotective potential of Caralluma umbellata Haw. (Asclepiadaceae) (C. umbellata ) against paracetamol-induced hepatotoxicity in vitro and in vivo experimental models. Methods: Preliminary analysis for antioxidant and hepatoprotective property was evaluated for methanolic (MCU), aqueous (ACU) and hydro methanolic (HCU) extracts of C. umbellata using in vitro cell-free antioxidant such as DPPH, ABTS, nitric oxide, lipid peroxidation models and cell based hepatoprotective study using BRL3A cells. In vivo, hepatoprotective activity was studied in paracetamol treated male Wistar albino rats. Furthermore, molecular mechanism behind the protective effect of MCU was explored by RT PCR technique by utilizing cytochrome P450 (CYP) CYP2E1. Results:C. umbellata extracts especially, MCU showed a better antioxidant property. MCU offered significant dose-dependent protection against paracetamol-induced hepatic damage in both in vitro and in vivo assays by improving all the biochemical findings towards the normal range. In a mechanism-based study, MCU has offered significant down-regulation (p < 0.05) of CYP2E1. These findings were in line with the hepatoprotective activity findings where MCU showed significant protection. Conclusion: In conclusion, these findings suggest that MCU possess hepatoprotective activity. One of the possible mechanisms behind the protective effect of MCU is found to be inhibition of CYP2E1. PMID- 29713600 TI - Spectrophotometric analysis of thrombolytic activity: SATA assay. AB - Introduction: Measurement of thrombolytic activity is crucial for research and development of novel thrombolytics. It is a key factor in the assessment of the effectiveness of conventionally used thrombolytic therapies in the clinic. Previous methods used for the assessment of thrombolytic activity are often associated with some drawbacks such as being costly, time-consuming, complex with low accuracy. Here, we introduce a simple, economic, relatively accurate and fast method of spectrophotometric analysis of thrombolytic activity (SATA) assay, standardized by tissue plasminogen activator (tPA), which can quantitatively measure in vitro thrombolytic activity. Methods: Blood clots were formed, uniformly, by mixing citrated whole blood with partial thromboplastin time (PTT) reagent, together with calcium chloride. Then, designated concentrations of tPA were added to the samples, and the released red blood cells from each clot were quantified using spectrophotometry (lambdamax=405nm) as an indicator of thrombolytic activity. The accuracy of the method was tested by assessment of dose-responsibility against R2 value obtained by linear equation and measurement of the limit of detection (LOD) and limit of quantification (LOQ). The SATA assay was validated in comparison with some currently used techniques. Results: A linear relationship was obtained between different concentrations of tPA versus the spectrophotometric absorbance of the related dilutions of lysed clots, at lambdamax=405nm. Calculated R2 values were greater than 0.9; with LOD of 0.90 ug/mL of tPA (436.50IU) and LOQ of 2.99 ug/mL of tPA (1450.15IU). Conclusion: Conclusively, the SATA assay is a very simple quantitative method with repeatable and reproducible results for estimating the potency of an unknown thrombolytic agent, and calculating the activity as delicate as 1 ug/mL of tPA (485 IU/mL of thrombolytic dose). PMID- 29713601 TI - A novel B- and helper T-cell epitopes-based prophylactic vaccine against Echinococcus granulosus. AB - Introduction: In this study, we targeted the worm stage of Echinococcus granulosus to design a novel multi-epitope B- and helper T-cell based vaccine construct for immunization of dogs against this multi-host parasite. Methods: The vaccine was designed based on the local Eg14-3-3 antigen (Ag). DNA samples were extracted from the protoscoleces of the infected sheep's liver, and then subjected to the polymerase chain reaction (PCR) with 14-3-3 specific forward and reverse primers. For the vaccine designing, several in silico steps were undertaken. Three-dimensional (3D) structure of the local Eg14-3-3 Ag was modeled by EasyModeller software. The protein modeling accuracy was then analyzed via various validation assays. Potential transmembrane helix, signal peptide, post translational modifications and allergenicity of Eg14-3-3 were evaluated as the preliminary measures of B-cell epitopes (BEs ) prediction. Having used many web servers, a well-designed process was carried out for improved prediction of BEs. High ranked linear and conformational BEs were utilized for engineering the final vaccine construct. Possible T-helper epitopes (TEs) were identified by the molecular docking between 13-mer fragments of the Eg14-3-3 Ag and two high frequent dog class II MHC alleles (i.e., DLA-DRB1*01101 and DRB1*01501). The epitopes coverage was evaluated by Shannon's variability plot. Results: The final designed construct was analyzed based on different physicochemical properties, which was then codon optimized for high-level expression in Escherichia coli k12. This minigene construct is the first dog-specific epitopic vaccine construct that is established based on TEs with high-binding affinity to canine MHC alleles. Conclusion: This in silico study is the first part of a multi-antigenic vaccine designing work that represents as a novel dog-specific vaccine against E. granulosus. Here, we present key data on the step-by-step methodologies used for designing this de novo vaccine, which is under comprehensive in vivo investigations. PMID- 29713602 TI - Chemiluminescence based immunoassay for the detection of heroin and its metabolites. AB - Introduction: Continuous use of opiates causes drug-related illnesses, which poses an alarming situation to develop sensitive detection platform. In this study, a highly sensitive and reliable chemiluminescence immunoassay (CI) has been developed for the detection of heroin and its major metabolites in spiked urine samples. Methods: To develop robust immunoassay, monoacetyl morphine-bovine serum albumin (MAM-BSA) conjugate was synthesized and characterized thoroughly by physicochemical techniques. The anti-MAM antibodies were developed, labeled with horseradish peroxidase (HRP) and immunoassay was developed to detect the presence of target drug in spiked urine samples. Results: A competitive CI was developed, where heroin, MAM, morphine, and codeine concentration were ranged from 0-1000 ng/ mL in spiked urine samples and limit of detection were 80, 95, 90, 75 pg/ mL. Conclusion: The developed CI is highly sensitive, specific, point of care, cost effective and can be used as a routine technique for quantitative analysis for screening of narcotic drugs. PMID- 29713603 TI - Combating atherosclerosis with targeted nanomedicines: recent advances and future prospective. AB - Introduction: Cardiovascular diseases (CVDs) is recognized as the leading cause of mortality worldwide. The increasing prevalence of such disease demands novel therapeutic and diagnostic approaches to overcome associated clinical/social issues. Recent advances in nanotechnology and biological sciences have provided intriguing insights to employ targeted Nanomachines to the desired location as imaging, diagnosis, and therapeutic modalities. Nanomedicines as novel tools for enhanced drug delivery, imaging, and diagnosis strategies have shown great promise to combat cardiovascular diseases. Methods: In the current study, we intend to review the most recent studies on the nano-based strategies for improved management of CVDs. Results: A cascade of events results in the formation of atheromatous plaque and arterial stenosis. Furthermore, recent studies have shown that nanomedicines have displayed unique functionalities and provided de novo applications in the diagnosis and treatment of atherosclerosis. Conclusion: Despite some limitations, nanomedicines hold considerable potential in the prevention, diagnosis, and treatment of various ailments including atherosclerosis. Fewer side effects, amenable physicochemical properties and multi-potential application of such nano-systems are recognized through various investigations. Therefore, it is strongly believed that with targeted drug delivery to atherosclerotic lesions and plaque, management of onset and progression of disease would be more efficient than classical treatment modalities. PMID- 29713604 TI - Nutritional Screening Tools among Hospitalized Children: from Past and to Present. AB - Increased awareness of the importance of nutrition among hospitalized children has increased the use of nutrition screening tool (NST). However, it is not well known the NST for hospitalized children. Therefore, the purpose of this study is to understand the past and present state of adult and child NST and discuss the pros and cons of each NST. PMID- 29713605 TI - Comparison of Endoscopic and Histological Findings between Typical and Atypical Celiac Disease in Children. AB - Purpose: Celiac disease is a common non-communicable disease with varied presentations. Purpose of this study was to find the duodeno-endoscopic features in celiac disease and to compare duodeno-endoscopic and histological findings between typical and atypical celiac disease in children. Methods: Hospital based observational study was conducted at Sir Padampat Mother and Child Health Institute, Jaipur from June 2015 to May 2016. Patients were selected and divided in two groups- typical and atypical celiac disease based upon the presenting symptoms. Upper gastrointestinal endoscopy and duodenal biopsy was performed for serology positive patients. Results were analysed using appropriate statistical test of significance. Results: Out of 101 enrolled patients, 47.5% were male. Age ranged from 1 to 18 years. Study showed that 54.5% were typical and 45.5% were atypical. Patients presenting with atypical symptoms were predominantly of older age group. On endoscopy, scalloping, mosaic pattern, reduced fold height and absent fold height; and in histology, advanced Marsh stage were significantly higher in the typical group. Conclusion: Awareness of atypical presentations as well as duodeno-endoscopic features may have considerable practical importance for the diagnosis of celiac disease in children. Scalloping, mosaic pattern, reduced fold height and nodularity are main endoscopic markers of celiac disease in children. Endoscopic markers of duodenal mucosa may be important in early diagnosis of celiac disease, in children subjected to endoscopy for atypical presentations or indication other than suspected celiac disease. PMID- 29713606 TI - Usefulness of Assessment of Stool Form by the Modified Bristol Stool Form Scale in Primary Care Pediatrics. AB - Purpose: Rome criteria are considered the gold standard for diagnosing functional constipation. The modified Bristol stool form scale (m-BSFS) was validated to measure stool form in children. However, neither the potential use of the m-BSFS as a tool to facilitate the diagnosis of potential constipation, nor the agreement between m-BSFS and stool consistency by Rome has been studied. Our objective is to determine if m-BSFS is a reliable tool to facilitat detection of constipation; and the agreement between stool form by m-BSFS and hard stool criteria in Rome. Methods: A survey tool with the Rome III criteria and the m BSFS was developed. A Likert-scale addressed frequency of each stool form on the m-BSFS. Responses to Rome III and m-BSFS were compared. Results: The sensitivity and specificity of the m-BSFS was 79.2% and 66.0% respectively; and in children <4 years. improved to 81.2% and 75.0% respectively. There was poor agreement between hard stools by m-BSFS and the painful or hard bowel movement question of Rome Criteria. Conclusion: The potential utility of m-BSFS as a reasonably good tool to facilitate the diagnosis of potential constipation in children is shown. The poor agreement between painful or hard stool question in Rome III, and ratings for hard stool on the m-BSFS illustrates that one's perception may differ between a question and a picture. A useful pictorial tool to appraise stool form may, thus, be a favorable complement in the process of enquiry about bowel habits in well-child care. PMID- 29713607 TI - Laxative Choice and Treatment Outcomes in Childhood Constipation: Clinical Data in a Longitudinal Retrospective Study. AB - Purpose: Functional constipation (FC) is a common gastrointestinal (GI) problem affecting children's well-being and quality of life. Although polyethylene glycol (PEG) is recommended as the first line therapy, it is not always applicable in lower socioeconomic populations. Hence, this study aimed to compare clinical courses of FC in children treated with different medications in order to identify prognostic factors related to treatment outcomes. Methods: We reviewed the medical records of patients aged <=15 years diagnosed with FC according to the Rome IV criteria from 2007 to 2015 at the GI clinic, Songklanagarind Hospital. Baseline characteristic, medical history, and treatment outcomes were collected at first and subsequent visits. Results: Exactly 104 patients (median age at diagnosis, 2.8 years) were diagnosed with FC. The number of follow-up visits per patient ranged from 1 to 35. The median duration of follow-up was 18.0 months (range, 6.0-84.2 months). PEG was given to 21% of patients. During the follow up period, 76% of patients experienced first recovery with a median time to recovery of 9.8 months. There were no significant differences in time until first recovery and relapse between patients who received and those who did not receive PEG (p=0.99 and 0.06, respectively). Age >6 years, normal defecation frequency, no history of cow's milk protein allergy, and use of laxatives were associated with successful outcomes. Conclusion: Treatment outcomes between patients who had and never had PEG demonstrated no significant difference in our study. Hence, current practices in laxative prescriptive patterns may be effective. PMID- 29713608 TI - Investigation of Blood Betatrophin Levels in Obese Children with Non-Alcoholic Fatty Liver Disease. AB - Purpose: The prevalence of obesity has significantly increased among children and adolescents worldwide and is becoming an important health care problem in parallel with the increased prevalence of obesity pediatric non-alcoholic fatty liver disease. Betatrophin is a newly define hormone that is commonly secreted by liver and plays role in glucose tolerance. This study aimed to investigate the relationship between serum betatrophin levels and non-alcoholic fatty liver disease in obese children. Methods: The study included 40 obese children with a body mass index (BMI) above 95th centile, and 35 non-obese subjects with a BMI 3 85th centile, whose age and gender were similar to those of the patient group. For the evaluation of metabolic parameters fasting serum glucose, insulin, alanine aminotransferase, aspartate aminotransferase, lipid profile and serum betatrophin levels were measured. Total cholesterol: high-density lipoprotein cholesterol and low-density lipoprotein cholesterol: high-density lipoprotein cholesterol ratios were calculated as "atherogenic indices." Results: Serum betatrophin levels of the obese subjects were similar to that of non-obese subjects (p=0.90). Betatrophin levels were not correlated with the metabolic parameters. Conclusion: In the present study, levels of betatrophin are not different between obese and insulin resistant children and non-obese subjects, and they are not correlated with atherogenic indices. To elucidate the exact role of betatrophin in obesity, further studies are required to identify the betatrophin receptor and/or other possible cofactors. PMID- 29713610 TI - The Analysis of Factors Causing the High Prevalence of Child Obesity in Jeju Island. AB - Purpose: For 3 consecutive years from 2012-2014, we analyzed the causative factors for why the Jeju Island had the highest obesity prevalences of school children among the 15 provinces in Korea. Methods: From our analysis of 28,026 elementary school children with obesity or normal weight in the 15 provinces, we analyzed 12 factors related to eating habits, exercise habits, lifestyle, and mental health. The differences between the obese and normal weight children were researched. Finally, Jeju was compared with Seoul, which has the lowest obesity prevalence in school age children. Statistical analysis was performed using the chi square test of PASW Statistics ver. 18.0. Results: Compared to the normal weight group, the obese group had significantly higher rates of consuming soft drinks (p<0.001), fast food intake (p=0.019), skipping breakfast (p<0.001), insufficient sleep (p<0.001), bullying experiences (p=0.001) and runaway impulses (p=0.012). Compared to Seoul, Jeju Island had significantly higher rates of Ramen intake (3.4% vs. 5.4%, p=0.021) and meat intake (46.0% vs. 52.9%, p=0.003). On the other hand, Jeju Island was significantly lower than was Seoul in their fruit intake (83.4% vs. 67.1%, p<0.001), vegetable intake (71.4% vs. 64.2%, p=0.001), and intense physical activity (63.4% vs. 47.7%, p<0.001). Meanwhile, insufficient sleep (15.4% vs. 9.6%, p<0.001) and runaway impulses (5.6% vs. 3.3%, p=0.027) in children were significantly lower in Jeju Island than in Seoul. Conclusion: The results of the obesity factor analysis of elementary school students in Jeju Island can be used as useful educational material for lowering the obesity prevalence in Jeju community. PMID- 29713609 TI - Accuracy of the 2008 Simplified Criteria for the Diagnosis of Autoimmune Hepatitis in Children. AB - Purpose: Classical criteria for diagnosis of autoimmune hepatitis (AIH) are intended as research tool and are difficult to apply at patient's bedside. We aimed to study the accuracy of simplified criteria and the concordance with the expert diagnosis based on the original criteria. Methods: A cohort of children under study for liver disorder was selected through consecutive sampling to obtain the prevalence of AIH within the group of differential diagnoses. AIH was defined, based on classical criteria, through committee review of medical reports. Validity indicators of the simplified criteria were obtained in an intention to diagnose approach. Optimal cut-off and the area under the receiver operating characteristic (ROC) curve were calculated. Results: Out of 212 cases reviewed, 47.2% were AIH. For the optimal cut-off (6 points), the simplified criteria showed a sensitivity of 72.0% and a specificity of 96.4%, with a 94.7% positive and a 79.4% negative predictive value. The area under the ROC curve was 94.3%. There was a good agreement in the pre-treatment concordance between the classical and the simplified criteria (kappa index, 0.775). Conclusion: Simplified criteria provide a moderate sensitivity for the diagnosis of AIH, but may help in indicating treatment in cases under suspicion with 6 or more points. PMID- 29713611 TI - Chylomicron Retention Disease: a Description of a New Mutation in a Very Rare Disease. AB - Chylomicron retention disease, also known as Anderson's disease, is a rare hereditary hypocholesterolemic disorder, recessive inherited, characterized by nonspecific symptoms as abdominal distension, steatorrhea, and vomiting associated with failure to thrive. We describe a patient with failure to thrive, chronic diarrhea and steatorrhea who the diagnosis of chylomicron retention disease was established after several months of disease progression. The genetic study confirmed a homozygosity mutation in SAR1B gene, identifying a mutation never previous described [c.83_84delTG(p.Leu28Argfs*7)]. With this case report the authors aim to highlight for this very rare cause of failure to thrive and for the importance of an attempting diagnosis, in order to start adequate management with low fat diet supplemented with fat-soluble vitamins, reverting the state of malnutrition and avoiding possible irreversible and desvantating complications. PMID- 29713612 TI - Antibiotics-Associated Hemorrhagic Colitis Caused by Klebsiella oxytoca: Two Case Reports. AB - Nowadays, Klebsiella oxytoca is described as a causative organism for antibiotic associated hemorrhagic colitis (AAHC). Here we report two cases of pediatric AAHC, from which K. oxytoca was cultured after starting amoxicillin-clavulanate or amoxicillin treatment. The patients developed severe abdominal pain and a large amount of bloody diarrhea. K. oxytoca was obtained in intestinal fluid culture of a boy through the colonoscopy. On the other hand, colonic tissue culture and intestinal fluid culture were negative of the other patient. K. oxytoca was detected in stool culture when he was admitted. These cases showed characteristic endoscopic findings of segmental hemorrhagic colitis, and both boys recovered spontaneously within 2-3 days after they stopped taking the antibiotics. Therefore, in children who develop relatively large amount of bloody diarrhea after antibiotic treatment, we should consider AAHC caused by K. oxytoca. PMID- 29713613 TI - Acute Gastritis and Splenic Infarction Caused by Epstein-Barr Virus. AB - Epstein-Barr virus (EBV) infection can be presented with various clinical manifestations and different levels of severity when infected. Infectious mononucleosis, which is most commonly caused by EBV infection in children and adolescents, is a clinical syndrome characterized by fatigue, malaise, fever, sore throat, and generalized lymphadenopathy. But rarely, patients with infectious mononucleosis may present with gastrointestinal symptoms and complicated by gastritis, splenic infarction, and splenic rupture. We encountered a 16-year-old girl who presented with fever, fatigue, and epigastric pain. Splenic infarction and EBV-associated gastritis were diagnosed by using esophagogastroduodenoscopy and abdominal computed tomography. Endoscopy revealed a generalized hyperemic nodular lesion in the stomach, and the biopsy findings were chronic gastritis with erosion and positive in situ hybridization for EBV. As splenic infarction and acute gastritis are rare in infectious mononucleosis and are prone to be overlooked, we must consider these complications when an infectious mononucleosis patient presents with gastrointestinal symptom. PMID- 29713615 TI - Lung Nodule Detection via Deep Reinforcement Learning. AB - Lung cancer is the most common cause of cancer-related death globally. As a preventive measure, the United States Preventive Services Task Force (USPSTF) recommends annual screening of high risk individuals with low-dose computed tomography (CT). The resulting volume of CT scans from millions of people will pose a significant challenge for radiologists to interpret. To fill this gap, computer-aided detection (CAD) algorithms may prove to be the most promising solution. A crucial first step in the analysis of lung cancer screening results using CAD is the detection of pulmonary nodules, which may represent early-stage lung cancer. The objective of this work is to develop and validate a reinforcement learning model based on deep artificial neural networks for early detection of lung nodules in thoracic CT images. Inspired by the AlphaGo system, our deep learning algorithm takes a raw CT image as input and views it as a collection of states, and output a classification of whether a nodule is present or not. The dataset used to train our model is the LIDC/IDRI database hosted by the lung nodule analysis (LUNA) challenge. In total, there are 888 CT scans with annotations based on agreement from at least three out of four radiologists. As a result, there are 590 individuals having one or more nodules, and 298 having none. Our training results yielded an overall accuracy of 99.1% [sensitivity 99.2%, specificity 99.1%, positive predictive value (PPV) 99.1%, negative predictive value (NPV) 99.2%]. In our test, the results yielded an overall accuracy of 64.4% (sensitivity 58.9%, specificity 55.3%, PPV 54.2%, and NPV 60.0%). These early results show promise in solving the major issue of false positives in CT screening of lung nodules, and may help to save unnecessary follow-up tests and expenditures. PMID- 29713614 TI - The Relation of Obesity-Related Hormonal and Cytokine Levels With Multiple Myeloma and Non-Hodgkin Lymphoma. AB - This article presents the first detailed overview of the mechanisms that may underlie the relation of obesity with B-cell non-Hodgkin lymphomas (NHLs) and multiple myeloma (MM). Epidemiologic studies, including meta-analyses of prospective cohorts, have reported that the risks of NHL and MM are significantly increased in obese, relative to normal weight, women and men. Accumulating experimental and clinical evidence suggests that inflammatory cytokines, hyperinsulinemia, and sex hormones could play a role in the association of obesity with B-cell NHL and MM carcinogenesis. There is, however, a paucity of data published from appropriate large prospective cohort studies, and studies concurrently measuring these correlated factors, to formally determine the likely biologic factors driving the relationship of obesity with NHL and MM. Additional strengths and weaknesses of the current literature, as well as study design issues that need to be considered in conducting these studies, such as the exclusion of type 2 diabetics or postmenopausal women using hormone therapy, are discussed. PMID- 29713616 TI - Energy Requirements in Critically Ill Patients. AB - During the management of critical illness, optimal nutritional support is an important key for achieving positive clinical outcomes. Compared to healthy people, critically ill patients have higher energy expenditure, thereby their energy requirements and risk of malnutrition being increased. Assessing individual nutritional requirement is essential for a successful nutritional support, including the adequate energy supply. Methods to assess energy requirements include indirect calorimetry (IC) which is considered as a reference method, and the predictive equations which are commonly used due to the difficulty of using IC in certain conditions. In this study, a literature review was conducted on the energy metabolic changes in critically ill patients, and the implications for the estimation of energy requirements in this population. In addition, the issue of optimal caloric goal during nutrition support is discussed, as well as the accuracy of selected resting energy expenditure predictive equations, commonly used in critically ill patients. PMID- 29713617 TI - Community-Based Policies and Support for Free Drinking Water Access in Outdoor Areas and Building Standards in U.S. Municipalities. AB - We examined community-level characteristics associated with free drinking water access policies in U.S. municipalities using data from a nationally representative survey of city managers/officials from 2,029 local governments in 2014. Outcomes were 4 free drinking water access policies. Explanatory measures were population size, rural/urban status, census region, poverty prevalence, education, and racial/ethnic composition. We used multivariable logistic regression to test differences and presented only significant findings. Many (56.3%) local governments had at least one community plan with a written objective to provide free drinking water in outdoor areas; municipalities in the Northeast and South regions and municipalities with <= 50% of non-Hispanic whites were less likely and municipalities with larger population size were more likely to have a plan. About 59% had polices/budget provisions for free drinking water in parks/outdoor recreation areas; municipalities in the Northeast and South regions were less likely and municipalities with larger population size were more likely to have it. Only 9.3% provided development incentives for placing drinking fountains in outdoor, publicly accessible areas; municipalities with larger population size were more likely to have it. Only 7.7% had a municipal plumbing code with a drinking fountain standard that differed from the statewide plumbing code; municipalities with a lower proportion of non-Hispanic whites were more likely to have it. In conclusion, over half of municipalities had written plans or a provision for providing free drinking water in parks, but providing development incentives or having a local plumbing code provision were rare. PMID- 29713618 TI - Relationship between Nutrition Intake and Estimated Glomerular Filtration Rate in Korean Adults (30-65 years) from the Korea National Health and Nutrition Examination Survey 2013-2014. AB - This study aimed to examine the relationship between nutrition intake and estimated glomerular filtration rate (eGFR) indicating kidney function in Korean individuals without diabetes or cardiovascular disease. Study participants from the Korea National Health and Nutrition Examination Survey 2013-2014 (n = 4,378, 30-65 years) were classified by their eGFR levels (mL/min/1.732 m2): >= 120 (n = 299), 119-105 (n = 789), 104-90 (n = 1,578), 89-60 (n = 1,685), < 60 (n = 27). After adjusted for confounding factors (age, sex, cigarette smoking, alcohol drinking, total caloric intake [TCI], income status, education level, body mass index, and physical activity), blood pressure, low-density lipoprotein (LDL) cholesterol, aspartate aminotransferase, alanine aminotransferase, blood urea nitrogen, creatinine, fasting glucose, and glycated hemoglobin were higher, and high density lipoprotein cholesterol levels were lower in participants with lower eGFR levels than those with higher eGFR levels. n-3 fatty acid (FA) and n-6 FA (% of TCI/day) intake were also significantly higher in participants with higher eGFR levels than in those with lower eGFR levels. Based on the above results, participants were subdivided into 3 groups according to n-6 FA intake levels (Q1: >= 2.93%, n = 1,462; Q2: 2.92%-1.88%, n = 1,463; Q3: < 1.88%, n = 1,453). People consuming higher n-6 FAs, particularly the Q1 group showed higher eGFR levels and lower levels of LDL cholesterol and creatinine. In conclusion, higher intake of n 6 FAs within the range of dietary reference may be beneficial to maintain healthy kidney function. PMID- 29713619 TI - Low Handgrip Strength Is Not Associated with Type 2 Diabetes Mellitus and Hyperglycemia: a Population-Based Study. AB - Type 2 diabetes mellitus (DM) is commonly linked to muscle weakness and metabolic abnormalities which increase healthcare costs. The study was undertaken to investigate if low handgrip strength, as a marker of muscle weakness, is associated with hyperglycemia and/or DM in Brazilian subjects. In a cross sectional design, 415 individuals of both sexes (46.7% male) were interviewed by a questionnaire and the DM diagnostic was self-reported. Anthropometric measurements, such as weight, height, body mass index (BMI), arm circumference, mid-arm and calf circumference and handgrip strength, were obtained by trained nutritionists. Blood glucose concentrations were determined by portable monitor analysis. Student's t-test was applied to compare DM cases with non-diabetic individuals, and logistic regression analysis was performed to verify the odds for becoming diabetic or having altered glycemia and p < 0.05 was considered as significant. From 415 subjects, 9.2% (n = 35) were classified as DM. DM patients had significantly higher age, BMI, casual glycemia and lower handgrip strength and normalized (to body weight) handgrip strength (NHS) when compared with non diabetic patients. Individuals with low NHS have 2.7 odds ratio to DM without adjustment for covariate (crude model, p = 0.006) and have 2.7 times higher the likelihood of DM than individuals with high NHS after adjusting for age (model 1, p = 0.006); however, this association disappeared after further adjusting for sex. In conclusion, low handgrip strength normalized or not to body weight, was not associated with hyperglycemia and DM diagnosis. PMID- 29713620 TI - The Effect of Pycnogenol Supplementation on Plasma C-Reactive Protein Concentration: a Systematic Review and Meta-Analysis. AB - Pycnogenol is a standardized extract from the bark of the French maritime pine. The aim of the present systematic review and meta-analysis was to clarify the effect of Pycnogenol supplementation on C-reactive protein (CRP) concentration. To identify eligible studies in order to find clinical trials which examined the effect of Pycnogenol supplementation on the level of CRP in adult participants, PubMed, Scopus, and Google Scholar were systematically searched until December 2017. Mean of CRP was collected to estimate the effect size of the supplementation. Potential sources of heterogeneity were explored by subgroup analysis. Five trials including 324 participants were included in this meta analysis. Pooled effect size showed significant effect of Pycnogenol supplementation on CRP (-1.22 mg/dL, 95% confidence interval, -2.43, -0.003; I2 = 99%, pheterogeneity < 0.001). When the meta-analysis was subgrouped by dose of Pycnogenol, heterogeneity was attenuated in > 150 mg/d category (I2 = 0.0%, p = 0.42). There was significant difference between-subgroup heterogeneity (p < 0.001). Furthermore, no evidence of publication bias for CRP (p = 0.27, Begg's test and p = 0.62, Egger's test) was seen. Present systematic review and meta analysis suggested Pycnogenol consumption can decrease the level of CRP and have anti-inflammatory effect. So, Pycnogenol as an anti-inflammatory agent might be a priority in interventions. Further studies with large-scale and better design are needed to confirm this result. PMID- 29713621 TI - Hypouricemic Effect of Ethanol Extract of Aster glehni Leaves in Potassium Oxonate-Induced Hyperuricemic Rats. AB - The prevalence of gout is increasing worldwide, and control of serum uric acid level has been regarded as one of the therapeutic methods for gout. Inhibition of xanthine oxidase (XO) activity which can oxidize hypoxanthine to uric acid has been commonly proposed to decrease serum uric acid level. The aim of this study was to demonstrate the hypouricemic effect of ethanol extract of Aster glehni leaves (EAG) by in vitro and in vivo study in potassium oxonate (PO)-induced hyperuricemic rats. EAG possessed 132.5 +/- 6.8 mg QE/g of total flavonoid and showed antioxidant activity. EAG showed in vitro and in vivo inhibitory activity against XO and significantly decreased serum uric acid level in PO-induced hyperuricemic rats without liver toxicity. These results show that EAG significantly attenuates hyperuricemia by inhibiting XO activity, which resulted in the decrease of serum uric acid level. Therefore, EAG might possess a potential therapeutic ability for improving gout. PMID- 29713622 TI - Nutritional Care in Iranian Intensive Care Units. AB - Intensive care units (ICUs) provides intensive treatment medicine to avoid complications such as malnutrition, infection and even death. As very little is currently known about the nutritional practices in Iranian ICUs, this study attempted to assess the various aspects of current nutrition support practices in Iranian ICUs. We conducted a cross-sectional study on 150 critically ill patients at 18 ICUs in 12 hospitals located in 2 provinces of Iran from February 2015 to March 2016. Data were collected through interview with supervisors of ICUs, medical record reviews and direct observation of patients during feeding. Our study showed that hospital-prepared enteral tube feeding formulas are the main formulas used in Iranian hospitals. None of the dietitians worked exclusively an ICU and only 30% of patients received diet counselling. Regular monitoring of nutritional status, daily energy and protein intake were not recorded in any of the participating ICUs. Patients were not monitored for anthropometric measurements such as mid-arm circumference (MAC) and electrolyte status. The nasogastric tube was not switched to percutaneous endoscopic gastrostomy or jejunostomy (PEG/PEGJ) in approximately 85% of patients receiving long-term enteral nutrition (EN) support. Our findings demonstrated that the quality of nutritional care was inappropriate in Iranian ICUs and improvement of nutritional care services within Iranian ICUs is necessary. PMID- 29713623 TI - Nutrition Intervention through Interdisciplinary Medical Treatment in Hospice Patients: From Admission to Death. AB - The demand for hospice services as well as for 'well-dying' of terminal patients is increasing as patient financial burden is decreasing due to National Health Insurance coverage for hospice care. Hospice institutions utilize interdisciplinary teams comprising doctors, nurses, dietitians, and other health staffs to provide comprehensive patient management. This report examined the nutritional status of a hospice patient from admission to death as well as the nutrition management of this patient in the hospice ward through nutrition interventions performed by a dietitian in the interdisciplinary team. The patient in the present case was a 74-year-old man diagnosed with pancreatic head cancer who died after 26 days of hospice care following transfer from the general ward. During hospice care, the dietitian monitored the patient's nutritional status and performed 8 nutrition interventions, but his oral intake decreased as the patient's symptoms worsened. The average energy intake rates were 30% and 17% of required rates for oral and artificial nutrition, respectively. In line with a report suggesting that the main focus of nutrition in palliative care should be on improving the quality of life and reducing worry in patients, rather than aggressive nutritional management, there is a need for nutrition interventions that are personalized to individual patients by monitoring progress and offering continuous counseling from the time of admission. In addition, further studies such as comparative analysis of nutritional management in Korean hospice ward will be needed for better nutrition management for terminally ill patients. PMID- 29713624 TI - Deadly Mass Shootings, Mental Health, and Policies and Regulations: What We Are Obligated to Do! PMID- 29713625 TI - Development and Implementation of a Pediatric Palliative Care Program in a Developing Country. AB - Background: Palliative care is recognized as an important component of care for children with cancer and other life-limiting conditions. In resource limited settings, palliative care is a key component of care for children with cancer and other life-limiting conditions. Globally, 98% of children who need palliative care live in low- or middle-income countries, where there are very few palliative care services available. There is limited evidence describing the practical considerations for the development and implementation of sustainable and cost effective palliative care services in developing countries. Objectives: Our aim is to describe the key considerations and initiatives that were successful in planning and implementing a hospital-based pediatric palliative care service specifically designed for a resource-limited setting. Setting: Bangabandu Sheikh Mujib Medical University (BSMMU) is a tertiary referral hospital in Bangladesh. Local palliative care services are very limited and focused on adult patients. In partnership with World Child Cancer, a project establishing a pediatric palliative care service was developed for children with cancer at BSMMU. Results: We describe four key elements which were crucial for the success of this program: (1) raising awareness and sensitizing hospital administrators and clinical staff about pediatric palliative care; (2) providing education and training on pediatric palliative care for clinical staff; (3) forming a pediatric palliative care team; and (4) collecting data to characterize the need for pediatric palliative care. Conclusion: This model of a hospital-based pediatric palliative care service can be replicated in other resource-limited settings and can be expanded to include children with other life-limiting conditions. The development of pilot programs can generate interest among local physicians to become trained in pediatric palliative care and can be used to advocate for the palliative care needs of children. PMID- 29713626 TI - Peptide Modified ZnO Nanoparticles as Gas Sensors Array for Volatile Organic Compounds (VOCs). AB - In this work a peptide based gas sensor array based of ZnO nanoparticles (ZnONPs) has been realized. Four different pentapeptides molecularly modeled for alcohols and esters having cysteine as a common spacer have been immobilized onto ZnONPs. ZnONPs have been morphologically and spectroscopically characterized. Modified nanoparticles have been then deposited onto quartz crystal microbalances (QCMs) and used as gas sensors with nitrogen as carrier gas. Analysis of the pure compounds modeled demonstrated a nice fitting of modeling with real data. The peptide based ZnONPs had very low sensitivity to water, compared to previously studied AuNPs peptide based gas sensors allowing the use of the array on samples with high water content. Real samples of fruit juices have been assayed; stability of the signal, good repeatability, and discrimination ability of the array was achieved. PMID- 29713627 TI - A Comparison of Growth on Mercuric Chloride for Three Lemnaceae Species Reveals Differences in Growth Dynamics That Effect Their Suitability for Use in Either Monitoring or Remediating Ecosystems Contaminated With Mercury. AB - Mercury (Hg) is a toxic heavy metal that can alter the ecological balance when it contaminates aquatic ecosystems. Previously, researchers have used various Lemnaceae species either to monitor and/or remove heavy metals from freshwater systems. As Hg contamination is a pressing issue for aquatic systems worldwide, we assessed its impact on the growth of three commonly species of Lemnaceae- Lemna gibba 6745, Lemna minor 6580 and Spirodela polyrhiza 5543. We exposed plants to different concentrations of mercuric chloride (HgCl2) and monitored their growth, including relative growth rate, frond number (FN), and fresh weight (FW). These data were coupled with measurements of starch content, levels of photosynthetic pigment and the activities of antioxidant substances. The growth of all three lines showed significant negative correlations with Hg concentrations, and starch content, photosynthetic pigment, soluble protein and antioxidant enzymes levels were all clearly affected. Our results indicate that the L. gibba line used in this study was the most suitable of the three for biomonitoring of water contaminated with Hg. Accumulation of Hg was highest in the S. polyrhiza line with a bioconcentration factor over 1,000, making this line the most suitable of the three tested for use in an Hg bioremediation system. PMID- 29713628 TI - The Effects of Parenteral K1 Administration in Pseudoxanthoma Elasticum Patients Versus Controls. A Pilot Study. AB - Introduction: Pseudoxanthoma elasticum (PXE) is a rare disease caused by mutations in the ABCC6 gene. Vitamin K1 is involved in the posttranslational carboxylation of some proteins related to inhibition of the calcification process. Our aim was to investigate, in patients affected by PXE, baseline levels of vitamin K1-dependent proteins and -metabolites and whether parenteral administration of phytomenadione was effective in modulating their levels. Methods: We included eight PXE patients with typical clinical symptoms (skin, retina, and vascular calcification) and two ABCC6 causative mutations; 13 clinically unaffected first-degree patients' relatives (9 carrying one ABCC6 mutation and 4 non-carriers). We assessed urinary vitamin K1 metabolites and serum Glu- and Gla-OC, Gas6 and undercaboxylated prothrombin (PIVKA-II), at baseline and after 1 and 6 weeks after a single intramuscular injection of 10 mg vitamin K1. Results: Comparison of PXE patients, heterozygous, and non-carriers revealed differences in baseline levels of serum MK-4 and of urinary vitamin K metabolites. The response to phytomenadione administration on vitamin K-dependent proteins was similar in all groups. Conclusion: The physiological axis between vitamin K1 and vitamin K-dependent proteins is preserved; however, differences in the concentration of vitamin K metabolites and of MK-4 suggest that vitamin K1 metabolism/catabolism could be altered in PXE patients. PMID- 29713629 TI - Helminths and Cancers From the Evolutionary Perspective. AB - Helminths include free-living and parasitic Platyhelminthes and Nematoda which infect millions of people worldwide. Some Platyhelminthes species of blood flukes (Schistosoma haematobium, Schistosoma japonicum, and Schistosoma mansoni) and liver flukes (Clonorchis sinensis and Opisthorchis viverrini) are known to be involved in human cancers. Other helminths are likely to be carcinogenic. Our main goals are to summarize the current knowledge of human cancers caused by Platyhelminthes, point out some helminth and human biomarkers identified so far, and highlight the potential contributions of phylogenetics and molecular evolution to cancer research. Human cancers caused by helminth infection include cholangiocarcinoma, colorectal hepatocellular carcinoma, squamous cell carcinoma, and urinary bladder cancer. Chronic inflammation is proposed as a common pathway for cancer initiation and development. Furthermore, different bacteria present in gastric, colorectal, and urogenital microbiomes might be responsible for enlarging inflammatory and fibrotic responses in cancers. Studies have suggested that different biomarkers are involved in helminth infection and human cancer development; although, the detailed mechanisms remain under debate. Different helminth proteins have been studied by different approaches. However, their evolutionary relationships remain unsolved. Here, we illustrate the strengths of homology identification and function prediction of uncharacterized proteins from genome sequencing projects based on an evolutionary framework. Together, these approaches may help identifying new biomarkers for disease diagnostics and intervention measures. This work has potential applications in the field of phylomedicine (evolutionary medicine) and may contribute to parasite and cancer research. PMID- 29713630 TI - Novel Antimicrobials for the Treatment of Clostridium difficile Infection. AB - The current picture of Clostridium difficile infection (CDI) is alarming with a mortality rate ranging between 3% and 15% and a CDI recurrence rate ranging from 12% to 40%. Despite the great efforts made over the past 10 years to face the CDI burden, there are still gray areas in our knowledge on CDI management. The traditional anti-CDI antimicrobials are not always adequate in addressing the current needs in CDI management. The aim of our review is to give an update on novel antimicrobials for the treatment of CDI, considering the currently available evidences on their efficacy, safety, molecular mechanism of action, and their probability to be successfully introduced into the clinical practice in the near future. We identified, through a PubMed search, 16 novel antimicrobial molecules under study for CDI treatment: cadazolid, surotomycin, ridinilazole, LFF571, ramoplanin, CRS3123, fusidic acid, nitazoxanide, rifampin, rifaximin, tigecycline, auranofin, NVB302, thuricin CD, lacticin 3147, and acyldepsipeptide antimicrobials. In comparison with the traditional anti-CDI antimicrobial treatment, some of the novel antimicrobials reviewed in this study offer several advantages, i.e., the favorable pharmacokinetic and pharmacodynamic profile, the narrow-spectrum activity against CD that implicates a low impact on the gut microbiota composition, the inhibitory activity on CD sporulation and toxins production. Among these novel antimicrobials, the most active compounds in reducing spore production are cadazolid, ridinilazole, CRS3123, ramoplanin and, potentially, the acyldepsipeptide antimicrobials. These antimicrobials may potentially reduce CD environment spread and persistence, thus reducing CDI healthcare-associated acquisition. However, some of them, i.e., surotomycin, fusidic acid, etc., will not be available due to lack of superiority versus standard of treatment. The most CD narrow-spectrum novel antimicrobials that allow to preserve microbiota integrity are cadazolid, ridinilazole, auranofin, and thuricin CD. In conclusion, the novel antimicrobial molecules under development for CDI have promising key features and advancements in comparison to the traditional anti-CDI antimicrobials. In the near future, some of these new molecules might be effective alternatives to fight CDI. PMID- 29713631 TI - Molecular Mechanisms of Proteinuria in Focal Segmental Glomerulosclerosis. AB - Focal segmental glomerulosclerosis (FSGS) is the most common primary glomerular disease resulting in end-stage renal disease in the USA and is increasing in prevalence worldwide. It is a diverse clinical entity with idiopathic, genetic, metabolic, infectious, and other causes that culminate in a characteristic histologic pattern of injury. Proteinuria is a hallmark of FSGS as well as other primary and secondary glomerular disorders. The magnitude of proteinuria at disease onset and during treatment has prognostic implications for renal survival as well as associated cardiovascular morbidity and mortality. Significant advances over the last two decades have shed light on the molecular architecture of the glomerular filtration barrier. The podocyte is the target cell for injury in FSGS. A growing list of disease-causing gene mutations encoding proteins that regulate podocyte survival and homeostasis has been identified in FSGS patients. Several pathogenic and regulatory pathways have been uncovered that result in proteinuria in rodent models and human FSGS. The recurrence of proteinuria and FSGS after kidney transplantation is supporting evidence for the role of a circulating permeability factor in disease pathogenesis. These advances reviewed herein have significant implications for disease classification and therapeutic drug development for FSGS. PMID- 29713632 TI - Antimetabolic Effects of Polyphenols in Breast Cancer Cells: Focus on Glucose Uptake and Metabolism. AB - In the last years, metabolic reprogramming became a new key hallmark of tumor cells. One of its components is a deviant energetic metabolism, known as Warburg effect-an aerobic lactatogenesis-characterized by elevated rates of glucose uptake and consumption with high-lactate production even in the presence of oxygen. Because many cancer cells display a greater sensitivity to glucose deprivation-induced cytotoxicity than normal cells, inhibitors of glucose cellular uptake (facilitative glucose transporter 1 inhibitors) and oxidative metabolism (glycolysis inhibitors) are potential therapeutic targets in cancer treatment. Polyphenols, abundantly contained in fruits and vegetables, are dietary components with an established protective role against cancer. Several molecular mechanisms are involved in the anticancer effect of polyphenols, including effects on apoptosis, cell cycle regulation, plasma membrane receptors, signaling pathways, and epigenetic mechanisms. Additionally, inhibition of glucose cellular uptake and metabolism in cancer cell lines has been described for several polyphenols, and this effect was shown to be associated with their anticarcinogenic effect. This work will review data showing an antimetabolic effect of polyphenols and its involvement in the chemopreventive/chemotherapeutic potential of these dietary compounds, in relation to breast cancer. PMID- 29713633 TI - Two Family B DNA Polymerases From Aeropyrum pernix, Based on Revised Translational Frames. AB - Living organisms are divided into three domains, Bacteria, Eukarya, and Archaea. Comparative studies in the three domains have provided useful information to understand the evolution of the DNA replication machinery. DNA polymerase is the central enzyme of DNA replication. The presence of multiple family B DNA polymerases is unique in Crenarchaeota, as compared with other archaeal phyla, which have a single enzyme each for family B (PolB) and family D (PolD). We analyzed PolB1 and PolB3 in the hyperthermophilic crenarchaeon, Aeropyrum pernix, and found that they are larger proteins than those predicted from the coding regions in our previous study and from public database annotations. The recombinant larger PolBs exhibited the same DNA polymerase activities as previously reported. However, the larger PolB3 showed remarkably higher thermostability, which made this enzyme applicable to PCR. In addition, the high tolerance to salt and heparin suggests that PolB3 will be useful for amplification from the samples with contaminants, and therefore it has a great potential for diagnostic use in the medical and environmental field. PMID- 29713635 TI - Detection of Tick-Borne Pathogens in Lambs Undergoing Prophylactic Treatment Against Ticks on Two Swedish Farms. AB - Tick-borne pathogens (TBPs), especially Anaplasma phagocytophilum, cause disease in grazing livestock. Tick prophylaxis is, therefore, a routine practice in sheep flocks in Sweden, especially in central, southern, and coastal areas of the country where ixodid ticks (Ixodes ricinus and Haemaphysalis punctata) are present. In the present study, the status of infection by A. phagocytophilum and other TBPs in lambs treated with tick prophylaxis has been assessed serologically and with polymerase chain reaction (PCR). Blood samples (n = 78) from lambs (n = 20) subjected to regular tick prophylactic treatment (flumethrin, Bayticol(r)) at two sites in different regions in Sweden (Ostergotland, Gotland) were collected on four occasions from May until July 2013. The severity of clinical signs in Anaplasma-infected animals is known to differ between these two regions. In total, 20% of blood samples were PCR-positive for A. phagocytophilum. Serological analyses showed that 33% of all collected samples were positive for A. phagocytophilum, while 2.5% were positive for Borrelia burgdorferi s.l. and 13% for tick-borne encephalitis virus (TBEV). Percentages of lambs positive were 75 and 45% for A. phagocytophilum antibodies and DNA, respectively, while 10 and 45% were serologically positive for B. burgdorferi s.l. and TBEV, respectively. Sequencing of partial 16S rRNA genes from Anaplasma PCR positive samples revealed presence of A. phagocytophilum in all animals in Ostergotland, while sequences consistent with A. phagocytophilum as well as A. capra and A. bovis were found on the island of Gotland. This is the first report of the occurrence of the latter two species in Sweden. PMID- 29713634 TI - Cell-Based Therapies for Joint Disease in Veterinary Medicine: What We Have Learned and What We Need to Know. AB - Biological cell-based therapies for the treatment of joint disease in veterinary patients include autologous-conditioned serum, platelet-rich plasma, and expanded or non-expanded mesenchymal stem cell products. This narrative review outlines the processing and known mechanism of action of these therapies and reviews current preclinical and clinical efficacy in joint disease in the context of the processing type and study design. The significance of variation for biological activity and consequently regulatory approval is also discussed. There is significant variation in study outcomes for canine and equine cell-based products derived from whole blood or stem cell sources such as adipose and bone marrow. Variation can be attributed to altering bio-composition due to factors including preparation technique and source. In addition, study design factors like selection of cases with early vs. late stage osteoarthritis (OA), or with intra articular soft tissue injury, influence outcome variation. In this under regulated field, variation raises concerns for product safety, consistency, and efficacy. Cell-based therapies used for OA meet the Food and Drug Administration's (FDA's) definition of a drug; however, researchers must consider their approach to veterinary cell-based research to meet future regulatory demands. This review explains the USA's FDA guidelines as an example pathway for cell-based therapies to demonstrate safety, effectiveness, and manufacturing consistency. An understanding of the variation in production consistency, effectiveness, and regulatory concerns is essential for practitioners and researchers to determine what products are indicated for the treatment of joint disease and tactics to improve the quality of future research. PMID- 29713636 TI - The Pathobiology of the Meniscus: A Comparison Between the Human and Dog. AB - Serious knee pain and related disability have an annual prevalence of approximately 25% on those over the age of 55 years. As curative treatments for the common knee problems are not available to date, knee pathologies typically progress and often lead to osteoarthritis (OA). While the roles that the meniscus plays in knee biomechanics are well characterized, biological mechanisms underlying meniscus pathophysiology and roles in knee pain and OA progression are not fully clear. Experimental treatments for knee disorders that are successful in animal models often produce unsatisfactory results in humans due to species differences or the inability to fully replicate disease progression in experimental animals. The use of animals with spontaneous knee pathologies, such as dogs, can significantly help addressing this issue. As microscopic and macroscopic anatomy of the canine and human menisci are similar, spontaneous meniscal pathologies in canine patients are thought to be highly relevant for translational medicine. However, it is not clear whether the biomolecular mechanisms of pain, degradation of extracellular matrix, and inflammatory responses are species dependent. The aims of this review are (1) to provide an overview of the anatomy, physiology, and pathology of the human and canine meniscus, (2) to compare the known signaling pathways involved in spontaneous meniscus pathology between both species, and (3) to assess the relevance of dogs with spontaneous meniscal pathology as a translational model. Understanding these mechanisms in human and canine meniscus can help to advance diagnostic and therapeutic strategies for painful knee disorders and improve clinical decision making. PMID- 29713637 TI - Relevant Measures to Prevent the Spread of African Swine Fever in the European Union Domestic Pig Sector. AB - During the past decade, African swine fever (ASF) has spread from the Caucasus region to eastern European Union countries affecting domestic pig and wild boar populations. In order to avert ASF spread, mitigation measures targeting both populations have been established. However, despite these efforts, ASF has been reported in thirteen different countries (Georgia, Azerbaijan, Armenia, the Russian Federation, Ukraine, Belarus, Estonia, Latvia, Lithuania, Poland, Moldova, Czech Republic, and Romania). In the absence of an effective vaccine or treatment to ASF, introduction and spread of ASF onto domestic pig farms can only be prevented by strict compliance to control measures. This study systematically reviewed available measures to prevent the spread of ASF in the EU domestic pig sector distinguishing between commercial, non-commercial, and outdoor farms. The search was performed in PubMed and using a common browser. A total of 52 documents were selected for the final review process, which included scientific articles, reports, EU documents and official recommendations, among others. From this literature review, 37 measures were identified as preventive measures for the introduction and spread of ASF. Subsequently, these measures were assessed by ASF experts for their relevance in the mitigation of ASF spread on the three mentioned types of farms. All experts agreed that some of the important preventive measures for all three types of farms were: the identification of animals and farm records; strict enforcement of the ban on swill feeding; and containment of pigs, so as to not allow direct or indirect pig-pig and/or pig wild boar contacts. Other important preventive measures for all farms were education of farmers, workers, and operators; no contact between farmers and farm staff and external pigs; appropriate removal of carcasses, slaughter residues, and food waste; proper disposal of manure and dead animals, and abstaining from hunting activities during the previous 48 h (allowing a 48 h interval between hunting and being in contact with domestic pigs). Finally, all experts identified that the important preventive measures for non-commercial and outdoor farms is to improve access of those farms to veterinarians and health services. PMID- 29713638 TI - Omeprazole Minimally Alters the Fecal Microbial Community in Six Cats: A Pilot Study. AB - Although they have historically been thought of as safe medications, proton pump inhibitors such as omeprazole have been associated with an increased risk of enteric, particularly Clostridium difficile, infections in people. In cats, omeprazole is often the first choice acid suppressant prescribed for the treatment of upper gastrointestinal (GI) ulceration and bleeding. Despite this, no studies to date have explored the effect of omeprazole on the feline fecal microbiome and metabolome. Therefore, the purpose of this pilot study was to evaluate the effect of prolonged omeprazole administration on the fecal microbiome and metabolome in healthy cats to identify targets for analysis in a larger subset of cats with GI disease. A within-subjects, before and after, pilot study was performed whereby six healthy adult cats received 60 days of placebo (250 mg lactose PO q 12 h) followed by 5 mg (0.83-1.6 mg/kg PO q 12 h) omeprazole. On days 0, 30, and 60 of placebo and omeprazole therapy, the fecal microbiome and metabolome were characterized utilizing 16S ribosomal RNA sequencing by Illumina and untargeted mass spectrometry-based methods, respectively. Omeprazole administration resulted in no significant changes in the global microbiome structure or richness. However, transient changes were noted in select bacterial groups with omeprazole administration resulting in an increased sequence percentage of Streptococcus, Lactobacillus, Clostridium, and Faecalibacterium spp. and a decreased sequence percentage of Bifidobacterium spp. Significance was lost for all of these bacterial groups after adjustment for multiple comparisons. The fecal concentration of O-acetylserine and aminomalonate decreased with omeprazole therapy, but significance was lost after adjustment for multiple comparisons. The results of this pilot study conclude that omeprazole has a mild and transient impact on the fecal microbiome and metabolome when orally administered to healthy cats for 60 days. Based on the findings of this pilot study, evaluation of the effect of omeprazole specifically on Streptococcus, Lactobacillus, Clostridium, Faecalibacterium, and Bifidobacterium spp. is warranted in cats with primary GI disease. PMID- 29713639 TI - From Feline Idiopathic Ulcerative Dermatitis to Feline Behavioral Ulcerative Dermatitis: Grooming Repetitive Behaviors Indicators of Poor Welfare in Cats. AB - Feline idiopathic head-and-neck dermatitis-also named feline idiopathic ulcerative dermatitis (IUD)-is considered as a rare skin disease of unknown origin. It is usually associated with a crusted, non-healing, self-induced ulcer occurring most commonly on the dorsal or lateral neck or between the scapula where self-grooming by scratching occurs. Usually, IUD is diagnosed after exclusion of other causes of pruritus. In feline medicine, self-induced alopecia is recognized as a behavioral disorder (abnormal repetitive behavior) due to excessive licking, which is an amplification of a normal maintenance behavior. Such repetitive behaviors, like self-induced alopecia or self-induced wounds, are named stereotypies and considered as indicators of poor welfare. The objectives of our study were to determine, first, if the repetitive behavior associated with self-induced wounds was related to a poor welfare, and, second, if improving the welfare in the cat's environment would lead to healing, thanks to environmental enrichment. We recruited 13 cats diagnosed with IUD by a dermatologist. These cats were referred to a behaviorist for welfare evaluation. A welfare score was attributed using a new 21-point welfare scale. The median score of the 13 IUD cats was 16, while the median score of 35 healthy cats was 7 (significant difference, p < 0.001). Major modifications of the cat's environment and the human-cat relationship were then recommended for IUD cats. Within 15 days after environment modifications, ulcerative lesions were healed and welfare scores improved significantly (median score of 6, significantly different from the score before environmental modifications), being similar to healthy cats (no significant differences). Only one cat was treated with a psychotropic drug, owners being reluctant to improve environmental modifications. These results suggest that feline IUD is a behavioral disorder indicative of poor welfare and that it requires management by behavior specialists, proposing environmental modifications. We hence propose to rename this affection to "behavioral ulcerative dermatitis," given that welfare scores were significantly different from healthy cats, and that environmental modifications modified welfare scores and lead to successful healing in all cases. PMID- 29713640 TI - The Use of Ropivacaine in Therapeutic Treatment of Oral Aphthosis. AB - The use of anaesthetic drugs in the treatment of oral aphthosis is one of the pharmaceutical possibilities that a doctor can use for the most painful forms. Normally, Lidocaine or Diclofenac is used to treat this disease, but they can be used for a very limited time and so they are of little practical use. In this study, the authors have used Ropivacaine whose pharmaceutical kinetics allows the analgesic effect to be active for 60 to 90 minutes. In our research, we compared 8 groups of patients who have been given 3 principal pharmaceutical products: one group was given an anaesthetic drug, one had a topical medication administered which is often used for the treatment of aphthous lesions, and the last group was given a multivitamin. These pharmaceutical products were used alone and in various possible combinations in the 8 groups. The results of this study are very interesting and show that in all the groups that used anaesthetics there was more satisfaction on the patients' part because their pain level became more manageable right after the first application of the drug and the patients could carry on with their normal lives. PMID- 29713641 TI - Treatment of Elderly Patients with Colorectal Cancer. AB - Colorectal cancer (CRC) is one of the leading causes of cancer-related deaths worldwide. As society ages, the number of elderly patients with CRC will increase. The percentage of patients with right-sided colon cancer and the incidence of microsatellite instability are higher in elderly than in younger patients with CRC. Moreover, the higher incidence of comorbid diseases in elderly patients indicates the need for less invasive treatment strategies. For example, care should be taken in performing additional surgery after endoscopic submucosal dissection for elderly patients with high-risk T1 CRC. Minimally invasive surgery, such as laparoscopic colectomy, would be preferable for elderly patients with CRC. Chemotherapy for elderly patients requires careful monitoring for adverse events. The aim of this review is to summarize the clinicopathological features of CRC in elderly patients, optical surgical strategies, including endoscopic and laparoscopic resection, and chemotherapeutic strategies, including postoperative adjuvant chemotherapy and systemic chemotherapy for unresectable CRC. PMID- 29713643 TI - Magnitude of Neural Tube Defects and Associated Risk Factors at Three Teaching Hospitals in Addis Ababa, Ethiopia. AB - There is scarcity of data on prevalence of neural tube defects (NTDs) in lower income countries. Local data are important to understand the real burden of the problem and explore risk factors to design and implement preventive approaches. This study aimed to determine prevalence and risk factors of NTDs. A hospital based cross-sectional and unmatched case-control study was conducted at three teaching hospitals of Addis Ababa University. NTDs were defined as cases of anencephaly, spina bifida, and encephalocele based on ICD-10 criteria. The prevalence of NTDs was calculated per 10,000 births for both birth and total prevalence. During seven months, we observed 55 cases of NTDs out of 8677 births after 28 weeks of gestation-birth prevalence of 63.4 per 10,000 births (95% confidence interval (CI), 51-77). A total of 115 cases were medically terminated after 12 weeks of gestation. Fifty-six of these terminations (48.7%) were due to NTDs. Thus, total prevalence of NTDs after 12 weeks' gestation is 126 per 10,000 births (95% CI, 100-150). Planned pregnancy (adjusted odds ratio (aOR), 0.47; 95% CI, 0.24-0.92), male sex (aOR, 0.56; 95% CI, 0.33-0.94), normal or underweight body mass index (aOR, 0.49; 95%, 0.29-0.95), and taking folic acid or multivitamins during first trimester (aOR, 0.47; 95%, 0.23-0.95) were protective of NTDs. However, annual cash family income less than $1,300 USD (aOR, 2.5; 95%, 1.2-5.5), $1,300-1,800 USD (aOR, 2.8; 95%, 1.3-5.8), and $1,801-2,700 USD (aOR, 2.6; 95%, 1.2-5.8) was found to be risk factors compared to income greater than $2,700 USD. The prevalence of NTDs was found to be high in this setting. Comprehensive preventive strategies focused on identified risk factors should be urgently established. More studies on prevention strategies, including folic acid supplementations, should be conducted in the setting. PMID- 29713642 TI - Patient-Specific Surgical Implants Made of 3D Printed PEEK: Material, Technology, and Scope of Surgical Application. AB - Additive manufacturing (AM) is rapidly gaining acceptance in the healthcare sector. Three-dimensional (3D) virtual surgical planning, fabrication of anatomical models, and patient-specific implants (PSI) are well-established processes in the surgical fields. Polyetheretherketone (PEEK) has been used, mainly in the reconstructive surgeries as a reliable alternative to other alloplastic materials for the fabrication of PSI. Recently, it has become possible to fabricate PEEK PSI with Fused Filament Fabrication (FFF) technology. 3D printing of PEEK using FFF allows construction of almost any complex design geometry, which cannot be manufactured using other technologies. In this study, we fabricated various PEEK PSI by FFF 3D printer in an effort to check the feasibility of manufacturing PEEK with 3D printing. Based on these preliminary results, PEEK can be successfully used as an appropriate biomaterial to reconstruct the surgical defects in a "biomimetic" design. PMID- 29713644 TI - The Therapeutic Effects after Transplantation of Whole-Layer Olfactory Mucosa in Rats with Optic Nerve Injury. AB - Background: Existing evidence suggests the potential therapy of transplanting olfactory ensheathing cells (OEC) either alone or in combination with neurotrophic factors or other cell types in optic nerve injury (ONI). However, clinical use of autologous OEC in the acute stages of ONI is not possible. On the other hand, acute application of heterologous transplantation may bring the issue of immune rejection. The olfactory mucosa (OM) with OEC in the lamina propria layer is located in the upper region of the nasal cavity and is easy to dissect under nasal endoscopy, which makes it a candidate as autograft material in acute stages of ONI. To investigate the potential of the OM on the protection of injured neurons and on the promotion of axonal regeneration, we developed a transplantation of syngenic OM in rats with ONI model. Methods: After the right optic nerve was crushed in Lewis rats, pieces of syngenic whole-layer OM were transplanted into the lesion. Rats undergoing phosphate buffered saline (PBS) injection were used as negative controls (NC). The authors evaluated the regeneration of retinal ganglion cells (RGCs) and axons for 3, 7, 14, and 28 days after transplantation. Obtained retinas and optic nerves were analyzed histologically. Results: Transplantations of OM significantly promoted the survival of retinal ganglion cells (RGCs) and axonal growth of RGCs compared with PBS alone. Moreover, OM group was associated with higher expression of GAP-43 in comparison with the PBS group. In addition to the potential effects on RGCs, transplantations of OM significantly decreased the expression of GFAP in the retinas, suggesting inhibiting astrocyte activation. Conclusions: Transplantation of whole-layer OM in rats contributes to the neuronal survival and axon regeneration after ONI. PMID- 29713645 TI - A Long Temporal Study of Parasitism in Asexual-Sexual Populations of Carassius gibelio: Does the Parasite Infection Support Coevolutionary Red Queen Dynamics? AB - Carassius gibelio is an extraordinary cyprinid species exhibiting both sexual and asexual reproduction. We hypothesized that parasitism selection is one of the potential mechanisms contributing to the coexistence of the two reproductive forms of C. gibelio living in the same habitat. We performed a four-year study to investigate the dynamics of parasite infection in C. gibelio. According to the Red Queen prediction, the asexual form is a target of parasite adaptation due to its low genetic variability. Both sexual and gynogenetic forms of C. gibelio exhibited similar levels of prevalence, with monogeneans being the most frequently observed parasite group. We observed the temporal dynamics of parasite infection in the last year of investigation, when both forms were more strongly parasitized. The sexual form was more parasitized by ectoparasites in the first and last years and less parasitized by nematodes in the last year when compared to the gynogenetic form. We found no trend of high parasite infection in gynogenetic mtDNA haplotypes. We conclude that Red Queen dynamics is not the mechanism driving parasite infection in sexual-gynogenetic C. gibelio over a long time scale. Alternatively, we suggest that the dynamics of parasite infection in this complex may be generated by multiple mechanisms. PMID- 29713646 TI - Mutational Profiling of Non-Small-Cell Lung Cancer Resistant to Osimertinib Using Next-Generation Sequencing in Chinese Patients. AB - Purpose: To identify the somatic mutated genes for optimal targets of non-small cell lung cancer after resistance to osimertinib treatment. Patients and Methods: Study patients all had advanced lung adenocarcinoma and acquired resistance to osimertinib as a second- or third-line treatment. These patients had harboring EGFR T790M mutation before osimertinib treatment, which was confirmed by Amplification Refractory Mutation System (ARMS) PCR or Next-Generation Sequencing (NGS). After resistance to osimertinib treatment, tumor tissue was collected by core needle biopsy. DNA was extracted from 15 * 5 um sliced section of formalin fixed paraffin-embedded (FFPE) material and NGS was done. The genetic changes were analyzed. Results: A total of 9 Chinese patients were studied, 5 females and 4 males, age 51-89 years. After progression with osimertinib treatment, core needle biopsy was performed and next-generation sequencing was performed. Nine patients had harboring 62 point mutations, 2 altered gene copies, 2 amplifications, and 1 EML4-ALK gene fusion. No MET or HER2 amplification was found in this cohort study. Nine patients still maintained initial EGFR 19 del or L858R activating mutations, while 7 of them kept EGFR T790M mutations. Among the 7 patients, 5 had secondary EGFR C797S and/or C797G mutations, which all happened in the same allele with T790M mutation. All patients were treated with targets therapies, chemotherapy, or best supportive care (BSC) in accordance with NGS genetic results and patients' performance status; 7 of them are still alive and 2 of them died of disease progression at last follow-up. Conclusions: EGFR C797S/G mutation and the same one presented on the same allele with EGFR T790M mutation were the most common mutation feature and played a key role in resistance to osimertinib in Chinese patients with NSCLC. Tumor cells losing T790M mutation and maintaining EGFR activating mutation might benefit from first-generation EGFR-TKI treatment. PMID- 29713647 TI - A Prospective, Randomized, Double-Blind, Parallel-Group, Placebo-Controlled Study Evaluating Meniscal Healing, Clinical Outcomes, and Safety in Patients Undergoing Meniscal Repair of Unstable, Complete Vertical Meniscal Tears (Bucket Handle) Augmented with Platelet-Rich Plasma. AB - Objective: The present study aimed to investigate the effectiveness and safety of platelet-rich plasma (PRP) application in arthroscopic repair of complete vertical tear of meniscus located in the red-white zone. Methods: This single center, prospective, randomized, double-blind, placebo-controlled, parallel-arm study included 37 patients with complete vertical meniscus tears. Patients received an intrarepair site injection of either PRP or sterile 0.9% saline during an index arthroscopy. The primary endpoint was the rate of meniscus healing in the two groups. The secondary endpoints were changes in the International Knee Documentation Committee (IKDC) score, Knee Injury and Osteoarthritis Outcome Score (KOOS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), and analog scale (VAS) in the two groups at 42 months. Results: After 18 weeks, the meniscus healing rate was significantly higher in the PRP-treated group than in the control group (85% versus 47%, P = 0.048). Functional outcomes were significantly better 42 months after treatment than at baseline in both groups. The IKDC score, WOMAC, and KOOS were significantly better in the PRP-treated group than in the control group. No adverse events were reported during the study period. Conclusions: The findings of this study indicate that PRP augmentation in meniscus repair results in improvements in both meniscus healing and functional outcome. PMID- 29713648 TI - Complications of Diabetes 2017. PMID- 29713649 TI - Treatment Discontinuation and Clinical Events in Type 2 Diabetes Patients Treated with Dipeptidyl Peptidase-4 Inhibitors or NPH Insulin as Third-Line Therapy. AB - Objective: To compare dipeptidyl peptidase-4 (DPP-4) inhibitors with neutral protamine Hagedorn (NPH) insulin, in terms of effectiveness and safety for the management of patients with type 2 diabetes mellitus (DM2) not controlled on metformin and sulfonylureas. Methods: A retrospective cohort study of individuals with DM2 newly dispensed with either DPP-4 inhibitors or NPH as third-line therapy, after metformin and sulfonylurea. Treatment discontinuation, macrovascular outcomes, and hypoglycemia were compared using multivariable Cox regression models, adjusted for sex, age, year of cohort entry, place of residence, hypertension, past history of hypoglycemia, diabetic ketoacidosis, comorbidities, and number of visits to emergency departments, outpatient physician, and hospitalizations. Results: Treatment discontinuation and hypoglycemia occurred more frequently with NPH than with DPP-4 inhibitor users. In the adjusted Cox model, the use of NPH compared to that of DPP-4 inhibitors was associated with a higher risk of discontinuation (HR: 1.33; 95% CI 1.27-1.40) and hypoglycemia (HR: 2.98; 95% CI 2.72-3.28). Risk of cardiovascular events was similar across groups. Conclusions: This real-world analysis suggests that DM2 patients initiating third-line therapy with NPH have poorer control of diabetes when compared to DPP-4 inhibitor initiators. PMID- 29713650 TI - Application of Metabolomics to Study Effects of Bariatric Surgery. AB - Bariatric surgery was born in the 1950s at the University of Minnesota. From this time, it continues to evolve and, by the same token, gives new or better possibilities to treat not only obesity but also associated comorbidities. Metabolomics is also a relatively young science discipline, and similarly, it shows great potential for the comprehensive study of the dynamic alterations of the metabolome. It has been widely used in medicine, biology studies, biomarker discovery, and prognostic evaluations. Currently, several dozen metabolomics studies were performed to study the effects of bariatric surgery. LC-MS and NMR are the most frequently used techniques to study main effects of RYGB or SG. Research has yield many interesting results involving not only clinical parameters but also molecular modulations. Detected changes pertain to amino acid, lipids, carbohydrates, or gut microbiota alterations. It proves that including bariatric surgery to metabolic surgery is warranted. However, many molecular modulations after those procedures remain unexplained. Therefore, application of metabolomics to study this field seems to be a proper solution. New findings can suggest new directions of surgery technics modifications, contribute to broadening knowledge about obesity and diseases related to it, and perhaps develop nonsurgical methods of treatment in the future. PMID- 29713651 TI - Novel Mechanisms Modulating Palmitate-Induced Inflammatory Factors in Hypertrophied 3T3-L1 Adipocytes by AMPK. AB - Objective: A growing body of evidence indicates that AMP-activated protein kinase (AMPK) contributes to not only energy metabolic homeostasis but also the inhibition of inflammatory responses. However, the underlying mechanisms remain unclear. To elucidate the role of AMPK, in this study, we observed the effects of AMPK activation on monocyte chemoattractant protein-1 (MCP-1) release in mature 3T3-L1 adipocytes. Methods: We observed signal transduction pathways regulating MCP-1, which increased in obese adipocytes, in an in vitro model of hypertrophied 3T3-L1 adipocytes preloaded with palmitate. Results: Palmitate-preloaded cells exhibited significant increase in MCP-1 release and triglyceride (TG) deposition. Increased MCP-1 release and TG deposition were significantly decreased by an AMPK activator. In addition, the AMPK activator not only markedly diminished MCP-1 secretion but also augmented phosphorylation of nuclear factor-kappaB (NF-kappaB) and extracellular signal-regulated kinase (ERK) 1/2. In contrast, MCP-1 release suppression was abolished by the AMPK inhibitor compound C and the MEK inhibitor U0126. Conclusions: MCP-1 release from hypertrophied adipocytes is suppressed by AMPK activation through the NF-kappaB and ERK pathways. These findings provide evidence that AMPK plays a crucial role in ameliorating obesity-induced inflammation. PMID- 29713653 TI - Comparison of clinical outcomes between femtosecond laser-assisted versus conventional phacoemulsification. AB - Background: To compare femtosecond laser-assisted versus conventional phacoemulsification in terms of visual and refractive outcomes, cumulative dissipated energy, anterior chamber inflammation and endothelial cell loss. Methods: In this retrospective cohort study, records of eyes that underwent femtosecond laser-assisted cataract surgery (FLACS) or conventional phacoemulsification (CP) were reviewed. The Victus femtosecond laser (Bausch and Lomb, Germany) was used to carry out corneal incisions, anterior capsulotomy, and lens fragmentation in FLACS procedures. Manifest refraction spherical equivalence (MRSE), uncorrected distance visual acuity (UDVA), corrected distance visual acuity (CDVA), cumulative dissipated energy (CDE), postoperative cells and flare and endothelial cell count data were collected. Subgroup analysis of the visual acuity tests was performed based on the type of intraocular lens implanted (monofocal, monofocal toric, multifocal, multifocal toric, accommodating). Results: A total of 735 eyes were included in the study (296 eyes for the FLACS group and 439 eyes for the CP group). At one year follow-up, 120 eyes comprised the FLACS group and 265 eyes for the CP group. MRSE in the FLACS group was - 0.16 +/- 0.58 D and - 0.20 +/- 0.52 D in the CP group (P = 0.50). UDVA in the FLACS group was 20/25 (mean logMAR 0.12 +/- 0.13) and 20/25 (mean logMAR 0.11 +/- 0.13) in the CP group (P = 0.48). CDVA was 20/20 (mean logMAR 0.03 +/- 0.07) in the FLACS group and 20/20 (mean logMAR 0.02 +/- 0.06) in the CP group (P = 0.15). No statistically significant trend was seen for FLACS versus CP by intraocular type for visual acuity. CDE for the different cataract grades ranged from 6.97 +/- 5.74 to 29.02 +/- 16.07 in the FLACS group and 7.59 +/- 6.42 to 35.69 +/- 18.30 in the CP group. The FLACS group was significantly lower for post-operative central corneal edema (P = 0.05), cells and flare (P = 0.01), and endothelial cell loss (P = 0.04). Conclusions: Femtosecond laser-assisted cataract surgery and conventional phacoemulsification had similar refractive and visual outcomes. Phacoemulsification energy, anterior chamber inflammation and corneal endothelial cell loss were less in the femtosecond laser group. PMID- 29713652 TI - Natural Killer Cells from Malignant Pleural Effusion Are Endowed with a Decidual Like Proangiogenic Polarization. AB - Natural killer (NK) cells are crucial in tumor recognition and eradication, but their activity is impaired in cancer patients, becoming poorly cytotoxic. A particular type of NK cells, from the decidua, has low cytotoxicity and shows proangiogenic functions. We investigated whether NK cells from peripheral blood (PB) and pleural effusions of patients develop decidual-like NK phenotype and whether exposure to IL-2 can restore their killing ability in the presence of pleural fluids. NK cells from pleural effusion of patients with inflammatory conditions (iPE, n = 18), primary tumor (ptPE, n = 18), and metastatic tumor (tmPE, n = 27) acquired the CD56brightCD16- phenotype. NK cells from both ptPE and tmPE showed increased expression for the CD49a and CD69 decidual-like (dNK) markers and decreased levels of the CD57 maturation marker. NK from all the PE analyzed showed impaired degranulation capability and reduced perforin release. PE-NK cells efficiently responded to IL-2 stimulation in vitro. Addition of TGFbeta or cell-free pleural fluid to IL-2 in the culture medium abrogated NK cell CD107a and IFNgamma expression even in healthy donors (n = 14) NK. We found that tmPE-NK cells produce VEGF and support the formation of capillary-like structures in endothelial cells. Our results suggest that the PE tumor microenvironment can shape NK cell polarization towards a low cytotoxic, decidual like, highly proangiogenic phenotype and that IL-2 treatment is not sufficient to limit this process. PMID- 29713654 TI - Transplant Drug Interactions and a Word of Caution for the HIV Provider. A Case Report. AB - Electronic medical record platforms fail to support provider alerts when a drug is discontinued. Protease inhibitors, often boosted by ritonavir or cobicistat, increase the serum concentration of calcineurin inhibitors. This case demonstrates acute liver transplant rejection in an HIV-positive recipient due to a failure to recognize the loss of protease inhibitor interaction with his immunosuppressive regimen. PMID- 29713655 TI - Hydrogen Deuterium Exchange Mass Spectrometry of Oxygen Sensitive Proteins. AB - The protocol detailed here describes a way to perform hydrogen deuterium exchange coupled to mass spectrometry (HDX-MS) on oxygen sensitive proteins. HDX-MS is a powerful tool for studying the protein structure-function relationship. Applying this technique to anaerobic proteins provides insight into the mechanism of proteins that perform oxygen sensitive chemistry. A problem when using HDX-MS to study anaerobic proteins is that there are many parts that require constant movement into and out of an anaerobic chamber. This can affect the seal, increasing the likelihood of oxygen exposure. Exposure to oxygen causes the cofactors bound to these proteins, a common example being FeS clusters, to no longer interact with the amino acid residues responsible for coordinating the FeS clusters, causing loss of the clusters and irreversible inactivation of the protein. To counteract this, a double vial system was developed that allows the preparation of solutions and reaction mixtures anaerobically, but also allows these solutions to be moved to an aerobic environment while shielding the solutions from oxygen. Additionally, movement isn't limited like it is in an anaerobic chamber, ensuring more consistent data, and fewer errors during the course of the reaction. PMID- 29713656 TI - Non-integrated acellular dermal matrix in breast reconstruction: a case report. AB - Acellular Dermal Matrices have become increasing popular in breast reconstruction especially in the last decade. There is a debate on whether Acellular Dermal Matrices increase the risk of complications or not. Common complications include infection, wound dehiscence, necrosis, seroma, haematoma, capsular contracture, extrusion, loss of implant and reconstruction failure. Non-integration is not listed as a typical complication to the use of Acellular Dermal Matrices. We report a case of a completely non-integrated Acellular Dermal Matrix following breast reconstruction in a patient without significant risk factors. PMID- 29713657 TI - The Impact of University Sanctions on Cannabis Use: Individual Difference Factors that Predict Change in Cannabis Use. AB - Over one-third of college students use cannabis, yet the majority of students experiencing cannabis-use problems are not interested in seeking treatment. Therefore, the campus judicial process following a violation of university cannabis policies may be an important point of intervention. This study examined whether cannabis use decreased following being sanctioned by the university for violation of campus drug policy. We also identified individual difference factors related to changes in post-infraction use. University students (N = 98, 73.1% White, 88.2% Male) were referred to participate in a brief motivational intervention study as a component of their sanctions following violation of campus cannabis policies. Data were collected during the intake appointment. Approximately 91% of participants reported decreased post-infraction cannabis use and 58% of the sample reported abstinence in the month prior to intake. The following variables were significantly related to both abstinence or to reducing frequent use (from at least four times per month to less frequently): using less frequently prior to their infraction, descriptive friend norms, and enhancement motives. The following variables were significantly related only to reducing frequent use: injunctive norms regarding parents and expansion motives. Students sanctioned for cannabis violations appear to decrease cannabis use post infraction. Thus, results support campus efforts to sanction students for violation of campus cannabis use policies. Identification of individual difference variables that predict post-infraction change in cannabis use can inform treatment and prevention efforts. PMID- 29713659 TI - Dopamine and Proximity in Motivation and Cognitive Control. AB - Cognitive control - the ability to override a salient or prepotent action to execute a more deliberate one - is required for flexible, goal-directed behavior, and yet it is subjectively costly: decision-makers avoid allocating control resources, even when doing so affords more valuable outcomes. Dopamine likely offsets effort costs just as it does for physical effort. And yet, dopamine can also promote impulsive action, undermining control. We propose a novel hypothesis that reconciles opposing effects of dopamine on cognitive control: during action selection, striatal dopamine biases benefits relative to costs, but does so preferentially for "proximal" motor and cognitive actions. Considering the nature of instrumental affordances and their dynamics during action selection facilitates a parsimonious interpretation and conserved corticostriatal mechanisms across physical and cognitive domains. PMID- 29713658 TI - Regulation of habit formation in the dorsal striatum. AB - Habits are an essential and pervasive component of our daily lives that allow us to efficiently perform routine tasks. But their disruption contributes to the symptoms that underlie many psychiatric diseases. Emerging data are revealing the cellular and molecular mechanisms of habit formation in the dorsal striatum. New data suggest that in both the dorsolateral and dorsomedial striatum histone deacetylase (HDAC) activity acts as a critical negative regulator of the transcriptional processes underlying habit formation. In this review, we discuss this recent work and draw conclusions relevant to the treatment of diseases marked by maladaptive habits. PMID- 29713662 TI - Move Over Caco-2 Cells: Human-Induced Organoids Meet Gut-on-a-Chip. PMID- 29713661 TI - Single-Cell Computational Strategies for Lineage Reconstruction in Tissue Systems. AB - Function at the organ level manifests itself from a heterogeneous collection of cell types. Cellular heterogeneity emerges from developmental processes by which multipotent progenitor cells make fate decisions and transition to specific cell types through intermediate cell states. Although genetic experimental strategies such as lineage tracing have provided insights into cell lineages, recent developments in single-cell technologies have greatly increased our ability to interrogate distinct cell types, as well as transitional cell states in tissue systems. From single-cell data that describe these intermediate cell states, computational tools have been developed to reconstruct cell-state transition trajectories that model cell developmental processes. These algorithms, although powerful, are still in their infancy, and attention must be paid to their strengths and weaknesses when they are used. Here, we review some of these tools, also referred to as pseudotemporal ordering algorithms, and their associated assumptions and caveats. We hope to provide a rational and generalizable workflow for single-cell trajectory analysis that is intuitive for experimental biologists. PMID- 29713660 TI - Esophageal 3D Culture Systems as Modeling Tools in Esophageal Epithelial Pathobiology and Personalized Medicine. AB - The stratified squamous epithelium of the esophagus shows a proliferative basal layer of keratinocytes that undergo terminal differentiation in overlying suprabasal layers. Esophageal pathologies, including eosinophilic esophagitis, gastroesophageal reflux disease, Barrett's esophagus, squamous cell carcinoma, and adenocarcinoma, cause perturbations in the esophageal epithelial proliferation-differentiation gradient. Three-dimensional (3D) culture platforms mimicking in vivo esophageal epithelial tissue architecture ex vivo have emerged as powerful experimental tools for the investigation of esophageal biology in the context of homeostasis and pathology. Herein, we describe types of 3D culture that are used to model the esophagus, including organotypic, organoid, and spheroid culture systems. We discuss the development and optimization of various esophageal 3D culture models; highlight the applications, strengths, and limitations of each method; and summarize how these models have been used to evaluate the esophagus under homeostatic conditions as well as under the duress of inflammation and precancerous/cancerous conditions. Finally, we present future perspectives regarding the use of esophageal 3D models in basic science research as well as translational studies with the potential for personalized medicine. PMID- 29713663 TI - Parietal Cell Death by Cytokines. PMID- 29713664 TI - Estrogen-Mediated Effects Underlie Gender Bias in Inflammatory Bowel Disease. PMID- 29713665 TI - Proteomic Study Defines How Alcohol Alters ER Structure and Redox Proteome to Trigger ER Stress and Acinar Cell Pathology in Pancreatitis. PMID- 29713666 TI - Mapping the Duodenal Crypt-Villus Transport Axis. PMID- 29713667 TI - The Novel Role of Lgr5 as a Regulator of Cell Homeostasis and Disease of the Gastric Oxyntic Mucosa. PMID- 29713668 TI - Mutant KRAS Exosomes Influence the Metabolic State of the Colon Microenvironment. PMID- 29713669 TI - OSTalpha-OSTbeta Guards the Ileal Enterocyte From the Accumulation of Toxic Levels of Bile Acids. PMID- 29713670 TI - Human Fetal Enterospheres: New Tools for the Study of Necrotizing Enterocolitis. PMID- 29713671 TI - Esophageal Adenocarcinomas: A Need for Speed Driven by Immune Pathways That Have Druggable Targets. PMID- 29713672 TI - On and Off: A Dual Role for Cysteine Protease Autoprocessing of C difficile Toxin B on Cytotoxicity vs Proinflammatory Toxin Actions? PMID- 29713673 TI - A Sabbatical: The Gift That Keeps on Giving. PMID- 29713674 TI - Microfluidic Organ-on-a-Chip Models of Human Intestine. AB - Microfluidic organ-on-a-chip models of human intestine have been developed and used to study intestinal physiology and pathophysiology. In this article, we review this field and describe how microfluidic Intestine Chips offer new capabilities not possible with conventional culture systems or organoid cultures, including the ability to analyze contributions of individual cellular, chemical, and physical control parameters one-at-a-time; to coculture human intestinal cells with commensal microbiome for extended times; and to create human-relevant disease models. We also discuss potential future applications of human Intestine Chips, including how they might be used for drug development and personalized medicine. PMID- 29713676 TI - Novel temperature-controlled RFA probe for treatment of blocked metal biliary stents in patients with pancreaticobiliary cancers: initial experience. AB - Background and study aims: Radiofrequency ablation (RFA) is used to treat blocked biliary stents in patients with pancreaticobiliary (PB) tumors with varying results. We report our experience with a novel temperature-controlled probe for treatment of blocked metal stents. Patients and methods: Patients with histologically proven PB cancers and a blocked biliary stents were treated using ELRATM electrode (Taewoong Medical) under fluoroscopic guidance. Demographics, clinical outcome, stricture diameter improvements, complications and mortality at 30 days were prospectively recorded. Results: Nine procedures were performed on seven patients (4 male, 3 female); mean age 65.33 (range 56 - 82 years). Mean stricture diameter prior to RFA was 1.13 mm (SD +/- 0.54) and 4.42 mm (SD +/- 1.54) following RFA ( P < 0.0001). Five of seven patients (71 %) required additional stents to ensure optimal drainage. There were no procedure-related complications. Mean follow-up was 193.55 days (range 31 - 540) and three of nine patients (33 %) died due to terminal cancer. Conclusion : These are the first reported data on use of a temperature-controlled RFA catheter in humans to treat blocked metal biliary stents. The device is safe but further randomized trials are required to establish the efficacy and survival benefits of this probe. PMID- 29713675 TI - Evaluation of a new stent for EUS-guided pancreatic duct drainage: long-term follow-up outcome. AB - Background and study aims: Endoscopic ultrasonography-guided pancreatic duct drainage (EUS-PD) has been reported as an alternative for failed conventional endoscopic retrograde cholangiopancreatography (ERCP). However, there are few dedicated devices for EUS-PD. Recently, we have developed a new plastic stent dedicated to EUS-PD and have conducted a feasibility study to evaluate its efficacy. In the current study, we evaluated the long-term efficacy of this new plastic stent. Patients and methods: Thirty patients (61 +/- 14.3 years old, 14 men) with acute recurrent pancreatitis caused by a stricture in the main pancreatic duct (MPD) or stenotic pancreatoenterostomy were treated at our institution using our recently developed 7Fr plastic stent between August 2013 and April 2017. Results: The stent was placed successfully in all patients (30/30) and early clinical success was achieved in all of them. Early adverse events (AEs) occurred in seven patients (23.3 %), namely, self-limited abdominal pain (n = 5), mild pancreatitis (n = 1), and bleeding which required transcatheter arterial embolization (n = 1). Two patients died of primary disease and three were lost to follow-up. The remaining 25 patients were followed up after initial EUS-PD for a median of 23 months (range, 6 - 44 months). Twenty patients required regular stent exchange (3 times; range, 1 - 12 times). Spontaneous stent dislodgement was observed in six patients. Four patients wanted their stents removed 1 year after the initial intervention. Twelve patients (48 %) had regular stent exchange 1 year after the initial intervention. Three patients converted to standard transpapillary pancreatic duct stenting by conventional ERCP. Finally, nine patients (36 %) had complete stent removal either intentionally or by spontaneous dislodgement without any symptoms. Conclusion: The new plastic stent for EUS-PD was associated with not only short term technical success but also long-term clinical success in the majority of patients evaluated in this study. PMID- 29713677 TI - Narrow band imaging efficiency in evaluation of mucosal healing/relapse of ulcerative colitis. AB - Background and study aims: Mucosal healing is a current treatment target in ulcerative colitis (UC), while histological remission is another target. The aim of this study was to evaluate the efficiency of magnified narrow band imaging (NBI) findings of mucosal healing and their relationship with histological activity and prognosis. Patients and methods: Patients with UC who underwent total colonoscopy between January 2010 and December 2012 with left-sided or total colitis type UC and achieved clinical remission with an endoscopic Mayo score of 0 or 1 were included. Each colon section was observed with white light and magnified NBI, with the colonoscopy being repeated at 1-year follow-up. We assessed the relationships of magnified NBI with histological disease activity and prognosis. Magnified NBI findings were divided into three categories; honeycomb-like blood vessels (BV-H), blood vessels shaped like bare branches (BV BB), and blood vessels shaped like vines (BV-V). Results: Fifty-two patients were included. The percentage of remitted mucosa with BV-BB was 37 %, while that of mucosa with scars with BV-H was 35 %. BV-H and BV-BB did not show pathological activity (12/292 and 8/299, respectively), while BV-V showed high pathological activity (27/33, 81 %). There was a correlation between magnified NBI findings and pathological findings ( P < 0.01). The odds ratio for inflammation activity at 1-year follow-up was 14.2 for BV-BB (95 % CI, 3.3 - 60.9). Conclusion: Magnified NBI findings showed a good relationship with histological activity. This suggests that we could estimate histological activity without biopsy, and also the possibility of predicting relapse over the following year. PMID- 29713678 TI - Step-up training for colorectal and gastric ESD and the challenge of ESD training in the proximal colon: results from a German Center. AB - Background and study aims: The endoscopic submucosal dissection (ESD) of cancerous and precancerous lesions in the gastrointestinal (GI) tract is an effective but difficult-to-learn procedure, especially for Western endoscopists. We developed a step-up training protocol and evaluated its outcome on a single endoscopist using specific performance measures. Patients and methods: The training protocol included a 12-month period of 50 observational and supervised ESD cases as well as 24 animal procedures. After completion of the protocol, ESD competency was evaluated in the first 30 independent ESD cases. Majority of lesions were located in the stomach and rectum. Performance measures included R0 resection rate, complication rate and resection speed. Results: R0 resection rate was 93 %, complication rate was 7 % and median resection speed was 6,77 cm 2 /h. 1 case of delayed perforation with subsequent hemicolectomy occurred in the descending colon. Conclusion: The ESD step-up training protocol used in this study on a single endoscopist showed excellent outcomes for lesions in the rectum and stomach. However, ESD training in the upper colon remains a challenge. PMID- 29713679 TI - Risk factors for advanced duodenal and ampullary adenomatosis in familial adenomatous polyposis: a prospective, single-center study. AB - Background and study aims: To determine the clinical features associated with advanced duodenal and ampullary adenomas in familial adenomatous polyposis. Secondarily, we describe the prevalence and clinical significance of jejunal polyposis. Patients and methods: This is a single center, prospective study of 62 patients with familial adenomatous polyposis. Duodenal polyposis was classified according to Spigelman and ampullary adenomas were identified. Patients with Spigelman III and IV duodenal polyposis underwent balloon assisted enteroscopy. Predefined groups according to Spigelman and presence or not of ampullary adenomas were related to the clinical variables: gender, age, family history of familial adenomatous polyposis, type of colorectal surgery, and type of colorectal polyposis. Results: Advanced duodenal polyposis was present in 13 patients (21 %; 9 male) at a mean age of 37.61 +/- 13.9 years. There was a statistically significant association between family history of the disease and groups according to Spigelman ( P = 0.03). Seven unrelated patients (6 male) presented ampullary adenomas at a mean age of 36.14 +/- 14.2 years. The association between ampullary adenomas and extraintestinal manifestations was statistically significant in multivariate analysis ( P = 0.009). Five endoscopic types of non-ampullary adenoma were identified, showing that lesions larger than 10 mm or with a central depression presented foci of high grade dysplasia. Among 28 patients in 12 different families, a similar Spigelman score was identified; 10/12 patients (83.3 %) who underwent enteroscopy presented small tubular adenomas with low grade dysplasia in the proximal jejunum. Conclusions: Advanced duodenal polyposis phenotype may be predictable from disease severity in a first degree relative. Ampullary adenomas were independently associated with the presence of extraintestinal manifestations. PMID- 29713680 TI - Evolution of features of chronic pancreatitis during endoscopic ultrasound-based surveillance of individuals at high risk for pancreatic cancer. AB - Background and study aims : During endoscopic ultrasound (EUS)-based pancreatic ductal adenocarcinoma (PDAC)-surveillance in asymptomatic individuals, features of chronic pancreatitis (CP) are often detected. Little is known about the prevalence and progression of these features. The aim of this study was to quantify these features, assess the interobserver agreement, assess possible associated factors, and assess the natural course during 3 years of follow-up. Patients and methods : Two experienced endosonographers reviewed anonymized sequential EUS videos of participants in PDAC surveillance that were obtained in 2012 and 2015 for features of CP. Descriptives, agreement analyses, univariate and multivariate analyses for possible risk factors, and repeated measures analyses to assess intra-individual changes over time were performed. Results : A total of 42 EUS videos of 21 participants were reviewed. Any feature of CP was present in 86 % (2012) and 81 % (2015) of participants, with a mean of 2.5 features per individual. The overall interobserver agreement was almost perfect at 83 %. No baseline factors were significantly associated with features of CP. Features did not change over time, except for hyperechoic foci without shadowing, which decreased intra-individually (beta = - 1.6, P = 0.005). Conclusions : This blinded study shows features of CP to be highly prevalent in individuals at high risk of developing pancreatic cancer. No baseline factors were associated with presence of these features. CP features did not increase intra-individually over a 3-year period. Longer follow-up and pathological examination of pancreatic resection specimens will be essential to learn whether EUS detection and follow up of these CP features bear clinical relevance. PMID- 29713681 TI - Porous Substrates Promote Endothelial Migration at the Expense of Fibronectin Fibrillogenesis. AB - Porous substrates have gained increased usage in cell studies and tissue mimetic applications because they can partition distinct cell types while still allowing important biochemical crosstalk. In the presented work, we investigated how porous substrates with micron and submicron features influence early cell migration and the associated ECM establishment, which can critically affect the rate of cell coverage on the substrate and the ensuing tissue organization. We showed through time-lapse microscopy that cell speed and migratory distance on membranes with 0.5 MUm pores were nearly two-fold of those observed on nonporous membranes, while values on membranes with 3.0 MUm pores fell in between. Although the cell directionality ratio and the persistence time was unaffected by the presence of pores, the cells did exhibit directionality preferences based on the hexagonal pore patterning. Fibronectin fibrillogenesis exhibited a distinct inverse relationship to cell speed, as the fibrils formed on the nonporous control were significantly longer than those on both types of porous substrates. We further confirmed on a per cell basis that there is a negative correlation between fibronectin fibril length and cell speed. The observed trade-off between early cell coverage and ECM establishment thus warrants consideration in the selection or the engineering of the ideal porous substrate for tissue mimetic applications and may help guide future cell studies. PMID- 29713683 TI - On the enigmatic birth of the Pacific Plate within the Panthalassa Ocean. AB - The oceanic Pacific Plate started forming in Early Jurassic time within the vast Panthalassa Ocean that surrounded the supercontinent Pangea, and contains the oldest lithosphere that can directly constrain the geodynamic history of the circum-Pangean Earth. We show that the geometry of the oldest marine magnetic anomalies of the Pacific Plate attests to a unique plate kinematic event that sparked the plate's birth at virtually a point location, surrounded by the Izanagi, Farallon, and Phoenix Plates. We reconstruct the unstable triple junction that caused the plate reorganization, which led to the birth of the Pacific Plate, and present a model of the plate tectonic configuration that preconditioned this event. We show that a stable but migrating triple junction involving the gradual cessation of intraoceanic Panthalassa subduction culminated in the formation of an unstable transform-transform-transform triple junction. The consequent plate boundary reorganization resulted in the formation of a stable triangular three-ridge system from which the nascent Pacific Plate expanded. We link the birth of the Pacific Plate to the regional termination of intra-Panthalassa subduction. Remnants thereof have been identified in the deep lower mantle of which the locations may provide paleolongitudinal control on the absolute location of the early Pacific Plate. Our results constitute an essential step in unraveling the plate tectonic evolution of "Thalassa Incognita" that comprises the comprehensive Panthalassa Ocean surrounding Pangea. PMID- 29713682 TI - Whole-genome sequence analysis shows that two endemic species of North American wolf are admixtures of the coyote and gray wolf. AB - Protection of populations comprising admixed genomes is a challenge under the Endangered Species Act (ESA), which is regarded as the most powerful species protection legislation ever passed in the United States but lacks specific provisions for hybrids. The eastern wolf is a newly recognized wolf-like species that is highly admixed and inhabits the Great Lakes and eastern United States, a region previously thought to be included in the geographic range of only the gray wolf. The U.S. Fish and Wildlife Service has argued that the presence of the eastern wolf, rather than the gray wolf, in this area is grounds for removing ESA protection (delisting) from the gray wolf across its geographic range. In contrast, the red wolf from the southeastern United States was one of the first species protected under the ESA and was protected despite admixture with coyotes. We use whole-genome sequence data to demonstrate a lack of unique ancestry in eastern and red wolves that would not be expected if they represented long divergent North American lineages. These results suggest that arguments for delisting the gray wolf are not valid. Our findings demonstrate how a strict designation of a species under the ESA that does not consider admixture can threaten the protection of endangered entities. We argue for a more balanced approach that focuses on the ecological context of admixture and allows for evolutionary processes to potentially restore historical patterns of genetic variation. PMID- 29713684 TI - Ultrahigh sensitivity of methylammonium lead tribromide perovskite single crystals to environmental gases. AB - One of the limiting factors to high device performance in photovoltaics is the presence of surface traps. Hence, the understanding and control of carrier recombination at the surface of organic-inorganic hybrid perovskite is critical for the design and optimization of devices with this material as the active layer. We demonstrate that the surface recombination rate (or surface trap state density) in methylammonium lead tribromide (MAPbBr3) single crystals can be fully and reversibly controlled by the physisorption of oxygen and water molecules, leading to a modulation of the photoluminescence intensity by over two orders of magnitude. We report an unusually low surface recombination velocity of 4 cm/s (corresponding to a surface trap state density of 108 cm-2) in this material, which is the lowest value ever reported for hybrid perovskites. In addition, a consistent modulation of the transport properties in single crystal devices is evidenced. Our findings highlight the importance of environmental conditions on the investigation and fabrication of high-quality, perovskite-based devices and offer a new potential application of these materials to detect oxygen and water vapor. PMID- 29713685 TI - Multi-watt, multi-octave, mid-infrared femtosecond source. AB - Spectroscopy in the wavelength range from 2 to 11 MUm (900 to 5000 cm-1) implies a multitude of applications in fundamental physics, chemistry, as well as environmental and life sciences. The related vibrational transitions, which all infrared-active small molecules, the most common functional groups, as well as biomolecules like proteins, lipids, nucleic acids, and carbohydrates exhibit, reveal information about molecular structure and composition. However, light sources and detectors in the mid-infrared have been inferior to those in the visible or near-infrared, in terms of power, bandwidth, and sensitivity, severely limiting the performance of infrared experimental techniques. This article demonstrates the generation of femtosecond radiation with up to 5 W at 4.1 MUm and 1.3 W at 8.5 MUm, corresponding to an order-of-magnitude average power increase for ultrafast light sources operating at wavelengths longer than 5 MUm. The presented concept is based on power-scalable near-infrared lasers emitting at a wavelength near 1 MUm, which pump optical parametric amplifiers. In addition, both wavelength tunability and supercontinuum generation are reported, resulting in spectral coverage from 1.6 to 10.2 MUm with power densities exceeding state-of the-art synchrotron sources over the entire range. The flexible frequency conversion scheme is highly attractive for both up-conversion and frequency comb spectroscopy, as well as for a variety of time-domain applications. PMID- 29713686 TI - Flexible active-matrix organic light-emitting diode display enabled by MoS2 thin film transistor. AB - Atomically thin molybdenum disulfide (MoS2) has been extensively investigated in semiconductor electronics but has not been applied in a backplane circuitry of organic light-emitting diode (OLED) display. Its applicability as an active drive element is hampered by the large contact resistance at the metal/MoS2 interface, which hinders the transport of carriers at the dielectric surface, which in turn considerably deteriorates the mobility. Modified switching device architecture is proposed for efficiently exploiting the high-k dielectric Al2O3 layer, which, when integrated in an active matrix, can drive the ultrathin OLED display even in dynamic folding states. The proposed architecture exhibits 28 times increase in mobility compared to a normal back-gated thin-film transistor, and its potential as a wearable display attached to a human wrist is demonstrated. PMID- 29713687 TI - Implementing a Single-Session Nurse-Led Assessment Clinic into a Gender Service. AB - The Royal Children's Hospital Gender Service offers support, assessment, and medical care to transgender and gender diverse children and adolescents in Victoria, Australia. Referrals have rapidly increased leading to extended wait times. In response, a single-session nurse-led assessment clinic (SSNac) was introduced as the clinical entry point to the service, during which a biopsychosocial assessment is undertaken, and information, education, and support are provided. Outcomes of the SSNac include a significant reduction in wait times and a timely clinical triage system. This article documents the creation and implementation of SSNac to offer a template for use in other gender services. PMID- 29713688 TI - Nurse Practitioner Knowledge, Attitudes, and Beliefs When Caring for Transgender People. AB - Purpose: The aim of this study was to explore Nurse Practitioner (NP) knowledge, attitudes, and beliefs when working with transgender people and to inform about Practitioner education needs. Methods: A qualitative descriptive design was used to explore (NP) experiences. Focused semistructured interviews were conducted in 2016 with 11 (N=11) NPs in the northeastern United States who represent various years of experience and encounters with transgender patients. The interviews explored NP knowledge attitudes and beliefs when caring for transgender patients and described their overall experiences in rendering care in the clinical setting. The interviews were professionally transcribed and analyzed independently and jointly by two investigators using conventional content analysis. Results: Four main themes and six subthemes were identified: Main themes include personal and professional knowledge gaps, fear and uncertainty, caring with intention and pride, and creating an accepting environment. Conclusions: NPs in this study perceive gaps in their knowledge that threaten their ability to deliver quality, patient-centered care to transgender patients, despite their best intentions. These findings have implications for changes in nursing practice, education, and research needed to address vital gaps in the healthcare of transgender people. PMID- 29713689 TI - Improving rates of implantable cardioverter defibrillator deactivation in end-of life care. AB - Implantable cardioverter defibrillators (ICDs) save lives in selected patients at risk of sudden cardiac death. However, in patents suffering with terminal illness, ICD therapy could pose a risk of unnecessary futile shocks which could lead to undignified discomfort in their final days of life. National guidelines advise that patients approaching the end of their natural life should be offered a compassionate choice of having their defibrillator deactivated. Following an actual clinical incident involving a patient receiving avoidable ICD shocks in his final hours, we identified shortcomings in communication and gaps in knowledge about ICD management in end-of-life care. We developed a quality improvement programme targeting training and educational support to general physicians and nurses at our large District General Hospital. A series of interventions were delivered including Grand Round presentation, departmental seminars and publicity posters. In parallel, we introduced a local protocol for implementing ICD deactivation which was published on our intranet for Trust-wide accessibility. Following interventions, we examined the clinical notes of each end-of-life care patient who died with an ICD in situ over a 6-month observation period and recorded the proportion who received consent-guided ICD deactivation versus died with an active ICD in situ because no deactivation discussion had been offered. Before our interventions in 2015, 0 out of 10 eligible patients (0%) received consent-guided ICD deactivation. Six months into our campaign to encourage healthcare workers to undertake advance care planning discussion in 2016, 7 out of 13 eligible patients (54%) received consent-guided ICD deactivation and no patients received shocks in their final month of life. This programme was successful in raising awareness of this emerging issue, improving physician knowledge and delivering patient choice as well as contributing to safe and compassionate end-of-life care. PMID- 29713690 TI - Improving medication reconciliation at hospital admission, discharge and ambulatory care through a transition of care team. AB - Medication reconciliation is an important component to the care of hospitalised patients and their safe transition to the ambulatory setting. In our Family Medicine Hospitalist Service, patient care is frequently transferred between the various physicians, residents, nurses and eventually to a separate group of providers who provide ambulatory management. Due to frequent transitions of care, there was no clear ownership of the medication reconciliation process. To improve the medication reconciliation process, a Transition of Care Team composed of registered nurses was created to oversee the entire reconciliation process. The team engaged the patient and their family, when needed, contacted patients' pharmacies and their providers, reconciled the patients' hospital medication list with the ambulatory list at hospital admission and within 24 hours of discharge, and attended the hospital follow-up visit to verify medications and provide continuity of care. Implementation of the team allowed for additional investigative resources, redundancy in preventing errors and early recovery should an error occur. The percent of medications with error after implementation of the Transition of Care Team was reduced from 131/386 (33.9%) to 147/787 (18.7%) at hospital admission, 81/354 (22.9%) to 42/834 (5.0%) at discharge and 43/337 (12.8%) to 6/809 (0.7%) at follow-up visit (two proportion tests, p<0.001). In addition, the percent of charts without any errors improved at hospital discharge from 8/31 (25.8%) to 46/70 (65.7%) and at hospital follow-up visit from 16/31 (51.6%) to 64/70 (91.4%) (two-proportion test, p<0.001). Previously viewed as three separate reconciliations occurring at admission, discharge and hospital follow-up, the approach to medication reconciliation was reframed as a continuous process occurring throughout the hospitalisation and hospital follow-up resulting in improved reconciliation accuracy and safer transitions to the ambulatory setting. PMID- 29713691 TI - Improving inpatient warfarin therapy safety using a pharmacist-managed protocol. AB - Introduction: Safe management of warfarin in the inpatient setting can be challenging. At the Mayo Clinic hospitals in Rochester, Minnesota, we set out to improve the safety of warfarin management among surgical and non-surgical inpatients. Methods: A multidisciplinary team designed a pharmacist-managed warfarin protocol (PMWP) which designated warfarin dosing to inpatient pharmacists with guidance from computerised dosing algorithms. Ordering this protocol was ultimately designed as an 'opt out' practice. The primary improvement measure was frequency of international normalised ratio (INR) greater than 5; secondary measures included adoption rate of the protocol, a counterbalance INR metric (INR <1.7 three days after first inpatient warfarin dose), and complication rates, including bleeding and thrombosis events. An interrupted time series analysis was conducted to compare outcomes. Results: Among over 50 000 inpatient warfarin recipients, the PMWP was adopted for the majority of both surgical and non-surgical inpatients during the study period (1 January 2005 to 31 December 2011). The primary improvement measure decreased from 5.6% to 3.4% for medical patients and from 5.2% to 2.4% for surgical patients during the preimplementation and postimplementation periods, respectively. The INR counterbalance measure did not change. Postoperative bleeding decreased from 13.5% to 11.1% among surgical patients, but bleeding was unchanged among medical patients. Conclusion: Our PMWP led to achievement of improved INR control for inpatient warfarin recipients and to less near-term bleeding among higher risk, surgical patients. PMID- 29713694 TI - How iMALDI can improve clinical diagnostics. AB - Protein mass spectrometry (MS) is an indispensable tool to detect molecular signatures that can be associated with cellular dysregulation and disease. Despite its huge success in the life sciences, where it has led to novel insights into disease mechanisms and the identification of potential protein biomarkers, protein MS is rarely used for clinical protein assays. While conventional matrix assisted laser desorption/ionization (MALDI) MS is not compatible with complex samples, liquid chromatography-MS (LC-MS)-based assays may be too complex and may lack the robustness and ease of automation required for routine use in the clinic. Therefore, clinical protein assays are dominated by immunohistochemistry and immunoassays which, however, often lack standardization and fully depend on antibody specificity. Immuno-MALDI (iMALDI) MS may overcome these hurdles by utilizing anti-peptide antibodies for the specific enrichment of targeted analytes and on-target detection of the captured analytes, thus combining the unique properties of MS for the unambiguous detection and quantitation of analytes with a workflow that can be fully automated. Here we discuss the requirements for clinical protein assays, the pitfalls of existing methods, how iMALDI has been successfully used to quantify endogenous peptides and proteins from clinical samples, as well as its potential as a powerful tool for companion diagnostics in the light of precision medicine. PMID- 29713693 TI - Clot stability as a determinant of effective factor VIII replacement in hemophilia A. AB - Background: Factor VIII (FVIII) replacement is standard of care for patients with hemophilia A (HemA); however, patient response does not always correlate with FVIII levels. We hypothesize this may be in part due to the physical properties of clots and contributions of fibrin, platelets, and erythrocytes, which may be important for hemostasis. Objective: To understand how FVIII contributes to effective hemostasis in terms of clot structure and mechanical properties. Patients/Methods: In vitro HemA clots in human plasma or whole blood were analyzed using turbidity waveform analysis, confocal microscopy, and rheometry with or without added FVIII. In vivo clots from saphenous vein puncture in wild type and HemA mice with varying FVIII levels were examined using scanning electron microscopy. Results: FVIII profoundly affected HemA clot structure and physical properties; added FVIII converted the open and porous fibrin meshwork and low stiffness of HemA clots to a highly branched and dense meshwork with higher stiffness. Platelets and erythrocytes incorporated into clots modulated clot properties. The clots formed in the mouse saphenous vein model contained variable amounts of compressed erythrocytes (polyhedrocytes), fibrin, and platelets depending on the levels of FVIII, correlating with bleeding times. FVIII effects on clot characteristics were dose-dependent and reached a maximum at ~25% FVIII, such that HemA clots formed with this level of FVIII resembled clots from unaffected controls. Conclusions: Effective clot formation can be achieved in HemA by replacement therapy, which alters the architecture of the fibrin network and associated cells, thus increasing clot stiffness and decreasing clot permeability. PMID- 29713692 TI - Multimodal Regulation of Circadian Glucocorticoid Rhythm by Central and Adrenal Clocks. AB - Adrenal glucocorticoids (GCs) control a wide range of physiological processes, including metabolism, cardiovascular and pulmonary activities, immune and inflammatory responses, and various brain functions. During stress responses, GCs are secreted through activation of the hypothalamic-pituitary-adrenal axis, whereas circulating GC levels in unstressed states follow a robust circadian oscillation with a peak around the onset of the active period of a day. A recent advance in chronobiological research has revealed that multiple regulatory mechanisms, along with classical neuroendocrine regulation, underlie this GC circadian rhythm. The hierarchically organized circadian system, with a central pacemaker in the suprachiasmatic nucleus of the hypothalamus and local oscillators in peripheral tissues, including the adrenal gland, mediates periodicities in physiological processes in mammals. In this review, we primarily focus on our understanding of the circadian regulation of adrenal GC rhythm, with particular attention to the cooperative actions of the suprachiasmatic nucleus central and adrenal local clocks, and the clinical implications of this rhythm in human diseases. PMID- 29713695 TI - Influence of oil phase composition on the antifungal and mycotoxin inhibitory activity of clove oil nanoemulsions. AB - The influence of oil composition on the physical properties and antifungal and mycotoxin inhibitory activity of clove oil-in-water nanoemulsions was investigated. Physically stable clove oil-in-water nanoemulsions could be fabricated by incorporating either >=75 wt% of corn oil or >=50 wt% of medium chain triacylglycerol (MCT) into clove oil before homogenization to prevent Ostwald ripening. The clove oil-in-water nanoemulsions with mean diameters of <150 nm showed high physical stability over 30 days storage. The antifungal activity of physically stable clove oil nanoemulsions was further evaluated using effective concentration (EC) and inhibitory activity towards mycotoxin production in two chemotypes of Fusarium graminearum isolates. The composition of the oil phase, i.e., ripening inhibitor type and concentration, in clove oil-in-water nanoemulsions had a remarkable impact on antifungal activity as well as inhibition of mycotoxin production. In general, under the same clove oil concentration in oil phase, the addition of MCT decreased the antifungal and mycotoxin inhibitory activity of clove oil more than corn oil. Compared with the bulk clove oil, this study also indicated that the mycotoxin inhibitory activity of clove was significantly enhanced when encapsulated in nanoemulsions. These results have important implications for the design of essential oil based nanoemulsions as effective antifungal and detoxification delivery systems in the food or other industries. PMID- 29713696 TI - The role of ionic liquids in the biocatalytic evaluation of bisphenol levels as contaminant: an automatic approach. AB - An automatic assay was developed that is intended to be a generic tool for evaluation of a horseradish peroxidase activity in different ionic liquids (ILs). Ionic liquids with different characteristics were used and their effects on the enzymatic reaction, were compared with those obtained with conventional organic solvents. In addition, ILs were tested as solvents for the enzyme substrate (bisphenol A (BPA)). ILs were shown to be a good alternative to conventional organic solvents from either the effect on enzymatic activity or the solubilization of bisphenol. Since bisphenol A is an endocrine disruptor frequently used in plastic industries, it was also applied the developed enzymatic methodology for quantification of this compound in real beverage samples. To increase the sensitivity (already increased by the use of an IL) and the selectivity of the methodology, a sample pre-treatment using a molecular recognition solid phase extraction was applied. Finally, the methodology presented detection and quantification limits of 7.73 * 10-4 and 1.29 * 10-3 mmol L-1 and a linear range up to 1.00 mmol L-1, allowing accurate and reliable quantifications of bisphenol in beer and cola drink samples. This work confirmed the potential of a sequential injection analysis (SIA) system as a simple, versatile, robust, and rapid analytical tool for automating enzymatic assays in ILs medium and, at the same time, showed it to be a relevant automatic alternative for routine determinations of bisphenol A in food samples. PMID- 29713697 TI - Ultra-long-term cycling stability of an integrated carbon-sulfur membrane with dual shuttle-inhibiting layers of graphene "nets" and a porous carbon skin. AB - An integrated carbon-sulfur (CSG/PC) membrane with dual shuttle-inhibiting layers was prepared by inserting graphene "nets" and a porous carbon (PC) skin, and the membrane achieved an extraordinary cycling stability up to 1000 cycles with an average Coulombic efficiency of ~100%. PMID- 29713702 TI - Exploiting the conformational-selection mechanism to control the response kinetics of a "smart" DNA hydrogel. AB - The sequence-specific hybridization and molecular recognition properties of DNA support the construction of stimulus-responsive hydrogels with precisely controlled crosslink geometry. Here we show that, as predicted by the conformational selection mechanism, the response kinetics of such a hydrogel can be tuned over orders of magnitude by modulating the thermodynamic stability of its crosslinks. PMID- 29713703 TI - Unexpected arene ligand exchange results in the oxidation of an organoruthenium anticancer agent: the first X-ray structure of a protein-Ru(carbene) adduct. AB - The first X-ray structures of adducts formed between a RuII(N-heterocyclic carbene)(eta6-p-cymene) compound and a protein are reported. Coordination to the protein induced the cleavage of the cymene ligand and EPR spectroscopy demonstrated the oxidation of the Ru centre. PMID- 29713705 TI - U- to Z-shape isomerization in a Pt2Ag2 framework containing pyridyl-NHC ligands. AB - Synthesis and isomerization of a heteropolynuclear Pt2Ag2 complex containing pyridyl N-heterocyclic carbene (NHC) ligands are reported. The Pt2Ag2 complex could take two geometrical isomers possessing a twisted U-shaped structure and a Z-shaped structure. The rate of the isomerization reaction depended on the concentration of the solution, implying that the reaction took place through an intermolecular process. PMID- 29713706 TI - Co oxide nanostructures for electrocatalytic water-oxidation: effects of dimensionality and related properties. AB - A facile hydrothermal synthesis route was explored to obtain various nanostructures of Co oxide for applications in electrocatalytic water-splitting. The effect of reaction time and metal precursor ions on the morphology of synthesized nanostructures was studied in detail with the aid of a scanning electron microscope. By systematic optimization of the synthesis parameters, Co oxide nanostructures with single dimensionality were obtained in the form of 0D nanoparticles (NPs), 1D nanowires (NWs), 2D nanosheets (NSs) and 3D nanocrystals (NCs). The effectiveness of the developed nanostructures towards oxygen evolution reaction (OER) was studied and a promising OER activity was recorded for all the samples. Amongst all the developed catalysts, Co(OH)2 NPs showed the lowest overpotential of 339 mV to achieve a current density of 10 mA cm-2, which is even lower than that of noble-metal oxides such as the commercial RuO2 catalyst (370 mV). The specific effect of different parameters such as BET surface area, phase, crystallographic orientation of surface lattice planes, electroactive surface area and surface active species on the OER performance was studied. It was found that the Co3O4 phase is more active for the OER, compared to the Co(OH)2 phase. However, Co(OH)2 NPs showed the best OER performance owing to their higher BET surface area, thereby underlining the significance of the catalyst surface area. The effect of the number of active surface atoms was demonstrated by estimating the electroactive surface area of all Co3O4 nanostructures. It was also shown that the formation of CoO2 species (Co(IV)) on the surface is more beneficial for the OER as compared to the formation of CoOOH species (Co(III)). Finally, the robustness of the developed Co3O4 nanostructures was established by performing a recycling test for the OER (1000 cycles) and the observed change in the catalytic activity was correlated with morphological variation. PMID- 29713707 TI - Enhancing circular dichroism by chiral hotspots in silicon nanocube dimers. AB - Circular dichroism (CD) spectroscopy, which measures the differential absorption of circularly polarized light with opposite handedness, is an important technique to detect and identify chiral molecules in chemistry, biology and life sciences. However, CD signals are normally very small due to the intrinsically weak chirality of molecules. Here we theoretically investigate the generation of chiral hotspots in silicon nanocube dimers for CD enhancement. Up to 15-fold enhancement of the global optical chirality is obtained in the dimer gap, which boosts the CD signal by one order of magnitude without reducing the dissymmetry factor. This chiral hotspot originates from the simultaneous enhancement of magnetic and electric fields and their proper spatial overlap. Our findings could lead to integrated devices for CD spectroscopy, enantioselective sensing, sorting and synthesis. PMID- 29713708 TI - A mobile precursor determines protein resistance on nanostructured surfaces. AB - Biomaterials are often engineered with nanostructured surfaces to control interactions with proteins and thus regulate their biofunctions. However, the mechanism of how nanostructured surfaces resist or attract proteins together with the underlying design rules remains poorly understood at a molecular level, greatly limiting attempts to develop high-performance biomaterials and devices through the rational design of nanostructures. Here, we study the dynamics of nonspecific protein adsorption on block copolymer nanostructures of varying adhesive domain areas in a resistant matrix. Using surface plasmon resonance and single molecule tracking techniques, we show that weakly adsorbed proteins with two-dimensional diffusivity are critical precursors to protein resistance on nanostructured surfaces. The adhesive domain areas must be more than tens or hundreds of times those of the protein footprints to slow down the 2D-mobility of the precursor proteins for their irreversible adsorption. This precursor model can be used to quantitatively analyze the kinetics of nonspecific protein adsorption on nanostructured surfaces. Our method is applicable to precisely manipulate protein adsorption and resistance on various nanostructured surfaces, e.g., amphiphilic, low-surface-energy, and charged nanostructures, for the design of protein-compatible materials. PMID- 29713709 TI - Towards deriving Ni-rich cathode and oxide-based anode materials from hydroxides by sharing a facile co-precipitation method. AB - Although intensive studies have been conducted on layered transition metal oxide(TMO)-based cathode materials and metal oxide-based anode materials for Li ion batteries, their precursors generally follow different or even complex synthesis routes. To share one route for preparing precursors of the cathode and anode materials, herein, we demonstrate a facile co-precipitation method to fabricate Ni-rich hydroxide precursors of Ni0.8Co0.1Mn0.1(OH)2. Ni-rich layered oxide of LiNi0.8Co0.1Mn0.1O2 is obtained by lithiation of the precursor in air. An NiO-based anode material is prepared by calcining the precursor or multi walled carbon nanotubes (MWCNTs) incorporated precursors. The pre-addition of ammonia solution can simplify the co-precipitation procedures and the use of an air atmosphere can also make the heat treatment facile. LiNi0.8Co0.1Mn0.1O2 as the cathode material delivers a reversible capacity of 194 mA h g-1 at 40 mA g-1 and a notable cycling retention of 88.8% after 100 cycles at 200 mA g-1. This noticeable performance of the cathode arises from a decent particle morphology and high crystallinity of the layered oxides. As the anode material, the MWCNTs incorporated oxides deliver a much higher reversible capacity of 811.1 mA h g-1 after 200 cycles compared to the pristine oxides without MWCNTs. The improvement on electrochemical performance can be attributed to synergistic effects from MWCNTs incorporation, including reinforced electronic conductivity, rich meso pores and an alleviated volume effect. This facile and sharing method may offer an integrated and economical approach for commercial production of Ni-rich electrode materials for Li-ion batteries. PMID- 29713710 TI - Mobilities of iodide anions in aqueous solutions for applications in natural dye sensitized solar cells. AB - Dye-sensitized solar cells (DSSCs) composed of aqueous electrolytes represent an environmentally friendly, low-cost, and concrete alternative to standard DSSCs and typical solar cells. Although flammable and toxic organic-solvent-based electrolytes have so far been employed more than simpler (iodide) aqueous solutions, recently recorded efficiencies of water-based DSSCs suggest a trend inversion in the near future. Here, we present a study, based on both experiments and ab initio molecular dynamics simulations, in which assessments on the efficiencies of three water electrolytes commonly employed in DSSCs (i.e., LiI, NaI, and KI) are reported. In particular, by atomistically tracing the ability of the iodides as charge carriers and by experimentally measuring the generated currents, we demonstrate that NaI aqueous solutions are more efficient electrolytes than LiI and KI - in descending order - in transporting electrons in DSSCs under bias. Monitoring the role played by the hydration shells of the ionic species under an electric field, we interpret, by first-principles, the various iodide mobilities. This finding, when combined with general considerations on the cation-induced effects on the TiO2 electronic structure, is able to account for the distinct efficiencies of the investigated electrolytes. PMID- 29713711 TI - From jamming to collective cell migration through a boundary induced transition. AB - Cell monolayers provide an interesting example of active matter, exhibiting a phase transition from flowing to jammed states as they age. Here we report experiments and numerical simulations illustrating how a jammed cellular layer rapidly reverts to a flowing state after a wound. Quantitative comparison between experiments and simulations shows that cells change their self-propulsion and alignment strength so that the system crosses a phase transition line, which we characterize by finite-size scaling in an active particle model. This wound induced unjamming transition is found to occur generically in epithelial, endothelial and cancer cells. PMID- 29713715 TI - Combining autophagy-inducing peptides and brefeldin A delivered by perinuclear localized mesoporous silica nanoparticles: a manipulation strategy for ER-phagy. AB - Autophagic degradation of the endoplasmic reticulum (ER-phagy) has been found to play a critical role in human sensory neuropathy. So far, however, specific and efficient intervention means for ER-phagy remain unexplored. Herein, brefeldin A (BFA), a blocking agent on protein transport between the ER and Golgi, was screened from ER stress inducers. BFA was then delivered to the perinuclear area co-localized with the ER by a mesoporous silica nanoparticle-based drug-carrier functionalized with autophagy-inducing peptides of TAT-beclin 1 (MSNs-BFA), to evoke a perturbation of ER-phagy. The molecular mechanism of ER-phagy regulated by BFA was explored by biochemical evaluation including time-lapse live-cell fluorescence imaging. We found that MSNs-BFA treatment caused a lower mRNA/protein expression level of FAM134b even under a compensation of autophagic flux in U2OS cells, and resulted in ER-expansion. The fragmentation of the ER was blocked as a response to ER stress mediated by inactivation of the AKT/TSC/mTOR pathway. Our work developed an efficient external manipulation strategy to regulate ER-phagy and may contribute to the therapeutic application of autophagy related major human diseases. PMID- 29713716 TI - Synthesis, structures and luminescence properties of amine-bis(N-heterocyclic carbene) copper(i) and silver(i) complexes. AB - A series of Ag(i) and Cu(i) complexes [Ag3(L1)2][PF6]3 (8), [Ag3(L2)2][PF6]3 (9), [Cu(L1)][PF6] (10) and [Cu(L2)][PF6] (11) have been synthesized by reactions of the tridentate amine-bis(N-heterocyclic carbene) ligand precursors [H2L1][PF6]2 (6) and [H2L2][PF6]2 (7) with Ag2O and Cu2O, respectively. Complexes 10 and 11 can also be obtained by transmetalation of 8 and 9, respectively, with 3.0 equiv. of CuCl. A heterometallic Cu/Ag-NHC complex [Cu2Ag(L1)2(CH3CN)2][PF6]3 (12) is formed by the reaction of 8 with 2.0 equiv. of CuCl. All complexes have been characterized by NMR, electrospray ionization mass spectrometry (ESI-MS), and single-crystal X-ray diffraction studies. The luminescence properties of 10-12 in solution and the solid state have been studied. At room temperature, 10-12 exhibit evident luminescence in solution and the solid state. The emission wavelengths are found to be identical at 483 nm in CH3CN, but they are 484, 480 and 592 nm in the solid state for 10-12, respectively. These results suggest that 12 dissociates into two molecules of 10 and Ag(i) ions in solution. Complex 12 is the first luminescent heterometallic Cu/Ag-NHC complex. PMID- 29713717 TI - Solvent-modulation of the structure and dimensionality in lanthanoid-anilato coordination polymers. AB - We show the key role that the size and shape of the solvent molecules may play in the dimensionality and structure of a series of lanthanoid-chloranilato coordination polymers. We report the synthesis, structure and magnetic properties of six different coordination polymers prepared with Er(iii) and chloranilato (C6O4Cl22- = 3,6-dichloro-2,5-dihydroxy-1,4-benzoquinone) and six different solvents: [Er2(C6O4Cl2)3(H2O)6].10H2O (1), [Er2(C6O4Cl2)3(FMA)6].4FMA.2H2O (2) (FMA = formamide = NH2CHO), [Er2(C6O4Cl2)3(DMSO)4].2DMSO.2H2O (3) (DMSO = dimethy sulfoxide = Me2SO), [Er2(C6O4Cl2)3(DMF)6] (4) (DMF = dimethylformamide = Me2NCHO), [Er2(C6O4Cl2)3(DMA)4] (5) (DMA = dimethylacetamide = Me2NC(Me)O) and [Er2(C6O4Cl2)3(HMPA)(H2O)3].H2O (6) (HMPA = hexamethylphosphormamide = (Me2N)3PO). We show how the different solvent molecules modulate and determine important structural parameters such as the coordination number and geometry, the shape and distortions of the cavities, the presence of solvent molecules in these cavities, the interlayer space and even the dimensionality of the structure. PMID- 29713719 TI - Osteocalcin facilitates calcium phosphate ion complex growth as revealed by free energy calculation. AB - The nanoscopic structural and thermodynamic basis of biomolecule-regulated assembly and crystallization of inorganic solids have a tremendous impact on the rational design of novel functional nanomaterials, but are concealed by many difficulties in molecular-level characterization. Here we demonstrate that the free energy calculation approach, enabled by combining advanced molecular simulation techniques, can unravel the structural and energetic mechanisms of protein-mediated inorganic solid nucleation. It is observed that osteocalcin (OCN), an important non-collagenous protein involved in regulating bone formation, promotes the growth of nanosized calcium phosphate (CaP) ion clusters from a supersaturated solution. Free energy calculation by umbrella sampling indicates that this effect by OCN is prominent at the scale of 1 to 3 nm ion association complexes (IACs). The binding interactions between gamma-carboxyl glutamate and the C-terminal and, interestingly, the arginine side chains of OCN and IACs stabilize under-coordinated IACs, thus promoting their growth. The promoter effect of OCN on the enlargement and further aggregation of IACs into cluster assemblies of tens of nm are confirmed by conventional molecular dynamics simulation and dynamic light scattering experiments. To the best of our knowledge, this is the first time that the free energy landscape of the early stages of CaP nucleation is shown. The free energy change as a function of IAC size shares the feature of decreasing monotonically as shown previously for the calcium carbonate system. Therefore, the nucleation of both these major biominerals apparently involves an initial phase of liquid-like ionic aggregates. The structural and thermodynamic information regarding OCN-CaP interactions amplifies the current understanding of biomineralization mechanisms at the nanoscale, with general relevance to biomolecule-tuned fabrication of inorganic materials. PMID- 29713718 TI - Fundamental study of hydrogen-attachment-induced peptide fragmentation occurring in the gas phase and during the matrix-assisted laser desorption/ionization process. AB - Mass spectrometry with hydrogen-radical-mediated fragmentation techniques has been used for the sequencing of proteins/peptides. The two methods, matrix assisted laser desorption/ionization in-source decay (MALDI-ISD) and hydrogen attachment/abstraction dissociation (HAD) are known as hydrogen-radical-mediated fragmentation techniques. MALDI-ISD occurs during laser induced desorption processes, whereas HAD utilizes the association of hydrogen with peptide ions in the gas phase. In this study, the general mechanisms of MALDI-ISD and HAD of peptides were investigated. We demonstrated the fragmentation of four model peptides and investigated the fragment formation pathways using density functional theory (DFT) calculations. The current experimental and computational joint study indicated that MALDI-ISD and HAD produce aminoketyl radical intermediates, which immediately undergo radical-induced cleavage at the N-Calpha bond located on the C-terminal side of the radical site, leading to the c'/z fragment pair. In the case of MALDI-ISD, the z fragments undergo a subsequent reaction with the matrix to give z' and matrix adducts of the z fragments. In contrast, the c' and z fragments react with hydrogen atoms during the HAD processes, and various fragment species, such as c, c', z and z', were observed in the HAD-MS/MS mass spectra. PMID- 29713720 TI - Real-time detection and monitoring of the drug resistance of single myeloid leukemia cells by diffused total internal reflection. AB - Real-time detection and monitoring of the drug resistance of single cells have important significance in clinical diagnosis and therapy. Traditional methods operate a number of times for each individual concentration, and innovation is required for the design of more simple and efficient manipulation platforms with necessary higher sensitivity. Here, we have developed a novel diffused total internal reflection (TIR) method to perform drug metabolism and cytotoxicity analysis of trapped myeloid leukemia cells. Molm-13 cells, a type of acute myeloid leukemia cell, were chosen and injected into the device and fittingly captured by cell traps. Differing from previous studies, a series of different concentrations of azelaic acid (AZA) drug could be used from 0 mM to 50 mM through convection and diffusion processes in a single chip, with each concentration region featuring 50 cells, with a total of 549 cell trapping units. Thanks to the high sensitivity of the TIR method, only cells with the same drug concentration could be illuminated in the detection process. By adjusting the incident angle, we could exactly detect and monitor the drug resistance of the cells using different drug concentrations and the experimental resolution of the drug concentration was as small as 5 mM. Images of the membrane integrity and morphology of the cells in the bright field were measured and we also monitored the cell viabilities in the dark field over 2 hours. The effects of AZA on the Molm-13 cells were explored in different concentrations at the single cell level. Compared with the results of the traditional MTT assay method, the experimental results are more simple and accurate. A cell death of 5% at an AZA concentration of 5 mM was observed after 30 minutes, while a concentration of 40 mM corresponded to a 98% cell death. The designed method in this study provides a novel toolkit to control and monitor drug resistance at the single cell level more easily with higher sensitivity and we believe it has significant potential application in single cell quality assessment and medicine analysis in clinical practice. PMID- 29713722 TI - Magnetic field effects on coenzyme B12- and B6-dependent lysine 5,6-aminomutase: switching of the J-resonance through a kinetically competent radical-pair intermediate. AB - The environmental magnetic field is beneficial to migratory bird navigation through the radical-pair mechanism. One of the continuing challenges in understanding how magnetic fields may perturb biological processes is that only a very few field-sensitive examples have been explored despite the prevalence of radical pairs in enzymatic reactions. We show that the reaction of adenosylcobalamin- and pyridoxal-5'-phosphate-dependent lysine 5,6-aminomutase proceeds via radical-pair intermediates and is magnetic field dependent. The 5' deoxyadenosyl radical from adenosylcobalamin abstracts a C5(H) from the substrate to yield a {cob(ii)alamin - substrate} radical pair wherein the large spin-spin interaction (2J = 8000 gauss) locks the radical pair in a triplet state, as evidenced by electron paramagnetic resonance spectroscopy. Application of an external magnetic field in the range of 6500 to 8500 gauss triggers intersystem crossing to the singlet {cob(ii)alamin - substrate} radical-pair state. Spin conserved H back-transfer from deoxyadenosine to the substrate radical yields a singlet {cob(ii)alamin-5'-deoxyadenosyl} radical pair. Spin-selective recombination to adenosylcobalamin decreased the enzyme catalytic efficiency kcat/Km by 16% at 7600 gauss. As a mechanistic probe, observation of magnetic field effects successfully demonstrates the presence of a kinetically significant radical pair in this enzyme. The study of a pronounced high-field level-crossing characteristic through an immobilized radical pair with a constant exchange interaction deepens our understanding of how a magnetic field may interact with an enzyme. PMID- 29713723 TI - The very long-term physical aging of glassy polymers. AB - The thermodynamic behavior of glasses well below the glass transition temperature (Tg) is scarcely explored due to the long time scales required for such investigation. Here, we characterize the thermodynamic state of several polymer glasses aged for about 30 years at room temperature, that is, at more than 100 K below their respective Tg(s). To this aim we employ differential scanning calorimetry (DSC), which, via specific heat, allows characterizing the enthalpy attained after a certain aging protocol and the way the glass with such an enthalpy devitrifies when heated. We complement these results with extensive DSC studies on these polymers aged under the same conditions of temperature for time scales ranging from minutes to months. The main outcome of the present work is that these polymers aged under these conditions reach a plateau in the enthalpy with partial enthalpy recovery and devitrify well below Tg. This result provides compelling evidence for the existence of a fast mechanism of equilibrium recovery, beyond the standard slow one in proximity of Tg. The analogy with other kinds of glasses is highlighted, stigmatizing the universality of such behavior. Finally, the way the fast mechanism of equilibrium recovery could be exploited to obtain glasses with a low energy state is discussed. PMID- 29713724 TI - pH-Induced transformation of ligated Au25 to brighter Au23 nanoclusters. AB - Thiolate-protected gold nanoclusters have recently attracted considerable attention due to their size-dependent luminescence characterized by a long lifetime and large Stokes shift. However, the optimization of nanocluster properties such as the luminescence quantum yield is still a challenge. We report here the transformation of Au25Capt18 (Capt labels captopril) nanoclusters occurring at low pH and yielding a product with a much increased luminescence quantum yield which we have identified as Au23Capt17. We applied a simple method of treatment with HCl to accomplish this transformation and we characterized the absorption and emission of the newly created ligated nanoclusters as well as their morphology. Based on DFT calculations we show which Au nanocluster size transformations can lead to highly luminescent species such as Au23Capt17. PMID- 29713725 TI - Narrow-gap physical vapour deposition synthesis of ultrathin SnS1-xSex (0 <= x <= 1) two-dimensional alloys with unique polarized Raman spectra and high (opto)electronic properties. AB - Here we report ultrathin SnS1-xSex alloyed nanosheets synthesized via a narrow gap physical vapour deposition approach. The SnS1-xSex alloy presents a uniform quadrangle shape with a lateral size of 5-80 MUm and a thickness of several nanometers. Clear orthorhombic symmetries and unique in-plane anisotropic properties of the 2D alloyed nanosheets were found with the help of X-ray diffraction, high resolution transmission electron microscopy and polarized Raman spectroscopy. Moreover, 2D alloyed field-effect transistors were fabricated, exhibiting a unipolar p-type semiconductor behavior. This study also provided a lesson that the thickness of the alloyed channels played the major role in the current on/off ratio, and the high ratio of 2.10 * 102 measured from a large ultrathin SnS1-xSex device was two orders of magnitude larger than that of previously reported SnS, SnSe nanosheet based transistors because of the capacitance shielding effect. Obviously enhanced Raman peaks were also found in the thinner nanosheets. Furthermore, the ultrathin SnS0.5Se0.5 based photodetector showed a highest responsivity of 1.69 A W-1 and a short response time of 40 ms under illumination of a 532 nm laser from 405 to 808 nm. Simultaneously, the corresponding highest external quantum efficiency of 392% and detectivity of 3.96 * 104 Jones were also achieved. Hopefully, the narrow-gap synthesis technique provides us with an improved strategy to obtain large ultrathin 2D nanosheets which may tend to grow into thicker ones for stronger interlayer van der Waals forces, and the enhanced physical and (opto)electrical performances in the obtained ultrathin SnS1-xSex alloyed nanosheets prove their great potential in the future applications for versatile devices. PMID- 29713726 TI - Detection of 16alpha-Hydroxyestrone-histone 1 Adduct as High-Affinity Antigen for Rheumatoid Arthritis Autoantibodies. AB - Increased concentrations of 16alpha-hydroxyestrone (16alpha-OHE1) have been observed in rheumatoid arthritis (RA), but the underlying mechanism of this remains elusive. Here we aimed to identify the role played by 16alpha-OHE1 in RA. In 40 RA patients, the specificities of antibodies from the sera of these patients were checked by direct binding, inhibition ELISA, and quantitative precipitation titration. Competition ELISA was also used for the estimation of 16alpha-OHE1 in the serum of different RA patients. RA IgG from a patient's sera showed strong recognition to 16alpha-OHE1-H1 (histone 1) adduct in comparison to control subjects (p < 0.001), as the formation of this adduct brings out various biochemical changes that might generate neo-epitopes, which have been well recognized by these antibodies. The affinity of RA antibodies for 16alpha-OHE1-H1 (1.10 * 10- 7 M) was high, as detected by the Langmuir plot. Comparing RA patients to the controls, no significant differences were detected in the level of 16alpha-OHE1 or 2-hydroxyestrone/16alpha-OHE1 ratio. 16alpha-OHE1-H1 might have an antigenic role and function as a high-affinity antigen for RA autoantibodies and, therefore, could be used as a biomarker for this disease. PMID- 29713727 TI - [Chronic inflammatory liver diseases]. PMID- 29713728 TI - Empagliflozin in women with type 2 diabetes and cardiovascular disease - an analysis of EMPA-REG OUTCOME(r). AB - AIMS/HYPOTHESIS: The global epidemic of type 2 diabetes affects women and men equally; however, the relative impact on the cardiovascular (CV) system appears greater for women than men when compared with peers without diabetes. Furthermore, women are often under-represented in CV outcome trials, resulting in less certainty about the impact of CV prevention therapies across the sexes. The EMPA-REG OUTCOME(r) trial, which included 28.5% women, found that empagliflozin, given in addition to standard of care, reduced the risk of CV death by 38%, heart failure (HF) hospitalisation by 35% and a composite endpoint for incident or worsening nephropathy by 39%. Here we report a secondary analysis of the trial to determine the relative effects of empagliflozin in women vs men. METHODS: The population studied were individuals with type 2 diabetes (HbA1c 53-86 mmol/mol [7 10%] and eGFR >30 ml min-1 [1.73 m]-2), with established atherosclerotic CV disease. Individuals were randomised to receive empagliflozin 10 mg or 25 mg, or placebo once daily in addition to standard of care, and followed. The trial continued until >=691 individuals had experienced an adjudicated event included in the primary outcome. All CV outcome events, including HF hospitalisations and deaths were prospectively adjudicated by blinded clinical events committees. RESULTS: At baseline, the demographic profile of the 2004 women (age +/- standard deviation 63.6 +/- 8.8 years) compared with the 5016 men (age 63.0 +/- 8.6 years) in the trial was largely similar, with the exception that LDL-cholesterol was numerically higher in women (2.5 +/- 1.0 vs 2.1 +/- 0.9 mmol/l), consistent with lower rates of lipid-lowering therapies (75.4% vs 83.2%). Women were also less likely to have smoked (31.5% vs 69.9%). The annualised incidence rate for women in the placebo group was numerically lower than in men for CV death (1.58% vs 2.19%), numerically higher for HF hospitalisation (1.75% vs 1.33%) and similar for renal events (7.22% vs 7.75%). We did not detect any effect modification by sex within the statistical power restrictions of the analysis for CV death, HF hospitalisation and incident or worsening nephropathy (interaction p values 0.32, 0.20 and 0.85, respectively). Compared with placebo, empagliflozin increased the rates of genital infections in both women (2.5% vs 10.0%) and men (1.5% vs 2.6%). CONCLUSIONS/INTERPRETATION: CV death, HF hospitalisation and incident or worsening nephropathy rate reductions induced by empagliflozin were not different between women and men. PMID- 29713729 TI - Widening socioeconomic inequalities in Australian suicide, despite recent declines in suicide rates. AB - PURPOSE: This study aims to investigate trends in socioeconomic inequalities of suicide from 1979 to 2013 for Australian males and females aged 15-34 years and 35-64 years. METHODS: Data on suicides and population were obtained from national registries. An area-based measure of socioeconomic status (SES) was used, and categorized into low, middle, and high SES areas. Suicide rates for each SES groups were estimated using a negative binomial regression model, adjusted for confounders. Socioeconomic inequalities in suicide were assessed using absolute and relative risk of low-to-high SES areas. Secular changes in socioeconomic inequalities were assessed using trend tests for relative risk. RESULTS: For young males, there was an increase in socioeconomic inequality driven by a significant decrease in suicide rates in high SES areas. For older males, inequality in suicide increased by 29%, which was related to a marked increase in suicide rates in low SES areas. Inequalities in both young and older female suicides also increased. These increases occurred when corresponding suicide rates in high SES areas decreased. CONCLUSIONS: Recent widening socioeconomic inequalities in Australian suicide have been primarily associated with declines in suicide rates in high SES areas. However, an increasing inequality in older male suicide is linked with low SES. Efforts targeting people from poor areas, especially older males, should be considered when developing suicide prevention strategy. PMID- 29713730 TI - Prostaglandin E2 and IL-23 interconnects STAT3 and RoRgamma pathways to initiate Th17 CD4+ T-cell development during rheumatoid arthritis. AB - BACKGROUND: The chronic inflammation associated with rheumatoid arthritis (RA) leads to focal and systemic bone erosion of the joints resulting in a crippling disability. Recent reports indicate an increase in the incidence of RA in the coming years, placing a significant burden on healthcare resources. The incidence of RA is observed to be increasing with age and a significant proportion of those new cases will be aggressively erosive. FINDINGS: The altered physiology, due to immune disturbances, contributes towards RA pathogenesis. The imbalance of inflammatory cytokines and non-cytokine immune modulators such as prostaglandin E2 (PGE2) and IL-23-induced pathogenic IL-17, plays a crucial role in persistent inflammation and bone degradation during RA. However, the molecular mechanism of IL-23, a key cytokine, and PGE2 in the development and perpetuation of IL-17 producing effector Th17 cells is poorly understood. CONCLUSION: This review focuses on research findings that provide insight into the contribution of PGE2 and IL-23 during the development of pathogenic Th17 cells. We also highlight the key transcriptional factors required for Th17 development and therapeutic strategies to disrupt the interaction between IL-23 and IL-17 to prevent the end organ damage in RA. PMID- 29713731 TI - Genetic characterization of Vitis germplasm collected from the southwestern US and Mexico to expedite Pierce's disease-resistance breeding. AB - Pierce's disease (PD) limits the cultivation of Vitis vinifera grape cultivars in California, across the southern United States and into South America. Resistance has been well characterized in V. arizonica, and one resistance locus has been identified (PdR1). However, resistance is poorly characterized in most other grape species. We tested a wide range of Vitis species from the southwestern United States for resistance to PD and used nuclear and chloroplast markers to phenotypically and genetically select a diverse set of resistant accessions. Chloroplast SSR markers identified 11 maternal lineage lines within the set of 17 (14 new and three previously identified) PD resistant accessions. A total of 19 breeding populations (F1 and pseudo-BC1) were developed with the 14 PD resistant accessions, and a total of 705 seedlings were analyzed for PD resistance. Using a limited mapping approach, 12 SSR markers, linked to the PdR1 locus, were used to genotype the breeding populations and phenotypic data were analyzed. Nine accessions had a major resistance quantitative trait locus (QTL) within the genomic region containing PdR1. The phenotypic data for these three resistant accessions, ANU67, b41-13, and T03-16, did not associate with PdR1 linked markers, indicating that their resistance is located in other regions of the genome. These three accessions were identified as candidates for use in the development of framework maps with larger populations capable of detecting additional and unique loci for PD resistance breeding and the stacking of PD resistance genes. PMID- 29713732 TI - Unilateral pulmonary venous occlusion caused by a localized pericardial clot. PMID- 29713733 TI - Psychopathology prior to critical illness and the risk of delirium onset during intensive care unit stay. PMID- 29713735 TI - A New Oval Advancement Flap Design for Reconstruction of Pilonidal Sinus Defect. AB - BACKGROUNDS: Pilonidal sinus is a common chronic disease of the sacrococcygeal region. Although many surgical methods have been described for treating pilonidal sinus disease, controversy still exists as to the best surgical technique. The aim of this study is to present a new modified advancement flap technique named "omega flap" for the treatment of pilonidal sinus disease. MATERIALS AND METHODS: This study included 18 patients with pilonidal sinus who were treated between March 2012 and August 2014. All cases underwent oval excision and omega advancement flap reconstruction. Defect size, postoperative complications, postoperative pain, painless sitting time, patient satisfaction and recurrence were evaluated retrospectively. RESULTS: All patients were discharged on the first postoperative day. There was no flap necrosis. No recurrence and no major complication were observed during follow-up period. The outcomes were also satisfactory regarding functionally and aesthetically, and the patients were satisfied with the results. CONCLUSIONS: Presented method has a different geometry than classical advancement flap methods. Our technique provides two layered repair with minimal tension and off-midline closure for the reconstruction of pilonidal sinus defect. It is easily performed, reliable, associated with no recurrens and good aesthetic results. PMID- 29713734 TI - Advances in critical care management of patients undergoing cardiac surgery. AB - Cardiac surgery has been evolving to include minimally invasive, hybrid and transcatheter techniques. Increasing patient age and medical complexity means that critical care management needs to adapt and evolve. Recent advances have occurred in several areas, including ventilation, haemodynamics and mechanical circulatory support, bleeding and coagulation, acute kidney injury, and neurological management. This narrative review describes standard care, recent advances, and future areas of research in the critical care management of patients undergoing cardiac surgery. PMID- 29713736 TI - Accessory head of the extensor carpi radialis longus muscle merging with extensor carpi radialis brevis muscle. AB - PURPOSE: The retention and capture functions of hand can be achieved by the consistent manner work of the extensor and flexor muscles. Therefore, it is important to know variations of the extensor and flexor muscles. METHODS: During an educational dissection, accessory heads of the extensor carpi radialis longus muscle were found on the right side in a Korean cadaver. RESULTS: The extensor carpi radialis longus muscle was originated from the lateral supracondylar ridge of the humerus and trifurcated into three heads as lateral, intermediated, and medial heads. The lateral and intermediated heads merged and inserted to the base of the second metacarpal bone. However, medial head of extensor carpi radialis longus muscle was merged with the extensor carpi radialis brevis muscle. CONCLUSIONS: Knowledge of the variations of the ECRL is important for surgeons because the presence of the ECRL variations increases the incidence of iatrogenic injuries during surgery and invasive procedures. PMID- 29713737 TI - Evaluation of the pulley function of the hamulus of the hamate for the flexor tendons. AB - PURPOSE: The aim of this study was to measure the curvature radii of the finger flexor tendons on CT acquired using tendon conditions to examine whether the hamulus of the hamate functions as a pulley of the flexor tendon. METHODS: The subjects were 20 healthy volunteers (40 hands) (14 males and 6 females, mean age: 27.5 years old). Their hands were imaged in extension and flexion of the fingers on CT. The curvature radii of the little and middle finger flexor tendons at the hamulus of the hamate were calculated. RESULTS: The curvature radii of the little and middle finger flexor tendons were 24.8 +/- 7.3 and 327.1 +/- 343.9 mm in finger extension, respectively, and 21.3 +/- 5.3 and 265.1 +/- 202.9 mm in finger flexion, respectively. The curvature radius of the little finger flexor tendon was significantly smaller than that of the middle finger flexor tendon in both finger extension and flexion (P < 0.01). CONCLUSIONS: Our study suggested that the hamulus of the hamate functions as a pulley for the little finger flexor tendon. PMID- 29713739 TI - Barium upper GI series in adults: a surgeon's perspective. AB - Barium upper GI series performed by an interested and competent radiologist is still a very useful study to evaluate a variety of esophagogastric disorders. It usually provides information complementary to upper endoscopy and other foregut studies. Barium upper GI series is an important part of the diagnostic workup for gastroesophageal reflux disease, hiatal hernia, and esophageal motility disorders including achalasia. It is also an important part of the follow-up after operation for these common problems and after other operations such as resection or bariatric surgery. The GI radiologist should be an important member of the foregut surgery team. PMID- 29713738 TI - Fetal median sacral artery anatomy study by micro-CT imaging. AB - PURPOSE: The median sacral artery (MSA) is the termination of the dorsal aorta, which undergoes a complex regression and remodeling process during embryo and fetal development. The MSA contributes to the pelvic vascularization and may be injured during pelvic surgery. The embryological steps of MSA development, anastomosis formation and anatomical variations are linked, but not fully understood. METHODS: The pelvic vascularization and more precisely the MSA of a human fetus at 22 weeks of gestation (GW) were studied using micro-CT imaging. Image treatment included arterial segmentations and 3D visualization. RESULTS: At 22 GW, the MSA was a well-developed straight artery in front of the sacrum and was longer than the abdominal aorta. Anastomoses between the MSA and the internal pudendal arteries and the superior rectal artery were detected. No evidence was found for the existence of a coccygeal glomus with arteriovenous anastomosis. CONCLUSIONS: Micro-CT imaging and 3D visualization helped us understand the MSA central role in pelvic vascularization through the ilio-aortic anastomotic system. It is essential to know this anastomotic network to treat pathological conditions, such as sacrococcygeal teratomas and parasitic ischiopagus twins (for instance, fetus in fetu and twin-reversed arterial perfusion sequence). PMID- 29713740 TI - Radiogenomics in renal cell carcinoma. AB - Radiogenomics, a field of radiology investigating the association between the imaging features of a disease and its gene expression pattern, has expanded considerably in the last few years. Recent advances in whole-genome sequencing of clear cell renal cell carcinoma (ccRCC) and the identification of mutations with prognostic significance have led to increased interest in the relationship between imaging and genomic data. ccRCC is particularly suitable for radiogenomic analysis as the relative paucity of mutated genes allows for more straightforward genomic-imaging associations. The ultimate aim of radiogenomics of ccRCC is to retrieve additional data for accurate diagnosis, prognostic stratification, and optimization of therapy. In this review article, we will present the state-of-the art of radiogenomics of ccRCC, and after briefly reviewing updates in genomics, we will discuss imaging-genomic associations for diagnosis and staging, prognosis, and for assessment of optimal therapy in ccRCC. PMID- 29713741 TI - Magnetic resonance imaging of common, uncommon, and rare implantation sites in ectopic pregnancy. AB - OBJECTIVE: To review the MRI appearances of tubal and non-tubal implantation sites in ectopic pregnancy. CONCLUSION: Transvaginal ultrasound is the primary imaging modality in ectopic pregnancy and MRI is used as a problem-solving tool in selected indications as detailed in the article. MRI features of tubal, interstitial, cervical, cesarean scar, cornual, ovarian, abdominal, and heterotopic pregnancies are provided to familiarize the radiologists with their appearances thereby assisting them in making early and accurate diagnosis. PMID- 29713742 TI - Assessment of Heavy and Trace Metals in Surface Soil Nearby an Oil Refinery, Saudi Arabia, Using Geoaccumulation and Pollution Indices. AB - The present study deals with the measurement of heavy and trace metals in the soils of Ras Tanura city nearby one of the oldest and largest oil refineries located on Arabian Gulf, eastern Saudi Arabia. Metals were analyzed in 34 surface soil samples using plasma atomic emission spectrometer (ICPE-9820). The result showed that the mean values of the metals concentrations were in the order: Cd > Mo > Tb > Ce > Hf > Eu > Yb > U > Sm > Rb > Cr > Ni > Pb > Sc > Cs > Zn > Lu > Co. The mean values of Cd (39.9 mg/kg), Mo (13.2 mg/kg), Eu (4.01 mg/kg), Hf (6.09 mg/kg), Tb (8.23 mg/kg), and Yb (3.88) in soil samples were higher than the background values in soil and the world average. The obtained results indicated to elevated levels of Cd and Mo in most samples, with mean concentrations exceeded the background levels by 113 times for Cd and 5 times for Mo. Pollution index (PI) and Geoaccumulation (Igeo) for each metal were calculated to assess the metal contamination level of surface soil in the study area. The assessment results of PI and Igeo revealed a significant pollution by Cd, Mo, Eu, Hf, Tb, and Yb in most of sampling sites nearby Ras Tanura refinery. PMID- 29713743 TI - Polychlorinated Biphenyls in Surface Soil from North-East India: Implication for Sources Apportionment and Health-Risk Assessment. AB - Although India never manufactured polychlorinated biphenyls (PCBs), evidence suggests the prevalence of PCBs in multi-environmental matrices. Despite the high level of PCBs that has been detailed in the major urban areas of India, little is known about the fate and sources of PCBs in Northeast India (NEI). This motivated us to investigate the contamination level and sources of PCBs in the surface soil. In this study, the environmental concentration and sources of 25 PCBs were investigated in surface soil (n = 60) from three states of NEI (lower Assam, Manipur, and Tripura). Additionally, the relationship between soil organic carbon (SOC) and PCBs was studied to investigate the role of SOC in the distribution of PCBs. Overall, the concentration of ?25PCBs ranged from 2950 to 16,700 pg/g dw (median 7080 pg/g dw), 3580-21,100 pg/g dw (median 11,500 pg/g dw), and 2040 11,000 pg/g dw (median 4270 pg/g dw) in Assam, Manipur, and Tripura, respectively. Low-chlorinated PCBs were more prevalent than highly chlorinated PCBs. PCB-49 was identified as the most abundant in soil, followed by PCB-52, and accounted for 13% and 12.9% of ?25PCBs, respectively. With respect to land use categories, high ?25PCBs were related to grassland areas and proximity to the roadside soil. The principal component analysis indicated emissions from technical PCB mixtures, combustion of municipal wastes/residential wood, incineration of hospital wastes, and e-waste recycling/disposal sites are the real sources of PCBs. Marginally, a moderate-to-weak correlation of SOC with ?25PCBs (R2 = 0.144, p < 0.05) and their homologs (R2 = 0.280-0.365, p < 0.05) indicated the little role of SOC in the dispersion of PCBs. The estimated toxic equivalency of dioxin-like PCBs suggested that PCB-126 is the most toxic contaminant to endanger the human population. PMID- 29713745 TI - Comment on Cho et al.: Mobile-bearing unicompartmental knee arthroplasty in old aged patients demonstrates superior short-term clinical outcomes to open-wedge high tibial osteotomy in middle-aged patients with advanced isolated medial osteoarthritis. PMID- 29713746 TI - The treatment of chronic radial head dislocation in Monteggia fracture without annular ligament reconstruction. AB - INTRODUCTION: The treatment of neglected radial head dislocation after missed Monteggia fracture dislocation in children is a controversial issue. The purpose of this study is to report our clinical experience in the treatment of the condition without annular ligament reconstruction. METHOD: This is a retrospective review of 20 patients between 2008 and 2014. Procedures included open reduction of the radial head and ulnar lengthening angulation osteotomy. In cases of unstable radial head reduction, a trans-capitellar K wire was applied. The pre- and post-operative radiographs were available for evaluation as well as the Mayo Elbow Performance Index (MEPI). RESULTS: The average pre-operative elbow extension-flexion arc was 99.5 degrees and pronation-supination arc was 151 degrees . At last follow-up, the flexion of elbow had significant improvement (from 110 degrees to 124 degrees ), while the average pronation and supination arc decreased, most in pronation (from 75 degrees to 65 degrees ). Post operatively, MEPI scored higher, especially in elbow pain and stability. Patients underwent surgery within one year of injury had better functional outcome than those injured over one year. The patients required trans-capitellar K wire for unstable radial head reduction and were in the older age group. At final follow up, the reduction of radial head was maintained in all cases except two with mild subluxations of the radial head in radiographs. Two cases required radial shaft shortening to facilitate the reduction because of proximal migration of the radius. CONCLUSION: For neglected radial head dislocation following Monteggia fracture dislocation, we presented our surgical strategy to reduce the radial head without annual ligament reconstruction. Our patients functionally benefited from the procedure with significant improvement in elbow pain and stability, as well as improved flexion of the elbow with stable radial head reduction. LEVEL OF EVIDENCE: IV. PMID- 29713747 TI - The prognostic value of positron emission tomography/computed tomography in rheumatoid arthritis patients with methotrexate-associated lymphoproliferative disorders. AB - Recently, methotrexate-associated lymphoproliferative disorders (MTX-LPDs) in rheumatoid arthritis (RA) have been found to commonly occur in association with iatrogenic immunodeficiency. Several factors have been reported to be related to the prognosis. We herein investigate the efficacy of 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in predicting the prognosis of MTX-LPD. We performed a retrospective analysis of the clinical features, characteristics, and outcomes of 18 patients with MTX-LPDs who were treated from 2004 to 2015. All of the patients were diagnosed with MTX-LPD based on the histological examination of biopsy specimens. Spontaneous regression was detected after the cessation of MTX in 5 of 18 cases (28%). The maximum standardized uptake value (SUVmax) of the FDG uptake on PET/CT was significantly lower, and the maximum size of the LPD-associated tumor was significantly smaller among the patients who showed spontaneous regression (p = 0.01, p = 0.04, respectively). Both the SUVmax and the maximum tumor size were related to better overall survival (p = 0.02, p = 0.04, respectively). Thus, PET/CT can be used to predict spontaneous regression and the prognosis at the diagnosis of MTX/LPD. Cases that showed spontaneous regression never relapsed during the follow-up period, despite the usage of several anti-rheumatoid arthritis drugs, including biological agents. The early detection of LPDs and the early cessation of MTX are important for the management of RA patients. An evaluation by F-FDG-PET/CT can be useful for predicting spontaneous regression and the prognosis. PMID- 29713744 TI - Skin neurogenic inflammation. AB - The epidermis closely interacts with nerve endings, and both epidermis and nerves produce substances for mutual sustenance. Neuropeptides, like substance P (SP) and calcitonin gene-related protein (CGRP), are produced by sensory nerves in the dermis; they induce mast cells to release vasoactive amines that facilitate infiltration of neutrophils and T cells. Some receptors are more important than others in the generation of itch. The Mas-related G protein-coupled receptors (Mrgpr) family as well as transient receptor potential ankyrin 1 (TRPA1) and protease activated receptor 2(Par2) have important roles in itch and inflammation. The activation of MrgprX1 degranulates mast cells to communicate with sensory nerve and cutaneous cells for developing neurogenic inflammation. Mrgprs and transient receptor potential vanilloid 4 (TRPV4) are crucial for the generation of skin diseases like rosacea, while SP, CGRP, somatostatin, beta endorphin, vasoactive intestinal peptide (VIP), and pituitary adenylate cyclase activating polypeptide (PACAP) can modulate the immune system during psoriasis development. The increased level of SP, in atopic dermatitis, induces the release of interferon (IFN)-gamma, interleukin (IL)-4, tumor necrosis factor (TNF)-alpha, and IL-10 from the peripheral blood mononuclear leukocytes. We are finally starting to understand the intricate connections between the skin neurons and resident skin cells and how their interaction can be key to controlling inflammation and from there the pathogenesis of diseases like atopic dermatitis, psoriasis, and rosacea. PMID- 29713748 TI - Bilateral adrenal hemorrhage as a manifestation of extramedullary hematopoiesis in a patient with primary myelofibrosis. PMID- 29713749 TI - A rare case of an acquired factor V inhibitor in a patient with myelodysplastic syndrome during azacitidine treatment. PMID- 29713750 TI - Correction to: Wnt/beta-catenin signaling mediates the suppressive effects of diallyl trisulfide on colorectal cancer stem cells. AB - Unfortunately, the online published article has error in Figure 4. The correct Figure 4 is given here. PMID- 29713751 TI - Bioaccumulation and Distribution of Hexabromocyclododecane Isomers in Duck Tissues. AB - Eighty ducks (Sheldrake, Anas platyrhynchos) from Zhejiang Province, China were fed capsules containing commercialized hexabromocyclododecanes (HBCDs) at low (0.8 mg/kg/day) or high (1.6 mg/kg/day) exposure level, or only maize starch for 21 days. Then the next 21 days was set as depuration period. Ducks were euthanizated at 0, 7, 14 and 21 days after last dose and ten duck tissues including skin, tongue, intestines, heart, gizzard, muscle, liver, lung, brain and blood were sampled, separately. Three HBCDs including alpha-HBCD, beta-HBCD and gamma-HBCD in duck tissue samples were analyzed. At the end of depuration period, the total HBCDs concentration in skin was significantly higher than those in the other tissues (p < 0.05). The elimination rates of the three isomers in skin, tongue, intestines, heart, gizzard and brain were in the order beta- > gamma- > alpha-HBCD. The enantioselectivity of three HBCDs enantiomers was also studied in ten duck tissues. It was shown that the EF (enrichment factor) for two gamma-HBCD enantiomers was significant lower than 0.5 (p < 0.05) in gizzard, heart, muscle, tongue, intestinal and liver at the end of depuration day, showing a selective accumulation of (+)-gamma-HBCD in these tissues. This study provided a reference for evaluation on the accumulation of the persistent contamination of HBCDs in edible poultry. PMID- 29713752 TI - [A mobile app for patients suffering from kidney stones]. AB - BACKGROUND AND OBJECTIVES: Kidney stone disease has become an important worldwide socioeconomic issue. However, metaphylaxis fails due to low compliance rates. Therefore, we developed a mobile app (StoneMD: Kidney Stones) for patients with kidney stones to increase compliance in stone metaphylaxis. MATERIALS AND METHODS: To identify the most appropriate design of the app, we searched through the App Store and the Google Play Store and integrated the clinical recommendations of the European Association of Urology (EAU) and the American Urological Association (AUA). To test the value of this app, a questionnaire was developed in which the patient should answer questions about the drinking behavior and the subjective use of the app in the field of metaphylaxis. RESULTS: StoneMD: Kidney Stones offers the opportunity to calculate the individual risk of a new stone episode. In addition, the app offers several features to raise awareness of lifestyle modification, including hydration as metaphylaxis of urolithiasis, reminder of inserted ureteral stents and document the self-measured urine pH. A total of 49 patients participated in the questionnaire: 89.8% (n = 46) of these patients had a smartphone, 73.9% reported a daily intake of <2.5 l, 76.5% of these patients believe that their drinking behavior is positively influenced by the app, 71.7% stated that the app for relapse prevention is more suitable than traditional information brochures, 56.5% want to continue to use the app. CONCLUSIONS: StoneMD: Kidney Stones is the first mobile app for stone metaphylaxis. StoneMD might help to improve patient compliance and might lower the risk of stone formation. PMID- 29713753 TI - Poly(N-isopropylacrylamide) microgel-based etalons for the label-free quantitation of estradiol-17beta in aqueous solutions and milk samples. AB - A novel estradiol-17beta (E2) biosensor was constructed from poly(N isopropylacrylamide) (pNIPAm) microgel-based etalons by modification of their outermost Au layer with an E2 binding 75-mer DNA aptamer. When E2 is not present in the solution, the aptamer forms a loose/linear structure that allows ions to pass through and into the microgel layer. The ions can change the solvation state of the microgels, which changes the optical properties of the etalon. When E2 is present in the solution, the aptamer binds the E2 and undergoes a conformational change to a form that can block the diffusion of salt ions into the microgel layer. This blocking decreases the response of the device to salt exposure, which can be related to the concentration of E2 in solution. Using this approach, E2 sensor showed a dynamic range of 0.9-200 pg/mL with a calculated detection limit of 0.9 pg/mL (3.2 pM) E2, and the lowest measured concentration of E2 is 5.0 pg/mL. This sensor also showed low cross reactivity with progesterone, a similar steroid hormone. Moreover, this sensor could be regenerated five times without losing its sensitivity. Finally, we demonstrated that the sensor could also be used to quantify E2 in commercial skim and 2% milk, as well as farm milk directly without any pre-treatment. The successful quantitation of E2 in unprocessed milk demonstrates its potential use as a "cow-side" testing device for the dairy industry. Graphical abstract ?. PMID- 29713754 TI - The contribution of lot-to-lot variation to the measurement uncertainty of an LC MS-based multi-mycotoxin assay. AB - Multi-mycotoxin determination by LC-MS is commonly based on external solvent based or matrix-matched calibration and, if necessary, the correction for the method bias. In everyday practice, the method bias (expressed as apparent recovery RA), which may be caused by losses during the recovery process and/or signal/suppression enhancement, is evaluated by replicate analysis of a single spiked lot of a matrix. However, RA may vary for different lots of the same matrix, i.e., lot-to-lot variation, which can result in a higher relative expanded measurement uncertainty (U r ). We applied a straightforward procedure for the calculation of U r from the within-laboratory reproducibility, which is also called intermediate precision, and the uncertainty of RA (ur,RA). To estimate the contribution of the lot-to-lot variation to U r , the measurement results of one replicate of seven different lots of figs and maize and seven replicates of a single lot of these matrices, respectively, were used to calculate U r . The lot-to-lot variation was contributing to ur,RA and thus to U r for the majority of the 66 evaluated analytes in both figs and maize. The major contributions of the lot-to-lot variation to ur,RA were differences in analyte recovery in figs and relative matrix effects in maize. U r was estimated from long-term participation in proficiency test schemes with 58%. Provided proper validation, a fit-for-purpose U r of 50% was proposed for measurement results obtained by an LC-MS-based multi-mycotoxin assay, independent of the concentration of the analytes. PMID- 29713755 TI - Prognostic factors and prognostic models for renal cell carcinoma: a literature review. AB - PURPOSE: Following curative treatment for localised renal cell carcinoma (RCC), up to 30% of patients develop tumour recurrence. Prognostic scores are essential to guide individualised surveillance protocols, patient counselling and potentially in the future to guide adjuvant therapy. In metastatic RCC, prognostic scores are routinely used for treatment selection in clinical practice as well as in all major trials. METHODS: We performed a literature review on the current evidence based on prognostic factors and models for localised and metastatic RCC. RESULTS: A number of prognostic factors have been identified, of which tumour node metastasis classification remains the most important. Multiple prognostic models and nomograms have been developed for localised disease, based on a combination of tumour stage, grade, subtype, clinical features, and performance status. However, there is poor level of evidence for their routine use. Prognostic scores for patients with metastatic RCC receiving targeted treatments are used routinely, but have limited accuracy. Molecular markers can improve the accuracy of established prognostic models, but frequently lack external, independent validation. CONCLUSION: Several factors and models predict prognosis of localised and metastatic RCC. They represent valuable tools to provide estimates of clinically important endpoints, but their accuracy should be improved further. Validation of molecular markers is a future research priority. PMID- 29713756 TI - Perceptual manifestations of auditory modulation during speech planning. AB - Recent studies have provided electrophysiological evidence that the auditory system's response to externally generated auditory stimuli during speech planning is modulated in comparison to its responses to identical stimuli during no speaking control conditions. In this study, we examined whether such neural modulations during speech planning result in measurable perceptual modulations. In a two-interval forced choice intensity discrimination paradigm, participants were asked to judge the intensity of a standard tone (with constant intensity), played during a fixation period, relative to the intensity of a comparison tone (with varying intensity), played during speech planning or during no-speaking conditions (silent reading and passive listening). Psychometric functions were fitted to participants' responses in each condition; psychometric functions were used to calculate the point of subjective equality (as a measure of perceptual threshold) and the slope of the psychometric functions (as a measure of perceptual uncertainty). We found that the point of subjective equality in the speaking condition was statistically significantly larger than that in the no speaking conditions. In addition, slope values in the speaking and listening conditions were statistically significantly smaller than slope value in the silent reading condition. Together, these results suggest that previously reported electrophysiological modulations of the auditory system during speech planning may have perceptual manifestations, such as increases in perceptual thresholds and uncertainty of perceptual thresholds in an intensity discrimination task. PMID- 29713757 TI - Availability of attention affects time-to-contact estimation. AB - To estimate the time-to-contact (TTC) of a moving object, numerous studies have focused on the type of information or gaze strategy used by the observer. However, it remains to be determined whether and how attention could affect TTC estimation. In particular, how does TTC estimation operate when less attention is available? To answer this question, we conducted two experiments in which the participants had to perform an absolute (Experiment 1) or relative (Experiment 2) prediction-motion task, either alone (i.e., in single-task condition) or along with a secondary, visual working-memory task (i.e., in dual-task condition). In both experiments, we found that TTC estimation was superior in dual-task condition relative to single-task condition. This finding suggests that the reduction of available attention actually improves TTC estimation. We discuss possible explanations as well as theoretical implications for this seemingly counter-intuitive finding. Further research is needed to investigate if (in)attention facilitates or only shifts TTC estimation. PMID- 29713758 TI - Bothersome tinnitus : Cognitive behavioral perspectives. AB - Tinnitus is not traceable to a single disease or pathology, but merely a symptom, which is distressing to some but not all individuals able to perceive it. The experience of tinnitus does not equate to tinnitus distress. Tinnitus suffering might be understood as a function of tinnitus-related distress in that bothersome tinnitus is an illness rather than a disease. In bothersome (distressing) tinnitus, the perception of the characteristic sound is a very disturbing and bothersome experience because of maladaptive psychological responses. Several cognitive and behavioral theoretical frameworks attempting to explain the nature and cause of tinnitus suffering have been introduced in and will be summarized here. Current treatment approaches are generally based on models that aim to: alleviate the perceptional experience by focusing on the tinnitus perception for habituation or even soothing purposes; decrease awareness of the sound by attentional training and cognitive interventions; decrease the maladaptive responses and the resulting distress by behavioral methods (i. e., exposure). The cognitive behavioral fear-avoidance model may offer an integrative cognitive behavioral approach that can lead to a new set of paradigms for studying the underlying mechanisms explaining chronic tinnitus suffering as well for developing innovative strategies to treat bothersome tinnitus. PMID- 29713760 TI - Cell division cycle 7 is a potential therapeutic target in oral squamous cell carcinoma and is regulated by E2F1. AB - Cell division cycle 7 (Cdc7) plays important roles in the regulation of the initiation of DNA replication throughout S phase. Whether inhibition of Cdc7 has a direct antitumour effect in oral squamous cell carcinoma (OSCC) remains unclear. In this study, XL413, a novel Cdc7 inhibitor, markedly inhibited the viability of OSCC cells but not that of non-tumour primary cells. There was a synergistic effect between XL413 and DNA-damaging agents (e.g. cisplatin and 5 fluorouracil) on OSCC in vitro and in vivo. Moreover, XL413 exhibited a notable antitumour effect on OSCC patients with high Cdc7 expression in mini patient derived xenografts model. The proliferation was significantly inhibited in OSCC cells after Cdc7 silencing. Cdc7 knockdown significantly induced apoptosis in OSCC cell lines. Furthermore, we demonstrated that Cdc7 was overexpressed and transcriptionally regulated by E2F1 in OSCC by using chromatin immunoprecipitation and luciferase assays. Our results reveal that XL413 has an excellent antitumour effect in OSCC. Importantly, it does not inhibit the proliferation of non-tumour cells. These findings suggest that the overexpression of Cdc7 promotes progression in OSCC and that inhibition of Cdc7 is a very promising therapy for OSCC patients. PMID- 29713761 TI - HMGB proteins involved in TOR signaling as general regulators of cell growth by controlling ribosome biogenesis. AB - The number of ribosomes and their activity need to be highly regulated because their function is crucial for the cell. Ribosome biogenesis is necessary for cell growth and proliferation in accordance with nutrient availability and other external and intracellular signals. High-mobility group B (HMGB) proteins are conserved from yeasts to human and are decisive in cellular fate. These proteins play critical functions, from the maintenance of chromatin structure, DNA repair, or transcriptional regulation, to facilitation of ribosome biogenesis. They are also involved in cancer and other pathologies. In this review, we summarize evidence of how HMGB proteins contribute to ribosome-biogenesis control, with special emphasis on a common nexus to the target of rapamycin (TOR) pathway, a signaling cascade essential for cell growth and proliferation from yeast to human. Perspectives in this field are also discussed. PMID- 29713762 TI - Prolonged survival in secondary glioblastoma following local injection of targeted alpha therapy with 213Bi-substance P analogue. AB - BACKGROUND: Glioblastoma multiforme (GBM), the most common malignant brain tumor, mainly manifests as a primary de novo and less frequently as a secondary glial neoplasm. GBM has been demonstrated to overexpress the NK-1 receptor and substance P can be used as a ligand for targeted therapy. Alpha emitters, e.g. 213Bi, that deposit their high energy within a short range allow the selective irradiation of tumor cells while sparing adjacent neuronal structures. MATERIAL AND METHODS: Among 50 glioma patients of different subtypes that have to date been treated with targeted alpha therapy at the Medical University Warsaw, we report here the data on nine patients with secondary GBM. Following surgery, chemo- and radiotherapy, recurrent GBM was treated by intracavitary injection of 1-6 doses of 0.9-2.3 GBq 213Bi- DOTA-[Thi8,Met(O2)11]-substance P (213Bi-DOTA-SP) in 2-month intervals. 68Ga-DOTA-[Thi8,Met(O2)11]-substance P (68Ga-DOTA-SP) was co-injected with the therapeutic doses to assess biodistribution using PET/CT. Therapeutic response was monitored with MRI. RESULTS: Treatment with activities ranging from 1.4 to 9.7 (median 5.8) GBq 213Bi- DOTA-SP was well tolerated with only mild transient adverse reactions, mainly headaches due to a transient perfocal edema reaction. The median progression free survival and overall survival time following the initiation of alpha therapy was 5.8 and 16.4 months, respectively. The median overall survival time from the first diagnosis was 52.3 months. Two out of nine patients are still alive 39 and 51 months, respectively, after the initiation of the therapy. CONCLUSIONS: Targeted alpha therapy of secondary GBM with 213Bi-DOTA-SP is safe and well tolerated and may evolve as a promising novel therapeutic option for secondary GBM. PMID- 29713763 TI - Assessing FDG-PET diagnostic accuracy studies to develop recommendations for clinical use in dementia. AB - BACKGROUND: FDG-PET is frequently used as a marker of synaptic damage to diagnose dementing neurodegenerative disorders. We aimed to adapt the items of evidence quality to FDG-PET diagnostic studies, and assess the evidence available in current literature to assist Delphi decisions for European recommendations for clinical use. METHODS: Based on acknowledged methodological guidance, we defined the domains, specific to FDG-PET, required to assess the quality of evidence in 21 literature searches addressing as many Population Intervention Comparison Outcome (PICO) questions. We ranked findings for each PICO and fed experts making Delphi decisions for recommending clinical use. RESULTS: Among the 1435 retrieved studies, most lacked validated measures of test performance, an adequate gold standard, and head-to-head comparison of FDG-PET and clinical diagnosis, and only 58 entered detailed assessment. Only two studies assessed the accuracy of the comparator (clinical diagnosis) versus any kind of gold-/reference-standard. As to the index-test (FDG-PET-based diagnosis), an independent gold-standard was available in 24% of the examined papers; 38% used an acceptable reference standard (clinical follow-up); and 38% compared FDG-PET-based diagnosis only to baseline clinical diagnosis. These methodological limitations did not allow for deriving recommendations from evidence. DISCUSSION: An incremental diagnostic value of FDG-PET versus clinical diagnosis or lack thereof cannot be derived from the current literature. Many of the observed limitations may easily be overcome, and we outlined them as research priorities to improve the quality of current evidence. Such improvement is necessary to outline evidence-based guidelines. The available data were anyway provided to expert clinicians who defined interim recommendations. PMID- 29713764 TI - Novel use of 177Lu-DOTA-RGD2 in treatment of 68Ga-DOTA-RGD2-avid lesions in papillary thyroid cancer with TENIS. PMID- 29713765 TI - Scapholunate instability: improved detection with semi-automated kinematic CT analysis during stress maneuvers. AB - OBJECTIVES: To evaluate the diagnostic performance of radioulnar deviation (RUD) and clenching fist (CF) maneuvers for the evaluation of scapholunate dissociation (SLD) using quantitative kinematic CT. METHODS: Thirty-seven patients with suspected scapholunate instability were prospectively evaluated with kinematic CT. Two radiologists independently evaluated the SLD during RUD and CF maneuvers. Various dynamic parameters describing SLD were compared (maximal value, variation coefficient and range) in patients with and without scapholunate ligament ruptures confirmed by CT arthrography. RESULTS: SLD in CF varied from 3.17 +/- 0.38 to 3.24 +/- 0.80 mm in controls and from 4.11 +/- 0.77 and 4.01 +/- 0.85 mm in patients with scapholunate ligament ruptures for reader 1 and 2 (p < 0.009). SLD in RUD varied from 3.35 +/- 0.51 and 3.01 +/- 0.78 mm in controls and from 4.51 +/- 1.26 to 4.42 +/- 1.75 mm in patients with scapholunate ligament ruptures for reader 1 and 2 (p varied from 0.001 to 0.002). The inter-observer variability was better for RUD (ICC = 0.85 versus 0.6 for RUD and CF respectively). CONCLUSION: Analysis of SLD using kinematic CT has shown significant measurement differences between the groups with or without scapholunate instability with good diagnostic performance. KEY POINTS: * Kinematic CT can quantitatively assess scapholunate dissociation. * SLD analysis on kinematic CT has excellent reproducibility with radioulnar deviation maneuver. * Scapholunate dissociation was significantly different in patients with and without instability. * Diagnostic performance for scapholunate instability identification was better with radioulnar deviation. PMID- 29713766 TI - Evaluation of T categories for pure ground-glass nodules with semi-automatic volumetry: is mass a better predictor of invasive part size than other volumetric parameters? AB - OBJECTIVES: This study aimed to investigate the diagnostic advantage of nodule mass in differentiating invasive pulmonary adenocarcinomas (IPAs) among pure ground-glass nodules (pGGNs) over other volumetric measurements. Another aim of this study was to analyse the correlation between volumetric measurements on computed tomography (CT) scans and the pathological invasive component size. METHODS: This Institutional Review Board-approved retrospective study included 117 patients (men:women = 53:64; mean age, 57.3 years) with 117 pGGNs. Semi automatic segmentation was performed for all nodules, and volumetric measurements, such as nodule volume, attenuation, mass, two-dimensional (2D) average diameter and three-dimensional (3D) longest diameter, were obtained. Receiver operating characteristic (ROC) curve analyses were performed to evaluate the diagnostic performances of the volumetric parameters in discriminating IPAs. Spearman correlation coefficients were calculated between the volumetric measurements and the invasive component size. RESULTS: Area under the ROC curve for mass was 0.792 (95% CI, 0.691-0.872) in non-enhanced CT and 0.730 (95% CI, 0.607-0.832) in contrast-enhanced CT. Nodule mass was not superior to 2D average diameter for the differentiation of IPAs in both non-enhanced (0.792 vs 0.780; p = 0.501) CT and contrast-enhanced CT scans (0.730 vs 0.700; p = 0.319). The correlation between the volumetric measurements (mass, 3D longest diameter and 2D average diameter) and the invasive component size was moderate (Spearman's rho, 0.401-0.422) in non-enhanced CT and weak (Spearman's rho, 0.276-0.310) in contrast-enhanced CT. CONCLUSIONS: Nodule mass measurement had no strength over other volumetric parameters for the prediction of pathological invasiveness in the diagnosis of pGGNs. KEY POINTS: * Mass is not superior to other volumetric measurements for the diagnosis of pure ground-glass nodules. * Mass and two dimensional average diameter exhibited comparable performance for the discrimination of invasive adenocarcinomas among pure ground-glass nodules. * The diagnostic performance of volumetric measurements was lower on contrast-enhanced CT scans. * The correlation between the volumetric measurements and the invasive component size was moderate on non-enhanced CT scans and weak on contrast enhanced CT scans. PMID- 29713767 TI - Monitoring skeletal muscle chronic fatty degenerations with fast T1-mapping. AB - OBJECTIVES: To develop a fast, high-resolution T1-mapping sequence dedicated to skeletal muscle imaging, and to evaluate the potential of T1 as a robust and sensitive biomarker for the monitoring of chronic fatty degenerations in a dystrophic disease. METHODS: The magnetic resonance imaging sequence consisted of the acquisition of a 1,000-radial-spokes FLASH echo-train following magnetisation inversion, resulting in 10s scan time per slice. Temporal image series were reconstructed using compressed sensing and T1 maps were computed using Bloch simulations. Ten healthy volunteers and 30 patients suffering from Becker muscular dystrophy (BMD) participated in this prospective study, in order to evaluate the repeatability, the precision and the sensitivity of the proposed approach. Intramuscular fat fraction (FF) was also measured using a standard three-point Dixon method. The protocol was approved by a local ethics committee. RESULTS: The mean T1 evaluated in the thighs muscles of healthy volunteers was 1,199 +/- 45 ms, with a coefficient of reproducibility of 2.3%. Mean T1 values were statistically decreased in the thighs of BMD patients and were linearly correlated with intramuscular FF (R = -0.98). CONCLUSIONS: T1-mapping is a good candidate for fast, sensitive and quantitative monitoring of fatty infiltrations in neuromuscular disorders. KEY POINTS: * A T1 mapping sequence dedicated to skeletal muscle imaging was implemented. * The acquisition time was 10 s per slice. * Muscle T1 values were significantly decreased in dystrophic muscles compared to healthy muscles. * T1 values correlated with intramuscular fat fraction measured by three-point Dixon. * T1 represents an alternative biomarker for monitoring fatty infiltrations in neuromuscular disorders. PMID- 29713768 TI - Is it painful to be different? Sciatic nerve anatomical variants on MRI and their relationship to piriformis syndrome. AB - OBJECTIVES: To investigate the purported relationship between sciatic nerve variant anatomy and piriformis syndrome. METHODS: Over 49 months, 1039 consecutive noncontrast adult hip MRIs were completed for various clinical indications. Repeat and technically insufficient studies were excluded. Radiologists categorized sciatic nerve anatomy into Beaton and Anson anatomical types. Chart review using our institution's cohort search and navigation tool determined the prevalence of the explicit clinical diagnosis of piriformis syndrome (primary endpoint) and sciatica and buttock pain (secondary endpoints). A Z-test compared the prevalence of each diagnosis in the variant anatomy and normal groups. RESULTS: Seven hundred eighty-three studies were included, with sciatic nerve variants present in 150 hips (19.2%). None of the diagnoses had a statistically significant difference in prevalence between the variant and normal hip groups. Specifically, piriformis syndrome was present in 11.3% of variant hips compared with 9.0% of normal hips (p = 0.39). CONCLUSIONS: There were no significant differences in the prevalence of piriformis syndrome, buttock pain, or sciatica between normal and variant sciatic nerve anatomy. This large-scale correlative radiologic study into the relationship between sciatic nerve variants and piriformis syndrome calls into question this purported relationship. KEY POINTS: * Large retrospective study relating variant sciatic nerve anatomy, present in 19.2% of hip MRIs, and piriformis syndrome * While sciatic nerve variant anatomy has previously been implicated in piriformis syndrome in small studies, no relationship was identified between sciatic nerve variants and piriformis syndrome. PMID- 29713770 TI - Comprehensive morphologic and functional imaging of heart transplant patients: first experience with dynamic perfusion CT. AB - OBJECTIVES: We aimed to assess the diagnostic performance of a combined protocol with coronary computed tomography angiography (CCTA) and stress CT perfusion imaging (CTP) in heart transplant patients for comprehensive morphological and functional imaging. METHODS: In this prospective study, 13 patients undergoing routine follow-up 8+/-6 years after heart transplantation underwent CCTA and dynamic adenosine stress CTP using a third-generation dual-source CT scanner, cardiac magnetic resonance (MR) adenosine stress perfusion imaging at 1.5 T, and catheter coronary angiography. In CCTA stenoses >50% luminal diameter narrowing were noted. Myocardial perfusion deficits were documented in CTP and MR. Quantitative myocardial blood flow (MBF) was calculated with CTP. Left ventricular ejection fraction was determined on cardiac MR cine images. Radiation doses of CT were determined. RESULTS: One of the 13 patients had to be excluded because of severe motion artifacts. CCTA identified three patients with stenosis >50%, which were confirmed with catheter coronary angiography. CTP showed four patients with stress-induced myocardial hypoperfusion, which were confirmed by MR stress perfusion imaging. Quantitative analysis of global MBF showed lower mean values as compared to known reference values (MBF under stress 125.5 +/- 34.5 ml/100 ml/min). Average left ventricular ejection fraction was preserved (56 +/- 5%). CONCLUSIONS: In heart transplant patients, a comprehensive CT protocol for the assessment of morphology and function including CCTA and CTP showed good concordance to results from MR perfusion imaging and catheter coronary angiography. KEY POINTS: * Stress CT perfusion imaging enables the detection of myocardial ischemia * CT myocardial perfusion imaging can be combined with coronary computed tomography angiography * Combining perfusion and coronary CT imaging is accurate in heart transplant patients * CT myocardial perfusion imaging can be performed at a reasonable radiation dose. PMID- 29713769 TI - Optic radiations are thinner and show signs of iron deposition in patients with long-standing remitting-relapsing multiple sclerosis: an enhanced T2*-weighted angiography imaging study. AB - OBJECTIVE: This study aimed to investigate iron deposition and thickness and signal changes in optic radiation (OR) by enhanced T2*-weighted angiography imaging (ESWAN) in patients with relapsing-remitting multiple sclerosis (RRMS) with unilateral and bilateral lesions or no lesions. METHODS: Fifty-one RRMS patients (42 patients with a disease duration [DD] >= 2 years [group Mor], nine patients with a DD < 2 years [group Les]) and 51 healthy controls (group Con) underwent conventional magnetic resonance imaging (MRI) and ESWAN at 3.0 T. The mean phase value (MPV) of the OR was measured on the phase image, and thickness and signal changes of the OR were observed on the magnitude image. RESULTS: The average MPVs for the OR were 1,981.55 +/- 7.75 in group Mor, 1,998.45 +/- 2.01 in group Les, and 2,000.48 +/- 5.53 in group Con. In group Mor, 28 patients with bilateral OR lesions showed bilateral OR thinning with a heterogeneous signal, and 14 patients with unilateral OR lesions showed ipsilateral OR thinning with a heterogeneous signal. In the remaining nine patients without OR lesions and in group Con, the bilateral OR had a normal appearance. In the patients, a negative correlation was found between DD and OR thickness and a positive correlation was found between MPV and OR thickness. CONCLUSIONS: We confirmed iron deposition in the OR in the RRMS patients, and the OR thickness was lower in the patients than in the controls. KEY POINTS: * Enhanced T 2* -weighted magnetic resonance angiography (ESWAN) provides new insights into multiple sclerosis (MS). * Focal destruction of the optic radiation (OR) is detectable by ESWAN. * Iron deposition in OR can be measured on ESWAN phase image in MS patients. * OR thickness was lower in the patients than in the controls. * Iron deposition and thickness changes of the OR are associated with disease duration. PMID- 29713771 TI - Diffusion tensor magnetic resonance imaging of breast cancer: associations between diffusion metrics and histological prognostic factors. AB - OBJECTIVES: To investigate whether quantitative diffusion metrics derived from diffusion tensor imaging (DTI) are associated with histological prognostic factors in breast cancer patients. METHODS: This retrospective study was approved by the institutional review board, and informed consent was waived. Between 2016 and 2017, 251 consecutive women (mean age, 53.8 years) with breast cancer (230 invasive, 21 in situ) who underwent preoperative magnetic resonance (MR) imaging with DTI were identified. Diffusion gradients were applied in 20 directions (b values, 0 and 1,000 s/mm2). DTI metrics - mean diffusivity (MD) and fractional anisotropy (FA) - were measured for breast lesions and contralateral normal breast by two radiologists and were correlated with histological findings using the Mann-Whitney U-test and linear regression analysis. RESULTS: MD and FA were significantly lower for breast cancers than for normal fibroglandular tissues (1.03 +/- 0.25*10-3 mm2/s vs. 1.60 +/- 0.19*10-3 mm2/s, p < 0.001 and 0.29 +/- 0.09 vs. 0.33 +/- 0.06, p < 0.001, respectively). Significant differences were observed in MD between invasive cancer and ductal carcinoma in situ lesions (p < 0.001). Multivariate linear analysis showed that larger size (>2 cm) (p = 0.007), high histological grade (grade 3) (p = 0.045) and axillary node metastasis (p = 0.009) were significantly associated with lower MD in invasive breast cancer patients. Larger size (p < 0.001) and high histological grade (p = 0.025) were significantly associated with lower FA. CONCLUSIONS: DTI-derived diffusion metrics, such as MD and FA, are associated with histological prognostic factors in breast cancer patients. KEY POINTS: * MD was significantly lower for breast cancers than for normal breast tissues. * FA was significantly lower for breast cancers than for normal breast tissues. * Reduced DTI metrics were associated with poor prognostic factors of breast cancer. * DTI may provide valuable information concerning biological aggressiveness in breast cancer. PMID- 29713772 TI - The imaging of the dizzy patient: computed tomography versus magnetic resonance imaging. PMID- 29713773 TI - Feasibility of balanced steady-state free precession sequence at 1.5T for the evaluation of hepatic steatosis in obese children and adolescents. AB - OBJECTIVES: To determine the feasibility of balanced steady-state free precession (b-SSFP) imaging for measuring hepatic steatosis in obese children and adolescents, using proton magnetic resonance spectroscopy (1H MRS) as reference standard. METHODS: 182 obese Chinese paediatric patients underwent conventional T1-weighted dual echo MRI, 1H MRS and b-SSFP imaging for non-invasive assessment of hepatic steatosis. RESULTS: There was a strong positive correlation between liver fat fraction (FF) on T1-weighted dual echo MRI and 1H MRS-determined liver fat content (LFC) (r = 0.964, p < .001), and a strong negative correlation between the ratio of liver signal intensity (SI) to spleen SI (L/S) on b-SSFP and LFC (r = -0.896, p < .001). ROC curve analysis based on a diagnostic threshold of 1H MRS-determined LFC >50 mg/g (>5 % by wet weight) showed areas under the curves for FF and L/S at 0.989 (0.976-1.000) and 0.926 (0.888-0.964), respectively. Optimal FF and L/S cut-off values identified patients with hepatic steatosis with 97.9 % and 86.5 % sensitivity and 93.4 % and 93.4 % specificity, respectively. CONCLUSIONS: Following further validation, b-SSFP at 1.5T has potential as a feasible technique for evaluation of hepatic steatosis in obese paediatric patients with limited breath-holding capacity. KEY POINTS: * L/S on b-SSFP images closely correlated with 1 H MRS-determined LFC. * b-SSFP has high diagnostic accuracy for hepatic steatosis in obese children. * 100% of obese paediatric subjects are imaged successfully using b-SSFP sequence. * b-SSFP has potential to evaluate hepatic steatosis in children with poor breath-hold. PMID- 29713774 TI - Diagnostic value of six MRI features for central neurocytoma. AB - OBJECTIVES: To increase our understanding of the imaging features of central neurocytoma (CN) and improve the preoperative MRI diagnosis accuracy. METHODS: Preoperative MR images of 30 CNs and another 68 intraventricular non-CN tumours were analysed by one experienced neuroradiologist retrospectively to identify previously reported features and new features of CN. Six blinded radiologists independently reviewed all these MRI images, and scored all characteristic features on a five-point scale. Diagnostic value was assessed by the area under the receiver operating characteristic curve (AUC); sensitivity, specificity and accuracy were also calculated. RESULTS: In addition to the 'scalloping' sign, 'broad-based attachment' sign and 'soap-bubble' sign, three new MRI features of CN were identified, including the 'peripheral cysts' sign, 'fluid-fluid level' sign and the 'gemstone' sign. The scalloping sign showed the highest AUC value (0.82), followed by the peripheral cysts sign (0.75) and broad-based attachment sign (0.75). The scalloping sign exhibited the highest specificity (82%), followed by the fluid-fluid level sign (79%) and gemstone (78%) sign. The broad based attachment sign (85%) was the most sensitive feature, followed by the soap bubble sign (84%) and peripheral cysts sign (77%). CONCLUSION: There are six characteristic MRI features that help to improve the preoperative diagnostic accuracy of CN. KEY POINTS: * This study is the largest magnetic resonance imaging (MRI) cohort on central neurocytoma (CN). * Three new features helpful for the diagnosis of CN were reported. * Diagnostic value of six MRI features of CN was preliminarily determined. PMID- 29713775 TI - Tibial tuberosity to trochlear groove distance and its association with patellofemoral osteoarthritis-related structural damage worsening: data from the osteoarthritis initiative. AB - OBJECTIVES: To determine whether the tibial tuberosity-to-trochlear groove (TT TG) distance is associated with concurrent patellofemoral joint osteoarthritis (OA)-related structural damage and its worsening on 24-month follow-up magnetic resonance imaging (MRI) in participants in the Osteoarthritis Initiative (OAI). METHODS: Six hundred subjects (one index knee per participant) were assessed. To evaluate patellofemoral OA-related structural damage, baseline and 24-month semiquantitative MRI Osteoarthritis Knee Score (MOAKS) variables for cartilage defects, bone marrow lesions (BMLs), osteophytes, effusion, and synovitis were extracted from available readings. The TT-TG distance was measured in all subjects using baseline MRIs by two musculoskeletal radiologists. The associations between baseline TT-TG distance and concurrent baseline MOAKS variables and their worsening in follow-up MRI were investigated using regression analysis adjusted for variables associated with tibiofemoral and patellofemoral OA. RESULTS: At baseline, increased TT-TG distance was associated with concurrent lateral patellar and trochlear cartilage damages, BML, osteophytes, and knee joint effusion [cross-sectional evaluations; overall odds ratio 95% confidence interval (OR 95% CI): 1.098 (1.045-1.154), p < 0.001]. In the longitudinal analysis, increased TT-TG distance was significantly related to lateral patellar and trochlear cartilage, BML, and joint effusion worsening (overall OR 95% CI: 1.111 (1.056-1.170), p < 0.001). CONCLUSIONS: TT-TG distance was associated with simultaneous lateral patellofemoral OA-related structural damage and its worsening over 24 months. Abnormally lateralized tibial tuberosity may be considered as a risk factor for future patellofemoral OA worsening. KEY POINTS: * Excessive TT-TG distance on MRI is an indicator/predictor of lateral patellofemoral-OA. * TT-TG is associated with simultaneous lateral-patellofemoral OA (6-17% chance-increase for each millimeter increase). * TT-TG is associated with longitudinal (24-months) lateral-patellofemoral-OA (5-15% chance-increase for each millimeter). PMID- 29713776 TI - Reliable and fast volumetry of the lumbar spinal cord using cord image analyser (Cordial). AB - OBJECTIVE: To validate the precision and accuracy of the semi-automated cord image analyser (Cordial) for lumbar spinal cord (SC) volumetry in 3D T1w MRI data of healthy controls (HC). MATERIALS AND METHODS: 40 3D T1w images of 10 HC (w/m: 6/4; age range: 18-41 years) were acquired at one 3T-scanner in two MRI sessions (time interval 14.9+/-6.1 days). Each subject was scanned twice per session, allowing determination of test-retest reliability both in back-to-back (intra session) and scan-rescan images (inter-session). Cordial was applied for lumbar cord segmentation twice per image by two raters, allowing for assessment of intra and inter-rater reliability, and compared to a manual gold standard. RESULTS: While manually segmented volumes were larger (mean: 2028+/-245 mm3 vs. Cordial: 1636+/-300 mm3, p<0.001), accuracy assessments between manually and semi automatically segmented images showed a mean Dice-coefficient of 0.88+/-0.05. Calculation of within-subject coefficients of variation (COV) demonstrated high intra-session (1.22-1.86%), inter-session (1.26-1.84%), as well as intra-rater (1.73-1.83%) reproducibility. No significant difference was shown between intra- and inter-session reproducibility or between intra-rater reliabilities. Although inter-rater reproducibility (COV: 2.87%) was slightly lower compared to all other reproducibility measures, between rater consistency was very strong (intraclass correlation coefficient: 0.974). CONCLUSION: While under-estimating the lumbar SCV, Cordial still provides excellent inter- and intra-session reproducibility showing high potential for application in longitudinal trials. KEY POINTS: * Lumbar spinal cord segmentation using the semi-automated cord image analyser (Cordial) is feasible. * Lumbar spinal cord is 40-mm cord segment 60 mm above conus medullaris. * Cordial provides excellent inter- and intra-session reproducibility in lumbar spinal cord region. * Cordial shows high potential for application in longitudinal trials. PMID- 29713777 TI - Editorial comment: the future of compositional MRI for cartilage. AB - This editorial comment refers to the article: "Detection of early cartilage damage: feasibility and potential of gagCEST imaging at 7T" by Brinkhof et al, Eur Radiol 2018. PMID- 29713778 TI - Initial experience of an investigational 3T MR scanner designed for use on neonatal wards. AB - OBJECTIVES: MR imaging of neonates is difficult for many reasons and a major factor is safe transport to the MR facilities. In this article we describe the use of a small, investigational 3-T MR customised for brain imaging and sited on a neonatal unit of a tertiary centre in the UK, which is in contrast to a 300-m journey to the whole-body MR scanner used at present for clinical cases. METHODS: We describe our methods for preparing babies for safe transport and scanning on an investigational 3-T MR scanner on a neonatal unit and the development of appropriate MR sequences. The MR scanner does not have CE marking at present so this early development work was undertaken on normal neonates whose parents consented to a research examination. RESULTS: Fifty-two babies were scanned and there were no serious adverse events. The MR examinations were considered to be diagnostically evaluable in all 52 cases and in 90% the imaging was considered to be at least as good as the quality obtained on the 1.5-T scanner currently used for clinical cases. CONCLUSION: We have shown that this investigational 3-T MR scanner can be used safely on a neonatal unit and we have refined the MR sequences to a point that they are clinically usable. KEY POINTS: * Access to neonatal MR imaging is limited. * We describe an investigational 3-T MR scanner site on a neonatal unit. * The scanner produces images suitable for clinical practice. PMID- 29713779 TI - Extracardiac findings at cardiac MR imaging: a single-centre retrospective study over 14 years. AB - OBJECTIVES: To determine the prevalence and significance of extracardiac findings (ECF) in a large set of cardiac magnetic resonance (MR) imaging examinations. METHODS: The institutional review board (IRB) of the Charite approved this retrospective, single-centre study. A total of 4376 cardiac MR imaging reports of 3553 patients (age 37.4 +/- 20 years, 60.8 % male) examined from 2000 to 2014 were included. Findings with a recommendation for follow-up were considered "major ECF". To analyse the association of indication, age and gender with ECF, Poisson regression and computed incidence rate ratios (IRR) were evaluated. RESULTS: The overall prevalence of ECF was 34% (95% confidence interval [CI] 32.5 35.6%). Major ECF were present in 3.4% (95% CI 2.9-4.1%) while findings that changed patient management were found in 0.9% (95% CI 0.7-1.3%). In the cases of congenital heart disease, ECF prevalence was higher compared to myocarditis (IRR, 6.0; 95% CI 5.1-7.1%; p < 0.001), while the prevalence of major ECF was lower (IRR, 0.2; 95% CI 0.02-0.51%; p < 0.05). Older patient age was associated with more nonvascular ECF (p < 0.001). Female patients had the same probability of having an ECF as male patients (IRR, 1.04; 95% CI 0.95-1.1%; p = 0.43). CONCLUSION: ECF in cardiac MR imaging are present in about every third patient while relevant ECF that change patient management can be found in about one out of 100 patients. Our data suggest that it is important to involve well-trained radiologists in reading cardiac MR images, which often reveal ECF if congenital heart disease is the clinical indication. KEY POINTS: * Extracardiac findings are present in about every third patient. * Relevant ECF changing patient management are found in one out of 100 findings. * Chance of ECF is high in patients with CHD and vascular indications. PMID- 29713781 TI - Cardiac implanted electronic devices and MRI safety in 2018-the state of play. AB - : Traditionally, the presence of cardiac implanted electronic devices (CIEDs) was a contra-indication to magnetic resonance (MR) imaging. Professional groups from around the world are releasing updated guidelines for the imaging of MR conditional and legacy CIEDs, reflecting increasing evidence that this can be performed safely when strict protocols are followed. KEY POINTS: * The presence of a pacemaker or automatic implanted cardioverter defibrillator is no longer an absolute contraindication to magnetic resonance imaging. * Strict protocols enable diagnostic quality images to be obtained with minimal risk. * Close collaboration among radiologists, cardiologists and device manufacturer representatives is required. PMID- 29713780 TI - Quantitative parameters of CT texture analysis as potential markersfor early prediction of spontaneous intracranial hemorrhage enlargement. AB - OBJECTIVE: To objectively quantify intracranial hematoma (ICH) enlargement by analysing the image texture of head CT scans and to provide objective and quantitative imaging parameters for predicting early hematoma enlargement. METHODS: We retrospectively studied 108 ICH patients with baseline non-contrast computed tomography (NCCT) and 24-h follow-up CT available. Image data were assessed by a chief radiologist and a resident radiologist. Consistency analysis between observers was tested. The patients were divided into training set (75%) and validation set (25%) by stratified sampling. Patients in the training set were dichotomized according to 24-h hematoma expansion >= 33%. Using the Laplacian of Gaussian bandpass filter, we chose different anatomical spatial domains ranging from fine texture to coarse texture to obtain a series of derived parameters (mean grayscale intensity, variance, uniformity) in order to quantify and evaluate all data. The parameters were externally validated on validation set. RESULTS: Significant differences were found between the two groups of patients within variance at V1.0 and in uniformity at U1.0, U1.8 and U2.5. The intraclass correlation coefficients for the texture parameters were between 0.67 and 0.99. The area under the ROC curve between the two groups of ICH cases was between 0.77 and 0.92. The accuracy of validation set by CTTA was 0.59-0.85. CONCLUSION: NCCT texture analysis can objectively quantify the heterogeneity of ICH and independently predict early hematoma enlargement. KEY POINTS: * Heterogeneity is helpful in predicting ICH enlargement. * CTTA could play an important role in predicting early ICH enlargement. * After filtering, fine texture had the best diagnostic performance. * The histogram-based uniformity parameters can independently predict ICH enlargement. * CTTA is more objective, more comprehensive, more independently operable, than previous methods. PMID- 29713782 TI - Gd-EOB-DTPA-enhanced MRI for quantitative assessment of liver organ damage after partial hepatic ischaemia reperfusion injury: correlation with histology and serum biomarkers of liver cell injury. AB - OBJECTIVE: To evaluate Gd-EOB-DTPA-enhanced MRI for quantitative assessment of liver organ damage after hepatic ischaemia reperfusion injury (IRI) in mice. METHODS: Partial hepatic IRI was induced in C57Bl/6 mice (n = 31) for 35, 45, 60 and 90 min. Gd-EOB-DTPA-enhanced MRI was performed 1 day after surgery using a 3D FLASH sequence. A subgroup of n = 9 animals with 60 min IRI underwent follow-up with MRI and histology 7 days after IRI. The total liver volume was determined by manual segmentation of the entire liver. The volume of functional, contrast enhanced liver parenchyma was quantified by a region growing algorithm (visual threshold) and an automated segmentation (Otsu's method). The percentages of functional, contrast-enhanced and damaged non-enhanced parenchyma were calculated according to these volumes. MRI data was correlated with serum liver enzyme concentrations and histologically quantified organ damage using periodic acid Schiff (PAS) staining. RESULTS: The percentage of functional (contrasted) liver parenchyma decreased significantly with increasing ischaemia times (control, 94.4 +/- 3.3%; 35 min IRI, 89.3 +/- 4.1%; 45 min IRI, 87.9 +/- 3.3%; 60 min IRI, 68 +/ 10.5%, p < 0.001 vs. control; 90 min IRI, 55.9 +/- 11.5%, p < 0.001 vs. control). The percentage of non-contrasted liver parenchyma correlated with histologically quantified liver organ damage (r = 0.637, p < 0.01) and serum liver enzyme elevations (AST r = 0.577, p < 0.01; ALT r = 0.536, p < 0.05). Follow-up MRI visualized recovery of functional liver parenchyma (71.5 +/- 8.7% vs. 84 +/- 2.1%, p < 0.05), consistent with less histological organ damage on day 7. CONCLUSION: We demonstrated the feasibility of Gd-EOB-DTPA-enhanced MRI for non-invasive quantification of damaged liver parenchyma following IRI in mice. This novel methodology may refine the characterization of liver disease and could have application in future studies targeting liver organ damage. KEY POINTS: * Prolonged ischaemia times in partial liver IRI increase liver organ damage. * Gd EOB-DTPA-enhanced MRI at hepatobiliary phase identifies damaged liver volume after hepatic IRI. * Damaged liver parenchyma quantified with MRI correlates with histological liver damage. * Hepatobiliary phase Gd-EOB-DTPA-enhanced MRI enables non-invasive assessment of recovery from liver injury. PMID- 29713783 TI - A high rate of tibial plateau fractures after early experience with patient specific instrumentation for unicompartmental knee arthroplasties. AB - PURPOSE: Patient-specific instrumentation (PSI) for unicompartmental knee arthroplasty (UKA) has been available for a few years. However, limited literature is available on this subject. Hence, the aim of this cohort study is to evaluate the 2 years' results of our first experiences with the use of PSI in UKA. It is hypothesised that there is no advantage in rate of adverse events and in radiological and functional outcomes in comparison to literature on the conventional method. METHODS: This cohort included 129 knees of 122 patients, operated by one surgeon. Outcome measures were the rate of adverse events (AEs); implant position as determined on radiographs; the accuracy of the default and approved planning of the implant sizes and the patient-reported outcome measures (PROMs) preoperatively, and at 3, 12 and 24 months, postoperatively. RESULTS: A total of 6 (4.9%) AEs were observed in this study, with 4 (3.3%) tibial fractures being the main complication. The mean postoperative biomechanical axis was 176.4 degrees and in the majority of cases, the radiographic criteria, as determined by the manufacturer, were met. The tibial component showed 20 (16.4%) outliers in the sagittal and 3 (2.5%) outliers in the frontal plane. There were no outliers of the femoral component. For the femoral and tibial components, respectively, in 125 (96.9%) and 79 (61.7%) cases, there was an agreement between approved planning and implanted component size. All PROMs improved significantly after surgery. CONCLUSION: Tibial fracture was the most common AE, probably related to the transition from cemented to uncemented UKA. Perioperative modifications to the surgical technique were made in order to prevent this AE. Improvements should be made to the operation technique of the uncemented tibial plateau to obtain an adequate placement and at the same time reduce the risk for tibial fracture. The PSI technique was a reliable tool for the placement of the femoral component. Functional outcome was in line with literature on the conventional method. It is strongly recommended that the surgeon approves every preoperative plan, in order to optimise the accuracy during the PSI surgery. LEVEL OF EVIDENCE: III. PMID- 29713784 TI - Limited evidence for adipose-derived stem cell therapy on the treatment of osteoarthritis. AB - PURPOSE: The purpose of this systematic review is to evaluate the effects of adipose derived mesenchymal stem cells (ADSCs) in the treatment of osteoarthritis (OA) in the clinical setting. METHODS: A literature search was performed in the MEDLINE, EMBASE, and The Cochrane Library Database up to January 2017 for inclusion and exclusion criteria. Criteria for inclusion were clinical studies demonstrating the effects of ADSCs on OA, and written in English. The following variables were analyzed: donor site, volume of adipose tissue, preparation of ADSCs, clinical outcomes, and complication rate. RESULTS: Sixteen studies (knee: 14 studies, multiple joints: 1 study, ankle: 1 study) were included in this systematic review. All of the studies prepared ADSCs in the form of the stromal vascular fraction (SVF). Inconsistencies between studies were found with regards to reported clinical variability, donor sites of SVF, and reported clinical outcomes. Nine studies used either platelet-rich plasma (PRP) (7/16) or fibrin (4/16) or both PRP and Fibrin (1/16), as an adjunct at time of SVF injection. All of the studies reported an improvement in clinical outcomes with the use of SVF. Five studies reported a 90% satisfaction rate, and no study reported any complications with liposuction. Five studies reported on complications, with a 5% incidence of swelling and pain. CONCLUSIONS: This systematic review demonstrated that ADSCs are currently used in the form of SVF. While SVF may produce favorable clinical outcomes with minimal risk of side effects on osteoarthritis, the variability in the data and the use of biological adjuvants have confounded the effectiveness of ADSCs. This study will help surgeons understand the limitations in the literature on ADSCs. LEVEL OF EVIDENCE: Level IV, systematic review of level IV studies. PMID- 29713785 TI - Regulation of somatostatin receptor 2 in the context of antidepressant treatment response in chronic mild stress in rat. AB - RATIONALE: The role of somatostatin and its receptors for the stress-related neuropsychiatric disorders has been widely raised. Recently, we have also demonstrated the involvement of somatostatin receptor type 2-sst2R and dopamine receptor type 2-D2R in stress. OBJECTIVE: In this context, we decided to find if these receptors are involved in response to antidepressant treatment in animal model of depression-chronic mild stress (CMS). METHODS: Here, we report data obtained following 7-week CMS procedure. The specific binding of [125I]Tyr3 Octreotide to sst2R and [3H]Domperidone to D2R was measured in the rat brain, using autoradiography. Additionally, the level of dopamine and metabolites was measured in the rat brain. RESULTS: In the final baseline test after 7 weeks of stress, the reduced consumption of sucrose solution was observed (controls vs the stressed animals (6.25 0.16 vs. 10.39 0.41; p < 0.05). Imipramine was administered for the next 5 weeks, and it reversed anhedonia in majority of animals (imipramine-reactive); however, in some animals, it did not (imipramine non-reactive). Two-way repeated measures ANOVA revealed significant effects of stress and treatment and time interaction [F(16, 168) = 3.72; p < 0.0001], n = 10 per groups. We observed decreased binding of [125I]Tyr3-Octreotide in most of rat brain regions in imipramine non-reactive groups of animals. The decrease of D2R after stress in striatum and nucleus accumbens and no effect of imipramine were observed. In the striatum and prefrontal cortex, the significant role of stress and imipramine in dopamine levels was observed. CONCLUSIONS: The results obtained in binding assays, together with dopamine level, indicate the involvement of sst2R receptors for reaction to antidepressant treatment. Besides, the stress context itself changes the effect of antidepressant drug. PMID- 29713786 TI - Interest of new alkylsulfonylhydrazide-type compound in the treatment of alcohol use disorders. AB - RATIONALE: Recent preclinical research suggested that histone deacetylase inhibitors (HDACIs) and specifically class I HDAC selective inhibitors might be useful to treat alcohol use disorders (AUDs). OBJECTIVE: The objective of this study was to find a new inhibitor of the HDAC-1 isoenzyme and to test its efficacy in an animal model of AUDs. METHODS: In the present study, we prepared new derivatives bearing sulfonylhydrazide-type zinc-binding group (ZBG) and evaluated these compounds in vitro on HDAC-1 isoenzyme. The most promising compound was tested on ethanol operant self-administration and relapse in rats. RESULTS: We showed that the alkylsulfonylhydrazide-type compound (ASH) reduced by more than 55% the total amount of ethanol consumed after one intracerebroventricular microinjection, while no effect was observed on motivation of the animals to consume ethanol. In addition, one ASH injection in the central amygdala reduced relapse. CONCLUSIONS: Our study demonstrated that a new compound designed to target HDAC-1 is effective in reducing ethanol intake and relapse in rats and further confirm the interest of pursuing research to study the exact mechanism by which such inhibitor may be useful to treat AUDs. PMID- 29713787 TI - Cognitive profile of ketamine-dependent patients compared with methamphetamine dependent patients and healthy controls. AB - BACKGROUND: Ketamine has emerged as a major substance of abuse worldwide and has been listed with methamphetamine (METH) as two of the most widely available illicit substances in Taiwan. Only a few studies have examined the long-term consequences of chronic and heavy ketamine abuse. We compared the cognitive function of ketamine-dependent patients with that of METH-dependent patients and healthy controls. METHODS: We recruited 165 participants (58 ketamine-dependent and 49 METH-dependent patients who sought treatment and 58 healthy controls) and evaluated them by using a cognitive test battery, the Brief Assessment of Cognition in Schizophrenia, with scores being estimated in reference to normative data in general population. RESULTS: The ketamine-dependent patients had significantly poorer performance than did the controls in many cognitive tests, including verbal memory, motor speed, verbal fluency, and attention and processing speed, and the battery as a whole. METH-dependent patients exhibited poorer function in motor speed, verbal fluency, and attention and processing speed. The ketamine group performed poorer than did METH group in the domains of verbal memory, working memory, and attention and processing speed and the composite battery scores. A previous experience of ketamine-induced psychotomimetic symptoms, using higher doses of ketamine, and longer abstinence appeared to be associated with performance in some tests; however, the significance disappeared after multiple comparison correction. CONCLUSIONS: The ketamine-dependent patients had impaired cognitive function, and METH-dependent patients exhibited intermediate performance between ketamine-dependent patients and healthy controls. Given the growing population of ketamine abusers, public education on the cognitive consequences should be provided. PMID- 29713788 TI - Acute drug effects on habitual and non-habitual responding in crossed high alcohol preferring mice. AB - RATIONALE: Drug reward plays a central role in acquiring drug-seeking behavior. However, subjects may continue using drugs despite negative consequences because self-administration becomes habitual, and divorced from outcome values. Although a history of drug and alcohol use expedite habit acquisition, and in spite of the fact that self-administration leads to intoxication, the acute effects of drugs on habitual responding are not well understood. OBJECTIVES: We sought to observe how acute ethanol and amphetamine affect the balance between habitual and goal directed behavior, as measured by a fluid-reinforced operant conditioning task. METHODS: Selectively bred crossed high-alcohol-preferring (cHAP) mice were trained on an operant conditioning task reinforced on a variable interval schedule with 1% banana solution, which was subsequently devalued via LiCl pairing in half the animals. Ethanol (1.0 g/kg), amphetamine (2.0 mg/kg), or saline was administered prior to a post-devaluation test. RESULTS: Overall, mice showed habitual behavior, but when divided into high- or low-responding groups based on training response rates, saline-treated, low-responding animals devalued, while saline-treated high-responding animals did not. Furthermore, amphetamine elicited devaluation even in high-responding animals, while ethanol prevented devaluation even in low-responding animals. CONCLUSIONS: These data show that ethanol shifts animals toward behaving habitually. This may illuminate why alcohol-intoxicated individuals display impaired judgment about the relative merits of drinking, and potentially serve as a mechanism by which intoxicated subjects resume previously devalued behaviors, such as comorbid drug use. These findings also show that high variable interval response rates facilitate a shift from goal-directed to habitual behavior. PMID- 29713789 TI - An improved within-session self-adjusting delay discounting procedure for the study of choice impulsivity in rats. AB - RATIONALE: Delay-discounting procedures involving choice between small immediate rewards and large delayed rewards are used to study impulsivity in rodents. Improving existing procedures may provide new insights into the neurobiological mechanisms underlying decision-making processes. OBJECTIVES: To develop a novel delay-discounting procedure that adjusts the delay value within individual sessions based on the rat's most recent choices. METHODS: Compared to previously developed procedure, we required a more consistent demonstration of preference, five consecutive choices of the large or small reward, a criterion that is more likely to reflect deliberate choice by the animal, as opposed to two consecutive choices. In addition, delays were changed in steps of 5 s (rather than 1 s), because 5-s increments should be more easily discriminated and may produce a more distinct effect on choice. We characterized the procedure behaviorally by manipulating the duration of the session and the consecutive choice criterion, and we investigated the stability of the behavior upon interruption of training. We also characterized the procedure pharmacologically by investigating the effects of dopaminergic compounds. RESULTS: Our procedures allowed obtaining two complementary measures of delay discounting: (1) the percentage of choices of the delay option and (2) the mean adjusting delay, an index of the delay that animals choose more frequently. We found that our procedure rapidly establishes a baseline of choice behavior that remains stable over time and is highly sensitive to manipulations of the dopaminergic system. CONCLUSIONS: This procedure may provide a useful tool for investigating the neurobiology of inter-temporal choice and decision-making. PMID- 29713791 TI - New concepts in anaerobic digestion processes: recent advances and biological aspects. AB - Waste treatment and the simultaneous production of energy have gained great interest in the world. In the last decades, scientific efforts have focused largely on improving and developing sustainable bioprocess solutions for energy recovery from challenging waste. Anaerobic digestion (AD) has been developed as a low-cost organic waste treatment technology with a simple setup and relatively limited investment and operating costs. Different technologies such as one-stage and two-stage AD have been developed. The viability and performance of these technologies have been extensively reported, showing the supremacy of two-stage AD in terms of overall energy recovery from biomass under different substrates, temperatures, and pH conditions. However, a comprehensive review of the advantages and disadvantages of these technologies is still lacking. Since microbial ecology is critical to developing successful AD, many studies have shown the structure and dynamics of archaeal and bacterial communities in this type of system. However, the role of Eukarya groups remains largely unknown to date. In this review, we provide a comprehensive review of the role, abundance, dynamics, and structure of archaeal, bacterial, and eukaryal communities during the AD process. The information provided could help researchers to select the adequate operational parameters to obtain the best performance and biogas production results. PMID- 29713792 TI - Increasing L-threonine production in Escherichia coli by engineering the glyoxylate shunt and the L-threonine biosynthesis pathway. AB - L-threonine is an important amino acid that can be added in food, medicine, or feed. Here, the influence of glyoxylate shunt on an L-threonine producing strain Escherichia coli TWF001 has been studied. The gene iclR was deleted, and the native promoter of the aceBA operon was replaced by the trc promoter in the chromosome of TWF001, the resulting strainTWF004 could produce 0.39 g L-threonine from1 g glucose after 36-h flask cultivation. Further replacing the native promoter of aspC by the trc promoter in the chromosome of TWF004 resulted in the strain TWF006. TWF006 could produce 0.42 g L-threonine from 1 g glucose after 36 h flask cultivation. Three key genes in the biosynthetic pathway of L-threonine, thrA * (a mutated thrA), thrB, and thrC were overexpressed in TWF006, resulting the strain TWF006/pFW01-thrA * BC. TWF006/pFW01-thrA * BC could produce 0.49 g L threonine from 1 g glucose after 36-h flask cultivation. Next, the genes asd, rhtA, rhtC, or thrE were inserted into the plasmid TWF006/pFW01-thrA * BC, and TWF006 was transformed with these plasmids, resulting the strains TWF006/pFW01 thrA * BC-asd, TWF006/pFW01-thrA * BC-rhtA, TWF006/pFW01-thrA * BC-rhtC, and TWF006/pFW01-thrA * BC-thrE, respectively. These four strains could produce more L-threonine than the control strain, and the highest yield was produced by TWF006/pFW01-thrA * BC-asd; after 36-h flask cultivation, TWF006/pFW01-thrA * BC asd could produce 15.85 g/l L-threonine, i.e., 0.53 g L-threonine per 1 g glucose, which is a 70% increase relative to the control strain TWF001. The results suggested that the combined engineering of glyoxylate shunt and L threonine biosynthesis pathway could significantly increase the L-threonine production in E. coli. PMID- 29713793 TI - Involvement of MaSom1, a downstream transcriptional factor of cAMP/PKA pathway, in conidial yield, stress tolerances, and virulence in Metarhizium acridum. AB - Flo8/Som1, which functions downstream from the cyclic AMP (cAMP)-dependent protein kinase A (PKA) pathway, plays important roles in hyphal development, spore formation, and virulence in yeast and several filamentous fungi. However, the functions of Som1 in entomopathogenic fungi are still a mystery. In this study, MaSom1, a Flo8/Som1 homolog, was identified and functionally characterized in a model entomopathogenic fungus Metarhizium acridum. Similar to Flo8/Som1 in other fungi, MaSom1 mainly localized to the nucleus in M. acridum. Disruption of MaSom1 reduced conidial yield, delayed conidial germination, and impaired the fungal tolerances to heat and UV-B. The expression levels of some genes involved in defenses of heat shock and UV-B radiation were significantly reduced in DeltaMaSom1. MaSom1 is also important for cell wall integrity and conidial surface structures in M. acridum. Some genes related to fungal cell wall synthesis were downregulated in DeltaMaSom1. Bioassays showed that DeltaMaSom1 had a dramatically decreased virulence after both topical inoculation and intrahemocoel injection of the fungus in locusts. Moreover, inactivation of MaSom1 reduced appressorium formation, diminished fungal growth in locust hemolymph in vitro, and enhanced insect immune responses. Taken together, these results indicate that disruption of MaSom1 leads to a decline of fungal virulence because of impairments in conidial germination and appressorium formation, reduction of fungal growth in host hemolymph, and enhancement of insect immune responses owing to the changes in conidial surface structures. PMID- 29713790 TI - Metagenome, metatranscriptome, and metaproteome approaches unraveled compositions and functional relationships of microbial communities residing in biogas plants. AB - The production of biogas by anaerobic digestion (AD) of agricultural residues, organic wastes, animal excrements, municipal sludge, and energy crops has a firm place in sustainable energy production and bio-economy strategies. Focusing on the microbial community involved in biomass conversion offers the opportunity to control and engineer the biogas process with the objective to optimize its efficiency. Taxonomic profiling of biogas producing communities by means of high throughput 16S rRNA gene amplicon sequencing provided high-resolution insights into bacterial and archaeal structures of AD assemblages and their linkages to fed substrates and process parameters. Commonly, the bacterial phyla Firmicutes and Bacteroidetes appeared to dominate biogas communities in varying abundances depending on the apparent process conditions. Regarding the community of methanogenic Archaea, their diversity was mainly affected by the nature and composition of the substrates, availability of nutrients and ammonium/ammonia contents, but not by the temperature. It also appeared that a high proportion of 16S rRNA sequences can only be classified on higher taxonomic ranks indicating that many community members and their participation in AD within functional networks are still unknown. Although cultivation-based approaches to isolate microorganisms from biogas fermentation samples yielded hundreds of novel species and strains, this approach intrinsically is limited to the cultivable fraction of the community. To obtain genome sequence information of non-cultivable biogas community members, metagenome sequencing including assembly and binning strategies was highly valuable. Corresponding research has led to the compilation of hundreds of metagenome-assembled genomes (MAGs) frequently representing novel taxa whose metabolism and lifestyle could be reconstructed based on nucleotide sequence information. In contrast to metagenome analyses revealing the genetic potential of microbial communities, metatranscriptome sequencing provided insights into the metabolically active community. Taking advantage of genome sequence information, transcriptional activities were evaluated considering the microorganism's genetic background. Metaproteome studies uncovered enzyme profiles expressed by biogas community members. Enzymes involved in cellulose and hemicellulose decomposition and utilization of other complex biopolymers were identified. Future studies on biogas functional microbial networks will increasingly involve integrated multi-omics analyses evaluating metagenome, transcriptome, proteome, and metabolome datasets. PMID- 29713794 TI - Comparison of the diagnostic potential of three anti-citrullinated protein antibodies as adjuncts to rheumatoid factor and CCP in a cohort of South African rheumatoid arthritis patients. AB - PURPOSE: A retrospective comparison of the prevalence and diagnostic value of anti-Sa, anti-CEP-1, and anti-MCV autoantibodies relative to those of the established autoantibodies, composite RF and anti-CCP-IgG used routinely for RA diagnosis as a component of the ACR 2010 criteria, in a cohort of disease modifying anti-rheumatic drug naive African RA patients (n = 75). METHODS: Serum concentrations of anti-Sa, anti-CEP-1 and anti-MCV autoantibodies were measured using ELISA procedures, while anti-CCP-IgG antibodies were determined by fluorescence enzyme immunoassay, and composite RF by latex-enhanced laser nephelometry. RESULTS: The seropositivity frequencies of anti-Sa, anti-CEP-1 and anti-MCV antibodies for the RA patients were 82, 72, 85%, respectively, while that of anti-CCP-IgG and RF was 87% for both. Overall, anti-MCV demonstrated the best specificity, positive predictive value (PPV), odds ratio and positive likelihood ratio of all the types of autoantibody tested. CONCLUSION: These observations in this unique cohort of RA patients indicated novel associations of all three autoantibodies in regard to HLA-SE risk alleles, disease severity and tobacco use that were not reported before. Elevated anti-Sa titers designated a propensity of higher disease and high-risk alleles in our cohort. Anti-CEP-1 association with HLA-SE homozygosity and high-risk alleles is also novel in this group. Of note, measurement of anti-MCV antibodies on presentation, either as an adjunctive or even as a stand-alone test, surpassed all other biomarkers investigated here and, therefore, may add value to clinical management. PMID- 29713795 TI - Digital health: a new dimension in rheumatology patient care. AB - The new digital health innovations have opened up several opportunities to help the clinicians, patients and other caregivers of rheumatology healthcare system in maximizing efficiencies resulting in better patient outcomes. In the global context, digital health technology has the potential to bridge the distance gap between all the key stakeholders involved in rheumatology health care. In this review, we update on the recent advances in the field of digital health and highlight unique features of these technologies which would help in routine care. Application of technology in any form to enable, facilitate or enhance the quality of care is the foundation of digitised care. The components could be smartphone apps, sensors, video, social media platforms or messenger platforms, wearables or a combination of these enabling healthcare delivery and overcoming the constraints of distance, location and time. Digital therapeutics have started evolving and an important step in this direction is the involvement of FDA in the approval process. Speciality specific apps, personalised patient education as per disease status, remote specialist consultations or virtual health coach to guide on lifestyle modifications are some of the developments which have been facilitated by increased digitization in all walks of life. Assisted care with the help of robots rendering care in the hospitals or an intelligent robot guiding a patient by voice and visual sense at home are already at the threshold of entering the mainstream of patient care. Wearable devices equipped with powerful sensors are coming handy in keeping a watch on patient symptoms all the time and providing useful insights on disease progression, clinical response or complications. In chronic care such as rheumatology the implications, possibilities and benefits seem unprecedented. Real time data analytics and artificial intelligence are helping the clinicians, healthcare systems and policy makers optimise the resources and improve patient outcomes. Digitization of healthcare has gained momentum in the recent years and it is envisaged that it could be a catalyst to change, bridge the quality of care and most important democratise the healthcare access across the globe. However, more data, efficacy and objective results are needed which would be fulfilled by ongoing observational studies, clinical trials, systematic review and meta-analysis to further establish the role of digital health in the realms of patient care. PMID- 29713797 TI - Whole egg consumption and cortical bone in healthy children. AB - : Eggs contain bioactive compounds thought to benefit pediatric bone. This cross sectional study shows a positive link between childhood egg intake and radius cortical bone. If randomized trials confirm our findings, incorporating eggs into children's diets could have a significant impact in preventing childhood fractures and reducing the risk of osteoporosis. INTRODUCTION: This study examined the relationships between egg consumption and cortical bone in children. METHODS: The cross-sectional study design included 294 9-13-year-old black and white males and females. Three-day diet records determined daily egg consumption. Peripheral quantitative computed tomography measured radius and tibia cortical bone. Body composition and biomarkers of bone turnover were assessed using dual energy X-ray absorptiometry and ELISA, respectively. RESULTS: Egg intake was positively correlated with radius and tibia cortical bone mineral content (Ct.BMC), total bone area, cortical area, cortical thickness, periosteal circumference, and polar strength strain index in unadjusted models (r = 0.144 0.224, all P < 0.050). After adjusting for differences in race, sex, maturation, fat-free soft tissue mass (FFST), and protein intakes, tibia relationships were nullified; however, egg intake remained positively correlated with radius Ct.BMC (r = 0.138, P = 0.031). Egg intake positively correlated with total body bone mineral density, BMC, and bone area in the unadjusted models only (r = 0.119 0.224; all P < 0.050). After adjusting for covariates, egg intake was a positive predictor of radius FFST (beta = 0.113, P < 0.050) and FFST was a positive predictor of Ct.BMC (beta = 0.556, P < 0.050) in path analyses. There was a direct influence of egg on radius Ct.BMC (beta = 0.099, P = 0.035), even after adjusting for the mediator, FFST (beta = 0.137, P = 0.020). Egg intake was positively correlated with osteocalcin in both the unadjusted (P = 0.005) and adjusted (P = 0.049) models. CONCLUSION: If the positive influence of eggs on Ct.BMC observed in this study is confirmed through future randomized controlled trials, whole eggs may represent a viable strategy to promote pediatric bone development and prevent fractures. PMID- 29713796 TI - Is calcifediol better than cholecalciferol for vitamin D supplementation? AB - Modest and even severe vitamin D deficiency is widely prevalent around the world. There is consensus that a good vitamin D status is necessary for bone and general health. Similarly, a better vitamin D status is essential for optimal efficacy of antiresorptive treatments. Supplementation of food with vitamin D or using vitamin D supplements is the most widely used strategy to improve the vitamin status. Cholecalciferol (vitamin D3) and ergocalciferol (vitamin D2) are the most widely used compounds and the relative use of both products depends on historical or practical reasons. Oral intake of calcifediol (25OHD3) rather than vitamin D itself should also be considered for oral supplementation. We reviewed all publications dealing with a comparison of oral cholecalciferol with oral calcifediol as to define the relative efficacy of both compounds for improving the vitamin D status. First, oral calcifediol results in a more rapid increase in serum 25OHD compared to oral cholecalciferol. Second, oral calcifediol is more potent than cholecalciferol, so that lower dosages are needed. Based on the results of nine RCTs comparing physiologic doses of oral cholecalciferol with oral calcifediol, calcifediol was 3.2-fold more potent than oral cholecalciferol. Indeed, when using dosages <= 25 MUg/day, serum 25OHD increased by 1.5 +/- 0.9 nmol/l for each 1 MUg cholecalciferol, whereas this was 4.8 +/- 1.2 nmol/l for oral calcifediol. Third, oral calcifediol has a higher rate of intestinal absorption and this may have important advantages in case of decreased intestinal absorption capacity due to a variety of diseases. A potential additional advantage of oral calcifediol is a linear dose-response curve, irrespective of baseline serum 25OHD, whereas the rise in serum 25OHD is lower after oral cholecalciferol, when baseline serum 25OHD is higher. Finally, intermittent intake of calcifediol results in fairly stable serum 25OHD compared with greater fluctuations after intermittent oral cholecalciferol. PMID- 29713798 TI - Hypocalcemia and bone mineral density changes following denosumab treatment in end-stage renal disease patients: a meta-analysis of observational studies. AB - The incidence of hypocalcemia and bone mineral density (BMD) changes in end-stage renal disease (ESRD) patients on denosumab remains unclear. We performed this meta-analysis to assess the incidence of denosumab-associated hypocalcemia and effects of denosumab on BMD in ESRD patients. A literature search was conducted using MEDLINE, EMBASE, and Cochrane Database from inception through November 2017 to identify studies evaluating incidence of denosumab-associated hypocalcemia and changes in serum calcium, phosphate, alkaline phosphatase (ALP), parathyroid hormone (PTH), and BMD from baseline to post-treatment course of denosumab in ESRD patients. Study results were pooled and analyzed using a random-effect model. The protocol for this meta-analysis is registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42017081074). Six observational studies with a total of 84 ESRD patients were enrolled. The pooled estimated incidence of hypocalcemia during denosumab treatment was 42% (95% CI 29-55%, I2 = 0%). Hypocalcemia occurred approximately 7 to 20 days after the first dose and reached nadir of low calcium levels in the first 2 weeks up to 2 months. However, there were no significant changes in serum calcium or phosphate from baseline to post-treatment course (>= 3 months after treatment) with mean differences [MDs] of 0.20 mg/dL (95% CI, - 0.30 to 0.69 mg/dL) and - 0.10 mg/dL (95% CI, - 0.70 to 0.49 mg/dL). There were significant reductions in ALP and PTH levels with standardized mean differences (SMDs) of - 0.65 (95% CI - 1.13 to - 0.16) and - 1.89 (95% CI - 3.44 to - 0.34), respectively. There were significant increases in T-scores with MDs of 0.39 (95% CI 0.10 to 0.69) and 0.79 (95% CI 0.60 to 0.98) for lumbar spine and femoral neck, respectively. Our study demonstrates the estimated incidence of denosumab-associated hypocalcemia in dialysis patients of 42%. From baseline to post-treatment course, although there are no differences in serum calcium and phosphate, our findings suggest significant reductions in ALP and PTH and a significant increase in BMD. Currently, denosumab should not be considered as the treatment of choice in ESRD patients until more safety and efficacy data are available. PMID- 29713799 TI - Genetic profiling of decreased bone mineral density in an independent sample of Caucasian women. AB - : Genetic risk of low bone mineral density in women remains unclear. This study found that a large percentage of Caucasian women have a high genetic risk of osteoporosis, and genetic risk scores are significantly associated with BMD variation in a bone healthy sample of Caucasian women. INTRODUCTION: We aimed to examine the distribution of risk alleles in an independent sample and to determine if such genetic components are associated with bone mineral density (BMD) variation in the sample. METHODS: Existing genotype data of 1205 women in the cross-sectional Genomic Wide Scans for Female Osteoporosis Gene Study (GWSFO) were analyzed. Multi-loci genetic risk scores (GRSs) based on 62 BMD-associated single nucleotide polymorphisms (SNPs) were calculated. Regression analysis was employed to assess the association between GRSs and BMD. To examine the effect of SNPs clustered within key pathways associated with the development of osteoporosis, subtype weighted GRS specific to WNT signaling (6 SNPs), RANK-RANKL OPG (3 SNPs), and mesenchymal stem differentiation (3 SNPs) were generated for analysis. RESULTS: The unweighted GRS ranged from 48 to 80. One third of the women carried 66% risk alleles. After adjusting for age, height, and body weight, each unit increase of weighted GRS was associated with a decrease in BMD of 0.097 at femur (p < 0.0001) and 0.110 (p < 0.0001) at lumbar spine. The weighted GRS accounted for only 3.17-4.52% of BMD variance. The WNT signaling pathway GRS (6 SNPs) and the RANK-RANKL-OPG signaling pathway GRS (3 SNPs) both were significantly associated with decreased BMD at femur neck (p = 0.0004 and p = 0.0063, respectively) and lumbar spine (p < 0.0001 and p = 0.0001, respectively), while the mesenchymal stem cell differentiation pathway (3 SNPs) GRSs were associated only with the lumbar spine BMD (p = 0.045). CONCLUSIONS: A substantially large percentage of healthy Caucasian women have a high genetic risk of osteoporosis. Weighted GRS was significantly associated with decreased BMD. The contribution of subtype GRS to the BMD variation differs by specific biological pathway and skeletal regions. PMID- 29713800 TI - Effect of flunitrazepam as an oral hypnotic on 24-hour blood pressure in healthy volunteers. AB - PURPOSE: The present study was carried out in order to assess the effects of chronic administration of flunitrazepam (as an oral hypnotic) on 24-h blood pressure (BP) and heart rate (HR) in healthy young adults. MATERIALS AND METHODS: Following a 2-week placebo run-in period, 28 healthy volunteers (13 males and 15 females) between 21 and 30 years were randomized to receive either flunitrazepam 1 mg or placebo (both administered once a day in the evening) for 4 weeks in two cross-over periods; each separated by a 2-week placebo period. At the end of each study period, non-invasive 24-h BP and HR ambulatory monitoring was performed. RESULTS: Flunitrazepam produced a significant decrease in nighttime systolic blood pressure (SBP) (- 6.4 mmHg) and diastolic blood pressure (DBP) (- 4.1 mmHg) (both P < 0.05 vs placebo) without affecting nocturnal HR. During the morning hours, significantly higher values of SBP (+ 7.4 mmHg, P < 0.01), DBP (+ 3.4 mmHg, P < 0.05) and HR (+ 3.9 beats/min, P < 0.05) were observed in the flunitrazepam group compared to the placebo-treated group. No significant differences were noted between the two groups during afternoon and evening hours. CONCLUSIONS: These results suggest that chronic oral administration of 1 mg flunitrazepam as a hypnotic agent causes a significant nocturnal fall in BP and a transient rebound increase of both BP and HR at awakening in the morning. Mechanisms underlying these cardiovascular effects remain unclear, although the direct vasodilatory effect, which is typical of flunitrazepam (with consequent reflex counter-regulatory responses), and the attenuation of baroreflex sensitivity are likely to play a major role. PMID- 29713802 TI - [Prism adaptation test versus long-term prism treatment prior to squint surgery]. PMID- 29713801 TI - Forensic age estimation using computed tomography of the medial clavicular epiphysis: a systematic review. AB - Medicolegal physicians are increasingly called upon to aid in determining the administrative age group affiliation of refugees with questionable unaccompanied minor claims. According to guidelines for forensic age assessment, age differentiation along the 18-year-old cut-off relies on clavicular ossification. The thin-slice computed tomography scan (TSCTs) of the medial clavicular epiphysis (MCE) is one of the methods contributing to this assessment, though it is not yet universally accepted. The aim of this systematic review was to identify scientific papers where age was assessed using TSCTs of the MCE and to observe whether this examination was reproducible and reliable in estimating a person's age relative to the 18-year-old threshold. A search algorithm was applied to several databases to identify articles in accordance with the PRISMA (Preferred Reporting Items for Systematic-Reviews and Meta-Analyses) statement. One boxplot per article was constructed, separating by stage of maturation and sex. The 13 articles selected represented a sample of 5605 individuals (3396 males, 2209 females) aged 10 to 35 years. All individuals classified as stages 4 and 5 were aged 18 years or older. The same result was obtained concerning stage 3c, except in one article. The results thus appear reliable and reproducible, in particular, with respect to the 18-year-old threshold; medicolegal physicians should be able to estimate that all individuals in stages 4 and 5 are at least 18 years old. Additional studies applied to several other populations in the world should complement the selected studies. PMID- 29713803 TI - [Bartonella neuroretinitis : An atypical manifestation of cat scratch disease]. AB - Cat scratch disease (CSD) typically manifests as a febrile lymphadenopathy and is caused by a Bartonella henselae infection after contact with cats. This article describes the case of an atypical presentation of CSD in a 52-year-old patient with acute unilateral loss of vision and headache without fever or lymphadenopathy. Funduscopic examination showed an optic disc swelling and macular star exsudates, pathognomonic for infectious neuroretinitis. A Bartonella henselae infection was confirmed serologically. Systemic antibiotic combination therapy was initiated with doxycycline and rifampicin for 6 weeks resulting in good morphological and functional results. A Bartonella neuroretinitis should be considered in the differential diagnosis of patients with loss of vision and papilledema, even in the absence of fever or lymphadenopathy. Immediate serological testing and initiation of antibiotics are important for the outcome. PMID- 29713804 TI - [Deep learning to support therapy decisions for intravitreal injections]. AB - Significant progress has been made in artificial intelligence and computer vision research in recent years. Machine learning methods excel in a wide variety of tasks where sufficient data are available. We describe the application of a deep convolutional neural network for the prediction of treatment indication with anti vascular endothelial growth factor (VEGF) medications based on central retinal optical coherence tomography (OCT) scans. The neural network classifier was trained with OCT images acquired during routine treatment at the University of Regensburg over the years 2008-2016. In over 95% of the cases the treatment indication was accurately predicted based on a singular OCT B scan without human intervention. Despite promising classification the results of deep learning techniques, should always be controlled by the treating physician because false classification can never be excluded due to the probabilistic nature of the method. PMID- 29713805 TI - [Controversies in prisma pretreatment prior to squint surgery]. PMID- 29713806 TI - An inducible MAO-B mouse model of Parkinson's disease: a tool towards better understanding basic disease mechanisms and developing novel therapeutics. AB - Several studies have suggested that increases in astrocytic monoamine oxidase B (MAO-B) levels in conjunction with Parkinson's disease (PD) may contribute to subsequent neuropathology associated with the disorder. MAO-B inhibitors are currently widely used as symptomatic therapeutics for PD and, although somewhat controversial, these drugs may also exhibit disease-modifying properties. To obtain a better understanding of the potential role of MAO-B in disease neuropathology, we created an inducible astrocyte-specific transgenic MAO-B mouse model. Here, we summarize findings associated with this model, including neuropathological PD features associated with it. PMID- 29713807 TI - Throughfall, stemflow, and interception characteristics of coniferous forest ecosystems in the western black sea region of Turkey (Daday example). AB - This study aims to identify precipitation, throughfall, stemflow, precipitation, and interception processes in pure black pine, pure Scots pine, and mixed black pine-Scots pine forest ecosystems and present the precipitation partitioning according to different stand types. Throughfall and stemflow measurements were performed using five standard precipitation gauges in a pilot area established to represent pure black pine, pure Scots pine, and mixed black pine-Scots pine stands in the Bezirgan Basin. The total precipitation was measured in an open field close to the study area. Throughfall values were calculated as the percentage of precipitation measured in an open field. According to the results of the study, the throughfall values were 69.8% in black pine, 73.9% in Scots pine, and 77.7% in the mixed black pine-Scots pine stands; the stemflow values were 2.6% in black pine, 5.9% in Scots pine, and 3.1% in the mixed black pine Scots pine stands; the amounts of precipitation reaching the forest floor were 72.3% in black pine, 79.8% in Scots pine, and 80.7% in the mixed black pine-Scots pine stands; and the interception values were found to be 27.7% in black pine, 20.2% in Scots pine, and 19.2% in the mixed black pine-Scots pine stands. PMID- 29713808 TI - A matter of proportion? Associational effects in larval anuran communities under fish predation. AB - In Batesian mimicry, a species lacking defences against predators benefits from mimicking the aposematic signal of a defended species, while the model may incur the costs of reduced defensive efficacy. Similar reciprocal indirect effects may emerge even when the signal is not mimicked; termed associational effects, such interactions are well known in plants sharing herbivores but have received little attention in animal studies. We investigated associational interactions in a system where unequally defended prey (chemically defended Bufo bufo and undefended Rana temporaria tadpoles), sharing general morphology but not an aposematic signal, were exposed to predation by the carp Cyprinus carpio along a gradient of relative prey abundance. In the absence of fish, the assemblage composition had no effect on the survival of Rana, while that of Bufo decreased with increasing abundance of Rana. Fish reduced the survival of tadpoles from both species. However, increased relative abundance of Bufo in the community led to enhanced survival in both Bufo and Rana. Increasing relative proportions of heterospecifics reduced metamorph mass only in Bufo, indicating greater sensitivity to interspecific competition compared to Rana; the effect was reduced in the presence of fish. Our results show that undefended non-mimetic prey enjoy reduced predation with increasing relative abundance of chemically defended prey, which in turn suffer greater mortality with an increasing proportion of the undefended species. Associational resistance/susceptibility, driven by current assemblage composition, not by selection for resemblance, can shape the dynamics of mixed communities of defended and undefended prey in the absence of mimicry. PMID- 29713809 TI - Environmental fate and effect of biodegradable electro-spun scaffolds (biomaterial)-a case study. AB - Poly-epsilon-caprolactone (PCL) based medical devices are increasingly produced and thus, their presence in the environment is likely to increase. The present study analysed the biodegradation of PCL electro-spun scaffolds (alone) and PCL electro-spun scaffolds coated with human recombinant (hR) collagen and Bovine Achilles tendon (BAT) collagen in sewage sludge and in soil. Additionally, an eco toxicological test with the model organism Enchytraeus crypticus was performed to assess environmental hazard of the produced materials in soils. The electro-spun scaffolds were exposed to activated sludge and three different soils for various time periods (0-7-14-21-28-56-180 days); subsequently the degradation was determined by weight loss and microscopical analysis. Although no toxicity occurred in terms of Enchytraeus crypticus reproduction, our data indicate that biodegradation was dependent on the coating of the material and exposure condition. Further, only partial PCL decomposition was possible in sewage treatment plants. Collectively, these data indicate that electro-spun PCL scaffolds are transferred to amended soils. PMID- 29713811 TI - Timing and documentation of key events in neonatal resuscitation. AB - : Only a minority of babies require extended resuscitation at birth. Resuscitations concerning babies who die or who survive with adverse outcomes are increasingly subject to medicolegal scrutiny. Our aim was to describe real-life timings of key resuscitation events observed in a historical series of newborns who required full resuscitation at birth. Twenty-seven babies born in our centre over a 10-year period had an Apgar score of 0 at 1 min and required full resuscitation. The median (95% confidence interval) postnatal age at achieving key events were commencing cardiac compressions, 2.0 (1.5-4.0) min; endotracheal intubation, 3.8 (2.0-6.0) min; umbilical venous catheterisation 9.0 (7.5-12.0) min; and administration of first adrenaline dose 10.0 (8.0-14.0) min. CONCLUSION: The wide range of timings presented from real-life cases may prove useful to clinicians involved in medical negligence claims and provide a baseline for quality improvements in resuscitation training. What is Known: * Only a minority of babies require extended resuscitation at birth; these cases are often subject to medicolegal interrogation * Timings of key resuscitation events are poorly described and documentation of resuscitation events is often lacking yet is open to medicolegal scrutiny What is New: * We present a wide range of real-life timings of key resuscitation events during the era of routine newborn life support training * These timings may prove useful to clinicians involved in medical negligence claims and provide a baseline for quality improvements in resuscitation training. PMID- 29713810 TI - The Role of Interleukin-10 in the Pathophysiology of Preeclampsia. AB - PURPOSE OF REVIEW: The pathophysiology of preeclampsia is complex and not entirely understood. A key feature in preeclampsia development is an immunological imbalance that shifts the maternal immune response from one of tolerance towards one promoting chronic inflammation and endothelial dysfunction. As a key regulator of immunity, IL-10 not only has immunomodulatory activity, but also directly benefits vasculature and promotes successful cellular interactions at the maternal-fetal interface. Here we focus on the mechanisms by which the dysregulation of IL-10 may contribute to the pathophysiology of preeclampsia. RECENT FINDINGS: Dysregulation of IL-10 has been demonstrated in various animal models of preeclampsia. Decreased IL-10 production in both placenta and peripheral blood mononuclear cells has been reported in human studies, but with inconsistent results. The significance of IL-10 in preeclampsia has shifted from a key biomarker to one with therapeutic potential. As such, a better understanding of the role of this cytokine in the pathophysiology of preeclampsia is of paramount importance. PMID- 29713812 TI - Undocumented children in the Amsterdam region: an analysis of health, school, and living circumstances. AB - : Undocumented migrants are people who do not have a valid residence permit. There are only estimates about how many undocumented migrants are living in the European Union; the number of children among them is unclear. Studies about undocumented children are scarce and little is known about their living situation and their access to health care. Therefore, we aimed to estimate the number of undocumented children in the population of visitors of our primary care clinic for undocumented patients. Moreover, we explored whether these children's rights with respect to health care, education, and living circumstances were met. All undocumented adult patients visiting the clinic between September 1, 2016 and December 31, 2016 received a questionnaire. In total, 267 undocumented adults responded; 30% of them had children, and 15% had one or more undocumented children living in the Netherlands. Eleven percent of those undocumented children did not attend school, 17% was not vaccinated, 83% did not have a general practitioner, and 30% did not have a permanent place of residence. CONCLUSION: There are probably a considerable number of undocumented children in the Netherlands; our study estimated a percentage of 17% of the undocumented population. Not all their basic human rights are met; more awareness among people involved with child and health policies is needed. What is Known: * There are only estimates of the number of undocumented migrants in the European Union, the number of children among them is not clear. * Studies about undocumented children are scarce and little is known about their living circumstances and access to health care. What is New: * A substantial number of undocumented children do not go to school, are not vaccinated, and do not have a general practitioner. * The hidden group of undocumented children, whose basic human rights are not met, need special attention when they or their caregivers present at a health care facility. PMID- 29713813 TI - Gastrointestinal complications after lung transplantation in Japanese patients. AB - PURPOSE: Gastrointestinal complications after lung transplantation (LTx) are an important postoperative morbidity associated with malnutrition and the malabsorption of drugs. We reviewed our experience of managing gastrointestinal complications after LTx. METHODS: Between June, 2008 and April, 2017, 160 lung transplants were performed at our institution, as living-donor lobar lung transplants in 77 patients, and as deceased-donor lung transplants in 83. We reviewed, retrospectively, the incidence, type and management of gastrointestinal complications. RESULTS: Among the 160 LTx recipients, 58 (36.3%) suffered a collective 70 gastrointestinal complications, the most frequent being gastroparesis, followed by gastroesophageal reflux disease. Two complications were managed surgically, by Nissen fundoplication for gastroesophageal reflux disease in one recipient and Hartmann's operation for sigmoid colon perforation in one. The other 68 complications were managed medically. Two patients died of complications: one, of aspiration pneumonia caused by gastroparesis; and one, of panperitonitis caused by a gastric ulcer. There were no significant differences in overall survival or chronic lung allograft dysfunction-free survival between the patients with and those without gastrointestinal complications. CONCLUSIONS: Gastrointestinal complications are not uncommon in LTx recipients and may be serious; therefore, early detection and appropriate treatment are imperative. Surgical management is required for some complications, but most can be managed medically. PMID- 29713814 TI - Prenatal intervention for the management of congenital diaphragmatic hernia. AB - Congenital diaphragmatic hernia (CDH) is the result of incomplete formation of the diaphragm that occurs during embryogenesis. The defect in the diaphragm permits the herniation of abdominal organs into the thoracic cavity contributing to the impairment of normal growth and development of the fetal lung. In addition to the hypoplastic lung, anomalies of the pulmonary arterioles worsen the pulmonary hypertension that can have detrimental effects in severe cases. Most cases of CDH can be effectively managed postnatally. Advances in neonatal and surgical care have resulted in improved outcomes over the years. When available, extracorporeal membrane oxygenation can provide temporary cardiorespiratory support for those not effectively supported by mechanical ventilation. In spite of these advances, very severe cases of CDH still carry a very high mortality and morbidity rate. Advances in imaging and evaluation now allow for early and accurate prenatal diagnosis of CDH, thereby identifying those at greatest risk who may benefit from prenatal intervention. This review article discusses some of the surgical and non-surgical prenatal interventions in the management of isolated severe congenital diaphragmatic hernia. PMID- 29713815 TI - Regular voluntary running has favorable histological effects on doxorubicin induced kidney toxicity in Wistar rats. AB - Knowing the therapeutic effects of regular physical exercise on kidney toxicity induced by a single dose of doxorubicin (DOX) in animal models, the aim of this study is to verify the effectiveness of regular voluntary running on kidney histology after a prolonged DOX administration, mimicking a chemotherapy protocol. Thirty-four male Wistar rats were randomly divided into two clusters: DOX (n = 17) and SSS (sterile saline solution, n = 17), receiving a weekly intraperitoneal injection of DOX (2 mg/kg) or vehicle for 7 weeks, respectively. Two weeks after the last injection, five animals from each cluster (SSSG, n = 5; DOXG, n = 5) were euthanized, while the remaining ones were divided into sedentary (DOXsed, n = 6; SSSsed, n = 6) and active subgroups (DOXact, n = 6; SSSact, n = 6). Active animals were placed individually in cages with a running wheel for regular voluntary activity. After 2 months, the animals were euthanized and kidneys were histologically examined. Compared to SSSG, kidneys from DOXG revealed higher levels of damage, more collagen content and thickening of Bowman's capsule (p < .05). The levels of damage and thickness of Bowman's capsule increased in DOXsed as compared to DOXG (p < .05). Compared to DOXsed, the DOXact presented an overall improvement in kidney structure (p < .05), with a decrease in collagen content and of the thickness of Bowman's capsule. The results allow concluding that regular voluntary running attenuate the long-term harmful effects on kidney structure induced by a prolonged DOX treatment. These results, supporting the potential benefit of physical activity in patients under DOX treatment, need to be tested in humans. PMID- 29713816 TI - Comparison between wide-angle OCT angiography and ultra-wide field fluorescein angiography for detecting non-perfusion areas and retinal neovascularization in eyes with diabetic retinopathy. AB - PURPOSE: To compare the ability of wide-angle optical coherence tomography angiography (OCTA) with that of ultra-wide field fluorescein angiography (UWFFA) to detect non-perfusion areas (NPAs) or retinal neovascularization (NV) in eyes with diabetic retinopathy (DR). METHODS: Patients with DR underwent UWFFA using the Optos(r) panoramic 200Tx imaging system and wide-angle OCTA with 12 * 12 mm fields of five visual fixations using the PLEX Elite 9000(r). We compared the abilities of UWFFA and OCTA to detect NPAs and NV. RESULTS: Fifty-eight eyes of 33 patients (mean age, 60.0 years old; female/male, 16/17) with DR were evaluated. NPAs were detected in 47 out of 58 eyes using UWFFA and in 48 eyes using OCTA. NVs were detected in 25 out of the 58 eyes using UWFFA and in 26 eyes using OCTA. The sensitivity for detection of NPA using OCTA was 0.98, and the specificity was 0.82. The sensitivity for detection of NV was 1.0, and the specificity was 0.97. CONCLUSION: The wide-angle OCTA seems to be clinically useful for the detection of NPAs or NV. PMID- 29713817 TI - 23G pars plana vitrectomy for vitreal floaters: prospective assessment of subjective self-reported visual impairment and surgery-related risks during the course of treatment. AB - PURPOSE: Quantifying the subjective impairment due to floaters based on an indication-specific questionnaire and setting its change between prior to and 3/12 months after elective vitrectomy in relation to surgical risks. METHODS: Single-arm longitudinal observational multicenter study. Sixty-four floater patients underwent 23G pars plana vitrectomy; simultaneous phacoemulsification was excluded. An overall self-rated impairment index (SRI) and sub-indices SRI were calculated on the basis of a modified Visual Quality of Life questionnaire (VQoL), which addresses general vision, glare, near-sight problems and mobility of floaters. SRI ranged from 0 to 100% (maximum impairment). Secondary endpoints included corrected visual acuity and complications. RESULTS: Data were collected prior to and 3 (n = 64) and 12 (n = 62) months after surgery. The median overall SRI improved (44, 12, 11%) with a statistically significant median reduction of 69% (95% confidence interval 50-89%) 3 months postop. The median sub-SRIs improved for glare (50, 17, 17%), near sight problems (50, 17, 8%), and mobility of floaters (43, 5, 0%). Sixteen eyes needed cataract surgery during follow-up (10 showed cataract already prior to vitrectomy). Eight complications were reported (6 intra-operative retinal holes, 2 post-operative retinal detachments). CONCLUSION: For the majority of floater patients, subjective impairment was profoundly reduced by vitrectomy. Benefits of surgery prevailed despite complications. PMID- 29713818 TI - Right ventriculo-arterial uncoupling and impaired contractile reserve in obese patients with unexplained exercise intolerance. AB - BACKGROUND: Right ventricular (RV) dysfunction and heart failure with preserved ejection fraction may contribute to exercise intolerance in obesity. To further define RV exercise responses, we investigated RV-arterial coupling in obesity with and without development of exercise pulmonary venous hypertension (ePVH). METHODS: RV-arterial coupling defined as RV end-systolic elastance/pulmonary artery elastance (Ees/Ea) was calculated from invasive cardiopulmonary exercise test data in 6 controls, 8 obese patients without ePVH (Obese-ePVH) and 8 obese patients with ePVH (Obese+ePVH) within a larger series. ePVH was defined as a resting pulmonary arterial wedge pressure < 15 mmHg but >= 20 mmHg on exercise. Exercise haemodynamics were further evaluated in 18 controls, 20 Obese-ePVH and 17 Obese+ePVH patients. RESULTS: Both Obese-ePVH and Obese+ePVH groups developed exercise RV-arterial uncoupling (peak Ees/Ea = 1.45 +/- 0.26 vs 0.67 +/- 0.18 vs 0.56 +/- 0.11, p < 0.001, controls vs Obese-ePVH vs Obese+ePVH respectively) with higher peak afterload (peak Ea = 0.31 +/- 0.07 vs 0.75 +/- 0.32 vs 0.88 +/- 0.62 mL/mmHg, p = 0.043) and similar peak contractility (peak Ees = 0.50 +/- 0.16 vs 0.45 +/- 0.22 vs 0.48 +/- 0.17 mL/mmHg, p = 0.89). RV contractile reserve was highest in controls (DeltaEes = 224 +/- 80 vs 154 +/- 39 vs 141 +/- 34% of baseline respectively, p < 0.001). Peak Ees/Ea correlated with peak pulmonary vascular compliance (PVC, r = 0.53, p = 0.02) but not peak pulmonary vascular resistance (PVR, r = - 0.20, p = 0.46). In the larger cohort, Obese+ePVH patients on exercise demonstrated higher right atrial pressure, lower cardiac output and steeper pressure-flow responses. BMI correlated with peak PVC (r = - 0.35, p = 0.04) but not with peak PVR (r = 0.24, p = 0.25). CONCLUSIONS: Exercise RV arterial uncoupling and reduced RV contractile reserve further characterise obesity-related exercise intolerance. RV dysfunction in obesity may develop independent of exercise LV filling pressures. PMID- 29713819 TI - Evaluation of the risk factors for ventricular arrhythmias secondary to QT prolongation induced by papaverine injection during coronary flow reserve studies using a 4 Fr angio-catheter. AB - Estimation of the fractional flow reserve (FFR) is considered to be an established method by which to assess stable coronary artery stenosis. Induction of maximal coronary hyperemia is important during the FFR procedure. Papaverine has been reported to increase the risk of ventricular arrhythmia (VA). The purpose of the present study was to discover predictors of papaverine-induced VAs developing during FFR measurement. A total of 213 clinically stable patients were included in the study. FFRs were determined after intracoronary papaverine administration (12 mg into the left and 8 mg into the right coronary arteries). We compared patients in whom VA did and did not develop in terms of clinical and electrocardiogram characteristics. FFR measurements were performed on 244 lesions (133 in the left anterior descending arteries, 43 in the left circumflex arteries, and 68 in the right coronary arteries). We found that the QTc interval was prolonged in all patients after papaverine administration (average post administration QTc interval = 569 +/- 89 ms; average DeltaQTc interval = 144 +/- 80 ms). VA developed in three patients with significantly prolonged QT intervals (average post-administration QTc interval = 639 +/- 19 ms, average DeltaQTc interval = 220 +/- 64 ms, p < 0.02) and transitioned from torsade de pointes to ventricular fibrillation. Bradycardia (< 50 beats/min), hypokalemia (serum K < 3.5 mEp/L), and low left ventricular function (ejection fraction (EF) < 50%) were associated with VA (bradycardia, p < 0.01; hypokalemia, p < 0.01; low left ventricular function, p < 0.01). Three-vessel disease was significantly predictive of VA (p < 0.003). In the three-vessel group, the complications of low left ventricular function, hypokalemia, and bradycardia were significantly associated with VA (p < 0.045). Three-vessel disease is a predictor of the development of VA during FFR measurement performed with the aid of papaverine, especially if accompanied by one or more of the following: low left ventricular function, hypokalemia, or bradycardia. PMID- 29713820 TI - Diagnostic value of electrocardiographic P-wave characteristics in atrial fibrillation recurrence and tachycardia-induced cardiomyopathy after catheter ablation. AB - Abnormal P-wave characteristics were reportedly associated with left ventricular interstitial fibrosis as defined by cardiac magnetic resonance images. The objective of this study is to investigate the utility of P-wave characteristics to predict atrial fibrillation (AF) recurrence and the recovery of left ventricular systolic dysfunction (LVSD) after catheter ablation (CA) for AF. Two hundred and five AF patients (109 paroxysmal and 96 persistent) who underwent CA were enrolled. We measured maximum P-wave duration (max PWD) and P-wave terminal force in lead V1 (PTFV1) calculated as a product of P-wave terminal amplitude (PTaV1) and duration (PTdV1) in lead V1 during sinus rhythm. AF recurrence was noted in 50 patients at 12 months after CA. Patients with AF recurrence had a higher prevalence of persistent AF, a larger left atrial volume, and a longer max PWD than those without. We divided the patients into 2 groups: 156 patients with left ventricular ejection fraction (LVEF) > 45% and 49 patients with LVEF <= 45% (Low-EF group). In Low-EF group, tachycardia-induced cardiomyopathy (TIC) was defined as improvement in LVEF >= 15% or LVEF >= 50% at 5 months after CA. TIC and non-TIC groups consisted of 37 and 12 patients, respectively. Max PWD, PTFV1, PTdV1, and PTaV1 were significantly greater in non-TIC-group than in TIC-group. PTFV1 had the highest diagnostic accuracy to discriminate between TIC and no-TIC groups; cut-off value for PTFV1 was determined as 56.7 mV ms (area under the ROC curve = 0.80; 75% sensitivity; and 76% specificity). Max PWD was a useful predictor of AF recurrence and the complete recovery of LVSD after CA. PTFV1 had the highest diagnostic accuracy to discriminate between TIC and no-TIC-groups. PMID- 29713821 TI - Marine-influenced microbial communities inhabit terrestrial hot springs on a remote island volcano. AB - Raoul Island is a subaerial island volcano approximately 1000 km northeast of New Zealand. Its caldera contains a circumneutral closed-basin volcanic lake and several associated pools, as well as intertidal coastal hot springs, all fed by a hydrothermal system sourced from both meteoric water and seawater. Here, we report on the geochemistry, prokaryotic community diversity, and cultivatable abundance of thermophilic microorganisms of four terrestrial features and one coastal feature on Raoul. Hydrothermal fluid contributions to the volcanic lake and pools make them brackish, and consequently support unusual microbial communities dominated by Planctomycetes, Chloroflexi, Alphaproteobacteria, and Thaumarchaeota, as well as up to 3% of the rare sister phylum to Cyanobacteria, Candidatus Melainabacteria. The dominant taxa are mesophilic to moderately thermophilic, phototrophic, and heterotrophic marine groups related to marine Planctomycetaceae. The coastal hot spring/shallow hydrothermal vent community is similar to other shallow systems in the Western Pacific Ocean, potentially due to proximity and similarities of geochemistry. Although rare in community sequence data, thermophilic methanogens, sulfur-reducers, and iron-reducers are present in culture-based assays. PMID- 29713822 TI - Improving Viscosity and Stability of a Highly Concentrated Monoclonal Antibody Solution with Concentrated Proline. AB - PURPOSE: To explain the effects of the osmolyte proline on the protein-protein interactions (PPI), viscosity and stability of highly concentrated antibody solutions in contrast to other neutral osmolytes. METHODS: The viscosity of ~225 mg/mL mAb solutions was measured with proline, glycine and trehalose as a function of pH and co-solute concentration up to 1.3 M. The stability was assessed via turbidity as well as size exclusion chromatography after 4 weeks storage at 40 degrees C. The PPI strength was assessed qualitatively via the high concentration diffusion rate by dynamic light scattering. RESULTS: Increasing proline significantly reduced the mAb viscosity and increased the colloidal stability at pH 6, but not at pH 5 further from the mAb pI. In contrast, glycine and trehalose did not improve the viscosity nor stability. The normalized diffusion coefficient at high concentration, which is inversely proportional to the attractive PPI strength, increased with proline concentration but decreased with increasing glycine. CONCLUSIONS: Proline demonstrated greater efficacy for improving mAb viscosity and stability in contrast to glycine and trehalose due to its amphipathic structure and partial charge on the pyrrolidine side chain. These properties likely allow proline to screen the attractive electrostatic and hydrophobic interactions that promote self-association and high viscosities. Binary proline-histidine formulations also demonstrated greater viscosity reduction effects than histidine alone at the same total co-solute concentration, while maintaining a lower total solution osmolarity. PMID- 29713823 TI - Higher visceral fat area/subcutaneous fat area ratio measured by computed tomography is associated with recurrence and poor survival in patients with mid and low rectal cancers. AB - PURPOSE: Obesity is thought to influence postoperative complications and recurrence of mid and low rectal cancer (MLRC) because of intraoperative technical difficulties. However, few reports have described the relationship between obesity indices and the clinical outcomes of MLRC. This study aimed to investigate the association between visceral obesity on computed tomography (CT) and oncolofical outcomes after surgery for MLRC and identify the obesity index that most accurately reflects clinical outcomes. METHODS: We investigated 125 patients who underwent curative resection for MLRC between 2004 and 2010. Visceral fat area (VFA) was defined as the umbilicus-level intra-abdominal adipose tissue area measured by CT. Body mass index (BMI), total fat area, VFA, subcutaneous fat area (SFA) and VFA/SFA ratio (V/S ratio) were analysed. RESULTS: The median follow-up time was 60.3 months (range, 38.2-122.6 months). Recurrence was detected in 28 (22.4%) patients. Among the various obesity indices, recurrence was significantly associated with V/S ratio only (1.02 +/- 0.45 versus 0.86 +/- 0.34; P = 0.046). Stage, preoperative carcinoembryonic antigen level, V/S ratio, lymphatic invasion and perineural invasion were significantly associated with recurrence on univariate analysis, while only V/S ratio (P = 0.019; 95% confidence interval, 1.22 to 9.09) was significantly associated with recurrence on multivariate analysis. Disease-free and overall survival of the obese group (V/S ratio > 1.0) were shorter than those of the non-obese group. CONCLUSIONS: V/S ratio is the optimal obesity index for predicting stage I-III MLRC recurrence. PMID- 29713824 TI - George Huntington (1850-1916). PMID- 29713825 TI - Reduced retinal nerve fiber layer (RNFL) thickness in ALS patients: a window to disease progression. AB - OBJECTIVES: To assess RNFL thickness in ALS patients and compare it to healthy controls, and to detect possible correlations between RNFL thickness in ALS patients and disease severity and duration. METHODS: Study population consisted of ALS patients and age- and sex-matched controls. We used the revised ALS functional rating scale (ALSFRS-R) as a measure of disease severity. RNFL thickness in the four quadrants were measured with a spectral domain OCT (Topcon 3D, 2015). RESULTS: We evaluated 20 ALS patients (40 eyes) and 25 healthy matched controls. Average RNFL thickness in ALS patients was significantly reduced compared to controls (102.57 +/- 13.46 compared to 97.11 +/- 10.76, p 0.04). There was a significant positive correlation between the functional abilities of the patients based on the ALSFRS-R and average RNFL thickness and also RNFL thickness in most quadrants. A linear regression analysis proved that this correlation was independent of age. In ALS patients, RNFL thickness in the nasal quadrant of the left eyes was significantly reduced compared to the corresponding quadrant in the right eyes even after adjustment for multiplicity (85.80 +/- 23.20 compared to 96.80 +/- 16.96, p = 0.008). CONCLUSION: RNFL thickness in ALS patients is reduced compared to healthy controls. OCT probably could serve as a marker of neurodegeneration and progression of the disease in ALS patients. RNFL thickness is different among the right and left eyes of ALS patients pointing to the fact that asymmetric CNS involvement in ALS is not confined to the motor system. PMID- 29713826 TI - Pathologic significance of AKT, mTOR, and GSK3beta proteins in oral squamous cell carcinoma-affected patients. AB - Phosphatidylinositol-3-kinases are kinases that lead to AKT phosphorylation and thus mTOR and GSK3beta activation. These proteins are linked to tumorigenesis, but their roles in driving cervical lymph node (CLN) metastasis of oral squamous cell carcinoma (OSCC) cells are unknown. This study aimed to investigate the role of AKT, mTOR, and GSK3beta proteins in the occurrence of CLN metastasis in OSCC patients. Ninety and 18 paraffin-embedded OSCC and oral mucosa samples were included, respectively. We divided our OSCC patients into non-metastasizing (PNM) and metastasizing (PM) groups, and the expression of total AKT, pAKT1Thr308, pAKTSer473, GSK3beta, pGSK3betaSer9, and pmTORSer2448 was analyzed by immunohistochemistry. The mean expression of GSK3beta, pGSK3betaSer9, total AKT, and pmTOR2448 was always higher in the OSCC tissues than that in the controls. A positive correlation was also found among these proteins. Total AKT, pmTORSer2448, and pGSK3betaSer9 expression was significantly higher in the PNM and PM groups than that in the control group. However, only GSK3beta expression was significantly higher in the PM group compared with the PNM group. High expression levels of GSK3beta and pGSK3betaSer9 were significantly associated with CLN metastasis, but only GSK3beta remained an independent predictor of CLN metastasis. pGSK3betaSer9 and CLN metastasis were associated with a poor prognosis, but only the latter remained an independent prognostic parameter. Kaplan-Meier survival curves showed that pGSK3betaSer9 and CLN metastasis were significantly related to reduced survival rates. These results suggest that AKT and mTOR proteins are involved in OSCC biology and that GSK3beta itself may drive CLN metastatic spread of OSCC cells. PMID- 29713828 TI - A Novel Feature Level Fusion for Heart Rate Variability Classification Using Correntropy and Cauchy-Schwarz Divergence. AB - Heart rate variability (HRV) analysis has become a widely used tool for monitoring pathological and psychological states in medical applications. In a typical classification problem, information fusion is a process whereby the effective combination of the data can achieve a more accurate system. The purpose of this article was to provide an accurate algorithm for classifying HRV signals in various psychological states. Therefore, a novel feature level fusion approach was proposed. First, using the theory of information, two similarity indicators of the signal were extracted, including correntropy and Cauchy-Schwarz divergence. Applying probabilistic neural network (PNN) and k-nearest neighbor (kNN), the performance of each index in the classification of meditators and non meditators HRV signals was appraised. Then, three fusion rules, including division, product, and weighted sum rules were used to combine the information of both similarity measures. For the first time, we propose an algorithm to define the weights of each feature based on the statistical p-values. The performance of HRV classification using combined features was compared with the non-combined features. Totally, the accuracy of 100% was obtained for discriminating all states. The results showed the strong ability and proficiency of division and weighted sum rules in the improvement of the classifier accuracies. PMID- 29713829 TI - Bariatric surgery increases risk of bone fracture. AB - INTRODUCTION: The purpose of this study was to determine the long-term incidence of bone fracture after bariatric surgery, identify specific risk factors for fracture, and compare these data to baseline risk in a comorbidity-matched morbidly obese population. We hypothesize that, despite prior studies with conflicting results, bariatric surgery increases a patient's long-term risk of fracture. METHODS: All patients who underwent bariatric surgery at a single institution 1985-2015 were reviewed. Univariate analysis of patient demographic data including comorbidities, insurance payer status, procedure type, and BMI was performed. Multivariate logistic regression was used to identify independent predictors of fracture in this population. Finally, we identified a propensity matched control group of morbidly obese patients from our institutional Clinical Data Repository in the same timeframe who did not undergo bariatric surgery to determine expected rate of fracture without bariatric surgery. RESULTS: A total of 3439 patients underwent bariatric surgery, with 220 (6.4%) patients experiencing a bone fracture at mean follow-up of 7.6 years. On multivariate logistic regression, independent predictors of increased fracture included tobacco use and Roux-en-Y gastric bypass while private insurance and race were protective (table). Additionally, 1:1 matching on all comorbidity and demographic factors identified 3880 patients (1940 surgical patients) with equal propensity to undergo bariatric surgery. Between the propensity-matched cohorts, patients who had a history of bariatric surgery were more than twice as likely to experience a fracture as those who did not (6.4 vs. 2.7%, p < 0.0001). CONCLUSIONS: This study of bariatric surgery patients at our institution identified several independent predictors of postoperative fracture. Additionally, these long-term data demonstrate patients who had bariatric surgery are at a significantly increased risk of bone fracture compared to a propensity matched control group. Future efforts need to focus on nutrient screening and risk modification to reduce the impact of this long-term complication. PMID- 29713830 TI - Developments and Control of Biocompatible Conducting Polymer for Intracorporeal Continuum Robots. AB - Dexterity of robots is highly required when it comes to integration for medical applications. Major efforts have been conducted to increase the dexterity at the distal parts of medical robots. This paper reports on developments toward integrating biocompatible conducting polymers (CP) into inherently dexterous concentric tube robot paradigm. In the form of tri-layer thin structures, CP micro-actuators produce high strains while requiring less than 1 V for actuation. Fabrication, characterization, and first integrations of such micro-actuators are presented. The integration is validated in a preliminary telescopic soft robot prototype with qualitative and quantitative performance assessment of accurate position control for trajectory tracking scenarios. Further, CP micro-actuators are integrated to a laser steering system in a closed-loop control scheme with displacements up to 5 mm. Our first developments aim toward intracorporeal medical robotics, with miniaturized actuators to be embedded into continuum robots. PMID- 29713831 TI - Checkpoint Inhibitors in the Treatment of Breast Cancer. AB - PURPOSE OF REVIEW: The treatment landscape for many cancers has dramatically changed with the development of checkpoint inhibitors. This article will review the literature concerning the use of checkpoint inhibitors in breast cancer. RECENT FINDINGS: The histological subtype of BC with the strongest signal of efficacy has been triple-negative breast cancer (TNBC). Early trials of single agent checkpoint inhibitors did not demonstrate a uniformly positive signal. Clinical studies suggest response rates between 5 and 10% in pretreated patients and roughly 20-25% for untreated advanced TNBC. However, in the small subset of patients who do respond, the response is often durable. More encouraging results have been reported with their use in combination with chemotherapy in the neoadjuvant setting. Larger phase III studies are underway to confirm these earlier findings. An immune-directed therapeutic approach for the management of BC is underway, and it is likely that combination therapy will be required to achieve a level of efficacy worthy of use in the BC treatment paradigm. These agents are not without both economic and clinical toxicity; therefore, it is imperative that we identify patients most likely to benefit from these therapies through well-designed biologically plausible clinical studies and by evaluating novel combinatorial approaches with informative biomarker driven correlative studies. PMID- 29713832 TI - Assessment of myofascial medialization following posterior component separation via transversus abdominis muscle release in a cadaveric model. AB - PURPOSE: Posterior component separation (PCS) via the transversus abdominis release (TAR) procedure continues to gain popularity. However, neither the physiologic basis nor the extent of myofascial medialization after TAR is established. We aimed to assess both anterior and posterior rectus fascia (AF and PF) medialization following each step of the TAR procedure. METHODS: Ten fresh cadavers underwent PCS via TAR. Steps included midline laparotomy (MLL), retrorectus dissection (RRD), incision of the posterior rectus sheath (IPL), transversus abdominis muscle division (TAD), and retromuscular dissection (RMD). Medial advancement of AF and PF was measured following application of 2.5, 5.0 lb, and maximal tension to the fascial edge. Values are represented as mean advancement past midline in centimeters. RESULTS: MLL allowed advancement of 2.5, 3.7, and 4.9 cm. RRD provided advancement of 4.1, 5.9, and 7.6 cm for AF and 4.4, 6.2, and 7.5 cm for PF. IPL provided advancement of 4.2, 6.1, and 8.0 cm for AF and 4.6, 6.6, and 8.3 cm for PF. TAD provided advancement of 4.5, 6.6, and 8.6 cm for AF and 5.3, 7.5, and 9.5 cm for PF. RMD provided advancement of 5.5, 7.9, and 9.9 cm for AF and 6.9, 9.6, and 11.2 cm for PF. Overall, the complete TAR procedure provided AF advancement of 102% and PF advancement of 129%, over baseline. CONCLUSIONS: The TAR procedure provides for substantial medial advancement of both anterior and posterior myofascial components of the abdominal wall. Retromuscular dissection deep to the divided transversus abdominis muscle appears to be the key step of the procedure, allowing for effective reconstruction of very wide (~ 20 cm) defects. PMID- 29713833 TI - Astragalus affects fecal microbial composition of young hens as determined by 16S rRNA sequencing. AB - The gut microbiota play important roles in the degradation of chemical compounds of herbal medicines (HMs). However, little information regarding the interplay between HMs and the gut microbiota is available. Thus, the aim of this study was to investigate the composition of the fecal microbiota of young (age, 11 weeks) hens fed a conventional diet containing a crude Astragalus (0.5%) additive for 21 days (group A) vs. controls (group B) that were fed only conventional feed. The fecal contents of 14-week-old hens were collected for DNA extraction, and then the V3 and V4 hyper-variable regions of the 16S rRNA gene were amplified and analyzed using high-throughput sequencing technology. A distinctive difference in microbial diversity was observed between the two groups. The microbial composition of hens fed a diet supplemented with Astragalus was greater than that of the control group. At the genus level, Lactobacillus was more abundant in group A than group B (p < 0.05). Importantly, this study is the first to report the observation of a novel Romboutsia sp. in the feces of hens. However, Romboutsia was less abundant in group A than group B (17.94 vs. 33.98%, respectively, p < 0.05). The microbial community differed significantly between the two groups at the genus level, suggesting that Astragalus modulates the composition of the fecal microbiota. Based on these differences, these findings provide fresh insights into the application of Astragalus in the poultry industry, as well as a better understanding of the interplay between HMs and the gut microbiota. PMID- 29713834 TI - The Phenotypic Effects of Exosomes Secreted from Distinct Cellular Sources: a Comparative Study Based on miRNA Composition. AB - Exosomes are nano-sized vesicles composed of lipids, proteins, and nucleic acids. Their molecular landscape is diverse, and exosomes derived from different cell types have distinct biological activities. Since exosomes are now being utilized as delivery vehicles for exogenous therapeutic cargoes, their intrinsic properties and biological effects must be understood. We performed miRNA profiling and found substantial differences in the miRNA landscape of prostate cancer (PC3) and human embryonic kidney (HEK) 293 exosomes with little correlation in abundance of common miRNAs (R2 = 0.16). Using a systems-level bioinformatics approach, the most abundant miRNAs in PC3 exosomes but not HEK exosomes were predicted to significantly modulate integrin signaling, with integrin-beta3 loss inducing macrophage M2 polarization. PC3 but not HEK exosomes downregulated integrin-beta3 expression levels by 70%. There was a dose-dependent polarization of RAW 264.7 macrophages toward an M2 phenotype when treated with PC3-derived exosomes but not HEK-derived exosomes. Conversely, HEK exosomes, widely utilized as delivery vehicles, were predicted to target cadherin signaling, with experimental validation showing a significant increase in the migratory potential of MCF7 breast cancer cells treated with HEK exosomes. Even widely utilized exosomes are unlikely to be inert, and their intrinsic activity ought to be assessed before therapeutic deployment. PMID- 29713835 TI - Physical Activity and Breast Cancer: an Opportunity to Improve Outcomes. AB - PURPOSE OF REVIEW: To review current data regarding physical activity and breast cancer including cancer risk, cancer prognosis, treatment-related side effects, and patient-reported outcomes. We will summarize current physical activity guidelines for cancer survivors and discuss opportunities to study and implement physical activity programs in cancer survivors. RECENT FINDINGS: Observational evidence suggests that physical activity is associated with a reduced risk of developing breast cancer, a reduced risk of breast cancer recurrence, and improved breast cancer-specific and all-cause mortality. Studies also show that physical activity improves factors important to quality of life such as chemotherapy-related fatigue and the aromatase inhibitor-induced musculoskeletal syndrome. Physical activity is an important component of breast cancer survivorship. Challenges exist in conducting clinical trials of physical activity and implementing current guidelines, yet there are significant opportunities to advance the field through translational research efforts and utilization of available community resources. PMID- 29713836 TI - Retrospective Analysis of Clinical Performance of an Estonian Speech Recognition System for Radiology: Effects of Different Acoustic and Language Models. AB - The aim of this study was to analyze retrospectively the influence of different acoustic and language models in order to determine the most important effects to the clinical performance of an Estonian language-based non-commercial radiology oriented automatic speech recognition (ASR) system. An ASR system was developed for Estonian language in radiology domain by utilizing open-source software components (Kaldi toolkit, Thrax). The ASR system was trained with the real radiology text reports and dictations collected during development phases. The final version of the ASR system was tested by 11 radiologists who dictated 219 reports in total, in spontaneous manner in a real clinical environment. The audio files collected in the final phase were used to measure the performance of different versions of the ASR system retrospectively. ASR system versions were evaluated by word error rate (WER) for each speaker and modality and by WER difference for the first and the last version of the ASR system. Total average WER for the final version throughout all material was improved from 18.4% of the first version (v1) to 5.8% of the last (v8) version which corresponds to relative improvement of 68.5%. WER improvement was strongly related to modality and radiologist. In summary, the performance of the final ASR system version was close to optimal, delivering similar results to all modalities and being independent on user, the complexity of the radiology reports, user experience, and speech characteristics. PMID- 29713839 TI - Participation in HIV Behavioral Research: Unanticipated Benefits and Burdens. AB - HIV behavioral research has provided an invaluable knowledge base for effective approaches to behavioral challenges along the HIV care cascade. Little attention has been paid to tracking unanticipated effects of research participation, whether negative or positive. We used qualitative methods to elicit impressions of unanticipated effects of participation in behavioral research. An instrument was developed and piloted to assess positive (emotional gains, practical gains, HIV prevention knowledge and skills gains) and negative (emotional stress, discomfort with research) unanticipated effects. Participants (N = 25) from five projects, including men who have sex with men, adults who use substances, and youth, reported multiple positive unanticipated effects (sexual and drug risk reduction, goal setting, improvements in self-esteem and mood, relationship gains, health care behavior gains, knowledge and introspection gains) and rare unanticipated negative effects. Developing a systematic tool of unanticipated positive and negative effects of participation in behavioral research is a crucial next step. PMID- 29713837 TI - Current Options and Emerging Biomaterials for Periprosthetic Joint Infection. AB - PURPOSE OF REVIEW: Infection in the setting of total joint arthroplasty, referred to as periprosthetic joint infection (PJI), is a devastating complication requiring prolonged and costly treatment. The unique environment around an artificial joint and ability of surrounding tissues to sequester bacteria collectively make prevention, diagnosis, and treatment of this condition challenging. In light of the unique pathogenesis of PJI, this review explores the limitations of contemporary treatments and discusses novel treatment options. RECENT FINDINGS: Recent advancements in local antibiotic delivery platforms for preventing and treating PJI include titanium nanotube arrays, synthetic polymers, resorbable hydrogels, and cyclodextrin-based drug delivery options. In particular, cyclodextrins have facilitated great advancements in other clinical disorders and have demonstrated early promise as a future option in the arena of PJI. Novel treatment modalities for PJI optimize the implant surfaces to prevent bacterial biofilm formation or provide prolonged intra-articular antibiotic dosing to eradicate bacteria. PMID- 29713838 TI - Acceptability of Antiretroviral Pre-exposure Prophylaxis from a Cohort of Sexually Experienced Young Transgender Women in Two U.S. Cities. AB - Emtricitabine/tenofovir disoproxil fumarate as pre-exposure prophylaxis (PrEP) can prevent HIV infection among at-risk individuals, including young transgender women (YTW). We used baseline data from 230 HIV-uninfected YTW (ages 16-29 years) who were enrolled in Project LifeSkills during 2012-2015. We examined factors associated with perceived acceptability of PrEP use (mean score = 23.4, range 10.0-30.0). Participants were largely transgender women of color (67%) and had a mean age of 23 years (SD = 3.5). In an adjusted multiple linear regression model, PrEP interest (beta = 3.7, 95% CI 2.2-5.2) and having a medical provider who meets their health needs (beta = 2.9, 95% CI 1.3-4.4) was associated with higher PrEP acceptability scores, whereas younger age (21-25 vs 26-29 years) (beta = 2.0, 95% CI - 3.6 to - 0.4) and reporting transactional sex in the past 4 months (beta = - 1.5, 95% CI - 3.0 to - 0.1) was associated with lower PrEP acceptability scores (all p values < 0.05). Enhancing PrEP-related interventions by addressing the unique barriers to uptake among YTW of younger age or those with history of transactional sex could bolster PrEP acceptability for this population. PMID- 29713840 TI - Using Goal Achievement Training in juvenile justice settings to improve substance use services for youth on community supervision. AB - BACKGROUND: The link between substance use and involvement in the juvenile justice system has been well established. Justice-involved youth tend to have higher rates of drug use than their non-offending peers. At the same time, continued use can contribute to an elevated risk of recidivism, which leads to further, and oftentimes more serious, involvement with the juvenile justice system. Because of these high rates of use, the juvenile justice system is well positioned to help identify youth with substance use problems and connect them to treatment. However, research has found that only about 60% of juvenile probation agencies screen all youth for substance involvement, and even fewer provide comprehensive assessment or help youth enroll in substance use treatment. METHOD: This paper describes an integrated training curriculum that was developed to help juvenile justice agencies improve their continuum of care for youth probationers with substance use problems. Goal Achievement Training (GAT) provides a platform for continuous quality improvement via two sessions delivered onsite to small groups of staff from juvenile justice and behavioral health agencies. In the first session, participants are taught to identify goals and goal steps for addressing identified areas of unmet need (i.e., screening, assessment, and linkage to treatment services). In the second session, participants learn principles and strategies of data-driven decision-making for achieving these goals. This paper highlights GAT as a model for the effective implementation of cost-efficient training strategies designed to increase self-directed quality improvement activities that can be applied to any performance domain within juvenile justice settings. Efforts to monitor implementation fidelity of GAT within the specific context of the juvenile justice settings are highlighted. DISCUSSION: Challenges to setting the stage for process improvement generally, as well as specific hurdles within juvenile justice settings are discussed, as are next steps in disseminating findings regarding the fidelity to and effectiveness of GAT in this unique context. TRIAL REGISTRATION: Clinical Trials Registration number - NCT02672150 . PMID- 29713841 TI - Comparative study using fractional carbon dioxide laser versus glycolic acid peel in treatment of pseudo-acanthosis nigricans. AB - Pseudo-acanthosis nigricans is a common dermatological disorder that is usually difficult to treat secondary to maceration of the skin from excessive sweating, obesity, or associated with endocrine disorders. Fractional photothermolysis and chemical peeling have been reported to improve the condition. To determine whether fractional CO2 laser resurfacing or glycolic acid peel is more effective and safe option for therapy. Twenty Egyptian patients were included in the study where each patient was subjected to three sessions of both fractional CO2 on the right side of the neck and glycolic acid peel 70% on the left side of the neck. All patients were evaluated by a scoring system Acanthosis Nigricans Area and Severity Index (ANASI) score and three blinded dermatologists before and after treatment. Clinical improvement on the side treated by glycolic acid peel showed 43% improvement while the side treated by fractional CO2 showed 19% improvement. Glycolic acid peel shows superior results to fractional CO2 due to accelerated induced exfoliation, yet still fractional CO2 results are promising due to a presumably long-term improvement of skin texture. PMID- 29713843 TI - A co-utilization strategy to consume glycerol and monosaccharides by Rhizopus strains for fumaric acid production. AB - The ability of Rhizopus oryzae to produce fumaric acid in the presence of glycerol and/or various monosaccharides as carbon sources was examined for seventeen different strains of this fungi. These strains were tested in shake flask cultures on media containing glycerol and seven different carbohydrates, including glucose, fructose, galactose, mannose, xylose, arabinose, and rhamnose. An interesting and applicationally useful phenomenon was observed. This work presents a new approach to the conventional microbiological method of producing fumaric acid. In the presence of 40 g/l glycerol as the sole carbon source, fumaric acid production reached 0.16-6.1 g/l after 192 h. When monosaccharides were used as a single carbon source, the maximum fumaric acid concentration was much higher; for example, 19.8 g/l was achieved when 40 g/l xylose was used. In the co-fermentation of xylose (40 g/l) and glycerol (20 g/l), post-culture broth contained approx. 28.0 g/l of fumaric acid with a process yield of 0.90 g/g after 168 h. The production of fumaric acid by Rhizopus oryzae was also increased in the dual presence of glycerol and monosaccharides like fructose, galactose, and mannose. However, results obtained on glucose-glycerol-based medium did not follow this trend, showing instead complete utilization of glucose with significant glycerol consumption, but unexpectedly low final amounts of fumaric acid and process yields. Understanding how Rhizopus oryzae utilize various carbon sources may provide alternative avenues of fumaric acid fermentation. PMID- 29713842 TI - Effects of low-level laser therapy on soft and hard tissue healing after endodontic surgery. AB - The aim of this prospective study was to examine possible benefits of low-level laser therapy (LLLT) on soft and hard tissue healing after endodontic surgery. Seventy-six endo-surgery cases on maxillary incisors were included. The patients were assigned randomly into control and laser groups. In the laser group, gallium aluminum-arsenide (GaAlAs) diode laser irradiation (810 nm, 129 mW, 3.87 J/cm2) was performed immediately after surgery and daily for postoperative 7 days from buccal and palatal surfaces (5 min for each side). In the control group, patients were not subjected laser therapy. The patients were compared in terms of pain, clinical and radiological findings, and life quality indexes [Oral Health Impact Profile-14 (OHIP-14) and General Oral Health Assessment Index (GOHAI)]. Seventy one patients completed the study (n = 37 for control group, n = 34 for laser group). The laser group showed better results in edema, wound healing, and the number of analgesic tablets used on the 1st, 3rd, and 7th postoperative days. Significant reduction in ecchymoses was observed in the laser group on the postop 3rd and 7th days. The patients had significantly lower pain on the 1st and 3rd postop days in laser group. The laser group showed significantly better results in OHIP-14 and GOHA indexes on postop days 1 and 3. The laser group showed significantly favorable results in terms of bone density, defect volume and area, and periapical index in the postop 3rd month. This study concluded that LLLT improved soft and hard tissue healing after endodontic surgery and also showed favorable effects on pain and life quality of patients especially in the early phase of healing period. PMID- 29713844 TI - The Origin of Species by Means of Mathematical Modelling. AB - Darwin described biological species as groups of morphologically similar individuals. These groups of individuals can split into several subgroups due to natural selection, resulting in the emergence of new species. Some species can stay stable without the appearance of a new species, some others can disappear or evolve. Some of these evolutionary patterns were described in our previous works independently of each other. In this work we have developed a single model which allows us to reproduce the principal patterns in Darwin's diagram. Some more complex evolutionary patterns are also observed. The relation between Darwin's definition of species, stated above, and Mayr's definition of species (group of individuals that can reproduce) is also discussed. PMID- 29713846 TI - Cross-species referential signalling events in domestic dogs (Canis familiaris). AB - Referential gestures are used by a signaller to draw a recipient's attention to a specific object, individual or event in the environment. These gestures have received much research attention in relation to human and non-human primates with great apes being shown to possess impressive gestural repertoires. Domestic dogs (Canis familiaris) meanwhile provide an ideal non-primate candidate for investigating referential signalling due to their unique relationship with humans that centres on non-verbal communication with frequent interaction. Here we observed 37 pet dogs in their own homes. Owners recorded 242 videos containing 47 potential referential gesture events. We analysed those recordings to reveal evidence of 19 referential gestures performed by domestic dogs during everyday communicative bouts with humans, showing that the gestures conform to the five features of referential signalling. Our study exposes impressive gesturing abilities in a non-primate mammal; especially when viewed in the context of the cross-species rather than intraspecific communication. PMID- 29713845 TI - Regularity of self-reported daily dosage of mood stabilizers and antipsychotics in patients with bipolar disorder. AB - BACKGROUND: Polypharmacy is often prescribed for bipolar disorder, yet medication non-adherence remains a serious problem. This study investigated the regularity in the daily dosage taken of mood stabilizers and second generation antipsychotics. METHODS: Daily self-reported data on medications taken and mood were available from 241 patients with a diagnosis of bipolar disorder who received treatment as usual. Patients who took the same mood stabilizer or second generation antipsychotic for >= 100 days were included. Approximate entropy was used to determine serial regularity in daily dosage taken. Generalized estimating equations were used to estimate if demographic or clinical variables were associated with regularity. RESULTS: There were 422 analysis periods available from the 241 patients. Patients took drugs on 84.4% of days. Considerable irregularity was found, mostly due to single-day omissions and dosage changes. Drug holidays (missing 3 or more consecutive days) were found in 35.8% of the analysis periods. Irregularity was associated with an increasing total number of psychotropic drugs taken (p = 0.009), the pill burden (p = 0.026), and the percent of days depressed (p = 0.049). CONCLUSION: Despite low missing percent of days, daily drug dosage may be irregular primarily due to single day omissions and dosage changes. Drug holidays are common. Physicians should expect to see partial adherence in clinical practice, especially with complex drug regimens. Daily dosage irregularity may impact the continuity of drug action, contribute to individual variation in treatment response, and needs further study. PMID- 29713847 TI - Stimulation of mouse vibrissal follicle growth by recombinant human fibroblast growth factor 20. AB - OBJECTIVES: To explore potential effects of recombinant human fibroblast growth factor 20 (rhFGF20) in the growth of cultured mouse vibrissal follicles. RESULTS: The growth of cultured mouse vibrissal follicles was significantly induced by rhFGF20 in a dose dependent pattern in the in vitro vibrissal follicle organ culture model. However, too high concentration of rhFGF20 could inhibit the growth of vibrissal follicles. We further demonstrated that rhFGF20 stimulated the proliferation of hair matrix cells and activated Wnt/beta-catenin signaling pathway. CONCLUSIONS: The rhFGF20 might be a potential therapeutic agent to treat hair loss disorders. PMID- 29713849 TI - Subjective and objective assessment of fish sperm motility: when the technique and technicians matter. AB - Fish sperm motility is nowadays considered the best sperm quality biomarker in fish, and can be evaluated both by subjective and computerized methods. With the aim to compare the precision and accuracy of both techniques, fish sperm samples were assessed by subjective methods and by a computer-assisted sperm analysis (CASA-Mot) system, and simultaneously by three different technicians with different degrees of expertise on the sperm quality analysis. Statistical dispersion parameters (CV, coefficient of variation; and RG, range) were estimated in order to determine the precision and accuracy of the techniques and the influence of laboratory staff on sperm motion assessments. Concerning precision, there were not much significant differences between the technical support staff (high, medium, and low experimented technician), and statistical dispersion parameters were quite similar between them independent of the technique used and the sperm motility class analyzed. However, concerning accuracy, experimented technician reported subjective motility values very closed to the values provided by the CASA-Mot system, only 10 percentage points away from the data provided by a CASA-Mot system. However, medium and low experimented technicians often overestimate the CASA-Mot values, and amplitudes up to 30 percentage points were detected in several sperm assessments. To sum up, both the technique (subjective or objective) and the technician (degree of expertise) became key factors in order to reach accurate motility estimations, so the use of both qualified staff and novel CASA-Mot systems seems to be a critical requirement for obtaining satisfying results in fish species with similar motility patterns. PMID- 29713850 TI - Experience Focussed Counselling with Voice Hearers: Towards a Trans-diagnostic Key to Understanding Past and Current Distress-A Thematic Enquiry. AB - As it is increasingly evident that distressing voices can be linked to traumatic events across diagnoses, there is a need for new transdiagnostic interventions for persons with voice hearing related distress. Twenty-five interviews with voice hearers and mental health professionals explored the trans-diagnostic suitability of Experience Focussed Counselling (EFC) compared to Treatment As Usual. An Applied Thematic Analysis was used. Themes identified were: intervention applicability; impact of regular treatment before study; impact of EFC process; process of working with voices; impact of regular treatment during study; views on treatment or approach. The EFC focus was considered helpful across diagnoses. The findings support EFC as a transdiagnostic intervention. PMID- 29713848 TI - GOLPH3 promotes glioma progression via facilitating JAK2-STAT3 pathway activation. AB - INTRODUCTION: Our recent work reported that GOLPH3 promotes glioma progression via inhibiting endocytosis and degradation of EGFR. The current study aimed to explore the potential regulating mechanism of GOLPH3 on JAK2-STAT3 signaling, a downstream effector of EGFR, in glioma progression. METHODS: The expression of JAK2, STAT3 and GOLPH3 in glioma tissues was detected by western blotting, tissue microarray and immunohistochemistry. The U251 and U87 cells with GOLPH3 down regulation or over-expression were generated by lentivirus system. The effects of GOLPH3 on the activity of JAK2 and STAT3 were detected by western blotting and reverse transcription polymerase chain reaction. Co-immunoprecipitation was used to detect the association of GOLPH3 with JAK2 and STAT3. Cell proliferation was detected by CCK8 and EdU assay. RESULTS: The level of JAK2, STAT3 and GOLPH3 were significantly up-regulated and exhibited pairwise correlation in human glioma tissues. The level of p-JAK2 and p-STAT3, as well as the mRNA and protein levels of cyclin D1 and c-myc, two target genes of STAT3, decreased after GOLPH3 down regulation, while they increased after GOLPH3 over-expression both in U251 and U87 cells. Interestingly, GOLPH3, JAK2 and STAT3 existed in the same protein complex and GOLPH3 affected the interaction of JAK2 and STAT3. Importantly, down regulation of STAT3 partially abolished cell proliferation induced by GOLPH3 over expression. CONCLUSIONS: GOLPH3 may act as a scaffold protein to regulate JAK2 STAT3 interaction and then its activation, which therefore mediates the effect of GOLPH3 on cell proliferation. PMID- 29713851 TI - Assessment of Complementary Treatment with Yiqi Fumai Lyophilized Injection on Acute Decompensated Ischemic Heart Failure (ACT-ADIHF): Rationale and Design of a Multicenter, Randomized, Controlled Trial. AB - BACKGROUND: Heart failure (HF) is the end stage of many heart diseases, and ischemic heart disease (IHD) is the primary cause. Yiqi Fumai lyophilized injection, a contemporary Chinese medicine preparation, widely used in the treatment of IHF patients, shows clinical efficacy on improving symptoms and cardiac function, but the quality of the current literature does not address multiple important issues. This article describes a protocol for assessment of complementary treatment with Yiqi Fumai lyophilized injection in acute decompensated IHD. METHODS: The protocol is designed as a multicenter randomized controlled trial to assess the efficacy and safety of complementary treatment with Yiqi Fumai lyophilized injection on acute decompensated IHD. This trial will be carried out in 37 hospitals in China and expected to enroll 666 inpatients with acute decompensated IHF due to coronary heart disease. On the basis of standardized western medications, patients are randomized to either the treatment group (250 ml 5% glucose / sodium injection + 5.2 g Yiqi Fumai lyophilized injection) or the control group for 7 days and follow-up for 30 +/- 3 and 60 +/- 3 days. The primary outcome is change in brain natriuretic peptide (BNP) concentrations. The secondary outcomes are composite endpoint, left ventricular ejection fraction, blood troponin T/I, cardiothoracic ratio, life quality scale, scores of the four traditional Chinese medicine (TCM) diagnostic methods. DISCUSSION: Standardized western medications together with TCM have been extensively used in China and have developed into a comprehensive treatment model. The trial will provide clinical research evidence for application of complementary treatment with intravenous Yiqi Fumai lyophilized injection on decompensated IHF. TRIAL REGISTRATION: This study protocol has been listed in the Chinese Clinical Trial Registry (registration number: ChiCTR-IPR-15007396, http://www.chictr.org.cn/showproj.aspx?proj=12370 ) on November 6, 2015. PMID- 29713852 TI - Correction to: Assessment of the 1% of Patients with Consistent < 15% Reduction in Low-Density Lipoprotein Cholesterol: Pooled Analysis of 10 Phase 3 ODYSSEY Alirocumab Trials. AB - The original version of this article unfortunately contained a mistake in the Discussion section. PMID- 29713853 TI - Herd characteristics and management practices associated with bulk tank milk quality of dairy herds in southeastern Brazil. AB - This study identified the association of management practices and herd characteristics with milk quality of bulk tanks in southeastern, Brazil. Milk samples were collected weekly during 8 weeks from 63 dairy herds. Bulk tanks were evaluated for total bacteria (TBC), preliminary incubation (PIC), pasteurization (PC), coliform (CC), and somatic cell counts (SCC). Associations found were type of milking system utilized in the farm with TBC, PIC, and SCC; the use of gloves for milking with TBC and PIC; sanitation of milking equipment prior to milking with PC and CC; strip cup testing of cows with PC; teat washing prior to milking with SCC; pre-milking teat disinfection with TBC and CC; post-dipping with TBC and SCC; and the alkaline-acid washing procedure of milking equipment with PIC and PC. The regression analysis explained the variation of bulk tank PC (- 0.47 log cfu/mL) due to the adoption of strip cup test (P = 0.036) and, by 0.366 log cfu/mL due to alkaline and acid washing of milking equipment (P = 0.036). Herringbone milking systems adopted on farms represented a change of - 0.11 log cfu/mL on the log SCC (P = 0.048). Findings may provide a guideline to prioritize efforts aimed at improving milk quality at the farm level in Brazil. PMID- 29713854 TI - Menopausal hormone therapy and the risk of breast cancer by histological type and race: a meta-analysis of randomized controlled trials and cohort studies. AB - PURPOSE: This meta-analysis investigated the association between the risk of breast cancer and hormone replacement therapy (HRT). Various stratified analyses were performed according to race (Asian/Westerner), HRT type [all hormone therapies, estrogen-only therapy (ET), or combined estrogen-progestin therapy (EPT)], histological breast cancer type (ductal/lobular/mixed ductal-lobular), and estrogen receptor status (ER-positive/ER-negative). METHODS: A literature search was performed using Pubmed, Embase, and KoreaMed. Twenty-five epidemiological studies including 23 cohort studies and two randomized controlled trials were included in this meta-analysis. RESULTS: Using a random-effects model, HRT use was found to be positively associated with the risk of breast cancer with a pooled hazard ratio (HR) of 1.33 [95% confidence interval (CI) 1.24, 1.44]. Compared with ET, EPT was more strongly associated with breast cancer risk. EPT was associated with both ductal and lobular breast cancer risks [for ductal breast cancer, HR = 1.51 (95% CI 1.28, 1.78); for lobular breast cancer, HR = 1.38 (95% CI 1.20, 1.60)]. According to ER status, all HRTs were associated with the risk of ER-positive breast cancer, but not with that of ER negative breast cancer. CONCLUSIONS: Asian HRT users had a higher risk of breast cancer than western HRT users. Both ET and EPT were significantly associated with the risk of all breast cancer histological types and ER-positive breast cancer. PMID- 29713855 TI - Case report: acute hydrops and spontaneous corneal perforation in a patient with keratoconus treated with colchicine for familial Mediterranean fever. AB - PURPOSE: To report a rare case of spontaneous corneal perforation after hydrops in keratoconus patients who suffer from familial Mediterranean fever and was treated systemically with Colchicine. METHODS: Case report. RESULTS: We report a case of a 30-year-old male with keratoconus and familial Mediterranean fever treated with colchicine, presented with acute hydrops in his left eye, which progressed to a spontaneous corneal perforation. Attempts to treat the perforation with cyanoacrylate glue failed, and he underwent penetrating keratoplasty with an excellent visual outcome. CONCLUSION: Colchicine treatment may have had a role in the pathogenesis of this rare case. PMID- 29713856 TI - The numerical study on specialized treatment strategies of enhanced external counterpulsation for cardiovascular and cerebrovascular disease. AB - Traditional clinical mode of enhanced external counterpulsation is not targeted for different diseases. Specialized strategies in the treatment of enhanced external counterpulsation for coronary heart disease and cerebral ischemic stroke are supposed to be distinguished. The goal of treatment for coronary heart disease is diastolic blood pressure/systolic blood pressure = Q >= 1.2 after counterpulsation, while the goal of treatment for cerebral ischemic stroke is the improvement of mean arterial pressure. A computational lumped parameter model was established for the simulation of hemodynamic effect of enhanced external counterpulsation on two diseases. Vessel collapse was considered during the simulation of counterpulsation. Based on different pressurized and decompressed rate, pressurized moment, pressure duration, and pressure amplitude, different counterpulsation modes were applied to the model and the immediate hemodynamic effects were compared. Results showed that the pressure duration and pressure amplitude had most influence on two diseases. For cerebral ischemic stroke, the longer pressure duration and the higher pressure amplitude of thighs, the higher mean arterial pressure; while for coronary heart disease, the value of Q was highest when the pressure end moment was 0.6 s during a 0.88-s cardiac cycle, and Q had a linear increase in the pressure amplitude of buttocks, but little change with the increase of calves and thighs pressure amplitude. For patients with coronary heart disease, the pressure duration was not supposed to be too long to avoid the increase of systolic blood pressure, and the improvement of pressure amplitude of buttocks could promise a positive treatment effect for coronary heart disease. While for patients with cerebral ischemic stroke, both the long pressure duration of each part and the high pressure amplitude of thighs could result in the systolic blood pressure and diastolic blood pressure have a certain increase, thus promoting the maximum mean arterial pressure and a best treatment. Graphical abstract The specialized treatment strategies of EECP for cardiovascular and cerebrovascular disease. PMID- 29713857 TI - Case of successful IVF treatment of an oligospermic male with 46,XX/46,XY chimerism. AB - INTRODUCTION: We present a case of an infertile male with 46,XX/46,XYchimerism fathering a child after ICSI procedure. METHODS: Conventional cytogenetic analysis on chromosomes, derived from lymphocytes, using standard Q-banding procedures with a 450-550-band resolution and short-tandem-repeat analysis of 14 loci. RESULTS: Analysis of 20 metaphases from lymphocytes indicated that the proband was a karyotypic mosaic with an almost equal distribution between male and female cell lines. In total, 12 of 20 (60%) metaphases exhibited a normal female karyotype 46,XX, while 8 of 20 (40%) metaphases demonstrated a normal male karyotype 46,XY. No structural chromosomal abnormalities were present. Out of 14 STR loci, two loci (D18S51 and D21S11) showed four different alleles in peripheral blood, buccal mucosal cells, conjunctival mucosal cells, and seminal fluid. In three loci (D2S1338, D7S820, and vWA), three alleles were detected with quantitative differences that indicated presence of four alleles. In DNA extracted from washed semen, four alleles were detected in one locus, and three alleles were detected in three loci. This pattern is consistent with tetragametic chimerism. There were no quantitative significant differences in peak heights between maternal and paternal alleles. STR-analysis on DNA from the son confirmed paternity. CONCLUSION: We report a unique case with 46,XX/46,XY chimerism confirmed to be tetragametic, demonstrated in several tissues, with male phenotype and no genital ambiguity with oligospermia fathering a healthy child after IVF with ICSI procedure. PMID- 29713859 TI - Skilled migration and health outcomes in developing countries. AB - Many studies have found that health outcomes decline when health professionals leave the country, but do such results remain consistent in gender- and income disaggregated skilled migration? To help uncover explanations for such a pro migration nature of health outcomes, the present study revisits this topic but allows for associations of skilled migration with mortality and life expectancy to differ between male and female, and between low- and high-income countries. Using a panel of 133 developing countries as source and 20 OECD countries as destination from 1980 to 2010 allowing the coefficient on emigration across different education levels to differ, the study finds the negative effect of high skilled emigration on health outcomes. Such effect is more pronounced for high skilled female migration than those for male and for low-income countries than for middle-and high-income countries. Results also show that such adverse effect is larger for African countries than non-African ones. However, the low-skilled migration appears to be insignificant to affect health outcomes in developing countries. Thus, skilled migration is detrimental to longevity in developing countries but unskilled migration is not. PMID- 29713858 TI - Chia Oil Extraction Coproduct as a Potential New Ingredient for the Food Industry: Chemical, Physicochemical, Techno-Functional and Antioxidant Properties. AB - The aim of this work was to characterize the coproduct obtained from chia oil production (cold-pressing) with a view to its possible application in new food product development. For this characterization, the following determinations were made: proximate composition, physicochemical analysis, techno-functional properties, total phenolic and flavonoid content, polyphenolic profile and antioxidant capacity (using four different methods). Chia coproduct showed significantly higher levels of proteins and total dietary fiber and lower levels of fats than chia seeds, pointing to the promising nature of this coproduct as an ingredient of food formulations since it remains a source of high biological value proteins and total dietary fiber (as chia seeds themselves) but with a lower energy value. This chia coproduct presents similar techno-functional properties to the original chia seeds and significantly higher levels of polyphenolic compounds and, consequently, higher antioxidant activity. PMID- 29713860 TI - First time description of early lead failure of the Linox Smart lead compared to other contemporary high-voltage leads. AB - PURPOSE: Early lead failure has recently been reported in ICD patients with Linox SD leads. We aimed to compare the long-term performance of the following lead model Linox Smart SD with other contemporary high-voltage leads. METHODS: All patients receiving high-voltage leads at our center between November 2009 and May 2017 were retrospectively analyzed. Lead failure was defined as the occurrence of one or more of the following: non-physiological high-rate episodes, low- or high voltage impedance anomalies, undersensing, or non-capture. RESULTS: In total, 220 patients were included (Linox Smart SD, n = 113; contemporary lead, n = 107). During a median follow-up of 3.8 years (IQR 1.6-5.9 years), a total of 16 (14 in Linox Smart SD and 2 in contemporary group) lead failures occurred, mostly due to non-physiological high-rate sensing or impedance abnormalities. Lead failure incidence rates per 100 person-years were 2.9 (95% CI 1.7-4.9) and 0.6 (95% CI 0.1-2.3) for Linox Smart SD compared to contemporary leads respectively. Kaplan Meier estimates of 5-year lead failure rates were 14.0% (95% CI 8.1-23.6%) and 1.3% (95% CI 0.2-8.9%), respectively (log-rank p = 0.028). Implantation of a Linox Smart SD lead increased the risk of lead failure with a hazard ratio (HR) of 4.53 (95% CI 1.03-19.95, p = 0.046) and 4.44 (95% CI 1.00-19.77, p = 0.05) in uni- and multivariable Cox models. CONCLUSIONS: The new Linox Smart SD lead model was associated with high failure rates and should be monitored closely to detect early signs of lead failure. PMID- 29713863 TI - Multiscale analyses on a massive immigration process of Sogatella furcifera (Horvath) in south-central China: influences of synoptic-scale meteorological conditions and topography. AB - Mass landings of migrating white-backed planthopper, Sogatella furcifera (Horvath), can lead to severe outbreaks that cause heavy losses for rice production in East Asia. South-central China is the main infestation area on the annual migration loop of S. furcifera between the northern Indo-China Peninsula and mainland China; however, rice planthopper species are not able to survive in this region over winter. In this study, a trajectory analysis of movements from population source areas and a spatiotemporal dynamic analysis of mesoscale and synoptic weather conditions from 7 to 10 May 2012 were conducted using the weather research and forecasting (WRF) model to identify source areas of immigrants and determine how weather and topographic terrain influence insect landing. A sensitivity experiment was conducted with reduced topography using the WRF model to explain the associations among rainfall, topography, and light-trap catches of S. furcifera. The trajectory modeling results suggest that the source areas of S. furcifera immigrants into south-central China from 8 to 10 May were mainly southern Guangxi, northern Vietnam, and north-central Vietnam. The appearance of enormous catches of immigrant S. furcifera coincided with a period of rainstorms. The formation of transporting southerly winds was strongly associated with the topographic terrain. Additionally, the rainfall distribution and intensity over south-central China significantly decreased when topography was reduced in the model and were directly affected by wind circulation, which was associated with mountainous terrain that caused strong convection. This study indicates that migrating populations of S. furcifera were carried by the southwesterly low-level jets and that topographically induced convergent winds, precipitation, low temperatures, and wind shear acted as key factors that led to massive landings. PMID- 29713864 TI - [Success quotas in exercise questions in the discipline of rheumatology in preparation for the written state examination in German universities from 2012 to 2016 : Evaluation of the AMBOSS databank according to professorships in rheumatology with and without freedom of instruction in German universities]. AB - The discipline rheumatology is underrepresented in German universities with only seven professorial chairs with freedom of instruction. The teaching positions with and without freedom of instruction are associated with a different quantity of teaching. The effect of the teaching position on the quality of teaching and on the training of medical students is unclear. In order to approach the answer to this question we have evaluated 2,610,217 examination questions from 32,166 students over a time period of 4 years according to location and freedom of instruction, which are documented on the teaching platform AMBOSS. In total, in the evaluated examination performance in the discipline of rheumatology, the majority of students just about achieved the grade of "sufficient". Locations with freedom of instruction had significantly better grades; however, these differences had no relevance with respect to the complete state examination. The examination pressure on German medical students to learn for the examination discipline of rheumatology can be estimated as rather low. PMID- 29713861 TI - The increasing importance of environmental conditions in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is the most common neurodegenerative disease affecting motor neurons (MNs). Although a small percentage of ALS has a familial origin, the vast majority of cases are sporadic in which genetic factors and environment interact with each other leading to disease onset in genetically predisposed individuals. In the current model of the disease, each individual has a determined genetic load, some degree of cell degeneration related to age and several risky environmental exposures. In this scenario, MN degeneration would occur when the sum of these factors reach a certain threshold. To date, an extensive list of environmental factors has been associated to ALS, including different categories, such as exposure to heavy metals and other toxicants, cyanotoxins or infectious agents. In addition, in recent years, lifestyle and other demographic parameters are gaining relevance in the genesis of the disease. Among them, physical activity, nutrition, body mass index, cardiovascular risk factors, autoimmune diseases and cancer are some of the conditions which have been related to the disease. In this review, we will discuss the potential mechanisms of environmental conditions in motor neuron degeneration. Understanding the role of each one of these factors as well as their interactions appears as a crucial step in order to develop new preventive, diagnostic and therapeutic approaches for ALS patients. PMID- 29713865 TI - [Getting older with rheumatoid arthritis-is there a burnout of the disease?] AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease. Synovitis is the main pathology and can lead to a progressive destruction of the joints. It is often said that RA "burns out", implying that the inflammation decreases spontaneously in the long term, mostly severe course of RA and reaches a stage with a stable absence of joint inflammation, even without treatment. To test this concept we analyzed the published evidence. Data of historic long-term inception cohorts of patients who have never been treated with antirheumatic drugs and patients who received conventional disease-modifying antirheumatic drugs (DMARD), show that the disease stays active with sustained radiological progression in the majority of patients. At best, the disease can show a milder course with time or a stage of absence of joint inflammation can be reached if patients responded very well to initial drug treatment. Terminating DMARD treatment in this situation bears the risk of a latent progressive joint destruction, the appearance of extra-articular manifestations and an increase in the cardiovascular risk. Hence there is no evidence for the existence of a "burnt out" RA with stable inactive disease without drug treatment in the long-term course. In a modern treatment strategy of RA following the treat-to-target principle and aiming at remission, the term "burnt out" RA should no longer be used. PMID- 29713866 TI - [Complex treatments in rheumatology and geriatrics - Challenges - Differences - Chances]. AB - With the introduction of the German diagnostic-related groups (G-DRG) system in 2003, remuneration according to DRG was also implemented for the disciplines of rheumatology and geriatrics. For acute inpatient treatment in the field of rheumatology the specialized complex rheumatological treatment (OPS code 8-983) and the related DRG-I97Z (rheumatological complex treatment for diseases and disorders of the musculoskeletal system and connective tissue) were assigned to the DRG system in 2005 and 2006, respectively. The early complex geriatric rehabilitation (OPS code 8-550) is a tool in the treatment of older patients affected by rheumatism. In this article the challenges of realizing complex therapies are described using the examples of OPS code 8-983 and 8-550 and their structural and procedural differences are outlined. Acute inpatient treatment of patients severely affected by a rheumatic disease as well as of multimorbid geriatric patients with rheumatism is supported by the implementation of the respective complex therapy. PMID- 29713867 TI - Treatment of adult idiopathic inflammatory myopathies with conventional immunosuppressive drugs : Results of a retrospective study. AB - OBJECTIVES: To gain information about the efficacy of immunosuppressive drugs as first-, second-, and third-line treatment of idiopathic inflammatory myopathies (IIM). METHODS: 112 treatment cycles of 63 patients with dermatomyositis (n = 23), polymyositis (n = 33), overlap syndromes (n = 4), and undifferentiated connective tissue diseases (n = 3) were analyzed by retrospective chart analysis. Data regarding muscle strength, muscle enzymes, treatment duration, and treatment discontinuation were collected. RESULTS: Azathioprine (38 cycles) and methotrexate (MTX; 24 cycles) were applied significantly longer than glucocorticoid monotherapy (9 cycles; 25 +/- 21, 26 +/- 29 and 7 +/- 4 months, respectively; p < 0.05). MTX and azathioprine achieved a significant reduction of serum creatine kinase (CK), with MTX showing more marked effects. Treatment cycles with immunosuppressants other than MTX or azathioprine (n = 22) or with combinations of immunosuppressive drugs (n = 19) were mostly applied as third line therapy, indicating their application in more refractory cases. Significant improvement of muscle strength was confined to MTX and azathioprine and to the first-line treatment. 8% of MTX patients withdrew due to the lack of efficacy, compared with 29% of patients taking azathioprine and 6 of 9 patients taking glucocorticoid monotherapy. In the 12 patients with Jo-1 syndrome, MTX treatment was effective for a longer time than azathioprine (44 +/- 21 months vs. 27 +/- 24 months, p < 0.05). CONCLUSION: Our data confirm the effectiveness of MTX and azathioprine in the treatment of inflammatory myopathies and stress the importance of a potent first-line therapy. PMID- 29713868 TI - A genome-wide analysis of the flax (Linum usitatissimum L.) dirigent protein family: from gene identification and evolution to differential regulation. AB - KEY MESSAGE: Identification of DIR encoding genes in flax genome. Analysis of phylogeny, gene/protein structures and evolution. Identification of new conserved motifs linked to biochemical functions. Investigation of spatio-temporal gene expression and response to stress. Dirigent proteins (DIRs) were discovered during 8-8' lignan biosynthesis studies, through identification of stereoselective coupling to afford either (+)- or (-)-pinoresinols from E coniferyl alcohol. DIRs are also involved or potentially involved in terpenoid, allyl/propenyl phenol lignan, pterocarpan and lignin biosynthesis. DIRs have very large multigene families in different vascular plants including flax, with most still of unknown function. DIR studies typically focus on a small subset of genes and identification of biochemical/physiological functions. Herein, a genome-wide analysis and characterization of the predicted flax DIR 44-membered multigene family was performed, this species being a rich natural grain source of 8-8' linked secoisolariciresinol-derived lignan oligomers. All predicted DIR sequences, including their promoters, were analyzed together with their public gene expression datasets. Expression patterns of selected DIRs were examined using qPCR, as well as through clustering analysis of DIR gene expression. These analyses further implicated roles for specific DIRs in (-)-pinoresinol formation in seed-coats, as well as (+)-pinoresinol in vegetative organs and/or specific responses to stress. Phylogeny and gene expression analysis segregated flax DIRs into six distinct clusters with new cluster-specific motifs identified. We propose that these findings can serve as a foundation to further systematically determine functions of DIRs, i.e. other than those already known in lignan biosynthesis in flax and other species. Given the differential expression profiles and inducibility of the flax DIR family, we provisionally propose that some DIR genes of unknown function could be involved in different aspects of secondary cell wall biosynthesis and plant defense. PMID- 29713869 TI - A zebrafish model of foxe3 deficiency demonstrates lens and eye defects with dysregulation of key genes involved in cataract formation in humans. AB - The Forkhead box E3 (FOXE3) gene encodes a transcription factor with a forkhead/winged helix domain that is critical for development of the lens and anterior segment of the eye. Monoallelic and biallelic deleterious sequence variants in FOXE3 cause aphakia, cataracts, sclerocornea and microphthalmia in humans. We used clustered regularly interspaced short palindromic repeats/Cas9 injections to target the foxe3 transcript in zebrafish in order to create an experimental model of loss of function for this gene. Larvae that were homozygous for an indel variant, c.296_300delTGCAG, predicting p.(Val99Alafs*2), demonstrated severe eye defects, including small or absent lenses and microphthalmia. The lenses of the homozygous foxe3 indel mutants showed more intense staining with zl-1 antibody compared to control lenses, consistent with increased lens fiber cell differentiation. Whole genome transcriptome analysis (RNA-Seq) on RNA isolated from wildtype larvae and larvae with eye defects that were putative homozygotes for the foxe3 indel variant found significant dysregulation of genes expressed in the lens and eye whose orthologues are associated with cataracts in human patients, including cryba2a, cryba1l1, mipa and hsf4. Comparative analysis of this RNA-seq data with iSyTE data identified several lens-enriched genes to be down-regulated in foxe3 indel mutants. We also noted upregulation of lgsn and crygmxl2 and downregulation of fmodb and cx43.4, genes that are expressed in the zebrafish lens, but that are not yet associated with an eye phenotype in humans. These findings demonstrate that this new zebrafish foxe3 mutant model is highly relevant to the study of the gene regulatory networks conserved in vertebrate lens and eye development. PMID- 29713870 TI - ELMOD3, a novel causative gene, associated with human autosomal dominant nonsyndromic and progressive hearing loss. AB - Autosomal dominant nonsyndromic hearing loss (ADNSHL) is a highly genetically heterogeneous disorder. Up to date only approximately 37 ADNSHL-causing genes have been identified. The goal of this study was to determine the causative gene in a five-generation Chinese family with ADNSHL. A Chinese family was ascertained. Simultaneously, two affected individuals and one normal hearing control from the family were analyzed by whole exome capture sequencing. To assess the functional effect of the identified variant, in-vitro studies were performed. novel missense variant, c.512A>G (p.His171Arg) in exon 8 of the ELMO domain-containing 3 (ELMOD3) gene, was identified as a causative variant in this family affected by late-onset and progressive ADNSHL. The variant was validated by Sanger sequencing and found to co-segregate with the phenotype within the pedigree and was absent in 500 ethnically matched unrelated normal hearing control subjects. To our knowledge, this is the first report of a family with ADNSHL caused by ELMOD3 mutation. Western blots and immunofluorescence staining demonstrated that p.His171Arg resulted in abnormal expression levels of ELMOD3 and abnormal subcellular localization. Furthermore, the analysis of the stability of the wild-type (WT) and mutant ELMOD3 protein shows that the decay of p.His171Arg is faster than that of the WT, suggesting a shorter halflife of the c.512A > G variant. A novel variant in the ELMOD3 gene, encoding a member of the engulfment and cell motility (ELMO) family of GTPase-activating proteins, was identified for the first time as responsible for ADNSHL. PMID- 29713872 TI - Evidence for the Adaptive Learning Function of Work and Work-Themed Play among Aka Forager and Ngandu Farmer Children from the Congo Basin. AB - Work-themed play may allow children to learn complex skills, and ethno-typical and gender-typical behaviors. Thus, play may have made important contributions to the evolution of childhood through the development of embodied capital. Using data from Aka foragers and Ngandu farmer children from the Central African Republic, we ask whether children perform ethno- and gender-typical play and work activities, and whether play prepares children for complex work. Focal follows of 50 Aka and 48 Ngandu children were conducted with the aim of recording children's participation in 12 categories of work and work-themed play. Using these data, we test a set of hypotheses regarding how age, gender, ethnicity, and task complexity influence children's activities. As hypothesized, we find performance of work-themed play is negatively correlated with age. Contrary to our hypothesis, children do not play more than they work at complex tasks, but they work more than they play at simple ones. Gender and ethnicity are associated with play and work at culturally salient activities, despite availability of other gender and other-ethnicity social partners. Our findings show that ethnic and gender biases are apparent in the play and work behavior of Aka and Ngandu children. Moreover, our results show that play helps both forager and farmer children learn complex skills, consistent with play having an adaptive learning function. PMID- 29713874 TI - Esophageal Adenocarcinoma Lymphatic Drainage with ICG Fluorescence Imaging. PMID- 29713871 TI - Continued Interest and Controversy: Vitamin D in HIV. AB - PURPOSE OF REVIEW: Vitamin D (VitD) deficiency is highly prevalent among HIV infected individuals. Given the overlapping risk for several chronic disease and immunomodulatory outcomes from both long-standing HIV and VitD deficiency, there is great interest in clarifying the clinical role of VitD for this population. RECENT FINDINGS: Recent studies have expanded our knowledge regarding the epidemiology and mechanisms of VitD deficiency-associated outcomes in the setting of HIV. Clinical trials focusing on VitD supplementation have demonstrated a positive impact on bone mineral density in subgroups of HIV-infected individuals initiating ART or on suppressive ART regimens; however, significant heterogeneity exists between studies and data are less consistent with other clinical outcomes. Further research is needed to clarify uncertainly in several domains, including identifying patients at greatest risk for poor outcomes from VitD deficiency, standardizing definitions and measurement techniques, and better quantifying the benefits and risks of VitD supplementation across different demographic strata for skeletal and extra-skeletal outcomes. PMID- 29713873 TI - Post-ET and Post-PV Myelofibrosis: Updates on a Distinct Prognosis from Primary Myelofibrosis. AB - PURPOSE OF REVIEW: The purpose of this review is to help doctors in the management of patients with post-polycythemia (PPV) and post-essential thrombocythemia (PET) myelofibrosis (MF) facing diagnostic criteria, prognostication, and treatment possibilities. RECENT FINDINGS: Diagnostic criteria of primary myelofibrosis (PMF) have been recently updated from the WHO classification. A clear-cut distinction between pre-fibrotic and overt PMF has been done. Concerning PPV and PET MF, the criteria come from 2008. Prognostication of PMF has been well established on clinical criteria, but recent molecular acquisitions will improve the strategy. For PPV and PET MF, the new MYSEC-PM is helpful for prediction of survival. JAK2-inhibitors and stem cell transplant are the two critical therapeutic approaches in myelofibrosis. Differences between PMF and SMF substantiate the efforts underway to adequately stratify SMF patients with ad hoc prognostic tools and to use such categorization to evaluate available treatment modalities. PMID- 29713875 TI - Impact of Synchronous Liver Resection on the Perioperative Outcomes of Patients Undergoing CRS-HIPEC. AB - BACKGROUND: While liver resection (LR) and cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) are commonly performed for hepatic and peritoneal metastases, respectively, the safety of synchronous LR and CRS-HIPEC has not been established. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) databases from 2005 to 2016 were used to identify patients who underwent CRS-HIPEC. Demographic, clinical, and perioperative outcomes were compared among patients who underwent CRS-HIPEC with and without synchronous LR. RESULTS: Among 1168 patients who underwent CRS-HIPEC, 100 (8.6%) underwent synchronous LR and 1068 (91.4%) did not. The most common primary diagnosis was unspecified (65.3%) followed by appendix (16.0%) and colorectal (12.5%). Among patients who underwent CRS-HIPEC plus LR, the majority had a partial hepatectomy (96.0%), while a small subset underwent trisegmentectomy (2.0%) or hemihepatectomy (2.0%). Patients who underwent CRS-HIPEC plus LR underwent a greater number of operative procedures (8.3 +/- 2.5 vs 6.7 +/- 2.5, p < 0.001), had a longer operative time (520.7 +/- 155.3 vs 454.6 +/- 160.7 min, p = 0.001), had a longer hospital length of stay (16.7 +/- 15.6 vs 11.1 +/- 11.5 days, p < 0.001), were more likely to require reoperation (13.0 vs 6.9%, p = 0.03), and experienced greater 30-day morbidity (47.0 vs 27.4%, p < 0.001), but not mortality (3.0 vs 1.4%, p = 0.22). On multivariate logistic regression, LR was strongly associated with increased risk of postoperative morbidity even after controlling for potential confounders (OR 1.65, 95% CI 1.03-2.64). CONCLUSIONS: Simultaneous LR and CRS-HIPEC was associated with increased operative time, length of hospital stay, reoperation, and postoperative morbidity compared to CRS-HIPEC alone. For patients with synchronous hepatic and peritoneal metastases, a staged operative approach should be considered. PMID- 29713876 TI - Because it's 2018: women in Canadian anesthesiology. PMID- 29713877 TI - In reply to "Because it's 2018: Women in Canadian Anesthesiology". PMID- 29713878 TI - Cardiac computed tomography as a viable alternative to echocardiography to detect vegetations and perivalvular complications in patients with infective endocarditis. AB - PURPOSE: We considered cardiac computed tomography (CT) as a possible alternative modality to echocardiography in the assessment of infective endocarditis (IE). We evaluated the diagnostic capability of preoperative CT. MATERIALS AND METHODS: We retrospectively evaluated the depiction of vegetations and perivalvular complications in preoperative cardiac CT images of 14 patients diagnosed with IE who required surgical intervention, who were seen at our institution from May 30, 2008 to February 3, 2017. We compared the CT findings with those of TTE and TEE assessments, and intraoperative findings. RESULTS: Cardiac CT correctly identified intraoperatively proven vegetations in 12 out of 13 (92.3%) patients and demonstrated 100% sensitivity and positive predictive value in depicting vegetations in the aortic valve and 100% sensitivity, specificity, positive predictive value, and negative predictive value in depicting pseudoaneurysm as perivalvular complications. CT offered superior identification of pseudoaneurysm to that with echocardiography and detected vegetations as small as 6 mm in maximal length. Vegetation size correlated well between TEE and CT. CONCLUSION: Favorable comparison of CT and echocardiography in detecting vegetations and perivalvular complications in patients diagnosed with IE suggested potential for expansion in the use of CT for evaluating organic lesions in patients suspected or diagnosed with IE. PMID- 29713879 TI - Evaluation of Pharmacist Involvement in Outpatient Transitions of Care. PMID- 29713880 TI - Number of grant applications needed to fund research faculty: a probabilistic analysis. PMID- 29713881 TI - On the Value of the Primary Care Physician. PMID- 29713882 TI - The Elusive and Illusive Quest for Diagnostic Safety Metrics. PMID- 29713883 TI - It Is Time to Liberate Hospitals from Profit-Centered Care. PMID- 29713884 TI - Gout and Hypothyroidism in the Elderly: an Observational Cohort Study Using U.S. Medicare Claims Data. PMID- 29713885 TI - Supracricoid partial laryngectomy for radiorecurrent laryngeal cancer: a systematic review of the literature and meta-analysis. AB - PURPOSE: The objective of the current systematic review with meta-analysis was to report the pooled survival outcomes of supracricoid partial laryngectomy in the setting of radiorecurrent laryngeal cancer to investigate if and when an organ sparing surgical treatment is adequate. METHODS: The search included all original papers from 1990 to December 2017. The search terms included the following: cricohyoepiglottopexy; cricohyoidopexy; cricohyopexy; horizontal laryngectomy; and partial, subtotal, supracricoid, and supraglottic laryngectomy. Inclusion criteria were as follows: (1) data clearly distinguish results of partial laryngeal procedures; (2) clear description of tumor stage and selection criteria; (3) clear description or derivability of local control and survival rates. RESULTS: Eleven out of 270 papers were analyzed, and a total of 251 cases were included. Two-year LC, 3-year DFS, and 5-year OS were 92, 80, and 79%, respectively. Heterogenicity evaluated with the I2 parameter was 14, 0, 0%, respectively. The larynx preservation rate was 85.2%, the decannulation rate was 92.1%, and swallowing recovery was 96.5% (PEG dependence and the aspiration pneumonia rate were 3.5 and 6.4%, respectively). CONCLUSIONS: SCPL is oncologically sound, guaranteeing a high percentage of success. The homogeneity of data should encourage the use of SCPL as salvage treatment for recurrent LSCC. PMID- 29713887 TI - Direct restoration of endodontically treated maxillary central incisors: post or no post at all? AB - OBJECTIVES: The aim of this ex-vivo study was to evaluate the impact of cavity size and glass-fiber post (GFP) placement on the load capability of endodontically treated maxillary incisors directly restored with resin composite. MATERIALS AND METHODS: Ninety-six extracted human maxillary central incisors were endodontically treated and distributed to four groups (n = 24): access cavity (A), access cavity and uni-proximal class III cavity (U), access cavity and bi proximal class III cavity (B), and decoronated tooth (D). Specimens were restored with resin composite, and 12 specimen of each group received an adhesively placed glass-fiber post (P). Prior to linear loading, specimens were exposed to thermo mechanical loading (TCML). Statistical analysis was performed using log-rank test after TCML, Kruskall-Wallis and Mann-Whitney U test to compare load capabilities (Fmax). RESULTS: Significantly more failures occurred in group D for specimens without GFP during TCML (p = 0.001). Fmax (mean (SD) in N was (A) 513 (124), (AP) 554 (201), (U) 438 (171), (UP) 537 (232) (B) 483 (219), (BP) 536 (281), D 143 (181), and DP 500 (331), and differed significantly among groups (p = 0.003). Pair-wise comparison revealed lower Fmax values for group D compared to all other groups (p < 0.034) except group DP. CONCLUSIONS: Endodontically treated maxillary central incisors with cavity sizes up to bi-proximal class III may be successfully directly restored with resin composite. Post placement shows no additional effect except for decoronated endodontically treated incisors. CLINICAL RELEVANCE: Endodontically treated incisors with access cavities to class III cavities can be successfully restored with resin composite. Post placement for decoronated ETT is recommended. PMID- 29713886 TI - Comparison of narrow band imaging and the Storz Professional Image Enhancement System for detection of laryngeal and hypopharyngeal pathologies. AB - OBJECTIVE: The aim of this study was to compare narrow band imaging (NBI) endoscopy and Storz Professional Image Enhancement System (SPIES) in observing epithelial and/or subepithelial microvascular irregularities and pathologies. METHODS: A total of 73 patients with laryngeal or hypopharyngeal lesions were investigated using high-definition NBI endoscopy preoperatively in local anesthesia and using SPIES system intraoperatively in general anesthesia from August 2016 to October 2017. Superficial vascular structures were classified preoperatively (NBI) and intraoperatively (SPIES) according to descriptive guidelines of vascular changes by Arens. All lesions were endoscopically evaluated and divided according to the histological examination into four groups (A-benign lesions, B-recurrent respiratory papillomatosis, C-low-grade dysplasia, D-high-grade dysplasia, carcinoma in situ or invasive squamous cell carcinoma), and results were compared with NBI and SPIES optical biopsy. RESULTS: Benign lesions (polyps, cysts, chronic inflammation, hyperkeratosis) were histologically confirmed in 26/73 (35.6%) cases and identified by NBI in 20/26 lesions (76.9%) and in 20/26 cases (76.9%) by SPIES, respectively. Recurrent respiratory papillomatosis was confirmed in 16/73 (21.9%) and detected in 15/16 cases (93.8%) by NBI and in 16/16 cases (100.0%) by SPIES. Low-grade dysplasia (mild and moderate dysplasia) was histologically detected in 7/73 patients (9.6%) and accurately identified by NBI in 6/7 (85.7%) and by SPIES in 6/7 (85.7%) cases, respectively. Histopathological features of severe dysplasia, carcinoma in situ or invasive squamous cell carcinoma were detected in 24/73 (32.9%) patients. According to the NBI endoscopy the suspected vascular neoangiogenesis was recognized in 19/24 cases (79.2%) and in 18/24 cases (75.0%) using SPIES endoscopy. Sensitivity and specificity of NBI endoscopy and SPIES system in correct prediction of histological diagnosis of already detected lesions were 83.0 and 98.0% and 86.0 and 96.0%, respectively. Results of NBI/SPIES endoscopy and histopathological features of laryngeal and hypopharyngeal lesions were compared and the level of agreement was 81.43%, kappa index kappa = 0.7428 (95% CI 0.682-0.832) (p < 0.001) by NBI endoscopy and 81.16%, kappa index kappa = 0.7379 (95% CI 0.638-0.880) (p < 0.001) by SPIES endoscopy, respectively. The agreement was confirmed as substantial and strong. Level of agreement of both endoscopic methods was 92.54%, kappa index kappa = 0.8965 (95% CI 0.877-0.954) (p < 0.001), agreement was confirmed as almost perfect. Between NBI and SPIES endoscopic imaging methods is no significant differentiation. CONCLUSION: Both methods, NBI endoscopy and SPIES system, are comparable in detection and analysis of superficial neoangiogenesis, typical for benign lesion and for precancerous or cancerous changes in larynx and hypopharynx. PMID- 29713888 TI - Gingival crevicular fluid levels of human beta-defensin-1 in type 2 diabetes mellitus and periodontitis. AB - OBJECTIVES: Human beta-defensin (hBD)-1 is an important gatekeeper of the gingiva against constant bacterial challenge, and glucose levels are involved in its optimal expression. The aims of the study were to investigate hBD-1 levels in gingival crevicular fluid (GCF) and to compare these levels between type 2 diabetics with or without periodontitis and healthy individuals. MATERIALS AND METHODS: Altogether, 81 subjects were included in the study: 21 subjects with type 2 diabetes mellitus (T2DM) suffering from generalized periodontitis (T2DM + GP), 18 systemically healthy generalized periodontitis patients (GP), 18 periodontally healthy T2DM subjects (T2DM + H), and 24 systemically and periodontally healthy subjects (control). Plaque index (PI), gingival index (GI), probing pocket depth (PPD), and clinical attachment level (CAL) were recorded, and GCF samples were collected. hBD-1 levels in GCF were measured using ELISA. RESULTS: hBD-1 levels were significantly reduced in the T2DM + GP and GP groups. Although PI and GI scores were similar in both periodontally healthy groups, hBD 1 levels were lower in the T2DM + H group. In the whole population, hBD-1 levels correlated negatively with all periodontal parameters. CONCLUSIONS: Both diabetes and periodontitis affect hBD-1 levels in GCF. CLINICAL RELEVANCE: The altered levels of hBD-1 in GCF of diabetics might be associated with the susceptibility of diabetics to periodontitis. PMID- 29713889 TI - Acellular dermal matrix allograft versus free gingival graft: a histological evaluation and split-mouth randomized clinical trial. AB - OBJECTIVES: This split-mouth controlled randomized clinical trial evaluated clinical and histological results of acellular dermal matrix allograft (ADM) compared to autogenous free gingival graft (FGG) for keratinized tissue augmentation. MATERIAL AND METHODS: Twenty-five patients with the absence or deficiency of keratinized tissue (50 sites) were treated with FGG (control group) and ADM (test group). Clinical parameters included keratinized tissue width (KTW) (primary outcome), soft tissue thickness (TT), recession depth (RD), probing depth (PD), and clinical attachment level (CAL). Esthetic perception was evaluated by patients and by a calibrated periodontist using visual analog scale (VAS). Histological analysis included biopsies of five different patients from both test and control sites for each evaluation period (n = 25). The analysis included percentage of connective tissue components, epithelial luminal to basal surface ratio, tissue maturation, and presence of elastic fibers. Data were evaluated by ANOVA complemented by Tukey's tests (p < 0.05). RESULTS: After 6 months, PD and CAL demonstrated no differences between groups. ADM presented higher RD compared to FGG in all periods. Mean tissue shrinkage for control and test groups was 12.41 versus 55.7%. TT was inferior for ADM group compared to FGG. Esthetics perception by professional evaluation showed superior results for ADM. Histomorphometric analysis demonstrated higher percentage of cellularity, blood vessels, and epithelial luminal to basal surface ratio for FGG group. ADM group presented higher percentage of collagen fibers and inflammatory infiltrate. CONCLUSIONS: Both treatments resulted in improvement of clinical parameters, except for RD. ADM group presented more tissue shrinkage and delayed healing, confirmed histologically, but superior professional esthetic perception. CLINICAL RELEVANCE: This study added important clinical and histological data to contribute in the decision-making process between indication of FGG or ADM. PMID- 29713890 TI - Pain perception following epithelialized gingival graft harvesting: a randomized clinical trial. AB - OBJECTIVES: The aim of this study was to compare the effects of a hemostatic collagen sponge and a collagen sponge sealed with a bio-adhesive material on the palatal donor sites with the purpose of minimizing postoperative pain after epithelialized gingival graft (EGG) harvesting. MATERIAL AND METHODS: The present study consisted of 44 EGGs harvested in 44 patients. In the control group, a hemostatic collagen sponge was applied over the palatal wound, while the test group was treated with additional cyanoacrylate. Patients were observed for 14 days, evaluating the pain level by using the visual analogic scale. The consumption of analgesic during the postoperative period, the willingness for retreatment and the characteristic of the graft were also analyzed. RESULTS: Statistically significant differences in pain perception were found between test and control groups in each of the studied days (p < 0.01). Analgesic consumption was lower in the test group (p < 0.01). Graft width < 14 mm was found to be associated with lower discomfort (p < 0.01). CONCLUSIONS: Adding an additional layer of cyanoacrylate over a hemostatic collagen sponge on the palatal wound following EGG harvesting was found to be successful in minimizing the postoperative discomfort and the need for analgesics. CLINICAL RELEVANCE: Postoperative pain after palatal tissue harvesting can be successfully minimized if the donor site open wound is protected with an external layer of cyanoacrylate over a collagen sponge. PMID- 29713892 TI - What is This Image? 2018: Image 1. PMID- 29713891 TI - Comparison of light propagation in dental tissues and nano-filled resin-based composite. AB - OBJECTIVE: This study used three LASERs (red, green, and blue) with a spectrophotometer to compare the light propagation for the following: absorption (A), transmittance (T), attenuation (K), and scattering anisotropy coefficient (g) in dental tissues and nano-filled resin-based composites. This study used three distinct incremental build-up techniques, which included one shade (body), two shades (enamel and dentin), and three shades (enamel, transparent, and dentin). METHODS: Twenty human, un-erupted, recently extracted third molars (shade B1) were used to obtain 40 tooth slabs. The samples were randomized and equally distributed into four experimental groups. The Positive Control Group included dental tissues with enamel, dento-enamel junction DEJ, and dentin; the Technique 1 group (T1) included one shade tissues, B1B; the Technique 2 group (T2) included two-shades tissues, A2Dentin and B1Enamel; and the Technique 3 group (T3) included three shade tissues, A2Dentin, Transparent, and B1Enamel. Cavity preparation was standardized, and, using the spectrophotometer, each specimen was irradiated by three LASERs. A voltmeter recorded the light-output signal, and from this raw data, the following optical constants (A, T, K, g) were calculated. RESULTS: ANOVA, followed by a post hoc Tukey's test (p < 0.05), revealed that absorption and transmittance in dental tissues were significantly different when comparing the three build-up technique groups. However, when examining attenuation coefficient, there was no significant difference in dental tissues for T2 and T3 as analyzed by blue and red lasers. There was also no significant difference among the three lasers for T2 and T3. There was also no significant effect of the types of experiments on the value of scattering anisotropy factor g for blue laser among the four experimental groups. CONCLUSION: Within the limitations of this study, none of the build-up techniques were able to reproduce the dental tissues optical properties, and T2 and T3 resulted in a similar pattern of light propagation. CLINICAL SIGNIFICANCE: The clinical success of restorative procedures depends on selecting materials and techniques that emulate the natural tooth and provide long-term stability in color and optical properties. PMID- 29713893 TI - Property and human genetic information. AB - Do donors (of samples from which genetic information is derived) have some sort of pre-legal (moral) or legal property right to that information? In this paper, we address this question from both a moral philosophical and a legal point of view. We argue that philosophical theories about property do not seem to support a positive answer: We have not mixed our labour with our genes, and the human genome cannot be said to be a fitting object for private ownership based on some idea of self-ownership. An analysis of the term 'property' as seen from a legal perspective yields the conclusion that property is, at best, a linguistic prop whose real content has to be defined at least partially conventionally. Relevant interests that may be seen to be protected seem to be interests of privacy or interests against exploitation. To the extent that the logic behind the patent system holds true limiting incentives decreases innovation in society. A balancing of interest must take place, and we have to make sure that patent protection serves general societal interests and not just those of special interest groups be that inventors or donors. PMID- 29713894 TI - Fluoxetine is Neuroprotective in Early Brain Injury via its Anti-inflammatory and Anti-apoptotic Effects in a Rat Experimental Subarachnoid Hemorrhage Model. AB - Fluoxetine, an anti-depressant drug, has recently been shown to provide neuroprotection in central nervous system injury, but its roles in subarachnoid hemorrhage (SAH) remain unclear. In this study, we aimed to evaluate whether fluoxetine attenuates early brain injury (EBI) after SAH. We demonstrated that intraperitoneal injection of fluoxetine (10 mg/kg per day) significantly attenuated brain edema and blood-brain barrier (BBB) disruption, microglial activation, and neuronal apoptosis in EBI after experimental SAH, as evidenced by the reduction of brain water content and Evans blue dye extravasation, prevention of disruption of the tight junction proteins zonula occludens-1, claudin-5, and occludin, a decrease of cells staining positive for Iba-1, ED-1, and TUNEL and a decline in IL-1beta, IL-6, TNF-alpha, MDA, 3-nitrotyrosine, and 8-OHDG levels. Moreover, fluoxetine significantly improved the neurological deficits of EBI and long-term sensorimotor behavioral deficits following SAH in a rat model. These results indicated that fluoxetine has a neuroprotective effect after experimental SAH. PMID- 29713895 TI - Mutant Huntingtin Causes a Selective Decrease in the Expression of Synaptic Vesicle Protein 2C. AB - Huntington's disease (HD) is a neurodegenerative disease caused by a polyglutamine expansion in the huntingtin (Htt) protein. Mutant Htt causes synaptic transmission dysfunctions by interfering in the expression of synaptic proteins, leading to early HD symptoms. Synaptic vesicle proteins 2 (SV2s), a family of synaptic vesicle proteins including 3 members, SV2A, SV2B, and SV2C, plays important roles in synaptic physiology. Here, we investigated whether the expression of SV2s is affected by mutant Htt in the brains of HD transgenic (TG) mice and Neuro2a mouse neuroblastoma cells (N2a cells) expressing mutant Htt. Western blot analysis showed that the protein levels of SV2A and SV2B were not significantly changed in the brains of HD TG mice expressing mutant Htt with 82 glutamine repeats. However, in the TG mouse brain there was a dramatic decrease in the protein level of SV2C, which has a restricted distribution pattern in regions particularly vulnerable in HD. Immunostaining revealed that the immunoreactivity of SV2C was progressively weakened in the basal ganglia and hippocampus of TG mice. RT-PCR demonstrated that the mRNA level of SV2C progressively declined in the TG mouse brain without detectable changes in the mRNA levels of SV2A and SV2B, indicating that mutant Htt selectively inhibits the transcriptional expression of SV2C. Furthermore, we found that only SV2C expression was progressively inhibited in N2a cells expressing a mutant Htt containing 120 glutamine repeats. These findings suggest that the synaptic dysfunction in HD results from the mutant Htt-mediated inhibition of SV2C transcriptional expression. These data also imply that the restricted distribution and decreased expression of SV2C contribute to the brain region selective pathology of HD. PMID- 29713896 TI - Pink1 -/- Rats Show Early-Onset Swallowing Deficits and Correlative Brainstem Pathology. AB - Parkinson disease (PD) compromises oropharyngeal swallowing, which negatively affects quality of life and contributes to aspiration pneumonia. Dysphagia often begins early in the disease process, and does not improve with standard therapies. As a result, swallowing deficits are undertreated in the PD population. The Pink1 -/- rat is used to model PD, and demonstrates widespread brainstem neuropathology in combination with early-onset sensorimotor dysfunction; however, to date, swallowing behaviors have not been evaluated. To test the hypothesis that Pink1 -/- rats demonstrate early-onset differences in swallowing, we analyzed within-subject oropharyngeal swallowing using videofluoroscopy. Pink1 -/- and wildtype (WT) controls at 4 (Pink1 -/- n = 16, WT = 16) and 8 (Pink1 -/- n = 12, WT = 12) months of age were tested. The average and maximum bolus size was significantly increased in Pink1 -/- rats at both 4 and 8 months. Bolus average velocity was increased at 8 months for all animals; yet, Pink1 -/- animals had significantly increased velocities compared to WT at 8 months. The data show a significant reduction in mastication rate for Pink1 -/- rats at 8 months suggesting the onset of oromotor dysfunction begins at this time point. Relationships among swallowing variables and neuropathological findings, such as increased alpha-synuclein protein in the nucleus ambiguus and reductions in noradrenergic cells in the locus coeruleus in the Pink1 -/- rats, were determined. The presence of early oropharyngeal swallowing deficits and relationships to brainstem pathology in Pink1-/- rat models of PD indicate that this may be a useful model of early swallowing deficits and their mechanisms. These findings suggest clinical implications for early detection and management of dysphagia in PD. PMID- 29713897 TI - Coordination of Pharyngeal and Laryngeal Swallowing Events During Single Liquid Swallows After Oral Endotracheal Intubation for Patients with Acute Respiratory Distress Syndrome. AB - To evaluate timing and duration differences in airway protection and esophageal opening after oral intubation and mechanical ventilation for acute respiratory distress syndrome (ARDS) survivors versus age-matched healthy volunteers. Orally intubated adult (>= 18 years old) patients receiving mechanical ventilation for ARDS were evaluated for swallowing impairments via a videofluoroscopic swallow study (VFSS) during usual care. Exclusion criteria were tracheostomy, neurological impairment, and head and neck cancer. Previously recruited healthy volunteers (n = 56) served as age-matched controls. All subjects were evaluated using 5-ml thin liquid barium boluses. VFSS recordings were reviewed frame-by frame for the onsets of 9 pharyngeal and laryngeal events during swallowing. Eleven patients met inclusion criteria, with a median (interquartile range [IQR]) intubation duration of 14 (9, 16) days, and VFSSs completed a median of 5 (4, 13) days post-extubation. After arrival of the bolus in the pharynx, ARDS patients achieved maximum laryngeal closure a median (IQR) of 184 (158, 351) ms later than age-matched, healthy volunteers (p < 0.001) and it took longer to achieve laryngeal closure with a median (IQR) difference of 151 (103, 217) ms (p < 0.001), although there was no significant difference in duration of laryngeal closure. Pharyngoesophageal segment opening was a median (IQR) of - 116 (- 183, 1) ms (p = 0.004) shorter than in age-matched, healthy controls. Evaluation of swallowing physiology after oral endotracheal intubation in ARDS patients demonstrates slowed pharyngeal and laryngeal swallowing timing, suggesting swallow-related muscle weakness. These findings may highlight specific areas for further evaluation and potential therapeutic intervention to reduce post extubation aspiration. PMID- 29713898 TI - Pharmacogenetics of Chemotherapy-Induced Cardiotoxicity. AB - PURPOSE OF REVIEW: The goal of this review is to summarize current understanding of pharmacogenetics and pharmacogenomics in chemotherapy-induced cardiotoxicity. RECENT FINDINGS: Most of the studies rely on in vitro cytotoxic assays. There have been several smaller scale candidate gene approaches and a handful of genome wide studies linking genetic variation to susceptibility to chemotherapy-induced cardiotoxicity. Currently, pharmacogenomic testing of all childhood cancer patients with an indication for doxorubicin or daunorubicin therapy for RARG rs2229774, SLC28A3 rs7853758, and UGT1A6*4 rs17863783 variants is recommended. There is no recommendation regarding testing in adults. There is clear evidence pointing to the role of pharmacogenetics and pharmacogenomics in cardiotoxicity susceptibility to chemotherapeutic agents. Larger scale studies are needed to further identify susceptibility markers and to develop pharmacogenomics-based risk profiling to improve quality of life and life expectancy in cancer survivors. PMID- 29713900 TI - Correction to: Acanthamoeba of three morphological groups and distinct genotypes exhibit variable and weakly inter-related physiological properties. AB - The authors recognized a mistake in Abstract and in the Discussion section. PMID- 29713899 TI - Global Diversity and Distribution of Hantaviruses and Their Hosts. AB - Rodents represent 42% of the world's mammalian biodiversity encompassing 2,277 species populating every continent (except Antarctica) and are reservoir hosts for a wide diversity of disease agents. Thus, knowing the identity, diversity, host-pathogen relationships, and geographic distribution of rodent-borne zoonotic pathogens, is essential for predicting and mitigating zoonotic disease outbreaks. Hantaviruses are hosted by numerous rodent reservoirs. However, the diversity of rodents harboring hantaviruses is likely unknown because research is biased toward specific reservoir hosts and viruses. An up-to-date, systematic review covering all known rodent hosts is lacking. Herein, we document gaps in our knowledge of the diversity and distribution of rodent species that host hantaviruses. Of the currently recognized 681 cricetid, 730 murid, 61 nesomyid, and 278 sciurid species, we determined that 11.3, 2.1, 1.6, and 1.1%, respectively, have known associations with hantaviruses. The diversity of hantaviruses hosted by rodents and their distribution among host species supports a reassessment of the paradigm that each virus is associated with a single-host species. We examine these host-virus associations on a global taxonomic and geographical scale with emphasis on the rodent host diversity and distribution. Previous reviews have been centered on the viruses and not the mammalian hosts. Thus, we provide a perspective not previously addressed. PMID- 29713902 TI - Occurrence of two novel actinospore types (Cnidaria: Myxozoa) in fish farms in Mato Grosso do Sul state, Brazil. AB - We investigated the involvement of oligochaetes in the life cycles of fresh water myxozoan parasites in Brazil. In a fish farm in the State of Mato Grosso do Sul, we examined 192 oligochaetes and found that two (1%) released Aurantiactinomyxon type actinospores. We identified infected oligochaetes by morphology: both were Pristina synclites, from family Naididae. This is the first report of the involvement of this species in the life cycle of myxozoans. Small-subunit ribosomal DNA sequences of Aurantiactinomyxon type 1 (1882 nt) and Aurantiactinomyxon type 2 (1900 nt) did not match any previously sequenced myxozoan in the NCBI database, with the highest BLAST search similarities of 83% with Myxobolus batalhensis MF361090 and 93% with Henneguya maculosus KF296344, respectively, and the two aurantiactinomyxons were only 75% similar to each other (over ~ 1900 bases). Phylogenetic analyses showed that Aurantiactinomyxon type 1 had closest affinities with myxozoans from fish hosts in Order Characiformes, and Aurantiactinomyxon type 2 had affinities with myxozoans from fish of Order Siluriformes. PMID- 29713901 TI - Efficacy of larvicides for the control of dengue, Zika, and chikungunya vectors in an urban cemetery in southern Mexico. AB - Many countries in Latin America have recently experienced outbreaks of Zika and chikungunya fever, in additional to the usual burden imposed by dengue, all of which are transmitted by Aedes aegypti in this region. To identify potential larvicides, we determined the toxicity of eight modern insecticides to A. aegypti larvae from a colony that originated from field-collected insects in southern Mexico. The most toxic compounds were pyriproxyfen (which prevented adult emergence) and lambda-cyhalothrin, followed by spinetoram, imidacloprid, thiamethoxam, and acetamiprid, with chlorantraniliprole and spiromesifen the least toxic products. Field trails performed in an urban cemetery during a chikungunya epidemic revealed that insecticide-treated ovitraps were completely protected from the presence of Aedes larvae and pupae for 6 and 7 weeks in spinosad (Natular G30) and lambda-cyhalothrin-treated traps in both seasons, respectively, compared to 5-6 weeks for temephos granule-treated ovitraps, but was variable for pyriproxyfen-treated ovitraps with and 1 and 5 weeks of absolute control in the dry and rainy seasons, respectively. Insecticide treatments influenced the mean numbers of Aedes larvae + pupae in each ovitrap, mean numbers of eggs laid, and percentage of egg hatch over time in both trials. The dominant species was A. aegypti in both seasons, although the invasive vector Aedes albopictus was more prevalent in the rainy season (26.7%) compared to the dry season (10.2%). We conclude that the granular formulation of spinosad (Natular G30) and a suspension concentrate formulation of lambda-cyhalothrin proved highly effective against Aedes spp. in both the dry and rainy seasons in the cemetery habitat in this region. PMID- 29713903 TI - Ceratomyxa gouletti n. sp. (Myxosporea: Ceratomyxidae), a parasite of the red scorpionfish Scorpaena scrofa (L.) from Tunisian waters. AB - Ceratomyxa gouletti n. sp. is a new parasite described from the gallbladder of the red scorpionfish Scorpaena scrofa (Scorpaeniformes: Scorpaenidae) collected from La Goulette in the Northeast of Tunisia. The parasite develops disporic plasmodia, elliptical to ovoid in shape, measuring up to 33.1 +/- 3.6 (28.0-38.2) MUm in length and 12.5 +/- 2.1 (11.3-14.0) MUm in width. Mature spores are elongated transversely and crescent-shaped with rounded ends and unequal shell valves, measuring 8.1 +/- 1.27 (7.2-9.0) MUm in length and 32.0 +/- 2.5 (27.0 38.2) MUm in thickness. Sutural line is straight and visible between valves. Polar capsules are subspherical with 3.15 +/- 0.63 (2.7-3.6) MUm long and 1.9 +/- 0.14 (1.8-2.0) MUm wide. Posterior spore angle is slightly concave 160 degrees 175 degrees . Molecular analysis based on the small subunit 18S rDNA sequence shows that C. gouletti n. sp. is different from all other ceratomyxid species DNA sequences in GenBank. Phylogenetic trees clustered the new species with long branching Ceratomyxa species, and it was closely related to the species Ceratomyxa longipes from two gadid fish hosts with 89% bootstrap support. PMID- 29713904 TI - Gene expression changes in the retina after systemic administration of aldosterone. AB - PURPOSE: Retinal ganglion cell (RGC) loss associated with thinning of the retinal nerve fiber layer without elevated intraocular pressure (IOP) occurs after the systemic administration of aldosterone. Since it is important to determine the mechanism of cell death independent of the IOP, we examined gene expression changes in the retina after the systemic administration of aldosterone. METHODS: Following subcutaneous implantation of an osmotic minipump into the mid-scapular region of rats, we administered an 80 MUg/kg/day dose of aldosterone. Differences in the gene expression in the retina between normal rats and aldosterone-treated rats were investigated using microarrays. Real-time PCR was used to confirm the differential expression. RESULTS: Analysis of the microarray data sets revealed the upregulation of 24 genes and the downregulation of 24 genes of key apoptosis specific genes. Real-time PCR revealed 4 genes (Cdkn1a, Tbox5, Pf4, Vdr) were upregulated while 12 genes (Acvr1c, Asns, Bard1, Card9, Crh, Fcgr1a, Inhba, Kcnh8, Lck, Phlda1, Ptprc, Sh3rf1) were downregulated. CONCLUSIONS: Significant increases and decreases were noted in several genes after the systemic administration of aldosterone. Further studies will need to be undertaken in order to definitively clarify the role of these genes in the eyes of animals with normal-tension glaucoma. PMID- 29713905 TI - Auto-immune hepatitis in a patient with multiple sclerosis treated with alemtuzumab. PMID- 29713906 TI - A case of adult-onset poststreptococcal opsoclonus-myoclonus syndrome. PMID- 29713907 TI - Association of CALM1 rs3179089 Polymorphism with Ischemic Stroke in Chinese Han Population. AB - A quantitative transcriptomics analysis has reported that Calmodulin 1 (CALM1) is highly expressed in human brain tissues. This study aims to evaluate the relationship between CALM1 rs3179089 polymorphism and ischemic stroke (IS) in Chinese Han population. A total of 550 patients with IS and 550 control subjects were recruited and genotyped using Sequenom MassArray technology. The mRNA expression of CALM1 was measured using quantitative real-time polymerase chain reaction. CALM1 mRNA expression was significantly higher in patients with IS than that in control subjects (P = 0.006). The genomic frequency distribution was significantly different between female patients with IS and female controls (chi2 = 6.043, P = 0.047). In recessive model, CALM1 rs3179089 polymorphism was associated with the risk of IS in female patients. GG genotype significantly increased the risk of IS compared with the CC+GC genotype in females (OR 8.68, P = 0.042; adjusted OR 8.72, Padj = 0.042). Rs3179089 polymorphism was associated positively with plasmas D-Dimer of patients with IS in recessive model (betaa = 3.24, P = 0.018; betab = 3.20, Padj = 0.019). Moreover, rs3179089 polymorphism was related positively to thrombin time of patients with IS in addictive (betaa = 2.32, P = 0.005, betab = 2.26, Padj=0.006) and recessive model (betaa = 11.19, P = 0.001, betab = 11.13, Padj = 0.001). CALM1 expression was involved in the development of IS. CALM1 rs3179089 polymorphism was associated with IS risk in Chinese females, and related to blood coagulation of IS patients. PMID- 29713908 TI - When to trust our learners? Clinical teachers' perceptions of decision variables in the entrustment process. AB - INTRODUCTION: Clinical training programs increasingly use entrustable professional activities (EPAs) as focus of assessment. However, questions remain about which information should ground decisions to trust learners. This qualitative study aimed to identify decision variables in the workplace that clinical teachers find relevant in the elaboration of the entrustment decision processes. The findings can substantiate entrustment decision-making in the clinical workplace. METHODS: Focus groups were conducted with medical and veterinary clinical teachers, using the structured consensus method of the Nominal Group Technique to generate decision variables. A ranking was made based on a relevance score assigned by the clinical teachers to the different decision variables. Field notes, audio recordings and flip chart lists were analyzed and subsequently translated and, as a form of axial coding, merged into one list, combining the decision variables that were similar in their meaning. RESULTS: A list of 11 and 17 decision variables were acknowledged as relevant by the medical and veterinary teacher groups, respectively. The focus groups yielded 21 unique decision variables that were considered relevant to inform readiness to perform a clinical task on a designated level of supervision. The decision variables consisted of skills, generic qualities, characteristics, previous performance or other information. We were able to group the decision variables into five categories: ability, humility, integrity, reliability and adequate exposure. DISCUSSION: To entrust a learner to perform a task at a specific level of supervision, a supervisor needs information to support such a judgement. This trust cannot be credited on a single case at a single moment of assessment, but requires different variables and multiple sources of information. This study provides an overview of decision variables giving evidence to justify the multifactorial process of making an entrustment decision. PMID- 29713909 TI - Effects of Rifaximin on Central Responses to Social Stress-a Pilot Experiment. AB - Probiotics that promote the gut microbiota have been reported to reduce stress responses, and improve memory and mood. Whether and how antibiotics that eliminate or inhibit pathogenic and commensal gut bacteria also affect central nervous system functions in humans is so far unknown. In a double-blinded randomized study, 16 healthy volunteers (27.00 +/- 1.60 years; 9 males) received either rifaximin (600 mg/day) (a poorly absorbable antibiotic) or placebo for 7 days. Before and after the drug intervention, brain activities during rest and during a social stressor inducing feelings of exclusion (Cyberball game) were measured using magnetoencephalography. Social exclusion significantly affected (p < 0.001) mood and increased exclusion perception. Magnetoencephalography showed brain regions with higher activations during exclusion as compared to inclusion, in different frequency bands. Seven days of rifaximin increased prefrontal and right cingulate alpha power during resting state. Low beta power showed an interaction of intervention (rifaximin, placebo) * condition (inclusion, exclusion) during the Cyberball game in the bilateral prefrontal and left anterior cingulate cortex. Only in the rifaximin group, a decrease (p = 0.004) in power was seen comparing exclusion to inclusion; the reduced beta-1 power was negatively correlated with a change in the subjective exclusion perception score. Social stress affecting brain functioning in a specific manner is modulated by rifaximin. Contrary to our hypothesis that antibiotics have advert effects on mood, the antibiotic exhibited stress-reducing effects similar to reported effects of probiotics (supported by NeuroGUT, a EU 7th Framework Programme ITN no. 607652; ClinicalTrials.gov identifier number NCT02793193). PMID- 29713911 TI - Early intervention using high-precision radiotherapy preserved visual function for five consecutive patients with optic nerve sheath meningioma. AB - BACKGROUND: There has been a paradigm shift in the treatment for optic nerve sheath meningioma (ONSM) from surgery to fractionated stereotactic radiotherapy (FSRT) in other countries. However, FSRT has seldom been performed in Japan. The purpose of this retrospective study is to reconfirm the effectiveness of early intervention with precision radiotherapy for ONSM reported in our previous study. METHODS: Five consecutive patients with ONSM were retrospectively analyzed. All patients underwent intensity-modulated radiotherapy (IMRT) or FSRT. They received the early interventions between 1.5 and 7 months after deterioration of the disease. The median dose was 52.8 Gy (range 46.0-59.4 Gy) and the median number of fractions was 25 (range 22-33). RESULTS: All patients experienced reestablishment of vision at the median follow-up time of 36 months (range 18-54 months). Four of them noted early improvement of visual deficits during the treatment course (range 2-4 weeks) and the remaining patient improved 3 weeks after completion of IMRT. The median tumor reduction was 53% (range 39-75%). One patient with diabetes mellitus developed retinal bleeding as a result of radiation retinopathy 16 months after IMRT, although the doses were acceptable. The remaining 4 patients have no late toxicity at the follow-up time of 31-54 months. CONCLUSIONS: A paradigm shift is necessary from surgery to early intervention using precision radiotherapy for the treatment of ONSM in Japan. PMID- 29713910 TI - Employment status and termination among survivors of pediatric brain tumors: a cross-sectional survey. AB - BACKGROUND: Some childhood cancer survivors experience employment difficulties. This study aimed to describe pediatric brain-tumor survivors' employment status. METHODS: A cross-sectional, observational study was conducted, with questionnaires distributed to 101 pediatric brain-tumor survivors (aged 15 years or older) and their attending physicians from nine institutions in Japan. We compared category and time-series histories for participants' first-time employment using national census information. Factors related to delayed employment or early employment termination were examined using survival-time analyses. RESULTS: Excluding students and homemakers, 38 brain-tumor survivors (median age 27 years, with 15 years since diagnosis) were of working age. Of these, 12 (32%) were unemployed and 9 (24%) had never been employed. First-time employment occurred later for brain-tumor survivors than the general population, particularly in those with lower educational levels. The number of brain-tumor survivors whose first job was terminated within the first year was higher than that for the general population, particularly in male survivors and germ cell tumor survivors. Brain-tumor survivors described their working patterns (irregular), job types (specialist or professional), reasons for early termination (unsuitable job), and thoughts about working (they wished to serve their communities but lacked confidence). CONCLUSION: Brain-tumor survivors are associated with high unemployment rates and multiple unemployment-related factors. Education and welfare systems should identify individual methods of social participation for this group. PMID- 29713912 TI - Flavobacterium zaozhuangense sp. nov., a new member of the family Flavobacteriaceae, isolated from metolachlor-contaminated soil. AB - Strain ZZ-8T, a Gram-negative, aerobic, non-spore-forming, non-motile, yellow pigmented, rod-shaped bacterium, was isolated from metolachlor-contaminated soil in China. The taxonomic position was investigated using a polyphasic approach. Phylogenetic analysis based on 16S rRNA gene sequences revealed that strain ZZ-8T is a member of the genus Flavobacterium and shows high sequence similarity to Flavobacterium humicola UCM-46T (97.2%) and Flavobacterium pedocola UCM-R36T (97.1%), and lower (< 97%) sequence similarity to other known Flavobacterium species. Chemotaxonomic analysis revealed that strain ZZ-8T possessed MK-6 as the major respiratory quinone; and iso-C15:0 (28.5%), summed feature 9 (iso-C17:1 w9c/C16:0 10-methyl, 22.9%), iso-C17:0 3-OH (17.0%), iso-C15:0 3-OH (8.9%), iso C15:1 G (8.6%) and summed feature 3 (C16:1 w7c/C16:1 w6c, 5.7%) as the predominant fatty acids. The polar lipids of strain ZZ-8T were determined to be lipids, a glycolipid, aminolipids and phosphatidylethanolamine. Strain ZZ-8T showed low DNA-DNA relatedness with F. pedocola UCM-R36T (43.23 +/- 4.1%) and F. humicola UCM-46T (29.17 +/- 3.8%). The DNA G+C content was 43.3 mol%. Based on the phylogenetic and phenotypic characteristics, chemotaxonomic data and DNA-DNA hybridization, strain ZZ-8T is considered a novel species of the genus Flavobacterium, for which the name Flavobacterium zaozhuangense sp. nov. (type strain ZZ-8T = KCTC 62315 T = CCTCC AB 2017243T) is proposed. PMID- 29713913 TI - Osteonecrosis of the jaw in patients transitioning from bisphosphonates to denosumab treatment for osteoporosis. AB - Antiresorptive-related osteonecrosis of the jaw (ARONJ) is a rare but severe side effect of antiresorptive treatment with bisphosphonates or RANKL-antibody denosumab in patients with malignant diseases or osteoporosis. Whilst osteonecrosis of the jaw (ONJ) related to the administration of bisphosphonates (BPs) has been investigated for more than 1 decade now, only few data are available on denosumab-related ONJ, especially in patients with osteoporosis. From 2008 to 2016, 52 osteoporosis patients were treated with ARONJ in the Department of Oral and Maxillofacial Surgery, University Medical Center Freiburg, Germany. In all patients, a surgical regimen consisting of complete removal of necrotic bone, primary wound closure and perioperative i.v. antibiotic therapy was applied. Of the 52 patients, 38 developed ARONJ after BP monotherapy; in 11 patients, antiresorptive therapy had been transitioned from BPs to denosumab and 3 patients had received denosumab monotherapy. From July 2013, when the first patient with ONJ and transitioning therapy from BPs to denosumab presented to our department, to October 2016, we found recurrences in 17.6% of the patients with BP monotherapy and in 45.5% of the patients with transitioning therapy from BPs to denosumab. Transitioning antiresorptive therapy from BPs to denosumab may be an additional risk factor for developing ARONJ. In these patients, treatment of ARONJ-lesions seems to provoke more complications. An additional dental screening before transitioning should be initiated. Further studies are needed to evaluate if a first-line treatment with denosumab decreases the incidence of ARONJ in patients with osteoporosis and simplifies its treatment. PMID- 29713915 TI - Review of Issues About Classical Change Scores: A Multilevel Modeling Perspective on Some Enduring Beliefs. AB - Change scores obtained in pretest-posttest designs are important for evaluating treatment effectiveness and for assessing change of individual test scores in psychological research. However, over the years the use of change scores has raised much controversy. In this article, from a multilevel perspective, we provide a structured treatise on several persistent negative beliefs about change scores and show that these beliefs originated from the confounding of the effects of within-person change on change-score reliability and between-person change differences. We argue that psychometric properties of change scores, such as reliability and measurement precision, should be treated at suitable levels within a multilevel framework. We show that, if examined at the suitable levels with such a framework, the negative beliefs about change scores can be renounced convincingly. Finally, we summarize the conclusions about change scores to dispel the myths and to promote the potential and practical usefulness of change scores. PMID- 29713916 TI - "Blocking" and "Filtering": a Commentary on Mobile Technology, Racism, and the Sexual Networks of Young Black MSM (YBMSM). AB - While research investigates the role and influence of geo-social networking (GSN) applications on HIV, less is known about the impact of GSN functions on disease transmission. In our formative research on young Black men who have sex with men's (YBMSM) technology use patterns and preferences for a smartphone-based HIV prevention intervention, we found that study participants used GSN "block" and "filter" functions as protective mechanisms against racism and racial sexual discrimination. Yet, we suggest that these functions may unintentionally create restrictive sexual networks that likely increase their risk for disease transmission. As such, we contend that attention to the unintended effects of these protective mechanisms against racism on GSN applications is fundamentally a public health issue that requires more research and explicit intervention. Ultimately, we use this work to hypothesize the role of blocking and filtering as a strategy to avoid racism on GSN applications that may partly explain HIV disparities among YBMSM. PMID- 29713918 TI - High seroprevalence for Crimean-Congo haemorrhagic fever virus in ruminants in the absence of reported human cases in many regions of Bulgaria. AB - Crimean-Congo haemorrhagic fever (CCHF) is a severe tick-borne zoonotic disease in humans caused by CCHF virus. It has been observed in Bulgaria since 1952 and over the years more than 1600 cases have been reported in the country. Close contact with viraemic livestock was shown as one of the main causes of the infection. Detection of CCHF virus specific antibodies in livestock can be used as an indicator for virus circulation and risk assessment. CCHF seroprevalence was investigated in 843 cattle, 88 goats and 130 sheep, originating from all 28 districts of Bulgaria. CCHF virus-specific IgG antibodies were observed in 165 cattle (19.6, 95% CI 17.0-22.4%), in 20 goats (22.7, 95% CI 15.2-32.5%) and in 10 sheep (7.7, 95% CI 4.2-13.6%). The highest seroprevalence was detected in the district of Kardzhali, South Bulgaria (86.7, 95% CI 73.8-93.7%), a well-known focus of CCHF in humans. The other two districts with human CCHF cases, Blagoevgrad and Burgas, located in southwest and southeast Bulgaria, showed overall seroprevalences in livestock of 41.9% (95% CI 28.4-56.7%) and 31.3% (95% CI 22.2-42.1%), respectively. Seroprevalences in districts with no history of human CCHF cases varied between 55% (95% CI 39.8-69.3%) and 22.5% (95% CI 12.3 37.5%). These results suggest frequent CCHF virus infections even in regions without human CCHF cases and an enhanced risk of infection for humans in close contact with the infected livestock. PMID- 29713917 TI - Analysis of the environmental and host-related factors affecting the distribution of the tick Dermacentor marginatus. AB - Understanding and responding to the ecological, social and economic conditions that facilitate disease emergence and transmission represents a substantial challenge for epidemiologists and health professionals. In this article we integrate knowledge about the human and the vector population, to provide a context from which to examine the underlying causal factors of D. marginatus borne diseases emergence in the study area. Within this framework we analyse the biotic and abiotic factors that drive D. marginatus population dynamics and the role of its typical host for dispersal. These investigations suggest that D. marginatus is a tick species prone to spatially overlap its presence with human population presence. Then we consider the public health implications for the residents, when simply carrying out trivial outdoor activities may increase the risk to contact an infected tick. PMID- 29713920 TI - Epidemiological patterns of traumatic musculoskeletal injuries and non-traumatic disorders in Japan Self-Defense Forces. AB - BACKGROUND: The epidemiological patterns of musculoskeletal injuries or disorders in military personnel have not been well documented and a better understanding is required for proper preventative measures and treatment. Here, we investigated musculoskeletal injuries or disorders among members of the Japan Self-Defense Forces. METHODS: All orthopedic patients (n = 22,340) who consulted to Japan Self Defense Forces Hospitals were investigated for their type of injury or disorder, the injured body part, the mechanism, and the cause of injuries. RESULTS: Thirty nine percent of the cases were classified as traumatic injuries, and 61% were classified as non-traumatic disorders. Of the traumatic injury patients, the injured body part was the upper extremity in 32%, the trunk in 23%, and the lower extremities in 45% of the cases. The most common injured body location was the knee followed by the hand/finger and ankle. Exercise was the most common cause of injury, followed by traffic accident and military training. Contusions were the most common traumatic injuries, followed by sprains and fractures. Of non traumatic disorders, the lower extremities were reported as the injured part in 43% of the disorders. Lumbar spine disorders were the most common non-traumatic disorders, followed by tendon and joint disorders. CONCLUSIONS: Over one-third of orthopedic cases among members of the Japan Self-Defense Forces are traumatic injuries, with the knee being the body part most commonly injured and exercise being the leading cause of injury. PMID- 29713919 TI - Phosphodiesterase 4 and 7 inhibitors produce protective effects against high glucose-induced neurotoxicity in PC12 cells via modulation of the oxidative stress, apoptosis and inflammation pathways. AB - Diabetic neuropathy (DN) is the most common diabetic complication. It is estimated diabetic population will increase to 592 million by the year 2035. This is while at least 50-60% of all diabetic patients will suffer from neuropathy in their lifetime. Oxidative stress, mitochondrial dysfunction, apoptosis, and inflammation are crucial pathways in development and progression of DN. Since there is also no selective and effective therapeutic agent to prevent or treat high glucose (HG)-induced neuronal cell injury, it is crucial to explore tools by which one can reduce factors related to these pathways. Phosphodiesterase 4 and 7 (PDE 4 and 7) regulate oxidative damage, neurodegenaration, and inflammatory responses through modulation of cyclic adenosine monophosphate (cAMP) level, and thus can be as important drug targets for regulating DN. The aim of this study was to evaluate the protective effects of inhibitors of PDE 4 and 7, named rolipram and BRL5048, on HG-induced neurotoxicity in PC12 cells as an in vitro cellular model for DN and determine the possible mechanisms for theirs effects. We report that the PC12 cells pre-treatment with rolipram (2 MUM) and/or BRL5048 (0.2 MUM) for 60 min and then exposing the cells to HG (4.5 g/L for 72 h) or normal glucose (NG) (1 g/L for 72 h) condition show: (1) significant attenuation in ROS, MDA and TNF-a levels, Bax/Bcl-2 ratio, expression of caspase 3 and UCP2 proteins; (2) significant increase in viability, GSH/GSSG ratio, MMP and ATP levels. All these data together led us to propose PDE 4 and 7 inhibitors, and specifically, rolipram and BRL5048, as potential drugs candidate to be further studied for the prevention and treatment of DN. PMID- 29713921 TI - Health Economic Analysis of Antiplatelet Therapy for Acute Coronary Syndromes in the Context of Five Eastern Asian Countries. AB - BACKGROUND AND OBJECTIVE: The economic outcomes of dual antiplatelet therapy in East Asian patients are still unclear. We aimed to evaluate the economic outcomes of ticagrelor versus clopidogrel for patients with acute coronary syndrome (ACS) in China, Japan, Korea, Taiwan and Hong Kong. METHODS: A two-phase model consisting of a 1-year decision tree and a lifetime Markov model was used to estimate the economic outcomes. The data from the East Asian subgroup of Platelet Inhibition and Patient Outcomes (PLATO) and PHILO studies were used for the calculation of the events rate for ticagrelor and clopidogrel in the first 12 months, whereas the costs were obtained from East Asian sources and utility from the published literature. Sensitivity analyses were conducted to test model robustness. RESULTS: Ticagrelor showed the marginal lifetime quality-adjusted life-year (QALY) of 0.0050, 0.0091, 0.0107, 0.0050, and 0.0050 in China, Japan, Korea, Taiwan, and Hong Kong compared with clopidogrel, with marginal healthcare costs of (all values in US dollars) $562, $595, $975, $611, and $672, respectively. The marginal cost per QALY gained with ticagrelor was $112,051, $65,692, $91,207, $121,838, and $133,953 from a public healthcare system perspective of China, Japan, Korea, Taiwan, and Hong Kong, respectively. The sensitivity analysis showed consistent results. CONCLUSION: Treatment of ACS for 12 months with ticagrelor is not a cost-effective option for the prevention of thrombotic events in East Asia. PMID- 29713922 TI - The association between patient's compliance and age with the bonding failure of orthodontic brackets: a cross-sectional study. AB - BACKGROUND: An efficient orthodontic treatment must aim the best occlusal result in the shortest possible time. One of the factors that can interfere in this goal is the bracket debonding during the treatment. This study aimed at assessing the different factors related to brackets failure, highlighting age and patient cooperation with treatment. METHODS: The sample comprised 199 orthodontic patients of both genders (103 women and 96 men); divided into two groups adolescents (12 to 18 years old, 118 patients) and adults (19 to 59 years old, 81 patients). A questionnaire was applied regarding the motivation of patients to seek treatment and whether they had received information on appliance care; patients also filled out their level of cooperation with treatment in a visual analog scale (VAS). Additionally, other variables were assessed, such as the teeth with bracket debonding, the presence of deep overbite, and the use of bite plate. The Mann-Whitney test was used, and a 5% significance level was applied for analyses. RESULTS: It was observed that 20.1% of patients presented at least one tooth with bracket failure, and the lower arch was the most prevalent site (47.5%). Adolescents presented more debonding (25.4%) than adults (12.3%). Individuals with better VAS scores on cooperation sought treatment on their own (p = 0.042), were adults (p <= 0.001), and showed lower rate of failure of brackets (p <= 0.001). The factors related to malocclusion and treatment performed had no statistical significance. CONCLUSION: Greater cooperation was expected from adult individuals who sought treatment on their own and presented low rate of bracket failure. PMID- 29713923 TI - Directionality of the relationship between social well-being and subjective well being: evidence from a 20-year longitudinal study. AB - PURPOSE: Self-determination theory suggests that psycho-social well-being prospectively predicts subjective well-being. In contrast, the broaden-and-build theory of positive emotions suggests that subjective well-being has a positive impact on subsequent levels of psycho-social well-being. The present study sought to empirically disentangle the directionality of the relationship between subjective well-being and social well-being over time. METHODS: The study used three waves of survey data, with intervals of 10 years, from the Midlife in the United States (MIDUS) project, a representative longitudinal panel study of American adults (N = 2732). Cross-lagged panel modeling was used for data analysis. RESULTS: The results revealed that social well-being predicted increases in subsequent subjective well-being, whereas subjective well-being did not prospectively predict social well-being. Social well-being also demonstrated more stability over time than did subjective well-being. CONCLUSION: These findings suggest that optimal social functioning is more likely to be an antecedent to subjective well-being, not the other way around. The results are consistent with predictions guided by self-determination theory. PMID- 29713924 TI - How Stochasticity Influences Leading Indicators of Critical Transitions. AB - Many complex systems exhibit critical transitions. Of considerable interest are bifurcations, small smooth changes in underlying drivers that produce abrupt shifts in system state. Before reaching the bifurcation point, the system gradually loses stability ('critical slowing down'). Signals of critical slowing down may be detected through measurement of summary statistics, but how extrinsic and intrinsic noises influence statistical patterns prior to a transition is unclear. Here, we consider a range of stochastic models that exhibit transcritical, saddle-node and pitchfork bifurcations. Noise was assumed to be either intrinsic or extrinsic. We derived expressions for the stationary variance, autocorrelation and power spectrum for all cases. Trends in summary statistics signaling the approach of each bifurcation depend on the form of noise. For example, models with intrinsic stochasticity may predict an increase in or a decline in variance as the bifurcation parameter changes, whereas models with extrinsic noise applied additively predict an increase in variance. The ability to classify trends of summary statistics for a broad class of models enhances our understanding of how critical slowing down manifests in complex systems approaching a transition. PMID- 29713926 TI - Geochemical fractionation of metals and metalloids in tailings and appraisal of environmental pollution in the abandoned Musina Copper Mine, South Africa. AB - The economic benefits of mining industry have often overshadowed the serious challenges posed to the environments through huge volume of tailings generated and disposed in tailings dumps. Some of these challenges include the surface and groundwater contamination, dust, and inability to utilize the land for developmental purposes. The abandoned copper mine tailings in Musina (Limpopo province, South Africa) was investigated for particle size distribution, mineralogy, physicochemical properties using arrays of granulometric, X-ray diffraction, and X-ray fluorescence analyses. A modified Community Bureau of Reference (BCR) sequential chemical extraction method followed by inductively coupled plasma mass spectrometry/atomic emission spectrometry (ICP-MS/AES) technique was employed to assess bioavailability of metals. Principal component analysis was performed on the sequential extraction data to reveal different loadings and mobilities of metals in samples collected at various depths. The pH ranged between 7.5 and 8.5 (average ~ 8.0) indicating alkaline medium. Samples composed mostly of poorly grated sands (i.e. 50% fine sand) with an average permeability of about 387.6 m/s. Samples have SiO2/Al2O3 and Na2O/(Al2O3 + SiO2) ratios and low plastic index (i.e. PI ~ 2.79) suggesting non-plastic and very low dry strength. Major minerals were comprised of quartz, epidote, and chlorite while the order of relative abundance of minerals in minor quantities is plagioclase > muscovite > hornblende > calcite > haematite. The largest percentage of elements such as As, Cd and Cr was strongly bound to less extractable fractions. Results showed high concentration and easily extractable Cu in the Musina Copper Mine tailings, which indicates bioavailability and poses environmental risk and potential health risk of human exposure. Principal component analysis revealed Fe-oxide/hydroxides, carbonate and clay components, and copper ore process are controlling the elements distribution. PMID- 29713925 TI - Antiphospholipid antibody profile-based outcome of purely vascular and purely obstetric antiphospholipid syndrome. AB - Antiphospholipid syndrome (APLS) is caused by antiphospholipid autoantibodies, and manifests with vascular and/or obstetric complications. The factors associated with initial disease presentation and course are unknown. We assessed the antibody profile associated with disease presentation and with the development of vascular and obstetric complications in women with initially vascular or initially obstetric APLS. A review of records of APLS women at childbearing age followed at one center during 2006-2015. Of 126 women, median age at diagnosis 29 [23-37] years, 62 were initially diagnosed with purely obstetric APLS and 64 with purely vascular APLS. Baseline characteristics and antibody profile did not differ according to the initial diagnosis. At a mean follow-up duration of 61 +/- 23 months, 19 (30.6%) with initially obstetric disease, and 20 (31.3%) with initially vascular disease, developed vascular and obstetric complications, respectively (P = 1.0). Among those with triple positivity [lupus anticoagulant (LAC)+, anticardiolipin (ACL)+, anti beta2 glycoprotein I (AB2GPI)+], a higher proportion developed both obstetric and vascular complications, compared to those with single or double positivity (42.3 vs. 16.4%, P = 0.002). In multivariate analysis, the presence of LAC (P = 0.008), ACL IgG (P = 0.009) or AB2GPI IgG (P = 0.01) was the only independent predictor of the development of both obstetric and vascular complications. Almost one-third of women with initially vascular or initially obstetric APLS developed mixed disease. The antibody profile was the only prognostic marker for disease course. The association found between LAC, ACL IgG or AB2GPI IgG, and patient outcomes could contribute to risk stratification and individualized patient management. PMID- 29713927 TI - Antibiotic use in children with Kawasaki disease. PMID- 29713928 TI - Evaluation of parotid glands in healthy children and adolescents using shear wave elastography and superb microvascular imaging. AB - OBJECTIVES: We aim to determine parotid gland elasticity values from healthy children and adolescents using shear wave elastography (SWE). We also define the degree of vascularity using superb microvascular imaging (SMI), power Doppler (PD), and color Doppler (CD) and compare SMI with CD and PD. MATERIALS AND METHODS: A total of 100 cases, comprising 50 girls and 50 boys, with ages ranging from 3 to 17 years were included in this prospective study. SWE, SMI, PD, and CD measurements were taken from both parotid glands, and the relationships with sex, age, and body mass index (BMI) were determined. The SMI was compared with the PD and CD. RESULTS: The median elasticity values measured with SWE were 8.37 +/- 2.09 kPa and 1.68 +/- 0.26 m/s on the right and 8.33 +/- 2.04 kPa and 1.69 +/- 0.26 m/s on the left. There were significant positive correlations present for those aged below and above 10 years and for BMI with elasticity values. The median vascular spot numbers measured using SMI, PD, and CD were 5 +/- 1.70, 3.5 +/- 1.45, and 2 +/- 1.1 on the right and 4 +/- 1.7, 4 +/- 1.43, and 2 +/- 1.05 on the left, respectively. The median values obtained with SMI were significantly higher than the median values obtained with both PD and CD. CONCLUSION: This study determined the reference SWE, SMI, PD, and CD values for normal parotid glands in healthy children and adolescents. Elasticity values were affected by age and BMI. There was no correlation between vascularity values and age, sex, or BMI. SMI provided more detailed information about vascularity compared with the other methods. PMID- 29713931 TI - Fully robotic total pancreatectomy: technical aspects and outcomes. AB - Robotic total pancreatectomy (RTP) is a novel surgical approach currently performed by a select group of skilled surgeons. As robotic approaches to pancreatic surgery increase worldwide, rates of RTP are expected to increase. However, the standard technique is still evolving and several technical problems still require evaluation. Here, we describe our approach in a stepwise fashion and discuss solutions to overcome technical difficulties. PMID- 29713930 TI - Does robotic-assisted transabdominal preperitoneal (R-TAPP) hernia repair facilitate contralateral investigation and repair without compromising patient morbidity? AB - Inguinal hernia repair (IHR) is performed through either an open or minimally invasive approach (MIS). MIS allows for exploration and potential repair of an occult contralateral hernia. The aim of this study is to evaluate complications associated with intraoperative contralateral exploration and repair through robotic-assisted (da Vinci(r)) IHR. 652 robotic-assisted inguinal hernia procedures were uniformly and retrospectively collected from seven surgeons. Incidental contralateral findings were evaluated and populations with and without contralateral findings were compared in terms of demographics, operative characteristics and complications. This case series includes the earliest cases in each surgeon's robotic-assisted IHR experience. Seventy-one percent (71%) of patients presented with a unilateral hernia. Intraoperative/incidental contralateral ("occult") hernias were found in 12.3% of patients with a unilateral diagnosis. For patients with and without contralateral findings, there were no significant differences in demographics and baseline health characteristics. Perioperative morbidity was statistically similar between groups: intraoperative complications (0 vs 0.5%, p = 1.000), postoperative complications prior to discharge (0 vs 3.2%, p = 0.38) and from discharge through 30 days (5.3 vs 4.0%, p = 0.72), as well as readmissions and reoperations related to the repair within 30 days. Differences in setting of care, length of stay, rate of blood transfusions, concomitant procedures and conversions were nonsignificant. Mean operative time was longer in patients with a contralateral hernia by 19 min (p < 0.0001). Intraoperative contralateral exploration and subsequent repair during robotic-assisted IHR does not compromise perioperative patient morbidity. These study results support the increasing evidence for repair of contralateral, incidentally discovered inguinal hernias.Clinicaltrials.Gov ID number: NCT02684448. PMID- 29713929 TI - Coronary computed tomography angiography in the evaluation of intermediate risk asymptomatic individuals. AB - : Cardiovascular disease is still one of the main causes of death and an early identification of coronary artery disease (CAD) remains the primary step in clinical management of patients with cardiovascular risk factor. Coronary computed tomography angiography (CCTA) has shown high sensitivity in CAD detection and could be helpful as screening method. The purpose of this study was to assess the prevalence of coronary artery disease detected by CCTA in asymptomatic patients with an intermediate risk of CAD. MATERIALS AND METHODS: We retrospectively selected 185 asymptomatic patients with an intermediate Framingan Risk Score (mean age was 62.3 +/- 12.4 years); all patients underwent CCTA, using 640-slice CT. RESULTS: Atherosclerotic plaques were present in 112 out of 185 patients (60.5%); 56 subjects (30.2%) had mild stenosis, 49 (26.5%) moderate stenosis, only 3 patients (1.6%) had severe stenosis and in 4 cases (2.2%) the "blooming effect" did not allow for evaluation of the degree of stenosis. Among the positive cases, a high number of patients (44.6%) [50] showed coronary artery disease in one vessel, 33 patients (29.4%) in two vessels, 22 patients (19.6%) in three vessels and 5 patients in four vessels or more (4.5%). Patients with moderate stenosis were older, had hypertension in most cases, higher total cholesterol levels and more often were smokers. The radiation dose (mSv) dispensed to the patients was 3.7 +/- 1.6 mSv. CONCLUSION: High prevalence of coronary stenosis detected by low-dose CCTA in patients not properly classified by the traditional methods of risk stratification commonly used in clinical practice emphasizes the need to extend the risk stratification to other diagnostic tools with higher capability to detect CAD. PMID- 29713932 TI - Crowdsourced versus expert evaluations of the vesico-urethral anastomosis in the robotic radical prostatectomy: is one superior at discriminating differences in automated performance metrics? AB - Crowdsourcing from the general population is an efficient, inexpensive method of surgical performance evaluation. In this study, we compared the discriminatory ability of experts and crowdsourced evaluators (the Crowd) to detect differences in robotic automated performance metrics (APMs). APMs (instrument motion tracking and events data directly from the robot system) of anterior vesico-urethral anastomoses (VUAs) of robotic radical prostatectomies were captured by the dVLogger (Intuitive Surgical). Crowdsourced evaluators and four expert surgeons evaluated video footage using the Global Evaluative Assessment of Robotic Skills (GEARS) (individual domains and total score). Cases were then stratified into performance groups (high versus low quality) for each evaluator based on GEARS. APMs from each group were compared using the Mann-Whitney U test. 25 VUAs performed by 11 surgeons were evaluated. The Crowd displayed moderate correlation with averaged expert scores for all GEARS domains (r > 0.58, p < 0.01). Bland Altman analysis showed a narrower total GEARS score distribution by the Crowd compared to experts. APMs compared amongst performance groups for each evaluator showed that through GEARS scoring, the most common differentiated metric by evaluators was the velocity of the dominant instrument arm. The Crowd outperformed two out of four expert evaluators by discriminating differences in three APMs using total GEARS scores. The Crowd assigns a narrower range of GEARS scores compared to experts but maintains overall agreement with experts. The discriminatory ability of the Crowd at discerning differences in robotic movements (via APMs) through GEARS scoring is quite refined, rivaling that of expert evaluators. PMID- 29713933 TI - Correction to: Assessment of Local Adverse Reactions to Subcutaneous Immunoglobulin (SCIG) in Clinical Trials. AB - The article Assessment of Local Adverse Reactions to Subcutaneous Immunoglobulin (SCIG) in Clinical Trials, written by Mark Ballow, Richard L. Wasserman, Stephen Jolles, Helen Chapel, Mel Berger, Siraj A. Misbah, was originally published Online First without open access. PMID- 29713934 TI - Effects of Percutaneous LVAD Support on Right Ventricular Load and Adaptation. AB - Both operative and hemodynamic mechanisms have been implicated in right heart failure (RHF) following surgical left ventricular assist device (LVAD) implantation. We investigated the effects of percutaneous LVAD (pLVAD; Impella(r), Abiomed) support on right ventricular (RV) load and adaptation. We reviewed all patients receiving a pLVAD for cardiogenic shock at our institution between July 2014 and April 2017, including only those with pre- and post-pLVAD invasive hemodynamic measurements. Hemodynamic data was recorded immediately prior to pLVAD implantation and up to 96 h post-implantation. Twenty-five patients were included. Cardiac output increased progressively during pLVAD support. PAWP improved early post-pLVAD but did not further improve during continued support. Markers of RV adaptation (right ventricular stroke work index, right atrial pressure (RAP), and RAP to pulmonary artery wedge pressure ratio (RAP:PAWP)) were unchanged acutely implant but progressively improved during continued pLVAD support. Total RV load (pulmonary effective arterial elastance; EA) and resistive RV load (pulmonary vascular resistance; PVR) both declined progressively. The relationship between RV load and RV adaptation (EA/RAP and EA/RAP:PAWP) was constant throughout. Median vasoactive-inotrope score declined after pLVAD placement and continued to decline throughout support. Percutaneous LVAD support in patients with cardiogenic shock did not acutely worsen RV adaptation, in contrast to previously described hemodynamic effects of surgically implanted durable LVADs. Further, RV load progressively declined during support, and the noted RV adaptation improvement was load-dependent as depicted by constant EA/RA and EA/RAP:PAWP relationships. These findings further implicate the operative changes associated with surgical LVAD implantation in early RHF following durable LVAD. PMID- 29713935 TI - The Cost Effectiveness of Embedding a Behavioral Health Clinician into an Existing Primary Care Practice to Facilitate the Integration of Care: A Prospective, Case-Control Program Evaluation. AB - This project evaluated the cost effectiveness of integrating behavioral health services into a primary care practice using a prospective, case-control design. New Directions Behavioral Health collaborated with a large Kansas City primary care practice to integrate a licensed psychologist (i.e., behavioral health clinician) into the practice. Patient claims data were examined 21 months prior to and 14 months after the psychologist began providing full-time behavioral health services within the practice. Claims data from patients with Blue Cross Blue Shield of Kansas City insurance (BCBSKC) who had at least one encounter with the psychologist (N = 239) were compared to control patients (BCBSKC fully insured patients at large) to calculate cost savings. The results demonstrated that integrating behavioral health services into the practice was associated with $860.16 per member per year savings or 10.8% savings in costs for BCBSKC patients. Integrating behavioral health services into primary care may lead to reductions in health care costs. PMID- 29713936 TI - Contralateral Parkinson's disease in a patient with diabetic hemichorea. PMID- 29713937 TI - The goblet sign in the amnestic syndrome of the subcallosal artery infarct. AB - We here describe an acute-onset amnesic syndrome with evidence of an embolic infarction in the distribution of the subcallosal artery, a proximal branch of the anterior communicating artery. The infarction involved the corpus callosum genu and both fornices, giving a peculiar image on MRI that resembled a goblet. Although infrequent, the subcallosal artery infarction should be considered in the differential diagnosis of patients with an acute amnestic syndrome. We propose "the goblet sign" for the peculiar diffusion-weighted MRI image of the brain in this syndrome. PMID- 29713938 TI - The urgent neurological consultation in the population of the province of Ferrara, Italy. AB - In the province of Ferrara, Italy, the urgent neurological consultation (UNC) cases in the population correspond to the resident outpatients who undergo a UNC in the ER of the university hospital of Ferrara (UHFe). Thanks to this health organization a retrospective survey identified 612 UNC cases (range of age 7-102 years, median 67,5 years) in the study period giving a period prevalence rate of 173 per 100,000 (95% CI 159.3-187.3) which increased with age (chi2 for trend = 178.4 p < 0.001). The daily UNC cases (range 0-14, mean = 7.3, 95% CI 7.1-7.5) followed the Poisson distribution (goodness-of-fit test: lambda = 7.3, chi2 = 8082, 12 freedom degrees, p > 0.70). The prevalence rate decreased with the distance between the patients' residence and the UHFe (chi2 for trend = 82.9, p < 0.001). The commonest clinical conditions requiring UNCs were acute cerebrovascular disorders (28%), headache (14%), and vertigo (9%). The hospital admission rate was 32.5% which increased with age (chi2 for trend = 35.8, p < 0.001). The commonest discharge diagnoses of the admitted cases were ischemic stroke (57.3%), epilepsy (7%), TIA (6%), and intraparenchymal hemorrhage (5.5%). Acute cerebrovascular disease accounted for 69% of the discharge diagnoses. The survey showed that the UNCs' demand was higher than previous Italian data confirming that acute cerebrovascular disease is the most frequent acute neurological condition requiring attention in the ER. It also suggested that the UNCs could be poorly appropriate. These findings would require the healthcare administrators attention. PMID- 29713939 TI - Meta-analysis of the association between ZNF512B polymorphism rs2275294 and risk of amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS), the most common motor neuron disease, appears to result from the combination of genetic and environmental factors. Whether the rs2275294 polymorphism in the ZNF512B gene influences ALS risk is controversial. We meta-analysed the association between rs2275294 and ALS risk based on evidence published in the PubMed database. Five case-control studies involving 2559 patients with sporadic ALS and 5740 controls were analysed. Based on random-effects meta-analysis, the polymorphism rs2275294 was associated with increased risk of ALS disease in an allele model (C vs. T: OR 1.222, 95%CI 1.057 to 1.414, p = 0.007). The available evidence suggests that the ZNF512B polymorphism rs2275294 is associated with ALS risk. These results should be validated in large, well-designed studies, especially in non-Asian populations. PMID- 29713940 TI - Effects of reactive oxygen species and interplay of antioxidants during physical exercise in skeletal muscles. AB - A large number of researches have led to a substantial growth of knowledge about exercise and oxidative stress. Initial investigations reported that physical exercise generates free radical-mediated damages to cells; however, in recent years, studies have shown that regular exercise can upregulate endogenous antioxidants and reduce oxidative damage. Yet, strenuous exercise perturbs the antioxidant system by increasing the reactive oxygen species (ROS) content. These alterations in the cellular environment seem to occur in an exercise type dependent manner. The source of ROS generation during exercise is debatable, but now it is well established that both contracting and relaxing skeletal muscles generate reactive oxygen species and reactive nitrogen species. In particular, exercises of higher intensity and longer duration can cause oxidative damage to lipids, proteins, and nucleotides in myocytes. In this review, we summarize the ROS effects and interplay of antioxidants in skeletal muscle during physical exercise. Additionally, we discuss how ROS-mediated signaling influences physical exercise in antioxidant system. PMID- 29713941 TI - Single stab injuries. AB - Determining the manner of death in cases involving multiple stab injuries from a knife is generally straightforward. The medico-legal investigation of a stabbing death caused by a single stab injury from a knife comprises a smaller but potentially more problematic subset of forensic cases. We reviewed our institute's experience with single stab injuries and endeavored to identify features identified at the post-mortem examination which may aid in the differentiation between cases of homicide, suicide and accidental death. The single stab injury was to the left chest in the majority of deaths from homicide and from suicide. Clothing was nearly always involved in cases of homicide, but was also seen in cases of suicide. The knife was found in situ in 9 of the 11 cases of suicide involving a chest injury, but was not seen in any of the cases of homicide. There were no cases of an accidental single stab death from a knife in our records. Clinical data on accidental stab injuries was sought via a search of the medical records of a major tertiary referral hospital. A single non-fatal case of an accidental single stab injury from a knife was identified after the conclusion of our study period. Accidental stab injuries from a knife causing injury or death are rare. PMID- 29713942 TI - Results of The Comparative Study of 200 Cases: One Anastomosis Gastric Bypass vs Roux-en-Y Gastric Bypass. AB - INTRODUCTION: Obesity has experienced worldwide increase and surgery has become the treatment that has achieved the best results. Several techniques have been described; the most popular are vertical gastrectomy (GV) and the Roux-en-Y gastric bypass (RYGB). However, mini-gastric bypass/one anastomosis gastric bypass (MGB/OAGB) has gained popularity due to its simplicity and good results. OBJECTIVE: To comparatively evaluate the results of MGB/OAGB with those of RYGB with 1-year follow-up. METHODS: The paper presents a comparative case and control study of 100 patients that underwent MGB/OAGB surgery and another 100 with RYGB surgery, operated between 2008 and 2016. Patients were not submitted to revision surgery and had the following pre-operative variables: age 40.46 +/- 12.4 vs. 39.43 +/- 10.33 years; sex 64 and 54 women, 36 and 46 men; BMI 44.8 +/- 12.06 and 45.29 +/- 8.82 kg/m2; 50 and 54 cases with comorbidities, respectively, these being non-significant differences. RESULTS: The surgical time was 69.01 +/- 4.62 (OAGB) vs. 88.98 +/- 3.44 min; the time of hospitalization was 2 days, reaching a BMI of 27.7 +/- 7.85 and 29 +/- 4.52 kg/m2, with an excess weight loss 1 year after surgery of 89.4 vs. 85.9%, respectively. The morbidity rates are 9% for OAGB and 11% for the RYGB. There was a comorbidity resolution of 84.4 and 83.7% respectively, without mortality. CONCLUSIONS: The results show the benefits of both techniques, OAGB being the easiest to perform and with less surgical time. PMID- 29713944 TI - The role of line junctions in object recognition: The case of reading musical notation. AB - Previous work has shown that line junctions are informative features for visual perception of objects, letters, and words. However, the sources of such sensitivity and their generalizability to other object categories are largely unclear. We addressed these questions by studying perceptual expertise in reading musical notation, a domain in which individuals with different levels of expertise are readily available. We observed that removing line junctions created by the contact between musical notes and staff lines selectively impaired recognition performance in experts and intermediate readers, but not in novices. The degree of performance impairment was predicted by individual fluency in reading musical notation. Our findings suggest that line junctions provide diagnostic information about object identity across various categories, including musical notation. However, human sensitivity to line junctions does not readily transfer from familiar to unfamiliar object categories, and has to be acquired through perceptual experience with the specific objects. PMID- 29713943 TI - The association of diet, gut microbiota and colorectal cancer: what we eat may imply what we get. AB - Despite the success of colonoscopy screening and recent advances in cancer treatment, colorectal cancer (CRC) still remains one of the most commonly diagnosed and deadly cancers, with a significantly increased incidence in developing countries where people are adapting to Western lifestyle. Diet has an important impact on risk of CRC. Multiple epidemiological studies have suggested that excessive animal protein and fat intake, especially red meat and processed meat, could increase the risk of developing CRC while fiber could protect against colorectal tumorigenesis. Mechanisms have been investigated by animal studies. Diet could re-shape the community structure of gut microbiota and influence its function by modulating the production of metabolites. Butyrate, one of the short chain fatty acids (SCFAs), which act as a favorable source for colonocytes, could protect colonic epithelial cells from tumorigenesis via anti-inflammatory and antineoplastic properties through cell metabolism, microbiota homeostasis, antiproliferative, immunomodulatory and genetic/epigenetic regulation ways. In contrast, protein fermentation and bile acid deconjugation, which cause damage to colonic cells through proinflammatory and proneoplastic ways, lead to increased risk of developing CRC. In conclusion, a balanced diet with an increased abundance of fiber should be adopted to reduce the risk and prevent CRC. PMID- 29713945 TI - The role of shape recognition in figure/ground perception in infancy. AB - In this study we sought to determine whether infants, like adults, utilize previous experience to guide figure/ground processing. After familiarization to a shape, 5-month-olds preferentially attended to the side of an ambiguous figure/ground test stimulus corresponding to that shape, suggesting that they were viewing that portion as the figure. Infants' failure to exhibit this preference in a control condition in which both sides of the test stimulus were displayed as figures indicated that the results in the experimental condition were not due to a preference between two figure shapes. These findings demonstrate for the first time that figure/ground processing in infancy is sensitive to top-down influence. Thus, a critical aspect of figure/ground processing is functional early in life. PMID- 29713946 TI - Automated Risk Assessment for School Violence: a Pilot Study. AB - School violence has increased over the past ten years. This study evaluated students using a more standard and sensitive method to help identify students who are at high risk for school violence. 103 participants were recruited through Cincinnati Children's Hospital Medical Center (CCHMC) from psychiatry outpatient clinics, the inpatient units, and the emergency department. Participants (ages 12 18) were active students in 74 traditional schools (i.e. non-online education). Collateral information was gathered from guardians before participants were evaluated. School risk evaluations were performed with each participant, and audio recordings from the evaluations were later transcribed and manually annotated. The BRACHA (School Version) and the School Safety Scale (SSS), both 14 item scales, were used. A template of open-ended questions was also used. This analysis included 103 participants who were recruited from 74 different schools. Of the 103 students evaluated, 55 were found to be moderate to high risk and 48 were found to be low risk based on the paper risk assessments including the BRACHA and SSS. Both the BRACHA and the SSS were highly correlated with risk of violence to others (Pearson correlations>0.82). There were significant differences in BRACHA and SSS total scores between low risk and high risk to others groups (p-values <0.001 under unpaired t-test). In particular, there were significant differences in individual SSS items between the two groups (p-value <0.001). Of these items, Previous Violent Behavior (Pearson Correlation = 0.80), Impulsivity (0.69), School Problems (0.64), and Negative Attitudes (0.61) were positively correlated with risk to others. The novel machine learning algorithm achieved an AUC of 91.02% when using the interview content to predict risk of school violence, and the AUC increased to 91.45% when demographic and socioeconomic data were added. Our study indicates that the BRACHA and SSS are clinically useful for assessing risk for school violence. The machine learning algorithm was highly accurate in assessing school violence risk. PMID- 29713947 TI - 1H, 15N and 13C resonance assignments of the J-domain of co-chaperone Sis1 from Saccharomyces cerevisiae. AB - Protein folding in the cell is usually aided by molecular chaperones, from which the Hsp70 (Hsp = heat shock protein) family has many important roles, such as aiding nascent folding and participating in translocation. Hsp70 has ATPase activity which is stimulated by binding to the J-domain present in co-chaperones from the Hsp40 family. Hsp40s have many functions, as for instance the binding to partially folded proteins to be delivered to Hsp70. However, the presence of the J-domain characterizes Hsp40s or, by this reason, as J-proteins. The J-domain alone can stimulate Hsp70 ATPase activity. Apparently, it also maintains the same conformation as in the whole protein although structural information on full J proteins is still missing. This work reports the 1H, 15N and 13C resonance assignments of the J-domain of a Hsp40 from Saccharomyces cerevisiae, named Sis1. Secondary structure and order parameter prediction from chemical shifts are also reported. Altogether, the data show that Sis1 J-domain is highly structured and predominantly formed by alpha-helices, results that are in very good agreement with those previously reported for the crystallographic structure. PMID- 29713949 TI - Resveratrol Protects Purkinje Neurons and Restores Muscle Activity in Rat Model of Cerebellar Ataxia. AB - Cerebellar ataxia (CA) is regarded as a miscellaneous cluster of brain disorders related to the cerebellum. Resveratrol is a naturally occurring polyphenolic compound. Previous reports suggest that resveratrol confers neuroprotection in various animal models of brain damage. Indeed, we considered it invaluable to investigate whether a treatment with resveratrol has a therapeutic role against CA induced by 3-acetylpyridine (3-AP) in rats. In addition, no investigation has examined neuroprotective effect of resveratrol in rat model of CA. Initially, 3 AP administration generated CA rat models followed by intraperitoneal injection with resveratrol. Then, motor performance and muscle electromyography (EMG) activity were assessed. Moreover, the anti-apoptotic role of resveratrol in CA and its relationship to protection of Purkinje cells were explored. According to what we have found, resveratrol administration improved the muscle activity and movement coordination in 3-AP-lesioned rats. Also under resveratrol treatment, the total number of the Purkinje neurons increased whereas a reduction in apoptotic bodies was observed. In conclusion, post-treatment with resveratrol evidently ameliorated motor performance as well as muscle activity accompanied by a protection of Purkinje cells in ataxic rats. PMID- 29713948 TI - Association Study of ANRIL Genetic Variants and Multiple Sclerosis. AB - Multiple sclerosis (MS) is an autoimmune disorder of central nervous system with several genetic and environmental risk factors. Genes with regulatory roles on immune system have been implicated in its pathogenesis. Recently, long non-coding RNAs (lncRNAs) have been demonstrated to control some aspects of immune response. Among them is antisense non-coding RNA in the INK4 locus (ANRIL) whose involvement in NF-kappaB signaling pathway has been highlighted. In the current study, we evaluated the association between rs1333045, rs4977574, rs1333048, and rs10757278 variants of ANRIL and MS risk in a population of 410 Iranian MS patients and 410 healthy subjects. There was no significant difference in allele and genotype frequencies between MS patients and healthy subjects. However, haplotype analysis (rs1333045, rs1333048, rs4977574, and rs10757278 respectively) demonstrated protective effect of CCGG and TAAA haplotypes against MS (P values of 0.043 and 0.0026 respectively). In addition, TAGG and CCGA haplotypes were significantly associated with MS risk in the studied population (P values of 0.0065 and 0.024 respectively). The present study reveals a possible role for ANRIL in the pathogenesis of MS. PMID- 29713950 TI - Including Future Consumption and Production in Economic Evaluation of Interventions that Save Life-Years: Commentary. PMID- 29713951 TI - Accommodation and Health Costs of Deinstitutionalized People with Mental Illness Living in Residential Services in Brazil. AB - BACKGROUND: Health costs are the main hindrances for expanding community mental health services. Exploring patient profiles and cost predictors may be useful for optimising financial resources. However, the deinstitutionalisation process may burden health budgets in terms of supporting multiple community services based on varying levels of need. OBJECTIVE: This study assessed accommodation and health service costs, quality of life and clinical and psychosocial profiles among individuals receiving mental healthcare through residential services. Specific accommodation cost predictors were also verified. METHODS: Health costs were assessed from the perspective of a public health provider using a microcosting bottom-up approach at 20 residential services in Sao Paulo, Brazil. Instruments used to assess health costs and patient profiles included the Brazilian version of the Client Socio-demographic and Service Receipt Inventory (CSSRI), the Mini International Neuropsychiatric Interview (MINI), the Clinical Global Impression Severity Scale (CGI-S), the Independent Living Skills Survey (ILLS), the Social Behaviour Scale (SBS) and the Quality of Life Scale (QLS). RESULTS: One hundred and forty-seven residents, predominantly experiencing psychotic disorders, were interviewed. The geographical region and length of time spent living in residential services or in a psychiatric hospital predicted 66% of the variance in accommodation costs. The CGI-S and ILLS scores and years of education explained 52.7% of the variance in quality of life. CONCLUSION: Accommodation costs were not driven by patient profile variables, while region and time spent in a hospital or in residential services were the main cost predictors. Semi staffed homes may be an alternative for resource optimisation among individuals with mild impairment, particularly if strategies for psychosocial rehabilitation and improving quality of life are implemented. PMID- 29713952 TI - TISK 1.0: An easy-to-use Python implementation of the time-invariant string kernel model of spoken word recognition. AB - This article describes a new Python distribution of TISK, the time-invariant string kernel model of spoken word recognition (Hannagan et al. in Frontiers in Psychology, 4, 563, 2013). TISK is an interactive-activation model similar to the TRACE model (McClelland & Elman in Cognitive Psychology, 18, 1-86, 1986), but TISK replaces most of TRACE's reduplicated, time-specific nodes with theoretically motivated time-invariant, open-diphone nodes. We discuss the utility of computational models as theory development tools, the relative merits of TISK as compared to other models, and the ways in which researchers might use this implementation to guide their own research and theory development. We describe a TISK model that includes features that facilitate in-line graphing of simulation results, integration with standard Python data formats, and graph and data export. The distribution can be downloaded from https://github.com/maglab uconn/TISK1.0 . PMID- 29713953 TI - The EU-Emotion Voice Database. AB - In this study, we report the validation results of the EU-Emotion Voice Database, an emotional voice database available for scientific use, containing a total of 2,159 validated emotional voice stimuli. The EU-Emotion voice stimuli consist of audio-recordings of 54 actors, each uttering sentences with the intention of conveying 20 different emotional states (plus neutral). The database is organized in three separate emotional voice stimulus sets in three different languages (British English, Swedish, and Hebrew). These three sets were independently validated by large pools of participants in the UK, Sweden, and Israel. Participants' validation of the stimuli included emotion categorization accuracy and ratings of emotional valence, intensity, and arousal. Here we report the validation results for the emotional voice stimuli from each site and provide validation data to download as a supplement, so as to make these data available to the scientific community. The EU-Emotion Voice Database is part of the EU Emotion Stimulus Set, which in addition contains stimuli of emotions expressed in the visual modality (by facial expression, body language, and social scene) and is freely available to use for academic research purposes. PMID- 29713955 TI - Successful hemostatic management of major surgery for cervical spondylotic myelopathy in a patient with severe factor XI deficiency. AB - Factor XI deficiency (FXID) is a rare bleeding disorder caused by mutations in the F11 gene. Spontaneous bleeding in patients with factor XI deficiency is rare, but major bleeding may occur after surgery or trauma. The basic method for hemostatic treatment is replacement of the missing factor using FXI concentrate or fresh frozen plasma (FFP). We report the case of a 72-year-old male with severe FXID who underwent a laminoplasty under sufficient, but minimal, FFP transfusion. Through detailed monitoring of activated partial thromboplastin time (APTT) and FXI activity at the perioperative period, we succeeded in hemostatic management of major surgery without significant blood loss and fluid overload. From the course of this case, we found that measuring FXI activity is superior to measuring APTT. Furthermore, we identified a novel homozygous mutation in F11 [NM_000128.3:c.1041C > A:p.(Tyr347*)] by whole exome sequencing. PMID- 29713954 TI - Switching to nilotinib is associated with deeper molecular responses in chronic myeloid leukemia chronic phase with major molecular responses to imatinib: STAT1 trial in Japan. AB - The purpose of this clinical trial was to evaluate the efficacy of 2-year consolidation therapy using nilotinib (NIL) for achieving a molecular response (MR4.5, BCR-ABL1IS <= 0.0032% on the International Scale) in patients with chronic myeloid leukemia in the chronic phase (CML-CP) who had achieved a major molecular response (MMR, BCR-ABL1IS <= 0.1%) with imatinib (IM). We recruited 76 Japanese patients for this trial. Nilotinib 300 mg, twice daily, was administered for 2 years, and 74 patients were evaluated in the study. The median age was 55.0 years. The median duration of IM treatment was 69.0 months. All patients showed MMR at the time of entry into the study; the median time to MMR on IM therapy was 20.4 months. The proportion of patients who achieved MR4.5 increased over time. The rates of MR4.5 in the 74 evaluable patients were 27.0% [90% confidence interval (CI) (18.7-36.8%)] and 44.6% [90% CI (34.7-54.8%)] at 12 and 24 months, respectively. The frequency of ABCG2 421C/A + A/A was an independent predictive biomarker for achieving a 24-month MR4.5. Switching to NIL led to safer, deeper molecular responses in patients with MMR on long-term IM therapy for future treatment-free remission. PMID- 29713957 TI - Variable heart rate and a flexible mind: Higher resting-state heart rate variability predicts better task-switching. AB - The neurovisceral integration model proposes that heart rate variability (HRV) is linked to prefrontal cortex activity via the vagus nerve, which connects the heart and the brain. HRV, an index of cardiac vagal tone, has been found to predict performance on several cognitive control tasks that rely on the prefrontal cortex. However, the link between HRV and the core cognitive control function "shifting" between tasks and mental sets is under-investigated. Therefore, the present study tested the neurovisceral integration model by examining, in 90 participants, the relationship between vagally mediated resting state HRV and performance in a task-switching paradigm that provides a relatively process-pure measure of cognitive flexibility. As predicted, participants with higher resting-state HRV (indexed both by time domain and frequency domain measures) showed smaller switch costs (i.e., greater flexibility) than individuals with lower resting-state HRV. Our findings support the neurovisceral integration model and indicate that higher levels of vagally mediated resting state HRV promote cognitive flexibility. PMID- 29713956 TI - Repeated diazepam administration reversed working memory impairments and glucocorticoid alterations in the prefrontal cortex after short but not long alcohol-withdrawal periods. AB - The study was designed to assess whether repeated administration of diazepam (Valium(r), Roche)-a benzodiazepine exerting an agonist action on GABAA receptors may alleviate both the short (1 week, 1W) and long-term (6 weeks, 6W) deleterious effects of alcohol withdrawal occurring after chronic alcohol consumption (6 months; 12% v/v) in C57/BL6 male mice. More pointedly, we first evidenced that 1W and 6W alcohol-withdrawn mice exhibited working memory deficits in a sequential alternation task, associated with sustained exaggerated corticosterone rise and decreased pCREB levels in the prefrontal cortex (PFC). In a subsequent experiment, diazepam was administered i.p. for 9 consecutive days (1 injection/day) during the alcohol withdrawal period at decreasing doses ranging from 1.0 mg/kg to 0.25 mg/kg. Diazepam was not detected in the blood of withdrawn mice at the time of memory testing, occurring 24 hours after the last diazepam injection. Repeated diazepam administration significantly improved alternation rates and normalized levels of glucocorticoids and pCREB activity in the PFC in 1W but not in 6W withdrawn mice. Thus, repeated diazepam administration during the alcohol-withdrawal period only transitorily canceled out the working memory impairments and glucocorticoid alterations in the PFC of alcohol-withdrawn animals. PMID- 29713958 TI - Noise-Induced Variability of Immuno-PET with Zirconium-89-Labeled Antibodies: an Analysis Based on Count-Reduced Clinical Images. AB - PURPOSE: Positron emission tomography (PET) with Zirconium-89 (Zr-89)-labeled antibodies can be used for in vivo quantification of antibody uptake. Knowledge about measurement variability is required to ensure correct interpretation. However, no clinical studies have been reported on measurement variability of Zr 89 immuno-PET. As variability due to low signal-to-noise is part of the total measurement variability, the aim of this study was to assess noise-induced variability of Zr-89 -immuno-PET using count-reduced clinical images. PROCEDURES: Data were acquired from three previously reported clinical studies with [89Zr]antiCD20 (74 MBq, n = 7), [89Zr]antiEGFR (37 MBq, n = 7), and [89Zr]antiCD44 (37 MBq, n = 13), with imaging obtained 1 to 6 days post injection (D0-D6). Volumes of interest (VOIs) were manually delineated for liver, spleen, kidney, lung, brain, and tumor. For blood pool and bone marrow, fixed-size VOIs were used. Original PET list mode data were split and reconstructed, resulting in two count-reduced images at 50 % of the original injected dose (e.g., 37 MBq74inj). Repeatability coefficients (RC) were obtained from Bland-Altman analysis on standardized uptake values (SUV) derived from VOIs applied to these images. RESULTS: The RC for the combined manually delineated organs for [89Zr] antiCD20 (37 MBq74inj) increased from D0 to D6 and was less than 6 % at all time points. Blood pool and bone marrow had higher RC, up to 43 % for 37 MBq74inj at D6. For tumor, the RC was up to 42 % for [89Zr]antiCD20 (37 MBq74inj). For [89Zr]antiCD20, (18 MBq74inj), [89Zr]antiEGFR (18 MBq37inj), and [89Zr]antiCD44 (18 MBq37inj), measurement variability was independent of the investigated antibody. CONCLUSIONS: Based on this study, noise-induced variability results in a RC for Zr-89-immuno-PET (37 MBq) around 6 % for manually delineated organs combined, increasing up to 43 % at D6 for blood pool and bone marrow, assuming similar biodistribution of antibodies. The signal-to-noise ratio leads to tumor RC up to 42 %. PMID- 29713959 TI - Performance Evaluation of a Dedicated Preclinical PET/CT System for the Assessment of Mineralization Process in a Mouse Model of Atherosclerosis. AB - PURPOSE: The purpose of this study was to assess the impact of positron emission tomography/X-ray computed tomography (PET/CT) acquisition and reconstruction parameters on the assessment of mineralization process in a mouse model of atherosclerosis. PROCEDURES: All experiments were performed on a dedicated preclinical PET/CT system. CT was evaluated using five acquisition configurations using both a tungsten wire phantom for in-plane resolution assessment and a bar pattern phantom for cross-plane resolution. Furthermore, the radiation dose of these acquisition configurations was calculated. The PET system was assessed using longitudinal line sources to determine the optimal reconstruction parameters by measuring central resolution and its coefficient of variation. An in vivo PET study was performed using uremic ApoE-/-, non-uremic ApoE-/-, and control mice to evaluate optimal PET reconstruction parameters for the detection of sodium [18F]fluoride (Na[18F]F) aortic uptake and for quantitative measurement of Na[18F]F bone influx (Ki) with a Patlak analysis. RESULTS: For CT, the use of 1 * 1 and 2 * 2 binning detector mode increased both in-plane and cross-plane resolution. However, resolution improvement (163 to 62 MUm for in-plane resolution) was associated with an important radiation dose increase (1.67 to 32.78 Gy). With PET, 3D-ordered subset expectation maximization (3D-OSEM) algorithm increased the central resolution compared to filtered back projection (1.42 +/- 0.35 mm vs. 1.91 +/- 0.08, p < 0.001). The use of 3D-OSEM with eight iterations and a zoom factor 2 yielded optimal PET resolution for preclinical study (FWHM = 0.98 mm). These PET reconstruction parameters allowed the detection of Na[18F]F aortic uptake in 3/14 ApoE-/- mice and demonstrated a decreased Ki in uremic ApoE-/- compared to non-uremic ApoE-/- and control mice (p < 0.006). CONCLUSIONS: Optimizing reconstruction parameters significantly impacted on the assessment of mineralization process in a preclinical model of accelerated atherosclerosis using Na[18F]F PET. In addition, improving the CT resolution was associated with a dramatic radiation dose increase. PMID- 29713960 TI - Examining the role of context variability in memory for items and associations. AB - What properties of a word make it easy or difficult to remember? Word frequency and context variability are separate, closely related word properties that have disparate influences on memorability. The influence of word frequency changes depending on the memory task, with high-frequency words tending to be recalled better and low-frequency words to be recognized better. Conversely, low-context variability words tend to be remembered better across tasks. One proposed explanation for the low-variability advantage is that low-variability words are easier to associate with the experimental context, given that they are associated with fewer extra-experimental contexts. On the basis of this explanation, it has been suggested that the formation of interitem associations during encoding should interfere with the formation of item-to-context associations, attenuating the low-variability advantage. Across experiments, we tested whether focusing on interitem associations disrupted the low-variability advantage, by manipulating encoding tasks, test expectancy, final test condition, word frequency, and context variability. Focusing on interitem associations did not harm performance for low-variability words. Words low in both frequency and variability were recognized better, but word pairs composed of high-frequency, low-variability words were recognized better in associative recognition. On the basis of the data, we suggest that focusing on interitem associations does not come at the expense of item-to-context associations. Moreover, the data further support the idea that frequency and variability are distinct properties. PMID- 29713961 TI - A Systematic Literature Review and Network Meta-Analysis Comparing Once-Weekly Semaglutide with Other GLP-1 Receptor Agonists in Patients with Type 2 Diabetes Previously Receiving Basal Insulin. AB - INTRODUCTION: Once-weekly semaglutide is a glucagon-like peptide-1 (GLP-1) analogue that is currently available as 1.0 mg and 0.5 mg dose for the treatment of type 2 diabetes (T2D). Currently, no head-to-head trial investigating once weekly semaglutide as an add-on to basal insulin vs other GLP-1 receptor agonists (GLP-1 RAs) is available. The aim of this study was to conduct a network meta analysis (NMA) to assess the efficacy and safety of once-weekly semaglutide vs other GLP-1 RAs in patients with T2D inadequately controlled on basal insulin. METHODS: A systematic literature review was performed to identify all trials of GLP-1 RAs as an add-on to basal insulin in patients with T2D. Data at 24 +/- 4 weeks were extracted for efficacy and safety outcomes (feasible for analysis in an NMA), including the change from baseline in glycated hemoglobin (HbA1c), body weight, and systolic blood pressure, and the incidence of nausea, vomiting, and diarrhea. Data were synthesized using a NMA and a Bayesian framework. RESULTS: In total, eight studies were included across the base-case analyses. The results demonstrate that once-weekly semaglutide 1.0 mg was associated with significantly greater reductions in HbA1c (- 0.88% to - 1.39% vs comparators) and weight (- 1.49 to - 4.69 kg vs comparators) and similar odds of experiencing nausea, vomiting, or diarrhea vs all GLP-1 RA comparators. Once-weekly semaglutide 1.0 mg was also equally effective at reducing systolic blood pressure compared with liraglutide 1.8 mg. Once-weekly semaglutide 0.5 mg significantly reduced HbA1c vs the majority of other GLP-1 RAs, except liraglutide 1.8 mg QD. The odds of experiencing nausea were significantly lower with once-weekly semaglutide 0.5 mg compared with all GLP-1 RA comparators. CONCLUSION: Once-weekly semaglutide 1.0 mg as an add-on to basal insulin is likely to be the most efficacious GLP-1 RA for reducing HbA1c and weight from baseline after 6 months of treatment. The efficacy of once-weekly semaglutide is not associated with a significant increase in the incidence of gastrointestinal side-effects vs other GLP-1 RAs. FUNDING: Novo Nordisk. PMID- 29713962 TI - DEVOTE 5: Evaluating the Short-Term Cost-Utility of Insulin Degludec Versus Insulin Glargine U100 in Basal-Bolus Regimens for Type 2 Diabetes in the UK. AB - INTRODUCTION: The aim of this study was to evaluate the short-term cost-utility of insulin degludec (degludec) versus insulin glargine 100 units/mL (glargine U100) for the treatment of type 2 diabetes in the basal-bolus subgroup of the head-to-head cardiovascular (CV) outcome trial, DEVOTE. METHODS: A cost-utility analysis was conducted over a 2-year time horizon using a decision analytic model to compare costs in patients receiving once daily degludec or glargine U100, both as part of a basal-bolus regimen, in addition to standard care. Clinical outcomes and patient characteristics were taken exclusively from DEVOTE, whilst health related quality of life utilities and UK-specific costs (expressed in 2016 GBP) were obtained from the literature. The analysis was conducted from the perspective of the National Health Service. RESULTS: Degludec was associated with mean cost savings of GBP 28.78 per patient relative to glargine U100 in patients with type 2 diabetes at high CV risk. Cost savings were driven by the reduction in risk of diabetes-related complications with degludec, which offset the higher treatment costs relative to glargine U100. Degludec was associated with a mean improvement of 0.0064 quality-adjusted life-years (QALYs) compared with glargine U100, with improvements driven predominantly by lower rates of severe hypoglycemia with degludec versus glargine U100. Improvements in quality-adjusted life expectancy combined with cost neutrality resulted in degludec being dominant over glargine U100. Sensitivity analyses demonstrated that the incremental cost utility ratio was stable to variations in the majority of model inputs. CONCLUSION: The present short-term modeling analysis found that for the basal bolus subgroup of patients in DEVOTE, with a high risk of CV events, degludec was cost neutral (no additional costs) compared with glargine U100 over a 2-year time horizon in the UK setting. Furthermore, there were QALY gains with degludec, particularly due to the reduction in the risk of severe hypoglycemia. FUNDING: Novo Nordisk A/S. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT01959529. PMID- 29713963 TI - A Versatile Integrated Ambient Ionization Source Platform. AB - The pursuit of high-throughput sample analysis from complex matrix demands development of multiple ionization techniques with complementary specialties. A versatile integrated ambient ionization source (iAmIS) platform is proposed in this work, based on the idea of integrating multiple functions, enhancing the efficiency of current ionization techniques, extending the applications, and decreasing the cost of the instrument. The design of the iAmIS platform combines flowing atmospheric pressure afterglow (FAPA) source/direct analysis in real time (DART), dielectric barrier discharge ionization (DBDI)/low-temperature plasma (LTP), desorption electrospray ionization (DESI), and laser desorption (LD) technique. All individual and combined ionization modes can be easily attained by modulating parameters. In particular, the FAPA/DART&DESI mode can realize the detection of polar and nonpolar compounds at the same time with two different ionization mechanisms: proton transfer and charge transfer. The introduction of LD contributes to the mass spectrometry imaging and the surface-assisted laser desorption (SALDI) under ambient condition. Compared with other individual or multi-mode ion source, the iAmIS platform provides the flexibility of choosing different ionization modes, broadens the scope of the analyte detection, and facilitates the analysis of complex samples. Graphical abstract ?. PMID- 29713964 TI - Maximizing Selective Cleavages at Aspartic Acid and Proline Residues for the Identification of Intact Proteins. AB - A new approach for the identification of intact proteins has been developed that relies on the generation of relatively few abundant products from specific cleavage sites. This strategy is intended to complement standard approaches that seek to generate many fragments relatively non-selectively. Specifically, this strategy seeks to maximize selective cleavage at aspartic acid and proline residues via collisional activation of precursor ions formed via electrospray ionization (ESI) under denaturing conditions. A statistical analysis of the SWISS PROT database was used to predict the number of arginine residues for a given intact protein mass and predict a m/z range where the protein carries a similar charge to the number of arginine residues thereby enhancing cleavage at aspartic acid residues by limiting proton mobility. Cleavage at aspartic acid residues is predicted to be most favorable in the m/z range of 1500-2500, a range higher than that normally generated by ESI at low pH. Gas-phase proton transfer ion/ion reactions are therefore used for precursor ion concentration from relatively high charge states followed by ion isolation and subsequent generation of precursor ions within the optimal m/z range via a second proton transfer reaction step. It is shown that the majority of product ion abundance is concentrated into cleavages C-terminal to aspartic acid residues and N-terminal to proline residues for ions generated by this process. Implementation of a scoring system that weights both ion fragment type and ion fragment area demonstrated identification of standard proteins, ranging in mass from 8.5 to 29.0 kDa. Graphical Abstract ?. PMID- 29713965 TI - Chemical Mass Shifts in a Digital Linear Ion Trap as Analytical Identity of o-, m , and p-Xylene. AB - Chemical mass shifts between isomeric ions of o-, m-, and p-xylene were measured using a digital linear ion trap, and the directions and values of the shifts were found to be correlated to the collision cross sections of the isomers. Both forward and reverse scans were used and the chemical shifts for each pair of isomers in scans of opposite directions were in opposite signs. Using different voltage settings (namely the voltage dividing ratio-VDR) of the ion trap allows adding high order field components in the quadrupole field and results in larger chemical mass shifts. The differential chemical mass shift which combined the shifts from forward and reverse scans doubled the amount of chemical shift, e.g., 0.077 Th between o- and p-xylene, enough for identification of the type of isomer without using an additional ion mobility spectrometer. The feature of equal and opposite chemical mass shifts also allowed to null out the chemical mass shift by calculating the mean m/z value between the two opposite scans and remove or reduce the mass error caused by chemical mass shift. Graphical Abstract ?. PMID- 29713966 TI - Inhibiting and Remodeling Toxic Amyloid-Beta Oligomer Formation Using a Computationally Designed Drug Molecule That Targets Alzheimer's Disease. AB - Alzheimer's disease (AD) is rapidly reaching epidemic status among a burgeoning aging population. Much evidence suggests the toxicity of this amyloid disease is most influenced by the formation of soluble oligomeric forms of amyloid beta protein, particularly the 42-residue alloform (Abeta42). Developing potential therapeutics in a directed, streamlined approach to treating this disease is necessary. Here we utilize the joint pharmacophore space (JPS) model to design a new molecule [AC0107] incorporating structural characteristics of known Abeta inhibitors, blood-brain barrier permeability, and limited toxicity. To test the molecule's efficacy experimentally, we employed ion mobility mass spectrometry (IM-MS) to discover [AC0107] inhibits the formation of the toxic Abeta42 dodecamer at both high (1:10) and equimolar concentrations of inhibitor. Atomic force microscopy (AFM) experiments reveal that [AC0107] prevents further aggregation of Abeta42, destabilizes preformed fibrils, and reverses Abeta42 aggregation. This trend continues for long-term interaction times of 2 days until only small aggregates remain with virtually no fibrils or higher order oligomers surviving. Pairing JPS with IM-MS and AFM presents a powerful and effective first step for AD drug development. Graphical Abstract. PMID- 29713967 TI - Effects of glucosamine in patients with osteoarthritis of the knee: a systematic review and meta-analysis. AB - Osteoarthritis (OA) of the knee is one of the main causes of mobility decline in the elderly. Non-surgical treatments such as administration of supplements to strengthen the joint cartilage matrix have become popular not only for pain relief but also for joint preservation. Glucosamine has been used in many countries based on the increasing evidence of its effectiveness for OA. Although there are many previous studies and systematic reviews, the findings vary and different conclusions have been drawn. We aimed to review recent randomized controlled trials on glucosamine for knee OA to reveal up-to-date findings about this supplement. We also performed a meta-analysis of some of the outcomes to overcome the unsolved bias in each study. Eighteen articles written between 2003 and 2016 were analyzed. Many used visual analogue scale (VAS) pain scores and the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), which were assessed in our meta-analysis. We found a marginally favorable effect of glucosamine on VAS pain scores. The effect on knee function, as measured by the WOMAC, was small and not significant. A newly established knee OA scale, the Japanese Knee Osteoarthritis Measure (JKOM), is commonly used in Japan. Although the number of subjects was small, the JKOM meta-analysis indicated that glucosamine is superior to a placebo in alleviating knee OA symptoms. Given this, we concluded that glucosamine has the potential to alleviate knee OA pain. Further studies are needed to evaluate the effect of glucosamine on knee function and joint preservation, as well as to evaluate the combined effect with other components, such as chondroitin. PMID- 29713968 TI - Association of neuropathic-like pain characteristics with clinical and radiographic features in patients with ankylosing spondylitis. AB - Ankylosing spondylitis (AS) is a chronic, progressive, and inflammatory disorder and causes chronic back pain. It is not unusual for patients with AS to have symptoms similar to neuropathic pain. We aimed to investigate the neuropathic pain (NeP) component in patients with AS using the painDETECT questionnaire (PD Q) and to assess the relation between NeP and the disease characteristics of AS. A single-center prospective study was performed, including 105 patients. Patients with AS completed three questionnaires: PD-Q, Beck Depression Inventory (BDI), and Euro Quality of Life (EQ-5D) questionnaires. Patients were classified into three groups according to the PD-Q scores: nociceptive pain (NoP) (score <= 12), mixed pain (MP) (score 13-18), and NeP pain (score >= 19). Fifteen patients (14.2%) were classified into the NeP group, 22 (21.0%) in the MP group, and 68 (64.8%) in the NoP group. The questionnaires and clinical and radiographic findings were analyzed. Patients with NeP and MP scored worse on the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI); BDI; modified Stoke Ankylosing Spondylitis Spine Score; pain-visual analog scale (VAS); and EQ-5L index and showed an increased prevalence of enthesitis and peripheral arthritis. There were no differences in objective inflammatory markers. PD-Q scores were positively correlated with pain-VAS, BASDAI, BDI, and inversely correlated with EQ-5D index. Age, BASDAI, presence of current enthesitis, and BDI score were independently associated with PD-Q scores. The findings showed that NeP component in AS was associated with age, high disease activity, presence of current enthesitis, and depression. PMID- 29713969 TI - Rituximab for refractory rapidly progressive interstitial lung disease related to anti-MDA5 antibody-positive amyopathic dermatomyositis. AB - To report our experience in using rituximab (RTX) for treating refractory rapidly progressive interstitial lung disease (RP-ILD) complicating anti-melanoma differentiation-associated gene 5 antibody (anti-MDA5 Ab)-positive amyopathic dermatomyositis (ADM). Medical records of four ADM patients with refractory RP ILD treated with RTX therapy were reviewed retrospectively. All four patients were tested positive for anti-MDA5 Ab and failed to respond to high-dose systemic steroid and other intensive immunosuppressive therapies. Respiratory symptoms, lung function tests, and high-resolution computed tomography (HRCT) of the chest were compared before and after the first course of RTX. After RTX treatment, all four patients had improvement in the respiratory symptoms in terms of New York Heart Association classification. Two patients successfully had their supplementary oxygen therapy weaned off. The lung function tests were significantly better in all patients. The HRCT showed improvement in three patients while the other one remained static. The recalcitrant vasculitic rashes associated with the anti-MDA5 Ab were also better in all patients. The average daily prednisolone dose dropped from 20 to 6.25 mg post-treatment. None of the patients died throughout the follow-up period which ranged from 6 months to 2 years. However, two patients developed chest infection and one wound infection within 6 months after the RTX infusion. Our results suggest that RTX may be a useful therapy for anti-MDA5 Ab-positive ADM associated with RP-ILD. However, infection is the major risk. PMID- 29713970 TI - Trends of metals enrichment in deposited particulate matter at semi-arid area of Iran. AB - The presence and enrichment of heavy metals in dust depositions have been recognized as an emerging environmental health issues in the urban and industrial areas. In this study, the deposition of some metals was found in Qom, a city located in a semi-desert area in Iran that is surrounded by industrial areas. Dust deposition samples were collected using five sampling stations during a year. Dust samples were digested applying acidic condition and then, the metal content was analyzed using inductively coupled plasma technology (ICP-OES). Comparative results showed the following order, from the maximum to the minimum concentration (mg/kg dust) of elements: Ca > Al > Fe > Mg > Ti > Si > K > B > Sr > Mn > P > Ba > Cr > Zn > Ni > Sn > Pb > V > Na > Cu > Co > U > Li > Ce > Ag. The differences among the average concentrations of metals in the five stations were not significant (p value > 0.05). The average concentration of some metals increased significantly during cold seasons. In this study, the cluster analysis (CA) and princicipal component analysis (PCA) were applied, and relationships among some elements in different clusters were found. In addition, the geo accumulation and enrichment analysis revealed that the following metals had been enriched more than the average values: boron, silver, tin, uranium, lead, zinc, cobalt, chromium, lithium, nickel, strontium, and coper. The presence of thermal power plant, pesticide manufacturing plants, publishing centers, traffic jam, and some industrial areas around the city has resulted in the enrichment of some metals (particularly in cold seasons with atmospheric stable conditions) in dust deposition. PMID- 29713971 TI - Selective bioaccumulation, biomagnification, and dissipation of hexachlorocyclohexane isomers in a freshwater food chain. AB - Hexachlorocyclohexane isomers (HCHs) are persistent organic pollutants (POPs), having potential risks to humans and ecosystem. This work evaluated the propensity of organisms to accumulate, eliminate, and transfer HCHs along the food chain (Tubifex tubifex and common carp (Cyprinus carpio)). The accumulation of HCHs from water by worms and carp was observed, and the concentrations increased with exposure time. After 8 days, the HCH concentrations in organisms remained stable. The accumulation factor (AF) values of HCHs in T. tubifex were higher than those in carp, indicating that the bioaccumulation abilities of HCHs in T. tubifex were higher than those in carp. The contaminated worms as a dietary source in the food chain led to significantly higher bioaccumulation in carp. The biomagnification factor (BMF) values of HCH isomers were all greater than 1. In the dissipation experiments, the elimination was fast and the half-lives were shorter than 2.5 days. The enantioselective accumulation and dissipation of alpha HCH enantiomers were observed in worms and carp (food chain), and the enantiomeric differences should be taken into consideration in the study of contaminants risk assessment. The results on trophic transfer of HCHs in a freshwater food chain should be helpful for better understanding the fate, transport, and transfer of HCHs in freshwater environments. PMID- 29713972 TI - Maximum cadmium limits establishment strategy based on the dietary exposure estimation: an example from Chinese populations and subgroups. AB - Dietary exposure to cadmium (Cd) in the Chinese population is currently a public health concern. China's national standard for maximum limits (MLs) of Cd in foods needs to be assessed. The objective of this research is to estimate the impacts of different Cd MLs intakes from selected foods and food groups and to provide scientific evidence for ML establishment. Food consumption data were taken from the Chinese National Diet and Nutrition Survey. Cd contamination data were obtained from the National Food Contamination Monitoring Program. A beta binomial normal (BBN) model was applied in the probabilistic assessment. Different possible ML scenarios for rice were selected to assess the impact of different MLs on Cd concentration and intake. More than 70% of children aged 2-6 years and over 30% of the general population have a dietary daily Cd intake above provisional tolerable daily intake (PTMId). Cd intake changed greatly relative to baseline when different possible MLs were used, but the changes were not as large when compared among the different possible MLs. Cd exposure in China, especially for children, is a public health concern. It is recommended that the ML for rice be held at 0.2 mg/kg. PMID- 29713973 TI - Enantioselective analysis and degradation of isofenphos-methyl in vegetables by liquid chromatography-tandem mass spectrometry. AB - The enantioselective degradation of isofenphos-methyl in cowpea, cucumber, and pepper under field conditions was investigated to elucidate the enantioselective environmental behaviors of this pesticide. The concentrations of the enantiomers were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS). The degradation rates of isofenphos-methyl enantiomers were the fastest in cowpea, followed by cucumber and pepper, with half-lives ranging from 1.48 to 8.06 days. The enantioselective degradation of isofenphos-methyl was characterized by calculating and comparing the values of enantiomer fraction (EF) and enantiomeric selectivity (ES). The degradation rates and enantioselectivities of isofenphos methyl were different for the three vegetables. (R)-(-)-isofenphos-methyl was degraded faster than (S)-(+)-isofenphos-methyl in cowpea and cucumber, whereas (S)-(+)-isofenphos-methyl underwent preferential degradation in pepper. These results could serve as a reference for the study of enantioselective behavior of isofenphos-methyl in plants and further food safety evaluation, where the enantiomeric differences should be considered in the risk assessment. PMID- 29713974 TI - Modeling the risk of water pollution by pesticides from imbalanced data. AB - The pollution of ground and surface waters with pesticides is a serious ecological issue that requires adequate treatment. Most of the existing water pollution models are mechanistic mathematical models. While they have made a significant contribution to understanding the transfer processes, they face the problem of validation because of their complexity, the user subjectivity in their parameterization, and the lack of empirical data for validation. In addition, the data describing water pollution with pesticides are, in most cases, very imbalanced. This is due to strict regulations for pesticide applications, which lead to only a few pollution events. In this study, we propose the use of data mining to build models for assessing the risk of water pollution by pesticides in field-drained outflow water. Unlike the mechanistic models, the models generated by data mining are based on easily obtainable empirical data, while the parameterization of the models is not influenced by the subjectivity of ecological modelers. We used empirical data from field trials at the La Jailliere experimental site in France and applied the random forests algorithm to build predictive models that predict "risky" and "not-risky" pesticide application events. To address the problems of the imbalanced classes in the data, cost sensitive learning and different measures of predictive performance were used. Despite the high imbalance between risky and not-risky application events, we managed to build predictive models that make reliable predictions. The proposed modeling approach can be easily applied to other ecological modeling problems where we encounter empirical data with highly imbalanced classes. PMID- 29713975 TI - Integrated ecological floating bed treating wastewater treatment plant effluents: effects of influent nitrogen forms and sediments. AB - In recent years, the treatment of wastewater treatment plant (WWTP) effluent has gained increasing attention. However, researches on the relationships between nitrogen forms and nitrogen removal efficiency are very limited. Based on the fact that the nitrogen forms in the WWTP effluent may vary as the season changes, the nitrogen removal efficiencies of an integrated ecological floating bed (IEFB) was studied under different influent nitrogen forms. In addition, the effects of sediments in the system were also quantified during the experiment. Results showed that the total nitrogen (TN) removal rates of the IEFB were 25.61 +/- 5.72% and 60.03 +/- 7.00%, respectively, when the main influent nitrogen forms are nitrate and ammonia. The sediments in the system also played vital roles in the removal processes: when the sediments were covered with a polyethylene membrane, the total nitrogen (TN) removal rate of the system dropped from 27.86 +/- 5.53% to 14.78 +/- 4.97%, and the total phosphorus (TP), from 58.77 +/- 6.20% to 33.51 +/- 25.52%. PMID- 29713976 TI - The combined effect of Bassa 50EC and Vitashield 40EC on the brain acetylcholinesterase activity in climbing perch (Anabas testudineus). AB - The combined effect of Vitashield 40EC (chlorpyrifos ethyl-CPF) and Bassa 50EC (fenobucarb-F) was compared with the effects from exposure to the two pesticides separately, by measuring the brain acetylcholinesterase (AChE) activity in climbing perch fingerlings (Anabas testudineus). The experiment was conducted under controlled laboratory conditions and included three treatments containing 0.173 mg/L of CPF, 1.137 mg/L of F, 0.173 mg/L of CPF + 1.137 mg/L of F (M), and a control. The inhibition of the brain AChE activity in fish exposed to F was weaker and shorter than in fish exposed to CPF. The inhibition by the mixture of CPF and F was significantly lower and less prolonged than the inhibition by only CPF but significantly higher than the inhibition by only F. PMID- 29713977 TI - Pimpinella anisum essential oil nanoemulsions against Tribolium castaneum insecticidal activity and mode of action. AB - The red flour beetle, Tribolium castaneum Herbst (Coleoptera: Tenebrionidae), is an economically important pest of stored products. As possible alternative to conventional insecticides for its management, plant essential oils have gained interest owing to their effectiveness and eco-friendly features. However, they also show some drawbacks, such as low stability, poor water solubility and diffusion, and limited persistence in the environment. A good strategy to overcome these disadvantages is represented by green nanotechnologies. Herein, we developed a nanoemulsion based on the essential oil from Pimpinella anisum L. (Apiaceae) containing 81.2% of (E)-anethole and evaluated its toxicity on T. castaneum adults and F1 progeny, as well as its morphological and histological impact. The aniseed oil nanoemulsion was characterized by the formation of a semi solid interphase between oil and water; mean drop size was 198.9 nm, PDI was 0.303, zeta potential was - 25.4 +/- 4.47 mV, and conductivity was 0.029 mS/cm. The nanoemulsion showed toxicity on T. castaneum (LC50 = 9.3% v/v), with a significant impact on its progeny. Morphological and histological damages triggered by feeding and exposure to the aniseed nanoemulsion were analyzed by scanning electron microscopy (SEM) and light microscopy. Overall, our findings showed that the development of nanoemulsions allows to improve the stability of P. anisum essential oil enhancing its efficacy against stored grain pests and contributing to reduce the use of harmful synthetic insecticides. PMID- 29713978 TI - Immobilization of Eu and Ho from synthetic acid mine drainage by precipitation with Fe and Al (hydr)oxides. AB - Use of lime to mitigate acid mine drainage is, in general, accompanied by precipitation of iron (Fe) and aluminium (Al) (hydr)oxides which may increase the removal of trace elements from water. This work aimed to evaluate the precipitation of Fe/Al (hydr)oxides to remove rare earth elements (REE) from contaminated water and the stability of precipitates. Two sets of 60-day syntheses were carried out using different Fe/Al/REE molar ratios, for europium (Eu) and holmium (Ho). The pH was periodically adjusted to 9.0, and the stability of the resulting precipitates was evaluated by water-soluble and BCR extractable phases, namely (1) acid soluble, extracted by 0.11 mol L-1 acetic acid; (2) reducible, extracted with 0.5 mol L-1 hydroxylamine hydrochloride; and (3) oxidisable, extracted with 8.8 mol L-1 hydrogen peroxide efficiencies of the water treatments for both Eu and Ho that were higher than 99.9% irrespective to the Fe/Al/REE molar ratios. Water-soluble phases of Eu and Ho were lower than 0.01% of the total contents in the precipitates. Recoveries from precipitates by Bureau Communautaire de Reference (BCR) sequential extractions increased with increasing concentrations of Eu and Ho. Acetic acid extracted higher amounts of REE, but Eu recovery was superior to Ho. Lepidocrocite was formed as Eu concentration increased which decreased its stability in the precipitates. PMID- 29713979 TI - Molecular surveillance of Vittaforma-like microsporidia by a small-volume procedure in drinking water source in Taiwan: evidence for diverse and emergent pathogens. AB - Vittaforma corneae belongs to microsporidia, which include over 1500 species of opportunistic obligate intracellular fungi infecting almost all known animal taxa. Although outbreaks of ocular infections caused by waterborne V. corneae have been reported in recent years, little is known about the occurrence of this pathogen in aquatic environments. In this study, 50 water samples from rivers and reservoirs around Taiwan in two seasons were analyzed to explore the presence of this pathogen in natural aquatic environments. A high detection rate of Vittaforma-like amplicons (94%; 47/50) was observed in the water samples when examined by nested PCR with primer pairs specific to the small ribosomal subunit (SSU) rRNA gene. After electrophoresis, many lanes showed multiband patterns with expected molecular weights. After confirmation by DNA sequencing and by sequence alignment in the NCBI database, we identified a variety of Vittaforma-like microsporidia with weak sequence similarity, with approximately 85% identity to V. corneae, thus indicating high diversity of microsporidia in aquatic environments. Phylogenetic analysis showed clear-cut microsporidian clade classification and indicated that the most Vittaforma-like microsporidia in this study belong to clade IV and cluster into four major groups. The first group is similar to the microsporidia associated with ocular microsporidiosis. The second group is associated with the diarrheal pathogens, whereas the third and fourth groups are a novel group and a zoonotic group, respectively. This study provides abundant sequencing information, which will be useful for future molecular biological studies on microsporidia. Because microsporidia are important pathogens of animals and humans, it is urgently necessary to determine via a survey whether there are species with potential threats that have not yet been revealed. PMID- 29713980 TI - CHOP/caspase-3 signal pathway involves in mitigative effect of selenium on lead induced apoptosis via endoplasmic reticulum pathway in chicken testes. AB - Lead (Pb) is an environmental pollutant. Selenium (Se) has alleviative effect on Pb poisoning. However, mitigative effect of Se on Pb-induced apoptosis has not been unclear via endoplasmic reticulum (ER) pathway in chicken testes. The aim of this study was to investigate mitigative effect of Se on apoptosis induced by Pb poisoning via ER pathway in chicken testes. Sixty male chickens (7-day-old) were randomly divided into the control group offered drinking water (DW) and basic diet (BD) (0.49 mg/kg Se), the Se group offered DW and BD containing Na2SeO3 (SeBD) (1.00 mg/kg Se), the Pb group offered DW containing (CH3OO)2Pb (PbDW) (350.00 mg/L Pb) and BD, and the Pb + Se group offered PbDW and SeBD; and were fed for 90 days. The following contents were performed as follows: histology; antioxidant indexes (reduced glutathione (GSH), malondialdehyde (MDA), glutathione peroxidase (GPx), glutathione S-transferase (GST), and superoxide dismutase (SOD)); mRNA expressions of ER-related genes (glucose-related protein 78 (GRP78), protein kinase-like ER kinase (PERK), eukaryotic initiation factor 2alpha (eIF2alpha), activating transcription factor 4 (ATF4), and enhancer binding protein homologous protein (CHOP)); and apoptosis-related genes (cysteine aspartic protease (caspase)-3 and caspase-12) in chicken testes. The results indicated that Pb poisoning caused histological changes; increased MDA content; decreased the content of GSH and the activities of GPx, GST, and SOD; and upregulated mRNA expressions of the above five ER-related genes and two apoptosis related genes in the chicken testes. Se alleviated Pb-induced oxidative stress, ER stress, and apoptosis via CHOP/caspase-3 signal pathway in the chicken testes. PMID- 29713981 TI - Effect of EDTA and citric acid on absorption of heavy metals and growth of Moso bamboo. AB - The effect of EDTA and citric acid on accumulation, toxicity of heavy metals (Cu, Zn, Cd, and Pb), and growth of Moso bamboo was investigated in current experiment. The availability of heavy metals in soil and its uptake by plants has indicated toxicity. The results revealed that EDTA and citric acid has reduced biomass of Moso bamboo but non-significant difference in biomass was observed compared with control. Application of EDTA (10 mmol kg-1) has significantly improved copper (Cu) by 56.5 and 84.9% in roots and above ground parts of plants. Application of EDTA (10 mmol kg-1) has significantly enhanced lead (Pb) by 51.8 and 210.8% in roots and above ground parts of Moso bamboo. Furthermore, treatment of EDTA has significantly improved activities of water-soluble Cd, Cu, and Pb in soil by 98.9, 70.1, and 73.1 times compared with control. In case of contents of diethylenetriaminepentaacetic acid (DTPA)-extractable metals, the treatment of EDTA (10 mmol kg-1) has produced maximum increase of 244.5 mg kg-1 Zn and 157.9 mg kg-1 Pb, respectively. It is concluded that effect of EDTA was superior compared with citric acid for improvement of phytoremediation potential of Moso bamboo. PMID- 29713982 TI - The impact of environmental pollution on public health expenditure: dynamic panel analysis based on Chinese provincial data. AB - In recent years, along with rapid economic growth, China's environmental problems have become increasingly prominent. At the same time, the level of China's pollution has been growing rapidly, which has caused huge damages to the residents' health. In this regard, the public health expenditure ballooned as the environmental quality deteriorated in China. In this study, the effect of environmental pollution on residents' health expenditure is empirically investigated by employing the first-order difference generalized method of moments (GMM) method to control for potential endogeneity. Using a panel data of Chinese provinces for the period of 1998-2015, this study found that the environmental pollution (represented by SO2 and soot emissions) would indeed lead to the increase in the medical expenses of Chinese residents. At the current stage of economic development, an increase in SO2 and soot emissions per capita would push up the public health expenditure per capita significantly. The estimation results are quite robust for different types of regression specifications and different combinations of control variables. Some social and economic variables such as public services and education may also have remarkable influences on residential medical expenses through different channels. PMID- 29713983 TI - Fluorescent characteristic and compositional change of dissolved organic matter and its effect on heavy metal distribution in composting leachates. AB - Composting leachates were collected to investigate the fluorescent characteristic and compositional change of dissolved organic matter (DOM) and the effects of the DOM and nutrients on heavy metal distribution during a leachate combination treatment process. Excitation-emission matrix (EEM) fluorescence spectra showed that, with the progress of the treatment units, the content of fulvic-like, humic like, and protein-like substances gradually decreased. One fulvic-like component (C1), three humic-like components (C2, C3, and C4), and three protein-like components (C5, C6, and C7) were identified in the leachate DOM by parallel factor analysis. Anaerobic-aerobic processes removed a large fraction of the tyrosine-like component (C7) and tryptophan-like component (C6) and a small amount of humic-like component (C2), while the membrane bioreactor showed a good removal effect on protein-like component. The ultra-filtration membrane treatment had a removal effect on fulvic-like and humic-like component and other recalcitrant compounds, while the reverse osmosis treatment had a good removal effect on both humic-like and protein-like components. Correlation analysis indicated that Mn and Cr were primarily associated with protein-like components and nutrients in the composting leachates. Ni and Pb were bound to fulvic-like, humic-like, and protein-like components, Co and Zn interacted with inorganic nitrogen and total phosphorus, and Cd only interacted with inorganic nitrogen. PMID- 29713984 TI - Biomarkers of Barrett's Esophagus: From the Laboratory to Clinical Practice. AB - The currently recommended approach to managing cancer risk for patients with Barrett's esophagus is endoscopic surveillance including a biopsy protocol to sample the esophageal tissue randomly to detect dysplasia. However, there are numerous limitations in this practice that rely on the histopathological grading of dysplasia alone to make clinical decisions. The availability of in silico models demonstrating the potential cost-effectiveness of biomarker-based stratification has increased interest in finding a clinically relevant "Barrett's biomarker." The success of endoscopic eradication therapy in preventing neoplastic progression of dysplastic Barrett's esophagus has promoted the desire to stratify non-dysplastic Barrett's esophagus to those with "high risk" that may benefit from endotherapy. Furthermore, on the other end of the spectrum, there is interest in searching for a "low risk" marker that may identify those that would not likely benefit from endoscopy screening or surveillance. This review highlights recent data from the genomics (r)evolution revealing new genetic biomarkers of susceptibility to the development of Barrett's esophagus and novel pathways for its neoplastic progression, addresses the development of new modes of tissue sampling and imaging to detect early neoplasia in Barrett's esophagus, and discusses current progress in moving biomarkers from the laboratory into clinical practice in the era of precision medicine. PMID- 29713985 TI - Advanced Age Does Not Negatively Impact Health-Related Quality of Life in Inflammatory Bowel Disease. AB - BACKGROUND: Health-related quality of life (HRQoL) is significantly impacted in patients with inflammatory bowel disease (IBD). Many studies have assessed HRQoL in patients of all ages, and few focus on the elderly. AIM: To determine the influence of advanced age (> 65 years) and age at diagnosis on patients with IBD. METHODS: This is a retrospective study of prospectively collected data from a single IBD tertiary referral center. Patients had disease activity indices [Harvey-Bradshaw index (HBI), Ulcerative Colitis Disease Activity Index (UCDAI), and Short Inflammatory Bowel Disease Questionnaire (SIBDQ)] recorded during every clinic visit. Three groups of patients: > 65 years, 41-64 years, and < 40 years with > 5 SIBDQ entries were included. Influence of disease type, disease duration, extent of involvement, and comorbidities such as cardiovascular (CV) disease, pulmonary disease, diabetes mellitus (DM), and psychological disorders were noted as confounders. Statistical analysis was performed using ANOVA, Pearson correlation, and logistic regression model. RESULTS: Disease severity indices significantly affected SIBDQ score in both Crohn's disease (CD) and ulcerative colitis (UC) (p < 0.001 for HBI in CD, p < 0.001 UCDAI in UC). Disease extent (p = 0.011) and psychological disorders (p < 0.001) significantly affected SIBDQ score in CD. Chronological age, age at diagnosis, disease duration, number of clinic visits, CV disease, pulmonary disease, and DM were not significant predictors of SIBDQ score (p > 0.05). CONCLUSIONS: HRQoL was negatively influenced by disease extent and psychological disorders in CD but not in UC patients. Advanced age was not a predictor of poor HRQoL in both CD and UC. PMID- 29713986 TI - Point-Counterpoint: Screening and Surveillance for Barrett's Esophagus, Is It Worthwhile? AB - The exponential rise in incidence of esophageal adenocarcinoma (EAC), paired with persistently poor survival, continues to drive efforts to improve and optimize screening and surveillance practices. While advancements in endoscopic therapy have generated a shift in management and significantly improved the outcomes of patients with early-stage EAC, the majority of prevalent EAC continues to be diagnosed at advanced stages, remaining ineligible for curative therapy. Barrett's esophagus (BE) screening, when applied to high-yield target populations, using minimally or noninvasive accurate tests, followed by endoscopic surveillance to detect prevalent or incident dysplasia/EAC (which can then be treated successfully) is the cornerstone of the current BE management paradigm. While supported by some empiric evidence and attractive, this approach faces a number of challenges, which are also balanced by numerous recent advances in these areas. In this manuscript, we review the rationale, supportive evidence, current challenges, and recent progress in BE screening and surveillance. PMID- 29713987 TI - Low Rates of Dermatologic Care and Skin Cancer Screening Among Inflammatory Bowel Disease Patients. AB - BACKGROUND: Dermatologic manifestations of inflammatory bowel disease (IBD) are common, and certain IBD medications increase the risk of skin cancer. AIMS: To define the rates of care and factors associated with dermatologic utilization with a focus on skin cancer screening. METHODS: We utilized a prospective, natural history IBD research registry to evaluate all outpatient healthcare encounters from 2010 to 2016. Gastrointestinal, dermatologic and primary care visits per individual were identified. We calculated the proportion of patients obtaining care, categorized primary indications for dermatologic visits, determined the incidence of melanoma and non-melanoma skin cancers, and used logistic regression to determine factors associated with dermatology utilization. RESULTS: Of the 2127 IBD patients included, 452 (21.3%) utilized dermatology over the study period, and 55 (2.6%) had a total body skin examination at least once. The 452 patients incurred 1633 dermatology clinic visits, 278 dermatologic procedures, and 1108 dermatology telephone encounters. The most frequent indication was contact dermatitis or dermatitis. Factors associated with dermatology use were family history of skin cancer, employment, systemic steroids, longer disease duration, emergency room use, and the number of IBD related clinic visits. Between 8.3 and 11% of IBD patients recommended for skin cancer screening visited dermatology each year, and the resulting incidence of non-melanoma skin cancer was 35.4/10,000 [95% CI 23.3-51.5] and melanoma was 6.56/10,000 [95% CI 2.1-15.3]. CONCLUSIONS: Less than one in ten IBD patients obtain dermatologic care. Given the increased risk of skin cancers among IBD patients, an emphasis on education, prevention, and screening merits attention. PMID- 29713989 TI - Optimal duration of dual antiplatelet therapy for coronary artery disease. AB - The optimal duration of dual antiplatelet therapy (DAPT) for stable coronary artery disease and acute coronary syndrome is a complex decision. We review current literature on standard duration DAPT versus short duration DAPT (6 months or shorter) or extended duration DAPT (>12 months) after percutaneous coronary intervention with drug-eluting stent placement, and prolonged treatment after 12 months in acute coronary syndrome. Current guideline recommendations are summarised, including the use of risk scores for ischaemic and bleeding risk assessment. Because of the limitations of current risk scores, we propose multiple patient-related and procedure-related factors for the ischaemic and bleeding risk assessment aiding in personalised DAPT duration. PMID- 29713988 TI - In the Beginning was a Mutualism - On the Origin of Translation. AB - The origin of translation is critical for understanding the evolution of life, including the origins of life. The canonical genetic code is one of the most dominant aspects of life on this planet, while the origin of heredity is one of the key evolutionary transitions in living world. Why the translation apparatus evolved is one of the enduring mysteries of molecular biology. Assuming the hypothesis, that during the emergence of life evolution had to first involve autocatalytic systems which only subsequently acquired the capacity of genetic heredity, we propose and discuss possible mechanisms, basic aspects of the emergence and subsequent molecular evolution of translation and ribosomes, as well as enzymes as we know them today. It is possible, in this sense, to view the ribosome as a digital-to-analogue information converter. The proposed mechanism is based on the abilities and tendencies of short RNA and polypeptides to fold and to catalyse biochemical reactions. The proposed mechanism is in concordance with the hypothesis of a possible chemical co-evolution of RNA and proteins in the origin of the genetic code or even more generally at the early evolution of life on Earth. The possible abundance and availability of monomers at prebiotic conditions are considered in the mechanism. The hypothesis that early polypeptides were folding on the RNA scaffold is also considered and mutualism in molecular evolutionary development of RNA and peptides is favoured. PMID- 29713990 TI - Optimal treatment of patients with NSTE-ACS in the Dutch health care system. AB - In the current daily practice of acute coronary syndromes, patients experiencing non-ST-elevation acute coronary syndrome (NSTE-ACS) represent the majority of this population. In these patients it is of utmost importance to estimate both ischaemic and bleeding risk, with subsequent, and preferably tailored pharmacological and, if indicated, invasive treatment. In this paper we describe the several risk scores and evaluate which are most applicable to the Dutch health-care system. Furthermore, we provide an overview of the recommended pharmacological treatment in keeping with the European Society of Cardiology guidelines. An important topic of this paper is how to decide between early or delayed invasive strategies. We describe the recommendations of the European Society of Cardiology and evaluate to which level these should be applied to the Dutch health-care system. PMID- 29713991 TI - Assessment of Health Effects of Exogenous Urea: Summary and Key Findings. AB - PURPOSE OF REVIEW: Urea has been utilized as a reductant in diesel fuels to lower emission of nitrogen oxides, igniting interest in probable human health hazards associated with exposure to exogenous urea. Here, we summarize and update key findings on potential health effects of exogenous urea, including carcinogenicity. RECENT FINDINGS: No definitive target organs for oral exposure were identified; however, results in animal studies suggest that the liver and kidney could be potential target organs of urea toxicity. The available human subject literature suggests that the impact on lung function is minimal. Based on the literature on exogenous urea, we concluded that there was inadequate information to assess the carcinogenic potential of urea, or perform a quantitative assessment to derive reference values. Given the limited information on exogenous urea, additional research to address gaps for exogenous urea should include long-term cancer bioassays, two-generation reproductive toxicity studies, and mode-of-action investigations. PMID- 29713992 TI - Accelerometer-Derived Activity Phenotypes in Young Adults: a Latent Class Analysis. AB - PURPOSE: To identify "activity phenotypes" from accelerometer-derived activity characteristics among young adults. METHODS: Participants were young adults (n = 628, mean age, 22.1, SD 0.6) in the Raine Study in Western Australia. Sex specific latent class analyses identified sub-groups using eight indicators derived from 7-day hip-worn Actigraph GT3X+ accelerometers: daily steps, total daily moderate-to-vigorous physical activity (MVPA), MVPA variation, MVPA intensity, MVPA bout duration, sedentary-to-light ratio, sedentary-to-light ratio variation, and sedentary bout duration. RESULTS: Five activity phenotypes were identified for women (n = 324) and men (n = 304). Activity phenotype 1 for both women (35%) and men (30%) represented average activity characteristics. Phenotype 2 for women (17%) and men (16%) was characterized by below average total activity and MVPA (10.6 and 16.7 min of MVPA/day, women and men respectively). Phenotype 3 for women (15%) and men (23%) was characterized by below average total physical activity, average MVPA (32.6 and 36.5 min/day), high sedentary-light ratio and long sedentary bouts. Phenotype 4 differed between women (29%) and men (18%) but both had low sedentary-to-light ratios and shorter sedentary bouts. Finally, phenotype 5 in both women (4%) and men (12%) was characterized by extreme MVPA metrics (81.3 and 96.1 min/day). CONCLUSIONS: Five activity phenotypes were identified for each gender in this population of young adults which can help design targeted interventions to enhance or modulate activity phenotypes. PMID- 29713993 TI - Influences on Satisfaction with Reconstructed Breasts and Intimacy in Younger Women Following Bilateral Prophylactic Mastectomy: a Qualitative Analysis. AB - PURPOSE: The aim of this study was to explore the influences on satisfaction with reconstructed breasts and intimacy following bilateral prophylactic mastectomy (BPM) in younger women (< 35) with a strong family history of breast cancer. METHODS: Twenty-six women who had undergone BPM between 1 and6 years ago were recruited from New Zealand and Australia through a genetics clinic, registry, research cohort, and online (Mage = 31). Twenty-three were BRCA mutation carriers. Qualitative interviews guided by interpretative phenomenological analysis were conducted. RESULTS: Four themes were identified: satisfaction with breasts before surgery, outcome expectations, type of mastectomy, and open communication. Women who liked their breasts pre-BPM appeared less satisfied with their reconstructed breasts post-surgery, and women who disliked their breasts before BPM were more satisfied with their reconstructed breasts. Women with unrealistic expectations concerning the look and feel of reconstructed breasts were often unhappy with their reconstructed breasts and felt they did not meet their expectations. Unrealistic photos of breast reconstruction and satisfactory communication of realistic outcome expectations by surgeons or psychologists also appeared to influence satisfaction. Communication with partners prior to BPM appeared to improve satisfaction with intimacy post-BPM. CONCLUSIONS: The findings suggest that satisfaction with reconstructed breasts for younger women post-BPM appeared to be influenced by realistic outcome expectations and communication with others concerning reconstructed breast appearance and intimacy post-BPM. Implications for practice include discussion of realistic reconstructed breast appearance, referral to a psychologist to discuss sensitive issues, and accurate communication of surgical risks and consequences. PMID- 29713994 TI - Dimethyl Fumarate Limits Neuroinflammation and Oxidative Stress and Improves Cognitive Impairment After Polymicrobial Sepsis. AB - Sepsis is caused by a dysregulated host response to infection, often associated with acute central nervous system (CNS) dysfunction, which results in long-term cognitive impairment. Dimethyl fumarate (DMF) is an important agent against inflammatory response and reactive species in CNS disorders. Evaluate the effect of DMF on acute and long-term brain dysfunction after experimental sepsis in rats. Male Wistar rats were submitted to the cecal ligation and puncture (CLP) model. The groups were divided into sham (control) + vehicle, sham + NAC, sham + DMF, CLP + vehicle, CLP + NAC, and CLP + DMF. The animals were treated with DMF (15 mg/kg at 0 and 12 h after CLP, per gavage) and the administration of n acetylcysteine (NAC) (20 mg/kg; 3, 6, and 12 h after CLP, subcutaneously) was used as positive control. Twenty-four hours after CLP, cytokines, myeloperoxidase (MPO), nitrite/nitrate (N/N), oxidative damage to lipids and proteins, and antioxidant enzymes were evaluated in the hippocampus, total cortex, and prefrontal cortex. At 10 days after sepsis induction, behavioral tests were performed to assess cognitive damage. We observed an increase in cytokine levels, MPO activity, N/N concentration, and oxidative damage, a reduction in SOD and GPx activity in the brain structures, and cognitive damage in CLP rats. DMF treatment was effective in reversing these parameters. DMF reduces sepsis-induced neuroinflammation, oxidative stress, and cognitive impairment in rats subjected to the CLP model. PMID- 29713995 TI - Full Protection Against Soman-Induced Seizures and Brain Damage by LY293558 and Caramiphen Combination Treatment in Adult Rats. AB - Acute exposure to nerve agents induces status epilepticus (SE), which causes brain damage or death. LY293558, an antagonist of AMPA and GluK1 kainate receptors is a very effective anticonvulsant and neuroprotectant against soman; however, some neuronal damage is still present after treatment of soman-exposed rats with LY293558. Here, we have tested whether combining LY293558 with an NMDA receptor antagonist can eliminate the residual damage. For this purpose, we chose caramiphen (CRM), an antimuscarinic compound with NMDA receptor antagonistic properties. Adult male rats were exposed to 1.2 * LD50 soman, and at 20 min after soman exposure, were injected with atropine + HI-6, or atropine + HI-6 + LY293558 (15 mg/kg), or atropine + HI-6 + LY293558 + CRM (50 mg/kg). We found that (1) the LY293558 + CRM treatment terminated SE significantly faster than LY293558 alone; (2) after cessation of the initial SE, seizures did not return in the LY293558 + CRM-treated group, during 72 h of monitoring; (3) power spectrum analysis of continuous EEG recordings for 7 days post-exposure showed increased delta and decreased gamma power that lasted beyond 24 h post-exposure only in the rats who did not receive anticonvulsant treatment; (4) spontaneous recurrent seizures appeared on day 7 only in the group that did not receive anticonvulsant treatment; (5) significant neuroprotection was achieved by LY293558 administration, while the rats who received LY293558 + CRM displayed no neurodegeneration; (6) body weight loss and recovery in the LY293558 + CRM treated rats did not differ from those in control rats who were not exposed to soman. The data show that treatment with LY293558 + CRM provides full antiseizure and neuroprotective efficacy against soman. PMID- 29713996 TI - The Effects of Exposure to Mephedrone During Adolescence on Brain Neurotransmission and Neurotoxicity in Adult Rats. AB - According to the European Drug Report (2016), the use of synthetic cathinones, such as mephedrone, among young people has rapidly increased in the last years. Studies in humans indicate that psychostimulant drug use in adolescence increases risk of drug abuse in adulthood. Mephedrone by its interaction with transporters for dopamine (DAT) and serotonin (SERT) stimulates their release to the synaptic cleft. In animal studies, high repeated doses of mephedrone given to adolescent but not adult mice or rats induced toxic changes in 5-hydroxytryptamine (5-HT) neurons. The aim of our study was to investigate the effects of mephedrone given in adolescence on brain neurotransmission and possible neuronal injury in adult rats. Adolescent male rats were given mephedrone (5 mg/kg) for 8 days. In vivo microdialysis in adult rats showed an increase in dopamine (DA), 5-HT, and glutamate release in the nucleus accumbens and frontal cortex but not in the striatum in response to challenge dose in animals pretreated with mephedrone in adolescence. The 5-HT and 5-hydroxyindoleacetic acid contents decreased in the striatum and nucleus accumbens while DA turnover rates were decreased in the striatum and nucleus accumbens. The oxidative damage of DNA assessed with the alkaline comet assay was found in the cortex of adult rats. Therefore, the administration of repeated low doses of mephedrone during adolescence does not seem to induce injury to 5-HT and DA neurons. The oxidative stress seems to be responsible for possible damage of cortical cell bodies which causes maladaptive changes in serotonergic and dopaminergic neurons. PMID- 29713998 TI - A methodological approach to studying resilience mechanisms: demonstration of utility in age and Alzheimer's disease-related brain pathology. AB - The present work aims at providing a methodological approach for the investigation of resilience factors and mechanisms in normal aging, Alzheimer's disease (AD) and other neurodegenerative disorders. By expanding and re conceptualizing traditional regression approaches, we propose an approach that not only aims at identifying potential resilience factors but also allows for a differentiation between general and dynamic resilience factors in terms of their association with pathology. Dynamic resilience factors are characterized by an increasing relevance with increasing levels of pathology, while the relevance of general resilience factors is independent of the amount of pathology. Utility of the approach is demonstrated in age and AD-related brain pathology by investigating widely accepted resilience factors, including education and brain volume. Moreover, the approach is used to test hippocampal volume as potential resilience factor. Education and brain volume could be identified as general resilience factors against age and AD-related pathology. Beyond that, analyses highlighted that hippocampal volume may not only be disease target but also serve as a potential resilience factor in age and AD-related pathology, particularly at higher levels of tau-pathology (i.e. dynamic resilience factor). Given its unspecific and superordinate nature the approach is suitable for the investigation of a wide range of potential resilience factors in normal aging, AD and other neurodegenerative disorders. Consequently, it may find a wide application and thereby promote the comparability between studies. PMID- 29713997 TI - Identification of TAAR5 Agonist Activity of Alpha-NETA and Its Effect on Mismatch Negativity Amplitude in Awake Rats. AB - Mismatch negativity (MMN) is a well-defined component of human event-related potentials that reflects the pre-attentive, stimulus-discrimination process and is associated with involuntary switching of attention. MMN-like responses detected in animal models provide an opportunity to investigate the neural mechanisms of this process that involves several neurotransmitter and neuromodulator systems. Trace amines are believed to play a significant role in neuromodulation of synaptic transmission. The present study aimed to determine the role of trace amine-associated receptor 5 (TAAR5) in the MMN-like response in rats. First, using a bioluminescence resonance energy transfer (BRET) cAMP biosensor, we performed unbiased screening of TAAR5 ligands from a commercially available compound library (661 compounds) and identified 2-(alpha naphthoyl)ethyltrimethylammonium iodide (alpha-NETA) as a potent (EC50 150 nM) TAAR5 agonist. Then, we recorded auditory event-related potentials during an oddball paradigm in awake freely moving rats that were intraperitoneally injected with a vehicle or two doses of the putative TAAR5 agonist alpha-NETA. The MMN like response was increased by alpha-NETA 3 mg/kg dose, but not by 1 mg/kg dose or 0.9% saline solution. These results suggest that the MMN-like response in rats may be modulated, at least in part, through TAAR5-dependent processes. PMID- 29713999 TI - Implications of electrocardiographic frontal QRS axis on left ventricular diastolic parameters derived from electrocardiogram-gated myocardial perfusion single photon emission computed tomography. AB - BACKGROUND: Current electrocardiographic (ECG) machines report various variables including frontal QRS axis automatically. We tested the hypothesis that QRS axis is associated with left ventricular (LV) diastolic parameters derived from ECG gated myocardial perfusion single photon emission computed tomography (SPECT) independent of myocardial ischemia. METHODS: Ninety-three patients with preserved LV ejection fraction and no evidence of myocardial ischemia were enrolled based on ECG-gated SPECT. Peak filling rate (PFR), one-third mean filling rate (1/3 MFR) and time to peak filling (TTPF) were obtained as LV diastolic parameters. RESULTS: There were 82 male and 11 female patients with a mean age of 69 +/- 9 years. QRS axis ranged from - 40 degrees to 85 degrees (36 degrees +/- 31 degrees ). QRS axis was correlated with PFR (r = 0.28, p < 0.01), 1/3 MFR (r = 0.25, p = 0.02) and TTPF (r = - 0.21, p = 0.04). QRS axis was also correlated with age (r = - 0.23, p = 0.03), body mass index (BMI) (r = - 0.36, p < 0.01) and LV mass index (LVMI) (r = - 0.27, p < 0.01). Linear regression analysis showed that QRS axis was associated with PFR, 1/3 MFR and TTPF for LV diastolic function, but was not associated with these LV diastolic parameters after adjustment of various confounders. CONCLUSIONS: Our data suggest that QRS axis depends on age, BMI or LVMI, and serves as a surrogate marker of LV diastolic function. PMID- 29714000 TI - Design and Evaluation of Hydrophilic Matrix System for pH-Independent Sustained Release of Weakly Acidic Poorly Soluble Drug. AB - The aim of this research was to design and evaluate a hydrophilic matrix system for sustained release of glipizide, a weakly acidic poor soluble drug. A combination of inclusion complexation and microenvironmental pH modification techniques was utilized to improve the dissolution and pH-independent release of glipizide. Hydroxypropyl-beta-cyclodextrin (HP-beta-CD) was used as the complexation agent while sodium citrate and magnesium oxide (MgO) were used as model pH modifiers. The hydrophilic matrix tablets were prepared by powder direct compression and evaluated by in vitro dissolution study respectively in pH 6.8 and pH 1.2 dissolution media. The formulations containing MgO exhibited increased cumulative drug release from less than 40% in the reference formulation to 90% within 24 h in acidic media (pH 1.2). The release profile in acidic media was similar to the alkaline media (pH 6.8) with a similarity factor (f2) of 55.0, suggesting the weakening of the effect of pH on the dissolution efficiency of glipizide. The release profile fitted well into the Higuchi model and the dominant mechanism of drug release was Fickian diffusion while case II transport/polymer relaxation occurred. In conclusion, combining inclusion complexation agents and pH modifiers had improved the dissolution of glipizide as well as achieved the pH-independent release profile. PMID- 29714001 TI - Dry Gel Containing Optimized Felodipine-Loaded Transferosomes: a Promising Transdermal Delivery System to Enhance Drug Bioavailability. AB - Felodipine has a very low bioavailability due to first-pass metabolism. The aim of this study was to enhance its bioavailability by transdermal application. Felodipine-loaded transferosomes were prepared by thin-film hydration using different formulation variables. An optimized formula was designed using statistical experimental design. The independent variables were the used edge activator, its molar ratio to phosphatidylcholine, and presence or absence of cholesterol. The responses were entrapment efficiency of transferosomes, their size, polydispersity index, zeta potential, and percent drug released after 8 h. The optimized formula was subjected to differential scanning calorimetry studies and its stability on storage at 4 degrees C for 6 months was estimated. This formula was improved by incorporation of different permeation enhancers where ex vivo drug flux through mice skin was estimated and the best improved formula was formulated in a gel and lyophilized. The prepared gel was subjected to in vivo study using Plendil(r) tablets as a reference. According to the calculated desirability, the optimized transferosome formula was that containing sodium deoxycholate as edge activator at 5:1 M ratio to phosphatidylcholine and no cholesterol. The thermograms of this formula indicated the incorporation of felodipine inside the prepared vesicles. None of the tested parameters differed significantly on storage. The lyophilized gel of labrasol-containing formula was chosen for in vivo study. The relative bioavailability of felodipine from the designed gel was 1.7. In conclusion, topically applied lyophilized gel containing felodipine-loaded transferosomes is a promising transdermal delivery system to enhance its bioavailability. PMID- 29714002 TI - Ceramide-Fabricated Co-Loaded Liposomes for the Synergistic Treatment of Hepatocellular Carcinoma. AB - Combination therapy is one of the important methods to improve therapeutic effect on the treatment of hepatocellular carcinoma (HCC). Sorafenib (SF) is a canonical US Food and Drug Administration-approved multikinase molecule inhibitor against HCC. However, therapeutic benefit with Sorafenib alone was usually unsatisfactory. Ceramide (CE) is an endogenous bioactive sphingolipid, which has a strong potential to suppress various tumors. The combination of SF and CE was hoping to exert maximum synergistic antitumor effect through different tumor suppressible mechanisms. In this respect, SF and CE co-loaded liposomes (SF/CE liposomes) were developed to verify synergistic antitumor efficacy. The optimal molar ratio of SF and CE was determined through combination index. SF/CE liposomes were prepared by thin-film hydration method, which exhibited spherical or ellipsoidal shape. Particle size of SF/CE-liposomes was 174 +/- 4 nm with homogeneous distribution. Release profile of SF demonstrated that addition of CE imposed no significant impact on the release of SF. SF/CE-liposomes exhibited acceptable stability in different media and desirable storage stability over 30 days at 4 degrees C. In vitro cellular uptake confirmed that SF/CE-liposomes could be efficiently internalized into HepG2 cells. In vitro cytotoxicity evaluation indicated that SF/CE-liposomes exhibited higher cytotoxicity on HepG2 cells. IC50 value of SF/CE-liposomes was 11.5 +/- 0.44 MUM, which was significantly lower than that of SF-liposomes (**p < 0.01). Evaluation of in vivo synergistic effect on H22-bearing mice verified that SF/CE-liposomes achieved robust antitumor activity in preventing tumor growth. All results suggested that SF/CE-liposomes might be served as an efficient co-delivery system for improving therapeutic efficacy of HCC. PMID- 29714003 TI - Healthcare Databases for Drug Safety Research: Data Validity Assessment Remains Crucial. AB - Administrative healthcare utilization databases are frequently used either individually or as a component of aggregated data for evaluating drug safety issues without taking into account their known deficiencies. All too often insufficient evidence is provided about their validity for the purposes for which they are used. The assessment of data validity is a key constituent that should be included in drug safety research studies and should take a broad multifaceted approach that encompasses both diagnostic and drug exposure data. Drug safety researchers need to continue advancing their knowledge of the data resources they use and to ensure that they and the users of their research understand the limitations of the data that are the foundation on which their research is built. Fundamental issues regarding data validity should be addressed in each use of administrative data for drug safety research. PMID- 29714004 TI - Non-bleeding Adverse Events with the Use of Direct Oral Anticoagulants: A Sequence Symmetry Analysis. AB - INTRODUCTION: Postmarketing pharmacovigilance reports have raised concerns about non-bleeding adverse events associated with direct oral anticoagulants (DOACs), but only limited results are available from large claims databases. OBJECTIVE: The aim of this study was to assess the potential association between DOAC initiation and the onset of four types of non-bleeding adverse events by sequence symmetry analysis (SSA). METHODS: SSA was performed using nationwide data from the French National Healthcare databases (Regime General, 50 million beneficiaries) to assess a cohort of 386,081 DOAC new users for the first occurrence of four types of non-bleeding outcomes: renal, hepatic, skin outcomes identified by using hospitalization discharge diagnoses, and gastrointestinal outcomes by using medication reimbursement. Asymmetry in the distribution of each investigated outcome occurring before and after initiation of DOAC therapy was used to test the association between DOAC therapy and these outcomes. SSA inherently controls for time-constant confounders, and adjusted sequence ratios were computed after correcting for temporal trends. Negative (glaucoma) and positive (bleeding, depressive disorders) control outcomes were used and analyses were replicated on a cohort of 310,195 patients initiating a vitamin K antagonist (VKA). RESULTS: This study demonstrated the expected positive association between either DOAC or VKA therapy and hospitalised bleeding and initiation of antidepressant therapy, while no association was observed between either DOAC or VKA therapy and initiation of antiglaucoma medications. For DOAC therapy, signals were the associations with hepatic outcomes, including acute liver injury [for the 3-month time window, aSR3 = 2.71, 95% confidence interval (CI) 1.79-4.52]; gastrointestinal outcomes, including initiation of drugs for constipation and antiemetic drugs (aSR3 = 1.31, 95% CI 1.27-1.36; and 1.17, 95% CI 1.12-1.22, respectively); and kidney diseases (aSR3 = 1.33, 95% CI 1.29-1.37). CONCLUSION: Results of this nationwide study suggest that DOACs are associated with rare but severe liver injury and more frequent gastrointestinal disorders. A low risk of kidney injury with DOAC therapy can also not be excluded. PMID- 29714005 TI - Potentially Inappropriate Medication Prescribing and Risk of Unplanned Hospitalization among the Elderly: A Self-Matched, Case-Crossover Study. AB - INTRODUCTION/OBJECTIVES: An association between potentially inappropriate medication (PIM) use and adverse events has been established. However, PIM criteria for elderly patients and medical circumstance vary in different countries. We investigated the association between PIM use according to Japanese guidelines and unplanned hospitalization among elderly patients. DESIGN: A case crossover study was conducted. SETTING/PARTICIPANTS: We used the Japanese Medical Data Vision database of 17.9 million people from 270 acute care hospitals across Japan. Records from 247,897 patients aged >= 65 years with unscheduled admissions between January 2009 and December 2015 were analyzed. MEASUREMENTS: We defined PIM use according to the Japanese Guidelines for Medical Treatment and Its Safety in the Elderly and used conditional logistic regression analysis to fit self matched case-crossover models and compared each patient's PIM use over five case periods (1, 2, 4, 8, and 12 weeks) prior to each unplanned hospitalization. RESULTS: We found the highest odds ratios (ORs) of unscheduled admission related to PIM use in the 1-week case period [OR 4.15; 95% confidence interval (CI) 4.05 4.25], followed by the 2-week (OR 3.01; 95% CI 2.95-3.07), 4-week (OR 3.91; 95% CI 3.83-4.00), 8-week (OR 2.00; 95% CI 1.96-2.05), and 12-week case periods (OR 1.48; 95% CI 1.44-1.51). CONCLUSIONS: Elderly patients commonly used PIMs, especially antidiabetics and diuretics. PIM use was associated with a 1.5- to 4 fold increase in the ORs of unplanned hospitalization among them. PMID- 29714006 TI - Behavioral synchronization and affiliation: Dogs exhibit human-like skills. AB - Behavioral synchronization is evolutionary adaptive, fostering social cohesion. In humans, affiliation between partners is associated with a high level of behavioral synchronization; people show increased affiliation towards people who synchronize with them. Surprisingly, until recently, little was known about these phenomena at an interspecific level, which is, however, essential to better understand the respective roles of evolution and ontogeny. After presenting why dog-human dyads are a relevant biological model to study this field of social cognition, we review the recent findings about dog-human behavioral synchronization. We summarize recently published findings on behavioral synchronization and affiliation between dogs and humans. We also review results showing that genetic selection modulates behavioral synchronization propensity in dogs, emphasizing the role of genetic selection on dog's social behaviors towards humans. Finally, we discuss the possible evolutionary influences and proximate mechanisms of this phenomenon. We conclude that, as in humans, behavioral synchronization acts as a social glue between dogs and humans. After dogs' ability to use human-directional cues or to produce referential cues towards humans, we evidenced a new human-like social process in the dog, at the interspecfic level with humans. PMID- 29714007 TI - Numbers. PMID- 29714008 TI - An Introduction to Epitope Mapping. AB - Antibodies are protein molecules used routinely for therapeutic, diagnostic, and research purposes due to their exquisite ability to selectively recognize and bind a given antigen. The particular area of the antigen recognized by the antibody is called the epitope, and for proteinaceous antigens the epitope can be of complex nature. Information about the binding epitope of an antibody can provide important mechanistic insights and indicate for what applications an antibody might be useful. Therefore, a variety of epitope mapping techniques have been developed to localize such regions. Although the real picture is even more complex, epitopes in protein antigens are broadly grouped into linear or discontinuous epitopes depending on the positioning of the epitope residues in the antigen sequence and the requirement of structure. Specialized methods for mapping of the two different classes of epitopes, using high-throughput or high resolution methods, have been developed. While different in their detail, all of the experimental methods rely on assessing the binding of the antibody to the antigen or a set of antigen mimics. Early approaches utilizing sets of truncated proteins, small numbers of synthesized peptides, and structural analyses of antibody-antigen complexes have been significantly refined. Current state-of-the art methods involve combinations of mutational scanning, protein display, and high-throughput screening in conjunction with bioinformatic analyses of large datasets. PMID- 29714009 TI - Epitope Mapping of Antibody-Antigen Interactions with X-Ray Crystallography. AB - Therapeutic antibodies constitute one of the fastest areas of growth in the field of biologic drugs. A molecular understanding of how antibodies interact with their target antigens is known as epitope mapping. The data provided by epitope mapping is extremely valuable in the process of antibody humanization, as well as in vaccine design. In many cases the epitope recognized by the antibody is a complex, discontinuous 3D conformational epitope. Mapping the interactions of an antibody to a conformational epitope is difficult by many standard approaches. X ray crystallography is considered to be the gold standard of epitope mapping as it can provide a near atomic resolution model of the antibody-antigen interaction. An X-ray structure allows for inspection of specific antibody antigen interactions, even in the case of complex conformational epitopes. The method described here can be adapted for structure determination and epitope mapping of any antibody fragment to a simple or complex antigen. PMID- 29714010 TI - Mapping Antibody Epitopes by Solution NMR Spectroscopy: Practical Considerations. AB - Identifying an epitope, the region of the antigen in contact with an antibody, is useful in both basic and pharmaceutical research, as well as in vaccine design. Solution NMR spectroscopy is particularly well suited to the residue level characterization of intermolecular interfaces, including antibody-antigen interactions, and thus to epitope identification. Here, we describe the use of NMR for residue level characterization of protein epitopes, focusing on experimental protocols and practical considerations, highlighting advantages and drawbacks of the approach. PMID- 29714011 TI - Label-Free Cell-Based Assay for Characterization of Biomolecules and Receptors. AB - We present a method to study the interaction between biomolecules and receptors present on the cell surface. This enables studies of molecular interactions in a natural biological context. As the analyte interacts with the receptors still intact on the cell surface, the experimental data provides complete dynamics and complexity of the interaction, thereby generating highly informative data. Attana's cell-based biosensor platform can be used to obtain this information from a diverse range of interactions as described in these protocols, which detail how to grow or capture cells on a surface, how to stabilize and visualize the cells on the surface, and how to set up assays to measure detailed interaction kinetics directly on the cell surface. PMID- 29714012 TI - Probing Antibody Binding Sites on G Protein-Coupled Receptors Using Genetically Encoded Photo-Activatable Cross-Linkers. AB - We describe a methodology to map epitopes of monoclonal antibodies that bind to G protein-coupled receptors (GPCRs). The method relies on an amber codon suppression strategy to genetically encode photo-activatable cross-linkers, such as p-azido-L-phenylalanine (azF) or p-benzoly-L-phenylalanine (BzF), in GPCRs expressed in mammalian cells in culture. Individual receptor variants that harbor a site-specific photo-crosslinker residue can be assayed for functional activity in standard cell-based assays. The interaction sites between the receptor variants and an antibody can be mapped by determining which of the azF or BzF residues cross-link to the antibody upon UV irradiation. A whole cell enzyme linked immunosorbent assay (ELISA) is used to quantiate cross-linking efficiency. A binding "footprint" of the antibody of the surface of the receptor is obtained by comparing the sites of amino acid replacements that cause loss of antibody binding with those that create colvalent cross-links with bound antibody. The precision of the receptor-antibody binding-site map is determined by the number of mutants tested and whether or not high resolution crystal structures or homology models are available. The targeted photo-cross-linking method is complementary to loss-of-function mutagenesis and is especially useful to study anti-receptor antibodies with discontinuous epitopes. PMID- 29714013 TI - Rapid Mapping of Protein Binding Sites and Conformational Epitopes by Coupling Yeast Surface Display to Chemical Labeling and Deep Sequencing. AB - Delineating the precise regions on an antigen that are targeted by antibodies is important for the development of vaccines and antibody therapeutics. X-ray crystallography and NMR are considered the gold standard for providing precise information about these binding sites at atomic resolution. However, these are labor-intensive and require purified protein at high concentration. We have recently described [1] a rapid and reliable method that overcomes these constraints, using a panel of single cysteine mutants of the protein of interest and now provide protocols to facilitate its adoption. Mutants are displayed on the yeast cell surface either individually or as a pool, and labeled covalently with a cysteine specific probe. Binding site residues are inferred by monitoring loss of ligand or antibody binding by flow cytometry coupled to deep sequencing of sorted populations, or Sanger sequencing of individual clones. Buried cysteine residues are not labeled and library sizes are small, facilitating rapid identification of binding-site residues. The methodology was used to identify epitopes on the bacterial toxin CcdB targeted by twenty-four different monoclonal antibodies as well as by polyclonal sera. The method does not require purified protein or protein structural information and can be applied to a variety of display formats. PMID- 29714015 TI - B-Cell Epitope Mapping Using a Library of Overlapping Synthetic Peptides in an Enzyme-Linked Immunosorbent Assay. AB - This chapter describes a strategy for mapping linear B-cell epitopes of proteins using synthetic biotinylated peptides in an ELISA.A set of overlapping peptides were designed based upon a known amino acid sequence of the target protein, VapA (Virulence-associated Protein A) of the bacterium Rhodococcus equi, an important pulmonary pathogen in foals. The peptides synthesized as biotinylated peptides were coated directly onto micro titer plates which had been pre-coated with NeutrAvidinTM and used to screen sera from foals confirmed to have R. equi disease. A linear B-cell epitope was identified which corresponded to a 20 mer sequence of the VapA protein. PMID- 29714014 TI - Epitope Mapping Using Yeast Display and Next Generation Sequencing. AB - Monoclonal antibodies are the largest class of therapeutic proteins due in part to their ability to bind an antigen with a high degree of affinity and specificity. A precise determination of their epitope is important for gaining insights into their therapeutic mechanism of action and to help differentiate antibodies that bind the same antigen. Here, we describe a method to precisely and efficiently map the epitopes of multiple antibodies in parallel over the course of just several weeks. This approach is based on a combination of rational library design, yeast surface display, and next generation DNA sequencing and provides quantitative insights into the epitope residues most critical for the antibody-antigen interaction. As an example, we will use this method to map the epitopes of several antibodies that neutralize alpha toxin from Staphylococcus aureus. PMID- 29714016 TI - Array-In-Well Epitope Mapping of Phage-Displayed Antibodies. AB - Novel affinity reagents, such as single chain (scFv) antibody fragments, can be generated by isolating them from recombinant protein libraries using phage display selection. A successful selection process against a target protein can produce a number of binder candidates among which the desired binders are identified by screening and characterization of individual clones. Obtaining information on the binding properties, such as the binding epitope, already during the screening step helps to choose the most useful candidates for further development at early phase saving time and resources. To this end, we describe here an Array-in-Well-based screening procedure to perform activity testing and epitope mapping for filamentous phage-displayed scFvs in an integrated manner with a single assay. PMID- 29714017 TI - Epitope Mapping of Antibodies Using Bacterial Cell Surface Display of Gene Fragment Libraries. AB - The unique property of specific high affinity binding to more or less any target of interest has made antibodies tremendously useful in numerous applications. Hence, knowledge of the precise binding site (epitope) of antibodies on the target protein is one of the most important features for understanding its performance and determining its reliability in immunoassays. Here, we describe an updated protocol for high-resolution method for mapping epitopes of antibodies based on bacterial surface expression of antigen fragments followed by antibody based flow cytometric analysis. Epitopes are determined by DNA sequencing of the sorted antibody-binding cells followed by sequence alignment back to the antigen sequence. The method described here has been useful for the mapping of both monoclonal and polyclonal antibodies with varying sizes of epitopes. PMID- 29714018 TI - Discontinuous Epitope Mapping of Antibodies Using Bacterial Cell Surface Display of Folded Domains. AB - Knowledge of the exquisite-binding surface of an antibody on its target protein is of great value, in particular for therapeutic antibodies for understanding method of action and for stratification of patients carrying the necessary epitope for desired drug efficacy, but also for capture assays under native conditions. Several epitope mapping methodologies have been described for this purpose, with the laborious X-ray crystallography method being the ideal method for mapping of discontinuous epitopes in antibody-antigen crystal complexes and high-throughput peptide-based methods for mapping of linear epitopes. We here report on the usage of a bacterial surface display-based method for mapping of structural epitopes by display of folded domains on the surface of Gram positive bacteria, followed by domain-targeted mutagenesis and library analysis for the identification of key-residues by flow sorting and sequencing. Identified clones with reduced affinity are validated by single clone FACS and subsequent full length expression in mammalian cells for validation. PMID- 29714019 TI - Kinetic Analysis and Epitope Binning Using Surface Plasmon Resonance. AB - The ability to quantify binding affinity of molecular interactions is an essential component of drug development and life science research. This chapter outlines the practical use of surface plasmon resonance spectroscopy to monitor protein-protein interactions with an emphasis on basic experimental design. A short summary of epitope binning assays is also included. PMID- 29714020 TI - Epitope Binning of Human Monoclonal Antibodies in Classical Sandwich and In Tandem Orientation Using the Octet System Based on Biolayer Interferometry. AB - Epitope binning is a technique used to cluster different monoclonal antibodies by the specific region on the antigen that is recognized by the antibody. This is used to increase the likelihood of choosing lead antibodies with the desired biological activity by selecting antibodies from distinct bins, to confirm that biosimilars or biobetters bind to similar epitopes and to select reagents for diagnostic sandwich and/or ELISA-type assays. This protocol describes epitope binning of seven human monoclonal antibodies to a monovalent antigen in two orthogonal orientations; a classical sandwich and an in-tandem orientation using an eight-channel Octet system. PMID- 29714021 TI - Antibody Specificity Profiling Using Protein Microarrays. AB - Antibodies are the most widely used reagent for isolation and detection of specific proteins. However, using antibodies that are not highly specific in these studies can generate inaccurate and misleading data. Protein microarrays offer a platform by which antibody cross-reactivity against a broad range of cellular antigens can be simultaneously and quantitatively profiled. This protocol describes in detail the process of array pretreatment, antibody binding, washing, scanning and quantitative analysis of antibody specificity. PMID- 29714022 TI - High-Density Antigen Microarrays for the Assessment of Antibody Selectivity and Off-Target Binding. AB - With the increasing availability of collections of antibodies, their evaluation in terms of binding selectivity becomes an important but challenging task. Planar antigen microarrays are very suitable tools to address this task and provide a powerful proteomics platform for the characterization of the binding selectivity of antibodies toward thousands of antigens in parallel. In this chapter, we describe our in-house developed procedures for the generation of high-density planar antigen microarrays with over 21,000 features. We also provide the details of the assay protocol, which we routinely use for the assessment of binding selectivity of the polyclonal antibodies generated within the Human Protein Atlas. PMID- 29714023 TI - Multiplexed Antigen Bead Arrays for the Assessment of Antibody Selectivity and Epitope Mapping. AB - With the increasing number of binding reagents for affinity-based investigations of the human proteome, high-throughput tools for the characterization of the used reagents become essential. For the analysis of binding selectivity, bead-based antigen arrays offer a miniaturized and parallelized assay platform to meet such needs, as they enable two-dimensional multiplexing to analyze up to 384 samples against up to 500 analytes in a single round of analysis. In this chapter, we describe our protocols for the generation of multiplex bead arrays built on immobilized protein fragments, as well as biotinylated peptides. Combined together, these two versions of antigen arrays offer a versatile approach for multiplexed characterization of antibody binding selectivity, off-target interactions, as well as mapping for the amino acids of epitopes involved in antibody binding. PMID- 29714024 TI - Antibody Biomarker Discovery Via In Vitro Evolution of Peptides. AB - Antigen discovery and mapping strategies that enable the precise identification of serum antibody-binding epitopes in human diseases will be invaluable for translational diagnostics and therapeutic development. Protein and peptide library display screening techniques have shown utility for the discovery of antigens associated with disease onset and progression. Here, we describe a screening methodology using bacterial peptide library display to identify consensus families of disease-specific binding motifs to multiple pools of human serum antibodies. The sensitivity and specificity of identified disease-specific peptide motifs are then optimized using in vitro evolution techniques. PMID- 29714025 TI - Bioinformatics Tools for the Prediction of T-Cell Epitopes. AB - T-cell responses are activated by specific peptides, called epitopes, presented on the cell surface by MHC molecules. Binding of peptides to the MHC is the most selective step in T-cell antigen presentation and therefore an essential factor in the selection of potential epitopes. Several in-vitro methods have been developed for the determination of peptide binding to MHC molecules, but these are all costly and time-consuming. In consequence, significant effort has been dedicated to the development of in-silico methods to model this event. Here, we describe two such tools, NetMHCcons and NetMHCIIpan, for the prediction of peptide binding to MHC class I and class II molecules, respectively, involved in the activation pathways of CD8+ and CD4+ T cells. PMID- 29714026 TI - When and where in aging: the role of music on source monitoring. AB - Difficulties in source monitoring (SM) tasks observed in healthy older adults may be linked to associative memory deficits since SM requires individuals to correctly bind and later remember these bound features to discriminate the origin of a memory. Therefore, focusing attention on discriminating factors that may attenuate older adults' difficulties in attributing contextual information to memories is necessary. We investigated the effect of affective information on source monitoring in younger and older adults by manipulating the type of affective information (pictures and music) and assessing the ability to remember spatial and temporal source details for affective pictures encoded while listening to classical music. Older and younger adults viewed a series of affective IAPS pictures presented on the left or right side of the computer screen in two different lists. At test, participants were asked to remember if the picture was seen (right/left), in which list (list1/list2) or whether it was new. Results showed that spatial information was attributed better than temporal information and emotional pictures were attributed better than neutral pictures in both younger and older adults. In addition, although music significantly increased source memory performance in both younger and older participants compared to the white noise condition, the pleasantness of music differentially affected memory for source details. The authors discuss findings in terms of an interaction between music, emotion and cognition in aging. PMID- 29714027 TI - Self-monitoring to increase physical activity in patients with cardiovascular disease: a systematic review and meta-analysis. AB - BACKGROUND AND AIMS: It is important to encourage physical activity in patients with cardiovascular disease (CVD), and self-monitoring is considered to contribute to increased physical activity. However, the effects of self monitoring on CVD patients remain to be established. In this study, we examined the influence of self-monitoring on physical activity of patients with CVD via a systematic review and meta-analysis. METHODS: Screening of randomized controlled trials only was undertaken twice on PubMed (date of appraisal: August 29, 2017). The inclusion criteria included outpatients with CVD, interventions for them, daily step counts as physical activity included in the outcome, and self monitoring included in the intervention. Assessments of the risk of bias and meta analysis in relation to the mean change of daily step counts were conducted to verify the effects of self-monitoring. RESULTS: From 205 studies retrieved on PubMed, six studies were included, with the oldest study published in 2005. Participants included 693 patients of whom 541 patients completed each study program. Their mean age was 60.8 years, and the ratio of men was 79.6%. From these 6 studies, a meta-analysis was conducted with 269 patients of 4 studies including only RCTs with step counts in the intervention group and the control group, and self-monitoring significantly increased physical activity (95% confidence interval, 1916-3090 steps per day, p < 0.05). The average intervention period was about 5 months. Moreover, four studies involved intervention via the internet, and five studies confirmed the use of self-monitoring combined with other behavior change techniques. CONCLUSION: The results suggest that self monitoring of physical activity by patients with CVD has a significantly positive effect on their improvement. Moreover, the trend toward self-monitoring combined with setting counseling and activity goals, and increased intervention via the internet, may lead to the future development and spread of self-monitoring for CVD patients. PMID- 29714028 TI - The prevalence and health burden of malnutrition in Belgian older people in the community or residing in nursing homes: results of the NutriAction II study. AB - INTRODUCTION: In 2008, the NutriAction study showed that (risk of) malnutrition was highly prevalent (57%) among Belgian older people living in the community or in a nursing home. In 2013, this study was repeated to re-evaluate the occurrence of malnutrition, as well as mobility problems and dependence in activities of daily living (ADL). METHODS: Health care professionals (HCPs) associated with homecare organizations and nursing homes across Belgium were invited to screen their patients and complete an online questionnaire. Nutritional status, presence of pre-specified comorbidities, mobility, and ADL dependency were assessed. RESULTS: In total, 3299 older patients were analysed: 2480 (86.3 +/- 6.3 years) nursing home (NH) residents and 819 (82.7 +/- 6.1 years) community dwelling (CD). Overall, 12% was malnourished (MNA-SF score < 8) and 44% was at risk of malnutrition (MNA-SF 8-11). The highest prevalence of (risk of) malnutrition was observed in NHs (63%) and in patients with dementia (CD: 68%; NH: 82%) or depression (CD: 68%; NH: 79%). Of all malnourished individuals, 49% was recognized as malnourished by HCPs and 13% of the malnourished recognized themselves as such. Mobility (stair climbing and walking) and ADL dependency (Belgian KATZ score) were impaired in older people with (risk of) malnutrition in comparison with individuals with normal nutritional status (p < 0.001). DISCUSSION: Despite public awareness initiatives, the prevalence of malnutrition remained stable among Belgian older people seen by HCPs in the period 2008-2013. Moreover, malnutrition is not well recognized. CONCLUSION: Under-recognition of malnutrition is problematic, because associated loss of mobility and independence may accelerate the transformation of frailty into disability in older people. PMID- 29714029 TI - A data-driven patient blood management strategy in liver transplantation. AB - BACKGROUND AND OBJECTIVES: Blood utilization during liver transplant has decreased, but remains highly variable due to many complex surgical and physiologic factors. Previous models attempted to predict utilization using preoperative variables to stratify cases into two usage groups, usually using entire blood units for measurement. We sought to develop a practical predictive model using specific transfusion volumes (in ml) to develop a data-driven patient blood management strategy. MATERIALS AND METHODS: This is a retrospective evaluation of primary liver transplants at a single institution from 2013 to 2015. Multivariable analysis of preoperative recipient and donor factors was used to develop a model predictive of intraoperative red-blood-cell (pRBC) use. RESULTS: Of 256 adult liver transplants, 207 patients had complete transfusion volume data for analysis. The median intraoperative allogeneic pRBC transfusion volume was 1250 ml, and the average was 1563 +/- 1543 ml. Preoperative haemoglobin, spontaneous bacterial peritonitis, preoperative haemodialysis and preoperative international normalized ratio together yielded the strongest model predicting pRBC usage. When it predicted <1250 ml of pRBCs, all cases with 0 ml transfused were captured and only 8.6% of the time >1250 ml were used. This prediction had a sensitivity of 0.91 and a specificity of 0.89. If predicted usage was >2000 ml, 75% of the time blood loss exceeded 2000 ml. CONCLUSION: Patients likely to require low or high pRBC transfusion volumes were identified with excellent accuracy using this predictive model at our institution. This model may help predict bleeding risk for each patient and facilitate optimized blood ordering. PMID- 29714030 TI - Calciphylaxis in end-stage liver and renal disease patients before and after transplant. AB - Calciphylaxis is a rare vascular disorder characterized by calcification of arterioles which causes tissue inflammation and necrosis. It is associated with the metabolic disturbances seen in end-stage renal disease (ESRD) and has also been described in patients with cirrhosis with preserved kidney function. Characteristic calciphylaxis lesions are black eschars surrounded by retiform purpura, and the gold standard for diagnosis is skin biopsy. Reported 1-year mortality rates range between 45% and 80%. No treatment modality has been evaluated in a prospective randomized trial, and reports of treatment efficacy vary. Kidney transplant has been reported as a successful therapy for calciphylaxis; however, cases exist of the initial onset of calciphylaxis following kidney transplant as well as simultaneous liver-kidney (SLK) transplant. The decision to maintain a patient with end-stage renal and liver disease on the waiting list for SLK transplant following the onset of calciphylaxis must consider the high 1-year mortality associated with this condition. More research is necessary to understand how to allocate donor allografts to manage patients with calciphylaxis and ESRD and/or cirrhosis effectively. PMID- 29714031 TI - An uncommon presentation of alcoholic liver disease. PMID- 29714032 TI - Alemtuzumab vs anti-thymocyte globulin in patients transplanted from an unrelated donor after a reduced intensity conditioning. AB - OBJECTIVE: Relapse and graft-vs-host disease (GVHD) are still the main complications after allogeneic hematopoietic stem cell transplantation, especially in the setting of reduced intensity regimen (RIC) and unrelated donor. We compared here anti-thymocyte globulin (ATG) or alemtuzumab as GVHD prophylaxis in patients with myeloid disease transplanted after RIC and from an unrelated donor. METHOD: ATG and alemtuzumab patients have been matched by age, gender, HLA matching, comorbidities and cytogenetics risk (119 patients in each group). RESULTS: After matching, we found that ATG decreased the risk of relapse (HR: 0.55, P = .0049) and improved relapse-free survival (RFS, HR: 0.70, P = .042). The improved RFS with ATG was more pronounced in CMV-positive patients but was not influenced by disease risk. Regarding overall survival, GVHD-free relapse free survival and transplant-related mortality, the risk was similar using ATG or alemtuzumab. CONCLUSION: Even if GVHD risk is lowered by alemtuzumab use, it does not translate in better outcome due to higher risk of relapse. PMID- 29714033 TI - Molecular networks in plant-pathogen holobiont. AB - Plant immune receptors enable detection of a multitude of microbes including pathogens. The recognition of microbes activates various plant signaling pathways, such as those mediated by phytohormones. Over the course of coevolution with microbes, plants have expanded their repertoire of immune receptors and signaling components, resulting in highly interconnected plant immune networks. These immune networks enable plants to appropriately respond to different types of microbes and to coordinate immune responses with developmental programs and environmental stress responses. However, the interconnectivity in plant immune networks is exploited by microbial pathogens to promote pathogen fitness in plants. Analogous to plant immune networks, virulence-related pathways in bacterial pathogens are also interconnected. Accumulating evidence implies that some plant-derived compounds target bacterial virulence networks. Thus, the plant immune and bacterial virulence networks intimately interact with each other. Here, we highlight recent insights into the structures of the plant immune and bacterial virulence networks and the interactions between them. We propose that small molecules derived from plants and/or bacterial pathogens connect the two molecular networks, forming supernetworks in the plant-bacterial pathogen holobiont. PMID- 29714035 TI - Myocardial extracellular volume quantified by magnetic resonance is increased in cirrhosis and related to poor outcome. AB - BACKGROUND & AIMS: The underlying pathogenesis of cirrhotic cardiomyopathy remains unclear. Structural myocardial changes including diffuse fibrosis may be involved and can be accurately assessed by cardiac MRI (CMR) with quantification of the extracellular volume (ECV).This is the first application of this technique in patients with cirrhosis. We aimed to investigate the presence of diffuse myocardial fibrosis and to determine the relation to disease severity, cardiac function and outcome. METHODS: A prospective study including 52 cirrhotic patients and 10 healthy controls. All patients underwent CMR with ECV quantification, tissue Doppler echocardiography, and biochemical assessments. Patients were followed up for a median of 25 months with registration of death and liver transplantation (LT). RESULTS: Myocardial ECV was higher in the patients compared with healthy controls (31.2 +/- 6 vs 27.4 +/- 3%, P = .04). Furthermore, ECV increased across the Child Pugh A/B/C classes (26.9 +/- 4/31.5 +/- 5/34.4 +/- 6%, P = .02). Four-teen patients experienced the composite end point of death/LT during follow-up and these patients had higher ECV (33.2 +/- 4 vs 30.4 +/- 6%, P = .04). In a univariate Cox regression analysis ECV was associated with poor transplant-free survival (HR 3.6 [1.1-11.6]; P = .03). However, MELD and CRP remained the strongest predictors in a multivariate analysis. ECV correlated with cardiac index (r = 0.44, P = .001), CRP (r = 0.46, P = .001), proANP (r = 0.50, P < .001), and proBNP (r = 0.40, P = .005). CONCLUSIONS: Myocardial ECV is increased in patients with cirrhosis and seems related to disease severity and transplant-free survival. These changes most likely reflect subclinical diffuse myocardial fibrosis and may represent a structural element of cirrhotic cardiomyopathy. PMID- 29714034 TI - Cannabidiol reverses attentional bias to cigarette cues in a human experimental model of tobacco withdrawal. AB - BACKGROUND AND AIMS: Cannabidiol (CBD), a non-intoxicating cannabinoid found in cannabis, may be a promising novel smoking cessation treatment due to its anxiolytic properties, minimal side effects and research showing that it may modify drug cue salience. We used an experimental medicine approach with dependent cigarette smokers to investigate if (1) overnight nicotine abstinence, compared with satiety, will produce greater attentional bias (AB), higher pleasantness ratings of cigarette-related stimuli and increased craving and withdrawal; and (2) CBD in comparison to placebo, would attenuate AB, pleasantness of cigarette-related stimuli, craving and withdrawal and not produce any side effects. DESIGN: Randomized, double-blind cross-over study with a fixed satiated session followed by two overnight abstinent sessions. SETTING: UK laboratory. PARTICIPANTS: Thirty non-treatment-seeking, dependent cigarette smokers recruited from the community. INTERVENTION AND COMPARATOR: 800 mg oral CBD, or matched placebo (PBO) in a counterbalanced order MEASUREMENTS: AB to pictorial tobacco cues was recorded using a visual probe task and an explicit rating task. Withdrawal, craving, side effects, heart rate and blood pressure were assessed repeatedly. FINDINGS: When participants received PBO, tobacco abstinence increased AB (P = 0.001, d = 0.789) compared with satiety. However, CBD reversed this effect, such that automatic AB was directed away from cigarette cues (P = 0.007, d = 0.704) and no longer differed from satiety (P = 0.82). Compared with PBO, CBD also reduced explicit pleasantness of cigarette images (P = 0.011; d = 0.514). Craving (Bayes factor = 7.08) and withdrawal (Bayes factor = 6.95) were unaffected by CBD, but greater in abstinence compared with satiety. Systolic blood pressure decreased under CBD during abstinence. CONCLUSIONS: A single 800-mg oral dose of cannabidiol reduced the salience and pleasantness of cigarette cues, compared with placebo, after overnight cigarette abstinence in dependent smokers. Cannabidiol did not influence tobacco craving or withdrawal or any subjectively rated side effects. PMID- 29714036 TI - The end justifies the means: Rethinking ecotoxicological studies. PMID- 29714037 TI - Effectiveness of nonpharmacological interventions to reduce procedural anxiety in children and adolescents undergoing treatment for cancer: A systematic review and meta-analysis. AB - OBJECTIVE: Children and young people (CYP) with cancer undergo painful and distressing procedures. We aimed to systematically review the effectiveness of nonpharmacological interventions to reduce procedural anxiety in CYP. METHODS: Extensive literature searches sought randomised controlled trials that quantified the effect of any nonpharmacological intervention for procedural anxiety in CYP with cancer aged 0 to 25. Study selection involved independent title and abstract screening and full text screening by two reviewers. Anxiety, distress, fear, and pain outcomes were extracted from included studies. Where similar intervention, comparator, and outcomes presented, meta-analysis was performed, producing pooled effect sizes (Cohen's d) and 95% confidence intervals (95% CI). All other data were narratively described. Quality and risk of bias appraisal was performed, based on the Cochrane risk of bias tool. RESULTS: Screening of 11 727 records yielded 56 relevant full texts. There were 15 included studies, eight trialling hypnosis, and seven nonhypnosis interventions. There were large, statistically significant reductions in anxiety and pain for hypnosis, particularly compared with treatment as usual (anxiety: d = 2.30; 95% CI, 1.30-3.30; P < .001; pain: d = 2.16; 95% CI, 1.41-2.92; P < .001). Evidence from nonhypnosis interventions was equivocal, with some promising individual studies. There was high risk of bias across included studies limiting confidence in some positive effects. CONCLUSIONS: Evidence suggests promise for hypnosis interventions to reduce procedural anxiety in CYP undergoing cancer treatment. These results largely emerge from one research group, therefore wider research is required. Promising evidence for individual nonhypnosis interventions must be evaluated through rigorously conducted randomised controlled trials. PMID- 29714038 TI - The force and stiffness of myosin motors in the isometric twitch of a cardiac trabecula and the effect of the extracellular calcium concentration. AB - KEY POINTS: Fast sarcomere-level mechanics in intact trabeculae, which allows the definition of the mechano-kinetic properties of cardiac myosin in situ, is a fundamental tool not only for understanding the molecular mechanisms of heart performance and regulation, but also for investigating the mechanisms of the cardiomyopathy-causing mutations in the myosin and testing small molecules for therapeutic interventions. The approach has been applied to measure the stiffness and force of the myosin motor and the fraction of motors attached during isometric twitches of electrically paced trabeculae under different extracellular Ca2+ concentrations. Although the average force of the cardiac myosin motor (~6 pN) is similar to that of the fast myosin isoform of skeletal muscle, the stiffness (1.07 pN nm-1 ) is 2- to 3-fold smaller. The increase in the twitch force developed in the presence of larger extracellular Ca2+ concentrations is fully accounted for by a proportional increase in the number of attached motors. ABSTRACT: The mechano-kinetic properties of the cardiac myosin were studied in situ, in trabeculae dissected from the right ventricle of the rat heart, by measuring the stiffness of the half-sarcomere both at the twitch force peak (Tp ) of an electrically paced intact trabecula at different extracellular Ca2+ concentrations ([Ca2+ ]o ), and in the same trabecula after skinning and induction of rigor. Taking into account the contribution of filament compliance to half-sarcomere compliance and the lattice geometry, we found that the stiffness of the cardiac myosin motor is 1.07 +/- 0.09 pN nm-1 , which is slightly larger than that of the slow myosin isoform of skeletal muscle (0.6-0.8 pN nm-1 ) and 2- to 3-fold smaller than that of the fast skeletal muscle isoform. The increase in Tp from 61 +/- 4 kPa to 93 +/- 9 kPa, induced by raising [Ca2+ ]o from 1 to 2.5 mm at sarcomere length ~2.2 MUm, is accompanied by an increase of the half-sarcomere stiffness that is explained by an increase of the fraction of actin-attached motors from 0.08 +/- 0.01 to 0.12 +/- 0.02, proportional to Tp . Consequently, each myosin motor bears an average force of 6.14 +/- 0.52 pN independently of Tp and [Ca2+ ]o . The application of fast sarcomere-level mechanics to intact trabeculae to define the mechano-kinetic properties of the cardiac myosin in situ represents a powerful tool for investigating cardiomyopathy-causing mutations in the myosin motor and testing specific therapeutic interventions. PMID- 29714039 TI - Multicomponent Self-Assembly of Metallo-Supramolecular Macrocycles and Cages through Dynamic Heteroleptic Terpyridine Complexation. AB - Spontaneous formation of the heteroleptic cadmium(II) bis(terpyridine) complex under ambient conditions can be achieved by a combination of 6,6''-di(2,6 dimethoxylphenyl)-substituted and unsubstituted terpyridine-based ligands. Building on this dynamic heteroleptic complexation, diverse metallo supramolecular macrocycles and cages were readily assembled in quantitative yields from the predesigned multicomponent systems. The complementary ligation reinforced self-recognition to facilitate the shape-dependent self-sorting of a four-component dynamic library into two well-defined parallelograms. In addition, the subtle lability difference between homoleptic and heteroleptic complexes led to the site-selective CdII -ZnII transmetalation in the Sierpinski triangle. Facile construction of a dodecanuclear tetrahedral metallocage was also realized by using two self-recognizable tritopic building blocks. The photophysical study of the metallo-supramolecules assembled from the d10 metal ions revealed intense ligand-based photoluminescence in solution. The self-assembly strategy described here provides an efficient methodology for building pre-programmable, sophisticated supramolecular architectures furnished with photoactivity. PMID- 29714041 TI - A microfluidic glucose sensor incorporating a novel thread-based electrode system. AB - An electrochemical sensor for the detection of glucose using thread-based electrodes and fabric is described. This device is relatively simple to fabricate and can be used for multiple readings after washing with ethanol. The fabrication of the chip consisted of two steps. First, three thread-based electrodes (reference, working, and counter) were fabricated by painting pieces of nylon thread with either layered silver ink and carbon ink or silver/silver chloride ink. The threads were then woven into a fabric chip with a beeswax barrier molded around the edges in order to prevent leaks from the tested solutions. A thread based working electrode consisting of one layer of silver underneath two layers of carbon was selected to fabricate the final sensor system. Using the chip, a PBS solution containing glucose oxidase (GOx) (10 mg/mL), potassium ferricyanide (K3 [Fe(CN)6 ]) (10 mg/mL) as mediator, and different concentrations of glucose (0-25 mM), was measured by cyclic voltammetry (CV). It was found that the current output from the oxidation of glucose was proportional to the glucose concentrations. This thread-based electrode system is a viable sensor platform for detecting glucose in the physiological range. PMID- 29714040 TI - Mitoprotection preserves the renal vasculature in porcine metabolic syndrome. AB - NEW FINDINGS: What is the central question of this study? We hypothesized that chronic mitoprotection would decrease renal vascular remodelling and dysfunction in swine metabolic syndrome. What is the main finding and its importance? This study shows that experimental metabolic syndrome exerts renal microvascular and endothelial cell mitochondrial injury, which were attenuated by mitoprotection, underscoring the contribution of mitochondrial injury to the pathogenesis of metabolic syndrome-induced vascular damage. ABSTRACT: The metabolic syndrome (MetS) induces intrarenal microvascular disease, which may involve mitochondrial injury. The mitochondrial cardiolipin-targeting peptide elamipretide (ELAM) improves the microcirculation in post-stenotic kidneys, but its ability to attenuate MetS-induced renal vascular damage is unknown. We hypothesized that chronic treatment with ELAM would decrease renal vascular remodelling and function in swine MetS. Pigs were studied after 16 weeks of diet-induced MetS, MetS treated for the last 4 weeks with daily injections of ELAM (0.1 mg kg-1 ), and lean control (Lean) animals (n = 6 each). Single-kidney regional perfusion, blood flow and glomerular filtration rate were measured with multi-detector computed tomography (CT). Peritubular capillary (PTC) endothelial cell (EC) mitochondrial density and cardiolipin content were assessed in situ, as were PTC EC apoptosis and oxidative stress. The spatial density of PTCs (Haematoxylin and Eosin staining) and renal microvessels (micro-CT), and renal artery endothelial function (organ bath) were characterized. Regional perfusion and serum creatinine were preserved in MetS pigs, but renal blood flow and glomerular filtration rate were higher compared with Lean. Mitochondrial density and cardiolipin content were diminished in MetS PTC-ECs, but improved in ELAM-treated pigs, as did PTC density. Elamipretide also attenuated PTC-EC oxidative stress and apoptosis. Furthermore, ELAM improved renal microvascular density, decreased microvascular remodelling and restored endothelial nitric oxide expression and endothelium dependent relaxation of renal artery segments. In conclusion, MetS-induced mitochondrial alterations might contribute to renal PTC and microvascular loss and might impair renal artery endothelial function in pigs. Mitoprotection with ELAM preserved a hierarchy of renal vessels, underscoring its potential to ameliorate renal vascular injury in MetS. PMID- 29714042 TI - Non-small cell lung carcinoma metastatic cells in a pericardial effusion. PMID- 29714043 TI - Vasomotion as an oscillatory sign of functional impairment in the human internal thoracic artery: A study based on risk factors and vessel reactivity. AB - NEW FINDINGS: What is the central question of this study? Vasomotion has been viewed as a rhythmic oscillation of the vascular tone that is physiologically important for optimal tissue perfusion. Also, it has been studied primarily in the microcirculation. However, the precise underlying mechanisms and the physiological significance remain unknown. What is the main finding and its importance? Vasomotion is not specific to the microcirculation, as shown by our findings. In human arteries from patients undergoing cardiac surgery, an increased incidence was associated with endothelial dysfunction settings. Therefore, this oscillatory behaviour might be a signal of functional impairment and not of integrity. ABSTRACT: Vasomotion has been defined as the rhythmic oscillation of the vascular tone, involved in the control of the blood flow and subsequent tissue perfusion. Our aims were to study the incidence of vasomotion in the human internal thoracic artery and the correlation of this phenomenon with the clinical profile and parameters of vascular reactivity. In our study, vasomotion was elicited with a single-dose contractile stimulation of noradrenaline (10 MUm) in internal thoracic artery segments, from patients undergoing coronary artery bypass grafting, mounted in tissue organ bath chambers. The incidence was 29.1%. Vessel samples with vasomotion presented significantly higher contractility in response to both potassium chloride (maximal response or Emax of 7.65 +/- 5.81 mN versus 4.52 +/- 3.73 mN in control vessels, P = 0.024) and noradrenaline (Emax of 7.60 +/- 5.93 mN versus 2.96 +/- 4.41 mN in control vessels, P < 0.001). Predictive modelling through multivariable logistic regression analysis showed that female sex (odds ratio = 9.82) and increasing maximal response to noradrenaline (odds ratio = 1.19, per 1 mN increase) were associated with a higher probability of the occurrence of vasomotion, whereas increasing kidney function (expressed as estimated glomerular filtration rate) was associated with a lower probability (odds ratio = 0.97, per 1 ml min-1 (1.73 m)-2 ]. Our results provide a characterization of the phenomenon of vasomotion in the internal thoracic artery and suggest that vasomotion might be associated with endothelial dysfunction settings, as determined by a multivariable analysis approach. Considering the associations observed in our results, vasomotion might be a signal of functional impairment and not of integrity. PMID- 29714044 TI - Incongruence between women's survey- and interview-determined decision control preferences: A mixed methods study of decision-making in metastatic breast cancer. AB - OBJECTIVE: Women with metastatic breast cancer face numerous, complex treatment and advance care planning (ACP) decisions. Our aim was to develop a better understanding of women with metastatic breast cancer's decision-making preferences overtime and relative to specific types of decisions. METHODS: Convergent, parallel mixed-methods study. Participants completed the Control Preferences Scale (CPS) and a semi-structured interview of decision-making experiences at enrollment (T1; n = 22) and when facing a decision or 3 months later (T2; n = 19). We categorized women's decision-making experience descriptions into one of the CPS decisional styles and compared them to their CPS response. We constructed an analytic grid that aligned the interview-determined treatment and ACP decisional preferences with the CPS categories at T1 and T2 and calculated Cohen's kappa coefficient and congruence percentages. RESULTS: Participants (n = 22) were White (100%), averaged 62 years, married (54%), retired (45%), and had a bachelor's degree (45%). Congruence between CPS response and interview-determined treatment preferences at T1 was 32% (kappa = 0.083) and 33% (kappa = 0.120) at T2. Congruence between CPS survey response and interview determined ACP preferences at T1 was 22.7% (kappa =0.092) at T1 and 11% (kappa = 0.011) at T2. CONCLUSIONS: Although women selected a "shared" treatment decision making style using the CPS validated tool, when interviewed their descriptions generally reflected a passive process in which they followed the oncologists' treatment suggestions. Future research should explore whether the incongruence between stated and actual decision-making style is a function of misinterpreting the CPS choices or a true inconsistency that could lead to adverse consequences such as decisional regret. PMID- 29714045 TI - Aspiration cytology of a scalp lump. PMID- 29714046 TI - Rapid preparation of molecularly imprinted polymers by custom-made microwave heating for analysis of atrazine in water. AB - The rapid preparation of an atrazine-imprinted polymer in a cost-effective custom made microwave reactor was demonstrated. The polymerization reaction was accelerated by microwave heating, and the preparation time was greatly shortened (to 1 h). The resulting polymer was successfully applied as solid-phase extraction adsorbent for the selective extraction and preconcentration of atrazine in environmental water samples. The binding capacity of the polymer was 1.11 mg/g polymer. The polymer provided selectivity with higher recovery of atrazine than of other interfering related contaminants. The proposed method had good limits of detection and quantitation at 0.20 and 0.60 ng/mL, respectively. The recoveries were from 83 to 89% at two spiking levels, with relative standard deviations less than 5%. This method was successfully applied to determine the atrazine levels in environmental water samples. PMID- 29714047 TI - Toward tunable dynamic repression using CRISPRi. AB - CRISPR interference (CRISPRi) is widely utilized for regulation of target gene expression by repressing transcription. Simple design rules for the single guide RNA (sgRNA) and multiplexity won this method immense popularity. However, quantitative control of the expression levels at varying degrees in a dynamic manner using CRISPRi has been regarded difficult. To deal with this limitation, Fontana et al. modulated the expression levels of the components of CRISPRi, the deactivated Cas9 (dCas9), and the sgRNAs, using various constitutive or inducible promoters (Fontana et al., Biotechnol. J. 2018, 13, 1800069). They found that the expression level of sgRNA is the key to controlling CRISPRi. Modulation of sgRNA expression levels enabled quantitative tuning of the CRISPRi-regulated gene expression level. This approach is expected to be easily applied to diverse applications owing to its simplicity compared to the conventional approaches that modified target sequence or changed the expression level of dCas9. PMID- 29714048 TI - Catalytic Transformation of Cellulose and Its Derivatives into Functionalized Organic Acids. AB - Cellulose is a promising renewable and abundant resource for the production of high-value chemicals, in particular, organic oxygenates, because of its high oxygen/carbon ratio. The sustainable production of hydroxycarboxylic acids and dicarboxylic acids, such as gluconic/glucaric acid, lactic acid, 2,5 furandicarboxylic acid, adipic acid, and terephthalic acid, most of which are monomers of key polymers, have attracted much attention in recent years. The synthesis of these organic acids from cellulose generally involves several tandem reaction steps, and thus, multifunctional catalysts that can catalyze the selective activation of specific C-O or C-C bonds hold the key. This review highlights recent advances in the development of efficient catalytic systems and new strategies for the selective conversion of cellulose or its derived carbohydrates into functionalized organic acids. The reaction mechanism is discussed to offer deep insights into the regioselective cleavage of C-O or C-C bonds. PMID- 29714049 TI - Palladium-Catalyzed Divergent Arylation of Triazolopyridines: A Computational Study. AB - The mechanisms for new palladium-catalyzed divergent reactions of triazolopyridines were investigated by means of DFT calculations. Previously, it was observed experimentally that cross-coupling at the C7-position of triazolopyridines occurred when a strong base was used, whereas the reaction could be diverted to the C3-position if a weak base was employed. Calculations suggest that a strong base, such as tert-butoxide, can easily deprotonate C7-H, independent of the palladium metal, and deliver the preactivated substrate to palladium, which can reductively eliminate the final product. Without a strong base, the palladium(II) center reacts with the ring-opened diazo imine isomer of triazolopyridine to initially form a palladium(II)-carbene intermediate, which undergoes migratory insertion followed by beta-hydride elimination to afford a 1,1-disubstituted alkene. PMID- 29714050 TI - Maternal Metabolomic Profile and Fetal Programming of Offspring Adiposity: Identification of Potentially Protective Lipid Metabolites. AB - SCOPE: The fetal programming paradigm posits that the origins of obesity can be traced, in part, to the intrauterine period of life. However, the mechanisms underlying fetal programming are not well understood, and few studies have measured offspring adiposity in the neonatal period. The aim of this study is to identify maternal metabolites, and their determinants, that are associated with neonatal adiposity. METHODS AND RESULTS: A targeted metabolomics approach is applied to analyze plasma samples collected across gestation from a well characterized cohort of 253 pregnant women participating in a prospective study at the University of California, Irvine. Whole-body dual X-ray absorptiometry (DXA) imaging of body composition is obtained in N = 121 newborns. Statistical models are adjusted for potential confounders and multiple testing. The authors identify six alkyl-linked phosphatidylcholines (PCae), containing fatty acid 20:4, that are significantly and negatively associated with neonatal body fat percentage. Factors indicating higher socioeconomic status, non-Hispanic ethnicity, and higher nonesterified fatty acid percentages are positively associated with these PCae. CONCLUSIONS: The polyunsaturated fatty acid 20:4 contained in PCae may exert a beneficial effect with respect to future propensity for obesity development. Prepregnancy and early pregnancy factors are determinants of these PCae, highlighting the importance of addressing preconceptional conditions for fetal programming of newborn adiposity. PMID- 29714051 TI - Copper/Diboron-Mediated Intramolecular Oxygenation and Allylation/Benzylation of Nitroalkynes for the Synthesis of C2-Quaternary Indolin-3-ones. AB - A direct strategy for intramolecular transfer oxygenation of alkynes and cycloisomerization of 2-nitroalkynes to synthesize a wide range of C2-quaternary indolin-3-ones was developed by a copper/diboron system. The desired allylation, benzylation and propargylation products were obtained in moderate to excellent yields with good functional group tolerance. The mechanism study indicated that this protocol involved a radical process. PMID- 29714052 TI - Tetrafluorination of Aromatic Azide Yields a Highly Efficient Staudinger Reaction: Kinetics and Biolabeling. AB - The development of highly efficient bioorthogonal reactions is of paramount importance for the research fields of biomaterials and chemical biology. We found that the o,o'-difluorinated aromatic azide was able to react with triphenylphosphine to produce water-stable phosphanimine. To further improve the efficiency of this kind of nonhydrolysis Staudinger reaction, a tetrafluorinated aromatic azide was employed to develop a faster nonhydrolysis Staudinger reaction with a rate of up to 51 m-1 s-1 , as revealed by high-performance liquid chromatography (HPLC) analysis and fluorescence kinetics. As a proof-of-concept study, the highly efficient Staudinger reaction was successfully used for chemoselective fluorescence labeling of proteins and nucleic acids (DNA and RNA) as well as for protein polyethyleneglycol (PEG)ylation. We believe that this bioorthogonal reaction can provide a broadly useful tool for various bioconjugations. PMID- 29714053 TI - Sulforaphane Upregulates the Heat Shock Protein Co-Chaperone CHIP and Clears Amyloid-beta and Tau in a Mouse Model of Alzheimer's Disease. AB - SCOPE: Sulforaphane is an herbal isothiocyanate enriched in cruciferous vegetables. Here, the authors investigate whether sulforaphane modulates the production of amyloid-beta (Abeta) and tau, the two main pathological factors in Alzheimer's disease (AD). METHODS AND RESULTS: A triple transgenic mouse model of AD (3 * Tg-AD) is used to study the effect of sulforaphane. Oral gavage of sulforaphane reduces protein levels of monomeric and polymeric forms of Abeta as well as tau and phosphorylated tau in 3 * Tg-AD mice. However, sulforaphane treatment do not affect mRNA expression of amyloid precursor protein or tau. As previous studies show that Abeta and tau metabolism are influenced by a heat shock protein (HSP) co-chaperone, C-terminus of HSP70-interacting protein (CHIP), the authors examine whether sulforaphane can modulate CHIP. The authors find that sulforaphane treatment increase levels of CHIP and HSP70. Furthermore, observations of CHIP-deficient primary neurons derived from 3 * Tg-AD mice suggest that sulforaphane treatment increase CHIP level and clear the accumulation of Abeta and tau. Finally, sulforaphane ameliorated memory deficits in 3 * Tg-AD mice as reveal by novel object/location recognition tests and contextual fear conditioning tests. CONCLUSION: These results demonstrate that sulforaphane treatment upregulates CHIP and has the potential to decrease the accumulation of Abeta and tau in patients with AD. PMID- 29714054 TI - Severity of congenital heart defects associated with assisted reproductive technologies: Case series and review of the literature. AB - OBJECTIVE: Assisted reproductive technology (ART) has been associated with a higher incidence of congenital anomalies, including a specific increase in the rate of congenital heart defects (CHD). In this study, the rate of CHD in pregnancies resulting from ART at a single high-risk pregnancy referral center are compared to the published literature. METHODS: Pregnancies were screened by fetal echocardiography for the indication of ART over a 2-year period. CHD were classified as either mild or severe based on the need for postnatal surgical intervention. Results were compared to findings from a literature review of studies examining CHD in pregnancies resulting from ART since 1980. RESULTS: Over the course of two years, 363 fetuses in 264 pregnancies from our cohort were screened for CHD. The incidence of mild CHD in fetuses from ART pregnancies was 2.75% (10 out of 363 fetuses). None of the affected fetuses had severe CHD. Review of the literature yielded 20 studies since 1980 that examined CHD in pregnancies resulting from ART. Composite data from the studies was described based on characterization of severity of the CHD anomalies. The incidence of mild CHD in ART pregnancies was 2.2%, compared to 1% in non-ART pregnancies (out of 332,157 infants). The incidence of severe CHD in ART pregnancies and naturally conceived pregnancies was 1.4% and 1.2%, respectively (out of 661,455 infants). The incidence of unspecified CHD in ART pregnancies was 1.8%, compared to 1% in naturally conceived pregnancies (out of 1,593,277 infants). CONCLUSION: The greatest increase in risk appears to be for mild CHD (nonsurgical), which may inform counseling of patients prior to use of assisted reproductive technologies. PMID- 29714055 TI - In vitro fertilization (IVF): Where are we now? PMID- 29714056 TI - Selection of preimplantation embryos using time-lapse microscopy in in vitro fertilization: State of the technology and future directions. AB - In this review, our aim is to give an overview of the state of the technology and clinical outcomes of time-lapse microscopy in improving embryo selection as a key step in in vitro fertilization (IVF). Using traditional incubators, morphologic assessment of the fertilized embryos is limited to snapshots at a few discrete points in time, reducing the amount of information that could potentially be obtained. Time-lapse monitoring overcomes this limitation without exposing the embryos to environmental changes. Moreover, time-lapse may introduce new dynamic markers of embryo competence as well as a versatile embryo evaluation and provides novel information regarding human embryo development. In the last few years, various algorithms have been developed correlating the kinetics of early embryo development to blastocyst formation, implantation potential, chromosomal content and live birth rate. There is not yet a universally accepted algorithm, and significant knowledge gaps remain that can provide opportunities for further research in this field. PMID- 29714057 TI - Large for gestational age and macrosomia in singletons born after frozen/thawed embryo transfer (FET) in assisted reproductive technology (ART). AB - Increase in success rates with frozen embryo transfer (FET) and reduced risk of ovarian hyperstimulation syndrome (OHSS) and multiple pregnancies has lead to a steady rise in FET. Further, FET is associated with lower risk of prematurity and low birth weight in singletons, when compared with fresh transfer. However, there is a growing concern of increased risk of large for gestational (LGA) and/or macrosomic children after FET. Macrosomic/LGA births have a higher risk of cesarean section, fetal hypoxia and stillbirth. Improvements in cryopreservation techniques indicate that FET is a trend expected to continue and a freeze-all policy has lately been introduced. With this review, we wished to evaluate the association between FET and LGA and/or macrosomia. We searched electronic databases on January 12, 2018. Ten studies on LGA and six studies on macrosomia were eligible for meta-analysis. We found that the risk of LGA in FET was increased 1.5-fold (AOR = 1.50 95% CI 1.44-1.57 p < 0.001) compared to fresh cycles and 1.3-fold (AOR = 1.31 95% CI 1.20-1.43 p < 0.001) compared to natural conception (NC). Similarly we found a 1.7-fold increased risk of macrosomia in FET compared to fresh transfer (AOR = 1.71 95% CI 1.59-1.83 p < 0.001) and a 1.4 fold increased risk compared to NC (AOR = 1.42 95% CI 1.17-1.71 p < 0.001). Whether the increased risk of LGA and macrosomia is associated with higher long term health risks remains unknown. Future studies should explore epigenetics modifications in children born after FET and predictors of long-term diseases need to be examined further with longitudinal studies. PMID- 29714058 TI - The impact of contemporary preimplantation genetic screening and diagnosis on the detection of aneuploidy and inherited genetic diseases. AB - Pre-implantation genetic screening and diagnosis represent important tools for embryo selection in patients undergoing in vitro fertilization. Methods have evolved in recent years and it can be challenging to remain up to date on the current technology. This review article seeks to provide an overview of pre implantation genetic screening and diagnosis methods, the associated clinical outcomes, and the limitations of this technology. PMID- 29714059 TI - Blocking the Thiol at Cysteine-322 Destabilizes Tau Protein and Prevents Its Oligomer Formation. AB - Abnormal accumulation of tau protein into oligomers contributes to neuronal dysfunction. Reduction of tau level is potentially able to prevent its accumulation. Here we uncover a critical role of the free thiol at Cys-322 in determining tau stability. We found that the application of thiol-blocking agents like NEM or MMTS blocks this thiol, by which it destabilizes tau protein and prevents its oligomer formation. Furthermore, we identified a tau-interacting protein, selenoprotein W, which attenuates tau accumulation by forming disulfide linkage between SelW Cys-37 and tau Cys-322. These findings provide a promising strategy to prevent tau accumulation and oligomer formation. PMID- 29714061 TI - Egg White-Derived Antihypertensive Peptide IRW (Ile-Arg-Trp) Inhibits Angiotensin II-Stimulated Migration of Vascular Smooth Muscle Cells via Angiotensin Type I Receptor. AB - Excessive proliferation, inflammation, oxidative stress, and migration induced by angiotensin II (Ang II), occurring in vascular smooth muscle cells (VSMCs) during vascular remodelling, are major pathogenesis of hypertension. Antihypertensive peptides derived from food proteins are promising alternatives in preventing/treating hypertension and associated complications. In addition to reducing high blood pressure in spontaneously hypertensive rats, egg white ovotransferrin-derived antihypertensive IRW (Ile-Arg-Trp) was shown to exert antiproliferative, antioxidant, and anti-inflammatory effects in A7r5 cells (a vascular smooth muscle cell line) against Ang II stimulation, further indicating its potential in retarding vascular remodelling. Since its regulatory role in migration of VSMC is unclear, the objective of this study was to evaluate the antimigrant activity of IRW in Ang II-stimulated A7r5 cells. It was found that IRW could downregulate matrix metallopeptidase 9 (MMP9) expression and inhibit migration of Ang II-stimulated A7r5 cells, which was associated with inactivation of p38/MAPK signaling. More importantly, the antimigrant activity of IRW in Ang II-stimulated A7r5 cells was dependent on angiotensin type I receptor (AT1R). Our study provided the first evidence that egg ovotransferrin-derived antihypertensive peptide IRW inhibited migration of VSMCs. PMID- 29714062 TI - Highly Sensitive Detection of Caspase-3/7 Activity in Living Mice Using Enzyme Responsive 19F MRI Nanoprobes. AB - Highly sensitive imaging of enzymatic activities in the deep tissues of living mammals provides useful information about their biological functions and for developing new drugs; however, such imaging is challenging. 19F magnetic resonance imaging (MRI) is suitable for noninvasive visualization of enzymatic activities without endogenous background signals. Although various enzyme responsive 19F MRI probes have been developed, most cannot be used for in vivo imaging because of their low sensitivity. Recently, we developed unique nanoparticles, called FLAMEs, that are composed of a liquid perfluorocarbon core and a robust silica shell, and demonstrated their outstanding sensitivity in vivo. Here, we report a highly functionalized nanoprobe, FLAME-DEVD 2, with an OFF/ON 19F MRI switch for detecting caspase-3/7 activity based on the paramagnetic relaxation enhancement effect. To improve the cleavage efficiency of peptides by caspase-3, we designed a novel Gd3+ complex-conjugated peptide, DEVD X ( X = 1, 2), which is a substrate peptide sequence tandemly repeated X times, and demonstrated that DEVD 2 showed faster cleavage kinetics than DEVD 1. By incorporating this novel concept into a signal activation strategy, FLAME-DEVD 2 showed a high 19F MRI signal enhancement rate in response to caspase-3 activity. After intravenous injection of FLAME-DEVD 2 and an apoptosis-inducing reagent, caspase-3/7 activity in the spleen of a living mouse was successfully imaged by 19F MRI. This imaging platform shows great potential for highly sensitive detection of enzymatic activities in vivo. PMID- 29714060 TI - A Review of Single-Nucleotide Polymorphisms in Orexigenic Neuropeptides Targeting G Protein-Coupled Receptors. AB - Many physiological pathways are involved in appetite, food intake, and the maintenance of energy homeostasis. In particular, neuropeptides within the central nervous system have been demonstrated to be critical signaling molecules for modulating appetite. Both anorexigenic (appetite-decreasing) and orexigenic (appetite-stimulating) neuropeptides have been described. The biological effects of these neuropeptides can be observed following central administration in animal models. This review focuses on single nucleotide polymorphisms (SNPs) in six orexigenic neuropeptides: agouti-related protein (AGRP), galanin, melanin concentrating hormone (MCH), neuropeptide Y (NPY), orexin A, and orexin B. Following a brief summary of the neuropeptides and their orexigenic activities, reports associating SNPs within the orexigenic neuropeptides to energy homeostasis, food intake, obesity, and BMI in humans are reviewed. Additionally, the NIH tool Variation Viewer was utilized to identify missense SNPs within the mature, biologically active neuropeptide sequences. For SNPs found through Variation Viewer, a concise discussion on relevant pharmacological structure activity relationship studies for select SNPs is included. This review is meant to update reported orexigenic neuropeptide SNPs and demonstrate the potential utility of genomic sequence databases for finding SNPs that may result in altered receptor signaling for neuropeptide pathways associated with appetite. PMID- 29714063 TI - Correction to N,O pi-Conjugated 4-Substituted 1,3-Thiazole BF2 Complexes: Synthesis and Photophysical Properties. PMID- 29714064 TI - Transforming growth factor superfamily ligands and links to tumorigenesis. PMID- 29714065 TI - The mandate and work of ICRP Committee 3 on radiological protection in medicine. AB - The mandate of Committee 3 of the International Commission on Radiological Protection (ICRP) is concerned with the protection of persons and unborn children when ionising radiation is used in medical diagnosis, therapy, and biomedical research. Protection in veterinary medicine has been newly added to the mandate. Committee 3 develops recommendations and guidance in these areas. The most recent documents published by ICRP that relate to radiological protection in medicine are 'Radiological protection in cone beam computed tomography' (ICRP Publication 129) and 'Radiological protection in ion beam radiotherapy' (ICRP Publication 127). A report in cooperation with ICRP Committee 2 entitled 'Radiation dose to patients from radiopharmaceuticals: a compendium of current information related to frequently used substances' (ICRP Publication 128) has also been published. 'Diagnostic reference levels in medical imaging' (ICRP Publication 135), published in 2017, provides specific advice on the setting and use of diagnostic reference levels for diagnostic and interventional radiology, digital imaging, computed tomography, nuclear medicine, paediatrics, and multi-modality procedures. 'Occupational radiological protection in interventional procedures' was published in March 2018 as ICRP Publication 139. A document on radiological protection in therapy with radiopharmaceuticals is likely to be published in 2018. Work is in progress on several other topics, including appropriate use of effective dose in collaboration with the other ICRP committees, guidance for occupational radiological protection in brachytherapy, justification in medical imaging, and radiation doses to patients from radiopharmaceuticals (an update to ICRP Publication 128). Committee 3 is also considering the development of guidance on radiological protection in medicine related to individual radiosusceptibility, in collaboration with ICRP Committee 1. PMID- 29714066 TI - Effect of ankle-foot orthoses on gait, balance and gross motor function in children with cerebral palsy: a systematic review and meta-analysis. AB - OBJECTIVE: To determine the effects of ankle-foot orthoses (AFOs) on gait, balance, gross motor function and activities of daily living in children with cerebral palsy. DATA SOURCES: Five databases were searched (Pubmed, Psycinfo, Web of Science, Academic Search Premier and Cochrane Library) before January 2018. REVIEW METHODS: Studies of the effect of AFOs on gait, balance, gross motor function and activities of daily living in children with cerebral palsy were included. Articles with a modified PEDRO score >= 5/9 were selected. Data regarding population, AFO, interventions and outcomes were extracted. When possible, standardized mean differences (SMDs) were calculated from the outcomes. RESULTS: Thirty-two articles, corresponding to 56 studies (884 children) were included. Fifty-one studies included children with spastic cerebral palsy. AFOs increased stride length (SMD = 0.88, P < 0.001) and gait speed (SMD = 0.28, P < 0.001), and decreased cadence (SMD = -0.72, P < 0.001). Gross motor function scores improved (Gross Motor Function Measure (GMFM) D (SMD = 0.30, P = 0.004), E (SMD = 0.28, P = 0.02), Pediatric Evaluation of Disability Inventory (PEDI) (SMD = 0.57, P < 0.001)). Data relating to balance and activities of daily living were insufficient to conclude. Posterior AFOs (solid, hinged, supra-malleolar, dynamic) increased ankle dorsiflexion at initial contact (SMD = 1.65, P < 0.001) and during swing (SMD = 1.34, P < 0.001), and decreased ankle power generation in stance (SMD = -0.72, P < 0.001) in children with equinus gait. CONCLUSION: In children with spastic cerebral palsy, there is strong evidence that AFOs induce small improvements in gait speed and moderate evidence that AFOs have a small to moderate effect on gross motor function. In children with equinus gait, there is strong evidence that posterior AFOs induce large changes in distal kinematics. PMID- 29714067 TI - Class III malocclusion and bilateral cross-bite in an adult patient treated with miniscrew-assisted rapid palatal expander and aligners. AB - This case report describes the use of a miniscrew-assisted rapid palatal expander and aligners to correct bilateral cross-bite and crowding in an adult patient with a Class III skeletal pattern. A digitally designed surgical guide was three dimensionally printed and used to accurately insert four miniscrews into the palate; these were employed to anchor a novel miniscrew-assisted rapid palatal expander appliance without any dental anchorage. Cone-beam computed tomograms before and after miniscrew-assisted rapid palatal expander treatment demonstrated the orthopedic expansion of the maxilla without dental tipping. The patient was then fitted with aligners to correct crowding and malocclusion. This case report demonstrates the successful treatment of an adult patient with a narrow maxilla and bilateral cross-bite using a nonsurgical, conservative treatment. PMID- 29714068 TI - Effects of different force magnitudes on corticotomy-assisted orthodontic tooth movement in rats. AB - OBJECTIVES: To investigate the effects of light and heavy forces with corticotomy on tooth movement rate, alveolar bone response, and root resorption in a rat model. MATERIALS AND METHODS: The right and left sides of 40 male Wistar rats were randomly assigned using the split-mouth design to two groups: light force with corticotomy (LF) and heavy force with corticotomy (HF). Tooth movement was performed on the maxillary first molars using a nickel-titanium closed-coil spring delivering either 10 g (light force) or 50 g (heavy force). Tooth movement and alveolar bone response were assessed by micro-computed tomography (micro-CT) at day 0 as the baseline and on days 7, 14, 21, and 28. Root resorption was examined by histomorphometric analysis at day 28. RESULTS: Micro-CT analysis showed a significantly greater tooth movement in the HF group at days 7 and 14 but no difference in bone volume fraction at any of the observed periods. Histomorphometric analysis found no significant difference in root resorption between the LF and HF groups at day 28. CONCLUSIONS: Heavy force with corticotomy increased tooth movement at days 7 and 14 but did not show any difference in alveolar bone change or root resorption. PMID- 29714069 TI - Kynos Through Time: Decorated Pottery Sherds from Eleven Strata of a Homeric Greek Site. AB - Excavations at the Kynos settlement, a Homeric site and the home of an early school of key Greek pictorial pottery painting, revealed extensive remains of several chronological horizons which continuously span the period from Middle Helladic (~2100 BC) to Byzantine times (330 AD onwards), along with thousands of decorated sherds. The scope of the present study is the exploration of the technological traits of this pottery, which would contribute substantially to the archaeological understanding of the site. Samples from a sizeable assembly of decorated sherds were studied by means of analytical techniques, i.e., scanning electron microscopy-energy dispersive X-ray (SEM-EDX) analyzer, micro X-ray fluorescence (MUXRF), and portable X-ray fluorescence (pXRF). Results indicate that the dark decorations have been achieved by versions of the iron reduction (IRe) technique using mostly materials identical to those of the red decorations, while for the white decorations contrast-enhancing Ca-Mg-enriched clays were used. All coexisting red and dark hues reflect similar compositions while the color difference is due to the thicker application of the darker decorations, which are thus not affected by the last oxidative firing stage of the IRe technique. X-ray fluorescence analysis focusing on several clay-origin markers shows that only a minority of samples is of non-local character and continuity in Kynos pottery tradition, at least as far as raw materials is suggested. Some of the local body-clays exhibit a puzzling enhanced level of Ni, Cu, and Zn at a nearly fixed ratio. Finally, we find that XRF may provide valuable nondestructive analysis in the case of fine pottery decorative layers of cultural significance. PMID- 29714070 TI - Knee extensor muscle weakness and radiographic knee osteoarthritis progression. AB - Background and purpose - Knee extensor (KE) muscle weakness is a modifiable feature commonly observed in individuals with knee osteoarthritis (KOA) and constitutes a potential target for patient-specific interventions. Therefore, in this study, we explored whether KE weakness is associated with radiographic (medial and/or lateral) KOA progression and how this relationship differs depending on frontal plane knee alignment and sex. Patients and methods - We studied 3,075 knees (1,961 participants, 58% female) from the Osteoarthritis Initiative with radiographic Kellgren-Lawrence grade 1-3. Peak KE torque (Nm/kg) was assessed at baseline, and progression defined as fixed-location joint space width loss (>= 0.7mm) in medial and lateral tibiofemoral compartments from baseline to 4-year follow-up. Knee-based generalized estimating equations, stratified by alignment (malaligned vs. neutral), estimated the relative risk (RR) of progression for those in the lowest (and middle) vs. highest KE torque group (split by tertiles). Secondary analyses explored whether this relationship was compartmental- or sex-specific. Results - Being in the lowest (or middle) compared with the highest torque group increased the risk of progression in neutrally aligned knees (relative risk [RR] 1.2 [95% CI 1.0-1.4]; and 1.2 [CI 1.0 1.4], respectively), but not after adjusting for age, sex, BMI, pain, and radiographic severity. In secondary analyses, women with neutral alignment in the lowest compared with the highest torque group had significantly increased risk of lateral compartment progression independent of age, BMI, disease severity, and pain (RR 1.3 [CI 1.0-1.8]). No association was observed between KE torque and KOA progression in men, irrespective of alignment. Interpretation - These results identify a potentially important clinical phenotype: KE weakness may be a more important risk factor for radiographic KOA progression in women without knee malalignment. PMID- 29714071 TI - The Irish approach to postaccident preparedness. AB - Ireland does not have any nuclear installations, but a nuclear accident at a site elsewhere, particularly in Europe, could result in widespread but low-level contamination of the Irish environment. Ireland's National Emergency Plan for Nuclear Accidents was established, following the Chernobyl accident, for the national response to a nuclear accident abroad affecting Ireland. It has since been extended to also cover domestic radiological emergencies for which a national-level input is required to support the local response. This paper describes the approach taken to developing and maintaining arrangements for a nuclear accident abroad. The use of hazard assessments to prioritise resource use and planned protective actions, and the specifics of Ireland's situation in terms of location, governance, economy, and available resources have heavily influenced the preparedness arrangements. In particular, the importance of the ingestion pathway to projected doses, together with the significance of agricultural exports to the Irish economy, has had a key influence on the arrangements in place. PMID- 29714072 TI - Do we have an opioid crisis in Scandinavia? Time to act? PMID- 29714073 TI - Migration of all-polyethylene compared with metal-backed tibial components in cemented total knee arthroplasty. AB - Background and purpose - With a rapidly increasing population in need of total knee arthroplasty (TKA), there is renewed interest in cost-saving all polyethylene designs. Differences between metal-backed and all-polyethylene designs in initial component migration assessed by radiostereometric analysis (RSA), a proven predictor for late aseptic loosening, have been scantily reported. The purpose of this study was to compare implant migration and clinical outcomes of all-polyethylene tibial components versus metal-backed trays of similar geometrical shape. Patients and methods - In this randomized controlled trial, 59 patients received a cemented Triathlon condylar-stabilizing implant (Stryker, Mahwah, NJ, USA) with either an all-polyethylene (n = 29) or a metal backed tibial component (n = 30). RSA measurements and clinical scores (the Knee Society Score, Forgotten Joint Score, and Knee Osteoarthritis and Injury Outcome Score) were evaluated at baseline and postoperatively at 3, 12, and 24 months. A linear mixed-effects model was used to analyze the repeated measurements. Results - A statistically significant difference in mean migration after 2 years was found in favor of the all-polyethylene group, with a mean maximum total point motion of 0.61 mm (95% CI 0.49-0.74) versus 0.81 mm (95% CI 0.68-0.96) for the cemented group (p = 0.03). However, this difference was smaller and not statistically significant after post hoc adjustment for surgeon effect. Both groups showed comparable improvements on all clinical outcome scores over time. Interpretation - The Triathlon all-polyethylene tibial component showed less migration, suggesting a lower risk of late loosening as compared with its metal backed counterpart. However, the found surgeon effect warrants further investigation. PMID- 29714074 TI - JNK1/2 and ERK1/2 provides vital clues about tumor recurrence and survival in hepatocellular carcinoma patients. AB - AIM: To explore JNK1/2 and ERK1/2 activation in hepatocellular carcinoma (HCC) patients. PATIENTS & METHODS: Phosphorylated-JNK1/2 and -ERK1/2 (p-JNK1/2 and p ERK1/2) expressions were determined and analyzed in 104 unique HCC tissue specimens. RESULTS: Expression of p-JNK1/2 and p-ERK1/2 was not correlated with clinicopathological characteristics. High p-JNK1/2 and low p-ERK1/2 expressions predicated significantly lower tumor recurrence for HCC patients. However, HCC patients with low p-JNK1/2 and high p-ERK1/2 had higher tumor recurrence. Moreover, p-JNK1/2 positively, but p-ERK1/2 negatively, associated with overall survival (OS) and recurrence-free survival (RFS) in HCC patients. In addition, HCC patients with simultaneous low p-JNK1/2 and high p-ERK1/2 had poorer OS and RFS. On the contrary, patients with high p-JNK1/2 and low p-ERK1/2 presented better OS and RFS. CONCLUSION: HCC patients with low p-JNK1/2 and high p-ERK1/2 either independently or simultaneously, had significantly higher tumor recurrence and worse OS. PMID- 29714075 TI - Prevalence and imaging characteristics of nasopharyngeal and eustachian tube tonsilloliths in 2244 patients determined using computed tomography. AB - OBJECTIVES:: Nasopharyngeal tonsilloliths (NT) and eustachian tube tonsilloliths (ET) are not as well-known to radiologists as palatine and lingual tonsilloliths. The aim of this investigation was to determine the prevalence and imaging characteristics of NT and ET using CT and panoramic radiographs. METHODS:: We retrospectively assessed the scans of 2244 patients who underwent consecutive CT and panoramic radiographs of the maxillofacial region. The prevalence, size, number, and position of NT and ET were analysed. RESULTS:: NT and ET were detected in 14 (0.6%) and 6 (0.3%) of 2244 patients on CT, respectively, but they were undetectable on panoramic radiographs. No significant difference was found in the prevalence with respect to sex. Although there was also no significant difference in the prevalence among age groups, tonsilloliths were most commonly noted in patients over 40 years old; they appeared as small and round calcified bodies, ranging from 1 to 3 mm in diameter. All NT were found 0 to 3 mm beneath the nasopharyngeal mucosal surface. CONCLUSIONS:: The prevalence of NT and ET on CT was lower than that of palatine and lingual tonsilloliths. However, since they are encountered more frequently than clinically significant calcifying diseases such as retropharyngeal calcific tendinitis, clinicians should be able to correctly diagnose NT and ET based on their anatomical features. PMID- 29714076 TI - Proton therapy technology evolution in the clinic: impact on radiation protection. AB - The use of proton therapy as a treatment modality is becoming more widespread in conventional radiation therapy practice. Commercialisation and introduction of compact systems has led to embedding of proton therapy facilities in existing hospital environments. In addition, technologically, proton therapy is currently undergoing an important evolution, moving from passive scattering delivery techniques to active pencil beam scanning, adopting image guidance techniques from conventional radiotherapy and introducing various range verification techniques in the clinic. An overview is given of today's technological evolution of proton therapy in clinical environments, and its impact on aspects of radiation protection. PMID- 29714077 TI - Determining the Humidity-Dependent Ortho-to- Para Ratio of Water Vapor at Room Temperature Using Terahertz Spectroscopy. AB - The origin of the water spin isomers observed under various physico-chemical conditions is of great interest, including that of H2O molecules in the gas phase. Here, terahertz time-domain spectroscopy (THz-TDS) was used to study the humidity-dependent ortho-to- para (O/P) ratio of water vapor at room temperature. The relative contents of para and ortho molecules were obtained by fitting the absorption lines of water vapor showing the relationship between the spin isomer contents and humidity. Larger O/P ratios with values of ~3.2 were observed at lower humidity (<20%) due to the stronger attractive forces of para molecules. The concentration of the ortho isomers then began to decrease at higher humidity (>20%) due to the preferential formation of dimers and clusters at increasing concentrations. Thus, the ratio gradually decreased with increasing humidity. PMID- 29714078 TI - Overexpression of p21-activated kinase 2 is correlated with high-grade oral squamous cell carcinomas. AB - AIM: p21-activated kinase 2 (PAK2) is overexpressed in several tumors but the expression of PAK2 in oral squamous cell carcinomas (OSCCs) remains unclear. MATERIALS & METHODS: Immunohistochemistry was performed on human tissue microarrays containing 165 primary OSCC, 48 oral epithelial dysplasia and 43 normal oral mucosa. RESULTS: PAK2 expression was increased in primary OSCC compared with normal mucosa and significantly increased in primary OSCC grade III compared with grade I, but independent of overall survival rate. Moreover, the expression of PAK2 was statistically correlated with Lck/Yes novel tyrosine kinase (LYN), zinc finger transcription factor Slug, tumor-associated macrophage marker CD163 and LAG3. CONCLUSION: Overexpression of PAK2 in OSCC may be associated with an advanced pathology grade. PMID- 29714079 TI - A Direct Quantitative Raman Method for the Measurement of Dissolved Bisulfate in Acid-Sulfate Fluids. AB - Raman spectroscopy has been applied to the quantitative analysis of the concentration of bisulfate in acid-sulfate fluids at different temperatures. The quantitative analysis method is based on the peak area ratios of [Formula: see text](nu1) and H2O (nu2), where PA([Formula: see text]/H2O) = [[Formula: see text]] * (0.0066 * T + 1.3070) at a temperature range of 0-100 C. We found that the molal scattering coefficient of bisulfate increases slightly at the elevated temperature may be due to the changes of fraction of water molecules that are hydrogen-bonded. The method can also be applied to analyze physicochemical parameters of other acid fluids, such as hydrogen phosphate, bicarbonate, etc., and especially to the in situ detection of deep sea acid-sulfate hydrothermal fluids in the future. PMID- 29714080 TI - Study of Higher Diffraction Order Contribution in a Flat Field Grating Spectrograph Using a High-Order Harmonic Source. AB - An experimental study has been carried out to characterize and investigate the performance of a flat-field grating spectrograph (FFGS) for higher diffraction order in the wavelength range of 80-170 A. An aberration-corrected, mechanically ruled spherical grating with variable line spacing was used as a dispersive element in the spectrograph. The study was carried out using high-order harmonic radiation generated by an interaction of Ti:sapphire laser pulses with inert gas filled cells. It was observed that the fraction of photons diffracted in the second diffraction order to that of the first order is as high as ~ 65% at ~ 80 A wavelength, which reduces to ~ 15% at ~ 150 A, whereas for the third diffraction order, the fraction was substantially lower, ~ 15% at ~ 100 A. The observed results match well with reflectivity calculated using REFLEC software and also with the measurement carried out using INDUS-1 reflectivity beamline at RRCAT, Indore. The use of a high-order harmonic source for the study is advantageous, as the higher diffraction order contribution can be estimated from a single spectral image, which can be recorded in a single laser shot. The study will be useful for estimation of conversion efficiency-photon flux of a source using a variable line spaced (VLS) grating based spectrograph/monochromator. PMID- 29714081 TI - Sentinel lymph node biopsy management after neoadjuvant treatment for breast cancer care. PMID- 29714082 TI - An overview of which health domains to consider and when to apply them in measurement-based care for depression and anxiety disorders. AB - INTRODUCTION: Measurement-based care (MBC) transfers the scientific principle from controlled clinical trials to the daily routine treatment to improve the care of patients with anxiety and depression. AIM: Within the pharmacopsychometric triangle in which the domain of desired clinical effect of treatment is balanced against the domain of undesired treatment side effects in terms of the domain of restored well-being. The relevance of these domains both in the controlled clinical trials and in the MBC trials will be tested. METHODS: The MBC trials are compared with the controlled clinical trials focusing on the health domains of symptoms reduction (anxiety/depression), side effects of treatment, self-reported quality of life and social functioning. RESULTS: The amount of MBC trials was found rather sparse but information emerged demonstrating that the full clinician-rated Hamilton Depression Scale (HAM-D17) was sufficient for the identification of patients being in need of treatment and the HAM-D6 subscale was valid as outcome measure. From the patient-reported domains, the full Symptom Checklist (SCL-90), the 10-item anxiety/depression subscale (SCL-10) was found valid as symptom outcome. From the full Patient Reported Inventory of Side-Effects (PRISE), a subscale including Clinician Action of Response (CAR) for side effects to antidepressants was found valid (PRISE CAR), as was the World Health Organization subscale (WHO-5) for the measure of quality of life. CONCLUSION: The pharmacopsychometric triangle is also important in the MBC trials for improving the care of patients with anxiety and depression. However, the amount of MBC trials is still rather sparse. PMID- 29714083 TI - Investigation of the Cross-Section Stratifications of Icons Using Micro-Raman and Micro-Fourier Transform Infrared (FT-IR) Spectroscopy. AB - The cross-section stratifications of samples, which were removed from six icons, are studied using optical microscopy, micro-Raman spectroscopy, and micro-Fourier transform infrared (FT-IR) spectroscopy. The icons, dated from the 14th to 19th centuries, are prominent examples of Byzantine painting art and are attributed to different artistic workshops of northern Greece. The following materials are identified in the cross-sections of the icon samples using micro-Raman spectroscopy: anhydrite; calcite; carbon black; chrome yellow; cinnabar; gypsum; lead white; minium; orpiment; Prussian blue; red ochre; yellow ochre; and a paint of organic origin which can be either indigo ( Indigofera tinctoria L. and others) or woad ( Isatis tinctoria L.). The same samples are investigated using micro-FT-IR which leads to the following identifications: calcite; calcium oxalates; chrome yellow; gypsum; kaolinite; lead carboxylates; lead sulfate (or quartz); lead white; oil; protein; Prussian blue; saponified oil; shellac; silica; and tree resin. The study of the cross-sections of the icon samples reveals the combinations of the aforementioned inorganic and organic materials. Although the icons span over a long period of six centuries, the same stratification comprising gypsum ground layer, paint layers prepared by modified "egg tempera" techniques (proteinaceous materials mixed with oil and resins), and varnish layer is revealed in the investigated samples. Moreover, the presence of three layers of varnishes, one at the top and other two as intermediate layers, in the cross-section analysis of a sample from Virgin and Child provide evidence of later interventions. PMID- 29714084 TI - Hydrothermal Transformation of Inorganic and Biogenic Silica as Studied Using in Situ Hydrothermal Infrared Microspectroscopy. AB - Infrared (IR) spectral changes with time of biogenic and inorganic silica have been examined using in situ IR micro-spectroscopy by using an original hydrothermal diamond cell. Centric diatoms (diameters = 100-350 um) and silica gels (C-300, Wako Chemicals) were heated at 125-185 C range with a pressure of 3 MPa. Decreases of 950 cm-1 (Si-OH) peak heights could be fitted by a combination of exponential and linear decreases (y = A1 exp (-k1t) - k0 t + A0). The first order rate constants k1 [s-1] for Si-OH decreases of diatoms and silica gels are similar but the activation energy was lower for diatoms (61 kJcmol-1 < 106 kJcmol 1). The first-order rate constants k1 [s-1] for Si-OH decreases of diatoms and silica gels are much faster than reported hydrothermal transformation rates of silica (Opal A to Opal CT and Opal CT to quartz). These results indicate that the exponential Si-OH decreases observed in biogenic and inorganic silica during hydrothermal reactions are considered to correspond to dehydration-condensation reactions in the amorphous states (Si-OH + HO-Si -> Si-O-Si). In fact, band area ratios 1220 cm-1/1120 cm-1 increased exponentially indicating more bridging of Si O-Si. On the other hand, the linear decreases of Si-OH of silica gels (k0 [s-1]) were considered to be due to dissolution of silica. By using the grain size and density of silica gels, the zero-order dissolution rate constants k0* [molcm-2cs 1] were calculated from k0 [s-1]. The obtained dissolution rates k0* are larger than reported values for silica glass and quartz. The zero-order dissolution rates k0 [s-1] for diatoms are similar to those for silica gels but with a lower activation energy (32 kJcmol-1 < 60 kJcmol-1). The smaller activation energy values for diatoms than silica gels both for the first and zero-order decrease rates of Si-OH might indicate catalytic effects of organic components bound to biogenic silica for the dehydration-condensation reaction and dissolution. The present in situ hydrothermal IR micro-spectroscopy is useful for characterizing transformation of amorphous materials including inorganic-organic composites. PMID- 29714085 TI - Development of a Rapid Coal Analyzer Using Laser-Induced Breakdown Spectroscopy (LIBS). AB - Determination of coal quality plays a major role in coal-fired power plants and coal producers for optimizing the utilization efficiency and controlling the quality. In this work, a rapid coal analyzer based on laser-induced breakdown spectroscopy (LIBS) was developed for rapid quality analysis of pulverized coal. The structure of the LIBS apparatus was introduced in detail. To avoid time consuming and complicated sample preparation, a pulverized feeding machine was designed to form a continuously stable coal particle flow. The standard deviation (SD) of characteristic peaks was used to estimate the spectral valid data in this experiment. Coupled with cluster analysis, artificial neural networks and genetic algorithm are employed as a nonlinear regression method in order to indicate the relationship between coal quality and the corresponding plasma spectra. It is shown that the average absolute error of ash, volatile matter, fixed carbon, and gross calorific value for the validation set is 0.82%, 0.85%, 0.96%, and 0.48 MJ/kg. The average standard deviation of repeated samples is 1.64%, 0.92%, 1.08%, and 0.86 MJ/kg, showing a high sample-to-sample repeatability. This rapid coal analyzer is capable of performing reliable and accurate analysis of coal quality. PMID- 29714086 TI - A dosimetric evaluation on applying RTOG-based and CT/MRI-based delineation methods to brachial plexus in radiotherapy of nasopharyngeal carcinoma treated with helical tomotherapy. AB - OBJECTIVE: In radiotherapy of nasopharyngeal carcinoma (NPC) patients, the brachial plexus (BP) situated at both sides of the neck is often irradiated to high dose. This study was to evaluate different BP delineation methods and analyse the dosimetric consequences when applying BP dose constraints in radiotherapy planning of NPC. METHODS: 15 NPC cases radically treated with helical tomotherapy were recruited. Apart from the original treatment plan (Plan A), two new plans (Plans B and C) with additional BP dose constraints were computed using the same planning CT images, structures and planning parameters. Plan B consisted of BP contours based on Radiation Therapy Oncology Group (RTOG) endorsed atlas; while those in Plan C were based on MR images registered with the planning CT images. RESULTS: The mean BP volume by RTOG method was 19.04 +/- 3.50 cm3 vs 10.44 +/- 2.00 cm3 by CT/MRI method. The mean BP overlapping volume between the two contouring methods was 1.9 cm3 (0.38-4.03 cm3). There was significant difference between two methods (p < 0.001). The average Dmax, Dmean, D5%, D10% and D15% of both sides of BP in Plan A were significantly higher than those in both Plan B and Plan C. There were no significant dose differences in the targets and organs at risk (OARs) after applying dose constraints in Plan B and Plan C. CONCLUSION: RTOG method was recommended since larger BP volume provided better protection. Applying BP dose constraints during tomotherapy plan optimisation for NPC patients could significantly reduce the BP dose (p < 0.05) without compromising the doses to the targets and other OARs. Advances in knowledge: This is the first study comparing the delineation method based on RTOG endorsed atlas with the conventional CT/MRI delineation method for BP in tomotherapy of NPC patients. Our results showed that BP dose could be significantly reduced after applying the dose constraints without compromising the doses to the target volumes and other OARs. The RTOG method was more favoured as it gave a relatively larger BP volume and therefore offered better organ sparing. PMID- 29714088 TI - Screening for women at midlife: we need to remain vigilant. PMID- 29714087 TI - Letter to the Editor Regarding "Stroke After Minor Head Trauma in Infants and Young Children With Basal Ganglia Calcification: A Lenticulostriate Vasculopathy?" PMID- 29714089 TI - History of a brief time: reflections of the first female President. PMID- 29714091 TI - Phenotypic and Molecular-Phylogenetic Analysis Provide Novel Insights into the Diversity of Curtobacterium flaccumfaciens. AB - A multiphasic approach was used to decipher the phenotypic features, genetic diversity, and phylogenetic position of 46 Curtobacterium spp. strains isolated from dry beans and other annual crops in Iran and Spain. Pathogenicity tests, resistance to arsenic compounds, plasmid profiling and BOX-PCR were performed on the strains. Multilocus sequence analysis (MLSA) was also performed on five housekeeping genes (i.e., atpD, gyrB, ppk, recA, and rpoB) of all the strains, as well as five pathotype strains of the species. Pathogenicity test showed that six out of 42 strains isolated in Iran were nonpathogenic on common bean. Despite no differences found between pathogenic and nonpathogenic strains in their plasmid profiling, the former were resistant to different concentrations of arsenic, while the latter were sensitive to the same concentrations. Strains pathogenic on common bean were polyphyletic with at least two evolutionary lineages (i.e., yellow-pigmented strains versus red/orange-pigmented strains). Nonpathogenic strains isolated from solanaceous vegetables were clustered within either the strains of C. flaccumfaciens pv. flaccumfaciens or different pathovars of the species. The results of MLSA and BOX-PCR analysis were similar to each other and both methods were able to discriminate the yellow-pigmented strains from the red/orange-pigmented strains. A comprehensive study of a worldwide collection representing all five pathovars as well as nonpathogenic strains of C. flaccumfaciens is warranted for a better understanding of the diversity within this phytopathogenic bacterium. PMID- 29714090 TI - Substrate stiffness-dependent exacerbation of endothelial permeability and inflammation: mechanisms and potential implications in ALI and PH (2017 Grover Conference Series). AB - The maintenance of endothelial barrier integrity is absolutely essential to prevent the vascular leak associated with pneumonia, pulmonary edema resulting from inhalation of toxins, acute elevation to high altitude, traumatic and septic lung injury, acute lung injury (ALI), and its life-threatening complication, acute respiratory distress syndrome (ARDS). In addition to the long-known edemagenic and inflammatory agonists, emerging evidences suggest that factors of endothelial cell (EC) mechanical microenvironment such as blood flow, mechanical strain of the vessel, or extracellular matrix stiffness also play an essential role in the control of endothelial permeability and inflammation. Recent studies from our group and others have demonstrated that substrate stiffening causes endothelial barrier disruption and renders EC more susceptible to agonist-induced cytoskeletal rearrangement and inflammation. Further in vivo studies have provided direct evidence that proinflammatory stimuli increase lung microvascular stiffness which in turn exacerbates endothelial permeability and inflammation and perpetuates a vicious circle of lung inflammation. Accumulating evidence suggests a key role for RhoA GTPases signaling in stiffness-dependent mechanotransduction mechanisms defining EC permeability and inflammatory responses. Vascular stiffening is also known to be a key contributor to other cardiovascular diseases such as arterial pulmonary hypertension (PH), although the precise role of stiffness in the development and progression of PH remains to be elucidated. This review summarizes the current understanding of stiffness-dependent regulation of pulmonary EC permeability and inflammation, and discusses potential implication of pulmonary vascular stiffness alterations at macro- and microscale in development and modulation of ALI and PH. PMID- 29714093 TI - Reply to Letter on "Stroke After Minor Head Trauma in Infants and Young Children With Basal Ganglia Calcification: A Lenticulostriate Vasculopathy?" PMID- 29714092 TI - Cotton Leaf Curl Disease: Which Whitefly Is the Vector? AB - Cotton leaf curl disease is one of the most significant constraints to the production of cotton. In the past decades our understanding of the begomoviruses (family Geminiviridae) causing the disease has improved, but little is known regarding transmission of these viruses by the different species of whiteflies in the Bemisia tabaci complex. We compared transmission efficiency of cotton leaf curl Multan virus (CLCuMuV), one of the major begomoviruses associated with cotton leaf curl disease, by four whitefly species, of which two are indigenous to Asia and two are invasive worldwide. Only the indigenous Asia II 1 species was able to transmit this virus with high efficiency. By quantifying the virus and using immunoflorescence assays, we found that the differential transmission was associated with the varying efficiency of CLCuMuV to cross the midgut of various whitefly species. Further, we verified the role of coat protein in the whitefly transmission of CLCuMuV. Based on a phylogenetic analysis of the virus coat proteins, we found that most begomoviruses associated with cotton leaf curl disease might share similar whitefly transmission characteristics. These findings advance our understanding of the nature of cotton leaf curl disease and provide information for the development of control and preventive strategies against this disease. PMID- 29714095 TI - Impact of Obesity on Fosphenytoin Volume of Distribution in Pediatric Patients. AB - The impact of body habitus on fosphenytoin pharmacokinetics is poorly understood in pediatric patients. This retrospective, single-center review examined differences in fosphenytoin volume of distribution (VD) between children with normal and obese body habitus. From 2013 to 2015, patients 2 to 18 years of age who received a loading dose of fosphenytoin were identified. Thirty-seven patients met inclusion criteria. Mean total serum phenytoin concentration was 25.3 +/- 6.5 MUg/mL in the nonobese group and 29.5 +/- 7.6 MUg/mL in the obese group ( P = .09). VD was not significantly different between obese and nonobese groups, 0.92 +/- 0.26 L/kg and 0.97 +/- 0.48 L/kg ( P = .76), respectively. In contrast to adult studies, these data suggest that fosphenytoin dose adjustments for obese children may be unnecessary. PMID- 29714097 TI - Thinking Outside the Box about Cognitive Impairment and Intensive Care Unit Survivorship. PMID- 29714096 TI - Identification of Chemotaxis Compounds in Root Exudates and Their Sensing Chemoreceptors in Plant-Growth-Promoting Rhizobacteria Bacillus amyloliquefaciens SQR9. AB - Chemotaxis-mediated response to root exudates, initiated by sensing-specific ligands through methyl-accepting chemotaxis proteins (MCP), is very important for root colonization and beneficial functions of plant-growth-promoting rhizobacteria (PGPR). Systematic identification of chemoattractants in complex root exudates and their sensing chemoreceptors in PGPR is helpful for enhancing their recruitment and colonization. In this study, 39 chemoattractants and 5 chemorepellents, including amino acids, organic acids, and sugars, were identified from 98 tested components of root exudates for the well-studied PGPR strain Bacillus amyloliquefaciens SQR9. Interestingly, mutant stain SQR9Delta8mcp, with all eight putative chemoreceptors completely deleted, lost the chemotactic responses to those 44 compounds. Gene complementation, chemotaxis assay, and isothermal titration calorimetry analysis revealed that McpA was mainly responsible for sensing organic acids and amino acids, while McpC was mostly for amino acids. These two chemoreceptors may play important roles in the rhizosphere chemotaxis of SQR9. In contrast, the B. amyloliquefaciens-unique chemoreceptor McpR was specifically responsible for arginine, and residues Tyr 78, Thr-131, and Asp-162 were critical for arginine binding. This study not only deepened our insights into PGPR-root interaction but also provided useful information to enhance the rhizosphere chemotaxis mobility and colonization of PGPR, which will promote their application in agricultural production. PMID- 29714098 TI - Predicting the Future of Cystic Fibrosis Lung Disease: Gene Expression Holds Some of the Answers. PMID- 29714099 TI - Less Is More: Learning from Variation in Pulmonary Embolism Care. PMID- 29714101 TI - Unintended Consequences of Quality-of-Care Measures. PMID- 29714100 TI - Acute Decompensation after Hemodialysis in a Patient with Pericardial Effusion. PMID- 29714102 TI - Beyond the Beck's Triad: The Use of Point-of-Care Ultrasound for Diagnosis and Treatment of Shock. PMID- 29714103 TI - Traffic-related Air Pollution, Lung Function, and Host Vulnerability. New Insights from the PARIS Birth Cohort. AB - RATIONALE: Although the effects of traffic-related air pollution on respiratory exacerbations have been well documented, its impact on lung function in childhood remains unclear. OBJECTIVES: Our aim was to investigate the associations of prenatal, early, and lifetime traffic-related air pollution exposure with lung function at 8-9 years studying possible effect modification by sex, sensitization at 8-9 years, and early lower respiratory tract infections. METHODS: We conducted this study among 788 children from the PARIS (Pollution and Asthma Risk: an Infant Study) birth cohort. Lung function tests were performed during the medical examination at 8-9 years. Traffic-related air pollution exposure during each trimester of pregnancy was estimated using nitrogen oxides background measurements. Postnatal traffic-related air pollution exposure was assessed by a nitrogen oxides air dispersion model at both residential and daycare/school addresses. Associations between lung function and traffic-related air pollution exposure were analyzed by multiple linear regression models. RESULTS: Higher prenatal nitrogen oxides levels, especially during the second trimester of pregnancy, were associated with a lower forced expiratory flow at 25-75% of the forced vital capacity, but there were no significant associations between prenatal nitrogen oxide levels and forced vital capacity, forced expiratory volume during 1 second, or the forced expiratory volume during 1 second/forced vital capacity ratio overall. Postnatal traffic-related air pollution exposure was associated with lower lung function among children with early lower respiratory tract infections or sensitization at 8-9 years, but not in the full cohort. In children with early repeated lower respiratory tract infections, an interquartile increase in lifetime nitrogen oxides exposure was associated with both a lower forced expiratory volume during 1 second (-62.6 ml; 95% confidence interval = -107.0 to -18.1) and forced vital capacity (-55.7 ml; 95% confidence interval = -109.5 to -1.8), but was not associated with the forced expiratory volume during 1 second/forced vital capacity ratio. There was an association between greater early postnatal nitrogen oxide exposure and a lower forced expiratory volume during 1 second/forced vital capacity ratio among sensitized children (-0.65%; 95% confidence interval = -1.25 to -0.05). CONCLUSIONS: This study sheds new light, suggesting associations between postnatal traffic-related air pollution exposure and reduced lung function may be enhanced by early, repeated lower respiratory tract infections or allergic sensitization. PMID- 29714104 TI - When Antimicrobial Therapy Is Not Enough: Respiratory Failure in a Patient with Chronic Granulomatous Disease. PMID- 29714105 TI - Management of Comorbid Chronic Obstructive Pulmonary Disease and Cardiovascular Disease. Moving Past the Agony of the beta-Receptor Debate. PMID- 29714106 TI - Meta-analysis of the efficacy and acceptability of cognitive-behavioural therapy for Arab adult populations experiencing anxiety, depression or post-traumatic stress disorder. AB - A meta-analysis of the literature of cognitive behaviour therapy (CBT) with Arab adult populations experiencing anxiety, depression or post-traumatic stress disorder (PTSD) was conducted. Nine studies (n = 536) met the eligibility criteria. Three of the nine studies (33%) were randomised control trials using waitlist control groups. All studies (100%) reported a statistically significant reduction in psychological symptoms at post-treatment with large effect sizes for anxiety (effect size, 95% confidence interval) (1.44 [1.29, 1.59]), depression (1.26 [1.16, 1.35]) and PTSD (2.08 [1.94, 2.23]). Six out of the nine studies (67%) collated follow-up data and reported that reductions of psychological symptoms were maintained at follow-up. An average dropout rate of 26% indicated good overall acceptability. Five out of nine (55%) of the trials reported diagnostic remission rates and of those trials the mean remission rate was 31%). Five of the nine eligible studies (55%) delivered remotely via Internet or telephone were found to have similar effect sizes as face-to-face CBT. The current meta-analysis indicates the potential of CBT, delivered either face-to face or via internet, as efficacious and acceptable interventions for the treatment of anxiety, depression and PTSD for Arab adult populations. PMID- 29714107 TI - Intermittent Esotropia in 4 Patients With Allan-Herndon-Dudley Syndrome. AB - Allan-Herndon-Dudley syndrome is a rare X-linked neurologic condition caused by mutations in monocarboxylate transporter 8 ( MCT8), which leads to deficient thyroid hormone transport. Typical features include severe cognitive impairment, truncal hypotonia, spastic paraplegia, weakness, and speech difficulties. Minimal literature exists describing the ocular findings in patients with Allan-Herndon Dudley syndrome. We describe 4 male siblings affected with Allan-Herndon-Dudley syndrome with a novel nonsense mutation (Q90X) in the MCT8 protein. All affected siblings presented with classic findings of Allan-Herndon-Dudley syndrome, and each of the siblings also developed intermittent esotropia. This group of affected siblings represents the first consistent documentation of strabismus in Allan-Herndon-Dudley syndrome, suggesting a possible association between this clinical finding and the neurologic syndrome. PMID- 29714108 TI - Gabapentin to Prevent Acute Pain after Tonsillectomy. PMID- 29714109 TI - Response to "Gabapentin to Prevent Acute Pain after Tonsillectomy". PMID- 29714110 TI - Highlights from the Current Issue: May 2018. PMID- 29714111 TI - A response to the Chief Medical Officer's report on Genomic Medicine: a catalyst for transformation. PMID- 29714112 TI - Beyond the didactic lecture: pharmacogenomics in pharmacy education. PMID- 29714113 TI - Noninvasive prenatal testing: a survey of young (future) parents in Flanders. AB - AIM: To explore the opinions of young (future) parents toward noninvasive prenatal testing. MATERIALS & METHODS: A questionnaire was administrated. RESULTS: A total of 1006 surveys were completed by visitors of 40 secondhand clothing fairs spread equally over Flanders (Belgium). The respondents expressed an overall positive opinion toward the use and implementation of a noninvasive prenatal test (NIPT). Most respondents claimed that they would test their unborn child for genetic disorders, even if this was to result in a termination of the pregnancy. CONCLUSION: The participants agreed nearly unanimously that NIPT must be offered to pregnant women with an increased risk of having a child with a genetic disorder, but they were also positive about extending NIPT screening to all pregnant women. PMID- 29714114 TI - Toward greater understanding of patient decision-making around genome sequencing. AB - In the era of next-generation sequencing, it is essential to collect and understand the patient outcomes that result from this new technology. One critical determinant of these is the process by which individuals first decide whether and how to pursue genome sequencing. In this perspective article, we examine the literature on adult patient decision-making in genome sequencing and identify current research gaps to address. Several studies have explored the motivations and concerns of patients undergoing sequencing; less attention has been paid to those who decline sequencing or to individuals from lower socioeconomic groups. Many factors that might play a role in the decision to pursue or decline sequencing, including trust, family dynamics and barriers to access, have yet to be explored fully. Future research that captures the experience of the wider population will produce a more generalizable understanding of the clinical, psychosocial, and economic outcomes of pursuing or declining sequencing. PMID- 29714115 TI - Personalized Medicine: Foreword. PMID- 29714117 TI - Predictive value of big endothelin-1 on outcomes in patients with myocardial infarction younger than 35 years old. AB - AIM: The predictive value of big endothelin-1 (ET-1) for cardiovascular outcomes in myocardial infarction (MI) patients younger than 35 years old has not been characterized. METHODS: A total of 565 consecutive MI patients younger than 35 years old were studied and followed up for 37.78 +/- 24.9 months. RESULTS: Multivariable Cox regression analysis showed that big ET-1 was positively correlated with major adverse cardiovascular events [MACEs] (odds ratio: 3; 95% CI: 1.92-4.68; p < 0.001). The area under receiver operating characteristics curve showing the predictive value of big ET-1 on MACEs was 0.67. CONCLUSION: The study first demonstrated that big ET-1 was an independent predictor for MACEs in MI patients younger than 35 years old. PMID- 29714116 TI - A comparison of Australian and French families affected by sarcoma: perceptions of genetics and incidental findings. AB - AIM: To compare Australian and French perceptions of genetics and preferences regarding the return of incidental findings. METHODS: Participants from the International Sarcoma Kindred Study received a survey at intake to cancer referral units. A total of 1442 Australian and 479 French individuals affected by sarcoma and their unaffected family members responded to four hypothetical scenarios depicting hereditary conditions of varying treatability and severity. RESULTS: Australians' preference for the return of incidental findings was consistently higher than French for all scenarios. Country group differences were significant for two scenarios when individual characteristics were controlled through multivariable analyses. CONCLUSION: Findings support the need for guidelines that are sensitive to sociocultural context and promote autonomous decision-making. PMID- 29714119 TI - Erratum. PMID- 29714118 TI - Prediction of response to targeted and immune checkpoint therapies. AB - Targeted therapies continue to be key components of cancer treatment. New approaches to detection of acquired resistance at the genomic level, in combination with new therapies, help to overcome the challenges that are seen frequently, rapidly and broadly across tumor pathologies, and provide opportunities for cancer management. In the last several years, a new breed of modalities called immune checkpoint inhibitors have come to the forefront of clinically effective treatments. A plethora of rapid approvals and early access initiatives have seen anti-cytotoxic T-lymphocyte-associated antigen-4, and particularly anti-programmed death receptor-1 therapies, deployed in a number of tumor indications of high unmet need. With the rise of immune checkpoint inhibition, and the broader resurgence in the immuno-oncology field, we are facing challenges in the prediction of response. PMID- 29714120 TI - Pharmacogenomic-guided dosing for warfarin: too little too late? PMID- 29714121 TI - How advances in personalized medicine will change rheumatology. PMID- 29714122 TI - ALK-rearranged adenocarcinoma transformed to small-cell lung cancer: a new entity with specific prognosis and treatment? AB - Driving molecular mutations such as rearrangement of ALK and EGFR mutation is present in 5-10% of non-small-cell lung cancer. Tyrosine kinase inhibitors have shown good efficacy and thus become the standard of care. However, tumors have developed several resistance mechanisms against tyrosine kinase inhibitors, including transformation to small-cell lung carcinoma (SCLC). Transformation to SCLC after administration of anti-EGFR in EGFR-mutated adenocarcinoma has been well documented. Similarly, it appears that the same transformation happens in ALK-rearranged adenocarcinoma after the use of anti-ALK. In fact, to date eight cases have been reported in the literature. We aimed in this paper to focus on the characteristics, prognosis and treatment of these transformed SCLC. PMID- 29714123 TI - How genome editing could be used in the treatment of cardiovascular diseases. PMID- 29714124 TI - Clinical application of pharmacogenetics in pain management. AB - There is growing experience translating genomic data into clinical practice, as seen with the Implementing GeNomics In pracTicE (IGNITE) network. A primary example is the influence of CYP2D6 genotype on the beneficial and adverse effects of some opioids. Clinical recommendations exist to guide drug therapy based on CYP2D6 genotype for codeine, tramadol, oxycodone and hydrocodone, although the level of supporting evidence differs by drug. Limited evidence also supports the use of genetic data to guide other medications in chronic pain therapy, including tricyclic antidepressants and celecoxib. Pragmatic clinical trial data are needed in this area to better understand the impact of diverse populations, therapeutic interventions and clinical care environments on genotype-guided drug therapy for chronic pain. PMID- 29714125 TI - Multivariate analysis for coronary heart disease in heterozygote familial hypercholesterolemia patients. AB - AIM: rs599839 polymorphism has been related with low levels of cholesterol and reduced coronary heart disease (CHD). METHODS: We investigated the frequency of this polymorphism in patients with heterozygous familial hypercholesterolemia (HeFH) in the Spanish familial hypercholesterolemia cohort, 230 with and 202 without CHD. Results & discussion: A lower G-allele prevalence was observed in HeFH patients with CHD with respect to controls, 35 versus 45%, respectively (p = 0.029), suggesting a protective effect. However, it was found that there was no association between rs599839 alleles and CHD in the multivariate analysis. CONCLUSION: The frequency of the protective G-allele of the rs599839 polymorphism was lower in HeFH patients with CHD compared with those HeFH patients without CHD. However, its role in HeFH may be masked by very high levels of cholesterol. PMID- 29714126 TI - Corrigendum. PMID- 29714127 TI - Novel AKT1 mutations associated with cell-cycle abnormalities in gastric carcinoma. AB - AIM: The aim of this study is to identify the AKT1 gene mutation driven pathogenicity in gastric cancer for Mizo population. METHODS: 50 diffuse-type gastric tumors were analyzed for AKT1 exon 2 and 14 mutations. Cell-cycle aberration was analyzed in the AKT1-mutated samples and the stability of the protein as well as exonic splicing enhancer motifs were examined. RESULTS: The novel mutations, 15553T >A and 25376C >G might affect the exonic splicing enhancers and silencers. Significant decline was observed in the S-phase population in the tumor cells with 15553T >A and 15579G >C mutations suggesting the arrest of G1 phase. CONCLUSION: The present study is a novel finding of the possible role of AKT1 mutations which might help to identify gastric cancer patients. PMID- 29714128 TI - Association of genetic polymorphisms in immune-related lncRNA with osteoarthritis susceptibility in Chinese Han population. AB - AIM: Immune-related lncRNA may influence osteoarthritis (OA) susceptibility. We conducted this study to assess whether the genetic variants in several immune related lncRNA influence OA susceptibility. METHODS: The current research genotyped four SNPs in 306 OA patients and 316 healthy controls, including PRNCR1 rs7463708, PRNCR1 rs1456315, PRNCR1 rs16901946 and KIF13B1 rs643472, to investigate their associations with OA susceptibility. RESULTS: We identified that PRNCR1 rs1456315 was associated with OA susceptibility in Chinese Han population (recessive model: odds ratio = 2.24; 95% CI: 1.05-4.81; additive model: odds ratio = 1.36; 95% CI: 1.03-1.80). CONCLUSION: Individuals with PRNCR1 rs1456315 mutant G allele were more likely to suffer from OA in Chinese Han population. PMID- 29714129 TI - Personalized medicine in inflammatory cardiomyopathy. AB - Inflammatory cardiomyopathy is the result of persistent myocardial inflammation which can arise from both infectious or noninfectious causes. While most patients with acute myocarditis recover, up to 20% develop inflammatory cardiomyopathy with chronic heart failure. The interaction between host factors and factors of the agent that triggered myocardial inflammation must be considered to fully understand the individual mechanism of disease. Several inflammatory biomarkers, histology, immunohistochemistry, advanced imaging technologies as well as molecular high-throughput sequencing techniques help to identify disease pathways and to establish a comprehensive, individualized treatment approach, which can include anti-inflammatory medication, antiviral drugs and heart failure therapy. This might help to prevent transition from acute inflammation to persistent heart failure and to restore cardiac function. PMID- 29714130 TI - Erratum. PMID- 29714131 TI - Functional consequences of genetic variation in sodium channel modifiers in early onset lone atrial fibrillation. AB - AIM: We investigated the effect of variants in genes encoding sodium channel modifiers SNTA1 and GPD1L found in early onset atrial fibrillation (AF) patients. PATIENTS & METHODS: Genetic screening in patients with early onset lone AF revealed three variants in GPD1L and SNTA1 in three AF patients. Functional analysis was performed by patch-clamp electrophysiology. RESULTS: Co-expression of GPD1L or its p.A326E variant with NaV1.5 did not alter INa density or current kinetics. SNTA1 shifted the peak-current by -5 mV. The SNTA1-p.A257G variant significantly increased INa. SNTA1-p.P74L did not produce functional changes. CONCLUSION: Although genetic variation of sodium channel modifiers may contribute to development of AF at a molecular level, it is unlikely a monogenic cause of the disease. PMID- 29714132 TI - miR-7 Replacement Therapy in Parkinson's Disease. AB - The present review examines whether the microRNA 7 (miR-7) holds potential for slowing Parkinson's disease (PD) progression. First, the accurate expression of miR-7 allows for normal development, physiology, and neurogenesis in the central nervous system, also keeping alpha-synuclein (alpha-Syn) at the physiological level. Second, patients with PD and parkinsonian MPTP-induced animals exhibit a significant decrease of miR-7 in brain areas associated with dopaminergic neurodegeneration. Depletion of miR-7 in the substantia nigra of clinical samples is related to alpha-Syn accumulation, loss of dopaminergic cells, and reduction of dopamine in the striatum. Therefore, the goal of a miR-7- replacement therapy is to downregulate alpha-Syn and other PD-related genes, achieving multi-target benefits regarding oxidative stress, mitochondrial health, cell glycolysis, apoptosis, and inhibition of inflammasome activation. While a disease-modifying drug is a major unmet need for the clinical management of PD, an miR-7 replacement therapy presents a striking potential against critical mechanisms of neuropathology. Such innovative treatment would reduce alpha-Syn accumulation in the Lewy bodies and preserve remaining neurons yet viable at the time of diagnosis, thus slowing disease progression from the early phase of PD characterized by a relatively mild motor impairment to an advanced and more disabling stage. PMID- 29714133 TI - Drugs for targeted therapies of Alzheimer's disease. AB - Alzheimer's disease (AD) is one type of neurodegenerative diseases which is prevalent in the elderly. Beta-amyloid (Abeta) plaques and phosphorylated tau induced neurofibrillary tangles are two pathological hallmarks of this disease and the corresponding pathological pathways of these hallmarks are considered as the therapeutic targets. There are many drugs scheduled for pre-clinical and clinical trial that target to inhibit the initiators of pathological Abeta and tau aggregates as well as critical Abeta secretases and kinases in tau hyperphosphorylation. In addition, studies in disease gene variations, and detection of key prognostic effectors in early development are also important for AD control. The discovery of potential drug targets contributed to targeted therapy in a stage-dependent manner, However, there are still some issues that cause concern such as the low bioavailability and low efficacy of candidate drugs from clinical trial reports. Therefore, modification of drug candidates and development of delivery agents are essential and critical. With other medical advancements like cell replacement therapy, there is hope for the cure of Alzheimer's disease in the foreseeable future. PMID- 29714134 TI - Medicinal Chemistry of Potassium Channel Modulators: An update of Recent Progress (2011-2017). AB - BACKGROUND: Potassium (K+) channels participate in many physiological processes, cardiac function, cell proliferation, neuronal signaling, muscle contractility, immune function, hormone secretion, osmotic pressure, changes in gene expression, and are involved in critical biological functions, and in a variety of diseases. Potassium channels represent a large family of tetrameric membrane proteins. Potassium channels activation reduces excitability, whereas channel inhibition increases excitability. OBJECTIVE: Small molecule K+ channel activators and inhibitors interact with voltage-gated, inward rectifying, and two-pore tandem potassium channels. Due to their involvement in biological functions, and in a variety of diseases, small molecule as potassium channel modulators have received great scientific attention. METHOD: In this review, we have compiled the literatures, patents and patent applications (2011 to 2017) related to different chemical class of potassium channel openers and blockers as therapeutic agents for the treatment of various diseases. Many different chemical class of selective small molecule have emerged as potassium channel modulators over the past years. CONCLUSION: This review discussed the current understanding of medicinal chemistry research in the field of potassium channel modulators to update the key advances in this field. PMID- 29714135 TI - Natural alkaloids intervening the insulin pathway: new hopes for anti-diabetic agents? AB - BACKGROUND: Accumulating experimental data support the capacity of natural compounds to intervene in complicated molecular pathways underlying the pathogenesis of certain human morbidities. Among them, diabetes is now a world's epidemic associated with increased risk of death; thus, the detection of novel anti-diabetic agents and/or adjuvants is of vital importance. Alkaloids represent a diverse group of natural products with a range of therapeutic properties; during the last 20 years published research on their anti-diabetic capacity has been tremendously increased. PURPOSE: To discuss current concepts on the anti diabetic impact of certain alkaloids, with special reference to their molecular targets throughout the insulin-signaling pathway. METHODOLOGY: Upon in-depth search in the SCOPUS and PUBMED databases, literature on alkaloids with insulin secretion/sensitization properties was critically reviewed. RESULTS: In-vitro and in-vivo evidence support the effect of berberine, trigonelline, piperine, oxymatrine, vindoneline, evodiamine and neferine on insulin-signaling and related cascades in beta-cells, myocytes, adipocytes, hepatocytes and other cells. Associated receptors, kinases, hormones and cytokines, are affected in terms of gene transcription, protein expression, activity and/or phosphorylation. Pathophysiological processes associated with insulin resistance, beta-cell failure, oxidative stress and inflammation, as well as clinical phenotype are also influenced. DISCUSSION: Growing evidence suggest the ability of specific alkaloids to intervene in the insulin-signal transduction pathway, reverse molecular defects resulting in insulin resistance and glucose intolerance and improve disease complications, in-vitro and in-vivo. Future in-depth molecular studies are expected to elucidate their exact mechanism of action, while large clinical trials are urgently needed to assess their potential as anti-diabetic agents. PMID- 29714136 TI - Insights on melatonin as an active pharmacological molecule in cancer prevention: what's new? AB - Along with playing an important role in circadian rhythm, melatonin is thought to play a significant role in preventing cells from damage, as well as in the inhibition of growth and in triggering of apoptosis in malignant cells. Its relationship with circadian rhythms, energetic homeostasis, diet, and metabolism, is fundamental to achieve a better comprehension of how melatonin has been considered a chemopreventive molecule, though very few papers dealt with this issue. In this article, we tried to review the most recent evidence regarding the protective as well as the antitumoral mechanisms of melatonin, as related to diet and metabolic balance. From different studies, it was evident that an intracellular antioxidant defense mechanism is activated by upregulating an antioxidant gene battery in the presence of high-dose melatonin in malignant cells. Like other broad-spectrum antioxidant molecules, melatonin plays a vital role in killing tumor cells, preventing metastasis, and simultaneously keeping normal cells protected from oxidative stress and other types of tissue damage. PMID- 29714137 TI - Multifunctional mesoporous silica nanoparticles for cancer therapy and imaging. AB - BACKGROUND: Cancer is a wide spread disease and has high mortality rate. Popular conventional treatment encompasses chemotherapy, radiation and surgical resection. However these treatments imparts lots of toxicity problems to patients mostly due to their non-selectiveness nature which invokes drug resistances and severe side-effects. OBJECTIVES: In this regard, nanotechnology has claimed to be a smart technology that provides system with the ability of targeting drugs to the specific sites. With the used of nanotechnology various nanomaterials that are widely used as drug delivery vehicle are created for biomedical applications. Amongst various diversified nanovehicles, mesoporous silica nanoparticles (MSNs) has attracted enormous attention due to their structural characteristics, great surface areas, tunable pore diameters, good thermal and chemical stability, excellent biocompatibility along with ease of surface modification. Furthermore, the drug release from MSNs can be tailored through various stimuli response gatekeeper systems. The ordered structure of MSNs are extremely suitable for loading of high amount of drug molecules with controlled delivery for targeting the cancer tissues via enhanced permeability and retention effect or further with surface modification it can also be actively targeted by various ligands. METHODS: The review article emphases about the common synthetic methods and current advancement of MSNs usages for stimuli response drug delivery, immunotherapy as well as theranostic ability for cancer. CONCLUSION: Although MSNs are becoming the promising tool for more efficient and safer cancer therapy, however, additional translational studies are required to explore its multifunctional ability in clinical setting. PMID- 29714138 TI - Natural Products: Key Prototypes to Drug Discovery Against Neglected Diseases Caused by Trypanosomatids. AB - BACKGROUND: Neglected tropical diseases are a group of infections caused by microorganisms and viruses that affect mainly poor regions of the world. In addition, most available drugs are associated with long periods of treatment and high toxicity which limits the application and patient compliance. Investment in research and development is not seen as an attractive deal by the pharmaceutical industry since the final product must ideally be cheap, not returning the amount invested. Natural products have always played an important source for bioactive compounds and are advantageous over synthetic compounds when considering the unique structural variety and biological activities. On the other hand, isolation difficulties and low yields, environmental impact and high cost usually limit their application as drug per se. OBJECTIVE: In this review, the use of natural products as prototypes for the semi-synthesis or total synthesis, as well as natural products as promising hits are covered, specifically regarding compounds with activities against trypanosomatids such as Trypanosoma spp. and Leishmania spp. METHOD: Selected reports from literature with this approach were retrieved. CONCLUSION: As summary, it can be concluded that natural products are an underestimated source for designing novel agents against these parasites. PMID- 29714139 TI - Advance and Application of DNA-functionalized Nanoparticles. AB - DNA-functionalized nanoparticle (DfNP) technology, the integration of DNA with nanotechnology, has emerged over recent decades as a promising biofunctionalization tool in the light of biotechnological approaches. The development of DfNPs has exhibited significant potential for several biological and biomedical applications. In this review, we focus on the mechanism of a series of DNA-NP nanocomposites and highlight the superstructures of DNA-based NPs. We also summarize its applications of these nanocomposites in cell imaging, cancer therapy and bioanalytical detection. PMID- 29714140 TI - Omalizumab in the Therapy of Pediatric Asthma. AB - BACKGROUND: Eosinophilic asthma is driven by Th2 immune response and is usually characterized by the increase of total serum IgE levels and/or specific IgE that express single or multiple allergen sensitization. In such an immuno-pathological background, the anti-IgE therapy, namely omalizumab, found its main clinical utility and recommendation to treat severe asthma. OBJECTIVE: In this mini review, we summarized the most relevant immuno-pathological and clinical evidences supporting the use of omalizumab in the therapy of pediatric asthma. Furthermore, we provided the main practical points for its use in the therapeutic management of asthmatic children. METHOD: Through the binding of serum free IgE, omalizumab impairs not only the effector phase of IgE-mediated asthma, but also affects the IgE biology and the related immune response, globally. Here, the history of omalizaumab has been shortly reviewed from its preclinical development to its clinical validation in pediatric asthma. Thus, recent patents regarding anti-IgE therapy have been discussed. CONCLUSION: Omalizumab significantly improved the clinical management of severe and uncontrolled pediatric asthma; however, pre-treament IgE levels limited the use of omalizumab in some patients and the cost of the therapy is still relevant. Moreover, the optimal duration of the treatment with omalizumab in children has to be determined. Finally, the recent generation of a mutant IgE-Fc fragment being resistant to omalizumab binding might open further therapeutic applications, in addition to second generation anti-IgE antibodies. PMID- 29714141 TI - Blocking IL-6/GP130 signaling inhibits cell viability/proliferation, glycolysis, and colony forming activity in human pancreatic cancer cells. AB - BACKGROUND: Elevated production of the pro-inflammatory cytokine interleukin-6 (IL-6) and dysfunctions of IL-6 signaling promotes tumorigenesis and are associated with poor survival outcomes in multiple cancer types. Recent studies showed that the IL-6/GP130/STAT3 signaling pathway plays a pivotal role in pancreatic cancer development and maintenance. OBJECTIVE: We aim to develop effective treatments through inhibition of IL-6/GP130 signaling in pancreatic cancer. METHOD: The effects on cell viability and cell proliferation were measured by MTT and BrdU assays respectively. The effects on glycolysis was determined by cell-based assays to measure lactate levels. Protein expression changes were evaluated by western blotting and immunoprecipitation. SiRNA transfection was used to knock down estrogen receptor alpha gene expression. Colony forming ability was determined by colony forming cell assay. RESULTS: We demonstrated that IL-6 can induce pancreatic cancer cell viability/proliferation and glycolysis. We also showed that a repurposing FDA-approved drug bazedoxifene could inhibit the IL-6/IL-6R/GP130 complexes. Bazedoxifene also inhibited JAK1 binding to IL-6/IL-6R/GP130 complexes and STAT3 phosphorylation. In addition, bazedoxifene inhibited IL-6 mediated cell viability/proliferation and glycolysis in pancreatic cancer cells. Consistently, other IL-6/GP130 inhibitors SC144 and evista showed similar inhibition of IL-6 stimulated cell viability, cell proliferation and glycolysis. Furthermore, all three IL-6/GP130 inhibitors reduced the colony forming ability of pancreatic cancer cells. CONCLUSION: Our findings demonstrated that IL-6 stimulates pancreatic cancer cell proliferation, survival and glycolysis, and supported persistent IL-6 signaling is a viable therapeutic target for pancreatic cancer using IL-6/GP130 inhibitors. PMID- 29714142 TI - Efficacy and safety of antigen-specific immunotherapy in the treatment of patients with non-small-cell lung cancer: a systematic review and meta-analysis. AB - BACKGROUND AND OBJECTIVE: We performed this systematic review and meta-analysis to assess the efficacy and safety of antigen-specific immunotherapy (Belagenpumatucel-L, MAGE-A3, L-BLP25, and TG4010) in the treatment of patients with non-small-cell lung cancer (NSCLC). METHOD: A comprehensive literature search on PubMed, Embase, and Web of Science were conducted. Eligible studies were clinical trials of patients with NSCLC who received the antigen-specific immunotherapy. Pooled hazard ratios (HRs) with 95% confidence intervals (95%CIs) were calculated for overall survival (OS), progression free survival (PFS). Pooled risk ratios (RRs) were calculated for overall response rate (ORR) and the incidence of adverse events. RESULTS: In total, six randomized controlled trials (RCTs) with 4,806 patients were included. Pooled results showed that, antigen specific immunotherapy did not significantly prolong OS (HR=0.92, 95%CI: 0.83, 1.01; P=0.087) and PFS (HR=0.93, 95%CI: 0.85, 1.01; P=0.088), but improved ORR (RR=1.72, 95%CI: 1.11, 2.68; P=0.016). Subgroup analysis based on treatment agents showed that, tecemotide was associated with a significant improvement in OS (HR=0.85, 95%CI: 0.74, 0.99; P=0.03) and PFS (HR=0.70, 95%CI: 0.49, 0.99, P=0.044); TG4010 was associated with an improvement in PFS (HR=0.87, 95%CI: 0.75, 1.00, P=0.058). In addition, NSCLC patients who were treated with antigen specific immunotherapy exhibited a significantly higher incidence of adverse events than those treated with other treatments (RR=1.11, 95%CI: 1.00, 1.24; P=0.046). CONCLUSION: Our study demonstrated the clinical survival benefits of tecemotide and TG4010 in the treatment of NSCLC. However, these evidences might be limited by potential biases. Therefore, further well-conducted, large-scale RCTs are needed to verify our findings. PMID- 29714143 TI - Cutaneous Application of Celecoxib for Inflammatory and Cancer Diseases. AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) and particularly selective cyclooxygenase-2 (COX-2) inhibitors such as celecoxib (Cxb) are considered promising cancer chemopreventive for colon, breast, prostate, lung, and skin cancers. However, the clinical application to the prevention is limited by concerns about safety, potential to serious toxicity (mainly for healthy individuals), efficacy and optimal treatment regimen. Cxb exhibits advantages as potent anti-inflammatory and gastrointestinal tolerance compared with conventional NSAID's. Recent researches suggest that dermatological formulations of Cxb are more suitable than oral administration in treatment of cutaneous disease, including skin cancer. To date optimism has been growing regarding the exploration of the topical application of Cxb (in the prevention of skin cancers and treatment of cutaneous inflammation) or transdermal route reducing risks of systemic side effects. OBJECTIVE: This paper briefly summarizes our current knowledge of the development of the cutaneous formulations or delivery systems for Cxb as anti-inflammatory drug (for topical or transdermal application) as well its chemopreventive properties focused on skin cancer. CONCLUSION: new perspectives emerge from the growing knowledge, bringing innovative techniques combining the action of Cxb with other substances or agents which act in a different way, but complementary, increasing the efficacy and minimizing toxicity. PMID- 29714144 TI - Epigenetics in Metastatic Breast Cancer: Its Regulation and Implications in Diagnosis, Prognosis and Therapeutics. AB - Despite advances in the treatment regimen, the high incidence rate of breast cancer (BC) deaths is mostly caused by metastasis. Recently, the aberrant epigenetic modifications, which involve DNA methylation, histone modifications and microRNA (miRNA) regulations become attractive targets to treat metastatic breast cancer (MBC). In this review, the epigenetic alterations of DNA methylation, histone modifications and miRNA regulations in regulating MBC is discussed. The preclinical and clinical trials of epigenetic drugs such as the inhibitor of DNA methyltransferase (DNMTi) and the inhibitor of histone deacetylase (HDACi), as a single or combined regimen with other epigenetic drug or standard chemotherapy drug to treat MBCs are discussed. The combined regimen of epigenetic drugs or with standard chemotherapy drugs enhance the therapeutic effect against MBC. Evidences that epigenetic changes could have implications in diagnosis, prognosis and therapeutics for MBC are also presented. Several genes have been identified as potential epigenetic biomarkers for diagnosis and prognosis, as well as therapeutic targets for MBC. Endeavors in clinical trials of epigenetic drugs against MBC should be continued although limited success has been achieved. Future discovery of epigenetic drugs from natural resources would be an attractive natural treatment regimen for MBC. Further research is warranted in translating research into clinical practice with the ultimate goal of treating MBC by epigenetic therapy in the near future. PMID- 29714145 TI - Biological activity of the novel vinca alkaloids 4-chlorochablastine and 4 chlorochacristine AB - Vinca alkaloids are important cancer drugs belonging to the class of antimitotic agents. The most commonly used substances are vinblastine and vincristine, other compounds are vinorelbine and vinflunine. All of them are very effective drugs but their use is limited by severe side-effects including neurotoxicity and bone marrow depression. Therefore, it is very important to develop novel vinca alkaloids with similar efficacy but lower toxicity. Here, we analyzed two new compounds, 4-chlorochablastine and 4-chlorochacristine, with regard to their biological activity. These novel compounds were applied to a leukemia cell line at clinically relevant concentrations. For comparison, the established vinca alkaloids vinblastine, vincristine, vinorelbine, and vinflunine were also tested. Both novel substances decreased cellular proliferation. Apoptosis was found to be increased using two different methods reflecting early and late apoptosis. Cell cycle analysis revealed a clear decrease in G1-cells and an increase in G2/M cells indicating an arrest in mitosis. In general, 4-chlorochablastine and 4 chlorochacristine caused these effects at concentrations higher than those needed for vinblastine, vincristine, and vinorelbine, but the potency was approximately in the range of vinflunine. Taken together, the results show first indications that these novel vinca alkaloids might be effective and that they warrant further analysis. PMID- 29714146 TI - PRDM14: a potential target for cancer therapy. AB - PRDM14 belongs to PR domain-containing (PRDM) family. Although a precise understanding is focused on the function of PRDM14 maintains stemness and pluripotency in embryonic stem cells via epigenetic mechanisms, there are growing experimental evidences have been linked PRDM14 to human cancers. In adults, PRDM14 is low expression in human tissues. Aberrant PRDM14 expression is connected with various malignant histological types and solid cancers, where PRDM14 can act as a driver of oncogenic processes. Overexpression of RPDM14 enhanced cancer cells growth and reduced cancer cells sensitive to chemotherapeutic agents. Rather, reducing the expression of PRDM14 in cancer cells can enhance the therapeutic sensitivity of drugs to cancer cells, suggesting that aberrant PRDM14 may have a carcinogenic characteristic in tumor therapy and as a new molecular target. This review summarizes the structure and oncogenic properties of PRDM14 in different malignancies and suggests that PRDM14 may be a potential therapeutic molecular target for tumor treatment. PMID- 29714147 TI - Epithelial In vitro Differentiation of Mesenchymal Stem Cells. AB - Mesenchymal stem cells or mesenchymal stromal cells (MSCs) are non-hematopoietic stromal cells that reside in many human organs and have been isolated from a variety of adult or fetal tissues such as adipose tissue, bone marrow and umbilical cord Wharton's jelly, among others. Because they are a heterogeneous population, International Society for Cellular Therapy has established 3 minimum criteria to characterize MSCs in vitro: i) adherence to plastic, ii) differentiation potential (osteogenic, chondrogenic and adipogenic lineages) and iii) expression of specific surface antigens (CD73+, CD90+, CD105+, CD34-, CD45-, CD11b-, CD14-, CD19-, CD79a-, HLA-DR-). Because of these characteristics, MSCs are useful for different applications and studies, most of them related with regenerative biomedicine. Epithelial in vitro differentiation of MSCs, for clinical use, is one of the main objectives in this field, due to, on the one hand, the difficulties to establish epithelial cell cultures and, on the other hand, the immunomodulatory capacity of MSCs that could increase the success of transplantation. According to this and the information compiled from bibliography, production of epithelial cells differentiated in vitro from MSCs is a complex procedure and a lot of techniques and culture media are necessary to explore. The objective of this review is to show the different methods of epithelial in vitro differentiation and remark the need to further study for being capable of establishing specific cell lines of epithelial cells differentiated from autogenic or allogenic MSCs. PMID- 29714148 TI - Synthesis and Evaluation of 2-benzylidene-1-tetralone Derivatives for Monoamine Oxidase Inhibitory Activity. AB - BACKGROUND: Chalcone has been identified as a promising lead for the design of Monoamine Oxidase (MAO) inhibitors. This study attempted to discover potent and selective chalcone-derived MAO inhibitors by synthesising a series consisting of various cyclic chalcone derivatives. The cyclic chalcones were selected based on the possibility that their restricted structures would confer a higher degree of MAO isoform selectivity, and included the following chemical classes: 1-indanone, 1- tetralone, 1-benzosuberone, chromone, thiochromone, 4-chromanone and 4 thiochromanone. METHODS: The cyclic chalcone derivatives were synthesised via a one-pot Claisen-Schmidt condensation reaction. The MAO inhibitory properties of the chalcone derivatives were evaluated with the recombinant human MAO-A and MAO B enzymes and the potencies were expressed as the IC50 values. A selected inhibitor was docked into an active site model of MAO-B. RESULTS: The results showed that the cyclic chalcones are in general good potency, and in most instances specific inhibitors of the MAO-B isoform. Among these compounds, the 4 chromanone derivative was the most potent MAO-B inhibitor with an IC50 value of 0.156 uM. To further investigate the MAO inhibition of cyclic chalcones, a series of twenty-three 2-benzylidene-1-tetralone derivatives were synthesised and evaluated as MAO inhibitors. Most 2-benzylidene-1-tetralones possess good inhibitory activity and specificity for MAO-B with the most potent inhibitor displaying an IC50 value of 0.0064 uM, while the most potent MAO-A inhibitor possessed an IC50 value of 0.754 uM. CONCLUSION: This study thus shows that certain cyclic chalcones are human MAO-B inhibitors, compounds that could be suitable for the treatment of neurodegenerative disorders such as Parkinson's disease. PMID- 29714149 TI - Mupirocin resistance among Methicillin resistant Staphylococcus isolates in a tertiary health care center. AB - INTRODUCTION-Antibiotics have revolutionized medicine in many respects and countless lives have been saved, their discovery was a turning point in human history. Regrettably, the use of these wonder drugs has been accompanied by the rapid appearance of resistant strains. AIMS &OBJECTIVES-This study was carried out to with the aim to determine the rates of high-level and low-level mupirocin resistance in MRSA, to study the antimicrobial resistance pattern of mupirocin resistant MRSA and mupirocin-sensitive MRSA. MATERIAL &METHOD- This study was conducted on 100 Staphylococcus isolates recovered from pus samples.Conventional disc diffusion tests were used for detection of mupirocin resistance (mupirocin 5 MUg and 200MUg for detecting the MuL and the MuH strains).Susceptibility pattern of following antimicrobial agents routinely used for gram positive agents were also tested. RESULTS-Outof 100 Staphylococcus isolates processed during the study period in the department of microbiology, 74 were S.aureus and 26 were CoNS.Among S.aureus43.4% were MRSA and 56.6% were MSSA, whereas among CoNS 42% were methicillin resistant and 58% were methicillin sensitive.We observed 6.75% of high level mupirocin resistance among S aureus and 19.23% among CoNS. CONCLUSION We conclude that an increase in in-hospital mupirocin use is associated with a rapid increase in high-level resistance to mupirocin and resistance to other antibiotics in CoNS. This may have direct clinical consequences in the treatment of prosthetic infections and may, in the long term, increase the risk of high level resistance to mupirocin in S. aureus. PMID- 29714150 TI - Cinnamon Polyphenol Extract Exerts Neuroprotective Activity in Traumatic Brain Injury in Male Mice. AB - BACKGROUND: Cinnamon polyphenol extract is a traditional spice commonly used in different areas of the world for the treatment of different disease conditions which are associated with inflammation and oxidative stress. Despite many preclinical studies showing the anti-oxidative and antiinflammatory effects of cinnamon, the underlying mechanisms in signaling pathways via which cinnamon protects the brain after brain trauma remained largely unknown. However, there is still no preclinical study delineating the possible molecular mechanism of neuroprotective effects cinnamon polyphenol extract in Traumatic Brain Injury (TBI). The primary aim of the current study was to test the hypothesis that cinnamon polyphenol extract administration would improve the histopathological outcomes and exert neuroprotective activity through its antioxidative and anti inflammatory properties following TBI. METHODS: To investigate the effects of cinnamon, we induced brain injury using a cold trauma model in male mice that were treated with cinnamon polyphenol extract (10 mg/kg) or vehicle via intraperitoneal administration just after TBI. Mice were divided into two groups: TBI+vehicle group and TBI+ cinnamon polyphenol extract group. Brain samples were collected 24 h later for analysis. RESULTS: We have shown that cinnamon polyphenol extract effectively reduced infarct and edema formation which were associated with significant alterations in inflammatory and oxidative parameters, including nuclear factor-kappaB, interleukin 1-beta, interleukin 6, nuclear factor erythroid 2-related factor 2, glial fibrillary acidic protein, neural cell adhesion molecule, malondialdehyde, superoxide dismutase, catalase and glutathione peroxidase. CONCLUSION: Our results identify an important neuroprotective role of cinnamon polyphenol extract in TBI which is mediated by its capability to suppress the inflammation and oxidative injury. Further, specially designed experimental studies to understand the molecular cross-talk between signaling pathways would provide valuable evidence for the therapeutic role of cinnamon in TBI and other TBI related conditions. PMID- 29714151 TI - Vitamin D's Molecular Action Mechanism in Attention-Deficit/ Hyperactivity Disorder: A Review of Evidence. AB - BACKGROUND & OBJECTIVE: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous disorder characterized by hyperactivity, impulsivity and inattention. Children with ADHD have challenges with learning, behavior and psychosocial adjustments, sometimes retained into adulthood. The exact etiology of ADHD is unknown, and the pathophysiology of this disease is complex. Several hypotheses have been raised regarding ADHD pathogenesis, including serotonergic and catecholaminergic signalling pathway dysfunction, neurotropic-related factors, oxidative stress, or neuroinflammation. Vitamin D has an important protective effect against inflammation, oxidative stress and certain neurotrophic factors and neurotransmitter, as well as facilitating dopaminergic and serotonergic functions. Vitamin D levels in children with ADHD are lower than in healthy children, and thus may be involved in the pathogenesis of ADHD. These observations, therefore, confirm the neuroprotective role of vitamin D through multiple molecular mechanisms and can be considered as a promising target in understanding ADHD pathology. CONCLUSION: In this context, the present study reviews the molecular pathways of vitamin D in ADHD patients. PMID- 29714152 TI - The Need to Move from Describing to Evaluating the Effectiveness of Indigenous Drug and Alcohol Residential Rehabilitation Services: A Systematic Review. AB - BACKGROUND AND OBJECTIVES: Despite the importance of Indigenous drug and alcohol residential rehabilitation, the knowledge supporting these services is limited. This paper aims to: (i) identify the research output related to Indigenous drug and alcohol residential rehabilitation services; (ii) classify identified studies according to their methodology; and (iii) describe key characteristics of clients and services, and critique the research methods. METHODS: A PRISMA compliant search of 10 electronic databases for studies of Indigenous drug and alcohol residential rehabilitation services from Australia, United States, Canada and New Zealand, published between 1 January 2000 and 28 March 2016, was conducted. RESULTS: Of the 38 relevant studies, 20 were service descriptions, one was a thesis, 16 described treatment or client characteristics and one was a pre/post evaluation. No systematic reviews or the development or evaluation of measures was identified, with reviewed studies found to be of relatively low methodological quality. CONCLUSION: There are few published studies on Indigenous drug and alcohol residential rehabilitation services, an average of one paper per annum internationally, and only one treatment outcome evaluation. Three key features of the reviewed papers included (i) studied services were mostly located in regional areas; (ii) services provided multi-component programs, with little alignment between the models of care of other services; and (iii) the majority used qualitative, rather than quantitative methods. Client outcomes will likely improve if future research can establish best-practice, culturally acceptable models of care and increase the application of evidence-based, culturally validated quantitative evaluation measures to complement existing qualitative research. PMID- 29714153 TI - Thiamine and Alcohol for Brain Pathology: Super-imposing or Different Causative Factors for Brain Damage? AB - BACKGROUND: Drinking more than the recommended limits is a worldwide emerging problem, difficult to circumscribe, and alcohol-related brain damages are an under-recognized health problem. Alcohol-cognitive disruption can be considered as transient and recoverable if the alcohol consumption is limited and occasional; if not, it can progress to the so-called Alcohol-Related Dementia (ARD), or to the Wernicke encephalopathy, or it can even induce the Korsakoff syndrome, an irreversible and long-lasting medical condition. ARD still remains poorly diagnosed and addressed, despite having increased research interest being a frustrating condition, a relatively non-progressive, or even partially reversible condition in abstinent ex-drinkers. On the contrary, Wernicke encephalopathy, with its neurological symptoms (ocular coordination imbalance and gait ataxia), is a dramatic medical condition, potentially lethal which can lead towards Korsakoff dementia. The alcohol consumption is a strong reinforcing condition of the thiamine deficit, the main biochemical determinant factor that starts the cascade of the brain irreversible damaging events. CONCLUSION: Our review focuses on the possible common neural pathways of this three condition, on the biochemical basis of the damages, and tries to underline the strong need of better understanding the pathogenesis of the brain lesions, including epigenetics and the nutritional aspects of the problem. PMID- 29714154 TI - High Prevalence of Abandoned Needlesticks from Injecting Drug Users in Milton Keynes, UK: Analysing Access to Needle Exchange Centres and Drug Dependency Services. AB - BACKGROUND: In 2015, Milton Keynes (MK) Council waste management team shows an increase in the numbers of abandoned used needles being found across MK. MK is an area of high Human Immunodeficiency Virus (HIV) prevalence and high Hepatitis C (HCV) in People Who Inject Drugs (PWID), the overriding concern was for the safety of the public. METHODS: Analysis of data collection to understand the scale and spread of the problem, preventing/ reducing the incidence of abandoned needles and looking at access to the designated Drug Dependency Unit (DDU) and the Blood Borne Virus (BBV) service. Through data mapping, hotspot areas of used needles abandonment were analysed. RESULTS: Peak needle stick finds were in March and June 2015 mainly in areas of social deprivation and marginalisation where designated needle exchange points were identified. 174 reports of abandoned needles were reported between January 2015 and November 2015 with a total of 2379 individual needles. 87% of the total numbers of needles were found in just 8 estates. CONCLUSION: Tackling the issue of abandoned needles effectively should be done through a targeted, multi-agency approach. Reductions in needlestick abandonment can be strengthened through improving access to needle exchange points, DDU and BBV services, delivering high-quality harm reduction interventions and using data mapping in order to identify and target hot spot areas. PMID- 29714155 TI - Investigating the Isolation and Amplification of microRNAs for Forensic Body Fluid Identification. AB - BACKGROUND: The discovery of forensic DNA typing evolved molecular biology far beyond what could have been expected in terms of its forensic application, and now there exists other developments in molecular biology which are ready for application to forensic challenges. One such challenge is the identification of the body fluid source of stains recovered from evidence items and crime scenes. Currently, there are significant efforts in the research field to develop novel methods for the molecular identification of body fluids, with microRNAs (miRNAs) revealing great potential. MiRNAs have been shown to have high tissue specificity and are less susceptible to degradation as a result of their small size, which infers great advantages to their potential role for identifying forensically relevant body fluids. OBJECTIVE: This study investigated the isolation and amplification of miRNAs from forensically relevant body fluids. METHOD: Venous blood, menstrual blood, semen, saliva, and vaginal material samples were extracted using; miRNeasy(r) mini kit (Qiagen), mirVanaTM miRNA isolation kit (Ambion), and a modified mir- VanaTM method, and the quality/quantity of isolated miRNA was determined. miRNAs previously identified to show specificity for particular forensically relevant body fluids were examined. Real Time Quantitative PCR (RT-qPCR) was performed targeting 5 miRNAs of interest, miR-451, miR- 412, miR-891a, miR-205 and miR-124a. RESULTS: This study identified the miRNeasy(r) mini kit as the optimal method of the three methods investigated for the extraction of miRNAs from body fluids and further validates a selection of miRNAs previously suggested as potential biomarkers. CONCLUSION: This research highlights the potential of miRNAs as novel markers for the identification of forensically relevant body fluids. PMID- 29714156 TI - Case Report: Atypical Cutaneous Manifestations of Tularemia after Horsefly Bite. AB - Tularemia is an infectious zoonosis caused by Francisella tularensis, an aerobic, noncapsulated, Gram-negative coccobacillus. It is more common in the northern hemisphere, and there are sporadic reports in non-endemic areas. The bacterium is usually transmitted by the bite or feces of a tick or other arthropods such as mosquitoes and horseflies. We report a case of an Italian patient with tularemia after a horsefly bite. PMID- 29714157 TI - Factors Associated with Wuchereria bancrofti Microfilaremia in an Endemic Area of Mali. AB - Although Wuchereria bancrofti (Wb), the causative agent of lymphatic filariasis, is endemic throughout Mali, the prevalence of Wb microfilaremia (Mf) can vary widely between villages despite similar prevalence of infection as assessed by circulating antigen. To examine this variation, cross-sectional data obtained during screening prior to an interventional study in two neighboring villages in Mali were analyzed. The overall prevalence of Wb, as assessed by Wb CAg (circulating antigen), was 50.3% among 373 participants, aged 14-65. Wuchereria bancrofti Mf-positive and negative individuals appeared randomly distributed across the two villages (Moran's I spatial statistic = -0.01, Z score =0.1, P>0.05). Among the 187 subjects positive for Wb CAg, 117 (62.5%) had detectable Mansonella perstans microfilaremia (Mp Mf) and 64 (34.2%) had detectable Wb microfilaremia. The prevalence of Mp microfilaremia was 73.4% in the Wb Mf positive group (as compared to 56.9% in the Wb Mf-negative group; p=0.01), and median Wb Mf load was increased in co-infected subjects (267Mf/ml vs 100 Mf/ml; p<0.001). In multivariate analysis, village of residence, Mp Mf positivity and gender were significantly associated with Wb Mf positivity. After controlling for age, gender, and village of residence, the odds of being Wb Mf positive was 2.67 times higher in Mp positive individuals (95% confidence interval [1.42-5.01]). Given the geographical overlap between Mp and Wb in Africa, a better understanding of the distribution and prevalence of Mp could assist national lymphatic filariasis control programs in predicting areas of high Wb Mf prevalence that may require closer surveillance. PMID- 29714158 TI - Mosquito Infectivity and Parasitemia after Controlled Human Malaria Infection. AB - Controlled Human Malaria Infection (CHMI) has become an increasingly important tool for the evaluation of drugs and vaccines. Controlled Human Malaria Infection has been demonstrated to be a reproducible model; however, there is some variability in time to onset of parasitemia between volunteers and studies. At our center, mosquitoes infected with Plasmodium falciparum by membrane feeding have variable and high salivary gland sporozoite load (mean 78,415; range 26,500 160,500). To determine whether this load influences parasitemia after CHMI, we analyzed data from 13 studies. We found no correlation between the sporozoite load of a mosquito batch and time to parasitemia or parasite density of first wave parasitemia. These findings support the use of infected mosquito bite as a reproducible means of inducing P. falciparum infection and suggest that within this range, salivary gland sporozoite load does not influence the stringency of a CHMI. PMID- 29714159 TI - Burden and Risk Factors of Antimicrobial Use in Children Less Than 5 Years of Age with Diarrheal Illness in Rural Bangladesh. AB - Antimicrobial overuse contributes to antimicrobial resistance. Empiric use of antimicrobials for diarrheal illness is warranted only in a minority of cases, because of its self-limiting nature and multifactorial etiology. This study aims to describe the factors contributing to antimicrobial overuse for diarrheal disease among children less than 5 years of age in rural Bangladesh. A total of 3,570 children less than 5 years of age presenting with diarrhea in a tertiary level hospital were enrolled in the study. The rate of antimicrobial use at home was 1,395 (39%), compared with 2,084 (89%) during a hospital visit. In a multivariate analysis, factors associated with antimicrobial use at home included residence located more than 5 miles from a hospital; use of zinc and oral rehydration salts at home; vomiting; greater than 10 stools per 24 hours; diarrheal duration greater than 3 days; and rotavirus diarrhea (P < 0.05 for all). Characteristics of children more likely to be given antimicrobials in a health-care setting included greater than 10 stools per 24 hours; duration of diarrhea greater than 3 days; use of antimicrobials before hospital presentation; fever (>= 37.8 degrees C); rectal straining; and Shigella infection (P < 0.05 for all). The most commonly used drugs in rotavirus diarrhea were azithromycin and erythromycin, both before hospital presentation and during hospital admission. Our study underscores the importance of diligent vigilance on the rationale use of antimicrobials both at home and in health-care facilities with a special concern for children less than 5 years of age living in rural Bangladesh. PMID- 29714160 TI - Increased Human Incidence of West Nile Virus Disease near Rice Fields in California but Not in Southern United States. AB - Anthropogenic land use change, including agriculture, can alter mosquito larval habitat quality, increase mosquito abundance, and increase incidence of vector borne disease. Rice is a staple food crop for more than half of the world's population, with ~1% of global production occurring within the United States (US). Flooded rice fields provide enormous areas of larval habitat for mosquito species and may be hotspots for mosquito-borne pathogens, including West Nile virus (WNV). West Nile virus was introduced into the Americas in 1999 and causes yearly epidemics in the US with an average of approximately 1,400 neuroinvasive cases and 130 deaths per year. We examined correlations between rice cultivation and WNV disease incidence in rice-growing regions within the US. Incidence of WNV disease increased with the fraction of each county under rice cultivation in California but not in the southern US. We show that this is likely due to regional variation in the mosquitoes transmitting WNV. Culex tarsalis was an important vector of WNV in California, and its abundance increased with rice cultivation, whereas in rice-growing areas of the southern US, the dominant WNV vector was Culex quinquefasciatus, which rarely breeds in rice fields. These results illustrate how cultivation of particular crops can increase disease risk and how spatial variation in vector ecology can alter the relationship between land cover and disease. PMID- 29714161 TI - Ventricular Neurocysticercosis: A Severe Form of the Disease Waiting for Well Designed Therapeutic Trials. PMID- 29714162 TI - Exhaled Nitric Oxide is Not a Biomarker for Pulmonary Tuberculosis. AB - To reduce transmission of tuberculosis (TB) in resource-limited countries where TB remains a major cause of mortality, novel diagnostic tools are urgently needed. We evaluated the fractional concentration of exhaled nitric oxide (FeNO) as an easily measured, noninvasive potential biomarker for diagnosis and monitoring of treatment response in participants with pulmonary TB including multidrug resistant-TB in Lima, Peru. In a longitudinal study however, we found no differences in baseline median FeNO levels between 38 TB participants and 93 age-matched controls (13 parts per billion [ppb] [interquartile range (IQR) = 8 26] versus 15 ppb [IQR = 12-24]), and there was no change over 60 days of treatment (15 ppb [IQR = 10-19] at day 60). Taking this and previous evidence together, we conclude FeNO is not of value in either the diagnosis of pulmonary TB or as a marker of treatment response. PMID- 29714163 TI - Congenital Chagas Disease in the United States: Cost Savings through Maternal Screening. AB - Chagas disease, caused by Trypanosoma cruzi, is transmitted by insect vectors through transfusions, transplants, insect feces in food, and from mother to child during gestation. Congenital infection could perpetuate Chagas disease indefinitely, even in countries without vector transmission. An estimated 30% of infected persons will develop lifelong, potentially fatal, cardiac or digestive complications. Treatment of infants with benznidazole is highly efficacious in eliminating infection. This work evaluates the costs of maternal screening and infant testing and treatment of Chagas disease in the United States. We constructed a decision-analytic model to find the lower cost option, comparing costs of testing and treatment, as needed, for mothers and infants with the lifetime societal costs without testing and the consequent morbidity and mortality due to lack of treatment or late treatment. We found that maternal screening, infant testing, and treatment of Chagas disease in the United States are cost saving for all rates of congenital transmission greater than 0.001% and all levels of maternal prevalence above 0.06% compared with no screening program. Newly approved diagnostics make universal screening cost saving with maternal prevalence as low as 0.008%. The present value of lifetime societal savings due to screening and treatment is about $634 million saved for every birth year cohort. The benefits of universal screening for T. cruzi as part of routine prenatal testing far outweigh the program costs for all U.S. births. PMID- 29714164 TI - Case Report: Hemianopia: From Suspected Glioblastoma to the Diagnosis of Ectopic Schistosomiasis Haematobium Infection in a Traveler Returning from the Republic of the Congo. AB - Schistosomiasis due to Schistosoma haematobium is a widespread disease usually affecting the urinary tract associated with hematuria and kidney disorders. Neurological damage is rarely reported and symptoms are nonspecific and may suggest brain tumors such as glioma. We describe the first double ectopic haematobium schistosomiasis case involving the brain and intestine. PMID- 29714167 TI - Virological and immunological responses to raltegravir and dolutegravir in the gut-associated lymphoid tissue of HIV-infected men and women. AB - BACKGROUND: Raltegravir (RTG) and dolutegravir (DTG) have different pharmacokinetic patterns in the gastrointestinal tract. To determine if this results in pharmacodynamic differences, we compared HIV RNA, HIV DNA and immunological markers in gut-associated lymphoid tissue (GALT) of HIV-infected participants receiving RTG or DTG with tenofovir+emtricitabine (TDF/FTC). METHODS: GALT specimens from the terminal ileum, splenic flexure and rectum were obtained by colonoscopy at a single time point in 20 adults treated with RTG (n=10) or DTG (n=10) with HIV RNA <50 copies/ml. Flow cytometry, drug concentrations, and HIV RNA and DNA were analysed in tissue. CD4/8+ T-cells were tested for gammadelta TCR, and markers of T-cell activation and exhaustion. Data are reported as median (Q1-Q3). RESULTS: A total of 15 men and 5 women were enrolled. There was no difference in time since HIV diagnosis for those on RTG (9.5 [4-22] years) and DTG (17 [1-24] years; P=0.6), although time on RTG (5.4 [2.3-6.7] years) was greater than DTG (1.0 [0.1-1.5] years; P<0.001). Concentrations of RTG and DTG in rectal tissue were similar to previous reports: median tissue:plasma ratio was 11.25 for RTG and 0.44 for DTG. RNA:DNA ratios were 1.14 (0.18-5.10) for the RTG group and 0.90 (0.30-18.87) for the DTG group (P=0.95). No differences (P>=0.1) between CD4+ and CD8+ T-cell markers were found. CONCLUSIONS: RTG produced higher tissue exposures than DTG, but no significant differences in GALT HIV RNA, DNA or most immunological markers were observed. ClinicalTrials.gov NCT02218320. PMID- 29714165 TI - Distinct chromatin functional states correlate with HIV latency reactivation in infected primary CD4+ T cells. AB - Human immunodeficiency virus (HIV) infection is currently incurable, due to the persistence of latently infected cells. The 'shock and kill' approach to a cure proposes to eliminate this reservoir via transcriptional activation of latent proviruses, enabling direct or indirect killing of infected cells. Currently available latency-reversing agents (LRAs) have however proven ineffective. To understand why, we used a novel HIV reporter strain in primary CD4+ T cells and determined which latently infected cells are reactivatable by current candidate LRAs. Remarkably, none of these agents reactivated more than 5% of cells carrying a latent provirus. Sequencing analysis of reactivatable vs. non-reactivatable populations revealed that the integration sites were distinguishable in terms of chromatin functional states. Our findings challenge the feasibility of 'shock and kill', and suggest the need to explore other strategies to control the latent HIV reservoir. PMID- 29714168 TI - In pursuit of barrierless transition metal dichalcogenides lateral heterojunctions. AB - There is an increasing need to understand interfaces between two-dimensional materials to realize an energy efficient boundary with low contact resistance and small heat dissipation. In this respect, we investigated the impact of charge and substitutional atom doping on the electronic transport properties of the hybrid metallic-semiconducting lateral junctions, formed between metallic (1T and 1T d ) and semiconducting (1H) phases of MoS2 by means of first-principles and non equilibrium Green function formalism based calculations. Our results clearly revealed the strong influence of the type of interface and crystallographic orientation of the metallic phase on the transport properties of these systems. The Schottky barrier height, which is the dominant mechanism for contact resistance, was found to be as large as 0.63 eV and 1.19 eV for holes and electrons, respectively. We found that armchair interfaces are more conductive as compared to zigzag termination due to the presence of the metallic Mo zigzag chains that are directed along the transport direction. In order to manipulate these barrier heights we investigated the influence of electron doping of the metallic part (i.e. 1T d -MoS2). We observed that the Fermi level of the hybrid system moves towards the conduction band of semiconducting 1H-MoS2 due to filling of 4d-orbital of metallic MoS2, and thus the Schottky barrier for electrons decreases considerably. Besides electron doping, we also investigated the effect of substitutional doping of metallic MoS2 by replacing Mo atoms with either Re or Ta. Due to its valency, Re (Ta) behaves as a donor (acceptor) and reduces the Schottky barrier for electrons (holes). Since Re and Ta based transition metal dichalcogenides crystallize in either the 1T d or 1T phase, substitutional doping with these atom favors the stabilization of the 1T d phase of MoS2. Co-doping of hybrid structure results in an electronic structure, which facilities easy dissociation of excitons created in the 1H part. PMID- 29714166 TI - Differential inputs to striatal cholinergic and parvalbumin interneurons imply functional distinctions. AB - Striatal cholinergic (ChAT) and parvalbumin (PV) interneurons exert powerful influences on striatal function in health and disease, yet little is known about the organization of their inputs. Here using rabies tracing, electrophysiology and genetic tools, we compare the whole-brain inputs to these two types of striatal interneurons and dissect their functional connectivity in mice. ChAT interneurons receive a substantial cortical input from associative regions of cortex, such as the orbitofrontal cortex. Amongst subcortical inputs, a previously unknown inhibitory thalamic reticular nucleus input to striatal PV interneurons is identified. Additionally, the external segment of the globus pallidus targets striatal ChAT interneurons, which is sufficient to inhibit tonic ChAT interneuron firing. Finally, we describe a novel excitatory pathway from the pedunculopontine nucleus that innervates ChAT interneurons. These results establish the brain-wide direct inputs of two major types of striatal interneurons and allude to distinct roles in regulating striatal activity and controlling behavior. PMID- 29714169 TI - Porous Si nanowires for highly selective room-temperature NO2 gas sensing. AB - We report the room-temperature sensing characteristics of Si nanowires (NWs) fabricated from p-Si wafers by a metal-assisted chemical etching method, which is a facile and low-cost method. X-ray diffraction was used to the the study crystallinity and phase formation of Si NWs, and product morphology was examined using scanning electron microscopy (SEM) and transmission electron microscopy (TEM). After confirmation of Si NW formation via the SEM and TEM micrographs, sensing tests were carried out at room temperature, and it was found that the Si NW sensor prepared from Si wafers with a resistivity of 0.001-0.003 Omega.cm had the highest response to NO2 gas (Rg/Ra = 1.86 for 50 ppm NO2), with a fast response (15 s) and recovery (30 s) time. Furthermore, the sensor responses to SO2, toluene, benzene, H2, and ethanol were nearly negligible, demonstrating the excellent selectivity to NO2 gas. The gas-sensing mechanism is discussed in detail. The present sensor can operate at room temperature, and is compatible with the microelectronic fabrication process, demonstrating its promise for next generation Si-based electronics fused with functional chemical sensors. PMID- 29714170 TI - Synaptic behaviors of thin-film transistor with a Pt/HfO x /n-type indium-gallium zinc oxide gate stack. AB - We report a variety of synaptic behaviors in a thin-film transistor (TFT) with a metal-oxide-semiconductor gate stack that has a Pt/HfO x /n-type indium-gallium zinc oxide (n-IGZO) structure. The three-terminal synaptic TFT exhibits a tunable synaptic weight with a drain current modulation upon repeated application of gate and drain voltages. The synaptic weight modulation is analog, voltage-polarity dependent reversible, and strong with a dynamic range of multiple orders of magnitude (>104). This modulation process emulates biological synaptic potentiation, depression, excitatory-postsynaptic current, paired-pulse facilitation, and short-term to long-term memory transition behaviors as a result of repeated pulsing with respect to the pulse amplitude, width, repetition number, and the interval between pulses. These synaptic behaviors are interpreted based on the changes in the capacitance of the Pt/HfO x /n-IGZO gate stack, the channel mobility, and the threshold voltage that result from the redistribution of oxygen ions by the applied gate voltage. These results demonstrate the potential of this structure for three-terminal synaptic transistor using the gate stack composed of the HfO x gate insulator and the IGZO channel layer. PMID- 29714171 TI - Superconductivity in Li-intercalated bilayer arsenene and hole-doped monolayer arsenene: a first-principles prediction. AB - Using first-principles calculations, we find Li-intercalated bilayer arsenene with AB stacking is dynamically stable, which is different from pristine bilayer with AA stacking. Electron-phonon coupling of the stable Li-intercalated bilayer arsenene are dominated by the low frequency vibrational modes (E"(1), [Formula: see text](1), E'(1) and acoustic modes) and lead to an superconductivity with T c = 8.68 K with isotropical Eliashberg function. Small biaxial tensile strain (2%) can improve T c to 11.22 K due to the increase of DOS and phonon softening. By considering the fully anisotropic Migdal-Eliashberg theory, T c are found to be enhanced by 50% and exhibits a single anisotropic gap nature. In addition, considering its nearly flat top valence band which is favorable for high temperature superconductivity, we also explore the superconducting properties of hole-doped monolayer arsenene under different strains. the unstrained monolayer arsenene superconducts at T c = 0.22 K with 0.1 hole/cell doping. By applying 3% biaxial strain, T c can be lifted up strikingly to 6.69 K due to a strong Fermi nesting of the nearly flat band. Then T c decreases slowly with strain. Our findings provide another insight to realize 2D superconductivity and suggest that the strain is crucial to further enhance the transition temperature. PMID- 29714172 TI - Dielectric function, critical points, and Rydberg exciton series of WSe2 monolayer. AB - The complex dielectric function ([Formula: see text]) of WSe2 monolayer grown by atomic layer deposition is investigated using spectroscopic ellipsometry. Band structure parameters are obtained by standard line-shape analysis of the second energy-derivative of [Formula: see text] spectra. The fundamental band gap is observed at 2.26 eV, corresponds to transition between valence band (VB) maximum at the K point and conduction band (CB) minimum at Q point in the Brillouin zone (BZ). Two strong so-called A and B excitonic peaks in [Formula: see text] spectra originate from vertical transitions from spin-orbit split (0.43 eV) VB to CB at K point of the BZ. Binding energies of A and B exactions are 0.71 and 0.28 eV, respectively. Well resolved five excited excitons states has been detected within the spectral region between A and B. Energy profile of the Rydberg series shows significant deviation from the hydrogenic behavior, discussed in connection with the 2D hydrogen model. Results presented here will improve our understanding about the optical response of 2D materials and will help to design better optoelectronic applications and validate theoretical considerations. PMID- 29714173 TI - Bond compressibility and bond Gruneisen parameters of CdTe. AB - Extended x-ray absorption fine structure (EXAFS) at the Cd K edge and diffraction patterns have been measured on CdTe as a function of pressure from 100 kPa (1 bar) to 5 GPa using a cell with nano-polycrystalline diamond anvils and an x-ray focussing scanning spectrometer. Three phases-zincblende (ZB), mixed cinnabar-ZB and rocksalt (RS)-are well distinguished in different pressure intervals. The bond compressibility measured by EXAFS in the ZB phase is slightly smaller than the one measured by diffraction and decreases significantly faster when the pressure increases; the difference is attributed to the effect of relative vibrations perpendicular to the Cd-Te bond. The parallel mean square relative displacement (MSRD) decreases, the perpendicular MSRD increases when the pressure increases, leading to an increasing anisotropy of relative atomic vibrations. A constant-temperature bond Gruneisen parameter (GP) has been evaluated for the ZB phase and compared with the constant-pressure bond GP measured in a previous experiment; an attempt is made to connect the bond GPs measured by EXAFS and the more familiar thermodynamic GP and mode GPs; the comparisons suggest the inadequacy of the quasi-harmonic approximation to deal with the local vibrational properties sampled by EXAFS. PMID- 29714174 TI - SLS-2 - the upgrade of the Swiss Light Source. AB - An upgrade of the Swiss Light Source (SLS) is planned for 2021-2024 and includes the exchange of the existing storage ring by a new one providing about 40-50 times lower emittance in user operation mode. This will extend the performance of SLS in particular in the fields of coherent imaging, full-field tomography, soft X-ray angle-resolved photoelectron spectroscopy and resonant inelastic X-ray scattering. A science case and a conceptual design for the machine have been established. As a summary of these reports, the novel lattice design, undulator developments and scientific highlights are presented. PMID- 29714175 TI - Pulse intensity characterization of the LCLS nanosecond double-bunch mode of operation. AB - The recent demonstration of the 'nanosecond double-bunch' operation mode, i.e. two X-ray pulses separated in time between 0.35 and hundreds of nanoseconds and by increments of 0.35 ns, offers new opportunities to investigate ultrafast dynamics in diverse systems of interest. However, in order to reach its full potential, this mode of operation requires the precise characterization of the intensity of each X-ray pulse within each pulse pair for any time separation. Here, a transmissive single-shot diagnostic that achieves this goal for time separations larger than 0.7 ns with a precision better than 5% is presented. It also provides real-time monitoring feedback to help tune the accelerator parameters to deliver double pulse intensity distributions optimized for specific experimental goals. PMID- 29714176 TI - XFEL experiments: jitter of pump-probe time delays and pulse intensities. AB - Jitter of XFEL signals due to fluctuations in shot-to-shot time delays and intensities are explored in the frame of a statistical theory of X-ray diffraction from liquids. Deformed signals are calculated at different levels of pump-probe jitter. A new method is proposed to eliminate these distortions. PMID- 29714177 TI - A convolutional neural network-based screening tool for X-ray serial crystallography. AB - A new tool is introduced for screening macromolecular X-ray crystallography diffraction images produced at an X-ray free-electron laser light source. Based on a data-driven deep learning approach, the proposed tool executes a convolutional neural network to detect Bragg spots. Automatic image processing algorithms described can enable the classification of large data sets, acquired under realistic conditions consisting of noisy data with experimental artifacts. Outcomes are compared for different data regimes, including samples from multiple instruments and differing amounts of training data for neural network optimization. PMID- 29714178 TI - Hybrid modelling of a high-power X-ray attenuator plasma. AB - X-ray gas attenuators act as stress-free high-pass filters for synchrotron and free-electron laser beamlines to reduce the heat load in downstream optical elements without affecting other properties of the X-ray beam. The absorption of the X-ray beam triggers a cascade of processes that ionize and heat up the gas locally, changing its density and therefore the X-ray absorption. Aiming to understand and predict the behaviour of the gas attenuator in terms of efficiency versus gas pressure, a hybrid model has been developed, combining three approaches: an analytical description of the X-ray absorption; Monte Carlo for the electron thermalization; and a fluid treatment for the electron diffusion, recombination and excited-states relaxation. The model was applied to an argon filled attenuator prototype built and tested at the European Synchrotron Radiation Facility, at a pressure of 200 mbar and assuming stationary conditions. The results of the model showed that the electron population thermalizes within a few nanoseconds after the X-ray pulse arrival and it occurs just around the X-ray beam path, recombining in the bulk of the gas rather than diffusing to the attenuator walls. The gas temperature along the beam path reached 850 K for 770 W of incident power and 182 W m-1 of absorbed power. Around 70% of the absorbed power is released as visible and UV radiation rather than as heat to the gas. Comparison of the power absorption with the experiment showed an overall agreement both with the plasma radial profile and power absorption trend, the latter within an error smaller than 20%. This model can be used for the design and operation of synchrotron gas attenuators and as a base for a time-dependent model for free-electron laser attenuators. PMID- 29714179 TI - Magnetic assessment and modelling of the Aramis undulator beamline. AB - Within the SwissFEL project at the Paul Scherrer Institute (PSI), the hard X-ray line (Aramis) has been equipped with short-period in-vacuum undulators, known as the U15 series. The undulator design has been developed within the institute itself, while the prototyping and the series production have been implemented through a close collaboration with a Swiss industrial partner, Max Daetwyler AG, and several subcontractors. The magnetic measurement system has been built at PSI, together with all the data analysis tools. The Hall probe has been designed for PSI by the Swiss company SENIS. In this paper the general concepts of both the mechanical and the magnetic properties of the U15 series of undulators are presented. A description of the magnetic measurement equipment is given and the results of the magnetic measurement campaign are reported. Lastly, the data reduction methods and the associated models are presented and their actual implementation in the control system is detailed. PMID- 29714180 TI - Quick X-ray reflectivity using monochromatic synchrotron radiation for time resolved applications. AB - A new technique for the parallel collection of X-ray reflectivity (XRR) data, compatible with monochromatic synchrotron radiation and flat substrates, is described and applied to the in situ observation of thin-film growth. The method employs a polycapillary X-ray optic to produce a converging fan of radiation, incident onto a sample surface, and an area detector to simultaneously collect the XRR signal over an angular range matching that of the incident fan. Factors determining the range and instrumental resolution of the technique in reciprocal space, in addition to the signal-to-background ratio, are described in detail. This particular implementation records ~5 degrees in 2theta and resolves Kiessig fringes from samples with layer thicknesses ranging from 3 to 76 nm. The value of this approach is illustrated by showing in situ XRR data obtained with 100 ms time resolution during the growth of epitaxial La0.7Sr0.3MnO3 on SrTiO3 by pulsed laser deposition at the Cornell High Energy Synchrotron Source (CHESS). Compared with prior methods for parallel XRR data collection, this is the first method that is both sample-independent and compatible with the highly collimated, monochromatic radiation typical of third-generation synchrotron sources. Further, this technique can be readily adapted for use with laboratory-based sources. PMID- 29714181 TI - The fractional Fourier transform as a simulation tool for lens-based X-ray microscopy. AB - The fractional Fourier transform (FrFT) is introduced as a tool for numerical simulations of X-ray wavefront propagation. By removing the strict sampling requirements encountered in typical Fourier optics, simulations using the FrFT can be carried out with much decreased detail, allowing, for example, on-line simulation during experiments. Moreover, the additive index property of the FrFT allows the propagation through multiple optical components to be simulated in a single step, which is particularly useful for compound refractive lenses (CRLs). It is shown that it is possible to model the attenuation from the entire CRL using one or two effective apertures without loss of accuracy, greatly accelerating simulations involving CRLs. To demonstrate the applicability and accuracy of the FrFT, the imaging resolution of a CRL-based imaging system is estimated, and the FrFT approach is shown to be significantly more precise than comparable approaches using geometrical optics. Secondly, it is shown that extensive FrFT simulations of complex systems involving coherence and/or non monochromatic sources can be carried out in minutes. Specifically, the chromatic aberrations as a function of source bandwidth are estimated, and it is found that the geometric optics greatly overestimates the aberration for energy bandwidths of around 1%. PMID- 29714182 TI - Characterization of the surface contamination of deep X-ray lithography mirrors exposed to synchrotron radiation. AB - In deep X-ray lithography (DXRL), synchrotron radiation is applied to pattern polymer microstructures. At the Synchrotron Laboratory for Micro and Nano Devices (SyLMAND), Canadian Light Source, a chromium-coated grazing-incidence X-ray double-mirror system is applied as a tunable low-pass filter. In a systematic study, the surface conditions of the two mirrors are analyzed to determine the mirror reflectivity for DXRL process optimization, without the need for spectral analysis or surface probing: PMMA resist foils were homogeneously exposed and developed to determine development rates for mirror angles between 6 mrad and 12 mrad as well as for white light in the absence of the mirrors. Development rates cover almost five orders of magnitude for nominal exposure dose (deposited energy per volume) values of 1 kJ cm-3 to 6 kJ cm-3. The rates vary from case to case, indicating that the actual mirror reflectivity deviates from that of clean chromium assumed for the experiments. Fitting the mirror-based development rates to the white-light case as a reference, reflectivity correction factors are identified, and verified by experimental and numerical results of beam calorimetry. The correction factors are related to possible combinations of a varied chromium density, chromium oxidation and a carbon contamination layer. The best fit for all angles is obtained assuming 7.19 g cm-3 nominal chromium density, 0.5 nm roughness for all involved layers, and an oxide layer thickness of 25 nm with a carbon top coat of 50 nm to 100 nm. A simulation tool for DXRL exposure parameters was developed to verify that the development rates for all cases do coincide within a small error margin (achieving a reduction of the observed errors by more than two orders of magnitude) if the identified mirror surface conditions are considered when calculating the exposure dose. PMID- 29714183 TI - A sagittally confined high-resolution spectrometer in the 'water window'. AB - The authors report a novel scheme for a grazing-incidence spectrometer forming an excellent meridional flat field in its detector domain to deliver the desired spectral resolution throughout the full designated spectral range, while reducing the sagittal astigmatism substantially to enhance the spectral intensity. The optical properties of the system are thoroughly investigated and optimized, and the detector plane is fitted well to the meridional or sagittal focal curves. The authors demonstrated that a resolving power of 6000-18000 could be achieved within the 'water window' (2-5 nm) for an effective meridional source size of 200 um (r.m.s.), and it would be further improved to 20000-40000 if the source size was confined to 50 um (r.m.s.). PMID- 29714184 TI - Simulations of X-ray diffraction of shock-compressed single-crystal tantalum with synchrotron undulator sources. AB - Polychromatic synchrotron undulator X-ray sources are useful for ultrafast single crystal diffraction under shock compression. Here, simulations of X-ray diffraction of shock-compressed single-crystal tantalum with realistic undulator sources are reported, based on large-scale molecular dynamics simulations. Purely elastic deformation, elastic-plastic two-wave structure, and severe plastic deformation under different impact velocities are explored, as well as an edge release case. Transmission-mode diffraction simulations consider crystallographic orientation, loading direction, incident beam direction, X-ray spectrum bandwidth and realistic detector size. Diffraction patterns and reciprocal space nodes are obtained from atomic configurations for different loading (elastic and plastic) and detection conditions, and interpretation of the diffraction patterns is discussed. PMID- 29714186 TI - Beam-induced redox transformation of arsenic during As K-edge XAS measurements: availability of reducing or oxidizing agents and As speciation. AB - During X-ray absorption spectroscopy (XAS) measurements of arsenic (As), beam induced redox transformation is often observed. In this study, the As species immobilized by poorly crystallized mackinawite (FeS) was assessed for the susceptibility to beam-induced redox reactions as a function of sample properties including the redox state of FeS and the solid-phase As speciation. The beam induced oxidation of reduced As species was found to be mediated by the atmospheric O2 and the oxidation products of FeS [e.g. Fe(III) (oxyhydr)oxides and intermediate sulfurs]. Regardless of the redox state of FeS, both arsenic sulfide and surface-complexed As(III) readily underwent the photo-oxidation upon exposure to the atmospheric O2 during XAS measurements. With strict O2 exclusion, however, both As(0) and arsenic sulfide were less prone to the photo-oxidation by Fe(III) (oxyhydr)oxides than NaAsO2 and/or surface-complexed As(III). In case of unaerated As(V)-reacted FeS samples, surface-complexed As(V) was photocatalytically reduced during XAS measurements, but arsenic sulfide did not undergo the photo-reduction. PMID- 29714185 TI - Radiation-driven rotational motion of nanoparticles. AB - Focused synchrotron beams can influence a studied sample via heating, or radiation pressure effects due to intensity gradients. The high angular sensitivity of rotational X-ray tracking of crystalline particles via their Bragg reflections can detect extremely small forces such as those caused by field gradients. By tracking the rotational motion of single-crystal nanoparticles embedded in a viscous or viscoelastic medium, the effects of heating in a uniform gradient beam and radiation pressure in a Gaussian profile beam were observed. Changes in viscosity due to X-ray heating were measured for 42 um crystals in glycerol, and angular velocities of 10-6 rad s-1 due to torques of 10-24 N m were measured for 340 nm crystals in a colloidal gel matrix. These results show the ability to quantify small forces using rotation motion of tracer particles. PMID- 29714187 TI - Influence of the core-hole effect on optical properties of magnesium oxide (MgO) near the Mg L-edge region. AB - The influence of the core-hole effect on optical properties of magnesium oxide (MgO) is established through experimental determination of optical constants and first-principles density functional theory studies. Optical constants (delta and beta) of MgO thin film are measured in the spectral region 40-300 eV using reflectance spectroscopy techniques at the Indus-1 synchrotron radiation source. The obtained optical constants show strong core exciton features near the Mg L edge region, causing significant mismatch with Henke's tabulated values. On comparing the experimentally obtained optical constants with Henke's tabulated values, an edge shift of ~3.0 eV is also observed. Distinct evidence of effects of core exciton on optical constants (delta and beta) in the near Mg L-edge absorption spectra are confirmed through first-principles simulations. PMID- 29714188 TI - Investigation of the multiplet features of SrTiO3 in X-ray absorption spectra based on configuration interaction calculations. AB - Synchrotron-based L2,3-edge absorption spectra show strong sensitivities to the local electronic structure and chemical environment. However, detailed physical information cannot be extracted easily without computational aids. Here, using the experimental Ti L2,3-edges absorption spectrum of SrTiO3 as a fingerprint and considering full multiplet effects, calculations yield different energy parameters characterizing local ground state properties. The peak splitting and intensity ratios of the L3 and L2 set of peaks are carefully analyzed quantitatively, giving rise to a small hybridization energy around 1.2 eV, and the different hybridization energy values reported in the literature are further addressed. Finally, absorption spectra with different linearly polarized photons under various tetragonal crystal fields are investigated, revealing a non-linear orbital-lattice interaction, and a theoretical guidance for material engineering of SrTiO3-based thin films and heterostructures is offered. Detailed analysis of spectrum shifts with different tetragonal crystal fields suggests that the eg crystal field splitting is a necessary parameter for a thorough analysis of the spectra, even though it is not relevant for the ground state properties. PMID- 29714189 TI - Thickness-dependent structural characteristics for a sputtering-deposited chromium monolayer and Cr/C and Cr/Sc multilayers. AB - The interior structure, morphology and ligand surrounding of a sputtering deposited chromium monolayer and Cr/C and Cr/Sc multilayers are determined by various hard X-ray techniques in order to reveal the growth characteristics of Cr based thin films. A Cr monolayer presents a three-stage growth mode with sudden changes occurring at a layer thickness of ~2 nm and beyond 6 nm. Cr-based multilayers are proven to have denser structures due to interfacial diffusion and layer growth mode. Cr/C and Cr/Sc multilayers have different interfacial widths resulting from asymmetry, degree of crystallinity and thermal stability. Cr/Sc multilayers present similar ligand surroundings to Cr foil, whereas Cr/C multilayers are similar to Cr monolayers. The aim of this study is to help understand the structural evolution regulation versus layer thickness and to improve the deposition technology of Cr-based thin films, in particular for obtaining stable Cr-based multilayers with ultra-short periods. PMID- 29714190 TI - Quantitative study of the influence of swimming therapy on osteoporosis rat models based on synchrotron radiation computed tomogaphy. AB - Osteoporosis is a bone disease with a variety of causes, leading to bone pain and fragility to fracture. Major treatment methods include nutrition therapy, exercise therapy, drug therapy and surgical treatment, among which exercise therapy, such as swimming, is the most effective. To investigate the optimal swimming therapy regime for postmenopausal women, the effects of eight weeks of different intensity swimming exercises were studied in rat models. After the swimming program, lumbar vertebrae were dissected from all the rats and scanned by synchrotron radiation computed tomography (SRCT). Histomorphometry analysis and finite-element analysis were carried out on the trabecular structure of the L4 lumbar based on the acquired SRCT slices. Histomorphometry analysis showed that swimming can alleviate the decrease in bone strength induced by estrogen deficiency, and moderate-intensity swimming was found to have the most significant effect. PMID- 29714191 TI - Development of an X-ray imaging system to prevent scintillator degradation for white synchrotron radiation. AB - The high flux of the white X-ray beams from third-generation synchrotron light sources can significantly benefit the development of high-speed X-ray imaging, but can also bring technical challenges to existing X-ray imaging systems. One prevalent problem is that the image quality deteriorates because of dust particles accumulating on the scintillator screen during exposure to intense X ray radiation. Here, this problem has been solved by embedding the scintillator in a flowing inert-gas environment. It is also shown that the detector maintains the quality of the captured images even after days of X-ray exposure. This modification is cost-efficient and easy to implement. Representative examples of applications using the X-ray imaging system are also provided, including fast tomography and multimodal phase-contrast imaging for biomedical and geological samples. PMID- 29714192 TI - Wavelet processing and digital interferometric contrast to improve reconstructions from X-ray Gabor holograms. AB - In this work, the application of an undecimated wavelet transformation together with digital interferometric contrast to improve the resulting reconstructions in a digital hard X-ray Gabor holographic microscope is shown. Specifically, the starlet transform is used together with digital Zernike contrast. With this contrast, the results show that only a small set of scales from the hologram are, in effect, useful, and it is possible to enhance the details of the reconstruction. PMID- 29714193 TI - High-speed tomography under extreme conditions at the PSICHE beamline of the SOLEIL Synchrotron. AB - In situ microtomography at high pressure and temperature has developed rapidly in the last decade, driven by the development of new high-pressure apparatus. It is now routinely possible to characterize material under high pressure with acquisition times for tomograms of the order of tens of minutes. Here, advantage was taken of the possibility to combine the use of a pink beam projected through a standard Paris-Edinburgh press in order to demonstrate the possibility to perform high-speed synchrotron X-ray tomography at high pressure and temperature allowing complete high-resolution tomograms to be acquired in about 10 s. This gives direct visualization to rapidly evolving or unstable systems, such as flowing liquids or reacting components, and avoids assumptions in the interpretation of quenched samples. Using algebraic reconstruction techniques allows the missing angle artefacts that result from the columns of the press to be minimized. PMID- 29714194 TI - Synchrotron X-ray microbeam dosimetry with a 20 micrometre resolution scintillator fibre-optic dosimeter. AB - Cancer is one of the leading causes of death worldwide. External beam radiation therapy is one of the most important modalities for the treatment of cancers. Synchrotron microbeam radiation therapy (MRT) is a novel pre-clinical therapy that uses highly spatially fractionated X-ray beams to target tumours, allowing doses much higher than conventional radiotherapies to be delivered. A dosimeter with a high spatial resolution is required to provide the appropriate quality assurance for MRT. This work presents a plastic scintillator fibre optic dosimeter with a one-dimensional spatial resolution of 20 um, an improvement on the dosimeter with a resolution of 50 um that was demonstrated in previous work. The ability of this probe to resolve microbeams of width 50 um has been demonstrated. The major limitations of this method were identified, most notably the low-light signal resulting from the small sensitive volume, which made valley dose measurements very challenging. A titanium-based reflective paint was used as a coating on the probe to improve the light collection, but a possible effect of the high-Z material on the probes water-equivalence has been identified. The effect of the reflective paint was a 28.5 +/- 4.6% increase in the total light collected; it did not affect the shape of the depth-dose profile, nor did it explain an over-response observed when used to probe at low depths, when compared with an ionization chamber. With improvements to the data acquisition, this probe design has the potential to provide a water-equivalent, inexpensive dosimetry tool for MRT. PMID- 29714195 TI - First-principles X-ray absorption dose calculation for time-dependent mass and optical density. AB - A dose integral of time-dependent X-ray absorption under conditions of variable photon energy and changing sample mass is derived from first principles starting with the Beer-Lambert (BL) absorption model. For a given photon energy the BL dose integral D(e, t) reduces to the product of an effective time integral T(t) and a dose rate R(e). Two approximations of the time-dependent optical density, i.e. exponential A(t) = c + aexp(-bt) for first-order kinetics and hyperbolic A(t) = c + a/(b + t) for second-order kinetics, were considered for BL dose evaluation. For both models three methods of evaluating the effective time integral are considered: analytical integration, approximation by a function, and calculation of the asymptotic behaviour at large times. Data for poly(methyl methacrylate) and perfluorosulfonic acid polymers measured by scanning transmission soft X-ray microscopy were used to test the BL dose calculation. It was found that a previous method to calculate time-dependent dose underestimates the dose in mass loss situations, depending on the applied exposure time. All these methods here show that the BL dose is proportional to the exposure time D(e, t) ? K(e)t. PMID- 29714196 TI - Effects of soft X-ray radiation damage on paraffin-embedded rat tissues supported on ultralene: a chemical perspective. AB - Radiation damage is an important aspect to be considered when analysing biological samples with X-ray techniques as it can induce chemical and structural changes in the specimens. This work aims to provide new insights into the soft X ray induced radiation damage of the complete sample, including not only the biological tissue itself but also the substrate and embedding medium, and the tissue fixation procedure. Sample preparation and handling involves an unavoidable interaction with the sample matrix and could play an important role in the radiation-damage mechanism. To understand the influence of sample preparation and handling on radiation damage, the effects of soft X-ray exposure at different doses on ultralene, paraffin and on paraffin-embedded rat tissues were studied using Fourier-transform infrared (FTIR) microspectroscopy and X-ray microscopy. Tissues were preserved with three different commonly used fixatives: formalin, glutaraldehyde and Karnovsky. FTIR results showed that ultralene and paraffin undergo a dose-dependent degradation of their vibrational profiles, consistent with radiation-induced oxidative damage. In addition, formalin fixative has been shown to improve the preservation of the secondary structure of proteins in tissues compared with both glutaraldehyde and Karnovsky fixation. However, conclusive considerations cannot be drawn on the optimal fixation protocol because of the interference introduced by both substrate and embedding medium in the spectral regions specific to tissue lipids, nucleic acids and carbohydrates. Notably, despite the detected alterations affecting the chemical architecture of the sample as a whole, composed of tissue, substrate and embedding medium, the structural morphology of the tissues at the micrometre scale is essentially preserved even at the highest exposure dose. PMID- 29714197 TI - Synchrotron radiation external beam rotational radiotherapy of breast cancer: proof of principle. AB - The principle of rotational summation of the absorbed dose for breast cancer treatment with orthovoltage X-ray beams was proposed by J. Boone in 2012. Here, use of X-ray synchrotron radiation for image guided external beam rotational radiotherapy treatment of breast cancer is proposed. Tumor irradiation occurs with the patient in the prone position hosted on a rotating bed, with her breast hanging from a hole in the bed, which rotates around a vertical axis passing through the tumor site. Horizontal collimation of the X-ray beam provides for whole breast or partial breast irradiation, while vertical translation of the bed and successive rotations allow for irradiation of the full tumor volume, with dose rates which permit also hypofractionated treatments. In this work, which follows a previous preliminary report, results are shown of a full series of measurements on polyethylene and acrylic cylindrical phantoms carried out at the Australian Synchrotron, confirmed by Geant4 Monte Carlo simulations, intended to demonstrate the proof of principle of the technique. Dose measurements were carried out with calibrated ion chambers, radiochromic films and thermoluminescence dosimeters. The photon energy investigated was 60 keV. Image guidance may occur with the transmitted beam for contrast-enhanced breast computed tomography. For a horizontal beam collimation of 1.5 cm and rotation around the central axis of a 14 cm-diameter polyethylene phantom, a periphery-to center dose ratio of 14% was measured. The simulations showed that under the same conditions the dose ratio decreases with increasing photon energy down to 10% at 175 keV. These values are comparable with those achievable with conventional megavoltage radiotherapy of breast cancer with a medical linear accelerator. Dose painting was demonstrated with two off-center 'cancer foci' with 1.3 Gy and 0.6 Gy target doses. The use of a radiosensitizing agent for dose enhancement is foreseen. PMID- 29714198 TI - X-ray beam-position feedback system with easy-to-use beam-position monitor. AB - X-ray beam-position stability is indispensable in cutting-edge experiments using synchrotron radiation. Here, for the first time, a beam-position feedback system is presented that utilizes an easy-to-use X-ray beam-position monitor incorporating a diamond-fluorescence screen. The acceptable range of the monitor is above 500 um and the feedback system maintains the beam position within 3 um. In addition to being inexpensive, the system has two key advantages: it works without a scale factor for position calibration, and it has no dependence on X ray energy, X-ray intensity, beam size or beam shape. PMID- 29714199 TI - Study of melanin localization in the mature male Calopteryx haemorrhoidalis damselfly wings. AB - Damselflies Calopteryx haemorrhoidalis exhibiting black wings are found in the western Mediterranean, Algeria, France, Italy, Spain and Monaco. Wing pigmentation is caused by the presence of melanin, which is involved in physiological processes including defence reactions, wound healing and sclerotization of the insect. Despite the important physiological roles of melanin, the presence and colour variation among males and females of the C. haemorrhoidalis species and the localization of the pigment within the wing membrane remain poorly understood. In this study, infrared (IR) microspectroscopy, coupled with the highly collimated synchrotron IR beam, was employed in order to identify the distribution of the pigments in the wings at a high spatial resolution. It was found that the melanin is localized in the procuticle of the C. haemorrhoidalis damselfly wings, distributed homogeneously within this layer, and not associated with the lipids of the epicuticle. PMID- 29714200 TI - A scanning transmission X-ray microscope at the Pohang Light Source. AB - A scanning transmission X-ray microscope is operational at the 10A beamline at the Pohang Light Source. The 10A beamline provides soft X-rays in the photon energy range 100-2000 eV using an elliptically polarized undulator. The practically usable photon energy range of the scanning transmission X-ray microscopy (STXM) setup is from ~150 to ~1600 eV. With a zone plate of 25 nm outermost zone width, the diffraction-limited space resolution, ~30 nm, is achieved in the photon energy range up to ~850 eV. In transmission mode for thin samples, STXM provides the element, chemical state and magnetic moment specific distributions, based on absorption spectroscopy. A soft X-ray fluorescence measurement setup has been implemented in order to provide the elemental distribution of thicker samples as well as chemical state information with a space resolution of ~50 nm. A ptychography setup has been implemented in order to improve the space resolution down to 10 nm. Hardware setups and application activities of the STXM are presented. PMID- 29714201 TI - MX2: a high-flux undulator microfocus beamline serving both the chemical and macromolecular crystallography communities at the Australian Synchrotron. AB - MX2 is an in-vacuum undulator-based crystallography beamline at the 3 GeV Australian Synchrotron. The beamline delivers hard X-rays in the energy range 4.8 21 keV to a focal spot of 22 * 12 um FWHM (H * V). At 13 keV the flux at the sample is 3.4 * 1012 photons s-1. The beamline endstation allows robotic handling of cryogenic samples via an updated SSRL SAM robot. This beamline is ideal for weakly diffracting hard-to-crystallize proteins, virus particles, protein assemblies and nucleic acids as well as smaller molecules such as inorganic catalysts and organic drug molecules. The beamline is now mature and has enjoyed a full user program for the last nine years. This paper describes the beamline status, plans for its future and some recent scientific highlights. PMID- 29714202 TI - Fast XANES fluorescence imaging using a Maia detector. AB - A new fast X-ray absorption spectroscopy scanning method was recently implemented at the Hard X-ray Microprobe endstation P06, PETRA III, DESY, utilizing a Maia detector. Spectromicroscopy maps were acquired with spectra for X-ray absorption near-edge structure (XANES) acquisition in the sub-second regime. The method combines XANES measurements with raster-scanning of the sample through the focused beam. The order of the scanning sequence of the axes, one beam energy axis and two (or more) spatial axes, is a variable experimental parameter and, depending on it, the dwell at each location can be either single and continuous (if the energy axis is the inner loop) or in shorter discontinuous intervals (if a spatial axis is innermost). The combination of improved spatial and temporal resolution may be necessary for rapidly changing samples, e.g. for following in operando chemical reactions or samples highly susceptible to beam damage where the rapid collection of single XANES spectra avoids issues with the emergence of chemical changes developing from latent damage. This paper compares data sets collected on a specially designed test pattern and a geological thin-section scanning the energy as inner, middle and outer axis in the sequence. The XANES data of all three scanning schemes is found to show excellent agreement down to the single-pixel level. PMID- 29714203 TI - Quanty4RIXS: a program for crystal field multiplet calculations of RIXS and RIXS MCD spectra using Quanty. AB - Some initial instructions for the Quanty4RIXS program written in MATLAB(r) are provided. The program assists in the calculation of 1s 2p RIXS and 1s 2p RIXS-MCD spectra using Quanty. Furthermore, 1s XAS and 2p 3d RIXS calculations in different symmetries can also be performed. It includes the Hartree-Fock values for the Slater integrals and spin-orbit interactions for several 3d transition metal ions that are required to create the .lua scripts containing all necessary parameters and quantum mechanical definitions for the calculations. The program can be used free of charge and is designed to allow for further adjustments of the scripts. PMID- 29714204 TI - Integrated beamline control and data acquisition for small-angle X-ray scattering at the P12 BioSAXS beamline at PETRAIII storage ring DESY. AB - The versatility of small-angle X-ray scattering (SAXS) as a structural biology method is apparent by its compatibility with many experimental set-ups. Most advanced SAXS studies are conducted at dedicated synchrotron beamlines yielding high beam brilliance, throughput and temporal resolution. However, utilizing the full potential of the method while preserving a high degree of automation provides a challenge to any SAXS beamline. This challenge is especially pertinent at the P12 BioSAXS beamline of the EMBL at the PETRAIII Synchrotron DESY (Hamburg, Germany), optimized and dedicated to scattering of macromolecular solutions. Over 200 unique set-ups are possible at this beamline offering various functionalities, including different temporal and spatial resolutions. Presented here is a beamline control and data-acquisition software, BECQUEREL, designed to maximize flexibility and automation in the operation of P12. In the frame of a single intuitive interface the control system allows for convenient operation with all hardware set-ups available at P12 including a robotic sample changer, in line size-exclusion chromatography, stop-flow devices, microfluidic spinning disk and various in-air settings. Additional functionalities are available to assist the data-collection procedure for novice users, and also routine operation of the support staff. PMID- 29714205 TI - Sample cell for studying liquid interfaces with an in situ electric field using X ray reflectivity and application to clay particles at oil-oil interfaces. AB - Commissioning results of a liquid sample cell for X-ray reflectivity studies with an in situ applied electrical field are presented. The cell consists of a Plexiglas container with lateral Kapton windows for air-liquid and liquid-liquid interface studies, and was constructed with grooves to accept plate electrodes on the walls parallel to the direction of the beam. Both copper and ITO plate electrodes have been used, the latter being useful for simultaneous optical studies. Commissioning tests were made at the I07 beamline of the Diamond Light Source. PMID- 29714207 TI - Laser-induced ultrasonic imaging for measurements of solid surfaces in optically opaque liquids [Invited]. AB - The paper describes a novel laser ultrasonic profilometry method which uses pulsed laser radiation for imaging of the surface profile of solid objects in optically opaque liquids by scattering of ultrasonic waves. Algorithms for the construction of laser ultrasonic images and for profile segmentation are presented. An experimental setup for profile measurements is described. It allows reconstructing of laser ultrasonic images with a frame rate of 10 Hz and performing an automated 3D scanning of samples. The results of the experimental testing of laser ultrasonic profilometry on duralumin samples are presented. The approximation error of duralumin cylinder surface profile measurements in water is 15 MUm. The results are compared to those obtained by x-ray tomography. PMID- 29714208 TI - Generation of coherent acoustic beams in solids by mixing of counterpropagating, detuned optical beams [Invited]. AB - We model the generation of coherent acoustic beams in a homogeneous solid from the interference of two oppositely propagating, detuned optical laser beams. This configuration is reciprocal to Brillouin light scattering in the backward interaction arrangement. Generation of a confined ultrasound beam is predicted, close to the Brillouin frequency. Optoacoustic gain spectra and beam shapes are obtained numerically using a finite element model. The acoustic spectra are non symmetrical, i.e., non-Lorentzian, and result from excitation of the continuum of bulk elastic waves. The acoustic beam width correspondingly varies with detuning frequency and optical beam waist. PMID- 29714209 TI - Plasmonic enhancement of mid- and far-infrared acousto-optic interaction [Invited]. AB - We present a concept of an acousto-optical device with plasmonic efficiency enhancement at a 10.6 MUm wavelength. Interaction of light, Rayleigh surface acoustic wave, and surface plasmon polariton excited via prism coupling using Otto geometry enhances the diffraction efficiency. In the case of Otto geometry, the surface acoustic wave affects both the refraction index of the optical medium and the air gap thickness between the prism and the metal. Dependencies of the reflective coefficient of the prism-air-metal system on gap thickness and dielectric permittivity modulation were analyzed. The analytical results were confirmed by experimental measurements of the angular spectrum of the reflected beam. PMID- 29714206 TI - Curcumin Treatment is Associated with Increased Expression of the N-Methyl-D Aspartate Receptor (NMDAR) Subunit, NR2A, in a Rat PC12 Cell Line Model of Alzheimer's Disease Treated with the Acetyl Amyloid-beta Peptide, Abeta(25-35). AB - BACKGROUND The aim of this study was to investigate the effect of curcumin treatment on the expression of the N-methyl-D-aspartate receptor (NMDAR) subunit, NR2A, in a rat PC12 cell line treated with the acetyl amyloid-beta peptide, Abeta(25-35), in an in vitro model of Alzheimer's disease. MATERIAL AND METHODS PC12 cells, derived from rat phaeochromocytoma, were treated for 24 hours with increasing concentrations of curcumin (5, 10, 20, 30 uM/L) in the presence of the acetyl amyloid-beta peptide, Abeta(25-35). A Cell Counting Kit-8 (CCK-8) assay was used to determine cell viability, and flow cytometry was used to measure cell apoptosis. In the supernatant of the treated PC12 cells, Western blotting was used to measure the cell injury biomarker, lactate dehydrogenase (LDH), and the biomarker for oxidative stress, malondialdehyde (MDA). Expression of the N-methyl D-aspartate receptor (NMDAR) subunit, NR2A, was analyzed by Western blotting and quantitative reverse transcription-polymerase chain reaction (qRT-PCR). RESULTS Curcumin treatment protected the rat PC12 cells from Ab(25-35)-induced reduction in cell viability, apoptosis, release of LDH, and MDA production. Curcumin treatment of PC12 cells was associated with increased expression of the NMDAR subunit, NR2A. CONCLUSIONS The findings of this study showed a neuroprotective effect of curcumin treatment in an in vitro model of Alzheimer's disease that was associated with the increased expression of the NMDAR subunit, NR2A. PMID- 29714210 TI - Study of the spectral bandwidth of a double-pass acousto-optic system [Invited]. AB - Acousto-optic tunable filters are known as efficient instruments for spectral and spatial filtering of light. In this paper, we analyze the bandwidth dependence of a double-pass filter. The interaction geometry chosen allows the simultaneous diffraction of the ordinary and the extraordinary optical modes by a single ultrasonic frequency. We present the main parameters of a custom device (design, optical range, driving frequency) and experimental results concerning the angular deviation of the beams including the effect of optical birefringence. The spectral resolution and the side lobes' significance are discussed. Spectral bandwidth of such a system is analyzed. PMID- 29714211 TI - Acousto-optic visualization of optical wavefronts [Invited]. AB - The paper presents a short survey on theoretical and experimental investigations of an acousto-optic (AO) method of optical wavefront visualization proposed and developed at Moscow State University. The method is based on angular selectivity of Bragg diffraction. It is shown that distribution of light intensity in the visualized image is proportional to the phase gradient in the AO interaction plane. Spatial resolution and contrast of the visualized image are determined primarily by the divergence angle of the acoustic beam. Most attention in the paper is concentrated on the problem of AO visualization of two-dimensional phase objects. The important advantage of the AO method consists of the possibility of optical field phase-structure registration in the presence of amplitude modulation of the initial optical field. Examples of computer simulations as well as some experimental results are presented for illustration of the potentialities of this method. PMID- 29714212 TI - Multispectral phase imaging based on acousto-optic filtration of interfering light beams [Invited]. AB - Acousto-optic spectral selection of light is an effective technique for interference imaging at multiple wavelengths. In this paper, we show that, depending on the location of the acousto-optical tunable filter relative to the interferometer, it is possible to enhance important characteristics of the whole system: spectral contrast, insensitivity to ambient light, performance stability, and measurement accuracy. We analyze theoretically and compare experimentally a quantitative phase imaging system based on a Mach-Zehnder interferometer with one and two acousto-optical filters located in the illumination or/and in the output channels. Visibility of the interference patterns and noise root mean square in the calculated phase maps are estimated for all cases at room temperature. It is shown that acousto-optic filtration of interfering light beams in the output channel ensures better contrast of the interference pattern and, therefore, provides better stability and higher precision of the phase measurements. PMID- 29714213 TI - Acousto-optic tunable filter spectrometers in space missions [Invited]. AB - Spectrometers employing acousto-optic tunable filters (AOTFs) rapidly gain popularity in space, and in particular on interplanetary missions. They allow for reducing volume, mass, and complexity of the instrumentation. To date, space operations of 11 AOTF spectrometers are reported in the literature. They were used for analyzing ocean color, greenhouse gases, atmospheres of Mars and Venus, and for lunar mineralogy. More instruments for the Moon, Mars, and asteroid mineralogy are in flight, awaiting launch, or in the state of advanced development. The AOTFs are used in point (pencil-beam) spectrometers for selecting echelle diffraction orders, or in hyper-spectral imagers and microscopes. We review the AOTF-employing devices flown in space or ready to set off. The paper considers basic principles of the AOTF and science applications of the AOTF spectrometers, and describes developed instruments in some detail. We also address some advanced developments for future missions and plans. In addition, we discuss lessons learned during instrument design, build, calibration, and exploitation, and advantages and limitations in implementing the AOTF-based systems in space instrumentation. PMID- 29714214 TI - Active underwater detection with an array of atomic magnetometers. AB - We report on a 2*2 array of radio-frequency atomic magnetometers in a magnetic induction tomography configuration. Active detection, localization, and real-time tracking of conductive, nonmagnetic targets are demonstrated in air and saline water. Penetration in different media and detection are achieved thanks to the sensitivity and tunability of the sensors, and to the active nature of magnetic induction probing. We obtained a 100% success rate for automatic detection and a 93% success rate for automatic localization in air and water, up to 190 mm away from the sensor plane (100 mm underwater). We anticipate magnetic induction tomography with arrays of atomic magnetometers finding applications in civil engineering and maintenance, the oil and gas industry, geological surveys, marine science, archeology, search and rescue, and security and surveillance. PMID- 29714215 TI - Optimal wavelength selection strategy in temporal phase unwrapping with projection distance minimization. AB - Micro Fourier transform profilometry (MUFTP) is a recently developed computational framework for high-speed dynamic 3D shape measurement of transient scenes based on fringe projection. It has been demonstrated that by using high frame-rate fringe projection hardware, MUFTP can achieve accurate, denser, unambiguous, and motion-artifact-free 3D reconstruction at a speed up to 10,000 Hz. MUFTP utilizes a temporal phase unwrapping algorithm, so-called projection distance minimization (PDM), in which multiple wavelengths are used to solve the phase ambiguity optimally in the maximum-likelihood sense. However, it has been found that the choice of the wavelengths is essential to the unambiguous measurement range as well as the unwrapping reliability in the presence of noise. In this work, the relations between the wavelength combination and the noise resistance ability of PDM are analyzed and investigated in detail by analytical, emulational, and experimental means. This leads to a qualitative conclusion that the noise resistance ability of PDM is fundamentally determined by the value of each item in wavelength ratio: a smaller value of each item in wavelength ratio means better noise resistance ability in phase unwrapping. Our result provides a guideline for optimal wavelengths selection in order to improve the noise resistance ability of a practical fringe projection system. Simulations and experiments based on a microscopic fringe projection system are demonstrated to validate the correctness of our conclusion. PMID- 29714216 TI - Dual-wavelength dispersion characterization of confocal Fabry-Perot interferometers. AB - Optical resonators simultaneously resonating at different wavelengths are of interest in passive as well as active optical cavities. Dual-wavelength lasers, optical parametric amplifiers and spectrometers, e.g., in high spectral resolution lidar (HSRL) are effectively improved by employing multiply resonant cavities. In particular, HSRL allows us to measure aerosol optical properties without a priori hypotheses. Here we analyze optical dispersion in a HSRL prototype, based on a confocal Fabry-Perot interferometer (CFPI), developed to work at 532 nm (the lidar excitation wavelength). The presence of dispersion should be accounted for when realizing an effective HSRL because a second beam is required to obtain sufficient locking stability. We have performed an experiment in order to measure the dispersion contributions coming from cavity mirror coating and air and evaluate the stability of the transmission peaks in order to optimize the performances of HSRL. PMID- 29714217 TI - Eightfold optical encoder with high-density grating. AB - A novel grating interferometer configuration with eightfold optical subdivision to achieve ultrahigh resolution using a special symmetrical prism is proposed. The optical subdivision is enhanced by four times compared to traditional linear optical encoders. In this work, we take advantage of a high linear density grating of 1780 lines/mm, which is combined with an eightfold optical subdivision configuration. As a result, a high resolution of 68.6 pm is achieved. The apparatus adopts a symmetrical measurement configuration to reduce the error arising from environmental fluctuations. The verification experiments involve high optical subdivision, long- and short-range displacement measurement, and stability, with all results compared to those obtained with a commercial interferometer. The excellent agreement of the results demonstrates the effectiveness of our proposed system. PMID- 29714218 TI - Spectral-differential-based unmixing for multispectral photoacoustic imaging. AB - We propose the use of a spectral differential method (SDM) to emphasize the spectral peaks of multispectral photoacoustic images. Because contrast agent signals have spectral peaks at the contrast agent absorption peak, the SDM can selectively emphasize contrast agent signals. Unlike the conventional spectral fitting method (SFM), the SDM does not require reference background spectra and, consequently, does not suffer from separation error caused by the deviation of reference spectra from the measured spectra. We performed multispectral photoacoustic imaging of tissue-mimicking phantoms and subcutaneous tumors of mice injected with small organic molecule-based contrast agents. Contrast agent images obtained by the SDM were clearer than those obtained by SFM. PMID- 29714219 TI - Two-core single-polarization optical fiber with a large hollow coated bimetallic layer. AB - A two-core hollow optical fiber for a polarizer based on surface plasmon resonance (SPR) is proposed and studied by the full-vector finite-element method. The proposed fiber consists of two circular cores, inner cladding, outer cladding, and a large central air hole. The two cores are arranged symmetrically in inner cladding and couple weakly with the air hole. There is no cross talk between cores because they are insulated by the air hole. A nanodimension Ag/Au bimetallic layer can be coated on the inner surface of the central air hole to support SPR. The numerical results show that single polarization of two cores is achieved simultaneously at the wavelength of 1.310 MUm, due to strong coupling between the TM mode and the surface plasmon polariton mode. The extinction ratio 40.90 dB with 3 mm length is obtained, and the confinement loss of TE mode is 0.19 dB/cm. Moreover, the resonance wavelength is tunable by varying the refractive index of materials in the central air hole. The scheme is helpful for coupling an all-fiber polarizer with multicore polarization maintaining fibres (PMFs) and makes possible application in in-fiber integrated interferometric sensors while maintaining polarization. PMID- 29714220 TI - Packaging of InGaN stripe-shaped light-emitting diodes. AB - We demonstrate the fabrication of InGaN/GaN stripe-shaped light-emitting diodes (LEDs) in flip-chip packaging (FC-LED) and vertically mounted packaging (VM-LED). Compared to conventionally packaged LEDs, these packaging schemes enhance light output and emission divergence in ways favorable for general lighting applications. The FC-LED can sustain efficiency at high current operations due to effective heat sinking, while the VM-LED excels at light extraction efficiency due to the exposure of two large emission surfaces. Together with the properties of low luminous exitance and emission uniformity, the stripe-shaped LEDs are ideal for the assembly of luminaires. An LED light tube comprising a continuous linear array of 10 stripe-shaped LED chips has been assembled. The optical performance of the light tube is compared to another light tube assembled with conventional square-shaped LED chips (with and without external diffuser) by confocal microscopy. It is found that emission uniformity of the stripe-shaped LED tube is significantly improved, with a threefold increase in illumination area, without efficiency loss associated with diffusers. PMID- 29714221 TI - Simultaneous polarimeter retrievals of microphysical aerosol and ocean color parameters from the "MAPP" algorithm with comparison to high-spectral-resolution lidar aerosol and ocean products. AB - We present an optimal-estimation-based retrieval framework, the microphysical aerosol properties from polarimetry (MAPP) algorithm, designed for simultaneous retrieval of aerosol microphysical properties and ocean color bio-optical parameters using multi-angular total and polarized radiances. Polarimetric measurements from the airborne NASA Research Scanning Polarimeter (RSP) were inverted by MAPP to produce atmosphere and ocean products. The RSP MAPP results are compared with co-incident lidar measurements made by the NASA High-Spectral Resolution Lidar HSRL-1 and HSRL-2 instruments. Comparisons are made of the aerosol optical depth (AOD) at 355 and 532 nm, lidar column-averaged measurements of the aerosol lidar ratio and Angstrom exponent, and lidar ocean measurements of the particulate hemispherical backscatter coefficient and the diffuse attenuation coefficient. The measurements were collected during the 2012 Two-Column Aerosol Project (TCAP) campaign and the 2014 Ship-Aircraft Bio-Optical Research (SABOR) campaign. For the SABOR campaign, 73% RSP MAPP retrievals fall within +/-0.04 AOD at 532 nm as measured by HSRL-1, with an R value of 0.933 and root-mean-square deviation of 0.0372. For the TCAP campaign, 53% of RSP MAPP retrievals are within 0.04 AOD as measured by HSRL-2, with an R value of 0.927 and root-mean-square deviation of 0.0673. Comparisons with HSRL-2 AOD at 355 nm during TCAP result in an R value of 0.959 and a root-mean-square deviation of 0.0694. The RSP retrievals using the MAPP optimal estimation framework represent a key milestone on the path to a combined lidar+polarimeter retrieval using both HSRL and RSP measurements. PMID- 29714222 TI - Stigmatic broadband imaging spectrometer with a high numerical aperture. AB - An advanced Dyson spectrometer has been presented for broadband stigmatic imaging. The spectrometer, with large enough axial spaces and lateral separation among the slit, the imaging plane, and the hemispherical lens, is composed of a thin hemispherical lens and two spherical lenses in the same material, and a reflection concave grating. The new spectrometer design maintains excellent optical performances and decreases inherent stray light of the concentric spectrometer with a high numerical aperture, which owns better engineering applicability. PMID- 29714223 TI - Research on characteristics of symmetric optothermal microactuators. AB - This paper proposes and studies symmetric optothermal microactuators (OTMAs) which are directly controlled by a laser beam. Based on the principle of thermal flux, a theoretical model is established to describe the laser-induced temperature rises and optothermal expansions of the OTMAs' expansion arms. Temperature rise distributions of the arms with lengths of 590, 990, and 2260 MUm are simulated separately, which reveals that, under 2 mW laser irradiation, the maximum temperature rises are invariably less than 75.9 degrees C. Simulations are also made to consider optothermal expansions of the arms caused by laser irradiation, which turns out that expansion increases considerably when the arm's length increases from 250 to 1000 MUm, while insignificantly between 1250 and 2500 MUm. Under a laser beam of 2 mW power, experiments on three microfabricated OTMAs have been further conducted, which demonstrate that the OTMAs are capable of generating maximum deflections of 7.3, 11.3, and 13.6 MUm, and that the growth of deflection is comparatively obvious in the case when the total length changes from 750 to 1200 MUm, while insignificant for the range between 1200 and 2380 MUm. With regard to simulations and experiments, it has been proved that the OTMAs are capable of implementing direct laser-controlled microactuation in which only about 2 mW laser power is demanded. Moreover, it has been proved that twofold total length or arm length does not correspondingly result in doubling the deflection, nor the expansion. Therefore, total length/expansion arm's length around or less than 1200/1000 MUm is more appropriate for obtaining satisfactory characteristics of OTMAs, which may be potentially applied in MEMS/MOEMS and micro-/nano-technology. PMID- 29714224 TI - Acquisition of a full-resolution image and aliasing reduction for a spatially modulated imaging polarimeter with two snapshots. AB - A snapshot imaging polarimeter using spatial modulation can encode four Stokes parameters allowing instantaneous polarization measurement from a single interferogram. However, the reconstructed polarization images could suffer a severe aliasing signal if the high-frequency component of the intensity image is prominent and occurs in the polarization channels, and the reconstructed intensity image also suffers reduction of spatial resolution due to low-pass filtering. In this work, a method using two anti-phase snapshots is proposed to address the two problems simultaneously. The full-resolution target image and the pure interference fringes can be obtained from the sum and the difference of the two anti-phase interferograms, respectively. The polarization information reconstructed from the pure interference fringes does not contain the aliasing signal from the high-frequency component of the object intensity image. The principles of the method are derived and its feasibility is tested by both computer simulation and a verification experiment. This work provides a novel method for spatially modulated imaging polarization technology with two snapshots to simultaneously reconstruct a full-resolution object intensity image and high quality polarization components. PMID- 29714225 TI - Terahertz detection of alcohol using a photonic crystal fiber sensor. AB - Ethanol is widely used in chemical industrial processes as well as in the food and beverage industry. Therefore, methods of detecting alcohol must be accurate, precise, and reliable. In this content, a novel Zeonex-based photonic crystal fiber (PCF) has been modeled and analyzed for ethanol detection in terahertz frequency range. A finite-element-method-based simulation of the PCF sensor shows a high relative sensitivity of 68.87% with negligible confinement loss of 7.79*10 12 cm-1 at 1 THz frequency and x-polarization mode. Moreover, the core power fraction, birefringence, effective material loss, dispersion, and numerical aperture are also determined in the terahertz frequency range. Owing to the simple fiber structure, existing fabrication methods are feasible. With the outstanding waveguiding properties, the proposed sensor can potentially be used in ethanol detection, as well as polarization-preserving applications of terahertz waves. PMID- 29714226 TI - Correction of interferogram data acquired using a focal plane FT-IR spectrometer system. AB - Interferogram data acquired using the focal plane of a Fourier transform infrared (FT-IR) spectrometer acquisition system was processed for the purpose of calculating the noise equivalent spectral radiation. This study introduces the composition of the acquisition system based on a focal plane FT-IR spectrometer and analyzes the cause of ordinate drifting and abscissa shifting. The influence of these problems on system noise is analyzed quantitatively through mathematical calculations. Correction algorithms and methods are introduced to solve these problems. These can correct the error of interferogram data based on the FT-IR acquisition system. PMID- 29714227 TI - Profiled absorber design illuminated uniformly by parabolic reflectors. AB - In this paper, a general method is proposed in order to develop a special absorber profile that receives sunlight from parabolic reflectors uniformly. Different parameters were taken into consideration while performing the simulation including reflector focal length, collector length, and concentration ratio. The total power reflected to the absorber was calculated by accounting for the Fresnel angular dependency and the shadowing effect by the absorber. Furthermore, a verification method based on the ray tracing technique was also developed in order to verify that uniform illumination was achieved. The uniformity of the sunlight flux onto the absorber is expected to improve solar system efficiency and extend its life service. Therefore, the validated absorber profile design in this theoretical work can be useful for applications which employ parabolic concentrators with the concern of reaching higher performance by achieving a uniform concentration ratio on the absorber. PMID- 29714228 TI - Gain investigation of Perylene-Red-doped PMMA for stimulated luminescent solar concentrators. AB - Luminescent solar concentrators (LSCs) utilizing stimulated emission by a seed laser are a promising approach to overcome the limitations of conventional LSCs, with a significant reduction of the photovoltaic material. In our previous work, we demonstrated the principle of a stimulated LSC (s-LSC) and correspondingly developed a model for quantifying the output power of such a system, taking into account different important physical parameters. The model suggested Perylene Red (PR) dye as a potential candidate for s-LSCs. Here, we experimentally investigate the gain of PR-doped polymethyl methacrylate (PMMA) required for s-LSCs using a single pump wavelength (instead of the solar spectrum) as a proof of principle. The results found from the experiment are well matched with the previously developed numerical model except for gain saturation, which occurs at a comparatively small seed laser signal power. To investigate the gain saturation, two approaches were taken: investigating (i) spectral hole burning and (ii) triplet state absorption. Experimental investigation of spectral hole burning with PR dyes showed a small effect on the gain saturation. We developed a general state model considering triplet state absorption of the PR dyes for the second approach. The state model suggests that the PR dyes suffer from significant triplet state absorption loss, which obstructs the normal operation of the PR based s-LSC system. PMID- 29714229 TI - Effect of laser shock peening on electrochemical corrosion resistance of IN718 superalloy. AB - The effects of laser shock peening (LSP) treatment with different impacts on surface roughness, micro-hardness, microstructural observations, residual stress, and electrochemical corrosion resistance of IN718 superalloy were investigated. Results show that the corrosion potential increases to -0.4863 V, -0.2956 V, and -0.3578 V, and the corrosion rate reduces 66.10%, 79.08%, and 84.07% for 2 LSP impacts, 4 LSP impacts, and 6 LSP impacts, respectively, compared with the untreated one. In addition, LSP treatment has an important influence on grain refinement, which increases micro-hardness, reduces roughness of a surface, and also results in a compressive residual stress on a surface, both of which can be responsible for the electrochemical corrosion improvement. Finally, corrosion morphology under scanning electron microscopy demonstrates that LSP is an effective method to prevent the corrosion micro-crack propagation and improve the corrosion resistance. Also, with an increase in laser impacts, the electrochemical corrosion resistance will be further improved. PMID- 29714230 TI - Design tool for circular photonic crystal fibers supporting orbital angular momentum modes. AB - We propose a design tool for the family of circular photonic crystal fiber (C PCF) supporting orbital angular momentum modes. The calibrated normalized parameters for the C-PCF family are presented. The information about the cutoff condition of modes, the number of modes supported in fibers, and the effective index difference between adjacent modes can be obtained by using the design tool. Also, the mode properties, such as confinement loss, effective mode area (Aeff), and spin-orbital coupling are analyzed using the design tool. At the end of paper, we also give some fiber design examples by using the design tool. PMID- 29714231 TI - Theoretical surface type classifier based on a waveform model of a satellite laser altimeter and its performance in the north of Greenland. AB - Current land-cover classification methods using ICESat/GLAS's (Ice, Cloud, and land Elevation Satellite/Geoscience Laser Altimeter System) datasets are based on empirical thresholds or machine learning by training multiple GLAS parameters, e.g., the reflectivity and elevation of the target and width, amplitude, kurtosis, and skewness of the return waveform. A theoretical classifier is derived based on a waveform model of an actual laser altimeter illuminating the sea surface. With given system parameters and the sea surface wind corresponding to the location of a laser footprint (the wind can be calculated by using the National Centers for Environmental Prediction dataset), a precise theoretical waveform can be generated as a reference. Compared with the measured waveform, a weighted total difference, which is very sensitive to small-scale sea ice within the laser footprint, can be calculated to classify the GLAS measured data as open water. In the north of Greenland, after discarding the saturated GLAS data, the new theoretical classifier performed better [overall accuracy (OA)=95.62%, Kappa coefficient=0.8959] compared to the classical support vector machine (SVM) classifier (OA=90.44%, Kappa=0.7901), but the SVM classifier showed a better result for the user's accuracy of sea ice. Benefiting from the synergies of the theoretical and SVM classifiers, the integrated theoretical and SVM classifier achieved excellent accuracy (OA=98.21%, Kappa=0.9588). In the future, the new ICESat-2 photon counting laser altimeter will also construct a "waveform" (elevation distribution) by selecting the photon cloud, and thus, this new analytical method will be potentially useful for detecting open water in the Arctic. PMID- 29714232 TI - QEPAS sensor for breath analysis: a behavior of pressure. AB - The measurement of trace gases has increasingly become a key technique in healthcare and other medical applications. Quartz-enhanced photoacoustic spectroscopy (QEPAS) is a suitable method that can provide the required characteristics in such applications for a comparatively low cost and small size. The quantitative detection and a low detection limit are also required by applications. In this paper, we present new results on sensing biomedically relevant gases using the on-beam QEPAS technique with some newly developed tunable high-power single-mode laser diodes based on GaSb material. The data processing and detection limit determination are done by a field programmable gate array device, as well as an automatic measurement of the resonance frequency. PMID- 29714233 TI - Development of an optical defect inspection algorithm based on an active contour model for large steel roller surfaces. AB - On-site measurements and defect detection are of great importance for precision ground steel rollers due to their large dimension and weight. In addition to dimensional error, form accuracy, surface roughness, and surface/sub-surface cracks, there also exist optical defect requirements for steel roller surfaces, e.g., speckles, chatter marks, or feed traces. Since rollers with optical defects will always duplicate the defect patterns onto the metal sheet or foil during rolling, it is necessary as well as significant to scrutinize the roller surface after grinding. In industrial practice, defects are investigated mainly by experienced engineers through naked-eye inspections along particular directions and under appropriate illumination conditions. This is usually subjective and inconsistent. In this paper, a machine vision system is developed, to add onto the roller grinder, that is capable of acquiring the roller's surface image with high and consistent quality. In addition, to identify defects with fuzzy boundaries, intensity inhomogeneity, and complex background textures, an improved segmentation algorithm is developed based on an active contour without edges model. Furthermore, qualitative and quantitative comparisons of the proposed algorithm with the Chan-Vese model, the local binary fitting model, and the globally signed region pressure force model are carried out. The comparisons prove that the proposed method performs with better accuracy and robustness for fuzzy and inhomogeneous defect segmentation and consumes generally less computational time. PMID- 29714234 TI - Improved identification of the solution space of aerosol microphysical properties derived from the inversion of profiles of lidar optical data, part 3: case studies. AB - We conclude our series of publications on the development of the gradient correlation method (GCM), which can be used for an improved stabilization of the solution space of particle microphysical parameters derived from measurements with multiwavelength Raman and high-spectral-resolution lidar (3 backscatter +2 extinction coefficients). We show results of three cases studies. The data were taken with a ground-based multiwavelength Raman lidar during the Saharan Mineral Dust Experiment in the Cape Verde Islands (North Atlantic). These cases describe mixtures of dust with smoke. For our data analysis we separated the contribution of smoke to the total signal and only used these optical profiles for the test of GCM. The results show a significant stabilization of the solution space of the particle microphysical parameter retrieval on the particle radius domain from 0.03 to 10 MUm, the real part of the complex refractive index domain from 1.3 to 1.8, and the imaginary part from 0 to 0.1. This new method will be included in the Tikhonov Advanced Regularization Algorithm, which is a fully automated, unsupervised algorithm that is used for the analysis of data collected with the worldwide first airborne 3 backscatter +2 extinction high-spectral-resolution lidar developed by NASA Langley Research Center. PMID- 29714235 TI - Measurement of grating groove density using multiple diffraction orders and one standard wavelength. AB - A new method for measuring grating groove density is proposed using multiple diffraction orders and one standard wavelength to eliminate the eccentricity effect originated from the rotation of a diffraction grating. Based on the Littman configuration for autocollimation, the groove density can be obtained by measuring the internal angles between the zeroth-order and two nonzeroth-order diffracted beams for one laser wavelength at a certain incident angle. The method was applied to measure the groove density of a plane grating with a nominal groove density of 651 lines/mm, where the mean value of this grating was measured to be 650.76 lines/mm with a relative measurement error DeltaN/N of 3.8*10-5. PMID- 29714236 TI - Generation of near-diffraction-limited, high-power supercontinuum from 1.57 MUm to 12 MUm with cascaded fluoride and chalcogenide fibers. AB - We generate a supercontinuum (SC) spectrum ranging from 1.57 MUm to 12 MUm (20 dB bandwidth) with a soft glass fiber cascade consisting of ZrF4-BaF2-LaF3-AlF3-NaF fiber, As2S3 fiber, and As2Se3 fiber pumped by a nanosecond thulium master oscillator power amplifier system. The highest on-time average power generated is 417 mW at 33% duty cycle. We observe a near-diffraction-limit beam quality across the wavelength range from 3 MUm to 12 MUm, even though the As2Se3 fiber is multimode below 12 MUm. Our study also shows that parameters of the As2Se3 fiber, such as numerical aperture, core size, and core/cladding composition, have significant effects on the long wavelength edge of the generated SC spectrum. Our results suggest that the high numerical aperture of 0.76 and low-loss As2Se3/GeAs2Se5 core/cladding material all contribute to broad SC generation in the long-wave infrared spectral region. Also, among our results, 10 MUm core diameter selenide fiber yields the best spectral expansion, while the 12 MUm core diameter selenide fiber yields the highest output power. PMID- 29714237 TI - High-sensitivity humidity sensing of side-polished optical fiber with polymer nanostructure cladding. AB - This paper presented a high-sensitivity humidity sensor comprised of a side polished fiber with polymer nanostructure cladding, which was constructed by dehydrating dichromate gelatin film on the polished surface. Due to the intermodal interference of the core mode and cladding mode, two main transmission dips were observed at 1184.4 nm and 1325.6 nm. These two transmission dips showed significant sensitivity to humidity. The position of transmission dip at 1325.6 nm shifted 22 nm while the relative humidity (RH) changed from 30% RH to 50% RH. The humidity sensitivity was up to 1.12 nm/% RH, and its linear correlation was 98.45%. The humidity sensing characteristic of nanostructure cladding fiber was successfully demonstrated. This novel sensor is compatible with optical fiber systems and has high potential in optical sensing applications. PMID- 29714238 TI - Resolution enhancement of wide-field interferometric microscopy by coupled deep autoencoders. AB - Wide-field interferometric microscopy is a highly sensitive, label-free, and low cost biosensing imaging technique capable of visualizing individual biological nanoparticles such as viral pathogens and exosomes. However, further resolution enhancement is necessary to increase detection and classification accuracy of subdiffraction-limited nanoparticles. In this study, we propose a deep-learning approach, based on coupled deep autoencoders, to improve resolution of images of L-shaped nanostructures. During training, our method utilizes microscope image patches and their corresponding manual truth image patches in order to learn the transformation between them. Following training, the designed network reconstructs denoised and resolution-enhanced image patches for unseen input. PMID- 29714239 TI - Steep large film thickness measurement with off-axis terahertz digital holography reconstructed by a direct Fourier and Hermite polynomial. AB - In this paper, we enhance the steepness of film thickness edge in terahertz off axis digital holography by employing a reconstruction method based on a direct Fourier and Hermite polynomial function. The method is applied to samples of 110 MUm and 80 MUm step heights to extract the phase images in real time. Use of this method reduces the resolution factor by around one half, representing around a 50% decrease in critical dimension as compared with conventional measurements. The method is very promising and opens the route to potential applications in the fields of microlithography. PMID- 29714240 TI - Turning a conventional camera into a 3D camera with an add-on. AB - We propose to add an optical component in front of a conventional camera to improve depth estimation performance of depth from defocus (DFD), an approach based on the relation between defocus blur and depth. The add-on overcomes ambiguity and the dead zone, which are the fundamental limitations of DFD with a conventional camera, by adding an optical aberration to the whole system that makes the blur unambiguous and measurable for each depth. We look into two optical components: the first one adds astigmatism and the other one chromatic aberration. In both cases, we present the principle of the add-on and experimental validations on real prototypes. PMID- 29714241 TI - Demonstration of an optical directed half-subtracter using integrated silicon photonic circuits. AB - An integrated silicon photonic circuit consisting of two silicon microring resonators (MRRs) is proposed and experimentally demonstrated for the purpose of half-subtraction operation. The thermo-optic modulation scheme is employed to modulate the MRRs due to its relatively simple fabrication process. The high and low levels of the electrical pulse signal are utilized to define logic 1 and 0 in the electrical domain, respectively, and the high and low levels of the optical power represent logic 1 and 0 in the optical domain, respectively. Two electrical pulse sequences regarded as the operands are applied to the corresponding micro heaters fabricated on the top of the MRRs to achieve their dynamic modulations. The final operation results of bit-wise borrow and difference are obtained at their corresponding output ports in the form of light. At last, the subtraction operation of two bits with the operation speed of 10 kbps is demonstrated successfully. PMID- 29714242 TI - Diffraction characteristics of a Laguerre-Gaussian beam through a Maksutov Cassegrain optical system. AB - Maksutov-Cassegrain (MC) systems are widely used in long-range free-space optical (FSO) communication. In this study, analytical expressions for the diffraction field of a Laguerre-Gaussian (LG) beam passing through an MC system have been derived. The numerical results reveal that, in the long-range FSO system, the replacement of a Gaussian beam by the LG beam enhances the emission efficiency of the MC. Furthermore, the MC has a shaping effect on the LG beam, and the orbital angular momentum of the LG beam is not dispersed when the beam is diffracted by the MC. PMID- 29714243 TI - Powder sum-frequency generation as a versatile method for infrared optical alignment. AB - The sum-frequency generation (SFG) in potassium dihydrogen phosphate (KDP) powder with MUm-grade particle size is successfully demonstrated under various experimental conditions. Two focused beams of 870 nm and 1369 nm are used for SFG excitation. SFG is observed under different excitation energies. The SFG intensity shows isotropy with different observation azimuths. The intersection angle between two excitation beams is not limited by conventional phase-matching conditions, and it owns the flexibility of a very large allowed range, e.g., it can be 0 degrees ~100 degrees in this work. The polarization combination of excitation beams is not limited either. Thanks to the non-toxicity, low price, and low SFG threshold properties of KDP material and the optical flexibility, this powder SFG technology is a versatile method and is expected to be applied to various situations of optical alignment, e.g., surface SFG, four-wave mixing, coherent anti-Stokes Raman spectroscopy, multi-color laser excitation, etc. The effect of potential powder SFG-assisted optical alignments is also discussed. Extension of this method to multi-beams, tight focusing beams, and plasmonic polariton devices is proposed. PMID- 29714244 TI - 3D profiling of rough silicon carbide surfaces by coherence scanning interferometry using a femtosecond laser. AB - We test an erbium-doped fiber femtosecond laser for its potential as a light source for a coherence scanning interferometer for large field-of-view profiling of rough silicon carbide (SiC) surfaces. This infrared fiber pulse laser is able to provide a relatively long temporal coherence length of ~30 MUm to be appropriate for coherence scanning of rough surfaces. At the same time, it offers a high degree of spatial coherence comparable to that of a monochromatic continuous wave laser to achieve a large measurement field of view. In addition, the highly maintained linear polarization of the pulse laser source permits overcoming the low specular reflectance of rough SiC surfaces by polarization based optical power splitting control between the reference and measurement arms. PMID- 29714245 TI - Study on spectral and refractive index sensing characteristics of etched excessively tilted fiber gratings. AB - We investigated the spectral and refractive index (RI) sensing characteristics of the excessively tilted fiber grating (Ex-TFG) with different cladding diameters. The Ex-TFG is inscribed in standard single-mode fiber, and the cladding reduces from 125 MUm to around 15 MUm by the chemical etching method. Experimental results show that the number of cladding modes decreases, and the spacing of adjacent resonance peaks becomes larger and larger with the reduction of the cladding diameter in the observed wavelength range of 1250-1650 nm. The average RI sensitivity in the index region of 1.33-1.38, the one near 1.33, and the one at around 1.38 of the etched Ex-TFG with a diameter of 15 MUm is ~6.3, ~5.3, and ~6.67 fold compared to those of the no-etched Ex-TFG, respectively. Also, the RI sensing performances of the etched Ex-TFG with a diameter smaller than 30 MUm are better than those of the Ex-TFG inscribed in SM1500 (4.2 MUm/80 MUm) fiber in the index region of 1.33. The proposed micronano Ex-TFG has higher RI sensitivity and a more compact structure in biosensing applications, compared to the standard Ex TFGs and Ex-TFGs inscribed in SM1500 fiber. PMID- 29714246 TI - Optical measurements of dynamic wetting and dynamic contact angle. AB - We present a method of optical measurement of the dynamic wetting, the dynamic contact angles, and the changes of the dynamic curved liquid surface corresponding to dynamic wetting, which uses the critical light reflection from dynamic curved liquid surfaces due to the dynamic wetting. When an expanded and collimated laser beam impinges on the dynamic curved liquid surfaces at glancing incidence, the special reflection patterns, which correspond to the different states of the dynamic wetting, are observed. Based on an analytic relation between the bright/dark region width and the height of down-/up-curved liquid surfaces, we proposed a method of optical measurement. In the experiment, a rod such as iron, copper, or aluminum is immersed at constant speed (u=0.2 mm/s) into a liquid bath and withdrawn out gradually. We measured the changing curve of the dynamic contact angle of the iron rod and the characterization of the dynamic curved liquid surface of the iron rod. PMID- 29714247 TI - Influence of passive facet of multilayer diffractive optical elements. AB - The effect of a passive facet on diffraction efficiency of multilayer diffraction optical elements (MLDOEs) was analyzed, and the mathematical model of polychromatic integral diffraction efficiency affected by a passive blazed facet for MLDOEs is presented. We found the passive facet could cause a significant reduction in polychromatic integral diffraction efficiency in the working waveband. The reduction of diffraction efficiency is quantitatively described by the shielding effect, which is caused by the sidewall slope of sawtooth-shaped MLDOEs. Through rigorous calculations, our shielding model is consistent with the numerical results. The analysis results can be utilized for fabrication of MLDOEs, and our shielding model of the passive facet can be applied to predict the optical performance of MLDOEs and refractive-diffractive hybrid imaging optical systems. PMID- 29714248 TI - No-reference stereoscopic image quality assessment guided by visual hierarchical structure and binocular effects. AB - Stereoscopic image quality assessment (SIQA) is an essential technique for modern 3D image and video processing systems serving as performance evaluators and monitors. However, the study on SIQA remains immature due to the complexity of the human visual system (HVS) and binocular effects that binocular vision brings about. To overcome the difficulties, a novel method is proposed that extracts and quantifies image quality-aware features related to cortex areas in charge of visual quality perception, rather than attempting to rigorously simulate the biological processing in HVS, so that the predicting accuracy is preserved while the computational complexity remains moderate. Meanwhile, binocular effects including binocular rivalry and visual discomfort are taken into consideration. Moreover, the proposed method can be operated completely without the assistance of reference images, indicating its wide practical usages. Compared to state-of the-art works, our method shows evident superiority in terms of effectiveness and robustness. PMID- 29714249 TI - Compact optical image amplifier pumped by a sub-nanosecond Nd:YAG microlaser. AB - A compact sub-nanosecond optical image amplifier is proposed and demonstrated. It is pumped by an actively Q-switched diode-pumped Nd:YAG microlaser in virtue of the optical parametric amplification (OPA) technique and quasi-phase-matching scheme. Experimental results show that the optical image gain reaches 15.4 dB under a pump intensity of 15.3 MW/cm2. The influence of parametric fluorescence noise on the amplified image is obvious above 10 dB gain. The signal-to-noise ratio degradation of the amplifier image characterized by the noise figures is in sheer contrast with theoretical expectations. It shows that the experimental noise figure value reaches 2.2 dB, larger than the theoretical result of 0.7 dB at 15 dB gain. PMID- 29714250 TI - Effects of auxiliary atmospheric state parameters on the aerosol optical properties retrieval errors of high-spectral-resolution lidar. AB - A detailed assessment is carried out in relation to the influence of the uncertainties associated with the input auxiliary atmospheric state parameters on retrieving aerosol optical properties from high-spectral-resolution lidar (HSRL) observations. The study starts from a review of the main spectral structure of the Rayleigh backscattering followed by evaluating the temperature effects on a backscattering cross section of atmospheric molecules based on numerical simulation. It shows that the transmittance of the background interference filter should be taken into account, depending on the full width at half maximum, although overall temperature dependence is negligible. Based on the Taylor expansion of the Tenti S6 model, the systematic errors arising from input temperature and pressure profiles are analyzed. It is demonstrated that the atmospheric pressure profiles have limited effects on the inversion results of aerosol optical parameters, as the atmospheric pressure is usually quite stable. The relative errors of the aerosol backscatter coefficient mainly stem from temperature profile errors and highly depend on the aerosol concentration. Quantitatively, the aerosol backscatter coefficient error could be larger than 5% with a 3 K deviation of temperature when the backscatter ratio is larger than 1.1. The accuracy of aerosol extinction coefficient retrieval is affected not only by the error in temperature, but also by the error in temperature lapse rate; the retrieval accuracy is more sensitive to the latter than the former. Further analysis based on the sounding temperature data shows that the variation of the temperature inversion layer during the night could induce a bias larger than 0.04 km-1 on the aerosol extinction coefficient retrieval. Therefore, the time resolution of temperature measurement from sounding balloons twice per day is too low to obtain an accurate retrieval of the aerosol optical properties from the HSRL. PMID- 29714251 TI - Influences of surface defects on the laser-induced damage performances of KDP crystal. AB - When potassium dihydrogen phosphate (KDP) crystals are exposed to high-energy laser irradiation, the pre-existing surface defects may act as damage precursors and will reduce the lifespan of the crystal components. Although it has been found that different kinds of surface defects exhibit distinct damage characteristics, the influence of surface defects on the laser-induced damage performance of KDP crystal is not yet clear. In this paper, KDP surface defects have been characterized by multiple measuring methods and classified into five categories according to their structure features. Laser-induced damage tests were then carried out to investigate the laser-induced damage thresholds of different kinds of KDP surface defects as well as the evolution of the morphology of damage sites. The results of the experiment indicate that the damage thresholds of cracks, fracture pits, and surface protuberances are between 6 and 11 J/cm2 (355 nm, 3 ns, similarly hereinafter), which are much lower than the thresholds of plastic scratches, discontinuous scratches, and a defect-free KDP surface. In addition, it has been found that fluorescence enhancement is just a necessary condition for reduction of damage thresholds. Finally, reasons for the formation of the most threatening KDP surface defects have been analyzed and corresponding suppression measures have been proposed for increasing the surface damage thresholds of the crystal components. PMID- 29714252 TI - Design and analysis of a worm gear turntable off-axis assembly method in a three grating monochromator. AB - To solve the problem where the actual grating aperture decreases with an increasing scanning angle during the scanning of a three-grating monochromator, we propose an off-axis assembly method for the worm gear turntable that makes it possible to suppress this aperture reduction. We simulated and compared the traditional assembly method with the off-axis assembly method in the three grating monochromator. Results show that the actual grating aperture can be improved by the off-axis assembly method. In fact, for any one of the three gratings, when the monochromator outputs the longest wavelength in the corresponding wavelength band, the actual grating aperture increases by 45.93%. Over the entire monochromator output band, the actual grating aperture increased by an average of 32.56% and can thus improve the monochromator's output energy. Improvement of the actual grating aperture can also reduce the stray light intensity in the monochromator and improve its output signal-to-noise ratio. PMID- 29714253 TI - Design of two-dimensional diffractive optical elements for beam shaping of multicolor light-emitting diodes. AB - To achieve a cellular network in visible light communication, the illumination areas covered by red, green, and blue light-emitting diodes (LEDs) forming a white LED should be of the same size with uniform intensity distribution. In this paper, the iterative algorithm for the design of multicolor-oriented two dimensional diffractive optical elements (DOEs) is improved. Simulation results indicate that almost the same size of the diffraction patterns of the DOE illuminated by multicolor LEDs is achieved with good uniformity of the intensity distribution. PMID- 29714254 TI - Solar spectrum matching with white OLED and monochromatic LEDs. AB - In this paper, the solar spectrum matching in the visible range of 380-780 nm with white organic light-emitting diode (OLED) and monochromatic light-emitting diodes (LEDs) is investigated. The correlation index (R2) is used to evaluate the difference between the matching spectrum and the solar spectrum. The optimal combination is obtained by the least squares method. We also perform subtraction experiments to find the optimal combination. We utilize a common white OLED device design and just change the species of monochromatic LEDs used. We report and evaluate different degrees of matching effects. The results show that the correlation index of the best combination can reach 94.09% with white OLED and 36 monochromatic LEDs. We define three levels of performance as an evaluation system in accordance with the matching effect. The level is excellent with an R2 above 90.14%. The good level is from 86.65% to 58.28%. From 42.08% to 33.06% is the reasonable level. Compared with other methods, using white OLED combined with monochromatic LEDs achieves the best solar spectrum matching effect. The results can be applied to different requirements of engineering practice. PMID- 29714255 TI - Influence investigation on ranging performance for range-gated Geiger-mode avalanche photodiode ladar. AB - The ranging performance for Geiger-mode avalanche photodiode (Gm-APD) laser detection and ranging (ladar) is mainly evaluated by range accuracy and precision; although Gm-APD ladar can evaluate the ranging performance of the exact position, it is not helpful to comprehensively evaluate the influence on the ranging of each parameter in the whole gate. Due to the target echo's stochastic trigger making the delay adjustment inaccurate, the position of the echo in the gate is stochastic in the actual detection process, so the theoretical calculation may not be able to make ladar ranging performance clear. As to this question, based on the central limit theorem, and assuming the position of the target in the gate obeys Gaussian distribution, while also combining the Gm-APD triggering probability model, we propose the mean ranging accuracy and precision theory to objectively evaluate the ranging performance. At the same time, we combine the theory with the ladar ranging equation to investigate the effect of parameters such as laser transmitting energy, pulse width, gate width, target range, and noise intensity on ranging performance. The results show high transmitting energy, narrow gate width, short target range, and low noise intensity make mean ranging accuracy and precision low. The narrow pulse width will result in lower mean ranging accuracy and high mean ranging precision. Wide pulse width has the opposite effect; through comprehensive comparison, 10~30 ns pulse width is more reasonable. According to theoretical analysis results, to achieve ladar's high ranging performance, we put forward concrete measures for improvement-reducing the gate width, enhancing laser energy, using a narrowband filter to reduce false alarm of noise, etc., consequently the research in this paper has significance for the Gm-APD ladar experimental parameter selection. PMID- 29714256 TI - Optical phase conjugation of diffused light with infinite gain by using gated two color photorefractive crystal LiNbO3:Cu:Ce. AB - Light focusing in multiple scattering circumstances is important in biomedical imaging, manipulation, and therapy. Until now, many traditional photorefractive crystals have been used to generate an optical phase conjugated wavefront in an analogue time-reversed optical focusing technology. However, owing to erasure of a volume hologram during a reading procedure, the optical energy gain can never reach unity, limiting its application in delivering more energy into a target area. In this work, we investigated a gated two-color photorefractive crystal LiNbO3:Cu:Ce to generate optical phase conjugation of diffused light with infinite gain. PMID- 29714257 TI - Phase-sensitive optical time domain reflectometer with ultrafast data processing based on GPU parallel computation. AB - The sensing performance of a phase-sensitive optical time domain reflectometer (phi-OTDR) has been sufficiently improved, thanks to plenty of valuable research in recent years. However, in the literature, there is hardly any attention aimed at enhancing the data processing capability of the system, the necessity and significance of which are undisputed. This paper, for the first time to the best of our knowledge, analyzed the intrinsic superiority of employing GPU parallel computation in phi-OTDR for improving the data processing capability and presented a comprehensive performance evaluation. Three typical, frequently implemented algorithms in phi-OTDR-moving average, batch fast Fourier transform, and batch correlation dimension computation-are carried out where CPU-based programs and counterpart GPU-based programs are, respectively, developed. Their time-consuming performances in different data scales are experimentally tested and compared. The experiment results show that in each case, employing GPU parallel computation can significantly enhance the system's data processing capacity, thus providing a feasible and efficient way of guaranteeing real-time operation with the growing data scale. PMID- 29714258 TI - Smart design of a long-period fiber grating refractive index sensor based on dual peak resonance near the phase-matching turning point. AB - This paper presents a smart design way for the long-period fiber grating (LPFG) refractive index sensor, which is based on high sensitivity of LPFG near phase matching turning point (PMTP) to the surrounding refractive index (SRI). On the basis of the coupled mode theory of LPFG, cladding etching and film coating have opposite effects on the shift of the dual peaks. Therefore, an LPFG can be controlled by the cladding etching and film coating successively, until it operates near PMTP. Experimentally, an LPFG operating near PMTP was fabricated, and the glycerol solution concentration monitoring test was performed. The results show that the sensitivity of this LPFG to the SRI is as high as 5602 nm/refractive index unit. PMID- 29714259 TI - Dual-plane slightly off-axis digital holography based on a single cube beam splitter. AB - In order to recover the holographic object information, a method based on the recording of two digital holograms, not only at different planes but also in a slightly off-axis scheme, is presented. By introducing a pi-phase shift in the reference wave, the zero-order diffracted term and the twin image are removed in the frequency domain during the processing of the recorded holograms. We show that the zero-order elimination by the phase-shifted holograms is better than working with weak-order beam and average intensity removal methods. For recording experimentally two pi-shifted holograms at different planes slightly off-axis, a single cube beam splitter is used. Computer simulations and experimental results, carried out to validate our proposal, show a high accuracy of pi/14 that can be comparable with phase-shifting digital holography. For high fringe spacing, our proposal could be applied in electron holography, avoiding high voltage in a biprism. PMID- 29714260 TI - Automated collimation testing by determining the statistical correlation coefficient of Talbot self-images. AB - In this paper, we propose a simple, fast, and accurate technique for detection of collimation position of an optical beam using the self-imaging phenomenon and correlation analysis. Herrera-Fernandez et al. [J. Opt.18, 075608 (2016)JOOPDB0150-536X10.1088/2040-8978/18/7/075608] proposed an experimental arrangement for collimation testing by comparing the period of two different self images produced by a single diffraction grating. Following their approach, we propose a testing procedure based on correlation coefficient (CC) for efficient detection of variation in the size and fringe width of the Talbot self-images and thereby the collimation position. When the beam is collimated, the physical properties of the self-images of the grating, such as its size and fringe width, do not vary from one Talbot plane to the other and are identical; the CC is maximum in such a situation. For the de-collimated position, the size and fringe width of the self-images vary, and correspondingly the CC decreases. Hence, the magnitude of CC is a measure of degree of collimation. Using the method, we could set the collimation position to a resolution of 1 MUm, which relates to +/-0.25 MU radians in terms of collimation angle (for testing a collimating lens of diameter 46 mm and focal length 300 mm). In contrast to most collimation techniques reported to date, the proposed technique does not require a translation/rotation of the grating, use of complicated phase evaluation algorithms, or an intricate method for determination of period of the grating or its self-images. The technique is fully automated and provides high resolution and precision. PMID- 29714261 TI - Design methods to generate a computer hologram for improving image quality. AB - In order to suppress the speckle noise on a holographic display, we propose two design methods to initialize the phase to generate a computer hologram illuminating with partially coherent light. We introduce an initial phase of the image in consideration of the relationship of gray value among adjacent pixels when generating the computer hologram. After simulations, we compare these two methods and conclude that one is better than the other in terms of running speed or quality of the reconstructed image. Finally, we perform experiments to verify the theory. It is expected that these methods can greatly enhance the quality of reconstructed images and could be widely applied in the holographic field in the future. PMID- 29714262 TI - Active control of an edge-mode-based plasmon-induced absorption sensor. AB - We investigate the formation and evolution of plasmon-induced absorption (PIA) effect in a three-dimensional graphene waveguide structure. The PIA window is formed by near-field coupling of the graphene edge mode, the extremely destructive interference between the radiative mode and sub-radiative mode of graphene nanoribbons. The resonance intensity has a significant dependence on the coupling distance between the graphene nanoribbons. At the same time, it is particularly sensitive to the refractive index of the environment, which is promising for sensing devices. In addition, the resonant wavelength can be actively controlled by changing the Fermi energy of graphene. Moreover, it can be seen that the group time delay of the PIA window reaches -0.28 ps, which is a good candidate for ultrafast light application. Finally, additional graphene nanoribbons can also form a double-channel PIA window. Our work may provide an excellent platform for controlling the optical transmission of highly integrated plasmonic components. PMID- 29714263 TI - Light sheet fluorescence microscopic imaging for the primary breakup of diesel and gasoline sprays with real-world fuels. AB - This paper describes the adaptation of the laser-induced fluorescence measurement technique for the investigation of the primary breakup of modern diesel and gasoline direct injection sprays. To investigate the primary breakup, a microscopic technique is required, and with the help of special tracer dyes, a high fluorescence signal can be achieved in the visible range of the electromagnetic spectrum, resulting in good image quality with a nonintensified camera. Besides the optimization of the optical setup for the microscopic field of view, different tracer dyes are compared, and their solubility and fluorescence are tested in the desired surrogate and real-world fuels. As a tracer, the phenoxazine dye Nile Red was found to provide sufficient solubility in alkanes as well as suitable emission and excitation spectrum for the use of the second-harmonic frequency of a Nd:YAG laser (532 nm). The good quantum efficiency delivered by Nile Red also meant that single-shot images clearly showing spray structures in regions measuring up to 3 mm by 3 mm around the nozzle outlet could be recorded. Compared to relatively easy shadowgraph techniques and complex and costly x-ray synchrotron measurements, light sheet fluorescence microscopic imaging is not overly complex yet delivers excellent data on spray structures as well as qualitative fuel distribution. PMID- 29714264 TI - All-optical tunable power splitter based on a surface plasmonic two-mode interference waveguide. AB - In this paper, we have introduced a surface plasmonic two-mode interference (SPTMI) coupler having a silicon core, GaAsInP side cladding, and silver top and bottom cladding as an optical power splitter. A wide range of tunability from the 50?50 splitting ratio to 1?99 is achieved by refractive index modulation of the GaAsInP cladding with application of varying optical pulse power. The coupling length of the SPTMI-based splitter is ~11.5 times less than that of a previously reported optical power splitter based on multimode waveguide holograms. The proposed optical power splitter has potential in development of large-scale integrated circuits due to its compactness and high fabrication tolerance. PMID- 29714265 TI - Acousto-Optics 2017: introduction to the feature issue. AB - The editors of Acousto-Optics 2018 provide an overview of the featured papers in the context of the 13th School of Acousto-Optics and Applications from which the articles were drawn. PMID- 29714266 TI - Secure free-space communication, turbulence mitigation, and other applications using acousto-optic chaos. AB - Use of acousto-optic (A-O) chaos via the feedback loop in a Bragg cell for signal encryption began as a conceptual demonstration around 2008. Radio frequency (RF) chaos from a hybrid A-O feedback device may be used for secure communications of analog and digital signals. In this paper, modulation of RF chaos via first-order feedback is discussed with results corroborated by nonlinear dynamics, bifurcation maps, and Lyapunov analyses. Applications based on encryption with profiled optical beams, and extended to medical and embedded steganographic data, and video signals are discussed. It is shown that the resulting encryption is significantly robust with key tolerances potentially less than 0.1%. Results are also presented for the use of chaotic encryption for image restoration during propagation through atmospheric turbulence. PMID- 29714267 TI - Rapid acousto-optic focus tuning for improvement of imaging performance in confocal microscopy [Invited]. AB - We demonstrate the application of focus-tunable acousto-optic lens technology in confocal microscopy for a high-speed axial scanning of the object. The advantages of the proposed approach include high axial scan rate, no mechanical sample movement, no additional non-symmetric aberrations, and the control of the effective depth of focus. The acousto-optic lens operating at the focus tuning rate of 300 kHz is developed and implemented in scanning laser confocal microscopy. The performance of the instrumentation is presented using test targets. Rapid focus tuning may enhance in vivo three-dimensional imaging in confocal microscopy. PMID- 29714268 TI - Acousto-optic control of internal acoustic reflection in tellurium dioxide crystal in case of strong elastic energy walkoff [Invited]. AB - Peculiar cases of acoustic wave propagation and reflection may be observed in strongly anisotropic acousto-optical crystals. A tellurium dioxide crystal serves as a prime example of such media, since it possesses record indexes of acoustic anisotropy. We studied one of the unusual scenarios of acoustic incidence and reflection from a free crystal-vacuum boundary in paratellurite. The directions of the acoustic waves in the (001) plane of the crystal were determined, and their basic characteristics were calculated. The carried-out acousto-optic experiment at the wavelength of light 532 nm and the acoustic frequency 73 MHz confirmed the theoretical predictions. The effects examined in the paper include the acoustic wave propagation with the record walkoff angle 74 degrees . We also observed the incidence of the wave on the boundary at the angle exceeding 90 degrees . Finally, we registered the close-to-back reflection of acoustic energy following the incidence. One of the stunning aspects is the distribution of energy between the incident and the back-reflected wave. The unusual features of the acoustic wave reflections pointed out in the paper are valuable for their possible applications in acousto-optic devices. PMID- 29714269 TI - Measuring photoelastic coefficients with Schaefer-Bergmann diffraction. AB - A novel technique for measuring the relative photoelastic coefficients using Schaefer-Bergmann diffraction is introduced and applied to fused silica and alpha BaB2O4. The measurements of fused silica agree with the accepted values to within 0.4%, and the alpha-BaB2O4 measurements are verified with results presented in this paper from the established Dixon method. PMID- 29714270 TI - Wavelength characterization of an acousto-optic notch filter for unpolarized near infrared light. AB - A cascaded system of two acousto-optical cells is proposed and experimentally demonstrated for optical notch rejection filtering in the spectral range from 1400 nm to 1600 nm. Two similar paratellurite acousto-optical devices for unpolarized light are used in a free-space gap of a fiber line. Compensation for birefringence in anisotropic paratellurite devices provides a diffraction regime that is insensitive to polarization of light. High extinction ratios up to 40 dB are measured. PMID- 29714271 TI - Acousto-optic filters based on the superposition of diffraction fields [Invited]. AB - Methods for the calculation of the acousto-optic (AO) transfer functions forming as a result of superposition of two AO fields with similar and orthogonal light polarizations are proposed. Specific calculations are made on the basis of the parameters widely used in practice with uni-axial gyrotropic crystal paratellurite. It is revealed that the resulting field is generally very inhomogeneous but contains domains with two-dimensional behavior properties. These domains can be used for two-dimensional image edge enhancement based on Fourier processing. Theoretical conclusions are verified by means of the optical image Fourier processing with the spatial frequency AO paratellurite filters. PMID- 29714272 TI - Investigation of ultrasonic action effects in quantum heterolasers. AB - The influence of alternating strains on the spectral characteristics of the radiation of quantum-dimensional heterolasers is studied experimentally and theoretically. A brief review of the previously obtained results of the study of the deformation effect on the frequency spectrum of radiation is presented. A detailed analysis of the results obtained recently in the study of the influence of ultrasonic strain on the polarization properties of laser structures of various compositions is carried out. An anomalously large effect of rotation of polarization by ultrasonic strain has been found in laser structures on quantum dots. PMID- 29714273 TI - Interference of phase-shifted chirped laser pulses for secure free-space optical communications. AB - A new method concerning secure free-space communications by means of chirped laser pulse interference is proposed. Physical-layer security of the link is ensured by encoding the data in a relative phase difference between two spatially separated beams. The possible architecture of the dual-node link is discussed based on acousto-optic elements for signal modulation and detection. PMID- 29714274 TI - Wide-band white light sparse-aperture Fizeau imaging interferometer testbed for a distributed small-satellites constellation. AB - Under the background of astronomical observation by a distributed small satellites constellation, a Fizeau imaging interferometer testbed (FIIT) was designed and constructed at National Astronomical Observatories of the Chinese Academy of Sciences in the past four years that achieved wide-band white light (400-700 nm) phased imaging at laboratory with a field of view (FOV) ~2 arcmin. This study presents the design of FIIT, which is mainly composed of a light source module for simulating infinite objects, three sub-telescopes in a Golay-3 distribution (i.e., equilateral triangle), three tip/tilt correction modules and optical path delay modules, as well as three detecting telescopes and one beam combining telescope for phased imaging. The three detecting telescopes could determine the piston and tip/tilt errors, which could be compensated for by optical path delay modules and fast steering mirrors in a close-loop mode. The performance of FIIT is also derived analytically and simulated by a ray-tracing model. The tolerance analysis of the pupil geometry and magnification matching are also performed for achieving a better FOV. The optical test of each module could efficiently validate them to achieve diffraction limit imaging. The preliminary experimental results for both point source and extend scene could sufficiently demonstrate the phased mode imaging of FIIT, thus validating the good prospects of this technique in the future. PMID- 29714275 TI - Efficient solution to the stagnation problem of the particle swarm optimization algorithm for phase diversity. AB - The phase diversity (PD) technique needs optimization algorithms to minimize the error metric and find the global minimum. Particle swarm optimization (PSO) is very suitable for PD due to its simple structure, fast convergence, and global searching ability. However, the traditional PSO algorithm for PD still suffers from the stagnation problem (premature convergence), which can result in a wrong solution. In this paper, the stagnation problem of the traditional PSO algorithm for PD is illustrated first. Then, an explicit strategy is proposed to solve this problem, based on an in-depth understanding of the inherent optimization mechanism of the PSO algorithm. Specifically, a criterion is proposed to detect premature convergence; then a redistributing mechanism is proposed to prevent premature convergence. To improve the efficiency of this redistributing mechanism, randomized Halton sequences are further introduced to ensure the uniform distribution and randomness of the redistributed particles in the search space. Simulation results show that this strategy can effectively solve the stagnation problem of the PSO algorithm for PD, especially for large-scale and high-dimension wavefront sensing and noisy conditions. This work is further verified by an experiment. This work can improve the robustness and performance of PD wavefront sensing. PMID- 29714276 TI - Numerical modeling of the effect of multiple incoherent layers in Cu(In,Ga)Se2 solar cells based on the equispaced thickness averaging method. AB - We investigate the effect of multiple incoherent layers on the optical characteristics of Cu(In,Ga)Se2 (CIGS) solar cells, based on the equispaced thickness averaging method (ETAM). The studied multiple incoherent layers consist of a glass cover layer, surface flattening layer, and transparent conducting layer, whose respective thicknesses are larger than the coherence length of sunlight (~0.6 MUm). An independent equispaced thickness is added to each incoherent layer and the coherent simulation results, obtained by the finite element method, are averaged over a combination of the equispaced thicknesses. By applying the proposed method, we calculated the reflectance spectra in planar and surface-textured CIGS solar cells. Considering the planar structure, the calculation results based on the ETAM are in good agreement with the exact analytical solution based on the generalized transfer matrix method. The statistical deviation from the exact solution was calculated with respect to the number of the equispaced thicknesses in each incoherent layer. When only four equispaced thicknesses are used, the calculated deviation from the exact solution rapidly decreases to 1% for planar and 10% for surface-textured CIGS solar cells, which demonstrates that the effect of the multiple incoherent layers can be efficiently calculated based on the ETAM in thin-film solar cells. PMID- 29714277 TI - Multiple light scattering in metallic ejecta produced under intense shockwave compression. AB - A roughened metallic plate, subjected to intense shock wave compression, gives rise to an expanding ejecta particle cloud. Photonic Doppler velocimetry (PDV), a fiber-based heterodyne velocimeter, is often used to track ejecta velocities in dynamic compression experiments and on nanosecond time scales. Shortly after shock breakout at the metal-vacuum interface, a particular feature observed in many experiments in the velocity spectrograms is what appear to be slow-moving ejecta, below the free-surface velocity. Using Doppler Monte Carlo simulations incorporating the transport of polarization in the ejecta, we show that this feature is likely to be explained by the multiple scattering of light, rather than by possible collisions among particles, slowing down the ejecta. As the cloud expands in a vacuum, the contribution of multiple scattering decreases due to the limited field of view of the pigtailed collimator used to probe the ejecta, showing that the whole geometry of the system must be taken into account in the calculations to interpret and predict PDV measurements. PMID- 29714278 TI - GaN-based mid-power flip-chip light-emitting diode with high -3 dB bandwidth for visible light communications. AB - By directly flip-chip soldering three mid-power light-emitting diode (LED) chips with periodic micro-via-holes on ceramic substrates, -3 dB modulation bandwidths of 49.9 MHz, 58.8 MHz, and 25 MHz are obtained at the driving current of 170 mA. To the best of our knowledge, these are the reported highest -3 dB bandwidth values for flip-chip power-type LEDs (FC-LEDs) at the low-bias current levels. Moreover, good radiant powers are also achieved: 180.2 mW, 168.8 mW, and 233.8 mW at 150 mA, respectively. With a gold wire-free feature, the fabricated FC-LEDs could offer an opportunity to miniaturize the package volume of a LED module for illumination and free-space high-speed VLC dual-usage applications. PMID- 29714279 TI - Technique for two-dimensional displacement field determination using a reliability-guided spatial-gradient-based digital image correlation algorithm. AB - This paper proposed a novel in-plane displacement field measurement algorithm using an optical flow strategy. We built a linear illumination model between images before and after deformation to guarantee intensity invariability. We used image upsampling and a reliability-guided strategy to find the matching points accurate to 0.5 pixels in the reference and deformed images. The criterion to determine the reliability is zero-mean normalized cross-correlation coefficient. Afterward, we used the brightness constancy constraint combined with Lucas-Kanade optical flow constraint in a specific image region to obtain an overdetermined linear equation. We applied the noniterative least-squares algorithm to solve the equations and to achieve the displacement offsets. This research utilized multithread calculation to handle the complete cracking applications. We estimated the computing efficiency and calculation precision of the proposed method through a series of experimental speckle patterns. All results demonstrated the correctness, effectiveness, and robustness of the proposed method. PMID- 29714280 TI - Emissivity determination using the photoacoustic effect. AB - We show that emissivities in the near infrared can be determined relative to a reference surface employing the photoacoustic effect. The photoacoustic cell is equipped with two windows and a pair of synchronously moving chopping wheels so that the cell alternately views the test and the reference surface. The acoustic signals produced in the cell are detected with a microphone and that output is fed to a lock-in amplifier. The temperature of the test surface is varied to produce a null in the lock-in amplifier, which permits determination of a relative emissivity. Results of measurements for several plastic and metal surfaces are reported. PMID- 29714281 TI - Validity of the instrument transfer function for fringe projection metrology. AB - When fringe projection profilometry is used for measuring texture on rough surfaces, the measurement resolution is subject to the spatial frequency response of the instrument. The instrument transfer function (ITF) is a good metric to quantify this property. A valid ITF analysis requires the system to be linear. In this paper, we investigate the validity of using ITF to characterize the spatial resolution of a fringe projection system. Approximate linearity is shown through a mathematical analysis and simulation. We also demonstrate a practical method for measuring ITF using a stepped surface. The measured ITF is compared with an ITF prediction, which is simulated with a theoretical model. PMID- 29714282 TI - Effect of electron avalanche breakdown on a high-purity semi-insulating 4H-SiC photoconductive semiconductor switch under intrinsic absorption. AB - High-power photoconductive semiconductor switching devices were fabricated from a high-purity, semi-insulating 4H-SiC wafer. A highly n-doped GaN subcontact layer was inserted between the contact metal and the high-resistivity SiC wafer. The minimum ON-state resistance of the device was less than 1 ohm when the energy of a 355 nm laser was 10.5 mJ with a bias voltage of 6 kV. The maximum device lifetime is 3151 pulses, after which the device completely fails. The failure mechanisms are determined using several analysis methods. Under a strong electric field, the failure mechanism differs for the two electrodes. Near the edge of the anode electrode, the switch is damaged due to the thermal stress caused by impact ionization. At the edge of the cathode electrode, the electrode erosion is the main reason for the failure to operate for long periods of time. These two different damage mechanisms are both important factors influencing the device performance. The electron avalanche breakdown at the edge of the anode electrode causes the formation of cracks between the electrodes, which is the root cause of the switch failure. PMID- 29714283 TI - Reducing the minimum range of a RGB-depth sensor to aid navigation in visually impaired individuals. AB - The introduction of RGB-depth (RGB-D) sensors harbors a revolutionary power in the field of navigational assistance for the visually impaired. However, RGB-D sensors are limited by a minimum detectable distance of about 800 mm. This paper proposes an effective approach to decrease the minimum range for navigational assistance based on a RGB-D sensor of RealSense R200. A large-scale stereo matching between two infrared (IR) images and a cross-modal stereo matching between one IR image and RGB image are incorporated for short-range depth acquisition. The minimum range reduction is critical not only for avoiding obstacles up close, but also in the enhancement of traversability awareness. Overall, the minimum detectable distance of RealSense is reduced from 650 mm to 60 mm with qualified accuracy. A traversable line is created to give feedback to visually impaired individuals through stereo sound. The approach is proved to have usefulness and reliability by a comprehensive set of experiments and field tests in real-world scenarios involving real visually impaired participants. PMID- 29714284 TI - Vibration identification based on Levenberg-Marquardt optimization for mitigation in adaptive optics systems. AB - When high performance is expected, vibrations are becoming a burning issue in adaptive optics systems. For mitigation of these vibrations, in this paper, we propose a method to identify the vibration model. The nonlinear least squares algorithm named the Levenberg-Marquardt method is adapted to acquire the model parameters. The experimental validation of the high performance of vibration mitigation associated with our identification method has been accomplished. Benefiting from this method, vibrations have been significantly suppressed using linear quadratic Gaussian control, where the root-mean-square of the residual vibrations has been reduced down to a portion of a microradian. Moreover, the experimental results show that with the model identified, vibrations ranging from wide low-frequency perturbation to high-frequency vibration peaks can be dramatically mitigated, which is superior to classical control strategies. PMID- 29714285 TI - Arbitrary trapezoidal illumination generation method based on variable slits for optical lithography. AB - Trapezoidal illumination is an effective approach to improve the integrated uniformity of light intensity in a step-and-scan lithographic system. When different laser pulses are utilized, the optimal trapezoidal illumination varies. In addition, if the coherence factor takes different values, the outline of the trapezoidal illumination varies as well, directly affecting the integrated uniformity of light intensity. To reduce the impact of variations in trapezoidal illumination, a newly designed method for generating arbitrary trapezoidal illuminations using variable slits is proposed. The performance of our method after adjusting the trapezoidal outline for different coherence factors in different illumination modes was verified through optical simulations. Compared to the traditional method, the proposed strategy to realize arbitrary trapezoidal illuminations based on variable slits can obtain the best outlines for illumination, calculated by balancing pulse quantization error and energy losses. Furthermore, when different coherence factors are applied, the outline of the generated trapezoidal illumination can always be maintained by simply moving the blades an appropriate distance. PMID- 29714286 TI - Morphologies and optical and electrical properties of InGaN/GaN micro-square array light-emitting diode chips. AB - InGaN/GaN micro-square array light-emitting diode (LED) chips (micro-chips) have been prepared via the focused ion beam (FIB) etching technique, which can not only reduce ohmic contact degradation but also control the aspect ratio precisely in three-dimensional (3D) structure LED (3D-LED) device fabrication. The effects of FIB beam current and micro-square array depth on morphologies and optical and electrical properties of the micro-chips have been studied. Our results show that sidewall surface morphology and optical and electrical properties of the micro chips degrade with increased beam current. After potassium hydroxide etching with different times, an optimal current-voltage and luminescence performance can be obtained. Combining the results of cathodoluminescence mappings and light output current characteristics, the light extraction efficiency of the micro-chips is reduced as FIB etch depth increases. The mechanisms of micro-square depth on light extraction have been revealed by 3D finite difference time domain. PMID- 29714287 TI - Lensless light-field imaging with Fresnel zone aperture: quasi-coherent coding. AB - We propose a new type of lensless camera enabling light-field imaging for focusing after image capture and show its feasibilities with some prototyping. The camera basically consists only of an image sensor and Fresnel zone aperture (FZA). Point sources making up the subjects to be captured cast overlapping shadows of the FZA on the sensor, which result in overlapping straight moire fringes due to multiplication of another virtual FZA in the computer. The fringes generate a captured image by two-dimensional fast Fourier transform. Refocusing is possible by adjusting the size of the virtual FZA. We found this imaging principle is quite analogous to a coherent hologram. Not only the functions of still cameras but also of video cameras are confirmed experimentally by using the prototyped cameras. PMID- 29714288 TI - Assessment and removal of additive noise in a complex optical coherence tomography signal based on Doppler variation analysis. AB - In this study, we investigate and validate a novel approach to assess and remove additive noise for optical coherence tomography (OCT) imaging. Our method first generates a map of additive noise for the OCT image through Doppler variation analysis. We then remove the additive noise from the real and imaginary parts of the complex OCT signal through pixelwise Wiener filtering. Our results show that the method described in this manuscript improves the sensitivity of OCT imaging and preserves the spatial resolution without the need to modify the imaging apparatus and data acquisition protocol. PMID- 29714289 TI - Characterization of aerosol optical properties using multiple clustering techniques over Zanjan, Iran, during 2010-2013. AB - Discrimination of aerosol types is very important, because different aerosols are created from diverse sources having different chemical, physical, and optical properties. In the present study, we have analyzed the seasonal classification of aerosol types by multiple clustering techniques, using AERosol Robotic NETwork (AERONET) data during 2010-2013 over Zanjan, Iran. We found that aerosol optical depth (AOD) showed pronounced seasonal variations of a summer high and winter low. Conversely, the values of the Angstrom exponent (AE) in winter and fall were higher than in spring and summer, which confirmed the presence of fine particles, while the low value of AE in the summer and spring represented the existence of coarse particles. Single Scattering Albedo (SSA) variations revealed the presence of scattering aerosols like dust in spring, summer, and fall while the dominance of absorbing-type aerosols in winter were also observed. The influence of local anthropogenic activities has caused a higher concentration of fine aerosols, and a higher fine mode fraction (FMF) of AOD in winter was recorded. Classification of aerosol types was carried out by analyzing different aerosol properties such as AOD versus AE, extinction Angstrom exponent (EAE) versus SSA, EAE versus absorption Angstrom exponent (AAE), FMF AOD versus EAE, and SSA versus FMF AOD. The analysis revealed the presence of dust and polluted dust in spring, summer, and fall in the atmosphere of Zanjan. Urban/industrial aerosols were available in all seasons, especially in fall and winter. The mixed aerosols existed in all seasons over the study location; however, no biomass burning aerosols were found. The Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observations (CALIPSO) aerosol subtype profiles showed the dominance of dust and polluted dust in spring and summer. However, the presence of polluted dust and industrial smoke during fall and winter were also noted over the study site. PMID- 29714290 TI - Channel correlation and BER performance analysis of coherent optical communication systems with receive diversity over moderate-to-strong non Kolmogorov turbulence. AB - In this paper, new expressions of the channel-correlation coefficient and its components (the large- and small-scale channel-correlation coefficients) for a plane wave are derived for a horizontal link in moderate-to-strong non-Kolmogorov turbulence using a generalized effective atmospheric spectrum which includes finite-turbulence inner and outer scales and high-wave-number "bump". The closed form expression of the average bit error rate (BER) of the coherent free-space optical communication system is derived using the derived channel-correlation coefficients and an alpha-MU distribution to approximate the sum of the square root of arbitrarily correlated Gamma-Gamma random variables. Analytical results are provided to investigate the channel correlation and evaluate the average BER performance. The validity of the proposed approximation is illustrated by Monte Carlo simulations. This work will help with further investigation of the fading correlation in spatial diversity systems. PMID- 29714291 TI - Spatial hole burning in thin-disk lasers and twisted-mode operation. AB - Spatial hole burning prevents single-frequency operation of thin-disk lasers when the thin disk is used as a folding mirror. We present an evaluation of the saturation effects in the disk for disks acting as end mirrors and as folding mirrors, explaining one of the main obstacles toward single-frequency operation. It is shown that a twisted-mode scheme based on a multi-order quarter-wave plate combined with a polarizer provides an almost complete suppression of spatial hole burning and creates an additional wavelength selectivity that enforces efficient single-frequency operation. PMID- 29714292 TI - Image quality degradation of object-color metamer mismatching in digital camera color reproduction. AB - Metamer mismatching is a phenomenon where two objects that are colorimetrically indistinguishable under one lighting condition become distinguishable under another one. Due to the unavailability of spectral information, metamer mismatching introduces an inherent uncertainty into cameras' color reproduction. To investigate the degree of image quality degradation by the metamer mismatching, a large spectral reflectance database was compiled in this study to search the object-color metamers sets of the spectra in hyperspectral images. Then, metamer-degraded images were constructed and compared with the ground truth images by directional statistics-based color similarity index image quality assessment metrics to evaluate the perceptual image degradation. The results indicate that the object-color metamer mismatching has only little impact on the image quality degradation, whereas the inappropriate selection of color correction matrices involved with the illumination metamerism is the primary factor for the accuracy decrease in the digital camera color reproduction. PMID- 29714293 TI - Micro-analysis model for material removal mechanisms of bonnet polishing. AB - There have been many researches concerning the modeling for material removal mechanisms of bonnet polishing (BP) based on the well-known Preston model. However, various parameters involved in the BP process are not formulated and considered in the classical model, such as slurry characteristics, pad properties, bonnet features, and processing conditions. In this paper, a micro analysis model capturing those parameters is proposed based on the mutual interaction of the slurry, pad, and workpiece among the BP interfaces with the micro-contact theory and the tribology theory. The proposed model is validated by comparison with the experimental data, and good agreement can be obtained. According to the analysis of key parameters, the proposed model is capable of providing some insight into the material removal mechanisms of BP, and even those cannot be explained properly by the classical Preston model. PMID- 29714294 TI - Wavelength modulation technique-based photoacoustic spectroscopy for multipoint gas sensing. AB - A multipoint gas sensing scheme based on photoacoustic spectroscopy was proposed. Multiple photoacoustic spectroscopy (PAS) gas cells (resonant frequency f0=5.0 kHz) were connected in series for the multipoint gas sensing with wavelength modulation technique. The PAS signal was excited by modulating the tunable distributed feedback laser diode wavelength at f0/2 using a changing driving current. The gas concentration of each gas cell was obtained by the PAS signal, which was demodulated by the lock-in amplifier. A multipoint PAS experiment to detect the water vapor at 1368.597 nm was implemented to verify the scheme we presented. With the three PAS gas cells, the linear response to the water vapor concentration of our sensors achieved 0.9978, 0.99591, and 0.99617, and their minimum detection limits were 479, 662, and 630 ppb, respectively. PMID- 29714296 TI - High-speed flame chemiluminescence imaging using time-multiplexed structured detection. AB - In this work, high-speed flame chemiluminescence has been obtained by using the time-multiplexed structured detection (TMSD) imaging method from a single snapshot. TMSD sheers the time lapse into the spatial frequency shifts, which allows multiple high-speed images to be frequency upshifted into distinct spatial frequency regions from the original image. A cumulative exposure captured in a single snapshot image contains distinct time evolution. Each distinct image is demultiplexed and recovered by hyperdyne mixing with the modulation frequency. TMSD is an optical frequency domain analog to carrier frequency modulation in radio and microwave detections. Specifically, a digital micromirror device (DMD) spatially modulates flame chemiluminescence just prior to the camera. Spatial frequency of each distinct image is mixed between the original spatial frequency components and DMD modulation pattern frequency, resulting in a coded snapshot. The high-speed flame chemiluminescence image is recovered by demodulation. TMSD is similar to structured illumination used in super-resolution microscopy, but offers more advantages, for it does not alternate incident illumination light. Since DMDs are available with speeds up to 40 kHz, this technique shows promise as a cost-effective means of high-speed imaging and diagnostics of combustion phenomena. PMID- 29714295 TI - KTN-based high-speed axial and lateral scanning technique for an optical coherence tomography system and application to dental imaging. AB - A high-speed 840 nm based polarization-sensitive time domain optical coherence tomography (PSOCT) technique is proposed and demonstrated based on the quadratic electro-optic property of potassium tantalate niobate (KTN) crystals. A longitudinal (axial) scanning depth of ~10 MUm is obtained for an applied AC voltage of 600 V, at 1000 Hz and temperature maintained around 40 degrees C. The OCT system with the KTN-based electro-optic delay line combined with a linear actuation is extended to image an early dental demineralization. For enhanced contrast by the elimination of the strong surface reflection from the sample and high-speed imaging, the quadratic electro-optically tunable PSOCT technique is proposed and demonstrated. Further, a lateral scanning range of 490 MUm is also demonstrated by controlling the KTN temperature at 35 degrees C for an applied voltage of 600 V on the tooth sample. This KTN-based quadratic electro-optic delay line combined with lateral scan approach provides an automated high-speed two-dimensional scanning of samples of interest. PMID- 29714297 TI - Pedestal-free 25-GHz subpicosecond optical pulse source for 16 * 25-Gb/s OTDM based on phase modulation and dual-stage nonlinear compression. AB - An optical pulse generation scheme based on an ultra-short chirped seed pulse generator followed by a dual-stage fiber-based nonlinear pulse processing stage is proposed and demonstrated experimentally. After phase modulation and linear chirp compensation, optical seed pulse with a duty cycle of 9.8% and an obvious pedestal is obtained. By soliton compression and Mamyshev reshaping, a pedestal free optical pulse with a duty cycle of 2% and an extinction ratio of 27 dB is achieved. The optical pulse source is further applied in a 16*25-Gb/s on-off keying optical time-division multiplexing transmitter. PMID- 29714298 TI - Thermo-optic dispersion formula for BaGa4Se7. AB - This paper reports on the thermo-optic dispersion formula for BaGa4Se7 that provides a good reproduction of the temperature-dependent phase-matching conditions for type-1 and type-2 second-harmonic generation of a Nd:YAG laser pumped AgGaS2 optical parametric oscillator (OPO) and a CO2 laser in the 0.901 10.5910 MUm spectral range, as well as the published data points for a Nd:YAG laser-pumped OPO at lambdai=3.9040 MUm when combined with the Sellmeier equations of the present authors [Appl. Opt.56, 2978 (2017)APOPAI0003 693510.1364/AO.56.002978]. PMID- 29714299 TI - Measurement accuracy of FBG used as a surface-bonded strain sensor installed by adhesive. AB - Material and dimensional properties of surface-bonded fiber Bragg gratings (FBGs) can distort strain measurement, thereby lowering the measurement accuracy. To accurately assess measurement precision and correct obtained strain, a new model, considering reinforcement effects on adhesive and measured object, is proposed in this study, which is verified to be accurate enough by the numerical method. Meanwhile, a theoretical strain correction factor is obtained, which is demonstrated to be significantly sensitive to recoating material and bonding length, as suggested by numerical and experimental results. It is also concluded that a short grating length as well as a thin but large-area (preferably covering the whole FBG) adhesive can enhance the correction precision. PMID- 29714300 TI - Modeling the optical field in off-axis integrated-cavity-output spectroscopy using the decentered Gaussian beam model. AB - Off-axis integrated-cavity-output spectroscopy (OA-ICOS) is widely used in trace gas detection and isotopic analysis for its enhanced sensitivity as well as robustness against optical instability. However, its sensitivity is ultimately limited by the spurious coupling noise formed in the cavity, and much of the design and optimization process relies on empirical iterations while quantitative analysis is lacking. In this paper, we develop a method to model the optical field in OA-ICOS based on the decentered Gaussian beam model, which is a generalization for large tilting angles as compared with previously developed models. From the optical field, the cavity transmission spectrum for different cavity configurations or input beam conditions can be calculated, and the fringe noise level can be derived. Results show that an optimum combination of input laser beam and off-axis alignment exists to fully suppress the interference fringes. Factors affecting the fringe noise level, including a mismatch between the input beam and the cavity, optical alignment conditions, and deviation from the re-entrant condition, are studied thoroughly. The developed method can serve to guide the design and optimization of OA-ICOS systems. PMID- 29714301 TI - Morphology and growth properties of nano- and submicrometer-scale initial damage sites under 355 nm wavelength pulsed laser irradiation. AB - The initial damage of optical elements under irradiation of a 355 nm wavelength nano-second pulsed laser below the laser-induced damage threshold mainly includes nano- and submicrometer-scale craters. The morphology and growth characteristics of such small-scale damage, which are different from those of larger-scale damage, have not been fully clarified. In this study, laser-induced nano- and submicrometer-scale initial damage of fused silica was investigated by atomic force microscope. The morphology of craters and ejecta was analyzed, and the relationship between the structure characteristics and the irradiation parameters was obtained. In addition, the growth and evolution features under multipulsed laser irradiation were classified. PMID- 29714302 TI - DERS substrate based on NERS-SERS interaction in integrated microfluidic detection. AB - The systematic simulation study of a structure with nanogap-enhanced Raman scattering and surface-enhanced Raman scattering (NERS-SERS) substrate is presented. This double-enhanced Raman scattering (DERS) substrate with coupling between the localized surface plasmons of noble metal nanosphere colloids and surface plasmon polaritons of a 1D sinusoidal noble metal nanograting is analyzed. With the excitation light wavelength at 785 nm, the key structure parameters of noble metal nanospheres and sinusoidal noble metal nanogratings are deduced by FDTD. With the optimal DERS substrate, the SERS enhancement factor (EF) can be 9 orders of magnitude as possible. The DERS substrate was fabricated, and an extra SERS effect was demonstrated by experiments. This DERS substrate will be integrated with microfluidics in the next work, with the purpose of in situ, real-time, continuous detection of trace water soluble gas-phase or airborne agents, such as trace explosives in air. PMID- 29714303 TI - Optical manipulation of nematic colloids at the interfaces in azo-dye-doped liquid crystals. AB - This study demonstrates the optical manipulation of colloids dispersed in azo-dye doped liquid crystals (DDLCs) where the accumulation occurs at the interfaces of the phase domains. We explain the mechanism related to the formation of the domains and the movement of the colloids in DDLCs with respect to the isomerization of azo-dye molecules via the illumination of laser beams. The colloids are dragged to the interfaces of the isotropic/nematic domain and the air bubble/isotropic domain by molecular interaction and Marangoni flows. PMID- 29714304 TI - Talbot effect with partially coherent interfering Bessel beams. AB - We studied the free-space propagation of interfering partially coherent Bessel beams. The partially coherent superimposed Bessel beams were generated by diffracting a spatially incoherent light by two concentric circular slits. We observed a Talbot effect in the random intensity pattern and in the intensity correlation. We showed that the Talbot length depends only on the radii of the circular slits. We explained this effect on the basis of the plane-wave decomposition of spatially random fields. PMID- 29714305 TI - Optimized laser-induced breakdown spectroscopy for determination of xenobiotic silver in monosodium glutamate and its verification using ICP-AES. AB - Laser-induced breakdown spectroscopy (LIBS) was applied as a potential tool for the determination of xenobiotic metal in monosodium glutamate (MSG). In order to achieve a high-sensitivity LIBS system required to determine trace amounts of metallic silver in MSG and to attain the best detection limit, the parameters used in our experiment (impact of focusing laser energy on the intensity of LIBS emission signals, the influence of focusing lens distance on the intensity of LIBS signals, and time responses of the plasma emissions) were optimized. The spectra of MSG were obtained in air using a suitable detector with an optical resolution of 0.06 nm, covering a spectral region from 220 to 720 nm. Along with the detection of xenobiotic silver, other elements such as Ca, Mg, S, and Na were also detected in MSG. To determine the concentration of xenobiotic silver in MSG, the calibration curve was plotted by preparing standard samples having different silver abundances in an MSG matrix. The LIBS results of each sample were cross verified by analyzing with a standard analytical technique such as inductively coupled plasma-atomic emission spectroscopy (ICP-AES). Both (LIBS and ICP-AES) results were in mutual agreement. The limit of detection of the LIBS setup was found to be 0.57 ppm for silver present in MSG samples. PMID- 29714306 TI - 1164.4 nm and 1174.7 nm dual-wavelength Nd : GdVO4/Cr4+ : YAG/YVO4 passively Q switched Raman microchip laser. AB - A synchronous pulsed, dual-wavelength Raman laser at 1164.4 nm and 1174.7 nm has been demonstrated in a Nd:GdVO4/Cr4+:YAG/YVO4 passively Q-switched Raman microchip laser (PQSRML). The 1164.4 nm and 1174.7 nm dual-wavelength first-order Stokes laser oscillation is attributed to the conversion of the 1063.2 nm and 1063.43 nm two-longitudinal-mode fundamental lasers with Raman frequency shifts of 816 cm-1 and 890 cm-1, respectively. Stable dual-wavelength Raman laser pulses with nearly equal spectral intensities have been achieved independent of the pump power. A pulse repetition rate as high as 139.4 kHz has been achieved with T0=85%, and the pulse width has been shortened to 825 ps with T0=70%. A dual wavelength Raman laser with sub-nanosecond pulse width and peak power of over 1 kW has been achieved in the Nd:GdVO4/Cr4+:YAG/YVO4 PQSRML. PMID- 29714307 TI - Producing an efficient, collimated, and thin annular beam with a binary axicon. AB - We propose and demonstrate a method to produce a thin and highly collimated annular beam that propagates similarly to an ideal thin Gaussian ring beam, maintaining its excellent propagation properties. Our optical configuration is composed of a binary axicon, a circular binary phase grating, and a lens, making it robust and well suited for high-power lasers. It has a near-perfect circular profile with a dark center, and its large radius to waist ratio is achieved with high conversion efficiency. The measured profile and propagation are in excellent agreement with a numerical Fourier simulation we perform. PMID- 29714308 TI - Optical device for the precision control of the electric field in the focus of a beam. AB - We present a common-path optical device consisting of four optical components that produce a laser field consisting of two sub-beams with one radially polarized and the other linearly polarized. In the focus, the radially polarized sub-beam produces longitudinal polarization while the linearly polarized sub-beam produces polarization perpendicular to the propagation direction. By rotating the optical components, the orientation of the resulting electric field in the focus can be continuously varied in any direction. Estimates of the angular resolution of the device are given within the paraxial approximation. PMID- 29714309 TI - Underwater hyperspectral imaging: a new tool for marine archaeology. AB - By applying an underwater hyperspectral imager (UHI) to a selection of archaeological artifacts, we have found spectral signatures that are representative of materials likely to be present at wreck sites. By successfully using the signatures to classify a subset of said artifacts placed on the seabed at 61 m depth, we demonstrate that it is possible to detect archaeological objects of interest in UHI data acquired by a remotely operated vehicle. Correct UHI classification of rust and glass bottles in situ on a historical wreck site further supports the viability of the method for marine archaeological applications. PMID- 29714310 TI - Bifocal dual reflector system for active terahertz imaging. AB - This paper introduces a method for optimizing the terahertz (THz) imaging resolution in a specified field of view (FoV) for a scanning dual reflector system (Gregory or Cassegrain system) based on the theory of field curvature. The authors built a Gregory scanning system to verify the ability of this method. The operating frequency of the verification system is 220 GHz, the FoV at a specified distance of 8 m is approximately 50 cm * 100 cm, and the imaging resolution throughout the entire FoV is better than 3 cm. Experimental results show that the imaging resolution of the classical dual reflector system can be optimized, and the proposed verification system can realize active THz imaging of the human body. PMID- 29714311 TI - Pt thermal atomic layer deposition for silicon x-ray micropore optics. AB - We fabricated a silicon micropore optic using deep reactive ion etching and coated by Pt with atomic layer deposition (ALD). We confirmed that a metal/metal oxide bilayer of Al2O3~10 nm and Pt ~20 nm was successfully deposited on the micropores whose width and depth are 20 MUm and 300 MUm, respectively. An increase of surface roughness of sidewalls of the micropores was observed with a transmission electron microscope and an atomic force microscope. X-ray reflectivity with an Al Kalpha line at 1.49 keV before and after the deposition was measured and compared to ray-tracing simulations. The surface roughness of the sidewalls was estimated to increase from 1.6+/-0.2 nm rms to 2.2+/-0.2 nm rms. This result is consistent with the microscope measurements. Post annealing of the Pt-coated optic at 1000 degrees C for 2 h showed a sign of reduced surface roughness and better angular resolution. To reduce the surface roughness, possible methods such as the annealing after deposition and a plasma-enhanced ALD are discussed. PMID- 29714312 TI - Confined-doped fiber for effective mode control fabricated by MCVD process. AB - A confined-doped fiber was fabricated by a modified chemical vapor deposition (MCVD) process based on refractive index matching technology. With theory and experiments, we compared the confined-doped fiber and normal-doped fiber. We found that the confined-doped fiber with a core of 35 MUm and 0.07 numerical aperture could achieve single-mode output and improve the beam quality from 2.8 to 1.5 in the fiber laser. Meanwhile, it still possesses high laser efficiency and has good stability of beam quality with the increase in pump power. It suggests that the confined-doped fiber with a MCVD process may be the key material for a high-power fiber laser with excellent beam quality. PMID- 29714313 TI - Extended visual range during solar eclipses. AB - During the solar eclipse on 21 August 2017, observed from Rexburg, Idaho, the eastern horizon for a short time period close to totality showed the contours of the Grand Teton mountain range from distances between about 80 and 90 km. In most of the partial phase before and after the eclipse, the visual range was below 80 km and the mountains could not be seen by the naked eye because of wildfire smoke in the air. We present photographic evidence of extension of the visual range during the eclipse and explain it in terms of a simple model for the daytime visual range. In this model, contrast between a black object and the sky increases whenever the ratio of nearby to distant air light reduces. As a consequence, we predict asymmetries with regard to totality and also that similar phenomena may be observed if part of the line of sight close to the observer is in deep shade of a thick cloud cover. PMID- 29714314 TI - Completely blind image quality assessment via image gray-scale fluctuations and fractal dimension analysis. AB - State-of-the-art no-reference image quality assessment methods usually learn to evaluate image quality by regression from the human subjective scores of a training set. Their dependence on the regression algorithm and human subjective scores may limit the practical application of such methods. In this paper, we propose a completely blind image quality assessment method that is highly unsupervised and training free. We first use a specific image primitive to analyze the image gray-scale fluctuation and use this result as one of the image quality assessment features. The box-counting method is then used to evaluate the image fractal dimension, and the result is used as the other feature. Finally, the two features are combined together, and a formula is introduced to calculate a comprehensive image quality feature, which is used to measure the image quality. Experimental results on four open databases show that the newly proposed method correlates well with the human subjective judgments of diversely distorted images. PMID- 29714315 TI - Stable passively Q-switched erbium-doped fiber laser incorporating a PbS quantum dots polystyrene composite film based saturable absorber. AB - We demonstrated a passively Q-switched erbium-doped fiber laser (EDFL) using PbS quantum dots in polystyrene films (QDPFs) as saturable absorbers (SAs). Compared to other SAs, PbS QDPFs have advantages of broad absorption range, high quantum yield, low cost, and facile preparation. We have successfully generated stable Q switched pulses with an average output power of 40.19 mW, a single pulse energy of 586.1 nJ, a repetition rate of 68.04 kHz, a pulse width of 3.9 MUs, and a signal-to-noise ratio of 50.5 dB under 660 mW pump power. The output of the EDFL has been monitored for 5 consecutive hours under laboratory conditions to show stable operation of the laser system. PMID- 29714316 TI - Design of a graphene-based dual-slot hybrid plasmonic electro-absorption modulator with high-modulation efficiency and broad optical bandwidth for on-chip communication. AB - The hybrid plasmonic effect with lower loss and comparable light confinement than surface plasmon polariton opens new avenues for strengthening light-matter interactions with low loss. Here, we propose and numerically analyze a graphene based electro-absorption modulator (EAM) with high-modulation efficiency and broad optical bandwidth using a dual-slot hybrid plasmonic waveguide (HPW), which consists of a central dual-slot HPW connected with two taper transitions and two additional dual-slot HPWs for coupling it with the input and output silicon nanowires, where graphene layers are located at the bottom and top side of the whole dual-slot HPW region. By combining the huge light enhancement effect of the dual-slot HPW and graphene's tunable conductivity, we obtain a high-modulation efficiency (ME) of 1.76 dB/MUm for the graphene-based dual-slot HPW (higher ME of 2.19 dB/MUm can also be obtained). Based upon this promising result, we further design a graphene-based hybrid plasmonic EAM, achieving a modulation depth (MD) of 15.95 dB and insertion loss of 1.89 dB @1.55 MUm, respectively, in a total length of only 10 MUm, where its bandwidth can reach over 500 nm for keeping MD>15 dB; MD can also be improved by slightly increasing the device length or shrinking the waveguide thickness, showing strong advantages for applying it into on-chip high-performance silicon modulators. PMID- 29714317 TI - Off-axis digital holography with multiplexed volume Bragg gratings. AB - We report on an optical imaging design based on common-path off-axis digital holography, using a multiplexed volume Bragg grating. In the reported method, a reference optical wave is made by deflection and spatial filtering through a volume Bragg grating. This design has several advantages, including simplicity, stability, and robustness against misalignment. PMID- 29714318 TI - Application of laser-induced breakdown spectroscopy for real-time detection of contamination particles during the manufacturing process. AB - A stand-off laser-induced breakdown spectroscopy (LIBS) system was developed to determine the elemental composition of contamination particles during semiconductor manufacturing. It successfully detected laboratory-generated monodisperse (size=200 nm and 300 nm) CaCl2 particles and internally mixed particles of CaCl2, MgCl2, NaCl, and KCl. Temperature and pressure effects on the LIBS emission signals were investigated. The peak area and signal-to-noise ratio of the emission lines increased with the temperature (25 degrees C-250 degrees C). Stronger emission lines were observed at higher pressure. Although temperature and pressure affect the LIBS signals, the developed stand-off LIBS could be employed for real-time detection of the elemental composition of contamination particles. PMID- 29714319 TI - Discrete vector frozen waves in generalized Lorenz-Mie theory: linear, azimuthal, and radial polarizations. AB - This work aims to provide additional theoretical investigation of a promising class of nondiffracting vector beams-the discrete vector frozen waves (FWs)-in the generalized Lorenz-Mie theory. The exact beam shape coefficients for unsymmetrized FWs with linear, azimuth, and radial polarizations are given in analytic form, thus extending previous derivations based on circularly symmetric Davis or aplanatic Bessel beams. Owing to their unique properties, it is believed that FWs will become important wave fields in optical tweezers, optical system alignment, remote sensing, optical bistouries, atom guiding, and so on. The present analysis is therefore fully justified. PMID- 29714320 TI - Silicon waveguide grating coupler based on a segmented grating structure. AB - We present the simulation, fabrication, and experimental results of a high efficiency and wide-bandwidth segmented waveguide grating coupler on a silicon-on insulator platform for near vertical optical coupling between the waveguide and optical fiber. The coupler comprises segmented gratings, which can increase vertical coupling to the optical fiber and reduce backward reflection. The proposed grating coupler has a 3 dB bandwidth of 71.4 nm and a coupling efficiency of 51.7% at a wavelength of 1550 nm. Compared with the standard uniform waveguide grating coupler, the coupling efficiency was improved by 25.64%. PMID- 29714321 TI - Algorithm for pose estimation based on objective function with uncertainty weighted measuring error of feature point cling to the curved surface. AB - This paper is concerned with the anisotropic and non-identical gray distribution of feature points clinging to the curved surface, upon which a high precision and uncertainty-resistance algorithm for pose estimation is proposed. Weighted contribution of uncertainty to the objective function of feature points measuring error is analyzed. Then a novel error objective function based on the spatial collinear error is constructed by transforming the uncertainty into a covariance weighted matrix, which is suitable for the practical applications. Further, the optimized generalized orthogonal iterative (GOI) algorithm is utilized for iterative solutions such that it avoids the poor convergence and significantly resists the uncertainty. Hence, the optimized GOI algorithm extends the field-of view applications and improves the accuracy and robustness of the measuring results by the redundant information. Finally, simulation and practical experiments show that the maximum error of re-projection image coordinates of the target is less than 0.110 pixels. Within the space 3000 mm*3000 mm*4000 mm, the maximum estimation errors of static and dynamic measurement for rocket nozzle motion are superior to 0.065 degrees and 0.128 degrees , respectively. Results verify the high accuracy and uncertainty attenuation performance of the proposed approach and should therefore have potential for engineering applications. PMID- 29714322 TI - Homography estimation by two PClines Hough transforms and a square-radial checkerboard pattern. AB - The homography matrix is crucial for many optical metrology applications, such as three-dimensional surface imaging by structured-light projection. In this paper, a straightforward homography estimation method using the image of three particular points on the reference plane is proposed. For this, a new square radial checkerboard pattern designed to generate three sets of concurrent lines is proposed. The lines and points of interest are detected using two PClines Hough transforms. Relevant concepts such as parallel coordinates and the used Hough transforms are explained. The usefulness of our proposal is verified experimentally. PMID- 29714323 TI - Holographic formation and diffractive properties of hybrid periodic structures. AB - The paper presents formation processes and diffraction properties of hybrid periodic structures such as volume gratings with refractive index modulation, on the surface of which relief gratings are formed. It is shown experimentally that relief gratings with significant diffraction properties in used photopolymer materials are formed in a narrow range of exposure parameters. It is established that the formation of a relief grating on the surface of a volume grating leads to significant changes in the selective properties of structures. We also consider possible applications of hybrid structures. PMID- 29714324 TI - Thin-film-based optical fiber Fabry-Perot interferometer used for humidity sensing. AB - A thin-film-based optical fiber Fabry-Perot interferometer that consists of ZrO2 and SiO2 porous thin films is designed and fabricated by electron beam physical vapor deposition. Since the SiO2 porous thin film has the capability of water adsorption, the proposed Fabry-Perot interferometer is appropriate to detect humidity. Experimental results show that the prepared sensor has a humidity detection range from 0.06% RH to 70% RH. A cycling test shows that the humidity sensor has a responding or recover time of 4 s and good repeatability among different humidity environments. Especially, the proposed humidity sensor is insensitive to temperature variation and suitable for the detection of low relative humidity. PMID- 29714325 TI - Substrate aberration and correction for meta-lens imaging: an analytical approach. AB - Meta-lenses based on flat optics enabled a fundamental shift in lens production providing an easier manufacturing process with an increase in lens profile precision and a reduction in size and weight. Here we present an analytical approach to correct spherical aberrations caused by light propagation through the substrate by adding a substrate-corrected phase profile, which differs from the original hyperbolic one. A meta-lens encoding the new phase profile would yield diffraction-limited focusing and an increase of up to 0.3 of its numerical aperture without changing the radius or focal length. In tightly focused laser spot applications such as direct laser lithography and laser printing, a substrate-corrected meta-lens can reduce the spatial footprint of the meta-lens. PMID- 29714326 TI - Compensating additional optical power in the central zone of a multifocal contact lens forminimization of the shrinkage error of the shell mold in the injection molding process. AB - This study aims to develop a compensating method to minimize the shrinkage error of the shell mold (SM) in the injection molding (IM) process to obtain uniform optical power in the central optical zone of soft axial symmetric multifocal contact lenses (CL). The Z-shrinkage error along the Z axis or axial axis of the anterior SM corresponding to the anterior surface of a dry contact lens in the IM process can be minimized by optimizing IM process parameters and then by compensating for additional (Add) powers in the central zone of the original lens design. First, the shrinkage error is minimized by optimizing three levels of four IM parameters, including mold temperature, injection velocity, packing pressure, and cooling time in 18 IM simulations based on an orthogonal array L18 (21*34). Then, based on the Z-shrinkage error from IM simulation, three new contact lens designs are obtained by increasing the Add power in the central zone of the original multifocal CL design to compensate for the optical power errors. Results obtained from IM process simulations and the optical simulations show that the new CL design with 0.1 D increasing in Add power has the closest shrinkage profile to the original anterior SM profile with percentage of reduction in absolute Z-shrinkage error of 55% and more uniform power in the central zone than in the other two cases. Moreover, actual experiments of IM of SM for casting soft multifocal CLs have been performed. The final product of wet CLs has been completed for the original design and the new design. Results of the optical performance have verified the improvement of the compensated design of CLs. The feasibility of this compensating method has been proven based on the measurement results of the produced soft multifocal CLs of the new design. Results of this study can be further applied to predict or compensate for the total optical power errors of the soft multifocal CLs. PMID- 29714327 TI - Film thickness measurement based on nonlinear phase analysis using a Linnik microscopic white-light spectral interferometer. AB - Based on white-light spectral interferometry and the Linnik microscopic interference configuration, the nonlinear phase components of the spectral interferometric signal were analyzed for film thickness measurement. The spectral interferometric signal was obtained using a Linnik microscopic white-light spectral interferometer, which includes the nonlinear phase components associated with the effective thickness, the nonlinear phase error caused by the double objective lens, and the nonlinear phase of the thin film itself. To determine the influence of the effective thickness, a wavelength-correction method was proposed that converts the effective thickness into a constant value; the nonlinear phase caused by the effective thickness can then be determined and subtracted from the total nonlinear phase. A method for the extraction of the nonlinear phase error caused by the double-objective lens was also proposed. Accurate thickness measurement of a thin film can be achieved by fitting the nonlinear phase of the thin film after removal of the nonlinear phase caused by the effective thickness and by the nonlinear phase error caused by the double-objective lens. The experimental results demonstrated that both the wavelength-correction method and the extraction method for the nonlinear phase error caused by the double objective lens improve the accuracy of film thickness measurements. PMID- 29714328 TI - Wavelength-dependent excess permittivity as indicator of kerosene in diesel oil. AB - Adulteration of diesel oil by kerosene is a serious problem because of air pollution resulting from car exhaust gases. The objective of this study was to develop a relatively simple optical measurement and data analysis method to screen low-adulterated diesel oils. For this purpose, we introduce the utilization of refractive index measurement with a refractometer, scanning of visible-near-infrared transmittance, transmittance data inversion using the singly subtractive Kramers-Kronig relation, and exploitation of so-called wavelength-dependent relative excess permittivity. It is shown for three different diesel oil grades, adulterated with kerosene, that the excess permittivity is a powerful measure for screening fake diesel oils. The excess relative permittivity of such binary mixtures also reveals hidden spectral fingerprints that are neither visible in dispersion data alone nor in spectral transmittance measurements alone. We believe that the excess permittivity data are useful in the case of screening adulteration of diesel oil by kerosene and can further be explored for practical sensing solutions, e.g., in quality inspection of diesel oils in refineries. PMID- 29714329 TI - Temperature-dependent optical constants of liquid isopropanol, n-butanol, and n decane. AB - Liquid isopropanol, n-butanol, and n-decane are combustible organic compounds that are frequently used in theoretical and experimental researches on fuel combustion. In this work, the temperature-dependent optical constants of liquid isopropanol, n-butanol, and n-decane in the region 500-5500 cm-1 at ambient pressure are measured using the combined ellipsometry-transmission method. In the combined method, the optical constants are first measured by a modified ellipsometry method, and then the absorption indices for weak absorption regions are obtained by the transmission method using the refractive indices measured by the modified ellipsometry method. The refractive indices of liquid isopropanol, n butanol, and n-decane are within the range from 1.3 to 1.45 in the studied wavelength and temperature region. The absorption indices of these liquids range from 10-5 to 10-1. In the temperature range studied, the refractive indices decrease with increasing temperature in an approximately linear manner, but the effects of the temperature on the absorption indices are much smaller. The characteristic wavenumbers of the main absorption peaks are consistent with the vibrational frequencies of major functional groups. PMID- 29714330 TI - Size reduction of Ge-on-Si photodetectors via a photonic bandgap. AB - This work shrinks down the size of Ge-on-Si photodetectors to reduce the dark current and maintain the optical responsivity by surrounding photonic crystals. Numerical simulation shows that the employment of photonic crystal in the Si slab effectively prohibits the radiation modes from those guided outgoing waves and facilitates light cyclic absorption in the epitaxial Ge region. A photodetector with a 5 MUm long Ge absorption region is demonstrated with a dark current of 150 nA (1 MUA up to 70 degrees C), a 3 dB bandwidth of 17 GHz, and a responsivity of 0.75 A/W. PMID- 29714331 TI - kW-level 1030 nm polarization-maintained fiber laser with narrow linewidth and near-diffraction-limited beam quality. AB - kW-level 1030 nm polarization-maintained fiber laser with narrow linewidth and near-diffraction-limited beam quality is demonstrated. Theoretical simulations based on the power balance equation are first performed to optimize the system parameters of the 1030 nm ytterbium-doped fiber laser for the maximum suppression of amplified spontaneous emission (ASE). With the optimized parameters, both the copumped and counterpumped MOPA lasers are implemented to obtain an output power of >1 kW. In both cases, the ASE suppression ratio reaches 40 dB with a 3 dB linewidth of about 0.14 nm, and the polarization extinction ratio is about 12 dB at 1 kW of output power. The beam quality starts degrading at 900 W of output power in the copumped structure, but maintains nearly single mode (Mx2,My2)=(1.07,1.12) until power is over 1 kW in the counterpumped structure. PMID- 29714332 TI - Spectral Monte Carlo simulation of collimated solar irradiation transfer in a water-filled prismatic louver. AB - The Monte Carlo model was developed to simulate the collimated solar irradiation transfer and energy harvest in a hollow louver made of silica glass and filled with water. The full solar spectrum from the air mass 1.5 database was adopted and divided into various discrete bands for spectral calculations. The band averaged spectral properties for the silica glass and water were obtained. Ray tracing was employed to find the solar energy harvested by the louver. Computational efficiency and accuracy were examined through intensive comparisons of different band partition approaches, various photon numbers, and element divisions. The influence of irradiation direction on the solar energy harvest efficiency was scrutinized. It was found that within a 15 degrees polar angle of incidence, the harvested solar energy in the louver was high, and the total absorption efficiency reached 61.2% under normal incidence for the current louver geometry. PMID- 29714333 TI - Inverse Gaussian gamma distribution model for turbulence-induced fading in free space optical communication. AB - We introduce an alternative distribution to the gamma-gamma (GG) distribution, called inverse Gaussian gamma (IGG) distribution, which can efficiently describe moderate-to-strong irradiance fluctuations. The proposed stochastic model is based on a modulation process between small- and large-scale irradiance fluctuations, which are modeled by gamma and inverse Gaussian distributions, respectively. The model parameters of the IGG distribution are directly related to atmospheric parameters. The accuracy of the fit among the IGG, log-normal, and GG distributions with the experimental probability density functions in moderate to-strong turbulence are compared, and results indicate that the newly proposed IGG model provides an excellent fit to the experimental data. As the receiving diameter is comparable with the atmospheric coherence radius, the proposed IGG model can reproduce the shape of the experimental data, whereas the GG and LN models fail to match the experimental data. The fundamental channel statistics of a free-space optical communication system are also investigated in an IGG distributed turbulent atmosphere, and a closed-form expression for the outage probability of the system is derived with Meijer's G-function. PMID- 29714334 TI - Analysis of the influence of installation tilt error on the tool setting accuracy by laser diffraction. AB - In the ultra-precision machining process, it is important to detect the tool workpiece distance by the laser diffraction effect. However, there is no absolute ideal situation for the tool setting of laser diffraction. It is necessary to consider the influence of installation tilt error on the tool setting accuracy and its compensation. In this paper, referring to the ideal optical axis, the influences of the incident laser tilt, CCD tilt, and rectangular orifice tilt on the peak position of the diffraction fringes in the CCD phase are modeled and analyzed to determine the relative effects on the tool setting accuracy for tool workpiece distance detection. The tilt angle of the incident laser is measured by extracting the CCD pixel position, where the central peak point is located. The CCD tilt angle is detected by extracting the CCD pixel positions, where the first degree peak points are located. The inclination direction and the inclination angle of the rectangular orifice are detected by extracting the bending direction and the bending degree of the fringes in the horizontal direction, and the error compensation is performed according to the inclination angle. This study establishes a compensation method for installing tilt error, and the optimized installation process parameters can be acquired under certain experimental conditions according to the experimental data to ensure the results' accuracy. PMID- 29714335 TI - Hybrid method to estimate two-layered superficial tissue optical properties from simulated data of diffuse reflectance spectroscopy. AB - An iterative curve fitting method has been applied in both simulation [J. Biomed. Opt.17, 107003 (2012)JBOPFO1083-366810.1117/1.JBO.17.10.107003] and phantom [J. Biomed. Opt.19, 077002 (2014)JBOPFO1083-366810.1117/1.JBO.19.7.077002] studies to accurately extract optical properties and the top layer thickness of a two layered superficial tissue model from diffuse reflectance spectroscopy (DRS) data. This paper describes a hybrid two-step parameter estimation procedure to address two main issues of the previous method, including (1) high computational intensity and (2) converging to local minima. The parameter estimation procedure contained a novel initial estimation step to obtain an initial guess, which was used by a subsequent iterative fitting step to optimize the parameter estimation. A lookup table was used in both steps to quickly obtain reflectance spectra and reduce computational intensity. On simulated DRS data, the proposed parameter estimation procedure achieved high estimation accuracy and a 95% reduction of computational time compared to previous studies. Furthermore, the proposed initial estimation step led to better convergence of the following fitting step. Strategies used in the proposed procedure could benefit both the modeling and experimental data processing of not only DRS but also related approaches such as near-infrared spectroscopy. PMID- 29714336 TI - Focus shaping by tailoring arbitrary hybrid polarization states that have a combination of orthogonal linear polarization bases. AB - We report a focus shaping method by tailoring hybrid states of polarization of arbitrary polarized beams that have a combination of orthogonal linear polarization bases. Such hybridly polarized beams comprising linear, elliptical, and circular polarizations in the beam cross section, have completely different optical properties compared to the scalar and locally linear-polarized vector beams. We demonstrate that, apart from the orientation of the local polarization state, another two degrees of freedom including the local ellipticity and the handedness in the beam cross section can be used in focus shaping. Square-shaped patterns, multiple foci, three-dimensional optical cages, optical needles, and channels can be obtained due to the increased control without any additional phase or amplitude modulations. PMID- 29714337 TI - Temperature-dependent LITT effect in c axis inclined BiCuSeO thin films. AB - Light-induced transverse thermoelectric (LITT) effect in c axis inclined BiCuSeO thin films was investigated in the temperature range of 80-300 K by using three different lasers with the wavelength changing from visible to mid-IR. Obvious open-circuit voltage signals were all detected when the film surface was illuminated by these lasers, and the amplitude Vp of the induced voltage signals was found to increase with the measured temperature. The improvement of Vp at a higher temperature can be explained by the enhanced anisotropy of the Seebeck coefficient as well as the reduced thermal conductivity of the film. This work demonstrates the potential application of BiCuSeO thin film as a broadband light detector working at wide temperature ranges, including a very low temperature environment. PMID- 29714338 TI - Twin scanning lidars for accurate measurement of lower tropospheric aerosols by numerical approximation. AB - In order to improve accuracy of aerosol measurements, a novel method using twin scanning lidars is presented; this method is able to overcome the incomplete overlap range of vertical lidar as well as provide 2D spatial distributions. The scanning lidar setups in the opposite directions are employed as remote sensing tools. Aerosol measurements are performed with cross scanning from the ground to the height of interest. Aerosol optical properties are retrieved using numerical approximation, in which differences between the measured values and the constructed values of the logarithmic range-square-corrected lidar data in the cross-scanning region are minimized. In the data retrieval, we utilize a matrix formulation, in which a Cartesian 2D range-height-indicator diagram is constructed. To verify this method, scanning measurements by ultraviolet Mie scanning lidar performed at different time intervals were taken as the cross scanning measurements from the twin scanning lidars. With the retrieved spatial distributions of aerosol optical properties, such as aerosol backscatter, aerosol extinction, and lidar ratio, the regional aerosol studies showed that aerosol loading was relatively small and in the presence of multiple layers, which may be influenced by airflow from long-range transportation and cause a large impact on the local environment. To conclude, the presented method using twin scanning lidars is feasible for aerosol measurement in the application of horizontally atmospheric inhomogeneity. PMID- 29714339 TI - Development of an inverse distance weighted active infrared stealth scheme using the repulsive particle swarm optimization algorithm. AB - Treatments for detection by infrared (IR) signals are higher than for other signals such as radar or sonar because an object detected by the IR sensor cannot easily recognize its detection status. Recently, research for actively reducing IR signal has been conducted to control the IR signal by adjusting the surface temperature of the object. In this paper, we propose an active IR stealth algorithm to synchronize IR signals from the object and the background around the object. The proposed method includes the repulsive particle swarm optimization statistical optimization algorithm to estimate the IR stealth surface temperature, which will result in a synchronization between the IR signals from the object and the surrounding background by setting the inverse distance weighted contrast radiant intensity (CRI) equal to zero. We tested the IR stealth performance in mid wavelength infrared (MWIR) and long wavelength infrared (LWIR) bands for a test plate located at three different positions on a forest scene to verify the proposed method. Our results show that the inverse distance weighted active IR stealth technique proposed in this study is proved to be an effective method for reducing the contrast radiant intensity between the object and background up to 32% as compared to the previous method using the CRI determined as the simple signal difference between the object and the background. PMID- 29714340 TI - Double Donut Schmidt Camera, a wide-field, large-aperture, and lightweight space telescope for the detection of ultrahigh energy cosmic rays. AB - A wide-field, large-aperture, and lightweight Schmidt configuration has been studied for a space mission proposal named Extreme Universe Space Observatory free flyer (EUSO-FF). EUSO-FF will be devoted to the study of ultrahigh energy cosmic rays, i.e., with energy >5*1019 eV, through the detection of UV fluorescence light emitted by air showers in the Earth's atmosphere. The proposed telescope has a field of view of about 50 degrees and an entrance pupil diameter of 4.2 m. The mirror is deployable and segmented to fit the diameter of the launcher fairing; the corrector is a lightweight annular corona. PMID- 29714341 TI - Evaluation of sea-surface photosynthetically available radiation algorithms under various sky conditions and solar elevations. AB - In this study, we report on the performance of satellite-based photosynthetically available radiation (PAR) algorithms used in published oceanic primary production models. The performance of these algorithms was evaluated using buoy observations under clear and cloudy skies, and for the particular case of low sun angles typically encountered at high latitudes or at moderate latitudes in winter. The PAR models consisted of (i) the standard one from the NASA-Ocean Biology Processing Group (OBPG), (ii) the Gregg and Carder (GC) semi-analytical clear-sky model, and (iii) look-up-tables based on the Santa Barbara DISORT atmospheric radiative transfer (SBDART) model. Various combinations of atmospheric inputs, empirical cloud corrections, and semi-analytical irradiance models yielded a total of 13 (11 + 2 developed in this study) different PAR products, which were compared with in situ measurements collected at high frequency (15 min) at a buoy site in the Mediterranean Sea (the "BOUee pour l'acquiSition d'une Serie Optique a Long termE," or, "BOUSSOLE" site). An objective ranking method applied to the algorithm results indicated that seven PAR products out of 13 were well in agreement with the in situ measurements. Specifically, the OBPG method showed the best overall performance with a root mean square difference (RMSD) (bias) of 19.7% (6.6%) and 10% (6.3%) followed by the look-up-table method with a RMSD (bias) of 25.5% (6.8%) and 9.6% (2.6%) at daily and monthly scales, respectively. Among the four methods based on clear-sky PAR empirically corrected for cloud cover, the Dobson and Smith method consistently underestimated daily PAR while the Budyko formulation overestimated daily PAR. Empirically cloud-corrected methods using cloud fraction (CF) performed better under quasi-clear skies (CF<0.3) with an RMSD (bias) of 9.7%-14.8% (3.6%-11.3%) than under partially clear to cloudy skies (0.30.7), however, all methods showed larger RMSD differences (biases) ranging between 32% and 80.6% (-54.5%-8.7%). Finally, three methods tested for low sun elevations revealed systematic overestimation, and one method showed a systematic underestimation of daily PAR, with relative RMSDs as large as 50% under all sky conditions. Under partially clear to overcast conditions all the methods underestimated PAR. Model uncertainties predominantly depend on which cloud products were used. PMID- 29714342 TI - Performance analysis of waveguide-mode resonant optical filters with stochastic design parameters. AB - The performance of optical filters with resonant waveguide gratings is investigated numerically in a stochastic context, assuming random fluctuations of various design variables. Specifically, we derive stochastic models based on polynomial chaos expansions, whose involved coefficients are obtained by computing spectral projections via sparse-grid quadrature. The latter exploits purely deterministic results from a rigorous coupled-wave analysis solver and requires less simulation data than standard Monte Carlo (MC) techniques. The statistical moments of the filter's spectral response are calculated reliably, as the comparison against reference results from MC analysis verifies, and the extraction of the Sobol indices reveals the structure's sensitivity with respect to specific design parameters. Moreover, the present analysis clearly points out that neglecting even small geometric variations in the filter design may produce misleading conclusions regarding the corresponding performance, with undesirable consequences in real-life applications. PMID- 29714343 TI - Investigation of one-way absorption properties in an asymmetric photonic crystal containing a semiconductor defect. AB - We theoretically study the one-way absorption in two 1D defective asymmetric photonic crystals, air/(DB)NA(BD)M/air and air/(DB)NA(BD)MA(DB)NA(BD)M/air, where A and B are dielectrics, D is the semiconductor, n-InSb, and N, M are stack numbers with N?M. It is revealed that their absorption spectra exhibit one-way properties. We also find that the number of one-way absorption peaks depends on the symmetry and number of defect layers, which are similar to the defect modes in the transmittance spectra of the usual symmetry photonic crystals. Additionally, effects of the incident angles for both TE and TM waves on the one way feature are also presented. At a large incident angle, the TE wave is almost reflected, whereas the TM wave can have a partial absorption. PMID- 29714344 TI - Frequency stability of a pulsed optically pumped atomic clock with narrow Ramsey linewidth. AB - In general, the linewidth of the Ramsey central fringe (RCF) is equal to 1/(2T), where T is the Ramsey free-evolution time. We demonstrate that the RCF linewidth of a pulsed optically pumped (POP) atomic clock with orthogonal polarization detection based on the magneto-optical rotation effect can be narrowed down to 1/(4T). The Allan deviation of the POP atomic clock decreases from 2.4*10-13tau 1/2 to 1.4*10-13tau-1/2. This corresponds to an improvement in the frequency stability by about 60%. We also estimate the main noise sources that limit the short-term frequency stability of the POP atomic clock. PMID- 29714345 TI - Omnidirectional narrow optical filters for circularly polarized light in a nanocomposite structurally chiral medium. AB - We consider the propagation of electromagnetic waves throughout a nanocomposite structurally chiral medium consisting of metallic nanoballs randomly dispersed in a structurally chiral material whose dielectric properties can be represented by a resonant effective uniaxial tensor. It is found that an omnidirectional narrow pass band and two omnidirectional narrow band gaps are created in the blue optical spectrum for right and left circularly polarized light, as well as narrow reflection bands for right circularly polarized light that can be controlled by varying the light incidence angle and the filling fraction of metallic inclusions. PMID- 29714346 TI - Fast quality-guided phase unwrapping algorithm through a pruning strategy: applications in dynamic interferometry. AB - The quality-guided phase unwrapping algorithm is one of the most employed spatial algorithms due to its computational efficiency and robustness. It uses a quality map to guide the unwrapping process such that pixels are processed according to their quality values from highest to lowest. Several improvements have been proposed during the last few years with the purpose of using it in time-demanding applications. However, many of the proposals depend on the distribution of the values on the given quality map. In this paper, a novel pruning strategy based on a red-black tree data structure is proposed, whose complexity time is independent of the distribution of the given quality map. We take advantage of the partial ordering of the branches in a red-black tree together with a pruning strategy to speed up the unwrapping process. Experimental results, using real and simulated data, show that the complexity time of our proposal improves the existing quality guide-based algorithms. Also, a series of interferometric patterns of a time varying phase distribution experiment have been processed showing that our proposal can be used for real-time applications. The source code of the implemented algorithms is publicly available. PMID- 29714347 TI - Decomposition method for fast computation of gigapixel-sized Fresnel holograms on a graphics processing unit cluster. AB - A parallel computation method for large-size Fresnel computer-generated hologram (CGH) is reported. The method was introduced by us in an earlier report as a technique for calculating Fourier CGH from 2D object data. In this paper we extend the method to compute Fresnel CGH from 3D object data. The scale of the computation problem is also expanded to 2 gigapixels, making it closer to real application requirements. The significant feature of the reported method is its ability to avoid communication overhead and thereby fully utilize the computing power of parallel devices. The method exhibits three layers of parallelism that favor small to large scale parallel computing machines. Simulation and optical experiments were conducted to demonstrate the workability and to evaluate the efficiency of the proposed technique. A two-times improvement in computation speed has been achieved compared to the conventional method, on a 16-node cluster (one GPU per node) utilizing only one layer of parallelism. A 20-times improvement in computation speed has been estimated utilizing two layers of parallelism on a very large-scale parallel machine with 16 nodes, where each node has 16 GPUs. PMID- 29714348 TI - Polarization modulation by means of tunable polarization gratings in an azobenzene side-chain liquid-crystalline polymer film. AB - Polarization modulation was achieved by means of a new type of grating recorded with two 532 nm beams at varying polarization angles in an azobenzene side-chain liquid-crystalline polymer film through light regulation instead of voltage control. In contrast to conventional polarization holographic gratings, the polarization state of the +/- first-order diffracted beams of the recorded gratings depended strongly on angles between polarization directions of two recording beams, while the polarization state of the second-order diffraction remained unchanged. With the polarization angle changing from 0 to 90 deg, the +/ first-order diffraction efficiency increased from 5.15% to 10.53%. Diffraction properties of the recorded gratings were attributed to the combination of polarization holographic gratings and amplitude gratings based on the calculation of Jones matrices and polarization holographic theory. PMID- 29714349 TI - 10.3-W actively Q-switched Nd:YVO4/YVO4 folded coupled-cavity Raman laser at 1176 nm. AB - We report herein an efficient actively Q-switched Nd:YVO4/YVO4 intracavity Raman laser operating at 1176 nm. Factors such as resonator geometry and pumping scheme are optimized to strengthen the power scalability and the conversion efficiency of the intracavity Raman laser. With a folded coupled cavity adopted to make full use of the high pump intensity on the Raman crystal, the first-order Stokes output of 10.32 W at 1176 nm is achieved under the incident pump power of 39 W and pulse repetition frequency of 160 kHz. The corresponding optical efficiency reaches 26.4%, and even higher efficiency of 27.8% is obtained at lower incident pump of 34.4 W. PMID- 29714350 TI - Improving the spatial resolution of volume Bragg grating two-dimensional monochromatic images. AB - Higher spatial resolution indicates sharper recognition ability in applications. To improve the spatial resolution of volume Bragg grating spectral imagers, quantitative wave vector theory is used to elucidate the formation mechanism of diffraction blur, and the corresponding optimal design approaches are put forward. The simulation results show that the main factors for the spectral image blur are the chromatic blur and diffraction aberration, while the central wavelength deviation further deteriorates these. To deal with these factors, one must optimize the grating period, thickness, slant angle, and refractive index, as well as compress the divergence angle of the incident beam. After optimization under the guidance of the newly defined integrated merit functions, the experimental results show that the optimized smeared point-spread function is reduced by about an order of magnitude. The horizontal spatial resolution of the recorded two-dimensional monochromatic images is improved to 14.3 lines/mm under diffuse reflection illumination. PMID- 29714351 TI - Correction to: Use of diaphragm thickening fraction combined with rapid shallow breathing index for predicting success of weaning from mechanical ventilator in medical patients. AB - [This corrects the article DOI: 10.1186/s40560-018-0277-9.]. PMID- 29714352 TI - Correction to: Guidelines for recognition of occupational cancers in Korea: the results of scientific review by Korean Society of Occupational and Environmental Medicine (2013-2016). AB - [This corrects the article DOI: 10.1186/s40557-018-0223-2.]. PMID- 29714353 TI - Correction to: Familial intellectual disability as a result of a derivative chromosome 22 originating from a balanced translocation (3;22) in a four generation family. AB - [This corrects the article DOI: 10.1186/s13039-017-0349-x.]. PMID- 29714354 TI - Verification of land-atmosphere coupling in forecast models, reanalyses and land surface models using flux site observations. AB - We confront four model systems in three configurations (LSM, LSM+GCM, and reanalysis) with global flux tower observations to validate states, surface fluxes, and coupling indices between land and atmosphere. Models clearly under represent the feedback of surface fluxes on boundary layer properties (the atmospheric leg of land-atmosphere coupling), and may over-represent the connection between soil moisture and surface fluxes (the terrestrial leg). Models generally under-represent spatial and temporal variability relative to observations, which is at least partially an artifact of the differences in spatial scale between model grid boxes and flux tower footprints. All models bias high in near-surface humidity and downward shortwave radiation, struggle to represent precipitation accurately, and show serious problems in reproducing surface albedos. These errors create challenges for models to partition surface energy properly and errors are traceable through the surface energy and water cycles. The spatial distribution of the amplitude and phase of annual cycles (first harmonic) are generally well reproduced, but the biases in means tend to reflect in these amplitudes. Interannual variability is also a challenge for models to reproduce. Our analysis illuminates targets for coupled land-atmosphere model development, as well as the value of long-term globally-distributed observational monitoring. PMID- 29714356 TI - Corrigendum: Response: Commentary: Facial Width-to-Height Ratio (fWHR) Is Not Associated With Adolescent Testosterone Levels. AB - [This corrects the article on p. 160 in vol. 9, PMID: 29520245.]. PMID- 29714357 TI - Joint Intensity Fusion Image Synthesis Applied to Multiple Sclerosis Lesion Segmentation. AB - We propose a new approach to Multiple Sclerosis lesion segmentation that utilizes synthesized images. A new method of image synthesis is considered: joint intensity fusion (JIF). JIF synthesizes an image from a library of deformably registered and intensity normalized atlases. Each location in the synthesized image is a weighted average of the registered atlases; atlas weights vary spatially. The weights are determined using the joint label fusion (JLF) framework. The primary methodological contribution is the application of JLF to MRI signal directly rather than labels. Synthesized images are then used as additional features in a lesion segmentation task using the OASIS classifier, a logistic regression model on intensities from multiple modalities. The addition of JIF synthesized images improved the Dice-Sorensen coefficient (relative to manually drawn gold standards) of lesion segmentations over the standard model segmentations by 0.0462 +/- 0.0050 (mean +/- standard deviation) at optimal threshold over all subjects and 10 separate training/testing folds. PMID- 29714358 TI - Dice Overlap Measures for Objects of Unknown Number: Application to Lesion Segmentation. AB - The Dice overlap ratio is commonly used to evaluate the performance of image segmentation algorithms. While Dice overlap is very useful as a standardized quantitative measure of segmentation accuracy in many applications, it offers a very limited picture of segmentation quality in complex segmentation tasks where the number of target objects is not known a priori, such as the segmentation of white matter lesions or lung nodules. While Dice overlap can still be used in these applications, segmentation algorithms may perform quite differently in ways not reflected by differences in their Dice score. Here we propose a new set of evaluation techniques that offer new insights into the behavior of segmentation algorithms. We illustrate these techniques with a case study comparing two popular multiple sclerosis (MS) lesion segmentation algorithms: OASIS and LesionTOADS. PMID- 29714359 TI - Corrigendum: Environmental Impacts of Plant-Based Diets: How Does Organic Food Consumption Contribute to Environmental Sustainability? AB - [This corrects the article on p. 8 in vol. 5, PMID: 29479530.]. PMID- 29714360 TI - Erratum. AB - [This corrects the article DOI: 10.1055/a-0597-3578.]. PMID- 29714361 TI - Erratum: MicroRNA 302b-3p/302c-3p/302d-3p inhibits epithelial-mesenchymal transition and promotes apoptosis in human endometrial carcinoma cells [Erratum]. AB - [This corrects the article on p. 1275 in vol. 11, PMID: 29563806.]. PMID- 29714362 TI - RE: Efficacy and Safety of Radiofrequency Ablation for Benign Thyroid Nodules: A Prospective Multicenter Study. PMID- 29714363 TI - Erratum: Publisher's Note: "A particle manipulation method and its experimental study based on opposed jets" [Biomicrofluidics 12, 024110 (2018)]. AB - [This corrects the article DOI: 10.1063/1.5020600.]. PMID- 29714364 TI - An insight into more factors affecting adherence to medications in the elderly. PMID- 29714365 TI - A versatile method for the determination of photochemical quantum yields via online UV-Vis spectroscopy. AB - We have developed a simple method for determining the quantum yields of photo induced reactions. Our setup features a fibre coupled UV-Vis spectrometer, LED irradiation sources, and a calibrated spectrophotometer for precise measurements of the LED photon flux. The initial slope in time-resolved absorbance profiles provides the quantum yield. We show the feasibility of our methodology for the kinetic analysis of photochemical reactions and quantum yield determination. The typical chemical actinometers, ferrioxalate and ortho-nitrobenzaldehyde, as well as riboflavin, a spiro-compound, phosphorus- and germanium-based photoinitiators for radical polymerizations and the frequently utilized photo-switch azobenzene serve as paradigms. The excellent agreement of our results with published data demonstrates the high potential of the proposed method as a convenient alternative to the time-consuming chemical actinometry. PMID- 29714366 TI - Horseradish peroxidase-catalyzed hydrogelation for biomedical applications. AB - Hydrogels catalyzed by horseradish peroxidase (HRP) serve as an efficient and effective platform for biomedical applications due to their mild reaction conditions for cells, fast and adjustable gelation rate in physiological conditions, and an abundance of substrates as water-soluble biocompatible polymers. In this review, we highlight the tunable characteristics and use of the HRP-catalyzed hydrogels and provide a brief overview of various substrates employed in the HRP system for different biomedical applications of the resultant hydrogels. In addition, we discuss and summarize the biocompatibility, possible functionalization, and biofabrication process. Finally, the future prospective of the HRP crosslinking system is highlighted with biomedical applications. PMID- 29714367 TI - Morphology controlled graphene-alloy nanoparticle hybrids with tunable carbon monoxide conversion to carbon dioxide. AB - Selective oxidation of CO to CO2 using metallic or alloy nanoparticles as catalysts can solve two major problems of energy requirements and environmental pollution. Achieving 100% conversion efficiency at a lower temperature is a very important goal. This requires sustained efforts to design and develop novel supported catalysts containing alloy nanoparticles. In this regard, the decoration of nanoalloys with graphene, as a support for the catalyst, can provide a novel structure due to the synergic effect of the nanoalloys and graphene. Here, we demonstrate the effect of nano-PdPt (Palladium-Platinum) alloys having different morphologies on the catalytic efficiency for the selective oxidation of CO. Efforts were made to prepare different morphologies of PdPt alloy nanoparticles with the advantage of tuning the capping agent (PVP - polyvinyl pyrollidone) and decorating them on graphene sheets via the wet chemical route. The catalytic activity of the G-PdPt hybrids with an urchin-like morphology has been found to be superior (higher % conversion at 135 degrees C lower) to that with a nanoflower morphology. The above experimental observations are further supported by molecular dynamics (MD) simulations. PMID- 29714368 TI - Decoding real space bonding descriptors in valence bond language. AB - Real space bonding descriptors are orbital invariant indices that can be obtained independently of the theoretical framework used to compute a given wavefunction. Here we show how to use them to read in real space some widely used concepts in Valence Bond (VB) theory, such as ionic/covalent characters or covalent-ionic resonance energies. All of these are essential ingredients used when building VB chemical insight. Electron number distribution functions are employed to directly map ionic and covalent weights with real space delocalization indices. We show that covalency, understood as delocalization, emerges in position space from the fluctuation of electron populations. This is mapped in VB to covalent-ionic resonance. The reasons why this is not so in the standard language of non orthogonal VB are examined. A simple real space ionic character index that maintains the essence of its VB equivalent is defined and examined in simple model systems. The conclusions of this work ease travelling among the sometimes conflicting molecular orbital, real space, and valence bond interpretations in chemical bonding theory. PMID- 29714371 TI - Nonconventional regeneration of redox enzymes - a practical approach for organic synthesis? AB - Oxidoreductases have become useful tools in the hands of chemists to perform selective and mild oxidation and reduction reactions. Instead of mimicking native catalytic cycles, generally involving costly and unstable nicotinamide cofactors, more direct, NAD(P)-independent methodologies are being developed. The promise of these approaches not only lies with simpler and cheaper reaction schemes but also with higher selectivity as compared to whole cell approaches and their mimics. PMID- 29714374 TI - Highly hindered 2-(aryl-di-tert-butylsilyl)-N-methyl-imidazoles: a new tool for the aqueous 19F- and 18F-fluorination of biomolecule-based structures. AB - A new class of silicon-based fluoride acceptors with a C-linked heterocycle as the leaving group was synthesized in one step from commercial chemicals, and linked to biomolecules. The resulting conjugates were efficiently 19F-fluorinated in aqueous mixtures, and switching to 18F-labelling provided nucleoside- and peptide-based bioconjugates with excellent molar activities suitable for biological applications. PMID- 29714375 TI - The ortho-substituent on 2,4-bis(trifluoromethyl)phenylboronic acid catalyzed dehydrative condensation between carboxylic acids and amines. AB - 2,4-Bis(trifluoromethyl)phenylboronic acid is a highly effective catalyst for dehydrative amidation between carboxylic acids and amines. Mechanistic studies suggest that a 2 : 2 mixed anhydride is expected to be the only active species, and the ortho-substituent of boronic acid plays a key role in preventing the coordination of amines to the boron atom of the active species, thus accelerating the amidation. This catalyst works for alpha-dipeptide synthesis. PMID- 29714377 TI - Local crystal structure in the vicinity of Cr in doped AlN thin films studied by X-ray absorption spectroscopy. AB - This article reports the detailed X-ray absorption spectroscopy (XAS) study of Al1-xCrxN (x = 4, 6, 11%) thin films synthesized by the reactive magnetron co sputtering technique. All these films were crystallized with a hexagonal wurtzite structure with preferential orientation along the a-axis without the formation of any secondary phases. Surface chemical analysis to evaluate the Cr concentration was carried out using X-ray photoelectron spectroscopy. The study confirmed the presence of AlN and Cr in bonding with N. The local crystal structure around the Cr dopant in the as-synthesized and annealed thin films has been analyzed by both the X-ray absorption near-edge structure (XANES) and extended X-ray absorption fine structure (EXAFS) techniques. From XAS, it was found that Cr replaced the Al atom in the AlN lattice and led to a localized CrN species with distorted tetrahedral AlN in the absence of Cr clustering. The bond lengths of (Cr-N)ax, (Cr-N)bs and Cr-Al, extracted from the EXAFS fitting, were found to decrease with the Cr concentration for both the as-synthesized and annealed thin films due to the enhancement of p-d hybridization between the dopant and the host atoms. However, in the annealed 11% Cr film, the bond lengths are larger than the other and tend to match the Cr-N geometry in CrN. PMID- 29714378 TI - Microscopic properties of ionic liquid/organic semiconductor interfaces revealed by molecular dynamics simulations. AB - Electric double-layer transistors based on ionic liquid/organic semiconductor interfaces have been extensively studied during the past decade because of their high carrier densities at low operation voltages. Microscopic structures and the dynamics of ionic liquids likely determine the device performance; however, knowledge of these is limited by a lack of appropriate experimental tools. In this study, we investigated ionic liquid/organic semiconductor interfaces using molecular dynamics to reveal the microscopic properties of ionic liquids. The organic semiconductors include pentacene, rubrene, fullerene, and 7,7,8,8 tetracyanoquinodimethane (TCNQ). While ionic liquids close to the substrate always form the specific layered structures, the surface properties of organic semiconductors drastically alter the ionic dynamics. Ionic liquids at the fullerene interface behave as a two-dimensional ionic crystal because of the energy gain derived from the favorable electrostatic interaction on the corrugated periodic substrate. PMID- 29714380 TI - Phosphorization boosts the capacitance of mixed metal nanosheet arrays for high performance supercapacitor electrodes. AB - Binary transition metal phosphides hold immense potential as innovative electrode materials for constructing high-performance energy storage devices. Herein, porous binary nickel-cobalt phosphide (NiCoP) nanosheet arrays anchored on nickel foam (NF) were rationally designed as self-supported binder-free electrodes with high supercapacitance performance. Taking the combined advantages of compositional features and array architectures, the nickel foam supported NiCoP nanosheet array (NiCoP@NF) electrode possesses superior electrochemical performance in comparison with Ni-Co LDH@NF and NiCoO2@NF electrodes. The NiCoP@NF electrode shows an ultrahigh specific capacitance of 2143 F g-1 at 1 A g 1 and retained 1615 F g-1 even at 20 A g-1, showing excellent rate performance. Furthermore, a binder-free all-solid-state asymmetric supercapacitor device is designed, which exhibits a high energy density of 27 W h kg-1 at a power density of 647 W kg-1. The hierarchical binary nickel-cobalt phosphide nanosheet arrays hold great promise as advanced electrode materials for supercapacitors with high electrochemical performance. PMID- 29714381 TI - An ammonia detecting mechanism for organic transistors as revealed by their recovery processes. AB - Organic thin film transistor (OTFT) based gas sensors have demonstrated promising applications, owing to their advantages of high selectivity and room temperature operation, accompanied by their low cost, large scale manufacture, and flexibility. However, the understanding of the sensing mechanism is far from clear. Herein, we reveal the sensing mechanism of an organic transistor sensor for ammonia (NH3) detection through studying the recovery behavior in various atmospheres. Inspired by the significant difference in the recovery of the transistor sensor in N2 and in air, we deduced that the operation mechanism should not only involve the NH3-film interaction. Among a series of recovery processes, only upon exposure to wet air can the sensors completely recover in a certain time. Such a phenomenon, coupled with the transistor's performance evolution under vacuum, directly evidenced the existence of a pre-doping effect in the transistor by water (H2O) in ambient air. As a result, the response to the NH3 analyte is actually a de-doping process via reaction with the H2O. The full recovery in wet air is attributable to re-doping by H2O. Density functional theory (DFT) calculations were employed to assist the understanding of such a sensing mechanism. This study could help in the understanding of the sensing processes in many organic semiconductor based sensors. PMID- 29714382 TI - Long sought synthesis of quaternary phosphonium salts from phosphine oxides: inverse reactivity approach. AB - Quaternary phosphonium salts (QPS), a key class of organophosphorus compounds, have previously only been available by routes involving nucleophilic phosphorus. We report the realisation of the opposite approach to QPS utilising phosphine oxides as the electrophilic partner and Grignard reagents as nucleophiles. The process is enabled through the crucial intermediacy of the derived halophosphonium salts. The route does not suffer from the slow kinetics and limited availability of many parent phosphines and a broad range of QPS were prepared in excellent yields. PMID- 29714383 TI - Push-pull quinoidal porphyrins. AB - A family of push-pull quinoidal porphyrin monomers has been prepared from a meso formyl porphyrin by bromination, thioacetal formation, palladium-catalyzed coupling with malononitrile and oxidation with DDQ. Attempts at extending this synthesis to a push-pull quinoidal/cumulenic porphyrin dimer were not successful. The crystal structures of the quinoidal porphyrins indicate that there is no significant contribution from singlet biradical or zwitterionic resonance forms. The crystal structure of an ethyne-linked porphyrin dimer shows that the torsion angle between the porphyrin units is only about 3 degrees , in keeping with crystallographic results on related compounds, but contrasting with the torsion angle of about 35 degrees predicted by computational studies. The free-base quinoidal porphyrin monomers form tightly pi-stacked layer structures, despite their curved geometries and bulky aryl substituents. PMID- 29714385 TI - Soft and flexible poly(ethylene glycol) nanotubes for local drug delivery. AB - Nanotubes are emerging as promising materials for healthcare applications but the selection of clinically relevant starting materials for their synthesis remains largely unexplored. Here we present, for the first time, the synthesis of poly(ethylene glycol) (PEG) based nanotubes via the photopolymerization of poly(ethylene glycol) diacrylate and other diacrylate derivatives within the pores of anodized aluminum oxide templates. Template-assisted synthesis allowed the manufacture of a diverse set of polymeric nanotubes with tunable physical characteristics including diameter (~200-400 nm) and stiffness (405-902 kPa). PEG nanotubes were subjected to cytotoxicty assessment in cell lines and primary stem cells and showed excellent cytocompatability (IC50 > 120 MUg ml-1). Nanotubes were readily drug loaded but released the majority of the drug over 5 days. Direct administration of drug loaded nanotubes to human orthotopic breast tumors substantially reduced tumor growth and metastasis and outperformed i.v. administration at the equivalent dose. Overall, this nanotube templating platform is emerging as a facile route for the manufacture of poly(ethylene glycol) nanotubes. PMID- 29714387 TI - Revealing the role of NH4VO3 treatment in Ni-rich cathode materials with improved electrochemical performance for rechargeable lithium-ion batteries. AB - Although Ni-rich layered oxides are considered a candidate of next-generation cathode materials, their inherent properties, such as surface lithium residues and structural destruction, cause detrimental electrochemical performance, especially at elevated temperatures. Here, a facile ball-milling method is proposed to remove the lithium residues and enhance the electrochemical performance of LiNi0.6Co0.2Mn0.2O2. After NH4VO3 treatment, a lithium ion conductive Li3VO4 coating layer is found on the LiNi0.6Co0.2Mn0.2O2 surface at heat-treatment temperatures of 300 and 450 degrees C, with a small part of vanadium ions diffusing into the surface lattice. When the temperature surpasses 600 degrees C, almost all vanadium ions dope into the bulk structure. The complex relationships between the post-sintering temperature and surface structure and their impact on electrochemical properties are discussed in detail. Electrochemical tests show that 0.5 wt% NH4VO3 treated LiNi0.6Co0.2Mn0.2O2 at 450 degrees C exhibits much improved cycling stability (96.1% cycling retention at 0.5C after 100 cycles and 97.2% after 50 cycles at 55 degrees C), rate capability (117.0 mA h g-1 at 5C), and storage property (4683 ppm lithium residue amount after storing in air for 7 days). Such superior performance is ascribed to the Li3VO4 coating layer that inhibits the electrolyte decomposition and helps create a stable and thinner cathode-electrolyte interface, resulting in decreased interfacial resistance. In addition, this coating layer suppresses internal micro stress and phase transformation from a layered to spinel and rock-salt structure, which increases the structural integrity of LiNi0.6Co0.2Mn0.2O2 during repeated charge-discharge cycling. PMID- 29714389 TI - Polyoxometalate precursors for precisely controlled synthesis of bimetallic sulfide heterostructure through nucleation-doping competition. AB - Molybdenum disulfide (MoS2)-based bimetallic sulfides have drawn increasing research attention because of their unique structures and properties. Herein, a one-pot hydrothermal synthesis method is proposed to grow a series of bimetallic sulfides on carbon cloth (M-Mo-S/CC, M = Co, Ni, Fe) using Anderson-type polyoxometalates (POMs) as bimetallic sources for the first time. An ideal model of M-Mo-S/CC was used to study the growth process through the nucleation-doping competition mechanism. It is proved for the first time that M-Mo-S/CC possess certain compositions of bimetallic sulfides rather than metal doped MoS2 structures because the nucleation reaction is predominant in the nucleation doping competition. Moreover, the nucleation rates of different metals can be compared to study the different morphologies of M-Mo-S/CC because Anderson-type POMs have fixed bimetal proportions and precise structures. Co-Mo-S and Ni-Mo-S show spherical heterostructures with CoS2 or NiS mainly inside and interconnected MoS2 nanosheets outside, while Fe-Mo-S exhibits uniform nanosheet morphology without stacking. As electrodes for alkaline water electrolysis, M-Mo-S/CC with different compositions and morphologies exhibit a variety of activities. Particularly, among the M-Mo-S/CC samples, Co-Mo-S/CC achieves the best performance for hydrogen evolution reaction, oxygen evolution reaction and overall water splitting. This study presents a facile strategy of using POMs as bimetallic precursors for studying the growth mechanism as well as the water electrolysis performances of MoS2-based bimetallic sulfides. PMID- 29714391 TI - Photooxidation of oxazolidine molecular switches: uncovering an intramolecular ionization facilitated cyclization process. AB - Photooxidation of oxazoline (OXA) molecular switches through media-induced intramolecular ionization is reported. The formation of the photooxidation product occurs by attack of the flexible donor group (-CH2CH2OH) to the adjacent C[double bond, length as m-dash]C with 1O2 as the oxidant. The novel seven membered ring sub-structure of the photooxidation product was inferred by HRMS, IR and 1H NMR spectroscopy. Additionally, acid released from solvent photolysis was found to affect the product formation and efficiency of the photooxidation. PMID- 29714390 TI - Self-assembled materials and supramolecular chemistry within microfluidic environments: from common thermodynamic states to non-equilibrium structures. AB - Self-assembly is a crucial component in the bottom-up fabrication of hierarchical supramolecular structures and advanced functional materials. Control has traditionally relied on the use of encoded building blocks bearing suitable moieties for recognition and interaction, with targeting of the thermodynamic equilibrium state. On the other hand, nature leverages the control of reaction diffusion processes to create hierarchically organized materials with surprisingly complex biological functions. Indeed, under non-equilibrium conditions (kinetic control), the spatio-temporal command of chemical gradients and reactant mixing during self-assembly (the creation of non-uniform chemical environments for example) can strongly affect the outcome of the self-assembly process. This directly enables a precise control over material properties and functions. In this tutorial review, we show how the unique physical conditions offered by microfluidic technologies can be advantageously used to control the self-assembly of materials and of supramolecular aggregates in solution, making possible the isolation of intermediate states and unprecedented non-equilibrium structures, as well as the emergence of novel functions. Selected examples from the literature will be used to confirm that microfluidic devices are an invaluable toolbox technology for unveiling, understanding and steering self assembly pathways to desired structures, properties and functions, as well as advanced processing tools for device fabrication and integration. PMID- 29714392 TI - Regio- and stereospecific Friedel-Crafts alkylation of indoles with spiro epoxyoxindoles. AB - A highly efficient strategy for the regio- and stereospecific Friedel-Crafts alkylation of indoles with spiro-epoxyoxindoles has been developed in the mixed solvents of HFIP/H2O (1 : 9) without the use of catalysts. This protocol provides an atomically economical, catalyst-free and simple route for the construction of synthetically useful 3-(3-indolyl)-oxindole-3-methanols in high yields. Starting from optically active spiro-epoxyoxindoles a variety of enantiospecific 3-(3 indolyl)-oxindole-3-methanols could be obtained in high yields with complete retention of enantioselectivity. PMID- 29714393 TI - Near-field exciton imaging of chemically treated MoS2 monolayers. AB - The exciton-dominated light emission of two-dimensional (2D) semiconductors is determined largely by the doping state and the formation of defects. Extensive studies have shown that chemical treatment critically modifies the doping state and defect state of chemical vapor deposition (CVD)-grown or exfoliated monolayer MoS2 (1L-MoS2), suggesting a promising possibility for engineering the optoelectronic properties of 2D semiconductors. However, chemical treatment inevitably modifies both the doping state and defect states, and their independent roles in the exciton emission of 1L-MoS2 have been difficult to study, significantly limiting the practical and reliable uses of chemical treatment to improve the optical properties of 1L-TMDs. Herein, we used near field imaging and spectroscopy to investigate the effects of chemical treatment on the exciton emission of 1L-MoS2. CVD-grown 1L-MoS2 was treated with bis(trifluoromethane)-sulfonimide (TFSI) or 7,7,8,8-tetracyanoquinodimethane (TCNQ), and nanoscale maps of neutral exciton and trion emission before and after chemical treatment were obtained with 80 nm spatial resolution. A comparison of the local spatial and spectral compositions of neutral excitons and trions suggested that the p-doping effect of TFSI was especially strong around local defects, whereas electron depletion by TCNQ was spatially uniform. The specific reaction of TFSI to defect locations observed in our study provides the clue for the reason that TFSI is notably effective at improving the light emission of 1L MoS2. PMID- 29714394 TI - Synthesis of multi-substituted dihydrofurans via palladium-catalysed coupling between 2,3-alkadienols and pronucleophiles. AB - Multi-substituted dihydrofurans were obtained from a palladium-catalysed coupling reaction between 2,3-alkadienols and ketones bearing an electron-withdrawing group at the alpha-position. Methanol as a solvent was essential for the initial dehydrative substitution to suppress the competitive hydroalkylation of the diene moiety. The substitution would be followed by intramolecular hydroalkoxylation under the same catalysis. PMID- 29714395 TI - Cocoa procyanidins modulate transcriptional pathways linked to inflammation and metabolism in human dendritic cells. AB - Foods rich in polyphenols such as procyanidins (PC) have been proposed to have anti-inflammatory properties, and we have previously reported inhibition of lipopolysaccharide (LPS)-induced inflammatory cytokine secretion in human dendritic cells (DCs) by PC derived from cocoa. To explore the mechanistic basis of this inhibition, here we conducted transcriptomic analysis on DCs cultured with either LPS or LPS combined with oligomeric cocoa PC. Procyanidins suppressed a number of genes encoding cytokines and chemokines such as CXCL1, but also genes involved in the cGMP pathway such as GUCY1A3 (encoding guanylate cyclase soluble subunit alpha-3). Upregulated genes were involved in diverse metabolic pathways, but notably two of the four most upregulated genes (NMB, encoding neuromedin B and ADCY3, encoding adenyl cyclase type 3) were involved in the cAMP signalling pathway. Gene-set enrichment analysis demonstrated that upregulated gene pathways were primarily involved in nutrient transport, carbohydrate metabolism and lysosome function, whereas down-regulated gene pathways involved cell cycle, signal transduction and gene transcription, as well as immune function. qPCR analysis verified differential expression of GUCY1A3, ADCY3, NMB as well as a number of other genes, and marked suppression of LPS-induced CXCL1 and IL-23 protein secretion was also observed. Thus, our results confirm a marked anti inflammatory effect of PC in human DCs, which may be related mechanistically to second-messenger function and metabolic activity. Our results provide a foundation to further investigate metabolic pathways altered by PC during intestinal inflammation, and further encourage investigation of the health promoting potential of PC-rich functional foods. PMID- 29714396 TI - Tailoring lumazine synthase assemblies for bionanotechnology. AB - Nanoscale compartments formed by hierarchical protein self-assembly are valuable platforms for nanotechnology development. The well-defined structure and broad chemical functionality of protein cages, as well as their amenability to genetic and chemical modification, have enabled their repurposing for diverse applications. In this review, we summarize progress in the engineering of the cage-forming enzyme lumazine synthase. This bacterial nanocompartment has proven to be a malleable scaffold. The natural protein has been diversified to afford a family of unique proteinaceous capsules that have been modified, evolved and assembled with other components to produce nanoreactors, artificial organelles, delivery vehicles and virus mimics. PMID- 29714398 TI - Impact of human platelet lysate on the expansion and chondrogenic capacity of cultured human chondrocytes for cartilage cell therapy. AB - High hopes have been pinned on regenerative medicine strategies in order to prevent the progression of cartilage damage to osteoarthritis, particularly by autologous chondrocyte implantation (ACI). The loss of chondrocyte phenotype during in vitro monolayer expansion, a necessary step to obtain sufficient cell numbers, may be a key limitation in ACI. In this study, it was determined whether a shorter monolayer expansion approach could improve chondrogenic differentiation. The effects of two supplement types, foetal bovine serum (FBS) and StemulateTM (a commercial source of human platelet lysate), on the expansion and re-differentiation potential of human chondrocytes, isolated from five individuals, were compared. Chondrocytes were expanded with 10 % FBS or 10 % StemulateTM. Pellets were cultured for 28 d in chondrogenic differentiation medium and assessed for the presence of cartilage matrix molecules and genes associated with chondrogenicity. StemulateTM significantly enhanced the proliferation rate [average population doubling times: FBS, 25.07 +/- 6.98 d (standard error of the mean, SEM) vs. StemulateTM, 13.10 +/- 2.57 d (SEM)]. Sulphated glycosaminoglycans (sGAG), total collagen and qRT-PCR analyses of cartilage genes showed that FBS-expanded chondrocytes demonstrated significantly better chondrogenic capacity than StemulateTM-expanded chondrocytes. Histologically, FBS-expanded chondrocyte pellets appeared to be more stable, with a more intense staining for toluidine blue, indicating a greater chondrogenic capacity. Although StemulateTM positively influenced chondrocyte proliferation, it had a negative effect on chondrogenic differentiation potential. This suggested that, in the treatment of cartilage defects, StemulateTM might not be the ideal supplement for expanding chondrocytes (which maintained a chondrocyte phenotype) and, hence, for cell therapies (including ACI). PMID- 29714399 TI - Translating phototherapeutic indices from in vitro to in vivo photodynamic therapy with bacteriochlorins. AB - OBJECTIVE: To compare hydrophilic and lipophilic bacteriochlorin photosensitizers in the photodynamic therapy of cancer, and relate their properties and in vitro phototoxicities to the efficacy of in vivo PDT treatments. MATERIALS AND METHODS: Photochemical characterization of a hydrophilic bacteriochlorin (F2 BOH) photosensitizer, and its use in PDT was compared with the performance of a closely related but water-insoluble bacteriochlorin (F2 BMet or redaporfin). Biodistribution, pharmacokinetics, skin photosensitivity, PDT efficacy and immune responses of two bacteriochlorins were compared. PDT in vitro employed CT26 colon carcinoma cells. BALB/c mice bearing CT26 cells were treated according to a protocol where the illumination of the subcutaneous tumor is performed 15 minute after intravenous administration of the photosensitizer, while it is in the vascular compartment (vascular-PDT). RESULTS: F2 BOH has photochemical properties comparable to redaporfin and both are promising photosensitizers for PDT. Although, F2 BOH is 10 times less phototoxic in vitro than redaporfin, the phototoxicity of F2 BOH in vascular-PDT is comparable to that of redaporfin. This is consistent with the fact that the vasculature is the main target of vascular PDT. F2 BOH-PDT led to long-term cures and stimulation of the immune system. CONCLUSION: F2 BOH is soluble in aqueous media, photostable, has a convenient elimination half-life of 44 hours and leads to very low skin photosensitivity one week after administration. F2 BOH and redaporfin are both very phototoxic in vascular-PDT, but this could not be anticipated from their widely different phototherapeutic indices in vitro. PDT with F2 BOH enabled long-term cures of BALB/c mice with subcutaneously implanted CT26 tumors, and the cured mice rejected tumor re-inoculation one year after the treatment. Lasers Surg. Med. 50:451-459, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29714397 TI - Recent advances in ruthenium-based olefin metathesis. AB - Ruthenium-based olefin metathesis catalysts, known for their functional group tolerance and broad applicability in organic synthesis and polymer science, continue to evolve as an enabling technology in these areas. A discussion of recent mechanistic investigations is followed by an overview of selected applications. PMID- 29714400 TI - Bifunctional Electrocatalysts for Overall Water Splitting from an Iron/Nickel Based Bimetallic Metal-Organic Framework/Dicyandiamide Composite. AB - Pyrolysis of a bimetallic metal-organic framework (MIL-88-Fe/Ni)-dicyandiamide composite yield a Fe and Ni containing carbonaceous material, which is an efficient bifunctional electrocatalyst for overall water splitting. FeNi3 and NiFe2 O4 are found as metallic and metal oxide compounds closely embedded in an N doped carbon-carbon nanotube matrix. This hybrid catalyst (Fe-Ni@NC-CNTs) significantly promotes the charge transfer efficiency and restrains the corrosion of the metallic catalysts, which is shown in a high OER and HER activity with an overpotential of 274 and 202 mV, respectively at 10 mA cm-2 in alkaline solution. When this bifunctional catalyst was further used for H2 and O2 production in an electrochemical water-splitting unit, it can operate in ambient conditions with a competitive gas production rate of 1.15 and 0.57 MUL s-1 for hydrogen and oxygen, respectively, showing its potential for practical applications. PMID- 29714401 TI - Potential-Dependent, Switchable Ion Selectivity in Aqueous Media Using Titanium Disulfide. AB - The selective removal of ions by an electrochemical process is a promising approach to enable various water-treatment applications such as water softening or heavy-metal removal. Ion intercalation materials have been investigated for their intrinsic ability to prefer one specific ion over others, showing a preference for (small) monovalent ions over multivalent species. In this work, we present a fundamentally different approach: tunable ion selectivity not by modifying the electrode material, but by changing the operational voltage. We used titanium disulfide, which shows distinctly different potentials for the intercalation of different cations and formed binder-free composite electrodes with carbon nanotubes. Capitalizing on this potential difference, we demonstrated controllable cation selectivity by online monitoring the effluent stream during electrochemical operation by inductively coupled plasma optical emission spectrometry of aqueous 50 mm CsCl and MgCl2 . We obtained a molar selectivity of Mg2+ over Cs+ of 31 (strong Mg preference) in the potential range between -396 mV and -220 mV versus Ag/AgCl. By adjusting the operational potential window from 219 mV to +26 mV versus Ag/AgCl, Cs+ was preferred over Mg2+ by 1.7 times (Cs preference). PMID- 29714402 TI - Progress in Lanthionine and Protected Lanthionine Synthesis. AB - Lanthionine (Lan), a non-proteinogenic natural amino acid, is an essential component of peptidoglycan found in the cell wall of Fusobacterium species. Lan and beta-methyllanthionine are also key constituents in lantibiotics, a prevalent class of peptide antibiotics. The development of those new antibacterial drugs with enhanced properties is the focus of recent research. Since multiple isomers of Lan are possible, a regio- and diastereoselective synthesis is challenging. This comprehensive review summarizes the known chemical syntheses of lanthionine from various precursors (e.g., beta-chloroalanine, cystine, dehydroalanine, beta iodoalanine, aziridine, serine lactone, sulfamidate) since 1941. Methods for preparation of unprotected, protected, orthogonally protected, and mutually orthogonally protected lanthionine with relevant experimental details and perspectives on their usefulness are provided. The potential of these Lan derivatives is illustrated by one recent application. PMID- 29714404 TI - Pectus Carinatum: Factors That Contribute to Success and Failure of Nonoperative Treatment. AB - BACKGROUND: Pectus carinatum is a congenital chest wall deformity characterized by protrusion ofthe sternum and ribs. External bracing has been the gold standard treatment for this condition for the past 20 years. PURPOSE: The primary purpose of the study was to identify factors that contribute to treatment success of bracing for patients with pectus carinatum. The secondary aim was to identify the optimal age to recommend bracing for pectus carinatum. METHODS: 176 patients who were evaluated for a brace for pectus carinatum were contacted to participate in an online survey about their experience. A retrospective chart review was conducted on patients who participated in the survey. RESULTS: Subjects rated themselves as more confident afterbracing(P=.002). Patients who hadfamily sup- port, and no documented complaints (P = .024) and (P = .009) respectively, were more likely to say they had made the right choice to wear the brace. CONCLUSIONS: This study demonstrated that family support and fewer complaints are predictors of success for the brace. PMID- 29714403 TI - Effect of an Educational Intervention on the Accuracy of Data Submitted to a National Quality Registry. AB - BACKGROUND: We hypothesize that data-entry errors within the National Cardiovascular Data Registry(r) (NCDR) ICD RegistryTM may be an important reason behind labeling many cases as nonevidence-based. OBJECTIVE: To describethe frequency of data-entry errors in implantable cardioverter-defibrillator (lCD) implant data from our institution and develop a plan for quality improvement using the Deming cycle. METHODS AND RESULTS: We assessed data of patient report forms from2007to 2010 and compared these data with forms submitted from 2011 to 2012 after implementation of a continuous multicomponent staff education and training program. Of 211 ICD implants between 2007 and 2010, 36 (17%) were labeled nonevidence-based. Twenty-four (11.4%) resulted from misclassification due to data entry errors and 12 (5.7%) were actual nonevidence-based. Postintervention, review of 97 submitted patients' data revealed one (1%) data entry error and three (3.1%) actual nonevidence-based implants. CONCLUSIONS: Multicomponent educational intervention was effective in reducing errors in data sub- mitted to the NCDR ICD Registry. PMID- 29714405 TI - Peripheral Tibial Nerve Stimulation for Overactive Bladder Syndrome: Treatment Success and Patient Satisfaction. AB - OBJECTIVE: To evaluate the success rate and patient satisfaction ofperipheral tibial nerve stimulation (PTNS) therapy. METHOD: Retrospective cohort study assessing PTNS treatment success and patient satisfaction. RESULTS: Data from 34 women were included. On average, patients were 70.2 (+/- 12) years of age, had a BMI of 29.9 (+/- 8.9) kg/M2, and traveled 11.2 (+/- 12.3) miles to receive weekly PTNS treatments. Overall, 22 patients (64.7%) were satisfied, four (11.8%) unsatisfied, and eight (23.5%) undecided. Those who were satisfied completed an average of 10.9 treatments (+/- 2.4), those who were unsatisfied completed an average of 9.5 treatments (+/- 2.6), and those left undecided completed an average of 7.2 treatments (+/- 4.3). The fourth treatment visit was the most likely to predict whether a patient would be satisfied or unsatisfied by the 12th treatment. CONCLUSION: Overall the success of the PTNS therapy was 64.7%, consistent with previous studies. Most patients note improvement after the fourth treatment. PMID- 29714406 TI - Injuries Associated with Subdural Hematoma: A Study of the National Trauma Data Bank. AB - Of 92030 patients with subdural hematoma (SDH) in the National Trauma Data Bank (NTDB), 55729 had fall mechanisms of injury (61%), while 36301 had other traumatic mechanisms (nonfall, 39%). For nonfall mechanisms, the three associated injuries with the highest incidence were: skull fractures (43.3%), rib/sternum injuries (25.0%), and thoracic organ injuries (24.0%). For fall mechanisms, the three associated injuries with the highest incidence were: skull fractures (19.0%), spinal injuries (7.1%), and upper extremity fractures (6.8%). Mortality was associated with age and most studied associated injuries (odds ratios ofup to 2.04). 'This study conveys an important clinical point: even though traditional teaching highlights the risk of noncontiguous spine fractures in patients with a known spine fracture, the risk of a noncontiguous spine fracture is higher when dealing with a patient with SDH. This is underscored by the fact that mortality is higher for SDH patients with other associated injuries. PMID- 29714407 TI - Durable Complete Response of Primary CNS Lymphoma in an 80-Year-Old Patient with Retroviral Infection. AB - People aging with human immunodeficiencyvirus (HIV) present a unique set of challenges for their providers. Cardiovascular, metabolic, neurodegenerative, and renal disorders, and certain cancers are more common in this cohort, which is attributed to elevated rates of inflammation. Although survival remains compromised, integration of efficacious antiretrovirals and high-dose methotrexate (HD-MTX) was shown to improve clinical results in HIV-infected patients with primary central nervous system lymphoma (PCNSL). However, optimal management of PCNSL in the elderly is not known. We present the case of an 80 year-old patientwith HIV-associated PCNSL who achieved a durable complete response with HD-MTX andrituximab. He remains in complete remission 18 months after the diagnosis. Our case supports using the HD-MTX/rituximab combination in the very old subjects with HIV-related PCNSL. PMID- 29714408 TI - Tragus Piercing Presenting as a Novel Risk Factor with Magnetic Resonance Imaging. AB - Although magnetic resonance imaging (MRI) excels in a number of medical imaging utilities, one of its particular attraction is the lack of ionizing radiation. However, MRI scans are associated with their own unique safety concerns. We encountered two cases of lost tragus piercings presenting as a novel risk factor in MRI safety. The lost tragus piercings caused temporary discomfort and pain but were able to be removed without complication. Heightened awareness for this potential source of patient harm, particularly with more individuals obtaining body piercings, is necessary for appropriate patient screening. PMID- 29714409 TI - Pseudo-Atrial Flutter Secondary to a Chest Wall Percussion Device. AB - Pseudo-atrial flutter is an EKG artifact that mimics a true atrial flutter. We report a case of pseudo-atrial flutter in a 67-year-old male with quadriplegia and ventilator dependence due to amyotrophic lateral sclerosis (ALS) who was hospitalized for respite care. Ihe pseudo-atrial flutterwas found to be due to percussions from a built-in chest wall percussion device in a hospital mattress used for chest physiotherapy. PMID- 29714410 TI - Bilateral Giant Cell Arteritis Presenting as Bilateral Sudden Vision Loss. AB - Giant cell arteritis (GCA) is the most common form of primary vasculitis and it mainly involves large to medium sized vessels. It is also referred to as temporal arteritis as it primarily affects the temporal artery. Ocular involvement frequently occurs in GCA; if not promptly diagnosed, it can cause devastating ocular complications including complete vision loss and permanent blindness. In the majority of cases, it is unilateral; however, there are rare instances where bilateral ocular involvement is reported. In our report, we present the case of a patient presenting with bilateral sudden vision loss associated with GCA. PMID- 29714411 TI - [Advances in the concept of treatment of erectile dysfunction]. AB - Erectile dysfunction (ED) seriously influences the quality of life of the patients and their partners. There are various methods for the treatment of ED, with medication as the first choice. This paper reviews the advances in the concept of treatment of ED, including regular treatment, maximal therapeutic effects, primary diseases inducing ED, and humanistic environment and ideal goal of ED treatment, aiming to help further understand the therapeutic concept and improve clinical management of the disease. PMID- 29714412 TI - [Expressions of TRPV1 and TRPA1 in the dorsal root ganglion in the rat model of orchialgia]. AB - Objective: To explore the expressions of transient receptor potential vanilloid 1 (TRPV1) and TRP ankyrin 1 (TRPA1) in the dorsal root ganglion (DRG) and their action mechanisms in the rat model of orchialgia. METHODS: The models of orchialgia were established in male SD rats by injection of 2% acetic acid into the testis. Then the number of spontaneous pain responses and withdrawal latency in the model rats were recorded by behavioral tests and the expressions of TRPV1 and TRPA1 in T13-L1 DRGs determined by RT-qPCR, Western blot and immunofluorescence staining. RESULTS: Compared with the normal control rats, the orchialgia models showed a significant increase in the number of spontaneous pain responses (0.13 +/- 0.35 vs 22.63 +/- 3.42, P<0.01) and a decrease in the withdrawal latency at 4 hours after injection ([12.75 +/- 1.50] vs [4.85 +/- 1.00] s, P<0.05). The mRNA expressions of both TRPV1 and TRPA1 were observed in the membrane of the neurons in the DRG, the former increased by 1.77 times and the latter by 1.75 times that of the control (P<0.05). CONCLUSIONS: The expressions of TRPV1 and TRPA1 were up-regulated in the DRG of the rat models of orchialgia, which may be involved in the allodynia and hyperalgesia of the rats. PMID- 29714413 TI - [Expression of AXL enhances docetaxel-resistance of prostate cancer cells]. AB - Objective: To explore the effect of the AXL expression on the chemosensitivity of prostate cancer PC-3 and DU145 cells to docetaxel and possible mechanisms. METHODS: Using Western blot, we examined the expressions of the AXL protein, p AXL and Gas6 in the docetaxel-resistant PC-3 (PC-3-DR) and DU145 (DU145-DR) cells stimulated with gradually increased concentrations of docetaxel. We transfected the PC-3 and DU145 cells with negative NC ShRNA and AXL-ShRNA, respectively, which were confirmed to be effective, detected the proliferation, apoptosis and cycle distribution of the cells by CCK8, MTT and flow cytometry after treated with the AXL-inhibitor MP470 and/or docetaxel, and determined the expression of the ABCB1 protein in the PC-3-DR and DU145-DR cells after intervention with the AXL-inhibitor R428 and/or docetaxel. RESULTS: The expression of the AXL protein in the PC-3 and DU145 cells was significantly increased after docetaxel treatment (P <0.05). The expressions AXL and p-AXL were remarkably higher (P <0.05) while that of Gas6 markedly lower (P <0.05) in the PC-3 and DU145 than in the PC-3-DR and DU145-DR cells. The inhibitory effect of docetaxel on the proliferation and its enhancing effect on the apoptosis of the PC-3 and DU145 cells were significantly decreased at 48 hours after AXL transfection (P <0.05). MP470 obviously suppressed the growth and promoted the apoptosis of the PC-3-DR and DU145-DR cells, with a higher percentage of the cells in the G2/M phase when combined with docetaxel than used alone (P <0.05). R428 markedly reduced the expression of ABCB1 in the PC-3-DR and DU145-DR cells, even more significantly in combination with docetaxel than used alone (P <0.05). CONCLUSIONS: The elevated expression of AXL enhances the docetaxel-resistance of PC-3 and DU145 prostate cancer cells and AXL intervention improves their chemosensitivity to docetaxel, which may be associated with the increased cell apoptosis in the G2/M phase and decreased expression of ABCB1. PMID- 29714414 TI - [Expressions of JNK and p-JNK in advanced prostate cancer and their clinical implications]. AB - Objective: To investigate the expressions of JNK and p-JNK in advanced prostate cancer (PCa) and benign prostatic hyperplasia (BPH) and their implications. METHODS: Using immunohistochemistry, we detected the expressions of JNK and p-JNK proteins in 40 cases of paraffin wax-embedded PCa and 21 cases of BPH tissues and analyzed their relationships with advanced PCa and BPH as well as with the pathologic features of advanced PCa. RESULTS: Statistically significant differences were not found in the positive expression rate of the JNK protein between BPH and PCa (42.86% vs 52.50%, P>0.05), non-metastatic and metastatic PCa (53.85% vs 51.85%, P >0.05), Gleason <=7 and Gleason >7 (58.82% vs 47.82%, P >0.05), PSA <=20 MUg/L and PSA >20 MUg/L (57.14% vs 51.52%, P >0.05), or survival >5 yr and survival <=5 yr (60.00% vs 45.00%, P >0.05), nor in the expression level of p-JNK between BPH and PCa (33.33% vs 35.00%, P >0.05), non-metastatic and metastatic PCa (30.77% vs 37.03%, P >0.05), Gleason <=7 and Gleason >7 (35.29% vs 34.78%, P >0.05), or PSA <=20 MUg/L and PSA >20 MUg/L (43.75% vs 10.93%, P >0.05). However, the expression of p-JNK was significantly higher in the survival >5 yr than in the survival <=5 yr group of the PCa patients (50.00% vs 20.00%, P <0.05). CONCLUSIONS: PCa patients with highly expressed p-JNK have a longer survival time and the high positive rate of p-JNK is associated with the prognosis of PCa. PMID- 29714415 TI - [Correlation between prostatic parameters of transrectal ultrasonography and age in patients with benign prostatic hyperplasia]. AB - Objective: To investigate the correlation of prostatic parameters of transrectal ultrasonography with age in patients with benign prostatic hyperplasia (BPH) and the patterns of prostatic enlargement in different age groups of the patients. METHODS: We retrospectively studied the reports of transrectal ultrasonography for 1 739 outpatients with BPH from January 2010 to December 2015, who were divided into four age groups, 50-59, 60-69, 70-79, and =>=80 years. We analyzed the patterns of prostatic enlargement in different age groups. RESULTS: The transrectal ultrasonographic prostatic parameters, most significantly the transitional zone index (TZI), of the BPH patients were positively correlated with age. And the prostatic parameters were gradually increased with aging, with statistically significant differences among different age groups (P <0.05). The prostate was enlarged most quickly between 50 and 69 years of age. CONCLUSIONS: There is a positive correlation between age and prostatic parameters of transrectal ultrasonography, particularly the transitional zone index, in patients with BPH, which indicates that TZI can serve as one of the best criteria in evaluating BPH. The volume of the prostate, especially that of the transitional zone, is increased with aging, reaching the peak between 50 and 69 years, which is of great significance for further study of the development and progression of BPH. PMID- 29714416 TI - [Chinese parents' attitudes toward and their satisfaction with circumcision for 6 14 years old children]. AB - Objective: To investigate the attitudes of the parents toward circumcision for 6 14 years old children and their satisfaction with the results. METHODS: We performed circumcision in the Department of Urology of Zhongda Hospital for 220 children aged 6-14 years from 220 families between January 2010 and August 2016, including 70 cases of traditional and 150 cases of Shang Ring circumcision. We conducted telephone follow-ups among the parents of the patients concerning the decision-maker, reasons and regret for circumcision, acceptance of a second operation, source of information, satisfaction with surgical results, and reasons for dissatisfaction. RESULTS: Most decisions for circumcision were made by the father, chiefly for health and hygiene. Their main sources of information on circumcision were Internet and friends. The parents of 29 patients were dissatisfied for long recovery or peri- and post-operative pain, including 19 cases (27.1%, 19/70) of traditional and 10 cases (6.7%, 10/150) of Shang Ring circumcision, with statistically significant differences between the two groups (P <0.05). CONCLUSIONS: Most parents were satisfied with circumcision, and the main reasons for dissatisfaction were long recovery and pain. The rate of satisfaction with Shang Ring circumcision was higher than that with traditional circumcision. Shang Ring circumcision is recommended for children aged 6-14 years old. PMID- 29714417 TI - [Correlation of abnormal topological properties of the white matter fibers connecting the left amygdale with psychogenic erectile dysfunction]. AB - Objective: To explore the topological properties of the degree and strength of nodes in the binary and weighted brain white matter networks of the patients with psychogenic erectile dysfunction (pED) and analyze the changes of myelin integrity, number and length of the white matter fibers in the topological space. METHODS: Diffusion tensor imaging data were obtained from 21 patients with pED and 24 healthy controls matched in sex, age, and years of education and subjected to preprocessing. The whole cerebral cortex was divided into 90 regions, followed by fiber tracking, construction of the binary and weighted white matter networks, and calculation of the node degrees and connectivity strengths in different brain regions. The property values were compared between the two groups using the two sample t-test, the results were corrected by multiple testing correction, and the correlation of the property values with the erectile function of the patients was subjected to Pearson's correlation analysis. RESULTS: Compared with the healthy controls, the pED patients showed significantly decreased node degree of the left triangular part of inferior frontal gyrus (IFG) (7.54+/-1.44 vs 5.95+/-1.28, t = 3.88, corrected P = 0.02), medial orbital part of superior frontal gyrus (SFG) (10.08+/-3.60 vs 6.29+/-3.30, t = -3.67, corrected P = 0.02), and amygdala (6.50+/-2.11 vs 4.29+/-1.31, t = -4.16, corrected P = 0.01) in the binary networks, as well as the connectivity strength of the left triangular part of IFG (2.50+/-0.68 vs 1.72+/-0.50, t = -4.35, corrected P = 0.01), medial orbital part of SFG (3.17+/-0.97 vs 2.08+/-1.10, t = -3.53, corrected P = 0.03), and amygdala (1.80+/-0.69 vs 1.11+/-0.39, t = -4.03, corrected P = 0.01) in the fractional anisotropy (FA) weighted networks. The node degree of the left amygdala was negatively correlated with the total score (r = -0.47,P = 0.04), second item score (r = -0.46, P = 0.03), and third item score of IIEF-5 (r = -0.45, P = 0.04) in the pED patients. CONCLUSIONS: The myelin integrity of the white matter fibers in the left frontal lobe and amygdale is impaired in pED patients, which leads to the aberrant generation, processing and regulation of their emotions. The decreased pivotal role and importance of the white matter fibers connecting the left amygdale may be associated with pED. PMID- 29714418 TI - [Sperm chromatin structure assay versus sperm chromatin dispersion test in detecting sperm DNA integrity and correlation of sperm DNA fragmentation with semen parameters]. AB - Objective: Sperm DNA fragmentation (SDF) is widely used to predict male infertility and the methods of detecting SDF are varied. This study aimed to compare two methods of SDF detection and investigate the correlation between SDF and sperm quality. METHODS: Using sperm chromatin structure assay (SCSA) and sperm chromatin dispersion test (SCD), we detected SDF in 108 semen samples collected in the Center of Reproduction and Genetics of Suzhou Municipal Hospital. We compared the results of the two methods and analyzed the correlations of SDF routine semen parameters, sperm morphology and the age of the patients. RESULTS: A significant consistency was found in the SDF index (DFI) between the two methods (P<0.01). The DFI was correlated negatively with sperm motility, the percentage of progressively motile sperm, and that of morphologically normal sperm (P <0.01), but positively with the teratozoospermia index (P <0.01 in SCSA and P <0.05 in SCD). The DFI measured by SCSA showed a significantly positive correlation with the patients' age (P <0.01), but not that obtained by SCD. CONCLUSIONS: The results of both SCSA and SCD play an important role in predicting sperm quality. As a clinical index, the DFI has a predictive value for male infertility. However, the results of different detecting methods vary widely, which calls for further studies on their standardization. PMID- 29714419 TI - [Real-time transrectal ultrasonography in seminal vesiculoscopy]. AB - Objective: To compare three different pathways for transurethral seminal vesiculoscopy (SVS) and investigate the reliability and efficiency of transrectal ultrasonography (TRUS)-guided SVS (TRUS-SVS). METHODS: We retrospectively analyzed 90 cases of seminal vesiculoscopy conducted directly through the ejaculatory duct or prostatic utricle or under the guide of TRUS. We compared the success rate and complications among the three approaches. RESULTS: Operations were successfully performed in 87 (96.67%) of the 90 cases, 30 through the ejaculatory duct, 37 via the prostatic utricle, and 20 under the guide of TRUS, the operation time ranging from 25 to 75 minutes. Sperm was detected from the seminal vesicle fluid in (92.06%) of the azoospermia patients (58/63) during the surgery and in 77.78% of them (49/63) in semen analysis at 1 week postoperatively. Fifteen hematospermia and 12 spermatocystitis patients were cured. Postoperative follow-up found 20 cases of water-like semen and 3 cases of orchiepididymitis, but no such complications as retrograde ejaculation, incontinence, or rectourethral fistula. CONCLUSIONS: Transejaculatory duct and transprostatic utricle pathways are two common approaches to SVS, while TRUS-SVS may achieve a higher success rate and avoid injury of both the prostate and the rectum. PMID- 29714420 TI - [Embedding sutures of single inner- and outer-prepuce flap for the treatment of concealed penis: A report of 37 cases]. AB - Objective: To evaluate the clinical effect of embedding sutures of single inner- and outer-prepuce flap in the treatment of concealed penis. METHODS: This retrospective analysis included 37 cases of concealed penis treated by embedding sutures of single inner- and outer-prepuce flap between July 2011 and May 2015. Catheters were pulled out from the patients within 24 hours and the dressing removed about 1 week after surgery. All the patients were followed up for 12-24 months postoperatively for evaluation of the long-term outcomes of surgery. RESULTS: One-stage wound healing was achieved in all the patients. No foreskin flap necrosis, inflammation, edema, voiding dysfunction, or painful erection was found during the follow-up. The penises were extended by 2-4 cm. No complications were observed axcept 8 cases of mild prepuce edema, which all subsided with 6 months postoperatively. CONCLUSIONS: Embedding sutures of single inner- and outer prepuce flap, with the advantages of simple operation, rapid recovery and few complications, is a desirable surgical option for the treatment of concealed penis. PMID- 29714421 TI - [Risk factors for the complications of primary hypospadias urethroplasty with the urethral plate reserved]. AB - Objective: To investigate the risk factors for the complications of urethroplasty in patients with primary hypospadias by postoperative follow-up observation. METHODS: We retrospectively analyzed 110 cases of primary hypospadias repair performed from November 2010 to October 2015, including 70 cases of tubularized incised plate (TIP) urethroplasty and 40 cases of inlay internal preputial graft (IIPG) urethroplasty, all with the urethral plate reserved. We followed up the patients for 15.6-36 months, (27.3 +/- 0.52) mo for those with and (26.9 +/- 0.22) mo for those without complications. The mean age of the two groups of patients was (7.5 +/- 0.2) and (7.0 +/- 0.5) yr, respectively. RESULTS: The follow-up data were collected from all the patients, 17 (15.5%) with and 93 (84.5%) without complications. The success rate of surgery was 84.5%. There were no statistically significant differences in the follow-up time and age between the two groups of patients (P >0.05). Single-factor analysis of variance showed significant differences between the complication and non-complication groups in the preoperative urethral opening (P <0.01), ventral penile curvature (P <0.01), and length of urethral defect (P = 0.04), while multiple linear regression analysis exhibited that only ventral curvature was associated with the postoperative complications of the patients (OR = 1.12, 95% CI: 1.06-1.19, P<0.01). CONCLUSIONS: We chose single-stage urethroplasty with the urethral plate reserved for the treatment of primary hypospadias and achieved satisfactory outcomes. Ventral penile curvature is an independent risk factor for the complications of primary hypospadias, and a higher degree of curvature is associated with a higher incidnece of complications. PMID- 29714422 TI - [Effects of Kudzu Root plus Cinnamon Granules on prostatic hyperplasia in mice]. AB - Objective: To explore the effects of Kudzu Root plus Cinnamon Granules (KR+C) on prostatic hyperplasia (PH) in mice. METHODS: Sixty 4-week-old Kunming male mice were randomly divided into six groups: blank control, PH model, high-, medium- and low-dose KR+C, and finasteride control. All the mice except those in the blank control group were subcutaneously injected with testosterone propionate (5 mg / [kg.d]) at 7 days after surgical castration. The animals of different groups were treated intragastrically with different doses of KR+C, finasteride, and normal saline respectively for 3 weeks and then sacrificed for weighing of the prostate, calculation of the prostatic index, observation of the morphological changes in the prostate after HE staining, determination of the expressions of FGF2, Ki67 and TGF-beta1 by immunohistochemistry, detection of 5alpha-reductase activity by ELISA, and measurement of the apoptosis index of the prostatic cells by TUNEL. RESULTS: Compared with the model controls, the mice of the other groups showed significantly reduced prostatic volume (P <0.05), prostatic index (P <0.05), expressions of FGF2, Ki67 and TGF-beta1, and activity of 5 alpha reductase (P <0.05), but remarkably increased apoptosis index of the prostatic cells (P <0.05). However, no statistically significant differences were observed in the above parameters between the finasteride control and the three KR+C groups (P>0.05). CONCLUSIONS: KR+C can reduce the prostatic volume of PH mice by decreasing the activity of 5alpha- reductase, inhibiting the expressions of FGF2, Ki67 and TGF-beta1, and promoting the apoptosis of prostatic cells. PMID- 29714423 TI - [Yijingfang for the treatment of asthenospermia: A randomized controlled clinical trial]. AB - Objective: To investigate the clinical therapeutic effects of Yijingfang, a Chinese medicinal liquid, on asthenospermia. METHODS: We randomly divided 450 asthenospermia patients into a treatment group (n = 300) and a control group (n = 150), the former treated with Yijingfang once half a dose, bid, and the latter with Wuziyanzong Pills (9 g, bid) + L-carnitine oral liquid (10 ml, bid), both for 3 months. Before and at 1, 2, and 3 months after medication, we compared the semen volume, sperm concentration, percentages of progressively motile sperm (PMS) and total motile sperm (TMS), and semen liquefaction time between the two groups of patients. RESULTS: No statistically significant difference was observed in the semen parameters between the treatment and control groups before medication (P >0.05). In comparison with the baseline, the treatment group showed significant differences at 1, 2, and 3 months after medication in sperm concentration ([35.96 +/- 8.50] vs [49.66 +/- 10.91], [55.21 +/- 11.46], [74.90 +/- 13.07] *106/ml, P <0.01), PMS ([19.72 +/- 2.06] vs [23.81 +/- 2.56], [26.12 +/- 2.34], and [32.17 +/- 1.62] %, P <0.01) and TMS ([28.86 +/- 2.70] vs [34.17 +/- 3.43], [36.59 +/- 3.36], and [47.08 +/- 2.97] %, P <0.01), but not in the semen volume ([3.35 +/- 0.99] vs [3.15 +/- 1.06], [3.12 +/- 0.90], and [3.27 +/- 0.78] ml, P >0.05) or semen liquefaction time ([32.31 +/- 8.15] vs [31.68 +/- 3.14], [30.38 +/- 3.44], and [30.86 +/- 2.42] min, P >0.05); the control group exhibited similar results at the three time points in sperm concentration ([36.85 +/- 6.88] vs [40.53 +/- 8.32], [47.51 +/- 12.73], and [56.14 +/- 11.98] *106/ml, P <0.01), PMS ([20.26 +/- 2.73] vs [25.17 +/- 2.64], [27.23 +/- 2.25], and [31.89+/-2.27] %, P <0.01), and TMS ([30.03 +/- 2.67] vs [33.89+/-2.26], [37.38+/ 4.79], and [40.35+/-3.06] %, P <0.01), but not in the semen volume ([3.03 +/- 1.09] vs [3.16+/-1.78], [3.15+/-0.96], and [3.12+/-0.65] ml, P >0.05) or semen liquefaction time ([30.25 +/- 5.20] vs [29.36+/-4.25], [28.21+/-3.26], and [28.33+/-3.59] min, P >0.05). There were statistically significant differences between the treatment and control groups in the increase rates of sperm concentration and TMS after medication (P <0.01) but not in that of PMS (P >0.05). CONCLUSIONS: Yijingfang is an effective drug for the treatment of asthenospermia, which can regulate the spermatogenesis, increase the percentage of PMS, and improve the total sperm motility of the patients. PMID- 29714424 TI - [Genetic genes associated with oligospermia, asthenospermia and teratospermia: Advances in studies]. AB - Approximately 2,300 genes are found to be associated with spermiogenesis and their expressions play important roles in the regulation of spermiogenesis. In recent years, more and more attention has been focused on the studies of the genes associated with oligospermia, asthenospermia and teratospermia and their molecular mechanisms. Some genes, such as GSTM1, DNMT3L, and CYP1A1, have been shown to be potentially associated with oligospermia; some, such as CATSPER1, CRISP2, SEPT4, TCTE3, TEKT4, and DNAH1, with asthenospermia; and still others, such as DPY19L2 and AURKC, with teratospermia. These findings have provided a molecular basis for the studies of the pathogenesis of oligospermia, asthenospermia and teratospermia, as well as a new approach to the exploration of new diagnostic and therapeutic techniques. PMID- 29714425 TI - [Laboratory techniques for the diagnosis of prostate cancer: An update]. AB - The prevalence of prostate cancer is increasing, which is one of the leading causes of malignancy-associated deaths of males. Because the early symptoms of prostate cancer are not obvious, 20% of the patients have metastasis at the time of initial diagnosis. The low rate of early diagnosis of prostate cancer has contributed to a higher mortality rate in China than in Europe and the United States. Highly specific and sensitive diagnostic markers exist in the blood, urine and semen of prostate cancer patients. Combined laboratory techniques can improve the rate of the early diagnosis of prostate cancer, help early treatment, and prolong the survival of the patients. PMID- 29714426 TI - [Human papillomavirus infection and male reproductive health]. AB - Human papillomavirus (HPV) infection is one of the worldwide sexually transmitted diseases (STD), and the DNA of HPV can exist in the normal epithelium of reproductive organs of both men and women. Because the majority of HPV infections are asymptomatic, healthy HPV-carriers become the main source of the infection. Studies show that HPV infection in men is correlated with STD, infertility, tumor of reproductive organs, and infection in the sexual partners. Therefore, measures should be taken to reduce male HPV infection, including circumcision, fewer sexual partners, and condom use. PMID- 29714427 TI - Electrocardiograms: a guide to rhythm recognition for emergency nurses. AB - Electrocardiogram (ECG) is one of the most commonly performed investigations in emergency departments (EDs), and is an extremely useful adjunct that guides diagnosis, prognosis and treatment. In most cases nurses are the first healthcare professional to assess patients and record an ECG, yet anecdotal evidence suggests that few emergency nurses review, interpret and act on ECG findings. Research suggests this may be due to lack of confidence in, or knowledge about, interpretation of results, often because of inadequate training. This article aims to help emergency nurses understand and interpret the cardiac rhythms commonly encountered on ECGs in EDs, to enable them to support earlier diagnosis and treatment. It describes a simple, five-step method for evaluating the main components of cardiac rhythm. PMID- 29714428 TI - Parents' views on toilet training: a cross-sectional study in Flanders. AB - AIMS: The goals of this research were to investigate parents' perceptions of toilet training and their beliefs and views on how to toilet train children. METHODS: Questionnaires were provided to parents of healthy children, aged 18-72 months, who were or had just finished toilet training. There were 928 questionnaires returned (38% response rate). After correcting for age compliance with the range stated in the study, 832 parents remained. RESULTS: The data confirm a postponement of the age at which children start to potty train and the age at which they are toilet training. Fifty per cent (n=401) of the parents start because the child will soon be attending nursery school and only 27% (n=226) start toilet training because their child shows certain readiness signs. The latter group will significantly end toilet training sooner. Constipation is common and varies considerably in its severity, the complaint should not be ignored. No significant relationship between toilet training and the general family situation - parental status, working status or educational level - was found, suggesting that these factors do not have a significant impact. CONCLUSION: Proper education of parents in toilet training and readiness signs could reduce the uncertainties that exist. In that way, toilet training could be carried out more efficiently and at the right time for the child. PMID- 29714429 TI - Recent therapeutic developments in spinal muscular atrophy AB - Proximal spinal muscular atrophy (SMA) is an inherited neurodegenerative disease with a heterogeneous clinical phenotype. Although there is no cure for SMA, several strategies are currently being developed. In this review, we summarize the ongoing clinical trials and molecular mechanisms of successful approaches to SMA treatment. PMID- 29714430 TI - Reliability and validity of the Turkish Nose Obstruction Symptom Evaluation (NOSE) scale AB - Background/aim: The aim of this study was to validate the Turkish Nasal Obstruction Symptom Evaluation (T-NOSE) scale.Materials and methods: The NOSE scale was translated into Turkish. A prospective study was conducted involving adult subjects with nasal obstruction and a control group. The patients were divided into three groups, namely nasal septum deviation (NSD), septoplasty, and control groups. Internal consistency, test-retest reliability, validity, responsiveness, and the magnitude of the effect of surgery were all investigated.Results: In total, 253 subjects were enrolled in the study. Cronbach's alpha was 0.938 and 0.942 upon test and retest, respectively, which proved good internal consistency. The mean kappa value was 0.82, indicating a high level of reproducibility. The difference between postoperative and control groups was not statistically significant (P < 0.05). The T-NOSE score of the NSD group was 65.67 +/- 16.77, while it was 10.75 +/- 12.25 for the control group (P < 0.01). The mean score improved following septoplasty (P < 0.001). The magnitude of the effect of surgery was considered high. The correlation between the visual analogue scale and NOSE scores was 0.948. Conclusion: The T-NOSE scale is a valid instrument with good internal consistency, reliability, reproducibility, validity, and responsiveness. PMID- 29714431 TI - Emotion regulation and premedication success relationship in children who underwent general anesthesia AB - Background/aim: This study aims to investigate the relationship between emotion regulation characteristics and the efficacy of midazolam premedication.Materials and methods: Sixty-threechildren, aged3 to 8 years old,with tonsillectomy and/or adenoidectomy and taking premedication with midazolam (Group 2) or without premedication (Group 1), were included in this study. The behavioral and emotional status of the children was evaluated with the Conners Parent Rating Scale-48 (CPRS-48) and Emotion Regulation Checklist (ERC). Age, sex, body weight, response to intravenous (IV) cannulation and mask, hemodynamic data, preoperative sedation scores [Wilton Sedation Scale (WSS)], postoperative pain intensity [Objective Pain Scale (OPS)], and emergence agitation (EA) level [Pediatric Anesthesia Emergence Delirium (PAED)] were recorded.Results: A total of 90.6% patients were quiet and sleepy in Group 2, and 25.8% in Group 1. The mean scores of OPS and PAED were higher in Group 1, and the percentage of patients with PAED score of >10 was 51.6% in Group 1 and 18.8% in Group 2 (P < 0.05). In Group 1, a significant correlation was found between PAED scores and WSS and the subfactors of the CPRS-48 (P < 0.05). A correlation was found between WSS and subfactors of ERS in Group 1 (P < 0.05). Conclusion: The incidence of anxiety and postoperative EA is increased in children with emotion regulation disorder, and midazolam premedication reduced the frequency of EA. PMID- 29714432 TI - Extracorporeal membrane oxygenation support in neonates: a single center experience in Turkey AB - Background/aim: Extracorporeal membrane oxygenation (ECMO) is a form of life support for patients with respiratory failure, cardiac failure, or both. The aim of this study was to evaluate neonates supported with ECMO and report our experience as a Turkish neonatal intensive care unit. Materials and methods: We retrospectively reviewed 11 newborn infants treated with ECMO at Ankara University for respiratory and cardiac failure. We reported the demographic, diagnostic, laboratory, and clinical data of the patients.Results: Eleven patients (9 male, 2 female) received ECMO support with a mean gestational age of 39.1 +/- 1.6 weeks and mean birth weight of 3513 +/- 506 g. Six patients received venoarterial (VA) ECMO and five patients received venovenous (VV) ECMO. Mean age at initiation and duration of ECMO was 7.2 +/- 7.4 days (2-24 days) and 10.4 +/- 4.9 days (5-21 days), respectively. Mean oxygenation index (OI) before ECMO was 48.5 +/- 5.7. ECMO was withdrawn from one patient due to severe brain injury. The survival rate for ECMO was 73% and the survival rate to discharge was 64%, whereas the survival rate in congenital diaphragmatic hernia (CDH) cases was 40%. Conclusion: Our early results from ECMO for neonates are encouraging. Identification of patients for ECMO support and timely referral will offer a survival opportunity to complex neonatal cases. PMID- 29714433 TI - Peritoneal dialysis in neonates: six years of single center experience AB - Background/aim: Peritoneal dialysis (PD) is generally considered the practical dialysis modality for neonates in the treatment of acute kidney injury (AKI) and metabolic disturbances. The aim of this study was to evaluate the indications, complications, and outcomes of PD between January 2011 and December 2016. Materials and methods: This study included all 56 neonates that underwent PD over six years in our neonatal intensive care unit (NICU). A retrospective chart review was performed for all patients in our institution.Results: The incidence of PD was 1.32% (56/4230 patients) during this period. Mean birth weight of the patients was 2267.77 +/- 1060.63 (540-5050) g. Thirty-four (60.7%) patients were premature. Fourteen patients (25%) were in the postoperative period of cardiac surgery due to congenital cardiac defects, fourteen patients (25%) were diagnosed with metabolic diseases, one patient had hypoxic ischemic encephalopathy, and another patient had severe pulmonary hypertension. Conclusion: In the acute setting of a neonatal intensive care unit, PD performed in a neonate provides a technically simple method of steady fluid, solute removal, and correction of electrolyte abnormalities. A trocar catheter appears safe even in premature babies, and closed three-way stopcock system seems to be reliable at the bedside in NICUs. PMID- 29714434 TI - A statistical approach to evaluate the performance of cardiac biomarkers in predicting death due to acute myocardial infarction: time-dependent ROC curve AB - Background/aim: Myoglobin, cardiac troponin T, B-type natriuretic peptide (BNP), and creatine kinase isoenzyme MB (CK-MB) are frequently used biomarkers for evaluating risk of patients admitted to an emergency department with chest pain. Recently, time-dependent receiver operating characteristic (ROC) analysis has been used to evaluate the predictive power of biomarkers where disease status can change over time. We aimed to determine the best set of biomarkers that estimate cardiac death during follow-up time. We also obtained optimal cut-off values of these biomarkers, which differentiates between patients with and without risk of death. A web tool was developed to estimate time intervals in risk.Materials and methods: A total of 410 patients admitted to the emergency department with chest pain and shortness of breath were included. Cox regression analysis was used to determine an optimal set of biomarkers that can be used for estimating cardiac death and to combine the significant biomarkers. Time-dependent ROC analysis was performed for evaluating performances of significant biomarkers and a combined biomarker during 240 h. The bootstrap method was used to compare statistical significance and the Youden index was used to determine optimal cut-off values. Results: Myoglobin and BNP were significant by multivariate Cox regression analysis. Areas under the time dependent ROC curves of myoglobin and BNP were about 0.80 during 240 h, and that of the combined biomarker (myoglobin + BNP) increased to 0.90 during the first 180 h.Conclusion: Although myoglobin is not clinically specific to a cardiac event, in our study both myoglobin and BNP were found to be statistically significant for estimating cardiac death. Using this combined biomarker may increase the power of prediction. Our web tool can be useful for evaluating the risk status of new patients and helping clinicians in making decisions. PMID- 29714435 TI - Does glycerol have an effect on pain during nasal packing removal AB - Background/aim: The aim of this study was to investigate the efficacy of lubricating and moistening of Merocel nasal packs with glycerol on reducing pain and bleeding during nasal packing removal in patients who had undergone endoscopic sinus surgery or with epistaxis. Materials and methods: Fifty patients were included in the study. Glycerol was used on one side while saline was used on the other side of the same patient as a control. All patients were blinded to which side received glycerol and which side received saline. In the glycerol group, glycerol was infiltrated into the Merocel packing in the nasal cavity. In the saline group, 0.9% saline solution was infiltrated into the Merocel packing in the other nasal cavity of the same patient. Both applications were performed 15 min before removal of the packs. The patients were asked to score the severity of the pain that occurred in both nasal passages according to a visual analog scale (VAS). Bleeding was recorded as mild (no bleeding), moderate (leakage), and severe (active bleeding requiring intervention). Results: The mean VAS score was significantly lower in the glycerol group than in the saline group (3.02 vs. 4.86, P < 0.05). Although no significant difference was observed between the groups in the amount of bleeding, lower amounts of bleeding were seen in the side that received glycerol.Conclusion: Administration of glycerol is a cost effective and easily performed method of analgesia for nasal packing removal in patients who undergo endoscopic sinus surgery or with epistaxis. PMID- 29714436 TI - Analysis of partial AZFc (gr/gr, b1/b3, and b2/b3) deletions in Iranianoligozoospermia candidates for intracytoplasmic sperm injection (ICSI) AB - Background/aim: Infertility is a main health issue. The human Y chromosome contains essential genes for spermatogenesis, especially those located on four major intervals defined as AZFa, AZFb, AZFc, and AZFd. A partial deletion of the AZFc region is reported as a significant risk factor for oligo-/azoospermia. The main purpose of this study was to investigate the prevalence of partial deletions in the AZFc region (gr/gr, b1/b3, and b2/b3) in Iranian oligozoospermic candidates for intracytoplasmic sperm injection. Materials and methods: Multiplex PCR was used to assess the micro and partial deletions in 60 oligozoospermia infertile and 80 fertile men. Results: Two cases (3.33%) showed AZFb deletion but no microdeletion was detected in the control samples. In the AZFc region, 20% of the patients showed deletions, in which 15% and 5% showed gr/gr and b2/b3 deletions, respectively. However, 10% of the healthy individuals also showed partial deletions, including gr/gr (7.5%) and b2/b3 (2.5%). No significant correlation was detected between the presence of gr/gr microdeletion in patients and controls (P > 0.05). Conclusion: Our study showed that the partial AZFc deletions are not associated with male infertility in Iranian subjects. PMID- 29714437 TI - The association of neuropathic pain and disease activity, functional level, andquality of life in patients with ankylosing spondylitis: a cross-sectional study AB - Background/aim: Increased neuropathic pain (NP) symptoms are seen in rheumatologic diseases such as fibromyalgia, osteoarthritis, and rheumatoid arthritis, but no studies have demonstrated a relationship between ankylosing spondylitis (AS) and NP except for a brain imaging study. The aim of this study was to estimate the presence of NP in patients with AS and to investigate how NP was related to disease activity, functional status, and quality of life. Materials and methods: A total of 100 AS patients (71 males and 29 females; median age: 37 years, range: 18-71 years) were included in the study. Pain (visual analog scale (VAS) and the painDETECT questionnaire), disease activity (Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Maastricht Ankylosing Spondylitis Enthesitis Score (MASES), Patient Global Assessment of Disease Activity (PGA), and Ankylosing Spondylitis Disease Activity Score (ASDAS)), functional level (Bath Ankylosing Spondylitis Functional Index (BASFI)), and health-related quality of life (36-Item Short Form Survey (SF-36)) were evaluated. Patients were divided into two groups. Group 1 included patients with possible or likely NP symptoms (painDETECT score of >=13) and Group 2 included patients without NP symptoms (painDETECT score of <13).Results: Low back pain-VAS, peripheral joint-VAS, BASDAI, PGA, ASDAS, and BASFI scores were significantly higher in Group 1 compared to those of Group 2 (P < 0.05). The SF-36 physical component (PC) score was significantly lower in Group 1 compared to that of Group 2 (P < 0.05). There were no significant differences between the groups regarding SF-36 mental component (MC) scores, erythrocyte sedimentation rate (ESR), and C-reactive protein (CRP) values and MASES scores. Total painDETECT scores correlated positively with low back pain-VAS, peripheral joint-VAS, morning stiffness-VAS, BASDAI, ASDAS-CRP, ASDAS-ESR, PGA, BASFI, and MASES scores and ESR values, and inversely with SF 36 PC scores. Conclusion: Our results suggest that AS patients should be evaluated in terms of NP in order not to underestimate NP. If clinicians find evidence of likely NP, they should treat the patient with drugs that target NP. PMID- 29714438 TI - Is thermal balloon ablation in women with previous cesarean delivery successful? AB - Background/aim: Endometrial ablation is used to treat heavy menstrual bleeding in women who do not respond to standard therapy. This study aimed to compare treatment success in women with previous cesarean delivery and vaginal delivery who were subjected to thermal balloon ablation.Materials and methods: This cohort study enrolled women with symptoms of heavy menstrual bleeding who had major health problems and were considered as high-risk patients for hysterectomy. Patients were divided into two groups, vaginal delivery and cesarean section (C section). Thermal balloon ablation was performed under general or regional anesthesia on days 3-5 of the menstrual cycle. Treatment success was compared between the two groups at 12 months.Results: This study involved 63 women with a mean age of 44.14 +/- 6.56 years. Of these, 33 patients (54.1%) had a history of cesarean section and revealed positive results (69.7%) after 1 year of treatment. Age <= 45 years and uterine length < 9 cm were significantly associated with treatment success in women with a previous C section.Conclusion: Thermal balloon ablation is a possible therapeutic option to treat menorrhagia occurring as a result of benign causes in women with previous C section deliveries. The results are particularly successful in younger women with shorter uterine depth. PMID- 29714439 TI - Comparison of the effects of diclofenac potassium and tenoxicam on postoperative pain, swelling, and trismus following third molar surgery AB - Background/aim: This study aimed to compare two nonsteroidal antiinflammatory agents in relation to pain, swelling, and trismus following impacted third molar surgery. Materials and methods: The study was a randomized and a double-blinded study and included 50 healthy individuals. After the operation, patients were randomly assigned to 2 groups in which diclofenac potassium and tenoxicam were used. Impacted third molars were surgically extracted with local anesthesia. Pain was assessed postoperatively by visual analog scale at the 2nd, 6th, 8th, 12th, 24th, and 48th hours and on the 3rd, 5th, and 7th days. Swelling was evaluated using the method of Ustun et al. and trismus was measured with calipers on the postoperative 3rd and 7th days. Results: There was statistically significant difference between the groups in VAS levels at the 2nd and 6th hours; however, VAS levels of the tenoxicam group were significantly lower as compared to diclofenac potassium at the 8th, 12th, 24th, and 48th hours and on the 3rd, 5th, and 7th days (P < 0.05, P < 0.01). No difference was noted regarding trismus and swelling between the groups. Conclusion: Diclofenac potassium and tenoxicam are similarly effective for reduction of swelling and trismus following the extraction of mandibular third molars; however, tenoxicam surpasses diclofenac potassium for controlling pain. PMID- 29714440 TI - The impact of visit-to-visit systolic blood pressure variability on residual renal function and left ventricular hypertrophy in peritoneal dialysis patients AB - Background/aim: Blood pressure (BP) variability is more closely associated with adverse outcomes than 'usual' BP in the general population. Residual renal function (RRF) and left ventricular hypertrophy (LVH) are thought to be predictors of poor outcome in dialysis patients. However, only a few studies have focused on BP variation and its link to RRF, LVH, and outcome in peritoneal dialysis (PD) patients. Therefore, we aimed to explore the effect of visit-to-visit BP variability on RRF and LVH in continuous ambulatory PD (CAPD) patients.Materials and methods: We performed an observational study that included all prevalent PD patients between 1 February 2006 and 31 January 2007. All patients underwent BP measurements, pulse wave velocity (PWV), cardiac ultrasound, and biochemical examination during the 1-year observation. Patients were divided into the HBPV group (higher BP variability) and LBPV group (lower BP variability) based on the standard deviation of systolic BP (SBP).Results: There were 70 patients recruited for the final analysis. Patients with HBPV had a higher SBP as compared to patients with LBPV at baseline. Renal Kt/V decreased significantly from 0.50 +/- 0.49 to 0.32 +/- 0.35 (P < 0.01) in HBPV group (but not in the LBPV group) during follow-up. Patients with HBPV also showed a higher left ventricular mass index (LVMI) and PWV than those with LBPV at the end of follow-up. Conclusion: Our study suggests that BP variability may affect RRF in PD patients. PD patients with HBPV had a faster decline in RRF and higher PWV and LVH. PMID- 29714441 TI - Introduction PMID- 29714442 TI - Changes of serum sPD-1 levels in HBeAg-positive chronic hepatitis B patients with entecavir treatment and correlation with curative effect AB - Background/aim: This study aimed to assess expression changes of serum sPD-1 levels in HBeAg-positive chronic hepatitis B patients with entecavir treatment and explore the correlation with the curative effect.Materials and methods: A total of 220 HBeAg-positive CHB patients and 207 healthy individuals were included. sPD-1 levels and virological and biochemical responses were assessed at baseline and at 12, 24, and 48 weeks in CHB patients after antiviral therapy.Results: sPD-1 levels in HBeAg-positive CHB patients before treatment were significantly lower than those of healthy controls. After entecavir treatment, sPD-1 levels increased gradually over time. At 48 weeks after entecavir treatment, sPD-1 amounts in the HBeAg seroconversion group were significantly higher than the values of the HBeAg-negative and HBeAg positive groups. sPD-1 levels in patients with alanine aminotransferase (ALT) returning to normal were significantly higher than in those with ALT not returning to normal. sPD-1 levels in treated patients with no HBV-DNA were significantly higher than in those with HBV-DNA remaining positive. sPD-1 was negatively correlated with ALT and HBV-DNA at 12, 24, and 48 weeks after entecavir treatment. Conclusion: sPD-1 may play a certain role in chronic hepatitis B and has a close relationship with the curative effect of entecavir. PMID- 29714443 TI - Risk factor assessment for breast cancer in North Cyprus: a comprehensivecase control study of Turkish Cypriot women AB - Background/aim: This case-control study aims to assess the strength of associations between reproductive, lifestyle, sociodemographic, and dietary factors as well as other potential breast cancer risks and breast cancer (BC) in a North Cyprus population. Materials and methods: The study includes 408 BC patients and 412 age-matched controls recruited from Near East Hospital and Dr. Burhan Nalbantoglu State Hospital in North Cyprus. Information regarding clinical and epidemiological characteristics was collected through a standardized interview. Age-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression before and after adjusting for the potential confounders. Results: In addition to various recognized BC risk factors, strong associations with BC were reported from women with fertility drugs used for >6 cycles (OR = 3.305, 95% CI 1.850-5.906, P < 0.001), depression (OR = 2.10, 95% CI 1.33-3.30, P < 0.001), exposure to radiation (OR = 1.74, 95% CI 1.02-2.98, P = 0.041), and excess consumption of oil (OR = 2.703, 95% CI 1.62-4.48, P < 0.001) and sugar (OR = 3.42, 95% CI 1.39-8.40, P = 0.007). Parental consanguinity (OR = 0.16, 96% CI 0.09-0.30, P < 0.001) and daily water intake of 1-2 L (OR = 0.36, 95% CI 0.19-0.66, P < 0.001) were strong protective factors. Conclusion: Our results demonstrate the presence of classical as well as several additional BC risks. The findings will be of great benefit in establishing adequate evidence-based awareness and preventative measures in the North Cyprus population. PMID- 29714444 TI - Association of serum leptin with serum estradiol in relation to breast carcinogenesis:a comparative case-control study between pre- and postmenopausal women AB - Background/aim: The aims of this study were to observe the interhormonal relationship of serum leptin with serum estradiol and to compare pre- and postmenopausal women for possible implications in breast carcinogenesis. Materials and methods: This comparative case-control study encompasses 175 breast cancer patients and 175 age-, sex-, and BMI-matched healthy controls. For comparison, the subjects were divided into pre- and postmenopausal groups according to their menstrual history. Blood samples were analyzed for serum leptin and serum estradiol by the ELISA method. Results: Higher mean values of serum estrogen and leptin were observed in breast cancer cases among both the pre- and postmenopausal groups. While estimating the association of serum leptin with serum estradiol, a weak positive (r = 0.186) but statistically significant (P = 0.022) correlation was found among the premenopausal subjects, while a moderate positive association (r = 0.556) was found among the postmenopausal subjects, which had high statistical significance (P = 0.001). Furthermore, correlation coefficients (r) of the pre- and postmenopausal groups were compared using Fisher r-to-z transformation and found to have a statistically significant difference (z = 4.03, P = 0.0001). Conclusion: The findings of this study suggest the mitogenic effects of leptin on mammary tissue via augmenting peripheral estrogen production more significantly among postmenopausal subjects. Thus, the therapeutic modulation of leptin may be a potential adjuvant treatment for breast cancer patients with high levels of leptin along with high estrogen concentration as a consequence. PMID- 29714445 TI - Pooled analysis of 163 published tuberculous peritonitis cases from Turkey AB - Background/aim: Tuberculous peritonitis may be difficult to diagnose due to its insidious and variable clinical manifestations as well as characteristics similar to malignancy. In this study, case reports from Turkey over the last 10 years were reviewed systematically using pooled analysis. Materials and methods: Thirty four suitable articles were found and 163 tuberculous peritonitis cases were included in the study. Results: The mean age was 34.1 years (17-79 years), and 146 (98.6%) of the patients were female and 17 (10.4%) were male. The most common complaints of these patients were abdominal pain (77.4%) and abdominal distention (73.5%). Ascites in the abdomen (75%), fever (42%), abdominal tenderness (33%), and abdominal distention (30.7%) were the most common physical examination findings. The mean adenosine deaminase level was 120.3 IU/L. In the subsets of patients with relevant data, acid-fast bacilli were found in 23.3%, culture was positive in 22.2%, and Mycobacterium tuberculosis polymerase chain reaction was positive in 20%. In abdominal imaging, ascites was reported in 92%. Elevated serum CA-125 was reported in 96.7% of the patients. Of 105 patients with data available following the antituberculous therapy prognosis, four (3.8%) died and the other 101 (96.2%) showed good treatment response. Conclusion: Tuberculous peritonitis should be kept in mind during the differential diagnosis of patients admitted with the triad of ascites, fever, and abdominal distention. PMID- 29714446 TI - Association between elevated red blood cell distribution widthand long-term mortality in acute pulmonary embolism AB - Background/aim: The prognostic value of the red cell distribution width (RDW) as a cost-effective and noninvasive test in acute pulmonary embolism (PE) is still unknown. We aimed to investigate the prognostic value of the admission RDW level in the long-term survival of PE patients. Materials and methods: In this registry-based, prospective cohort study, a total of 378 patients (mean age: 60.4 +/- 17.11 years, 47.4% female) who presented with acute PE were enrolled. All the clinical data for each patient were obtained from our institutional PE registry. The follow-up was performed at a median time of 17 months. The primary endpoint was death at follow-up. Results: The mean RDW in study patients was 14.67 +/- 2.13. The all-cause mortality rate during the follow-up was 15.6% (n = 59). After adjustment for potential confounders, the relationship between RDW and long-term mortality showed a trend of a significant level (hazard ratio: 1.109; 95% CI, 0.998-1.232; P = 0.053). We divided patients into 3 groups based on the European Society of Cardiology's classification. As we moved from the low risk to the higher risk categories, the mean RDW increased significantly (P = 0.037). Conclusion: It seems there may be an independent association between RDW at presentation and PE mortality within 17 months. PMID- 29714447 TI - Low levels of vitamin D are associated with nosocomial infectionsbut not with short-term mortality in critically ill patients AB - Background/aim: A prospective observational study was conducted to determine the relationship between vitamin D deficiency and nosocomial infections among intensive care unit (ICU) patients. Materials and methods: Demographic data, season of admission, vitamin D levels at admission, premorbid lifestyle scores, comorbid conditions, and admission diagnosis were recorded in 306 ICU patients. Infections that developed at least 48 h after admission to the ICU were the primary outcome, and ICU, hospital, and 1-year mortality were the secondary outcomes. Infections were evaluated for 28 days, and for the entire duration of ICU stay independently. Multiple logistic regression analysis was performed to control for confounding factors that were statistically significant in univariate analysis. Results: All infection and mortality rates were significantly higher in low 25 (OH) D groups in univariate analysis. After adjusting for confounding factors, infection rates remained higher in the deficient group. However, ICU and hospital mortality did not show any statistically significant difference between deficient and nondeficient groups. Only the 1-year mortality rate was significantly higher among patients with 25 (OH) D levels less than 20 ng/mL. Conclusion: Low vitamin D levels are significantly associated with ICU-related infections but not with ICU or hospital mortality. However, further studies are needed to identify the role of vitamin D deficiency in predicting ICU outcomes. PMID- 29714448 TI - Clinical significance of imaging findings for atlantoaxial rotatory subluxation in children AB - Background/aim: This study evaluated the usefulness of measuring the atlantodental interval (ADI) and lateral atlantodental spaces (LADSs) by retrospectively analyzing the imaging data of children of various ages with and without atlantoaxial rotatory subluxation (AARS). Materials and methods: The data of 495 children who underwent cranial computed tomography were collected. Among these children, 255 children were clinically diagnosed with AARS while 240 children were not. ADI and LADS values were measured. Results: The difference in mean ADI between children with and without AARS in all age groups was statistically significant (t-test, all P < 0.05). In children without AARS, the 95% reference range for ADI was <3.2 mm. The difference in the variance of bilateral lateral atlantodental spaces (VBLADSs) between children with and without AARS in all age groups was statistically significant (rank-sum test, all P < 0.05), with a 95% reference range of 0-2.20 mm (D-test).Conclusion: The ADI is a well-known and frequently used parameter and is not new, but there is little research about this in China and here we confirm its application in Chinese children. The LADS is not a frequently used parameter, but it does not significantly differ. The VBLADS parameter is new and significant in this manuscript. We concluded that VBLADSs of >2.2 mm are useful indicators for the diagnosis of AARS in patients <=14 years old. Finally, it can be concluded that ADI of >=3.2 mm and VBLADS of >2.2 mm are useful indicators for the diagnosis of AARS in patients <=14 years old. Widened LADSs would not be helpful in the diagnosis of AARS in children. PMID- 29714449 TI - Effect of mometasone furoate nasal spray on the DNA of nasal mucosal cells AB - Background/aim: Allergic rhinitis (AR) is a respiratory disease caused by inflammation of the nasal mucosa. Intranasal corticosteroids (ICs) are an effective treatment for AR; however, their use has been associated with atrophy in nasal mucosae. Because DNA damage has been linked to several chronic diseases, we hypothesize that use of ICs could cause DNA damage in nasal mucosa cells, leading to mucosal atrophy and septal perforation.Materials and methods: Sixty patients with moderate or severe AR were divided randomly into two groups. Mometasone furoate (MF) and antihistamine tablets (desloratadine) were given to the study (IC) group. Physiologic saline and desloratadine were given to the control ((serum physiologic (SP)) group. Nasal irrigation fluid was taken from patients before study commencement and after 4 weeks of treatment. The comet assay was applied to detect DNA damage in nasal mucosa cells.Results: Nineteen patients were excluded, leaving a study population of 41 patients (IC group: 17 patients; SP group: 24 patients). Genotoxic damage was evaluated by comet assay. Conclusion: Treatment with MF spray for 4 weeks does not cause DNA breaks within cells in the nasal mucosa. These results could form the basis of clinical trials involving treatment with different ICs over longer treatment periods. PMID- 29714450 TI - Obstructive sleep apnea syndrome is associated with impaired pulmonaryartery distensibility and right ventricular systolic dysfunction AB - Background/aim: We investigated whether obstructive sleep apnea syndrome (OSAS) has any impact on pulmonary artery distensibility (PAD) and right ventricular (RV) function. Materials and methods: Subjects were categorized according to apnea-hypopnea index (AHI) as follows: controls (n = 17 and AHI < 5), mild-to moderate OSAS (n = 22 and AHI = 5-30), and severe OSAS (n = 29 and AHI > 30). All subjects underwent transthoracic echocardiography after polysomnography to assess PAD and RV function. PAD was recorded as M-Mode trace of the right pulmonary artery and was defined as (PAmax -PAmin/PAmin) * 100. S' was measured by means of TDI of the lateral annulus of the RV using apical four-chamber view.Results: Patients with severe OSAS demonstrated impaired RV longitudinal systolic function (S') compared to the other groups (P < 0.05). Impaired pulmonary vasculature elastic properties as reflected by decreased PAD were more prevalent in severe OSAS (26.2 +/- 5.7%) compared to the controls (29.9 +/- 4.6%; P < 0.05) and mild to-moderate OSAS (29.0 +/- 4.1%; P < 0.05). An inverse relation between PAD (P < 0.05), RV myocardial performance index (MPI) (P < 0.05), and AHI was demonstrated. S' also correlated with PAD (P < 0.05). Conclusion: PAD is a significant tool to evaluate pulmonary vasculature stiffening and is well correlated with disease severity in OSAS. Further, impaired PAD may lead to RV systolic dysfunction. PMID- 29714451 TI - [Analysis of Bioelectrical Impedance for Identification]. AB - Based on bioelectrical impedance theory and pattern recognition algorithm,we in this study measured varieties of people's bioelectrical impedance in hands and identified different people according to their bioelectrical impedance.We designed a bioelectrical impedance collection circuit with AD5933 chip to measure the impedance in different people's hands,and we obtained the bioelectrical impedance spectrum for each person under 1-100 kHz electrical stimulation.We calculated the segmentation slopes of bioelectrical impedance spectrum,and took the slopes as characteristic parameters.In order to promote the recognition rate and prevent the overfitting of the model,we divided the people into the training set and the test set,and designed a 3layer back propagation neural network model to train and test the samples.The results showed that back propagation neural network model could identify the test set effectively.The recognition rate of the training sets was as high as 97.62%,recognition rate of validation sets was88.79%,recognition rate of test sets was 86.34%,and the synthetical recognition rate was 94.22%.It gives a clue that the network can perfectly recognize people in the training network as well as strangers that comes from the outside of the tests.Our work can verify the feasibility and reliability of using bioelectrical impedance and pattern recognition algorithm for identification,and can provide a simple and supplementary way to identify people. PMID- 29714452 TI - Increased micronucleus count predicts malignant behavior in pleural effusion fluid AB - Background/aim: Micronucleus (MN) frequency is used as a biomarker of chromosomal damage, genome instability, and cancer risk. The aim of this study was to evaluate the diagnostic usefulness of MN frequency to differentiate between malignant and benign pleural effusion samples.Materials and methods: Retrospectively, 78 pleural fluid cytology samples (including 20 cases of benign reactive mesothelial cells, 22 cases of suspicious cytology, and 36 cases of malignant cytology) were examined. The number of micronucleated cells in 1000 well-preserved cells was counted. Statistical tests were performed to compare the study groups. Recover operating characteristics (ROC) curve analysis was performed to suggest a cut-off value for predicting malignant behavior.Results: We evaluated a total of 78 cases of pleural effusion cytology. The number of micronucleated cells was significantly higher in cases with malignant outcome compared to cases with benign outcome. We observed that malignant samples had more micronucleated cells than suspicious ones, and suspicious cases had more micronucleated cells than reactive ones. There was a significant difference among all study groups. In addition, the frequency of MN-containing cells in suspicious cases correlates well with their outcomes.Conclusion: The results of this study reveal that there is an absolute, consistent, and proportional relationship between MN counts and malignancy in cytological samples of pleural effusions. MN scoring may be a helpful diagnostic tool for distinguishing malignant effusions from benign ones, and may be used as an adjunct tool to predict malignant behavior in challenging cases. PMID- 29714453 TI - Positive effect of restrictions on antibiotic consumption AB - Background/aim: This study aimed to examine the change in the etiology of hospital infections with restricting and releasing of group 2 carbapenems (G2C) (meropenem/imipenem/doripenem). Materials and methods: This study was planned in three periods. Study period 1 (SP-1): Carbapenems were prescribed without restriction by infectious disease specialists. SP-2: G2C prescription was restricted. SP-3: Carbapenem prescription was released. Results: In total, 4443 cases [1053 in SP-1 (23.7%), 1332 in SP-2 (29.9%), and 2085 in SP 3 (46.9%)] were included in the study. Infection rates were 11%, 6.5%, and 7.9% in SP-1, SP-2, and SP-3, respectively (P = 0.001). Acinetobacter spp.-related hospital infection rates were 3.9%, 1.2%, and 1.8%, in SP-1, SP-2, and SP-3, respectively (P = 0.0001). Infection related mortality in SP-1, SP-2, and SP-3 was 7.3%, 5%, and 3.8%, respectively (P = 0.001). Conclusion: Hospital-acquired Acinetobacter infections, antibiotic consumption, and infection-related mortality were decreased significantly with the restriction of G2C. Positive behaviors that were obtained during the restricted period were continued with release of restriction. PMID- 29714454 TI - Microbiological and clinical data analysis of 32 patientswith Nocardia infections in Yantai AB - Background/aim:Nocardia is an opportunistic pathogen that mostly affects hosts with immune deficiencies. Recently, the widespread use of immunosuppressive agents and antitumor drugs has led to an increasing number of Nocardia infections being reported. However, it is difficult to confirm this diagnosis owing to the slow growth of the bacterium and its complex resultant clinical manifestations, potentially delaying treatment and increasing mortality. Thus, further knowledge on the clinical characteristics of Nocardia infection is required. Hence, this study aimed to review the demographics, comorbidities, clinical presentation, microbiology, treatment, and outcomes of Nocardia infections in Yantai.Materials and methods:This is a retrospective study including 32 patients identified to have Nocardia infection from the Yantai Yuhuangding Hospital. The relevant patient samples were collected by two researchers, while the other researchers analyzed the relevant data.Results:The male to female ratio among the 32 patients was 3:5, and 23 patients (71.9%) were immunocompromised. Pulmonary sites of infection were the most common (65.6% of patients). N. brasiliensis infections were present in 25.0% and N.asteroides infections were present in 21.9% of patients. Because of limited biotechnological resources, Nocardia spp. in 50.0% of cases were not classified. The TMP-SMX resistance rate among isolates was 9.4%. All isolates were susceptible to amikacin, ceftriaxone, and imipenem.Conclusion:In Yantai, immunocompromised patients predominate among cases of Nocardia infection. The rate of occurrence was higher in females than in males. Because of potential TMP-SMX resistance, treatment for Nocardia infection should be based on drug susceptibility or should include combination therapy. PMID- 29714455 TI - [Thalamocortical Neural Mass Model Simulation and Study Based on Field Programmable Gate Array]. AB - Using the computer to imitate the neural oscillations of the brain is of great significance for the analysis of brain functions.Thalamocortical neural mass model(TNMM)reflects the mechanisms of neural activities by establishing the relationships between the thalamus and the cortex,which contributes to the understanding of some specific cognitive functions of the brain and the neural oscillations of electroencephalogram(EEG)rhythms.With the increasing complexity and scale of neural mass model,the performance of conventional computer system can not achieve rapid and large-scale model simulation.In order to solve this problem,we proposed a computing method based on Field Programmable Gate Array(FPGA)hardware in this study.The Altera's DSP Builder module combined with MATLAB/Simulink was used to achieve the construction of complex neural mass model algorithm,which is transplanted to the FPGA hardware platform.This method takes full advantage of the ability of parallel computing of FPGA to realize fast simulation of large-scale and complex neural mass models,which provides new solutions and ideas for computer implementation of neural mass models. PMID- 29714456 TI - Hand infection in patients with diabetes: a series of17 cases and a pooled analysis of the literature AB - Background/aim: The aim of this study was to report the clinical characteristics and the treatment outcomes of hand infections in diabetic patients and to review the literature.Materials and methods: The medical records of 17 patients with diabetic hand infections admitted to the Diabetic Foot Care Center of two different clinics from January 2012 to October 2017 were reviewed. To perform the pooled analysis, published series (32 studies) were searched in two international databases (www.scopus.com and www.pubmed.com). Results: Of the 17 patients (mean age 61.7 +/- 8.5 years), 8 (47.1%) were female. All cases were type 2 diabetes mellitus. The mean duration of diabetes was 9.0 +/ 5.96 years and the mean HbA1c was 7.86 +/- 1.88%. There was necrosis in 8 patients (47.1%). The most common causes were injury during saw and hammer use in 5 patients (29.4%) and injury due to inappropriate nail cutting in 3 patients (17.6 %). Nine (52.9%) patients were operated on. No patients underwent any major amputations or died. In 32 publications, 704 patients with diabetic hand infections were found. The average age was 53.43 years (n = 591) and 84.29% of patients (322/382) were found to have type 2 DM. The mean duration of diabetes was 4.12 years (n = 317) and the mean HbA1c was 10.58% (n = 140). The rate of surgical operation was 74.59% (323/433).Conclusion: Diabetic hand injuries often occur when using hand tools such as hammers, saws, and knives, and when cutting nails. It is necessary to use conservative treatment rather than amputation. These patients should consult experienced health care professionals. PMID- 29714457 TI - [Research of Partial Least Squares Decoding Method for Motion Intent]. AB - Due to the sparsity of brain encoding,the neural ensemble signals recorded by microelectrode arrays contain a lot of noise and redundant information,which could reduce the stability and precision of decoding of motion intent.To solve this problem,we proposed a decoding method based on partial least squares(PLS)feature extraction in our study.Firstly,we extracted the features of spike signals using the PLS,and then classified them with support vector machine(SVM)classifier,and decoded them for motion intent.In this study,we decoded neural ensemble signals based on plus-maze test.The results have shown that the proposed method had a better stability and higher decoding accuracy,due to the PLS combined with classification model which overcame the shortcoming of PLS regression that was easily affected by accumulated effect of noise.Meanwhile,the PLS method extracted fewer features with more useful information in comparison with common feature extraction method.The decoding accuracy of real data sets were 93.59%,84.00% and 83.59%,respectively. PMID- 29714458 TI - Increased concentrations of serum nesfatin-1 levels in childhoodwith idiopathic chronic malnutrition AB - Background/aim: Nesfatin-1, an anorexigenic molecule, seems to play a role in appetite regulation and energy homeostasis. The goal of this study was to evaluate the relation of nesfatin-1 with anthropometric and metabolic (ghrelin, leptin) parameters in children with idiopathic chronic malnutrition.Materials and methods: The study included 37 underweight and 38 healthy children who were similar regarding age, sex, and pubertal status. Anthropometric and biochemical (nesfatin-1, ghrelin, and leptin levels) variables were assessed. Results: A total of 37 underweight subjects (mean age 10.5 +/- 2.6 years) and 38 heathy subjects (mean age 10.3 +/- 2.3 years) were recruited. Underweight children had significantly higher nesfatin-1 (2.76 +/- 0.4 vs. 1.56 +/- 0.7, P < 0.001) and lower leptin levels (2.21 +/- 2.0 vs. 5.21 +/- 2.4, P < 0.001) than those of the control subjects. Nesfatin-1 levels were significantly associated with only leptin levels, after adjusting for age and BMI (r = -0.371, P = 0.001).Conclusion: The present study is the first to evaluate nesfatin-1 levels in relation with anthropometric and metabolic parameters in children with chronic malnutrition, who were subsequently found to have significantly higher nesfatin-1 levels. Our study underlines that nesfatin-1 may play a role in the development of malnutrition by inhibiting food intake in children. PMID- 29714459 TI - Microdeletion and mutation analysis of the SHOX gene in patientswith idiopathic short stature with FISH and sequencing AB - Background/aim:The aim of this study was to investigate the prevalence of the microdeletions and mutationsof the SHOX gene in children with idiopathic short stature (ISS) by the usage of fluorescence in situhybridization (FISH) and direct sequencing technique.Materials and methods:Thirty-seven children referred to our clinic because of short stature were classified as having ISS after clinical examination. Chromosome analyses, FISH analysis of the SHOX gene, and direct sequencing of the coding exons of SHOX, through the second to the sixth exon, in 24 of the 37 patients were also performed. Results:All children had normal karyotypes and the SHOX gene region was found to be intact in all. No mutation was detected in the exonic sequences and exon/intron boundaries of the SHOX gene in 24 children analyzed. Conclusion:No mutation was detected in the exonic sequences and exon/intron boundaries of the SHOX gene and this indicated that the prevalence of the SHOX mutations can differ according to the selection criteria, used methods, sample size, and population. PMID- 29714460 TI - Factors associated with social anxiety disorder in a groupof obese Turkish female patients AB - Background/aim: Mental disorders may accompany obesity. This study aims to evaluate the association between social anxiety disorder (SAD) and obesity and the risk factors for SAD in obese female patients.Materials and methods: A total of 114 obese patients and 110 healthy controls were included. The Beck Anxiety Inventory (BAI), Beck Depression Inventory (BDI), State and Trait Anxiety Inventory (STAI I-II), and Liebowitz Social Anxiety Scale (LSAS) were administered to assess anxiety, depression, and social anxiety levels. Scale scores were analyzed statistically. Results: The rate of SAD in obese female patients was found to be 8.8%. Anxiety, depression, and social anxiety levels were significantly higher in the obesity group compared to the control group (P < 0.05). According to linear regression analyses, a significant association between LSAS anxiety level and age, prior surgery, social support, history of being teased, BDI, and BAI was found. Conclusion: The present study shows that many factors are related to obesity and SAD in obese female patients. The clinical implications of these findings should be considered. Interventions for these factors may help prevent SAD in obese female patients. PMID- 29714461 TI - The Brazelton Neonatal Behavioral Assessment Scale:A validity and reliability study in a Turkish sample AB - Background/aim: The aim of the Brazelton Neonatal Behavioral Assessment Scale (BNBAS) is to gather a comprehensive profile of neonatal functioning by describing the full range of neonatal behavior, including competencies and strengths, as well as difficulties or deviations. This instrument has proved to be of great clinical value by detecting infants at risk for later developmental problems. This work was conducted methodologically with the aim of a Turkish validity and reliability study of the BNBAS. Materials and methods: The study was conducted in a large tertiary hospital in Turkey. After establishing content and language validity, the BNBAS was applied to 380 newborns aged 1-3 days and test-retest analysis was performed for 60 newborns 52-55 days later in the first phase. The validity and reliability study of the BNBAS included behavior and support subscales, while reflex items were not included. Results: In the study, 5 items were excluded from the original BNBAS after the factor analysis. Cronbach alpha was found as 0.974 (30 items). The behavior subscale consisted of 23 items and the support subscale consisted of 7 items. Newborns showed good overall tone and activity level and low amounts of irritable behavior. Conclusion: It may be recommended to use the BNBAS as a valid and reliable measurement tool in neonatal behavioral evaluation by physicians and nurses. PMID- 29714462 TI - Comparison of percutaneous nephrostomy and double J stent insymptomatic pregnancy hydronephrosis treatment AB - Background/aim: We aimed to compare the success rate of percutaneous nephrostomy (PCN) and double J stenting (DJS) in the treatment of symptomatic pregnancy hydronephrosis. Materials and methods: Diagnosis and grading of hydronephrosis were performed by urinary ultrasound (USG) and Doppler mode was used for evaluation of renal arterial resistivity index (RI). Patients were divided into two groups according to the method used for the treatment of hydronephrosis: group A (PCN, n = 38) and group B (DJS, n = 46). A P value < 0.05 was considered significant.Results: The number of patients requiring second intervention was higher in group B (P = 0.0018) and time to secondary intervention was significantly earlier in group B also (P = 0.0025). The number of tertiary intervention was again higher in group B (5/16 vs. 1/6) and the need for tertiary intervention was higher in patients who underwent DJS implantation as a secondary intervention than those who underwent PCN (5/11 vs. 1/11, P = 0.0012). The time to tertiary intervention was longer in patients with PCN than in those with DJS (P = 0.0048).Conclusion: PCN may be preferred to DJS in symptomatic pregnancy hydronephrosis because it requires fewer re-interventions after longer times. PMID- 29714463 TI - A survey on rectal bleeding in children, a report from Iran AB - Background/aim: Studies on the epidemiology of rectal bleeding in children are limited in Iran. Our aim was to assess etiologies of rectal bleeding in children in Iran. Materials and methods: We enrolled 730 children with rectal bleeding. All the patients underwent colonoscopy, and 457 were further evaluated with histopathology. Results: According to colonoscopy and histopathology, respectively, inflammatory bowel disease (IBD) (29.4%, 15.8%), nodular hyperplasia (NH) (24.9%, 10%), and juvenile polyposis (JP) (12.6%, 9.9%) were the most common causes of rectal bleeding. Other conditions were solitary rectal ulcer (5.3%), chronic colitis (4.6%), allergic colitis (3.3%), focal colitis (1.3%), and infectious colitis (1.1%). In colonoscopy, there were no significant differences in the distribution of pathologies regarding sex, while the youngest and oldest mean ages were found for patients with NH (4.6 +/- 3.9 years, P < 0.0001) and those with normal appearance (8.1 +/- 4.4 years, P < 0.0001) respectively. Based on histopathologic reports, the youngest patients were diagnosed with infectious colitis (4.6 +/- 2.8 years), while patients with chronic colitis were the oldest (9.2 +/- 4.6 years, P = 0.003). Conclusion: JP, NH, and IBD constituted the most common etiologies of rectal bleeding in our patients. It is recommended to perform a complete diagnostic approach to accurately assess rectal bleeding in children. PMID- 29714464 TI - Insulin-like growth factor-1 receptor expression in pediatric tumors: a comparative immunohistochemical study AB - Background/aim: Insulin-like growth factor-1 receptor (IGF-1R) is a pivotal receptor tyrosine kinase involved in the cell cycle and malignant tumor transformation. It is differentially expressed in various types of tumors. We aimed to determine the expression of IGF-1R in different pediatric tumors and to shed light on possible new indications of anti-IGF-1R treatment approaches.Materials and methods: A total of 147 specimens were analyzed according to their expression of IGF-1R. Specimens included those from rhabdomyosarcomas, Wilms tumors, Ewing sarcoma/primitive neuroectodermal tumors, peripheral neuroblastic tumors, acute lymphoblastic lymphoma, Hodgkin lymphoma, Burkitt lymphoma, retinoblastoma, pleuropulmonary blastoma, Langerhans cell histiocytosis, endodermal sinus tumors (ESTs), and myeloid sarcoma. Analysis was performed on tissue sections by immunohistochemically staining for IGF-1R expression.Results: All six specimens of EST cases showed positivity for IGF-R1. Additionally, about 56% of the Hodgkin lymphoma, 80% of the rhabdomyosarcoma, and 70% of the Wilms tumor specimens showed positivity for IGF-R1 expression.Conclusion: All ESTs examined in our study expressed IGF-1R and to our knowledge this is the first report regarding ESTs and IGF-1R expression. IGF-1R could be included among confirmatory markers for ESTs and, from a therapeutic viewpoint, ESTs should also be examined for IGF-1R expression for beneficial regimens. PMID- 29714465 TI - The relationship between vitamin D deficiency and erythrocytesedimentation rate in patients with diabetes AB - Background/aim: Vitamin D deficiency in diabetic patients has been shown to be associated with some inflammatory markers. However, its relationship with erythrocyte sedimentation rate (ESR) is still unknown. The aim of this study was to investigate the relationship between vitamin D deficiency and ESR in patients with type 2 diabetes mellitus (T2DM). Materials and methods: This cross-sectional study was conducted with 294 consecutive patients with T2DM. Serum levels of 25-hydroxyvitamin D, glycemic parameters, lipids, ESR, and C-reactive protein were measured. Patients were evaluated according to 25-hydroxyvitamin D levels as having vitamin D deficiency, vitamin D insufficiency, and vitamin D sufficiency. Results: ESR was found to be higher in patients with vitamin D deficiency than in patients who were vitamin D-sufficient (P < 0.001), and ESR was negatively correlated with 25-hydroxyvitamin D level (r = -0.265, P < 0.001). HbA1c and postprandial glucose levels were higher in patients with vitamin D deficiency than vitamin D-sufficient patients (P = 0.005 and P = 0.019, respectively). In receiver operating curve analysis, an ESR value of 14.5 mm/h had 70.1% sensitivity and 50.3% specificity for the prediction of vitamin D deficiency.Conclusion: The present study revealed that ESR is higher in T2DM patients with vitamin D deficiency than patients with sufficient vitamin D. There was an inverse association between ESR and vitamin D levels. Furthermore, vitamin D deficiency was related to poor glycemic control. PMID- 29714467 TI - A simplified cell culture model for research on intestinal inflammation AB - Background/aim: The aim of this study was to combine some easy and economical defined methods and constitute a comprehensive cell culture model to use in the bowel diseases characterized by inflammation.Materials and methods: Induction of inflammation was performed using lipopolysaccharide (LPS) or a cytokine mixture (TNF-alpha: 10 ng/mL; IFN-gamma: 100 ng/mL; IL-1beta: 1 ng/mL). IEC-6 cells were grown to confluence and serum-starved, wounds were constituted, and progress of cell migration into the wounds was photographed at 0, 2, 4, 6, 8, 10, 12, and 24 h in the presence or absence of an inflammatory environment. Cells were then grown and multiple scratches were performed to replicate the conditions of migration assay. Nitric oxide synthase-2 (iNOS) and cyclooxygenase-2 (COX-2) protein expressions were assessed. Results: Cells covered 88% of the initial wound at 24 h in the control group, 54% in the LPS group, and 35% in the cytokine mixture group. LPS and the cytokine mixture were also found to independently increase iNOS and COX-2 expressions. Conclusion: Our study, being inexpensive and practical, describes a model that integrates some methods to constitute a basic model for bowel diseases characterized by inflammation. It can be integrated as a preliminary experiment for etiopathogenesis and drug research studies. PMID- 29714466 TI - The relation between isolated micropenis in childhood with CAGand GGN repeat polymorphisms in the androgen receptor gene AB - Background/aim:In micropenis cases accompanied by external genital abnormalities such as hypospadias and cryptorchidism, infertility and spermatogenic failures have been reported to correlate with androgen receptor (AR) geneCAG and GGN repeat polymorphisms. While there is one study on isolated micropenis and CAG repeats, no study related to GGN repeats has been reported.We investigated the relation between CAG and GGN repeats in the AR gene with development of penislength in boys with isolated micropenis. Materials and methods:A total of 24 Turkish boys with isolated micropenis (<-2.5 SD) and 64 healthy controls who had normal basal serum gonadotropin levels were examined. Genotyping was performed by DNA sequencing of the patients and controls.Results:The distribution of CAG and GGN repeat lengths in our patients and controls was within the normal range and did not significantly differ between the patients and the controls.Conclusion:CAG repeat length in the AR constitutes one of multiple genetic factors relevant to the development of isolated micropenis, and the expansion of this repeat can be detected as a likely modifying factor. Moreover, the interactions of other genes that may be involved in the etiology of isolated micropenis with CAG and GGN repeats have to be taken into consideration. PMID- 29714468 TI - Effects of different drug treatments on the proliferation of human ovarian carcinoma cell line MDAH-2774 AB - Background/aim: In this study, the effects of resveratrol as a natural polyphenol compound, gemcitabine as an antimetabolite that has nucleoside structure analogous to deoxycytidine, and para-aminophenol-derived paracetamol were investigated with single and combined applications in monolayers of the MDAH-2774 human ovarian cancer cell line. Materials and methods: Drugs were evaluated in cell culture with respect to cell proliferation, cell cytotoxicity (trypan blue dye exclusion test), synthesis phase of cell cycle, and cell structure in 24, 48, 72, and 96 h. Result: Resveratrol and gemcitabine diminished both cell proliferation and cell cycle synthesis phase indication in monolayer cell cultures (P < 0.05). All combination groups showed similar effects that were mainly more effective in respect to single usage of resveratrol and gemcitabine in monolayer cell cultures.Conclusion: The effects of gemcitabine, resveratrol, and paracetamol were investigated in monolayers of the MDAH-2774 human ovarian cancer cell line and a decrease in cell number in cell cycle synthesis phase, prevention of cell proliferation, and destruction of cell structure were observed. PMID- 29714470 TI - Correction to "Fluorescent Carbon Quantum Dots with Intrinsic Nucleolus-Targeting Capability for Nucleolus Imaging and Enhanced Cytosolic and Nuclear Drug Delivery". PMID- 29714469 TI - [Study on Non-invasive Detection of Atherosclerosis Based on Electrocardiogram and Pulse Wave Signals]. AB - Artery stiffness is a main factor causing the various cardiovascular diseases in physiology and pathology.Therefore,the development of the non-invasive detection of arteriosclerosis is significant in preventing cardiovascular problems.In this study,the characterized parameters indicating the vascular stiffness were obtained by analyzing the electrocardiogram(ECG)and pulse wave signals,which can reflect the early change of vascular condition,and can predict the risk of cardiovascular diseases.Considering the coupling of ECG and pulse wave signals,and the association with atherosclerosis,we used the ECG signal characteristic parameters,including RR interval,QRS wave width and T wave amplitude,as well as the pulse wave signal characteristic parameters(the number of peaks,20% main wave width,the main wave slope,pulse rate and the relative height of the three peaks),to evaluate the samples.We then built an assessment model of arteriosclerosis based on Adaptive Network-based Fuzzy Interference System(ANFIS)using the obtained forty sets samples data of ECG and pulse wave signals.The results showed that the model could noninvasively assess the arteriosclerosis by self-learning diagnosis based on expert experience,and the detection method could be further developed to a potential technique for evaluating the risk of cardiovascular diseases.The technique will facilitate the reduction of the morbidity and mortality of the cardiovascular diseases with the effective and prompt medical intervention. PMID- 29714471 TI - Stopping Autoinducer-2 Chatter by Means of an Indigenous Bacterium ( Acinetobacter sp. DKY-1): A New Antibiofouling Strategy in a Membrane Bioreactor for Wastewater Treatment. AB - Bacterial quorum quenching (QQ) by means of degrading signaling molecules has been applied to antibiofouling strategies in a membrane bioreactor (MBR) for wastewater treatment. However, the target signaling molecules have been limited to N-acyl homoserine lactones participating in intraspecies quorum sensing. Here, an approach to disrupting autoinducer-2 (AI-2) signaling molecules participating in interspecies quorum sensing was pursued as a next-generation antibiofouling strategy in an MBR for wastewater treatment. We isolated an indigenous QQ bacterium ( Acinetobacter sp. DKY-1) that can attenuate the expression of the quorum-sensing (QS) response through the inactivation of an autoinducer-2 signaling molecule, 4,5-dihydroxy-2,3-pentanedione (DPD), among four kinds of autoinducer-2 QS bacteria. DKY-1 released AI-2 QQ compounds, which were verified to be hydrophilic with a molecular weight of <400 Da. The addition of DKY-1 entrapping beads into an MBR significantly decreased DPD concentration and remarkably reduced membrane biofouling. This new approach, combining molecular biology with wastewater engineering, could enlarge the range of QQ-MBR for antibiofouling and energy savings in the field of wastewater treatment. PMID- 29714472 TI - Large-Velocity Saturation in Thin-Film Black Phosphorus Transistors. AB - A high saturation velocity semiconductor is appealing for applications in electronics and optoelectronics. Thin-film black phosphorus (BP), an emerging layered semiconductor, shows a high carrier mobility and strong mid-infrared photoresponse at room temperature. Here, we report the observation of high intrinsic saturation velocity in 7 to 11 nm thick BP for both electrons and holes as a function of charge-carrier density, temperature, and crystalline direction. We distinguish a drift velocity transition point due to the competition between the electron-impurity and electron-phonon scatterings. We further achieve a room temperature saturation velocity of 1.2 (1.0) * 107 cm s-1 for hole (electron) carriers at a critical electric field of 14 (13) kV cm-1, indicating an intrinsic current-gain cutoff frequency ~20 GHz.MUm for radio frequency applications. Moreover, the current density is as high as 580 MUA MUm-1 at a low electric field of 10 kV cm-1. Our studies demonstrate that thin-film BP outperforms silicon in terms of saturation velocity and critical field, revealing its great potential in radio-frequency electronics, high-speed mid-infrared photodetectors, and optical modulators. PMID- 29714474 TI - Toward a New Era of Designed Synthesis of Nanoporous Zeolitic Materials. AB - Due to their nanoporous framework structures, zeolites have been widely used as catalysts, adsorbents, and ion exchangers in many industrial fields. Discovering zeolitic materials with new structures and desired functions is one of the most important tasks in the zeolite community. Traditional zeolite discovery relies primarily on low-efficiency trial-and-error processes. So far, many computational and experimental efforts have been devoted to the designed synthesis of zeolitic materials, representing a promising highway toward function-led discovery of nanoporous materials. In particular, the design of structure-directing agents, the design of target zeolites via structure enumeration, and the reorganization of disassembled building layers have led to the discovery of dozens of unprecedented zeolitic structures in the past 5 years. In this Perspective, we briefly discuss these advances and describe the research efforts that are needed in the coming era of function-led zeolite discovery. PMID- 29714475 TI - Current Parallel Solid-Phase Synthesis of Drug-like Oxadiazole and Thiadiazole Derivatives for Combinatorial Chemistry. AB - Solid-phase organic synthesis is a powerful tool in the synthesis of small organic molecules and building of libraries of compounds for drug discovery. Heterocyclic compounds are important components of the drug discovery field as well and serve as a core for hundreds of marketed drugs. In particular, oxadiazole and thiadiazole cores are compounds of great interest due to their comprehensive biological activities and structural features. Therefore, a plethora of oxadiazole and thiadiazole synthesis methodologies have been reported to date, including solution and solid-phase synthesis methodologies. In this review, we concentrate on and summarize solid-phase synthetic approaches of the oxadiazole and thiadiazole derivatives. PMID- 29714476 TI - Intermetallic Ni2Ta Electrocatalyst for the Oxygen Evolution Reaction in Highly Acidic Electrolytes. AB - The identification of materials capable of catalyzing the oxygen evolution reaction (OER) in highly acidic electrolytes is a critical bottleneck in the development of many water-splitting technologies. Bulk-scale solid-state compounds can be readily produced using high-temperature reactions and therefore used to expand the scope of earth-abundant OER catalysts capable of operating under strongly acidic conditions. Here, we show that high temperature arc melting and powder metallurgy reactions can be used to synthesize electrodes consisting of intermetallic Ni2Ta that can catalyze the OER in 0.50 M H2SO4. Arc melted Ni2Ta electrodes evolve oxygen at a current density of 10 mA/cm2 for >66 h with corrosion rates 2 orders of magnitude lower than that of pure Ni. The overpotential required for pellets of polycrystalline Ni2Ta to produce a current density of 10 mA/cm2 is 570 mV. This strategy can be generalized to include other first-row transition metals, including intermetallic Fe2Ta and Co2Ta systems. PMID- 29714478 TI - Facile Synthesis of Dimeric Thioether-Macrocyclic Peptides with Antibody-like Affinity against Plexin-B1. AB - Macrocyclic peptides have gained increasing attention due to their ease of discovery through various in vitro display platforms as well as their potential in possessing favorable properties of both small molecule and antibody drug classes. It is well-known that the avidity achieved through the bivalent binding mode of antibodies gives rise to their slow dissociation rates and thus high potency as drug molecules. Here, we report the synthesis of dimeric thioether macrocyclic peptides through a branched synthesis approach allowing for synthesis of dimeric peptides in a comparable number of steps as monomers and tunability of linker lengths from 30 to 200 A. Applying this method to synthesize dimers of a model PlexinB1-binding macrocyclic peptide showed close to 300-fold increases in their apparent binding affinity, bringing the KD down from 8 nM to 30 pM as well as affording improved biological activities when compared to their monomeric counterparts. These enhancements demonstrate that this is a simple synthetic strategy to harness the benefits of bivalence that antibodies naturally possess. PMID- 29714477 TI - Effect of Magnetic Coupling on Water Proton Relaxivity in a Series of Transition Metal GdIII Complexes. AB - A fundamental challenge in the design of bioresponsive (or bioactivated) GdIII based magnetic resonance (MR) imaging probes is the considerable background signal present in the "preactivated" state that arises from outer-sphere relaxation processes. When sufficient concentrations of a bioresponsive agent are present (i.e., a detectable signal in the image), the inner- and outer-sphere contributions to r1 may be misinterpreted to conclude that the agent has been activated, when it has not. Of the several parameters that determine the observed MR signal of an agent, only the electron relaxation time ( T1e) impacts both the inner- and outer-sphere relaxation. Therefore, strategies to minimize this background signal must be developed to create a near zero-background (or truly "off" state) of the agent. Here, we demonstrate that intramolecular magnetic exchange coupling when GdIII is coupled to a paramagnetic transition metal provides a means to overcome the contribution of second- and outer-sphere contributions to the observed relaxivity. We have prepared a series of complexes with the general formula LMLn(MU-O2CCH3)(O2CCH3)2 (M = Co, Cu, Zn). Solid-state magnetic susceptibility measurements reveal significant magnetic coupling between GdIII and the transition metal ion. Nuclear magnetic relaxation dispersion (NMRD) analysis confirms that the observed differences in relaxivity are associated with the modulation of T1e at GdIII. These results clearly demonstrate that magnetic exchange coupling between GdIII and a transition metal ion can provide a significant decrease in T1e (and therefore the relaxivity of GdIII). This design strategy is being exploited to prepare new generations of preclinical bioresponsive MR imaging probes with near zero-background. PMID- 29714473 TI - DARK Classics in Chemical Neuroscience: Cathinone-Derived Psychostimulants. AB - Cathinone is a plant alkaloid found in khat leaves of perennial shrubs grown in East Africa. Similar to cocaine, cathinone elicits psychostimulant effects which are in part attributed to its amphetamine-like structure. Around 2010, home laboratories began altering the parent structure of cathinone to synthesize derivatives with mechanisms of action, potencies, and pharmacokinetics permitting high abuse potential and toxicity. These "synthetic cathinones" include 4 methylmethcathinone (mephedrone), 3,4-methylenedioxypyrovalerone (MDPV), and the empathogenic agent 3,4-methylenedioxymethcathinone (methylone) which collectively gained international popularity following aggressive online marketing as well as availability in various retail outlets. Case reports made clear the health risks associated with these agents and, in 2012, the Drug Enforcement Agency of the United States placed a series of synthetic cathinones on Schedule I under emergency order. Mechanistically, cathinone and synthetic derivatives work by augmenting monoamine transmission through release facilitation and/or presynaptic transport inhibition. Animal studies confirm the rewarding and reinforcing properties of synthetic cathinones by utilizing self-administration, place conditioning, and intracranial self-stimulation assays and additionally show persistent neuropathological features which demonstrate a clear need to better understand this class of drugs. This Review will thus detail (i) historical context of cathinone use and the rise of "dark" synthetic derivatives, (ii) structural features and mechanisms of synthetic cathinones, (iii) behavioral effects observed clinically and in animals under controlled laboratory conditions, and (iv) neurotransmitters and circuits that may be targeted to manage synthetic cathinone abuse in humans. PMID- 29714479 TI - Activation of Co(I) State in a Cobalt-Dithiolato Catalyst for Selective and Efficient CO2 Reduction to CO. AB - Reduction of CO2 holds the key to solving two major challenges taunting the society-clean energy and clean environment. There is an urgent need for the development of efficient non-noble metal-based catalysts that can reduce CO2 selectively and efficiently. Unfortunately, activation and reduction of CO2 can only be achieved by highly reduced metal centers jeopardizing the energy efficiency of the process. A carbon monoxide dehydrogenase inspired Co complex bearing a dithiolato ligand can reduce CO2, in wet acetonitrile, to CO with ~95% selectivity over a wide potential range and 1559 s-1 rate with a remarkably low overpotential of 70 mV. Unlike most of the transition-metal-based systems that require reduction of the metal to its formal zerovalent state for CO2 reduction, this catalyst can reduce CO2 in its formal +1 state making it substantially more energy efficient than any system known to show similar reactivity. While covalent donation from one thiolate increases electron density at the Co(I) center enabling it to activate CO2, protonation of the bound thiolate, in the presence of H2O as a proton source, plays a crucial role in lowering overpotential (thermodynamics) and ensuring facile proton transfer to the bound CO2 ensuring facile (kinetics) reactivity. A very covalent Co(III)-C bond in a Co(III)-COOH intermediate is at the heart of selective protonation of the oxygen atoms to result in CO as the exclusive product of the reduction. PMID- 29714481 TI - Unexpected Crystallographic Phase Transformation in Nonstoichiometric SrUO4- x: Reversible Oxygen Defect Ordering and Symmetry Lowering with Increasing Temperature. AB - In situ synchrotron powder X-ray diffraction measurements have demonstrated that SrUO4 undergoes a reversible phase transformation under reducing conditions at high temperatures, associated with the ordering of oxygen defects resulting in a lowering of crystallographic symmetry. When substoichiometric rhombohedral alpha SrUO4- x, in space group R3 m with disordered in-plane oxygen defects, is heated above 200 degrees C in a hydrogen atmosphere it undergoes a first order phase transformation to a (disordered) triclinic polymorph, delta-SrUO4- x, in space group P1. Continued heating to above 450 degrees C results in the appearance of superlattice reflections, due to oxygen-vacancy ordering forming an ordered structure delta-SrUO4- x. Cooling delta-SrUO4- x toward room temperature results in the reformation of the rhombohedral phase alpha-SrUO4- x with disordered defects, confirming the reversibility of the transformation. This suggests that the transformation, resulting from oxygen vacancy ordering, is not a consequence of sample reduction or decomposition, but rather represents a change in the energetics of the system. A strong reducing atmosphere is required to generate a critical amount of oxygen defects in alpha-SrUO4- x to enable the transformation to delta-SrUO4- x but once formed the transformation between these two phases can be induced by thermal cycling. The structure of delta-SrUO4- x at 1000 degrees C was determined using symmetry representation analysis, with the additional reflections indexed to a commensurate distortion vector k = ?1/4 1/4 3/4?. The ordered 2D layered triclinic structure of delta-SrUO4- x can be considered a structural distortion of the disordered 2D layered rhombohedral alpha-SrUO4- x structure through the preferential rearrangement of the in-plane oxygen vacancies. Ab initio calculations using density functional theory with self consistently derived Hubbard U parameter support the assigned ordered defect superstructure model. Entropy changes associated with the temperature dependent short-range ordering of the reduced U species are believed to be important and these are discussed with respect to the results of the ab initio calculations. PMID- 29714480 TI - An Enantioselective Cross-Dehydrogenative Coupling Catalysis Approach to Substituted Tetrahydropyrans. AB - An enantioselective cross-dehydrogenative coupling (CDC) reaction to access tetrahydropyrans has been developed. This process combines in situ Lewis acid activation of a nucleophile in concert with the oxidative formation of a transient oxocarbenium electrophile, leading to a productive and highly enantioselective CDC. These advances represent one of the first successful applications of CDC for the enantioselective couplings of unfunctionalized ethers. This system provides efficient access to valuable tetrahydropyran motifs found in many natural products and bioactive small molecules. PMID- 29714482 TI - Optimum Morphology of Mixed-Olivine Mesocrystals for a Li-Ion Battery. AB - In this present work, we report on the synthesis of micron-sized LiMn0.8Fe0.2PO4 (LMFP) mesocrystals via a solvothermal method with varying pH and precursor ratios. The morphologies of resultant LMFP secondary particles are classified into two major classes, flakes and ellipsoids, both of which are featured by the mesocrystalline aggregates where the primary particles constituting LMFP secondary particles are crystallographically aligned. Assessment of the battery performance reveals that the flake-shaped LMFP mesocrystals exhibit a specific capacity and rate capability superior to those of other mesocrystals. The origin of the enhanced electrochemical performance is investigated in terms of primary particle size, pore structure, antisite-defect concentration, and secondary particle shape. It is shown that the shape of the secondary particle has just as much of a significant effect on the battery performance as the crystallite size and antisite defects do. We believe that this work provides a rule of design for electrochemically favorable meso/nanostructures, which is of great potential for improving battery performance by tuning the morphology of particles on multilength scales. PMID- 29714483 TI - Superlubricity Enabled by Pressure-Induced Friction Collapse. AB - From daily intuitions to sophisticated atomic-scale experiments, friction is usually found to increase with normal load. Using first-principle calculations, here we show that the sliding friction of a graphene/graphene system can decrease with increasing normal load and collapse to nearly zero at a critical point. The unusual collapse of friction is attributed to an abnormal transition of the sliding potential energy surface from corrugated, to substantially flattened, and eventually to counter-corrugated states. The energy dissipation during the mutual sliding is thus suppressed sufficiently under the critical pressure. The friction collapse behavior is reproducible for other sliding systems, such as Xe/Cu, Pd/graphite, and MoS2/MoS2, suggesting its universality. The proposed mechanism for diminishing energy corrugation under critical normal load, added to the traditional structural lubricity, enriches our fundamental understanding about superlubricity and isostructural phase transitions and offers a novel means of achieving nearly frictionless sliding interfaces. PMID- 29714484 TI - Silylation of Aryl Halides with Monoorganosilanes Activated by Lithium Alkoxide. AB - Lithium alkoxide activates a monoorganosilane to generate a transient LiH/alkoxysilane complex, which quickly reacts with aryl and alkenyl halides at 25 degrees C to deliver a diorganosilane product. Experimental and theoretical studies suggest that the reaction includes nucleophilic attack of LiH on the halogen atom of the organic halide to generate a transient organolithium/alkoxysilane intermediate, which undergoes quick carbon-silicon bond formation within the complex. PMID- 29714485 TI - Why Do Silver Trimers Intercalated in DNA Exhibit Unique Nonlinear Properties That Are Promising for Applications? AB - Our investigation of one-photon absorption (OPA) and nonlinear optical (NLO) properties such as two-photon absorption (TPA) of silver trimer intercalated in DNA based on TDDFT approach allowed us to propose a mechanism responsible for large TPA cross sections of such NLO-phores. We present a concept that illustrates the key role of quantum cluster as well as of nucleotide bases from the immediate neighborhood. For this purpose, different surroundings consisting of guanine-cytosine and adenine-thymine such as (GCGC) and (ATAT) have been investigated that are exhibiting substantially different values of TPA cross sections. This has been confirmed by extending the immediate surroundings as well as using the two-layer quantum mechanics/molecular mechanics (QM/MM) approach. We focus on the cationic closed-shell system and illustrate that the neutral open shell system shifts OPA spectra into the NIR regime, which is suitable for applications. Thus, in this contribution, we propose novel NLO-phores inducing large TPA cross sections, opening the route for multiphoton imaging. PMID- 29714486 TI - Melanoma Imaging Using 18F-Labeled alpha-Melanocyte-Stimulating Hormone Derivatives with Positron Emission Tomography. AB - Melanocortin 1 receptor (MC1R) is specifically expressed in the majority of melanomas, a leading cause of death related to skin cancers. Accurate staging and early detection is crucial in managing melanoma. Based on the alpha-melanocyte stimulating hormone (alphaMSH) sequence, MC1R-targeted peptides have been studied for melanoma imaging, predominately for use with single-photon emission computed tomography, with few attempts made for positron emission tomography (PET). 18F is a commonly used PET isotope due to readily available cyclotron production, pure positron emission, and a favorable half-life (109.8 min). In this study, we aim to design and evaluate alphaMSH derivatives that enable radiolabeling with 18F for PET imaging of melanoma. We synthesized three imaging probes based on the structure of Nle4-cyclo[Asp5-His-d-Phe7-Arg-Trp-Lys10]-NH2 (Nle-CycMSHhex), with a Pip linker (CCZ01064), an Acp linker (CCZ01070), or an Aoc linker (CCZ01071). 18F labeling was enabled by an ammoniomethyl-trifluoroborate (AmBF3) moiety. In vitro competition binding assays showed subnanomolar inhibition constant ( Ki) values for all three peptides. The 18F radiolabeling was performed via a one-step 18F-19F isotope exchange reaction that resulted in high radiochemical purity (>95%) and good molar activity (specific activity) ranging from 40.7 to 66.6 MBq/nmol. All three 18F-labeled peptides produced excellent tumor visualization with PET imaging in C57BL/6J mice bearing B16-F10 tumors. The tumor uptake was 7.80 +/- 1.77, 5.27 +/- 2.38, and 5.46 +/- 2.64% injected dose per gram of tissue (%ID/g) for [18F]CCZ01064, [18F]CCZ01070, and [18F]CCZ01071 at 1 h post-injection (p.i.), respectively. Minimal background activity was observed except for kidneys at 4.99 +/- 0.20, 4.42 +/- 0.54, and 13.55 +/- 2.84%ID/g, respectively. The best candidate [18F]CCZ01064 was further evaluated at 2 h p.i., which showed increased tumor uptake at 11.96 +/- 2.31%ID/g and further reduced normal tissue uptake. Moreover, a blocking study was performed for CCZ01064 at 1 h p.i., where tumor uptake was significantly reduced to 1.97 +/- 0.60%ID/g, suggesting the tumor uptake was receptor mediated. In conclusion, [18F]CCZ01064 showed high tumor uptake, low normal tissue uptake, and fast clearance and is therefore a suitable and promising candidate for PET imaging of melanoma. PMID- 29714487 TI - Dual Phase Synergy Enabled Large Elastic Strains of Nanoinclusions in a Dislocation Slip Matrix Composite. AB - Freestanding nanomaterials (such as nanowires, nanoribbons, and nanotubes) are known to exhibit ultralarge elastic strains and ultrahigh strengths. However, harnessing their superior intrinsic mechanical properties in bulk composites has proven to be difficult. A recent breakthrough has overcome this difficulty by using a martensitic phase transforming matrix in which ultralarge elastic strains approaching the theoretical limit is achieved in Nb nanowires embedded in the matrix. This discovery, breaking a long-standing challenge, still limits our ability of harnessing the exceptional properties of nanomaterials and developing ultrahigh strength bulk materials to a narrow selection of phase transforming alloy matrices. In this study, we investigated the possibility to harness the intrinsic mechanical properties of nanoinclusions in conventional dislocation slip matrix based on a principle of synergy between the inclusion and the matrix. The small spacing between the densely populated hard and dislocation-impenetrable nanoinclusions departmentalize the plastic matrix into small domains to effectively impede dislocation motion within the matrix, inducing significant strengthening and large local elastic strains of the matrix, which in turn induced large elastic strains in the nanoinclusions. This dual phase synergy is verified in a Ti3Sn inclusions/B2-NiTi(Fe) plastic matrix model materials system. The maximum elastic strain of Ti3Sn inclusion obtained in the dislocation slip matrix is comparable to that achieved in a phase transforming matrix. This finding opens new opportunities for the development of high-strength nanocomposites. PMID- 29714488 TI - Excitonic Effects in Methylammonium Lead Halide Perovskites. AB - The exciton binding energy in methylammonium lead iodide (MAPbI3) is about 10 meV, around 1/3 of the available thermal energy ( kB T ~ 26 meV) at room temperature. Thus, exciton populations are not stable at room temperature at moderate photoexcited carrier densities. However, excitonic resonances dominate the absorption onset. Furthermore, these resonances determine the transient absorbance and transient reflectance spectra. The exciton binding energy is a reflection of the Coulomb interaction energy between photoexcited electrons and holes. As such, it serves as a marker for the strength of electron/hole interactions and impacts a variety of phenomena, such as, absorption, radiative recombination, and Auger recombination. In this Perspective, we discuss the role of excitons and excitonic resonances in the optical properties of lead-halide perovskite semiconductors. Finally, we discuss how the strong light-matter interactions induce an optical stark effect splitting the doubly spin degenerate ground exciton states and are easily observed at room temperature. PMID- 29714489 TI - Preferential Solvation Unveiled by Anomalous Conformational Equilibration of Porphyrin Dimers: Nucleation Growth of Solvent-Solvent Segregation. AB - Preferential solvation was explored using ethynylene- or butadiynylene-linked porphyrin dimers bearing 3,4,5-tri(( S)-3,7-dimethyloctyloxy)phenyl groups at the meso positions in binary hexafluorobenzene (C6F6) and cyclohexane (C6H12) mixture, expecting contrasting solvent affinity of the porphyrin core and the alkyl side chains toward the individual solvent component. Although the solvent polarity remained nearly constant along with the continuous variation of the solvent composition, the porphyrin dimer showed dramatic change in spectroscopic signatures, indicating the occurrence of preferential solvation. Because of small rotational barrier around the ethynylene and butadiynylene linkage, the torsional conformations of the porphyrin dimers varied from orthogonal to planar due to continuous variation of molar fraction of C6H12-C6F6 mixture. Thorough thermodynamic analyses inferred that nucleation as the enthalpic component and phase segregation as the entropic component operated preferential solvation. The porphyrin dimer nucleated the C6H12-C6F6 segregation, and the torsional conformation was diagnostic of the inversion of the interfacial curvature of the solvent segregation along with the continuous variation. PMID- 29714490 TI - Efficacy of Ketamine in Pediatric Sedation Dentistry: A Systematic Review. AB - BACKGROUND: Ketamine has been used as a safe and effective sedative to treat adults and children exhibiting high levels of anxiety or fear during dental treatment. Pediatric dentistry often involves patients with high levels of anxiety and fear and possibly few positive dental experiences. Patient management can involve behavioral approaches, as well as the use of sedation or general anesthesia with a variety of agents, including midazolam, diazepam, hydroxyzine, meperidine, and ketamine. The aim of this study was to investigate the clinical efficacy of ketamine use in pediatric sedation dentistry through systematic review and analysis. METHODS: A systematic review of publications between 1990 and 2015 was conducted using PubMed and MEDLINE databases maintained by the US National Library of Medicine and the National Institutes of Health. The keywords used were (ketamine) AND (dental OR dentistry) AND (sedation). The abstract and title of all potential publications were then screened for clinical trials and to remove non-English articles, non-human or animal trials, and other non-dental or non-relevant studies. RESULTS: A total of 1,657 citations were initially identified, reviewed, and screened, eventually resulting in inclusion of 25 clinical trials in this systematic review. Nineteen studies evaluated ketamine effects in pediatric dental sedation using oral (non-invasive) administration, three involved subcutaneous or intramuscular injection, and three were completed intravenously. Evidence analysis of these trials revealed the majority (n = 22/25) provided strong, positive evidence for the use of ketamine (alone or in combination) to reduce dental anxiety and behavioral non-compliance with the remainder suggesting equivocal results. Additional endpoints evaluated in some studies involved dosage, as well as time to achieve sedation effect. CONCLUSION: The use of ketamine (alone or in combination) can provide safe, effective, and timely sedation in pediatric patients regardless of the route of administration. PMID- 29714491 TI - Importance of Prototype Use for Implant-Supported Complete Fixed Dental Prosthesis (ICFDP). AB - Restorative material options for implant-supported complete fixed dental prostheses (ICFDP) have progressed from traditional metal-acrylic or metal ceramic combinations to today's monolithic zirconia or high-performance polymer designs. To avoid potential errors that may be introduced into the restorative process in the interim phase and to provide a more predictable clinical outcome of the definitive ICFDP, a clinical protocol utilizing a prototype prosthesis is described in this case report. PMID- 29714492 TI - Gum Drop Technique: Minimally Invasive Soft-Tissue Platelet-Rich Plasma Grafting for Marginal Soft-Tissue Recession. AB - Minimally invasive techniques for treatment of marginal soft-tissue recession, or root recession, are conducive to lower morbidity and less postoperative discomfort than techniques that employ surgical flaps. The gum drop technique (GDT) is a novel soft-tissue grafting procedure that combines minimally invasive incisions with blood derivatives from the patient to achieve root coverage. Demonstrating favorable healing without the need for a donor site to provide connective tissue, this papilla-preserving approach offers the benefits of an autogenous, biologically enhanced procedure. PMID- 29714493 TI - Internal Sinus Membrane Elevation in Patients With Less Than 5 mm Residual Bone Height. AB - Sinus membrane elevation can be accomplished through use of either a direct or indirect technique. The indirect or internal elevation technique lifts the sinus membrane by elevating it superiorly using osteotomes, with or without the use of grafting material. The authors reference a revolutionary randomized clinical trial in which tissue-level implants with a coronally flared design were placed in residual bone height of <=4 mm using an internal sinus membrane elevation technique and describe an adaptation of the procedure discussed in that study and its successful use in a prosthodontics residency program. PMID- 29714494 TI - Healthy Pregnancy: A Patient-Centered Approach to Counseling and Behavioral Change. AB - Many current myths and outdated practices exist regarding dental care for pregnant women. Additionally, many medical care providers fail to check pregnant patients for dental problems and refer them for dental care. Therefore, it is critical that dental healthcare providers and their medical colleagues are well informed of the risks and benefits of dental care throughout pregnancy and are equipped with the tools to discuss the importance of dental health with patients. Patient-centered interventions, such as motivational interviewing (MI), are effective tools to alter patient behaviors and fully engage patients as active participants in their care. This review provides a framework of patient-centered interventions to improve patient involvement in their oral and overall well being, offering methods and examples of a patient-centered approach, based on the fundamentals of MI. PMID- 29714495 TI - Cytocone Procedure: Conservative Repair of a Buccal Plate Dehiscence in Preparation for Implant Placement. AB - In type II sockets, the soft-tissue level is at or coronal to the cementoenamel junction, and part of the buccal plate is missing. In the esthetic zone, a patient with this type of situation often is not a good candidate for immediate implant placement until the osseous defect is repaired. Therefore, use of a conservative regenerative procedure to repair such a defective socket would be advantageous. The Cytocone procedure utilizes a nonresorbable dense polytetrafluorethylene (d-PTFE) barrier and modifies the classic "ice cream cone" technique to restore a buccal osseous defect without raising a labial flap. This article describes and illustrates the Cytocone procedure. PMID- 29714496 TI - Prosthetically Driven Computer-Guided Implant Placement and Restoration Using CEREC: A Case Report. AB - Developments in 3-dimentional (3D) diagnostic technology and advanced digital optical imaging have improved the predictability, safety, and efficiency of restoratively driven implant dentistry. Surgical procedures may now be performed in a single visit utilizing chairside, computer-aided design/computer-aided manufacturing technology and in situations when a two-stage implant protocol is indicated as demonstrated in this case. The CEREC(r) GALILEOS(r) integration workflow system was used to prosthetically plan and place an implant in the lower right mandibular first molar site, No. 30, which had been previously grafted following tooth extraction. Preoperative planning was performed, taking into consideration all anatomic landmarks, current tissue status, and restorative needs while incorporating cone-beam computed tomography data to design and mill a stable, tooth-supported surgical guide (CEREC Guide 2.0). After placement and subsequent osseointegration, the implant was restored chairside in a pre-doctoral treatment center. The Sirona TiBase system and VITA ENAMIC(r) IS block were used to produce an esthetically pleasing and clinically excellent screw-retained implant crown. PMID- 29714497 TI - Ridge Augmentation Simultaneous With Immediate Implant Placement: The Subperiosteal Tunneling Technique. AB - The efficacy of immediate implant placement has made it an appealing treatment modality in dentistry. Over the past several decades various surgical techniques to minimize the ridge collapse and other adverse changes that occur after tooth extraction have been advocated. This case series proposes a method of soft-tissue augmentation when multiple implants are being immediately placed. The authors describe a subperiosteal tunneling technique that achieves the dual purpose of graft containment/guided bone regeneration and soft-tissue augmentation around maxillary anterior implants. PMID- 29714499 TI - Periodontal Management: Time to Go Beyond Reduced Probing Depths. PMID- 29714498 TI - An Electronic Screening System for Oral Health Examination and Collection of Critical Data in a Nonclinical Setting: Validation Trial. AB - OBJECTIVE: To evaluate the reliability, ease, and efficiency of data entry for an oral health screening app that allows iPad(r) entry of data, including permanent versus deciduous teeth present, visual image comparison grading of demineralization/caries, fluorosis, periodontal inflammation, oral hygiene status, identification of sealants/restorations, dental trauma, orthodontic malocclusion, mandibular joint dysfunction, and early childhood caries. METHODS: 89 consented children were examined first by a public health dental hygienist in a dental office reception area and then by a dentist in a treatment operatory. The same research associate was used to prompt and record both examinations. RESULTS: The screenings prompted by the electronic oral health screening system were completed in 2 to 3 minutes each with favorable levels of comparison between examiners as assessed by weighted Kappa scores measuring 0.531 for all teeth examined, with the lower back teeth showing the greatest agreement (K = 0.601) and the upper back and upper front demonstrating less agreement (K = 0.446 and 0.468, respectively). Neither examiner identified any carious lesions among the lower front teeth. CONCLUSIONS: This study provides the first description of an oral health screening entry app with visual image comparisons and touchscreen data entry for efficient collection of oral health information. PMID- 29714500 TI - Cognitive enhancement of volatile oil from the stems of Schisandra chinensis Baill. in Alzheimer's disease rats. AB - The volatile oil (VO), extracted from the stems of Schisandra chinensis Baill. (SCS), was separated and identified by gas chromatography - mass spectrometry. The study was devised to investigate the effects of VO on oxidative stress and cognitive deficits induced by amyloid-beta (Abeta(1-42)). Alzheimer's disease (AD) models were established by injecting Abeta(1-42) into the rat hippocampus and the effects of learning and memory were observed by a Morris water maze test, immunohistological alterations, and correlative indicators covering nerve growth (brain-derived neurotrophic factor, glial-cell-derived trophic factor, and nerve growth factor), interleukin 1beta, tumor necrosis factor, superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), malondialdehyde (MDA), glial fibrillary acidic protein (GFAP), and microglial CD11b in AD rats. And activities of SOD, MDA, and GSH-Px were ameliorated by VO. The neurotrophic factors GFAP and microglial CD11b were noticeably improved in histopathologic changes. These data suggested that VO from SCS had potential activities for the prevention and treatment of AD. PMID- 29714502 TI - Trajectories of Global Self-Worth in Adolescents with ADHD: Associations with Academic, Emotional, and Social Outcomes. AB - Resilience models suggest that there are likely to be multiple trajectories of self-worth and that despite experiencing impairment, some youth with attention deficit/hyperactivity disorder (ADHD) may maintain a positive self-worth, which could buffer them against negative outcomes. The present study used a cohort sequential longitudinal design to evaluate developmental trajectories of global self-worth in a sample of 324 middle-school-age adolescents (71% male) diagnosed with ADHD between ages 11 and 14 in predicting outcomes at age 15. Sex, medication status, and ADHD/oppositional defiant disorder symptom severity were included as covariates in the models. Using growth mixture modeling, 3 distinct self-worth trajectory groups were identified: (a) high and increasing (44.4% of participants), (b) moderate and decreasing (48.8%), and (c) low and decreasing (6.8%). Participants with high and increasing global self-worth were less likely to exhibit co-occurring depressive symptoms and had better social functioning and higher grades at age 15 relative to those in either decreasing trajectory. Implications of these findings for monitoring and supporting positive global self worth for adolescents with ADHD are discussed. PMID- 29714501 TI - Automatic spectral imaging protocol and iterative reconstruction for radiation dose reduction in typical hepatic hemangioma computed tomography with reduced iodine load: a preliminary study. AB - OBJECTIVE: To evaluate the effect of automatic spectral imaging protocol selection (ASIS) and adaptive statistical iterative reconstruction (ASiR) technique in the reduction of radiation and contrast medium dose in typical hepatic hemangioma (HH) dual energy spectral CT (DEsCT). METHODS: 62 patients with suspected HH were randomly divided into two groups equally: Group A, conventional 120-kVp CT with standard iodine load; Group B, DEsCT with ASIS technique and reduced iodine load, two sets of monochromatic spectral images were reconstructed: 69 keV level with 30% ASiR (Group B1) and 52 keV level with 50% ASiR (Group B2). The radiation and total iodine dose, quantitative analysis (standard deviation value, contrast-to-noise and contrast enhancement ratio) and qualitative analysis were evaluated. RESULTS: No difference was observed in the standard deviation values, subjective image noise, and the diagnostic acceptability score among the three groups (p > 0.05). Contrast to noise [Group B2 vs A, B1 in arterial phase (AP): 19.51 +/- 6.29 vs 15.77 +/- 5.93, 11.46 +/- 2.84; Group B2 vs A, B1 in portal venous phase (PVP): 9.96 +/- 2.18 vs 8.19 +/- 3.04, 6.01 +/- 1.82], contrast enhancement ratio (Group B2 vs A, B1 in AP: 6.88 +/- 2.01 vs 5.47 +/- 2.01, 4.15 +/- 1.28; Group B2 vs A, B1 in PVP: 5.58 +/- 1.02 vs 4.54 +/- 1.13, 3.49 +/- 0.83), and the lesion conspicuity score (Group B2 vs A, B1 in AP: 3.93 +/- 0.26 vs 3.45 +/- 0.51, 3.10 +/- 0.49; Group B2 vs A, B1 in PVP: 3.90 +/- 0.31 vs 3.48 +/- 0.57, 3.14 +/- 0.44) for Group B2 were higher than those in Group A and B1 (p < 0.05). Compared to Group A, the radiation dose and total iodine dose in Group B were reduced by 30 and 41%, respectively (radiation dose in Group B vs A: 5.53 +/- 1.59 vs 7.91+/- 2.71 mSv; iodine dose in Group B vs A: 18.85 +/- 2.88 vs 31.78+/-3.89 ml; p < 0.05). CONCLUSION: DEsCT with ASIS and ASiR technique can reduce the radiation dose without image quality degradation as compared to the conventional 120-kVp CT. The monochromatic spectral images at 52 keV level with 50% ASiR allows the reduction in total iodine dose without deteriorating diagnostic performance. Advances in knowledge: ASIS combined with ASiR technique, by using monochromatic spectral images at 52 keV level, represents a feasible imaging protocol to reduce the radiation and total iodine dose in assessment of typical HH. PMID- 29714503 TI - Hyperplane-Approximation-Based Method for Many-Objective Optimization Problems with Redundant Objectives. AB - For a many-objective optimization problem with redundant objectives, we propose two novel objective reduction algorithms for linearly and, nonlinearly degenerate Pareto fronts. They are called LHA and NLHA respectively. The main idea of the proposed algorithms is to use a hyperplane with non-negative sparse coefficients to roughly approximate the structure of the PF. This approach is quite different from the previous objective reduction algorithms that are based on correlation or dominance structure. Especially in NLHA, in order to reduce the approximation error, we transform a nonlinearly degenerate Pareto front into a nearly linearly degenerate Pareto front via a power transformation. In addition, an objective reduction framework integrating a magnitude adjustment mechanism and a performance metric [Formula: see text] are also proposed here. Finally, to demonstrate the performance of the proposed algorithms, comparative experiments are done with two correlation-based algorithms, LPCA and NLMVUPCA, and with two dominance-structure-based algorithms, PCSEA and greedy [Formula: see text]MOSS, on three benchmark problems: DTLZ5(I,M), MAOP(I,M), and WFG3(I,M). Experimental results show that the proposed algorithms are more effective. PMID- 29714504 TI - Effectiveness of a Structured Teaching Program on Knowledge and Attitudes Toward HIV among Young Women in India. AB - India has the third highest number of persons living with HIV in the world. We evaluated the effectiveness of a structured teaching program on HIV-related knowledge and attitudes among 600 young women, aged 20-40 years, in India. This study employed a quasi-experimental pre-post design. Significant differences were found in the level of the participants' knowledge of (t = 78.89, p < .05) and attitudes toward (t = 64.14, p < .05) HIV after the intervention. Our findings suggest that the structured teaching program could be utilized in increasing young women's knowledge of, and improving their attitudes about, HIV. PMID- 29714505 TI - A Teaching Strategy to Facilitate Nursing Students' Translation of Global Health Learning from Classroom to the Community. AB - Integrating global health concepts in nursing curricula is important for a competent contemporary global nursing workforce. This article describes a teaching strategy that facilitates students' translation of global health content from classroom to the community. A community-academic partnership and a train-the trainers' approach to support community capacity for working with refugees was implemented. The Community-As-A Partner model was used as the guiding framework. Additionally, the DEAL model was used to support students' reflections on their clinical experiences. A quiz, reflections, participant evaluations, and student peer evaluations were used to assess students' clinical learning experiences. Key lessons learned are also presented. PMID- 29714506 TI - Improving the Documentation Process for Referrals into Diabetes Education: A Quality Improvement Project. AB - The purpose of this project was to standardize the referral and documentation process for diabetes education in patients with type 2 diabetes. The goal was to refer all eligible patients with type 2 diabetes into diabetes education. A standardized template within the clinical note was created to capture if the patients had ever received diabetes education. Use of this template by the clinician improved documentation about diabetes education and increased referrals into diabetes education programs. The findings of this project can be applied to other primary care clinics to help increase the historically low referrals rates into diabetes education. PMID- 29714507 TI - Normo-Carbohydrate Nutrition: Results from a Pilot Study. AB - This study was a test of the feasibility of educating a convenience sample about normo-carbohydrate nutrition (NCN). From May 2015 and May 2016, 51 participants were enrolled in this intervention study about NCN. Participants were measured for chest, waist, abdomen, and hip circumferences, weight, and height at start and month 1, 2, and 3. After 1 month, there was a significant reduction in hip circumference, weight, and BMI with similar findings after 2 and 3 months. Significant reductions in chest, hips, and weight among participants after repeated measures provide hope for this promising nutritional strategy. PMID- 29714508 TI - Implementation of a School-Based Bullying Program. AB - : A bully is defined as anyone who participates in any form of repetitive negative and hurtful behavior, with the intent of inflicting harm (Highmark & Center for Safe Schools, 2013). PURPOSE: The purpose of this project was to evaluate the feasibility of implementing a bullying awareness, prevention, and screening program for teachers and school nurses. METHODS: The sample included 174 fifth-graders from a public-school district in rural, southwestern Pennsylvania. Teachers received an educational program and students were screened for bullying using the PIPSQ. RESULTS: Although not a significant finding, there was an increase in teacher's knowledge post-education (p = 0.515). Although findings were not significant, the results of the PIPSQ revealed greater victimization in this school (M = 6.93), with bullying behaviors greater among boys (p = 0.000). CONCLUSIONS: The educational program and the PIPSQ tool appear to be a promising method to identify victimization and bullying within an elementary school setting; further research can determine significance of screening and faculty education. PMID- 29714510 TI - Does Non-Targeted Community CPR Training Increase Bystander CPR Frequency? AB - OBJECTIVE: Only 37% of out-of-hospital cardiac arrests (OHCA) receive bystander Cardiopulmonary resuscitation (CPR) in Kent County, MI. In May 2014, prehospital providers offered one-time, point-of-contact compression-only CPR training to 2,253 passersby at 7 public locations in Grand Rapids, Michigan. To assess the impact of this intervention, we compared bystander CPR frequency and clinical outcomes in regions surrounding training sites before and after the intervention, adjusting for prehospital covariates. We aimed to assess the effect of this broad, non-targeted intervention on bystander CPR frequency, type of CPR utilized, and clinical outcomes. We also tested for differences in geospatial variation of bystander CPR and clinical outcomes clustered around training sites. METHODS: Retrospective, observational, before-after study of adult, EMS-treated OHCA in Kent County from January 1, 2010 to December 31, 2015. We generated a 5 kilometer radius surrounding each training site to estimate any geospatial influence that training sites might have on bystander CPR frequency in nearby OHCA cases. Chi-squared, Fisher's exact, and t-tests assessed differences in subject features. Difference-in-differences analysis with generalized estimating equation (GEE) modeling assessed bystander CPR frequency, adjusting for training site, covariates (age, sex, witnessed, shockable rhythm, public location), and clustering around training sites. Similar modeling tested for changes in bystander CPR type, return of spontaneous circulation (ROSC), survival to hospital discharge, and cerebral performance category (CPC) of 1-2 at hospital discharge. RESULTS: We included 899 cases before and 587 cases post-intervention. Overall, we observed no increase in the frequency of bystander CPR or favorable clinical outcomes. We did observe an increase in compression-only CPR, but this was paradoxically restricted to OHCA cases falling outside radii around training sites. In adjusted modeling, the bystander CPR training intervention was not associated with bystander CPR frequency (beta -0.002; 95% CI -0.16, 0.15), compression-only CPR (beta -0.06; 95% CI -0.15, 0.02), ROSC (beta -0.06; 95% CI 0.21, 0.25), survival (beta -0.02; 95% CI -0.11, 0.06), or favorable neurologic outcome (beta -0.01; 95% CI -0.07, 0.09). CONCLUSIONS: We observed no impact in bystander CPR performance or outcomes from a blanket, non-targeted approach to community CPR education. The effect of targeted CPR education in locales with known low bystander CPR rates should be tested in this region. PMID- 29714511 TI - Promoting Honesty and Truthfulness When Things Go Wrong During Care Delivery for Sick Children. AB - Emeritus Professor and Editor-in-Chief Edward Alan Glasper discusses why children's nurses must fully adopt the duty of candour in care delivery, which in some countries is a legal obligation, to ensure that consumers of healthcare and their families are apologized to, and communicated with, openly and honestly when things have gone wrong in their care. PMID- 29714512 TI - Association of angiotensin receptor 2 gene polymorphisms with pregnancy induced hypertension risk. AB - OBJECTIVES: To investigate the association of polymorphisms and haplotypes of angiotensin receptor 2 (AT2R) gene with pregnancy induced hypertension (PIH) in Chinese Han women. METHODS: A case-control study was designed with 446 cases (gestational hypertension, GH: 124; pre-eclampsia, PE + eclampsia, E: 322) and 650 controls. rs5193, rs1403543 and rs12710567 of AT2R gene were genotyped. A logistic regression approach was applied to estimate the relationship between the polymorphisms and haplotypes of AT2Rgene with PIH risk. RESULTS: No relationship between AT2R gene polymorphisms and PIH was detected. The haplotype analysis also showed a negative result. CONCLUSIONS: rs5193, rs1403543 and rs12710567 of AT2R gene might have no effect on PIH risk among Chinese Han women. PMID- 29714513 TI - Perceptions of non-traditional tobacco products between asthmatic and non asthmatic college students. AB - OBJECTIVE: Electronic nicotine delivery systems (ENDS) use is common among college students and there are perceptions that ENDS are not as harmful as traditional cigarettes. The aim of this study was to examine differences in ENDS use, risk perceptions, and co-occurring smoking behaviors between college students with and without asthma. METHODS: The study consisted of a cross sectional online survey with a final sample size of 898 college students. The voluntary participation survey was disseminated to all undergraduate and graduate students at a mid-sized liberal arts university in the Southeast U.S. in the Fall of 2014. RESULTS: Approximately 19.7% reported that they had been previously diagnosed with asthma. Forty three percent of participants (n = 384) used ENDS in the past 30 days. Equivalent percentages of college students with asthma (46.9%) and college students without asthma (46.9%) have tried ENDS. Overall participants indicated that they perceived ENDS use as less (44%) or equally (38%) as harmful as cigarettes. College students with asthma had 2.85 (95% CI: 1.18-6.89) greater odds of being in the poly-user class, which was characterized by dual use of ENDS, combustible cigarettes, hookah, and marijuana. CONCLUSIONS: In this study, college students with asthma were similar to their peers with regard to their use of ENDS and related risk perceptions; however, a small subsample of those with asthma exhibited problematic smoking behaviors characterized by dual use of multiple tobacco products including marijuana. PMID- 29714514 TI - The Rules of Engagement: CTTI Recommendations for Successful Collaborations Between Sponsors and Patient Groups Around Clinical Trials. AB - OBJECTIVE: To identify the elements necessary for successful collaboration between patient groups and academic and industry sponsors of clinical trials, in order to develop recommendations for best practices for effective patient group engagement. METHODS: In-depth interviews, informed by a previously reported survey, were conducted to identify the fundamentals of successful patient group engagement. Thirty-two respondents from 3 sectors participated: patient groups, academic researchers, and industry. The findings were presented to a multistakeholder group of experts in January 2015. The expert group came to consensus on a set of actionable recommendations for best practices for patient groups and research sponsors. RESULTS: Interview respondents acknowledged that not all patient groups are created equal in terms of what they can contribute to a clinical trial. The most important elements for effective patient group engagement include establishing meaningful partnerships, demonstrating mutual benefits, and collaborating as partners from the planning stage forward. Although there is a growing appreciation by sponsors about the benefits of patient group engagement, there remains some resistance and some uncertainty about how best to engage. Barriers include mismatched expectations and a perception that patient groups lack scientific sophistication and that "wishful thinking" may cloud their recommendations. CONCLUSIONS: Patient groups are developing diverse skillsets and acquiring assets to leverage in order to become collaborators with industry and academia on clinical trials. Growing numbers of research sponsors across the clinical trials enterprise are recognizing the benefits of continuous and meaningful patient group engagement, but there are still mindsets to change, and stakeholders need further guidance on operationalizing a new model of clinical trial conduct. PMID- 29714515 TI - Assessing the Financial Value of Patient Engagement: A Quantitative Approach from CTTI's Patient Groups and Clinical Trials Project. AB - BACKGROUND: While patient groups, regulators, and sponsors are increasingly considering engaging with patients in the design and conduct of clinical development programs, sponsors are often reluctant to go beyond pilot programs because of uncertainty in the return on investment. We developed an approach to estimate the financial value of patient engagement. METHODS: Expected net present value (ENPV) is a common technique that integrates the key business drivers of cost, time, revenue, and risk into a summary metric for project strategy and portfolio decisions. We assessed the impact of patient engagement on ENPV for a typical oncology development program entering phase 2 or phase 3. RESULTS: For a pre-phase 2 project, the cumulative impact of a patient engagement activity that avoids one protocol amendment and improves enrollment, adherence, and retention is an increase in net present value (NPV) of $62MM ($65MM for pre-phase 3) and an increase in ENPV of $35MM ($75MM for pre-phase 3). Compared with an investment of $100,000 in patient engagement, the NPV and ENPV increases can exceed 500-fold the investment. This ENPV increase is the equivalent of accelerating a pre-phase 2 product launch by 21/2 years (11/2 years for pre-phase 3). CONCLUSIONS: Risk adjusted financial models can assess the impact of patient engagement. A combination of empirical data and subjective parameter estimates shows that engagement activities with the potential to avoid protocol amendments and/or improve enrollment, adherence, and retention may add considerable financial value. This approach can help sponsors assess patient engagement investment decisions. PMID- 29714516 TI - Use of Proprietary Names by Prescribers for Generic Products. AB - BACKGROUND: Proprietary names are often used when prescribing drug products in the United States. The purpose of this study is to describe prescribers' use of proprietary names for generic products, branded-generic names, on prescription orders and to identify prescribing practice trends to inform the development and evaluation of new proprietary names. METHODS: To identify Abbreviated New Drug Application (ANDA) with branded-generic names approved between January 2003 and December 2012, we utilized the database provided by the FDA Office of Communications, Drugs@FDA . A national outpatient retail prescription database, IMS's Vector One: National (VONA) was used to identify prescribing trends by examining data for branded-generic names identified in Drugs@FDA as they were written on prescriptions for years 2003 to 2012, the last year of data collection for VONA. IMS Health, IMS National Sales Perspectives (IMS NSP) was used to retrieve the date that product sales were first reported (launch date). RESULTS: Our search of Drugs@FDA identified 65 distinct branded-generic names approved between January 2003 and December 2012. Data show that most of these products with branded-generic names are written on prescriptions and sold to pharmacies within a year of FDA approval. In some cases, the use of branded-generic names persists for up to 9 years after drug approval. CONCLUSION: This descriptive study confirmed that branded-generic names are used in prescribing. Thus, evaluation of orthographic and phonetic similarities between proposed proprietary names and branded-generic names is necessary when formulating and evaluating new proprietary names. PMID- 29714517 TI - Introduction to the Special Section for Sources of Safety Data and Statistical Strategies for Design and Analysis. PMID- 29714518 TI - Sources of Safety Data and Statistical Strategies for Design and Analysis: Real World Insights. AB - BACKGROUND: Although randomized controlled clinical trials provide necessary information and serve as the basis for regulatory decision making, a significant gap exists between the evidence these trials provide and what the biomedical community needs. It is recognized that a wealth of data are routinely collected outside clinical trials. Such real-world data (RWD) are not of comparable quality, it does not have similar immunity from bias and confounding as data collected in randomized clinical trials, but it might offer additional understanding of the benefit-risk, provide new insights to different stakeholders, and aid in regulatory decision making. This can be especially true when rare but serious adverse events are considered because randomized clinical trials are often not large enough and have insufficient duration to address safety concerns fully. Also, the passage of the 21st Century Cures bill passed by Congress in 2016 means that several data sources outside traditional clinical trials will play a greater role in regulatory decision making. This manuscript is third in a series of articles from the American Statistical Association Biopharmaceutical Section Safety Working Group. METHODS: In this manuscript, authors reviewed some RWD sources and shared considerations for statistical strategies and methodologies needed to design and analyze observational safety studies and pragmatic trials. RESULTS: Authors presented case studies and shared recommendations for statistical methods necessary to design and analyze safety trials using RWD. CONCLUSIONS: RWD is an important source of safety data that contribute to the totality of safety information available to generate evidence for regulators, sponsors, payers, physicians, and patients. However, it is important to determine if such data are fit for purpose. PMID- 29714519 TI - Sources of Safety Data and Statistical Strategies for Design and Analysis: Clinical Trials. AB - BACKGROUND: There has been an increased emphasis on the proactive and comprehensive evaluation of safety endpoints to ensure patient well-being throughout the medical product life cycle. In fact, depending on the severity of the underlying disease, it is important to plan for a comprehensive safety evaluation at the start of any development program. Statisticians should be intimately involved in this process and contribute their expertise to study design, safety data collection, analysis, reporting (including data visualization), and interpretation. METHODS: In this manuscript, we review the challenges associated with the analysis of safety endpoints and describe the safety data that are available to influence the design and analysis of premarket clinical trials. RESULTS: We share our recommendations for the statistical and graphical methodologies necessary to appropriately analyze, report, and interpret safety outcomes, and we discuss the advantages and disadvantages of safety data obtained from clinical trials compared to other sources. CONCLUSIONS: Clinical trials are an important source of safety data that contribute to the totality of safety information available to generate evidence for regulators, sponsors, payers, physicians, and patients. This work is a result of the efforts of the American Statistical Association Biopharmaceutical Section Safety Working Group. PMID- 29714520 TI - Sources of Safety Data and Statistical Strategies for Design and Analysis: Postmarket Surveillance. AB - BACKGROUND: Safety data are continuously evaluated throughout the life cycle of a medical product to accurately assess and characterize the risks associated with the product. The knowledge about a medical product's safety profile continually evolves as safety data accumulate. METHODS: This paper discusses data sources and analysis considerations for safety signal detection after a medical product is approved for marketing. This manuscript is the second in a series of papers from the American Statistical Association Biopharmaceutical Section Safety Working Group. RESULTS: We share our recommendations for the statistical and graphical methodologies necessary to appropriately analyze, report, and interpret safety outcomes, and we discuss the advantages and disadvantages of safety data obtained from passive postmarketing surveillance systems compared to other sources. CONCLUSIONS: Signal detection has traditionally relied on spontaneous reporting databases that have been available worldwide for decades. However, current regulatory guidelines and ease of reporting have increased the size of these databases exponentially over the last few years. With such large databases, data mining tools using disproportionality analysis and helpful graphics are often used to detect potential signals. Although the data sources have many limitations, analyses of these data have been successful at identifying safety signals postmarketing. Experience analyzing these dynamic data is useful in understanding the potential and limitations of analyses with new data sources such as social media, claims, or electronic medical records data. PMID- 29714522 TI - Reporting of Randomized Clinical Trials Remains Far from Optimal. PMID- 29714521 TI - What to Know About Medicines With New Active Ingredients Approved in FY 2016 / 2016 in Japan and EU: A Brief Comparison of New Medicines Approved in Japan and the EU in 2016. AB - The Pharmaceuticals and Medical Devices Agency (PMDA) in Japan and the European Medicines Agency (EMA) have a long-standing experience of reviews of new medicines, and they meet their target pre-market review periods. In FY 2016 / 2016, 112 and 83 new medicines were approved in Japan and EU, respectively. Out of these medicines, 41 and 27 medicines containing new active ingredients were approved with total pre-market review periods of 209 days and 428 days in Japan and EU, respectively. Approximately one-third of these medicines were reviewed by the Agencies in close timing, within 1 year between pre-market review applications in Japan and in EU. Taking into account the increasing number of global clinical trials and constant number of consultations or scientific advice related to global clinical trials in Japan, it is clear that the importance of the continuous, collaborative relationship between EMA and PMDA is more and more crucial, as it does facilitate close and timely exchange of information and opinions on products and technologies under development. There already are effective collaborative frameworks between PMDA and EMA in addition to daily communication, and our findings support the development and best use of regulatory tools such as consultation services and scientific advice/protocol assistance for the benefit of the pharmaceutical industry but mostly of patients. PMID- 29714523 TI - Design of Brand Names of Medicines Considering Subjects' Preferences. AB - BACKGROUND: Only recently, regulations on the names of medicines were developed. Regulations are mainly focused on avoiding the approval of medicine names that may be confusing to others. Furthermore, legal requirements do not include testing for human factors, such as potential users' preferences. STUDY AIMS: To develop a set of new brand names of medicines, to determine subjects' preferred names, and to evaluate if the linguistic features of these names were related to subjects' preferences. METHODS: Forty-six new names linguistically equivalent to the Portuguese brand names of medicines were developed. A panel of 13 postgraduates on linguistic studies were purposively enrolled. Participants were required to select and categorize the 6 most preferred names. RESULTS: From the 29 selected names: 62.1% ended in consonants, 65.5% contained at least one syllable of the CVC type, and 62.1% presented final stress. Considering these 3 linguistic features, there were statistically significant differences between the preferred and underpreferred names: chi2 = 4.572, P = .032; chi2 = 5.599, P = .018; and chi2 = 4.572; P = .032, respectively. CONCLUSIONS: Some linguistic features of the evaluated names were related to subjects' preferences. Tests on subjects' preferences about the names of medicines may provide additional safety features addressed by the present regulations. PMID- 29714524 TI - Sources of Safety Data and Statistical Strategies for Design and Analysis: Transforming Data Into Evidence. AB - BACKGROUND: Safety evaluation is a key aspect of medical product development. It is a continual and iterative process requiring thorough thinking, and dedicated time and resources. METHODS: In this article, we discuss how safety data are transformed into evidence to establish and refine the safety profile of a medical product, and how the focus of safety evaluation, data sources, and statistical methods change throughout a medical product's life cycle. RESULTS: Some challenges and statistical strategies for medical product safety evaluation are discussed. Examples of safety issues identified in different periods, that is, premarketing and postmarketing, are discussed to illustrate how different sources are used in the safety signal identification and the iterative process of safety assessment. The examples highlighted range from commonly used pediatric vaccine given to healthy children to medical products primarily used to treat a medical condition in adults. These case studies illustrate that different products may require different approaches, and once a signal is discovered, it could impact future safety assessments. CONCLUSIONS: Many challenges still remain in this area despite advances in methodologies, infrastructure, public awareness, international harmonization, and regulatory enforcement. Innovations in safety assessment methodologies are pressing in order to make the medical product development process more efficient and effective, and the assessment of medical product marketing approval more streamlined and structured. Health care payers, providers, and patients may have different perspectives when weighing in on clinical, financial and personal needs when therapies are being evaluated. PMID- 29714525 TI - Patient Drug Safety Reporting: Diabetes Patients' Perceptions of Drug Safety and How to Improve Reporting of Adverse Events and Product Complaints. AB - BACKGROUND: Global health care manufacturer Novo Nordisk commissioned research regarding awareness of drug safety department activities and potential to increase patient feedback. Objectives were to examine patients' knowledge of pharmaceutical manufacturers' responsibilities and efforts regarding drug safety, their perceptions and experiences related to these efforts, and how these factors influence their thoughts and behaviors. Data were collected before and after respondents read a description of a drug safety department and its practices. METHODS: We conducted quantitative survey research across 608 health care consumers receiving treatment for diabetes in the United States, Germany, United Kingdom, and Italy. This research validated initial, exploratory qualitative research (across 40 comparable consumers from the same countries) which served to guide design of the larger study. RESULTS: Before reading a drug safety department description, 55% of respondents were unaware these departments collect safety information on products and patients. After reading the description, 34% reported the department does more than they expected to ensure drug safety, and 56% reported "more confidence" in the industry as a whole. Further, 66% reported themselves more likely to report an adverse event or product complaint, and 60% reported that they were more likely to contact a drug safety department with questions. The most preferred communication methods were websites/online forums (39%), email (27%), and telephone (25%). CONCLUSIONS: Learning about drug safety departments elevates consumers' confidence in manufacturers' safety efforts and establishes potential for patients to engage in increased self-monitoring and reporting. Study results reveal potentially actionable insights for the industry across patient and physician programs and communications. PMID- 29714526 TI - Brain intrinsic network connectivity in individuals with frequent tanning behavior. AB - BACKGROUND: Emergent studies suggest a bidirectional relationship between brain functioning and the skin. This neurocutaneous connection may be responsible for the reward response to tanning and, thus, may contribute to excessive tanning behavior. To date, however, this association has not yet been examined. OBJECTIVES: To explore whether intrinsic brain functional connectivity within the default mode network (DMN) is related to indoor tanning behavior. METHODS: Resting state functional connectivity (rsFC) was obtained in twenty adults (16 females) with a history of indoor tanning. Using a seed-based [(posterior cingulate cortex (PCC)] approach, the relationship between tanning severity and FC strength was assessed. Tanning severity was measured with symptom count from the Structured Clinical Interview for Tanning Abuse and Dependence (SITAD) and tanning intensity (lifetime indoor tanning episodes/years tanning). RESULTS: rsFC strength between the PCC and other DMN regions (left globus pallidus, left medial frontal gyrus, left superior frontal gyrus) is positively correlated with tanning symptom count. rsFC strength between the PCC and salience network regions (right anterior cingulate cortex, left inferior parietal lobe, left inferior temporal gyrus) is correlated with tanning intensity. CONCLUSION: Greater connectivity between tanning severity and DMN and salience network connectivity suggests that heightened self-awareness of salient stimuli may be a mechanism that underlies frequent tanning behavior. These findings add to the growing evidence of brain skin connection and reflect dysregulation in the reward processing networks in those with frequent tanning. PMID- 29714527 TI - Comparison of the Force Required for Dislodgement Between Secured and Unsecured Airways. AB - INTRODUCTION: Airway device placement and maintenance are of utmost importance when managing critically ill patients. The best method to secure airway devices is currently unknown. STUDY OBJECTIVE: We sought to determine the force required to dislodge 4 types of airways with and without airway securing devices. METHODS: We performed a prospective study using 4 commonly used airway devices (endotracheal tube [ETT], laryngeal mask airway [LMA], King laryngeal tube [King], and iGel) performed on 5 different mannequin models. All devices were removed twice per mannequin in random order, once unsecured and once secured as per manufacturers' recommendations; Thomas Tube Holder (Laerdal, Stavanger, Norway) for ETT, LMA, and King; custom tube holder for iGel. A digital force measuring device was attached to the exposed end of the airway device and gradually pulled vertically and perpendicular to the mannequin until the tube had been dislodged, defined as at least 4 cm of movement. Dislodgement force was reported as the maximum force recorded during dislodgement. We compared the relative difference in the secured and unsecured force for each device and between devices using a random-effects regression model accounting for variability in the manikins. RESULTS: The median dislodgment forces (interquartile range [IQR]) in pounds for each secured device were: ETT 13.3 (11.6, 14.1), LMA 16.6 (13.9, 18.3), King 21.7 (16.9, 25.1), and iGel 8 (6.8, 8.3). The median dislodgement forces for each unsecured device were: ETT 4.5 (4.3, 5), LMA 8.4 (6.8, 10.7), King 10.6 (8.2, 11.5), and iGel 3.9 (3.2, 4.2). The relative difference in dislodgement forces (95% confidence intervals) were higher for each device when secured: ETT 8.6 (6.2 to 11), LMA 8.8 (4.6 to 13), King 12.1 (7.2 to 16.6), iGel 4 (1.1 to 6.9). When compared to secured ETT, the King required greater dislodgement force (relative difference 8.6 [4.5-12.7]). The secured iGel required less force than the secured ETT (relative difference 4.8 [-8.9 to -0.8]). CONCLUSION: Compared with a secured device, an unsecured airway device requires only half the force to cause airway dislodgement. The secured King had the highest dislodgement force relative to the other studied devices. PMID- 29714528 TI - Intersections of Stigma, Mental Health, and Sex Work: How Canadian Men Engaged in Sex Work Navigate and Resist Stigma to Protect Their Mental Health. AB - Men engaged in sex work experience significant stigma that can have devastating effects for their mental health. Little is known about how male sex workers experience stigma and its effects on mental health or their strategies to prevent its effects in the Canadian context. This study examined the interrelationships between stigma and mental health among 33 Canadian indoor, male sex workers with a specific goal of understanding how stigma affected men's mental health and their protective strategies to mitigate against its effects. Men experienced significant enacted stigma that negatively affected their social supports and ability to develop and maintain noncommercial, romantic relationships. Men navigated stigma by avoidance and resisting internalization. Strategy effectiveness to promote mental health varied based on men's perspectives of sex work as a career versus a forced source of income. Programming to promote men's mental health must take into consideration men's diverse strategies and serve to build social supports. PMID- 29714529 TI - Pulmonary Embolism Part 1. PMID- 29714530 TI - Insights and Best Practices for Planning and Implementing Patient Advisory Boards. AB - A growing number of organizations-including pharmaceutical and biotechnology companies, foundations and associations-are routinely implementing patient advisory boards (PAB) given their high reported value for minimal relative investment. Organizations are typically implementing PABs to solicit patient voices and perspectives on a variety of areas such as protocol designs, clinical trial medicine kit designs, informed consent form designs, technology solutions, and patient communication materials. The Center for Information and Study on Clinical Research Participation (CISCRP) has planned, executed, and facilitated more than 30 PABs. In this article, the authors share lessons learned and best practices with regard to structure, format, and process for organizations wishing to adopt and implement PABs. The authors also provide metrics on the adoption and impact of PABs. PMID- 29714531 TI - The Early Preclinical Development Program for Locally Administered Investigational Medicinal Products in Ophthalmology: Preclinical Data Required for Starting a First-in-Human Clinical Trial in Europe-Basic Considerations and 2 Case Studies. AB - BACKGROUND: Although regulatory guidance defines which preclinical data are required in general before proceeding to first-in-human clinical trials, a certain level of flexibility exists in the actual planning, timing, and design of a drug development program. Developing an ophthalmic medicinal product adds additional challenges, since the eye is a complex organ with unique features and specialized ophthalmic guidance documents are sparse. METHODS: We analyzed the preclinical guidelines with a focus on European Union legislation and guidance documents provided by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). We elaborated the particularities specific to ophthalmic drug developments and deduced the preclinical knowledge needed to safely enter a first-in-human trial program. Two hypothetical medicinal products for ophthalmic indications were chosen and specificities for ophthalmic preclinical tests were elaborated. RESULTS AND CONCLUSION: We conclude that the preclinical program of ophthalmic medicines is flexible and differs, based on the intended use and the nature of the active substance. PMID- 29714532 TI - Mobile Health Applications for Caring of Older People: Review and Comparison. AB - BACKGROUND: Mobile devices and applications (apps) that act as access tools for health care management aid in the improvement of clinical decision making and patient outcomes. However, the tremendous amount of mobile health (mHealth) apps available in commercial app stores makes it hard for the lay users as well as health care professionals to choose the right one for their individual needs. The contents and features of these apps have not been systematically reviewed and compared. This study aims to assess the contents and features of mHealth apps for caring of older people. METHODS: A review and comparison of mHealth apps for caring of older people available in Google's Play Store (Android system) and Apple's App Store (iOS system) were performed. Systematic review of previous relevant literature were conducted. The assessment criteria used for comparison were requirement for Internet connection, information of disease, size of app, diagnostics and assessment tools, medical calculator, dosage recommendations and indications, clinical updates, drugs interaction checker, and information on disease management. RESULTS: Twenty-five mHealth apps were assessed. Medscape and Skyscape Medical Library are the most comprehensive mHealth apps for general drug information, medical references, clinical score, and medical calculator. Alzheimer's Disease Pocketcard and Confusion: Delirium & Dementia: A Bedside Guide apps are recommended for clinical assessment, diagnosis, drug information, and management of geriatric patients with Alzheimer disease, delirium, and dementia. CONCLUSIONS: More studies about mHealth apps for caring of older people are warranted to ensure the quality and reliability of the mHealth apps. PMID- 29714533 TI - Utility of Bayesian Single-Arm Design in New Drug Application for Rare Cancers in Japan: A Case Study of Phase 2 Trial for Sarcoma. AB - Investigational drugs for rare cancers are often approved based solely on a single-arm phase II trial that primarily evaluates response rate in Japan. Such trials typically use a fixed sample size determined on the basis of the frequentist manner. However, since predicting the speed of patient enrollment is challenging because of the disease rarity, the time needed to complete the enrollment of the fixed number of patients is prolonged in some cases. A Bayesian design without fixing the sample size is useful for single-arm phase II trials of rare cancers. However, the arbitrariness of prior distribution specifications and the frequentist operating characteristics are regulatory issues. We recently started a Bayesian single-arm phase II trial of nivolumab in patients with sarcoma for new drug application in Japan and examined the statistical rationale and design consideration. In the Bayesian design, we specify the minimum and maximum numbers of enrolled patients during the enrollment period and the prior distributions of response rates. Considering these parameters, we obtain the minimum number of responders needed for the positive conclusion of the efficacy of nivolumab for each sample size. Simulation studies demonstrated that the operating characteristics of this design would be acceptable from the frequentist view. The Bayesian design provided an adaptive decision rule for efficacy conclusion for the drug without fixing the sample size. We hope our trial's success will provide a new drug development option for rare cancers in Japan. PMID- 29714534 TI - Statistical Signal Process in R Language in the Pharmacovigilance Programme of India. AB - BACKGROUND: The Ministry of Health & Family Welfare, Government of India, initiated the Pharmacovigilance Programme of India (PvPI) in July 2010. The purpose of the PvPI is to collect data on adverse reactions due to medications, analyze it, and use the reference to recommend informed regulatory intervention, besides communicating the risk to health care professionals and the public. The goal of the present study was to apply statistical tools to find the relationship between drugs and ADRs for signal detection by R programming. METHODS: Four statistical parameters were proposed for quantitative signal detection. These 4 parameters are IC025, PRR and PRRlb, chi-square, and N11; we calculated these 4 values using R programming. We analyzed 78,983 drug-ADR combinations, and the total count of drug-ADR combination was 4,20,060. During the calculation of the statistical parameter, we use 3 variables: (1) N11 (number of counts), (2) N1. (Drug margin), and (3) N.1 (ADR margin). RESULTS: The structure and calculation of these 4 statistical parameters in R language are easily understandable. On the basis of the IC value (IC value >0), out of the 78,983 drug-ADR combination (drug ADR combination), we found the 8,667 combinations to be significantly associated. CONCLUSIONS: The calculation of statistical parameters in R language is time saving and allows to easily identify new signals in the Indian ICSR (Individual Case Safety Reports) database. PMID- 29714536 TI - Comparison of Serious Adverse Event Profiles Among Antirheumatic Agents Using Japanese Adverse Drug Event Report Database. AB - BACKGROUND: The association between drugs and adverse events (AEs) has been investigated using various AE databases. The aim of this study was to provide useful information for risk minimization of antirheumatic agents by investigating the safety profiles of antirheumatic agents using the Japanese Adverse Drug Event Report database (JADER), focusing on some important serious AEs (SAEs) and their relation to time. METHODS: Tumor necrosis factor-alpha inhibitors (TNF-Is), interleukin-6 inhibitors (IL-6-Is), and methotrexate (MTX) were selected as antirheumatic agents. Tuberculosis, malignant tumors, and bone marrow disorders were focused as typical SAEs. Disproportionate reporting of these SAEs was evaluated using the reporting odds ratio. Time to onset of each SAE was calculated using date information. RESULTS: Increased reporting odds ratios were observed in tuberculosis and malignant tumors associated with TNF-I, in tuberculosis and malignant tumors associated with IL-6-I, and in tuberculosis, malignant tumors, and bone marrow disorders associated with MTX. The median time to onset of the focused SAEs associated with TNF-I were 501, 681, and 254 days, respectively; those associated with IL-6-I were 387, 636, and 116 days; and those associated with MTX were 537, 1125, and 328 days. These results suggested different profiles for the focused SAEs. CONCLUSION: The time-to-onset profiles of the SAEs for TNF-I, IL-6-I, and MTX as antirheumatic agent were different among different SAEs, which suggests that they should be monitored carefully based on the profiles. The information from JADER is expected to contribute to the risk minimization of drugs in the actual clinical practice. PMID- 29714535 TI - An Alternative to Disproportionality: A Frequency-Based Method for Pharmacovigilance Data Mining. AB - BACKGROUND: Safety surveillance relies on mining of large pharmacovigilance (PV) databases to generate insights regarding the safe use of pharmaceutical products. The predominant approach to PV data mining involves computation of disproportionality scores for drug-adverse event (drug-AE) pairs. However, this approach requires a database to be sufficiently large, sufficiently diverse for the analysis to be reliably sensitive and specific, and fails to consider the particular safety profile of a product. OBJECTIVE: The present study proposes and tests a novel, frequency-based approach to PV data mining that (1) leverages product knowledge and historical drug-AE trends and (2) imposes no requirement for the size and diversity of the database to which it is applied. METHOD: A focus group of physicians and scientists was convened to identify quantitative characteristics of data trends that they consider informative when reviewing counts of adverse events for products under surveillance. Feedback was transferred into a series of decision rules that, when applied to adverse event counts, identifies adverse event trends that are classified as Continuing Trend, Emerging Trend, or No Trend. Regression analyses are completed to verify the presence of a linear trend; and categorical measures of association completed to compare this frequency-based approach to disproportionality scores in a simulated database. RESULTS: A significant, positive linear trend is present for the Continuing Trend and Emerging Trend categories ( P < .0001). There is a significant association between trend categorizations and disproportionality scores ( P < .0001). CONCLUSION: The proposed alternative frequency-based method for PV data mining would be useful where disproportionalities scores are not appropriate. Additionally, this method may be useful in conjunction with disproportionality scores, where appropriate, highlighting adverse events that are both reported disproportionately and have increasing trends. PMID- 29714537 TI - Sample Size for Biosimilar Trials: In Defense of Synthesis. AB - Biosimilars are biological products similar to, but not the same as, the innovator products. Both the European Medicines Agency and the Food and Drug Administration have released detailed guidance on the development of biosimilars. This guidance requires the pivotal phase 3 clinical study to have an equivalence design, which means that the study objective is to demonstrate that one treatment is neither "worse than" nor "better than" the other by some "clinically unimportant" amount. The most critical and controversial step in designing such a study is the choice of equivalence margin, as this determines the conclusion of the study. In this paper, we outline the methodology for determining an equivalence margin and, through case studies on biosimilar trastuzumab (HERCEPTIN ) and biosimilar bevacizumab (AVASTIN), explain the challenges of applying this in practice and why the synthesis method should be given greater consideration by regulatory authorities and biosimilar developers. PMID- 29714538 TI - Mobile Health Applications for Pediatric Care: Review and Comparison. AB - BACKGROUND: Despite the surge in mobile health (mHealth) applications (apps) about pediatric care in commercial app stores, to our knowledge, reviews of the quality of such apps are lacking. Consequently, it is a great challenge for health care professionals (HCPs) to identify appropriate and reliable mHealth apps for delivering health care services. Thus, we performed a structured review of the extant literature about mHealth apps in pediatric care and quality assessment of selected apps found in commercial app stores. METHODS: A review and comparison of mHealth apps in pediatric care found in Google's Play Store (Android system) and Apple's App Store (iOS system) were performed. For the structured review of the available literature, Google Scholar, PubMed, IEEE Xplore Digital Library, and Science Direct online databases were used for the literature search. The assessment criteria used for comparison included requirement for Internet connection, size of application, information on disease, diagnostic tools, medical calculator, information on disease treatments, dosage recommendations, and drug interaction checker. RESULTS: Fifty mHealth apps for general pediatric care and 8 mHealth apps for specific pediatric diseases were discussed in the literature. Of the 90 mHealth apps we reviewed, 27 that fulfilled the study criteria were selected for quality assessment. Medscape, Skyscape, and iGuideline scored the highest (score=7), while PediaBP scored the lowest (score=3). CONCLUSIONS: Medscape, Skyscape, and iGuideline are the most comprehensive mHealth apps for HCPs as quick references for pediatric care. More studies about mHealth apps in pediatric care are warranted to ensure the quality and reliability of mHealth apps. PMID- 29714539 TI - A Resource-Based Relative Value for Clinical Research Nurses' Workload. AB - BACKGROUND: This study was conducted to measure the relative value (RV) of clinical research nurses' (CRNs') workload based on the resource-based relative value scale. METHODS: A quantitative, descriptive research design was used. Data were collected from 70 CRNs in 7 clinical trial institutions using a structured questionnaire including time, technical effort, mental effort, and stress for each service. The RV of work (RVW) of each service was calculated by multiplying time and relative value of intensity based on "explaining the informed consent" as the reference service. RESULTS: The CRNs' RVW was the highest in "preparing auditing" and the lowest in "paying compensation" among 55 services. Ten services showed higher RV intensity than the reference service, 26 services were lower, and 18 services were equal to the reference service. While the service that showed the highest and lowest RVW was the same in 3 specialties (oncology, cardiology, and endocrinology), the rank of the other services was not consistent by specialty. CONCLUSION: The RVW derived from this study makes it easy to calculate each CRN's total workload, so we recommend that the managers use RVW to assign the new services or studies to a certain CRN. And, we also recommend future studies using an objective method such as observations to calculate the time of each service. PMID- 29714540 TI - Evaluation and Characterization of Health Economics and Outcomes Research in SAARC Nations. AB - OBJECTIVE: To identify, evaluate, and characterize the variety, quality, and intent of the health economics and outcomes research studies being conducted in SAARC (South Asian Association for Regional Cooperation) nations. METHODS: Studies published in English language between 1990 and 2015 were retrieved from Medline databases using relevant search strategies. Studies were independently reviewed as per Cochrane methodology and information on the type of research and outcomes were extracted. Quality of reporting was assessed. RESULTS: Of the 2638 studies screened from eight SAARC nations, a total of 179 were included for review (India = 140; Bangladesh = 12; Sri Lanka = 8; Pakistan = 7; Afghanistan = 5; Nepal = 4; Bhutan = 2; Maldives = 1). The broad study categories were cost effectiveness analyses (CEAs = 76 studies), cost analyses (35 studies), and burden of illness (BOI=26 studies). The outcomes evaluated were direct costs, indirect costs, and incremental cost-effectiveness ratio (ICER), quality-adjusted life-years (QALYs), and disability-adjusted life-years (DALYs). Cost of medicines, consultation and hospital charges, and monitoring costs were assessed as direct medical costs along with non-direct medical costs such as travel and food for patients and caregivers. The components of indirect costs were loss of income of patients and caregivers and loss of productivity. Quality of life (QoL) was assessed in 48 studies. The most commonly used instrument for assessing QoL was the WHO-Quality of Life BREF (WHOQOL-BREF) questionnaire (76%). The Quality of Health Economic Studies (QHES) score was used for quality assessment of full economic studies (44 studies). The mean QHES score was 43.76. CONCLUSION: This review identifies various patterns of health economic studies in eight SAARC nations. The quality of economic evaluation studies for health care in India, Bangladesh, Sri Lanka, Pakistan, Afghanistan, Nepal, Bhutan, and Maldives needs improvement. There is a need to generate the capacity of researchers to undertake quality economic evaluations as well as an orientation of the policy makers so that there is a demand for such studies as well as a scope for its use in policy making. PMID- 29714541 TI - Longitudinal Modeling Approaches to Assess the Association Between Changes in 2 Clinical Outcome Assessments. AB - BACKGROUND: Understanding how one clinical outcome assessment (COA) (eg, a patient-reported outcome [PRO]) relates to a second COA (eg, a clinician-reported outcome [ClinRO]) may provide insights into disease burden or treatment efficacy. We aimed to briefly review commonly used cross-sectional methods to evaluate the association between a PRO and a ClinRO and to demonstrate the advantages of longitudinal modeling approaches, particularly a joint mixed model for repeated measures (MMRM), to evaluate this association. METHODS: We generated an example longitudinal data set that included a PRO measured on an 11-point numeric rating scale and a binary ClinRO. The association between change in PRO score and ClinRO response at each time point was examined using 2 cross-sectional analyses: point biserial correlation and logistic regression. We conducted longitudinal analyses of the association between the 2 COAs across time points using MMRM and joint MMRM approaches. RESULTS: Point-biserial correlation and logistic regression analyses correctly captured the "built in" associations between the 2 COAs that strengthened over time, but each association was applicable only for a single time point. The MMRM approach provided correlations over time but only for a single outcome variable. The joint MMRM approach modeled the relationship between both outcome variables simultaneously, allowing for evaluation of the correlations both within and between the variables over time. CONCLUSION: Each analysis demonstrated the relationship between PRO score changes and ClinRO response. Longitudinal analysis methods, particularly the joint MMRM, allow for a more thorough examination of the correlations among the 2 outcomes than cross sectional analysis methods. PMID- 29714542 TI - Safety Reporting: It Can Enter the 21st Century-If We Let It. AB - This is a commentary about the evolution of safety reporting, the new FDA Draft Guidance on Safety Reporting and possible paths forward. PMID- 29714543 TI - Reports to Independent Data Monitoring Committees: An Appeal for Clarity, Completeness, and Comprehensibility. AB - BACKGROUND: Organizations presenting reports to independent data monitoring committees (IDMCs) should present data in a way that facilitates the ability of the IDMC to make informed judgments about the trial. METHODS: This paper reviews reports to IDMCs and suggests approaches an independent statistical reporting group (ISRG) might take to prepare clear, complete, and comprehensible reports. RESULTS: Sensible reporting by an ISRG and informed decision making by an IDMC require a productive partnership between the quantitative and clinical disciplines involved in a clinical trial. IDMC reports differ in structure and purpose from clinical study reports that summarize data at the end of a trial. The ISRG must have intellectual independence, recognizing that although the sponsor may be paying the bills, the ISRG is responsible to the IDMC. Ideally, it should have access to all data from the trial and should be capable of responding to requests from the IDMC without the sponsor's specific permission. The ISRG and sponsor must understand the differences between clean data at the end of the trial and data collected during the trial. To perform its role most effectively, the ISRG must collaborate with sponsor and IDMC clinicians to become conversant with the disease area, the product's mechanism of action, and the clinical relevance of important outcome measures. CONCLUSIONS: An IDMC is best served by an independent ISRG that will prepare clear, complete, and comprehensible reports. Given the complexities of interim data and IDMC requirements, the ISRG must be an active and informed participant in the monitoring process. PMID- 29714544 TI - Factors That Facilitate Regulatory Approval for Drug-Device Combination Products in the European Union and United States of America: A Mixed Method Study of Industry Views. AB - BACKGROUND: The regulatory environment is one of the key factors in successfully bringing an innovative medical product, like a drug-device combination product, to market. This paper offers insight into the experiences of those involved in obtaining regulatory approval of drug-device combination products in the European Union and the United States. METHODS: The research consisted of two phases, qualitative data collection (through semi-structured interviews) and analysis, followed by quantitative data collection (through an online survey) and analysis. RESULTS: A conceptual model was developed that depicted the facilitating factors for obtaining regulatory approval of a drug-device combination product, relevant to the European Union and United States systems, respectively. CONCLUSIONS: This model provides, for the first time, a comprehensive understanding of these factors, providing a foundation that could be adapted to reflect specific drug device combination products. This research demonstrated originality of approach in interviewing thought leaders in the life sciences sector as well as conducting a survey that spans two of the largest jurisdictions for drug-device combination products in the world. PMID- 29714545 TI - Value of Developing Plain Language Summaries of Scientific and Clinical Articles: A Survey of Patients and Physicians. AB - BACKGROUND: We sought to determine the value and feasibility of developing plain language summaries (PLS) of peer-reviewed articles for patients. METHODS: Members of the European Patients Academy on Therapeutic Innovation or UCB Pharma (N = 74) with a diagnosis of chronic disease, as well as a group of randomly selected neurologists in the US (N = 90) participated in online surveys. Two physicians, 5 patients, and 1 caregiver participated in interviews. RESULTS: Patient survey and interview participants reported that they routinely sought health-related information online. Articles in scientific journals were ranked the third most important source in the survey (47%), after general Internet searches (61%) and patient-specific websites (57%). Survey physicians were equivocal in their views; 46% rated PLS as valuable, 46% as neutral, and 8% as not valuable; however, 60% reported they would use them. A predominant theme emerging in patient interviews was the importance of knowledge and the sense of empowerment it engenders. Patients viewed PLS as tools to facilitate knowledge sharing and making important information accessible. In interviews, physicians noted the value of PLS in generating dialogue, saving time and streamlining communication with patients, as patients are not completely dependent on them for information. CONCLUSION: Our results indicate PLS could play an important role in the patient-physician dialogue. Although patients in this study tended to be more informed and engaged than the general patient population, with continued expansion of online platforms and open-access publishing, it is likely that greater numbers of patients will seek more specialized health-related information in the future. PMID- 29714546 TI - Impact of Risk-Benefit Perception and Trust on Medical Technology Acceptance in Relation to Drug and Device Lag: A Tripartite Cross-Sectional Survey. AB - BACKGROUND: New drug and medical device introduction in Japan usually lags behind that in the West. Many reports indicate that in Japan, the associated risks are considered greater than the benefits recognized in other countries. This study aimed to compare the relationship between risk-benefit perception and acceptance of medical technologies in 3 leading markets. METHODS: A tripartite cross sectional survey of the general public was used. In total, 3345 adults in the United Kingdom, the United States, and Japan participated, and sexes and age groups were equally represented. Questions about the perception of risk, benefit, and acceptance of medical and other scientific technologies, and trust of medical product providers or regulatory authorities were included. RESULTS: Five-step Likert coding for risk/benefit/acceptance of 4 medical items (x-rays, antibiotics, vaccines, and cardiac pacemakers) and 6 general items (such as automobiles and airplanes) were collected. Relationships between benefit perception and acceptance were linear for 4 medical technologies. The relationship had a similar slope but was shifted downward in Japan compared with the UK and US ( P < .01), suggesting a lower acceptance in Japan for all benefit perceptions. The trend was the same between risk perception and acceptance, except for slopes that were negative. Correspondence analysis showed a strong correlation among acceptance of medical technologies, benefits of medical technologies, trust in doctors, and trust in the Department of Health. The UK and US attributes were clustered with positive responses such as "useful," "acceptable," and "trustworthy," whereas Japan was clustered with intermediate to negative responses such as "neither" and "untrustworthy." CONCLUSIONS: Acceptance of medical technologies was low in Japan because of significant differences in trust for doctors and authorities compared with that in the UK and US. This is a possible basis for delays of 24 to 60 months for medical product approval in Japan. PMID- 29714547 TI - A Comparative Safety Profile Assessment of Oncolytic Virus Therapy Based on Clinical Trials. AB - Oncolytic virus therapy (OVT) represents a new class of therapeutic agents in cancer treatment. The molecular and cellular mechanisms of action of OVTs have been evaluated in nonclinical/clinical phase trials. Various genetically modified viruses have been developed as oncolytic agents, and the first approval of an OVT for clinical use was issued by the US Food and Drug Administration in 2015. In this context, more and more clinical development of OVTs is anticipated in the future. This article provides a risk assessment of OVT based on the safety data obtained from all clinical trials to date using a publicly available database. The most common adverse events (AEs) observed in clinical trials have been infection-related symptoms such as fatigue, chills, fever, and nausea; few serious AEs have been observed, regardless of the kind of virus or transfected genes. In vivo systemic infusion of OVTs demonstrated a high percentage of AEs, but most AEs were manageable using common drugs. This paper describes OVTs' specific safety/toxicity profiles and encourages the performance of further clinical trials of OVTs to address the most serious challenges anticipated in the development of OVTs as a new class of drugs for the treatment of cancer. PMID- 29714548 TI - Sample Size Determination for a 3-Treatment 3-Period Crossover Trial in Frequency Data. AB - BACKGROUND: To reduce the number of patients needed or increase the power of hypothesis testing for the parallel groups design, the crossover design has been often employed when one is studying noncurable chronic diseases. This article focuses attention on sample size calculation for testing non-inferiority and equality in frequency data under a 3-treatment 3-period crossover trial. METHOD: Under a multiplicative mixed effects model, this article provides asymptotic sample size calculation procedures for testing non-inferiority of an experimental treatment to a control treatment, as well as for simultaneously testing either of 2 treatments versus a placebo. To improve the performance of these asymptotic procedures in small-sample cases, this article further suggests a simple ad hoc adjustment. RESULTS: On the basis of Monte Carlo simulation, we demonstrate that the asymptotic test procedures proposed here can perform well with respect to Type I error. We find that the asymptotic sample size calculation procedures can generally perform well with respect to power when the resulting sample size is moderate or large. We further find that using the simple ad hoc adjustment can improve the performance of the proposed sample size calculation procedures, which are derived from large-sample theory, in small-sample cases. PMID- 29714550 TI - Effective Partnering in Conducting Benefit-Risk Patient Preference Studies: Perspectives From a Patient Advocacy Organization, a Pharmaceutical Company, and Academic Stated-Preference Researchers. AB - BACKGROUND: Formal incorporation of patients' perspectives is becoming increasingly important in medical product development and decision making. This article shares practical advice regarding how patient advocacy organizations, the pharmaceutical industry, and academic experts in stated-preference research can effectively partner on benefit-risk patient preference studies. METHODS: The authors partnered on a benefit-risk patient preference study related to the treatment of psoriasis. The authors from Duke Clinical Research Institute also share their experiences in collaborating with numerous other organizations in conducting benefit-risk patient preference studies. RESULTS: Upon initiation of the study partnership with appropriate experts, training is important to ensure all collaborators have a common understanding of the methodology, what objectives stated-preference methods can support, and expectations for the project. To the extent possible, partners should align on and document relevant clinical and logistical details prior to study implementation. During study implementation, partners should use good communication practices and document and maintain a record of any changes to the original plan. Presentation of the study results should be tailored to the particular audience, with the appropriate partner leading the presentation based on its format and audience. CONCLUSION: Partners from patient advocacy organizations, the pharmaceutical industry, and academia can effectively collaborate on benefit-risk patient preference studies with sufficient planning and ongoing communication. This article is a call for action for other organizations to engage in sharing of experiences regarding effective partnering in quantifying patient preferences in medical product development. PMID- 29714549 TI - Assessing the Benefit-Risk Profile for Pediatric Implantable Auditory Prostheses. AB - BACKGROUND/AIMS: Children with congenital cochleovestibular abnormalities associated with profound hearing loss have few treatment options if cochlear implantation does not yield benefit. An alternative is the auditory brainstem implant (ABI). Regulatory authority device approvals currently include a structured benefit-risk assessment. Such an assessment, for regulatory purposes or to guide clinical decision making, has not been published, to our knowledge, for the ABI and may lead to the design of a research program that incorporates regulatory authority, family, and professional input. METHODS: Much structured benefit-risk research has been conducted in the context of drug trials; here we apply this approach to device studies. A qualitative framework organized benefit (speech recognition, parent self-report measures) and risk (surgery- and device related) information to guide the selection of candidates thought to have potential benefit from ABI. RESULTS: Children with cochleovestibular anatomical abnormalities are challenging for appropriate assessment of candidacy for a cochlear implant or an ABI. While the research is still preliminary, children with an ABI appear to slowly obtain benefit over time. A team of professionals, including audiological, occupational, and educational therapy, affords maximum opportunity for benefit. CONCLUSIONS: Pediatric patients who have abnormal anatomy and are candidates for an implantable auditory prosthetic require an individualized, multisystems review. The qualitative benefit-risk assessment used here to characterize the condition, the medical need, potential benefits, risks, and risk management strategies has revealed the complex factors involved. After implantation, continued team support for the family during extensive postimplant therapy is needed to develop maximum auditory skill benefit. PMID- 29714551 TI - Use Effectiveness of Medical Devices: A Case Study on the Deployment of Ultrasonographic Devices. AB - BACKGROUND: In the sense of Act No. 123/2000 Coll., as amended (hereinafter referred to as "the Act"), a medical device is understood to be a wide range of resources, especially medical equipment. To implement innovative technologies in practice, it is becoming extremely important to be cost-conscious and effective. The aim of the article is to use an ultrasonographic device case study in a selected hospital to show the possibility of solving the use effectiveness of medical devices. METHODS: Within the first step, a summary of the use of ultrasonographic devices is developed in terms of performance number and time. Also, a summary of all costs for the last 5 years has been created. The analyzed ultrasonographic device set is evaluated in terms of activity indicators, profitability, and Du Pont decomposition. Revenues from the operation of individual instruments and payroll productivity are taken into account. All of this is evaluated in the context of the requirements of the department and the spectrum of ultrasonographic devices. RESULTS: The results show that the economic evaluation of device use efficiency, comparing the requirements of the department and spectrum of the devices, suggests a major revision in use of these devices and savings. CONCLUSION: The new design of the most profitable system differs significantly in the arrangement of individual ultrasonographic devices. The benefit of the study is not just a newly designed organization-specific arrangement, but it can be perceived as a modeling approach that can be used to analyze other sets of medical technology. PMID- 29714552 TI - Regional Differences During the ICH Regulatory Consultation Process Between the EU, US, and Japan. AB - With the globalization of the pharmaceutical industry, initiatives like the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) have emerged to tackle the increasingly complex regulatory environment and challenges. During the development of harmonised guidelines, regional regulatory agencies (European Medicines Agency, US Food and Drug Administration, and Japan's Ministry of Health, Labour and Welfare) collect comments of all their respective stakeholders through public consultation processes. This process should allow for extensive and comprehensive expert input. However, looking at the ICH public consultation process across regions in past years reveals that there is a different approach ICH regulatory parties use to publish the draft guideline as well as the time frames allotted for review and comment. In this study, we analysed the difference over the past 15 years between the timelines provided during the consultation process by the regulatory agencies of the ICH founding members. We showed that the EMA distributes the ICH draft guideline faster and allows a longer period for consultation compared to the FDA and the Japanese authority. PMID- 29714553 TI - Direct-to-Consumer Genetic Testing: Finding a Clear Path Forward. AB - Regulatory compliance in the direct-to-consumer genetic testing market is highly sophisticated as there are numerous federal, state, and ethical barriers to entry. In 2010, amid an underregulated market, 23andMe sought to do what few companies in the medical industry had attempted before-disregard the guidance and requests of the US Food and Drug Administration. This regulatory strategy effectively destined the company's Personal Genome Service for failure; however, the company changed course and has been granted several regulatory clearances. This exemplifies the importance of a healthy relationship with regulatory agencies, although challenges remain. The DTC industry continues to have a perplexing regulatory framework at both the federal and state level. There are also ethical concerns with the monetization of deidentified genetic health information, as genetic data have an inherent level of identifiability and are not fully protected by the Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule in these scenarios. Although some DTC tests are now cleared in the United States, the concern that a learned intermediary is needed for interpretation of results remains. The regulatory oversight of this market will need to continue to develop to ensure the protection of consumer health and privacy. PMID- 29714554 TI - Optimal Anti-cancer Drug Profiles for Effective Penetration of the Anti-cancer Drug Market by Generic Drugs in Japan. AB - BACKGROUND: The increased use of generic drugs is a good indicator of the need to reduce the increasing costs of prescription drugs. Since there are more expensive drugs compared with other therapeutic areas, "oncology" is an important one for generic drugs. The primary objective of this article was to quantify the extent to which generic drugs in Japan occupy each level of the Anatomical Therapeutic Chemical (ATC) classification system. METHODS: The dataset used in this study was created from publicly available information obtained from the IMS Japan Pharmaceutical Market database. Data on the total amount of sales and number of prescriptions for anti-cancer drugs between 2010 and 2016 in Japan were selected. The data were categorized according to the third level of the ATC classification system. RESULTS: All categories of the ATC classification system had increased market shares in Japan between 2010 and 2016. The barriers to market entry were relatively low in L01F (platinum anti-neoplastics), L01C (plant-based neoplastics), L02B (cytostatic hormone antagonists), and L01D (anti-neoplastic antibiotics) but were high in L02A (cytostatic hormones), L01H (protein kinase inhibitors), and L01B (anti-metabolites). CONCLUSIONS: Generic cancer drugs could bring savings to Japanese health care systems. Therefore, their development should be directed toward niche markets, such as L02A, L01H, and L01B, and not competitive markets. PMID- 29714555 TI - Comparison of Dissolution Profiles: A Statistician's Perspective. AB - Dissolution profile comparisons are used in the context of postapproval changes where the manufacturer has to demonstrate that the quality of the product is not affected by the change. Around this topic, basic statistical principles are in conflict with widely used interpretations of current guidelines, resulting in time-intensive discussions in pharmaceutical practice. From a statistician's perspective, the following suggestions could improve the situation regarding statistical analysis, inference, and interpretation: (1) A clear definition of the variability criterion for the similarity factor, such as that found in the EMA guideline, would be helpful. (2) Sample size recommendations should be interpreted as minimum, not as maximum, requirements. (3) In case of several batches per reference or test group, pooled comparisons should be performed instead of multiple batch-to-batch comparisons. (4) FDA Guideline recommendations concerning multivariate equivalence procedures for highly variable dissolution profiles are based on the state of statistical knowledge in 1997 and need to be updated. (5) The T2 test for equivalence is an appropriate method for comparing highly variable dissolution profiles. Application of the T2 test for equivalence enables reliable equivalence decisions and satisfies the intention of reaching scientific evidence in decision making. Software implementations of this test are available in R and SAS. The article is a summary of the poster of the same name presented at the DIA FDA Statistics Forum 2016. The poster took the third place in the poster award of the conference. PMID- 29714556 TI - Juvenile Animal Testing: Assessing Need and Use in the Drug Product Label. AB - BACKGROUND: Juvenile animal testing has become an established part of drug development to support safe clinical use in the human pediatric population and for eventual drug product label use. METHODS AND RESULTS: A review of European Paediatric Investigation Plan decisions showed that from 2007 to mid-2017, 229 drugs had juvenile animal work requested, almost exclusively incorporating general toxicology study designs, in rat (57.5%), dog (8%), mouse (4.5%), monkey (4%), pig (2%), sheep (1%), rabbit (1%), hamster (0.5%), and species not specified (21.5%). A range of therapeutic areas were found, but the most common areas were infectious diseases (15%), endocrinology (13.5%), oncology (13%), neurology (11%), and cardiovascular diseases (10%). Examination of major clinical indications within these therapeutic areas showed some level of consistency in the species of choice for testing and the pediatric age that required support. Examination of juvenile animal study findings presented in product labels raises questions around how useful the data are to allow prescribing the drug to a child. CONCLUSION: It is hopeful that the new ICH S11 guideline "Nonclinical Safety Testing in Support of Development of Pediatric Medicines" currently in preparation will aid drug developers in clarifying the need for juvenile animal studies as well as in promoting a move away from toxicology studies with a conventional design. This would permit more focused testing to examine identified areas of toxicity or safety concerns and clarify the presentation/interpretation of juvenile animal study findings for proper risk assessment by a drug prescriber. PMID- 29714557 TI - Analysis of the Risks and Benefits of New Chemical Entities Approved by the US Food and Drug Administration (FDA) and Subsequently Withdrawn From the US Market. AB - Benefit-risk evaluations of drugs have been conducted since the introduction of modern regulatory systems more than 50 years ago. Such judgments are typically made on the basis of qualitative or semiquantitative approaches, often without the aid of quantitative assessment methods, the latter having often been applied asymmetrically to place emphasis on benefit more so than harm. In an effort to preliminarily evaluate the utility of lives lost or saved, or quality-adjusted life-years (QALY) lost and gained as a means of quantitatively assessing the potential benefits and risks of a new chemical entity, we focused our attention on the unique scenario in which a drug was initially approved based on one set of data, but later withdrawn from the market based on a second set of data. In this analysis, a dimensionless risk to benefit ratio was calculated in each instance, based on the risk and benefit quantified in similar units. The results indicated that FDA decisions to approve the drug corresponded to risk to benefit ratios less than or equal to 0.136, and that decisions to withdraw the drug from the US market corresponded to risk to benefit ratios greater than or equal to 0.092. The probability of FDA approval was then estimated using logistic regression analysis. The results of this analysis indicated that there was a 50% probability of FDA approval if the risk to benefit ratio was 0.121, and that the probability approaches 100% for values much less than 0.121, and the probability approaches 0% for values much greater than 0.121. The large uncertainty in these estimates due to the small sample size and overlapping data may be addressed in the future by applying the methodology to other drugs. PMID- 29714558 TI - Assessing Study Start-up Practices, Performance, and Perceptions Among Sponsors and Contract Research Organizations. AB - BACKGROUND: Site identification, site selection, and study start-up have become the focus of improvement by organizations conducting clinical trials. METHODS: To examine and measure the process from site identification through site activation, Tufts Center for the Study of Drug Development (CSDD) conducted a comprehensive survey among pharmaceutical organizations, biotech companies, and contract research organizations (CROs). Responses from over 400 unique companies were gathered and analyzed. RESULTS: The results indicate that the start-up process is on average 5 to 6 months in total duration, and cycle times across all activities, including site identification, site selection, and study start-up, are faster for repeat sites than for new sites. Comparisons between sponsor and CROs indicate that CROs completed all site-related activities 6 to 11 weeks faster than sponsors. Other areas impacting cycle times were examined, including centralized versus decentralized functions, investment in technology, and organizational strategies that improve cycle time efficiency and performance. CONCLUSION: Tufts CSDD will explore this area in future research to gather additional insights into other factors that may be associated with speed and efficiency. PMID- 29714559 TI - Quality of Medicine Information in Product Information Leaflets: A Retrospective Audit. AB - BACKGROUND: Nonstandard product information leaflets (PIs) may lead to medication errors. We assessed the completeness, and compatibility of, essential information against reference sources in selected PIs of medicines used in Sri Lanka. METHODS: Hundred PIs each were used to assess completeness and compatibility of information, respectively. Availability of essential information was checked against drug regulations of the country. Clinical facts were matched against the British National Formulary and/or Australian Medicines Handbook for compatibility. PIs were categorized as "compatible" if all facts stated under each clinical information type were mentioned in at least one of the references; "partially compatible" if only some facts mentioned under each clinical information type were available in at least one of the references; and "totally incompatible" if none of the facts stated in each clinical information type were mentioned in both references. RESULTS: Of the 100 PIs, 28% did not include at least one of the essential information required by the regulations. Pharmacokinetic data, duration of treatment, overdose, and special dosage information were frequently missing. Nine types of clinical information in PIs matched with reference sources resulted in 900 cross-matches. Among the cross matches, 80 (8.9%) partial compatibilities and 8 (0.9%) total incompatibilities were encountered. Nearly half (48%) of the PIs had at least one incompatibility. CONCLUSION: Some PIs lacked important medicines information and were incompatible with known references. PIs need to be carefully prepared by medicine manufacturers and meticulously reviewed by regulatory authorities for accuracy and completeness. PMID- 29714560 TI - Patient Experience Data in US Food and Drug Administration (FDA) Regulatory Decision Making:: A Policy Process Perspective. AB - BACKGROUND: The influence of patient advocates on FDA regulatory decision making has increased. Despite enhanced engagement with FDA, there remain challenges to achieving the regulatory goals of patients within FDA's regulatory framework. Gaps exist between patient advocates' knowledge of the agency's processes and FDA's need for rigorous, clinically meaningful patient experience data. This study examined the policy process in which patient experience data are collected by patient advocates and provided to FDA for regulatory decision making. METHODS: Semistructured, narrative interviews were conducted with 14 professionals working in patient advocacy or at FDA. The purpose was to examine, in depth, participants' perceptions and experiences regarding this new regulatory process. Interviews were coded and examined for themes. RESULTS: The use of patient experience data by FDA is an evolving regulatory process. Participants identified a number of barriers and contributors to regulatory success. Well-organized and sophisticated patient advocacy groups with access to scientific and policy expertise are more likely to find success meeting FDA's patient experience data requirements. A conceptual model of this regulatory process was developed. CONCLUSIONS: Use of patient experience data by FDA has the potential to positively influence the regulation of medical products in the United States. Success within this new regulatory process will depend on clear guidance from FDA regarding the collection, analysis, and use of patient experience data. Patient advocacy groups must enhance internal capacity and expertise while engaging in substantive collaborations with FDA and other stakeholders in order to meaningfully contribute to the regulatory review of new therapeutics. PMID- 29714561 TI - Research Deviations in FDA-Regulated Clinical Trials: A Cross-Sectional Analysis of FDA Inspection Citations. AB - BACKGROUND: The US Food and Drug Administration (FDA) ensures clinical trials meet regulatory/ethical standards through inspections. If FDA Investigators observe potential violations of regulatory requirements during an inspection, a firm will receive a Form FDA 483, Inspectional Observations. Violations cited have resulted in the death of human research subjects, prosecution of research personnel, and denial of approval for new medical products. Objectives included the standardization of Violation Themes cited for analysis by inspection firm type, geographic location, and Violation Theme citation to provide insight into regulatory violations. METHODS: Cross-sectional analysis of citations published in public databases between October 1, 2005, and September 30, 2015, by the FDA for inspections under the Bioresearch Monitoring program. For each inspection citation, the main measure was the Code of Federal Regulation cited coded into a standardized Violation Theme for citation analysis. RESULTS: Under the Bioresearch Monitoring program, 3281 inspections received a Form FDA 483 in 2007 2015. FDA inspections have increased over this period but the rate of Form FDA 483 issuance has decreased. On average, Sponsor-Investigators received 4.41 citations per inspection compared to clinical researchers alone receiving 2.21. One-third of violations were related to adherence to investigational procedures followed by informed consent and study records issues. CONCLUSIONS: In the last decade, the number of violations observed under the Bioresearch Monitoring program has decreased; however, significant improvements can still be made regarding adherence to study procedures, the consenting of human research subjects, and creation of adequate and accurate study documentation. PMID- 29714562 TI - FDA Expectations for Demonstrating Interchangeability. AB - There is a great interest from global companies who are developing biosimilars to pursue interchangeability designation for commercialization of their products in the US. An interchangeability designation will not only allow the substitutability at the pharmacy level without the intervention of a health care provider but the first sponsor who is able to garner interchangeability designation will also receive 12 months of marketing exclusivity. This paper will highlight our current understanding of FDA expectations with regards to demonstrating interchangeability. PMID- 29714563 TI - The Safety Explorer Suite: Interactive Safety Monitoring for Clinical Trials. AB - BACKGROUND:: Frequent and thorough monitoring of patient safety is a requirement of clinical trials research. Safety data are traditionally reported in a tabular or listing format, which often translates into many pages of static displays. This poses the risk that clinically relevant signals will be obscured by the sheer volume of data reported. Interactive graphics enable the delivery of the vast scope of information found in traditional reports, but allow the user to interact with the charts in real time, focusing on signals of interest. METHODS:: Clinical research staff, including biostatisticians, project managers, and a medical monitor, were consulted to guide the development of a set of interactive data visualizations that enable key safety assessments for participants. The resulting "Safety Explorer" is a set of 6 interactive, web-based, open source tools designed to address the shortcomings of traditional, static reports for safety monitoring. RESULTS:: The Safety Explorer is freely available on GitHub as individual JavaScript libraries: Adverse Event Explorer, Adverse Event Timelines, Safety Histogram, Safety Outlier Explorer, Safety Results Over Time, and Safety Shift Plot; or in a single combined framework: Safety Explorer Suite. The suite can also be utilized through its R interface, the safetyexploreR package. CONCLUSIONS:: The Safety Explorer provides interactive charts that contain the same information available in standard displays, but the interactive interface allows for improved exploration of patterns and comparisons. Medical Monitors, Safety Review Boards, and Project Teams can use these tools to effectively track and analyze key safety variables and study endpoints. PMID- 29714564 TI - Research Misconduct in FDA-Regulated Clinical Trials: A Cross-sectional Analysis of Warning Letters and Disqualification Proceedings. AB - BACKGROUND: The US Food and Drug Administration (FDA) ensures that clinical trials meet regulatory and ethical standards through inspections of researchers, also known as clinical investigators. Inspections with significant regulatory/ethical violations may result in regulatory actions, such as a warning letter or a Notice of Initiation of Disqualification Proceedings and Opportunity to Explain (NIDPOE). Objectives included the standardization of regulatory violation themes cited by the FDA for novel analysis of published regulatory actions rate issued by study intervention type, violation theme by intervention type, and violation theme variation between regulatory action type. METHODS: Cross-sectional analysis of regulatory actions from October 1, 2006, to September 30, 2015, for inspections of researchers. For each FDA regulatory action, the main measure was the Code of Federal Regulations cited coded into a violation theme. Data were paired with FDA's published researcher inspection metrics to perform fiscal year analysis. RESULTS: The FDA conducted 6375 domestic inspections of researchers in 2007 to 2015: 360 had significant regulatory violations, and 194 received published regulatory actions. Since 2007, rates of significant deviations have decreased. Medical device researchers had higher rates of warning letter issuance than did biologic product researchers. In contrast, medical device researchers had lower rates of NIDPOE issuance as compared to rates of biologic or pharmaceutical researchers. Lack of researcher supervision and submission of false information were cited more frequently for NIDPOEs. CONCLUSIONS: Researcher compliance has significantly improved as evidenced by medical device researchers having the lowest rate of the most significant noncompliance. Disqualification is more likely to occur when researchers fail to supervise the trial or false information is submitted. PMID- 29714565 TI - Rethinking the Clinically Based Thresholds of TransCelerate BioPharma for Risk Based Monitoring. AB - BACKGROUND: The quality of data from clinical trials has received a great deal of attention in recent years. Of central importance is the need to protect the well being of study participants and maintain the integrity of final analysis results. However, traditional approaches to assess data quality have come under increased scrutiny as providing little benefit for the substantial cost. Numerous regulatory guidance documents and industry position papers have described risk based approaches to identify quality and safety issues. In particular, the position paper of TransCelerate BioPharma recommends defining risk thresholds to assess safety and quality risks based on past clinical experience. This exercise can be extremely time-consuming, and the resulting thresholds may only be relevant to a particular therapeutic area, patient or clinical site population. In addition, predefined thresholds cannot account for safety or quality issues where the underlying rate of observing a particular problem may change over the course of a clinical trial, and often do not consider varying patient exposure. METHODS: In this manuscript, we appropriate rules commonly utilized for funnel plots to define a traffic-light system for risk indicators based on statistical criteria that consider the duration of patient follow-up. Further, we describe how these methods can be adapted to assess changing risk over time. Finally, we illustrate numerous graphical approaches to summarize and communicate risk, and discuss hybrid clinical-statistical approaches to allow for the assessment of risk at sites with low patient enrollment. RESULTS: We illustrate the aforementioned methodologies for a clinical trial in patients with schizophrenia. CONCLUSIONS: Funnel plots are a flexible graphical technique that can form the basis for a risk-based strategy to assess data integrity, while considering site sample size, patient exposure, and changing risk across time. PMID- 29714566 TI - Clinical Trial Results Summary for Laypersons: A User Testing Study. AB - OBJECTIVE: To apply "user testing" to maximize readability and acceptability of a Clinical Trial Results Laypersons Summary-a new European requirement. METHODS: "User testing" (using questionnaire and semistructured interview) assessed whether people could find and understand key points. Findings were used to improve content and design, prior to retesting. Participants had a range of levels of health literacy and there was a higher education group. Participants accessed the summary on screen. In round 1 we tested 12 points of information. In round 2 a revised summary addressing round 1 findings was tested, leading to a third final version. RESULTS: In round 1, 2 of 12 points of information did not reach the target and interviews raised further format and content issues (some distracting technical explanations and inability to find or understand the 2 main study purposes). These findings informed revisions for the version tested in round 2, with 2 different points not reaching the target (inclusion criteria relating to duration of seasonal allergies and how researchers found out about participants' symptoms). Identified problems in both rounds were addressed and reflected in the final version. Despite improvements, participants did not consistently understand that summaries were intended for the public, or to only interpret results of single trials in the context of additional trials. All readers, including those with higher education, found the clear and straightforward language acceptable. CONCLUSIONS: Applying "user testing" resulted in a largely health-literate summary suitable for people across a range of backgrounds. PMID- 29714567 TI - Patient Reporting of Adverse Drug Reactions (ADRs): Survey of Public Awareness and Predictors of Confidence to Report. AB - BACKGROUND:: Many countries incorporate direct patient reporting of adverse drug reactions (ADRs) into their pharmacovigilance systems as patients provide a different insight into drug safety compared to health care professionals. This study aimed to examine public awareness about ADR reporting in Malaysia and patients' confidence in reporting ADRs. METHODS:: Using a cross-sectional design and convenient sampling, data were collected in public areas within Kuala Lumpur, Malaysia, via face-to-face interview with a structured questionnaire. Multivariate logistic regression analysis was used to identify the significant predictors of patients' confidence in ADR reporting. RESULTS:: Out of 860 consented respondents achieving a response rate of 73.5%, only 69 (8%) were aware of the Malaysian ADR monitoring system. The majority (60%) of the respondents indicated they had the confidence to report ADRs. Multivariate logistic regression analysis revealed that ease in completing the ADR reporting form was the strongest variable predictive of confidence to report ADRs (odds ratio [OR], 18.45; 95% confidence interval [CI], 10.55-32.25). Increased confidence in ADR reporting was also associated with education level. Respondents with a higher education level were more likely to be confident to report ADRs compared to those with primary or no formal education (OR, 2.49; 95% CI, 0.77-8.1). CONCLUSIONS:: Lack of awareness of the ADR monitoring system is still prevalent among Malaysian patients. The ease of completing the ADR form and education level are predictive of patient confidence to report ADRs. These factors should be considered in designing public promotional activities to encourage patient contributions to pharmacovigilance. PMID- 29714568 TI - Advancing the Practice of CRCs: Why Professional Development Matters. AB - Clinical research coordinators (CRCs) assume critical responsibilities central to the success of the research team. The complexity of their role requires essential professional qualifications. One barrier to professionalization, however, has been the inconsistent, or absent, competency-based training. This study explored participants' perceptions of training experiences designed to prepare them for the national certification exam. Focus group methodology was used to document their experiences. The findings showed that sustainable mentoring relationships developed, participant confidence levels increased, and anxiety about performance capacity diminished. Cognitive reframing of the work environment and CRC roles was facilitated by training that fostered sharing and social reinforcement of professional and personal identities. Findings from this study suggest that access to meaningful training and quality instruction supports the professionalization of CRCs. PMID- 29714569 TI - Anticancer Drug Prescription Patterns in Japan: Future Directions in Cancer Therapy. AB - BACKGROUND:: Despite their benefits, the rapid development of new cancer treatments has been a significant driver of increasing health care expenditures in the face of limited health care budgets. In this study, we analyzed the prescribing trends for anticancer drugs from 2010 through 2016 in Japan and sought to identify unique trends that could provide a basis for future medical economic research aiming to develop more efficacious and cost-effective cancer therapies. METHODS:: We used publicly available marketing data for anticancer drugs in Japan for 2010-2016. The drugs selected for this research were categorized according to the Anatomical Therapeutic Chemical Classification System. We investigated the overall anticancer drug market size, the number of anticancer drugs, the top 30 selling anticancer categories, sales and prescription volumes, and changes in sales and prescription volumes between 2010 and 2016 in the country. RESULTS:: The anticancer agent market expanded each year from 2010 to 2016, with sales exceeding 1 trillion yen in 2015. The proportion of molecular targeted drugs (antineoplastic mAbs and protein kinase inhibitors) among the top 30 selling anticancer categories has continued to increase, and both the sales and prescription volumes of these drugs exceeded those of drugs in other categories, suggesting that these treatments play a dominant role in cancer pharmacotherapy. CONCLUSION:: The availability and increasing use of innovative but more expensive targeted therapies were major drivers of increases in pharmaceutical expenditures for cancer treatment in Japan. Therefore, the effective use of genetic testing can mitigate these rising costs. PMID- 29714570 TI - Outdated Prescription Drug Labeling: How FDA-Approved Prescribing Information Lags Behind Real-World Clinical Practice. AB - BACKGROUND:: Prescription drug labeling is an authoritative source of information that guides the safe and effective use of approved medications. In many instances, however, labeling may fail to be updated as new information about drug efficacy emerges in the postmarket setting. When labeling becomes outdated, it loses its value for prescribers and undermines a core part of the FDA's mission to communicate accurate and reliable information to patients and physicians. METHODS:: We compared the number of drug uses indicated on product labels to the number of uses contained in a leading drug compendium for 43 cancer drugs approved between 1999 and 2011. We defined a "well-accepted off-label use" of a drug as one that was not approved by the FDA and received a category 1 or 2A evidence grade. RESULTS:: Of the 43 drugs reviewed in this study, 34 (79%) had at least one well-accepted off-label use. In total, 253 off-label uses were identified; 91% were well accepted, and 65% were in cancer types not previously represented on labeling. Off-patent drugs had more well-accepted off-label uses than brand-name drugs, on average (mean 13.7 vs 3.8, P = .018). CONCLUSIONS:: The labeling for many cancer drugs, particularly for older drugs, is outdated. Although FDA-approved labeling can never be fully aligned with real-world clinical practice, steps should be taken to better align the two when high quality data exist. Such steps, if taken, will assist patients and prescribers in discerning which uses of drugs are supported by the highest quality evidence. PMID- 29714571 TI - Clinical Study Design to Assess Both Short- and Long-term Efficacy in Addition to Group Sequential Test on Safety. AB - In clinical studies for disorders such as rheumatoid arthritis, type 2 diabetes mellitus, multiple sclerosis, osteoporosis, etc, sometimes the developers need to address safety concerns (eg, cardiovascular risk) in the phase III development, so that a large long-term safety study is needed before registration. This article does not contain any studies with human or animal subjects performed by any of the authors. Aiming for potential regulatory approval with a single confirmatory study, the authors suggest a design that assesses short-term efficacy (eg, signs or symptoms) and long-term efficacy (eg, structure or imaging), as well as safety (eg, major adverse cardiac events), for which a group sequential test is performed applying an alpha spending function. A graphical testing procedure is suggested for the data analysis. The testing procedure controls the family-wise type I error rate. The study may reach all or part of short-term efficacy, long-term efficacy, and/or safety objectives. It is possible to get market approval with a single confirmatory study that assesses short-term efficacy, long-term efficacy, and safety. PMID- 29714572 TI - What Drives Adoption of National Labels as Global Reference Labels? A Case Study With the JPI. AB - Pharmaceutical labeling describes the safe and effective use of an approved product. Such information may be provided to consumers and/or health care physicians, and available online or in the pack in a variety of different formats according to local or regional regulations. Depending on the Health Authority (HA), content within a nationally approved label is generally reliant on two primary sources, a Company Core Data Sheet (CCDS), and the text approved by the Health Authority. Content in the nationally approved label may differ from the CCDS for a variety of reasons. In some countries, HAs require the Marketing Authorization Holder (MAH) to base their national label on an already approved label in a "major market" economy, only approving changes to the label when there is evidence that the major market has already approved. In this paper, we examine recent steps taken by the Ministry of Health, Labour and Welfare (MHLW) and Pharmaceuticals and Medical Devices Agency (PMDA) to change labeling regulation in Japan in the context of the recently communicated national strategy, and assess whether this may impact on uptake of the J-PI as a reference label. Decreases in approval times by PMDA for new products, development of basic principles on multiregional clinical trials, greater transparency of content on the PMDA website, and increasing outreach to other Asian Agencies in recent years are highlighted. Labeling harmonization across regions, particularly of safety related information, represents a key factor in promoting patient safety and risk communication, and is a worthy topic for future ICH consideration. PMID- 29714573 TI - A Pilot Experiment in Responding to Individual Patient Requests for Compassionate Use of an Unapproved Drug: The Compassionate Use Advisory Committee (CompAC). AB - BACKGROUND: Janssen Research & Development, LLC, part of the Janssen pharmaceutical companies of Johnson & Johnson, and NYU School of Medicine partnered to establish the Compassionate Use Advisory Committee (CompAC) to evaluate the use of an independent, external, expert committee in ensuring transparent, fair, beneficent, evidence-based, and patient-focused compassionate access to investigational medicines, a public health challenge that has been an ongoing issue for over 3 decades. METHODS: To this end, NYU School of Medicine was responsible for the formation, member selection, and operation of CompAC, consisting of physicians, ethicists, and patient advocates, under Johnson & Johnson's sponsorship. RESULTS: A pilot was successfully run using CompAC to provide recommendations on compassionate use access to a Johnson & Johnson oncology investigational asset called daratumumab. CONCLUSION: This innovative model provides a framework that can be emulated by the industry globally. PMID- 29714574 TI - Strategic and Statistical Considerations on the QT Assessment of Volasertib. AB - Volasertib is a selective cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase (Plk). A potential for prolonged QT intervals was indicated with volasertib in preclinical studies and preliminary clinical data. As a result, electrocardiograms (ECGs) have been collected in all volasertib clinical trials to monitor potential cardiac effects. This article describes strategic and statistical methods prospectively planned to perform an integrated analysis of ECG data from available trials to evaluate volasertib's effect on cardiac repolarization, as reflected by changes in the duration of QT interval and other ECG-related endpoints. Methods to effectively cope with heterogeneity between trials (ie, differences in study designs) are discussed. These strategies may be useful for other investigational drugs for which QT risk assessment is required, but a thorough QT/QTc trial is not feasible, resulting in the need for an alternative approach. Volasertib therapy relevantly prolonged adjusted mean QTcF change from administration baseline following the first and subsequent infusions. The integrated analysis revealed that the volasertib effects on the mean QTc changes from baseline were transient and had resolved at 24 hours after start of the first infusion. There was no evidence for a long-term impact on the QTcF interval following multiple infusions with volasertib. PMID- 29714575 TI - Advancing a Framework for Regulatory Use of Real-World Evidence: When Real Is Reliable. AB - There is growing interest in regulatory use of randomized pragmatic trials and noninterventional real-world (RW) studies of effectiveness and safety, but there is no agreed-on framework for assessing when this type of evidence is sufficiently reliable. Rather than impose a clinical trial-like paradigm on RW evidence, like blinded treatments or complete, source-verified data, the framework for assessing the utility of RW evidence should be grounded in the context of specific study objectives, clinical events that are likely to be detected in routine care, and the extent to which systematic error (bias) is likely to impact effect estimation. Whether treatment is blinded should depend on how well the outcome can be measured objectively. Qualification of a data source should be based on (1) numbers of patients of interest available for study; (2) if "must-have" data are likely to be recorded, and if so, how and where; (3) the accessibility of systematic follow-up data for the time period of interest; and (4) the potential for systematic errors (bias) in data collection and the likely magnitude of any such bias. Accessible data may not be representative of an entire population, but still may provide reliable evidence about the experience of typical patients treated under conditions of conventional care. Similarly, RW data that falls short of optimal length of follow-up or study size may still be useful in terms of its ability to provide evidence for regulators for subgroups of special interest. Developing a framework to qualify RW evidence in the context of a particular study purpose and data asset will enable broader regulatory use of RW data for approval of new molecular entities and label changes. Reliable information about diverse populations and settings should also help us move closer to more affordable, effective health care. PMID- 29714576 TI - Unique Burdens of Pediatric Clinical Trials in Duchenne Muscular Dystrophy, April 20-21, 2017, Bethesda, Maryland, USA. AB - Recent increases in the number and breadth of clinical trials for patients with Duchenne muscular dystrophy (DMD) have engendered hope for a better future. Despite the overall enthusiasm by the DMD community for these trials, however, the burdens and pressures that they place on children with Duchenne muscular dystrophy and their families have become painfully apparent. In order to identify, and mediate, these challenges, Parent Project Muscular Dystrophy (PPMD) sponsored a meeting to examine some of these issues more closely in Bethesda, Maryland, on April 20-21, 2017. The meeting focused on key burdens for patients participating in clinical trials including technical (protocol complexity), financial, psychosocial and emotional issues, and informed consent. Participants recommended mitigation strategies falling into clinical, operations, regulatory, and ethical domains. The development of consensus action plans for short- and long-term enhancements in trials should facilitate discovery and development research for DMD patients. PMID- 29714577 TI - Relationship Between the Review Time and Various PMDA Consultations in Recent New Drug Approval Cases in Japan. AB - BACKGROUND:: It is considered important that the applicants and reviewers communicate well from the development stage and that both mutually understand the development strategy and application contents in conducting the review efficiently after the application is submitted. Therefore, we focus on Pharmaceuticals and Medical Devices Agency (PMDA) consultations from the viewpoint of communication before the application and clarify the issues to consider in the challenge to reduce the review time in terms of the relationship between the review time and various PMDA consultations. METHODS:: We investigated the relationship between the review time and various PMDA consultations for the drugs with new active ingredients approved in Japan using public information from the PMDA. RESULTS:: Review times tended to be shorter as more PMDA consultations were conducted. In standard review products, statistically significant differences were noted in the review times (median). When looking at the results of the cases of each category of PMDA consultations, variations in the review times were greater as the consultations were conducted in the later stages of clinical development. Review times tended to be shorter when prior assessment consultations were conducted. In standard review products, significant reductions were noted with the review time (median). CONCLUSIONS:: It was suggested that conducting more PMDA consultations might lead to shorter review times. Regarding the review times, variations from the standard review time could possibly be smaller by conducting PMDA consultations from the early stage of clinical development in Japan. It was suggested that review times could possibly be further reduced by conducting prior assessment consultations. PMID- 29714578 TI - Survey of Safety Information in the Investigator's Brochure: Inconsistencies and Recommendations. AB - A survey was undertaken to gain an understanding of current industry practices in the preparation of the safety information for the Investigator's Brochure (IB). Sixteen of a potential 25 respondents completed a survey (64% response rate). Five respondents represented pharmaceutical and biotech companies, and 11 were consultants or worked at contract research organizations for such companies. The results showed a lack of uniformity of practices. This may be due to the lack of harmonized regulations and guidelines, the lack of standardized terminology and definitions, and the lack of clarity regarding the purpose and content of the various safety-related sections of the IB. These sections, although interrelated, have different purposes, and the criteria and methodology used have to be appropriate for these purposes. It is recommended that regulations, guidelines, and terminology be harmonized worldwide to enable consistent reporting to regulatory authorities across regions, minimize duplication of work for companies that operate in different regions, and to provide meaningful safety information both to the investigator and regulatory authorities. Recently published information regarding the format and the content of a "Reference Safety Information" section provides clarity for this element of the IB, which can hopefully be adopted globally. Until further regulatory clarity is provided for other safety sections, recommended approaches are provided. PMID- 29714579 TI - The Use of Real-World Evidence and Data in Clinical Research and Postapproval Safety Studies. AB - BACKGROUND:: The adoption and use of real-world evidence (RWE) is becoming increasingly important to drug development and patient safety. METHODS:: The Tufts Center for the Study of Drug Development (CSDD) conducted a benchmark survey of pharmaceutical and biotechnology companies and contract research organizations in a number of areas that support real-world data (RWD) and evidence, including operations and performance areas. Data were gathered on organizational functions, staff, roles and responsibilities, and skill sets required. Also, current and future allocation of budgets and spending were examined as well as return on investment measures. A total of 30 unique companies responded to the survey. RESULTS:: Nearly all respondents (29/30 companies) reported that their organizations had an RWE function and most companies indicated that their RWE functions were increasing in size (21 companies). From a postapproval regulatory and labeling perspective, there were two primary areas for company use of RWD to generate evidence: one for postapproval safety studies, including decreasing the severity of a label warning or to support risk evaluation and mitigation strategies (REMS) (12/22 companies; 55%), which allows for real-world patient population data to inform safety decisions; and the other for postmarketing studies (13/23 companies; 57%). Developing greater insight into therapeutic area needs, gaining market access, and greater understanding of drug effectiveness were the top measures identified for return on investment for use of RWE. CONCLUSIONS:: Expanding the use of RWE in regulatory decision making and increasing uses of real-world data by sponsors will fill the gaps that are critically needed for drug development and safety. PMID- 29714580 TI - Advancing Drug Safety Through Prospective Pharmacovigilance. AB - Much has changed in a relatively short period of time. There is a raging debate over the level of evidence expected to first introduce a treatment to patients based on smaller, more adaptive data sets. Some argue for less data followed by postapproval follow-up, others for more adaptive clinical trial designs and end point modification driven by patient-focused drug development and use of real world evidence. The transition in both the review and postmarketing regulatory framework is happening in front of our eyes in real time. To improve the ability of patients to receive high-quality, safe, effective, and timely care, better information via pharmacovigilance must be a priority as the world's many regulatory systems build the capacity to harness electronic health information to improve health, care quality, and safety. Globally, the widely variable ability of nations to build reliable regulatory systems (from precise review to robust pharmacovigilance) is a dangerous source of health care inequality. Developing validated tools and techniques for "predictive pharmacovigilance" will assist all health systems in better understanding the risks and benefits of the medicines they regulate by understanding what should be happening once a new medicine moves from risk-benefit regulatory efficacy to real-world risk-effectiveness. This will be of particular utility for smaller regulatory agencies with fewer resources. By comparing preapproval predictive pharmacovigilance data, developing regulatory authorities will be able to better understand the potential gap between what was predicted and what was actually measured (via more traditional pharmacovigilance methodologies). Predictive pharmacovigilance recognizes the value of understanding the imperfect reporting of real-world clinical use and that the absence of reporting is, in itself, an important postmarketing signal. PMID- 29714581 TI - CRISPR-Cas9: A Precise Approach to Genome Engineering. AB - In the last few decades, genomic manipulation has made significant progress as a result of the development of recombinant DNA technologies; however, more often than not, these techniques have been costly and labor intensive. In contrast, recently developed next-generation sequencing (NGS) technologies have provided a cheaper, faster, and easier process to study genomics. In particular, an NGS technique emerged from bacterial CRISPR-associated protein-9 nuclease (Cas9) as a revolutionary method to modify, regulate, or mark specific genomic sequences on virtually any organism. A later adaptation of this bacterial defense mechanism that successfully and permanently edits dysfunctional genes and corrects missing proteins has resulted in a new era for disease genetic engineering. Clinical trials using this technique are already being performed, and the applicability of CRISPR-Cas9 techniques is actively being investigated using in vivo studies. However, the concept of genome correction poses great concerns from a regulatory perspective, especially in terms of security, so principles for the regulation of these methodologies are being established. We delved into CRISPR-Cas9 from its natural and ortholog origins to its engineered variants and behaviors to present its notable and diverse applications in the fields of biotechnology and human therapeutics. PMID- 29714582 TI - The Near-Term Viability and Benefits of eLabels for Patients, Clinical Sites, and Sponsors. AB - BACKGROUND: Current clinical trial labels are designed primarily to meet regulatory requirements. These labels have low patient and site utility, few are opened, and they have limited space and small fonts. As our world transitions from paper to electronic, an opportunity exists to provide patients with information about their investigational clinical trial product in a way that is more easily accessible, meets Health Authority requirements, and provides valuable additional information for the patient and caregiver. METHODS: A TransCelerate initiative was launched to understand the current regulatory and technology landscape for the potential use an electronic label (eLabel) for investigational medicinal products (IMPs). Concepts and an example proof of concept were developed intended to show the "art of the possible" for a foundational eLabel and a "universal printed label." In addition, possible patient-centric enhancements were captured in the eLabel proof of concept. These concepts were shared with Health Authorities as well as patient and site advisory groups to gather feedback and subsequently enhance the concepts. RESULTS: Feedback indicated that the concept of an eLabel provides value and concepts should continue to be pursued. While the Health Authorities engaged with did not express issues with the use of an eLabel per se, the reduction in the content on the paper label is not possible in some geographic locations due to existing regulations. CONCLUSIONS: There is nothing that prevents transmitting the label electronically in conjunction with current conventional labeling. While there are still some regulatory barriers that need to be addressed for reducing what is on the paper label, advancement toward a more patient-centric approach benefits stakeholders and will enable a fully connected patient-centric experience. The industry must start now to build the foundation. PMID- 29714583 TI - Recent Advances in Drug Development and Regulatory Science in China. AB - As the second largest pharmaceutical market with a great potential for future growth, China has drawn much attention from the global pharmaceutical community. With an increasing government investment in biomedical research, the domestic biopharmaceutical (biotechnological) companies in China are turning their attention to the development of innovative medicines and targeting the global market. To introduce innovative products to Chinese patients sooner, to improve the efficiency of its review and approval processes, and to harmonize its regulatory science with international standards, the China Food and Drug Administration (CFDA) has initiated a series of major changes to its policies and regulations. This paper presents a snapshot of China's pharmaceutical market, and research and development status, and introduces technical guidelines pertaining to clinical trials and new drug applications. The recent wave of ground-breaking reforms in CFDA's regulatory science is discussed. Examples of clinical trials and new drug applications are provided throughout the discussion. PMID- 29714584 TI - Product Approvability Recommendations From FDA Advisory Committees:: Inconsistently Sought, Indirectly Obtained. AB - BACKGROUND:: Divisions within the Food and Drug Administration (FDA) often convene meetings of advisory committees, also known as AdComm or Panel meetings. The purpose of many AdComm meetings is for the FDA to obtain outside advice and recommendations on whether to approve a new drug or medical device. Laws and regulations indicate that such Panels are to provide recommendations regarding the approvability of the drug or device by FDA. METHODS:: We examine recent AdComm meetings, including a systematic review of drugs and biologics AdComms between 2011 and 2016, to find whether FDA is obtaining Panel recommendations on drug and device approvability in accordance with these laws and regulations. (This article does not contain any studies with human or animal subjects performed by any of the authors.). RESULTS:: We find that Panel recommendations on approvability are often not obtained. We further find that, in most cases where Panel recommendations are obtained, voting procedures are such that those recommendations address product approvability in only an indirect manner. CONCLUSIONS:: While FDA rightly has the authority to exercise discretion in many aspects of the product approval process, we believe that it must obtain clear recommendations whenever it convenes a Panel to address product approvability. PMID- 29714585 TI - Corrigendum. PMID- 29714586 TI - Truth in Advertising: Disclosure of Participant Payment in Research Recruitment Materials. AB - The practice of paying research participants has received significant attention in the bioethics literature, but the focus has been almost exclusively on consideration of factors relevant to determining acceptable payment amounts. Surprisingly little attention has been paid to what happens once the payment amount is set. What are the ethical parameters around how offers of payment may be advertised to prospective participants? This article seeks to answer this question, focusing on the ethical and practical issues associated with disclosing information about payment, and payment amounts in particular, in recruitment materials. We argue that it is permissible-and indeed typically ethically desirable-for recruitment materials to disclose the amount that participants will be paid. Further, we seek to clarify the regulatory guidance on "emphasizing" payment in a way that can facilitate design and review of recruitment materials. PMID- 29714587 TI - Regional Approaches to Expedited Drug Development and Review: Can Regulatory Harmonization Improve Outcomes? AB - Drug regulatory agencies around the world have implemented programs to expedite drug development and review for promising new products for serious diseases. These programs are all intended to minimize delays in patient access to innovative medicines, and have used broadly similar strategies to shorten drug development and review timelines. However, they differ in many key respects, and some stakeholders have suggested that these differences create unnecessary barriers in the development and approval process, possibly leading to delays in access. In collaboration with FDA, the Duke-Margolis Center for Health Policy convened an expert workshop to elicit feedback from a broad range of stakeholders as to whether a lack of harmonization across expedited programs is interfering with the efficient development of new products and, if so, to explore strategies for addressing these challenges. This report provides a summary of key themes and major findings from that discussion. PMID- 29714589 TI - Strengthening Health Products Regulatory Systems to Enhance Access to Quality Health Products in the Asia-Pacific. AB - Asia-Pacific is a region of fast growing opportunity for biomedical research and marketing of new health products by pharmaceutical and medical device companies. While national regulatory authorities have the responsibility to ensure timely access to innovative, effective, and safe therapies, many face capacity and resource constraints that limit their ability to guarantee a robust regulatory system capable of licensing and monitoring novel medicines and medical devices, and tackling substandard and falsified products. The region's regulatory landscape is also fragmented with country-specific requirements that create barriers to entry for new health products. To help address these challenges, the Duke-National University of Singapore's (Duke-NUS) Centre of Regulatory Excellence (CoRE) was established in 2014 with the strategic goals to strengthen the region's regulatory agencies through capacity development, regulatory convergence, work sharing, and nurturing networks for leadership and systems innovation. A smart and mature regulatory system in Asia-Pacific is pivotal to promote biomedical innovation and enhance equitable, sustainable access of populations to quality health products that are safe and efficacious. PMID- 29714588 TI - Ethical Issues in Research Involving Participants With Opioid Use Disorder. AB - In the current epidemic of opioid use disorders, there is both a scientific and ethical imperative to develop effective medical and behavioral treatments for opioid addiction. Research in subject populations with active and ongoing drug addictions bring unique ethical considerations and challenges. Sponsors, researchers, and institutional review board (IRB) members should be familiar with these unique ethical and medical issues as they design, review, and conduct research planned for this population. Issues include those of informed consent and decision-making capacity of research participants, compensation for participation and concerns about undue inducement, forces that threaten the voluntary nature of research participation including the scarcity of available drug treatment programs, and ensuring that participants are aware of and understand risks that may continue after research participation such as increased risk of overdose after research-mandated drug abstinence. This manuscript discusses the current thinking on these issues. PMID- 29714590 TI - Incremental Cost-Effectiveness Ratio and Net Monetary Benefit: Promoting the Application of Value-Based Pricing to Medical Devices-A European Perspective. PMID- 29714591 TI - Investigation of the Study Characteristics Affecting Clinical Trial Quality Using the Protocol Deviations Leading to Exclusion of Subjects From the Per Protocol Set Data in Studies for New Drug Application: A Retrospective Analysis. AB - BACKGROUND: The concept of the risk-based approach has been introduced as an effort to secure the quality of clinical trials. In the risk-based approach, identification and evaluation of risk in advance are considered important. For recently completed clinical trials, we investigated the relationship between study characteristics and protocol deviations leading to the exclusion of subjects from Per Protocol Set (PPS) efficacy analysis. METHODS: New drugs approved in Japan in the fiscal year 2014-2015 were targeted in the research. The reasons for excluding subjects from the PPS efficacy analysis were described in 102 trials out of 492 in the summary of new drug application documents, which was publicly disclosed after the drug's regulatory approval. The author extracted these reasons along with the numbers of the cases and the study characteristics of each clinical trial. Then, the direct comparison, univariate regression analysis, and multivariate regression analysis was carried out based on the exclusion rate. RESULT: The study characteristics for which exclusion of subjects from the PPS efficacy analysis were frequently observed was multiregional clinical trials in study region; inhalant and external use in administration route; Anti-infective for systemic use; Respiratory system, Dermatologicals, and Nervous system in therapeutic drug under the Anatomical Therapeutic Chemical Classification. In the multivariate regression analysis, the clinical trial variables of inhalant, Respiratory system, or Dermatologicals were selected as study characteristics leading to a higher exclusion rate. CONCLUSIONS: The characteristics of the clinical trial that is likely to cause protocol deviations that will affect efficacy analysis were suggested. These studies should be considered for specific attention and priority observation in the trial protocol or its monitoring plan and execution, such as a clear description of inclusion/exclusion criteria in the protocol, development of training materials to site staff, and/or trial subjects as specific risk-alleviating measures. PMID- 29714592 TI - Use of Proxy Variables to Determine the Impact of Protocol Complexity on Clinical Research Site Productivity. AB - BACKGROUND: Research coordinators (or teams) are usually assigned to multiple studies of varying complexity at any one time, each with different and ever changing workloads. As a result, determining the impact of protocol complexity on productivity is not easily accomplished. Standard methods of effort tracking typically require oversight or create additional workload to the site staff under study; they are time-consuming, expensive, intrusive, and usually incomplete. METHODS: This article describes a novel method for determining the impact of protocol complexity on clinical research coordinator (CRC) or team productivity by using proxy variables in place of effort tracking. A protocol assessment tool that quantitates complexity is used to determine cumulative workload. RESULTS: Productivity graphs are generated for each CRC per month and can be followed over time to assess trends or for comparative analysis. CONCLUSION: The data provide managers with unique insights into the functional capacity of study coordinators and support staff. The goal is to optimize efficiency by applying a systematic decision process from performance and productivity trends. In addition to exploring the theory behind the method, this article begins a discussion on the use of this information in clinical research site management. PMID- 29714593 TI - Risk of Cleft Lip and/or Palate Associated With Antiepileptic Drugs: Postmarketing Safety Signal Detection and Evaluation of Information Presented to Prescribers and Patients. AB - BACKGROUND: The aim was to analyze safety data associated with the maternal use of antiepileptic drugs in pregnancy and to assess the risk of cleft lip and/or palate (CL/P) as an outcome in the neonate. A parallel objective was to assess the completeness of the safety information concerning pregnancy exposures in the Summary of Product Characteristics (SmPCs) and the Patient Information (PI) in the USA and the UK. METHODS: We analyzed individual case safety reports of CL/P associated with antiepileptic drugs in the FDA Adverse Event Reporting System. For the antiepileptic drugs with signals (EB05 >= 2), we reviewed Drug Analysis Prints for CL/P cases in the UK Medicines and Healthcare products Regulatory Agency (MHRA). We performed descriptive analyses of relevant SmPCs and PIs in the UK and the USA using a checklist of recommendations collected from the literature. RESULTS: In total 817 CL/P reports were identified for 12 antiepileptic drugs in the FDA Adverse Event Reporting System. Ten of the 12 antiepileptic drugs were associated with 156 CL/P cases in the MHRA Sentinel. Safety information concerning pregnancy was found to be more comprehensive in UK SmPCs than in the US equivalents. CONCLUSIONS: There is statistical disproportionality in individual case safety reports indicative of an increased risk of CL/P with 12 antiepileptic drugs studied. More studies are required to explore the association between in utero exposure to antiepileptic drugs and the risk of CL/P. There are inconsistencies between the UK and US safety labels. CL/P associated with antiepileptic drugs is an important topic and requires providing inclusive, unbiased, up-to-date information to prescribers and women of childbearing age. PMID- 29714594 TI - A Comparative Review of Marketing Authorization Decisions in Switzerland, the EU, and the USA. AB - BACKGROUND: In this study we compared Swissmedic's (SMC's) regulatory marketing authorization decisions to those of the US Food and Drug Administration (FDA) and European drug regulatory authorities (EU). We investigated the overall similarity of the regulatory decisions, approval, and postmarketing withdrawal rates in the 3 jurisdictions. In case regulatory decisions diverged, we analyzed the reasons for rejection of marketing authorization applications (MAAs). METHODS: The study comprises 255 new molecular entity (NME) MAAs assessed by SMC by the EU and FDA between 2005 through 2014. Study parameters included the regulatory decision, postmarketing withdrawal rates, and the official reasons for rejection. RESULTS: Regulatory decisions converged to a high degree among all 3 agencies (between 84% and 90%). SMC's average approval rate (84%) was slightly lower than those of the FDA (87%) and the EU (91%). Postmarketing withdrawal rates were generally low (4% 5%) but were 3 to 5 times higher when decisions among the drug regulatory authorities (DRAs) diverged. SMC's primary grounds for rejection were lack of efficacy (45%) and safety (40%). CONCLUSIONS: The 3 investigated DRAs adhere largely to the same scientific principles and regulatory guidelines; therefore, remaining disparities ought to be considered in a cultural, legal and public health priority context. PMID- 29714595 TI - Pharma Opportunities and Risks Multiply as Regulatory Reform Remakes APAC: Expanded Accelerated Pathways Challenge Developer Value Story, Evidence Collection, and Market Access Strategies. AB - Sweeping reforms in the largest markets of the Asia-Pacific region are transforming the regulatory and commercial landscape for foreign pharmaceutical companies. Japan, South Korea, and China are leading the charge, establishing mechanisms and infrastructure that both reflect and help drive international regulatory convergence and accelerate delivery of needed, innovative products to patients. In this rapidly evolving regulatory and commercial environment, drug developers can benefit from reforms and proliferating accelerated pathway (AP) frameworks, but only with regulatory and evidence-generation strategies tailored to the region. Otherwise, they will confront significant pricing and reimbursement headwinds. Although APAC economies are at different stages of development, they share a common imperative: to balance pharmaceutical innovation with affordability. Despite the complexity of meeting these sometimes conflicting demands, companies that focus on demonstrating and delivering value for money, and that price new treatments reasonably and sustainably, can succeed both for their shareholders and the region's patient population. PMID- 29714596 TI - Use of Proprietary Names by Prescribers When Prescribing Over-the-Counter (OTC) Drug Products. AB - BACKGROUND: To identify if proprietary names are used by health care practitioners when prescribing over-the-counter (OTC) drug products. These findings can inform evaluation of proposed proprietary names for both prescription and OTC drug products. METHODS: QuintilesIMS OTC International Market Tracking (QuintilesIMS OTCIMS) was used to identify top OTC drug products sold to the consumers from US retail store outlets in year 2011. QuintilesIMS's Vector One: National (VONA) was used to identify prescribers' use of proprietary names by examining drug use data from 2003 to 2011 for the top OTC products identified from QuintilesIMS OTCIMS. RESULTS: Of the 29 OTC drug products that have drug utilization data available, the data showed prescribers' use of proprietary names every year from 2003 to 2011 for 24 OTC drug products, and from 2004 to 2011 for 2 OTC drug products. The drug use data showed the use of proprietary name in some years but not all years from 2003 to 2011 for the remaining 3 OTC drug products. For the OTC drug products studied, prescribers used proprietary names for OTC products when prescribing them, and the use of proprietary names on prescriptions can vary during a 9-year period. CONCLUSION: This research identified that prescribers do prescribe OTC drug products using proprietary names. This prescribing practice confirms the need for the pharmaceutical industry, industry consultants, and regulators to consider the proprietary names of OTC drug products when formulating and evaluating new proprietary names for drugs. PMID- 29714597 TI - Youth Experience With Community Pharmacy Services and Their Perceptions Toward Implementation of Medication Therapy Management Services by Community Pharmacists in the Western Region of Saudi Arabia. AB - BACKGROUND: Pharmacists are the part of the health care team who can counsel patients on the most appropriate use of medications. This study aims to measure patients' experience with services provided by community pharmacists and their perceptions toward providing medication therapy management (MTM) services by community pharmacists in the Western Region of Saudi Arabia. In addition, this study aims to measure patients' willingness to pay (WTP) for participating in the MTM program led by community pharmacists. METHODS: Using a cross-sectional research design, a prevalidated questionnaire was developed and posted to respondents through either face-to-face interviews or online social media. All data were analyzed using SPSS, version 22.0, and all alpha values less than 0.05 were considered significant. RESULTS: A total of 953 responses were obtained in this study. Overall, 47.6% of the respondents always buy their medications from different community pharmacies, and 46.1% of respondents said that community pharmacists always respond to all of their questions. In addition, 96% of respondents perceived the MTM program to be beneficial for patient care. Moreover, 70.3% of respondents were willing to register in the MTM program if implemented at community pharmacies. CONCLUSION: Residents in the Western Region of Saudi Arabia highly appreciate the additional values of the MTM program if implemented by community pharmacists. Decisions makers should encourage community pharmacists to plan for MTM services. PMID- 29714598 TI - Comparison of Brief Summary Formats Through a Health Literacy Lens. AB - BACKGROUND: Print pharmaceutical advertisements in the United States require inclusion of a brief summary of side effects, warnings, precautions, and contraindications from the labeling. The full package insert, which sponsors have traditionally used to fulfill the brief summary requirement, does not adhere to health literacy best practices, limiting its value to consumers. This study compared the understandability and usability of brief summaries in 3 formats designed to be more consumer friendly. METHODS: Three brief summary formats were tested: (1) 2-column "Question and Answer"; (2) "Prescription Drug Facts Box," similar to current US over-the-counter drug facts labeling; and (3) "Health Literacy," based on clear communication principles. Researchers evaluated the formats using the Suitability Assessment of Materials (SAM) tool and conducted structured, scripted, one-on-one interviews (usability tests) with participants with estimated low to average education levels. This research was replicated across 2 therapeutic areas (type 2 diabetes and plaque psoriasis). RESULTS: SAM scores showed that the Health Literacy format outperformed the Question and Answer format and the Prescription Drug Facts Box format in both therapeutic areas, with both Health Literacy brief summaries rated on the SAM as "superior." Qualitative usability tests supported the SAM findings, with the Health Literacy format preferred consistently over the Question and Answer format, and more often than not over the Prescription Drug Facts Box format. CONCLUSIONS: Sponsors can employ a user-tested Health Literacy format to improve the understandability and usability of brief summaries with patients. PMID- 29714599 TI - Unresectable and Metastatic Melanoma of the Skin: Literature Review of Clinical Trials and Efficacy Endpoints Since 2000. AB - Advanced and metastatic melanoma has historically been one of the most difficult cancers to treat, with few treatment options. For over 20 years, dacarbazine chemotherapy was the only treatment approved by the US Food and Drug Administration for melanoma. In recent years, breakthroughs have been made in the areas of monoclonal antibody immunotherapies and genetically targeted therapies, leading to FDA approval of several new drugs for metastatic melanoma that have demonstrated improved patient response and survival. In an effort to understand the changing landscape of therapies for advanced and metastatic melanoma, we have reviewed 38 publicly available randomized clinical trials from http://ClinicalTrials.gov in metastatic and unresectable melanoma since the year 2000, to assess developments in the design and conduct of clinical trials over time and to compare the clinical efficacy of old and new therapies. We first present a brief history of FDA approvals of therapies for melanoma, followed by an exploration of trends in the patient population and demographics, eligibility criteria, and statistical methods of clinical trials over time. Next, we compare the efficacy results of old and new study treatments, examining the endpoints of progression-free survival, overall survival, and response rate. Overall, we find that the clinical trial population largely reflected the general population of patients with melanoma in demographic factors, with the exception of patient age. Our findings suggest that the developments of immunotherapies and targeted therapies have improved patient trial results on the discussed endpoints. PMID- 29714600 TI - Baseline Assessment of the Evolving 2017 eClinical Landscape. AB - The volume and diversity of data collected to support each clinical study has increased dramatically in response to the rising scope and complexity of global drug development programs. The Tufts Center for the Study of Drug Development conducted an online survey of 257 unique global companies-77% drug development sponsors and 23% contract service providers-to assess clinical data management practices and experiences. Study results indicate that companies are using an average of 6 different applications to support each clinical study and that companies are collecting a range of data types including that from case report forms, lab procedures, pharmacokinetics, biomarker, outcomes assessment, mobile health, and social media. Companies report that the primary electronic data capture (EDC) is capturing traditional data types but not many of the newer ones. Respondents report spending an average of 68.3 days to build and release a study database, 8.1 days between the patient visit and when that patient's data are entered into the EDC system, and 36.3 days on average to lock the database following the last patient last visit. Average cycle time durations are longer and more variable than those observed ten years ago. Subgroup differences (eg, by company size and company type) and factors contributing to data management cycle time and experience are discussed. PMID- 29714601 TI - Influence of Drug Lag on New Drug Label Revisions. AB - BACKGROUND: Drug lag (DL) in Japan has decreased in the last few years as a result of the globalization of drug development in the past decade, and new molecule entities (NMEs) with short DL are on the rise. The purpose of this study was to investigate the influence of DL on postmarketing safety of NMEs, by comparing the length of DL and the chronological trend of package insert revisions. METHODS: The number of label revisions occurring during 6 years after approval was investigated for 142 NMEs approved between 2000 and 2006. The NMEs were classified by the length of DL (2 years and 4 years), and the label revision trends by each label section and therapeutic categories were analyzed. RESULTS: The cumulative number of level revisions in the "Drug Interactions" and "Clinically Significant Adverse Reactions" sections in the first year after approval in the DL <2 years group was significantly greater than in the DL >=2 years group. In the chemotherapeutic category that showed the shortest DL, the first label revision occurred in 33.3% within the first year and in 66.7% by the second year, and label revisions were performed earlier than in any other therapeutic categories. CONCLUSIONS: These results suggest that the package inserts of NMEs with a shorter DL tend to be revised earlier and more frequently, and it requires more careful monitoring of safety information after product launch. PMID- 29714602 TI - Asthma control and adherence in newly diagnosed young and elderly adult patients with asthma in Turkey. AB - OBJECTIVE: This study aimed to evaluate the factors that affect asthma control and adherence to treatment in newly diagnosed elderly asthmatics in Turkey compared with younger patients. METHODS: This real-life prospective observational cohort study was conducted at 136 centers. A web-based questionnaire was administered to the patients who were followed up for 12 months. RESULTS: Analysis included 1037 young adult asthma patients (age <65 years) and 79 elderly asthma patients (age >=65 years). The percentage of patients with total control in the elderly and young groups were 33.9% and 37.1% at visit 1, 20.0% and 42.1% (p = 0.012) at visit 2, and 50.0% and 49.8% at visit 3, respectively. Adherence to treatment was similar for both groups. Visit compliance was better in the elderly group than in the young group at visit 1 (72.2% vs. 60.8%, p = 0.045), visit 2 (51.9% vs. 34.9%, p = 0.002), and visit 3 (32.9% vs. 19.4%, p = 0.004). Adherence to treatment increased with asthma control in both groups (both p < 0.001) but decreased with the presence of gastritis/ulcer, gastroesophageal reflux, and coronary artery disease in the elderly. CONCLUSIONS: Asthma control and adherence to treatment were similar for the elderly and young asthma patients, though the follow-up rate was lower in young patients. The presence of gastritis/ulcer, gastroesophageal reflux and coronary artery disease had negative impacts on the adherence to treatment in elderly adult patients. PMID- 29714603 TI - Growth differentiation factor 15 in a community-based sample: age-dependent reference limits and prognostic impact. AB - BACKGROUND: Despite the growing body of evidence on growth differentiation factor 15 (GDF-15) reference values for patients with existing cardiovascular disease, limited investigation has been dedicated to characterizing the distribution and prognostic impact of GDF-15 in predominantly healthy populations. Furthermore, current cutoff values for GDF-15 fail to account for the well-documented age dependence of circulating GDF-15. METHODS: From 810 community-dwelling older adults, we selected a group of apparently healthy participants (n = 268). From this sample, circulating GDF-15 was modeled using the generalized additive models for location scale and shape (GAMLSS) to develop age-dependent centile values. Unadjusted and adjusted Cox proportional hazards models were used to assess the association between the derived GDF-15 reference values (expressed as centiles) and all-cause mortality. RESULTS: Smoothed centile curves showed increasing GDF 15 with age in the apparently healthy participants. An approximately three-fold difference was observed between the 95th and 5th GDF-15 centiles across ages. In a median 8.0 years of follow-up, 97 all-cause deaths were observed in 806 participants with eligible values. In unadjusted Cox regression analyses, the hazard ratio (95% CI) for all-cause mortality per 25-unit increase in GDF-15 centile was 1.80 (1.48-2.20) and dichotomized at the 95th centile, >=95th versus <95th, was 3.04 (1.99-4.65). Age-dependent GDF-15 centiles remained a significant predictor of all-cause mortality in all subsequent adjusted models. CONCLUSIONS: Age-dependent GDF-15 centile values developed from a population of apparently healthy older adults are independently predictive of all-cause mortality. Therefore, GDF-15 reference values could be a useful tool for risk-stratification in a clinical setting. ClinicalTrials.gov Identifier: NCT01452178. PMID- 29714606 TI - Developing and Launching a Research Participant Registry. AB - BACKGROUND: A major challenge in clinical research today is the difficulty that studies have in meeting recruitment goals. Up to 48% of studies do not meet accrual goals within the specified timeframe, significantly delaying the progress of projects and the dissemination of findings. This pervasive problem is a recruitment crisis. We developed a representative, ethnically and racially diverse research participant registry in a predominantly rural state with high levels of health care disparities and minority populations. We sought input at each step of development from members of community advisory boards (CABs) across Arkansas. We report how community involvement in the development of the registry was implemented. METHODS: Members of CABs were partners in developing all aspects of the registry website, including the name, content, appearance, educational messages, and testimonials used. Constructs from the Health Belief Model informed the educational messages and supported the intense multimedia campaign used to launch and promote ongoing registrations. Using CAB guidance, community events were held throughout the state of Arkansas at venues with diverse racial and ethnic attendance. RESULTS: From April 1, 2016 to September 1, 2017, 4,002 people registered statewide who match the demographic profile of Arkansas. CONCLUSION: CAB involvement in the registry, multiple cues to action, and face-to-face contact with diverse lay audiences throughout the state were key components of the successful registry launch. PMID- 29714607 TI - Cardiodiabesity and Related Updates. PMID- 29714609 TI - Evolution of Drug Development: Integrating the Patient Perspective Into Early Research. AB - Soaring drug development costs, increasingly stringent regulatory requirements, and demanding market access environments have necessitated that pharmaceutical companies examine their research processes in order to provide novel and meaningful solutions for patients. In this paper, we describe an initiative that aims to incorporate a better appreciation of the exam room experience of both patients and practitioners into the drug development pathway from the earliest point of research. Focusing on 4 core pillars-medical value, patient need, scientific rationale, and market environment-an integrated analytic process is undertaken so as to facilitate early identification of ideal target populations and criteria that will need to be met for successful entry into the treatment continuum. Collaborative interactions with other specialist roles within the organization are also described. It is argued that understanding the unmet medical need and the risks and opportunities inherent in different development scenarios can help direct early research so as to encourage truly transformative health care solutions. PMID- 29714608 TI - A Comparative Study of Medical Device Regulations:: US, Europe, Canada, and Taiwan. AB - The medical device industry is an industry dealing with multiple types of products covering a wide range of applications. As the safety and effectiveness of medical devices are vital to human health, the products must be managed by strict regulations according to the different risk levels. A total product life cycle regulatory system including product design, manufacture, premarket gate keeping, and postmarket monitoring is a common framework for medical device regulations. However, the variety and innovativeness of medical devices are challenging the current regulatory frameworks. Hence, the competent authorities responsible for medical devices worldwide keep renewing their regulatory systems to ensure the safety and effectiveness of medical devices. This review aims to provide an informative review of the regulatory frameworks of medical devices in the United States, Europe, Canada, and Taiwan, with a particular focus on updated regulatory changes in these countries and the current status of global harmonization on medical devices. PMID- 29714610 TI - Industry and Patient Perspectives on Child Participation in Clinical Trials: The Pediatric Assent Initiative Survey Report. AB - BACKGROUND: Obtaining assent from children participating in clinical trials acknowledges autonomy and developmental ability to contribute to the consent process. This critical step in pediatric drug development remains poorly understood, with significant room for improving the clarity, efficiency, and implementation of the assent process. Beyond ethical necessity of informing children about their treatment, the assent process provides the advantages of including children in discussions about their diagnosis and treatment-allowing greater understanding of interventions included in the study. A formalized assent process acknowledges the child as a volunteer and provides a forum for questions and feedback. Legal, cultural, and social differences have historically prevented the development of clear, concise, and accessible materials to ensure children understand the clinical trial design. Published guidelines on obtaining pediatric assent are vague, with many decisions left to local institutional review boards and ethics committees, underscoring the need for collaboratively designed standards. To address this need, 2 surveys were conducted to quantify perspectives on assent in pediatric clinical trials. METHODS: Two digital surveys were circulated in the United States and internationally (October 2014 to January 2015). The first survey targeted children, parents, and/or caregivers. The second polled clinical trial professionals on their organizations' experience and policies regarding pediatric assent. RESULTS: Forty-five respondents completed the child and parent/caregiver survey; 57 respondents completed the industry survey. Respondents from both surveys detailed experiences with clinical trials and the impediments to securing assent, offering potential solutions to attaining assent in pediatric patients. CONCLUSIONS: An important opportunity exists for standardized practices and tools to ensure pediatric patients make well-informed decisions regarding their participation in clinical trials, using materials appropriate to their level of understanding. These tools would establish a baseline standard for the assent process and be made available to researchers, improving their ability to secure assent from young patients. PMID- 29714611 TI - Medical Writing Competency Model - Section 1: Functions, Tasks, and Activities. AB - This article provides Section 1 of the 2017 Edition 2 Medical Writing Competency Model that describes the core work functions and associated tasks and activities related to professional medical writing within the life sciences industry. The functions in the Model are scientific communication strategy; document preparation, development, and finalization; document project management; document template, standard, format, and style development and maintenance; outsourcing, alliance partner, and client management; knowledge, skill, ability, and behavior development and sharing; and process improvement. The full Model also includes Section 2, which covers the knowledge, skills, abilities, and behaviors needed for medical writers to be effective in their roles; Section 2 is presented in a companion article. Regulatory, publication, and other scientific writing as well as management of writing activities are covered. The Model was developed to aid medical writers and managers within the life sciences industry regarding medical writing hiring, training, expectation and goal setting, performance evaluation, career development, retention, and role value sharing to cross-functional partners. PMID- 29714612 TI - Medical Science Liaisons in Real-World Evidence Studies: Experience of AstraZeneca Russia. AB - There is no doubt that real-world evidence studies have the potential to improve and accelerate the development and delivery of safe and cost-effective innovative medicines to patients as well as influence the way we approach health and health care. Real-world evidence studies are a great challenge in terms of development and conduct, so there should be a good collaboration between the study team and clinical sites at all times, resulting eventually in timely and efficient enrollment. Engaging the sites and key external experts as early as possible during feasibility and routine visits, as well as highlighting the science rationale behind AstraZeneca's portfolio at investigator meetings and during medical science liaison (MSL) interactions, can create a positive impact on physician perception of a particular study and prioritization of patient recruitment in such studies. Therefore, we would like to underline the important role of MSLs in the risk-based monitoring setting of real-world evidence studies, with special attention to the studies with complicated patient profiles, tough timelines, and/or seasonal factors. This approach will be used further for other real world evidence projects of AstraZeneca Russia MC to ensure timelines and budget deliverables are met for the generation of high-quality evidence and eventually better health care for all of us. PMID- 29714613 TI - Statistical Interactions in a Clinical Trial. AB - New statisticians entering industry tend to "test statistical interactions" whenever there is a need. However, in many real-world applications, especially in clinical development of new drugs, most interactions need to be estimated, instead of tested. In this manuscript, the distinction between hypothesis testing and estimation will be articulated, and the use of statistical interactions in clinical development programs will be discussed. According to ICH E-9, the treatment by subgroup interaction should not be included in the prespecified primary statistical analysis model. The reasons behind this ICH E-9 recommendation are also clarified in this manuscript. PMID- 29714614 TI - Medical Writing Competency Model - Section 2: Knowledge, Skills, Abilities, and Behaviors. AB - This article provides Section 2 of the 2017 Edition 2 Medical Writing Competency Model that describes the knowledge, skills, abilities, and behaviors that professional medical writers need in order to perform effectively within the life sciences industry. What a medical writer should know, what they should be able to do, and how they should use this knowledge and these skills to facilitate their primary work function is a focus. Regulatory, publication, and other scientific writing as well as management of writing activities are covered. The full Model also includes Section 1, which covers the core work functions and associated tasks and activities related to professional medical writing within the life sciences industry; Section 1 is included in a companion article. The Model was developed to aid medical writers and managers within the life sciences industry regarding medical writing hiring, training, expectation and goal setting, performance evaluation, career development, retention, and role value sharing to cross-functional partners. PMID- 29714615 TI - Adverse Reactions to Radiopharmaceuticals: A Survey Based on Clinical Cases Using Criteria of Systematic Review. AB - Adverse reactions to radiopharmaceuticals are still not reported worldwide. However, the type of reaction may be severe and cause death. A review of the literature was performed using some criteria of a systematic review established by the Cochrane Collaboration. The results showed that there are a large number of adverse reactions to radiopharmaceuticals. Nuclear medicine staff must be aware of the possibility of adverse reaction with radiopharmaceuticals and find time to share this information with the radiopharmacist and the national pharmacovigilance system. PMID- 29714616 TI - Evaluation of Risk Versus Benefit Information in Direct-To-Consumer (DTC) Prescription Drug Television Advertisements. AB - BACKGROUND: The FDA's Presenting Risk Information draft guidance from May 2009 states that the time of risk versus benefit is a factor taken into consideration when evaluating audio and video direct-to-consumer (DTC) broadcasts. The objective of the study is to evaluate the proportion of risk narration on television (TV) advertisements in comparison to the actual proportion of serious adverse effects findings across select therapeutic areas. METHODS: The study reviews prescription drug TV advertisements between the years 2010 and 2015 separated by therapeutic class. Indicators to assess risk versus benefit are as follows: total benefit time, total risk time, total ad time, percentage proportion of risk, and number of serious adverse effects (SAEs) listed in the package insert. The objective is establishing proportion of risk-to-benefit narration across therapeutic areas and the proportion of risk narration compared to the number of SAEs in the package insert. These outcomes will reflect whether TV advertisements abide by the "fair balance" rule and if the time spent on risk narrations is proportional to the number of SAEs across therapeutic areas. RESULTS: An analysis of risk versus benefit showed that there was a vast range of percentage differences in risk versus benefit narration across the products selected. The majority of the products narrated showed a 40% to 60% risk-to benefit ratio. Six out of the 10 products evaluated communicated applicable black box warnings. There was variability among the SAE percentages presented between products. CONCLUSION: Lack of consistency exists between risks versus benefit proportions among different drug products. PMID- 29714617 TI - Pharmacotherapeutic Reports as Tools for Detecting Discrepancies in Continuity of Care. AB - BACKGROUND: The care transition is the time when more medication errors occur. The aim of this study is to analyze the usefulness of a pharmacotherapeutic report model at hospital discharge to prevent medication errors and to simplify pharmacotherapy during a patient's transition from the hospital to primary care. METHODS: Prospective study including patients diagnosed with chronic obstructive pulmonary disease who were admitted to a short-stay unit or an emergency room. Relevant variables were extracted from the patients' clinical history and SPSS software was used to carry out the statistical analysis. Direct costs were also calculated. RESULTS: 79.3% of patients were polymedicated, 15.5% of patients were identified as nonadherent to the treatment, 12.1% were users of alternative therapies, and 10.3% had been prescribed drugs that could be monitored. In 32.8% of the reports, reference was made to the primary care pharmacists with a view to resolve any pharmacotherapeutic discrepancies. A total of 132 discrepancies were identified, the majority being related to medicinal requirements (necessary/unnecessary medication). The major cause of drug-related problems (DRPs) were prescription errors. The drugs that were mainly involved in the onset of DRPs belonged to the R group, and the degree of simplification of the pharmacotherapy was 7.6%. The total cost avoided with the reconciliation was 200?/patient. CONCLUSION: A continuity program was implemented based on the drafting of a pharmacotherapeutic report, which allowed for detecting discrepancies and updating the patients' pharmacotherapeutic history, resulting in financial savings after its implementation. PMID- 29714618 TI - Development of Prescription Drug Information Leaflets: Impact of Cognitive Effort and Patient Involvement on Prescription Medication Information Processing. AB - OBJECTIVE: The objective of this study was to develop a one-page (1-page) prescription drug information leaflet (PILs) and assess their impact on the information processing variables, across 2 levels of patient involvement. METHODS: One-page PILs were developed using cognitive principles to lower mental effort and improve comprehension. An experimental, 3 * 2 repeated measures study was conducted to determine the impact of cognitive effort, manipulated using leaflet type on comprehension across 2 levels (high/low) of patient involvement. Adults (>=18 years) in a university setting in Houston were recruited for the study. Each participant was exposed to 3 different types of prescription drug information leaflet (the current practice, preexisting 1-page text-only, and 1 page PILs) for the 3 drugs (Celebrex, Ventolin HFA, Prezista) for a given involvement scenario. A prevalidated survey instrument was used to measure product knowledge, attitude toward leaflet, and intention to read. RESULTS: Multivariate analysis of variance indicated significant positive effect of cognitive effort, involvement, and their interaction effect across all measured variables. Mean scores for product knowledge, attitude toward leaflet, and intention to read were highest for PILs ( P < .001), indicating that PILs exerted lowest cognitive effort. Univariate and post hoc analysis indicate that product knowledge significantly increases with high involvement. CONCLUSION: Patients reading PILs have higher comprehension compared with the current practice and text-only prototype leaflets evaluated. Higher levels of involvement further improve participant knowledge about the drug, increase their intention to read the leaflet, and change their attitude toward the leaflet. Implementation of PILs would improve information processing for consumers by reducing their cognitive effort. PMID- 29714619 TI - Industry Perspective of Pediatric Drug Development in the United States: Involvement of the European Union Countries. AB - BACKGROUND: Efforts to promote the development of pediatric pharmacotherapy include regulatory frameworks and close collaboration between the US Food and Drug Administration and the European Medicines Agency. We characterized the current status of pediatric clinical trials conducted in the United States by the pharmaceutical industry, focusing on the involvement of the European Union member countries, to clarify the industry perspective. METHODS: Data on US pediatric clinical trials were obtained from ClinicalTrials.gov . Binary regression analysis was performed to identify what factors influence the likelihood of involvement of European Union countries. RESULTS: A total of 633 US pediatric clinical trials that met inclusion criteria were extracted and surveyed. Of these, 206 (32.5%) involved a European Union country site(s). The results of binary regression analysis indicated that attribution of industry, phase, disease area, and age of pediatric participants influenced the likelihood of the involvement of European Union countries in US pediatric clinical trials. Relatively complicated or large pediatric clinical trials, such as phase II and III trials and those that included a broad age range of participants, had a significantly greater likelihood of the involvement of European Union countries ( P < .05). CONCLUSION: Our results suggest that (1) the pharmaceutical industry utilizes regulatory frameworks in making business decisions regarding pediatric clinical trials, (2) disease area affects the involvement of European Union countries, and (3) feasibility of clinical trials is mainly concerned by pharmaceutical industry for pediatric drug development. Additional incentives for high marketability may further motivate pharmaceutical industry to develop pediatric drugs. PMID- 29714620 TI - New Benchmarks Characterizing Growth in Protocol Design Complexity. AB - The Tufts Center for the Study of Drug Development and Medidata Solutions Inc analyzed data from 9737 protocols and 130,601 investigative site contracts associated with these protocols to derive updated benchmarks characterizing protocol complexity. The results of the study indicate that protocol design complexity continues to grow rapidly. Nearly all phase I, II, and III complexity measures associated with protocol execution increased significantly (eg, P < .0001) from 2001-2005 to 2011-2015. These measures include the number of unique and total procedures performed per patient over the course of a study, the site work effort to administer protocol procedures, the number of study volunteer visits, and the total number of procedures performed per study volunteer visit. The total cost per planned study volunteer per visit also increased significantly (eg, P < .0001) as did the total cost per study volunteer across all planned study visits. Phase I protocols remain the most complex and the most demanding to execute. Phase III protocols have seen the most substantial growth in protocol complexity. Phase IV protocols saw only modest increases in executional complexity during the 10-year time horizon. The implications of the study findings are discussed. PMID- 29714621 TI - Comparative User Testing of Australian and UK Over-the-Counter Labels and Leaflets for Diclofenac. AB - BACKGROUND: Limited research has evaluated the consumer usability of written information available with similar over-the-counter (OTC) products in different countries. This study evaluated the usability of labels and leaflets for Australian and UK OTC diclofenac products and explored consumer perspectives on their design, content, usability, and potential improvements. METHODS: Australian and UK OTC diclofenac products were selected for user testing. Demographically matched groups of Australian and UK consumers were recruited to user test each label and leaflet set to determine whether 9 salient clinical messages could be found and understood. Consumer perspectives on the tested label and leaflet were explored using semi-structured interviews as part of user testing. RESULTS: Forty consumers user tested the Voltaren Rapid 25 (Australia) and Voltarol Pain-eze Extra Strength 25-mg tablets (UK) information (10 participants per brand per country). Dosage, maximum daily dose, and contraindications information was found and understood by most (>=9/10 per group), except the Voltaren dosage which was misunderstood by 4/20. However, 12/20 could not locate the maximum duration of continuous use in the Voltaren leaflet. Participants had difficulty determining that another nonsteroidal anti-inflammatory drug could not be used with diclofenac (7/20 and 9/20 understood this in the Voltaren and Voltarol groups, respectively). Suggested label and leaflet improvements included increased font size, bolding/highlighting, and color. CONCLUSION: When evaluated in both countries, not all key clinical information was effectively communicated by information accompanying Australian and UK diclofenac products. Improvements in how information is communicated are needed. PMID- 29714622 TI - Principles and Methods of Statistical Assessment of Abuse-Deterrent Opioids. AB - The FDA Guidance for Industry: Abuse-Deterrent Opioids-Evaluation and Labeling was published in April 2015. Since then questions have been raised regarding how to determine the relative abuse-deterrent (AD) effect of an AD formulation (a test product) compared to an immidiate release (IR) or NonAD extended release (ER) formulation of the same opioid (a positive control) and how to define a responder for responder analysis in clinical abuse potential studies. These questions are reasonable and important for the assessment of AD effect of an AD formulation. This article discusses the principles of the statistical assessment in this area and gives details on how to calculate sample size for the primary comparison in the study and how to perform the statistical analyses. In addition, the article also discusses the reason why the non-inferiority test is not proper for the comparison between a test product and an approved AD version of the same opioid product. Finally, a gatekeeping testing procedure is proposed for this comparison with an example. PMID- 29714623 TI - Multiplication in Egg Yolk and Survival in Egg Albumen of Genetically and Phenotypically Characterized Salmonella Enteritidis Strains. AB - Prompt refrigeration of eggs to prevent the multiplication of Salmonella Enteritidis to high levels during storage is an important practice for reducing the risk of egg-transmitted human illness. The efficacy of egg refrigeration for achieving this goal depends on the interaction among the location of contamination, the ability of contaminant strains to survive or multiply, and the rate at which growth-restricting temperatures are attained. The present study assessed the significance of several characterized genetic and phenotypic properties for the capabilities of 10 Salmonella Enteritidis isolates to multiply rapidly in egg yolk and survive for several days in egg albumen during unrefrigerated (25 degrees C) storage. The growth of small numbers of each Salmonella Enteritidis strain (approximately 101 CFU/mL) inoculated into egg yolk samples was determined after 6 and 24 h of incubation. The survival of larger numbers of Salmonella Enteritidis (approximately 105 CFU/mL) inoculated into albumen samples was determined at 24 and 96 h of incubation. In yolk, the inoculated Salmonella Enteritidis strains multiplied to mean levels of approximately 102.6 CFU/mL after 6 h of incubation and 108.3 CFU/mL after 24 h. In albumen, mean levels of approximately 104.6 CFU/mL Salmonella Enteritidis were maintained through 96 h. The concentrations of the various Salmonella strains after incubation in either yolk or albumen were distributed over relatively narrow ranges of values. Significant ( P < 0.01) differences observed among individual strains suggested that maintenance of the fimbrial gene sefD may have positive genetic selection value by improving fitness to grow inside egg yolk, whereas the antibiotic resistance gene blaTEM-1 tet(A) appeared to have negative genetic selection value by decreasing fitness to survive in egg albumen. PMID- 29714624 TI - Distribution of Radioactive Cesium during Milling and Cooking of Contaminated Buckwheat. AB - To clarify the behavior of radioactive cesium (Cs) in buckwheat grains during milling and cooking processes, parameters such as processing factor (Pf) and food processing retention factor (Fr) were evaluated in two lots of buckwheat grains, R1 and R2, with different concentrations of radioactive Cs. Three milling fractions, the husk, bran, and flour fractions, were obtained using a mill and electric sieve. The radioactive Cs (134Cs + 137Cs) concentrations in husk and bran were higher than that in grain, whereas the concentration in flour was lower than that in grain. Pf values for the flours of R1 and R2 were 0.60 and 0.80, respectively. Fr values for the flours of R1 and R2 were 0.28 and 0.53, respectively. Raw buckwheat noodles (soba) were prepared using a mixture of buckwheat flour and wheat flour according to the typical recipe and were cooked with boiling water for 0.5, 1, and 2 min, followed by rinsing with water. Pf values for the soba boiled for 2 min (optimal for eating) made with R1 and R2 were 0.34 and 0.40, respectively. Fr values for these R1 and R2 samples were 0.55 and 0.66, respectively. Pf and Fr values for soba boiled for different times for both R1 and R2 were less than 0.6 and 0.8, respectively. Thus, buckwheat flour and its product, soba, cooked by boiling, are considered acceptable for human consumption according to the standard limit for radioactive Cs in buckwheat grains. PMID- 29714625 TI - Prevalence and Antimicrobial Resistance Profile of Listeria Species Isolated from Farmed and On-Sale Rainbow Trout ( Oncorhynchus mykiss) in Western Iran. AB - Listeria species are important foodborne pathogens, among which L. monocytogenes and L. ivanovii cause human listeriosis. The purpose of this study was to evaluate the incidence and antimicrobial resistance profiles of Listeria species in farmed and on-sale rainbow trout ( Oncorhynchus mykiss) in Kurdistan province, western Iran. A total of 240 fresh rainbow trout fish (120 samples from farms and 120 samples from retail outlets) were collected and analyzed phenotypically for the presence of Listeria. All Listeria isolates were differentiated with molecular techniques, and L. monocytogenes strains were identified to serotype. The antibiotic susceptibility of all Listeria isolates also was determined. Among the 240 samples, 86 (35.83%) were contaminated with Listeria: 32 samples of farmed fish and 54 samples of on-sale fish. The prevalence among the 240 samples was 9.16% (22 samples) for L. monocytogenes, 6.66% (16 samples) for L. ivanovii, 3.75% (9 samples) for L. welshimeri, 4.99% (12 samples) for L. grayi, 7.5% (18 samples) for L. innocua, and 3.75% (9 samples) for L. seeligeri. The prevalences of the human pathogenic strains L. monocytogenes and L. ivanovii were 4.16% (5 samples) and 14.16% (17 samples) in farmed fish and 5.83% (7 samples) and 7.5% (9 samples) in on-sale fish, respectively. Of the 22 L. monocytogenes isolates, 15, 3, and 4 were identified as serotypes 4b, 1/2a, and 1/2b, respectively. The highest rates of antibiotic resistance among the 86 Listeria isolates was observed against tetracycline (62.79% of all isolates), enrofloxacin (56.97%), and ciprofloxacin (38.37%). Very high resistance was also detected against penicillin (36.04%) and ampicillin (34.88%). These results highlight the potential public health threat posed by fish contaminated with Listeria species, including L. monocytogenes, in the west of Iran. Regular monitoring of Listeria contamination, upgrading of sanitary conditions in the fish industry, and prudent use of antibiotics is strongly recommended in the region. At-risk individuals also should be aware of possible Listeria contamination in these fish. PMID- 29714626 TI - Factors Associated with Enhanced Gross Motor Progress in Children with Cerebral Palsy: A Register-Based Study. AB - AIM: To examine associations between interventions and child characteristics; and enhanced gross motor progress in children with cerebral palsy (CP). METHODS: Prospective cohort study based on 2048 assessments of 442 children (256 boys, 186 girls) aged 2-12 years registered in the Cerebral Palsy Follow-up Program and the Cerebral Palsy Register of Norway. Gross motor progress estimates were based on repeated measures of reference percentiles for the Gross Motor Function Measure (GMFM-66) in a linear mixed model. Mean follow-up time: 2.9 years. RESULTS: Intensive training was the only intervention factor associated with enhanced gross motor progress (mean 3.3 percentiles, 95% CI: 1.0, 5.5 per period of >=3 sessions per week and/or participation in an intensive program). Gross motor function was on average 24.2 percentiles (95% CI: 15.2, 33.2) lower in children with intellectual disability compared with others. Except for eating problems ( 10.5 percentiles 95% CI: -18.5, -2.4) and ankle contractures by age (-1.9 percentiles 95% CI: -3.6, -0.2) no other factors examined were associated with long-term gross motor progress. CONCLUSIONS: Intensive training was associated with enhanced gross motor progress over an average of 2.9 years in children with CP. Intellectual disability was a strong negative prognostic factor. Preventing ankle contractures appears important for gross motor progress. PMID- 29714627 TI - Fibroblast-Matrix Cross-Talk in Idiopathic Pulmonary Fibrosis: Cross-Links at the Crossroads. PMID- 29714628 TI - Collagen Biosynthesis in Pulmonary Fibrosis: Unraveling the Metabolic Web. PMID- 29714630 TI - Does Transforming Growth Factor-beta Induce Persistent Airway Obstruction after Asthma Exacerbations? PMID- 29714629 TI - Rescuing Decrepit Soluble Guanylate Cyclase: A Therapy for Sickle Cell Disease? PMID- 29714631 TI - Peroxisome Proliferator-activated Receptor gamma and Mitochondria: Drivers or Passengers on the Road to Pulmonary Hypertension? PMID- 29714633 TI - May Highlights/Papers by Junior Investigators/NIH News. PMID- 29714632 TI - Splice Wars: The Role of MLCK Isoforms in Ventilation-induced Lung Injury. PMID- 29714634 TI - Excavation of FOSL1 in the Ruins of KRAS-Driven Lung Cancer. PMID- 29714635 TI - Anoctamin-1: A Novel Mitochondrial Ion Channel Regulating Cellular Apoptosis and Proliferation? PMID- 29714636 TI - Extracellular vesicles released in response to respiratory exposures: implications for chronic disease. AB - Extracellular vesicles (EV) are secreted signaling entities that enhance various pathological processes when released in response to cellular stresses. Respiratory exposures such as cigarette smoke and air pollution exert cellular stresses and are associated with an increased risk of several chronic diseases. The aim of this review was to examine the evidence that modifications in EV contribute to respiratory exposure-associated diseases. Publications were searched using PubMed and Google Scholar with the search terms (cigarette smoke OR tobacco smoke OR air pollution OR particulate matter) AND (extracellular vesicles OR exosomes OR microvesicles OR microparticles OR ectosomes). All original research articles were included and reviewed. Fifty articles were identified, most of which investigated the effect of respiratory exposures on EV release in vitro (25) and/or on circulating EV in human plasma (24). The majority of studies based their main observations on the relatively insensitive scatter based flow cytometry of EV (29). EV induced by respiratory exposures were found to modulate inflammation (19), thrombosis (13), endothelial dysfunction (11), tissue remodeling (6), and angiogenesis (3). By influencing these processes, EV may play a key role in the development of cardiovascular diseases and chronic obstructive pulmonary disease and possibly lung cancer and allergic asthma. The current findings warrant additional research with improved methodologies to evaluate the contribution of respiratory exposure-induced EV to disease etiology, as well as their potential as biomarkers of exposure or risk and as novel targets for preventive or therapeutic strategies. PMID- 29714637 TI - Impact of safety training and interventions on training-transfer: targeting migrant construction workers. AB - Despite substantial efforts to improve construction safety training, the accident rate of migrant workers is still high. One of the primary factors contributing to the inefficacy of training includes information delivery gaps during training sessions (knowledge-transfer). In addition, there is insufficient evidence that these training programmes alone are effective enough to enable migrant workers to transfer their skills to the jobsite (training-transfer). This research attempts to identify and evaluate additional interventions to improve the transfer of acquired knowledge to the workplace. For this purpose, this study presents the first known experimental effort to assess the effect of interventions on migrant work groups in a multinational construction project in Qatar. Data analysis reveals that the adoption of training programmes with the inclusion of interventions significantly improves training-transfer. Construction safety experts can leverage the findings of this study to enhance training-transfer by increasing workers' safety performance and hazard identification ability. PMID- 29714638 TI - Mechanisms Behind Pyrroloquinoline Quinone Supplementation on Skeletal Muscle Mitochondrial Biogenesis: Possible Synergistic Effects with Exercise. AB - There is clear evidence that endurance exercise training elicits intramuscular adaptations that can lead to elevations in mitochondrial biogenesis, oxidative capacity, mitochondrial density, and mitochondrial function. Mitochondrial biogenesis is regulated by the activation of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator 1-alpha. This master regulator of mitochondrial biogenesis activates nuclear respiratory factors (NRF 1, NRF-2) and mitochondrial transcription factor A, which enables the expansion of mitochondrial size and transcription of mitochondrial DNA. Pyrroloquinoline quinone (PQQ) has been identified as a novel supplement that is involved in various physiological processes such as redox modulation, cellular energy metabolism, and mitochondrial biogenesis and is a potent antioxidant. Since both exercise and supplemental PQQ have mechanisms associated with mitochondrial biogenesis, it is plausible that a differential additive ergogenic benefit with PQQ can ensue. However, there is a major paucity of research exploring the role of PQQ in conjunction with exercise. In this respect, the purpose of the critical literature review will be to present a comprehensive overview of PQQ and the proposed mechanisms underlying mitochondrial biogenesis. Because exercise can instigate the molecular responses indicative of mitochondrial biogenesis, it is plausible that PQQ and exercise may instigate a synergistic response. Key teaching points * Endurance exercise training enables skeletal muscle adaptations that can induce increases in mitochondrial biogenesis, improve oxidative capacity, mitochondrial density, and mitochondrial function. * Pyrroloquinoline quinone (PQQ) has been identified as a novel supplement that is involved in physiological processes including redox modulation, cellular energy metabolism, mitochondrial biogenesis, and antioxidant potential. * There is emerging evidence to support that PQQ supplementation can upregulate the molecular signaling responses indicative of mitochondrial biogenesis within skeletal muscle. * If both endurance exercise and PQQ supplementation can elicit increases in the molecular responses indicative of mitochondrial biogenesis, it is possible that both PQQ and exercise may instigate a synergistic ergogenic response. * There is a scarcity of research exploring the possible role of PQQ supplementation with concomitant endurance exercise. Therefore, future research is necessary to investigate the ergogenic potential behind PQQ supplementation in conjunction with endurance exercise. PMID- 29714640 TI - Cannabis in End-of-Life Care: Examining Attitudes and Practices of Palliative Care Providers. AB - Medical cannabis research has become quite extensive, with indications ranging from glaucoma to chemotherapy-induced nausea. Despite increased interest in cannabis' potential medical uses, research barriers, cannabis legislation, stigma, and lack of dissemination of data contribute to low adoption for some medical populations. Of interest, cannabis use appears low in palliative care settings, with few guidelines available to palliative care providers. The present study sought to examine the attitudes, beliefs, and practices of palliative care providers regarding the use of cannabis for terminally ill patients. Palliative care providers (N = 426) completed a one-time online survey assessing these attitudes, beliefs, and practices. Results demonstrated that palliative care providers endorse cannabis for a wide range of palliative care symptoms, end-of life care generally, and as an adjuvant medication. Nevertheless, the gap between these beliefs and actual recommendation or prescription appears vast. Many who support the use of cannabis in palliative care do not recommend it as a treatment. These data suggest recommendations for healthcare providers and palliative care organizations. PMID- 29714641 TI - In vitro characterization of cutaneous immunotoxicity of immortalized human keratinocytes (HaCaT) exposed to reactive and disperse textile dyes. AB - Several synthetic dyes are used by textile industry for supplying the market of colored clothes. However, these chemicals have been associated with a variety of adverse human health effects, including textile dermatitis. Thus, there is a growing concern to identify textile dyes potentially as skin immunotoxicants. The aim of this in vitro study was to characterize the immunotoxic potential of reactive (Reactive Green 19 [RG19], Reactive Blue 2 [RB2], Reactive Black 5 [RB5]) and disperse (Disperse Red 1 [DR1]) textile dyes using a dermal cell line. For this purpose, a cell-based approach was conducted with immortalized human keratinocytes (KC) (HaCaT) using selected biomarkers of cutaneous inflammation including modulation of matrix metalloproteinases (MMP), oxidative stress such as reactive oxygen species (ROS) generation, and inflammatory cytokine profile. DR1 was the only dye able to trigger an immune response such as release of IL-12 cytokine, a potent co-stimulator of T helper 1 cell, which may be considered as a skin immunotoxicant. The reactive dyes including RB5 that were previously reported as skin sensitizers failed to induce inflammatory reactions under the conditions tested. The reactive dyes studied may pose a risk to human KC by induction of effects related to modulation of MMP-2 (RB5) and -9 (RB5 and RB2) and generation of ROS (RG19 and RB2). Thus, all these dyes need to be used with caution to avoid undesirable effects to consumers who may be exposed dermally. PMID- 29714642 TI - Women's experiences when unsure about whether or not to have an abortion in the first trimester. AB - Abortion during the first trimester is legal in most Western countries. However, deciding to terminate a pregnancy is a challenging process, and some women arrive at the abortion clinic still not absolutely certain. We explored the experiences of 13 pregnant Norwegian women struggling to finalize their decision, interviewing them before and after their decision. Verification of the pregnancy meant a new reality for the women. They started to consider their readiness, describing the experience as a lonely journey during which their values were challenged. A feeling of existential loneliness dominated the decision-making process and the implementation. PMID- 29714643 TI - Dietary Total Antioxidant Capacity and Cardiovascular Disease Risk Factors: A Systematic Review of Observational Studies. AB - OBJECTIVE: Measurement of dietary total antioxidant capacity (DTAC) is considered a new holistic dietary approach and assesses total antioxidants present in the overall diet. Our aim was to perform a comprehensive review of the literature on the association between DTAC and cardiovascular disease (CVD) risk factors. METHODS: PubMed, Web of Science, and Scopus were used to conduct a comprehensive search for articles published on this topic through September 2017. There was no limit on earliest year of publication. The search was based on the following keywords: dietary total antioxidant capacity, nonenzymatic antioxidant capacity, total radical-trapping antioxidant parameter, ferric reducing ability of plasma, oxygen radical absorbance capacity, Trolox equivalent antioxidant capacity, high density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL C), triglycerides (TG), total cholesterol (TC), waist circumference (WC), insulin resistance, homeostatic model assessment of insulin resistance (HOMA-IR), insulin, obesity, glucose, C-reactive protein (CRP), blood pressure (BP), and body mass index. In total, 16 papers were identified for inclusion in the present systematic review. RESULTS: Most well-designed studies that evaluated associations between DTAC and CVD risk factors showed inverse associations for fasting blood glucose, CRP, BP, and WC and positive associations for HDL-C. However, there was no association between DTAC and LDL-C or TC in any of the studies. Results regarding the association of DTAC with insulin, HOMA-IR, high sensitivity CRP, and TG in the published literature were inconsistent. CONCLUSIONS: Findings indicated a substantial association between high DTAC and most CVD-related risk factors. PMID- 29714644 TI - Functional outcomes in patients with co-occurring traumatic brain injury and spinal cord injury from an inpatient rehabilitation facility's perspective. AB - Objective To examine the occurrence and severity of co-occurring traumatic brain injury (TBI) in persons with traumatic spinal cord injury (SCI), i.e. dual diagnosis (DD), and to describe differences in functional outcomes between persons with DD and SCI only from an inpatient rehabilitation facility (IRF) perspective. Design Retrospective clinical chart review. Setting Acute Midwest SCI inpatient rehabilitation facility. Participants 256 persons age 18-80 years with acute traumatic SCI (AIS A-E, C1-S3 level of injury) from 2002-2012. Interventions Neuroimaging and electronic medical records were reviewed to identify those with co-occurring TBI. Outcomes were then compared between the SCI only and DD groups. Outcome Measures Length of stay (LOS), discharge location and functional independence measures (FIM) Results Forty-one percent of persons with traumatic SCI experienced co-occurring TBI. Rehabilitation LOS for the DD groups did not differ significantly from the SCI only group. Those with Moderate-Severe DD had significantly lower Total admission FIM (P < 0.001), Cognitive admission and discharge FIM (both P < 0.001) and Motor FIM efficiency scores (P = 0.03) compared to those with SCI only and were significantly less likely to discharge home (P = 0.05). Conclusions Persons admitted to IRFs with Moderate-Severe DD compared to those with SCI only are less efficient in obtaining motor skills and may require ongoing rehabilitation to safely return home. It is therefore imperative to initiate early discharge planning and educate rehabilitation team members and families on the additional time and resources necessary to achieve more successful outcomes in those with Moderate-Severe DD. PMID- 29714645 TI - Application of prioritization approaches to optimize environmental monitoring and testing of pharmaceuticals. AB - Pharmaceuticals are ubiquitous in the natural environment with concentrations expected to rise as human population increases. Environmental risk assessments are available for a small portion of pharmaceuticals in use, raising concerns over the potential risks posed by other drugs that have little or no data. With >1900 active pharmaceutical ingredients in use, it would be a major task to test all of the compounds with little or no data. Desk-based prioritization studies provide a potential solution by identifying those substances that are likely to pose the greatest risk to the environment and which, therefore, need to be considered a priority for further study. The aim of this review was to (1) provide an overview of different prioritization exercises performed for pharmaceuticals in the environment and the results obtained; and (2) propose a new holistic risk-based prioritization framework for drugs in the environment. The suggested models to underpin this framework are discussed in terms of validity and applicability. The availability of data required to run the models was assessed and data gaps identified. The implementation of this framework may harmonize pharmaceutical prioritization efforts and ensure that, in the future, experimental resources are focused on molecules, endpoints, and environmental compartments that are biologically relevant. PMID- 29714646 TI - Analysis of the number of flux chamber samples and study area size on the accuracy of emission rate measurements. AB - : Monte Carlo simulations were conducted on a set of flux chamber measurements at a landfill to estimate the relationship between the number of flux chamber samples and study area size on the emission rate measurement accuracy. The spatial variability of flux was addressed in the study by utilizing an existing flux chamber measurement data set that is one of the most dense flux chamber sampling arrays published to date for a landfill. At a probability of 95%, the Monte Carlo simulations indicated that achieving an accuracy within 10% with the flux chamber method is highly unlikely. An accuracy within 20% was achieved for small areas of less than about 0.2 hectares using 220 flux chamber measurements, but achieving this level of accuracy for area emission sources, of similar or greater variability, that are larger than this is highly unlikely. An accuracy within 30% was achieved up to the Full Area of about 0.4 hectares if more than approximately 120 samples were obtained. Even for an accuracy within 50%, at least 40 flux chamber measurements were needed for the Full Area of about 0.4 hectares. Available methods of estimating the number of samples required were compared to the Monte Carlo simulation results. The Monte Carlo simulations indicate that, in general, more samples are required than determined from an existing statistical method, which is a function of the mean and standard deviation of the population. Specifying the number of samples based on a regulatory method results in very poor accuracy. A modification to the statistical method for estimating the number of samples, or for estimating an accuracy for a given probability and number of samples, is proposed. IMPLICATIONS: The flux chamber method is the most widely used method of measuring fugitive emission rates from area sources. However, extrapolation of a set of individual flux chamber samples to a larger area results in area flux measurement values of unknown accuracy. Quantification of the accuracy of the extrapolation of a set of flux chamber measurements would be beneficial for understanding the confidence that can be placed on the measurement results. Guidance as to the appropriate number of flux chamber measurements to achieve a desired level of accuracy would benefit flux chamber method practitioners. PMID- 29714647 TI - The evolving landscape of criteria for evaluating tumor response in the era of cancer immunotherapy: From Karnofsky to iRECIST. AB - The objective response is an important endpoint to evaluate clinical activity of new anticancer drugs. Standardized criteria for evaluating response are needed for comparing results of different trials and represent the basis for advances in cancer therapy. Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 are the most used in clinical practice and in clinical trials; however, they are not able to capture atypical responses seen with immunotherapy drugs. We describe the evolution of response criteria with a special focus on the immune-related criteria. PMID- 29714648 TI - Metastatic breast cancers: Estimates for Italy. AB - PURPOSE: Breast is the leading site of cancer onset and death in Italy. Cases diagnosed in stage IV or that progress in metastatic phase represent a specific and challenging task for oncologists. Estimates on the burden of breast cancer (BC) in stage IV in Italy are not available. METHODS: We applied mortality incidence age-specific ratios measured in the United States in 2013 for BC in stage IV at diagnosis (de novo) or following a previous diagnosis in a localized stage (distant recurrence) to the age-specific BC deaths observed in Italy in 2014. The US mortality-prevalence age-specific ratios were used for estimating de novo and distant recurrence prevalent metastatic BC. RESULTS: In 2014 in Italy, there were 12,330 deaths due to BC. We estimated that in the same year about 3400 BC were newly diagnosed in stage IV (7.1% of all the new cases); moreover, more than 10,000 other BC progressed to stage IV. In addition, in 2014, the overall number of BC in stage IV, whenever diagnosed, was about 37,100 (5.6% of all the estimated prevalent BC). CONCLUSIONS: These estimates quantify, for the first time in Italy, the burden of BC in stage IV, at diagnosis or during the clinical course, providing useful figures for clinicians and policy makers. PMID- 29714649 TI - Personalized therapy based on sequential molecular analysis leads to 30 months of survival in a patient with diffuse unresectable gastric linitis plastica. AB - INTRODUCTION: Diffuse gastric cancer is associated with poor prognosis. We report a patient with metastatic gastric linitis plastica harboring human epidermal growth factor receptor 2 ( HER2) activating mutation and HER2 amplification. CASE DESCRIPTION: The patient received 5-fluorouracil/folinic acid and oxaliplatin combined with trastuzumab/pertuzumab, resulting in disease control for 8 months. Second-line therapy with nivolumab and trastuzumab/pertuzumab was well-tolerated, with macroscopic peritoneal response. Following ovarian progression and surgical resection of ovarian metastases, immunohistochemistry of PD-L1 was negative; proteomics demonstrated normal expression of HER2 and absence of PD-L1, while genomics showed HER2 amplification, suggesting mechanisms of escape to dual HER2 blockade by downregulation of HER2 and to nivolumab by the absence of PD-L1. Based upon this and nonexpression of biomarkers of taxane resistance, therapy was changed to paclitaxel. Two and a half years after diagnosis, the patient is undergoing treatment, with excellent performance status. CONCLUSIONS: Molecular analysis and personalized therapy can help optimize treatment in difficult-to treat cancers. PMID- 29714650 TI - Real-time view of anesthetic solution spread during an ultrasound-guided thoracic paravertebral block. AB - BACKGROUND: Thoracic paravertebral block is a technique for perioperative analgesia in patients undergoing thoracic, chest wall, or breast surgery, or for pain management with rib fractures, which can be performed with or without ultrasound guidance. The ultrasound guidance technique can be used to identify the thoracic paravertebral space, guide needle placement, monitor the spread of local anesthetic (LA) solution, and reduce complications such as pleural puncture and pneumothorax. The possibility of assessing anesthetic spread in real time using ultrasound guidance during paravertebral block offers numerous advantages, including the immediate and accurate identification of the extent of nervous block, with a consequent reduction of LA dose. The real-time visualization of spread may be used to achieve good anesthetic cover by administering the block at a single level, thus reducing complications normally associated with the technique. CASE SUMMARY: This case report describes the use of ultrasound-guided thoracic paravertebral block, at thoracic (T) 4 and 5 levels, in a patient undergoing breast surgery for perioperative analgesia. The authors were able to witness cranial diffusion of LA at T3-T4 in real time, and measure the increase in space between the costotransverse ligament and pleura, as an indication of anesthetic spread, at T2-T3 and T6-T7 levels. CONCLUSIONS: This is the first known case in the literature of direct viewing of LA diffusion in a paravertebral space other than the one in which the block is administered and may open important scenarios for the improvement of anesthesia technique. PMID- 29714651 TI - Hypereosinophilic syndrome preceding a diagnosis of B-cell lymphoma. AB - INTRODUCTION: Hypereosinophilic syndrome (HES) is a rare condition characterized by eosinophilia and organ destruction secondary to eosinophilic infiltration. The coexistence of primary B-cell lymphoma and hypereosinophilic syndrome is extremely rare. We present a case of HES that preceded the diagnosis of diffuse large B-cell lymphoma. CASE REPORT: A 70-year-old man presented with a 3-month history of diarrhea and 30-pound weight loss. Complete blood count showed a white blood cell count of 7452/uL with eosinophils of 42% (absolute eosinophil count 3130). Colonoscopy showed eosinophilic infiltrate in the lamina propria and muscularis mucosa. Bone marrow biopsy showed elevated myeloid: erythroid ratio (6:1), increased mature and immature eosinophilic infiltration (10% of nucleated cells). Molecular studies were negative for Fip1-like1-platelet-derived growth factor receptor alpha (FIP1L1-PDGFRA) translocation and PDGFRB and FGFR mutations, indicating nonclonal eosinophilia. Treatment was initiated with prednisone (1 mg/kg) and hydroxyurea 500 mg twice daily. He responded with complete resolution of symptoms. Five months later, the patient presented with right lower quadrant pain. Abdominal/pelvis computed tomography (CT) showed bulky right inguinal lymphadenopathy and biopsy revealed CD10+ diffuse large B-cell lymphoma (DLBCL). Further staging workup showed the stage to be IIB. He received 6 cycles of chemotherapy and involved field radiation therapy. He achieved complete remission. CONCLUSION: Reviewing the literature indicates only one case of similar presentation with concomitant HES and DLBCL. Eosinophilia is routinely encountered in clinical practice and as such physicians must be aware of the rarer, more malevolent underlying associations of this condition so as to aid early diagnosis and prompt treatment. PMID- 29714652 TI - Real-world evidence in metastatic renal cell carcinoma. AB - Real-world evidence has played an important role in expanding our knowledge on the treatment and prognostication of advanced renal cell carcinoma. This type of data has been particularly helpful in providing a better understanding of groups that are traditionally excluded from randomized controlled trials. The International mRCC Database Consortium (IMDC) represents the largest collection of real-world data on patients with advanced kidney cancer treated with targeted therapies. The IMDC prognostic model has been used to stratify patients in contemporary clinical trials and to provide risk-directed treatment selection in everyday clinical practice. More recently, it has been shown to predict response to first-line combination immunotherapy in the phase III CheckMate 214 clinical trial. In this review, we highlight the real-world evidence associated with the treatment of mRCC. We focus on first-line therapy, as well as second-line and third-line therapeutic options, including novel immuno-oncology agents. We also address the real-world evidence for the use of cytoreductive nephrectomy in advanced renal cell carcinoma in the targeted therapy era. PMID- 29714653 TI - Colorectal cancer and brain metastases: An aggressive disease with a different response to treatment. AB - INTRODUCTION: Brain metastases (BM) are rare in colorectal cancer (CRC) and are associated with a dismal prognosis. This work aims to report the rate of BM in CRC patients treated in a single institution, along with survival and prognostic factors. METHODS: Medical charts for patients with histologically proven CRC were retrospectively reviewed. RESULTS: A total of 538 patients were identified, of whom 33% developed any metastatic disease and 4.4% presented BM. Lung was the most frequently associated metastatic site (in 68% of the cases). The only factor independently associated with BM development was the presence of metastatic disease at the time of initial presentation. The median duration from initial diagnosis to BM development was 38.6 months (SD 29.1 months). Median survival after BM development was 62 days (95% confidence interval [CI] 56-68). Patients diagnosed with BM within 1 year of cancer diagnosis responded significantly better to treatment than those who acquired BM later, with a median survival after BM diagnosis of 261 days versus 61 days, respectively ( p = .002). Patients with BM who received antiangiogenic therapy had an improved median survival compared to those who did not (151 days vs 59 days, p = 0.02; hazard ratio for death 0.29 [95% CI 0.09-0.94]). CONCLUSION: CRC with BM is an aggressive disease resistant to standard treatment and is associated with poor outcomes. Adding antiangiogenic therapy might be of value for those patients. Patients with BM developing early in the disease course might respond better to treatment. PMID- 29714654 TI - Comments on: The social phenomenon of "Christmas Balls," the song of the adolescent patients of the Youth Project. PMID- 29714655 TI - Localized morphea after breast implant for breast cancer: A case report. AB - PURPOSE: Early breast cancer follow-up guidelines for patients who underwent surgery suggest a regular and accurate clinical examination of the breast area, for an early identification of cutaneous or subcutaneous breast cancer relapse. Nonetheless, breast skin lesions arising in patients treated with mastectomy for breast cancer can be caused by several diseases. A series of diagnostic hypotheses should be considered, not only focusing on cutaneous metastasis, but also on dermatologic and systemic diseases. CASE REPORT: In February 2015, a 37 year-old patient underwent a right subcutaneous mastectomy for stage IIA breast cancer. Five months after beginning adjuvant chemotherapy, she noted hyperpigmentation and thickening of the skin on the right breast. Differential diagnosis included local relapse, skin infection, lymphoma, or primary cutaneous disease, and a skin biopsy was performed. The histopathologic specimen showed full-thickness sclerosis, with features of localized morphea. Therapy with clobetasol was prescribed, with progressive resolution of the thickness. The collaboration between many professionals in a multidisciplinary team (oncologist, dermatologist, plastic surgeon, and pathologist) was crucial to achieving the diagnosis. CONCLUSION: In the literature, some articles describe correlation between connective tissue diseases and silicone breast implants, but the pathogenetic mechanisms are unknown. We report a rare case of breast morphea after positioning a silicone implant in a patient who had undergone mastectomy. This clinical report represents an interesting model of multidisciplinary management of a patient with breast cancer who developed an uncommon dermatologic disease. Further studies are needed to clarify the association between silicone implants and breast morphea. PMID- 29714657 TI - On the diagnosis of malignant pleural mesothelioma: A necropsy-based study of 171 cases (1997-2016). AB - BACKGROUND: Malignant pleural mesothelioma (MPM) diagnosis is known to be difficult. We report on the diagnostic elements available in life in an MPM necropsy case series and describe the frequency of non-neoplastic asbestos related diseases as biological exposure indices. METHODS: We reviewed pathologic and clinical records of an unselected series of autopsies (1977-2016) in patients with MPM employed in the Monfalcone shipyards or living with shipyard workers. We assessed the consistency with autopsy results of diagnoses based on, respectively, radiologic, cytologic, and histologic findings, with and without immunophenotyping. RESULTS: Data on 171 cases were available: for 169, autopsy confirmed the MPM diagnosis. In life, 119 cases had histologic confirmation of diagnosis, whereas 7 were negative; all cases without immunophenotypization were autoptic MPMs. Cytology alone had been positive in 18 autoptic MPM cases, negative in 14. Radiologic imaging alone had been positive in another 16, negative in 11. In the 2 cases not confirmed at autopsy, MPM had been suspected by chest computed tomography only. Bilateral pleural plaques were found in 144 and histologic evidence of asbestosis in 62 cases. CONCLUSIONS: Autopsies confirmed 169/171 cases, including cases that would not be considered as certain based on diagnosis in life. Radiologic imaging, cytologic examination of pleural effusions, or both combined had low sensitivity but high positive predictive value: when they are positive, proceeding to thoracoscopy should be justified. MPM has been correctly diagnosed even without immunohistochemistry. The prevalence of pleural plaques and asbestosis was high due to severity of asbestos exposures in these cases. PMID- 29714656 TI - The added value of chemical shift MRI in the preoperative diagnosis of thymolipoma. AB - Thymolipoma is a rare tumor of the thymus. Classic radiologic findings of thymolipoma include fatty masses of the anterior mediastinum in conjunction with the thymus. Differential diagnosis with other more aggressive entities like liposarcoma and teratoma can be challenging. We report a case where chemical shift magnetic resonance imaging helped in the differential diagnosis. PMID- 29714658 TI - Entering the third decade of experience with octreotide LAR in neuroendocrine tumors: A review of current knowledge. AB - Gastroenteropancreatic neuroendocrine tumors (NETs) are a relatively rare group of heterogeneous neoplasms. The most significant advance in therapy of NETs has been the advent of the somatostatin analog octreotide, which represents a cornerstone in their management and dramatically changed the therapeutic landscape. Octreotide long-acting release (LAR) was developed to overcome some of the limitations of octreotide. Several clinical studies, including PROMID and RADIANT-2, have validated the clinical benefits of octreotide LAR in NETs, with tumor shrinkage in about 10% of patients and tumor stabilization in roughly half of cases. While the use of octreotide LAR is well-consolidated in NETs, some open questions remain. These include the use of high-dose octreotide LAR, as there is evidence that higher dose may provide longer disease control, and nonstandard treatment schedules, with administration every 21 days instead of 28 days, as well as their use in combination with targeted agents or peptide receptor radiotherapy in clinical practice. After 3 decades of clinical experience with octreotide LAR, the drug has a well-established safety profile. It is well tolerated and treatment discontinuations due to adverse events are uncommon. One exception is cholelithiasis, which may increase with longer duration of treatment. According to the literature data, octreotide LAR is currently recommended in both functioning and nonfunctioning advanced NETs. This review summarizes the available clinical data with octreotide LAR and also provides future perspectives on its possible uses in patients with NETs. PMID- 29714659 TI - Prostate-specific antigen associates with extensive lymph node invasion in high risk prostate cancer. AB - OBJECTIVE: To evaluate clinical predictors of lymph node invasion (LNI) in patients with high-risk prostate cancer undergoing radical prostatectomy (RP) with extended pelvic lymph node dissection (ePLND). METHODS: A contemporary cohort of 116 patients, who underwent ePLND during RP, was retrospectively evaluated. Patients were classified into 3 groups including cases without LNI (group 1), with 1 to 3 positive nodes (group 2; limited LNI), and with more than 3 positive nodes (group 3; extensive LNI). The multinomial logistic regression model (multivariate analysis) evaluated the risk of LNI. RESULTS: Overall, 30 patients (25.9%) had LNI, which was limited in 17 cases (14.7%) and extensive in 13 subjects (11.2%). Median prostate-specific antigen (PSA) was higher in cases with limited (11.4 ng/mL) or extensive (23.5 ng/mL) LNI than cases without (7.3 ng/mL) and the difference was significant ( p <.0001). Median proportion of biopsy-positive cores was higher in limited (0.64) or extensive (0.54) LNI than cases without (0.34) and the difference was significant ( p < .0001). The distribution of other factors did not show any significant difference among the groups. On multivariate analysis, only higher values of PSA significantly affected the odds of extensive LNI when compared to cases without (odds ratio, 1.054; p = .005); PSA showed a fair discrimination power (area under the curve 0.792). CONCLUSION: PSA was the only independent predictor of extensive LNI and could be an important preoperative factor for stratifying high-risk patients. PMID- 29714660 TI - Second pelvic recurrence of rectal cancer successfully treated with a re reirradiation (3rd radiation course). AB - INTRODUCTION: In case of pelvic recurrence of colorectal cancer, reirradiation of previously irradiated patients may increase the rate of salvage radical resection. Due to the high cumulative dose, one of the main concerns is radiation induced lumbosacral plexopathy. This report describes multiple irradiations of a lesion adjacent to the lumbosacral plexus, using a highly selective technique, which allows optimal sparing of such a critical structure. Case description A 53 year-old woman treated in 2008 for a locally advanced rectal adenocarcinoma with preoperative pelvic irradiation and concomitant chemotherapy followed by surgery had disease recurrence in 2011 and underwent a second course of pelvic radiotherapy. In December 2015, magnetic resonance imaging showed a single local recurrence infiltrating the muscle next to the right lumbosacral plexus and close to the cauda equina. Repeat reirradiation was planned. The total dose deriving from the previous treatment plans was assessed by nonrigid image registration using the dedicated tool implemented in MIM 6.1.7 (MIMvista Corp., Cleveland, OH). The treatment was performed with Cyberknife (Accuray, Sunnyvale, CA) with a schedule of 20 Gy in 5 fractions (4 Gy per fraction). The dose was prescribed to 70% isodose and target coverage was 97%. Two months after the treatment, magnetic resonance imaging showed a decreased signal and stable disease with no change in tumor size. Conclusions This case report suggests that pelvic re-reirradiation might be a possibility in very carefully selected cases of rectal cancer, using high-precision radiation modalities. PMID- 29714661 TI - MEF2C promotes gefitinib resistance in hepatic cancer cells through regulating MIG6 transcription. AB - INTRODUCTION: Mitogen-inducible gene 6 ( MIG6) holds a special position in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance. As MIG6 regulates the activity of EGFR signal pathway negatively, high level of MIG6 can increase the EGFR TKI resistance of cancer cells, and limit the therapeutic action of EGFR TKI, such as gefitinib or erlotinib. Therefore, better understanding of the molecular mechanisms underlying the regulation of EGFR TKI resistance holds great value in cancer therapy. METHODS: In our study, we mainly explored the function of transcription activator, myocyte enhancer factor 2C (MEF2C), on MIG6 expression as well as gefitinib-resistant ability of hepatic cancer cells. RESULTS: Our results indicated that both MEF2C and MIG6 could be upregulated in gefitinib-resistant cancer tissues and cancer cell lines compared with gefitinib-sensitive ones. Chromatin immunoprecipitation assay and dual luciferase assay showed that MEF2C could bind to the MEF2C element in the promoter sequence of MIG6 and promote the transcription of MIG6. This effect increased the gefitinib-resistant ability of cancer cells. Therefore, MEF2C knockdown inhibited the gefitinib resistance and limited the proliferation of hepatic cancer cells in vitro and in vivo, while overexpression of MEF2C showed opposite effect on cancer cell proliferation. CONCLUSION: Our study provides novel insight into the regulation mechanism of MIG6 and suggests potential implications for the therapeutic strategies of gefitinib resistance through inhibiting MEF2C in hepatic cancer cells. PMID- 29714662 TI - Safety of concurrent adjuvant radiotherapy and chemotherapy for locally advanced soft tissue sarcoma. AB - INTRODUCTION:: This retrospective study analyzes the safety and feasibility of concurrent chemoradiotherapy (CRT) in adjuvant treatment of soft tissue sarcoma (STS). METHODS:: A total of 158 patients with STS were retrospectively analyzed. Anthracycline-based computed tomography was performed in high-risk patients. Acute radiotherapy toxicity and chemotherapy-related toxicity were assessed according to the Common Terminology Criteria for Adverse Events 4.0; late radiotherapy toxicity was recorded according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. RESULTS:: Fifty-four (34.2%) patients received CRT. Mean follow up was 5.4 years (range .2-21.1 years). Local DFS-recurrence-free survival, distant DFS-relapse free survival, and overall survival were 79.1%, 76.4%, and 64.6%, respectively, at last follow-up. Leukopenia occurred in 11.4% of patients. Skin acute toxicity developed in 60.1% of patients and determined interruption of radiotherapy treatment in 19 (12%) patients. Nineteen patients (12%) experienced moderate fibrosis (grade 2). Mild and moderate joint stiffness was recorded in 16 (10.1%) patients. Size >=5 cm was the only predictor of local recurrence at multivariate analysis (hazard ratio [HR] 9.65, 95% confidence interval [CI] 1.28-72.83, p = .028). Age and stage resulted as independent distant relapse predictors (HR 4.77, 95% CI 1.81-12.58, p = .002 and HR 4.83, CI 1.41-16.57, p = .012, respectively). At Cox regression univariate analysis, Karnofsky Performance Status, size, and stage were significant survival predictors (HR 2.23, 95% CI 1.02-4.87, p = .045; HR 2.88, 95% CI 1.10-7.52, p = .031; HR 2.59, 95% CI 1.11-6.04, p = .028). CONCLUSIONS:: Concurrent CRT is a well-tolerated treatment option with no additional toxicity compared to exclusive radiotherapy or sequential CRT. PMID- 29714663 TI - Assessment of bowel and anal sphincter function after neoadjuvant chemoradiotherapy in locally advanced rectal cancer. AB - PURPOSE: To report long-term effects on anorectal function and bowel disorders and late toxicity rate of preoperative chemoradiotherapy in patients with locally advanced rectal cancer. METHODS: Between 2000 and 2016, 201 patients treated with different neoadjuvant schedules of chemotherapy and radiotherapy doses were retrospectively analyzed. The Memorial Sloan-Kettering Cancer Center score was used for the evaluation of anal sphincter function. RESULTS: The median follow-up time was 68 months (interquartile range 35-113 months). Radical resection was performed in 188 (93.5%) patients with a pathologic complete response rate of 26.4%. Overall sphincter function resulted excellent in 105 (52.2%) patients, good in 13 (6.5%), fair in 10 (5.0%), and poor (incontinence) in 40 (19.9%), with a persistent stoma rate of 16.4%. A further evaluation on 194 patients showed an improvement of sphincter function after 2 years in 11.9% of them. Seventy-three patients presenting stoma or poor sphincter function were re-evaluated for quality of life (QoL) indexes. Twenty-one (29%), 19 (26%), and 24 (33%) of them declared some variations concerning well-being, fatigue, and ability to perform daily activities. The 5-year overall survival, disease-free survival, and local recurrence rates were 88.0% +/- 2.6%, 86.3% +/- 2.5%, and 94.6% +/- 1.9%, respectively. CONCLUSIONS: In our study, neoadjuvant chemoradiotherapy was associated with good results in terms of sphincter function, late toxicities, and QoL indexes. A routine use of assessment scales could contribute to a better selection of patients with increased risk of developing functional disorders who could benefit from neoadjuvant therapy. PMID- 29714664 TI - Predictive value of dual-time 18F-FDG PET/CT to distinguish primary lung and metastatic adenocarcinoma in solitary pulmonary nodule. AB - AIMS AND BACKGROUND: Distinction between primary lung adenocarcinoma and metastatic adenocarcinoma from extrapulmonary origin in solitary pulmonary nodule (SPN) is crucial for cancer treatment. We investigated the predictive role of dual-time-point 18F-FDG PET/CT to distinguish primary and metastatic lung adenocarcinoma in SPN. METHODS: A total of 96 consecutive patients with newly diagnosed SPN and biopsy-proven adenocarcinoma were enrolled in this study, retrospectively (54 male; 42 female; age 59.68 +/- 8.2 years). They all underwent dual-time-point 18F-FDG PET/CT at 60 minutes (early) for whole body and 120 minutes (delayed) for chest region after FDG injection. Maximum standardized uptake values (early SUVmax and delayed SUVmax) and retention index (RI) were acquired for analysis. Final pathology results were confirmed by surgical specimens. RESULTS: Metastatic adenocarcinoma showed significantly higher early SUVmax, delayed SUVmax, and RI compared to primary lung adenocarcinoma. Delayed SUVmax and RI presented superior diagnostic performance for prediction of metastatic adenocarcinoma than early 18F-FDG PET/CT. Among metastatic adenocarcinoma, metastasis from colorectal origin showed significantly higher RI than from other origins. In addition, RI significantly predicted metastatic adenocarcinoma from colorectal cancer than early or delayed SUVmax. CONCLUSIONS: Dual-timepoint 18F-FDG PET/CT can be useful to distinguish primary and metastatic lung adenocarcinoma in SPN. Furthermore, it may also be useful to predict metastatic adenocarcinoma from colorectal origin. PMID- 29714665 TI - Stereotactic body radiotherapy for lung oligometastases: Literature review according to PICO criteria. AB - Exhaustive criteria and definitive data to identify the ideal lung oligometastatic patient as a candidate for stereotactic body radiotherapy (SBRT) are lacking. Three distinct cohorts of oligometastatic patients could be distinguished: (1) patients with upfront diagnosis of oligometastases (synchronous or metachronous); (2) patients with oligorecurrent disease in terms of relapsed oligometastatic phase; (3) oligoprogressive patients after cytoreductive treatment. The aim of the present review is to analyze available data concerning the efficacy/safety of SBRT for oligometastatic/oligoprogressive/oligorecurrent lung metastases. PMID- 29714666 TI - Relationships among unmet needs, depression, and anxiety in non-advanced cancer patients. AB - INTRODUCTION: In oncology settings, less attention is given to patients' unmet needs and to existential and emotional distress compared to physical symptoms. We aimed to evaluate correlations between unmet needs and emotional distress (self reported anxiety and depression) in a consecutive cohort of cancer patients. The influence of sociodemographic and clinical factors was also considered. METHODS: A total of 300 patients with cancer recruited from an outpatient Supportive Care Unit of a Comprehensive Cancer Centre completed the Need Evaluation Questionnaire and the Edmonton Symptom Assessment System (ESAS). Unmet needs covered 5 distinct domains (informational, care/assistance, relational, psychoemotional, and material). RESULTS: After removal of missing data, we analyzed data from 258 patients. Need for better information on future health concerns (43%), for better services from the hospital (42%), and to speak with individuals in the same condition (32%) were the most frequently reported as unmet. Based on the ESAS, 27.2% and 17.5% of patients, respectively, had a score of anxiety or depression >3 and needed further examination for psychological distress. Female patients had significantly higher scores for anxiety ( p < .001) and depression ( p = .008) compared to male patients. Unmet needs were significantly correlated with both anxiety ( rs = .283) and depression ( rs = .284). Previous referral to a psychologist was significantly associated with depression scores ( p = .015). Results were confirmed by multiple regression analysis. CONCLUSIONS: Screening for unmet needs while also considering sociodemographic and clinical factors allows early identification of cancer patients with emotional distress. Doing so will enable optimal management of psychological patient-reported outcomes in oncology settings. PMID- 29714667 TI - Long-term outcomes after radiosurgery for glomus jugulare tumors. AB - AIMS AND BACKGROUND: The treatment of glomus jugulare tumors (GJT) remains controversial due to high morbidity. Historically, these tumors have primarily been managed surgically. The purpose of this retrospective review was to assess the tumor and clinical control rates as well as long-term toxicity of GJT treated with radiosurgery. METHODS: Between 1993 and 2014, 30 patients with GJT (31 tumors) were managed with radiosurgery. Twenty-one patients were female and the median age was 59 years. Twenty-eight patients (93%) were treated with radiosurgery, typically at 14 Gy ( n = 26), and 2 patients (7%) with stereotactic radiosurgery. Sixteen cases (52%) had undergone prior surgery. RESULTS: The mean follow-up was 4.6 years (range 1.5-12). Crude overall survival, tumor control, clinical control, and long-term grade 1 toxicity rates were 97%, 97%, 97%, and 13% (4/30), respectively. No statistically significant risk factor was associated with lower tumor control in our series. Univariate analysis showed a statistically significant association between patients having 1 cranial nerve (CN) involvement before radiosurgery and a higher risk of lack of improvement of symptoms (odds ratio 5.24, 95% confidence interval 1.06-25.97, p = .043). CONCLUSIONS: Radiosurgery is an effective and safe treatment modality for GJT. Patients having 1 CN involvement before radiosurgery show a higher risk of lack of improvement of symptoms. PMID- 29714669 TI - Blood neutrophil-to-lymphocyte ratio is associated with prognosis in advanced gastrointestinal stromal tumors treated with imatinib. AB - INTRODUCTION: Neutrophil-to-lymphocyte ratio (NLR) was shown to be prognostic in several solid malignancies. There are limited data about predictive/prognostic value of NLR during targeted therapy of patients with advanced gastrointestinal stromal tumors (GIST). The aim of this study was to asses a clinical value of this ratio in patients with advanced GIST. METHODS: Between 2001 and 2016, 385 patients with metastatic/unresectable GIST treated initially with imatinib were included in the analysis. In all patients, the NLR was assessed at the baseline, after 3 months of treatment, and upon disease progression (or last observation). The cutoff values for NLR were set at 2.7 and 5.4. Kaplan-Meier survival probability estimation with log-rank test and Cox proportional hazards model were used for analysis. RESULTS: Median progression-free survival (PFS) on imatinib treatment was 44.8 months, 5-year rate 43%; median overall survival (OS) 87.2 months, 10-year rate 36.3%. NLR >2.7 at baseline was significantly associated with poorer OS and PFS: median OS was 89.3 months (95% confidence interval [CI] 80.2-115) for NLR ratio <=2.7 vs 59.4 months (95% CI 48.6-82) for NLR >2.7 ( p < .001); median PFS was 59.4 vs 32.7 ( p < .001), respectively. In multivariate model adjusted for mitotic index and driver mutation in the tumor ( KIT exon 11 mutation versus other), NLR ratio was proven to be statistically significant (hazard ratio 1.09; 95% CI 1.01-1.19; p = .030). Among patients with disease progression, NLR >2.7 assessed at the third month of treatment was linked with significantly shorter median time to progression (7.5 vs 19 months). CONCLUSIONS: Our results demonstrate the usefulness of NLR as a prognostic and predictive marker as well as a marker for treatment monitoring in patients with advanced GIST treated with imatinib. PMID- 29714668 TI - 223Ra-chloride therapy in men with hormone-refractory prostate cancer and skeletal metastases: Real-world experience. AB - BACKGROUND: Radium-223 (223Ra) chloride, an alpha emitter, has been shown to improve overall survival (OS) and pain control, and to delay skeletal-related events, in patients with castration-resistant prostate cancer (CRPC) and bone metastases. Our retrospective observational study presents the first Italian experience on the efficacy and safety of 223Ra therapy in routine clinical practice. METHODS: A total of 83 patients with metastatic CRPC were treated with 223Ra at 3 Italian centers between August 2013 and August 2016. 223Ra-chloride (55 kBq/kg) was administered every 4 weeks for a total of 6 cycles. Primary endpoints were OS and progression-free survival (PFS). Secondary endpoints included toxicity, pain evaluation using numeric rating scale (NRS), symptomatic skeletal-related events and biomarkers response. RESULTS: Patients had a median age of 75 (range 53-89) years. The majority of men showed a Gleason score of 7, 8, or 9. Forty-one patients completed 6 treatment cycles; 33 stopped treatment before completing 6 cycles. Nine were still receiving therapy at the time of data collection. At the end of therapy, NRS pain scores significantly improved ( p < .000001). OS was a mean of 10.1 months, while median OS had not been attained. According to Kaplan-Meier estimation, OS and PFS were 17.5 and 7.7 months, respectively. There was a significant correlation between OS and PFS with the number of 223Ra cycles; patients receiving all 6 cycles experienced the major benefit from the therapy. 223Ra was well-tolerated. CONCLUSIONS: 223Ra alpha therapy is an important therapeutic option for men with CRPC and symptomatic skeletal metastases. PMID- 29714670 TI - Prognostic role of PIK3CA and TP53 in human papillomavirus-negative oropharyngeal cancers. AB - BACKGROUND: Human papilloma virus (HPV)-negative oropharyngeal squamous cell carcinomas (OPCs) have a poorer prognosis and best management is an unmet need. We studied the prognostic role of epidermal growth factor receptor (EGFR) and PIK3CA amplifications and TP53 functional status. METHODS: Between 1992 and 2000, 90 consecutive patients with OPCs were treated with surgery, followed by radiotherapy in case of high-risk pathologic features. Of those, 73 cases were HPV-negative and therefore were selected for molecular analysis ( PIK3CA and EGFR fluorescent in situ hybridization [FISH] analysis and TP53 mutation analysis). RESULTS: FISH analyses of EGFR and PIK3CA were successfully conducted on 69 and 63 of 73 tumor samples, respectively. EGFR alterations were detected in 43% of patients but just 7% showed amplification. Seven cases (11%) carried PIK3CA amplification and 18 (29%) gene gain or high polysomy. TP53 was detected as nonfunctional in 24 of 67 (36%) successfully analyzed cases. Both univariable and multivariable analysis showed statistically significantly worse disease-free survival (DFS) for patients with PIK3CA disomy compared to those with gene gain or high polysomy. No differences in overall survival or DFS for EGFR and TP53 alteration were evident. The combined evaluation of PIK3CA and TP53 showed that PIK3CA gene copy number gain separated a population with better outcome, defining an overall worse prognosis population (disomy) now clearly further divided according to TP53 functional status. CONCLUSION: PIK3CA gene copy number increase is associated with a favorable clinical outcome in HPV-negative OPCs treated with surgery +/- postoperative radiotherapy. In patients without PIK3CA alteration, TP53 nonfunctional mutations are associated with poor prognosis. PMID- 29714671 TI - Dynamics of submaximal effort soccer instep kicking. AB - During a soccer match, players are often required to control the ball velocity of a kick. However, little information is available for the fundamental qualities associated with kicking at various effort levels. We aimed to illustrate segmental dynamics of the kicking leg during soccer instep kicking at submaximal efforts. The instep kicking motion of eight experienced university soccer players (height: 172.4 +/- 4.6 cm, mass: 63.3 +/- 5.2 kg) at 50, 75 and 100% effort levels were recorded by a motion capture system (500 Hz), while resultant ball velocities were monitored using a pair of photocells. Between the three effort levels, kinetic adjustments were clearly identified in both proximal and distal segments with significantly different (large effect sizes) angular impulses due to resultant joint and interaction moments. Also, players tended to hit an off centre point on the ball using a more medial contact point on the foot and with the foot in a less upright position in lower effort levels. These results suggested that players control their leg swing in a context of a proximal to distal segmental sequential system and add some fine-tuning of the resultant ball velocity by changing the manner of ball impact. PMID- 29714672 TI - Milieu interieur: Defining the boundaries of a healthy immune response for improved vaccination strategies. AB - Immune responses in human populations are highly variable, with this variability presenting challenges for vaccine design. As such a better understanding of the factors that determine this variability will help in the development of precision vaccination strategies. The Milieu Interieur consortium was established to address this challenge through a definition of the normal boundaries of a healthy immune response, and the characterization of their genetic and environmental determinants. To do this we have implemented standardized tools for monitoring functional immune responses at the proteomic and transcriptional level, which have been applied to a 1,000 healthy donor cohort. This approach has recently allowed us to quantify the extent of genetic control of cellular variability and transcriptional responses to infection. Initial findings on the influence of age, sex, and genetics may already be included in considerations for improved vaccine development, and ongoing analysis will further define the factors behind inter individual variability in diverse immune responses. This approach will help to guide the development of the next generation of vaccines that will take into account differences in populations and eventually individuals. PMID- 29714673 TI - Measurement of Whole-Brain and Gray Matter Atrophy in Multiple Sclerosis: Assessment with MR Imaging. AB - Purpose To compare available methods for whole-brain and gray matter (GM) atrophy estimation in multiple sclerosis (MS) in terms of repeatability (same magnetic resonance [MR] imaging unit) and reproducibility (different system/field strength) for their potential clinical applications. Materials and Methods The softwares ANTs-v1.9, CIVET-v2.1, FSL-SIENAX/SIENA-5.0.1, Icometrix-MSmetrix-1.7, and SPM-v12 were compared. This retrospective study, performed between March 2015 and March 2017, collected data from (a) eight simulated MR images and longitudinal data (2 weeks) from 10 healthy control subjects to assess the cross sectional and longitudinal accuracy of atrophy measures, (b) test-retest MR images in 29 patients with MS acquired within the same day at different imaging unit field strengths/manufacturers to evaluate precision, and (c) longitudinal data (1 year) in 24 patients with MS for the agreement between methods. Tissue segmentation, image registration, and white matter (WM) lesion filling were also evaluated. Multiple paired t tests were used for comparisons. Results High values of accuracy (0.87-0.97) for whole-brain and GM volumes were found, with the lowest values for MSmetrix. ANTs showed the lowest mean error (0.02%) for whole brain atrophy in healthy control subjects, with a coefficient of variation of 0.5%. SPM showed the smallest mean error (0.07%) and coefficient of variation (0.08%) for GM atrophy. Globally, good repeatability (P > .05) but poor reproducibility (P < .05) were found for all methods. WM lesion filling technique mainly affected ANTs, MSmetrix, and SPM results (P < .05). Conclusion From this comparison, it would be possible to select a software for atrophy measurement, depending on the requirements of the application (research center, clinical trial) and its goal (accuracy and repeatability or reproducibility). An improved reproducibility is required for clinical application. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29714674 TI - MR Imaging Features May Help Predict Gene Expression in Retinoblastoma, with Possible Therapeutic Implications. PMID- 29714675 TI - Whole-Body MR Angiography: Assessing the Global Burden of Cardiovascular Disease. PMID- 29714676 TI - Perfusion MR Imaging of Breast Cancer: Insights Using "Habitat Imaging". PMID- 29714677 TI - Monitoring Cerebral Perfusion Changes after Revascularization in Patients with Moyamoya Disease by Using Arterial Spin-labeling MR Imaging. AB - Purpose To determine whether arterial spin-labeling (ASL) magnetic resonance (MR) imaging could be used to identify changes in cerebral blood flow (CBF), collateral blood flow, and anastomosis site patency after revascularization in patients with moyamoya disease. Materials and Methods This retrospective study was conducted in 145 patients with moyamoya disease who underwent middle cerebral artery (MCA)-superficial temporal artery anastomosis. Preoperative, early postoperative, and late postoperative ASL and digital subtraction angiography images were analyzed. In the MCA territory, absolute CBF (hereafter, CBFMCA) and normalized CBF values adjusted to nonanastomosis side (hereafter, nCBFMCA) and to cerebellum (hereafter, nCBFCbll) were calculated. Collateral grading in the MCA territory was assessed according to Alberta Stroke Program Early CT Score methodology, and anastomosis site patency were also assessed. Changes in CBF were compared by using one-way analysis of variance with Bonferroni correction for multiple comparisons. Intermodality agreement was determined by kappa statistics. Results Significant increases in CBFMCA, nCBFMCA, and nCBFCbll were found after revascularization (preoperative and postoperative values of CBFMCA, 35.2 mL/100 g per minute +/- 7.8 [mean +/- standard deviation] and 51.5 mL/100 g per minute +/- 12.0; nCBFMCA, 0.73 mL/100 g per minute +/- 0.14 and 1.01 mL/100 g per minute +/- 0.18; nCBFCbll, 0.74 mL/100 g per minute +/- 0.12 and 1.12 mL/100 g per minute +/ 0.16; all P < .001). Agreements for collateral grading and anastomosis patency between ASL MR imaging and digital subtraction angiography were moderate to good, with weighted kappa values of 0.77 (95% confidence interval: 0.73, 0.81) and 0.57 (95% confidence interval: 0.37, 0.76), respectively. Conclusion ASL MR imaging can be used to identify perfusion changes in patients with moyamoya disease after revascularization as a noninvasive monitoring tool. PMID- 29714678 TI - Thyroid Nodules in Pediatric Patients: Sonographic Characteristics and Likelihood of Cancer. AB - Purpose To determine the relationship between demographic and sonographic characteristics of thyroid nodules and malignancy in a pediatric population. Materials and Methods All thyroid nodules in patients younger than 19 years that underwent ultrasound (US)-guided fine-needle aspiration biopsy between January 2004 and July 2017 were retrospectively identified. Age, sex, and background appearance of the thyroid gland were recorded for each patient, and sonographic characteristics and pathologic diagnosis were recorded for each nodule. Demographic and sonographic characteristics were assessed to determine which were associated with malignancy. Categorical and continuous variables and interobserver variability were assessed. Results A total of 404 nodules in 314 patients (82.8% female) (age range, 2-18 years; mean age, 14.9 years) were analyzed. A total of 77 nodules (19.1%) were malignant, the majority of which were papillary thyroid carcinoma (n = 68 [88.3%]). The likelihood of malignancy did not differ between boys and girls (27.8% vs 22.7%, P = .64), nor did it differ between prepubertal and pubertal patients (18.8% vs 19.1%, P > .99). The cancer rate in patients with a solitary nodule was higher than that in patients with multiple nodules (29.4% vs 14.2%, P = .003). Sonographic characteristics associated with malignant nodules included larger size, solid parenchyma, taller than-wide shape, presence of speckled calcifications, lack of a smooth margin, and presence of abnormal lymph nodes. Interobserver variability for assessment of sonographic characteristics ranged from moderate to very strong. Conclusion In children with thyroid nodules, solitary nodules, larger nodule size, solid parenchyma, taller-than-wide shape, speckled calcifications, irregular margins, and abnormal lymph nodes raise concern for malignancy. PMID- 29714679 TI - MR Imaging Features of Retinoblastoma: Association with Gene Expression Profiles. AB - Purpose To identify associations between magnetic resonance (MR) imaging features and gene expression in retinoblastoma. Materials and Methods A retinoblastoma MR imaging atlas was validated by using anonymized MR images from referral centers in Essen, Germany, and Paris, France. Images were from 39 patients with retinoblastoma (16 male and 18 female patients [the sex in five patients was unknown]; age range, 5-90 months; inclusion criterion: pretreatment MR imaging). This atlas was used to compare MR imaging features with genome-wide messenger RNA (mRNA) expression data from 60 consecutive patients obtained from 1995 to 2012 (35 male patients [58%]; age range, 2-69 months; inclusion criteria: pretreatment MR imaging, genome-wide mRNA expression data available). Imaging pathway associations were analyzed by means of gene enrichment. In addition, imaging features were compared with a predefined gene expression signature of photoreceptorness. Statistical analysis was performed with generalized linear modeling of radiology traits on normalized log2-transformed expression values. P values were corrected for multiple hypothesis testing. Results Radiogenomic analysis revealed 1336 differentially expressed genes for qualitative imaging features (threshold P = .05 after multiple hypothesis correction). Loss of photoreceptorness gene expression correlated with advanced stage imaging features, including multiple lesions (P = .03) and greater eye size (P < .001). The number of lesions on MR images was associated with expression of MYCN (P = .04). A newly defined radiophenotype of diffuse-growing, plaque-shaped, multifocal tumors displayed overexpression of SERTAD3 (P = .003, P = .049, and P = .06, respectively), a protein that stimulates cell growth by activating the E2F network. Conclusion Radiogenomic biomarkers can potentially help predict molecular features, such as photoreceptorness loss, that indicate tumor progression. Results imply a possible role for radiogenomics in future staging and treatment decision making in retinoblastoma. PMID- 29714680 TI - Intratumoral Spatial Heterogeneity at Perfusion MR Imaging Predicts Recurrence free Survival in Locally Advanced Breast Cancer Treated with Neoadjuvant Chemotherapy. AB - Purpose To characterize intratumoral spatial heterogeneity at perfusion magnetic resonance (MR) imaging and investigate intratumoral heterogeneity as a predictor of recurrence-free survival (RFS) in breast cancer. Materials and Methods In this retrospective study, a discovery cohort (n = 60) and a multicenter validation cohort (n = 186) were analyzed. Each tumor was divided into multiple spatially segregated, phenotypically consistent subregions on the basis of perfusion MR imaging parameters. The authors first defined a multiregional spatial interaction (MSI) matrix and then, based on this matrix, calculated 22 image features. A network strategy was used to integrate all image features and classify patients into different risk groups. The prognostic value of imaging-based stratification was evaluated in relation to clinical-pathologic factors with multivariable Cox regression. Results Three intratumoral subregions with high, intermediate, and low MR perfusion were identified and showed high consistency between the two cohorts. Patients in both cohorts were stratified according to network analysis of multiregional image features regarding RFS (log-rank test, P = .002 for both). Aggressive tumors were associated with a larger volume of the poorly perfused subregion as well as interaction between poorly and moderately perfused subregions and surrounding parenchyma. At multivariable analysis, the proposed MSI-based marker was independently associated with RFS (hazard ratio: 3.42; 95% confidence interval: 1.55, 7.57; P = .002) adjusting for age, estrogen receptor (ER) status, progesterone receptor status, human epidermal growth factor receptor type 2 (HER2) status, tumor volume, and pathologic complete response (pCR). Furthermore, imaging helped stratify patients for RFS within the ER-positive and HER2-positive subgroups (log-rank test, P = .007 and .004) and among patients without pCR after neoadjuvant chemotherapy (log-rank test, P = .003). Conclusion Breast cancer consists of multiple spatially distinct subregions. Imaging heterogeneity is an independent prognostic factor beyond traditional risk predictors. PMID- 29714681 TI - Prevalence and Distribution of Atherosclerosis in a Low- to Intermediate-Risk Population: Assessment with Whole-Body MR Angiography. AB - Purpose To quantify the burden and distribution of asymptomatic atherosclerosis in a population with a low to intermediate risk of cardiovascular disease. Materials and Methods Between June 2008 and February 2013, 1528 participants with 10-year risk of cardiovascular disease less than 20% were prospectively enrolled. They underwent whole-body magnetic resonance (MR) angiography at 3.0 T by using a two-injection, four-station acquisition technique. Thirty-one arterial segments were scored according to maximum stenosis. Scores were summed and normalized for the number of assessable arterial segments to provide a standardized atheroma score (SAS). Multiple linear regression was performed to assess effects of risk factors on atheroma burden. Results A total of 1513 participants (577 [37.9%] men; median age, 53.5 years; range, 40-83 years) completed the study protocol. Among 46 903 potentially analyzable segments, 46 601 (99.4%) were interpretable. Among these, 2468 segments (5%) demonstrated stenoses, of which 1649 (3.5%) showed stenosis less than 50% and 484 (1.0%) showed stenosis greater than or equal to 50%. Vascular stenoses were distributed throughout the body with no localized distribution. Seven hundred forty-seven (49.4%) participants had at least one stenotic vessel, and 408 (27.0%) participants had multiple stenotic vessels. At multivariable linear regression, SAS correlated with age (B = 3.4; 95% confidence interval: 2.61, 4.20), heart rate (B = 1.23; 95% confidence interval: 0.51, 1.95), systolic blood pressure (B = 0.02; 95% confidence interval: 0.01, 0.03), smoking status (B = 0.79; 95% confidence interval: 0.44, 1.15), and socioeconomic status (B = -0.06; 95% confidence interval: -0.10, 0.02) (P < .01 for all). Conclusion Whole-body MR angiography identifies early vascular disease at a population level. Although disease prevalence is low on a per-vessel level, vascular disease is common on a per-participant level, even in this low- to intermediate-risk cohort. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29714682 TI - Postmortem CT Angiography Compared with Autopsy: A Forensic Multicenter Study. AB - Purpose To determine if postmortem computed tomography (CT) and postmortem CT angiography help to detect more lesions than autopsy in postmortem examinations, to evaluate the strengths and weaknesses of each method, and to define their indications. Materials and Methods Postmortem CT angiography was performed on 500 human corpses and followed by conventional autopsy. Nine centers were involved. All CT images were read by an experienced team including one forensic pathologist and one radiologist, blinded to the autopsy results. All findings were recorded for each method and categorized by anatomic structure (bone, organ parenchyma, soft tissue, and vascular) and relative importance in the forensic case (essential, useful, and unimportant). Results Among 18 654 findings, autopsies helped to identify 61.3% (11 433 of 18 654), postmortem CT helped to identify 76.0% (14 179 of 18 654), and postmortem CT angiography helped to identify 89.9% (16 780 of 18 654; P < .001). Postmortem CT angiography was superior to autopsy, especially at helping to identify essential skeletal lesions (96.1% [625 of 650] vs 65.4% [425 of 650], respectively; P < .001) and vascular lesions (93.5% [938 of 1003] vs 65.3% [655 of 1003], respectively; P < .001). Among the forensically essential findings, 23.4% (1029 of 4393) were not detected at autopsy, while only 9.7% (428 of 4393) were missed at postmortem CT angiography (P < .001). The best results were obtained when postmortem CT angiography was combined with autopsy. Conclusion Postmortem CT and postmortem CT angiography and autopsy each detect important lesions not detected by the other method. More lesions were identified by combining postmortem CT angiography and autopsy, which may increase the quality of postmortem diagnosis. Online supplemental material is available for this article. PMID- 29714683 TI - Abdominopelvic 1.5-T and 3.0-T MR Imaging in Healthy Volunteers: Relationship to Formation of DNA Double-Strand Breaks. AB - Purpose To investigate the relationship between abdominopelvic magnetic resonance (MR) imaging and formation of DNA double-strand breaks (DSBs) in peripheral blood lymphocytes among a cohort of healthy volunteers. Materials and Methods Blood samples were obtained from 40 healthy volunteers (23 women and 17 men; mean age, 27.2 years [range, 21-37 years]) directly before and 5 and 30 minutes after abdominopelvic MR imaging performed at 1.5 T (n = 20) or 3.0 T (n = 20). The number of DNA DSBs in isolated blood lymphocytes was quantified after indirect immunofluorescent staining of a generally accepted DSB marker, gamma-H2AX, by means of high-throughput automated microscopy. As a positive control of DSB induction, blood lymphocytes from six volunteers were irradiated in vitro with x rays at a dose of 1 Gy (70-90 keV). Statistical analysis was performed by using a Friedman test. Results No significant alteration in the frequency of DNA DSB induction was observed after MR imaging (before imaging: 0.22 foci per cell, interquartile range [IQR] = 0.54 foci per cell; 5 minutes after MR imaging: 0.08 foci per cell, IQR = 0.39 foci per cell; 30 minutes after MR imaging: 0.09 foci per cell, IQR = 0.63 foci per cell; P = .057). In vitro radiation of lymphocytes with 1 Gy led to a significant increase in DSBs (0.22 vs 3.43 foci per cell; P = .0312). The frequency of DSBs did not differ between imaging at 1.5 T and at 3.0 T (5 minutes after MR imaging: 0.23 vs 0.06 foci per cell, respectively [P = .57]; 30 minutes after MR imaging: 0.12 vs 0.08 foci per cell [P = .76]). Conclusion Abdominopelvic MR imaging performed at 1.5 T or 3.0 T does not affect the formation of DNA DSBs in peripheral blood lymphocytes. PMID- 29714684 TI - SET-9 and SET-26 are H3K4me3 readers and play critical roles in germline development and longevity. AB - C. elegans SET-9 and SET-26 are highly homologous paralogs that share redundant functions in germline development, but SET-26 alone plays a key role in longevity and heat stress response. Whereas SET-26 is broadly expressed, SET-9 is only detectable in the germline, which likely accounts for their different biological roles. SET-9 and SET-26 bind to H3K4me3 with adjacent acetylation marks in vitro and in vivo. In the soma, SET-26 acts through DAF-16 to modulate longevity. In the germline, SET-9 and SET-26 restrict H3K4me3 domains around SET-9 and SET-26 binding sites, and regulate the expression of specific target genes, with critical consequence on germline development. SET-9 and SET-26 are highly conserved and our findings provide new insights into the functions of these H3K4me3 readers in germline development and longevity. PMID- 29714685 TI - A SLC4 family bicarbonate transporter is critical for intracellular pH regulation and biomineralization in sea urchin embryos. AB - Efficient pH regulation is a fundamental requisite of all calcifying systems in animals and plants but with the underlying pH regulatory mechanisms remaining largely unknown. Using the sea urchin larva, this work identified the SLC4 HCO3- transporter family member SpSlc4a10 to be critically involved in the formation of an elaborate calcitic endoskeleton. SpSlc4a10 is specifically expressed by calcifying primary mesenchyme cells with peak expression during de novo formation of the skeleton. Knock-down of SpSlc4a10 led to pH regulatory defects accompanied by decreased calcification rates and skeleton deformations. Reductions in seawater pH, resembling ocean acidification scenarios, led to an increase in SpSlc4a10 expression suggesting a compensatory mechanism in place to maintain calcification rates. We propose a first pH regulatory and HCO3- concentrating mechanism that is fundamentally linked to the biological precipitation of CaCO3. This knowledge will help understanding biomineralization strategies in animals and their interaction with a changing environment. PMID- 29714686 TI - Oligomerization of a molecular chaperone modulates its activity. AB - Molecular chaperones alter the folding properties of cellular proteins via mechanisms that are not well understood. Here, we show that Trigger Factor (TF), an ATP-independent chaperone, exerts strikingly contrasting effects on the folding of non-native proteins as it transitions between a monomeric and a dimeric state. We used NMR spectroscopy to determine the atomic resolution structure of the 100 kDa dimeric TF. The structural data show that some of the substrate-binding sites are buried in the dimeric interface, explaining the lower affinity for protein substrates of the dimeric compared to the monomeric TF. Surprisingly, the dimeric TF associates faster with proteins and it exhibits stronger anti-aggregation and holdase activity than the monomeric TF. The structural data show that the dimer assembles in a way that substrate-binding sites in the two subunits form a large contiguous surface inside a cavity, thus accounting for the observed accelerated association with unfolded proteins. Our results demonstrate how the activity of a chaperone can be modulated to provide distinct functional outcomes in the cell. PMID- 29714687 TI - Synthetic hormone-responsive transcription factors can monitor and re-program plant development. AB - Developmental programs sculpt plant morphology to meet environmental challenges, and these same programs have been manipulated to increase agricultural productivity (Doebley et al., 1997; Khush, 2001). Hormones coordinate these programs, creating chemical circuitry (Vanstraelen and Benkova, 2012) that has been represented in mathematical models (Refahi et al., 2016; Prusinkiewicz et al., 2009); however, model-guided engineering of plant morphology has been limited by a lack of tools (Parry et al., 2009; Voytas and Gao, 2014). Here, we introduce a novel set of synthetic and modular hormone activated Cas9-based repressors (HACRs) in Arabidopsis thaliana that respond to three hormones: auxin, gibberellins and jasmonates. We demonstrate that HACRs are sensitive to both exogenous hormone treatments and local differences in endogenous hormone levels associated with development. We further show that this capability can be leveraged to reprogram development in an agriculturally relevant manner by changing how the hormonal circuitry regulates target genes. By deploying a HACR to re-parameterize the auxin-induced expression of the auxin transporter PIN FORMED1 (PIN1), we decreased shoot branching and phyllotactic noise, as predicted by existing models (Refahi et al., 2016; Prusinkiewicz et al., 2009). PMID- 29714688 TI - Combinatorial programming of human neuronal progenitors using magnetically-guided stoichiometric mRNA delivery. AB - Identification of optimal transcription factor expression patterns to direct cellular differentiation along a desired pathway presents significant challenges. We demonstrate massively combinatorial screening of temporally-varying mRNA transcription factors to direct differentiation of neural progenitor cells using a dynamically-reconfigurable magnetically-guided spotting technology for localizing mRNA, enabling experiments on millimetre size spots. In addition, we present a time-interleaved delivery method that dramatically reduces fluctuations in the delivered transcription factor copy numbers per cell. We screened combinatorial and temporal delivery of a pool of midbrain-specific transcription factors to augment the generation of dopaminergic neurons. We show that the combinatorial delivery of LMX1A, FOXA2 and PITX3 is highly effective in generating dopaminergic neurons from midbrain progenitors. We show that LMX1A significantly increases TH-expression levels when delivered to neural progenitor cells either during proliferation or after induction of neural differentiation, while FOXA2 and PITX3 increase expression only when delivered prior to induction, demonstrating temporal dependence of factor addition. PMID- 29714689 TI - Temporospatial induction of homeodomain gene cut dictates natural lineage reprogramming. AB - Understanding how cellular identity naturally interconverts with high efficiency and temporospatial precision is crucial for regenerative medicine. Here, we revealed a natural midgut-to-renal lineage conversion event during Drosophila metamorphosis and identified the evolutionarily-conserved homeodomain protein Cut as a master switch in this process. A steep Wnt/Wingless morphogen gradient intersects with a pulse of steroid hormone ecdysone to induce cut expression in a subset of midgut progenitors and reprogram them into renal progenitors. Molecularly, ecdysone-induced temporal factor Broad physically interacts with cut enhancer-bound Wnt pathway effector TCF/beta-catenin and likely bridges the distant enhancer and promoter region of cut through its self-association. Such long-range enhancer-promoter looping could subsequently trigger timely cut transcription. Our results therefore led us to propose an unexpected poising-and bridging mechanism whereby spatial and temporal cues intersect, likely via chromatin looping, to turn on a master transcription factor and dictate efficient and precise lineage reprogramming. PMID- 29714690 TI - Multivalency regulates activity in an intrinsically disordered transcription factor. AB - The transcription factor ASCIZ (ATMIN, ZNF822) has an unusually high number of recognition motifs for the product of its main target gene, the hub protein LC8 (DYNLL1). Using a combination of biophysical methods, structural analysis by NMR and electron microscopy, and cellular transcription assays, we developed a model that proposes a concerted role of intrinsic disorder and multiple LC8 binding events in regulating LC8 transcription. We demonstrate that the long intrinsically disordered C-terminal domain of ASCIZ binds LC8 to form a dynamic ensemble of complexes with a gradient of transcriptional activity that is inversely proportional to LC8 occupancy. The preference for low occupancy complexes at saturating LC8 concentrations with both human and Drosophila ASCIZ indicates that negative cooperativity is an important feature of ASCIZ-LC8 interactions. The prevalence of intrinsic disorder and multivalency among transcription factors suggests that formation of heterogeneous, dynamic complexes is a widespread mechanism for tuning transcriptional regulation. PMID- 29714692 TI - Lidocaine turns 70: the evolution of dental local anesthesia. PMID- 29714691 TI - A semiretired general dentist's journey. PMID- 29714693 TI - Oral dysesthesia: uncomfortable aberrant sensations. PMID- 29714694 TI - Centric relation records for implant overdentures. PMID- 29714695 TI - The role of dental care providers in the management of patients prescribed bisphosphonates: brief clinical guidance. AB - Dental care providers are likely to see patients who take bisphosphonates for various medical conditions, including osteoporosis, bony metastatic tumors, multiple myeloma, breast cancer, and prostate cancer. Bisphosphonates accumulate in areas of high bone turnover, leading to suppression of bone turnover and the aging of keratocytes. These adverse effects predispose the maxillary and mandibular bone to development of medication-related osteonecrosis of the jaw (MRONJ), specifically among oncology patients treated with intravenous bisphosphonate therapy. Studies have shown that stopping bisphosphonate therapy, temporarily (drug holiday) or permanently, is not significantly effective. The effectiveness of a drug holiday is likely limited due to the pharmacologic activity of bisphosphonates and their persistent, long-term effect on bone. Therefore, patients should not be discouraged from taking bisphosphonates for an existing medical condition. A dental health assessment by an oral surgeon, a dental specialist, or a well-trained general dental practitioner is highly recommended prior to treatment with bisphosphonate. The evaluating clinician must attempt to eliminate or mitigate risk factors to prevent the development of MRONJ. It is crucial for dental care providers to recognize the clinical signs and symptoms of MRONJ, including its radiographic appearance. In cases of any suspicious oral lesion, early referral to an oral surgeon is crucial. It is better to avoid dental extractions during the active period of treatment and to treat the tooth carefully with nonsurgical root canal treatment instead. This review provides brief clinical guidance for dental care providers regarding management of patients prescribed bisphosphonates and ways to help minimize patients' risk of developing MRONJ. PMID- 29714696 TI - Root canal preparation in 3-rooted maxillary premolars through hand, rotary, and reciprocating techniques: a microcomputed tomography evaluation. AB - Endodontic management of 3-rooted maxillary premolars is a challenge due to their complex anatomy and narrow root canal walls. This study aimed to evaluate, by microcomputed tomography (MUCT), the apical enlargement and centering ability promoted by hand, rotary, and reciprocating instrumentation in 3-rooted maxillary premolars. Eighteen teeth were divided into 3 groups (n = 6) according to the preparation technique: crown-down hand, rotary, and reciprocating instrumentation. Instruments with similar apical diameters were used (25 and 40 mm for buccal and palatal canals, respectively). Centering ability and canal enlargement were evaluated through the comparison of MUCT images obtained before and after instrumentation. Distances of 0, 2, 4, and 6 mm from the apical stop were considered. Differences between canal areas before and after instrumentation were calculated. In addition, distances between the original canal center and the prepared canal center at the apical stop were measured in both the mesiodistal and buccopalatal directions. Significant differences in enlargement areas and centering ability among the techniques were determined using 2-way analysis of variance and Tukey post hoc test (P > 0.05). Root canal enlargement was similar for all techniques. Excessive enlargement was observed in only a few specimens, and root perforation did not occur. Some specimens presented untreated canal areas. In mesiobuccal and distobuccal roots, reciprocating instrumentation promoted more centered preparations than hand instrumentation when measured in the mesiodistal direction (P > 0.05). There were no other statistically significant differences. The results established that hand, rotary, and reciprocating techniques presented similar safety margins for instrumentation of the apical third of 3-rooted maxillary premolars. Reciprocating instrumentation presented some advantages over hand preparation regarding centering ability. PMID- 29714697 TI - Evaluation of the marginal integrity of a bioactive restorative material. AB - This in vitro study evaluated the marginal microleakage of a bioactive restorative with other restorative materials in standard Class V preparations. Sixty previously extracted, noncarious human molars were randomly assigned to 3 experimental groups (n = 20): a bioactive composite resin, a universal hybrid composite resin, and a resin-modified glass ionomer restorative. Class V cavities were prepared on the facial or lingual surface of each tooth so that coronal margins were located in enamel and apical margins in cementum (dentin). After the cavity preparations were restored with the appropriate material, the specimens were artificially aged in water baths. The root apices were sealed with utility wax, the tooth surfaces were coated with nail varnish to within 1 mm of the restoration, and specimens were immersed in 1% methylene dye solution for 8 hours. The teeth were invested in clear polymer resin, sectioned longitudinally, and examined under a stereomicroscope to assess dye penetration. Nonparametric scores indicated that microleakage was significantly greater at the apical margins than the coronal margins for all groups (P > 0.0001). The specimens restored with the bioactive material exhibited greater microleakage at both the coronal and apical margins than did specimens restored with the composite resin or resin-modified glass ionomer material, although the differences were not statistically significant (P > 0.05). Based on the results of the present study, the type of restorative material did not appear to have a significant influence on microleakage. Rather, the marginal position (coronal versus apical) of the restoration was the determining factor in microleakage. PMID- 29714698 TI - Foreign bodies in the interior of the maxillary sinus: diagnosis by cone beam computed tomography. AB - To avoid complications, the intimate relation between the maxillary sinus and dental roots deserves attention during surgical procedures. Accidental introduction of foreign bodies, such as dental implants, may irritate the maxillary sinus mucosa, causing sinusitis. Cone beam computed tomography (CBCT) has been proven to be suitable for diagnosis in these cases by providing the exact location of the foreign body. The present article reports 3 cases of foreign bodies inside the maxillary sinus associated with inflammatory processes. Imaging examinations, such as CBCT, are an important tool to assist dentists in diagnosing the presence of foreign bodies in the interior of the maxillary sinus. PMID- 29714699 TI - Clinical characterization and treatment outcome of patients with burning mouth syndrome. AB - Burning mouth syndrome (BMS) is a complex condition that affects the oral cavity, and data regarding effective treatment are limited. The purpose of this study was to explore the demographic and clinical information along with treatment outcomes for patients with BMS treated in a large referral center. Clinical records of the Oral Medicine Clinic at the University of Florida College of Dentistry were retrospectively searched for patients diagnosed between 2009 and 2014. Clinical data and treatment effectiveness were recorded. The records of 64 patients were included in this study. Women represented the majority of patients (81.2%), and the average age of all patients was 65 years. The most common systemic diseases were hypertension (59.4%), psycho-logical disorders (51.6%), and gastroesophageal reflux disease (50.0%). The majority of patients were taking 5 or more medications (70.3%). Treatment frequency and efficacy were as follows: a-lipoic acid, 47.5% frequency (57 prescribed treatments of 120 total treatments) and lasting improvement reported with 45.6% of prescribed treatments; clonazepam, 17.5% frequency (21/120) and improvement reported with 33.0% of prescribed treatments; oral disintegrating clonazepam, 15.8% frequency (19/120) and improvement reported with 52.6% of prescribed treatments; and topical vitamin E, 5.0% frequency (6/120) and improvement reported with 33.0% of prescribed treatments. Chi-square analysis indicated that a significantly better response to treatment was reported by women (P = 0.010) and patients who reported involvement limited to the tongue rather than multifocal oral involvement (P = 0.040); however, the significant relationships did not persist when the variables were evaluated together using logistic regression analysis. No other clinical or demographic features showed significant differences in response to treatment. Although treatment effectiveness in this study was variable and limited for some regimens due to infrequent usage, many of the patients reported alleviation of symptoms. PMID- 29714700 TI - Bioactive endodontic materials for everyday use: a review. AB - Bioceramic materials are at the forefront of modern dentistry. Bioactive bioceramic endodontic materials promote pulpal and periapical tissue healing and are easy to use. Dentists can choose among many endodontic materials, depending on their needs. This article highlights the major differences among commercially available bioactive tricalcium silicate bioceramics, commonly known as mineral trioxide aggregate materials, to enable dentists to make appropriate decisions in the selection of these materials. PMID- 29714701 TI - Delayed tooth reimplantation with 4-year follow-up: the management of ankylosis during facial growth. AB - This case report describes the consequences of delayed (24 hours) reimplantation of an avulsed maxillary central incisor, findings over a 4-year follow-up period, and the management of ankylosis during facial growth. After a traumatic event, a 10-year-old boy was taken to a hospital emergency department due to injuries to his face, including avulsion of the maxillary left central incisor. Despite the short amount of time before arriving at the hospital (10 minutes) and use of the correct storage medium (milk), the tooth was not reimplanted, and the parents did not receive instructions to seek dental treatment. The next day, the child was brought to a dental school because he objected to the loss of his tooth. The treatment chosen was delayed tooth reimplantation. At the 1-year follow-up, the reimplanted tooth was infraoccluded, and periapical radiography revealed signs of ankylosis and initial replacement root resorption. At the 2- and 3-year follow-up examinations, resorption and infraocclusion of the central incisor had progressed. In this case, the delayed reimplantation resulted in ankylosis that had a significant clinical impact due to the patient's facial growth. Direct resin restoration of the reimplanted tooth was therefore performed 3 years after trauma. Despite continued resorption and infraocclusion of the tooth observed 4 years posttrauma, the esthetic, low-cost treatment was well accepted, and the patient's quality of life was improved until definitive treatment can be performed. PMID- 29714702 TI - Effect of fiber inserts on gingival margin microleakage of Class II bulk-fill composite resin restorations. AB - This study evaluated the effect of fiber inserts combined with composite resins on enamel and dentin margin microleakage. The fiber inserts were used with high- (x-tra fil) and low-viscosity (x-tra base) bulk-fill composite resins and as well as conventional composite resins (Grandio and Grandio Flow). In 96 sound, recently extracted molars, 2 standardized Class II cavities were prepared. The teeth were randomly divided into 8 groups of 12 teeth each, based on composite resin type and presence or absence of fiber inserts: groups 1 and 2, x-tra fil with and without fiber inserts, respectively; groups 3 and 4, x-tra base with and without fiber inserts; groups 5 and 6, Grandio with and without fiber inserts; and groups 7 and 8, Grandio Flow liner (gingival floor)/Grandio (remainder of cavity) with and without fiber inserts. In all the groups, a 2-step etch-and rinse adhesive was used. The specimens were processed in a dye penetration technique to determine microleakage percentages. Data were analyzed with analysis of variance, Tukey, and t tests. There was significantly less leakage at the enamel margins than the dentin margins. Fiber reinforcement significantly decreased enamel microleakage in all the groups, with no significant differences among the groups. Concerning dentin microleakage, there were no significant differences among the 4 groups without fiber inserts, while a significant difference was detected in groups 2 (x-tra fil plus fiber) and 8 (Grandio Flow plus fiber/Grandio). Fibers significantly improved dentin sealing in groups 2 and 8. These findings suggest that a fiber insert reinforcing bulk-fill and conventional composite resins might improve enamel sealing in shallow Class II cavi-ties. The effect of fiber reinforcement on the dentin margins of deep cavities depended on the viscosity of the composite resins; fiber reinforcement was effective for flowable bulk-fill and conventional composite resin restorations. PMID- 29714703 TI - Effect of root canal obturation with calcium silicate materials on pH change in simulated root resorption defects. AB - This study evaluated the effect of 3 commercially available calcium silicate materials (CSMs) on pH changes in simulated root resorption defects. Simulated root resorption defects were prepared on the facial root surface of 40 mandibular premolars. The depth of each defect was individually calculated to standardize the remaining dentin thickness to 1 mm. Prepared canals were obturated with the 3 CSMs. Ten specimens were kept as controls, filled with unbuffered normal saline. The pH measurements were taken at 1 hour, 6 hours, 1 day, 1 week, 2 weeks, 3 weeks, 1 month, and 2 months. All CSM groups exhibited an initial alkaline pH of 9.0-9.7. The pH decreased to 8.0-8.5 after 2 months of storage. There were no significant differences between pH measurements at other time intervals. The CSM groups exhibited higher pH levels than the control group. The results showed that intracanal placement of the CSMs maintained initial pH levels of 9.0-9.7 inside the simulated resorption defects; these measurements gradually decreased to 8.0 8.5 over the span of 2 months. PMID- 29714704 TI - Depth of cure of proximal composite resin restorations using a new perforated metal matrix. AB - The purpose of this study was to compare the depths of cure of a proximal box preparation filled in bulk with various approaches: filled with a bulk-fill or conventional composite; placed with a new perforated metal matrix, a traditional metal matrix, or a clear matrix; and polymerized with either occlusal-only or tri sited light curing. After tri-sited curing, the use of the new perforated metal matrix band resulted in a depth of cure that was not significantly different from that achieved with the use of metal bands (removed during curing) or transparent matrix bands. Adequate polymerization was obtained at depths of more than 5.0 mm for the bulk-fill composite and more than 4.0 mm for the conventional composite when tri-sited light curing was used. Tri-sited light curing resulted in a significantly greater depth of cure than occlusal-only curing. The perforated metal band may be used as an alternative to the use of solid metal bands or transparent matrix bands to provide similar depths of cure for composite resins, with the possible benefits of malleability and the ability to leave the band in place during tri-sited light curing. PMID- 29714705 TI - Potential erosive effect of mouthrinses on enamel and dentin. AB - This in vitro study measured the pH values, titratable acidity (TA), and erosive potential of commercially available mouthrinses. A pH analysis of 6 mouthrinses (Listerine Total Care, Listerine Ultraclean, Listerine Original, Crest Pro Health, Scope Classic, and ACT Total Care) was performed using a calibrated pH meter, and the neutralizable acidity was measured by titrating the mouthwashes against 0.1 M of sodium hydroxide. A gravimetric analysis was performed by submerging human enamel and dentin specimens in 5 mL of each mouthrinse for a total of 2 weeks. Specimens were weighed on a calibrated analytical balance at baseline, 24 hours, 48 hours, 96 hours, 1 week, and 2 weeks, and finally the loss of mass was calculated. The differences in erosive potential among the 6 mouthrinses were verified using nonparametric tests (Kruskal-Wallis and Mann- Whitney). The level of significance was set at 0.05. The mouthrinses were found to have the following mean pH/ TA values: Crest Pro-Health, 7.05/0.00; ACT Total Care, 6.31/5.44; Scope Classic, 5.18/0.42; Listerine Original, 3.98/9.26; Listerine Total Care, 3.43/5.88; and Listerine Ultraclean, 3.87/10.36. A significant correlation between pH and TA was observed for this dataset (P > 0.0001). No statistically significant difference in enamel loss among the groups was observed (P = 0.0631). However, a significant difference in dentin loss was observed among the 6 mouthrinses (P = 0.0011). Within the limitations of this in vitro study, it can be concluded that some mouthrinses have a pH lower than the critical pH of enamel and dentin. There is a significant association between acidic pH values and higher TA. Some of the tested mouthrinses presented an erosive potential on dentin. PMID- 29714706 TI - Conservative approach for molar-incisor hypomineralization: a case report and 7 year follow-up. AB - Molar-incisor hypomineralization (MIH) can result in minor injuries or major structural loss, especially in incisors and molars. Patients with MIH seek dental treatment early, usually in childhood. Choosing the best treatment option during this stage can be a challenge. Because these patients still present a mixed dentition, the use of prosthetic appliances is not usually the best option. This case report with a 7-year follow-up presents an overview of a conservative approach for the restoration of teeth affected by MIH. A 10-year-old girl presented with permanent molars and incisors that exhibited qualitative defects of enamel characteristic of MIH. During the restoration phase, direct resin modified glass ionomer cement (RMGIC) restorations were placed in all 4 first molars with the aid of acetate crowns, which were used to facilitate reconstruction of the tooth morphology. The maxillary incisors were previously treated by another dentist, and the mandibular incisors were treated later, since they were not the main complaint of the patient at the time. During 7 years of follow-up, the RMGIC restorations proved to be a good option, presenting greater longevity in a molar with minor structural defects and requiring repair or replacement in molars with larger structural defects. Despite some failures and the necessity for new restorations, the patient conveyed satisfaction with the treatment and reported no tooth sensitivity, and there was no recurrence of caries. During this follow-up period, the defective mandibular incisors were treated first with enamel microabrasion, which proved esthetically unsatisfactory, and then with direct composite resin veneers. The results in this patient suggest that use of RMGIC may be a feasible conservative option for tooth restoration in young patients with a mixed dentition when permanent molars exhibit extensive structural loss associated with MIH. PMID- 29714707 TI - Robust real-time extraction of respiratory signals from PET list-mode data. AB - Respiratory motion, which typically cannot simply be suspended during PET image acquisition, affects lesions' detection and quantitative accuracy inside or in close vicinity to the lungs. Some motion compensation techniques address this issue via pre-sorting ('binning') of the acquired PET data into a set of temporal gates, where each gate is assumed to be minimally affected by respiratory motion. Tracking respiratory motion is typically realized using dedicated hardware (e.g. using respiratory belts and digital cameras). Extracting respiratory signals directly from the acquired PET data simplifies the clinical workflow as it avoids handling additional signal measurement equipment. We introduce a new data-driven method 'combined local motion detection' (CLMD). It uses the time-of-flight (TOF) information provided by state-of-the-art PET scanners in order to enable real time respiratory signal extraction without additional hardware resources. CLMD applies center-of-mass detection in overlapping regions based on simple back positioned TOF event sets acquired in short time frames. Following a signal filtering and quality-based pre-selection step, the remaining extracted individual position information over time is then combined to generate a global respiratory signal. The method is evaluated using seven measured FDG studies from single and multiple scan positions of the thorax region, and it is compared to other software-based methods regarding quantitative accuracy and statistical noise stability. Correlation coefficients around 90% between the reference and the extracted signal have been found for those PET scans where motion affected features such as tumors or hot regions were present in the PET field-of-view. For PET scans with a quarter of typically applied radiotracer doses, the CLMD method still provides similar high correlation coefficients which indicates its robustness to noise. Each CLMD processing needed less than 0.4 s in total on a standard multi-core CPU and thus provides a robust and accurate approach enabling real-time processing capabilities using standard PC hardware. PMID- 29714708 TI - Insight into nuclear body formation of phytochromes through stochastic modelling and experiment. AB - Spatial relocalization of proteins is crucial for the correct functioning of living cells. An interesting example of spatial ordering is the light-induced clustering of plant photoreceptor proteins. Upon irradiation by white or red light, the red light-active phytochrome, phytochrome B, enters the nucleus and accumulates in large nuclear bodies (NBs). The underlying physical process of nuclear body formation remains unclear, but phytochrome B is thought to coagulate via a simple protein-protein binding process. We measure, for the first time, the distribution of the number of phytochrome B-containing NBs as well as their volume distribution. We show that the experimental data cannot be explained by a stochastic model of nuclear body formation via simple protein-protein binding processes using physically meaningful parameter values. Rather modelling suggests that the data is consistent with a two step process: a fast nucleation step leading to macroparticles followed by a subsequent slow step in which the macroparticles bind to form the nuclear body. An alternative explanation for the observed nuclear body distribution is that the phytochromes bind to a so far unknown molecular structure. We believe it is likely this result holds more generally for other nuclear body-forming plant photoreceptors and proteins. PMID- 29714709 TI - Enhanced antibacterial efficacy of selective laser melting titanium surface with nanophase calcium phosphate embedded to TiO2 nanotubes. AB - Selective laser melting (SLM) has promising prospects in manufacturing customized implants, however the rough surface of SLM titanium specimen can facilitate bacterial adherence and biofilm formation, which is a risk to implant success. Therefore, surface modification is required to enhance its antibacterial efficacy. Sandblasting, anodization and electrochemical deposition were applied to construct a novel composite nanostructure of nanophase calcium phosphate embedded to TiO2 nanotubes on microrough SLM titanium substrates (NTN). NTN samples were compared with TiO2 nanotubes (NT) samples, mechanical polished (MP) samples and untreated SLM titanium samples. Surface characterization were analyzed using scanning electron microscope, energy dispersive spectroscopy, x ray photoelectron spectroscopy, x-ray diffraction, a three dimensional profilometer and a contact angle measuring device. Bacteria adhesion assay for bacteria colony counting and bacteria LIVE/DEAD staining was conducted using Streptococcus mutans and Streptococcus sanguinis. Both S. mutans and S. sanguinis adherence on SLM samples were significantly higher than on NTN, NT and MP samples. The antibacterial efficacy of NTN samples was superior compared to NT and had no significant difference with MP samples, despite the fact that NTN samples had much rougher surface than MP samples. This study elucidates an efficient method to enhance antibacterial efficacy on rough SLM surfaces, which contributes to its application in dental and other biomedical implants. PMID- 29714710 TI - Markerless positional verification using template matching and triangulation of kV images acquired during irradiation for lung tumors treated in breath-hold. AB - Lung tumors treated in breath-hold are subject to inter- and intra-breath-hold variations, which makes tumor position monitoring during each breath-hold important. A markerless technique is desirable, but limited tumor visibility on kV images makes this challenging. We evaluated if template matching + triangulation of kV projection images acquired during breath-hold stereotactic treatments could determine 3D tumor position. Band-pass filtering and/or digital tomosynthesis (DTS) were used as image pre-filtering/enhancement techniques. On board kV images continuously acquired during volumetric modulated arc irradiation of (i) a 3D-printed anthropomorphic thorax phantom with three lung tumors (n = 6 stationary datasets, n = 2 gradually moving), and (ii) four patients (13 datasets) were analyzed. 2D reference templates (filtered DRRs) were created from planning CT data. Normalized cross-correlation was used for 2D matching between templates and pre-filtered/enhanced kV images. For 3D verification, each registration was triangulated with multiple previous registrations. Generally applicable image processing/algorithm settings for lung tumors in breath-hold were identified. For the stationary phantom, the interquartile range of the 3D position vector was on average 0.25 mm for 12 degrees DTS + band-pass filtering (average detected positions in 2D = 99.7%, 3D = 96.1%, and 3D excluding first 12 degrees due to triangulation angle = 99.9%) compared to 0.81 mm for band-pass filtering only (55.8/52.9/55.0%). For the moving phantom, RMS errors for the lateral/longitudinal/vertical direction after 12 degrees DTS + band-pass filtering were 1.5/0.4/1.1 mm and 2.2/0.3/3.2 mm. For the clinical data, 2D position was determined for at least 93% of each dataset and 3D position excluding first 12 degrees for at least 82% of each dataset using 12 degrees DTS + band-pass filtering. Template matching + triangulation using DTS + band-pass filtered images could accurately determine the position of stationary lung tumors. However, triangulation was less accurate/reliable for targets with continuous, gradual displacement in the lateral and vertical directions. This technique is therefore currently most suited to detect/monitor offsets occurring between initial setup and the start of treatment, inter-breath-hold variations, and tumors with predominantly longitudinal motion. PMID- 29714711 TI - Direct CP violation in [Formula: see text]: Standard Model Status. AB - In 1988 the NA31 experiment presented the first evidence of direct CP violation in the [Formula: see text] decay amplitudes. A clear signal with a [Formula: see text] statistical significance was later established with the full data samples from the NA31, E731, NA48 and KTeV experiments, confirming that CP violation is associated with a [Formula: see text] quark transition, as predicted by the Standard Model. However, the theoretical prediction for the measured ratio [Formula: see text] has been a subject of strong controversy along the years. Although the underlying physics was already clarified in 2001, the recent release of improved lattice data has revived again the theoretical debate. We review the current status, discussing in detail the different ingredients that enter into the calculation of this observable and the reasons why seemingly contradictory predictions were obtained in the past by several groups. An update of the Standard Model prediction is presented and the prospects for future improvements are analysed. Taking into account all known short-distance and long-distance contributions, one obtains [Formula: see text], in good agreement with the experimental measurement. PMID- 29714712 TI - Thermodynamics of finite systems: a key issues review. AB - A little over ten years ago, Campisi, and Dunkel and Hilbert, published papers claiming that the Gibbs (volume) entropy of a classical system was correct, and that the Boltzmann (surface) entropy was not. They claimed further that the quantum version of the Gibbs entropy was also correct, and that the phenomenon of negative temperatures was thermodynamically inconsistent. Their work began a vigorous debate of exactly how the entropy, both classical and quantum, should be defined. The debate has called into question the basis of thermodynamics, along with fundamental ideas such as whether heat always flows from hot to cold. The purpose of this paper is to sum up the present status-admittedly from my point of view. I will show that standard thermodynamics, with some minor generalizations, is correct, and the alternative thermodynamics suggested by Hilbert, Hanggi, and Dunkel is not. Heat does not flow from cold to hot. Negative temperatures are thermodynamically consistent. The small 'errors' in the Boltzmann entropy that started the whole debate are shown to be a consequence of the micro-canonical assumption of an energy distribution of zero width. Improved expressions for the entropy are found when this assumption is abandoned. PMID- 29714713 TI - Molecular jenga: the percolation phase transition (collapse) in virus capsids. AB - Virus capsids are polymeric protein shells that protect the viral cargo. About half of known virus families have icosahedral capsids that self-assemble from tens to thousands of subunits. Capsid disassembly is critical to the lifecycles of many viruses yet is poorly understood. Here, we apply a graph and percolation theory to examine the effect of removing capsid subunits on capsid stability and fragmentation. Based on the structure of the icosahedral capsid of hepatitis B virus (HBV), we constructed a graph of rhombic subunits arranged with icosahedral symmetry. Though our approach neglects dependence on energetics, time, and molecular detail, it quantitatively predicts a percolation phase transition consistent with recent in vitro studies of HBV capsid dissociation. While the stability of the capsid graph followed a gradual quadratic decay, the rhombic tiling abruptly fragmented when we removed more than 25% of the 120 subunits, near the percolation threshold observed experimentally. This threshold may also affect results of capsid assembly, which also experimentally produces a preponderance of 90 mer intermediates, as the intermediate steps in these reactions are reversible and can thus resemble dissociation. Application of percolation theory to understanding capsid association and dissociation may prove a general approach to relating virus biology to the underlying biophysics of the virus particle. PMID- 29714714 TI - A novel approach to EPID-based 3D volumetric dosimetry for IMRT and VMAT QA. AB - Intensity modulated radiation therapy (IMRT) and volumetric modulated arc therapy (VMAT) are relatively complex treatment delivery techniques and require quality assurance (QA) procedures. Pre-treatment dosimetric verification represents a fundamental QA procedure in daily clinical routine in radiation therapy. The purpose of this study is to develop an EPID-based approach to reconstruct a 3D dose distribution as imparted to a virtual cylindrical water phantom to be used for plan-specific pre-treatment dosimetric verification for IMRT and VMAT plans. For each depth, the planar 2D dose distributions acquired in air were back projected and convolved by depth-specific scatter and attenuation kernels. The kernels were obtained by making use of scatter and attenuation models to iteratively estimate the parameters from a set of reference measurements. The derived parameters served as a look-up table for reconstruction of arbitrary measurements. The summation of the reconstructed 3D dose distributions resulted in the integrated 3D dose distribution of the treatment delivery. The accuracy of the proposed approach was validated in clinical IMRT and VMAT plans by means of gamma evaluation, comparing the reconstructed 3D dose distributions with Octavius measurement. The comparison was carried out using (3%, 3 mm) criteria scoring 99% and 96% passing rates for IMRT and VMAT, respectively. An accuracy comparable to the one of the commercial device for 3D volumetric dosimetry was demonstrated. In addition, five IMRT and five VMAT were validated against the 3D dose calculation performed by the TPS in a water phantom using the same passing rate criteria. The median passing rates within the ten treatment plans was 97.3%, whereas the lowest was 95%. Besides, the reconstructed 3D distribution is obtained without predictions relying on forward dose calculation and without external phantom or dosimetric devices. Thus, the approach provides a fully automated, fast and easy QA procedure for plan-specific pre-treatment dosimetric verification. PMID- 29714715 TI - Estimation of lung absorption parameters for oxides of 238Pu. AB - Following inhalation of an aerosol of relatively insoluble particles, it is usually found that the fractional dissolution rate of material retained in the lungs decreases with time, and the amount remaining undissolved can be represented simply by a decreasing exponential function with two or more components. A few exceptions are known, in which the dissolution rate increases with time. The most important in the context of radiological protection is probably that of 238Pu dioxide. Several published comprehensive data sets, from animal studies and accidental human exposures, have been analysed using the Human Respiratory Tract Model (HRTM) of the International Commission on Radiological Protection. The HRTM contains a simplified representation of particle dissolution in the respiratory tract, suitable for routine radiological protection purposes. Still, it was found to have sufficient flexibility to represent the measurement data in most of these cases. Although the 238Pu dioxide showed a wide range of behaviour in the different studies, there was good agreement between the absorption behaviour modelled for two studies involving 'ceramic' 238Pu dioxide as used in spacecraft radioisotope thermoelectric generators: a long-term experimental study in dogs and an accidental exposure involving a group of workers. PMID- 29714716 TI - Y-90 SPECT ML image reconstruction with a new model for tissue-dependent bremsstrahlung production using CT information: a proof-of-concept study. AB - While the yield of positrons used in Y-90 PET is independent of tissue media, Y 90 SPECT imaging is complicated by the tissue dependence of bremsstrahlung photon generation. The probability of bremsstrahlung production is proportional to the square of the atomic number of the medium. Hence, the same amount of activity in different tissue regions of the body will produce different numbers of bremsstrahlung photons. Existing reconstruction methods disregard this tissue dependency, potentially impacting both qualitative and quantitative imaging of heterogeneous regions of the body such as bone with marrow cavities. In this proof-of-concept study, we propose a new maximum-likelihood method that incorporates bremsstrahlung generation probabilities into the system matrix, enabling images of the desired Y-90 distribution to be reconstructed instead of the 'bremsstrahlung distribution' that is obtained with existing methods. The tissue-dependent probabilities are generated by Monte Carlo simulation while bone volume fractions for each SPECT voxel are obtained from co-registered CT. First, we demonstrate the tissue dependency in a SPECT/CT imaging experiment with Y-90 in bone equivalent solution and water. Visually, the proposed reconstruction approach better matched the true image and the Y-90 PET image than the standard bremsstrahlung reconstruction approach. An XCAT phantom simulation including bone and marrow regions also demonstrated better agreement with the true image using the proposed reconstruction method. Quantitatively, compared with the standard reconstruction, the new method improved estimation of the liquid bone:water activity concentration ratio by 40% in the SPECT measurement and the cortical bone:marrow activity concentration ratio by 58% in the XCAT simulation. PMID- 29714717 TI - Dosimetric factors for diagnostic nuclear medicine procedures in a non-reference pregnant phantom. AB - This study evaluates the impact of using non-reference fetal models on the fetal radiation dose from diagnostic radionuclide administration. The six-month pregnant phantoms including fetal models at the 10th and 90th growth percentiles were constructed at either end of the normal range around the 50th percentile and implemented in the Monte Carlo N-Particle code version MCNPX 2.6. This code has then been used to evaluate the 99mTc S factors of the target organs of interest, as this is the most commonly used radionuclide in nuclear medicine procedures. Substantial variations were observed in the S factors between the 10th/90th percentile phantoms from the 50th percentile phantom, with the greatest difference being 38.6%. When the source organs were in close proximity to, or inside the fetal body, the 99mTc S factors presented strong statistical correlations with fetal body habitus. The trends observed in the S factors and the differences between various percentiles were justified by the source organs' masses, and chord length distributions. The results of this study showed that fetal body habitus had a considerable effect on fetal dose (on average up to 8.4%) if constant fetal biokinetic data were considered for all fetal weight percentiles. However, a smaller variation on fetal dose (up to 5.3%) was obtained if the available biokinetic data for the reference fetus were scaled by fetal mass. PMID- 29714718 TI - Factors that affect error potentials during a grasping task: toward a hybrid natural movement decoding BCI. AB - OBJECTIVE: In this manuscript, we consider factors that may affect the design of a hybrid brain-computer interface (BCI). We combine neural correlates of natural movements and interaction error-related potentials (ErrP) to perform a 3D reaching task, focusing on the impact that such factors have on the evoked ErrP signatures and in their classification. APPROACH: Users attempted to control a 3D virtual interface that simulated their own hand, to reach and grasp two different objects. Three factors of interest were modulated during the experimentation: (1) execution speed of the grasping, (2) type of grasping and (3) mental strategy (motor imagery or real motion) used to produce motor commands. Thirteen healthy subjects carried out the protocol. The peaks and latencies of the ErrP were analyzed for the different factors as well as the classification performance. MAIN RESULTS: ErrP are evoked for erroneous commands decoded from neural correlates of natural movements. The analysis of variance (ANOVA) analyses revealed that latency and magnitude of the most characteristic ErrP peaks were significantly influenced by the speed at which the grasping was executed, but not the type of grasp. This resulted in an greater accuracy of single-trial decoding of errors for fast movements (75.65%) compared to slow ones (68.99%). SIGNIFICANCE: Understanding the effects of combining paradigms is a first step to design hybrid BCI that optimize decoding accuracy and can be deployed in motor substitution and neuro-rehabilitation applications. PMID- 29714719 TI - Optimisation of environmental remediation: how to select and use the reference levels. AB - A number of past industrial activities and accidents have resulted in the radioactive contamination of large areas at many sites around the world, giving rise to a need for remediation. According to the International Commission on Radiological Protection (ICRP) and International Atomic Energy Agency (IAEA), such situations should be managed as existing exposure situations (ExESs). Control of exposure to the public in ExESs is based on the application of appropriate reference levels (RLs) for residual doses. The implementation of this potentially fruitful concept for the optimisation of remediation in various regions is hampered by a lack of practical experience and relevant guidance. This paper suggests a generic methodology for the selection of numeric values of relevant RLs both in terms of residual annual effective dose and derived RLs (DRLs) based on an appropriate dose assessment. The value for an RL should be selected in the range of the annual residual effective dose of 1-20 mSv, depending on the prevailing circumstances for the exposure under consideration. Within this range, RL values should be chosen by the following assessment steps: (a) assessment of the projected dose, i.e. the dose to a representative person without remedial actions by means of a realistic model as opposed to a conservative model; (b) modelling of the residual dose to a representative person following application of feasible remedial actions; and (c) selection of an RL value between the projected and residual doses, taking account of the prevailing social and economic conditions. This paper also contains some recommendations for practical implementation of the selected RLs for the optimisation of public protection. The suggested methodology used for the selection of RLs (in terms of dose) and the calculation of DRLs (in terms of activity concentration in food, ambient dose rate, etc) has been illustrated by a retrospective analysis of post Chernobyl monitoring and modelling data from the Bryansk region, Russia, 2001. From this example, it follows that analysis of real data leads to the selection of an RL from a relatively narrow annual dose range (in this case, about 2-3 mSv), from which relevant DRLs can be calculated and directly used for optimisation of the remediation programme. PMID- 29714720 TI - Nucleon axial radius and muonic hydrogen-a new analysis and review. AB - Weak capture in muonic hydrogen (MUH) as a probe of the chiral properties and nucleon structure predictions of quantum chromodynamics (QCD) is reviewed. A recent determination of the axial-vector charge radius squared, [Formula: see text], from a model independent z expansion analysis of neutrino-nucleon scattering data is employed in conjunction with the MuCap measurement of the singlet muonic hydrogen capture rate, [Formula: see text], to update the induced pseudoscalar nucleon coupling [Formula: see text] derived from experiment, and [Formula: see text] predicted by chiral perturbation theory. Accounting for correlated errors this implies [Formula: see text], confirming theory at the 8% level. If instead, the predicted expression for [Formula: see text] is employed as input, then the capture rate alone determines [Formula: see text], or together with the independent z expansion neutrino scattering result, a weighted average [Formula: see text]. Sources of theoretical uncertainty are critically examined and potential experimental improvements are described that can reduce the capture rate error by about a factor of 3. Muonic hydrogen can thus provide a precise and independent [Formula: see text] value which may be compared with other determinations, such as ongoing lattice gauge theory calculations. The importance of an improved [Formula: see text] determination for phenomenology is illustrated by considering the impact on critical neutrino-nucleus cross sections at neutrino oscillation experiments. PMID- 29714722 TI - An optimal filter for short photoplethysmogram signals. AB - A photoplethysmogram (PPG) contains a wealth of cardiovascular system information, and with the development of wearable technology, it has become the basic technique for evaluating cardiovascular health and detecting diseases. However, due to the varying environments in which wearable devices are used and, consequently, their varying susceptibility to noise interference, effective processing of PPG signals is challenging. Thus, the aim of this study was to determine the optimal filter and filter order to be used for PPG signal processing to make the systolic and diastolic waves more salient in the filtered PPG signal using the skewness quality index. Nine types of filters with 10 different orders were used to filter 219 (2.1s) short PPG signals. The signals were divided into three categories by PPG experts according to their noise levels: excellent, acceptable, or unfit. Results show that the Chebyshev II filter can improve the PPG signal quality more effectively than other types of filters and that the optimal order for the Chebyshev II filter is the 4th order. PMID- 29714721 TI - Interpreting heterogeneity in intestinal tuft cell structure and function. AB - Intestinal tuft cells are a morphologically unique cell type, best characterized by striking microvilli that form an apical tuft. These cells represent approximately 0.5% of gut epithelial cells depending on location. While they are known to express chemosensory receptors, their function has remained unclear. Recently, numerous groups have revealed startling insights into intestinal tuft cell biology. Here, we review the latest developments in understanding this peculiar cell type's structure and function. Recent advances in volumetric microscopy have begun to elucidate tuft cell ultrastructure with respect to its cellular neighbors. Moreover, single-cell approaches have revealed greater diversity in the tuft cell population than previously appreciated and uncovered novel markers to characterize this heterogeneity. Finally, advanced model systems have revealed tuft cells' roles in mucosal healing and orchestrating type 2 immunity against eukaryotic infection. While much remains unknown about intestinal tuft cells, these critical advances have illuminated the physiological importance of these previously understudied cells and provided experimentally tractable tools to interrogate this rare cell population. Tuft cells act as luminal sensors, linking the luminal microbiome to the host immune system, which may make them a potent clinical target for modulating host response to a variety of acute or chronic immune-driven conditions. PMID- 29714723 TI - High-throughput density-functional perturbation theory phonons for inorganic materials. AB - The knowledge of the vibrational properties of a material is of key importance to understand physical phenomena such as thermal conductivity, superconductivity, and ferroelectricity among others. However, detailed experimental phonon spectra are available only for a limited number of materials, which hinders the large scale analysis of vibrational properties and their derived quantities. In this work, we perform ab initio calculations of the full phonon dispersion and vibrational density of states for 1521 semiconductor compounds in the harmonic approximation based on density functional perturbation theory. The data is collected along with derived dielectric and thermodynamic properties. We present the procedure used to obtain the results, the details of the provided database and a validation based on the comparison with experimental data. PMID- 29714724 TI - Experimental investigation on feedback insensitivity in semiconductor ring lasers. AB - The insensitivity to optical feedback is experimentally measured for a semiconductor ring laser (SRL) and compared to that of a Fabry-Perot laser (FPL) fabricated with the same technology and on the same material. An analysis of the optical spectra reveals that the SRL remains nearly unaffected for values of optical feedback as strong as -23 dB. Furthermore, through both optical linewidth and self-mixing measurements, we show that the tolerance to feedback in SRLs is 25-30 dB stronger than in FPLs. This property makes SRLs very interesting candidates for the development of feedback-insensitive optical sources. PMID- 29714725 TI - Resonant-state expansion for open optical systems: generalization to magnetic, chiral, and bi-anisotropic materials. AB - The resonant-state expansion, a recently developed powerful method in electrodynamics, is generalized here for open optical systems containing magnetic, chiral, or bi-anisotropic materials. It is shown that the key matrix eigenvalue equation of the method remains the same, but the matrix elements of the perturbation now contain variations of the permittivity, permeability, and bi anisotropy tensors. A general normalization of resonant states in terms of the electric and magnetic fields is presented. PMID- 29714726 TI - Observation of soliton molecules in a spatiotemporal mode-locked multimode fiber laser. AB - We report on the first experimental observation, to the best of our knowledge, of soliton molecules in a spatiotemporal mode-locked multimode fiber (MMF) laser. By adjusting the waveplates inside the cavity, not only the spatiotemporal mode locking state with a stable single pulse but also soliton molecules are observed. Various soliton molecules, including soliton pairs, soliton triplets, and soliton quartets with different pulse separations, are achieved. Transition of different operation states with pump power is given. The results would be beneficial for further understanding of the nonlinear dynamics in spatiotemporal mode-locked MMF lasers. PMID- 29714727 TI - Edge modes of scattering chains with aperiodic order. AB - We study the scattering resonances of one-dimensional deterministic aperiodic chains of electric dipoles using the vectorial Green's matrix method, which accounts for both short- and long-range electromagnetic interactions in open scattering systems. We discover the existence of edge-localized scattering states within fractal energy gaps with characteristic topological band structures. Notably, we report and characterize edge-localized modes in the classical wave analogues of the Su-Schrieffer-Heeger (SSH) dimer model, quasiperiodic Harper and Fibonacci crystals, as well as in more complex Thue-Morse aperiodic systems. Our study demonstrates that topological edge-modes with characteristic power-law envelope appear in open aperiodic systems and coexist with traditional exponentially localized ones. Our results extend the concept of topological states to the scattering resonances of complex open systems with aperiodic order, thus providing an important step towards the predictive design of topological optical metamaterials and devices beyond tight-binding models. PMID- 29714728 TI - Cooke-Triplet tweezers: more compact, robust, and efficient optical tweezers. AB - We present a versatile three-lens optical design to improve the overall compactness, efficiency, and robustness for optical tweezers based applications. The design, inspired by the Cooke-Triplet configuration, allows for continuous beam magnifications of 2-10*, and axial as well as lateral focal shifts can be realized without switching lenses or introducing optical aberrations. We quantify the beam quality and trapping stiffness and compare the Cooke-Triplet design with the commonly used double Kepler design through simulations and direct experiments. Optical trapping of 1 and 2 MUm beads shows that the Cooke-Triplet possesses an equally strong optical trap stiffness compared to the double Kepler lens design but reduces its lens system length by a factor of 2.6. Finally, we demonstrate how a Twyman-Green interferometer integrated in the Cooke-Triplet optical tweezers setup provides a fast and simple method to characterize the wavefront aberrations in the lens system and how it can help in aligning the optical components perfectly. PMID- 29714729 TI - Femtosecond-written long-period gratings in fluoride fibers. AB - Long-period gratings induced in fluoride glass fibers using femtosecond laser pulses at 800 nm are, to the best of our knowledge, demonstrated for the first time. By means of tightly confined ultrashort laser pulses, smooth periodic lines of refractive index changes are induced along the fiber core. Taking advantage of heat accumulation effects in the focal volume, attenuation peaks down to -24 dB, with sharp and predictable spectral resonances, were obtained. Thermal annealing of the grating up to 250 degrees C yielded a significant reduction of the induced refractive index change. The gratings could find applications in various integrated mid-infrared optical devices, such as optical notch filters in fiber amplifiers. PMID- 29714730 TI - Mode-locked thulium-doped fiber laser with chemical vapor deposited molybdenum ditelluride. AB - A passively mode-locked thulium-doped fiber (TDF) laser was realized by employing chemical vapor deposited few-layer molybdenum ditelluride (MoTe2) as a saturable absorber (SA). The few-layer MoTe2 film was transferred onto the waist of a microfiber and then incorporated into a TDF laser with a typical all-fiber ring cavity configuration. Stable soliton pulses emitting at 1930.22 nm were obtained with a 3 dB bandwidth of 4.45 nm, a pulse duration of 952 fs, and an average power of 36.7 mW. PMID- 29714731 TI - Robust soliton crystals in a thermally controlled microresonator. AB - We demonstrate robust soliton crystals generation with a fixed frequency pump laser through a thermoelectric-cooler-based thermal-tuning approach in a butterfly-packaged complementary-metal-oxide-semiconductor-compatible microresonator. Varieties of soliton crystal states, exhibiting "palm-like" optical spectra that result from the strong interactions between the dense soliton ensembles and reflect their temporal distribution directly, are experimentally observed by sweeping one cavity resonance across the pump frequency from the blue-detuned side by reducing the operating temperature of the resonator. Benefitting from the tiny intra-cavity energy change, repeatable interconversion between the chaotic modulation instability and stable soliton crystal states can be successfully achieved via simple tuning of the temperature or pump power, showing the easy accessibility and excellent stability of such soliton crystals. This work could facilitate microresonator-based optical frequency combs towards a portable, adjustable, and low-cost system while avoiding the requirements of delicate frequency-sweeping pump techniques. PMID- 29714733 TI - Propagation and refraction of left-handed plasmons on a semiconducting substrate covered by graphene. AB - We show that a plasmonic semiconductor substrate can support highly confined surface plasmons when it is covered by a graphene layer. This occurs when the imaginary part of graphene conductivity and real part of the effective permittivity of the surrounding medium become simultaneously negative. Full-wave electromagnetic simulations demonstrate the occurrence of negative refraction and two-dimensional lensing at the interface separating regions supporting conventional right-handed graphene plasmons and left-handed surface plasmon polaritons. PMID- 29714732 TI - Nanobomb optical coherence elastography. AB - Wave-based optical elastography is rapidly emerging as a powerful technique for quantifying tissue biomechanical properties due to its noninvasive nature and high displacement sensitivity. However, current approaches are limited in their ability to produce high-frequency waves and highly localized mechanical stress. In this Letter, we demonstrate that the rapid liquid-to-gas phase transition of dye-loaded perfluorocarbon nanodroplets ("nanobombs") initiated by a pulsed laser can produce highly localized, high-frequency, and broadband elastic waves. The waves were detected by an ultra-fast line-field low-coherence holography system. For comparison, we also excited waves using a focused micro-air-pulse. Results from tissue-mimicking phantoms showed that the nanobombs produced elastic waves with frequencies up to ~9 kHz, which was much greater than the ~2 kHz waves excited by the air-pulse. Consequently, the nanobombs enabled more accurate quantification of sample viscoelasticity. Combined with their potential for functionalization, the nanobombs show promise for accurate and highly specific noncontact all-optical elastography. PMID- 29714734 TI - Sparse-fast-Fourier-transform-based quick synchronization for optical direct detection orthogonal frequency division multiplexing systems. AB - Orthogonal frequency division multiplexing (OFDM) has always been a promising candidate for optical access networks. However, it is very sensitive to synchronization errors and requires complex digital signal processing to eliminate this influence, thus increasing the computation complexity, delay, and system cost, which hampers its applications in cost-sensitive and low-latency scenarios of future optical access networks. To deal with this issue, a sparse fast-Fourier-transform (FFT)-based quick synchronization algorithm for optical direct detection OFDM systems is proposed and demonstrated with greatly reduced computation complexity. Detailed simulations and experimental verifications along 50 km standard single-mode-fiber transmission prove the efficiency, accuracy, and feasibility of the sparse-FFT-based synchronization technique in cost- and delay sensitive applications for next-generation optical access networks. PMID- 29714735 TI - Photon pair generation with tailored frequency correlations in graded-index multimode fibers. AB - We study theoretically the generation of photon pairs with controlled spectral correlations via the four-wave mixing process in graded-index multimode optical fibers (GIMFs). We show that the quantum correlations of the generated photons in GIMFs can be preserved over a wide spectral range for a tunable pump source. Therefore, GIMFs can be utilized as quantum-state-preserving tunable sources of photons. In particular, we have shown that it is possible to generate factorable two-photon states, which allow for heralding of pure-state single photons without the need for narrowband spectral post filtering. We also elaborate on the possibility of simultaneously generating correlated and uncorrelated photon pairs in the same optical fiber. PMID- 29714736 TI - Distributed fiber sparse-wideband vibration sensing by sub-Nyquist additive random sampling. AB - The round-trip time of the light pulse limits the maximum detectable vibration frequency response range of phase-sensitive optical time domain reflectometry (phi-OTDR). Unlike the uniform laser pulse interval in conventional phi-OTDR, we randomly modulate the pulse interval so that an equivalent sub-Nyquist additive random sampling (sNARS) is realized for every sensing point of the long interrogation fiber. For a phi-OTDR system with 10 km sensing length, the sNARS method is optimized by theoretical analysis and Monte Carlo simulation, and the experimental results verify that a wideband sparse signal can be identified and reconstructed. Such a method can broaden the vibration frequency response range of phi-OTDR, which is of great significance in sparse-wideband-frequency vibration signal detection. PMID- 29714737 TI - Residue number system arithmetic based on integrated nanophotonics. AB - The residue number system (RNS) enables dimensionality reduction of an arithmetic problem by representing a large number as a set of smaller integers, where the number is decomposed by prime number factorization. These reduced problem sets can then be processed independently and in parallel, thus improving computational efficiency and speed. Here, we show an optical RNS hardware representation based on integrated nanophotonics. The digit-wise shifting in RNS arithmetic is expressed as spatial routing of an optical signal in 2*2 hybrid photonic plasmonic switches. Here, the residue is represented by spatially shifting the input waveguides relative to the routers' outputs, where the moduli are represented by the number of waveguides. By cascading the photonic 2*2 switches, we design a photonic RNS adder and a multiplier forming an all-to-all sparse directional network. The advantage of this photonic arithmetic processor is the short (10's ps) computational execution time given by the optical propagation delay through the integrated nanophotonic router. Furthermore, we show how photonic processing in-the-network leverages the natural parallelism of optics such as wavelength-division-multiplexing in this RNS processor. A key application for such a photonic RNS engine is the functional analysis of convolutional neural networks. PMID- 29714738 TI - Practical gigahertz quantum key distribution robust against channel disturbance. AB - Quantum key distribution (QKD) provides an attractive solution for secure communication. However, channel disturbance severely limits its application when a QKD system is transferred from the laboratory to the field. Here a high-speed Faraday-Sagnac-Michelson QKD system is proposed that can automatically compensate for the channel polarization disturbance, which largely avoids the intermittency limitations of environment mutation. Over a 50 km fiber channel with 30 Hz polarization scrambling, the practicality of this phase-coding QKD system was characterized with an interference fringe visibility of 99.35% over 24 h and a stable secure key rate of 306 k bits/s over seven days without active polarization alignment. PMID- 29714739 TI - Using temperature to reduce noise in quantum frequency conversion. AB - Quantum frequency conversion is important in quantum networks to interface nodes operating at different wavelengths and to enable long-distance quantum communication using telecommunications wavelengths. Unfortunately, frequency conversion in actual devices is not a noise-free process. One main source of noise is spontaneous Raman scattering, which can be reduced by lowering the device operating temperature. We explore frequency conversion of 1554 nm photons to 837 nm using a 1813 nm pump in a periodically poled lithium niobate waveguide device. By reducing the temperature from 85 degrees C to 40 degrees C, we show a three-fold reduction in dark count rates, which is in good agreement with theory. PMID- 29714740 TI - Flexible approach to vibrational sum-frequency generation using shaped near infrared light. AB - We describe a new approach that expands the utility of vibrational sum-frequency generation (vSFG) spectroscopy using shaped near-infrared (NIR) laser pulses. We demonstrate that arbitrary pulse shapes can be specified to match experimental requirements without the need for changes to the optical alignment. In this way, narrowband NIR pulses as long as 5.75 ps are readily generated, with a spectral resolution of about 2.5 cm-1, an improvement of approximately a factor of 3 compared to a typical vSFG system. Moreover, the utility of having complete control over the NIR pulse characteristics is demonstrated through nonresonant background suppression from a metallic substrate by generating an etalon waveform in the pulse shaper. The flexibility afforded by switching between arbitrary NIR waveforms at the sample position with the same instrument geometry expands the type of samples that can be studied without extensive modifications to existing apparatuses or large investments in specialty optics. PMID- 29714741 TI - Selection of target elements for laser-produced plasma soft x-ray sources. AB - We demonstrated the upper limitation to the number of shots, i.e., target lifetime, together with the number of photons emitted in the water-window soft x ray spectral region from a number of targets used as sources in this spectral region, for multi-shot irradiation at the same position on the target surface. The spectra involved result from unresolved transition arrays originating from n=3-n=4 transitions in medium-Z element plasmas and from n=4-n=4 transitions originating in high-Z plasmas. The output flux was maintained for the highest number of shots in the case of the high melting point element molybdenum, and the total output in the water window was 7.7*1013 photons/sr at a laser power density of 1.2*1014 W/cm2. PMID- 29714742 TI - Single-exposure full-field multi-depth imaging using low-coherence holographic multiplexing. AB - We present a new interferometric imaging approach that allows for multiple-depth imaging in a single acquisition, using off-axis low-coherence holographic multiplexing. This technique enables sectioned imaging of multiple slices within a thick sample, in a single image acquisition. Each slice has a distinct off-axis interference fringe orientation indicative of its axial location, and the camera acquires the multiplexed hologram containing the different slices at once. We demonstrate the proposed technique for amplitude and phase imaging of optically thick samples. PMID- 29714743 TI - Enhanced photon-phonon cross-Kerr nonlinearity with two-photon driving. AB - We propose a scheme to significantly enhance the cross-Kerr (CK) nonlinearity between photons and phonons in a quadratically coupled optomechanical system (OMS) with two-photon driving. This CK nonlinear enhancement originates from the parametric-driving-induced squeezing and the underlying nonlinear optomechanical interaction. Moreover, the noise of the squeezed mode can be suppressed completely by introducing a squeezed vacuum reservoir. As a result of this dramatic nonlinear enhancement and the suppressed noise, we demonstrate the feasibility of the quantum nondemolition measurement of the phonon number in an originally weak coupled OMS. In addition, the photon-phonon blockade phenomenon is also investigated in this regime, which allows for performing manipulations between photons and phonons. This Letter offers a promising route towards the potential application for the OMS in quantum information processing and quantum networks. PMID- 29714744 TI - Flexible and broadly tunable infrared light source based on shaped sub-10-fs pulses for a multimodal microscopy setup. AB - We present a versatile approach for mid-infrared spectroscopy through the flexible control of a difference-frequency-generation (DFG) process by femtosecond (fs) pulse shaping and spectral focusing. Based on a broadband sub-10 fs oscillator, the spectral position and spectral resolution can be independently selected within the molecular fingerprint region of more than 2000 cm-1. A spectral resolution better than 20 cm-1 can be achieved, which depends solely on the pulse shaper configuration. An absorption experiment on a polystyrene reference sample finally validates the concept and opens the door for an additional modality in nonlinear multimodal microscopy setups. PMID- 29714745 TI - Fast hyperspectral phase and amplitude imaging in scattering tissue. AB - Hyperspectral imaging in scattering tissue generally suffers from low light collection efficiency. In this Letter, we propose a microscope based on Fourier transform spectroscopy and oblique back-illumination microscopy that provides hyperspectral phase and amplitude images of thick, scattering samples with high throughput. Images can be acquired at >0.1 Hz rates with spectral resolution better than 200 cm-1, over a wide spectral range of 450-1700 nm. Proof-of principle demonstrations are presented with chorioallantoic membrane of a chick embryo, illustrating the possibility of high-resolution hemodynamics imaging in thick tissue, based on transmission contrast. PMID- 29714746 TI - Deformable mirror for wavefront shaping of infrared radiation. AB - We present proof-of-principle results on terahertz wavefront shaping by means of a deformable mirror (DM). The DM is based on a reflective gold-coated steel membrane pushed by 35 powerful stepper actuators to enable a surface deformation of up to 1 mm out of equilibrium. The maximum excursion is equivalent to 10 wavelengths of the terahertz source centered at 3 THz and, thus, offers excellent opportunities for shaping the terahertz wavefront and beam intensity profile. As a proof of principle, we demonstrate terahertz focal spot optimization towards the diffraction limit, focal depth shifting, and terahertz imaging application. The large aperture DM offers new opportunities for the wavefront manipulation demanded by high-field terahertz science. The extreme excursion range of the DM will be beneficial for beam shaping at other wavelengths, such as visible and UV. PMID- 29714747 TI - Frequency upconverted amplified spontaneous emission and lasing from inorganic perovskite under simultaneous six-photon absorption. AB - Multiphoton pumped stimulated emission requires simultaneous absorption of photons for the creation of population inversion to sustain optical amplification. Recently, stimulated emission by simultaneous absorption of up to five photons has been realized. To achieve more diverse nonlinear optical applications, it is desired to have more photons involved in the upconversion process. Here, we demonstrate unambiguously frequency upconverted amplified spontaneous emission and lasing via simultaneous six-photon absorption from inorganic perovskite. Our finding allows the utilization of inorganic perovskite as the novel alternative for higher-order multiphoton fluorescent applications. PMID- 29714748 TI - Nonlinear pulse compression in a gas-filled multipass cell. AB - We present an efficient method for compressing sub-picosecond pulses at 200 W average power with 2 mJ pulse energy in a multipass cell filled with different gases. We demonstrate spectral broadening by more than a factor of five using neon, argon, and nitrogen as nonlinear media. The 210 fs input pulses are compressed down to 37 fs and 35 GW peak power with a beam quality factor of 1.3*1.5 at a power throughput of >93%. This concept represents an excellent alternative to hollow-core fiber-based compression schemes and optical parametric amplifiers (OPAs). PMID- 29714749 TI - Multimodality endoscopic optical coherence tomography and fluorescence imaging technology for visualization of layered architecture and subsurface microvasculature. AB - Endoscopic imaging technologies, such as endoscopic optical coherence tomography (OCT) and near-infrared fluorescence, have been used to investigate vascular and morphological changes as hallmarks of early cancer in the gastrointestinal tract. Here we developed a high-speed multimodality endoscopic OCT and fluorescence imaging system. Using this system, the architectural morphology and vasculature of the rectum wall were obtained simultaneously from a Sprague Dawley rat in vivo. This multimodality imaging strategy in a single imaging system permits the use of a single imaging probe, thereby improving prognosis by early detection and reducing costs. PMID- 29714750 TI - Stretched graded-index multimode optical fiber as a saturable absorber for erbium doped fiber laser mode locking. AB - A novel mode-locking method based on the nonlinear multimode interference in the stretched graded-index multimode optical fiber (GIMF) is proposed in this Letter. The simple device geometry, where the light is coupled in and out of the stretched GIMF via single-mode fibers, is demonstrated to exhibit the temporal intensity discrimination required for mode locking. The nonlinear saturable absorber (SA) characteristics of the device are controllable by simply adjusting the strength of the stretching applied. The modulation depth of the device, which consists of ~23.5 cm GIMF, is tuned from 10.37% to 22.27%. Such a simple SA enables the wavelength-switchable mode-locking operation in a ring Er-doped fiber laser, and ultrafast pulses with a pulse width of 506 fs at 1572.5 nm and 416 fs at 1591.4 nm were generated. The versatility and simplicity of the SA device, together with the possibility of scaling the pulse energy, make it highly attractive in ultrafast photonics. PMID- 29714751 TI - Reconfigurable broadband mode (de)multiplexer based on an integrated thermally induced long-period grating and asymmetric Y-junction. AB - We propose a reconfigurable broadband mode (de)multiplexer based on a thermally induced long-period grating integrated with an asymmetric Y-junction. Either of the two spatial modes of a two-mode waveguide launched into the grating end of the device can be switched into either of the two output ports of the Y-junction by controlling the electric power applied to the electrode heater that induces the grating. Our typical device fabricated with polymer material that has a length of ~14 mm shows a mode selectivity higher than 12 dB over the C+L band at a switching power of 198 mW. The device could find applications in reconfigurable mode-division-multiplexing systems. PMID- 29714752 TI - Selectively transporting small chiral particles with circularly polarized Airy beams. AB - Based on the full wave simulation, we demonstrate that a circularly polarized vector Airy beam can selectively transport small chiral particles along a curved trajectory via the chirality-tailored optical forces. The transverse optical forces can draw the chiral particles with different particle chirality towards or away from the intensity maxima of the beam, leading to the selective trapping in the transverse plane. The transversely trapped chiral particles are then accelerated along a curved trajectory of the Airy beam by the chirality-tailored longitudinal scattering force, rendering an alternative way to sort and/or transport chiral particles with specified helicity. Finally, the underlying physics of the chirality induced transverse trap and de-trap phenomena are examined by the analytical theory within the dipole approximation. PMID- 29714753 TI - Adaptive spatiotemporal optical pulse front tilt using a digital micromirror device and its terahertz application. AB - We report a new method to temporally and spatially manipulate the pulse front tilt (PFT) intensity profile of an ultrashort optical pulse using a commercial microelectromechanical system, also known as a digital micromirror device (DMD). For our demonstration, we show terahertz generation in a lithium niobate crystal using the PFT pumping scheme derived from a DMD chip. The adaptive functionality of the DMD could be a convenient alternative to the more conventional grating required to generate a laser beam with a PFT intensity profile that is typically used for efficient optical rectification in noncollinear phase-matching conditions. In contrast to a grating, PFT using DMD does not suffer from wavelength dispersion, and exhibits overlap properties between grating and a stair-step echelon mirror. PMID- 29714754 TI - High-harmonic generation in solids driven by subcycle midinfrared pulses from two color filamentation. AB - Carrier-envelope-phase (CEP) controlled subcycle midinfrared pulses generated through two-color filamentation have been applied for high-harmonic (HH) generation in a crystalline silicon (Si) membrane. The HH spectrum reaches the ultraviolet region (<300 nm), beyond the direct band gap of Si. The shape of the HH spectrum strongly depends on the CEP. The complex CEP dependence can be explained with the interference between different orders of the harmonics. The complete waveform characterization of the subcycle driver pulse using frequency resolved optical gating capable of CEP determination plays a crucial role for investigation of the subcycle dynamics. PMID- 29714756 TI - Terahertz super-resolution imaging using four-wave mixing in graphene. AB - A perfect lens made from negative refraction (NR) materials is utilized to overcome the diffraction limit. However, these NR lenses are realized by metamaterials, which suffer from high losses, and the volume is bulky. In this Letter, we propose a terahertz NR lens by using a four-wave mixing (FWM) process in graphene. NR is demonstrated because of the phase matching along the surface of graphene. Evanescent waves that store high spatial frequency information can be converted into propagating waves in the nonlinear NR process. An image with subwavelength resolution is reconstructed at the FWM wavelength. Theoretical analysis and numerical simulations are performed to demonstrate the capability of such imaging. The lens has a subwavelength resolution of around lambda/5. The lens needs low field intensity due to the strong nonlinear response of graphene in the terahertz frequency. This Letter may have applications in terahertz microscopy. PMID- 29714755 TI - FSI-based non-cooperative target absolute distance measurement method using PLL correction for the influence of a nonlinear clock. AB - We propose a frequency swept interferometry (FSI)-based absolute distance measurement method that can be used to measure a noncooperative target located at a distance of 10s of m. In this method, an external cavity laser serves as the frequency tuning laser, and a single frequency laser and two acoustic optical modulators (AOMs) are used to measure the optical path difference (OPD) variation during the frequency tuning, which can correct the Doppler effect. A phase-locked loop (PLL) is introduced to synchronize the nonlinearities between the OPD variation measurement signal and the absolute distance measurement signal, improving the signal-to-noise ratio (SNR) of the OPD variation measurement signal. The distance to a noncooperative target located at 15 m is experimentally measured using this method, and a precision of 3.43 MUm is obtained. PMID- 29714757 TI - Highly efficient coupling of crystalline microresonators to integrated photonic waveguides. AB - Crystalline optical whispering gallery mode resonators made from alkaline earth fluorides can achieve exceptionally large optical finesse, and are used in a variety of applications, from frequency stabilization and narrow linewidth lasers, to low-noise microwave generation or soliton Kerr frequency combs. Here we demonstrate an efficient coupling method to resonators of these materials, which employs photonic integrated waveguides on a chip based on silicon nitride. By converting a mode from silicon nitride to a free-hanging silica waveguide on a silicon chip, coupling to a crystalline resonator is achieved with a high extinction, while preserving a quality factor exceeding 200 million. This compact, heterogeneous integration of ultra-high Q-factor crystalline resonators with photonic waveguides provides a proof of concept for wafer scale integration and robust, compact packaging for a wide range of applications. PMID- 29714758 TI - Model-free deflectometry for freeform optics measurement using an iterative reconstruction technique. AB - We present a novel model-free iterative data-processing approach that improves surface reconstruction accuracy for deflectometry tests of unknown surfaces. This new processing method iteratively reconstructs the surface, leading to reduced error in the final reconstructed surface. The method was implemented in a deflectometry system, and a freeform surface was tested and compared to interferometric test results. The reconstructed departure from interferometric results was reduced from 15.80 MUm RMS with model-based deflectometry down to 5.20 MUm RMS with the iterative technique reported here. PMID- 29714759 TI - Isolated attosecond pulse in the water window from many-cycle laser-driven plasma mirrors without pulse engineering. AB - High-order harmonic generation from relativistic laser-driven plasma mirrors is an attractive route to produce highly energetic attosecond pulses in the extreme ultraviolet to x-ray regime. To achieve an isolated attosecond pulse (IAP) driven by many-cycle intense laser pulses, pulse engineering techniques such as polarization modulation and wavefront rotation, are usually needed. Here we show that it is possible to generate an IAP without pulse engineering. Through particle-in-cell simulations, it is found that plasma mirrors can be rapidly heated and deformed in a relatively long preplasma regime. Intense IAP in the high-frequency spectral region is given rise once when the mirror parameters are suitable. The results may offer a new route to generate a bright IAP source for various applications such as bio-imaging and electronic dynamic studies. PMID- 29714760 TI - Ultrafast time-stretch microscopy based on dual-comb asynchronous optical sampling. AB - The ultrafast time-stretch microscopy based on a single-pixel detector has become a hotspot of the research, owing to its high sensitivity compared to those pixel sensors. However, gigahertz or tens of gigahertz acquisition bandwidth is required for this scheme, resulting in great expense for the whole imaging system and hindering its wide applications. In this Letter, a dual-comb asynchronous optical sampling is applied for the conventional time-stretch microscopy, whose ultrafast temporal axis is magnified by 9200 times. The acquisition bandwidth requirement is thus greatly relaxed, and 320 kHz bandwidth successfully resolves 2.3 MUm spatial resolution with tens of kilohertz frame rate. PMID- 29714761 TI - Coherent virtual absorption for discretized light. AB - Coherent virtual absorption (CVA) is a recently introduced phenomenon for which exponentially growing waves incident on a conservative optical medium are neither reflected nor transmitted, at least transiently. CVA has been associated with complex zeros of the scattering matrix and can be regarded as the time reversal of the decay process of a quasi-mode sustained by the optical medium. Here we consider CVA for discretized light transport in coupled resonator optical waveguides or waveguide arrays and show that a distinct kind of CVA, which is not related to the complex zero excitation of quasi-modes, can be observed. This result suggests that a scattering matrix analysis cannot fully capture CVA phenomena. PMID- 29714762 TI - Narrowband double-filtering hyperspectral imaging based on a single AOTF. AB - A method of spectral resolution improvement was presented based on the double filtering in a single AOTF. A special narrowband hyperspectral imaging system using this single-AOTF double-filtering method was established. The spectral bandwidth of double-filtered spectra was 39% narrower than that of the single filtered optical signal experimentally. We achieved hyperspectral images of the resolution target with better image resolutions than the single-filtering images because of the improved spectral resolution after the double-filtering process. PMID- 29714763 TI - Continuously tunable orbital angular momentum generation controlled by input linear polarization. AB - In this Letter, we theoretically and experimentally demonstrate a new method to generate tunable orbital angular momentum (OAM) by continuously changing the angle of linear polarization of the input light. We use the Fourier series of left- and right-hand projections to prove that the average OAM smoothly varied from l=-1 to l=1 with the angle of LP of input light changing from 0 to pi, which is fulfilled by an electrical polarization controller. PMID- 29714764 TI - Time domain diffuse Raman spectrometer based on a TCSPC camera for the depth analysis of diffusive media. AB - We present a time domain diffuse Raman spectrometer for depth probing of highly scattering media. The system is based on, to the best of our knowledge, a novel time-correlated single-photon counting (TCSPC) camera that simultaneously acquires both spectral and temporal information of Raman photons. A dedicated non contact probe was built, and time domain Raman measurements were performed on a tissue mimicking bilayer phantom. The fluorescence contamination of the Raman signal was eliminated by early time gating (0-212 ps) the Raman photons. Depth sensitivity is achieved by time gating Raman photons at different delays with a gate width of 106 ps. Importantly, the time domain can provide time-dependent depth sensitivity leading to a high contrast between two layers of Raman signal. As a result, an enhancement factor of 2170 was found for our bilayer phantom which is much higher than the values obtained by spatial offset Raman spectroscopy (SORS), frequency offset Raman spectroscopy (FORS), or hybrid FORS SORS on a similar phantom. PMID- 29714765 TI - All-optically tunable buffer for single photons. AB - We demonstrate a photon buffer for quantum communication systems via a quantum frequency conversion-dispersion technique based on Bragg scattering four-wave mixing. The all-fiber setup is capable of imparting all-optical and continuously tunable delays onto single photons with minimal photon noise and absorption. Tunable delays up to 23 times the photon duration are demonstrated with on/off efficiencies as high as 55%. PMID- 29714766 TI - Electro-mechanical control of an on-chip optical beam splitter containing an embedded quantum emitter. AB - We demonstrate electro-mechanical control of an on-chip GaAs optical beam splitter containing a quantum dot single-photon source. The beam splitter consists of two nanobeam waveguides, which form a directional coupler (DC). The splitting ratio of the DC is controlled by varying the out-of-plane separation of the two waveguides using electromechanical actuation. We reversibly tune the beam splitter between an initial state, with emission into both output arms, and a final state with photons emitted into a single output arm. The device represents a compact and scalable tuning approach for use in III-V semiconductor integrated quantum optical circuits. PMID- 29714767 TI - Simultaneous three-wavelength unwrapping using external digital holographic multiplexing module. AB - We present an external interferometric setup that is able to simultaneously acquire three wavelengths of the same sample instance without scanning or multiple exposures. This setup projects onto the monochrome digital camera three off-axis holograms with rotated fringe orientations, each from a different wavelength channel, without overlap in the spatial-frequency domain, and thus allows the full reconstruction of the three complex wavefronts from the three wavelength channels. We use this new setup for three-wavelength phase unwrapping, allowing phase imaging of thicker objects than possible with a single wavelength, but without the increased level of noise. We demonstrate the proposed technique for micro-channel profiling and label-free cell imaging. PMID- 29714768 TI - Optical vortices generated by edge dislocations in electro-convective instability arrays of nematic liquid crystals. AB - We demonstrated by means of interferometry that optical vortices can be generated by diffraction of a laser beam from a birefringent nematic liquid crystal that spontaneously creates a periodic array of electro-convective domains and edge dislocations under an applied electric field. The diffracted beam of order m produced by an elementary dislocation comprises a number |m| of distinct optical vortices, each with unit topological charge. Birefringent liquid crystal arrays provide a fast, convenient, and promising way of generating and studying optical vortices. The used materials are inexpensive, fabrication processes are simple, and both input polarization and applied field can be used as external controls to switch the optical vortices on and off. PMID- 29714769 TI - Interplay between spontaneous decay rates and Lamb shifts in open photonic systems. AB - In this Letter, we describe the modified decay rate and photonic Lamb (frequency) shift of quantum emitters in terms of the resonant states of a neighboring photonic resonator. This description illustrates a fundamental distinction in the behaviors of closed (conservative) and open (dissipative) systems: the Lamb shift is bounded by the emission linewidth in closed systems while it overcomes this limit in open systems. PMID- 29714770 TI - Absolute frequency of cesium 6S1/2-6D3/2 hyperfine transition with a precision to nuclear magnetic octupole interaction. AB - We have determined the fundamental frequency of the cesium atom 6S1/2-6D3/2 two photon transition, for the first time, to our knowledge. Moreover, our high resolution scheme made it possible to address the influence of the nuclear magnetic octupole on the hyperfine structure. We found that the octupole interaction hyperfine constant deduced from the cesium 6D-level has a value nearly eight times larger than what has been deduced from the 6P-level. PMID- 29714771 TI - Gouy phase shift measurement using interferometric second-harmonic generation. AB - We report on a simple way to directly measure the Gouy phase shift of a strongly focused laser beam. This is accomplished by using a recent technique, namely, interferometric second-harmonic generation. We expect that this method will be of interest in a wide range of research fields, from high-harmonic and attosecond pulse generation to femtochemistry and nonlinear microscopy. PMID- 29714772 TI - Silicon-based hybrid demultiplexer for wavelength- and mode-division multiplexing. AB - A silicon-based hybrid demultiplexer for wavelength-division multiplexing (WDM) and mode-division multiplexing (MDM) is proposed and demonstrated by integrating an M-channel-mode demultiplexer and N-channel WDM filters based on microring resonators (MRRs) with box-like responses. For the mode demultiplexer, the 2k-th output port is connected with the (2k+1)-th output port through the bus waveguide for the k-th MRR array, so that each MRR-based optical filter works bi directionally and provides two drop ports. As an example, a 32-channel hybrid MDM WDM demultiplexer is realized by integrating a 4-channel mode demultiplexer based on dual-core adiabatic tapers and two bi-directional MRR-based WDM filters with eight wavelength-channels. For the fabricated hybrid demultiplexer, the excess loss is 0.5-5 dB, the intermode cross talk is -16.5 to -23.5 dB, and the cross talks between the adjacent and nonadjacent wavelength channels are about -25 dB and -35 dB, respectively. PMID- 29714773 TI - Endoscopic optical coherence tomography enables morphological and subnanometer vibratory imaging of the porcine cochlea through the round window. AB - A highly phase stable hand-held (HH) endoscopic system has been developed for optical coherence tomography and vibrometry. Designed to transit the ear canal to the middle ear space and peer through the round window (RW), it is capable of imaging the vibratory function of the cochlear soft tissues with subnanometer scale sensitivity. A side-looking, 9 cm long rigid endoscope with a distal diameter of 1.2 mm, was able to fit within the RW niche and provide imaging access. The phase stability was achieved in part by fully integrating a Michelson interferometer into the HH device. Ex vivo imaging of a domestic pig demonstrated the system's ability for functional vibratory imaging of the cochlea via the RW. PMID- 29714774 TI - Probing electron-atom collision dynamics in gas plasma by high-order harmonic spectroscopy. AB - Plasma is a complex system involving diverse collisional processes and interactions, such as electron-impact excitation, ionization, recombination, etc. One of the most important methods for studying the properties and dynamics of plasma is to analyze the radiations from plasma. Here, we demonstrate the high order harmonic (HH) spectroscopy for probing the complex electron-atom collision (EAC) dynamics in a laser-induced gas plasma. These measurements were carried out by using an elliptically polarized pump and a time-delayed linearly polarized probe. The HH spectra from argon and krypton plasmas were recorded by scanning the time delay up to hundreds of picoseconds. We found that the delay-dependent HH yield contains three distinct regions, i.e., the first enhancement, the subsequent suppression, and the final restoration regions. A qualitative analysis shows that these features are clear signatures of the EAC processes and interactions involved in the delay-dependent HH spectroscopy. PMID- 29714775 TI - Orbital angular momentum transition of light using a cylindrical vector beam. AB - We demonstrate that using a single cylindrical vector (CV) beam in two-mode fibers, the orbital angular momentum of light can be switched among -1, 0, and 1. The input CV beam can be a conventional radial and azimuthal polarization distribution or a generalized CV beam, and we first use and verify that a rocking long period fiber grating generates the tunable generalized CV beam. Because of using a single CV beam as the light source, this approach not only provides an increased stability compared to the conventional superposed eigenmodes method, but also builds a bridge between the polarization singularity beams and the phase singularity beams. PMID- 29714776 TI - Integrated all-optical programmable logic array based on semiconductor optical amplifiers. AB - The all-optical programmable logic array (PLA) is one of the most important optical complex logic devices that can implement combinational logic functions. In this Letter, we propose and experimentally demonstrate an integrated all optical PLA at the operation speed of 40 Gb/s. The PLA mainly consists of a delay interferometer (DI) and semiconductor optical amplifiers (SOAs) of different lengths. The DI is used to pre-code the input signals and improve the reconfigurability of the scheme. The longer SOAs are nonlinear media for generating canonical logic units (CLUs) using four-wave mixing. The shorter SOAs are used to select the appropriate CLUs by changing the working states; then reconfigurable logic functions can be output directly. The results show that all the CLUs are realized successfully, and the optical signal-to-noise ratios are above 22 dB. The exclusive NOR gate and exclusive OR gate are experimentally demonstrated based on output CLUs. PMID- 29714777 TI - Quadrature detection for self-mixing interferometry. AB - We establish a new quadrature detection system for self-mixing interferometry using two photodiodes and a 22.5-deg rotated beam splitter. The method is based on a rotating beam splitter placed between the laser diode and the measured object, and two quadrature self-mixing signals can be obtained. Then, an arctangent phase algorithm can be used to demodulate the quadrature signal to acquire the object vibration information. This method simplifies the self-mixing signal demodulation process and allows us to demodulate the vibrating displacement more easily. The experimental results demonstrate the feasibility of quadrature detection for self-mixing optical measurement. This Letter provides guidance for the design of self-mixing interferometers. PMID- 29714778 TI - Angular momentum switching and orthogonal field construction of C-points. AB - In this Letter, we take on the non-trivial problem of transforming a C-point singularity into its orthogonal state by switching its angular momentum components. For homogeneous distribution, orthogonal transformation is a trivial operation using a single half-wave plate. For C-point singularity, this entails a change in the handedness without disturbing the index, followed by rotation of the state of polarizations in the distribution. Swapping the spin angular momentum (SAM) components of C-point singularities leads to index and handedness inversion, whereas, switching of orbital angular momentum (OAM) components results only in handedness inversion. By changing the SAM and OAM components in sequence, a C-point can be transformed into its orthogonal state. While experimentally demonstrating this, a spiral phase plate, which is a phase element, is shown to perform polarization transformation operation. PMID- 29714779 TI - Efficient point-by-point Bragg gratings fabricated in embedded laser-written silica waveguides using ultrafast Bessel beams. AB - We demonstrate highly efficient Bragg gratings written point-by-point by sequential single-pulse ultrashort Bessel laser beams in laser photoinscribed single-mode waveguides in bulk fused silica. The use of chirped non-diffractive Bessel beams determines a strong Bragg resonance in a weak-to-strong transitional regime, augmenting to a record value of 40 dB/cm at 1550 nm in the third order. The Bessel-induced refractive index modulation is negative and localized to sub micrometer (200 nm) transverse scales. The strong light confinement in Bessel beams ensuring uniform one-dimensional void conditions thus allows for enhanced precision in the Bragg grating waveguide design. We demonstrate flexible fabrication of multiplexed waveguide gratings for multiple and tunable spectral resonances. PMID- 29714780 TI - Measurement of differential modal group delay of a few-mode fiber using a Fourier domain mode-locked laser. AB - We propose and experimentally demonstrate a method for measuring the differential modal group delay (DMGD) of a few-mode fiber using a Fourier domain mode-locked laser (FDML). We use the fast frequency-swept, wavelength-tunable output of the FDML in order to perform time domain measurements of interference of the modes, which is further postprocessed to extract the DMGD. We demonstrate the measurement of DMGD for a commercial two-mode fiber over the C-band. This method is not limited by the magnitude of DMGD or the number of modes and is minimally affected by time-dependent polarization and mode fluctuations, environmental noise, and spectral resolution of instruments. PMID- 29714781 TI - Higher-order cladding mode excitation of femtosecond-laser-inscribed tilted FBGs. AB - We study the modal behavior of plane-by-plane femtosecond laser fabricated tilted fiber Bragg gratings (FBGs). The focus is on the differential strain and temperature sensitivities between the cladding mode resonances of an nth grating order and those of the (n-i)th orders (with i=1-n), which are collocated in the same wavelength range. Whereas the Bragg mode exhibits an axial strain sensitivity of 1.2 pm/MUepsilon, we experimentally show that the strain sensitivity of ultrahigh-order cladding modes is negative and at -1.99 pm/MUepsilon in the same spectral window. Using a finite element mode solver, the modal refractive index value is computed to be well below 1, thus confirming that these modes, in reality, are leaky modes. PMID- 29714782 TI - Phase imaging and synthetic aperture super-resolution via total internal reflection microscopy. AB - Total internal reflection microscopy is mainly used in its fluorescence mode and is the reference technique to image fluorescent proteins in the vicinity of cell membranes. Here, we show that this technique can easily become a phase microscope by simply detecting the coherent signal resulting from the interference between the field scattered by the probed sample and the total internal reflection. Moreover, combining several illumination angles permits generating synthetic aperture reconstructions with improved resolutions compared to standard label free microscopy techniques. PMID- 29714783 TI - Strong confinement of optical fields using localized surface phonon polaritons in cubic boron nitride. AB - Phonon polaritons (PhPs) are long-lived electromagnetic modes that originate from the coupling of infrared (IR) photons with the bound ionic lattice of a polar crystal. Cubic-boron nitride (cBN) is such a polar, semiconductor material which, due to the light atomic masses, can support high-frequency optical phonons. Here we report on random arrays of cBN nanostructures fabricated via an unpatterned reactive ion etching process. Fourier-transform infrared reflection spectra suggest the presence of localized surface PhPs within the reststrahlen band, with quality factors in excess of 38 observed. These can provide the basis of next generation IR optical components such as antennas for communication, improved chemical spectroscopies, and enhanced emitters, sources, and detectors. PMID- 29714784 TI - Phase-dependent laser acceleration of electrons with symmetrically driven silicon dual pillar gratings. AB - We present the demonstration of phase-dependent laser acceleration and deflection of electrons using a symmetrically driven silicon dual pillar grating structure. We show that exciting an evanescent inverse Smith-Purcell mode on each side of a dual pillar grating can produce hyperbolic cosine acceleration and hyperbolic sine deflection modes, depending on the relative excitation phase of each side. Our devices accelerate sub-relativistic 99.0 keV kinetic energy electrons by 3.0 keV over a 15 MUm distance with accelerating gradients of 200 MeV/m with 40 nJ, 300 fs, 1940 nm pulses from an optical parametric amplifier. These results represent a significant step towards making practical dielectric laser accelerators for ultrafast, medical, and high-energy applications. PMID- 29714785 TI - Filamentation of mid-IR pulses in ambient air in the vicinity of molecular resonances. AB - Properties of filaments ignited by multi-millijoule, 90 fs mid-infrared pulses centered at 3.9 MUm are examined experimentally by monitoring plasma density, losses, spectral dynamics and beam profile evolution at different focusing strengths. By changing from strong (f=0.25 m) to loose (f=7 m) focusing, we observe a shift from plasma-assisted filamentation to filaments with low plasma density. In the latter case, filamentation manifests itself by beam self symmetrization and spatial self-channeling. Spectral dynamics in the case of loose focusing is dominated by the nonlinear Raman frequency downshift, which leads to the overlap with the CO2 resonance in the vicinity of 4.2 MUm. The dynamic CO2 absorption in the case of 3.9 MUm filaments with their low plasma content is the main mechanism of energy losses and, either alone or together with other nonlinear processes, contributes to the arrest of intensity. PMID- 29714786 TI - Coherent injection of light into an absorbing scattering medium with a microscopic pore. AB - We demonstrate that interplay between absorption and scattering in a dielectric medium with a microscopic pore gives rise to eigenchannels concentrated in the pore. Such a circumvention of attenuation leads to high transmission. By exciting such eigenchannels in a disordered nanophotonic system with a wavefront shaping technique, we experimentally confirm enhanced injection at depths exceeding the limiting length scales set by scattering, absorption, and diffraction. PMID- 29714787 TI - Observation of an optical spring with a beam splitter. AB - We present the experimental observation of an optical spring without the use of an optical cavity. The optical spring is produced by interference at a beam splitter and, in principle, does not have the damping force associated with optical springs created in detuned cavities. The experiment consists of a Michelson-Sagnac interferometer (with no recycling cavities) with a partially reflective GaAs microresonator as the beam splitter that produces the optical spring. Our experimental measurements at input powers of up to 360 mW show the shift of the optical spring frequency as a function of power and are in excellent agreement with theoretical predictions. In addition, we show that the optical spring is able to keep the interferometer stable and locked without the use of external feedback. PMID- 29714788 TI - 2.6 mJ/100 Hz CEP-stable near-single-cycle 4 MUm laser based on OPCPA and hollow-core fiber compression. AB - A carrier-envelope-phase-stable near-single-cycle mid-infrared laser based on optical parametric chirped pulse amplification and hollow-core fiber compression is demonstrated. A 4 MUm laser pulse with 11.8 mJ energy is delivered from a KTA based optical parametric chirped pulse amplification (OPCPA) with 100 Hz repetition rate, and compressed to 105 fs by a two-grating compressor with efficiency over 50%. Subsequently, the pulse spectrum is broadened by employing a krypton gas-filled hollow-core fiber. Then, the pulse duration is further compressed to 21.5 fs through a CaF2 bulk material with energy of 2.6 mJ and energy stability of 0.9% RMS, which is about 1.6 cycles for a 4 MUm laser pulse. The carrier envelope phase of the near-single-cycle 4 MUm laser pulse is passively stabilized with 370 mrad. PMID- 29714789 TI - New autofocus and reconstruction method based on a connected domain. AB - In this Letter, we propose a new method for auto-focusing and reconstruction without defocus noise in optical scanning holography. By using a connected domain (CD) to calculate the area of different domains, which are labeled by a connected component, the focus distance can be found via the smallest area of each CD. Meanwhile, the sectional images without defocus noise can also be reconstructed based on the labeled domains. The effectiveness of this method has been verified with a simulation and experiments. PMID- 29714790 TI - Fast and robust standard-deviation-based method for bulk motion compensation in phase-based functional OCT. AB - Phase-based optical coherence tomography (OCT), such as OCT angiography (OCTA) and Doppler OCT, is sensitive to the confounding phase shift introduced by subject bulk motion. Traditional bulk motion compensation methods are limited by their accuracy and computing cost-effectiveness. In this Letter, to the best of our knowledge, we present a novel bulk motion compensation method for phase-based functional OCT. Bulk motion associated phase shift can be directly derived by solving its equation using a standard deviation of phase-based OCTA and Doppler OCT flow signals. This method was evaluated on rodent retinal images acquired by a prototype visible light OCT and human retinal images acquired by a commercial system. The image quality and computational speed were significantly improved, compared to two conventional phase compensation methods. PMID- 29714791 TI - Focusing short-wavelength surface plasmons by a plasmonic mirror. AB - Emerging applications in nanotechnology, such as superresolution imaging, ultra sensitive biomedical detection, and heat-assisted magnetic recording, require plasmonic devices that can generate intense optical spots beyond the diffraction limit. One of the important drawbacks of surface plasmon focusing structures is their complex design, which is significant for ease of integration with other nanostructures and fabrication at low cost. In this study, a planar plasmonic mirror without any nanoscale features is investigated that can focus surface plasmons to produce intense optical spots having lateral and vertical dimensions of lambda/9.7 and lambda/80, respectively. Intense optical spots beyond the diffraction limit were produced from the plasmonic parabolic mirror by exciting short-wavelength surface plasmons. The refractive index and numerical aperture of the plasmonic parabolic mirror were varied to excite short-wavelength surface plasmons. Finite-element method simulations of the plasmonic mirror and scanning near-field optical microscopy experiments have shown very good agreement. PMID- 29714792 TI - Microwave-assisted Rydberg electromagnetically induced transparency: publisher's note. AB - This publisher's note corrects an error on page 1 in Opt. Lett.43, 1822 (2018).OPLEDP0146-959210.1364/OL.43.001822. PMID- 29714793 TI - Towards femtosecond-level intrinsic laser synchronization at fourth generation light sources. AB - In this Letter, the proof of principle for a scheme providing intrinsic femtosecond-level synchronization between an external laser system and fourth generation light sources is presented. The scheme is applicable at any accelerator-based light source that is based on the generation of coherent radiation from ultrashort electron bunches such as superradiant terahertz (THz) facilities or X-FELs. It makes use of a superradiant THz pulse generated by the accelerator as an intrinsically synchronized gate signal for electro-optical slicing. We demonstrate that the scheme enables a reduction of the timing instability by more than 2 orders of magnitude. This demonstration experiment thereby proves that intrinsically synchronized time-resolved experiments utilizing laser and accelerator-based radiation pulses on few tens of femtosecond (fs) to few fs timescales are feasible. PMID- 29714794 TI - Dual-channel operation in a synchronously pumped optical parametric oscillator for the generation of broadband mid-infrared coherent light sources. AB - We report, to the best of our knowledge, a novel approach for generating broadband mid-infrared (mid-IR) light by implementing a dual-channel scheme in a synchronously pumped optical parametric oscillator (SPOPO). Two-channel operation was achieved by inserting a prism pair and two reflection mirrors inside an optical parametric oscillator (OPO) cavity. Pumped by a Yb-fiber laser, the OPO generated an idler wave at ~3150 nm with a -10 dB bandwidth of ~13.2 THz, which was twice as much as that of the pump source. This scheme represents a promising technical route to transform conventional SPOPOs into a device capable of generating mid-IR light with very broad instantaneous bandwidth. PMID- 29714795 TI - Humidity-swing mechanism for CO2 capture from ambient air. AB - A humidity-swing polymeric sorbent captures CO2 from ambient air at room temperature simply by changing the humidity level. To date there has been no direct experimental evidence to characterize the chemical mechanism for this process. In this report we describe the use of solid-state NMR to study the humidity-swing CO2 absorption/desorption cycle directly. We find that at low humidity levels CO2 is absorbed as HCO3-. At high humidity levels, HCO3- is replaced by hydrated OH- and the absorbed CO2 is released. PMID- 29714796 TI - The influence of surface functionalization on thermal transport and thermoelectric properties of MXene monolayers. AB - The newest members of a two-dimensional material family, involving transition metal carbides and nitrides (called MXenes), have garnered increasing attention due to their tunable electronic and thermal properties depending on the chemical composition and functionalization. This flexibility can be exploited to fabricate efficient electrochemical energy storage (batteries) and energy conversion (thermoelectric) devices. In this study, we calculated the Seebeck coefficients and lattice thermal conductivity values of oxygen terminated M2CO2 (where M = Ti, Zr, Hf, Sc) monolayer MXene crystals in two different functionalization configurations (model-II (MD-II) and model-III (MD-III)), using density functional theory and Boltzmann transport theory. We estimated the thermoelectric figure-of-merit, zT, of these materials by two different approaches, as well. First of all, we found that the structural model (i.e. adsorption site of oxygen atom on the surface of MXene) has a paramount impact on the electronic and thermoelectric properties of MXene crystals, which can be exploited to engineer the thermoelectric properties of these materials. The lattice thermal conductivity kappal, Seebeck coefficient and zT values may vary by 40% depending on the structural model. The MD-III configuration always has the larger band gap, Seebeck coefficient and zT, and smaller kappal as compared to the MD-II structure due to a larger band gap, highly flat valence band and reduced crystal symmetry in the former. The MD-III configuration of Ti2CO2 and Zr2CO2 has the lowest kappal as compared to the same configuration of Hf2CO2 and Sc2CO2. Among all the considered structures, the MD-II configuration of Hf2CO2 has the highest kappal, and Ti2CO2 and Zr2CO2 in the MD-III configuration have the lowest kappal. For instance, while the band gap of the MD-II configuration of Ti2CO2 is 0.26 eV, it becomes 0.69 eV in MD-III. The zTmax value may reach up to 1.1 depending on the structural model of MXene. PMID- 29714797 TI - Compositional ripening of particle-stabilized drops in a three-liquid system. AB - We present experimental studies of two aqueous drops, stabilized by colloidal silica, which are placed close to each other in a bath of toluene, ethanol and surplus colloidal silica. If one of the drops is enriched in ethanol while the other is pure water then we observe the spontaneous formation of small droplets at the surface of the water drop closest to its neighbour. These droplets are then observed to form all along the path to the ethanol enriched drop until they make a complete bridge. We relate this behaviour to the diffusion pathways on the underlying three-fluid phase diagram. We argue that the phenomena is a version of compositional ripening where the transfer of the dispersed phase leads to the spontaneous formation of droplets in the continuous phase. We show that, while the large drops are particle-stabilized, the spontaneously formed droplets are not. Instead the presence of surplus particles leads to the droplets gelling as an elastic bridge. The phenomenology at long times and at low particle concentrations becomes increasingly surprising. PMID- 29714798 TI - Screening tools for the bioconcentration potential of monovalent organic ions in fish. AB - Currently the bioaccumulation potential of organic chemicals is assessed in a first tier approach via their octanol-water partition coefficient. This approach has been developed for neutral chemicals and cannot work for ionizable and ionic chemicals because the latter have different sorption-mechanisms and -preferences. Thus, suitable screening tools for the bioconcentration potential of ionic and ionizable chemicals need to be developed because it cannot be expected that these chemicals are non-bioaccumulative per se. Here, we present such screening tools for monovalent ions and ionizable chemicals based on calibrated sorption models for membrane lipids, structural proteins and albumin. The molecular descriptors used for these models arise from quantum chemical calculations and are based on COSMO-RS theory. When we applied our screening tools to 1839 preselected chemicals from the REACH registration data base, we identified 187 chemicals as potentially bioconcentrating (still ignoring any kind of metabolism). Among these were carbon and sulphur based aromatic and aliphatic acids mostly with a rather high molecular surface area. We hope that this outcome will trigger further research on ion specific sorption mechanisms and lead to a re-evaluation of the bioconcentration potential of ionic chemicals. PMID- 29714804 TI - Outstanding Reviewers for Lab on a Chip in 2017. PMID- 29714801 TI - Chemo-enzymatic synthesis of isotopically labeled nicotinamide riboside. AB - As a cofactor for numerous reactions, NAD+ is found widely dispersed across many maps of cellular metabolism. This core redox role alone makes the biosynthesis of NAD+ of great interest. Recent studies have revealed new biological roles for NAD+ as a substrate for diverse enzymes that regulate a broad spectrum of key cellular tasks. These NAD+-consuming enzymes further highlight the importance of understanding NAD+ biosynthetic pathways. In this study, we developed a chemo enzymatic synthesis of isotopically labeled NAD+ precursor, nicotinamide riboside (NR). The synthesis of NR isotopomers allowed us to unambiguously determine that NR is efficiently converted to NAD+ in the cellular environment independent of degradation to nicotinamide, and it is incorporated into NAD+ in its intact form. The versatile synthetic method along with the isotopically labeled NRs will provide powerful tools to further decipher the important yet complicated NAD+ metabolism. PMID- 29714805 TI - Molecular engineering of logic gate types by module rearrangement in 'Pourbaix Sensors': the effect of excited-state electric fields. AB - Two types of fluorescent logic gates are accessed from two different arrangements of the same modular components, one as an AND logic gate (1) and the other as a PASS 0 logic gate (2). The logic gates were designed with an 'electron-donor spacer1-fluorophore-spacer2-receptor' format and demonstrated in 1 : 1 (v/v) methanol/water. The molecules consist of ferrocene as the electron donor, 4 aminonaphthalimide as the fluorophore and a tertiary alkylamine as the receptor. In the presence of high H+ and Fe3+ levels, regioisomers 1a and 1b switch 'on' as AND logic gates with fluorescence enhancement ratios of 16-fold and 10-fold, respectively, while regioisomers 2a and 2b are functionally dormant, exhibiting no fluorescence switching. The PASS 0 logic of 2a and 2b results from the transfer of an electron from the excited state fluorophore to the ferrocenium unit under oxidising conditions as predicted by DFT calculations. Time-resolved fluorescence spectroscopy provided lifetimes of 8.3 ns and 8.1 ns for 1a and 1b, respectively. The transient signal recovery rate of 1b is ~10 ps while that of 2b is considerably longer on the nanosecond timescale. The divergent logic attributes of 1 and 2 highlight the importance of field effects and opens up a new approach for regulating logic-based molecules. PMID- 29714808 TI - ? PMID- 29714807 TI - [Time to limit the use of antibiotics in rosacea!] AB - Rosacea is a chronic inflammatory disease with facial erythema and papulopustules. It is common in middle-aged/elderly persons and often affects self-perception and social well-being. It is generally classified into four subtypes. Improved understanding of pathophysiology has resulted in novel treatment approaches, but routine management in health care usually follows old trails. Most patients are managed in primary care. Greater attention to the reduced skin barrier, avoidance of exacerbating factors, better topicals and encouragement to topical maintenance treatment should reduce the use of oral tetracyclines. Low-dose isotretinoin is reserved for treatment-resistant patients, but relapses are frequent unlike its use in acne. In order to reduce antibiotic use, we propose that patients should be referred to a dermatologist for optimization of therapy including consideration of isotretinoin following tetracycline treatment of a maximum of 4-6 months. PMID- 29714809 TI - ? PMID- 29714810 TI - Divergent effects of strontium and calcium-sensing receptor positive allosteric modulators (calcimimetics) on human osteoclast activity. AB - BACKGROUND AND PURPOSE: Strontium ranelate, a drug approved and until recently used for the treatment of osteoporosis, mediates its effects on bone at least in part via the calcium-sensing (CaS) receptor. However, it is not known whether bone-targeted CaS receptor positive allosteric modulators (PAMs; calcimimetics) represent an alternative (or adjunctive) therapy to strontium (Sr2+ o ). EXPERIMENTAL APPROACH: We assessed three structurally distinct calcimimetics [cinacalcet, AC-265347 and a benzothiazole tri-substituted urea (BTU-compound 13)], alone and in combination with extracellular calcium (Ca2+ o ) or Sr2+ o , in G protein-dependent signalling assays and trafficking experiments in HEK293 cells and their effects on cell differentiation, tartrate-resistant acid phosphatase (TRAP) activity and hydroxyapatite resorption assays in human blood derived osteoclasts. KEY RESULTS: Sr2+ o activated CaS receptor-dependent signalling in HEK293 cells in a similar manner to Ca2+ o , and inhibited the maturation, TRAP expression and hydroxyapatite resorption capacity of human osteoclasts. Calcimimetics potentiated Ca2+ o - and Sr2+ o -mediated CaS receptor signalling in HEK293 cells with distinct biased profiles, and only cinacalcet chaperoned an endoplasmic reticulum-retained CaS mutant receptor to the cell surface in HEK293 cells, indicative of a conformational state different from that engendered by AC-265347 and BTU-compound 13. Intriguingly, only cinacalcet modulated human osteoclast function, reducing TRAP activity and profoundly inhibiting resorption. CONCLUSION AND IMPLICATIONS: Although AC-265347 and BTU compound 13 potentiated Ca2+ o - and Sr2+ o -induced CaS receptor activation, they neither replicated nor potentiated the ability of Sr2+ o to inhibit human osteoclast function. In contrast, the FDA-approved calcimimetic, cinacalcet, inhibited osteoclast TRAP activity and hydroxyapatite resorption, which may contribute to its clinical effects on bone mineral density LINKED ARTICLES: This article is part of a themed section on Molecular Pharmacology of GPCRs. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v175.21/issuetoc. PMID- 29714811 TI - Gallbladder carcinoma: An analysis of the national cancer data base to examine hispanic influence. AB - BACKGROUND: Gallbladder cancer (GBC) is a lethal disease with high incidence among Hispanics. Overall survival (OS) among races/ethnicities has not been described using the most recent National Cancer Database. This study hypothesized that prognosis is worse for Hispanics compared to similar non-Hispanic populations. METHODS: Patients with GBC were identified from the National Cancer Database and categorized as White, Black, Hispanic, and Other. Descriptive statistics, OS, and Cox regression were examined. RESULTS: The study identified 12 952 patients. Median age was 71 years and 68.8% were female. The study characterized 69.8% White, 13.9% Black, 11.0% Hispanic, and 5.4% other patients. A 5-year OS curves differed, with survival highest in Hispanic patients (27% vs 23% Other, 18% White, and 17% Black, P < 0.001). Hispanics presented at younger ages (67 vs 72 years, P < 0.001), were more likely to be uninsured (17.3% vs 3.9% P < 0.001), had lower income (P < 0.001), and education levels (P < 0.001) compared to Whites. Following multivariable modeling, treatment at an academic facility (HR 0.90, 95%CI 0.84-0.97) and year of diagnosis (HR 0.90, 95%CI 0.88 0.92) related to survival. Hispanic ethnicity did not show significance (P = 0.207). DISCUSSION: Hispanic ethnicity exhibits the highest OS for GBC, but after adjusting for covariates, this influence is not significant. PMID- 29714812 TI - Synthesis of Renewable meta-Xylylenediamine from Biomass-Derived Furfural. AB - We report the synthesis of biomass-derived functionalized aromatic chemicals from furfural, a building block nowadays available in large scale from low-cost biomass. The scientific strategy relies on a Diels-Alder/aromatization sequence. By controlling the rate of each step, it was possible to produce exclusively the meta aromatic isomer. In particular, through this route, we describe the synthesis of renewably sourced meta-xylylenediamine (MXD). Transposition of this work to other furfural-derived chemicals is also discussed and reveals that functionalized biomass-derived aromatics (benzaldehyde, benzylamine, etc.) can be potentially produced, according to this route. PMID- 29714813 TI - Statin use associated with lower risk of epilepsy after intracranial haemorrhage: A population-based cohort study. AB - AIMS: To examine the association between statin use before and after intracranial haemorrhage (ICH) and the risk of poststroke epilepsy (PSE). METHODS: Patients with new-onset ICH between 2004 and 2012 were identified from the Taiwan National Health Insurance Research Database. The main outcome was the occurrence of epilepsy after stroke. Multivariable Cox regression modelling was used to estimate the association between statin use and the risk of PSE, with poststroke medication exposures being treated as time-dependent variables. RESULTS: A total of 7435 patients with ICH were enrolled with a median follow-up of 17.6 months. Within the study cohort, 709 patients developed PSE. Poststroke, but not prestroke, stain use was associated with a reduced risk of PSE (adjusted hazard ratio 0.62, 95% confidence interval 0.42-0.90, P = 0.01). In subanalyses, a trend of a dose-response relationship was observed. A significant PSE risk reduction was correlated with a higher cumulative statin dose. Moreover, the risk of PSE was lower in patients receiving moderate-to-high-intensity statin therapy (adjusted hazard ratio 0.37, 95% confidence interval 0.18-0.75, P = 0.01). Lipophilic and hydrophilic statins were similar with regard to their associations with the reduced risk of PSE. CONCLUSIONS: Statin therapy may reduce the risk of PSE after ICH, especially with moderate-to-high therapy intensity. Further research is needed to understand the mechanisms underlying the potential protective effects of statins against PSE in this patient population. PMID- 29714814 TI - A Redox-Active Bridging Ligand to Promote Spin Delocalization, High-Spin Complexes, and Magnetic Multi-Switchability. AB - A dinuclear CoII complex, [Co2 (tphz)(tpy)2 ]n+ (n=4, 3 or 2; tphz: tetrapyridophenazine; tpy: terpyridine), has been assembled using the redox active and strongly complexing tphz bridging ligand. The magnetic properties of this complex can be tuned from spin-crossover with T1/2 ~470 K for the pristine compound (n=4) to single-molecule magnet with an ST =5/2 spin ground state when once reduced (n=3) to finally a diamagnetic species when twice reduced (n=2). The two successive and reversible reductions are concomitant with an increase of the spin delocalization within the complex, promoting remarkably large magnetic exchange couplings and high-spin species even at room temperature. PMID- 29714815 TI - B-Heterocyclic Carbene Arising from Charge Shift: A Computational Verification. AB - 1-Borabicyclo[1.1.0]but-2(3)-ene (1BB) is a singlet biradical with two single electrons that can form an ionic resonance structure through a charge shift. The ionic resonance structure is a B-heterocyclic carbene (BHC), which can act as a carbene, Lewis base, or L- and Z-type ligand, to give adducts and complexes. Through a range of quantum methods, four types of stable compounds (A-D) derived from 1BB have been designed. These compounds retain the unique features of 1BB. As a consequence, the structures, stability, and Wiberg bond indices of the Lewis adducts of A-D with Lewis acids (BePh2 , BH3 , AlH3 , AlCl3 , C5 BH5 , and C13 BH9 ) and CuI , AgI , and AuI complexes have been investigated. Results show that A-D can indeed react as carbenes. Interestingly, compounds A-D, as L-type ligands, can attach to BePh2 , BH3 , AlH3 , AlCl3 , C5 BH5 , C13 BH9 , and CuCl and form compounds with planar tetracoordinate carbon (ptC), whereas Z-type ligands A-D can bind to AgCl and AuCl to provide complexes with planar tetracoordinate boron (ptB). In addition, the binuclear complexes of ClX(1BB)CuCl (X=Ag, Au) have been studied and A-D behave as both L- and Z-type ligands, in which these complexes contain both ptC and ptB. Thus, a novel method for designing compounds with ptC and ptB is presented. These rationally designed compounds involve the elements of carbene, ptC, ptB, and L- and Z-type ligands, and are expected to be unique and useful in experimental chemistry once they are synthesized. PMID- 29714816 TI - Sentinel lymph node metastasis in primary cutaneous basosquamous carcinoma. A cross-sectional study. AB - BACKGROUND AND OBJECTIVES: Basosquamous carcinoma (BSC) is a rare, biologically aggressive tumor. This cross-sectional study aims to define risk factors for subclinical nodal metastasis in primary BSC, and identify the patients who would benefit from routine sentinel node biopsy (SLNB) as part of the initial management. METHODS: A total of 142 patients, with histologically proven BSC without palpable lymph nodes, underwent SLNB after the initial excision. Clinicopathological features and demographics were analyzed between the patients with detected micrometastasis (SLNM) and those with negative SLN. RESULTS: In 7.7% patients, subcapsular and <0.1 mm SLNM were found. The frequency of SLNM was 0.9%, 11.8%, and 80.0% in patients with maximum lesion diameter <= 2 cm, 2.1-3.0 cm and >3.0 cm, respectively (P < 0.001) and was strongly associated with perineural (P < 0.001; OR = 26.46, 95% CI = 5.62-124.52) and lymphatic invasion (P < 0.001; OR = 17.35, 95% CI = 4.44-67.91). Within 18-84 months, no recurrence or metastasis were observed in SLNM positive patients. False negative SLNB rate of 15.4% was recorded. CONCLUSION: Cutaneous BSC is associated with early nodal metastatic potential. Tumor size >2 cm, lymphatic and perineural invasion are significant determinants for SLN micrometastasis. In the absence of palpable lymphadenopathy, wide resection and SLNB with long-term follow-up are highly recommended in these patients. PMID- 29714817 TI - Supramolecular Reassembly of Self-Exfoliated Ionic Covalent Organic Nanosheets for Label-Free Detection of Double-Stranded DNA. AB - Ionic covalent organic nanosheets (iCONs), a member of the two-dimensional (2D) nanomaterials family, offer a unique functional platform for a wide range of applications. Herein, we explore the potential of an ethidium bromide (EB)-based covalent organic framework (EB-TFP) that self-exfoliates in water resulting in 2D ionic covalent organic nanosheets (EB-TFP-iCONs) for the selective detection of double-stranded DNA (dsDNA). In an aqueous medium, the self-exfoliated EB-TFP iCONs reassemble in the presence of dsDNA resulting in hybrid EB-TFP-iCONs-DNA crystalline nanosheets with enhanced fluorescence at 600 nm. Detailed steady state and time-resolved emission studies revealed that the reassembly phenomenon was highly selective for dsDNA when compared to single-stranded DNA (ssDNA), which allowed us to use the EB-TFP-iCONs as a 2D fluorescent platform for the label-free detection of complementary DNA strands. PMID- 29714818 TI - Synthesis of beta-Substituted gamma-Aminobutyric Acid Derivatives through Enantioselective Photoredox Catalysis. AB - beta-Substituted chiral gamma-aminobutyric acids feature important biological activities and are valuable intermediates for the synthesis of pharmaceuticals. Herein, an efficient catalytic enantioselective approach for the synthesis of beta-substituted gamma-aminobutyric acid derivatives through visible-light induced photocatalyst-free asymmetric radical conjugate additions is reported. Various beta-substituted gamma-aminobutyric acid analogues, including previously inaccessible derivatives containing fluorinated quaternary stereocenters, were obtained in good yields (42-89 %) and with excellent enantioselectivity (90-97 % ee). Synthetically valuable applications were demonstrated by providing straightforward synthetic access to the pharmaceuticals or related bioactive compounds (S)-pregabalin, (R)-baclofen, (R)-rolipram, and (S)-nebracetam. PMID- 29714819 TI - Complete Posterior Sagittal Anorectal Mobilization (PSAM): A new surgical approach for pediatric pelvic-perineal tumor resections. AB - INTRODUCTION: Diffuse or massive tumors involving the perineal and pelvic compartments may require aggressive surgical treatment in children. The authors, propose and present their results using a Posterior Sagittal Anorectal Mobilization (PSAM) METHODS: The oncologic patient is placed in a prone position with the pelvis elevated, without a previous colostomy. A 10 Ch bladder catheter is positioned. A midline sagittal incision is performed from the coccyx to the posterior margin of the anus. Fine electrocautery is used to obtain an accurate dissection all around the anal margin itself. The incisional so involves the midline dissection into the perineal body. Reconstruction is achieved by the classical pelvic-perineal anatomical structure approximation. RESULTS: The authors describe for the first time a novel posterior anorectal mobilization technique for four children with pelvic-perineal tumors. No intraoperative or post-operative complications occurred. The oldest boy presented at follow-up a complete normal faecal and urinary continence (Krickenbeck criteria). CONCLUSION: The presented technical approach, defined as PSAM, is completely suitable for surgical resection of perineal-pelvic tumors, without the need of more invasive operations including transpubic dissection and/or anorectal split. Moreover, nervous and muscular sphincter structures are easily identified and preserved. PMID- 29714820 TI - Controlling the Self-Metalation Rate of Tetraphenylporphyrins on Cu(111) via Cyano Functionalization. AB - The reaction rate of the self-metalation of free-base tetraphenylporphyrins (TPPs) on Cu(111) increases with the number of cyano groups (n=0, 1, 2, 4) attached at the para positions of the phenyl rings. The findings are based on isothermal scanning tunneling microscopy (STM) measurements. At room temperature, all investigated free-base TPP derivatives adsorb as individual molecules and are aligned with respect to densely packed Cu substrate rows. Annealing at 400 K leads to the formation of linear dimers and/or multimers via CN-Cu-CN bonds, accompanied by self-metalation of the free-base porphyrins following a first order rate equation. When comparing the non-cyano-functionalized and the tetracyano-functionalized molecules, we find a decrease of the reaction rate by a factor of more than 20, corresponding to an increase of the activation energy from 1.48 to 1.59 eV. Density functional theory (DFT) calculations give insights into the influence of the peripheral electron-withdrawing cyano groups and explain the experimentally observed effects. PMID- 29714821 TI - Atmospheric deposition and exceedances of critical loads from 1800-2025 for the conterminous United States. AB - Atmospheric deposition of nitrogen (N) and sulfur (S) has increased dramatically over pre-industrial levels, with many potential impacts on terrestrial and aquatic ecosystems. Quantitative thresholds, termed "critical loads" (CLs), have been developed to estimate the deposition rate above which damage is thought to occur. However, there remains no comprehensive comparison of when, where, and over what time periods individual CLs have been exceeded. We addressed this knowledge gap by combining several published data sources for historical and contemporary deposition, and overlaying these on six CL types from the National Critical Loads Database (NCLDv2.5; terrestrial acidification, aquatic acidification, lichen, nitrate leaching, plant community composition, and forest tree health) to examine exceedances from 1800 to 2011. We expressed CLs as the minimum, 10th, and 50th percentiles within 12-km grid cells. Minimum CLs were relatively uniform across the country (200-400 eq.ha-1 .yr-1 ), and have been exceeded for decades beginning in the early 20th century. The area exceeding minimum CLs peaked in the 1970s and 1980s, exposing 300,000 to 3 million km2 (depending on the CL type) to harmful levels of deposition, with a total area exceeded of 5.8 million km2 (~70% of the conterminous United States). Since then, deposition levels have dropped, especially for S, with modest reductions in exceedance by 2011 for all CL types, totaling 5.2 million km2 in exceedance. The 10th and 50th percentile CLs followed similar trends, but were not consistently available at the 12-km grid scale. We also examined near-term future deposition and exceedances in 2025 under current air quality regulations, and under various scenarios of climate change and additional nitrogen management controls. Current regulations were projected to reduce exceedances of any CL from 5.2 million km2 in 2011 to 4.8 million km2 in 2025. None of the additional N management or climate scenarios significantly affected areal exceedances, although exceedance severity declined. In total, it is clear that many CLs have been exceeded for decades, and are likely to remain so in the short term under current policies. Additionally, we suggest many areas for improvement to enhance our understanding of deposition and its effects to support informed decision making. PMID- 29714822 TI - Mixing Halogens To Assemble an All-Inorganic Layered Perovskite with Warm White Light Emission. AB - Most of single-component white-light-emitting materials focus on organic inorganic hybrid perovskites, metal-organic frameworks, as well as all-inorganic semiconductors. In this work, we successfully assembled an all-inorganic layered perovskite by mixing two halogens of distinct ionic radii, namely, Rb2 CdCl2 I2 , which emits "warm" white light with a high color rendering index of 88. To date, Rb2 CdCl2 I2 is the first single-component white-light-emitting material with an all-inorganic layered perovskite structure. Furthermore, Rb2 CdCl2 I2 is thermally highly stable up to 575 K. A series of luminescence measurements show that the white-light emission arises from the lattice deformation, which are closely related to the [CdCl4 I2 ]2- octahedra with high distortion from the distinct ionic radii of Cl and I. The first-principles calculations reveal that both the Cl and I components make significant contributions to the electronic band structures of Rb2 CdCl2 I2 . These findings indicate that mixing halogens is an effective route to design and synthesize new single-component white-light emitting materials. PMID- 29714823 TI - Compartmentalization of Incompatible Polymers within Metal-Organic Frameworks towards Homogenization of Heterogeneous Hybrid Catalysts for Tandem Reactions. AB - New catalytic systems that contain incompatible catalytic sites were constructed by the in situ polymerization of acidic and basic polymers into metal-organic frameworks, which resulted in highly porous, recyclable, and durable catalytic composites with excellent compartmentalization, so that opposing agents were spatially isolated. These synthesized hybrid catalysts exhibited excellent catalytic activity for one-pot "wolf and lamb" reactions (deacetalization/Knoevenagel or Henry), which was attributed to their unique characteristic of having a locally homogeneous, but globally heterogeneous, structure. PMID- 29714824 TI - Physiologically-based pharmacokinetic model of vaginally administered dapivirine ring and film formulations. AB - AIMS: A physiologically-based pharmacokinetic (PBPK) model of the vaginal space was developed with the aim of predicting concentrations in the vaginal and cervical space. These predictions can be used to optimize the probability of success of vaginally administered dapivirine (DPV) for HIV prevention. We focus on vaginal delivery using either a ring or film. METHODS: A PBPK model describing the physiological structure of the vaginal tissue and fluid was defined mathematically and implemented in MATLAB. Literature reviews provided estimates for relevant physiological and physiochemical parameters. Drug concentration-time profiles were simulated in luminal fluids, vaginal tissue and plasma after administration of ring or film. Patient data were extracted from published clinical trials and used to test model predictions. RESULTS: The DPV ring simulations tested the two dosing regimens and predicted PK profiles and area under the curve of luminal fluids (29 079 and 33 067 mg h l-1 in groups A and B, respectively) and plasma (0.177 and 0.211 mg h l-1 ) closely matched those reported (within one standard deviation). While the DPV film study reported drug concentration at only one time point per patient, our simulated profiles pass through reported concentration range. CONCLUSIONS: HIV is a major public health issue and vaginal microbicides have the potential to provide a crucial, female controlled option for protection. The PBPK model successfully simulated realistic representations of drug PK. It provides a reliable, inexpensive and accessible platform where potential effectiveness of new compounds and the robustness of treatment modalities for pre-exposure prophylaxis can be evaluated. PMID- 29714827 TI - Recent Publications of Interest. PMID- 29714826 TI - An assessment of assumptions and uncertainty in deuterium-based estimates of terrestrial subsidies to aquatic consumers. AB - The deuterium ratio (2 H/1 H) in tissue is often used to estimate terrestrial subsidies to aquatic consumers because of strongly differentiated values between terrestrial and aquatic primary producers. However, quantitative deuterium-based analyses of terrestrial resource assimilation are highly dependent on several poorly defined assumptions. We explored the sensitivity of these estimates to assumptions regarding environmental water contributions to consumer deuterium content (omega) and algal photosynthetic hydrogen discrimination (epsilonH ). We also tested whether 13 C/12 C and 2 H/1 H-based estimates of terrestrial resource assimilation give similar outcomes. The average of the 12 experiments that have directly estimated proportional contributions of environmental water to consumer tissue 2 H/1 H was 0.27 +/- 0.11 (mean +/- SD), with similar values for invertebrates and fish. Conversely, of the 28 field studies that have used 2 H/1 H to characterize aquatic food webs, all but one assume a value that is less than our current best estimate, usually substantially less. A reanalysis of the raw data from four recent case studies indicates the calculated terrestrial contribution to aquatic consumers is extremely sensitive to this assumption. When the authors' original assumptions were used (i.e., omega = 0.16 +/- 0.05), the estimated proportional contribution of terrestrial resources to aquatic consumers (thetaT ) averaged 29 +/- 17%, and when omega = 0.27 was used the average estimated assimilation of allochthonous resources was ~0.00. A compilation of published photosynthetic hydrogen discrimination values for microalgae averaged epsilonH = -150 +/- 270/00 (SD, n = 99), and a sensitivity analysis showed the outcomes of these calculations were also strongly influenced by uncertainty in epsilonH . There was no statistical association between 13 C/12 C and 2 H/1 H based estimates of terrestrial subsidies (r = -0.12, n = 274). This analysis indicates that the assumptions in deuterium-based estimates of terrestrial resource assimilation are highly influential but poorly constrained; therefore, the impact of these assumptions on calculated outputs must be carefully assessed and thoroughly reported. Due to the highly uncertain assumptions inherent in deuterium-based analyses, we urge much more caution when using this approach to estimate terrestrial subsidies to consumers in aquatic ecosystems. PMID- 29714825 TI - Multi-center retrospective study of the prognosis and treatment outcomes of Japanese oral squamous cell carcinoma patients with single lymph node metastasis and extra nodal extension. AB - BACKGROUND: Oral squamous cell carcinoma (OSCC) containing single lymph node metastasis (pN1) with extra nodal extension (ENE) is a rare clinical situation. Therefore, it is unclear whether pN1 with ENE is at high risk of recurrence among the OSCC population, or whether postoperative radiotherapy (RT)/concomitant chemoradiotherapy (CCRT) is effective in these cases. OBJECTIVES: The purpose of this retrospective study was to investigate the prognosis and compare between no postoperative therapy and postoperative RT/CCRT in pN1 with ENE OSCC patients. METHODS: Clinicopathological data and treatment modalities were investigated. The evaluated endpoints were overall survival (OS) and type of recurrence. RESULTS: The 3-year cumulative OS rates for the pN1 only, multiple lymph node metastasis (MLM) only, ENE + MLM, and ENE + pN1 groups were 77.2%, 66.8%, 43.3%, and 66.6%, respectively. In the ENE + pN1 group, the most common cause of death in the surgery only group was from regional failure. The surgery + RT/CCRT group was associated with better disease-specific survival and OS rates than the surgery only groups (P < 0.05). CONCLUSIONS: The prognosis of ENE + pN1 was not as poor as that of ENE + MLM, although both these groups feature ENE. Adjuvant therapy (RT/CCRT) after surgery is recommend for cases of ENE + pN1. PMID- 29714828 TI - Interactive effects of climate change and biodiversity loss on ecosystem functioning. AB - Climate change and biodiversity loss are expected to simultaneously affect ecosystems, however research on how each driver mediates the effect of the other has been limited in scope. The multiple stressor framework emphasizes non additive effects, but biodiversity may also buffer the effects of climate change, and climate change may alter which mechanisms underlie biodiversity-function relationships. Here, we performed an experiment using tank bromeliad ecosystems to test the various ways that rainfall changes and litter diversity may jointly determine ecological processes. Litter diversity and rainfall changes interactively affected multiple functions, but how depends on the process measured. High litter diversity buffered the effects of altered rainfall on detritivore communities, evidence of insurance against impacts of climate change. Altered rainfall affected the mechanisms by which litter diversity influenced decomposition, reducing the importance of complementary attributes of species (complementarity effects), and resulting in an increasing dependence on the maintenance of specific species (dominance effects). Finally, altered rainfall conditions prevented litter diversity from fueling methanogenesis, because such changes in rainfall reduced microbial activity by 58%. Together, these results demonstrate that the effects of climate change and biodiversity loss on ecosystems cannot be understood in isolation and interactions between these stressors can be multifaceted. PMID- 29714829 TI - The duality of ocean acidification as a resource and a stressor. AB - Ecologically dominant species often define ecosystem states, but as human disturbances intensify, their subordinate counterparts increasingly displace them. We consider the duality of disturbance by examining how environmental drivers can simultaneously act as a stressor to dominant species and as a resource to subordinates. Using a model ecosystem, we demonstrate that CO2 driven interactions between species can account for such reversals in dominance; i.e., the displacement of dominants (kelp forests) by subordinates (turf algae). We established that CO2 enrichment had a direct positive effect on productivity of turfs, but a negligible effect on kelp. CO2 enrichment further suppressed the abundance and feeding rate of the primary grazer of turfs (sea urchins), but had an opposite effect on the minor grazer (gastropods). Thus, boosted production of subordinate producers, exacerbated by a net reduction in its consumption by primary grazers, accounts for community change (i.e., turf displacing kelp). Ecosystem collapse, therefore, is more likely when resource enrichment alters competitive dominance of producers, and consumers fail to compensate. By recognizing such duality in the responses of interacting species to disturbance, which may stabilize or exacerbate change, we can begin to understand how intensifying human disturbances determine whether or not ecosystems undergo phase shifts. PMID- 29714831 TI - Navigating Changes while Advocating for the Physician Community and Safety of Patients. PMID- 29714830 TI - Pacific Decadal and El Nino oscillations shape survival of a seabird. AB - Understanding and modeling population change is urgently needed to predict effects of climate change on biodiversity. High trophic-level organisms are influenced by fluctuations of prey quality and abundance, which themselves may depend on climate oscillations. Modeling effects of such fluctuations is challenging because prey populations may vary with multiple climate oscillations occurring at different time scales. The analysis of a 28-yr time series of capture-recapture data of a tropical seabird, the Nazca Booby (Sula granti), in the Galapagos, Ecuador, allowed us to test for demographic effects of two major ocean oscillations occurring at distinct time-scales: the inter-annual El Nino Southern Oscillation (ENSO) and inter-decadal oscillations. As expected for a tropical seabird, survival of fledgling birds was highly affected by extreme ENSO events; by contrast, neither recruitment nor breeding participation were affected by either ENSO or decadal oscillations. More interesting, adult survival, a demographic trait that canalizes response to environmental variations, was unaffected by inter-annual ENSO oscillations yet was shaped by the Pacific Decadal Oscillation and small pelagic fish regime. Adult survival decreased during oceanic conditions associated with higher breeding success, an association probably mediated in this species by costs of reproduction that reduce survival when breeding attempts end later. To our knowledge, this is the first study suggesting that survival of a vertebrate can be vulnerable to a natural multidecadal oscillation. PMID- 29714832 TI - Successful Therapy with Nivolumab in Metastatic Renal Cell Carcinoma After Multiple Prior Treatments. AB - Renal cell carcinoma (RCC) is responsible for 80 to 85 percent of all primary renal malignancies. In the United State%, there are about 63,000 new cases and almost :14,000 deaths per year from RCC. Surgical resection of localized RCC can be curative but many patients eventually recur. Immunotherapy appears to be a promising new modality for many malignancies, including RCC. Nivolumab, a specific immunotherapy agent indicated for advanced RCC, may restore antitumor immunity and allow for greater progression-free survival by targeting proteins that negatively regulate T cell immunity. This case study aims to demonstrate the integration of nivolumab into the management of a patient with advanced RCC and provide a stimulus for further investigation and research into this treatment modality. PMID- 29714833 TI - MSD CONTEMPORARY VETERAN PROJECT An effort to record the military service of Delaware physicians for the Archives of the Medical Society of Delaware. PMID- 29714834 TI - APPROVED: Comprehensive Cardiac Center Advanced Certification Program. PMID- 29714835 TI - Clarifications and Expectation Understanding Updates to the Life Safety Standards. PMID- 29714836 TI - CLARIFICATION: Use of Secure Text Messaging for Patient Care Orders Is Not Acceptable. PMID- 29714837 TI - Joint Commission Emergency Management Standards Help Organizations Address Catastrophic Floodinq. PMID- 29714838 TI - Keep the fire burning. PMID- 29714839 TI - What's next?. PMID- 29714840 TI - ADA House meets in Denver. Approves three-year marketing effort to drive patients to members' chairs. PMID- 29714841 TI - Organize a charitable project for this season of giving. PMID- 29714842 TI - Are you a problem solver?. PMID- 29714844 TI - G.V Black was right. PMID- 29714843 TI - Your generosity makes a difference to many. PMID- 29714845 TI - Top Standards Compliance Data Announced for 2015. PMID- 29714846 TI - Sentinel Event Statistics Released for 2015. PMID- 29714847 TI - Sentinel Event New Alert Focuses on Suicide Ideation. PMID- 29714848 TI - Flavor-First Chef. PMID- 29714849 TI - 9 Life-Changing Breakffiroughs. PMID- 29714850 TI - NEW ALTERNATIVE TREATMENTS. PMID- 29714851 TI - Frozen Pizza. PMID- 29714852 TI - Meal Replacements Are They for You? PMID- 29714853 TI - Smairt Snacking BYPASS JUNK FOOD AND PICK HEALTHY GO-TO SNACKS. PMID- 29714854 TI - YOUR WEIGHT Managing Weight and Well-being. PMID- 29714855 TI - Take 5. Working Your Core in the Workplace. PMID- 29714856 TI - IL-23, IFN-alpha, and IFN-beta in the vaginal fluid of patients suffering from vulvovaginal candidosis. AB - : Purpose of the investigation: Vulvovaginal candidosis (VVC) is a common vaginal infection affecting almost 75% of all women once per lifetime. Vaginal associated immunity is important in the protection against VVC. The purpose of this study was to evaluate a potential role of IL-23, IFN-alpha, and IFN-beta in the local immune response against VVC. MATERIALS AND METHODS: The study included 202 non pregnant women; 71 patients with clinical symptoms of VVC and 131 asymptomatic patients served as control. IL-23, IFN-alpha, and IFN-beta were measured in the vaginal fluid by ELISA. Microbiological cultures were used for Candida detection. RESULTS: C. albicans was detected in 67.6% of patients, C. glabrata in 2 1.1% of patients, and 5.6% were infected with C. krusei or coinfected with C. albicans and C. krusei. Levels of IL-23 (p < 0.001) and IFN-beta (p < 0.017) were significantly lower in the VVC group. IFN-alpha was elevated in the VVC group compared to the asymptomatic patients (p < 0.001). CONCLUSION: IL-23 and IEFN beta seem to play a protective role against VVC. Decreased levels in VVC patients suggest a compromised local immune response at the time of occurrence of symptoms. In contrast, IFN-alpha seems to be released once the infection has occurred. These cytokines may be prospective targets in the treatment and prevention of primary and recurrent vaginal infections with Candida species. PMID- 29714857 TI - The use of percutaneous cholecystostomy in the treatment of acute cholecystitis during pregnancy. AB - The purpose of this study was to investigate the efficacy of precutaneous cholecystostomy (PC) in treatment of acute cholecystitis during pregnancy. The author retrospectively evaluated six pregnant patients who underwent PC for acute cholecystitis between 1994 and 2014. The median age of the patients were 31 years (22-36). Two patients were in first trimester and the others in third trimester. All patients were underwent medical therapy before PC; since no improvement was observed in their complaints and physical examination findings, the author performed PC. All patients underwent LC following PC. PC is a safe, alternative treatment modality for palliative purposes in pregnant patients with acute cholecystitis who are unresponsive to medical therapy or who have comorbid conditions making surgery risky, or in acute cholecystitis cases occurring in third trimester of pregnancy to reach postpartum period when surgery is safer. PMID- 29714858 TI - Delayed umbilical cord clamping in cesarean section reduces postpartum bleeding and the rate of severe asphyxia. AB - PURPOSE OF INVESTIGATION: To explore the effect of delayed umbilical cord clamping in cesarean section on outcomes of mothers and newborns. MATERIALS AND METHODS: A total of 338 pregnant women under cesarean section were randomly divided into two groups: study group with delayed umbilical cord clamping after pulsation loss, and control group with early clamping within 60 seconds after birth. RESULTS: There were no significant differences in hemoglobin and hematocrit in newborn cord blood, the highest bilirubin after birth, Apgar scores at one and five minutes after birth, and in the occurrence of neonatal hyperbilirubinemia or application of phototherapy. There were significant differences in placental residual blood, the amount of postpartum bleeding, hemoglobin and hematocrit in newborn heel blood, and the rate of neonatal resuscitation after ten minutes in both groups. CONCLUSION: Umbilical cord clamping should be employed after pulsation loss to avoid adverse effect of early clamping. PMID- 29714859 TI - Effect of exercise while utilizing a device with an arm compression sleeve to reduce lymphedema. AB - BACKGROUND: Lymphedema is one complication of breast cancer treatment and there is no consensus that identified one single therapy in the treatment of lymphedema; therfore an association of methods is recommended and one of these is exercising. The aim of this study was to evaluate the utilization of exercising with a facilitating device along with an arm compression sleeve to reduce the size of lymphedematous arms. MATERIALS AND METHODS: Thirty women from a rehabilitation group with arm lymphedema resulting from the surgical, chemotherapeutic, and radiotherapeutic treatment of breast cancer were enrolled sequentially on arriving in the clinic. While sitting in an upright position and wearing an arm compression sleeve, patients were submitted to a one-hour session of active exercising consisting of four 12-minute stints with three-minute intervals to rest. The change in lymphedema was evaluated by water volumetry before and immediately after the session. The active exercising device is similar to the pedaling system of a bicycle. The paired t-test was employed for statistical analysis. An alpha error of 5% (p-value < 0.05) was considered acceptable. RESULTS: A statistically significant reduction (p-value < 0.004) was noted in the size of the arm. CONCLUSION: Active exercising using a facilitating device and under supervision may reduce the size of lymphedematous arms. PMID- 29714860 TI - A comparison of maternal outcomes in complicated vaginal and cesarean deliveries. AB - OBJECTIVE: The purpose of this study was to compare general characteristics, laboratory data, and maternal outcomes of patients who experienced complications in the first 24 hours after a normal vaginal delivery or cesarean section (C section). This way, the authors intended to determine the results of complications in these patients. MATERIALS AND METHODS: Data of patients referred from the peripheral care centers to the present tertiary care center in the first 24 hours after a vaginal delivery or C-section due to the presence of various complications were screened retrospectively from 2009 to 2013. Clinical and demographic characteristics, laboratory parameters, indications for C-section, mortality rates, maternal morbidities, surgical and medical treatments administered in the clinic, as well as operations performed in other care centers were noted. RESULTS: A total of 330 patients were included in this study. Of these patients, 285 constituted the postoperative group (C-sections) whereas 45 constituted the postpartum (vaginal deliveries) group. There was no statistically significant difference between the two groups in demographic characteristics, results of laboratory parameters, maternal morbidity, and mortality rates. Requirement of hysterectomy and relaparotomy was significantly higher in the postoperative group. CONCLUSIONS: In the early follow-up, it was found that complicated C-sections and vaginal deliveries had similar results. However, it should also be mentioned that higher requirement of hysterectomy and relaparotomy emerged as an undesirable condition among the postoperative patients in this study. With this in mind, mode of delivery should be selected according to the overall health status of the patient and indications for C-section. PMID- 29714861 TI - A study of the dietary intakes by the pre-pregnancy body mass index in pregnant women. AB - The authors analyzed the difference in weight gain and nutrition, according to the BMI before pregnancy. They divided 91 subjects into BMI group I (normal weight) and BMI group 2 (overweight) before pregnancy. In general, the BMI before pregnancy did not influence weight gain but, in the BMI group 2, the intakes of all of cholesterol, total fatty acids, vitamin B 12, iron, and copper were significantly higher. Neither group exhibited sufficient intake of vitamin B 1, vitamin B2, niacin, vitamin B6, folic acid, calcium, magnesium, iron, or zinc. Pre-pregnancy weight management and nutrition during pregnancy is very important. PMID- 29714862 TI - A comparative immunohistochemical investigation of the consequences of chorioamnionitis on the developing human fetal spleen. AB - INTRODUCTION: The objective of this study was to determine the effects of chorioamnionitis on the extracellular matrix (ECM) structural glycoproteins of the developing human fetal spleen, and their influence on the haematopoiesis and spleen immune system compared to controls. MATERIALS AND METHODS: After elective induced pregnancy termination due to chorioamnionitis or voluntary abortion, paraffin-embedded specimens from the spleen and respective fetal membranes of 90 fetuses were investigated by immunohistochemistry for presence of ECM structural glycoproteins, haematopoietic, and lymphoid cells. Conventional histological examination of the relative fetal membranes was performed. RESULTS: The present results showed no quantitative variations in the expression of the ECM glycoproteins and haematopoietic lineages of the fetal spleen parenchyma at the end of first trimester (in both groups). At the second and third trimesters, acute chorioamnionitis showed a decreased number of the aforementioned proteins, with an increase of granulopoiesis and CD34 progenitor/stem haematopoietic cells. The immune system of the spleen during the third trimester demonstrated a decrease of both B and T lymphocytes, in comparison with controls. CONCLUSIONS: These results suggest that toxins and cytokines generated during chorioamnionitis, seem to influence ECM structural glycoproteins synthesis and release in fetal splenic parenchyma by reducing them, and probably cause further disorders of haematopoiesis and lymphopoiesis. PMID- 29714863 TI - Predictive value of procalcitonin and IL-6 versus cervical length for the admission-to-delivery interval in preterm labour. AB - OBJECTIVE: The authors aimed to determine whether concentrations of IL-6 and procalcitonin in maternal circulation can be used and compared with cervical length to predict the admission-to-delivery interval in preterm labour. MATERIALS AND METHODS: Forty patients complicated with preterm labour between 24-34 weeks of gestation and having preterm birth were included in the study group. Fortyfour healthy pregnant women at similar gestational ages and having term labour ('> 37 weeks) were included in control group. Maternal concentrations of IL-6 was measured by an enzyme-linked immunosorbent assay (ELISA) and procalcitonin was measured by immunoturbidimetry with using human procalcitonin reagent kit. Transvaginal ultrasound to assess cervical length was perforned. RESULTS: Receiver operator characteristic (ROC) analysis results of IL-6 and procalcitonin for prediction of preterm delivery (PTD)< 48 hours, < seven days, <32 weeks, < 34 weeks, and < 37 weeks were not statistically significant (p > 0.05). ). It was shown through ROC analysis, that only cervical length had area under curve (AUC) 0.692 (0.511-0.873,p = 0.044) at cut off value <= 3.64 cm, AUC 0.758 (0.574 0.943, p = 0.015) at cut off value <= 3.50 cm, AUC 0.716 (0.553-0.879,p = 0.032) at cut off value < 3.80 cm, in predicting PTD within seven days, <32 weeks and < 37 week, respectively. CONCLUSION: This study suggests that in preterm labour, although IL-6 and procalcitonin have unsatisfactory predictive value for the admission-to-delivery interval, cervical length has better predictive values for the admission-to-delivery interval. PMID- 29714864 TI - Long-term results of tension-free vaginal tape and pubovaginal sling in the treatment of stress urinary incontinence in female patients. AB - OBJECTIVES: To report the long-term outcome of tension-free vaginal tape (TVT) and pubovaginal sling (PVS) in the treatment of stress urinary incontinence (SUI) in female patients. MATERIALS AND METHODS: The long-term objective and subjective results of female patients who were previously randomized in a single blind study to two arms, TVT or PVS, between 2000 and 2004, were evaluated. The patients were asked if they were satisfied with the results of the procedure and if they would recommend it to a friend or relative. The assessment included a physical examination and cough-induced stress test. Satisfaction levels were assessed by Likert-type scale. Cure was described as absence of urine leakage in any circumstances, while improvement was characterized as subjective improvement of SUI without complete resolution. RESULTS: One hundred women with SUI underwent surgery at the present medical center between 2000 and 2004. A total of 52 patients were followed clinically for objective and subjective assessment. Seventeen were interviewed only by telephone. The objective cure rate was 81.5% and 84%, where as subjective cure rate was 70.3% and 71.9%, for TVT versus PVS, respectively (p > 0.05). After an average follow-up of 10.5 years, there was no difference in clinical outcome, satisfaction scores, and postoperative complications between the two groups. CONCLUSION: Both TVT and PVS are safe and effective treatments for SUI in fe- male patients, with acceptable success rate in long term follow-up. PMID- 29714865 TI - Knowledge and attitude changes of pregnant women regarding prenatal screening and diagnostic tests after counselling. AB - OBJECTIVES: This study aimed to reveal the knowledge level of pregnant women about prenatal diagnostic tests, Down syndrome (DS) and amniocentesis, their attitudes toward uptaking these tests, undergoing amniocentesis, and the termination of pregnancy. It also aimed to evaluate the effects of providing information, as well as a written information brochure about all the issues concerning women's knowledge and attitudes. MATERIALS AND METHODS: The gynecologists provided verbal and written information on prenatal screening tests (PSTs) and invasive prenatal diagnostic tests. Data were collected using an anonymous questionnaire, which was designed by the researchers on the basis of the literature. RESULTS: Knowledge of both DS and amniocentesis was found to be significantly higher after the education (p = 0.000 and p = 0.000, respectively). Attitudes toward amniocentesis changed significantly after the education. CONCLUSIONS: This study has shown that women had an inadequate knowledge about PSTs, DS, and amniocentesis. It has also revealed that education provided by gynecologists along with a written brochure of information tended to increase women's knowledge about PSTs. PMID- 29714866 TI - Pregnancy outcomes in Chinese urban women at a very advanced maternal age. AB - AIM: To compare the maternal-fetal outcomes in Chinese urban women at the maternal age of 40 years with those aged between 35 and 39 years. MATERIALS AND METHODS: In this retrospective study, women in a single-center that delivered from January 1 to December 31, 2013, were included. The authors divided the subjects into two groups according to the age, and evaluated the obstetric history, delivery mode, incidence of obstetric diseases, and neonatal outcomes of each group. RESULTS: They enrolled 1,965 pregnant women in total. The women between 35 to 39 years of age reached 1,727 (87.9%), and the remaining 238 (12.1%) were women >= 40-years-old. The incidence rates of in vitro fertilization (IVF,p < 0.01), gestational diabetes mellitus (GDM) (p < 0.05), and hypertension (p < 0.05) for the elder group were higher than the younger group. Furthermore, women >= 40-years-old were associated with a higher rate of cesarean section (84.0% vs. 67.6%,p < 0.001) compared with the younger group, varying significantly on intrauterine infection (1.5% vs. 0.5%,p < 0.05), IVF (6.5% vs. 3.2%,p < 0.01), and maternal request (41.0% vs. 30.6%,p < 0.001). No significant differences in neonatal outcomes were found and no neonatal deaths were recorded for the two groups. CONCLUSIONS: These results showed an increase risk of pregnancy complications for the women giving birth at >= 40 years of age, yet most of them still carried a favorable pregnancy and neonatal outcome, similar to the younger women. PMID- 29714867 TI - Follow-up study of symptomatic submucous fibroids after hysteroscopic myomectomy. AB - PURPOSE OF INVESTIGATION: This study aimed to estimate the effectiveness of hysteroscopic myomectomy for symptomatic submucous uterine fibroids and to identify prognostic factors for persistent or recurrent symptoms. MATERIALS AND METHODS: A total of 237 patients who underwent hysteroscopic myomectomy were divided into three groups according to the classification of the European Society for Gynaecological Endoscopy: Type 0 (n=116), Type I (n=97), and Type II (n=24). Medical records and videotape records of all patients were retrospectively reviewed. RESULTS: Improvement of symptoms was achieved in 100% of Types 0 and I, and 66.7% of Type II. The five-year cumulative symptom-free rates after hysteroscopic myomectomy were 96.7% +/- 1.9%, 87.8% 6.7%, and 44.5% +/- 12.7% in Types 0, I, and II, respectively. The mean symptom-free periods were 46.2 +/- 2.6, 47.7 +/- 2.7, and 24.7 +/- 6.3 months in Types 0, I, and II, respectively. Logistic regression analysis showed that co-existence of other myomas and Type II were independent prognostic factors for recurrence of symptoms. CONCLUSION: Type I fibroids are a good indication for hysteroscopic myomectomy. In Type II, some patients feel that their symptoms improve, but this curative effect could be temporary. PMID- 29714868 TI - Hysterosalpingography prior to the gonadotropin stimulated intrauterine insemination improves clinical pregnancy rates in women with unexplained infertility. AB - PURPOSE OF INVESTIGATION: Gonadotropin stimulated intrauterine insemination (IUI) cycles performed following one month after hysterosalpingography (HSG) are associated with improvement in clinical pregnancy rates in unexplained infertile couples. MATERIALS AND METHODS: A retrospective cohort study was performed between 2008 and 2014. A total of 92 unexplained infertile couples undergoing their first cycle IUI stimulated by gonadotropins were included in the analysis. Participants were classified into two groups according to IUI cycles performed one month (Group A, n = 25 cycles) or longer than one month (Group B, n = 67 cycles) after the HSG procedure. RESULT: The overall clinical pregnancy rate was found as 25% (23 clinical pregnancies / 92 cycles). Clinical pregnancy rate was 44 % (11/25) for Group A and 17.9 % (12/67) for Group B. In Group A, there were significantly higher clinical pregnancy rates compared to Group B (OR: 3.6, 95% CI, 1.3-9.8; p = 0.012). CONCLUSIONS: It has been demonstrated that fertility improving effect of HSG was most prominent in the first six months after procedure. Likewise, in gonadotropin stimulated IUI cycles performed following one month after HSG, there seems to be an improvement in pregnancy rates in unexplained couples. In unexplained cases, it may be a reasonable approach to plan IUI cycles in the first month after HSG in clinical practice. PMID- 29714869 TI - Medication use during pregnancy and drug information resources utilized by pregnant women in Jordan. AB - PURPOSE: This study was designed to investigate medication use among Jordanian pregnant women, and to evaluate their level of awareness about safety of medication use during pregnancy. MATERIALS AND METHODS: Pregnant women who attended the Obstetrics and Gynecology Clinics at the largest hospital in North of Jordan area were interviewed using a questionnaire. The questionnaire included questions about demographics, medication use during pregnancy, and resources of information regarding medication use in pregnancy. RESULTS: Two hundred and forty pregnant women agreed to participate in the study and were interviewed with a response rate of 94.5%. Folic acid (93.8%) was the most frequently used medication during pregnancy followed by multivitamins (57.9%), iron supplements (55.8%), and paracetamol (41.7%). The majority (82.1%) considered first trimester to be the most critical period in which drugs ingestion can cause harm to the fetus. The great majority relied on physicians (90.4%) to be their main source of information followed by pharmacists (15.4%). CONCLUSIONS: Folic acid was the most frequently used medication during pregnancy and the majority of participants took medications based on physician's recommendations. However, there were also cases of self-medication. PMID- 29714870 TI - Maintenance of the parturient in the left lateral position after spinal anesthesia with plain levobupivacaine for cesarean section reduces hypotension: a randomized study. AB - PURPOSE OF INVESTIGATION: Hypotension during spinal anesthesia is a main concern in cesarean delivery. The authors hypothesized that keeping parturients in a prolonged left lateral position before turning them to a supine position with left lateral tilt would reduce the incidence of hypotension without jeopardizing the quality of anesthesia. MATERIALS AND METHODS: Randomized comparative unblinded prospective study. This randomized comparative prospective study was conducted at Gaziantep University Hospital between June and December 2011. Sixty parturients undergoing cesarean section were included. Patients were randomized to two groups: turning to the supine position with left lateral tilt immediately or 15 minutes after subarachnoid injection of 2.5 ml 0.5% plain levobupivacaine in the left lateral position. Loss of pinprick sensation to T6 was accepted as adequate for cesarean section, and surgery proceeded. Characteristics of anesthesia; incidences of hypotension, bradycardia, and other adverse events, and ephedrine use were assessed. RESULTS: Compared with the supine group, parturients kept in a lateral position for 15 minutes showed marked reductions in the incidence of hypotension (33.3% vs. 83.3%, p < 0.001) and adverse events related to hypotension, such as nausea and vomiting (16.7% vs. 57.3%, p <0.001). In addition, ephedrine consumption per hypotension case was significantly reduced in the lateral group (5.4 +/- 4.7 vs. 8.9 +/- 5.8 mg; p < 0.00 1). CONCLUSIONS: Keeping parturients in the lateral position for 15 minutes before turning them to the supine position for cesarean section can provide reliable spinal anesthesia with a lower incidence and severity of hypotension and nausea/vomiting. PMID- 29714871 TI - Preliminary experience in uterine artery embolization for second trimester pregnancy induced labor with complete placenta previa, placenta implantation, and pernicious placenta previa. AB - OBJECTIVE: To explore the application of uterine artery embolization (UAE) in complete placenta previa, placenta implantation, and pernicious placenta previa during second trimester pregnancy induced labor. MATERIALS AND METHODS: From April 2013 to April 2014, the present hospital admitted 12 cases of second trimester complete placenta previa, placenta implantation, and pernicious placenta previa. Six of 12 cases at first were given UAE before cesarean section or labor induction. The other six cases, which were introduced into the present hospital after a failed embolization, underwent UAE, followed by hysteroscopy or curettage or laparotomy. RESULT: None of the 12 patients underwent hysterectomy. The average blood loss of six patients with UAE was 383 ml and the average hospitalization was 8.66 days. While the remaining six patients without embolization in advance experienced 1,533 ml mean blood loss and 18 days in average stay. Among 12 patients, seven reported abdominal pain following embolization, four had a fever, and two had nausea and vomiting. Nine patients were followed-up and the menstrual cycles of seven returned to normal in one+ month, one in two+ months, and one suffered amenorrhea. Among the same nine patients, six menstruated regularly, two had menstrual disorders, and one had amenorrhea. No serious short- and long-term complications were observed. CONCLUSION: UAE is the safe method to avoid serious bleeding due to complete placenta previa, placenta implantation, and pernicious placenta previa with second-trimester pregnancy termination. PMID- 29714872 TI - Cesarean section: requested mode of delivery?. AB - AIM: To constitute accurate policies for reducing the cesarean section (C/S) the authors evaluated the attitudes and knowledge of health workers and public population towards the mode of delivery, C/S on demand, and delivery complications in a large population. MATERIALS AND METHODS: 1,892 female volunteers in reproductive age were enrolled in the study and 589 of them were health workers. Patients were evaluated with questionnaire about their delivery mode and their answers were analyzed. RESULTS: The overall cesarean rate of the study population was 45.4%. This rate were 51.4% and 28.2%, respectively, for the health workers and public group (p < 0.001). Medical indication ratio ivere 57.7% and 40.1% for the healthcare group and the public population respectively and 20.2% of health workers and 13.9% of the public group had C/S by their preference without any medical indications (p < 0.001). CONCLUSION: C/S rate is high in Turkey and an action plan is needed to decrease the rate. When a patient's preference towards the mode of the delivery is C/S on demand, obstetricians, in their capacity as patient advocate, should help guide their patient through the sophisticated detailed medical information toward a decision that respects both the patient's attitude and the physician's obligation to optimize the health of both the mother and the newborn. PMID- 29714873 TI - Uterine-fundal hypoechoic mass: a possible ultrasound sign for cesarean scar pregnancy. AB - PURPOSE OF INVESTIGATION: Cesarean scar pregnancy (CSP) is a life-threatening condition that requires early pregnancy termination. Its early ultrasound diagnosis is clinically important; however, previous studies focused on the CSP site itself. The present study was conducted to investigate the authors' clinical impression that a uterine-fundal hypoechoic mass is more frequently observed in CSP. Such a finding, if confirmed, may contribute to ultrasound diagnosis of CSP. The authors also determined the relationship between the treatment strategy and outcome, with special emphasis on conditions eventually requiring uterine artery embolization (UAE). MATERIALS AND METHODS: This was a case-control study of CSP, and the authors analyzed all 14 women that were treated in this single tertiary institute over a period of ten years. Control subjects consisted of all pregnant women with prior cesarean section (CS) but no CSP. RESULTS: Patients with CSP were significantly more likely to have a hypoechoic mass than controls (42.9 vs. 15.4%, respectively; p = 0.028). On confining results to a "fundal" hypoechoic mass, only CSP(+) patients showed it (CSP vs. control: 28.6 vs. 0%, respectively; p < 0.001). Six (43%: 6/14) received UAE: four following vaginal evacuation (artificial or spontaneous), and two for bleeding after methotrexate (MTX) treatment. CONCLUSION: Patients with CSP more frequently had a uterine-fundal hypoechoic mass, whose detection may trigger a detailed observation of the CSP site, possibly leading to CSP diagnosis. PMID- 29714874 TI - The evaluation of regret status in women following tubal ligation in Turkey. AB - BACKGROUND: Tubal ligation (TL) is increasingly common worldwide. Women may regret after undergoing this permanent form of contraception. This study aimed to investigate the regret rate and the causes of regret in women following TL in Turkey. Materials and Meth- ods: This questionnaire-based study included 253 women interviewed via telephone at least one year after TL. The women were grouped as regretful (n3 1), satisfied (n=170), and undecided (n=52) according to their answers to two questions. The ones who were undecided were excluded from the study. The comparison between the answers of regretful and satisfied women were performed using the Student t- test and the Chi Square test. RESULTS: The rate of regret after TL was 12-15%. The factors increasing the regret rate were TL before the age of 30, absence of spouse's support, and the thought of inability to have children in future. The percentage of patients stating that they accepted the TL procedure without comprehending its permanent nature or experienced health problems after TL was higher among less-educated women and these were the factors increasing regret rates. CONCLUSIONS: TL should be performed in women older than 30 years, after an adequate amount of information suited to the educational level of the patient and with full support of the patient's spouse. PMID- 29714875 TI - Pro-inflammatory and anti-inflammatory cytokine profiles in fetal growth restriction. AB - The purpose of this investigation was to measure cytokine production by maternal peripheral blood lymphocytes from women with intrauterine growth restriction (IUGR) and from healthy pregnant women, and to investigate the relationship between cytokine profiles and IUGR. Thirty-six women with IUGR and 22 control healthy pregnant women with normal fetal growth were studied. Levels of pro inflammatory cytokines (IFNy, TNFa, IL-8, IL-12, IL-18, IL-23) and anti inflammatory cytokines (IL-4, IL- 10, IL-13) produced by mitogen-stimulated peripheral blood mononuclear cells were measured by ELISA. Levels of the anti inflammatory cytokine IL-4 were higher in normal pregnancy compared to IUGR, indicating an anti-inflammatory bias. Levels of the pro-inflammatory cytokines IL 6, TNFalpha, and IL-12 were significantly higher and levels of the anti inflammatory cytokine IL- 10 lower in IUGR with placental insufficiency than in IUGR without placental insufficiency, suggesting a stronger pro-inflammatory bias in IUGR with placental insufficiency. Ratios of pro- to anti-inflammatory cytokines suggest a dominance of pro-inflammatory cytokines. The authors conclude that an increased pro-inflammatory cytokine bias is observed in IUGR compared to normal pregnancy, and an increased pro-inflammatory cytokine dominance is seen in IUGR with placental insufficiency compared to IUGR without placental insufficiency. PMID- 29714876 TI - Cognitive and socio-emotional development and manifestation of learning disabilities of 8- to 10-year-old children born after intracytoplasmatic sperm injection compared to naturally conceived children. AB - OBJECTIVE: The purpose of the present study was to investigate the cognitive and socio-emotional development, as well as the mani- festation of learning disabilities of eight- to ten-year-old children born after intracytoplasmatic sperm injection (ICSI). MATERIALS AND METHODS: Developmental outcomes of 40 children born after ICSI were compared with those of 40 children born after spontaneous conception (SC). Outcome measures included the Raven's Progressive Matrices Test, Child Behavior Checklist (CBCL), and Athina Test of Learning Difficulties. RESULTS: Regarding cognitive development, ICSI children tend to obtain a similar intelligence score with SC children on Raven's Test. No significant differences were noted on CBCL's syndrome and abilities' profiles, and on Athina Test. CONCLUSIONS: ICSI and SC children show a comparable cognitive and socio-emotional development and have the same chances of manifesting learning disabilities. None of the demographic factors taken into consideration (age, sex of the child, and educational level of the parents) nor the mode of conception seem to affect their well-being. PMID- 29714877 TI - Maternal and neonatal outcomes in pregnancy induced hypertension: an observational study. AB - : Hypertension during pregnancy has been extensively studied due to significant maternal morbidity, mortality, and perinatal mortality that may result. The outcome in hypertensive disorders in pregnancy vary significantly across populations and between institutions serving the same populace. OBJECTIVE: In the present study, the authors sought to determine the outcome for mother and fetus with pregnancy induced hypertension (PIH) in a rural community at a tertiary care center at Thrissur Medical College, Kerala, India. MATERIALS AND METHODS: The authors included all singleton pregnancies with hypertensive disease that had deliveries in our institution in a six-month period excluding the ones with pre existing hypertension and other comorbidities. RESULTS: 46.5% ofthe patients required a cesarean section, 37.2% had pre-term labor, 52.4% had low birth weight, and 9.4% unfortunately were stillborn. DISCUSSION: These results emphasize the need for screening and close follow-up of hypertension in pregnancy for safeguarding fetal and maternal wellbeing. Even after practicing the current standard of care, the higher rate of complications associated with PIH is unacceptable. The authors feel that unique management protocols should be implemented for different patient populations, based on ethnicity, lifestyle, and availability of medical resources. PMID- 29714878 TI - The relation between causes and onset time of polyhydramnios. AB - The aim of this analysis was to investigate the onset time and significance of maximum volume of polyhydraminios and whether the tter was associated with causes. This was a retrospective cohort study between 2012 and 2014. A total number of 68 singleton pregancies were analyzed. Gestational age at onset of polyhydramnios was 30.0 +/- 2.8 (25-36) weeks in maternal factor, 30.0 +/- 3.5 (25- 7) weeks in fetal factor, and 32.3 +/- 2.0 (27-37) weeks in idiopathic factor. Median of maximum amniotic fluid index (AFI) was gnificantly late onset in idiopathic factor. Diabetes, gestational or pre-existing, was present in all of women (ten cases) in maternal facror. Higher AFI was found to be associated with an increased frequency of prenatally detected congenital anomalies. Abnormal fetal kary- type noted in 18/45 (40%) cases of polyhydramnios. Polyhydramnios diagnosed on ultrasound requires further maternal and fetal iagnostic tests. PMID- 29714879 TI - Comparison of GnRH antagonist and agonist mini-dose long protocols in infertile cases undergoing controlled ovarian hyperstimulation. AB - AIM: The purpose of the present study was to determine if there is a difference between multi-dose gonadotropin releasing hormone (GnRH) antagonist protocol and long GnRH agonist protocol. MATERIALS AND METHODS: This retrospective study compared the data pertaining to patients chosen as per predetermined acceptance criteria, 113 of whom were administered multi-dose antagonist protocol for controlled ovarian hyperstimulation (COH) while 133 were administered long agonist protocol for COH at Suleymaniye Teaching Hospital of Obstetrics and Gynecology. RESULTS: While cancellation rate was found to be significantly higher in antagonist group (17.7% vs 11.28%), the number of follicles > 14 mm and > 16 mm, E2 level, and the number of retrieved oocytes on the day of hCG trigger were significantly lower in the same group. However, there was no difference between fertilization rates and embryonic development rates. The pregnancy rates per transfer and per cycle were found to be 40.9% and 31.7%, respectively; in the antagonist group they were lower, though not significantly, when compared to agonist group (44.1% and 39.1%, respectively). Ongoing pregnancy rates were found to be similar between the groups. CONCLUSION: GnRH antagonist treatment protocol has a level of efficacy similar to agonist treatment protocol in terms of pregnancy results for all groups. PMID- 29714880 TI - The effects of formoterol on the serum, peritoneal VEGF, MDA, and VEGF levels in the ovaries and endometrium of rats with OHSS. AB - PURPOSE: To investigate the effects of formoterol (a beta2-adrenoreceptor agonist) on serum and peritoneal fluid VEGF, malondialdehyde (MDA) levels, and on VEGF-stained cell counts in the ovaries and endometrium of rats with ovarian hyperstimulation syndrome (OHSS) within the framework of immunohistochemical analysis. MATERIALS AND METHODS: A total of 28 immature female Wistar rats were randomly divided into four groups. Three groups were given ten IU pregnant mare serum gonadotropin/day on days 22-25 of life. They were administered 30 IU hCG on day 26 of life to mimic OHSS. On days 26 and 27 of life, 24 mcg/kg/day formoterol in group 3 and 48 mcg/kg formoterol in group 4 were administered intraperitoneally per animal. RESULTS: Although, there were no statistically significant differences between the groups in terms of serum and peritoneal fluid VEGF or MDA levels (serum VEGF: p = 0.28 1, peritoneal VEGF: p = 0.674, serum MDA: p = 0.543, peritoneal MDA: p = 0.506), there was a significant difference between the control and the OHSS placebo groups (p = 0.013) regarding the VEGF in the ovarian cortex. There was a significant difference between the control and the other groups in terms of ovarian stroma (p = 0.001), and there was also a statistically significant difference between the OHSS placebo and the other groups regarding VEGF in the endometrium (OHSS placebo vs. control group p = 0.002, OHSS placebo vs. the formoterol 24 mcg/kg group, p = 0.008, and OHSS placebo vs. the formoterol 48 mcg/kg group, p = 0.001). CONCLUSIONS: Formoterol represents a potential novel strategy for the management of OHSS. Further studies, including those examining the dosage of formoterol, are warranted. PMID- 29714881 TI - The effect of leflunomide on the transplanted endometriosis lesions in SD rats. AB - OBJECTIVE: To investigate the effects of the leflunomide (LEF) on the size of the transplanted endometriosis (EMS) lesions and trans- forming growth factor (TGF) beta1gray level in SD rats. MATERIALS AND METHODS: EMS was surgically induced in rats by autologous trans- plantation and the focal volume was also measured. The rats were divided into three groups: group A: normal SD rats, group B: rats irrigated by one ml-kg-1d-1 saline for three weeks, and group C: rats irrigated by 35 mg-kg-1d-1 LEF for three weeks. The rats were then sacrificed and measured their focal volume and TGF-beta1 gray value with immunohistochemical method. RESULTS: The sizes of the focal volume in group C were significantly reduced compared to the rats before feeding, and the volume in group C was smaller than group B after feeding and so was the TGF-beta1. CONCLUSION: LEF could be a new therapeutic drug for EMS. PMID- 29714882 TI - Sympathetic neural hyperalgesia edema syndrome as a cause of autoimmune hearing loss. AB - PURPOSE: To describe another previous unreported manifestation of the sympathetic neural hyperalgesia edema syndrome - autoimmune hearing loss. MATERIALS AND METHODS: Dextroamphetamine sulfate 30 mg extended release capsules was given to a woman to try to help her conceive since, with her pelvic pain, chronic fatigue syndrome, and diarrhea, it was thought that an inflammatory condition related to permeation of unwanted chemicals into endometrial tissue related to the sympathetic neural hyperalgesia edema syndrome could be inhibiting her failure from conceiving despite three cycles of embryo transfer. RESULTS: Not only did the symptoms mentioned above disappear, but she also noted marked improvement of hearing loss that had been present for several years. The improvement in hearing was documented by audiology tests and had not responded to many months of 15 mg/day prednisone. CONCLUSIONS: Autoimmune hearing loss (diagnosis established by her ear nose and throat specialist) should be added to the long list of manifestation of the sympathetic neural hyperalgesia edema syndrome. PMID- 29714883 TI - Adnexal torsion in early pregnancy after assisted reproduction: can the adnexa be saved?. AB - Adnexal torsion occurs when the ovary and fallopian tube twist on the axis created between the infundibulopelvic ligament and the utero-ovarian ligament. The symptoms are mostly unspecific and diagnosis is therefore not simple. Early diagnosis is essential to preserve organ function and fertility. The increased use of assisted reproductive technologies has led to an increase in the risk of adnexal torsion, particularly in pregnant women or women with ovarian hyperstimulation syndrome (OHSS). A gestational age eight-week pregnant woman who received in vitro fertilization (IVF) came to the clinic and was suspected of adnexal torsion. The patient underwent an operation and the biopsy histologically confirmed ischemia. Here the authors report a case with comparison to other studies, the early diagnosis, and early operation that could save adnexa. PMID- 29714884 TI - A case report of a patient with high beta-hCG levels after operation because of primary broad ligament pregnancy. AB - INTRODUCTION: A broad ligament pregnancy is an extremely rare condition and diagnosis is frequently missed and finally made during laparotomy. This is a case of a young patient with high serum beta-human chorionic gonadotropin (beta-hCG) levels after operation because of broad ligament pregnancy. CASE REPORT: A 31 year-old multipara complained of intermittent lower abdominal pain with vaginal bleeding for four months. A color ultrasonography revealed a cystic mass in the left attachment area, indicating an interstitial tubal pregnancy. However, trophoblastic disease could not be excluded. She accepted conservative treatment with methotrexate (MTX) at first, but observation showed that conservative treatment was slow and accompanied with liver function damage. Therefore, exploratory laparotomy was performed. Intraoperative situations and postoperative pathology confirmed broad ligament pregnancy. Her serum p- hCG was sustained at a high level for three months after operation. Her examinations of serum, CT, and ultrasonography could explain this situation. CONCLUSION: Primary broad ligament pregnancy refers to pregnancy where implantation of the fertilized ovum occurs directly between the two leaves of the broad ligament. The gravid substance was removed, however serum beta-hCG could not gradually re- turn to normal levels. This case should be followed-up closely to prevent adverse outcomes. PMID- 29714885 TI - Low-dose gonadotropin-releasing hormone agonist therapy (draw-back therapy) for successful long-term management of adenomyosis associated with cerebral venous and sinus thrombosis from low-dose oral contraceptive use. AB - : The authors report a case of cerebral venous and sinus thrombosis (CVST) in a patient receiving a low-dose estrogen-progestin combination (oral contraceptives, OCs) for uterine adenomyosis. She was switched to gonadotropin-releasing hormone agonist (GnRHa) draw-back therapy, which was successfully administered long-term. CASE: The patient was a 38-year-old nulligravida with a history of smoking. She presented to this hospital with dysmenorrhea and postmenstrual lower abdominal pain. Adenomyosis was diagnosed using ultrasound and magnetic resonance imaging. She was instructed to stop smoking and was administered low-dose OCs. CVST occurred 18 months later. OC therapy was halted, and only antiplatelet therapy was administered. After six months, her chief complaint symptoms intensified, therefore GnRHa draw-back therapy was administered after obtaining informed consent. No uterine enlargement was observed, and the abdominal pain resolved. During 2.5 years of therapy, her bone density levels remained within normal limits. CVST did not recur and no other thromboses were observed. PMID- 29714886 TI - Ectopic pregnancy occurring in the remnant tube of a previous adnexectomy: a case report. AB - Ectopic pregnancy occurring in the same region is a comparatively rare disease, but sometimes it is very serious to patients if it is delayed. The authors present a case of spontaneous ectopic pregnancy occurring in the ipsilateral salpingectomy stump of a previous adnexectomy that was successfully removed via laparoscopic surgery without complication. This case may support the idea of intrauterine transmigration of a fertilized egg as an etiology of spontaneous ectopic pregnancy. Thus, the potential for ectopic pregnancy in the tubal remnant in cases of previous salpingectomy or adnexectomy needs to be carefully considered. PMID- 29714887 TI - Retroperitoneal endometriosis in postmenopausal woman causing deep vein thrombosis: case report and review of the literature. AB - Endometriosis is an uncommon disease in postmenopausal women (PMW), ranging from 2% to 5% of cases, and it is very important to exclude neoplastic transformation of the endometrium. The authors would like to introduce the case of a 63-year-old overweight patient with abdominal pain associated to pain and swelling of the left inferior limb occurring for approximately six weeks. The CT X-ray of the abdomen revealed the presence of a retroperitoneal mass causing deep vein thrombosis because of extrinsic compression of the left iliac vein. Following removal of the pelvic masses with laparotomy, the histological exam revealed an endometriosis. The CT X-ray carried out after a month postoperatively revealed the root canal treatment of the left femoral vein with a considerable decrease of the thrombosis of homolateral external iliac veins. Despite the endometriosis, it is uncommon in women who have reached menopause and must be considered in the differential diagnosis of pelvic masses. PMID- 29714888 TI - 18q deletion is difficult to detect by prenatal diagnosis: a report of two cases and a discussion of the literature. AB - Fetuses with 18q deletion have few structural abnormalities, therefore ultrasound is unlikely to detect this anomaly. Prenatal chro- mosome microarray is a powerful tool in detecting subtle cytogenetic abnormalities such as 18q deletion. PMID- 29714889 TI - Resolution of hydrops fetalis caused by atrioventricular block: good postnatal evolution with terbutaline treatment. AB - INTRODUCTION: Complete atrioventricular block (CAVB) is rarely seen, as it occurs in only 1:11 000 to 1:20 000 newborns. There is a serious risk of mortality in CAVB, mainly in those cases associated with hydrops, fetal cardiac frequency <= 55 beats/minute, and premature delivery. CASE REPORT: Case of complete atrioventricular block with a poor prognosis (hydrops fetalis and foetal cardiac frequency < 5 beats/minute) caused by anti-La and anti-Ro antibodies. Intrauterine symptoms improved after treatment with terbutaline, permit- ting foetal viability and successful postnatal treatment with a cardiac pacemaker. DISCUSSION: In case of complete atrioventricular block of cause autoimmune with poor prognosis should be treated with positive inotropic drugs, anticholinergics or b-mimetic in the attempt to maintain adequate ventricular frequency, and thus prevent hydrops fetalis from occurring. PMID- 29714890 TI - Rosacea fulminans during pregnancy. AB - BACKGROUND: Rosacea fulminans (RF) is a severe form of facial dermatosis presenting with a sudden onset of numerous facial pustules, papules, and erythema. During pregnancy its treatment may be difficult and can have an impact on obstetrical outcomes. CASE: A 37-year-old woman during the 37th week of her fourth pregnancy presented RF that was associated with ocular manifestations. The usual treatment with isotretinoin was contraindicated during pregnancy and the patient started an alternative treatment with prednisone and azithromycin. After delivery at 38 weeks of gestational age, there was a significant improvement. CONCLUSION: RE is a severe dermatological disease with unknown etiology and with a rapid improvement in the immediate postpartum period. PMID- 29714892 TI - Idiopathic spontaneous hemoperitoneum during pregnancy. AB - Spontaneous hemoperitoneum is defined as bleeding within the peritoneal cavity of non-traumatic and non-iatrogenic etiology. It is a rare and life-threatening condition during pregnancy. Spontaneous hemoperitoneum is considered idiopathic when the source of bleeding is not detected during the exploratory laparotomy. The authors report two cases of spontaneous hemoperitoneum during pregnancy with sudden onset of abdominal pain during the third trimester of their pregnancy. Cesarean section was performed for fetal distress. In both cases, hemoperitoneum with a large quantity of blood was found, but the source of bleeding could not be identified during surgical exploration. PMID- 29714891 TI - A rare case of abdominal pregnancy. AB - An extrauterine abdominal pregnancy is a very rare form of ectopic pregnancy in which implantation occurs within the peritoneal cavity, and outside the fallopian tube and ovary. It easily causes misdiagnosis and is closely related to maternal health. Only a few reported cases have been treated using laparoscopy. The authors report a case involving an extrauterine abdominal pregnancy diagnosed during laparoscopy located near the rectum. A 39-year-old gravida 3 para 1 who had a cesarean delivery 16 years ago was referred to the present department for evaluation of vaginal bleeding for 47 days. No abdominal tenderness was demonstrated on physical examination. The vaginal examination revealed an enlarged uterus. An ultrasound scan showed an empty uterine cavity. Adjacent to the right ovary, a mixed echo was noted in which a yolk sac was visible. A heart rate was detected. The serum beta hCG was 11,198 mIU/mL. Laparoscopic surgery was performed. On the right side of the sacral ligament there was a 3x3x2.5 cm purple blue mass adherent to the rectum. The pregnancy was excised and removed from the abdomen in an endo-bag, and hemostasis was assured. During the postoperative course, intramuscular methotrexate therapy was administered (20 mg/m2 twice a week x 5). The patient was discharged on the 26th post-operative day; she was asymptomatic and had no complaints. The serum beta hCG level was 3.98 IU/l at the time of discharge. This case shows that laparoscopic treatment of abdominal pregnancy is safe and feasible, and when necessary, can assist drug therapy. PMID- 29714893 TI - Intravenous acetaminophen for the treatment of intrapartum fever and resolution of fetal tachycardia: a novel use for an old medication. AB - This case series demonstrates a potential new role for the use of intravenous (IV) acetaminophen. The authors reviewed two cases, whereby patients that developed intrapartum fever leading to fetal tachycardia were effectively treated with IV acetaminophen, leading to rapid reduction of maternal temperature and resolution of fetal tachycardia. Both patients had an uncomplicated vaginal delivery of healthy neonates. Intravenous acetaminophen, with its increased bioavailability and more rapid onset of action, may have benefit in the intrapartum setting by reducing adverse neonatal and maternal outcomes associated with febrile morbidity. PMID- 29714894 TI - Historians Must Continue to Lead. PMID- 29714896 TI - Olympic Nursing. PMID- 29714895 TI - Two Narratives, One History: Mary Seacole and Florence Nightingale. PMID- 29714897 TI - Reflection on Events of August 11-12, 2017, Charlottesville, Virginia. PMID- 29714898 TI - Transorbital Lobotomy at Eastern State Hospital, 1951-1954. PMID- 29714899 TI - Well, Tell Me What You Really Think! PMID- 29714900 TI - [Effects of Geometrical Dimensions and Material Properties on the Rotation Characteristics of Head]. AB - The validated finite element head model(FEHM)of a 3-year-old child,a 6-year-old child and a 50 th percentile adult were used to investigate the effects of head dimension and material parameters of brain tissues on the head rotational responses based on experimental design.Results showed that the effects of head dimension and directions of rotation on the head rotational responses were not significant under the same rotational loading condition,and the same results appeared in the viscoelastic material parameters of brain tissues.However,the head rotational responses were most sensitive to the shear modulus(G)of brain tissues relative to decay constant(beta)and bulk modulus(K).Therefore,the selection of material parameters of brain tissues is most important to the accuracy of simulation results,especially in the study of brain injury criterion under the rotational loading conditions. PMID- 29714901 TI - [Finite Element Analysis of Biomechanics of Cervical Spine after Dynamic Cervical Implant Surgery]. AB - This study aims to investigate the range of motion(ROM)and the stress variation in the intervertebral disc and the vertebral body on adjacent segments and the influence of force transmission mode after the dynamic cervical implant(DCI)surgery.Two types of surgery,DCI implantation and interbody fusion were used to establish the finite element model of the cervical C5,6segment degeneration treatment.The ROM and the adjacent discs and vertebral body stresses of two procedures under flexion,extension,lateral bending and axial rotation working conditions were analyzed.The results showed that ROM of the surgical segment in DCI model was well preserved and could restore to the normal ROM distributions(reduction of the amplitude was less than 25%),and the kinetic characteristics of adjacent segments was less affected.In fusion surgery model,however,ROM of the surgical segment was reduced by 86%-91%,while ROM,disc stress and vertebral stress of adjacent segments were increased significantly,and stress of the C5 vertebral body was increased up to 171.21%.Therefore DCI surgery has relatively small influence on cervical ROM and stress.The study provides a theoretical basis for DCI and fusion surgery in clinic. PMID- 29714902 TI - [Development and Validation of a Three-Dimensional Finite Element Model of Inferior Cervical Spinal Segments C(4-7) for a Healthy Person]. AB - This study aims to develop and validate a three-dimensional finite element model of inferior cervical spinal segments C4-7of a healthy volunteer,and to provide a computational platform for investigating the biomechanical mechanism of treating cervical vertebra disease with Traditional Chinese Traumotology Manipulation(TCTM).A series of computed tomography(CT)images of C4-7segments were processed to establish the finite element model using softwares Mimics 17.0,Geromagic12.0,and Abaqus 6.13.A reference point(RP)was created on the endplate of C4 and coupled with all nodes of C4.All loads(+/-0.5,+/-1,+/-1.5and+/ 2Nm)were added to the RP for the six simulations(flexion,extension,lateral bending and axial rotation).Then,the range of motion of each segment was calculated and compared with experimental measurements of in vitro studies.On the other hand,1Nm moment was loaded on the model to observe the main stress regions of the model in different status.We successfully established a detail model of inferior cervical spinal segments C4-7of a healthy volunteer with 591 459 elements and 121 446 nodes which contains the structure of the vertebra,intervertebral discs,ligaments and facet joints.The model showed an accordance result after the comparison with the in vitro studies in the six simulations.Moreover,the main stress region occurred on the model could reflect the main stress distribution of normal human cervical spine.The model is accurate and realistic which is consistent with the biomechanical properties of the cervical spine.The model can be used to explore the biomechanical mechanism of treating cervical vertebra disease with TCTM. PMID- 29714903 TI - [Research on Adaptive Balance Adjustment of Lower Limb Joints and Muscles in the Process of Unexpected Slip]. AB - Aiming at the gait instability phenomenon under disturbed conditions,domestic and foreign scholars have done some research works,but the relationship between the independent balancing act with the surface electromyographic and gait parameters in the process of instability has yet rarely been involved.In this study,using the gait analysis combined with electromyographic signal analysis,we investigated balance adjustment mechanism of joints and muscles of the human lower limb under the condition of walking on the level trail and after foot heel touching the ground and unexpected sliding.Studying 10 healthy subjects with the unified shoes,we acquired and analyzed the changing rule of the lower limb joint torque,joint angle,and the surface electromyographic of the main muscle groups involved in situations of dry or oid trails.Studies showed that when accident sliding happened,the body would increase ankle dorsiflexion torque moment,knee unbend torque and straight angle,and meanwhile increase the torque of hip extension,and timely adjust muscle activation time(Followed by activation of Tibialis anterior muscle->Rectus femoris->Gastrocnemius->Femoral biceps)to adjust the center of gravity,to maintain balance of the body,and to avoid falling down.The results of the research could be used to explore new ideas and to provide a certain reference value for preventing slip damage,rehabilitation training and development of lower limb walker. PMID- 29714904 TI - [Research on Three-dimensional Temperature Field Reconstruction in Biological Tissue Based on Multi-island Genetic Algorithm]. AB - The nondestructive reconstruction of three-dimensional(3D)temperature field in biological tissue is always an important problem to be resolved in biomedical engineering field.This paper presents a novel method of nondestructive reconstruction of 3Dtemperature field in biological tissue based on multi-island genetic algorithm(MIGA).By this method,the resolving of inverse problem of bio heat transfer is transformed to be a solving process of direct problem.An experiment and its corresponding simulation were carried out to verify the feasibility and reliability.In the experiment a high purity polypropylene material,whose thermophysical parameters were similar to the fat tissue being tested,were adopted so that it could avoid the negative results created by the other factors.We set the position P(x,y,z)as the point heat source in the biological tissue and its temperature t as optimization variable,got the experimental temperature values of the points in a module surface,subtracted them from the corresponding simulating temperature values in the same module surface,and then took the sum of absolute value.We took it as the objective function of successive iteration.It was found that the less the target value was,the more optimal the current variables,i.e.the heat source position and the temperature values,were.To improve the optimization efficiency,a novel establishment method of objective function was also provided.The simulating position and experimental position of heat source were very approximate to each other.When the optimum values are determined,the corresponding 3D temperature field is also confirmed,and the temperature distribution of arbitrary section can be acquired.The MIGA can be well applied in the reconstruction of 3Dtemperature field in biological tissue.Because of the differences between the MIGA and the traditional numerical methods,we do not have to acquire all the data of surface.It is convenient and fast,and shows a prosperous application future. PMID- 29714905 TI - [Design and Realization of Personalized Corneal Analysis Software Based on Corneal Topography System]. AB - As the most important refraction part in the optical system,cornea possesses characteristics which are important parameters in ophthalmology clinical surgery.During the measurement of the cornea in our study,we acquired the corneal data of Orbscan II corneal topographer in real time using the Hook technology under Windows,and then took the data into the corneal analysis software.We then further analyzed and calculated the data to obtain individual Q-value of overall corneal 360semi-meridian.The corneal analysis software took Visual C++ 6.0as development environment,used OpenGL graphics technology to draw three-dimensional individual corneal morphological map and the distribution curve of the Q value,and achieved real-time corneal data query.It could be concluded that the analysis would further extend the function of the corneal topography system,and provide a solid foundation for the further study of automatic screening of corneal diseases. PMID- 29714906 TI - [Detection of Solitary Pulmonary Nodules Based on Geometric Features]. AB - The possibility of solitary pulmonary nodules tending to lung cancer is very high in the middle and late stage.In order to detect the middle and late solitary pulmonary nodules,we present a new computer-aided diagnosis method based on the geometric features.The new algorithm can overcome the disadvantage of the traditional algorithm which can't eliminate the interference of vascular cross section.The proposed algorithm was implemented by multiple clustering of the extracted geometric features of region of interest(ROI)through K-means algorithm,including degree of slenderness,similar degree of circle,degree of compactness and discrete degree.The 232 lung CT images were selected from Lung Image Database Consortium(LIDC)database to do contrast experiment.Compared with the traditional algorithm,the detection rate of the new algorithm was 92.3%,and the error rate was 14.8%.At the same time,the detection rate of the traditional algorithm was only 83.9%,and the error rate was 78.2%.The results show that the proposed algorithm can mark the solitary pulmonary nodules more accurately and reduce the error rate due to precluding the disturbance of vessel section. PMID- 29714907 TI - [Numerical Analysis of Two-stage Axial Blood Pump Based on Blood Damage]. AB - The implantable miniaturized axial blood pump works at a high rotational speed,which increases the risk of blood damage.In this article,we aimed to reduce the possibility of hemolysis and thrombosis by designing a twostage axial blood pump.Under the operation conditions of flow rate 5L/min and outlet pressure of 100 mm Hg,we carried out the numerical simulation on the two-stage and single stage blood pumps to compare the hemolysis and platelet activation state.The results turned out that the hemolysis index of two-stage axial blood pump was better while the platelet activation state was worse than those of single stage design.On the index of hemolysis level and platelet activation state,the design of the two-stage pump with the low and high-head impeller combination was better than the two-stage pump with the equal heads,or the high and low-head impeller combination.In terms of reducing the risk of blood damage for implantable miniaturized axial blood pump,the research result can provide some theoretical basis and new design ideas. PMID- 29714908 TI - [Research of New Coloration Biochip Reader Based on Charge-coupled Device]. AB - Aiming at long signal acquisition time,low flux,bad signal-to-noise ratio and low intelligence in coloration biochip reader,a new kind of rapid device with high flux was developed.The device consisted of hardware system and software system.It used a charge-coupled device(CCD)as the photoelectric sensor elements and obtained the biochip microarray image.The device integrated the embedded operating system based on i.MX6 chip.The microarray image processing,data analysis and result output were achieved through the code information of the software chip.Experiments with the standard grayscale sheet and standard format chip were carried out.The results showed that the maximum measurement error was less than 0.1%,the value of R2 was 98.7%,and the value of CV was1.096 1%.The comparison results of 200 samples showed that detection performance of the proposed device was better than that of the same kind of marketed equipment. PMID- 29714909 TI - [Research and Design of a Blue and Green Light Emitting Diode Phototherapy System Based on Fly Eye Lens for Jaundice]. AB - Light emitting diode(LED)can be used in the treatment of jaundice.Blue and green LED irradiation affected with the newborn is currently considered the most effective treatment of the jaundice in the world.A jaundice phototherapy system with blue and green LED as light source utilizing fly eye lens array was built to achieve uniform illumination in the present study.AMC7150 chip was used to build the constant current drive module,and AT89C52 MCU and LCD12864 LCD screen were used to build the human-computer interaction module.Based on national particular phototherapy equipment requirements(YY0669-2008)for the safety,we designed and implemented a phototherapy system which spot area was 250mm*500mm,blue light irradiance reached 2mW/cm2,green light irradiance reached 1.5mW/cm2,and the uniformity of light was over 90%.Compared with the traditional system,the new one designed in this study has better therapeutic effect,higher biological safety,easier to achieve man-machine interaction,and more economical and convenient. PMID- 29714910 TI - [Feasibility Study on Digital Signal Processor and Gear Pump of Uroflowmeter Calibration Device]. AB - It will cause hidden trouble on clinical application if the uroflowmeter is out of control.This paper introduces a scheme of uroflowmeter calibration device based on digital signal processor(DSP)and gear pump and shows studies of its feasibility.According to the research plan,we analyzed its stability,repeatability and linearity by building a testing system and carried out experiments on it.The flow test system is composed of DSP,gear pump and other components.The test results showed that the system could produce a stable water flow with high precision of repeated measurement and different flow rate.The test system can calibrate the urine flow rate well within the range of 9~50mL/s which has clinical significance,and the flow error is less than 1%,which meets the technical requirements of the calibration apparatus.The research scheme of uroflowmeter calibration device on DSP and gear pump is feasible. PMID- 29714911 TI - [Detection of Hepatitis C Virus by Reverse Transcription-loop Mediated Isothermal Amplification]. AB - Hepatitis C virus(HCV)do harm to people's health.The present study aims to establish a simple HCV detection method by reverse transcription-loop mediated isothermal amplification technique(RT-LAMP).A total of75 clinical samples were collected and pre-detected by fluorescence quantitative-polymerase chain reaction(FQ-PCR),which was considered as the gold standard.Firstly,four common primers were designed according to the conservative 5'UTR region of HCV on the NCBI website to establish an integrated RT-LAMP reaction system.Then,the reaction efficiency was evaluated by adding Taq DNA polymerase to the conventional system.The specificity of RTLAMP was evaluated by observing the length of fragment after endonuclease digestion and by a templates exchange assay,the sensitivity of RT-LAMP was evaluated by detection of diluted clinical templates.The results were compared with that of reverse transcription polymerase chain reaction(RT-PCR).At the same time,the performance was judged using calcein and hydroxynaphthol blue(HNB)stain methods,The two results were compared with that of electrophoresis method.At last,75 clinical samples were detected by both RT-LAMP and RT-PCR methods.Results showed that the reaction efficiency was increased 20 minutes after adding Taq DNA polymerase to the normal RT-LAMP system.RT-LAMP showed good specificity,the digestion length was consistent with our expectation(216bp)after restriction endonuclease cleavage assay,and only the templates of HCV were amplified using the common RT-LAMP primers.After detection of diluted temples,the sensitivity of RT-LAMP was 10IU/tube,which was 10 fold higher than that of PCR.In addition,the results using calcein and HNB stain methods were the same with that of electrophoresis method.After detection of all 75 clinical samples,the results indicated that RT-LAMP had worse consistency with RT-PCR(P<0.05,Kappa=0.375).However,RT-LAMP,on the contrary,showed good consistency with FQ-PCR(P>0.05,Kappa=0.762).In conclusion,RT-LAMP has characteristics of simplicity,specificity and sensitivity,and this technique is suitable for the primary care hospitals. PMID- 29714912 TI - [Research on Potential Role of Receptor-interacting Protein Kinase 1 in Phenotype Switching of Vascular Smooth Muscle Cells]. AB - Vascular smooth muscle cells(VSMCs)phenotype switching plays an essential role in the pathogenesis of various vascular diseases.The present study aims to investigate the role of receptor-interacting protein kinases 1(RIPK1)in VSMCs phenotypic switching induced by AngiotensinII(AngII).Expression of mRNA and protein of RIPK1,markers of VSMCs phenotypic switching and secretion,phosphorylation of the P65 subunit of NF-kappaB were measured by real time PCR and Western blot.Meanwhile,EdU incorporation assay and wound scratch assay were performed to determine the cell proliferation and migration respectively.At the same time,Necrostatin-1(Nec-1,an known RIPK1inhibitor)and RIPK1-specific small interference RNA(siRNA)were used to inhibit the expression of RIPK1.The experimental data demonstrated that the mRNA and protein levels of RIPK1 and P65phosphorylation were increased significantly in the process of VSMC phenotypic switching induced by Ang II.Moreover,the expression of RIPK1 and P65phosphorylation were significantly down-regulated in VSMCs pretreated with Nec 1or transfected with RIPK1-siRNA.Furthermore,the proliferation,secretion and migration of VSMCs were also markedly suppressed after inhibition of RIPK1 by Nec 1or its specific siRNA.The results suggested that RIPK1 might be involved in VSMC phenotypic switching induced by Ang II,which was possibly via up-regulating the NF-kappaB signaling pathway. PMID- 29714913 TI - [Induction of Apoptosis of Human Cisplatin-resistance Lung Cancer Cells with MPPa photodynamic Therapy]. AB - Lung cancer is the leading cause of cancer-related deaths worldwide.Despite the development and use of several targeting drugs for lung cancer therapy,the five year survival rate has remained as low as 15%for the past three decades.Cisplatin based chemotherapy is considered the first-line therapeutic strategy for lung cancer.However,developments of chemoresistance is a major obstacle for the successful treatment.Therefore,the development of novel therapy against cisplatin resistance lung cancer is imperative.Photodynamic therapy(PDT),which is a non invasive combinatorial therapeutic modality using light,photosensitizer(PS)and oxygen,may provide an unprecedented tool to develop more effective treatments.To provide experimental basis for its application in cisplatin-resistance lung cancer,we will discuss the biological effects of MPPa-photodynamic therapy in human cisplatin-resistance lung cancer cells in this article.Human cisplatin resistance lung cancer cells A549/DDP were co-cultured with MPPa(0,1,2,4,8,16MUmol/L)and exposed to light(0,0.6,1.2,2.4,3.6,4.8J/cm2),and cell viability was determined with CCK-8assay.Flow cytometry was used to detect apoptosis,DCFH-DA staining was employed to observe reactive oxygen species(ROS),and Western blot was used to detect the expressions of B-cell lymphoma-2(Bcl-2)protein and Bcl-2associated X protein(Bax).The proliferation of A549/DDP cells was suppressed by PDT.The apoptotic rate in the PDT group was significantly higher than that in the control,MPPa or light group(P<0.05).The level of ROS was increased.The expression of Bax was increased,and that of Bcl 2was decreased.MPPa-photodynamic therapy can significantly suppress cell viability,and induce apoptosis in human cisplatin-resistance lung cancer cells. PMID- 29714914 TI - [Experimental Study of Remifentanil-poly-caprolactone Infusion through Abdominal Aorta against Spinal Cord Ischemia-Reperfusion Injury]. AB - The present study was to investigate the effects of infusing remifentanil-poly caprolactone(REM-PCL)through the abdominal aorta on spinal cord ischemia reperfusion injury(SCIRI).The model of SCIRI was created by clamping the infrarenal aortic in thirty-six New Zealand white rabbits,which were randomly divided into sham group(group S),control group(group C),and REM-PCL group(group R)with 12 rabbits in each one.The spinal cord microcirculatory blood flow(SCMBF)and blood flow rate(BFR)were monitored before ischemia,15 min,30min,60 min and 120 min after reperfusion,respectively.Neurologic Function was evaluated before ischemia,6h,12hand24 hafter reperfusion.The concentration of serum neuron specific enolase(NSE),interleukin-lbeta(IL-lbeta)and interleukin-8(IL-8)were monitored before ischemia,45 min after ischemia,30 min,60min,6h,12 hand 24hafter reperfusion.The abnormal rate of motor neuron of spinal cord tissues and the level of superoxide dismutase(SOD),reactive oxygen species(ROS),glutathione peroxidase(GSH-PX),malondialdehyde(MDA),total anti-oxidation capacity(T-AOC)and mitochondrial swelling degree(MSD)in neural mitochondria were determined before ischemia,45 min after clamping,60 min and 120 min after reperfusion.As a result,the neural mitochondrial SOD,GSH-PX and T-AOC decreased while ROS,MDA,MSD,IL-lbeta,IL-8and NSE distinctly increased after clamping of the abdominal aorta as compared to the value before ischemia in group C(P<0.01).Neurologic function scores recovered more rapidly in group R than those in group C during reperfusion(P<0.01).The neural mitochondrial SOD,GSH-PX and T AOC were distinctly higher while ROS,MDA,MSD,IL-lbeta,IL-8and NSE were distinctly lower in group R than those in group C(P<0.01).The abnormal rate of motor neuron was significantly higher in group C during reperfusion than that in group R(P<0.01).It has been shown that the intra-aortic REM-PCL infusion can alleviate SCIRI by inhibiting inflammatory response and improving mitochondrial anti oxidation capacity. PMID- 29714915 TI - [Research on Association between Ataxia Telangiectasia Mutated(ATM)Gene Single Nucleotide Polymorphism Rs189037 C>T and Essential Hypertension]. AB - This study aimed to explore the possible association between single nucleotide polymorphism(SNP)rs189037C>T in the promoter region of ataxia telangiectasia mutated(ATM)gene and essential hypertension(EH).We performed a case-control study to collect randomly 369 hospitalized patients aged 50 years and above.They were divided into EH group(190patients)and control group(179subjects)according to the diagnostic criteria of hypertension.The SNP rs189037 genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism.The genotype frequencies of ATM gene polymorphism rs189037 for the whole sample were33.9% CC,48.0% CT,and 18.1% TT.There was no significant difference in the genotype frequency distributions of the SNP rs189037 between EH and control groups(P=0.619).After adjustment of the major confounding factors,the SNP rs189037 was still not associated with EH(P>0.05).We further analyzed data from different groups divided by genders and age respectively,and the relationship was retained(P>0.05).In addition,we found that the percentage of the TT genotype was much lower in coronary artery disease(CAD)patients than those in the CC or CT genotype(OR=0.49,95% CI=0.26~0.90,P=0.021).In conclusion,our study suggests that SNP rs189037 in the promoter of ATM gene is not associated with EH.But it is related to the incidence of CAD,and TT genotype seems to be a protective factor for CAD. PMID- 29714916 TI - [A New Algorithmic Method to Detect Ventricular Fibrillation Using Electrocardiogram Signals During Cardiopulmonary Resuscitation by Artificial Pressing]. AB - On account of the mechanical disturbance of external chest pressing to electrocardiogram(ECG)signal,the ECG rhythm cannot be identified reliably during the cardio-pulmonary resuscitation period.Whereas the possibility of successful resuscitation will be lowered due to interrupted external chest pressing,a new filtering algorithm,enhanced leastmean-square(eLMS)algorithm,was proposed and developed in our laboratory.The algorithm can filter the disturbance of external chest pressing without the support of hardware reference signal and correctly identify ventricular fibrillation(VF)rhythm and normal sinus rhythm in case of uninterrupted external chest pressing.Without other reference signals,this algorithm realizes filtering only through the interrupted electrocardiograma(cECG)signal.It was verified with ECG signal and disturbance signal under different signal to noise ratios and contrasted with other mature algorithms.The verification results showed that the identification effect of eLMS was superior to those of others under different signal to noise ratios.Furthermore,ECG rhythm can be correctly identified only through cECG signal.This algorithm not only reduces the research and development(R&D)costs of automated external defibrillator but also raises the identification accuracy of ECG rhythm and the possibility of successful resuscitation. PMID- 29714917 TI - [Distortion Correction and Intensity Inhomogeneity Correction of Glomerulus Transmission Electron Microscope Image]. AB - In order to get high-resolution glomerulus image with large field of view(FOV),stitching multiple small FOV images with high-resolution is necessary.Directly stitching images without properly correction is not acceptable and cannot afford any significant assistance in pathological diagnosis for intensity inhomogeneity and geometric distortion.Therefore we proposed a method of distortion correction and intensity inhomogeneity correction of glomerulus transmission electron microscope(TEM)image.In this paper,we firstly describe how these two distortions degrade images.Secondly,based on the TEM imaging system,image acquisition model and distortion correction model were proposed.Then according to these two models,distortions were greatly degraded and stitching results were improved by respectively applying two corrections,intensity inhomogeneity correction and geometric distortion correction.With the method proposed here,the result was improved significantly and stripes,fuzzy and artifacts were decreased dramatically.Our method has been proved to be valid to solve the problems of TEM glomerulus image distortion and at the same time to improve the result of multiple TEM glomerulus image stitching. PMID- 29714918 TI - [Applications of Wavelet Transform Combining Empirical Mode Decomposition in EEG Analysis with Music Intervention]. AB - In the present paper,wavelet transform and empirical mode decomposition(EMD)are combined to extracted the features of electroencephalogram(EEG)signal with music intervention,and to achieve a better classification accuracy rate and reliability in emotional assessment in order to provide a support for music therapy.The data were from Database for Emotion Analysis using Physiological Signals(DEAP).Based on wavelet transformalpha,betaandthetarhythms were extracted at frontal(F3,F4),temporal(T7,T8)and central regions(C3,C4).Based on the EMD,the intrinsic mode function(IMF)was analyzed and extracted.Furthermore,average energy and amplitude difference of IMF were analyzed and obtained.The support vector machine was used to assess the state of emotion in order to support music therapy.According to this algorithm,the classification accuracy rate could reach 100% between no emotions,positive emotions and negative emotions,which made a 10%improvement between positive and negative emotion recognition.Effective evaluation result between positive and negative emotions was achieved.The states of emotion would influence the effect of music therapy,undoubtedly,the classification accuracy rate increasing of emotional assessment will further help improve the effect of music therapy and provide a better support to the therapy. PMID- 29714919 TI - [Design and Implementation of a Medical Nitric Oxide Flow Control Device]. AB - Medical nitric oxide(NO)flow control system plays an important role in lowering pulmonary hypertension.The design requirements,overall scheme,delivery system and hardware circuits of a medical NO flow control system were introduced in this paper.Particularly,we proposed the design of NO delivery system and hardware circuits in detail.To deliver nitric oxide of a variable concentration,the designed system needs to work with a ventilator.The system can adjust and monitor the inhaled nitric oxide concentrations and send out sound and light alarms when the inhaled nitric oxide concentrations are out of the set range.To validate reliability and efficacy,we measured specifications such as linearity,stability and response time of the proposed NO flow control system by continuously administering nitric oxide into inspiratory circuit to deliver nitric oxide of variable concentrations to a test lung.The experiments showed that these specifications can meet the desired requirements. PMID- 29714920 TI - [Visualization and Quantitative Analysis of the Blood Flow Fields in Aortic Arch by Vector Flow Mapping in Normal Human Bodies]. AB - To visualize and quantify the hemodynamics in the aortic arch in normal individuals,we used velocity distribution,retrograde flow,vortex formation,and mean energy loss(mEL)at different cardiac cycles in our study.We performed Vector flow mapping(VFM)analysis by using echocardiography in 87 healthy volunteers.The results showed that1 in different sections of the aortic arch,a skewed peak flow velocity(Vp)always appeared in the period of rapid ejection but in different distribution.The systolic flow in the entire aortic arch rose rapidly from near zero at the point of iso-volumetric contraction to the peak velocity at the period of rapid ejection,and then decreased gradually;2In the period of iso volumetric relaxation,retrograde flow and vortex were observed in all subjects in the inner wall of the entire aortic arch;and3 The change rule of mEL in the entire aortic arch was similar to that of flow velocity.VFM can provide insights into the intra-aortic arch flow patterns,and offer essential fundamentals about flow features associated with common aortic diseases. PMID- 29714921 TI - [A Fuzzy Logic Model-based Advisory System for Mechanical Ventilation]. AB - In the clinical practice,the mechanical ventilation is a very important assisting method to improve the patients' breath.Whether or not the parameters set for the ventilator are correct would affect the pulmonary gas exchange.In this study,we try to build an advisory system based on the gas exchange model for mechanical ventilation using fuzzy logic.The gas exchange mathematic model can simulate the individual patient's pulmonary gas exchange,and can help doctors to learn the patient's exact situation.With the fuzzy logic algorithm,the system can generate ventilator settings respond to individual patient,and provide advice to the doctors.It was evaluated in 10 intensive care patient cases,with mathematic models fitted to the retrospective data and then used to simulate patient response to changes in therapy.Compared to the ventilator set only as part of routine clinical care,the present system could reduce the inspired oxygen fraction,reduce the respiratory work,and improve gas exchange with the model simulated outcome. PMID- 29714922 TI - [Computer-aided Diagnosis in Dynamic Contrast-Enhanced Magnetic Resonance Imaging of Malignant Tumor:A Technical Review of Current Research]. AB - Dynamic contrast-enhanced magnetic resonance imaging(DCE-MRI)may provide more information in diagnosis of malignant tumor compared to conventional magnetic resonance imaging(MRI).Nowadays,in order to utilize the information expediently and efficiently,many researchers are aiming at the development of computer-aided diagnosis(CAD)of malignant tumor based on DCE-MRI.In this review,we survey the research in this field and summarize the literature in four parts,i.e.1image preprocessing--noise reduction and image registration;2region of interests(ROI)segmentation;3feature extraction--exploring the image characteristics by analyzing the ROI quantitatively;4tumor lesion recognition and classification--distinguishing and classifying tumor lesions by learning the features of ROI.We summarize the application of CAD techniques of DCE-MRI for cancer diagnosis and,finally,give some discussion on how to improve the efficiency of CAD in the future research. PMID- 29714923 TI - [Mechano-electric Feedback and Atrial Fibrillation]. AB - Atrial fibrillation is a common and refractory atrial arrhythmia.Changes of atrial mechanical circumstances are closely related to the occurrence and maintenance of atrial fibrillation.Mechanical factors can increase the automaticity,slow conduction velocity and shorten the effective refractory period of the atrium by causing electrical and structural remodeling,and eventually increase the inducibility of atrial fibrillation.The intracellular calcium level,function and structure of cytoskeleton,local renin-angiotensin system,integrin and mitogen-activated protein kinases(MAPKs)pathway might take part in the process.Here we analyze and review the underlining mechano-electric feedback process of atrial fibrillation and its related research in order to provide a theoretical basis for further research and elucidating of the mechanical mechanism of atrial fibrillation. PMID- 29714924 TI - [Application of Microspheres in Calcium Phosphate Cement System]. AB - Calcium phosphate cement(CPC)has been widely used as bone fillers because of its excellent bioactivity and biocompatibility.Meanwhile,CPC is also an attractive candidate for the incorporation of drug or microspheres,because the preparing procedure avoids sintering and heating release.This paper summarizes the clinical applications of microspheres incorporated in CPC from the aspects of sustained drug release,accelerated degradation,porous structure and improved mechanical properties.The paper is aimed to analyze the methods and principles of microspheres loaded CPC,and so as to lay a foundation for the further research of improving and manufacturing the CPC with ideal properties. PMID- 29714925 TI - [Research Advancement on the Carriers and Controlled-release Systems of Bone Morphogenetic Proteins]. AB - Bone morphogenetic protein(BMPs)has been so far regarded as one of the highly potent osteoinductive growth factors.Recombinant human bone morphogenetic proteins have been utilized extensively in the disciplines of orthopedics,stomatology,etc.For clinical application,BMPs are usually loaded in carriers with a controlled-release system,to maintain concentration to induce de novo bone formation at the desired site.In this article,the research advancements of the carriers and release systems of BMP are reviewed. PMID- 29714926 TI - [Research Advances in Regeneration of Soft Tissue with Small Intestinal Submucosa]. AB - Small intestinal submucosa(SIS)is a natural decellularized extracellular matrix material.Due to its excellent biocompatibility,unique biomechanical properties and biological activity,it has been widely used as a scaffold in regenerative medicine.This article reviews the recent progress in the characterization and medical application of SIS respectively.The specific biological properties of the SIS,as well as its interaction with cells,are highlighted.Some of the SIS products and clinical cases are also reviewed and discussed. PMID- 29714927 TI - [Effect of Caveolae/Caveolin-1on Osteogenic Differentiation of Mesenchymal Stem Cells]. AB - Mesenchymal stem cells(MSCs)have the property of osteogenic induction.As a result,using the property of MSCs to treat the fractures and bone defects has become a new treatment modality with the development of cell and tissue engineering technology.Caveolae is a flask-shaped membrane microdomain in cell membrane,which composed primarily of cholesterol,sphingolipids and proteins.Caveolin-1is one of the main protein component.Caveolae is the integrator of cell signals,and many signal molecules gather here to bind with caveolin-1protein to regulate cell proliferation,differentiation and other life activities.This paper presents a review about Caveolae/Caveolin-1biologic effects on cell differentiation of MSCs. PMID- 29714928 TI - [Research on Clinical Electrocardiogram Classification Algorithm Based on Ensemble Learning]. AB - With the increasing number of electrocardiogram(ECG)data,extensive application requirements of computer-aided ECG analysis have occurred.In the paper,we propose a variety of strategies to improve the performance of clinical ECG classification algorithm based on Lead Convolutional Neural Network(LCNN).Firstly,we obtained two classifiers by using different preprocessing methods and training methods in the study.Then,we applied the multiple output prediction method to both of them independently.Finally,the Bayesian approach was employed to fuse them.Tests conducted using more than 150 000 ECG records showed that the proposed method had an accuracy of 85.04% and the area under receiver operating characteristic curve(AUC)was 0.918 5,which significantly outperforms traditional methods based on feature extraction techniques. PMID- 29714929 TI - [Adaptive Cardiopulmonary Resuscitation Artifacts Elimination Algorithm Based on Empirical Mode Decomposition and Independent Component Analysis]. AB - Artifacts produced by chest compression during cardiopulmonary resuscitation(CPR)seriously affect the reliability of shockable rhythm detection algorithms.In this paper,we proposed an adaptive CPR artifacts elimination algorithm without needing any reference channels.The clean electrocardiogram(ECG)signals can be extracted from the corrupted ECG signals by incorporating empirical mode decomposition(EMD)and independent component analysis(ICA).For evaluating the performance of the proposed algorithm,a back propagation neural network was constructed to implement the shockable rhythm detection.A total of 1 484 corrupted ECG samples collected from pigs were included in the analysis.The results of the experiments indicated that this method would greatly reduce the effects of the CPR artifacts and thereby increase the accuracy of the shockable rhythm detection algorithm. PMID- 29714930 TI - [Detrended Fluctuation Analysis of Electroencephalogram of Patients with Sleep Apnea Syndrome]. AB - Sleep apnea syndrome(SAS)is a kind of harmful systemic sleep disorder with high incidence,and the pathological mechanism of it is complicated and the diagnosis and treatment are difficult.Mining the characteristic information of SAS from the single or small physiological signal is a hot topic in the research of sleep disorders in recent years.In our study shown in this paper,the detrended fluctuation analysis(DFA)was used to analyze sleep electroencephalogram(EEG)of SAS patients and normal healthy persons based on the non-stationary and nonlinear characteristics.It was found that in both groups,the scaling exponents increased gradually with the deepening of sleep,and in the rapid eye movement(REM)stage,the scaling exponents decreased.The scaling exponents of SAS group were significantly higher than those of the healthy group.The performance of SAS diagnosis based on scaling exponents was evaluated with receiver operator characteristic(ROC)curve.The optimal threshold value 0.81 for the SAS and normal control were obtained,corresponding to the sensitivity 94.4%,specificity 99.2%,and area under curve(AUC)was 0.994.The results show that DFA scaling exponents have a good discrimination power and accuracy for the SAS,which provide a new theoretical basis for SAS diagnosis. PMID- 29714931 TI - [Automatic Sleep Stage Classification Based on an Improved K-means Clustering Algorithm]. AB - Sleep stage scoring is a hotspot in the field of medicine and neuroscience.Visual inspection of sleep is laborious and the results may be subjective to different clinicians.Automatic sleep stage classification algorithm can be used to reduce the manual workload.However,there are still limitations when it encounters complicated and changeable clinical cases.The purpose of this paper is to develop an automatic sleep staging algorithm based on the characteristics of actual sleep data.In the proposed improved K-means clustering algorithm,points were selected as the initial centers by using a concept of density to avoid the randomness of the original K-means algorithm.Meanwhile,the cluster centers were updated according to the'Three-Sigma Rule'during the iteration to abate the influence of the outliers.The proposed method was tested and analyzed on the overnight sleep data of the healthy persons and patients with sleep disorders after continuous positive airway pressure(CPAP)treatment.The automatic sleep stage classification results were compared with the visual inspection by qualified clinicians and the averaged accuracy reached 76%.With the analysis of morphological diversity of sleep data,it was proved that the proposed improved K-means algorithm was feasible and valid for clinical practice. PMID- 29714932 TI - [An Assessment Method of Electroencephalograph Signals in Severe Disorders of Consciousness Based on Entropy]. AB - This paper explores a methodology used to discriminate the electroencephalograph(EEG)signals of patients with vegetative state(VS)and those with minimally conscious state(MCS).The model was derived from the EEG data of 33 patients in a calling name stimulation paradigm.The preprocessing algorithm was applied to remove the noises in the EEG data.Two types of features including sample entropy and multiscale entropy were chosen.Multiple kernel support vector machine was investigated to perform the training and classification.The experimental results showed that the alpha rhythm features of EEG signals in severe disorders of consciousness were significant.We achieved the average classification accuracy of 88.24%.It was concluded that the proposed method for the EEG signal classification for VS and MCS patients was effective.The approach in this study may eventually lead to a reliable tool for identifying severe disorder states of consciousness quantitatively.It would also provide the auxiliary basis of clinical assessment for the consciousness disorder degree. PMID- 29714933 TI - [Pretreatment Research Based on Left and Right Hand Motor Imagery for Single channel Electroencephalogram]. AB - Most of electroencephalogram(EEG)acquired by multi-channels is difficult to be applied to the singlechannel brain-computer interface(BCI)in the EEG analysis method based on left and right hand motor imagery.The present research applied an improved independent component analysis(ICA)method to realize pretreatment of the EEG effectively.Firstly,data drift was removed through linear drift correction.Secondly,the number of virtual channels were increased by applying delayed window data and some EEG artifacts which are namely electrooculogram(EOG)and electrocardiogram(ECG)were removed by ICA.Finally,the average instantaneous energy characteristics were calculated and classified through the instantaneous amplitude which was solved by applying Hilbert-Huang transform(HHT).The experiment proves that the method completes the EEG pretreatment and improves classification ratio of single-channel EEG,and lays a foundation of single-channel and portable BCI. PMID- 29714934 TI - [Influence of Restricting the Ankle Joint Complex Motions on Gait Stability of Human Body]. AB - The purpose of this study is to determine how restricting inversion-eversion and pronation-supination motions of the ankle joint complex influences the stability of human gait.The experiment was carried out on a slippery level ground walkway.Spatiotemporal gait parameter,kinematics and kinetics data as well as utilized coefficient of friction(UCOF)were compared between two conditions,i.e.with restriction of the ankle joint complex inversion-eversion and pronation-supination motions(FIXED)and without restriction(FREE).The results showed that FIXED could lead to a significant increase in velocity and stride length and an obvious decrease in double support time.Furthermore,FIXED might affect the motion angle range of knee joint and ankle joint in the sagittal plane.In FIXED condition,UCOF was significantly increased,which could lead to an increase of slip probability and a decrease of gait stability.Hence,in the design of a walker,bipedal robot or prosthetic,the structure design which is used to achieve the ankle joint complex inversion-eversion and pronation-supination motions should be implemented. PMID- 29714938 TI - [Image Fusion of Dyna CT and Digital Subtraction Angiography for Arteriovenous Malformations]. AB - Both Dyna CT,a rotational faultage reconstructed technique,and digital subtraction angiography(DSA)play important roles in the diagnosis and treatment of arteriovenous malformations(AVM).Three-dimensional Dyna CT can provide the spatial information of AVM nidus,while two-dimensional DSA can provide the time information for distinguishing arteries and veins.To illustrate the location relationship of the nidus,arteries and veins at the same time,these two imaging modalities need to be fused.In this paper,a two-dimensional to three-dimensional back projection and growing method is proposed,which realizes the image fusion of two-dimensional DSA and threedimensional Dyna CT and achieves the differentiation of arteries and veins in Dyna CT.The experimental results showed that the fusion image could present both the position information of AVM nidus and the dynamic information of the blood vessels.Therefore,the proposed method can help surgeons locate the AVM abnormality and make operation plan more accurately. PMID- 29714939 TI - [Research on Segmentation Method of Lung with Juxta-pleural Tumor Based on the Improved Active Shape Model]. AB - Lung segmentation is the premise of the computer aided diagnosis of lung cancer.The traditional segmentation method based on local low-level features can not get the correct result when a tumor is connected with pleura due to their similar computed tomography(CT)values.Moreover,because the big size of tumor leads to the loss of a large part of lung area,the traditional segmentation methods of lung with juxta-pleural nodule whose diameter is less than 3cm are not suitable.Acitve shape model(ASM)combined with prior shape and low level features might be appropriate.But the search steps in conventional ASM is an optimization method based on the least square,which is sensitive to outlier marker points,and it makes profile update to the transition area of normal lung tissue and tumor rather than a true lung contour.To solve the problem,we proposed an improved ASM algorithm.Firstly,we identified these outlier marker points by distance,and then gave the different searching functions to the abnormal and normal marker points.And the search processing should be limited in volume of interesting(VOI).We selected 30 lung images with juxta-pleural tumors,and got the overlap rate with the gold standard as 93.6%.The experimental results showed that the improved ASM could get good segmentation results for the lungs with juxta pleural tumors,and the running time of the algorithm could be tolerated in clinical. PMID- 29714940 TI - [Near-infrared Spectra Noninvasive Measurement Method of Blood Oxygen Saturation Based on the"M+N"Theory]. AB - "M+N"theory can be used as a method to improve the prediction accuracy in spectral analysis.The measured component,M kinds of non-measurement component,and N kinds of outside interference are induced into the entire measuring system,with the impact of"M"factors and "N"factors on the measurement accuracy considered systematically and comprehensively.Our human experiment system testing blood oxygen saturation based on "M+N"theory has been established.Dynamic spectrum method was used to eliminate the effects of different persons and different measuring parts which belonged to the system error of"N"factors.And then the D value estimation was used to eliminate the effects of motion pseudo signal which belonged to the random error of"M"factors.Sixty two groups of valid data were obtained.The prediction model of blood oxygen saturation was built based on partial least squares regression method.The correlation coefficient and relative error were 0.796 8and +/-0.026 6,while the result of oximeter was 0.595 7and relative error was+/-0.076 0,respectively.The results show that the prediction accuracy of the measurement method based on the"M+N"theory is much higher than that of the oximeter. PMID- 29714941 TI - [Experimental Study on Influence of Driving Speed on Foam Stability in Sclerotherapy for the Treatment of Varicose Veins]. AB - Foam sclerotherapy is one of the major therapies for varicose veins in lower limbs.It is important to know the influence factor of foam stability which is beneficial to curative effect.The present experiment explored influence of 9kinds of driving speed on foam stability when using the method of Tessari.Syringes of 5mL were chosen to do this experiment which was carried out at the liquid gas ratio of 1?4and the environment temperature of 20 C.A home-made automatic sclerosing foam preparation equipment was used to prepare the foam.A camera recorded the entire process of foam decay.And foam stability indexes which includes drainage time,half-life,foam half-life volume and the drainage rate curve,were analyzed.The results showed that when driving speed ranged from 100mm/s to 275mm/s,foam drainage time and the half-life showed a trend of rising.When the driving velocity was greater than 275mm/s,the foam drainage time and half-life time reduced a little.The largest drainage time and the half-life differences were 340.0% and 118.8% compared to their minimum value.Meanwhile the pressure increased with the increase of driving speed,so that the solubility of carbon dioxide increased and the foam half-life volume decreased with the increase of the driving speed.It can be concluded that when using the method of Tessari to prepare sclerosing foam,driving speed has a significant effect on its stability.With driving speed increasing,foam decay mechanism changes from gas diffusion to liquid drainage as the main function,so the foam stability increased at first and then decreased later.The foam is relatively more stable at the speed of 275mm/s,which could be considered as the best driving speed. PMID- 29714942 TI - [Fabrication and Performance Study of Polydimethylsiloxane Intraocular Lens]. AB - To simplify the production process of intraocular lens(IOL)and to solve the problem of lacking adjustable ability,we proposed a novel soft IOL with large scale adjustable ability and rigid haptics based on heat-assisted method,and gravity-assisted method.Polydimethylsiloxane(PDMS)and rigid material--polymethyl methacrylate(PMMA)were used as the materials for fabricating optical lens(PDMS)and haptics(PDMS and PMMA)through changing the weight ratio of the solution.A lens-smartphone microscopy system was established to replace the traditional digital microscopy to measure the tiny displacements and shape changes.The PDMS lens has excellent optical property through an experiment in which the maximum optical power was around 273.2D.Experimental results indicated that the maximum optical power of PMMA IOL was 129.3D,and that in PDMS IOL,however,was only 56.0D.Thus,the rigid PMMA-IOL has a larger adjustable range.The production process of PDMS was mold-free,rapid,real-time,and highly repeatable and there was no need for a rigorous experimental environment either.This creative processing technology reduced the manufacturing steps from which an optical lens with high transmittance and high resolution,as well as hatics with accurate dimensions,were obtained.The rigidity of haptics affected more intensely than other factors did for improving the pre-displacement and changing the appearance of PDMS lens.Even though the rigidity of PMMA haptics is large enough for accommodating,there are many drawbacks during manufacturing.It is unavailable to rapid fabricate IOL using PMMA.Thus,further work will be required to alter the weight ratio of PDMS material,increase the rigidity,and enhance the adjustable ability of PDMS IOL. PMID- 29714943 TI - [Preparation and Property Investigation of Vancomycin Loaded Calcium Sulfate Hemihydrate/Silk Fibroin Microsphere Artificial Bone Composites with Different Concentration]. AB - With silk fibroin and vancomycin(VCM)as carrier and drug model,respectively,we prepared silk fibroin microspheres(SFM)with different concentration using the water-in-oil emulsion solvent diffusion method.We further developed VCM loaded calcium sulfate hemihydrates(CSH)/SFM artificial bone composites.In this study,surface morphology of the materials was observed using scanning electron microscope(SEM).Structure of the materials was studied with Fourier transform infrared spectroscopy(FTIR).Antibacterial activity of the materials was validated with the inhibition zone test.Drug release property of materials was evaluated using ultraviolet/visible spectrophotometry.Mechanical property of the materials was tested using computer-controlled electronic universal testing machine.The results showed that silk fibroin concentration had no significant effect on molecular conformation and antibacterial property of the SFM.The average diameter of SFM increased and the release rate decreased gradually as the silk fibroin concentration increased.The release rate decreased and the compressive fracture work increased as the silk fibroin concentration increased when adding SFM to CSH.This composite had partly corrected the disadvantages of CSH including the high brittleness and initial burst release.The research would have a good application foreground in the clinical treatment of infectious bone defect. PMID- 29714945 TI - [Comprehensive Evaluation of Biological Activity in Different Passage Populations of Mesenchymal Stem Cells Derived from Bone Marrow in Ovariectomy Osteoporotic Rats]. AB - This study aimed to comprehensively evaluate the biological activity in different passage populations of mesenchymal stem cells(BMSCs)derived from bone marrow in ovariectomy osteoporotic rats(named OVX-rBMSCs),providing experimental basis for new osteoporotic drug development and research.OVX-rBMSCs were isolated and cultured in vitro by the whole bone marrow adherent screening method.The morphological observation,cell surface markers(CD29,CD45,CD90)detection,cell proliferation,induced differentiation experimental detection were performed to evaluate the biological activity of Passage 1,2,3,4populations(P1,P2,P3,P4)OVX rBMSCs.The results showed that whole bone marrow adherent culture method isolated and differentially subcultured OVXrBMSCs.The morphology of P4 OVX-rBMSCs was identical fibroblast-like and had the characteristics of ultrastructure of stem cells.The CD29 positive cells rate,CD90 positive cells rate,cell proliferation index,and the osteogenic,adipogenic,chondrogenic differentiation capacities of P4 OVX-rBMSCs were significantly better than those of other populations(P<0.05).OVX rBMSCs purity and biological activity were gradually optimized with the passaged,and among them P4 cells were superior to all the other populations.Based on these results,we report that the P4OVX-rBMSCs model developed in this study can be used to develop a new and effective medical method for osteoporotic drug screening. PMID- 29714944 TI - [Experimental Comparison Research between Two Kinds of Modified Poly(lactic acid)Material In Vitro]. AB - This study aims to compare two kinds of modified poly(lactic acid)(PLA)materials:PLA-chitosan(PLA-CTS)and PLA-poly(glycolic acid)(PLA-PGA).PLA CTS and PLA-PGA scaffolds were prepared and observed under electron microscope.The scaffold porosity was calculated and the pH of the degradation solution was measured.Then rat olfactory ensheathing cells(OECs)were cultivated,and mixed cultured respectively with two scaffolds as two groups.The proliferation,adhesion rate and growth condition of the OECs were observed and compared between the two groups.Results showed that both the prepared PLA-CTS and PLA-PGA scaffolds were threedimensional porous structure and the porosity of PLA CTS was 91%,while that of PLA-PGA was 87%.The pH of degradation solution decreased gradually,of which PLA-PGA fell faster than PLA-CTS.After added to the two scaffolds,most OECs could grow well,and there were no significant differences between the two groups on MTT test and nuclei number determined by fluorescent microscope.However,the cell adhesion rate of PLA-CTS group was significantly higher than that of PLA-PGA.It can be concluded that compared with PLA-PGA,PLA CTS might be a better choice as OECs scaffold. PMID- 29714946 TI - [Effects of Mechanical Stretch on Expression of Airway Remodeling Associated Factors in Human Bronchial Epithelioid Cells]. AB - This study is aimed to investigate the effects of mechanical stretch on the expression of transforming growth factor-beta1(TGF-beta1)and fibroblast growth factor-2(FGF-2),and the signaling pathway in human bronchial epithelioid(16HBE)cells under mechanical stretch.Using loading device with flexible substrate(FX-4000T)to stretch 16 HBE cells,we found that the stretching elongation was 15%,at frequency of 1Hz,stretching for 0.5h,1h,1.5hand 2h.Choosing the higher expression of TGF-beta1,FGF-2and Ca2+group to carry out intervention experiments,we used the cells pretreated with canonical transient receptor potential 1(TRPC1)channel antagonist SKF96365,protein kinase C(PKC)inhibitor HA 100,and thereafter mechanical stretch to interpose.Compared with those in the blank control group,TGF-beta1and FGF-2'protein and mRNA,intracellular Ca2+fluorescence intensity were higher,and the differences were statistically significant(P<0.05)at the 4time points,0.5h,1h,1.5h and 2h.At 0.5h,the increasing rate was the highest.TGF-beta1protein and mRNA,FGF-2protein and mRNA,intracellular Ca2+luorescence intensity in the stretch+SKF96365and stretch+ HA-100 intervented group were decreased,the differences were statistically significant than those in 0.5hstretch group(P<0.05)without intervention.The expression of TGF-beta1,FGF-2 was up-regulated in 16 HBE cells under mechanical stretch,PKC,TRPC1,and Ca2+may participate in the signal path. PMID- 29714947 TI - [Analysis of the Characteristics of Infantile Small World Neural Network Node Properties Correlated with the Influencing Factors]. AB - We applied resting-state functional magnetic resonance imaging(rfMRI)combined with graph theory to analyze 90 regions of the infantile small world neural network of the whole brain.We tried to get the following two points clear:1 whether the parameters of the node property of the infantile small world neural network are correlated with the level of infantile intelligence development;2 whether the parameters of the infantile small world neural network are correlated with the children's baseline parameters,i.e.,the demographic parameters such as gender,age,parents' education level,etc.Twelve cases of healthy infants were included in the investigation(9males and 3females with the average age of 33.42+/ 8.42 months.)We then evaluated the level of infantile intelligence of all the cases and graded by Gesell Development Scale Test.We used a Siemens 3.0T Trio imaging system to perform resting-state(rs)EPI scans,and collected the BOLD functional Magnetic Resonance Imaging(fMRI)data.We performed the data processing with Statistical Parametric Mapping 5(SPM5)based on Matlab environment.Furthermore,we got the attributes of the whole brain small world and node attributes of 90 encephalic regions of templates of Anatomatic Automatic Labeling(ALL).At last,we carried out correlation study between the above mentioned attitudes,intelligence scale parameters and demographic data.The results showed that many node attributes of small world neural network were closely correlated with intelligence scale parameters.Betweeness was mainly centered in thalamus,superior frontal gyrus,and occipital lobe(negative correlation).The r value of superior occipital gyrus associated with the individual and social intelligent scale was-0.729(P=0.007);degree was mainly centered in amygdaloid nucleus,superior frontal gyrus,and inferior parietal gyrus(positive correlation).The r value of inferior parietal gyrus associated with the gross motor intelligent scale was 0.725(P=0.008);efficiency was mainly centered in inferior frontal gyrus,inferior parietal gyrus,and insular lobe(positive correlation).The r value of inferior parietal gyrus associated with the language intelligent scale was 0.738(P=0.006);Anoda cluster coefficient(anodalCp)was centered in frontal lobe,inferior parietal gyrus,and paracentral lobule(positive correlation);Node shortest path length(nlp)was centered in frontal lobe,inferior parietal gyrus,and insular lobe.The distribution of the encephalic regions in the left and right brain was different.However,no statistical significance was found between the correlation of monolithic attributes of small world and intelligence scale.The encephalic regions,in which node attributes of small world were related to other demographic indices,were mainly centered in temporal lobe,cuneus,cingulated gyrus,angular gyrus,and paracentral lobule areas.Most of them belong to the default mode network(DMN).The node attributes of small world neural network are widely related to infantile intelligence level,moreover the distribution is characteristic in different encephalic regions.The distribution of dominant encephalic is in accordance the related functions.The existing correlations reflect the ever changing small world nervous network during infantile development. PMID- 29714948 TI - [Correlations between Fractional Flow Reserve and Coronary Artery Stenosis Based on the Stenosis Position and Coronary Dominant Type]. AB - For coronary artery diseases,imaging diagnosis is usually used to guide the treatment.However,it can only reflect the geometric characteristics of the disease but does not determine the hemodynamically significant stenosis.This study was aimed to investigate the relationship between angiographic and functional severity of coronary artery stenosis and to improve the diagnostic value of imaging.39 patients with 55 stenosis vessels were included in this study.The correlation between FFR and stenosis rate was analyzed with the medical statistical analysis method,and the influence of the position of stenosis and coronary dominant type on the correlation was discussed.By regression analysis,the stenosis rate of left anterior descending artery of right dominant type showed a significant correlation with FFR value(r~0.79,P<0.000 1)after grouping with position and the dominant type.Due to the significance of a value of the FFR<0.80 in determining inducible ischemia,the diagnostic accuracy of myocardial ischemia by the stenosis rate increased from 70.9% to 82.8% after grouping.Sensitivity(from 72.2% to 78.6%)and specificity(from 70.3%to 86.7%)were also significantly improved.This study indicates that the position of stenosis and the coronary dominant type are significant influence factors on the correlation between FFR and stenosis rate.Consideration of these two factors in the diagnosis of myocardial ischemia by imaging will be helpful to improve the effectiveness of diagnosis. PMID- 29714949 TI - [Feasibility Study of Dual-source Computed Tomography High-pitch Scan Mode in Preoperative Evaluation of Aortic Stenosis Referred to Transcatheter Aortic Valve Implantation]. AB - The purpose of this study was to explore the feasibility of dual-source computed tomography(DSCT)highpitch scan mode in the preoperative evaluation of severe aortic stenosis(AS)referred to transcatheter aortic valve implantation(TAVI).Thirty patients with severe AS referred for TAVI underwent cervico-femoral artery joint DSCT angiography.Measurement and calculation of contrast,contrast noise ratio(CNR)and noise of aorta and access vessels were performed.The intra-and inter-observer reproducibilities for assessing aortic root and access vessels were evaluated.Evaluation of shape and plagues of aorta and access vessels was performed.The contrast,CNR and noise of aorta and access vessels were 348.2~457.9HU,12.2~30.3HU and 19.1~48.1 HU,respectively.There were good intra-and inter-observer reproducibilities in assessing aortic root and access vessels by DSCT(mean difference:-0.73~0.79 mm,r=0.90~0.98,P<0.001;mean difference:-0.70~0.73 mm,r=0.90~0.96,P<0.001).In the 30 patients,the diameters of external iliac artery,femeral artery or subclavian artery were less than 7mm in 5cases(16.7%),marked calcification in bilateral common iliac arteries in 1case(3.3%)and marked soft plaque in left common iliac artery in 1case(3.3%).DSCT high-pitch scan mode was feasible in the preoperative evaluation of aorta and access vessels in patients with AS referred for TAVI. PMID- 29714950 TI - [Design and Implementation of a Portable Forced Oscillation Respiration Resistance Detector]. AB - This paper proposes a forced oscillation respiration resistance detector which has the characteristics of portable and friendly interface,with remote transmission function.STM32 is used to produce single frequency or complex frequency oscillation signal.In the experiments,the signal was magnified by the power amplifier to drive speaker to generate oscillates airflow into the subject's oral cavity.The analog to digital coverter of STM32 was used to measure the signals obtained by the pressure sensor and the flow sensor,and then the operation parameters were to be displayed on the TFT-LCD touch screen,and could also be transferred to the master computer.Simulated lung and volunteerism were used to verify the reliability of the detector.The test results showed that the system was reliable,and it achieved the significance in respiratory impedance detecting. PMID- 29714951 TI - [Experimental Research on Detection of Breast Carcinoma and Adjacent Tissues Based on Open-ended Coaxial Probe Tumor Sensor with Radio Frequencies]. AB - This study aimed to verify whether the open-ended coaxial line tumor sensor with radio frequency was effective or not in detecting the differences in permittivity and conductivity between the breast malignant tissues and adjacent tissues.Sixteen breast infiltrating ductal carcinoma samples were freshly obtained from the department of general surgery in Zhujiang Hospital.The permittivity and conductivity of cancerous nidus points of breast samples,3cm adjacent tissue points and 5cm adjacent tissue points were detected respectively by the open-ended coaxial line tumor sensor with radio frequency noninvasively in conjunction with vector network analyzer at the frequency ranging from 42.85~500 MHz.All the detected points were marked.After finishing the detection,we conducted postoperative pathological examinations on all the marked points.According to the statistics,there were statistically significant differences between the breast cancerous tissues and the 3cm adjacent tissues for the dielectric properties(P<0.01).There were statistically significant differences between the breast cancerous tissues and the 5cm adjacent tissues for the dielectric properties(P<0.01).There was no statistically significant difference in the dielectric properties between the 3cm adjacent tissues and 5cm adjacent tissues(P>0.05).Both the 3cm adjacent tissues and5 cm adjacent tissues were found no breast cancer cell infiltration.The results indicated that the open ended coaxial line tumor sensor at radio frequency could be effective in detecting the differences in permittivity and conductivity between breast cancerous tissues and adjacent tissues and,therefore,it may have a potential prospect in making a final diagnosis to confirm whether the detected breast tissue is malignant or not. PMID- 29714952 TI - [Implementation of V1 Area Contour Integration Mechanism and Attention Selection Based on Excitation-Inhibition Intersecting Cortical Model]. AB - This paper aims to utilize the intersecting cortical model(ICM),which imitates the biological neural cells sync pulse,to preliminary research about the contour integration mechanism and the selection of attention.The idea of"Excitement Inhibition"oscillation is introduced into the ICM,and meanwhile,the target contour chain code is used as the high-level feedback to control the input.Thus,we propose the Excitation-Inhibition-ICM which contains both the BUTTON-UP and the TOP-DOWN mechanism.The experimental results showed that the proposed model could effectively suppress noise to make the smooth edge synchronization issue,thus completing the process of BOTTOM-UP.The introduction of the target contour chain code can obtain consistent target outline with the input target chain code,but other targets cannot form a closed contour since they do not match with the input target chain code,so as to realize the TOP-DOWN mechanism.The results proved that our proposed model could imitate the contour integration mechanism and the selection of attention of the visual cortex V1. PMID- 29714953 TI - [Design of a Low-power-consuming Magnetoelastic Sensor Detecting System Based on STM32]. AB - Magnetoelastic(ME)sensors,characterized by wireless,passive,low cost and high sensitivity,have widespread applications in various fields.However,its defects of large volume,high power consumption,poor portability and inconveniency for use limit the application prospects of the ME sensors.To solve this problem,the present paper shows a portable,low-power,resonance-type ME sensor detecting system based on STM32.The experimental results indicated that this detecting system allowed the ME sensor to complete the measurement of resonant frequency in different medium and different concentration,with a frequency resolution of less than 1Hz,and the resonant frequency ratio of ME sensors in different sizes 0.933 8,closing the theoretical value of 0.942 3.Moreover,compared with the traditional impedance analyzer combined detecting system and the existing integrated detecting system,the present system has a power consumption of 0.68 Win operation and of only 2.20 mW in the dormancy mode.Therefore,the system can not only replace the original impedance analyzer combined detecting system,but also significantly improve the power control of the existing integrated detecting system,exhibiting the advantages of higher integration,portable measurement,and fine suitability for long-term monitoring. PMID- 29714954 TI - [Quantitative Evaluation of Regularity of Finger Tapping Movement for Patients with Parkinson's disease]. AB - Finger tapping test is a common testing item for patients with Parkinson's disease(PD)in clinical neurology.It mainly evaluates the fine motor function of patient's hand in three aspects:amplitude,speed and regularity of the movement.This paper focused on the quantitative assessment of regularity of finger tapping movement for PD patients.The movement signals of thumb and index finger were recorded by using inertial sensor unit in the process of tapping test.Two nonlinear dynamic indexes,approximate entropy(ApEn)and sample entropy(SampEn),were calculated,and then the values were statistically analyzed.The experimental results indicated that both indexes had significant differences between patient group and control group.Moreover,the indexes had relatively high correlation with the scores of corresponding unified Parkinson's disease rating scale(UPDRS)item rated by clinical clinician,which illustrated that these two indexes could reflect the injury level of the repetitive finger movement.So,as a reliable method,it can be provided to the clinical evaluation of hand movement function for PD patients. PMID- 29714955 TI - [Study of Algorithms Reconstructing Gene Regulatory Network with Resampling and Conditional Mutual Information]. AB - Reconstruction of gene regulatory networks(GRNs)from large-scale expression data can mine the potential causality relationship among the genes and help understand the complex regulatory mechanisms.It is of utmost interest and has become a challenging computational problem for understanding the complex regulatory mechanisms in cellular systems.For the past decades,numerous theoretical and computational approaches have been introduced for inferring the GRNs.However,all existing methods of inferring GRNs from gene expression profiles have their strengths and weaknesses.In particular,many properties of GRNs,such as topology sparseness and non-linear dependence,are generally in regulation mechanism but are seldom taken into account simultaneously in one computational method.Some information theory algorithms do not recover the true positive edges that may have been deleted in an earlier computing process.These interaction relationships may reflect the actual relationship of genes.To overcome these disadvantages and to further enhance the precision and robustness of inferred GRNs,we presented an ensemble method,to infer GRNs from gene expression data by adopting two strategies of resampling and arithmetic mean fusion in this work.In this algorithm,the jackknife resampling procedure was first employed to form a series of sub-datasets of gene expression data,then the conditional mutual information was used to generate the corresponding sub-networks from the sub-datasets,and the final GRN was inferred by integrating these sub-networks with an arithmetic mean fusion strategy.Compared with those of the state-of-the-art algorithm on the benchmark synthetic GRNs datasets from the DREAM3 challenge and a real SOS DNA repair network,the results show that our method outperforms significantly LP,LASSO and ARANCE methods,and has a high and robust performance. PMID- 29714957 TI - [A Review of Electrical Property Tomography for Human Tissues]. AB - In recent years,the technologies based on the electrical properties(EPs)of human tissue,such as electrical impedance tomography(EIT)and magnetic resonance electrical impedance tomography(MREIT),have become one of the most popular research subjects in biomedicine.Compared with EIT and MREIT,the magnetic resonance electrical property tomography(MR-EPT)is a new technique using nondestructive EPs method.MR-EPT reconstructs the electrical conductivity and permittivity of the biological tissues based on the radio frequency field of the magnetic resonance imaging(MRI)system.It can obtain an accurate and high resolution image without current injection.In this paper,several methods for the EPs are reviewed,especially the MR-EPT.The theory,advantages and prospects of MR EPT's are elaborated.The method of specific absorption rate(SAR)based on it is also introduced.MR-EPT is deserved further research and should be given more attention by the researchers.All this evolution based on MREPT can give new energy to the medical diagnosis. PMID- 29714956 TI - [Research Progress of Implantable Biosensors for Continuous Glucose Monitoring]. AB - Continuous glucose monitoring plays an important role in severe diabetic patients.However,there is no available commercial implanted glucose biosensor for long-term clinic application.This paper firstly introduces the classification of biosensors for continuous glucose monitoring,and then discusses the failure mechanism for implanted biosensors.After that,it points out the routes and tips to improve the life time of the biosensor,and finally looks forward to the future development of implanted glucose biosensors. PMID- 29714958 TI - [Effect of Lysophosphatidic Acid on Cell Migration and Its Relative Molecular Mechanisms]. AB - Lysophosphatidic acid(LPA)is a pluripotent lipid mediator and acts via different G-protein-couple LPA receptors.LPA has significant effects on several cellular biological behaviours,such as cell migration,invasion,proliferation and differentiation,etc.Cell migration is essential for tumor progression,and vital for stem cell to repair injured tissues.Increasing evidences have demonstrated that LPA dramatically affects migration capacity of various cells,particularly cancer cells and stem cells.In this paper,we review the effect of LPA on migration of cancer cells and stem cells,and discuss the underlying mechanisms.A better understanding of this process will shed new light on tissue regeneration and the prevention of tumor progression. PMID- 29714959 TI - [Research Advances of Diagnostic Value of Magnetic Resonance Imaging in Dilated Cardiomyopathy]. AB - Dilated cardiomyopathy(DCM)is a highly prevalent disease which has multiple clinical manifestations and pathological features.With the characteristics of multi-sequence and multi-parameter,cardiac magnetic resonance imaging(MRI)can accurately assess the morphology,function and tissue characterization of heart,and provide comprehensive information for diagnosis of DCM.This review focuses on the sequences and clinical applications of MRI evaluation in DCM in order to provide additional information for clinical diagnosis,treatment and prognosis. PMID- 29714961 TI - [Expression of Galectin-3 in Differentiated Thyroid Carcinoma and Human Bone Marrow Endothelial Cell Marker and Study and Application of the 18F Fluordeoxyglucose Imaging]. AB - Galectin-3and human bone marrow endothelial cell marker(HBME-1),which play an important role in tumor growth and metastasis,are good markers for thyroid cancer.The diagnosis specificity and accuracy for thyroid cancers have been increased with the application of 18F-fluordeoxyglucose(18F-FDG)positron emission tomography/computed tomography(PET/CT).The value of Galectin-3,HBME-1expression and 18F-FDG imaging in differentiated thyroid carcinoma is reviewed in the present paper. PMID- 29714960 TI - [Research Progress of Micro-arc Oxidation Surface Treatment of Magnesium Alloy]. AB - An oxide ceramic coating can be formed on the surface of magnesium alloy by micro arc oxidation so that the corrosion resistance of the magnesium alloy can be enhanced.In this paper,ageneral overview of the surface treatment of micro-arc oxidation on the surface of magnesium alloy is presented,the related research on the treatment of several kinds of magnesium alloys is introduced in detail,and a brief introduction of biological activity of magnesium alloy due to micro-arc oxidation is given.Finally,the technical advantages and existing problems are summarized. PMID- 29714962 TI - [A Classification Algorithm for Epileptic Electroencephalogram Based on Wavelet Multiscale Analysis and Extreme Learning Machine]. AB - The automatic classification of epileptic electroencephalogram(EEG)is significant in the diagnosis and therapy of epilepsy.A classification algorithm for epileptic EEG based on wavelet multiscale analysis and extreme learning machine(ELM)is proposed in this paper.Firstly,wavelet multiscale analysis is applied to the original EEG to extract its sub-bands.Then,two nonlinear methods,i.e.Hurst exponent(Hurst)and sample entropy(SamEn)are used to the feature extraction of EEG and its sub-bands.Finally,ELM algorithm is employed in epileptic EEG classification with the nonlinear features.The proposed method in this paper achieved 99.5% classification accuracy for the discrimination between epileptic ictal and interictal EEG.The result implies that this method has good prospects in the diagnosis and therapy of epilepsy. PMID- 29714964 TI - [Automatic Epileptic Electroencephalogram Detection during Normal,Interictal and Ictal Periods Combining Feature Extraction Based on Sample Entropy and Wavelet Packet Energy with Real AdaBoost Algorithm]. AB - Electroencephalogram(EEG)analysis has been widely used in disease diagnosis.The EEG detection of the patients with epilepsy can be used to make judgments about patients' conditions in time,which is of great practical value.Therefore,the techniques of automatic detection,diagnosis and classification of epileptic EEG signals are urgently needed.In order to realize fast and accurate automatic detection and classification of the EEG signals during the normal,interictal and ictal periods of epilepsy,we propose an automatic classification and recognition method which combines the Real Adaboost algorithm based on error-correcting output codes(ECOC)with a feature extraction method based on sample entropy(SampEn)and wavelet packet energy in this paper.In the present study,we used the sample entropy of input signals and the energy of some parts of frequency bands as features,and then we classified the extracted features with the method combining ECOC with Real AdaBoost algorithm.In order to test the validity,we used the epilepsy database from the University of Bonn.The database has 5groups of EEG signals,which contains the data of normal people with their eyes open or closed,the data collected inside and outside of the epileptic foci from patients during their interictal period and the data from patients during their ictal period.The results showed that the method had strong abilities of classification and recognition of the EEG signals,and especially the recognition rate had been improved significantly.The average recognition rate of the EEG signals with different features during the three periods of the five groups mentioned above can reach 96.78%,which is superior to those with algorithms recorded in many other literatures.The method has better stability,processing speed and potential of real-time application,and it plays a supporting role in the prediction and detection of epilepsy in clinical practice. PMID- 29714963 TI - Green Space Visits among Adolescents: Frequency and Predictors in the PIAMA Birth Cohort Study. AB - BACKGROUND: Green space may influence health through several pathways, for example, increased physical activity, enhanced social cohesion, reduced stress, and improved air quality. For green space to increase physical activity and social cohesion, spending time in green spaces is likely to be important. OBJECTIVES: We examined whether adolescents visit green spaces and for what purposes. Furthermore, we assessed the predictors of green space visits. METHODS: In this cross-sectional study, data for 1911 participants of the Dutch PIAMA (Prevention and Incidence of Asthma and Mite Allergy) birth cohort were analyzed. At age 17, adolescents reported how often they visited green spaces for physical activities, social activities, relaxation, and to experience nature and quietness. We assessed the predictors of green space visits altogether and for different purposes by log-binomial regression. RESULTS: Fifty-three percent of the adolescents visited green spaces at least once a week in summer, mostly for physical and social activities. Adolescents reporting that a green environment was (very) important to them visited green spaces most frequently {adjusted prevalence ratio (PR) [95% confidence interval (CI)] very vs. not important: 6.84 (5.10, 9.17) for physical activities and 4.76 (3.72, 6.09) for social activities}. Boys and adolescents with highly educated fathers visited green spaces more often for physical and social activities. Adolescents who own a dog visited green spaces more often to experience nature and quietness. Green space visits were not associated with the objectively measured quantity of residential green space, i.e., the average normalized difference vegetation index (NDVI) and percentages of urban, agricultural, and natural green space in circular buffers around the adolescents' homes. CONCLUSIONS: Subjective variables are stronger predictors of green space visits in adolescents than the objectively measured quantity of residential green space. https://doi.org/10.1289/EHP2429. PMID- 29714965 TI - [Epilepsy Electroencephalogram Signal Analysis Based on Improved k-nearest Neighbor Network]. AB - The study of complex networks has become a hot research area of electroencephalogram signal.Electroencephalogram time series generated by the network keeps node information of network,so studying the time series from the network can also achieve the purpose of study epileptic electroencephalogram.In this paper,we propose a method to analyze epileptic electroencephalogram based on time series which is based on improved k-nearest neighbor network.The results of the experiment showed that studying power spectrum of time series from network was easier than power spectrum of time series directly generated from the original brain data to distinguish between normal controls and epileptic patients.In addition,studying the clustering coefficient of improved k-nearest neighbor network was able to distinguish between normal persons and patients with epilepsy.This study can provide important reference for the study of epilepsy and clinical diagnosis. PMID- 29714966 TI - [Research on the Effects of 20Hz Frequency Somatosensory Vibration Stimulation on Electroencephalogram Features]. AB - Somatosensory vibration can stimulate somatosensory area of human body,and this stimulation is tranferred to somatosensory nerves,and influences the somatic cortex,which is on post-central gyrus and paracentral lobule posterior of cerebral cortex,so that it alters the functional status of brain.The aim of the present study was to investigate the neural mechanism of brain state induced by somatosensory vibration.Twelve subjects were involved in the 20 Hz vibration stimulation test.Linear and nonlinear methods,such as relative change of relative power(RRP),Lempel-Ziv complexity(LZC)and brain network based on cross mutual information(CMI),were applied to discuss the change of brain under somatosensory vibration stimulation.The experimental results showed the frequency following response(FFR)by RRP of spontaneous electroencephalogram(EEG)in 20 Hz vibration,and no obvious change by LZC.The information transmission among various cortical areas enhanced under 20 Hz vibration stimulation.Therefore,20 Hz somatosensory vibration may be able to adjust the functional status of brain. PMID- 29714967 TI - [Research on Diagnosis Algorithm of Parkinson's Disease Based on Speech Sample Multi-edit and Random Forest]. AB - Parkinson's disease(PD)diagnosis based on speech data has been proved to be an effective way in recent years.There are still some problems on preprocessing samples,ensemble learning,and so on.The problems can further cause misleading of classifiers,unsatisfactory classification accuracy and stability.This paper proposed a new diagnosis algorithm of PD by combining multi-edit sample selection method and random forest.At the end of it,this paper presents a group of experiments carried out with the newest public datasets.Experimental results showed that this proposed algorithm realized the classification of the samples and the subjects of PD.Furthermore,it achieved average classification accuracy of 100% and obtained improvement of up to 29.44% compared to those provided by the subjects.This paper proposes a new speech diagnosis algorithm for PD based on instance selection;and the method algorithm has a higher and more stable classification accuracy,compared with the other algorithms. PMID- 29714968 TI - [A Multi-segment Foot Model for Gait Simulation Based on Automatic Dynamic Analysis of Mechanical Systems]. AB - This study aims to establish a multi-segment foot model which can be applied in dynamic gait simulation.The effectiveness and practicability of this model were verified afterwards by comparing simulation results with those of previous researches.Based on a novel hybrid dynamic gait simulator,bone models were imported into automatic dynamic analysis of mechanical systems(ADAMS).Then,they were combined with ligaments,fascia,muscle and plantar soft tissue that were developed in ADMAS.Multi-segment foot model was consisted of these parts.Experimental data of human gait along with muscle forces and tendon forces from literature were used to drive the model and perform gait simulation.Ground reaction forces and joints revolution angles obtained after simulation were compared with those of previous researches to validate this model.It showed that the model developed in this paper could be used in the dynamic gait simulation and would be able to be applied in the further research. PMID- 29714969 TI - [Analysis and Optimization of the Temperature Retard between Sample and Air Based on Nucleic Acid Amplification System Heated by Air]. AB - It is the main method for amplifying the specific gene to use the nucleic acid amplification system to accomplish polymerase chain reaction(PCR).The temperature retard between heat source and sample exists in the heating and cooling progresses of most nucleic acid amplification system.The retard would result in the problem that the sample would take a long time to reach the set temperature and the problem would reduce the speed of integrate reaction.Non-specific products would be created in the process of amplification when the sample cannot reach the set temperature within a certainly time and the amplified efficiency would be reduced.A miniaturization nucleic acid amplification system heated by air was designed in this study according to the principle of air-heated nucleic acid amplification system and the characteristics of the PCR instrument Smart cycler.The heat transfer process was analyzed and the heat transfer time was calculated.The actual temperature was measured in real time,and the temperature curves were fitted.The heating time was chosen by analysis results and data fitting and the air temperature was changed,while the sample temperature was recorded.The retard between sample and air was optimized by choosing the best curve of sample temperature.The temperature retard between sample and air was reduced sharply and the required time of integrate progress is shortened to 50%.We confirmed from the amplification experiment of Listeria monocytogenes that the improved system could complete 3cycles within 4minutes,and the amplification effect was good.The amplification speed and effect could be improved effectively by optimizing the delay between sample and air. PMID- 29714970 TI - [Research on Control of the Cardiovascular System Based on a Left Ventricular Assist Device]. AB - We propose a control model of the cardiovascular system coupled with a rotary blood pump in the present paper.A new mathematical model of the rotary heart pump is presented considering the hydraulic characteristics and the similarity principle of pumps.A seven-order nonlinear spatial state equation adopting lumped parameter is used to describe the combined cardiovascular-pump model.Pump speed is used as the control variable.To achieve sufficient perfusion and to avoid suction,a feedback strategy based on minimum(diastolic)pump flow is used in the control model.The results showed that left ventricular assist device(LVAD)could improve hemodynamics of the cardiovascular system of the patient with heart failure in open loop.When rotation speed was 9,000r/min,cardiac output reached 82mL/s while the initial cardiac output was only 34mL/s without the LVAD support.When the rotation speed was above 12 800r/min,suction was found because the high rotating speed resulted in insufficient venous return volume.Suction was avoided by adopting the feedback control.The model reveals the interaction of LVAD and the cardiovascular system,which provides theoretical basis for the therapy of heart failure in the left ventricular and for the design of a physiological control strategy. PMID- 29714971 TI - [Study on Relationship between Assessment of Vascular Function Using Digital Fingertip Thermal Monitoring and Pulse Wave Velocity]. AB - Early detection of vascular function plays an important role in the prevention and treatment of cardiovascular diseases(CVDs).This paper reports the main studies of the effectiveness of fingertip temperature curve in digital thermal monitoring(DTM)for predicting CVDs,as well as the relationship between parameters from DTM and pulse wave velocity(PWV)detection.A total of 112 subjects [age(42.18+/-12.28)years,50% male,37 with known CVDs]underwent DTM and PWV detection.Results showed that most of parameters related to CVDs were from the declining stage of the digital thermal signal.Binary Logistic regression models were built,and the best one was chosen by ten-fold validation to predict CVDs.Consistency was great between the detection result of PWV and that of the Logistic model of DTM parameters.Parameters from DTM also contained information for early detecting of vascular stiffness.This study indicates that the fingertip temperature curve in DTM has a potential application for predication of CVDs,and it would be used to access vascular function in the initial stage of CVDs. PMID- 29714972 TI - [Classification Studies in Patients with Alzheimer's Disease and Normal Control Group Based on Three-dimensional Texture Features of Hippocampus Magnetic Resonance Images]. AB - This study aims to explore the diagnosis in patients with Alzheimer's disease(AD)based on magnetic resonance(MR)images,and to compare the differences of bilateral hippocampus in classification and recognition.MR images were obtained from 25 AD patients and 25 normal controls(NC)respectively.Three dimensional texture features were extracted from bilateral hippocampus of each subject.The texture features that existed significant differences between AD and NC were used as the features in a classification procedure.Back propagation(BP)neural network model was built to classify AD patients from healthy controls.The classification accuracy of three methods,which were principal components analysis,linear discriminant analysis and non-linear discriminant analysis,was obtained and compared.The correlations between bilateral hippocampal texture parameters and Mini-Mental State Examination(MMSE)scores were calculated.The classification accuracy of nonlinear discriminant analysis with a neural network model was the highest,and the classification accuracy of right hippocampus was higher than that of the left.The bilateral hippocampal texture features were correlated to MMSE scores,and the relative of right hippocampus was higher than that of the left.The neural network model with three-dimensional texture features could recognize AD patients and NC,and right hippocampus might be more helpful to AD diagnosis. PMID- 29714973 TI - [Ultrasound Simulation of Carotid Artery Plaque and System Implementation]. AB - A method of ultrasonic simulation based on the FIELD II software platform for carotid artery plaque was proposed according to the analysis for geometrical shape,tissue characteristics and acoustic properties of carotid artery plaques in clinic,and then a simulation system was developed by using the MATLAB graphical user interface(GUI).In the simulation and development,a three-dimensional geometric model of blood vessel with plaques was set up by using the metaball implicit surface technique,and a tissue model was established based on the scatterers with spatial position of gamma random distribution.Comparison of the statistical and geometrical characteristics from simulated ultrasound B-mode images with those based on clinical ones and preset values,the results fully demonstrated the effectiveness of the simulation methods and system. PMID- 29714974 TI - [Research on Detection Method with Wearable Respiration Device Based on the Theory of Bio-impedance]. AB - Considering the importance of the human respiratory signal detection and based on the Cole-Cole bio-impedance model,we developed a wearable device for detecting human respiratory signal.The device can be used to analyze the impedance characteristics of human body at different frequencies based on the bio-impedance theory.The device is also based on the method of proportion measurement to design a high signal to noise ratio(SNR)circuit to get human respiratory signal.In order to obtain the waveform of the respiratory signal and the value of the respiration rate,we used the techniques of discrete Fourier transform(DFT)and dynamic difference threshold peak detection.Experiments showed that this system was valid,and we could see that it could accurately detect the waveform of respiration and the detection accuracy rate of respiratory wave peak point detection results was over 98%.So it can meet the needs of the actual breath test. PMID- 29714975 TI - [Research and Design of Respiratory Impedance Measurement System Based on Forced Oscillation Technique]. AB - Forced oscillation technique(FOT)is an active method to test pulmonary function,which can derive the mechanical characteristics of the respiratory system with liner system identification theory by pushing in an oscillation air signal and measuring the changes of output pressure and flow.A pulmonary function determination system was developed based on the FOT in this paper.Several critical technologies of this determination system were analyzed,including the selection criteria of oscillation air generator,pressure and flow sensor,the signal design of oscillation air generator,and the synchronous sampling of pressure and flow data.A software program on LabVIEW platform was set up to control the determination system and get the measuring data.The performance of sensors and oscillation air generator was verified.According to the frequency response curve of the pressure,the amplitude of driving signal to the oscillation air generator was corrected at the frequency range between 4~40 Hz.A simulation experiment was carried out to measure the respiratory impedance of the active model lung ASL5000 and the results were close to the setting values of the model lung.The experiment testified that the pulmonary function determination system based on FOT had performance good enough to provide a tool for the in-depth research of the mechanical properties of the respiratory system. PMID- 29714976 TI - [A Treatment Plan Dose Interpolation Algorithm Based on Gradient Feature in Intensity-modulated Radiation Therapy]. AB - The dose data produced by treatment plan system(TPS)in intensity-modulated radiation therapy(IMRT)has many gradient edge points.Considering this feature we proposed a new interpolation algorithm called treatment plan dose interpolation algorithm based on gradient feature in intensity-modulated radiation therapy(TDAGI),which improves the Canny algorithm to detect the gradient edge points and non-edge points by using the gradient information in the dose data plane.For each gradient edge point,the corresponding gradient profile was traced and the profile's sharpness was calculated,and for each non-edge point,the dispersion was calculated.With the sharpness or dispersion,the kernel coefficients of bi-cubic interpolation can be obtained and can be used as the central point to complete the bi-cubic interpolation calculation.Compared with bi cubic interpolation and bilinear interpolation,the TDAGI algorithm is more accurate.Furthermore,the TDAGI algorithm has the advantage of gradient keeping.Therefore,TDAGI can be used as an alternative method in the dose interpolation of TPS in IMRT. PMID- 29714977 TI - [Preparation and Characterization of Chitosan-Poloxamer-based Antibacterial Hydrogel Containing Silver Nanoparticles]. AB - In order to solve the problem of high cytotoxicity in vitro of nano-silver antibacterial gel,and the problem of large nano-silver particle size and size distribution,this study prepared nano-silver antibacterial gel with better biocompatibility and good antibacterial effect by using physical cross-linking method and using poloxamer as dispersant when prepared nano-silver.In this study,nano-silver was prepared by photo-initiator method and by adding poloxamer as a dispersant,and then UV-visible absorption spectrum test and scanning electron microscopy(SEM)test were carried out using prepared nano-silver mixture and particles after drying respectively.The gel was prepared through adjusting its pH value by using sodium bicarbonate,and then pH value test,SEM test for cross-section of gel,swelling ratio test,viscosity test,inhibition zone test and in vitro cytotoxicity test were carried out.The test results showed that the maximum absorption wavelength of prepared nano-silver,using poloxamer as dispersant and ultra-pure water as solvent,was 414 nm,and the average nano-silver size was about 60 nm.The prepared nano-silver using poloxamer as dispersant had smaller particle diameter and narrower particle size distribution than those using PVP as dispersant.Similarly,the prepared nano-silver using ultra-pure water as solvent also had smaller particle diameter and narrower particle size distribution than those using distilled water as solvent.The pH value of the prepared gel was between 5.8~6.1.The dried gel section had many holes.The water absorption of gel was fine and the viscosity of gel was fit to coat on the gauze.In addition,the prepared gel with nano-silver had greater ability to inhibit Escherichia coli and Staphyloccocus aureus at the concentrations of 24,18 and 12MUg/mL.And the biocompatibility of the prepared gel with nano-silver was good when the concentration below 24MUg/mL.Based on the above features,the nano silver antibacterial gel could be used in the treatment of burn or other wounds. PMID- 29714978 TI - [Effects of Different Preservation Methods on Mechanical Properties of Mouse Femur]. AB - In order to establish the best procedure to store the femur samples from the biomechanical viewpoint,we compared the effects of different storage methods on the mechanical properties of mouse femurs.We obtained femurs surgically from twenty C57BL/6Jfemale mice,12 weeks old,and randomly divided them into 5groups,i.e.fresh control group,4% paraformaldehyde fixation group,4Cstorage group,-20Cstorage group and-80Cstorage group,respectively,with five mice in each group.For the three low-temperature storage groups,each group was stored for 1week,2months,6months at their respective temperatures.After rewarming,three point bending test was performed to test the load and deflection changes.The results showed that both the elastic modulus and deflection decreased significantly in the 4% paraformaldehyde group.The maximum load and elastic modulus of the samples in the 4 C group after one week storage was significantly reduced;The mechanical properties were close to the fresh control group in the 20C group stored for 2months but the maximum load was also reduced after 6months.However,mechanical properties,such as elastic load,maximum load and elastic modulus,were not changed obviously in the-80 C storage group.Accordingly, 80 C cryopreservation had little influence on the mechanical properties of bone tissues,which proved that the temperature-80 Cis a suitable one for long-term preservation. PMID- 29714979 TI - [Effects of Tumor Necrosis Factor Alpha on the Expression of Matrix Metalloproteinases and Tissue Inhibitors of Matrix Metalloproteinases in Keratoconus Fibroblasts]. AB - The aim of this article is to study the effect of tumor necrosis factor alpha(TNF alpha)on the expression of matrix metalloproteinases(MMPs)and tissue inhibitors of matrix metalloproteinases(TIMPs)in keratoconus fibroblasts in vitro.Normal cornea and keratoconus fibroblasts were extracted using enzyme digestion method and were cultured in the medium containing TNF-alpha(0,10 and 100ng/mL).The expression of MMPs proteins in the supernatant of corneal fibroblasts and the expression of TIMPs in the normal cornea and keratoconus fibroblasts were detected by Western blot and real-time quantitative polymerase chain reaction respectively.The active form of MMP1 could be detected in the supernatant of keratoconus fibroblasts and upregulated by TNF-alpha.TNF-alphacould increase the protein expression of MMP2,MMP3,MMP9 in the supernatant of keratoconus fibroblasts and decrease the gene expression of TIMP1,TIMP2 in keratoconus fibroblasts.The increased MMPs and the decreased TIMPs can increase the degradation of the extracellular matrix.TNF-alphamay play an important role in the occurrence and development of keratoconus by regulating the expression of MMPs/TIMPs. PMID- 29714980 TI - [Application of (18)F-fluorodeoxyglucose Metabolic Imaging in Diagnosis and Treatment of Cervical Cancer]. AB - The main purpose of this study is to evaluate the clinical value of 18F fluorodeoxyglucose(18 F-FDG)metabolism imaging in accurate staging and prognosis prediction before treatment of cervical cancer.18F-FDG single photon emission computed tomography(SPECT/CT)was performed before treatment on 27 patients with cervical cancer and was analyzed retrospectively.All the images were analyzed by image fusion software.Meanwhile,primary tumor size and T/B,lymph nodes size and T/B were measured by software.Comparison of the relationship between primary tumor T/B of cervix and clinic pathological factors was performed using SPSS17.0.The diagnosis was established according to pathology results of surgery or/and multi-modalities of imaging and clinical following up.The results showed that the primary tumor T/B value of cervix was 5.9(3.2).With the increased clinical stage,T/B of primary tumor value was significantly increased(P<0.05).The T/B value in patients>=IIa stage was significantly higher than those of<=Ib stage.There were no significant correlations between T/B value and primary tumor size,lymph-node metastasis,and histological type(P>0.05).Thirteen lymph nodes were detected by 18F-FDG imaging in 27 patients with cervical cancer.For diagnosing lymph nodes metastasis,the sensitivity,specificity,accuracy,positive and negative predictive value by 18F-FDG imaging were 75.0%,78.9%,77.8%,60.0% and 88.2%,respectively.The T/B value of all lymph nodes was 6.3(3.5),in which T/B value of distant metastasis was significantly higher than that of the pelvic metastasis(P<0.05).There were no significant correlations between T/B value and the size of lymph nodes(P>0.05).Uterine body uptaking FDG were discovered in 17 patients and 15 cases were then pathologically proved.Two of 15 cases were cancerous invasion of uterine body,and the other 13 cases were physiological changes of endometrial,and the T/B value of the former was significantly higher than that of the latter(P<0.05).There were positive correlation between invasion of uterine body and lymph nodes metastasis(P<0.05).In conclusion,18F-FDG imaging has an obvious value for the diagnosis of outside pelvic and distant lymph node metastasis,uterine body infiltrated,and accurate staging.Primary focal T/B value of cervical cancer associates with the clinical stage,which can reflect the risk of patients,and were useful to preliminarily predict the prognosis of cervical cancer. PMID- 29714981 TI - [Two-dimensional Sinoatrial Node Modeling Based on the Calcium Clock and Its Quantitative Analysis]. AB - The new mechanisms of automaticity controlled by the calcium and membrane clocks in sinoatrial node are helpful to revealing the sinus arrhythmia,but the present calcium dynamic model is only on the single cell level.In the present study,a central and peripheral single cell model was developed,and by exponentially changing the cell membrane capacitance,size,conductance and gap junction from the center to the periphery,a two-dimensional inhomogeneous sinus and atrial model was created on the basis of the anatomical structure.Five-point difference and finite element methods were used to process the internal grids and the borders.Irregular borders were defined by creating segment trial functions.Quantitative experiments suggested the consistency of the central and peripheral action potentials with related reports in amplitude,cycle length,maximum diastolic potential and upstroke velocity.Functions of the calcium and membrane clocks on the leading pacemaker site and upstroke velocity as well as the effects of the atrial premature beat on the sinus automaticity were also in good agreement with those in other studies.The developed model is helpful for deeply studying relative roles of the calcium and membrane clocks in automaticity and the relations with electrical activities in atrium.At the same time it will lay the foundation for building three-dimensional sinus and atrial organic models. PMID- 29714982 TI - [From Grid Cells to Place Cells:A Gauss Distribution Activation Function Model]. AB - It has been found that in biological studies,the simple linear superposition mathematical model cannot be used to express the feature mapping relationship from multiple activated grid cells' grid fields to a single place cell's place field output in the hippocampus of the cerebral cortex of rodents.To solve this problem,people introduced the Gauss distribution activation function into the area.We in this paper use the localization properties of the function to deal with the linear superposition output of grid cells' input and the connection weights between grid cells and place cells,which filters out the low activation rate place fields.We then obtained a single place cell field which is consistent with biological studies.Compared to the existing competitive learning algorithm place cell model,independent component analysis method place cell model,Bayesian positon reconstruction method place cell model,our experimental results showed that the model on the neurophysiological basis can not only express the feature mapping relationship between multiple activated grid cells grid fields and a single place cell's place field output in the hippocampus of the cerebral cortex of rodents,but also make the algorithm simpler,the required grid cells input less and the accuracy rate of the output of a single place field higher. PMID- 29714991 TI - Issues in Geriatric Care: Foreword. PMID- 29714992 TI - Issues in Geriatric Care: Maintaining Health and Vigor. AB - Medicare covers annual wellness visits that are scheduled separately from regular medical appointments. These visits focus on prevention and health maintenance to help patients achieve successful aging, which is defined as living to old age without disability while also maintaining high physical and psychological levels of functioning and social engagement. To achieve these goals, most adults should perform at least 150 min/week of moderate-intensity exercise and maintain an optimal body mass index (ie, 23 to 32 kg/m2). Healthy diets for most older adults include 1 to 1.2 g/kg/day of protein, with more for individuals with serious acute or chronic conditions. A varied vitamin-rich diet should be consumed. In the absence of deficiencies, vitamin supplements are unnecessary. Neither testosterone nor growth hormone supplementation is recommended. When patients have difficulty sleeping, physicians should assess for conditions affecting sleep and promote good sleep hygiene rather than prescribe hypnotics. Screening for depression and assessing driving safety are important. Smoking cessation and limiting alcohol ingestion to small amounts have benefits even in older age. Cancer screening should be offered only to patients with life expectancy of at least 10 years and who understand the risks and benefits. PMID- 29714993 TI - Issues in Geriatric Care: Falls. AB - One in three older adults falls each year. There are approximately 2.5 million falls among older adults treated in emergency departments. Falls account for 87% of all fractures in this age group. The biggest risk factor for falling is a history of falls. Other risk factors include frailty, sedative and anticholinergic drugs, polypharmacy, and a variety of medical conditions. Current recommendations are that all patients age 65 years and older should be asked about falls each year. Patients also can be screened for fall risk with a variety of approaches including questionnaires and the Timed Up & Go test. For patients who have fallen or are at risk, care should focus on correcting reversible home environmental factors that predispose to falls, minimizing the use of drugs with sedating properties, addressing vision conditions, recommending physical exercise (including balance, strength, and gait training), and managing postural hypotension as well as foot conditions and footwear. In addition, vitamin D and calcium supplementation should be considered. For patients needing anticoagulation for medical reasons, an assessment must balance fall risk (and thus bleeding from a fall) versus the risk of discontinuing anticoagulation (eg, sustaining an embolic stroke from atrial fibrillation). PMID- 29714994 TI - Issues in Geriatric Care: Alzheimer Disease. AB - Alzheimer disease (AD) occurs in 8.8% of older US adults and is the sixth leading cause of death among older adults. Medicare annual wellness visits require screening for cognitive impairment but do not specify screening methods. Numerous screening instruments are available. If results are positive, evaluation with well-validated assessment tools is needed. If cognitive impairment is confirmed, laboratory tests and imaging studies should be obtained to rule out reversible etiologies. If patients meet diagnostic criteria for AD, clinicians should educate patients and families on the expected course and help them complete advance directives. Nutrition, behavioral issues, patient safety issues, and physical activity should be addressed. Physicians should screen for and manage concomitant depression. Troublesome behaviors should be managed with nonpharmacotherapeutic measures first. Pain should be considered as a possible cause of behavior. Antipsychotics should be reserved for select cases in which safety is an issue. Drugs for improving cognition can be prescribed but these typically result in short-term improvements and do not prevent disease progression. These drugs should be discontinued if adverse effects occur or when dementia worsens. Research on anti-amyloid and anti-tau protein drugs is promising but has not yet led to useful breakthroughs. PMID- 29714995 TI - Issues in Geriatric Care: Medical Decision-Making. AB - Medical decision-making capacity (DMC), which is determined by clinicians, is the ability of patients to understand information about options for their care, express a choice among those options, appreciate the benefits and risks of those options, and explain the reasoning behind their particular choice. DMC differs from competence, which is a legal concept concerning the mental ability of individuals to be responsible for their decisions and actions. A variety of instruments can be used to assess DMC. If it is determined that a patient lacks DMC, clinicians have an ethical obligation to seek out a surrogate decision maker. Surrogates ideally should be chosen by the patient in advance. In the absence of such designated surrogates, state laws outline who can serve in this role. Clinicians should seek informed consent for treatment, except in emergency situations. A shared decision-making process is ideal. This involves sharing treatment options with patients and supporting them in making choices based on their values and preferences. The best case/worst case approach to explaining treatment options is useful for helping patients to make appropriate choices in difficult situations. Palliative care teams and family meetings also can be helpful in facilitating decision-making. PMID- 29714996 TI - Conjugated Polyelectrolyte Blend with Polyethyleneimine Ethoxylated for Thickness Insensitive Electron Injection Layers in Organic Light-Emitting Devices. AB - Electron injection layers (EILs) based on a simple polymer blend of polyethyleneimine ethoxylated (PEIE) and poly[(9,9-bis(3'-(( N, N-dimethyl)- N ethylammonium)-propyl)-2,7-fluorene)- alt-2,7-(9,9-dioctylfluorene)] (PFN-Br) can suppress the dependence of organic light-emitting device (OLED) performance on thickness variation compared with single PEIE or PFN-Br EILs. PEIE and PFN-Br were compatible with each other and PFN-Br uniformly mixed in the PEIE matrix. PFN-Br in PEIE formed more fluorene-fluorene pairs than PFN-Br alone. In addition, PEIE:PFN-Br blends reduced the work function (WF) substantially compared with single PEIE or PFN-Br polymer. PEIE:PFN-Br blends were applied to EILs in fluorescent polymer-based OLEDs. Optimized PEIE:PFN-Br blend EIL-based devices presented lower driving voltages and smaller dependences of device performance on EIL thickness than single PEIE or PFN-Br-based devices. These improvements were attributed to electron-transporting fluorene moieties, increased fluorene-fluorene pairs working as channels of electron transport, and the large WF reduction effect of PEIE:PFN-Br blends. PMID- 29714997 TI - Derivatives of Ribosome-Inhibiting Antibiotic Chloramphenicol Inhibit the Biosynthesis of Bacterial Cell Wall. AB - Here, we describe the preparation and evaluation of alpha,beta-unsaturated carbonyl derivatives of the bacterial translation inhibiting antibiotic chloramphenicol (CAM). Compared to the parent antibiotic, two compounds containing alpha,beta-unsaturated ketones (1 and 4) displayed a broader spectrum of activity against a panel of Gram-positive pathogens with a minimum inhibitory concentration range of 2-32 MUg/mL. Interestingly, unlike the parent CAM, these compounds do not inhibit bacterial translation. Microscopic evidence and metabolic labeling of a cell wall peptidoglycan suggested that compounds 1 and 4 caused extensive damage to the envelope of Staphylococcus aureus cells by inhibition of the early stage of cell wall peptidoglycan biosynthesis. Unlike the effect of membrane-disrupting antimicrobial cationic amphiphiles, these compounds did not rapidly permeabilize the bacterial membrane. Like the parent antibiotic CAM, compounds 1 and 4 had a bacteriostatic effect on S. aureus. Both compounds 1 and 4 were cytotoxic to immortalized nucleated mammalian cells; however, neither caused measurable membrane damage to mammalian red blood cells. These data suggest that the reported CAM-derived antimicrobial agents offer a new molecular scaffold for development of novel bacterial cell wall biosynthesis inhibiting antibiotics. PMID- 29714998 TI - Polycyclic Sulfoximines as New Scaffolds for Drug Discovery. AB - The design and synthesis of three novel polycyclic scaffolds containing sulfoximines are presented in this work, which exemplify that sulfoximines represent a real opportunity for the discovery of new drug candidates. Additionally, the structures present at least two points of diversification and contain a high level of sp3-character, hence being very interesting 3D scaffolds. The compounds synthesized were added to the compound collection of the European Lead Factory. PMID- 29714999 TI - Two-Dimensional Phosphorene-Derived Protective Layers on a Lithium Metal Anode for Lithium-Oxygen Batteries. AB - Lithium-oxygen (Li-O2) batteries are desirable for electric vehicles because of their high energy density. Li dendrite growth and severe electrolyte decomposition on Li metal are, however, challenging issues for the practical application of these batteries. In this connection, an electrochemically active two-dimensional phosphorene-derived lithium phosphide is introduced as a Li metal protective layer, where the nanosized protective layer on Li metal suppresses electrolyte decomposition and Li dendrite growth. This suppression is attributed to thermodynamic properties of the electrochemically active lithium phosphide protective layer. The electrolyte decomposition is suppressed on the protective layer because the redox potential of lithium phosphide layer is higher than that of electrolyte decomposition. Li plating is thermodynamically unfavorable on lithium phosphide layers, which hinders Li dendrite growth during cycling. As a result, the nanosized lithium phosphide protective layer improves the cycle performance of Li symmetric cells and Li-O2 batteries with various electrolytes including lithium bis(trifluoromethanesulfonyl)imide in N,N-dimethylacetamide. A variety of ex situ analyses and theoretical calculations support these behaviors of the phosphorene-derived lithium phosphide protective layer. PMID- 29715000 TI - Cytotoxicity of Gallium-Indium Liquid Metal in an Aqueous Environment. AB - Eutectic gallium-indium alloy (EGaIn) liquid metal is highly conductive, moldable, and extremely deformable and has attracted significant attention for many applications, ranging from stretchable electronics to drug delivery. Even though EGaIn liquid metal is generally known to have low toxicity, the toxicity of the metal, rather than a salt form of Ga or In, has not been systematically studied yet. In this paper, we investigate the time-dependent concentration of the ions released from EGaIn liquid metal in an aqueous environment and their cytotoxicity to human cells. It is observed that only the Ga ion is dominantly released from EGaIn when no external agitation is applied, whereas the concentration of the In ion drastically increases with sonication. The cytotoxicity study reveals that all human cells tested are viable in the growth media with naturally released EGaIn ions, but the cytotoxicity becomes significant with sonication-induced EGaIn releasates. On the basis of the comparative study with other representative toxic elements, that is, Hg and Cd, it could be concluded that EGaIn is reasonably safe to use in an aqueous environment; however, it should be cautiously handled when any mechanical agitation is applied. PMID- 29715001 TI - Modulation of Catalytic Promiscuity during Hydrogen Sulfide Oxidation. AB - The mitochondrial sulfide oxidation pathway prevents the toxic accumulation of hydrogen sulfide (H2S), a signaling molecule that is maintained at low steady state concentrations. Sulfide quinone oxidoreductase (SQR), an inner mitochondrial membrane-anchored protein, catalyzes the first and committing step in this pathway, oxidizing H2S to persulfide. The catalytic cycle comprises sulfide addition to the active site cysteine disulfide in SQR followed by sulfur transfer to a small molecule acceptor, while a pair of electrons moves from sulfide, to FAD, to coenzyme Q. While its ability to oxidize H2S is well characterized, SQR exhibits a remarkable degree of substrate promiscuity in vitro that could undermine its canonical enzyme activity. To assess how its promiscuity might be contained in vivo, we have used spectroscopic and kinetic analyses to characterize the reactivity of alternate substrates with SQR embedded in nanodiscs ( ndSQR) versus detergent-solubilized enzyme ( sSQR). We find that the membrane environment of ndSQR suppresses the unwanted addition of GSH but enhances sulfite addition, which might become significant under pathological conditions characterized by elevated sulfite levels. We demonstrate that methanethiol, a toxic sulfur compound produced in significant quantities by colonic and oral microbiota, can add to the SQR cysteine disulfide and also serve as a sulfur acceptor, potentially interfering with sulfide oxidation when its concentrations are elevated. These studies demonstrate that the membrane environment and substrate availability combine to minimize promiscuous reactions that would otherwise disrupt sulfide homeostasis. PMID- 29715002 TI - Machine Learning in Computer-Aided Synthesis Planning. AB - Computer-aided synthesis planning (CASP) is focused on the goal of accelerating the process by which chemists decide how to synthesize small molecule compounds. The ideal CASP program would take a molecular structure as input and output a sorted list of detailed reaction schemes that each connect that target to purchasable starting materials via a series of chemically feasible reaction steps. Early work in this field relied on expert-crafted reaction rules and heuristics to describe possible retrosynthetic disconnections and selectivity rules but suffered from incompleteness, infeasible suggestions, and human bias. With the relatively recent availability of large reaction corpora (such as the United States Patent and Trademark Office (USPTO), Reaxys, and SciFinder databases), consisting of millions of tabulated reaction examples, it is now possible to construct and validate purely data-driven approaches to synthesis planning. As a result, synthesis planning has been opened to machine learning techniques, and the field is advancing rapidly. In this Account, we focus on two critical aspects of CASP and recent machine learning approaches to both challenges. First, we discuss the problem of retrosynthetic planning, which requires a recommender system to propose synthetic disconnections starting from a target molecule. We describe how the search strategy, necessary to overcome the exponential growth of the search space with increasing number of reaction steps, can be assisted through a learned synthetic complexity metric. We also describe how the recursive expansion can be performed by a straightforward nearest neighbor model that makes clever use of reaction data to generate high quality retrosynthetic disconnections. Second, we discuss the problem of anticipating the products of chemical reactions, which can be used to validate proposed reactions in a computer-generated synthesis plan (i.e., reduce false positives) to increase the likelihood of experimental success. While we introduce this task in the context of reaction validation, its utility extends to the prediction of side products and impurities, among other applications. We describe neural network based approaches that we and others have developed for this forward prediction task that can be trained on previously published experimental data. Machine learning and artificial intelligence have revolutionized a number of disciplines, not limited to image recognition, dictation, translation, content recommendation, advertising, and autonomous driving. While there is a rich history of using machine learning for structure-activity models in chemistry, it is only now that it is being successfully applied more broadly to organic synthesis and synthesis design. As reported in this Account, machine learning is rapidly transforming CASP, but there are several remaining challenges and opportunities, many pertaining to the availability and standardization of both data and evaluation metrics, which must be addressed by the community at large. PMID- 29715003 TI - Self-Healing in Carbon Nitride Evidenced As Material Inflation and Superlubric Behavior. AB - All known materials wear under extended mechanical contacting. Superlubricity may present solutions, but is an expressed mystery in C-based materials. We report negative wear of carbon nitride films; a wear-less condition with mechanically induced material inflation at the nanoscale and friction coefficient approaching ultralow values (0.06). Superlubricity in carbon nitride is expressed as C-N bond breaking for reduced coupling between graphitic-like sheets and eventual N2 desorption. The transforming surface layer acts as a solid lubricant, whereas the film bulk retains its high elasticity. The present findings offer new means for materials design at the atomic level, and for property optimization in wear critical applications like magnetic reading devices or nanomachines. PMID- 29715004 TI - Super-resolution Imaging of Individual Human Subchromosomal Regions in Situ Reveals Nanoscopic Building Blocks of Higher-Order Structure. AB - It is widely recognized that the higher-order spatial organization of the genome, beyond the nucleosome, plays an important role in many biological processes. However, to date, direct information on even such fundamental structural details as the typical sizes and DNA content of these higher-order structures in situ is poorly characterized. Here, we examine the nanoscopic DNA organization within human nuclei using super-resolution direct stochastic optical reconstruction microscopy (dSTORM) imaging and 5-ethynyl-2'-deoxyuridine click chemistry, studying single fully labeled chromosomes within an otherwise unlabeled nuclei to improve the attainable resolution. We find that, regardless of nuclear position, individual subchromosomal regions consist of three different levels of DNA compaction: (i) dispersed chromatin; (ii) nanodomains of sizes ranging tens of nanometers containing a few kilobases (kb) of DNA; and (iii) clusters of nanodomains. Interestingly, the sizes and DNA content of the nanodomains are approximately the same at the nuclear periphery, nucleolar proximity, and nuclear interior, suggesting that these nanodomains share a roughly common higher-order architecture. Overall, these results suggest that DNA compaction within the eukaryote nucleus occurs via the condensation of DNA into few-kb nanodomains of approximately similar structure, with further compaction occurring via the clustering of nanodomains. PMID- 29715005 TI - Nanoparticle-Enhanced Plasmonic Biosensor for Digital Biomarker Detection in a Microarray. AB - Nanoplasmonic devices have become a paradigm for biomolecular detection enabled by enhanced light-matter interactions in the fields from biological and pharmaceutical research to medical diagnostics and global health. In this work, we present a bright-field imaging plasmonic biosensor that allows visualization of single subwavelength gold nanoparticles (NPs) on large-area gold nanohole arrays (Au-NHAs). The sensor generates image heatmaps that reveal the locations of single NPs as high-contrast spikes, enabling the detection of individual NP labeled molecules. We implemented the proposed method in a sandwich immunoassay for the detection of biotinylated bovine serum albumin (bBSA) and human C reactive protein (CRP), a clinical biomarker of acute inflammatory diseases. Our method can detect 10 pg/mL of bBSA and 27 pg/mL CRP in 2 h, which is at least 4 orders of magnitude lower than the clinically relevant concentrations. Our sensitive and rapid detection approach paired with the robust large-area plasmonic sensor chips, which are fabricated using scalable and low-cost manufacturing, provides a powerful platform for multiplexed biomarker detection in various settings. PMID- 29715006 TI - High-Yield Spin Labeling of Long RNAs for Electron Paramagnetic Resonance Spectroscopy. AB - Site-directed spin labeling is a powerful tool for investigating the conformation and dynamics of biomacromolecules such as RNA. Here we introduce a spin labeling strategy based on click chemistry in solution that, in combination with enzymatic ligation, allows highly efficient labeling of complex and long RNAs with short reaction times and suppressed RNA degradation. With this approach, a 34 nucleotide aptamer domain of the preQ1 riboswitch and an 81-nucleotide TPP riboswitch aptamer could be labeled with two labels in several positions. We then show that conformations of the preQ1 aptamer and its dynamics can be monitored in the absence and presence of Mg2+ and a preQ1 ligand by continuous wave electron paramagnetic resonance spectroscopy at room temperature and pulsed electron electron double resonance spectroscopy (PELDOR or DEER) in the frozen state. PMID- 29715008 TI - Toward Small-Diameter Carbon Nanotubes Synthesized from Captured Carbon Dioxide: Critical Role of Catalyst Coarsening. AB - Small-diameter carbon nanotubes (CNTs) often require increased sophistication and control in synthesis processes, but exhibit improved physical properties and greater economic value over their larger-diameter counterparts. Here, we study mechanisms controlling the electrochemical synthesis of CNTs from the capture and conversion of ambient CO2 in molten salts and leverage this understanding to achieve the smallest-diameter CNTs ever reported in the literature from sustainable electrochemical synthesis routes, including some few-walled CNTs. Here, Fe catalyst layers are deposited at different thicknesses onto stainless steel to produce cathodes, and atomic layer deposition of Al2O3 is performed on Ni to produce a corrosion-resistant anode. Our findings indicate a correlation between the CNT diameter and Fe metal layer thickness following electrochemical catalyst reduction at the cathode-molten salt interface. Further, catalyst coarsening during long duration synthesis experiments leads to a 2* increase in average diameters from 3 to 60 min durations, with CNTs produced after 3 min exhibiting a tight diameter distribution centered near ~10 nm. Energy consumption analysis for the conversion of CO2 into CNTs demonstrates energy input costs much lower than the value of CNTs-a concept that strictly requires and motivates small diameter CNTs-and is more favorable compared to other costly CO2 conversion techniques that produce lower-value materials and products. PMID- 29715007 TI - Quantitative Observation of Threshold Defect Behavior in Memristive Devices with Operando X-ray Microscopy. AB - Memristive devices are an emerging technology that enables both rich interdisciplinary science and novel device functionalities, such as nonvolatile memories and nanoionics-based synaptic electronics. Recent work has shown that the reproducibility and variability of the devices depend sensitively on the defect structures created during electroforming as well as their continued evolution under dynamic electric fields. However, a fundamental principle guiding the material design of defect structures is still lacking due to the difficulty in understanding dynamic defect behavior under different resistance states. Here, we unravel the existence of threshold behavior by studying model, single-crystal devices: resistive switching requires that the pristine oxygen vacancy concentration reside near a critical value. Theoretical calculations show that the threshold oxygen vacancy concentration lies at the boundary for both electronic and atomic phase transitions. Through operando, multimodal X-ray imaging, we show that field tuning of the local oxygen vacancy concentration below or above the threshold value is responsible for switching between different electrical states. These results provide a general strategy for designing functional defect structures around threshold concentrations to create dynamic, field-controlled phases for memristive devices. PMID- 29715009 TI - Nanoparticle Counting by Microscopic Digital Detection: Selective Quantitative Analysis of Exosomes via Surface-Anchored Nucleic Acid Amplification. AB - Exosomes are nanosized vesicles secreted by cells, with a lipid bilayer membrane and protein and nucleic acid contents. Here, we present the first method for the selective and quantitative analysis of exosomes by digital detection integrated with nucleic acid-based amplification in a microchip. An external biocompatible anchor molecule conjugated with DNA oligonucleotides was anchored in the lipid bilayer membrane of exosomes via surface self-assembly for total exosome analysis. Then, specific antibody-DNA conjugates were applied to label selective exosomes among the total exosomes. The DNA-anchored exosomes were distributed into microchip chambers with one or fewer exosomes per chamber. The signal from the DNA on the exosomes was amplified by a rapid isothermal nucleic acid detection assay. A chamber with an exosome exhibited a positive signal and was recorded as 1, while a chamber without an exosome presented a negative signal and was recorded as 0. The 10100101 digital signals give the number of positive chambers. According to the Poisson distribution, the exosome stock concentration was calculated by the observed fraction of positive chambers. The findings showed that nanoscale particles can be digitally detected via DNA-mediated signal amplification in a microchip with simple microscopic settings. This approach can be integrated with multiple types of established nucleic acid assays and provides a versatile platform for the quantitative detection of various nanosomes, from extracellular vesicles such as exosomes and enveloped viruses to inorganic and organic nanoparticles, and it is expected to have broad applications in basic research areas as well as disease diagnosis and therapy. PMID- 29715010 TI - Single Day Construction of Multigene Circuits with 3G Assembly. AB - The ability to rapidly design, build, and test prototypes is of key importance to every engineering discipline. DNA assembly often serves as a rate limiting step of the prototyping cycle for synthetic biology. Recently developed DNA assembly methods such as isothermal assembly and type IIS restriction enzyme systems take different approaches to accelerate DNA construction. We introduce a hybrid method, Golden Gate-Gibson (3G), that takes advantage of modular part libraries introduced by type IIS restriction enzyme systems and isothermal assembly's ability to build large DNA constructs in single pot reactions. Our method is highly efficient and rapid, facilitating construction of entire multigene circuits in a single day. Additionally, 3G allows generation of variant libraries enabling efficient screening of different possible circuit constructions. We characterize the efficiency and accuracy of 3G assembly for various construct sizes, and demonstrate 3G by characterizing variants of an inducible cell-lysis circuit. PMID- 29715011 TI - Synthesis and Characterization of Metal-Encapsulating Si16 Cage Superatoms. AB - Nanoclusters, aggregates of several to hundreds of atoms, have been one of the central issues of nanomaterials sciences owing to their unique structures and properties, which could be found neither in nanoparticles with several nanometer diameters nor in organometallic complexes. Along with the chemical nature of each element, properties of nanoclusters change dramatically with size parameters, making nanoclusters strong potential candidates for future tailor-made materials; these nanoclusters are expected to have attractive properties such as redox activity, catalysis, and magnetism. Alloying of nanoclusters additionally gives designer functionality by fine control of their electronic structures in addition to size parameters. Among binary nanoclusters, binary cage superatoms (BCSs) composed of transition metal (M) encapsulating silicon cages, M@Si16, have unique cage structures of 16 silicon atoms, which have not been found in elemental silicon nanoclusters, organosilicon compounds, and silicon based clathrates. The unique composition of these BCSs originates from the simultaneous satisfaction of geometric and electronic shell-closings in terms of cage geometry and valence electron filling, where a total of 68 valence electrons occupy the superatomic orbitals of (1S)2(1P)6(1D)10(1F)14(2S)2(1G)18(2P)6(2D)10 for M = group 4 elements in neutral ground state. The most important issue for M@Si16 BCSs is fine-tuning of their characters by replacement of the central metal atoms, M, based on one-by one adjustment of valence electron counts in the same structure framework of Si16 cage; the replacement of M yields a series of M@Si16 BCSs, based on their superatomic characteristics. So far, despite these unique features probed in the gas-phase molecular beam and predicted by quantum chemical calculations, M@Si16 have not yet been isolated. In this Account, we have focused on recent advances in synthesis and characterizations of M@Si16 BCSs (M = Ti and Ta). A series of M@Si16 BCSs (M = groups 3 to 5) was found in gas-phase molecular beam experiments by photoelectron spectroscopy and mass spectrometry: formation of halogen-, rare gas-, and alkali-like superatoms was identified through one-by-one tuning of number of total valence electrons. Toward future functional materials in the solid state, we have developed an intensive, size-selected nanocluster source based on high-power impulse magnetron sputtering coupled with a mass spectrometer and a soft-landing apparatus. With scanning probe microscopy and photoelectron spectroscopy, the structure of surface-immobilized BCSs has been elucidated; BCSs can be dispersed in an isolated form using C60 fullerene decoration of the substrate. The intensive nanocluster source also enables the synthesis of BCSs in the 100-mg scale by coupling with a direct liquid-embedded trapping method into organic dispersants, enabling their structure characterization as a highly symmetric "metal-encapsulating tetrahedral silicon-cage" (METS) structure with Frank-Kasper geometry. PMID- 29715012 TI - Mobile Phone Ratiometric Imaging Enables Highly Sensitive Fluorescence Lateral Flow Immunoassays without External Optical Filters. AB - Paper-based diagnostic tests based on the lateral flow immunoassay concept promise low-cost, point-of-care detection of infectious diseases, but such assays suffer from poor limits of detection. One factor that contributes to poor analytical performance is a reliance on low-contrast chromophoric optical labels such as gold nanoparticles. Previous attempts to improve the sensitivity of paper based diagnostics include replacing chromophoric labels with enzymes, fluorophores, or phosphors at the expense of increased fluidic complexity or the need for device readers with costly optoelectronics. Several groups, including our own, have proposed mobile phones as suitable point-of-care readers due to their low cost, ease of use, and ubiquity. However, extant mobile phone fluorescence readers require costly optical filters and were typically validated with only one camera sensor module, which is inappropriate for potential point-of care use. In response, we propose to couple low-cost ultraviolet light-emitting diodes with long Stokes-shift quantum dots to enable ratiometric mobile phone fluorescence measurements without optical filters. Ratiometric imaging with unmodified smartphone cameras improves the contrast and attenuates the impact of excitation intensity variability by 15*. Practical application was shown with a lateral flow immunoassay for influenza A with nucleoproteins spiked into simulated nasal matrix. Limits of detection of 1.5 and 2.6 fmol were attained on two mobile phones, which are comparable to a gel imager (1.9 fmol), 10* better than imaging gold nanoparticles on a scanner (18 fmol), and >2 orders of magnitude better than gold nanoparticle-labeled assays imaged with mobile phones. Use of the proposed filter-free mobile phone imaging scheme is a first step toward enabling a new generation of highly sensitive, point-of-care fluorescence assays. PMID- 29715013 TI - Kinetic Characterization of PA1225 from Pseudomonas aeruginosa PAO1 Reveals a New NADPH:Quinone Reductase. AB - The pa1225 gene of Pseudomonas aeruginosa strain PAO1 was cloned, and the resulting enzyme (PA1225) was purified and revealed to be an NADPH:quinone reductase. By using kinetics, fluorescence, and mass spectrometric analyses, PA1225 was shown to utilize FAD to transfer a hydride ion from NADPH to quinones. The enzyme could also use NADH, but with an efficiency that was 40-fold lower than that of NADPH as suggested by the kcat/ Km values at pH 6.0. Similar initial rates of reaction were determined with 1,4-benzoquinone and 2,6-dimethoxy-1,4 benzoquinone in the range between 25 and 200 MUM, suggesting a low Km value for the quinone-oxidizing substrate. The lack of inhibition by NADP+ versus NADPH at saturating concentrations of 1,4-benzoquinone was consistent with a ping-pong bi bi mechanism. The reductive half-reaction at pH 6.0 had Kd values of 0.07 mM with NADPH and 1.8 mM with NADH; the kred for flavin reduction was independent of pH with values of ~10 s-1 with NADPH and ~5 s-1 with NADH. Thus, the enzyme specificity for the reducing substrate arises primarily from a tighter binding of NADPH than of NADH. At pH 6.0, the kcat value with NADPH and 1,4-benzoquinone was 10.1 s-1, consistent with the hydride transfer from NADPH to FAD being fully rate limiting for the overall turnover of the enzyme. The enzyme showed negligible NADPH oxidase and azoreductase activities. This study enables annotation of the pa1225 gene as NADPH:quinone reductase, elucidates the enzymatic function of PA1225 in P. aeruginosa PAO1, and establishes that PA1225 is not an azoreductase as previously proposed. PMID- 29715014 TI - Examining Natural Attenuation and Acute Toxicity of Petroleum-Derived Dissolved Organic Matter with Optical Spectroscopy. AB - Groundwater samples containing petroleum-derived dissolved organic matter (DOMHC) originating from the north oil body within the National Crude Oil Spill Fate and Natural Attenuation Research Site near Bemidji, MN, USA were analyzed by optical spectroscopic techniques (i.e., absorbance and fluorescence) to assess relationships that can be used to examine natural attenuation and toxicity of DOMHC in contaminated groundwater. A strong correlation between the concentration of dissolved organic carbon (DOC) and absorbance at 254 nm ( a254) along a transect of the DOMHC plume indicates that a254 can be used to quantitatively assess natural attenuation of DOMHC. Fluorescence components, identified by parallel factor (PARAFAC) analysis, show that the composition of the DOMHC beneath and adjacent to the oil body is dominated by aliphatic, low O/C compounds ("protein-like" fluorescence) and that the composition gradually evolves to aromatic, high O/C compounds ("humic-/fulvic-like" fluorescence) as a function of distance downgradient from the oil body. Finally, a direct, positive correlation between optical properties and Microtox acute toxicity assays demonstrates the utility of these combined techniques in assessing the spatial and temporal natural attenuation and toxicity of the DOMHC in petroleum-impacted groundwater systems. PMID- 29715015 TI - Quinine-Promoted, Enantioselective Boron-Tethered Diels-Alder Reaction by Anomeric Control of Transition-State Conformation. AB - Diels-Alder reactions of tethered vinyl-metal species offer the opportunity to fashion highly functionalized diol intermediates for synthesis. We have developed the first enantioselective boron-tethered Diels-Alder reaction using quinine as a chiral promoter. Quinine recovery, enantioselectivity enhancement, and manipulation of the cyclohexene core are also investigated. DFT modeling calculations confirm the role of quinine as a bidentate ligand enhancing reaction rates. The enantioselectivity of the cycloaddition is proposed to originate from a boron-centered anomeric effect. PMID- 29715016 TI - Intramolecular Diels-Alder Approaches to the Decalin Core of Verongidolide: The Origin of the exo-Selectivity, a DFT Analysis. AB - Verongidolide is a natural macrolactone recently isolated from a New Caledonia sponge, Verongidolae. The structure of this natural product is similar to the structure of superstolides, also isolated from a New Caledonian sponge, Neosiphonia superstes. From a biological point of view, verongidolide and superstolides A and B present potent cytotoxicity against human oral carcinoma KB (0.3 nM). By comparing the 1H NMR chemical shifts as well as the coupling constants, we conclude that verongidolide possesses a cis-decalin core and we hypothesize that the relative configuration of the cis-decalin core is similar to the one of superstolide A. To verify this hypothesis, intramolecular and transannular Diels-Alder reactions were attempted to construct the decalin core. Unexpectedly, the selectivity of the Diels-Alder reactions was exo and an in depth DFT calculation of the key reaction mechanism was achieved in order to understand the factors controlling this unexpected selectivity. PMID- 29715017 TI - Refining Collective Coordinates and Improving Free Energy Representation in Variational Enhanced Sampling. AB - Collective variables are used often in many enhanced sampling methods, and their choice is a crucial factor in determining sampling efficiency. However, at times, searching for good collective variables can be challenging. In a recent paper, we combined time-lagged independent component analysis with well-tempered metadynamics in order to obtain improved collective variables from metadynamics runs that use lower quality collective variables [ McCarty, J.; Parrinello, M. J. Chem. Phys. 2017 , 147 , 204109 ]. In this work, we extend these ideas to variationally enhanced sampling. This leads to an efficient scheme that is able to make use of the many advantages of the variational scheme. We apply the method to alanine-3 in water. From an alanine-3 variationally enhanced sampling trajectory in which all the six dihedral angles are biased, we extract much better collective variables able to describe in exquisite detail the protein complex free energy surface in a low dimensional representation. The success of this investigation is helped by a more accurate way of calculating the correlation functions needed in the time-lagged independent component analysis and from the introduction of a new basis set to describe the dihedral angles arrangement. PMID- 29715018 TI - Stereoselective Synthesis of Pyrroloisoindolone and Pyridoisoindolone via aza Prins Cyclization of Endocyclic N-Acyliminium Ions. AB - A simple methodology has been developed for the synthesis of substituted pyrroloisoindolone and pyridoisoindolone via aza-Prins cyclization of endocyclic N-acyliminium ions, which are derived from the triflic acid treatment of regioselectively reduced N-homopropargyl imides in excellent yields. The reaction is highly diastereoselective, and only one diastereoisomer is formed during the reaction. The methodology can be utilized for the synthesis of pyrimidoisoindole. PMID- 29715019 TI - Arbutin Derivatives Isolated from Ancient Proteaceae: Potential Phytochemical Markers Present in Bellendena, Cenarrhenes, and Persoonia Genera. AB - Extensive phytochemical studies of the paleoendemic Tasmanian Proteaceae species Bellendena montana, Cenarrhenes nitida, and Persoonia gunnii were conducted employing pressurized hot water extraction. As part of these studies, six novel glycosides were isolated, including rare examples of glycoside-containing natural products featuring tiglic acid esters. These polar molecules may represent potential phytochemical markers in ancient Proteaceae. PMID- 29715021 TI - Isoindolinones, Phthalides, and a Naphthoquinone from the Fruiting Body of Daldinia concentrica. AB - A chemical investigation of the ascomycetes of Daldinia concentrica was performed using silica gel column chromatography, ODS column chromatography, and preparative HPLC. Two new isoindolinone compounds, daldinans B (1) and C (2), two new phthalide compounds, daldinolides A (3) and B (4), and a new naphthoquinone, daldiquinone (5), were isolated together with two known compounds (6 and 7). The structures of 1, 2, and 5 were established using NMR, MS, and IR methods, and the structures of 3 and 4 were determined by derivatization from known compounds (6 and 7). 5 exhibited antiangiogenesis activity against HUVECs (IC50 = 7.5 MUM). PMID- 29715022 TI - Access to Chiral HWE Reagents by Rhodium-Catalyzed Asymmetric Arylation of gamma,delta-Unsaturated beta-Ketophosphonates. AB - Asymmetric arylation of gamma,delta-unsaturated beta-ketophosphonates with arylboronic acids is reported. By using the ( R)-diene* ligated rhodium(I) chloride complex as a catalyst under none basic conditions, the corresponding beta-ketophosphonates bearing a delta-chiral center were obtained in high yields (up to 99%) with good to excellent enantioselectivities (up to >99% ee). The enantioenriched products can be readily converted to diverse chiral beta'-aryl enones by the Horner-Wadsworth-Emmons reaction. PMID- 29715023 TI - Discovery of 4,7-Diamino-5-(4-phenoxyphenyl)-6-methylene-pyrimido[5,4- b]pyrrolizines as Novel Bruton's Tyrosine Kinase Inhibitors. AB - An alternative medicinal chemistry approach was conducted on Bruton's tyrosine kinase (BTK) inhibitor 1 (ibrutinib) by merging the pyrazolo[3,4- d]pyrimidine component into a tricyclic skeleton. Two types of compounds were prepared, and their biochemical activities on BTK as well as stereochemistry effects were determined. Structural optimization focusing on the reactive binding group to BTK Cys481 and on the metabolic site guided by metabolic study were conducted. 7S was identified as the most potent showing an IC50 value of 0.4 nM against BTK and 16 nM against BTK-dependent TMD8 cells. Compared to 1, 7S was slightly more selective with strong inhibition on the B-cell receptor signaling pathway. In a TMD8 cell-derived animal xenograft model, 7S showed a relative tumor volume of 5.3 at 15 mg/kg QD dosage that was more efficacious than 1 (RTV 6.6) at a higher dose of 25 mg/kg QD. All these results suggest 7S as a new BTK inhibitor worthy of further profiling. PMID- 29715024 TI - Rate Constants and H-Atom Product Yields for the Reactions of O(1D) Atoms with Ethane and Acetylene from 50 to 296 K. AB - The gas phase reactions of atomic oxygen in its first excited state with ethane and acetylene have been investigated in a continuous supersonic flow reactor over the temperature range from 50 to 296 K. O(1D) atoms were produced by the pulsed laser photolysis of ozone at 266 nm. Two different types of experiments, kinetics measurements and H-atom product yield determinations, were performed by detecting O(1D) atoms and H(2S) atoms, respectively, by vacuum ultraviolet laser-induced fluorescence. The measured rate constants are in agreement with previous work at room temperature, and little or no temperature dependence was observed as the temperature was decreased to 50 K. H-atom yields were found to be independent of temperature for the reaction of O(1D) with ethane. These product yields are discussed in the context of earlier dynamics measurements at higher temperature. Due to the influence of secondary reactions, no H-atom yields could be obtained for the reaction of O(1D) with acetylene. PMID- 29715025 TI - Synergistic Effects of Nitrogen and Potassium on Quantitative Limitations to Photosynthesis in Rice ( Oryza sativa L.). AB - The inhibition of the net CO2 assimilation ( A) during photosynthesis is one of the major physiological effects of both nitrogen (N) and potassium (K) deficiencies on rice growth. Whether the reduction in A arises from a limitation in either the diffusion and biochemical fixation of CO2 or photochemical energy conversion is still debated in relation to N and K deficiencies. In this study, the gas exchange parameters of rice under different N and K levels were evaluated and limitations within the photosynthetic carbon capture process were quantified. A was increased by 17.3 and 12.1% for the supply of N and K, respectively. The suitable N/K ratio should be maintained from 1.42 to 1.50. The limitation results indicated that A is primarily limited by the biochemical process. The stomatal conductance ( LS), mesophyll conductance ( LM), and biochemical ( LB) limitations were regulated by 26.6-79.9, 24.4-54.1, and 44.1-75.2%, respectively, with the N and K supply. PMID- 29715026 TI - Do Bistable Steric Poisson-Nernst-Planck Models Describe Single-Channel Gating? AB - Experiments measuring currents through single protein channels show unstable currents, a phenomena called the gating of a single channel. Channels switch between an "open" state with a well-defined single amplitude of current and "closed" states with nearly zero current. The existing mean-field theory of ion channels focuses almost solely on the open state. The physical modeling of the dynamical features of ion channels is still in its infancy and does not describe the transitions between open and closed states nor the distribution of the duration times of open states. One hypothesis is that gating corresponds to noise induced fast transitions between multiple steady (equilibrium) states of the underlying system. In this work, we aim to test this hypothesis. Particularly, our study focuses on the (high-order) steric Poisson-Nernst-Planck (PNP)-Cahn Hilliard model since it has been successful in predicting permeability and selectivity of ionic channels in their open state and since it gives rise to multiple steady states. We show that this system gives rise to a gatinglike behavior, but that important features of this switching behavior are different from the defining features of gating in biological systems. Furthermore, we show that noise prohibits switching in the system of study. The above phenomena are expected to occur in other PNP-type models, strongly suggesting that one has to go beyond overdamped (gradient flow) Nernst-Planck type dynamics to explain the spontaneous gating of single channels. PMID- 29715027 TI - Living Light-Induced Crystallization-Driven Self-Assembly for Rapid Preparation of Semiconducting Nanofibers. AB - Well-defined nanostructures composed of conjugated polymers have attracted significant attention due to their intriguing electronic and optical properties. However, precise control of the size and uniformity of these semiconducting nanostructures is still rare and challenging, despite recent advances in strategies to obtain self-assembled nanostructures with narrow dispersions. Herein, we demonstrate the preparation of fluorescent conjugated block copolymers by one-shot polymerization and rapid formation of nanofibers in a few minutes via light-induced crystallization-driven self-assembly, driven by facile cis-to- trans photoisomerization of its poly( p-phenylenevinylene) blocks. Furthermore, living self-assembly was possible, allowing not only nanofibers with excellent length control and narrow size distribution but also ABA triblock comicelles and gradient comicelles, to be produced by seeded growth. Lastly, the seeded growth could be activated and deactivated repeatedly by switching the light on and off, analogous to light-induced living radical polymerization. PMID- 29715028 TI - Mass Spectrometry and Theoretical Investigation of VN n+ ( n = 8, 9, and 10) Clusters. AB - VN n+ clusters were generated by laser ablation and analyzed by mass spectrometry. The results showed that VN8+, VN9+, and VN10+ clusters were formed, and the mass peak of VN8+ is dominant in the spectrum. The VN8+ cluster was further investigated by a photodissociation experiment with 266 nm photons. Density functional theory calculations were conducted at the M06-2X/6-311+G(d,p) level to search for stable structures of VN n+ ( n = 8, 9, and 10) and their neutral counterparts. The theoretical calculations revealed that the most stable structure of VN8+ is in the form of V(N2)4+ with D 4h symmetry. The binding energy from the calculation is in good agreement with that obtained from the photodissociation experiments. The global minimum structures of VN8, VN9+/0, and VN10+/0 contain a similar substructure of the N4 ring and exhibit energy properties. The most stable structure of VN9+ is in the form of (eta2-N4)V+N(N2)2 with C1 symmetry, while that of VN10+ is in the form of (eta4-N4)V+(N2)3 with C s symmetry. For neutral VN8, VN9, and VN10, (eta4-N4)V(N2)2, (eta4-N4)V(N3)(N2), and (eta4-N4)V(N2)3 are their ground-state structures, with decomposition into one V atom, and corresponding quantities of N2 can release energies of about 50.20, 96.28, and 57.76 kcal/mol, respectively. PMID- 29715029 TI - Interlocking Molecular Gear Chains Built on Surfaces. AB - Periodic chains of molecular gears in which molecules couple with each other and rotate on surfaces have been previously explored by us theoretically using ab initio simulation tools. On the basis of the knowledge and experience gained about the interactions between neighboring molecular gears, we here explore the transmission of rotational motion and energy over larger distances, namely, through a longer chain of gear-like passive "slave" molecules. Such microscopic gears exhibit quite different behaviors compared to rigid cogwheels in the macroscopic world due to their structural flexibility affecting intermolecular interaction. Here, we investigate the capabilities of such gear chains and reveal the mechanisms of the transmission process in terms of both quantum-level density functional theory (DFT) and simple classical mechanics. We find that the transmission of rotation along gear chains depends strongly on the gear-gear distance: short distances can cause tilting of gears and even irregular "creep then-jump" (or "stick-slip") motion or expulsion of gears; long gear-gear distances cause weak coupling between gears, slipping and skipping. More importantly, for transmission of rotation at intermediate gear-gear distances, our modeling clearly exhibits the relative roles of several important factors: flexibility of gear arms, axles, and supports, as well as resulting rotational delays, slippages, and thermal and other effects. These studies therefore allow better informed design of future molecular machine components involving motors, gears, axles, etc. PMID- 29715030 TI - Nanoparticle Organization Controls Their Potency as Universal Glues for Gels. AB - Nanoparticles have been recently shown to act as universal glues for both synthetic and biological gels, providing a tunable, cheap, and general solution to the centuries-old problem of sticking soft materials together. The design of new adhesive solutions based on this platform, however, requires an understanding of how nanoparticles' design parameters concur to determine the final adhesion strength. Here, we use coarse-grained modeling and molecular dynamics simulations to investigate such links. Our main aim is to show that, at experimentally relevant concentrations, adhesion is strongly influenced by the way nanoparticles organize at the interface, resulting in non-monotonous reinforcement behavior. Our findings represent an important step toward rationalizing this new class of nanoparticle-based adhesives. PMID- 29715031 TI - Stainless Steel-Mediated Hydrogen Generation from Alkanes and Diethyl Ether and Its Application for Arene Reduction. AB - Hydrogen gas can be generated from simple alkanes (e.g., n-pentane, n-hexane, etc.) and diethyl ether (Et2O) by mechanochemical energy using a planetary ball mill (SUS304, Fritsch Pulverisette 7), and the use of stainless steel balls and vessel is an important factor to generate the hydrogen. The reduction of organic compounds was also accomplished using the in-situ-generated hydrogen. While the use of pentane as the hydrogen source facilitated the reduction of the olefin moieties, the arene reduction could proceed using Et2O. Within the components (Fe, Cr, Ni, etc.) of the stainless steel, Cr was the metal factor for the hydrogen generation from the alkanes and Et2O, and Ni metal played the role of the hydrogenation catalyst. PMID- 29715033 TI - Electronic Structure of a Self-Assembled Monolayer with Two Surface Anchors: 6 Mercaptopurine on Au(111). AB - The electronic structure of aromatic and aliphatic thiols on Au(111) has been extensively studied in relation to possible applications in molecular electronics. In this work, the effect on the electronic structure of an additional anchor to the S-Au bond using 6-mercaptopurine as a model system has been investigated. Results from X-ray photoelectron spectroscopy, near-edge X-ray absorption fine structure spectroscopy, and density functional theory (DFT) confirm that this molecule adsorbs on Au(111) with S-Au and iminic N-Au bonds. Combined ultraviolet photoelectron spectroscopy and DFT data reveal that formation of the 6MP self-assembled monolayer generates a molecular dipole perpendicular to the surface, with negative charges residing at the metal/monolayer interface and positive charges at the monolayer/vacuum interface, which lowers the substrate work function. Scanning tunneling microscopy shows two surface molecular domains: a well-ordered rectangular lattice where molecules are tilted on average 30 degrees with respect to the substrate and aligned 6MP islands where molecules are standing upright. Finally, we found a new electronic state located at -1.7 eV with respect to the Fermi level that corresponds to a localized pi molecular state, while the state corresponding to the N-Au bond is hybridized with Au d electrons and stabilized at much lower energies (-3 eV). PMID- 29715032 TI - Nanoplasmonic Sensing and Capillary Electrophoresis for Fast Screening of Interactions between Phosphatidylcholine Biomembranes and Surfactants. AB - Nanoplasmonic sensing (NPS), based on localized surface plasmon resonance, with sensors composed of glass covered with golden nanodisks and overlaid with a SiO2 coating was applied in this study. Egg phosphatidylcholine (eggPC), being an easily accessible membrane-forming lipid, was used for preparation of biomimicking membranes. Small unilamellar vesicles with an approximate hydrodynamic diameter of 30 nm, formed by sonication in 4-(2 hydroxyethyl)piperazine-1-ethanesulfonic acid buffer, were adsorbed within 10 min on the sensor surface either as intact vesicles or as a planar bilayer. The adsorbed biomembrane systems were further utilized for interaction studies with four different well-known surfactants (negatively and positively charged, zwitterionic, and nonionic) and each surfactant was tested at concentrations below and above the critical micelle concentration (CMC). Our results allowed the evaluation of different NPS patterns for every particular supported membrane system, surfactant, and its concentration. The most significant effect on the membrane was achieved upon the introduction of zwitterionic surfactant micelles, which in fact completely solubilized and removed the lipid membranes from the sensor surface. Other surfactant micelles interacted with the membranes and formed mixed structures remaining on the sensor surface. The studies performed at the concentrations below the CMCs of the surfactants showed that different mixed systems were formed. Depending on the supported membrane system and the type of surfactant, the mixed systems indicated different formation kinetics. Additionally, the final water rinse revealed the stability of the formed systems. To investigate the effect of the studied surfactants on the overall surface charge of the biomembrane, capillary electrophoresis (CE) experiments were carried out in parallel with the NPS analysis. The electroosmotic flow mobility of an eggPC-coated fused silica capillary was used to measure the total surface charge of the biomembrane after its treatment with the surfactants. Our results indicated in general good correlation between CE and NPS data. However, some discrepancies were seen while applying either zwitterionic or positively charged surfactants. This confirmed that CE analysis was able to provide additional data about the investigated systems. Taken together, the combination of NPS and CE proved to be an efficient way to describe the nature of interactions between biomimicking membranes and amphiphilic molecules. PMID- 29715034 TI - Effect of Cavity Size of Mesoporous Silica on Short DNA Duplex Stability. AB - We studied the stabilities of short (4- and 3-bp) DNA duplexes within silica mesopores modified with a positively charged trimethyl aminopropyl (TMAP) monolayer (BJH pore diameter 1.6-7.4 nm). The DNA fragments with fluorescent dye were introduced into the pores, and their fluorescence resonance energy transfer (FRET) response was measured to estimate the structuring energies of the short DNA duplexes under cryogenic conditions (temperature 233-323 K). The results confirmed the enthalpic stability gain of the duplex within size-matched pores (1.6 and 2.3 nm). The hybridization equilibrium constants found for the size matched pores were 2 orders of magnitude larger than those for large pores (>=3.5 nm), and this size-matching effect for the enhanced duplex stability was explained by a tight electrostatic interaction between the duplex and the surface TMAP groups. These results indicate the requirement of the precise regulation of mesopore size to ensure the stabilization of hydrogen-bonded supramolecular assemblies. PMID- 29715036 TI - Development of a Small Molecule Tubulysin B Conjugate for Treatment of Carbonic Anhydrase IX Receptor Expressing Cancers. AB - Carbonic anhydrase IX (CAIX) is a membrane-spanning zinc metalloenzyme that catalyzes the reversible consumption of CO2 and water to form H+ + HCO3-. Many human cancers upregulate CAIX to help control the pH in their hypoxic microenvironments. The consequent overexpression of CAIX on malignant cells and low expression on normal tissues render CAIX a particularly attractive target for small molecule inhibitors, antibody-drug conjugates, and ligand-targeted drugs. In this study, CAIX-targeted fluorescent reporter molecules were initially exploited to investigate CAIX-specific binding to multiple cancer cell lines, where they were shown to display potent and selective binding to CAIX positive cells. A small molecule CAIX-targeted tubulysin B conjugate was then synthesized and examined for its ability to kill CAIX-expressing tumor cells in vitro. Potent therapeutic conjugates were subsequently tested in vivo and demonstrated to eliminate solid human tumor xenografts in murine tumor models without exhibiting overt signs of toxicity. Because most solid tumors contain hypoxic regions where CAIX is overexpressed, development of a method to selectively deliver drugs to these hypoxic regions could aid in the therapy of otherwise difficult to treat tumors. PMID- 29715037 TI - Total 3s Emission Yield as Bulk-Sensitive Probe for a True Soft X-ray Absorption Spectrum? AB - The detection of the true soft X-ray absorption typically needs specially prepared submicrometer thin samples for transmission measurements. Bulk experiments instead have to rely on yield methods, for example, electron yield with limitations for insulating samples, sensitivity to applied fields, and with limited bulk sensitivity. Fluorescence yield methods instead do not have those limitations but have been found to deviate, in general, from the absorption spectrum. We demonstrate that restricting the detection to the 3s fluorescence channel (with the detector at a special angle where all polarizations contribute equally) restores the true X-ray absorption spectrum for all 3d-metal L2,3 edges. These theoretically derived results are rationalized by the lack of 3s-3d interaction in the core-excited state. Comparing X-ray absorption versus 3s-PFY for arbitrary detection geometries for both linear and circular polarized light, deviations appear that can become as large as 15%. PMID- 29715035 TI - Polycrystallinity of Lithographically Fabricated Plasmonic Nanostructures Dominates Their Acoustic Vibrational Damping. AB - The study of acoustic vibrations in nanoparticles provides unique and unparalleled insight into their mechanical properties. Electron-beam lithography of nanostructures allows precise manipulation of their acoustic vibration frequencies through control of nanoscale morphology. However, the dissipation of acoustic vibrations in this important class of nanostructures has not yet been examined. Here we report, using single-particle ultrafast transient extinction spectroscopy, the intrinsic damping dynamics in lithographically fabricated plasmonic nanostructures. We find that in stark contrast to chemically synthesized, monocrystalline nanoparticles, acoustic energy dissipation in lithographically fabricated nanostructures is solely dominated by intrinsic damping. A quality factor of Q = 11.3 +/- 2.5 is observed for all 147 nanostructures, regardless of size, geometry, frequency, surface adhesion, and mode. This result indicates that the complex Young's modulus of this material is independent of frequency with its imaginary component being approximately 11 times smaller than its real part. Substrate-mediated acoustic vibration damping is strongly suppressed, despite strong binding between the glass substrate and Au nanostructures. We anticipate that these results, characterizing the optomechanical properties of lithographically fabricated metal nanostructures, will help inform their design for applications such as photoacoustic imaging agents, high-frequency resonators, and ultrafast optical switches. PMID- 29715038 TI - Total Syntheses of Stoloniferol B and Penicitol A, and Structural Revision of Fusaraisochromanone. AB - The first total synthesis of stoloniferol B and penicitol A has been achieved. Stoloniferol B, which is the common structure of citrinin derivatives, has been constructed by a sequential elaboration that includes a stereoselective vinylogous Mukaiyama aldol reaction, a thermal esterification with methyl acetoacetate, an intramolecular Michael reaction, and a vinylogous Dieckmann cyclization. The enantiomer of the proposed structure of fusaraisochromanone and ( S)-7-hydroxy-3-(( R)-1-hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran-1(3 H) one (the enantiomer of a natural stoloniferol derivative) also have been synthesized. The synthesis revised the structure of fusaraisochromanone to ( S)-7 hydroxy-3-(( R)-1-hydroxyethyl)-5-methoxy-3,4-dimethylisobenzofuran-1(3 H)-one. PMID- 29715039 TI - Toward Improved Understanding of the Interactions between Poorly Soluble Drugs and Cellulose Nanofibers. AB - Cellulose nanofibers (CNFs) have interesting physicochemical and colloidal properties that have been recently exploited in novel drug-delivery systems for tailored release of poorly soluble drugs. The morphology and release kinetics of such drug-delivery systems heavily relied on the drug-CNF interactions; however, in-depth understanding of the interactions was lacking. Herein, the interactions between a poorly soluble model drug molecule, furosemide, and cationic cellulose nanofibers with two different degrees of substitution are studied by sorption experiments, Fourier transform infrared spectroscopy, and molecular dynamics (MD) simulation. Both MD simulations and experimental results confirmed the spontaneous sorption of drug onto CNF. Simulations further showed that adsorption occurred by the flat aryl ring of furosemide. The spontaneous sorption was commensurate with large entropy gains as a result of release of surface-bound water. Association between furosemide molecules furthermore enabled surface precipitation as indicated by both simulations and experiments. Finally, sorption was also found not to be driven by charge neutralization, between positive CNF surface charges and the furosemide negative charge, so that surface area is the single most important parameter determining the amount of sorbed drug. An optimized CNF-furosemide drug-delivery vehicle thus needs to have a maximized specific surface area irrespective of the surface charge with which it is achieved. The findings also provide important insights into the design principles of CNF-based filters suitable for removal of poorly soluble drugs from wastewater. PMID- 29715040 TI - Composition-Tunable Formamidinium Lead Mixed Halide Perovskites via Solvent-Free Mechanochemical Synthesis: Decoding the Pb Environments Using Solid-State NMR Spectroscopy. AB - Mixed-halide lead perovskites are becoming of paramount interest in the optoelectronic and photovoltaic research fields, offering band gap tunability, improved efficiency, and enhanced stability compared to their single halide counterparts. Formamidinium-based mixed halide perovskites (FA-MHPs) are critical to obtaining optimum solar cell performance. Here, we report a solvent-free mechanochemical synthesis (MCS) method to prepare FA-MHPs, starting with their parent compounds (FAPbX3; X = Cl, Br, I), achieving compositions not previously accessible through the solvent synthesis (SS) technique. By probing local Pb environments in MCS FA-MHPs using solid-state nuclear magnetic resonance spectroscopy, along with powder X-ray diffraction for long-range crystallinity and reflectance measurements to determine the optical band gap, we show that MCS FA-MHPs form atomic-level solid solutions between Cl/Br and Br/I MHPs. Our results pave the way for advanced methods in atomic-level structural understanding while offering a one-pot synthetic approach to prepare MHPs with superior control of stoichiometry. PMID- 29715041 TI - Generic and Scalable Method for the Preparation of Monodispersed Metal Sulfide Nanocrystals with Tunable Optical Properties. AB - A rational synthetic method that produces monodisperse and air-stable metal sulfide colloidal quantum dots (CQDs) in organic nonpolar solvents using octyl dithiocarbamic acid (C8DTCA) as a sulfur source, is reported. The fast decomposition of metal-C8DTCA complexes in presence of primary amines is exploited to achieve this purpose. This novel technique is generic and can be applied to prepare diverse CQDs, like CdS, MnS, ZnS, SnS, and In2S3, including more useful and in-demand PbS CQDs and plasmonic nanocrystals of Cu2S. Based on several control reactions, it is postulated that the reaction involves the in situ formation of a metal-C8DTCA complex, which then reacts in situ with oleylamine at slightly elevated temperature to decompose into metal sulfide CQDs at a controlled rate, leading to the formation of the materials with good optical characteristics. Controlled sulfur precursor's reactivity and stoichiometric reaction between C8DTCA and metal salts affords high conversion yield and large scale production of monodisperse CQDs. Tunable and desired crystal size could be achieved by controlling the precursor reactivity by changing the reaction temperature and reagent ratios. Finally, the photovoltaic devices fabricated from PbS CQDs displayed a power conversion efficiency of 4.64% that is comparable with the reported values of devices prepared with PbS CQDs synthesized by the standard methods. PMID- 29715042 TI - Toward Realistic Large-Area Cell Membrane Mimics: Excluding Oil, Controlling Composition, and Including Ion Channels. AB - Capacitance measurements provide unique insights into the thickness, compressibility, and composition of large-area membrane bilayers and are used here in addition to demonstrate the successful incorporation of model ion channels. The simultaneous ability to control the bilayer size, manipulate tension, and optically monitor and electrically stimulate freestanding membranes enables precise determination of their specific capacitance and thickness across a wide range of areas. We confirm that membranes formed by this recently developed technique have capacitive properties similar to those formed by existing protocols, including solvent-free approaches, and discuss the effect using either hexadecane or squalene as the oil solvent. The results obtained here are relevant for other methods where lipid membranes are reconstituted from a bulk oil solvent. Because biological membranes have a diverse phospholipid profile, we show that the technique can successfully reconstitute membranes with binary composition mixtures. As an outlook, we show the capability of model membrane proteins, specifically alpha-hemolysin and alamethicin, to be incorporated into the formed bilayers and measure ion transport. PMID- 29715043 TI - Enantioselective Decarboxylative Alkylation of beta-Keto Acids to ortho-Quinone Methides as Reactive Intermediates: Asymmetric Synthesis of 2,4-Diaryl-1 benzopyrans. AB - A novel and efficient asymmetric synthesis of 2,4-diaryl-1-benzopyrans via enantioselective decarboxylative alkylation of beta-keto acids to o-QM intermediates, followed by sequential cyclization and dehydration, has been developed. The synthetically useful chiral 2,4-diaryl-1-benzopyran derivatives were obtained in moderate to high yields and high enantioselectivities through a one-pot, two-step sequence. This approach offers a facile way to prepare chiral 2,4-diaryl-1-benzopyran derivatives with a wide range of functional group tolerance. PMID- 29715044 TI - Corrigendum. AB - Berruto M, Delcogliano M, de Caro F, et al. Treatment of large knee osteochondral lesions with a biomimetic scaffold: results of a multicenter study of 49 patients at 2-year follow-up. Am J Sports Med. 2014;42(7):1607-1617. (Original DOI: 10.1177/0363546514530292) The first two authors are equal contributors to this article. The following footnote should have been included: M.B. and M.D. contributed equally to this article as first authors. PMID- 29715045 TI - Corrigendum. AB - Nwachukwu BU, So C, Schairer WW, Shubin Stein BE, Strickland SM, Green DW, Dodwell ER. Economic decision model for first-time traumatic patellar dislocations in adolescents. Am J Sports Med. 2017;45(10):2267-2275. (Original DOI: 10.1177/0363546517703347) In the above article, the fourth author's last name was misspelled as Shubin-Stein. It should have appeared as Shubin Stein. PMID- 29715046 TI - Treatment of a Child with Autism Spectrum Disorder and Food Refusal Due to Restricted and Repetitive Behaviors. PMID- 29715047 TI - Not all light transmission aggregation assays are created equal: qualitative differences between light transmission and 96-well plate aggregometry. AB - In this short article, submitted as part of the review on platelet function testing, we illustrate the quantitative and qualitative differences between classical light transmission aggregometry (LTA) and 96-well plate aggregometry. We show that responses to platelet agonists and antagonists differ depending upon the method of aggregation testing. For example, in 96-well aggregometry, responses to collagen are strongly inhibited by P2Y12 receptor antagonists while in LTA they are much less affected. Furthermore, we explore the importance of differences in the mechanical environment upon platelet aggregation. We emphasize that LTA and 96-well aggregometry are not interchangeable assays. These two assays are best used as complementary tests to explore platelet function in depth. PMID- 29715048 TI - beta-Adrenergic receptors control brown adipose UCP-1 tone and cold response without affecting its circadian rhythmicity. AB - Brown adipose tissue (BAT) thermogenic functions are primarily mediated by uncoupling protein (UCP)-1. Ucp1 gene expression is highly induced by cold temperature, via sympathetic nervous system and beta-adrenergic receptors (betaARs). Ucp1 is also repressed by the clock gene Rev-erbalpha, contributing to its circadian rhythmicity. In this study, we investigated mice lacking betaARs (beta-less mice) to test the relationship between betaAR signaling and the BAT molecular clock. We found that in addition to controlling the induction of Ucp1 and other key BAT genes at near freezing temperatures, betaARs are essential for the basal expression of BAT Ucp1 at room temperature. Remarkably, although basal Ucp1 expression is low throughout day and night in beta-less mice, the circadian rhythmicity of Ucp1 and clock genes in BAT is maintained. Thus, the requirement of betaAR signaling for BAT activity is independent of the circadian rhythmicity of Ucp1 expression and circadian oscillation of the molecular clock genes. On the other hand, we found that betaARs are essential for the normal circadian rhythms of locomotor activity. Our results demonstrate that in addition to controlling the BAT response to extreme cold, betaAR signaling is necessary to maintain basal Ucp1 tone and to couple BAT circadian rhythmicity to the central clock.-Razzoli, M., Emmett, M. J., Lazar, M. A., Bartolomucci, A. beta-Adrenergic receptors control brown adipose UCP-1 tone and cold response without affecting its circadian rhythmicity. PMID- 29715049 TI - Pregnancy Achieved Using Donor Eggs in Cancer Survivors with Treatment-Induced Ovarian Failure: Obstetric and Perinatal Outcome. AB - BACKGROUND: Egg donation is a common fertility treatment in female cancer survivors with reproductive wish and iatrogenic ovarian failure. We examined whether women previously treated for cancer have a higher risk of pregnancy complications after egg donation treatments when compared to women without cancer history. METHODS: In this prospective cohort treated during 2003-2015 at a single center, 31 women with previous history of cancer achieved 25 deliveries and 212 women without cancer history achieved 244 deliveries. All egg donor treatments were performed with a strict policy of single embryo transfer to reduce pregnancy and perinatal complications. Data were analyzed using logistic regression with adjustment for relevant confounders, to estimate adjusted odds ratios (aORs) and 95% confidence intervals (CIs) for perinatal and obstetric outcomes. Women without previous history of cancer were used as the reference group in the regression models. RESULTS: Women with a history of cancer presented with a significantly increased risk of pregnancy complications, including preterm birth (aOR 5.54, 95% CI 2.01-15.31) and preeclampsia (aOR 2.79, 95% CI 1.07-7.34), compared to women without cancer history. CONCLUSIONS: The findings of this study suggest that the risks of preterm birth and preeclampsia in women with prior cancers who become pregnant by egg donor treatment significantly exceed those of women without cancer history undergoing similar treatments. As pregnancies using donor eggs are already acknowledged of higher risk for hypertensive pathologies, this study alerts toward characterization of specific increased risks in women who are cancer survivors to provide adapted pregnancy monitoring. PMID- 29715051 TI - Immunization during pregnancy. AB - INTRODUCTION: Vaccination in pregnancy has been shown to be effective for the prevention of influenza and pertussis in infants, providing support for similar strategies to prevent group B streptococcus and respiratory syncytial virus infections that represent a large burden in pediatric population. Areas covered: This review addresses the principle of maternal immunization, efficacy and safety of both pertussis and seasonal influenza vaccines and presents available data on group B streptococcus and respiratory syncytial virus that are in development for administration during pregnancy. Expert commentary: Complementary data is needed to help in understanding pertussis vaccine mechanisms, improving influenza vaccine efficacy and addressing the interference phenomenon which is when maternal antibodies interfere with the infant vaccine response. Several knowledge gaps need to be filled in group B streptococcus and respiratory syncytial virus vaccines research. PMID- 29715050 TI - Diabetes During Pregnancy: Surveillance, Preconception Care, and Postpartum Care. AB - Diabetes during pregnancy can adversely affect the health of women and infants. In this report, we provide an overview of the state of the science, and highlight Centers for Disease Control and Prevention (CDC) activities related to (1) surveillance of preexisting and gestational diabetes mellitus (GDM); (2) preconception care for women with preexisting diabetes; (3) postpartum diabetes screening among women with GDM-affected pregnancies; and (4) preventing the progression to Type 2 diabetes among women with GDM-affected pregnancies through lifestyle intervention programs. Improving preconception care, increasing postpartum diabetes screening rates, and promoting lifestyle interventions in the postpartum period all provide opportunities to improve the health of women and their infants. PMID- 29715052 TI - Antiproliferative Activity of Extracts of Campomanesia adamantium (Cambess.) O. Berg and Isolated Compound Dimethylchalcone Against B16-F10 Murine Melanoma. AB - Campomanesia adamantium, a native species of the Brazilian Cerrado, is characterized as a natural source of phenolic compounds and has known potential anticancer activities. This study aimed to evaluate the chemical profile of dichloromethane extracts of pulp (DEGPU) and peel (DEGPE) from the fruits of C. adamantium and to identify compounds with antiproliferative effects in vitro against melanoma cells by sulforhodamine B (SRB) assay, apoptosis induction assay, caspase-3 activation assay, nitric oxide (NO) release in coculture of B16 F10 cells and murine peritoneal macrophages. The chemical profiles of DEGPU and DEGPE were analyzed by high performance liquid chromatography coupled to diode array detector and mass spectrometer using the electrospray ionization interface (HPLC-DAD-ESI-MS/MS). Thirteen compounds were identified in both extracts and the chromatographic study of the most active extract in SRB assay DEGPU (GI50 of 16.17 MUg/mL) resulted in the isolation of seven compounds. The isolated compound dimethylchalcone (DMC) had the highest antiproliferative activity against B16-F10 with a GI50 of 7.11 MUg/mL. DEGPU extract activated caspase-3 in 29% of cells at 25 MUg/mL and caused a 50% decrease in NO release in coculture. DEGPU can be characterized as a source of bioactive compounds such as DMC, as seen from its antiproliferative effect in vitro by inducing B16-F10 cells to undergo apoptosis, essential feature in the search for new anticancer drugs. PMID- 29715053 TI - A Review of Myopia Control with Atropine. AB - Myopia is a global public health issue with a worldwide prevalence of ~30% and is estimated to rise to 50% by 2050. In addition to the burden associated with routine management of the condition, high myopia predisposes the eye to sight threatening complications such as myopic maculopathy and glaucoma in adult life. Controlling onset and progression of myopia at a young age can reduce the risk of morbidity associated with high myopia. Progression of myopia can be slowed with various optical, environmental, and pharmaceutical strategies, of which atropine has proven to be the most effective. High-dose atropine (0.5%-1%) is the most effective, but it has significant trade-offs with respect to rebound of myopia on discontinuation and side effects such as photophobia and difficulty with near work (decreased accommodation). Low doses of atropine have been trialed and show a dose-dependent efficacy. However, its mode of action on the ocular tissues leading to slowing eye growth remains unclear and multiple mechanisms and sites in the eye have been postulated to play a role. This review summarizes the role of atropine in controlling myopia and the mechanisms studied to date. PMID- 29715054 TI - Efficacy and effectiveness of high-dose versus standard-dose influenza vaccination for older adults: a systematic review and meta-analysis. AB - BACKGROUND: Influenza is responsible for a significant disease burden annually, especially in older adults. This study reviews the relative vaccine efficacy or effectiveness (rVE) of high-dose inactivated trivalent influenza vaccine (HD IIV3) compared to standard-dose influenza vaccines (SD-IIV3) in adults >=65 against influenza-associated outcomes to inform evidence-based decision-making to shift clinical practice and standard of care in this population. METHODS: A systematic review was conducted for studies assessing the rVE of HD-IIV3 against probable/laboratory-confirmed influenza-like illness (ILI), hospital admissions, and death in adults >=65. Results from individual seasons were meta-analyzed and a random-effects model was used to estimate pooled rVEs. RESULTS: After screening 992 studies, seven studies were meta-analyzed. HD-IIV3 demonstrated better protection against ILI compared to SD-IIV3 (rVE = 19.5%; 95% CI: 8.6-29.0%). HD IIV3 was also more effective at preventing hospital admissions from all-causes (rVE = 9.1%; 95% CI: 2.4-15.3%), as well as from influenza (rVE = 17.8%; 95% CI: 8.1-26.5%), pneumonia (rVE = 24.3%, 95% CI: 13.9-33.4%), and cardiorespiratory events (rVE = 18.2%; 95% CI: 6.8-28.1%). rVE against post-influenza mortality was 22.2% (95% CI: -18.2-48.8%) and 2.5% (95% CI: -5.2-9.5%) against all-cause mortality. CONCLUSIONS: Available evidence suggests HD-IIV3 is more effective than SD-IIV3 at reducing the clinical outcomes associated with influenza infection in older adults and should be considered for routine use in the 65+ population. PMID- 29715055 TI - Next-Generation Drugs Targeting the Cereblon Ubiquitin Ligase. PMID- 29715056 TI - Venetoclax for Patients With Chronic Lymphocytic Leukemia With 17p Deletion: Results From the Full Population of a Phase II Pivotal Trial. AB - Purpose Venetoclax is an orally bioavailable B-cell lymphoma 2 inhibitor. US Food and Drug Administration and European Medicines Agency approval for patients with 17p deleted relapsed/refractory chronic lymphocytic leukemia [del(17p) CLL] was based on results from 107 patients. An additional 51 patients were enrolled in a safety expansion cohort. Extended analysis of all enrolled patients, including the effect of minimal residual disease (MRD) negativity on outcome, is now reported. Patients and Methods Overall, 158 patients with relapsed/refractory or previously untreated (n = 5) del(17p) CLL received venetoclax 400 mg per day after an initial dose ramp up. Responses were based on 2008 International Workshop on Chronic Lymphocytic Leukemia criteria, with monthly physical exams and blood counts. Computed tomography scan was mandatory at week 36, after which assessment made was by clinical evaluation. Marrow biopsy was performed when complete remission was suspected. MRD was assessed by flow cytometry. Results Patients had a median of two prior therapies (range, zero to 10 therapies), 71% had TP53 mutation, and 48% had nodes that were >= 5 cm. Median time on venetoclax was 23.1 months (range, 0 to 44.2 months) and median time on study was 26.6 months (range, 0 to 44.2 months). For all patients, investigator-assessed objective response rate was 77% (122 of 158 patients; 20% complete remission) and estimated progression-free survival at 24 months was 54% (95% CI, 45% to 62%). For 16 patients who received prior kinase inhibitors, objective response rate was 63% (10 of 16 patients) and 24-month progression-free survival estimate was 50% (95% CI, 25% to 71%). By intent-to-treat analysis, 48 (30%) of 158 patients achieved MRD below the cutoff of 10-4 in blood. Common grade 3 and 4 adverse events were hematologic and managed with supportive care and/or dose adjustments. Conclusion Venetoclax achieves durable responses and was well tolerated in patients with del(17p) CLL. A high rate of blood MRD < 10-4 was achieved in this high-risk population. PMID- 29715057 TI - How to evaluate potential non-specific effects of vaccines: the quest for randomized trials or time for triangulation? AB - INTRODUCTION: Emerging evidence suggests that vaccines, in addition to their disease-specific effects, have important non-specific effects (NSEs), which contribute to their overall effect on mortality and morbidity. Immunological studies have shown that NSEs are biologically plausible. Many advocate that randomized controlled trials (RCTs) with overall mortality or morbidity as the outcome are the only way forward to confirm or refute NSEs. Areas covered: We discuss the limitations of using RCTs only as a tool to evaluate NSEs of vaccines. Such RCTs can be ethically problematic, they are time consuming and expensive. Furthermore, they only assess the NSEs in a given context, but it is inherent in the concept of NSEs that the NSEs of a given vaccine are modified by other immunomodulatory conditions. As an alternative, we propose that triangulation of RCTs and observational studies, merging multiple lines of evidence with different underlying bias structures, can build a strong argument for causality. We examine two examples related to measles vaccine and oral polio vaccine. Expert commentary: Using RCTs alone to evaluate NSEs of vaccines severely limits the possibilities for studying NSEs. Results from both RCTs and non-RCT studies should be triangulated to strengthen causal interpretation. PMID- 29715058 TI - Corneal Endothelial Changes in Behcet's Patients with Inactive Ocular Involvement. AB - PURPOSE: The purpose of this article is to evaluate alterations in the corneal endothelial layer in Behcet's disease (BD) with inactive ocular involvement using specular microscopy. MATERIALS AND METHODS: Thirty-three eyes of 33 BD patients who had at least one anterior segment involvement and no active inflammation in the last 3 months were included in the study (group 1). Twenty-seven of the 33 BD patients had an anterior uveitis attack and six of them had a panuveitis (both anterior and posterior involvement) attack. Thirty-three eyes of 33 age- and sex matched healthy subjects were enrolled in the control group (group 2). Corneal endothelial cell density (CD), coefficient of variation (CV), hexagonal cell ratio (HEX), and central corneal thickness (CCT) were measured using specular microscopy (Konan Medical, Nishinomiya, Japan), and the results were compared between groups. RESULTS: The mean CD was 2739 +/- 164.18 cells/mm2 in group 1 and 2922 +/- 107.60 cells/mm2 in group 2 (p = 0.001). The mean CV was 32.9 +/- 4.76 in group 1 and 28.5 +/- 3.06 in group 2 (p = 0.001). The mean HEX was 44.7 +/- 6.51 in group 1 and 49.7 +/- 6.10 in group 2 (p = 0.019). The mean CCT was 545.75 +/- 40.89 MU in group 1 and 545.66 +/- 30.09 MU in group 2 (p > 0.05). CONCLUSIONS: Ocular attacks in our BD patients may have caused permanent changes in the corneal endothelial layer. However, these changes did not lead to corneal decompensation, but further studies are necessary to confirm these results. PMID- 29715059 TI - Human papillomavirus vaccination and the role of herd effects in future cancer control planning: a review. AB - INTRODUCTION: Vaccine herd effects are the indirect protection that vaccinated persons provide to those who remain susceptible to infection, due to the reduced transmission of infections. Herd effects have been an important part of the discourse on how to best implement human papillomavirus (HPV) vaccines and prevent HPV-related diseases. Areas covered: In this paper, we review the theory of HPV vaccine herd effects derived from mathematical models, give an account of observed HPV vaccine herd effects worldwide, and examine the implications of vaccine herd effects for future cervical cancer screening efforts. Expert commentary: HPV vaccine herd effects improve the cost-effectiveness of vaccinating preadolescent girls, but contribute to making gender-neutral vaccination less economically efficient. Vaccination coverage and sexual mixing patterns by age are strong determinants of herd effects. Many countries worldwide are starting to observe reductions in HPV-related outcomes likely attributable to herd effects, most notably declining anogenital warts in young men, and declining HPV-16/18 infection prevalence in young unvaccinated women. Policy makers making recommendations for cervical cancer screening will have to consider HPV vaccination coverage and herd effects, as these will affect the positive predictive value of screening and the risk of cervical cancer in unvaccinated women. PMID- 29715060 TI - Ameloblastic Carcinoma In Situ: Review of Literature and a Case Presentation in a Pediatric Patient. AB - Ameloblastic carcinomas are rare malignant lesions with 3 mandibular pediatric cases reported in the literature. We present a case of ameloblastic carcinoma in situ in a 15-year-old male with a right mandibular cystic lesion on computed tomography. The incisional biopsy revealed plexiform ameloblastoma. Due to the infiltrating and aggressive nature of the tumor, the patient underwent hemimandibulectomy and immediate reconstruction with a vascularized osteocutaneous fibula free flap. The final pathology was read as ameloblastic carcinoma in situ. Given the rarity of this disease in the pediatric population, this case report may be a valuable addition to the current literature. PMID- 29715061 TI - Guidelines for the Ethical Publication of Facial Photographs and Review of the Literature. AB - Facial photography presents a unique ethical dilemma, as faces are difficult to deidentify for publication. We performed a review of the literature to examine current guidelines for the publication of facial photographs. We also reviewed societies' websites, journal requirements, and ethical and legal aspects of confidentiality. Most articles emphasized the importance of consent for photography and publication. Masking is not appropriate, but some journals continue to allow masking. Most legislation allows patients to restrict the uses of photographs. In the end, it is imperative to protect patient privacy by obtaining consent for photograph publication after full disclosure of risks, and specific recommendations are provided regarding a comprehensive consent process. PMID- 29715062 TI - Vasculitis and Thrombosis due to the Sea Lion Lungworm, Parafilaroides decorus, in a Guadalupe Fur Seal ( Arctocephalus philippii townsendi). AB - A free-ranging, male, yearling Guadalupe fur seal ( Arctocephalus philippii townsendi) died due to multifocal verminous vasculitis with thrombosis and several embolic infarcts in liver, kidney, and brain. Nematodes extracted from lung blood vessels were identified as Parafilaroides decorus, a parasite normally found in alveoli of California sea lions ( Zalophus californianus). PMID- 29715063 TI - LEPTOSPIRA ANTIBODIES DETECTED IN WILDLIFE IN THE USA AND THE US VIRGIN ISLANDS. AB - From 2011 to 2017, 4,534 serum samples from 13 wildlife species collected across the US and in one territory (US Virgin Islands) were tested for exposure to Leptospira serovars Bratislava, Canicola, Grippotyphosa, Hardjo, Icterohaemorrhagiae, and Pomona. Of 1,759 canids, 1,043 cervids, 23 small Indian mongooses ( Herpestes auropunctatus), 1,704 raccoons ( Procyon lotor), and five striped skunks ( Mephitis mephitis), 27.0, 44.4, 30.4, 40.8, and 60%, respectively, were antibody positive for any of the six serovars. The most commonly detected serovars across all species were Bratislava and Grippotyphosa. Our results indicate that Leptospira titers are very common in a wide variety of wildlife species. These species may act as important reservoirs in the epidemiological cycle of the pathogen. Additional studies to determine the relationship between serologic evidence and shedding of the pathogen by wildlife are necessary to better understand the risk. PMID- 29715064 TI - CATTLE ( BOS TAURUS) RESIST CHRONIC WASTING DISEASE FOLLOWING ORAL INOCULATION CHALLENGE OR TEN YEARS' NATURAL EXPOSURE IN CONTAMINATED ENVIRONMENTS. AB - We conducted a 10-yr study to establish whether chronic wasting disease (CWD) was readily transmissible to domestic cattle ( Bos taurus) following oral inoculation or by cohousing cattle with captive cervids in outdoor research facilities where CWD was enzootic. Calves ( n=12) were challenged orally on one occasion using brain homogenate derived from CWD-infected mule deer ( Odocoileus hemionus). Five uninoculated cattle served as unchallenged controls. Two other groups of cattle ( n=10-11/group) were housed outdoors for 10 yr in captive cervid research facilities. The environmentally challenged cattle were exposed to CWD-associated prions through common paddocks, feed, and water and via direct daily contact with known and potentially infected mule deer or wapiti ( Cervus canadensis) throughout the decade-long study period. None of the exposed cattle developed neurologic disease during the study. We euthanized cattle surviving to 10 yr postchallenge and examined all for lesions or disease-associated prion protein (PrPd) by histopathology, immunohistochemistry, and western immunoblot analysis of central nervous system and lymphoid tissue. None had evidence of PrPd accumulation. We conclude that the risks of CWD transmission to cattle following oral inoculation or after prolonged exposure to contaminated environments are low. PMID- 29715066 TI - State performance in pluripotent and adult stem cell research, 2009-2016. AB - AIM: To examine how the geographic distribution of pluripotent and adult stem cell research publications within the USA differs from other areas of biomedical research. MATERIALS & METHODS: Publication count data for pluripotent stem cell research, adult stem cell research and a comparison group representative of biomedical research more broadly were collected and analyzed for each US state from 2009 to 2016. RESULTS: The distribution of pluripotent stem cell research differed from the other fields with overperformance in pluripotent stem cell research observed in California, as well as Wisconsin, Massachusetts, Maryland and Connecticut. CONCLUSION: Our analysis suggests that permissive state stem cell policy may be one of the several factors contributing to strong state performance in pluripotent stem cell research. PMID- 29715067 TI - The variable role of SIRT1 in the maintenance and differentiation of mesenchymal stem cells. AB - SIRT1 is an NAD+-dependent deacetylase that acts as a nutrient sensitive regulator of longevity. SIRT1 also acts as a key regulator of mesenchymal stem cells (MSCs), adult stem cells that give rise to tissues such as bone, fat, muscle and cartilage. This review focuses on how SIRT1 regulates the self renewal, multipotency and differentiation of MSCs. The variable role of SIRT1 in promoting the differentiation of MSCs towards certain lineages, while repressing others, will be examined within the broader context of aging, calorie restriction, and regenerative medicine. Finally, recent animal and human studies will be highlighted which paint an overall salutary role for SIRT1 in protecting MSCs (and resulting tissues) from age-related atrophy and dysfunction. PMID- 29715068 TI - Application of 3D-printed patient-specific skeletal implants augmented with autologous skeletal stem cells. AB - Joint replacements have proved a medical success providing symptomatic relief and return to mobility in many patients with arthritis. However, multiple revision surgeries due to joint failure can result in complex revision scenarios with significant bone tissue loss, in an elderly population, which poses a significant clinical challenge. Computer-aided design-computer-assisted manufacturing (CAD CAM) prototyped bespoke implants are currently being used as an alternative and innovative approach for joint restoration in salvage cases, while the incorporation of autologous skeletal stem cells to optimize regenerative capacity can enhance implant osseointegration. We present a case series of 11 patients with severe disability and significant bone loss due to failed joint replacements. The choice of CAD-CAM prototyped joint implants enhanced with autologous skeletal stem cells resulted in significant patient-reported clinical and radiological improvements. PMID- 29715069 TI - Introducing the RegMedNet Award for Cultivating Excellence. PMID- 29715070 TI - Cell-based therapy for the treatment of female stress urinary incontinence: an early cost-effectiveness analysis. AB - AIM: To perform an early cost-effectiveness analysis of in vitro expanded myoblasts (IVM) and minced myofibers versus midurethral slings (MUS) for surgical treatment of female stress urinary incontinence. METHODS: Cost-effectiveness and sensitivity analyses were performed using a decision tree comprising previously published data and expert opinions. RESULTS & CONCLUSION: In the base case scenario, MUS was the cost-effective strategy with a negative incremental cost effectiveness ratio compared with IVM and a positive incremental cost effectiveness ratio compared with minced myofibers. However, the sensitivity analysis indicates that IVM may become an alternative providing greater effect at a higher cost. With the possibility of becoming more effective, IVM treatment would be advantageous over MUS given its reduced invasiveness and lower risks of complications. PMID- 29715071 TI - Accelerated healing of a diabetic foot ulcer using autologous stromal vascular fraction suspended in platelet-rich plasma. AB - We describe the case of a Type I diabetic patient with a refractory foot ulcer that remained unhealed for 2 years despite conventional therapy. Autologous adipose-derived stromal vascular fraction suspended in autologous platelet-rich plasma was applied to the wound, which completely healed within 1 month. The wound remained closed with no complications for a 2-year follow-up. Reporting of this and similar cases may lead to larger clinical trials that will prove the efficacy of this therapy that may offer accelerated healing and lessen the financial burden of more expensive therapeutic modalities. PMID- 29715074 TI - An Interview with Michel Sadelain, MD, PhD. PMID- 29715072 TI - International Comparison of Abdominal Fat Distribution Among Four Populations: The ERA-JUMP Study. AB - BACKGROUND: Abdominal fat distribution varies across groups with different races or environments. Whether environmental factors, apart from racial differences, affect abdominal fat distribution is unknown. METHODS: We compared the abdominal fat distribution of four groups; different races with similar environments (Caucasians vs. Japanese Americans), different environments with an identical race (Japanese Americans vs. Japanese), and similar races with similar environments (Japanese vs. Koreans). A population-based sample of 1212 men aged 40-49 were analyzed: 307 Caucasians and 300 Japanese Americans in the United States, 310 Japanese in Japan, and 295 Koreans in Korea. We compared the proportion of visceral adipose tissue area to total abdominal adipose tissue area (VAT%) and other factors that can affect abdominal fat distribution (smoking, alcohol use, physical activity levels, and metabolic factors). RESULTS: VAT% was significantly higher in Japanese and Koreans than in Japanese Americans and Caucasians (50.0, 48.5, 43.2, 41.0%, respectively, P < 0.001). Even after adjustment for possible confounders, the significant VAT% difference remained in comparing groups with identical race but different environments (i.e., Japanese vs. Japanese Americans). In contrast, comparing groups with different races but similar environments (i.e., Caucasians vs. Japanese Americans), VAT% was not significantly different. Comparing groups with similar races and similar environments (i.e., Japanese vs. Koreans), VAT% did not significantly differ. CONCLUSIONS: Environmental differences, apart from racial differences, affect the difference in abdominal fat distribution across different groups in middle-aged men. PMID- 29715075 TI - Driving CARs Across New Borders. PMID- 29715073 TI - Gluteal Loading Versus Sham Exercises to Improve Pain and Dysfunction in Postmenopausal Women with Greater Trochanteric Pain Syndrome: A Randomized Controlled Trial. AB - OBJECTIVES: The aim of the current study was to determine the effects of education with targeted or sham exercise on pain and function in postmenopausal women with greater trochanteric pain syndrome (GTPS). BACKGROUND: Conservative management of GTPS is poorly described, and to date, there have been no studies on education with exercise as an intervention for GTPS. Ninety-four postmenopausal women with GTPS were recruited to participate in this study. MATERIALS AND METHODS: Participants were randomized to receive one of two 12-week exercise programs (GLoBE vs. sham). Participants received education on avoiding tendon compression with appropriate activity modification. The Victorian Institute of Sport Assessment-Gluteal tendon (VISA-G) was examined at baseline, 12, and 52 weeks. Secondary outcomes included hip pain and function questionnaires (Hip dysfunction and Osteoarthritis Outcome Score (HOOS), Oxford Hip Score (OHS), and Lateral Hip Pain questionnaire), a global rating of change in symptom questionnaire, and a quality of life measure (Assessment of Quality of Life [AQoL]-8D). Differences between groups were analyzed using intention to treat with analysis of covariance, per-protocol analysis, and responder analysis. RESULTS: Responders to the GLoBE intervention had significantly better VISA-G, HOOS, OHS, and lateral hip pain questionnaire scores compared to responders in the sham group. However, intention to treat analyses showed no between-group differences for the GLoBE intervention and sham exercise groups. Significant improvement in VISA-G score was found for both programs at 12- and 52-weeks time points (p < 0.001). CONCLUSION: Lack of treatment effect was found with the addition of an exercise program to a comprehensive education on GTPS management. The improved outcomes of the responders in the GLoBE group indicate that there may be a subgroup of patients with a GTPS diagnosis that benefit from a GLoBE intervention program. PMID- 29715076 TI - Preface. PMID- 29715077 TI - Commentary: Let the Time Fly: Dopamine is the Arbiter. PMID- 29715078 TI - Mapping of the US Domestic Influenza Virologic Surveillance Landscape. AB - Influenza virologic surveillance is critical each season for tracking influenza circulation, following trends in antiviral drug resistance, detecting novel influenza infections in humans, and selecting viruses for use in annual seasonal vaccine production. We developed a framework and process map for characterizing the landscape of US influenza virologic surveillance into 5 tiers of influenza testing: outpatient settings (tier 1), inpatient settings and commercial laboratories (tier 2), state public health laboratories (tier 3), National Influenza Reference Center laboratories (tier 4), and Centers for Disease Control and Prevention laboratories (tier 5). During the 2015-16 season, the numbers of influenza tests directly contributing to virologic surveillance were 804,000 in tiers 1 and 2; 78,000 in tier 3; 2,800 in tier 4; and 3,400 in tier 5. With the release of the 2017 US Pandemic Influenza Plan, the proposed framework will support public health officials in modeling, surveillance, and pandemic planning and response. PMID- 29715079 TI - Sinusoidal Obstruction Syndrome (Veno-occlusive Disease) Following Hematopoietic Stem Cell Transplant: Insights and Therapeutic Advances. AB - Hepatic sinusoidal obstruction syndrome (SOS) is a rare fatal clinical entity seen following hematopoietic stem cell transplant (HSCT). It is more commonly reported to occur following allogeneic HSCT compared to autologous HSCT. Historically, it is known as hepatitis following HSCT. It is thought that endothelial damage to the hepatic venules leading to occlusion of the terminal hepatic venules and hepatic sinusoids is the trigger for the development of SOS. Several risk factors have been associated with this condition. Some of these risk factors are patient related while others are transplant process related. Given the high mortality of this condition, early identification of high-risk patients with severe disease is of utmost importance. The management of SOS varies depending on the severity of the disease. Mild to moderate disease has a good outcome with supportive measures alone, while severe presentation of the disease requires a more aggressive management. Defibrotide is the only Food and Drug Administration-approved therapy and it is reserved for severe cases of SOS. The role of defibrotide as a prophylactic therapy remains under investigation. PMID- 29715080 TI - Molecular Mechanisms of Breast Cancer Metastasis and Potential Anti-metastatic Compounds. AB - Throughout the world, breast cancer is among the major causes of cancer-related death and is the most common cancer found in women. The development of cancer molecular knowledge has surpassed the novel concept of cancer biology and unraveled principle targets for anticancer drug developments and treatment strategies. Metastatic breast cancer cells acquire their aggressive features through several mechanisms, including augmentation of survival, proliferation, tumorigenicity, and motility-related cellular pathways. Clearly, natural product derived compounds have since long been recognized as an important source for anticancer drugs, several of which have been shown to have promising anti metastasis activities by suppressing key molecular features supporting such cell aggressiveness. This review provides the essential details of breast cancer, the molecular-based insights into metastasis, as well as the effects and mechanisms of potential compounds for breast cancer therapeutic approaches. As the abilities of cancer cells to invade and metastasize are addressed as the hallmarks of cancer, compounds possessing anti-metastatic effects, together with their defined molecular drug action could benefit the development of new drugs as well as treatment strategies. PMID- 29715081 TI - Estimation of Risk of Normal-tissue Toxicity Following Gastric Cancer Radiotherapy with Photon- or Scanned Proton-beams. AB - BACKGROUND/AIM: Gastric cancer (GC) radiotherapy involves irradiation of large tumour volumes located in the proximities of critical structures. The advantageous dose distributions produced by scanned-proton beams could reduce the irradiated volumes of the organs at risk (OARs). However, treatment-induced side effects may still appear. The aim of this study was to estimate the normal tissue complication probability (NTCP) following proton therapy of GC, compared to photon radiotherapy. PATIENTS AND METHODS: Eight GC patients, previously treated with volumetric-modulated arc therapy (VMAT), were retrospectively planned with scanned proton beams carried out with the single-field uniform-dose (SFUD) method. A beam-specific planning target volume was used for spot positioning and a clinical target volume (CTV) based robust optimisation was performed considering setup- and range-uncertainties. The dosimetric and NTCP values obtained with the VMAT and SFUD plans were compared. RESULTS: With SFUD, lower or similar dose-volume values were obtained for OARs, compared to VMAT. NTCP values of 0% were determined with the VMAT and SFUD plans for all OARs (p>0.05), except for the left kidney (p<0.05), for which lower toxicity was estimated with SFUD. CONCLUSION: The NTCP reduction, determined for the left kidney with SFUD, can be of clinical relevance for preserving renal function after radiotherapy of GC. PMID- 29715082 TI - Efficacy of Asparaginase Erwinia chrysanthemi With and Without Temozolomide Against Glioma Cells and Intracranial Mouse Medulloblastoma. AB - BACKGROUND: Anti-metabolites are less-myelosuppressive than DNA-damaging anticancer drugs and may be useful against brain tumors. MATERIALS AND METHODS: We evaluated the asparagine/glutamine-deaminating agent Erwinaze with/without temozolomide against brain tumor cells and mouse medulloblastomas. RESULTS: Erwinaze treatment of cell lines and neurospheres led to dose-dependent reductions of cells (reversible by L-glutamine), with half maximal inhibitory concentrations (IC50s) of 0.12->10 IU/ml. Erwinaze at <1 IU/ml reduced temozolomide IC50s by 3.6- to 13-fold (300-1,200 MUM to 40-330 MUM). Seven-week old SMO/SMO mice treated with Erwinaze (regardless of temozolomide treatment) had better survival 11 weeks post-therapy, compared to those not treated with Erwinaze (81.25% vs. 46.15, p=0.08). Temozolomide-treated mice developed 10% weight loss, impairing survival. All 16 mice treated with temozolomide (regardless of Erwinaze treatment) succumbed by 40-weeks of age, whereas 5/8 animals treated with Erwinaze alone and 2/6 controls survived (p=0.035). CONCLUSION: Erwinaze enhances cytotoxicity of temozolomide in vitro, and improves survival in SMO/SMO mice, likely by reducing cerebrospinal fluid glutamine. Temozolomide-associated toxicity prevented demonstration of any potential combinatorial advantage with Erwinaze in vivo. PMID- 29715083 TI - Effect of Tissue Factor on Colorectal Cancer Stem Cells. AB - BACKGROUND/AIM: Tissue factor (TF) expression increases cancer stem cell (CSC) activity in breast and lung cancer. There are ongoing studies focused on targeting CSCs via anti-TF treatment, for breast and lung cancer therapy. Herein, the aim was to determine whether targeting TF could have an anti-CSC therapeutic role in colorectal cancer (CRC). MATERIALS AND METHODS: Evaluation of colonosphere-forming efficiency (CFE) and aldehyde dehydrogenase (ALDH) expression level was used to quantify CSC activity in two CRC cell lines, after TF knockdown (TFKD) or TF over-expression (TFOE). RESULTS: TFKD resulted in increased levels of ALDH in SW620 (1.31+/-0.04-fold, p<0.001) and DLD-1 (1.63+/ 0.14-fold, p=0.04) cells. CFE was increased in SW620 (1.21+/-0.23% vs. 2.03+/ 0.29%, p=0.01) and DLD-1 (0.41+/-0.12% vs. 0.68+/-0.9%, p=0.01) cells. Conversely, TFOE decreased ALDH expression (0.72+/-0.04-fold, p=0.001) and CFE (0.33+/-0.05% vs. 0.66+/-0.14%, p=0.006) in DLD-1, but had no impact on SW620 cells. CONCLUSION: In the examined CRC cell lines, TF expression was inversely related to CSC activity suggesting that anti-TF therapies may not have a role in CRC treatment. PMID- 29715084 TI - Oxidative DNA Damage Induced by Pirarubicin, an Anthracycline Anticancer Agent, in the Presence of Copper(II). AB - BACKGROUND/AIM: One mechanism of the anticancer action of anthracyclines is believed to be oxidative DNA damage. Previously, we reported that doxorubicin induced oxidative DNA damage in the presence of Cu(II). However, the mechanism of pirarubicin-induced oxidative DNA damage has not been well clarified. MATERIALS AND METHODS: DNA damage by pirarubicin in the presence of Cu(II) was analyzed using pBR322 plasmid DNA. O2*- derived from pirarubicin in the presence of Cu(II) was detected by cytochrome c reduction. RESULTS: Pirarubicin induced DNA damage in the presence of Cu(II). Scavenger experiments suggest that reactive species are generated from H2O2 and Cu(I). Pirarubicin induced O2*- production in the presence of Cu(II). CONCLUSION: These findings suggest that pirarubicin plus Cu(II) induces oxidative DNA damage in a similar manner to doxorubicin, and Cu(II)-mediated oxidative DNA damage may serve as a common mechanism for antitumor effects of anthracyclines. PMID- 29715085 TI - Chemerin in a Mouse Model of Non-alcoholic Steatohepatitis and Hepatocarcinogenesis. AB - BACKGROUND/AIM: Non-alcoholic steatohepatitis (NASH) is a risk factor for hepatocellular carcinoma (HCC). The adipokine chemerin protects from HCC and is reduced in human HCC. In this study, chemerin expression was analyzed in a murine model of NASH-HCC. MATERIALS AND METHODS: Serum and hepatic chemerin, and ex vivo chemerin receptor activation were monitored in NASH and NASH-HCC in mice fed a low-methionine diet deficient in choline after initiation of tumors by injection of diethylnitrosamine. RESULTS: In non-tumorous liver tissues, the extent of hepatic steatosis, and the levels of proteins regulating hepatic lipids and liver fibrosis were similar in NASH and NASH-associated HCC. Systemic and hepatic chemerin, and chemerin receptor activation were not changed in HCC. Liver tumors only developed in diethylnitrosamine-injected mice and their number was increased in NASH. Chemerin protein was induced in liver in NASH, but was unchanged in HCC tissues. CONCLUSION: Hepatic and serum chemerin and ex vivo analyzed chemerin receptor activation do not differ in murine NASH-associated HCC when compared to NASH. Hepatic tumors still develop despite high endogenous levels of serum and liver chemerin protein. PMID- 29715086 TI - The Expression of Riboflavin Transporters in Human Colorectal Cancer. AB - BACKGROUND/AIM: Riboflavin transport in enterocytes is mediated by three translocators: RFVT3 located on the apical membrane, and RFVT1 and RFVT2 on the basolateral membrane. The aim of this study was to investigate whether the expression levels of RFVTs are altered in human colorectal cancer (CRC). MATERIALS AND METHODS: In human colon adenocarcinoma cell lines (CaCo2, DLD-1, HT 29) and in tissues of patients with CRC, gene and protein expression levels were evaluated by real time-polymerase chain reaction and western blotting. Intracellular flavin content was determined by high-performance liquid chromatography. RESULTS: RFVT3 and RFVT2 gene and protein expression levels were higher in DLD-1 and HT-29 compared to Caco2 cells. In HT-29 cells, the RFVT1 protein level was drastically lower. These differences are presumably responsible for the higher total flavin content in DLD-1 and HT-29 cells. In tumor tissues of patients with CRC, RFVT1 content was reduced at both protein and mRNA levels compared to normal mucosa. RFVT3 and RFVT2 gene expression levels were increased, while protein expression was reduced, with a small reduction in riboflavin amount. CONCLUSION: This study provides first evidence that transcription/translation of RFVTs are profoundly altered in CRC. PMID- 29715087 TI - Tumor Cell-selective Synergism of TRAIL- and ATRA-induced Cytotoxicity in Breast Cancer Cells. AB - BACKGROUND/AIM: One of the major problems in breast cancer treatment is pharmacoresistance. Therefore, exploration of treatment alternatives is of clinical relevance. The present work focused on tumor cell-inhibiting effects of a combination of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and all trans retinoic acid (ATRA) in breast cancer cells. MATERIALS AND METHODS: Breast cancer cell lines (BT-20, BT-474, MDA-MB-231, MDA-MB-436, MDA-MB-453, MCF 7, SKBR3, T47D, ZR-75-1) and the mammary epithelial cell line MCF-10A were treated with TRAIL and ATRA alone and in combination. Cell viability was assessed via 3-(4,5)-dimethylthiahiazo(-z-yl)-3,5-di-phenytetrazoliumromide (MTT) assay, the potential of cell colony formation via clonogenic assay, cell death induction via cell-cycle analysis by fluorescence-activated cell sorting (FACS), terminal deoxynucleotidyltransferase-mediated UTP nick end labeling (TUNEL) assay and Cell death detection ELISAPLUS, expression of apoptosis and TRAIL pathway proteins via western blot and cell surface expression of TRAIL receptor 1 (DR4) via FACS analysis. RESULTS: TRAIL and ATRA evoked synergistic inhibition of breast cancer cell viability based on cytostatic and cytotoxic mechanisms. This correlated with augmented fragmentation of nuclear DNA, up-regulation of TRAIL receptor, down regulation of cyclin D1 and enhancement of caspase activity. MCF-10A cells were merely slightly susceptible to TRAIL and ATRA. CONCLUSION: The cytostatic and cytotoxic effects of the combination of TRAIL and ATRA are tumor cell-selective. PMID- 29715088 TI - Application of Albumin-embedded Magnetic Nanoheaters for Release of Etoposide in Integrated Chemotherapy and Hyperthermia of U87-MG Glioma Cells. AB - BACKGROUND/AIM: Malignant gliomas remain refractory to several therapeutic approaches and the requirement for novel treatment modalities is critical to combat this disease. Etoposide is a topoisomerase-II inhibitor, which promotes DNA damage and apoptosis of cancer cells. In this study, we prepared albumin with embedded magnetic nanoparticles and etoposide for in vitro evaluation of combined hyperthermia and chemotherapy. MATERIAL AND METHODS: Magnetic nanoparticles were prepared by a modified co-precipitation method in the presence of human serum albumin and etoposide. A cellular proliferation assay was used to determine the effects of these nanostructures on the viability of U87 glioma cells in an alternating magnetic field. RESULTS: The in vitro experiments showed that cell viability decreased to 59.4% after heat treatment alone and to 53.8% on that with free etoposide, while combined treatment resulted in 7.8% cell viability. CONCLUSION: Integrating hyperthermia and chemotherapy using albumin co-embedded magnetic nanoheaters and etoposide may represent a promising therapeutic option for glioblastoma. PMID- 29715089 TI - Potent Antitumour Effects of Novel Pentabromobenzylisothioureas Studied on Human Glial-derived Tumour Cell Lines. AB - BACKGROUND/AIM: Tumours of astroglial origin are the most common primary brain malignancy characterized by infiltrative growth and resistance to standard antitumour therapy. Glioma progression is thought to be related to various intracellular signal transduction pathways that involve the activation of protein kinases. Protein kinases play important roles in cell differentiation, proliferation, and survival. Recently, novel, specific inhibitors of constitutively active serine/threonine kinases and structurally similar isothiourea derivatives were suggested to induce apoptosis and inhibit proliferation in several types of human cancer cells. MATERIALS AND METHODS: In this study, we examined the cytotoxic and proapoptotic activities of selected modified pentabromobenzyl isothioureas (ZKKs) in an adult human glioblastoma (T98G) and a subependymal giant cell astrocytoma cell (SEGA) line. We evaluated cell proliferation, viability, and apoptosis. RESULTS: Two pentabromobenzyl isothiourea bromide derivatives, ZKK-13 and N,N,N'-trimethyl-ZKK1 (TRIM), exhibited the most potent cytotoxic and proapoptotic efficacies against human glioma-derived cells, even at a very low concentration (1 MUM). ZKK-13 (25-50 MUM) inhibited cell growth by approximately 80-90% in 24 and 48 h of treatment. We showed that selected ZKKs exerted antiproliferative activity against astroglial neoplastic cells of both low- and high-grade tumour malignancy classes. No synergistic effects were detected when ZKKs were combined with serine/threonine kinase inhibitors. CONCLUSION: Our findings indicated that modified ZKKs show promise for the treatment of glioma-derived brain tumours. PMID- 29715090 TI - Radiation Gene-expression Signatures in Primary Breast Cancer Cells. AB - BACKGROUND/AIM: In breast cancer (BC) care, radiation therapy (RT) is an efficient treatment to control localized tumor. Radiobiological research is needed to understand molecular differences that affect radiosensitivity of different tumor subtypes and the response variability. The aim of this study was to analyze gene expression profiling (GEP) in primary BC cells following irradiation with doses of 9 Gy and 23 Gy delivered by intraoperative electron radiation therapy (IOERT) in order to define gene signatures of response to high doses of ionizing radiation. MATERIALS AND METHODS: We performed GEP by cDNA microarrays and evaluated cell survival after IOERT treatment in primary BC cell cultures. Real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) was performed to validate candidate genes. RESULTS: We showed, for the first time, a 4-gene and a 6-gene signature, as new molecular biomarkers, in two primary BC cell cultures after exposure at 9 Gy and 23 Gy respectively, for which we observed a significantly high survival rate. CONCLUSION: Gene signatures activated by different doses of ionizing radiation may predict response to RT and contribute to defining a personalized biological-driven treatment plan. PMID- 29715091 TI - Podoplanin Expression as a Prognostic Factor in Gastric Cancer. AB - BACKGROUND/AIM: Several recent studies have suggested that podoplanin (PDPN) expression correlates with malignant potential in various types of cancers. We investigated the expression pattern of PDPN and its clinical significance in gastric cancer. MATERIALS AND METHODS: We assessed the immunohistochemical expression of PDPN in 91 gastric cancer tissues of patients who underwent curative surgery and evaluated the relationship between the expression levels and clinicopathological factors. RESULTS: The tumor cells themselves revealed no expression of PDPN. However, PDPN was expressed in spindle-shaped stromal cells surrounding tumors in certain cases. PDPN-positive stromal cells significantly correlated with a larger tumor, advanced T- and N-stages, and lymphatic and vascular invasion. Multivariate analysis indicated that PDPN expression in spindle-shaped stromal cells (p=0.030) as well as N-stage (p=0.023) are independent prognostic factors. CONCLUSION: Our findings demonstrated the PDPN expression in spindle-shaped stromal cells of patients with gastric cancers has a prognostic significance. Intensive chemotherapy and close follow-up should be recommended for these patients. PMID- 29715092 TI - Tyrosine Kinase Inhibition in HPV-related Squamous Cell Carcinoma Reveals Beneficial Expression of cKIT and Src. AB - BACKGROUND/AIM: Therapeutic options of locally advanced or metastatic head and neck squamous cell carcinoma (HNSCC) are limited. Src and cKIT are key protein regulators for local tumor progression. The aim of the study was to investigate the therapeutic potential of targeted therapies in human squamous cell carcinoma (HNSCC) in vitro. Therefore, the influence of the selective tyrosine kinase inhibitors niotinib, dasatinib, erlotinib, gefitinib and afatinib on Src and cKIT expression in Human papilloma virus (HPV)-positive and HPV-negative squamous cancer cells (SCC) was analyzed in vitro. MATERIALS AND METHODS: ELISA was performed to evaluate the expression of Src and cKIT under the influence of nilotinib, dasatinib, erlotinib, gefitinib and afatinib (10 MUmol/l) in HPV negative and HPV-positive SCC (24-96 h of incubation). RESULTS: Gefitinib significantly increased cKIT expression in HPV-positive and HPV-negative cells whereas nilotinib and afatinib decreased cKIT expression in HPV-positive SCC. The influence of tyrosine kinase inhibitors in HPV-negative SCC was marginal. Surprisingly, Src expression was significantly increased by all tested tyrosine kinase inhibitors in HPV-positive SCC. CONCLUSION: The results revealed beneficial and unexpected information concerning the interaction of selective tyrosine kinase inhibitors and the tumor biology of HNSCC. PMID- 29715093 TI - Impact of the Lok-bar for High-precision Radiotherapy with Tomotherapy. AB - BACKGROUND/AIM: Patient immobilization systems are used to establish a reproducible patient position relative to the couch. In this study, the impact of conventional lok-bars for CT-simulation (CIVCO-bar) and treatment (iBEAM-bar) were compared with a novel lok-bar (mHM-bar) in tomotherapy. MATERIALS AND METHODS: Verification was obtained as follows: i. artifacts in CT images; ii. dose attenuation rate of lok-bar, compared to without lok-bar; and iii. dose differences between the calculated and measured absorbed doses. RESULTS: With the CIVCO-bar, there were obvious metal artifacts, while there were nearly no artifacts with the mHM-bar. The mean dose attenuation rates with the mHM-bar and iBEAM-bar were 1.31% and 2.28%, and the mean dose difference was 1.55% and 1.66% for mHM-bar and iBEAM-bar. CONCLUSION: Using the mHM-bar reduced artifacts on the CT image and improved dose attenuation are obtained. The lok-bar needs to be inserted as a structure set in treatment planning with tomotherapy. PMID- 29715094 TI - Combined Gemcitabine and Metronidazole Is a Promising Therapeutic Strategy for Cancer Stem-like Cholangiocarcinoma. AB - BACKGROUND/AIM: Metronidazole (MNZ) is a common antibiotic that exerts disulfiram like effects when taken together with alcohol. However, the relationship between MNZ and aldehyde dehydrogenase (ALDH) activity remains unclear. This study investigated whether MNZ reduces cancer stemness by suppressing ALDH activity and accordingly reducing the malignancy of cholangiocarcinoma (CCA). MATERIALS AND METHODS: We developed gemcitabine (GEM)-resistant TFK-1 cells and originally established CCA cell line from a patient with GEM-resistant CCA. Using these cell lines, we analyzed the impacts of MNZ for cancer stem cell markers, invasiveness, and chemosensitivity. RESULTS: MNZ reduced ALDH activity in GEM-resistant CCA cells, leading to decreased invasiveness and enhanced chemosensitivity. MNZ diminished the invasiveness by inducing mesenchymal-epithelial transition and enhancing chemosensitivity by increasing ENT1 (equilibrative nucleoside transporter 1) and reducing RRM1 (ribonucleotide reductase M1). CONCLUSION: MNZ reduced cancer stemness in GEM-resistant CCA cells. Combined GEM and MNZ would be a promising therapeutic strategy for cancer stem-like CAA. PMID- 29715096 TI - Moesin Involvement in Oral Carcinogenesis of the Lower Lip. AB - BACKGROUND/AIM: This study analyzed moesin immunoexpression in 91 lip squamous cell carcinomas and its influence in patients' prognosis. MATERIALS AND METHODS: Moesin immunoexpression was evaluated at the invasive tumor front by a semi quantitative score method. The association of moesin with the clinicopathological variables was analyzed by the Chi-square test, the survival rates were calculated by Kaplan-Meier and the survival curves compared using the log-rank test. RESULTS: The expression of moesin was strong at the invasive tumor front and weak/negative in differentiated cells such as keratin pearls. There was no association between moesin expression and the clinicopathological variables, but there was a tendency for patients with lip cancer and strong moesin expression to have lower 5- and 10-year overall and disease-free survival rates. CONCLUSION: Our results confirm the participation of moesin in oral carcinogenesis and suggest that this protein can influence the survival rates of patients with lip squamous cell carcinoma. PMID- 29715095 TI - The Immune Checkpoint Molecule CD200 Is Associated with Tumor Grading and Metastasis in Bladder Cancer. AB - BACKGROUND: We examined the expression of CD200, a ligand of immune tolerance, in transitional cell carcinoma of the human bladder (TCC). MATERIALS AND METHODS: CD200 was analyzed by immunohistochemistry (IHC) in 90 patients with suspected TCC lesions of the bladder. Expression of CD200 was exemplarily validated by quantitative reverse transcription polymerase chain reaction and western blot analysis. RESULTS: CD200 was detectable at mRNA and protein levels in TCC homogenate and TCC cell lines (T24, UMUC3). TCC tissues showed significantly higher CD200 expression (p<0.005) than normal bladder tissues. CD200 signals were also higher in metastasized compared to localized TCC (p<0.05). CD200 was significantly correlated to tumor grading (p<0.001) and was strongest in the subgroup with high-grade G2 TCC (vs. low-grade G2 p<0.05). CONCLUSION: This is the first report of CD200 expression in patients with TCC. The significant correlation between CD200 expression and tumor grading may suggest CD200 as a potential target and marker for immunotherapeutic approaches. PMID- 29715097 TI - Demethoxycurcumin Suppresses Migration and Invasion of Human Cervical Cancer HeLa Cells via Inhibition of NF-kappaB Pathways. AB - BACKGROUND/AIM: Demethoxycurcumin (DMC), one of the curcuminoids present in turmeric, has been shown to induce cell death in many human cancer cell lines, however, there has not been any investigation on whether DMC inhibits metastatic activity in human cervical cancer cells in vitro. In the present study, DMC at 2.5-15 MUM decreased cell number, thus, we used IC20 (7.5 MUM) for further investigation of its anti-metastatic activity in human cervical cancer HeLa cells. MATERIALS AND METHODS: The wound healing, migration, invasion, zymography, and western blotting assays were used to investigate the effects of DMC on HeLa cells. RESULTS: The wound healing assay was used to show that DMC suppressed cell movement of HeLa cells. Furthermore, the trans-well chamber assay was used to show that DMC suppressed HeLa cell migration and invasion. Gelatin zymography assay did not show any significant effects of DMC on the gelatinolytic activity (MMP-2 and -9) in conditioned media of HeLa cells treated by DMC. Western blotting showed that DMC significantly reduced protein levels of GRB2, MMP-2, ERK1/2, N-cadherin and Ras but increased the levels of E-cadherin and NF-kappaB in HeLa cells. Confocal laser microscopy indicated that DMC increased NF-kappaB in HeLa cells confirming the results from Western blotting. CONCLUSION: DMC may be used as a novel anti-metastatic agent for the treatment of human cervical cancer in the future. PMID- 29715098 TI - The Combination of Flavokawain B and Daunorubicin Induces Apoptosis in Human Myeloid Leukemic Cells by Modifying NF-kappaB. AB - BACKGROUND/AIM: Flavokawain B (FKB), is a natural chalcone isolated from kava root that induces apoptosis in cancer cells. Herein we investigated the effects of combination of FKB and daunorubicin (DNR) on human leukemic cells. MATERIALS AND METHODS: Cell viability and death were assessed by the MTS assay and flow cytometry. NK-kappaB was detected by western blotting. RESULTS: FKB alone and in combination with DNR reduced the viable cell numbers of four leukemic cell lines. FKB itself induced apoptosis of an acute myeloid cell line, HL-60. Because the additive effect of DNR and FKB was most obvious in HL-60 cells, subsequent experiments were performed with HL-60 cells. Combined treatment of the two compounds increased NF-kappaB activation at 12 h. CONCLUSION: A combination treatment of DNR and FKB may improve the anticancer effects of DNR in DNR resistant acute myeloid leukemia. PMID- 29715099 TI - Clinicopathological Characteristics and KRAS Mutation Status of Endometrial Mucinous Metaplasia and Carcinoma. AB - BACKGROUND/AIM: Mucinous metaplasia of the endometrium occurs as a spectrum of epithelial alterations ranging from the formation of simple, tubular glands to architecturally complex glandular proliferation with intraglandular papillary projection and cellular tufts. Endometrial mucinous metaplasia often presents a diagnostic challenge in endometrial curettage. MATERIALS AND METHODS: We analyzed the clinicopathological characteristics and the mutation status for V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) of 11 cases of endometrial mucinous metaplasia. Electronic medical record review and histopathological examination were performed. KRAS mutation status was analyzed using a pyrosequencing technique. RESULTS: Cases were classified histopathologically into simple (5/11) or papillary (6/11) mucinous metaplasias. All (6/6) papillary mucinous metaplasias were associated with atypical hyperplasia/endometrioid intraepithelial neoplasia (AH/EIN; 1/6) or carcinoma (5/6), whereas in a single patient with simple mucinous metaplasia, grade 1 endometrioid carcinoma was incidentally detected. The difference in frequency of association of the metaplasia with AH/EIN or carcinoma was significant (p=0.015). KRAS mutations were identified in five out of six cases of papillary mucinous metaplasias, comprising three cases with G12D and two with G12V mutations; the frequency of KRAS mutation was significantly higher (p=0.015) than in cases of simple mucinous metaplasia (0/5). CONCLUSION: Papillary mucinous metaplasia is frequently associated with endometrial neoplastic lesions. The high incidence of KRAS mutations in papillary mucinous metaplasia suggests that papillary mucinous metaplasia may be a precancerous lesion of a certain subset of mucinous carcinomas of the endometrium. PMID- 29715100 TI - Expression of Zinc Finger and BTB Domain-containing 7A in Colorectal Carcinoma. AB - BACKGROUND/AIM: Previous studies have revealed that zinc finger and BTB domain containing 7A (ZBTB7A), an important proto-oncogene, plays multiple roles in carcinogenesis and is up-regulated in several human malignancies. However, the expression of ZBTB7A in colorectal carcinoma (CRC) has seldom been documented. In this study, we investigated the differential expression of ZBTB7A in CRC cell lines and tissues. MATERIALS AND METHODS: Expression levels of ZBTB7A mRNA and protein were examined in CRC cell lines. ZBTB7A protein expression was also evaluated in tissue samples of normal colonic mucosa, high-grade dysplasia, and CRC using immunohistochemical staining. RESULTS: All CRC cell lines exhibited significantly higher ZBTB7A mRNA expression levels than did normal colonic epithelial cells. The ZBTB7A protein expression levels were clearly higher in the CRC cell lines than in the normal colonic epithelial cells. Consistent with the cell line data, immunostaining revealed that there were significant differences in ZBTB7A protein expression between tissue samples of CRC and normal colonic mucosa (p=0.048) and high-grade dysplasia (p=0.015). In addition, metastatic CRC exhibited significantly higher ZBTB7A protein expression levels than primary CRC (p=0.027). CONCLUSION: We demonstrated that ZBTB7A expression is up-regulated in CRC cell lines and tissues. Our data suggest that ZBTB7A is involved in the development and progression of CRC. PMID- 29715101 TI - Identification of Functional Thyroid Stimulating Hormone Receptor and TSHR Gene Mutations in Hepatocellular Carcinoma. AB - BACKGROUND/AIM: Extra-thyroid expression of thyroid stimulating hormone (TSH) receptor (TSHR) has been reported in normal liver tissues, but never assessed in hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Paired cancerous and non cancerous HCC tissues were analyzed with TSHR expression assays. TSHR functional assessments and sequence analysis for the TSHR exon-10 were performed. RESULTS: TSHR overexpression was found in 150/197 (76.1%) HCCs. Higher TSHR expression was associated with unfavorable postoperative outcomes. Immunohistochemical analysis revealed predominantly nuclei/peri-nuclei localization of TSHR in cancerous tissues but cell membrane localization in non-cancerous parts. TSH stimulation on hepatoma cells resulted in increased cyclic adenosine monophosphate levels with altered cell sensitivity to cisplatin. Gene mutations leading to TSHR truncation were detected in 8/81 (9.9%) HCC tissues. CONCLUSION: Overexpression of TSHR was found in a great majority of HCC tissues and associated with unfavorable prognosis. Cell-based experiments and gene mutation analysis suggested that TSHR in HCCs was functional. PMID- 29715102 TI - Pharmacokinetics, Biodistribution, and Toxicity Evaluation of Anti-SEMA3A (F11) in In Vivo Models. AB - BACKGROUND/AIM: The aim of our study was to investigate the pharmacokinetics (PK), tissue distribution and toxicity of F11 antibody to semaphorin 3A in mouse models and explore its anti-angiogenic and tumor-inhibitory effect. MATERIALS AND METHODS: Patient-derived xenograft (PDX) models were established via subcutaneous implantation of glioblastoma multiforme (GBM) cells and treated with F11. RESULTS: F11 significantly attenuated tumor growth and angiogenesis in the GBM PDX model. Within the range of administered doses, the PK of F11 in serum demonstrated a linear fashion, consistent with general PK profiles of soluble antigen-targeting antibodies. Additionally, the clearance level was detected at between 4.63 and 7.12 ml/d/kg, while the biological half-life was measured at 6.9 and 9.4 days. Tissue distribution of F11 in kidney, liver and heart was consistent with previously reported antibody patterns. However, the presence of F11 in the brain was an interesting finding. CONCLUSION: Collectively, our results revealed angiogenic and tumor-inhibitory effect of F11 antibody and its potential therapeutic use within a clinical framework based on PK, biodistribution and toxicity evaluation in mouse models. PMID- 29715103 TI - Bidirectional Regulation of COX-2 Expression Between Cancer Cells and Macrophages. AB - BACKGROUND/AIM: Our aim was to investigate the crosstalk between tumor and immune cells (M2 macrophages) and its effects on cyclo-oxygenase-2 (COX2) regulation in canine mammary tumors (CMT). MATERIALS AND METHODS: Sh1b CMT cells and human BT474 mammary or HT29 colon cancer cells were co-cultured with canine peripheral blood mononuclear cells (PBMCs) or with macrophage-like differentiated THP1 monocytes (dTHP1). Intracellular COX2 expression by PBMCs, dTHP1 and cancer cells was evaluated by flow cytometry. RESULTS: Co-culturing of Sh1b and canine PBMCs induced COX2 overexpression in CMT cells. In turn, COX2 expression by PBMCs, mostly CD68+ macrophages, was attenuated by co-culture with Sh1b (p=0.0001). In accordance, co-culture with dTHP1 prompted intracellular production of COX2 in both Sh1b CMT cells and HT29 human colon cancer cells and reduced production of COX2 in BT474 human mammary cancer cells. The intracellular COX2 expression from dTHP1 decreased when treated with conditioned medium from cultured Sh1b and HT29 cancer cells. CONCLUSION: Bidirectional COX2 regulation between cancer and monocytes/macrophages might shape a tolerogenic tumor microenvironment in CMT. PMID- 29715104 TI - Hypermethylation of BRCA1 Gene in Meningioma in Elderly Males. AB - BACKGROUND/AIM: Breast cancer 1, early onset (BRCA1) gene is expressed in the cells of the breast and other tissues, where it plays a role in cell-cycle regulation, transcription, repair of DNA double-stranded breaks, ubiquitination, transcriptional regulation as well as other functions, such as cell response regulation to mitogenic signals triggered by estrogens. Considering that meningioma shows greater tumor growth during pregnancy, can express estrogen receptors and proliferate in response to estrogenic stimulation, the hypothesis that this type of tumor may share molecular mechanisms that involve exposure to estrogen should be investigated. Therefore, the aim of the present study was to investigate the BRCA1 gene methylation profile in meningioma. MATERIALS AND METHODS: Methylation-specific polymerase chain reaction (PCR) assay was performed on 50 meningioma samples from male and female patients. Statistical analysis was carried out using Fisher's exact test. RESULTS: The most important finding of this study was that 100% of the male patients over 55 years with meningioma showed BRCA1 methylated in their tumor cells. CONCLUSION: The silencing of BRCA1 through hypermethylation seems to play an important role in meningioma. PMID- 29715105 TI - Preparation and In Vitro and In Vivo Characterization of the Tumor-specific Antigen-derived Peptide as a Potential Candidate for Targeting Human Epidermal Growth Factor Receptor 2-positive Breast Carcinomas. AB - BACKGROUND/AIM: The human epidermal growth factor receptor (HER2) is considered as one of the most well-characterized tumor-associated antigens for cancer therapy and plays an important role in the growth and progression of breast cancer. Overexpression of HER2 in various cancers and the availability of its extracellular region makes it a clinically useful target for the development of tumor-antigen specific agents. In this study, we have prepared a HER2-targeted hybrid peptide as a single-photon emission computed tomography (SPECT) imaging probe and evaluated its tumor targeting potential in subcutaneous HER2-positive breast cancer xenograft models. MATERIALS AND METHODS: The HER2-targeted hybrid peptide was prepared by solid-phase peptide synthesis and radiolabeled with 99mTc by the ligand exchange method. In vitro tumor cell binding properties of 99mTc HER2 were evaluated in HER2-positive (SKBR3) and ER-positive (MCF7 and T47D) breast cancer cell lines. In vivo tumor targeting characteristics were investigated in both SKBR3 (HER2-positive) and MDA-MB-231 (HER2-negative) xenografted animal models. RESULTS: A high labeling efficiency of greater than 95% was achieved when HER2 peptide was radiolabeled with 99mTc by the standard ligand exchange method. 99mTc-HER2 displayed a high binding affinity (Kd=49.95+/ 14.11 nM) to HER2-positive SKBR3 cell line whereas in the case of the ER-positive cell lines (MCF-7 and T47D), the binding affinity was found to be 2-3-fold lower than SKBR3. In vivo tumor uptake in nude mice with SKBR3 tumor xenografts was 2.81+/-0.79% ID/g as early as 60 min p.i. The uptake in SKBR3 tumors was always higher than the uptake in the blood and muscle, with good tumor-to-blood and tumor-to-muscle ratios. In contrast, low accumulation in ER-positive tumors (MCF7 and T47D) was observed compared to HER2-positive SKBR3 tumor mice. A low to moderate (less than 5% ID/g) accumulation and retention of 99mTc-HER2 was found in most of the major organs excluding the kidneys in both healthy and tumor bearing mice. CONCLUSION: In view of its ability to detect HER2-positive breast cancer cells in vivo, 99mTc-HER2-targeted peptide may be a promising tumor imaging probe and warrants further investigation. PMID- 29715106 TI - 3D Culture Represents Apoptosis Induced by Trastuzumab Better than 2D Monolayer Culture. AB - BACKGROUND: Our hypothesis was that three-dimensional (3D) culture better represents differential in vivo responses to trastuzumab between PIK3CA-wild-type (wt) and mutant (mt) cell lines than does two-dimensional (2D) culture. MATERIALS AND METHODS: Apoptosis and cell signaling proteins were evaluated in response to trastuzumab with and without BKM120, a pan-phosphatidylinositol 3-kinase (PI3K) inhibitor, using western blot analysis of four breast cancer cell lines with human epidermal growth factor receptor 2 (HER2) amplification. RESULTS: Increased expression of cleaved poly (ADP-ribose) polymerase (PARP) was observed only in 3D cultured PIK3CA-wt lines in response to trastuzumab, but not in 2D-cultured PIK3CA-wt or PIK3CA-mt lines. Decrease in the ratio of phosphorylated (p-)AKT to AKT in response to trastuzumab was more profound in PIK3CA-wt cells than in PIK3CA-mt cells in 3D culture, while the difference between PIK3CA genotypes was less apparent in 2D culture. Treatment with BKM120 and trastuzumab resulted in a stronger increase in cleaved PARP than either treatment alone. CONCLUSION: 3D Culture appears to better represent trastuzumab-induced apoptosis and resistance to trastuzumab associated with PIK3CA mutation. PMID- 29715107 TI - Analysis of MSH2 Loss of Heterozygosity, Expression, and IVS10+12G>A Polymorphism in Sporadic Colon Cancer. AB - BACKGROUND: mutS homolog 2 (MSH2) deficiency may be involved in the development of microsatellite instability found in certain sporadic colorectal tumors. In addition to mutations or loss of heterozygosity resulting in complete loss of MSH2 function, polymorphisms affecting MSH2 expression have been also identified. Therefore, the aim of this study was to examine MSH2 status in sporadic colon cancer. MATERIALS AND METHODS: MSH2 status was examined at the DNA, RNA and protein levels through loss of heterozygosity (LOH) analysis, quantitative real time PCR and immunohistochemistry. MSH2 IVS10+12A>G polymorphism was examined by real-time single nucleotide polymorphism genotyping. RESULTS: MSH2 LOH was more frequent in tumors larger than 5 cm (p=0.032), mRNA expression was also significantly lower and the same expression pattern was present in the corresponding normal mucosa of the same patient (p=0.013 and p=0.008, respectively). No association was found between IVS10+12A>G polymorphism and susceptibility to sporadic colon cancer. CONCLUSION: Altered MSH2 expression detected in sporadic colon tumors pointing to its role in colorectal tumorigenesis without a hereditary component. PMID- 29715108 TI - 2-Phenylnaphthyridin-4-one Derivative LYF-11 Inhibits Interleukin-6-mediated Epithelial-to-Mesenchymal Transition via the Inhibition of JAK2/STAT3 Signaling Pathway in MCF-7 Cells. AB - BACKGROUND/AIM: Breast tumor interleukin-6 (IL-6) level increases with tumor grade, and elevated serum IL-6 correlates with poor survival in patients with breast cancer. Epithelial-mesenchymal transition (EMT) phenotypes are associated with enhanced metastasis and unfavorable clinical outcome in breast cancer. Therefore, we examined whether IL-6 induced EMT phenotype characterized in breast cancer cells. MATERIALS AND METHODS: MCF-7 cells treated with different concentrations (10-50 ng/ml) of IL-6 for 24 and 48 h. Western blotting, flow cytometry, and cell migration assay were used to test whether IL-6 promoted tumor initiating ability in MCF-7 cells. RESULTS: In this study, we found that the induction of EMT by IL-6 resulted in the acquisition of mesenchymal traits and the increase of tumor-initiating ability in MCF-7 cells. Moreover, we found that 2-phenylnaphthy-ridin-4-one derivatives were able to repress IL-6 induced EMT phenotype and tumor-initiating ability. Among these deriveratives, LYF-11 possessed the most potential inhibitory activity. LYF-11 effectively inhibited IL 6-induced EMT phenotype and tumor-initiating ability via the inhibition of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway. CONCLUSION: Our results suggest a connection between IL-6 receptor activity and EMT phenotype, and tumor-initiating ability. Moreover, LYF 11 is a potential compound for breast cancer therapy by targeting JAK2/STAT3 signaling pathway. PMID- 29715109 TI - Fatty Acids of CLA-enriched Egg Yolks Can Induce Mitochondrial Pathway of Apoptosis in MCF-7 Breast Cancer Cells. AB - BACKGROUND: Fatty acids from conjugated linoleic acid (CLA)-enriched egg yolk suppressed the viability of the MCF-7 cancer line more effectively than non enriched egg yolk. Herein we aimed to determine the molecular mechanisms by analysing the expression and activation of proteins involved in cellular stress and apoptosis signaling. MATERIALS AND METHODS: Forty-eight Isa Brown laying hens (26-week-old) were fed a fortified (0.75% CLA) or a control diet (0% CLA) for 4 months. Collected eggs were used to obtain CLA-enriched (EFA-CLA) or non-enriched (EFA) fatty acid extracts for the treatment of the MCF-7 cancer cell line. Protein levels were analysed by PathScan(r) Stress and Apoptosis Signalling Antibody Array and western blot method. RESULTS: Treatment with EFA-CLA led to activation of caspase signalling as main effector of apoptosis. It also increased levels of pro-apoptotic B-cell lymphoma 2 family proteins as well as promoted the release of cytochrome c, second mitochondria-derived activator of caspase and mitochondrial serine protease from mitochondria to the cytoplasm. EFA-CLA increased levels of tumour protein 53 and mothers against decapentaplegic homolog 2 tumour suppressors, and activated p38 mitogen-activated protein kinases and stress-activated protein kinase/c-Jun NH2-terminal kinase proteins. Finally, treatment down-regulated anti-apoptotic extracellular signal-regulated protein kinases 1 and 2, RAC-alpha serine/threonine-protein kinase, heat-shock protein 27, inhibitor of nuclear factor kappabeta, transforming growth factor beta activated kinase 1 and survivin proteins. CONCLUSION: Taken together, our results suggest that activation of the mitochondrial apoptotic pathway may be a potential mechanism of EFA-CLA action. PMID- 29715110 TI - Human Polyomaviruses Are Not Frequently Present in Cancer of the Salivary Glands. AB - BACKGROUND/AIM: Malignant tumors of the salivary glands are rare and heterogeneous, with more than 20 subtypes, and classified mainly by histopathology. Their diagnosis is often challenging and their etiology unknown. Here, the possible association between human polyomaviruses (PyVs) and one or more salivary gland tumor subtypes was examined. MATERIALS AND METHODS: Ninety one primary tumors, including 12 subtypes and eight corresponding metastases, were analyzed for the presence of DNA of 10 different human PyV species by a bead based multiplex assay using polymerase chain reaction and Luminex analyses. RESULTS: Three samples, one adenocarcinoma (not otherwise specified), one adenoid cystic carcinoma, and one mucoepidermoid carcinoma were found to be positive. However, the amount of MCPyV DNA in these tumors was estimated to be less than one genome per tumor cell. CONCLUSION: The analysis of DNA from 10 human PyVs in a large number of malignant salivary gland cancers did not implicate any of these human PyVs as an important causative agent in any of the 12 subtypes studied. PMID- 29715111 TI - Chemotherapy or Combined Modality Therapy for Early-stage Hodgkin Lymphoma. AB - BACKGROUND/AIM: Optimizing treatment of early-stage Hodgkin lymphoma (HL) requires balancing cure with potential acute and late toxicities from treatment. We reviewed our institutional experience with chemotherapy alone (ChT) versus combined modality therapy (CMT). MATERIALS AND METHODS: Patients with stage I-II classical HL in a complete response (CR) by functional imaging after chemotherapy were included. Progression-free survival (PFS) and overall survival (OS) were calculated and a multivariate analysis (MVA) was performed. RESULTS: A total of 136 patients with a CR to chemotherapy were identified. Consolidation radiation therapy (RT) was administered to 117 while 19 received no further therapy. PFS (5 years) was 97% with CMT and 84% with chemotherapy alone (p=0.02). Long-term (10 year) survival was no different (96 vs. 94%, p=0.8). On MVA, CMT improved PFS. Secondary malignancies were rare and no cardiac events were observed. CONCLUSION: Consolidation RT results in superior PFS in early-stage Hodgkin lymphoma with minimal added toxicity. PMID- 29715112 TI - Low-dose LNG-IUS as Therapy for Endometrial Hyperplasia. A Prospective Cohort Pilot Study. AB - BACKGROUND/AIM: Progestin therapy has been accepted as therapy for low- and medium-risk endometrial hyperplasia. The aim of this study was to investigate the efficacy of the low-dose levonorgestrel-impregnated intrauterine system (LNG-IUS) 13.5 mg (Jaydess(r), Bayer Pharmaceuticals, Berlin, Germany) as therapy for endometrial hyperplasia. PATIENTS AND METHODS: A total of 21 women with histologically-verified endometrial hyperplasia were prospectively treated with LNG-IUS Jaydess. Therapy duration was 6 months (n=16) or 3-6 weeks (n=5) depending on individual risk (low- and medium-risk versus high-risk) for co existent or future endometrial carcinoma. Paired endometrial biopsies were sampled prior to and after therapy and classified according to the WHO94 classification system and D-score. RESULTS: All women with low- and medium risk endometrial hyperplasia had-therapy response. In the group of women with high risk endometrial hyperplasia only 40% (two out of five) obtained a therapy response. CONCLUSION: Low-dose LNG-IUS Jaydess was proven to be an excellent therapy option for low- and medium-risk endometrial hyperplasia. For patients with high-risk endometrial hyperplasia hysterectomy or LNG-IUS therapy under close surveillance is advised. PMID- 29715114 TI - Disparities of Immunotherapy Utilization in Patients with Stage III Cutaneous Melanoma: A National Perspective. AB - BACKGROUND/AIM: Immunotherapy combined with surgery is associated with better survival than surgery alone in patients with advanced melanoma. This study examined the utilization of immunotherapy in relation to population characteristics and the associated survival benefit. MATERIALS AND METHODS: This was a retrospective cohort study utilizing the US National Cancer Database. The study population included 6,165 adult patients (>=18 years) with stage III cutaneous melanoma (median follow-up=32 months). RESULTS: A total of 1,854 patients underwent immunotherapy in addition to surgery, which was associated with a survival benefit over surgery alone (hazard ratio(HR)=0.66, 95% confidence interval(CI)=0.56-0.77, p<0.001). Older age, presence of comorbidities, Medicaid/Medicare insurance, and living in a community with lower average education level were associated with less immunotherapy utilization (all p<0.05). No statistically significant racial disparity in immunotherapy usage was found (p=0.07). CONCLUSION: Compared to other demographic factors, insurance status was associated with the greatest disparities in immunotherapy utilization and mortality for patients who underwent surgery for advanced melanoma. PMID- 29715113 TI - Double KRAS and BRAF Mutations in Surgically Treated Colorectal Cancer Liver Metastases: An International, Multi-institutional Case Series. AB - BACKGROUND: While previously believed to be mutually exclusive, concomitant mutation of Kirsten rat sarcoma viral oncogene homolog (KRAS)- and V-raf murine sarcoma b-viral oncogene homolog B1 (BRAF)-mutated colorectal carcinoma (CRC), has been described in rare instances and been associated with advanced-stage disease. The present case series is the first to report on the implications of concurrent KRAS/BRAF mutations among surgically treated patients, and the largest set of patients with surgically treated colorectal liver metastasis (CRLM) and data on KRAS/BRAF mutational status thus far described. CASE SERIES: We present cases from an international, multi-institutional cohort of patients that underwent hepatic resection for CRLM between 2000-2015 at seven tertiary centers. The incidence of KRAS/BRAF mutation in patients with CRLM was 0.5% (4/820). Of these cases, patient 1 (T2N1 primary, G13D/V600E), patient 2 (T3N1 primary, G12V/V600E) and patient 3 (T4N2 primary, G13D/D594N) succumbed to their disease within 485, 236 and 79 days respectively, post-hepatic resection. Patient 4 (T4 primary, G12S/G469S) was alive 416 days after hepatic resection. CONCLUSION: The present case series suggests that the incidence of concomitant KRAS/BRAF mutations in surgical cohorts may be higher than previously hypothesized, and associated with more variable survival outcomes than expected. PMID- 29715115 TI - Preoperative Pulmonary Function Tests (PFTs) and Outcomes from Resected Early Stage Non-small Cell Lung Cancer (NSCLC). AB - BACKGROUND: Preoperative pulmonary function tests (PFTs) predict operative morbidity and mortality after resection in lung cancer. However, the impact of preoperative PFTs on overall outcomes in surgically-resected stage I and II non small cell lung cancer (NSCLC) has not been well studied. PATIENTS AND METHODS: This is a retrospective study of 149 patients who underwent surgical resection as first-line treatment for stage I and II NSCLC at a single center between 2003 and 2014. PFTs [forced expiratory volume in 1 sec (FEV1), Diffusing Capacity (DLCO)], both absolute values and percent predicted values were categorized into quartiles. The Kaplan-Meier method and Cox regression analysis were used to determine whether PFTs predicted for overall survival (OS). Logistic regression was used to estimate the risk of postoperative complications and length of stay (LOS) greater than 10 days based on the results of PFTs. RESULTS: The median age of the cohort was 68 years. The cohort was predominantly males (98.6%), current or ex-smokers (98%), with stage I NSCLC (82.76%). The majority of patients underwent a lobectomy (n=121, 81.21%). The predominant tumor histology was adenocarcinoma (n=70, 47%) followed by squamous cell carcinoma (n=61, 41%). The median follow-up of surviving patients was 53.2 months. DLCO was found to be a significant predictor of OS (HR=0.93, 95% CI=0.87-0.99; p=0.03) on univariate analysis. Although PFTs did not predict for postoperative complications, worse PFTs were significant predictors of length of stay >10 days. CONCLUSION: Preoperative PFTs did not predict for survival from resected early-stage NSCLC, but did predict for prolonged hospital stay following surgery. PMID- 29715116 TI - First French Pilot Quality Assessment of the EndoPredict Test for Early Luminal Breast Carcinoma. AB - BACKGROUND/AIM: Genomic signatures are needed for the determination of prognosis in patients with early stage, estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancers. EndoPredict test is a RNA-based multigene assay that assesses the risk of 10-year relapse in this context. Quality assessment is a mandatory requirement for a laboratory to address the analytical quality of these molecular analyses. The aim of the study was to demonstrate the robustness of this prognostic test, its usefulness for the patient's treatment strategy, at the national level. MATERIALS AND METHODS: This study presents a pilot quality assessment (QA) of the EndoPredict test using composite design, including the follow-up of internal control values (qREF) of the 12 genes of the assay for 151 independent tests and one formalin-fixed paraffin embedded (FFPE) breast cancer sample. The evaluation of the test was performed by comparing the results of six independent medical laboratories. RESULTS: All measures were highly reproducible and quantification of the qREF showed a standard deviation of less than 0.50 and a coefficient of variation always of <2%. All laboratories found concordant results for the breast cancer samples. The mean EndoPredict (EP) score for the breast cancer sample was 4.97+/ 0.24. The mean of EPclin score was 3.07+/-0.05. CONCLUSION: This first French independent reported QA assessed the robustness and reproducibility of the EndoPredict test. Such a simple composite design could represent an adapted QA for an expensive diagnostic test. PMID- 29715117 TI - Micropapillary Structures in Colorectal Cancer: An Anoikis-resistant Subpopulation. AB - BACKGROUND/AIM: Micropapillary structures (MIPs) are focal piles of columnar cells without extracellular matrix contact, and common in serrated colorectal carcinoma (CRC). In order to characterize biology of MIPs in colorectal cancer (CRC), the proliferation and apoptosis rates, and survivin expression were compared between MIPs and other cancer epithelial cells of CRC (non-MIPs). MATERIALS AND METHODS: We assessed 46 samples of normal colorectal mucosa, 62 carcinomas and 54 polyps for proliferation (Ki67), apoptosis (M30), and survivin expression by immunohistochemistry. RESULTS: MIPs in carcinoma showed lower rates of proliferation and apoptosis than non-MIPs. A low rate of apotosis in MIPs was associated with poor prognosis in local carcinoma. In normal crypts, nuclear-to cytoplasmic transition of survivin indicated epithelial cell maturation. Cancer cases showed increased cytoplasmic expression of survivin than normal mucosa and polyps. However, MIPs showed lower nuclear and cytoplasmic survivin expression than non-MIPs. Our findings suggest that MIPs represent a biologically distinct subpopulation of carcinoma cells with features of anoikis resistance and possibly quiescence. PMID- 29715118 TI - Utilization of Neoadjuvant Intensity-modulated Radiation Therapy for Rectal Cancer in the United States. AB - BACKGROUND/AIM: Advances in technology have expanded the use of intensity modulated radiotherapy (IMRT). The goal of this study was to investigate trends in the utilization of IMRT for rectal cancer (RC) in USA. MATERIALS AND METHODS: The National Cancer Database was queried for RC patients receiving neoadjuvant chemoradiotherapy with either IMRT or three-dimensional conformal radiation therapy (3DCRT). Differences in factors associated with receipt of 3DCRT versus IMRT were determined and temporal trends were analyzed. RESULTS: From 2005 to 2009, IMRT utilization increased, but remained constant and roughly equivalent to 3DCRT from 2010 to 2014. Patients who received IMRT were more likely to have T4 disease (p=0.014), while patients diagnosed in 2004-2006 (p<0.0001) and 2007-2008 (p=0.015) were less likely to receive IMRT. There were no significant differences in postoperative outcomes between patients receiving 3DCRT and IMRT. CONCLUSION: IMRT utilization initially increased, but is now used at similar frequencies to 3DCRT and offers similar short-term postoperative outcomes. PMID- 29715119 TI - Eribulin Promotes Antitumor Immune Responses in Patients with Locally Advanced or Metastatic Breast Cancer. AB - BACKGROUND/AIM: Several proteins involved in immune regulation and the relationship among these, the tumor microenvironment, and clinical outcomes of eribulin treatment were evaluated in advanced or metastatic breast cancer patients. PATIENTS AND METHODS: This retrospective cohort study comprised 52 eribulin-treated locally advanced or metastatic breast cancer patients. Cancer tissue samples were obtained before and after treatment in 10 patients. Immunohistochemistry was performed to determine programmed death (PD)-1, CD8, and forkhead box P3 (FOXP3) expression by stromal tumor-infiltrating lymphocytes, and PD-ligand (L1) and PD-L2 expression by cancer cells. RESULTS: Of the 10 patients, 5 were responders (partial response) and 5 were non-responders (stable disease, 2; progressive disease, 3) to eribulin. PD-1, PD-L2, and FOXP3 expression became negative in 5 patients, PD-L1 expression became negative in 6 patients, and CD8 expression became positive in 3 patients after treatment. The response to eribulin was significantly associated with PD-L1 and FOXP3 negative conversion (p=0.024 and 0.004, respectively). The change in E-cadherin expression (positive or negative) was also correlated with the changes in PD-L1 and FOXP3 (p=0.024 and 0.004, respectively). Kaplan-Meier analysis with log-rank tests revealed that progression-free survival and time-to-treatment failure were significantly longer in patients with PD-L1 and FOXP3 negative conversion (p=0.012 and 0.001; p=0.049 and 0.018, respectively). CONCLUSION: The efficacy of eribulin may be attributed to its biological effects on the immune system (reduction of PD-L1 and FOXP3 expression) through epithelial-mesenchymal transition suppression, and vascular remodeling and improvement of the tumor microenvironment. PMID- 29715120 TI - Single-stranded DNA (ssDNA) Labeling Index Is Related to Risk Grade in Patients with Gastrointestinal Stromal Tumors. AB - BACKGROUND/AIM: The main objective of the present study was to evaluate the significance of apoptosis in the Fletcher's risk classification for gastrointestinal stromal tumors (GISTs). MATERIALS AND METHODS: Apoptotic cells were identified by immunostaining for single-stranded DNA (ssDNA). We assigned each GIST to one of four risk groups: very low risk, n=32; low risk, n=53; intermediate risk, n=15; high risk, n=6). RESULTS: The mean ssDNA labeling index for each group was 8.0+/-44.2, 20.1+/-86.5, 18.7+/-38.6 and 5.7+/-5.7, respectively. Fletcher's risk classification for GISTs correlated significantly with the ssDNA labeling index (p=0.002). CONCLUSION: The ssDNA labeling index and Ki-67 labeling index were the most significant factors corresponding to the risk grade of GISTs. These findings suggest that the ssDNA labeling index might be useful for predicting aggressive biological behavior of GISTs. PMID- 29715121 TI - Correlation Between Ktrans and Microvessel Density in Different Tumors: A Meta analysis. AB - BACKGROUND/AIM: Dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) is a technique based on the measurement of the signal intensity of the investigated tissue before, during, and after administration of an intravenous contrast agent. DCE MRI parameters can reflect tumor angiogenesis and, therefore, can provide information about tumor behavior. The purpose of this meta-analysis was to analyze the reported data regarding associations between Ktrans (volume transfer constant) and microvessel density (MVD) in different tumors. PATIENTS AND METHODS: For this meta-analysis the MEDLINE library was screened for associations between Ktrans and MVD in different tumors up to July 2017. After thorough reviewing, the present analysis included 16 studies. The following data were extracted from the literature: authors, year of publication, number of patients, tumor type, MR scanners, study design, and correlation coefficients. RESULTS: The identified correlation coefficients ranged from -0.65 to 0.75. The calculated pooled correlation coefficient was 0.23 (95%CI=0.07-0.38). Furthermore, correlation coefficients for every tumor entity were calculated: rectal cancer: rho=-0.07 (95%CI=-0.56-0.43); prostatic cancer: rho=0.08 (95%CI=-0.06-0.23); glioma: rho=0.70 (95%CI=0.64-0.75). CONCLUSION: Our meta-analysis showed different correlations between Ktrans and MVD in several tumors. PMID- 29715122 TI - Postoperative Hypofractionated Radiotherapy for Prostate Cancer. AB - AIM: To retrospectively investigate outcomes, and acute and late complications following postoperative hypofractionated 3D conformal radiotherapy. PATIENTS AND METHODS: Sixty-nine consecutive patients underwent radical prostatectomy. Radiotherapy was delivered to the prostatic fossa by means of a7-fieldLINACwith 6 15 MV to a total dose of 62.5 Gy in 25 fractions (2.5 Gy per fraction) in five consecutive weeks. RESULTS: Median follow-up was 54.7 months (range=38-76 months). Five-year overall survival, metastasis-free survival and biochemical relapse-free survival were 91.1%, 84.6% and 66.7%, respectively. Grade 2 or more genitourinary and gastrointestinal acute toxicity was reported in 12% and 5% of patients, respectively. Urinary incontinence grade 2 or more was recorded in 19%. CONCLUSION: Postoperative radiotherapy either in the adjuvant or salvage setting resulted in acceptable rates of acute and late toxicity with good tumor control while reducing overall treatment time. Confirmatory results from an ongoing prospective trial are awaited. PMID- 29715123 TI - Takotsubo Cardiomyopathy Developed After Two-stage Surgery for Double Primary Lung Cancer. AB - Takotsubo cardiomyopathy (TC) is a syndrome characterized by transient local systolic dysfunction of the left ventricle with no evidence of coronary artery disease or acute plaque rupture. We present the case of 71-year-old woman who developed TC after two-stage surgery for double primary lung cancer. On computed tomography, lung nodules were identified in the left upper and right middle lobes. Based on the diagnosis of double primary lung cancer, we performed two stage surgery (left upper lobectomy followed by right middle lobectomy). One day after the second surgery, respiratory failure developed. Electrocardiography showed ST segment elevation, serum troponin levels were elevated, and chest x-ray showed acute pulmonary edema. Cardiac catheterization showed no coronary artery disease and apical akinesia. Based on these findings, we diagnosed TC and the patient recovered with supportive treatment. PMID- 29715124 TI - Candidate MicroRNA Biomarkers of Therapeutic Response to Sunitinib in Metastatic Renal Cell Carcinoma: A Validation Study in Patients with Extremely Good and Poor Response. AB - BACKGROUND/AIM: Targeted therapy with the tyrosine kinase inhibitor sunitinib is used in the first line of metastatic renal cell carcinoma (mRCC) treatment. The aim of the present study was independent validation of microRNAs (miRNAs) identified in previous studies as biomarkers predicting response to sunitinib therapy. MATERIALS AND METHODS: Based on a literature search, 10 miRNAs were chosen from six relevant studies as candidates for validation: miR-155, miR-484, miR-221, miR-222, miR-425, miR-133, miR-410, miR-141, miR-628 and miR-942. Validation of these miRNAs was performed on cohort of 56 patients with mRCC with extremely good or poor response responses to sunitinib treatment using quantitative reverse transcription-polymerase chain reaction. Patients were divided into either responding (n=24) or non-responding (n=32) groups to sunitinib treatment according to Response Evaluation Criteria in Solid Tumors and progression-free survival (PFS). All patients in the responding group had PFS longer than 18 months, PFS of non-responders was shorter than 6 months in all cases. RESULTS: miR-942 and miR-133 were confirmed as being differentially expressed in tumors of responding and non-responding patients. It was not possible to validate the predictive value of other tested miRNAs, however, expression of miR-221 and miR-425 tended to be positively associated with therapeutic response (p<0.1). We further developed a model based on the combination of miR-942 and miR-133 expression, that enabled identification of non responding patients with mRCC with sensitivity of 78% and specificity of 79% (area under the curve=0.8071). CONCLUSION: Following further independent validation, detection of these miRNAs may prevent unnecessary and costly approaches to therapy in non-responding patients with mRCC. PMID- 29715125 TI - Safety and Feasibility of Single-port Surgery for Colon Cancer in Octogenarians. AB - BACKGROUND/AIM: The use of single-port surgery (SPS) in elderly patients with colon cancer remains controversial. The aim of this study was to evaluate the clinical outcomes of elderly patients who underwent SPS. PATIENTS AND METHODS: Consecutive patients >80 years old of age who underwent SPS (n=86) or multi-port surgery (MPS) (n=40) for colon cancer from January 2008 to December 2014 were analyzed. Short-term and long-term outcomes were compared between groups. RESULTS: The morbidity rate in the SPS was significantly lower than that in the MPS (p=0.027). Length of hospital stay in the SPS was significantly shorter than that in the MPS (p=0.016). Similar oncological outcomes were observed in the groups. The 3-year disease-free survival rate, the 5-year overall survival rate and the 5-year cancer-specific survival rate did not differ significantly between groups. CONCLUSION: SPS is safe and can provide clinical outcomes comparable to those of MPS in octogenarians with colon cancer. PMID- 29715126 TI - Predicting the Risk of Developing New Cerebral Lesions After Stereotactic Radiosurgery or Fractionated Stereotactic Radiotherapy for Brain Metastases from Renal Cell Carcinoma. AB - AIM: To create an instrument for estimating the risk of new brain metastases after stereotactic radiosurgery (SRS) or fractionated stereotactic radiotherapy (FSRT) alone in patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: In 45 patients with 1-3 brain metastases, seven characteristics were analyzed for association with freedom from new brain metastases (age, gender, performance score, number and sites of brain metastases, extra-cerebral metastasis, interval from RCC diagnosis to SRS/FSRT). RESULTS: Lower risk of subsequent brain lesions after RT was associated with single metastasis (p=0.043) and supratentorial involvement only (p=0.018). Scoring points were: One metastasis=1, 2-3 metastases=0, supratentorial alone=1, infratentorial with/without supratentorial=0. Scores of 0, 1 and 2 points were associated with 6-month rates of freedom from subsequent brain lesions of 25%, 74% and 92% (p=0.008). After combining groups with 1 and 2 points, 6-month rates were 25% for those with 0 points and 83% for those with 1-2 points (p=0.002). CONCLUSION: Two groups were identified with different risks of new brain metastases after SRS or FSRT alone. High-risk patients may benefit from additional whole-brain irradiation. PMID- 29715127 TI - Adherence to Guidelines During Follow-up of Endometrial Cancer: Analysis of French Health Insurance Database. AB - BACKGROUND/AIM: Recommendations for endometrial cancer (EC) follow-up after treatment include regular clinical examinations without further systematic investigation. The objectives of our study were to examine adherence to follow-up guidelines in patients who underwent surgery for EC and identify associated variables. PATIENTS AND METHODS: Patients who underwent surgery for EC between 2005 and 2014 were identified among the Echantillon Generaliste des Beneficiaires. The adherence to guidelines was defined by fewer than two investigations performed, including vaginal smear, CA 125 evaluation and imaging during two postoperative years. RESULTS: Among the 314 women identified, a gap between recommendations and practices was observed in 48.1%. This gap was more frequently observed in patients who underwent surgery before 2011, in private institutions and in institutions performing less than 20 hysterectomies for EC per year and who had Long Duration Disease declaration for EC. CONCLUSION: A gap between recommendations and practices for the follow-up was observed in almost half of the patients with EC. Updating the recommendations in 2010 may have improved compliance with the recommendations. PMID- 29715128 TI - Correlation Between Disease Stage and the Presence of Viable Circulating Tumor Cells in Endometrial Cancer. AB - BACKGROUND/AIM: The presence of circulating tumor cells (CTCs) in the peripheral blood of patients with solid tumors is associated with a poor prognosis. However, there are limited data concerning the detection of CTCs in endometrial cancer (EC). The aim of this study was to evaluate the presence of CTCs in the peripheral blood of patients with EC. MATERIALS AND METHODS: Peripheral blood samples from 92 patients who underwent a surgical procedure were evaluated using MetaCell(r) separation technology for CTCs. RESULTS: CTCs were detected in 69 (75%) patients with EC. CONCLUSION: CTCs were detected in a higher percentage of patients than in other studies. The results showed that the technology applied in this study can efficiently capture viable tumor cells in the blood that can be cultured while maintaining their original phenotype. This paper discusses the first successful culturing of human circulating endometrial cancer cells for further downstream functional and molecular characterization. PMID- 29715129 TI - Second Opinion Reviews for Cancer Diagnoses in Anatomic Pathology: A Comprehensive Cancer Center's Experience. AB - AIM: The objective of this study was to define the rates of discrepancy between outside pathological diagnoses and secondary reviews. MATERIALS AND METHODS: We assessed the rates of discordance between outside diagnoses and secondary reviews, categorizing by organ site and minor or major (affecting patient care) discordances. RESULTS: A total of 9,289 consecutive surgical pathology (SP) and cytopathology (CP) cases reviewed in 2015 were identified. For 8,191 outside SP cases reviewed, the overall discordance rate (DR) was 14.2% (2.2% major, 12.0% minor). Specifically, neuropathology had the highest DR (10.9%), cutaneous and breast the lowest (1.1% each). Among 1,098 CP cases, the total DR was 13.7% (3.0% major, 10.7% minor). The majority of CP cases (1,066) were non-gynecological and had a total DR of 13.4% (2.7% major, 10.7% minor). CONCLUSION: While major DR was low, certain subspecialties had high DRs. This project can help identify areas where focused education could help improve pathological diagnostic accuracy for cancer. PMID- 29715130 TI - Osteoscopic Surgery of Giant Cell Tumor of Bone for Preservation of Proximal Fibula. AB - BACKGROUND: Osteoscopy is a minimally-invasive endoscopic technique for inspecting lesions inside bone marrow cavities. We describe the feasibility of osteoscopic surgery of giant cell tumor of bone (GCTB) in order to preserve the proximal fibula, and thereby achieve immediate recovery and avoid complications. PATIENTS AND METHODS: Five patients with GCTB in the proximal fibula were treated using osteoscopic curettage with adjuvants (argon plasma coagulation and cementation). Functional outcome was evaluated by knee stability, Musculoskeletal Tumor Society (MSTS) rating, and Tegner score. Oncological outcome was evaluated for local recurrence and pulmonary metastasis. RESULTS: Regarding functional outcome, knee instability was negative in all cases. Mean MSTS rating was 100%. Tegner scores were the same as those prior to surgery. Neither local recurrence nor pulmonary metastasis were found. CONCLUSION: Osteoscopic surgery is feasible for immediate and complete recovery, and can improve quality of life for patients with GCTB of the proximal fibula with satisfactory oncological outcome. PMID- 29715131 TI - Clinical Significance of Subcellular Localization of Maspin in Patients with Pathological Stage IA Lung Adenocarcinoma. AB - BACKGROUND/AIM: Maspin is a tumor-suppressor protein and its prognostic value in lung adenocarcinoma has been reported. However, little is known about the clinical impact of subcellular localization of maspin in early-stage lung adenocarcinoma. We aimed to evaluate the clinical significance of subcellular localization of maspin in patients with pathological stage (p-stage) IA lung adenocarcinoma categorized by the new eighth edition TNM classification. PATIENTS AND METHODS: We immunohistochemically analyzed 181 tissue samples from p-stage IA1 (n=37), IA2 (n=92) and IA3 (n=52) lung adenocarcinomas using antibody for maspin. RESULTS: The 181 cases fell into five predominant subtypes: lepidic (n=32), acinar (n=97), papillary (n=30), solid (n=20) and micropapillary (n=2). The frequencies of maspin staining were: cytoplasmic-only in 24.9%; pancellular (nuclear and cytoplasmic) in 8.8%; nuclear-only in 0.6%; no staining in 65.7%. Cytoplasmic-only staining significantly correlated with high pathological T classification (p=0.039), lymphatic invasion (p=0.002) and poorer tumor differentiation (p=0.002). The patients were followed-up for 12-151 months (median=74 months), and the cytoplasmic-only staining significantly correlated with shorter disease-free survival (DFS) (p=0.034) and disease-specific survival (DSS) (p=0.036) by log-rank tests. In Cox's multivariate analysis, lymphatic invasion had the most significant effect on shorter DFS and DSS. CONCLUSION: The expression of maspin in the cytoplasm alone could be useful for predicting unfavorable prognoses in patients with p-stage IA lung adenocarcinoma. PMID- 29715132 TI - Synchronous Pancreatic Ductal Adenocarcinoma and Hepatocellular Carcinoma: Report of a Case and Review of the Literature. AB - Two or more histologically distinct malignancies diagnosed during the same hospital admission are uncommon, but they do exist. Cases with synchronous primary pancreatic ductal adenocarcinoma and hepatocellular carcinoma are rarely seen. This is a case report of a 56 years old Caucasian female with the chief complaint of jaundice over a duration of 10 days. CT imaging findings revealed a 3.5 cm ill-defined pancreatic head mass and a 1.5 cm liver mass in the segment 5. EUS-FNA cytology showed pancreatic head ductal adenocarcinoma (PDAC). Liver biopsy revealed a well differentiated hepatocellular carcinoma (HCC). The patient underwent a pancreaticoduodenectomy and the pathology revealed a pancreatic ductal adenocarcinoma extending into peripancreatic soft tissue, portal vein and vascular groove with perineural invasion. This is a unique and challenging case with the coexistence of a primary PDAC and a primary HCC. To the best of our knowledge, this is the first documented case of synchronous PDAC and HCC in the English literature. The diagnosis and treatment of the two entities are discussed. PMID- 29715133 TI - Cytoreductive Nephrectomy in Elderly Patients with Metastatic Renal Cell Carcinoma in the Targeted Therapy Era. AB - BACKGROUND/AIM: The role of cytoreductive nephrectomy (CN) for metastatic renal cell cancer (mRCC) is not clearly understood after the approval of targeted therapies, particularly in the elderly population. The aim of this study was to compare survivals between patients who did and did not receive CN. PATIENTS AND METHODS: The SEER-18 database was utilized in order to identify elderly patients with mRCC to compare overall survival (OS) and cancer-specific survival (CSS) between patients who did or did not receive CN between February 2006 and 2012. Kaplan-Meier curve and log rank test were used to compare OS and CSS between these two arms. Cox proportional hazard model was used for multivariate analysis and statistical significance was defined as p<=0.05. RESULTS: There was a significant survival benefit for those who received CN compared to those who did not receive CN (median OS: 18 months vs. 4 months, p<0.001; median CSS: 21 months vs. 5 months, p<0.001). CONCLUSION: CN offered significant survival benefit, even in elderly patients with metastatic renal cell cancer. PMID- 29715134 TI - The Alcohol Dehydrogenase Isoenzyme as a Potential Marker of Pancreatitis. AB - BACKGROUND/AIM: Human pancreas parenchyma contains various alcohol dehydrogenase (ADH) isoenzymes and also possesses aldehyde dehydrogenase (ALDH) activity. The altered activities of ADH and ALDH in damaged pancreatic tissue in the course of pancreatitis are reflected in the human serum. The aim of this study was to investigate a potential role of ADH and ALDH as markers for acute (AP) and chronic pancreatitis (CP). PATIENTS AND METHODS: Serum samples were collected for routine biochemical investigations from 75 patients suffering from acute pancreatitis and 70 patients with chronic pancreatitis. Fluorometric methods were used to measure the activity of class I and II ADH and ALDH activity. The total ADH activity and activity of class III and IV isoenzymes were measured by a photometric method. RESULTS: There was a significant increase in the activity of ADH III isoenzyme (15.06 mU/l and 14.62 mU/l vs. 11.82 mU/l; p<0.001) and total ADH activity (764 mU/l and 735 mU/l vs. 568 mU/l) in the sera of patients with acute pancreatitis or chronic pancreatitis compared to the control. The diagnostic sensitivity for ADH III was about 84%, specificity was 92 %, positive and negative predictive values were 93% and 87% respectively in acute pancreatitis. Area under the Receiver Operating Curve (ROC) curve for ADH III in AP and CP was 0.88 and 0.86 respectively. CONCLUSION: ADH III has a potential role as a marker of acute and chronic pancreatitis. PMID- 29715135 TI - Comparable Efficacy of Idelalisib Plus Rituximab and Ibrutinib in Relapsed/refractory Chronic Lymphocytic Leukemia: A Retrospective Case Matched Study of the Polish Adult Leukemia Group (PALG). AB - BACKGROUND/AIM: There is limited amount of data available on the comparative efficacy of ibrutinib and idelalisib, the B-cell receptor inhibitors (BCRi) newly approved for relapsed/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (r/r CLL/SLL) treatment. The aim of our study was to analyze and compare the outcomes of real-world r/r CLL/SLL patients treated with these two BCRi in outside clinical trials. PATIENTS AND METHODS: A comparative case matched 1:2 analysis was performed on idelalisib combined with rituximab and ibrutinib efficacy in 102 patients with r/r CLL/SLL from two observational studies of the Polish Adult Leukemia Group (PALG). RESULTS: Both therapies produced similar overall response rates (idelalisib plus rituximab 76.4% and ibrutinib 72.1%). Median progression-free survival (PFS) and overall survival (OS) in both groups were not reached. Furthermore, no significant difference was observed between both BCRi regimens in regard to PFS (HR=0.75, 95% CI=0.30-1.86, p=0.55) and OS (HR=0.65, 95%CI=0.26-1.68, p=0.39). CONCLUSION: In summary, the results of this retrospective analysis suggest that idelalisib combined with rituximab and ibrutinib therapies have comparable activity in r/r CLL/SLL in daily clinical practice. PMID- 29715136 TI - Calcium Phosphate Cement in the Surgical Management of Benign Bone Tumors. AB - BACKGROUND/AIM: This study assessed the mid- to long-term outcomes of calcium phosphate cement (CPC) implantation in benign bone tumor surgery. PATIENTS AND METHODS: Between 2000 and 2015, 130 patients underwent CPC implantation in benign bone tumor surgery. Radiographic findings and clinical outcomes were retrospectively evaluated. RESULTS: The mean follow-up period was 52 months. CPC filling immediately after surgery was sufficient, regardless of the amount of CPC used and the usage of adjuvant substances, which resulted in 92% of the patients' radiological results being classified as good or excellent. Significantly more patients had better CPC filling among patients with less hemorrhage and patients with tourniquet. The number of patients with good or excellent CPC filling had significantly increased by the final follow-up. CONCLUSION: CPC is a useful bone substitute for benign bone tumor surgery providing excellent osteoconductivity and long-lasting stability without internal fixation. PMID- 29715137 TI - Nephrometry Scores: The Effect of Imaging on Routine Read-out and Prediction of Outcome of Nephron-sparing Surgery. AB - BACKGROUND/AIM: This study investigated the impact of available preoperative imaging on the reliability and predictive accuracy of RENAL and PADUA nephrometry scoring systems for renal tumors. PATIENTS AND METHODS: Five urologists determined RENAL and PADUA scores using preoperative imaging data (computed tomography and magnetic resonance imaging) of 100 patients admitted for partial nephrectomy with the following combinations: T0: transverse planes without excretory phase (EP), TC0: transverse and coronal planes without EP, TC1: transverse and coronal planes with EP. Reference standard was obtained by a uro radiologist. Ischemia time was used as surrogate for surgical complexity. RESULTS: Assignment of EP significantly reduced interobserver-variability among urologists (p<0.0001). Predictive accuracy for surgical complexity or correct assignment to nephrometry risk groups did not depend on image planes or EP. CONCLUSION: Interobserver variability, but not predictive accuracy of nephrometric systems, is affected by additional usage of EP. PMID- 29715138 TI - Comparing Image-guided targeted Biopsies to Radical Prostatectomy Specimens for Accurate Characterization of the Index Tumor in Prostate Cancer. AB - AIM: To evaluate the accuracy of multiparametric magnetic resonance-transrectal ultrasound fusion targeted biopsy (TBx) in the characterization of the index tumor, as confirmed by association with radical prostatectomy (RP) specimens. PATIENTS AND METHODS: A total of 152 patients with TBx-confirmed prostate cancer (PCa) underwent robot-assisted RP. Stained whole-mount histological sections were used as the reference standard. All lesions with a volume >0.5 ml and/or pathological Gleason score (GS) >6 were defined as clinically significant PCa. The index lesion was defined as the largest tumor focus within the prostate gland. RESULTS: The pathological index tumours included: 147 lesions (96.7%) with a volume >0.5 ml and five (3.3%) with a volume <=0.5 ml, but with a pathological GS >=7; 135 (88.8%) were located in the peripheral zone. TBx accuracy in the detection of the correct site of the index lesion by reference standard was 82.2%. Sensitivity, specificity, positive and negative predictive value were: 82.3%, 50.4%, 82.8% and 49.7%, respectively. The primary/secondary Gleason grade and GS of the 152 index tumors were properly estimated in 130 (85.5%), 115 (75.6%) and 127 (83.6%) cases, respectively. The concordance of TBx with pathological GS was 83.6%. The rate of up-grading and down-grading of TBx Gleason sum was 12.2% and 4.2%, respectively. CONCLUSION: TBx has a high sensitivity for characterization of index lesions, with a good concordance for topographic and Gleason grading accuracy between biopsy and surgical specimens. PMID- 29715139 TI - Bone Mineral Density as a Potential Predictive Factor for Luminal-type Breast Cancer in Postmenopausal Women. AB - BACKGROUND/AIM: We performed a case-control study to evaluate whether bone mineral density (BMD) can be considered a potential predictive factor for luminal type breast cancer (BC), that could be useful in constructing a predictive risk model. MATERIALS AND METHODS: The medical records of 297 postmenopausal women with luminal-type node-negative BC who underwent lumbar-spine dual-energy X-ray absorptiometry (DXA) with BMD measurement before surgery, were analyzed and compared with those of 297 age-matched randomly selected healthy controls. The correlations between women's reproductive history, including the age at menarche and menopause, parity, oral contraceptives and hormone replacement therapy (HRT) use, the results of DXA, and BC risk were evaluated in univariate and multivariate analyses. RESULTS: Overall, 168 (28.3%) women had osteoporosis and/or osteopenia (low BMD). Both bone alterations were protective factors for BC, especially when they were considered together (p=0.001). Only the interval between menarche and menopause (MMI), dichotomized at 37.5 years as an optimal cut-off, and the HRT use reached a statistical significance (p<0.01) as risk factors. The three parameters were independent because they remained significant in the stepwise logistic regression analysis. The area under the receiver operating characteristic (ROC) curve (AUC) obtained with the model was 0.694 (95%CI=0.694-0.731). CONCLUSION: This hypothesized predictive model is fairly accurate and could identify patients at increased risk of developing luminal-type BC in a population of postmenopausal women who performed DXA, simply based on their history. PMID- 29715140 TI - Depression in Choroidal Melanoma Patients Treated with Proton Beam Radiotherapy. AB - AIM: To determine depression in patients with choroidal melanoma (CM) treated with proton beam radiotherapy. PATIENTS AND METHODS: This was a cross-sectional study including 50 patients with CM (50% males, mean age=49.88+/-6.34 years) and 46 age- and sex-matched healthy controls (52% males, mean age=48.60+/-8.05 years). Participants completed the Patient Health Questionnaire-9 (PHQ-9) and the Zung Self-Rating Depression Scale (SDS) questionnaires. RESULTS: There was a considerable difference in visual acuity as logarithm of the minimum angle of resolution (logMAR) between the patient and control groups (1.16+/-0.97 and 0.04+/-0.05 logMAR, respectively, p<0.0001). Both PHQ-9 and SDS scores differed significantly between the two groups (10.18+/-4.68 and 8.07+/-4.90, p=0.04; and 47.94+/-12.56 and 39.91+/-8.80, p=0.004, respectively). Scores appeared to be positively correlated with logMAR visual acuity (Spearman rho=0.700, p<0.0001 for PHQ-9; and 0.767, p<0.0001 for SDS), and they were also correlated to each other (Spearman rho=0.759, p<0.0001). CONCLUSION: Patients with CM having undergone proton beam therapy seem to be more depressed compared to a sample of healthy individuals, and the level of depression is correlated with their visual acuity. PMID- 29715141 TI - Liver-dominant Breast Cancer Metastasis: A Comparative Outcomes Study of Chemoembolization Versus Radioembolization. AB - AIM: To compare toxicity, response, and survival outcomes of patients with hepatic metastases from breast cancer who underwent transarterial chemoembolization (TACE) or radioembolization (TARE). MATERIALS AND METHODS: A retrospective review was carried out of all patients who underwent TACE or TARE for liver-dominant breast cancer metastases between January 2006 and March 2016 at an academic medical center in the United States. RESULTS: Seventeen patients in the TACE group and 30 patients in the TARE group received 32 TACE and 49 TARE treatments, respectively. Median follow-up was 9 months. Both groups had similar background variables. More all-grade adverse events were seen in the TACE group (71% vs. 44%; p=0.02). Median overall survival in the TACE group was 4.6 months compared to 12.9 months in the TARE group (p=0.2349). Treatment type was not an independent prognostic factor. CONCLUSION: TARE is better tolerated than TACE for the treatment of liver-dominant breast cancer metastasis. There was a trend towards improved survival with TARE; however, it did not approach statistical significance. Larger studies are needed to validate these findings. PMID- 29715142 TI - Chemotherapy Plus Bevacizumab as Neoadjuvant or Conversion Treatment in Patients with Colorectal Liver Metastases. AB - AIM: To evaluate the efficacy of chemotherapy plus bevacizumab as neoadjuvant or conversion treatment for colorectal liver metastases (CLM). PATIENTS AND METHODS: A retrospective chart review was carried out of 74 patients with CLM treated with neoadjuvant or conversion chemotherapy plus bevacizumab. RESULTS: The overall response rate was 63.4%. An optimal morphological response by computed tomography was reported in 35% of patients. The rate of complete resection was 71.6%. Complete or major pathological response (pR) was attained in 58.2%. The median overall survival (OS) was not reached. Median progression-free (PFS) and relapse free (RFS) survival were 14.6 and 8.7 months. Among patients reaching an optimal pR, median OS was not reached (p=0.08), and a trend towards longer RFS and PFS was seen. CONCLUSION: Neoadjuvant or conversion chemotherapy with bevacizumab is an active and tolerable option for CLM with minimal post-surgery complications. Optimal pR is associated with a longer OS and a trend for prolonged PFS and RFS. PMID- 29715143 TI - Recent Trends in HPV Infection and Type Distribution in Greece. AB - BACKGROUND/AIM: This study gives an insight into recent trends for Human papillomavirus (HPV)-specific infection and its fluctuation over the years 2011 2016. MATERIALS AND METHODS: A total of 2,417 Caucasian women between the age of 18 and 71 years underwent their annual gynaecologic examination at the Outpatient Gynaecological Clinic in the study period. RESULTS: Overall HPV prevalence was 43.9%, and high-risk HPV accounted for 31.3%. HPV16 was the most common high-risk type followed by HPV51 and HPV31. HPV positivity was higher in those with low- and high-grade squamous intraepithelial lesions (HSILs) than in women with a normal cytological test. HPV infection was highest in 2011.The prevalence of single infections remained higher than multiple infections over the entire study period. HPV16 prevalence was very high in the first years of the study and HPV18 exhibited highest prevalence in 2011. Younger women exhibited a significant increase in HPV infection from 2014. Overall HPV infection decreased over the study period. CONCLUSION: These data suggest that HPV vaccination might reduce the frequency of HSILs and cervical cancer and are useful for the development of a national screening programme. PMID- 29715144 TI - Successful Distal Gastrectomy for Gastric Cancer with Child-Pugh Class B Alcoholic Liver Cirrhosis. AB - Extended lymph node dissection in patients with gastric cancer with liver cirrhosis can lead to severe morbidity and mortality, especially in those with Child-Pugh class B or C cirrhosis. We, herein, report a case of advanced gastric cancer with alcoholic liver cirrhosis that was successfully treated by surgery. A 58-year-old male patient was diagnosed with gastric cancer with alcoholic liver cirrhosis Child-Pugh class B. A red blood cell transfusion was performed to treat cancer-related hemorrhage; however, the patient's hemoglobin level did not improve and distal gastrectomy with D1 lymph node dissection was subsequently performed to prevent further bleeding. He was able to leave the hospital at postoperative day 16 without severe complication. Patients with liver cirrhosis can undergo distal gastrectomy with D1 lymph nodes dissection even in those with Child-Pugh class B. PMID- 29715145 TI - Liver Function in Areas of Hepatic Venous Congestion After Hepatectomy for Liver Cancer: 99mTc-GSA SPECT/CT Fused Imaging Study. AB - Background/Aim: The sacrifice of a major hepatic vein can cause hepatic venous congestion (HVC). We evaluated the effects of HVC on regional liver function using the liver uptake value (LUV), that was calculated from 99m Tc-labeled galactosyl-human-serum-albumin ( 99m Tc-GSA) single-photon emission computed tomography (SPECT) /contrast-enhanced computed tomography (CE-CT) fused images. Patients and Methods: Sixty-two patients underwent 99m Tc-GSA SPECT/CE-CT prior to hepatectomy for liver cancer and at 7 days after surgery were divided into groups with (n=8) and without HVC (n=54). In the HVC group, CT volume (CTv) and LUV were separately calculated in both congested and non-congested areas. Results: The remnant LUV/CTv of the HVC group was significantly smaller than that of the non-HVC group (p<0.01). The mean functional ratio was 0.47+/-0.05, and all ratios were >=0.39. Conclusion: After hepatectomy with sacrifice of major hepatic vein, liver function per unit volume in the congested areas was approximately 40% of that in the non-congested areas. PMID- 29715146 TI - A Genitourinary Cancer-specific Scoring System for the Prediction of Survival in Patients with Bone Metastasis: A Retrospective Analysis of Prostate Cancer, Renal Cell Carcinoma, and Urothelial Carcinoma. AB - AIM: The aim of this study was to develop a risk scoring system specific to patients with bone metastasis of genitourinary cancer. MATERIALS AND METHODS: This study included 180 patients with bone metastasis of three major types of genitourinary cancer: prostate cancer (n=111), renal cell carcinoma (n=43,), and urothelial carcinoma (n=26). Clinical factors at diagnosis of bone metastasis were evaluated to identify independent prognostic factors. RESULTS: Multivariate analysis showed that type of primary cancer, poor performance status, the presence of visceral metastases, high Glasgow prognostic score and elevated neutrophil-to-lymphocyte ratio were independently predictive of poor prognosis. Patients were able to be classified by the prognostic risk score into four prognostic groups with low, intermediate, high, and very high risk. CONCLUSION: This risk scoring system could be useful for predicting survival of patients with bone metastasis of genitourinary cancer and in making decisions on appropriate treatments for them. PMID- 29715147 TI - Relationship and Predictive Role of the Dual Expression of FGFR and IL-8 in Metastatic Renal Cell Carcinoma Treated with Targeted Agents. AB - BACKGROUND/AIM: The expression of IL-8 and FGFR has been related to prognosis and pathological features in renal cell carcinoma. We investigated the relationship between IL-8 and FGFR and the outcome in metastatic renal cell carcinoma (mRCC) patients. MATERIALS AND METHODS: Clinical data and histological samples of patients affected by mRCC and treated with targeted agents were reviewed. The expression of proteins was assessed using immunohistochemistry. RESULTS: FGFR1, FGFR2, and IL-8 were found to be expressed in 16%, 30%, and 50% of cases, respectively. Significant correlations were found between selected proteins. A lack of expression of FGFR2 and IL8 was found to be correlated with increased progression-free survival (PFS). The survival rate at 24 months was 44%, 38%, and 79% of those expressing both, one, or none of the evaluated proteins, respectively (p=0.047). CONCLUSION: This analysis found a relationship between the expression of IL-8 and FGFR2 in mRCC patients treated with targeted agents. PMID- 29715148 TI - A Score to Identify Patients with Brain Metastases from Colorectal Cancer Who May Benefit from Whole-brain Radiotherapy in Addition to Stereotactic Radiosurgery/Radiotherapy. AB - AIM: To design a tool to predict the probability of new cerebral lesions after stereotactic radiosurgery/radiotherapy for patients with 1-3 brain metastases from colorectal cancer. PATIENTS AND METHODS: In 21 patients, nine factors were evaluated for freedom from new brain metastases, namely age, gender, Karnofsky performance score (KPS), tumor type, number, maximum total diameter of all lesions and sites of cerebral lesions, extra-cranial metastases, and time from cancer diagnosis to irradiation. RESULTS: Freedom from new lesions was positively associated with KPS of 90-100 (p=0.013); maximum total diameter <=15 mm showed a trend for positive association (p=0.09). Points were assigned as: KPS 70-80=1 point, KPS 90-100=2 points, maximum diameter <=15 mm=2 points and maximum diameter >15 mm=1 point. Six-month rates of freedom from new lesions were 29%, 45% and 100% for those with total scores of 2, 3 and 4 points, respectively, with corresponding 12-month rates of 0%, 45% and 100% (p=0.027). CONCLUSION: This study identified three risk groups regarding new brain metastases after stereotactic irradiation. Patients with 2 points could benefit from additional whole-brain radiotherapy. PMID- 29715149 TI - Successful Treatment of Growing Teratoma Syndrome of the Lung by Surgical Resection: A Case Report and Literature Review. AB - Growing teratoma syndrome (GTS) of the lung is extremely rare, and there are very few reports on this condition. This is a case report of GTS of the lung that was successfully treated by resection. A 19-year-old man, who had been diagnosed with a testicular tumor, lung metastases and left hilar lymph node metastasis, underwent surgical resection for left testicular cancer. After orchiectomy and chemotherapy, the patient was successfully treated with wedge resection of the right upper lobe and left upper lobectomy. In conclusion, the current case suggests that some patients with GTS might be successfully treated by surgical resection. PMID- 29715150 TI - Image-guided Stereotactic Body Radiotherapy in Metastatic Prostate Cancer. AB - BACKGROUND/AIM: In the last years, the use of Image Guided Stereotactic Radiotherapy (IG-SBRT) in patients with metastatic prostate cancer has increased. In this study, we aimed to assess the role of IG-SBRT in terms of local control and safety in patients with metastatic prostate cancer. MATERIALS AND METHODS: Primary and secondary endpoints of this prospective observational study were local control and safety related to IG-SBRT. All lesions were treated with 24 Gy as a single fraction or 27 Gy in 3 fractions. After SBRT, Systemic therapies were administered only after the occurrence of more than three synchronous active lesions in oligometastatic patients (patients with less than 4 active synchronous lesions) or new lesions occurrence in patients with more than 3 synchronous lesions. RESULTS: From April 2011 to June 2017, 78 metastatic lesions (32 bone and 46 node) from 51 patients with prostate cancer were treated. After a median follow-up of 18.5 months (range=3-103 months), only 2 lesions (4%) relapsed inside the radiation field. All local recurrences were located on the bone. Estimated 12 and 24 months local control ratios were 98.7 and 97.4%, respectively. Except for one case, toxicity greater than G2 was not recorded. CONCLUSION: IG-SBRT is safe and can be considered as a valid therapy in patients with metastatic prostate cancer requiring a long-lasting metastases control. PMID- 29715151 TI - Genomic Instability in Buccal Mucosal Cells of Municipal Street Sweepers as Evaluated by Micronucleus Test. AB - BACKGROUND/AIM: Since street sweepers comprises a group of workers who are in daily contact with rubbish, dust and air pollution, the aim of this study was to evaluate potential cytotoxic and mutagenic effects in buccal mucosa cells of street sweepers. MATERIALS AND METHODS: A total of 20 male street sweepers aged from 22 to 56 years were included in the experimental group. A total of 20 men matched by age were used as the control group. Cytotoxicity and mutagenicity were analyzed by micronucleus test in buccal mucosal cells. RESULTS: Statistically significant differences (p<0.05) in the frequency of micronuclei was detected in the street sweepers when compared to the control group. No remarkable differences were found to other metanuclear alterations indicative for cytotoxicity such as pyknosis, karyolysis, and karryorhexis when compared to matched controls. CONCLUSION: Taken together, our results indicate that street sweepers comprise an at-risk group as a result of increased mutagenicity found to buccal mucosa cells. PMID- 29715152 TI - Transition Rate from EGFR-TKI to Cytotoxic Chemotherapy Patients with EGFR Mutation-positive Lung Adenocarcinoma. AB - BACKGROUND/AIM: The transition rate from first-line epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) to cytotoxic chemotherapy (Ct) is poor. The prognosis according to treatment sequence and the reasons patients could not shift from first-line EGFR-TKIs to Ct were herein analyzed. PATIENTS AND METHODS: Overall, 159 epidermal growth factor receptor mutation-positive adenocarcinoma patients were enrolled in this study. RESULTS: The median survival times of EGFR-TKIs combined with Ct and EGFR-TKIs were 59.8 months and 22.5 months, respectively (p<0.001) and of patients who received EGFR-TKIs first and Ct first were 38.8 months and 66.4 months, respectively (p=0.016). The main reasons patients could not make the transition to Ct was worsening of performance status and patient's preference. CONCLUSION: EGFR-TKIs and Ct lead to a good prognosis in EGFR mutation-positive adenocarcinoma patients. It is necessary to consider the timing when changing the treatment strategy before treatment options are limited. PMID- 29715153 TI - Long-term Postoperative Nutritional Status Affects Prognosis Even After Infectious Complications in Gastric Cancer. AB - AIM: This study was designed to investigate the clinical impact of postoperative serum albumin level on severe postoperative complications (SPCs) and prognosis. MATERIALS AND METHODS: Data for a total of 728 consecutive patients who underwent curative gastrectomy for gastric cancer between 2004 and 2013 were retrospectively analyzed. From these patients, a propensity score-matched analysis was performed based on 14 clinicopathological and surgical factors. RESULTS: Short-term decrease in postoperative serum albumin level was not associated with the occurrence of SPCs. Regarding long-term decrease in serum albumin level, a decrease of >=0.5 g/dl at 3 months did not affect the long-term survival of patients without SPCs, but was related to a significantly poorer prognosis in patients with SPCs. By multivariate analysis, long-term decrease of serum albumin level was an independent prognostic factor in patients with SPCs. CONCLUSION: Long-term postoperative nutritional status as shown by a low level of albumin was related to prognosis in patients with SPCs. PMID- 29715154 TI - Radiotherapy Plus Total Androgen Block Versus Radiotherapy Plus LHRH Analog Monotherapy for Non-metastatic Prostate Cancer. AB - BACKGROUND/AIM: Patients with locally advanced prostate cancer are generally treated with radiotherapy (RT) which can be combined with hormonal therapy. RT plus monotherapy with luteinizing hormone-releasing hormone (LHRH) analog triptorelin was compared to RT plus total androgen block (TAB). PATIENTS AND METHODS: A retrospective study was carried out on patients with locally advanced prostate cancer comparing RT plus monotherapy versus RT plus TAB. RESULTS: For overall survival, no differences between patients receiving RT with monotherapy and those treated with TAB were observed. A trend favoring use of TAB was found for progression-free survival. No differences in late gastrointestinal and genitourinary toxicities were reported. CONCLUSION: This study suggests that monotherapy with LHRH is as effective as TAB, which is important in selecting appropriate treatment considering that TAB can have higher risks of adverse events and reduce the quality of life of patients. PMID- 29715155 TI - Acquired EGFR T790M Mutation After Relapse Following EGFR-TKI Therapy: A Population-based Multi-institutional Study. AB - AIM: To describe the prevalence and determinants of acquired epidermal growth factor receptor (EGFR) T790M gene mutation in a clinical practice setting. MATERIALS AND METHODS: We performed a retrospective chart review study between January 2013 and November 2017 across multiple institutes, covering a population of 3 million people. RESULTS: We reviewed the charts of 233 patients non-small cell lung cancer with EGFR mutations. Of them, 99 (42.5%) patients had acquired T790M mutations in EGFR. Patients >=75 years old and patients with an exon 19 deletion had higher rates of acquired T790M mutation than did younger patients and those with an exon 21 L858R mutation. In 75 patients treated with afatinib, 34 (45.3%) patients had acquired T790M mutation. The sensitivity of T790M mutation detection was lower in plasma specimens than in biopsy specimens. CONCLUSION: This population-based study confirms previous studies and highlights potential determinants of acquired T790M mutation to be considered in clinical practice. PMID- 29715156 TI - Elevated Neutrophil-to-Lymphocyte Ratio Predicts Survival in Patients with Advanced Gastric Cancer Treated with Trastuzumab Combination Chemotherapy. AB - BACKGROUND/AIM: This study investigated the clinical prognostic relevance of the neutrophil-to-lymphocyte ratio (NLR) in patients with human epidermal receptor 2 (HER2)-positive metastatic advanced gastric cancer (AGC) treated with combination chemotherapy including trastuzumab. PATIENTS AND METHODS: This is a retrospective analysis of 73 patients diagnosed with metastatic AGC who were treated with trastuzumab combination chemotherapy. NLR was calculated as the neutrophil count divided by the lymphocyte count. A cut-off value of 3 was selected, which classified patients into two categories, low (<=3.0) or high (>3.0). RESULTS: In the univariate analysis, the high-NLR patients showed a significantly shorter progression-free survival (PFS) and overall survival (OS) than the low-NLR patients (PFS, p=0.012, OS, p=0.047). In the multivariate analysis, the high NLR was independently associated with a shorter PFS (p=0.015) and OS (p=0.040). CONCLUSION: This study found that a high NLR was associated with a shorter PFS and OS in patients with HER2-positive gastric cancer treated with trastuzumab. PMID- 29715157 TI - Elevated Neutrophil-to-Lymphocyte-ratio and Platelet-to-Lymphocyte Ratio in Myelofibrosis: Inflammatory Biomarkers or Representatives of Myeloproliferation Itself? AB - BACKGROUND/AIM: We aimed to investigate clinical associations of inflammatory biomarkers neutrophil-to-lymphocyte-ratio (NLR) and platelet-to-lymphocyte-ratio (PLR) in patients with myelofibrosis, myeloproliferative neoplasm with inflammatory background. PATIENTS AND METHODS: We retrospectively analyzed a cohort of 102 myelofibrosis patients. NLR and PLR were assessed in addition to other disease-specific parameters. RESULTS: NLR and PLR were significantly higher in myelofibrosis than in healthy controls. Higher NLR was significantly associated with Janus-kinase-2 (JAK2)-mutation, wild-type-Calreticulin (CALR), older age and parameters reflecting increased proliferative potential of disease (higher leukocytes, higher hemoglobin, larger spleen-size), whereas there was no significant association with C-reactive-protein (CRP). Higher PLR was significantly associated with absence of blast-phase-disease, absence of constitutional-symptoms, lower percentage-of-circulatory-blasts, smaller spleen size and lower CRP. In the Cox-regression-model, higher-NLR (HR=2.76; p=0.004), lower-PLR (HR=1.99; p=0.042) and Dynamic-International-Prognostic-System (DIPSS) (HR=3.26; p<0.001) predicted inferior survival independently of each other. CONCLUSION: In the context of myelofibrosis, elevated NLR and PLR are more likely to represent myeloproliferation itself and not necessary the extent of inflammation. PMID- 29715158 TI - Re-irradiation Using Intensity-modulated Radiotherapy for Recurrent and Second Primary Head and Neck Cancer. AB - BACKGROUND/AIM: Information on re-irradiation (re-RT) for recurrent and second primary head and neck cancer is limited. Herein, a description of our long-term experience of re-RT for previously irradiated head and neck cancer is provided. MATERIALS AND METHODS: A retrospective review was performed for 73 consecutive patients re-irradiated for head and neck cancer between 2006 and 2015. Re-RT targets encompassed only the recurrent gross tumor and had tight margins (5-10 mm). RESULTS: Salvage surgery was performed on 28 (38%) patients before re-RT and 53 (73%) patients received chemotherapy concurrent with re-RT. The median interval between initial and re-RT was 31 months and the median cumulative dose of the two irradiations was 126 Gy (biologically equivalent to 2 Gy fractionation). With a median survival of 33 months, locoregional recurrence after re-RT developed in 37 patients (51%; 25 infield, 12 outfield). In multivariate analysis, higher re-RT dose (>=66 Gy), longer time interval (>2 years), and use of concurrent chemotherapy were associated with improved locoregional recurrence-free survival (all p<0.05). Additionally, performance status, additional surgical resection, and longer interval were associated with better overall survival (p=0.006, 0.021, 0.004, respectively). Clinically significant acute and late toxicities occurred in 14% and 22% of evaluable patients, but no grade 5 toxicity was observed. CONCLUSION: Moderate safety and acceptable toxicity was found after re-RT using tight margins, sufficient radiation dose, and daily image guidance. Encouraging local control and survival were obtained, similar to historical data using 1-2 cm margins. PMID- 29715159 TI - Utilization of Hysterectomy Following Chemoradiation for IB2/IIA2 Cervical Cancer in the National Cancer Data Base. AB - BACKGROUND/AIM: Performing hysterectomy following chemoradiotherapy (CRT) for IB2/IIA2 cervical cancer is highly controversial. This study evaluated national practice patterns in utilization of post-CRT hysterectomy in the United States compared to CRT alone, as well as outcomes. MATERIALS AND METHODS: The National Cancer Database was queried for patients with newly diagnosed IB2/IIA2 cervical cancer. Multivariable logistic regression analysis assessing factors predictive of undergoing post-CRT hysterectomy. Kaplan-Meier analysis evaluated overall survival (OS) and Cox proportional hazards modeling determined variables associated with OS. RESULTS: Altogether, 1,691 patients met the inclusion criteria; 1,551 (92%) received CRT alone, and 140 (8%) underwent subsequent hysterectomy. Patients with tumors >=8 cm were more likely to undergo hysterectomy. Patients who underwent additional hysterectomy, likely a higher risk cohort, displayed OS comparable to those receiving CRT alone. CONCLUSION: Greater tumor size was associated with hysterectomy following CRT for IB2/IIA2 cervical cancer in the United States. These patients achieve OS comparable to those receiving standard-of-care CRT. PMID- 29715161 TI - Renal Pelvis Carcinoma with Renal Vein or Inferior Vena Cava Involvement Linked to Early-onset Lung Metastasis Based on CT Scan Diagnosis. AB - BACKGROUND/AIM: Renal pelvis cancer with invasion of the renal vein or inferior vena cava (IVC) carries a poor prognosis. The present study investigated whether early-onset lung metastasis in these patients contributes to their poor outcome. PATIENTS AND METHODS: Data were retrospectively collected from hospitalized patients with metastatic renal pelvis urothelial cancer. The parameters used to estimate the risk of lung metastasis were based on computed tomographic (CT) scans. The parameters included sex, age (<=65 years or >65 years), site (right or left side), metastasis to para-aortic lymph nodes (LNs), suspicion of peritoneal spread, IVC involvement, and renal vein involvement. There were 71 cases including: 40 (56%) patients with lung metastasis (22 early-onset and 18 late onset), 68 (96%) with suspicion of peritoneal spread, 38 (54%) with para-aortic LN metastasis, 10 (14%) with IVC involvement, and 53 (74%) with renal vein involvement. Sixty-four cases were evaluated to estimate the risk of lung metastasis. RESULTS: Tumor involvement in the IVC (p=0.01) and in the renal vein (p<0.00001) were high risk factors for lung metastasis. CONCLUSION: Tumor involvement of the renal vein or IVC is linked to early-onset lung metastasis in renal pelvis cancer based on CT scan diagnosis. PMID- 29715160 TI - The Emerging Role of Laparoscopic Liver Resection in the Treatment of Recurrent Hepatocellular Carcinoma: A Systematic Review. AB - BACKGROUND/AIM: Tumor recurrence complicates more than half of patients at 5 years after primary hepatocellular carcinoma (HCC) resection. Repeat open liver resection (ROLR) is the standard procedure for patients eligible for repeat resection, whereas laparoscopic repeat liver resection (RLLR) has been proposed as an alternative approach. The aim of this systematic review is to evaluate studies reporting on outcomes of RLLR for recurrent HCC (rHCC). MATERIALS AND METHODS: A comprehensive search of the literature was undertaken. RESULTS: A total of 11 studies, 6 non-comparative and 5 comparative (RLLR versus ROLR), which reported outcomes for 165 patients who underwent RLLR, were included in our review. RLLRs were associated with reduced blood loss, shorter hospital stay, lower conversion to ROLR and lower morbidity rates. CONCLUSION: Selected patients with rHCC who undergo RLLR, benefit in terms of short-term outcomes. Larger prospective trials will elucidate the impact of RLLR on long-term outcomes and establish treatment guidelines. PMID- 29715162 TI - Prognostic Impact of Postoperative C-reactive Protein for Non-small Cell Lung Cancer Following Lobectomy. AB - BACKGROUND/AIM: C-reactive protein (CRP) is associated with cancer progression; however, the prognostic impact of postoperative CRP remains controversial. The aim of this study was to investigate the prognostic significance of postoperative CRP in patients with resected non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: A total of 198 consecutive patients with NSCLC that had undergone lobectomy were retrospectively reviewed. CRP was measured on postoperative days 1, 3, and 5. Patients were divided into two groups according to the median of CRP on postoperative day 3 (CRP3); the high and low CRP3 groups (n=99, respectively). RESULTS: Five-year overall survival was significantly higher in the high CRP3 group than the low CRP3 (75.3% vs. 86.5%; p=0.016), as was the 5-year recurrence free survival (62.7% vs. 73.0%; p=0.016). Multivariate analysis revealed that high CRP3 was associated with a favorable prognosis (hazard ratio(HR)=0.36; p<0.001). CONCLUSION: High CRP3 may be a favorable prognostic predictor in patients with NSCLC following lobectomy. PMID- 29715163 TI - The Role of Soluble CD40L Ligand in Human Carcinogenesis. AB - BACKGROUND: The role of CD40/CD40L in carcinogenesis is widely examined. The mechanisms linking the CD40/CD40L system and the soluble form of CD40 ligand (sCD40L) with neoplasia are nowadays a topic of intensive research. CD40L and sCD40L belong to the TNF superfamily and are molecules with a proinflammatory role. A variety of cells express CD40L such as the immune system cells, the endothelial cells and activated platelets. Although many medications such as statins have been shown to reduce sCD40L, it is still debated whether specific treatments targeting the CD40/CD40L system will prove to be effective against carcinogenesis in the near future. MATERIALS AND METHODS: A comprehensive search of the Pubmed Database was conducted for English-language studies using a list of key words. RESULTS: At diagnosis, serum samples of patients with neoplasia contained higher levels of sCD40L than healthy controls, suggesting that sCD40L may play a predictive role in human carcinogenesis. CONCLUSION: Patients with neoplasia had higher circulating sCD40L levels and it is likely that sCD40L may have a predictive role. It is still unclear whether sCD40L can be used as a therapeutic target. PMID- 29715164 TI - Early Versus Delayed Use of Ultrasound-Assisted Catheter-Directed Thrombolysis in Patients With Acute Submassive Pulmonary Embolism. AB - OBJECTIVES: The effect of early vs delayed use of ultrasound-assisted catheter directed thrombolysis (USAT) on invasive hemodynamics and in-hospital outcomes in patients with acute submassive pulmonary embolism (PE) is not well known. METHODS: We evaluated 41 patients with submassive PE to study the association of early USAT (<=24 hours; n = 21) vs delayed USAT (>24 hours; n = 20) with change in invasive hemodynamic measures from pre USAT to post USAT. RESULTS: Significantly greater improvement was observed in the early USAT group compared to the delayed group for median cardiac index (0.6 L/min/m2 [IQR, 0.4-1.1 L/min/ m2] vs 0.4 L/min/m2 [IQR, 0.1-0.6 L/min/m2]; P=.03), median pulmonary vascular resistance (3.4 Wood units [IQR, 2.5-4.1 Wood units] vs 0.5 Wood units [IQR, 0.2 1.3 Wood units]; P<.001), and mean right ventricular stroke work index (3.5 +/- 2.0 g-m/m2/beat vs 2.3 +/- 1.6 g-m/m2/beat; P=.04). Although not statistically significant, a trend in favor of early treatment was found for improvement in mean right ventricle to left ventricle diameter ratio (0.38 +/- 0.17 vs 0.33 +/- 0.21; P=.40), mean pulmonary artery pressure (8.4 +/- 7.1 mm Hg vs 5.3 +/- 5.2 mm Hg; P=.13), and median pulmonary artery pulsatility index (1.14 [IQR, 2.01-0.45] vs 0.65 [IQR, 0.22-1.78]; P=.49). The mean postprocedural length of stay was significantly lower in the early-USAT group (6.0 +/- 2.7 days vs 10.1 +/- 7.0 days; P=.02). Three patients experienced moderate bleeding (2 patients in the early-USAT group and 1 patient in the delayed-USAT group) and no major bleeds or in-hospital mortality occurred. CONCLUSION: Early USAT was associated with greater improvement in pulmonary hemodynamics and shorter postprocedural length of stay compared with delayed USAT in patients with acute submassive PE. PMID- 29715165 TI - Implementation of a Low Frame-Rate Protocol and Noise-Reduction Technology to Minimize Radiation Dose in Transcatheter Aortic Valve Replacement. AB - OBJECTIVES: Limiting radiation exposure is necessary in radiological procedures. This study evaluates the impact of a radiological low frame-rate protocol in a standard angiographic system and the implementation of a noise-reduction technology (NRT) on patient radiation exposure during transcatheter aortic valve replacement (TAVR). METHODS: Transfemoral TAVR procedures performed between February 2016 and February 2017 were analyzed according to two angiographic systems, Standard and NRT, and further divided in four subgroups: (1) Standard 15 frames per second (fps) with 15 fps for both fluoroscopy and cine acquisitions; (2) Standard 7.5 fps with 7.5 fps for both fluoroscopy and cine acquisitions; (3) NRT 15 fps with 15 fps for both fluoroscopy and cine acquisitions; and (4) NRT 7.5 fps with 15 fps for fluoroscopy and 7.5 fps for cine acquisitions. Study endpoints were kerma area product (KAP) and cumulative air kerma at interventional reference point (AK at IRP). RESULTS: Significant differences were found in KAP (153 Gy.cm2 [IQR, 95-234 Gy.cm2] vs 78.3 Gy.cm2 [IQR, 54.4-103.5 Gy.cm2]; P<.001) and AK at IRP (1.454 Gy [IQR, 0.893-2.201 Gy] vs 0.620 Gy [IQR, 0.437-0.854 Gy]; P<.001) between Standard system and NRT. Within the procedures conducted with Standard protocol, a reduction of KAP and AK at IRP was found between Standard 15 fps and Standard 7.5 fps groups (184 Gy.cm2 [IQR, 128-262 Gy.cm2] vs 106.8 Gy.cm2 [IQR, 76.87-181 Gy.cm2] [P<.01] and 0.973 Gy [IQR, 0.642 1.786 Gy] vs 0.64 Gy [IQR, 0.489-0.933 Gy] [P<.01], respectively). CONCLUSIONS: The present study suggests that the low frame-rate protocol in Standard system and NRT implementation allows a marked reduction of patient radiation exposure in TAVR procedures. PMID- 29715166 TI - A Comprehensive Evidence-Based Decision Algorithm for Assisting Clinicians and Patients With Stable Ischemic Heart Disease in Selecting Revascularization Strategy in Multivessel Disease. AB - We propose an evidenced-based algorithm for the selection of revascularization strategy (coronary artery bypass surgery, percutaneous coronary intervention, or optimal medical therapy) to be applied in multivessel, non-acute coronary syndrome presentations. This algorithm provides a highly effective tool that is comprehensible to both physicians and patients. PMID- 29715167 TI - Spiral Pseudodissection of a Tortuous Internal Mammary Artery Graft. AB - Images and videos help describe a high-risk coronary intervention of an elongated and extremely tortuous LIMA graft to the LAD. LIMA had a complete 360 degrees loop at the mid segment, followed by severe tortuosity and a subtotal occlusion at the anastomosis. PMID- 29715168 TI - Persistent Left Superior Vena Cava: Imaging Correlation. AB - In this heart failure patient, TEE images confirm the presence of the persistent left SVC with a dilated coronary sinus, severe mitral regurgitation, and aortic stenosis. Computed tomography reveals an isolated persistent left SVC and rules out anomalous pulmonary vein drainage or additional congenital disease. PMID- 29715169 TI - Coronary Bypass Graft Pseudoaneurysm Successfully Treated by PTFE-Covered Jostent GraftMaster. AB - A 60-year-old male presented 12 months after CABG surgery with a large pulsatile sternal mass. CT scan of the chest demonstrated a pseudoaneurysm originating from the mid saphenous vein graft to the PDA measuring 7.7 x 7.2 x 6.0 cm. After a multidisciplinary consultation, a decision was made to place a Jostent GraftMaster to completely seal the communication of the extravasation. PMID- 29715170 TI - Treatment of Diffuse Right Coronary Aneurysmal Disease With Standard Drug-Eluting Stent Scaffolding of Polytetrafluoroethylene-Covered Stents. AB - Demonstration of a novel technique to safely exclude long aneurysmal segments that require multiple covered stents in a single segment. In addition, these images and video series demonstrate the usefulness of balloon-assisted GuideLiner tracking to pass bulky equipment to the distal segments of heavily diseased vessels. PMID- 29715171 TI - Bleeding Heart and Coronary Cameral Fistulae. AB - This letter addresses an article regarding coronary-cameral fistula after septal myomectomy published in the December 2017 issue of the Journal of Invasive Cardiology and authored by Walters D, et al. PMID- 29715172 TI - How Hedstrom files fail during clinical use? A retrieval study based on SEM, optical microscopy and micro-XCT analysis. AB - This study was conducted to evaluate the failure mechanism of clinically failed Hedstrom (H)-files. Discarded H-files (n=160) from #8 to #40 ISO sizes were collected from different dental clinics. Retrieved files were classified according to their macroscopic appearance and they were investigated under scanning electron microscopy (SEM) and X-ray micro-computed tomography (mXCT). Then the files were embedded in resin along their longitudinal axis and after metallographic grinding and polishing, studied under an incident light microscope. The macroscopic evaluation showed that small ISO sizes (#08-#15) failed by extensive plastic deformation, while larger sizes (>=#20) tended to fracture. Light microscopy and mXCT results coincided showing that unused and plastically deformed files were free of internal defects, while fractured files demonstrate the presence of intense cracking in the flute region. SEM analysis revealed the presence of striations attributed to the fatigue mechanism. Secondary cracks were also identified by optical microscopy and their distribution was correlated to fatigue under bending loading. Experimental results demonstrated that while overloading of cutting instruments is the predominating failure mechanism of small file sizes (#08-#15), fatigue should be considered the fracture mechanism for larger sizes (>=#20). PMID- 29715173 TI - A quantitative LC-MS/MS method for insulin-like growth factor 1 in human plasma. AB - BACKGROUND: Insulin-like growth factor 1 (IGF1) is a biomarker with various applications in medicine and also in doping control. METHODS: A liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed that employs 15N-IGF1 as an internal standard. The method features urea-based IGF1/IGFBP-complex dissociation which is directly followed by tryptic digestion. Following solid-phase extraction (SPE) sample clean-up of the digest, IGF1 is detected by means of two signature peptides that enable quantification of total IGF1 as well as discrimination between IGF1 proteoforms with 'native' and modified or extended N-terminal sequences. RESULTS: Our method is capable of measuring plasma IGF1 concentrations over the clinically relevant range of 10 1000 ng/mL and was validated according to regulatory guidelines. Comparison with the IDS-iSYS IGF1 immunoassay revealed good correlation (R2>0.97) and no proportional bias between both assays was observed after normalizing the results against the WHO reference standard for IGF1 (02/254). Evaluation of several commercially available IGF1 preparations showed varying responses which were due to inconsistencies in purity and absolute amount of IGF1 present in these products. CONCLUSIONS: Our LC-MS/MS method introduces urea-based dissociation of IGF1/IGFBP-complexes to enable reliable quantification of IGF1 in plasma. Furthermore, the method is able to detect clinically relevant IGF1 levels without an enrichment procedure at the protein-level and thereby minimizes the risk of losing IGF1 proteoforms during sample preparation. PMID- 29715174 TI - Computer-assisted interventions in the clinical laboratory process improve the diagnosis and treatment of severe vitamin B12 deficiency. AB - BACKGROUND: Severe vitamin B12 deficiency can result in serious complications if undiagnosed or untreated. Our aim was to test the efficacy of interventions in the laboratory process to improve the detection and the treatment of severe vitamin B12 deficiency. METHODS: Quasi-experimental investigation with a retrospective 7-year pre-intervention period and 29-month post-intervention follow-up in a university hospital. Two interventions were designed to improve the detection and treatment of subjects with vitamin B12 deficiency: the laboratory information system (LIS) automatically added seru vitamin B12 (s vitamin B12) based on certain conditions; and created a comment in the report and scheduled an appointment with the general practitioner (GP). We calculated the number of new diagnoses of severe vitamin deficiency (s-vitamin B12 <73.8 pmol/L) and the proportion of identified patients that were correctly treated in the pre- and post-intervention periods. We compared the number of tests needed to detect a new case when ordered by GPs vs. added by the strategy. Finally, we investigated the economic cost of each new case. RESULTS: The strategy added 699 s-vitamin B12 and detected 66 new cases of severe vitamin deficiency. The number of tests needed to identify a new case when s-vitamin B12 was ordered by GPs was 187, as opposed to 10 when added through the intervention (p<0.001). The intervention reagent cost was ?26.7 per new case. In the post-intervention cohort, 88% of patients were correctly treated, as opposed to 52% in the pre-intervention (p<0.001). CONCLUSIONS: Interventions in the clinical laboratory process improved the diagnosis and treatment of severe vitamin B12 deficiency. PMID- 29715175 TI - Prognostic implications of detectable cardiac troponin I below the 99th percentile in patients admitted to an emergency department without acute coronary syndrome. AB - BACKGROUND: Detectable troponin below the 99th percentile may reflect an underlying cardiac abnormality which might entail prognostic consequences. This study aimed to investigate the prognosis of patients admitted to an emergency department (ED) with detectable troponin below the 99th percentile reference limit who did not present with an acute coronary syndrome (ACS). METHODS: We analysed the clinical data of all consecutive patients admitted to the ED during the years 2012 and 2013 in whom cardiac troponin was requested by the attending clinician (cTnI Ultra Siemens, Advia Centaur). Patients with troponin below the 99th percentile of the reference population (40 ng/L) and who did not have a diagnosis of ACS were selected, and their mortality was evaluated in a 2-year follow-up. RESULTS: A total of 2501 patients had a troponin level below the reference limit, with 43.9% of those showing detectable levels (>6 ng/L and <40 ng/L). Patients with detectable levels were elderly and had a higher prevalence of cardiovascular history and more comorbidities. The total mortality in the 2 year follow-up was 12.4% in patients with detectable troponin and 4.5% in patients with undetectable troponin (p<0.001). In the Cox multivariate regression analysis, the detectable troponin was an independent marker of mortality at 2 years (HR 1.62, 95% CI 1.07-2.45, p=0.021). CONCLUSIONS: Detectable troponin I below the 99th percentile is associated with higher mortality risk at 2-year follow-up in patients admitted to the ED who did not present with ACS. PMID- 29715176 TI - Procalcitonin guidance in patients with lower respiratory tract infections: a systematic review and meta-analysis. AB - Although effective for bacterial lower respiratory tract infections (LRTIs), antibiotic treatment is often incorrectly prescribed for non-bacterial LRTIs. Procalcitonin has emerged as a promising biomarker to diagnose bacterial infections and guide antibiotic treatment decisions. As part of a regulatory submission to the U.S. Food and Drug Administration, this systematic review and meta-analysis summarizes the effects of procalcitonin-guided antibiotic stewardship on antibiotic use and clinical outcomes in adult LRTI patients. PubMed and the Cochrane Database of Systematic Reviews were searched for English language randomized controlled trials published between January 2004 and May 2016. Random and fixed effects meta-analyses were performed to study efficacy (initiation of antibiotics, antibiotic use) and safety (mortality, length of hospital stay). Eleven trials were retained, comprising 4090 patients. Procalcitonin-guided patients had lower odds of antibiotic initiation (odds ratio: 0.26; 95% confidence interval [CI]: 0.13-0.52) and shorter mean antibiotic use (weighted mean difference: -2.15 days; 95% CI: -3.30 to -0.99) compared to patients treated with standard care. Procalcitonin use had no adverse impact on mortality (relative risk: 0.94; 95% CI: 0.69-1.28) and length of hospital stay (weighted mean difference: -0.15 days; 95% CI: -0.60 to 0.30). Procalcitonin guidance reduces antibiotic initiation and use among adults with LRTIs with no apparent adverse impact on length of hospital stay or mortality. PMID- 29715177 TI - Updated review of postmortem biochemical exploration of hypothermia with a presentation of standard strategy of sampling and analyses. AB - Hypothermia is defined as a core body temperature below 35 degrees C and can be caused by environmental exposure, drug intoxication, metabolic or nervous system dysfunction. This lethal pathology with medico-legal implications is complex to diagnose because macroscopic and microscopic lesions observed at the autopsy and the histological analysis are suggestive but not pathognomonic. Postmortem biochemical explorations have been progressively developed through the study of several biomarkers to improve the diagnosis decision cluster. Here, we present an updated review with novel biomarkers (such as catecholamines O-methylated metabolites, thrombomodulin and the cardiac oxyhemoglobin ratio) as well as some propositional interpretative postmortem thresholds and, to the best of our knowledge, for the first time, we present the most adapted strategy of sampling and analyses to identify biomarkers of hypothermia. For our consideration, the most relevant identified biomarkers are urinary catecholamines and their O methylated metabolites, urinary free cortisol, blood cortisol, as well as blood, vitreous humor and pericardial fluid for ketone bodies and blood free fatty acids. These biomarkers are increased in response either to cold-mediated stress or to bioenergetics ketogenesis crisis and significantly contribute to the diagnosis by exclusion of death by hypothermia. PMID- 29715178 TI - National surveys on internal quality control for blood gas analysis and related electrolytes in clinical laboratories of China. AB - BACKGROUND: Internal quality control (IQC) is essential for precision evaluation and continuous quality improvement. This study aims to investigate the IQC status of blood gas analysis (BGA) in clinical laboratories of China from 2014 to 2017. METHODS: IQC information on BGA (including pH, pCO2, pO2, Na+, K+, Ca2+, Cl-) was submitted by external quality assessment (EQA) participant laboratories and collected through Clinet-EQA reporting system in March from 2014 to 2017. First, current CVs were compared among different years and measurement systems. Then, percentages of laboratories meeting five allowable imprecision specifications for each analyte were calculated, respectively. Finally, laboratories were divided into different groups based on control rules and frequency to compare their variation trend. RESULTS: The current CVs of BGA were significantly decreasing from 2014 to 2017. pH and pCO2 got the highest pass rates when compared with the minimum imprecision specification, whereas pO2, Na+, K+, Ca2+, Cl- got the highest pass rates when 1/3 TEa imprecision specification applied. The pass rates of pH, pO2, Na+, K+, Ca2+, Cl- were significantly increasing during the 4 years. The comparisons of current CVs among different measurement systems showed that the precision performance of different analytes among different measurement systems had no regular distribution from 2014 to 2017. The analysis of IQC practice indicated great progress and improvement among different years. CONCLUSIONS: The imprecision performance of BGA has improved from 2014 to 2017, but the status of imprecision performance in China remains unsatisfying. Therefore, further investigation and continuous improvement measures should be taken. PMID- 29715179 TI - On the complexity of hemostasis and the need for harmonization of test practice. PMID- 29715181 TI - Harmonization of External Quality Assessment Schemes and their role - clinical chemistry and beyond. PMID- 29715180 TI - beta-Trace protein in hemodialysis - comparison of different therapy modalities and high flux dialyzers. PMID- 29715182 TI - Remission of relapsing polychondritis after successful treatment of myelodysplastic syndrome with azacitidine: a case and review of the literature. AB - BACKGROUND: Relapsing polychondritis (RP) is a rare autoimmune disorder, and myelodysplastic syndrome (MDS) is accompanied by RP at variable rates. Herein, we report a case with RP and MDS who responded dramatically to 5-azacitidine for MDS. CASE PRESENTATION: With conventional immunosuppressive treatment, our patient had several episodes of different side effects, including infections. With the diagnosis of MDS and initiation of azacitidine treatment, all the manifestations of RP disappeared, and remission was achieved for MDS. Although he had relapses of either RP or MDS after several years of azacitidine treatment, all relapses were controlled well with the initiation of azacitidine treatment every time. CONCLUSIONS: Azacitidine should be kept in mind as a treatment option for RP patients with MDS. PMID- 29715183 TI - c-Fos expression in the hypothalamic paraventricular nucleus after a single treatment with a typical haloperidol and nine atypical antipsychotics: a pilot study. AB - OBJECTIVE: The aim of the present study was to find out whether acute effect of different doses of selected antipsychotics including aripiprazole (ARI), amisulpride (AMI), asenapine (ASE), haloperidol (HAL), clozapine (CLO), risperidone (RIS), quetiapine (QUE), olanzapine (OLA), ziprasidone (ZIP), and paliperidone (PAL) may have a stimulatory impact on the c-Fos expression in the hypothalamic paraventricular nucleus (PVN) neurons. METHODS: Adult male Wistar rats weighing 280-300 g were used. They were injected intraperitoneally with vehicle or antipsychotics in the following doses (mg/kg of b.w.): ARI (1, 10, 30), AMI (10, 30), ASE (0.3), HAL (1.0, 2.0), CLO (10, 20), RIS (0.5, 2.0), QUE (10, 20), OLA (5, 10), ZIP (10, 30), and PAL (1.0). Ninety min later, the animals were anesthetized with Zoletil and Xylariem and sacrificed by a transcardial perfusion with 60 ml of saline containing 450 MUl of heparin (5000 IU/l) followed by 250 ml of fixative containing 4% paraformaldehyde in 0.1 M phosphate buffer (PB, pH 7.4). The brains were postfixed in a fresh fixative overnight, washed two times in 0.1 M PB, infiltrated with 30% sucrose for 2 days at 4 degrees C, frozen at -80 degrees C for 120 min, and cut into 30 MUm thick serial coronal sections at -16 degrees C. c-Fos profiles were visualized by nickel intensified DAB immunohistochemistry and examined under Axio-Imager A1 (Zeiss) light microscope. RESULTS: From ten sorts of antipsychotics tested, only six (ARI-10, CLO-10 and CLO-20, HAL-2, AMI-30, OLA-10, RIS-2 mg/kg b.w.) induced distinct c Fos expression in the PVN. The antipsychotics predominantly targeted the medial parvocellular subdivision of the PVN. CONCLUSIONS: The present pilot study revealed c-Fos expression increase predominantly in the PVN medial parvocellular subdivision neurons by action of only several sorts of antipsychotics tested indicating that this structure of the brain does not represent a common extra striatal target area for all antipsychotics. PMID- 29715184 TI - Mutations in SURF1 are important genetic causes of Leigh syndrome in Slovak patients. AB - OBJECTIVES: Leigh syndrome is a progressive early onset neurodegenerative disease typically presenting with psychomotor regression, signs of brainstem and/or basal ganglia disease, lactic acidosis, and characteristic magnetic resonance imaging findings. At molecular level, deficiency of respiratory complexes and/or pyruvate dehydrogenase complex is usually observed. Nuclear gene SURF1 encodes an assembly factor for cytochrome c-oxidase complex of the respiratory chain and autosomal recessive mutations in SURF1 are one of the most frequent causes of cytochrome c oxidase-related Leigh syndrome cases. Here, we aimed to elucidate the genetic basis of Leigh syndrome in three Slovak families. METHODS AND RESULTS: Three probands presenting with Leigh syndrome were selected for DNA analysis. The first proband, presenting with atypical LS onset without abnormal basal ganglia magnetic resonance imaging findings, was analyzed with whole exome sequencing. In the two remaining probands, SURF1 was screened by Sanger sequencing. Four different heterozygous mutations were identified in SURF1: c.312_321delinsAT:p.(Pro104Profs*1), c.588+1G>A, c.823_833+7del:p. (?) and c.845_846del:p.(Ser282Cysfs*9). All the mutations are predicted to have a loss-of function effect. CONCLUSIONS: We identified disease-causing mutations in all three probands, which points to the important role of SURF1 gene in etiology of Leigh syndrome in Slovakia. Our data showed that patients with atypical Leigh syndrome phenotype without lesions in basal ganglia may benefit from the whole exome sequencing method. In the case of probands presenting the typical phenotype, Sanger sequencing of the SURF1 gene seems to be an effective method of DNA analysis. PMID- 29715185 TI - Darapladib inhibits atherosclerosis development in type 2 diabetes mellitus Sprague-Dawley rat model. AB - OBJECTIVE: Increase in the low-density lipoprotein (LDL) level in diabetes mellitus and atherosclerosis is related to lipoprotein associated phospholipase A2 (Lp-PLA2). Lp-PLA2 is an enzyme that produces lysophosphatidylcholine (LysoPC) and oxidized nonesterified fatty acids (oxNEFA). LysoPC regulates inflammation mediators, including intra-cellular adhesion molecule-1 (ICAM-1). Darapladib is known as a Lp-PLA2 specific inhibitor. The aim of this study was to reveal the effect of darapladib on the foam cell number, inducible nitric oxide synthase (iNOS), and ICAM-1 expression in aorta at early stages of the atherosclerosis in type 2 diabetes mellitus Sprague-Dawley rat model. METHODS: Thirty Sprague-Dawley male rats were divided into 3 main groups: control, rats with type 2 diabetes mellitus (T2DM), and T2DM rats treated with darapladib (T2DM-DP). Each group was divided into 2 subgroups according the time of treatment: 8-week and 16-week treatment group. Fasting blood glucose, insulin resistance, and lipid profile were measured and analyzed to ensure T2DM model. The foam cells number were detected using hematoxylin-eosin (HE) staining and the expression of iNOS and ICAM-1 was analyzed using double immunofluorescence staining. RESULTS: Induction of T2DM in male Sprague-Dawley rats after high fat diet and streptozotocin injection was confirmed by elevated levels of total cholesterol and LDL and increased fasting glucose and insulin levels compared to controls after both times of treatment. Moreover, T2DM in rats induced a significant increase (p<0.05) in the foam cells number and iNOS and ICAM-1 expression in aorta compared to controls after both treatment times. Darapladib treatment significantly reduced (p<0.05) foam cells number as well as iNOS expression in aorta in rats with T2DM after both treatment times. A significant decrease (p<0.05) in ICAM-1 expression in aorta was observed after darapladib treatment in rats with T2DM only after 8 weeks of treatment. CONCLUSION: Our data indicate that darapladib can decrease the foam cells number, iNOS, and ICAM-1 expression in aorta at the early stages of atherosclerosis in T2DM rat model. PMID- 29715186 TI - Glucometabolic effects of single and repeated exposure to forced-swimming stressor in Sprague-Dawley rats. AB - OBJECTIVES: We aimed to evaluate the effects of a single (acute) and repeated (chronic) exposure to forced-swimming stressor on glucose tolerance, insulin sensitivity, lipid profile and glycogen content in male rats. METHODS: Thirty adult male Sprague-Dawley rats (12 weeks old) were divided randomly into five groups: control group, single exposure (SE) to forced-swim stressor, repeated exposure to forced-swim stressor for 7 days (RE7), 14 days (RE14) and 28 days (RE28). Glucose tolerance test and Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) were undertaken on fasting rats to obtain glucose and insulin profiles. ELISA was performed to assess plasma insulin and corticosterone levels. Total cholesterol, triglyceride, high- and low-density lipoproteins, hepatic and skeletal glycogen content were also determined. RESULTS: Repeated exposure to stressor induced glucose intolerance and insulin resistance in the experimental rats. Results showed that all RE groups exhibited a significantly higher area under the curve compared with others (p=0.0001); similarly, HOMA-IR increased (p=0.0001) in all RE groups compared with control. Prolonged exposure to stressor significantly increased the plasma insulin and corticosterone levels but decreased the glycogen content in the liver and skeletal muscle when compared with the control group. Additionally, chronic stressor significantly increased the total cholesterol and triglyceride levels, however, acute stressor produced significantly elevated high-density lipoproteins level. CONCLUSIONS: In conclusion, repeated exposure to forced-swimming stressor induced glucose intolerance and insulin resistance in rats by disrupting the insulin sensitivity as well as heightening the glycogenolysis in the liver and skeletal muscle. Acute stressor was unable to cause glucose intolerance and insulin resistance but it appears that may have a positive effect on the lipid metabolism. PMID- 29715187 TI - Possible association of ghrelin/obestatin balance with cardiometabolic risk in obese subjects with Helicobacter pylori. AB - OBJECTIVES: Helicobacter pylori (H. pylori) is a common gastric infection associated with extragastric conditions. The association between H. pylori infection and obesity is unclear. H. pylori may affect gut hormones involved in food intake and energy expenditure. The aim of this study is to evaluate ghrelin/obestatin balance and leptin in obese subjects with H. pylori infection. METHODS: Sixty healthy volunteers were divided into: obese and non-obese groups. Each group was divided into H. Pylori positive or H. pylori negative. Anthropometric parameters, H. pylori status, serum glucose, insulin level, and lipid profile were estimated with calculation of Homeostasis Model Assessment Insulin Resistance (HOMA-IR). Serum levels of ghrelin, obestatin, and leptin were evaluated. RESULTS: Significant increase was found in serum glucose, insulin and HOMA-IR ratio in obese subjects with positive H. pylori as compared to other groups. H. pylori positive obese subjects showed significantly increased ghrelin, ghrelin/obestatin balance, and leptin with a significant decrease in obestatin as compared to negative subjects. Ghrelin/obestatin ratio positively correlated with weight, body mass index, waist, glucose, insulin, HOMA-IR, leptin, cholesterol, triglycerides, low density cholesterol and also with H. pylori antigen in the same group. CONCLUSIONS: It can be concluded that ghrelin, obestatin, and leptin are affected by presence of H. pylori seropositivity in obese subjects. The higher ghrelin levels and ghrelin/obestatin ratio with lowered obestatin could be considered as a gastro-protective effect against inflammation induced by H. pylori. PMID- 29715188 TI - Possible protective effect of curcumin on the thyroid gland changes induced by sodium fluoride in albino rats: light and electron microscopic study. AB - OBJECTIVES: Thyroid gland regulates the body's metabolic rate and plays an exquisitely important role in the human health. Fluoride exposure can affect thyroid function. Curcumin is a potent antioxidant that works through several mechanisms. The aim of the present study was to demonstrate the hormonal, histological, and ultrastructural changes occurred in the thyroid gland induced by exposure to sodium fluoride (NaF) and study the possible protective effect of curcumin on the NaF-induced effects. METHODS: Thirty male albino rats were randomly divided into 3 equal groups (10 rats each): the control group, NaF group, and NaF+Curcumin (NaF+Cur) group. Thyroid-stimulating hormone (TSH), triiodothyronine (T3) and thyroxine (T4) levels were assayed and thyroid tissues processed for light and transmission electron microscopic study. RESULTS: In NaF group, serum T3 and T4 levels were significantly decreased whereas TSH level was significantly increased compared to the control group. Thyroid tissues showed flattening of the epithelial lining with several follicular cell degenerations, hyperplasia, decreased colloid, disrupted basement membrane, cytoplasmic vacuolations, degenerated mitochondria, widening of rough endoplasmic reticulum cisternae, and vascular congestion compared to the control group. In the NaF+Cur group, serum TSH levels were significantly decreased in comparison with NaF group and no significant difference in comparison with the control group. Thyroid sections appeared apparently normal compared to the control group and NaF group. CONCLUSIONS: Sodium fluoride affected both the function and structure of the thyroid gland while curcumin was protective against these toxic effects. PMID- 29715189 TI - Co-exposure to endocrine disruptors: effect of bisphenol A and soy extract on glucose homeostasis and related metabolic disorders in male mice. AB - OBJECTIVES: Bisphenol A (BPA) is a xenoestrogen, which is commonly used as a monomer of polycarbonate plastics food containers and epoxy resins. Little is known about the interaction effects between xeno- and phyto- estrogens on glucose homeostasis or other metabolic disorders. The aim of this study was to examine effects of individual or combined exposure to low doses of BPA and soy extract on glucose metabolism in mice with the goal to establish its potential mechanisms. METHODS: Fifty-four male mice were randomly divided into six groups. Mice were treated with soy extract at 60 or 150 mg/kg by daily gavage with or without subcutaneously administration of BPA (100 MUg/kg/day) for four weeks at the same time, while the control group received a vehicle. Serum levels of fasting glucose, insulin, adiponectin, testosterone, malondialdehyde (MDA), and total antioxidant capacity (TAC) were measured. Homeostatic model assessment-beta cell function (HOMA-beta) index was also determined. RESULTS: BPA exposure induced hyperglycemia and significantly reduced HOMA-beta, serum levels of insulin, adiponectin, testosterone, and TAC and noticeably enhanced MDA in BPA group compared to control one. While treatment with soy extract in high dose (150 mg/kg) significantly decreased the levels of fasting blood glucose and MDA and notably improved the serum levels of insulin, HOMA-beta, and TAC compared to BPA group. CONCLUSION: Soy extract may protect against some adverse effects of BPA. These findings represent the first report suggesting a potential effect between soy extract and BPA in low doses, however, further studies are needed to confirm these results. PMID- 29715190 TI - Incidence of congenital hypothyroidism in China: data from the national newborn screening program, 2013-2015. AB - BACKGROUND: Congenital hypothyroidism (CH) is one of the most frequent, preventable causes of mental retardation. Little has been reported on the epidemiological characteristics of CH in China. We aimed to estimate the incidence of CH in China and investigate its geographical variation. METHODS: We analyzed data from the nationwide newborn screening program for CH between 2013 and 2015. Poisson regression was used to generate the odds ratios (ORs) and 95% confidence intervals (CIs) between the rates of CH and selected demographic characteristics and assess the potential association between CH incidence and geographical locations. RESULTS: A total of 18,666 patients with CH were identified from 45.2 million newborns, yielding an overall incidence rate of 4.13 per 10,000 live births. Compared with those in the remote area, regardless of infant sex, a higher incidence risk for CH was present in newborns in coastal areas and inland areas (females: OR=2.00, 95% CI: 1.86-2.16 and OR=1.74, 95% CI: 1.61-1.87, respectively; males: OR=1.70, 95% CI: 1.59-1.83 and OR=1.52, 95% CI: 1.42-1.63, respectively). Additionally, the highest risk of CH for thyroid stimulating hormone (TSH) screening values <40 mU/L was observed among neonates in the coastal areas, while TSH screening values of 70-100 mU/L were observed among those in the inland areas. CONCLUSIONS: The overall incidence of CH is high in China. The significant geographical variations of CH incidence are presented in this study. PMID- 29715191 TI - Five novel ALMS1 gene mutations in six patients with Alstrom syndrome. AB - BACKGROUND: Alstrom syndrome is a rare autosomal recessive inherited disorder caused by mutations in the ALMS1 gene. METHODS: We describe the clinical and five novel mutational screening findings in six patients with Alstrom syndrome from five families in a single center with distinct clinical presentations of this condition. RESULTS: Five novel mutations in ALMS1 in exon 8 and intron 17 were identified, one of them was a compound heterozygous: c.2259_2260insT, p.Glu754*; c.2035C>T p.Arg679*; c.2259_2260insT, p.Glu754*; c.5969C>G, p.Ser1990*; c.6541C>T, p. Gln2181*/c.11666-2A>G, splicing. One patient had gallstones, this association, to our knowledge, has not been reported in Alstrom syndrome previously. CONCLUSIONS: Early diagnosis of Alstrom syndrome is often difficult in children and adolescents, because many of the clinical features develop over time. Early diagnosis can initiate an effective managemen of this condition, and it will help to reduce future damage. PMID- 29715192 TI - Does initial dosing of levothyroxine in infants with congenital hypothyroidism lead to frequent dose adjustments secondary to iatrogenic hyperthyroidism on follow-up? AB - BACKGROUND: Congenital hypothyroidism (CH) is the most common preventable cause of intellectual disability. The recommended starting dose of levothyroxine (LT4) is between 10 and 15 MUg/kg, an extremely wide range. We hypothesized that a sizable proportion of newborns treated for CH at the higher end of the dosage range become biochemically hyperthyroid at a follow-up visit. METHODS: This study is a retrospective chart review of infants with CH between 2002 and 2012. RESULTS: Of the 104 patients included in this analysis, the average age at diagnosis was 11 days and the average starting dose of LT4 was 12+/-2.5 MUg/kg. At follow-up, 36.5% required a dose reduction because of iatrogenic hyperthyroxinemia, 51% required no dose adjustment and 12.5% required a dose increase due to an elevated thyroid stimulating hormone (TSH). The starting doses of LT4 for those requiring a dose reduction, those not requiring an adjustment and those requiring an increase in the dose were 13.2+/-2.4, 11.5+/-2.1 and 10.3+/-2.6 MUg/kg/day, respectively (p<=0.0001). Of the 34% of infants treated with an initial dose of >12.5 MUg/day, 57.1% required a dose reduction at follow up, compared to 26.1% of those whose initial starting dose was <=12.5 MUg/kg/day (p=0.007). CONCLUSIONS: Following the guidelines for initiating therapy for CH, 36.5% of the infants required a dose reduction for iatrogenic hyperthyroxinemia. These infants received a higher dose of LT4 than the infants who either required no adjustment or required an increase in the dose. A narrower range for initial dosing in CH may be appropriate. PMID- 29715193 TI - Severe lactic acidosis in an extremely low birth weight infant due to thiamine deficiency. AB - BACKGROUND: In this case report, we present a preterm newborn with persistent lactic acidosis who received total parenteral nutrition (TPN) that lacked thiamine. CASE PRESENTATION: A 28-week-old, 750 g female infant was born with an Apgar score of 8 at the 5th minute. Umbilical cord blood gas levels, including lactate level, were normal, and she was admitted to our neonatal intensive care unit (NICU). Achieving full enteral feeding was not possible due to gastric residues and abdominal distention, making the patient dependent on TPN during the first 2 weeks of life. An insidious increase in lactic acid levels and uncompensated metabolic acidosis were apparent from the 23rd day of life. Severe metabolic acidosis was persistent despite massive doses of bicarbonate. The acidosis resolved dramatically within 6 h when the patient was administered with thiamine. CONCLUSIONS: Although TPN is life saving in the NICU, meticulous attention must be paid to provide all essential macro- and micro-nutrients. PMID- 29715195 TI - Maternal medicine: an evolving discipline. PMID- 29715196 TI - Enhanced photocatalytic activity of wool fibers having titanium dioxide nanoparticles formed inside their cortex. AB - A wool-TiO2 nanoparticle composite material having TiO2 nanoparticles both infiltrated in the matrix between macrofibrils inside cortical cells of wool fibers and grafted on the fiber surface is obtained in this study, and the wool nanoparticle composite material is found to have highly photocatalytic activities with an extremely narrow band gap of 2.8 eV. The wool fibers are obtained using three successive technical steps: wool fibers are swollen by using lithium bromide, then saturated with tetrabutyl titanate ethanol solution and subsequently treated in boiling water. It was demonstrated that the chemical bonds formed between the as-synthesized TiO2 nanoparticles and the wool fibers swollen by lithium bromide include C-Ti4+(Ti3+), N-Ti4+(Ti3+), O-Ti3+, and S Ti4+(Ti3+) bonds. The modified wool fibers have shown markedly improved photocatalytic efficiency due to their enhanced visible light absorption capability, which is much better than the (N-doped) TiO2 coated wool fibers. In contrast, TiO2 modified wool fibers swollen by using formic acid have poorer photoactivity, this might be due to the elimination of trivalent titanium between TiO2 nanoparticles and the wool fibers. PMID- 29715194 TI - Trends in the use of puberty blockers among transgender children in the United States. AB - BACKGROUND: The objective of the study was to identify national trends in the utilization of histrelin acetate implants among transgender children in the United States. METHODS: We analyzed demographic, diagnostic and treatment data from 2004 to 2016 on the use of histrelin acetate reported to the Pediatric Health Information System (PHIS) to determine the temporal trends in its use for transgender-related billing diagnoses, e.g. "gender identity disorder". Demographic and payer status data on this patient population were also collected. RESULTS: Between 2004 and 2016, the annual number of implants placed for a transgender-related diagnosis increased from 0 to 63. The average age for placement was 14 years. Compared to natal females, natal males were more likely to receive implants (57 vs. 46) and more likely to have implants placed at an older age (62% of natal males vs. 50% of natal females were >=;13 years; p<0.04). The majority of children were White non-Hispanic (White: 60, minority: 21). When compared to the distribution of patients treated for precocious puberty (White: 1428, minority: 1421), White non-Hispanic patients were more likely to be treated with a histrelin acetate implant for a transgender-related diagnosis than minority patients (p<0.001). This disparity was present even among minority patients with commercial insurance (p<0.001). CONCLUSIONS: Utilization of histrelin acetate implants among transgender children has increased dramatically. Compared to natal females, natal males are more likely to receive implants and also more likely to receive implants at an older age. Treated transgender patients are more likely to be White when compared to the larger cohort of patients being treated with histrelin acetate for central precocious puberty (CPP), thus identifying a potential racial disparity in access to medically appropriate transgender care. PMID- 29715197 TI - Inorganic fullerene-like molybdenum selenide with good biocompatibility synthesized by laser ablation in liquids. AB - The fabrication of inorganic fullerene-like nanoparticles (IFNPs) is an attractive idea due to their unique structures and various potential applications. To date, IFNPs have been made from numerous compounds with layered two-dimensional structures, based on various synthetic methods. Here we have demonstrated for the first time that inorganic fullerene-like molybdenum selenide nanoparticles (MoSe2 IFNPs) can be synthesized by laser ablating a molybdenum selenide target in 30 vol % ethanol/water mixture at ambient temperature and pressure. The formation mechanism was proposed to elucidate the production of MoSe2 IFNPs in the process of laser ablation in liquids (LAL). The appropriate solvent facilitates the condensation of the plasma plume created by LAL to planar MoSe2. Then, laser-induced high temperature and high pressure lead to the formation of a vacancy in the planar MoSe2, causing the generation of nucleation and growth of the MoSe2 IFNPs. In addition, a CCK-8 (cell counting kit-8) assay and a cell viability assay were performed to examine the cytotoxic behavior and the effect on cell viability of MoSe2 IFNPs. The results show that MoSe2 IFNPs are reasonably nontoxic and biocompatible with the given cells, showing they have significant potential in biomedical applications. PMID- 29715198 TI - Full spectral optical modeling of quantum-dot-converted elements for light emitting diodes considering reabsorption and reemission effect. AB - Quantum dots (QDs) have attracted significant attention in light-emitting diode (LED) illumination and display applications, owing to their high quantum yield and unique spectral properties. However, an effective optical model of quantum dot-converted elements (QDCEs) for (LEDs) that entirely considers the reabsorption and reemission effect is lacking. This suppresses the design of QDCE structures and further investigation of light-extraction/conversion mechanisms in QDCEs. In this paper, we proposed a full spectral optical modeling method for QDCEs packaged in LEDs, entirely considering the reabsorption and reemission effect, and its results are compared with traditional models without reabsorption or reemission. The comparisons indicate that the QDCE absorption loss of QD emission light is a major factor decreasing the radiant efficacy of LEDs, which should be considered when designing QDCE structures. According to the measurements of fabricated LEDs, only calculation results that entirely consider reabsorption and reemission show good agreement with experimental radiant efficacy, spectra, and peak wavelength at the same down-conversion efficiency. Consequently, it is highly expected that QDCE will be modeled considering the reabsorption and reemission events. This study provides a simple and effective modeling method for QDCEs, which shows great potential for their structure designs and fundamental investigations. PMID- 29715199 TI - Cxcr4-haploinsufficient bone marrow transplantation corrects leukopenia in an unconditioned WHIM syndrome model. AB - For gene therapy of gain-of-function autosomal dominant diseases, either correcting or deleting the disease allele is potentially curative. To test whether there may be an advantage of one approach over the other for WHIM (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome - a primary immunodeficiency disorder caused by gain-of-function autosomal dominant mutations in chemokine receptor CXCR4 - we performed competitive transplantation experiments using both lethally irradiated WT (Cxcr4+/+) and unconditioned WHIM (Cxcr4+/w) recipient mice. In both models, hematopoietic reconstitution was markedly superior using BM cells from donors hemizygous for Cxcr4 (Cxcr4+/o) compared with BM cells from Cxcr4+/+ donors. Remarkably, only approximately 6% Cxcr4+/o hematopoietic stem cell (HSC) chimerism after transplantation in unconditioned Cxcr4+/w recipient BM supported more than 70% long-term donor myeloid chimerism in blood and corrected myeloid cell deficiency in blood. Donor Cxcr4+/o HSCs differentiated normally and did not undergo exhaustion as late as 465 days after transplantation. Thus, disease allele deletion resulting in Cxcr4 haploinsufficiency was superior to disease allele repair in a mouse model of gene therapy for WHIM syndrome, allowing correction of leukopenia without recipient conditioning. PMID- 29715201 TI - Article Summaries for May 2018 Psychosomatic Medicine, Volume 80, Issue 4. PMID- 29715202 TI - Alignment of Nursing Professional Development With Organizations' Strategic Priorities. PMID- 29715200 TI - TRAF4-mediated ubiquitination of NGF receptor TrkA regulates prostate cancer metastasis. AB - Receptor tyrosine kinases (RTKs) are important drivers of cancers. In addition to genomic alterations, aberrant activation of WT RTKs plays an important role in driving cancer progression. However, the mechanisms underlying how RTKs drive prostate cancer remain incompletely characterized. Here we show that non proteolytic ubiquitination of RTK regulates its kinase activity and contributes to RTK-mediated prostate cancer metastasis. TRAF4, an E3 ubiquitin ligase, is highly expressed in metastatic prostate cancer. We demonstrated here that it is a key player in regulating RTK-mediated prostate cancer metastasis. We further identified TrkA, a neurotrophin RTK, as a TRAF4-targeted ubiquitination substrate that promotes cancer cell invasion and found that inhibition of TrkA activity abolished TRAF4-dependent cell invasion. TRAF4 promoted K27- and K29-linked ubiquitination at the TrkA kinase domain and increased its kinase activity. Mutation of TRAF4-targeted ubiquitination sites abolished TrkA tyrosine autophosphorylation and its interaction with downstream proteins. TRAF4 knockdown also suppressed nerve growth factor (NGF) stimulated TrkA downstream p38 MAPK activation and invasion-associated gene expression. Furthermore, elevated TRAF4 levels significantly correlated with increased NGF-stimulated invasion-associated gene expression in prostate cancer patients, indicating that this signaling axis is significantly activated during oncogenesis. Our results revealed a posttranslational modification mechanism contributing to aberrant non-mutated RTK activation in cancer cells. PMID- 29715203 TI - Transforming Orientation Through a Tiered Skills Acquisition Model. AB - The tiered skills acquisition model (TSAM) is an effective method for structuring the clinical unit orientation. The orientee gradually assumes increased responsibilities based on advancing through tiers of skills from simple to complex. This article focuses on TSAM implemented at a teaching hospital with 188 newly licensed registered nurses. TSAM has increased nurses' confidence, role satisfaction, retention, reduced overall length of orientation by 18%, and increased the number of patient experiences by 45%. PMID- 29715204 TI - Instruments to Evaluate Nurse Residency Programs: A Review of the Literature. AB - The purpose of this literature review was to explore evaluation instruments used by nurse residency programs to evaluate outcomes. The 15 studies found yielded 26 instruments, and all instruments were subjective, dated, and varied in how they were used. Nursing professional development practitioners should use a combination of reliable, valid, and current evaluation methods to appraise their nurse residency programs in order to demonstrate program quality and effectiveness. PMID- 29715205 TI - Helping High School Students Explore Nursing Careers in a Summer Internship Program. AB - Although nursing remains the most trusted profession in the United States, it is still challenging to attract high school students due to a perception that nursing may not be as intellectual, challenging, or prestigious as other careers in health care. Nursing professional development practitioners can create an opportunity to change this perception by engaging high school students through a summer internship program. The Student Career Opportunity Outreach Program embeds high school students in the hospital environment, enabling them to be a part of a clinical area and engage with nurses in a meaningful way. This article aims to explain the components of the summer internship program for high school students in a pediatric academic medical center and discuss findings from a survey exploring career choices pre- and postprogram as well as other outcome measures. PMID- 29715206 TI - Implementation of a Standardized Evaluation Tool to Improve Preceptor Confidence. AB - Preceptors guide the transition of new graduate nurses into practice. Having access to evidence-based tools for evaluation of new graduate nurses promotes preceptor confidence and consistent measures of performance. The Norwegian Nurse Competence Scale was implemented across three acute care organizations for evaluation of new graduate nurse performance. After implementing a standardized process to evaluate new graduate nurses, individual summary scores ranged from 17 25 (preintervention) to 20-25 (postintervention), indicating mid to high levels of preceptor confidence. PMID- 29715207 TI - Preparing Nurse Leaders in Nursing Professional Development: Leadership Programs. PMID- 29715208 TI - Innovation in Quality Improvement: The Redesign of a Perioperative Residency. PMID- 29715209 TI - A Case for Mindfulness: Simulation-Based Six Strategy Framework. PMID- 29715210 TI - Natural Wonder. PMID- 29715211 TI - ANPD's Call to Convention: Be Part of the Magic! PMID- 29715212 TI - A Transparent Tracking System for Competency-Based Orientation: One Children's Hospital Transport Unit Experience. AB - When nurses are hired for positions that require lengthy, highly specialized in house orientation, their failure to complete orientation on time can lead to staffing shortages. In this article, we report the use of a transparent tracking system to monitor nurses' progress through a competency-based orientation program. By monitoring progress and detecting lapses, immediate remediation can be offered to those who need it, and staffing shortages thereby are avoided. PMID- 29715214 TI - Instruments to Evaluate Nurse Residency Programs: A Review of the Literature. PMID- 29715213 TI - Disruptive Technology: Saving Money and Inspiring Engagement in Professional Staff. AB - Competent, efficient, and cost-effective delivery of professional development is a challenge in health care. Collaboration of teaching methodologies with academia and acute care offers fresh perspectives and delivery methods that can facilitate optimal outcomes. One multihospital system introduced the academic "flipped classroom" model to its acute care setting and integrated it into professional development requirements. The concept of the flipped classroom requires independent student engagement prior to classroom activities versus the traditional classroom lecture model. Results realized a cost savings in 2 years of $28,737 in addition to positive employee engagement. PMID- 29715216 TI - Sports-Related Concussions in Children: Differences in Care and Expectations When Seen in an Emergency Department Versus a Sports Medicine Clinic. AB - OBJECTIVES: Patient and parent expectations can potentially influence management of care. We compared expectations in the diagnosis of concussion between patients who presented to a pediatric emergency department (ED) and those who presented to a sports medicine clinic, and if there was a difference in computed tomography (CT) scans performed. METHODS: Head-injured athletes aged 8 to 18 years presenting to a pediatric ED and a sports medicine clinic were enrolled. Both groups completed questionnaires on their understanding of concussion and expectations of care. Charts were then reviewed. RESULTS: Forty patients were enrolled in the study: 23 from a pediatric ED and 17 from a sports medicine clinic. Forty-one percent of athletes received a head CT in the pediatric ED versus 12% of those in the clinic population with no abnormal findings (P = 0.04). Forty-one percent of athletes and 48% of parents in the pediatric ED setting reported that a CT was "necessary" to diagnose concussion versus 18% in both groups from the clinic (P = 0.12, P = 0.07). Athletes presenting to the clinic were more likely to have been evaluated by an athletic trainer after the injury than those presenting to the pediatric ED (80% vs 23%, P = 0.004). CONCLUSIONS: Patients and parents who presented to a pediatric ED for sports related head injury had a trend toward higher expectations of a CT scan being necessary to diagnose concussion and did have a higher rate of CT scans performed. Education of athletes and parents engaging in organized sports may be worthwhile to assist in setting expectations in diagnosis of concussion. PMID- 29715218 TI - Current Approach to the Diagnosis and Management of Shoulder Dislocation in Children. PMID- 29715217 TI - Current Approach to the Diagnosis and Management of Shoulder Dislocation in Children. AB - Shoulder dislocations are a common presentation to the emergency department. Although many cases may be diagnosed by history and clinical examination alone, imaging may help diagnose more challenging cases. Three-view radiographs are important for identifying subtle posterior dislocations, and ultrasonography has been gaining evidence as an alternate diagnostic modality. Intra-articular lidocaine and nerve blocks may improve pain control and reduce the need for procedural sedation. Multiple, evidence-based reduction techniques are described including tips for improving success. Immobilization strategies and follow-up are also discussed. PMID- 29715219 TI - Sixty Years On: Ponseti Method for Clubfoot Treatment Produces High Satisfaction Despite Inherent Tendency to Relapse. AB - BACKGROUND: Developed at the University of Iowa in 1950, the Ponseti method to manage idiopathic clubfoot deformity was slow to gain wide acceptance until the mid-1990s. There is a paucity of intermediate and long-term outcome studies involving this technique, with nearly all such studies coming from a single institution. The purpose of this study is to report the contemporary outcome of patients with clubfoot deformity whose feet were managed with the Ponseti method and who were followed to >=5 years old, to provide outcome expectations for parents and for clinicians managing patients with idiopathic clubfoot. METHODS: Families of infants seen in our clinic diagnosed with idiopathic clubfoot since July 2006 were prospectively invited to participate in our institutional review board-approved study. Patients who received no prior outside treatment and had a minimum follow-up to the age of 5 years were included. Demographic, treatment, and outcome data were collected. To provide an array of outcome measures, both the Dallas outcome criteria and the Roye disease-specific instrument (DSI) were used. RESULTS: One hundred and one patients met the inclusion criteria. The mean length of follow-up (and standard deviation) was 81.1 +/- 17.1 months. Initial correction was achieved in all feet. Thirty-seven percent of families reported that they were adherent with the bracing protocol; 68% of patients had >=1 relapse, and 38% underwent a tendon transfer. With the Dallas criteria, 62% had outcomes rated as good, 38% had outcomes rated as fair, and no patient had an outcome rated as poor. With the Roye DSI, most families were generally very satisfied with the function and appearance of the feet. CONCLUSIONS: Satisfactory results at intermediate follow-up were achieved using the Ponseti method. However, despite a better understanding of the Ponseti method and the importance of longer post-corrective brace use, the need for anterior tibial tendon transfer remains an important adjunct to the Ponseti method. Brace adherence also continues to be a critical clinical issue. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29715220 TI - Patency Test of Vascular Anastomosis with Assistance of High-Speed Video Recording in Digit Replantation. AB - BACKGROUND: Quality assessment of vascular anastomosis primarily depends on the experience of the treating surgeon. This highlights the need for an objective index. The main goal of our study was to establish a method of assessing the quality of vascular anastomosis in digit replantation. METHODS: A total of 182 digits from 141 patients were included in this study. The patients underwent replantation of completely amputated digits between June 1, 2015, and February 1, 2017. Patency tests of arterial and venous anastomoses were conducted for each replantation and recorded on digital video at 1,000 frames per second. We divided the study into 2 phases. In phase I (103 digits from 80 patients), we investigated whether the refilling velocity ratio (RVR) was associated with replantation failure. In phase II (79 digits from 61 patients), we adopted the RVR as a guiding parameter during surgery and compared the replantation success rate with that of the historical control of phase I. RESULTS: In phase I, ischemia time (>12 hours), arterial RVR (<0.4), and venous RVR sum (<1.0) were significantly associated with the rate of replantation failure in 82 cases with single arterial anastomosis. In phase II, we set the arterial RVR goal to 0.4 and venous RVR sum goal to 1.0. Under the guidance of the RVR test, the survival rate significantly increased compared with that of the historical control of phase I (96% versus 87%; p = 0.037). CONCLUSIONS: The patency test, with assistance of high-speed video recording, is a useful tool that can improve the success rate of digit replantation. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29715222 TI - Alpha Defensin Lateral Flow Test for Diagnosis of Periprosthetic Joint Infection: Not a Screening but a Confirmatory Test. AB - BACKGROUND: Determination of alpha defensin in synovial fluid has shown promising results for diagnosing periprosthetic joint infection (PJI). The purposes of our study were to assess the performance of alpha defensin lateral flow (ADLF) test for the diagnosis of acute and chronic PJI using 3 classification systems and to compare its performance with the synovial fluid leukocyte count. METHODS: Patients in whom aspiration of a prosthetic hip or knee joint was performed before revision arthroplasty were prospectively included. In addition to standard diagnostic tests, the ADLF test was performed in synovial fluid. Patients were classified as having PJI or aseptic failure according to the definition criteria of the Musculoskeletal Infection Society (MSIS), the Infectious Diseases Society of America (IDSA), and the proposed criteria of the European Bone and Joint Infection Society (EBJIS). The performance of the ADLF test and the leukocyte count was compared using the McNemar chi-square test. RESULTS: Of 212 included patients, 151 (71%) had a knee prosthesis and 61 (29%) had a hip prosthesis. PJI was diagnosed in 45 patients (21%) using the MSIS criteria, in 55 patients (26%) using the IDSA criteria and in 79 patients (37%) using the proposed EBJIS criteria. The sensitivity of the ADLF test was 84% (95% confidence interval [CI], 71% to 94%) with the MSIS criteria, 67% (95% CI, 53% to 79%) with the IDSA criteria, and 54% (95% CI, 43% to 66%) with the proposed EBJIS criteria. The ADLF test showed high specificity using all classification criteria (96% to 99%) and represented the most specific preoperative test for PJI, especially in the early postoperative period (91%; 95% CI, 59% to 100%). Using the proposed EBJIS definition criteria, the sensitivity of the leukocyte count was significantly higher than that of the ADLF test (86% [95% CI, 76% to 93%] compared with 54% [95% CI, 43% to 66%]; p < 0.001), particularly in chronic PJI (81% compared with 44%, respectively; p < 0.001). CONCLUSIONS: The ADLF test was rapid and highly specific for diagnosing PJI (>95%). However, its sensitivity was limited (54% to 84%) and it should therefore not be used for screening, but rather as a confirmatory test for PJI. LEVEL OF EVIDENCE: Diagnostic Level I. See Instructions for Authors for a complete description of levels of evidence. PMID- 29715221 TI - Concomitant Ankle Osteoarthritis Is Related to Increased Ankle Pain and a Worse Clinical Outcome Following Total Knee Arthroplasty. AB - BACKGROUND: Occasionally, patients experience new or increased ankle pain following total knee arthroplasty (TKA). The aims of this study were to determine (1) how the correction of varus malalignment of the lower limb following TKA affected changes in alignment of the ankle and hindfoot, (2) the difference in changes in alignment of the ankle and hindfoot between patients with and without ankle osteoarthritis (OA), and (3) whether the rate of ankle pain and the clinical outcome following TKA differed between the 2 groups. METHODS: We retrospectively reviewed prospectively collected data of 56 patients (99 knees) treated with TKA. Among these cases, concomitant ankle OA was found in 24 ankles. Radiographic parameters of lower-limb, ankle, and hindfoot alignment were measured preoperatively and 2 years postoperatively. In addition, ankle pain and clinical outcome 2 years after TKA were compared between patients with and without ankle OA. RESULTS: The orientation of the ankle joint line relative to the ground improved from 9.4 degrees of varus to 3.4 degrees of varus, and the valgus compensation of the hindfoot for the varus tilt of the ankle joint showed a 2.2 degrees decrease following TKA. Patients in the group with ankle OA showed decreased flexibility of the hindfoot resulting in less preoperative valgus compensation (p = 0.022) compared with the group without ankle OA. The postoperative hindfoot alignment was similar between the 2 groups because of the smaller amount of change in patients with ankle OA. The group with ankle OA had a higher rate of increased ankle pain (38% compared with 16%) as well as a worse Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score (mean of 22.2 compared with 14.2) following TKA. CONCLUSIONS: A considerable proportion of patients who underwent TKA had concomitant ankle OA with reduced flexibility of the hindfoot. These patients experienced increased ankle pain following TKA and a worse clinical outcome. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29715223 TI - Quality of Care in Hip Fracture Patients: The Relationship Between Adherence to National Standards and Improved Outcomes. AB - BACKGROUND: Optimizing the perioperative care of patients with a hip fracture is a key health-care priority. We aimed to determine whether adherence to the Scottish Standards of Care for Hip Fracture Patients (SSCHFP) was associated with improved patient outcomes. METHODS: In this retrospective cohort study of prospectively collected data from the Scottish National Hip Fracture Audit, we assessed adherence to the SSCHFP in 21 Scottish hospitals over a 9-month period in 2014 and examined the effect of the guidelines on 30 and 120-day mortality, length of hospital stay, and discharge destination. RESULTS: A total of 1,162 patients who were >=50 years old and admitted with a hip fracture were included. There was a significant association between low adherence to the SSCHFP and increased mortality at 30 and 120 days (odds ratio [OR], 3.58 [95% confidence interval (CI), 1.75 to 7.32; p < 0.001] and 2.01 [95% CI, 1.28 to 3.12; p = 0.003], respectively). Low adherence was associated with a reduced likelihood of a short length of stay (OR, 0.58; 95% CI, 0.42 to 0.78; p < 0.0001), but increased odds of discharge to a high-care setting (OR, 1.63; 95% CI, 1.12 to 2.36; p = 0.01). Early physiotherapy input and occupational therapy input were associated with a reduced likelihood of discharge to a high-care setting (OR, 0.64 [95% CI, 0.44 to 0.98; p = 0.04] and 0.34 [95% CI, 0.23 to 0.48; p <0.001], respectively). CONCLUSIONS: Adherence to the SSCHFP is associated with better patient outcomes. These findings confirm the clinical utility of the SSCHFP and support their use as a benchmarking tool to improve quality of care for hip fractures. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29715224 TI - Effect of Tranexamic Acid on Blood Loss, D-Dimer, and Fibrinogen Kinetics in Adult Spinal Deformity Surgery. AB - BACKGROUND: Antifibrinolytics such as tranexamic acid reduce operative blood loss and blood product transfusion requirements in patients undergoing surgical correction of scoliosis. The factors involved in the unrelenting coagulopathy seen in scoliosis surgery are not well understood. One potential contributor is activation of the fibrinolytic system during a surgical procedure, likely related to clot dissolution and consumption of fibrinogen. The addition of tranexamic acid during a surgical procedure may mitigate the coagulopathy by impeding the derangement in D-dimer and fibrinogen kinetics. METHODS: We retrospectively studied consecutive patients who had undergone surgical correction of adult spinal deformity between January 2010 and July 2016 at our institution. Intraoperative hemostatic data, surgical time, estimated blood loss, and transfusion records were analyzed for patients before and after the addition of tranexamic acid to our protocol. Each patient who received tranexamic acid and met inclusion criteria was cohort-matched with a patient who underwent a surgical procedure without tranexamic acid administration. RESULTS: There were 17 patients in the tranexamic acid cohort, with a mean age of 60.7 years, and 17 patients in the control cohort, with a mean age of 60.9 years. Estimated blood loss (932 +/- 539 mL compared with 1,800 +/- 1,029 mL; p = 0.005) and packed red blood-cell transfusions (1.5 +/- 1.6 units compared with 4.0 +/- 2.1 units; p = 0.001) were significantly lower in the tranexamic acid cohort. In all single-stage surgical procedures that met inclusion criteria, the rise of D-dimer was attenuated from 8.3 +/- 5.0 MUg/mL in the control cohort to 3.3 +/- 3.2 MUg/mL for the tranexamic acid cohort (p < 0.001). The consumption of fibrinogen was 98.4 +/- 42.6 mg/dL in the control cohort but was reduced in the tranexamic acid cohort to 60.6 +/- 35.1 mg/dL (p = 0.004). CONCLUSIONS: In patients undergoing spinal surgery, intravenous administration of tranexamic acid is effective at reducing intraoperative blood loss. Monitoring of D-dimer and fibrinogen during spinal surgery suggests that tranexamic acid impedes the fibrinolytic pathway by decreasing consumption of fibrinogen and clot dissolution as evidenced by the reduced formation of D-dimer. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29715225 TI - Modified Scarf Osteotomy with Medial Capsule Interposition for Hallux Valgus in Rheumatoid Arthritis: A Study of Cases Including Severe First Metatarsophalangeal Joint Destruction. AB - BACKGROUND: Arthrodesis of the first metatarsophalangeal (MTP) joint has been recommended for severe hallux valgus deformity in patients with rheumatoid arthritis (RA). However, with the progress of medical treatment of RA, joint preservation surgery has recently been performed. The aim of this study was to investigate the clinical and radiographic outcomes of modified Scarf osteotomy with medial capsule interposition for RA cases including severe destruction of the first MTP joint and to evaluate risk factors for recurrence. METHODS: A retrospective observational study of 76 cases (60 patients) followed for a mean of 35.3 months (range, 24 to 56 months) after a modified Scarf osteotomy was performed. Scores on the Japanese Society for Surgery of the Foot (JSSF) RA foot and ankle scale, the JSSF hallux scale, and a self-administered foot evaluation questionnaire (SAFE-Q) were determined along with preoperative and postoperative radiographic parameters. RESULTS: There was a significant improvement, from preoperatively to final follow-up, in the mean JSSF RA foot and ankle score (from 52.2 to 76.9 points) and the mean JSSF hallux score (from 38.2 to 74.5 points). There was a recurrence (hallux valgus angle [HVA] of >20 degrees ) in 12 feet (16%). The preoperative DAS28-CRP score (disease activity score [based on 28 joints in the body]-C-reactive protein score) and intermetatarsal angles between the first and second metatarsals (M1M2A) and between the first and fifth metatarsals (M1M5A) were significantly greater in the recurrence group, as were the HVA, M1M2A, M1M5A, and Hardy grade at 3 months after surgery. There was a significant negative correlation between the preoperative DAS28-CRP score and the JSSF RA foot and ankle score at final follow-up (beta = -0.39, p = 0.02) and a significant positive correlation between the preoperative DAS28-CRP score and the HVA at final follow-up (beta = 0.44, p = 0.001). CONCLUSIONS: The modified Scarf osteotomy with medial capsule interposition for hallux valgus deformity improved clinical and radiographic outcomes in RA cases with severe destruction of the first MTP joint. Increased preoperative M1M2A and M1M5A; incomplete reduction of the sesamoid bone; and the HVA, M1M2A, and M1M5A at 3 months after surgery should be evaluated as they are associated with recurrence of the deformity. The preoperative DAS28-CRP score was associated with the clinical and radiographic outcomes after surgery. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29715226 TI - Development and Evaluation of a Preoperative Risk Calculator for Periprosthetic Joint Infection Following Total Joint Arthroplasty. AB - BACKGROUND: Preoperative identification of patients at risk for periprosthetic joint infection (PJI) following total hip arthroplasty (THA) or total knee arthroplasty (TKA) is important for patient optimization and targeted prevention. The purpose of this study was to create a preoperative PJI risk calculator for assessing a patient's individual risk of developing (1) any PJI, (2) PJI caused by Staphylococcus aureus, and (3) PJI caused by antibiotic-resistant organisms. METHODS: A retrospective review was performed of 27,717 patients (12,086 TKAs and 31,167 THAs), including 1,035 with confirmed PJI, who were treated at a single institution from 2000 to 2014. A total of 42 risk factors, including patient characteristics and surgical variables, were evaluated with a multivariate analysis in which coefficients were scaled to produce integer scores. External validation was performed with use of data on 29,252 patients who had undergone total joint arthroplasty (TJA) at an independent institution. RESULTS: Of the 42 risk factors studied, 25 were found not to be significant risk factors for PJI. The most influential of the remaining 17 included a previous open surgical procedure, drug abuse, a revision procedure, and human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). The areas under the curves were 0.83 and 0.84 for any PJI, 0.86 and 0.83 for antibiotic-resistant PJI, and 0.86 and 0.73 for S. aureus PJI in the internal and external validation models, respectively. The rates of PJI were 0.56% and 0.61% in the lowest decile of risk scores and 15.85% and 20.63% in the highest decile. CONCLUSIONS: In this large cohort study, we were able to identify and validate risk factors and their relative weights for predicting PJI. Factors such as prior surgical procedures and high-risk comorbidities should be considered when determining whether TJA is indicated and when counseling patients. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29715227 TI - Comparison of Direct Perioperative Costs in Treatment of Unstable Distal Radial Fractures: Open Reduction and Internal Fixation Versus Closed Reduction and Percutaneous Pinning. AB - BACKGROUND: As the United States transitions to value-based insurance, bundled payments, and capitated models, it is paramount to understand health-care costs and resource utilization. The financial implications of open reduction and internal fixation (ORIF) with a volar locking plate for management of unstable distal radial fractures have not been established. We aimed to elucidate cost differences between ORIF and closed reduction and percutaneous pinning (CRPP). Our hypothesis was that ORIF has greater direct perioperative costs than CRPP but that the costs equilibrate over time. METHODS: We reviewed financial data for 40 patients prospectively enrolled and randomized to undergo CRPP or ORIF for treatment of a closed, displaced, unstable distal radial fracture. Clinical and functional outcomes, hospital-associated direct perioperative costs, postoperative care and therapy costs, and costs for additional procedures were compared. Cost data were stratified into perioperative, 90-day, and 1-year periods, and were reported utilizing cost ratios (CRs) relative to the CRPP cohort. Statistical analysis was performed with chi-square and independent samples t tests with an alpha level of <0.05. RESULTS: Seventeen patients underwent CRPP and 23 underwent ORIF with a volar plate. Patients who underwent ORIF incurred greater 90-day (CR = 2.03/1.0, p < 0.001) and 1-year (CR = 1.60/1.0, p < 0.001) direct costs than those who underwent CRPP. The differential was greatest in the immediate perioperative period and gradually decreased over time. Operating room fees (CR = 1.7/1.0, p < 0.001), operating room implants, anesthesia (CR = 1.8/1.0, p < 0.001), and total perioperative costs (CR = 2.7/1.0, p < 0.001) were significantly greater in the ORIF cohort. Rehabilitation and cast technician costs were comparable (CR = 0.9/1.0 [ORIF/CRPP], p = 0.69). At 1 year, the CR for all costs of decreased to 1.6/1.0 (ORIF/CRPP, p < 0.001). Compared with the CRPP cohort, the ORIF cohort demonstrated significantly better functional outcomes at 6, 9, and 12 weeks and similar outcomes at 1 year. CONCLUSIONS: ORIF for a displaced, unstable distal radial fracture incurred greater direct costs than CRPP. Although implant costs for ORIF provided the greatest cost differential, additional procedures and higher clinic costs in the CRPP cohort narrowed the 90-day and 1-year cost gaps. LEVEL OF EVIDENCE: Economic Level II. See Instructions for Authors for a complete description of levels of evidence. PMID- 29715228 TI - Cervical Facet Orientation Varies with Age in Children: An MRI Study. AB - BACKGROUND: Within the spine, mobility and stability are principles that drive anatomic morphology. Based on radiographic measurements, the orientation of cervical facet joints has been proven to change throughout child growth. However, because of the mainly cartilaginous composition of the vertebrae in the young child, the lack of osseous landmarks makes radiograph-based measurements unreliable. The aims of our study were to evaluate the change in the sagittal orientation of the cervical facet joints with age based on magnetic resonance imaging (MRI) of asymptomatic children and to compare it to the changes in vertebral body dimensions. METHODS: Sagittal images passing through the center of the facet joint or through the center of the vertebral body were used to assess facet orientation at every cervical level. Anteroposterior facet orientation was defined as the angle between the superior facet and a line perpendicular to the posterior wall of the vertebral body. Vertical was defined as parallel to the posterior wall; horizontal was defined as perpendicular to the posterior wall. Vertebral body height and anteroposterior diameter were measured as well. RESULTS: MRI data of the normal cervical spine of 90 children who were 2 months to 18 years of age, obtained for neurologic evaluation, were used for this study. For each level from C3 to C7, there was a positive correlation between facet orientation and age (R = 0.498, p < 0.001). The facet joints were the most vertical at C3 (43.9 degrees ) and C7 (49.6 degrees ), whereas C5 had the most horizontal facets (39.4 degrees ). The greatest rate of change in facet orientation was observed between 6 and 9 years of age. CONCLUSIONS: Our results demonstrate that facets become more vertical as a function of age. However, other parameters than age must be considered to explain the variation of facet orientation. At C3 and C7, the facet orientation was more vertical, which may increase stability. In between, C5 facets were shallower, which may increase mobility and flexion-extension range of motion. PMID- 29715229 TI - Lateralization of the Tibial Tubercle in Recurrent Patellar Dislocation: Verification Using Multiple Methods to Evaluate the Tibial Tubercle. AB - BACKGROUND: The tibial tubercle deviation associated with recurrent patellar dislocation (RPD) has not been studied sufficiently. New methods of evaluation were used to verify the extent of tubercle deviation in a group with patellar dislocation compared with that in a control group, the frequency of patients who demonstrated a cutoff value indicating that tubercle transfer was warranted on the basis of the control group distribution, and the validity of these methods of evaluation for diagnosing RPD. METHODS: Sixty-six patients with a history of patellar dislocation (single in 19 [SPD group] and recurrent in 47 [RPD group]) and 66 age and sex-matched controls were analyzed with the use of computed tomography (CT). The tibial tubercle-posterior cruciate ligament (TT-PCL) distance, TT-PCL ratio, and tibial tubercle lateralization (TTL) in the SPD and RPD groups were compared with those in the control group. Cutoff values to warrant 10 mm of transfer were based on either the minimum or -2SD (2 standard deviations below the mean) value in the control group, and the prevalences of patients in the RPD group with measurements above these cutoff values were calculated. The area under the curve (AUC) in receiver operating characteristic (ROC) curve analysis was used to assess the effectiveness of the measurements as predictors of RPD. RESULTS: The mean TT-PCL distance, TT-PCL ratio, and TTL were all significantly greater in the RPD group than in the control group. The numbers of patients in the RPD group who satisfied the cutoff criteria when they were based on the minimum TT-PCL distance, TT-PCL ratio, and TTL in the control group were 11 (23%), 7 (15%), and 6 (13%), respectively. When the cutoff values were based on the -2SD values in the control group, the numbers of patients were 8 (17%), 6 (13%), and 0, respectively. The AUC of the ROC curve for TT-PCL distance, TT-PCL ratio, and TTL was 0.66, 0.72, and 0.72, respectively. CONCLUSIONS: The extent of TTL in the RPD group was not substantial, and the percentages of patients for whom 10 mm of medial transfer was indicated were small. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29715230 TI - Operating-Room Airflow Technology and Infection Prevention. PMID- 29715231 TI - What's Important: Harmony in Orthopaedics. PMID- 29715232 TI - Academic Influence and Its Relationship to Industry Payments in Orthopaedic Surgery. AB - BACKGROUND: The Hirsch index (h-index) quantifies research publication productivity for an individual, and has widely been considered a valuable measure of academic influence. In 2010, the Physician Payments Sunshine Act (PPSA) was introduced as a way to increase transparency regarding U.S. physician-industry relationships. The purpose of this study was to investigate the relationship between industry payments and academic influence as measured by the h-index and number of publications among orthopaedic surgeons. We also examined the relationship of the h-index to National Institutes of Health (NIH) funding. METHODS: The h-indices of faculty members at academic orthopaedic surgery residency programs were obtained using the Scopus database. The PPSA web site was used to abstract their 2014 industry payments. NIH funding data were obtained from the NIH web site. Mann-Whitney U testing and Spearman correlations were used to explore the relationships. RESULTS: Of 3,501 surgeons, 78.3% received nonresearch payments, 9.2% received research payments, and 0.9% received NIH support. Nonresearch payments ranged from $6 to $4,538,501, whereas research payments ranged from $16 to $517,007. Surgeons receiving NIH or industry research funding had a significantly higher mean h-index and number of publications than those not receiving such funding. Surgeons receiving nonresearch industry payments had a slightly higher mean h-index and number of publications than those not receiving these kinds of payments. Both the h-index and the number of publications had weak positive correlations with industry nonresearch payment amount, industry research payment amount, and total number of industry payments. CONCLUSIONS: There are large differences in industry payment size and distribution among academic surgeons. The small percentage of academic surgeons who receive industry research support or NIH funding tend to have higher h indices. For the overall population of orthopaedic surgery faculty, the h-index correlates poorly with the dollar amount and the total number of industry research payments. Regarding nonresearch industry payments, the h-index also appears to correlate poorly with the number and the dollar amount of payments. These results are encouraging because they suggest that industry bias may play a smaller role in the orthopaedic literature than previously thought. PMID- 29715233 TI - Evaluation of the Content and Accessibility of Web Sites for Accredited Orthopaedic Trauma Surgery Fellowships. AB - BACKGROUND: Orthopaedic trauma fellowship applicants use online-based resources when researching information on potential U.S. fellowship programs. The 2 primary sources for identifying programs are the Orthopaedic Trauma Association (OTA) database and the San Francisco Match (SF Match) database. Previous studies in other orthopaedic subspecialty areas have demonstrated considerable discrepancies among fellowship programs. The purpose of this study was to analyze content and availability of information on orthopaedic trauma surgery fellowship web sites. METHODS: The online databases of the OTA and SF Match were reviewed to determine the availability of embedded program links or external links for the included programs. Thereafter, a Google search was performed for each program individually by typing the program's name, followed by the term "orthopaedic trauma fellowship." All identified fellowship web sites were analyzed for accessibility and content. Web sites were evaluated for comprehensiveness in mentioning key components of the orthopaedic trauma surgery curriculum. By consensus, we refined the final list of variables utilizing the methodology of previous studies on the topic. RESULTS: We identified 54 OTA-accredited fellowship programs, offering 87 positions. The majority (94%) of programs had web sites accessible through a Google search. Of the 51 web sites found, all (100%) described their program. Most commonly, hospital affiliation (88%), operative experiences (76%), and rotation overview (65%) were listed, and, least commonly, interview dates (6%), selection criteria (16%), on-call requirements (20%), and fellow evaluation criteria (20%) were listed. Programs with >=2 fellows provided more information with regard to education content (p = 0.0001) and recruitment content (p = 0.013). Programs with Accreditation Council for Graduate Medical Education (ACGME) accreditation status also provided greater information with regard to education content (odds ratio, 4.0; p = 0.0001). Otherwise, no differences were seen by region, residency affiliation, medical school affiliation, or hospital affiliation. CONCLUSIONS: The SF Match and OTA databases provide few direct links to fellowship web sites. Individual program web sites do not effectively and completely convey information about the programs. The Internet is an underused resource for fellow recruitment. The lack of information on these sites allows for future opportunity to optimize this resource. PMID- 29715234 TI - Does the Ponseti Method for Clubfoot Treatment Stand Up to the March of Time?: Commentary on an article by Lewis E. Zionts, MD, et al.: "Sixty Years On: Ponseti Method for Clubfoot Treatment Produces High Satisfaction Despite Inherent Tendency to Relapse". PMID- 29715235 TI - "Moneyball" Comes to Replantation: How We Assess Our Work: Commentary on an article by Hongyi Zhu, MD, et al.: "Patency Test of Vascular Anastomosis with Assistance of High-Speed Video Recording in Digit Replantation". PMID- 29715236 TI - Intraoperative Coagulopathy 101: Are Antifibrinolytics the Answer and How Do They Work?: Commentary on an article by Ryan P. Pong, MD, et al.: "Effect of Tranexamic Acid on Blood Loss, D-Dimer, and Fibrinogen Kinetics in Adult Spinal Deformity Surgery". PMID- 29715237 TI - Joint Preservation in the Rheumatoid Forefoot: Commentary on an article by Junichi Kushioka, MD, et al.: "Modified Scarf Osteotomy with Medial Capsule Interposition for Hallux Valgus in Rheumatoid Arthritis. A Study of Cases Including Severe First Metatarsophalangeal Joint Destruction". PMID- 29715238 TI - Catch the Biased Researcher if You Can: Commentary on an article by Rafael A. Buerba, MD, MHS, et al.: "Academic Influence and Its Relationship to Industry Payments in Orthopaedic Surgery". PMID- 29715240 TI - Is gonadotropin stimulation bad for oocytes? AB - PURPOSE OF REVIEW: Gonadotrophin in IVF increases the number of oocytes retrieved, and many doctors regard a high number of oocytes as a measurement of success in IVF. Thus, the dogma of more oocytes provides better IVF success has been broadly accepted. However, some European fertility specialists have argued against this concept, saying fewer eggs might, in some instances, be a better option for the patient. RECENT FINDINGS: The concept of 'one size fits all' stimulation in artificial reproductive technologies is not broadly supported by the current literature. The ovarian stimulation strategy has to be viewed in relation to cost, infrastructure and economics, expectations from the doctors and the patients, and more importantly the local legislation. Furthermore, also luteal phase, epigenetic factors and patient safety is a matter of concern. Studies show that in the fresh cycle, ovarian stimulation might have an impact on the epigenetics, quality of the embryo and increase the risk of ovarian hyper stimulation. Strategies like agonist triggering or 'freeze all' can help during a fresh cycle. However, there is an ongoing debate whether these strategies might increase time to pregnancy or not. SUMMARY: In conclusion, each fertility clinic setup has its own benefits and gonadotropin hyperstimulation in IVF has to be related to this and the specific patient demographic in the clinic; however, epigenetics and time to pregnancy are still issues open to debate. PMID- 29715242 TI - Modulation of cardiovascular risk factors. PMID- 29715243 TI - Control of serum triglyceride levels by the apolipoprotein C3 gene and its relationship to cardiovascular disease. PMID- 29715244 TI - PURE and simple? A new perspective on the impact of diet on hyperlipidemia and cardiovascular risk. PMID- 29715246 TI - Clinical trials. PMID- 29715245 TI - Multifaceted functions of macrophages in atherosclerosis. PMID- 29715248 TI - Emergency Nurse Practitioners State by State: A Call to Action. PMID- 29715249 TI - Acute Headache in the Emergency Department: Is Lumbar Puncture Still Necessary to Rule Out Subarachnoid Hemorrhage? AB - The purpose of the Research to Practice column is to review current primary journal articles that directly affect the practice of the advanced practice nurse (APN) in the emergency department. This review examines the findings of Carpenter et al. (2016) from their article, "Spontaneous Subarachnoid Hemorrhage: A Systematic Review and Meta-Analysis Describing the Diagnostic Accuracy of History, Physical Exam, Imaging, and Lumbar Puncture With an Exploration of Test Thresholds." The authors concluded that although no history or physical examination finding can be used to rule in or rule out spontaneous subarachnoid hemorrhage (SAH), the complaint of neck stiffness can increase the likelihood of SAH. In addition, the authors concluded that noncontrast head computed tomography (CT) is accurate in ruling out/in SAH when performed within 6 hr of symptom onset in adults with symptoms consistent with SAH and that the traditional gold standard of confirmatory lumbar puncture after a negative head CT scan is only helpful in patients with a very high pretest probability of SAH. By applying the evidence-based criteria presented in this study, the emergency department APN can confidently rule out SAH and reduce patient risks from unnecessary invasive and costly testing. PMID- 29715250 TI - Pneumoperitoneum. AB - Pneumoperitoneum, usually seen as free air under the diaphragm, is a finding that can be seen on plain abdominal radiographs, signifying a leakage of air, usually from a perforation in the gastrointestinal tract. There are several other potential pathways from other body compartments for air to enter the abdominal cavity. Pneumoperitoneum does not always signify bowel rupture, as it can also result from pneumomediastinum and pneumothorax, and in patients who are being mechanically ventilated. Patient history and physical examination can assist in a preliminary diagnosis before diagnostic imaging. Plain chest/abdominal radiograph or computed tomographic scan of the abdomen can be diagnostic of pneumoperitoneum. Surgical versus nonsurgical conservative observation is determined on the basis of the cause and amount of free air. PMID- 29715251 TI - Time Spent in the Emergency Department and Outcomes in Patients With Severe Sepsis and Septic Shock. AB - A majority of patients with severe sepsis and septic shock are first evaluated in the emergency department (ED). Methods such as screening tools have proven advantageous in earlier identification, allowing for timely initiation of treatment. Delay in symptom presentation and ED overcrowding contribute to deferment of sepsis bundle components and admission. To examine the impact of time from ED arrival to inpatient admission on mortality and length of stay (LOS) in patients with severe sepsis or septic shock. A retrospective analysis of adult patients with severe sepsis or septic shock was completed for those presenting between January 2013 and December 2014. Patients were dichotomized on the basis of the length of time from completed triage in the ED to intensive care unit (ICU) admission (at less than 6 hr and at 6 hr or more). Of the 294 patients screened, 172 patients (58.5%) met inclusion criteria (n = 70 cases at less than 6 hr; n = 102 at 6 hr or more). Mean wait time from ED arrival to ICU admission was 470.7 +/- 333.9 min (range = 84-2,390 min). Groups were similar in baseline, disease severity, and bundle characteristics. There were no differences in the less than 6-hr group compared with the 6-hr-or-more group in rates of 30-day mortality (37.1% vs. 32.4%; p = 0.52), as well as in-hospital (27.1% vs. 23.5%; p = 0.59) or 90-day mortality (42.9% vs. 34.3%; p = 0.26). There were also no differences in hospital or ICU LOS. Timing of transfer from the ED to the ICU was not found to impact mortality or LOS. These results suggest that the ED can provide similar sepsis care to that in the ICU when transfer is delayed in patients with sepsis. PMID- 29715252 TI - Ocular Chemical Burns Secondary to Accidental Administration of e-Cigarette Liquid. AB - Chemical burns to the eye represent a true ocular emergency, requiring immediate and proficient attention to preserve visual function. Although there have been very few reports of serious ocular burns secondary to the accidental administration of electronic cigarette liquid, this case report discusses the risk of same because of product confusion between electronic cigarette liquid and ocular preparations. This article presents a patient's case including patient history and management in the emergency department. The significance of chemical burns to the eye and its management is discussed in relation to significance to clinical practice for all nurses, nurse practitioners, and physicians working in the emergency department. PMID- 29715253 TI - Recognizing Measles, Mumps, and Rubella in the Emergency Department. AB - Measles, mumps, and rubella have impacted millions of American lives over the last 100 years. During the last century, researchers have identified viral diseases, developed a combination vaccine, and have continued ongoing research when outbreaks have occurred. Despite the high incidence of vaccinated individuals, these highly communicable diseases continue to flourish within clusters of outbreaks throughout the United States. Emergency medicine providers play a key role in early recognition and diagnosis of the disease. The proper management and reporting reflect the emphasis on prevention of widespread outbreaks. PMID- 29715255 TI - An Emergency Medicine Residency for Nurse Practitioners: The New York Presbyterian-Weill Cornell Medicine Experience. AB - Growing numbers of nurse practitioners (NPs) are entering emergency medicine at a time when emergency departments are experiencing an increasing practice intensity and acuity. In this context, to further prepare NPs for a career in emergency medicine, postgraduate educational programs have emerged in the United States: from post-master's programs with 300-400 clinical hours in emergency medicine to intense residency or fellowship tracks with 2,000-3,000 clinical hours of training. This article describes the development and general organization of one such residency at New York Presbyterian Hospital-Weill Cornell Medical Center, while also noting several broader trends in emergency medicine and emergency NPs in the workforce. PMID- 29715256 TI - An Interprofessional Web-Based Teaching Module to Enhance Competency of the Advanced Practice Nursing Clinical Education in the Emergency Department. AB - Many advanced practice registered nursing (APRN) students struggle to thrive in their clinical rotation due to the wide variability in their clinical knowledge. To address the variability and gaps in knowledge, we created an interprofessional web-based, self-directed curriculum for APRN students that is clinically relevant and specific to the emergency department (ED) rotation. The modules are a product of collaboration between the medical, nursing, and pharmacy faculty at an academic medical center. This web-based curricular preceptorship model that incorporates new technology and innovation in clinical rotations can provide an opportunity to enhance the clinical education of the APRN students in the ED. PMID- 29715257 TI - Evaluation of Richmond Agitation Sedation Scale (RASS) in Mechanically Ventilated in the Emergency Department. AB - The purpose of this study was to assess Richmond Agitation Sedation Scale (RASS) goal implementation in mechanically ventilated patients sedated in the emergency department (ED), compliance with RASS, and goal achievement. This study was a retrospective chart review at a large Level I trauma academic medical center. Patients who were intubated in the ED or en route to the ED between October 1, 2013, and October 1, 2014, were eligible for inclusion if they met the following criteria: aged 18 years or older, 24 hr or more on mechanically ventilated support receiving continuous sedation and/or analgesia during the first 48 hr of admission, and a hospital stay of 6 days or more. There were 205 patients identified; 104 failed inclusion, 101 were enrolled, and 62 were excluded. Thirty nine patients (94.9%) had an RASS goal implemented in the ED, of which 37 patients (81.1%) had an RASS goal set by an ED physician. Assessment of the RASS was found to be inconsistent, as 56.8% of patients were evaluated by an ED nurse within 1 hr of sedative initiation. Of the 37 patients who had an RASS goal in the ED, 18.9% achieved their goal in the ED. A review of sedation prescribing revealed that 39% received a regimen of varied combinations of continuous infusions of propofol, dexmedetomidine, and midazolam throughout admission, 33% received a regimen of 2 of the aforementioned drugs, and 28% received only propofol. Median extubation time was 129 hr. Seven patients expired within 180 days of admission. The assessment of the RASS was a common practice, but there were inconsistencies in measurement. A limited number of patients achieved their RASS goal in the ED. These results support a provider and nursing knowledge deficit regarding RASS goal setting, proper documentation of RASS measurement, and the need for appropriate assessments. PMID- 29715258 TI - Comparison of Sepsis-3 Criteria Versus SIRS Criteria in Screening Patients for Sepsis in the Emergency Department. AB - The objective of our study was to assess the percentage of patients who met qSOFA criteria, SIRS criteria, both, or none of either criterion and received an International Classification of Diseases, Tenth Revision (ICD-10) code for sepsis after admission from the emergency department (ED). This was a single-center retrospective chart review of medical patients admitted through the ED. Patients were included if they were older than 18 years, were admitted to an inpatient unit through the ED, and received antibiotics within 48 hr of admission. All patients included were evaluated for the presence of SIRS and qSOFA criteria and then stratified into 1 of 4 groups. Group 1 consisted of patients who exhibited neither SIRS criteria nor qSOFA criteria (fewer than 2 of both SIRS and qSOFA criteria). Group 2 consisted of patients with only SIRS criteria (more than 2 SIRS criteria but fewer than 2 qSOFA criteria). Group 3 consisted of patients with only qSOFA criteria (more than 2 qSOFA criteria but fewer than 2 SIRS criteria), and Group 4 consisted of patients with both qSOFA and SIRS criteria (more than 2 qSOFA and SIRS criteria). A of total 100 patients were included, with 49 patients stratified into Group 1, 37 into Group 2, 2 into Group 3, and 12 into Group 4. With respect to the primary endpoint, Group 1 had a total of 7 patients (14.3%) who received an ICD-10 code for sepsis or septic shock, Group 2 had 15 patients (40.5%), Group 3 had 1 patient (50%), and Group 4 had 9 patients (75%). The utilization of both qSOFA and SIRS criteria resulted in a higher percentage of patients who were designated an ICD-10 code for sepsis whereas patients who did not exhibit either criterion still had roughly 15% of patients designated an ICD-10 code for sepsis. PMID- 29715261 TI - The Glaucoma Italian Pediatric Study (GIPSy): 1-Year Results: Erratum. PMID- 29715259 TI - Taking Stock: Tell Us What You Think. PMID- 29715263 TI - Downregulation of MiR-199b-5p Inducing Differentiation of Bone-Marrow Mesenchymal Stem Cells (BMSCs) Toward Cardiomyocyte-Like Cells via HSF1/HSP70 Pathway. AB - BACKGROUND Bone-marrow mesenchymal stem cells (BMSCs) are pluripotent stem cells with potent self-renewal and differentiation ability that are widely used in transplantation of cell therapy. But the mechanism on microRNA (miRNA) regulating stem cell differentiation is complicated and unclear. The aim of this study was to investigate whether miR-199b-5p is involved in differentiation of cardiomyocyte-like cells and identify potential signal pathways in BMSCs. MATERIAL AND METHODS Mouse BMSCs were treated with 5-azacytidine and transfected by miR-199b-5p mimic and inhibitor, respectively. qRT-PCR was used to detect the expression of miR-199b-5p in BMSCs, 5-azacytidine treated BMSCs, and neonatal murine cardiomyocytes. The expression of cardiac specific genes and the HSF1/HSP70 signal pathway were examined by qRT-PCR or western blotting. The proliferation and migration of BMSCs were evaluated by CCK-8 assay and wound healing assay. RESULTS The expression of miR-199b-5p decreased gradually in the process of differentiation of BMSCs toward cardiomyocyte-like cells. The expression of cardiac specific genes and HSF1/HSP70 were increased in the miR 199b-5p inhibitor group; however, the miR-199b-5p mimic group presented an opposite result. Both the miR-199b-5p inhibitor group and the miR-199b-5p mimic group had no influence on BMSCs proliferation and migration. Using lentivirus vectors bearing HSF1 shRNA to silence HSF1 and HSP70, the anticipated elevated expression effect of cardiac specific genes induced by miR-199b-5p inhibitor was suppressed. CONCLUSIONS Downregulation of miR-199b-5p induced differentiation of BMSCs toward cardiomyocyte-like cells partly via the HSF1/HSP70 signaling pathway, and had no influence on BMSCs proliferation and migration. PMID- 29715264 TI - Living with marginal coral communities: Diversity and host-specificity in coral associated barnacles in the northern coral distribution limit of the East China Sea. AB - Corals and their associated fauna are extremely diverse in tropical waters and form major reefs. In the high-latitude temperate zone, corals living near their distribution limit are considered marginal communities because they are particularly extremely sensitive to environmental and climatic changes. In this study, we examined the diversity and host usage of coral-associated barnacles on Jeju Island, Korea, the northern coral distribution limit in the East China Sea. In this study, only three coral-associated barnacles-from two genera in two subfamilies-were collected. The Pyrgomatinid barnacles Cantellius arcuatus and Cantellius cf. euspinulosum were found only on the corals Montipora millepora and Alveopora japonica, respectively. The Megatrematinid barnacle Pyrgomina oulastreae, relatively a generalist, was found on Psammocora spp. (both profundacella and albopicta) and Oulastrea crispata corals. The host usage of these three barnacles does not overlap. DNA barcode sequences of the C. arcuatus specimens collected in the present study matched those collected in Kochi in Japan, Taiwan, Malaysia and Papua New Guinea, suggesting that this species has a wide geographical distribution. C. arcuatus covers a wider host range in Taiwan waters, inhabiting Montipora spp. and Porites spp., which suggests that the host specificity of coral-associated barnacles varies with host availability. C. cf. euspinulosum probably has a very narrow distribution and host usage. The sequences of C. cf. euspinulosum on Jeju Island do not match those of any known sequences of Cantellius barnacles in the Indo-Pacific region. P. oulastreae probably prefers cold water because it has been reported in temperate regions. Coral-associated barnacles in marginal communities have considerably lower diversity than their subtropical and tropical counterparts. When host availability is limited, marginal coral-associated barnacles exhibit higher host specificity than those in subtropical and tropical reef systems. PMID- 29715265 TI - Mice lacking the transcriptional regulator Bhlhe40 have enhanced neuronal excitability and impaired synaptic plasticity in the hippocampus. AB - Bhlhe40 is a transcription factor that is highly expressed in the hippocampus; however, its role in neuronal function is not well understood. Here, we used Bhlhe40 null mice on a congenic C57Bl6/J background (Bhlhe40 KO) to investigate the impact of Bhlhe40 on neuronal excitability and synaptic plasticity in the hippocampus. Bhlhe40 KO CA1 neurons had increased miniature excitatory post synaptic current amplitude and decreased inhibitory post-synaptic current amplitude, indicating CA1 neuronal hyperexcitability. Increased CA1 neuronal excitability was not associated with increased seizure severity as Bhlhe40 KO relative to +/+ (WT) control mice injected with the convulsant kainic acid. However, significant reductions in long term potentiation and long term depression at CA1 synapses were observed in Bhlhe40 KO mice, indicating impaired hippocampal synaptic plasticity. Behavioral testing for spatial learning and memory on the Morris Water Maze (MWM) revealed that while Bhlhe40 KO mice performed similarly to WT controls initially, when the hidden platform was moved to the opposite quadrant Bhlhe40 KO mice showed impairments in relearning, consistent with decreased hippocampal synaptic plasticity. To investigate possible mechanisms for increased neuronal excitability and decreased synaptic plasticity, a whole genome mRNA expression profile of Bhlhe40 KO hippocampus was performed followed by a chromatin immunoprecipitation sequencing (ChIP-Seq) screen of the validated candidate genes for Bhlhe40 protein-DNA interactions consistent with transcriptional regulation. Of the validated genes identified from mRNA expression analysis, insulin degrading enzyme (Ide) had the most significantly altered expression in hippocampus and was significantly downregulated on the RNA and protein levels; although Bhlhe40 did not occupy the Ide gene by ChIP-Seq. Together, these findings support a role for Bhlhe40 in regulating neuronal excitability and synaptic plasticity in the hippocampus and that indirect regulation of Ide transcription may be involved in these phenotypes. PMID- 29715266 TI - Population structure in Argentina. AB - We analyzed 391 samples from 12 Argentinian populations from the Center-West, East and North-West regions with the Illumina Human Exome Beadchip v1.0 (HumanExome-12v1-A). We did Principal Components analysis to infer patterns of populational divergence and migrations. We identified proportions and patterns of European, African and Native American ancestry and found a correlation between distance to Buenos Aires and proportion of Native American ancestry, where the highest proportion corresponds to the Northernmost populations, which is also the furthest from the Argentinian capital. Most of the European sources are from a South European origin, matching historical records, and we see two different Native American components, one that spreads all over Argentina and another specifically Andean. The highest percentages of African ancestry were in the Center West of Argentina, where the old trade routes took the slaves from Buenos Aires to Chile and Peru. Subcontinentaly, sources of this African component are represented by both West Africa and groups influenced by the Bantu expansion, the second slightly higher than the first, unlike North America and the Caribbean, where the main source is West Africa. This is reasonable, considering that a large proportion of the ships arriving at the Southern Hemisphere came from Mozambique, Loango and Angola. PMID- 29715267 TI - Comparative metabolomics of aging in a long-lived bat: Insights into the physiology of extreme longevity. AB - Vespertilionid bats (Mammalia: Order Chiroptera) live 3-10 times longer than other mammals of an equivalent body size. At present, nothing is known of how bat fecal metabolic profiles shift with age in any taxa. This study established the feasibility of using a non-invasive, fecal metabolomics approach to examine age related differences in the fecal metabolome of young and elderly adult big brown bats (Eptesicus fuscus) as an initial investigation into using metabolomics for age determination. Samples were collected from captive, known-aged big brown bats (Eptesicus fuscus) from 1 to over 14 years of age: these two ages represent age groups separated by approximately 75% of the known natural lifespan of this taxon. Results showed 41 metabolites differentiated young (n = 22) and elderly (n = 6) Eptesicus. Significant differences in metabolites between young and elderly bats were associated with tryptophan metabolism and incomplete protein digestion. Results support further exploration of the physiological mechanisms bats employ to achieve exceptional longevity. PMID- 29715268 TI - Job exposure to the public in relation with alcohol, tobacco and cannabis use: Findings from the CONSTANCES cohort study. AB - OBJECTIVES: To examine the associations between job exposure to the public (e.g., customers, guests, users of a public service, patients) and alcohol, tobacco and cannabis use. METHODS: From the French population-based CONSTANCES cohort, 16,566 men and 17,426 women currently working were included between 2012 and 2016. They reported their exposure to the public (daily versus no daily), and among the daily exposed participants (10,323 men and 13,318 women), the frequency of stressful exposure (often versus rarely). Dependent variables were: chronic alcohol consumption (<1(1), 1-27(1-13), 28-42(14-28), >42(28) drinks per week in men(women)), heavy episodic drinking (never, at most once a month, more than once a month), alcohol use risk with Alcohol Use Disorders Identification Test (mild, dangerous, problematic or dependence), tobacco use (non-smoker, former smoker, 1 9, 10-19, >19 cigarettes per day) and cannabis use (never, not in past year, less than once a month, once a month or more). Logistic regressions provided odds ratios of substance use, stratifying for gender and adjusting for sociodemographic confounders, depression, effort-reward imbalance and perceived health status. RESULTS: Exposed men had higher risks of alcohol (chronic alcohol consumption, heavy episodic drinking and alcohol use risk), tobacco and cannabis use. Exposed women had higher risks of tobacco and cannabis use. In men, stressful exposure was associated with increased risks of heavy episodic drinking, tobacco and cannabis use. In women, stressful exposure was associated with increased risks of chronic alcohol consumption, alcohol use risk, tobacco and cannabis use. All these findings remained significant in multivariable analyses, taking into account sociodemographic variables, depressive symptoms, perceived health status and effort-reward imbalance. CONCLUSIONS: Interventions to reduce emotional job demand should systematically integrate assessment and prevention measures of addictive behaviors. Vulnerable workers may be offered more specific interventions to reduce the impact of exposure to the public on their substance use. PMID- 29715269 TI - Low offspring survival in mountain pine beetle infesting the resistant Great Basin bristlecone pine supports the preference-performance hypothesis. AB - The preference-performance hypothesis states that ovipositing phytophagous insects will select host plants that are well-suited for their offspring and avoid host plants that do not support offspring performance (survival, development and fitness). The mountain pine beetle (Dendroctonus ponderosae), a native insect herbivore in western North America, can successfully attack and reproduce in most species of Pinus throughout its native range. However, mountain pine beetles avoid attacking Great Basin bristlecone pine (Pinus longaeva), despite recent climate-driven increases in mountain pine beetle populations at the high elevations where Great Basin bristlecone pine grows. Low preference for a potential host plant species may not persist if the plant supports favorable insect offspring performance, and Great Basin bristlecone pine suitability for mountain pine beetle offspring performance is unclear. We infested cut bolts of Great Basin bristlecone pine and two susceptible host tree species, limber (P. flexilis) and lodgepole (P. contorta) pines with adult mountain pine beetles and compared offspring performance. To investigate the potential for variation in offspring performance among mountain pine beetles from different areas, we tested beetles from geographically-separated populations within and outside the current range of Great Basin bristlecone pine. Although mountain pine beetles constructed galleries and laid viable eggs in all three tree species, extremely few offspring emerged from Great Basin bristlecone pine, regardless of the beetle population. Our observed low offspring performance in Great Basin bristlecone pine corresponds with previously documented low mountain pine beetle attack preference. A low preference-low performance relationship suggests that Great Basin bristlecone pine resistance to mountain pine beetle is likely to be retained through climate-driven high-elevation mountain pine beetle outbreaks. PMID- 29715270 TI - Nanosecond pulsed electric fields promoting the proliferation of porcine iliac endothelial cells: An in vitro study. AB - Currently, nanosecond pulsed electric fields (nsPEFs) with short pulse duration and non-thermal effects have various potential applications in medicine and biology, especially in tumor ablation. Additionally, there are a few investigations on its proliferative effects in the normal cell. Clinically, proliferation of endothelial cells can perhaps accelerate the stent endothelialization and reduce the risk of acute thrombosis. To explore the feasibility using nsPEFs to induce proliferation of endothelial cells, in this study, porcine iliac endothelial (PIEC) cell line was cultured and tested by CCK 8 assay after nsPEFs treatment. The results reflected that nsPEFs with low field strength (100ns, 5 kV/cm, 10 pulses) had a significant proliferative effect with an increase in the PIEC cell growth of 16% after a 48 hour' post-treatment. To further understand the mechanism of cell proliferation, intracellular Ca2+ concentration was measured through fluo-4 AM and reactive oxygen species assay was applied to estimate the level of intracellular reactive oxygen species (ROS). Finally, the total nitric oxide assay for NO production in the cultured medium was evaluated. An enhanced concentration of intracellular Ca2+ and ROS were observed, while the concentration of extracellular NO also increased after nsPEFs treatment. Such experimental results demonstrated that nsPEFs with appropriate pulse parameters could effectively enhance cell proliferation on PIEC cells, and the cell proliferation associated strongly with the changes of intracellular Ca2+ concertation, ROS and NO production induced by nsPEFs treatment. This in vitro preliminary study indicates that as a novel physical doping, the nsPEFs have potential in stimulating endothelial cells to accelerate stent endothelialization. PMID- 29715272 TI - One-year survival rate and healthcare costs after cardiac arrest in Taiwan, 2006 2012. AB - OBJECTIVES: The annual increase in costs and the quality of life of survivors of cardiac arrest are major concerns. This study used National Health Insurance Research Database (NHIRD) of Taiwan to evaluate the 1-year survival rate and the annual healthcare costs of survivors after cardiac arrest. METHODS: This retrospective, fixed-cohort study conducted from 2006 to 2012, involved 2 million individuals randomly selected from the NHIRD of Taiwan. Adult patients at least 18 years old who were diagnosed with cardiac arrest were enrolled. Survival was followed up for 1 year. RESULTS: In total, 2,256 patients were enrolled. The survivor cohort accounted for 4% (89/2256) of the study population. There were no significant differences in the demographic characteristics of the survival and non-survival cohorts, with the exceptions of gender (male: survival vs. non survival, 50.6% vs. 64.5%, p = 0.007), diabetes mellitus (49.4% vs. 35.8%, p = 0.009), and acute coronary syndrome (44.9% vs. 31.9%, p = 0.010). Only 38 (1.7%) patients survived for > 1 year. The mean re-admission to hospital during the 1 year follow up was 73.5 (SD: 110.2) days. The mean healthcare cost during the 1 year follow up was $12,953. Factors associated with total healthcare costs during the 1-year follow up were as follows: city or county of residence, being widowed, and Chronic Obstructive Pulmonary Disease (city or county of residence, beta: 23,604, p < 0.001; being widowed, beta: 25,588, p = 0.049; COPD, beta: 14,438, p = 0.024). CONCLUSIONS: There was a great burden of the annual healthcare costs of survivors of cardiac arrest. Socioeconomic status and comorbidity were major confounders of costs. The outcome measures of cardiac arrest should extend beyond the death, and encompass destitution. These findings add to our knowledge of the health economics and indicate future research about healthcare of cardiac arrest survivors. PMID- 29715271 TI - Directed fusion of cardiac spheroids into larger heterocellular microtissues enables investigation of cardiac action potential propagation via cardiac fibroblasts. AB - Multicellular spheroids generated through cellular self-assembly provide cytoarchitectural complexities of native tissue including three-dimensionality, extensive cell-cell contacts, and appropriate cell-extracellular matrix interactions. They are increasingly suggested as building blocks for larger engineered tissues to achieve shapes, organization, heterogeneity, and other biomimetic complexities. Application of these tissue culture platforms is of particular importance in cardiac research as the myocardium is comprised of distinct but intermingled cell types. Here, we generated scaffold-free 3D cardiac microtissue spheroids comprised of cardiac myocytes (CMs) and/or cardiac fibroblasts (CFs) and used them as building blocks to form larger microtissues with different spatial distributions of CMs and CFs. Characterization of fusing homotypic and heterotypic spheroid pairs revealed an important influence of CFs on fusion kinetics, but most strikingly showed rapid fusion kinetics between heterotypic pairs consisting of one CF and one CM spheroid, indicating that CMs and CFs self-sort in vitro into the intermixed morphology found in the healthy myocardium. We then examined electrophysiological integration of fused homotypic and heterotypic microtissues by mapping action potential propagation. Heterocellular elongated microtissues which recapitulate the disproportionate CF spatial distribution seen in the infarcted myocardium showed that action potentials propagate through CF volumes albeit with significant delay. Complementary computational modeling revealed an important role of CF sodium currents and the spatial distribution of the CM-CF boundary in action potential conduction through CF volumes. Taken together, this study provides useful insights for the development of complex, heterocellular engineered 3D tissue constructs and their engraftment via tissue fusion and has implications for arrhythmogenesis in cardiac disease and repair. PMID- 29715274 TI - Dissection of genotype * environment interactions for mucilage and seed yield in Plantago species: Application of AMMI and GGE biplot analyses. AB - Genotype * environment interaction (GEI) is an important aspect of both plant breeding and the successful introduction of new cultivars. In the present study, additive main effects and multiplicative interactions (AMMI) and genotype (G) main effects and genotype (G) * environment (E) interaction (GGE) biplot analyses were used to identify stable genotypes and to dissect GEI in Plantago. In total, 10 managed field trials were considered as environments to analyze GEI in thirty genotypes belonging to eight Plantago species. Genotypes were evaluated in a drought stress treatment and in normal irrigation conditions at two locations in Shiraz (Bajgah) for three years (2013-2014- 2015) and Kooshkak (Marvdasht, Fars, Iran) for two years (2014-2015). Three traits, seed yield and mucilage yield and content, were measured at each experimental site and in natural Plantago habitats. AMMI2 biplot analyses identified genotypes from several species with higher stability for seed yield and other genotypes with stable mucilage content and yield. P. lanceolata (G26), P. officinalis (G10), P. ovata (G14), P. ampleexcaulis (G11) and P. major (G4) had higher stability for seed yield. For mucilage yield, G21, G18 and G20 (P. psyllium), G1, G2 and G4 (P. major), G9 and G10 (P. officinalis) and P. lanceolata were identified as stable. G13 (P. ovata), G5 and G6 (P. major) and G30 (P. lagopus) had higher stability for mucilage content. No one genotype was found to have high levels of stability for more than one trait but some species had more than one genotype exhibiting stable trait performance. Based on trait variation, GGE biplot analysis identified two representative environments, one for seed yield and one for mucilage yield and content, with good discriminating ability. The identification of stable genotypes and representative environments should assist the breeding of new Plantago cultivars. PMID- 29715273 TI - Neurofibromatosis type 2 tumor suppressor protein is expressed in oligodendrocytes and regulates cell proliferation and process formation. AB - The neurofibromatosis type 2 (NF2) tumor suppressor protein Merlin functions as a negative regulator of cell growth and actin dynamics in different cell types amongst which Schwann cells have been extensively studied. In contrast, the presence and the role of Merlin in oligodendrocytes, the myelin forming cells within the CNS, have not been elucidated. In this work, we demonstrate that Merlin immunoreactivity was broadly distributed in the white matter throughout the central nervous system. Following Merlin expression during development in the cerebellum, Merlin could be detected in the cerebellar white matter tract at early postnatal stages as shown by its co-localization with Olig2-positive cells as well as in adult brain sections where it was aligned with myelin basic protein containing fibers. This suggests that Merlin is expressed in immature and mature oligodendrocytes. Expression levels of Merlin were low in oligodendrocytes as compared to astrocytes and neurons throughout development. Expression of Merlin in oligodendroglia was further supported by its identification in either immortalized cell lines of oligodendroglial origin or in primary oligodendrocyte cultures. In these cultures, the two main splice variants of Nf2 could be detected. Merlin was localized in clusters within the nuclei and in the cytoplasm. Overexpressing Merlin in oligodendrocyte cell lines strengthened reduced impedance in XCELLigence measurements and Ki67 stainings in cultures over time. In addition, the initiation and elongation of cellular projections were reduced by Merlin overexpression. Consistently, cell migration was retarded in scratch assays done on Nf2-transfected oligodendrocyte cell lines. These data suggest that Merlin actively modulates process outgrowth and migration in oligodendrocytes. PMID- 29715275 TI - Hedgehog inhibition mediates radiation sensitivity in mouse xenograft models of human esophageal adenocarcinoma. AB - BACKGROUND: The Hedgehog (Hh) signaling pathway is active in esophageal adenocarcinoma (EAC). We used a patient-derived murine xenograft (PDX) model of EAC to evaluate tumour response to conventional treatment with radiation/chemoradiation with or without Hh inhibition. Our goal was to determine the potential radioresistance effects of Hh signaling and radiosensitization by Hh inhibitors. METHODS: PDX models were treated with radiation, chemotherapy or combined chemoradiation. Tumour response was measured by growth delay. Hh transcript levels (qRT-PCR) were compared among frozen tumours from treated and control mice. 5E1, a monoclonal SHH antibody, or LDE225, a clinical SMO inhibitor (Novartis(r)) inhibited Hh signaling. RESULTS: Precision irradiation significantly delayed xenograft tumour growth in all 7 PDX models. Combined chemoradiation further delayed growth relative to either modality alone in three of six PDX models. Following irradiation, two of three PDX models demonstrated sustained up-regulation of Hh transcripts. Combined LDE225 and radiation, and 5E1 alone delayed growth relative to either treatment alone in a Hh-responsive PDX model, but not in a non-responsive model. CONCLUSION: Hh signaling mediates the radiation response in some EAC PDX models, and inhibition of this pathway may augment the efficacy of radiation in tumours that are Hh dependent. PMID- 29715277 TI - Metal cofactor modulated folding and target recognition of HIV-1 NCp7. AB - The HIV-1 nucleocapsid 7 (NCp7) plays crucial roles in multiple stages of HIV-1 life cycle, and its biological functions rely on the binding of zinc ions. Understanding the molecular mechanism of how the zinc ions modulate the conformational dynamics and functions of the NCp7 is essential for the drug development and HIV-1 treatment. In this work, using a structure-based coarse grained model, we studied the effects of zinc cofactors on the folding and target RNA(SL3) recognition of the NCp7 by molecular dynamics simulations. After reproducing some key properties of the zinc binding and folding of the NCp7 observed in previous experiments, our simulations revealed several interesting features in the metal ion modulated folding and target recognition. Firstly, we showed that the zinc binding makes the folding transition states of the two zinc fingers less structured, which is in line with the Hammond effect observed typically in mutation, temperature or denaturant induced perturbations to protein structure and stability. Secondly, We showed that there exists mutual interplay between the zinc ion binding and NCp7-target recognition. Binding of zinc ions enhances the affinity between the NCp7 and the target RNA, whereas the formation of the NCp7-RNA complex reshapes the intrinsic energy landscape of the NCp7 and increases the stability and zinc affinity of the two zinc fingers. Thirdly, by characterizing the effects of salt concentrations on the target RNA recognition, we showed that the NCp7 achieves optimal balance between the affinity and binding kinetics near the physiologically relevant salt concentrations. In addition, the effects of zinc binding on the inter-domain conformational flexibility and folding cooperativity of the NCp7 were also discussed. PMID- 29715276 TI - Comparative analysis of distinctive transcriptome profiles with biochemical evidence in bisphenol S- and benzo[a]pyrene-exposed liver tissues of the olive flounder Paralichthys olivaceus. AB - Flounder is a promising model species for environmental monitoring of coastal regions. To assess the usefulness of liver transcriptome profiling, juvenile olive flounder Paralichthys olivaceus were exposed to two pollutants, bisphenol S (BPS) and benzo[a]pyrene (BaP), which have different chemical characteristics and have distinct modes of metabolic action in teleost. Six hours after intraperitoneal injection with BPS (50 mg/kg bw) or BaP (20 mg/kg bw), liver transcriptomes were analyzed using the Illumina Hiseq 3000 platform. Interestingly, the transcriptome was highly sensitive and was distinctively expressed in response to each chemical. The primary effect of BPS was significantly increased transcription of egg process and vitellogenesis related genes, including vitellogenins (vtg1, vtg2), zona pellucida sperm-binding proteins (zp3, zp4), and estrogen receptors (eralpha, erbeta), with increases in plasma 17beta-estradiol (E2) and vitellogenin (VTG) concentrations. Following BaP treatment, detoxification- and biotransformation-related genes such as cyp1a1 and UDP-glucuronosyltransferase (ugt1a1) were significantly increased, with an increase in EROD activity. In both transcriptomes, mRNA expression of genes involved in antioxidant defense systems was increased, while genes involved in innate immunity were decreased upon BPS or BaP exposure with a decrease in complement activity. This study provides useful insight into the chemical specific hepatic transcriptional response of P. olivaceus and suggests a basis for further studies examining biomarker application of liver transcriptomes for environmental pollution. PMID- 29715278 TI - Bacterial versus human thymidylate synthase: Kinetics and functionality. AB - Thymidylate Synthase (TSase) is a highly conserved enzyme that catalyzes the production of the DNA building block thymidylate. Structurally, functionally and mechanistically, bacterial and mammalian TSases share remarkable similarities. Because of this closeness, bacterial enzymes have long been used as model systems for human TSase. Furthermore, while TSase inhibitors have long served as chemotherapeutic drugs, no TSase inhibitor serves as an antibiotic. Despite their high resemblance, the mammalian TSases are distinct in a few known aspects, such as having a N-terminal tail and two insertions in the primary sequence and active/inactive conformations. Here, we aim to comprehensively characterize human (hs) TSase and delineate its contrasts and the similarities to the well-studied Escherichia coli (ec) TSase. We found that, in contrast to ecTSase, Mg2+ does not enhance reaction rates for hsTSase. The temperature dependence of intrinsic kinetic isotope effects (KIEs), on the other hand, suggests that Mg2+ has little or no impact on the transition state of hydride transfer in either enzyme, and that the transition state for the hydride transfer in hsTSase is looser than in ecTSase. Additionally, the substrates' binding order is strictly ordered for ecTSase but slightly less ordered for hsTSase. The observed kinetic and functional differences between bacterial and human enzymes may aid in the development of antibiotic drugs with reduced toxicity. PMID- 29715279 TI - Free-living and laboratory gait characteristics in patients with multiple sclerosis. AB - BACKGROUND: Wearable sensors offer the potential to bring new knowledge to inform interventions in patients affected by multiple sclerosis (MS) by thoroughly quantifying gait characteristics and gait deficits from prolonged daily living measurements. The aim of this study was to characterise gait in both laboratory and daily life conditions for a group of patients with moderate to severe ambulatory impairment due to MS. To this purpose, algorithms to detect and characterise gait from wearable inertial sensors data were also validated. METHODS: Fourteen patients with MS were divided into two groups according to their disability level (EDSS 6.5-6.0 and EDSS 5.5-5.0, respectively). They performed both intermittent and continuous walking bouts (WBs) in a gait laboratory wearing waist and shank mounted inertial sensors. An algorithm (W-CWT) to estimate gait events and temporal parameters (mean and variability values) using data recorded from the waist mounted sensor (Dynaport, Mc Roberts) was tested against a reference algorithm (S-REF) based on the shank-worn sensors (OPAL, APDM). Subsequently, the accuracy of another algorithm (W-PAM) to detect and classify WBs was also tested. The validated algorithms were then used to quantify gait characteristics during short (sWB, 5-50 steps), intermediate (iWB, 51-100 steps) and long (lWB, >100 steps) daily living WBs and laboratory walking. Group means were compared using a two-way ANOVA. RESULTS: W-CWT compared to S-REF showed good gait event accuracy (0.05-0.10 s absolute error) and was not influenced by disability level. It slightly overestimated stride time in intermittent walking (0.012 s) and overestimated highly variability of temporal parameters in both intermittent (17.5%-58.2%) and continuous walking (11.2% 76.7%). The accuracy of W-PAM was speed-dependent and decreased with increasing disability. The ANOVA analysis showed that patients walked at a slower pace in daily living than in the laboratory. In daily living gait, all mean temporal parameters decreased as the WB duration increased. In the sWB, the patients with a lower disability score showed, on average, lower values of the temporal parameters. Variability decreased as the WB duration increased. CONCLUSIONS: This study validated a method to quantify walking in real life in people with MS and showed how gait characteristics estimated from short walking bouts during daily living may be the most informative to quantify level of disability and effects of interventions in patients moderately affected by MS. The study provides a robust approach for the quantification of recognised clinically relevant outcomes and an innovative perspective in the study of real life walking. PMID- 29715280 TI - Efficient estimation of Pareto model: Some modified percentile estimators. AB - The article proposes three modified percentile estimators for parameter estimation of the Pareto distribution. These modifications are based on median, geometric mean and expectation of empirical cumulative distribution function of first-order statistic. The proposed modified estimators are compared with traditional percentile estimators through a Monte Carlo simulation for different parameter combinations with varying sample sizes. Performance of different estimators is assessed in terms of total mean square error and total relative deviation. It is determined that modified percentile estimator based on expectation of empirical cumulative distribution function of first-order statistic provides efficient and precise parameter estimates compared to other estimators considered. The simulation results were further confirmed using two real life examples where maximum likelihood and moment estimators were also considered. PMID- 29715281 TI - Real life management of patients hospitalized with multiple myeloma in France. AB - BACKGROUND: Patients with multiple myeloma included in prospective clinical trials are highly selected and therefore are expected not to be representative of the entire patient population. Additionally recommendations based on literature data and randomized trials are not systematically implemented in all patients. We sought to determine how patients hospitalized with a diagnosis of multiple myeloma are currently treated in France. METHODS AND FINDINGS: We performed a nation-wide search using the Programme de Medicalisation des Systemes d'Information (PMSI) database which includes anonymous data for all patients hospitalized in France. We identified newly diagnosed cases in 2012 and analyzed the number and duration of hospital stays, coexisting conditions and treatment modalities with data available until the end of 2015. A diagnosis of multiple myeloma was determined for the first time during a hospitalization in France in 2012 in 6,282 patients (3,234 males and 3,048 females). The median age at diagnosis was 74 years (72 in males and 76 in females). A majority (55.3%) of patients were diagnosed and treated in a single heath center, including 37% in a university hospital and 52% in a non-university public hospital. Comorbidities potentially impacting on myeloma treatment were present in 57.5% of patients at diagnosis, and 15% had an associated diagnosis of another neoplasia. Intensive therapies with stem cell transplants were performed in 1033 patients (16% of total), the majority of which were aged less than 65 (881 patients, 85.3%). Stem cell transplants were performed more frequently in males while the distance between the site of residence and the transplant center had no impact on likelihood of receiving a transplant. Only 60% of patients less than 65 years old who were treated for their disease underwent intensification with stem cell transplant within the 4-year follow-up period. CONCLUSIONS: A large majority of patients hospitalized with a diagnosis of multiple myeloma are elderly, in particular females, and not eligible for transplants. Among the patients aged less than 65 and receiving therapy for their disease, 40% do not undergo transplants. These data emphasize the need for alternative therapies. PMID- 29715282 TI - Long-term changes in the planktonic cnidarian community in a mesoscale area of the NW Mediterranean. AB - In the present work, possible long-term changes in the planktonic cnidarian community were investigated by analyzing (1) species and community spatial distribution patterns, (2) variations in abundance and (3) changes in species richness during three mesoscale surveys representative of the climatic and anthropogenic changes that have occurred during the last three decades (years: 1983, 2004 and 2011) in the NW Mediterranean. These surveys were conducted during the summer (June) along the Catalan coast. All surveys covered the same area, used the same sampling methodology, and taxonomic identification was conducted by the same team of experts. An increase in the abundance of total cnidaria was found from 1983 to 2011. The siphonophore Muggiaea atlantica and the hydromedusa Aglaura hemistoma were the most abundant species, while Muggiaea kochii presented the largest abundance increment over time. Temperature was the main environmental parameter driving significant differences in the cnidarian community composition, abundance and spatial distribution patterns among the surveys. Our results suggest that in the current climate change scenario, warm-water species abundances will be positively favored, and the community will suffer changes in their latitudinal distribution patterns. We consider it extremely important to study and monitor gelatinous zooplankton in mesoscale spatial areas to understand not only long-term changes in abundances but also changes in their spatial distributions since spatial changes are sensitive indicators of climate change. PMID- 29715283 TI - Leukoaraiosis and risk of intracranial hemorrhage and outcome after stroke thrombolysis. AB - BACKGROUND: The impact of leukoaraiosis on the risk of symptomatic intracerebral hemorrhage (SICH) after stroke thrombolysis is conflicting, and the data on Asian populations are lacking. Therefore, in this study, we assessed the association between leukoaraiosis and SICH, and the association between leukoaraiosis and the 90-day functional outcome in the Asian population. METHODS: Data were collected from a two-center prospective registry of acute ischemic stroke patients given intravenous tissue plasminogen activator between 2006 and 2014. A total of 614 pretreatment brain CT and 455 posttreatment MRI were retrospectively assessed using two different rating scales for the presence of leukoaraiosis. Outcome measures were the occurrence of SICH with three definitions and any hemorrhage after thrombolysis and functional outcome at 3 months. RESULTS: Of the 614 patients assessed, 30.3% showed severe leukoaraiosis on the baseline brain CT. The SICH rate was 4.6% - 7.2% based on different definitions, and overall, 24.9% of patients showed any post-tPA hemorrhage. No association was observed between the severity of leukoaraiosis and SICH, regardless of having used different leukoaraiosis rating scales or as assessment using different imaging modalities. However, severe leukoaraiosis was independently associated with poor functional outcome at 3 months (OR 1.96, 95% C1 1.24-3.11, P = 0.004) after adjustment for confounders. CONCLUSIONS: Our results showed no association between leukoaraiosis and the risk of SICH. Although the presence of severe leukoaraiosis predicted a poor functional outcome after stroke, IV thrombolysis might not be withheld in acute ischemic stroke patients solely based on the presence of severe leukoaraiosis on pre-thrombolytic CT scans. PMID- 29715284 TI - Symbols in motion: Flexible cultural boundaries and the fast spread of the Neolithic in the western Mediterranean. AB - The rapid diffusion of farming technologies in the western Mediterranean raises questions about the mechanisms that drove the development of intensive contact networks and circulation routes between incoming Neolithic communities. Using a statistical method to analyze a brand-new set of cultural and chronological data, we document the large-scale processes that led to variations between Mediterranean archaeological cultures, and micro-scale processes responsible for the transmission of cultural practices within farming communities. The analysis of two symbolic productions, pottery decorations and personal ornaments, shed light on the complex interactions developed by Early Neolithic farmers in the western Mediterranean area. Pottery decoration diversity correlates with local processes of circulation and exchange, resulting in the emergence and the persistence of stylistic and symbolic boundaries between groups, while personal ornaments reflect extensive networks and the high level of mobility of Early Neolithic farmers. The two symbolic productions express different degrees of cultural interaction that may have facilitated the successful and rapid expansion of early farming societies in the western Mediterranean. PMID- 29715285 TI - Is a clean river fun for all? Recognizing social vulnerability in watershed planning. AB - Watershed planning can lead to policy innovation and action toward environmental protection. However, groups often suffer from low engagement with communities that experience disparate impacts from flooding and water pollution. This can limit the capacity of watershed efforts to dismantle pernicious forms of social inequality. As a result, the benefits of environmental changes often flow to more empowered residents, short-changing the power of watershed-based planning as a tool to transform ecological, economic, and social relationships. The objectives of this paper are to assess whether the worldview of watershed planning actors are sufficiently attuned to local patterns of social vulnerability and whether locally significant patterns of social vulnerability can be adequately differentiated using conventional data sources. Drawing from 35 in-depth interviews with watershed planners and community stakeholders in the Milwaukee River Basin (WI, USA), we identify five unique definitions of social vulnerability. Watershed planners in our sample articulate a narrower range of social vulnerability definitions than other participants. All five definitions emphasize spatial and demographic characteristics consistent with existing ways of measuring social vulnerability. However, existing measures do not adequately differentiate among the spatio-temporal dynamics used to distinguish definitions. In response, we develop two new social vulnerability measures. The combination of interviews and demographic analyses in this study provides an assessment technique that can help watershed planners (a) understand the limits of their own conceptualization of social vulnerability and (b) acknowledge the importance of place-based vulnerabilities that may otherwise be obscured. We conclude by discussing how our methods can be a useful tool for identifying opportunities to disrupt social vulnerability in a watershed by evaluating how issue frames, outreach messages, and engagement tactics. The approach allows watershed planners to shift their own culture in order to consider socially vulnerable populations comprehensively. PMID- 29715286 TI - Retraction: The Early Stage Formation of PI3K-AMPAR GluR2 Subunit Complex Facilitates the Long Term Neuroprotection Induced by Propofol Post-Conditioning in Rats. PMID- 29715287 TI - Multisectoral prioritization of zoonotic diseases in Uganda, 2017: A One Health perspective. AB - BACKGROUND: Zoonotic diseases continue to be a public health burden globally. Uganda is especially vulnerable due to its location, biodiversity, and population. Given these concerns, the Ugandan government in collaboration with the Global Health Security Agenda conducted a One Health Zoonotic Disease Prioritization Workshop to identify zoonotic diseases of greatest national concern to the Ugandan government. MATERIALS AND METHODS: The One Health Zoonotic Disease Prioritization tool, a semi-quantitative tool developed by the U.S. Centers for Disease Control and Prevention, was used for the prioritization of zoonoses. Workshop participants included voting members and observers representing multiple government and non-governmental sectors. During the workshop, criteria for prioritization were selected, and questions and weights relevant to each criterion were determined. We used a decision tree to provide a ranked list of zoonoses. Participants then established next steps for multisectoral engagement for the prioritized zoonoses. A sensitivity analysis demonstrated how criteria weights impacted disease prioritization. RESULTS: Forty eight zoonoses were considered during the workshop. Criteria selected to prioritize zoonotic diseases were (1) severity of disease in humans in Uganda, (2) availability of effective control strategies, (3) potential to cause an epidemic or pandemic in humans or animals, (4) social and economic impacts, and (5) bioterrorism potential. Seven zoonotic diseases were identified as priorities for Uganda: anthrax, zoonotic influenza viruses, viral hemorrhagic fevers, brucellosis, African trypanosomiasis, plague, and rabies. Sensitivity analysis did not indicate significant changes in zoonotic disease prioritization based on criteria weights. DISCUSSION: One Health approaches and multisectoral collaborations are crucial to the surveillance, prevention, and control strategies for zoonotic diseases. Uganda used such an approach to identify zoonoses of national concern. Identifying these priority diseases enables Uganda's National One Health Platform and Zoonotic Disease Coordination Office to address these zoonoses in the future with a targeted allocation of resources. PMID- 29715288 TI - Population need for primary eye care in Rwanda: A national survey. AB - BACKGROUND: Universal access to Primary Eye Care (PEC) is a key global initiative to reduce and prevent avoidable causes of visual impairment (VI). PEC can address minor eye conditions, simple forms of uncorrected refractive error (URE) and create a referral pathway for specialist eye care, thus offering a potential solution to a lack of eye health specialists in low-income countries. However, there is little information on the population need for PEC, including prevalence of URE in all ages in Sub-Saharan Africa. METHODS: A national survey was conducted of people aged 7 and over in Rwanda in September-December 2016. Participants were selected through two-stage probability proportional to size sampling and compact segment sampling. VI (visual acuity<6/12) was assessed using Portable Eye Examination Kit (PEEK); URE was detected using a pinhole and presbyopia using local near vision test. We also used validated questionnaires to collect socio-demographic and minor eye symptoms information. Prevalence estimates for VI, URE and need for PEC (URE, presbyopia with good distance vision, need for referrals and minor eye conditions) were age and sex standardized to the Rwandan population. Associations between age, sex, socio economic status and the key outcomes were examined using logistic regression. RESULTS: 4618 participants were examined and interviewed out of 5361 enumerated (86% response rate). The adjusted population prevalence of VI was 3.7% (95%CI = 3.0-4.5%), URE was 2.2% (95%CI = 1.7-2.8%) and overall need for PEC was 34.0% (95%CI = 31.8-36.4%). Women and older people were more likely to need PEC and require a referral. CONCLUSIONS: Nearly a third of the population in Rwanda has the potential to benefit from PEC, with greater need identified in older people and women. Universal access to PEC can address unmet eye health needs and public health planning needs to ensure equitable access to older people and women. PMID- 29715289 TI - Quantifying in situ phenotypic variability in the hydraulic properties of four tree species across their distribution range in Europe. AB - Many studies have reported that hydraulic properties vary considerably between tree species, but little is known about their intraspecific variation and, therefore, their capacity to adapt to a warmer and drier climate. Here, we quantify phenotypic divergence and clinal variation for embolism resistance, hydraulic conductivity and branch growth, in four tree species, two angiosperms (Betula pendula, Populus tremula) and two conifers (Picea abies, Pinus sylvestris), across their latitudinal distribution in Europe. Growth and hydraulic efficiency varied widely within species and between populations. The variability of embolism resistance was in general weaker than that of growth and hydraulic efficiency, and very low for all species but Populus tremula. In addition, no and weak support for a safety vs. efficiency trade-off was observed for the angiosperm and conifer species, respectively. The limited variability of embolism resistance observed here for all species except Populus tremula, suggests that forest populations will unlikely be able to adapt hydraulically to drier conditions through the evolution of embolism resistance. PMID- 29715290 TI - Exome array analysis of adverse reactions to fluoropyrimidine-based therapy for gastrointestinal cancer. AB - Fluoropyrimidines, including 5-fluororacil (5FU) and its pro-drug Capecitabine, are the common treatment for colorectal, breast, neck and head cancers-either as monotherapy or in combination therapy. Adverse reactions (ADRs) to the treatment are common and often result in treatment discontinuation or dose reduction. Factors contributing to ADRs, including genetic variation, are poorly characterized. We performed exome array analysis to identify genetic variants that contribute to adverse reactions. Our final dataset consisted of 504 European ancestry individuals undergoing fluoropyrimidine-based therapy for gastrointestinal cancer. A subset of 254 of these were treated with Capecitabine. All individuals were genotyped on the Illumina HumanExome Array. Firstly, we performed SNP and gene-level analyses of protein-altering variants on the array to identify novel associations the following ADRs, which were grouped into four phenotypes based on symptoms of diarrhea, mucositis, and neutropenia and hand-and foot syndrome. Secondly, we performed detailed analyses of the HLA region on the same phenotypes after imputing the HLA alleles and amino acids. No protein altering variants, or sets of protein-altering variants collapsed into genes, were associated with the main outcomes after Bonferroni correction. We found evidence that the HLA region was enriched for associations with Hand-and-Foot syndrome (p = 0.023), but no specific SNPs or HLA alleles were significant after Bonferroni correction. Larger studies will be required to characterize the genetic contribution to ADRs to 5FU. Future studies that focus on the HLA region are likely to be fruitful. PMID- 29715291 TI - Interference with DNA repair after ionizing radiation by a pyrrole-imidazole polyamide. AB - Pyrrole-imidazole (Py-Im) polyamides are synthetic non-genotoxic minor groove binding small molecules. We hypothesized that Py-Im polyamides can modulate the cellular response to ionizing radiation. Pre-treatment of cells with a Py-Im polyamide prior to exposure to ionizing radiation resulted in a delay in resolution of phosphorylated gamma-H2AX foci, increase in XRCC1 foci, and reduced cellular replication potential. RNA-sequencing of cell lines exposed to the polyamide showed induction of genes related to the ultraviolet radiation response. We observed that the polyamide is almost 10-fold more toxic to a cell line deficient in DNA ligase 3 as compared to the parental cell line. Alkaline single cell gel electrophoresis reveals that the polyamide induces genomic fragmentation in the ligase 3 deficient cell line but not the corresponding parental line. The polyamide interferes directly with DNA ligation in vitro. We conclude that Py-Im polyamides may be further explored as sensitizers to genotoxic therapies. PMID- 29715292 TI - Correction: Heart rate variability among women undergoing in vitro fertilization treatment: Its predictive ability for pregnancy. AB - [This corrects the article DOI: 10.1371/journal.pone.0193899.]. PMID- 29715293 TI - Correction: Successional dynamics of marine fouling hydroids (Cnidaria: Hydrozoa) at a finfish aquaculture facility in the Mediterranean Sea. AB - [This corrects the article DOI: 10.1371/journal.pone.0195352.]. PMID- 29715294 TI - Correction: Treatment combining aliskiren with paricalcitol is effective against progressive renal tubulointerstitial fibrosis via dual blockade of intrarenal renin. AB - [This corrects the article DOI: 10.1371/journal.pone.0181757.]. PMID- 29715295 TI - Mobility limitations related to reduced pulmonary function among aging people with chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of disability. We aimed to analyse the impact of reduced pulmonary function on non respiratory impairments and mobility activity limitations in an elderly population with COPD and to elucidate which specific limitations on mobility are related to reduced pulmonary function. METHODS: Cross-sectional study of 110 patients with COPD, recruited from public and university hospital. The effect of impaired pulmonary function on the risk of non-respiratory impairments and mobility limitations was analysed using validated measures, including: the 6 Minute Walk Test (6MWT), skeletal muscle strength, the Short Physical Performance Battery (SPPB), and self-reported mobility questionnaire. Multivariate analysis was used to control for confounders such as age, sex, height, education, and cigarette smoking. RESULTS: Greater impairment of pulmonary function was associated with less distance walked during the 6MWT, poorer SPPB scores, and greater risk of self-reported mobility limitations (p<0.05). Lower forced expiratory volume in 1 s was also associated with a greater risk of limitations in carrying items under 10 pounds (4.54 kg), walking alone up and down a flight of stairs, and walking two or three neighbourhood blocks. There was no clear statistical relationship between pulmonary function impairment and skeletal muscle strength. CONCLUSIONS: Impaired pulmonary function was associated with the 6MWT score and limitations on performance-based and self-reported mobility activities, but not with skeletal muscle strength among elderly COPD patients. PMID- 29715296 TI - Effects of isomaltodextrin in postprandial lipid kinetics: Rat study and human randomized crossover study. AB - Isomaltodextrin (IMD) is a novel dietary fiber-like polysaccharide: a type of alpha-glucan produced from starch using enzymes derived from microorganisms. The results of cohort studies show that dietary fiber can prevent cardiovascular disorders caused by lifestyle-related diseases such as metabolic syndrome. Inhibition of excess fat absorption by dietary fiber is known to be one of the mechanisms, and it is also known that the actions of dietary fiber vary depending on factors such as its structure or origin. Thus, we investigated the inhibitory actions of IMD on fat absorption, and analyzed its mechanism of action. In rats, the absorption of fat given by gavage was significantly lower at 1, 2, and 6 hours after IMD administration than after vehicle administration. In humans, IMD was associated with a lesser increase in blood triglycerides in subjects whose blood triglycerides were otherwise apt to rise. We also found by in vitro emulsion studies that IMD, which had no effect on digestive enzyme activity or emulsion formation, stabilized the micro size micelle by inducing enlarged micelle particle size and increased zeta potential. In conclusion, the mechanism of inhibition of fat absorption by IMD may be a delay in micelle particles accessing the intestinal epithelium through changes in the surface structure and the physical properties of the micelle particles. PMID- 29715297 TI - Effect of the natural arsenic gradient on the diversity and arsenic resistance of bacterial communities of the sediments of Camarones River (Atacama Desert, Chile). AB - Arsenic (As), a highly toxic metalloid, naturally present in Camarones River (Atacama Desert, Chile) is a great health concern for the local population and authorities. In this study, the taxonomic and functional characterization of bacterial communities associated to metal-rich sediments from three sites of the river (sites M1, M2 and M3), showing different arsenic concentrations, were evaluated using a combination of approaches. Diversity of bacterial communities was evaluated by Illumina sequencing. Strains resistant to arsenic concentrations varying from 0.5 to 100 mM arsenite or arsenate were isolated and the presence of genes coding for enzymes involved in arsenic oxidation (aio) or reduction (arsC) investigated. Bacterial communities showed a moderate diversity which increased as arsenic concentrations decreased along the river. Sequences of the dominant taxonomic groups (abundances >=1%) present in all three sites were affiliated to Proteobacteria (range 40.3-47.2%), Firmicutes (8.4-24.8%), Acidobacteria (10.4 17.1%), Actinobacteria (5.4-8.1%), Chloroflexi (3.9-7.5%), Planctomycetes (1.2 5.3%), Gemmatimonadetes (1.2-1.5%), and Nitrospirae (1.1-1.2%). Bacterial communities from sites M2 and M3 showed no significant differences in diversity between each other (p = 0.9753) but they were significantly more diverse than M1 (p<0.001 and p<0.001, respectively). Sequences affiliated with Proteobacteria, Firmicutes, Acidobacteria, Chloroflexi and Actinobacteria at M1 accounted for more than 89% of the total classified bacterial sequences present but these phyla were present in lesser proportions in M2 and M3 sites. Strains isolated from the sediment of sample M1, having the greatest arsenic concentration (498 mg kg-1), showed the largest percentages of arsenic oxidation and reduction. Genes aio were more frequently detected in isolates from M1 (54%), whereas arsC genes were present in almost all isolates from all three sediments, suggesting that bacterial communities play an important role in the arsenic biogeochemical cycle and detoxification of arsenical compounds. Overall, results provide further knowledge on the microbial diversity of arsenic contaminated fresh-water sediments. PMID- 29715298 TI - Fast and simple tool for the quantification of biofilm-embedded cells sub populations from fluorescent microscopic images. AB - Fluorescent staining is a common tool for both quantitative and qualitative assessment of pro- and eukaryotic cells sub-population fractions by using microscopy and flow cytometry. However, direct cell counting by flow cytometry is often limited, for example when working with cells rigidly adhered either to each other or to external surfaces like bacterial biofilms or adherent cell lines and tissue samples. An alternative approach is provided by using fluorescent microscopy and confocal laser scanning microscopy (CLSM), which enables the evaluation of fractions of cells subpopulations in a given sample. For the quantitative assessment of cell fractions in microphotographs, we suggest a simple two-step algorithm that combines single cells selection and the statistical analysis. To facilitate the first step, we suggest a simple procedure that supports finding the balance between the detection threshold and the typical size of single cells based on objective cell size distribution analysis. Based on a series of experimental measurements performed on bacterial and eukaryotic cells under various conditions, we show explicitly that the suggested approach effectively accounts for the fractions of different cell sub-populations (like the live/dead staining in our samples) in all studied cases that are in good agreement with manual cell counting on microphotographs and flow cytometry data. This algorithm is implemented as a simple software tool that includes an intuitive and user-friendly graphical interface for the initial adjustment of algorithm parameters to the microphotographs analysis as well as for the sequential analysis of homogeneous series of similar microscopic images without further user intervention. The software tool entitled BioFilmAnalyzer is freely available online at https://bitbucket.org/rogex/biofilmanalyzer/downloads/. PMID- 29715299 TI - A bi-objective integer programming model for partly-restricted flight departure scheduling. AB - The normal studies on air traffic departure scheduling problem (DSP) mainly deal with an independent airport in which the departure traffic is not affected by surrounded airports, which, however, is not a consistent case. In reality, there still exist cases where several commercial airports are closely located and one of them possesses a higher priority. During the peak hours, the departure activities of the lower-priority airports are usually required to give way to those of higher-priority airport. These giving-way requirements can inflict a set of changes on the modeling of departure scheduling problem with respect to the lower-priority airports. To the best of our knowledge, studies on DSP under this condition are scarce. Accordingly, this paper develops a bi-objective integer programming model to address the flight departure scheduling of the partly restricted (e.g., lower-priority) one among several adjacent airports. An adapted tabu search algorithm is designed to solve the current problem. It is demonstrated from the case study of Tianjin Binhai International Airport in China that the proposed method can obviously improve the operation efficiency, while still realizing superior equity and regularity among restricted flows. PMID- 29715300 TI - Public versus internal conceptions of addiction: An analysis of internal Philip Morris documents. AB - BACKGROUND: Tobacco addiction is a complex, multicomponent phenomenon stemming from nicotine's pharmacology and the user's biology, psychology, sociology, and environment. After decades of public denial, the tobacco industry now agrees with public health authorities that nicotine is addictive. In 2000, Philip Morris became the first major tobacco company to admit nicotine's addictiveness. Evolving definitions of addiction have historically affected subsequent policymaking. This article examines how Philip Morris internally conceptualized addiction immediately before and after this announcement. METHODS AND FINDINGS: We analyzed previously secret, internal Philip Morris documents made available as a result of litigation against the tobacco industry. We compared these documents to public company statements and found that Philip Morris's move from public denial to public affirmation of nicotine's addictiveness coincided with pressure on the industry from poor public approval ratings, the Master Settlement Agreement (MSA), the United States government's filing of the Racketeer Influenced and Corrupt Organizations (RICO) suit, and the Institute of Medicine's (IoM's) endorsement of potentially reduced risk products. Philip Morris continued to research the causes of addiction through the 2000s in order to create successful potentially reduced exposure products (PREPs). While Philip Morris's public statements reinforce the idea that nicotine's pharmacology principally drives smoking addiction, company scientists framed addiction as the result of interconnected biological, social, psychological, and environmental determinants, with nicotine as but one component. Due to the fragmentary nature of the industry document database, we may have missed relevant information that could have affected our analysis. CONCLUSIONS: Philip Morris's research suggests that tobacco industry activity influences addiction treatment outcomes. Beyond nicotine's pharmacology, the industry's continued aggressive advertising, lobbying, and litigation against effective tobacco control policies promotes various nonpharmacological determinants of addiction. To help tobacco users quit, policy makers should increase attention on the social and environmental dimensions of addiction alongside traditional cessation efforts. PMID- 29715301 TI - TMSOTf assisted synthesis of 2'-deoxy-2'-[18F]fluoro-beta-D arabinofuranosylcytosine ([18F]FAC). AB - [18F]FAC (2'-deoxy-2'-[18F]fluoro-beta-D-arabinofuranosylcytosine, 1) is a versatile probe for imaging deoxycytidine kinase (dCK) expression levels in vivo. dCK is responsible for phosphorylation of deoxycytidine (dC, 2) and other nucleoside analogs, plays a key role in immune activation and has demonstrated to be one of the key enzymes in activating nucleoside based drugs including gemcitabine. Reported synthesis of [18F]FAC is high yielding but is quite challenging requiring bromination using HBr and careful drying of excess HBr which is critical for successful synthesis. Here in we report a simplified trimethylsilyl trifluoromethanesulfonate (TMSOTf) assisted synthesis of [18F]FAC eliminating the need of bromination and drying. [18F]FAC (beta-anomer) was synthesized with average isolated decay corrected yield of 10.59 + 4.2% (n = 6) with radiochemical purity of >98% and total synthesis time of 158 + 19 min. PMID- 29715302 TI - Modeling an enhanced ridesharing system with meet points and time windows. AB - With the rising of e-hailing services in urban areas, ride sharing is becoming a common mode of transportation. This paper presents a mathematical model to design an enhanced ridesharing system with meet points and users' preferable time windows. The introduction of meet points allows ridesharing operators to trade off the benefits of saving en-route delays and the cost of additional walking for some passengers to be collectively picked up or dropped off. This extension to the traditional door-to-door ridesharing problem brings more operation flexibility in urban areas (where potential requests may be densely distributed in neighborhood), and thus could achieve better system performance in terms of reducing the total travel time and increasing the served passengers. We design and implement a Tabu-based meta-heuristic algorithm to solve the proposed mixed integer linear program (MILP). To evaluate the validation and effectiveness of the proposed model and solution algorithm, several scenarios are designed and also resolved to optimality by CPLEX. Results demonstrate that (i) detailed route plan associated with passenger assignment to meet points can be obtained with en route delay savings; (ii) as compared to CPLEX, the meta-heuristic algorithm bears the advantage of higher computation efficiency and produces good quality solutions with 8%~15% difference from the global optima; and (iii) introducing meet points to ridesharing system saves the total travel time by 2.7%-3.8% for small-scale ridesharing systems. More benefits are expected for ridesharing systems with large size of fleet. This study provides a new tool to efficiently operate the ridesharing system, particularly when the ride sharing vehicles are in short supply during peak hours. Traffic congestion mitigation will also be expected. PMID- 29715303 TI - Health insurance coverage with or without a nurse-led task shifting strategy for hypertension control: A pragmatic cluster randomized trial in Ghana. AB - BACKGROUND: Poor access to care and physician shortage are major barriers to hypertension control in sub-Saharan Africa. Implementation of evidence-based systems-level strategies targeted at these barriers are lacking. We conducted a study to evaluate the comparative effectiveness of provision of health insurance coverage (HIC) alone versus a nurse-led task shifting strategy for hypertension control (TASSH) plus HIC on systolic blood pressure (SBP) reduction among patients with uncontrolled hypertension in Ghana. METHODS AND FINDINGS: Using a pragmatic cluster randomized trial, 32 community health centers within Ghana's public healthcare system were randomly assigned to either HIC alone or TASSH + HIC. A total of 757 patients with uncontrolled hypertension were recruited between November 28, 2012, and June 11, 2014, and followed up to October 7, 2016. Both intervention groups received health insurance coverage plus scheduled nurse visits, while TASSH + HIC comprised cardiovascular risk assessment, lifestyle counseling, and initiation/titration of antihypertensive medications for 12 months, delivered by trained nurses within the healthcare system. The primary outcome was change in SBP from baseline to 12 months. Secondary outcomes included lifestyle behaviors and blood pressure control at 12 months and sustainability of SBP reduction at 24 months. Of the 757 patients (389 in the HIC group and 368 in the TASSH + HIC group), 85% had 12-month data available (60% women, mean BP 155.9/89.6 mm Hg). In intention-to-treat analyses adjusted for clustering, the TASSH + HIC group had a greater SBP reduction (-20.4 mm Hg; 95% CI -25.2 to 15.6) than the HIC group (-16.8 mm Hg; 95% CI -19.2 to -15.6), with a statistically significant between-group difference of -3.6 mm Hg (95% CI -6.1 to 0.5; p = 0.021). Blood pressure control improved significantly in both groups (55.2%, 95% CI 50.0% to 60.3%, for the TASSH + HIC group versus 49.9%, 95% CI 44.9% to 54.9%, for the HIC group), with a non-significant between-group difference of 5.2% (95% CI -1.8% to 12.4%; p = 0.29). Lifestyle behaviors did not change appreciably in either group. Twenty-one adverse events were reported (9 and 12 in the TASSH + HIC and HIC groups, respectively). The main study limitation is the lack of cost-effectiveness analysis to determine the additional costs and benefits, if any, of the TASSH + HIC group. CONCLUSIONS: Provision of health insurance coverage plus a nurse-led task shifting strategy was associated with a greater reduction in SBP than provision of health insurance coverage alone, among patients with uncontrolled hypertension in Ghana. Future scale-up of these systems-level strategies for hypertension control in sub-Saharan Africa requires a cost-benefit analysis. TRIAL REGISTRATION: ClinicalTrials.gov NCT01802372. PMID- 29715304 TI - A method for extracting high-quality total RNA from plant rich in polysaccharides and polyphenols using Dendrobium huoshanense. AB - Acquiring high quality RNA is the basis of plant molecular biology research, plant genetics and other physiological investigations. At present, a large number of nucleotide isolation methods have been exploited or modified, such as commercial kits, CTAB, SDS methods and so on. Due to the nature of different plants, extraction methods vary. Moreover, efficiency of certain approach cannot be guaranteed due to composition of different plants and extracting high quality RNA from plants rich in polysaccharides and polyphenols are often difficult. The physical and chemical properties of polysaccharides which are similar to nucleic acids and other secondary metabolites will be coprecipitated with RNA irreversibly. Therefore, how to remove polysaccharides and other secondary metabolites during RNA extraction is the primary challenge. Dendrobium huoshanense is an Orchidaceae perennial herb that is rich in polysaccharides and other secondary metabolites. By using D. huoshanense as the subject, we improved the method originated from CHAN and made it suitable for plants containing high amount of polysaccharides and polyphenols. The extracted total RNA was clear and non-dispersive, with good integrity and no obvious contamination with DNA and other impurities. And it was also evaluated by gel electrophoresis, nucleic acid quantitative detector and PCR assessment. Thus, as a simple approach, it is suitable and efficient in RNA isolation for plants rich in polysaccharides and polyphenols. PMID- 29715305 TI - Prevalence, incidence and correlates of low risk HPV infection and anogenital warts in a cohort of women living with HIV in Burkina Faso and South Africa. AB - OBJECTIVE: To report the prevalence and incidence of low-risk human papillomavirus infection (LR-HPV) and anogenital warts (AGW) among women living with HIV (WLHIV) in Burkina Faso (BF) and South Africa (SA), and to explore HIV related factors associated with these outcomes. METHODS: We enrolled 1238 WLHIV (BF = 615; SA = 623) aged 25-50 years and followed them at three time points (6, 12 and 16 months) after enrolment. Presence of AGW was assessed during gynaecological examination. Cervico-vaginal swabs for enrolment and month 16 follow-up visits were tested for HPV infection by Inno-LiPA(r) genotyping. Logistic regression was used to assess risk factors for prevalent infection or AGW. Cox regression was used to assess risk factors for incident AGW. RESULTS: Women in SA were more likely than those in BF to have prevalent LR-HPV infection (BF: 27.1% vs. SA: 40.9%; p<0.001) and incident LR-HPV infection (BF: 25.8% vs. SA: 31.6%, p = 0.05). Prevalence of persistent LR-HPV was similar in the two countries (BF: 33.3% vs. SA: 30.4%; p = 0.54), as were prevalence and incidence of AGW (Prevalence: BF: 7.5% vs. SA: 5.7%; p = 0.21; Incidence: BF: 2.47 vs. SA: 2.33 per 100 person-years; p = 0.41). HPV6 was associated with incident AGW (BF: adjusted Hazard Ratio (aHR) = 4.88; 95%CI: 1.36-17.45; SA: aHR = 5.02; 95%CI: 1.40-17.99). Prevalent LR-HPV (BF: adjusted Odds Ratio [aOR = 1.86]; 95%CI: 1.01 3.41; SA: aOR = 1.75; 95%CI: 0.88-3.48); persistent LR-HPV (BF: aOR = 1.92; 95%CI: 0.44-8.44; SA: aOR = 2.81; 95%CI: 1.07-7.41) and prevalent AGW (BF: aOR = 1.53; 95%CI: 0.61-3.87; SA: aOR = 4.11; 95%CI: 1.20-14.10) were each associated with low CD4+ counts (i.e. <200 vs. >500 cells/MUL). Duration of ART and HIV plasma viral load were not associated with any LR-HPV infection or AGW outcomes. CONCLUSION: LR-HPV infection and AGW are common in WLHIV in sub-Saharan Africa. Type-specific HPV vaccines and effective ART with immunological reconstitution could reduce the burden of AGW in this population. PMID- 29715306 TI - Pentoxifylline, dexamethasone and azithromycin demonstrate distinct age-dependent and synergistic inhibition of TLR- and inflammasome-mediated cytokine production in human newborn and adult blood in vitro. AB - INTRODUCTION: Neonatal inflammation, mediated in part through Toll-like receptor (TLR) and inflammasome signaling, contributes to adverse outcomes including organ injury. Pentoxifylline (PTX), a phosphodiesterase inhibitor which potently suppresses cytokine production in newborn cord blood, is a candidate neonatal anti-inflammatory agent. We hypothesized that combinations of PTX with other anti inflammatory agents, the steroid dexamethasone (DEX) or the macrolide azithromycin (AZI), may exert broader, more profound and/or synergistic anti inflammatory activity towards neonatal TLR- and inflammasome-mediated cytokine production. METHODS: Whole newborn and adult blood was treated with PTX (50-200 MUM), DEX (10-10-10-7 M), or AZI (2.5-20 MUM), alone or combined, and cultured with lipopolysaccharide (LPS) (TLR4 agonist), R848 (TLR7/8 agonist) or LPS/adenosine triphosphate (ATP) (inflammasome induction). Supernatant and intracellular cytokines, signaling molecules and mRNA were measured by multiplex assay, flow cytometry and real-time PCR. Drug interactions were assessed based on Loewe's additivity. RESULTS: PTX, DEX and AZI inhibited TLR- and/or inflammasome mediated cytokine production in newborn and adult blood, whether added before, simultaneously or after TLR stimulation. PTX preferentially inhibited pro inflammatory cytokines especially TNF. DEX inhibited IL-10 in newborn, and TNF, IL-1beta, IL-6 and interferon-alpha in newborn and adult blood. AZI inhibited R848-induced TNF, IL-1beta, IL-6 and IL-10, and LPS-induced IL-1beta and IL-10. (PTX+DEX) synergistically decreased LPS- and LPS/ATP-induced TNF, IL-1beta, and IL-6, and R848-induced IL-1beta and interferon-alpha, while (PTX+AZI) synergistically decreased induction of TNF, IL-1beta, and IL-6. Synergistic inhibition of TNF production by (PTX+DEX) was especially pronounced in newborn vs. adult blood and was accompanied by reduction of TNF mRNA and enhancement of IL10 mRNA. CONCLUSIONS: Age, agent, and specific drug-drug combinations exert distinct anti-inflammatory effects towards TLR- and/or inflammasome-mediated cytokine production in human newborn blood in vitro. Synergistic combinations of PTX, DEX and AZI may offer benefit for prevention and/or treatment of neonatal inflammatory conditions while potentially limiting drug exposure and toxicity. PMID- 29715307 TI - Recognition and management of acute kidney injury in children: The ISN 0by25 Global Snapshot study. AB - BACKGROUND: In low and middle-income countries, reliable data on the epidemiology of childhood acute kidney injury (AKI) is lacking. The Global Snapshot, conducted by the ISN "0by25" AKI initiative, was a world-wide cross-sectional, observational study to evaluate AKI in hospitalized patients. Here we report the pediatric results of this study. PATIENTS AND METHODS: We prospectively collected data on children who met the Kidney Disease Improving Global Outcomes AKI criteria during a 10-week window in late 2014. AKI risk factors, etiological factors, management and outcomes were recorded using standardized forms and protocols. Countries were classified according to their 2014 gross national income (GNI) per person into high-income countries (HIC), upper-middle income countries (UMIC) and low and low-middle income countries (LLMIC). Need for renal replacement therapy, mortality, and renal recovery were assessed 7 days after AKI diagnosis or at hospital discharge, whichever came first. RESULTS: 92 centers from 41 countries collected data on 354 pediatric AKI patients; 53% of the children developed AKI while hospitalized and 47% in the community. The most common etiological factors for AKI differed across GNI categories as well as between patients with community-acquired vs. hospital-acquired AKI. Children from HIC were younger, and larger proportion of AKI in this group were due to post surgical complications vs. other etiologies when compared to other income categories. In patients with hypotension as the cause of AKI, the adjusted risk of death was almost 10-fold higher compared to patients without hypotension as an etiological factor for AKI development. Mortality was similar within AKI stages in HIC and UMIC. In LLMIC, patients with the highest AKI level of severity had higher mortality than patients in higher income categories. Patients from LLMIC and UMIC had a 57-fold and 11 fold higher adjusted risk of death, respectively, compared to patients from HIC. CONCLUSION: In resource-limited countries, pediatric AKI-associated mortality is disproportionately higher when compared to high-resource areas, especially among patients with more severe AKI. PMID- 29715308 TI - Analysis of dual energy spectral CT and pathological grading of clear cell renal cell carcinoma (ccRCC). AB - OBJECTIVE: To discuss the dual energy spectral computer tomography (CT) imaging features of the pathological grading of clear cell renal cell carcinoma (ccRCC) and the correlation between spectral CT imaging features and pathology. MATERIALS AND METHODS: We performed analyses of 62 patients with confirmed diagnosis of ccRCC. All patients underwent non-enhanced CT and dual-phase (cortex phase, CP and parenchyma phase, PP) contrast-enhanced CT with dual energy spectral mode. The subjects were pathologically divided into two groups: low-grade group (Fuhrman 1/2) and high-grade group (Fuhrman 3/4). The CT value of each lesion was measured on the monochromatic image at 70 keV. The normalized iodine concentrations (NIC) and the slope of the spectrum curve were calculated. The qualitative morphological parameters, including tumor shape, calcification, pseudocapsule, necrosis, and enhancement mode, were compared between the two groups. The quantitative data were compared using Student's t-test, and the enumeration data were analyzed using the chi-square test between low-grade and high-grade ccRCC.Receiver operating characteristic curve was used to determine the sensitivity and specificity of the quantitative parameters in two groups. RESULTS: The CT value, NIC, and mean slope of the low-grade group were increased compared with the high-grade group during CP (P = 0.001, P = 0.043, and P<0.001, respectively). The CT did not differ significantly during PP (P = 0.134); however, the NIC and mean slope varied considerably in the low grade compared with the high-grade group (P = 0.048, P = 0.017, respectively). The CT threshold value, NIC, and slope had high sensitivity and specificity in differentiating low grade ccRCC from high-grade ccRCC. The tumor shape, pseudocapsule, and necrosis differed significantly between the two groups (P<0.05). CONCLUSIONS: Dual energy spectral CT with the quantitative analysis of iodine concentration and qualitative analysis of morphological characteristics increases the accuracy of diagnosing the pathological grade of ccRCC. PMID- 29715310 TI - FusionHub: A unified web platform for annotation and visualization of gene fusion events in human cancer. AB - Gene fusion is a chromosomal rearrangement event which plays a significant role in cancer due to the oncogenic potential of the chimeric protein generated through fusions. At present many databases are available in public domain which provides detailed information about known gene fusion events and their functional role. Existing gene fusion detection tools, based on analysis of transcriptomics data usually report a large number of fusion genes as potential candidates, which could be either known or novel or false positives. Manual annotation of these putative genes is indeed time-consuming. We have developed a web platform FusionHub, which acts as integrated search engine interfacing various fusion gene databases and simplifies large scale annotation of fusion genes in a seamless way. In addition, FusionHub provides three ways of visualizing fusion events: circular view, domain architecture view and network view. Design of potential siRNA molecules through ensemble method is another utility integrated in FusionHub that could aid in siRNA-based targeted therapy. FusionHub is freely available at https://fusionhub.persistent.co.in. PMID- 29715309 TI - Identification of cancer-related miRNA-lncRNA biomarkers using a basic miRNA lncRNA network. AB - LncRNAs are regulatory noncoding RNAs that play crucial roles in many biological processes. The dysregulation of lncRNA is thought to be involved in many complex diseases; lncRNAs are often the targets of miRNAs in the indirect regulation of gene expression. Numerous studies have indicated that miRNA-lncRNA interactions are closely related to the occurrence and development of cancers. Thus, it is important to develop an effective method for the identification of cancer-related miRNA-lncRNA interactions. In this study, we compiled 155653 experimentally validated and predicted miRNA-lncRNA associations, which we defined as basic interactions. We next constructed an individual-specific miRNA-lncRNA network (ISMLN) for each cancer sample and a basic miRNA-lncRNA network (BMLN) for each type of cancer by examining the expression profiles of miRNAs and lncRNAs in the TCGA (The Cancer Genome Atlas) database. We then selected potential miRNA-lncRNA biomarkers based on the BLMN. Using this method, we identified cancer-related miRNA-lncRNA biomarkers and modules specific to a certain cancer. This method of profiling will contribute to the diagnosis and treatment of cancers at the level of gene regulatory networks. PMID- 29715311 TI - Unmanned aerial systems-based remote sensing for monitoring sorghum growth and development. AB - Unmanned Aerial Vehicles and Systems (UAV or UAS) have become increasingly popular in recent years for agricultural research applications. UAS are capable of acquiring images with high spatial and temporal resolutions that are ideal for applications in agriculture. The objective of this study was to evaluate the performance of a UAS-based remote sensing system for quantification of crop growth parameters of sorghum (Sorghum bicolor L.) including leaf area index (LAI), fractional vegetation cover (fc) and yield. The study was conducted at the Texas A&M Research Farm near College Station, Texas, United States. A fixed-wing UAS equipped with a multispectral sensor was used to collect image data during the 2016 growing season (April-October). Flight missions were successfully carried out at 50 days after planting (DAP; 25 May), 66 DAP (10 June) and 74 DAP (18 June). These flight missions provided image data covering the middle growth period of sorghum with a spatial resolution of approximately 6.5 cm. Field measurements of LAI and fc were also collected. Four vegetation indices were calculated using the UAS images. Among those indices, the normalized difference vegetation index (NDVI) showed the highest correlation with LAI, fc and yield with R2 values of 0.91, 0.89 and 0.58 respectively. Empirical relationships between NDVI and LAI and between NDVI and fc were validated and proved to be accurate for estimating LAI and fc from UAS-derived NDVI values. NDVI determined from UAS imagery acquired during the flowering stage (74 DAP) was found to be the most highly correlated with final grain yield. The observed high correlations between UAS-derived NDVI and the crop growth parameters (fc, LAI and grain yield) suggests the applicability of UAS for within-season data collection of agricultural crops such as sorghum. PMID- 29715312 TI - A catalog of potential putative functional variants in psoriasis genome-wide association regions. AB - Psoriasis is a common inflammatory skin disease, with considerable genetic contribution. Genome-wide association studies have successfully identified a number of genomic regions for the risk of psoriasis. However, it is challenging to pinpoint the functional causal variants and then further decipher the genetic mechanisms underlying each region. In order to prioritize potential functional causal variants within psoriasis susceptibility regions, we integrated the genetic association findings and functional genomic data publicly available, i.e. histone modifications in relevant immune cells. We characterized a pervasive enrichment pattern of psoriasis variants in five core histone marks across immune cells/tissues. We discovered that genetic alleles within psoriasis association regions might influence gene expression levels through significantly affecting the binding affinities of 17 transcription factors. We established a catalog of 654 potential functional causal variants for psoriasis and suggested that they significantly overlapped with causal variants for autoimmune diseases. We identified potential causal variant rs79824801 overlay with the peaks of five histone marks in primary CD4+ T cells. Its alternative allele affected the binding affinity of transcription factor IKZF1. This study highlights the complex genetic architecture and complicated mechanisms for psoriasis. The findings will inform the functional experiment design for psoriasis. PMID- 29715313 TI - Circulating pentraxin 3 is positively associated with chronic hyperglycemia but negatively associated with plasma aldosterone concentration. AB - Pentraxin 3 (PTX3) is reported to be a vascular inflammation marker providing prognostic information of vasculopathy. Until today, however, the effect of aldosterone or oxidative stress on the regulation of PTX3 is unknown. In present study, we investigated to find regulative factors, especially aldosterone and oxidative stress, on PTX3. Serum PTX3 levels were measured in 75 patients (45 male and 30 women, aged 55.1+/-13.4 year-old (mean+/-SD)) with various endocrine disorders including 47 with diabetes, 24 with primary aldosteronism (PA). All participants were free from cardio vascular diseases and diabetic retinopathy. Serum PTX3 level was significantly lower in patients with PA than without PA and was significantly higher in patients with diabetes than without diabetes. PTX3 was significantly correlated with glycated hemoglobin (HbA1c), urinary albumin excretion (UAE) and plasma aldosterone concentration (PAC) (r = 0.431, P<0.001; r = 0.313, P = 0.009; r = -0.375, P = 0.004). A stepwise multiple regression analysis chose HbA1c and UAE as independent determinants of PTX3 (beta = 0.282, P<0.001; beta = 0.783, P<0.001). On the other hand, PTX3 was not significantly correlated with HbA1c and UAE but significantly negatively correlated with PAC in patients with diabetes. Therefore, it might be suggested that PTX3 is positively regulated by chronic hyperglycemia but negatively regulated by aldosterone, and is associated with urinary albumin excretion as a micro vasculopathy. PMID- 29715314 TI - The burden of acute respiratory infections in Ecuador 2011-2015. AB - BACKGROUND: Burden of disease studies intend to improve public health decision making and to measure social and economic impact in population. The objective of this study was to describe the burden of acute respiratory infections (ARI) in Ecuador between 2011 and 2015. METHODS: Five-year period morbidity and mortality data available from national agencies of statistics was analyzed to estimate the burden of disease attributable to acute respiratory infections. Cases and deaths registered were grouped according to their ICD-10 code into three diagnostic groups: Acute upper respiratory infections (J00-J06), Influenza and pneumonia (J09-J18), and Bronchitis and other acute lower respiratory infections (J20-J22, J85, J86). Disability-adjusted life years stratified by diagnostic and age group were calculated using the "DALY" package for R. The productivity loss in monetary terms was estimated using the human capital method. RESULTS: Over the 5-year period studied there were a total of 14.84 million cases of acute respiratory infections, with 17 757 deaths reported (0.12%). The yearly burden of disease ranged between 98 944 to 118 651 disability-adjusted life years, with an estimated average loss of productivity of US$152.16 million (+/-19.6) per year. Approximately 99% of the burden can be attributed to years life lost due to premature mortality in population under 5 years old and over 60 years-old. CONCLUSIONS: The burden of acute respiratory infections remained steady during the analyzed period. Evidence-based prevention and control policies to tackle acute respiratory infections in Ecuador should focus on the population at extreme ages of life. PMID- 29715316 TI - Useful field of view test performance throughout adulthood in subjects without ocular disorders. AB - Previous research has shown an age-related decline in Useful Field of View (UFOV) test performance, which measures the duration required to extract relevant information from a scene in three subtasks. However, these results are mostly based on data that may have been confounded by (age-related) ocular diseases. We examined UFOV performance in subjects aged 19.5 to 70.3 years to investigate how UFOV performance changes throughout adulthood. All subjects underwent a thorough ophthalmological examination to exclude ocular disorders. We also examined some elementary visual functions, i.e., near and far visual acuity, crowding and contrast sensitivity. We investigated whether these functions were related to age and whether they could explain a possible age-related decline in UFOV performance. The subjects (n = 41) performed very well on almost every measure and reached far better UFOV and visual acuity scores than those reported by other studies that relied on self-reported absence of ocular pathology. We did not find significant relationships between age and any of the elementary visual functions or the first two UFOV subtasks (R2UFOV1 = 0.03, p = 0.25; R2UFOV2 = 0.07, p = 0.10). However, we found an age-related decline in performance on the third UFOV subtask (R2UFOV3 = 0.36, p < 0.001), which was unrelated to performance on the elementary visual function tasks. Our results show that performance on the first two UFOV subtasks as well as central elementary visual functions may remain high in the absence of obvious ophthalmological pathology. PMID- 29715315 TI - A PKC-MARCKS-PI3K regulatory module links Ca2+ and PIP3 signals at the leading edge of polarized macrophages. AB - The leukocyte chemosensory pathway detects attractant gradients and directs cell migration to sites of inflammation, infection, tissue damage, and carcinogenesis. Previous studies have revealed that local Ca2+ and PIP3 signals at the leading edge of polarized leukocytes play central roles in positive feedback loop essential to cell polarization and chemotaxis. These prior studies showed that stimulation of the leading edge Ca2+ signal can strongly activate PI3K, thereby triggering a larger PIP3 signal, but did not elucidate the mechanistic link between Ca2+ and PIP3 signaling. A hypothesis explaining this link emerged, postulating that Ca2+-activated PKC displaces the MARCKS protein from plasma membrane PIP2, thereby releasing sequestered PIP2 to serve as the target and substrate lipid of PI3K in PIP3 production. In vitro single molecule studies of the reconstituted pathway on lipid bilayers demonstrated the feasibility of this PKC-MARCKS-PI3K regulatory module linking Ca2+ and PIP3 signals in the reconstituted system. The present study tests the model predictions in live macrophages by quantifying the effects of: (a) two pathway activators-PDGF and ATP that stimulate chemoreceptors and Ca2+ influx, respectively; and (b) three pathway inhibitors-wortmannin, EGTA, and Go6976 that inhibit PI3K, Ca2+ influx, and PKC, respectively; on (c) four leading edge activity sensors-AKT-PH-mRFP, CKAR, MARCKSp-mRFP, and leading edge area that report on PIP3 density, PKC activity, MARCKS membrane binding, and leading edge expansion/contraction, respectively. The results provide additional evidence that PKC and PI3K are both essential elements of the leading edge positive feedback loop, and strongly support the existence of a PKC-MARCKS-PI3K regulatory module linking the leading edge Ca2+ and PIP3 signals. As predicted, activators stimulate leading edge PKC activity, displacement of MARCKS from the leading edge membrane and increased leading edge PIP3 levels, while inhibitors trigger the opposite effects. Comparison of the findings for the ameboid chemotaxis of leukocytes with recently published findings for the mesenchymal chemotaxis of fibroblasts suggests that some features of the emerging leukocyte leading edge core pathway (PLC-DAG-Ca2+ PKC-MARCKS-PIP2-PI3K-PIP3) may well be shared by all chemotaxing eukaryotic cells, while other elements of the leukocyte pathway may be specialized features of these highly optimized, professional gradient-seeking cells. More broadly, the findings suggest a molecular mechanism for the strong links between phospho MARCKS and many human cancers. PMID- 29715317 TI - Candidate gene identification of ovulation-inducing genes by RNA sequencing with an in vivo assay in zebrafish. AB - We previously reported the microarray-based selection of three ovulation-related genes in zebrafish. We used a different selection method in this study, RNA sequencing analysis. An additional eight up-regulated candidates were found as specifically up-regulated genes in ovulation-induced samples. Changes in gene expression were confirmed by qPCR analysis. Furthermore, up-regulation prior to ovulation during natural spawning was verified in samples from natural pairing. Gene knock-out zebrafish strains of one of the candidates, the starmaker gene (stm), were established by CRISPR genome editing techniques. Unexpectedly, homozygous mutants were fertile and could spawn eggs. However, a high percentage of unfertilized eggs and abnormal embryos were produced from these homozygous females. The results suggest that the stm gene is necessary for fertilization. In this study, we selected additional ovulation-inducing candidate genes, and a novel function of the stm gene was investigated. PMID- 29715318 TI - Computational identification, characterization and validation of potential antigenic peptide vaccines from hrHPVs E6 proteins using immunoinformatics and computational systems biology approaches. AB - High-risk human papillomaviruses (hrHPVs) are the most prevalent viruses in human diseases including cervical cancers. Expression of E6 protein has already been reported in cervical cancer cases, excluding normal tissues. Continuous expression of E6 protein is making it ideal to develop therapeutic vaccines against hrHPVs infection and cervical cancer. Therefore, we carried out a meta analysis of multiple hrHPVs to predict the most potential prophylactic peptide vaccines. In this study, immunoinformatics approach was employed to predict antigenic epitopes of hrHPVs E6 proteins restricted to 12 Human HLAs to aid the development of peptide vaccines against hrHPVs. Conformational B-cell and CTL epitopes were predicted for hrHPVs E6 proteins using ElliPro and NetCTL. The potential of the predicted peptides were tested and validated by using systems biology approach considering experimental concentration. We also investigated the binding interactions of the antigenic CTL epitopes by using docking. The stability of the resulting peptide-MHC I complexes was further studied by molecular dynamics simulations. The simulation results highlighted the regions from 46-62 and 65-76 that could be the first choice for the development of prophylactic peptide vaccines against hrHPVs. To overcome the worldwide distribution, the predicted epitopes restricted to different HLAs could cover most of the vaccination and would help to explore the possibility of these epitopes for adaptive immunotherapy against HPVs infections. PMID- 29715319 TI - Population-based study of chlamydial and gonococcal infections among women in Shenzhen, China: Implications for programme planning. AB - This study was aimed to estimate the prevalences of chlamydia (CT) and gonococcal (NG) infections and explore risk factors associated with the CT infection among women in Shenzhen, China. We collected socio-demographic and clinical data from women (aged 20-60) and determined positivity of CT or NG by nucleic acid amplification test (NAAT) with self-collected urine specimens. We estimated prevalence of CT and NG and determined risk factors associated with CT infection. Among 9,207 participants, 4.12% (95% confidence interval [CI], 3.71%-4.53%) tested positive for CT and 0.17% (95% CIs, 0.09%-0.25%) for NG. Factors significantly associated with CT infection included being an ethnic minority (ethnicity other than Han China) (Adjusted odds ratio [AOR], 1.9; 95% CI, 1.2 3.0), using methods other than condom for contraception (AOR, 1.5; 95% CI, 1.2 1.8), having a history of adverse pregnancy outcomes (AOR, 1.4; 95% CI, 1.1-1.8), and experiencing reproductive tract symptoms in the past three months (AOR, 1.3; 95% CI, 1.0-1.7). we found that CT infection is prevalent among women in Shenzhen, China and associated with both demographic and behavioral factors. A comprehensive CT screening, surveillance and treatment programme targeting this population is warranted. PMID- 29715320 TI - Deciphering the binding behavior of flavonoids to the cyclin dependent kinase 6/cyclin D complex. AB - Flavonoids, a class of natural compounds with variable phenolic structures, have been found to possess anti-cancer activities by modulating different enzymes and receptors like CDK6. To understand the binding behavior of flavonoids that inhibit the active CDK6, molecular dynamics (MD) simulations were performed on six inhibitors, chrysin (M01), fisetin (M03), galangin (M04), genistein (M05), quercetin (M06) and kaempferol (M07), complexed with CDK6/cyclin D. For all six flavonoids, the 3'-OH and 4'-OH of B-ring were found to be favorable for hydrogen bond formation, but the 3-OH on the C-ring and 5-OH on the A-ring were unfavorable, which were confirmed by the MD simulation results of the test molecule, 3', 4', 7-trihydroxyflavone (M15). The binding efficiencies of flavonoids against the CDK6/cyclin D complex were mainly through the electrostatic (especially the H-bond force) and vdW interactions with residues ILE19, VAL27, ALA41, GLU61, PHE98, GLN103, ASP163 and LEU152. The order of binding affinities of these flavonoids toward the CDK6/cyclin D was M03 > M01 > M07 > M15 > M06 > M05 > M04. It is anticipated that the binding features of flavonoid inhibitors studied in the present work may provide valuable insights for the development of CDK6 inhibitors. PMID- 29715321 TI - Correction: A novel association rule mining approach using TID intermediate itemset. AB - [This corrects the article DOI: 10.1371/journal.pone.0179703.]. PMID- 29715322 TI - Clinical analysis of fungal keratitis in patients with and without diabetes. AB - We compared the clinical characteristics, treatments, and prognoses of fungal keratitis in patients with and without diabetes. Patients diagnosed with fungal keratitis at Shandong Eye Institute between January 2010 and December 2016 were retrospectively reviewed and classified as diabetic and nondiabetic groups. One hundred-and-eleven patients (111 eyes) with diabetes and 740 patients (740 eyes) without diabetes were included. The diabetic patients showed significantly older (p< 0.05) and lower male:female ratio (p<0.05). Plants trauma was the primary risk factor in both groups, and there was no significant difference of pathogen type (the most common was Fusarium genus, followed by Alternaria and Aspergillus genera). Multivariate logistic regression analyses revealed that diabetes and topical glucocorticoid use were the independent risk factors for the severity of fungal keratitis. The recurrent infection rate between the diabetic and nondiabetic patients during the follow-up (6 to 24 months) after penetrating keratoplasty (PKP) was not significantly different. Although the recurrent epithelial defect, rejection, and best-corrected visual acuity were similar between the patients with matched bed/graft size (7.75/8.0 mm) in the two groups 1 year after PKP, the incidence of delayed re-epithelialization (>7 days) was significantly higher in diabetic patients (3/10 versus 2/43 in nondiabetic patients, p<0.05). More specially, the diabetic patients with the duration >=10 years showed more significantly delayed re-epithelialization than those with the diabetic duration less than 10 years (3/5 versus 1/26, p<0.05). In conclusion, the diabetes mellitus is an independent risk factor that affect the severity of fungal keratitis. Corneal re-epithelialization was significantly delayed after PKP in the diabetic patients, especially with the duration >=10 years. PMID- 29715324 TI - Correction: Characterizing the metabolic phenotype of intestinal villus blunting in Zambian children with severe acute malnutrition and persistent diarrhea. AB - [This corrects the article DOI: 10.1371/journal.pone.0192092.]. PMID- 29715323 TI - Virological and immunological failure of HAART and associated risk factors among adults and adolescents in the Tigray region of Northern Ethiopia. AB - BACKGROUND: Human immunodeficiency virus/Acquired immunodeficiency syndrome associated morbidity and mortality has reduced significantly since the introduction of highly active antiretroviral therapy. As a result of increasing access to highly active antiretroviral therapy, the survival and quality of life of the patients has significantly improved globally. Despite this promising result, regular monitoring of people on antiretroviral therapy is recommended to ensure whether there is an effective treatment response or not. This study was designed to assess virological and immunological failure of highly active antiretroviral therapy users among adults and adolescents in the Tigray region of Northern Ethiopia, where scanty data are available. METHODS: A retrospective follow up study was conducted from September 1 to December 30, 2016 to assess the magnitude and factors associated with virological and immunological failure among 260 adults and adolescents highly active antiretroviral therapy users who started first line ART between January 1, 2008 to March 1, 2016. A standardized questionnaire was used to collect socio-demographic and clinical data. SPSS Version21 statistical software was used for analysis. Bivariate and multivariate logistic regression analyses were conducted to identify factors associated to virological and immunological failure. Statistical association was declared significant if p-value was <= 0.05. RESULT: A total of 30 (11.5%) and 17 (6.5%) participants experienced virological and immunological failure respectively in a median time of 36 months of highly active antiretroviral therapy. Virological failure was associated with non-adherence to medications, aged < 40 years old, having CD4+ T-cells count < 250 cells/MUL and male gender. Similarly, immunological failure was associated with non-adherence, tuberculosis co infection and Human immunodeficiency virus RNA >=1000 copies/mL. CONCLUSIONS: The current result shows that immunological and virological failure is a problem in a setting where highly active antiretroviral therapy has been largely scale up. The problem is more in patients with poor adherence. This will in turn affect the global targets of 90% viral suppression by 2020. This may indicate the need for more investment and commitment to improving patient adherence in the study area. PMID- 29715325 TI - Correction: Empirical mode decomposition processing to improve multifocal-visual evoked-potential signal analysis in multiple sclerosis. AB - [This corrects the article DOI: 10.1371/journal.pone.0194964.]. PMID- 29715326 TI - Correction: Renal Cells Express Different Forms of Vimentin: The Independent Expression Alteration of these Forms is Important in Cell Resistance to Osmotic Stress and Apoptosis. AB - [This corrects the article DOI: 10.1371/journal.pone.0068301.]. PMID- 29715327 TI - Correction: A sibling method for identifying vQTLs. AB - [This corrects the article DOI: 10.1371/journal.pone.0194541.]. PMID- 29715328 TI - Correction: Application of a qPCR Assay in the Investigation of Susceptibility to Malaria Infection of the M and S Molecular Forms of An. gambiae s.s. in Cameroon. AB - [This corrects the article DOI: 10.1371/journal.pone.0054820.]. PMID- 29715329 TI - A new crystal form of Aspergillus oryzae catechol oxidase and evaluation of copper site structures in coupled binuclear copper enzymes. AB - Coupled binuclear copper (CBC) enzymes have a conserved type 3 copper site that binds molecular oxygen to oxidize various mono- and diphenolic compounds. In this study, we found a new crystal form of catechol oxidase from Aspergillus oryzae (AoCO4) and solved two new structures from two different crystals at 1.8-A and at 2.5-A resolutions. These structures showed different copper site forms (met/deoxy and deoxy) and also differed from the copper site observed in the previously solved structure of AoCO4. We also analysed the electron density maps of all of the 56 CBC enzyme structures available in the protein data bank (PDB) and found that many of the published structures have vague copper sites. Some of the copper sites were then re-refined to find a better fit to the observed electron density. General problems in the refinement of metalloproteins and metal centres are discussed. PMID- 29715331 TI - Lightness matching and perceptual similarity. AB - Lightness constancy is the ability to perceive surface reflectance correctly despite substantial changes in lighting intensity. A classic view is that lightness constancy is the result of a "discounting" of lighting intensity, and this continues to be a prominent view today. Logvinenko and Maloney (2006) have proposed an alternative approach to understanding lightness constancy, in which observers do not make explicit estimates of reflectance, and lightness constancy is instead based on a perceptual similarity metric that depends on both the reflectance and the illuminance of surfaces viewed under different lighting conditions. Here we compare these two views using a novel, free-adjustment reflectance-matching task. We test whether observers can match reflectance in a task where they are free to adjust both the illuminance and the reflectance of the match stimulus over a wide range. We find that observers can match reflectance under these conditions, which supports the view that observers make explicit estimates of reflectance. We also compare performance in this free adjustment task using physical objects and computer-rendered images as stimuli. We find that lightness constancy is good in both cases, but with some evidence of a glow-related artifact with computer-rendered stimuli. PMID- 29715330 TI - Sensing CA 15-3 in point-of-care by electropolymerizing O-phenylenediamine (oPDA) on Au-screen printed electrodes. AB - This work presents an alternative device for cancer screening in liquid biopsies. It combines a biomimetic film (i) with electrochemical detection (ii). The biomimetic film (i) was obtained by electro-polymerizing amine-substituted benzene rings around a CA 15-3 target. This protein target was previously adsorbed on a gold (Au) support and incubated in charged monomers (4 Styrenesulfonate sodium and 3-Hydroxytyraminium chloride). The protein was further eliminated by enzymatic activity, leaving behind vacant sites for subsequent rebinding. Electrochemical detection (ii) was achieved on an Au working electrode, designed on commercial screen-printed electrodes. Raman spectroscopy, atomic force microscopy and ellipsometric readings were used to follow the chemical modification of the Au surface. The ability of the material to rebind CA15-3 was monitored by electrochemical techniques. The device displayed linear responses to CA15-3 ranging from 0.25 to 10.00 U/mL, with detection limits of 0.05 U/mL. Accurate results were obtained by applying the sensor to the analysis of CA15-3 in PBS buffer and in serum samples. This biosensing device displayed successful features for the detection of CA 15-3 and constitutes a promising tool for breast cancer screening procedures in point-of care applications. Moreover, its scale-up seems feasible as it contains a plastic antibody assembled in situ, in less than 1 minute, and the analysis of serum takes less than 30 minutes. PMID- 29715332 TI - Orientation-selective contrast adaptation measured with SSVEP. AB - Exposure to oriented luminance contrast patterns causes a reduction in visual sensitivity specifically for the adapter orientation. This orientation selectivity is probably the most studied aspect of contrast adaptation, but it has rarely been measured with steady-state visually evoked potentials (SSVEPs), despite their becoming one of the more popular methods of human neuroscience. Here, we measured orientation selective adaptation by presenting a plaid stimulus of which the horizontal and vertical grating reversed contrast at different temporal frequencies, while recording EEG signals from occipital visual areas. In three experiments, we compared SSVEP responses to the plaid before and after adaptation. All experiments showed a significant decrease in SSVEP response at the frequency of the adapter orientation, whereas such an effect was absent for the frequency of the orthogonal orientation. Adaptation also led to robust phase delays, selectively for the SSVEP frequency corresponding to the adapter orientation. These results demonstrate the efficiency of SSVEPs for measuring orientation selective adaptation; the method can measure changes in both amplitude and phase, simultaneously for two orientations. PMID- 29715333 TI - Visual search accelerates during adolescence. AB - We studied changes in visual-search performance and behavior during adolescence. Search performance was analyzed in terms of reaction time and response accuracy. Search behavior was analyzed in terms of the objects fixated and the duration of these fixations. A large group of adolescents (N = 140; age: 12-19 years; 47% female, 53% male) participated in a visual-search experiment in which their eye movements were recorded with an eye tracker. The experiment consisted of 144 trials (50% with a target present), and participants had to decide whether a target was present. Each trial showed a search display with 36 Gabor patches placed on a hexagonal grid. The target was a vertically oriented element with a high spatial frequency. Nontargets differed from the target in spatial frequency, orientation, or both. Search performance and behavior changed during adolescence; with increasing age, fixation duration and reaction time decreased. Response accuracy, number of fixations, and selection of elements to fixate upon did not change with age. Thus, the speed of foveal discrimination increases with age, while the efficiency of peripheral selection does not change. We conclude that the way visual information is gathered does not change during adolescence, but the processing of visual information becomes faster. PMID- 29715334 TI - Internal Viscosity-Dependent Margination of Red Blood Cells in Microfluidic Channels. AB - Cytoplasmic viscosity-dependent margination of red blood cells (RBC) for flow inside microchannels was studied using numerical simulations, and the results were verified with microfluidic experiments. Wide range of suspension volume fractions or hematocrits was considered in this study. Lattice Boltzmann method for fluid-phase coupled with spectrin-link method for RBC membrane deformation was used for accurate analysis of cell margination. RBC margination behavior shows strong dependence on the internal viscosity of the RBCs. At equilibrium, RBCs with higher internal viscosity marginate closer to the channel wall and the RBCs with normal internal viscosity migrate to the central core of the channel. Same margination pattern has been verified through experiments conducted with straight channel microfluidic devices. Segregation between RBCs of different internal viscosity is enhanced as the shear rate and the hematocrit increases. Stronger separation between normal RBCs and RBCs with high internal viscosity is obtained as the width of a high aspect ratio channel is reduced. Overall, the margination behavior of RBCs with different internal viscosities resembles with the margination behavior of RBCs with different levels of deformability. Observations from this work will be useful in designing microfluidic devices for separating the subpopulations of RBCs with different levels of deformability that appear in many hematologic diseases such as sickle cell disease (SCD), malaria, or cancer. PMID- 29715335 TI - Genomes of Distinctive Species Reveal Clues to Human Health and Disease. PMID- 29715336 TI - Incorrect Cervical Length Category Definitions. PMID- 29715337 TI - Incorrectly Described Data. PMID- 29715338 TI - Insulin vs Glyburide for Gestational Diabetes. PMID- 29715339 TI - New Option for Patients With Advanced Hodgkin Lymphoma. PMID- 29715340 TI - Blood Glucose Readings Made Possible Via Smartphone. PMID- 29715341 TI - Progress in Lead Test Investigation. PMID- 29715342 TI - Management of Dyspepsia. PMID- 29715344 TI - Breast Cancer Screening in 2018: Time for Shared Decision Making. PMID- 29715345 TI - Private and Public Sector Responses to Climate Change. PMID- 29715346 TI - Sugar in War Time. PMID- 29715347 TI - Changes in Synthetic Opioid Involvement in Drug Overdose Deaths in the United States, 2010-2016. PMID- 29715348 TI - The National Resident Matching Program and Competition for Employment. PMID- 29715349 TI - Cervical Pessary and Spontaneous Preterm Birth. PMID- 29715350 TI - Quality of Life in Patients With Glioblastoma Treated With Tumor-Treating Fields. PMID- 29715351 TI - Cervical Pessary and Spontaneous Preterm Birth-Reply. PMID- 29715352 TI - The National Resident Matching Program and Competition for Employment-Reply. PMID- 29715353 TI - Quality of Life in Patients With Glioblastoma Treated With Tumor-Treating Fields Reply. PMID- 29715354 TI - Effect of Atropine With Propofol vs Atropine With Atracurium and Sufentanil on Oxygen Desaturation in Neonates Requiring Nonemergency Intubation: A Randomized Clinical Trial. AB - Importance: Propofol or a combination of a synthetic opioid and muscle relaxant are both recommended for premedication before neonatal intubation but have yet to be compared. Objective: To compare prolonged desaturation during neonatal nasotracheal intubation after premedication with atropine-propofol vs atropine atracurium-sufentanil treatment. Design, Setting, and Participants: Multicenter, double-blind, randomized clinical trial (2012-2016) in 6 NICUs in France that included 173 neonates requiring nonemergency intubation. The study was interrupted due to expired study kits and lack of funding. Interventions: Eighty nine participants were randomly assigned to the atropine-propofol group and 82 to the atropine-atracurium-sufentanil group before nasotracheal intubation. Main Outcomes and Measures: The primary outcome was prolonged desaturation (Spo2 <80% lasting > 60 seconds), using intention-to-treat analysis using mixed models. Secondary outcomes assessed the characteristics of the procedure and its tolerance. Results: Of 173 neonates randomized (mean gestational age, 30.6 weeks; mean birth weight, 1502 g; 71 girls), 171 (99%) completed the trial. Of 89 infants, 53 (59.6%) in the atropine-propofol group vs 54 of 82 (65.9%) in the atropine-atracurium-sufentanil group achieved the primary outcome (adjusted RD, 6.4; 95% CI, -21.0 to 8.1; P = .38). The atropine-propofol group had a longer mean procedure duration than did the atropine-atracurium-sufentanil group (adjusted RD, 1.7 minutes; 95% CI, 0.1-3.3 minutes; P = .04); a less frequent excellent quality of sedation rate, 51.7% (45 of 87) vs 92.6% (75 of 81; P < .001); a shorter median time to respiratory recovery, 14 minutes (IQR, 8-34 minutes) vs 33 minutes (IQR, 15-56 minutes; P = .002), and shorter median time to limb movement recovery, 18 minutes (IQR, 10-43 minutes) vs 36 minutes (IQR, 19-65 minutes; P = .003). In the 60 minutes after inclusion, Spo2 was preserved significantly better in the atropine-propofol group (time * treatment interaction P = .02). Of the atropine-propofol group 20.6% had head ultrasound scans that showed worsening intracranial hemorrhaging (any or increased intraventricular hemorrhage) in the 7 days after randomization vs 17.6% in the atropine-atracurium sufentanil group (adjusted RD, 1.2; 95% CI, -13.1 to 15.5, P = .87). Severe adverse events occurred in 11% of the atropine-propofol group and in 20% of the atropine-atracurium-sufentanil group. Conclusions and Relevance: Among neonates undergoing nonemergency nasotracheal intubation, the frequency of prolonged desaturation did not differ significantly between atropine used with propofol or atropine used with atracurium and sufentanil. However, the study may have been underpowered to detect a clinically important difference, and further research may be warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT01490580, EudraCT number: 2009-014885-25. PMID- 29715356 TI - Laparoscopic Cholecystectomy. PMID- 29715355 TI - Effect of Glyburide vs Subcutaneous Insulin on Perinatal Complications Among Women With Gestational Diabetes: A Randomized Clinical Trial. AB - Importance: Randomized trials have not focused on neonatal complications of glyburide for women with gestational diabetes. Objective: To compare oral glyburide vs subcutaneous insulin in prevention of perinatal complications in newborns of women with gestational diabetes. Design, Settings, and Participants: The Insulin Daonil trial (INDAO), a multicenter noninferiority randomized trial conducted between May 2012 and November 2016 (end of participant follow-up) in 13 tertiary care university hospitals in France including 914 women with singleton pregnancies and gestational diabetes diagnosed between 24 and 34 weeks of gestation. Interventions: Women who required pharmacologic treatment after 10 days of dietary intervention were randomly assigned to receive glyburide (n=460) or insulin (n=454). The starting dosage for glyburide was 2.5 mg orally once per day and could be increased if necessary 4 days later by 2.5 mg and thereafter by 5 mg every 4 days in 2 morning and evening doses, up to a maximum of 20 mg/d. The starting dosage for insulin was 4 IU to 20 IU given subcutaneously 1 to 4 times per day as necessary and increased according to self-measured blood glucose concentrations. Main Outcomes and Measures: The primary outcome was a composite criterion including macrosomia, neonatal hypoglycemia, and hyperbilirubinemia. The noninferiority margin was set at 7% based on a 1-sided 97.5% confidence interval. Results: Among the 914 patients who were randomized (mean age, 32.8 [SD, 5.2] years), 98% completed the trial. In a per-protocol analysis, 367 and 442 women and their neonates were analyzed in the glyburide and insulin groups, respectively. The frequency of the primary outcome was 27.6% in the glyburide group and 23.4% in the insulin group, a difference of 4.2% (1-sided 97.5% CI, infinity to 10.5%; P=.19). Conclusion and Relevance: This study of women with gestational diabetes failed to show that use of glyburide compared with subcutaneous insulin does not result in a greater frequency of perinatal complications. These findings do not justify the use of glyburide as a first-line treatment. Trial Registration: clinicaltrials.gov Identifier: NCT01731431. PMID- 29715358 TI - Oblivion. PMID- 29715359 TI - Chronic Hepatitis B Infection: A Review. AB - Importance: More than 240 million individuals worldwide are infected with chronic hepatitis B virus (HBV). Among individuals with chronic HBV infection who are untreated, 15% to 40% progress to cirrhosis, which may lead to liver failure and liver cancer. Observations: Pegylated interferon and nucleos(t)ide analogues (lamivudine, adefovir, entecavir, tenofovir disoproxil, and tenofovir alafenamide) suppress HBV DNA replication and improve liver inflammation and fibrosis. Long-term viral suppression is associated with regression of liver fibrosis and reduced risk of hepatocellular carcinoma in cohort studies. The cure (defined as hepatitis B surface antigen loss with undetectable HBV DNA) rates after treatment remain low (3%-7% with pegylated interferon and 1%-12% with nucleos[t]ide analogue therapy). Pegylated interferon therapy can be completed in 48 weeks and is not associated with the development of resistance; however, its use is limited by poor tolerability and adverse effects such as bone marrow suppression and exacerbation of existing neuropsychiatric symptoms such as depression. Newer agents (entecavir, tenofovir disoproxil, and tenofovir alafenamide) may be associated with a significantly reduced risk of drug resistance compared with older agents (lamivudine and adefovir) and should be considered as the first-line treatment. Conclusions and Relevance: Antiviral treatment with either pegylated interferon or a nucleos(t)ide analogue (lamivudine, adefovir, entecavir, tenofovir disoproxil, or tenofovir alafenamide) should be offered to patients with chronic HBV infection and liver inflammation in an effort to reduce progression of liver disease. Nucleos(t)ide analogues should be considered as first-line therapy. Because cure rates are low, most patients will require therapy indefinitely. PMID- 29715361 TI - Assessment of Mechanical Characteristics of Ankle-Foot Orthoses. AB - Recent designs of ankle-foot orthoses (AFOs) have been influenced by the increasing demand for higher function from active individuals. The biomechanical function of the individual and device is dependent upon the underlying mechanical characteristics of the AFO. Prior mechanical testing of AFOs has primarily focused on rotational stiffness to provide insight into expected functional outcomes; mechanical characteristics pertaining to energy storage and release have not yet been investigated. A pseudostatic bench testing method is introduced to characterize compressive stiffness, device deflection, and motion of solid ankle, anterior floor reaction, posterior leaf spring, and the intrepid dynamic exoskeletal orthosis (IDEO) AFOs. Each of these four AFOs, donned over a surrogate limb, were compressively loaded at different joint angles to simulate the foot-shank orientation during various subphases of stance. In addition to force-displacement measurements, deflection of each AFO strut and rotation of proximal and supramalleolar segments were analyzed. Although similar compressive stiffness values were observed for AFOs designed to reduce ankle motion, the corresponding strut deflection profile differed based on the respective fabrication material. For example, strut deflection of carbon-fiber AFOs resembled column buckling. Expanded clinical test protocols to include quantification of AFO deflection and rotation during subject use may provide additional insight into design and material effects on performance and functional outcomes, such as energy storage and release. PMID- 29715362 TI - Characterizing the HeartMate II Left Ventricular Assist Device Outflow Using Particle Image Velocimetry. AB - Ventricular assist devices (VADs) are implanted in patients with a diseased ventricle to maintain peripheral perfusion as a bridge-to-transplant or as destination therapy. However, some patients with continuous flow VADs (e.g., HeartMate II (HMII)) have experienced gastrointestinal (GI) bleeding, in part caused by the proteolytic cleavage or mechanical destruction of von Willebrand factor (vWF), a clotting glycoprotein. in vitro studies were performed to measure the flow located within the HMII outlet cannula under both steady and physiological conditions using particle image velocimetry (PIV). Under steady flow, a mock flow loop was used with the HMII producing a flow rate of 3.2 L/min. The physiological experiment included a pulsatile pump operated at 105 BPM with a ventricle filling volume of 50 mL and in conjunction with the HMII producing a total flow rate of 5.0 L/min. Velocity fields, Reynolds normal stresses (RNSs), and Reynolds shear stresses (RSSs) were analyzed to quantify the outlet flow's potential contribution to vWF degradation. Under both flow conditions, the HMII generated principal Reynolds stresses that are, at times, orders of magnitude higher than those needed to unfurl vWF, potentially impacting its physiological function. Under steady flow, principal RNSs were calculated to be approximately 500 Pa in the outlet cannula. Elevated Reynolds stresses were observed throughout every phase of the cardiac cycle under physiological flow with principal RNSs approaching 1500 Pa during peak systole. Prolonged exposure to these conditions may lead to acquired von Willebrand syndrome (AvWS), which is accompanied by uncontrollable bleeding episodes. PMID- 29715363 TI - Hip Joint Contact Pressure Distribution During Pavlik Harness Treatment of an Infant Hip: A Patient-Specific Finite Element Model. AB - Developmental dysplasia of the hip (DDH) in infants under 6 months of age is typically treated by the Pavlik harness (PH). During successful PH treatment, a subluxed/dislocated hip is spontaneously reduced into the acetabulum, and DDH undergoes self-correction. PH treatment may fail due to avascular necrosis (AVN) of the femoral head. An improved understanding of mechanical factors accounting for the success/failure of PH treatment may arise from investigating articular cartilage contact pressure (CCP) within a hip during treatment. In this study, CCP in a cartilaginous infant hip was investigated through patient-specific finite element (FE) modeling. We simulated CCP of the hip equilibrated at 90 deg flexion at abduction angles of 40 deg, 60 deg, and 80 deg. We found that CCP was predominantly distributed on the anterior and posterior acetabulum, leaving the superior acetabulum (mainly superolateral) unloaded. From a mechanobiological perspective, hypothesizing that excessive pressure inhibits growth, our results qualitatively predicted increased obliquity and deepening of the acetabulum under such CCP distribution. This is the desired and observed therapeutic effect in successful PH treatment. The results also demonstrated increase in CCP as abduction increased. In particular, the simulation predicted large magnitude and concentrated CCP on the posterior wall of the acetabulum and the adjacent lateral femoral head at extreme abduction (80 deg). This CCP on lateral femoral head may reduce blood flow in femoral head vessels and contribute to AVN. Hence, this study provides insight into biomechanical factors potentially responsible for PH treatment success and complications. PMID- 29715364 TI - Quantitative Analysis of Tissue Damage Evolution in Porcine Liver With Interrupted Mechanical Testing Under Tension, Compression, and Shear. AB - In this study, the damage evolution of liver tissue was quantified at the microstructural level under tensile, compression, and shear loading conditions using an interrupted mechanical testing method. To capture the internal microstructural changes in response to global deformation, the tissue samples were loaded to different strain levels and chemically fixed to permanently preserve the deformed tissue geometry. Tissue microstructural alterations were analyzed to quantify the accumulated damages, with damage-related parameters such as number density, area fraction, mean area, and mean nearest neighbor distance (NND). All three loading states showed a unique pattern of damage evolution, in which the damages were found to increase in number and size, but decrease in NND as strain level increased. To validate the observed damage features as true tissue microstructural damages, more samples were loaded to the above-mentioned strain levels and then unloaded back to their reference state, followed by fixation. The most major damage-relevant features at higher strain levels remained after the release of the external loading, indicating the occurrence of permanent inelastic deformation. This study provides a foundation for future structure-based constitutive material modeling that can capture and predict the stress-state dependent damage evolution in liver tissue. PMID- 29715365 TI - Evaluation of Automatically Quantified Foveal Avascular Zone Metrics for Diagnosis of Diabetic Retinopathy Using Optical Coherence Tomography Angiography. AB - Purpose: To describe an automated algorithm to quantify the foveal avascular zone (FAZ), using optical coherence tomography angiography (OCTA), and to compare its performance for diagnosis of diabetic retinopathy (DR) and association with best corrected visual acuity (BCVA) to that of extrafoveal avascular area (EAA). Methods: We obtained 3 * 3-mm macular OCTA scans in diabetic patients with various levels of DR and healthy controls. An algorithm based on a generalized gradient vector flow (GGVF) snake model detected the FAZ, and metrics assessing FAZ size and irregularity were calculated. We compared the automated FAZ segmentation to manual delineation and tested the within-visit repeatability of FAZ metrics. The correlations of two conventional FAZ metrics, two novel FAZ metrics, and EAA with DR severity and BCVA, as determined by Early Treatment Diabetic Retinopathy Study (ETDRS) charts, were assessed. Results: Sixty-six eyes from 66 diabetic patients and 19 control eyes from 19 healthy participants were included. The agreement between manual and automated FAZ delineation had a Jaccard index > 0.82, and the repeatability of automated FAZ detection was excellent in eyes at all levels of DR severity. FAZ metrics that incorporated both FAZ size and shape irregularity had the strongest correlation with clinical DR grade and BCVA. Of all the tested OCTA metrics, EAA had the greatest sensitivity in differentiating diabetic eyes without clinical evidence of retinopathy, mild to moderate nonproliferative DR (NPDR), and severe NPDR to proliferative DR from healthy controls. Conclusions: The GGVF snake algorithm tested in this study can accurately and reliably detect the FAZ, using OCTA data at all DR severity grades, and may be used to obtain clinically useful information from OCTA data regarding macular ischemia in patients with diabetes. While FAZ metrics can provide clinically useful information regarding macular ischemia, and possibly visual acuity potential, EAA measurements may be a better biomarker for DR. PMID- 29715366 TI - Differential CXC and CX3C Chemokine Expression Profiles in Aqueous Humor of Patients With Specific Endogenous Uveitic Entities. AB - Purpose: To determine the levels of the neutrophil chemoattractants CXCL1, CXCL2, CXCL5, CXCL6, and CXCL8, the T helper 1 chemoattractants CXCL9, CXCL10 and CXCL11, the lymphoid chemokines CXCL12 and CXCL13 and the soluble form of the transmembrane chemokines CXCL16 and CX3CL1, in aqueous humor samples from patients with specific uveitic entities. Methods: Aqueous humor samples from patients with active uveitis associated with Behcet's disease (n = 13), sarcoidosis (n = 8), HLA-B27-related inflammation (n = 12), Vogt-Koyanagi-Harada (VKH) disease (n = 12), and healthy controls (n = 9) were assayed with the use of a multiplex assay. Results: All chemoattractant levels were significantly higher in all patients than in the controls. The levels of all neutrophil chemoattractants and CXCL10, CXCL16, and CX3CL1 were significantly higher in nongranulomatous uveitis (Behcet's disease and HLA-B27-associated uveitis) than in granulomatous uveitis (sarcoidosis and VKH disease), whereas the levels of the B cell chemoattractant CXCL13 were significantly higher in granulomatous uveitis than in nongranulomatous uveitis. CXCL13 levels were highest in the patients with VKH disease. CXCL9, CXCL11, and CXCL12 levels did not differ significantly. Conclusions: Inflammation in nongranulomatous uveitis appears to be driven by neutrophils and T helper 1 lymphocytes, whereas B lymphocytes may contribute to the inflammatory process in granulomatous uveitis, particularly in VKH disease. PMID- 29715368 TI - Cross-Inhibition of Norrin and TGF-beta Signaling Modulates Development of Retinal and Choroidal Vasculature. AB - Purpose: Norrin is essential for the formation of the retinal vasculature during development and promotes its repair after damage via activation of Wnt/beta catenin signaling. Since retinal TGF-beta signaling has essentially opposite effects on the retinal vasculature we investigated if and how Norrin inhibits TGF beta signaling, and vice versa. Methods: Eyes from transgenic mice with an overexpression of Norrin (betaB1-Norrin) and/or active TGF-beta (betaB1-TGF beta1) in the lens were generated and analyzed by light microscopy, immunohistochemistry, and TUNEL. Further on, protein as well as mRNA levels were investigated by Western blot analyses and real-time RT-PCR, respectively. Results: In betaB1-TGF-beta1 mice, the lack of retinal vascular development and choriocapillaris maintenance was rescued when transgenic Norrin was additionally overexpressed in the eye. In addition, retinal Wnt/beta-catenin signaling and the levels of SMAD7, an inhibitor of the canonical TGF-beta pathway, were substantially suppressed in retinae of betaB1-TGF-beta1 mice. In contrast, Norrin normalized Wnt/beta-catenin signaling and SMAD7 levels in double transgenic mice. Moreover, in retinae of betaB1-TGF-beta1 mice, the amounts of phosphorylated SMAD3, a downstream mediator of TGF-beta signaling, were increased compared to those of betaB1-Norrin/betaB1-TGF-beta1 mice. In vitro, Norrin substantially reduced the TGF-beta-mediated induction of target genes, an effect that was blocked by Dickkopf-1, a specific inhibitor of Wnt/beta-catenin signaling. Conclusions: High amounts of TGF-beta in the eye cause a substantial reduction in the activity of Wnt/beta-catenin signaling. This effect is inhibited in the presence of high amounts of Norrin, which further induce the expression of SMAD7 to inhibit TGF-beta signaling. PMID- 29715367 TI - Conditional Deletion of AP-2alpha and AP-2beta in the Developing Murine Retina Leads to Altered Amacrine Cell Mosaics and Disrupted Visual Function. AB - Purpose: The combined action of the activating protein-2 (AP-2) transcription factors, AP-2alpha and AP-2beta, is important in early retinal development, specifically in the formation of horizontal cells. However, in previous studies, it was not possible to analyze postnatal development and function of additional retinal subtypes. Methods: We used a double conditional deletion of AP-2alpha and AP-2beta from the retina to further examine the combinatory role of these genes in retinal cell patterning and function in postnatal adult mice as measured by Voronoi domain area and nearest-neighbor distance spatial analyses and ERGs, respectively. Results: Conditional deletion of both AP-2alpha and AP-2beta from the retina resulted in a variety of abnormalities, including the absence of horizontal cells, defects in the photoreceptor ribbons in which synapses failed to form, along with evidence of aberrant amacrine cell arrangement. Although no significant changes in amacrine cell population numbers were observed in the double mutants, significant irregularities in the mosaic patterning of amacrine cells was observed as demonstrated by both Voronoi domain areas and nearest neighbor distances analyses. These changes were further accompanied by an alteration in the retinal response to light as recorded by ERGs. In particular, in the double-mutant mice lacking AP-2alpha and AP-2beta, the b-wave amplitude, representative of interneuron signal processing, was significantly reduced compared with control littermates. Conclusions: Together these findings demonstrate the requirement for both AP-2alpha and AP-2beta in proper amacrine mosaic patterning and a normal functional light response in the retina. PMID- 29715370 TI - Getting Away From it All: The Importance of Vacation and Downtime Recovery From Work. PMID- 29715369 TI - Clinical Outcomes of Fixed Versus As-Needed Use of Artificial Tears in Dry Eye Disease: A 6-Week, Observer-Masked Phase 4 Clinical Trial. AB - Purpose: To evaluate the clinical effects of using fixed (four times daily [QID]) versus as-needed (PRN) dosing of an artificial tear product (polyethylene glycol/propylene glycol [PEG/PG]; Systane Ultra) in individuals with dry eye disease. Methods: In this prospective, multicenter, observer-masked, active control, parallel-group trial, participants were randomized (1:2 allocation) to receive 1 drop of PEG/PG QID (n = 34) or PRN (n = 63) for 28 days. The primary endpoint was change from baseline in the total ocular surface staining (TOSS) score (according to the Oxford scale) at day 28. Results: At day 28, the change from baseline in least squares mean (LSM) TOSS scores for QID and PRN groups were -1.19 and -0.94, respectively (treatment difference [TD]: -0.26; 95% confidence interval [CI]: -infinity to 0.21; P = 0.184); superiority of QID versus PRN dosing was not established, as the upper limit of one-sided 95% CI for TD was not <0 (prespecified limit). At day 28, for QID and PRN groups, the LSM change from baseline in Impact of Dry Eye on Everyday Life (IDEEL) scores was symptom-bother, -7.0 and -2.94 (TD: -4.06, P = 0.037); treatment effectiveness, 2.43 and 0.16 (TD: 2.28, P = 0.278); and treatment-related inconvenience, -11.56 and -2.77 (TD: -8.8, P = 0.996), respectively. Incidence of adverse events was low (<=3.2%) in both the groups; no serious adverse events were reported. Conclusions: QID dosing of PEG/PG was not superior to PRN dosing in terms of ocular staining. The IDEEL symptom-bother score favored QID dosing, suggesting that regular use of artificial tears may provide better symptomatic relief than PRN use. (ClinicalTrials.gov number, NCT02446015.). PMID- 29715371 TI - Trauma-Informed Care as Part of Nursing School Curricula. PMID- 29715372 TI - Drugs to Treat Anxiety Disorders. PMID- 29715373 TI - Case Study Application for Psychopharmacology With Borderline Personality Disorder. AB - Using an evolving case study, the current article demonstrates the principles of working with a client who has borderline personality disorder in relation to medications. The case study poses questions for the reader to consider and answers at the end of the article. [Journal of Psychosocial Nursing and Mental Health Services, 56(5), 16-19.]. PMID- 29715374 TI - Aripiprazole-Induced Neutropenia: Case Report and Literature Review. AB - Aripiprazole is a third-generation atypical antipsychotic medication, which is widely used for various psychiatric disorders across the lifespan. Aripiprazole can cause side effects including headache, insomnia, agitation, nervousness, lightheadedness, dizziness, somnolence, akathisia, and weight gain. Neutropenia is a less frequent side effect of aripiprazole. The current article reviews a case of a 10-year-old African American boy who developed neutropenia with aripiprazole. It is important for clinicians to be aware of this rare side effect. [Journal of Psychosocial Nursing and Mental Health Services, 56(5), 21 24.]. PMID- 29715375 TI - "Self Portrait" by Karin Teresa Fain. PMID- 29715376 TI - The Photophysics of Polythiophene Nanoparticles for Biological Applications. AB - In this work the photophysics of poly(3-hexylthiophene) nanoparticles (NPs) is investigated in the context of their biological applications. The NPs, made as colloidal suspensions in aqueous buffers, present a distinct absorption band in the low-energy region. On the basis of systematic analysis of absorption and transient absorption (TA) spectra taken under different pH conditions, this band is associated with charge-transfer states generated by the polarization of loosely bound polymer chains and originating from complexes formed with electron withdrawing species. Importantly, the ground-state depletion of these states upon photoexcitation is active even on microsecond timescales, thus suggesting that they act as precursor states for long-living polarons; this could be beneficial for cellular stimulation. Preliminary transient absorption microscopy results for NPs internalized within the cells reveal the presence of long-living species, further substantiating their relevance in biointerfaces. PMID- 29715377 TI - Photosynthetic tolerance to non-resource stress influences competition importance and intensity in an invaded estuary. AB - In an attempt to clarify the role of environmental and biotic interactions on plant growth, there has been a long-running ecological debate over whether the intensity and importance of competition stabilizes, increases or decreases across environmental gradients. We conducted an experiment in a Chinese estuary to investigate the effects of a non-resource stress gradient, soil salinity (from 1.40/00 to 19.00/00 salinity), on the competitive interactions between native Phragmites australis and invasive Spartina alterniflora. We linked these effects to measurements of photosynthetic activities to further elucidate the underlying physiological mechanism behind the competitive interactions and the driver of invasion. The experiments revealed that while biomass of both species decreased in the presence of the other, competition did not alter photosynthetic activity of either species over time. P. australis exhibited high photosynthetic activity, including low chlorophyllase activity, high chlorophyll content, high stomatal conductance and high net photosynthetic rate, at low salinity. Under these conditions, P. australis experienced low competitive intensity, leading to high biomass production and competitive exclusion of S. alterniflora. The opposite was observed for S. alterniflora: while competitive intensity experienced by P. australis increased with increasing salinity, and photosynthetic activity, biomass, competitive dominance and the importance of competition for P. australis growth decreased, those of S. alterniflora were stable. These findings demonstrate that S. alterniflora invasion driven by competitive exclusion are likely to occur and expand in high salinity zones. The change in the nature of competition along a non-resource stress gradient differs between competitors likely due to differences in photosynthetic tolerance to salinity. The driver of growth of the less-tolerant species changes from competition to non-resource stress factors with increasing stress levels, whereas competition is constantly important for growth of the more-tolerant species. Incorporating metrics of both competition intensity and importance, as well as linking these competitive outcomes with physiological mechanisms, is crucial to understanding, predicting, and mediating the effects of invasive species in the future. PMID- 29715378 TI - GOODBYE, INJECTIONS. Implanted strings of protected beta cells could help the body produce insulin once again. PMID- 29715379 TI - Training Day. Choose the best personal trainer for you. PMID- 29715380 TI - Discarding Sharps. Easy ways to trash your needles, lancets, and other sharps safely. PMID- 29715381 TI - That's Life. Getting life insurance when you have diabetes. PMID- 29715382 TI - Fungal Facts. How to spot and prevent yeast infections. PMID- 29715383 TI - Baby Steps. Sleepless nights? Schedule out the window? Parents with diabetes share survival tips. PMID- 29715384 TI - Feel Calmer Now. 9 ways to ease stress from diabetes care. PMID- 29715385 TI - 25 TIPS FOR BETTER LIVING WITH DIABETES. PMID- 29715386 TI - How your brain tricks you into eating more. PMID- 29715387 TI - CELLIST ALISA WEILERSTEIN TALKS MUSIC, MOTHERHOOD, AND THE KEY TO BLOOD GLUCOSE CONTROL. PMID- 29715388 TI - Neuropathy is excruciating for some people. Here's why-and how you can treat it. PMID- 29715389 TI - The Vegetarian's Dilemma. A meatless diet may offer significant health benefits. But is it right for someone managing diabetes? PMID- 29715390 TI - Goodnight, Glucose. The link between poor sleep and blood glucose control. PMID- 29715391 TI - The Lowdown. How to avoid severe hypoglycemia. PMID- 29715392 TI - Victory Lap. More states are adopting Safe at School plans. PMID- 29715393 TI - Step IT UP. How many steps a day move you toward better health? PMID- 29715394 TI - Health Checklist. Your guide to 9 basic diabetes tests and screenings for adults. PMID- 29715395 TI - TAKE SOME STEPS TO MAKE YOUR MOVE A LITTLE BIT EASIER, WHETHER YOU'RE RELOCATING TO A HOME ACROSS TOWN, ACROSS THE COUNTRY, OR AROUND THE GLOBE. Here, people who have made the big move SHARE TH EIR TIPS AND TRICKS for managing diabetes when they change from one address to another. PMID- 29715396 TI - Researchers are working on vaccines that could one day spell the end of type 1 diabetes. PMID- 29715397 TI - Going through menopause can be tough. Here are some top tips for weathering the change. PMID- 29715398 TI - Murder in the Pancreas. PMID- 29715399 TI - For some, knowledge is power. For others, ignorance is pure bliss. PMID- 29715400 TI - Contrast sensitivity assessment in primary open angle glaucoma and ocular hypertension. AB - INTRODUCTION: Contrast sensitivity assessment is an important additional examination, which enables the full insight into the patient's quality of vision, and early diagnosis of visual disturbances. MATERIAL AND METHODS: Forty six patients (92 eyes) with primary open angle glaucoma or ocular hypertension were enrolled in the study. The enrolment criteria were full or almost full visual acuity and the patients with visual field defects or any other ocular disease were excluded. Contrast sensitivity was assessed both under photopic and mesopic conditions (with and without glare) using the Functional Vision Analyzer separately for each eye. Furthermore, the retinal nerve fiber layer (RNFL) thickness was measured using scanning laser polarimetry (GDx). RESULTS: Contrast sensitivity was significantly reduced under both mesopic and photopic conditions in patients with primary open angle glaucoma or ocular hypertension. CONCLUSIONS: Evaluation of contrast sensitivity is a valuable diagnostic test, which enables the assessment of visual dysfunction in patients with primary open angle glaucoma or ocular hypertension persisting despite good visual acuity. PMID- 29715401 TI - Central corneal thickness and intraocular pressure before the intravitreal administration of ranibizumab and in the early period following the injection. AB - The aim of the study was to determine the differences in the central corneal thickness and intraocular pressure measured before intravitreal administration of ranibizumab and at 30 to 60 minutes after the injection. The intraocular pressure was analysed as a stand-alone parametre and in correlation with the central corneal thickness. 72 patients (144 eyes) were enrolled. The treated eyes were compared to the fellow, non-treated eyes. The mean central corneal thickness in a treated eye was 558 /Im and 596,MUm at baseline (before the injection) and after the injection, respectively (p< 0.05). The mean intraocular pressure not correlated to the central corneal thickness in a treated eye 15.29 mmHg and 16.83 mmHg at baseline and post-injection, respectively (p< 0.05). When assessed in correlation with the central corneal thickness, the intraocular pressure did not increase post-injection in the treated eyes. PMID- 29715402 TI - An implantation of multifocal lenses LS-313 MF30, Mplus and MplusX models, during and after posterior vitrectomy in patients treated for various diseases of the retina. AB - PURPOSE: A retrospective analysis of visual function and postoperative complaints in patients after posterior vitrectomy and multifocal Mplus or MplusX intraocular lens implantation. MATERIAL AND METHODS: 14 patients (14 eyes) were enrolled in the study. All patients underwent posterior vitrectomy due to underlying retinal pathologies. A combined procedure of phacovitrectomy was performed in some patients, whereas others underwent a separate cataract extraction as a second stage of treatment. The Mplus or MplusX intraocular lenses were implanted in all cases and the postoperative visual function and patient complaints were analysed. RESULTS: Multifocal lens explantation was not necessary in any case. Good uncorrected distance and near visual acuity was achieved in most cases. When implanted prior to vitrectomy, the intraocular lenses did not limit the view into the posterior segment, so precise manipulations within the macula and peripheral retina were feasible. The right choice between Mplus and MplusX minimises the rate of postoperative complaints. Conslusions: The multifocal Mplus and MplusX intraocular lenses offer a good alternative for patients who need posterior vitrectomy and still want to achieve good uncorrected distance and near visual acuity. PMID- 29715403 TI - Prevalence of ocular abnormalities in prediabetic patients. AB - AIM: The aim of our study was to evaluate the prevalence of ocular abnormalities in prediabetic individuals. MATERIAL AND METHODS: 61 subjects aged 37-78 (41 women, 20 men), with impaired fasting glucose and/or impaired glucose tolerance, were enrolled in the study and compared to 30 healthy volunteers, aged 39-75 (20 women, 10 men), without prediabetes and history of previous ocular diseases. Both groups of patients underwent a complete physical examination, biochemical tests and ophthalmic examination: visual acuity testing, intraocular pressure measurement, anterior and posterior segment evaluation, fundus photographs, optical coherence tomography, colour vision and letter contrast sensitivity tests. RESULTS: The prevalence rates of various ocular abnormalities in prediabetic subjects as compared to healthy controls were as follows: acquired colour vision impairment 8.2% vs. 0% (p<0.05), signs of retinopathy: 9.8% vs. 0% (p<0.05), cataract: 32.8%/ vs. 6.7% (p<0.05), and corneal surface disorders: 19.7% vs. 3.3% (p<0.05). Optical coherence tomography revealed increased prevalence of posterior vitreous detachments and epiretinal membranes in prediabetic individuals as compared to healthy controls. There were no statistically significant differences in central retinal thickness, mean visual acuity and mean intraocular pressure between the two groups. CONCLUSION: Patients with prediabetes present with numerous ocular abnormalities. The prevalence of ocular disorders in prediabetic subjects is significantly higher as compared to healthy population. Regular ophthalmic monitoring seems to be essential at this stage of hyperglycemic disorders. A dedicated prevention and screening programs should be implemented in prediabetic population in order to early detect ocular abnormalities and identify individuals at risk of other diabetic complications. PMID- 29715404 TI - High-definition optical coherent tomography findings in acute solar retinopathy - a case series. AB - The paper reports the case series of solar retinopathy. High definition optical coherence tomography examinations performed within 2 days after solar light induced injury indicated a characteristic retinal disorder - a curved, hyper reflective lesion extending from the retinal pigment epithelium at the fovea to the parafoveal outer plexiform layer. The findings correspond to the layout of photoreceptor cells whose injury in patients with solar retinopathy is confirmed by histological studies reported in available publications. PMID- 29715405 TI - Retinoblastoma in Patients with 13q deletion syndrome - case series. AB - Deletion of the long arm of chromosome 13 (13q deletion syndrome) is very rare chromosomal aberration which causes mental retardation and multiple congenital malformations. Furthermore, it is associated with the increased risk of retinoblastoma. The aim of the paper was to present two cases of retinoblastomna in children with 13q deletion syndrome, discussing the diagnostic and therapeutic management, clinical manifestation and the importance of genetic testing which helps to determine the type of retinoblastoma and may also contribute to the diagnosis of other congenital abnormalities associated with intraocular tumors. PMID- 29715406 TI - Artificial iris implantation in a male with post-traumatic aniridia - case report. AB - Artificial iris implantation in a 38-year-old patient with post-traumatic aniridia is reported. The patient was assaulted in May 2013 and suffered a blunt trauma to his left eye. Directly after the assault, he was treated at the local hospital, where the upper eyelid wound and the lacerations of bulbar conjunctiva were sutured. One month later, he underwent a combined procedure of cataract extraction and anterior vitrectomy without the implantation of an intraocular lens. Next, he was hospitalised in our department, where apart from medical treatment of secondary, post-traumatic glaucoma, he was diagnosed with aphakia and almost complete aniridia. Afterhis intraocular pressure normalized, he had an artificial' iris prosthesis and intraocular lens implanted. The surgery was uneventful. The patient was very satisfied with the surgery. He reported a significant symptomatic improvement and resolution of photo-phobia and glare. The aesthetic result was very good. The customized artificial iris may be an effective treatment option in traumatic aniridia. It may improve the quality of life, as it reduces the unwanted optical phenomena occurring in aniridia. Furthermore, it offers excellent aesthetic result. PMID- 29715407 TI - Nasally located congenital optic disc pit with concomitant maculopathy. AB - Optic disc pit is a congenital optic disc anomaly, which can be associated with maculopathy. The case of an unusually nasally located pit with concomitant maculopathy in a 64-year-old woman is presented. PMID- 29715408 TI - Use of nonsteroidal anti-inflammatory drugs in diabetic retinopathy. AB - INTRODUCTION: Diabetic macular edema, a manifestation of diabetic retinopathy, occurs more frequently in type 2 diabetes mellitus. There is evidence that inflammation plays a prominent role in the pathogenesis. A number of pro inflammatory cytokines are consistently elevated in the vitreous of patients with advanced stages of diabetic retinopathy. Nonsteroidal anti-inflammatory drugs inhibit the catalytic activity of the cyclooxygenase isoenzymes COX-1 and COX-2, the key enzymes in inflammatory processes. PURPOSE: To present current knowledge of benefits and limitations of using nonsteroidal anti-inflammatory drugs in diabetic retinopathy. CONCLUSIONS: Nonsteroidal anti-inflammatory druds may be considered as an adjuvant treatment in diabetic retinopathy especially in patients with diabetic macular edema. PMID- 29715409 TI - The use of mineralocorticoid receptor antagonists in chronic central serous chorioretinopathy. AB - AIM: To assess the effect of eplerenone on macular structure and function in patients with chronic central serous chorioretinopathy. MATERIAL AND METHODS: 17 eyes of 16 patients (aged 32-66 years) with chronic central serous chorioretinopathy treated at the Department of Ophthalmology and Ocular Oncology, Jagiellonian University in Cracow were enrolled. The duration of symptoms ranged between 4 and 24 months. The patients were dosed with eplerenone according to the scheme: first 25 mg/day for a week, then 50 mg/day for 3 months. The baseline examination and two follow-up visits (after 1-1,5 months and after 3-4 months respectively) involved best corrected visual acuity (Snellen, decimal scale), central retinal thickness in optical coherence tomography and visual disturbances in Amsler test. RESULTS: The mean best corrected visual acuity improved from 0.61 (+/-0.25) to 0.67 (+/-0.28) and 0.72 (+/-0.28) at the first and second follow-up appointment, respectively. Central retinal thickness declined from 367 MUm (+/ 70) to 264 MUm (+/-50) and 248 MUm (+/-50) at the first and second follow up appointment, respectively (p<0.05). Amsler test findings improved in 10 eyes (58.8%), while the deterioration in central vision remained unchanged in 7 eyes (41.2%) at the first follow up appointment. During the second follow-up appointment, though, Amsler test improvement was reported in 7 eyes (50%), while the deterioration in central vision remained unchanged in 7 eyes (50%). CONCLUSIONS: Our study suggests that eplerenone may provide an alternative treatment of chronic central serous chorioretinopathy, especially in patients with known contraindications to or ineligible for other treatments (for instance, retinal laser photocoagulation). Further randomized controlled trial is required. PMID- 29715410 TI - Changes in the central nervous system of prematurely born children. AB - Preterm birth adversely affects the maturation of the central nervous system, including the process of white matter myelination, still incomplete at this stage. Prematurity is also a risk factor for the future visual impairment. Decreased visual acuity in premature infants observed during their development, may be caused by both retinopathy of prematurity and the damage to the central nervous system. Owing to the development of new magnetic resonance imaging techniques such as diffusion imaging and diffusion tensor imaging, a detailed evaluation of changes to the cerebral white matter microstructure is now possible. As postulated in the newly published literature, ocular pathologies in premature infants may be related to abnormalities within the corpus callosum. Modern imaging techniques prove to be of the essencewhen facing diagnostic challenges in premature infants presenting with visual disturbances. PMID- 29715411 TI - Experimental studies on medical treatments of retinal dystrophies with a particular focus on ABCA4 retinopathies. AB - Retinal dystrophies are a group of hereditary diseases varying in clinical and etiological aspects. The most common central retinal dystrophy is Stargardt's disease, which is mainly caused by mutations in the ABCA4 gene. Dysfunction of the ABCA4 gene product leads to accumulation of toxic metabolites of the visual cycle and consequently to the loss of photoreceptors and surrounding retinal pigment epithelial cells. This study summarizes various pharmacological attempts aimed at slowing the progression of retinal dystrophies, especially ABCA4 retinopathies. PMID- 29715412 TI - Experimenal studies On cell and gene therapies for retinal dystrophies with a particular focus On ABCA4 retinopathies. AB - Retinal dystrophies lead to gradual irreversible vision deterioration. The ABCA4 retinopathies constitute an important group of retinal dystrophies. However, there are no effective therapies available for this group of diseases. Yet, with the advent of Molecular therapies, the development of prospective therapeutic approaches seems feasible. The paper summarizes recent advances in gene and cell therapy that may be implemented in retinal dystrophies, especially in ABCA4 associated diseases. PMID- 29715413 TI - The use of intrastromal corneal ring segments in patients with myopia and keratoconus. AB - Intrastromal corneal ring segments were primary used for correcting myopia ranging from -0.5 to -3.0 diopters. Nowadays, the most common indication of PMMA insertion in the world is keratoconus-associated astigmatism. The aim of this paper is to provide an overview of using of intracorneal ring segments in myopia and keratoconus. The addressed issues include commercially available ring models, indications and contraindications for ring implantation as well as the recommended surgical techniques. The efficacy of ring implantation in other conditions, such as post-LASIK ectasia and corneal transplantation is also discussed based on literature review. Additionally, the combined procedure of intracorneal ring segment implantation and cor- neal collagen cross-linking is mentioned as one of the latest trends. PMID- 29715414 TI - Zygmunt Kramsztyk (1849-1920) - the most outstanding medical philosopher among Polish ophthalmologists of the 19th and 20th centuries. AB - Zygmunt Kramsztyk (1849-1920) was a Polish ophthalmologist of Jewish origin, the founder of the ,,Medical Critique" magazine. He studied medicine at the Main School of Warsaw and Imperial University of Warsaw, graduating in 1 872, and completed his PhD in 1879 submitting the dissertation entitled "On changes perceived in eyes of leukaemic patients". From 1880 to 1904 he was the head of the Ophthalmic Ward at the Orthodox Jew Hospital in Warsaw. In 1898 he was appointed the chief physician in that hospital, remaining in this role for the next 4 years. Zygmunt Kramsztyk wrote critiques, essays and popular science articles. He penned many works on ophthalmology. He also wrote a textbook entitled "Clinical symptoms of eye diseases". PMID- 29715415 TI - [Research on Control System of an Exoskeleton Upper-limb Rehabilitation Robot]. AB - In order to help the patients with upper-limb disfunction go on rehabilitation training,this paper proposed an upper-limb exoskeleton rehabilitation robot with four degrees of freedom(DOF),and realized two control schemes,i.e.,voice control and electromyography control.The hardware and software design of the voice control system was completed based on RSC-4128 chips,which realized the speech recognition technology of a specific person.Besides,this study adapted self-made surface eletromyogram(sEMG)signal extraction electrodes to collect sEMG signals and realized pattern recognition by conducting sEMG signals processing,extracting time domain features and fixed threshold algorithm.In addition,the pulse-width modulation(PWM)algorithm was used to realize the speed adjustment of the system.Voice control and electromyography control experiments were then carried out,and the results showed that the mean recognition rate of the voice control and electromyography control reached 93.1%and 90.9%,respectively.The results proved the feasibility of the control system.This study is expected to lay a theoretical foundation for the further improvement of the control system of the upper-limb rehabilitation robot. PMID- 29715416 TI - [Complexity Analysis of Physiological Signals Using Encoding Lempel-Ziv Algorithm]. AB - To distinguish the randomness and chaos characteristics of physiological signals and to keep its performance independent of the signal length and parameters are the key judgement of performance of a complexity algorithm.We proposed an encoding Lempel-Ziv(LZ)complexity algorithm to try to explicitly discern between the randomness and chaos characteristics of signals.Our study also compared the effects of length of time series,the sensitivity to dynamical properties change of time series and quantifying the complexity between gauss noise and 1/f pink noise ELZ with those from classic LZ(CLZ),multi-state LZ(MLZ),sample entropy(SampEn)and permutation entropy(PE).The experimental results showed ELZ could not only distinguish the randomness and chaos characteristics of time series on all time length(i.e.100,500,5 000),but also reflected exactly that the complexity of gauss noise was lower than that of pink noise,and responded change of dynamic characteristics of time series in time.The congestive heart failure(CHF)RR Interval database and the normal sinus rhythm(NSR)RR Interval database created by Massachusetts Institute of Technology(MIT)and Boston Beth Israel Hospital(BIH)were used as real data in our study.The results revealed that the ELZ could show the complexity of congestive heart failure which was lower than that of normal sinus rhythm during all lengths of time series(P<0.01),and the ELZ algorithm had better generalization ability and was independent of length of time series. PMID- 29715417 TI - [Wearable Devices for Movement Monitoring of Patients with Parkinson's Disease]. AB - Quantitative assessment of the symptoms of Parkinson's disease is the key for precise diagnosis and treatment and essential for long term management over years.The challenges of quantitative assessment on Parkinson's disease are rich information,ultra-low load,long term and large range monitoring in free-moving condition.In this paper,we developed wearable devices with multiple sensors to monitor and quantify the movement symptoms of Parkinson's disease.Five wearable sensors were used to record motion signals from bilateral forearms,legs and waist.A local area network based on low power Wi-Fi technology was built for long distance wireless data transmission.A software was developed for signal recording and analyzing.The size of each sensor was 39mm*33mm*16mm and the weight was 18 g.The sensors were rechargeable and able to run 12 hours.The wireless transmission radius is about 45 m.The wearable devices were tested in patients and normal subjects.The devices were reliable and accurate for movement monitoring in hospital. PMID- 29715418 TI - [Development of Automatic Preparation Device of Sclerosing Foam Based on Tessari Method]. AB - Based on the principle of manual preparation of sclerosing foam with Tessari method,using the analysis of user requirements and combining it with theory of mechanics,we designed an automatic equipment.The device could be used to replace the manual operation,and could overcome the shortcomings of manual sclerosing foam preparation,such as the difficulty in controlling of pushing speed and stroke and poor reproducibility.This automatic device has the functions of adjustable pushing speed,pushing frequency,pushing stroke and is suitable for a variety of different types of syringes.It can not only provide quantitative parameters for the study of foam properties,but also be used for the standardization of clinical sclerosing foam.The experimental study on"the effect of pushing speed on the stability of foam"was carried out with using the device,and the experimental results were quite satisfactory. PMID- 29715419 TI - [Research Progress and Prospect of Applications of Finite Element Method in Lumbar Spine Biomechanics]. AB - Based on the application of finite element analysis in spine biomechanics,the research progress of finite element method applied in lumbar spine mechanics is reviewed and the prospect is forecasted.The related works,including lumbar ontology modeling,clinical application research,and occupational injury and protection,are summarized.The main research areas of finite element method are as follows:new accurate modeling process,the optimized simulation method,diversified clinical effect evaluation,and the clinical application of artificial lumbar disc.According to the recent research progress,the application prospects of finite element method,such as automation and individuation of modeling process,evaluation and analysis of new operation methods and simulation of mechanical damage and dynamic response,are discussed.The purpose of this paper is to provide the theoretical reference and practical guidance for the clinical lumbar problems by reviewing the application of finite element method in the field of the lumbar spine biomechanics. PMID- 29715420 TI - [Research Progress of Automatic Right Ventricle Segmentation Based on Cardiac Cine Magnetic Resonance Image]. AB - Heart diseases seriously threaten people's health.More and more functional evaluation of cardiac right ventricle has been considered in the clinical diagnosis in addition to the classical functional evaluation of cardiac left ventricle.It is very important to evaluate the functional parameters of right ventricle in clinical heart disease diagnosis,especially when the ejection fraction of left ventricle is very low.Right ventricular segmentation is needed for the functional evaluation.However,right ventricular segmentation has been difficult due to its thin myocardium,complex structure and significant individual variability.Cine cardiac magnetic resonance image is a golden standard in clinical functional evaluation of cardiac ventricle.In the present paper,we summarize the classic segmentation approaches,evaluation methods and their development,which can help the researchers in the related field have a quick and basic understanding to the right ventricle segmentation. PMID- 29715421 TI - [Advances of Function of Prussian Blue Nano-materials in Cancer Diagnosis and Therapy]. AB - Prussian blue(PB),a kind of ferrous ferricyanide composed of Fe2+and Fe3+,has been approved by Food and Drug Administration(FDA,USA)as an oral drug for the treatment of thallium and cesium poisoning.The biosafety of PB has been proved by long-term clinical trials.In recent years,PB nano-materials have attracted intensive research interests for medical application,especially for tumor imaging and treatment of cancer.Compared to other nano-materials,PB has potential advantage in medical application due to the high biosafety.This paper reviews the new advances in the functions of cancer diagnosis and therapy of PB nano materials. PMID- 29715422 TI - [Research Progress and Development Prospect of Biomedical Plate]. AB - Different generations of biomedical materials are analyzed in this paper.The current clinical uses of plates made of metals,polymers or composite materials are evaluated,and nano hydroxyapatite/polylactic acid composites and carbon/carbon composite plates are introduced as emphasis.It is pointed out that the carbon/carbon composites are of great feasibility and advantage as a new generation of biomedical materials,especially in the field of bone plate.Compared to other biomaterials,carbon/carbon composites have a good biocompatibility and mechanical compatibility because they have similar elastic modulus,porosity and density to that of human bones.With the development of the technology in knitting and material preparation,carbon/carbon composite plates have a good application prospect. PMID- 29715423 TI - [Advances in Researches on the Relations between miRNA-143/miRNA-145 and Colorectal Cancer]. AB - Colorectal cancer is one of the most common malignant diseases that threatens human being's health.With researches on microRNAs(miRNAs)getting deeper and wider,more evidences revealed that a great many of miRNAs have been involved in the development of colorectal cancer and have the potential to become the biomarker for early diagnosis,prediction of prognosis and recurrence of colorectal cancer.MiRNA-143/miRNA-145 are significantly reduced in several cancers,including colorectal cancer,showing an antitumorigenic activity.In the present article,we make a brief review on the advances in the researches on miRNA 143/miRNA-145 and colorectal cancer to provide guidance for further explorations of the mechanism and target therapy of this disease. PMID- 29715424 TI - Intrinsic Conformational Preferences and Interactions in alpha-Synuclein Fibrils: Insights from Molecular Dynamics Simulations. AB - Amyloid formation by the intrinsically disordered alpha-synuclein protein is the hallmark of Parkinson's disease. We present atomistic Molecular Dynamics simulations of the core of alpha-synuclein using enhanced sampling techniques to describe the conformational and binding free energy landscapes of fragments implicated in fibril stabilization. The theoretical framework is derived to combine the free energy profiles of the fragments into the reaction free energy of a protein binding to a fibril. Our study shows that individual fragments in solution have a propensity toward attaining non-beta conformations, indicating that in a fibril beta-strands are stabilized by interactions with other strands. We show that most dimers of hydrogen-bonded fragments are unstable in solution, while hydrogen bonding stabilizes the collective binding of five fragments to the end of a fibril. Hydrophobic effects make further contributions to the stability of fibrils. This study is the first of its kind where structural and binding preferences of the five major fragments of the hydrophobic core of alpha synuclein have been investigated. This approach improves sampling of intrinsically disordered proteins, provides information on the binding mechanism between the core sequences of alpha-synuclein, and enables the parametrization of coarse grained models. PMID- 29715425 TI - Synthesis and Cell Interaction of Statistical l-Arginine-Glycine-l-Aspartic Acid Terpolypeptides. AB - Copolymerizations and terpolymerizations of N-carboxyanhydrides (NCAs) of glycine (Gly), Ndelta-carbobenzyloxy-l-ornithine (Z-Orn), and beta-benzyl-l-aspartate (Bz Asp) were investigated. In situ 1H NMR spectroscopy was used to monitor individual comonomer consumptions during binary and ternary copolymerizations. The six relevant reactivity ratios were determined from copolymerizations of the NCAs of amino acids via nonlinear least-squares curve fitting. The reactivity ratios were subsequently used to maximize the occurrence of the Asp-Gly-Orn ( DGR') sequence in the terpolymers. Terpolymers with variable probability of occurrence of DGR' were prepared in the lab. Subsequently, the ornithine residues on the terpolymers were converted to l-arginine (R) residues via guanidination reaction after removal of the protecting groups. The resulting DGR terpolymers translate to traditional peptides and proteins with variable RGD content, due to the convention in nomenclature that peptides are depicted from N- to C-terminus, whereas the NCA ring-opening polymerization is conducted from C- to N-terminus. The l-arginine containing terpolymers were evaluated for cell interaction, where it was found that neuronal cells display enhanced adhesion and process formation when plated in the presence of statistical DGR terpolymers. PMID- 29715426 TI - The Lgamma Phase of Pulmonary Surfactant. AB - To determine how different components affect the structure of pulmonary surfactant, we measured X-ray scattering by samples derived from calf surfactant. The surfactant phospholipids demonstrated the essential characteristics of the Lgamma phase: a unit cell with a lattice constant appropriate for two bilayers, and crystalline chains detected by wide-angle X-ray scattering (WAXS). The electron density profile, obtained from scattering by oriented films at different relative humidities (70-97%), showed that the two bilayers, arranged as mirror images, each contain two distinct leaflets with different thicknesses and profiles. The detailed structures suggest one ordered leaflet that would contain crystalline chains and one disordered monolayer likely to contain the anionic compounds, which constitute ~10% of the surfactant phospholipids. The spacing and temperature dependence detected by WAXS fit with an ordered leaflet composed of dipalmitoyl phosphatidylcholine. Physiological levels of cholesterol had no effect on this structure. Removing the anionic phospholipids prevented formation of the Lgamma phase. The cationic surfactant proteins inhibited Lgamma structures, but at levels unlikely related to charge. Because the Lgamma phase, if arranged properly, could produce a self-assembled ordered interfacial monolayer, the structure could have important functional consequences. Physiological levels of the proteins, however, inhibit formation of the Lgamma structures at high relative humidities, making their physiological significance uncertain. PMID- 29715427 TI - Acoustic Mode Hybridization in a Single Dimer of Gold Nanoparticles. AB - The acoustic vibrations of single monomers and dimers of gold nanoparticles were investigated by measuring for the first time their ultralow-frequency micro-Raman scattering. This experiment provides access not only to the frequency of the detected vibrational modes but also to their damping rate, which is obscured by inhomogeneous effects in measurements on ensembles of nano-objects. This allows a detailed analysis of the mechanical coupling occurring between two close nanoparticles (mediated by the polymer surrounding them) in the dimer case. Such coupling induces the hybridization of the vibrational modes of each nanoparticle, leading to the appearance in the Raman spectra of two ultralow-frequency modes corresponding to the out-of-phase longitudinal and transverse (with respect to the dimer axis) quasi-translations of the nanoparticles. Additionally, it is also shown to shift the frequency of the quadrupolar modes of the nanoparticles. Experimental results are interpreted using finite-element simulations, which enable the unambiguous identification of the detected modes and despite the simplifications made lead to a reasonable reproduction of their measured frequencies and quality factors. The demonstrated feasibility of low-frequency Raman scattering experiments on single nano-objects opens up new possibilities to improve the understanding of nanoscale vibrations with this technique being complementary with single nano-object time-resolved spectroscopy as it gives access to different vibrational modes. PMID- 29715428 TI - Kinetics of Huperzine A Dissociation from Acetylcholinesterase via Multiple Unbinding Pathways. AB - The dissociation of huperzine A (hupA) from Torpedo californica acetylcholinesterase ( TcAChE) was investigated by 4 MUs unbiased and biased all atom molecular dynamics (MD) simulations in explicit solvent. We performed our study using memetic sampling (MS) for the determination of reaction pathways (RPs), metadynamics to calculate free energy, and maximum-likelihood estimation (MLE) to recover kinetic rates from unbiased MD simulations. Our simulations suggest that the dissociation of hupA occurs mainly via two RPs: a front door along the axis of the active-site gorge (pwf) and through a new transient side door (pws), i.e., formed by the Omega-loop (residues 67-94 of TcAChE). An analysis of the inhibitor unbinding along the RPs suggests that pws is opened transiently after hupA and the Omega-loop reach a low free-energy transition state characterized by the orientation of the pyridone group of the inhibitor directed toward the Omega-loop plane. Unlike pws, pwf does not require large structural changes in TcAChE to be accessible. The estimated free energies and rates agree well with available experimental data. The dissociation rates along the unbinding pathways are similar, suggesting that the dissociation of hupA along pws is likely to be relevant. This indicates that perturbations to hupA- TcAChE interactions could potentially induce pathway hopping. In summary, our results characterize the slow-onset inhibition of TcAChE by hupA, which may provide the structural and energetic bases for the rational design of the next generation slow-onset inhibitors with optimized pharmacokinetic properties for the treatment of Alzheimer's disease. PMID- 29715429 TI - Bent Bonds (tau) and the Antiperiplanar Hypothesis-The Chemistry of Cyclooctatetraene and Other C8H8 Isomers. AB - The bent bond/antiperiplanar hypothesis (BBAH) has been applied to the thermal rearrangements of cyclooctatetraene and related C8H8 isomers. This novel orbital model shows that pyramidal singlet diradical intermediates produced from thermal vibrational states of C8H8 isomers account for their chemical reactivity. PMID- 29715430 TI - pH-Responsive Janus Film Constructed with Hydrogen-Bonding Assembly and Dopamine Chemistry. AB - Poly(acrylic acid) (PAA) was partially grafted with dopamine (PAA-dopa), and then layer-by-layer assembled with poly(vinylpyrrolidone) (PVPON) to prepare hydrogen bonded (PVPON/PAA-dopa) n film. Polydopamine (PDA) was deposited on (PVPON/PAA dopa) n film in the presence of oxidant, and hence the whole (PVPON/PAA-dopa) nPDA film was cross-linked. (PVPON/PAA-dopa) nPDA could be utilized as a platform to produce the free-standing Janus film because of the easy detaching process and various chemical reactivity of PDA layer. Ag nanoparticles were formed on (PVPON/PAA-dopa) nPDA film by electroless metallization. 1 H,1 H,2 H,2 H Perfluorodecanethiol (PFDT) was used to further modify the film through Michael addition. After detaching from the substrate, (PVPON/PAA-dopa)20PDA/Ag/PFDT exhibits reversible swelling-shrinking behavior as the pH value changes. This free-standing film shows Janus character, one side is hydrophobic, whereas the other side is hydrophilic. In addition, the hydrophobic surface exhibits a surface-enhanced Raman scattering effect, whereas the hydrophilic side does not. PMID- 29715431 TI - Imaging Plasmon Hybridization of Fano Resonances via Hot-Electron-Mediated Absorption Mapping. AB - The inhibition of radiative losses in dark plasmon modes allows storing electromagnetic energy more efficiently than in far-field excitable bright plasmon modes. As such, processes benefiting from the enhanced absorption of light in plasmonic materials could also take profit of dark plasmon modes to boost and control nanoscale energy collection, storage, and transfer. We experimentally probe this process by imaging with nanoscale precision the hot electron driven desorption of thiolated molecules from the surface of gold Fano nanostructures, investigating the effect of wavelength and polarization of the incident light. Spatially resolved absorption maps allow us to show the contribution of each element of the nanoantenna in the hot-electron driven process and their interplay in exciting a dark plasmon mode. Plasmon-mode engineering allows control of nanoscale reactivity and offers a route to further enhance and manipulate hot-electron driven chemical reactions and energy conversion and transfer at the nanoscale. PMID- 29715432 TI - Calcium-Mediated Allostery of the EGF Fold. AB - The epidermal growth factor (EGF)-like domain is one of the most abundant disulfide-containing domains in nature and is involved in many cellular processes critical to life. Although many EGF-like domains participate in calcium-dependent functions by responding to the local calcium concentration, little is known about how this responsiveness is programmed at the molecular level. Here, we reveal the structural and environmental determinants underpinning the folding of a synthetic analogue of the EGF-A domain (from the low-density lipoprotein receptor). We show that calcium sensitivity is enabled by an allosteric folding pathway, in which calcium binding is connected to the peptide core through local inter-residue interactions. In the absence of calcium, the fold favors disorder because the inherently weak core is insufficient to stabilize the active form, resulting in substantial loss in activity of 2 orders of magnitude. The EGF-A fold, which can freely transition between active and disordered states, is volatile, and we found it to be intolerant of mutations, unlike other disulfide-rich peptides that have been used as stabilizing frameworks. This volatility is beneficial for modularity/plasticity and appears to have evolved for such a purpose, allowing cellular pathways to sense and respond to environmental cues. PMID- 29715433 TI - Photochemical Aging of Beijing Urban PM2.5: HONO Production. AB - Photochemical aging represents an important transformation process of aerosol particles in the atmosphere, which greatly influences the physicochemical properties and the environmental impact of aerosols. In this work, we find that Beijing urban PM2.5 aerosol particles release substantial HONO, a significant precursor of *OH radicals, into the gas phase during the photochemical aging process. The generation of HONO exhibits a high correlation with the amount of nitrate in PM2.5. The formation rate of HONO becomes gradually decreased with the irradiation time, but can be restored by introducing the acidic proton, indicative of the essential role of the acidic proton in the HONO production. Other environmental factors such as relative humidity, light intensity, and reaction temperature also possess important influences on HONO production. The normalized photolysis rate constant for HONO ( JHNO3->HONO) is in the range of 1.22 * 10-5 s-1 ~ 4.84 * 10-4 s-1, which is 1-3 orders of magnitude higher than the reported photolysis rate constant of gaseous HNO3. The present study implies that the photochemical aging of Beijing PM2.5 is an important atmospheric HONO production source. PMID- 29715434 TI - Clinical and molecular profile of newborns with confirmed or suspicious congenital adrenal hyperplasia detected after a public screening program implementation. AB - OBJECTIVE: To describe the results obtained in a neonatal screening program after its implementation and to assess the clinical and molecular profiles of confirmed and suspicious congenital adrenal hyperplasia cases. METHODS: A cross-sectional study was conducted. Newborns with suspected disease due to high 17 hydroxyprogesterone levels and adjusted for birth weight were selected. Classical congenital adrenal hyperplasia (salt-wasting and simple virilizing forms) was diagnosed by an increase in 17-hydroxyprogesterone levels as confirmed in the retest, clinical evaluation, and genotype determined by SNaPshot and multiplex ligation-dependent probe amplification. RESULTS: After 24 months, 15 classic congenital adrenal hyperplasia cases were diagnosed in a total of 217,965 newborns, with an estimated incidence of 1:14,531. From 132 patients, seven non classical and 14 heterozygous patients were screened for CYP21A2 mutations, and 96 patients presented false positives with wild type CYP21A2. On retest, increased 17-hydroxyprogesterone levels were found in classical congenital adrenal hyperplasia patients and showed significant correlation with genotype related classical genital adrenal hyperplasia. The most frequent mutations were IVS2-13A/C>G followed by gene deletion or rearrangement events in the classical form. In non-classical and heterozygous diseases, p.Val282Leu was the most common mutation. CONCLUSIONS: The results underscore the effectiveness of congenital adrenal hyperplasia neonatal screening in the public health system and indicate that the adopted strategy was appropriate. The second sample collection along with genotyping of suspected cases helped to properly diagnose both severe and milder cases and delineate them from false positive patients. PMID- 29715435 TI - Serum FBLN1 and STK31 as biomarkers of colorectal cancer and their ability to noninvasively differentiate colorectal cancer from benign polyps. AB - PURPOSE: The aim of this work is to evaluate Fibulin-1 (FBLN1) and serine threonine kinase-31 (STK31) as colorectal cancer (CRC) tumour markers and their ability to differentiate it from colorectal benign lesions. MATERIAL AND METHODS: In this case-control study, FBLN1 and STK31 serum levels were measured in 120 participants; 49 CRC patients (group I), 26 patients with benign colorectal polyps (group II) and 45 healthy controls (group III). RESULTS: The means of serum FBLN1 were 1.02 +/- 0.95, 6.36 +/- 2.55 and 6.26 +/- 2.76 in group I, II and III respectively. Significant lower levels were found in group I compared to group II and III (both p < 0.001) with no significant difference between group II and III (p = .983). The means of serum STK31 were 13.51 +/- 7.67, 5.98 +/- 3.3 and 1.37 +/- 1.22 in group I, II and III respectively with significant differences in-between the 3 groups (p < 0.001). Both FBLN1 and STK31 were superior to CEA as CRC screening biomarkers; with sensitivity 90.1% and 93% respectively and specificity 93.9% and 95.9% respectively. FBLN1 differentiated CRC from benign polyps with 91.8% sensitivity and 100% specificity. STK31 differentiated CRC from benign polyps with 93.9% sensitivity and 84.6% specificity. CONCLUSION: FBLN1 and STK31 can be possible screening and differentiating biomarkers of CRC. PMID- 29715436 TI - Detection of HER2 amplification in formalin-fixed paraffin-embedded breast carcinoma tissue with digital PCR using two TFF3 sequences as internal reference. AB - PURPOSE: Droplet digital PCR (ddPCR) is a highly accurate method to determine DNA concentration and detect copy number variations. We developed an approach to assess HER2 gene amplification status using ddPCR with two sequences of TFF3 as reference probes. EXPERIMENTAL DESIGN: 76 templates of carcinoma DNA were prepared from formalin-fixed paraffin-embedded (FFPE) tissues. Digital PCR assay of the copy number of HER2 and TFF3 DNA was performed on the samples. The results were compared to prior fluorescent in-situ hybridation (FISH) assays performed on the same samples. RESULTS: The ddPCR assay had high concordance with the conventionally used immunohistochemistry (IHC) and FISH methods. The ddPCR method returned fewer indeterminate results than IHC. Concordance between a ddPCR plus FISH method and IHC plus FISH can rise to 98.7% (75/76) after validation is carried out. CONCLUSION: It's potentially possible to improve the sensitivity and specifity of HER2 ddPCR assays using reference sequences not co-localized with HER2 on chromosome 17, and combining results from multiple sequences. Adopting an approach based on ddPCR HER2 assays plus FISH could lead to reduced costs, labour, and time consumption compared to current IHC plus FISH standard, while not losing precision. PMID- 29715438 TI - Making Pleural Pressure Positive Again. PMID- 29715437 TI - A Factor Analysis of Functional Independence and Functional Assessment Measure Scores Among Focal and Diffuse Brain Injury Patients: The Importance of Bifactor Models. AB - OBJECTIVE: To explore the factor structure of the UK Functional Independence Measure and Functional Assessment Measure (FIM+FAM) among focal and diffuse acquired brain injury patients. DESIGN: Criterion standard. SETTING: A National Health Service acute acquired brain injury inpatient rehabilitation hospital. PARTICIPANTS: Referred sample of adults (N=447) admitted for inpatient treatment following an acquired brain injury significant enough to justify intensive inpatient neurorehabilitation INTERVENTION: Not applicable. OUTCOME MEASURE: Functional Independence Measure and Functional Assessment Measure. RESULTS: Exploratory factor analysis suggested a 2-factor structure to FIM+FAM scores, among both focal-proximate and diffuse-proximate acquired brain injury aetiologies. Confirmatory factor analysis suggested a 3-factor bifactor structure presented the best fit of the FIM+FAM score data across both aetiologies. However, across both analyses, a convergence was found towards a general factor, demonstrated by high correlations between factors in the exploratory factor analysis, and by a general factor explaining the majority of the variance in scores on confirmatory factor analysis. CONCLUSIONS: Our findings suggested that although factors describing specific functional domains can be derived from FIM+FAM item scores, there is a convergence towards a single factor describing overall functioning. This single factor informs the specific group factors (eg, motor, psychosocial, and communication function) after brain injury. Further research into the comparative value of the general and group factors as evaluative/prognostic measures is indicated. PMID- 29715439 TI - Invited Commentary. PMID- 29715440 TI - Lung Transplantation in Tuberculosis. PMID- 29715441 TI - Stress and Quality of Life for Taiwanese Women Who Underwent Infertility Treatment. AB - OBJECTIVE: To describe the psychological stress and quality of life experienced by women who underwent fertility treatment in Taiwan. DESIGN: Cross-sectional, correlational study. SETTING: Recruitment was conducted and questionnaires administered at a reproductive medicine center in Chiayi City, Taiwan. PARTICIPANTS: Informed consent to participate was obtained from 126 women who sought fertility treatment at the center. METHODS: The Chinese Fertility Problem Inventory and Fertility Quality of Life scale were used to measure participants' levels of fertility-related stress and fertility-related quality of life. Descriptive statistics, correlation, and regression analysis were used. RESULTS: Overall, participants reported low levels of fertility-related stress and fertility-related quality of life; however, they had relatively high levels of stress related to need for parenthood. Women who were older, had greater body mass indexes, and consumed coffee regularly had lower fertility-related quality of life. Social and relationship concerns and stress related to need for parenthood were significant predictors of low fertility-related quality of life. CONCLUSION: In a culture in which childbearing is generally an expectation and an important part of family life, women who experience infertility are at risk to experience fertility-related stress. Social support and family consultation might be offered to improve women's fertility-related quality of life. PMID- 29715442 TI - Hydrogen peroxide extracellular concentration in the ventrolateral medulla and its increase in response to hypoxia in vitro: Possible role of microglia. AB - Hydrogen peroxide (H2O2) is a messenger involved in both damaging neuroinflammatory responses and physiological cell communication. The ventrolateral medulla, which regulates several vital functions including breathing and blood pressure, is highly influenced by hydrogen peroxide, whose extracellular levels could be determined by hypoxia and microglial activity, both of which modulate ventrolateral medulla function. Therefore, in this study we aimed to test whether different patterns of hypoxia and/or putative microglial modulators change extracellular hydrogen peroxide in the ventrolateral medulla by using an enzymatic reactor online sensing procedure specifically designed for this purpose. With this new technique, we detected extracellular levels of hydrogen peroxide in the ventrolateral medulla in vitro, which spontaneously fluctuated. These fluctuations are reduced by minocycline, a putative microglial inhibitor, and by the microglial toxin liposomal clodronate. Suitably, lipopolysaccharide increases extracellular hydrogen peroxide, while minocycline and liposomal clodronate reduce this increase. Application of blue light to slices with microglia expressing channelrhodopsin-2 also increases extracellular hydrogen peroxide. Moreover, long-lasting and intermittent hypoxia (as well as subsequent reoxygenation) increase extracellular hydrogen peroxide to similar levels, which is partially prevented by minocycline. The effect of long-lasting hypoxia was reproduced in vivo. Overall, our data show that changes in oxygen concentration, and possibly microglial function, modulate extracellular H2O2 levels in the ventrolateral medulla, which could influence the function of this neural circuit under normal and pathological conditions related to inflammation and/or hypoxia. PMID- 29715443 TI - The salience network and human personality: Integrity of white matter tracts within anterior and posterior salience network relates to the self-directedness character trait. AB - A prevailing topic in personality neuroscience is the question how personality traits are reflected in the brain. Functional and structural networks have been examined by functional and structural magnetic resonance imaging, however, the structural correlates of functionally defined networks have not been investigated in a personality context. By using the Temperament and Character Inventory (TCI) and Diffusion Tensor Imaging (DTI), the present study assesses in a sample of 116 healthy participants how personality traits proposed in the framework of the biopsychosocial theory of personality relate to white matter pathways delineated by functional network imaging. We show that the character trait self-directedness relates to the overall microstructural integrity of white matter tracts constituting the salience network as indicated by DTI-derived measures. Self directedness has been proposed as the executive control component of personality and describes the tendency to stay focused on the attainment of long-term goals. The present finding corroborates the view of the salience network as an executive control network that serves maintenance of rules and task-sets to guide ongoing behavior. PMID- 29715445 TI - Effect of running exercise on the number of the neurons in the hippocampus of young transgenic APP/PS1 mice. AB - To investigate the effect of running exercise on the number of the neurons in the hippocampus of young APP/PS1 mice, twenty 6-month-old male APP/ PS1 transgenic mice were randomly divided into the APP/PS1 control (AD control) group and the APP/PS1 running (AD running) group (10 mice per group), and ten wild-type mice of the littermate were regarded as the wild-type (WT) group. The AD running mice ran on motorized treadmill machiene for 4 months, while the WT mice and AD control mice were housed in standard condition without running. Then, Morris water maze tests (MWM) were used to assess the special learning and memory abilities of mice in three groups. The stereological methods were used to quantitatively evaluate the volume of the hippocampus, CA1/2, CA3 and the dentate gyrus (DG) and count the number of the neurons in CA1/2, CA3 and DG. We found that 4-month running effectively shortened the escape latency of young APP/PS1 control mice in MWM. More importantly, 4-month running effectively increased the volumes of the hippocampus, CA1/2, CA3 and DG and increased the number of neurons in CA1/2, CA3 and DG in young APP/PS1 mice. The present results suggested that 4-month running has significant beneficial effects on the spatial learning and memory capacities of young APP/PS1 mice and could delay the progress of atrophy of hippocampus and the neuron death in CA1/2, CA3 and DG in young APP/PS1 mice. PMID- 29715444 TI - Dynamic duo - FMRP and TDP-43: Regulating common targets, causing different diseases. AB - RNA binding proteins play essential roles during development and aging, and are also involved in disease pathomechanisms. RNA sequencing and omics analyses have provided a window into systems level alterations in neurological disease, and have identified RNA processing defects among notable disease mechanisms. This review focuses on two seemingly distinct neurological disorders, the RNA binding proteins they are linked to, and their newly discovered functional relationship. When deficient, Fragile X Mental Retardation Protein (FMRP) causes developmental deficits and autistic behaviors while TAR-DNA Binding Protein (TDP-43) dysregulation causes age dependent neuronal degeneration. Recent findings that FMRP and TDP-43 associate in ribonuclear protein particles and share mRNA targets in neurons highlight the critical importance of translation regulation in synaptic plasticity and provide new perspectives on neuronal vulnerability during lifespan. PMID- 29715447 TI - Erratum. PMID- 29715446 TI - WITHDRAWN: A Randomized Controlled Trial Comparing Between Titanium Osteosynthesis and Biodegradable Osteosynthesis in Access Mandibulotomy for Oral Malignancy. AB - Available online April 7, 2018. This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal. PMID- 29715448 TI - Evaluation of Staff Satisfaction After Implementation of a Surgical Safety Checklist in the Ambulatory of an Oral and Maxillofacial Surgery Department and its Impact on Patient Safety. AB - PURPOSE: Safety checklists in medicine have been shown to be effective in the prevention of complications and adverse events in patients undergoing surgery. Such checklists are not as common in dentistry. The aims of this study were to propose a safety checklist for the ambulatory treatment of patients undergoing oral and implant surgery and to assess its impact on patient safety and staff satisfaction. MATERIALS AND METHODS: After implementation of a surgical safety checklist in the ambulatory treatment of patients undergoing oral and implant surgeries, a questionnaire regarding staff satisfaction and safety-related parameters was randomly administered. Incidents, complications, and adverse events were documented. Outcomes with (n = 40 surgeries) and without (n = 40 surgeries) use of the checklist were analyzed and compared. RESULTS: Staff reported high satisfaction with the use of the checklist, which demonstrably improved team communication and lowered stress levels during surgery. There was a statistically significantly higher frequency of reported incidents without the use of the checklist (n = 43) than with the use of the checklist (n = 10; P = .000). Most incidents were reported in the context of pre- and post-procedural processes. CONCLUSIONS: Safety checklists help to improve work processes, optimize communication, and lower stress levels. Their use in clinical dental practice is recommended. PMID- 29715449 TI - Superficial Parotidectomy Versus Partial Superficial Parotidectomy: A Comparison of Complication Rates, Operative Time, and Hospital Stay. AB - PURPOSE: The type and extent of surgery for benign parotid tumors are a subject of debate. We aimed to measure and compare hospital stay, operative time, and complication rates associated with superficial parotidectomy (SP) and partial superficial parotidectomy (PSP). MATERIALS AND METHODS: This retrospective cohort study included all patients who underwent surgery for benign parotid gland tumors in our tertiary center between January 2006 and March 2014 and were followed up for at least 3 years. The predictor variable was the type of parotidectomy, and the main outcome parameters were operative time, hospital stay, and postoperative complications. The demographic characteristics (age and gender), clinical history, and preoperative findings were obtained from patient records. The Kolmogorov-Smirnov test, Mann-Whitney U test, and chi2 test were used to analyze the data. P < .05 was considered statistically significant. RESULTS: The sample was composed of 321 patients (184 men and 137 women) with a mean age of 54.0 +/- 14.7 years (range, 18 to 87 years). Of these, 190 underwent SP and 131 underwent PSP. Pleomorphic adenoma was the most common tumor (83 patients, 53%), followed by Warthin tumor (50 patients, 32%). The mean hospital stay was 6.7 +/- 2.3 days in the SP group and 4.8 +/- 2.4 days in the PSP group (P < .001). The mean operative times in the SP and PSP groups were 134.0 +/- 24.6 and 92.1 +/- 21.9 minutes, respectively (P < .001). The overall complication rates were 21.6% and 12.2% in the SP and PSP groups, respectively (P = .031). No tumor recurrence was observed in either group. CONCLUSIONS: Compared with the SP group, the PSP group had shorter operative and hospital stay durations and fewer postoperative complications with a comparable recurrence rate. Therefore, PSP should be considered in suitable cases. PMID- 29715451 TI - Cell surface damage and morphological changes in Oenococcus oeni after freeze drying and incubation in synthetic wine. AB - The aim of the present study was to evaluate the effects of freeze-drying in the presence of trehalose as a cryoprotectant, followed by incubation in synthetic wine, on surface damage, viability and l-malic acid consumption of the oenological strain Oenococcus oeni UNQOe 73.2. After freeze-drying, no significant differences were observed in the number of viable cells (for both acclimated and non-acclimated cultures) respect to the fresh culture. In contrast, loss of viability was observed after wine incubation for 24 h, being acclimated freeze-dried cells the best conditions for this. After the preservation process, small changes in cell morphology were observed by Atomic Force Microscopy (AFM). The Zeta potential and AFM showed that 24 h of wine incubation was enough to induce several cell surface modifications. Plate count data allowed us to establish that surface damage is an important factor for loss of viability, regardless of the acclimation treatment. Although the number of surviving O. oeni cells decreased dramatically after incubation in synthetic wine for 15 days, the consumption of l-malic acid was higher than 70%, with freeze dried cells showing a better performance than fresh cultures. These results demonstrate that O. oeni freeze-dried cultures could be applied to direct wine inoculation, to conduct malolactic fermentation, maintaining its technological properties and reducing the time and costs of the winemaking process. PMID- 29715450 TI - RACking up ceramide-induced islet beta-cell dysfunction. AB - The International Diabetes Federation predicts that by 2045 the number of individuals afflicted with diabetes will increase to 629 million. Furthermore, ~352 million individuals with impaired glucose tolerance are at increased risk for developing diabetes. Several mechanisms have been proposed for the onset of metabolic dysfunction and demise of the islet beta-cell leading to the pathogenesis of diabetes. It is widely accepted that the onset of type 2 diabetes is due to an intricate interplay between genetic expression of the disease and a multitude of factors including increased oxidative and endoplasmic reticulum stress consequential to glucolipotoxicity and inflammation. Compelling experimental evidence from in vitro and in vivo studies implicates intracellular generation of ceramide (CER), a biologically-active sphingolipid, as a trigger in the onset of beta-cell demise under above pathological conditions. Recent pharmacological and molecular biological evidence affirms regulatory roles for Ras-related C3 botulinum toxin substrate 1 (Rac1), a small G protein, in the islet beta-cell function in health and diabetes. In this Commentary, we overviewed the emerging evidence implicating potential cross-talk between Rac1 and ceramide signaling pathways in the onset of metabolic dysregulation of the islet beta-cell culminating in impaired physiological insulin secretion, loss of beta-cell mass and the onset of diabetes. Further, we propose a model depicting contributory roles of defective protein lipidation (prenylation) pathway in the induction of metabolic defects in the beta-cell under metabolic stress conditions. Potential avenues for the identification of novel therapeutic targets for the prevention/treatment of diabetes and its associated complications are highlighted. PMID- 29715452 TI - Local administration of mangiferin prevents experimental inflammatory mechanical hyperalgesia through CINC-1/epinephrine/PKA pathway and TNF-alpha inhibition. AB - Steroidal and non-steroidal anti-inflammatory drugs (NSAIDs) are widely used to control inflammatory pain, but there is a risk of gastrointestinal bleeding and increased heart failure risk. The search for new drugs remains ongoing, and natural products are a source for potential new compounds. Mangiferin, a natural xanthone C-glucoside, has demonstrated biological activity, including anti inflammatory and analgesic properties, but it's mechanisms are poorly understood. In this study, we investigated the mechanisms underlying the anti-inflammatory and analgesic effects of local administration of mangiferin. We employed an electronic von Frey apparatus to evaluate mechanical hyperalgesia induced by carrageenan in rats. Mangiferin (150-1200 ug/paw), administered locally into the hindpaw, prevented hyperalgesia in a dose-dependent - 150 ug (- 9%), 300 ug (- 27%, P < 0.01), 600 ug (- 77%, P < 0.001) and 1000 ug (- 93%, P < 0.001) - and local manner. Mangiferin showed decreased levels of TNF-alpha (P < 0.001) and CINC-1 (P < 0.001), but not IL-1beta; it also prevented neutrophil migration (P < 0.01), but not the increased COX-2 expression in peripheral tissue challenged with carrageenan. To further explore the mechanisms of mangiferin actions, rats were injected with modulators of inflammation and nociception; mangiferin prevented hyperalgesia induced by IL-1beta (P < 0.01), CINC-1 (P < 0.01), epinephrine (P < 0.01), 8-Br-cAMP (P < 0.01) or capsaicin (P < 0.01), but not that induced by PGE2 or alpha,beta-MeATP. Our study shows that mangiferin has anti-inflammatory and analgesic properties when locally administrated. The control of the inflammatory response and mechanical hyperalgesia by mangiferin depends on the inhibition of TNF-alpha production/release and the CINC1/epinephrine/PKA pathway, supporting its marked inhibition of inflammatory mechanical hyperalgesia. PMID- 29715453 TI - Role of Wnt4/beta-catenin, Ang II/TGFbeta, ACE2, NF-kappaB, and IL-18 in attenuating renal ischemia/reperfusion-induced injury in rats treated with Vit D and pioglitazone. AB - Renal ischemia-reperfusion injury (I/RI) remains a critical clinical situation. Several evidence revealed the potential reno-protective effects of Vitamin D and/or pioglitazone, on renal I/RI. This study addresses the possible involvement of the Wnt4/beta-catenin signaling, p-S536NF-kappaBp65, PPARgamma, Ang II/TGF beta, and ACE2 as potential effectors to vitamin D and pioglitazone-mediated renoprotective effects. Two sets of Sprague-Dawley rats (n = 30 rat each), were randomized into sham, I/R, Vit D "alfacalcidol" (5 ng/kg/day), pioglitazone (5 mg/kg/day), and Vit D + pioglitazone groups. In all groups renal biochemical parameters, as well as inflammatory and structural profiles were assessed, besides the expression/contents of Wnt4/beta-catenin and pS536-NF-kappaBp65. All treatments started 7 days before I/RI and animals were killed 24 h after I/RI in the first set, while those in the 2nd set continued their treatments for 14 days. After 24 h, all pre-treatments impeded theI/R effect on neutrophils recruitment, p-S536NF-kappaBp65, IL-18, NGAL, caspase-3, AngII, ACE-2, PPARgamma and TGF-beta, besides the expression of Wnt4 and ACE-2 with notable reflection on histological changes. Two weeks after I/RI, except a marked up regulation in Wnt4 expression and a striking elevation in the beta-catenin content, the magnitude of the injurious events was relatively less pronounced, an effect that was mostly augmented by the different treatments. The current study pledges a promising and novel reno-protective role of the administration of Vit D and pioglitazone entailing a potential involvement of ICAM-1, MPO, NF-kappaB, Ang II, ACE2, TGFbeta, and a modulation of Wnt4/beta-catenin pathway. PMID- 29715454 TI - Effect of polygodial and its direct derivatives on the mammalian Na+/K+-ATPase activity. AB - The sesquiterpene polygodial is an agonist of the transient receptor potential vanilloid 1 (TRPV1). Our group recently reported the synthesis and anticancer effects of polygodial and its derivatives, and showed that these compounds retain activity against apoptosis- and multidrug-resistant cancer cells. Herein, we tested the inhibitory effect of these compounds on the activity of the enzyme Na+/K+-ATPase (NKA) from kidney (alpha1 isoform) and brain (alpha2 and alpha3 isoforms) guinea pig extracts. Polygodial (1) displayed a dose-dependent inhibition of both kidney and brain purified NKA preparations, with higher sensitivity for the cerebral isoforms. Polygo-11,12-diol (2) and C11,C12 pyridazine derivative (3) proved to be poor inhibitors. Unsaturated ester (4) and 9-epipolygodial (5) inhibited NKA preparations from brain and kidney, with the same inhibitory potency. Nevertheless, they did not achieve maximum inhibition even at higher concentration. Comparing the inhibitory potency in crude homogenates and purified preparations of NKA, compounds 4 and 5 revealed a degree of selectivity toward the renal enzyme. Kinetic studies showed a non-competitive inhibition for Na+ and K+ by compounds 1, 4 and 5 and for ATP by 1 and 4. However, compound 5 presented a competitive inhibition type. Furthermore, K+ activated p-nitrophenylphosphatase activity of these purified preparations was not inhibited by 1, 4 and 5, suggesting that these compounds acted in the initial phase of the enzyme's catalytic cycle. These findings suggest that the antitumor action of polygodial and its analogues may be linked to their NKA inhibitory properties and reinforce that NKA may be an important target for cancer therapy. PMID- 29715455 TI - Regulatory effect of nicotine on the differentiation of Th1, Th2 and Th17 lymphocyte subsets in patients with rheumatoid arthritis. AB - Previous research has demonstrated that nicotine have protective role in rheumatoid arthritis (RA). However, the immunologic mechanisms of nicotine's effect have not been fully elucidated. Herein, the effects of nicotine on the differentiation of Th1, Th2, and Th17 cells were assessed. Peripheral blood mononuclear cells (PBMCs) and CD4+T cells were separated from patients with RA. PBMCs were stimulated with anti-CD3/anti-CD28 in the absence or presence of nicotine. CD4+T cells were cultured in the Th cell differentiation condition in the absence of nicotine or nicotine and alpha- bungarotoxin (alphaBgt) (the antagonist of nicotine) combined. Levels of T cell cytokines were detected with ELISA and flow cytometry. The expression of specific transcription factors (retinoic orphan re- ceptor c (RORc), T-box transcription factor (T-bet), and GATA Binding Protein 3 (GATA-3)) and signaling molecules (P-ERK1/2 and T-ERK1/2) were determined by Western blot. The results showed nicotine reduced IL-17A and increased IL-4 produced by stimulated PBMCs. During Th17 differentiation conditions, nicotine reduced the levels of IL-17A and RORc, induced the phosphorylation of ERK1/2. Meanwhile, nicotine increased the levels of IL-4 and GATA3 during Th2 differentiation. alpha-Bgt blocked the effects of nicotine on Th2 and Th17 differentiation. However, nicotine had no effect on the expression of IFN-gamma and T-bet in CD4+T cells during Th1differentiation. These results demonstrate that nicotine suppresses Th17 differentiation, promotes Th2 differentiation and improves Th1/Th2 imbalance in RA patients, providing a new justification for its application in the treatment of rheumatoid arthritis. PMID- 29715456 TI - Long noncoding RNA PVT1 inhibits interferon-alpha mediated therapy for hepatocellular carcinoma cells by interacting with signal transducer and activator of transcription 1. AB - Long noncoding RNA (LncRNA) PVT1 has recently been reported to be involved in the development of hepatocellular carcinoma (HCC) and hsigh expression of oncogenic PVT1 is associated with poor prognosis of HCC. Interferon-alpha (IFN-alpha) has been used in clinic for HCC therapy. However, whether PVT1 is involved in the IFN alpha therapy for HCC is completely unknown. Our study found that high PVT1 expression in HCC cells is associated with high unmethylation in PVT1 promoter region. IFN-alpha treatment further increases PVT1 expression in HCC cells by enhancing H3K4me3 modification on the promoter. Furthermore, PVT1 knockdown enhances IFN-alpha-induced HCC cell apoptosis by promoting phosphorylation of signal transducer and activator of transcription 1 (STAT1) and upregulating IFN stimulated genes expression. Moreover, PVT1 specifically interacts with STAT1 in HCC cells. Taken together, these results for the first time indicate that IFN alpha treatment promotes oncogenic PVT1 expression in HCC cells, which interacts with STAT1 to inhibit IFN-alpha signaling, ultimately blocking IFN-alpha-induced cells apoptosis, suggesting that lncRNA PVT1 may be a potential target to improve IFN-alpha-mediated HCC immunotherapies. PMID- 29715457 TI - SPG6 supports development of acute myeloid leukemia by regulating BMPR2-Smad-Bcl 2/Bcl-xl signaling. AB - Acute myeloid leukemia (AML) is the most common acute leukemia affecting adults. To effectively treat AML, new molecular targets and therapeutic approaches must be identified. In silico analysis of several available databases of AML patients showed that the expression of Spastic Paraplegia 6 Protein (SPG6) significantly inversely correlates with the overall survival of AML patients. To determine whether SPG6 supports AML development, we employed an shRNA-encoding lentivirus system to inhibit SPG6 expression in human AML cells including NB4 and MV4-11 cells. Knockdown expression of SPG6 resulted in decreased cell growth and elevated apoptosis of these leukemia cells. Notably, the SPG6 deficiency resulted in higher BMPR2 expression indicating that BMPR2 signaling contributes to AML pathogenesis. Furthermore, SPG6 deficiency promoted phosphorylation of Smad1/5/9 and decreased transcription of Bcl-2 and Bcl-xl. Our study suggests that SPG6 contributes to AML pathogenesis, and suggests that inhibition of SPG6 may be novel strategy for treating human AML. PMID- 29715458 TI - LncRNA FIRRE/NF-kB feedback loop contributes to OGD/R injury of cerebral microglial cells. AB - Stroke is one of the leading causes for serious long-term neurological disability. LncRNAs have been investigated to be dysregulated in ischemic stroke. However, the underlying mechanisms of some specific lncRNAs have not been clearly clarified. To determine lncRNA-mediated regulatory mechanism in ischemic stroke, we constructed OGD/R injury model of cerebral microglial cells. Microarray analysis was carried out and analyzed that lncRNA functional intergenic repeating RNA element (FIRRE) was associated with OGD/R injury. Based on the molecular biotechnology, we demonstrated that FIRRE could activate NF-kB signal pathway. Meanwhile, the activated NF-kB promoted FIRRE expression in OGD/R-treated cerebral microglial cells. Therefore, FIRRE and NF-kB formed a positive feedback loop to promote the transcription of NLRP3 inflammasome, thus contributed to the OGD/R injury of cerebral microglial cells. All findings in this study may help to explore novel and specific therapeutic target for ischemic stroke. PMID- 29715459 TI - Mesenchymal stem cells drive paclitaxel resistance in ErbB2/ErbB3-coexpressing breast cancer cells via paracrine of neuregulin 1. AB - We had previously demonstrated that increased expression of ErbB3 is required for ErbB2-mediated paclitaxel resistance in breast cancer cells. In the present study, we have explored the possible role of mesenchymal stem cells (MSCs) in regulating the paclitaxel-sensitivity of ErbB2/ErbB3-coexpressing breast cancer cells. We show that human umbilical cord-derived MSCs express significantly higher level of neuregulin-1 as compared with ErbB2/ErbB3-coexpressing breast cancer cells themselves. Coculture or treatment with conditioned medium of MSCs not only decreases the anti-proliferation effect of paclitaxel on ErbB2/ErbB3 coexpressing breast cancer cells, but also significantly inhibits paclitaxel induced apoptosis. We further demonstrate that this MSCs-drived paclitaxel resistance in ErbB2/ErbB3-coexpressing breast cancer cells could be attributed to upregulation of Survivin via paracrine effect of NRG-1/ErbB3/PI-3K/Akt signaling, as either specific knockdown expression of ErbB3, or blocking of downstream PI 3K/Akt signaling, or specific inhibition of Survivin can completely reverse this effect. Moreover, targeted knockdown of NRG-1 expression in MSCs abrogates theirs effect on paclitaxel sensitivity of ErbB2/ErbB3-coexpressing breast cancer cells. Taken together, our study indicate that paracrine of NRG-1 by MSCs induces paclitaxel resistance in ErbB2/ErbB3-coexpressing breast cancer cells through PI 3K/Akt signaling-dependent upregulation of Survivin. Our findings suggest that simultaneously targeting mesenchymal stem cells in tumor microenvironment may be a novel strategy to overcome paclitaxel resistance in patients with ErbB2/ErbB3 coexpressing breast cancer. PMID- 29715460 TI - Long non-coding RNA CASP5 promotes the malignant phenotypes of human glioblastoma multiforme. AB - BACKGROUND: Long non-coding RNAs (lncRNAs) have been demonstrated to be intensively involved in the development of various carcinomas, including glioblastoma multiforme (GBM). However, only a few of them have been well characterized. LncRNA CASP5 have been found to be up-regulated in GBM tissues compared with normal tissues in a microarray-based lncRNA profiling study. In the present study, we further explored the biological role of lncRNA CASP5 in GBM. METHODS: We examined the expression level of lncRNA CASP5 in GBM tissues as well as GBM cell lines. CCK-8 assay, flow cytometric analysis, western blotting, orthotopic GBM model as well as transwell assay were performed to investigate the biological role of CASP5. RESULTS: We observed that lncRNA CASP5 was highly expressed in GBM tissues and cell lines. Knockdown of CASP5 greatly inhibited GBM proliferation and resulted in G1 cell cycle arrest along with higher apoptosis ratios in vitro and in vivo, while overexpression led to the opposite phenomenon. Furthermore, the migration and invasion ability of GBM cells were significantly decreased after CASP5 down-regulation, while increased migration and invasion can be observed after CASP5 up-regulation. CONCLUSION: We demonstrate for the first time the potential oncogenic role of lncRNA CASP5 which may be helpful for identifying novel therapeutic targets in GBM. PMID- 29715462 TI - Development of a novel isolation unit for entomophthoralean fungi. AB - Entomophthoralean fungi are important natural enemies of pests and highly co evolved with their hosts. However, successful isolation of entomophthoralean fungi can be difficult due to their fastidious culture requirements; this is an important obstacle to research on Entomophthorales. In this study, we designed an isolation unit and evaluated it against the conventional 'descending conidia' isolation method. There was no difference in contamination rate between the methods (78% and 76% clean isolations) despite the isolation unit not requiring laminar-flow facilities. Furthermore, more conidia were collected in the new isolation unit than using a standard method. The isolation unit is efficient, convenient and is operational in the field. PMID- 29715461 TI - Direct visualization of the Wntless-induced redistribution of WNT1 in developing chick embryos. AB - Paracrine Wnt signals are critical regulators of cell proliferation, specification, and differentiation during embryogenesis. Consistent with the discovery that Wnt ligands are post-translationally modified with palmitoleate (a 16 carbon mono-unsaturated fatty acid), our studies show that the vast majority of bioavailable chick WNT1 (cWNT1) produced in stably transfected L cells is cell associated. Thus, it seems unlikely that the WNT1 signal is propagated by diffusion alone. Unfortunately, the production and transport of vertebrate Wnt proteins has been exceedingly difficult to study as few antibodies are able to detect endogenous Wnt proteins and fixation is known to disrupt the architecture of cells and tissues. Furthermore, vertebrate Wnts have been extraordinarily refractory to tagging. To help overcome these obstacles, we have generated a number of tools that permit the detection of WNT1 in palmitoylation assays and the visualization of chick and zebrafish WNT1 in live cells and tissues. Consistent with previous studies in fixed cells, live imaging of cells and tissues with overexpressed cWNT1-moxGFP shows predominant localization of the protein to a reticulated network that is likely to be the endoplasmic reticulum. As PORCN and WLS are important upstream regulators of Wnt gradient formation, we also undertook the generation of mCherry-tagged variants of both proteins. While co-expression of PORCN-mCherry had no discernible effect on the localization of WNT1-moxGFP, co-expression of WLS-mCherry caused a marked redistribution of WNT1 moxGFP to the cell surface and cellular projections in cultured cells as well as in neural crest and surface ectoderm cells in developing chick embryos. Our studies further establish that the levels of WLS, and not PORCN, are rate limiting with respect to WNT1 trafficking. PMID- 29715463 TI - Histopathological variables in liver metastases of patients with stage IV colorectal cancer: potential prognostic relevance of poorly differentiated clusters. AB - The prognosis of patients with colorectal liver metastases (LMs) is mostly established on clinical variables or on the anatomic extent of colorectal cancer (CRC). Histopathological factors of LMs which may actually reflect the biological aggressiveness of the tumor are not routinely considered to define the risk of worse clinical outcome in those patients. The number of poorly differentiated clusters (PDCs) of neoplastic cells in primary CRC is associated with metastatic risk and bad prognosis, but PDC presence in LMs has been barely analyzed thus far. We assessed PDC presence in the histological slides of surgically resected and synchronous LMs in 63 patients with CRC who had been not submitted to any neoadjuvant treatments. Then, we analyzed its association with patients' cancer specific survival (CSS) or progression-free survival. The presence of PDCs (P = .016) and PDC localization at tumor edge of LMs (P = .0004) were significantly associated with shorter CSS. PDC presence at the periphery of LMs and positive resection margin were independent prognostic variables for CSS. PDC localization at the tumor edge of LMs was a significant (P = .0079) and independent prognosticator of shorter progression-free survival. Our data suggest that PDC presence and peripheral localization in LMs may be relevant to predict outcome and useful for clinical decision making in patients with colorectal synchronous LMs. PMID- 29715464 TI - Spermidine/spermine N1-acetyltransferase-mediated polyamine catabolism regulates beige adipocyte biogenesis. AB - OBJECTIVE: Cold and beta3-adrenergic receptor (AR) agonists activate beige adipocyte biogenesis in white adipose tissue (WAT). The two stimuli also induce expression of inflammatory cytokines in WAT. The low-grade inflammation may further promote WAT browning. However, the mechanisms to reconcile these two biological processes remain to be elucidated. In this study, we aim to investigate the roles of the rate-limiting polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase (SAT1) in regulating beige adipocyte biogenesis and inflammation. METHODS: Adipose-specific SAT1 knockout mice (SAT1 aKO) were generated by crossing adiponectin-cre to SAT1-lox/lox mice. Metabolic phenotype was investigated. Primary pre-adipocytes were isolated from inguinal WAT (iWAT) and differentiated to adipocytes for studying beige adipocyte biogenesis. RESULT: The expression and enzymatic activity of SAT1 were up regulated in iWAT upon cold and beta3-AR stimulation. SAT1-aKO mice developed late-onset obesity on a high-fat diet with impaired cold-induced beige adipocyte biogenesis and energy expenditure. RNA-seq analysis of iWAT from cold-challenged SAT1-aKO mice revealed that, in addition to beige adipocyte biogenesis signatures, the immune response markers were highly enriched among reduced genes. In cultured adipocytes, SAT1 overexpression or pharmacological activation with N1, N11-diethylnorspermine (DENSpm) elevated oxygen consumption and increased the expression of beige adipocyte marker UCP1 and PGC-1alpha. DENSpm treatment of adipocytes also increased the expression of inflammatory genes. SAT1 activation enhanced hydrogen peroxide production in adipocytes. Antioxidant N-acetylcysteine abrogated the elevated UCP1 expression and reversed some inflammatory genes induced by SAT1 activation. CONCLUSIONS: SAT1 activation plays a key role in cold and beta3-AR agonist-induced beige adipocyte biogenesis and low-grade inflammation. PMID- 29715465 TI - Up-regulation of miR-122 protects against neuronal cell death in ischemic stroke through the heat shock protein 70-dependent NF-kappaB pathway by targeting FOXO3. AB - Dysfunction of the microRNA (miRNA) network has been emerging as a main regulator in ischemic stroke. Recently, studies have linked the deregulation of miR-122 to ischemic stroke. However, the specific role and molecular mechanism of miR-122 in ischemic stroke remain to be further investigated. Here, we found that miR-122 was decreased in mouse N2A neuroblastoma (N2A) cells after oxygen-glucose deprivation (OGD) and mouse brain after transient middle cerebral artery occlusion (MCAO). OGD treatment significantly increased N2A cell death and Caspase-3 activity, and decreased Bcl-2 protein expression. In addition, MCAO treatment induced severe mouse brain infarction, mitochondrial reactive oxygen species (ROS) production, and long-term neurological deficit. Gain-of-miR-122 function significantly suppressed OGD- and MCAO-induced injures in vitro and in vivo. Subsequently, miR-122 was validated to directly bind to the predicted 3' untranslated region (3'-UTR) of FOXO3 gene, and the inhibitory effects of miR-122 on ischemic injury in vitro and in vivo were overturned by FOXO3 overexpression. Moreover, our results further revealed that miR-122-FOXO3 axis functioned via the heat shock protein 70 (HSP-70)-mediated NF-kappaB pathway. Collectively, our data suggest that miR-122 inhibits ischemic neuronal death through the HSP-70 dependent NF-kappaB pathway by targeting FOXO3. These findings raise the possibility that this regulatory net may contribute to the pathogenesis of the ischemic brain injury in stroke. PMID- 29715466 TI - Feraheme(r) suppresses immune function of human T lymphocytes through mitochondrial damage and mitoROS production. AB - Despite attractive properties for both therapeutic and diagnostic applications, the clinical use of iron oxide nanoparticles (IONPs) is limited to iron replacement in severely anemic patient populations. While several studies have reported about the immunotoxicity of IONPs, the mechanisms of this toxicity are mostly unknown. We conducted a mechanistic investigation using an injectable form of IONP, Feraheme(r). In the cultures of primary human T cells, Feraheme induced miotochondrial oxidative stress and resulted in changes in mitochondrial dynamics, architecture, and membrane potential. These molecular events were responsible for the decrease in cytokine production and proliferation of mitogen activated T cells. The induction of mitoROS by T cells in response to Feraheme was insufficient to induce total redox imbalance at the cellular level. Consequently, we resolved this toxicity by the addition of the mitochondria specific antioxidant MitoTEMPO. We further used these findings to develop an experimental framework consisting of critical assays that can be used to estimate IONP immunotoxicity. We explored this framework using several immortalized T-cell lines and found that none of them recapitulate the toxicity observed in the primary cells. Next, we compared the immunotoxicity of Feraheme to that of other FDA-approved iron-containing complex drug formulations and found that the mitochondrial damage and the resulting suppression of T-cell function are specific to Feraheme. The framework, therefore, can be used for comparing the immunotoxicity of Feraheme with that of its generic versions, while other iron based complex drugs require case-specific mechanistic investigation. PMID- 29715467 TI - Diversity of peptidic and proteinaceous toxins from social Hymenoptera venoms. AB - Among venomous animals, Hymenoptera have been suggested as a rich source of natural toxins. Due to their broad ecological diversity, venom from Hymenoptera insects (bees, wasps and ants) have evolved differentially thus widening the types and biological functions of their components. To date, insect toxinology analysis have scarcely uncovered the complex composition of bee, wasp and ant venoms which include low molecular weight compounds, highly abundant peptides and proteins, including several allergens. In Hymenoptera, these complex mixtures of toxins represent a potent arsenal of biological weapons that are used for self defense, to repel intruders and to capture prey. Consequently, Hymenoptera venom components have a broad range of pharmacological targets and have been extensively studied, as promising sources of new drugs and biopesticides. In addition, the identification and molecular characterization of Hymenoptera venom allergens have allowed for the rational design of component-resolved diagnosis of allergy, finally improving the outcome of venom immunotherapy (VIT). Until recently, a limited number of Hymenoptera venoms had been unveiled due to the technical limitations of the approaches used to date. Nevertheless, the application of novel techniques with high dynamic range has significantly increased the number of identified peptidic and proteinaceous toxins. Considering this, the present review summarizes the current knowledge about the most representative Hymenoptera venom peptides and proteins which are under study for a better understanding of the insect-caused envenoming process and the development of new drugs and biopesticides. PMID- 29715468 TI - Immunomodulatory effects of selected cyanobacterial peptides in vitro. AB - Cyanobacteria produce many biologically active metabolites synthesized via nonribosomal synthetic pathways such as cyclic microcystins (MCs) and linear aeruginosins (Aers). The present study aimed to investigate the effects of different MC variants and the newly isolated aerugenosin Aer-865 on macrophages, which represent one of the key effector cells within the innate immune responses. Specifically, our study included RAW 264.7 macrophage activation associated with production of cytotoxic and cytostatic nitric oxide (NO) as well as pro inflammatory mediators like tumor necrosis factor alpha (TNFalpha) and interleukin 6 (IL-6). From the compounds investigated, commonly occurring MC variants (-RR, -YR) and Aer-865 had no significant effects within the non cytotoxic concentrations tested, i.e. 0.001-1 MUM for MCs and 0.1-50 MUM for Aer 865. In contrast to known immunoactive MC-LR, the negligible immunomodulatory potential of tested MC congeners could be related to their differences in structure. The knowledge of MC structure-specific activities contributes to the understanding of complex toxicity of different MC variants and most importantly their mixtures. This study is one of the first study that evaluate the effect of larger set of cyanobacterial peptides on macrophages and compare their immunomodulatory potential. PMID- 29715469 TI - Electrolytic lesions to the anterior hypothalamus-preoptic area disrupt maternal nest-building in intact and ovariectomized, steroid-treated rabbits. PMID- 29715470 TI - Omega-3 and omega-6 polyunsaturated fatty acids: Dietary sources, metabolism, and significance - A review. AB - Linoleic acid (LA) (n-6) and alpha-linolenic acid (ALA) (n-3) are essential fatty acids (EFAs) as they cannot be synthesized by humans or other higher animals. In the human body, these fatty acids (FAs) give rise to arachidonic acid (ARA, n-6), eicosapentaenoic acid (EPA, n-3), and docosahexaenoic acid (DHA, n-3) that play key roles in regulating body homeostasis. Locally acting bioactive signaling lipids called eicosanoids derived from these FAs also regulate diverse homeostatic processes. In general, ARA gives rise to pro-inflammatory eicosanoids whereas EPA and DHA give rise to anti-inflammatory eicosanoids. Thus, a proportionally higher consumption of n-3 PUFAs can protect us against inflammatory diseases, cancer, cardiovascular diseases, and other chronic diseases. The present review summarizes major sources, intake, and global consumption of n-3 and n-6 PUFAs. Their metabolism to biosynthesize long-chain PUFAs and eicosanoids and their roles in brain metabolism, cardiovascular disease, obesity, cancer, and bone health are also discussed. PMID- 29715472 TI - Structural Basis for Human DNA Polymerase Kappa to Bypass Cisplatin Intrastrand Cross-Link (Pt-GG) Lesion as an Efficient and Accurate Extender. AB - Cisplatin (cis-diamminedichloroplatinum) is a common chemotherapeutic drug that reacts with the N7 atoms of adjacent guanines in DNA to form the Pt-1,2-d(GpG) intrastrand cross-link (Pt-GG), a major product to block DNA replication. Translesion DNA synthesis has been implicated in chemoresistance during cisplatin treatment of cancer due to Pt-GG lesion bypass. Gene knockdown studies in human cells have indicated a role for polkappa during translesion synthesis of the Pt GG lesion. However, the bypass activity of polkappa with cisplatin lesions has not been well characterized. In this study, we investigated polkappa's ability to bypass Pt-GG lesion in vitro and determined two crystal structures of polkappa in complex with Pt-GG DNA. The ternary complex structures represent two consecutive stages of lesion bypass: nucleotide insertion opposite the 5'G (Pt-GG2) and primer extension immediately after the lesion (Pt-GG3). Our biochemical data showed that polkappa is very efficient and accurate in extending DNA primers after the first G of the Pt-GG lesion. The structures demonstrate that the efficiency and accuracy is achieved by stably accommodating the bases with the cisplatin adduct in the active site for proper Watson-Crick base pairing with the incoming nucleotide in both the second insertion and post-insertion complexes. Our studies suggest that polkappa works as an extender for efficient replication of the Pt-GG lesion in cells. This work holds promise for considering polkappa, along with poleta, as potential targets for drug design, which together could improve the efficacy of cisplatin treatment for cancer therapy. PMID- 29715471 TI - Functional and Biochemical Characterization of Dib1's Role in Pre-Messenger RNA Splicing. AB - The spliceosome is a dynamic macromolecular machine that undergoes a series of conformational rearrangements as it transitions between the several states required for accurate splicing. The transition from the B to Bact is a key part of spliceosome assembly and is defined by the departure of several proteins, including essential U5 component Dib1. Recent structural studies suggest that Dib1 has a role in preventing premature spliceosome activation, as it is positioned adjacent to the U6 snRNA ACAGAGA and the U5 loop I, but its mechanism is unknown. Our data indicate that Dib1 is a robust protein that tolerates incorporation of many mutations, even at positions thought to be key for its folding stability. However, we have identified two temperature-sensitive mutants that stall in vitro splicing prior to the first catalytic step and block assembly at the B complex. In addition, Dib1 readily exchanges in splicing extracts despite being a central component of the U5 snRNP, suggesting that the binding site of Dib1 is flexible. Structural analyses show that the overall conformation of Dib1 and the mutants are not affected by temperature, so the temperature sensitive defects most likely result from altered interactions between Dib1 and other spliceosomal components. Together, these data lead to a new understanding of Dib1's role in the B to Bact transition and provide a model for how dynamic protein-RNA interactions contribute to the correct assembly of a complex molecular machine. PMID- 29715473 TI - Stabilization of Ca2+ signaling in cardiac muscle by stimulation of SERCA. AB - AIMS: In cardiac muscle, phosphorylation of the RyRs is proposed to increase their Ca2+ sensitivity. This mechanism could be arrhythmogenic via facilitation of spontaneous Ca2+ waves. Surprisingly, the level of Ca2+ inside the SR needed to initiate such waves has been reported to increase upon beta-adrenergic stimulation, an observation which cannot be easily reconciled with elevated Ca2+ sensitivity of the RyRs. We tested the hypothesis that this change of Ca2+ wave threshold could occur indirectly, subsequent to SERCA stimulation. METHODS AND RESULTS: Cytosolic and intra-SR Ca2+ waves were simultaneously recorded with confocal line-scan imaging in intact and permeabilized mouse cardiomyocytes using Rhod-2 and Fluo-5-N, respectively. We analyzed changes of several Ca2+ signaling parameters during specific SERCA stimulation by ochratoxin A (OTA), jasmonate or the Fab fragment of a phospholamban antibody. SERCA stimulation resulted in a substantial increase of the threshold for Ca2+ wave initiation. Faster Ca2+ transient decay and SR refilling confirmed SERCA acceleration. CONCLUSIONS: These results suggest that isolated SERCA stimulation can elevate the intra-SR threshold for the generation of Ca2+ waves, independently of RyR phosphorylation. Simultaneously, fractional Ca2+ release and wave amplitudes are reduced. Thus, SERCA stimulation appears to exert a negative feed-back on the Ca2+-induced Ca2+ release mechanisms sustaining the waves. Thereby, it may be profoundly antiarrhythmic. This may be clinically relevant when therapies are applied to stimulate the SERCA activity (e.g. SERCA overexpression with gene therapy, future small molecule SERCA stimulators). PMID- 29715474 TI - TRPV4 inhibition prevents paclitaxel-induced neurotoxicity in preclinical models. AB - Paclitaxel is a cytotoxic drug which frequently causes sensory peripheral neuropathy in patients. Increasing evidence suggests that altered intracellular calcium (Ca2+) signals play an important role in the pathogenesis of this condition. In the present study, we examined the interplay between Ca2+ release channels in the endoplasmic reticulum (ER) and Ca2+ permeable channels in the plasma membrane in the context of paclitaxel mediated neurotoxicity. We observed that in small to medium size dorsal root ganglia neurons (DRGN) the inositol trisphosphate receptor (InsP3R) type 1 was often concentrated in the periphery of cells, which is in contrast to homogenous ER distribution. G protein-coupled designer receptors were used to further elucidate phosphoinositide mediated Ca2+ signaling: This approach showed strong InsP3 mediated Ca2+ signals close to the plasma membrane, which can be amplified by Ca2+ entry through TRPV4 channels. In addition, our results support a physical interaction and partial colocalization of InsP3R1 and TRPV4 channels. In the context of paclitaxel-induced neurotoxicity, blocking Ca2+ influx through TRPV4 channels reduced cell death in cultured DRGN. Pretreatment of mice with the pharmacological TRPV4 inhibitor HC067047 prior to paclitaxel injections prevented electrophysiological and behavioral changes associated with paclitaxel-induced neuropathy. In summary, these results underline the relevance of TRPV4 signaling for the pathogenesis of paclitaxel-induced neuropathy and suggest novel preventive strategies. PMID- 29715476 TI - Epigenetic upregulation of CXCL12 expression contributes to the acquisition and maintenance of morphine-induced conditioned place preference. AB - Addiction and rewarding effect is a primary side effect of morphine, which is commonly used to relieve the acute or chronic pain. Several lines of evidence have suggested that inflammation response in the VTA contributes to morphine induced reward (conditioned place preference, CPP), while the mechanism are poorly understood. The present study showed that repeated morphine conditioning persistently increased the expression of CXCL12 mRNA and protein in VTA. Furthermore, inhibition of CXCL12 prevented the acquisition and maintenance, but not the expression, of morphine-induced CPP in rodent. In addition, molecular analysis revealed that morphine conditioning increased the occupancy of p-STAT3 in the specific binding site (-1667/-1685) of CXCL12 promoter regions, and enhanced the interaction between acetyltransferase p300 and STAT3, and, hence, induced the histone H4 hyperacetylation in the promoter region and facilitated the transcription and expression of CXCL12 in VTA. Collectively, these results, for the first time, provided the evidence that persisted increase of VTA CXCL12 via epigenetic mechanism mediated the acquisition and maintenance, but not the expression, of morphine CPP. PMID- 29715477 TI - Simultaneous Retrodialysis by Calibrator for Rapid In Vivo Recovery Determination in Target Site Microdialysis. AB - Concentrations in the interstitial tissue space are of clinical interest for many antibiotics and can be directly measured by microdialysis. Quantitative microdialysis strongly depends on reliable recovery estimates obtained from a suitable calibrator. Cefazolin (CFZ) is frequently used as a prophylactic antibiotic to prevent surgical site infections. This study aimed to develop a reliable and rapid calibration technique for CFZ microdialysis using cefuroxime (CFR) as a calibrator, which is applied simultaneously in the opposite direction via retrodialysis. Liquid chromatography-tandem mass spectrometry method was used for the measurement of both CFZ and CFR in microdialysate. Results from in vitro microdialysis experiments confirmed that CFR does not interfere with physicochemical properties of CFZ, and the loss of CFR is proportional to the gain of CFZ in microdialysis studies. Therefore, the validated bioanalytical assay is suitable to be applied in clinical microdialysis study of CFZ where microdialysis probes are simultaneously calibrated by retrodialysis of CFR. This approach shortens the overall sampling time of in vivo microdialysis studies significantly since calibration and sampling can be performed simultaneously and not in sequence as usually done. It also eliminates the necessary washout period if probe calibration is carried out before the actual sampling time. PMID- 29715475 TI - RhoA activation in axotomy-induced neuronal death. AB - After spinal cord injury (SCI) in mammals, severed axons fail to regenerate, due to both extrinsic inhibitory factors, e.g., the chondroitin sulfate proteoglycans (CSPGs) and myelin-associated growth inhibitors (MAIs), and a developmental loss of intrinsic growth capacity. The latter is suggested by findings in lamprey that the 18 pairs of individually identified reticulospinal neurons vary greatly in their ability to regenerate their axons through the same spinal cord environment. Moreover, those neurons that are poor regenerators undergo very delayed apoptosis, and express common molecular markers after SCI. Thus the signaling pathways for retrograde cell death might converge with those inhibiting axon regeneration. Many extrinsic growth-inhibitory molecules activate RhoA, whereas inhibiting RhoA enhances axon growth. Whether RhoA also is involved in retrograde neuronal death after axotomy is less clear. Therefore, we cloned lamprey RhoA and correlated its mRNA expression and activation state with apoptosis signaling in identified reticulospinal neurons. RhoA mRNA was expressed widely in normal lamprey brain, and only slightly more in poorly-regenerating neurons than in good regenerators. However, within a day after spinal cord transection, RhoA mRNA was found in severed axon tips. Beginning at 5 days post-SCI RhoA mRNA was upregulated selectively in pre-apoptotic neuronal perikarya, as indicated by labelling with fluorescently labeled inhibitors of caspase activation (FLICA). After 2 weeks post-transection, RhoA expression decreased in the perikarya, and was translocated anterogradely into the axons. More striking than changes in RhoA mRNA levels, RhoA was continuously active selectively in FLICA-positive neurons through 9 weeks post-SCI. At that time, almost no neurons whose axons had regenerated were FLICA-positive. These findings are consistent with a role for RhoA activation in triggering retrograde neuronal death after SCI, and suggest that RhoA may be a point of convergence for inhibition of both axon regeneration and neuronal survival after axotomy. PMID- 29715478 TI - Development of Novel Indole-3-Aldehyde-Loaded Gastro-Resistant Spray-Dried Microparticles for Postbiotic Small Intestine Local Delivery. AB - Considering the recent evidence on the therapeutic potential of postbiotics, this study focused on 2 main goals: (1) to develop an enteric microparticle (MP) formulation for intestinal localized delivery of indole-3-aldehyde (3-IAld) (a microbial-derived metabolite produced by the host's lactobacilli during the catabolic pathway of tryptophan) and (2) to provide support in the employment of spray-drying as innovative one-step manufacturing technique for enteric products. For this purpose, special attention was taken in the knowledge of the influence of equipment setup and feedstock properties on MP enteric behavior. Eudragit(r) S100 and L100 and ethyl cellulose were used as wall materials and NaOH and ethanol solutions as solvent systems. 3-IAld loading was maintained at 10% w/w. As postulated, feedstock properties influenced spray-drying regime. In addition, they prevailed over other spray-drying process factors in determining MP enteric behavior. Albeit the high buckling regime that produced crumped particles, gastro resistance was obtained by spray-drying 2:1 Eudragit(r) S100:L100 with 30% w/w ethyl cellulose in ethanol solution. These results support the use of spray drying as a method for manufacturing gastro-resistant MP. The obtained 3-IAld loaded enteric MP will be useful to investigate novel postbiotic-based treatments in different therapeutic areas. PMID- 29715479 TI - High-Throughput In-Use and Stress Size Stability Screening of Protein Therapeutics Using Algorithm-Driven Dynamic Light Scattering. AB - Stability of therapeutic proteins (TPs) is a critical quality attribute that impacts both safety and efficacy of the drug. Size stability is routinely performed during and after biomanufacturing. Dynamic light scattering (DLS) is a commonly used technique to characterize hydrodynamic size of the TPs. Herein, we have developed a novel method to evaluate in-use and thermal stress stability of TPs using algorithm-driven high-throughput DLS. Five marketed TPs were tested under the guidance of customized algorithms. The TPs were evaluated at relevant temperature conditions as well as under dilution and thermal stress for size stability. We found that the TPs were stable under the in-use conditions tested; however, sample loss due to evaporation can lead to large protein aggregates. A combined assessment of autocorrelation function and photos of sample well could be useful in formulation screening. Dilution of TPs also has an impact on the hydrodynamic size. Thermal stress experiments showed the importance of using different data processing methods to access size distribution. Polydispersity index was useful in evaluating sample heterogeneity. Herein, we show that algorithm-driven high-throughput DLS can provide additional supportive information during and after biomanufacturing and the potential to be used in a quality control environment. PMID- 29715480 TI - A novel assay to evaluate action selection in escape behavior. AB - BACKGROUND: How experience and individuality shape action selection remains a major question in neuroscience. Visually-evoked escape behavior within Drosophila melanogaster provides a robust model to study these mechanisms within neural circuits but requires novel assays to circumvent limitations of current behavior assays. METHOD: Here we describe and characterize a simple, low to moderate cost, and flexible assay for studying visually-evoked escape responses in tethered flies. This assay consists of a DLP projector, cylindrical rear projection screen, and an automated flight interruption motor all controlled within a MATLAB environment. RESULTS: We find this assay effectively recapitulates fly behaviors previously observed in free behavior assays, and provides a novel opportunity to investigate the behavior of individual flies over the course of numerous stimulus presentations. COMPARISON TO EXISTING METHODS: Current Drosophila escape assays do not permit multiple stimulus presentations and can be highly complex and expensive to implement. CONCLUSIONS: This assay provides an effective system to further identify neural components and mechanisms underlying action selection within parallel sensorimotor pathways. PMID- 29715481 TI - Mapping of neuron soma size as an effective approach to delineate differences between neural populations. AB - BACKGROUND: A single histological marker applied to a slice of tissue often reveals myriad cytoarchitectonic characteristics that can obscure differences between neuron populations targeted for study. Isolation and measurement of a single feature from the tissue is possible through a variety of approaches, however, visualizing the data numerically or through graphs alone can preclude being able to identify important features and effects that are not obvious from direct observation of the tissue. NEW METHOD: We demonstrate an efficient, effective, and robust approach to quantify and visualize cytoarchitectural features in histologically prepared brain sections. We demonstrate that this approach is able to reveal small differences between populations of neurons that might otherwise have gone undiscovered. RESULTS & COMPARISON WITH EXISTING METHOD(S): We used stereological methods to record the cross-sectional soma area and in situ position of neurons within sections of the cat, monkey, and human visual system. The two-dimensional coordinate of every measured cell was used to produce a scatter plot that recapitulated the natural spatial distribution of cells, and each point in the plot was color-coded according to its respective soma area. The final graphic display was a multi-dimensional map of neuron soma size that revealed subtle differences across neuron aggregations, permitted delineation of regional boundaries, and identified small differences between populations of neurons modified by a period of sensory deprivation. CONCLUSIONS: This approach to collecting and displaying cytoarchitectonic data is simple, efficient, and provides a means of investigating small differences between neuron populations. PMID- 29715482 TI - PGRP-LB homolog acts as a negative modulator of immunity in maintaining the gut microbe symbiosis of red palm weevil, Rhynchophorus ferrugineus Olivier. AB - Many notorious insect pests live in the symbiotic associations with gut microbiota. However, the mechanisms underlying how they host their gut microbiota are unknown. Most gut bacteria can release peptidoglycan (PGN) which is an important antigen to activate the immune response. Therefore, how to keep the appropriate gut immune intensity to host commensals while to efficiently remove enteropathogens is vital for insect health. This study is aimed at elucidating the roles of an amidase PGRP, Rf PGRP-LB, in maintaining the gut-microbe symbiosis of Red palm weevil (RPW), Rhynchophorus ferrugineus Olivier. RfPGRP-LB is a secreted protein containing a typical PGRP domain. The existence of five conservative amino acid residues, being required for amidase activity, showed that RfPGRP-LB is a catalytic protein. Expression analysis revealed abundance of RfPGRP-LB transcripts in gut was dramatically higher than those in other tissues. RfPGRP-LB could be significantly induced against the infection of Escherichia coli. In vitro assays revealed that rRfPGRP-LB impaired the growth of E. coli and agglutinated bacteria cells obviously, suggesting RfPGRP-LB is a pathogen recognition receptor and bactericidal molecule. RfPGRP-LB knockdown reduced the persistence of E. coli in gut and load of indigenous gut microbiota significantly. Furthermore, the community structure of indigenous gut microbiota was also intensively altered by RfPGRP-LB silence. Higher levels of the antimicrobial peptide, attacin, were detected in guts of RfPGRP-LB silenced larvae than controls. Collectively, RfPGRP-LB plays multiple roles in modulating the homeostasis of RPW gut microbiota not only by acting as a negative regulator of mucosal immunity through PGN degradation but also as a bactericidal effector to prevent overgrowth of commensals and persistence of noncommensals. PMID- 29715483 TI - Deciphering the genomes of 16 Acanthamoeba species does not provide evidence of integration of known giant virus-associated mobile genetic elements. AB - Giant viruses infect protozoa, especially amoebae of the genus Acanthamoeba. These viruses possess genetic elements named Mobilome. So far, this mobilome comprises provirophages which are integrated into the genome of their hosts, transpovirons, and Maverick/Polintons. Virophages replicate inside virus factories within Acanthamoeba and can decrease the infectivity of giant viruses. The virophage infecting CroV was found to be integrated in the host of CroV, Cafeteria roenbergensis, thus protecting C. roenbergensis by reduction of CroV multiplication. Because of this unique property, assessment of the mechanisms of replication of virophages and their relationship with giant viruses is a key element of this investigation. This work aimed at evaluating the presence and the dynamic of these mobile elements in sixteen Acanthamoeba genomes. No significant traces of the integration of genomes or sequences from known virophages were identified in all the available Acanthamoeba genomes. These results brought us to hypothesize that the interactions between mimiviruses and their virophages might occur through different mechanisms, or at low frequency. An additional explanation could be that our knowledge of the diversity of virophages is still very limited. PMID- 29715485 TI - Measuring the cost and effect of current community consultation and public disclosure techniques in emergency care research. AB - AIM: U.S. federal regulations for research involving exception from informed consent (EFIC) include stipulations for community consultation (CC) and public disclosure (PD) (FDA 21 CFR 50.24). Published descriptions of PD campaigns include letters to community leaders, media outreach, paid advertising, and community meetings. Whether or not these activities provide measurable impact is unknown, as few prior works have evaluated PD activities with probabilistic polling. The aim of this study is to use polling to assess how much public awareness PD efforts generate. METHODS: A 3-month PD campaign similar in scope and scale to PD campaigns described in several recent publications was implemented across a large urban county (pop. 2.55 million). PD included a study website (www.evktrial.org), letters to 300 community leaders/organizations, bilingual media outreach and also phased roll-outs, weeks apart, of newspaper advertisements, mass e-mail messaging, and paid advertising in Facebook(r) and Twitter(r) augmented by volunteer social media outreach. During PD we used repeated zip code-targeted online polling via Google Consumer Surveys(r) to assess community awareness of the proposed EFIC study. RESULTS: Over 3-months all source exposures to >1 million individuals were estimated, generating ~5,000 website visits (12-month cumulative, ~9000). However, general community awareness evaluated through repeated county-wide polling never rose above baseline measurements. CC/PD campaign costs were estimated at $60,000 (USD). CONCLUSION: A PD campaign in scope and scale common for EFIC studies may not provide measurable impact in a community. Investigators, review boards and regulators could consider these findings when re-examining and/or creating policies for PD for EFIC studies. PMID- 29715484 TI - B cell MHC class II signaling: A story of life and death. AB - MHC class II regulates B cell activation, proliferation, and differentiation during cognate B cell-T cell interaction. This is, in part, due to the MHC class II signaling in B cells. Activation of MHC Class II in human B cells or "primed" murine B cells leads to tyrosine phosphorylation, calcium mobilization, AKT, ERK, JNK activation. In addition, crosslinking MHC class II with monoclonal Abs kill malignant human B cells. Several humanized anti-HLA-DR/MHC class II monoclonal Abs entered clinical trials for lymphoma/leukemia and MHC class II-expressing melanomas. Mechanistically, MHC class II is associated with a wealth of transmembrane proteins including the B cell-specific signaling proteins CD79a/b, CD19 and a group of four-transmembrane proteins including tetraspanins and the apoptotic protein MPYS/STING. Furthermore, MHC class II signals are compartmentalized in the tetraspanin-enriched microdomains. In this review, we discuss our current understanding of MHC class II signaling in B cells focusing on its physiological significance and the therapeutic potential. PMID- 29715486 TI - Human papilloma virus (HPV) 18 proteins E6 and E7 up-regulate ABC transporters in oropharyngeal carcinoma. Involvement of the nonsense-mediated decay (NMD) pathway. AB - Oropharyngeal cancer incidence increased dramatically in the last decades, being infection with human papillomaviruses (HPV) a determinant of this trend. Concerning etiology, treatment response and prognosis, HPV+ and HPV- oropharyngeal cancers constitute different disease entities. The underlying molecular background is not completely understood. ATP-binding cassette (ABC) transporters mediate the efflux of anticancer drugs and are regulated by changes in the intracellular milieu. Furthermore, a role in cancer pathogenesis besides drug transport was reported. We evaluated the effect of transfection with E6 and E7 oncogenes from HPV16 and HPV18 on ABC transporters in oropharyngeal cancer cells. HPV18E6/E7 up-regulated P-glycoprotein (P-gp), multidrug resistance associated protein 1 (MRP1) and MRP2 expression in HNO206 cells and breast cancer resistance protein (BCRP) in HNO206 and HNO413 cells. While P-gp was regulated translationally, MRP1, MRP2 and BCRP up-regulation resulted from mRNA stabilization. For MRP1 and MRP2, the nonsense-mediated decay pathway was involved. In general, resistance to substrates of up-regulated transporters was increased. Transfection with oncogenes individually indicated a major role of HPV18E7. Our findings suggest ABC transporters as molecular players leading to differences in the pathogenesis of HPV+ and HPV- oropharyngeal cancer. PMID- 29715487 TI - Potent insect gut binding lectin from Sclerotium rolfsii impart resistance to sucking and chewing type insects in cotton. AB - Cotton is an important crop that is continuously cultivated around the world. However, its production has decreased in recent times due to wide ranging insects and also current practices of using synthetic insecticides that are not precise and their residues impairing the biodiversity. Hence, the search for newer classes of efficient entomotoxic proteins continues. Genetically modified cotton crops with cry genes from Bacillus thuringiensis, have been cultivated across the world, which overcome the chewing type insect menace. In the present study, we assess the development of transgenic cotton plants by Agrobacterium, wherein the confirmed kanamycin resistant T0 plants were advanced to T1 generation and the gene integration was studied by molecular analysis. Western blot and ELISA assays demonstrated the expression of 0.46% lectin of the total soluble leaf proteins. In planta bioassay showed 69% of aphid, Aphis gossypii population reduction with T1 generation plants. Whereas 100% insect mortality is occurred in Spodoptera litura larvae by 96 h. Present findings shows the potent insecticidal effect of Sclerotium rolfsii lectin on sucking (homopteran) and chewing (lepidopteron) insects, underlining its significance and strengthening genetic resources in cotton breeding against different order insect pests. PMID- 29715488 TI - Advanced multigene expression system for Nannochloropsis salina using 2A self cleaving peptides. AB - Even though there has been much interest in genetic engineering of microalgae, its progress has been slow due to the difficulty and limitation of available techniques. Currently, genetic modification in most microalgal strains is confined to single gene transformation. Here, a multigene expression system for the oleaginous model strain Nannochloropsis salina was developed with glycine serine-glycine spacer linked 2A self-cleaving peptides (2A) for the first time. An efficiency test of the four most widely used 2As revealed that two different types of 2As T2A and E2A have the best performance in N. salina with a maximum cleavage rate of nearly 45%. The system was able to express the linked sequence of the selection marker shble and the fluorescence protein sfCherry with intact functions. Because 2A enabled multigene expression in the single cassette form, the use of 2A also reduced the vector size, which along with the stronger promoter resulted in a 9-fold increase in the transformation efficiency. Furthermore, confirmative screening accuracy of more than 90% was observed. Hence, the 2A applied vector system is expected to be beneficial in microalgal research field because it enables multigene expression as well as offering improved transformation and screening efficiency. PMID- 29715489 TI - Pistacia lentiscus oil attenuates memory dysfunction and decreases levels of biomarkers of oxidative stress induced by lipopolysaccharide in rats. AB - Pistacia lentiscus L. is a well-known medicinal plant that has been used for its antioxidant, anti-inflammatory, neuroprotective, and hepatoprotective effects. However, the neuroprotective effect of Pistacia lentiscus oil (PLo) of has not been reported. The present study was designed to examine the neuroprotective and hepatoprotective effects of PLo aigainst lipopolysaccharide (LPS)-induced memory impairment and oxidative damage in rats. Twenty-four adult male Wistar rats were equally divided into three groups. The first group was kept as a control. In the second group, LPS was given at the single dose of 1 mg/kg intraperitoneally (i.p.). In the third group, PLo (3.3 mL/kg; per orally (p.o.)) was administered daily for 15 days, and challenged with LPS (1 mg/kg; i.p. injection two h before behavioral test). Thereafter, memory was assessed using spatial object recognition test. Cholinesterase activity and oxidative stress response were estimated in brain tissues and liver. PLo attenuated LPS-induced memory impairment in spatial object recognition test (p < 0.05). LPS treatment caused significant oxidative damage via induction of lipid peroxidation and reductions antioxidant defense system potency in the brain tissue and liver. Moreover, LPS increased brain activity of acetylcholinesterase and butyrylcholinesterase activity in the liver. The present results suggest that the beneficial effects of PLo on memory impairment of LPS-treated rats may be due to its protective effects against oxidative stress damage presumably via its antioxidant property. PMID- 29715490 TI - An antidepressant-related pharmacological signature for positive allosteric modulators of alpha2/3-containing GABAA receptors. AB - Data from transgenic animals and novel pharmacological agents has realigned scientific scrutiny on the therapeutic potential of positive allosteric modulators (PAMs) of alpha2/3-containing GABAA receptors. Evidence for analgesic, anticonvulsant, and anxiolytic activity of alpha2/3-selective PAMs has been presented along with the clinical potential for a milder motor-impacting profile compared to non-selective GABAA receptor PAMs. A new series of alpha2/3-selective PAMs was recently introduced which has anxiolytic and anticonvulsant activity in rodent models. These molecules also produce efficacy against pain in multiple animal models. Additionally, co-morbid states of depression are prevalent among patients with pain and patients with anxiety. Compounds were shown to be selective for alpha2 and alpha3 constructs over alpha1 (except KRM-II-82), alpha4, alpha5, and alpha6 proteins in electrophysiological assays in transfected HEK-293T cells. Utilizing the forced-swim assay in mice that detects conventional and novel antidepressant drugs, we demonstrate for the first time that alpha2/3 selective PAMs are active in the forced-swim assay at anxiolytic-producing doses. In contrast, activity in a related model, the tail-suspension test, was not observed. Diazepam was not active in the forced-swim assay when given alone but produced an antidepressant-like effect in mice when given in conjunction with the alpha1-preferring antagonist, beta-CCT, that attenuated the motor-impairing effects of diazepam. We conclude that these alpha2/3-selective PAMs deserve further scrutiny for their potential treatment of major depressive disorder. If effective, such a mechanism could add a beneficial antidepressant component to the anxiolytic, analgesic, and anticonvulsant spectrum of effects of these compounds. PMID- 29715491 TI - Recent updates and challenges on the regulation of precision medicine: The United States in perspective. AB - The rapid progress in "omics", such as genomics, metabolomics, microbiomics, has paved the path for precision medicine and revolutionized the development of drugs and devices promising to meet unmet medical needs. The aim of the present study was to investigate the current regulatory framework established by the United States Food and Drug Administration (USFDA) and to identify challenges and concerns through study of related literatures in the PubMed database. We found that efforts were made to facilitate the implementation of precision medicine through organizational reform, publication of guidance documents, and continuous post-market surveillance. The challenges identified included the critical, fundamental structural requirements of databases, essential regulatory considerations for market approval, and the appropriate clinical use such as whole genomic sequencing tests especially for a newborn or even fetus. These issues are worth further research to devise an integral approach involving scientific, ethical, legal, and social considerations. PMID- 29715492 TI - Subchronic toxicity study in rats evaluating genetically modified DAS-81419-2 soybean. AB - A 90-day feeding study in rats was conducted to evaluate the subchronic oral toxicity of genetically modified (GM) DAS-81419-2 soybean. Wistar rats were fed with diets containing toasted soybean meal produced from DAS-81419-2 soybean grain that expresses the Cry1F, Cry1Ac, and Pat proteins or containing conventional soybean at doses of 30.0%, 15.0%, 7.5%, or 0% (control group) for 90 consecutive days. The general behavior, body weight and food consumption were observed. At the middle and end of the experiment, blood, serum, and urine samples were collected for biochemical assays. At the conclusion of the study, the internal organs were weighed and histopathological examination was completed. The rats exhibited free movement and shiny coats without any abnormal symptoms or abnormal secretions in their noses, eyes, or mouths. There were no adverse effects on body weight in GM soybean groups and conventional soybean groups. No biological differences in hematological, biochemical, or urine indices were observed. No significant differences in relative organ weights were detected between the experimental groups and the control group. No histopathological changes were observed. Under the conditions of this study, DAS-81419-2 soybean did not cause any treatment-related effects in Wistar rats following 90 days of dietary administration. PMID- 29715493 TI - Spleen development is modulated by neonatal gut microbiota. AB - The full development of the mammalian immune system occurs after birth upon exposure to non self-antigens. The gut is the first site of bacterial colonization where it is crucial to create the appropriate microenvironment able to balance effector or tolerogenic responses to external stimuli. It is a well established fact that at mucosal sites bacteria play a key role in developing the immune system but we ignore how colonising bacteria impact the maturation of the spleen. Here we addressed this issue. Taking advantage of the fact that milk SIgA regulates bacterial colonization of the newborn intestine, we generated immunocompetent mice born either from IgA pro-efficient or IgA deficient females. Having demonstrated that SIgA in maternal milk modulates neonatal gut microbiota by promoting an increased diversity of the colonizing species we also found that immunocompetent pups, not exposed to milk SIgA, fail to properly develop the FDC network and primary follicles in the spleen compromising the response to T dependent antigens. The presence of a less diverse microbiota with a higher representation of pathogenic species leads to a fast replenishment of the marginal zone and the IgM plasma cell compartment of the spleen as well as IgA plasma cells in the gut. PMID- 29715494 TI - Prime visibility moderates implicit anger and sadness effects on effort-related cardiac response. AB - Based on the Implicit-Affect-Primes-Effort (IAPE) model (Gendolla, 2012, 2015), an experiment investigated the effect of affect primes' visibility on effort mobilization during cognitive processing. Participants worked on a short-term memory task with integrated sadness vs. anger primes that were presented suboptimally (briefly and masked) vs. optimally (long and visible). Effort was assessed as cardiovascular response, especially cardiac pre-ejection period (PEP). To monitor performance, we assessed response accuracy and reaction times. In accordance with the IAPE model, PEP reactivity was stronger in the sadness prime condition than in the anger-prime condition-but only when the primes were suboptimally presented. Effects on response accuracy revealed a corresponding pattern. The results suggest that prime visibility is a boundary condition of anger and sadness primes' effect on effort mobilization. PMID- 29715496 TI - Cross-talk between insulin signalling and LPS responses in mouse macrophages. AB - The effect of insulin priming on Il-10 expression, regulation of inflammatory cytokines and participation of intra-cellular signalling events, primarily ERK1/2 and PI3K/Akt, has been investigated in high glucose (HG) and/or lipopolysaccharide (LPS)-induced murine macrophages. Our results demonstrate that congruent with sharp increase in ERK1/2 and CREB phosphorylation, insulin stimulation in vitro promotes significant increase in Il-10 expression in mouse peritoneal macrophage and RAW 264.7 cells, both positive for anti-IRbeta. Pharmacological inhibition of MEK/MAPK, but not PI3K/Akt cascade, abrogates CREB phosphorylation and Il-10 synthesis indicating functional relevance of insulin action. Conversely, priming with PI3K inhibitor wortmannin prevents insulin attenuation of HG- and/or LPS-induced p38 MAPK and NF-kappaB activation, Tnf alpha, Il-1beta expression as well as NO production. Congruent with reduced Il-10 expression, MEK inhibition abrogates insulin action allowing significant increase in Tlr4 expression and LPS response indicating insulin-induced Il-10 might have pivotal influence in regulation of chronic as well as acute inflammatory response. PMID- 29715495 TI - Category-based attentional guidance can operate in parallel for multiple target objects. AB - The question whether the control of attention during visual search is always feature-based or can also be based on the category of objects remains unresolved. Here, we employed the N2pc component as an on-line marker for target selection processes to compare the efficiency of feature-based and category-based attentional guidance. Two successive displays containing pairs of real-world objects (line drawings of kitchen or clothing items) were separated by a 10 ms SOA. In Experiment 1, target objects were defined by their category. In Experiment 2, one specific visual object served as target (exemplar-based search). On different trials, targets appeared either in one or in both displays, and participants had to report the number of targets (one or two). Target N2pc components were larger and emerged earlier during exemplar-based search than during category-based search, demonstrating the superior efficiency of feature based attentional guidance. On trials where target objects appeared in both displays, both targets elicited N2pc components that overlapped in time, suggesting that attention was allocated in parallel to these target objects. Critically, this was the case not only in the exemplar-based task, but also when targets were defined by their category. These results demonstrate that attention can be guided by object categories, and that this type of category-based attentional control can operate concurrently for multiple target objects. PMID- 29715498 TI - Linking gut microbiota to cardiovascular disease and hypertension: Lessons from chronic kidney disease. AB - Bidirectional interactions exist between the kidneys and the gut. These interactions are commonly referred to as the gut-kidney axis. Chronic kidney disease (CKD) leads to disturbances of the gut ecosystem. Key features include the increase of protein fermentation at the expense of carbohydrate fermentation and a disrupted epithelial barrier. A disturbed gut ecosystem may contribute to the high burden of cardiovascular disease in patients with CKD. The present review discusses the impact of CKD on the gut microenvironment and provides an update as to how gut dysbiosis and a leaky gut may be linked to accelerated cardiovascular disease and hypertension. PMID- 29715497 TI - Deletion of fetoplacental Fshr inhibits fetal vessel angiogenesis in the mouse placenta. AB - It has been shown in both human and mouse placentas that follicle stimulating hormone receptor (FSHR) is expressed in fetal vascular endothelium. There are conflicting reports, however, on the role of FSH to stimulate angiogenesis in vitro in cultured endothelial cells from umbilical veins. Therefore, in this study we undertook an in vivo approach utilizing Fshr null mice to definitively address this question. In the context where all pregnant dams have identical Fshr genotypes, we generated fetuses and associated fetal portions of placenta that were Fshr wt or Fshr null and analyzed angiogenesis within the placental labyrinths. Quantitative morphometric analyses of placentas obtained at mid gestation revealed that the percentage of the placenta composed of labyrinth is significantly decreased in Fshr null placentas relative to wt placentas. Furthermore, data presented demonstrate that within the Fshr null labyrinths, fetal vessel angiogenesis was significantly reduced relative to wt labyrinths. The results obtained with this combination of in vivo and genetic approaches conclusively demonstrate that signaling through endothelial FSHR does indeed stimulate angiogenesis and that placental Fshr is essential for normal angiogenesis of the fetal placental vasculature. PMID- 29715499 TI - New and upcoming treatments in antiphospholipid syndrome: A comprehensive review. AB - Current therapeutic recommendations for thrombosis prevention in patients with antiphospholipid syndrome (APS) are limited to anticoagulation with vitamin K antagonists (VKA) or heparins and to anti-platelet aggregating agents. Maintaining optimized anticoagulation to prevent recurrent thrombosis or bleeding remains a therapeutic challenge. Although there are important ongoing trials with direct oral anticoagulants, they still aim the same target. New insights about pathophysiology in APS have revealed a myriad of potential pathways to be investigated as treatment targets. A radical shift from a hematological/coagulative approach to an immunological one will probably represent the near future of APS treatment. We reviewed the therapeutic trends and potential future treatments. PMID- 29715500 TI - Exploiting polymer blending approach for fabrication of buccal chitosan-based composite sponges with augmented mucoadhesive characteristics. AB - In the course of application and modernization of buccal dosage forms, lyophilized sponges for transmucosal drug delivery symbolize one of the most attractive approaches. Chitosan (CS) has been extensively investigated as a forming material of different buccal dosage forms including sponges. However, CS based buccal delivery systems suffer from many limitations like weak adhesion strength and poor tensile properties. So, for the first time, the current study focused on the polymer blending approach to enhance the mucoadhesive properties of buccal CS-based composite sponges. Composite sponges were prepared using lyophilization technique. Thorough in-vitro characterization of the proposed sponges was performed including mechanical strength determination, Fourier transform infrared spectroscopic analysis (FT-IR), surface pH, % moisture content, water uptake capacity, viscosity and % porosity assessments. Furthermore, the surface topology of selected sponges was viewed using scanning electron microscope. The mucoadhesive properties of sponges were tested both ex vivo and in-vivo. Among all fabricated sponges, sponges fabricated of CS:HPMC (1:1) showed the best physicochemical characteristics suitable for buccal applications. Incorporation of HPMC into CS-sponges significantly enhanced the mucoadhesion time to 6 h, while CS-sponges lost contact after around 10 min. Preliminary stability study showed CS:HPMC sponges stored in low humidity conditions maintain their soft texture and mucoadhesive properties for one month. PMID- 29715501 TI - Pharmacology study of a chimeric decoy receptor trap fusion protein on retina neovascularization by dual blockage of VEGF and FGF-2. AB - BACKGROUND: Clinical anti-vascular epithelial growth factor (VEGF) therapy trials faced a major challenge due to upregulated expression of other pro-angiogenic factors, such as fibroblast growth factor-2 (FGF-2). RC28, a novel recombinant dual decoy receptor IgG1 Fc-fusion protein, can block VEGFA and FGF-2 simultaneously. It is designed for the treatment of neovascular age-related macular degeneration and other pathological ocular neovascularization. The present study investigated the prevention efficacy of RC28 on choroidal neovascularization (CNV) in a monkey model and compared to the other mono VEGF antagonists; biodistribution and pharmacokinetics performance were also investigated. METHODS: ELISA and endothelial cell proliferation, migration, and tubule formation assay evaluated the bioactivity of RC28 in vitro, and an initial comparison was made among the mono target antagonists, Bevacizumab (Avastin), Ranibizumab (Lucentis), Aflibercept (EYLEA), Conbercept (KH902), and Ranibizumab (Lucentis). Laser-induced CNV in monkeys, and both VEGF and FGF-2 serum levels were detected in animals before and after the CNV model were induced. RC28 prevention efficacy was compared to other VEGF antagonists on CNV with respect to the incidence of CNV and several ophthalmic examinations. Ocular and systemic levels of RC28 were analyzed by 89Zr-labeled RC28 after single intravitreal administration for the biodistribution and pharmacokinetic profiles. RESULTS: RC28 is a unique fusion protein with high affinity to both VEGF and FGF-2, and beneficial to in vitro and in vivo bioactivity. The in vivo pharmacological studies demonstrated that the incidence of CNV formation was largely reduced in RC28 treatment groups with a low dosage as compared to other VEGF antagonist control groups. Furthermore, traces of RC28 were detected as dispersing from eyeballs to the liver after 20 days, and a prolonged half-time pharmacokinetic profile was exhibited. PMID- 29715502 TI - A multimodal investigation of impulsivity as a moderator of the relation between momentary elevations in negative internal states and subsequent dietary lapses. AB - Suboptimal outcomes from behavioral weight loss (BWL) treatments are partially attributable to accumulated instances of non-adherence to dietary prescriptions (i.e., dietary lapses). Results identifying negative internal triggers for dietary lapses are inconsistent, potentially due to individual differences that impact how individuals respond to cues. Impulsivity is one factor that likely influences reactivity to internal states. We examined three dimensions of impulsivity (delay discounting, inhibitory control, and negative urgency) as moderators of the relation between affective and physical states and subsequent dietary lapses at the beginning of BWL. Overweight/obese adults (n = 189) completed behavioral and self-reported measures of impulsivity at baseline of BWL and an ecological momentary assessment (EMA) protocol across the first two weeks of treatment to report on affective/physical states and instances of dietary lapses. Results indicated that baseline negative urgency, but not delay discounting or inhibitory control, was positively associated with overall lapse risk. Moderation analyses indicated that poorer inhibitory control strengthened the relation between momentary increases in stress and subsequent dietary lapse, and higher negative urgency strengthened the relation between increases in loneliness and dietary lapse. Negative urgency also moderated the impact of momentary hunger on subsequent dietary lapse risk in an unexpected direction, such that higher negative urgency weakened the relation between hunger and subsequent lapse. Results lend partial and tentative support for the moderating role of impulsivity on the relation between internal states and lapse likelihood. With replication, the development and testing of personalized treatment components based on baseline impulsivity level may be warranted. PMID- 29715503 TI - Repeated toluene exposure increases the excitability of layer 5 pyramidal neurons in the prefrontal cortex of adolescent rats. AB - Despite serious health effects, volatile industrial products containing toluene are deliberately inhaled for their psychoactive actions, mainly among adolescents and young adults. Chronic toluene inhalation induces multiple alterations at the cellular and behavioral level; however, modifications of neuronal networks associated with the reward system after repeated toluene exposure are not thoroughly characterized. Here we used whole-cell recordings to determine the effects of repeated exposure to toluene (1000, 4000 or 8000 ppm for 30 min, twice a day, for ten days) on the neurophysiological properties of prelimbic layer 5 pyramidal neurons of the medial prefrontal cortex (mPFC) in adolescent male Wistar rats. Neurons from animals repeatedly exposed to toluene showed a concentration-dependent increase in action potential firing discharge. This increase was related to a reduction of the small-conductance calcium-activated potassium current (after-hyperpolarization current, IAHP) that controls the firing frequency of neurons. Likewise, toluene altered the kinetics of the action potential. The hyperexcitability seen in toluene-exposed animals was also associated with an increase in the glutamatergic spontaneous synaptic activity converging on mPFC neurons. In summary, repeated toluene exposure enhances the excitability of prelimbic layer 5 pyramidal neurons of the mPFC in adolescent rats. PMID- 29715504 TI - The biology and evolution of the Dilp8-Lgr3 pathway: A relaxin-like pathway coupling tissue growth and developmental timing control. AB - Many insects, like cockroaches, moths, and flies, can regenerate tissues by extending the growth-competent phases of their life cycle. The molecular and cellular players mediating this coordination between tissue growth and developmental timing have been recently discovered in Drosophila. The insulin/relaxin-like peptide, Dilp8, was identified as a factor communicating abnormal growth status of Drosophila larval imaginal discs to the neuroendocrine centers that control the timing of the onset of metamorphosis. Dilp8 requires a neuronal relaxin receptor for this function, the Leucine rich repeat containing G protein coupled receptor, Lgr3. A review of current data supports a model where imaginal disc-derived Dilp8 acts on four central nervous system Lgr3-positive neurons to activate cyclic-AMP signaling in an Lgr3-dependent manner. This causes a reduction in ecdysone hormone production by the larval endocrine prothoracic gland, which leads to a delay in the onset of metamorphosis and a simultaneous slowing down in the growth rates of healthy imaginal tissues, promoting the generation of proportionate individuals. We discuss reports indicating that the Dilp8-Lgr3 pathway might have other functions at different life history stages, which remain to be elucidated, and review molecular evolution data on invertebrate genes related to the relaxin-pathway. The strong conservation of the relaxin pathway throughout animal evolution contrasts with instances of its complete loss in some clades, such as lepidopterans, which must coordinate growth and developmental timing using another mechanism. Research into these areas should generate exciting new insights into the biology of growth coordination, the evolution of the relaxin signaling pathway, and likely reveal unforeseen functions in other developmental stages. PMID- 29715506 TI - Similar bowtie structures and distinct largest strong components are identified in the transcriptional regulatory networks of Arabidopsis thaliana during photomorphogenesis and heat shock. AB - Photomorphogenesis and heat shock are critical biological processes of plants. A recent research constructed the transcriptional regulatory networks (TRNs) of Arabidopsis thaliana during these processes using DNase-seq. In this study, by strong decomposition, we revealed that each of these TRNs can be represented as a similar bowtie structure with only one non-trivial and distinct strong component. We further identified distinct patterns of variation of a few light-related genes in these bowtie structures during photomorphogenesis. These results suggest that bowtie structure may be a common property of TRNs of plants, and distinct variation patterns of genes in bowtie structures of TRNs during biological processes may reflect distinct functions. Overall, our study provides an insight into the molecular mechanisms underlying photomorphogenesis and heat shock, and emphasizes the necessity to investigate the strong connectivity structures while studying TRNs. PMID- 29715505 TI - The exceptional sensitivity of brain mitochondria to copper. AB - Wilson disease (WD) is characterized by a disrupted copper homeostasis resulting in dramatically increased copper levels, mainly in liver and brain. While copper damage to mitochondria is an established feature in WD livers, much less is known about such detrimental copper effects in other organs. We therefore assessed the mitochondrial sensitivity to copper in a tissue specific manner, namely of isolated rat liver, kidney, heart, and brain mitochondria. Brain mitochondria presented with exceptional copper sensitivity, as evidenced by a comparatively early membrane potential loss, profound structural changes already at low copper dose, and a dose-dependent reduced capacity to produce ATP. This sensitivity was likely due to a copper-dependent attack on free protein thiols and due to a decreased copper reactive defense system, as further evidenced in neuroblastoma SHSY5Y cells. In contrast, an increased production of reactive oxygen species was found to be a late-stage event, only occurring in destroyed mitochondria. We therefore propose mitochondrial protein thiols as major targets of mitochondrial copper toxicity. PMID- 29715507 TI - The mitochondrial effects of embelin are independent of its MAP kinase regulation: Role of p53 in conferring selectivity towards cancer cells. AB - Amongst various therapeutic properties of the natural product embelin, its anti cancer effects are being extensively studied. We observed that, embelin induced apoptosis in A549 cells lacking functional mitochondria (rho0 cells) indicating that its mitochondrial effects are not primarily responsible for its anti-cancer activity. However, p38 mediated activation of p53 was found to play a pivotal role in governing the apoptotic activity of embelin due to the following observations: a time-dependent activation of p53 and apoptosis by embelin; selective inhibition of p38 inhibited embelin-induced p53 levels. Overall, therapeutic strategies involving embelin and activators of p38 MAP kinase may improve the selective targeting of cancer cells. PMID- 29715508 TI - Gut metabolome meets microbiome: A methodological perspective to understand the relationship between host and microbe. AB - It is well established that gut microbes and their metabolic products regulate host metabolism. The interactions between the host and its gut microbiota are highly dynamic and complex. In this review we present and discuss the metabolomic strategies to study the gut microbial ecosystem. We highlight the metabolic profiling approaches to study faecal samples aimed at deciphering the metabolic product derived from gut microbiota. We also discuss how metabolomics data can be integrated with metagenomics data derived from gut microbiota and how such approaches may lead to better understanding of the microbial functions. Finally, the emerging approaches of genome-scale metabolic modelling to study microbial co metabolism and host-microbe interactions are highlighted. PMID- 29715509 TI - Relationship between knee joint contact forces and external knee joint moments in patients with medial knee osteoarthritis: effects of gait modifications. AB - OBJECTIVE: To evaluate 1) the relationship between the knee contact force (KCF) and knee adduction and flexion moments (KAM and KFM) during normal gait in people with medial knee osteoarthritis (KOA), 2) the effects on the KCF of walking with a modified gait pattern and 3) the relationship between changes in the KCF and changes in the knee moments. METHOD: We modeled the gait biomechanics of thirty five patients with medial KOA using the AnyBody Modeling System during normal gait and two modified gait patterns. We calculated the internal KCF and evaluated the external joint moments (KAM and KFM) against it using linear regression analyses. RESULTS: First peak medial KCF was associated with first peak KAM (R2 = 0.60) and with KAM and KFM (R2 = 0.73). Walking with both modified gait patterns reduced KAM (P = 0.002) and the medial to total KCF ratio (P < 0.001) at the first peak. Changes in KAM during modified gait were moderately associated with changes in the medial KCF at the first peak (R2 = 0.54 and 0.53). CONCLUSIONS: At the first peak, KAM is a reasonable substitute for the medial contact force, but not at the second peak. First peak KFM is also a significant contributor to the medial KCF. At the first peak, walking with a modified gait reduced the ratio of the medial to total KCF but not the medial KCF itself. To determine the effects of gait modifications on cartilage loading and disease progression, longitudinal studies and individualized modeling, accounting for motion control, would be required. PMID- 29715510 TI - Hierarchical Organization Within the Ventral Premotor Cortex of the Macaque Monkey. AB - Recent studies have revealed that the ventral premotor cortex (PMv) of nonhuman primates plays a pivotal role in various behaviors that require the transformation of sensory cues to appropriate actions. Examples include decision making based on various sensory cues, preparation for upcoming motor behavior, adaptive sensorimotor transformation, and the generation of motor commands using rapid sensory feedback. Although the PMv has frequently been regarded as a single entity, it can be divided into at least five functionally distinct regions: F4, a dorsal convexity region immediately rostral to the primary motor cortex (M1); F5p, a cortical region immediately rostral to F4, lying within the arcuate sulcus; F5c, a ventral convexity region rostral to F4; and F5a, located in the caudal bank of the arcuate sulcus inferior limb lateral to F5p. Among these, F4 can be further divided into dorsal and ventral subregions (F4d and F4v), which are involved in forelimb and orofacial movements, respectively. F5p contains "mirror neurons" to understand others' actions based on visual and other types of information, and F4d and F5p work together as a functional complex involved in controlling forelimb and eye movements, most efficiently in the execution and completion of coordinated eye-hand movements for reaching and grasping under visual guidance. In contrast, F5c and F5a are hierarchically higher than the F4d, F5p, and F5v complexes, and play a role in decision-making based on various sensory discriminations. Hence, the PMv subregions form a hierarchically organized integral system from decision-making to eye-hand coordination under various behavioral circumstances. PMID- 29715511 TI - Increased Neuroligin 2 Levels in the Postsynaptic Membrane in Spinal Dorsal Horn may Contribute to Postoperative Pain. AB - Neuroligin 2 is a synaptic cell adhesion molecule that is mainly located in inhibitory synapses and is crucial in the regulation of synapse function through protein-protein interactions. However, researchers have not clearly determined whether neuroligin 2 is involved in the development of postoperative pain. In the current study, Western blot, immunofluorescence staining and co immunoprecipitation were used to examine the critical role of neuroligin 2 in postoperative pain hypersensitivity. A small interfering ribonucleic acid (siRNA) targeting neuroligin 2 was used to inhibit neuroligin 2 expression. Our data found that plantar incision induced postoperative pain hypersensitivity, which was characterized by paw withdrawal threshold and cumulative pain score. The upregulation of neuroligin 2 and GluR1 expression in the postsynaptic membranes of ipsilateral spinal dorsal horn was observed at 3 h and 1 day after plantar incision. Additionally, at 3 h after plantar incision, the amount of PSD-95 that was co-immunoprecipitated with neuroligin 2 antibody was significantly increased in the ipsilateral dorsal horn, as compared to that of the control group. Intrathecal pretreatment of siRNA-targeting neuroligin 2 to reduce the neuroligin 2 expression in the spinal cord significantly inhibited the pain hypersensitivity and reduced the synaptic targeting of GluR1 in ipsilateral dorsal horns. Our study indicates that the incision-induced interaction between neuroligin 2 and PSD-95 and subsequent synaptic targeting of GluR1 in ipsilateral dorsal horns contribute to postoperative pain hypersensitivity. PMID- 29715512 TI - HMGB1 contributes to adriamycin-induced cardiotoxicity via up-regulating autophagy. AB - Adriamycin (ADR) is one of the most widely used and effective anthracycline antitumor agents in the treatment of certain hematological malignancies and solid tumors. However, the severe cardiotoxicity of ADR limits its clinical application. So far, the mechanism of the cardiotoxicity of ADR has not been completely clarified. In our research, cardiomyocyte autophagy and cardiac damage were observed in accompany ADR treatment, and autophagy appeared earlier than cardiac damage. Inhibition of autophagy by silencing ATG7 improved the survival rate of cardiomyocytes treated with ADR. The release of HMGB1 increased after ADR treatment, and silencing HMGB1 could reverse cardiomyocyte damage by attenuating autophagy. In addition, the expression of YAP was decreased, and overexpressing YAP down-regulated HMGB1 and alleviated cardiomyocyte damage. These results indicated that autophagy was the leading cause of ADR-induced cardiotoxicity, and HMGB1 played a vital role in the process of up-regulating autophagy. PMID- 29715513 TI - Characterization of superparamagnetic iron oxide nanoparticle-induced apoptosis in PC12 cells and mouse hippocampus and striatum. AB - Superparamagnetic iron oxide nanoparticles (SPIONs) have been widely used as theranostic drug-carrier and MRI contrast agent. Their potential effects are still in blank while SPIONs are used for brain. The present study aims to investigate SPIONs' neurotoxicity in vitro and in vivo using stereotaxic technique. By co-incubating SPIONs with dopaminergic neuronal PC12 cells, we found that SPIONs had a dose-dependent cytotoxic in PC12 cells at 60-200 ug/mL but not at 10-50 ug/mL, it reduced cell viability, decreased the capacity of PC12 cells to extend neurites in response to nerve growth factor (NGF), induced a reduction of the tyrosine hydroxylase protein, while increasing PC12 cell apoptosis. Accordingly, the no-observed-adverse-effect level (NOAEL) of current SPIONs was 50 ug/mL in vitro, which would be useful for human health risk assessment. While directly injecting the SPIONs into the dorsal striatum or hippocampus, 7 and 14 days after surgery, nanoparticles decreased the TH+ fiber density in both the dorsal striatum and the hippocampus. A behavioral evaluation demonstrated that SPIONs attenuated the animals' motor coordination and spatial memory, as evaluated by the rotarod test and the Morris water maze. We further examined mitogen-activated protein kinase (MAPK) activation and found that c-Jun N-terminal kinase (JNK) was activated after SPIONs treatment. It suggests that the SPIONs-induced neurotoxicity might be mediated through the JNK signaling pathway. SPIONs could possibly induce neurotoxic effects on the dorsal striatum and hippocampus. PMID- 29715514 TI - Up-regulated miR-29c inhibits cell proliferation and glycolysis by inhibiting SLC2A3 expression in prostate cancer. AB - Prostate cancer (PCa) is the most commonly cancer in male worldwide. However, the molecular mechanisms underlying the progression of PCa remain unclear. MiR-29c was reported to be down-regulated in several kinds of tumors. Here, we for the first time demonstrated miR-29c was down-regulated in PCa samples. SLC2A3, a regulator of glycolysis, was validated as a direct target of miR-29c. Moreover, functional studies showed miR-29c could inhibit cell growth, induce apoptosis and deceased the rate of glucose metabolism. Accordingly, we identified miR-29c acted as a tumor-suppressor and was down-regulated in PCa. We thought this study will provide useful information to explore the potential candidate biomarkers for diagnosis and prognosis targets of PCa. PMID- 29715515 TI - Contribution of microRNA-149, microRNA-146a, and microRNA-196a2 SNPs in colorectal cancer risk and clinicopathological features in Tunisia. AB - BACKGROUND AND AIM: Colorectal cancer (CRC) is a worldwide leading cause of mortality. Genetic studies have associated single nucleotide polymorphisms in genes encoding microRNAs with CRC risk but results are mostly inconclusive across variable ethnicities. In this study, we investigated the association of hsa-mir 149 rs2292832 C/T, hsa-mir-146a rs2910164 G/C and hsa-mir-196a2 rs11614913 C/T and explored their roles in clinicopathological features of CRC progression in an Eastern Tunisian cohort. SUBJECTS AND METHODS: Three hundred thirteen subjects were enrolled in our retrospective study including 152 CRC cases and 161 controls. Genotyping was assayed by RFLP-PCR (Restriction Fragment Length Polymorphism-Polymerase Chain Reaction) method. SPSS v.18.0, R and SNP Stats online software performed statistical analysis. RESULTS: Significantly higher hsa mir-149C/T rs2292832 minor allele frequency was associated with increased risk of CRC [p = .03; OR = 1.54 (1.08-2.19)]. In addition, significant crude associations of hsa-mir-149C/T rs2292832 polymorphism were detected under codominant, dominant and additive models of inheritance. After adjusting for covariates and performing FDR correction, these associations did not remain. No associations were detected for hsa-mir-146a G/C rs2910164 and hsa-mir-196a2 C/T rs11614913. When performing stratified analysis of clinicopathological features according to genotypes, a significant association (p = .004) was found between hsa-mir-146a G/C rs2910164 and tumour differentiation grade. Regression analysis according to CRC progression features had demonstrated a trend toward significance in overdominant model of inheritance for hsa-mir-149C/T rs2292832 with a protective effect [p = .05; OR = 0.51 (0.26-1.02)]. CONCLUSION: Hsa-mir-149C/T rs2292832 and hsa-mir 146a G/C rs2910164 may influence CRC risk in an ethnicity-dependent manner by interfering with CRC progression parameters in Tunisian cohort. PMID- 29715516 TI - Predicting vasovagal syncope from heart rate and blood pressure: A prospective study in 140 subjects. AB - BACKGROUND: We developed a vasovagal syncope (VVS) prediction algorithm for use during head-up tilt with simultaneous analysis of heart rate (HR) and systolic blood pressure (SBP). We previously tested this algorithm retrospectively in 1155 subjects, showing sensitivity 95%, specificity 93%, and median prediction time 59 seconds. OBJECTIVE: The purpose of this prospective, single-center study of 140 subjects was to evaluate this VVS prediction algorithm and to assess whether retrospective results were reproduced and clinically relevant. The primary endpoint was VVS prediction: sensitivity and specificity >80%. METHODS: In subjects referred for 60 degrees head-up tilt (Italian protocol), noninvasive HR and SBP were supplied to the VVS prediction algorithm: simultaneous analysis of RR intervals, SBP trends, and their variability represented by low-frequency power-generated cumulative risk, which was compared with a predetermined VVS risk threshold. When cumulative risk exceeded threshold, an alert was generated. Prediction time was duration between first alert and syncope. RESULTS: Of the 140 subjects enrolled, data were usable for 134. Of 83 tilt-positive subjects (61.9%), 81 VVS events were correctly predicted by the algorithm, and of 51 tilt negative subjects (38.1%), 45 were correctly identified as negative by the algorithm. Resulting algorithm performance was sensitivity 97.6% and specificity 88.2%, meeting the primary endpoint. Mean VVS prediction time was 2 minutes 26 seconds +/- 3 minutes 16 seconds (median 1 minute 25 seconds). Using only HR and HR variability (without SBP), mean prediction time reduced to 1 minute 34 seconds +/- 1 minute 45 seconds (median 1 minute 13 seconds). CONCLUSION: The VVS prediction algorithm is a clinically relevant tool and could offer applications, including providing a patient alarm, shortening tilt-test time, and triggering pacing intervention in implantable devices. PMID- 29715517 TI - Biosynthesis of D-glucaric acid from sucrose with routed carbon distribution in metabolically engineered Escherichia coli. AB - D-glucaric acid is a promising platform compound used to synthesize many other value-added or commodity chemicals. The engineering of Escherichia coli for efficiently converting D-glucose to D-glucaric acid has been attempted for several years, with mixed sugar fermentation recently gaining growing interests due to the increased D-glucaric acid yield. Here, we co-expressed cscB, cscA, cscK, ino1, miox, udh, and suhB in E. coli BL21 (DE3), functionally constructing an unreported route from sucrose to D-glucaric acid. Further deletion of chromosomal zwf, pgi, ptsG, uxaC, gudD, over-expression of glk, and use of a D fructose-dependent translation control system for pgi enabled the strain to use sucrose as the sole carbon source while achieving a high product titer and yield. The titer of D-glucaric acid in M9 medium containing 10 g/L sucrose reached ~1.42 g/L, with a yield of ~0.142 g/g on sucrose. PMID- 29715518 TI - Methacholine induces extracellular matrix production by human airway smooth muscle cells through beta-catenin signaling. AB - Altered extracellular matrix (ECM) production by airway smooth muscle cells (ASMCs) is an important feature of airway remodeling. Muscarinic receptor agonists contribute to ECM production in vivo, but the mechanisms involved remain unclear. This study attempted to investigate the role of methacholine in promoting ECM production by human ASMCs (HASMCs) and the underlying mechanism. We found that methacholine induced the expression of collagen I protein and multiple ECM genes. beta-catenin signaling was activated in this process upon GSK3beta phosphorylation, leading to upregulation of total and active beta-catenin. Silencing beta-catenin by specific small interfering RNA (siRNA) or with the beta catenin inhibitor, PKF115-584, decreased collagen I expression. Conversely, overexpression of active beta-catenin by adenoviruses carrying the S33Y-beta catenin mutant increased the methacholine-induced collagen I expression. Furthermore, methacholine induced TGF-beta expression in HASMCs, while pan-TGF beta-neutralizing antibody only partially decreased collagen I expression. These findings suggest that methacholine induced ECM production through beta-catenin signaling and partially through TGF-beta. PMID- 29715519 TI - Oxidative Stress Contributes to Fracture/Cast-Induced Inflammation and Pain in a Rat Model of Complex Regional Pain Syndrome. AB - : Clinical evidence suggests that vitamin C (Vit C) may protect against the development of complex regional pain syndrome (CRPS) after fracture or surgery. Tibia fracture followed by 4 weeks of cast immobilization (fracture/cast) in rats results in nociceptive, vascular, and bone changes resembling clinical CRPS. In this study, fracture/cast rats were treated with the oxidative stress inhibitors Vit C, N-acetyl cysteine, or 4-hydroxy-2,2,6,6-tetramethylpiperidin-1-oxyl to examine their effects on CRPS-related nociceptive and vascular changes. Administration of these agents significantly reduced fracture/cast-induced cutaneous allodynia by 64 to 78%, muscle hyperalgesia by 34 to 40%, and hind limb unweighting by 48 to 89%. Treatments with Vit C and N-acetyl cysteine reduced the oxidative stress markers malondialdehyde in the skin, muscle, and sciatic nerve, and lactate in the gastrocnemius muscle of the fracture/cast limb. Furthermore, Vit C treatment inhibited the post-fracture upregulation of substance P and calcitonin gene-related peptide in the sciatic nerve and the increased expression of the pain-related inflammatory mediators, including interleukin (IL)-6, and nerve growth factor in the skin and IL-1beta, and IL-6 in the muscle of the post fracture/cast limb. These data suggest that oxidative stress may contribute to the nociceptive features of the rat CRPS model. PERSPECTIVE: Vit C reduced the CRPS-like signs, oxidative stress, and the upregulation of neuropeptide production and inflammatory mediators observed after tibia fracture and casting in rats. Limiting oxidative stress by use of Vit C or alternative strategies could reduce the risk of developing CRPS after surgery or other forms of trauma. PMID- 29715520 TI - "I Was a Little Surprised": Qualitative Insights From Patients Enrolled in a 12 Month Trial Comparing Opioids With Nonopioid Medications for Chronic Musculoskeletal Pain. AB - : Chronic musculoskeletal pain is a major public health problem. Although opioid prescribing for chronic pain has increased dramatically since the 1990s, this practice has come under scrutiny because of increases in opioid-related harms and lack of evidence for long-term effectiveness. The Strategies for Prescribing Analgesics Comparative Effectiveness (SPACE) trial was a pragmatic 12-month randomized trial comparing the benefits and harms of opioid versus nonopioid medications for chronic musculoskeletal pain. The current qualitative study was designed to better understand trial results by exploring patients' experiences, including perceptions of medications, experiences with the intervention, and whether expectations were met. Thirty-four participants who were purposefully sampled based on treatment group and intervention response participated in semistructured interviews. The constant comparison method guided analysis. Results revealed that participants often held strong beliefs about opioid medications, which sometimes changed during the trial as they gained experience with medications; participants described a wide variety of experiences with treatment effectiveness, regardless of study group or their response to the intervention; and participants highly valued the personalized pain care model used in SPACE. PERSPECTIVE: SPACE trial results indicated no advantage for opioid over nonopioid medications. Qualitative findings suggest that, for both treatment groups, preexisting expectations and anticipated improvement in pain shaped experiences with and responses to medications. The personalized pain care model was described as contributing to positive outcomes in both groups. PMID- 29715521 TI - How should a fixed budget of dwell time be spent in scanning electron microscopy to optimize image quality? AB - In scanning electron microscopy, the achievable image quality is often limited by a maximum feasible acquisition time per dataset. Particularly with regard to three-dimensional or large field-of-view imaging, a compromise must be found between a high amount of shot noise, which leads to a low signal-to-noise ratio, and excessive acquisition times. Assuming a fixed acquisition time per frame, we compared three different strategies for algorithm-assisted image acquisition in scanning electron microscopy. We evaluated (1) raster scanning with a reduced dwell time per pixel followed by a state-of-the-art Denoising algorithm, (2) raster scanning with a decreased resolution in conjunction with a state-of-the art Super Resolution algorithm, and (3) a sparse scanning approach where a fixed percentage of pixels is visited by the beam in combination with state-of-the-art inpainting algorithms. Additionally, we considered increased beam currents for each of the strategies. The experiments showed that sparse scanning using an appropriate reconstruction technique was superior to the other strategies. PMID- 29715523 TI - Muscle morphology and performance in master athletes: A systematic review and meta-analyses. AB - INTRODUCTION: The extent to which chronic exercise training preserves age-related decrements in physical function, muscle strength, mass and morphology is unclear. Our aim was to conduct a systematic review of the literature to determine to what extent chronically trained master athletes (strength/power and endurance) preserve levels of physical function, muscle strength, muscle mass and morphology in older age, compared with older and younger controls and young trained individuals. METHODS: The systematic data search included Medline, EMBASE, SPORTDiscus, CINAHL and Web of Science databases. INCLUSION CRITERIA: i) master athletes mean exercise training duration >=20 years ii) master athletes mean age of cohort >59 years) iii) at least one measurement of muscle mass/volume/fibre type morphology and/or strength/physical function. RESULTS: Fifty-five eligible studies were identified. Meta-analyses were carried out on maximal aerobic capacity, maximal voluntary contraction and body composition. Master endurance athletes (42.0 +/- 6.6 ml kg-1 min-1) exhibited VO2max values comparable with young healthy controls (43.1 +/- 6.8 ml kg-1 min-1, P = .84), greater than older controls (27.1 +/- 4.3 ml kg-1 min-1, P < 0.01) and master strength/power athletes (26.5 +/- 2.3 mlkg-1 min-1, P < 0.01), and lower than young endurance trained individuals (60.0 +/- 5.4 ml kg-1 min-1, P < 0.01). Master strength/power athletes (0.60 (0.28-0.93) P < 0.01) and young controls (0.71 (0.06-1.36) P < 0.05) were significantly stronger compared with the other groups. Body fat% was greater in master endurance athletes than young endurance trained (-4.44% (-8.44 to -0.43) P < 0.05) but lower compared with older controls (7.11% (5.70-8.52) P < 0.01). CONCLUSION: Despite advancing age, this review suggests that chronic exercise training preserves physical function, muscular strength and body fat levels similar to that of young, healthy individuals in an exercise mode-specific manner. PMID- 29715524 TI - New zonal structure and transition of the membrane to mammillae in the eggshell of chicken Gallus domesticus. AB - Avian eggshell is a typical bio-engineered ceramics characterized by layer structures. These layers are categorized mainly by the form of crystalline calcite. Whether there exist other layer structures, how the membrane layer is transformed to the carbonate one, what form the carbonate takes after the transition. These questions remain to be clarified. Here we examine the eggshell of chicken Gallus domesticus by optical microscope, scanning electron microscope and transmission electron microscope. We find that there exists another layer structure defined by variation of organic matrices. The transition from the membrane to the mammillary cones is implemented through the calcium reserve assemblies or the mammillary cores. The integrity of the transitional structure was weakens as the reserved calcium is displaced, and loses completely in about 10 days of incubation. As the first deposited carbonate layer after the transition, the mammillary cones comprise amorphous calcium carbonate and clusters/assemblies of calcite crystallites the size about a nanometer, plus bubble pores extending preferentially in the lateral direction. Our results provide new insights into the structure and component of the avian eggshell, and may help decipher the constitution of the bio-ceramics in the perspective of material science. PMID- 29715522 TI - YTH Domain: A Family of N6-methyladenosine (m6A) Readers. AB - Like protein and DNA, different types of RNA molecules undergo various modifications. Accumulating evidence suggests that these RNA modifications serve as sophisticated codes to mediate RNA behaviors and many important biological functions. N6-methyladenosine (m6A) is the most abundant internal RNA modification found in a variety of eukaryotic RNAs, including but not limited to mRNAs, tRNAs, rRNAs, and long non-coding RNAs (lncRNAs). In mammalian cells, m6A can be incorporated by a methyltransferase complex and removed by demethylases, which ensures that the m6A modification is reversible and dynamic. Moreover, m6A is recognized by the YT521-B homology (YTH) domain-containing proteins, which subsequently direct different complexes to regulate RNA signaling pathways, such as RNA metabolism, RNA splicing, RNA folding, and protein translation. Herein, we summarize the recent progresses made in understanding the molecular mechanisms underlying the m6A recognition by YTH domain-containing proteins, which would shed new light on m6A-specific recognition and provide clues to the future identification of reader proteins of many other RNA modifications. PMID- 29715525 TI - Cell division control in Caulobacter crescentus. AB - Caulobacter crescentus is a free-living Alphaproteobacterium that thrives in oligotrophic environments. This review focuses on the regulatory network used by this bacterium to control the levels of cell division proteins, their organization inside the cell and their activity as a function of the cell cycle. Strikingly, C. crescentus makes frequent use of master transcriptional regulators and epigenetic signals, most likely to synchronize cell division with other events of the cell cycle. In addition, cellular metabolism and DNA damage sensors emerge as central players regulating cell division in response to changing environmental conditions. PMID- 29715526 TI - Innate immune gene polymorphisms and their association with neonatal sepsis. PMID- 29715527 TI - Correlation of CD81 and SCARB1 polymorphisms on virological responses in Iranian patients with chronic hepatitis C virus genotype 1. AB - The cluster of differentiation 81 (CD81) and scavenger receptor class B member 1 (SCARB1) plays an important role in the entry of hepatitis C virus (HCV). We assessed the correlation of five single nucleotide polymorphisms (SNPs) of CD81 (rs800136, rs2651842, rs2522012, rs800146, and rs708564) and SCARB1 rs10846744 polymorphisms with treatment responses in 395 treatment-naive patients with chronic HCV (CHC) genotype 1 treated with pegylated interferon-alpha and ribavirin (pegIFN-alpha/RBV). The frequency of rapid virologic response (RVR), complete early virologic response (cEVR) and sustained virologic response (SVR) were 57.2%, 55.2%, and 58.2%, respectively. RVR, cEVR, and SVR were significantly associated with CD81 rs800136 (CC), CD81 rs2651842 (AA), CD81 rs708564 (TT), and SCARB1 rs10846744 (CC). High rates of RVR, cEVR, and SVR were reported for the CD81 rs800136 (CC), CD81 rs2651842 (AA), and CD81 rs708564 (TT) genotypes when correlated with higher levels of low-density lipoprotein (LDL) and lower levels of high-density lipoprotein (HDL) as well as lower levels of HDL and LDL in the SCARB1 rs10846744 (CC) genotype. In addition, patients with GG genotype had higher fasting blood glucose (FBS) level than those with CC genotype. In conclusion, CD81 and SCARB1 SNPs may serve as powerful predictor factors for treatment responses in CHC patients, and this effect is correlated with serum lipoprotein and FBS levels. PMID- 29715528 TI - Functional analysis of duck, goose, and ostrich 2'-5'-oligoadenylate synthetase. AB - Up-to-date the flavivirus infection in avian taxa is not clearly defined. Several reports have demonstrated that many viruses belonging to Flaviviridae may cause diseases in poultry species; however, the susceptibility of other avian species is variable and still unclear. In human and mice, the 2'-5'-oligoadenylate synthetase (OAS) proteins are associated with resistance to the flavivirus infection as well as other virus infections. However, the avian OAS proteins are rarely studied. In our previous studies, we confirmed that the chicken OAS-like protein (chOASL) expressed OAS-enzymatic activity (the classical OAS/RNase L dependent pathway) as well as the anti-flavivirus activity (the putative OAS/RNase L-independent pathway). Therefore, the current study aimed at functional analysis of avian OAS proteins from duck, goose, and ostrich. The duOASL, goOASL, and osOAS1 proteins expressed enzymatic activity as well as chOASL, whereas osOASL expressed little enzymatic activity. On the other hand, duOASL, goOASL, and osOASL possessed significant antiviral activity against West Nile virus (WNV)-replicon replication as well as chOASL, whereas osOAS1 did not. In addition, similar to chOASL, their antiviral activity was independent of RNase L activation. These results suggest that OASL is the only OAS protein in the duck and goose as well as chicken and possesses both OAS-enzymatic and anti-flavivirus activities, whereas the ostrich possesses both OAS1 and OASL proteins with sharing the functional activities, OAS-enzymatic and anti-flavivirus activities, respectively. It is of interest that the ostrich undergoes differential process in OAS gene evolution from other poultries and thus possesses different molecular mechanism in antiviral activity. PMID- 29715529 TI - Mediators of two selective prevention interventions targeting both obesity and eating disorders. AB - The present study tested hypothesized mechanisms underlying the effects of two selective prevention interventions targeting both obesity and eating disorders (Healthy Weight and the newly developed Project Health), relative to video control. Tests examined mediation for the significant weight gain prevention and eating disorder symptom prevention effects previously reported. College students (N = 364; 72% women) with weight concerns were randomized to condition and assessed for 2-years post-intervention. Project Health participants had significant improvements in 2 of the 7 proposed mediators relative to comparisons (i.e., cognitive dissonance, the unhealthy Western dietary pattern) but change in these variables did not mediate its effect on long-term BMI change. Two variables emerged as full mediators of the eating disorder prevention effects for both experimental interventions: body dissatisfaction and negative affect. Analyses failed to support the exploratory hypothesis that change in eating disorder symptoms mediated the effects of condition on BMI gain. This report is the among the first to examine mediation for programs aimed at preventing both weight gain and eating disorders, particularly in mixed-gender groups. Mediational analyses are essential in identifying the mechanism of intervention action, which can inform improvements to prevention programs. PMID- 29715530 TI - Characterizing the corticomotor connectivity of the bilateral ankle muscles during rest and isometric contraction in healthy adults. AB - The investigation of the corticomotor connectivity (CMC) to leg muscles is an emerging research area, and establishing reliability of measures is critical. This study examined the measurement reliability and the differences between bilateral soleus (SOL) and tibialis anterior (TA) CMC in 21 neurologically intact adults. Using single pulse transcranial magnetic stimulation (TMS), each muscle's CMC was assessed twice (7 +/- 2 days apart) during rest and active conditions. CMC was quantified using a standardized battery of eight measures (4/condition): motor threshold during resting (RMT), motor evoked potential amplitude and latency (raw and normalized to height) in both conditions, contralateral silent period (CSP) during active. Using two reliability metrics (intraclass correlation coefficient and coefficient of variation of method error; good reliability: >=0.75 and <=15, respectively) and repeated-measures ANOVA, we investigated the reliability and Muscle X Body Side interaction. For both muscles, RMT, resting raw and normalized latencies, and active raw latency demonstrated good reliability, while CSP had good reliability only for TA. Amplitude did not demonstrate good reliability for both muscles. SOL CMC was significantly different from TA CMC for all measures but CSP; body side had no significant effect. Therefore, only certain measures may reliably quantify SOL and TA CMC while different CMC (except CSP) between SOL and TA suggests dissimilar corticospinal drive to each muscle regardless of the side. PMID- 29715531 TI - Honokiol nanoparticles based on epigallocatechin gallate functionalized chitin to enhance therapeutic effects against liver cancer. AB - This study aims to design a novel nano-sized anticancer drug delivery system that can enhance the therapeutic effects of the loaded drug. With this idea in mind, this work reported the design and characterization of epigallocatechin-3-gallate (EGCG) functionalized chitin (CH) derivative, and its application in nano-drug delivery system. The EGCG-functionalized CH (CE) polymer was firstly prepared and characterized. The nanoparticles (NPs) of CE-loaded honokiol (HK), which was prepared by ionic crosslinking, exhibited a size of 80 nm, zeta potential of +33.8 mV, and spherical morphology. The antitumor activity of the CE-HK NPs in vitro and in vivo was investigated and compared to free HK. As a result, the CE HK NPs can effectively inhibited cell proliferation of HepG2 cell by inhibiting more cells in the G2/M phase and decreasing mitochondrial membrane potential. The CE-HK NPs (40 mg/kg) inhibited tumor growth by 83.55% (p < 0.05), which was far higher than the 30.15% inhibition of free HK (40 mg/kg). The proposed delivery system exhibits better tumor selectivity and growth reduction both in vitro and in vivo, and does not induce any side effects. Therefore, the CE-HK NPs may act as an effective delivery system of liver cancer agent HK. PMID- 29715532 TI - Receptor-mediated PLGA nanoparticles for glioblastoma multiforme treatment. AB - Glioblastoma multiforme is the most lethal type of brain tumor and the established therapy only extends patients survival to approximately one year. Its first-line treatment is based on of chemotherapy with the alkylating agent temozolomide (TMZ). As many other chemotherapeutic drugs, TMZ presents several limitations as high toxicity and low bioavailability. The delivery of TMZ using poly(lactic-co-glycolic acid) nanoparticles is proposed in this work. Stable nanoparticles functionalized with a OX26 type monoclonal antibody for transferrin receptor were developed, targeting the glioblastoma tumor cells, since these cells are known for overexpressing this receptor. The release profile of TMZ from the nanoparticles was studied mimicking physiological conditions, and targeted cellular internalization was also investigated. Two glioblastoma cell lines - U215 and U87 - were used to evaluate the in vitro cytotoxicity of the drug, showing that the prepared nanocarriers enhance the anticancer activity of TMZ. The functionalization with the monoclonal antibody for transferrin receptor proved to be advantageous in enhancing the cellular internalization in glioblastoma cells. PMID- 29715533 TI - Lycopene loaded whey protein isolate nanoparticles: An innovative endeavor for enhanced bioavailability of lycopene and anti-cancer activity. AB - The work entails a novel strategy of formulating the lycopene loaded whey protein isolate nanoparticles (LYC-WPI-NPs) solely using the rational blend of biomacromolecule without using equipment-intensive techniques. The LYC-WPI-NPs were fabricated as a substantial drug delivery platform, with maximum entrapment, spatial and controlled release manners, exceptional plasma concentration, and perspective for discrepancy delivery of therapeutics. Prepared nano-formulations were measured in ultra-fine size (100-350 nm) with sphere-shaped. The percent lycopene entrapment of prepared LYC-WPI-NPs was estimated in the range to 50 and 65%. In vitro percent cumulative release study demonstrated deaden and extended release i.e. approximately 75% following 16th h. The in vitro percent cell survival (cytotoxicity study) of prepared nanoparticles was evaluated against MCF 7 breast cancer cells by MTT based colorimetric assay. Sub-cellular localization of lycopene when delivered by LYC-WPI-NPs was assessed by HPLC (high performance liquid chromatography). The WPI-NPs enhance the oral bioavailability of lycopene by controlling its release from nano-formulation and facilitating its absorption through lymphatic pathways. Prophylactic anticancer efficacy of LYC-WPI-NPs was evaluated thereafter on experimentally induced breast cancer animal model. Conclusively, it may quite reasonable that lycopene loaded protein nanoparticles are competent to improve the biopharmaceutical attributes of lycopene and demonstrated prophylactic anticancer activity, decrease tumor proliferation and increase the survival rate of treated animals, thus signifying their feasible usefulness in cancer therapeutic and intervention. PMID- 29715534 TI - microRNA-107 inhibits gastric cancer cell proliferation and metastasis by targeting PI3K/AKT pathway. AB - The present study was aimed to investigate the effect of miR-107 transfection on gastric cancer cell growth. Results from qRT-PCR revealed that level of miR-107 in SGC-7901 and MKN1 cell lines was down-regulated in comparison to the normal cells, GES-1. CCK-8 assay revealed a significant reduction in the proliferation of SGC-7901 cells on transfection with miR-107. The tumor growth was very slow in the mice implanted with SGC-7901/miR-107 compared to those bearing SGC-7901/miR NC. In SGC-7901 cells metastasis potential after miR-107 transfection was examined using wound-healing and Transwell invasion assays. The migration as well as invasion potential of SGC-7901 cells was significantly lower on transfection with miR-107. The activity of luciferase was reduced markedly in SGC-7901 cells co-transfected with miR-107 mimic compared to miR-NC. However, miR-107 mimic co transfection did not affect the luciferase activity in SGC-7901 cells bearing mutant-type BDNF 3'UTR. Western blot assay showed that miR-107 overexpression causes inhibition of BDNF mRNA and protein expression in SGC-7901 cells. The CCK8 assay showed that pBDNF transfection prevented miR-107 mediated inhibition of SGC 7901 cell proliferation. miR-107 mimic transfection inhibited expression of BDNF and activation of PI3K (p-PI3K) and AKT (p-AKT) in SGC-7901 cells. In order to confirm whether activation of PI3K and AKT by miR-107 mimic involves inhibition of BDNF, the cells were co-transfected with si-BDNF. The results revealed that si BDNF transfection led to inhibition of BDNF expression and PI3K and AKT activation in SGC-7901 cells. In summary, the present study demonstrates that miR 107 expression inhibits proliferation and metastasis in gastric cancer cells. Therefore, miR-107 acts as tumor inhibitor for gastric cancer through targeting BDNF expression. Thus miR-107 can be used for treatment of gastric cancer. PMID- 29715535 TI - Plant nutraceuticals (Quercetrin and Afzelin) capped silver nanoparticles exert potent antibiofilm effect against food borne pathogen Salmonella enterica serovar Typhi and curtail planktonic growth in zebrafish infection model. AB - Purified plant nutraceuticals afzelin and quercetrin from an edible plant- Crotolaria tetragona was employed for the fabrication of silver nanoparticles (AgNPs) by a sunlight mediated process. From among a panel of strains tested, AgNPs displayed potent bacteriostatic and bactericidal effect against P. aeruginosa and S. Typhi. Time kill studies revealed green synthesized AgNPs displayed comparable bactericidal effect with chemically synthesized AgNPs against S. Typhi. Antibiofilm potential of AgNPs showed that they were highly effective at sub MIC concentrations in causing 50% biofilm inhibition against food borne pathogen S. Typhi implying that antibiofilm effect is independent of antibacterial effect, which was evidenced by fluorescent imaging and SEM imaging. Mechanistic studies revealed that reduced cell surface hydrophobicity, decreased surface adherence, loss of membrane potential contributed to antibiofilm potential of afzelin/quercetrin AgNPs. Green synthesized afzelin/quercetrin AgNPs were also relatively less toxic and more effective in curtailing bioburden of S. Typhi in infected zebrafish by > 3 log fold. Ability of sunlight reduced afzelin/quercetrin NPs to mitigate planktonic mode of growth in vitro and in vivo and curtail biofilm formation of S. Typhi in vitro demonstrates its potential to curtail food borne pathogen in planktonic and biofilm mode of growth. PMID- 29715536 TI - Evaluation of Caco-2 cells response to Listeria monocytogenes virulence factors by RT-PCR. AB - Listeria monocytogenes expresses various virulence factors enabling the invasion and multiplying in host cells, and together induces cytokines transcription. In order to explore the relationship between virulence factors of L. monocytogenes wild-type EGD-e and cellular response in human colonic epithelial cell line(Caco 2), we constructed mutant strains with in-frame deletions of critical virulence genes of inlA, inlB, hly, actA and virulence regulatory factor prfA from EGD-e, respectively. Compared with EGD-e, mutant strains showed significantly decreased invasion and apoptosis in Caco-2 cells. However, mutant strains were capable to evoke cytokines transcription of interleukin-8 (IL-8), mononuclear chemoattractant protein-1 (MCP-1), tumor necrosis factor-a (TNF-a), interleukin 1beta (IL-1beta), interleukin-6 (IL-6) and CXCL-2 production in Caco-2 cells. Interestingly, EGD-e Deltahly-infected Caco-2 cells showed a significant decrease of IL-6, IL-8 and MCP-1 transcription compared with EGD-e at 1 h post-infection. Simultaneously, EGD-e DeltainlB-infected cells showed a decrease in IL-6 transcription, while EGD-e DeltaactA-infected cells reflected a decrease in MCP-1 transcription. Virulence genes play a role in inflammatory transcription, but the interaction between pathogenic bacteria and the host cells predominates in inflammatory transcription. Overall, the data showed cellular response of Caco-2 cells infected with EGD-e mutant strains. PMID- 29715537 TI - Resveratrol prevents cognitive deficits induced by chronic unpredictable mild stress: Sirt1/miR-134 signalling pathway regulates CREB/BDNF expression in hippocampus in vivo and in vitro. AB - Chronic unpredictable mild stress (CUMS) leads to neuropsychiatric disorders, such as depression, anxiety and cognitive impairment. Resveratrol is a natural polyphenol existed in polygonum cuspidatum and has been demonstrated to be a potent activator of Sirtuin 1 (Sirt1). Previous studies reported that resveratrol treatment ameliorated CUMS-induced depressive-like behavior and cognitive deficits through upregulating cAMP response element-binding protein (CREB) and brain derived neurotrophic factor (BDNF) expression. However, the upstream signalling pathway mediating CREB/BDNF expression and then exerting a protective role on cognitive function remains unclear. The present study aims to investigate the possible mechanism of resveratrol on CUMS-induced cognitive deficits. Male Sprague Dawley rats were adminstrated resveratrol (40 and 80 mg/kg) every day for 4 consecutive weeks before exposure to CUMS procedure. Morris Water Maze test was used to appraise spatial learing and memory of rats. Sirt1/miR-134 signalling pathway and CREB/BDNF expression in hippocampus of rats were measured. We also explored Sirt1/miR-134 signalling pathway and CREB/BDNF expression in primary cultured hippocampus neurons with resveratrol (25, 50 and 100 MUmol/L) treatment. We found that resveratrol treatment prevented spatial learing and memory impairment induced by CUMS. Meanwhile the potential mechanism of resveratrol was associated with increased levels of Sirt1, CREB phosphorylation (p-CREB), CREB, BDNF and decreased levels of miR-134 in vivo and in vitro. In conclusion, our study showed that the neuroprotective effect of resveratrol on CUMS-induced cognitive impairment may rely on activating Sirt1/miR-134 pathway and then upregulating its downstream CREB/BDNF expression in hippocampus. PMID- 29715539 TI - 5-HT6 receptor agonist EMD386088 impairs behavioral flexibility and working memory. AB - Serotonin 6 (5-HT6) receptors are primarily expressed in the central nervous system and to an even further extent brain regions responsible for learning and memory. Recent studies have demonstrated 5-HT6 receptor involvement in pathophysiological processes highlighting their therapeutic possibilities. Most research concerning the effects of 5-HT6 receptor modulation has focused on blockade despite paradoxical findings that 5-HT6 agonists and antagonists can both have pro-cognitive effects. The current experiments examine the effects of the 5-HT6 receptor agonist EMD386088 on behavioral flexibility and working memory. C57BL/6J mice received systemic injections of either 0, 2, or 4 mg/kg EMD386088 before being tested on probabilistic reversal learning, spontaneous alternation, and locomotor activity. In the probabilistic reversal learning task, the high dose of 4 mg/kg significantly impaired performance requiring more trials to reach criterion. The same dose significantly increased perseverative type errors, suggesting that the probabilistic reversal learning impairment was due to an inability to inhibit the previously learned choice pattern, rather than maintaining the new optimal choice pattern. Acute EMD386088 administration at 2 mg/kg significantly impaired spontaneous alternation performance, while the high dose of 4 mg/kg did not reach significance. These learning impairments were not due to an overall locomotor impairment as evidenced by comparable locomotor activity scores. Acute systemic 5-HT6 receptor activation with EMD386088 led to impaired behavior flexibility and working memory performance. Current findings support previous research suggesting that novel therapeutics directed at down regulation of 5-HT6 receptors may be effective in attenuating working memory and behavioral flexibility impairments commonly found in neuropsychiatric disorders such as Alzheimer's and schizophrenia. PMID- 29715540 TI - Vibralactone derivatives containing gamma, delta, epsilon-lactone cores from cultures of the basidiomycete Boreostereum vibrans. AB - Five vibralactone derivatives containing gamma, delta, epsilon-lactone cores, namely vibralactones X (1), Y (2), and Z1-Z3 (3-5), together with the known vibralactone, have been isolated from cultures of the basidiomycete Boreostereum vibrans. Compounds 3-5 possessed a novel bis-gamma-lactone group which was found in vibralactone derivatives for the first time. Compounds 3 and 5 exhibited moderate cytotoxicities to human cancer cell lines referring to that of cisplatin. PMID- 29715538 TI - Age- and sex-dependent effects of methamphetamine on cognitive flexibility and 5 HT2C receptor localization in the orbitofrontal cortex of Sprague-Dawley rats. AB - Adolescents and females experience worse outcomes of drug use compared to adults and males. This could result from age- and sex-specific consequences of drug exposure on brain function and cognitive behavior. In the current study, we examined whether a history of intravenous methamphetamine (METH) self administration impacted cognitive flexibility and 5-HT2CR localization in the orbitofrontal cortex (OFC) in an age- and sex-dependent manner. Strategy shifting was assessed in male and female Sprague-Dawley rats that had self-administered METH (0.08 mg/kg/inf) or received non-contingent infusions of saline during periadolescence or young adulthood. After all rats reached adulthood, they were tested in an operant strategy shifting task and their brains were subsequently analyzed using immunofluorescence to quantify co-localization of 5-HT2C receptors with parvalbumin interneurons in the OFC. We found that adolescent-onset females were the only group impaired during discrimination and reversal learning, but they did not exhibit changes in localization of 5-HT2C receptors. In contrast, adult-onset males exhibited a significant increase in co-localization of 5-HT2C receptors within parvalbumin interneurons in the left hemisphere of the OFC. These studies reveal that age and sex differences in drug-induced deficits in reversal learning and 5-HT2CR co-localization with parvalbumin interneurons are dissociable and can manifest independently. In addition, these data highlight the potential for certain treatment approaches to be more suitable in some populations compared to others, such as alleviating drug-induced cognitive deficits as a focus for treatment in adolescent females. PMID- 29715541 TI - Cytotoxic benzylbenzofuran derivatives from Dorstenia kameruniana. AB - Chromatographic separation of the extract of the roots of Dorstenia kameruniana (family Moraceae) led to the isolation of three new benzylbenzofuran derivatives, 2-(p-hydroxybenzyl)benzofuran-6-ol (1), 2-(p-hydroxybenzyl)-7-methoxybenzofuran-6 ol (2) and 2-(p-hydroxy)-3-(3-methylbut-2-en-1-yl)benzyl)benzofuran-6-ol(3) (named dorsmerunin A, B and C, respectively), along with the known furanocoumarin, bergapten (4). The twigs of Dorstenia kameruniana also produced compounds 1-4 as well as the known chalcone licoagrochalcone A (5). The structures were elucidated by NMR spectroscopy and mass spectrometry. The isolated compounds displayed cytotoxicity against the sensitive CCRF-CEM and multidrug-resistant CEM/ADR5000 leukemia cells, where compounds 4 and 5 had the highest activities (IC50 values of 7.17 MUM and 5.16 MUM, respectively) against CCRF-CEM leukemia cells. Compound 5 also showed cytotoxicity against 7 sensitive or drug-resistant solid tumor cell lines (breast carcinoma, colon carcinoma, glioblastoma), with IC50 below 50 MUM, whilst 4 showed selective activity. PMID- 29715542 TI - Four new spirobenzylisoquinoline N-oxide alkaloids from the whole plant of Corydalis hendersonii. AB - Encouraged by the anti-myocardial ischemic effect of Corydalis hendersonii ethanol extract, a chemical reinvestigation of the whole plant of C. hendersonii was performed, which led to the isolation of four new spirobenzylisoquinoline N oxide alkaloids, hendersines C-F (1-4), along with seven known isoquinoline alkaloids (5-11). The structures of the new isolates including absolute configurations were elucidated by the analysis of spectroscopic data and comparison of the experimental and calculated electronic circular dichroism (ECD) data. Compound 1 inhibited the NO production in lipopolysaccharide (LPS)-induced RAW 264.7 cells with an IC50 value of 70.3 MUM, and increased the cell viabilities with 40.0 +/- 3.9% against the oxygen glucose deprivation injury in H9c2 cells at 40 MUM. PMID- 29715543 TI - New steroidal saponins from the roots of Solanum melongena L. AB - Phytochemical investigation of the roots of Solanum melongena L. resulted in the isolation of six new steroidal saponins, including five new cholestane saponins (1-5) and one new steroidal alkaloid (6), along with one new natural product (7) and three know steroids (8-10). The structures of all isolated compounds were determined by 1D and 2D NMR experiments and by comparison of their spectroscopic and physical data with literature values. The inhibitory activities on nitric oxide (NO) production stimulated by lipopolysaccharide (LPS) in a RAW 264.7 cell line were assayed for all the isolated compounds. Compounds 1, 2 and 4-9 exhibited moderate inhibition of NO production with IC50 values ranging from 12.6 to 59.5 MUM. PMID- 29715544 TI - Semantic memory in developmental amnesia. AB - Patients with developmental amnesia resulting from bilateral hippocampal atrophy associated with neonatal hypoxia-ischaemia typically show relatively preserved semantic memory and factual knowledge about the natural world despite severe impairments in episodic memory. Understanding the neural and mnemonic processes that enable this context-free semantic knowledge to be acquired throughout development without the support of the contextualised episodic memory system is a serious challenge. This review describes the clinical presentation of patients with developmental amnesia, contrasts its features with those reported for adult onset hippocampal amnesia, and analyses the effects of variables that influence the learning of new semantic information. PMID- 29715545 TI - Multiple system atrophy and CAG repeat length: A genetic screening of polyglutamine disease genes in Italian patients. AB - Multiple system atrophy (MSA) is an adult onset, progressive, neurodegenerative disorder of unknown etiology characterized by autonomic dysfunction, parkinsonism (MSA-P) and cerebellar ataxia (MSA-C). The phenotypic spectrum may present overlapping features with other neurodegenerative diseases, particularly the autosomal dominant inherited polyglutamine disorders. To investigate the possible contribution of CAG expansions in the MSA phenotype, we analyzed the triplet repeat length in the autosomal dominant causative genes for spinocerebellar ataxia (SCA) type 1, 2, 3, 6, 7, 17, dentatorubral-pallidoluysian atrophy (DRPLA) and Huntington disease (HD) in a cohort of 246 Italian MSA patients. As comparison, 223 controls were also analyzed. The alleles were classified on the basis of CAG repeat length as "normal", "intermediate" or "expanded" according to literature. The MSA patients (101 men/145 women) had a mean age at onset of 58 years and a mean age at genetic testing of 63 years. MSA-C patients had significantly younger age at onset and at examination in comparison to MSA-P (p < 0.0001). We identified a SCA1 intermediate allele in a MSA-C subject (36 CAG), a SCA2 intermediate allele in a MSA-P patient (31 CAG), and a pathologically expanded SCA2 allele (36 CAG) in a patient initially misdiagnosed as MSA-C. No intermediate or expanded SCA alleles were detected in controls. The distribution of CAG repeat length was similar among groups except for SCA1 gene that showed a higher percentage of longer normal alleles in MSA-C as compared to MSA-P and controls (p < 0.0001). This study supports the utility of polyQ genetic testing in the differential diagnosis of MSA, and may suggest a possible role of SCA1 repeat length as risk factor for MSA-C. SCA1 and SCA2 genetic screening is recommended in MSA Italian patients. PMID- 29715547 TI - Anagliptin inhibits neointimal hyperplasia after balloon injury via endothelial cell-specific modulation of SOD-1/RhoA/JNK signaling in the arterial wall. AB - Intimal hyperplasia is one of the major complications after stenting, but the underlying mechanisms remain unclear. Our previous study found that the dipeptidyl peptidase IV (DPP-4) inhibitor, Anagliptin, suppresses intimal hyperplasia after balloon injury. Here, we further investigated the effects of Anagliptin on endothelial cell (EC) migration after balloon injury. The results showed that Anagliptin administration significantly reduced intimal hyperplasia by stimulating the migration of endothelial cells, but had no effect on the medial area after balloon injury. Anagliptin elevated the total plasma activity of SOD by up-regulating the level of SOD-1, but not SOD-2, after balloon injury. Meanwhile, pre-incubation with Anagliptin suppressed the hydrogen peroxide mediated formation of oxidant species and apoptosis in HUVECs. In vitro pre incubation with Anagliptin promoted the migration of HUVECs via the SOD 1/RhoA/JNK signaling pathway mediating the formation of F-actin. Collectively, the DPP-4 inhibitor, Anagliptin, regulates SOD-1/RhoA/ JNK-mediated HUVECs migration. The results suggest that Anagliptin could serve as a potential drug to prevent intimal hyperplasia formation after balloon injury. PMID- 29715546 TI - TDP-43 interacts with mitochondrial proteins critical for mitophagy and mitochondrial dynamics. AB - Transactive response DNA-binding protein of 43 kDa (TDP-43) functions as a heterogeneous nuclear ribonucleoprotein and is the major pathological protein in frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis/motor neuron disease (ALS/MND). TDP-43 pathology may also be present as a comorbidity in approximately 20-50% of sporadic Alzheimer's disease cases. In a mouse model of MND, full-length TDP-43 increases association with the mitochondria and blocking the TDP-43/mitochondria interaction ameliorates motor dysfunction. Utilizing a proteomics screen, several mitochondrial TDP-43-interacting partners were identified, including voltage-gated anion channel 1 (VDAC1) and prohibitin 2 (PHB2), a crucial mitophagy receptor. Overexpression of TDP-43 led to an increase in PHB2 whereas TDP-43 knockdown reduced PHB2 expression in cells treated with carbonyl cyanide m-chlorophenylhydrazone (CCCP), an inducer of mitophagy. These results suggest that TDP-43 expression contributes to metabolism and mitochondrial function however we show no change in bioenergetics when TDP-43 is overexpressed and knocked down in HEK293T cells. Furthermore, the fusion protein mitofusin 2 (MFN2) interacts in complex with TDP-43 and selective expression of human TDP-43 in the hippocampus and cortex induced an age-dependent change in Mfn2 expression. Mitochondria morphology is altered in 9-month-old mice selectively expressing TDP-43 in an APP/PS1 background compared with APP/PS1 littermates. We further confirmed TDP-43 localization to the mitochondria using immunogold labeled TDP-43 transmission electron microscopy (TEM) and mitochondrial isolation methods There was no increase in full-length TDP-43 localized to the mitochondria in APP/PS1 mice compared to wild-type (littermates); however, using C- and N-terminal-specific TDP-43 antibodies, the N terminal (27 kDa, N27) and C-terminal (30 kDa, C30) fragments of TDP-43 are greatly enriched in mitochondrial fractions. In addition, when the mitochondrial peptidase (PMPCA) is overexpressed there is an increase in the N-terminal fragment (N27). These results suggest that TDP-43 processing may contribute to metabolism and mitochondrial function. PMID- 29715548 TI - Posttranslational regulation of CYP2J2 by nitric oxide. AB - Nitric oxide (NO) is an essential signaling molecule in the body, regulating numerous biological processes. Beside its physiological roles, NO affects drug metabolism by modulating the activity and/or expression of cytochrome P450 enzymes. Previously, our lab showed that NO generation caused by inflammatory stimuli results in CYP2B6 degradation via the ubiquitin-proteasome pathway. In the current study, we tested the NO-mediated regulation of CYP2J2 that metabolizes arachidonic acids to bioactive epoxyeicosatrienoic acids, as well as therapeutic drugs such as astemizole and ebastine. To investigate the effects of NO on CYP2J2 expression and activity, Huh7 cells stably transduced with CYP2J2 with a C-terminal V5 tag were treated with dipropylenetriamine-NONOate (DPTA), a NO donor. The level of CYP2J2 proteins were decreased in a time- and concentration-dependent manner, and the activity was also rapidly inhibited. However, mRNA expression was not altered and the protein synthesis inhibitor cycloheximide did not attenuate DPTA-mediated downregulation of CYP2J2. Removal of DPTA from the culture media quickly restored the activity of remaining CYP2J2, and no further CYP2J2 degradation occurred. To determine the mechanism of CYP2J2 down-regulation by NO, cells were treated with DPTA in the presence or absence of protease inhibitors including proteasomal, lysosomal and calpain inhibitors. Remarkably, the down-regulation of CYP2J2 by NO was attenuated by calpeptin, a calpain inhibitor. However, other calpain inhibitors or calcium chelator show no inhibitory effects on the degradation. The proteasome inhibitor bortezomib showed small but significant restoration of CYP2J2 levels although stimulated ubiquitination of CYP2J2 was not detected. In conclusion, these data suggest that NO regulates CYP2J2 posttranslationally and NO-evoked CYP2J2 degradation undergoes ubiquitin-independent proteasomal degradation pathway unlike CYP2B6. PMID- 29715549 TI - Selenophosphate synthetase 1 and its role in redox homeostasis, defense and proliferation. AB - Selenophosphate synthetase (SEPHS) synthesizes selenophosphate, the active selenium donor, using ATP and selenide as substrates. SEPHS was initially identified and isolated from bacteria and has been characterized in many eukaryotes and archaea. Two SEPHS paralogues, SEPHS1 and SEPHS2, occur in various eukaryotes, while prokaryotes and archaea have only one form of SEPHS. Between the two isoforms in eukaryotes, only SEPHS2 shows catalytic activity during selenophosphate synthesis. Although SEPHS1 does not contain any significant selenophosphate synthesis activity, it has been reported to play an essential role in regulating cellular physiology. Prokaryotic SEPHS contains a cysteine or selenocysteine (Sec) at the catalytic domain. However, in eukaryotes, SEPHS1 contains other amino acids such as Thr, Arg, Gly, or Leu at the catalytic domain, and SEPHS2 contains only a Sec. Sequence comparisons, crystal structure analyses, and ATP hydrolysis assays suggest that selenophosphate synthesis occurs in two steps. In the first step, ATP is hydrolyzed to produce ADP and gamma-phosphate. In the second step, ADP is further hydrolyzed and selenophosphate is produced using gamma-phosphate and selenide. Both SEPHS1 and SEPHS2 have ATP hydrolyzing activities, but Cys or Sec is required in the catalytic domain for the second step of reaction. The gene encoding SEPHS1 is divided by introns, and five different splice variants are produced by alternative splicing in humans. SEPHS1 mRNA is abundant in rapidly proliferating cells such as embryonic and cancer cells and its expression is induced by various stresses including oxidative stress and salinity stress. The disruption of the SEPHS1 gene in mice or Drosophila leads to the inhibition of cell proliferation, embryonic lethality, and morphological changes in the embryos. Targeted removal of SEPHS1 mRNA in insect, mouse, and human cells also leads to common phenotypic changes similar to those observed by in vivo gene knockout: the inhibition of cell growth/proliferation, the accumulation of hydrogen peroxide in mammals and an unidentified reactive oxygen species (ROS) in Drosophila, and the activation of a defense system. Hydrogen peroxide accumulation in SEPHS1-deficient cells is mainly caused by the down-regulation of genes involved in ROS scavenging, and leads to the inhibition of cell proliferation and survival. However, the mechanisms underlying SEPHS1 regulation of redox homeostasis are still not understood. PMID- 29715550 TI - Berberine exerts antioxidant effects via protection of spiral ganglion cells against cytomegalovirus-induced apoptosis. AB - Cytomegalovirus (CMV) is the leading cause of sensorineural hearing loss (SNHL) in children because of its damage to the cochlea and spiral ganglion cells. Therefore, it has become a top priority to devise new methods to effectively protect spiral ganglion cells from damage. Berberine (BBR) has gained attention for its vast beneficial biological effects through immunomodulation, and its anti inflammatory and anti-apoptosis properties. However, the effect of BBR on spiral ganglion cells and molecular mechanisms are still unclear. This study aims to investigate whether BBR has an anti-apoptosis effect in CMV-induced apoptosis in cultured spiral ganglion cells and explore the possible mechanism. In this study, TUNEL and MTT assays significantly demonstrated that low doses of BBR did not promote cell apoptosis and they also inhibited the CMV-induced cultured spiral ganglion cell apoptosis. Immunofluorescence and Western blot assays indicated that the anti-apoptosis effect of BBR was related to Nox3. Mitochondrial calcium and Western blot assays revealed that NMDAR1 mediated this anti-apoptosis effect. Our results demonstrated that BBR exerted an anti-apoptosis effect against CMV in cultured spiral ganglion cells, and the mechanism is related to NMDAR1/Nox3 mediated mitochondrial reactive oxygen species (ROS) generation. PMID- 29715551 TI - Severe infections in critically ill solid organ transplant recipients. AB - BACKGROUND: Severe infections are among the most common causes of death in immunocompromised patients admitted to the intensive care unit. The epidemiology, diagnosis and treatment of these infections has evolved in the last decade. AIMS: We aim to provide a comprehensive review of these severe infections in this population. SOURCES: Review of the literature pertaining to severe infections in critically ill solid organ transplant recipients. PubMed and Embase databases were searched for documents published since database inception until November 2017. CONTENT: The epidemiology of severe infections has changed in the immunocompromised patients. This population is presenting to the intensive care unit with specific transplantation procedure-related infections, device associated infections, a multitude of opportunistic viral infections, an increasing number of nosocomial infections and bacterial diseases with a more limited therapeutic armamentarium. Both molecular diagnostics and imaging techniques have had substantial progress in the last decade, which will, we hope, translate into faster and more precise diagnoses, as well as more optimal empirical treatment de-escalation. IMPLICATIONS: The key clinical elements to improve the outcome of critically ill solid organ transplant recipients depend on the knowledge of geographic epidemiology, specific surgical procedures, net state of immunosuppression, hospital microbial ecology, aggressive diagnostic strategy and search for source control, rapid initiation of antimicrobials and minimization of iatrogenic immunosuppression. PMID- 29715552 TI - Monoclonal antibodies as anti-infective products: a promising future? AB - BACKGROUND: The paucity of licensed monoclonal antibodies (mAbs) in the infectious diseases arena strongly contrasts with the ready availability of these therapeutics for use in other conditions. AIMS: This narrative review aims to assess the potential of monoclonal antibody-based interventions for infectious diseases. SOURCES: A review of the literature via the Medline database was performed and complemented by published official documents on licensed anti infective mAbs. In addition, ongoing trials were identified through a search of the clinical trial registration platform ClinicalTrials.gov. CONTENT: We identified the few infections for which mAbs have been added to the therapeutic armamentarium and stressed their potential in representing a readily available protection tool against biothreats and newly emerging and reemerging infectious agents. In reviewing the historical context and main features of mAbs, we assert a potentially wider applicability and cite relevant examples of ongoing therapeutic developments. Factors hindering successful introduction of mAbs on a larger scale are outlined and thoughts are offered on how to possibly address some of these limitations. IMPLICATIONS: mAbs may represent important tools in treating or preventing infections occurring with reasonably sufficient prevalence to justify demand and for which existing alternatives are not deemed fully adequate. Future initiatives need to address the prohibitive costs encountered in the development process. The feasibility of more large-scale administration of alternative modalities merits further exploration. In order to ensure optimal prospect of regulatory success, an early dialogue with competent authorities is encouraged. PMID- 29715553 TI - Development and validation of baseline, perioperative and at-discharge predictive models for postsurgical prosthetic joint infection. AB - OBJECTIVES: To develop and validate baseline, perioperative and at-discharge risk scoring systems for postsurgical prosthetic joint infection (PJI) in patients undergoing arthroplasty. METHODS: A multicentre prospective cohort study of patients undergoing hip and knee arthroplasty was performed. Patients were randomly assigned (2:1) to a derivation cohort (DC) or a validation cohort (VC). Multivariable predictive models of PJI were constructed at baseline (preoperative period), perioperative (adding perioperative variables) and at-discharge (adding wound state at discharge). The predictive ability of the models and scores was evaluated by area under the receiving operating characteristic curves (AUROC). RESULTS: The DC and VC included 2324 and 1245 patients, respectively. Baseline model included total hip arthroplasty (THA), revision arthroplasty (RA), Charlson index and obesity. The AUROC for the score was 0.75 and 0.78 in the DC and VC, respectively. Perioperative model included THA, RA, obesity, National Nosocomial Infections Surveillance (NNIS) index >=2, significant wound bleeding and superficial surgical site infection; the AUROC was 0.81 and 0.77 in the DC and VC, respectively. The at-discharge model included THA, RA, obesity, NNIS index >=2, superficial surgical site infection and high-risk wound; the AUROC was 0.82 and 0.84 in the DC and VC, respectively. A score >=8 points provided 99% negative predictive values for all models. CONCLUSIONS: Simple scores for predicting PJI at three different moments of care in patients undergoing arthroplasty were developed and validated. The scores allow early and accurate identification of high-risk individuals in whom enhanced preventive measures and follow-up may be needed. Further external validation is needed. PMID- 29715554 TI - Rehmannia glutinosa polysaccharide promoted activation of human dendritic cells. AB - In our previous study, we showed that Rehmannia glutinosa polysaccharide (RGP) treatment induced maturation of dendritic cells (DCs) and that it had an anticancer effect in mice. The effect of RGP has not been studied in human DCs, including monocyte-derived DCs (MDDCs) and peripheral blood DCs (PBDCs). In this study, we examined DC activation by RGP in human cells. The dendritic morphology of RGP-treated MDDCs was substantially altered as compared with that of phosphate buffered saline (PBS)-treated control cells. Moreover, RGP treatment markedly decreased phagocytic activity and increased expression levels of co-stimulatory molecules in MDDCs. In addition, RGP treatment elevated the production of proinflammatory cytokines. Furthermore, RGP-induced activation of MDDCs was dependent on the phosphorylation of extracellular signal-regulated kinase (ERK), p38, and c-Jun N-terminal kinase (JNK). RGP-treated MDDCs promoted upregulation of T-cell activation, including proliferation and interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) production. Analysis of the effect of RGP in PBDC subsets revealed that it induced upregulation of co-stimulatory molecule expression and proinflammatory cytokine production. These data suggest that RGP may function as an immune stimulatory molecule in humans. PMID- 29715555 TI - Structural characterization and immunomodulatory activity of exopolysaccharides from submerged culture of Auricularia auricula-judae. AB - Submerged culture of Auricularia auricula-judae has been documented, but there have been few studies on the structural characterization and medicinal properties of its exopolysaccharides. In present study, two exopolysaccharides, named CEPSN 1 and CEPSN-2, were isolated from submerged culture of A. auricula-judae, and their structural features as well as immunomodulatory activity were analyzed. The two exopolysaccharides both had a backbone chain composed of (1 -> 4)-alpha-d glucose residues in glucopyranose type. At the tested concentration range of 50 200 MUg/mL, CEPSN-1 and CEPSN-2 not only showed non-toxicity to RAW 264.7 cells, but also could promote the release of NO and cytokines (IL-6, IL-10 and TNF alpha) in the cells. The release of NO was significantly enhanced by the two exopolysaccharides at 100 MUg/mL (p < 0.05). The IL-10 secretion was significantly increased by 1.80 and 1.61-fold, compared to the control after treatment with 50 MUg/mL of CEPSN-1 and CEPSN-2, respectively (p < 0.05). These results demonstrated that, though their structural feature were different from that of polysaccharides from fruit body, exopolysaccharides of A. auricula-judae from submerged culture with the backbone of (1 -> 4)-alpha-D-glucan could be explored as potential immunomodulatory agents for the application in complementary medicine or functional foods. PMID- 29715556 TI - Chitosan-alginate nano-carrier for transdermal delivery of pirfenidone in idiopathic pulmonary fibrosis. AB - Pirfenidone (PFD) is one of the pyridine family components with anti inflammatory, antifibrotic effects and US FDA approved for the treatment of idiopathic pulmonary fibrosis (IPF). Presently, PFD is administered orally and this has setbacks. Hence, it is important to eliminate the pharmacotherapeutic limitations of PFD. This research was carried out to study the possibility of transdermal delivery of PFD using chitosan-sodium alginate nanogel carriers. In order to synthesize chitosan-sodium alginate nanoparticles loaded with PFD, the pre-gelation method was used. Scanning electron microscopy (SEM), transmission electron microscopy (TEM), dynamic light scattering (DLS), and Fourier-transform infrared spectroscopy (FTIR) analyses were used for the characterization. Drug encapsulation and release manner were studied using UV spectroscopy. Ex vivo permeation examinations were performed using Franz diffusion cell and fluorescence microscopy. The results showed that nanoparticles having spherical morphology and size in the range of 80 nm were obtained. In vitro drug release profile represents sustained release during 24 h, while 50% and 94% are the loading capacity and efficiency, respectively. Also, the skin penetration of PFD loaded in nanoparticles was significantly increased as compared to PFD solution. The obtained results showed that synthesized nanoparticles can be considered as promising carriers for PFD delivery. PMID- 29715558 TI - Extraction of polysaccharide from fruits of Cordia dichotoma G. Forst using acid precipitation method and its physicochemical characterization. AB - The objective of the present work was to isolate and characterize polysaccharide from fruits of Cordia dichotoma G. Forst. (Family Boraginaceae). Polysaccharide was isolated by using 1% Hydrochloric acid solution. The isolated polysaccharide was tested for physicochemical characteristics such as solubility, pH (1% w/w in water), swelling capacity, loss on drying, ash value, bulk and tapped density, Carr's capacity, Hausner's ratio and angle of repose. Also isolated polysaccharide was characterized by Differential scanning colorimeter (DSC), Estimation of total sugar content, Rheological study and infrared spectroscopy (FT-IR). The isolated mucilage showed positive results for Molisch's test and negative for Ruthenium red test which indicated presence of carbohydrate and gum. The result of physicochemical characteristics reveals that isolated Cordia dichotoma polysaccharide possesses good flow properties. The total polysaccharide content of Cordia dichotoma polymer isolate was found to be 86.24% (w/w). From this study it can be concluded that the polysaccharide isolated from Cordia dichotoma fruits has the required properties and could be used as an excipient for pharmaceutical dosage forms. PMID- 29715557 TI - Native and recombinant phospholipases A2 of Scorpio maurus venom glands impair angiogenesis by targeting integrins alpha5beta1 and alphavbeta3. AB - We recently purified an heterodimeric phospholipase A2 named Sm-PLGV from the venom glands of scorpion Scorpio maurus containing a Long chain, a penta-peptide insertion, which is cut out during the maturation, followed by a short chain. Three recombinant forms of Sm-PLGV were produced in Escherichia coli: rPLA2(+5) containing the full-length sequence including the penta-peptide insert, rPLA2(-5) a fused continuous chain of the Long and the short chains without the penta peptide and the Long chain alone without the short one. In this study, we showed that Sm-PLGV, rPLA2(+5) and rPLA2(-5) displayed more potent anti-angiogenic properties than the recombinant Long chain and the short chain obtained by chemical synthesis. These phospholipases A2 inhibited in a dose-dependent manner adhesion, migration and invasion of human microvascular endothelial cells through the alteration of alpha5beta1 and alphavbeta3 integrins function. Using MatrigelTM and chick chorioallantoic membrane assays, we demonstrated that Sm PLGV, rPLA2(+5) and rPLA2(-5) significantly inhibited both in vitro and in vivo angiogenesis. We also showed a clear dissociation of the anti-angiogenic effect of Sm-PLGV and its catalytic activity. This is the first study describing an anti angiogenic effect for recombinant scorpion venom enzymes. PMID- 29715559 TI - Functional characterization of GH7 endo-1,4-beta-glucanase from Aspergillus fumigatus and its potential industrial application. AB - A gene encoding an endo-1,4-beta-glucanase (Afu6g01800) from A. fumigatus was cloned into the vector pET-28a(+) and expressed in the E. coli strain RosettaTM (DE3) pLysS. Sequence analysis indicated that the enzyme Af-EGL7 belonged to the GH7 family. The gene Af-egl7 encoded a protein comprising 460 amino acids, with a CBM1 domain at residues 424-460 and molecular mass of 52 kDa, as estimated by SDS PAGE. This enzyme was optimally active at pH and temperatures ranging from 4.5 to 5.5 and from 40 to 60 degrees C, respectively. Mn2+ addition significantly enhanced the Af-EGL7 cellulase activity by 233%, whereas SDS addition fully inhibited this activity. Higher activity was observed toward beta-glucan than toward xyloglucan and CM-Cellulose, suggesting that the enzyme corresponds to a beta-1,3-1,4-glucanase. qRT-PCR in different culture media helped to establish the time-course expression profile. Different polysaccharides induced the gene Af egl7 in a time-dependent manner; in the particular case of the substrate sugarcane exploded bagasse (SEB), Af-egl7 was induced 2500-fold. Upon addition to a commercial cellulase cocktail, Af-EGL7 significantly improved SEB saccharification, which suggested that the enzyme Af-EGL7 had great potential to hydrolyze complex biomass. From a biotechnological point of view, A. fumigatus Af EGL7 is a promising candidate to enhance enzyme cocktails used in biorefineries such as consolidated bioprocessing. PMID- 29715560 TI - How "resistant" is artemisinin resistant malaria? - The risks of ambiguity using the term "resistant" malaria. AB - In scientific discourse, few would consider the widely used term resistance as ambiguous. The definition and usage of the term antimicrobial resistance revolves around the concept that microorganisms change in ways that render antimicrobial medications clinically ineffective. Because artemisinins have become the cornerstone for antimalarial therapy, the widely used term artemisinin resistance in scientific literature is highly alarming. Naturally, many people will assume that artemisinin resistance must essentially be the same as antimicrobial resistance, which means it is clinically ineffective. However, this is incorrect, and the WHO defines artemisinin resistance differently to antimicrobial resistance as "partial/relative resistance". This means that parasite clearance times are increased but does not automatically mean that artemisinins have become clinically inefficacious. Is the ambiguous use of the term resistance justified and appropriate, although it might be misleading biomedical researchers, the media, policy makers and possibly attending physicians? Science is also about clear and unambiguous use of terminology, so that a message is accurately communicated and understood. Ambiguity can lead to misunderstandings, and misunderstandings can cause wrong actions; unnecessarily so. PMID- 29715561 TI - Low blood eosinophil counts are not always a reliable marker of clinical response to mepolizumab in severe asthma. PMID- 29715562 TI - Idiopathic Nonhistaminergic Acquired Angioedema Versus Hereditary Angioedema. AB - BACKGROUND: The mechanism of idiopathic nonhistaminergic acquired angioedema (InH AAE) has not yet been precisely elucidated. This condition is characterized by recurrent angioedema without wheals. OBJECTIVE: To study the clinical features of InH-AAE, and to make, for the first time, independent comparisons with hereditary angioedema of unknown origin (U-HAE), as well as with hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE). METHODS: We compared the clinical parameters of 46 patients with InH-AAE with those of 27 patients suffering from U HAE, as well as of 73 patients with C1-INH-HAE. RESULTS: The mean age at the onset of symptoms was 36 years in InH-AAE, 13 years in C1-INH-HAE, and 29 years in U-HAE. More than 12 edematous episodes occurred over a year in 56% of patients with InH-AAE, in 59% of those with C1-INH-HAE, and in 48% of those with U-HAE. Edema of the extremities, of the upper airways, and of the gastrointestinal tract was more common in patients with C1-INH-HAE (92%, 51%, and 75%, respectively). These manifestations occurred less frequently in patients with InH-AAE (54%, 28%, and 20%) and in patients with U-HAE (37%, 29%, and 20%). By contrast, facial edema occurred in only 15% of patients with C1-INH-HAE, but in 67% of patients with InH-AAE and in 59% of patients with U-HAE. CONCLUSIONS: The clinical manifestations of patients with InH-AAE were different from those of patients with C1-INH-HAE. This may indicate different processes underlying edema formation in these disease forms. The close resemblance of the clinical manifestations in InH-AAE and U-HAE might suggest a similarity between the pathophysiology of these conditions. PMID- 29715563 TI - Recurrent anaphylaxis during cardiac catheterization due to ethylene oxide. PMID- 29715564 TI - Risk Factors for Return to the Emergency Department for Asthma: A Population Based Study. AB - BACKGROUND: A substantial proportion of patients with asthma return after being discharged from the emergency department (ED). Given the high economic burden of acute care claims, and the impact on productivity and quality of life, a better understanding of risk factors for ED return is of interest. OBJECTIVE: To quantify the rate and determine factors associated with return to the ED for asthma within 1 year of an initial ED visit for asthma. METHODS: Individuals aged 5 to 99 years living in Ontario, Canada, with an ED visit for asthma in the period 2008 to 2014 were included. Descriptive statistics were used to compare those with an ED return with those without an ED return. An adjusted modified Poisson regression model was used to estimate the relative risk of ED return for asthma within 1 year after the initial discharge. RESULTS: In total, 58,366 individuals met the inclusion criteria. At 1-year follow-up, 12.1% returned to the ED at least once. Younger age, being materially deprived, and having chronic obstructive pulmonary disease were significantly associated with increased risk of ED return within 1 year after the initial visit. CONCLUSIONS: Nearly 1 in 8 individuals with a first ED visit for asthma returned to the ED within a year of the initial ED discharge. Targeting those at risk for ED return may help improve health care costs, productivity, and quality of life. PMID- 29715565 TI - In vivo and in vitro activity of a bis-arylidenecyclo-alkanone against fluconazole-susceptible and -resistant isolates of Candida albicans. AB - OBJECTIVES: Candida albicans is a commensal organism and opportunistic pathogen associated both with superficial (mucosal and cutaneous) and systemic infections. Extensive use of antifungal agents has led to reduced susceptibility to the few existing drugs, which has encouraged the search for novel antifungal agents. Therefore, the present study investigated the antifungal activity of 2,6-bis[(E) (4-pyridyl)methylidene]cyclohexanone (PMC) against C. albicans. METHODS: The in vitro activity of PMC was evaluated against C. albicans. Additionally, an invertebrate infection model in Caenorhabditis elegans as well as two infected murine models of oral and systemic candidiasis were used to determine the antifungal efficacy of PMC in vivo. RESULTS: Minimum inhibitory concentrations (MICs) of PMC ranged from 4-32MUg/mL against nine clinical and two reference C. albicans isolates. Interestingly, PMC inhibited filamentation in vitro at subinhibitory concentrations similar to fluconazole. PMC also showed low toxicity against murine macrophages and human erythrocytes. In the invertebrate infection model, PMC was efficient in prolonging survival of C. elegans infected with C. albicans SC5314. Treatment with PMC was efficient both in murine models of systemic and oral candidiasis and was similar to that observed with conventional drug treatments (nystatin and fluconazole). CONCLUSIONS: The results of this study indicate the therapeutic potential of PMC as it was able to inhibit filamentation of C. albicans in vitro. These alterations to the fungi by PMC resulted in a reduction of oral and systemic infection in mice. In conclusion, we present promising evidence of the anticandidal activity of PMC in vitro and in vivo. PMID- 29715566 TI - Indexing sensory plasticity: Evidence for distinct Predictive Coding and Hebbian learning mechanisms in the cerebral cortex. AB - The Roving Mismatch Negativity (MMN), and Visual LTP paradigms are widely used as independent measures of sensory plasticity. However, the paradigms are built upon fundamentally different (and seemingly opposing) models of perceptual learning; namely, Predictive Coding (MMN) and Hebbian plasticity (LTP). The aim of the current study was to compare the generative mechanisms of the MMN and visual LTP, therefore assessing whether Predictive Coding and Hebbian mechanisms co-occur in the brain. Forty participants were presented with both paradigms during EEG recording. Consistent with Predictive Coding and Hebbian predictions, Dynamic Causal Modelling revealed that the generation of the MMN modulates forward and backward connections in the underlying network, while visual LTP only modulates forward connections. These results suggest that both Predictive Coding and Hebbian mechanisms are utilized by the brain under different task demands. This therefore indicates that both tasks provide unique insight into plasticity mechanisms, which has important implications for future studies of aberrant plasticity in clinical populations. PMID- 29715567 TI - Bronchopulmonary dysplasia predictor scale validation in preterm newborns in two neonatal units at 2600 m above sea level. AB - INTRODUCTION: Bronchopulmonary dysplasia (BPD) is common in premature babies. It is difficult to predict the risk of developing this disease and its definition is not well characterized in high altitude cities. OBJECTIVE: To determine the operating characteristics of a BPD predictive scale for in preterm infants based on a classical BPD definition and one adjusted for altitude. MATERIALS AND METHOD: Observational, analytical, longitudinal study with infants gestational age <=32 weeks admitted at two University Hospital's in the city of Bogota, Colombia between June 2010 and December 2016. The 2001 NIH consensus definition for BPD was used and a definition with an altitude adjustment. Perinatal data, and the Romagnoli scale variables for the 3rd and 5th days were described. Score operational characteristics in relation to BPD frequency are measured using the two definitions. RESULTS: 335 patients were included. The median birth weight was 1335 g and GA was 31 weeks. For the BPD classical definition, the incidence was 85%, whereas after adjusting for altitude it was 20%. The scale score showed good overall discrimination (ROC curve, AUC 0.81-0.86). The sensitivity for the classical definition with a high cut point of 4 was between 93-98% and the adjusted for altitude was 28-37%. The specificity for the same cut was 28-32% with the classical definition and 96% with the adjusted one. CONCLUSIONS: The scale using the classical definition has high sensitivity, but it is not specific; adjusting the definition for altitude decreases sensitivity but increases specificity. New cutoffs points are needed on the scale or a change in the weight for the variables included in the model in order to be used in our high-altitude population. PMID- 29715568 TI - Transposable elements and polyploid evolution in animals. AB - Polyploidy in animals is much less common than in plants, where it is thought to be pervasive in all higher plant lineages. Recent studies have highlighted the impact of polyploidization and the associated process of diploidy restoration on the evolution and speciation of selected taxonomic groups in the animal kingdom: from vertebrates represented by salmonid fishes and African clawed frogs to invertebrates represented by parasitic root-knot nematodes and bdelloid rotifers. In this review, we focus on the unique and diverse roles that transposable elements may play in these processes, from marking and diversifying subgenome specific chromosome sets before hybridization, to influencing genome restructuring during rediploidization, to affecting subgenome-specific regulatory evolution, and occasionally providing opportunities for domestication and gene amplification to restore and improve functionality. There is still much to be learned from the future comparative genomic studies of chromosome-sized and haplotype-aware assemblies, and from postgenomic studies elucidating genetic and epigenetic regulatory phenomena across short and long evolutionary distances in the metazoan tree of life. PMID- 29715569 TI - Acoustic Neuroma Treated with Stereotactic Radiosurgery: Follow-up of 335 Patients. AB - OBJECTIVE: To determine the clinical and radiologic outcome of patients with acoustic neuroma (AN) treated with linear accelerator (LINAC) or CyberKnife-based stereotactic radiosurgery with respect to tumor control, preservation of serviceable hearing, and toxicity. METHODS: A retrospective monocentric analysis including all patients who underwent single-fraction LINAC- or CyberKnife-based radiosurgery for AN between 1991 and 2015. Patient data were analyzed in terms of radiologic and clinical tumor control (no further intervention needed), treatment related complications, preservation of serviceable hearing, and objectified hearing loss using pure tone average levels. RESULTS: We included 335 patients (median age 58.2 years, treated either by LINAC-based [n = 270] or CyberKnife [n = 65] stereotactic radiosurgery). The median tumor volume was 1.1 mL (0.1-23.7 mL). The median radiation dose was 12 Gy (LINAC 12 Gy, 11-20 Gy; CyberKnife 13 Gy, 12-13 Gy) at an isodose level of 71.7% (LINAC 68.3%, 31.9%-86.2%; CyberKnife 80%, 65%-81%). The median follow-up was 30 months (LINAC 43 months, 2-224 months; CyberKnife 13 months, 4-37 months). Clinical tumor control was 98%, 89%, and 88% at 2, 5, and 10 years. The objective actuarial hearing preservation rate was 89%, 80%, and 55% at 1, 2, and 5 years. New symptoms were observed in 11.3% and classified as Common Terminology Criteria for Adverse Events grade 1/2, apart from 4 patients (1.2%), who developed Common Terminology Criteria for Adverse Events grade 3. CONCLUSIONS: Our study shows that in AN, high tumor control and considerable hearing preservation rates can be achieved by single-dose radiosurgery at low toxicity rates, resulting in a positive impact on long-term clinical outcome. PMID- 29715570 TI - What Tactics Should a Surgeon Choose to Treat a Black Extracerebral Tumor? A Case Report of Psammomatous Melanotic Schwannoma of the Meckel Cave and Literature Review. AB - BACKGROUND: Neoplasms located in the Meckel cave account for 0.2%-0.5% of all intracranial tumors. This area is the site of many types of pathologic lesions, most often trigeminal nerve schwannomas and meningiomas. Melanin-containing tumors are rare in this area. These tumor types can be suspected if the magnetic resonance characteristics of a tumor has some differences in comparison with other types of central nervous system neoplasms. In fact, differential diagnosis of melanotic tumors is based mainly on the histopathologic criteria and immunohistochemical profile. This article presents a case report of melanotic schwannoma of the Meckel cave and a literature review of the problem. CASE DESCRIPTION: A 23-year-old man underwent a 2-stage surgery for a dumbbell pigmented mass lesion located in the Meckel cave. No signs of recurrence were seen on follow-up magnetic resonance imaging (MRI) 3.5 years after the operation. CONCLUSIONS: Melanin-containing tumor can be suspected in the presence of radiologic characteristics, such as a hyperintense MRI signal on T1-weighted images and a hypointense signal on T2-weighted images. If a black extracerebral tumor is detected, the main course of surgical treatment is maximal excision despite it possibly being a malignant melanoma and the temptation to perform partial resection because of an unfavorable prognosis. Chemotherapy can be justified in the presence of an aggressive melanotic schwannoma. PMID- 29715571 TI - Length of Thromboprophylaxis in Patients Operated on for a High-Grade Glioma: A Retrospective Study. AB - OBJECTIVE: High-grade gliomas are associated with venous thromboembolism (VTE). This retrospective study with a parallel cohort design investigated influence of continuing prophylactic anticoagulation after discharge on rate of VTE and intracranial hemorrhage (ICH) in patients operated on for high-grade glioma. METHODS: Consecutive adult patients who underwent subtotal or gross total resection for high-grade glioma at a single institution were included. Multivariable logistic regression analysis was used to investigate the association between duration of thromboprophylaxis (dalteparin administered 21 days vs. 0-7 days) and occurrence of VTE and ICH within 21 or 90 days after surgery, corrected for known risk factors. RESULTS: Of 301 included patients, 166 received short-term thromboprophylaxis, and 135 received prolonged thromboprophylaxis. In multivariable analysis, prolonged thromboprophylaxis was not significantly associated with occurrence of VTE within 21 days (3.0% vs. 1.2%; P = 0.24) or 90 days (8.9% vs. 4.8%; P = 0.09) after surgery; however, prolonged prophylaxis was associated with occurrence of ICH (5.9% vs. 0.6%; P = 0.03). Additionally, immobility (P = 0.03) and high body mass index (P = 0.02) were associated with occurrence of VTE. CONCLUSIONS: Prophylactic anticoagulation for 21 days postoperatively was not associated with a decreased rate of VTE compared with thromboprophylaxis until discharge. ICH was more common with prolonged thromboprophylaxis. These results provide insufficient evidence to extend duration of prophylaxis beyond hospitalization. Large-scale randomized prospective studies are needed to clarify safety, efficacy, and optimal timing of postoperative thromboprophylaxis in patients with high-grade glioma. PMID- 29715572 TI - Risk Factors for Perioperative Blood Transfusions in Adult Spinal Deformity Surgery. AB - OBJECTIVE: Adult spinal deformity (ASD) surgery is associated with a high rate of perioperative blood transfusions, and it is important to understand the risk factors for perioperative blood transfusions to implement strategies to reduce transfusions. The aim of this study was to identify independent risk factors of perioperative blood transfusions in patients undergoing surgery for ASD. METHODS: A retrospective cohort study was performed using the American College of Surgeons National Surgical Quality Improvement Program database from 2010 to 2014. Adult patients undergoing surgery for ASD were separated into 2 cohorts based on whether they received a perioperative blood transfusion. Univariate and multivariate regression models were used to identify risk factors for blood transfusion. RESULTS: In our cohort of 5805 patients, 27.1% received a blood transfusion. Multivariate regression analysis showed that patient-specific risk factors were age 65 years or older (odds ratio [OR], 1.74; 95% confidence interval [CI], 1.49-2.03; P < 0.001), American Society of Anesthesiologists classification of 3 or greater (OR, 1.18; 95% CI, 1.01-1.37; P = 0.033), cardiac comorbidity (OR, 1.21; 95% CI, 1.03-1.41; P = 0.018) and bleeding disorder (OR, 2.01; 95% CI, 1.10-3.66; P = 0.023). Surgery-specific risk factors were a posterior approach (OR, 4.25; 95% CI, 3.46-5.22; P < 0.001), pelvic fixation (OR, 1.73; 95% CI, 1.36-2.20; P < 0.001), and osteotomy (OR, 2.08; 95% CI, 1.71-2.51; P < 0.001). Longer operative time was also a risk factor with a duration dependent effect on the odds of blood transfusion. CONCLUSIONS: Recognition of patient- and surgery-specific risk factors for perioperative blood transfusion is important to identify patients who are at high risk and to implement strategies to minimize intraoperative blood loss and decrease healthcare costs. PMID- 29715573 TI - Primary Ewing Sarcoma of Frontotemporal Bone in Geriatric Patient. AB - BACKGROUND: Ewing sarcoma is a rare primary malignant bone tumor, which mainly affects children and adolescents. Calvarial bone involvement and its appearance in elderly patients are extremely rare. CASE DESCRIPTION: We presented a 68-year old female patient with headache and right frontotemporal swelling. Imaging studies showed a right frontotemporal mass expanding to the Sylvian fissure. The patient underwent total resection of the mass, and pathologic evaluation ensured the diagnosis of primary Ewing sarcoma. The patient had adjuvant radiotherapy and chemotherapy after surgery. CONCLUSIONS: Prognosis and efficiency of treatment for primary Ewing sarcoma of skull are unclear in elderly patients because of the sarcoma's rare appearance. Therefore more clinical evaluation is necessary. This case is the oldest patient presented in the literature. PMID- 29715574 TI - Insights from parents of a child with leukaemia and healthcare professionals about sharing illness and treatment information: A qualitative research study. AB - BACKGROUND: Many parents report a strong desire to take on information-giving roles, and believe they are best positioned to discuss their child's illness with their child. Healthcare professionals have a supporting role to reduce the burden on parents who feel responsible for conveying information to their child and other family members. OBJECTIVE: To examine parents' and healthcare professionals' perceptions of roles in receiving and communicating information when a child is diagnosed with and treated for acute lymphoblastic leukaemia. DESIGN, SETTING AND PARTICIPANTS: We used the principles of a grounded theory approach. This was a single site study, recruiting from a principal children's cancer treatment centre in the United Kingdom. The sample included parents of children receiving and completed treatment for acute lymphoblastic leukaemia (n = 28), and healthcare professionals (n = 34). METHODS: Methods included individual interviews, face-to-face and telephone, focus groups, and an online forum. FINDINGS: Communication 'touch points' are many over the course of a child's cancer journey. We describe often 'mismatched' communication encounters where those seeking information and those providing information have different goals. Healthcare professionals in the encounter have expertise at the outset while parents have less expertise, but this expertise grows over time and this can increase the perceptions of this 'mismatch' and create different challenges. CONCLUSIONS: Considered in the context of middle range transition theory, we might suggest that parental foreground (seeking information directly) and background (passive actors) roles are the result of differing levels of uncertainty, and depend on the situation and preferences and child and family needs that may present differently over time in different contexts. Our work contributes to the emerging consensus that communication is more than a core set of skills that healthcare professionals just need to learn: clear specifications of mutual roles, responsibilities and a shared understanding of goals is also essential. PMID- 29715576 TI - Prognostic factors and the management of anaplastic meningioma. AB - OBJECTIVES: Anaplastic meningiomas (AMs)tend to have a higher local recurrence rate and metastasize. but few studies have reported on the prognosis and management of patients with AM, this study aimed to increase the understanding of the prognosis, management and history of AM. PATIENTS AND METHODS: All patients (n = 56) underwent surgeries in our hospital between December 2008 and January 2016. Postoperative pathology reports confirmed the diagnosis of AM. Prognostic factors and the management were analysed in this study. AM was then divided into two groups. One group was primary AM, the other group was secondary AM. RESULTS: Of all the 56 AM patients, 31 were male and 25 were female (male to female ratio of 1.24:1). The 1-, 3-, and 5-year progression-free survival (PFS) rates were 78.6%, 41.1% and 29.7%, respectively, and the corresponding overall survival (OS) rates were 82.1%, 50.1% and 45.0%, respectively. Homogeneous contrast might be a potential better prognostic factor for PFS (HR = 1.824, P = 0.083). Treatment with postoperative radiotherapy (PRT) was significantly associated with longer PFS (HR = 0.390, P = 0.007) and OS (HR = 0.376, P = 0.008) according to univariate analysis. Gross-total resection (GTR) was a favourable factor for PFS (HR = 2.059, P = 0.035) and OS (HR = 2.802, P = 0.004). CONCLUSION: Achieving GTR is a favourable treatment strategy for patients with AM in our study and patients receiving PRT after resection is essential. PMID- 29715575 TI - Advances in therapeutic targeting of the DNA damage response in cancer. AB - The DNA damage response (DDR) is a series of pathways and processes required to repair lesions to DNA. These pathways range from repairing strand breaks to the double helix, damaged bases formed after oxidation or deamination, inaccurate DNA replication resulting in mispaired base alignment, intrastrand crosslinks that trigger cell death, and a plethora of other genomic insults. The DDR is believed to be a critical component of radio and chemoresistance in many cancers as well, with the tumor's ability to repair therapy induced damage being an important tool used to survive traditional chemotherapeutic agents. Here we summarize advances made in specifically targeting DDR proteins in cancer therapy and project on the potential breakthroughs and pitfalls to arise as the field progresses. PMID- 29715577 TI - Are older patients with solitary spinal metastases fit for total en-bloc surgery? AB - OBJECTIVE: Due to radical resection, total en-bloc spondylectomy (TES) is associated with significant levels of surgical injury and spinal instability, particularly in elderly patients with solitary spinal metastases (SM), whether the possible benefits outweigh the risk requires intense consideration. Our aim was to compare and analyze the impact of age on patient prognosis. PATIENTS AND METHODS: This study investigated TES in 78 consecutive patients with solitary SM, who were divided into Group A (>65 years, n = 32) and group B (<60 years of age, n = 46). Surgical outcomes were assessed according to survival time, local recurrence, neurological function, pain, and quality of life before and after surgery. Differences between groups were statistically compared using analysis of variance (ANOVA) or chi-square tests. RESULTS: There was no significant difference between the two groups in terms of surgery duration, blood loss, blood transfusion or the duration of hospital stay (p > 0.05). Furthermore, there was no significant difference in the median survival time between the two groups (p > 0.05). However, the perioperative complication rate in group A was higher than that in group B (p < 0.05). There was no significant difference in terms of local recurrence rate when compared between group A and group B (p > 0.05), and there were no significant differences in terms of improvements in neurological function, Visual Analogue Scale and Karnofsky scores of patients between the two groups (p > 0.05). CONCLUSION: Older patients can experience survival and local recurrence rates that were similar to those of younger patients. Although older patients are at increased risk of perioperative complications, this factor does not appear to lead to serious adverse outcomes. Older patients are still good candidates to receive TES to cure solitary SM after careful preparation and strict selection. PMID- 29715578 TI - Leisure time physical activity of people with chronic spinal cord injuries. AB - OBJECTIVE: The aim of this study was to evaluate the nature of LTPA performed by patients with incomplete spinal cord injury a minimum of 12 months after injury. Therefore, the study investigates the impact of injury location on the form and frequency of LTPA, time between injury and commencement of LTPA, motivations to undertake such physical activity, as well as factors which reduce participation. PATIENT AND METHODS: The study included 75 patients aged 18-60. The number of patients according to injury location was as follows: 25 cervical (C = 25), 25 thoracial (Th = 25) and 25 lumbar (L = 25) spine injuries. Data concerning injury type and location was obtained from the patients' medical records and included results of clinical examinations and neuroimaging. To evaluate LTPA, a custom questionnaire was designed, and functional mobility assessments were obtained with the Barthel Index (BI). RESULTS: The study demonstrated that LTPA participation among examined SCI patients declined. At the time of the study, more than half of the patients (65%) declared participation in physical activity, mainly in the form of individually performed exercises. However, the frequency of LTPA was significantly lower compared with the period prior to injury (59% of persons). Engagement in LTPA was determined based on functional mobility, and the latter was measured with BI (r = 0.42, p < 0.001). More than half of the subjects (60%) were physically active within the first three years post injury. Exercising sessions occurred usually 3 to 5 times per week (40%). The motivating factors for committing to LTPA primarily included subjects' independent decisions (35%), followed by encouragement from another disabled person (20%). Barriers preventing from LTPA were related to architecture and transportation, and they accounted for 58% of cases where no LTPA was performed. CONCLUSIONS: Spinal cord injury negatively impacts LTPA by reducing its frequency. Functional mobility of patients with spinal cord injury determines their participation levels in LTPA. The first three years after injury is the period during which engagement and commitment to LTPA is developed. PMID- 29715579 TI - Role of calcium permeable channels in dendritic cell migration. AB - Calcium ion (Ca2+) is an essential second messenger involved in multiple cellular and subcellular processes. Ca2+ can be released and sensed globally or locally within cells, providing complex signals of variable amplitudes and time-scales. The key function of Ca2+ in the regulation of acto-myosin contractility has provided a simple explanation for its role in the regulation of immune cell migration. However, many questions remain, including the identity of the Ca2+ stores, channels and upstream signals involved in this process. Here, we focus on dendritic cells (DCs), because their immune sentinel function heavily relies on their capacity to migrate within tissues and later on between tissues and lymphoid organs. Deciphering the mechanisms by which cytoplasmic Ca2+ regulate DC migration should shed light on their role in initiating and tuning immune responses. PMID- 29715581 TI - Equal kinematics and visual context but different purposes: Observer's moral rules modulate motor resonance. AB - Motor resonance is considered to be an index of the automatic under threshold motor replica of the observed action. Similar actions may be quite different in terms of long-term goals (e.g., grasp to eat vs grasp to throw) and, recently, it has been proposed that the distal goal subtly modulates movements execution, and that observers automatically use these differences in kinematics to discriminate between different intentions. This interpretation is in line with computational approaches proposing that in the agent the generative process causes that intention shapes the kinematics, and in the observer the recognition process causes that the kinematics cues the intention. Given the close entanglement between the two processes, here we investigated whether the mere knowledge of agent's intentions induces in the observer a generative process able to modulate motor resonance. We used transcranial magnetic stimulation to examine motor evoked potentials in the Opponens Pollicis muscle to verify if observer's knowledge of agent's positive, negative, or neutral intentions on a third person influences corticospinal excitability during observation of the same action performed with equal kinematics, and in the same visual context. Results showed that the observation of an action executed with the intention to induce negative effects determined a reduction of motor resonance, revealing the presence of a specific inhibition to reenact an action that results in unpleasant consequences in the other. These data suggest that the information at the intention level activates a generative process which overcomes the replica of kinematics at the goal level, and shapes motor resonance according with observer's mind and not with agent's intention, revealing the possibility of a mere cognitive influence on motor resonance based on individual's ethical values. PMID- 29715580 TI - Expression of p27 and c-Myc by immunohistochemistry in breast ductal cancers in African American women. AB - OBJECTIVES: Proteins p27 and c-Myc are both key players in the cell cycle. While p27, a tumor suppressor, inhibits progression from G1 to S phase, c-Myc, a proto oncogene, plays a key role in cell cycle regulation and apoptosis. The objective of our study was to determine the association between expression of c-Myc and the loss of p27 by immunohistochemistry (IHC) in the four major subtypes of breast cancer (BC) (Luminal A, Luminal B, HER2, and Triple Negative) and with other clinicopathological factors in a population of 202 African-American (AA) women. MATERIALS AND METHODS: Tissue microarrays (TMAs) were constructed from FFPE tumor blocks from primary ductal breast carcinomas in 202 AA women. Five micrometer sections were stained with a mouse monoclonal antibody against p27 and a rabbit monoclonal antibody against c-Myc. The sections were evaluated for intensity of nuclear reactivity (1-3) and percentage of reactive cells; an H-score was derived from the product of these measurements. RESULTS: Loss of p27 expression and c-Myc overexpression showed statistical significance with ER negative (p < 0.0001), PR negative (p < 0.0001), triple negative (TN) (p < 0.0001), grade 3 (p = 0.038), and overall survival (p = 0.047). There was no statistical significant association between c-Myc expression/p27 loss and luminal A/B and Her2 overexpressing subtypes. CONCLUSION: In our study, a statistically significant association between c-Myc expression and p27 loss and the triple negative breast cancers (TNBC) was found in AA women. A recent study found that constitutive c Myc expression is associated with inactivation of the axin 1 tumor suppressor gene. p27 inhibits cyclin dependent kinase2/cyclin A/E complex formation. Axin 1 and CDK inhibitors may represent possible therapeutic targets for TNBC. PMID- 29715582 TI - Does dynamic information about the speaker's face contribute to semantic speech processing? ERP evidence. AB - Face-to-face interactions characterize communication in social contexts. These situations are typically multimodal, requiring the integration of linguistic auditory input with facial information from the speaker. In particular, eye gaze and visual speech provide the listener with social and linguistic information, respectively. Despite the importance of this context for an ecological study of language, research on audiovisual integration has mainly focused on the phonological level, leaving aside effects on semantic comprehension. Here we used event-related potentials (ERPs) to investigate the influence of facial dynamic information on semantic processing of connected speech. Participants were presented with either a video or a still picture of the speaker, concomitant to auditory sentences. Along three experiments, we manipulated the presence or absence of the speaker's dynamic facial features (mouth and eyes) and compared the amplitudes of the semantic N400 elicited by unexpected words. Contrary to our predictions, the N400 was not modulated by dynamic facial information; therefore, semantic processing seems to be unaffected by the speaker's gaze and visual speech. Even though, during the processing of expected words, dynamic faces elicited a long-lasting late posterior positivity compared to the static condition. This effect was significantly reduced when the mouth of the speaker was covered. Our findings may indicate an increase of attentional processing to richer communicative contexts. The present findings also demonstrate that in natural communicative face-to-face encounters, perceiving the face of a speaker in motion provides supplementary information that is taken into account by the listener, especially when auditory comprehension is non-demanding. PMID- 29715583 TI - Does inhibition cause forgetting after selective retrieval? A reanalysis and failure to replicate. AB - Retrieval practice can produce forgetting, but it remains unclear using only behavioral data whether this forgetting is caused by targeted inhibition versus interference. Therefore, Wimber et al. (2015) used pattern classifier analyses of fMRI data to track individual memories in a novel variant of retrieval induced forgetting. After initial learning, people recalled target images across selective retrieval practice trials, and cortical activity patterns gradually became more similar to those evoked by the target pictures (i.e., pattern enhancement) and less similar to those evoked by competing pictures (i.e., pattern suppression). The key question was whether this inhibition of competing memories would cause forgetting. Wimber et al. found a significant forgetting effect (p<.01) on a subsequent forced choice picture recognition test, with lower accuracy for competitors than for baseline items. Because fMRI data is correlative, a causal interpretation of the data would require, at a minimum, more forgetting following cortical pattern suppression (as occurred for competitors) than cortical pattern enhancement (as occurred for targets). The interaction necessary to reach this conclusion was significant (p=.041). However, reanalyzing the original data revealed that the interaction depended on the decision to code missing responses as equivalent to choosing the wrong picture. Even if missing trials reflected memory failures, at worst they would produce 50/50 guessing, rather than an error every time. Treating these trials as missing, or setting them to chance performance, resulted in no reliable forgetting difference between competitors and targets. Because this might reflect inadequate statistical power, we undertook two replication attempts of the behavioral paradigm, failing both times to observe more forgetting for competitors than targets. In fact, we failed to find any forgetting at all. We conclude that the study of Wimber et al. does not support the conclusion that forgetting is caused by targeted inhibition. PMID- 29715585 TI - On the interaction of the highly charged peptides casocidins with biomimetic membranes. AB - Casocidin I and II (CI and CII) are structurally related antimicrobial peptides made of 39 and 31 amino acids, respectively, which derive from natural proteolytic processing of alphas2-casein and adopt an ordered alpha-helical structure in biomimetic membranes. Their putative membrane-permeabilizing activity was investigated at Hg-supported self-assembled monolayers (SAMs) and at tethered bilayer lipid membranes (tBLMs); the latter consisted of a monolayer of 2,3,di-O-phytanyl-sn-glycerol-1-tetraethylene-glycol-d,l-alpha lipoic acid ester thiolipid (DPTL), with a dioleoylphosphatidylcholine (DOPC) or dioleoylphosphatidylserine (DOPS) monolayer on top of it. Interaction of CI and CII with these biomimetic membranes was studied by four electrochemical techniques at pH 3, 5.4 and 6.8. Peptide incorporation in tBLMs was attempted via scans of electrochemical impedance spectra. Experiments demonstrated that CI and CII penetrate SAMs as well as the distal DOPC monolayer of DPTL/DOPC tBLMs, but not the proximal phytanyl monolayer, with the only exception of CII at pH 5.4. Conversely, CII permeabilized DPTL/DOPS tBLMs to a moderate extent at all investigated pH values by forming holes across the membrane, but not ion channels. Structural distribution of charged residues seemed to prevent CII from having a hydrophobic side of the alpha-helix capable of stabilizing a regular ion channel in the lipid matrix. PMID- 29715584 TI - DUOX2-mediated production of reactive oxygen species induces epithelial mesenchymal transition in 5-fluorouracil resistant human colon cancer cells. AB - The therapeutic benefits offered by 5-fluorouracil (5-FU) are limited because of the acquisition of drug resistance, the main cause of treatment failure and metastasis. The ability of the cancer cells to undergo epithelial-mesenchymal transition (EMT) contributes significantly to cancer metastatic potential and chemo-resistance. However, the underlying molecular mechanisms of 5-FU-resistance have remained elusive. Here, we show that reactive oxygen species (ROS), produced by dual oxidase 2 (DUOX2), promote 5-FU-induced EMT. First, we showed that 5-FU resistant SNUC5 colon cancer cells (SNUC5/FUR cells) undergo EMT by analyzing the expression of EMT markers such as N-cadherin, vimentin and E-cadherin. In addition, we found that the resistant cells expressed higher levels of Snail, Slug, Twist and Zeb1, which are all critical EMT regulators and had enhanced migratory and invasive capabilities. Furthermore, SNUC5/FUR cells had increased level of DUOX2, resulting in increased ROS level. This effect was due to the enhanced binding of the ten eleven translocation 1 (TET1) demethylase to the DUOX2 promoter in the SNUC5/FUR cells. Importantly, silencing of TET1 reversed the effects of 5-FU on the cells. Finally, the antioxidant N-acetylcysteine attenuated the effects of 5-FU on EMT and metastasis. Our study demonstrates the existence of a TET1/DUOX2/ROS/EMT axis that could play a role in colon cancer chemo-resistance and the aggressiveness of this cancer. PMID- 29715586 TI - Biological effects in photodynamic treatment combined with electropermeabilization in wild and drug resistant breast cancer cells. AB - Electrochemotherapy became one of the therapeutic protocols successfully used in oncology. However, biological effects occurring in cells, especially those which are drug resistant, have not been studied thoroughly. This study presents response of wild and drug resistant breast cancer cells to classical photodynamic therapy with Photofrin or experimental photodynamic therapy with cyanine IR-775, combined with electroporation. Photodynamic reaction or electroporation alone had no cytotoxic effect, but their combination significantly disturbed cellular functions. Applying electroporation allowed the drugs to increase its accumulation, especially for a poorly permeant cyanine in drug resistant cells. FACS analysis showed that even at relatively mild electric field, ca. 90% of cells were permeabilized. High intracellular concentration of drugs triggered the cellular defense system through increased expression of glutathione S-transferase and multidrug resistance proteins (MDR1 and MRP7), particularly in drug resistant cells. Finally, expressively decreased cell metabolism and proliferation, as well as formation of apoptotic bodies and fragmentation of cells were observed after the combined treatment. The results show that electroporation can be used for effective delivery of photosensitizers, even to drug resistant breast cancer cells, which was not tested before. This shows that electro-photodynamic treatment could be a promising approach to overcome a problem of drug resistance in cancer cells. PMID- 29715587 TI - Ex vivo vessel wall thickness measurements of the human circle of Willis using 7T MRI. AB - BACKGROUND AND AIMS: MRI can detect intracranial vessel wall thickening before any luminal stenosis is present. Apart from representing a vessel wall lesion, wall thickening could also reflect normal (age-related) variations in vessel wall thickness present throughout the intracranial arterial vasculature. The aim of this study was to perform vessel wall thickness measurements of the major intracranial arteries in ex vivo circle of Willis (CoW) specimens using 7T MRI, to obtain more detailed information about wall thickness variations of the intracranial arteries. METHODS: Fifteen human CoW specimens were scanned at 7T MRI with an ultrahigh-resolution T1-weighted sequence. Five specimens were used for validation of MRI measurements with histology and evaluation of inter-rater reliability and agreement. The other 10 specimens from patients with (n = 5) and without (n = 5) cerebrovascular disease were used for vessel wall thickness measurements over the entire length of the major arterial segments of the CoW using MRI only. RESULTS: MRI measurements showed excellent agreement with histology. Mean wall thickness varied from 0.45 to 0.66 mm, minimum wall thickness from 0.31 to 0.42 mm, maximum wall thickness from 0.52 to 0.86 mm, and normalized wall index from 0.64 to 0.75. On average, vessel walls were thicker for symptomatic patients compared to asymptomatic patients. CONCLUSIONS: High resolution MRI enables accurate measurement of vessel wall thickness in ex vivo CoW specimens. Vessel wall thickness measurements over the entire length of segments showed considerable variation both within and between arterial segments of patients. PMID- 29715588 TI - Thalamocortical function in developing sensory circuits. AB - Thalamocortical activity patterns, both spontaneous and evoked, undergo a dramatic shift in preparation for the onset of rich sensory experience (e.g. birth in humans; eye-opening in rodents). This change is the result of a switch from thalamocortical circuits tuned for transmission of spontaneous bursting in sense organs, to circuits capable of high resolution, active sensory processing. Early 'pre-sensory' tuning uses amplification generated by corticothalamic excitatory feedback and early-born subplate neurons to ensure transmission of bursts, at the expense of stimulus discrimination. The switch to sensory circuits is due, at least in part, to the coordinated remodeling of inhibitory circuits in thalamus and cortex. Appreciation of the distinct rules that govern early circuit function can, and should, inform translational studies of genetic and acquired developmental dysfunction. PMID- 29715589 TI - Stigma at every turn: Health services experiences among people who inject drugs. AB - BACKGROUND: People who inject drugs (PWID) encounter varying forms of stigma in health services contexts, which can contribute to adverse outcomes. We explored the lived experience of stigma among PWID to elucidate pathways by which stigma influences health care access and utilization. METHODS: We conducted 46 qualitative interviews with PWID in California's Central Valley between March and December 2015, as part of a multi-phase, multi-method study examining implementation of a new pharmacy syringe access law. A "risk environment" framework guided our data collection and we used a deductive/inductive approach to analyze the qualitative data. RESULTS: Participants repeatedly cited the impact of stigma on syringe access, particularly in the context of meso-level pharmacist interactions. They described being denied syringe purchase as stigmatizing and embarrassing, and these experiences discouraged them from attempting to purchase syringes under the new pharmacy access law. Participants described feeling similarly stigmatized in their meso-level interactions with first responders and hospital staff, and associated this stigmatization with delayed and substandard medical care for overdoses and injection-related infections. Drug treatment was another area where stigma operated against PWID's health interests; participants described macro-level public stigma towards methadone (e.g., equating methadone treatment with illicit drug use) as discouraging participation in this evidence-based treatment modality and justifying exclusion of methadone patients from recovery support services like sober living and Narcotics Anonymous. CONCLUSION: Stigma played an undeniably important role in PWID's experiences with health services access and utilization in the Central Valley. Our study illustrates the need to develop and test interventions that target drug use stigma at both structural and individual levels to minimize adverse effects on PWID health. PMID- 29715590 TI - Interventions to increase testing, linkage to care and treatment of hepatitis C virus (HCV) infection among people in prisons: A systematic review. AB - BACKGROUND: While the burden of chronic hepatitis C virus (HCV) infection is significantly higher among people in prisons compared to the general population, testing and treatment uptake remain suboptimal. The aim of this systematic review was to synthesize evidence on the effectiveness of interventions to increase HCV testing, linkage to care and treatment uptake among people in prisons. METHODS: We searched Medline (Ovid 1996-present), Embase (Ovid 1996-present), and the Cochrane Central Register of Controlled Trials for English language articles published between January 2007 and November 2017. Studies evaluating interventions to enhance HCV testing, linkage to care and treatment uptake for people in prison were included. Two independent reviewers evaluated articles selected for full-text review. Disagreements were resolved by consensus. RESULTS: A total of 475 unique articles were identified, 29 were eligible for full text review, and six studies were included. All but one study was conducted in the pre direct-acting antiviral (DAA) era; no studies were conducted in low- or middle income countries. Of the six studies, all but one focused on testing. Only two were randomised controlled trials; the remaining were single arm studies. Interventions to enhance HCV testing in prison settings included combination risk based and birth-cohort screening strategies, on-site nurse-led opt-in screening clinics with pre-test counselling and education, and systematic dried blood spot testing. All interventions increased HCV testing, but risk of study bias was high in all studies. Interventions to enhance linkage to care included facilitated referral for HCV assessment and scheduling of specialist appointments; however, risk of study bias was critical. CONCLUSIONS: There is a lack of recent data on interventions to improve the HCV care cascade in people in prisons. With the introduction of short-course, well-tolerated DAAs, rigorous controlled studies evaluating interventions to improve testing, linkage and treatment uptake for people in prison are necessary. PMID- 29715592 TI - Fucoidan/VEGF-based surface modification of decellularized pulmonary heart valve improves the antithrombotic and re-endothelialization potential of bioprostheses. AB - Decellularized porcine heart valves offer promising potential as biocompatible prostheses. However, this procedure alter matrix fibres and glycans, leading to lower biomechanical resistance and increased their thrombotic potential. Therefore, their durability is limited due to calcification and weak regeneration in vivo. Surface modifications are highly requested to improve the scaffolds re endothelialization required to restore functional and haemocompatible heart valve. Fucoidan, a natural sulphated polysaccharide, carries antithrombotic and anti-inflammatory properties and is known to enhance endothelial adhesion and proliferation when associated with vascular endothelial growth factor (VEGF). Based on these features, we constructed fucoidan/VEGF polyelectrolyte multilayer film (PEM) coated valve scaffold in an attempt to develop functional heart valve bioprosthesis. We investigated the haemocompatibility of the PEM coated valve scaffolds, the adhesion and growth potential of endothelial cells (HUVECs) in flow, as well as long term culture with stem cells. Fucoidan/VEGF PEM coated scaffolds demonstrated antithrombotic and non-calcifying properties. The PEM application increased HUVECs adhesion in flow (6 h) and HUVECs viability over time (72 h). HUVECs were well spread and aligned in flow direction. Interestingly, stem cells infiltration was improved by the PEM coating at 21 days. Thus, the fucoidan/VEGF PEM is a promising surface modification to obtain valve bioprostheses for clinical applications with increased antithrombotic and re-endothelialization potential. PMID- 29715591 TI - Porphyrins and flavins as endogenous acceptors of optical radiation of blue spectral region determining photoinactivation of microbial cells. AB - It is shown that exposure of suspensions of gram-positive Staphylococcus aureus, gram-negative Escherichia coli and yeast-like fungi Candida albicans to laser radiation of blue spectral region with 405 and 445 nm causes their growth inhibition without prior addition of exogenous photosensitizers. It is experimentally confirmed that compounds of flavin type capable of sensitizing the formation of reactive oxygen species can act as acceptors of optical radiation of blue spectral region determining its antimicrobial effect along with endogenous metal-free porphyrins (the role of endogenous porphyrins has been confirmed earlier by a number of researchers). The participation of these compounds in the antimicrobial effect of laser radiation is supported by the registration of porphyrin and flavin fluorescence in extracts of microbial cells upon excitation by radiation used to inactivate the pathogens. In addition, the intensity of the porphyrin fluorescence in extracts of microbial cells in the transition from radiation with lambda = 405 nm to radiation with lambda = 445 nm decreases by 15 30 times, whereas the photosensitivity of the cells under study in this transition decreases only 3.7-6.2 times. The contribution of porphyrin photosensitizers is most pronounced upon exposure to radiation with lambda = 405 nm (absorption maximum of the Soret band of porphyrins), and flavins - upon exposure to radiation with lambda = 445 nm (maximum in the flavin absorption spectrum and minimum in the absorption spectrum of porphyrins). The ratio between the intensity of the porphyrin and flavin components in the fluorescence spectrum of extracts depends on the type of microbial cells. PMID- 29715593 TI - Microdevice arrays with strain sensors for 3D mechanical stimulation and monitoring of engineered tissues. AB - Native and engineered tissue development are regulated by the integrative effects of multiple microenvironmental stimuli. Microfabricated bioreactor array platforms can efficiently dissect cue-response networks, and have recently integrated critical 2D and 3D mechanical stimulation for greater physiological relevance. However, a limitation of these approaches is that assessment of tissue functional properties is typically limited to end-point analyses. Here we report a new deformable membrane platform with integrated strain sensors that enables mechanical stretching or compression of 3D cell-hydrogel arrays and simultaneous measurement of hydrogel construct stiffness in situ. We tested the ability of the integrated strain sensors to measure the evolution of the stiffness of cell hydrogel constructs for two cases. First, we demonstrated in situ stiffness monitoring of degradable poly (ethylene glycol)-norbornene (PEG-NB) hydrogels embedded with mesenchymal stromal cells (MSCs) and cultured with or without cyclic tensile stimulation for up to 15 days. Whereas statically-cultured hydrogels degraded and softened throughout the culture period, mechanically stimulated gels initially softened and then recovered their stiffness corresponding to extensive cell network and collagen production. Second, we demonstrated in situ measurement of compressive stiffening of MSC-seeded PEG-NB gels cultured statically under osteogenic conditions, corresponding to increased mineralization and cellularization. This measurement technique can be generalized to other relevant bioreactor and organ-on-a-chip platforms to facilitate online, non-invasive, and high-throughput functional analysis, and to provide insights into the dynamics of engineered tissue development that are otherwise not available. PMID- 29715594 TI - Involvement of neural crest and paraxial mesoderm in oral mucosal development and healing. AB - Tissue engineering therapies using adult stem cells derived from neural crest have sought accessible tissue sources of these cells because of their potential pluripotency. In this study, the gingiva and oral mucosa and their associated stem cells were investigated. Biopsies of these tissues produce neither scarring nor functional problems and are relatively painless, and fresh tissue can be obtained readily during different chairside dental procedures. However, the embryonic origin of these cells needs to be clarified, as does their evolution from the perinatal period to adulthood. In this study, the embryonic origin of gingival fibroblasts were determined, including gingival stem cells. To do this, transgenic mouse models were used to track neural crest derivatives as well as cells derived from paraxial mesoderm, spanning from embryogenesis to adulthood. These cells were compared with ones derived from abdominal dermis and facial dermis. Our results showed that gingival fibroblasts are derived from neural crest, and that paraxial mesoderm is involved in the vasculogenesis of oral tissues during development. Our in vitro studies revealed that the neuroectodermal origin of gingival fibroblasts (or gingival stem cells) endows them with multipotential properties as well as a specific migratory and contractile phenotype which may participate to the scar-free properties of the oral mucosa. Together, these results illustrate the high regenerative potential of neural crest-derived stem cells of the oral mucosa, including the gingiva, and strongly support their use in cell therapy to regenerate tissues with impaired healing. PMID- 29715595 TI - Design of a vascularized synthetic poly(ethylene glycol) macroencapsulation device for islet transplantation. AB - The use of immunoisolating macrodevices in islet transplantation confers the benefit of safety and translatability by containing transplanted cells within a single retrievable device. To date, there has been limited development and characterization of synthetic poly(ethylene glycol) (PEG)-based hydrogel macrodevices for islet encapsulation and transplantation. Herein, we describe a two-component synthetic PEG hydrogel macrodevice system, designed for islet delivery to an extrahepatic islet transplant site, consisting of a hydrogel core cross-linked with a non-degradable PEG dithiol and a vasculogenic outer layer cross-linked with a proteolytically sensitive peptide to promote degradation and enhance localized vascularization. Synthetic PEG macrodevices exhibited equivalent passive molecular transport to traditional microencapsulation materials (e.g., alginate) and long-term stability in the presence of proteases in vitro and in vivo, out to 14 weeks in rats. Encapsulated islets demonstrated high viability within the device in vitro and the incorporation of RGD adhesive peptides within the islet encapsulating PEG hydrogel improved insulin responsiveness to a glucose challenge. In vivo, the implementation of a vasculogenic, degradable hydrogel layer at the outer interface of the macrodevice enhanced vascular density within the rat omentum transplant site, resulting in improved encapsulated islet viability in a syngeneic diabetic rat model. These results highlight the benefits of the facile PEG platform to provide controlled presentation of islet-supportive ligands, as well as degradable interfaces for the promotion of engraftment and overall graft efficacy. PMID- 29715596 TI - Complex network theory for the identification and assessment of candidate protein targets. AB - In this work we use complex network theory to provide a statistical model of the connectivity patterns of human proteins and their interaction partners. Our intention is to identify important proteins that may be predisposed to be potential candidates as drug targets for therapeutic interventions. Target proteins usually have more interaction partners than non-target proteins, but there are no hard-and-fast rules for defining the actual number of interactions. We devise a statistical measure for identifying hub proteins, we score our target proteins with gene ontology annotations. The important druggable protein targets are likely to have similar biological functions that can be assessed for their potential therapeutic value. Our system provides a statistical analysis of the local and distant neighborhood protein interactions of the potential targets using complex network measures. This approach builds a more accurate model of drug-to-target activity and therefore the likely impact on treating diseases. We integrate high quality protein interaction data from the HINT database and disease associated proteins from the DrugTarget database. Other sources include biological knowledge from Gene Ontology and drug information from DrugBank. The problem is a very challenging one since the data is highly imbalanced between target proteins and the more numerous nontargets. We use undersampling on the training data and build Random Forest classifier models which are used to identify previously unclassified target proteins. We validate and corroborate these findings from the available literature. PMID- 29715597 TI - A systematic review of game technologies for pediatric patients. AB - Children in hospital are subjected to multiple negative stimuli that may hinder their development and social interactions. Although game technologies are thought to improve children's experience in hospital, there is a lack of information on how they can be used effectively. This paper presents a systematic review of the literature on the existing approaches in this context to identify gaps for future research. A total of 1305 studies were identified, of which 75 were thoroughly analyzed according to our review protocol. The results show that the most common approach is to design mono-user games with traditional computers or monitor-based video consoles, which serve as a distractor or a motivator for physical rehabilitation for primary school children undergoing fearful procedures such as venipuncture, or those suffering chronic, neurological, or traumatic diseases/injures. We conclude that, on the one hand, game technologies seem to present physical and psychological benefits to pediatric patients, but more research is needed on this. On the other hand, future designers of games for pediatric hospitalization should consider: 1. The development for kindergarten patients and adolescents, 2. Address the psychological impact caused by long-term hospitalization, 3. Use collaboration as an effective game strategy to reduce patient isolation, 4. Have purposes other than distraction, such as socialization, coping with emotions, or fostering physical mobility, 5. Include parents/caregivers and hospital staff in the game activities; and 6. Exploit new technological artifacts such as robots and tangible interactive elements to encourage intrinsic motivation. PMID- 29715598 TI - Administration of oxytocin during spontaneous labour: A national vignette-based study among midwives. AB - OBJECTIVE: (1) to assess variations in oxytocin use by midwives during spontaneous labour (indication, dose, moment), and (2) to identify factors potentially associated with oxytocin administration. DESIGN: descriptive cross sectional study using a case-vignette and questionnaire among French midwives from November 2015 to May 2016. METHODS: Midwives were asked to complete an online survey including a case-vignette with hourly partograms of a slowly progressing labour, and a short self-administered questionnaire. Two choices were proposed with each hourly partogram: administration of oxytocin or expectant management. Midwives who selected oxytocin were then asked about the dose, dose increment and dose-increase delay. The questionnaire asked the midwives about work experience, day or night work, and organisational factors. FINDINGS: The study included 204 midwives. At some point during the case-vignette, 159 (77.9%) midwives responded that they would use oxytocin. Answers demonstrated variations in oxytocin administration for initial doses, dose-increments and dose-increase delays. Specifically, a substantial majority of respondents chose high doses of oxytocin (64.1% at doses exceeding 2 mIU/min) and short dose-increase delays (62.9% under 30 min). Excessive administration of oxytocin by midwives was significantly associated with the number of births per year in their maternity unit, midwives' workload (p < 0.001), overload of delivery rooms (p < 0.001) and lack of protocol (22% versus 55.6%, p < 0.001). Midwives considered that their use of oxytocin was related mainly to an overburdened department (48.5%). KEY CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: We observed overuse of oxytocin, influenced by organisational factors. Every maternity unit should implement a protocol and/or checklist for oxytocin administration to reduce variation in practice and improve safety of care by using evidence-based clinical indications, initial doses, dose-increments and dose-increase delays. Modifying the organisation of care appears necessary to reduce hospital patient volume or increase staffing to ensure that the number of midwives on duty matches the activity in the delivery room without causing excess work or stress to midwives. PMID- 29715599 TI - Lanostane-type C31 triterpenoid derivatives from the fruiting bodies of cultivated Fomitopsis palustris. AB - Fifteen undescribed and five known lanostane-type C31 triterpenoid derivatives were isolated from the aqueous EtOH extract of the fruiting bodies of cultivated Fomitopsis palustris. Their structures were identified from the spectroscopic data and chemical degradation studies. The structures of palustrisoic acids A and H were confirmed by X-ray crystallography. Polyporenic acid B showed strong cytotoxicity against the HCT116, A549, and HepG2 cell lines with IC50 values of 8.4, 12.1, and 12.2 MUM, respectively. Palustrisolides A, C, and G displayed weak cytotoxicity. PMID- 29715600 TI - Caudatan A, an undescribed human kidney-type glutaminase inhibitor with tetracyclic flavan from Ohwia caudata. AB - Human kidney-type glutaminase (KGA) is an important target that is often over expressed in many cancer cells but very few effective inhibitors of this enzyme have yet reached clinical trials. Caudatan A and caudatan B, two undescribed tetracyclic flavans with an unusual ether bond between the C-4 and C-2' were isolated from the roots of Ohwia caudata (Thunb.) H.Ohashi. Caudatan A exhibited stronger inhibitory activity and caudatan B showed moderate effect from the results of inhibitory activities evaluations on KGA. The molecular docking and primary structure-activity relationship analysis revealed that the less steric hindrance at ring A was necessary to the effect. Therefore, combined its better solubility than that of bis-2-(5-phenylacetimido-1,2,4-thiadiazol-2-yl)ethyl sulfide (BPTES), caudatan A might be the potential candidate as the inhibitor of KGA for further studies. PMID- 29715601 TI - Longitudinal changes in persistent organic pollutants (POPs) from 2001 to 2009 in a sample of elderly Swedish men and women. AB - BACKGROUND: Prospective cohort studies evaluating the temporal trends of background-level persistent organic pollutants (POPs) and their potential negative health effects in humans are needed. OBJECTIVE: The objectives of this study are to examine the five year longitudinal trend in chlorinated and brominated (Cl/Br) POP concentrations in a sample of elderly individuals and to investigate the relationship between gender, changes in body weight, plasma lipid levels and POP concentrations. METHODS: In the population-based Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study, plasma samples were collected from the same individuals over a 5 year period. Originally 992 subjects (all aged 70) were sampled between 2001 and 2004 and 814 returning subjects (all aged 75) were sampled again from 2006 to 2009. Plasma concentrations of 16 polychlorinated biphenyls (PCBs), 5 organochlorine pesticides (OCPs), octachlorinated dibenzo-p-dioxin (OCDD), and one polybrominated diphenylether (BDE 47) were determined using high-throughput 96 well plate solid phase extraction and gas chromatography-high resolution mass spectrometry (GC-HRMS). RESULTS: During the 5-year follow-up, plasma concentrations of all POPs significantly decreased (p < 0.00001). Median reductions ranged from 4% (PCB105) to 45% (PCB 99), with most reductions being in the 30-40% range. For most POPs, a larger decline was seen in men than in women. The relationship between the weight change and change in POP concentrations was generally negative, but a positive relationship between lipid levels and POP concentrations when expressed as wet-weight was observed. In general, similar changes in POP concentrations and their relationships to body weight were observed regardless of using either wet-weight (pg/mL) or lipid-normalized (ng/g lipid) concentrations. CONCLUSION: In this longitudinal cohort study, gender and minor, but varying changes in body weight and lipid levels greatly influenced the individual-based changes in POP concentrations. In general, our findings suggest that men and women with larger decreases in body weight and greater increases in lipid levels have the slowest decline in body burden of POPs. Based on the results from this study, either wet-weight or lipid normalized concentrations can be used to determine the percent change in POP concentrations and their relationships to physiological changes and differences. PMID- 29715603 TI - Pro-technological and functional characterization of lactic acid bacteria to be used as starters for hemp (Cannabis sativa L.) sourdough fermentation and wheat bread fortification. AB - Lactic acid bacteria were isolated from hemp (Cannabis sativa L.) flour, spontaneously fermented dough, and type I sourdough. Isolates were identified and further selected based on pro-technological, nutritional and functional properties. Lactobacillus plantarum/s5, Pediococcus acidilactici/s5, and Leuconostoc mesenteroides/s1 were used as mixed starter to produce hemp sourdough. Significant decreases of the concentration of phytic acid, condensed tannins, and total saponins were observed during fermentation. The in vitro protein digestibility increased up to 90%. Experimental wheat breads were made adding 5% to 15% (w/w) hemp sourdough to the formula, characterized, and compared to baker's yeast wheat bread manufactured without hemp sourdough. The use of hemp sourdough improved the textural features of wheat bread, without adversely affect the sensory profile. Proportionally to the fortification with hemp sourdough, protein digestibility of the breads increased, while the predicted glycemic index significantly decreased (87 vs 100%). This work demonstrated that the fermentation with selected starters improved nutritional functionality of hemp flour, allowing its large-scale use in different food applications, meeting the consumers and producers request for novel fermented baked goods with a well balanced nutritional profile. PMID- 29715602 TI - Characterization of spoilage markers in modified atmosphere packaged iceberg lettuce. AB - Fresh cut iceberg lettuce spoilage was studied considering the microbial and biochemical activity, the formation of volatile organic compounds (VOC) and consumer acceptability. Lettuce was packaged under three different packaging conditions and stored at 4 degrees C for 10 days: anaerobic packaging (ANAER), equilibrium modified atmosphere packaging with 3% O2 (EMAP) and perforated packages (AIR). Results indicated a clear distinction between packaging conditions. EMAP and AIR resulted in a short shelf life (<=5.6 days) which was limited due to browning, leading to consumer rejection as assessed via the Weibull hazard analysis method, while no off-odors were detected. Culture- independent 16 s rRNA gene amplicon sequencing revealed Pseudomonas spp. as the dominating species. In contrast, under ANAER conditions, lactic acid bacteria dominated with genera of Leuconostoc spp. and Lactococcus spp. proliferating, while also oligotypes of Pseudomonas spp. were found. Spoilage under ANAER occurred after 6.6 days and it was related to strong fermentative-like off-odors that were present by the end of storage. As revealed by selective ion flow tube mass spectrometry (SIFT-MS), these odors were associated with several VOCs such as: ethanol, 3-methyl-1-butanol, 2,3-butanediol, (Z)-3-hexen-1-ol, hexanal, acetic acid, ethyl acetate and dimethyl sulfide. Panelists rejected the iceberg lettuce due to the formation of off-odors while the overall appearance remained good throughout the study. Hence a sensor based technology incorporated in the packaging, detecting VOCs and in particular ethanol as dominant compound, could serve as a spoilage indicator for ANAER packed lettuce, which proved to have the longest shelf life. PMID- 29715604 TI - Ultrasonic wave propagation in ternary intermetallic CeCuGe compound. AB - The elastic and ultrasonic properties of the hexagonal intermetallic CeCuGe ternary compound have been evaluated along unique axis at room temperature. Higher order elastic constants have been calculated for CeCuGe compound using Lennard-Jones interaction potential model. The ultrasonic velocity, Debye average velocity, thermal relaxation time and acoustic coupling constant are evaluated along unique axis of the crystal and the temperature dependent ultrasonic velocities are evaluated along different angles with unique axis of the crystal. Finally temperature dependent ultrasonic attenuation is evaluated to extract important information about the material. PMID- 29715605 TI - Effects of ultrasonic vibration on the compression of pure titanium. AB - The technology of ultrasonic vibration assisted plastic forming possesses a great many merits, such as reducing the deformation resistance and friction, as well as improving the surface quality of parts. In this study, the ultrasonic vibration assisted compression tests were carried out on pure titanium in order to improve its formability. The results indicating that the ultrasonic vibration had no effort on elastic deformation, and the temperature of material only increased by 6 degrees C after compression with applying the ultrasonic vibration. Therefore the influence of temperature increase on reduction of flow stress could be ignored. After excluding interface friction and temperature effects, ultrasonic vibration can still decline the flow stress, the mechanism of deformation includes ultrasonic softening, stress superposition and strain hardening. In the intermittent vibration tests, the material shows the residual softening effect after stopping vibration. By observing the microstructure of material with SEM, it shows that the ultrasonic vibration can promote the generation of deformation twins, causing the grain refinement and the reduction of the twins, which is the major factor of affecting the residual softening effect. PMID- 29715606 TI - Examining internal and external job resources in child welfare: Protecting against caseworker burnout. AB - Given intense job demands, it is not surprising that job burnout is a consistent threat to the well-being and retention of the child welfare workforce. Guided by central postulates of the Job Demands and Resources (JD-R) model which suggests that job burnout develops because of experiences of high work demands coupled with low resources in the workplace, we applied a conceptual model of job burnout (client and work related) that accounts for both internal and external resources available to child welfare workers. Findings among child welfare caseworkers from three states (N = 1917) indicate that job demands (stress and time pressure) were positively related to client- and work-related burnout. Additionally, both internal and external resources moderated the relationships between job demands and client- and work-related burnout. Study findings have workforce management implications in the child welfare sector, including the role resources might play in mitigating the negative impact of job demands on burnout in the child welfare workforce. PMID- 29715607 TI - Conscious motor control impairs attentional processing efficiency during precision stepping. AB - BACKGROUND: Current evidence suggests that fall-related anxiety can impair attentional processing efficiency during gait in both young and older adults, reducing the cognitive resources available for carrying out concurrent tasks (i.e., holding a conversation whilst walking or planning the safest route for navigation). RESEARCH QUESTION: It has been suggested that fall-related anxiety may impair processing efficiency by directing attention 'internally', towards consciously controlling and monitoring movement. The present study aimed to evaluate this interpretation. METHODS: Fifteen healthy young adults performed a precision stepping task during both single- and dual-task (completing the stepping task while simultaneously performing an arithmetic task), under three conditions: (1) Baseline; (2) Threat (walking on a platform raised 1.1 m above ground), and; (3) Internal focus of attention (cues/instructions to direct attention towards movement processing). RESULTS: We observed significantly greater cognitive dual-task costs (i.e., poorer performance on the arithmetic task) during Threat compared to Baseline, with the greatest costs observed in individuals reporting the highest levels of Threat-induced conscious motor processing. Significantly greater cognitive dual-task costs were also observed during the Internal condition, confirming the assumption that consciously attending to movement reduces cognitive resources available for carrying out a secondary task during gait. These results were accompanied with significantly poorer stepping accuracy in dual-task trials during both Threat and Internal. SIGNIFICANCE: These findings support previous attempts to rationalise attentional processing inefficiencies observed in anxious walkers as being a consequence of an anxiety-induced internal focus of attention. PMID- 29715608 TI - Workplace victimization risk and protective factors for suicidal behavior among active duty military personnel. AB - BACKGROUND: Workplace victimization is a potential risk factor for suicidal behaviors (SB) among military personnel that has been largely overlooked. This paper examines both the impact of workplace victimization on reported SB and several potential protective factors associated with such suicidal behaviors in a large sample of active duty soldiers. METHODS: A case-control study was conducted with 71 soldiers who reported SB in the past 12 months, each matched on sociodemographic characteristics to two others without reported suicidal behaviors. A multiple regression model was estimated to assess the effects of risk and protective factors while controlling for other variables. RESULTS: SB was associated with several aspects of victimization, mental health and substance abuse conditions, pain, impulsivity, stressors, negative life events, work-family conflict, active coping behaviors and positive military-related factors. Controlling for other variables, those with SB were more likely to have sought mental health or substance abuse services, to be depressed, anxious, impulsive, and less resilient than non-SB personnel. LIMITATIONS: Study limitations included the use of retrospective self-report data, absence of some known SB predictors, and a population restricted to active duty Army personnel. CONCLUSIONS: SB among active duty personnel is associated with victimization since joining the military and is protected by resiliency. These findings suggest that in addition to the usual mental health factors, these additional predictors should be accounted for in SB intervention and prevention planning for active duty personnel. PMID- 29715609 TI - The impact of pre- and perinatal factors on psychopathology in adulthood. AB - BACKGROUND: There is considerable evidence that pre- and post-natal factors are associated with a wide range of psychopathology in offspring during childhood and adolescence. OBJECTIVE: The main aims of the present study were to examine the associations between pre- and perinatal factors and psychopathology in offspring during adulthood, and to explore whether family factors (i.e., family cohesion, mother's social support, and father's social support) mediate these relationships. METHOD: Information on pre- and perinatal events was collected from biological mothers of the participants (N = 315) when they were between 14 and 18 years who were then followed up until they reached age 30. RESULTS: Maternal obstetric history and illness during first year were significant predictors of offspring anxiety disorder. Maternal emotional health predicted offspring affective disorder. Difficult delivery and breast feeding predicted disruptive disorder. The relationship between maternal obstetric history/emotional health and anxiety/affective disorder was no longer significant after controlling for family cohesion. LIMITATIONS: The information was based on maternal recall when their offspring were between 14 and 18 years which may be subjected to recall bias. CONCLUSION: The association between pre- and postnatal factors and psychopathology of offspring during adulthood is mediated by familial factors. PMID- 29715610 TI - Meta-analysis: Second generation antidepressants and headache. AB - BACKGROUND: To assess the risk of headache associated with commonly prescribed antidepressant medications and to examine the impact of medication class, pharmacodynamics and dosage on risk of headache. METHODS: We searched PubMed to identify all randomized, double-blind, placebo-controlled trials examining the efficacy of second generation antidepressant medications in the treatment of adults with depression, anxiety or obsessive-compulsive disorders. We used a fixed-effect meta-analysis to examine the pooled risk ratio of headache reported as a side-effect in adults treated with second generation antidepressants compared to placebo. We used stratified subgroup analysis and meta-regression to examine the effects of medication type, class, dosage, indication, and receptor affinity profile on the measured risk of headache. RESULTS: SSRIs were associated with a significantly increased risk of headache (RR = 1.06, 95%CI = 1.00-1.13, z = 2.0, p = 0.045) when compared to placebo. There was no significant difference (test for subgroup differences chi2 = 2.2, df = 1, p = 0.14) in the risk of headache between SSRIs and SNRIs (RR = 0.97, 95%CI = 0.88-1.06, p = 0.63). There was no significant difference in the relative risk of headache with second generation antidepressants based on diagnostic indication, pharmacological properties and dosage of medications. The only antidepressants that were found to be significantly associated with increased risk of headache compared to placebo were bupropion (RR = 1.22, 95%CI = 1.06-1.41, z = 2.73, p = 0.006) and escitalopram (RR = 1.18, 95%CI = 1.01-1.37, z = 2.11, p = 0.04). LIMITATIONS: The small number of studies that examined side effects within fixed-dose trials may have limited the power to examine the association between medication dosing and risk of headache. Additionally, reporting bias could potentially occur non randomly across agents and therefore effect meta-analysis results. CONCLUSIONS: Headaches reported after the initiation of second generation antidepressant medications are more likely to be coincidental than a treatment-emergent side effect of these medications. PMID- 29715611 TI - Associations between short-term exposure to ambient sulfur dioxide and increased cause-specific mortality in 272 Chinese cities. AB - BACKGROUND: Ambient sulfur dioxide (SO2) remains a major air pollutant in developing countries, but epidemiological evidence about its health effects was not abundant and inconsistent. OBJECTIVES: To evaluate the associations between short-term exposure to SO2 and cause-specific mortality in China. METHODS: We conducted a nationwide time-series analysis in 272 major Chinese cities (2013 2015). We used the over-dispersed generalized linear model together with the Bayesian hierarchical model to analyze the data. Two-pollutant models were fitted to test the robustness of the associations. We conducted stratification analyses to examine potential effect modifications by age, sex and educational level. RESULTS: On average, the annual-mean SO2 concentrations was 29.8 MUg/m3 in 272 cities. We observed positive and associations of SO2 with total and cardiorespiratory mortality. A 10 MUg/m3 increase in two-day average concentrations of SO2 was associated with increments of 0.59% in mortality from total non-accidental causes, 0.70% from total cardiovascular diseases, 0.55% from total respiratory diseases, 0.64% from hypertension disease, 0.65% from coronary heart disease, 0.58% from stroke, and 0.69% from chronic obstructive pulmonary disease. In two-pollutant models, there were no significant differences between single-pollutant model and two-pollutant model estimates with fine particulate matter, carbon monoxide and ozone, but the estimates decreased substantially after adjusting for nitrogen dioxide, especially in South China. The associations were stronger in warmer cities, in older people and in less-educated subgroups. CONCLUSIONS: This nationwide study demonstrated associations of daily SO2 concentrations with increased total and cardiorespiratory mortality, but the associations might not be independent from NO2. PMID- 29715612 TI - A metal-organic framework with large 1-D channels and rich OH sites for high efficiency chloramphenicol removal from water. AB - High-efficiency removal of chloramphenicol (CAP) drug from waste water still faces a large challenge up to date. Herein, we report the first metal-organic framework-based adsorbent (PCN-222) for CAP and effective removal was achieved. PCN-222 exhibits a large adsorption capacity of 370 mg g-1, superior to some other MOFs and various reported adsorbents; and more importantly, the adsorption equilibrium can be quickly obtained at only 58 s. Besides, ~99.0% of CAP can be removed from water in the low concentrations (including the concentrations found in real water). Further investigation indicates that H-bond interaction, electrostatic interaction and the special pore structure of PCN-222 all play important effects on the high-efficiency removal of CAP. Therefore, our work may provide a novel perspective for removing CAP or other antibiotic drugs from contaminated water. PMID- 29715613 TI - Role of poly-beta-amino-esters hydrolysis and electrostatic attraction in gentamicin release from layer-by-layer coatings. AB - Layer-by-layer (LbL) deposition is a versatile technique that has been employed in numerous industrial applications i.e. biomaterials, drug delivery and electronics to confer peculiar properties to the system. When LbL is employed for drug delivery, the active molecule is sandwiched between layers of polyelectrolytes and the release is controlled by the diffusion of the drug through the layers and the possible hydrolysis of the coating (delamination). Poly-beta-amino-esters (PBAEs) are a class of hydrolysable polyelectrolytes that have been widely used in DNA delivery and for LbL on medical devices. Their use allowed the controlled release of antibiotics and other bioactive compounds from the surface of medical devices without cytotoxic effects. The general accepted consensus is that drug released from LbL coating assembled using PBAEs is the results of the polymer hydrolysis; however, no attention has been paid to the role of the electrostatic attraction between PBAE and the other polyelectrolyte utilised in the LbL assembly. In this work, we prepared LbL coatings on the surface of silica nanoparticles entrapping gentamicin as model drug and demonstrated that the drug release from PBAEs containing LbL coatings is predominantly controlled by the electrostatic attraction between opposite charged electrolytes. The positive charge of PBAE decreased from pH = 5 to pH = 7.4 while alginate negative charges remained unchanged in this pH range while PBAE hydrolysis kinetics was faster, as determined with Gel Permeation Chromatography (GPC), in acidic conditions. When PBAE were employed in the LbL construct higher levels of drug were released at pH = 7.4 than at pH = 5; additionally, replacing PBAE with chitosan (the charge of chitosan is not influenced in this pH range) resulted in comparable gentamicin release kinetics at pH = 5. PMID- 29715614 TI - Corrosion resistance and antibacterial properties of polysiloxane modified layer by-layer assembled self-healing coating on magnesium alloy. AB - Magnesium (Mg) alloys have shown great potential in biomedical materials due to their biocompatibility and biodegradability. However, rapid corrosion rate, which is an inevitable obstacle, hinders their clinical applications. Besides, it is necessary to endow Mg alloys with antibacterial properties, which are crucial for temporary implants. In this study, silver nanoparticles (AgNPs) and polymethyltrimethoxysilane (PMTMS) were introduced into AZ31 Mg alloys via layer by-layer (LbL) assembly and siloxane self-condensation reaction. The characteristics of the composite films were investigated by SEM, UV-vis, FT-IR, and XRD measurements. Corrosion resistance of the samples was measured by electrochemical and hydrogen evolution tests. Antibacterial activities of the films against Staphylococcus aureus were evaluated by plate-counting method. The results demonstrated that the composite film with smooth and uniform morphologies could enhance the corrosion resistance of Mg alloys owing to the physical barrier and the self-healing functionality of polysiloxane. Moreover, the composite coating possessed antibacterial properties and could prolong the release of assembled silver ions. PMID- 29715615 TI - Miniaturization of thiol-organosilica nanoparticles induced by an anionic surfactant. AB - Thiol-organosilica nanoparticles are a promising nanomaterial for biomedical applications. The enhanced permeability and retention (EPR) effect is useful for tumor targeting within the biomedical applications of nanomaterials, and nanomaterials with a size of less than 200 nm exhibit the maximum EPR effect. However, the synthesis of thiol-organosilica nanoparticles with a diameter of less than 200 nm is not efficient for the yield using the present conventional synthetic methods. Herein, we report the development of an efficient synthetic method of thiol-organosilica nanoparticles with a diameter of less than 200 nm using an anionic surfactant and discuss its mechanism. Compared with the conventional synthetic methods, a greater than 10-fold miniaturization of thiol organosilica nanoparticles and an approximately 40-fold increase in the production efficiency of small thiol-organosilica nanoparticles were achieved using the sodium dodecyl sulfate (SDS)-addition synthetic method or sodium dodecylbenzenesulfonate (SDBS)-addition synthetic method. This is the first report about the miniaturization of organosilica nanoparticles induced by an anionic surfactant. The SDS-addition synthetic method or SDBS-addition synthetic method will accelerate the biomedical applications of thiol-organosilica nanoparticles. PMID- 29715616 TI - A surfactant-free microemulsion consisting of water, ethanol, and dichloromethane and its template effect for silica synthesis. AB - A new type of surfactant-free microemulsion (SFME) containing water/ethanol/dichloromethane was constructed, and three microregions water-in dichloromethane (W/O), bicontinuous (B.C.) and dichloromethane-in-water (O/W) regions were identified. The polarity environment of the SFME was investigated. Solid silica nanoparticle (SSN) was selected as a model nanomaterial to investigate the feasibility of the water/ethanol/dichloromethane SFME for the preparation of nanomaterials. In the O/W SFME region of the microemulsions, uniform spherical solid silica nanoparticles (SSNs) were synthesized. Under the same experimental conditions, they are of smaller particle size and have narrower range of diameter distribution, than the SSNs synthesized from ethanol and water mixture. The effects of tetraethylorthosilicate concentration (CTEOS), ammonia hydroxide concentration ( [Formula: see text] ) and dichloromethane content on the size and morphology of the SSNs were investigated. The average diameters of the SSNs increased with increasing CTEOS and [Formula: see text] . However, the effect of increasing [Formula: see text] on the particle size is more significant. The time evolution of the morphology and diameter of the SSNs were also investigated to elucidate the growth mechanism for the SSNs synthesized in the O/W SFMEs. PMID- 29715617 TI - Debromination of polybrominated diphenyl ethers (PBDEs) and their conversion to polybrominated dibenzofurans (PBDFs) by UV light: Mechanisms and pathways. AB - Polybrominated diphenyl ethers (PBDEs) are typical flame retardant that have arose widely environmental concerns. Previous studies have found that PBDEs can generate lower BDEs and polybrominated dibenzofuran (PBDFs) under UV exposure, but these two processes were not well understood. In this study, we have investigated them through the case study of three BDE congeners (i.e. BDE-29, BDE 25 and BDE-21), which all have an ortho-, a meta- and a para-bromine substituents. The results shows that the vulnerability rank order of brominated position for these three BDE congeners are totally different, the bromine substituent at each position (ortho-, meta- or para-) can be preferentially removed, indicating it is not scientific to summarize the debromination pathways of PBDEs by comparing the brominated position. The lowest unoccupied molecular orbital (LUMO) of PBDEs in first excited state are well consistent with their actual debromination pathways, suggesting it is a good descriptor to predict the photodebromination pathways of PBDEs. In addition, the PBDEs with an ortho bromine substituent can generate lower PBDFs, and the first step is to generate lower BDEs with an ortho-carbon radical, followed by ring closure reaction to generate PBDFs. PMID- 29715618 TI - Research on the removal mechanism of antimony on alpha-MnO2 nanorod in aqueous solution: DFT + U method. AB - Although previous papers have reported the desorption process of antimony (Sb) ions adsorbed on alpha-MnO2 nanomaterials, some trace Sb(OH)4- molecular observed in experiments have not been understood clearly. Using two models as popular bulk surface and new microfacet, several parameters, such as adsorption energy, bond length, total density of state (TDOS) and activation energy, were calculated to research and analyze the catalytic reaction of Sb oxides on alpha-MnO2. The results show that the bulk surface model has the "mirror effect" in revealing the catalytic property of alpha-MnO2 nanorods. Using MnO2[(100 * 110)] microfacet model, a new molecular Sb(OH)4- molecular appears in the reaction process of Sb(OH)3 + H2O -> Sb(OH)4- + H+. Further comparing the geometric morphology and TDOS of Sb(OH)4- with Sb(OH)6- molecular, it is found that their bonding length, dihedral and energy orbital of bonding peaks are too close to set the Sb(OH)4- as the precursor product of Sb(OH)6- molecular. Then the desorption process of Sb ions on alpha-MnO2 nanorods is virtually transformed into Sb(OH)3 -> Sb(OH)4- -> Sb(OH)6- way in aqueous solution. Thus, our findings open an avenue for detailed and comprehensive theoretical studies of catalytic reaction by nanomaterials. PMID- 29715619 TI - Automated glycan assembly as an enabling technology. AB - Access to complex carbohydrates remains a limiting factor for the development of the glycosciences. Automated glycan assembly (AGA) has accelerated and simplified the synthetic process and, with the first commercially available instrument and building blocks, glycan synthesis can now be practiced by any chemist. All classes of glycans, including sulfated or sialylated carbohydrates and polysaccharides as long as 50mers are now accessible owing to optimized reaction conditions and new methodologies. These synthetic glycans have helped to understand many biological functions and to advance diagnostic and vaccine development. Establishing detailed structure-function relationships will eventually enable the production of unnatural materials with tuned properties. PMID- 29715620 TI - The innovation of cryo-SEM freeze-fracturing methodology demonstrated on high pressure frozen biofilm. AB - In this study we present an innovative method for the preparation of fully hydrated samples of microbial biofilms of cultures Staphylococcus epidermidis, Candida parapsilosis and Candida albicans. Cryo-scanning electron microscopy (cryo-SEM) and high-pressure freezing (HPF) rank among cutting edge techniques in the electron microscopy of hydrated samples such as biofilms. However, the combination of these techniques is not always easily applicable. Therefore, we present a method of combining high-pressure freezing using EM PACT2 (Leica Microsystems), which fixes hydrated samples on small sapphire discs, with a high resolution SEM equipped with the widely used cryo-preparation system ALTO 2500 (Gatan). Using a holder developed in house, a freeze-fracturing technique was applied to image and investigate microbial cultures cultivated on the sapphire discs. In our experiments, we focused on the ultrastructure of the extracellular matrix produced during cultivation and the relationships among microbial cells in the biofilm. The main goal of our investigations was the detailed visualization of areas of the biofilm where the microbial cells adhere to the substrate/surface. We show the feasibility of this technique, which is clearly demonstrated in experiments with various freeze-etching times. PMID- 29715621 TI - Elevated miR-20b-5p expression in peripheral blood mononuclear cells: A novel, independent molecular biomarker of favorable prognosis in chronic lymphocytic leukemia. AB - MicroRNA-20b-5p (miR-20b-5p) is part of the miR-106a/363 cluster and a member of the cancer-related miR-17 family. miR-20b-5p regulates important transcription factors, including hypoxia-inducible factor 1 (HIF1) and signal transducer and activator of transcription 3 (STAT3). Recently, the dysregulation of miR-20b-5p expression has been observed in many B-cell lymphomas and T-cell leukemias. In this research study, we examined the putative prognostic value of miR-20b-5p in CLL. Therefore, total RNA was isolated from peripheral blood mononuclear cells (PBMCs) collected from 88 CLL patients; next, total RNA was polyadenylated and first-strand cDNA was synthesized, using an oligo-dT-adapter primer. miR-20b-5p expression was quantified using an in-house-developed real-time quantitative PCR assay. Kaplan-Meier OS analysis and bootstrap univariate Cox regression showed that high miR-20b-5p expression predicts better OS for CLL patients (p < 0.001). Interestingly, miR-20b-5p overexpression retains its favorable prognostic role in CLL patients of intermediate risk or stratified according to established prognostic factors [CD38 expression and mutational status of the immunoglobulin heavy chain variable (IGHV) region]. In conclusion, miR-20b-5p is a potential independent molecular biomarker of favorable prognosis in CLL. PMID- 29715622 TI - Comparison of forensic photo-documentation to a photogrammetric solution using the multi-camera system "Botscan". AB - As forensic science technologies progress, digital photography has become outdated for certain documentations that require exact measurements. Recording three-dimensional objects on a two-dimensional photograph leads to a potential loss of relevant information. Photogrammetry has been utilized to record persons, objects or crime scenes and prevents this loss. Photogrammetry enables accurate documentation and visualization of events or matching of injuries and injury causing instruments. To reduce inaccuracies during photogrammetric recording, a multi camera device, Botscan by Botspot, can be used to record living persons in three-dimensional space (3D). The device can record a full body in a fraction of a second, which leads to a significant reduction of inaccuracies due to movement. Photogrammetric measurements were compared with measurements from forensic photographs to evaluate the applicability of this device for medical forensic documentation of injuries. For this purpose, a mannequin fitted with different types of artificial injuries was used as an example. The results showed that the photogrammetric measurements obtained using the software Agisoft PhotoScan were more accurate than the measurements from the forensic photographs. PMID- 29715624 TI - An accurate empirical method to predict the adsorption strength for pi-orbital contained molecules on two dimensional materials. AB - To obtain the adsorption strength is the key point for materials design and parameters optimization in chemical engineering. Here we report a simple but accuracy method to estimate the adsorptive energies by counting the number of pi orbital involved atoms based on theoretical computations for hexagonal boron nitride (h-BN) and graphene. Computational results by density function theory (DFT) as well as spin-component scaled second-order Moller-Plesset perturbation theory (SCS-MP2) both confirm that the adsorptive energies correlate well with the number of pi-orbital involved atoms for pi-orbital contained molecules. The selected molecules (adsorbates) are commonly used in chemical industry, which contains C, N, S, O atoms. The predicted results for the proposed formulas agree well with the current and previous DFT calculated values both on h-BN and graphene surfaces. Further, it can be also used to predict the adsorptive energies for small pi-orbital contained molecules on BN and carbon nanotubes. The interaction type for these adsorptions is typical pi-pi interaction. Further investigations show that the physical origin of these interactions source from the polar interactions between the adsorbents and adsorbates. Hence, for separation or removal of aromatic molecules, how to modify the aromaticity and polarity of both adsorbents and adsorbates will be the key points for experiments. PMID- 29715625 TI - Cost benefit study of a safety campaign's impact on road safety. AB - The aim of this paper is to identify a break in the development trend of the time series of the number of fatal, light and heavy injuries in traffic accidents and compare the progress caused by the media campaign named "Think or you'll pay! "in the Czech Republic over the period 2000-2015. The campaign focuses on the age group of drivers under the age of 25 and the most common cause of their traffic accidents as the drivers in this age category are the most vulnerable group in road traffic. The campaign uses a method in which it tries to influence behaviour by negative action, or by causing negative emotions. The authors concentrate on the effects of mass media campaigns in the long-term development of accidents in the Czech Republic and a financial evaluation of the road safety campaign "Think or you'll pay! "by comparing the campaign costs, the cost of road fatalities, and the cost savings from the perspective of government expenditures. The secondary source data for the chart analysis and interpolation according to the criteria of analytical and mechanical balancing time series, the Chow test and Quandt Likelihood Ratio test, choosing the appropriate model trend of accidents and consequences of traffic accidents were obtained from the Czech Ministry of Transport, the database of The Losses due to Traffic Accident Rates (CZRSO) and the Czech Association of Victims of Traffic Accidents (CSODN, 2015) from period of 1990 till 2016. The impact of the media campaign "Think or you'll pay!", measured by enumerating the costs was compared with the number of fatalities in the years immediately after the campaign and the impact of the media campaign was evaluated and recognised. The conclusion and the highlights summarize the findings of research and the limits of media campaign evaluation approach. PMID- 29715626 TI - A comparison of freeway median crash frequency, severity, and barrier strike outcomes by median barrier type. AB - Median-crossover crashes are among the most hazardous events that can occur on freeways, often resulting in severe or fatal injuries. The primary countermeasure to reduce the occurrence of such crashes is the installation of a median barrier. When installation of a median barrier is warranted, transportation agencies are faced with the decision among various alternatives including concrete barriers, beam guardrail, or high-tension cable barriers. Each barrier type differs in terms of its deflection characteristics upon impact, the required installation and maintenance costs, and the roadway characteristics (e.g., median width) where installation would be feasible. This study involved an investigation of barrier performance through an in-depth analysis of crash frequency and severity data from freeway segments where high-tension cable, thrie-beam, and concrete median barriers were installed. A comprehensive manual review of crash reports was conducted to identify crashes in which a vehicle left the roadway and encroached into the median. This review also involved an examination of crash outcomes when a barrier strike occurred, which included vehicle containment, penetration, or re direction onto the travel lanes. The manual review of crash reports provided critical supplementary information through narratives and diagrams not normally available through standard fields on police crash report forms. Statistical models were estimated to identify factors that affect the frequency, severity, and outcomes of median-related crashes, with particular emphases on differences between segments with varying median barrier types. Several roadway-, traffic-, and environmental-related characteristics were found to affect these metrics, with results varying across the different barrier types. The results of this study provide transportation agencies with important guidance as to the in service performance of various types of median barrier. PMID- 29715623 TI - Weak vaccinia virus-induced NK cell regulation of CD4 T cells is associated with reduced NK cell differentiation and cytolytic activity. AB - Natural killer (NK) cells control antiviral adaptive immune responses in mice during some virus infections, but the universality of this phenomenon remains unknown. Lymphocytic choriomeningitis virus (LCMV) infection of mice triggered potent cytotoxic activity of NK cells (NKLCMV) against activated CD4 T cells, tumor cells, and allogeneic lymphocytes. In contrast, NK cells activated by vaccinia virus (VACV) infection (NKVACV) exhibited weaker cytolytic activity against each of these target cells. Relative to NKLCMV cells, NKVACV cells exhibited a more immature (CD11b-CD27+) phenotype, and lower expression levels of the activation marker CD69, cytotoxic effector molecules (perforin, granzyme B), and the transcription factor IRF4. NKVACV cells expressed higher levels of the inhibitory molecule NKG2A than NKLCMV cells. Consistent with this apparent lethargy, NKVACV cells only weakly constrained VACV-specific CD4 T-cell responses. This suggests that NK cell regulation of adaptive immunity, while universal, may be limited with viruses that poorly activate NK cells. PMID- 29715627 TI - Why do drivers become safer over the first three months of driving? A longitudinal qualitative study. AB - Drivers are at high crash risk when they begin independent driving, with liability decreasing steeply over the first three months. Their behavioural development, and other changes underlying improved safety are not well understood. We adopted an innovative longitudinal qualitative design, with thirteen newly qualified drivers completing a total of 36 semi-structured interviews, one, two and three months after acquiring a full UK driving license. The interviews probed high-risk factors for new drivers, as well as allowing space for generating novel road safety issues. Analysis adopted a dual deductive and inductive interpretative thematic approach, identifying three super-ordinate themes: (1) Improvements in car control skills and situation awareness; (2) A reduction in the thrill of taking risks when driving against a background of generally increasing driving speed; (3) Early concerns about their social status in the eyes of other road users during the early stages of driving, which may put pressure on them to drive faster than they felt comfortable with. The study provides important new leads towards understanding how novice driving becomes safer over the first few months of driving, including how well-studied concepts of driving skill and style may change during development of independent driving, and bringing the less rigorously studied concept of social status into focus. PMID- 29715628 TI - Role of Bacillus cereus GS-5 strain on simultaneous nitrogen and phosphorous removal from domestic wastewater in an inventive single unit multi-layer packed bed bioreactor. AB - This work evaluates the performance efficiency of a newly developed single unit packed bed bioreactor for nutrient removal from domestic wastewater. The packing materials, including dolochar, and a mixture of waste organic solid substance, were immobilized with a simultaneous nitrifying, denitrifying and phosphate removing bacterial strain, Bacillus cereus GS-5 and packed in the bioreactor alternatively in multiple layers. The bioreactor was operated continuously for a period of 70 days using both synthetic and real domestic wastewater (NH4+-N 30 100 mg/L, NO3--N 10-100 mg/L, PO43--P 5-20 mg/L and COD 250-1000 mg/L). The innovative single unit bioreactor exhibited simultaneous removal of NH4+-N (87.1 93.1%), NO3--N (69.4-88.4%), PO43--P (84-100%), and even COD (69.8-92.1%), in a remarkable disparity to traditional distinct aerobic-anaerobic treatment systems. This work advocated for a promising and feasible application prospect of the developed single unit packed bed bioreactor in domestic wastewater treatment emphasizing on nutrient removal. PMID- 29715629 TI - Influence of biomass pretreatment on upgrading of bio-oil: Comparison of dry and hydrothermal torrefaction. AB - The dry and hydrothermal torrefacation of on Camellia Shell (CS) was carried on three different devices- batch autoclave, quartz tube, and auger reactor. The torrefied bio-char products were investigated via TGA, elemental analysis and industrial analysis. Moreover, the pyrolysis and catalytic pyrolysis properties of torrefied bio-char were investigated. The results showed torrefaction significantly influenced the content of hemicellulose in CS. And hydrothermal torrefaction via batch autoclave and dry torrefaction via auger reactors promoted the hemicellulose to strip from the CS. Quartz tube and auger reactor were beneficial for devolatilization and improving heat value of torrefied bio-char. The result showed that the main products were phenols and acids. And hydrothermal torrefaction pretreatment effectively reduced the acids content from 34.5% to 13.2% and enriched the content of phenols (from 27.23% to 60.05%) in bio-oil due to the decreasing of hemicellulos in torrefied bio-char. And the catalyst had slight influence on the bio-oil distribution. PMID- 29715630 TI - Control of partial nitrification using pulse aeration for treating digested effluent of swine wastewater. AB - Three sequencing batch reactors (SBRs) were used to investigate the influence of pulse frequencies on the partial nitrification (PN) process in this study. At a total aeration time of 6 min each hour, the aerated frequencies of R1, R2 and R3 were 6, 3 and 2 time h-1. During the steady period (117-143d), the nitrite accumulation rates (NARs) were 90.80%, 90.71% and 90.23% in R1, R2 and R3, respectively, indicating a steady nitritation was acquired. Activity measurements of the sludge samples taken at day 138 showed the activity of nitrite oxidating bacteria (NOB) was 0, indicating NOBs were successfully suppressed. The ratio of NO2--N to NH4+-N in the effluent of R3 was 1.35, which most closely matched the influent of Anammox process. However, the energy efficiency evaluation showed that R1 had the highest actual oxygen transfer efficiency (AOTE) and dynamical efficiency (DE). PMID- 29715631 TI - Silicon improves growth and alleviates oxidative stress in rice seedlings (Oryza sativa L.) by strengthening antioxidant defense and enhancing protein metabolism under arsanilic acid exposure. AB - Organoarsenic arsanilic acid (ASA) contamination of paddy soil is a serious but less concerned hazard to agriculture and health of people consuming rice as staple food, for rice is one major pathway of arsenic (As) exposure to human food. To date little research has studied the effect of ASA on biochemical process of rice. Silicon (Si) application is able to reduce the toxicities of heavy metals in numerous plants, but little information about ASA. This work investigated whether and how Si influenced alleviation of ASA toxicity in rice at biochemical level to have a better understanding of defense mechanism by Si against ASA stress. Results showed that ASA reduced rice growth, disturbed protein metabolism, increased lipid peroxidation but decreased the efficiencies of antioxidant activities compared to control plants, more severe in roots than in shoots. The addition of Si in ASA-stressed rice plants noticeably increased growth and development as well as soluble protein contents, but decreased malondialdehyde (MDA) contents in ASA-stressed rice plants, suggesting that Si did have critical roles in ASA detoxification in rice. Furthermore, increased superoxide dismutase (SOD), catalase (CAT) and peroxidase (POD) activities along with elevated glutathione (GSH) and ascorbic acid (AsA) contents implied the active involvement of ROS scavenging and played, at least in part, to Si-mediated alleviation of ASA toxicity in rice, and these changes were related to rice genotypes and tissues. The study provided physio-chemical mechanistic evidence on the beneficial effect of Si on organoarsenic ASA toxicity in rice seedlings. PMID- 29715632 TI - Acute waterborne cadmium toxicity in the estuarine pulmonate mud snail, Amphibola crenata. AB - Freshwater pulmonate snails are sensitive to trace metals, but to date, the sensitivity of estuarine pulmonate snails to these important environmental toxicants is undescribed. Using the estuarine mud snail Amphibola crenata, effects of a 48-h exposure to waterborne cadmium (Cd) were investigated. The 48-h median lethal concentration (LC50) was 50.4 mg L-1, a value higher than that previously reported for any gastropod mollusc. Cadmium levels in the tissues of mud snails were highest in the viscera (digestive gland and gonad), with the foot muscle and remaining tissue compartment (kidney, mantle, remaining digestive tissues and heart) displaying significantly lower concentrations. Over a Cd exposure concentration range of 0-32 mg L-1, Amphibola exhibited reduced oxygen consumption and elevated ammonia excretion in response to increasing Cd, the latter effect likely reflecting a switch to protein metabolism. This finding was supported by a declining oxygen: nitrogen ratio (O:N) as exposure Cd concentration increased. Other energy imbalances were noted, with a decrease in tissue glycogen (an effect strongly correlated with Cd burden in the viscera and foot muscle) and an elevated haemolymph glucose observed. An increase in catalase activity in the visceral tissues was recorded, suggestive of an effect of Cd on oxidative stress. The magnitude of this effect was correlated with tissue Cd burden. The induction of antioxidant defence mechanisms likely prevented an increase in levels of lipid peroxidation, which were unchanged relative to Cd exposure concentration in all measured tissues. PMID- 29715633 TI - The detoxification effect of vitamin C on zearalenone toxicity in piglets. AB - Zearalenone (ZEN), one of the more virulent mycotoxins occurred in various cereals and feed during recent decades and made serious health hazards to plants, animals and humans. Vitamin C (Vc) has been shown to be an effective antidote to zearalenone. In this paper, the effects of diets containing zearalenone on the growth performance, genital organ and immunoglobulin of weaning piglets and the toxicity alleviation of vitamin C were studied. Piglets were weaned at 21 days of age and 32 healthy female hybrid weaning piglets (Duroc * Landrace * Large white) with a mean weight of 12.27 +/- 0.30 kg were randomly selected. The thirty-two female weaning piglets were divided into four treatment groups according to body weight: control; basal diet + vitamin C (150 mg/kg); basal diet + 1.0 mg/kg ZEN; basal diet + 1 mg/kg ZEN+vitamin C (150 mg/kg). There were eight replicates in each group. The test period was twenty-eight days. The results demonstrated that dietary zearalenone could significantly increase the length, width and area of vulva (P < 0.05), the genital organ coefficient (P < 0.05), the level of IgA, IgG and IgM (P < 0.05), the level of BUN, CRE, AST and TBIL (P < 0.05), and significantly decrease the level of E2, PROG, LH and FSH (P < 0.05). However, the addition of 150 mg/kg vitamin C to dietary zearalenone prevented deformities in the vulva, decrease in immune response capacity, changes in serum biochemical indicators and disorders in hormones level of the piglets that received the diet containing only zearalenone. In conclusion, feeding ZEN of 1.0 mg/kg can result in a deleterious effect on piglets, which was totally or partly ameliorated by dietary supplementation of vitamin C at concentrations about 150 mg/kg diet. This study systematically investigated the inhibition mechanism of vitamin C on ZEN induced reproductive toxicity, immunotoxicity and hematological toxicity of piglets, and which provided new ideas for reducing the harm of mycotoxins to the animals through means of nutrition regulation. PMID- 29715635 TI - Design, synthesis, biological evaluation, structure-activity relationship study, and mode of action of 2-phenol-4,6-dichlorophenyl-pyridines. AB - Human DNA topoisomerases (Topos) are essential nuclear enzyme whose level of expression is potential indicator for prediction of responsive result of chemotherapy. Topos has become a key cellular target for most of the anticancer agents that regulates topological problems of DNA during cellular metabolic processes such as replication, transcription, and recombination. Inspired by previous studies of 2,4,6-trisubstituted pyridines to find out safer and effective topoisomerase targeted anticancer agent, twenty-seven 2-phenol-4,6 dichlorophenyl-pyridines were designed, synthesized, and tested for their topo I and IIalpha inhibitory and anti-proliferative activity. Most of the dichlorinated meta- and para-phenolic series compounds (1-18) exhibited potent and selective topo IIalpha inhibition along with significant anti-proliferative activity in the HCT-15 and T47D cell lines compared to the positive control, etoposide. Interestingly, dichlorinated ortho-phenolic series compounds (19-27) exhibited potent and dual topo inhibition but very weak anti-proliferative activity in the tested cancer cell lines. Structure-activity relationship with previously synthesized compounds revealed the importance of chlorine moiety to improve the potency of topo inhibitory activity. Further mechanistic study confirmed that compounds 2 and 12 acted as non-intercalative specific topo IIalpha catalytic inhibitor with less DNA damage, and induced G1 arrest and apoptosis in HCT-15 and T47D cell lines, respectively. PMID- 29715634 TI - Fenbuconazole exposure impacts the development of zebrafish embryos. AB - Fenbuconazole (FBZ), a triazole-containing fungicide, is widely used in agriculture and horticulture. In the present study, the development and cardiac functioning were observed and determined in zebrafish embryos exposed to FBZ at 5, 50 and 500 ng/L nominal concentrations for 72 h. The results showed that 500 ng/L FBZ significantly increased pericardial edema rate, spine curvature rate, disturbed cardiac function, and led a shortened lower jaw. The transcription of genes such as tbx5, nkx2.5, tnnt2, gata4, bmp2b, myl7 was altered, which might be responsible for the cardiac developmental and functioning defects in the larvae. The deformation in bone development might be related with the impaired transcription levels of shh and bmp2b. The transcription of cyp26a1 (encoding retinoic acid metabolism enzyme) was significantly up-regulated in the 500 ng/L group, which might be a reason causing the teratogenic effect of FBZ. These results suggest that FBZ could have toxic effects on embryonic development, which should be considered in the risk evaluation of FBZ application. PMID- 29715636 TI - New alpha-Glucosidase inhibitors from the resins of Boswellia species with structure-glucosidase activity and molecular docking studies. AB - Phytochemical investigation of the oleo-gum resins from Boswellia papyrifera afforded one new triterpene, named 3alpha-hydroxyurs-5:19-diene (1) together with twelve known compounds including eight triterpenoids (2-9), two diterpenoids (10 and 11) and two straight chain alkanes (12 and 13). Similarly ten more known compounds were isolated from the resin of Boswellia sacra including one triterpene (20) and nine boswellic acids (14-19 and 21-23). Herein the compound 2 was first time reporting from natural source along with complete NMR assignment, while compounds 3-11 are known, but reported for the first time from the resin of B. papyrifera. The structure elucidation was done by advance spectroscopic 1D and 2D NMR techniques viz., 1H, 13C, DEPT, HSQC, HMBC, and COSY, and NEOSY, ESI-MS and compared with the reported literature. All compounds were evaluated for their alpha-glucosidase inhibitory activity and as result eight of them 1, 3, 10, 11, 15, and 17-19 were found significantly active against alpha-glucosidase with an IC50 value ranging from 15.0 +/- 0.84 to 80.3 +/- 2.33 uM, while 21 exhibited moderate activity with IC50 of 799.9 +/- 4.98 uM. Furthermore, two compounds 24 and 25 were synthesised from 16 and 17 to see the effect of carboxyl group in structural-activity relationship (SAR) study. Compounds 24 and 25 retained good alpha-glucosidase inhibition as compared to 16 and 17, indicating that carboxylic group play a key role in SAR. In addition, the aforementioned activity of all the active compounds was first time reported for their alpha-glucosidase inhibition potential. The molecular docking studies showed that all the active compounds well accommodate in the active site of the enzyme. Moreover pharmacokinetic properties of the compounds were predicted in silico, suggesting that the compounds possess drug like properties and excellent ADMET profile. PMID- 29715637 TI - Effects of nutrient ratios and carbon dioxide bio-sequestration on biomass growth of Chlorella sp. in bubble column photobioreactor. AB - Photobioreactor technology, especially bubble column configuration, employing microalgae cultivation (e.g., Chlorella sp.), is an ideal man-made environment to achieve sufficient microalgae biomass through its strictly operational control. Nutrients, typically N and P, are necessary elements in the cultivation process, which determine biomass yield and productivity. Specifically, N:P ratios have certain effects on microalgae's biomass growth. It is also attractive that microalgae can sequester CO2 by using that carbon source for photosynthesis and, subsequently, reducing CO2 emission. Therefore, this study aims to investigate the effect of N:P ratios on Chlorella sp.'s growth, and to study the dynamic of CO2 fixation in the bubble column photobioreactor. According to our results, N:P ratio of 15:1 could produce the highest biomass yield (3568 +/- 158 mg L-1). The maximum algae concentration was 105 * 106 cells mL-1, receiving after 92 h. Chlorella sp. was also able to sequester CO2 at 28 +/- 1.2%, while the specific growth rate and carbon fixation rate were observed at 0.064 h-1 and 68.9 +/- 1.91 mg L-1 h-1, respectively. The types of carbon sources (e.g., organic and inorganic carbon) possessed potential impact on microalgae's cultivation. PMID- 29715638 TI - Liquid by-products from fish canning industry as sustainable sources of omega3 lipids. AB - Fish canning industry generates large amounts of liquid wastes, which are discarded, after proper treatment to remove the organic load. However, alternative treatment processes may also be designed in order to target the recovery of valuable compounds; with this procedure, these wastewaters are converted into liquid by-products, becoming an additional source of revenue for the company. This study evaluated green and economically sustainable methodologies for the extraction of omega3 lipids from fish canning liquid by products. Lipids were extracted by processes combining physical and chemical parameters (conventional and pressurized extraction processes), as well as chemical and biological parameters. Furthermore, LCA was applied to evaluate the environmental performance and costs indicators for each process. Results indicated that extraction with high hydrostatic pressure provides the highest amounts of omega3 polyunsaturated fatty acids (3331,5 mg L-1 effluent), apart from presenting the lowest environmental impact and costs. The studied procedures allow to obtain alternative, sustainable and traceable sources of omega3 lipids for further applications in food, pharmaceutical and cosmetic industries. Additionally, such approach contributes towards the organic depuration of canning liquid effluents, therefore reducing the overall waste treatment costs. PMID- 29715639 TI - Racial residential segregation and racial disparities in stillbirth in the United States. AB - We examined whether current and/or persistent racial residential segregation is associated with black-white stillbirth disparities among 49,969 black and 71,785 white births from the Consortium on Safe Labor (2002-2008). Black-white segregation was measured using the dissimilarity index and the isolation index, categorized into population-based tertiles. Using hierarchical logistic models, we found low and decreasing levels of segregation were associated with decreased odds of stillbirth, with blacks benefitting more than whites. Decreasing segregation may prevent approximately 900 stillbirths annually among U.S. blacks. Reducing structural racism, segregation in particular, could help reduce black white stillbirth disparities. PMID- 29715640 TI - Visualization of rotator cuff tear morphology by radial magnetic resonance imaging. AB - The objective of this study was to investigate whether rotator cuff tear morphology could be visualized using radial MRI. We retrospectively investigated 52 shoulders that underwent preoperative MRI and arthroscopy for a complete rotator cuff tear. The tear length and width were measured using oblique coronal, axial, and radial MRI. Arthroscopic findings were compared with the tear morphology. Tear morphology was visualized using oblique coronal and axial MRI for 24 of the 52 shoulders (46%), and radial MRI for all 52 shoulders. Radial MRI data for 49 of 52 shoulders (94%) were concordant with the arthroscopic findings. PMID- 29715641 TI - Structural and optical properties of antimony-germanate-borate glass and glass fiber co-doped Eu3+ and Ag nanoparticles. AB - In the paper analysis of structural and luminescent properties of antimony germanate-borate glasses and glass fiber co-doped with 0.6AgNO3/0.2Eu2O3are presented. Heat treatment of the fabricated glass and optical fiber (400 degrees C, 12 h) enabled to obtain Ag nanoparticles (NPs) with average size 30-50 nm on their surface. It has been proofed that silver ions migrate to the glass surface, where they are reduced to Ag0 nanoparticles. Simultaneously, FTIR analysis showed that heat treatment of the glass and optical fiber increases the local symmetry of the Eu3+ site. PMID- 29715642 TI - Dissolved Mn(III) in water treatment works: Prevalence and significance. AB - Dissolved Mn(III) has been identified at all stages throughout a Water Treatment Works (WTW) receiving inflow from a peaty upland catchment in NE England. Ninety percent of the influent total manganese into the WTW is particulate Mn, in the form of Mn oxide (>0.2 MUm). Approximately 9% (mean value, n = 22, range of 0 100%) of the dissolved (<0.2 MUm) influent Mn is present as dissolved Mn(III). Mn(III) concentrations are highest (mean of 49% of total dissolved Mn; n = 26, range of 17-89%) within the WTW where water comes into contact with the organic rich sludges which are produced as waste products in the WTW. These Mn(III) containing wastewaters are recirculated to the head of the works and constitute a large input of Mn(III) into the WTW. This is the first report of Mn(III) being identified in a WTW. The ability of Mn(III) to act as both an oxidant and a reductant is of interest to the water industry. Understanding the formation and removal of Mn(III) within may help reduce Mn oxide deposits in pipe networks. Further understanding how the ratio of Mn(III) to Mn(II) can be used to optimise dissolved Mn removal would save the water industry significant money in reducing discoloration 'events' at the customers' tap. PMID- 29715643 TI - Improved blackwater disinfection using potentiodynamic methods with oxidized boron-doped diamond electrodes. AB - Electrochemical disinfection (ECD) has become an important blackwater disinfection technology. ECD is a promising solution for the 2 billion people without access to conventional sanitation practices and in areas deficient in basic utilities (e.g., sewers, electricity, waste treatment). Here, we report on the disinfection of blackwater using potential cycling compared to potentiostatic treatment methods in chloride-containing and chloride-free solutions of blackwater (i.e., untreated wastewater containing feces, urine, and flushwater from a toilet). Potentiodynamic treatment is demonstrated to improve disinfection energy efficiency of blackwater by 24% and 124% compared to static oxidation and reduction methods, respectively. The result is shown to be caused by electrochemical advanced oxidation processes (EAOP) and regeneration of sp2 surface-bonded carbon functional groups that serve the dual purpose of catalysts and adsorption sites of oxidant intermediates. Following 24 h electrolysis in blackwater, electrode fouling is shown to be minimized by the potential cycling method when compared to equivalent potentiostatic methods. The potential cycling current density is 40% higher than both the static oxidative and reductive methods. This work enhances the understanding of oxygen reduction catalysts using functionalized carbon materials and electrochemical disinfection anodes, both of which have the potential to bring a cost-effective, energy efficient, and practical solution to the problem of disinfecting blackwater. PMID- 29715644 TI - Incidence of somatic and F+ coliphage in Great Lake Basin recreational waters. AB - There is a growing interest for the use of coliphage as an alternative indicator to assess fecal pollution in recreational waters. Coliphage are a group of viruses that infect Escherichia coli and are considered as potential surrogates to infer the likely presence of enteric viral pathogens. We report the use of a dead-end hollow fiber ultrafiltration single agar layer method to enumerate F+ and somatic coliphage from surface waters collected from three Great Lake areas. At each location, three sites (two beaches; one river) were sampled five days a week over the 2015 beach season (n = 609 total samples). In addition, culturable E. coli and enterococci concentrations, as well as 16 water quality and recreational area parameters were assessed such as rainfall, turbidity, dissolved oxygen, pH, and ultra violet absorbance. Overall, somatic coliphage levels ranged from non-detectable to 4.39 log10 plaque forming units per liter and were consistently higher compared to F+ (non-detectable to 3.15 log10 PFU/L), regardless of sampling site. Coliphage concentrations weakly correlated with cultivated fecal indicator bacteria levels (E. coli and enterococci) at 75% of beach sites tested in study (r = 0.28 to 0.40). In addition, ultraviolet light absorption and water temperature were closely associated with coliphage concentrations, but not fecal indicator bacteria levels suggesting different persistence trends in Great Lake waters between indicator types (bacteria versus virus). Finally, implications for coliphage water quality management and future research directions are discussed. PMID- 29715645 TI - Fouling resilient perforated feed spacers for membrane filtration. AB - The improvement of feed spacers with optimal geometry remains a key challenge for spiral-wound membrane systems in water treatment due to their impact on the hydrodynamic performance and fouling development. In this work, novel spacer designs are proposed by intrinsically modifying cylindrical filaments through perforations. Three symmetric perforated spacers (1-Hole, 2-Hole, and 3-Hole) were in-house 3D-printed and experimentally evaluated in terms of permeate flux, feed channel pressure drop and membrane fouling. Spacer performance is characterized and compared with standard no perforated (0-Hole) design under constant feed pressure and constant feed flow rate. Perforations in the spacer filaments resulted in significantly lowering the net pressure drop across the spacer filled channel. The 3-Hole spacer was found to have the lowest pressure drop (50%-61%) compared to 0-Hole spacer for various average flow velocities. Regarding permeate flux production, the 0-Hole spacer produced 5.7 L m-2.h-1 and 6.6 L m-2.h-1 steady state flux for constant pressure and constant feed flow rate, respectively. The 1-Hole spacer was found to be the most efficient among the perforated spacers with 75% and 23% increase in permeate production at constant pressure and constant feed flow, respectively. Furthermore, membrane surface of 1-Hole spacer was found to be cleanest in terms of fouling, contributing to maintain higher permeate flux production. Hydrodynamic understanding of these perforated spacers is also quantified by performing Direct Numerical Simulation (DNS). The performance enhancement of these perforated spacers is attributed to the formation of micro-jets in the spacer cell that aided in producing enough unsteadiness/turbulence to clean the membrane surface and mitigate fouling phenomena. In the case of 1-Hole spacer, the unsteadiness intensity at the outlet of micro-jets and the shear stress fluctuations created inside the cells are higher than those observed with other perforated spacers, resulting in the cleanest membrane surface. PMID- 29715646 TI - Effect of MUM Fe addition, mild heat and solar UV on sulfate radical-mediated inactivation of bacteria, viruses, and micropollutant degradation in water. AB - In this work, solar disinfection (SODIS) was enhanced by moderate addition of Fe and sodium peroxydisulfate (PDS), under solar light. A systematic assessment of the activating factors was performed, firstly isolated, then in pairs and concluded in the combined Fe/heat/solar UV-PDS activation process. Solar light was the most effective (single) activator, and its combination with Fe and heat (double activation) yielded high level of synergies (up to S = 2.13). The triple activation was able to reduce the bacterial load up to 6-log in less than 1 h, similarly to the photo-Fenton process done in comparison (SODIS alone: >5 h). Fe oxides were suitable activators of PDS under the same conditions while the presence of organic matter enhanced bacterial inactivation by the triple activated PDS process. The degradation of a (selected) mixture of micropollutants (i.e. drugs, pesticides) was also achieved in similar order of magnitude, and faster than the photo-Fenton process. Finally, the removal of a viral pathogen indicator (MS2 bacteriophage) was attained at minute-range residence times. The aforementioned facts indicate the suitability of the mild, combined process, as a potential SODIS enhancement, producing safe drinking water for sunny and especially for developing countries. PMID- 29715647 TI - Citric acid assisted Fenton-like process for enhanced dewaterability of waste activated sludge with in-situ generation of hydrogen peroxide. AB - Fenton's reagent has been widely used to enhance sludge dewaterability. However, drawbacks associated with hydrogen peroxide (H2O2) in Fenton's reagents exist, since it is a hazardous chemical and shows carcinogenicity, explosivity, instability, and corrosivity. Moreover, initial acidification and subsequent neutralization are needed as optimal conditions for homogeneous Fenton conditioning and final filtrate discharge. In this study, a Fenton-like process for the enhanced dewaterability of waste activated sludge with in-situ generation of H2O2 and without extra pH adjustment was firstly proposed, namely citric acid (CA)-assisted oxygen activation in an air/nano zero-valent iron (nZVI) system and chemical re-coagulation with polydiallyldimethylammonium chloride (PDMDAAC). Using the response surface methodology (RSM), the optimal doses of CA, nZVI, and PDMDAAC were determined to be 13, 33, and 9 mg g-1 dry solids (DS), respectively. This composite conditioner showed a good dewatering capability compared with the raw sludge, e.g. the capillary suction time decreased from 130.0 to 9.5 s. The enhanced sludge dewaterability was further confirmed by laboratory-scale diaphragm filter press dewatering tests, which produced a lower cake moisture content compared with the raw sludge, and the final pH of the filtrate was close to neutrality. The citric acid promoted the production of H2O2 and Fe(II)/Fe(III) species, the degradation of protein in tightly-bound extracellular polymeric substances, and the decomposition of protein-N in the solid phase of sludge, resulting a greater conversion of bound water to free water. The results of electron spin resonance indicated that the hydroxyl radicals were mainly responsible for the decomposition of proteinaceous compounds. The subsequent chemical re-coagulation with PDMDAAC can make the zeta potential of sludge samples less negative, reduce the repulsive electrostatic interactions, and agglomerate the smaller particles into larger aggregates, thus enhancing sludge dewaterability. PMID- 29715648 TI - Chemical cleaning-associated generation of dissolved organic matter and halogenated byproducts in ceramic MBR: Ozone versus hypochlorite. AB - This study characterized the dissolved organic matter (DOM) and byproducts generated after the exposure of activated sludge to ozone and NaClO in ceramic MBR. It was found that NaClO triggered more significant release of DOM than ozone. Proteins with the molecular weight greater than 20 kDa and humic acid like substances were the principal components of DOM generated by NaClO, while ozone was found to effectively degrade larger biopolymers to low molecular weight substances. The results showed that more than 80% of DOM generated by NaClO and ozone could pass through the 0.2-MUm ceramic membrane. Furthermore, total organic chlorine (TOCl) was determined to be the principal species of halogenated byproducts in both cases, while the generation of TOCl by NaClO was much more significant than that by ozone. Only a small fraction of TOCl was removed by the 0.2-MUm ceramic membrane. More importantly, the toxic bioassays further revealed that the supernatant of sludge suspension and permeate in the MBR with NaClO cleaning exhibited higher developmental toxicity to the polychaete embryos than those by ozone. The results clearly showed that on-line chemical cleaning with ozone should be a more eco-friendly and safer approach for sustaining long-term membrane permeability in ceramic MBR. PMID- 29715649 TI - Allogeneic mesenchymal stem cell transplantation in healthy equine superficial digital flexor tendon: A study of the local inflammatory response. AB - The superficial digital flexor tendon (SDFT) is a structure frequently affected by injuries in high-performance athletic horses, and there are limited therapeutic options. Regenerative medicine has evolved significantly in treating different illnesses. However, understanding the cellular behaviour during mesenchymal stem cell (MSC) transplantation in healthy tissues is not fully known yet. To address the inflammatory response induced by allogeneic MSC transplantation, this study evaluated the local inflammatory response after the application of allogeneic adipose tissue-derived mesenchymal stem cells (AT-MSCs) in the equine tendon compared to an autologous transplant and the control group. Eighteen thoracic limbs (TL) in nine animals were divided into three groups and subjected to the application of AT-MSCs in the healthy tendon. In the allogeneic group (Gallog), the animals received an allogeneic AT-MSC application in the TL. The autologous group (Gauto) received an application of autologous cells in the TL, and in the control group (Gcont), phosphate-buffered saline (PBS) was applied. There were no significant differences among the evaluated groups in the physical, morphological, thermography, and ultrasonography analyses. A higher number of CD3-positive lymphocytes was observed in the Gauto group compared to the control (P < 0.05). Additionally, we did not observe different expressions of CD172 and microvascular density among the groups. The allogeneic transplantation of AT-MSCs did not result in an adverse or inflammatory reaction that compromised the use of these cells in this experiment. Their behaviour was similar to that of autologous transplantation. PMID- 29715650 TI - Demography and risk factor of suicidal behavior in Bangladesh: A cross-sectional observation from patients attending a suicide prevention clinic of Bangladesh. PMID- 29715651 TI - Decriminalization of suicide in Pakistan - Treatment not punishment. PMID- 29715652 TI - Longitudinal associations between biomarkers of inflammation and changes in depressive symptoms in diabetic patients. PMID- 29715653 TI - Evaluation of previous substance dependence genome-wide significant findings in a Spanish sample. AB - BACKGROUND: Substance dependence is a chronic and relapsing disorder explained by genetic and environmental risk factors. The aim of our study is to replicate previous genome-wide significant (GWS) hits identified in substance dependence in general or in cocaine dependence in particular using an independent sample from Spain. METHODS: We evaluated, in a Spanish sample of 1711 subjects with substance dependence (1011 of them cocaine dependent) and 1719 control individuals, three SNPs identified as GWS in previous studies: rs1868152 and rs2952621 (located near LINC02052 and LINC01854, respectively), associated with substance dependence, and rs2629540 (in the first intron of FAM53B), associated with cocaine dependence. RESULTS: We replicated the association between rs2952621 and substance dependence under the dominant model (P = 0.020), with the risk allele (T) being the same in our sample and in those two reported previously. We then performed a meta analysis of the two samples used in the original study that reported the association of rs2952621 with substance dependence (Collaborative Studies on Genetics of Alcoholism (COGA) and Study of Addiction: Genetics and Environment (SAGE)) together with our Spanish sample. The meta-analysis of 3747 cases and 4043 controls confirmed the association (OR = 1.26, 95% CI = 1.15-1.39). CONCLUSIONS: The rs2952621 variant, located downstream from the yet uncharacterized gene LINC01854, is associated with substance dependence in our Spanish sample. Further research is needed to understand its contribution to the susceptibility to substance dependence. PMID- 29715654 TI - Relationship between the duration of methamphetamine use and psychotic symptoms: A two-year prospective cohort study. AB - BACKGROUND: Psychosis is a key harm associated with methamphetamine (MA) use. This study examined the relationship between the duration of MA use and risk of psychotic symptoms. METHODS: A cohort of 528 individuals with chronic MA use was followed for two years after leaving treatment center in Guangdong, China. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale at baseline and four follow-up visits (6, 12, 18 and 24 months after baseline). MA use during the past six months was investigated at each assessment. Generalized Estimating Equations for longitudinal panel data were developed to examine the risk of MA-associated psychotic symptoms among individuals with different durations of MA use. 340 MA users who completed at least one follow-up were included in the analysis. RESULTS: During 6-month intervals, participants who reported MA use showed a two-fold increase in the risk of psychotic symptoms compared to those with no MA use (odds ratio [OR] = 2.15, 95% confidence interval [CI] = 1.33-3.49). A dose-response effect was found between the duration of MA use and the risk of psychotic symptoms (continued 12-month MA use vs. no use: OR = 2.84, 95% CI = 1.39-5.77; continued 18-month MA use vs. no use: OR = 9.93, 95% CI = 3.58-27.57). There was no assessment for 24-month intervals due to a small sample size of the continuous use group. CONCLUSIONS: Longer periods of MA use predicted a higher risk of experiencing psychotic symptoms. Early prevention of MA use could help reduce the risk of psychosis in MA users. PMID- 29715655 TI - Risk assessment considerations for plant protection products and terrestrial life stages of amphibians. AB - Some amphibians occur in agricultural landscapes during certain periods of their life cycle and consequently might be exposed to plant protection products (PPPs). While the sensitivity of aquatic life-stages is considered to be covered by the standard assessment for aquatic organisms (especially fish), the situation is less clear for terrestrial amphibian life-stages. In this paper, considerations are presented on how a risk assessment for PPPs and terrestrial life-stages of amphibians could be conducted. It discusses available information concerning the toxicity of PPPs to terrestrial amphibians, and their potential exposure to PPPs in consideration of aspects of amphibian biology. The emphasis is on avoiding additional vertebrate testing as much as possible by using exposure-driven approaches and by making use of existing vertebrate toxicity data, where appropriate. Options for toxicity testing and risk assessment are presented in a flowchart as a tiered approach, progressing from a non-testing approach, to simple worst-case laboratory testing, to extended laboratory testing, to semi field enclosure tests and ultimately to full-scale field testing and monitoring. Suggestions are made for triggers to progress to higher tiers. Also, mitigation options to reduce the potential for exposure of terrestrial life-stages of amphibians to PPPs, if a risk were identified, are discussed. Finally, remaining uncertainties and research needs are considered by proposing a way forward (road map) for generating additional information to inform terrestrial amphibian risk assessment. PMID- 29715656 TI - Advanced biological activated carbon filter for removing pharmaceutically active compounds from treated wastewater. AB - Through their release of effluents, conventional wastewater treatment plants (WWTPs) represent a major pollution point sources for pharmaceutically active compounds (PhACs) in water bodies. The combination of a biological activated carbon (BAC) filter coupled with an ultrafiltration (UF) unit was evaluated as an advanced treatment for PhACs removal at pilot scale. The BAC-UF pilot plant was monitored for one year. The biological activity of the biofilm that developed on the granular activated carbon (GAC) particles and the contribution of this biofilm to the overall removal of PhACs were evaluated. Two different phases were observed during the long-term monitoring of PhACs removal. During the first 9200 bed volumes (BV; i.e., before GAC saturation), 89, 78, 83 and 79% of beta blockers, psychiatric drugs, antibiotics and a mix of other therapeutic groups were removed, respectively. The second phase was characterized by deterioration of the overall performances during the period between 9200 and 13,800 BV. To quantify the respective contribution of adsorption and biodegradation, a lab scale setup was operated for four months and highlighted the essential role played by GAC in biofiltration units. Physical adsorption was indeed the main removal mechanism. Nevertheless, a significant contribution due to biological activity was detected for some PhACs. The biofilm contributed to the removal of 22, 25, 30, 32 and 35% of ciprofloxacin, bezafibrate, ofloxacin, azithromycin and sulfamethoxazole, respectively. PMID- 29715657 TI - A field experimental study on non-methane hydrocarbon (NMHC) emissions from a straw-returned maize cropping system. AB - Non-methane hydrocarbons (NMHCs) play an important role in the atmospheric environment. However, NMHC emissions from agricultural fields, especially their variations with straw return, are poorly understood. Therefore, a field study comprising two treatments, i.e., (1) S0 (straw removal) and (2) S1 (incorporation of maize straw at a rate of 9000 kg ha-1), was conducted in a straw-returned maize cropping system to characterize NMHC emissions as well as to estimate the effect of straw return on those emissions. Using a Gas Chromatography-Mass Spectrometer (GC-MS) method, 28 types of NMHCs were identified. The total NMHC emission from S0 was 2018 g ha-1, where 1-methyl-3-propyl-benzene, (1 methylethyl)-benzene, and toluene were obviously predominant, whereas the total NMHC emission from S1 was 1903 g ha-1, where 1-methyl-3-propyl-benzene, 2-methyl pentane, and (1-methylethyl)-benzene were the main species. The results showed that straw return had opposing effects on NMHC emissions, ranging from -55.4% to 478.6%. Overall, the total NMHC emission with returned straw alone decreased by 2963 ng kg straw-1 h-1. Furthermore, NMHC fluxes had higher correlations with soil temperature than with soil moisture or pH. Notably, the higher correlations of NMHC fluxes with 10 cm soil temperature than with 5 cm soil temperature indicate that soil in the deeper layer might play a more important role in NMHC fluxes. The results also suggest that more field study is needed to accurately estimate the effect of straw return on NMHC emissions from agroecosystems and fully understand its underlying mechanism. PMID- 29715658 TI - Coniferous coverage as well as catchment steepness influences local stream nitrate concentrations within a nitrogen-saturated forest in central Japan. AB - High concentrations of nitrate have been detected in streams flowing from nitrogen-saturated forests; however, the spatial variations of nitrate leaching within those forests and its causes remain poorly explored. The aim of this study is to evaluate the influences of catchment topography and coniferous coverage on stream nitrate concentrations in a nitrogen-saturated forest. We measured nitrate concentrations in the baseflow of headwater streams at 40 montane forest catchments on Mount Tsukuba in central Japan, at three-month intervals for 1 year, and investigated their relationship with catchment topography and with coniferous coverage. Although stream nitrate concentrations varied from 0.5 to 3.0 mgN L-1, those in 31 catchments consistently exceeded 1 mgN L-1, indicating that this forest had experienced nitrogen saturation. A classification and regression tree analysis with multiple environmental factors showed that the mean slope gradient and coniferous coverage were the best and second best, respectively, at explaining inter-catchment variance of stream nitrate concentrations. This analysis suggested that the catchments with steep topography and high coniferous coverage tend to have high nitrate concentrations. Moreover, in the three-year observation period for five adjacent catchments, the two catchments with relatively higher coniferous coverage consistently had higher stream nitrate concentrations. Thus, the spatial variations in stream nitrate concentrations were primarily regulated by catchment steepness and, to a lesser extent, coniferous coverage in this nitrogen-saturated forest. Our results suggest that a decrease in coniferous coverage could potentially contribute to a reduction in nitrate leaching from this nitrogen-saturated forest, and consequently reduce the risk of nitrogen overload for the downstream ecosystems. This information will allow land managers and researchers to develop improved management plans for this and similar forests in Japan and elsewhere. PMID- 29715659 TI - How much water is required for coal power generation: An analysis of gray and blue water footprints. AB - Although water resource shortage is closely connected with coal-based electricity generation, relevant water footprint analyses remain limited. This study aims to address this limitation by conducting a water footprint analysis of coal-based electricity generation in China for the first time to inform decision-makers about how freshwater consumption and wastewater discharge can be reduced. In China, 1 kWh of electricity supply obtained 1.78 * 10-3 m3 of gray water footprint in 2015, and the value is 1.3 times the blue water footprint score of 1.35 * 10-3 m3/kWh. Although water footprint of 1 kWh of electricity supply decreased, the national total gray water footprint increased significantly from 2006 to 2015 with increase in power generating capacity. An opposite trend was observed for blue water footprint. Indirect processes dominated the influence of gray water footprint, whereas direct freshwater consumption contributed 63.6% to blue water footprint. Ameliorating key processes, including transportation, direct freshwater consumption, direct air emissions, and coal washing could thus bring substantial environmental benefits. Moreover, phosphorus, mercury, hexavalent chromium, arsenic, COD, and BOD5 were key substances of gray water footprint. Results indicated that the combination of railway and water transportation should be prioritized. The targeted transition toward high coal washing rate and pithead power plant development provides a possibility to relieve environmental burdens, but constraints on water resources in coal production sites have to be considered. PMID- 29715660 TI - Effects of dietary ramie powder at various levels on carcass traits and meat quality in finishing pigs. AB - This study investigated the effects of ramie (0, 3, 6, 9, or 12%) included in finishing diets on carcass traits and meat quality of Xiangcun black pigs. Results showed that ramie decreased (linear, P < .05) backfat depth while it increased (linear, P < .05) loin-eye area. A quadratic effect of shear force in longissimus thoracis (LT) was observed, and the lowest value was noted in the 6% ramie group. Protein content in LT was linearly increased by ramie (linear, P < .01). Meanwhile, dietary ramie linearly decreased lipogenic genes mRNA levels and fiber cross-sectional area, but it linearly increased total fiber number of LT. These results suggest that ramie included in the diet <9% is an effective feed crop to partly improve carcass trait and muscle chemical composition without negatively affecting growth performance, and the underlying mechanism may be due to the changed lipogenic potential and myofiber characteristics induced by ramie. PMID- 29715661 TI - The use of synthetic and natural vitamin D sources in pig diets to improve meat quality and vitamin D content. AB - This study investigated the effects of synthetic and natural sources of vitamin D biofortification in pig diets on pork vitamin D activity and pork quality. One hundred and twenty pigs (60 male, 60 female) were assigned to one of four dietary treatments for a 55 d feeding period. The dietary treatments were (1)50 MUg vitamin D3/kg of feed; (2)50 MUg of 25-hydroxvitamin D3/kg of feed (25-OH-D3); (3)50 MUg vitamin D2/kg of feed; (4)50 MUg vitamin D2-enriched mushrooms/kg of feed (Mushroom D2). The pigs offered the 25-OH-D3 diet exhibited the highest (P < 0.001) serum total 25-hydroxyvitamin D concentration and subsequently exhibited the highest (P < 0.05) Longissimus thoracis (LT) total vitamin D activity. Mushroom D2 and 25-OH-D3 supplementation increased pork antioxidant status. The vitamin D2-enriched mushrooms improved (P < 0.05) pig performance, carcass weight and LT colour. In conclusion, 25-OH-D3 is the most successful source for increasing pork vitamin D activity, while Mushroom D2 may be a new avenue to improve animal performance and pork quality. PMID- 29715662 TI - Antimicrobial effect of different peroxyacetic acid and hydrogen peroxide formats against spores of Clostridium estertheticum. AB - "Blown pack" spoilage is primarily caused by Clostridium estertheticum. The primary source of contamination is probably pelts, faeces and soil during opening cuts and de-hiding. Peroxyacetic acid (POAA) based fogs are commonly included in an abattoir's routine cleaning process. Hydrogen peroxide (H2O2) is a powerful oxidizing agent that penetrates microbe cell walls causing cell death. In this study, we compared the ability of H2O2 and OXYSAN ZS (POAA containing 1 hydroxyethylidine-1,1-diphosphonic acid as a stabilizer) in different formats to inactivate C. estertheticum spores. Hydrogen peroxide treatment using PhytagelTM gel as carrier was effective on fleece against both naturally contaminating microflora and C. estertheticum spores. This is the first time an antimicrobial treatment has been shown to inactivate C. estertheticum spores on such a complex and highly contaminated matrix. Both H2O2 and OXYSAN ZS treatments inactivated C. estertheticum spores on stainless steel indicating their potential use as an in plant decontamination procedure or inclusion in routine in-process cleaning. PMID- 29715663 TI - Toward the enhancement of sensory profile of sausage "Merguez" with chickpea protein concentrate. AB - The influence of different Chickpea Protein Concentrates (CPC) addition at different levels (CPC: 1.5, 2.5 and 5% (w/w)) on physico-chemical, textural and hedonic properties of formulated and cooked sausage "Merguez" were investigated. The obtained results exhibited that CPC addition increased protein content of "Merguez" sausage and improved the process yield. Significant differences were noticed on the cooking loss and textural properties for "Merguez" sausages formulated with 5% of CPC compared to the control (p < 0.05). Hedonic analysis showed that protein addition had no significant effect on sausages taste. However, sausage texture and global acceptability were markedly improved (p < 0.05). These results suggest that CPC could be an important alternative source of protein additive for the improvement of the physico-chemical, textural and sensorial properties of meat sausages. PMID- 29715664 TI - Effects of breeds, tissues and genders on purine contents in pork and the relationships between purine content and other meat quality traits. AB - The purine contents of animal foods are becoming widely concerned because excess intake of purine increases the risk of hyperuricemia and gout. In this study, we investigated the impacts of breed, tissue and sex on pork purine content and its correlations with multiple meat quality traits. Among six pig breeds, the average value of total purine contents (TP) in longissimus lumborum muscle was lowest in Chinese Laiwu pigs (114.2 mg/100 g) while highest in Chinese Bamaxiang mini pigs (139.3 mg/100 g). Considerable variations in TP were observed within most breeds, as well as among twelve pork organs with the range from 7 to 245 mg/100 g. However, no significant differences in TP were found between barrows and gilts. Intriguingly, lower purine content in meat was significantly associated with higher ultimate pH, better meat color and more abundant intramuscular fat content and marbling. The results thus suggest that the selection of low-purine pig species is available, which may simultaneously improve other meat quality traits. PMID- 29715665 TI - Unsaturated fat fraction from lard increases the oxidative stability of minced pork. AB - Lard from pork back fat was dry fractionated based on crystallization temperature, resulting in fractions with a ratio of saturated to unsaturated fatty acids of 1.10 and 0.61. Lean minced pork was mixed with the saturated and unsaturated fat fraction and stored in modified atmosphere (80% O2 and 20% CO2) at 5 degrees C for 2, 5, 7, 9, and 12 days under light to investigate the effect on oxidative stability of lipids and proteins. The saturated fat group developed higher TBARS values and lower levels of free thiol groups during storage, indicating that the unsaturated fat fraction in minced pork promoted increased oxidative stability of both lipids and proteins. A higher content of alpha tocopherol in the unsaturated fat fraction suggests that the differences in oxidative stability is causatively linked to the balance between the fatty acid composition and content of antioxidants. The TBARS values and free thiol content were negatively correlated, suggesting a relationship between lipid and protein oxidation. PMID- 29715666 TI - Origin discrimination of defatted pork via trace elements profiling, stable isotope ratios analysis, and multivariate statistical techniques. AB - This study verified the origin of 346 defatted Korean and non-Korean pork samples via trace elements profiling, and C and N stable isotope ratios analysis. The analyzed elements were 6Li, 7Li, 10B, 11B, 51V, 50Cr, 52Cr, 53Cr, 55Mn, 58Ni, 60Ni, 59Co, 63Cu, 65Cu, 64Zn, 66Zn, 69Ga, 71Ga, 75As, 82Se, 84Sr, 86Sr, 87Sr, 88Sr, 85Rb, 94Mo, 95Mo, 97Mo, 107Ag, 109Ag, 110Cd, 111Cd, 113Cd, 112Cd, 114Cd, 116Cd, 133Cs, 206Pb, 207Pb, and 208Pb. Content (mg/kg) of 51V (0.012), 50Cr (0.882), 75As (0.017), 85Rb (57.7), and 87Sr (46.3) were high in Korean pork samples whereas 6Li, 7Li, 59Co, 55Mn, 58Ni, 84Sr, 86Sr, 88Sr, 111Cd, and 133Cs were found higher in non-Korean samples. The results of discriminant analysis showed that the trace elements content and stable isotope ratios were significant for the discrimination of geographical origins with a perfect discrimination rate of 100%. PMID- 29715667 TI - Development of chemically activated N-enriched carbon adsorbents from urea formaldehyde resin for CO2 adsorption: Kinetics, isotherm, and thermodynamics. AB - Nitrogen enriched carbon adsorbents with high surface areas were successfully prepared by carbonizing the low-cost urea formaldehyde resin, followed by KOH activation. Different characterization techniques were used to determine the structure and surface functional groups. Maximum surface area and total pore volume of 4547 m2 g-1 and 4.50 cm3 g-1 were found by controlling activation conditions. The optimized sample denoted as UFA-3-973 possesses a remarkable surface area, which is found to be one of the best surface areas achieved so far. Nitrogen content of this sample was found to be 22.32%. Dynamic CO2 uptake capacity of the carbon adsorbents were determined thermogravimetrically at different CO2 concentrations (6-100%) and adsorption temperatures (303-373 K) which have a much more relevance for the flue gas application. Highest adsorption capacity of 2.43 mmol g-1 for this sample was obtained at 303 K under pure CO2 flow. Complete regenerability of the adsorbent over four adsorption-desorption cycles was obtained. Fractional order kinetic model provided best description of adsorption over all adsorption temperatures and CO2 concentrations. Heterogeneity of the adsorbent surface was confirmed from the Langmuir and Freundlich isotherms fits and isosteric heat of adsorption values. Exothermic, spontaneous and feasible nature of adsorption process was confirmed from thermodynamic parameter values. The combination of high surface area and large pore volume makes the adsorbent a new promising carbon material for CO2 capture from power plant flue gas and for other relevant applications. PMID- 29715668 TI - Soil organic carbon pool's contribution to climate change mitigation on marginal land of a Mediterranean montane area in Italy. AB - To evaluate the mitigation potential provided by the SOC pool, we investigated the impact of woody encroachment in the 0-30 cm depth of mineral soil across a natural succession from abandoned pastures and croplands to broadleaves forests on the central Apennine in Italy. In parallel, to assess the effect of the land use change (LUC) from cropland to pasture, a series of pastures established on former agricultural sites, abandoned at different time in the past, were also investigated. Our results show that woody encroachment on former pastures and croplands contributes largely to mitigate climate change, with an increase of the original SOC stock of 45% (40.5 Mg C ha-1) and 120% (66.5 Mg C ha-1), respectively. Also the LUC from croplands to pastures, greatly contributes to climate change mitigation trough a SOC increase of about 80% of the original SOC (45.9 Mg C ha-1). The management of abandoned lands represent a crucial point in the mitigation potential of agriculture and forestry activities, and particularly the role of the SOC pool. A policy effort should focus on minimizing the risk of speculative management options, particularly when the value of woody biomass become convenient to supply new energy systems allowing monetizing a long term forests productivity. In conclusion, despite both the land abandonment and the LUC can have a different impact on the SOC pool under different climatic conditions, these results can be useful to improve the SOC estimates in the National greenhouse gases Inventory at country level. PMID- 29715669 TI - Removal of lead and fluoride from contaminated water using exhausted coffee grounds based bio-sorbent. AB - Water pollution by industrial and anthropogenic actives has become a serious threat to the environment. World Health Organization (WHO) has identified that lead and fluoride amid the environmental pollutants are most poisonous water contaminants with devastating impact on the human race. The present work proposes a study on economical bio-adsorbent based technique using exhausted coffee grounds in the removal of lead and fluoride contaminants from water. The exhausted coffee grounds gathered from industrial wastes have been acid-activated and examined for their adsorption capacity. The surface morphology and elemental characterization of pre-and-post adsorption operations by FESEM, EDX and FTIR spectral analysis confirmed the potential of the exhausted coffee ground as successful bio-sorbent. However, thermodynamic analysis confirmed the adsorption to be spontaneous physisorption with Langmuir mode of homogenous monolayer deposition. The kinetics of adsorption is well defined by pseudo second order model for both lead and fluoride. A significant quantity of lead and fluoride is removed from the synthetic contaminated water by the proposed bio-sorbent with the respective sorption capabilities of 61.6 mg/g and 9.05 mg/g. However, the developed bio-sorbent is also recyclable and is capable of removing the lead and fluoride from the domestic and industrial waste-water sources with an overall removal efficiency of about 90%. PMID- 29715670 TI - Influences of water quality and climate on the water-energy nexus: A spatial comparison of two water systems. AB - As drinking water supply systems plan for sustainable management practices, impacts from future water quality and climate changes are a major concern. This study aims to understand the intraannual changes of energy consumption for water treatment, investigate the relative importance of water quality and climate indicators on energy consumption for water treatment, and predict the effects of climate change on the embodied energy of treated, potable water at two municipal drinking water systems located in the northeast and southeast US. To achieve this goal, a life cycle assessment was first performed to quantify the monthly energy consumption in the two drinking water systems. Regression and relative importance analyses were then performed between climate indicators, raw water quality indicators, and chemical and energy usages in the treatment processes to determine their correlations. These relationships were then used to project changes in embodied energy associated with the plants' processes, and the results were compared between the two regions. The projections of the southeastern US water plant were for an increase in energy demand resulted from an increase of treatment chemical usages. The northeastern US plant was projected to decrease its energy demand due to a reduced demand for heating the plant's infrastructure. The findings indicate that geographic location and treatment process may determine the way climate change affects drinking water systems. PMID- 29715671 TI - Patterns of plant diversity loss and species turnover resulting from land abandonment and intensification in semi-natural grasslands. AB - Land-use changes cause biodiversity loss in semi-natural ecosystems worldwide. Biotic homogenization has led to biodiversity loss, mainly through declines in species composition turnover. Elucidating patterns of turnover in species composition could enhance our understanding of how anthropogenic activities affect community assembly. Here, we focused on whether the decreasing patterns in plant diversity and turnover of species composition resulting from land-use change vary in two regions. We estimated the species diversity and composition of semi-natural grasslands surrounding paddy fields in satoyama landscapes. We examined the differences in species diversity and composition across three land use types (abandoned, traditional, and intensified) in two regions (Hyogo and Niigata Prefectures, Japan), which were characterized by different climatic conditions. We then assessed alpha-, beta-, and gamma-diversity to compare the patterns of diversity losses in the two regions as a result of land-use changes. In each region, gamma-diversity was consistently higher in the traditional sites compared to abandoned or intensified sites. The analyses revealed that most of the beta-diversity in traditional sites differed significantly from those of abandoned and intensified sites in both regions. However, the beta-diversity of total and perennial species did not differ between traditional and abandoned sites in the Hyogo region. We noted that the beta-diversity of total and perennial species in intensified sites was much lower than that in the traditional sites of the Niigata region. Overall, the patterns of alpha- and gamma-diversity loss were similar in both study regions. Although the biotic homogenization was caused by intensified land-use in the Niigata region, this hypothesis did not completely explain the loss of biodiversity in the abandoned sites in the Hyogo region. The present study contributes to the growing body of work investigating changes in biodiversity as a result of both biotic homogenization and differentiation in semi-natural ecosystems. Conservationists and policy makers should focus on patterns of species composition responded to land-use changes that continue to increase worldwide. PMID- 29715672 TI - Impacts of aeration management and polylactic acid addition on dissolved organic matter characteristics in intensified aquaponic systems. AB - Aquaponics as a potential alternative for conventional aquaculture industry has increasingly attracted worldwide attention in recent years. However, the sustainable application of aquaponics is facing a growing challenge. In particular, there is a pressing need to better understand and control the accumulation of dissolved organic matter (DOM) in aquaponics with the aim of optimizing nitrogen utilization efficiency. This study was aiming for assessing the characteristics of DOM in the culture water and the relationship with the nitrogen transformations in different intensified aquaponic systems with hydroponic aeration supplement and polylactic acid (PLA) addition. Two enhancing attempts altered the quantity of DOM in aquaponic systems significantly with a varying DOM content of 21.98-45.65 mg/L. The DOM could be represented by four identified fluorescence components including three humic -like materials (83-86%) and one tryptophan-like substance (14-17%). The fluorescence intensities of humic acid-like components were decreased significantly after the application of intensifying strategies, which indicating that two enhancing attempts possibly affected humic acid-like fluorescence. Variation of optical indices also suggested the reductions of water DOM which could be impacted by the enhancing nitrogen treatment processes. These findings will benefit the potential applications and sustainable operation of these strategies in aquaponics. PMID- 29715673 TI - Composite wastewater treatment by aerated electrocoagulation and modified peroxi coagulation processes. AB - Treatment of composite wastewater generating from the industrial estates is a great challenge. The present study examines the applicability of aerated electrocoagulation and modified peroxi-coagulation processes for removing color and COD from composite wastewater. Iron plates were used as anodes and cathodes in both electrochemical processes and experiments were carried out in a working volume of 2 L. Aeration enhanced the efficiency of electrocoagulation process significantly. More than 50% of COD and 60% of color were removed after 1 h of electrocoagulation process operated at pH 3 and applied voltage of 1 V. Efficiency of the modified peroxi-coagulation process was significantly higher than that of aerated electrocoagulation. COD and color removal efficiencies of the modified peroxi-coagulation process were found as 77.7% and 97%, respectively after 1 h of electrolysis operated at 1 V, solution pH 3 and 50 mM hydrogen peroxide addition. This improved efficiency of modified peroxi-coagulation compared to aerated electrocoagulation is mainly due to the attack of in-situ generated hydroxyl radicals. PMID- 29715674 TI - Experimental studies on the enhanced performance of lightweight oil recovery using a combined electrocoagulation and magnetic field processes. AB - On marine oil spill, inflammable lightweight oil has characteristics of explosion risk and contamination of marine enviroment, therefore treatment of stable emulsion with micron oil droplets is urgent. This study aimed to propose a combined electrocoagulation and magnetic field processes to enhance performance of lightweight oil recovery with lower energy consumption. The effects of current density, electrolysis time, strength and direction of magnetic field on the overall treatment efficiency of the reactor were explored. Furthermore, the comparison between coupling device and only electrocoagulation through tracking oil removal in nine regions between the electrodes. The results were shown that the permanent magnets applied was found to enhance demulsification process within electrocoagulation reactor. For a given current density of 60 A m-2 at 16 min, Lorentz force downward was proved to promote the sedimentation of coagulants. As the magnetic field strength increases from 20 to 60 mT, oil removal efficiency was observed to increase and then decrease, and simultaneously energy consumption reduced and then present constantly. The results were found that the magnetic field strength of 40 mT was optimal within electrocoagulation reactor, which can not only diminishe difference of mass transfer rate along the height of vertical plate but also consume lowest energy. PMID- 29715676 TI - Bluetooth gas sensing module combined with smartphones for air quality monitoring. AB - This study addresses the development of a miniaturized (60 * 60 mm) Wireless Sensing Module (WSM) for environmental application and air quality detection. The proposed prototype has six sensors: one for humidity, one for ambient temperature (SHT21 from Sensirion), and four for gas detection (MiCS-4514, MiCS-5526 and MiCS 5914 from SGX Sensortech). The core of the system is based on a high performance 8-bit microcontroller, model PIC18F46K80, from Microchip. The obtained data values were transmitted to the Smartphone through a Bluetooth communication module and a home-developed Android app. The discrimination capability of the module is tested with 10 volatile organic compounds (acetone, acetic acid, benzene, ethanol, ethyl acetate, ethylbenzene, formaldehyde, toluene, xylene, and dimethylacetamide) and the effect of humidity and drift of the sensors is also studied. Results show that 88.33% and 92.22% success rates in classification stage are obtained using Multilayer Perceptron with BackPropagation Learning algorithm and Radial-Basis based Neural Networks, respectively. PMID- 29715675 TI - Photocatalytic degradation of naphthalene using calcined FeZnO/ PVA nanofibers. AB - Recently, the incorporation of metal oxide nanoparticles into polymers has gained great attention owing to their ample of applications. The green mediated synthesis Fe-doped ZnO nanoparticles have been incorporated into PVA nanofibers through electro spinning for the application of photocatalytic degradation. The PVA polymer concentration was optimized to obtain uniform fibers without beads. The Fe-doped ZnO nanofibers were characterized by various analyzing techniques. The results show that good physicochemical with high surface area, uniformity in fiber with an average diameter ranges from 150 to 300 and 50-200 nm for un calcined and calcined Fe-doped ZnO nanofiber respectively. The photocatalytic activity of nanofibers was examined by the degradation of naphthalene. The efficiency was observed 96 and 81% for calcined and un-calcined nanofibers, respectively. The reusable efficacy of Fe-doped ZnO calcined nanofiber as a catalyst was studied. These studies corroborated that the calcined Fe-doped ZnO nanofiber as promising material for catalytic applications. PMID- 29715677 TI - Radium geochemical monitoring in well waters at regional and local scales: an environmental impact indicator-based approach. AB - To assess radium (226Ra) as a potential indicator of impact in well waters, we investigated its behavior under natural conditions using a case study approach. 226Ra geochemistry was investigated in 67 private wells of southeastern New Brunswick, Canada, a region targeted for potential shale gas exploitation. Objectives were to i) establish 226Ra baseline in groundwater; ii) characterize 226Ra spatial distribution and temporal variability; iii) characterize 226Ra partitioning between dissolved phase and particulate forms in well waters; and iv) understand the mechanisms controlling 226Ra mobility under natural environmental settings. 226Ra levels were generally low (median = 0.061 pg L-1, or 2.2 mBq L-1), stable over time, and randomly distributed. A principal component analysis revealed that concentrations of 226Ra were controlled by key water geochemistry factors: the highest levels were observed in waters with high hardness, and/or high concentrations of individual alkaline earth elements (i.e. Mg, Ca, Sr, Ba), high concentrations of Mn and Fe, and low pH. As for partitioning, 226Ra was essentially observed in the dissolved phase (106 +/- 19%) suggesting that the geochemical conditions of groundwater in the studied regions are prone to limit 226Ra sorption, enhancing its mobility. Overall, this study provided comprehensive knowledge on 226Ra background distribution at local and regional scales. Moreover, it provided a framework to establish 226Ra baselines and determine which geochemical conditions to monitor in well waters in order to use this radionuclide as an indicator of environmental impact caused by anthropogenic activities (e.g. unconventional shale gas exploitation, uranium mining, or nuclear generating power plants). PMID- 29715678 TI - Tracing the sources of iodine species in a non-saline wastewater. AB - There are two types of wastewater in Hong Kong, non-saline and saline wastewaters. When it comes to disinfection, iodide is an important inorganic ion in concern because it may involve in the formation of iodinated disinfection byproducts, which show significantly higher toxicity than their brominated and chlorinated analogues. In this study, it was found that a non-saline wastewater in Hong Kong contained an unexpected high level of iodine. To trace the iodine sources of this non-saline wastewater, the information of the corresponding area was collected to find the possible iodine sources; then, the water samples from the possible iodine sources were collected; the concentrations of iodine species (iodide, iodate and organic iodine) in these collected water samples were determined; finally, the contribution percentages of iodine species from different sources were calculated. The results revealed that a specific domestic wastewater was the major iodine source, contributing to 68.6% of total iodine, 66.3% of iodide, 57.0% of iodate, and 112% of organic iodine in the non-saline wastewater, while landfill leachate, industrial and hospital wastewaters were the minor iodine sources, contributing to 6.6%, 3.1%, and 3.0% of total iodine in the non-saline wastewater, respectively. Furthermore, it was found that the extensive use of salt might result in high levels of iodine in the domestic wastewater and thus lead to the high level of iodine in the non-saline wastewater. PMID- 29715680 TI - Effect of African-American race on cancer specific mortality differs according to clear cell vs. non-clear cell histologic subtype in metastatic renal cell carcinoma. AB - AIM: To test the effect of African-American race on cancer specific mortality (CSM) in clear cell metastatic renal cell carcinoma (ccmRCC) and non-ccmRCC. PATIENTS AND METHODS: Within Surveillance, Epidemiology and End Results registry (2001-2014), we identified patients with ccmRCC and non-ccmRCC. We relied on propensity score (PS) matching to reduce the effect of inherent differences between African-American vs. Caucasian patients. After PS matching that included access to cytoreductive nephrectomy (CNT), cumulative incidence, competing-risks regression (CRR) models and landmark analyses tested the effect of race on CSM. RESULTS: Before PS matching, African-American patients accounted for 7.0 and 24.5% of respectively ccmRCC (N = 6742) and non-ccmRCC patients (N = 766). After PS matching, African-American patients accounted for 22.3 and 33.5% of respectively ccmRCC (N = 2050) and non-ccmRCC (N = 391) matched cohorts. In multivariable CRR models focusing on ccmRCC, higher CSM was recorded in African Americans (HR:1.27, p < 0.001). Conversely, in non-ccmRCC, lower CSM was recorded in African-Americans (HR:0.54, p < 0.001). Landmark analyses rejected the hypothesis of immortal time bias. CONCLUSION: African-Americans experienced higher CSM in ccmRCC. Conversely, African-Americans experienced lower CSM, when diagnosed with non-ccmRCC. These differences are independent of access to CNT and warrant further study since they may have an impact on efficacy or access to systemic therapies. PMID- 29715679 TI - Development of a hematocrit-insensitive device to collect accurate volumes of dried blood spots without specialized skills for measuring clozapine and its metabolites as model analytes. AB - Dried blood spots have been used as alternatives to traditional plasma and serum samples. We have now developed new devices, named volumetric absorptive paper disc (VAPD) and mini-disc (VAPDmini), to collect accurate volumes of dried blood spots in a simple manner and without the need for additional instruments. VAPD consists of a filter paper disc and a filter paper sheet with holes slightly larger than the disc. The disc is fixed in one such hole without direct contact with the filter sheet. VAPDmini is a scaled-down version of the same device. When several drops of whole blood are applied, the disc becomes saturated and any excess sample is absorbed by the surrounding filter sheet. Accuracy and precision of sampling were assessed by determining the levels of clozapine and its metabolites as target analytes by liquid-liquid extraction and high-performance liquid chromatography with coulometric detection. In addition, differences in analyte recovery were within +/-15% for all analytes in samples with 30-60% hematocrit, suggesting that VAPD and VAPDmini are insensitive to hematocrit for the analytes tested. The devices were also validated for analyte concentrations in the range 50-1000 ng/mL, and the limit of detection and lower limit of quantification were 5-17 ng/mL and 15-51 ng/mL, respectively. Intra- and inter day precision ranged from 3% to 13%, whereas accuracy ranged from a -14% to 12% bias. Analytes were stable in the devices for at least 2 weeks at room temperature. Collectively, these results indicate that sampling using VAPD and VAPDmini is comparable to conventional hole punch sampling of entire dried blood spots, even for samples obtained from patients treated with clozapine. Importantly, the devices were also found to be suitable for sample self collection. PMID- 29715681 TI - Editorial. PMID- 29715682 TI - Comparative transcriptomic analysis of the roots of intercropped peanut and maize reveals novel insights into peanut iron nutrition. AB - Intercropping is a vital technology in resource-limited agricultural systems with low inputs. Peanut/maize intercropping enhances iron (Fe) nutrition in calcareous soil. In this study, the transcriptome of peanut and maize roots was analyzed by suppression subtractive hybridization (SSH) and microarray analysis separately. We constructed four SSH libraries using the cDNA of peanut roots based on two cropping patterns: monocropping and intercropping, and two growth stages: vegetative stage and reproductive stage. Lib M1, I1, M2 and I2 comprised 53, 51, 37 and 54 genes, respectively. Six and four transporters were found in the two intercropping-specific SSH libraries, which may facilitate Fe acquisition and protoplasmic homeostasis of metal ions and anions. Specifically, AhNARMP1 and MTP may play a role in boosting Fe nutrition during the vegetative stage. The expression of MYC2 was also upregulated by intercropping, while an ethylene responsive transcription factor was downregulated during two growth periods. Microarrays indicated that homocysteine S-methyltransferase and serine acetyltransferase 1 upregulated in intercropped maize roots, which directly associated with methionine biosynthesis. It may account for the enhanced phytosiderophore released capacity in intercropping, which benefited the Fe nutrition of intercropped peanut in reproductive stage. Two aminocyclopropane-1 carboxylic acid synthase oxidase genes, which are related to ethylene biosynthesis, were downregulated in maize root by intercropping. Taken together with our previous proteomic work, the results indicated that intercropping enhances jasmonate signaling and weakens ethylene signaling in peanut and maize roots, which may improve ecological adaptation of the peanut plant to intercropping systems. PMID- 29715683 TI - Feeling short on time: trends, consequences, and possible remedies. AB - This review highlights recent research on time shortage, which has been broadly classified into three streams. Building upon decades of time use survey and diary findings, the trends and demographics stream document the latest longitudinal changes in perceptions of time shortage (including a recent decline) and provides an increasingly clear picture of who is hardest hit by time shortage. Meanwhile, the consequences stream has underscored that although time shortage has myriad negative outcomes, busyness and time pressure are not all bad news. Last, the nascent remedies stream has largely sought to ameliorate time shortage not by altering people's actual, objective temporal resources, but instead by offering safeguards against or shifting people's perceptions of time shortage. PMID- 29715684 TI - Biased Dropout and Crossmap Dropout: Learning towards effective Dropout regularization in convolutional neural network. AB - Training a deep neural network with a large number of parameters often leads to overfitting problem. Recently, Dropout has been introduced as a simple, yet effective regularization approach to combat overfitting in such models. Although Dropout has shown remarkable results on many deep neural network cases, its actual effect on CNN has not been thoroughly explored. Moreover, training a Dropout model will significantly increase the training time as it takes longer time to converge than a non-Dropout model with the same architecture. To deal with these issues, we address Biased Dropout and Crossmap Dropout, two novel approaches of Dropout extension based on the behavior of hidden units in CNN model. Biased Dropout divides the hidden units in a certain layer into two groups based on their magnitude and applies different Dropout rate to each group appropriately. Hidden units with higher activation value, which give more contributions to the network final performance, will be retained by a lower Dropout rate, while units with lower activation value will be exposed to a higher Dropout rate to compensate the previous part. The second approach is Crossmap Dropout, which is an extension of the regular Dropout in convolution layer. Each feature map in a convolution layer has a strong correlation between each other, particularly in every identical pixel location in each feature map. Crossmap Dropout tries to maintain this important correlation yet at the same time break the correlation between each adjacent pixel with respect to all feature maps by applying the same Dropout mask to all feature maps, so that all pixels or units in equivalent positions in each feature map will be either dropped or active during training. Our experiment with various benchmark datasets shows that our approaches provide better generalization than the regular Dropout. Moreover, our Biased Dropout takes faster time to converge during training phase, suggesting that assigning noise appropriately in hidden units can lead to an effective regularization. PMID- 29715685 TI - Discovery and description of a new serogroup 7 Streptococcus pneumoniae serotype, 7D, and structural analysis of 7C and 7D. AB - Streptococcus pneumoniae is characterised into 92 serotypes based on antigenic reactions of commercial rabbit sera to the capsular polysaccharides. During development of a bioinformatic serotyping tool (PneumoCaT), an isolate exhibited a novel codon at residue 385 of the glycosyltransferase gene wcwK encoding a distinct amino acid, which differentiates genogroup 7. Investigation by repeat serotyping and Quellung reaction revealed a novel pattern of factor sera with the isolate reacting very strongly with 7f, but also with 7e factor sera. The structure of the capsular polysaccharide was determined by NMR spectroscopy to be an approximately 5:1 combination of the structures of 7C and 7B, respectively, and the structure of 7C was also elucidated. All data from whole genome sequencing, NMR spectroscopy, production of antisera and serotyping of the novel 7 strain shows that it is a new serotype, which will be named in the Danish nomenclature as 7D. PMID- 29715686 TI - Portable X-ray fluorescence system to measure Th and U concentrations. AB - This study reports the results obtained in the analysis of waste material samples generated by the industries of phosphate fertilizers, in particular, the use of specific filters in a portable X-ray fluorescence system, a simple equipment allowing the characterization, identification and quantification of low concentrations of Th and U (ppm). The industrial byproduct is classified as a Technologically-Enhanced, Naturally-Occurring Radioactive Material - TENORM, and therefore requires monitoring for its radio-toxic activity due to the presence of radioactive thorium and uranium families. From the results obtained, it is concluded that this technique is able to determine the contents of these elements to concentrations of tens of ppm in measurements of about 300 s, and a small sample amount (~0.1 g). PMID- 29715687 TI - High blood lead levels are associated with lead concentrations in households and day care centers attended by Brazilian preschool children. AB - BACKGROUND: A previous study observed high blood lead levels (BLL) in preschool children attending 50 day care centers (DCC) in Sao Paulo, Brazil. OBJECTIVE: To identify whether lead levels found in both homes and DCC environments are associated with high blood lead levels. METHODS: Children attending 4 DCCs, quoted here as NR, VA, PS and PF, were divided into two groups according to BLL: high exposure (HE: >=13.9 MUg/dL; 97.5 percentile of the 2013 year sample) and low exposure (LE: <5 MUg/dL). For in situ lead measurements (lead paint mode: mg/cm2 and ROHS mode: MUg/g) in the children's households and in the DCC environments, a field portable X-ray-fluorescence analyzer was used. Multiple logistic regressions were performed to control for confounding factors. Odds ratios were adjusted for age, sex, day care center's measured lead, and tobacco. RESULTS: In an NR DCC building, 33.8% of the measurements had lead levels >600 MUg/g, whereas such levels were observed in 77.1% of NR playground measurements. In VA DCC, 22% and 23% of the measurements in the building and in the playgrounds had levels higher than 600 MUg/g, respectively. The percentage of high lead levels in the children's houses of the LE group was 5.9% (95% CI: 4.3-7.6%) and 13.2 (95% CI: 8.3-18.0%) in the HE group. Moreover, a significant association was found between high BLLs and lead levels found both in households and DCCs (p < 0.001). Most of the high lead measurements were found in tiles and playground equipment. CONCLUSIONS: Lead exposure estimated from the DCCs, where children spend about 10 h/day, can be as relevant as their household exposure. Therefore, public authorities should render efforts to provide a rigorous surveillance for lead-free painting supplies and for all objects offered to children. PMID- 29715688 TI - Impact of copper nanoparticles and ionic copper exposure on wheat (Triticum aestivum L.) root morphology and antioxidant response. AB - Copper nanoparticles (nCu) are widely used in industry and in daily life, due to their unique physical, chemical, and biological properties. Few studies have focused on nCu phytotoxicity, especially with regard to toxicity mechanisms in crop plants. The present study examined the effect of 15.6 MUM nCu exposure on the root morphology, physiology, and gene transcription levels of wheat (Triticum aestivum L.), a major crop cultivated worldwide. The results obtained were compared with the effects of exposing wheat to an equivalent molar concentration of ionic Cu (Cu2+ released from CuSO4) and to control plants. The relative growth rate of roots decreased to approximately 60% and the formation of lateral roots was stimulated under nCu exposure, possibly due to the enhancement of nitrogen uptake and accumulation of auxin in lateral roots. The expression of four of the genes involved in the positive regulation of cell proliferation and negative regulation of programmed cell death decreased to 50% in the Cu2+ treatment compared to that of the control, while only one gene was down-regulated to about half of the control in nCu treatment. This explained the decreased root cell proliferation and higher extent of induced cell death in Cu2+- than in nCu exposed plants. The increased methane dicarboxylic aldehyde accumulation (2.17 fold increase compared with the control) and decreased antioxidant enzyme activities (more than 50% decrease compared with the control) observed in the Cu2+ treatment in relation to the nCu treatment indicated higher oxidative stress in Cu2+- than in nCu-exposed plants. Antioxidant (e.g., proline) synthesis was pronouncedly induced by nCu to scavenge excess reactive oxygen species, alleviating phytotoxicity to wheat exposed to this form of Cu. Overall, oxidative stress and root growth inhibition were the main causes of nCu toxicity. PMID- 29715689 TI - Simultaneous removal of Cu2+ and bisphenol A by a novel biochar-supported zero valent iron from aqueous solution: Synthesis, reactivity and mechanism. AB - In this study, a novel biochar-supported zero valent iron (BC-nZVI) was synthesized through a green method. A high performance on the simultaneous removal of Cu2+ and bisphenol A (BPA) by a combination of BC-nZVI with persulfate (BC-nZVI/PS) system was successfully achieved. The simultaneous efficiencies of Cu2+ and BPA could reach 96 and 98% within 60 min, respectively. Both HO* and SO4*- were two major reactive species in BC-nZVI/PS system, and SO4*- was primary radical responsible for the degradation of BPA. Four kinds of Cu species, such as Cu(OH)2, CuO, Cu2O and Cu0 were generated via the adsorption and reduction of the BC-nZVI, whereas six kinds of products of BPA including p-isopropenyl phenol and 4-isopropylphenol were generated via the combined oxidation of SO4*- and HO*. The possible reaction mechanism for the simultaneous removal of Cu2+ and BPA by BC nZVI/PS system contained a synergistic effect between the reduction of Cu2+ and the oxidation of BPA. This is the first report on the feasibility of the remediation of coexistence of heavy metal and organic compound in aquatic environment using the BC-nZVI/PS system. PMID- 29715691 TI - VP-Nets : Efficient automatic localization of key brain structures in 3D fetal neurosonography. AB - Three-dimensional (3D) fetal neurosonography is used clinically to detect cerebral abnormalities and to assess growth in the developing brain. However, manual identification of key brain structures in 3D ultrasound images requires expertise to perform and even then is tedious. Inspired by how sonographers view and interact with volumes during real-time clinical scanning, we propose an efficient automatic method to simultaneously localize multiple brain structures in 3D fetal neurosonography. The proposed View-based Projection Networks (VP Nets), uses three view-based Convolutional Neural Networks (CNNs), to simplify 3D localizations by directly predicting 2D projections of the key structures onto three anatomical views. While designed for efficient use of data and GPU memory, the proposed VP-Nets allows for full-resolution 3D prediction. We investigated parameters that influence the performance of VP-Nets, e.g. depth and number of feature channels. Moreover, we demonstrate that the model can pinpoint the structure in 3D space by visualizing the trained VP-Nets, despite only 2D supervision being provided for a single stream during training. For comparison, we implemented two other baseline solutions based on Random Forest and 3D U-Nets. In the reported experiments, VP-Nets consistently outperformed other methods on localization. To test the importance of loss function, two identical models are trained with binary corss-entropy and dice coefficient loss respectively. Our best VP-Net model achieved prediction center deviation: 1.8 +/- 1.4 mm, size difference: 1.9 +/- 1.5 mm, and 3D Intersection Over Union (IOU): 63.2 +/- 14.7% when compared to the ground truth. To make the whole pipeline intervention free, we also implement a skull-stripping tool using 3D CNN, which achieves high segmentation accuracy. As a result, the proposed processing pipeline takes a raw ultrasound brain image as input, and output a skull-stripped image with five detected key brain structures. PMID- 29715690 TI - Evaluation of targeted and untargeted effects-based monitoring tools to assess impacts of contaminants of emerging concern on fish in the South Platte River, CO. AB - Rivers in the arid Western United States face increasing influences from anthropogenic contaminants due to population growth, urbanization, and drought. To better understand and more effectively track the impacts of these contaminants, biologically-based monitoring tools are increasingly being used to complement routine chemical monitoring. This study was initiated to assess the ability of both targeted and untargeted biologically-based monitoring tools to discriminate impacts of two adjacent wastewater treatment plants (WWTPs) on Colorado's South Platte River. A cell-based estrogen assay (in vitro, targeted) determined that water samples collected downstream of the larger of the two WWTPs displayed considerable estrogenic activity in its two separate effluent streams. Hepatic vitellogenin mRNA expression (in vivo, targeted) and NMR-based metabolomic analyses (in vivo, untargeted) from caged male fathead minnows also suggested estrogenic activity downstream of the larger WWTP, but detected significant differences in responses from its two effluent streams. The metabolomic results suggested that these differences were associated with oxidative stress levels. Finally, partial least squares regression was used to explore linkages between the metabolomics responses and the chemical contaminants that were detected at the sites. This analysis, along with univariate statistical approaches, identified significant covariance between the biological endpoints and estrone concentrations, suggesting the importance of this contaminant and recommending increased focus on its presence in the environment. These results underscore the benefits of a combined targeted and untargeted biologically-based monitoring strategy when used alongside contaminant monitoring to more effectively assess ecological impacts of exposures to complex mixtures in surface waters. PMID- 29715696 TI - Robotic-Arm Assisted Total Knee Arthroplasty Demonstrated Greater Accuracy and Precision to Plan Compared with Manual Techniques. AB - This study determined if robotic-arm assisted total knee arthroplasty (RATKA) allows for more accurate and precise bone cuts and component position to plan compared with manual total knee arthroplasty (MTKA). Specifically, we assessed the following: (1) final bone cuts, (2) final component position, and (3) a potential learning curve for RATKA. On six cadaver specimens (12 knees), a MTKA and RATKA were performed on the left and right knees, respectively. Bone-cut and final-component positioning errors relative to preoperative plans were compared. Median errors and standard deviations (SDs) in the sagittal, coronal, and axial planes were compared. Median values of the absolute deviation from plan defined the accuracy to plan. SDs described the precision to plan. RATKA bone cuts were as or more accurate to plan based on nominal median values in 11 out of 12 measurements. RATKA bone cuts were more precise to plan in 8 out of 12 measurements (p <= 0.05). RATKA final component positions were as or more accurate to plan based on median values in five out of five measurements. RATKA final component positions were more precise to plan in four out of five measurements (p <= 0.05). Stacked error results from all cuts and implant positions for each specimen in procedural order showed that RATKA error was less than MTKA error. Although this study analyzed a small number of cadaver specimens, there were clear differences that separated these two groups. When compared with MTKA, RATKA demonstrated more accurate and precise bone cuts and implant positioning to plan. PMID- 29715697 TI - Epidemiology and Outcome of Major Congenital Malformations in a Large German County. AB - INTRODUCTION: Congenital malformations are associated with substantial neonatal morbidity and mortality. Furthermore, only sparse data are available on the modalities of care provided to and the associated clinical outcomes in affected neonates. In this study, we focused on five malformations that require surgery during the neonatal period: duodenal stenosis and atresia (DA), gastroschisis (GA), omphalocele (OM), congenital diaphragmatic herniation (CDH), and esophageal atresia (EA). MATERIALS AND METHODS: We reviewed the Hessian neonatal registry (2010-2015) to identify records including the ICD-10 (International Classification of Diseases, Tenth Edition) codes for the aforementioned diagnoses and identified 283 patients who were affected by at least one of these conditions. Multiple regression analyses were performed to further identify risk factors for mortality and extended length of hospital stay. RESULTS: The incidence rates per 10,000 live births and inhospital mortality rates were as follows: DA: 1.79 and 3.6%; GA: 1.79 and 1.8%; OM: 1.60 and 24%; CDH: 1.32 and 27.5%; and EA: 2.67 and 11.1%, respectively. Thirty-three percent of the patients had not been born in a perinatal center in which corrective surgeries were performed. The following risk factors were significantly associated with early mortality: trisomy 13 and 18, congenital heart defects, prematurity, and high risk malformations (OM and CDH). The predictors of length of stay were as follows: gestational age, number of additional malformations, and treatment in the center with the highest patient volume. CONCLUSION: Epidemiology and outcome of major congenital malformations in Hesse, Germany, are comparable to previously published data. In addition, our data revealed a volume-outcome association with regard to the length of hospital stay. PMID- 29715698 TI - Antenatal Vitamin D Preserves Placental Vascular and Fetal Growth in Experimental Chorioamnionitis Due to Intra-amniotic Endotoxin Exposure. AB - BACKGROUND: Chorioamnionitis (CA) is associated with a high risk for the development of bronchopulmonary dysplasia (BPD) after preterm birth, but mechanisms that increase susceptibility for BPD and strategies to prevent BPD are uncertain. As a model of CA, antenatal intra-amniotic (IA) endotoxin (ETX) exposure alters placental structure, causes fetal growth restriction, increases perinatal mortality, and causes sustained cardiorespiratory abnormalities throughout infancy. Vitamin D (Vit D) has been shown to have both anti inflammatory and proangiogenic properties. Antenatal IA treatment with Vit D (1,25-(OH)2D3) during IA ETX exposure improves survival and increases vascular and alveolar growth in infant rats. Whether IA ETX causes decreased placental vascular development and if the protective effects of prenatal Vit D treatment are due to direct effects on the fetus or to improved placental vascular development remain unknown. OBJECTIVE: The objective of this study was to determine if IA ETX impairs placental vascular development and Vit D metabolism, and whether 1,25-(OH)2D3 treatment improves placental vascularity after IA ETX exposure during late gestation in pregnant rats. DESIGN/METHODS: Fetal rats were exposed to ETX (10 mg), ETX + 1,25-(OH)2D3 (1 ng/mL), 1,25-(OH)2D3 (1 ng/mL), or saline (control) via IA injection at E20 and delivered 2 days later. To assess placental vascular development, histologic sections from the placenta were stained for CD31 and vessel density per high power field (HPF) was determined and analyzed using Matlab software. To determine the effects of ETX on placental Vit D metabolism, Vit D receptor (VDR) and activity of the Vit D conversion enzyme, CYP27B1, were assayed from placental homogenates. Angiogenic mediators were measured by reverse transcription polymerase chain reaction by RNA extracted from placental tissue. RESULTS: IA ETX reduced placenta and newborn birth weights by 22 and 20%, respectively, when compared with controls (placental weight: 0.60 vs. 0.47 g; p < 0.0001; birth weight: 4.68 vs. 5.88 g; p < 0.0001). IA 1,25-(OH)2D3 treatment increased birth weight by 12% in ETX-exposed pups (5.25 vs. 4.68 g; p < 0.001). IA ETX decreased placental vessel density by 24% in comparison with controls (1,114 vs. 848 vessels per HPF; p < 0.05). Treatment with IA 1,25 (OH)2D3 increased placenta vessel density twofold after ETX exposure (1,739 vs. 848); p < 0.0001), and increased vessel density compared with saline controls by 56% (1,739 vs. 1,114; p < 0.0001). IA ETX decreased both VDR and CYP27B1 expression by 83 and 35%, respectively (p < 0.01). CONCLUSION: IA ETX decreases placental growth and vessel density and decreases placental VDR and CYP27B1 protein expression, and that antenatal 1,25-(OH)2D3 restores placental weight and vessel density, as well as birth weight. We speculate that 1,25-(OH)2D3 treatment preserves placental function in experimental CA and that these effects may be mediated by increased vascular growth. PMID- 29715699 TI - Effect of Gestational and Lactational Exposure to DEHP, DINP, and DEP on Intestinal Morphology, Disaccharidases, and Alkaline Phosphatase in Rats during Postnatal Development. AB - INTRODUCTION: The diesters of 1,2-benzenedicarboxylic acid (phthalic acid), commonly known as phthalates, are used primarily as plasticizers of polyvinyl chloride and as additives in consumer and personal care products. OBJECTIVE: This study was designed to evaluate the impact of in utero and postnatal exposure to diisononyl phthalate (DINP), diethylhexyl phthalate (DEHP), and diethyl phthalate (DEP) on gut maturation in a Wistar rat model. MATERIALS AND METHODS: Pregnant females were gavaged from day 8 of gestation through postnatal day (pd) 30 with 0 (vehicle control), DEHP (380 mg/kg/d), DINP (380 mg/kg/d), or DEP (800 mg/kg/d) dissolved in corn oil. Intestinal samples have been collected at 0, 7, 14, 21, and 30 pd for histological and biochemical analysis. The mitotic index has been evaluated based on the expression of Ki-67 antigen. RESULTS: All tested phthalate treatments have significantly decreased the body as well as the organ's weight (p < 0.001). DINP exposure resulted in severe villous atrophy, while DEHP treated group was characterized by lymphoepithelial lesions. In addition, a significant decrease of the Ki-67 proliferation index was observed in the youngest rats (0 and 7 days) upon the various treatments (p < 0.0001): , whereas at day 30, an increased numbers of Ki-67 positive cells were observed in DEHP and DEP but bot DINP group. Lactase and sucrase activities were inhibited by DEP in contrast to DINP and DEHP which increased enzymes activity (p < 0.05). CONCLUSION: Our results suggest that exposure to phthalates during gestational and lactational phases negatively impacts the development of the small intestine. PMID- 29715700 TI - Lung Ultrasound Findings in Congenital Pulmonary Airway Malformation. AB - BACKGROUND AND OBJECTIVE: Congenital pulmonary airway malformation (CPAM) is a group of rare congenital malformations of the lung and airways. Lung ultrasound (LU) is increasingly used to diagnose neonatal respiratory diseases since it is quick, easy to learn, and radiation-free, but no formal data exist for congenital lung malformations. We aimed to describe LU findings in CPAM neonates needing neonatal intensive care unit (NICU) admission and to compare them with a control population. METHODS: A retrospective review of CPAM cases from three tertiary academic NICUs over 3 years (2014-2016) identified five patients with CPAM who had undergone LU examination. LU was compared with chest radiograms and computed tomography (CT) scans that were used as references. RESULTS: CPAM lesions were easily identified and corresponded well with CT scans; they varied from a single large cystic lesion, multiple hypoechoic lesions, and/or consolidation. The first two LU findings have not been described in other respiratory conditions and were not found in controls. CONCLUSION: We provide the first description of LU findings in neonates with CPAM. LU may be used to confirm antenatally diagnosed CPAM and to suspect CPAM in infants with respiratory distress if cystic lung lesions are revealed. Further studies are necessary to define the place of LU in the management of CPAM. PMID- 29715701 TI - Application of Stem Cells to Infertility Treatment with Emphasis on Mesenchymal Stem Cells and Ovarian Stem Cells. AB - Stem cells are a population of undifferentiated cells that originated from embryonic and fetal stages of development. Stem cells possess the potency to produce cells that ultimately form different tissues and organs. They are considered as potential alternative novel therapeutic agents for patients suffering from infertility due to their unlimited source and high differentiation potency. There are several studies that have shown that different types of stem cells (mesenchymal stem cells, embryonic, endometrial, and ovarian stem cells) can be differentiated into both spermatozoa and oocytes in vitro, proving their potential clinical use in management and cure of infertility issues. Furthermore, mouse model studies have shown that ovarian stem cells, when cultured in vitro, can differentiate into a mature oocyte; however, there are still a lot of debates and complications attached to this concept. In addition, this is yet to be established using human ovarian stem cells, but, if established, would be a novel fertility preservation and treatment technique for women with infertility-related complications. This review gives comprehensive details of the available clinical application of stem cells in infertility treatment. PMID- 29715702 TI - Incidence and Risk Factors for Right Ventricular Outflow Tract Obstruction after the Arterial Switch Operation. AB - BACKGROUND: The aim of this study was to evaluate the incidence and risk factors for the development of right ventricular outflow tract obstruction (RVOTO) after the arterial switch operation (ASO). METHODS: Between 1983 and 2014, a total of 688 patients underwent ASO. RVOTO was defined as any obstruction of the right ventricular outflow tract (RVOT) requiring reintervention. RESULTS: RVOTO developed in 79 patients (11%) at a median time of 3.8 years (range, 1 day-23.6 years) after ASO. Freedom from RVOT reintervention was 96 +/- 1, 89 +/- 1, and 83 +/- 2% at 1, 10, and 25 years, respectively. Independent risk factors for the development of RVOTO in a Cox's regression model were side-by-side great arteries (p < 0.001), aortic arch anomalies (p < 0.001), use of a pericardial patch for augmentation of the coronary buttons (p < 0.001), and a peak gradient more than 20 mm Hg over the RVOT at discharge (p < 0.001). CONCLUSION: The incidence of RVOTO after ASO is not negligible. Complex morphology, such as side-by-side great arteries and aortic arch anomalies influences the development of RVOTO. PMID- 29715703 TI - ICU Readmission after Cardiac Surgery-Still a Matter of Concern? AB - BACKGROUND: Despite improvements in diagnostics and perioperative care, readmission to intensive care unit (ICU) after cardiac surgery is still a severe drawback for patients with considerable morbidity, mortality, and costs. Aim of this retrospective analysis was to disentangle independent risk factors for ICU readmission. MATERIAL AND METHODS: Between 01/2004 and 12/2012, 336 out of 9,555 (3.5%) patients undergoing cardiac surgery at the Department of Cardiothoracic Surgery in Regensburg (Germany) were readmitted to ICU. A matched-pair analysis (readmission vs control group) was conducted, matching for gender, age, and surgical procedure. Operations included coronary artery bypass grafting, valve reconstruction/replacement, aortic surgery, combined procedures, and others. Mean follow-up was 6.2 +/- 2.3 years. RESULTS: Median age of the readmitted patients was 71 years (65; 76), and the majority was male (67.9%). Median logistic Euroscore as a parameter for perioperative risk was significantly higher as compared with the control group (5.8 vs 5.2, p = 0.045) as was the prevalence of comorbidities including hypertension, chronic obstructive pulmonary disease, prior myocardial infarction, stroke, and PAOD. Most common reasons for readmission were cardiopulmonary instability (27.4%), respiratory failure (20.8%), and surgery for deep sternal infection (8.6%). Twenty-one percent required more than one readmission. Overall mortality was significantly higher in readmitted patients (21.1 vs 12.5%). CONCLUSIONS: In conclusion, readmission to the ICU after cardiac surgery is a rare complication that is still associated with excessive mortality. Establishment of an intermediate care unit proved to be an excellent means to reduce ICU stay without endangering post-surgery patients and significantly reduced the ICU readmission rate. PMID- 29715704 TI - Benefits and Risks of Prophylactic Cerebrospinal Fluid Catheter and Evoked Potential Monitoring in Symptomatic Spinal Cord Ischemia Low-Risk Thoracic Endovascular Aortic Repair. AB - BACKGROUND: To assess risks and benefits of a standardized strategy to prevent symptomatic spinal cord ischemia (SSCI) after thoracic endovascular repair (TEVAR) using routine cerebrospinal fluid (CSF) catheter placement and evoked potential (EP) monitoring. METHODS: One hundred and ninety-five patients underwent 223 SSCI low-risk TEVAR procedures between 1998 and 2014. CSF catheter was used to measure CSF pressure and drain CSF if necessary throughout the procedure and up to 24 hours thereafter. EPs were used to monitor spinal cord integrity throughout the procedure. RESULTS: Underlying pathologies included descending thoracic aortic aneurysm in 115 (52%), type B aortic dissection in 85 (38%), traumatic aortic rupture in 16 (7%), and others in 7 (3%) patients. CSF catheter was inserted before TEVAR in 116 procedures (52%). Active CSF draining was required in 29 patients (25%). The CSF catheter caused no major and 11 (10%) minor complications. EP were monitored during 88 (40%) procedures. We observed a reduction in the amplitude, prolonged latencies, or complete signal loss in nine procedures. There were no EP monitoring-related complications. SSCI incidence was higher in patients without CSF drainage (0.8% vs 4.7%, p = 0.031). CONCLUSION: Use of CSF drainage is associated with a significant lower incidence of SSCI after SSCI low-risk TEVAR than nonuse, whereas the complication rate associated with CSF drainage insertion or removal is very low. Routine EP monitoring is a useful tool to detect immediate arterial inflow obstruction to the spinal cord. The combination of these two methods serves as a safe and reliable standardized strategy in reducing the incidence of SSCI to a minimum. PMID- 29715705 TI - Randomized (CO)mparison of (TRI)fecta and (P)erimount Magna Ease Supraannular Aortic Xenografts-CO.TRI.P Study. AB - BACKGROUND: Modern supraannular aortic xenografts offer a special design, thus providing maximized opening area for improved hemodynamics. The aim of this study was a prospectively randomized comparison of the Trifecta and the Perimount Magna Ease valves based on metric annulus sizing. METHODS: A total of 100 patients with aortic stenosis undergoing aortic valve replacement (AVR) with or without concomitant procedures were prospectively included. After decalcification of the annulus, stratified intraoperative randomization was performed. The diameter of the aortic annulus was measured using metric Hegar dilators and randomization was based on this metric annulus diameter. Exercise echocardiography was performed at 10-month follow-up. RESULTS: Mean age was 69 years, with 36% female. Predominant implanted valve sizes were 23 mm (39%) and 25 mm (32%). Unadjusted mean pressure gradient was significantly lower and effective orifice area larger for the Trifecta group (10.8 +/- 5 vs. 13.2 +/- 4 mm Hg, p = 0.02 and 1.93 +/- 0.39 vs. 1.70 +/- 0.30 cm2, p = 0.002) at discharge. In patients with small annuli, based on the metric annulus size there were no significant differences in gradients or the orifice area. At exercise echocardiography follow-up, there were no significant hemodynamic differences between both prostheses. CONCLUSIONS: The Trifecta and the Perimount Magna Ease prostheses both show excellent hemodynamic performance after AVR. In patients with larger annuli, the Trifecta valve seems to be even superior to the Magna Ease, which may be advantageous in obese patients. PMID- 29715706 TI - Needlescopic Video-Assisted Thoracic Bilateral T4 Sympathicotomy for the Treatment of Primary Palmar Hyperhidrosis: An Analysis of 200 Cases. AB - BACKGROUND: Primary palmar hyperhidrosis (PPH) is featured by aberrantly perspiration of the hands, which may bring a lot of inconvenience to patient's daily life and work. The purpose of this study is to summarize the clinical effect of needlescopic video-assisted thoracic bilateral T4 sympathicotomy for the treatment of PPH. PATIENTS AND METHODS: Between January 2009 and March 2014, 200 patients received needlescopic video-assisted thoracic bilateral T4 sympathicotomy. We, respectively, took two 5-mm incisions in the third intercostal space on the anterior axillary line and in the fifth intercostal space on the middle axillary line. After collapsing left lung, needlescopic exploration was the first step to determine the targeted sympathetic chain through the third intercostal space. Electric coagulation hook was inserted from another port to cut T4 sympathetic chain and the bypassing nerve fibers for 2 to 3 cm along the surface of the fourth rib. Right thoracic cavity was also administered the same procedure. The palmar temperature was recorded before and after sympathicotomy. The symptom improvement, operative complications, patients' recovery, and satisfaction were evaluated. FINDING: One hundred and ninety-seven patients uneventfully received two 5-mm port bilateral sympathicotomy, and another 3 patients with extensive pleural adhesions completed the surgery through enlarging the third intercostal incision to 2 cm without conversion to open surgery. All operative procedures were completed in 15 to 35 minutes. The hospital stay was 2 to 4 days. The palmar temperature increased by 2.0 +/- 0.5 degrees C, and hyperhidrosis immediately disappeared in both hands after surgery. The efficacy rate was 100%. The postoperative complications such as hemorrhage, hemopneumothorax, bradycardia, or Horner's syndrome had no occurrence. During 6 to 60 months follow-up, mild compensatory sweating of buttock, back, and thigh occurred in 30 patients (15%) at 2 to 5 days after surgery and gradually disappeared at postoperative 15 to 30 days or longer time. All patients were greatly satisfied with the effect with better confidence and quality of life. Until now, no recurrent palmar hyperhidrosis happened. CONCLUSION: Needlescopic video-assisted thoracic bilateral T4 sympathicotomy could reach an excellent and immediate result of treating PPH. It is a safe, convenient, and minimally invasive method appropriate for wide clinical use. PMID- 29715707 TI - Rib Radiography versus Chest Computed Tomography in the Diagnosis of Rib Fractures. AB - BACKGROUND: The accurate diagnosis of rib fractures is important in chest trauma. Diagnostic images following chest trauma are usually obtained via chest X ray, chest computed tomography, or rib radiography. This study evaluated the diagnostic characteristics of rib radiography and chest computed tomography. METHODS: Seventy-five rib fracture patients who underwent both chest computed tomography and rib radiography between April 2008 and December 2013 were included. Rib radiographs, centered on the site of pain, were taken from two directions. Chest computed tomography was performed using a 16-row multidetector scanner with 5-mm slice-pitch without overlap, and axial images were visualized in a bone window. RESULT: In total, 217 rib fractures were diagnosed in 75 patients. Rib radiography missed 43 rib fractures in 24 patients. The causes were overlap with organs in 15 cases, trivial fractures in 21 cases, and injury outside the imaging range in 7 cases. Left lower rib fractures were often missed due to overlap with the heart, while middle and lower rib fractures were frequently not diagnosed due to overlap with abdominal organs. Computed tomography missed 21 rib fractures in 17 patients. The causes were horizontal fractures in 10 cases, trivial fractures in 9 cases, and insufficient breath holding in 1 case. CONCLUSION: In rib radiography, overlap with organs and fractures outside the imaging range were characteristic reasons for missed diagnoses. In chest computed tomography, horizontal rib fractures and insufficient breath holding were often responsible. We should take these challenges into account when diagnosing rib fractures. PMID- 29715708 TI - The Feasibility of Thoracoscopic Left Pneumonectomy. AB - OBJECTIVE: In this study, we describe our experience with video-assisted thoracoscopic surgery (VATS) left pneumonectomy as a treatment for advanced malignant and benign diseases. METHODS: Patients who underwent VATS left pneumonectomy in our clinic between October 2013 and August 2017 were retrospectively evaluated. VATS pneumonectomy was successfully completed in 46 patients. We reviewed and analyzed the characteristics of the patients in addition to intraoperative parameters, chest tube duration, length of hospital stay, morbidity, and mortality. RESULTS: A total of 46 patients underwent VATS left pneumonectomy. Of these, 43 patients had malignant tumors and 3 patients had destroyed lung. The histologic types were squamous cell carcinoma in 24 patients, adenocarcinoma in 11, large cell carcinoma in 2, sarcomatoid carcinoma in 1, follicular dendritic cell sarcoma in 1, and small cell carcinoma in 4. Primary lung cancers were classified as stage IA1 in 2 patients, IA2 in 2, IA3 in 1, IB in 3, IIA in 3, IIB in 11, IIIA in 18, and IIIB in 3. The mean operation time was 160.54 +/- 43.44 minutes, and the mean blood loss was 401.09 +/- 284.32 mL. There was no perioperative mortality and no secretion retention and bronchopleural fistula. Arrhythmia was found in three patients. Pneumonia was found in four patients. The median follow-up time in this cohort was 25 months. A total of 15 patients (34.8%) developed recurrent diseases, 12 developed distant or multiple metastasis, and 3 developed locoregional recurrence. CONCLUSION: VATS pneumonectomy is a safe, feasible treatment for complicated diseases that induces acceptable damage and has lower morbidity. PMID- 29715709 TI - Dissection of Incomplete Fissure Using Electrocautery Is a Safe and Acceptable Method for Thoracoscopic Right Upper Lobectomy. AB - OBJECTIVE: The incidence of prolonged air leak may be highest after right upper lobectomy due to incomplete minor fissure. The objective of this study was to compare the efficacy of direct electrocautery division and suture with that of a fissureless technique during thoracoscopic right upper lobectomy with incomplete fissure. METHODS: One hundred and two patients underwent right upper lobectomy between January 2016 and December 2016. Of these, 60 patients underwent a right upper lobectomy conducted using the fissureless technique (group A), and 42 consecutive patients underwent a right upper lobectomy via electrocautery division of the fissure and suture (group B). The preoperative, operative, and postoperative parameters were compared between the two groups. RESULTS: The electrocautery and suture group had a higher incidence of prolonged air leak (> 5 days) (30% [12/40] vs 11% [7/62], p = 0.00), a higher incidence of air leakage (20 [32%] vs 38 [95%], p = 0.00), a longer air leak duration (days) (4.93 +/- 0.86 vs 3.00 +/- 1.60 days, p = 0.00), a longer duration of chest tube (mean 5.30 +/- 1.20 vs 3.13 +/- 1.88 days, p = 0.00), and a lower hospitalization cost (6463.28 +/- 958.30 vs 7459.07 +/- 1185.00 ?, p = 0.00) than did the fissureless technique group. No differences were observed with respect to patient characteristics, operative characteristics, perioperative mortality, or duration of hospital stay after surgery. CONCLUSIONS: The number of patients with prolonged air leak was higher in the electrocautery group. However, electrocautery does not prolong overall length of stay and decreases hospitalization costs. Dissection of incomplete fissure using electrocautery is a safe and acceptable method for thoracoscopic right upper lobectomy. PMID- 29715710 TI - Timing of ECMO Initiation Impacts Survival in Influenza-Associated ARDS. AB - In the past decade, extracorporeal membrane oxygenation (ECMO) has emerged as an innovative therapy for influenza-associated acute respiratory distress syndrome (ARDS). Despite its promising results, the ideal timing of ECMO initiation for these patients remains unclear. Retrospective analysis of a single institution experience with venovenous ECMO for influenza-induced ARDS was performed. Twenty one patients were identified and categorized into early (0-2 days), standard (3-6 days), or late (more than 7 days) cannulation cohorts. Patients cannulated within 48 hours of admission had 80% survival rate at 90 days. Comparatively, the standard and late cannulation cohorts had an observed 90-day survival rate of 60 and 16.7%, respectively. PMID- 29715711 TI - Effects of Fengliao-Changweikang in Diarrhea-predominant Irritable Bowel Syndrome Rats and Its Mechanism Involving Colonic Motility. AB - Background/Aims: This study was designed to investigate the effect of Fengliao Changweikang (FLCWK) in diarrhea-predominant irritable bowel syndrome (IBS-D) rats and explore its underlying mechanisms. Methods: IBS-D model rats were induced by neonatal maternal separation (NMS) combined with restraint stress (RS). In in vivo experiments, the model rats were randomly divided into 5 groups: NMS + RS, FLCWK (low dose, middle dose, and high dose), and pinaverium bromide. The normal control (no handling) rats were classified as the NH group. The therapeutic effect of FLCWK was evaluated by fecal characteristics, electromyographic response and abdominal withdrawal reflex scores. In in vitro experiments, the model rats were randomly divided into 2 groups: NMS + RS, FLCWK (middle dose), and no handling rats were used as the NH group. The differences in basic tension and ACh-induced tension of isolated colonic longitudinal smooth muscle strips (CLSMs) among the 3 groups were observed. In addition, different inhibitors (nifedipine, TMB-8, L-NAME, methylene blue, and 4-AP) were pretreated to explore the underlying mechanisms. Results: In in vivo experiments, fecal characteristics, electromyographic response, and abdominal withdrawal reflex scores significantly improved in the FLCWK group, compared with the NMS + RS group. In in vitro experiments, the basic tension and ACh-induced tension of CLSMs in IBS-D rats were significantly inhibited by FLCWK. After pre-treatment with different inhibitors, the ACh-induced tension of CLSMs in each group showed no significant difference. Conclusions: FLCWK manifested curative effect in IBS-D rats by inhibiting colonic contraction. The underlying mechanisms may be related to regulatory pathway of nitric oxide/cGMP/Ca2+ and specific potassium channels. PMID- 29715712 TI - Back out of Locking Pin with Hinge Fracture after High Tibial Osteotomy. AB - Low-profile fixation devices for medial opening wedge high tibial osteotomy (OWHTO) were developed in order to avoid skin irritation and additional invasion. However, the low-profile system is associated with additional risks. We report three cases of locking pin back out with the low-profile locking plate system for medial OWHTO. PMID- 29715713 TI - Femoral Periprosthetic Fractures after Total Knee Arthroplasty: New Surgically Oriented Classification with a Review of Current Treatments. AB - Purpose: As the number of total knee arthroplasties (TKAs) increases, the incidence of femoral periprosthetic fractures after TKA is also increasing. This review aimed to suggest a new surgically oriented classification system for femoral periprosthetic fractures. Methods: We investigated the classifications, and current treatment trends for femoral periprosthetic fractures after TKA by means of a thorough review of the relevant literature. Results: Numerous studies reported good results of surgical treatment with modern fixatives including locking compression plates and retrograde intramedullary nails. However, few classifications of femoral periprosthetic fractures reflect the recent developments in surgical treatment. Conclusions: We recommend that surgical management be considered the first-line treatment for femoral periprosthetic fractures after TKA. Our new classification will help in deciding the surgical treatment option for femoral periprosthetic fractures after TKA. PMID- 29715714 TI - A Report of Two Cases of Adventitial Cystic Disease of the Popliteal Artery. AB - Two patients were admitted to our department because of recent aggravation of claudication in the leg, which was exacerbated by walking. They were diagnosed as having a Baker cyst or acute thrombosis in the popliteal fossa at another hospital. There was no evidence of ischemia, and the ankle brachial index was normal. Computed tomography and magnetic resonance imaging were performed, revealing a cystic mass of the popliteal artery (PA). Intraoperatively, the cystic lesion was found within the adventitia of the PA; based on the biopsy findings, both patients were diagnosed as having adventitial cystic disease of the PA. PMID- 29715715 TI - Treatment of Recurrent Hemarthrosis after Total Knee Arthroplasty. AB - Purpose: The purpose of this study is to evaluate the incidence and treatment of recurrent hemarthrosis after total knee replacement (TKR). Materials and Methods: Among a total of 5,510 patients who underwent TKR from March 2000 to October 2016, patients who had two or more bleeding 2 weeks after surgery were studied. Conservative treatments were performed for all cases with symptoms. In patients who did not respond to conservative treatment several times, embolization was performed. We retrospectively evaluated the postoperative bleeding time, bleeding frequency, treatment method, and outcome. Results: Seventeen (0.3%) of the 5,510 patients developed recurrent hemarthrosis. Bleeding occurred at an average of 2 years 3 months after the operation. Joint aspiration was performed 3.5 times (range, 2 to 10 times) on average, and 14 cases (82.3%) were treated with conservative treatment. In 3 patients with severe bleeding and hemorrhage, embolization was performed. Conclusions: Recurrent hemarthrosis after TKR is a rare disease with a low incidence of 0.3% and usually could be treated by conservative treatment. If recurrences occur repeatedly, embolization through angiography or surgical treatment may be considered, but the results are not satisfactory and careful selection of treatment modalities is warranted. PMID- 29715716 TI - The Learning Curve for Biplane Medial Open Wedge High Tibial Osteotomy in 100 Consecutive Cases Assessed Using the Cumulative Summation Method. AB - Purpose: The purpose of this study was to investigate whether surgical experience could improve surgical competency in medial open wedge high tibial osteotomy (MOWHTO). Materials and Methods: One hundred consecutive cases of MOWHTO were performed with preoperative planning using the Miniaci method. Surgical errors were defined as under- or overcorrection, excessive posterior slope change, or the presence of a lateral hinge fracture. Each of these treatment failures was separately evaluated using the cumulative summation test for learning curve (LC CUSUM). Results: The LC-CUSUM showed competency in prevention of undercorrection, excessive posterior slope change, and lateral hinge fracture after 27, 47, and 42 procedures, respectively. However, the LC-CUSUM did not signal achievement of competency in prevention of overcorrection after 100 procedures. Furthermore, the failure rate for overcorrection showed an increasing tendency as surgical experience increased. Conclusions: Surgical experience may improve the surgeon's competency in prevention of undercorrection, excessive posterior slope change, and lateral hinge fracture. However, it may not help reduce the incidence of overcorrection even after performance of 100 cases of MOWHTO over a period of 6 years. PMID- 29715718 TI - The origin and function of pleasure. AB - Currently, most cognitive scientists view the brain as a general-purpose computer and the processes of mind as software algorithms running on this neural architecture. From this perspective, conscious feelings, like pleasure, play no functional role in controlling human behaviour. This paper proposes that such computational theories are based on a false premise; namely, that the external world is full of light, sounds, smells, and tastes that can be detected through our senses. An alternative viewpoint, evolutionary functionalism, considers the world to be composed of energy/matter and views conscious experiences, like pleasure, as evolved emergent properties of biological tissue. From this perspective, natural selection has favoured conscious experiences that serve as evaluations of (feelings), or discriminations among (sensations) those aspects of the physical and social world that are biologically relevant. Over generations, it is the functional usefulness of these emergent properties that has shaped the neural architecture that underlies them. PMID- 29715717 TI - Antiviral and Anti-Inflammatory Activities of Pochonin D, a Heat Shock Protein 90 Inhibitor, against Rhinovirus Infection. AB - Human rhinoviruses (HRV) are one of the major causes of common cold in humans and are also associated with acute asthma and bronchial illness. Heat-shock protein 90 (Hsp90), a molecular chaperone, is an important host factor for the replication of single-strand RNA viruses. In the current study, we examined the effect of the Hsp90 inhibitor pochonin D, in vitro and in vivo, using a murine model of human rhinovirus type 1B (HRV1B) infection. Our data suggested that Hsp90 inhibition significantly reduced the inflammatory cytokine production and lung damage caused by HRV1B infection. The viral titer was significantly lowered in HRV1B-infected lungs and in Hela cells upon treatment with pochonin D. Infiltration of innate immune cells including granulocytes and monocytes was also reduced in the bronchoalveolar lavage (BAL) by pochonin D treatment after HRV1B infection. Histological analysis of the lung and respiratory tract showed that pochonin D protected the mice from HRV1B infection. Collectively, our results suggest that the Hsp90 inhibitor, pochonin D, could be an attractive antiviral therapeutic for treating HRV infection. PMID- 29715719 TI - What is an unconscious emotion?(The case for unconscious "liking"). AB - Ever since William James, psychologists of emotion have tended to view affective states as intrinsically conscious. We argue that nonconscious affect also exists, and focus specifically on the possibility of unconscious "liking". We present evidence that positive and negative affective reactions can be elicited subliminally, while a person is completely unaware of any affective reaction at all (in addition to being unaware of the causal stimulus). Despite the absence of any detectable subjective experience of emotion, subliminally induced unconscious "liking" can influence later consumption behaviour. We suggest that unconscious "liking" is mediated by specific subcortical brain systems, such as the nucleus accumbens and its connections. Ordinarily, conscious liking (feelings of pleasure) results from the interaction of separate brain systems of conscious awareness with those core processes of unconscious affect. But under some conditions, activity in brain systems mediating unconscious core "liking" may become decoupled from conscious awareness. The result is a genuinely unconscious emotion. PMID- 29715720 TI - Spontaneous facial expressions of happy bowlers and soccer fans. AB - Kraut and Johnston (1979) found surprisingly few smiles in large samples of bowlers and hockey fans during happy events--unless they were simultaneously engaged in social interaction. A limitation of their studies is that there was no direct test of subjects' actual emotional experience at the moments in which they were observed. This article reports two field studies in which emotions were reported by bowlers and by soccer fans. Analysing facial behaviour of those who reported happiness, we found a low probability of smiling in the absence of social interaction (.09 for bowlers and .07 for soccer fans) and a high probability of smiling during social interaction (.78 and .70). These findings question the common assumption that smiles are an indicator of happiness per se, and support the alternative hypothesis of a more complex and indirect relationship between smiling and happiness. PMID- 29715721 TI - Approaching awe, a moral, spiritual, and aesthetic emotion. AB - In this paper we present a prototype approach to awe. We suggest that two appraisals are central and are present in all clear cases of awe: perceived vastness, and a need for accommodation, defined as an inability to assimilate an experience into current mental structures. Five additional appraisals account for variation in the hedonic tone of awe experiences: threat, beauty, exceptional ability, virtue, and the supernatural. We derive this perspective from a review of what has been written about awe in religion, philosophy, sociology, and psychology, and then we apply this perspective to an analysis of awe and related states such as admiration, elevation, and the epiphanic experience. PMID- 29715722 TI - Antiphonal laughter between friends and strangers. AB - Drawing from an affect-induction model of laughter (Bachorowski & Owren, 2001; Owren & Bachorowski, 2002), we propose that "antiphonal" laughter--that is, laughter that occurs during or immediately after a social partner's laugh--is a behavioural manifestation of a conditioned positive emotional response to another individual's laugh acoustics. To test hypotheses concerning the occurrence of antiphonal laughter, participants (n = 148) were tested as part of either same- or mixed-sex friend or stranger dyads, and were audiorecorded while they played brief games intended to facilitate laugh production. An index of antiphonal laughter for each dyad was derived using Yule's Q. Significantly more antiphonal laughter was produced in friend than in stranger dyads, and females in mixed-sex dyads produced more antiphonal laughter than did their male partners. Antiphonal laughter may therefore reflect a mutually positive stance between social partners, and function to reinforce shared positive affective experiences. PMID- 29715723 TI - The content and structure of laypeople's concept of pleasure. AB - Five studies were conducted to map the content and structure of laypeople's conceptions of pleasure. Instances of the pleasure concept collected in Study 1 consisted predominantly of objects, events or persons described as sources of pleasure. Content analysis suggested that the pleasure category, like emotional response categories, might be formed at an implicit level where various pleasure antecedents are grouped based on common phenomenological qualities of the affective experience. Studies 2 and 3a showed that the pleasure category possesses a graded structure and fuzzy boundaries. Results further revealed that, either when explicitly presented with labels (Study 3b) or left to their own implicit categories during a sorting task (Study 4), laypeople represented pleasure as a hierarchical concept in which differentiated pleasure types (i.e., intellectual, emotional, social and physical) were subsumed under a higher level unitary form of pleasure. In this structure, unitary and differentiated pleasures shared a set of common affective qualities but were also distinguishable by unique and distinctive affective characteristics (Study 5). Ties to prior theories of pleasure and implications for decision making and behavioural research are discussed. PMID- 29715724 TI - Pleasure as a sign you can attend to something else: Placing positive feelings within a general model of affect. AB - Positive feelings are considered within the framework of a general model of origins and functions of affect. This model treats affect as reflecting the error signal of a feedback loop managing rate of incentive-seeking (and threat avoidant) behaviour. In this view, positive feelings represent a sign that things are going better than necessary and are presumed to induce coasting. A tendency to coast is seen as facilitating the shift of attention and effort to other behavioural domains, where they may be needed more or where unforeseen opportunities have arisen. Such a function for positive feelings would permit the person both to maintain satisfactory standing with regard to multiple goals and to take advantage of unforeseen opportunities, thus providing adaptive value. Comparisons are made to other recently developed ideas concerning the functions of positive feelings. PMID- 29715725 TI - Introduction: The return of pleasure. PMID- 29715726 TI - Pleasure and displeasure from the body: Perspectives from exercise. AB - The affective changes associated with acute exercise have been studied extensively in exercise and health psychology, but not in affective psychology. This paper presents a summary of the relevant findings and a tentative theoretical model. According to this model, affective responses to exercise are jointly influenced by cognitive factors, such as physical self-efficacy, and interoceptive (e.g., muscular or respiratory) cues that reach the affective centres of the brain via subcortical routes. Furthermore, the balance between these two determinants is hypothesised to shift as a function of exercise intensity, with cognitive factors being dominant at low intensities and interoceptive cues gaining salience as intensity approaches the individual's functional limits and the maintenance of a physiological steady-state becomes impossible. PMID- 29715727 TI - The pleasures of sex: An empirical investigation. AB - This study examined associations between the pleasurability of various sexual activities and behavioural experience with these activities. Participants were 145 female and 78 male undergraduates. Participants rated the pleasurability of various sexual activities (vaginal intercourse, anal intercourse, receiving oral sex, performing oral sex, masturbation by a partner, and self-masturbation) and answered questions about their experience with these sexual activities. Vaginal intercourse, receiving oral sex, and being masturbated by a partner received the highest,pleasure ratings. For behaviours other than vaginal intercourse and receiving oral sex, pleasure ratings were significantly higher among respondents who had engaged in the activity. Pleasure ratings for several different sexual behaviours were intercorrelated. Participants who scored high on a pleasure index were more sexually experienced, engaged in more frequent sexual activity, and reported having more sex partners. Results are interpreted within the context of an evolutionary theory which suggests that pleasure motivates sexual behaviour. PMID- 29715728 TI - Dissociations between implicit and explicit attitudes toward phobic stimuli. AB - The present study explored the presence of complaint-specific implicit associations in the domain of spider fear. Participants' implicit negative associations with spider cues were measured in highly fearful (n = 18) and explicitly nonfearful individuals (n = 19). To increase the reliability of the present study, two indices of implicit associations were used: a modified implicit association test (IAT), and an affective Simon paradigm (ASP). To test the stability of the IAT and the ASP, participants were tested twice. At the explicit level the attitude to spider cues was far more negative for high fear participants than for no fear participants. In contrast, high and low fear participants displayed very similar negative associations with spiders at the implicit level. Indicating their resistance to practice effects the ASP and IAT revealed similar results on both occasions. The dual attitude in low fear individuals suggests that the nonfearful individual is the one who can suppress the automatic negative spider stereotype, whereas the phobic individual is the one who does not attempt or is not able to control the negative associations with spider cues. PMID- 29715729 TI - BRIEF REPORT. AB - This study examined the different facets of emotional intelligence, alexithymia, and mood awareness. Undergraduate students (N = 129) completed the Trait Meta Mood Scale (TMMS), the Toronto Alexithymia Scale (TAS-20), and the Mood Awareness Scale (MAS). A factor analysis revealed two dimensions, attention to and clarity of emotions, that cut across all three instruments. These two dimensions were differentially associated with personality, as measured by the neuroticism, extraversion, and openness to experience portions of the NEO-FFI, and with performance on an emotional Stroop task. We discuss the implications for the conceptualisation of broad constructs such as emotional intelligence and alexithymia, as well as the potential utility of more narrowly defined individual differences. PMID- 29715730 TI - The effects of happy and angry expressions on identity and expression memory for unfamiliar faces. AB - We investigated the influence of happy and angry expressions on memory for new faces. Participants were presented with happy and angry faces in an intentional or incidental learning condition and were later asked to recognise the same faces displaying a neutral expression. They also had to remember what the initial expressions of the faces had been. Remember/know/guess judgements were made both for identity and expression memory. Results showed that faces were better recognised when presented with a happy rather than an angry expression, but only when learning was intentional. This was mainly due to an increase of the "remember" responses for happy faces when encoding was intentional rather than incidental. In contrast, memory for emotional expressions was not different for happy and angry faces whatever the encoding conditions. We interpret these findings according to the social meaning of emotional expressions for the self. PMID- 29715731 TI - Semantic effects in lexical access: Evidence from single-word naming. AB - Cognitive psychologists have not devoted much attention to semantic and emotional effects early in word recognition, assuming instead that such effects are primarily post-perceptual. Some evidence of such early effects does exist, but it relies exclusively on a less-than-ideal experimental task, the lexical decision task. In the current study, participants heard words over headphones and repeated them into a microphone as quickly as possible (single-word naming). The Danger and Usefulness of word referents were significantly related to naming times, independent of effects such as word length, familiarity, onset characteristics, stress, neighbourhood density, and concreteness. Results are discussed in terms of the adaptive benefit of making quick classifications along these dimensions, and against a backdrop of evidence from several widely divergent areas of research. PMID- 29715732 TI - Mood and the generation effect. AB - Three experiments address the assumptions, derived from a dual-force model, that positive mood supports assimilative (knowledge-driven) processes whereas negative mood supports accommodative (stimulus-driven) functions, and that mood-selective recall (mood congruency) is mainly a matter of assimilation. The generation effect paradigm was borrowed from memory research to test these assumptions. In Experiment 1, the theoretical variable, degree of assimilation, was operationalised by the ease with which stimulus meaning could be generated from word fragments. In Experiment 2, self-generated stimuli (assimilation) were compared to experimenter-provided stimuli (accommodation). As predicted, positive mood supported assimilation which in turn enhanced mood-congruent recall. In Experiment 3, retrieval mood rather than encoding mood was manipulated. In this situation, positive mood facilitated the recall of all self-generated information, whether congruent or not. The empirical results are generally consistent with the predictions derived from the dual-force framework. PMID- 29715733 TI - Implicit memory for negative and positive social information in individuals with and without social anxiety. AB - Studies of memory bias for threat-relevant information in individuals with social anxiety have produced mixed results. These discrepancies may be because investigators have studied different memory processes or have used different memory tasks. We employed a video clarity judgement task to investigate implicit (capacity-free, automatic, unconscious) memory and a recognition task to investigate explicit (effortful, strategic, conscious) memory for threat in socially anxious individuals and nonanxious controls. Implicit memory for "old" (i.e., seen before) videos was defined as rating "old" videos as more clear than "new" (i.e., never seen before) videos. We created brief video clips that involved an actor or actress approaching the camera and commenting on some aspect of the viewer's actions, physical appearance, or belongings. Twenty-four videos were positive (e.g., "I really like your shoes"), and 24 were negative (e.g., "That is a horrible haircut"). Results revealed that the video clarity test was an effective measure of implicit memory. Furthermore, socially anxious individuals showed a larger implicit memory index for negative videos than did nonanxious and dysphoric controls. No group differences emerged for implicit memory for positive videos. Similarly, groups did not differ in recognition of, or false alarms for, positive and negative videos. These results demonstrate the role of implicit memory in social anxiety implying that information about threat may be automatically primed in these individuals. PMID- 29715734 TI - Adaptive social reasoning in depressed mood and depressive vulnerability. AB - In this study we evaluate the evolutionary hypothesis that depressed states are associated with more adaptive reasoning about social risks, such as defeat or rejection. A total of 78 women were administered one of two mood inductions (depressed vs. neutral), followed by four Wason selection reasoning tasks (truth detection, cheater-detection, and two social risk tasks addressing attachment and social competition risks). Those in the depressed mood condition gave significantly more correct responses on a task requiring participants to reason about social competition. There were no significant differences on performance for the other reasoning tasks between the two mood induction conditions. Furthermore, measures of two dimensions of depression prone personality (sociotropy and autonomy) were associated with less adaptive reasoning about social risks. These results suggest that mildly depressed states may indeed facilitate adaptive reasoning within certain domains, whereas vulnerability to depression may be associated with a relative impairment in reasoning about social risks. PMID- 29715735 TI - Don't look now: Attentional avoidance of emotionally valenced cues. AB - It is often assumed that emotional stimuli receive high priority for processing, and that the distinction between positive and negative valence is fundamental. However, studies of attention to symbolic stimuli, such as words of different valence, have proved inconclusive. In four experiments, control over the emotional attributes of previously neutral line sketches was achieved by associating them with valenced captions. When these newly valenced sketches were paired with neutral stimuli in an attentional search task, they elicited equivalent attentional avoidance. In contrast, in a final experiment, strongly valenced colour pictures captured attention. We suggest that a mechanism acting to limit unnecessary interruptions of ongoing behaviour can inhibit processing of relatively mild emotional stimuli. PMID- 29715736 TI - Mode and tempo relative contributions to "happy-sad" judgements in equitone melodies. AB - Judgement of emotion conveyed by music is determined notably by mode (major minor) and tempo (fast-slow). This suggestion was examined using the same set of equitone melodies, in two experiments. Melodies were presented to nonmusicians who were required to judge whether the melodies sounded "happy" or "sad" on a 10 point scale. In order to assess the specific and relative contributions of mode and tempo to these emotional judgements, the melodies were manipulated so that the only verying characteristic was either the mode or the tempo in two "isolated" conditions. In two further conditions, mode and tempo manipulations were combined so that mode and tempo either converged towards the same emotion (Convergent condition) or suggested opposite emotions (Divergent condition). The results confirm that both mode and tempo determine the "happy-sad" judgements in isolation, with the tempo being more salient, even when tempo salience was adjusted. The findings further support the view that, in music, structural features that are emotionally meaningful are easy to isolate, and that music is an effective and reliable medium to study emotions. PMID- 29715737 TI - Anger, coping, and frontal cortical activity: The effect of coping potential on anger-induced left frontal activity. AB - The present research tested whether relative left midfrontal cortical activity would be greater when individuals believed they could engage in behaviour to ameliorate an anger-inducing situation as compared to when they believed they could do nothing. The research also examined whether relative left midfrontal cortical activity would relate to behaviors aimed at ameliorating the anger inducing situation, when individuals believed they could do something. To test these primary hypotheses, university students who were opposed to a tuition increase at their university were exposed to a pilot radio editorial that argued for increased tuition, and their electroencephalographic (EEG) activity, self reported emotions, and behavioural responses were then collected. Prior to hearing the editorial, participants were led to believe that the tuition increase would definitely occur or that the tuition increase may occur and that petitions were being circulated to attempt to prevent it. Results supported the primary hypotheses and also revealed that relative left midfrontal activity was associated with anger in response to the editorial and that the effects were specific to the midfrontal cortical regions. PMID- 29715738 TI - Ability versus vulnerability: Beliefs about men's and women's emotional behaviour. AB - In the present research we investigated gender-specific beliefs about emotional behaviour. In Study 1, 180 respondents rated the extent to which they agreed with different types of beliefs (prescriptive, descriptive, stereotypical, and contra stereotypical) regarding the emotional behaviour of men and women. As anticipated, respondents agreed more with descriptive than with prescriptive beliefs, and more with stereotypical than with contra-stereotypical beliefs. However, respondents agreed more with stereotypical beliefs about the emotional behaviour of women than with those about men. These results were replicated in Study 2 with a sample of 75 students and 80 nonstudents. In Study 3, a sample of 279 respondents rated the extent of agreement with the same items, this time with respect to then own emotional behaviour. A similar pattern of results was obtained, although agreement rates were higher than in Study 1 and 2. PMID- 29715739 TI - Automatic affective priming of recently acquired stimulus valence: Priming at SOA 300 but not at SOA 1000. AB - In a recent series of studies, it was demonstrated that originally neutral stimuli that were predictive of an electrocutaneous stimulus in a differential aversive conditioning procedure not only acquired "signal-value" but also acquired a negative affective valence. These affective changes were not only evident from the evaluative ratings scales, but also from the data of an affective priming procedure. This response-latency based priming procedure has recently been employed as an indirect and unobtrusive index of stimulus valence (attitudes) (e.g., Fazio, Jackson, Dunton, & Williams, 1995). In the present experiment, the use of the affective priming procedure as an indirect measure of stimulus valence was further explored. Results showed that aversively conditioned stimuli revealed their newly acquired valence in this priming procedure. As predicted, this effect was obtained at the short SOA (300 ms) but not at the long SOA (1000 ms). The significant SOA X Priming interaction suggests that the affective priming procedure is less or not affected by demand effects and (self presentational) response strategies. This makes the affective priming effect and excellent and unobtrusive measure of affective valence and an interesting alternative to subjective rating scales in situations where demand effects might otherwise influence responding. The results are also related to recent research on conditioning models of the acquisition of anxiety disorders, and to research on the co-occurrence of expectancy learning and affective learning within these models. PMID- 29715740 TI - Counterfactuals, emotions, and context. AB - Participants recalled either a negative academic or interpersonal experience, and the relations among counterfactual thinking, negative emotions, and attributions of blame and control were examined. Situational context effects on attribution, counterfactual thinking, and emotion were observed, indicating a greater tendency toward self-focused cognition and emotion in the academic context than in the interpersonal context. Consistent with recent theorising, upward counterfactual thinking was associated with negative emotions of guilt, shame, regret, disappointment, and sadness. However, there was no indication that downward counterfactual thinking regulated emotion as previous literature suggests. Implications for functional and process theories of counterfactual thinking are discussed. PMID- 29715741 TI - Interpersonal reactions toward depression and anger. AB - Two studies examined the effect of interpersonal attitude on reactions toward others' expression of anger or depression, Participants read a story in which their schoolmate experienced a negative event and expressed anger or depression, and reported their perceptions, affective reactions, and behavioural intentions such as support or rejection. The results indicated that an expression of anger elicited more negative reactions than an expression of depression only when a person whom participants disliked expressed the emotion. Furthermore, structural equation modelling indicated that the effect of interpersonal attitude on sympathy, blame, and support intention was mediated by the perception of the distressfulness of the event. The discussion considered the processes through which the expression of negative emotions evokes positive or negative interpersonal reactions. PMID- 29715742 TI - Disentangling schematic and conceptual processing: A test of the Interacting Cognitive Subsystems framework. AB - Central to the Interacting Cognitive Subsystems framework (ICS) is the assertion that meaning exists at both the propositional and implicational levels. This assertion was tested by having 26 fast-year undergraduates make speeded judgements of emotional expression and emotional content in separate tasks on 120 single recorded words. Propositional meaning was represented by the content of the words while implicational meaning was conveyed by the expression of the word. In two tasks, participants decided whether the content or the expression of the word was emotional or neutral. In the expression task main effects were found for expression but not for content. In the content task main effects were found for both content and expression with an interaction between the two factors. Some congruency effects were evident in both tasks. Predictions of the framework concerning the independent processing and eventual integration of these two levels of meaning were partially supported. The significance of separating conceptual and schematic processing for other models of multilevel cognitive processing is addressed. PMID- 29715743 TI - Memory bias for emotional facial expressions in major depression. AB - Sixteen clinically depressed patients and sixteen healthy controls were presented with a set of emotional facial expressions and were asked to identify the emotion portrayed by each face. They, were subsequently given a recognition memory test for these faces. There was no difference between the groups in terms of their ability to identify emotion between from faces. All participants identified emotional expressions more accurately than neutral expressions, with happy expressions being identified most accurately. During the recognition memory phase the depressed patients demonstrated superior memory for sad expressions, and inferior memory for happy expressions, relative to neutral expressions. Conversely, the controls demonstrated superior memory for happy expressions, and inferior memory for sad expressions, relative to neutral expressions. These results are discussed in terms of the cognitive model of depression proposed by Williams, Watts, MacLeod, and Mathews (1997). PMID- 29715744 TI - BRIEF REPORT. AB - The emotional Stroop task has been widely used to examine attentional bias in a variety of psychological disorders. In one format of this task, words are presented to participants in a mixed randomised or quasi-randomised sequence. We present data from two independent studies involving smokers, the results of which show that words appearing after smoking-related items in the mixed sequence are responded to more slowly than words appearing after neutral items. These carry over effects may reduce the size of emotional Stroop effects on the mixed Stroop task. We discuss the implications of these carry-over effects for research using the emotional Stroop task. PMID- 29715745 TI - Attentional resource allocation to emotional events: An ERP study. AB - The effects of experimentally induced emotions on task-related processing resources were investigated in two studies designed as dual-task-like paradigms. In Experiment 1, 24 participants viewed a series of affective pictures inducing positive, negative, and neutral emotional states. In Experiment 2, 24 participants imagined emotionally laden life events. Simultaneously to the emotion-inducing procedure, and during a neutral single-task condition, the participants performed auditory oddball discrimination tasks. In this paradigm, the amplitude of the oddball-evoked P3 component of the event-related brain potential reflects the allocation of processing resources to task-related processes. In both studies, the P3 amplitude was smaller in the negative as well as in the positive emotional condition, compared to the two neutral conditions. The results support the assumption that negative emotions get a higher processing priority and can drain on task-related processing resources. In addition, they extend the hypothesis to the effects of positive emotions. PMID- 29715746 TI - The effects of feelings of guilt on the behaviour of uncooperative individuals in repeated social bargaining games: An affect-as-information interpretation of the role of emotion in social interaction. AB - In two studies we found that feelings of guilt provoke individuals to cooperate in repeated social bargaining games (a prisoner's dilemma in Study 1 and an ultimatum game in Study 2). Feelings of guilt were either experimentally manipulated (Study 1) or assessed via self-report (Study 2) after participants had played one round of a social bargaining game. As predicted, individuals who experienced feelings of guilt (compared to individuals who felt no guilt) after pursuing a non-cooperative strategy in the first round of play, displayed higher levels of cooperation in the subsequent round of play (even one week later). Results are discussed in terms of an "affect-as-information" model, which suggests that non-cooperating individuals who experience the negative affective state associated with guilt in a social bargaining game may be using this feeling state as "information" about the future costs of pursuing an uncooperative strategy. Because in guilt the focus is on the specific, individuals are capable of ridding themselves of this emotional state through action (Lewis, 1993, p. 570). PMID- 29715747 TI - The representation of characters' emotional responses: Do readers infer specific emotions? AB - This paper argues that emotional inferences about characters in a text are not as specific as previously assumed (DeVega, Diaz, & Leon, 1997; DeVega, Leon, & Diaz 1996; Gernsbacher, Goldsmith, & Robertson, 1992; Gernsbacher, Hollada, & Robertson, 1998; Gernsbacher & Robertson, 1992). The emotional information inferred by readers does not differentiate between emotions that are similar, though not identical. In both Experiments 1 and 2, participants read the stories used by Gernsbacher et al. (1992). Results from Experiment 1 (off-line) show that participants judged several emotions consistent with the same story. In Experiment 2 (on-line), participants took longer to read target sentences containing emotions mismatching the stories, but there was no difference between target sentences containing different matching emotions as determined by Experiment 1. Results from Experiments 1 and 2 suggest that the emotional information readers infer from the stories is too broad to determine a specific emotion. The results are consistent with the idea that a general emotional response is evoked, which is compatible with one or more specific emotions. PMID- 29715748 TI - Why wasn't O.J. convicted? Emotional coherence in legal inference. AB - This paper evaluates four competing psychological explanations for why the jury in the O.J. Simpson murder trial reached the verdict they did: explanatory coherence, Bayesian probability theory, wishful thinking, and emotional coherence. It describes computational models that provide detailed simulations of juror reasoning for explanatory coherence, Bayesian networks, and emotional coherence, and argues that the latter account provides the most plausible explanation of the jury's decision. PMID- 29715749 TI - Contextual questions prevent mood primes from maintaining experimentally induced dysphoria. AB - We investigated the effects of questions designed to increase a wider awareness of the context in which moods occur on mood-maintaining primes in induced dysphoria. These questions were incorporated, with the primes (negative Velten mood induction statements) into a scrambled sentence task. In Study 1, contextual questions produced a significantly greater reduction in despondency compared to control questions. Study 2 replicated this finding and also demonstrated that contextual questions reduced corrugator EMG response to repeated despondency inducing statements. The results indicate that contextual questions can prevent negative primes from maintaining depressed mood, consistent with Brewin's (1989) suggestion that one mechanism of psychotherapy is reducing the activation of situationally accessible negative representations. PMID- 29715750 TI - Children's ability to control the facial expression of laughter and smiling: Knowledge and behaviour. AB - A total of 64 children, aged 7 and 10, watched a clown performing three sketches rated as very funny by the children. Two experimental conditions were created by asking half of the participants to suppress their laughter. Facial expressions were videotaped and analysed with FACS. For both ages, the results show a significant shorter duration (but not a lower frequency) of episodes of laughter and Duchenne smiles, and greater frequency of facial control movements in the suppression compared to the free expression group. The detailed results on individual facial action units used to control amusement expressions suggest hypotheses on the nature of the underlying processes. The participants' explicit knowledge of their control strategies was assessed through standardised interviews. Although behavioural control strategies were reported equally frequently by the two age groups, 10-year-olds verbalised more mental control strategies than 7-year-olds. This theoretically expected difference was not related to the actual ability to control facial expression. This result challenges the commonly held assumption that explicit knowledge of control strategies results in a greater ability to execute such control in ongoing social interactions. PMID- 29715751 TI - BRIEF REPORT. AB - Two studies are reported. In the first, 69 undergraduate students were asked to complete a questionnaire in which they reported one stressful incident they had experienced in the previous four weeks, and the appraisals, core relational themes, and emotions they experienced at the time. Without warning, one week later they were asked to consider the same incident and report their appraisals and emotions. Only scores on two of 41 variables differed across occasions. Data from the first time of completion were added to those of another group of students to form a total sample of 156 participants. These data were then used to test the model of appraisals, core relational themes, and emotion of Smith and colleagues (e.g. Smith and Lazarus, 1993). The model was tested on four emotions: anger, guilt, anxiety, and sadness, and accounted for between eighteen and forty eight percent of the explained variance of each measure. Contrary to the study's hypotheses, emotion-focussed coping potential added to the variance explained in measures of guilt and anger. The results are discussed in the context of the cognition-emotion literature. PMID- 29715752 TI - Impact of particulate sediment, bentonite and barite (oil-drilling waste) on net fluxes of oxygen and nitrogen in Arctic-boreal sponges. AB - To meet the increasing global energy demand, expanding exploration for oil and gas reserves as well as associated drilling activities are expected in the Arctic boreal region where sponge aggregations contribute to up to 90% of benthic biomass. These deep-water sponges along with their microbial endobionts play key roles in the nitrogen cycling in Arctic-boreal ecosystems. This study aimed to investigate the effects of drilling discharges and associated sediment resuspension events on net fluxes of oxygen, ammonium, nitrate and nitrite in three common deep-water sponge species in the form of explants. Sponges were exposed to suspended bentonite and barite, the primary particulate compounds in drilling waste, as well as suspended natural sediment particles for a period of 33 days (on average 10 mg L-1 for 12 h day-1). The exposure period was followed by a pollution abatement period for a further 33 days. No sponge mortality was observed during the experiment. However, exposure to these particles, especially to barite, led to reduced oxygen consumption by up to 33% that was linearly correlated with reduced nitrite/nitrate release by the sponges. The changes in net fluxes were accompanied by decreased tissue oxygenation by up to 54% within the sponges. These findings reveal the effects of fine particles on sponge metabolic processes by reducing aerobic respiration and microbial nitrification, and possibly by favouring anaerobic processes such as microbial denitrification. Most of the sponge responses recovered to their control levels upon the pollution abatement period, but the effects caused by barite may not be reversible. Our findings provide the first insight into the ecological consequences of oil and gas drilling activities on sponge-mediated nitrogen cycling in the Arctic-boreal region. PMID- 29715753 TI - A freshwater diatom challenged by Zn: Biochemical, physiological and metabolomic responses of Tabellaria flocculosa(Roth) Kutzing. AB - Freshwater ecosystems are under threatening anthropogenic pressures worldwide, namely by metals. Diatoms are used as water quality indicators, but the influence of micronutrients such as Zn and its impacts are poorly understood. Thus, our study aimed to elucidate the tolerance level, the cellular targets and the responses to counteract Zn toxicity of freshwater diatoms by exposing Tabellaria flocculosa, isolated from a Zn contaminated stream. Biochemical, physiological and metabolomic approaches were used. It was demonstrated that Zn is toxic to T. flocculosa at concentrations occurring in contaminated environments. At low stress (30 MUg Zn/L) few alterations in the metabolome were observed, but the enzymatic (SOD, CAT) and molecular (GSH, GSSG) antioxidant systems were induced, protecting cells from oxidative stress. At moderate stress (500 MUg Zn/L) the main changes occurred in the metabolome (increases in fatty acids, amino acids, terpenoids, glycerol and phosphate, decreases in sucrose and lumichrome) with a moderate increase in cell damage (LPO and PC). The concerted action of all these mechanisms resulted in a non-significant decrease of growth, explaining the survival of this T. flocculosa strain in an environment with this Zn concentration. At the highest stress level (1000 MUg Zn/L) the metabolome was identical to 500 MUg Zn/L, and the induction of antioxidant systems and extracellular ion chelation (exopolysaccharides, frustulins) were the main responses to the increase of Zn toxicity. However, these mechanisms were unable to effectively abrogate cellular damage and growth reduction was observed. Moreover, the decrease in sucrose and especially in lumichrome should be tested as new specific markers of Zn toxicity. The information obtained in this study can assist in environmental risk assessment policies, support the prediction of diatom behaviour in highly impacted Zn environments, such as mining scenarios, and may help develop new indices, which include alterations induced by metals. PMID- 29715754 TI - In vivo evaluation of antitumoral and antiangiogenic effect of imiquimod-loaded polymeric nanoparticles. AB - The chemotherapeutic agent imiquimod (Imq) is used to treat skin cancers, the most common type of human cancer. However, the high incidence of local and systemic side effects associated with its use as well as its low skin permeation impair patient compliance and therapeutic effectiveness To overcome these limitations, nanostructured systems such as nanoparticles can be a promising alternative. Nanoparticles are submicron particles (size less than 1000 nm) with high surface area that facilitates the interaction and cellular uptake by biological membranes. Therefore, the aim of the present work is to evaluate antiangiogenic effect and antitumoral activity of imiquimod-loaded nanoparticles compared to market Imq formulation. Polymeric nanoparticles containing Imq were obtained by the technique of precipitation of preformed polymer. Antiangiogenic activity of the formulations was determined in chicken embryo chorioallantoic membrane (CAM) and its chemopreventive potential was evaluate during multistage DMBA and croton oil model of skin carcinogenesis in mice. Nanoparticles containing Imq presented antiangiogenic activity superior than negative control, placebo dispersion and market Imq (p < 0.05) in the CAM model and also significantly reduced the number and size of papillomas compared to all other groups. These results suggest, therefore, that the obtained delivery system can be an alternative to treat diseases related to vessels formation and also potentially increase cutaneous permeation and efficacy of poor soluble drugs normally used to treat cutaneous diseases. PMID- 29715755 TI - Oleuropein and hydroxytyrosol protect rats' pups against bisphenol A induced hypothyroidism. AB - Bisphenol A (BPA) can disturb the endocrine system and the organs that respond to endocrine signals in organisms, indirectly exposed during prenatal and/or early postnatal life. The present study was designed to assess the protective effect of phenolic compounds from olive leaves against BPA induced thyroid dysfunction and growth perturbation in young rats during lactation. The BPA disrupting effect on thyroid function was investigated by measuring changes in plasma levels of thyroid hormones. Free triiodothyronine (FT3) and thyroxine (FT4) were decreased in young rats breast-fed from mothers treated with bisphenol A. This effect was associated with an increase in the plasma level of thyroid-stimulating hormone (TSH). The histological and immunohistochemical study of the thyroid gland revealed a disturbance in morphological structure and thyroid cells function. Thyroid dysfunction led to a disruption in the skeletal bone growth of young rats. In fact, the infrared microspectroscopic analysis and histological examination of femoral bone showed significant changes in their histoarchitecture associated with a perturbation in the mechanism of bone tissue mineralization. The administration of oleuropein or hydroxytyrosol in BPA treated lactating mothers improved the thyroid cells function by enhancing thyroid hormone levels. Moreover, these phenolics increased the body growth characterized by an amelioration in the structure and the microstructure of femoral bone tissue. HPLC analysis of rats-breast milk indicated the presence of oleuropein and hydroxytyrosol, which could contribute to the protective effect against bisphenol A induced hypothyroidism in pups rats. PMID- 29715756 TI - Arctigenin: A two-edged sword in ischemia/reperfusion induced acute kidney injury. AB - Arctigenin (ATG) is one of the main active substances in fruit derived from Arctium lappa L. Previous studies have reported that ATG have antitumor, neuroprotective, antioxidant, antifibrosis and anti-inflammatory functions. However, the actions of ATG in kidney with acute injury following ischemia/ reperfusion (I/R) is still uncertain. In our study, mice were subjected to kidney I/R by having the kidney pedicles clamped and administered with vehicle or ATG (1, 3 or 9 mg/kg/d) via oral gavage for 7 consecutive days prior to I/R. Notably, ATG aggravated kidney I/R injury with the concentration increases. Multiple biochemical assays and histological examination showed ATG significantly alleviated the inflammatory response as reflected by a decreased expression of proinflammatory cytokine, TLR4/MyD88, and NF-kappaB, along with the infiltration of CD68+ macrophage and CD11b+Gr1+ neutrophil in the kidneys. Meanwhile, ATG alleviated I/R-induced oxidative stress proved by increasing kidney manganese superoxide dismutase and glutathione peroxidase activity but reducing levels of malonaldehyde and inducible nitric oxide synthase. On the contrary, apoptosis was significantly increased in kidneys of ATG-treated mice compared with vehicle treated controls, especially in tubular cells. There were increased numbers of TUNEL positive cells and increased Bcl-2, Bax, cleaved-caspase-3, and cleaved caspase-9 expression. The current study demonstrates that pretreatment of ATG aggravates I/R induced acute kidney injury by increasing apoptosis of tubular cells despite reducing infiltrating inflammatory cells and proinflammatory cytokine. PMID- 29715757 TI - Madecassoside prevents acute liver failure in LPS/D-GalN-induced mice by inhibiting p38/NF-kappaB and activating Nrf2/HO-1 signaling. AB - Madecassoside (MA), a triterpenoid saponin isolated from Centella asiatica, exerts various pharmacological activities including antioxidative and anti inflammatory effects. The aim of this study was to explore the protective effect of MA in the treatment of lipopolysaccharide (LPS) and D-galactosamine (D-GalN) induced acute liver failure(ALF) in mice. We hypothesized that MA administration may decrease the degree of liver injury caused by LPS/D-GalN. In this study, we investigated this hypothesis by treating a mouse model of LPS/D-GalN-induced liver injury with MA. Our study demonstrated that MA (20 mg/kg and 40 mg/kg) treatment for 10 days attenuated LPS/D-GalN-induced liver injury by protecting liver function, suppressing the production of inflammatory cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta and IL-6, and recovering antioxidant enzyme activity. MA also significantly suppressed LPS stimulated protein levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase (COX)-2 by blocking the phosphorylation of p38 mitogen-activated protein kinase (MAPK) and eukaryotic transcription factor nuclear factor-kappa B (NF-kappaB). In addition, MA treatment enhanced protein levels of heme oxygenase (HO)-1 and anti-oxidant enzymes (superoxide dismutase, catalase, and glutathione peroxidase) through the upregulation of nuclear factor E2-related factor 2 (Nrf2) in LPS-stimulated liver injury. These results suggest that MA is a promising agent for the treatment of LPS/D-GalN-induced liver injury that could serve as a candidate for the development of a hepatoprotective drug against ALF. PMID- 29715758 TI - NGF and PI3K/Akt signaling participate in the ventral motor neuronal protection of curcumin in sciatic nerve injury rat models. AB - OBJECTIVE: It has been reported that sciatic nerve injury (SNI) leads to degeneration, damage, and apoptosis of motor neurons. Nerve growth factor (NGF) plays a pivotal role in regeneration and reestablishment of neuronal function via activating PI3K/Akt survival signaling pathways. Curcumin owns neuroprotective effect following brain injury. In the present study, we attempt to investigate underlying mechanism of neuroprotective effect of curcumin through elucidating its correlation with NGF and PI3K/Akt signaling pathways in vitro and in vivo. METHODS: PC-12 cells were exposed H2O2 in order to induce neuron cell injury and cells were then treated with curcumin. Caspase-3, NGF level and Akt phosphorylation were determined using flow cytometry and western blotting. Then, cells were treated with NGF specific siRNA followed by measurement of apoptosis, NGF and Akt phosphorylation levels. In animal model, rats were subjected to SNI and then randomly designated into four different groups: curcumin, curcumin + LY294002, curcumin + NGF shRNA, and negative controls and 12 rats in each group (n = 12). After four weeks of continuous treatment, tissue samples were obtained and subjected to TUNEL, NeuN double staining and western blotting. RESULTS: Curcumin significantly reduced the number of apoptotic cells induced by H2O2 and this effect was associated with upregulation of TrkA, Akt and downregulation of p17. ProNGF level was significantly decreased while mature NGF level was increased with curcumin treatment. When NGF was suppressed, anti-apoptotic effect of curcumin was attenuated. In addition, inhibition of PI3K/Akt results in increased apoptotic rate compared to vehicles following curcumin treatment which was reflected by decreased p17, Ki67, and cyclin D1. Suppression of NGF and inhibition of PI3K led to increased neuron cell death through increasing proNGF and decreasing mNGF, Akt, TrkA, p75NTR, and p17. CONCLUSION: Our findings revealed that curcumin exerts its protective effect against injured neurons through stimulating NGF release which further activates TrkA and PI3K/Akt cell survival signaling. PMID- 29715759 TI - Cardioprotective effect of Amaranthus tricolor extract in isoprenaline induced myocardial damage in ovariectomized rats. AB - Red spinach (Amaranthus tricolor) has been reported to possess many benefits and medicinal properties and used as a part of traditional medicine in Ayurveda and Siddha. The aim of the study was to investigate the effects of Amaranthus tricolor on isoproterenol-induced oxidative stress, fibrosis, and myocardial damage in ovariectomized rats. Ovariectomy surgery was conducted to remove both ovaries from the rats. After recovery, rats were administered with ISO subcutaneously (50 mg/kg) twice a week and were treated with ethanolic extracts of A. tricolor. This investigation showed that the level of oxidative stress markers was significantly increased while the superoxide dismutase (SOD) activity decreased in ISO administered ovariectomized rats. A. tricolor extract and atenolol treatment prevented the rise of malondialdehyde, nitric oxide and advanced protein oxidation product. Moreover, elevated activities of AST, ALT, and CK-MB enzymes were also lowered by both atenolol and A. tricolor treatment. Increased uric acid and creatinine levels were also normalized by atenolol, and A. Tricolor treatment in ISO administered ovariectomized rats. ISO-induced ovariectomized rats also showed massive inflammatory cell infiltration, fibrosis and iron deposition in heart compared to sham rats. Atenolol and A. tricolor treatment prevented the inflammatory cells infiltration, fibrosis, and iron deposition. These results suggest that A. tricolor treatment may protect against ISO administered myocardial infarction in ovariectomized rats probably by preventing inflammation, oxidative stress, and fibrosis. Further research is warranted to examine molecular mechanism of cardioprotective effect of A. tricolor. PMID- 29715760 TI - Study on the adiabaticity criterion of the thermally-guided very-large-mode-area fiber. AB - The adiabaticity criterion of the thermally-guided very-large-mode-area (TG VLMA) fiber is presented based on the mode-coupling theory firstly, to the best of our knowledge. The requirement for the adiabatic propagation of fundamental mode is discussed systematically. It is revealed that the pump absorption plays the most important role and the adiabaticity criterion can be met as long as it is small enough. Then, the effects of the configuration parameters of TG VLMA fiber on the up-limitation of pump absorption for the adiabaticity criterion are investigated. It is found that for the straight TG VLMA fiber, reducing the initial refraction index and inner-cladding diameter and utilizing the bi-directional pumping scheme are beneficial to the adiabatic propagation of fundamental mode. The bent TG VLMA fiber is also studied. It is found that the bent fiber is much more difficult to meet the adiabaticity criterion than the straight one. The results show that even with the 100-cm bend radius, the pump absorption should be smaller than 1 dB/m to meet the adiabaticity criterion. It is suggested that enlarging the core-to cladding ratio can be helpful for loosening the adiabaticity criterion of bent TG VLMA fiber. These pertinent results can provide significant guidance for understanding and designing the TG VLMA fiber and pertinent lasers and amplifiers. PMID- 29715761 TI - Generating a three-dimensional hollow spot with sub-diffraction transverse size by a focused cylindrical vector wave. AB - A three-dimensional (3D) hollow spot is of great interest for a wide variety of applications such as microscopy, lithography, data storage, optical manipulation, and optical manufacturing. Based on conventional high-numerical-aperture objective lenses, various methods have been proposed for the generation of 3D hollow spots for different polarizations. However, conventional optics are bulky, costly, and difficult to integrate. More importantly, they are diffraction limited in nature. Owing to their unique properties of small size, light weight, and ease of integration, planar lenses have become attractive as components in the development of novel optical devices. Utilizing the concept of super oscillation, planar lenses have already shown great potential in the generation of sub-diffraction, or even of super-oscillatory features, in propagating optical waves. In this paper, we propose a binary-phase planar lens with an ultra-long focal length (300lambda) for the generation of a 3D hollow spot with a cylindrical vector wave. In addition, we experimentally demonstrate the formation of such a hollow spot with a sub-diffraction transverse size of 0.546lambda (smaller than the diffraction limit of 0.5lambda/NA, where NA denotes the lens numerical aperture) and a longitudinal size of 1.585lambda. The ratio of central minimum intensity to the central ring peak intensity is less than 3.7%. Such a planar lens provides a promising way to achieve tight 3D optical confinement for different uses that might find applications in super-resolution microscopy, nano lithography, high-density data storage, nano-particle optical manipulation, and nano-optical manufacturing. PMID- 29715762 TI - Inscription and analysis of non-uniform diffraction gratings in azobenzene molecular glass thin films. AB - Non-uniform surface relief diffraction gratings were laser-inscribed on azobenzene molecular glass thin films using a modified Lloyd's mirror interferometer. The azobenzene films were exposed to an adjustable interference pattern produced by the recombination of collimated and spherically divergent laser wave fronts. The localized pitch, grating vector orientation and depth of the resulting non-uniform gratings were measured using an atomic force microscope and a theoretical model was analytically developed to explain the experimental results. The fabricated gratings exhibited a chirping or pitch variation along the imposed X-axis as well as an angular change in the grating vector orientation along the imposed Y-axis. Studies were conducted on various non-uniform grating configurations having central pitches of 500 nm, 1000 nm, 1500 nm and 2000 nm. PMID- 29715763 TI - Pure adaptive interferometer for free form surfaces metrology. AB - A pure adaptive interferometer is proposed for optical free form surfaces metrology without auxiliary devices such as the wavefont sensors and deflectometry systems for DM monitoring. In this method, the DM surface monitoring and free form surface measurement are achieved simultaneously in only one interferometer. The polarizing optics divide the interferometer into two partial common path interferometric system, which provide the null test for tested free form surface and non-null test for the DM surface. The final figure error of the free form surface is extracted by ray tracing. Experiments proving the feasibility of this interferometer is shown. PMID- 29715764 TI - Time-domain characteristics of ultrafast transverse mode switching based on Si nanowires. AB - We investigate the potential of an ultrafast transverse mode switch based on silicon on insulator (SOI) platform for the switching applications in the spatial division multiplexing (SDM) systems. The impact of waveguide geometry, operation wavelength, pulse width of the pump and probe waves, as well as the temporal delay between the pulses are discussed with a special focus on the temporal switching windows of the switch. The optimized switching performances are further applied to a switching node in a hybrid optical time division-multiplexing (OTDM) and SDM system. The switching energy of the Si-based switch is shown to be potentially smaller than that of the Si3N4 based integration platform. PMID- 29715765 TI - Dual-pulse laser ignition of ethylene-air mixtures in a supersonic combustor. AB - To reduce the energy of an individual laser pulse, dual-pulse laser ignitions (LIs) at various pulse intervals were investigated in a Mach 2.92 scramjet engine fueled with ethylene. For comparison, experiments on a single-pulse LI were also performed. Schlieren visualization and high-speed photography were employed to observe the ignition processes simultaneously. The results indicate that the energy of an individual laser pulse can be reduced by half via a dual-pulse LI method as compared with a single-pulse LI with the same total energy. The reduction of the individual laser pulse energy degrades the requirements on the laser source and the beam delivery system, which facilitates the practical application of LI in hypersonic vehicles. A pulse interval shorter than 40 MUs is suggested for dual-pulse LI in the present study. Because of the intense heat loss and radical dissipation in high-speed flows, the pulse interval for dual pulse LI should be short enough to narrow the spatial distribution of the initial flame kernel. PMID- 29715766 TI - Widely-tunable, narrow-linewidth III-V/silicon hybrid external-cavity laser for coherent communication. AB - We demonstrate a III-V/silicon hybrid external cavity laser with a tuning range larger than 60 nm at the C-band on a silicon-on-insulator platform. A III-V semiconductor gain chip is hybridized into the silicon chip by edge-coupling the silicon chip through a Si3N4 spot size converter. The demonstrated packaging method requires only passive alignment and is thus suitable for high-volume production. The laser has a largest output power of 11 mW with a maximum wall plug efficiency of 4.2%, tunability of 60 nm (more than covering the C-band), and a side-mode suppression ratio of 55 dB (>46 dB across the C-band). The lowest measured linewidth is 37 kHz (<80 kHz across the C-band), which is the narrowest linewidth using a silicon-based external cavity. In addition, we successfully demonstrate all silicon-photonics-based transmission of 34 Gbaud (272 Gb/s) dual polarization 16-QAM using our integrated laser and silicon photonic coherent transceiver. The results show no additional penalty compared to commercially available narrow linewidth tunable lasers. To the best of our knowledge, this is the first experimental demonstration of a complete silicon photonic based coherent link. This is also the first experimental demonstration of >250 Gb/s coherent optical transmission using a silicon micro-ring-based tunable laser. PMID- 29715767 TI - Ultrafast PM fiber ring laser mode-locked by nonlinear polarization evolution with short NPE section segments. AB - We demonstrate a nonlinear polarization evolution (NPE) mode-locked polarization maintaining (PM) Yb-doped fiber laser with short NPE section segments by setting proper splicing angle. With a theoretical analysis, we propose that an appropriate deviation splicing angle exists to maximize the adjustable range of transmission modulation. The simulation results are highly consistent with theoretical conclusions. Experimentally, using the optimal splicing angle predicted by the theoretical calculation, we have achieved an environmentally stable mode-locking fiber laser at 111-MHz repetition rate with corresponding pulse energy of 0.47 nJ. Additionally, the noise performance of this PM fiber laser is characterized. The measured RMS timing jitter and amplitude noise are 6.41 fs and 0.0052% respectively (1 kHz-10 MHz), which are competitive to the low phase noise performance of the typical fiber laser. PMID- 29715768 TI - Significant suppression of Rayleigh scattering loss in silica glass formed by the compression of its melted phase. AB - We propose the formation of silica glass with improved optical transport properties by compressing its melted phase with a hot isostatic pressure machine at high pressure and temperature. The lowest Rayleigh scattering loss was obtained for the glass held at 200 MPa and 2073 K for 4 h. The observed loss corresponds to 0.07 dB/Km at 1.55 MUm, which is about half of the loss in conventional silica glass fiber. The decrease in the loss was well explained in terms of the decrease in the size of the sub-nanometer-sized structural voids observed by positron annihilation lifetime spectroscopy in silica glass. The achievement of high transparency and strong confinement of light represents a promising result for the development of future fiber-core media. PMID- 29715769 TI - 300 Gb/s IM/DD based SDM-WDM-PON with laserless ONUs. AB - A low-cost, high-speed SDM-WDM-PON architecture is proposed by using a multi-core fiber (MCF) and intensity modulation/directly detection (IM/DD). One of the MCF cores is used for sending laser sources from optical line terminal (OLT) to optical network unit (ONU), thus facilitating laserless and colorless ONUs, and providing ease of network management and maintenance. In addition, the wavelengths of the ONUs are controlled on the OLT side, which also enables flexible optical networks. Thanks to the low inter-core crosstalk of a MCF, downstream (DS) and upstream (US) signals are transmitted independently in different cores of the MCF, not only increasing the aggregated capacity but also avoiding the Rayleigh backscattering noise. Finally, a proof-of-principle experiment is performed by using a 7-core fiber, achieving 300 /120 Gb/s aggregated capacity for DS and US (3 * cores, 4 * wavelengths, 25/10 Gb/s per wavelength), respectively. PMID- 29715770 TI - Numerical demonstration of neuromorphic computing with photonic crystal cavities. AB - We propose a new design for a passive photonic reservoir computer on a silicon photonics chip which can be used in the context of optical communication applications, and study it through detailed numerical simulations. The design consists of a photonic crystal cavity with a quarter-stadium shape, which is known to foster interesting mixing dynamics. These mixing properties turn out to be very useful for memory-dependent optical signal processing tasks, such as header recognition. The proposed, ultra-compact photonic crystal cavity exhibits a memory of up to 6 bits, while simultaneously accepting bitrates in a wide region of operation. Moreover, because of the inherent low losses in a high-Q photonic crystal cavity, the proposed design is very power efficient. PMID- 29715771 TI - Maximum-likelihood analysis of axial displacement in fluorescence phase-shifting interferometry. AB - Fluorescence phase-shifting interferometry (FPSI) is an optical technique that coherently combines the phase-shifted 4pi steradian emission wavefronts of a single fluorescent emitter to obtain multiple interferograms from which the emitter axial displacement can be retrieved with high precision. Here, we study the axial displacement sensitivity in 4-step FPSI within the framework of maximum likelihood (ML) phase estimation. Using Monte-Carlo simulations, we show that regardless of the method used to preprocess the measured interferograms, the variance of the ML estimate of the axial displacement approaches the Cramer-Rao lower bound and is closely limited from above by the variance of the classical 4 step phase shifting estimator. The difference between these lower and upper bounds depends on the interferogram visibility and signal-to-noise-ratio (SNR), with a percentage change of up to 29% that yields an absolute change of a few sub nanometers to some nanometers for SNRs larger than ~5. Our results suggest that for these levels of SNR, the use of the computationally simpler classical 4-step phase shifting estimation can be adequate to accurately determine axial displacements in FPSI, as we also experimentally verified. FPSI interferograms with lower SNR but good visibility can benefit from the use of the ML estimator, provided that the spatiotemporal phase stability of the FPSI system is high. PMID- 29715772 TI - High power, high efficiency, continuous-wave supercontinuum generation using standard telecom fibers. AB - We demonstrate a simple module for octave spanning continuous-wave supercontinuum generation using standard telecom fiber. This module can accept any high power ytterbium-doped fiber laser as input. The input light is transferred into the anomalous dispersion region of the telecom fiber through a cascade of Raman shifts. A recently proposed Raman laser architecture with distributed feedback efficiently performs these Raman conversions. A spectrum spanning over 1000nm (>1 octave) from 880 to 1900nm is demonstrated. The average power from the supercontinuum is ~34W with a high conversion efficiency of 44%. Input wavelength agility is demonstrated with similar supercontinua over a wide input wavelength range. PMID- 29715773 TI - ASI aurora search: an attempt of intelligent image processing for circular fisheye lens. AB - The circular fisheye lens exhibits an approximately 180 degrees angular field-of view (FOV), which is much larger than that of an ordinary lens. Thus, images captured with a circular fisheye lens are distributed non-uniformly with spherical deformation. Along with the fast development of deep neural networks for normal images, how to apply it to achieve intelligent image processing for a circular fisheye lens is a new task of significant importance. In this paper, we take the aurora images captured with all-sky-imagers (ASI) as a typical example. By analyzing the imaging principle of ASI and the magnetic characteristics of the aurora, a deformed region division (DRD) scheme is proposed to replace the region proposals network (RPN) in the advanced mask regional convolutional neural network (Mask R-CNN) framework. Thus, each image can be regarded as a "bag" of deformed regions represented with CNN features. After clustering all CNN features to generate a vocabulary, each deformed region is quantified to its nearest center for indexing. On the stage of an online search, a similarity score is computed by measuring the distances between regions in the query image and all regions in the data set, and the image with the highest value is outputted as the top rank search result. Experimental results show that the proposed method greatly improves the search accuracy and efficiency, demonstrating that it is a valuable attempt of intelligent image processing for circular fisheye lenses. PMID- 29715774 TI - Focal shift in metasurface based lenses. AB - In this paper, the focal shift issues of squared metasurface lenses are investigated. Axial intensity distribution formula of the squared planar lens model is obtained by utilizing traditional diffraction theories combining with the Fresnel approximation method. Fresnel integral and Cornu spiral are adopted to obtain the relations between the relative focal shift and Fresnel number, which can be used to predict the shift for different Fresnel numbers. In the far infrared region (at 10.6MUm), a group of C-shaped nanoantennas are designed to cover the phase shift from 0 to 2pi and simulations also performed by using finite-difference time-domain (FDTD) method. Several lenses are arranged by those resonators, and simulation results of focusing performance are in good agreement with the theoretical prediction. It's expected that this work will provide a better solution for the design of lens in the infrared integrated optical systems. PMID- 29715775 TI - Error analysis of the spectral shift for partial least squares models in Raman spectroscopy. AB - Raman spectroscopy paired with the partial least squares (PLS) method is commonly used for quantitative or qualitative analysis of complex samples. However, spectral shift induced by different Raman spectroscopy, different environment or different measured time will decrease the accuracy of the PLS model. In this work, the processing algorithms that improve the accuracy by removing the noise, background and varying sources of other spectral interference were first reviewed. The error induced by the spectral shift was analyzed and the formulas of the error were derived. The formulas were then used to calculate the theoretical error in the example of discriminating human and nonhuman blood. A comparison of the actual errors obtained from the mathematical method and experiment with the theoretical value demonstrated the effectiveness of the equation. The compensation for nonhuman blood according to the average error demonstrated the improvement of the accuracy. Finally, the non-uniform sampling of the Raman shift by charge-coupled device (CCD) was considered in the error equation. An accurate error equation was obtained. This work could help improve the stability of PLS models in the case of the spectral shift of the spectrometer in Raman spectroscopy. PMID- 29715776 TI - Timing resolution studies of the optical part of the AFP Time-of-flight detector. AB - We present results of the timing performance studies of the optical part and front-end electronics of the time-of-flight subdetector prototype for the ATLAS Forward Proton (AFP) detector obtained during the test campaigns at the CERN-SPS test-beam facility (120 GeV pi+ particles) in July 2016 and October 2016. The time-of-flight (ToF) detector in conjunction with a 3D silicon pixel tracker will tag and measure protons originating in central exclusive interactions p + p -> p + X + p, where the two outgoing protons are scattered in the very forward directions. The ToF is required to reduce so-called pileup backgrounds that arise from multiple proton interactions in the same bunch crossing at high luminosity. The background can fake the signal of interest, and the extra rejection from the ToF allows the proton tagger to operate at the high luminosity required for the measurement of the processes. The prototype detector uses fused silica bars emitting Cherenkov radiation as a relativistic particle passes through them. The emitted Cherenkov photons are detected by a multi-anode micro-channel plate photomultiplier tube (MCP-PMT) and processed by fast electronics. PMID- 29715777 TI - Simulation study of a high-order mode terahertz radiation source based on an orthogonal grating waveguide and multiple sheet electron beams. AB - Generally, it is difficult for the common backward wave oscillator (BWO) to produce powerful THz radiation when the operating frequency increases to a high level such as over 1 THz due to the very small structural dimensions. The concept of generating powerful THz radiation from the interaction between high-order mode THz wave and multiple sheet electron beams is a promising solution to address the issue. For the high-order mode operation, a novel orthogonal grating waveguide is proposed, which is relatively ease of fabrication compared with the overmoded structure based on the double staggered grating waveguide. A high-order mode BWO based on the orthogonal grating waveguide and multiple sheet electron beams is studied by simulations. Particle-in-cell simulations show that the BWO can provide over 1.08 W power in the frequency range of 1.18-1.30 THz. Such a methodology opens up a new way to extend the BWO's operating frequency to a higher level and provides a potential solution for developing compact powerful THz radiation sources with wide tunable bandwidth. PMID- 29715778 TI - Optimal integration of wide field illumination and holographic optical tweezers for multimodal microscopy with ultimate flexibility and versatility. AB - We introduce one-of-a-kind optical microscope that we have developed through optimized integration of wide-field and focused-light microscopies. This new instrument has accomplished operation of the same laser for both wide field illumination and holographic focused beam illumination interchangeably or simultaneously in a way scalable to multiple lasers. We have demonstrated its powerful capability by simultaneously carrying out Epi-fluorescence, total internal reflection fluorescence microscopy, selective plane illumination microscopy, and holographic optical tweezers with five lasers. Our instrument and the optical design will provide researchers across diverse fields, cell-biology and biophysics in particular, with a practical guidance to build an all-around multimodal microscope that will further inspire the development of novel hybrid microscopy experiments. PMID- 29715779 TI - 12.5 Gbit/s discretely tunable InP-on-silicon filtered feedback laser with sub nanosecond wavelength switching times. AB - A heterogeneously integrated InP-on-silicon fast tunable filtered feedback laser is demonstrated. The laser device consists of a main Fabry-Perot cavity connected to an integrated arrayed waveguide grating of which the outputs form external cavities in which semiconductor optical amplifiers can be switched to provide single-mode operation and tunability. The laser can operate at four different wavelengths whereby switching between each wavelength channel is done within one nanosecond. For each wavelength channel 12.5 Gbit/s NRZ-OOK direct modulation is demonstrated. The combination of fast wavelength switching with straightforward wavelength control and high-speed direct modulation characteristics make the demonstrated laser structure very attractive for use in optical packet or burst switching systems. PMID- 29715780 TI - Femtosecond laser induced breakdown spectroscopy based standoff detection of explosives and discrimination using principal component analysis. AB - We report the standoff (up to ~2 m) and remote (~8.5 m) detection of novel high energy materials/explosive molecules (Nitroimidazoles and Nitropyrazoles) using the technique of femtosecond laser induced breakdown spectroscopy (LIBS). We utilized two different collection systems (a) ME-OCT-0007 (commercially available) and (b) Schmidt-Cassegrain telescope for these experiments. In conjunction with LIBS data, principal component analysis was employed to discriminate/classify the explosives and the obtained results in both configurations are compared. Different aspects influencing the LIBS signal strength at far distances such as fluence at target, efficiency of collection system etc. are discussed. PMID- 29715781 TI - Anisotropic diffraction induced by orbital angular momentum during propagations of optical beams. AB - It is demonstrated that the orbital angular momentum (OAM) carried by the elliptic beam without the phase-singularity can induce the anisotropic diffraction (AD). The quantitative relation between the OAM and its induced AD is analytically obtained by a comparison of two different kinds of (1+2)-dimensional beam propagations: the linear propagations of the elliptic beam without the OAM in an anisotropic medium and that with the OAM in an isotropic one. In the former case, the optical beam evolves as the fundamental mode of the eigenmodes when its ellipticity is the square root of the anisotropic parameter defined in the paper; while in the latter case, the fundamental mode exists only when the OAM carried by the optical beam equals a specific one called a critical OAM. The OAM always enhances the beam-expanding in the major-axis direction and weakens that in the minor-axis direction no matter the sign of the OAM, and the larger the OAM, the stronger the AD induced by it. Besides, the OAM can also make the elliptic beam rotate, and the absolute value of the rotation angle is no larger than pi/2 during the propagation. PMID- 29715782 TI - Optimising superoscillatory spots for far-field super-resolution imaging. AB - Optical superoscillatory imaging, allowing unlabelled far-field super-resolution, has in recent years become reality. Instruments have been built and their super resolution imaging capabilities demonstrated. The question is no longer whether this can be done, but how well: what resolution is practically achievable? Numerous works have optimised various particular features of superoscillatory spots, but in order to probe the limits of superoscillatory imaging we need to simultaneously optimise all the important spot features: those that define the resolution of the system. We simultaneously optimise spot size and its intensity relative to the sidebands for various fields of view, giving a set of best compromises for use in different imaging scenarios. Our technique uses the circular prolate spheroidal wave functions as a basis set on the field of view, and the optimal combination of these, representing the optimal spot, is found using a multi-objective genetic algorithm. We then introduce a less computationally demanding approach suitable for real-time use in the laboratory which, crucially, allows independent control of spot size and field of view. Imaging simulations demonstrate the resolution achievable with these spots. We show a three-order-of-magnitude improvement in the efficiency of focusing to achieve the same resolution as previously reported results, or a 26 % increase in resolution for the same efficiency of focusing. PMID- 29715783 TI - Accurate calibration of geometrical error in reflective surface testing based on reverse Hartmann test. AB - The deflectometry provides a powerful metrological technique enabling the high precision testing of reflective surfaces with high dynamic range, such as aspheric and freeform surfaces. In the fringe-illumination deflectometry based on reverse-Hartmann-test configuration, the calibration of system geometry is required to achieve "null" testing. However, the system miscalibration can introduce a significant systematic error in the testing results. A general double step calibration method, which is based on the low-order Zernike aberration optimization and high-order aberration separation, is proposed to separate and eliminate the geometrical error due to system miscalibration. Both the numerical simulation and experiments have been performed to validate the feasibility of the proposed calibration method. The proposed method provides a general way for the accurate calibration of system geometrical error, avoids the over-correction and is feasible for the testing of various complex freeform surfaces. PMID- 29715784 TI - Space-borne profiling of atmospheric thermodynamic variables with Raman lidar: performance simulations. AB - The performance of a space-borne water vapour and temperature lidar exploiting the vibrational and pure rotational Raman techniques in the ultraviolet is simulated. This paper discusses simulations under a variety of environmental and climate scenarios. Simulations demonstrate the capability of Raman lidars deployed on-board low-Earth-orbit satellites to provide global-scale water vapour mixing ratio and temperature measurements in the lower to middle troposphere, with accuracies exceeding most observational requirements for numerical weather prediction (NWP) and climate research applications. These performances are especially attractive for measurements in the low troposphere in order to close the most critical gaps in the current earth observation system. In all climate zones, considering vertical and horizontal resolutions of 200 m and 50 km, respectively, mean water vapour mixing ratio profiling precision from the surface up to an altitude of 4 km is simulated to be 10%, while temperature profiling precision is simulated to be 0.40-0.75 K in the altitude interval up to 15 km. Performances in the presence of clouds are also simulated. Measurements are found to be possible above and below cirrus clouds with an optical thickness of 0.3. This combination of accuracy and vertical resolution cannot be achieved with any other space borne remote sensing technique and will provide a breakthrough in our knowledge of global and regional water and energy cycles, as well as in the quality of short- to medium-range weather forecasts. Besides providing a comprehensive set of simulations, this paper also provides an insight into specific possible technological solutions that are proposed for the implementation of a space-borne Raman lidar system. These solutions refer to technological breakthroughs gained during the last decade in the design and development of specific lidar devices and sub-systems, primarily in high-power, high-efficiency solid-state laser sources, low-weight large aperture telescopes, and high-gain, high-quantum efficiency detectors. PMID- 29715785 TI - Ultra-compact mode (de) multiplexer based on subwavelength asymmetric Y-junction. AB - We propose and experimentally demonstrate a novel multimode ultra-compact mode (de)multiplexer for highly integrated on-chip mode-division multiplexing systems. This device is composed of a wide divergence angle asymmetric Y-junction based on subwavelength structure and optimized using an inverse design method. The proposed device occupied a footprint of only 2.4 * 3 um2. The measured insertion loss and crosstalk were less than 1dB and -24 dB from 1530 nm to 1590 nm for both TE0 mode and TE1 mode, respectively. Likewise, a three mode multiplexer is also designed and fabricated with a compact footprint of 3.6 * 4.8 um2. Furthermore, our scheme could also be expanded to include more modes. PMID- 29715786 TI - High-power and high-speed wavelength-swept amplified spontaneous emission source. AB - In this work, we report the development of an external-cavity wavelength-swept amplified spontaneous emission (ASE) source with high output power and high tuning speed based on an efficient electro-optic effect of beam deflection. The wavelength-swept ASE source is capable of delivering stable output power with averaged intensity of 100 mW in a wide spectrum tuning range of over 80 nm around the wavelength of 1550 nm. The light source will have important applications in optical communications, biomedical imaging, spectral analysis and sensing. PMID- 29715787 TI - Depth and thermal sensor fusion to enhance 3D thermographic reconstruction. AB - Three-dimensional geometrical models with incorporated surface temperature data provide important information for various applications such as medical imaging, energy auditing, and intelligent robots. In this paper we present a robust method for mobile and real-time 3D thermographic reconstruction through depth and thermal sensor fusion. A multimodal imaging device consisting of a thermal camera and a RGB-D sensor is calibrated geometrically and used for data capturing. Based on the underlying principle that temperature information remains robust against illumination and viewpoint changes, we present a Thermal-guided Iterative Closest Point (T-ICP) methodology to facilitate reliable 3D thermal scanning applications. The pose of sensing device is initially estimated using correspondences found through maximizing the thermal consistency between consecutive infrared images. The coarse pose estimate is further refined by finding the motion parameters that minimize a combined geometric and thermographic loss function. Experimental results demonstrate that complimentary information captured by multimodal sensors can be utilized to improve performance of 3D thermographic reconstruction. Through effective fusion of thermal and depth data, the proposed approach generates more accurate 3D thermal models using significantly less scanning data. PMID- 29715788 TI - Wafer-scale nanopatterning using fast-reconfigurable and actively-stabilized two beam fiber-optic interference lithography. AB - A fast-reconfigurable and actively-stabilized fiber-optic interference lithography system is demonstrated in this paper. Employment of fiber-optic components greatly enhances the flexibility of the whole system, simplifies its optical alignment, and suppresses the interference of mechanical vibrations. Active stabilization is implemented in the system and evaluated through modeling and experiment. We demonstrate 3-inch-diameter wafer-scale patterning of 240-nm period grating lines with a sub-50-nm linewidth and an aspect ratio over 3. Two dimensional patterns of different geometries and dimensions are also demonstrated to show the versatility of our system. Step-and-repeat exposure is demonstrated with independently controlled patterning fields of 2*2cm2 large. PMID- 29715789 TI - Doubly differential star-16-QAM for fast wavelength switching coherent optical packet transceiver. AB - A coherent optical packet transceiver based on doubly differential star 16-ary quadrature amplitude modulation (DD-star-16-QAM) is presented for spectrally and energy efficient reconfigurable networks. The coding and decoding processes for this new modulation format are presented, simulations and experiments are then performed to investigate the performance of the DD-star-16-QAM in static and dynamic scenarios. The static results show that the influence of frequency offset (FO) can be cancelled out by doubly differential (DD) coding and the correction range is only limited by the electronic bandwidth of the receivers. In the dynamic scenario with a time-varying FO and linewidth, the DD-star-16-QAM can overcome the time-varying FO, and the switching time of around 70 ns is determined by the time it takes the dynamic linewidth to reach the requisite level. This format can thus achieve a shorter waiting time after switching tunable lasers than the commonly used square-16-QAM, in which the transmission performance is limited by the frequency transients after the wavelength switch. PMID- 29715790 TI - Experimental observation of wave localization at the Dirac frequency in a two dimensional photonic crystal microcavity. AB - Trapping light within cavities or waveguides in photonic crystals is an effective technology in modern integrated optics. Traditionally, cavities rely on total internal reflection or a photonic bandgap to achieve field confinement. Recent investigations have examined new localized modes that occur at a Dirac frequency that is beyond any complete photonic bandgap. We design Al2O3 dielectric cylinders placed on a triangular lattice in air, and change the central rod size to form a photonic crystal microcavity. It is predicted that waves can be localized at the Dirac frequency in this device without photonic bandgaps or total internal reflections. We perform a theoretical analysis of this new wave localization and verify it experimentally. This work paves the way for exploring localized defect modes at the Dirac point in the visible and infrared bands, with potential applicability to new optical devices. PMID- 29715791 TI - Black phosphorus Q-switched and mode-locked mid-infrared Er:ZBLAN fiber laser at 3.5 MUm wavelength. AB - With the proposal of dual-wavelength pumping (DWP) scheme, DWP Er:ZBLAN fiber lasers at 3.5 MUm have become a fascinating area of research. However, limited by the absence of suitable saturable absorber, passively Q-switched and mode-locked fiber lasers have not been realized in this spectral region. Based on the layer dependent bandgap and excellent photoelectric characteristics of black phosphorus (BP), BP is a promising candidate for saturable absorber near 3.5 MUm. Here, we fabricated a 3.5-MUm saturable absorber mirror (SAM) by transferring BP flakes onto a Au-coated mirror. With the as-prepared BP SAM, we realized Q-switching and mode-locking operations in the DWP Er:ZBLAN fiber lasers at 3.5 MUm. To the best of our knowledge, it is the first time to achieve passively Q-switched and mode locked pulses in 3.5 MUm spectral region. The research results will not only promote the development of 3.5-MUm pulsed fiber lasers but also open the photonics application of two-dimensional materials in this spectral region. PMID- 29715792 TI - pH measurements in 16-nL-volume solutions using terahertz chemical microscopy. AB - Terahertz chemical microscopy has been developed for measuring the pH of a solution using only a small volume. The microsolution wells were fabricated on the surface of the sensing plate using a conventional photolithograph technique. Because the pH value can be calculated from the amplitude of a terahertz wave directly radiated from a sensing plate by a femtosecond laser irradiation, this method does not require any reference electrode in the solution. Thus, pH measurement can be achieved with a volume as small as 16 nL. PMID- 29715793 TI - Development of an imaging gas correlation spectrometry based mid-infrared camera for two-dimensional mapping of CO in vehicle exhausts. AB - Real-time imaging of CO in vehicle exhaust was demonstrated using a gas correlation spectrometry based mid-infrared camera for the first time. The novel gas-correlation imaging technique is used to eliminate the spectral interferences from background radiation and other major combustion products, and reduce the influences of the optical jitter and temperature variations, thereby identifying and quantifying the gas. We take several spectral factors into account for the instrument design, concentration calibration and data evaluation, including atmospheric transmission, radiation interference, as well as the spectral response of infrared camera, filter and gas cell. A calibration method based on the molecular spectroscopy and radiative transfer equation is developed to identify the numerical relationship between the CO concentration * length and the measured image intensity. Two-dimensional CO distribution of vehicle exhaust with a time resolution of 50 Hz and detection limit of 20 ppm * meter is achieved when the distance between optical equipment and engine nozzle is 3 m. The gas correlation spectrometry based mid-infrared camera shows a great potential as a future technique to monitor vehicle pollution emissions quantitatively and visually. PMID- 29715794 TI - MO detector (MOD): a dual-function optical modulator-detector for on-chip communication. AB - While augmenting network on chips (NoC) with photonic links enables high bandwidth communication, the overhead for photonics is rather large, mainly driven by bulky footprints and the multi-functionality of transceivers. The latter requires, in addition to a photon source, signal modulation and detection. If the NoC were photonically augmented at every network point to enable all-to all connectivity, the resulting photonic overhead would be excessive. Besides, the high bandwidth of a single optical bus may be sufficient to supply the data sharing demand of a network. Spatial signal routing is a necessary function of data communication in NoCs. However, if photonic links are used to augment electronics, an energy-costly optical-electrical-optical (OEO) conversion is required since routing is currently executed in the electronic domain. Here we show a novel integrated broadband hybrid photonic-plasmonic device termed an MO detector featuring dual light modulation and detection. With 10 dB extinction ratio and 0.8 dB insertion loss at the modulation state and 0.7 A/W responsivity at the detection state based on the finite-different time-domain simulation, this transceiver-like device (i) eliminates the OEO conversion, (ii) reduces optical losses from photodetectors via bypassing the photodetector when not needed, and (iii) enables cognitive routing strategies for network-on-chips. As such, the MO detector acts as a micrometer-compact transceiver for next-generation NoCs. PMID- 29715795 TI - Compact system for near edge X-ray fine structure (NEXAFS) spectroscopy using a laser-plasma light source. AB - We present a compact laboratory system for near edge soft X-ray fine structure (NEXAFS) spectroscopy that was developed using a laser-plasma light source. The source is based on a double stream gas puff target. The plasma is formed by the interaction of a laser beam with the double stream gas puff target approach. The laser plasma source was optimized for efficient soft X-ray emission from a krypton/helium target in the range of 1.5 to 5 nm wavelength. This emission is used to acquire simultaneously the emission and absorption spectra of soft X-ray light from the source and from the investigated sample using a grazing incidence spectrometer. The measurements in the transmission mode reveal the features near the carbon K-alpha absorption edge of thin PET film. From those features, the composition of the sample was successfully obtained. The data are in agreement with synchrotron measurements. In the paper, the detailed information about the source, its optimization, the system, spectral measurements and the results are presented and discussed. PMID- 29715796 TI - Injection locking of optomechanical oscillators via acoustic waves. AB - Injection locking is an effective technique for synchronization of oscillator networks and controlling the phase and frequency of individual oscillators. As such, exploring new mechanisms for injection locking of emerging oscillators is important for their usage in various systems. Here, we present the first demonstration of injection locking of a radiation pressure driven optomechanical oscillator (OMO) via acoustic waves. As opposed to previously reported techniques (based on pump modulation or direct application of a modulated electrostatic force), injection locking of OMO via acoustic waves does not require optical power modulation or physical contact with the OMO and it can be easily implemented on various platforms to lock different types of OMOs independent of their size and structure. Using this approach we have locked the phase and frequency of two distinct modes of a microtoroidal silica OMO to a piezoelectric transducer (PZT). We have characterized the behavior of the injection locked OMO with three acoustic excitation configurations and showed that even without proper acoustic impedance, matching the OMO can be locked to the PZT and tuned over 17 kHz with only -30 dBm of RF power fed to the PZT. The high efficiency, simplicity, and scalability of the proposed approach paves the road toward a new class of photonic systems that rely on synchronization of several OMOs to a single or multiple RF oscillators with applications in optical communication, metrology, and sensing. Beyond its practical applications, injection locking via acoustic waves can be used in fundamental studies in quantum optomechanics where thermal and optical isolation of the OMO are critical. PMID- 29715797 TI - Investigation of regime switching from mode locking to Q-switching in a 2 um InGaSb/AlGaAsSb quantum well laser. AB - A two-section InGaSb/AlGaAsSb single quantum well (SQW) laser emitting at 2 MUm is presented. By varying the absorber bias voltage with a fixed gain current at 130 mA, passive mode locking at ~18.40 GHz, Q-switched mode locking, and passive Q-switching are observed in this laser. In the Q-switched mode locking regimes, the Q-switched RF signal and mode locked RF signal coexist, and the Q-switched lasing and mode-locked lasing happen at different wavelengths. This is the first observation of these three pulsed working regimes in a GaSb-based diode laser. An analysis of the regime switching mechanism is given based on the interplay between the gain saturation and the saturable absorption. PMID- 29715798 TI - Enhanced UV absorption of GaN photodiodes with a ZnO quantum dot coating layer. AB - Light absorption at the surface of a photodiode can be enhanced by employing nanostructures smaller than the wavelength of interest. In this study, a ZnO quantum dot (QD) coating layer was investigated for improving the light absorption of gallium nitride (GaN) ultraviolet (UV) photodiodes. A GaN surface coated with a ZnO QD solution exhibited significantly lower surface reflection than an uncoated GaN surface, which, in turn, improved the responsivity of the GaN photodiode. In comparison with other nanostructure or multilayer thin film processes, the proposed ZnO QD coating process is simple and effective in enhancing UV light absorption. PMID- 29715799 TI - Measuring vector field correlations using diffraction. AB - We present a method for efficiently measuring the 2 * 2 correlation matrix for paraxial partially coherent beams by using diffraction from small apertures and obstacles. Several representations for this matrix function of four spatial variables are discussed and illustrated with experimental results, including various alternative definitions of the spatial degree of coherence. PMID- 29715800 TI - Negative refractive index metamaterial with high transmission, low reflection, and low loss in the terahertz waveband. AB - The refractive index is a basic parameter of materials which it is essential to know for the manipulation of electromagnetic waves. However, there are no naturally occurring materials with negative refractive indices, and high performance materials with negative refractive indices and low losses are demanded in the terahertz waveband. In this paper, measurements by terahertz time domain spectroscopy (THz-TDS) demonstrate a metamaterial with a negative refractive index n of -4.2 + j0.17, high transmitted power of 81.5%, low reflected power of 4.3%, and a high figure of merit (FOM = |Re(n)/Im(n)|) of 24.2 at 0.42 THz. The terahertz metamaterial with these unprecedented properties can provide various attractive terahertz applications such as superlenses with resolutions beyond the diffraction limit in terahertz continuous wave imaging. PMID- 29715801 TI - Proof-of-concept of a multimodal laparoscope for simultaneous NIR/gamma/visible imaging using wavelength division multiplexing. AB - An optical/nuclear hybrid surgical technique using ICG-99mTc-nanocolloid can improve lesion detectability by detecting both fluorescence and gamma signals. However, a hybrid multimodal laparoscope that can obtain both NIR and gamma images is not available yet. In this work, we present a proof-of-concept study of a prototype multimodal laparoscope that can provide simultaneous NIR/gamma/visible imaging using wavelength division multiplexing. The performances of optical and gamma imaging were evaluated using a USAF 1951 negative resolution target and 99mTc-filled tumor-like sources, respectively. Simultaneous NIR/gamma/visible images of two Eppendorf tubes containing a mixture of 99mTc-ICG are presented. PMID- 29715802 TI - Different surface plasmon coupling behaviors of a surface Al nanoparticle between TE and TM polarizations in a deep-UV light-emitting diode. AB - The formulations and numerical algorithms of a three-level model for studying the Purcell effect produced by the scattering of an air/AlGaN interface and the surface plasmon (SP) coupling effect induced by a surface Al nanoparticle in a two-polarization emission system to simulate the transverse-electric- (TE-) and transverse-magnetic- (TM-) polarized emissions in an AlxGa1-xN/AlyGa1-yN (y > x) quantum well (QW) are built. In reasonably selected ranges of Al content for an AlGaN QW to emit deep-ultraviolet (UV) light, the enhancement (suppression) of TE (TM-) polarized emission is mainly caused by the SP-coupling (interface scattering) effect. Different from a two two-level model, in the three-level model the TE- and TM-polarized emissions compete for electron in the shared upper state, which is used for simulating the conduction band, such that either interface-scattering or SP-coupling effect becomes weaker. In a quite large range of emission wavelength, in which the intrinsic emission is dominated by TM polarization, with the interface-scattering and SP-coupling effects, the TE polarized emission becomes dominant for enhancing the light extraction efficiency of a deep-UV light-emitting diode. PMID- 29715803 TI - Weakly-coupled 4-mode step-index FMF and demonstration of IM/DD MDM transmission. AB - Weakly coupled-mode division multiplexing (MDM) over few-mode fibers (FMF) for short-reach transmission has attracted great interest, which can avoid multiple input-multiple-output digital signal processing (MIMO-DSP) by greatly suppressing modal crosstalk. In this paper, step-index FMF supporting 4 linearity polarization (LP) modes for MIMO-free transmission is designed and fabricated for the first time, to our knowledge. Modal crosstalk of the fiber is suppressed by increasing the mode effective refractive index differences. The same fabrication method as standard single-mode fiber is adopted so that it is practical and cost effective. The mode multiplexer/demultiplexer (MUX/DEMUX) consists of cascaded mode-selective couplers (MSCs), which are designed and fabricated by tapering the proposed FMF with single-mode fiber (SMF). The mode MUX and DEMUX achieve very low modal crosstalk not only for the multiplexing/demultiplexing but also for the coupling to/from the FMF. Based on the fabricated FMF and mode MUX/DEMUX, we successfully demonstrate the first simultaneous 4-modes (LP01, LP11, LP21 & LP31) 10-km FMF transmission with 10-Gb/s intensity modulation and MIMO-free direct detection (IM/DD). The modal crosstalk of the whole transmission link is successfully suppressed to less than -16.5 dB. The experimental results indicate that FMF with simple step-index structure supporting 4 weakly-coupled modes is feasible. PMID- 29715804 TI - Polarization-sensitive pulse reconstruction by momentum-resolved photoelectron streaking. AB - The precise knowledge of the electric field in close proximity to metallic and dielectric surfaces is a prerequisite for pump-probe experiments aiming at the control of dynamic surface processes. We describe a model to reconstruct this electric field in immediate surface proximity from data taken in photoelectron THz-streaking experiments with an angle-resolved electron analyzer. Using Monte Carlo simulations we are able to simulate streaking experiments on arbitrary surfaces with a variety of initial electron momentum distributions and to reconstruct the effective electric field at the surface. Our results validate the approach and suggest energy regimes for optimal pulse reconstruction. PMID- 29715805 TI - On-chip broadband silicon thermo-optic 2?2 four-mode optical switch for optical space and local mode switching. AB - We present a silicon thermo-optic 2?2 four-mode optical switch optimized for optical space switching plus local optical mode switching. Four asymmetric directional couplers are utilized for mode multiplexing and de-multiplexing. Sixteen 2?2 single-mode optical switches based on balanced thermally tunable Mach Zehnder interferometers are exploited for switching function. The measured insertion losses are 8.0~12.2 dB and the optical signal-to-noise ratios are larger than 11.2 dB in the wavelength range of 1525~1565 nm. The optical links in "all-bar" and "all-cross" states exhibit less than 2.0 dB and 1.4 dB power penalties respectively below 10-9 bit error rates for 40 Gbps data transmission. PMID- 29715806 TI - Topographically induced homeotropic alignment of liquid crystals on self assembled opal crystals. AB - The surface of multilayered opal crystals resulted in homeotropic alignment of liquid crystal (LC), originated from the surface topography of opal crystals rather than a chemical nature of the nanoparticles. The polar anchoring energy (5.51 * 10-5 J/m2) of the crystal surface for nematic LC molecules was in a similar range to the conventional polyimide alignment layer (2.11 * 10-5 J/m2) used for commercial applications. The critical length scale for anchoring transition was approximately Lw = ~1 MUm. If a diameter of particle d << 1 MUm for opal crystals, LC molecules preferred to anchor vertically to the surface to minimize elastic free energy of bulk LCs. The LC favored a planar anchoring if d >> 1 MUm. The results provide crucial insights to understand the homeotropic alignment of LCs on solid surfaces and therefore offer opportunities to develop novel materials for a vertical alignment of LCs. PMID- 29715807 TI - High precision wavefront control in point spread function engineering for single emitter localization. AB - Point spread function (PSF) engineering is used in single emitter localization to measure the emitter position in 3D and possibly other parameters such as the emission color or dipole orientation as well. Advanced PSF models such as spline fits to experimental PSFs or the vectorial PSF model can be used in the corresponding localization algorithms in order to model the intricate spot shape and deformations correctly. The complexity of the optical architecture and fit model makes PSF engineering approaches particularly sensitive to optical aberrations. Here, we present a calibration and alignment protocol for fluorescence microscopes equipped with a spatial light modulator (SLM) with the goal of establishing a wavefront error well below the diffraction limit for optimum application of complex engineered PSFs. We achieve high-precision wavefront control, to a level below 20 mlambda wavefront aberration over a 30 minute time window after the calibration procedure, using a separate light path for calibrating the pixel-to-pixel variations of the SLM, and alignment of the SLM with respect to the optical axis and Fourier plane within 3 MUm (x/y) and 100 MUm (z) error. Aberrations are retrieved from a fit of the vectorial PSF model to a bead z-stack and compensated with a residual wavefront error comparable to the error of the SLM calibration step. This well-calibrated and corrected setup makes it possible to create complex '3D+lambda' PSFs that fit very well to the vectorial PSF model. Proof-of-principle bead experiments show precisions below 10 nm in x, y, and lambda, and below 20 nm in z over an axial range of 1 MUm with 2000 signal photons and 12 background photons. PMID- 29715808 TI - Engineering equations for characterizing nonlinear laser intensity propagation in air with loss: erratum. AB - We present an erratum regarding the x-axis label in several figures, and one equation citation correction. PMID- 29715809 TI - Amplifier-free 200-Gb/s tandem SSB doubly differential QPSK signal transmission over 80-km SSMF with simplified receiver-side DSP. AB - We numerically demonstrate 80-km standard single-mode fiber transmission without optical amplification, dispersion compensation or carrier recovery using 200-Gb/s tandem single sideband modulated doubly differential QPSK. Simulation results show that doubly differential encoding enables practically constant system performance for frequency offsets within +/- 2.3 GHz and allows a linewidth tolerance of 2.5 * 10-3 at 1-dB receiver sensitivity penalty. Employing 2.9-MHz linewidth lasers, the receiver sensitivity penalty at 7% HD-FEC threshold for 80 km transmission is less than 0.2 dB. By adding a 12-symbol decision feedback in the 2nd differential operation of doubly differential decoding, the receiver sensitivity is improved by 3.7 dB. PMID- 29715810 TI - Thermo-optic tuning of a packaged whispering gallery mode resonator filled with nematic liquid crystal. AB - Thermo-optic tuning of whispering gallery modes (WGMs) in a nematic liquid crystal-filled thin-walled capillary tube resonator is reported. WGMs were excited by the evanescent field from a tapered optical fiber. Tapered optical fiber fabrication and reduction of wall thickness of the capillary tube was carried out by a ceramic micro-heater brushing technique. A simple and robust packaging technique is demonstrated to ensure stable and repeatable operation of the device. Tunability of WGMs with temperature was demonstrated with a sensitivity of 267.5 +/- 2.5 pm/ degrees C. The demonstrated thermo-optic method for WGMs tuning is potentially useful for many tunable photonic devices and sensors. PMID- 29715811 TI - Experimental realization of SWAP operation on hyper-encoded qubits. AB - Hyper-encoding enables storing several qubits in a single photon using its different degrees of freedom like polarization and spatial ones. This approach enables feasible implementation of multi-qubit operations. One of the basic manipulations of two or more qubits is to swap their quantum state. Here we report on feasible and stable experimental implementation of a deterministic single photon two-qubit SWAP gate that interchanges path and polarization qubits. We discuss the principle of its operation and give detailed information about experimental demonstration employing two Mach-Zehnder interferometers with one common arm. The gate characterization is done by full quantum process tomography using photons produced by heralded single-photon source. The achieved quantum process fidelity reached more than 0.94 with an effective phase uncertainty of the whole setup, evaluated by means of Allan deviation, below 2.5 deg for 2.5 h without any active stabilization. Our design provides a contribution to the hyper encoded linear quantum optics toolbox. PMID- 29715812 TI - Simulating ultra-intense femtosecond lasers in the 3-dimensional space-time domain. AB - Femtosecond petawatt (fs-PW) lasers, with femtosecond pulses and sub-meter-sized beams, could be easily distorted by spatiotemporal coupling (STC). In 2016, a femtosecond terawatt pulsed beam was experimentally reconstructed in the 3 dimensional (3D) space-time domain for the first time, and showing STC induced distortions. Referring to recently developed laser techniques, traditional first order STCs can be controlled and then removed. However, the complex STC induced by wavefront errors in a meter-sized grating compressor, where the spatial and spectral coordinates of beams and pulses are coupled, would introduce a non negligible and complicated distortion. Herein, we theoretically simulated this complex STC in the 3D space-time/spectrum domain and presented its evolution with various factors, which opens a new perspective to analyze CPA lasers in the 3D domain. PMID- 29715813 TI - Optimizing band-edge slow light in silicon-on-insulator waveguide gratings. AB - A systematic analysis of photonic bands and group index in silicon grating waveguides is performed, in order to optimize band-edge slow-light behavior in integrated structures with low losses. A combination of numerical methods and perturbation theory is adopted. It is shown that a substantial increase of slow light bandwidth is achieved when decreasing the internal width of the waveguide and the silicon thickness in the cladding region. It is also observed that a reduction of the internal width does not undermine the performance of an adiabatic taper. PMID- 29715814 TI - Numerical optimization of the extraction efficiency of a quantum-dot based single photon emitter into a single-mode fiber. AB - We present a numerical method for the accurate and efficient simulation of strongly localized light sources, such as quantum dots, embedded in dielectric micro-optical structures. We apply the method in order to optimize the photon extraction efficiency of a single-photon emitter consisting of a quantum dot embedded into a multi-layer stack with further lateral structures. Furthermore, we present methods to study the robustness of the extraction efficiency with respect to fabrication errors and defects. PMID- 29715815 TI - Next generation smart window display using transparent organic display and light blocking screen. AB - Transparent organic light emitting diodes (TOLED) have widespread applications in the next-generation display devices particularly in the large size transparent window and interactive displays. Herein, we report high performance and stable attractive smart window displays using facile process. Advanced smart window display is realized by integrating the high performance light blocking screen and highly transparent white OLED panel. The full smart window display reveals a maximum transmittance as high as 64.2% at the wavelength of 600 nm and extremely good along with tunable ambient contrast ratio (171.94:1) compared to that of normal TOLED (4.54:1). Furthermore, the performance decisive light blocking screen has demonstrated an excellent optical and electrical characteristics such as i) high transmittance (85.56% at 562nm) at light-penetrating state, ii) superior absorbance (2.30 at 562nm) in light interrupting mode, iii) high optical contrast (85.50 at 562 nm), iv) high optical stability for more than 25,000 cycle of driving, v) fast switching time of 1.9 sec, and vi) low driving voltage of 1.7 V. The experimental results of smart window display are also validated using optical simulation. The proposed smart window display technology allows us to adjust the intensity of daylight entering the system quickly and conveniently. PMID- 29715816 TI - Theoretical analyses of an injection-locked diode-pumped rubidium vapor laser. AB - Diode-pumped alkali lasers (DPALs) have drawn much attention since they were proposed in 2001. The narrow-linewidth DPAL can be potentially applied in the fields of coherent communication, laser radar, and atomic spectroscopy. In this study, we propose a novel protocol to narrow the width of one kind of DPAL, diode pumped rubidium vapor laser (DPRVL), by use of an injection locking technique. A kinetic model is first set up for an injection-locked DPRVL with the end-pumped configuration. The laser tunable duration is also analyzed for a continuous wave (CW) injection-locked DPRVL system. Then, the influences of the pump power, power of a master laser, and reflectance of an output coupler on the output performance are theoretically analyzed. The study should be useful for design of a narrow linewidth DPAL with the relatively high output. PMID- 29715817 TI - Polarization-orthogonal filament array induced by birefringent crystals in air. AB - We demonstrate the generation of filament array with orthogonal polarizations in air by using specifically designed wedge-type birefringent quartz plates. Experimental results show that the number of the generated filaments can be expressed as N = 2n wherenis the number of quartz plates inserted in the laser propagation path. By manipulating the optic axis of the quartz plates with respect to the polarization direction of the input laser pulse, the generated filaments can be separated into two parts with the polarization directions perpendicular with each other. The separation distance between the adjacent filaments is found to be linearly dependent on the focal length of external focusing lens. Our results provide a simple and efficient way to generate regular and reproductive femtosecond filament array in air. PMID- 29715818 TI - Broadband microwave absorption utilizing water-based metamaterial structures. AB - In this paper, broadband microwave absorbers utilizing water-based metamaterial structure elements have been proposed and investigated. We employ water into the metamaterial structure unit-cell of the absorber as primary resonant elements such as the water-droplet, or water-tube structure. By investigating the resonant modes and the coupling between the water elements and the surrounding dielectrics, it is found the inherent multi-resonance of the proposed metamaterial structures could result in a broadband microwave absorption. For water-droplets design, 90% microwave absorption has been achieved from 7.5 GHz to 15 GHz, while for water-tube design, a much broader bandwidth from 5 GHz to 15 GHz is obtained for nearly 90% microwave absorption. The broadband absorption performance has been verified by both full wave simulation and experimental measurement. We believe the proposed broadband water-based absorber may find some applications in microwave stealth and electromagnetic compatibility technology. PMID- 29715819 TI - Tunable dual-band graphene-based infrared reflectance filter. AB - We experimentally demonstrated an actively tunable optical filter that controls the amplitude of reflected long-wave-infrared light in two separate spectral regions concurrently. Our device exploits the dependence of the excitation energy of plasmons in a continuous and unpatterned sheet of graphene on the Fermi-level, which can be controlled via conventional electrostatic gating. The filter enables simultaneous modification of two distinct spectral bands whose positions are dictated by the device geometry and graphene plasmon dispersion. Within these bands, the reflected amplitude can be varied by over 15% and resonance positions can be shifted by over 90 cm-1. Electromagnetic simulations verify that tuning arises through coupling of incident light to graphene plasmons by a grating structure. Importantly, the tunable range is determined by a combination of graphene properties, device structure, and the surrounding dielectrics, which dictate the plasmon dispersion. Thus, the underlying design shown here is applicable across a broad range of infrared frequencies. PMID- 29715820 TI - Nonlinear optical property of a Bi-doped GaAs semiconductor saturable absorber. AB - By using an Open-Aperture Z-scan technique with both femtosecond and nanosecond laser pulses at 1064nm, the nonlinear optical properties of GaAs and Bi-doped GaAs, including the saturable absorption property and reverse saturable absorption property are systematically measured and analyzed directly in detail. Compared to pure GaAs, Bi-doped GaAs has a lower saturation intensity, wider saturable absorption energy region, lower two-photon absorption coefficient, better saturable absorption response and stronger optical limiting response. The results suggest that the incorporation of Bismuth in GaAs is an effective way of improving the nonlinear optical properties of GaAs, which provide crucial experimental evidence for that the characteristics of the passively Q-switched laser with Bi-doped GaAs saturable absorber is better than pure GaAs. PMID- 29715821 TI - Design and fabrication of a compact off-axis see-through head-mounted display using a freeform surface. AB - Head-mounted display (HMD) has been widely used in many fields, and most existing HMDs are complex and typically non-aesthetically pleasing. In this paper, a novel compact, lightweight and wearable off-axis HMD with freeform surface is reported. It is challenging to achieve large field of view (FOV) and maintain compact structure simultaneously for this type system. In this design, the compact off axis HMD consists of a tilted ellipsoid combiner and a four pieces relay lenses. It offers a diagonal FOV of 30 degrees , and an exit pupil diameter of 7 mm. No diffractive surfaces are used, thus avoiding the effect of stray light and ghost image in previous designs. The x-y polynomial freeform surface is adopted in the relay lens for improving the image quality and minimizing the structure size. Analytical expressions to determine the initial structure of HMD has been given, while structure constrains, optimization strategy and tolerance analysis are also described in details. The optical system is easy to manufacture by ordinary method which is beneficial for mass production. Further, a prototype of this compact HMD is successfully implemented with good imaging performance. The compact structure of HMD makes it well suited for integrating a normal glass, significantly advancing the application of HMD in people's daily life. PMID- 29715822 TI - Amplitude fluctuations for optical waves propagation through non-Kolmogorov coronal solar wind turbulence channels. AB - Optical communication has a great potential for the future deep space communication, while the amplitude fluctuations caused by the coronal solar wind irregularities has been a challenging topic during superior solar conjunction. In this paper, a closed-form amplitude fluctuations expression for optical waves propagation through non-Kolmogorov solar wind turbulence is derived by establishing a generalized coronal turbulence spectrum model. The profound impact of the coronal parameters on the bit error rate (BER) performance of the free space optical system is also investigated based on the derived amplitude fluctuations model. The derived expression allows easy analysis of the evolution of the amplitude fluctuations and, in particular, an understanding of the imposed effects caused by the parameters during the waves propagation. The combined effect of the optical wavelength, non-Kolmogorov spectral index, turbulence outer scale, relative solar wind density fluctuation factor, and link distance on amplitude fluctuations are evaluated. Numerical calculations show that these parameters produce obvious effects on the amplitude fluctuations and the BER. The large optical wavelength can mitigate the influence of the coronal turbulence. Our results have potential applications for evaluating the link performance of the future deep space communication. PMID- 29715823 TI - Polarization properties of stochastic electromagnetic beams modulated by a wavefront-folding interferometer. AB - We consider the field generated by a wavefront-folding interferometer which is illuminated by a stochastic electromagnetic beam. The specular property and anti specular property are discussed in the vector case. Take electromagnetic Gaussian Schell-model beam as an example, we investigate the spectral density, the spectral degree of coherence, the spectral degree of polarization as well as the state of polarization of the polarized portion of the field on propagation. Results show that the polarization properties including the degree of polarization, the orientation angle and the degree of ellipse can be adjusted by the phase difference of the interferometer and the phase retardation introduced by the prism. The results may be applied in free-space optical communication. PMID- 29715824 TI - Intracavity deformable mirror for beam quality improvement and power enhancement of a passively Q-switched laser. AB - The performance of the passively Q-switched (PQS) laser deteriorates under high pumping power for the intracavity thermally induced wavefront distortion (thermal distortion for short). A new intracavity deformable mirror (DM) is proposed to compensate the thermal distortion of a PQS laser in this paper. The thermal distortion of the PQS laser is measured using the active deflectometry method. A simulation model is built to investigate the influences of the DM structure parameters on the surface shape of the DM (DMSS). Simulation results indicate that the DMSS matches well with the measured thermal distortion in the PQS laser at the given pumping current. Based on the simulation results, a low-cost, compact intracavity DM consisting of a mirror unit, a heater unit, a cooler unit and a base unit is built and used in the PQS laser. The DMSS is measured by a Zygo interferometer and coincides with the simulation result. In the improved PQS laser experiment, the optimum heater temperatures for the maximum output power and minimum M2 at different pumping currents are measured and given. The output stability of the PQS laser with the DM is tested. By adjusting the heater temperature, the PQS laser could achieve optimum performance in different environmental temperatures with good temperature adaptability. Experiment results verify that the PQS laser with the designed DM could achieve high output power and good beam quality at high pumping currents, as the DM prominently compensates the thermal distortion in the laser. PMID- 29715825 TI - High brightness energetic pulses delivered by compact microchip-MOPA system. AB - High brightness compact microchip-seeded MOPA system was realized. Implementing a microchip preamplifier stage acting as gain aperture element lead to excellent output beam quality with M2 = 1.4. At maximum amplification level, 235 mJ (0.4 GW) of output energy (power) was measured. Analysis of the effect of the preamplifier showed that this element increases the available beam intensity by two orders of magnitude without significant increase in system footprint. Final beam brightness was 18 PW/sr.cm2. PMID- 29715826 TI - All-fiber 3D vector displacement (bending) sensor based on an eccentric FBG. AB - We demonstrate a fiber-optic 3D vector displacement sensor based on the monitoring of Bragg reflection from an eccentric grating inscribed in a depressed cladding fiber using the femtosecond laser side-illumination and phase-mask technique. The compact sensing probe consists of a short section of depressed cladding fiber (DCF) containing eccentrically positioned fiber Bragg gratings. The eccentric grating breaks the cylindrical symmetry of the fiber cross-section and further has bending orientation-dependence. The generated fundamental resonance is strongly sensitive to bending of the fiber, and the direction of the bending plane can be determined from its responses. When integrated with axis strain monitoring, the sensor achieves a 3D vector displacement measurement via simple geometric analysis. PMID- 29715827 TI - Broadband enhancement of Cerenkov second harmonic generation in a sunflower spiral nonlinear photonic crystal. AB - We present an experimental study on the Cerenkov second harmonic emission in a novel sunflower spiral array of ferroelectric domains in LiNbO3 crystal. The spiral patterns offer a diffusive, circularly symmetric distribution of reciprocal lattice vectors, thereby enabling enhanced emission of the Cerenkov beam in a broad spectral range. Instead of the traditional electric field poling, the sunflower spiral patterns are fabricated here by using our pioneering method of ferroelectric domain engineering with ultrafast light. This all-optical method gives access to high quality domain structures with short periods, which is beneficial for efficient Cerenkov harmonic generation. PMID- 29715828 TI - Fano-resonance in one-dimensional topological photonic crystal heterostructure. AB - We theoretically realize the Fano resonance with a high quality factor of 106 using a structure, which is constructed from three one-dimensional photonic crystals and a defect layer. The emerged Fano resonance can be attributed to the weak coupling between a Fabry-Perot cavity mode and a topological edge state mode provided by the topological photonic crystal heterostructure. Moreover, we experimentally reproduce this Fano resonance in the optical communication range with a high quality of 104. This may be useful reference for the study of applications of photonic topological states in integrated photonic devices and information processing chips. PMID- 29715829 TI - Improvement of long-term stability of hollow-core photonic-crystal fiber optic gyro based on single-polarization resonator. AB - To improve long-term stability, we present a single-polarization resonator optic gyro based on a hollow-core photonic-crystal fiber (HCPCF), utilizing a micro optical polarizing coupler formed by pairs of collimators and a series of polarization-dependent devices. We build the mathematical model of the polarization noise of the proposed gyro and experimentally validate the elimination of the undesired polarization eigenstate, which is the basis of the system's improved long-term stability. We use multi-modulation to suppress the backscattering noise and the closed-loop detection method to eliminate the effect of fluctuating output power on the gyro bias. A long-term bias stability of 20 degrees /h is successfully demonstrated. PMID- 29715830 TI - Laser heterodyne interference signal processing method based on phase shift of reference signal. AB - A novel signal processing method based on phase shift of reference signal is proposed for heterodyne interferometer. The integer fringe counting method based on overflow judgment and compensation can realize longtime and correct integer number measurement. In order to eliminate the influence of jitter in measurement signals on combination of integer and fraction fringe counting, the reference signal with phase shift of 180 degrees is used to obtain integer compensating number to compensate the unstable integer number in unstable phase zone, which guarantees the correct combination of integer and fraction fringe counting. The principle of the proposed signal processing was described in detail. The static and dynamic resolution of the proposed method were discussed. A signal processing board based on FPGA was developed, and three tests were performed to verify the feasibility of the proposed method. A displacement measurement experimental setup was constructed, and two experiments verified the effectiveness of proposed method in application of an interferometer to realize precision displacement and testing of a stage. PMID- 29715831 TI - Adaptive water-air-water data information transfer using orbital angular momentum. AB - With the increasing demands for underwater monitoring and military applications, underwater wireless optical communication (UWOC) is desired to be an alternative approach to provide higher data rate than acoustic communication. Twisted light carrying orbital angular momentum (OAM) has recently gained increasing interest in diverse areas, especially in free-space and fiber-based optical communications. OAM-based UWOC between underwater and aerial users, a promising technique to enable a variety of applications, which however, has not yet been reported so far. Here we experimentally demonstrate an adaptive water-air-water data information transfer using OAM. According to the feedback information of the received intensity distribution, the reflection element is adjusted for mitigating the misalignment-induced degradation effect due to water level change. The experimental results show favorable performance of the feedback-assisted water-air-water twisted light data information transfer. PMID- 29715832 TI - Optimum power allocation for uniform illuminance in indoor visible light communication. AB - In this paper an optimal power allocation scheme is proposed to acheive uniform illuminance. Regular arrays and random geometries are considered for an arrangement of the source LEDs. Uniform illuminance is accomplished by considering the variance of the received power on the receiver plane as metric and framing it as a convex optimization problem. Numerical results show that the quality factor of random geometries are superior to fixed geometries. While preserving uniformity, the cost of the system can be reduced when random geometries are used. PMID- 29715833 TI - Bi-directional propagation leaky modes in a periodic chain of dielectric circular rods. AB - In this paper, a periodic chain composed of two-dimensional dielectric cylindrical inclusions was studied based on the Fourier series expansion method with perfectly matched layers. Phase and attenuation constants associated with guided modes, forward propagation leaky modes, and backward propagation leaky modes, were conceptually proposed and numerically examined. In particular, the relationships between the backward propagation mode, leaky mode, and propagation constant were explained in the second-order Bragg reflection region. This simple structure was investigated with the goal of realizing an efficient guiding device. Phase and attenuation constant results were compared with the results obtained using the Lattice Sums technique with the T-matrix approach and FDTD method; very good agreement was observed between these methods. PMID- 29715834 TI - Discrete fringe phase unwrapping algorithm based on Kalman motion estimation for high-speed I/Q-interferometry. AB - A discrete fringe phase unwrapping algorithm (DFPUA) based on Kalman motion estimation is proposed to accurately demodulate the phases of I/Q-interferometers with deeply under-sampled quadrature signals, thus to break through the limitations of the Nyquist frequency for high-speed measurement. The basic concept of DFPUA is to estimate the current displacement according to the former motion state, then confirm the actual phase integer number by comparing the estimated phase decimal with the actual phase decimal; in this way, peak acceleration/jerk instead of peak velocity becomes the factor that determines the sampling rate. Two types of DFPUA including velocity estimation and velocity acceleration estimation are illustrated in detail. Simulation experiment results indicate that the DFPUA realizes a significant reduction in the sampling rate and the amount of data for low frequency vibration measurement, proposing a practical approach for high-speed and long-time measurement such as ultra-low frequency vibration calibration. PMID- 29715835 TI - Angular lens. AB - We propose a single phase-only optical element that transforms different orbital angular momentum (OAM) modes into localized spots at separated angular positions on a transverse plane. We refer to this element as an angular lens since it separates out OAM modes in a manner analogous to how a converging lens separates out transverse wave-vector modes at the focal plane. We also simulate the proposed angular lens using a spatial light modulator and experimentally demonstrate its working. Our work can have important implications for OAM-based classical and quantum communication applications. PMID- 29715836 TI - Interferometric spatial mode analyzer with a bucket detector. AB - A spatial mode analyzer based on a Michelson interferometer with a bucket detector is experimentally implemented. The delay line in the interferometer is an optical implementation of the fractional Fourier transform (fFT) which enables the spatial mode analysis of a given input field in the Hermite-Gaussian (HG) mode basis. Modal weights for both 1D and 2D input fields are experimentally measured. Results for input fields comprising of multiple HG modes are also presented. PMID- 29715837 TI - Experimental investigation in nodal aberration theory (NAT) with a customized Ritchey-Chretien system: third-order coma. AB - Nodal aberration theory (NAT) describes the aberration properties of optical systems without symmetry. NAT was fully described mathematically and investigated through real-ray tracing software, but an experimental investigation is yet to be realized. In this study, a two-mirror Ritchey-Chretien telescope was designed and built, including testing of the mirrors in null configurations, for experimental investigation of NAT. A feature of this custom telescope is a high-precision hexapod that controls the secondary mirror of the telescope to purposely introduce system misalignments and quantify the introduced aberrations interferometrically. A method was developed to capture interferograms for multiple points across the field of view without moving the interferometer. A simulation result of Fringe Zernike coma was generated and analyzed to provide a direct comparison with the experimental results. A statistical analysis of the measurements was conducted to assess residual differences between simulations and experimental results. The interferograms were consistent with the simulations, thus experimentally validating NAT for third-order coma. PMID- 29715838 TI - Temporal electronic speckle pattern interferometry for real-time in-plane rotation analysis. AB - A temporal electronic speckle pattern interferometry (ESPI) system is proposed for in-plane rotation measurement. The relationship between the rotation angle and the phase change distribution is established and the rotation direction is indicated by the sign of the partial differential of the phase change distribution. Temporal phase modulation is applied in the proposed symmetric illumination ESPI system. The phase is recovered by the temporal intensity analysis method which uses the temporal evolution history of the light intensity. The system can perform dynamic measurements and provide results in off-line real time. Preliminary experiments were carried out with a continuously rotating target to show the feasibility and the dynamic feature of the temporal ESPI system. At present, the mean absolute error of the experiment is 0.39 arcsec. PMID- 29715839 TI - High-port low-latency optical switch architecture with optical feed-forward buffering for 256-node disaggregated data centers. AB - Departing from traditional server-centric data center architectures towards disaggregated systems that can offer increased resource utilization at reduced cost and energy envelopes, the use of high-port switching with highly stringent latency and bandwidth requirements becomes a necessity. We present an optical switch architecture exploiting a hybrid broadcast-and-select/wavelength routing scheme with small-scale optical feedforward buffering. The architecture is experimentally demonstrated at 10Gb/s, reporting error-free performance with a power penalty of <2.5dB. Moreover, network simulations for a 256-node system, revealed low-latency values of only 605nsec, at throughput values reaching 80% when employing 2-packet-size optical buffers, while multi-rack network performance was also investigated. PMID- 29715840 TI - Chromatic diversity: a new approach for characterizing spatiotemporal coupling of ultrashort pulses. AB - Two-dimensional chromatic aberrations are characterized by a single-shot scheme based on a simultaneous measurement of chromatically diversified focal spots. The chromatic diversity is introduced by a 2-D grating with holographic defocus terms. The chromatic aberrations in the beam are either subtracted or added by the additional known chromatic aberrations in the grating, depending on the diffraction order. By analyzing the asymmetry in the size of diffracted focal spots, input beam chromatic aberrations can be deduced. Theoretical discussions and experimental results are presented. PMID- 29715841 TI - Photonic orbital angular momentum transfer and magnetic skyrmion rotation. AB - Magnetic skyrmions are chiral quasiparticles that show promise for future spintronic applications such as skyrmion racetrack memories and logic devices because of their topological stability, small size (typically ~ 3 - 500 nm), and ultralow threshold force to drive their motion. On the other hand, the ability of light to carry and deliver orbital angular momentum (OAM) in the form of optical vortices has attracted a lot of interest. In this work, we predict a photonic OAM transfer effect, by studying the dynamics of magnetic skyrmions subject to Laguerre-Gaussian optical vortices, which manifests a rotational motion of the skyrmionic quasiparticle around the beam axis. The topological charge of the optical vortex determines both the magnitude and the handedness of the rotation velocity of skyrmions. In our proposal, the twisted light beam acts as an optical tweezer to enable us displacing skyrmions over large-scale defects in magnetic films to avoid being captured. PMID- 29715842 TI - Asymmetrical damage growth of multilayer dielectric gratings induced by picosecond laser pulses. AB - We experimentally investigated the laser damage growth behavior of multilayer dielectric gratings (MLDGs) by the picosecond pulses at 1053nm. The damage growth threshold of 2.43J/cm2 is significantly lower than the 20/1 damage threshold of 3.06 J/cm2. Once the damage site is initiated, the damage area grows linearly with shot number and saturates after sufficient shots due to the Gaussian spot. The barycenter of the growing damage site deviates from the laser spot center and their distance increases with the shot number, which indicates the asymmetry of the damage growth along the laser propagation axis. The growth rate of the damage site along the laser propagation direction is larger than that in the reverse direction by a factor of ~1.8 for various fluences. The comparison of the experimental and numerical results reveals that the asymmetrical intensity modulation induced by the damage sites causes the asymmetry in growth. The revealed characteristics and mechanisms of the damage growth can be of great significance to predict the lifetime of the MLDGs in high-power laser systems. PMID- 29715843 TI - Analytical modeling of dual-frequency solid-state lasers including a buffer reservoir for noise cancellation. AB - A theoretical model describing the dynamical behavior of dual-frequency solid state lasers including a buffer reservoir (BR) is presented. It relies on the introduction of two additional coupled rate equations describing the interaction of the two laser modes with the BR. The relative intensity noise is derived by taking into account the fluctuations of both pump intensity and intra-cavity photons. This modelling approach accurately predicts the experimental noise spectra obtained with an Er,Yb:glass dual-frequency laser implemented in different cavity architecture configurations. The mode coupling strength in the BR is shown to rule the reduction efficiency of the excess noise lying at the in phase and anti-phase frequencies. PMID- 29715844 TI - Transfer-printing-based integration of a III-V-on-silicon distributed feedback laser. AB - An electrically pumped DFB laser integrated on and coupled to a silicon waveguide circuit is demonstrated by transfer printing a 40 * 970 MUm2 III-V coupon, defined on a III-V epitaxial wafer. A second-order grating defined in the silicon device layer with a period of 477 nm and a duty cycle of 75% was used for realizing single mode emission, while an adiabatic taper structure is used for coupling to the silicon waveguide layer. 18 mA threshold current and a maximum single-sided waveguide-coupled output power above 2 mW is obtained at 20 degrees C. Single mode operation around 1550 nm with > 40 dB side mode suppression ratio (SMSR) is realized. This new integration approach allows for the very efficient use of the III-V material and the massively parallel integration of these coupons on a silicon photonic integrated circuit wafer. It also allows for the intimate integration of III-V opto-electronic components based on different epitaxial layer structures. PMID- 29715845 TI - Multi-branch fiber comb with relative frequency uncertainty at 10-20 using fiber noise difference cancellation. AB - In multi-branch combs, the comb outputs from the branches suffer from different fiber noises, which often limit the uncertainty of the combs referring a highly stable optical frequency. To overcome this limitation, we introduced fiber noise difference cancellation to multi-branch fiber combs. We detected and phase-locked the beat notes between the branch outputs and a common 1542 nm continuous wave laser. A piezo-electric transducer-based fiber stretcher was installed in each branch except for the branch used as the cancellation reference. We fabricated two quasi-identical combs with this mechanism and confirmed the relative frequency uncertainty by comparing them. The cancellation improved the frequency uncertainty to a low level of 10-20 at a 100000-s averaging time. PMID- 29715846 TI - High-power nanosecond pulse generation from an integrated Tm-Ho fiber MOPA over 2.1 MUm. AB - In this paper, we report on high-power stable nanosecond pulse generation at ~2.1 MUm from an integrated Tm-Ho all-fiber master oscillator power amplifier (MOPA) system. A total output power of 128.5 W is generated from the Tm-Ho hybrid MOPA, with an average power of 99.1 W from Ho emission at 2116 nm; the corresponding pulse repetition frequency and pulse width are 161 kHz and 322 ns, respectively, leading to a peak power of 1.91 kW. The Tm-Ho integrated master oscillator is designed to operate at 1980 and 2116 nm, where the former wavelength serves as the pump of the Ho-doped fiber. Stable laser pulses are generated from both the Tm and Ho oscillators owing to mutual modulation of emission from the two lasers. The prospects for further scaling in output power at ~2.1 MUm using Tm-Ho integrated MOPA system are discussed. PMID- 29715847 TI - One- and two-dimensional modes in the complex Ginzburg-Landau equation with a trapping potential. AB - We propose a new mechanism for the stabilization of confined modes in lasers and semiconductor microcavities holding exciton-polariton condensates, with spatially uniform linear gain, cubic loss, and cubic self-focusing or defocusing nonlinearity. We demonstrated that the commonly known background instability driven by the linear gain can be suppressed by a combination of a harmonic oscillator trapping potential and effective diffusion. Systematic numerical analysis of one- and two-dimensional (1D and 2D) versions of the model reveals a variety of stable modes, including stationary ones, breathers, and quasi-regular patterns filling the trapping area in the 1D case. In 2D, the analysis produces stationary modes, breathers, axisymmetric and rotating crescent-shaped vortices, stably rotating complexes built of up to 8 individual vortices, and, in addition, patterns featuring vortex turbulence. Existence boundaries for both 1D and 2D stationary modes are found in an exact analytical form, and an analytical approximation is developed for the full stationary states. PMID- 29715848 TI - Nonlinear dynamic of picosecond pulse propagation in atmospheric air-filled hollow core fibers. AB - Atmospheric air-filled hollow core (HC) fibers, representing the simplest yet reliable form of gas-filled hollow core fiber, show remarkable nonlinear properties and have several interesting applications such as pulse compression, frequency conversion and supercontinuum generation. Although the propagation of sub-picosecond and few hundred picosecond pulses are well-studied in air-filled fibers, the nonlinear response of air to pulses with a duration of a few picoseconds has interesting features that have not yet been explored fully. Here, we experimentally and theoretically study the nonlinear propagation of ~6 ps pulses in three different types of atmospheric air-filled HC fiber. With this pulse length, we were able to explore different nonlinear characteristics of air at different power levels. Using in-house-fabricated, state-of-the-art HC photonic bandgap, HC tubular and HC Kagome fibers, we were able to associate the origin of the initial pulse broadening process in these fibers to rotational Raman scattering (RRS) at low power levels. Due to the broadband and low loss transmission window of the HC Kagome fiber we used, we observed the transition from initial pulse broadening (by RRS) at lower powers, through long-range frequency conversion (2330 cm-1) with the help of vibrational Raman scattering, to broadband (~700 nm) supercontinuum generation at high power levels. To model such a wide range of nonlinear processes in a unified approach, we have implemented a semi-quantum model for air into the generalized nonlinear Schrodinger equation, which surpasses the limits of the common single damping oscillator model in this pulse length regime. The model has been validated by comparison with experimental results and provides a powerful tool for the design, modeling and optimization of nonlinear processes in air-filled HC fibers. PMID- 29715849 TI - Interactive floating full-parallax digital three-dimensional light-field display based on wavefront recomposing. AB - Advanced three-dimensional (3D) imaging techniques can acquire high-resolution 3D biomedical and biological data, but available digital display methods show this data in restricted two dimensions. 3D light-field displays optically reconstruct realistic 3D image by carefully tailoring light fields, and a natural and comfortable 3D sense of real objects or scenes is expected. An interactive floating full-parallax 3D light-field display with all depth cues is demonstrated with 3D biomedical and biological data, which are capable of achieving high efficiency and high image quality. A compound lens-array with two pieces of lens in each lens unit is designed and fabricated to suppress the aberrations and increase the viewing angle. The optimally designed holographic functional screen is used to recompose the light distribution from the lens-array. The imaging distortion can be decreased to less than 1.9% from more than 20%. The real time interactive floating full-parallax 3D light-field image with the clear displayed depth of 30 cm can be perceived with the right geometric occlusion and smooth parallax in the viewing angle of 45 degrees , where 9216 viewpoints are used. PMID- 29715850 TI - DSP-free 'coherent-lite' transceiver for next generation single wavelength optical intra-datacenter interconnects. AB - We propose a DSP-free coherent-lite system that requires neither high-speed DSP nor high-resolution signal converters for deployment inside datacenters over single mode fiber links with reaches of 10 km and less. The removal of converters and DSP, in which some subsystems are fundamental for successful coherent detection, is enabled by either replacing DSP subsystems with optics having equivalent functions or by re-engineering the system. We validate in a proof-of concept experiment the proposed DSP-free system using 50 Gbaud DP-16QAM delivering 400 Gb/s over 10 km of single mode fiber (SMF) below the KP4 forward error correction (FEC) threshold of 2.2 * 10-4. In addition, we perform a detailed experimental parametric study of the coherent-lite system in which various system parameters are swept such as baud rate, reach, laser power and laser linewidth. Our results verify that the coherent-lite system can be realized using low-cost DFB lasers with linewidths of a few hundred kHz. Moreover, we compare the performance of the coherent-lite system with that of a conventional coherent transceiver leveraging the full DSP stack. Then, we evaluate the power consumption savings achieved by the coherent-lite scheme relative to a classic DSP-based coherent system. Assuming a CMOS node ranging from 28 to 7 nm for DSP implementation, our estimate shows that the coherent-lite scheme can save 95 to 78% of the power consumed by the following subsystems: analog-to-digital converters, chromatic dispersion compensation, 2 * 2 MIMO polarization demultiplexing and carrier recovery. Finally, we compare the power consumption of the coherent-lite scheme with more standard 400G IM-DD systems utilizing either eight or four parallel WDM lanes (8 * 50G and 4 * 100G). The coherent-lite system is found to have similar module power consumption requirements as a corresponding 4 * 100G IM-DD system while bringing the benefits of coherent detection including improved sensitivity and higher spectral efficiency leading to fewer light sources per transceiver module. To the best of our knowledge, this work represents the first experimental demonstration of a DSP-free coherent-lite system for single channel 400G datacenter 10 km interconnects, a potential attractive solution due to its scalability to future 800G and 1.6T intra datacenter optical interconnects. PMID- 29715851 TI - Frequency response of dual-drive silicon photonic modulators with coupling between electrodes. AB - We characterize the electro-optic frequency response of a four-port traveling wave dual-drive modulator with relatively strong coupling amongst the electrodes. We show that the electro-optic frequency response of the MZM can still be predicted with the 2*2 cascaded matrix model if the MZM is symmetric and differentially driven. PMID- 29715852 TI - Holographic beam-shaping diffractive diffusers fabricated by using controlled laser speckle. AB - A method for fabricating diffractive holographic optical diffusers is reported, allowing a high degree of control of the resulting diffuser characteristics. The method consists of recording a laser speckle pattern using a single carrier beam, with controlled speckle size and shape, in an acrylamide-based volume photopolymer. The multiple interferences that create the speckle pattern form the hologram. Results are presented verifying the diffusers are volume holographic in nature and the speckle pattern is recorded accurately in the photopolymer. Diffusers recorded by this method are analysed to characterise the optical performance of the diffusers and to illustrate their beam-shaping capabilities, particularly in producing asymmetric beam outputs. PMID- 29715854 TI - Sub-4 fs laser pulses at high average power and high repetition rate from an all solid-state setup. AB - The generation of high average power, carrier-envelope phase (CEP) stable, near single-cycle pulses at a repetition rate of 100 kHz is demonstrated using an all solid-state setup. By exploiting self-phase modulation in thin quartz plates and air, the spectrum of intense pulses from a high-power, high repetition rate non collinear optical parametric chirped pulse amplifier (NOPCPA) is extended to beyond one octave, and pulse compression down to 3.7 fs is achieved. The octave spanning spectrum furthermore allows performing straightforward f-to-2f interferometry by frequency-doubling the long-wavelength part of the spectrum. Excellent CEP-stability is demonstrated for extended periods of time. A full spatio-spectral characterization of the compressed pulses shows only minor asymmetries between the two perpendicular beam axes. We believe that the completed system represents the first laser system satisfying all requirements for performing high repetition rate attosecond pump-probe experiments with fully correlated detection of all ions and electrons produced in the experiment. PMID- 29715853 TI - Regularized reconstruction of absorbing and phase objects from a single in-line hologram, application to fluid mechanics and micro-biology. AB - Reconstruction of phase objects is a central problem in digital holography, whose various applications include microscopy, biomedical imaging, and fluid mechanics. Starting from a single in-line hologram, there is no direct way to recover the phase of the diffracted wave in the hologram plane. The reconstruction of absorbing and phase objects therefore requires the inversion of the non-linear hologram formation model. We propose a regularized reconstruction method that includes several physically-grounded constraints such as bounds on transmittance values, maximum/minimum phase, spatial smoothness or the absence of any object in parts of the field of view. To solve the non-convex and non-smooth optimization problem induced by our modeling, a variable splitting strategy is applied and the closed-form solution of the sub-problem (the so-called proximal operator) is derived. The resulting algorithm is efficient and is shown to lead to quantitative phase estimation on reconstructions of accurate simulations of in line holograms based on the Mie theory. As our approach is adaptable to several in-line digital holography configurations, we present and discuss the promising results of reconstructions from experimental in-line holograms obtained in two different applications: the tracking of an evaporating droplet (size ~ 100MUm) and the microscopic imaging of bacteria (size ~ 1MUm). PMID- 29715855 TI - Precise and highly-sensitive Doppler-free two-photon absorption dual-comb spectroscopy using pulse shaping and coherent averaging for fluorescence signal detection. AB - We demonstrated Doppler-free two-photon absorption dual-comb spectroscopy of 5S1/2 - 5D5/2 and 5D3/2 transitions of Rb. We employed simple pulse-shaping of the dual-comb source and eliminated Doppler-broadening backgrounds, which cause fitting errors of the Doppler-free signals. Moreover, to improve sensitivity, we investigated the coherence in dual-comb fluorescence signals and the coherent averaging method was applied to fluorescence dual-comb detection for the first time. The detection sensitivity was significantly improved by coherent averaging to reduce the noise floor. Observed Doppler-free spectra was fitted to Voigt profiles and we performed absolute frequency determination with a precision of about 100 kHz. PMID- 29715856 TI - Retrieval of aerosol properties and water-leaving reflectance from multi-angular polarimetric measurements over coastal waters. AB - Ocean color remote sensing is an important tool to monitor water quality and biogeochemical conditions of ocean. Atmospheric correction, which obtains water leaving radiance from the total radiance measured by satellite-borne or airborne sensors, remains a challenging task for coastal waters due to the complex optical properties of aerosols and ocean waters. In this paper, we report a research algorithm on aerosol and ocean color retrieval with emphasis on coastal waters, which uses coupled atmosphere and ocean radiative transfer model to fit polarized radiance measurements at multiple viewing angles and multiple wavelengths. Ocean optical properties are characterized by a generalized bio-optical model with direct accounting for the absorption and scattering of phytoplankton, colored dissolved organic matter (CDOM) and non-algal particles (NAP). Our retrieval algorithm can accurately determine the water-leaving radiance and aerosol properties for coastal waters, and may be used to improve the atmospheric correction when apply to a hyperspectral ocean color instrument. PMID- 29715857 TI - Investigation of antenna-coupled Nb5N6 microbolometer THz detector with substrate resonant cavity. AB - Fabricating resonant cavities with conventional methods to improve the coupling efficiency of a detector in the terahertz (THz) region is difficult for the wavelength is too long. Here, we propose a solution by using the substrate cavity effect given that the substrate wavelength and thickness of the preparation device are in the same order. The planar dipole antenna-coupled Nb5N6 microbolometers with different substrate thicknesses were fabricated. The interference effect of the substrate cavity on the optical voltage response of the detector is analyzed experimentally and theoretically. The experimental results show that the optical response of the detector is determined by the length of the substrate cavity. Thus, the THz devices with different detection frequencies can be designed by changing the substrate cavity length. Furthermore, on the basis of this substrate cavity effect, an asymmetric coupled Fabry-Perot (FP) cavity is constituted by simply placing a movable metallic planar mirror at the backside of the Si substrate. The incident THz radiation on the Nb5N6 microbolometer can be effectively manipulated by changing the substrate-mirror distance to modulate the phase relation between the reflect wave and the incident wave. The distinct radiation control can be observed, and the experiments can be well explained by numerically analyzing the responsivity dynamics that highlights the role of the FP cavity effect during radiation. All of the results discussed here can be extended to a broad range of frequency and other type of THz detectors. PMID- 29715858 TI - Generator of arbitrary classical photon statistics. AB - We propose and experimentally demonstrate a device for generating light with arbitrary classical photon-number distribution. We use programmable acousto optical modulation to control the intensity of light within the dynamic range of more than 30 dB and inter-level transitions faster than 500 ns. We propose a universal method that allows the high-fidelity generation of user-defined photon statistics. Extremely high precision <0.001 can be reached for lower photon numbers, and faithful tail behavior can be reached for very high photon numbers. We demonstrate arbitrary statistics generation for up to 500 photons. The proposed device can produce any classical light statistics with given parameters including Poissonian, super-Poissonian, thermal, and heavy-tailed distributions like log-normal. The presented method can be used to simulate communication channels, calibrate the response of photon-number-resolving detectors, or probe physical phenomena sensitive to photon statistics. PMID- 29715859 TI - Ho:KY(WO4)2 thin-disk laser passively Q-switched by a GaSb-based SESAM. AB - A Holmium thin-disk laser based on a 3 at.% Ho:KY(WO4)2 / KY(WO4)2 epitaxy and single-bounce pumping by a 1960 nm Tm-fiber laser is passively Q-switched with a GaSb-based quantum-well semiconductor saturable absorber mirror. It generates an average output power of 551 mW at 2056 nm with a slope efficiency of 44% (with respect to the absorbed pump power). The best pulse characteristics (energy and duration) are 4.1 MUJ / 201 ns at a repetition rate of 135 kHz and the conversion efficiency with respect to the continuous-wave regime is as high as 93%. PMID- 29715860 TI - Mode-locked Er-doped fiber laser based on PbS/CdS core/shell quantum dots as saturable absorber. AB - Previously, PbS/CdS core/shell quantum dots with excellent optical properties have been widely used as light-harvesting materials in solar cell and biomarkers in bio-medicine. However, the nonlinear absorption characteristics of PbS/CdS core/shell quantum dots have been rarely investigated. In this work, PbS/CdS core/shell quantum dots were successfully employed as nonlinear saturable absorber (SA) for demonstrating a mode-locked Er-doped fiber laser. Based on a film-type SA, which was prepared by incorporating the quantum dots with the polyvinyl alcohol (PVA), mode-locked Er-doped operation with a pulse width of 54 ps and a maximum average output power of 2.71 mW at the repetition rate of 3.302 MHz was obtained. Our long-time stable results indicate that the CdS shell can effectively protect the PbS core from the effect of photo-oxidation and PbS/CdS core/shell quantum dots were efficient SA candidates for demonstrating pulse fiber lasers due to its tunable absorption peak and excellent saturable absorption properties. PMID- 29715861 TI - Stability and interaction of few-cycle pulses in a Kerr medium. AB - The different aspects of few-cycle pulse dynamics governed by the regularized short pulse equation (RSPE) are reported. It is shown that the RSPE provides an accurate description of the dynamics of the few-cycle pulse whose duration is larger than a single optical period when the few-cycle pulse's spectrum is in the medium's anomalous dispersion regime. The approximate solutions of the RSPE are constructed from the soliton solutions of the nonlinear Schrodinger (NLS) equation. We demonstrate numerically that the stability of these few-cycle pulses strongly depends on their pulse duration. Furthermore, the interactions of the two and three few-cycle pulses are studied. When pulse parameters are suitably chosen, we show the elastic collision, inelastic collision and repulsive interaction between these multi few-cycle pulses. It is revealed that the interactions of the multi few-cycle pulses rely heavily on their pulse duration. PMID- 29715862 TI - Symmetrical dual D-shape photonic crystal fibers for surface plasmon resonance sensing. AB - Symmetrical dual D-shape photonic crystal fibers (PCFs) for surface plasmon resonance (SPR) sensing are designed and analyzed by the finite element method (FEM). The performance of the sensor is remarkably enhanced by the directional power coupling between the two fibers. We study the influence of the structural parameters on the performance of the sensor as well as the relationship between the resonance wavelengths and analyze refractive indexes between 1.36 and 1.41. An average spectral sensitivity of 14660 nm/RIU can be achieved in this sensing range and the corresponding refractive index resolution is 6.82 * 10-6 RIU. The characteristics of a single D-shape PCF-SPR sensor with the same structural parameters are compared with those of the dual PCFs sensor and the latter has distinct advantages concerning the spectral sensitivity, resolution, amplitude sensitivity, and figure of merits (FOM). PMID- 29715863 TI - Highly confined surface plasmon polaritons in the ultraviolet region. AB - Surface plasmon polaritons are commonly believed to be a future basis for the next generation of optoelectronic and all-optical devices. To achieve this, it is critical that the surface plasmon polariton modes be strongly confined to the surface and have a sufficiently long propagation length and a nanosize wavelength. As of today, in the visible part of the spectrum, these conditions are not satisfied for any type of surface plasmon polaritons. In this paper, we demonstrate that in the ultraviolet range, surface plasmon polaritons propagating along a periodically nanostructured aluminum-dielectric interface have all these properties. Both the confinement length and the wavelength of the mode considered are smaller than the period of the structure, which can be as small as 10 nm. At the same time, the propagation length of new surface plasmon-polaritons can reach dozens of its wavelengths. These plasmon polaritons can be observed in materials that are uncommon in plasmonics such as aluminum. The suggested modes can be used for miniaturization of optical devices. PMID- 29715864 TI - Sub-200 femtosecond dispersion-managed soliton ytterbium-doped fiber laser based on carbon nanotubes saturable absorber. AB - Ultrafast fiber laser light sources attract enormous interest due to the booming applications they are enabling, including long-distance communication, optical metrology, detecting technology of infra-biophotons, and novel material processing. In this paper, we demonstrate 175 fs dispersion-managed soliton (DMS) mode-locked ytterbium-doped fiber (YDF) laser based on single-walled carbon nanotubes (SWCNTs) saturable absorber (SA). The output DMSs have been achieved with repetition rate of 21.2 MHz, center wavelength of 1025.5 nm, and a spectral width of 32.7 nm. The operation directly pulse duration of 300 fs for generated pulse is the reported shortest pulse width for broadband SA based YDF lasers. By using an external grating-based compressor, the pulse duration could be compressed down to 175 fs. To the best of our knowledge, it is the shortest pulse duration obtained directly from YDF laser based on broadband SAs. In this paper, SWCNTs-SA has been utilized as the key optical component (mode locker) and the grating pair providing negative dispersion acts as the dispersion controller. PMID- 29715865 TI - Facile large-area autofocusing Raman mapping system for 2D material characterization. AB - Two-dimensional (2D) materials have attracted tremendous research interests due to their intriguing properties and promising applications. As one of the most typical 2D material characterization methods, however, the conventional Raman mapping only works within few-hundreds micrometers range at a time due to the focus depth constraint and the non-ideal level of the substrate. To implement wafer-scale Raman scanning, large-area autofocusing Raman mapping (LARM) is highly desirable. Here, we present a modified centroid method to build a facile LARM system in which the Raman excitation laser is employed as the focus laser, reducing the system cost and complexity. Based on identifying the shape of the semicircle laser reflection image, a self-written autofocusing algorithm allows a real-time adjusting the focus position during the large-scale scanning. As a state-of-the-art demonstration, the thickness distribution of both few layer WS2 triangle domains sparsely located in sub-millimeter range and polycrystalline continuous MoS2 film up to 2-inch scale can be well-revealed. Our results may shed light on wafer-scale nondestructive optical characterization of 2D materials. PMID- 29715866 TI - Robust wavenumber and dispersion calibration for Fourier-domain optical coherence tomography. AB - Many Fourier-domain optical coherence tomography (FD-OCT) systems sample the interference fringes with a non-uniform wavenumber (k) interval, introducing a chirp to the signal that depends on the path length difference underlying each fringe. A dispersion imbalance between sample and reference arms also generates a chirp in the fringe signal which, in contrast, is independent of depth. Fringe interpolation to obtain a signal linear in k and compensate dispersion imbalance is critical to achieving bandwidth-limited axial resolution. In this work, we propose an optimization-based algorithm to perform robust and automated calibration of FD-OCT systems, recovering both the interpolation function and the dispersion imbalance. Our technique relies on the fact that the unique function that correctly linearizes the fringe data in k space produces a depth-independent chirp. The calibration procedure requires experimental data corresponding to a single reflector at various depth locations, which can easily be obtained by acquiring data while moving a sample mirror in depth. We have tested both spectral domain OCT and swept source OCT systems with various nonlinearities. Results indicate that the proposed calibration method has excellent performance on a wide range of data sets and enables nearly constant resolution at all imaging depths. An implementation of the algorithm is available online. PMID- 29715867 TI - Software-defined reconfigurable VCSEL-based transmission. AB - We propose and demonstrate a programmable and self-adaptive VCSEL-based transponder for short-reach applications that is easily extensible up to access and metro scenarios. The transponder presents a monitoring system that feeds the transponder controller in order to maintain the proper transmission performance. The emerging NETCONF protocol including the YANG model controls and manages the transponder. NETCONF messages are reported for two reference scenarios - uncooled and cooled systems - together with performance at varying environment conditions. For the uncooled scenario heating processes on the board are emulated with various dynamics, the effect on the performance of a 25 Gbps WDM channel is checked through optical power monitoring and the control plane reacts so as to optimize the performance by suitably controlling the bias current. For slow temperature variations the system is able to avoid service outage whereas for variations faster than 1.3 degrees C/s outage occurs and corresponding notifications are opportunely triggered. For the cooled scenario, an optical power loss is emulated with consequent service outage, leading to a reconfiguration of the transponder data rate from 25 to 10 Gbps, so as to recover successful transmission. PMID- 29715868 TI - Phase measurement by using a forced delay-line oscillator and its application for an acoustic fiber sensor. AB - We demonstrate, theoretically and experimentally, a new method to measure small changes in the cavity length of oscillators. The method is based on the high sensitivity of the phase of forced delay-line oscillators to changes in their cavity length. The oscillator phase is directly detected by mixing the oscillator output with the injected signal. We describe a comprehensive theoretical model for studying the signal and the noise at the output of a general forced delay line oscillator with an instantaneous gain saturation and an amplitude-to-phase conversion. The results indicate that the magnitude and the bandwidth of the oscillator response to a small perturbation can be controlled by adjusting the injection ratio and the injected frequency. For signals with a frequency that is smaller than the device bandwidth, the oscillator noise is dominated by the noise of the injected signal. This noise is highly suppressed by mixing the oscillator output with the injected signal. Hence, the device sensitivity at frequencies below its bandwidth is limited only by the internal noise that is added in a single roundtrip in the oscillator cavity. We demonstrate the use of a forced oscillator as an acoustic fiber sensor in an optoelectronic oscillator. A good agreement is obtained between theory and experiments. The magnitude of the output signal can be controlled by adjusting the injection ratio while the noise power at low frequencies is not enhanced as in sensors that are based on a free-running oscillator. PMID- 29715869 TI - Theoretical description and design of nanomaterial slab waveguides: application to compensation of optical diffraction. AB - Planar optical waveguides made of designable spatially dispersive nanomaterials can offer new capabilities for nanophotonic components. As an example, a thin slab waveguide can be designed to compensate for optical diffraction and provide divergence-free propagation for strongly focused optical beams. Optical signals in such waveguides can be transferred in narrow channels formed by the light itself. We introduce here a theoretical method for characterization and design of nanostructured waveguides taking into account their inherent spatial dispersion and anisotropy. Using the method, we design a diffraction-compensating slab waveguide that contains only a single layer of silver nanorods. The waveguide shows low propagation loss and broadband diffraction compensation, potentially allowing transfer of optical information at a THz rate. PMID- 29715870 TI - Magnetic plasmons in a simple metallic nanogroove array for refractive index sensing. AB - Magnetic plasmons (MPs) refer to the coupling of external electromagnetic waves with a strong magnetic response induced inside the nanostructures. MPs have been widely employed as artificial magnetic atoms to fabricate negative-permeability or negative-refractive-index metamaterials with peculiar electromagnetic properties. Here, we propose a refractive index sensing by utilizing the MP resonances excited in a simple one-dimensional (1D) metallic nanogroove array. We demonstrate a sensitivity up to 1200 nm/RIU with a figure of merit (FOM*) of 15 thanks to the MP resonances that are extremely sensitive to the surrounding media. Importantly, the influence of the local environment effects on the sensing ability is studied. An equivalent inductor-capacitor (LC) model is used to give a precise quantitative description of the sensing performance and reveal the underlying mechanism. Such a MP-based sensor with the ease of fabrication may provide great potentials in designing broadband sensing devices with high performance and compactness. PMID- 29715871 TI - Leaky mode integrated optical fibre refractometer. AB - A route to monitor external refractive indices greater than the core index of the waveguide is presented. Initial application utilizes an integrated optical fibre (IOF) platform due to its potential for use in harsh environment sensing. IOF is fabricated using a bespoke flame hydrolysis deposition process to fuse an optical fibre to a planar substrate achieving an optical quality, ruggedized glass layer between the fibre and substrate was fabricated. The presented refractometer is created by direct UV writing of multiple fibre Bragg gratings into an etched (22 MUm diameter) optical fibre post fabrication. Linear regression analysis is applied to quantify propagation loss by monitoring each FBG's back reflected power. The device operates with a sensitivity of approximately 350 dB/cm/RIU at a refractive index of 1.451 at 1550 nm. Numerical simulations using a transfer matrix method are presented and potential routes for development are discussed. PMID- 29715872 TI - Observation of guided acoustic-wave Brillouin scattering noise and its compensation in digital coherent optical fiber transmission. AB - We describe the first observation of guided acoustic-wave Brillouin scattering (GAWBS) phase noise in a digital coherent optical fiber transmission. GAWBS noise, which is a forward lightwave generated by thermally excited vibration modes in a cylindrical fiber structure, occurs coherently not only in a signal at a single carrier frequency, but also in modulated wide-band optical signals. Since the signal-to-GAWBS-noise ratio is independent of signal power, it has caused problems in various fields including quantum optics. We point out that GAWBS noise exists even in a digital coherent transmission system such as quadrature amplitude modulation (QAM) and degrades the transmission performance since the phase noise is inevitably included within the bandwidth of the transmitted data. We propose two analogue and one digital method to compensate for the GAWBS noise and demonstrate improved performance in a QAM digital coherent transmission. PMID- 29715873 TI - Matching optimization for SFS-structured interferometers with step-index fibers. AB - Axial-aligned SFS-structured interferometers with step-index fibers hold advantages of easy fabrication, high stability, and extremely low cost, while low extinction ratio of the interferometer remains challenging. Here, we investigate the influence of core radius and refractive index of the fibers adopted in the interferometer on its extinction ratio and coupling loss, aiming to achieve the extinction ratio above 15dB - this criterion is applicable for practical use. The improvement of extinction ratio values presented in experiment was from 2dB to 7dB, which match perfectly with theoretical values, therefore demonstrates the effectiveness of the theoretical conclusion. PMID- 29715874 TI - Dual-lasing channel quantum cascade laser based on scattering-assisted injection design. AB - A dual lasing channel Terahertz Quantum Cascade laser (THz QCL) based on GaAs/Al0.17Ga0.83As material system is demonstrated. The device shows the lowest reported threshold current density (550A/cm2 at 50K) of GaAs/AlxGa1-xAs material system based scattering-assisted (SA) structures and operates up to a maximum lasing temperature of 144K. Dual lasing channel operation is investigated theoretically and experimentally. The combination of low frequency emission, dual lasing channel operation, low lasing threshold current density and high temperature performance make such devices ideal candidates for low frequency applications, and initiates the design strategy for achieving high-temperature performance terahertz quantum cascade laser with wide frequency coverage at low frequency. PMID- 29715875 TI - Coupling of a light-emitting diode with surface plasmon polariton or localized surface plasmon induced on surface silver gratings of different geometries. AB - A metal grating on top of a light-emitting diode (LED) with a designed grating period for compensating the momentum mismatch can enhance the surface plasmon polariton (SPP) coupling effect with the quantum wells (QWs) to improve LED performance. Here, we demonstrate the experimental results showing that the induced localized surface plasmon (LSP) resonance on such a metal grating can dominate the QW coupling effect for improving LED performance, particularly when grating ridge height is large. The finding is illustrated by fabricating Ag gratings on single-QW, green-emitting LEDs of different p-type thicknesses with varied grating ridge height and width such that the distance between the grating ridge tip and the QW can be controlled. Reflection spectra of the Ag grating structures are measured and simulated to identify the SPP or LSP resonance behaviors at the QW emission wavelength. The measured results of LED performances show that in the LED samples under study, both SPP and LSP couplings can lead to significant enhancements of internal quantum efficiency and electroluminescence intensity. At the designated QW emission wavelength, with a grating period theoretically designed for momentum matching, the LSP coupling effect is stronger, when compared with SPP coupling. PMID- 29715876 TI - Quality assessment of terahertz time-domain spectroscopy transmission and reflection modes for graphene conductivity mapping. AB - We present a comparative study of electrical measurements of graphene using terahertz time-domain spectroscopy in transmission and reflection mode, and compare the measured sheet conductivity values to electrical van der Pauw measurements made independently in three different laboratories. Overall median conductivity variations of up to 15% were observed between laboratories, which are attributed mainly to the well-known temperature and humidity dependence of non-encapsulated graphene devices. We conclude that terahertz time-domain spectroscopy performed in either reflection mode or transmission modes are indeed very accurate methods for mapping electrical conductivity of graphene, and that both methods are interchangeable within measurement uncertainties. The conductivity obtained via terahertz time-domain spectroscopy were consistently in agreement with electrical van der Pauw measurements, while offering the additional advantages associated with contactless mapping, such as high throughput, no lithography requirement, and with the spatial mapping directly revealing the presence of any inhomogeneities or isolating defects. The confirmation of the accuracy of reflection-mode removes the requirement of a specialized THz-transparent substrate to accurately measure the conductivity. PMID- 29715877 TI - High angular resolution visible light positioning using a quadrant photodiode angular diversity aperture receiver (QADA). AB - The increasing use of white LEDs for indoor illumination provides a significant opportunity for Visible Light Positioning (VLP). The challenge is to design a small, unobtrusive sensor that can be incorporated into mobile devices to provide accurate measurements for triangulation. We present experimental results for a novel angle of arrival (AOA) detector that has been designed for use in a VLP system. The detector is composed of a transparent aperture in an opaque screen that is located above a quadrant photodiode (PD), separated by a known vertical distance. Light passing through the aperture from an LED casts a light spot onto the quadrant PD. The position of this spot, coupled with knowledge of the height of the aperture above the quadrant PD, provides sufficient information to determine both the incident and polar angles of the light. Experiments, using a prototype detector, show that detector is capable of accurate estimation of AOA. The root mean square errors (rMSE) were less than 0.11 degrees for all the measured positions on the test bed, with 90% of positions having an rMSE of less than 0.07 degrees . PMID- 29715878 TI - Infrared-laser-induced ultrafast modulation on the spectrum of an extreme ultraviolet attosecond pulse. AB - We present a theoretical investigation of the isolated extreme-ultraviolet (XUV) attosecond pulse propagating in the ionizing gas induced by a synchronized strong infrared (IR) laser, with the numerical solution of the nonadiabatic one dimensional propagation model. Upon scanning the relative delay between the XUV and the IR pulse, it is found that the delay-dependent XUV transmission spectrogram exhibits the unique pattern that is controllable by the chirp of the XUV pulse. Furthermore, we demonstrate that this kind of spectrum modulation can be attributed to the term of the light energy loss involved in the propagation equation. The characteristics of the spectrum modulation dependent on the XUV chirp might provide an all-optical way for the reconstruction of the XUV spectral phase. PMID- 29715879 TI - Large aperture liquid crystal lens array using a composited alignment layer. AB - A liquid crystal (LC) lens array with high light control power and a large aperture using a composited alignment layer is proposed. In our design, the alignment layer is not only used for getting a uniform arrangement of LC molecule, but also for getting a lens-like refractive index distribution in the LC layer when a voltage is applied. Through simple technology processes, a tunable focal length LC lens array with a millimeter scale diameter can be achieved. Furthermore, the maximum phase difference of the proposed LC lens array can achieve 105.38pi. So, the proposed LC lens array has a high light control power. PMID- 29715880 TI - Wavelength modulation spectroscopy for recovering absolute absorbance. AB - A highly sensitive, calibration-free method, wavelength modulation - direct absorption spectroscopy (WM-DAS), is proposed by extracting the characteristic frequencies of modulated laser intensity. This method combines the advantages of measuring absolute absorbance profile from calibration-free DAS with the enhanced noise rejection and high sensitivity of WMS. The preliminary validation experiment of H2O transitions shows that the WM-DAS method improves the accuracy of the absorbance profile measurement with a best-fit standard residual of 4.9 * 10-5. This new method might inspire new approaches to high-precision measurement of spectral line parameters and gas information with weak absorptions or industrial applications. PMID- 29715881 TI - Sinusoidal phase modulating absolute distance measurement interferometer combining frequency-sweeping and multi-wavelength interferometry. AB - A sinusoidal phase modulating absolute distance measurement (ADM) interferometer combining frequency-sweeping interferometry (FSI) and multi-wavelength interferometry (MWI) is proposed in this paper. The swept frequency in FSI and the wavelengths for MWI are calibrated by an optical frequency comb, so the distance measurement can be directly traced back to the SI definition of a meter. With a simple optical structure, an ADM interferometer consisting of a measurement interferometer and a monitor interferometer is constructed without polarization optics. A near-infrared external cavity diode laser (ECDL) calibrated by an optical frequency comb is used as a work source of the measurement interferometer for frequency sweeping and hopping. The monitor interferometer using a He-Ne laser runs parallel to the measurement interferometer to monitor the fluctuation of the measured distance during the measurement. Experiments for absolute distance measurements in a range of 8.25 m were carried out to verify the feasibility of the proposed ADM interferometer. The experimental results show that the maximum measurement error is less than 1 MUm compared with an incremental-type laser interferometer. PMID- 29715882 TI - High-accuracy range-sensing system based on FMCW using low-cost VCSEL. AB - Long-range shape measurement with high accuracy is needed for precision manufacturing of large-scale parts such as turbines, compressors, and trains. We have developed a high-accuracy ranging system based on frequency-modulated continuous-wave (FMCW) technology. Our system has two unique features. First, it achieves high-accuracy range measurement by directly modulating a low-cost vertical-cavity surface-emitting laser (VCSEL) at high sweep rates. The nonlinearity of the optical frequency sweep is compensated for by resampling through a reference interferometer. Second, an optical fiber with multiple fiber Bragg grating (FBG) structures is used for distance calibration. Ranging accuracy better than 10 MUm is achieved at 2 m distance. Three-dimensional (3D) imaging of 10-cubic-meter volume has been obtained by combining the FMCW ranging with a galvanometer scanner. PMID- 29715883 TI - Experimental study of modulation waveforms for entraining the spikes emitted by a semiconductor laser with optical feedback. AB - The entrainment phenomenon, by which an oscillator adjusts its natural rhythm to an external periodic signal, has been observed in many natural systems. Recently, attention has focused on which are the optimal conditions for achieving entrainment. Here we use a semiconductor laser with optical feedback, operating in the low-frequency fluctuations (LFFs) regime, as a testbed for a controlled entrainment experiment. In the LFF regime the laser intensity displays abrupt spikes, which can be entrained to a weak periodic signal that directly modulates the laser pump current. We compare the performance of three modulation waveforms for producing 1:1 locking (one spike is emitted in each modulation cycle), as well as higher order locking regimes. We characterize the parameter regions where high-quality locking occurs, and those where the laser emits spikes which are not entrained to the external signal. The role of the modulation amplitude and frequency, and the role of the dc value of the laser pump current (that controls the natural spike frequency) in the entrainment quality are discussed. PMID- 29715884 TI - Robust enhancement of high harmonic generation via attosecond control of ionization. AB - High-harmonic generation (HHG) is a powerful tool to generate coherent attosecond light pulses in the extreme ultraviolet. However, the low conversion efficiency of HHG at the single atom level poses a significant practical limitation for many applications. Enhancing the efficiency of the process defines one of the primary challenges in the application of HHG as an advanced XUV source. In this work, we demonstrate a new mechanism, which in contrast to current methods, enhances the HHG conversion efficiency purely on a single particle level. We show that using a bichromatic driving field, sub-optical-cycle control and enhancement of the tunnelling ionization rate can be achieved, leading to enhancements in HHG efficiency by up to two orders of magnitude. Our method advances the perspectives of HHG spectroscopy, where isolating the single particle response is an essential component, and offers a simple route toward scalable, robust XUV sources. PMID- 29715885 TI - Femtosecond laser filaments for rapid and flexible writing of fiber Bragg grating. AB - A new beam delivery method is introduced for controlling filament formation in optical fiber that enables point-by-point writing of 1st order fiber Bragg gratings (FBGs) with single femtosecond laser pulses. Uniform filament tracks with azimuthal symmetry were formed fully through the 9.3 um core waveguide by a modified immersion focusing method to eliminate astigmatism by the cylindrical fiber shape. Filament arrays were precisely assembled inside of single-mode fiber, generating strong FBG resonances in the telecommunication band. Laser exposure control within this unique thin-grating geometry were key to manipulating the relative strength of the Bragg and cladding mode resonances while also independently tailoring their spectral resolution and features. This filament-by-filament writing rapidly forms gratings with highly flexible pattern control to tune wavelength, or introduce optical defects, demonstrated by a pi shifted FBG having a sharp 25 pm resonance embedded within a broader Bragg peak. PMID- 29715886 TI - Non-iterative method for phase retrieval and coherence characterization by focus variation using a fixed star-shaped mask. AB - A novel non-iterative phase retrieval method is proposed and demonstrated with a proof-of-principle experiment. The method uses a fixed specially designed mask and through-focus intensity measurements. It is demonstrated that this method is robust to spatial partial coherence in the illumination, making it suitable for coherent diffractive imaging using spatially partially coherent light, as well as for coherence characterization. PMID- 29715887 TI - Intense electroluminescence from Al2O3/Tb2O3 nanolaminate films fabricated by atomic layer deposition on silicon. AB - Intense electroluminescence (EL) from Tb3+ ions in the Al2O3/Tb2O3 nanolaminate films is achieved in a metal-oxide-semiconductor structure fabricated on silicon, utilizing atomic layer deposition. Precisely controlling of the nanolaminates enables the study on the influence of the atomic Tb layers and the distance between every dopant layers on the EL mechanism. The EL intensity decreases with excessive Tb dopant cycles due to the reduction of optically active Tb3+ ions. Cross-relaxation among adjacent Tb2O3 dopant layers depopulates the excited ions in 5D3 level and contributes to the green EL from 5D4 level, which strongly depends on the Al2O3 sublayer thickness with a critical value of ~3 nm. The 543 nm green EL from Tb3+ ions shows maximum power density of 3.37 mW cm-2 and external quantum efficiency up to 0.73%. Further promotion of efficiency is realized by adopting thicker luminescent layer and Al2O3 cladding layer. PMID- 29715888 TI - New LED-based high-brightness incoherent light source in the SWIR. AB - The first LED-pumped luminescent concentrator (LC) emitting in the short-wave infrared (SWIR) is reported. Low cost LEDs (at 940 nm) are used to pump a Yb,Er:Glass LC emitting at 1550 nm. The optical conversion efficiency of the system is optimized and studied in detail for several optical configurations. A total of 128 LEDs having an emitting surface of 1 mm2 and an irradiance of 51.6 W/cm2, corresponding to a total pump power of 66 W, are used. Optimizing the output power out of a 100-mm-long LC in a continuous wave regime, a power of 850 mW is extracted from the 2.5 x 2 mm2 LC emitting surface area. The optical efficiency is then 1.29%. The performance of this luminescent concentrator is higher by one order of magnitude in term of radiance compared to an LED emitting at the same wavelength. PMID- 29715889 TI - Optimization of MgF2-deposition temperature for far UV Al mirrors. AB - Progress towards far UV (FUV) coatings with enhanced reflectance is invaluable for future space missions, such as LUVOIR. This research starts with the procedure developed to enhance MgF2-protected Al reflectance through depositing MgF2 on a heated aluminized substrate [Quijada et al., Proc. SPIE 8450, 84502H (2012)] and it establishes the optimum deposition temperature of the MgF2 protective film for Al mirrors with a reflectance as high as ~90% at 121.6 nm. Al films were deposited at room temperature and protected with a MgF2 film deposited at various temperatures ranging from room temperature to 350 degrees C. It has been found that mirror reflectance in the short FUV range continuously increases with MgF2 deposition temperature up to 250 degrees C, whereas reflectance decreases at temperatures of 300 degrees C and up. The short-FUV reflectance of mirrors deposited at 250 degrees C only slightly decreased over time by less than 1%, compared to a larger decay for standard coatings prepared at room temperature. Al mirrors protected with MgF2 deposited at room temperature that were later annealed displayed a similar reflectance enhancement that mirrors protected at high temperatures. MgF2 and Al roughness as well as MgF2 density were analyzed by x-ray grazing incidence reflectometry. A noticeable reduction in both Al and MgF2 roughness, as well as an increase of MgF2 density, were measured for films deposited at high temperatures. On the other hand, it was found a strong correlation between the protective-layer deposition temperature (or post deposition annealing temperature) and the pinhole open area in Al films, which could be prevented with a somewhat thicker Al film. PMID- 29715890 TI - Gain dependent self-phasing in a two-core coherently combined fiber laser. AB - The influence of the Kramers-Kronig phase is demonstrated in a coherently combined fiber laser where other passive phasing mechanisms such as wavelength tuning have been suppressed. A mathematical model is developed to predict the lasing supermode and is supported by experimental measurements of the gain, phase, and power. The results show that the difference in Kramers-Kronig phase arising from a difference in gain between the two arms partially compensates for an externally applied phase error. PMID- 29715891 TI - Two-dimensional beam-steering device using a doubly periodic Si photonic-crystal waveguide. AB - We demonstrate a nonmechanical, on-chip optical beam-steering device using a photonic-crystal waveguide with a doubly periodic structure that repeats the increase and decrease of the hole diameter. We fabricated the device using a complementary metal-oxide-semiconductor process. We obtained a beam-deflection angle of 24 degrees in the longitudinal direction, while maintaining a divergence angle of 0.3 degrees . Four such waveguides were integrated, and one was selected by a Mach-Zehnder optical switch. We obtained lateral beam steering by placing a cylindrical lens above these waveguides. By combining the lateral and longitudinal beam steering, we were able to scan the collimated beam in two dimensions, with 80 * 4 resolution points. PMID- 29715892 TI - Investigation on quantitative uniformity evaluation for directional backlight auto-stereoscopic displays. AB - This work provides a quantitative evaluation on the uniformity of auto stereoscopic 3D (AS3D) displays. The single-unit uniformity UM is defined to describe the display quality at different viewing positions, then the overall display quality of an AS3D system is determined by the inter-unit uniformity UM. As an example, the uniformity of a directional backlight 3D (DB3D) display is experimentally evaluated. Moreover, a visualized simulation is built to analyze the experimental results and optimize the optical system. By modifying the radiant features of the backlights, the entire uniformity of the DB3D displays can be effectively improved. We foresee this work helps to quantitatively evaluate the uniformity and improve design for any kinds of AS3D display type. PMID- 29715893 TI - Spectral engineering for circular-side square microlasers. AB - Spectral engineering has been demonstrated for the circular-side square microlasers with an output waveguide butt-coupled to one vertex. By carefully optimizing deformation parameter and waveguide connection angle, undesired high order transverse modes are suppressed while the mode Q factors and the transverse mode intervals are enhanced simultaneously for the low-order transverse modes. Dual-mode lasing with pure lasing spectra is realized experimentally for the circular-side square microlasers with side lengths of 16 MUm, and the transverse mode intervals can be adjusted from 0.54 to 5.4 nm by changing the deformation parameter. Due to the enhanced mode confinement, single-mode lasing with a side mode suppression-ratio of 36 dB is achieved for a 10MUm-side-length circular-side square microlaser with a 1.5MUm-wide waveguide. PMID- 29715894 TI - Twenty years of terahertz imaging [Invited]. AB - The birth of terahertz imaging approximately coincides with the birth of the journal Optics Express. The 20th anniversary of the journal is therefore an opportune moment to consider the state of progress in the field of terahertz imaging. This article discusses some of the compelling reasons that one may wish to form images in the THz range, in order to provide a perspective of how far the field has come since the early demonstrations of the mid-1990's. It then focuses on a few of the more prominent frontiers of current research, highlighting their impacts on both fundamental science and applications. PMID- 29715896 TI - The harmonic state of quantum cascade lasers: origin, control, and prospective applications [Invited]. AB - The recently discovered ability of the quantum cascade laser to produce a harmonic frequency comb has attracted new interest in these devices for both applications and fundamental laser physics. In this review we present an extensive experimental phenomenology of the harmonic state, including its appearance in mid-infrared and terahertz quantum cascade lasers, studies of its destabilization induced by delayed optical feedback, and the assessment of its frequency comb nature. A theoretical model explaining its origin as due to the mutual interaction of population gratings and population pulsations inside the laser cavity will be described. We explore different approaches to control the spacing of the harmonic state, such as optical injection seeding and variation of the device temperature. Prospective applications of the harmonic state include microwave and terahertz generation, picosecond pulse generation in the mid infrared, and broadband spectroscopy. PMID- 29715897 TI - Twenty years of Optics Express: invited review articles. AB - Editor-in-Chief Andrew M. Weiner announces a series of invited review and perspective articles for Optics Express's 20th Anniversary celebration, and introduces the first three to be published. PMID- 29715895 TI - Several new directions for ultrafast fiber lasers [Invited]. AB - Ultrafast fiber lasers have the potential to make applications of ultrashort pulses widespread - techniques not only for scientists, but also for doctors, manufacturing engineers, and more. Today, this potential is only realized in refractive surgery and some femtosecond micromachining. The existing market for ultrafast lasers remains dominated by solid-state lasers, primarily Ti:sapphire, due to their superior performance. Recent advances show routes to ultrafast fiber sources that provide performance and capabilities equal to, and in some cases beyond, those of Ti:sapphire, in compact, versatile, low-cost devices. In this paper, we discuss the prospects for future ultrafast fiber lasers built on new kinds of pulse generation that capitalize on nonlinear dynamics. We focus primarily on three promising directions: mode-locked oscillators that use nonlinearity to enhance performance; systems that use nonlinear pulse propagation to achieve ultrashort pulses without a mode-locked oscillator; and multimode fiber lasers that exploit nonlinearities in space and time to obtain unparalleled control over an electric field. PMID- 29715898 TI - Strain sensing based on strain to radio-frequency conversion of optical frequency comb. AB - We propose an optical frequency comb (OFC)-based strain sensing method, namely OFC sensing cavity, which is capable of radio-frequency (RF)-based strain measurement. We developed a null-method-based strain sensing system with a comb spacing-stabilized OFC generator. We realized strain measurement from 1.83 uepsilon to 1800 uepsilon with a sensing fiber length of 20 mm. The measurable strain frequency range of the developed strain sensing system was from 0 to 310 Hz. Owing to the use of RF-based strain measurement, our approach would be a useful and powerful tool for sensing of strain or other physical quantities, and the concept of the OFC sensing cavity is a new aspect of OFC technology. PMID- 29715899 TI - Determination of the contributions of two simultaneous absorption orders using 2 beam action spectroscopy. AB - The concept of a 2-beam action (2-BA) spectroscopy was recently introduced as a method for determining the order of effective nonlinear absorption in multiphoton photoresists. Here we demonstrate that the 2-BA approach can be extended to any measureable observable generated by linear and/or nonlinear absorption. As an example, 2-beam constant-amplitude photocurrent spectroscopy is used to study absorption of a tightly focused, mode-locked or continuous-wave, 800 nm laser by a GaAsP photodiode. The effective order of the absorption process can be measured at any desired value of the photocurrent or photovoltage. A self-consistent framework is presented for using non-integral 2-BA exponents to determine the relative contributions of two absorption mechanisms of different order. The dependence of the ratio of the quadratic and linear contributions on the average excitation power is used to verify that these are the dominant orders of absorption in the photodiode with 800 nm excitation. PMID- 29715900 TI - Highly efficient all-optical beam modulation utilizing thermo-optic effects. AB - Suspensions of plasmonic nanoparticles can diffract optical beams due to the combination of thermal lensing and self-phase modulation. Here, we demonstrate extremely efficient optical continuous wave (CW) beam switching across the visible range in optimized suspensions of 5-nm Au and Ag nanoparticles in non polar solvents, such as hexane and decane. On-axis modulation of greater than 30 dB is achieved at incident beam intensities as low as 100 W/cm2 with response times under 200 MUs, at initial solution transparency above 70%. No evidence of laser-induced degradation is observed for the highest intensities used. Numerical modeling of experimental data reveals thermo-optic coefficients of up to -1.3 * 10-3 /K, which, to our knowledge, is the highest observed to date in such nanoparticle suspensions. PMID- 29715901 TI - Studying the fundamental limit of optical fiber links to the 10-21 level. AB - We present a hybrid fiber link combining effective optical frequency transfer and evaluation of performances with a self-synchronized two-way comparison. It enables us to detect the round-trip fiber noise and each of the forward and backward one-way fiber noises simultaneously. The various signals acquired with this setup allow us to study quantitatively several properties of optical fiber links. We check the reciprocity of the accumulated noise forth and back over a bi directional fiber to the level of 3.1(+/-3.9) * 10-20 based on a 160000s continuous data. We also analyze the noise correlation between two adjacent fibers and show the first experimental evidence of interferometric noise at very low Fourier frequency. We estimate redundantly and consistently the stability and accuracy of the transferred optical frequency over 43 km at 4 * 10-21 level after 16 days of integration and demonstrate that a frequency comparison with instability as low as 8 * 10-18 would be achievable with uni-directional fibers in urban area. PMID- 29715902 TI - Polarization-filtering and polarization-maintaining low-loss negative curvature fibers. AB - We propose a polarization-filtering and polarization-maintaining negative curvature fiber in which two nested resonant tubes are added to a standard negative curvature fiber with one ring of tubes. The coupling between the glass modes in the nested resonant tubes and the fundamental core modes is used to increase the birefringence and differential loss for the fundamental core modes in the two polarizations. We show computationally that the birefringence and the loss ratio between the modes in the two polarizations can reach 10-5 and 850, respectively. Meanwhile, the low-loss mode has a loss that is lower than 0.02 dB/m. The relatively simple design of this polarization-maintaining negative curvature fiber will be useful in hollow-core fiber devices that are sensitive to polarization effects, such as fiber lasers, fiber interferometers, and fiber sensors. PMID- 29715903 TI - Adaptive piston correction of sparse aperture systems with stochastic parallel gradient descent algorithm. AB - A phased sparse aperture system provides an economic solution to get high resolution images with less volume and weight. The crucial point of such systems is adaptive correction of piston, that is, a close-loop control aiming at stabilizing the optical path differences within a fraction of the wavelength. In this paper, we present an autonomous phasing approach using stochastic parallel gradient descent algorithm through optimization of image quality. The synthetic system can be phased by iteratively commanding piston actuators without any additional optics. Simulations are first performed to test the validity. Then experimental results based on a binocular telescope testbed are presented, showing that our proposed close-loop control of piston correction doesn't only work with both laser and white-light point sources, but also with an extended object. PMID- 29715904 TI - Wideband slow short-pulse propagation in one-thousand slantingly coupled L3 photonic crystal nanocavities. AB - Coupled cavities have been used previously to realize on-chip low-dispersion slow light waveguides, but the bandwidth was usually narrower than 10 nm and the total length was much shorter than 1 mm. Here we report long (0.05-2.5 mm) slow-light coupled cavity waveguides formed by using 50, 200, and 1,000 L3 photonic crystal nanocavities with an optical volume smaller than (lambda/n)3, slanted from Gamma K orientation. We demonstrate experimentally the formation of a single-mode wideband coupled cavity mode with a bandwidth of up to 32nm (4THz) in telecom C band, generated from the ultra-narrow-band (~300 MHz) fundamental mode of each L3 nanocavity, by controlling the cavity array orientation. Thanks to the ultrahigh Q nanocavity design, coupled cavity waveguides longer than 1 mm exhibited low loss and allowed time-of-flight dispersion measurement over a bandwidth up to 22 nm by propagating a short pulse over 1,000 coupled L3 nanocavities. The highly dense slanted array of L3 nanocavity demonstrated unprecedentedly high cavity coupling among the nanocavities. The scheme we describe provides controllable planar dispersion-managed waveguides as an alternative to W1-based waveguides on a photonic crystal chip. PMID- 29715905 TI - Short pulse generation from a passively mode-locked fiber optical parametric oscillator with optical time-stretch. AB - We propose a passively mode-locked fiber optical parametric oscillator assisted with optical time-stretch. Thanks to the lately developed optical time-stretch technique, the onset oscillating spectral components can be temporally dispersed across the pump envelope and further compete for the parametric gain with the other parts of onset oscillating sidebands within the pump envelope. By matching the amount of dispersion in optical time-stretch with the pulse width of the quasi-CW pump and oscillating one of the parametric sidebands inside the fiber cavity, we numerically show that the fiber parametric oscillator can be operated in a single pulse regime. By varying the amount of the intracavity dispersion, we further verify that the origin of this single pulse mode-locking regime is due to the optical pulse stretching and compression. PMID- 29715906 TI - Highly efficient holograms based on c-Si metasurfaces in the visible range. AB - This paper reports on the first hologram in transmission mode based on a c-Si metasurface in the visible range. The hologram shows high fidelity and high efficiency, with measured transmission and diffraction efficiencies of ~65% and ~40%, respectively. Although originally designed to achieve full phase control in the range [0-2pi] at 532 nm, these holograms have also performed well at 444.9 nm and 635 nm. The high tolerance to both fabrication and wavelength variations demonstrate that holograms based on c-Si metasurfaces are quite attractive for diffractive optics applications, and particularly for full-color holograms. PMID- 29715907 TI - All-organic switching polarizer based on polymer waveguides and liquid crystals. AB - This paper reports on the design, fabrication and characterization of an all organic photonic integrated circuit working as a switching polarizer for visible light (630nm), combining organic waveguides and liquid crystals that can be electrically driven. The device was made in commercially available epoxy by laser direct writing lithography. A device with a 2dB loss and a 20dB extinction ratio for both polarizations, was simulated; the manufactured devices proved the working principle of the design. The results have led to the design of a switching polarization splitter, in which a careful choice of waveguide material and liquid crystal can lead to devices working on a wide range of wavelengths. PMID- 29715908 TI - In situ high temperature microwave microscope for nondestructive detection of surface and sub-surface defects. AB - An in situ high temperature microwave microscope was built for detecting surface and sub-subsurface structures and defects. This system was heated with a self designed quartz lamp radiation module, which is capable of heating to 800 degrees C. A line scanning of a metal grating showed a super resolution of 0.5 mm (lambda/600) at 1 GHz. In situ scanning detections of surface hole defects on an aluminium plate and a glass fiber reinforced plastic (GFRP) plate were conducted at different high temperatures. A post processing algorithm was proposed to remove the background noises induced by high temperatures and the 3.0 mm-spaced hole defects were clearly resolved. Besides, hexagonal honeycomb lattices were in situ detected and clearly resolved under a 1.0 mm-thick face panel at 20 degrees C and 50 degrees C, respectively. The core wall positions and bonding width were accurately detected and evaluated. In summary, this in situ microwave microscope is feasible and effective in sub-surface detection and super resolution imaging at different high temperatures. PMID- 29715909 TI - Template-stripped nanoaperture tweezer integrated with optical fiber. AB - We demonstrate an optical trapping technique that integrates the light guiding of an optical fiber with the field localization of a nanoaperture in a gold film. A key innovation of our technique is to use template-stripping for easy planar fabrication without the need for nanofabrication on the tip itself. As a proof of principle, we demonstrate the trapping of 20 nm and 30 nm polystyrene nanoparticles in solution, as observed by a jump in the transmitted laser intensity through the aperture. We use the finite difference time domain technique to simulate this intensity jump with the addition of a nanoparticle in the aperture, showing reasonable agreement with the experimental data. This simple nano-aperture optical fiber tip eliminates the need for a microscope setup while allowing for trapping nanoparticles, so it is anticipated to have applications in biology (e.g. viruses), biophysics (e.g. protein interactions), physics (e.g. quantum emitters), and chemistry (e.g. colloidal particles). PMID- 29715910 TI - Linear and nonlinear optical characterization of self-assembled, large-area gold nanosphere metasurfaces with sub-nanometer gaps: errata. AB - We correct a nomenclature error for the plasmon ruler equation used to fit the simulation data in Fig. 2(d) [Opt. Express24, 27360 (2016)]. PMID- 29715911 TI - Variability of the reflectance coefficient of skylight from the ocean surface and its implications to ocean color. AB - The value and spectral dependence of the reflectance coefficient (rho) of skylight from wind-roughened ocean surfaces is critical for determining accurate water leaving radiance and remote sensing reflectances from shipborne, AERONET Ocean Color and satellite observations. Using a vector radiative transfer code, spectra of the reflectance coefficient and corresponding radiances near the ocean surface and at the top of the atmosphere (TOA) are simulated for a broad range of parameters including flat and windy ocean surfaces with wind speeds up to 15 m/s, aerosol optical thicknesses of 0-1 at 440nm, wavelengths of 400-900 nm, and variable Sun and viewing zenith angles. Results revealed a profound impact of the aerosol load and type on the spectral values of rho. Such impacts, not included yet in standard processing, may produce significant inaccuracies in the reflectance spectra retrieved from above-water radiometry and satellite observations. Implications for satellite cal/val activities as well as potential changes in measurement and data processing schemes are discussed. PMID- 29715912 TI - Resolution-enhanced heterodyne laser interferometer with differential configuration for roll angle measurement. AB - A high resolution roll measurement heterodyne interferometer with differential configurations is proposed in this paper. The proposed interferometer is composed of a pair of measurement beams providing environmental noise immunity. The structure is designed and the mathematic model based on Jones' matrix for measuring the roll angle is established. Sensitivity is enhanced dramatically because of the opposite phase shift directions of two signals. An experimental setup is built and an amplification factor of 270 is obtained. Correspondingly, a roll angle resolution of 0.13 arcsec is attained using a phase meter with detecting resolution of 0.01 degrees . PMID- 29715914 TI - Ultrashort and broadband silicon polarization splitter-rotator using fast quasiadiabatic dynamics. AB - We propose an ultrashort and broadband silicon mode-conversion polarization splitter-rotator (PSR) consisting of a taper and a Y-junction both designed by the fast quasiadiabatic dynamics (FAQUAD). The FAQUAD is used to homogeneously distribute adiabaticity over the length of the PSR, providing shortcut to adiabaticity at a shorter device length. The total length of the silicon PSR is 39.2 MUm. For a wavelength range from 1.5 MUm to 1.6 MUm, the PSR exhibits a good performance with > 88% transmission and > 11.4 dB extinction ratio (ER). Simulations also show that the designed devices have good fabrication tolerance. PMID- 29715913 TI - Nonlinear silicon nitride waveguides based on a PECVD deposition platform. AB - In this work, we present a nonlinear silicon nitride waveguide. These waveguide are fabricated by readily available PECVD, conventional contact UV-lithography and high-temperature annealing techniques, thus dramatically reducing the processing complexity and cost. By patterning the waveguide structures firstly and then carrying out a high-temperature annealing process, not only sufficient waveguide thickness can be achieved, which gives more freedom to waveguide dispersion control, but also the material absorption loss in the waveguides be greatly reduced. The linear optical loss of the fabricated waveguide with a cross section of 2.0 * 0.58 um2 was measured to be as low as 0.58 dB/cm. The same loss level is demonstrated over a broad wavelength range from 1500 nm to 1630 nm. Moreover, the nonlinear refractive index of the waveguide was determined to be ~6.94 * 10-19 m2/W, indicating that comparable nonlinear performance with their LPCVD counterparts is expected. These silicon nitride waveguides based on a PECVD deposition platform can be useful for the development of more complicated on-chip nonlinear optical devices or circuits. PMID- 29715915 TI - HCN ppt-level detection based on a QEPAS sensor with amplified laser and a miniaturized 3D-printed photoacoustic detection channel. AB - Ultra-high sensitive and stable detection of hydrogen cyanide (HCN) based on a quartz-enhanced photoacoustic spectroscopy (QEPAS) sensor was realized using an erbium-doped fiber amplifier (EDFA) as well as a miniaturized 3D-printed photoacoustic detection channel (PADC) for the first time. A HCN molecule absorption line located at 6536.46 cm-1 was selected which was in the range of the EDFA emission spectrum. The detection sensitivity of the reported EDFA-QEPAS sensor was enhanced significantly due to the high available EDFA excitation laser power. A 3D printing technique was used to develop the compact PADC, resulting in a size of 29 * 15 * 8 mm3 and a mass of ~5 g in order to improve the sensor stability and implement sensor applications requiring a compact size and light weight. At atmospheric pressure, room temperature and a 1 s acquisition time, a minimum detection limit (MDL) of 29 parts per billion (ppb) was achieved, corresponding to a normalized noise equivalent absorption (NNEA) coefficient of 1.08 * 10-8 cm-1W/Hz-1/2. The long-term performance and the stability of the HCN EDFA-QEPAS sensor system were investigated using an Allan deviation analysis. It indicated that the MDL can be improved to 220 parts per trillion (ppt) with an integration time of 300 s, which demonstrated this compact, integrated and miniaturized 3D-printed PADC based sensor had an excellent stability. PMID- 29715916 TI - Photonic generation of linearly chirped microwave waveforms using a monolithic integrated three-section laser. AB - Photonic generation of linearly chirped microwave waveforms (LCMWs) using a monolithic integrated three-section laser is experimentally demonstrated in this work. All three sections of the laser cavity, including the front DFB section, phase section and rear DFB section, have the same active layer, which can avoid the butt-joint re-growth process. The gratings in both DFB sections are fabricated by the Reconstruction Equivalent Chirp technique, which can significantly decrease the difficulties in realizing precise grating structure. By adjusting the integrated three-section semiconductor laser to work in the period-one (P1) state and applying a sweeping signal to the front DFB section, the beating signal, i.e., an LCMW with a large time bandwidth product (TBWP), can be generated. In the current proof-of-concept experiment, an LCMW with a large TBWP up to 5.159 * 105 is generated, of which the bandwidth and the duration time are 6.7 GHz and 77 us respectively. The compressed pulse width is 150 ps. In addition, by adjusting the bias currents of the rear DFB section and front DFB section as well as the amplitude of the sweeping signals, LCMWs with tunable center frequency and tunable bandwidth can be achieved. PMID- 29715917 TI - High performance all-fiber temperature sensor based on coreless side-polished fiber wrapped with polydimethylsiloxane. AB - A novel fiber structure, coreless side-polished fiber (CSPF) that is wrapped by polydimethylsiloxane (PDMS), is demonstrated to be highly sensitive to temperature because of the high refractive index sensitivity of the CSPF and the large thermal optic coefficient of the PDMS. Our numerical and experimental results show that the several dips in the transmitted spectra of PDMSW-CSPF is originated from the multimode interference (MMI) in the CSPF and will blueshift with the increase of temperature. Furthermore, for such a PDMSW-CSPF, we investigate its temperature sensing characteristics and the influences of residual thickness (RT) and dip wavelength on the sensitivity both numerically and experimentally. In the temperature range of 30~85 degrees C, the PDMSW-CSPF with RT = 43.26 MUm exhibits a high temperature sensitivity of -0.4409 nm/ degrees C, the high linearity of 0.9974, and the high stability with low standard deviation of 0.141 nm. Moreover, in the cycle experiments, where the environmental temperature was set to automatically increase and then decrease, the PDMSW-CSPF exhibits a low relative deviation of sensitivity (RSD) of down to +/- 0.068%. Here, the RSD is defined as the ratio of sensitivity deviation to the average sensitivity measured in the heating/cooling cycle experiments. The lower RSD indicates that PDMSW-CSPF has better reversibility than other fiber structure. The investigations also show that the sensitivity of the PDMSW-CSPF could be enhanced further by reducing the residual thickness and choosing the dip at a longer wavelength. PMID- 29715918 TI - Frequency accurate coherent electro-optic dual-comb spectroscopy in real-time. AB - Electro-optic dual-comb spectrometers have proved to be a promising technology for sensitive, high-resolution and rapid spectral measurements. Electro-optic combs possess very attractive features like simplicity, reliability, bright optical teeth, and typically moderate but quickly tunable optical spans. Furthermore, in a dual-comb arrangement, narrowband electro-optic combs are generated with a level of mutual coherence that is sufficiently high to enable optical multiheterodyning without inter-comb stabilization or signal processing systems. However, this valuable tool still presents several limitations; for instance, on most systems, absolute frequency accuracy and long-term stability cannot be guaranteed; likewise, interferometer-induced phase noise restricts coherence time and limits the attainable signal-to-noise ratio. In this paper, we address these drawbacks and demonstrate a cost-efficient absolute electro-optic dual-comb instrument based on a frequency stabilization mechanism and a novel adaptive interferogram acquisition approach devised for electro-optic dual-combs capable of operating in real-time. The spectrometer, completely built from commercial components, provides sub-ppm frequency uncertainties and enables a signal-to-noise ratio of 10000 (intensity noise) in 30 seconds of integration time. PMID- 29715919 TI - Characterization of a fully integrated heterogeneous silicon/III-V colliding pulse mode-locked laser with on-chip feedback. AB - A fully integrated heterogeneous silicon/III-V colliding pulse mode-locked laser with tunable on-chip optical feedback operating in the O-band is extensively investigated. The 19-GHz colliding pulsed laser operates in a wide mode-locking regime with good mode locking quality. By precisely controlling the strength and phase of the on-chip optical feedback signal, the laser exhibits clear periodic pulse shortening effects. The RF 3 dB linewidth was reduced by a factor of 4.7 down to 6 kHz, as compared to the free running state. PMID- 29715920 TI - CVD SiC deformable mirror with monolithic cooling channels. AB - We propose a novel deformable mirror (DM) for adaptive optics in high power laser applications. The mirror is made of a Silicon carbide (SiC) faceplate, and cooling channels are embedded monolithically inside the faceplate with the chemical vapor desposition (CVD) method. The faceplate is 200 mm in diameter and 3 mm in thickness, and is actuated by 137 stack-type piezoelectric transducers arranged in a square grid. We also propose a new actuator influence function optimized for modelling our DM, which has a relatively stiffer faceplate and a higher coupling ratio compared with other DMs having thin faceplates. The cooling capability and optical performance of the DM are verified by simulations and actual experiments with a heat source. The DM is proved to operate at 1 kHz without the coolant flow and 100 Hz with the coolant flow, and the residual errors after compensation are less than 30 nm rms (root-mean-square). This paper presents the design, fabrication, and optical performance of the CVD SiC DM. PMID- 29715921 TI - Four-port mode-selective silicon optical router for on-chip optical interconnect. AB - We propose and demonstrate a four-port mode-selective optical router on a silicon on-insulator platform. The passive routing property ensures that the router consumes no power to establish the optical links. For each port, input signals with different modes are selectively routed to the target ports through the pre designed architecture. In general, the device intrinsically supports broadcasting of multiplexed signals from one port to the other three ports through mode division multiplexing. In some applications, the input signal from one port would only be sent to another port as in reconfigurable optical routers. The prototype is constructed by mode multiplexers/de-multiplexers and single-mode interconnect waveguides between them. The insertion losses for all optical links are lower than 8.0 dB, and the largest optical crosstalk values are lower than -18.7 dB and -22.0 dB for the broadcasting and port-to-port routing modes, respectively, at the wavelength range of 1525-1565 nm. In order to verify the routing functionality, a 40-Gbps bidirectional data transmission experiment is performed. The device offers a promising building block for passive routing by utilizing the dimension of the modes. PMID- 29715922 TI - Freeform engineered disordered metalenses for super-resolution imaging and communication. AB - Effective transmission of information through scattering media has been of great importance in imaging systems and beneficial to high capacity wireless communication. Despite numerous attempts to achieve high-resolution sub diffraction-limited imaging through employing the engineered structures such as the so-called metamaterials or utilizing techniques like time reversal methods, the proposed ideas suffer from the fundamental limitations for design and practical realization. In this paper, we investigate disorder-based engineered scattering structures and introduce a novel technique for achieving super resolution based on designing and employing engineered all-dielectric medium. We show that disorder in the proposed design can be exploited to significantly modify the information content of scattered fields in the far-field region. Under the presence of the designed structures, using computational methods, signals associated with ultra sub-wavelength features of the illuminating sources can be enhanced and extracted from the far-field image. Not only can the presented approach lead to remarkable enhancement of resolution in such systems, but also orthogonal transmission channels are attainable when the closely-packed sources are excited properly. The latter provides a new scheme for encoding and multiplexing signals leading to the enhancement of information capacity in emerging information processing systems. The design procedure and physical constraints are studied and discussed. PMID- 29715923 TI - Dynamic tailoring of surface plasmon polaritons through incident angle modulation. AB - Dynamic tailoring of the propagating surface plasmon polaritons (SPPs) through incident angle modulation is proposed and numerically demonstrated. The generation and tailoring mechanism of the SPPs are discussed. The relationship formula between the incident angle and the generated SPP wave vector direction is theoretically derived. The correctness of the formula is verified with three different approaches using finite difference time domain method. Using this formula, the generated SPP wave vector direction can be precisely modulated by changing the incident angle. The precise modulation results of two dimensional Bessel-like SPP beam and SPP bottle beam array are given. The results can deepen the understanding of the generation and modulation mechanism of the SPPs. PMID- 29715924 TI - On line rates, information rates, and spectral efficiencies in probabilistically shaped QAM systems. AB - We carefully revisit the definitions of line rates, information rates, and spectral efficiencies in probabilistically shaped optical transmission systems. Generally accepted definitions for uniform quadrature amplitude modulation (QAM) systems are extended to more generally apply to systems with probabilistically shaped QAM, as well as to systems using pilot symbols of different QAM order than the information symbols. Based on the proper definitions, we correct erroneous claims in a recently reported work. PMID- 29715925 TI - Narrowband diode laser pump module for pumping alkali vapors. AB - We describe a method of line narrowing and frequency-locking a diode laser stack to an alkali atomic line for use as a pump module for Diode Pumped Alkali Lasers. The pump module consists of a 600 W antireflection coated diode laser stack configured to lase using an external cavity. The line narrowing and frequency locking is accomplished by introducing a narrowband polarization filter based on magneto-optical Faraday effect into the external cavity, which selectively transmits only the frequencies that are in resonance with the 62S1/2 -> 62P3/2 transition of Cs atoms. The resulting pump module has demonstrated that a diode laser stack, which lases with a line width of 3 THz without narrowbanding, can be narrowed to 10 GHz. The line narrowed pump module produced 518 Watts that is 80% of the power generated by the original broadband diode laser stack. PMID- 29715926 TI - Generation of optical vortex array along arbitrary curvilinear arrangement. AB - We propose an approach for creating optical vortex array (OVA) arranged along arbitrary curvilinear path, based on the coaxial interference of two width controllable component curves calculated by modified holographic beam shaping technique. The two component curve beams have different radial dimensions as well as phase gradients along each beam such that the number of phase singularity in the curvilinear arranged optical vortex array (CA-OVA) is freely tunable on demand. Hybrid CA-OVA that comprises of multiple OVA structures along different respective curves is also discussed and demonstrated. Furthermore, we study the conversion of CA-OVA into vector mode that comprises of polarization vortex array with varied polarization state distribution. Both simulation and experimental results prove the performance of the proposed method of generating a complex structured vortex array, which is of significance for potential applications including multiple trapping of micro-sized particles. PMID- 29715927 TI - Correlation between electrical direct current resistivity and plasmonic properties of CMOS compatible titanium nitride thin films. AB - Damping distances of surface plasmon polariton modes sustained by different thin titanium nitride (TiN) films are measured at the telecom wavelength of 1.55 MUm. The damping distances are correlated to the electrical direct current resistivity of the films sustaining the surface plasmon modes. It is found that TiN/Air surface plasmon mode damping distances drop non-linearly from 40 to 16MUm as the resistivity of the layers increases from 28 to 130MUOmega.cm, respectively. The relevance of the direct current (dc) electrical resistivity for the characterization of TiN plasmonic properties is investigated in the framework of the Drude model, on the basis of parameters extracted from spectroscopic ellipsometry experiments. By probing a parametric space of realistic values for parameters of the Drude model, we obtain a nearly univocal dependence of the surface plasmon damping distance on the dc resistivity demonstrating the relevance of dc resistivity for the evaluation of the plasmonic performances of TiN at telecom frequencies. Finally, we show that better plasmonic performances are obtained for TiN films featuring a low content of oxygen. For low oxygen content and corresponding low resistivity, we attribute the increase of the surface plasmon damping distances to a lower confinement of the plasmon field into the metal and not to a decrease of the absorption of TiN. PMID- 29715928 TI - Hyperspectral imaging for the spectral measurement of far-field beam divergence angle and beam uniformity of a supercontinuum laser. AB - A new novel method, hyperspectral imaging (HSI), is presented in this work to measure the beam divergence angle and beam profile uniformity of supercontinuum lasers. The obtained results of divergence angles are consistent with theoretically calculated values. The uniformity of different-size projected Gaussian beams was measured through referencing the data sets provided by HSI camera under the wavelength variation. HSI, compared with traditional methods, is much faster and capable of providing critical reference to supercontinuum output parameters measurements and practical application in far-field situation. PMID- 29715929 TI - Nanocrystalline silicon optomechanical cavities. AB - Silicon on insulator photonics has offered a versatile platform for the recent development of integrated optomechanical circuits. However, there are some constraints such as the high cost of the wafers and limitation to a single physical device level. In the present work we investigate nanocrystalline silicon as an alternative material for optomechanical devices. In particular, we demonstrate that optomechanical crystal cavities fabricated of nanocrystalline silicon have optical and mechanical properties enabling non-linear dynamical behaviour and effects such as thermo-optic/free-carrier-dispersion self-pulsing, phonon lasing and chaos, all at low input laser power and with typical frequencies as high as 0.3 GHz. PMID- 29715930 TI - Non-paraxial idealized polarizer model. AB - An idealized polarizer model that works without the structural and material information is derived in the spatial frequency domain. The non-paraxial property is fully included and the result takes a simple analytical form, which provides a straight-forward explanation for the crosstalk between field components in non paraxial cases. The polarizer model, in a 2 * 2-matrix form, can be conveniently used in cooperation with other computational optics methods. Two examples in correspondence with related works are presented to verify our polarizer model. PMID- 29715931 TI - Achieving superresolution with illumination-enhanced sparsity. AB - Recent advances in superresolution fluorescence microscopy have been limited by a belief that surpassing two-fold resolution enhancement of the Rayleigh resolution limit requires stimulated emission or the fluorophore to undergo state transitions. Here we demonstrate a new superresolution method that requires only image acquisitions with a focused illumination spot and computational post processing. The proposed method utilizes the focused illumination spot to effectively reduce the object size and enhance the object sparsity and consequently increases the resolution and accuracy through nonlinear image post processing. This method clearly resolves 70nm resolution test objects emitting ~530nm light with a 1.4 numerical aperture (NA) objective, and, when imaging through a 0.5NA objective, exhibits high spatial frequencies comparable to a 1.4NA widefield image, both demonstrating a resolution enhancement above two-fold of the Rayleigh resolution limit. More importantly, we examine how the resolution increases with photon numbers, and show that the more-than-two-fold enhancement is achievable with realistic photon budgets. PMID- 29715932 TI - Wide field fluorescence epi-microscopy behind a scattering medium enabled by speckle correlations. AB - Fluorescence microscopy is widely used in biological imaging, however scattering from tissues strongly limits its applicability to a shallow depth. In this work we adapt a methodology inspired from stellar speckle interferometry, and exploit the optical memory effect to enable fluorescence microscopy through a turbid layer. We demonstrate efficient reconstruction of micrometer-size fluorescent objects behind a scattering medium in epi-microscopy, and study the specificities of this imaging modality (magnification, field of view, resolution) as compared to traditional microscopy. Using a modified phase retrieval algorithm to reconstruct fluorescent objects from speckle images, we demonstrate robust reconstructions even in relatively low signal to noise conditions. This modality is particularly appropriate for imaging in biological media, which are known to exhibit relatively large optical memory ranges compatible with tens of micrometers size field of views, and large spectral bandwidths compatible with emission fluorescence spectra of tens of nanometers widths. PMID- 29715933 TI - One-dimensional angular-measurement-based stitching interferometry. AB - In this work, we present one-dimensional stitching interferometry based on the angular measurement for high-precision mirror metrology. The tilt error introduced by the stage motion during the stitching process is measured by an extra angular measurement device. The local profile measured by the interferometer in a single field of view is corrected using the measured angle before the piston adjustment in the stitching process. Comparing to the classical software stitching technique, the angle measuring stitching technique is more reliable and accurate in profiling mirror surface at the nanometer level. Experimental results demonstrate the feasibility of the proposed stitching technique. Based on our measurements, the typical repeatability within 200 mm scanning range is 0.5 nm RMS or less. PMID- 29715934 TI - Supercontinuum generation in an Er-doped figure-eight passively mode-locked fiber laser. AB - A supercontinuum source based on a figure-eight Er-doped fiber ring cavity has been experimentally demonstrated with low repetition rate. The proposed configuration of the experiment is a figure-eight fiber laser grounded in Nonlinear Optical Loop Mirror (NOLM) technique. A broad spectrum of approximately 410 nm spanning the range 1315-1725 nm at the level of 30 dB can be obtained at a given average power of 2.6 mW and without any amplifier. Such wide spectrum can be directly achieved in the fiber resonator, which makes the structure compact and robust. By changing the pump power, the temporal pulse width can be adjusted accordingly. The pulse width is about 4 ns at the pump power of around 240 mW. The broadband spectrum was generated directly from the fiber resonator, which can be easily applied in numerous areas, such as the optical frequency metrology, optical spectroscopy, optical coherence tomography, optical communications, and medical sciences. PMID- 29715935 TI - 7.5 W blue light generation at 452 nm by internal frequency doubling of a continuous-wave Nd-doped fiber laser. AB - We present the first frequency-doubled neodymium-doped fiber laser generating multi-watt CW power near 450 nm. A bow-tie resonator incorporating a LBO nonlinear crystal is integrated within a Nd-doped fiber laser emitting near 900 nm. This scheme achieves an IR to blue conversion efficiency close to 55% without any active control of the internal resonant cavity. As a result, up to 7.5 W of linearly-polarized blue power is generated, with beam quality factors Mx2 ~1.0 and My2 ~1.5. A simple numerical model has been developed to optimize and analyse the IR to blue conversion efficiency in the resonant cavity. Performance limitations and prospects for further improvements are discussed. PMID- 29715936 TI - Laboratory demonstration of a broadband six-level phase mask coronagraph. AB - The six-level phase mask (SLPM) can be used in a focal plane as an efficient coronagraph [Opt. Express 22, 1884 (2014)]. It has several advantages: high contrast imaging in broadband with small inner working angle; easy fabrication at low cost by photolithography and reactive ion etching processes; easy implementation with no need of pupil apodization. We present in this paper the first laboratory results demonstrating the high performance of a SLPM with an unobscured pupil. The on-axis attenuation reaches 2 * 10-5 at lambda = 800 nm and is better than 10-4 over a 10% spectral bandwidth and better than 10-3 over a 20% bandwidth. Finally, the detection of a planet can be achieved down to 1 lambda/D. PMID- 29715937 TI - Investigation on improvement of lateral resolution of continuous wave STED microscopy by standing wave illumination. AB - In this paper, we report the enhancement of resolution of continuous wave (CW) stimulated emission depletion (STED) microscopy by a novel method of structured illumination of an excitation beam. Illumination by multiple excitation beams through the specific pupil apertures with high in-plane wave vectors leads to interference of diffracted light flux near the focal plane, resulting in the contraction of the point spread function (PSF) of the excitation. Light spot reduction by the suggested standing wave (SW) illumination method contributes to make up much lower depletion efficiency of the CW STED microscopy than that of the pulsed STED method. First, theoretical analysis showed that the full width at half maximum (FWHM) of the effective PSF on the detection plane is expected to be smaller than 25% of that of conventional CW STED. Second, through the simulation, it was elucidated that both the donut-shaped PSF of the depletion beam and the confocal optics suppress undesired contribution of sidelobes of the PSF by the SW illumination to the effective PSF of the STED system. Finally, through the imaging experiment on 40-nm fluorescent beads with the developed SW-CW STED microscopy system, we obtained the result which follows the overall tendency from the simulation in the aspects of resolution improvement and reduction of sidelobes. Based on the obtained result, we expect that the proposed method can become one of the strategies to enhance the resolution of the CW STED microscopy. PMID- 29715938 TI - Improving axial resolution for holographic tracking of colloids and bacteria over a wide depth of field by optimizing different factors. AB - Improving the axial resolution for multiparticle three-dimensional (3D) holographic tracking is crucial but challenging. Here we study the impacts of incident light power, uniformity of the illumination as well as image pixel size on the axial tracking resolution for digital holographic microscopy (DHM). We demonstrate that the resolution highly depends on the image pixel size and the uniformity of the illumination. A 3D localization algorithm based on local intensity-maxima searching and a Gaussian fit to the integrated intensity of the reconstructed lateral images along the axial direction proves a robust strategy to enhance the axial resolution for colloids and bacteria within a wide depth of field over several tens of micrometers. PMID- 29715939 TI - Graphene patterns supported terahertz tunable plasmon induced transparency. AB - The tunable plasmonic induced transparency has been theoretically investigated based on graphene patterns/SiO2/Si/polymer multilayer structure in the terahertz regime, including the effects of graphene Fermi level, structural parameters and operation frequency. The results manifest that obvious Fano peak can be observed and efficiently modulated because of the strong coupling between incident light and graphene pattern structures. As Fermi level increases, the peak amplitude of Fano resonance increases, and the resonant peak position shifts to high frequency. The amplitude modulation depth of Fano curves is about 40% on condition that the Fermi level changes in the scope of 0.2-1.0 eV. With the distance between cut wire and double semi-circular patterns increases, the peak amplitude and figure of merit increases. The results are very helpful to develop novel graphene plasmonic devices (e.g. sensors, modulators, and antenna) and find potential applications in the fields of biomedical sensing and wireless communications. PMID- 29715940 TI - Revealing hidden scenes by photon-efficient occlusion-based opportunistic active imaging. AB - The ability to see around corners, i.e., recover details of a hidden scene from its reflections in the surrounding environment, is of considerable interest in a wide range of applications. However, the diffuse nature of light reflected from typical surfaces leads to mixing of spatial information in the collected light, precluding useful scene reconstruction. Here, we employ a computational imaging technique that opportunistically exploits the presence of occluding objects, which obstruct probe-light propagation in the hidden scene, to undo the mixing and greatly improve scene recovery. Importantly, our technique obviates the need for the ultrafast time-of-flight measurements employed by most previous approaches to hidden-scene imaging. Moreover, it does so in a photon-efficient manner (i.e., it only requires a small number of photon detections) based on an accurate forward model and a computational algorithm that, together, respect the physics of three-bounce light propagation and single-photon detection. Using our methodology, we demonstrate reconstruction of hidden-surface reflectivity patterns in a meter-scale environment from non-time-resolved measurements. Ultimately, our technique represents an instance of a rich and promising new imaging modality with important potential implications for imaging science. PMID- 29715941 TI - Efficient half-harmonic generation of three-optical-cycle mid-IR frequency comb around 4 um using OP-GaP. AB - We report a broadband mid-infrared frequency comb with three-optical-cycle pulse duration centered around 4.2 um, via half-harmonic generation using orientation patterned GaP (OP-GaP) with ~43% conversion efficiency. We experimentally compare performance of GaP with GaAs and lithium niobate as the nonlinear element, and show how properties of GaP at this wavelength lead to generation of the shortest pulses and the highest conversion efficiency. These results shed new light on half-harmonic generation of frequency combs, and pave the way for generation of short-pulse intrinsically-locked frequency combs at longer wavelengths in the mid infrared with high conversion efficiencies. PMID- 29715942 TI - Magneto-optical imaging characteristics of weld defects under alternating magnetic field excitation. AB - This paper examines the characteristics of magneto-optical images of weld defects under alternating magnetic field excitation. Weld defects such as non penetration, surface cracks and sub-surface cracks were detected by a magneto optical imaging method. Magneto-optical imaging nondestructive testing experiments under alternating magnetic field excitation were carried out to detect the weld defects. Image processing methods which include contrast enhancement of original image, fused image, contrast enhancement of fused image were applied to extract the defect information of the magneto-optical images. What's more, the difference among the magneto-optical images of weld defects was obtained by contrast analysis. Experimental results show that non-penetration welding images possess significant differences in brightness and darkness, and this difference in cracks is smaller than non-penetrating ones. Under the same excitation conditions, the leakage flux of welds with non-penetration is stronger than that of weld cracks. PMID- 29715943 TI - Color rendering based on a plasmon fullerene cavity. AB - Fullerene in the plasmon fullerene cavity is utilized to propagate plasmon energy in order to break the confinement of the plasmonic coupling effect, which relies on the influential near-field optical region. It acts as a plasmonic inductor for coupling gold nano-islands to the gold film; the separation distances of the upper and lower layers are longer than conventional plasmonic cavities. This coupling effect causes the discrete and continuum states to cooperate together in a cavity and produces asymmetric curve lines in the spectra, producing a hybridized resonance. The effect brings about a bright and saturated displaying film with abundant visible colors. In addition, the reflection spectrum is nearly omnidirectional, shifting by only 5% even when the incident angle changes beyond +/- 60 degrees . These advantages allow plasmon fullerene cavities to be applied to reflectors, color filters, visible chromatic sensors, and large-area display. PMID- 29715944 TI - Analysis of high-frequency oscillations in mutually-coupled nano-lasers. AB - The dynamics of mutually coupled nano-lasers has been analyzed using rate equations which include the Purcell cavity-enhanced spontaneous emission factor F and the spontaneous emission coupling factor beta. It is shown that in the mutually-coupled system, small-amplitude oscillations with frequencies of order 100 GHz are generated and are maintained with remarkable stability. The appearance of such high-frequency oscillations is associated with the effective reduction of the carrier lifetime for larger values of the Purcell factor, F, and spontaneous coupling factor, beta. In mutually-coupled nano-lasers the oscillation frequency changes linearly with the frequency detuning between the lasers. For non-identical bias currents, the oscillation frequency of mutually coupled nano-lasers also increases with bias current. The stability of the oscillations which appear in mutually coupled nano-lasers offers opportunities for their practical applications and notably in photonic integrated circuits. PMID- 29715945 TI - Multifunctional paper strip based on GO-veiled Ag nanoparticles with highly SERS sensitive and deliverable properties for high-performance molecular detection. AB - The development of paper-based SERS substrates that can allow multi-component detection in real-word scenarios is of great value for applications in molecule detection under complex conditions. Here, a multifunctional SERS-based paper sensing substrate has been developed through the uniform patterning of high density arrays of GO-isolated Ag nanoparticles on the hydrophilic porous cellulose paper strip (GO@AgNP@paper). Wet-chemical synthesis was used to provide the cover of SERS hot spots on any part of the paper, not just limited surface deposition. In virtue of the inherent ability of paper to deliver analytes by the capillary force, the detection ability of the GO@AgNP@paper substrate was greatly promoted, allowing as low as 10-19M R6G detection from microliter-volume (50 MUL) samples. For the components with different polarity, the paper substrate can be used as an all-in-one machine to achieve the integration of separation and high sensitive detection for ultralow mixture components, which improves the practical application value of SERS-based paper devices. PMID- 29715946 TI - Directly using 8.8-km conventional multi-mode fiber for 6-mode orbital angular momentum multiplexing transmission. AB - Twisted light carrying orbital angular momentum (OAM), which featuring helical phase front, has shown its potential applications in diverse areas, especially in optical communications in free space and specially designed fibers, e.g. a vortex fiber. Instead of specially designed fibers extensively used in the reported OAM based fiber transmission experiments, here we demonstrate the viability of a conventional graded-index multi-mode fiber (MMF) for OAM multiplexing transmission with less digital signal processing (DSP) complexity. We demonstrate a 120-Gbit/s quadrature phase-shift keying (QPSK) signal transmission in an 8.8 km OM4 MMF by using OAM mode multiplexing with all the modes in the first two mode-groups (OAM01L, OAM01R, OAM+11L, OAM+11R, OAM-11L, OAM-11R) with only 2*2 and 4*4 multiple-input-multiple-output (MIMO) equalization. Moreover, we demonstrate the data-carrying two OAM mode groups multiplexing transmission over the 8.8-km MMF without MIMO equalization. These demonstrations may open up new perspectives to enable the realistic use of OAM-based MMF solution in data centers and super-computers. PMID- 29715947 TI - High frame-rate computational ghost imaging system using an optical fiber phased array and a low-pixel APD array. AB - To obtain a high imaging frame rate, a computational ghost imaging system scheme is proposed based on optical fiber phased array (OFPA). Through high-speed electro-optic modulators, the randomly modulated OFPA can provide much faster speckle projection, which can be precomputed according to the geometry of the fiber array and the known phases for modulation. Receiving the signal light with a low-pixel APD array can effectively decrease the requirement on sampling quantity and computation complexity owing to the reduced data dimensionality while avoiding the image aliasing due to the spatial periodicity of the speckles. The results of analysis and simulation show that the frame rate of the proposed imaging system can be significantly improved compared with traditional systems. PMID- 29715948 TI - Lithographic source and mask optimization with narrow-band level-set method. AB - Source and mask optimization (SMO) remains a key technique to improve the wafer image printability for technology nodes of 22 nm and beyond, enabling the continuation of the immersion lithography. In this paper, we propose a distance level-set regularized reformulation of the SMO maintaining the desired signed distance property, which secures stable curve evolution and accurate computation with a simpler and more efficient numerical implementation. Consequently, computation load caused by convolution operations and memory requirements of the electric-field caching technique (EFCT) is significantly eased by performing computation only in the narrow band; moreover, the convergence of the updating process is further improved by applying larger Euler time steps of the Courant Friedrichs-Lewy (CFL) condition with reduced optimization dimensionality. Simulation results of the proposed narrow-band level-set based SMO prove to improve the computation efficiency, memory usage and imaging performance of the full domain methods. PMID- 29715949 TI - High precision position sensor based on CPA in a composite multi-layered system. AB - We propose a scheme for high precision position sensing based on coherent perfect absorption (CPA) in a five-layered structure comprising three layers of metal dielectric composites and two spacer (air) layers. Both the outermost interfaces of the five layered medium are irradiated by two identical coherent light waves at the same angle of incidence. We first investigate the occurrence of CPA in a symmetric layered structure as a function of different system parameters for oblique incidence. Thereafter, by shifting the middle layer, beginning from one end of the structure to the other, we observe the periodic occurrence of extremely narrow CPA resonances at several positions of the middle layer. Moreover this phenomenon is seen to recur even at many other wavelengths. We discuss how the position sensitivity of this phenomenon can be utilized for designing a CPA based high precision position sensing device. PMID- 29715950 TI - Defining cylindrical space optical resonators through supported mode properties: inverse numerical process. AB - Faraday's and Ampere's laws are converted to matrix operator form and rearranged such that the unknown relative permittivity and relative permeability tensors can be determined. The material and geometry of cylindrically symmetric optical resonator structures are determined through the electric and magnetic field component profiles and complex angular frequency of a proposed localized state. This differs from the usual utilization of the electromagnetic wave equations, solving for states given the material properties and geometry. Thus the technique presented here is an inverse numerical process. The theoretical expressions are provided based on a Fourier-Bessel numerical approach which is highly suitable for cylindrical geometry resonators. Without loss of the generality of the technique, examples of resonant structure determination are presented for non magnetic and diagonal relative permittivity tensor. Axial field propagation is included to demonstrate the design capabilities related to optical fiber and photonic crystal fiber structures. PMID- 29715951 TI - Ultralow loss graphene-based hybrid plasmonic waveguide with deep-subwavelength confinement. AB - In this paper, we theoretically propose a novel graphene-based hybrid plasmonic waveguide (GHPW) consisting of a low-index rectangle waveguide between a high index cylindrical dielectric waveguide and the substrate with coated graphene on the surface. The geometric dependence of the mode characteristics on the proposed structure is analyzed in detail, showing that the proposed GHPW has a low loss and consequently a relatively long propagation distance. For TM polarization, highly confined modes guided in the low-index gap region between the graphene and the high-index GaAs and the normalized modal area is as small as 0.0018 (lambda2/4) at 3 THz. In addition to enabling the building of high-density integration of the proposed structure are examined by analyzing crosstalk in a directional coupler composed of two GHPWs. This structure also exhibits ultra-low crosstalk when a center-to-center separation between adjacent GHPWs is 32MUm, which shows great promise for constructing various terahertz integrated devices. PMID- 29715952 TI - Accuracy and stability improvement for meat species identification using multiplicative scatter correction and laser-induced breakdown spectroscopy. AB - An efficient method has been developed to identify meat species by using laser induced breakdown spectroscopy (LIBS). To improve the accuracy and stability of meat species identification, multiplicative scatter correction (MSC) was adopted to first pretreat the spectrum for correction of spectrum scatter. Then the corrected spectra were identified by using the K-nearest neighbor (KNN) model. The results showed that the identification rate improved from 94.17% to 100% and the prediction coefficient of variance (CV) decreased from 5.16% to 0.56%. This means that the accuracy and stability of meat species identification using MSC and LIBS simultaneously improved. In light of the findings, the proposed method can be a valuable tool for meat species identification using LIBS. PMID- 29715953 TI - Enhanced Back-Scatter in double-pass optical links with non-classic turbulence. AB - The average intensity, as well as the intensity-intensity correlation at one and two points of the He-Ne laser beam passing in the monostatic double-passage (21 meter long in single pass) atmospheric channel with a retro-reflector are measured experimentally. The non-classic turbulence is generated in two different ways: by means of a 1.8-meter long turbulent chamber with 3D distributed non classic turbulence and a localized hot air jet-stream applied to the beam in a transverse direction. The Enhanced Back Scatterer (EBS) effects produced by the two types of turbulence are compared as turbulence is placed at various locations along the channel. The data reveals the spatial stability of the EBS intensity in the detected beam in both cases, while the whole beam centroid generally appears to be off-centered, due to deterministic and random temperature gradients. The strongest EBS effect was observed with the localized turbulence placed close to the retro-reflector. The studied situations may appear in urban/industrial/coastal atmosphere and are of importance for free-space optical communications with retro-modulation. PMID- 29715954 TI - Holographic near-eye display system based on double-convergence light Gerchberg Saxton algorithm. AB - In this paper, a method is proposed to implement noises reduced three-dimensional (3D) holographic near-eye display by phase-only computer-generated hologram (CGH). The CGH is calculated from a double-convergence light Gerchberg-Saxton (GS) algorithm, in which the phases of two virtual convergence lights are introduced into GS algorithm simultaneously. The first phase of convergence light is a replacement of random phase as the iterative initial value and the second phase of convergence light will modulate the phase distribution calculated by GS algorithm. Both simulations and experiments are carried out to verify the feasibility of the proposed method. The results indicate that this method can effectively reduce the noises in the reconstruction. Field of view (FOV) of the reconstructed image reaches 40 degrees and experimental light path in the 4-f system is shortened. As for 3D experiments, the results demonstrate that the proposed algorithm can present 3D images with 180cm zooming range and continuous depth cues. This method may provide a promising solution in future 3D augmented reality (AR) realization. PMID- 29715955 TI - A cost-effective quasi-distributed liquid leakage sensor based on the polymer optical fiber and flexible lamp belt with LEDs. AB - A quasi-distributed liquid leakage (QDLL) sensor in local area is proposed and experimentally demonstrated, providing a real-time yet low-cost method than the existing local QDLL sensor. The sensor mainly consists of a flexible lamp belt (FLB) with light-emitting diodes (LEDs) and a polymer optical fiber (POF) processed with side-coupling structures. The side-coupling structures are illuminated by the LEDs one by one, forming a series of sensing probes. The lights are side-coupled into the POF through the side-coupling structure and pulse sequences are obtained from the power meters connected to the both ends of the POF. Each pulse represents a sensing probe, and the intensity of them increase when the coupling medium changes from air to liquid. The location of the leakage incident can be got by the position of each pulse in its output sequence. The influence of different side-coupling structures on side-coupling ratio are investigated. The experiment results validate the detection and localization abilities of the QDLL sensor along a 1 m-long POF with a spatial resolution of 0.1 m, which can be improved by adjusting the side-coupling structure. Furthermore, the temperature dependence is studied and can be compensated. PMID- 29715956 TI - Imaging through a projection screen using bi-stable switchable diffusive photon sieves. AB - We designed and demonstrated a liquid crystal (LC) photon sieve (PS) device which can be integrated on a conventional diffusive projection screen and switched to record images. The device fabrication method and assembly of it by using Smectic A (SmA) LC material is also presented. In the PS state, the device comprises diffusive elements, which simultaneously allow to image the scene in front of the device on a camera sensor behind itself and display another image projected onto the device. The image captured using the PS has acceptable visual quality. The projected images, from an external picture source, on the diffusive elements can be observed with a quality comparable to the full scattering state. The projected images are observed with almost no detectable features of the device at the observation distance. The device offers a built-in solution for eye-to-eye video conferencing applications. PMID- 29715957 TI - High-performance second-Stokes generation of a Nd:YVO4/YVO4 Raman laser based on a folded coupled cavity. AB - We report an actively Q-switched Nd:YVO4/YVO4 intracavity Raman laser at second Stokes wavelength of 1313.6 nm, which is capable of operating efficiently under pulse repetition frequency higher than 80 kHz. A folded coupled cavity is adopted to optimize the fundamental and the Stokes resonators individually and make full use of the high pump intensity on the Raman crystal. With relatively high output coupling of 82% at 1313 nm, the average output power of 5.16 W at 1313 nm is achieved under the incident pump power of 36.7 W. The cascaded Raman emission at both the first- and second-Stokes wavelength of 1176 and 1313 nm is investigated to discuss the optimization of the second-Stokes generation. PMID- 29715958 TI - Numerical investigation of narrowband infrared absorber and sensor based on dielectric-metal metasurface. AB - Metasurfaces are investigated intensively for biophotonics applications due to their resonant wavelength flexibly tuned in the near infrared region specially matching biological tissues. Here, we present numerically a metasurface structure combining dielectric resonance with surface plasmon mode of a metal plane, which is a perfect absorber with a narrow linewidth 10 nm wide and quality factor 120 in the near infrared regime. As a sensor, its bulk sensitivity and bulk figure of merit reach respectively 840 nm/RIU and 84/RIU, while its surface sensitivity and surface figure of merit are respectively 1 and 0.1/nm. For different types of adsorbate layers with the same thickness of 8 nm, its surface sensitivity and figure of merit are respectively 32.3 and 3.2/RIU. The enhanced electric field is concentrated on top of dielectric patch ends and in the patch ends simultaneously. Results show that the presented structure has high surface (and bulk) sensing capability in sensing applications due to its narrow linewidth and deep modulation depth. This could pave a new route toward dielectric-metal metasurface in biosensing applications, such as early disease detections and designs of neural stem cell sensing platforms. PMID- 29715959 TI - Power spectrum of refractive-index fluctuations in turbulent ocean and its effect on optical scintillation. AB - Recent simulations and experiments have shown that the viscous-range temperature spectrum in water can be well described by the Kraichnan spectral model. Motivated by this, a tractable expression is developed for the underwater temperature spectrum that is consistent with both the Obukhov-Corrsin law in the inertial range and the Kraichnan model in the viscous range. In analogy with the temperature spectrum, the formula for the salinity spectrum and the temperature salinity co-spectrum are also derived. The linear combination of these three scalar spectra constitutes a new form of the refractivity spectrum. This spectral model predicts a much stronger optical scintillation than the previous model. PMID- 29715960 TI - Temperature-scanning saturation cavity ring-down spectrometry for Doppler-free spectroscopy. AB - Saturation cavity ring-down spectroscopy (SCRDS) is a powerful Doppler-free spectroscopy means for measuring absolute frequencies of transitions at the ultra low uncertainties. We report in this paper a simple way to implement it by temperature scanning the cavity length, which circumvents the need for a complex optical cavity-length stabilization system based upon a piezoelectric actuator (PZT). To demonstrate this approach, the absolute frequencies of the two transitions, R6F1 of the 2v3 and Q9A1 of the 2v2 + v3 bands, of 12CH4, are determined to be 182 185 269.362(20) MHz and 182 187 617.543(39) MHz. The accuracy of measurements is improved by about 3-4 orders of magnitude when compared to those obtained with conventional spectroscopic methods. PMID- 29715961 TI - Prediction performance of reservoir computing system based on a semiconductor laser subject to double optical feedback and optical injection. AB - A reservoir computing (RC) system based on a semiconductor laser (SL) with double optical feedback and optical injection is proposed, and the prediction performance of such a system is numerically investigated via Santa Fe Time-Series Prediction task. The simulation results indicate that the RC system can yield a good prediction performance. Through optimizing some relevant operating parameters, ultra-fast information processing rates up to Gb/s level can be realized for the prediction error is below 3%. PMID- 29715962 TI - Optical gradient forces in PT-symmetric coupled-waveguide structures. AB - Optical gradient force in a parity-time (PT)-symmetric coupled-waveguide system is theoretically studied. We find that when the system evolves from PT-symmetric region to broken-PT-symmetric region, the normalized optical forces of the two eigenmodes decrease first and become the same when the exceptional point is reached. Besides, the optical force induced PT phase transition is demonstrated. It is worth noting that, when the system is in the broken-PT-symmetric region and the length of the waveguide is much longer than the propagation length of the lossy eigenmode, the total optical gradient force acting on the two waveguides will decrease with the decreasing of the gap. This work gives us a new understanding of integrated optomechanics by combining with PT symmetry. PMID- 29715963 TI - Resolution of spectral focusing in coherent Raman imaging. AB - In this manuscript, we present a detailed investigation of the impact of dispersion on the spectral resolution achievable by the application of spectral focusing in coherent Raman imaging. Our results reveal the detrimental effect of third order dispersion that limits the resolution for group delay dispersion of 100 000 fs2 and more. Experimental examples for the exact determination of the described effects are given as well as a condensed presentation of the known equations. We introduce useful approximations to the latter, which serve to facilitate the straightforward integration of spectral focusing into any multimodal microscope. PMID- 29715964 TI - Point-cloud noncontact metrology of freeform optical surfaces. AB - In this paper, we demonstrate the development of a point-cloud metrology method for the noncontact, high resolution, high precision testing of freeform surfaces. The method leverages swept source optical coherence tomography together with a common-path setup in the sample arm configured to mitigate the axial jitter caused by scanning and environmental perturbations. The lateral x-y scanning field was also rigorously evaluated for the sampling step, linearity, straightness, and orthogonality. Based on the finely engineered system hardware, a comprehensive system model was developed capable of characterizing the vertical displacement sensitivity and lateral scanning noise. The model enables predicting the point-cloud surface-metrology uncertainty map of any freeform surface and guiding the selection of optimum experimental conditions. A system was then assembled and experimentally evaluated first with flat and spherical standards to demonstrate the measurement uncertainty. Results of measuring an Alvarez freeform surface with 400-um peak-to-valley sag show 93 nm (< lambda/14) precision and 128 nm (< lambda/10) root-mean-square residual from the nominal shape. The high resolution measurements also reveal mid spatial frequency structures on the test part. PMID- 29715965 TI - Application of toluene LIF to transonic nozzle flows to identify zones of incomplete molecular mixing. AB - Toluene laser-induced fluorescence (LIF) has been applied to image the mixing deficit on the molecular level in the transonic wake of two different blunt-body injectors in a compressible accelerated nozzle flow. A single-color excitation and two-color detection scheme is employed to measure the signal red-shift caused by the quenching effect of molecular oxygen on the fluorescence of toluene, which reduces and red-shifts the LIF signal if both substances interact on a molecular level. To this end, toluene is injected alternatingly with O2-contaning and O2 free carrier gas into the air main flow. Differences of both signals mark regions where mixing on molecular level is incomplete. A zone of molecular mixing deficit extending several millimeters in stream-wise direction is identified. The effect of local variations in temperature on the sensitivity of this technique is discussed using photo-physical data measured in a stationary low-temperature cell. PMID- 29715966 TI - Raman-enhanced optical phase conjugator in WDM transmission systems. AB - Optical phase conjugation (OPC) can be applied to boost the performance of long haul transmission by mitigating the impairments from fiber nonlinearity. Unfortunately, noticeable nonlinear noise in the conjugator for optical orthogonal frequency division multiplexing (OFDM) systems often degrades the signal quality. In this paper, we demonstrate nonlinear distortion mitigation in OPC by introducing backward Raman amplification to the conjugator. Raman amplification allows a lower input signal power, thus suppressing the OPC distortion while maintaining the conjugated output power. We investigate the performances of Raman-enhanced OPC in both back-to-back (BTB) and transmission systems with 3 * 25 Gbaud optical OFDM signals. In the BTB OPC system, Raman amplification boosts the tolerance to system nonlinearity, achieving a 3-dB improvement in the output power, a 2.4-dB improvement in the Q factor, and a 6-dB improvement in the input dynamic range. In the transmission system with Raman enhanced OPC, the optimum launched power is increased by 2 dB and the maximum Q factor is increased by 0.4 dB compared to direct transmission. Similar performances are observed in all the wavelengths, indicating that our scheme works well with WDM transmission systems. PMID- 29715967 TI - Colour computer-generated holography for point clouds utilizing the Phong illumination model. AB - A technique integrating the bidirectional reflectance distribution function (BRDF) is proposed to generate realistic high-quality colour computer-generated holograms (CGHs). We build on prior work, namely a fast computer-generated holography method for point clouds that handles occlusions. We extend the method by integrating the Phong illumination model so that the properties of the objects' surfaces are taken into account to achieve natural light phenomena such as reflections and shadows. Our experiments show that rendering holograms with the proposed algorithm provides realistic looking objects without any noteworthy increase to the computational cost. PMID- 29715968 TI - Sub-10 optical-cycle passively mode-locked Tm:(Lu2/3Sc1/3)2O3 ceramic laser at 2 um. AB - A Tm-doped mixed sesquioxide ceramic laser is mode-locked near 2 um using InGaAsSb quantum-well semiconductor saturable absorber and chirped mirrors for dispersion compensation. Maximum average output power of 175 mW is achieved for a pulse duration of 230 fs at a repetition rate of 78.9 MHz with a 3% output coupler. Applying a 0.2% output coupler pulses as short as 63 fs are generated at 2.057 um. PMID- 29715969 TI - High-performance GeSn photodetector and fin field-effect transistor (FinFET) on an advanced GeSn-on-insulator platform. AB - We report the first demonstration of high-performance GeSn metal-semiconductor metal (MSM) photodetector and GeSn p-type fin field-effect transistor (pFinFET) on an advanced GeSn-on-insulator (GeSnOI) platform by complementary metal-oxide semiconductor (CMOS) compatible processes. The detection range of GeSn photodetector is extended beyond 2 um, with responsivities of 0.39 and 0.10 A/W at 1550 nm and 2003 nm, respectively. Through the insertion of an ultrathin Al2O3 Schottky-barrier-enhancement layer, the dark current IDark of the GeSn photodetector is suppressed by more than 2 orders of magnitude. An impressive IDark of ~65 nA was achieved at an operating voltage of 1.0 V. A frequency response measurement reveals the achievement of a 3-dB bandwidth of ~1.4 GHz at an illumination wavelength of 2 um. GeSn pFinFET with fin width (Wfin) scaled down to 15 nm was also fabricated on the GeSnOI platform, exhibiting a small subthreshold swing (S) of 93 mV/decade, a high drive current of 176 uA/um, and good control of short channel effects (SCEs). This work paves the way for realizing compact, low-cost, and multi-functional GeSn-on-insulator opto electronic integrated circuits. PMID- 29715970 TI - Three dimensional chiral plasmon rulers based on silver nanorod trimers. AB - The symmetry dependences of plasmon excitation modes are studied in 3D silver nanorod trimers. The degenerate plasmon modes split into chiral modes by breaking the inversion and mirror symmetry of the nanorod trimer through translation and/or rotation of the middle rod. With a translation operation, successive evolution of the circular dichroism (CD) spectrum can be achieved through gradual breaking of the inversion symmetry. An additional rotation operation produces even dramatic spectral changes due to breaking a quasi-mirror symmetry resulted from the same angular distance of the middle rod to the top and bottom rods. Especially, pairs of new chiral modes can be excited due to the contact of the middle rod with the top-bottom rod pair. The spectral changes in the simulations, which are also demonstrated experimentally, envision the 3D chiral nanorod trimer system as plasmon ruler for spatial configuration retrieval and dynamic bio process analysis at the single molecule level. PMID- 29715971 TI - Printed optical metamaterials composed of embedded silver nanoparticles for flexible applications. AB - For development of next-generation light control, a simple manufacturing technology to produce flexible metamaterials is a key component. Here, we report development of a printing method involving combination of a thermal nanoimprint method and a squeegeeing method, and demonstrate printed optical metamaterials made of commercially available ink consisting of silver nanoparticles. Optical evaluations of printed dipole resonators indicate dipole resonances corresponding to the structure lengths; these resonances are observed at wavelengths of 765 1346 nm. In particular, we report the important finding that, in metamaterials strongly affected by their constituent materials, a metamaterial structure made of the ink exhibits optical properties comparable to those produced by a vacuum deposition process. PMID- 29715972 TI - Choosing sensitivity to reduce X-ray dose in medical phase contrast imaging. AB - In medical X-ray imaging, phase contrast imaging is to measure refraction angles caused by the patient. The X-ray dose for a given image quality depends on the sensitivity of the setup, i.e. on the angular measurement range. Measurement ranges of existing phase contrast setups are either too high or too low for perfectly imaging a human finger in air: There is a gap in available measurement ranges, which prevents a reduction of X-ray dose. To fill the gap, this work proposes a novel variant of a Talbot-Lau interferometer. Instead of a single phase grating, it uses two phase gratings, each consisting of tiny prisms. The height of the prisms is an additional factor in the measurement range, which allows to fill the gap. The potential is a dose-reduction by a factor of 5.4 compared to Talbot-Lau setups of same post-patient length. Simulation results indicate a polychromatic visibility of up to 20%. PMID- 29715973 TI - Reconfigurable microwave signal processor with a phase shift of pi. AB - We propose and experimentally demonstrate a reconfigurable microwave signal processor, with a bandwidth up to tens of gigahertz. In this technique, any microwave signal processing function with a phase shift of pi could be performed by shaping the input optical intensity spectrum. The phase shift of pi is implemented by using a differential detection. Thanks to the broad bandwidth provided by the incoherent optical source and the high resolution of the user defined optical filter, the frequency response of our approach could be in a great agreement with that of an ideal signal processing function. In the experiment, temporal intensity Hilbert transformations and temporal intensity differentiations of Gaussian-like pulses with widths of 125ps, 85ps and 68ps are accurately achieved. PMID- 29715974 TI - Full-circle range and microradian resolution angle measurement using the orthogonal mirror self-mixing interferometry. AB - The self-mixing technique based on the traditional reflecting mirror has been demonstrated with great merit for angle sensing applications. In order to solve the problems of the narrow measurement angle range and low resolution in traditional angle measurement method, we proposed an angle measurement system using orthogonal mirror self-mixing interferometry combine an orthogonal mirror with designed mechanical linkage. It overcomes the shortcomings of traditional angle measurement methods and realized the angle measurement with microradian resolution in a full-circle range of 0 rad to 2pi rad. In the experiment, the measurement resolution can reach to 5.27 urad and the absolute error can lower to +/- 0.011urad, which satisfies the requirements of most high accuracy angle measurement. PMID- 29715975 TI - High resolution channeled imaging spectropolarimetry based on liquid crystal variable retarder. AB - A method for high spectral resolution channeled imaging spectropolarimetry (CISP) using a liquid crystal variable retarder (LCVR) is presented. Controlling the retardation of LCVR, the individual expanded channel, which takes up the whole detector, is obtained in each step. The resolution of recovered spectrum is increased largely, meanwhile the high resolution of image is maintained. The novel CISP system has the advantages of high throughput, compact and stable. It has no moving components and is easy to control as the retardation of LCVR is modulated by computer. The feasibility of that method is proved by the simulation results. PMID- 29715976 TI - Collisional dynamics in laser-induced plasmas: evidence for electron-impact excitation. AB - We have experimentally investigated the collisional dynamics in femtosecond-laser induced plasmas and presented the evidence for electron-impact excitation through enhanced high-order harmonic (HH) generation. The measurements were carried out by using an elliptically polarized pump pulse to induce the underdense plasmas and by using a time-delayed linearly polarized probe pulse to drive the HH generation from the plasmas. We found that the rise time of this enhanced HH generation was insensitive to the ellipticity degree (ED) of pump pulse but sensitive to its laser intensity (LI). With further comparison between physical scenarios and qualitative analysis, we demonstrated that the atomic excitation causing the HH enhancement should be attributed to the electron-impact excitation, i.e., the excitation from the collision between neutral atoms and electrons during the lifetime of the underdense plasma. PMID- 29715977 TI - Broad-band surface optical coupler based on a SiO2-capped vertically curved silicon waveguide. AB - A chip-surface optical coupler based on a vertically curved Si waveguide was demonstrated for coupling with high-numerical-aperture single-mode optical fibers with a mode-field diameter of 5 um. This device features a dome-like SiO2 coupler cap, which acts as collimation lens. We succeeded in fabricating this structure using an isotropic SiO2 deposition technique employing plasma-enhanced chemical vapor deposition and obtained a light output that approximates that of a 5-um waist Gaussian beam. The fabricated coupler showed a coupling loss of less than 4.2 dB and a 0.5-dB-loss bandwidth above 150 nm for TE-polarized light. PMID- 29715978 TI - CMOS compatible metamaterial absorbers for hyperspectral medium wave infrared imaging and sensing applications. AB - We experimentally demonstrate a CMOS compatible medium wave infrared metal insulator-metal (MIM) metamaterial absorber structure where for a single dielectric spacer thickness at least 93% absorption is attained for 10 separate bands centred at 3.08, 3.30, 3.53, 3.78, 4.14, 4.40, 4.72, 4.94, 5.33, 5.60 MUm. Previous hyperspectral MIM metamaterial absorber designs required that the thickness of the dielectric spacer layer be adjusted in order to attain selective unity absorption across the band of interest thereby increasing complexity and cost. We show that the absorption characteristics of the hyperspectral metamaterial structures are polarization insensitive and invariant for oblique incident angles up to 25 degrees making them suitable for practical implementation in an imaging system. Finally, we also reveal that under TM illumination and at certain oblique incident angles there is an extremely narrowband Fano resonance (Q > 50) between the MIM absorber mode and the surface plasmon polariton mode that could have applications in hazardous/toxic gas identification and biosensing. PMID- 29715979 TI - Incoherent beam combining of fiber lasers by an all-fiber 7 * 1 signal combiner at a power level of 14 kW. AB - We demonstrate an all-fiber 7 * 1 signal combiner with an output core diameter of 50 MUm for high power incoherent beam combining of seven self-made Yb-doped single-mode fiber lasers around a wavelength of 1080 nm and output power of 2 kW. 14.1 kW combined output power is achieved with a total transmission efficiency of higher than 98.5% and a beam quality of M2 = 5.37, which is close to the theoretical results based on finite-difference beam propagation technique. To the best of our knowledge, this is the highest output power ever reported for all fiber structure beam combining generation, which indicates the feasibility and potential of >10 kW high brightness incoherent beam combining based on an all fiber signal combiner. PMID- 29715980 TI - Highly-stable mode-locked PM Yb-fiber laser with 10 nJ in 93-fs at 6 MHz using NALM. AB - We demonstrate highly stable mode-locked Yb-doped fiber oscillators using a nonlinear amplifying loop mirror, delivering linearly polarized laser pulses with high energy at a low repetition rate of several MHz. These lasers are composed of polarization-maintaining fibers and fiber-based components without intra-cavity dispersion compensation. The spectral and temporal characteristics are systematically investigated at different repetition rates. Spectral bandwidth of 31 nm is realized in the case of 6 MHz repetition rate, and the pulse energy reaches 10 nJ. A pair of gratings compresses the output pulse to 93 fs. RMS power stability is as low as 0.04% in 10 hours, which shows excellent stability. We believe that this type of fiber oscillator is an ideal seed for further high power amplification. PMID- 29715981 TI - Saturation of water reflectance in extremely turbid media based on field measurements, satellite data and bio-optical modelling. AB - Evidence of water reflectance saturation in extremely turbid media is highlighted based on both field measurements and satellite data corrected for atmospheric effects. This saturation is obvious in visible spectral bands, i.e., in the blue, green and even red spectral regions when the concentration of suspended particulate matter (SPM) reaches then exceeds 100 to 1000 g.m-3. The validity of several bio-optical semi-analytical models is assessed in the case of highly turbid waters, based on comparisons with outputs of the Hydrolight radiative transfer model. The most suitable models allow to reproduce the observed saturation and, by inversion, to retrieve information on the SPM mass-specific inherent optical properties. PMID- 29715982 TI - Particle free optical imaging of flow field by liquid crystal polarization. AB - This paper proposes and demonstrates a particle free method for flow field visualizations by analyzing liquid crystal polarizations. The proposed concept is implemented by imaging of liquid crystal flow under microfluidic environment using a crossed polarization microscopy configuration. Fringe patterns give good representation of flow characterizations for different nozzle/diffuser microchannel designs. The obtained results demonstrate that the flow field under various conditions can be evaluated. Visualizations of the flow fields are carried out by the liquid crystal polarization induced fringe patterns in nozzle/diffuser microchannels. We achieve good match between the flow field obtained by LC polarization and the simulated one. It is envisaged that the proposed methodology can make a potential impact in flow field visualization studies and related analysis. PMID- 29715983 TI - Three-dimensional transformation optics for arbitrary coordinate systems: transforming conductive materials and boundaries. AB - A three-dimensional transformation optics method, leading to homogeneous materials, applicable to any non-Cartesian coordinate systems or waveguides/objects of arbitrary cross-sections is presented. Both the conductive boundary and internal material of the desired device is determined by the proposed formulation. The method is applicable to a wide range of waveguide, radiation, and cloaking problems, and is demonstrated for circular waveguide couplers and an external cloak. An advantage of the present method is that the material properties are simplified by appropriately selecting the conductive boundaries. For instance, a right-angle circular waveguide bend is presented which uses only one homogenous material. Also, transformation of conductive materials and boundaries are studied. The conditions in which the transformed boundaries remain conductive are discussed. In addition, it is demonstrated that negative infinite conductivity can be replaced with positive conductivity, without affecting the field outside the conductive boundary. It is also observed that a negative finite conductivity can be replaced with a positive one, by accepting some small errors. The general mathematical procedure and formulation for calculating the parametric surface equations of the conductive peripheries are presented. PMID- 29715984 TI - Estimation of suspended particulate matter in turbid coastal waters: application to hyperspectral satellite imagery. AB - An empirical algorithm is proposed to estimate suspended particulate matter (SPM) ranging from 0.675 to 25.7 mg L-1 in the turbid Pearl River estuary (PRE). Comparisons between model predicted and in situ measured SPM resulted in R2s of 0.97 and 0.88 and mean absolute percentage errors (MAPEs) of 23.96% and 29.69% by using the calibration and validation data sets, respectively. The developed algorithm demonstrated the highest accuracy when compared with existing ones for turbid coastal waters. The diurnal dynamics of SPM was revealed by applying the proposed algorithm to reflectance data collected by a moored buoy in the PRE. The established algorithm was implemented to Hyperspectral Imager for the Coastal Ocean (HICO) data and the distribution pattern of SPM in the PRE was elucidated. Validation of HICO-derived reflectance data by using concurrent MODIS/Aqua data as a benchmark indicated their reliability. Factors influencing variability of SPM in the PRE were analyzed, which implicated the combined effects of wind, tide, rainfall, and circulation as the cause. PMID- 29715985 TI - Joint atmospheric turbulence detection and adaptive demodulation technique using the CNN for the OAM-FSO communication. AB - A novel joint atmospheric turbulence (AT) detection and adaptive demodulation technique based on convolutional neural network (CNN) are proposed for the OAM based free-space optical (FSO) communication. The AT detecting accuracy (ATDA) and the adaptive demodulating accuracy (ADA) of the 4-OAM, 8-OAM, 16-OAM FSO communication systems over computer-simulated 1000-m turbulent channels with 4, 6, 10 kinds of classic ATs are investigated, respectively. Compared to previous approaches using the self-organizing mapping (SOM), deep neural network (DNN) and other CNNs, the proposed CNN achieves the highest ATDA and ADA due to the advanced multi-layer representation learning without feature extractors designed carefully by numerous experts. For the AT detection, the ATDA of CNN is near 95.2% for 6 kinds of typical ATs, in cases of both weak and strong ATs. For the adaptive demodulation of optical vortices (OV) carrying OAM modes, the ADA of CNN is about 99.8% for the 8-OAM system over the computer-simulated 1000-m free-space strong turbulent link. In addition, the effects of image resolution, iteration number, activation functions and the structure of the CNN are also studied comprehensively. The proposed technique has the potential to be embedded in charge-coupled device (CCD) cameras deployed at the receiver to improve the reliability and flexibility for the OAM-FSO communication. PMID- 29715986 TI - Double-hump solitons in fractional dimensions with a ????-symmetric potential. AB - We investigate the properties of double-hump solitons supported by the nonlinear Schrodinger equation featuring a combination of parity-time symmetry and fractional-order diffraction effect. Two classes of nonlinear states, i.e., out of-phase and in-phase solitons are found. Each class contains two families of solitons originating from the same linear mode in both focusing and defocusing nonlinear Kerr media. The critical phase-transition point increases monotonously with increasing Levy index. For strong gain and loss, out-of-phase solitons in focusing media are stable in a wide parameter window and are almost completely unstable in media with a defocusing nonlinearity. The stability of in-phase solitons is opposite to that of out-of-phase solitons. In-phase solitons in defocusing media are stable in their entire existence domains provided that the gain-loss strength is below a critical value. Meanwhile, the stability region shrinks with the decrease of Levy index. We, thus, put forward the first example of spatial solitons in fractional dimensions with a parity-time symmetry. PMID- 29715987 TI - Real-time 100 Gbps/lambda/core NRZ and EDB IM/DD transmission over multicore fiber for intra-datacenter communication networks. AB - A BiCMOS chip-based real-time intensity modulation/direct detection spatial division multiplexing system is experimentally demonstrated for both optical interconnects. 100 Gbps/lambda/core electrical duobinary (EDB) transmission over 1 km 7-core multicore fiber (MCF) is carried out, achieving KP4 forward error correction (FEC) limit (BER < 2E-4). Using optical dispersion compensation, 7 * 100 Gbps/lambda/core transmission of both non-return-to-zero (NRZ) and EDB signals over 10 km MCF transmission is achieved with BER lower than 7% overhead hard-decision FEC limit (BER < 3.8E-3). The integrated low complexity transceiver IC and analog signal processing approach make such a system highly attractive for the high-speed intra-datacenter interconnects. PMID- 29715988 TI - Coherent anti-Stokes Raman scattering as an effective tool for visualization of single-wall carbon nanotubes. AB - Strong vibrational coherent anti-Stokes Raman scattering (CARS) signal was observed in single-wall carbon nanotubes (SWCNTs) having three different average diameters (about 0.8 nm, 1.1 nm and 1.3 nm) under optical excitation close to electronic resonance energies of nanotubes. By varying the excitation power from 1 up to 200 uW an optimal regime for non-destructive investigation of nonlinear properties of SWCNTs was determined. The possibility to detect a strong coherent nonlinear signal from small SWCNT-bundles together with CARS advantages over Raman scattering, such as high imaging rate, open new opportunities for fast three-dimensional visualisation of SWCNTs in a polymer matrix. PMID- 29715989 TI - Six-state phase modulation for reduced crosstalk in a fiber optic gyroscope. AB - Electrical crosstalk in an interferometric fiber-optic gyroscope (IFOG) is regarded as the most significant factor influencing dead bands. Here, we present a six-state modulation (SSM) technique to reduce crosstalk. Compared to conventional four-state modulation (FSM) or square-wave modulation (SWM), the SSM reduces the correlation between modulation voltage and demodulation reference by separating their fundamental frequencies, and thus reduces the bias error induced by crosstalk. The measured dead band of a 1500-m IFOG is approximately 0.02 degrees /h using FSM and approximately 0.08 degrees /h using SWM, whereas there is no evidence of dead band using SSM. The IFOG using SSM also exhibits better angular random walk (ARW) and bias instability performance compared to the same IFOG using FSM or SWM. These results verify the crosstalk reduction effect of SSM. In theory, by using the relative intensity noise (RIN) suppressing technique with the optimal modulation depth of 2pi/3, the SSM can eliminate the crosstalk, which offers the potential for a high-performance IFOG with low noise, high sensitivity, wide dynamic range, and no dead band. PMID- 29715990 TI - Time-resolved multispectral imaging based on an adaptive single-pixel camera. AB - Time-resolved multispectral imaging has many applications in different fields, which range from characterization of biological tissues to environmental monitoring. In particular, optical techniques, such as lidar and fluorescence lifetime imaging, require imaging at the subnanosecond scales over an extended area. In this paper, we demonstrate experimentally a time-resolved multispectral acquisition scheme based on single-pixel imaging. Single-pixel imaging is an emerging paradigm that provides low-cost high-quality images. Here, we use an adaptive strategy that allows acquisition and image reconstruction times to be reduced drastically or full basis scans. Adaptive time-resolved multispectral imaging scheme can have significant applications in biological imaging, at scales from macroscopic to microscopic. PMID- 29715991 TI - Comparative study of high power Tm:YLF and Tm:LLF slab lasers in continuous wave regime. AB - We report on Tm:YLF and Tm:LLF slab lasers (1.5 x 11 x 20 mm3) end pumped from one end with a high-brightness 792 nm laser diode stack. These two lasers are compared under identical pump conditions in continuous-wave regime. A stronger negative thermal lens in Tm:LLF than in Tm:YLF is highlighted, making it more difficult to operate the Tm:LLF laser under stable lasing conditions. In a configuration where the high reflectivity cavity mirror has a radius of curvature of r = 150 mm, the Tm:YLF (Tm:LLF) laser produces a maximum output power of 150 W (143 W) for 428 W of incident pump power (respectively). For a second cavity configuration where the high reflectivity cavity mirror has a radius of curvature of r = 500 mm, the Tm:YLF laser produces a maximum output power of 164 W for 412 W of incident pump power and a 57% slope efficiency with respect to the absorbed pump power. The emitted wavelength of these two lasers are measured as a function of the output coupler reflectivity and it shows that Tm:LLF laser emits at a longer wavelength than Tm:YLF. PMID- 29715992 TI - Wavelength-scanning coherent OTDR for dynamic high strain resolution sensing. AB - Distributed vibration sensing in optical fibers opened entirely new opportunities and penetrated various sectors from security to seismic monitoring. Here, we demonstrate a most simple and robust approach for dynamic strain measurement using wavelength-scanning coherent optical time domain reflectometry (C-OTDR). Our method is based on laser current modulation and Rayleigh backscatter shift correlation. As opposed to common single-wavelength phase demodulation techniques, also the algebraic sign of the strain change is retrieved. This is crucial for the intended applications in structural health monitoring and modal analysis. A linear strain response down to 47.5 pepsilon and strain noise of 100 pepsilon/?Hz is demonstrated for repetition rates in the kHz range. A field application of a vibrating bridge is presented. Our approach provides a cost effective high-resolution method for structural vibration analysis and geophysical applications. PMID- 29715993 TI - Spoof plasmonic waveguide developed from coplanar stripline for strongly confined terahertz propagation and its application in microwave filters. AB - A novel planar terahertz (THz) plasmonic waveguide developed from coplanar stripline (CPS) is proposed for the first time to achieve strongly confined THz propagation performance based on the concept of spoof surface plasmon polaritons (SSPP). Guided-wave characteristics of the proposed plasmonic waveguide are theoretically investigated by eigen-mode simulation technique and finite difference time-domain solutions. It is found that the waveguide propagation characteristics can be directly manipulated by designing the SSPP unit cells, which exhibit flexible tuning ability of the asymptotic frequency and strong THz field confinement. The idea has been validated through fabricated filter experiments in microwave frequency regime by scaling up the geometry size of the proposed structure. The measured results illustrate high performance of the ultra wideband filter, in which the reflection coefficient is better than -10 dB from 3 to 13.1 GHz with the smallest and worst insertion losses of 2.2 dB and 5.6 dB, respectively. This work presents a new SSPP waveguide developed from CPS to realize the THz-wave propagation with strong field confinement, which may have promising potential applications in various integrated THz plasmonic devices. PMID- 29715994 TI - Linewidth-tolerant and multi-format carrier phase estimation schemes for coherent optical m-QAM flexible transmission systems. AB - Multi-format and linewidth-tolerant carrier phase estimation (CPE) is a vital part of digital signal processing (DSP) units for future elastic optical transmissions to relax the laser linewidth limitation. In this paper, an innovative CPE scheme outperforming existing CPEs in both universality and performance is presented and verified for multiple quadrature amplitude modulation (QAM) formats. Based on the technique of extended QPSK partitioning and quasi-linear approximation, accurate phase estimation is determined by calculating the intersection of two symmetric straight lines with very low complexity. Comprehensive simulation results of square 4/16/32/64-QAM not only demonstrate that the scheme can be applied to different modulation formats with a universal structure, i.e., indicate its flexibility in the format-adaptive elastic optical networks (EONs), but also show that the linewidth tolerance is greatly enhanced even in comparison with traditional BPS schemes. In addition, taking 64-QAM as an example, the computational efforts can be significantly reduced by a factor of 15.7 (or 10.3) in the form of multipliers (or adders). The slightly better OSNR performance is experimentally validated in polarization multiplexing 16GBaud 4/16-QAM systems respectively, which shows the potential application for flexible receiver-side DSP unit in EONs. PMID- 29715995 TI - Spatial resolution versus contrast trade-off enhancement in high-resolution surface plasmon resonance imaging (SPRI) by metal surface nanostructure design. AB - Surface plasmon resonance imaging (SPRI) is an optical near-field method used for mapping the spatial distribution of chemical/physical perturbations above a metal surface without exogenous labeling. Currently, the majority of SPRI systems are used in microarray biosensing, requiring only modest spatial resolution. There is increasing interest in applying SPRI for label-free near-field imaging of biological cells to study cell/surface interactions. However, the required resolution (sub-um) greatly exceeds what current systems can deliver. Indeed, the attenuation length of surface plasmon polaritons (SPP) severely limits resolution along one axis, typically to tens of um. Strategies to date for improving spatial resolution result in a commensurate deterioration in other imaging parameters. Unlike the smooth metal surfaces used in SPRI that support purely propagating surface modes, nanostructured metal surfaces support "hybrid" SPP modes that share attributes from both propagating and localized modes. We show that these hybrid modes are especially well-suited to high-resolution imaging and demonstrate how the nanostructure geometry can be designed to achieve sub-um resolution while mitigating the imaging parameter trade-off according to an application-specific optimum. PMID- 29715996 TI - Nonlinear equalization based on pruned artificial neural networks for 112-Gb/s SSB-PAM4 transmission over 80-km SSMF. AB - A pruning method of artificial neural network based nonlinear equalizer (ANN-NLE) is proposed and validated for single-sideband 4-ary pulse amplitude modulation (SSB-PAM4) in IM/DD system. As a classifier, ANN is capable to form a complex nonlinear boundary among different classifications, which is considered as an appropriate way to mitigate the nonlinear impairments in optical communication system. In this paper, first, we introduce the operation principle of the traditional linear equalizer (LE) and NLE such as volterra equalizer (VE). Then we make an analogy among the LE, VE and ANN-NLE. After that, a novel pruning method is applied to reduce the complexity of ANN. The BER performance of ANN-NLE outperforms VE after fiber transmission. After 60 km fiber transmission, ANN-NLE decreases the BER by about one order of magnitude compared to VE. By implementing the proposed pruning method, the connections of ANN reduced by a factor of 10x while keeping the BER under the threshold of 3.8x10-3. PMID- 29715997 TI - Faster light with competing absorption and gain. AB - We experimentally investigate the propagation of optical pulses through a fast light medium with competing absorption and gain. The combination of strong absorption and optical amplification in a potassium-based four-wave mixing process results in pulse peak advancements up to 88% of the input pulse width, more than 35* that which is achievable without competing absorption. We show that the enhancement occurs even when the total gain of the four-wave mixer is unity, thereby rendering the medium transparent. By varying the pulse width, we observe a transition between fast and slow light, and show that fast light is optimized for large pulse widths. PMID- 29715998 TI - Huygens' optical vector wave field synthesis via in-plane electric dipole metasurface. AB - We investigate Huygens' optical vector wave field synthesis scheme for electric dipole metasurfaces with the capability of modulating in-plane polarization and complex amplitude and discuss the practical issues involved in realizing multi modulation metasurfaces. The proposed Huygens' vector wave field synthesis scheme identifies the vector Airy disk as a synthetic unit element and creates a designed vector optical field by integrating polarization-controlled and complex modulated Airy disks. The metasurface structure for the proposed vector field synthesis is analyzed in terms of the signal-to-noise ratio of the synthesized field distribution. The design of practical metasurface structures with true vector modulation capability is possible through the analysis of the light field modulation characteristics of various complex modulated geometric phase metasurfaces. It is shown that the regularization of meta-atoms is a key factor that needs to be considered in field synthesis, given that it is essential for a wide range of optical field synthetic applications, including holographic displays, microscopy, and optical lithography. PMID- 29715999 TI - Conversion of retardation dispersion in self-organized smectic reactive mesogen compound and its dependence on the UV polymerization temperature and the molecular orientation. AB - We investigated the dependence of the dispersion of retardation on the UV polymerization temperature and the molecular orientation in a self-organized smectic host-guest reactive mesogen (RM) compound. The positive dispersion of retardation was converted to the negative dispersion of retardation with decreasing the UV-polymerization temperature. From the Fourier-transform infrared (FT-IR) dichroism measurement, it was found that more fractions of the guest molecules were aligned parallel to the smectic layer plane with decreasing the UV polymerization temperature. The guest molecules located in the inter-layer space absorb a longer wavelength of UV light compared to the host and induce the negative dispersion of retardation. PMID- 29716000 TI - Predictor-corrector framework for the sequential assembly of optical systems based on wavefront sensing. AB - Alignment of optical components is crucial for the assembly of optical systems to ensure their full functionality. In this paper we present a novel predictor corrector framework for the sequential assembly of serial optical systems. Therein, we use a hybrid optical simulation model that comprises virtual and identified component positions. The hybrid model is constantly adapted throughout the assembly process with the help of nonlinear identification techniques and wavefront measurements. This enables prediction of the future wavefront at the detector plane and therefore allows for taking corrective measures accordingly during the assembly process if a user-defined tolerance on the wavefront error is violated. We present a novel notation for the so-called hybrid model and outline the work flow of the presented predictor-corrector framework. A beam expander is assembled as demonstrator for experimental verification of the framework. The optical setup consists of a laser, two bi-convex spherical lenses each mounted to a five degree-of-freedom stage to misalign and correct components, and a Shack Hartmann sensor for wavefront measurements. PMID- 29716001 TI - Space-time adaptive control of femtosecond pulses amplified in a multimode fiber. AB - Ultrashort light pulse transport and amplification in a 1.3 m long step-index multimode fiber with gain and with weak coupling has been investigated. An adaptive shaping of the input wavefront, only based on the output intensity pattern, has led to an amplified pulse focused both in space (1/32) and in time (1/10) despite a strong modal group delay dispersion. Optimization of the input owing to the two-photon detection of the amplified signal permitted to excite the fastest and more intense principal mode of the fiber and to get an output pulse duration limited by group velocity dispersion. PMID- 29716002 TI - Pump-modulation-induced beam stabilization in high-power fiber laser systems above the mode instability threshold. AB - A new way of stabilizing the output beam of a fiber laser system operating above the mode instability threshold is described and the first proof-of-principle experimental results are presented. This technique, which relies on a modulation of the pump power, works by washing the thermally-induced refractive index grating out, which weakens the coupling efficiency between transverse modes. One of the main advantages of this simple, yet powerful, approach is that it can be easily incorporated in already existing fiber laser systems since it does not require any additional optical elements. Using this beam stabilization strategy, a significant pointing stability and beam quality improvement has been demonstrated up to an average power of ~600W, which is a factor of 2 above the mode instability threshold. PMID- 29716003 TI - Broadband FBG resonator seismometer: principle, key technique, self-noise, and seismic response analysis. AB - A broadband optical fiber seismometer based on FBG resonator is proposed for earthquake monitoring. The principle and key technique, high-resolution ultralow frequency wavelength interrogation by dual-laser swept frequency and beat frequency method, are discussed and analyzed. From the simulation and test results, the seismometer works at broadband range from 0.01 Hz to 10 Hz with a sensitivity of better than 330 pm/g and the wavelength resolution of the interrogation system is better than 0.001 pm/?Hz from 0.1 Hz to 10 Hz. A three channel correlation method is used to measure the self-noise of the seismometer. It reaches a noise level of 2.7 * 10-7 ms-2/?Hz@0.1 Hz, which is lower than the earth's background noise (the new high noise model, NHNM). An earthquake monitoring experiment is conducted in a low noise seismic station. The recorded seismic waves are analyzed, which suggests that the proposed seismometer has the ability to record the close microearthquake and distant great earthquake with a high signal-noise ratio (SNR). This is the first time that a FBG-based middle long period seismometer with lower self-noise than NHNM and large dynamic range (100 dB) is reported. PMID- 29716004 TI - Dynamical optical response of nematic liquid crystal cells through electrically driven Freedericksz transition: influence of the nematic layer thickness. AB - A dynamical optical characterization of planar nematic liquid-crystal cells electrically driven through the Freedericksz transition is presented. Our method involves applying voltage steps with different starting voltage close to the Freedericksz threshold. Measurements are performed on cells with various thickness, from a few microns up to 180um, and highlight the transient molecular disorder occurring close to the Freedericksz transition. We show that the transient disorder affects the molecular arrangement mainly in the reorientational plane of the splay motion induced by the planar cell geometry. Moreover, a disorder quantification in terms of optical transmission losses and temporal dynamics enables us to picture the Freedericksz transition. This characterization provides the identification of the electrical driving conditions for which the effect of the reorientational disorder is minimized. When comparing cells with various thicknesses, it results that thick cells are characterized by a much smoother transition with respect to the conventional step-like Freedericksz transition of the thin cells, hence, thick cells can be dynamically driven over a large range of voltages, even below the Freedericksz threshold. The results are discussed in view of novel electro-optical applications of thick layers of nematics. As an example, the experimental conditions for realizing a rapid birefringence scan and the achievement of a large and tunable group delay for femtosecond pulses are presented. PMID- 29716005 TI - Accurate evaluation of size and refractive index for spherical objects in quantitative phase imaging. AB - Measuring the average refractive index (RI) of spherical objects, such as suspended cells, in quantitative phase imaging (QPI) requires a decoupling of RI and size from the QPI data. This has been commonly achieved by determining the object's radius with geometrical approaches, neglecting light-scattering. Here, we present a novel QPI fitting algorithm that reliably uncouples the RI using Mie theory and a semi-analytical, corrected Rytov approach. We assess the range of validity of this algorithm in silico and experimentally investigate various objects (oil and protein droplets, microgel beads, cells) and noise conditions. In addition, we provide important practical cues for the analysis of spherical objects in QPI. PMID- 29716006 TI - Generation of tunable, high repetition rate optical frequency combs using on-chip silicon modulators. AB - We experimentally demonstrate tunable, highly-stable frequency combs with high repetition-rates using a single, charge injection based silicon PN modulator. In this work, we demonstrate combs in the C-band with over eight lines in a 20-dB bandwidth. We demonstrate continuous tuning of the center frequency in the C-band and tuning of the repetition-rate from 7.5GHz to 12.5GHz. We also demonstrate through simulations the potential for bandwidth scaling using an optimized silicon PIN modulator. We find that the time varying free carrier absorption due to carrier injection, an undesirable effect in data modulators, assists here in enhancing flatness in the generated combs. PMID- 29716007 TI - Cluster synchronization in symmetric VCSELs networks with variable-polarization optical feedback. AB - The cluster synchronization of mutually coupled vertical-cavity surface-emitting lasers (VCSELs) networks subject to variable-polarization optical feedback (VPOF) with symmetric structure is theoretically investigated. Zero-lag synchronization could be achieved between different VCSELs within same cluster in such networks, which is solely derived from the intrinsic symmetry of network topology. The influences of significant parameters of VCSELs networks on the stability of cluster synchronization are further discussed. Moreover, it is shown that the polarizer angle of optical feedback in VCSELs plays a particularly important role on the formation of cluster. PMID- 29716008 TI - Tailoring the spatio-temporal distribution of diffractive focused ultrashort pulses through pulse shaping. AB - Focusing control of ultrashort pulsed beams is an important research topic, due to its impact to subsequent interaction with matter. In this work, we study the propagation near the focus of ultrashort laser pulses of ~25 fs duration under diffractive focusing. We perform the spatio-spectral and spatio-temporal measurements of their amplitude and phase, complemented by the corresponding simulations. With them, we demonstrate that pulse shaping allows modifying in a controlled way not only the spatio-temporal distribution of the light irradiance in the focal region, but also the way it propagates as well as the frequency distribution within the pulse (temporal chirp). To gain a further intuitive insight, the role of diverse added spectral phase components is analyzed, showing the symmetries that arise for each case. In particular, we compare the effects, similarities and differences of the second and third order dispersion cases. PMID- 29716009 TI - Efficient tiled calculation of over-10-gigapixel holograms using ray-wavefront conversion. AB - In the calculation of large-scale computer-generated holograms, an approach called "tiling," which divides the hologram plane into small rectangles, is often employed due to limitations on computational memory. However, the total amount of computational complexity severely increases with the number of divisions. In this paper, we propose an efficient method for calculating tiled large-scale holograms using ray-wavefront conversion. In experiments, the effectiveness of the proposed method was verified by comparing its calculation cost with that using the previous method. Additionally, a hologram of 128K * 128K pixels was calculated and fabricated by a laser-lithography system, and a high-quality 105 mm * 105 mm 3D image including complicated reflection and translucency was optically reconstructed. PMID- 29716010 TI - Principle of beam generation in on-chip 2D beam pattern projecting lasers. AB - Integrable spatial-phase-modulating surface-emitting lasers, which utilize the band edge mode of two-dimensional photonic-crystals as resonators, project static arbitrary two-dimensional beam patterns from on-chip size. In this device, holes shifting from the lattice point of a two-dimensional photonic crystal provide spatial phase modulation to light waves, which form standing waves in the resonator. Thus far, the origin of the beam patterns has not been studied, especially the formation of subsidiary beam patterns against the designed beam pattern. In this work, we clarify the origin of beam patterns in two types of spatial phase modulating method, which impose in-plane shifting of holes according to circular and linear shift methods. Based on a theoretical study of spatial phase modulation, we reveal that the circular shift method provides a symmetric beam pattern, while the linear shift method causes an asymmetric beam pattern. Consequently, we demonstrated the asymmetric two-dimensional beam pattern by the linear shift method for the first time. PMID- 29716011 TI - Lensless Stokes holography with the Hanbury Brown-Twiss approach. AB - The recording and reconstruction of the Stokes parameter is of paramount importance for the description of the vectorial interference of light. Polarization holography provides a complete vectorial wavefront, however, direct recording and reconstruction of the hologram is not possible in a situation where the object is located behind the random scattering layer. The Stokes holography plays an important role in such situations and makes use of the Fourier transform relation between the Stokes parameters (SPs) at the scattering plane and the generalized Stokes parameters (GSPs) of the random field. In this paper, we propose and experimentally demonstrate the Stokes holography with the Hanbury Brown-Twiss (HBT) interferometer. We also propose and implement a lensless Fourier configuration for the Stokes holography. This permits us to reconstruct the wavefront from the GSPs at any arbitrary distance from the scattering plane. The application of the proposed technique is experimentally demonstrated for the 3D imaging of two different objects lying behind the random scattering medium. Depth information of the 3D objects is obtained by digitally propagating the generalized Stokes parameters to a different longitudinal distance. The quality of the reconstruction is assessed by measuring the overall visibility, efficiency, and PSNR of the reconstruction parameters. PMID- 29716012 TI - Quasi-phase-matched self-pumped optical parametric oscillation in a micro resonator. AB - Lasing and self-pumped optical parametric oscillation (self-OPO) are achieved in a high-Q whispering-gallery-mode micro-resonator, made of neodymium-doped lithium niobate. A laser process providing 5 mW output power at 1.08 MUm wavelength is sufficient to pump a self-OPO process within the same high-Q cavity. At 6 mW lasing output power, the sum of signal and idler output powers exceeds 1.2 mW. The wavelength of the generated light ranges from 1.5 to 3.8 MUm. Phase matching is provided by a radial quasi-phase-matching structure, which is generated by a current-controlled calligraphic poling technique. To the best of our knowledge, this is the first demonstration of a quasi-phase-matched self-pumped nonlinear optical process in a micro-resonator, as well as the first self-OPO in a micro resonator. The concept bears the potential for a highly integrated and wavelength tunable coherent light source at low cost. PMID- 29716013 TI - High-spatial-resolution ultrasonic sensor using a micro suspended-core fiber. AB - A high-resolution fiber-optic ultrasonic sensor based on a suspended-core fiber was designed and experimentally demonstrated. The intrinsic Fabry-Perot interferometer consisting of a micro suspended-core from acid corrosion of a grapefruit fiber proved highly sensitive to a wide range of ultrasonic wave (UW) frequencies. A compact interrogation system using spectral sideband filtering was constructed for UW detection. The sensor exhibited significantly improved spatial resolution and detection sensitivity by etching the suspended-core diameter to few microns. Sensor fabrication involves only fiber splicing and corrosion, which provide a self-shielding cladding surrounding and protecting the core from collisions. This sensor is an excellent candidate for high-quality UW detection. PMID- 29716014 TI - Continuous-wave whispering-gallery optical parametric oscillator based on CdSiP2. AB - Continuous-wave (cw) optical parametric oscillators (OPOs) are ideally suited for applications, for example high-resolution spectroscopy, that need coherent sources combining narrow-linewidth emission with good wavelength tunability. Here, we demonstrate for the first time cw OPOs based on a millimeter-sized whispering gallery resonator (WGR) made of cadmium silicon phosphide (CdSiP2). By employing a compact laser diode at 1.57-MUm wavelength for pumping, a cw OPO with wavelength tunability from 2.3 MUm to 5.1 MUm is realized based on such a resonator. The oscillation thresholds are in the milliwatt range. The maximum total power conversion efficiency reaches more than 15%. The intrinsic quality factor at 1.57 MUm is determined to be 3.5 * 106. This work suggests that CdSiP2 is a very promising alternative for constructing mid-infrared parametric devices. PMID- 29716015 TI - Composite filtering effect in a SESAM mode-locked fiber laser with a 3.2-GHz fundamental repetition rate: switchable states from single soliton to pulse bunch. AB - States that are switchable from single soliton to pulse bunch in a compact semiconductor saturable absorber mirror (SESAM) mode-locked fiber laser with a fundamental repetition rate of 3.2 GHz are experimentally investigated and further studied via simulations. A composite filtering effect comprising an intracavity low-finesse Fabry-Perot (FP) filter, an artificial optical low-pass filter, and a gain filter implements the state switching to pulse bunch. A numerical model is proposed to clarify the mechanism underlying the switching. It reveals that, for pulse interval ?T > tauA (relaxation time of the SESAM) in a pulse bunch, the laser operates in pulse-bound build up. In an inverse mechanism the state returns to single soliton, in which the ?T is obtained from the free spectral range Omegac of the intracavity FP filter by mechanically controlling the distance between the SESAM and gain fiber. This pulse bunch regime of operation ought to be amenable to a quasi-steady-state treatment. It represents an alternative emergence trait in the temporal domain between a main soliton with strong sidelobes in both sides and a bound soliton pair with weak sub-sidelobes. Another profile of the pulse bunch state is that the side peak amplitude in the autocorrelation trace is more than 50%, which is distinct and larger than that in the conventional bound state regime in fiber lasers. The optical spectra, radio frequency spectra, and frequency chirp are further analyzed. These numerical results agree well with the experimental ones within the variation range of the crucial values of Omegac and enable the explicit understanding of such behavior in SESAM mode-locked high-repetition-rate fiber lasers. PMID- 29716016 TI - Optimized criteria for angular parameter selection for the Chin-Shifrin integral transform inversion. AB - The accuracy of the particle size distribution (PSD) recovered from laser diffraction measurements by the Chin-Shifrin integral transform algorithm is reduced unless the proper angular parameters, including the lower and upper angular integration limits (thetamax and thetamin) and the angular resolution (Deltatheta), are used. To determine the selection criteria for these parameters, we use two metrics: the inversion error of the non-negative PSD, epsilon1, and the fitting error of the scattered laser light, epsilon2. By studying the variation of the minimum thetamax and epsilon2 with the particle size at different inversion errors, and by analyzing the inversion error, as thetamin and Deltatheta are varied, the optimized selection criteria for the minimum thetamax, thetamin and Deltatheta are obtained respectively. The inversion errors of the Chin-Shifrin algorithm with different selection criteria are compared, the different PSDs are recovered, and the optimal pixel selection range of the linear charge-coupled-device (CCD) array is determined according to the optimized selection criteria. Simulation results show that the optimized selection criteria for the angular parameters make the PSDs retrieved with the Chin-Shifrin algorithm more accurate. PMID- 29716017 TI - Interferometric profile measurement of optical-thickness by wavelength tuning with suppression of spatially uniform error. AB - Wavelength-tuning interferometry has been widely used for measuring the thickness variation of optical devices used in the semiconductor industry. However, in wavelength-tuning interferometry, the nonlinearity of phase shift causes a spatially uniform error in the calculated phase distribution. In this study, the spatially uniform error is formulated using Taylor series. A new 9-sample phase shifting algorithm is proposed, with which the uniform spatial phase error can be eliminated. The characteristics of 9-sample algorithm is discussed using Fourier representation and RMS error analysis. Finally, optical-thickness variation of transparent plate is measured using the proposed algorithm and wavelength-tuning Fizeau interferometer and the error is compared with 7-sample algorithm. PMID- 29716018 TI - Single-mode solarization-free hollow-core fiber for ultraviolet pulse delivery. AB - In this paper, we report anti-resonant silica hollow-core fibers (AR-HCFs) for solarization-free ultraviolet (UV) pulse transmission. The new fibers reported have lower attenuation than any previous HCFs for this spectral range. We report a single fiber that guides over a part of the UV-C and the whole of the UV-A spectral regions in adjacent transmission bands. A second AR-HCF is used for delivery of 17 nanosecond laser pulses at 266 nm at 30 kHz repetition rate. The fiber maintained a constant transmission, free of silica fluorescence and solarization-induced fiber degradation while delivering 0.46 MUJ pulses for a period of over one hour. By direct comparison, we demonstrate that the single mode AR-HCF significantly outperforms commercially-available high-OH and solarization-resistant silica multimode fibers for pulsed light delivery in this spectral range. PMID- 29716019 TI - Cascaded plasmonic superlens for far-field imaging with magnification at visible wavelength. AB - We experimentally demonstrate a novel design of a cascaded plasmonic superlens, which can directly image subwavelength objects with magnification in the far field at visible wavelengths. The lens consists of two cascaded plasmonic slabs. One is a plasmonic metasurface used for near field coupling, and the other one is a planar plasmonic lens used for phase compensation and thus image magnification. First, we show numerical calculations about the performance of the lens. Based on these results we then describe the fabrication of both sub-structures and their combination. Finally, we demonstrate imaging performance of the lens for a subwavelength double-slit object as an example. The fabricated superlens exhibits a lateral resolution down to 180 nm at a wavelength of 640 nm, as predicted by numerical calculations. This might be the first experimental demonstration in which a planar plasmonic lens is employed for near-field image magnification. Our results could open a way for designing and fabricating novel miniaturized plasmonic superlenses in the future. PMID- 29716020 TI - Column generation algorithms for virtual network embedding in flexi-grid optical networks. AB - Network virtualization provides means for efficient management of network resources by embedding multiple virtual networks (VNs) to share efficiently the same substrate network. Such virtual network embedding (VNE) gives rise to a challenging problem of how to optimize resource allocation to VNs and to guarantee their performance requirements. In this paper, we provide VNE algorithms for efficient management of flexi-grid optical networks. We provide an exact algorithm aiming to minimize the total embedding cost in terms of spectrum cost and computation cost for a single VN request. Then, to achieve scalability, we also develop a heuristic algorithm for the same problem. We apply these two algorithms for a dynamic traffic scenario where many VN requests arrive one-by one. We first demonstrate by simulations for the case of a six-node network that the heuristic algorithm obtains very close blocking probabilities to exact algorithm (about 0.2% higher). Then, for a network of realistic size (namely, USnet) we demonstrate that the blocking probability of our new heuristic algorithm is about one magnitude lower than a simpler heuristic algorithm, which was a component of an earlier published algorithm. PMID- 29716021 TI - Software-defined networking control plane for seamless integration of multiple silicon photonic switches in Datacom networks. AB - Silicon photonics based switches offer an effective option for the delivery of dynamic bandwidth for future large-scale Datacom systems while maintaining scalable energy efficiency. The integration of a silicon photonics-based optical switching fabric within electronic Datacom architectures requires novel network topologies and arbitration strategies to effectively manage the active elements in the network. We present a scalable software-defined networking control plane to integrate silicon photonic based switches with conventional Ethernet or InfiniBand networks. Our software-defined control plane manages both electronic packet switches and multiple silicon photonic switches for simultaneous packet and circuit switching. We built an experimental Dragonfly network testbed with 16 electronic packet switches and 2 silicon photonic switches to evaluate our control plane. Observed latencies occupied by each step of the switching procedure demonstrate a total of 344 us control plane latency for data-center and high performance computing platforms. PMID- 29716022 TI - Demonstration and characterization of ultrafast laser-inscribed mid-infrared waveguides in chalcogenide glass IG2. AB - The first demonstration and characterization of ultrafast laser-inscribed mid infrared (mid-IR) waveguides in Ge33As12Se55 chalcogenide glass (IG2) is presented. From mode profile and throughput measurements, combined with modelling, the characteristics of the waveguides inscribed in IG2 are studied at 7.8 MUm, and compared to those of waveguides inscribed in gallium lanthanum sulfide for reference. Two methods to estimate the local variation of refractive index induced by the inscription process are presented, which indicate a variation of ~0.010 to 0.015 across the inscription parameters investigated. This variation, together with a higher robustness of the material to inscription and large transparency covering the entire mid-IR spectral domain, suggest that IG2 has great potential for integrated optical applications in the mid-IR developed through the ultrafast laser inscription method. PMID- 29716023 TI - CdTe microwires as mid-infrared optical waveguides. AB - Cadmium telluride (CdTe) has been proven to be an attractive mid-infrared (MIR) material with a large refractive index (~2.68 at 4.5 MUm) and broadband transparency (~1 to 25 MUm). CdTe microwires (MWs) with diameters from a few to about ten micrometers were fabricated by a thermal evaporation process. MIR light was coupled into and guided through individual MWs. Excellent optical waveguiding properties of these MWs are experimentally obtained within MIR spectral range (up to 8.6 MUm), with waveguiding losses from 1.3 to 13 dB/cm. Our results show that CdTe MWs can be used as wavelength or subwavelength-width waveguides for MIR microphotonics or circuits. PMID- 29716024 TI - Spatiotemporal coherent noise in frequency-domain optical parametric amplification. AB - Frequency-domain optical parametric amplification (FOPA) is a new scheme that enables extremely broadband amplification of ultraintense pulses. The spatiotemporal coupling property of signal pulses can make the coherent noise of FOPA sharply different from that of conventional OPCPA. This paper presents a first theoretical study on the coherent noise produced in a FOPA system. We reveal that the coherent noise acquires the spatiotemporal coupling, and thus distinguishes the compressed signal pulse not only in time but also in space, which allows the suppression of coherent noise via optical manipulations in the spatial domain. The quantitative impacts of spatiotemporal coherent noise originated from the imperfections in either pump laser or crystal surfaces, are numerically studied. The result provides a new perspective on improving the coherent contrast of ultraintense lasers. PMID- 29716025 TI - Flight trajectory analysis of CuSn-droplets generated by laser drop on demand jetting, using stereoscopic high-speed imaging. AB - Laser drop on demand jetting of Cu-base braze droplets was proven a suitable method for joining wires to electrode structures of electronic devices, particularly if the electrical contacts need to withstand high thermal loads. During joining, a braze preform of 600 um diameter is placed inside a capillary, molten by a laser pulse and subsequently ejected from the capillary by inert gas overpressure similarly to conventional solder ball bumping processes. However, since the liquidus temperature of the used braze material of 990 degrees C is about 760 degrees C higher than of standard Sn-based solders used in electronics packaging, the system technology was modified significantly to enable jetting of CuSn alloys. In particular, the beam source emits a five times higher optical output power than standard machines designed for processing Sn-based solders. In addition, a modified capillary made from technical ceramic was machined, to withstand the significantly higher heating- and cooling rates during the process. In order to understand the influence of capillary geometry on droplet detachment, and flight trajectory, two capillary geometries were machined applying a picosecond laser ablation process. Subsequently, stereoscopic high speed videos of droplet detachment and flight phase were analyzed. Using this approach it is possible, to determine droplet flight trajectories, velocities and lateral positional deviations in dependency of relative inert gas overpressure inside the machining head, pulse power and capillary geometry. The findings indicate a significant influence of the capillary geometry and the applied overpressure on the droplet flight trajectory, whereas the role of the laser pulse power seems neglectable. PMID- 29716026 TI - Long working range light field microscope with fast scanning multifocal liquid crystal microlens array. AB - The light field microscope has the potential of recording the 3D information of biological specimens in real time with a conventional light source. To further extend the depth of field to broaden its applications, in this paper, we proposed a multifocal high-resistance liquid crystal microlens array instead of the fixed microlens array. The developed multifocal liquid crystal microlens array can provide high quality point spread function in multiple focal lengths. By adjusting the focal length of the liquid crystal microlens array sequentially, the total working range of the light field microscope can be much extended. Furthermore, in our proposed system, the intermediate image was placed in the virtual image space of the microlens array, where the condition of the lenslets numerical aperture was considerably smaller. Consequently, a thin-cell-gap liquid crystal microlens array with fast response time can be implemented for time multiplexed scanning. PMID- 29716027 TI - First-order optical spatial differentiator based on a guided-mode resonant grating. AB - We present an experimental demonstration of a subwavelength diffraction grating performing first-order differentiation of the transverse profile of an incident optical beam with respect to a spatial variable. The experimental results are in a good agreement with the presented analytical model suggesting that the differentiation is performed in transmission at oblique incidence and is associated with the guided-mode resonance of the grating. According to this model, the transfer function of the grating in the vicinity of the resonance is close to the transfer function of an exact differentiator. We confirm this by estimating the transfer function of the fabricated structure on the basis of the measured profiles of the incident and transmitted beams. The considered structure may find application in the design of new photonic devices for beam shaping, optical information processing, and analog optical computing. PMID- 29716028 TI - Digitally switchable multi-focal lens using freeform optics. AB - Optical technologies offering electrically tunable optical power have found a broad range of applications, from head-mounted displays for virtual and augmented reality applications to microscopy. In this paper, we present a novel design and prototype of a digitally switchable multi-focal lens (MFL) that offers the capability of rapidly switching the optical power of the system among multiple foci. It consists of a freeform singlet and a customized programmable optical shutter array (POSA). Time-multiplexed multiple foci can be obtained by electrically controlling the POSA to switch the light path through different segments of the freeform singlet rapidly. While this method can be applied to a broad range of imaging and display systems, we experimentally demonstrate a proof of-concept prototype for a multi-foci imaging system. PMID- 29716029 TI - Feature issue introduction: Advanced Solid-State Lasers 2017. AB - The Advanced Solid State Lasers 2017 Conference (ASSL) was held from October 1 to 5, 2017. It was an extraordinary conference at the Nagoya Congress Center in Nagoya, Japan. ASSL 2017 again suggested an impressive platform where miscellaneous perceptions with a variety of approaches to optics, photonics, sensing, laser technology, laser systems, and solid state lasers were presented. This international meeting was highly selective, leading to high level contributions through one plenary conference, 17 invited presentations, 70 regular talks, and 121 posters. The present joint issue of Optics Express and Optical Materials Express features 27 articles written by ASSL 2017 authors and covering the spectrum of solid-state lasers from materials research to sources, and from design innovation to applications. PMID- 29716030 TI - Ultrasonic imaging of seismic physical models using a fringe visibility enhanced fiber-optic Fabry-Perot interferometric sensor. AB - A fringe visibility enhanced fiber-optic Fabry-Perot interferometer based ultrasonic sensor is proposed and experimentally demonstrated for seismic physical model imaging. The sensor consists of a graded index multimode fiber collimator and a PTFE (polytetrafluoroethylene) diaphragm to form a Fabry-Perot interferometer. Owing to the increase of the sensor's spectral sideband slope and the smaller Young's modulus of the PTFE diaphragm, a high response to both continuous and pulsed ultrasound with a high SNR of 42.92 dB in 300 kHz is achieved when the spectral sideband filter technique is used to interrogate the sensor. The ultrasonic reconstructed images can clearly differentiate the shape of models with a high resolution. PMID- 29716031 TI - MTF measurements of a type-II superlattice infrared focal plane array sealed in a cryocooler. AB - In operational electro-optical systems, infrared focal plane arrays (IR FPA) are integrated in cryocoolers which induce vibrations that may strongly affect their modulation transfer function (MTF). In this paper, we present the MTF measurement of an IR FPA sealed in its cryocooler. The method we use to measure the MTF decorrelates operational constraints and the technological limitations of the IR FPA. The bench is based on the diffraction properties of a continuously self imaging grating (CSIG). The 26 um pixel size extracted from the MTF measurement is in good agreement with the expected value. PMID- 29716032 TI - Dual-comb spectroscopy with a single free-running thulium-doped fiber laser. AB - We demonstrate dual-comb spectroscopy in the vicinity of 2 um wavelength based on a single dual-wavelength dual-comb Thulium-doped fiber laser. The shared laser cavity ensures passively maintained mutual coherence between the two combs due to common mode environmental noise rejection. In a proof-of-principle experiment, the absorption characteristics caused by the water in the optical path that composes the dual-comb spectrometer are measured. The retrieved spectral positions of the water absorption dips match with the HITRAN database. PMID- 29716033 TI - Paraxial propagation of a class of Bessel-correlated fields. AB - The propagation of a novel class of paraxial spatially partially coherent beams exhibiting Bessel-type correlations is studied in free space and in paraxial optical systems. We show that, under certain conditions, such beams can have functionally identical forms of the absolute value of the complex degree of spatial coherence not only at the source plane and in the far zone, but also at all finite propagation distances. Under these conditions the degree of spatial coherence properties of the field is a shape-invariant quantity, but the spatial intensity distribution is only approximately shape-invariant. The main properties of this class of model beams are demonstrated experimentally by passing a coherent Gaussian beam through a rotating wedge and measuring the coherence of the ensuing beams with a Young-type interferometer realized with a digital micromirror device. PMID- 29716034 TI - Calibration of quasi-static aberrations in high-contrast astronomical adaptive optics with a pupil-modulated point-diffraction interferometer. AB - The direct detection and imaging of exoplanets requires the use of high-contrast adaptive optics (AO). In these systems quasi-static aberrations need to be highly corrected and calibrated. In order to achieve this, a high-sensitivity wavefront sensor, the pupil-modulated point-diffraction interferometer (m-PDI), is presented. This sensor modulates and retrieves both the phase and the amplitude of an incoming electric field. The theory behind the wavefront reconstruction, the visibility of fringes, chromatic effects and noise propagation are developed. Results show this interferometer has a wide chromatic bandwidth. For a bandwidth of Deltalambda = 50% in units of central wavelength, the visibility of fringes and the response of the WFS to low and high-order aberrations are almost unaffected with respect to the monochromatic case. The WFS is, in contrast, very sensitive to variations in the size of its pinhole. The size of the pinhole is shown to affect the sensor's linearity, the dynamic range and the amount of noise. Larger pinholes make the sensor less sensitive to low-order aberrations, but in turn also decrease the effects of misalignments. PMID- 29716035 TI - Study of fabrication reproducibility of two-mode optical fibers for mode division multiplexing with MIMO processing. AB - We propose a two-mode optical fiber (TMF) with a low sensitivity of differential modal group delay (DMD) to change of the core radius and the refractive index of the core in the index profile which are major factors for DMD deviation. This was done to achieve high reproducibility of fiber fabrication. The proposed TMF has a graded index (GI) core and a depressed inner cladding, and we optimize structural parameters. We fabricated different kinds of TMFs to confirm the low DMD sensitivity of our proposed fiber. The fabricated TMF showed that the DMD sensitivity to changes in core radius of the TMF was approximately 8 ps/km/MUm which is 98% smaller than that of a GI-TMF without a depressed inner cladding. PMID- 29716036 TI - Evaluation of phase retrieval approaches in magnified X-ray phase nano computerized tomography applied to bone tissue. AB - X-ray phase contrast imaging offers higher sensitivity compared to conventional X ray attenuation imaging and can be simply implemented by propagation when using a partially coherent synchrotron beam. We address the phase retrieval in in-line phase nano-CT using multiple propagation distances. We derive a method which extends Paganin's single distance method and compare it to the contrast transfer function (CTF) approach in the case of a homogeneous object. The methods are applied to phase nano-CT data acquired at the voxel size of 30 nm (ID16A, ESRF, Grenoble, France). Our results show a gain in image quality in terms of the signal-to-noise ratio and spatial resolution when using four distances instead of one. The extended Paganin's method followed by an iterative refinement step provides the best reconstructions while the homogeneous CTF method delivers quasi comparable results for our data, even without refinement step. PMID- 29716037 TI - Validation of the particle size distribution obtained with the laser in-situ scattering and transmission (LISST) meter in flow-through mode. AB - High spatial and temporal resolution estimates of the particle size distribution (PSD) in the surface ocean can enable improved understanding of biogeochemistry and ecosystem dynamics. Oceanic PSD measurements remain rare due to the time consuming, manual sampling methods of common particle sizing instruments. Here, we evaluate the utility of measuring particle size data at high spatial resolution with a commercially-available submersible laser diffraction particle sizer (LISST-100X, Sequoia Scientific), operating in an automated mode with continuously flowing seawater. The LISST PSD agreed reasonably well with discrete PSD measurements obtained with a Coulter Counter and data from the flow-through sampling Imaging Flow-Cytobot, validating our methodology. Total particulate area and Volume derived from the LISST PSD agreed well with beam-attenuation and particulate organic carbon respectively, further validating the LISST PSD. Furthermore, When compared to the measured spectral characteristics of particulate beam attenuation, we find a significant correlation. However, no significant relationship between the PSD and spectral particulate backscattering was found. PMID- 29716038 TI - Effective area measurement of few-mode fiber using far field scan technique with Hankel transform generalized for circularly-asymmetric mode. AB - We report on a measurement method for the effective area of the few-mode fiber. We derived a transform equation between a near-field pattern and a far-field pattern generalized for circularly-asymmetric higher-order modes of a cylindrical core, and enabled effective area measurement of the higher-order modes using high dynamic-range far-field scan technique and low-crosstalk mode multiplexer. The measured effective area values agreed well with the values that were numerically predicted using a finite-element method from the refractive index profile, when the modal crosstalk was suppressed. PMID- 29716039 TI - Aluminum nitride integrated photonics platform for the ultraviolet to visible spectrum. AB - We demonstrate a wide-bandgap semiconductor photonics platform based on nanocrystalline aluminum nitride (AlN) on sapphire. This photonics platform guides light at low loss from the ultraviolet (UV) to the visible spectrum. We measure ring resonators with intrinsic quality factor (Q) exceeding 170,000 at 638 nm and Q >20,000 down to 369.5 nm, which shows a promising path for low-loss integrated photonics in UV and visible spectrum. This platform opens up new possibilities in integrated quantum optics with trapped ions or atom-like color centers in solids, as well as classical applications including nonlinear optics and on-chip UV-spectroscopy. PMID- 29716040 TI - High-Q-factor Al2O3 micro-trench cavities integrated with silicon nitride waveguides on silicon. AB - We report on the design and performance of high-Q integrated optical micro-trench cavities on silicon. The microcavities are co-integrated with silicon nitride bus waveguides and fabricated using wafer-scale silicon-photonics-compatible processing steps. The amorphous aluminum oxide resonator material is deposited via sputtering in a single straightforward post-processing step. We examine the theoretical and experimental optical properties of the aluminum oxide micro trench cavities for different bend radii, film thicknesses and near-infrared wavelengths and demonstrate experimental Q factors of > 106. We propose that this high-Q micro-trench cavity design can be applied to incorporate a wide variety of novel microcavity materials, including rare-earth-doped films for microlasers, into wafer-scale silicon photonics platforms. PMID- 29716041 TI - Transverse modal control of wide-stripe high power semiconductor lasers using sampled grating. AB - A transverse Bragg resonance (TBR) waveguide semiconductor laser with sampled grating is proposed and analyzed. The transverse phase shift in the middle of the grating is realized by shifting half of the sampling period, resulting in a good single transverse mode resonance. The characteristics such as the modal gain, the electric field distribution, the near and far field beam patterns are theoretically studied. Since the sampled grating is designed by combining a uniform basic grating with a micrometer scale sampling pattern, it can be easily fabricated by holographic exposure and conventional photolithography with low cost. Therefore, the proposed method would be beneficial to volume fabrication of wide-stripe high power semiconductor lasers. PMID- 29716042 TI - Electro-optic deflectors deliver advantages over acousto-optical deflectors in a high resolution, ultra-fast force-clamp optical trap. AB - We characterized experimental artifacts arising from the non-linear response of acousto-optical deflectors (AODs) in an ultra-fast force-clamp optical trap and have shown that using electro-optical deflectors (EODs) instead eliminates these artifacts. We give an example of the effects of these artifacts in our ultra-fast force clamp studies of the interaction of myosin with actin filaments. The experimental setup, based on the concept of Capitanio et al. [Nat. Methods 9, 1013-1019 (2012)] utilizes a bead-actin-bead dumbbell held in two force-clamped optical traps which apply a load to the dumbbell to move it at a constant velocity. When myosin binds to actin, the filament motion stops quickly as the total force from the optical traps is transferred to the actomyosin attachment. We found that in our setup, AODs were unsuitable for beam steering due to non linear variations in beam intensity and deflection angle as a function of driving frequency, likely caused by low-amplitude standing acoustic waves in the deflectors. These aberrations caused instability in the force feedback loops leading to artifactual jumps in the trap position. We demonstrate that beam steering with EODs improves the performance of our instrument. Combining the superior beam-steering capability of the EODs, force acquisition via back-focal plane interferometry, and dual high-speed FPGA-based feedback loops, we apply precise and constant loads to study the dynamics of interactions between actin and myosin. The same concept applies to studies of other biomolecular interactions. PMID- 29716043 TI - Light output performance of red AlGaInP-based light emitting diodes with different chip geometries and structures. AB - We investigated the optical and electrical properties of red AlGaInP light emitting diodes (LEDs) as functions of chip size, p-cladding layer thickness, and the number of multi-quantum wells (MQWs). External quantum efficiency (EQE) decreased with decreasing chip size. The ideality factor gradually increased from 1.47 to 1.95 as the chip size decreased from 350 MUm to 15 MUm. This indicates that the smaller LEDs experienced larger carrier loss due to Shockley-Read-Hall nonradiative recombination at sidewall defects. S parameter, defined as ?lnL/?lnI, increased with decreasing chip size. Simulations and experimental results showed that smaller LEDs with 5 pairs of MQWs had over 30% higher IQE at 5 A/cm2 than the LED with 20 pairs of MQWs. These results show that the optimization of the number of QWs is needed to obtain maximum EQE of micro-LEDs. PMID- 29716044 TI - Cooperativity enhancement in buckled-dome microcavities with omnidirectional claddings. AB - We describe a theoretical study of dipole emitters inside buckled-dome Fabry Perot cavities with Si/SiO2-based omnidirectional Bragg mirrors. The low penetration depth of the mirrors contributes to low mode volumes, potentially enabling large enhancement of spontaneous emission into moderate-quality-factor cavity modes. Furthermore, the omnidirectional mirrors can significantly inhibit background emission. For a representative cavity operating in a fundamental spatial mode regime at lambda ~1550 nm, and an optimally located emitter, we predict simultaneous enhancement of emission into the cavity mode by ~120 and suppression of background emission by ~25, implying the potential for a cooperativity C ~1500. This is combined with Q ~103, significantly lower than is required to attain similar values of C without background inhibition, and thus implying better compatibility for broad line-width emitters. PMID- 29716045 TI - Plate-slot polymer waveguide modulator on silicon-on-insulator. AB - Electro-optic (EO) modulators are vital for efficient "electrical to optical" transitions and high-speed optical interconnects. In this work, we applied an EO polymer to demonstrate modulators on silicon-on-insulator substrates. The fabricated Mach-Zehnder interferometer (MZI) and ring resonator consist of a Si and TiO2 slot, in which the EO polymer was embedded to realize a low-driving and large bandwidth modulation. The designed optical and electrical constructions are able to provide a highly concentrated TM mode with low propagation loss and effective EO properties. The fabricated MZI modulator shows a pi-voltage-length product of 0.66 V.cm and a 3-dB bandwidth of 31 GHz. The measured EO activity is advantageous to exploit the ring modulator with a resonant tunability of 0.065 nm/V and a 3-dB modulation bandwidth up to 13 GHz. PMID- 29716046 TI - Designing optical 3D images encryption and reconstruction using monospectral synthetic aperture integral imaging. AB - This paper realizes an optical 3D images encryption and reconstruction by employing the geometric calibration algorithm to the monospectral synthetic aperture integral imaging system. This method has the simultaneous advantages of improving the quality of 3D images by eliminating the crosstalk from the unaligned cameras and increasing security of the multispectral 3D images encryption by importing the random generated maximum-length cellular automata into the Fresnel transform encoding algorithm. Furthermore, compared with the previous 3D images encryption methods of encrypting 3D multispectral information, the proposed method only encrypts monospectral data, which will greatly minimize the complexity. We present experimental results of 3D image encryption and volume pixel computational reconstruction to test and verify the performance of the proposed method. Experimental results validate the feasibility and robustness of our proposed approach, even under severe degradation. PMID- 29716047 TI - Electromagnetic behavior of dielectric objects on metallic periodically nanostructured substrates. AB - In this research, we investigate the electromagnetic behavior of a metallic thin film with a periodic array of subwavelength apertures when dielectric objects are located on it. The influence of size, geometry and optical properties of the objects on the transmission spectra is numerically analyzed. We study the sensitivity of this system to changes in the refractive index of the illuminated volume induced by the presence of objects with sizes from hundreds of nanometers (submicron-sized objects) to a few microns (micron-sized objects). Parameters such as the object volume within the penetration depth of the surface plasmon in the buffer medium or the contact surface between the object and the nanostructured substrate strongly affect the sensitivity. The proposed system models the presence of objects and their detection through the spectral shifts undergone by the transmission spectra. Also, we demonstrate that these can be used for obtaining information about the refractive index of a micron-sized object immersed in a buffer and located on the nanostructured sensitive surface. We believe that results found in this study can help biomedical researchers and experimentalists in the process of detecting and monitoring biological organisms of large sizes (notably, cells). PMID- 29716048 TI - Low-aberration beamline optics for synchrotron infrared nanospectroscopy. AB - Synchrotron infrared nanospectroscopy is a recently developed technique that enables new possibilities in the broadband chemical analysis of materials in the nanoscale, far beyond the diffraction limit in this frequency domain. Synchrotron infrared ports have exploited mainly the high brightness advantage provided by electron storage rings across the whole infrared range. However, optical aberrations in the beam produced by the source depth of bending magnet emission at large angles prevent infrared nanospectroscopy to reach its maximum capability. In this work we present a low-aberration optical layout specially designed and constructed for a dedicated synchrotron infrared nanospectroscopy beamline. We report excellent agreement between simulated beam profiles (from standard wave propagation and raytracing optics simulations) with experimental measurements. We report an important improvement in the infrared nanospectroscopy experiment related to the improved beamline optics. Finally, we demonstrate the performance of the nanospectroscopy endstation by measuring a hyperspectral image of a polar material and we evaluate the setup sensitivity by measuring ultra-thin polymer films down to 6 nm thick. PMID- 29716049 TI - 3D thickness distributions of plano lenses as a means of cavity pressure characterization in microinjection molding. AB - This work presents a novel nondestructive cavity pressure characterization approach in microinjection molding (MUIM) through measuring 3D part thickness distributions. For this purpose, a plano lens was designed and experiments based on Taguchi method were conducted. Both overall and local lens thickness distributions under various process conditions were analyzed in terms of their relevance with the cavity pressure during molding. Unexpectedly, a reliable linear regression model was developed fulfilling nondestructive multi-point or even continuous cavity pressure characterization with the overall lens thickness distribution. Furthermore, the topography of the constructed 3D thickness surface was found to depend on both process condition and measuring position. Finally, the process conditions were optimized for obtaining uniform distributions of both 3D thickness and cavity pressure. PMID- 29716050 TI - High-power widely tunable ps source in the visible light based on four wave mixing in optimized photonic crystal fibers. AB - We present a detailed study on the generation of widely tunable visible light through four wave mixing in specifically designed micro-structured fibers. The fiber's properties are optimized for an efficient conversion to the visible and near infrared with a combined tunability from 620 to 910 nm of a picosecond Yb doped tunable source for biomedical applications. PMID- 29716051 TI - Reflective all-sky thermal infrared cloud imager. AB - A reflective all-sky imaging system has been built using a long-wave infrared microbolometer camera and a reflective metal sphere. This compact system was developed for measuring spatial and temporal patterns of clouds and their optical depth in support of applications including Earth-space optical communications. The camera is mounted to the side of the reflective sphere to leave the zenith sky unobstructed. The resulting geometric distortion is removed through an angular map derived from a combination of checkerboard-target imaging, geometric ray tracing, and sun-location-based alignment. A tape of high-emissivity material on the side of the reflector acts as a reference that is used to estimate and remove thermal emission from the metal sphere. Once a bias that is under continuing study was removed, sky radiance measurements from the all-sky imager in the 8-14 MUm wavelength range agreed to within 0.91 W/(m2 sr) of measurements from a previously calibrated, lens-based infrared cloud imager over its 110 degrees field of view. PMID- 29716052 TI - Optofluidic droplet dye laser generated by microfluidic nozzles. AB - We present an optofluidic droplet dye laser that is generated by an array of microfluidic nozzles fabricated on a polycarbonate chip. A droplet resonator forms upon pressurizing the nozzle backside microfluidic channel. Multimode low threshold lasing is observed from individual microdroplets doped with dye. Additionally, droplets can be conveniently released from the nozzle by water rinsing from the top microfluidic channel and subsequently regenerated, and thus achieve optofluidic lasers on-demand. Our work demonstrates a new approach to generating on-chip laser source and laser arrays in a simple, reproducible, reconfigurable, and low-cost fashion. PMID- 29716053 TI - Security of subcarrier wave quantum key distribution against the collective beam splitting attack. AB - We consider a subcarrier wave quantum key distribution (QKD) system, where quantum encoding is carried out at weak sidebands generated around a coherent optical beam as a result of electro-optical phase modulation. We study security of two protocols, B92 and BB84, against one of the most powerful attacks for this class of systems, the collective beam-splitting attack. Our analysis includes the case of high modulation index, where the sidebands are essentially multimode. We demonstrate numerically and experimentally that a subcarrier wave QKD system with realistic parameters is capable of distributing cryptographic keys over large distances in presence of collective attacks. We also show that BB84 protocol modification with discrimination of only one state in each basis performs not worse than the original BB84 protocol in this class of QKD systems, thus significantly simplifying the development of cryptographic networks using the considered QKD technique. PMID- 29716054 TI - Paraxial propagation dynamics of the radially polarized Airy beams in uniaxial crystals orthogonal to the optical axis. AB - We study the paraxial propagation of the radially polarized Airy beams (RPAiBs) in uniaxial crystals orthogonal to the optical axis analytically and numerically. The propagation trajectory, the intensity and the radiation forces of the RPAiBs are investigated and the properties are elucidated by numerical examples in this paper. Results show that the RPAiBs evolve into the beams produced by the x direction electric field (RPAiXBs) and the y-direction electric field (PRAiYBs) which are totally different in uniaxial crystals. During the propagation, the intensity of the RPAiXBs transfers from the side lobe in the x-direction to the main lobe and finally returns to the side lobe in the x-direction again, but that of the RPAiYBs transfers from the side lobe in the y-direction to the main lobe and flows to the side lobe in the x-direction at last. The effect of the intensity focusing for the RPAiXBs can be modulated by the ratio of the extraordinary index (ne) to the ordinary index (no) in anisotropic medium, which contributes to the intensity focusing of the RPAiBs in a short distance a lot. We can adjust the intensity distribution especially the focusing position, the propagation trajectory and the radiation forces distributions of the RPAiXBs through choosing an appropriate value of the ratio of ne to no to meet the actual usage accordingly. PMID- 29716055 TI - 6.5 GHz Q-switched mode-locked waveguide lasers based on two-dimensional materials as saturable absorbers. AB - Two-dimensional (2D) materials have generated great interest in the past few years opening up a new dimension in the development of optoelectronics and photonics. In this paper, we demonstrate 6.5 GHz fundamentally Q-switched mode locked lasers with high performances in the femtosecond laser-written waveguide platform by applying graphene, MoS2 and Bi2Se3 as saturable absorbers (SAs). The minimum mode-locked pulse duration was measured to be as short as 26 ps in the case of Bi2Se3 SA. The maximum slope efficiency reached 53% in the case of MoS2 SA. This is the first demonstration of Q-switched mode-locked waveguide lasers based on MoS2 and Bi2Se3 in the waveguide platform. These high-performance Q switched mode-locked waveguide lasers based on 2D materials pave the way for practical applications of compact ultrafast photonics. PMID- 29716056 TI - Free space quantum key distribution using modulating retro-reflectors. AB - Quantum key distribution (QKD) can be used to produce a cryptographic key whose security is guaranteed by quantum mechanics. The range of fiber-based QKD links is limited, by loss, to a few hundred kilometers, and cannot be used between mobile platforms. Free space QKD can, in principle, overcome these limitations. In practice, very narrow beam divergences must be used, requiring highly accurate pointing of the transmitting terminal to the receiver. This makes deployment very difficult. Here we describe the experimental implementation of a new type of free space QKD link, using modulating retro-reflectors (MRR). The MRR-QKD link eases the pointing requirements by more than three orders of magnitude, from microradians to degrees, while maintaining the narrow beam divergence necessary for long-range communication links. The system uses new, high extinction surface normal multiple quantum well modulators with a modulation rate of 100 MHz. A laboratory-based BB84 QKD link using multiple quantum well MRRs is demonstrated, link budgets for possible applications are discussed, and security issues are considered. PMID- 29716057 TI - Ewald sphere construction for structural colors. AB - Disordered structures producing a non-iridescent color impression have been shown to feature a spherically shaped Fourier transform of their refractive-index distribution. We determine the direction and efficiency of scattering from thin films made from such structures with the help of the Ewald sphere construction which follows from first-order scattering approximation. This way we present a simple geometrical argument why these structures are well suited for creating short wavelength colors like blue but are hindered from producing long wavelength colors like red. We also numerically synthesize a model structure dedicated to produce a sharp spherical shell in reciprocal space. The reflectivity of this structure as predicted by the first-order approximation is compared to direct electromagnetic simulations. The results indicate the Ewald sphere construction to constitute a simple geometrical tool that can be used to describe and to explain important spectral and directional features of the reflectivity. It is shown that total internal reflection in the film in combination with directed scattering can be used to obtain long wavelength structural colors. PMID- 29716058 TI - Benchmarking five numerical simulation techniques for computing resonance wavelengths and quality factors in photonic crystal membrane line defect cavities. AB - We present numerical studies of two photonic crystal membrane microcavities, a short line-defect cavity with a relatively low quality (Q) factor and a longer cavity with a high Q. We use five state-of-the-art numerical simulation techniques to compute the cavity Q factor and the resonance wavelength lambda for the fundamental cavity mode in both structures. For each method, the relevant computational parameters are systematically varied to estimate the computational uncertainty. We show that some methods are more suitable than others for treating these challenging geometries. PMID- 29716059 TI - Colloidal crystal order and structure revealed by tabletop extreme ultraviolet scattering and coherent diffractive imaging. AB - Colloidal crystals with specific electronic, optical, magnetic, vibrational properties, can be rationally designed by controlling fundamental parameters such as chemical composition, scale, periodicity and lattice symmetry. In particular, silica nanospheres -which assemble to form colloidal crystals- are ideal for this purpose, because of the ability to infiltrate their templates with semiconductors or metals. However characterization of these crystals is often limited to techniques such as grazing incidence small-angle scattering that provide only global structural information and also often require synchrotron sources. Here we demonstrate small-angle Bragg scattering from nanostructured materials using a tabletop-scale setup based on high-harmonic generation, to reveal important information about the local order of nanosphere grains, separated by grain boundaries and discontinuities. We also apply full-field quantitative ptychographic imaging to visualize the extended structure of a silica close packed nanosphere multilayer, with thickness information encoded in the phase. These combined techniques allow us to simultaneously characterize the silica nanospheres size, their symmetry and distribution within single colloidal crystal grains, the local arrangement of nearest-neighbor grains, as well as to quantitatively determine the number of layers within the sample. Key to this advance is the good match between the high harmonic wavelength used (13.5nm) and the high transmission, high scattering efficiency, and low sample damage of the silica colloidal crystal at this wavelength. As a result, the relevant distances in the sample - namely, the interparticle distance (~124nm) and the colloidal grains local arrangement (~1MUm) - can be investigated with Bragg coherent EUV scatterometry and ptychographic imaging within the same experiment simply by tuning the EUV spot size at the sample plane (5MUm and 15MUm respectively). In addition, the high spatial coherence of high harmonics light, combined with advances in imaging techniques, makes it possible to image near-periodic structures quantitatively and nondestructively, and enables the observation of the extended order of quasi-periodic colloidal crystals, with a spatial resolution better than 20nm. In the future, by harnessing the high time resolution of tabletop high harmonics, this technique can be extended to dynamically image the three-dimensional electronic, magnetic, and transport properties of functional nanosystems. PMID- 29716060 TI - Improving performance of differential pulse coding modulation based digital mobile fronthaul employing noise shaping. AB - A differential pulse coding modulation with noise shaping (NS-DPCM) is proposed to achieve better error vector magnitude (EVM) performance in a digital mobile fronthaul. Compared to previous DPCM based digital mobile fronthaul, a feedback loop combined with a finite-impulse-response (FIR) filter is added to the quantizer of DPCM encoder to operate as a quantization noise shaping technique block. The noise shaping technique increases the signal-to-quantization noise ratio by reshaping the spectrum of the quantization noise. Therefore, the noise power is at a lower level in subcarriers of OFDM signal where data is modulated and at a higher level in the subcarriers where no data is modulated. Different from the noise shaping of delta-sigma modulation, the proposed scheme utilizes the existence of unused subcarriers of OFDM signal, thus does not require oversampling at the transmitter and low pass filter at the receiver. In the experiment, the proposed NS-DPCM based mobile fronthaul transmission is demonstrated in a 25-Gb/s PAM-4 intensity modulation-direct detection optical link. Compared to the existing DPCM based mobile fronthaul, significant EVM performance improvement is achieved using the same number of quantization bits. PMID- 29716061 TI - Objective visual comfort evaluation method based on disparity information and motion for stereoscopic video. AB - In this paper, we propose an objective evaluation method which considers three major factors affecting the visual comfort of viewing a stereoscopic video: the horizontal disparity, the vertical disparity, and the motion. Three experiments are conducted which aim to investigate the effect of three factors on visual comfort. The experimental results show that the visual comfort decreases with increasing the disparity magnitude and motion velocity. Both fast planar motion and depth motion have a negative impact on visual comfort. Finally, we verify the performance of the proposed whole evaluation measure. The experimental results show that the proposed objective evaluation method exhibits good consistency with the subjective evaluation results. PMID- 29716062 TI - Enhanced light extraction of plastic scintillator using large-area photonic crystal structures fabricated by hot embossing. AB - Plastic scintillators are widely used in various radiation measurement systems. However, detection efficiency and signal-to-noise are limited due to the total internal reflection, especially for weak signal detection situations. In the present investigation, large-area photonic crystals consisting of an array of periodic truncated cone holes were prepared based on hot embossing technology aiming at coupling with the surface of plastic scintillator to improve the light extraction efficiency and directionality control. The experimental results show that a maximum enhancement of 64% at 25 degrees emergence angle along Gamma-M orientation and a maximum enhancement of 58% at 20 degrees emergence angle along Gamma-K orientation were obtained. The proposed fabrication method of photonic crystal scintillator can avoid complicated pattern transfer processes used in most traditional methods, leading to a simple, economical method for large-area preparation. The photonic crystal scintillator demonstrated in this work is of great value for practical applications of nuclear radiation detection. PMID- 29716063 TI - Intermittent burst of a super rogue wave in the breathing multi-soliton regime of an anomalous fiber ring cavity. AB - We report the intermittent burst of a super rogue wave in the multi-soliton (MS) regime of an anomalous-dispersion fiber ring cavity. We exploit the spatio temporal measurement technique to log and capture the shot-to-shot wave dynamics of various pulse events in the cavity, and obtain the corresponding intensity probability density function, which eventually unveils the inherent nature of the extreme events encompassed therein. In the breathing MS regime, a specific MS regime with heavy soliton population, the natural probability of pulse interaction among solitons and dispersive waves exponentially increases owing to the extraordinarily high soliton population density. Combination of the probabilistically started soliton interactions and subsequently accompanying dispersive waves in their vicinity triggers an avalanche of extreme events with even higher intensities, culminating to a burst of a super rogue wave nearly ten times stronger than the average solitons observed in the cavity. Without any cavity modification or control, the process naturally and intermittently recurs within a time scale in the order of ten seconds. PMID- 29716064 TI - Fourier-based solving approach for the transport-of-intensity equation with reduced restrictions. AB - The transport-of-intensity equation (TIE) has been proven as a standard approach for phase retrieval. Some high efficiency solving methods for the TIE, extensively used in many works, is based on a Fourier transform (FT). However, several assumptions have to be made to solve the TIE by these methods. A common assumption is that there are no zero values for the intensity distribution allowed. The two most widespread Fourier-based approaches have further restrictions. One of these requires the uniformity of the intensity distribution and the other assumes the parallelism of the intensity and phase gradients. In this paper, we present an approach, which does not need any of these assumptions and consequently extends the application domain of the TIE. PMID- 29716065 TI - Dirac semimetals based tunable narrowband absorber at terahertz frequencies. AB - In this paper, a bulk Dirac semimetals (BDSs) based tunable narrowband absorber at terahertz frequencies is proposed and it has the attractive property of being polarization-independent at normal incidence because of its 90 degrees rotational symmetry. Numerical results show that the absorption bandwidth is about 1.469e-2 THz and the total quality factor Q, defined as Q = f0/Deltaf, reaches about 94.6, which can be attributed to the low power loss of the guided mode resonance in the dielectric layer. The simulation results are analyzed with coupled mode theory. Interestingly, on the premise of maintaining the absorbance at a level greater than 0.95, the absorption frequency can be tuned from 1.381 to 1.395 THz by varying the Fermi energy of BDSs from 50 to 80 meV. Our results may also provide potential applications in optical filter and bio-chemical sensing. PMID- 29716066 TI - Colour gamut mapping between small and large colour gamuts: Part I. gamut compression. AB - This paper describes an investigation into the performance of different gamut compression algorithms (GCAs) in different uniform colour spaces (UCSs) between small and large colour gamuts. Gamut mapping is a key component in a colour management system and has drawn much attention in the last two decades. Two new GCAs, i.e. vividness-preserved (VP) and depth-preserved (DP), based on the concepts of 'vividness' and 'depth' are proposed and compared with the other commonly used GCAs with the exception of spatial GCAs since the goal of this study was to develop an algorithm that could be implemented in real time for mobile phone applications. In addition, UCSs including CIELAB, CAM02-UCS, and a newly developed UCS, Jzazbz, were tested to verify how they affect the performance of the GCAs. A psychophysical experiment was conducted and the results showed that one of the newly proposed GCAs, VP, gave the best performance among different GCAs and the Jzazbz is a promising UCS for gamut mapping. PMID- 29716067 TI - Fiber in-line Mach-Zehnder interferometer based on a pair of short sections of waveguide. AB - A fiber in-line Mach-Zehnder interferometer based on a pair of femtosecond laser inscribed short sections of waveguide is presented. One short waveguide directs part of the propagating light from the fiber core to the cladding-air interface, and experiences multiple total internal reflections before taking back to the fiber core by the other short waveguide. The device is robust in structure, can be fabricated in a fast way and with a flexible manner, and has the capability of ambient refractive index sensing, which makes it highly desirable for many "lab in-fiber" applications. PMID- 29716068 TI - High-power modular LED-based illumination systems for mask-aligner lithography. AB - Mask-aligner lithography is traditionally performed using mercury arc lamps with wavelengths ranging from 250 nm to 600 nm with intensity peaks at the i, g and h lines. Since mercury arc lamps present several disadvantages, it is of interest to replace them with high power light emitting diodes (LEDs), which recently appeared on the market at those wavelengths. In this contribution, we present a prototype of an LED-based mask-aligner illumination. An optical characterization is made and the prototype is tested in a mask-aligner. Very good performances are demonstrated. The measured uniformity in the mask plane is 2.59 +/- 0.24 % which is within the uniformity of the standard lamp. Print tests show resolution of 1 micron in contact printing and of 3 microns in proximity printing with a proximity gap of 30 microns. PMID- 29716069 TI - Optical fiber micro-connector with nanometer positioning precision for rapid prototyping of photonic devices. AB - Prototyping of fiber-coupled integrated photonic devices requires robust and reliable way of docking optical fibers to other structures, often with sub-micron accuracy. We have developed an optical fiber micro-connector 3D-printed with Direct Laser Writing on a planar substrate. The connector provides fiber core precision positioning better than 120 nm and sustains cryogenic cycling without any signs of degradation. It can be fabricated and used on glass and non transparent substrates, including photonic integrated circuits, semiconductor samples, and microfluidic systems. PMID- 29716070 TI - Nonlinear error correction for FMCW ladar by the amplitude modulation method. AB - FMCW ladar is a kind of absolute distance measurement technology with high spatial resolution. However, the advantage of high spatial resolution is significantly covered up by the non-linearity of laser frequency sweep. One of the typical approaches for the nonlinearity is resample technology, which has residual phase error from the sample time delay mismatch between the clock signal and the measurement signal. We have proposed and demonstrated a novel amplitude modulation method for correcting the nonlinear error of FMCW technology. The optical structure of the method is comprised of two tandem fiber interferometers. The first interferometer is used to produce a carrier signal and the second one is used to load the range information on the amplitude of the carrier signal. In the end, the experimental result verifies that the nonlinear error can be suppressed effectively, the phase error from the mismatch has been eliminated observably, and the range resolution can be notably improved to 69MUm; the stability is 2.9MUm and the measurement precision is 4.3MUm. PMID- 29716071 TI - Thermally controlled Si photonic crystal slow light waveguide beam steering device. AB - The doubly periodic Si photonic crystal waveguide radiates the guided slow light into free space as an optical beam. The waveguide also functions as a beam steering device, in which the steering angle is changed substantially by a slight variation in the wavelength generated due to the large angular dispersion of the slow light. A similar function is obtained when the wavelength is fixed and the refractive index of the waveguide is changed. In this study, we tested two kinds of integrated heater structures and observed the beam steering using the thermo optic effect. For a p-i-p doped waveguide, the heating current was made to flow directly across the waveguide and a beam steering range of 21 degrees was obtained with a relatively low heating power and high-speed response of the order of 100 kHz, maintaining a narrow beam divergence of 0.1-0.3 degrees and a 120 resolution points. We also performed a preliminary life test of the device but did not observe any severe degradation in the temperature variation of 80-430 K for the duration up to 20-40 h. For a TiN heater device, we obtained the comparable beam steering characteristics, but the required heating power increased, and the response speed decreased drastically. PMID- 29716072 TI - Electro-optic phase matching in a Si photonic crystal slow light modulator using meander-line electrodes. AB - We demonstrate a Si photonic crystal waveguide Mach-Zehnder modulator that incorporates meander-line electrodes to compensate for the phase mismatch between slow light and RF signals. We first employed commonized ground electrodes in the modulator to suppress undesired fluctuations in the electro-optic (EO) response due to coupled slot-line modes of RF signals. Then, we theoretically and experimentally investigated the effect of the phase mismatch on the EO response. We confirmed that meander-line electrodes improve the EO response, particularly in the absence of internal reflection of the RF signals. The cut-off frequency of this device can reach 27 GHz, which allows high-speed modulation up to 50 Gbps. PMID- 29716073 TI - Estimation of the depth limit for percussion drilling with picosecond laser pulses. AB - We present a model to predict the final depth of percussion-drilled holes that are produced with picosecond laser pulses in metals. It is based on the assumption that boreholes always have conical geometries when the drilling process terminates. We show that the model is valid for various process parameters when drilling in stainless steel. This was even confirmed by drilling with 3 mJ pulses, which resulted in a 10 mm deep borehole without thermal damage. PMID- 29716074 TI - Design of retinal-projection-based near-eye display with contact lens. AB - We propose a design of a retinal-projection-based near-eye display for achieving ultra-large field of view, vision correction, and occlusion. Our solution is highlighted by a contact lens combo, a transparent organic light-emitting diode panel, and a twisted nematic liquid crystal panel. Its design rules are set forth in detail, followed by the results and discussion regarding the field of view, angular resolution, modulation transfer function, contrast ratio, distortion, and simulated imaging. PMID- 29716075 TI - All MBE grown InAs/GaAs quantum dot lasers on on-axis Si (001). AB - Directly grown III-V quantum dot (QD) laser on on-axis Si (001) is a good candidate for achieving monolithically integrated Si photonics light source. Nowadays, laser structures containing high quality InAs / GaAs QD are generally grown by molecular beam epitaxy (MBE). However, the buffer layer between the on axis Si (001) substrate and the laser structure are usually grown by metal organic chemical vapor deposition (MOCVD). In this paper, we demonstrate all MBE grown high-quality InAs/GaAs QD lasers on on-axis Si (001) substrates without using patterning and intermediate layers of foreign material. PMID- 29716076 TI - Broadband full-color multichannel hologram with geometric metasurface. AB - Due to the abilities of manipulating the wavefront of light with well-controlled amplitude, and phase and polarization, optical metasurfaces are very suitable for optical holography, enabling applications with multiple functionalities and high data capacity. Here, we demonstrate encoding two- and three-dimensional full color holographic images by an ultrathin metasurface hologram whose unit cells are subwavelength nanoslits with spatially varying orientations. We further show that it is possible to achieve full-color holographic multiplexing with such kind of geometric metasurfaces, realized by a synthetic spectrum holographic algorithm. Our results provide an efficient way to design multi-color optical display elements that are ready for fabrication. PMID- 29716077 TI - Semi-quantum noise randomized data encryption based on an amplified spontaneous emission light source. AB - The first semi-quantum noise randomized cipher based on amplified spontaneous emission (ASE) light source employing Y-00 protocol is proposed and demonstrated by a proof-of-principle experiment. As the signal carrier, ASE light can provide another fundamental uncertainty, namely, self-beating noise of ASE signal, which is much bigger than quantum shot noise of mesoscopic coherent state and also inevitable. By incorporating both the shot noise and beat noise of ASE signals, the security will be improved with a larger number of masked signals (NMS) under intrinsic noise. After formulating NMS and Q-factor in theory, we investigate the impacts of key system parameters on the security and transmission performances, respectively, in order to optimize the system design. To evidence the theoretical results, an experimental setup with balanced photodetector (BPD) as decoder is constructed. The local light modulated by M/2-ary running key is applied as optical threshold signal, which is fed into BPD together with the M-ary ASE signal, outputting the binary signal. Eventually, a 128-level Y-00 realization based on ASE source is realized at 2.5Gb/s over 100-km fiber. The experimental results agree with the theory in the trend, which indicate the validity and feasibility of the proposed scheme. PMID- 29716078 TI - Increasing data rate of an optical IMDD system using a cost-efficient dual-band transmission scheme based on RTZ DAC and sub-Nyquist sampling ADC. AB - A cost-efficient dual-band transmission scheme based on return-to-zero (RTZ)-mode digital-to-analog converter (DAC) and sub-Nyquist sampling analog-to-digital converter (ADC) is proposed in this paper. The scheme can increase the data rate and meanwhile halve the required sampling rate of the DAC/ADC in optical intensity modulation direct detection (IMDD) transmission system. Based on this scheme, we experimentally demonstrate a dual-band discrete Fourier transformation spread (DFT-S) OFDM intensity modulation direct detection (IMDD) system. Although the sampling rate of the DAC and ADC used in the receiver is only 5-GSa/s and there is no mixer and oscillator at the transmitter and receiver side, 22-km standard single-mode fiber (SSMF) transmission with up to 26.33-Gb/s data rate is successfully realized. The experimental results show that in the system, the first sub-band transmission based on 128-QAM mapping can achieve a bit error rate (BER) below 3.8 * 10-3. The second sub-band transmission based on 32-QAM mapping can achieve a BER below 2.4 * 10-2. The spectral efficiency (SE) of the first sub band signal is up to 6.14 bit/s/Hz and the SE of the second sub-band signal is up to 4.39 bit/s/Hz. PMID- 29716079 TI - Novel localized vibration-assisted magnetic abrasive polishing method using loose abrasives for V-groove and Fresnel optics finishing. AB - This paper presents a new localized vibration-assisted magnetic abrasive polishing (VAMAP) method using loose abrasives for V-groove and Fresnel optics finishing. The purpose is to improve the surface quality while maintaining the form of the microfeatures. This method allows abrasives to access the corners of the microfeatures and remove materials locally and uniformly by effectively controlling the magnetic field and vibration which overcomes the limitations of previous research. By using loose abrasives, the method achieved nanometer level surface roughness and damage-free surface while maintaining the form of the microfeatures. The results show that the surface roughness was reduced to about 7 nm Ra from the initial value of over 10 nm Ra while the microfeatures of V-groove and Fresnel optics were well maintained. At the same time, the surface defects including voids, scratches as well as tool marks were clearly removed. PMID- 29716080 TI - Optical bistability based on hyperbolic metamaterials. AB - We numerically demonstrate optical bistability in a nonlinear multilayer structure by utilizing the unique dispersion of hyperbolic metamaterials. The linear transmission is varied sharply with topological transition of isofrequency contour of the multilayer structure, and this non-resonant scheme enables realization of optical bistability with a short response time and a relatively low switching intensity. We have investigated exhaustively all possible topological transitions in the dispersion characteristics of the multilayer structure for optical bistability, and shown that the hyperbolic metamaterial (HMM) type transition from Type II to Type I, and the transition from Type II HMM to effective dielectric are suitable for realizing high-performances optical bistability. The proposed schemes can overcome the trade-off between a switching intensity and a response time in resonance based optical bistabilities. PMID- 29716081 TI - Flexible and tunable terahertz all-dielectric metasurface composed of ceramic spheres embedded in ferroelectric/ elastomer composite. AB - Terahertz (THz) all-dielectric metasurfaces made of high-index and low-loss resonators have attracted more and more attention due to their versatile properties. However, the all-dielectric metasurfaces in THz suffer from limited bandwidth and low tunability. Meanwhile, they are usually fabricated on flat and rigid substrates, and consequently their applications are restricted. Here, a simple approach is proposed and experimentally demonstrated to obtain a flexible and tunable THz all-dielectric metasurface. In this metasurface, micro ceramic spheres (ZrO2) are embedded in a ferroelectric (strontium titanate) / elastomer (polydimethylsiloxane) composite. It is shown that the Mie resonances in micro ceramic spheres can be thermally and reversibly tuned resulting from the temperature dependent permittivity of the ferroelectric / PDMS composite. This metasurface characterized by flexibility and tunability is expected to have a more extensive application in active THz devices. PMID- 29716082 TI - Multimode and single-mode fiber compatible graded-index multicore fiber for high density optical interconnect application. AB - We designed and fabricated a graded-index (GI) multicore fiber (MCF) compatible with both standard multimode and single-mode fiber for high density optical interconnect application in large-scale data centers. The proposed fiber supports long-distance multimode transmission at 850 nm as well as quasi-single mode transmission at 1310 nm and 1550 nm. The parameters of the GI-MCF have been optimized to obtain both a small differential mode delay at 850 nm and a small mode field diameter mismatch of less than 0.5 MUm with single-mode fiber at 1310 nm and 1550 nm with a negligible inter-core crosstalk. In experiment, we successfully realized the multimode operation over 1 km-long GI-MCF at 850 nm and the quasi-single mode operation over 12.4 km-long GI-MCF at 1310 nm and 1550 nm at a data rate of 7*10-Gb/s. The multi-wavelengths multicore transmission was demonstrated for the first time. The experiment results imply that the proposed GI-MCF satisfies various requirements in such as operating wavelength, accessible distance and interconnect density of large-scale data center, and can effectively reduce the fiber numbers and system complexity. PMID- 29716083 TI - Through-focus scanning optical microscopy with the Fourier modal method. AB - We propose a Fourier modal method (FMM) based through-focus scanning optical microscopy (TSOM) featuring sub-nano scale measurement tolerance. TSOM is very recently conceptualized non-destructive optical metrology technique just at the beginning stage of research. Nowadays the reliability and feasibility of TSOM concept is subject to controversy. We experimentally demonstrate stable nano scale metrology of the FMM-based TSOM for the verification of the TSOM metrology and provide a numerical tool for true nano-meter scale TSOM through devising the FMM based TSOM scheme. By considering the illumination light parameters of incidence angle, polarization, degree of coherence, illumination numerical aperture, and collection numerical apertures in the FMM modeling of TSOM image acquisition, we reach precise agreement between the calculated and experimentally measured TSOM images. The essential elements of the FMM based TSOM for achieving high-level consistency are elucidated. PMID- 29716084 TI - Enhanced dual-band absorption of molybdenum disulfide using a plasmonic perfect absorber. AB - In order to remarkably enhance its absorption capability, a tunable dual-band MoS2-based perfect absorber inspired by metal-insulator-metal (MIM) metamaterial is proposed. By using the finite-difference time-domain (FDTD) simulations, dual band perfect absorption peaks are realized in the visible light regime, and the absorptions of monolayer MoS2 are enhanced up to 57% and 80.5% at the peak wavelengths. By manipulating related structural parameters, the peak wavelengths of MoS2 absorption can be separately tuned in a wide wavelength range. Furthermore, the proposed absorber can tolerate a relatively wide range of incident angles and demonstrate polarization-dependence. PMID- 29716085 TI - Stability and internal interaction of multipole solitons in nonlocal PT-symmetric lattices. AB - We investigate the existence, stability and internal interaction of two dimensional multipole solitons in defocusing PT symmetric nonlocal nonlinear media. Compared with nonlocal fundamental solitons in PT-symmetric lattices, the multipole solitons reveal the novel internal interaction such as the oscillation of the gravity center. We consider the change of the gravity center of dipole solitons during propagation, and find that these dipole solitons have "breather like" or "competition" behavior in different nonlinearities. We also demonstrate that dipole solitons are easier to be stabilized under the intermediate nonlocality. Moreover, two more complicated multipole solitons are studied and it is found that there also exist the novel internal interaction for the multipole solitons. PMID- 29716086 TI - Second harmonic generation with full Poincare beams. AB - We report a concise yet efficient experiment to extend the study of full Poincare beams to incorporate the nonlinear optical effect. The main feature of our scheme is the employment of Type-II phase-matching KTP crystal to implement the second harmonic generation with structured vector light from invisible to visible region. Of particular interest is the revelation and visualization of the hidden topological structures transferred from the input polarization state to the output observable intensity patterns. The experimental results are in good agreement with the numerical simulations. Our present work provides us with the insight into the interaction of full Poincare beams with media in the nonlinear regime. PMID- 29716087 TI - High-order soliton evolution and pulse breaking-recovery in stretched ultrafast fiber lasers. AB - We present a new pulse regime in a stretched ultrafast fiber laser based on numerical simulations. The pulse breaking due to high-order soliton evolution in the passive fiber is recovered to a smooth pulse in the gain fiber with normal dispersion. The new pulse regime formed by the two nonlinear processes makes the ultrafast fiber laser generate ultra-broadband, ultrashort duration, high energy and large breathing ratio pulses. Our work gives insights into the nonlinear dynamics in fiber lasers and has potential for a better design of the stretched fiber lasers. PMID- 29716088 TI - Competing radiative and nonradiative decay of embedded ions states in dielectric crystals: theory, and application to Co2+:AgCl0.5Br0.5. AB - We present a generally applicable theoretical model describing excited-state decay lifetime analysis of metal ions in a host crystal matrix. In contrast to common practice, we include multi-phonon non-radiative transitions competitively to the radiative one. We have applied our theory to Co2+ ions in a mixed AgCl0.5Br0.5 crystal, and as opposed to a previous analysis, find excellent agreement between theory and experiment over the entire measured temperature range. The fit predicts a zero absolute temperature radiative lifetime taurad(0) = 5.5 ms, more than three times longer than the measured effective low temperature one taueff(0) = 1.48 ms. Furthermore, the fit configuration potential dissociation energy has been estimated as D = 2500 cm-1 and the lattice vibrational cutoff frequency as homegaco = 180 cm-1. We have experimentally verified the latter by optical reflection measurement in the far-IR. PMID- 29716089 TI - Orbital angular momentum generation method based on transformation electromagnetics. AB - Orbital angular momentum (OAM) vortex waves generated by conventional spiral phase plates and metasurfaces have been widely discussed. In this work, we propose an innovative OAM generation method based on transformation optics (TO). By solving Laplace's equation with specific boundary conditions, an oblate cylindrical shaped physical domain is designed to imitate a gradient shaped virtual domain which is able to generate a vortex beam upon reflection. As a proof-of-concept demonstration, a broadband all-dielectric microwave lens for vortex beam generation is presented with a topological charge of + 1. The corresponding far-field patterns as well as near-field helical phase and doughnut shaped amplitude distributions of the lens, obtained from numerical simulations, are reported along with a wide operational bandwidth spanning from 8 to 16 GHz. As a transformation method, the proposed TO technique provides an effective way to realize a conversion from plane waves to vortex waves, which can greatly facilitate the potential implementation of OAM waves in microwave wireless communication systems. PMID- 29716090 TI - Direct fabricating large-area nanotriangle structure arrays on tungsten surface by nonlinear lithography of two femtosecond laser beams. AB - Two-dimensional arrays of periodic nanostructures are fabricated on bulk tungsten surface within a single step using collinear propagation of two time-delayed femtosecond laser beams with orthogonal polarizations. It is surprisingly found that the geometric profile of the structure unit exhibits a triangle shape in hundred nanometer scales, and its spatial dimension can be modulated by the ambient air pressure ranging from 1 atm to 10-3 Pa. As the ambient air pressure decreases, the obtained surface structures display a large depth covered with nanowires. Physically, the formation of such triangle structures is originated from the transient physical correlations between the two laser-matter interaction processes, and also affected by the heat transfer effects of the surrounding air. In addition, the experimental measurements reveal that the minimum reflectivity of the nanotriangle surface structures is unprecedentedly reduced to as low as ~2.9% especially within the visible-infrared range. PMID- 29716091 TI - Hybridization-induced broadband terahertz wave absorption with graphene metasurfaces. AB - Electromagnetic (EM) wave absorption plays a vital role in photonics. While metasurfaces are proposed to absorb EM waves efficiently, most of them exhibit limited bandwidth and fixed functionalities. Here, we propose a broadband and tunable terahertz (THz) absorber based on a graphene-based metasurface, which is constructed by a single layer of closely patterned graphene concentric double rings and a metallic mirror separated by an ultrathin SiO2 layer. Plasmonic hybridization between two graphene rings significantly enlarges the absorption bandwidth, which can be further tuned by gating the graphene. Moreover, the specific design also makes our device insensitive to the incident angle and polarization state of impinging EM waves. Our results may inspire certain wave modulation-related applications, such as THz imaging, smart absorber, tunable sensor, etc. PMID- 29716092 TI - Selective coupling of Whispering Gallery Modes in film coated micro-resonators. AB - Whispering Gallery Mode (WGM) micro-resonators like microspheres or microtoroids are typically used as high-Q cavity substrate on which a functional film coating is deposited. In order to exploit the coating properties a critical step is the efficient excitation of WGMs mainly contained inside the deposited layer. We developed a simple method able to assess whether or not these modes are selectively excited. The method is based on monitoring the thermal shift of the excited resonance, which uniquely depends on the thermo-optic coefficient and on the thermal expansion coefficient of the material in which the mode is embedded. PMID- 29716093 TI - Laser-induced damage of fused silica optics at 355 nm due to backward stimulated Brillouin scattering: experimental and theoretical results. AB - Forward pump pulses with nanosecond duration are able to generate an acoustic wave via electrostriction through a few centimeters of bulk silica. Part of the incident energy is then scattered back on this sound wave, creating a backward Stokes pulse. This phenomenon known as stimulated Brillouin scattering (SBS) might induce first energy-loss, variable change of the temporal waveform depending on the location in the spatial profile making accurate metrology impossible, and moreover it might also initiate front surface damage making the optics unusable. Experiments performed on thick fused silica optics at 355 nm with single longitudinal mode pulses allowed us to detect, observe and quantify these backward pulses. Experimental results are first compared to theoretical calculations in order to strengthen our confidence in metrology. On this basis a phase-modulator has been implemented on the continuous-wave seeders of the lasers leading to pulses with a wide spectrum that suppress SBS and do not exhibit temporal overshoots that also reduce Kerr effects. The developed set-ups are used to check the reduction of the backward stimulated Brillouin scattering and they allow measuring with accuracy the rear surface damage of thick fused silica optics. PMID- 29716094 TI - All-fiber mid-infrared source tunable from 6 to 9 MUm based on difference frequency generation in OP-GaP crystal. AB - We report the first fully fiberized difference frequency generation (DFG) source, delivering a broadly tunable idler in the 6 to 9 MUm spectral range, using an orientation-patterned gallium phosphide (OP-GaP) crystals with different quasi phase matching periods (QPM). The mid-infrared radiation (MIR) is obtained via mixing of the output of a graphene-based Er-doped fiber laser at 1.55 MUm with coherent frequency-shifted solitons at 1.9 MUm generated in a highly nonlinear fiber using the same seed. The presented setup is the first truly all-fiber, all polarization maintaining, alignment-free DFG source reported so far. Its application to laser spectroscopy was demonstrated by the absorption spectrum measurement of nu4 band of methane in 7.5 - 8.3 um spectral range. The system simplicity and compactness paves the way for applications in field-deployable optical frequency comb spectroscopy systems for gas sensing. PMID- 29716095 TI - Robust optimization of the laser induced damage threshold of dielectric mirrors for high power lasers. AB - We report on a numerical optimization of the laser induced damage threshold of multi-dielectric high reflection mirrors in the sub-picosecond regime. We highlight the interplay between the electric field distribution, refractive index and intrinsic laser induced damage threshold of the materials on the overall laser induced damage threshold (LIDT) of the multilayer. We describe an optimization method of the multilayer that minimizes the field enhancement in high refractive index materials while preserving a near perfect reflectivity. This method yields a significant improvement of the damage resistance since a maximum increase of 40% can be achieved on the overall LIDT of the multilayer. PMID- 29716096 TI - Radiation resistant fiber Bragg grating in random air-line fibers for sensing applications in nuclear reactor cores. AB - This paper reports the testing results of radiation resistant fiber Bragg grating (FBG) in random air-line (RAL) fibers in comparison with FBGs in other radiation hardened fibers. FBGs in RAL fibers were fabricated by 80 fs ultrafast laser pulse using a phase mask approach. The fiber Bragg gratings tests were carried out in the core region of a 6 MW MIT research reactor (MITR) at a steady temperature above 600 degrees C and an average fast neutron (>1 MeV) flux >1.2 * 1014 n/cm2/s. Fifty five-day tests of FBG sensors showed less than 5 dB reduction in FBG peak strength after over 1 * 1020 n/cm2 of accumulated fast neutron dose. The radiation-induced compaction of FBG sensors produced less than 5.5 nm FBG wavelength shift toward shorter wavelength. To test temporal responses of FBG sensors, a number of reactor anomaly events were artificially created to abruptly change reactor power, temperature, and neutron flux over short periods of time. The thermal sensitivity and temporal responses of FBGs were determined at different accumulated doses of neutron flux. Results presented in this paper reveal that temperature-stable Type-II FBGs fabricated in radiation-hardened fibers can survive harsh in-pile conditions. Despite large parameter drift induced by strong nuclear radiation, further engineering and innovation on both optical fibers and fiber devices could lead to useful fiber sensors for various in-pile measurements to improve safety and efficiency of existing and next generation nuclear reactors. PMID- 29716097 TI - Random laser properties of Nd3+ crystal powders. AB - This work presents an overview of near infrared random lasing emitters based on a variety of neodymium (Nd3+)-doped crystal powders with different Nd3+ concentrations and different grain sizes. The pump-configuration used allows for an absolute measurement of both pumping and emitted energies. The results provide an absolute measure of the random laser efficiency and prove a relation of direct proportionality between the absorbance of the material and the laser slope efficiency. Likewise, they suggest a relationship close to an inverse proportionality between the absorbance and the threshold energy per unit area. The temporal behavior of the random laser emission shows noteworthy differences between local and spatially integrated registers. PMID- 29716098 TI - Speckle noise reduction of multi-frame optical coherence tomography data using multi-linear principal component analysis. AB - Optical coherence tomography (OCT) is an important interferometric diagnostic technique extensively applied in medical sciences. However, OCT images inevitably suffer from speckle noise, which reduces the accuracy of the diagnosis of ocular diseases. To deal with this problem, a speckle noise reduction method based on multi-linear principal component analysis (MPCA) is presented to denoise multi frame OCT data. To well preserve local image features, nonlocal similar 3D blocks extracted from the data are first grouped using k-means++ clustering method. MPCA transform is then performed on each group and the transform coefficients are shrunk to remove speckle noise. Finally, the filtered OCT volume is obtained by inverse MPCA transform and aggregation. Experimental results show that the proposed method outperforms other compared approaches in terms of both speckle noise reduction and fine detail preservation. PMID- 29716099 TI - Multi-focus TIE algorithm including partial spatial coherence and overlapping filters. AB - The transport of intensity equation (TIE) relates the variation of intensity of a wave-front along its mean direction of propagation with its phase. In experimental application, characteristic artefacts may affect the retrieved phase. These originate from inadequacies in estimating the axial derivative and the amplification of noise in the inversion of the TIE. To tackle these issues, images recorded at multiple planes of focus can be integrated into a multi-focus TIE (MFTIE) solution. This methodology relies on the efficient sampling of phase information in the spatial-frequency domain, typically by the definition of band pass filters implemented as a progression of sharp spatial frequency cut-offs. We present a convenient MFTIE implementation which avoids the need for recording images at very specific planes of focus and applies overlapping cut-offs, greatly simplifying the experimental application. This new approach additionally also accounts for partial spatial coherence in a flux-preserving framework. Using simulated data as well as experimental data from optical microscopy and electron microscopy we show that the frequency response of this MFTIE algorithm recovers efficiently a wide range of spatial frequencies of the phase that can be further extended by simple iterative refinement. PMID- 29716100 TI - High-order harmonic source spanning up to the oxygen K-edge based on filamentation pulse compression. AB - We present a 0.2 TW sub-two-cycle 1.8 um carrier-envelope-phase stable source based on two-stage pulse compression by filamentation for driving high-order harmonic generation extending beyond the oxygen K absorption edge. The 1 kHz repetition rate, high temporal resolution enabled by the short 11.8 fs driving pulse duration, and bright high-order harmonics generated in helium make this an attractive source for solid-state and molecular-dynamics studies. PMID- 29716101 TI - Depth perception based 3D holograms enabled with polarization-independent metasurfaces. AB - Metasurfaces consist of dielectric nanobrick arrays with different dimensions in the long and short axes can be used to generate different phase delays, predicting a new way to manipulate an incident beam in the two orthogonal directions separately. Here we demonstrate the concept of depth perception based three-dimensional (3D) holograms with polarization-independent metasurfaces. 4 step dielectric metasurfaces-based fan-out optical elements and holograms operating at 658 nm were designed and simulated. Two different holographic images with high fidelity were generated at the same plane in the far field for different polarization states. One can observe the 3D effect of target objects with polarized glasses. With the advantages of ultracompactness, flexibility and replicability, the polarization-independent metasurfaces open up depth perception based stereoscopic imaging in a holographic way. PMID- 29716102 TI - High-order mode direct oscillation of few-mode fiber laser for high-quality cylindrical vector beams. AB - Generation of high-order modes with high quality is important for the application of cylindrical vector beams in fibers. We experimentally demonstrated high-order LP11 mode generation and amplification with a broad bandwidth in an all few-mode fiber laser. A wavelength-division-multiplexing (WDM) mode selective coupler (MSC) is proposed to achieve efficient mode conversion from LP01 mode to LP11 mode, but also combine high-order LP11 modes at the wavelengths of 980/1550 nm. To the best of our knowledge, this is the first report on the high-order mode oscillation in an all few-mode fiber laser. LP11 mode and cylindrical vector beams including radially and azimuthally polarized beams are obtained with high modal purity. The purity of the generated high-order modes are all in excess of 95%. PMID- 29716103 TI - Fundamental performance of transverse wind estimator from Shack-Hartmann wave front sensor measurements. AB - Real time transverse wind estimation contributes to predictive correction which is used to compensate for the time delay error in the control systems of adaptive optics (AO) system. Many methods that apply Shack-Hartmann wave-front sensor to wind profile measurement have been proposed. One of the obvious problems is the lack of a fundamental benchmark to compare the various methods. In this work, we present the fundamental performance limits for transverse wind estimator from Shack-Hartmann wave-front sensor measurements using Cramer-Rao lower bound (CRLB). The bound provides insight into the nature of the transverse wind estimation, thereby suggesting how to design and improve the estimator in the different application scenario. We analyze the theoretical bound and find that factors such as slope measurement noise, wind velocity and atmospheric coherence length r0 have important influence on the performance. Then, we introduced the non-iterative gradient-based transverse wind estimator. The source of the deterministic bias of the gradient-based transverse wind estimators is analyzed for the first time. Finally, we derived biased CRLB for the gradient-based transverse wind estimators from Shack-Hartmann wave-front sensor measurements and the bound can predict the performance of estimator more accurately. PMID- 29716104 TI - Optical constants modelling in silicon nitride membrane transiently excited by EUV radiation. AB - We hereby report on a set of transient optical reflectivity and transmissivity measurements performed on silicon nitride thin membranes excited by extreme ultraviolet (EUV) radiation from a free electron laser (FEL). Experimental data were acquired as a function of the membrane thickness, FEL fluence and probe polarization. The time dependence of the refractive index, retrieved using Jones matrix formalism, encodes the dynamics of electron and lattice excitation following the FEL interaction. The observed dynamics are interpreted in the framework of a two temperature model, which permits to extract the relevant time scales and magnitudes of the processes. We also found that in order to explain the experimental data thermo-optical effects and inter-band filling must be phenomenologically added to the model. PMID- 29716105 TI - Suppressing the photobleaching and photoluminescence intermittency of single near infrared CdSeTe/ZnS quantum dots with p-phenylenediamine. AB - Intrinsic photobleaching and photoluminescence (PL) intermittency of single quantum dots (QDs), originating from photo-oxidation and photo-ionization respectively, are roadblocks for most single-dot applications. Here, we effectively suppress the photobleaching and the PL intermittency of single near infrared emitting QDs with p-phenylenediamine (PPD). The PPD cannot only be used as a high-efficient reducing agent to remove reactive oxygen species around QDs to suppress the photo-oxidation, but can also bond with the surface defect sites of single QDs to reduce electron trap states to suppress the photo-ionization. It is shown that the survival time of single QDs, the on-state probability of PL intensity traces, and the total number of emitted photons are significantly increased for single QDs in PPD compared with that on glass coverslip. PMID- 29716106 TI - Passively Q-switched single-frequency Nd:YVO4 ring laser with external feedback. AB - A compact diode-pumped Nd:YVO4 ring laser was developed for generation of relatively long (few tens nanoseconds) single-frequency pulses for high-spectral resolution LIDAR applications. Exploiting the feedback from an external mirror and Cr:YAG passive Q-switching with pulsed pump, unidirectional single-frequency operation with high quality ~50-ns, 80-uJ TEM00 pulses was achieved from 100 Hz to 10 kHz. Amplitude, duration and repetition rate stability of the pulses was better than 1%. PMID- 29716107 TI - Ultra-narrow linewidth quantum dot coherent comb lasers with self-injection feedback locking. AB - We have used an external cavity self-injection feedback locking (SIFL) system to simultaneously reduce the optical linewidth of over 39 individual wavelength channels of an InAs/InP quantum dot (QD) coherent comb laser (CCL). Linewidth reduction from a few MHz to less than 200 kHz is observed. Measured phase noise spectra clearly indicate a significant decrease in phase noise in the frequency range above 2 kHz. The RF beating signal between two adjacent channels also shows a substantial reduction in 3-dB linewidth from 10 kHz to 300 Hz with the SIFL system, and a corresponding drop in baseline level (-27 dB to -50 dB). PMID- 29716108 TI - Quantum squeezing in a modulated optomechanical system. AB - Quantum squeezing, as a typical quantum effect, is an important resource for many applications in quantum technologies. Here we propose a scheme for generating quantum squeezing, including the ponderomotive squeezing and the mechanical squeezing, in an optomechanical system, in which the radiation-pressure coupling and the mechanical spring constant are modulated periodically. In this system, the radiation-pressure interaction can be enhanced remarkably by the modulation induced mechanical parametric amplification. Moreover, the effective phonon noise can be suppressed completely by introducing a squeezed vacuum reservoir. This ultimately leads to that our scheme can achieve a controllable quantum squeezing. Numerical calculations show that our scheme is experimentally realizable with current technologies. PMID- 29716109 TI - Ultrafast multi-layer subtractive patterning. AB - Subtractive femtosecond laser machining using multiple pulses with different spatial intensity profiles centred on the same position on a sample has been used to fabricate surface relief structuring. A digital micromirror device was used as an intensity spatial light modulator, with a fixed position relative to the sample, to ensure optimal alignment between successive masks. Up to 50 distinct layers, 335 nm lateral spatial resolution and 2.6 um maximum depth structures were produced. The lateral dimensions of the structures are approximately 40 um. Surface relief structuring is shown to match intended depth profiles in a nickel substrate, and highly repeatable stitching of identical features in close proximity is also demonstrated. PMID- 29716110 TI - Non-contact printing of optical waveguides using capillary bridges. AB - Non-contact printing methods such as inkjet, electro hydrodynamic, and aerosol printing have attracted attention for their precise deposition of functional materials that are needed in printed electronics, optoelectronics, photonics, biotechnology, and microfluidics. In this article, we demonstrate printing of tapered optical waveguides with losses of 0.61 +/- 0.26 dB/cm, with the best performing structure achieving 0.19 dB/cm. Such continuous features are indispensable for successfully printing functional patterns, but they are often corrupted by capillary forces. The proposed inkjet printing method uses these forces to align liquid bridges into continuous features, enabling the printing of smooth lines on substrates with arbitrary contact angles. PMID- 29716111 TI - Implementation and characterization of a controllable dephasing channel based on coupling polarization and spatial degrees of freedom of light. AB - We present the experimental implementation and theoretical model of a controllable dephasing quantum channel using photonic systems. The channel is implemented by coupling the polarization and the spatial distribution of light that play, in the perspective of open quantum systems, the role of quantum system and environment, respectively. The capability of controlling our channel allows us to visualize its effects in a quantum system. Different from standard dephasing channels, our channel presents an exotic behavior in the sense that the evolution of a state, from a pure to a mixed state, shows an oscillatory behavior if tracked in the Bloch sphere. Additionally, we report the evolution of the purity and perform a quantum process tomography to obtain the chi matrix associated to our channel. PMID- 29716112 TI - Hybrid metasurfaces for microwave reflection and infrared emission reduction. AB - Controlling of electromagnetic wave radiation is of great importance in many fields. In this work, a hybrid metasurface (HMS) is designed to simultaneously reduce the microwave reflection and the infrared emission. The HMS is composed of the metal/dielectric/metal/dielectric/metal configuration. The reflection reduction at microwave frequencies mainly results from the phase cancellation technique, while the infrared emission reduction is due to the reflection of the metal with a high filling ration in the top layer. It has been analytically indicated that reflection reduction with an efficiency larger than 10 dB can be achieved in the frequency band of 8.2-18 GHz, and this has been well verified by the simulated and experimental results. Meanwhile, the designed HMS displays a low emission performance in the infrared band, with the emissivity less than 0.27 from 3 to 14 MUm. It is believed that our proposal may find the application of multispectral stealth technology. PMID- 29716113 TI - Experimental simulation of monogamy relation between contextuality and nonlocality in classical light. AB - The Clauser-Horne-Shimony-Holt (CHSH) inequality and the Klyachko-Can-Binicioglu Shumovski (KCBS) inequality present a tradeoff on the no-disturbance (ND) principle. Recently, the fundamental monogamy relation between contextuality and nonlocality in quantum theory has been demonstrated experimentally. Here we show that such a relation and tradeoff can also be simulated in classical optical systems. Using polarization, path and orbital angular momentum of the classical optical beam, in classical optical experiment we have observed the stringent monogamy relation between the two inequalities by implementing the projection measurement. Our results show the application prospect of the concepts developed recently in quantum information science to classical optical system and optical information processing. PMID- 29716114 TI - Bubble-on-fiber (BoF): a built-in tunable broadband acousto-optic sensor for liquid-immersible in situ measurements. AB - A new type of tunable broadband fiber-optic acousto-optic sensor was experimentally demonstrated by utilizing a bubble-on-fiber (BoF) interferometer. A single micro-bubble was generated by injecting a heating laser at lambda = 980 nm on the metalized facet of an optical fiber. The BoF formed a spherical micro cavity in water whose acoustic deformation was precisely detected by using a narrowband DFB laser at 1550 nm. The heating light and the interrogating light were fed into a single fiber probe by wavelength division multiplexing (WDM) realizing a small footprint all-fiber configuration. The diameter of the BoF was stabilized with a variation less than 0.5 nm by fast servo-control of the heating laser power. The stabilized BoF served as a Fabry-Perot cavity that can be deformed by acoustic perturbation, and a minimum detectable pressure level of as low as ~1 mPa/Hz1/2 was achieved in a frequency range of over 60 kHz in water at room temperature. Our proposed BoF technology can provide a tunable, flexible and all-fiber solution to detect minute acoustically driven perturbations combining high-precision interferometry. Due to the very small form-factor, the technique can find applications of liquid-immersible in situ measurements in bio molecular/cell detection and biochemical phenomena study. PMID- 29716115 TI - Electric dipole-quadrupole hybridization induced enhancement of second-harmonic generation in T-shaped plasmonic heterodimers. AB - In this work, we demonstrate computationally that electric dipole-quadrupole hybridization (EDQH) could be utilized to enhance plasmonic SHG efficiency. To this end, we construct T-shaped plasmonic heterodimers consisting of a short and a long gold nanorod with finite element method simulation. By controlling the strength of capacitive coupling between two gold nanorods, we explore the effect of EDQH evolution on the SHG process, including the SHG efficiency enhancement, corresponding near-field distribution, and far-field radiation pattern. Simulation results demonstrate that EDQH could enhance the SHG efficiency by a factor >100 in comparison with that achieved by an isolated gold nanorod. Additionally, the far-field pattern of the SHG could be adjusted beyond the well known quadrupolar distribution and confirms that EDQH plays an important role in the SHG process. PMID- 29716116 TI - Development of a spatial heterodyne Raman spectrometer with echelle-mirror structure. AB - Spatial heterodyne Raman spectroscopy is a spectroscopic detection technique that is particularly suitable for Raman measurements. The spectral range of traditional spatial heterodyne Raman spectrometer (SHRS) is limited by its spectral resolution and the number of detector elements. We propose an SHRS with an echelle-mirror structure that employs multiple diffraction orders to achieve a broad spectral coverage and high spectral resolution simultaneously. This SHRS is used to obtain the Raman spectra of organic liquids, inorganic solid targets, and mixed targets. Observations of aqueous solutions, and minerals are presented. In addition, anti-Stokes Raman shifts are also presented. The proposed SHRS technique shows good performance for broadband, high-resolution Raman measurements. PMID- 29716118 TI - Phase-shifted Solc-type filter based on thin periodically poled lithium niobate in a reflective geometry. AB - Configurable narrow bandwidth filters are indispensable components in optical communication networks. Here, we present an easily-integrated compact tunable filtering based on polarization-coupling process in a thin periodically poled lithium niobate (PPLN) in a reflective geometry via the transverse electro-optic (EO) effect. The structure, composed of an in-line polarizer and a thinned PPLN chip, forms a phase-shift Solc-type filter with similar mechanism to defected Bragg gratings. The filtering effect can be dynamically switched on and off by a transverse electric filed. Analogy of electromagnetically induced transparency (EIT) transmission spectrum and electrically controllable group delay is experimentally observed. The mechanism features tunable center wavelength in a wide range with respect to temperature and tunable optical delay to the applied voltage, which may offer another way for optical tunable filters or delay lines. PMID- 29716117 TI - Mid-infrared cascaded stimulated Raman scattering up to eight orders in As-S optical fiber. AB - Mid-infrared cascaded stimulated Raman scattering (SRS) is experimentally investigated in an As-S optical fiber which is fabricated based on As38S62 and As36S64 glasses and whose fiber loss is ~0.08 dB/m at1545 nm. Using a nanosecond laser operated at ~1545 nm as the pump source, mid-infrared cascaded SRS up to eight orders is obtained in a 16 m As-S fiber. To the best of our knowledge, this is the first demonstration of SRS of such high order in non-silica optical fibers, and it may contribute to developing tunable mid-infrared Raman fiber lasers using C-band pump sources. PMID- 29716119 TI - Growth and optical properties of Ag-Ti composite nanorods based on oblique angle co-deposition technique. AB - Ag-Ti composite nanorod structures with various Ag compositions were fabricated by the oblique angle co-deposition technique, and their optical transmission spectra are tuned by composition ratios of Ag and Ti, polarization directions, and deposition angles. Such tunable optical properties have potential applications in optoelectronics. Specially, for the Ag80 composite nanorod structures, there exists a wavelength, where it is isotropic. We also show that the transmission spectra of the Ag80 composite nanorod structure for the deposition angle of 87.5 degrees are greater than 90%, while the transmission spectra for the 75 degrees deposition angle are lower than 20%. Utilizing such a property, high or low transmission lenses can be designed. PMID- 29716120 TI - Fine tuning method for optimization of liquid crystal based polarimeters. AB - Liquid crystal variable retarders (LCVR) based polarimeters perform temporal polarization modulation by applying a sequence of driving voltages to introduce different optical retardances. However, even after a careful design and fabrication, manufacturing tolerances (i.e., slight optical axis misalignments, instrument residual polarization, optical activity in the LCVRs...) or the final system configuration (i.e., LCVRs in a convergent optical beam, thermal gradient across the clear aperture...) produce deviations from the ideal setup. As a consequence, all of these effects can reduce the polarimetric modulation efficiency of the device and, therefore, its signal-to-noise ratio. Hence, the voltage sequence applied according to the LCVR calibration curves may not be suitable to reach the optimal theoretical polarimetric efficiencies. In this work, a systematic fine tuning method for the LCVRs driving voltages is described an experimentally demonstrated. PMID- 29716121 TI - Optimum repetition rates for dual-comb spectroscopy. AB - The determination of the properties (i.e. line center, width, and amplitude) of a spectral line is simulated using a Monte Carlo method. For dual-comb spectroscopy, ideal repetition rates emerge for both the signal and LO combs that do not correspond to the repetition rates that possess the highest signal-to noise ratio. The determination is even more accurate when the repetition rates have an arbitrary near-harmonic ratio. The simulation results are generalized to allow for the comparison of any two spectroscopic systems (i.e. not just comb based systems) by performing the simulations as a function of the spectral point spacing and signal-to-noise ratio of the acquired data. PMID- 29716122 TI - Decision-feedback detection strategy for nonlinear frequency-division multiplexing. AB - By exploiting a causality property of the nonlinear Fourier transform, a novel decision-feedback detection strategy for nonlinear frequency-division multiplexing (NFDM) systems is introduced. The performance of the proposed strategy is investigated both by simulations and by theoretical bounds and approximations, showing that it achieves a considerable performance improvement compared to previously adopted techniques in terms of Q-factor. The obtained improvement demonstrates that, by tailoring the detection strategy to the peculiar properties of the nonlinear Fourier transform, it is possible to boost the performance of NFDM systems and overcome current limitations imposed by the use of more conventional detection techniques suitable for the linear regime. PMID- 29716123 TI - Sequential phase locking scheme for a filled aperture intensity coherent combination of beam arrays. AB - We present a novel phase locking scheme for the coherent combination of beam arrays in the filled aperture configuration. Employing a phase dithering mechanism for the different beams similar to LOCSET, dithering frequencies for sequential combination steps are reused. By applying an additional phase alternating scheme, this allows for the use of standard synchronized multichannel lock-in electronics for phase locking a large number of channels even when the frequency bandwidth of the employed phase actuators is limited. PMID- 29716124 TI - Double-range near-infrared acetylene detection using a dual spot-ring Herriott cell (DSR-HC). AB - Design and fabrication of a dual spot-ring Herriott cell (DSR-HC) were proposed. The sealed Herriott cell with a dimensional size of 5.5 cm * 9.2 cm * 32.1 cm, possessed two input/output coupling holes leading to two absorption path lengths of ~20 m and ~6 m, respectively. An acetylene (C2H2) sensor system with a double range was developed using the DSR-HC and wavelength modulation spectroscopy (WMS) technique. A near-infrared distributed feedback (DFB) laser was employed for targeting a C2H2 absorption line at 6521.2 cm-1. C2H2 concentration measurements were carried out by modulating the laser at a 5 kHz frequency and demodulating the detector signal with LabVIEW software. An Allan-Werle deviation analysis indicated that the limit of detection (LoD) for the two absorption path lengths of 20 m and 6 m are 7.9 parts-per-million in volume (ppmv) and 4.0 ppmv, respectively. The DSR-HC concept can be used to fabricate similar cells for single-gas detection requiring two different detection ranges as well as for dual gas detection requiring different absorption path lengths. PMID- 29716125 TI - Iterative matrix algorithm for high precision temperature and force decoupling in multi-parameter FBG sensing. AB - A new iterative matrix algorithm has been applied to improve the precision of temperature and force decoupling in multi-parameter FBG sensing. For the first time, this evaluation technique allows the integration of nonlinearities in the sensor's temperature characteristic and the temperature dependence of the sensor's force sensitivity. Applied to a sensor cable consisting of two FBGs in fibers with 80 um and 125 um cladding diameter installed in a 7 m-long coiled PEEK capillary, this technique significantly reduced the uncertainties in friction-compensated temperature measurements. In the presence of high friction induced forces of up to 1.6 N the uncertainties in temperature evaluation were reduced from several degrees Celsius if using a standard linear matrix approach to less than 0.5 degrees C if using the iterative matrix approach in an extended temperature range between -35 degrees C and 125 degrees C. PMID- 29716126 TI - Influence of energy-transfer upconversion and excited-state absorption on a high power Nd:YVO4 laser at 1.34 MUm. AB - A self-consistent theoretical model considering both energy-transfer upconversion (ETU) and excited-state absorption (ESA) effects, as well as the couplings among the temperature distribution in the laser crystal, the thermal fractional loading, the upper state population involved in the ETU and ESA effects, the laser output and other temperature-dependent parameters, was developed to simulate the behaviors of diode-end-pumped continuous-wave (CW) single-transverse mode (TEM00) lasers. Based on the theoretical and experimental investigations of the influences of ETU and ESA effects on laser performance, a high power CW TEM00 Nd:YVO4 1.34 MUm laser dual-end pumped at 880 nm was achieved with a maximum output power of 16 W. The measured laser beam quality was M2x = M2y = 1.17 and the stability of the laser output was better than +/- 0.9% in a given four hours. The theoretical predictions considering both ETU and ESA effects are in good agreement with experimental results. PMID- 29716127 TI - Multielemental self-absorption reduction in laser-induced breakdown spectroscopy by using microwave-assisted excitation. AB - The self-absorption effect seriously affects the accuracy of determination in laser-induced breakdown spectroscopy (LIBS). In this work, we proposed to reduce multielemental self-absorption within a wide spectral range (200-900 nm) by using microwave-assisted excitation in LIBS (MAE-LIBS). Self-absorption reduction of sodium (Na), potassium (K), aluminum (Al), silicon (Si), and calcium (Ca) in potassium feldspar using MAE-LIBS was investigated. The mechanisms of self absorption reduction in MAE-LIBS were also investigated. The results show that the serious self-absorption of spectral lines (Na and K) was reduced. The full widths at half maximum (FWHMs) of Na I 589.0 nm, Na I 589.6 nm, K I 766.5 nm, and K I 769.9 nm in potassium feldspar were reduced by 43%, 43%, 53%, and 47%, respectively. MAE-LIBS also has a little FWHM reduction for spectral lines with weak self-absorption. The results demonstrate that MAE-LIBS can simultaneously reduce multielemental self-absorption. PMID- 29716128 TI - Scaling effects in resonant coupling phenomena between fundamental and cladding modes in twisted microstructured optical fibers. AB - We show that in twisted microstructured optical fibers (MOFs) the coupling between the core and cladding modes can be obtained for helix pitch much greater than previously considered. We provide an analytical model describing scaling properties of the twisted MOFs, which relates coupling conditions to dimensionless ratios between the wavelength, the lattice pitch and the helix pitch of the twisted fiber. Furthermore, we verify our model using a rigorous numerical method based on the transformation optics formalism and study its limitations. The obtained results show that for appropriately designed twisted MOFs, distinct, high loss resonance peaks can be obtained in a broad wavelength range already for the fiber with 9 mm helix pitch, thus allowing for fabrication of coupling based devices using a less demanding method involving preform spinning. PMID- 29716129 TI - Color Fourier orthoscopic holography with laser capture and an LED display. AB - We present an end-to-end full color Fourier holographic imaging approach, which involves standard holographic recording with three wavelengths and an improved LED-driven display. It provides almost undistorted orthoscopic reconstruction of large objects in full color, which can be viewed with a naked eye. High quality reconstruction is preserved across large object depths, measured in meters, as shown theoretically and experimentally. Our imaging approach is based on capture, processing and display of the object wave fields without spherical phase factors. This efficient convention combined with a novel numerical propagator for confocal fields enables complete axial decoupling of both ends of the imaging chain, and consequently, free manipulation of axial position as well as size of the image without visible deformations and with minimal computation effort. PMID- 29716130 TI - Portable standoff spectrometer for hazard identification using integrated quantum cascade laser arrays from 6.5 to 11 um. AB - This article presents new spectroscopic results in standoff chemical detection that are enabled by monolithic arrays of Distributed Feedback (DFB) Quantum Cascade Lasers (QCLs), with each array element at a slightly different wavelength than its neighbor. The standoff analysis of analyte/substrate pairs requires a laser source with characteristics offered uniquely by a QCL Array. This is particularly true for time-evolving liquid chemical warfare agent (CWA) analysis. In addition to describing the QCL array source developed for long wave infrared coverage, a description of an integrated prototype standoff detection system is provided. Experimental standoff detection results using the man-portable system for droplet examination from 1.3 meters are presented using the CWAs VX and T mustard as test cases. Finally, we consider three significant challenges to working with droplets and liquid films in standoff spectroscopy: substrate uptake of the analyte, time-dependent droplet spread of the analyte, and variable substrate contributions to retrieved signals. PMID- 29716131 TI - Enhanced mid-infrared multi-bounce ATR spectroscopy for online detection of hydrogen peroxide using a supercontinuum laser. AB - A compact multi-bounce attenuated total reflection (ATR) probe combined with a Fabry-Perot filter spectrometer (FPFS) has been developed for detection of hydrogen peroxide used for oxidative gas scrubbing operating in the mid-infrared (MIR) spectral region. A novel MIR supercontinuum light source is employed to enhance the quantification capabilities of the sensor and is compared to a classical thermal emitter. An improvement of a factor of 4 in noise and approximately a factor of 3 in limit of detection is shown in this study allowing fast inline detection of aqueous hydrogen peroxide solutions around 0.1%. PMID- 29716132 TI - Multilevel quadrature amplitude multiplexing using coherently coupled orbital angular momentum modes. AB - Information can be encoded onto transverse spatial light modes, providing a platform that can improve the spectral efficiency of a communications link. Switching speed between these spatial modes and detection methods limit the information capacity of such links. This work demonstrates high speed capabilities of such a link. Transverse modes are created and switched at high rates by coherently coupling twisted light modes using passive optical elements in line with electro-optical modulators. Here we demonstrate the encoding and detection of two coherently coupled modes encoded with 0.5 Gbaud quadrature amplitude modulated (16- and 32-QAM) signals, for a 4X and 5X increase in spectral efficiency by exploiting both phase and amplitude of the coherently coupled modes. The receiver is able to successfully recover the signal with error rates below the forward error correction limit using passive optical techniques. The data rate of the system used is only limited by hardware, but similar devices are available that are capable of multi-Gigahertz operation. PMID- 29716133 TI - Variations of transparency derived from GOCI in the Bohai Sea and the Yellow Sea. AB - Secchi disk depth (Zsd), represents water transparency which is an intuitive indicator of water quality and can be used to derive inherent optical properties, chlorophyll-a concentrations, and primary productivity. In this study, the Zsd was derived from the Geostationary Ocean Color Imager (GOCI) data over the Bohai Sea (BHS) and the Yellow Sea (YS) using a regional tuned model. To validate the GOCI derived Zsd observations, in situ data, were collected for the BHS and YS regions. Results showed a good agreement between the GOCI derived Zsd observations and in situ measurements with a determination coefficient of 0.90, root mean square error of 2.17 m and mean absolute percent error of 24.56%. Results for diurnal variations showed an increasing trend of Zsd at the first and then decreasing, and all the maxima of Zsd in the central areas of the BHS and YS were found in the midday. For seasonal variations, higher values of Zsd, both in range and intensity, were observed in summer compared with those in winter. The reasons to explain the variations of Zsd have also been explored. Solar zenith angle (SOLZ) has an impact on the daily dynamics of Zsd, due to the influence of SOLZ on the attenuation of light radiation in water. The influence level of SOLZ on Zsd is largely determined by the water bodies' composition. The significant seasonal variations are mainly controlled by the stability of the water column stratification, because it can lead to the sediment resuspension and influence the growth and distribution of phytoplankton. Runoff and sediment discharge are not the main factors that impact the seasonal dynamics of Zsd. Tidal currents and mean currents may have influences on the variations of Zsd. However, due to the lack of in situ measurements to support, further studies are still needed. PMID- 29716134 TI - Observation of backward high-harmonic emission from solids. AB - We experimentally demonstrate backward emission of high-harmonics of a near infrared laser from MgO and Si crystals in the direction of specular reflection. We show that the variation of the high-harmonic power with the angle of incidence can be predicted with nonlinear reflection coefficients derived originally for perturbative nonlinearities. A comparison of transmission and reflection geometries suggests that backward-propagating high-harmonics are an excellent reference to study nonlinear propagation of intense light in solids. Backward emission will enable phase matching of the high-harmonic beam and the integration of the functionalities of extended gas-phase high-harmonic beamlines into a single optical element. The potential to achieve phase matching paves the way to solid-state based high-harmonic sources with higher flux than the best transmission-based sources, where high-harmonics are strongly absorbed by the crystal itself. PMID- 29716135 TI - Mathematical and diffractive modeling of self-healing. AB - To analyze the self-healing of a partially obstructed optical beam, we represent it by two orthogonal field components. The first component is an exact copy of the unobstructed beam, attenuated by a factor that is computed by a simple formula. The second component represents a pure distortion field, due to its orthogonality respect to the first one. This approach provides a natural measure of the beam damage, due to the obstruction, and the degree of self-healing, during propagation of the obstructed beam. As interesting results, derived in our approach, we obtain that the self-healing reaches a limit degree at the far field propagation domain, and that certain relatively small phase obstructions may produce a total damage on the beam. The theory is illustrated considering a Gaussian beam, distorted by different amplitude and phase obstructions. In the case of a soft Gaussian obstruction we obtain simple formulas for the far field limit values of the beam damage and the self-healing degree. PMID- 29716136 TI - 3D pulsed chaos lidar system. AB - We develop an unprecedented 3D pulsed chaos lidar system for potential intelligent machinery applications. Benefited from the random nature of the chaos, conventional CW chaos lidars already possess excellent anti-jamming and anti-interference capabilities and have no range ambiguity. In our system, we further employ self-homodyning and time gating to generate a pulsed homodyned chaos to boost the energy-utilization efficiency. Compared to the original chaos, we show that the pulsed homodyned chaos improves the detection SNR by more than 20 dB. With a sampling rate of just 1.25 GS/s that has a native sampling spacing of 12 cm, we successfully achieve millimeter-level accuracy and precision in ranging. Compared with two commercial lidars tested side-by-side, namely the pulsed Spectroscan and the random-modulation continuous-wave Lidar-lite, the pulsed chaos lidar that is in compliance with the class-1 eye-safe regulation shows significantly better precision and a much longer detection range up to 100 m. Moreover, by employing a 2-axis MEMS mirror for active laser scanning, we also demonstrate real-time 3D imaging with errors of less than 4 mm in depth. PMID- 29716137 TI - Beam drift and partial probe coherence effects in EUV reflective-mode coherent diffractive imaging. AB - While the industrial implementation of extreme ultraviolet lithography for upcoming technology nodes is becoming ever more realistic, a number of challenges have yet to be overcome. Among them is the need for actinic mask inspection. We report on reflective-mode lensless imaging of a patterned multi-layer mask sample at extreme ultraviolet wavelength that provides a finely structured defect map of the sample under test. Here, we present the imaging results obtained using ptychography in reflection mode at 6 degrees angle of incidence from the surface normal and 13.5 nm wavelength. Moreover, an extended version of the difference map algorithm is employed that substantially enhances the reconstruction quality by taking into account both long and short-term variations of the incident illumination. PMID- 29716138 TI - Integrated optoelectronic oscillator. AB - With the rapid development of the modern communication systems, radar and wireless services, microwave signal with high-frequency, high-spectral-purity and frequency tunability as well as microwave generator with light weight, compact size, power-efficient and low cost are increasingly demanded. Integrated microwave photonics (IMWP) is regarded as a prospective way to meet these demands by hybridizing the microwave circuits and the photonics circuits on chip. In this article, we propose and experimentally demonstrate an integrated optoelectronic oscillator (IOEO). All of the devices needed in the optoelectronic oscillation loop circuit are monolithically integrated on chip within size of 5*6cm2. By tuning the injection current to 44 mA, the output frequency of the proposed IOEO is located at 7.30 GHz with phase noise value of -91 dBc/Hz@1MHz. When the injection current is increased to 65 mA, the output frequency can be changed to 8.87 GHz with phase noise value of -92 dBc/Hz@1MHz. Both of the oscillation frequency can be slightly tuned within 20 MHz around the center oscillation frequency by tuning the injection current. The method about improving the performance of IOEO is carefully discussed at the end of in this article. PMID- 29716139 TI - Towards rewritable multilevel optical data storage in single nanocrystals. AB - Novel approaches for digital data storage are imperative, as storage capacities are drastically being outpaced by the exponential growth in data generation. Optical data storage represents the most promising alternative to traditional magnetic and solid-state data storage. In this paper, a novel and energy efficient approach to optical data storage using rare-earth ion doped inorganic insulators is demonstrated. In particular, the nanocrystalline alkaline earth halide BaFCl:Sm is shown to provide great potential for multilevel optical data storage. Proof-of-concept demonstrations reveal for the first time that these phosphors could be used for rewritable, multilevel optical data storage on the physical dimensions of a single nanocrystal. Multilevel information storage is based on the very efficient and reversible conversion of Sm3+ to Sm2+ ions upon exposure to UV-C light. The stored information is then read-out using confocal optics by employing the photoluminescence of the Sm2+ ions in the nanocrystals, with the signal strength depending on the UV-C fluence used during the write step. The latter serves as the mechanism for multilevel data storage in the individual nanocrystals, as demonstrated in this paper. This data storage platform has the potential to be extended to 2D and 3D memory for storage densities that could potentially approach petabyte/cm3 levels. PMID- 29716140 TI - All-fiber Mach-Zehnder interferometer for tunable two quasi-continuous points' temperature sensing in seawater. AB - An all-fiber Mach-Zehnder interferometer (MZI) for two quasi-continuous points' temperature sensing in seawater is proposed. Based on the beam propagation theory, transmission spectrum is designed to present two sets of clear and independent interferences. Following this design, MZI is fabricated and two points' temperature sensing in seawater are demonstrated with sensitivities of 42.69pm/ degrees C and 39.17pm/ degrees C, respectively. By further optimization, sensitivity of 80.91pm/ degrees C can be obtained, which is 3-10 times higher than fiber Bragg gratings and microfiber resonator, and higher than almost all similar MZI based temperature sensors. In addition, factors affecting sensitivities are also discussed and verified in experiment. The two points' temperature sensing demonstrated here show advantages of simple and compact construction, robust structure, easy fabrication, high sensitivity, immunity to salinity and tunable distance of 1-20 centimeters between two points, which may provide references for macroscopic oceanic research and other sensing applications based on MZIs. PMID- 29716141 TI - Characterization of weakly absorbing thin films by multiple linear regression analysis of absolute unwrapped phase in angle-resolved spectral reflectometry. AB - The simultaneous determination of t, n(lambda), and kappa(lambda) of thin films can be a tough task for the high correlation of fit parameters. The strong assumptions about the type of dispersion relation are commonly used as a consequence to alleviate correlation concerns by reducing the free parameters before the nonlinear regression analysis. Here we present an angle-resolved spectral reflectometry for the simultaneous determination of weakly absorbing thin film parameters, where a reflectance interferogram is recorded in both angular and spectral domains in a single-shot measurement for the point of the sample being illuminated. The variations of the phase recovered from the interferogram as functions of t, n, and kappa reveals that the unwrapped phase is monotonically related to t, n, and kappa, thereby allowing the problem of correlation to be alleviated by multiple linear regression. After removing the 2pi ambiguity of the unwrapped phase, the merit function based on the absolute unwrapped phase performs a 3D data cube with variables of t, n and kappa at each wavelength. The unique solution of t, n, and kappa can then be directly determined from the extremum of the 3D data cube at each wavelength with no need of dispersion relation. A sample of GaN thin film grown on a polished sapphire substrate is tested. The experimental data of t and [n(lambda), kappa(lambda)] are confirmed by the scanning electron microscopy and the comparison with the results of other related works, respectively. The consistency of the results shows the proposed method provides a useful tool for the determination of the thickness and optical constants of weakly absorbing thin films. PMID- 29716142 TI - Electrically-driven pure amplitude and frequency modulation in a quantum cascade laser. AB - We present pure amplitude modulation (AM) and frequency modulation (FM) achieved electrically in a quantum cascade laser (QCL) equipped with an integrated resistive heater (IH). The QCL output power scales linearly with the current applied to the active region (AR), but decreases with the IH current, while the emission frequency decreases with both currents. Hence, a simultaneous modulation applied to the current of the AR and IH sections with a proper relative amplitude and phase can suppress the AM, resulting in a pure FM, or vice-versa. The adequate modulation parameters depend on the applied modulation frequency. Therefore, they were first determined from the individual measurements of the AM and FM transfer functions obtained for a modulation applied to the current of the AR or IH section, respectively. By optimizing the parameters of the two modulations, we demonstrate a reduction of the spurious AM or FM by almost two orders of magnitude at characteristic frequencies of 1 and 10 kHz compared to the use of the AR current only. PMID- 29716143 TI - Numerical investigation of nematic liquid crystals in the THz band based on EIT sensor. AB - This paper introduces the concept of electromagnetically induced transparency (EIT) into the permittivity extraction of an anisotropic material-nematic liquid crystal (NLC). A novel two-step strategy is presented to extract the complex permittivity of the NLC at the THz band, which evaluates the relative permittivity tensor from the resonant frequencies and then determines the loss tangent from the quality factor Q of the EIT sensor. The proposed method features high accuracy due to the sharp resonance of the EIT sensor and also high robustness to the thickness of the NLC layer because only amplitude rather than phase information of the transmission coefficients is required. The NLC filled EIT sensor shows a sensitivity of 56.8 MUm/RIU (the resonance wavelength shift over the refractive index change unit (RIU)) and Figure of Merit (FoM) of 6.92. The uncertainty of the proposed technique in the relative permittivity and loss tangent is 3% and 8.2%, respectively. PMID- 29716145 TI - The Reading Comer. II. Why Randomize? PMID- 29716144 TI - All-optical transistor based on Rydberg atom-assisted optomechanical system. AB - We study the optical response of a double optomechanical cavity system assisted by two Rydberg atoms. The target atom is only coupled with one side cavity by a single cavity mode, and gate one is outside the cavities. It has been realized that a long-range manipulation of optical properties of a hybrid system, by controlling the Rydberg atom decoupled with the optomechanical cavity. Switching on the coupling between atoms and cavity mode, the original spatial inversion symmetry of the double cavity structure has been broken. Combining the controllable optical non-reciprocity with the coherent perfect absorption/transmission/synthesis effect (CPA/CPT/CPS reported by [ X.-B.Yan Opt. Express 22, 4886 (2014)], we put forward the theoretical schemes of an all optical transistor which contains functions such as a controllable diode, rectifier, and amplifier by controlling a single gate photon. PMID- 29716146 TI - Listserv-Welcome to A.S.P.E.N.'s Cyberspace Forum. PMID- 29716147 TI - Total Parenteral Nutrition During Pregnancy in a Patient Requiring Long-Term Nutrition Support. AB - BACKGROUND: Total parenteral nutrition (TPN) has been used successfully in preventing intrauterine growth retardation, premature labor, and perinatal morbidity and mortality associated with poor maternal nutrition. Parenteral nutrition support is provided in most instances for short intervals during pregnancy when oral intake is compromised, eg, hyperemesis gravidarum or during complications from comorbid conditions that develop or are exacerbated during pregnancy. Few reports describe continuous parenteral nutrition support from conception through labor and delivery. OBJECTIVE: To support successfully a 19 year-old woman on long-term TPN since age 8 years because of short bowel syndrome complicated by chronic pancreatitis. METHODS: Estimated energy requirements were based on indirect calorimetry and current recommendations for maternal weight gain for optimal fetal growth and development. A strategy was formulated to improve her low maternal weight during early pregnancy. RESULTS: The fetus grew normally throughout pregnancy. There were no significant metabolic or obstetric complications as a result of the parenteral support. CONCLUSIONS: Patients on long-term TPN can conceive successfully and carry a pregnancy to term without any adverse outcome for the mother or the fetus. TPN feeding during pregnancy and recommendations for maternal weight gain are reviewed. PMID- 29716148 TI - A Comparison of Outcomes in Demand Versus Schedule Formula-Fed Premature Infants. AB - This qualitative short-term study was designed to determine if preterm infants who are fed in response to their own feeding cues, gain weight at a faster rate than infants fed on a schedule that may not correspond with these cues. Self regulatory feeding behaviors have been studied by several previous investigators, and growing interest in neurobehavioral development of premature infants led to the hypothesis that ability to exhibit feeding cues is enhanced when premature infants are demand fed as opposed to being fed on a schedule. Furthermore, it was hypothesized that demand-fed premature infants may have a decreased length of stay when compared with schedule-fed infants. Results indicated that demand feeding may shorten hospital stay (31 days for the study group versus 33 days for the control group) and increase a premature infant's ability to exhibit feeding cues (demand-fed infants demonstrated and average of 10.5 feeding cues per day versus 4.6 feeding cues per day for the schedule-fed infants). PMID- 29716149 TI - Current Literature. PMID- 29716150 TI - The Use of Serum Albumin as a Prognostic or Nutritional Marker and The Pros and Cons of IV Albumin Therapy. AB - Serum albumin is a poor nutritional marker, but it is a good prognostic marker correlating with morbidity and mortality. However, IV albumin administration in hypoalbuminemic patients does not decrease tube feeding-associated diarrhea or intolerance, nor does it improve clinical outcome, so it is not cost-effective. In selected situations, colloid solutions may be helpful; however, nonprotein colloids are preferred and rarely is IV albumin indicated. PMID- 29716152 TI - Indirect Calorimetry Should Be Used. PMID- 29716151 TI - Methods of Restoring Patency to Occluded Feeding Tubes. AB - Obstruction of enteral tubes places clinicians at a therapeutic crossroad. One must either remove the current device and replace it, or remove the obstruction from the tube. The following article addresses issues related to clogged or obstructed enteral feeding tubes, and methods used to restore patency to these devices. Additionally, the article describes the approach the Nutritional Support Service at St. Mary of the Plains Hospital uses in restoring patency to occluded enteral feeding tubes. PMID- 29716153 TI - Serum Albumin: What Are We Using It for? PMID- 29716155 TI - The Practice-Industry Liaison. PMID- 29716154 TI - Should Predictive Equations or Indirect Calorimetry Be Used to Design Nutrition Support Regimens? Point-Counterpoint: Predictive Equations Should Be Used. PMID- 29716156 TI - Outcomes Research, Nutrition Care, and the Provider-Payer Relationship. PMID- 29716158 TI - How Important are Data? PMID- 29716157 TI - Effect of Acid Feeds on Feeding System Contamination. AB - BACKGROUND AND OBJECTIVE: Bacterial contamination of the enteral nutrition delivery system (FS) has been well described. Case reports and prospective cohort studies suggest that bacterial contamination is a cause of morbidity and mortality in the critically ill patient. Because bacterial growth and replication is pH dependent, we hypothesized that acidified enteral feedings would lower incidence of bacterial contamination of the FS and potentially infectious morbidity and mortality of critically ill patients. Our objective was to evaluate the effect of acidified enteral feedings on bacterial growth in the FS and subsequent gastric and tracheal bacterial growth. DESIGN: Randomized, double blind, placebo-controlled, multicenter study. SETTING: Eight mixed intensive care units at tertiary care hospitals. PATIENTS: We recruited mechanically ventilated critically ill patients expected to remain ventilated >=48 hours. We excluded patients with overt gastrointestinal bleeding, persistent acidemia, and renal failure requiring dialysis. We enrolled 120 patients: women, 38%; age, 57.6 +/- 19.3 years, and mean APACHE II score, 21.6 +/- 7.6. INTERVENTIONS: Vital High Nitrogen (Abbott Laboratories, Ross Products Division, Columbus, OH) was used as the standard feeding formula for the control group. Hydrochloric acid was added to achieve a pH to 3.5 in the experimental group. MAIN OUTCOME MEASURES: Microbial growth in the FS, stomach, and trachea. RESULTS: Compared with patients in the control group, patients who received acid feedings were less likely to have potentially pathogenic microorganisms in their FSs (19% versus 80% of patients [p <= .001] and 0.1 versus 0.8 organisms per specimen [p <= .001]). There were 151 organisms that were cultured in two or more sites. Of the 146 organisms cultured from the stomach, 22 (15%) were first cultured in the feeding system and 32 (22%) were cultured simultaneously in the feeding system and the stomach. Of the 58 organisms cultured in the trachea, 19 (33%) were first cultured in the feeding system and 6 (10%) were cultured simultaneously in the feeding system and the trachea. CONCLUSIONS: The feeding system is a frequent source of gastric and tracheal contamination. Acidified enteral feedings reduces contamination of the feeding system and therefore may have an impact on subsequent colonization and infection. Larger studies of acidified enteral feedings are needed to examine their effect on infectious morbidity and mortality. PMID- 29716160 TI - Cost and Outcome Issues Related to Enteral Feeding. PMID- 29716159 TI - Enteral Nutrition and Case Management: Education and Collaboration. PMID- 29716161 TI - Group II: Financial Measures in Cost Savings-Outcomes Studies: Enteral Devices. PMID- 29716164 TI - Public Policy Issues Related to Enteral Feeding. PMID- 29716162 TI - Group IV: Implementing Cost Savings across the Continuum of Care in Enteral Therapy. PMID- 29716165 TI - Closed Enteral Systems in the Intensive Care Unit: Evaluating Their Economic Impact. PMID- 29716167 TI - Coverage and Reimbursement for Enteral Feeding Devices in Nutrition Support. PMID- 29716166 TI - Promoting and Preserving the Quality of Clinical and Preventive Nutrition Care Services in the Twenty-First Century. PMID- 29716168 TI - Cost Savings and Improved Patient Care with Use of a Flush Enteral Feeding Pump. PMID- 29716170 TI - Managing in the New Medicare Environment: Implications of the Balanced Budget Act of 1997. PMID- 29716169 TI - Making Inferences from Scientific Research. PMID- 29716171 TI - Group I: Incorporating Nutrition Device Outcomes in Clinical Trials. PMID- 29716172 TI - Purchasing Enteral Feeding Products and Equipment for Administration: The Decision-Making Process. PMID- 29716174 TI - Group III: Research Agenda for Enteral Nutrition Support: What is the Next Step? PMID- 29716173 TI - Evaluating Conclusions from Clinical Trials and Implications for Reimbursement. PMID- 29716175 TI - Complications of Enteral Feeding. PMID- 29716176 TI - Temporal augmentation with calvarial onlay graft during pterional craniotomy for prevention of temporal hollowing. AB - BACKGROUND: Atrophy of muscle and fat often contributes to temporal hollowing after pterional craniotomy. However, the main cause is from the bony defect. Several methods to prevent temporal hollowing have been introduced, all with specific limitations. Autologous bone grafts are most ideal for cranial defect reconstruction. The authors investigated the effectiveness of bony defect coverage and temporal augmentation using pterional craniotomy bone flap. METHODS: This study was conducted in 100 patients who underwent brain tumor excision through pterional approach from 2015 to 2016. Group 1 underwent pterional craniotomy with temporal augmentation and group 2 without temporal augmentation. In group 1, after splitting the calvarial bone at the diploic space, the inner table was used for covering the bone defect and as an onlay graft for temporal augmentation. The outcome is evaluated by computed tomography at 1-year follow up. RESULTS: The mean operative time for temporal augmentation was 45 minutes. The mean follow-up was 12 months. The ratio of temporal thickness of operated side to non-operated side was 0.99 in group 1 and 0.44 in group 2, which was statistically different. The mean visual analogue scale score was 1.77 in group 1 and 6.85 in group 2. CONCLUSION: This study demonstrated a surgical technique using autologous bone graft for successfully preventing the temporal hollowing and improved patient satisfaction. PMID- 29716177 TI - Contouring of zygomatic soft tissue using bilateral free groin flaps in a Treacher Collins syndrome patient. AB - Treacher Collins syndrome is a congenital disorder that is characterized with a wide range of cranio-facial deformities. Zygomatic hypoplasia or aplasia is one of the key features, and surgical reconstruction of the consequent depression on the zygomatic area is deemed necessary by many patients. Various surgical options are available-injectables, alloplastic materials, autologous grafting, and autogenous tissue transfer. It depends on each patient which technique to use. Here, we present a clinical case, in which bilateral free groin flaps were adopted in attempt to resolve the remnant aesthetic deformity associated with zygomatic depression, despite a series of previous surgical efforts, in a 25-year old Treacher Collins syndrome male patient. PMID- 29716178 TI - Solitary mastocytoma presenting at birth. AB - Mastocytosis is a rare disease which occurs in both children and adults, and it can manifest as a solitary or multiple skin lesions. Both can cause cutaneous or systemic symptoms. Because of the heterogeneity of clinical presentation of mastocytosis and its rare prevalence, it can be hard to suspect the mastocytosis at the first time. Most solitary mastocytomas are about 1-5 cm in diameter and have features of brownish-yellow, minimally elevated plaques with a smooth shiny surface. This article presents a case of solitary mastocytoma which occurred in neonate and that we treated through surgical excision. In histopathological examination, it consisted of c-kit-positive mast cells. Although pediatric cutaneous mastocytosis might regress spontaneously, clinicians should keep in mind that it could be associated with systemic mastocytosis which involves hematopoietic system. PMID- 29716179 TI - Recent update of the 2017 Korean Association for the Study of the Liver (KASL) treatment guidelines of chronic hepatitis C: Comparison of guidelines from other continents, 2017 AASLD/IDSA and 2016 EASL. AB - The paradigm for the treatment of chronic hepatitis C (CHC) has been changed due to the development of direct acting antivirals (DAAs) of hepatitis C virus (HCV). The high sustained virologic response rate and ease of administration makes the DAAs approach ideal to contribute to the complete eradication of HCV. Currently, treatment options for individual patients vary depending on the genotype or subtype of HCV, presence or absence of liver cirrhosis, previous experience of antiviral treatment or resistance associated substitutions. Because of drug avalilability, cost-effectiveness, preference, compliance and greater possibility of desirable effects and presumed patient-important outcomes may vary between countries, treatment options for individual patients are different. The review focuses on the comparing the current treatment options for CHC in other continents with the 2017 Korea Association for the Study of the Liver guidelines. PMID- 29716180 TI - Current knowledge about Aelurostrongylus abstrusus biology and diagnostic AB - Feline aelurostrongylosis, caused by the lungworm Aelurostrongylus abstrusus, is a parasitic disease with veterinary importance. The female hatches her eggs in the bronchioles and alveolar ducts, where the larva develop into adult worms. L1 larvae and adult nematodes cause pathological changes, typically inflammatory cell infiltrates in thebronchi and the lung parenchyma. The level of infection can range from asymptomatic to the presence of severe symptoms and may be fatal for cats. Although coprological and molecular diagnostic methods are useful for A. abstrusus detection, both techniques can give false negative results due to the presence of low concentrations of larvae in faeces and the use of inadequate diagnostic procedures. The present study describes the biology of A. abstrusus, particularly the factors influencing its infection and spread in intermediate and paratenic hosts, and the parasitic interactions between A. abstrusus and other pathogens. PMID- 29716181 TI - The impact of fetal load of Hirudo verbana saline extract antigens on morphometrical, hematological and immunological parameters of rats in the early stages of post-embryonic development AB - The aim of the study was to determine the immunostimulatory effect of antigens from saline extract of the medicinal leech on the morphometric parameters of the body and major immunogenic organs of rats. Wild-type female rats were administered medicinal leech saline extract antigens intraperitoneally two weeks before and two weeks after mating (in total four injections). The offspring were examined, as were the mothers after feeding the offspring, at 1, 15, 30, 60 days after birth. The morphometric parameters of the animals were recorded. The animals were then decapitated under anesthesia and subjected to the following tests: morphometric parameters of immunogenic organs (spleen and thymus), total white blood cell count, red blood cell count, hemoglobin, color index and leukocyte formula. In addition, the absorption activity of neutrophils was examined: phagocyte index, phagocyte number, phagocytic capacity of the blood, the number of active phagocytes. From day 1, the medicinal leech antigens were associated with increased numbers of white blood cells and red blood cells, elevated hemoglobin level, increased absorption activity of neutrophils; however, the colour index remained in the normal range. These changes indicate that the antigens found in the saliva of medicinal leeches have an immune-stimulating influence on leucopoiesis, erythropoiesis and morphogenesis. PMID- 29716182 TI - Molecular characterization of Theileria equi infection in horse populations belonging to West Azerbaijan, Iran: insights into the importance of Equine Merozoite Antigen (EMA)-1 in its diagnosis AB - The major agent of equine piroplasmosis (EP), Theileria equi, contributes to significant losses in the equine industry. This study was designed to evaluate T. equi infection among horses from West Azerbaijan by microscopy and molecular approaches. One hundred and twenty six blood samples were collected from the jugular vein and placed in sterile tubes containing EDTA; these tubes were either used immediately for blood smears or stored at-20 degrees C for later examination by PCR. T. equi was detected in 3.2% and 27.7% of the animals examined using light microscopy and PCR methods, respectively. The prevalence of T. equi was higher in older animals (30.4%) than young equines (24.6%). Also, the females (31%) demonstrated higher T. equi infection rates than the males (23.6%).Additionally, while 12 horses housed with other animals were positive for T. equi, 23 not housed with other animals were found to be infected. No significant difference was found between infection rate and associated risk factors (age, sex, and housing with other animals). The results confirm a relatively high prevalence of T. equi in horses in the studyarea and also suggest that Equine Merozoite Antigen (EMA)-1 could be a strong candidate to develop diagnostic methods for T. equi infection. Due to the importance of EP in the equine industry, and the ability of animals to be lifelong carriers of T. equi, accurate and early diagnosis of the disease, based on specific antigens, is critical. Diagnosis wouldprovide basic information about its epidemiology, distribution and prevalence, especially in apparently healthy animals, and effective control and vaccine measures. PMID- 29716183 TI - Investigating in vitro anti-leishmanial effects of silibinin and silymarin on Leishmania major AB - Cutaneous leishmaniosis is an important zoonotic disease caused by various Leishmania species. The aim of this study was to investigate the effects of silibinin and silymarin on the in vitro growth and proliferation of promastigotes and amastigotes of Leishmania major compared to glucantime-treated parasites. The promastigotes and amastigotes of this parasite were treated with the two drugs, silibinin and silymarin, in several concentrations (25-100 MUM). The highest effect on promastigotes was for silymarin in concentration of 100 MUM with 90% and 91% death rate at hours 48 and 72, respectively. Regarding amastigotes, the highest effect at 48 hours was for silibinin in concentration of 100 MUM with 35% death rate. However, at 72 hours, silymarin showed the highest effect with 63% death rate in concentration of 100 MUM. The highest observed maximal 50% lethal concentration (LC50) for promastigotes was for silymarin with 19.34 MUM at 48 hours and 18.22 MUM at 72 hours. Likewise, maximal LC50 for amastigotes was for silymarin with 191 MUM at 48 hours and 24.27 MUM at 72 hours. Our findings demonstrated that both medications have suitable effects like Glucantime(r) on the parasite in vitro. Therefore, clinical assessment of the anti-leishmanial activity of silibinin and silymarin for treating the dermal lesions caused by L. major is recommended. PMID- 29716185 TI - Prevalence of cerebral toxoplasmosis among slaughtered sheep in Semnan, Iran AB - Toxoplasmosis is a zoonotic disease caused by Toxoplasma gondii. Felids are definitive hosts and all warm-blooded animals can be intermediate hosts. Some animals such as sheep, goats and pigs are sensitive to infection. In sheep production systems, toxoplamosis can cause abortion and economic loss. In public health, this disease can betransmitted to humans by the consumption of undercooked infected meat or other organs. In this study, T. gondii DNA was detected by B1 gene amplification in 140 randomly-selected brains of slaughtered sheep in Semnan, Iran. The prevalence of ovine cerebral toxoplasmosis was estimated using 95% confidence interval. The brain was selected as atarget organ because it gives the highest detection rates, and the results can be compared with previous data from other countries. Our findings indicate that T. gondii is present in ovine tissues and can be passed on to humans by consuming undercooked or raw meat and other organs such as the liver. The infection can be lethal for immunosuppressed individuals and can cause abortion or birth of infected children in pregnant woman. PMID- 29716186 TI - Redox-Responsive Biomimetic Polymeric Micelle for Simultaneous Anticancer Drug Delivery and Aggregation-Induced Emission Active Imaging. AB - Intelligent polymeric micelles have been developed as potential nanoplatforms for efficient drug delivery and diagnosis. Herein, we successfully prepared redox sensitive polymeric micelles combined aggregation-induced emission (AIE) imaging as an outstanding anticancer drug carrier system for simultaneous chemotherapy and bioimaging. The amphiphilic copolymer TPE-SS-PLAsp- b-PMPC could self assemble into spherical micelles, and these biomimetic micelles exhibited great biocompatibility and remarkable ability in antiprotein adsorption, showing great potential for biomedical application. Anticancer drug doxorubicin (DOX) could be encapsulated during the self-assembly process, and these drug-loaded micelles showed intelligent drug release and improved antitumor efficacy due to the quick disassembly in response to high levels of glutathione (GSH) in the environment. Moreover, the intracellular DOX release could be traced through the fluorescent imaging of these AIE micelles. As expected, the in vivo antitumor study exhibited that these DOX-carried micelles showed better antitumor efficacy and less adverse effects than that of free DOX. These results strongly indicated that this smart biomimetic micelle system would be a prominent candidate for chemotherapy and bioimaging. PMID- 29716187 TI - Unprecedented Cyclization Catalyzed by a Cytochrome P450 in Benzastatin Biosynthesis. AB - Benzastatins have unique structures probably derived from geranylated p aminobenzoic acids. The indoline and tetrahydroquinoline scaffolds are presumably formed by cyclization of the geranyl moiety, but the cyclization mechanism was unknown. We studied the benzastatin biosynthetic gene cluster of Streptomyces sp. RI18; functions of the six enzymes encoded by it were analyzed by gene disruption in a heterologous host and in vitro enzyme assays. We propose the biosynthetic pathway for benzastatins in which a cytochrome P450 (BezE) is responsible for the cyclization of geranylated p-acetoxyaminobenzoic acids; BezE catalyzes elimination of acetic acid to form an iron nitrenoid, nitrene transfer to form an aziridine ring, and nucleophilic addition of hydroxide ion to C-10 and chloride ion to C-9 to generate the indoline and tetrahydroquinoline scaffolds, respectively. Discovery of this enzyme, which should be termed cytochrome P450 nitrene transferase, provides an important insight into the functional diversity of cytochrome P450. PMID- 29716188 TI - Predictive Model of Linear Antimicrobial Peptides Active against Gram-Negative Bacteria. AB - Antimicrobial peptides (AMPs) have been identified as a potential new class of anti-infectives for drug development. There are a lot of computational methods that try to predict AMPs. Most of them can only predict if a peptide will show any antimicrobial potency, but to the best of our knowledge, there are no tools which can predict antimicrobial potency against particular strains. Here we present a predictive model of linear AMPs being active against particular Gram negative strains relying on a semi-supervised machine-learning approach with a density-based clustering algorithm. The algorithm can well distinguish peptides active against particular strains from others which may also be active but not against the considered strain. The available AMP prediction tools cannot carry out this task. The prediction tool based on the algorithm suggested herein is available on https://dbaasp.org. PMID- 29716189 TI - Molecular Design for Preparation of Hexagonal-Ordered Porous Films Based on Side Chain-Type Liquid-Crystalline Star Polymer. AB - Fabrication of regularly porous films by the breath-figure method has attracted much attention. The simple, low-cost technique uses the condensation of water droplets to produce these structures, but the phenomenon itself is complex, requiring control over many interacting parameters that change throughout the process. Developing a unified understanding for the molecular design of polymers to prepare ordered porous films is challenging, but required for further advancements. In this article, the effects of the chemical structure of polymers in the breath-figure technique were systematically explored using side-chain-type liquid-crystalline star polymers. The formation of porous films was affected by the structure of the polymers. Although the entire film surface of poly(11-[4-(4 cyanobiphenyl)oxy]undecyl methacrylate) (P11CB) had a hexagonal ordered porous structure over a certain Mn value, regularly arranged holes did not easily form in poly(methyl methacrylate) (PMMA), even though the main chain of PMMA is similar to that of P11CB. A comparison of P11CB and poly(11-[(1,1'-biphenyl)-4 yloxy]undecyl methacrylate) (P11B) (P11CB without cyano groups) showed that the local polar groups in hydrophobic polymers promoted the formation of ordered porous films. No holes were formed in poly(4-cyanobiphenyl methacrylate) (P0CB) (P11CB without alkyl spacers) films due to its hydrophilicity. The introduction of alkyl chains in P0CB allowed the preparation of honeycomb-structured films by increasing the internal tension. However, alkyl chains in the side chain alone did not result in a porous structure, as in the case of poly(undecyl methacrylate) (P11). Aromatic rings are also required to increase the Tg and improve film formability. In the present study, suitable molecular designs of polymers were found, specifically hydrophobic polymers with local polar groups, to form a regularly porous structure. Development of clear guidelines for the molecular design of polymers is the subject of our current research, which will enable the fabrication of porous films using various functional polymers. PMID- 29716190 TI - Structures and Adhesion Properties at Polyethylene/Silica and Polyethylene/Nylon Interfaces. AB - The molecular structures of buried interfaces of maleic anhydride grafted and ungrafted polyethylene films with silica and nylon surfaces were studied in situ using sum-frequency generation (SFG) vibrational spectroscopy. Grafting maleic anhydride to polyethylene altered the molecular structures at buried interfaces, including changing the orientation of polymer methylene groups and resulting in the presence of C?O groups at silica interfaces. These molecular level changes are correlated with enhanced adhesion properties, with ordered C?O groups and in plane orientation of the methylene groups associated with higher levels of adhesion. While improved adhesion was observed for grafted polyethylene at the nylon interface, no C?O groups were detected at the interface using SFG, for films thermally treated at 185 degrees C. In this case, either no C?O groups are present at the interface or they are disordered; the latter explanation is more likely, considering the observed improvement in adhesion. PMID- 29716191 TI - Light-Switchable Self-Assembly of Non-Photoresponsive Gold Nanoparticles. AB - Herein, an interesting light-induced self-assembly behavior from non photoresponsive gold nanoparticles (Au NPs) was reported. Specifically, a pH responsive amphiphile SPBwas developed that contained a particular phenylboronic acid moiety and showed excellent surface activity at the neutral and basic conditions, thereby stabilizing Au NPs well. Accordingly, the SPB-functionalized Au NPs showed strong pH dependence that there presented the pH-induced reversible self-assembly behavior. Furthermore, the introduction of a small amount of commercially available photoacid generator named diphenyliodonium nitrate (DIN) into the system could endow it with apparent light-switchable self-assembly behavior. The pH- and light-induced self-assembly behaviors of SPB-functionalized Au NPs in the absence and presence of DIN, respectively, were systematically studied by various techniques including UV-vis spectrum, transmission electron microscope, nuclear magnetic resonance, and Fourier transform infrared spectroscopy, which evidently confirmed that the stimuli-responsive self-assembly was controlled by the hydrogen-bonding interactions between phenylboronic acid moieties. Attributing to the light-induced obvious color change from bright-red to deep purple, the system was applied in particle imprinting successfully. PMID- 29716192 TI - Postprandial Metabolomics Response to Various Cooking Oils in Humans. AB - Lipids account for a high proportion of dietary calories, which greatly affect human health. As a result of differences in composition of fatty acid of individual cooking oils, certain biological effects of these oils may vary. This study aimed to compare postprandial metabolomic profiles of six commonly consumed cooking oils/fats. Adopting a switch-over experimental design ( n = 15), we carried out a human feeding study with six groups (control without oils, soybean oil, olive oil, palm oil, camellia oil, and tallow) and collected fasting and postprandial serum samples. The metabolomic profile was measured by ultra-high pressure liquid chromatography-quadrupole time of flight. We observed significant differences between the control group and experimental groups for 33 serum metabolites (false discovery rate; p < 0.05), which take part in lipid digestion, fatty acid metabolism, metabolism of pyrimidines and pyrimidine nucleosides, amino acid metabolism, neurobiology, and antioxidation. Sparse partial least squares discriminant analysis revealed distinct metabolomics patterns between monounsaturated fatty acid (MUFA) and saturated fatty acid oils, between soybean oil, olive oil, and palm oil, and between two MUFA-rich oils (olive and camellia oils). The present metabolomics study suggests shared and distinct metabolisms of various cooking oils/fats. PMID- 29716194 TI - Arynes and Cyclic Alkynes as Synthetic Building Blocks for Stereodefined Quaternary Centers. AB - We report a facile method to synthesize stereodefined quaternary centers from reactions of arynes and related strained intermediates using beta-ketoester derived substrates. The conversion of beta-ketoesters to chiral enamines is followed by reaction with in situ generated strained arynes or cyclic alkynes. Hydrolytic workup provides the arylated or alkenylated products in enantiomeric excesses as high as 96%. We also describe the one-pot conversion of a beta ketoester substrate to the corresponding enantioenriched alpha-arylated product. Computations show how chirality is transferred from the N-bound chiral auxiliary to the final products. These are the first theoretical studies of aryne trapping by chiral nucleophiles to set new stereocenters. Our approach provides a solution to the challenging problem of stereoselective beta-ketoester arylation/alkenylation, with formation of a quaternary center. PMID- 29716193 TI - Total Syntheses of Bulgecins A, B, and C and Their Bactericidal Potentiation of the beta-Lactam Antibiotics. AB - The bulgecins are iminosaccharide secondary metabolites of the Gram-negative bacterium Paraburkholderia acidophila and inhibitors of lytic transglycosylases of bacterial cell-wall biosynthesis and remodeling. The activities of the bulgecins are intimately intertwined with the mechanism of a cobiosynthesized beta-lactam antibiotic. beta-Lactams inhibit the penicillin-binding proteins, enzymes also critical to cell-wall biosynthesis. The simultaneous loss of the lytic transglycosylase (by bulgecin) and penicillin-binding protein (by beta lactams) activities results in deformation of the septal cell wall, observed microscopically as a bulge preceding bacterial cell lysis. We describe a practical synthesis of the three naturally occurring bulgecin iminosaccharides and their mechanistic evaluation in a series of microbiological studies. These studies identify potentiation by the bulgecin at subminimum inhibitory concentrations of the beta-lactam against three pathogenic Gram-negative bacteria and establish for the first time that this potentiation results in a significant increase in the bactericidal efficacy of a clinical beta-lactam. PMID- 29716196 TI - Glycine formation in CO2:CH4:NH3 ices induced by 0-70 eV electrons. AB - Glycine (Gly), the simplest amino-acid building-block of proteins, has been identified on icy dust grains in the interstellar medium, icy comets, and ice covered meteorites. These astrophysical ices contain simple molecules (e.g., CO2, H2O, CH4, HCN, and NH3) and are exposed to complex radiation fields, e.g., UV, gamma, or X-rays, stellar/solar wind particles, or cosmic rays. While much current effort is focused on understanding the radiochemistry induced in these ices by high energy radiation, the effects of the abundant secondary low energy electrons (LEEs) it produces have been mostly assumed rather than studied. Here we present the results for the exposure of multilayer CO2:CH4:NH3 ice mixtures to 0-70 eV electrons under simulated astrophysical conditions. Mass selected temperature programmed desorption (TPD) of our electron irradiated films reveals multiple products, most notably intact glycine, which is supported by control measurements of both irradiated or un-irradiated binary mixture films, and un irradiated CO2:CH4:NH3 ices spiked with Gly. The threshold of Gly formation by LEEs is near 9 eV, while the TPD analysis of Gly film growth allows us to determine the "quantum" yield for 70 eV electrons to be about 0.004 Gly per incident electron. Our results show that simple amino acids can be formed directly from simple molecular ingredients, none of which possess preformed C-C or C-N bonds, by the copious secondary LEEs that are generated by ionizing radiation in astrophysical ices. PMID- 29716197 TI - Role of internal motions and molecular geometry on the NMR relaxation of hydrocarbons. AB - The role of internal motions and molecular geometry on 1H NMR relaxation rates in liquid-state hydrocarbons is investigated using MD (molecular dynamics) simulations of the autocorrelation functions for intramolecular and intermolecular 1H-1H dipole-dipole interactions. The effects of molecular geometry and internal motions on the functional form of the autocorrelation functions are studied by comparing symmetric molecules such as neopentane and benzene to corresponding straight-chain alkanes n-pentane and n-hexane, respectively. Comparison of rigid versus flexible molecules shows that internal motions cause the intramolecular and intermolecular correlation-times to get significantly shorter, and the corresponding relaxation rates to get significantly smaller, especially for longer-chain n-alkanes. Site-by-site simulations of 1H's across the chains indicate significant variations in correlation times and relaxation rates across the molecule, and comparison with measurements reveals insights into cross-relaxation effects. Furthermore, the simulations reveal new insights into the relative strength of intramolecular versus intermolecular relaxation as a function of internal motions, as a function of molecular geometry, and on a site-by-site basis across the chain. PMID- 29716198 TI - In situ Raman and X-ray diffraction studies on the high pressure and temperature stability of methane hydrate up to 55 GPa. AB - High-temperature and high-pressure experiments were performed under 2-55 GPa and 298-653 K using in situ Raman spectroscopy and X-ray diffraction combined with externally heated diamond anvil cells to investigate the stability of methane hydrate. Prior to in situ experiments, the typical C-H vibration modes of methane hydrate and their pressure dependence were measured at room temperature using Raman spectroscopy to make a clear discrimination between methane hydrate and solid methane which forms through the decomposition of methane hydrate at high temperature. The sequential in situ Raman spectroscopy and X-ray diffraction revealed that methane hydrate survives up to 633 K and 40.3 GPa and then decomposes into solid methane and ice VII above the conditions. The decomposition curve of methane hydrate estimated by the present experiments is >200 K lower than the melting curves of solid methane and ice VII, and moderately increases with increasing pressure. Our result suggests that although methane hydrate may be an important candidate for major constituents of cool exoplanets and other icy bodies, it is unlikely to be present in the ice mantle of Neptune and Uranus, where the temperature is expected to be far beyond the decomposition temperatures. PMID- 29716199 TI - Reference dependence of the two-determinant coupled-cluster method for triplet and open-shell singlet states of biradical molecules. AB - We study the performance of the two-determinant (TD) coupled-cluster (CC) method which, unlike conventional ground-state single-reference (SR) CC methods, can, in principle, provide a naturally spin-adapted treatment of the lowest-lying open shell singlet (OSS) and triplet electronic states. Various choices for the TD-CC reference orbitals are considered, including those generated by the multi configurational self-consistent field method. Comparisons are made with the results of high-level SR-CC, equation-of-motion (EOM) CC, and multi-reference EOM calculations performed on a large test set of over 100 molecules with low-lying OSS states. It is shown that in cases where the EOMCC reference function is poorly described, TD-CC can provide a significantly better quantitative description of OSS total energies and OSS-triplet splittings. PMID- 29716200 TI - Stereodynamics of Ne(3P2) reacting with Ar, Kr, Xe, and N2. AB - Stereodynamics experiments of Ne(3P2) reacting with Ar, Kr, Xe, and N2 leading to Penning and associative ionization have been performed in a crossed molecular beam apparatus. A curved magnetic hexapole was used to state-select and polarize Ne(3P2) atoms which were then oriented in a rotatable magnetic field and crossed with a beam of Ar, Kr, Xe, or N2. The ratio of associative to Penning ionization was recorded as a function of the magnetic field direction for collision energies between 320 cm-1 and 500 cm-1. Reactivities are obtained for individual states that differ only in Omega, the projection of the neon total angular momentum vector on the inter-particle axis. The results are rationalized on the basis of a model involving a long-range and a short-range reaction mechanism. Substantially lower probability for associative ionization was observed for N2, suggesting that predissociation plays a critical role in the overall reaction pathway. PMID- 29716201 TI - Entropic elasticity based coarse-grained model of lipid membranes. AB - Various models for lipid bilayer membranes have been presented to investigate their morphologies. Among them, the aggressive coarse-grained models, where the membrane is represented by a single layer of particles, are computationally efficient and of practical importance for simulating membrane dynamics at the microscopic scale. In these models, soft potentials between particle pairs are used to maintain the fluidity of membranes, but the underlying mechanism of the softening requires further clarification. We have analyzed the membrane area decrease due to thermal fluctuations, and the results demonstrate that the intraparticle part of entropic elasticity is responsible for the softening of the potential. Based on the stretching response of the membrane, a bottom-up model is developed with an entropic effect explicitly involved. The model reproduces several essential properties of the lipid membrane, including the fluid state and a plateau in the stretching curve. In addition, the area compressibility modulus, bending rigidity, and spontaneous curvature display linear dependence on model parameters. As a demonstration, we have investigated the closure and morphology evolution of membrane systems driven by spontaneous curvature, and vesicle shapes observed experimentally are faithfully reproduced. PMID- 29716202 TI - Nonequilibrium quantum solvation with a time-dependent Onsager cavity. AB - We formulate a theory of nonequilibrium quantum solvation in which parameters of the solvent are explicitly depending on time. We assume in a simplest approach a spherical molecular Onsager cavity with a time-dependent radius. We analyze the relaxation properties of a test molecular point dipole in a dielectric solvent and consider two cases: (i) a shrinking Onsager sphere and (ii) a breathing Onsager sphere. Due to the time-dependent solvent, the frequency-dependent response function of the dipole becomes time-dependent. For a shrinking Onsager sphere, the dipole relaxation is in general enhanced. This is reflected in a temporally increasing linewidth of the absorptive part of the response. Furthermore, the effective frequency-dependent response function shows two peaks in the absorptive part which are symmetrically shifted around the eigenfrequency. By contrast, a breathing sphere reduces damping as compared to the static sphere. Interestingly, we find a non-monotonous dependence of the relaxation rate on the breathing rate and a resonant suppression of damping when both rates are comparable. Moreover, the linewidth of the absorptive part of the response function is strongly reduced for times when the breathing sphere reaches its maximal extension. PMID- 29716203 TI - Transient intermediates are populated in the folding pathways of single-domain two-state folding protein L. AB - Small single-domain globular proteins, which are believed to be dominantly two state folders, played an important role in elucidating various aspects of the protein folding mechanism. However, recent single molecule fluorescence resonance energy transfer experiments [H. Y. Aviram et al. J. Chem. Phys. 148, 123303 (2018)] on a single-domain two-state folding protein L showed evidence for the population of an intermediate state and it was suggested that in this state, a beta-hairpin present near the C-terminal of the native protein state is unfolded. We performed molecular dynamics simulations using a coarse-grained self-organized polymer model with side chains to study the folding pathways of protein L. In agreement with the experiments, an intermediate is populated in the simulation folding pathways where the C-terminal beta-hairpin detaches from the rest of the protein structure. The lifetime of this intermediate structure increased with the decrease in temperature. In low temperature conditions, we also observed a second intermediate state, which is globular with a significant fraction of the native like tertiary contacts satisfying the features of a dry molten globule. PMID- 29716204 TI - Demixing, surface nematization, and competing adsorption in binary mixtures of hard rods and hard spheres under confinement. AB - A molecular simulation study of binary mixtures of hard spherocylinders (HSCs) and hard spheres (HSs) confined between two structureless hard walls is presented. The principal aim of the work is to understand the effect of the presence of hard spheres on the entropically driven surface nematization of hard rod-like particles at surfaces. The mixtures are studied using a constant normal pressure Monte Carlo algorithm. The surface adsorption at different compositions is examined in detail. At moderate hard-sphere concentrations, preferential adsorption of the spheres at the wall is found. However, at moderate to high pressure (density), we observe a crossover in the adsorption behavior with nematic layers of the rods forming at the walls leading to local demixing of the system. The presence of the spherical particles is seen to destabilize the surface nematization of the rods, and the degree of demixing increases on increasing the hard-sphere concentration. PMID- 29716205 TI - Glassy dynamics of dense particle assemblies on a spherical substrate. AB - We study by molecular dynamics simulation a dense one-component system of particles confined on a spherical substrate. We more specifically investigate the evolution of the structural and dynamical properties of the system when changing the control parameters, the temperature and the curvature of the substrate. We find that the dynamics become glassy at low temperature, with a strong slowdown of the relaxation and the emergence of dynamical heterogeneity. The prevalent local 6-fold order is frustrated by curvature and we analyze in detail the role of the topological defects in the statics and the dynamics of the particle assembly. PMID- 29716206 TI - Principal component analysis acceleration of rovibrational coarse-grain models for internal energy excitation and dissociation. AB - The present work introduces a novel approach for obtaining reduced chemistry representations of large kinetic mechanisms in strong non-equilibrium conditions. The need for accurate reduced-order models arises from compression of large ab initio quantum chemistry databases for their use in fluid codes. The method presented in this paper builds on existing physics-based strategies and proposes a new approach based on the combination of a simple coarse grain model with Principal Component Analysis (PCA). The internal energy levels of the chemical species are regrouped in distinct energy groups with a uniform lumping technique. Following the philosophy of machine learning, PCA is applied on the training data provided by the coarse grain model to find an optimally reduced representation of the full kinetic mechanism. Compared to recently published complex lumping strategies, no expert judgment is required before the application of PCA. In this work, we will demonstrate the benefits of the combined approach, stressing its simplicity, reliability, and accuracy. The technique is demonstrated by reducing the complex quantum N2(Sigmag+1)-N(Su4) database for studying molecular dissociation and excitation in strong non-equilibrium. Starting from detailed kinetics, an accurate reduced model is developed and used to study non equilibrium properties of the N2(Sigmag+1)-N(Su4) system in shock relaxation simulations. PMID- 29716207 TI - Publisher's Note: "Multiconfiguration pair-density functional theory investigation of the electronic spectrum of MnO4-" [J. Chem. Phys. 148, 124305 (2018)]. PMID- 29716208 TI - Erratum: "The second virial coefficient of bounded Mie potentials" [J. Chem. Phys. 147, 214504 (2017)]. PMID- 29716209 TI - Excited state non-adiabatic dynamics of the smallest polyene, trans 1,3 butadiene. II. Ab initio multiple spawning simulations. AB - The excited state non-adiabatic dynamics of the smallest polyene, trans 1,3 butadiene (BD), has long been the subject of controversy due to its strong coupling, ultrafast time scales and the difficulties that theory faces in describing the relevant electronic states in a balanced fashion. Here we apply Ab Initio Multiple Spawning (AIMS) using state-averaged complete active space multistate second order perturbation theory [SA-3-CAS(4/4)-MSPT2] which describes both static and dynamic electron correlation effects, providing a balanced description of both the initially prepared bright 11Bu (pipi*) state and non adiabatically coupled dark 21Ag state of BD. Importantly, AIMS allows for on-the fly calculations of experimental observables. We validate our approach by directly simulating the time resolved photoelectron-photoion coincidence spectroscopy results presented in Paper I [A. E. Boguslavskiy et al., J. Chem. Phys. 148, 164302 (2018)], demonstrating excellent agreement with experiment. Our simulations reveal that the initial excitation to the 11Bu state rapidly evolves via wavepacket dynamics that follow both bright- and dark-state pathways as well as mixtures of these. In order to test the sensitivity of the AIMS results to the relative ordering of states, we considered two hypothetical scenarios biased toward either the bright 1Bu or the dark 21Ag state. In contrast with AIMS/SA-3 CAS(4/4)-MSPT2 simulations, neither of these scenarios yields favorable agreement with experiment. Thus, we conclude that the excited state non-adiabatic dynamics in BD involves both of these ultrafast pathways. PMID- 29716210 TI - Photoionization mass spectrometry of omega-phenylalkylamines: Role of radical cation-pi interaction. AB - Linear omega-phenylalkylamines of increasing alkyl chain length have been investigated employing synchrotron radiation in the photon energy range from 7 to 15 eV. These molecules have received considerable interest because they bear the skeleton of biologically relevant compounds including neurotransmitters and because of the possible interaction between the amino moiety and the phenyl ring. Recently, the contribution of this interaction has been assayed in both neutral and protonated species, pointing to a role of the polymethylene chain length. In this work, the ionization energy (IE) values of benzylamine (BA), 2 phenylethylamine (2-PEA), 3-phenylpropylamine (3-PPA), and 4-phenylbutylamine (4 PBA) were investigated in order to ascertain the impact of the different alkyl chain lengths and to verify an amino radical cation-pi interaction. The IEs obtained experimentally, 8.54, 8.37, 8.29, and 8.31 eV for BA, 2-PEA, 3-PPA and 4 PBA, respectively, show a decreasing trend that is discussed employing calculations at the CBS-QB3 level. Moreover, the appearance energy values for major fragments produced by the photofragmentation process are reported. PMID- 29716211 TI - Bravyi-Kitaev Superfast simulation of electronic structure on a quantum computer. AB - Present quantum computers often work with distinguishable qubits as their computational units. In order to simulate indistinguishable fermionic particles, it is first required to map the fermionic state to the state of the qubits. The Bravyi-Kitaev Superfast (BKSF) algorithm can be used to accomplish this mapping. The BKSF mapping has connections to quantum error correction and opens the door to new ways of understanding fermionic simulation in a topological context. Here, we present the first detailed exposition of the BKSF algorithm for molecular simulation. We provide the BKSF transformed qubit operators and report on our implementation of the BKSF fermion-to-qubits transform in OpenFermion. In this initial study of a hydrogen molecule we have compared BKSF, Jordan-Wigner, and Bravyi-Kitaev transforms under the Trotter approximation. The gate count to implement BKSF is lower than Jordan-Wigner but higher than Bravyi-Kitaev. We considered different orderings of the exponentiated terms and found lower Trotter errors than the previously reported for Jordan-Wigner and Bravyi-Kitaev algorithms. These results open the door to the further study of the BKSF algorithm for quantum simulation. PMID- 29716212 TI - Reaction fronts of the autocatalytic hydrogenase reaction. AB - We have built a model to describe the hydrogenase catalyzed, autocatalytic, reversible hydrogen oxidation reaction where one of the enzyme forms is the autocatalyst. The model not only reproduces the experimentally observed front properties, but also explains the found hydrogen ion dependence. Furthermore, by linear stability analysis, two different front types are found in good agreement with the experiments. PMID- 29716213 TI - On the equilibrium contact angle of sessile liquid drops from molecular dynamics simulations. AB - We present a new methodology to estimate the contact angles of sessile drops from molecular simulations by using the Gaussian convolution method of Willard and Chandler [J. Phys. Chem. B 114, 1954-1958 (2010)] to calculate the coarse-grained density from atomic coordinates. The iso-density contour with average coarse grained density value equal to half of the bulk liquid density is identified as the average liquid-vapor (LV) interface. Angles between the unit normal vectors to the average LV interface and unit normal vector to the solid surface, as a function of the distance normal to the solid surface, are calculated. The cosines of these angles are extrapolated to the three-phase contact line to estimate the sessile drop contact angle. The proposed methodology, which is relatively easy to implement, is systematically applied to three systems: (i) a Lennard-Jones (LJ) drop on a featureless LJ 9-3 surface; (ii) an SPC/E water drop on a featureless LJ 9-3 surface; and (iii) an SPC/E water drop on a graphite surface. The sessile drop contact angles estimated with our methodology for the first two systems are shown to be in good agreement with the angles predicted from Young's equation. The interfacial tensions required for this equation are computed by employing the test-area perturbation method for the corresponding planar interfaces. Our findings suggest that the widely adopted spherical-cap approximation should be used with caution, as it could take a long time for a sessile drop to relax to a spherical shape, of the order of 100 ns, especially for water molecules initiated in a lattice configuration on a solid surface. But even though a water drop can take a long time to reach the spherical shape, we find that the contact angle is well established much faster and the drop evolves toward the spherical shape following a constant-contact-angle relaxation dynamics. Making use of this observation, our methodology allows a good estimation of the sessile drop contact angle values even for moderate system sizes (with, e.g., 4000 molecules), without the need for long simulation times to reach the spherical shape. PMID- 29716214 TI - Surface tension of droplets and Tolman lengths of real substances and mixtures from density functional theory. AB - The curvature dependence of interfacial properties has been discussed extensively over the last decades. After Tolman published his work on the effect of droplet size on surface tension, where he introduced the interfacial property now known as Tolman length, several studies were performed with varying results. In recent years, however, some consensus has been reached about the sign and magnitude of the Tolman length of simple model fluids. In this work, we re-examine Tolman's equation and how it relates the Tolman length to the surface tension and we apply non-local classical density functional theory (DFT) based on the perturbed chain statistical associating fluid theory (PC-SAFT) to characterize the curvature dependence of the surface tension of real fluids as well as mixtures. In order to obtain a simple expression for the surface tension, we use a first-order expansion of the Tolman length as a function of droplet radius Rs, as delta(Rs) = delta0 + delta1/Rs, and subsequently expand Tolman's integral equation for the surface tension, whereby a second-order expansion is found to give excellent agreement with the DFT result. The radius-dependence of the surface tension of increasingly non-spherical substances is studied for n-alkanes, up to icosane. The infinite diameter Tolman length is approximately delta0 = -0.38 A at low temperatures. For more strongly non-spherical substances and for temperatures approaching the critical point, however, the infinite diameter Tolman lengths delta0 turn positive. For mixtures, even if they contain similar molecules, the extrapolated Tolman length behaves strongly non-ideal, implying a qualitative change of the curvature behavior of the surface tension of the mixture. PMID- 29716215 TI - Photodissociation dynamics of propanal and isobutanal: The Norrish Type I pathway. AB - The Norrish Type I photodissociation of two aliphatic aldehydes, propanal and isobutanal, has been investigated using velocity-map imaging. The HCO photoproduct of this reaction was probed using a 1+1 resonance-enhanced multiphoton ionization scheme via the 3p2Pi Rydberg state. The velocity map images of HCO+ were collected across a range of photolysis energies for both species from 30 500 to 33 000 cm-1 (lambda = 312-327 nm). The corresponding translational energy distributions show that the majority of the available energy goes into the translational motion of the products (55%-68%) with this fraction increasing as the T1 barrier is approached. Analysis of the translational energy distributions was also used to determine the aldehyde alpha C-C bond dissociation energies which were found to be 339.8 +/- 2.5 and 331.2 +/- 2.5 kJ/mol for propanal and isobutanal, respectively. These values were also found to be in good agreement with the computed dissociation energies using G4 and CCSD(T)/aug-cc pVTZ//M062X/aug-cc-pVTZ levels of theory. Furthermore, these dissociation energies, combined with the known DeltafH (0 K) of the reaction products, provided the DeltafH (0 K) of propanal and isobutanal which were calculated to be -167.3 +/- 2.5 and -184.0 +/- 2.5 kJ/mol, respectively. PMID- 29716216 TI - Selected-node stochastic simulation algorithm. AB - Stochastic simulations of biochemical networks are of vital importance for understanding complex dynamics in cells and tissues. However, existing methods to perform such simulations are associated with computational difficulties and addressing those remains a daunting challenge to the present. Here we introduce the selected-node stochastic simulation algorithm (snSSA), which allows us to exclusively simulate an arbitrary, selected subset of molecular species of a possibly large and complex reaction network. The algorithm is based on an analytical elimination of chemical species, thereby avoiding explicit simulation of the associated chemical events. These species are instead described continuously in terms of statistical moments derived from a stochastic filtering equation, resulting in a substantial speedup when compared to Gillespie's stochastic simulation algorithm (SSA). Moreover, we show that statistics obtained via snSSA profit from a variance reduction, which can significantly lower the number of Monte Carlo samples needed to achieve a certain performance. We demonstrate the algorithm using several biological case studies for which the simulation time could be reduced by orders of magnitude. PMID- 29716217 TI - Structural, electronic, and dynamical properties of liquid water by ab initio molecular dynamics based on SCAN functional within the canonical ensemble. AB - We perform ab initio molecular dynamics (AIMD) simulation of liquid water in the canonical ensemble at ambient conditions using the strongly constrained and appropriately normed (SCAN) meta-generalized-gradient approximation (GGA) functional approximation and carry out systematic comparisons with the results obtained from the GGA-level Perdew-Burke-Ernzerhof (PBE) functional and Tkatchenko-Scheffler van der Waals (vdW) dispersion correction inclusive PBE functional. We analyze various properties of liquid water including radial distribution functions, oxygen-oxygen-oxygen triplet angular distribution, tetrahedrality, hydrogen bonds, diffusion coefficients, ring statistics, density of states, band gaps, and dipole moments. We find that the SCAN functional is generally more accurate than the other two functionals for liquid water by not only capturing the intermediate-range vdW interactions but also mitigating the overly strong hydrogen bonds prescribed in PBE simulations. We also compare the results of SCAN-based AIMD simulations in the canonical and isothermal-isobaric ensembles. Our results suggest that SCAN provides a reliable description for most structural, electronic, and dynamical properties in liquid water. PMID- 29716218 TI - Dielectric boundary effects on the interaction between planar charged surfaces with counterions only. AB - Using Monte Carlo simulations in conjunction with periodic Green's function methods, we study the interaction between planar charged surfaces with point-like counterions only in the presence of dielectric boundaries. Based on the calculated pressure profiles, we derive phase diagrams featuring correlation induced negative pressure and thus attraction between the plates for large coupling parameters, i.e., low temperature or high surface charge and high ion valency. The counterion density profiles for low-dielectric and high-dielectric (metallic) surfaces are very different from the idealized case of a homogeneous dielectric constant. By contrast, the phase diagrams including the critical point and the two-phase coexistence region are rather insensitive to the presence of dielectric boundary effects. The single-image approximation that has been used in simulations before is by comparison with the exact formalism shown to be very accurate for low-dielectric surfaces but not for metallic surfaces. PMID- 29716219 TI - Sequencing of semiflexible polymers of varying bending rigidity using patterned pores. AB - We study the translocation of a semiflexible polymer through extended pores with patterned stickiness, using Langevin dynamics simulations. We find that the consequence of pore patterning on the translocation time dynamics is dramatic and depends strongly on the interplay of polymer stiffness and pore-polymer interactions. For heterogeneous polymers with periodically varying stiffness along their lengths, we find that variation of the block size of the sequences and the orientation results in large variations in the translocation time distributions. We show how this fact may be utilized to develop an effective sequencing strategy. This strategy involving multiple pores with patterned surface energetics can predict heteropolymer sequences having different bending rigidity to a high degree of accuracy. PMID- 29716220 TI - Deviation from equilibrium conditions in molecular dynamic simulations of homogeneous nucleation. AB - We present a comparison between Monte Carlo (MC) results for homogeneous vapour liquid nucleation of Lennard-Jones clusters and previously published values from molecular dynamics (MD) simulations. Both the MC and MD methods sample real cluster configuration distributions. In the MD simulations, the extent of the temperature fluctuation is usually controlled with an artificial thermostat rather than with more realistic carrier gas. In this study, not only a primarily velocity scaling thermostat is considered, but also Nose-Hoover, Berendsen, and stochastic Langevin thermostat methods are covered. The nucleation rates based on a kinetic scheme and the canonical MC calculation serve as a point of reference since they by definition describe an equilibrated system. The studied temperature range is from T = 0.3 to 0.65 epsilon/k. The kinetic scheme reproduces well the isothermal nucleation rates obtained by Wedekind et al. [J. Chem. Phys. 127, 064501 (2007)] using MD simulations with carrier gas. The nucleation rates obtained by artificially thermostatted MD simulations are consistently lower than the reference nucleation rates based on MC calculations. The discrepancy increases up to several orders of magnitude when the density of the nucleating vapour decreases. At low temperatures, the difference to the MC-based reference nucleation rates in some cases exceeds the maximal nonisothermal effect predicted by classical theory of Feder et al. [Adv. Phys. 15, 111 (1966)]. PMID- 29716221 TI - Excited state non-adiabatic dynamics of the smallest polyene, trans 1,3 butadiene. I. Time-resolved photoelectron-photoion coincidence spectroscopy. AB - The ultrafast excited state dynamics of the smallest polyene, trans-1,3 butadiene, were studied by femtosecond time-resolved photoelectron-photoion coincidence (TRPEPICO) spectroscopy. The evolution of the excited state wavepacket, created by pumping the bright 1Bu (pipi*) electronic state at its origin of 216 nm, is projected via one- and two-photon ionization at 267 nm onto several ionization continua. The results are interpreted in terms of Koopmans' correlations and Franck-Condon factors for the excited and cationic states involved. The known predissociative character of the cation excited states is utilized to assign photoelectron bands to specific continua using TRPEPICO spectroscopy. This permits us to report the direct observation of the famously elusive S1(21Ag) dark electronic state during the internal conversion of trans 1,3-butadiene. Our phenomenological analysis permits the spectroscopic determination of several important time constants. We report the overall decay lifetimes of the 11Bu and 21Ag states and observe the re-appearance of the hot ground state molecule. We argue that the apparent dephasing time of the S2(11Bu) state, which leads to the extreme breadth of the absorption spectrum, is principally due to large amplitude torsional motion on the 1Bu surface in conjunction with strong non-adiabatic couplings via conical intersections, whereupon nuclear wavepacket revivals to the initial Franck-Condon region become effectively impossible. In Paper II [W. J. Glover et al., J. Chem. Phys. 148, 164303 (2018)], ab initio multiple spawning is used for on-the-fly computations of the excited state non-adiabatic wavepacket dynamics and their associated TRPEPICO observables, allowing for direct comparisons of experiment with theory. PMID- 29716222 TI - On-top density functionals for the short-range dynamic correlation between electrons of opposite and parallel spin. AB - Separate, one-parameter, on-top density functionals are derived for the short range dynamic correlation between opposite and parallel-spin electrons, in which the electron-electron cusp is represented by an exponential function. The combination of both functionals is referred to as the Opposite-spin exponential cusp and Fermi-hole correction (OF) functional. The two parameters of the OF functional are set by fitting the ionization energies and electron affinities, of the atoms He to Ar, predicted by ROHF in combination with the OF functional to the experimental values. For ionization energies, the overall performance of ROHF OF is better than completely renormalized coupled-cluster [CR-CC(2,3)] and better than, or as good as, conventional density functional methods. For electron affinities, the overall performance of ROHF-OF is less impressive. However, for both ionization energies and electron affinities of third row atoms, the mean absolute error of ROHF-OF is only 3 kJ mol-1. PMID- 29716223 TI - Condensation and dissociation rates for gas phase metal clusters from molecular dynamics trajectory calculations. AB - In gas phase synthesis systems, clusters form and grow via condensation, in which a monomer binds to an existing cluster. While a hard-sphere equation is frequently used to predict the condensation rate coefficient, this equation neglects the influences of potential interactions and cluster internal energy on the condensation process. Here, we present a collision rate theory-molecular dynamics simulation approach to calculate condensation probabilities and condensation rate coefficients. We use this approach to examine atomic condensation onto 6-56-atom Au and Mg clusters. The probability of condensation depends upon the initial relative velocity (v) between atom and cluster and the initial impact parameter (b). In all cases, there is a well-defined region of b-v space where condensation is highly probable, and outside of which the condensation probability drops to zero. For Au clusters with more than 10 atoms, we find that at gas temperatures in the 300-1200 K range, the condensation rate coefficient exceeds the hard-sphere rate coefficient by a factor of 1.5-2.0. Conversely, for Au clusters with 10 or fewer atoms and for 14- and 28-atom Mg clusters, as cluster equilibration temperature increases, the condensation rate coefficient drops to values below the hard-sphere rate coefficient. Calculations also yield the self-dissociation rate coefficient, which is found to vary considerably with gas temperature. Finally, calculations results reveal that grazing (high b) atom-cluster collisions at elevated velocity (>1000 m s-1) can result in the colliding atom rebounding (bounce) from the cluster surface or binding while another atom dissociates (replacement). The presented method can be applied in developing rate equations to predict material formation and growth rates in vapor phase systems. PMID- 29716224 TI - First-order symmetry-adapted perturbation theory for multiplet splittings. AB - We present a symmetry-adapted perturbation theory (SAPT) for the interaction of two high-spin open-shell molecules (described by their restricted open-shell Hartree-Fock determinants) resulting in low-spin states of the complex. The previously available SAPT formalisms, except for some system-specific studies for few-electron complexes, were restricted to the high-spin state of the interacting system. Thus, the new approach provides, for the first time, a SAPT-based estimate of the splittings between different spin states of the complex. We have derived and implemented the lowest-order SAPT term responsible for these splittings, that is, the first-order exchange energy. We show that within the so called S2 approximation commonly used in SAPT (neglecting effects that vanish as fourth or higher powers of intermolecular overlap integrals), the first-order exchange energies for all multiplets are linear combinations of two matrix elements: a diagonal exchange term that determines the spin-averaged effect and a spin-flip term responsible for the splittings between the states. The numerical factors in this linear combination are determined solely by the Clebsch-Gordan coefficients: accordingly, the S2 approximation implies a Heisenberg Hamiltonian picture with a single coupling strength parameter determining all the splittings. The new approach is cast into both molecular-orbital and atomic-orbital expressions: the latter enable an efficient density-fitted implementation. We test the newly developed formalism on several open-shell complexes ranging from diatomic systems (Li?H, Mn?Mn, ...) to the phenalenyl dimer. PMID- 29716225 TI - A general range-separated double-hybrid density-functional theory. AB - A range-separated double-hybrid (RSDH) scheme which generalizes the usual range separated hybrids and double hybrids is developed. This scheme consistently uses a two-parameter Coulomb-attenuating-method (CAM)-like decomposition of the electron-electron interaction for both exchange and correlation in order to combine Hartree-Fock exchange and second-order Moller-Plesset (MP2) correlation with a density functional. The RSDH scheme relies on an exact theory which is presented in some detail. Several semi-local approximations are developed for the short-range exchange-correlation density functional involved in this scheme. After finding optimal values for the two parameters of the CAM-like decomposition, the RSDH scheme is shown to have a relatively small basis dependence and to provide atomization energies, reaction barrier heights, and weak intermolecular interactions globally more accurate or comparable to range separated MP2 or standard MP2. The RSDH scheme represents a new family of double hybrids with minimal empiricism which could be useful for general chemical applications. PMID- 29716226 TI - Kinetic energy definition in velocity Verlet integration for accurate pressure evaluation. AB - In molecular dynamics (MD) simulations, a proper definition of kinetic energy is essential for controlling pressure as well as temperature in the isothermal isobaric condition. The virial theorem provides an equation that connects the average kinetic energy with the product of particle coordinate and force. In this paper, we show that the theorem is satisfied in MD simulations with a larger time step and holonomic constraints of bonds, only when a proper definition of kinetic energy is used. We provide a novel definition of kinetic energy, which is calculated from velocities at the half-time steps (t - Deltat/2 and t + Deltat/2) in the velocity Verlet integration method. MD simulations of a 1,2-dispalmitoyl sn-phosphatidylcholine (DPPC) lipid bilayer and a water box using the kinetic energy definition could reproduce the physical properties in the isothermal isobaric condition properly. We also develop a multiple time step (MTS) integration scheme with the kinetic energy definition. MD simulations with the MTS integration for the DPPC and water box systems provided the same quantities as the velocity Verlet integration method, even when the thermostat and barostat are updated less frequently. PMID- 29716227 TI - Dynamical resonances of the deuterated CH2+ complex in the electronic ground state: A quantum wavepacket study. AB - We here investigate the effects of isotopic substituents on the vibrational energy levels of the CH2+ complex, supported by the electronic ground (1 2A') potential energy surface (PES) of the H + CH+ reaction. We calculate the transition state spectrum by Fourier transforming the time-autocorrelation function of the initial wavepacket (WP) chosen in the interaction region of the PES. Using the time-dependent WP approach, the dynamical resonances are identified as bound and quasibound in nature, and they are characterized in terms of the eigenfunctions and lifetimes. The present work on the isotopic variants [CHD+(CDH+) and CD2+] is compared with our earlier work [P. Sundaram et al., Phys. Chem. Chem. Phys. 19, 20172 (2017)] on the parent CH2+ species. The isotopic variants reveal a large number of peaks in the spectra and the eigenfunctions exhibit the systematic nodal progressions and periodic orbits, the same as in CH2+. While the CD2+ complex exactly mimics the resonance behaviors (local and hyperspherical modes) of the bound and quasibound CH2+ complex, the CHD+(CDH+) complex reveals only the local mode behaviors at low energies and significantly less number of resonance structures at high energies. Lifetime analysis of the isotopic variants implies that the CD2+ complex survives much longer than the CHD+(CDH+) complex and concludes the work by noting the following order in the decay profile of the deuterated CH2+ resonances as CH2+>CHD+(CDH+) >CD2+. PMID- 29716228 TI - ReaxFF molecular dynamics simulation of intermolecular structure formation in acetic acid-water mixtures at elevated temperatures and pressures. AB - The intermolecular structure formation in liquid and supercritical acetic acid water mixtures was investigated using ReaxFF-based molecular dynamics simulations. The microscopic structures of acetic acid-water mixtures with different acetic acid mole fractions (1.0 >= xHAc >= 0.2) at ambient and critical conditions were examined. The potential energy surface associated with the dissociation of acetic acid molecules was calculated using a metadynamics procedure to optimize the dissociation energy of ReaxFF potential. At ambient conditions, depending on the acetic acid concentration, either acetic acid clusters or water clusters are dominant in the liquid mixture. When acetic acid is dominant (0.4 <= xHAc), cyclic dimers and chain structures between acetic acid molecules are present in the mixture. Both structures disappear at increased water content of the mixture. It was found by simulations that the acetic acid molecules released from these dimer and chain structures tend to stay in a dipole dipole interaction. These structural changes are in agreement with the experimental results. When switched to critical conditions, the long-range interactions (e.g., second or fourth neighbor) disappear and the water-water and acetic acid-acetic acid structural formations become disordered. The simulated radial distribution function for water-water interactions is in agreement with experimental and computational studies. The first neighbor interactions between acetic acid and water molecules are preserved at relatively lower temperatures of the critical region. As higher temperatures are reached in the critical region, these interactions were observed to weaken. These simulations indicate that ReaxFF molecular dynamics simulations are an appropriate tool for studying supercritical water/organic acid mixtures. PMID- 29716229 TI - Free energy study of H2O, N2O5, SO2, and O3 gas sorption by water droplets/slabs. AB - Understanding gas sorption by water in the atmosphere is an active research area because the gases can significantly alter the radiation and chemical properties of the atmosphere. We attempt to elucidate the molecular details of the gas sorption of water and three common atmospheric gases (N2O5, SO2, and O3) by water droplets/slabs in molecular dynamics simulations. The system size effects are investigated, and we show that the calculated solvation free energy decreases linearly as a function of the reciprocal of the number of water molecules from 1/215 to 1/1000 in both the slab and the droplet systems. By analyzing the infinitely large system size limit by extrapolation, we find that all our droplet results are more accurate than the slab results when compared to the experimental values. We also show how the choice of restraints in umbrella sampling can affect the sampling efficiency for the droplet systems. The free energy changes were decomposed into the energetic DeltaU and entropic -TDeltaS contributions to reveal the molecular details of the gas sorption processes. By further decomposing DeltaU into Lennard-Jones and Coulombic interactions, we observe that the DeltaU trends are primarily determined by local effects due to the size of the gas molecule, charge distribution, and solvation structure around the gas molecule. Moreover, we find that there is a strong correlation between the change in the entropic contribution and the mean residence time of water, which is spatially nonlocal and related to the mobility of water. PMID- 29716230 TI - Joint refinement model for the spin resolved one-electron reduced density matrix of YTiO3 using magnetic structure factors and magnetic Compton profiles data. AB - In this paper, we propose a simple cluster model with limited basis sets to reproduce the unpaired electron distributions in a YTiO3 ferromagnetic crystal. The spin-resolved one-electron-reduced density matrix is reconstructed simultaneously from theoretical magnetic structure factors and directional magnetic Compton profiles using our joint refinement algorithm. This algorithm is guided by the rescaling of basis functions and the adjustment of the spin population matrix. The resulting spin electron density in both position and momentum spaces from the joint refinement model is in agreement with theoretical and experimental results. Benefits brought from magnetic Compton profiles to the entire spin density matrix are illustrated. We studied the magnetic properties of the YTiO3 crystal along the Ti-O1-Ti bonding. We found that the basis functions are mostly rescaled by means of magnetic Compton profiles, while the molecular occupation numbers are mainly modified by the magnetic structure factors. PMID- 29716231 TI - Convergence of high order memory kernels in the Nakajima-Zwanzig generalized master equation and rate constants: Case study of the spin-boson model. AB - The Nakajima-Zwanzig generalized master equation provides a formally exact framework to simulate quantum dynamics in condensed phases. Yet, the exact memory kernel is hard to obtain and calculations based on perturbative expansions are often employed. By using the spin-boson model as an example, we assess the convergence of high order memory kernels in the Nakajima-Zwanzig generalized master equation. The exact memory kernels are calculated by combining the hierarchical equation of motion approach and the Dyson expansion of the exact memory kernel. High order expansions of the memory kernels are obtained by extending our previous work to calculate perturbative expansions of open system quantum dynamics [M. Xu et al., J. Chem. Phys. 146, 064102 (2017)]. It is found that the high order expansions do not necessarily converge in certain parameter regimes where the exact kernel show a long memory time, especially in cases of slow bath, weak system-bath coupling, and low temperature. Effectiveness of the Pade and Landau-Zener resummation approaches is tested, and the convergence of higher order rate constants beyond Fermi's golden rule is investigated. PMID- 29716232 TI - Erratum: "New investigation of the nu3 C-H stretching region of 12CH4 through the analysis of high temperature infrared emission spectra" [J. Chem. Phys. 148, 134306 (2018)]. PMID- 29716233 TI - Direct dynamics simulations of the unimolecular dissociation of dioxetane: Probing the non-RRKM dynamics. AB - In a previous UB3LYP/6-31G* direct dynamics simulation, non-Rice-Ramsperger Kassel-Marcus (RRKM) unimolecular dynamics was found for vibrationally excited 1,2-dioxetane (DO); [R. Sun et al., J. Chem. Phys. 137, 044305 (2012)]. In the work reported here, these dynamics are studied in more detail using the same direct dynamics method. Vibrational modes of DO were divided into 4 groups, based on their characteristic motions, and each group excited with the same energy. To compare with the dynamics of these groups, an additional group of trajectories comprising a microcanonical ensemble was also simulated. The results of these simulations are consistent with the previous study. The dissociation probability, N(t)/N(0), for these excitation groups were all different. Groups A, B, and C, without initial excitation in the O-O stretch reaction coordinate, had a time lag to of 0.25-1.0 ps for the first dissociation to occur. Somewhat surprisingly, the C-H stretch Group A and out-of-plane motion Group C excitations had exponential dissociation probabilities after to, with a rate constant ~2 times smaller than the anharmonic RRKM value. Groups B and D, with excitation of the H-C-H bend and wag, and ring bend and stretch modes, respectively, had bi-exponential dissociation probabilities. For Group D, with excitation localized in the reaction coordinate, the initial rate constant is ~7 times larger than the anharmonic RRKM value, substantial apparent non-RRKM dynamics. N(t)/N(0) for the random excitation trajectories was non-exponential, indicating intrinsic non-RRKM dynamics. For the trajectory integration time of 13.5 ps, 9% of these trajectories did not dissociate in comparison to the RRKM prediction of 0.3%. Classical power spectra for these trajectories indicate they have regular intramolecular dynamics. The N(t)/N(0) for the excitation groups are well described by a two-state coupled phase space model. From the intercept of N(t)/N(0) with random excitation, the anharmonic correction to the RRKM rate constant is approximately a factor of 1.5. PMID- 29716234 TI - Impact of amphiphilic molecules on the structure and stability of homogeneous sphingomyelin bilayer: Insights from atomistic simulations. AB - Modulation of lipid membrane properties due to the permeation of amphiphiles is an important biological process pertaining to many applications in the field of pharmaceutics, toxicology, and biotechnology. Sphingolipids are both structural and functional lipids that constitute an important component of mechanically stable and chemically resistant outer leaflets of plasma membranes. Here, we present an atomistic molecular dynamics simulation study to appreciate the concentration-dependent effects of small amphiphilic molecules, such as ethanol, acetone, and dimethyl sulfoxide (DMSO), on the structure and stability of a fully hydrated homogeneous N-palmitoyl-sphingomyelin (PSM) bilayer. The study reveals an increase in the lateral expansion of the bilayer along with disordering of the hydrophobic lipid tails on increasing the concentration of ethanol. At higher concentrations of ethanol, rupturing of the bilayer is quite evident through the analysis of partial electron density profiles and lipid tail order parameters. For ethanol containing systems, permeation of water molecules in the hydrophobic part of the bilayer is allowed through local defects made due to the entry of ethanol molecules via ethanol-ethanol and ethanol-PSM hydrogen bonds. Moreover, the extent of PSM-PSM hydrogen bonding decreases with increasing ethanol concentration. On the other hand, acetone and DMSO exhibit minimal effects on the stability of the PSM bilayer at their lower concentrations, but at higher concentrations they tend to enhance the stability of the bilayer. The simulated potential of mean force (PMF) profiles for the translocation of the three solutes studied reveal that the free-energy of transfer of an ethanol molecule across the PSM lipid head region is lower than that for acetone and DMSO molecules. However, highest free-energy rise in the core hydrophobic part of the bilayer is observed for the DMSO molecule, whereas the ethanol and acetone PMF profiles show a lower barrier in the hydrophobic region of the bilayer. PMID- 29716235 TI - Size-asymmetrical Lennard-Jones solid solutions: Interstitials and substitutions. AB - We present simulation studies of solid solutions formed upon compression of mixtures of Lennard-Jones particles with diameter ratios 2:1 and 3:1. Grand canonical Monte Carlo (GCMC) and Gibbs-Duhem integration were used to determine the compositions of coexisting solid and liquid phases at several pressures and fixed temperature. Concentrations of small particles dissolved in interstitial sites of the large-particle lattice, under liquid-solid coexistence conditions, were determined directly from GCMC simulations. Indirect methods were used to calculate levels of small particles dissolved substitutionally, either singly or in plural, with the average number of small solutes occupying a lattice site vacated by a large particle increasing with higher pressure. In the cases studied, the fraction of small solutes occupying these substitutional sites was found to be small (2% or lower, depending on the mixture and conditions), but to stay roughly constant with increasing pressure. Structural and dynamic characteristics of the solid solutions are described and compared with reported characteristics of the related interstitial solid solution formed by hard spheres. PMID- 29716236 TI - Activity statistics in a colloidal glass former: Experimental evidence for a dynamical transition. AB - In a dense colloidal suspension at a volume fraction below the glass transition, we follow the trajectories of an assembly of tracers over a large time window. We define a local activity, which quantifies the local tendency of the system to rearrange. We determine the statistics of the time integrated activity, and we argue that it develops a low activity tail that comes together with the onset of glassy-like behavior and heterogeneous dynamics. These rare events may be interpreted as the reflection of an underlying dynamic phase transition. PMID- 29716237 TI - Toward the detection of the triatomic negative ion SPN-: Spectroscopy and potential energy surfaces. AB - High level theoretical calculations using coupled-cluster theory were performed to provide an accurate description of the electronic structure, spectroscopic properties, and stability of the triatomic negative ion comprising S, N, and P. The adiabatic electron affinities (AEAs) and vertical detachment energies (VDEs) of PNS, SPN, PSN, and cyc-PSN were calculated. The predicted AEA and VDE of the linear SPN isomer are large: 2.24 and 3.04 eV, respectively. The potential energy surfaces (PESs) of the lowest-lying electronic states of the SPN- isomer along the PN and SP bond lengths and bond angle were mapped. A set of spectroscopic parameters for SPN-, PNS-, and PSN- in their electronic ground states is obtained from the 3D PESs to help detect these species in the gas phase. The electronic excited state SPN-(12A") is predicted to be stable with a long lifetime calculated to be 189.7 MUs. The formation of SPN- in its electronic ground state through the bimolecular collision between S- + PN and N + PS- is also discussed. PMID- 29716238 TI - On the simultaneous inversion of micro-perforated panels' parameters: Application to single and double air-cavity backed systems. AB - This study deals with the deduction of parameters of Micro-Perforated Panel (MPP) systems from impedance tube data. It is shown that there is an ambiguity problem that exists between the MPP thickness and its open area ratio. This problem makes it difficult to invert the reflection coefficient data fitting and therefore to deduct the MPP parameters. A technique is proposed to reduce this ambiguity by using an equation that links the hole diameter to the open area ratio. Reflection coefficient data obtained for two specimens with different characteristics is employed for searching the MPP parameters using a simulated annealing algorithm. The results obtained demonstrate the effectiveness of this technique. PMID- 29716239 TI - Reduction of sound-evoked midbrain responses observed by functional magnetic resonance imaging following acute acoustic noise exposure. AB - Short duration and high intensity acoustic exposures can lead to temporary hearing loss and auditory nerve degeneration. This study investigates central auditory system function following such acute exposures after hearing loss recedes. Adult rats were exposed to 100 dB sound pressure level noise for 15 min. Auditory brainstem responses (ABRs) were recorded with click sounds to check hearing thresholds. Functional magnetic resonance imaging (fMRI) was performed with tonal stimulation at 12 and 20 kHz to investigate central auditory changes. Measurements were performed before exposure (0D), 7 days after (7D), and 14 days after (14D). ABRs show an ~6 dB threshold shift shortly after exposure, but no significant threshold differences between 0D, 7D, and 14D. fMRI responses are observed in the lateral lemniscus (LL) and inferior colliculus (IC) of the midbrain. In the IC, responses to 12 kHz are 3.1 +/- 0.3% (0D), 1.9 +/- 0.3% (7D), and 2.9 +/- 0.3% (14D) above the baseline magnetic resonance imaging signal. Responses to 20 kHz are 2.0 +/- 0.2% (0D), 1.4 +/- 0.2% (7D), and 2.1 +/- 0.2% (14D). For both tones, responses at 7D are less than those at 0D (p < 0.01) and 14D (p < 0.05). In the LL, similar trends are observed. Acute exposure leads to functional changes in the auditory midbrain with timescale of weeks. PMID- 29716240 TI - Simplex based three-dimensional eigenray search for underwater predictions. AB - A solution for the calculation of three-dimensional (3D) eigenrays based on Simplex optimization, implemented in a 3D Gaussian beam model, is investigated in this paper. The validation and performance of the solution were analyzed through comparisons against an equivalent (flat) two-dimensional waveguide, and against results of a tank scale experiment presented in Sturm and Korakas [(2013). J. Acoust. Soc. Am. 133(1), 108-118], in which cross-slope propagation in a wedge waveguide with a mild slope was considered. It was found that the search strategy based on Simplex optimization was able to calculate efficiently and accurately 3D eigenrays, thus providing predictions of arrival patterns along cross-slope range, which replicated elaborate patterns of mode shadow zones, intra-mode interference, and mode arrivals. A remarkable aspect of the search strategy was its ability to provide accurate values of initial eigenray elevation and azimuth, within the accuracy defined for the eigenray to arrive at the location of a given hydrophone. PMID- 29716241 TI - Erratum: Exploiting pattern transformation to tune phononic band gaps in a two dimensional granular crystal [J. Acoust. Soc. Am. 131, EL475-EL480 (2012)]. PMID- 29716242 TI - Fast raypath separation based on low-rank matrix approximation in a shallow-water waveguide. AB - Subspace algorithms based on higher-order cumulants were developed to achieve high-resolution separation in non-Gaussian processes. However, singular value decomposition (SVD) of a huge matrix is an unavoidable step of these algorithms. The memory space and running time required by the decomposition are super-linear with respect to the size of the matrix, which is prohibitive in terms of practical applications. Thus, in this paper, a fast raypath separation algorithm based on low-rank matrix approximation is proposed in a shallow-water waveguide. The experimental results illustrate that the proposed algorithm dramatically reduces the consumption of time and space, with arbitrarily small error, compared to conventional higher-order cumulant-based algorithms. PMID- 29716243 TI - Thermoacoustics: A Unifying Perspective for Some Engines and Refrigerators, Second Edition. PMID- 29716244 TI - A frame selective dynamic programming approach for noise robust pitch estimation. AB - The principles of the existing pitch estimation techniques are often different and complementary in nature. In this work, a frame selective dynamic programming (FSDP) method is proposed which exploits the complementary characteristics of two existing methods, namely, sub-harmonic to harmonic ratio (SHR) and sawtooth-wave inspired pitch estimator (SWIPE). Using variants of SHR and SWIPE, the proposed FSDP method classifies all the voiced frames into two classes-the first class consists of the frames where a confidence score maximization criterion is used for pitch estimation, while for the second class, a dynamic programming (DP) based approach is proposed. Experiments are performed on speech signals separately from KEELE, CSLU, and PaulBaghsaw corpora under clean and additive white Gaussian noise at 20, 10, 5, and 0 dB SNR conditions using four baseline schemes including SHR, SWIPE, and two DP based techniques. The pitch estimation performance of FSDP, when averaged over all SNRs, is found to be better than those of the baseline schemes suggesting the benefit of applying smoothness constraint using DP in selected frames in the proposed FSDP scheme. The VuV classification error from FSDP is also found to be lower than that from all four baseline schemes in almost all SNR conditions on three corpora. PMID- 29716245 TI - A wavenumber approach to quantifying the isotropy of the sound field in reverberant spaces. AB - This study proposes an experimental method for evaluating isotropy in enclosures, based on an analysis of the wavenumber spectrum in the spherical harmonics domain. The wavenumber spectrum, which results from expanding an arbitrary sound field into a plane-wave basis, is used to characterize the spatial properties of the observed sound field. Subsequently, the obtained wavenumber spectrum is expanded into a series of spherical harmonics, and the moments from this spherical expansion are used to characterize the isotropy of the wave field. The analytical framework is presented. The method is examined numerically and experimentally, based on array measurements in four chambers: two anechoic chambers (one with a single source and another with an array of 52 sources), a reverberation chamber, and the same reverberation chamber with a sample of absorbing material on the floor. The results indicate that the proposed methodology is suitable for assessing the isotropy of a sound field. PMID- 29716246 TI - Extending standard urban outdoor noise propagation models to complex geometries. AB - A hybrid method that combines a noise engineering method and the 2.5D boundary element method approximates outdoor sound propagation in large domains with complex objects more accurately than noise engineering methods alone and more efficiently than reference methods alone. Noise engineering methods (e.g., ISO 9613-2 or CNOSSOS-EU) efficiently approximate sound levels from roads, railways, and industrial sources in cities for simple, box-shaped geometries by first finding the propagation paths between the source and receiver, then applying attenuations (e.g., geometrical divergence and atmospheric absorption) to each path, and finally incoherently summing all of the path contributions. Standard engineering methods cannot model more complicated geometries but introducing an additional attenuation term quantifies the influence of complex objects. Calculating this extra attenuation term requires reference calculations but performing reference computations for each path is too computationally expensive. Thus, the extra attenuation term is linearly interpolated from a data table containing the corrections for many source/receiver positions and frequencies. The 2.5D boundary element method produces the levels for the real and simplified geometries and subtracting them yields a table of corrections. For a T-shaped barrier with two buildings, this approach reduces the mean error by approximately 2 dBA compared to a standard engineering method. PMID- 29716247 TI - Underwater acoustic source localization using generalized regression neural network. AB - In this paper, machine learning is introduced to source localization in underwater ocean waveguides. Source localization is regarded as a supervised learning regression problem and is solved by generalized regression neural network (GRNN). As a feed-forward network, GRNN is built using training data with fixed structure and configuration. The normalized sample covariance matrix (SCM) formed over a number of snapshots, and the corresponding source position are used as the input and output for GRNN. The source position can be estimated directly from the normalized SCM with GRNN; the proposed approach is thus in theory data driven. In addition, there is only one parameter, the spread factor, to be learned for GRNN. The optimal spread factor is determined using cross-validation. The regression method of GRNN is compared with the classification method of feed forward neural network (FNN), as well as the classical method of matched field processing (MFP) for vertical array data from the SWellEx-96 experiment. The results show that GRNN achieves a satisfactory localization performance that outperforms both FNN and MFP. The proposed approach provides an alternative way for underwater source localization, especially in the absence of a priori environmental information or an appropriate propagation model. PMID- 29716249 TI - Linear and nonlinear ultrasound simulations using the discontinuous Galerkin method. AB - A nodal discontinuous Galerkin (DG) code based on the nonlinear wave equation is developed to simulate transient ultrasound propagation. The DG method has high order accuracy, geometric flexibility, low dispersion error, and excellent scalability, so DG is an ideal choice for solving this problem. A nonlinear acoustic wave equation is written in a first-order flux form and discretized using nodal DG. A dynamic sub-grid scale stabilization method for reducing Gibbs oscillations in acoustic shock waves is then established. Linear and nonlinear numerical results from a two-dimensional axisymmetric DG code are presented and compared to numerical solutions obtained from linear and Khokhlov-Zabolotskaya Kuznetsov-based simulations in FOCUS. The numerical results indicate that these nodal DG simulations capture nonlinearity, thermoviscous absorption, and diffraction for both flat and focused pistons in homogeneous media. PMID- 29716250 TI - A finite element approach for the calculation of self and mutual radiation impedances of resonators. AB - A simulation method relying on the finite and infinite element techniques and a post-processing routine is introduced in this paper for the calculation of self and mutual radiation impedances of horns and acoustical resonators. The proposed procedure can be applied for the evaluation of the frequency dependent coupling impedance matrix of an arbitrary number of ducts in an arbitrary geometrical arrangement. The resulting impedance matrix can be utilized in a one-dimensional low-frequency waveguide model in order to calculate the input impedance or admittance function of the system. The applicability and usefulness of the proposed methodology is demonstrated by multiple simulation cases. PMID- 29716248 TI - Correlations between otoacoustic emissions and performance in common psychoacoustical tasks. AB - Performance was measured on seven common psychoacoustical tasks for about 75 highly trained subjects. Because some psychoacoustical outcomes varied by race, the subjects were partitioned into White and Non-White categories for analysis. Sex, race, and menstrual-cycle differences in performance are described in a companion paper [McFadden, Pasanen, Maloney, Leshikar, and Pho (2018). J. Acoust. Soc. Am. 143, 2338-2354]. Also measured for all subjects were three types of otoacoustic emissions (OAEs): spontaneous otoacoustic emissions (SOAEs), click evoked otoacoustic emissions (CEOAEs), and distortion-product otoacoustic emissions (DPOAEs). The experimental question was whether and how OAEs were correlated with psychoacoustical performance. In accord with past findings, the SOAEs and CEOAEs exhibited substantial sex and race differences, but the DPOAEs did not. Somewhat surprisingly, the correlations between OAEs and psychoacoustical performance were generally weak. No form of OAE was highly correlated with any psychoacoustical task for both sexes within a race category. Thus, there was no compelling evidence that the mechanisms underlying OAEs also contribute systematically to performance in any of the simultaneous or temporal masking tasks studied here. Especially surprising were the weak correlations between OAEs and detection of a tone in the quiet. Apparently individual differences in psychoacoustical performance reside more in post-cochlear (neural) mechanisms than in individual differences in the cochlear ("mechanical") mechanisms underlying the OAEs measured here. PMID- 29716251 TI - Hearing sensitivity to gliding rippled spectrum patterns. AB - The sensitivity of human hearing to gliding rippled spectrum patterns of sound was investigated. The test signal was 2-oct wide rippled noise with the ripples gliding along the frequency scale. Both ripple density and gliding velocity were frequency-proportional across the signal band; i.e., the density was specified in ripples/oct and the velocity was specified in oct/s and ripple/s. The listener was required to discriminate between a test signal with gliding ripples and a non rippled reference signal. Limits of gliding velocity were measured as a function of ripple density. The ripple gliding velocity limit decreased with an increasing ripple density: from 388.9 oct/s (388.9 ripple/s) at a ripple density of 1 ripple/oct to 11.3 oct/s (79.1 ripple/s) at a density of 7 ripple/oct. These tendencies could be approximated by log/log regression functions with slopes of 1.71 for the velocity expressed in oct/s and 0.71 for the velocity expressed in ripple/s. A qualitative model based on combined action of the excitation-pattern and the temporal-processing mechanism is suggested to explain the results. PMID- 29716252 TI - Erratum: Strength and wave parameters for sound propagation in random media [J. Acoust. Soc. Am. 141(3), 2079-2092 (2017)]. PMID- 29716253 TI - A distributed subband valley fusion (DSVF) method for low frequency broadband target localization. AB - A distributed subband valley fusion method is proposed in this paper for target localization for a multi-array fusion system. Instead of employing two-step processing like the traditional bearings-only target localization (BOTL) methods, the target location estimate is directly obtained from the intersection of the estimated bearing line of each array, which is automatically produced after applying a subband valley energy detection process to the reciprocal of the steered response power over predefined grid points. Bearing information at all frequencies and ranges are used to generate the bearing line and the intersection structure, leading to higher localization accuracy in comparison with the BOTL methods. In multiple-target situations, the data association problem is solved by distinguishing true targets from the ghost ones from the power and the number of bearing lines at the corresponding intersection grid point. The method is subsequently tested by the SWellEx-96 shallow water experiment data set. Simulation and experimental results demonstrate the localization accuracy of the proposed method. PMID- 29716254 TI - Estimation of polydispersity in aggregating red blood cells by quantitative ultrasound backscatter analysis. AB - Quantitative ultrasound techniques based on the backscatter coefficient (BSC) have been commonly used to characterize red blood cell (RBC) aggregation. Specifically, a scattering model is fitted to measured BSC and estimated parameters can provide a meaningful description of the RBC aggregates' structure (i.e., aggregate size and compactness). In most cases, scattering models assumed monodisperse RBC aggregates. This study proposes the Effective Medium Theory combined with the polydisperse Structure Factor Model (EMTSFM) to incorporate the polydispersity of aggregate size. From the measured BSC, this model allows estimating three structural parameters: the mean radius of the aggregate size distribution, the width of the distribution, and the compactness of the aggregates. Two successive experiments were conducted: a first experiment on blood sheared in a Couette flow device coupled with an ultrasonic probe, and a second experiment, on the same blood sample, sheared in a plane-plane rheometer coupled to a light microscope. Results demonstrated that the polydisperse EMTSFM provided the best fit to the BSC data when compared to the classical monodisperse models for the higher levels of aggregation at hematocrits between 10% and 40%. Fitting the polydisperse model yielded aggregate size distributions that were consistent with direct light microscope observations at low hematocrits. PMID- 29716256 TI - A comparison of three geoacoustic models using Bayesian inversion and selection techniques applied to wave speed and attenuation measurements. AB - Many geoacoustic models have been developed to study sandy sediments. In this work, Bayesian inference techniques are used to compare three such models: the VGS(lambda) model, the most recent of Buckingham's viscous grain-shearing models, the Biot-Stoll poroelastic model, and an extension to the Biot-Stoll model proposed by Chotiros called the corrected and reparametrized extended Biot (CREB) model. First, Bayesian inversion is applied to wave speed and attenuation measurements previously made in the laboratory to determine the degree to which each of the model input parameters can be resolved by wave speed and attenuation data. Then, Bayesian model selection techniques are utilized to assess the degree to which the predictions of these models match the measured data and to ascertain the Bayesian evidence in favor of each. Through these studies it is determined that the VGS(lambda) and CREB models outperform the Biot-Stoll model, both in terms of parameter resolution and in their ability to produce predictions in agreement with measurements. The VGS(lambda) model is seen to have the highest degree of Bayesian evidence in its favor. PMID- 29716255 TI - Acoustic vaporization threshold of lipid-coated perfluoropentane droplets. AB - Phase shift droplets vaporizable by acoustic stimulation offer the advantages of producing microbubbles as contrast agents in situ as well as higher stability and the possibility of achieving smaller sizes. Here, the acoustic droplet vaporization (ADV) threshold of a suspension of droplets with a perfluoropentane (PFP) core (diameter 400-3000 nm) is acoustically measured as a function of the excitation frequency in a tubeless setup at room temperature. The changes in scattered responses-fundamental, sub-, and second harmonic-are investigated, a quantitative criterion is used to determine the ADV phenomenon, and findings are discussed. The average threshold obtained using three different scattered components increases with frequency-1.05 +/- 0.28 MPa at 2.25 MHz, 1.89 +/- 0.57 MPa at 5 MHz, and 2.34 +/- 0.014 MPa at 10 MHz. The scattered response from vaporized droplets was also found to qualitatively match with that from an independently prepared lipid-coated microbubble suspension in magnitude as well as trends above the determined ADV threshold value. PMID- 29716257 TI - Assessing the importance of several acoustic properties to the perception of spontaneous speech. AB - Spoken language manifests itself as change over time in various acoustic dimensions. While it seems clear that acoustic-phonetic information in the speech signal is key to language processing, little is currently known about which specific types of acoustic information are relatively more informative to listeners. This problem is likely compounded when considering reduced speech: Which specific acoustic information do listeners rely on when encountering spoken forms that are highly variable, and often include altered or elided segments? This work explores contributions of spectral shape, f0 contour, target duration, and time varying intensity in the perception of reduced speech. This work extends previous laboratory-speech based perception studies into the realm of casual speech, and also provides support for use of an algorithm that quantifies phonetic reduction. Data suggest the role of spectral shape is extensive, and that its removal degrades signals in a way that hinders recognition severely. Information reflecting f0 contour and target duration both appear to aid the listener somewhat, though their influence seems small compared to that of short term spectral shape. Finally, information about time varying intensity aids the listener more than noise filled gaps, and both aid the listener beyond presentation of acoustic context with duration-matched silence. PMID- 29716258 TI - Song recorded near a super-group of humpback whales on a mid-latitude feeding ground off South Africa. AB - Humpback whales (Megaptera novaeangliae) are well known for their complex song which is culturally transmitted and produced by males. However, the function of singing behavior remains poorly understood. Song was observed from 57 min of acoustic recording in the presence of feeding humpback whales aggregated in the near-shore waters on the west coast of South Africa. The structural organization of the song components, lack of overlap between song units, and consistency in relative received level suggest the song was produced by one "singer." The unusual timing and location of song production adds further evidence of plasticity in song production. PMID- 29716259 TI - A computational flow-induced noise and time-reversal technique for analysing aeroacoustic sources. AB - A simulation technique to analyse flow-induced noise problems that combines computational fluid dynamics (CFD), the boundary element method (BEM) and an aeroacoustic time-reversal (TR) source localisation method is presented. Hydrodynamic data are obtained from a high-fidelity CFD simulation of flow past a body and aeroacoustic sources are extracted based on Lighthill's acoustic analogy. The incident pressure field on the body due to the aeroacoustic sources is combined with a BEM representation of the body to obtain the spectrum of the direct, scattered and total acoustic pressure fields at far-field microphone locations. The microphone data are then used as input for the time-reversal simulations which are implemented by numerically solving two-dimensional linearized Euler equations. Decomposing the far-field pressure enables the TR simulation of the direct, scattered and total acoustic fields to be performed separately which yields the location and nature of the corresponding aeroacoustic sources. To demonstrate the hybrid CFD-BEM-TR technique, the sound generated by a cylinder in low Mach number cross-flow is considered. The nature of the aeroacoustic sources at the vortex shedding frequency and its second harmonic for the direct, scattered and total fields are identified. PMID- 29716260 TI - Better-ear glimpsing with symmetrically-placed interferers in bilateral cochlear implant users. AB - For a frontal target in spatially symmetrically placed interferers, normal hearing (NH) listeners can use "better-ear glimpsing" to select time-frequency segments with favorable signal-to-noise ratio in either ear. With an ideal monaural better-ear mask (IMBM) processing, some studies showed that NH listeners can reach similar performance as in the natural binaural listening condition, although interaural phase differences at low frequencies can further improve performance. In principle, bilateral cochlear implant (BiCI) listeners could use the same better-ear glimpsing, albeit without exploiting interaural phase differences. Speech reception thresholds of NH and BiCI listeners were measured in three interferers (speech-shaped stationary noise, nonsense speech, or single talker) either co-located with the target, symmetrically placed at +/-60 degrees , or independently presented to each ear, with and without IMBM processing. Furthermore, a bilateral noise vocoder based on the BiCI electrodogram was used in the same NH listeners. Headphone presentation and direct stimulation with head related transfer functions for spatialization were used in NH and BiCI listeners, respectively. Compared to NH listeners, both NH listeners with vocoder and BiCI listeners showed strongly reduced binaural benefit from spatial separation. However, both groups greatly benefited from IMBM processing as part of the stimulation strategy. PMID- 29716261 TI - Effects of language experience and task demands on talker recognition by children and adults. AB - Talker recognition is a language-dependent process, with listeners recognizing talkers better when the talkers speak a familiar versus an unfamiliar language. This language familiarity effect (LFE) is firmly established in adults, but its developmental trajectory in children is not well understood. Some evidence suggests that the effect already exists in infancy, but little is known about how it unfolds in childhood. The present study explored whether the strength of the LFE increases in early childhood. Adults and children were tested in their native language and a foreign language using a "same-different" talker discrimination task and a "voice line-up" talker recognition task. Results showed that adults and 6-year-olds, but not 5-year-olds, exhibit a robust LFE, suggesting that the effect strengthens as children's language competence increases. For both adults and older children, the emergence of an LFE moreover appeared to be task dependent. This study contributes to a better understanding of how children develop mature talker recognition abilities and when children's processing of indexical and linguistic information in speech approaches adult-like levels. Furthermore, the findings reported here contribute to the debates regarding the origins of the LFE-a hallmark of adult talker recognition. PMID- 29716262 TI - Speech enhancement for cochlear implant recipients. AB - In this study, a single microphone speech enhancement algorithm is proposed to improve speech intelligibility for cochlear implant recipients. The proposed algorithm combines harmonic structure estimation with a subsequent statistical based speech enhancement stage. Traditional minimum mean square error (MMSE) based speech enhancement methods typically focus on statistical characteristics of the noise and track the noise variance along time dimension. The MMSE method is usually effective for stationary noise, but not as useful for non-stationary noise. To address both stationary and non-stationary noise, the current proposed method not only tracks noise over time, but also estimates the noise structure along the frequency dimension by exploiting the harmonic structure of the target speech. Next, the estimated noise is employed in the traditional MMSE framework for speech enhancement. To evaluate the proposed speech enhancement solution, a formal listener evaluation was performed with 6 cochlear implant recipients. The results suggest that a substantial improvement in speech intelligibility performance can be gained for cochlear implant recipients in noisy environments. PMID- 29716263 TI - A transverse isotropic equivalent fluid model combining both limp and rigid frame behaviors for fibrous materials. AB - Due to the manufacturing process, some fibrous materials like glasswool may be transversely isotropic (TI): fibers are mostly parallel to a plane of isotropy within which material properties are identical in all directions whereas properties are different along the transverse direction. The behavior of TI fibrous material is well described by the TI Biot's model, but it requires one to measure several mechanical parameters and to solve the TI Biot's equations. This paper presents an equivalent fluid model that can be suitable for TI materials under certain assumptions. It takes the form of a classical wave equation for the pressure involving an effective density tensor combining both limp and rigid frame behaviors of the material. This scalar wave equation is easily amenable to analytical and numerical treatments with a finite element method. Numerical results, based on the proposed model, are compared with experimental results obtained for two configurations with a fibrous material. The first concerns the absorption of an incident plane wave impinging on a fibrous slab and the second corresponds to the transmission loss of a splitter-type silencer in a duct. Both configurations highlight the effect of the sample orientation and give an illustration of the unusual TI behavior for fluids. PMID- 29716265 TI - Measurement of autoproduct fields in a Lloyd's mirror environment. AB - Conventional frequency-domain acoustic-field analysis techniques are typically limited to the bandwidth of the field under study. However, this limitation may be too restrictive, as prior work suggests that field analyses may be shifted to lower or higher frequencies that are outside the field's original bandwidth [Worthmann and Dowling (2017). J. Acoust. Soc. Am. 141(6), 4579-4590]. This possibility exists because below- and above-band acoustic fields can be mimicked by the frequency-difference and frequency-sum autoproducts, which are quadratic products of frequency-domain complex field amplitudes at a pair of in-band frequencies. For a point source in a homogeneous acoustic half-space with a flat, pressure-release surface (a Lloyd's mirror environment), the prior work predicted high correlations between the autoproducts and genuine out-of-band fields at locations away from the source and the surface. Here, measurements collected in a laboratory water tank validate predictions from the prior theory using 40- to 110 kHz acoustic pulses measured at ranges between 175 and 475 mm, and depths to 400 mm. Autoproduct fields are computed, and cross-correlations between measured autoproduct fields and genuine out-of-band acoustic fields are above 90% for difference frequencies between 0 and 60 kHz, and for sum frequencies between 110 and 190 kHz. PMID- 29716264 TI - Discovering acoustic structure of novel sounds. AB - Natural sounds have substantial acoustic structure (predictability, nonrandomness) in their spectral and temporal compositions. Listeners are expected to exploit this structure to distinguish simultaneous sound sources; however, previous studies confounded acoustic structure and listening experience. Here, sensitivity to acoustic structure in novel sounds was measured in discrimination and identification tasks. Complementary signal-processing strategies independently varied relative acoustic entropy (the inverse of acoustic structure) across frequency or time. In one condition, instantaneous frequency of low-pass-filtered 300-ms random noise was rescaled to 5 kHz bandwidth and resynthesized. In another condition, the instantaneous frequency of a short gated 5-kHz noise was resampled up to 300 ms. In both cases, entropy relative to full bandwidth or full duration was a fraction of that in 300-ms noise sampled at 10 kHz. Discrimination of sounds improved with less relative entropy. Listeners identified a probe sound as a target sound (1%, 3.2%, or 10% relative entropy) that repeated amidst distractor sounds (1%, 10%, or 100% relative entropy) at 0 dB SNR. Performance depended on differences in relative entropy between targets and background. Lower-relative-entropy targets were better identified against higher-relative-entropy distractors than lower-relative entropy distractors; higher-relative-entropy targets were better identified amidst lower-relative-entropy distractors. Results were consistent across signal processing strategies. PMID- 29716266 TI - Mass, height of burst, and source-receiver distance constraints on the acoustic coda phase delay method. AB - This research uses the acoustic coda phase delay method to estimate relative changes in air temperature between explosions with varying event masses and heights of burst. It also places a bound on source-receiver distance for the method. Previous studies used events with different shapes, height of bursts, and masses and recorded the acoustic codas at source-receiver distances less than 1 km. This research further explores the method using explosions that differ in mass (by up to an order of magnitude) and are placed at varying heights. Source receiver distances also cover an area out to 7 km. Relative air temperature change estimates are compared to complementary meteorological observations. Results show that two explosions that differ by an order of magnitude cannot be used with this method because their propagation times in the near field and their fundamental frequencies are different. These differences are expressed as inaccuracies in the relative air temperature change estimates. An order of magnitude difference in mass is also shown to bias estimates higher. Small differences in height of burst do not affect the accuracy of the method. An upper bound of 1 km on source-receiver distance is provided based on the standard deviation characteristics of the estimates. PMID- 29716267 TI - Magnetic resonance imaging based anatomical assessment of tongue impairment due to amyotrophic lateral sclerosis: A preliminary study. AB - Amyotrophic Lateral Sclerosis (ALS) is a neurological disorder, which impairs tongue function for speech and swallowing. A widely used Diffusion Tensor Imaging (DTI) analysis pipeline is employed for quantifying differences in tongue fiber myoarchitecture between controls and ALS patients. This pipeline uses both high resolution magnetic resonance imaging (hMRI) and DTI. hMRI is used to delineate tongue muscles, while DTI provides indices to reveal fiber connectivity within and between muscles. The preliminary results using five controls and two patients show quantitative differences between the groups. This work has the potential to provide insights into the detrimental effects of ALS on speech and swallowing. PMID- 29716268 TI - Numerical analyses of nonlinear behavior of microbubble contrast agents in ultrasound field and effective parameters. AB - This research aims to investigate the effects of some parameters on the nonlinear dynamics of an encapsulated microbubble. In the present study, the radial behavior of an encapsulated microbubble with modified Rayleigh-Plesset equation presented by Marmottant, van der Meer, Emmer, Versluis, de Jong, Hilgenfeldt, and Lohse [J. Acoust. Soc. Am. 118(6), 3499-3505 (2005)] is solved with matlab programming software. Radial dynamics of an individual microbubble for a free and coated state and effects of the added shell are also investigated. Results show that dilatational interfacial viscosity ( ks) of the shell and changes of surface tension have significant effects on the amplitude of oscillations, bubble dynamics, and bubble surface velocity. Regarding the fact that the velocity of the bubble surface has a significant role in stability and collapse of the bubble, it can be noted that this velocity is reduced considerably by adding the shell. Because of extensive usage of nonlinear microbubble oscillations in medical imaging techniques, the nonlinear response of a lipid-coated contrast agent called "compression-only" behavior is studied and effective parameters on this behavior are investigated. The results of bubble radius excursion reveal the fact that excitation frequency, pressure, and dilatational interfacial viscosity of the bubble affect the compression-only behavior. PMID- 29716270 TI - Speaking rhythmically improves speech recognition under "cocktail-party" conditions. AB - This study examines whether speech rhythm affects speech recognition under "cocktail-party" conditions. Against a two-talker masker, but not a speech spectrum noise masker, recognition of the last (third) keyword in a normal rhythmic sentence was significantly better than that of the first keyword. However, this word-position-related speech-recognition improvement disappeared for rhythmically hybrid target sentences that were constructed by grouping parts from different sentences with different artificially modulated rhythms (rates) (fast, normal, or slow). Thus, the normal rhythm with a constant rate plays a role in improving speech recognition against informational speech masking, probably through a build-up of temporal prediction for target words. PMID- 29716271 TI - Supra-aural transducer-related artifact contributes to overestimation of noise induced hearing loss. AB - This study compared the effects of supra-aural and insert receivers on the prevalence of noise-induced hearing loss (NIHL) in young adults. NIHL prevalence was found to be substantially higher when hearing thresholds were obtained with supra-aural compared to insert receivers on the same subjects. Real-ear sound pressure levels at 4000, 6000, and 8000 Hz were the major predictors of notched audiograms obtained with supra-aural headphones. Distortion-product otoacoustic emissions were not significantly different between ears with and without notched audiograms obtained with supra-aural headphones. The results demonstrated that supra-aural transducer-related artifacts can mimic a notch-like pattern leading to overestimation of NIHL prevalence. PMID- 29716272 TI - A higher-order "figure-8" sensor and an isotropic sensor-For azimuth-elevation bivariate direction finding. AB - A "p-u probe" (also known as a "p-v probe") comprises one pressure-sensor (which is isotropic) and one uni-axial particle-velocity sensor (which has a "figure-8" bi-directional spatial directivity). This p-u probe may be generalized, by allowing the figure-8 bi-directional sensor to have a higher order of directivity. This higher-order p-u probe has not previously been investigated anywhere in the open literature (to the best knowledge of the present authors). For such a sensing system, this paper is first (1) to develop closed-form eigen based signal-processing algorithms for azimuth-elevation direction finding; (2) to analytically derive the associated Cramer-Rao lower bounds (CRB), which are expressed explicitly in terms of the two constituent sensors' spatial geometry and in terms of the figure-8 sensor's directivity order; (3) to verify (via Monte Carlo simulations) the proposed direction-of-arrival estimators' efficacy and closeness to the respective CRB. Here, the higher-order p-u probe's two constituent sensors may be spatially displaced. PMID- 29716273 TI - The discrimination of voice cues in simulations of bimodal electro-acoustic cochlear-implant hearing. AB - In discriminating speakers' voices, normal-hearing individuals effectively use two vocal characteristics, vocal pitch (related to fundamental frequency, F0) and vocal-tract length (VTL, related to speaker size). Typical cochlear-implant users show poor perception of these cues. However, in implant users with low-frequency residual acoustic hearing, this bimodal electro-acoustic stimulation may provide additional voice-related cues, such as low-numbered harmonics and formants, which could improve F0/VTL perception. In acoustic noise-vocoder simulations, where added low-pass filtered speech simulated residual hearing, a strong bimodal benefit was observed for F0 perception. No bimodal benefit was observed for VTL, which seems to mainly rely on vocoder spectral resolution. PMID- 29716274 TI - Interface waves in multilayered plates. AB - In this paper, the characteristic equation of interface waves in multilayered plates is derived. With a reasonable assumption undertaken for the potential functions of longitudinal and shear waves in the nth layer medium, the characteristic equation of interface waves in the N-layered plate is derived and presented in a determinant form. The particle displacement and stress components are further presented in explicit forms. The dispersion curves and wave structures of interface waves in both a three-layered Al-Steel-Ti and a four layered Steel-Al-Steel-Ti plate are displayed subsequently. It is observed in dispersion curves that obvious dispersion occurs on the low frequency band, whereas the phase velocities converge to the corresponding true Stoneley wave mode velocities at high frequency, and the number of interface wave modes equals the number of interfaces in multilayered plates (if all individual interfaces satisfy the existence condition of Stoneley waves). The wave structures reveal that the displacement components of interface waves are relatively high at interfaces, and the amplitude distribution varies from frequency to frequency. In the end, a similarly structured three-layered Al-Steel-Ti plate is tested. In this experiment, theoretical group velocity and experimental group velocity are compared. According to the discussion and comparison, the predicted group velocities are in good agreement with the experimental results. Thus, the theory of interface wave in multilayered plates is proved. As a result, the proposed theoretical approach represents a leap forward in the understanding of how to promote the characteristic study and practical applications of interface waves in multilayered structures. PMID- 29716276 TI - Displacement of a bubble by acoustic radiation force into a fluid-tissue interface. AB - Microbubbles in an ultrasound beam experience a primary Bjerknes force, which pushes the microbubbles against a fluid-tissue interface and deforms the tissue. This interaction has been used to measure tissue elasticity and is a common interaction in many therapeutic and diagnostic applications, but the mechanisms of deformation, and how the deformation dynamic depends on the bubble and ultrasound parameters, remain unknown. In this study, a mathematical model is proposed for the displacement of a bubble onto a fluid-tissue interface and the tissue deformation in response to the primary Bjerknes force. First, a model was derived for static loading and the model's prediction of bubble-mediated tissue displacement and stresses in tissue were explored. Second, the model was updated for dynamic loading. The results showed that the bubble is both displaced by the applied force and changes its shape. The bubble displacement changes nonlinearly with the applied force. The stress values in tissue are quite high for a distance within one radius of the bubble from the bubble surface. The model proposed here is permissible in human tissue and can be used for biomedical ultrasound applications, including material characterization. PMID- 29716275 TI - Amplitude modulation detection with a short-duration carrier: Effects of a precursor and hearing loss. AB - This study tests the hypothesis that amplitude modulation (AM) detection will be better under conditions where basilar membrane (BM) response growth is expected to be linear rather than compressive. This hypothesis was tested by (1) comparing AM detection for a tonal carrier as a function of carrier level for subjects with and without cochlear hearing impairment (HI), and by (2) comparing AM detection for carriers presented with and without an ipsilateral notched-noise precursor, under the assumption that the precursor linearizes BM responses. Average AM detection thresholds were approximately 5 dB better for subjects with HI than for subjects with normal hearing (NH) at moderate-level carriers. Average AM detection for low-to-moderate level carriers was approximately 2 dB better with the precursor than without the precursor for subjects with NH, whereas precursor effects were absent or smaller for subjects with HI. Although effect sizes were small and individual differences were noted, group differences are consistent with better AM detection for conditions where BM responses are less compressive due to cochlear hearing loss or due to a reduction in cochlear gain. These findings suggest the auditory system may quickly adjust to the local soundscape to increase effective AM depth and improve signal-to-noise ratios. PMID- 29716277 TI - Effects of the container on structure function with impedance map analysis of dense scattering media. AB - Quantitative ultrasound (QUS) can be used to estimate acoustic properties of tissue microstructure. In one approach to QUS, the backscatter coefficient (BSC) is utilized to quantify and classify tissue state. From the BSC, parametric models can be constructed to relate the frequency-dependent BSC to geometrical properties of the underlying tissue. However, most of these parametric models are based on analytic expressions (e.g., Gaussian function) and not on actual tissue morphology. Impedance map analysis has been proposed to help identify sources of ultrasonic scattering in tissues and to develop improved models of scattering. Previously, two-dimensional impedance maps (2DZMs) were demonstrated to provide tissue models of three-dimensional (3D) structures for sparse scattering media. In the current study, 2DZMs analysis of dense scatterer media combining the structure function with impedance map analysis was studied through a series of simulations. The simulation analysis demonstrated that the correlation coefficient and power spectrum could be estimated for a dense collection of spheres using 2DZMs. The current finding implies that 2DZMs can capture information about the 3D spatial positions of scatterers in addition to information about the size and shape of the scatterers for a dense scattering media, which is expected to be encountered in many tissues. PMID- 29716278 TI - Perception of nonlinear distortion on emulation of frequency responses of headphones. AB - The equalization of headphones can force transducers to work in a non-linear condition, producing non-linear distortion. Depending on the headphone model and the reproduction level, that distortion can be audible. In this study, headphones of diverse quality and price were compelled to emulate the same target frequency response and the non-linear distortion was measured. A Diagonal Volterra model was used to simulate the different headphones with and without distortion. A perceptual test was carried out to determine the level of reproduction above which non-linear distortion is perceived for each headphone model. High correlation has been found between the level of detected distortion and retail prices of headphones. PMID- 29716279 TI - Type of activity and order of experimental conditions affect noise annoyance by identifiable and unidentifiable transportation noise. AB - Previous studies have shown that identifiability of sound sources influence noise annoyance levels. The aim of the present experiment was to additionally study the effects of actively performing a task versus a less active pastime on noise annoyance. This was done by asking participants to perform a task (task condition) or read a magazine of their choice (no-task condition), while listening to identifiable and unidentifiable samples of transportation noise at varying sound exposure levels (55-85 ASEL). Annoyance was higher for identifiable samples (recordings) than for unidentifiable transformed samples (with equal spectral energy and envelope). Although there was no main effect of activity type on noise annoyance, for the transformed samples, an interaction was found between activity type and sound exposure levels: annoyance started lower in the no-task condition, but rose more steeply with ascending exposure levels than was the case during task performance (large effect). When assessing order effects, it was found that annoyance was higher when the task condition came first, especially for lower sound exposure levels (large effects). It is therefore concluded that the type of activity and the condition order do influence noise annoyance but in interaction with exposure levels, the type of noise and habituation. PMID- 29716280 TI - Acoustic nonlinearity parameter measurements in a pulse-echo setup with the stress-free reflection boundary. AB - This paper describes the acoustic nonlinearity parameter (beta) determination for fluids using a pulse-echo method with the stress-free boundary. A newly derived beta formula requires the measurement of the fundamental and second harmonic displacements with appropriate corrections for attenuation, diffraction, and boundary reflection. Measurements are composed of two steps: receiver calibration and harmonic generation. The beta values calculated for water at several distances between the planar transducer and the water-air interface are in good agreement with literature, providing a validation for the method. PMID- 29716281 TI - Comparing phase-sensitive and phase-insensitive echolocation target images using a monaural audible sonar. AB - This paper describes phase-sensitive and phase-insensitive processing of monaural echolocation waveforms to generate target maps. Composite waveforms containing both the emission and echoes are processed to estimate the target impulse response using an audible sonar. Phase-sensitive processing yields the composite signal envelope, while phase-insensitive processing that starts with the composite waveform power spectrum yields the envelope of the autocorrelation function. Analysis and experimental verification show that multiple echoes form an autocorrelation function that produces near-range phantom-reflector artifacts. These artifacts interfere with true target echoes when the first true echo occurs at a time that is less than the total duration of the target echoes. Initial comparison of phase-sensitive and phase-insensitive maps indicates that both display important target features, indicating that phase is not vital. A closer comparison illustrates the improved resolution of phase-sensitive processing, the near-range phantom-reflectors produced by phase-insensitive processing, and echo interference and multiple reflection artifacts that were independent of the processing. PMID- 29716282 TI - Click reception in the harbor porpoise (Phocoena phocoena): Effects of electrode and contact transducer location on the auditory brainstem response. AB - Unlike terrestrial mammals that have unambiguous aerial sound transmission pathways via the outer ear and tympanum, sound reception pathways in most odontocetes are not well understood. Recent studies have used auditory brainstem response (ABR) measurements to examine sound reception pathways. This study sought to determine how sound source placements, recording electrode arrangements, and ABR peak analyses affect interpretations of sound reception in the harbor porpoise (Phocoena phocoena). Click stimuli were delivered in air from a contact transducer ("jawphone"). Early ABR peaks (representing auditory nerve responses), and later peaks reflecting higher brainstem activity, were analyzed across jawphone and recording electrode positions. Auditory nerve responses were similar for jawphone placements from the ipsilateral posterior mandible to the tip of the rostrum. Later peaks, however, suggested a possible region of highest sensitivity midway between the posterior mandible and the rostrum tip. These findings are generally similar to previous data for porpoises. In contrast to auditory nerve responses that were largest when recorded near the ipsilateral meatus, later ABR peaks were largest when recorded with a contralateral (opposing) electrode. These results provide information on the processes underlying peaks of the ABR, and inform stimulus delivery and ABR recording parameters in odontocete sound reception studies. PMID- 29716283 TI - Objective speech transmission improvements with a binaural cochlear implant sound coding strategy inspired by the contralateral medial olivocochlear reflex. AB - It has been recently shown that cochlear implant users could enjoy better speech reception in noise and enhanced spatial unmasking with binaural audio processing inspired by the inhibitory effects of the contralateral medial olivocochlear (MOC) reflex on compression [Lopez-Poveda, Eustaquio-Martin, Stohl, Wolford, Schatzer, and Wilson (2016). Ear Hear. 37, e138-e148]. The perceptual evidence supporting those benefits, however, is limited to a few target-interferer spatial configurations and to a particular implementation of contralateral MOC inhibition. Here, the short-term objective intelligibility index is used to (1) objectively demonstrate potential benefits over many more spatial configurations, and (2) investigate if the predicted benefits may be enhanced by using more realistic MOC implementations. Results corroborate the advantages and drawbacks of MOC processing indicated by the previously published perceptual tests. The results also suggest that the benefits may be enhanced and the drawbacks overcome by using longer time constants for the activation and deactivation of inhibition and, to a lesser extent, by using a comparatively greater inhibition in the lower than in the higher frequency channels. Compared to using two functionally independent processors, the better MOC processor improved the signal-to-noise ratio in the two ears between 1 and 6 decibels by enhancing head-shadow effects, and was advantageous for all tested target-interferer spatial configurations. PMID- 29716284 TI - Erratum: A theoretical and numerical study on the mechanics of vibro-acoustic modulation [J. Acoust. Soc. Am. 141(4), 2821-2831 (2017)]. PMID- 29716285 TI - An immersed interface method for the solution of the standard parabolic equation in range-dependent ocean environments. AB - A numerical approach for the treatment of irregular ocean bottoms within the framework of the standard parabolic equation is proposed. The present technique is based on the immersed interface method originally developed by LeVeque and Li [(1994). SIAM J. Numer. Anal. 31(4), 1019-1044]. The method conserves energy to high order accuracy and naturally handles generic range-dependent bathymetries, without requiring any additional specific numerical procedure. An illustration of its capabilities is provided by solving the well-known wedge problem. PMID- 29716286 TI - Application of the remote microphone method to active noise control in a mobile phone. AB - Mobile phones are used in a variety of situations where environmental noise may interfere with the ability of the near-end user to communicate with the far-end user. To overcome this problem, it might be possible to use active noise control technology to reduce the noise experienced by the near-end user. This paper initially demonstrates that when an active noise control system is used in a practical mobile phone configuration to minimise the noise measured by an error microphone mounted on the mobile phone, the attenuation achieved at the user's ear depends strongly on the position of the source generating the acoustic interference. To help overcome this problem, a remote microphone processing strategy is investigated that estimates the pressure at the user's ear from the pressure measured by the microphone on the mobile phone. Through an experimental implementation, it is demonstrated that this arrangement achieves a significant improvement in the attenuation measured at the ear of the user, compared to the standard active control strategy. The robustness of the active control system to changes in both the interfering sound field and the position of the mobile device relative to the ear of the user is also investigated experimentally. PMID- 29716287 TI - Pre-Sabine room acoustic design guidelines based on human voice directivity. AB - With the work of Wallace C. Sabine on the lecture hall of the Fogg Art Museum and concert hall of Boston Symphony Hall, a foundation for the field of architectural acoustics as a science was laid between 1895 and 1900. Prior to that, architects employed various notions in acoustic design. Previous studies by the authors have reviewed 18th and 19th century design guidelines that were based on the quantification of the perception threshold between direct sound and first order reflections, with these guidelines being followed in the design of several rooms with acoustical demands. This study reviews an alternate metric guideline, based on the directivity and propagation distance of the human voice, which was utilized in several halls also during the 18th and 19th centuries. The related acoustic experiments tested how far sound was perceivable towards the front, sides, and rear of a speaking person. These ratios were used in the acoustical design of at least five lecture halls, four theater halls, one opera hall, and one concert hall, constructed in Germany, England, and the USA. These historic designs, and comparisons to modern measures and guidelines, are reviewed. PMID- 29716288 TI - The noise susceptibility of various speech bands. AB - The degrading influence of noise on various critical bands of speech was assessed. A modified version of the compound method [Apoux and Healy (2012) J. Acoust. Soc. Am. 132, 1078-1087] was employed to establish this noise susceptibility for each speech band. Noise was added to the target speech band at various signal-to-noise ratios to determine the amount of noise required to reduce the contribution of that band by 50%. It was found that noise susceptibility is not equal across the speech spectrum, as is commonly assumed and incorporated into modern indexes. Instead, the signal-to-noise ratio required to equivalently impact various speech bands differed by as much as 13 dB. This noise susceptibility formed an irregular pattern across frequency, despite the use of multi-talker speech materials designed to reduce the potential influence of a particular talker's voice. But basic trends in the pattern of noise susceptibility across the spectrum emerged. Further, no systematic relationship was observed between noise susceptibility and speech band importance. It is argued here that susceptibility to noise and band importance are different phenomena, and that this distinction may be underappreciated in previous works. PMID- 29716289 TI - Numerical and analytic modelling of elastodynamic scattering within polycrystalline materials. AB - The elastodynamic behavior of polycrystalline cubic materials is studied through the fundamental propagation properties, the attenuation and wave speed, of a longitudinal wave. Predictions made by different analytical models are compared to both numerical and experimental results. The numerical model is based on a three-dimensional Finite Element (FE) simulation which provides a full-physics solution to the scattering problem. The three main analytical models include the Far-Field Approximation (FFA), the Self-Consistent Approximation (SCA) to the reference medium, and the herein derived Second Order Approximation (SOA). The classic Stanke and Kino model is also included, which by comparison to the SOA, reveals the importance of the distribution of length-scales described in terms of the two-point correlation function in determining scattering behavior. Further comparison with the FE model demonstrates that the FFA provides a simple but satisfactory approximation, whereas the SOA shows all-around excellent agreement. The experimental wave velocity data evaluated against the SOA and SC reveal a better agreement when the Voigt reference is used in second order models. The use of full-physics numerical simulations has enabled the study of wave behavior in these random media which will be important to inform the ongoing development of analytical models and the understanding of observations. PMID- 29716290 TI - Boundary layer noise subtraction in hydrodynamic tunnel using robust principal component analysis. AB - The acoustic study of propellers in a hydrodynamic tunnel is of paramount importance during the design process, but can involve significant difficulties due to the boundary layer noise (BLN). Indeed, advanced denoising methods are needed to recover the acoustic signal in case of poor signal-to-noise ratio. The technique proposed in this paper is based on the decomposition of the wall pressure cross-spectral matrix (CSM) by taking advantage of both the low-rank property of the acoustic CSM and the sparse property of the BLN CSM. Thus, the algorithm belongs to the class of robust principal component analysis (RPCA), which derives from the widely used principal component analysis. If the BLN is spatially decorrelated, the proposed RPCA algorithm can blindly recover the acoustical signals even for negative signal-to-noise ratio. Unfortunately, in a realistic case, acoustic signals recorded in a hydrodynamic tunnel show that the noise may be partially correlated. A prewhitening strategy is then considered in order to take into account the spatially coherent background noise. Numerical simulations and experimental results show an improvement in terms of BLN reduction in the large hydrodynamic tunnel. The effectiveness of the denoising method is also investigated in the context of acoustic source localization. PMID- 29716291 TI - Echolocation click source parameters of Australian snubfin dolphins (Orcaella heinsohni). AB - The Australian snubfin dolphin (Orcaella heinsohni) is endemic to Australian waters, yet little is known about its abundance and habitat use. To investigate the feasibility of Passive Acoustic Monitoring for snubfin dolphins, biosonar clicks were recorded in Cygnet Bay, Australia, using a four-element hydrophone array. Clicks had a mean source level of 200 +/- 5 dB re 1 MUPa pp, transmission directivity index of 24 dB, mean centroid frequency of 98 +/- 9 kHz, and a root mean-square bandwidth of 31 +/- 3 kHz. Such properties lend themselves to passive acoustic monitoring, but are comparable to similarly-sized delphinids, thus requiring additional cues to discriminate between snubfins and sympatric species. PMID- 29716292 TI - Comparison of passive acoustic soniferous fish monitoring with supervised and unsupervised approaches. AB - Passive acoustics has been used to investigate behavior and relative abundances of soniferous fish. However, because of noise interferences, it remains challenging to accurately analyze acoustic activities of soniferous fish. This study proposes a multi-method approach, which combines rule-based detector, periodicity-coded non-negative matrix factorization, and Gaussian mixture models. Although the three methods performed well when used to detect croaker choruses in quiet conditions, inconsistent results are observed in noisy conditions. A consistency matrix can provide insights regarding the bias of acoustic monitoring results. The results suggest that the proposed approach can reasonably improve passive acoustic monitoring of soniferous fish. PMID- 29716293 TI - Investigating the stability of frequency-dependent locally reacting surface boundary conditions in numerical acoustic models. AB - Numerical acoustic modeling enables simulation of sound propagation through bounded space. Recent research directed to refining Finite Difference Time Domain solutions for acoustic prediction has focused on emulating sound wave-surface interaction. Locally reacting surface properties are a popular choice for deriving boundary conditions that incorporate surface absorption properties. However, implementation of these boundary conditions, using the methods described in prevalent literature, is demonstrated here as unstable for complex room geometries. This work presents a reformulated implementation of frequency dependent locally reacting surface boundary conditions for Finite Difference Time Domain simulations that is empirically demonstrated to be robust against simulation instabilities. PMID- 29716294 TI - Sequential inversion of self-noise using adaptive particle filter in shallow water. AB - The geoacoustic inversion based on a horizontal towed array sonar receiving tow ship noise has demonstrated a promising technique for the parameter inversion in shallow water. In order to characterize the evolution of parameters in the time varying environment, the adaptive particle filter for the sequential inversion is presented in this paper. The inversion problem is formulated as a dynamic and nonlinear process in the Bayesian framework, due to the fact that the self-noise is recorded sequentially in space and time. To deal with the interparameter correlations and time-varying noise process, the adaptive sequential importance sampling is carried out based on the estimated covariance matrix of parameters that is updated on-line. And the particles are proposed with an adaptive shift to handle the rapidly varying parameters. The tonal components at low frequencies of the self-noise are used in the inversion. The sequential inversion method is verified through the processing of both synthetic data and the sea-trial data in the shallow water environment. The results show that the adaptive particle filter method can achieve a more stable and accurate estimate than successively running global optimization algorithms and can do better than particle filter inversion in a rapidly varying environment. PMID- 29716295 TI - Noise-robust speech triage. AB - A method is presented in which conventional speech algorithms are applied, with no modifications, to improve their performance in extremely noisy environments. It has been demonstrated that, for eigen-channel algorithms, pre-training multiple speaker identification (SID) models at a lattice of signal-to-noise ratio (SNR) levels and then performing SID using the appropriate SNR dependent model was successful in mitigating noise at all SNR levels. In those tests, it was found that SID performance was optimized when the SNR of the testing and training data were close or identical. In this current effort multiple i-vector algorithms were used, greatly improving both processing throughput and equal error rate classification accuracy. Using identical approaches in the same noisy environment, performance of SID, language identification, gender identification, and diarization were significantly improved. A critical factor in this improvement is speech activity detection (SAD) that performs reliably in extremely noisy environments, where the speech itself is barely audible. To optimize SAD operation at all SNR levels, two algorithms were employed. The first maximized detection probability at low levels (-10 dB <= SNR < +10 dB) using just the voiced speech envelope, and the second exploited features extracted from the original speech to improve overall accuracy at higher quality levels (SNR >= +10 dB). PMID- 29716297 TI - Defect imaging for plate-like structures using diffuse field. AB - Defect imaging utilizing a scanning laser source (SLS) technique produces images of defects in a plate-like structure, as well as spurious images occurring because of resonances and reverberations within the specimen. This study developed defect imaging by the SLS using diffuse field concepts to reduce the intensity of spurious images, by which the energy of flexural waves excited by laser can be estimated. The experimental results in the different frequency bandwidths of excitation waves and in specimens with different attenuation proved that clearer images of defects are obtained in broadband excitation using a chirp wave and in specimens with low attenuation, which produce diffuse fields easily. PMID- 29716298 TI - Hearing thresholds, for underwater sounds, of harbor seals (Phoca vitulina) at the water surface. AB - High-amplitude impulsive sounds produced by pile driving and airguns may result in hearing damage in nearby seals. By swimming at the water surface, seals may reduce their exposure to underwater sound, as sound pressure levels (SPLs) are often lower just below the surface than deeper in the water column. Seals can make physiological adjustments such that they can switch between having maximum sensitivity for either aerial or underwater sounds. This could mean that hearing sensitivity for underwater sounds is lower when swimming at the water surface (when hearing may be focused on aerial sounds) than when swimming at depth. To investigate this possibility, hearing thresholds of two female harbor seals were quantified psychophysically, while their heads were in the position normally adopted while swimming at the surface. The seals' hearing thresholds at the water surface were similar to each other and to previous measurements made at 1 m depth. When calculating the cumulative sound exposure level for hearing damage assessment, the SPL just below the water surface needs to be measured or modeled, and the proportion of time seals normally swim at the water surface needs to be estimated, to estimate the sound energy that reaches the seals' ears. PMID- 29716296 TI - Rapid adaptation to foreign-accented speech and its transfer to an unfamiliar talker. AB - How fast can listeners adapt to unfamiliar foreign accents? Clarke and Garrett [J. Acoust. Soc. Am. 116, 3647-3658 (2004)] (CG04) reported that native-English listeners adapted to foreign-accented English within a minute, demonstrating improved processing of spoken words. In two web-based experiments that closely follow the design of CG04, the effects of rapid accent adaptation are examined and its generalization is explored across talkers. Experiment 1 replicated the core finding of CG04 that initial perceptual difficulty with foreign-accented speech can be attenuated rapidly by a brief period of exposure to an accented talker. Importantly, listeners showed both faster (replicating CG04) and more accurate (extending CG04) comprehension of this talker. Experiment 2 revealed evidence that such adaptation transferred to a different talker of a same accent. These results highlight the rapidity of short-term accent adaptation and raise new questions about the underlying mechanism. It is suggested that the web-based paradigm provides a useful tool for investigations in speech adaptation. PMID- 29716299 TI - Objective detection and time-frequency localization of components within transient signals. AB - An automatic component detection method for overlapping transient pulses in multi component signals is presented and evaluated. The recently proposed scaled reassignment technique is shown to have the best achievable resolution for closely located Gaussian shaped transient pulses, even in heavy disruptive noise. As a result, the method automatically detects and counts the number of transients, giving the center times and center frequencies of all components with considerable accuracy. The presented method shows great potential for applications in several acoustic research fields, where coinciding Gaussian shaped transients are analyzed. The performance is tested on measured data from a laboratory pulse-echo setup and from a dolphin echolocation signal measured simultaneously at two different locations in the echolocation beam. Since the method requires little user input, it should be easily employed in a variety of research projects. PMID- 29716300 TI - Arrays of rectangular subcritical speech bands: Intelligibility improved by noise vocoding and expanding to critical bandwidths. AB - A previous study [Warren, Bashford, and Lenz (2017). J. Acoust. Soc. Am. 141, EL222-EL227] reported that arrays of subcritical width rectangular speech bands can produce near ceiling sentence intelligibility. The present study used noise vocoded subcritical band speech arrays with analysis bandwidths of 4%, 2%, 1%, or 0.5% of center frequency. Intelligibility decreased when analysis and noise carrier bandwidths were matched. However, expanding carrier noise bandwidths to a critical bandwidth of 1/3-octave (26%) produced array intelligibilities either equaling or substantially exceeding that of the original speech band arrays. Implications concerning bandwidth requirements of envelope processing and the redundancy of envelope cues are discussed. PMID- 29716301 TI - Level dominance effect and selective attention in a dichotic sample discrimination task. AB - Differences in individual listening patterns are reported for a dichotic sample discrimination task. Seven tones were drawn from normal distributions with means of 1000 or 1100 Hz on each trial. Even-numbered tones (2, 4, and 6) and odd numbered tones (1, 3, 5, and 7) were drawn, respectively, from distributions with a 50-Hz and 200-Hz standard deviation. Task difficulty was manipulated by presenting odd and even tones at different intensities. In easy conditions, high and low informative tones were presented at 70 dB and 50 dB, respectively. In difficult conditions, high informative and low informative tones were presented at 50 dB and 70 dB, respectively. Participants judged whether the sample was from high- or low-mean distribution. Decision weights, efficiency, and sensitivity showed a range of abilities to attend to high informative tones, with d' from 2.4 0.7. Most listeners showed a left-ear advantage, while no listeners showed a right ear advantage. Some listeners, but not all, showed no loudness dominance effect with the ability to selectively attend to quiet tones in difficult conditions. These findings show that the influence of an attentional strategy in dichotic listening can overcome the loudness dominance effect for some listeners. PMID- 29716302 TI - Effect of audibility on better-ear glimpsing as a function of frequency in normal hearing and hearing-impaired listeners. AB - Better-ear glimpsing (BEG) is an auditory phenomenon that helps understanding speech in noise by utilizing interaural level differences (ILDs). The benefit provided by BEG is limited in hearing-impaired (HI) listeners by reduced audibility at high frequencies. Rana and Buchholz [(2016). J. Acoust. Soc. Am. 140(2), 1192-1205] have shown that artificially enhancing ILDs at low and mid frequencies can help HI listeners understanding speech in noise, but the achieved benefit is smaller than in normal-hearing (NH) listeners. To understand how far this difference is explained by differences in audibility, audibility was carefully controlled here in ten NH and ten HI listeners and speech reception thresholds (SRTs) in noise were measured in a spatially separated and co-located condition as a function of frequency and sensation level. Maskers were realized by noise-vocoded speech and signals were spatialized using artificially generated broadband ILDs. The spatial benefit provided by BEG and SRTs improved consistently with increasing sensation level, but was limited in the HI listeners by loudness discomfort. Further, the HI listeners performed similar to NH listeners when differences in audibility were compensated. The results help to understand the hearing aid gain that is required to maximize the spatial benefit provided by ILDs as a function of frequency. PMID- 29716304 TI - Unknown beaked whale echolocation signals recorded off eastern New Zealand. AB - The echolocation signals of most beaked whale species are still unknown. In fact, out of the 22 species comprising the family Ziphiidae, only the echolocation pulses for 7 species have been clearly described. This study describes two distinct beaked whale echolocation signals recorded in the Cook Strait region using passive acoustic technology. These signals differ from previously described Ziphiid species clicks. A description of the time-frequency characteristics of the two signals is provided. Understanding the characteristics of these signals is necessary to correctly identify species from their echolocation signals and enables future monitoring of beaked whales using passive acoustics techniques. PMID- 29716303 TI - Differences in common psychoacoustical tasks by sex, menstrual cycle, and race. AB - The psychoacoustical literature contains multiple reports about small differences in performance depending upon the sex and phase of the menstrual cycle of the subjects. In an attempt to verify these past reports, a large-scale study was implemented. After extensive training, the performance of about 75 listeners was measured on seven common psychoacoustical tasks. For most tasks, the signal was a 3.0-kHz tone. The initial data analyses failed to confirm some past outcomes. Additional analyses, incorporating the limited information available about the racial background of the listeners, did confirm some of the past reports, with the direction and magnitude of the differences often diverging for the White and Non-White listeners. Sex differences and race differences interacted for six of the seven tasks studied. These interactions suggest that racial background needs to be considered when making generalizations about human auditory performance, and when considering failures of reproducibility across studies. Menstrual differences were small, but generally larger for Whites than Non-Whites. Hormonal effects may be responsible for the sex and cycle differences that do exist, and differences in intra-cochlear melanocytes may account for the race differences. PMID- 29716305 TI - Word final schwa is driven by intonation-The case of Bari Italian. AB - In order to convey pragmatic functions, a speaker has to select an intonation contour (the tune) in addition to the words that are to be spoken (the text). The tune and text are assumed to be independent of each other, such that any one intonation contour can be produced on different phrases, regardless of the number and nature of the segments they are made up of. However, if the segmental string is too short, certain tunes-especially those with a rising component-call for adjustments to the text. In Italian, for instance, loan words such as "chat" can be produced with a word final schwa when this word occurs at the end of a question. This paper investigates this word final schwa in the Bari variety in a number of different intonation contours. Although its presence and duration is to some extent dependent on idiosyncratic properties of speakers and words, schwa is largely conditioned by intonation. Schwa cannot thus be considered a mere phonetic artefact, since it is relevant for phonology, in that it facilitates the production of communicatively relevant intonation contours. PMID- 29716306 TI - The sound field of a rotating dipole in a plug flow. AB - An analytical far field solution for a rotating point dipole source in a plug flow is derived. The shear layer of the jet is modelled as an infinitely thin cylindrical vortex sheet and the far field integral is calculated by the stationary phase method. Four numerical tests are performed to validate the derived solution as well as to assess the effects of sound refraction from the shear layer. First, the calculated results using the derived formulations are compared with the known solution for a rotating dipole in a uniform flow to validate the present model in this fundamental test case. After that, the effects of sound refraction for different rotating dipole sources in the plug flow are assessed. Then the refraction effects on different frequency components of the signal at the observer position, as well as the effects of the motion of the source and of the type of source are considered. Finally, the effect of different sound speeds and densities outside and inside the plug flow is investigated. The solution obtained may be of particular interest for propeller and rotor noise measurements in open jet anechoic wind tunnels. PMID- 29716307 TI - Note: Sensitive fluorescence detection through minimizing the scattering light by anti-reflective nanostructured materials. AB - We demonstrate a new approach with fabrication of anti-reflective coating to substantially reduce the scattering light in an ultra-high vacuum during laser induced fluorescence (LIF) detection. To do so, the surface of the vacuum chamber in the detection region was blackened and coated with the special solar heat absorbing nanomaterials. We demonstrate that more than 97.5% of the stray light in the chamber spanning from near infrared to ultraviolet can be absorbed which effectively improves the signal to noise (S/N) ratio. With this technique, the LIF signal from the cold magnesium monofluoride molecules has been observed with an S/N ratio of ~4 times better than without that. PMID- 29716308 TI - Quantitative measurements of nanoscale permittivity and conductivity using tuning fork-based microwave impedance microscopy. AB - We report quantitative measurements of nanoscale permittivity and conductivity using tuning-fork (TF) based microwave impedance microscopy (MIM). The system is operated under the driving amplitude modulation mode, which ensures satisfactory feedback stability on samples with rough surfaces. The demodulated MIM signals on a series of bulk dielectrics are in good agreement with results simulated by finite-element analysis. Using the TF-MIM, we have visualized the evolution of nanoscale conductance on back-gated MoS2 field effect transistors, and the results are consistent with the transport data. Our work suggests that quantitative analysis of mesoscopic electrical properties can be achieved by near field microwave imaging with small distance modulation. PMID- 29716309 TI - Characterization of a medium-sized washer-gun for an axisymmetric mirror. AB - A new medium-sized washer gun is developed for a plasma start-up in a fully axisymmetric mirror. The gun is positioned at the east end of the Keda Mirror with AXisymmetricity facility and operated in the pulsed mode with an arc discharging time of 1.2 ms and a typical arc current of 8.5 kA with 1.5 kV discharge voltage. To optimize the operation, a systematic scan of the neutral pressure, the arc voltage, the bias voltage on a mesh grid 6 cm in front of the gun and an end electrode located on the west end of mirror, and the mirror ratio was performed. The streaming plasma was measured with triple probes in the three mirror cells and a diamagnetic loop in the central cell. Floating potential measurements suggest that the plasma could be divided into streaming and mirror confined plasmas. The floating potential for the streaming plasma is negative, with an electric field pointing inwards. The mirror-confined plasma has a typical lifetime of 0.5 ms. PMID- 29716310 TI - Sub-millisecond electron density profile measurement at the JET tokamak with the fast lithium beam emission spectroscopy system. AB - Diagnostic alkali atom (e.g., lithium) beams are routinely used to diagnose magnetically confined plasmas, namely, to measure the plasma electron density profile in the edge and the scrape off layer region. A light splitting optics system was installed into the observation system of the lithium beam emission spectroscopy diagnostic at the Joint European Torus (JET) tokamak, which allows simultaneous measurement of the beam light emission with a spectrometer and a fast avalanche photodiode (APD) camera. The spectrometer measurement allows density profile reconstruction with ~10 ms time resolution, absolute position calculation from the Doppler shift, spectral background subtraction as well as relative intensity calibration of the channels for each discharge. The APD system is capable of measuring light intensities on the microsecond time scale. However ~100 MUs integration is needed to have an acceptable signal to noise ratio due to moderate light levels. Fast modulation of the beam up to 30 kHz is implemented which allows background subtraction on the 100 MUs time scale. The measurement covers the 0.9 < rhopol < 1.1 range with 6-10 mm optical resolution at the measurement location which translates to 3-5 mm radial resolution at the midplane due to flux expansion. An automated routine has been developed which performs the background subtraction, the relative calibration, and the comprehensive error calculation, runs a Bayesian density reconstruction code, and loads results to the JET database. The paper demonstrates the capability of the APD system by analyzing fast phenomena like pellet injection and edge localized modes. PMID- 29716311 TI - A new multi-line cusp magnetic field plasma device (MPD) with variable magnetic field. AB - A new multi-line cusp magnetic field plasma device consisting of electromagnets with core material has been constructed with a capability to experimentally control the relative volume fractions of magnetized to unmagnetized plasma volume as well as accurate control on the gradient length scales of mean density and temperature profiles. Argon plasma has been produced using a hot tungsten cathode over a wide range of pressures 5 * 10-5 -1 * 10-3 mbar, achieving plasma densities ranging from 109 to 1011 cm-3 and the electron temperature in the range 1-8 eV. The radial profiles of plasma parameters measured along the non-cusp region (in between two consecutive magnets) show a finite region with uniform and quiescent plasma, where the magnetic field is very low such that the ions are unmagnetized. Beyond that region, both plasma species are magnetized and the profiles show gradients both in temperature and density. The electrostatic fluctuation measured using a Langmuir probe radially along the non-cusp region shows less than 1% (deltaIisat/Iisat < 1%). The plasma thus produced will be used to study new and hitherto unexplored physics parameter space relevant to both laboratory multi-scale plasmas and astrophysical plasmas. PMID- 29716312 TI - Design study of an YBCO-coated beam screen for the super proton-proton collider bending magnets. AB - In order to reduce the beam impedance and refrigeration power dramatically, we have designed a high temperature superconductor (HTS) coated beam screen to screen the cold chamber walls of the super proton-proton collider bending magnets from beam-induced heat loads. It employs an absorber, inspired by the future circular collider studies, to absorb the immense synchrotron radiation power of 12.8 W/m emitted from the 37.5 TeV proton beams. Such a structure has the advantage of decreasing the electron cloud effect and improving the beam vacuum. We have compared the critical magnetic field and current density and accessibility of two potential HTS materials for the beam screen, TlBa2Ca2Cu3O9 delta (Tl-1223) and Yttrium Barium Copper Oxide (YBCO) and finally chose YBCO for coating. The beam screen is tentatively designed to work at 55-70 K because of the limited development of the YBCO material. The thermal analysis with oxygen cooling fluid indicates that the YBCO conductor can maintain its superconductivity even if the synchrotron radiation hits the YBCO-coated surface and the mechanical analysis shows that the structure has the ability to resist the Lorenz force during magnet quenches. PMID- 29716313 TI - A soft switching with reduced voltage stress ZVT-PWM full-bridge converter. AB - This paper introduces a novel active snubber cell for soft switching pulse width modulation DC-DC converters. In the proposed converter, the main switch is turned on under zero voltage transition and turned off under zero voltage switching (ZVS). The auxiliary switch is turned on under zero current switching (ZCS) and turned off under zero current transition. The main diode is turned on under ZVS and turned off under ZCS. All of the other semiconductors in the converter are turned on and off with soft switching. There is no extra voltage stress on the semiconductor devices. Besides, the proposed converter has simple structure and ease of control due to common ground. The detailed theoretical analysis of the proposed converter is presented and also verified with both simulation and experimental study at 100 kHz switching frequency and 600 W output power. Furthermore, the efficiency of the proposed converter is 95.7% at nominal power. PMID- 29716314 TI - Laser frequency stabilization using a commercial wavelength meter. AB - We present the characterization of a laser frequency stabilization scheme using a state-of-the-art wavelength meter based on solid Fizeau interferometers. For a frequency-doubled Ti-sapphire laser operated at 461 nm, an absolute Allan deviation below 10-9 with a standard deviation of 1 MHz over 10 h is achieved. Using this laser for cooling and trapping of strontium atoms, the wavemeter scheme provides excellent stability in single-channel operation. Multi-channel operation with a multimode fiber switch results in fluctuations of the atomic fluorescence correlated to residual frequency excursions of the laser. The wavemeter-based frequency stabilization scheme can be applied to a wide range of atoms and molecules for laser spectroscopy, cooling, and trapping. PMID- 29716315 TI - Quantitative stress measurement of elastic deformation using mechanoluminescent sensor: An intensity ratio model. AB - The mechanoluminescent (ML) sensor is a newly developed non-invasive technique for stress/strain measurement. However, its application has been mostly restricted to qualitative measurement due to the lack of a well-defined relationship between ML intensity and stress. To achieve accurate stress measurement, an intensity ratio model was proposed in this study to establish a quantitative relationship between the stress condition and its ML intensity in elastic deformation. To verify the proposed model, experiments were carried out on a ML measurement system using resin samples mixed with the sensor material SrAl2O4:Eu2+, Dy3+. The ML intensity ratio was found to be dependent on the applied stress and strain rate, and the relationship acquired from the experimental results agreed well with the proposed model. The current study provided a physical explanation for the relationship between ML intensity and its stress condition. The proposed model was applicable in various SrAl2O4:Eu2+, Dy3+ based ML measurement in elastic deformation, and could provide a useful reference for quantitative stress measurement using the ML sensor in general. PMID- 29716316 TI - In situ/non-contact superfluid density measurement apparatus. AB - We present a double-coil apparatus designed to operate with in situ capability, which is strongly desired for superconductivity studies on recently discovered two-dimensional superconductors. Coupled with a scanning tunneling microscope, the study of both local and global superconductivity [for superconducting gap and superfluid density (SFD), respectively] is possible on an identical sample without sample degradations due to damage, contamination, or oxidation in an atmosphere. The performance of the double-coil apparatus was tested on atomically clean surfaces of non-superconducting Si(111)-7 * 7 and on superconducting films of 100 nm-thick Pb and 1.4 nm-ultrathin Pb. The results clearly show the normal to-superconductor phase transition for Pb films with a strong SFD. PMID- 29716317 TI - Constructing experimental devices for half-ton synthesis of gadolinium-loaded liquid scintillator and its performance. AB - This paper describes in brief features of various experimental devices constructed for half-ton synthesis of gadolinium(Gd)-loaded liquid scintillator (GdLS) and also includes the performances and detailed chemical and physical results of a 0.5% high-concentration GdLS. Various feasibility studies on useful apparatus used for loading Gd into solvents have been carried out. The transmittance, Gd concentration, density, light yield, and moisture content were measured for quality control. We show that with the help of adequate automated experimental devices and tools, it is possible to perform ton scale synthesis of GdLS at moderate laboratory scale without difficulty. The synthesized GdLS was satisfactory to meet chemical, optical, and physical properties and various safety requirements. These synthesizing devices can be expanded into massive scale next-generation neutrino experiments of several hundred tons. PMID- 29716318 TI - Deployment of quasi-digital sensor for high temperature molten salt level measurement in pyroprocessing plants. AB - Development of a liquid molten salt level sensor device that can detect the level of liquid molten salt in the process vessels of pyrochemical reprocessing of spent metallic fuels is detailed. It is proposed to apply a resistive-type pulsating sensor-based level measurement approach. There are no commercially available sensors due to limitations of high temperature, radiation, and physical dimensions. A compact, simple, rugged, low power, and high precise pulsating sensor-based level probe and simple instrumentation for the molten salt liquid level sensor to work in the extreme conditions has been indigenously developed, with high precision and accuracy. The working principle, design concept, and results have been discussed. This level probe is mainly composed of the variable resistor made up of ceramic rods. This resistor constitutes the part of resistance-capacitance-type Logic Gate Oscillator (LGO). A change in the molten salt level inside the tank causes a small change in the resistance which in turn changes the pulse frequency of the LGO. Thus the frequency, the output of the instrument that is displayed on the LCD of an embedded system, is a function of molten salt level. In the present design, the range of level measurement is about 10 mm. The sensitivity in position measurement up to 10 mm is ~2.5 kHz/mm. PMID- 29716319 TI - Note: Commercial SQUID magnetometer-compatible NMR probe and its application for studying a quantum magnet. AB - We present a compact nuclear magnetic resonance (NMR) probe which is compatible with a magnet of a commercial superconducting quantum interference device magnetometer and demonstrate its application to the study of a quantum magnet. We employ trimmer chip capacitors to construct an NMR tank circuit for low temperature measurements. Using a magnetic insulator MoOPO4 with S = 1/2 (Mo5+) as an example, we show that the T-dependence of the circuit is weak enough to allow the ligand-ion NMR study of magnetic systems. Our 31P NMR results are compatible with previous bulk susceptibility and neutron scattering experiments and furthermore reveal unconventional spin dynamics. PMID- 29716320 TI - Improving the viability and versatility of the E * B probe with an active cooling system. AB - A thermostatic E * B probe is designed to protect the probe body from the thermal effect of the plasma plume that has a significant influence on the resolution of the probe for high-power electric thrusters. An active cooling system, which consists of a cooling panel and carbon fiber felts combined with a recycling system of liquid coolants or an open-type system of gas coolants, is employed to realize the protection of the probe. The threshold for the design parameters for the active cooling system is estimated by deriving the energy transfer of the plasma plume-probe body interaction and the energy taken away by the coolants, and the design details are explained. The diagnostics of the LIPS-300 ion thruster with a power of 3 kW and a screen-grid voltage of 1450 V was implemented by the designed thermostatic E * B probe. The measured spectra illustrate that the thermostatic E * B probe can distinguish the fractions of Xe+ ions and Xe2+ ions without areas of overlap. In addition, the temperature of the probe body was less than 306 K in the beam region of the plasma plume during the 200-min-long continuous test. A thermostatic E * B probe is useful for enhancing the viability and versatility of equipment and for reducing uneconomical and complex test procedures. PMID- 29716321 TI - Optically coupled methods for microwave impedance microscopy. AB - Scanning Microwave Impedance Microscopy (MIM) measurement of photoconductivity with 50 nm resolution is demonstrated using a modulated optical source. The use of a modulated source allows for the measurement of photoconductivity in a single scan without a reference region on the sample, as well as removing most topographical artifacts and enhancing signal to noise as compared with unmodulated measurement. A broadband light source with a tunable monochrometer is then used to measure energy resolved photoconductivity with the same methodology. Finally, a pulsed optical source is used to measure local photo-carrier lifetimes via MIM, using the same 50 nm resolution tip. PMID- 29716322 TI - A tandem mass spectrometer for crossed-beam irradiation of mass-selected molecular systems by keV atomic ions. AB - In the present paper, we describe a new home-built crossed-beam apparatus devoted to ion-induced ionization and fragmentation of isolated biologically relevant molecular systems. The biomolecular ions are produced by an electrospray ionization source, mass-over-charge selected, accumulated in a 3D ion trap, and then guided to the extraction region of an orthogonal time-of-flight mass spectrometer. Here, the target molecular ions interact with a keV atomic ion beam produced by an electron cyclotron resonance ion source. Cationic products from the collision are detected on a position sensitive detector and analyzed by time of-flight mass spectrometry. A detailed description of the operation of the setup is given, and early results from irradiation of a protonated pentapeptide (leucine-enkephalin) by a 7 keV He+ ion beam are presented as a proof-of principle. PMID- 29716323 TI - A highly integrated single-mode 1064 nm laser with 8.5 kHz linewidth for dual wavelength active optical clock. AB - Without exploiting any frequency selective elements, we have realized a highly integrated, single-mode, narrow-linewidth Nd:YAG 1064 nm laser, which is end pumped by the 808.6 nm diode laser in an integrated invar cavity. It turns out that each 1064 nm laser achieves a most probable linewidth of 8.5 kHz by beating between two identical laser systems. The output power of the 1064 nm laser increases steadily as the 808.6 nm pump power is raised, which can be up to 350 mW. Moreover, the resonant wavelength of cavity grows continuously in a certain crystal temperature range. Such a 1064 nm laser will be frequency stabilized to an ultrastable cavity by using the Pound-Drever-Hall technique and used as the good cavity laser to lock the main cavity length of 1064/1470 nm good-bad cavity dual-wavelength active optical clock. PMID- 29716324 TI - Note: A simple magnetic field design for dichroic atomic vapor laser lock. AB - The dichroic atomic vapor laser lock (DAVLL) is a very useful scheme for frequency stabilization. A bias field on the order of 100 G is required to get the error signal for frequency locking. Here we report a simple design for the bias field with the permanent magnetic balls. It is really simple and easy to adjust the magnitude. Since the DAVLL lock is not sensitive to the bias field, such a design is very suitable. PMID- 29716325 TI - A novel compact low impedance Marx generator with quasi-rectangular pulse output. AB - In this paper, a novel low impedance compact Marx generator with near-square pulse output based on the Fourier theory is developed. Compared with the traditional Marx generator, capacitors with different capacity have been used. It can generate a high-voltage quasi-rectangular pulse with a width of 100 ns at low impedance load, and it also has high energy density and power density. The generator consists of 16 modules. Each module comprises an integrative single ended plastic case capacitor with a nominal value of 54 nF, four ceramic capacitors with a nominal value of 1.5 nF, a gas switch, a charging inductor, a grounding inductor, and insulators which provide mechanical support for all elements. In the module, different discharge periods from different capacitors add to the main circuit to form a quasi-rectangular pulse. The design process of the generator is analyzed, and the test results are provided here. The generator achieved pulse output with a rise time of 32 ns, pulse width of 120 ns, flat topped width (95%-95%) of 50 ns, voltage of 550 kV, and power of 20 GW. PMID- 29716326 TI - Fast readout algorithm for cylindrical beam position monitors providing good accuracy for particle bunches with large offsets. AB - A simple, analytically correct algorithm is developed for calculating "pencil" relativistic beam coordinates using the signals from an ideal cylindrical particle beam position monitor (BPM) with four pickup electrodes (PUEs) of infinitesimal widths. The algorithm is then applied to simulations of realistic BPMs with finite width PUEs. Surprisingly small deviations are found. Simple empirically determined correction terms reduce the deviations even further. The algorithm is then tested with simulations for non-relativistic beams. As an example of the data acquisition speed advantage, a Field Programmable Gate Array based BPM readout implementation of the new algorithm has been developed and characterized. Finally, the algorithm is tested with BPM data from the Cornell Preinjector. PMID- 29716327 TI - High spatial resolution detection of low-energy electrons using an event-counting method, application to point projection microscopy. AB - An event-counting method using a two-microchannel plate stack in a low-energy electron point projection microscope is implemented. 15 MUm detector spatial resolution, i.e., the distance between first-neighbor microchannels, is demonstrated. This leads to a 7 times better microscope resolution. Compared to previous work with neutrons [Tremsin et al., Nucl. Instrum. Methods Phys. Res., Sect. A 592, 374 (2008)], the large number of detection events achieved with electrons shows that the local response of the detector is mainly governed by the angle between the hexagonal structures of the two microchannel plates. Using this method in point projection microscopy offers the prospect of working with a greater source-object distance (350 nm instead of 50 nm), advancing toward atomic resolution. PMID- 29716328 TI - Magnetic effect in the test of the weak equivalence principle using a rotating torsion pendulum. AB - The high precision test of the weak equivalence principle (WEP) using a rotating torsion pendulum requires thorough analysis of systematic effects. Here we investigate one of the main systematic effects, the coupling of the ambient magnetic field to the pendulum. It is shown that the dominant term, the interaction between the average magnetic field and the magnetic dipole of the pendulum, is decreased by a factor of 1.1 * 104 with multi-layer magnetic shield shells. The shield shells reduce the magnetic field to 1.9 * 10-9 T in the transverse direction so that the dipole-interaction limited WEP test is expected at eta ? 10-14 for a pendulum dipole less than 10-9 A m2. The high-order effect, the coupling of the magnetic field gradient to the magnetic quadrupole of the pendulum, would also contribute to the systematic errors for a test precision down to eta ~ 10-14. PMID- 29716329 TI - A compact large-format streak tube for imaging lidar. AB - The streak tubes with a large effective photocathode area, large effective phosphor screen area, and high photocathode radiant sensitivity are essential for improving the field of view, depth of field, and detectable range of the multiple slit streak tube imaging lidar. In this paper, a high spatial resolution, large photocathode area, and compact meshless streak tube with a spherically curved cathode and screen is designed and tested. Its spatial resolution reaches 20 lp/mm over the entire Phi28 mm photocathode working area, and the simulated physical temporal resolution is better than 30 ps. The temporal distortion in our large-format streak tube, which is shown to be a non-negligible factor, has a minimum value as the radius of curvature of the photocathode varies. Furthermore, the photocathode radiant sensitivity and radiant power gain reach 41 mA/W and 18.4 at the wavelength of 550 nm, respectively. Most importantly, the external dimensions of our streak tube are no more than Phi60 mm * 110 mm. PMID- 29716330 TI - An introductory study using impedance spectroscopy technique with polarizable microelectrode for amino acids characterization. AB - Portable, low power, yet ultra-sensitive life detection instrumentations are vital to future astrobiology flight programs at NASA. In this study, initial attempts to characterize amino acids in an aqueous environment by electrochemical impedance spectroscopy (EIS) using polarizable (blocking) electrodes in order to establish a means of detection via their electrical properties. Seven amino acids were chosen due to their scientific importance in demonstrating sensitivity levels in the range of part per billion concentration. Albeit more challenging in real systems of analyst mixtures, we found individual amino acids in aqueous environment do exhibit some degree of chemical and physical uniqueness to warrant characterization by EIS. The polar amino acids (Asp, Glu, and His) exhibited higher electrochemical activity than the non-polar amino acids (Ala, Gly, Val, and Leu). The non-polar amino acids (Gly and Ala) also exhibited unique electrical properties which appeared to be more dependent on physical characteristics such as molecular weight and structure. At concentrations above 1 mM where the amino acids play a more dominant transport role within the water, the conductivity was found to be more sensitive to concentrations. At lower concentrations <1 mM, however, the polar amino acid solution conductivity remained constant, suggesting poor chemical activity with water. As revealed by equivalent circuit modeling, the relaxation times showed a 1-2 order of magnitude difference between polar and non-polar amino acids. The pseudo-capacitance from EIS measurements on sample mixtures containing salt water and individual amino acids revealed the possibility for improvement in amino acid selectivity using gold nanoporous surface enhanced electrodes. This work establishes important methodologies for characterizing amino acids using EIS combined with microscale electrodes, supporting the case for instrumentation development for life detection and origin of life programs. PMID- 29716331 TI - Error analysis of multi-needle Langmuir probe measurement technique. AB - Multi-needle Langmuir probe is a fairly new instrument technique that has been flown on several recent sounding rockets and is slated to fly on a subset of QB50 CubeSat constellation. This paper takes a fundamental look into the data analysis procedures used for this instrument to derive absolute electron density. Our calculations suggest that while the technique remains promising, the current data analysis procedures could easily result in errors of 50% or more. We present a simple data analysis adjustment that can reduce errors by at least a factor of five in typical operation. PMID- 29716332 TI - Spectral calibration of EBT3 and HD-V2 radiochromic film response at high dose using 20 MeV proton beams. AB - Radiochromic film is used extensively in many medical, industrial, and scientific applications. In particular, the film is used in analysis of proton generation and in high intensity laser-plasma experiments where very high dose levels can be obtained. The present study reports calibration of the dose response of Gafchromic EBT3 and HD-V2 radiochromic films up to high exposure densities. A 2D scanning confocal densitometer system is employed to carry out accurate optical density measurements up to optical density 5 on the exposed films at the peak spectral absorption wavelengths. Various wavelengths from 400 to 740 nm are also scanned to extend the practical dose range of such films by measuring the response at wavelengths removed from the peak response wavelengths. Calibration curves for the optical density versus exposure dose are determined and can be used for quantitative evaluation of measured doses based on the measured optical densities. It was found that blue and UV wavelengths allowed the largest dynamic range though at some trade-off with overall accuracy. PMID- 29716333 TI - Determining the refractive index of particles using glare-point imaging technique. AB - A method of measuring the refractive index of a particle is presented from a glare-point image. The space of a doublet image of a particle can be determined with high accuracy by using auto-correlation and Gaussian interpolation, and then the refractive index is obtained from glare-point separation, and a factor that may influence the accuracy of glare-point separation is explored. Experiments are carried out for three different kinds of particles, including polystyrene latex particles, glass beads, and water droplets, whose measuring accuracy is improved by the data fitting method. The research results show that the method presented in this paper is feasible and beneficial to applications such as spray and atmospheric composition measurements. PMID- 29716334 TI - High-resolution photoluminescence electro-modulation microscopy by scanning lock in. AB - Morphological inhomogeneities and structural defects in organic semiconductors crucially determine the charge accumulation and lateral transport in organic thin film transistors. Photoluminescence Electro-Modulation (PLEM) microscopy is a laser-scanning microscopy technique that relies on the modulation of the thin film fluorescence in the presence of charge-carriers to image the spatial distribution of charges within the active organic semiconductor. Here, we present a lock-in scheme based on a scanning beam approach for increasing the PLEM microscopy resolution and contrast. The charge density in the device is modulated by a sinusoidal electrical signal, phase-locked to the scanning beam of the excitation laser. The lock-in detection scheme is achieved by acquiring a series of images with different phases between the beam scan and the electrical modulation. Application of high resolution PLEM to an organic transistor in accumulation mode demonstrates its potential to image local variations in the charge accumulation. A diffraction-limited precision of sub-300 nm and a signal to noise ratio of 21.4 dB could be achieved. PMID- 29716335 TI - Synchronous radio-frequency FM signal generator using direct digital synthesizers. AB - A novel Radio-Frequency Frequency-Modulated (RF-FM) signal generation method is introduced and a prototype circuit developed to evaluate its functionality and performance. The RF-FM signal generator uses a modulated, voltage-controlled time delay to correspondingly modulate the phase of a 10 MHz sinusoidal reference signal. This modulated reference signal is, in turn, used to clock a Direct Digital Synthesizer (DDS) circuit resulting in an FM signal at its output. The modulating signal that is input to the voltage-controlled time delay circuit is generated by another DDS that is synchronously clocked by the same 10 MHz sine wave signal before modulation. As a consequence, all of the digital components are timed from a single sine wave oscillator that forms the basis of all timing. The resultant output signal comprises a center, or carrier, frequency plus a series of phase-synchronized sidebands having exact integer harmonic frequency separation. In this study, carrier frequencies ranging from 10 MHz to 70 MHz are generated with modulation frequencies ranging from 10 kHz to 300 kHz. The captured spectra show that the FM signal characteristics, amplitude and phase, of the sidebands and the modulation depth are consistent with the Jacobi-Anger expansion for modulated harmonic signals. PMID- 29716336 TI - Rapid tomographic reconstruction based on machine learning for time-resolved combustion diagnostics. AB - Optical tomography has attracted surged research efforts recently due to the progress in both the imaging concepts and the sensor and laser technologies. The high spatial and temporal resolutions achievable by these methods provide unprecedented opportunity for diagnosis of complicated turbulent combustion. However, due to the high data throughput and the inefficiency of the prevailing iterative methods, the tomographic reconstructions which are typically conducted off-line are computationally formidable. In this work, we propose an efficient inversion method based on a machine learning algorithm, which can extract useful information from the previous reconstructions and build efficient neural networks to serve as a surrogate model to rapidly predict the reconstructions. Extreme learning machine is cited here as an example for demonstrative purpose simply due to its ease of implementation, fast learning speed, and good generalization performance. Extensive numerical studies were performed, and the results show that the new method can dramatically reduce the computational time compared with the classical iterative methods. This technique is expected to be an alternative to existing methods when sufficient training data are available. Although this work is discussed under the context of tomographic absorption spectroscopy, we expect it to be useful also to other high speed tomographic modalities such as volumetric laser-induced fluorescence and tomographic laser-induced incandescence which have been demonstrated for combustion diagnostics. PMID- 29716337 TI - Single frequency thermal wave radar: A next-generation dynamic thermography for quantitative non-destructive imaging over wide modulation frequency ranges. AB - Single-Frequency Thermal Wave Radar Imaging (SF-TWRI) was introduced and used to obtain quantitative thickness images of coatings on an aluminum block and on polyetherketone, and to image blind subsurface holes in a steel block. In SF-TWR, the starting and ending frequencies of a linear frequency modulation sweep are chosen to coincide. Using the highest available camera frame rate, SF-TWRI leads to a higher number of sampled points along the modulation waveform than conventional lock-in thermography imaging because it is not limited by conventional undersampling at high frequencies due to camera frame-rate limitations. This property leads to large reduction in measurement time, better quality of images, and higher signal-noise-ratio across wide frequency ranges. For quantitative thin-coating imaging applications, a two-layer photothermal model with lumped parameters was used to reconstruct the layer thickness from multi-frequency SF-TWR images. SF-TWRI represents a next-generation thermography method with superior features for imaging important classes of thin layers, materials, and components that require high-frequency thermal-wave probing well above today's available infrared camera technology frame rates. PMID- 29716338 TI - Arbitrary digital pulse sequence generator with delay-loop timing. AB - We propose an idea of an electronic multi-channel arbitrary digital sequence generator with temporal granularity equal to two clock cycles. We implement the generator with 32 channels using a low-cost ARM microcontroller and demonstrate its capability to produce temporal delays ranging from tens of nanoseconds to hundreds of seconds, with 24 ns timing granularity and linear scaling of delay with respect to the number of delay loop iterations. The generator is optionally synchronized with an external clock source to provide 100 ps jitter and overall sequence repeatability within the whole temporal range. The generator is fully programmable and able to produce digital sequences of high complexity. The concept of the generator can be implemented using different microcontrollers and applied for controlling of various optical, atomic, and nuclear physics measurement setups. PMID- 29716339 TI - Non-linear quantization error reduction for the temperature measurement subsystem on-board LISA Pathfinder. AB - Laser Interferometer Space Antenna (LISA) Pathfinder is a mission to test the technology enabling gravitational wave detection in space and to demonstrate that sub-femto-g free fall levels are possible. To do so, the distance between two free falling test masses is measured to unprecedented sensitivity by means of laser interferometry. Temperature fluctuations are one of the noise sources limiting the free fall accuracy and the interferometer performance and need to be known at the ~10 MUK Hz-1/2 level in the sub-millihertz frequency range in order to validate the noise models for the future space-based gravitational wave detector LISA. The temperature measurement subsystem on LISA Pathfinder is in charge of monitoring the thermal environment at key locations with noise levels of 7.5 MUK Hz-1/2 at the sub-millihertz. However, its performance worsens by one to two orders of magnitude when slowly changing temperatures are measured due to errors introduced by analog-to-digital converter non-linearities. In this paper, we present a method to reduce this effect by data post-processing. The method is applied to experimental data available from on-ground validation tests to demonstrate its performance and the potential benefit for in-flight data. The analog-to-digital converter effects are reduced by a factor between three and six in the frequencies where the errors play an important role. An average 2.7 fold noise reduction is demonstrated in the 0.3 mHz-2 mHz band. PMID- 29716340 TI - Effective ion charge (Zeff) measurements and impurity behavior in KSTAR. AB - A visible bremsstrahlung detector array diagnostic system has been developed on the Korea Superconducting Tokamak Advanced Research (KSTAR) to view the whole minor radius in a narrow region of the continuum free of spectral lines. The interference filters coupled with photomultiplier tubes have been employed to determine the effective charge Zeff by using visible bremsstrahlung data during neutral beam injection in the KSTAR plasma. The Zeff profiles are typically flat for L-mode plasmas and evolve to hollow profiles during the H mode in the KSTAR. A comparison of the visible bremsstrahlung emission based on the calculated Zeff profiles is consistent with measured values of Zeff from a visible spectrometer in the core plasma. The electron temperature is measured by X-ray imaging crystal spectrometry, and electron density needed for the analysis is taken by the assumption of parabolic profiles of these parameters. The line of sight averaged local bremsstrahlung emissivity is determined with low uncertainty, and the radial emissivity is obtained by using the Abel inversion technique. In addition, a dependence of effective charge Zeff on the line-averaged electron density is evaluated, and Zeff is also determined to observe the effect of boronization. PMID- 29716341 TI - Erratum: "A combined segmented anode gas ionization chamber and time-of-flight detector for heavy ion elastic recoil detection analysis" [Rev. Sci. Instrum. 87, 103303 (2016)]. PMID- 29716342 TI - Comparison of methods applied in photoinduced transient spectroscopy to determining the defect center parameters: The correlation procedure and the signal analysis based on inverse Laplace transformation. AB - The procedure for determination of trap parameters by photo-induced transient spectroscopy is based on the Arrhenius plot that illustrates a thermal dependence of the emission rate. In this paper, we show that the Arrhenius plot obtained by the correlation method is shifted toward lower temperatures as compared to the one obtained with the inverse Laplace transformation. This shift is caused by the model adequacy error of the correlation method and introduces errors to a calculation procedure of defect center parameters. The effect is exemplified by comparing the results of the determination of trap parameters with both methods based on photocurrent transients for defect centers observed in tin-doped neutron irradiated silicon crystals and in gallium arsenide grown with the Vertical Gradient Freeze method. PMID- 29716343 TI - The development of high-voltage repetitive low-jitter corona stabilized triggered switch. AB - The high-power switch plays an important part in a pulse power system. With the trend of pulse power technology toward modularization, miniaturization, and accuracy control, higher requirements on electrical trigger and jitter of the switch have been put forward. A high-power low-jitter corona-stabilized triggered switch (CSTS) is designed in this paper. This kind of CSTS is based on corona stabilized mechanism, and it can be used as a main switch of an intense electron beam accelerator (IEBA). Its main feature was the use of an annular trigger electrode instead of a traditional needle-like trigger electrode, taking main and side trigger rings to fix the discharging channels and using SF6/N2 gas mixture as its operation gas. In this paper, the strength of the local field enhancement was changed by a trigger electrode protrusion length Dp. The differences of self breakdown voltage and its stability, delay time jitter, trigger requirements, and operation range of the switch were compared. Then the effect of different SF6/N2 mixture ratio on switch performance was explored. The experimental results show that when the SF6 is 15% with the pressure of 0.2 MPa, the hold-off voltage of the switch is 551 kV, the operating range is 46.4%-93.5% of the self-breakdown voltage, the jitter is 0.57 ns, and the minimum trigger voltage requirement is 55.8% of the peak. At present, the CSTS has been successfully applied to an IEBA for long time operation. PMID- 29716344 TI - Spatial measurement in rotating magnetic field plasma acceleration method by using two-dimensional scanning instrument and thrust stand. AB - A two-dimensional scanning probe instrument has been developed to survey spatial plasma characteristics in our electrodeless plasma acceleration schemes. In particular, diagnostics of plasma parameters, e.g., plasma density, temperature, velocity, and excited magnetic field, are essential for elucidating physical phenomena since we have been concentrating on next generation plasma propulsion methods, e.g., Rotating Magnetic Field plasma acceleration method, by characterizing the plasma performance. Moreover, in order to estimate the thrust performance in our experimental scheme, we have also mounted a thrust stand, which has a target type, on this movable instrument, and scanned the axial profile of the thrust performance in the presence of the external magnetic field generated by using permanent magnets, so as to investigate the plasma captured in a stand area, considering the divergent field lines in the downstream region of a generation antenna. In this paper, we will introduce the novel measurement instrument and describe how to measure these parameters. PMID- 29716345 TI - Compact high-sensitivity potentiometer for detection of low ion concentrations in liquids. AB - The compact potentiometer, based on an electronic circuit protected from electrostatic and electromagnetic interference, was developed for the measurement of low ion concentrations in liquids. The electronic circuit of the potentiometer, consisting of analogous and digital parts, enables the measurement of fA currents. This makes it possible to perform reliable measurements of ion concentrations in liquids that are as small as 10-8-10-7M. The instrument was tested using electrodes that were selective for tetraphenylphosphonium (TPP+) ions. It was demonstrated that the characteristic response time of the potentiometer electronic circuit to changes in the concentration of these ions in a liquid was in the order of 10 s. An investigation of TPP+ absorption by baker yeast has shown that this device can be successfully used for long term (several hours) measurements with zero signal drift, which was about 1 MUV/s. Finally, due to the small dimensions of the electronic circuit (7.5 * 2 * 1.5 cm), this potentiometer can be easily installed at a large apparatus in the laboratory condition (~25 degrees C), such as high pulsed electrical generators of magnetic fields that are used in electroporation studies of biological cells. PMID- 29716346 TI - Extension of the thermal porosimetry method to high gas pressure for nanoporosimetry estimation. AB - Standard pore size determination methods like mercury porosimetry, nitrogen sorption, microscopy, or X-ray tomography are not suited to highly porous, low density, and thus very fragile materials. For this kind of materials, a method based on thermal characterization has been developed in a previous study. This method has been used with air pressure varying from 10-1 to 105 Pa for materials having a thermal conductivity less than 0.05 W m-1 K-1 at atmospheric pressure. It enables the estimation of pore size distribution between 100 nm and 1 mm. In this paper, we present a new experimental device enabling thermal conductivity measurement under gas pressure up to 106 Pa, enabling the estimation of the volume fraction of pores having a 10 nm diameter. It is also demonstrated that the main thermal conductivity models (parallel, series, Maxwell, Bruggeman, self consistent) lead to the same estimation of the pore size distribution as the extended parallel model (EPM) presented in this paper and then used to process the experimental data. Three materials with thermal conductivities at atmospheric pressure ranging from 0.014 W m-1 K-1 to 0.04 W m-1 K-1 are studied. The thermal conductivity measurement results obtained with the three materials are presented, and the corresponding pore size distributions between 10 nm and 1 mm are presented and discussed. PMID- 29716347 TI - Spectroscopic method to study low charge state ion and cold electron population in ECRIS plasma. AB - The results of optical emission spectroscopy experiments probing the cold electron population of a 14 GHz Electron Cyclotron Resonance Ion Source (ECRIS) are reported. The study has been conducted with a high resolution spectrometer and data acquisition setup developed specifically for the diagnostics of weak emission line characteristic to ECRIS plasmas. The optical emission lines of low charge state ions and neutral atoms of neon have been measured and analyzed with the line-ratio method. The aforementioned electron population temperature of the cold electron population (Te < 100 eV) is determined for Maxwell-Boltzmann and Druyvesteyn energy distributions to demonstrate the applicability of the method. The temperature was found to change significantly when the extraction voltage of the ion source is turned on/off. In the case of the Maxwellian distribution, the temperature of the cold electron population is 20 +/- 10 eV when the extraction voltage is off and 40 +/- 10 eV when it is on. The optical emission measurements revealed that the extraction voltage also affects both neutral and ion densities. Based on the rate coefficient analysis with the aforementioned temperatures, switching the extraction voltage off decreases the rate coefficient of neutral to 1+ ionization to 42% and 1+ to 2+ ionization to 24% of the original. This suggests that switching the extraction voltage on favors ionization to charge states >=2+ and, thus, the charge state distributions of ECRIS plasmas are probably different with the extraction voltage on/off. It is therefore concluded that diagnostics results of ECRIS plasmas obtained without the extraction voltage are not depicting the plasma conditions in normal ECRIS operation. PMID- 29716348 TI - A coaxial-output capacitor-loaded annular pulse forming line. AB - A coaxial-output capacitor-loaded annular pulse forming line (PFL) is developed in order to reduce the flat top fluctuation amplitude of the forming quasi-square pulse and improve the quality of the pulse waveform produced by a Tesla-pulse forming network (PFN) type pulse generator. A single module composed of three involute dual-plate PFNs is designed, with a characteristic impedance of 2.44 Omega, an electrical length of 15 ns, and a sustaining voltage of 60 kV. The three involute dual-plate PFNs connected in parallel have the same impedance and electrical length. Due to the existed small inductance and capacitance per unit length in each involute dual-plate PFN, the upper cut-off frequency of the PFN is increased. As a result, the entire annular PFL has better high-frequency response capability. Meanwhile, the three dual-plate PFNs discharge in parallel, which is much closer to the coaxial output. The series connecting inductance between adjacent two modules is significantly reduced when the annular PFL modules are connected in series. The pulse waveform distortion is reduced when the pulse transfers along the modules. Finally, the shielding electrode structure is applied on both sides of the module. The electromagnetic field is restricted in the module when a single module discharges, and the electromagnetic coupling between the multi-stage annular PFLs is eliminated. Based on the principle of impedance matching between the multi-stage annular PFL and the coaxial PFL, the structural optimization design of a mixed PFL in a Tesla type pulse generator is completed with the transient field-circuit co-simulation method. The multi-stage annular PFL consists of 18 stage annular PFL modules in series, with the characteristic impedance of 44 Omega, the electrical length of 15 ns, and the sustaining voltage of 1 MV. The mixed PFL can generate quasi-square electrical pulses with a pulse width of 43 ns, and the fluctuation ratio of the pulse flat top is less than 8% when the pulse rise time is about 5 ns. PMID- 29716349 TI - Metallic-packaging fiber Bragg grating sensor based on ultrasonic welding for strain-insensitive temperature measurement. AB - In this paper, a metallic-packaging fiber Bragg grating temperature sensor characterized by a strain insensitive design is demonstrated. The sensor is fabricated by the one-step ultrasonic welding technique using type-II fiber Bragg grating combined with an aluminum alloy substrate. Finite element analysis is used to perform theoretical evaluation. The result of the experiment illustrates that the metallic-packaging temperature sensor is insensitive to longitudinal strain. The sensor's temperature sensitivity is 36 pm/ degrees C over the range of 50-110 degrees C, with the correlation coefficient (R2) being 0.999. The sensor's temporal response is 40 s at a sudden temperature change from 21 degrees C to 100 degrees C. The proposed sensor can be applied on reliable and precise temperature measurement. PMID- 29716350 TI - Enhancement of gravimetric forced flow through system to determine sorption, swelling, and mass transfer characteristics of liquid sorbents. AB - An existing apparatus for forced flow through of liquid sorbents has been enhanced with an optically accessible system including a transparent crucible, high pressure viewing cell, and camera. With this optical system, the active surface area between gas and liquid can be determined in situ for the first time under industrial process conditions while maintaining the accuracy of a magnetic suspension balance. Additionally, occurring swelling and the resulting buoyancy changes can now be corrected, further improving the quality of the data. Validation measurements focusing on the sorption isotherms, swelling, and bubble geometry of 1-butyl-3-methylimidazolium tetrafluoroborate with nitrogen at 303 K and up to 17 MPa, as well as with carbon dioxide at 303 K, 323 K, and 373 K at up to 3.5 MPa were completed. Absorption of nitrogen resulted in no observable volume change, whereas absorption of carbon dioxide resulted in temperature independent swelling of up to 9.8%. The gas bubble's structure and behavior during its ascend through the liquid was optically tracked in situ. Combining these two data sets with the absorption kinetics forms the basis to determine the measuring system independent mass transfer coefficients, which are applicable in other laboratory scale and industrial processes. PMID- 29716351 TI - Modeling and design of a two-axis elliptical notch flexure hinge. AB - As an important part of the joule balance system, the two-axis elliptical notch flexure hinge (TENFH) which typically consists of two single-axis elliptical notch flexure hinges was studied. First, a 6 degrees of freedom (6-DOF) compliance model was established based on the coordinate transformation method. In addition, the maximum stress of the TENFH was derived. The compliance and maximum stress model was verified using finite element analysis simulation. To decouple the attitude of the suspended coil system and reduce the offset between the centroid of the suspended coil mechanism and the mass comparator in the joule balance system, a new mechanical structure of TENFH was designed based on the compliance model and stress model proposed in this paper. The maximum rotation range is up to 10 degrees , and the axial load is more than 5 kg, which meets the requirements of the system. The compliance model was also verified by deformation experimentation with the designed TENFH. PMID- 29716352 TI - Combination of thermal and electric properties' measurement techniques in a single setup suitable for radioactive materials in controlled environments and based on the 3omega approach. AB - We have designed and developed a new experimental setup, based on the 3omega method, to measure thermal conductivity, heat capacity, and electrical resistivity of a variety of samples in a broad temperature range (2-550 K) and under magnetic fields up to 9 T. The validity of this method is tested by measuring various types of metallic (copper, platinum, and constantan) and insulating (SiO2) materials, which have a wide range of thermal conductivity values (1-400 W m-1 K-1). We have successfully employed this technique for measuring the thermal conductivity of two actinide single crystals: uranium dioxide and uranium nitride. This new experimental approach for studying nuclear materials will help us to advance reactor fuel development and understanding. We have also shown that this experimental setup can be adapted to the Physical Property Measurement System (Quantum Design) environment and/or other cryocooler systems. PMID- 29716353 TI - Design of a seismo-acoustic station for Antarctica. AB - In recent years, seismological studies in Antarctica have contributed plenty of new knowledge in many fields of earth science. Moreover, acoustic investigations are now also considered a powerful tool that provides insights for many different objectives, such as analyses of regional climate-related changes and studies of volcanic degassing and explosive activities. However, installation and maintenance of scientific instrumentation in Antarctica can be really challenging. Indeed, the instruments have to face the most extreme climate on the planet. They must be tolerant of very low temperatures and robust enough to survive strong winds. Moreover, one of the most critical tasks is powering a remote system year-round at polar latitudes. In this work, we present a novel seismo-acoustic station designed to work reliably in polar regions. To enable year-round seismo-acoustic data collection in such a remote, extreme environment, a hybrid powering system is used, integrating solar panels, a wind generator, and batteries. A power management system was specifically developed to either charge the battery bank or divert energy surplus to warm the enclosure or release the excess energy to the outside environment. Finally, due to the prohibitive environmental conditions at most Antarctic installation sites, the station was designed to be deployed quickly. PMID- 29716354 TI - FPGA based demodulation of laser induced fluorescence in plasmas. AB - We present a field programmable gate array (FPGA)-based system that counts photons from laser-induced fluorescence (LIF) on a laboratory plasma. This is accomplished with FPGA-based up/down counters that demodulate the data, giving a background-subtracted LIF signal stream that is updated with a new point as each laser amplitude modulation cycle completes. We demonstrate using the FPGA to modulate a laser at 1 MHz and demodulate the resulting LIF data stream. This data stream is used to calculate an LIF-based measurement sampled at 1 MHz of a plasma ion fluctuation spectrum. PMID- 29716355 TI - Design and characterization of a dead-time regime enhanced early photon projection imaging system. AB - Scattering of visible and near-infrared light in biological tissue reduces spatial resolution for imaging of tissues thicker than 100 MUm. In this study, an optical projection imaging system is presented and characterized that exploits the dead-time characteristics typical of photon counting modules based on single photon avalanche diodes (SPADs). With this system, it is possible to attenuate the detection of more scattered late-arriving photons, such that detection of less scattered early-arriving photons can be enhanced with increased light intensity, without being impeded by the maximum count rate of the SPADs. The system has the potential to provide transmittance-based anatomical information or fluorescence-based functional information (with slight modification in the instrumentation) of biological samples with improved resolution in the mesoscopic domain (0.1-2 cm). The system design, calibration, stability, and performance were evaluated using simulation and experimental phantom studies. The proposed system allows for the detection of very-rare early-photons at a higher frequency and with a better signal-to-noise ratio. The experimental results demonstrated over a 3.4-fold improvement in the spatial resolution using early photon detection vs. conventional detection, and a 1000-fold improvement in imaging time using enhanced early detection vs. conventional early photon detection in a 4-mm thick phantom with a tissue-equivalent absorption coefficient of MUa = 0.05 mm-1 and a reduced scattering coefficient of MUs' = 5 mm-1. PMID- 29716356 TI - Magnetic tweezers optimized to exert high forces over extended distances from the magnet in multicellular systems. AB - Magnetic tweezers are mainly divided into two classes depending on the ability of applying torque or forces to the magnetic probe. We focused on the second category and designed a device composed by a single electromagnet equipped with a core having a special asymmetric profile to exert forces as large as 230 pN-2.8 MUm Dynabeads at distances in excess of 100 MUm from the magnetic tip. Compared to existing solutions our magnetic tweezers overcome important limitations, opening new experimental paths for the study of a wide range of materials in a variety of biophysical research settings. We discuss the benefits and drawbacks of different magnet core characteristics, which led us to design the current core profile. To demonstrate the usefulness of our magnetic tweezers, we determined the microrheological properties inside embryos of Drosophila melanogaster during the syncytial stage. Measurements in different locations along the dorsal-ventral axis of the embryos showed little variation, with a slight increase in cytoplasm viscosity at the periphery of the embryos. The mean cytoplasm viscosity we obtain by active force exertion inside the embryos is comparable to that determined passively using high-speed video microrheology. PMID- 29716357 TI - Analysis of retarding field energy analyzer transmission by simulation of ion trajectories. AB - Retarding field energy analyzers (RFEAs) are used routinely for the measurement of ion energy distribution functions. By contrast, their ability to measure ion flux densities has been considered unreliable because of lack of knowledge about the effective transmission of the RFEA grids. In this work, we simulate the ion trajectories through a three-gridded RFEA using the simulation software SIMION. Using idealized test cases, it is shown that at high ion energy (i.e., >100 eV) the transmission is equal to the optical transmission rather than the product of the individual grid transparencies. Below 20 eV, ion trajectories are strongly influenced by the electric fields in between the grids. In this region, grid alignment and ion focusing effects contribute to fluctuations in transmission with ion energy. Subsequently the model has been used to simulate the transmission and energy resolution of an experimental RFEA probe. Grid misalignments reduce the transmission fluctuations at low energy. The model predicts the minimum energy resolution, which has been confirmed experimentally by irradiating the probe with a beam of ions with a small energy bandwidth. PMID- 29716358 TI - Controlled electromigration protocol revised. AB - Electromigration has evolved from an important cause of failure in electronic devices to an appealing method, capable of modifying the material properties and geometry of nanodevices. Although this technique has been successfully used by researchers to investigate low dimensional systems and nanoscale objects, its low controllability remains a serious limitation. This is in part due to the inherent stochastic nature of the process, but also due to the inappropriate identification of the relevant control parameters. In this study, we identify a suitable process variable and propose a novel control algorithm that enhances the controllability and, at the same time, minimizes the intervention of an operator. As a consequence, the algorithm facilitates the application of electromigration to systems that require exceptional control of, for example, the width of a narrow junction. It is demonstrated that the electromigration rate can be stabilized on pre-set values, which eventually defines the final geometry of the electromigrated structures. PMID- 29716359 TI - A hollow coaxial cable Fabry-Perot resonator for liquid dielectric constant measurement. AB - We report, for the first time, a low-cost and robust homemade hollow coaxial cable Fabry-Perot resonator (HCC-FPR) for measuring liquid dielectric constant. In the HCC design, the traditional dielectric insulating layer is replaced by air. A metal disk is welded onto the end of the HCC serving as a highly reflective reflector, and an open cavity is engineered on the HCC. After the open cavity is filled with the liquid analyte (e.g., water), the air-liquid interface acts as a highly reflective reflector due to large impedance mismatch. As a result, an HCC-FPR is formed by the two highly reflective reflectors, i.e., the air-liquid interface and the metal disk. We measured the room temperature dielectric constant for ethanol/water mixtures with different concentrations using this homemade HCC-FPR. Monitoring the evaporation of ethanol in ethanol/water mixtures was also conducted to demonstrate the ability of the sensor for continuously monitoring the change in dielectric constant. The results revealed that the HCC-FPR could be a promising evaporation rate detection platform with high performance. Due to its great advantages, such as high robustness, simple configuration, and ease of fabrication, the novel HCC-FPR based liquid dielectric constant sensor is believed to be of high interest in various fields. PMID- 29716360 TI - Cryocooler based test setup for high current applications. AB - A cryo-cooler based cryogenic test setup has been designed, fabricated, and tested. The setup incorporates two numbers of cryo-coolers, one for sample cooling and the other one for cooling the large magnet coil. The performance and versatility of the setup has been tested using large samples of high-temperature superconductor magnet coil as well as short samples with high current. Several un calibrated temperature sensors have been calibrated using this system. This paper presents the details of the system along with results of different performance tests. PMID- 29716361 TI - A novel flow sensor based on resonant sensing with two-stage microleverage mechanism. AB - The design, simulation, fabrication, and experiments of a novel flow sensor based on resonant sensing with a two-stage microleverage mechanism are presented in this paper. Different from the conventional detection methods for flow sensors, two differential resonators are adopted to implement air flow rate transformation through two-stage leverage magnification. The proposed flow sensor has a high sensitivity since the adopted two-stage microleverage mechanism possesses a higher amplification factor than a single-stage microleverage mechanism. The modal distribution and geometric dimension of the two-stage leverage mechanism and hair are analyzed and optimized by Ansys simulation. A digital closed-loop driving technique with a phase frequency detector-based coordinate rotation digital computer algorithm is implemented for the detection and locking of resonance frequency. The sensor fabricated by the standard deep dry silicon on a glass process has a device dimension of 5100 MUm (length) * 5100 MUm (width) * 100 MUm (height) with a hair diameter of 1000 MUm. The preliminary experimental results demonstrate that the maximal mechanical sensitivity of the flow sensor is approximately 7.41 Hz/(m/s)2 at a resonant frequency of 22 kHz for the hair height of 9 mm and increases by 2.42 times as hair height extends from 3 mm to 9 mm. Simultaneously, a detection-limit of 3.23 mm/s air flow amplitude at 60 Hz is confirmed. The proposed flow sensor has great application prospects in the micro autonomous system and technology, self-stabilizing micro-air vehicles, and environmental monitoring. PMID- 29716362 TI - Design and implementation of a shearing apparatus for the experimental study of shear displacement in rocks. AB - Fluid flow in the subsurface is not well understood in the context of "impermeable" geologic media. This is especially true of formations that have undergone significant stress fluctuations due to injection or withdrawal of fluids that alters the localized pressure regime. When the pressure regime is altered, these formations, which are often already fractured, move via shear to reduce the imbalance in the stress state. While this process is known to happen, the evolution of these fractures and their effects on fluid transport are still relatively unknown. Numerous simulation and several experimental studies have been performed that characterize the relationship between shearing and permeability in fractures; while many of these studies utilize measurements of fluid flow or the starting and ending geometries of the fracture to characterize shear, they do not characterize the intermediate stages during shear. We present an experimental apparatus based on slight modifications to a commonly available Hassler core holder that allows for shearing of rocks, while measuring the hydraulic and mechanical changes to geomaterials during intermediate steps. The core holder modification employs the use of semi-circular end caps and structural supports for the confining membrane that allow for free movement of the sheared material while preventing membrane collapse. By integrating this modified core holder with a computed tomography scanner, we show a new methodology for understanding the interdependent behavior between fracture structure and flow properties during intermediate steps in shearing. We include a case study of this device function which is shown here through shearing of a fractured shale core and simultaneous observation of the mechanical changes and evolution of the hydraulic properties during shearing. PMID- 29716364 TI - Performance of the fiber-optic low-coherent ground settlement sensor: From lab to field. AB - A fiber-optic low-coherent interferometry sensor was developed to measure the ground settlement (GS) in an accuracy of the micrometer. The sensor combined optical techniques with liquid-contained chambers that were hydraulically connected together at the bottom by using a water-filled tube. The liquid surface inside each chamber was at the same level initially. The optical interferometry was employed to read out the liquid level changes, which following the GS happened at the place where the chamber was put on and, thereby, the GS information was calculated. The laboratory effort had demonstrated its potential in the practical application. Here, the denoising algorithms on the measurement signal were carried out based on the specific environment to ensure the accuracy and stability of the system in field applications. After that, we extended this technique to the high-speed railway. The 5-days continuous measurement proved that the designed system could be applied to monitor the GS of the high-speed railway piers and approached an accuracy of +/-70 MUm in the field situation with a reference compensation sensor. So the performance of the sensor was suitable to the GS monitoring problem in the high-speed railway. There, the difficulties were to meet the monitoring requirement of both a large span in space and its quite tiny and slow changes. PMID- 29716365 TI - Functions to map photoelectron distributions in a variety of setups in angle resolved photoemission spectroscopy. AB - The distribution of photoelectrons acquired in angle-resolved photoemission spectroscopy can be mapped onto the energy-momentum space of the Bloch electrons in the crystal. The explicit forms of the mapping function f depend on the configuration of the apparatus as well as on the type of the photoelectron analyzer. We show that the existence of the analytic forms of f-1 is guaranteed in a variety of setups. The variety includes the case when the analyzer is equipped with a photoelectron deflector. Thereby, we provide a demonstrative mapping program implemented by an algorithm that utilizes both f and f-1. The mapping methodology is also usable in other spectroscopic methods such as momentum-resolved electron-energy loss spectroscopy. PMID- 29716366 TI - SQUID-detected FMR: Resonance in single crystalline and polycrystalline yttrium iron garnet. AB - Here two new techniques for the detection of broadband (100 MHz-20 GHz) ferromagnetic resonance (FMR)/ferrimagnetic resonance in single and poly crystalline materials, which rely on SQUID-based gradiometry detection of small changes in the magnetisation, are developed. In the first method, small changes in the along-the-applied-field projection of the coupled magnetic moment (Deltamz) are detected as the material is driven into resonance. Absolute measurement of the longitudinal component of the magnetisation and the resonance induced lowering of this moment makes estimation of the precession cone angle accessible, which is typically difficult to extract using conventional cavity or stripline based detection methods. The second method invokes the change in Deltamz with the resonance-induced thermal heating dmzdT. Magnetisation dynamics in bulk Y3Fe5O12 are observed over a broad range of experimental temperatures (4 K-400 K) and fields (10-500 mT). The inhomogeneous microwave excitation allows for the observation of higher magnetostatic modes and the convenient tracking of very broad resonances. The two SQUID-detection techniques when combined with conventional broadband vector network analyser-FMR, low-frequency magnetic susceptibility, and DC magnetometry, all easily realised, essentially concurrently, using the same module, greatly expand the amount of static and dynamic information accessible. PMID- 29716367 TI - Note: Comparison experimental results of the laser heterodyne interferometer for angle measurement based on the Faraday effect. AB - A laser heterodyne interferometer for angle measurement based on the Faraday effect is proposed. A novel optical configuration, designed by using the orthogonal return method for a linearly polarized beam based on the Faraday effect, guarantees that the measurement beam can return effectively even though an angular reflector has a large lateral displacement movement. The optical configuration and measurement principle are presented in detail. Two verification experiments were performed; the experimental results show that the proposed interferometer can achieve a large lateral displacement tolerance of 7.4 mm and also can realize high precision angle measurement with a large measurement range. PMID- 29716368 TI - Absolute ion detection efficiencies of microchannel plates and funnel microchannel plates for multi-coincidence detection. AB - Modern momentum imaging techniques allow for the investigation of complex molecules in the gas phase by detection of several fragment ions in coincidence. For these studies, it is of great importance that the single-particle detection efficiency epsilon is as high as possible, as the overall efficiency scales with epsilonn, i.e., the power of the number of detected particles. Here we present measured absolute detection efficiencies for protons of several micro-channel plates (MCPs), including efficiency enhanced "funnel MCPs." Furthermore, the relative detection efficiency for two-, three-, four-, and five-body fragmentation of CHBrClF has been examined. The "funnel" MCPs exhibit an efficiency of approximately 90%, gaining a factor of 24 (as compared to "normal" MCPs) in the case of a five-fold ion coincidence detection. PMID- 29716369 TI - The flush-mounted rail Langmuir probe array designed for the Alcator C-Mod vertical target plate divertor. AB - An array of flush-mounted and toroidally elongated Langmuir probes (henceforth called rail probes) have been specifically designed for the Alcator C-Mod's vertical target plate divertor and operated over multiple campaigns. The "flush" geometry enables the tungsten electrodes to survive high heat flux conditions in which traditional "proud" tungsten electrodes suffer damage from melting. The toroidally elongated rail-like geometry reduces the influence of sheath expansion, which is an important effect to consider in the design and interpretation of flush-mounted Langmuir probes. The new rail probes successfully operated during C-Mod's FY2015 and FY2016 experimental campaigns with no evidence of damage, despite being regularly subjected to heat flux densities parallel to the magnetic field exceeding ~1 GW m-2 for short periods of time. A comparison between rail and proud probe data indicates that sheath expansion effects were successfully mitigated by the rail design, extending the use of these Langmuir probes to incident magnetic field line angles as low as 0.5 degrees . PMID- 29716370 TI - OMNY-A tOMography Nano crYo stage. AB - For many scientific questions gaining three-dimensional insight into a specimen can provide valuable information. We here present an instrument called "tOMography Nano crYo (OMNY)," dedicated to high resolution 3D scanning x-ray microscopy at cryogenic conditions via hard X-ray ptychography. Ptychography is a lens-less imaging method requiring accurate sample positioning. In OMNY, this in achieved via dedicated laser interferometry and closed-loop position control reaching sub-10 nm positioning accuracy. Cryogenic sample conditions are maintained via conductive cooling. 90 K can be reached when using liquid nitrogen as coolant, and 10 K is possible with liquid helium. A cryogenic sample-change mechanism permits measurements of cryogenically fixed specimens. We compare images obtained with OMNY with older measurements performed using a nitrogen gas cryo-jet of stained, epoxy-embedded retina tissue and of frozen-hydrated Chlamydomonas cells. PMID- 29716371 TI - A multifunctional force microscope for soft matter with in situ imaging. AB - We present the multifunctional force microscope (MFM), a normal and lateral force measuring instrument with in situ imaging. In the MFM, forces are calculated from the normal and lateral deflection of a cantilever as measured via fiber optic sensors. The motion of the cantilever is controlled normally by a linear micro translation stage and a piezoelectric actuator, while the lateral motion of the sample is controlled by another linear micro-translation stage. The micro translation stages allow for travel distances that span 25 mm with a minimum step size of 50 nm, while the piezo has a minimum step size of 0.2 nm, but a 100 MUm maximum range. Custom-designed cantilevers allow for the forces to be measured over 4 orders of magnitude (from 50 MUN to 1 N). We perform probe tack, friction, and hydrodynamic drainage experiments to demonstrate the sensitivity, versatility, and measurable force range of the instrument. PMID- 29716372 TI - Systematic-error-free wavefront measurement using an X-ray single-grating interferometer. AB - In this study, the systematic errors of an X-ray single-grating interferometer based on the Talbot effect were investigated in detail. Non-negligible systematic errors induced by an X-ray camera were identified and a method to eliminate the systematic error was proposed. Systematic-error-free measurements of the wavefront error produced by multilayer focusing mirrors with large numerical apertures were demonstrated at the SPring-8 Angstrom Compact free electron LAser. Consequently, wavefront aberration obtained with two different cameras was found to be consistent with an accuracy better than lambda/12. PMID- 29716373 TI - Investigation of periodically driven systems by x-ray absorption spectroscopy using asynchronous data collection mode. AB - We report the development, testing, and demonstration of a setup for modulation excitation spectroscopy experiments at the Inner Shell Spectroscopy beamline of National Synchrotron Light Source - II. A computer algorithm and dedicated software were developed for asynchronous data processing and analysis. We demonstrate the reconstruction of X-ray absorption spectra for different time points within the modulation pulse using a model system. This setup and the software are intended for a broad range of functional materials which exhibit structural and/or electronic responses to the external stimulation, such as catalysts, energy and battery materials, and electromechanical devices. PMID- 29716374 TI - Development of an electron-ion coincidence apparatus for molecular-frame electron energy loss spectroscopy studies. AB - We report details of an electron-ion coincidence apparatus, which has been developed for molecular-frame electron energy loss spectroscopy studies. The apparatus is mainly composed of a pulsed electron gun, an energy-dispersive electron spectrometer, and an ion momentum imaging spectrometer. Molecular orientation dependence of the high-energy electron scattering cross section can be examined by conducting measurements of vector correlation between the momenta of the scattered electron and fragment ion. Background due to false coincidences is significantly reduced by introducing a pulsed electron beam and pulsing scheme of ion extraction. The experimental setup has been tested by measuring the inner shell excitation of N2 at an incident electron energy of 1.5 keV and a scattering angle of 10.2 degrees . PMID- 29716375 TI - Calibrated work function mapping by Kelvin probe force microscopy. AB - We propose and demonstrate the implementation of an alternative work function tip calibration procedure for Kelvin probe force microscopy under ultrahigh vacuum, using monocrystalline metallic materials with known crystallographic orientation as reference samples, instead of the often used highly oriented pyrolytic graphite calibration sample. The implementation of this protocol allows the acquisition of absolute and reproducible work function values, with an improved uncertainty with respect to unprepared highly oriented pyrolytic graphite-based protocols. The developed protocol allows the local investigation of absolute work function values over nanostructured samples and can be implemented in electronic structures and devices characterization as demonstrated over a nanostructured semiconductor sample presenting Al0.7Ga0.3As and GaAs layers with variable thickness. Additionally, using our protocol we find that the work function of annealed highly oriented pyrolytic graphite is equal to 4.6 +/- 0.03 eV. PMID- 29716376 TI - Metrological 2iOF fibre-optic system for position and displacement measurement with 31 pm resolution. AB - In the present paper, we describe a high sensitivity intensity fibre-optic displacement sensor with tens of picometre resolution combined with a sub picometre resolution interferometric calibration system. Both integrated components form the so-called "2 in one ferrule" system 2iOF. The design and construction of the presented device depend on integrating two sensors' systems within one fibre-optic measuring head, which allows performing in situ calibration process with no additional time-consuming adjustment procedure. The resolution of the 2iOF system is 31 pm/Hz1/2 obtained with an interferometric Fabry-Perot based calibration system-providing accuracy better than tens of fm/Hz1/2 within 1 MHz bandwidth in the measurement range of up to 100 MUm. The direct response from the intensity sensor is then the 2iOF output one. It is faster and more convenient to analyze in comparison, with much better resolution (3 orders of magnitude higher) but on the other hand also more time consuming and dependent on the absolute sample position interferometer. The proposed system is flexible and open to various applications. We will present the results of the piezoelectrical actuator displacement measurements, which were performed using the developed system. PMID- 29716377 TI - An experimental platform for triaxial high-pressure/high-temperature testing of rocks using computed tomography. AB - A conventional high-pressure/high-temperature experimental apparatus for combined geomechanical and flow-through testing of rocks is not X-ray compatible. Additionally, current X-ray transparent systems for computed tomography (CT) of cm-sized samples are limited to design temperatures below 180 degrees C. We describe a novel, high-temperature (>400 degrees C), high-pressure (>2000 psi/>13.8 MPa confining, >10 000 psi/>68.9 MPa vertical load) triaxial core holder suitable for X-ray CT scanning. The new triaxial system permits time-lapse imaging to capture the role of effective stress on fluid distribution and porous medium mechanics. System capabilities are demonstrated using ultimate compressive strength (UCS) tests of Castlegate sandstone. In this case, flooding the porous medium with a radio-opaque gas such as krypton before and after the UCS test improves the discrimination of rock features such as fractures. The results of high-temperature tests are also presented. A Uintah Basin sample of immature oil shale is heated from room temperature to 459 degrees C under uniaxial compression. The sample contains kerogen that pyrolyzes as temperature rises, releasing hydrocarbons. Imaging reveals the formation of stress bands as well as the evolution and connectivity of the fracture network within the sample as a function of time. PMID- 29716378 TI - Note: An absolute X-Y-Theta position sensor using a two-dimensional phase-encoded binary scale. AB - This Note presents a new absolute X-Y-Theta position sensor for measuring planar motion of a precision multi-axis stage system. By analyzing the rotated image of a two-dimensional phase-encoded binary scale (2D), the absolute 2D position values at two separated points were obtained and the absolute X-Y-Theta position could be calculated combining these values. The sensor head was constructed using a board-level camera, a light-emitting diode light source, an imaging lens, and a cube beam-splitter. To obtain the uniform intensity profiles from the vignette scale image, we selected the averaging directions deliberately, and higher resolution in the angle measurement could be achieved by increasing the allowable offset size. The performance of a prototype sensor was evaluated in respect of resolution, nonlinearity, and repeatability. The sensor could resolve 25 nm linear and 0.001 degrees angular displacements clearly, and the standard deviations were less than 18 nm when 2D grid positions were measured repeatedly. PMID- 29716379 TI - Simultaneous measurement of the dynamic emissivity and the radiance of the shocked Al/LiF interface in the near-infrared wavelength. AB - A novel method based on signal superimposing has been presented to simultaneously measure the dynamic emissivity and the radiance of a shocked sample/window interface in the near-infrared wavelength. In this method, we have used three rectangle laser pulses to illuminate the sample/window interface via an integrating sphere and expect that the reflected laser pulses from the sample/window interface can be superimposed on its thermal radiation at the shocked steady state by time precision synchronization. In the two proving trials, the second laser pulse reflected from the Al/LiF interface has been successfully superimposed on its thermal radiation despite large flyer velocity uncertainty. The dynamic emissivity and the radiance at 1064 nm have been obtained simultaneously from the superimposing signals. The obtained interface temperatures are 1842 +/- 82 K and 1666 +/- 154 K, respectively, the corresponding release pressures are 65.7 GPa and 62.6 GPa, and the deduced Hugonoit temperatures are consistent with the theoretical calculations. In comparison, the fitting temperatures from the gray body model are 300-500 K higher than our experimental measurement results and the theoretical calculations. PMID- 29716380 TI - Measurement of Ti-6Al-4V alloy ignition temperature by reflectivity detection. AB - Fires resulting from titanium combustion are complex and violent processes which can instantly burn a titanium alloy once ignited. The occurrence of titanium combustion is a disaster for aircraft. Accurate measurement of the ignition temperature of titanium alloys is of significance in preventing such fires and in investigating combustion-resistance properties. In this study, monochromatic temperature and emissivity measurement methods based on reflectivity detection were used to determine the ignition temperature of a titanium alloy. Experiments were carried out using a titanium burning apparatus. The temperatures of titanium in the oxidation stage before ignition and in the combustion stage during the ignition process were measured using wavelengths of 1050 nm and 940 nm, respectively. Experimental results showed that the ignition temperature of the titanium alloy could be measured by reflectivity detection and that measurement precision during thermal oxidation (500-900 degrees C) was +/-1 degrees C. The temperature of the ignition process ranged between 1653 and 1857 degrees C, and the ignition temperature was around 1680 degrees C. PMID- 29716381 TI - A microelectromechanical systems (MEMS) force-displacement transducer for sub-5 nm nanoindentation and adhesion measurements. AB - We present a highly sensitive force-displacement transducer capable of performing ultra-shallow nanoindentation and adhesion measurements. The transducer utilizes electrostatic actuation and capacitive sensing combined with microelectromechanical fabrication technologies. Air indentation experiments report a root-mean-square (RMS) force resolution of 1.8 nN and an RMS displacement resolution of 0.019 nm. Nanoindentation experiments on a standard fused quartz sample report a practical RMS force resolution of 5 nN and an RMS displacement resolution of 0.05 nm at sub-10 nm indentation depths, indicating that the system has a very low system noise for indentation experiments. The high sensitivity and low noise enables the transducer to obtain high-resolution nanoindentation data at sub-5 nm contact depths. The sensitive force transducer is used to successfully perform nanoindentation measurements on a 14 nm thin film. Adhesion measurements were also performed, clearly capturing the pull-on and pull-off forces during approach and separation of two contacting surfaces. PMID- 29716382 TI - An integrated single- and two-photon non-diffracting light-sheet microscope. AB - We describe a fluorescence optical microscope with both single-photon and two photon non-diffracting light-sheet excitations for large volume imaging. With a special design to accommodate two different wavelength ranges (visible: 400-700 nm and near infrared: 800-1200 nm), we combine the line-Bessel sheet (LBS, for single-photon excitation) and the scanning Bessel beam (SBB, for two-photon excitation) light sheet together in a single microscope setup. For a transparent thin sample where the scattering can be ignored, the LBS single-photon excitation is the optimal imaging solution. When the light scattering becomes significant for a deep-cell or deep-tissue imaging, we use SBB light-sheet two-photon excitation with a longer wavelength. We achieved nearly identical lateral/axial resolution of about 350/270 nm for both imagings. This integrated light-sheet microscope may have a wide application for live-cell and live-tissue three dimensional high-speed imaging. PMID- 29716383 TI - Invited Article: Refined analysis of synchrotron radiation for NIST's SURF III facility. AB - We have developed a new method for the exact calculation of synchrotron radiation for the National Institute of Standards and Technology Synchrotron Ultraviolet Radiation Facility, SURF III. Instead of using the Schwinger formula, which is only an approximation, we develop formulae based on Graf's addition theorem for Bessel functions and accurate asymptotic expansions for Hankel functions and Bessel functions. By measuring the radiation intensity profile at two distances from the storage ring, we also confirm an apparent vertical emittance that is consistent with the vertical betatron oscillations that are intentionally introduced to extend beam lifetime by spreading the electron beam spatially. Finally, we determine how much diffraction by beamline apertures enhances the spectral irradiance at an integrating sphere entrance port at the end station. This should eliminate small but treatable components of the uncertainty budget that one should consider when using SURF III or similar synchrotrons as standard, calculable sources of ultraviolet and other radiation. PMID- 29716384 TI - Note: Microelectrode-shielding tip for scanning probe electron energy spectroscopy. AB - We report a novel microelectrode-shielding tip (ME tip) for scanning probe electron energy spectroscopy (SPEES). The shielding effect of this tip is studied through comparing the detection efficiency with the normal tip by both experiment and simulation. The results show that the backscattering count rate detected by the SPEES instrument using the normal tip begins to decrease as the tip approaches to the sample surface within 21 MUm, while that using the ME tip only starts to drop off within 1 MUm. This indicates that the electron energy spectra can be measured with the ME tip at a much closer tip-sample distance. Furthermore, it is also demonstrated that the ME tip can be used to obtain topography of the sample surface in situ simultaneously. PMID- 29716385 TI - Atmospheric pressure reaction cell for operando sum frequency generation spectroscopy of ultrahigh vacuum grown model catalysts. AB - A new custom-designed ultrahigh vacuum (UHV) chamber coupled to a UHV and atmospheric-pressure-compatible spectroscopic and catalytic reaction cell is described, which allows us to perform IR-vis sum frequency generation (SFG) vibrational spectroscopy during catalytic (kinetic) measurements. SFG spectroscopy is an exceptional tool to study vibrational properties of surface adsorbates under operando conditions, close to those of technical catalysis. This versatile setup allows performing surface science, SFG spectroscopy, catalysis, and electrochemical investigations on model systems, including single crystals, thin films, and deposited metal nanoparticles, under well-controlled conditions of gas composition, pressure, temperature, and potential. The UHV chamber enables us to prepare the model catalysts and to analyze their surface structure and composition by low energy electron diffraction and Auger electron spectroscopy, respectively. Thereafter, a sample transfer mechanism moves samples under UHV to the spectroscopic cell, avoiding air exposure. In the catalytic cell, SFG spectroscopy and catalytic tests (reactant/product analysis by mass spectrometry or gas chromatography) are performed simultaneously. A dedicated sample manipulation stage allows the model catalysts to be examined from LN2 temperature to 1273 K, with gaseous reactants in a pressure range from UHV to atmospheric. For post-reaction analysis, the SFG cell is rapidly evacuated and samples are transferred back to the UHV chamber. The capabilities of this new setup are demonstrated by benchmark results of CO adsorption on Pt and Pd(111) single crystal surfaces and of CO adsorption and oxidation on a ZrO2 supported Pt nanoparticle model catalyst grown by atomic layer deposition. PMID- 29716386 TI - The Developmental Check-In: Development and initial testing of an autism screening tool targeting young children from underserved communities. AB - Children with autism spectrum disorder from low-income, minority families or those with limited English proficiency are diagnosed at a later age, or not at all, compared with their more advantaged peers. The Developmental Check-In is a new tool that could potentially be used to screen for autism that uses pictures to illustrate target behaviors. It was developed to enhance early identification of autism spectrum disorder in low literacy groups. The Developmental Check-In was tested in a sample of 376 children between the ages of 24 and 60 months, from underserved communities. It showed good ability to discriminate autism spectrum disorder from non-autism spectrum disorder (area-under-the-curve = 0.75) across the full age range represented in the sample. Twenty-six of the 28 Developmental Check-In items predicted the presence of autism spectrum disorder. Findings suggest that this pictorial tool may reduce linguistic and health literacy demands when screening for autism among vulnerable populations. PMID- 29716387 TI - Outcomes of Vancouver B2 and B3 periprosthetic femoral fractures after total hip arthroplasty in elderly patients. AB - INTRODUCTION: The objective was to evaluate clinical and radiological outcomes of Vancouver B2 and B3 periprosthetic femoral fractures in patients older than 65 years treated at our institution from 2000 to 2014. We compared the most common methods of fixation: a modular tapered rectangular titanium stem versus a monoblock tapered stem. METHODS: A retrospective review was performed with a minimum follow-up time of 2 years. Patient mobility in the period prior to the fracture and after fracture healing and functional results was assessed according to the Harris Hip Score. RESULTS: A total of 43 Vancouver B2 and B3 periprosthetic fractures fulfilled the inclusion criteria (31 type B2 and 13 type B3). The mean age was 78 years old (66-88 years). The mean follow-up time was 5 years (range 2-12 years). A Wagner stem was used in 19 patients and a modular rectangular stem was implanted in 24 patients. Although fracture union was achieved in 93% of the cases, the mean Harris Hip Score was 73 (34-87) and 41.9% of the patients did not return to their previous ambulatory levels ( p = 0.0049). Dislocation was the most common complication (16.3%). We have found association ( p = 0.07) between subsidence with a mean of 4.14 mm and dislocation. No difference was observed between B2 and B3 fractures or between modular and monoblock stems. DISCUSSION: Although we reported good results of fracture healing, there were functional impairment and a high rate of complications, especially dislocation, in Vancouver B2 and B3 periprosthetic fractures in elderly patients. PMID- 29716388 TI - Alice in Wonderland syndrome secondary to optical neuromyelitis caused by varicella. PMID- 29716389 TI - Reduced Pain Reports With Increasing Cognitive Impairment in Older Persons in New Zealand. AB - BACKGROUND: Conflicting findings prevail about pain in older persons with cognitive impairment. There is evidence of changed pain perception; however, pain is also underrecognized. Pain and cognitive impairment were examined in a national cohort of older persons assessed using the Home Care International Residential Assessment Instrument (interRAI-HC). METHODS: Participants were 41 459 aged 65+ years receiving a mandated needs assessment to access publicly funded services. InterRAI-HC pain severity and Cognitive Performance Scale analyses covaried for age, gender, and ethnicity. RESULTS: Milder pain prevalence increased with age, whereas daily severe-excruciating pain prevalence decreased with age. Daily severe-excruciating pain was reported by 18% of cognitively intact individuals decreasing to 8% in the severe cognitive impairment group. This relationship remained after covarying for age, sex, and ethnicity. Differences among dementia subtypes were found. CONCLUSION: Although severe pain reports decrease with increasing age and cognitive impairment, more nuanced research covarying for dementia severity and subtype is required. PMID- 29716390 TI - Influence of Nitrosative Stress on Fatigue During Childhood Leukemia Treatment. AB - The focus on a cure for childhood leukemia over the last three decades has resulted in survival rates of more than 80%. However, efforts to manage leukemia treatment symptoms have not kept pace with new therapies. Symptom toxicity during treatment can result in complications, treatment delays, and therapy dose reductions. Compromise in therapy can negatively influence the quality of life and, even more notably, jeopardize chances for long-term survival. This study examined biologic mechanisms that influence fatigue caused by increased reactive oxidative species (ROS) or actual failure of the antioxidant defense system due to genetic variation by investigating reactive nitrosative species, a "downstream" consequence of ROS. The specific aims of this study were to characterize the trajectory of nitrosative stress during acute lymphoblastic leukemia treatment and evaluate the influence of nitrosative stress on fatigue. A repeated measures design was used to evaluate the fatigue experienced by 186 children and adolescents, 3-18 years of age, with a diagnosis of leukemia during the most intense phase of treatment. An established biomarker of nitrosative stress, protein 3-nitrotyrosine (3NT) residues in the cerebral spinal fluid, was evaluated at diagnosis, postinduction, and consolidation phases of treatment. Higher fatigue was associated with higher 3NT levels at the beginning of treatment. Two distinct groups of children experienced either consistently high or consistently low 3NT levels across the treatment trajectory, from diagnosis to 12 months postinduction. Findings from this study support continued exploration into the phenotypic biochemical mechanisms that influence a reactive response to childhood cancer treatment. PMID- 29716391 TI - Elevated cholesterol among African American adults: the role of fatalistic attitudes about health. AB - OBJECTIVES: Cardiovascular disease (CVD) affects 47% of African-American adults (AAs) in the United States. Elevated cholesterol, the greatest risk factor for CVD, is highly prevalent among AAs, potentially as the result of engagement in behavioral risk factors. Religiosity has been associated with a beneficial effect in health promoting behaviors, yet findings have been mixed depending on methods employed. Religious health fatalism, defined as 'the belief that health outcomes are inevitable and/or determined by God', is a more specific domain of a religiosity that needs further exploration through scientific research. The purpose of the current study is to examine the relationship between RHFQ subscales and self-reported lifetime history of elevated cholesterol. METHODS: Participants (n = 135) were recruited from a large, predominately African American church. A multiple logistic regression model was used to test whether the three subscales of the Religious Health Fatalism Questionnaire (RHFQ) were cross-sectional predictors of self-reported lifetime history of elevated cholesterol. Sets of variables were entered into a stepwise logistic regression model with the first set (Block 1) including significant demographic variables and religiosity (i.e. sex, age, level of education, employment status and scores on the Lukwago Religiosity Scale score [LRS]. The three RHFQ subscales were entered into Block 2 as our predictors of interest. RESULTS: After adjusting for covariates, the likelihood of elevated cholesterol increased significantly (OR = 3.21, 95% CI = 1.81-5.69, p < .001) as Helpless Inevitability (RHFQ subscale) scores increased. CONCLUSIONS: A greater degree of Helpless Inevitability was found to be significantly associated with self-reported elevated cholesterol level. Future research is needed to further understand the complex interplay of factors associated with religiosity and fatalism that contribute to increased risk of elevated cholesterol among AAs. PMID- 29716392 TI - Injection drug use, food insecurity, and HIV-HCV co-infection: a longitudinal cohort analysis. AB - Injection drug use (IDU) and food insecurity (FI) are highly prevalent among individuals living with HIV-hepatitis C virus (HCV) co-infection. We quantified the association between IDU and FI among co-infected individuals using biannual data from the Canadian Co-infection Cohort (N = 608, 2012-2015). IDU (in the past six months) and IDU frequency (non-weekly/weekly in the past month) were self reported. FI (in the past six months) and FI severity (marginal FI, moderate FI, and severe FI) were measured using the Household Food Security Survey Module. Generalized estimating equations were used to estimate risk ratios (RR) quantifying the associations between IDU, IDU frequency, and FI with Poisson regression. The associations between IDU, IDU frequency, and FI severity were quantified by relative-risk ratios (RRR) estimated with multinomial regression. At the first time-point in the analytical sample, 54% of participants experienced FI in the past six months, 31% engaged in IDU in the six months preceding the FI measure, and 24% injected drugs in the past month. After adjustment for confounding, IDU in the past six months (RR = 1.15, 95% confidence interval [CI] = 1.04-1.28) as well as non-weekly (RR = 1.15, 95% CI = 1.02-1.29) and weekly IDU (RR = 1.21, 95% CI = 1.07-1.37) in the past month are associated with FI. Weekly IDU in the past month is also strongly associated with severe FI (RRR = 2.68, 95% CI = 1.47-4.91). Our findings indicate that there is an association between IDU and FI, particularly weekly IDU and severe FI. This suggests that reductions in IDU may mitigate FI, especially severe FI, in this vulnerable subset of the HIV positive population. PMID- 29716393 TI - Brief Report: Increase in Melanoma Incidence in Ontario. AB - BACKGROUND: Melanoma is a serious, potentially lethal disease. It is one of very few common cancers whose incidence is rising in North America. OBJECTIVES: The objective of this study was to examine trends in melanoma incidence in Ontario, Canada's most populous province, over the past 20 years. METHODS: Using data from the Ontario Cancer Registry (OCR), this retrospective cohort examined all incident cases of melanoma in Ontario from 1990 to 2012. Generalized linear modeling was used to evaluate changes in melanoma incidence over time, adjusting for age and sex using direct standardization with the 1991 Canadian census population. Tests for trend for changes in the distribution of cases by age, sex, socioeconomic status, and rurality status were also calculated. RESULTS: Our results show a statistically significant increasing incidence of melanoma in Ontario from 9.3 cases per 100 000 in 1990 to 18.0 cases per 100 000 in 2012 ( P for trend <.001, adjusted for age and sex). Incidence rates show stabilization from 2010 to 2012. CONCLUSION: Our study reveals a marked increase in melanoma incidence in Ontario, more than doubling over the past 20 years but with a stabilization more recently. Adequate availability of dermatology services may be important to ensure satisfactory care for the increased caseload and to ensure that cases may detected at an early stage with a good prognosis. PMID- 29716394 TI - Novel Biomarkers for Coronary Restenosis Occurrence After Drug-Eluting Stent Implantation in Patients With Diabetes Having Stable Coronary Artery Disease. AB - The purpose of the study was to assess whether the occurrence of restenosis is associated with CD45+ platelet count and neutrophil to lymphocyte ratio in patients with type 2 diabetes mellitus (DM) after drug-eluting stent (DES) implantation for stable coronary artery disease (CAD). The study comprised 126 patients, including 55 patients with type 2 DM and stable CAD who underwent elective coronary artery stenting with DES and follow-up angiography within 6 to 12 months. Blood samples were collected from each patient on the morning of the coronary angiography procedure. The variables related to in-stent restenosis were selected by logistic regression analysis. The logistic regression analysis showed that 2 inflammatory factors, CD45+ platelet count (odds ratio [OR] = 4.51, 95% confidence interval [CI]: 1.50-13.50, P = .007) and neutrophil to lymphocyte ratio (OR = 3.09, 95% CI: 1.05-9.10, P = .04), were significantly associated with the risk of in-stent restenosis after stenting with DES in patients with stable CAD and type 2 DM. A receiver operator characteristic curve analysis indicated that the area under the curve was 0.83% (0.05%; P < .001), which showed that the logistic model had good predictive accuracy (based on CD45+ platelet count and neutrophil to lymphocyte ratio) for the risk of in-stent restenosis development in DES in patients with CAD and type 2 DM. Two novel biomarkers of restenosis, CD45+ platelet count and neutrophil to lymphocyte ratio, may be effectively used to predict in-stent restenosis after DES implantation in patients with CAD and type 2 DM. PMID- 29716395 TI - Comparison of Postoperative Bleeding in Total Hip and Knee Arthroplasty Patients Receiving Rivaroxaban, Enoxaparin, or Aspirin for Thromboprophylaxis. AB - BACKGROUND: Guidelines recommend the use of multiple pharmacologic agents and/or mechanical compressive devices for prevention of venous thromboembolism, but preference for any specific agent is no longer given in regard to safety or efficacy. OBJECTIVE: To compare postoperative bleeding rates in patients receiving enoxaparin, rivaroxaban, or aspirin for thromboprophylaxis after undergoing elective total hip arthroplasty or total knee arthroplasty. METHODS: This retrospective cohort analysis evaluated patients who received thromboprophylaxis with either enoxaparin, rivaroxaban, or aspirin. All data were collected from the electronic medical record. The primary outcome was any postoperative bleeding. RESULTS: A total of 1244 patients were included with 366 in the aspirin, 438 in the enoxaparin, and 440 in the rivaroxaban arms. Those who received aspirin or enoxaparin were less likely to experience any bleeding compared to those patients who received rivaroxaban ( P < .05). There was also a lower rate of major bleeding in these groups, but the differences were not significant. CONCLUSIONS: Aspirin and enoxaparin conferred similar bleeding risks, and both exhibited less bleeding than patients who received rivaroxaban. PMID- 29716397 TI - Assessing Protective Factors for Adolescent Offending: A Conceptually Informed Examination of the SAVRY and YLS/CMI. AB - Although the Structured Assessment of Violence Risk in Youth (SAVRY) and the Youth Level of Service/Case Management Inventory (YLS/CMI) are among the most widely used adolescent risk assessment tools, they conceptualize and measure strengths differently. As such, in this study, we compared the predictive validity of SAVRY Protective Total and YLS/CMI Strength Total, and tested conceptual models of how these measures operate (i.e., risk vs. protective effects, direct vs. buffering effects, causal models). Research assistants conducted 624 risk assessments with 156 youth on probation. They rated protective factors at baseline, and again at 3-, 6-, 9-, and 12-month follow-up periods. The SAVRY Protective Total and YLS/CMI Strength Total inversely predicted any charges in the subsequent 2 years (area under the curve scores = 0.61 and 0.60, respectively, p < .05). Furthermore, when adolescents' protective total scores increased, their self-reported violence decreased, thus providing evidence that these factors might play a causally relevant role in reducing violence. However, protective factors did not provide incremental validity over risk factors. In addition, because these measures are brief and use a dichotomous rating system, they primarily captured deficits in protective factors (i.e., low scores). This suggests a need for more comprehensive measures. PMID- 29716396 TI - Bridging Hospital and Community Care for Homeless Adults with Mental Health Needs: Outcomes of a Brief Interdisciplinary Intervention. AB - OBJECTIVE:: This study examines health and service use outcomes and associated factors among homeless adults participating in a brief interdisciplinary intervention following discharge from hospital. METHOD:: Using a pre-post cohort design, 223 homeless adults with mental health needs were enrolled in the Coordinated Access to Care for the Homeless (CATCH) program, a 4- to 6-month interdisciplinary intervention offering case management, peer support, access to primary psychiatric care, and supplementary community services. Study participants were interviewed at program entry and at 3- and 6-month follow-up visits and assessed for health status, acute care service use, housing outcomes, mental health, substance use, quality of life, and their working alliance with service providers. Linear mixed models and generalized estimating equations were performed to examine outcomes longitudinally. Additional post hoc analyses evaluated differences between CATCH participants and a comparison group of homeless adults experiencing mental illness who received usual services over the same period. RESULTS:: In the pre-post analyses, CATCH participants had statistically significant improvements in mental and physical health status and reductions in mental health symptoms, substance misuse, and the number of hospital admissions. The strength of the working alliance between participants and their case manager was associated with reduced health care use and mental health symptoms. Post hoc analyses suggest that CATCH may be associated with statistically significant improvements in mental health symptoms in the study population. CONCLUSIONS:: A brief interdisciplinary intervention may be a promising approach to improving health outcomes among homeless adults with unmet health needs. Further rigorous research is needed into the effectiveness of brief interventions following discharge from hospital. PMID- 29716398 TI - Generalizability and Decision Studies of a Treatment Adherence Instrument. AB - Observational measurement of treatment adherence has long been considered the gold standard. However, little is known about either the generalizability of the scores from extant observational instruments or the sampling needed. We conducted generalizability (G) and decision (D) studies on two samples of recordings from two randomized controlled trials testing cognitive-behavioral therapy for youth anxiety in two different contexts: research versus community. Two doctoral students independently coded 543 session recordings from 52 patients treated by 13 therapists. The initial G-study demonstrated that context accounted for a disproportionately large share of variance, so we conducted G- and D-studies for the two contexts separately. Results suggested that reliable cognitive-behavioral therapy adherence studies require at least 10 sessions per patient, assuming 12 patients per therapists and two coders-a challenging threshold even in well funded research. Implications, including the importance of evaluating alternatives to observational measurement, are discussed. PMID- 29716400 TI - Corrigendum. PMID- 29716399 TI - Informed Consent in Pediatric Oncology: A Systematic Review of Qualitative Literature. AB - OBJECTIVE: Obtaining informed consent in pediatric cancer research can be subject to important ethical challenges because of the difficulty in distinguishing between care and research, which are interrelated. Pediatric oncologists also often conduct research, such as clinical trials, on their own patients, which may influence voluntary informed consent. This review aims to determine the ethical issues encountered in obtaining informed consent in pediatric oncology by identifying and summarizing the findings of existing qualitative studies on this topic. METHODS: A systematic review of qualitative studies was conducted. Medline, Embase, CINAHL, and PubMed were searched using the following terms: (oncolog* or cancer or hematol* or haematol* or leuk* or malign* or neoplasm*) and (child* or adolescent* or minor* or young people or pediatr* or paediatr*) and ethic* or moral*) and (qualitative or interview). Other sources were also mined to identify all relevant studies. The data analysis method used was thematic analysis. RESULTS: At the end of the search process, 2361 studies were identified. Duplicates were removed and irrelevant studies were excluded. After screening the full text of the remaining studies against our inclusion and exclusion criteria, 13 studies were included in the qualitative analysis. All studies were qualitative studies using semistructured and structured interviews, qualitative analysis of open-ended questions, and observation of informed consent conferences. Four themes were identified: parental comprehension of the trial and medical terms, influence of parental distress on decision-making, no offer of an alternative treatment, and influence of the doctor-parent relationship. CONCLUSION: Many ethical challenges affect the informed consent process. These challenges may include a lack of parental understanding, the potential influence of treating doctors, and vulnerability because of psychological status. All of these result in parents being unable to give well-informed and voluntary consent. Researchers are encouraged to adopt a stepwise approach during the informed consent process. PMID- 29716401 TI - Clinical accuracy of a patient-specific femoral osteotomy guide in minimally invasive posterior hip arthroplasty. AB - INTRODUCTION: Patient specific guides can be a valuable tool in improving the precision of planned femoral neck osteotomies, especially in minimally invasive hip surgery, where bony landmarks are often inaccessible. The aim of our study was to validate the accuracy of a novel patient specific femoral osteotomy guide for THR through a minimally invasive posterior approach, the direct superior approach (DSA). METHODS: As part of our routine preoperative planning 30 patients underwent low dose CT scans of their arthritic hip. 3D printed patient specific femoral neck osteotomy guides were then produced. Intraoperatively, having cleared all soft tissue from the postero-lateral neck of the enlocated hip, the guide was placed and pinned onto the posterolateral femoral neck. The osteotomy was performed using an oscillating saw and the uncemented hip components were implanted as per routine. Postoperatively, the achieved level of the osteotomy at the medial calcar was compared with the planned level of resection using a 3D/2D matching analysis (Mimics X-ray module, Materialise, Belgium). RESULTS: A total of 30 patients undergoing uncemented Trinity acetabular and TriFit TS femoral component arthroplasty (Corin, UK) were included in our analysis. All but one of our analysed osteotomies were found to be within 3 mm from the planned height of osteotomy. In one patient the level of osteotomy deviated 5 mm below the planned level of resection. CONCLUSION: Preoperative planning and the use of patient specific osteotomy guides provides an accurate method of performing femoral neck osteotomies in minimally invasive hip arthroplasty using the direct superior approach. LEVEL OF EVIDENCE: IV (Case series). PMID- 29716402 TI - [Significance of the examination of the metal element content of herbal extracts in adjuvant therapy]. AB - The consumption of herbal teas is becoming more and more popular nowadays both as luxury foods and a complementary part of medical therapy. Beside the organic agents of medicinal plants, the presence of inorganic ions is also relevant in exerting the favorable pharmacological effect. The author briefly summarizes the importance of some essential metal ions and their quantitative values in teas applied in the adjuvant therapy of diabetes and used as diuretics. The common feature of teas used in diabetes is that they contain a measurable amount of chromium and the concentration of most essential elements (such as K, Mg, Mn and Zn) is significant, which can be considered as a mineral source for some metal ions. Diuretic herbs have an outstanding K content, but from the point of view of diuresis, the large K/Na molar ratio above 50 is relevant. Orv Hetil. 2018; 159(18): 713-719. PMID- 29716403 TI - [Antioxidant effect of the fibre content of foods]. AB - Antioxidants have some health benefit, but up to now there was less attention paid to the antioxidant properties of dietary fibre. The antioxidant effect of dietary fibre is based on the polyphenol compounds bound to polysaccharide complexes, which are released in the gut and functioning as antioxidants. Another type of antioxidant, calcium fructoborate was also isolated from plant cell wall. It has a marked antioxidant capacity, however, its active component is not a polyphenol, but the boron. There are lots of food plants which have relatively high antioxidant dietary fibre content, thus they support the antioxidant defence of the gastrointestinal tract, and consequently the whole body. The important ones in human nutrition are for instance cereal grains, cabbage, grape pomace, coffee bean or guava. There are different polyphenol compounds in the antioxidant dietary fibres in the plants, therefore their antioxidant capacity varies, but it is approximately equivalent to 50-100 mg DL-alpha-tocopherol per gram. This antioxidant capacity is considerable, and would be suitable for the prevention of some, oxidative stress-related diseases, such as atherosclerosis or other cardiovascular diseases, and colorectal carcinoma. Orv Hetil. 2018; 159(18): 709 712. PMID- 29716404 TI - [The interpretation and integration of traditional Chinese phytotherapy into Western-type medicine with the possession of knowledge of the human genome]. AB - The terminology of traditional Chinese medicine (TCM) is hardly interpretable in the context of human genome, therefore the human genome program attracted attention towards the Western practice of medicine in China. In the last two decades, several important steps could be observed in China in relation to the approach of traditional Chinese and Western medicine. The Chinese government supports the realization of information databases for research in order to clarify the molecular biology level to detect associations between gene expression signal transduction pathways and protein-protein interactions, and the effects of bioactive components of Chinese drugs and their effectiveness. The values of TCM are becoming more and more important for Western medicine as well, because molecular biological therapies did not redeem themselves, e.g., in tumor therapy. Orv Hetil. 2018; 159(18): 696-702. PMID- 29716405 TI - [Microalgae as the source of natural products]. AB - More than 90% of herbal products and herbal medicines have been derived from higher plants recently, but due to independent circumstances, several photosynthetic microalgal species are in focus in this point of view. In the last 50 years, many carbohydrate-, peptide-, terpenoid-, alkaloid- and phenol-type components were described from algae because of the developing structural determination and analytical methods, algae mass production and also artificial algae technologies. At the same time, based partly on traditional causes and partly on the clinical and preclinical data of today, some dried products of algae are directly used as food supplements. Hereinafter, the historical background, economic significance and metabolic background of the mostly used microalgal species will be reviewed. The diverse metabolite production of these organisms will be demonstrated by some molecules with special bioactivity. Several preclinical and clinical studies will be described relating to the microalgal species Spirulina sp., Chlorella sp., Haematococcus sp. and Dunaliella sp. Orv Hetil. 2018; 159(18): 703-708. PMID- 29716406 TI - [Editor's commentary. Significance of plant origin agents in modern medicine]. PMID- 29716408 TI - [Health effects of sour cherries with unique polyphenolic composition in their fruits]. AB - Health effects of fruit consumption are confirmed by many studies. Such effects are attributed to the polyphenolic compounds accumulating in fruit skin and mesocarp tissues. They contribute to the regulation on transcriptional, post transcriptional and epigenetic levels. Since people consume much less fruits than the recommended quantities, a new approach includes the promotion of super fruits that are extremely rich sources of specific health compounds. A comparative analysis of Hungarian stone fruit cultivars detected a huge variability in fruit in vitro antioxidant capacity and total polyphenolic content. Two outstanding sour cherry cultivars ('Pipacs 1' and 'Fanal') were identified to accumulate elevated levels of polyphenolic compounds in their fruits. Sour cherries with different polyphenolic compositions were tested against alimentary induced hyperlipidemia using male Wistar rat model. Consumption of cherry fruit had different consequences for different cultivars: consumption of 'Pipacs 1' and 'Fanal' fruits resulted in 30% lower total cholesterol levels in the sera of hyperlipidemic animals after only 10 days of treatment. However, the consumption of 'Ujfehertoi furtos' fruit has not induced significant alterations in the same parameter. Other lipid parameters also reflected the short-term beneficial effects of 'Pipacs 1' and 'Fanal' fruits. We suggest that not only some tropical and berry fruits might be considered as super fruits but certain genotypes of stone fruits as well. These have indeed marked physiological effects. Since 'Pipacs 1' and 'Fanal' are rich sources of colourless polyphenolics (e.g., phenolic acids and isoflavonoids) and anthocyanins, respectively, the protective effects associated with their consumption can be attributed to different polyphenolic compounds. Orv Hetil. 2018; 159(18): 720-725. PMID- 29716409 TI - Association of angiotensin-converting enzyme gene I/D polymorphism with chronic obstructive pulmonary disease: a meta-analysis. AB - OBJECTIVES: We conducted a meta-analysis of published studies on the angiotensin converting enzyme ( ACE) gene insertion/deletion (I/D) polymorphism associated with the risk of chronic obstructive pulmonary disease, as well as with pulmonary function and circulating angiotensin-converting enzyme changes. METHODS: A literature search, quality assessment and data extraction were completed independently and in duplicate. RESULTS: A total of 16 articles were meta analysed, including 12 articles (2113 patients and 8786 controls) for chronic obstructive pulmonary disease risk and eight articles (11,664 subjects) for pulmonary and circulating phenotypes. In overall and subgroup analyses, no significance was noted between the I/D polymorphism and chronic obstructive pulmonary disease risk under all genetic models ( P>0.05), without heterogeneity or publication bias. Carriers of II, ID and II plus ID genotypes had significantly lower levels of circulating angiotensin-converting enzyme than those with the DD genotype (weighted mean difference -13.35, -8.13 and -10.74 U/L, respectively, P<0.001). For forced expiratory volume in one second (FEV1)/forced vital capacity, carriers of the DD genotype had marginally lower levels than those with the DD genotype (weighted mean difference -1.66, P=0.034). Furthermore in the case of FEV1 of 50% or greater of predicted FEV1, FEV1 was marginally lower in ID genotype carriers than DD genotype carriers (weighted mean difference -3.50, P=0.056). CONCLUSIONS: Our meta-analytical findings demonstrated that the ACE gene I/D polymorphism was not associated with the risk of chronic obstructive pulmonary disease. PMID- 29716410 TI - Screening for colorectal cancer in defunctioned colons. AB - OBJECTIVES: Population-based colorectal (bowel) cancer screening using faecal occult blood tests leads to a reduction in cause-specific mortality. However, in people where the colon is defunctioned, the use of standard faecal occult blood test is not appropriate. The aim of this study was to examine the current trends of clinical practice for colorectal cancer screening in people with defunctioned colons. METHODS: An online survey was performed using SurveyMonkey. All members of the Association of Coloproctology of Great Britain and Ireland were invited by email to participate. Reminders were sent to non-responders and partial responders till six weeks. All responses were included in our analysis. RESULTS: Of the 206 (34.59%) questionnaires completed, all questions were answered in 110 (55.8%). Among responders, 94 (85.4%) were colorectal consultant surgeons, 72% had worked in their current capacity for more than five years, and 105 (50.9%) had encountered colorectal cancer in defunctioned colons during their career. Some 72.2% of responders stated that a screening test for colorectal cancer in patients with defunctioned colons was currently not offered, or that they did not know whether or not it was offered in their area. CONCLUSIONS: Bowel screening in the United Kingdom is currently not offered to 72.2% of the age appropriate population with defunctioned colons. Among responding colorectal surgeons, 50% had encountered colorectal cancer in such patients. There is considerable variability in clinical practice regarding the optimal age for onset of screening, time interval, and the optimal modality to offer for screening in such cases. PMID- 29716411 TI - Characterization of Pharmacy Resident Interventions on an Academic Inpatient Internal Medicine Rotation. AB - PURPOSE: To characterize the clinical interventions of postgraduate year 1 (PGY 1) pharmacy residents on a required, 1-month, inpatient adult internal medicine service at an academic medical center. METHODS: The interventions completed by PGY-1 pharmacy residents on a required, adult internal medicine rotation were analyzed. Documentation of clinical interventions was performed by the PGY-1 residents, and the significance of the intervention was subsequently determined. Acceptance rates of clinical interventions were also documented and reviewed. RESULTS: A total of 2161 interventions were documented by 14 PGY-1 pharmacy residents between January 2016 and May 2017. Of these interventions, 2016 (93.3%) had a positive, or accepted, outcome. The significance of the majority of interventions was moderate (93.5%), indicating that either an improvement in drug therapy effectiveness, decreased hospital length of stay, reduction in cost, or prevention in harm had occurred. The most common intervention types were recommendations to add, change, or discontinue a medication therapy, completion of a pharmacy dosing consult or conducting an admission medication reconciliation. CONCLUSION: PGY-1 pharmacy residents have a positive impact on patient care in the inpatient adult internal medicine setting. PMID- 29716412 TI - Trends in asthma self-management skills and inhaled corticosteroid use during pregnancy and postpartum from 2004 to 2017. AB - OBJECTIVE: Asthma exacerbations and medication non-adherence are significant clinical problems during pregnancy. While asthma self-management education is effective, the number of education sessions required to maximise asthma management knowledge and inhaler technique and whether improvements persist postpartum, are unknown. This paper describes how asthma knowledge, skills, and inhaled corticosteroid (ICS) use have changed over time. METHODS: Data were obtained from 3 cohorts of pregnant women with asthma recruited in Newcastle, Australia between 2004 and 2017 (N = 895). Medication use, adherence, knowledge, and inhaler technique were compared between cohorts. Changes in self-management knowledge/skills and women's perception of medication risk to the fetus were assessed in 685 women with 5 assessments during pregnancy, and 95 women who had a postpartum assessment. RESULTS: At study entry, 41%, 29%, and 38% of participants used ICS in the 2004, 2007, and 2013 cohorts, respectively (p = 0.017), with 40% non-adherence in each cohort. Self-management skills of pregnant women with asthma did not improve between 2004 and 2017 and possession of a written action plan remained low. Maximum improvements were reached by 3 sessions for medications knowledge and one session for inhaler technique, and were maintained postpartum. ICS adherence was maximally improved after one session, but not maintained postpartum. Perceived risk of asthma medications on the fetus was highest for corticosteroid-containing medication; and was significantly reduced following education. CONCLUSIONS: There was a high prevalence of non-adherence and poor self-management skills in all cohorts. More awareness of the importance of optimal asthma management during pregnancy is warranted, since no improvements were observed over the past decade. PMID- 29716413 TI - Minimally invasive modified Camitz opponensplasty for severe carpal tunnel syndrome. AB - PURPOSE: We aimed to compare the clinical results and the complications between the minimally invasive modified Camitz opponensplasty and the conventional Camitz opponensplasty for severe carpal tunnel syndrome (CTS), and to evaluate the efficacy of the modified technique for CTS. METHODS: Twenty-eight hands in 24 patients with severe CTS who had disorder of the thumb opposition with thenar muscle atrophy (group 1) were treated by minimally invasive modified Camitz opponensplasty, passing the transferred palmaris longus (PL) tendon under the abductor pollicis brevis (APB) fascia using only palm and thumb incision, and no incision to either wrist crease or forearm. Ten hands in 10 patients (group 2) were treated by the conventional Camitz opponensplasty. Clinical evaluation was made by comparing the results before and after surgery for the angle of the thumb palmar abduction, pinch power, and grip strength. RESULTS: All clinical findings significantly improved after surgery compared with before surgery in all patients. In group 1, there were no complications including transferred tendon bowstring, painful wrist scar, or injury to the palmar cutaneous branch of the median nerve in all hands. Conversely, patients in group 2 had four painful wrist scars and nine bowstrings of the transferred tendon. CONCLUSIONS: Several complications have been considered to attribute to the long incision and an extensive dissection crossing the wrist crease from the palm to the wrist in the conventional Camitz procedure. The current modified Camitz opponensplasty by minimally invasive incision without straddling the wrist crease is a simple and effective procedure that can decrease the risk of painful scar around the wrist crease in severe CTS patients with disorder of thumb opposition. Additionally, this technique, by passing the transferred PL tendon under the APB fascia, is useful in restoring the thumb opposition immediately, and in preventing the bowstringing of the transferred tendon. PMID- 29716414 TI - What is the best lateral radiograph positioning technique for assessment of sagittal balance: A biomechanical study on influence of different arm positions. AB - PURPOSE: To evaluate the influence of different arm postures from the physiological standing position using force plate analysis of the gravity line. METHODS: Forty healthy volunteered university students were enrolled. Each subject assumed different standing positions including standing with arms resting on the side (control), with fist over the clavicle (clavicular position), with active shoulder flexion in 30 degrees , 60 degrees and 90 degrees with elbows extended (active flexion A), with hand rest on a bar with a static support (passive flexion P), and with hand rest on a bar with a drip stand (passive flexion D). The offset of the gravity line from the heel was measured by force plate analysis. The offset of the gravity line in different arm positions was compared with the control using paired t-test. RESULTS: The mean anterior offset of the gravity line in control position is 39.80% of the foot length. All testing positions showed anterior shift of the gravity line compared with the control position from 0.51% to 7.50%. There were statistically significant changes of the gravity line from the control position in all ( p < 0.05), except in the clavicular position ( p = 0.249). CONCLUSION: All testing positions cause anterior shifting of the center of gravity from the physiological standing position. Clavicular position is the best comparable posture to the physiological standing position in taking a lateral radiograph. We recommend using the clavicular position as the standard testing position in the assessment of the sagittal profile. PMID- 29716416 TI - Allogeneic transplantation for relapsed and refractory Hodgkin lymphoma: long term outcomes and graft-versus-host disease-free/relapse-free survival. AB - This monocentric retrospective study included 70 consecutive relapsed/refractory Hodgkin lymphoma (RR-HL) patients receiving reduced-intensity allogeneic stem cell transplantation (alloSCT). We evaluated overall and progression-free survival (OS, PFS), graft-versus host disease/relapse-free survival (GFRS), and chronic GVHD-free OS (cGVHD-free OS) defined as OS without moderate-to-severe cGVHD. Patients had a median age of 33 years (range, 18-60 years), 23% had refractory disease (SD/PD). Donors were HLA identical (39%), unrelated (30%), or haploidentical (31%). Median follow-up was 6.2 years. Five-year OS was 59% and PFS was 49%. NRM was 16% at 1 year. 44% of patients had cGVHD, and 14% moderate to-severe cGVHD at last follow-up. GFRS and cGVHD-free OS were 26 and 48% at 5 years. In multivariate analysis, resistant disease at alloSCT impacted survival and GFRS. In conclusion, disease response before alloSCT impacts survival and GFRS. GVHD outcomes may help comparing the long-term effects of the new salvage treatments that bridge patients to alloSCT. PMID- 29716417 TI - Influence of citric acid on the physical and biomineralization ability of freeze/thaw poly(vinyl alcohol) hydrogel. AB - This work reports the modification of freeze/thaw poly(vinyl alcohol) hydrogel using citric acid as the bioactive molecule for hydroxyapatite formation in simulated body fluid. Inclusion of 1.3 mM citric acid into the poly(vinyl alcohol) hydrogel showed that the mechanical strength, crystalline phase, functional groups and swelling ability were still intact. Adding citric acid at higher concentrations (1.8 and 2.3 mM), however, resulted in physically poor hydrogels. Presence of 1.3 mM of citric acid showed the growth of porous hydroxyapatite crystals on the poly(vinyl alcohol) surface just after one day of immersion in simulated body fluid. Meanwhile, a fully covered apatite layer on the poly(vinyl alcohol) surface plus the evidence of apatite forming within the hydrogel were observed after soaking for seven days. Gel strength of the soaked poly(vinyl alcohol)/citric acid-1.3 mM hydrogel revealed that the load resistance was enhanced compared to that of the neat poly(vinyl alcohol) hydrogel. This facile method of inducing rapid growth of hydroxyapatite on the hydrogel surface as well as within the hydrogel network can be useful for guided bone regenerative materials. PMID- 29716418 TI - Melatonin improves the therapeutic role of mesenchymal stem cells in diabetic rats. AB - : The present study aimed to investigate the role of bone marrow mesenchymal stem cells (MSCs) and/or melatonin (MT) for improvement of beta-cell functions in STZ diabetic rats. Male albino rats (130-150 g) were divided into six groups. CONTROL GROUP: received phosphate-buffered saline (PBS); melatonin group received melatonin (10 mg/kg b.wt./day for 2 months by oral gavage); diabetic untreated group; diabetic group treated with melatonin; diabetic group treated with MSCs (a single intravenous injection of 3 * 106 cell in PBS); and diabetic group co treated with stem cells and melatonin. The results showed significant improvement in glucose, insulin, total antioxidant, and malondialdehyde level in diabetic rats treated with either MSCs alone or in combination with melatonin. The imumuno histochemical analysis showed that MSCs and/or melatonin treatment reduced the rate of inflammation and apoptosis of the islet cells as well as increased the rate of pancreatic cell division. Such results were indicated by a significant improvement in the level of TNF-alpha, IL-10, PCNA, and caspase-3 to levels very close to the control. Co-treatment of MSCs and MT resulted in an improvement in the tissue of the pancreas and reduced number of damaged beta-cells. It can be concluded that co-treatment of stem cells and melatonin has a significant role in restoring the structural and functional efficiency of beta-cells in the pancreas more than stem cells alone. Such results may be due to the role of melatonin as an antioxidant in increasing the efficiency and vitality of stem cells. PMID- 29716419 TI - Lecture-based versus problem-based learning in ethics education among nursing students. AB - BACKGROUND: Moral reasoning is a vital skill in the nursing profession. Teaching moral reasoning to students is necessary toward promoting nursing ethics. OBJECTIVES: The aim of this study was to compare the effectiveness of problem based learning and lecture-based methods in ethics education in improving (1) moral decision-making, (2) moral reasoning, (3) moral development, and (4) practical reasoning among nursing students. RESEARCH DESIGN: This is a repeated measurement quasi-experimental study. Participants and research context: The participants were nursing students in a University of Medical Sciences in west of Iran who were randomly assigned to the lecture-based (n = 33) or the problem based learning (n = 33) groups. The subjects were provided nursing ethics education in four 2-h sessions. The educational content was similar, but the training methods were different. The subjects completed the Nursing Dilemma Test before, immediately after, and 1 month after the training. The data were analyzed and compared using the SPSS-16 software. Ethical considerations: The program was explained to the students, all of whom signed an informed consent form at the baseline. FINDINGS: The two groups were similar in personal characteristics (p > 0.05). A significant improvement was observed in the mean scores on moral development in the problem-based learning compared with the lecture-based group (p < 0.05). Although the mean scores on moral reasoning improved in both the problem-based learning and the lecture-based groups immediately after the training and 1 month later, the change was significant only in the problem-based learning group (p < 0.05). The mean scores on moral decision-making, practical considerations, and familiarity with dilemmas were relatively similar for the two groups. CONCLUSION: The use of the problem-based learning method in ethics education enhances moral development among nursing students. However, further studies are needed to determine whether such method improves moral decision making, moral reasoning, practical considerations, and familiarity with the ethical issues among nursing students. PMID- 29716420 TI - On Being More Amenable to Threatening Risk Messages Concerning Close Others (vis a-vis the Self). AB - People often respond defensively to risk messages impugning their own behavior. We explored whether people are more amenable to risk messages impugning a close other's behavior. In two experiments, participants learned how being overweight could influence their own cancer risk or that of an opposite-sex close other. As predicted, participants expressed higher affective risk perceptions (i.e., worry) and experiential risk perceptions for their close others than for themselves. Participants in the close other condition also reported greater interest in diagnostic testing and additional information (Experiment 1) and greater interest in consulting a provider and more plans for remediation (Experiment 2). These effects were mediated by a combination of worry and experiential risk perceptions. The self/other difference emerged even though participants endorsed the messages as believable and relevant; participants were simply more willing to extrapolate from the message to their close other's risk than to their own risk. PMID- 29716421 TI - Construing the Essence: The Effects of Construal Level on Genetic Attributions for Individual and Social Group Differences. AB - The present research links a nonsocial, contextual influence (construal level) to the tendency to endorse genetic attributions for individual and social group differences. Studies 1 to 3 show that people thinking in an abstract (vs. concrete) mind-set score higher on a measure of genetic attributions for individual and racial group differences. Study 4 showed that abstract (vs. concrete) construal also increased genetic attributions for novel groups. Study 5 explored the potential downstream consequences of construal on intergroup attitudes, and found that abstract (vs. concrete) construal led people to endorse genetic attributions in general and this was associated with increased anti-Black prejudice. PMID- 29716422 TI - Using Power as a Negative Cue: How Conspiracy Mentality Affects Epistemic Trust in Sources of Historical Knowledge. AB - Classical theories of attitude change point to the positive effect of source expertise on perceived source credibility persuasion, but there is an ongoing societal debate on the increase in anti-elitist sentiments and conspiracy theories regarding the allegedly untrustworthy power elite. In one correlational ( N = 275) and three experimental studies ( N = 195, N = 464, N = 225), we tested the novel idea that people who endorse a conspiratorial mind-set (conspiracy mentality) indeed exhibit markedly different reactions to cues of epistemic authoritativeness than those who do not: Whereas the perceived credibility of powerful sources decreased with the recipients' conspiracy mentality, that of powerless sources increased independent of and incremental to other biases, such as the need to see the ingroup in particularly positive light. The discussion raises the question whether a certain extent of source-based bias is necessary for the social fabric of a highly complex society. PMID- 29716423 TI - Risk Perceptions After Receiving Multiple Risk Feedback. AB - How do people respond to multiple risk feedback in a real-life context? Based on theoretical assumptions, three different predictions for risk perceptions were tested: (a) relative accuracy in risk perceptions, (b) self-defensive responses according to self-affirmation theory, and (c) compensatory responses according to the compensatory health belief model. Participants of a community health screening ( N = 725) received multiple risk indicator feedback for actual blood pressure, blood glucose, and blood lipid levels. Consistent multiple risk feedback profiles encompassed three consistent readings (three normal or three elevated readings). Mixed risk profiles included one elevated and two normal readings. Results indicate relative accuracy in responses: an elevated reading triggered higher risk perception of the respective risk factor. Importantly, the effect was not modulated by the presence of normal readings as assumed by the self-defensive or compensatory response perspective, indicating that people accurately integrate multiple risk indicator feedback as it is often provided in real life. PMID- 29716424 TI - Prenatal therapy for fetal cardiac disorders. AB - Fetal cardiac abnormalities are some of the commonest congenital disorders seen in prenatal life. They can be anatomical or functional and can develop de novo or as a consequence of either maternal or fetal disease. Untreated, morbidity and mortality rates are high for hypoplastic left heart disorders and for some fetal tachy and bradyarrhythmias. Optimum management strategies are often not clear because of the lack of knowledge about the precise natural history of some of these conditions. Prenatal therapy ranges from invasive fetal cardiac intervention to maternal administration of drugs for transplacental transfer to the fetus. This comprehensive review covers many fetal cardiac disorders and various prenatal therapeutic options that are available. PMID- 29716425 TI - Early Prediction of Intensive Care Unit-Acquired Weakness: A Multicenter External Validation Study. AB - OBJECTIVES: An early diagnosis of intensive care unit-acquired weakness (ICU-AW) is often not possible due to impaired consciousness. To avoid a diagnostic delay, we previously developed a prediction model, based on single-center data from 212 patients (development cohort), to predict ICU-AW at 2 days after ICU admission. The objective of this study was to investigate the external validity of the original prediction model in a new, multicenter cohort and, if necessary, to update the model. METHODS: Newly admitted ICU patients who were mechanically ventilated at 48 hours after ICU admission were included. Predictors were prospectively recorded, and the outcome ICU-AW was defined by an average Medical Research Council score <4. In the validation cohort, consisting of 349 patients, we analyzed performance of the original prediction model by assessment of calibration and discrimination. Additionally, we updated the model in this validation cohort. Finally, we evaluated a new prediction model based on all patients of the development and validation cohort. RESULTS: Of 349 analyzed patients in the validation cohort, 190 (54%) developed ICU-AW. Both model calibration and discrimination of the original model were poor in the validation cohort. The area under the receiver operating characteristics curve (AUC-ROC) was 0.60 (95% confidence interval [CI]: 0.54-0.66). Model updating methods improved calibration but not discrimination. The new prediction model, based on all patients of the development and validation cohort (total of 536 patients) had a fair discrimination, AUC-ROC: 0.70 (95% CI: 0.66-0.75). CONCLUSIONS: The previously developed prediction model for ICU-AW showed poor performance in a new independent multicenter validation cohort. Model updating methods improved calibration but not discrimination. The newly derived prediction model showed fair discrimination. This indicates that early prediction of ICU-AW is still challenging and needs further attention. PMID- 29716427 TI - The safety of dual bronchodilation on cardiovascular serious adverse events in COPD. AB - INTRODUCTION: Long-acting beta2-adrenoceptor (beta2-AR) agonists (LABAs) plus long-acting muscarinic antagonists (LAMAs) is the cornerstone for treating chronic obstructive pulmonary disease (COPD). LABA/LAMA combinations elicit clinical and functional synergistic interaction, and such an interaction should permit to reduce the dose of each monocomponent in the drug mixture to minimize the risk of adverse events (AEs). Overall, currently available LABA/LAMA fixed dose combinations (FDCs) combine the drugs at the same doses of formulations designed for a single drug. Therefore, concerns regarding the possible risk of cardiovascular AEs have been raised related to the use of LABA/LAMA FDCs in COPD patients. Areas covered: LABAs and LAMAs have a high potential to induce cardiovascular AEs by stimulating the beta2-AR receptors and inhibiting the muscarinic M2 receptors expressed in the heart. This review will explore the data published on the cardiovascular safety of dual bronchodilation therapy in COPD patients. Expert opinion: LABA/LAMA FDCs are characterized by an acceptable cardiovascular safety profile, at least in the COPD population enrolled in randomized clinical trials. Nevertheless, large real life studies suggest that dual bronchodilation therapy may increase the risk of cardiovascular AEs. Post marketing surveillance and observational studies are needed to adequately define the real cardiovascular safety profile of LABA/LAMA FDCs. PMID- 29716428 TI - The subset of patients with acute heart failure able to secrete relaxin-2 at pregnancy concentrations could have a longer survival: a pilot study. AB - OBJECTIVE: To investigate how many patients with acute heart failure (AHF) hypersecrete relaxin-2 concentrations similar to those of pregnant women and determine their long-term outcome. METHODS: In consecutive AHF patients relaxin-2 was quantified by ELISA sandwich method. Patients were divided into pregnancy like group (PLG, relaxin-2 >= 500 pg/mL) and control group (CG, relaxin-2 < 500 pg/mL). The primary outcome was all-cause death during follow-up. Secondary endpoints were prolonged hospitalisation (>10 days), combined endpoint (death, rehospitalisation, ED revisit) 30 days after discharge, and 30-day, one-year and three-year death rates. RESULTS: We included 814 patients [81 (SD = 9) years; 53.0% women] followed during 1.9 (SD 2.8) years; 517 (63.5%) died. Twenty patients (2.5%) formed the PLG (median relaxin-2 = 1459 pg/mL; IQR = 1722) and 794 the CG (median = 26; IQR = 44). There was no interaction with variables included on adjustment (age, sex, ischaemic cardiomyopathy, NT-proBNP, glycaemia, and sodium). PLG patients did not have better short-term secondary endpoints, but did show a significantly lower three-year mortality [ORadjusted = 0.17 (0.05 0.5), p = 0.003]. CONCLUSIONS: The small proportion of AHF patients achieving relaxin-2 concentrations similar to those observed in pregnancy may survive longer. PMID- 29716429 TI - Population genetic structure and phylogeography of sterlet (Acipenser ruthenus, Acipenseridae) in the Ob and Yenisei river basins. AB - The sterlet (Acipenser ruthenus Linnaeus, 1758) is a relatively small sturgeon widely distributed in Eurasian rivers from the Danube to the Yenisei. During the twentieth century, all wild sterlet populations have declined due to anthropogenic factors including: overfishing, poaching, construction of dams, and pollution. Despite the necessity of characterization both wild and captive stocks, few studies of population genetics have been performed thus far. Here we studied the genetic diversity and geographic structure of sterlet populations across the eastern range - Ob-Irtysh and Yenisei basins - by sequencing a 628-bp fragment of mitochondrial DNA control region. We identified 98 new haplotypes, delineated 12 haplogroups and estimated the time of basal haplogroup divergence within the species as over 8 million years ago. Our data suggest that Ob-Irtysh and Yenisei populations are isolated from each other and much lower genetic diversity is present in the Yenisei population than in the Ob-Irtysh population. Our data imply that sterlet populations in Siberian rivers underwent bottleneck or fragmentation, followed by subsequent population expansion. The data obtained here are important for sterlet population monitoring and restocking management. PMID- 29716430 TI - The best choice of equipment to obtain high quality standardised results in intra oral photography - a comparison between the common practice in the UK and the gold standard set by the literature. AB - Since digital technology made dental photography widely available, photographers have been trying to establish the 'gold standard' when obtaining intra-oral photographs. A basic knowledge of photographic principles, familiarity with particular dental techniques and a correct choice and use of equipment contribute significantly both to the standardisation and quality of photographs. A recent survey between members of the Institute of Medical Illustrators shed a light on the current practice in the UK. Medical photographers do not always have access to the full range of suitable equipment. A better selection of retractors and occlusal mirrors would undoubtedly contribute to higher quality images. PMID- 29716432 TI - Comparison of placental three-dimensional power Doppler indices and volume in the first and second trimesters of pregnancy complicated by gestational diabetes mellitus. AB - OBJECTIVE: To compare the changes of placental three-dimensional power Doppler indices and volume in the first and second trimesters of pregnancy with gestational diabetes mellitus (GDM). METHODS: This was a prospective case-control study of singleton pregnancies with risk factors for GDM. Data on placental vascular indices including vascularization index (VI), flow index (FI), and vascularization flow index (VFI), as well as placental volume were obtained and analyzed during the first and second trimesters between pregnant women with and without GDM. RESULTS: Of the 155 pregnant women enrolled, 31 developed GDM and 124 did not. VI and VFI were significantly lower in the GDM group during the first and second trimesters (VI: p = 0.023, and VFI: p = 0.014 in the first trimester; VI: p = 0.049, and VFI: p = 0.031 in the second trimester). However, the placental volume was similar in both groups during the first trimester, while it was significantly increased in the GDM group during the second trimester (p = 0.022). There were no significant differences in FI and uterine artery pulsatility index between the two groups. After adjustments in multivariate logistic regression analysis, significant differences were observed in the first trimester VFI (adjusted odds ratio (OR) 0.76, 95% confidence interval (CI) 0.61 0.93), second trimester VFI (adjusted or 0.83, 95% CI 0.71-0.96), and second trimester placental volume (adjusted or 1.03, 95% CI 1.01-1.05). CONCLUSION: Placental vascular indices can provide an insight into placental vascularization in GDM during early pregnancy. VFI rather than placental volume may be a sensitive sonographic marker in the first trimester of GDM placentas. PMID- 29716433 TI - Maternal mind-mindedness and its association with attachment: the case of Arab infants and mothers in Israel. AB - We examined the association between maternal Mind-Mindedness (MM) and secure attachment in an Arab sample in Israel. Seventy-six infant-mother dyads were observed during free play to assess maternal MM and in the Strange Situation Procedure to assess attachment. Mothers of secure infants were hypothesized to use more appropriate and fewer non-attuned mind-related comments than mothers of insecure infants. The results showed that mothers of secure infants used more appropriate mind-related comments than mothers of disorganized infants, with no significant differences compared to mothers of ambivalent infants. Also, mothers of secure infants used less non-attuned mind-related comments than both mothers of disorganized infants and mothers of ambivalent infants. In addition, the findings showed that: (1) mothers of secure infants were most likely to show the combination of high appropriate and low non-attuned mind-related comments; (2) mothers of disorganized infants were most likely to show the combination of high non-attuned and low appropriate mind-related comments; and (3) a nonsignificant trend indicated that mothers of ambivalent infants were most likely to show a combination of high appropriate and high non-attuned mind-related comments.The findings support the relevance of MM in an Arab sample. PMID- 29716434 TI - Effect of Sildenafil on Pulmonary Circulation and Cardiovascular Function in Near Term Fetal Sheep During Hypoxemia. AB - Sildenafil is a potential new treatment for placental insufficiency in human pregnancies as it reduces the breakdown of vasodilator nitric oxide. Pulmonary vasodilatation is observed in normoxemic fetuses following sildenafil administration. Placental insufficiency often leads to fetal hypoxemia that can cause pulmonary vasoconstriction and fetal cardiac dysfunction as evidenced by reduced isovolumic myocardial velocities. We tested the hypotheses that sildenafil, when given directly to the hypoxemic fetus, reverses reactive pulmonary vasoconstriction, increases left ventricular cardiac output by increasing pulmonary venous return, and ameliorates hypoxemic myocardial dysfunction. We used an instrumented sheep model. Fetuses were made hypoxemic over a mean (standard deviation) duration of 41.3 (9.5) minutes and then given intravenous sildenafil or saline infusion. Volume blood flow through ductus arteriosus was measured with an ultrasonic transit-time flow probe. Fetal left and right ventricular outputs and lung volume blood flow were calculated, and ventricular function was examined using echocardiography. Lung volume blood flow decreased and the ductus arteriosus volume blood flow increased with hypoxemia. There was a significant reduction in left ventricular and combined cardiac outputs during hypoxemia in both groups. Hypoxemia led to a reduction in myocardial isovolumic velocities, increased ductus venosus pulsatility, and reduced left ventricular myocardial deformation. Direct administration of sildenafil to hypoxemic fetus did not reverse the redistribution of cardiac output. Furthermore, fetal cardiac systolic and diastolic dysfunction was observed during hypoxemia, which was not improved by fetal sildenafil treatment. In conclusion, sildenafil did not improve pulmonary blood flow or cardiac function in hypoxemic sheep fetuses. PMID- 29716431 TI - Dendritic Spine Elimination: Molecular Mechanisms and Implications. AB - Dynamic modification of synaptic connectivity in response to sensory experience is a vital step in the refinement of brain circuits as they are established during development and modified during learning. In addition to the well established role for new spine growth and stabilization in the experience dependent plasticity of neural circuits, dendritic spine elimination has been linked to improvements in learning, and dysregulation of spine elimination has been associated with intellectual disability and behavioral impairment. Proper brain function requires a tightly regulated balance between spine formation and spine elimination. Although most studies have focused on the mechanisms of spine formation, considerable progress has been made recently in delineating the neural activity patterns and downstream molecular mechanisms that drive dendritic spine elimination. Here, we review the current state of knowledge concerning the signaling pathways that drive dendritic spine shrinkage and elimination and we discuss their implication in neuropsychiatric and neurodegenerative disease. PMID- 29716435 TI - Micromolar Zinc in Annexin A5 Anticoagulation as a Potential Remedy for RPRGL3 Associated Recurrent Pregnancy Loss. AB - Deficient expression of the placental anticoagulant annexin A5 (ANXA5) has been associated with thrombophilia-related pregnancy complications and ultimately with recurrent pregnancy loss (RPL). Carrier status of M2/ANXA5 ( RPRGL3), common ANXA5 promoter variant, has been identified as genetic cause of reduced ANXA5 levels and proposed as biomarker for successful anticoagulant treatment of RPL women. A murine model of AnxA5 loss of function displayed characteristic placental pathology and fetal loss that was alleviated through anticoagulant intervention. This study identified an alternative means of supplementing anticoagulation, through elevated ANXA5 expression. Physiological micromolar Zn2+ stimulated ANXA5 transcription, raising ANXA5 protein expression and surface abundance on BeWo and human umbilical vein endothelial cells (HUVEC), thus resulting in prolonged coagulation times. Zn2-fed AnxA5 functionally deficient pregnant mice showed a trend to increase litter size when primiparous that grew comparable to wild-type progeny in subsequent pregnancies. Elevated AnxA5 signal upon Zn2+ treatment was confirmed in murine placentae. Micromolar Zn2+ stimulated ANXA5 expression in cell culture directly and alleviated RPL in AnxA5 genetically deficient mice, without notable toxicity effects. PMID- 29716436 TI - Efficacy of Cladribine Tablets in high disease activity subgroups of patients with relapsing multiple sclerosis: A post hoc analysis of the CLARITY study. AB - BACKGROUND: In the CLARITY (CLAdRIbine Tablets treating multiple sclerosis orallY) study, Cladribine Tablets significantly improved clinical and magnetic resonance imaging (MRI) outcomes (vs placebo) in patients with relapsing remitting multiple sclerosis. OBJECTIVE: Describe two clinically relevant definitions for patients with high disease activity (HDA) at baseline of the CLARITY study (utility verified in patients receiving placebo) and assess the treatment effects of Cladribine Tablets 3.5 mg/kg compared with the overall study population. METHODS: Outcomes of patients randomised to Cladribine Tablets 3.5 mg/kg or placebo were analysed for subgroups using HDA definitions based on high relapse activity (HRA; patients with ?2 relapses during the year prior to study entry, whether on DMD treatment or not) or HRA plus disease activity on treatment (HRA + DAT; patients with ?2 relapses during the year prior to study entry, whether on DMD treatment or not, PLUS patients with ?1 relapse during the year prior to study entry while on therapy with other DMDs and ?1 T1 Gd+ or ?9 T2 lesions). RESULTS: In the overall population, Cladribine Tablets 3.5 mg/kg reduced the risk of 6-month-confirmed Expanded Disability Status Scale (EDSS) worsening by 47% vs placebo. A risk reduction of 82% vs placebo was seen in both the HRA and HRA + DAT subgroups (vs 19% for non-HRA and 18% for non-HRA + DAT), indicating greater responsiveness to Cladribine Tablets 3.5 mg/kg in patients with HDA. There were consistent results for other efficacy endpoints. The safety profile in HDA patients was consistent with the overall CLARITY population. CONCLUSION: Patients with HDA showed clinical and MRI responses to Cladribine Tablets 3.5 mg/kg that were generally better than, or at least comparable with, the outcomes seen in the overall CLARITY population. PMID- 29716437 TI - The Relationship Between Spectral Modulation Detection and Speech Recognition: Adult Versus Pediatric Cochlear Implant Recipients. AB - Adult cochlear implant (CI) recipients demonstrate a reliable relationship between spectral modulation detection and speech understanding. Prior studies documenting this relationship have focused on postlingually deafened adult CI recipients-leaving an open question regarding the relationship between spectral resolution and speech understanding for adults and children with prelingual onset of deafness. Here, we report CI performance on the measures of speech recognition and spectral modulation detection for 578 CI recipients including 477 postlingual adults, 65 prelingual adults, and 36 prelingual pediatric CI users. The results demonstrated a significant correlation between spectral modulation detection and various measures of speech understanding for 542 adult CI recipients. For 36 pediatric CI recipients, however, there was no significant correlation between spectral modulation detection and speech understanding in quiet or in noise nor was spectral modulation detection significantly correlated with listener age or age at implantation. These findings suggest that pediatric CI recipients might not depend upon spectral resolution for speech understanding in the same manner as adult CI recipients. It is possible that pediatric CI users are making use of different cues, such as those contained within the temporal envelope, to achieve high levels of speech understanding. Further investigation is warranted to investigate the relationship between spectral and temporal resolution and speech recognition to describe the underlying mechanisms driving peripheral auditory processing in pediatric CI users. PMID- 29716438 TI - Outcomes With a Self-Fitting Hearing Aid. AB - Self-fitting hearing aids (SFHAs)-devices that enable self-directed threshold measurements leading to a prescribed hearing aid (HA) setting, and fine-tuning, without the need for professional support-are now commercially available. This study examined outcomes obtained with one commercial SFHA, the Companion (SoundWorld Solutions), when support was available from a clinical assistant during self-fitting. Participants consisted of 27 experienced and 25 new HA users who completed the self-fitting process, resulting in 38 user-driven and 14 clinician-driven fittings. Following 12 weeks' experience with the SFHAs in the field, outcomes measured included the following: coupler gain and output, HA handling and management skills, speech recognition in noise, and self-reported benefit and satisfaction. In addition, the conventionally fitted HAs of 22 of the experienced participants who had user-driven fittings were evaluated. Irrespective of HA experience, the type of fitting (user- or clinician-driven) had no significant effect on coupler gain, speech recognition scores, or self reported benefit and satisfaction. Users selected significantly higher low frequency gain in the SFHAs when compared with the conventionally fitted HAs. The conventionally fitted HAs were rated significantly higher for benefit and satisfaction on some subscales due to negative issues with the physical design and implementation of the SFHAs, rather than who drove the fitting process. Poorer cognitive function was associated with poorer handling and management of the SFHAs. Findings suggest that with the right design and support, SFHAs may be a viable option to improve the accessibility of hearing health care. PMID- 29716439 TI - China Registry of Hepatitis B (CR-HepB): Protocol and implementation of a nationwide hospital-based registry of hepatitis B. AB - AIMS: The disease burden of chronic HBV infection in China remains high, although the rate of new infections has become extremely low. To facilitate real-world clinical study of chronic HBV infection, we established a nationwide hospital based electronic platform, named the China Registry of Hepatitis B (CR-HepB). METHODS: This internet-based registry for chronic hepatitis B recruited patients from tertiary or secondary hospitals that have particular interest and expertise in managing hepatitis B patients. The main inclusion criteria for the database were men or women with hepatitis B surface antigen positivity >= 6 months, hepatitis B e antigen positive or negative, with or without cirrhosis, and with or without treatment. At the first time of data entry, demographics, medical history, virology, biochemistry, hematology and radiology reports, as well as diagnosis and treatment information, are recorded. Registered patients then receive a standard of care and follow-up every three (optional) to six months (required) for changes in virology, biochemistry and radiology, as well as clinical progression. RESULTS AND CONCLUSIONS: To date, 47 hospitals have joined the CR-HepB. This platform can be used to demonstrate the clinical pattern and treatment profile of chronic HBV infection, evaluate long-term efficacy and safety of antiviral therapy and provide real-world evidence for policy-making in China. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT03108794. PMID- 29716440 TI - 3D printing process of oxidized nanocellulose and gelatin scaffold. AB - For tissue engineering applications tissue scaffolds need to have a porous structure to meet the needs of cell proliferation/differentiation, vascularisation and sufficient mechanical strength for the specific tissue. Here we report the results of a study of the 3D printing process for composite materials based on oxidized nanocellulose and gelatin, that was optimised through measuring rheological properties of different batches of materials after different crosslinking times, simulation of the pneumatic extrusion process and 3D scaffolds fabrication with Solidworks Flow Simulation, observation of its porous structure by SEM, measurement of pressure-pull performance, and experiments aimed at finding out the vitro cytotoxicity and cell morphology. The materials printed are highly porous scaffolds with good mechanical properties. PMID- 29716442 TI - 2017 European guideline for the screening, prevention and initial management of hepatitis B and C infections in sexual health settings. AB - This guideline updates the 2010 European guideline for the management of hepatitis B and C virus infections. It is primarily intended to provide advice on testing, prevention and initial management of viral hepatitis B and C for clinicians working in sexual health clinical settings in European countries. The guideline is in a new question and answer format based on clinical situations, from which population/intervention/comparison/outcome questions were formulated. Updates cover areas such as epidemiology, point-of-care tests for hepatitis B, hepatitis C risk and 'chemsex', and HIV pre-exposure prophylaxis and hepatitis B. We have also included a short paragraph on hepatitis E noting there is no evidence for sexual transmission. The guideline has been prepared in accordance with the Europe protocol for production available at http://www.iusti.org/regions/europe/pdf/2017/ProtocolForProduction2017.pdf. PMID- 29716441 TI - Viral proteins targeting host protein kinase R to evade an innate immune response: a mini review. AB - The innate immune system offers a first line of defense by neutralizing foreign pathogens such as bacteria, fungi, and viruses. These pathogens express molecules (RNA and proteins) that have discrete structures, known as the pathogen associated molecular patterns that are recognized by a highly specialized class of host proteins called pattern recognition receptors to facilitate the host's immune response against infection. The RNA-dependent Protein Kinase R (PKR) is one of the host's pattern recognition receptors that is a key component of an innate immune system. PKR recognizes imperfectly double-stranded non-coding viral RNA molecules via its N-terminal double-stranded RNA binding motifs, undergoes phosphorylation of the C-terminal kinase domain, ultimately resulting in inhibition of viral protein translation by inhibiting the guanine nucleotide exchange activity of eukaryotic initiation factor 2alpha. Not surprisingly, viruses have evolved mechanisms by which viral non-coding RNA or protein molecules inhibit PKR's activation and/or its downstream activity to allow viral replication. In this review, we will highlight the role of viral proteins in inhibiting PKR's activity and summarize currently known mechanisms by which viral proteins execute such inhibitory activity. PMID- 29716443 TI - Corticosteroids in liver and urine in Sicilian cattle by a LC-MS/MS method. AB - The presence of corticosteroid residues was assessed in urine and liver samples from livestock of Sicily. A total of 630 bovine samples were collected from farms and slaughterhouses. The samples were analysed using solid-phase extraction (SPE) coupled with ultra-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS). All the corticosteroids found were under the maximum residue limit imposed by Commission Regulation (EC) 37/2010. About 4% of liver samples showed dexamethasone levels above the limit of detection (LOD), with a mean of 1.5 +/- 0.2 ug kg-1. Betamethasone was found only in seven liver samples, with a mean of 1.6 +/- 0.1 ug kg-1. Furthermore, prednisolone and prednisone were found only in urine and liver samples from slaughterhouse, probably related to the high rate of stress for bovines. These results suggest good control practices adopted by Sicilian farms, able to ensure the quality of food products. PMID- 29716446 TI - A Systematic Review of Interventions to Improve Initiation of Mental Health Care Among Racial-Ethnic Minority Groups. AB - OBJECTIVE: The objective of this systematic review was to identify interventions to improve the initiation of mental health care among racial-ethnic minority groups. METHODS: The authors searched three electronic databases in February 2016 and independently assessed eligibility of 2,065 titles and abstracts on the basis of three criteria: the study design included an intervention, the participants were members of racial-ethnic minority groups and lived in the United States, and the outcome measures included initial access to or attitudes toward mental health care. The qualitative synthesis involved 29 studies. RESULTS: Interventions identified included collaborative care (N=10), psychoeducation (N=7), case management (N=5), colocation of mental health services within existing services (N=4), screening and referral (N=2), and a change in Medicare medication reimbursement policy that served as a natural experiment (N=1). Reduction of disparities in the initiation of antidepressants or psychotherapy was noted in seven interventions (four involving collaborative care, two involving colocation of mental health services, and one involving screening and referral). Five of these disparities-reducing interventions were tested among older adults only. Most (N=23) interventions incorporated adaptations designed to address social or cultural barriers to care. CONCLUSIONS: Interventions that used a model of integrated care reduced racial-ethnic disparities in the initiation of mental health care. PMID- 29716448 TI - The Disabling Effects of Mental Illness on My Education. PMID- 29716447 TI - Trends in Results of HBIPS National Performance Measures and Association With Year of Adoption. AB - OBJECTIVE: Multiple studies demonstrate a consistent pattern of improvement on quality measures among health care organizations after they begin collecting and reporting data. This study compared results on psychiatric performance measures among cohorts of hospitals with different characteristics that elected to begin reporting on the measures at various points in time. METHODS: Quarterly reporting of Hospital-Based Inpatient Psychiatric Services (HBIPS) measures to the Joint Commission was used to examine trends in performance among four hospital cohorts that began reporting in 2009 (N=243), 2011 (N=139), 2014 (N=137), or 2015 (N=372). The HBIPS measures address admission screening, restraint and seclusion use, justification of use of multiple antipsychotic medications, and discharge planning. Comparisons were based upon initial quarters of data reported and change rates. RESULTS: After adjustment for covariates, the analyses showed that all cohorts significantly improved across quarters for admission screening, justification of multiple antipsychotic medications, and discharge planning. Restraint hours significantly dropped over the initial reporting periods, but only for the 2009 and 2015 cohorts. Seclusion hours significantly dropped over the six reporting periods for all cohorts except 2011. CONCLUSIONS: Several differences were observed across cohorts in the rate of change between baseline and final measurement for various measures. In nearly every case, however, hospitals that began reporting measurement data earlier performed better than subsequent cohorts during the later cohorts' first quarter of reporting. PMID- 29716449 TI - Job Endings and Work Trajectories of Persons Receiving Supported Employment and Cognitive Remediation. AB - OBJECTIVE: This study examined job endings and work trajectories among participants in a study comparing the effects of adding cognitive remediation to supported employment among individuals who had not benefited from supported employment. METHODS: Data were from a controlled trial of 107 persons with serious mental illness enrolled in supported employment but who had not obtained or sustained competitive work. Participants were randomly assigned to enhanced supported employment only (with employment specialists trained to recognize cognitive difficulties and teach coping strategies) or to the Thinking Skills for Work program (enhanced supported employment plus cognitive remediation). For the 52 participants who worked, the two groups were compared on types of job endings, reasons for job endings, successful versus unsuccessful jobs, and work trajectories over the two-year study period. RESULTS: The two groups did not differ in types of job ending, although participants in Thinking Skills for Work were less likely than those in enhanced supported employment only to cite dissatisfaction with the job as a reason for the job ending. Participants in Thinking Skills for Work were also less likely to have an overall unsuccessful work trajectory, more likely to have only successful jobs, and more likely to be employed at the end of the study. CONCLUSIONS: The Thinking Skills for Work program appeared to help participants who had not benefited from supported employment stick with and master their jobs more effectively than those in enhanced supported employment only, resulting in better work trajectories over the course of the study. PMID- 29716450 TI - Evaluation of Surgical Instruments With Radiofrequency Identification Tags in the Operating Room. AB - BACKGROUND: Surgical instrument retention and instrument breakage compromise surgery quality and lead to medical malpractice. We developed an instrument tracking system that could alert surgeons to instrument retention during surgery and monitor instrument use to reduce the risk of breakage. METHODS: This prospective, experimental clinical trial included 15 patients undergoing inguinal hernia surgery or lumpectomy under general anesthesia at Saiseikai Kurihashi Hospital. Radiofrequency identification (RFID)-tagged surgical instruments were used, and a detection antenna was placed on a mayo stand during the operation. We analyzed the 1-loop detection ratio (OLDR)-that is, the capability of the antenna to detect devices in a single reading-and the total detection rate (TDR)-that is, the data accumulated for the duration of the operation-of the RFID-tagged instruments. RESULTS: Data analysis revealed that the OLDR was 95% accurate, whereas the TDR was 100% accurate. The antenna could not detect the RFID tag when there was interference from electrocautery noise radiation, and 6% of instrument movement was undetected by the antenna; however, the TDR and instrument use were detected at all times. CONCLUSIONS: Surgical instruments can be tracked during surgery, and this tracking can clarify the usage rate of each instrument and serve as a backup method of instrument counting. However, this study was conducted on a small scale, and RFID tags cannot be attached to small surgical instruments used in complex operations such as neurosurgery. Further efforts to develop a tracking system for these instruments are warranted. PMID- 29716451 TI - Pancreaticopleural fistula: a rare cause of pleural empyema. AB - AIM: Pancreaticopleural fistula (PPF) is a rare complication of acute or chronic pancreatitis. When the pancreatic duct disrupts, pancreatic fluid may leak into the retroperitoneum and fistulate into the pleural cavity. Patients usually present with thoracic complaints, making it hard to suspect an abdominal etiology. Although PPF is uncommon, one must consider this diagnosis in patients with thoracic complaints and a history of alcohol abuse or pancreatitis. METHODS: We present an illustrative case and review of the literature on PPF. RESULTS: A 47-year old man was presented with recurrent PPF due to pancreas divisum, pancreatic stones and chronic exudative pancreatitis, resulting in unilateral empyema. After initial conservative treatment, operative measures were needed. We report omentoplasty against the diaphragmatic hiatus in combination with VATS (video-assisted thoracoscopic surgery) thoracotomy with decortication and debridement as a feasible operative option for resolving PPF. CONCLUSION: PPF is a rare complication of pancreatitis. The diagnosis is difficult to make and can be confirmed by thoracocentesis and proper imaging, preferably MRCP. Treatment options include conservative, endoscopic (ERCP) or surgical measures. Omentoplasty positioned against the diaphragmatic hiatus is a feasible technique for closure of PPF. PMID- 29716452 TI - Reasons to Doubt the Reliability of Eyewitness Memory: Commentary on Wixted, Mickes, and Fisher (2018). AB - Wixted, Mickes, and Fisher (this issue) take issue with the common trope that eyewitness memory is inherently unreliable. They draw on a large body of mock crime research and a small number of field studies, which indicate that high confidence eyewitness reports are usually accurate, at least when memory is uncontaminated and suitable interviewing procedures are used. We agree with the thrust of Wixted et al.'s argument and welcome their invitation to confront the mass underselling of eyewitnesses' potential reliability. Nevertheless, we argue that there is a comparable risk of overselling eyewitnesses' reliability. Wixted et al.'s reasoning implies that near-pristine conditions or uncontaminated memories are normative, but there are at least two good reasons to doubt this. First, psychological science does not yet offer a good understanding of how often and when eyewitness interviews might deviate from best practice in ways that compromise the accuracy of witnesses' reports. Second, witnesses may frequently be exposed to preinterview influences that could corrupt reports obtained in best practice interviews. PMID- 29716453 TI - In the DNA Exoneration Cases, Eyewitness Memory Was Not the Problem: A Reply to Berkowitz and Frenda (2018) and Wade, Nash, and Lindsay (2018). AB - The available real-world evidence suggests that, on an initial test, eyewitness memory is often reliable. Ironically, even the DNA exoneration cases-which generally involved nonpristine testing conditions and which are usually construed as an indictment of eyewitness memory-show how reliable an initial test of eyewitness memory can be in the real world. We endorse the use of pristine testing procedures, but their absence does not automatically imply that eyewitness memory is unreliable. PMID- 29716454 TI - Rethinking the Reliability of Eyewitness Memory. AB - Although certain pockets within the broad field of academic psychology have come to appreciate that eyewitness memory is more reliable than was once believed, the prevailing view, by far, is that eyewitness memory is unreliable-a blanket assessment that increasingly pervades the legal system. On the surface, this verdict seems unavoidable: Research convincingly shows that memory is malleable, and eyewitness misidentifications are known to have played a role in most of the DNA exonerations of the innocent. However, we argue here that, like DNA evidence and other kinds of scientifically validated forensic evidence, eyewitness memory is reliable if it is not contaminated and if proper testing procedures are used. This conclusion applies to eyewitness memory broadly conceived, whether the test involves recognition (from a police lineup) or recall (during a police interview). From this perspective, eyewitness memory has been wrongfully convicted of mistakes that are better construed as having been committed by other actors in the legal system, not by the eyewitnesses themselves. Eyewitnesses typically provide reliable evidence on an initial, uncontaminated memory test, and this is true even for most of the wrongful convictions that were later reversed by DNA evidence. PMID- 29716455 TI - Five Popular Study Strategies: Their Pitfalls and Optimal Implementations. AB - Researchers' and educators' enthusiasm in applying cognitive principles to enhance educational practices has become more evident. Several published reviews have suggested that some potent strategies can help students learn more efficaciously. Unfortunately, for whatever reason, students do not report frequent reliance on these empirically supported techniques. In the present review, we take a novel approach, identifying study strategies for which students have strong preferences and assessing whether these preferred strategies have any merit given existing empirical evidence from the cognitive and educational literatures. Furthermore, we provide concrete recommendations for students, instructors, and psychologists. For students, we identify common pitfalls and tips for optimal implementation for each study strategy. For instructors, we provide recommendations for how they can assist students to more optimally implement these study strategies. For psychologists, we highlight promising avenues of research to help augment these study strategies. PMID- 29716456 TI - Who Decides What Is Acceptable Speech on Campus? Why Restricting Free Speech Is Not the Answer. AB - Recent protests on dozens of campuses have led to the cancellation of controversial talks, and violence has accompanied several of these protests. Psychological science provides an important lens through which to view, understand, and potentially reduce these conflicts. In this article, we frame opposing sides' arguments within a long-standing corpus of psychological research on selective perception, confirmation bias, myside bias, illusion of understanding, blind-spot bias, groupthink/in-group bias, motivated skepticism, and naive realism. These concepts inform dueling claims: (a) the protestors' violence was justified by a higher moral responsibility to prevent marginalized groups from being victimized by hate speech, versus (b) the students' right to hear speakers was infringed upon. Psychological science cannot, however, be the sole arbiter of these campus debates; legal and philosophical considerations are also relevant. Thus, we augment psychological science with insights from these literatures to shed light on complexities associated with positions supporting free speech and those protesting hate speech. We conclude with a set of principles, most supported by empirical research, to inform university policies and help ensure vigorous freedom of expression within the context of an inclusive, diverse community. PMID- 29716457 TI - Rethinking the Confident Eyewitness: A Reply to Wixted, Mickes, and Fisher. AB - In the current issue, Wixted, Mickes, and Fisher make the claim that eyewitness memory is not inherently unreliable. They also describe specific conditions under which an eyewitness's confidence can be a reliable indicator of accuracy in the context of both recall and recognition. We argue, however, that calculating the probative value of eyewitness evidence is more complicated than the authors acknowledge. In this commentary, we raise several concerns about the collection and assessment of eyewitness confidence in the real world. We also discuss how frequently the conditions specified by Wixted et al. are met in real cases. The potential for memory contamination is commonplace and can likely be outside the control of investigators. Moreover, there is reason to doubt that legal decision makers are sensitive to the myriad ways that eyewitness memory can be influenced. Because of this, we think eyewitness-memory scientists would do well to further research the intricacies of eyewitness confidence in the real world. PMID- 29716459 TI - Spoken-word production in Korean: A non-word masked priming and phonological Stroop task investigation. AB - Speech production studies have shown that phonological unit initially used to fill the metrical frame during phonological encoding is language specific, that is, a phoneme for English and Dutch, an atonal syllable for Mandarin Chinese, and a mora for Japanese. However, only a few studies chronometrically investigated speech production in Korean, and they obtained mixed results. Korean is particularly interesting as there might be both phonemic and syllabic influences during phonological encoding. The purpose of this study is to further examine the initial phonological preparation unit in Korean, employing a masked priming task (Experiment 1) and a phonological Stroop task (Experiment 2). The results showed that significant onset (and onset-plus, that is, consonant-vowel [CV]) effects were found in both experiments, but there was no compelling evidence for a prominent role for the syllable. When the prime words were presented in three different forms related to the targets, namely, without any change, with re syllabified codas, and with nasalised codas, there were no significant differences in facilitation among the three forms. Alternatively, it is also possible that participants may not have had sufficient time to process the primes up to the point that re-syllabification or nasalisation could have been carried out. In addition, the results of a Stroop task demonstrated that the onset phoneme effect was not driven by any orthographic influence. These findings suggest that the onset segment and not the syllable is the initial (or proximate) phonological unit used in the segment-to-frame encoding process during speech planning in Korean. PMID- 29716460 TI - Animacy and attentional processes: Evidence from the Stroop task. AB - In visual perception, evidence has shown that attention is captured earlier and held longer by animate than inanimate stimuli. The former are also remembered better than the latter. Thus, as far as attentional processes are concerned, animate entities have a privileged status over inanimate entities. We tested this hypothesis further using an adaptation of the Stroop paradigm. Adults had to categorise the colours of words that referred to either animate or inanimate concepts. In two experiments, we found that it took longer to process the ink colour of animate than inanimate words. Indeed, this effect was found when the words were presented in an oral animacy Stroop task (Experiment 1) and in a manual animacy Stroop task (Experiment 2). Using ex-Gaussian analyses and examining the distribution of RTs as a function of vincentiles per animacy condition, we did not find a specific localisation of the animacy effect. The findings are interpreted as providing further evidence that animates are prioritised in processing because their fitness value is higher than that of inanimates. PMID- 29716461 TI - Evaluation of optional fee structures for solid waste management in China. AB - A municipal solid waste fee has become an important means for the implementation of the waste management rendered by the government all around the world. Based on the ecological environmental compensation theory, this article constructs an analytical framework of waste charging from the perspective of public policy evaluation, to carry on the comprehensive comparison and analysis to the operability, feasibility, validity, rationality, and universality of the two modes of waste charging: Ration charge and unit-pricing modes. The results indicate that in the cities with large amounts of waste production, long time of waste charging, and high disposal rate, pilot projects should be carried out; and the government needs to improve the construction of associated laws and regulations. PMID- 29716462 TI - Ethical aspects of caring for partner care-givers of people with dementia. PMID- 29716463 TI - [Attachment and Externalizing Behavior Problems in Primary School Children with ADHD]. AB - Attachment and Externalizing Behavior Problems in Primary School Children with ADHD When examining children with ADHD, attachment research does not usually differentiate between the different clinical pictures within the disorder. This study examines attachment and ADHD in children who display a simple or unspecified form of ADHD, in order to be able to draw specific conclusions about this particular group. Attachment, ADHD symptoms as well as externalizing behavior problems were assessed from 93 children aged five to nine years, 48 of whom had an ADHD diagnosis. The distributions of attachment representations between children with ADHD and those without ADHD differ greatly. In addition, externalizing behavior problems differ between attachment classifications. Attachment seems to be an important factor in the etiology of ADHD, however, ADHD as well as externalizing behavior problems as a global construct are too unspecific to determine the influence of attachment on the disorder. Subsequent studies should first focus on specific symptom patterns within the clinical picture whereas clinical practice should consider the parent-child relation an important factor in the development as well as the treatment of ADHD. PMID- 29716464 TI - [Attachment Based Short Intervention During Inpatient Treatment of Adolescents]. AB - Attachment Based Short Intervention During Inpatient Treatment of Adolescents In clinical attachment research the established and economic Adult Attachment Projective Picture System (AAP) has been increasingly used in the past few years to assess the attachment representations in adults and recent studies demonstrated sufficient validity for assessing attachment representations in adolescents. Apart from coding attachment classifications, the AAP provides useful and clinically valid information concerning attachment related defences, aspects of capacity to act and synchrony in relationships and emotion regulation strategies with respect to attachment related traumatic experiences. These valuable aspects with respect to individual resources led to the conceptualization to implement the AAP in the therapeutic setting as a feedback tool. In this pilot case we report on an adolescent patient in an inpatient setting. The therapist received an individualized feedback on the patients' AAP to focus on specific attachment related themes used as a short intervention respective an add-on treatment. This paper presents the first results of this new approach by demonstrating the potential therapeutic effects and process of therapy. PMID- 29716465 TI - [Test Reviews]. PMID- 29716467 TI - [Editorial]. PMID- 29716468 TI - [Observation of Attachment Disorder Symptoms in Middle Childhood]. AB - Observation of Attachment Disorder Symptoms in Middle Childhood Attachment in childhood is mainly assessed by observation. In contrast, assessment of attachment disorder symptoms (RAD) is mainly based on caregiver reports. The present study uses a newly developed observation tool (Coding of Attachment Disorder Behavior in Children; Iwanski u. Zimmermann, 2013) to assess attachment disorder symptoms in a group of school-aged children from a risk group for the development of attachment disorder symptoms and non-clinical controls. In addition, caregiver reports on RAD symptoms are also assessed (Relationship Problems Questionnaire; Minnis, Rabe-Hesketh, Wolkind, 2002; Disturbances of Attachment Interview; Smyke u. Zeanah, 1999). Moreover, associations with children's self-concept (Harter, 2012) were studied. Results reveal that children at risk showed more inhibited and disinhibited attachment disorder symptoms and a more negative self-concept compared to non-clinical controls. RAD symptoms are shown in interaction with both the caregiver and a stranger. The use of a reliable and valid observation tool for the diagnostic of attachment disorder symptoms besides ratings of caregivers is recommended for clinical practice and research. PMID- 29716471 TI - [Treatment Satisfaction of Mothers with Postpartum Depression Concerning Circle of Security Intervention]. AB - Treatment Satisfaction of Mothers with Postpartum Depression Concerning Circle of Security Intervention Treatment satisfaction of mothers with postpartum depression who undergo mother-infant treatment is rarely examined, albeit seen as one aspect of treatment success. This study deals with maternal treatment satisfaction concerning the Circle of Security (COS) group intervention, compared to standard-mother-infant treatment (TAU), within a RCT trial. Treatment satisfaction was captured by the Fragebogen zur Beurteilung der Behandlung (FBB E) of 52 mothers assigned to COS or TAU at children's age between 16 to 18 months. Process quality as well as outcome quality was assessed. Process quality included the evaluation of treatment procedure, information supply, evidence and justification of the measures undertaken, therapist's competence and coordination ability as well as the quality of relationship between therapist and mother. Results showed overall good to high and marginally different treatment satisfaction between both groups. COS-mothers declared themselves significantly more satisfied with the child (FBB-E-subscale: Success concerning the infant) than TAU-mothers. Both groups showed higher treatment satisfaction with the process quality than with the outcome quality of intervention. Overall, COS seem to meaningfully foster the acknowledgment of the child. In mother-infant treatment, particular attention is warranted to aspects of the process quality that attain the mother's treatment satisfaction. PMID- 29716473 TI - Bursting Fracture of Balloon-Expandable Stent and Pseudoaneurysm Formation in the Left Common Iliac Artery and Endovascular Treatment With Graft Stent. AB - PURPOSE: To report successful endovascular treatment of a previously implanted balloon-expandable stent bursting fracture with concomitant large pseudoaneurysm formation in the left common iliac artery (LCIA). CASE REPORT: A 72-year-old man had been previously treated with balloon-expandable stents for severe stenotic lesion in the LCIA and left external iliac artery. Seven years later, the patient complained pain in both lower legs and back. Angiography demonstrated a 3.5-cm sized pseudoaneurysm in the LCIA with embedded metal fragments around the lesion. An endovascular treatment was selected using a limb extension graft for endovascular aortic aneurysm repair. The device was successfully deployed, and no endoleak was observed. At 1-month follow-up, computed tomography scan confirmed patency of the implanted stent graft devices in the LCIA and the absence of any endoleak. CONCLUSION: Endovascular approach using a limb extension graft stent for endovascular aortic aneurysm repair can be used for treating stent fracture related pseudoaneurysm in the common iliac artery. PMID- 29716474 TI - Feasibility of Cryopreserved Conduits for Complex Vascular Reconstruction in the Pediatric Population: The Case of a 3-Year-Old With Femoral Vessels Transections. AB - This report presents an unusual case of traumatic iliofemoral vessel transection in a 3-year-old patient successfully reconstructed using a cryopreserved greater saphenous conduit. Five years after injury, the patient continues to do well with normal ambulation. An arterial duplex demonstrated graft patency free of aneurysmal dilatation. These encouraging results suggest that the natural history of cryopreserved conduits may differ in the pediatric population and cryopreserved conduits could be used for complex vascular reconstructions. PMID- 29716475 TI - Contemporary Management and Outcome After Lower Extremity Fasciotomy in Non Trauma-Related Vascular Surgery. AB - INTRODUCTION: Acute compartment syndrome (ACS) is a challenging and recognized complication to vascular surgery revascularization. The aim of this study was to investigate the current epidemiology, management, and early outcomes of fasciotomy in vascular surgery. METHODS: Retrospective cohort study of all patients undergoing lower extremity fasciotomy at a single university center between January 2008 and December 2014. Patient demographics, operative techniques, and outcomes were analyzed. RESULTS: The cohort (n = 113 limbs; 107 patients; 48% women; mean age was 74 (12) years [range, 50-97 years]) included 81 (72%) limbs undergoing revascularization for acute limb ischemia, 7 (6.2%) limbs related to acute aortic disease, and 23 (20%) limbs undergoing elective vascular surgery. Five patients underwent bilateral lower extremity fasciotomy. In all, 64 (57%) limbs had signs of ACS and underwent a therapeutic fasciotomy, while 49 (43%) fasciotomies were prophylactic. There were 20 (18%) fasciotomies performed after endovascular interventions. A 4-compartment fasciotomy was performed in 82% (n = 93) of limbs with a double incision technique. Split thickness skin graft was required in 11% (12/112) and vacuum-assisted closure treatment in 11% (12/111). The mean length of stay in hospital was 11 (9) days. Most common complication was lower extremity nerve deficit 32% (33/104) followed by wound infection 30% (32/108). At 30-day follow-up, amputation rate was 13% (14/107 limbs) and mortality 23% (25/107 patients). In the multivariate logistic regression analysis, prophylactic fasciotomy was associated with amputation (odds ratio: 28.9; 95% confidence interval: 1.96-425; P = .014). CONCLUSION: Acute compartment syndrome is primarily related to acute ischemic conditions but occurs after both aortic or elective vascular procedures and endovascular treatments. There are significant complications related to lower extremity fasciotomy in vascular surgery. PMID- 29716476 TI - High Reintervention and Amputation Rates After Outpatient Atherectomy for Claudication. AB - Outpatient use of atherectomy for peripheral arterial disease has grown rapidly and outcomes are poorly understood. We analyzed outcomes of atherectomy done for claudication, comparing office and hospital outpatient settings. Analysis of Medicare Part B claims data was performed for incident femoral-popliteal or tibial-peroneal atherectomy from 2012 to 2014. Longitudinal analysis assessed services 18 months before, during, and up to 18 months after the incident peripheral vascular intervention (PVI). Differences between office-based and hospital outpatient-based settings were assessed using chi2 and Fisher exact tests. Comparing procedure settings, significant differences in race (femoral popliteal: P = .04, tibial-peroneal: P = .001), chronic renal failure (femoral popliteal: P = .002), and hypertension (femoral-popliteal: P = .01, tibial peroneal: P = .006) were found. Nine hundred twenty-four patients undergoing femoral-popliteal atherectomy were analyzed (262 office based, 662 hospital outpatient based); 42.7% of office-based and 36.9% of hospital outpatient-based femoral-popliteal atherectomy patients had repeat PVI within 18 months ( P = .10). Major amputation was performed in 2.3% and 3.2% of patients in office and hospital outpatient settings, respectively ( P = .47). Four hundred twenty-three patients undergoing tibial-peroneal atherectomy were analyzed (202 office based, 221 hospital outpatient based); 46.5% of office-based and 38.9% of hospital outpatient-based tibial-peroneal atherectomy patients had repeat PVI within 1 year ( P = .11). Major amputation was performed in 5.0% and 8.1% of patients in office and hospital outpatient settings, respectively ( P = .19). Our study demonstrates higher than expected rates of major amputation for patients undergoing peripheral arterial atherectomy with regard to previously reported rates. Further studies may be required to prove the efficacy and safety of atherectomy for occlusive disease in the femoral-popliteal and tibial-peroneal segments to ensure outcomes are not worse than the natural history of medically managed claudicants. PMID- 29716477 TI - Endovascular Repair of Three Concurrent Mycotic Pseudoaneurysms. AB - INTRODUCTION: Mycotic pseudoaneurysm has traditionally been repaired surgically with excision of the infected artery and revascularization via extra-anatomical or in situ bypass. There have been reports of endovascular repair for high-risk patients for formal surgical repair. We present a case of a patient with 3 large pseudoaneurysms arising from the right subclavian artery, descending thoracic aorta, and right popliteal artery treated with endovascular and hybrid intervention. CASE: A 74-year-old male with remote history of coronary artery bypass graft and recent sternoclavicular joint abscess developed 3 concurrent pseudoaneurysms arising from the right subclavian artery, distal descending thoracic aorta, and right popliteal artery. He underwent right axillary to common carotid bypass with endovascular stent graft placement in the distal innominate and proximal subclavian artery, and subsequently had thoracic endovascular aortic repair and right popliteal stent graft. Four months later, he presented with hemoptysis due to compression of the lung secondary to the pseudoaneurysm. He underwent right anterior thoracotomy and debridement of the pseudoaneurysm. Patient recovered from the procedure and discharged. CONCLUSION: Endovascular repair of mycotic pseudoaneurysm is an acceptable alternative for high-risk patients. Even when open approach became necessarily, endovascular stent graft decreased blood loss and morbidity. PMID- 29716478 TI - Bidirectional Transradial and Transfemoral Approach for Stent-Assisted Coil Embolization of Right Subclavian Artery Saccular Aneurysm. AB - Subclavian artery aneurysms are rare lesions that usually require treatment for complications. Bidirectional stent-assisted coil embolization is the most effective treatment of complex wide-necked aneurysms. The stents provide a rigid scaffold that allows coil deposition with reduced risk of coil herniation into the parent vessel lumen. Bidirectional transradial and transfemoral approaches contribute to stable procedure. We report a successful bidirectional stent assisted coil embolization of a saccular aneurysm of the subclavian artery as an alternative to stent graft implantation to diminish the risk of right vertebral artery occlusion. PMID- 29716479 TI - Iatrogenic Iliofemoral Vein Dissection: A Rare Complication of Femoral Artery Puncture. AB - Iatrogenic iliac vein dissection secondary to femoral artery puncture is a rare complication that has not yet been documented. A 55-year-old woman presented to our institution with acute right iliofemoral thrombosis 2 weeks after transfemoral cerebral angiography. She was previously healthy and was not taking any medication. Right iliofemoral vein dissection was diagnosed by computed tomography angiography and confirmed by conventional venography. The patient was treated endovascularly with stent insertion, and the venous outflow was patent on the 6-month follow-up computed tomography angiogram. PMID- 29716480 TI - Spontaneous Isolated Inferior Mesenteric Artery Dissection With Chronic Mesenteric Ischemia: Case Report and Endovascular Management. AB - We report the clinical details, imaging findings, and management for a 39-year old female presenting with recurrent episodes of pain in abdomen due to systemic lupus erythematous vasculitis associated with spontaneous isolated inferior mesenteric dissection. Spontaneous mesenteric artery dissection is an uncommon cause of mesenteric ischemia. Symptomatic spontaneous isolated inferior mesenteric artery (IMA) dissection is a rare condition, and its association with systemic lupus erythematosus is not previously described in the English literature. The optimal treatment options are debatable and include medical management, surgical reconstruction, and endovascular therapy. We wish to highlight spontaneous isolated IMA dissection as a rare etiology for chronic mesenteric ischemia and its management by endovascular methods. PMID- 29716482 TI - The early history of cardiac massage. PMID- 29716483 TI - Thinking beyond routine daily pathology testing in the intensive care unit. PMID- 29716484 TI - Effect on neonatal outcome of pharmacological interventions for attenuation of the maternal haemodynamic response to tracheal intubation: a systematic review. AB - The primary aim of this systematic review was to assess the effect on neonatal outcome of pharmacological interventions used for attenuation of the haemodynamic response to tracheal intubation in patients undergoing caesarean section under general anaesthesia. A systematic search of randomised controlled trials from 1990 to 2015 was conducted. The primary outcome measure was the Apgar score at five minutes and secondary outcomes were umbilical arterial blood gas parameters and neurological adaptive capacity scores. Twenty-seven randomised controlled trials (1,689 patients) were included in the qualitative synthesis. Only five studies using opioids (383 patients) and five studies using non-opioid analgesics (358 patients) were subjected to meta-analysis. The Apgar score at five minutes was significantly lower in neonates of opioid-treated mothers (mean difference: 0.29, 95% confidence interval -0.56 to -0.02, P-value=0.03) compared to mothers in the control group; the umbilical arterial pH was lower and there was a higher requirement for tactile stimulation in neonates. No difference was seen in Apgar scores of neonates of mothers administered non-opioid analgesics compared to placebo. No difference was observed in other parameters between opioid- or non opioid-treated mothers. This review suggests that opioid interventions for attenuation of the haemodynamic response to tracheal intubation in pregnant patients under general anaesthesia affect neonatal Apgar scores at five minutes in neonates but the difference did not appear to be clinically meaningful. We were unable to demonstrate any difference in safety. PMID- 29716485 TI - The effects of haemodilution with succinylated gelatin solution on coagulation in vitro as assessed by thromboelastometry and impedance (multiple electrode) aggregometry. AB - We investigated the in vitro viscoelastic changes of progressive haemodilution with succinylated gelatin (SG) solution compared with normal saline (NS) using rotational thromboelastometry (ROTEM(r)). Whole blood (WB) samples obtained from 20 healthy volunteers were diluted in vitro with SG solution or NS by 10%, 20% and 40%. Fibrinogen concentration and ROTEM (EXTEM, FIBTEM) variables including coagulation time (CT), clot formation time (CFT), alpha-angle, and maximum clot firmness (MCF) were measured in the undiluted sample and at each degree of haemodilution. Haemodilution with SG decreased FIBTEM MCF by 34.8% at 20% dilution (SG 20% haemodilution mean 9.1 [standard deviation, SD 2.7] mm versus WB, mean 13.9 [SD 3.4] mm) whereas this was observed only at 40% haemodilution with NS (mean 8.5 [SD 2.7] mm, 38.7% decrease). We found that 40% haemodilution with SG slowed clot formation (EXTEM CFT; SG 40%, mean 179 [SD 39] seconds versus WB mean 87.9 [SD 13.7] seconds; increased CFT by 103%), reduced clot strength by 23.5% (EXTEM MCF; SG 40% mean 47.7 [SD 3.4] mm versus WB mean 62.4 [SD 2.5] mm), and decreased fibrin formation (FIBTEM MCF; SG 40% mean 5.8 [SD 1.6] mm versus WB mean 13.9 [SD 3.4] mm); 58.4% decrease). The platelet contribution to clot strength (EXTEM MCF-FIBTEM MCF) was not changed by SG. We found that haemodilution of more than 20% with SG impaired coagulation greater than that observed with NS haemodilution in this in vitro study. This suggests that at 40% haemodilution with SG, a clinical scenario that could occur during resuscitation of a patient in grade IV haemorrhagic shock, impaired coagulation could occur. Frequent monitoring of coagulation is advised when SG solutions are administered rapidly during volume resuscitation. PMID- 29716486 TI - Validation of a revised Mandarin Chinese language version of the Postoperative Quality of Recovery Scale. AB - The aim of the study was to validate a revised Mandarin version of the Postoperative Quality of Recovery Scale (PostopQRS) and to apply the revised version in a Chinese population. In a prospective design, bilingual volunteers completed the scale at baseline, day one, day seven, and day 14 in both languages, with the order of language and parallel forms randomised. In addition, lung cancer patients undergoing open or video-assisted thoracoscopic surgery (VATS) completed the Mandarin version prior to surgery, day one, day three, day seven, day 14, one month, and three months postoperatively. Sixty-eight volunteers participated in the validation part of the study and in the clinical application, 93 lung cancer patients were included. The scores in the Mandarin version were equal to the English version in all domains at all timepoints including the word generation task, when the Mandarin morpheme was included in any part of the Mandarin word. However, Mandarin scores were lower in the word generation task if the morpheme was only included in the first part of the word. In addition, the Mandarin version was able to identify lower rates of overall recovery (P <0.01), nociceptive (P <0.01), emotive (P <0.01), and activities of daily living recovery (P=0.02) after open surgery compared to after VATS. The revised Mandarin version is equivalent to the English version for the cognitive domain, if morpheme substitution for the word generation task is allowed as any part of the word, and it is able to discriminate quality of recovery in Chinese patients. PMID- 29716487 TI - Non-invasive estimation of cardiac index in healthy volunteers. AB - The primary objective was to non-invasively measure the cardiac index (CI) and associated haemodynamic parameters of healthy volunteers and their changes with age. This was a single centre, prospective, observational study of healthy volunteers aged between 20 and 59 years, using the ClearSightTM (Edwards Life Sciences, Irvine, CA, USA) device. We recorded 514 observations in 97 participants. The mean CI was 3.5 l/min/m2 (95% confidence interval [95% CI] 3.4 to 3.7 l/min/m2). The mean stroke volume index (SVI) was 47 ml/m2 (95% CI 45 to 49 ml/m2) and the mean systemic vascular resistance index was 2,242 dyne.s/cm5/m2 (95% CI 2,124 to 2,365 dyne.s/cm5/m2). There was an inverse linear relationship between increasing age and CI (P <0.0001), which decreased by 0.044 l/min/m2 (95% CI -0.032 to -0.056 l/min/m2) per year. This change was mostly due to a decrease in SVI of 0.45 ml/m2 (95% CI 0.32 to 0.57 ml/m2) per year (P <0.0001). The mean CI of young healthy humans is approximately 3.5 l/min/m2 and declines by approximately 40 ml/min/m2 per year, mostly due to a decline in stroke volume (SV). These findings have significant implications regarding the clinical interpretation of haemodynamic parameters and the application of these results to individual patients. PMID- 29716488 TI - A two centre observational study of simultaneous pulse oximetry and arterial oxygen saturation recordings in intensive care unit patients. AB - The influence of variables that might affect the accuracy of pulse oximetry (SpO2) recordings in critically ill patients is not well established. We sought to describe the relationship between paired SpO2/SaO2 (oxygen saturation via arterial blood gas analysis) in adult intensive care unit (ICU) patients and to describe the diagnostic performance of SpO2 in detecting low SaO2 and PaO2. A paired SpO2/SaO2 measurement was obtained from 404 adults in ICU. Measurements were used to calculate bias, precision, and limits of agreement. Associations between bias and variables including vasopressor and inotrope use, capillary refill time, hand temperature, pulse pressure, body temperature, oximeter model, and skin colour were estimated. There was no overall statistically significant bias in paired SpO2/SaO2 measurements; observed limits of agreement were +/-4.4%. However, body temperature, oximeter model, and skin colour, were statistically significantly associated with the degree of bias. SpO2 <89% had a sensitivity of 3/7 (42.9%; 95% confidence intervals, CI, 9.9% to 81.6%) and a specificity of 344/384 (89.6%; 95% CI 86.1% to 92.5%) for detecting SaO2 <89%. The absence of statistically significant bias in paired SpO2/SaO2 in adult ICU patients provides support for the use of pulse oximetry to titrate oxygen therapy. However, SpO2 recordings alone should be used cautiously when SaO2 recordings of 4.4% higher or lower than the observed SpO2 would be of concern. A range of variables relevant to the critically ill had little or no effect on bias. PMID- 29716489 TI - Governance of rapid response teams in Australia and New Zealand. AB - Rapid response systems (RRS) in hospitals in Australia and New Zealand (ANZ) have been present for more than 20 years but governance of the efferent limb-the rapid response team (RRT)-has not been previously reported in detail. The objectives of this study were to describe current governance arrangements for RRTs within ANZ and contrast those against expected implementation, using the Australian Commission for Safety and Quality in Health Care National Standard 9 (S9) as a benchmark. Assessment focused on S9 subclauses 9.1.1 (governance and oversight), 9.1.2 (RRT implementation), 9.2.3 (data collection and dissemination), 9.2.4 (quality improvement), 9.5.2 (call reviews), 9.6.1 and 9.6.2 (basic and advanced life support [ALS] skill set). We identified public and private hospitals across ANZ from government-maintained registers. Those reasonably expected to have an RRT were contacted and invited to participate. Responses were obtained via an online anonymised questionnaire. Three hundred and forty-two hospitals were contacted, of whom 284 (83.0%) responded. Two hundred and thirty-two hospitals submitted data, and the other 52 declined to participate or did not have an RRT. In hospitals with an intensive care unit (ICU), intensivist attendance at RRT calls occurred less often outside office hours (odds ratio, OR, 0.49, 95% confidence interval, CI, 0.32 to 0.75]). Where intensivists were not on the RRT, consultation with them about calls also occurred less often outside office hours (OR 0.39, 95% CI 0.22 to 0.66). Consultation with patients' admitting specialists occurred more often during office hours versus out of hours RRT calls and in private versus public hospitals. The presence of ICU staff on the RRT decreased the likelihood of admitting specialists being consulted about RRT calls (OR 0.66, 95% CI 0.47 to 0.93). Most hospitals maintained databases of RRT calls and regularly audited RRT activity (92% and 90% respectively). However, most (63.7%) did not make that information available beyond their hospital or local network. We concluded that the majority of hospitals in the ANZ region had governance mechanisms for their RRT. However, there was a notable lack of consistency, especially around specialist involvement and audit processes. Although some findings from this study are reassuring, there is still potential for improvement. Further development of guidelines and the establishment of a regional RRS database may assist with achieving this. PMID- 29716490 TI - Strategies to reduce inappropriate laboratory blood test orders in intensive care are effective and safe: a before-and-after quality improvement study. AB - Unnecessary pathology tests performed in intensive care units (ICU) might lead to increased costs of care and potential patient harm due to unnecessary phlebotomy. We hypothesised that a multimodal intervention program could result in a safe and effective reduction in the pathology tests ordered in our ICU. We conducted a single-centre pre- and post-study using multimodal interventions to address commonly ordered routine tests. The study was performed during the same six month period (August to February) over three years: 2012 to 2013 (pre-intervention), 2013 to 2014 (intervention) and 2014 to 2015 (post-intervention). Interventions consisted of staff education, designing new pathology forms, consultant-led pathology test ordering and intensive monitoring for a six-month period. The results of the study showed that there was a net savings of over A$213,000 in the intervention period and A$175,000 in the post-intervention period compared to the pre-intervention period. There was a 28% reduction in the tests performed in the intervention period (P <0.0001 compared to pre-intervention period) and 26% in the post-intervention period (P <0.0001 compared to pre intervention period). There were no ICU or hospital mortality differences between the groups. There were no significant haemoglobin differences between the groups. A multimodal intervention safely reduced pathology test ordering in the ICU, resulting in substantial cost savings. PMID- 29716491 TI - Clinical practice variation in acute severe burn injury. AB - The New South Wales (NSW) Statewide Burn Injury Service Database was reviewed to identify variations in clinical practice with respect to care of severely burn injured patients in intensive care. We compared differences in practice relating to duration of endotracheal intubation and surgical grafting. In this retrospective observational study, we reviewed all intensive care unit (ICU) admissions to the two NSW adult burns centres, ICU A and ICU B, between January 2008 and December 2015. Data were analysed for association between duration of intubation and outcome. There were 855 admissions to adult ICU, with a significant difference in the percentage total body surface area (% TBSA) of burn and inhalation injury between patients in the two units. There was a significant difference in duration of intubation and ICU length of stay (LOS) between the units, which persisted when adjusted for age, % TBSA and inhalational injury. When analysing patients with more severe burns (>20% TBSA or intubated), the difference in duration of intubation remained significant (median of three days [interquartile range, IQR, 1-11 days] in A and 2 days [IQR 1-6 days] in B, P=0.003) as did ICU LOS (median 3 days [IQR 2-11 days] for A and 2 days [IQR 1-6 days] for B, P <0.0005). There was no significant difference in mortality between the two units for the severe or the more severe subgroup of burns when adjusted for age, % TBSA and inhalational injury (adjusted odds ratio, OR, for mortality 1.17 [95% confidence intervals 0.6 to 2.3, P=0.65]). There were significant differences in clinical practice, including duration of intubation, between the two ICUs. Longer intubation was associated with a longer ICU LOS, but was not associated with a difference in mortality. Large collaborative, prospective multicentre studies in severe burns are needed to identify best practice and variations in practice to determine if they are associated with increased mortality and/or cost. PMID- 29716492 TI - Extended duration regional analgesia for total knee arthroplasty: a randomised controlled trial comparing five days to three days of continuous adductor canal ropivacaine infusion. AB - There is a growing body of evidence in favour of continuous adductor canal block (CACB) for total knee arthroplasty. However, there are no studies describing the optimal duration of the infusion. At our institution the usual practice was to stop the infusion on day three. Our hypothesis was that extending the infusion to five days would improve analgesia and quality of recovery. A prospective, non blinded, randomised trial was undertaken. Patients received a continuous infusion of 0.2% ropivacaine via an adductor canal catheter for either three or five days. Primary outcome was pain while walking during the 24-hour period up to day five (numeric rating scale from 0 to 10). The minimum clinically important difference was set at 1.5 on the numeric rating scale. Secondary outcome measures included quality of recovery, mobility, pain while walking on postoperative day six, Oxford Knee Scores, and complications. Eighty-six patients were recruited with 43 randomised to each group. Seventy-eight were analysed. Median pain scores reported on day five were significantly better in the intervention group (1 versus 3, P=0.003). Furthermore, quality of recovery (QOR-15) scores were significantly better in the intervention group (133.6 versus 123.4, P=0.017). No statistically significant difference between groups was identified for other secondary outcome measures. CACB prolonged to five days provides superior analgesia and a higher quality of recovery on postoperative days four and five compared to a three-day infusion. This benefit did not extend beyond the period of infusion. PMID- 29716493 TI - An international survey evaluating factors influencing the use of total intravenous anaesthesia. AB - The purpose of this study was to evaluate factors influencing the use of propofol based total intravenous anaesthesia (TIVA)since despite TIVA being a well established technique, it is used far less frequently than volatile anaesthesia. Questions were formulated after reviewing the literature for perceived disadvantages of TIVA and meeting with a focus group consisting of both senior and junior anaesthestists from our department. Once the survey had been formulated, specialist anaesthetists from professional colleges and societies from several countries were invited to complete the survey on an electronic web based platform to allow evaluation of the respondent's rating of the importance of a range of factors in their decision not to use TIVA for a particular case. Basic descriptive statistics were determined using SPSS statistical software, while graphical depictions of data were handled using R for statistical analysis. A total of 763 survey responses were included in the final analysis and stratified according to the frequency of TIVA use. Among the infrequent users, issues such as additional effort, institutional preference, lack of real-time monitoring of propofol concentration, risk of missing drug delivery failure and increased turnaround time were among the top reasons mentioned. Interestingly, these issues were considered far less important among the frequent users when not choosing TIVA. We concluded that frequent and infrequent users respond quite differently to similar technical TIVA-related factors. Non-technical factors may play an important role in the infrequent user's decision not to use TIVA for a particular case. PMID- 29716494 TI - Is there more to the story of burnout in anaesthesiology trainees? PMID- 29716495 TI - In reply to Castro-Alves and Kendall. PMID- 29716496 TI - Burnout in anaesthesia trainees. PMID- 29716497 TI - Addressing burnout in anaesthetic trainees. PMID- 29716498 TI - Addressing burnout in anaesthesia trainees-reply. PMID- 29716499 TI - The use of a frailty index to predict adverse postoperative outcomes of older surgical patients. PMID- 29716500 TI - In reply to Liu. PMID- 29716501 TI - Medical Emergency Team calls within 24 hours of surgery and strategy for reduction. PMID- 29716502 TI - Discrepancy between factors associated with long-term outcome in very old patients referred to the intensive care unit, and prevalence of treatment limitations. PMID- 29716503 TI - Transversus abdominis plane catheters versus rectus sheath catheters-it's all in the placement. PMID- 29716504 TI - Combined use of C-MAC(r) videolaryngoscope and nasal videobronchoscope for critical airway rescue and intubation. PMID- 29716505 TI - Cord clamping in term and pre-term infants: how should clinicians proceed? PMID- 29716506 TI - Parechovirus: an important emerging infection in young infants. AB - Epidemics of human parechovirus (HPeV) causing disease in young children have occurred every 2 years in Australia since 2013. HPeV genotype 3 caused the epidemic from late 2017 to early 2018. Most HPeV infections cause no or mild symptoms including gastroenteritis or influenza-like illness. Characteristically, young infants present with fever, irritability and on occasions a diffuse rash ("red, hot and angry" babies). Severe disease can manifest as meningoencephalitis, seizures or sepsis-like presentations (including septic shock), or less common presentations including signs of surgical abdomen. Testing for HPeV by specific molecular tests is indicated in children younger than 6 months of age with characteristic presentations without another confirmed diagnosis including febrile illnesses with other suggestive features (eg, rash, seizures), sepsis syndromes (including shock), and suspected meningoencephalitis (which may be detected by magnetic resonance imaging only). There are no effective antiviral therapies. Treatment is primarily supportive, including management of complications. Some infants with severe HPeV infection may have adverse neurodevelopment. Follow-up by a paediatrician is recommended. PMID- 29716508 TI - Understanding statistical principles in linear and logistic regression. PMID- 29716509 TI - Children as haematopoietic stem cell donors: ethically challenging and legally complex. PMID- 29716510 TI - An authoritative reference for trainees and experienced paediatric nephrologists. PMID- 29716511 TI - Why are so many more adolescents presenting to our emergency departments with mental health problems? PMID- 29716512 TI - The rate of anterior cruciate ligament reconstruction in Australia is high: a national registry is needed. PMID- 29716513 TI - Developmental dysplasia of the hip: addressing evidence gaps with a multicentre prospective international study. AB - There is a lack of high quality evidence available to guide clinical practice in the treatment and management of developmental dysplasia of the hip (DDH). Evidence has been limited by persistent confusion on diagnostic and classification terminology, variability in surgeon decision making and a reliance on single centre, retrospective studies with small patient numbers. To address gaps in knowledge regarding screening, diagnosis and management of DDH, the International Hip Dysplasia Institute began a multicentre, international prospective study on infants with hips dislocated at rest. This review discusses the current state of screening, diagnostic and management practices in DDH and addresses important unanswered questions that will be critical in identifying best practices and optimising patient outcomes. There is insufficient evidence to support universal ultrasound screening; instead, selective screening should be performed by 6-8 weeks of age on infants with risk factors of breech presentation, family history, or history of clinical hip instability. Follow-up of infants with risk factors and normal initial screening should be considered to at least 6 months of age. Brace treatment is a sensible first-line treatment for management of dislocated hips at rest in infants < 6 months of age. Early operative reduction may be considered as there is insufficient evidence to support a protective role for the ossific nucleus in the development of avascular necrosis. PMID- 29716514 TI - Giving older people the opportunity to optimise their quality of life. PMID- 29716515 TI - Eye injury from toxic chemical mistaken for eye drops. PMID- 29716516 TI - A sporting life. PMID- 29716518 TI - Treemmer: a tool to reduce large phylogenetic datasets with minimal loss of diversity. AB - BACKGROUND: Large sequence datasets are difficult to visualize and handle. Additionally, they often do not represent a random subset of the natural diversity, but the result of uncoordinated and convenience sampling. Consequently, they can suffer from redundancy and sampling biases. RESULTS: Here we present Treemmer, a simple tool to evaluate the redundancy of phylogenetic trees and reduce their complexity by eliminating leaves that contribute the least to the tree diversity. CONCLUSIONS: Treemmer can reduce the size of datasets with different phylogenetic structures and levels of redundancy while maintaining a sub-sample that is representative of the original diversity. Additionally, it is possible to fine-tune the behavior of Treemmer including any kind of meta information, making Treemmer particularly useful for empirical studies. PMID- 29716519 TI - Association between anthropometric measures and cardiovascular disease (CVD) risk factors in Hainan centenarians: investigation based on the Centenarian's health study. AB - BACKGROUND: Centenarians refer to a special group who have outlived most of their fellows. Body shape and abdominal obesity have been identified as cardiovascular disease (CVD) risk factors. Our study aimed to evaluate the relationship between body mass index (BMI), waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) and CVD risk factors among male and female centenarians in Hainan province. METHODS: Five hundred thirty-seven centenarians aged between 100 and 115 (Mage = 107 years old) years participated in this study. Each participant received a standardized questionnaire and physical examination. We measured anthropometric variables (BMI, WC, WHR, WHtR, SBP and DBP) and serum lipid (TC, TG, HDL-C and LDL-C). RESULTS: 76.9% (n = 413) of the study subjects were female. TC, TG, LDL-C and HDL-C were significantly higher in female group than that of male group. BMI, WC and WHtR were well-correlated with the CVD risk factors. The anthropometric measures were negatively related with HDL-C levels and positively related with the other CVD risk factors. CONCLUSIONS: Hainan centenarians were short in stature and underweight. Moreover, female centenarians were often pear-shaped, while male centenarians were often apple-shaped. Further, BMI, WC and WHtR were well-correlated with the serum lipid, and TC, TG, LDL-C and HDL-C were significantly higher in females than males. Also, BMI, WC and WHtR were closely related to the incidence of dyslipidemia in females, including high TG, high LDL-C and low HDL-C. PMID- 29716520 TI - Bidirectional promoters exhibit characteristic chromatin modification signature associated with transcription elongation in both sense and antisense directions. AB - BACKGROUND: In contrast to unidirectional promoters wherein antisense transcription results in short transcripts which are rapidly degraded, bidirectional promoters produce mature transcripts in both sense and antisense orientation. To understand the molecular mechanism of how productive bidirectional transcription is regulated, we focused on delineating the chromatin signature of bidirectional promoters. RESULTS: We report generation and utility of a reporter system that enables simultaneous scoring of transcriptional activity in opposite directions. Testing of putative bidirectional promoters in this system demonstrates no measurable bias towards any one direction of transcription. We analyzed the NUP26L-PIH1D3 bidirectional gene pair during Retinoic acid mediated differentiation of embryonic carcinoma cells. In their native context, we observed that the chromatin landscape at and around the transcription regulatory region between the pair of bidirectional genes is modulated in concordance with transcriptional activity of each gene in the pair. We then extended this analysis to 974 bidirectional gene pairs in two different cell lines, H1 human embryonic stem cells and CD4 positive T cells using publicly available ChIP-Seq and RNA-Seq data. Bidirectional gene pairs were classified based on the intergenic distance separating the two TSS of the transcripts analyzed as well as the relative expression of each transcript in a bidirectional gene pair. We report that for the entire range of intergenic distance separating bidirectional genes, the expression profile of such genes (symmetric or asymmetric) matches the histone modification profile of marks associated with active transcription initiation and elongation. CONCLUSIONS: We demonstrate unique distribution of histone modification marks that correlate robustly with the transcription status of genes regulated by bidirectional promoters. These findings strongly imply that occurrence of these marks might signal the transcription machinery to drive maturation of antisense transcription from the bidirectional promoters. PMID- 29716521 TI - A phylogenetic analysis of the Primnoidae (Anthozoa: Octocorallia: Calcaxonia) with analyses of character evolution and a key to the genera and subgenera. AB - BACKGROUND: Previous phylogenetic analyses of primnoid octocorals utilizing morphological or molecular data have each recovered evolutionary relationships among genera that are largely incongruent with each other, with some exceptions. In an effort to reconcile molecular-based phylogenies with morphological characters, phylogenetic reconstructions were performed with 33 of 43 primnoid genera using four loci (mtMutS, COI, 28S and 18S), and ancestral state reconstructions were performed using 9 taxonomically relevant characters. In addition, an updated illustrated key to the current 48 genus-level (43 genera, 5 subgenera) primnoids is presented. RESULTS: Ancestral state reconstruction recovered the ancestral colony shape of primnoids as dichotomous planar. Convergence was detected among all 9 characters, and reversals to the character state of the common ancestor occurred in 4 characters. However, some characters were found to be informative. For example, the weak ascus scale of Metafannyella is not likely homologous to the ascus scales of Onogorgia and Fannyella, and the monophyly of two subgenera within Thouarella, which contain polyps in either whorls or an isolated arrangement, was supported. Phylogenetic analyses were generally consistent with previous studies, and resulted in the synonymy of one genus and a subgenus, the elevation of two subgenera, and the transfer of two species back to an original genus. For example, body wall ornamentation of Fanellia was re-evaluated, indicating a synonymy with Callogorgia; the utility of polyp arrangement for the subgenus Plumarella (Dicholaphis) was not supported, and is synonymized with the nominate subgenus Plumarella (Plumarella); the subgenera Plumarella (Faxiella) and Plumarella (Verticillata) are raised to generic status; and the two Plumarella species (P. diadema and P. undulata) are transferred back to Thouarella based on the homology of their marginal scales. CONCLUSIONS: Altogether, and similar to other octocorallian groups, these results indicate that many of the morphological characters examined among primnoids, particularly colony morphology, are labile and exhibit complex evolutionary histories. However, some morphological characters such as coordination of polyps, presence of the ascus body wall scale, number of rows of body wall scales, and number of marginal scales help identify many clades, and are suitable for robust systematic assessments among primnoids. PMID- 29716522 TI - The cytidine deaminase under-representation reporter (CDUR) as a tool to study evolution of sequences under deaminase mutational pressure. AB - BACKGROUND: Activation induced deaminase (AID) and apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like 3 (APOBEC3) are deaminases that mutate C to U on single-stranded DNA (ssDNA). AID is expressed primarily in germinal center B cells, where it facilitates affinity maturation and class-switch recombination. APOBEC3 are a family of anti-viral proteins that act as part of the intrinsic immune response. In both cases, there are particular sequence motifs, also known as "mutation motifs", to which these deaminases prefer to bind and mutate. RESULTS: We present a program, the cytidine deaminase under-representation reporter (CDUR) designed to statistically determine whether a given sequence has an under/over-representation of these mutation motifs. CDUR shows consitency with other studies of mutation motifs, as we show by analyzing sequences from the adeno-associated virus 2 (AAV2) and human papillomavirus (HPV). CONCLUSION: Using various shuffling mechanisms to generate different null model distributions, we can tailor CDUR to correct for metrics such as GC-content, dinucleotide frequency, and codon bias. PMID- 29716523 TI - Mice lacking galectin-3 (Lgals3) function have decreased home cage movement. AB - BACKGROUND: Galectins are a large family of proteins evolved to recognize specific carbohydrate moieties. Given the importance of pattern recognition processes for multiple biological tasks, including CNS development and immune recognition, we examined the home cage behavioral phenotype of mice lacking galectin-3 (Lgals3) function. Using a sophisticated monitoring apparatus capable of examining feeding, drinking, and movement at millisecond temporal and 0.5 cm spatial resolutions, we observed daily behavioral patterns from 10 wildtype male C57BL/6J and 10 Lgals3 constitutive knockout (Lgals3-/-; both cohorts aged 2-3 months) mice over 17 consecutive days. We performed a second behavioral assessment of this cohort at age 6-7 months. RESULTS: At both ages, Lgals3-/- mice demonstrated less movement compared to wildtype controls. Both forward locomotion and movement-in-place behaviors were decreased in Lgals3-/- mice, due to decreased bout numbers, initiation rates, and durations. We additionally noted perturbation of behavioral circadian rhythms in Lgals3-/- mice, with mice at both ages demonstrating greater variability in day-to-day performance of feeding, drinking, and movement (as assessed by Lomb-Scargle analysis) compared to wildtype. CONCLUSION: Carbohydrate recognition tasks performed by Lgals3 may be required for appropriate development of CNS structures involved in the generation and control of locomotor behavior. PMID- 29716524 TI - Cochlear morphology in the developing inner ear of the porcine model of spontaneous deafness. AB - BACKGROUND: Auditory function and cochlear morphology have previously been described in a porcine model with spontaneous WS2-like phenotype. In the present study, cochlear histopathology was further investigated in the inner ear of the developing spontaneous deafness pig. RESULTS: We found that the stria vascularis transformed into a complex tri-laminar tissue at embryonic 85 days (E85) in normal pigs, but not in the MITF-/- pigs. As the neural crest (NC) of cochlea was derived by melanocytes. MITF mutation caused failure of development of melanocytes which caused a subsequent collapse of cochlear duct and deficits of the epithelium after E100. Furthermore, the spiral ganglion neurons of cochlea in the MITF-/- pigs began to degenerate at postnatal 30 days (P30). Thus, our histopathological results indicated that the malformation of the stria vascularis was a primary defect in MITF-/- induced WT pigs which was resulted from the loss of NC-derived melanocytes. Subsequently, the cochleae underwent secondary degeneration of the vestibular organs. As the degeneration of spiral ganglion neurons happened after P30, it suggests that WS patients should be considered as candidates for cochlear implant. CONCLUSIONS: Our porcine model of MITF-M mutation may provide a crucial animal model for cochlear implant, cell therapy in patients with congenital hereditary hearing loss. PMID- 29716525 TI - Prognostic value of an automated bone scan index for men with metastatic castration-resistant prostate cancer treated with cabazitaxel. AB - BACKGROUND: A computer-assisted diagnostic system for analyzing bone scans (BONENAVI) calculates the automated bone scan index (aBSI). Here we evaluated the aBSI as a prognostic imaging biomarker for men with metastatic castration resistant prostate cancer (mCRPC) treated with cabazitaxel. METHODS: We retrospectively analyzed 48 patients who received cabazitaxel for mCRPC and evaluated the ability of the aBSI to predict overall survival (OS). The Cox proportional hazards model was used to investigate the associations between baseline aBSI at cabazitaxel treatment and OS with the clinical variables as follows: age, number of cycles of docetaxel, serum prostate-specific antigen, hemoglobin (Hb), lactate dehydrogenase (LDH), and alkaline phosphatase. We determined the C-index to evaluate the discriminatory ability of our models when we included or excluded the aBSI from the analyses. RESULTS: The median OS after cabazitaxel treatment was 10.0 months, and patients with aBSI <=1% achieved significantly longer OS compared with patients with aBSI >=1%. Multivariate analysis showed that age, Hb, LDH, and aBSI were independent prognostic factors of OS. Adding aBSI to the base model increased the C-index from 0.78 to 0.80. CONCLUSIONS: The aBSI may serve as a useful imaging biomarker for predicting OS among men with mCRPC treated with cabazitaxel. Prospective studies are required to establish the value of aBSI as prognostic imaging biomarker. PMID- 29716526 TI - NKX2.5 is expressed in papillary thyroid carcinomas and regulates differentiation in thyroid cells. AB - BACKGROUND: NKX2.5 is a transcription factor transiently expressed during thyroid organogenesis. Recently, several works have pointed out the oncogenic role of NKX2.5 in a variety of tumors. We therefore hypothesized that NKX2.5 could also play a role in thyroid cancer. METHODS: The validation of NKX2.5 expression was assessed by immunohistochemistry analysis in a Brazilian case series of 10 papillary thyroid carcinoma (PTC) patients. Then, the long-term prognostic value of NKX2.5 and its correlation with clinicopathologic features of 51 PTC patients was evaluated in a cohort with 10-years follow-up (1990-1999). Besides, the effect of NKX2.5 overexpression on thyroid differentiation markers and function was also investigated in a non-tumor thyroid cell line (PCCL3). RESULTS: NKX2.5 was shown to be expressed in most PTC samples (8/10, case series; 27/51, cohort). Patients who had tumors expressing NKX2.5 showed lower rates of persistence/recurrence (p = 0.013). Overexpression of NKX2.5 in PCCL3 cells led to: 1) downregulation of thyroid differentiation markers (thyrotropin receptor, thyroperoxidase and sodium-iodide symporter); 2) reduced iodide uptake; 3) increased extracellular H2O2 generation, dual oxidase 1 mRNA levels and activity of DuOx1 promoter. CONCLUSIONS: In summary, NKX2.5 is expressed in most PTC samples analyzed and its presence correlates to better prognosis of PTC. In vitro, NKX2.5 overexpression reduces the expression of thyroid differentiation markers and increases ROS production. Thus, our data suggests that NKX2.5 could play a role in thyroid carcinogenesis. PMID- 29716527 TI - Differentiation of orbital lymphoma and idiopathic orbital inflammatory pseudotumor: combined diagnostic value of conventional MRI and histogram analysis of ADC maps. AB - BACKGROUND: The overlap of morphological feature and mean ADC value restricted clinical application of MRI in the differential diagnosis of orbital lymphoma and idiopathic orbital inflammatory pseudotumor (IOIP). In this paper, we aimed to retrospectively evaluate the combined diagnostic value of conventional magnetic resonance imaging (MRI) and whole-tumor histogram analysis of apparent diffusion coefficient (ADC) maps in the differentiation of the two lesions. METHODS: In total, 18 patients with orbital lymphoma and 22 patients with IOIP were included, who underwent both conventional MRI and diffusion weighted imaging before treatment. Conventional MRI features and histogram parameters derived from ADC maps, including mean ADC (ADCmean), median ADC (ADCmedian), skewness, kurtosis, 10th, 25th, 75th and 90th percentiles of ADC (ADC10, ADC25, ADC75, ADC90) were evaluated and compared between orbital lymphoma and IOIP. Multivariate logistic regression analysis was used to identify the most valuable variables for discriminating. Differential model was built upon the selected variables and receiver operating characteristic (ROC) analysis was also performed to determine the differential ability of the model. RESULTS: Multivariate logistic regression showed ADC10 (P = 0.023) and involvement of orbit preseptal space (P = 0.029) were the most promising indexes in the discrimination of orbital lymphoma and IOIP. The logistic model defined by ADC10 and involvement of orbit preseptal space was built, which achieved an AUC of 0.939, with sensitivity of 77.30% and specificity of 94.40%. CONCLUSIONS: Conventional MRI feature of involvement of orbit preseptal space and ADC histogram parameter of ADC10 are valuable in differential diagnosis of orbital lymphoma and IOIP. PMID- 29716528 TI - PEST-containing nuclear protein mediates the proliferation, migration, and invasion of human neuroblastoma cells through MAPK and PI3K/AKT/mTOR signaling pathways. AB - BACKGROUND: PEST-containing nuclear protein (PCNP), a novel nuclear protein, is involved in cell proliferation and tumorigenesis. However, the precise mechanism of action of PCNP in the process of tumor growth has not yet been fully elucidated. METHODS: ShRNA knockdown and overexpression of PCNP were performed in human neuroblastoma cells. Tumorigenic and metastatic effects of PCNP were examined by tumor growth, migration, and invasion assays in vitro, as well as xenograft tumor assay in vivo. RESULTS: PCNP over-expression decreased the proliferation, migration, and invasion of human neuroblastoma cells and down regulation of PCNP showed reverse effects. PCNP over-expression increased protein expressions of cleaved caspase-3, cleaved caspase-8, cleaved caspase-9, and cleaved poly adenosine diphosphate-ribose polymerase, as well as ratios of B-cell lymphoma-2 (Bcl-2)-associated X protein/Bcl-2 and Bcl-2-associated death promoter/B-cell lymphoma-extra large in human neuroblastoma cells, however PCNP knockdown exhibited reverse trends. PCNP over-expression increased phosphorylations of extracellular signal-regulated protein kinase 1/2, p38, c-Jun N-terminal kinase, as well as decreased phosphorylations of phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR), nevertheless PCNP knockdown exhibited opposite effects. Furthermore, PCNP over-expression significantly reduced the growth of human neuroblastoma xenograft tumors by down regulating angiogenesis, whereas PCNP knockdown markedly promoted the growth of human neuroblastoma xenograft tumors through up-regulation of angiogenesis. CONCLUSIONS: PCNP mediates the proliferation, migration, and invasion of human neuroblastoma cells through mitogen-activated protein kinase and PI3K/AKT/mTOR signaling pathways, implying that PCNP is a therapeutic target for patients with neuroblastoma. PMID- 29716529 TI - Severe localised granulomatosis with polyangiitis (Wegener's granulomatosis) manifesting with extensive cranial nerve palsies and cranial diabetes insipidus: a case report and literature review. AB - BACKGROUND: Granulomatosis with polyangiitis (GPA, formerly Wegener's granulomatosis) is a multisystem vasculitis of small- to medium-sized blood vessels. Cranial involvement can result in cranial nerve palsies and, rarely, pituitary infiltration. CASE PRESENTATION: We describe the case of a 32 year-old woman with limited but severe GPA manifesting as progressive cranial nerve palsies and pituitary dysfunction. Our patient initially presented with localised ENT involvement, but despite treatment with methotrexate, she deteriorated. Granulomatous inflammatory tissue around the skull base resulted in cavernous sinus syndrome, facial nerve palsy, palsies of cranial nerves IX-XII (Collet Sicard syndrome), and the rare complication of cranial diabetes insipidus due to pituitary infiltration. The glossopharyngeal, vagus and accessory nerve palsies resulted in severe dysphagia and she required nasogastric tube feeding. Her neurological deficits substantially improved with treatment including high dose corticosteroid, cyclophosphamide and rituximab. CONCLUSIONS: This case emphasises that serious morbidity can arise from localised cranial Wegener's granulomatosis in the absence of systemic disease. In such cases intensive induction immunosuppression is required. Analysis of previously reported cases of pituitary involvement in GPA reveals that this rare complication predominantly affects female patients. PMID- 29716530 TI - Body weight definitions for evaluating a urinary diagnosis of acute kidney injury in patients with sepsis. AB - BACKGROUND: We hypothesized that the use of actual body weight might lead to more frequent misdiagnosis of acute kidney injury (AKI) than when ideal body weight is used in underweight and/or obese patients. We examined which definition of body weight is most effective in establishing a urinary diagnosis of AKI in septic patients. METHODS: Consecutive patients aged >= 20 years admitted to the intensive care unit of a university hospital between June 2011 and December 2016 were analyzed. Sepsis was defined in accordance with the Sepsis-3 criteria. AKI was defined as a urinary output of < 0.5 mL/kg/6h during intensive care unit stay. Patients were divided into one of four body mass index-based classes. The severity of illness and 90-day mortality were compared across the body mass index subgroups in patients diagnosed using the actual body weight or ideal body weight. RESULTS: Of 5764 patients, 569 septic patients were analyzed. One hundred and fifty-three (26.9%) and 140 (24.6%) patients were diagnosed as having AKI using actual body weight and ideal body weight, respectively. There were no significant differences in the severity of illness among these groups. Also, 90 day mortality did not differ significantly among these groups. According to body mass index, 90-day mortality significantly differed in patients diagnosed using their actual body weights (underweight vs. normal vs. overweight vs. obese: 76.7% vs. 39.5% vs. 26.0% vs. 35.7%, P = 0.033). CONCLUSION: Generally, using actual body weight to calculate the weight-adjusted hourly urine output for diagnosing AKI increased the sensitivity compared to ideal body weight, irrespective of the severity of illness in septic patients. Delayed diagnosis, however, was more common among underweight patients in this situation, and clinicians should be cautious when diagnosing urinary AKI using actual body weight. PMID- 29716531 TI - Generation of a PAX6 knockout glioblastoma cell line with changes in cell cycle distribution and sensitivity to oxidative stress. AB - BACKGROUND: The transcription factor PAX6 is expressed in various cancers. In anaplastic astrocytic glioma, PAX6 expression is inversely related to tumor grade, resulting in low PAX6 expression in Glioblastoma, the highest-grade astrocytic glioma. The aim of the present study was to develop a PAX6 knock out cell line as a tool for molecular studies of the roles PAX6 have in attenuating glioblastoma tumor progression. METHODS: The CRISPR-Cas9 technique was used to knock out PAX6 in U251 N cells. Viral transduction of a doxycycline inducible EGFP-PAX6 expression vector was used to re-introduce (rescue) PAX6 expression in the PAX6 knock out cells. The knock out and rescued cells were rigorously characterized by analyzing morphology, proliferation, colony forming abilities and responses to oxidative stress and chemotherapeutic agents. RESULTS: The knock out cells had increased proliferation and colony forming abilities compared to wild type cells, consistent with clinical observations indicating that PAX6 functions as a tumor-suppressor. Cell cycle distribution and sensitivity to H2O2 induced oxidative stress were further studied, as well as the effect of different chemotherapeutic agents. For the PAX6 knock out cells, the percentage of cells in G2/M phase increased compared to PAX6 control cells, indicating that PAX6 keeps U251 N cells in the G1 phase of the cell cycle. Interestingly, PAX6 knock out cells were more resilient to H2O2 induced oxidative stress than wild type cells. Chemotherapy treatment is known to generate oxidative stress, hence the effect of several chemotherapeutic agents were tested. We discovered interesting differences in the sensitivity to chemotherapeutic drugs (Temozolomide, Withaferin A and Sulforaphane) between the PAX6 expressing and non-expressing cells. CONCLUSIONS: The U251 N PAX6 knock out cell lines generated can be used as a tool to study the molecular functions and mechanisms of PAX6 as a tumor suppressor with regard to tumor progression and treatment of glioblastoma. PMID- 29716532 TI - Limb saving surgery for Ewing's sarcoma of the distal tibia: a case report. AB - BACKGROUND: Ewing's sarcoma is a primary malignant tumor of bone occurring mostly in childhood. Few effective reconstruction techniques are available after wide resection of Ewing's sarcoma at the distal end of the tibia. Reconstruction after wide resection is especially difficult in children, as it is necessary to consider the growth and activity of the lower limbs. CASE PRESENTATION: A 12-year old Japanese boy had presented with right lower leg pain at age 8 years. Imaging examination showed a bone tumor accompanied by a large extra-skeletal mass in the distal part of his tibia. The tumor was histologically diagnosed as Ewing's sarcoma. The patient received chemotherapy, followed by wide resection. Reconstruction consisted of a bone transport method involving external fixation of Taylor Spatial Frame. To prevent infection after surgery, the external fixation pin was coated with iodine. One year after surgery, the patient showed poor consolidation of bone, so iliac bone transplantation was performed on the extended bones and docking site of the distal tibia. After 20 months, tibia formation was good. Three years after surgery, there was no evidence of tumor recurrence or metastases; bone fusion was good, and he was able to run. CONCLUSIONS: The bone transport method is an effective surgical method of reconstruction after wide resection of a bone tumor at the distal end of the tibia, if a pin can be inserted into the distal bone fragment. Coating external fixation pins with iodine may prevent postoperative infection. PMID- 29716533 TI - Genome-wide copy number variant analysis reveals variants associated with 10 diverse production traits in Holstein cattle. AB - BACKGROUND: Copy number variation (CNV) is an important type of genetic variation contributing to phenotypic differences among mammals and may serve as an alternative molecular marker to single nucleotide polymorphism (SNP) for genome wide association study (GWAS). Recently, GWAS analysis using CNV has been applied in livestock, although few studies have focused on Holstein cattle. RESULTS: We describe 191 CNV detected using intensity data from over 700,000 SNP genotypes generated with the BovineHD Genotyping BeadChip (Illumina, San Diego, CA) in 528 Holstein cows. The CNV were used for GWAS analysis of 10 important production traits of 473 cattle related to feed intake, milk quality, and female fertility, as well as 2 composite traits of net merit and productive life. In total, we detected 57 CNV associated (P < 0.05 after false discovery rate correction) with at least one of the 10 phenotypes. Focusing on feed efficiency and intake-related phenotypes of residual feed intake and dry matter intake, we detected a single CNV associated with both traits which overlaps a predicted olfactory receptor gene OR2A2 (LOC787786). Additionally, 2 CNV within the RXFP4 (relaxin/insulin like family peptide receptor 4) and 2 additional olfactory receptor gene regions, respectively, were associated with residual feed intake. The RXFP4 gene encodes a receptor for an orexigenic peptide, insulin-like peptide 5 produced by intestinal L cells, which is expressed by enteric neurons. Olfactory receptors are critical for transmitting the effects of odorants, contributing to the sense of smell, and have been implicated in participating in appetite regulation. CONCLUSIONS: Our results identify CNV for genomic evaluation in Holstein cattle, and provide candidate genes, such as RXFP4, contributing to variation in feed efficiency and feed intake-related traits. These results indicate potential novel targets for manipulating feed intake-related traits of livestock. PMID- 29716534 TI - Comparative genomics of cocci-shaped Sporosarcina strains with diverse spatial isolation. AB - BACKGROUND: Cocci-shaped Sporosarcina strains are currently one of the few known cocci-shaped spore-forming bacteria, yet we know very little about the genomics. The goal of this study is to utilize comparative genomics to investigate the diversity of cocci-shaped Sporosarcina strains that differ in their geographical isolation and show different nutritional requirements. RESULTS: For this study, we sequenced 28 genomes of cocci-shaped Sporosarcina strains isolated from 13 different locations around the world. We generated the first six complete genomes and methylomes utilizing PacBio sequencing, and an additional 22 draft genomes using Illumina sequencing. Genomic analysis revealed that cocci-shaped Sporosarcina strains contained an average genome of 3.3 Mb comprised of 3222 CDS, 54 tRNAs and 6 rRNAs, while only two strains contained plasmids. The cocci-shaped Sporosarcina genome on average contained 2.3 prophages and 15.6 IS elements, while methylome analysis supported the diversity of these strains as only one of 31 methylation motifs were shared under identical growth conditions. Analysis with a 90% identity cut-off revealed 221 core genes or ~ 7% of the genome, while a 30% identity cut-off generated a pan-genome of 8610 genes. The phylogenetic relationship of the cocci-shaped Sporosarcina strains based on either core genes, accessory genes or spore-related genes consistently resulted in the 29 strains being divided into eight clades. CONCLUSIONS: This study begins to unravel the phylogenetic relationship of cocci-shaped Sporosarcina strains, and the comparative genomics of these strains supports identification of several new species. PMID- 29716535 TI - Predictive value of neutrophil to lymphocyte ratio in patients with acute ST segment elevation myocardial infarction after percutaneous coronary intervention: a meta-analysis. AB - BACKGROUND: The neutrophil to lymphocyte ratio (NLR) is an indicator of systemic inflammation and a prognostic marker in patients with acute coronary syndrome (ACS). This study aims to investigate the value of NLR to predict the in-hospital and long-term prognosis in patients with ST segment elevation myocardial infarction (STEMI) after percutaneous coronary intervention (PCI) by meta analysis. METHOD: The studies related to the prognosis of NLR and STEMI patients published in the Pubmed, Embase, and Ovid databases before June 2017 were retrieved. The relevant data were extracted. Review Manager Version 5.3 was used for meta-analysis. RESULTS: A total of 14 studies of 10,245 patients with STEMI after PCI were included. A significant difference was observed for mortality (P < 0.001; relative risk (RR) 3.32; 95% confidence interval (CI) 2.45-4.49), hospital cardiac mortality(P < 0.001; RR 3.22; 95% CI 2.25-4.60), all mortality (P < 0.001; RR 3.23; 95% CI 2.28-4.57), major adverse cardiovascular events (MACE) (P < 0.001; RR 2.00; 95% CI 1.62-2.46), in-stent thrombosis (P < 0.001; RR 2.72 95% CI 1.66-4.44), nonfatal myocardial infarction(MI) (P < 0.001; RR 1.93; 95%CI 1.43 2.61), angina (P = 0.007; RR 1.67; 95%CI 1.15-2.41), advanced heart failure (AHF) (P < 0.001; RR 1.81; 95% CI 1.48-2.21), arrhythmia (P = 0.002; RR 1.38; 95% CI 1.13-1.69), no reflow (P < 0.001; RR 2.28; 95% CI 1.46-3.57), long-term all mortality (P < 0.001; RR 3.82; 95% CI 2.94-4.96), cardiac mortality (P = 0.004; RR 3.02; 95% CI 1.41-6.45), MACE (P < 0.001; RR 2.49; 95% CI 1.47-4.23), and nonfatal MI (P = 0.46; RR 1.32; 95% CI 0.63-2.75). CONCLUSIONS: Meta-analysis shows that NLR is a predictor of hospitalization and long-term prognosis in patients with STEMI after PCI, but requires further confirmation by large randomized clinical trials. PMID- 29716536 TI - Dopamine D2 receptor gene polymorphisms and externalizing behaviors in children and adolescents. AB - BACKGROUND: Dopamine is involved in several cerebral physiological processes, and single nucleotide polymorphisms (SNP) in the dopamine D2 receptor gene (DRD2) have been associated with numerous neurological and mental disorders, including those involving alterations in cognitive and emotional processes. METHODS: The aim of this study was to evaluate the association between the SNPs c.957C > T (rs6277) and c.-585A > G (rs1799978) in the DRD2 gene and behavioral characteristics of children and adolescents based on an inventory of the Child Behavior Checklist (CBCL). Children and adolescents between 8 and 20 years old who were clinically followed-up were genotyped for the SNPs c.957C > T and c. 585A > G, and related to data of the CBCL/6-18 scale assessment performed with the help of caregivers. The chi-squared test was used to assess the differences in the frequencies of the C and T alleles in the polymorphism c.957C > T and of the A and G alleles in the polymorphism c.-585A > G with respect to the grouped CBCL scores at a significance level of 5%. Multiple logistic regression models were performed, to control whether sex and/or ethnicity could influence the results. RESULTS: Eighty-five patients were assessed overall, and the presence of the T allele (C/T and T/T) of DRD2 c.957C > T polymorphism was found to be significantly associated with the occurrence of defiant and oppositional problems and with attention and hyperactivity problems. There were no associations detected with polymorphism DRD2 c.-585A > G polymorphism. Both SNPs were in Hardy Weinberg-equilibrium. CONCLUSIONS: Although the findings of this study are preliminary, due to its small number of participants, the presence of T allele (C/T, T/T) in c.957C > T SNP was associated with difficulty in impulse control, self-control of emotions, and conduct adjustment, which can contribute to improving the identification of mental and behavioral phenotypes associated with gene expression. PMID- 29716537 TI - Accuracy of immediate antepartum ultrasound estimated fetal weight and its impact on mode of delivery and outcome - a cohort analysis. AB - BACKGROUND: The aim of the study was to investigate the accuracy of ultrasound derived estimated fetal weight (EFW) and to determine its impact on management and outcome of delivery. METHODS: In this single-center cohort analysis, women with a singleton term pregnancy in the beginning stages of labor were included. Women with immediately antepartum EFW (N = 492) were compared to women without ultrasound (N = 515). RESULTS: EFW was correct (deviation from birth weight <= 10%) in 72.2% (355/492) of patients with fetal biometry; 19.7% (97/492) were underestimated, and 8.1% (40/492) were overestimated. Newborns with a lower birth weight were more frequently overestimated, and newborns with higher birth weight were more frequently underestimated. The mean difference between EFW and real birth weight was - 114.5 g (standard deviation +/-313 g, 95% confidence interval 87.1-142.0). The rate of non-reassuring fetal heart tracing (9.8% vs. 1.9%, P < 0.001) and of caesarean delivery (9.1% vs. 5.0%, P = 0.013) was higher in women with EFW. Overestimation was associated with an increased risk for delivery by caesarean section (odds ratio 2.80; 95% confidence interval 1.2-6.5, P = 0.017). After adjustment, EFW remained associated with increased non-reassuring fetal heart tracing (odds ratio 4.73; 95% confidence interval 2.3-9.6) and caesarean delivery (odds ratio 1.86; 95% confidence interval 1.1-3.1). The incidence of perineal tears of grade 3/4, shoulder dystocia, postnatal depression and neonatal acidosis did not differ between groups. CONCLUSIONS: Antepartum ultrasound derived EFW does not improve maternal and fetal outcome and is therefore not recommended. PMID- 29716538 TI - Ventriculoperitoneal shunts in non-HIV cryptococcal meningitis. AB - BACKGROUND: Persistent and uncontrollable intracranial hypertension (ICH) and difficulty in reducing Cryptococcus count are severe problems in cryptococcal meningitis (CM) patients. The therapeutic effects of ventriculoperitoneal shunts (VPS) in non-HIV CM patients are not fully known, and the procedure is somewhat unusual. Here, our study offers a review to investigate the role of VPS in non HIV CM. METHODS: We retrospectively collected data on 23 non-HIV CM patients with and without ventriculomegaly from 2010 to 2016. Their demographic data, clinical manifestations, cerebrospinal fluid (CSF) features and outcomes were analysed. RESULTS: We found that non-HIV CM patients without ventriculomegaly were older, had earlier treatment times and had shorter symptom durations than CM patients with ventriculomegaly. In both groups, headache, vomiting, fever and loss of vision were the most common clinical features. CSF pressure and Cryptococcus count were significantly decreased after operation. VPS could provide sustained relief from ICH symptoms such as headache. 13% of patients had poor outcomes because of serious underlying disease, while 87% of patients had good outcomes. CONCLUSIONS: The use of a VPS is helpful in decreasing ICH and fungal overload in non-HIV CM patients, and VPS should be performed before CM patients present with symptoms of severe neurological deficit. PMID- 29716539 TI - Use of dietary supplements by pregnant women in Colombia. AB - BACKGROUND: During pregnancy, the need for certain nutrients increases. This study assessed the prevalence and socio-demographic factors associated with dietary supplement use in a representative sample of pregnant women in Colombia. METHOD: Data for this study were obtained from a cross-sectional, nationally representative survey (ENSIN, 2010). A total of 1856 pregnant women, 13-49 years of age, were recruited. The use of prenatal dietary supplements (Vitamins A, C or E) was treated as a binary outcome (used at some time or never sued during pregnancy when prescribed by a doctor) in multinomial analyses. Sociodemographic data and associated factors were assessed by computer-assisted personal interview technology. RESULTS: Of the sample, 1123 women (68.6%) reported taking prenatal dietary supplements at some stage during their pregnancy. Most users had a high socioeconomic level (79.5%), were in their third trimester of pregnancy (79.5%), were 30-49 years of age (74.0%), and lived in the central region of Colombia (73.8%). The multivariate logistic regression showed that third trimester of pregnancy (OR 6.2;95% CI 4.0 to 9.3), high educational level (OR 2.3; 95% CI 1.5 to 3.4), high socioeconomic level -SISBEN IV or more- (OR 2.0; 95% CI 1.4 to 2.8), residence in the Atlantic region (north) (OR 2.6; 95% CI 1.7 to 3.6), Eastern region (OR 2.0; 95% CI 1.3 to 3.1), central region (OR 2.6; 95% CI 1.7 to 3.9), Pacific region (west) (OR 1.5; 95% CI 1.0 to 2.3), and belonging to the mestizo (others) ethnic group (OR 1.2; 95% CI 1.0 to 2.6), were all associated with a higher probability of dietary supplement intake. CONCLUSION: The prevalence of prenatal dietary supplements in pregnant women in Colombia was found to be substantial. The variables significantly associated with their use were educational level, socioeconomic level, trimester of pregnancy, geographic level and ethnic group. These results indicate the necessity of implementing new health policies that guarantee uniform access to nutritional supplements for all population sectors, especially in countries, such as Colombia, who are currently undergoing a process of nutritional transition. PMID- 29716540 TI - Cost-of-illness studies in heart failure: a systematic review 2004-2016. AB - BACKGROUND: Heart failure is a major and growing medical and economic problem worldwide as 1-2% of the healthcare budget are spent for heart failure. The prevalence of heart failure has increased over the past decades and it is expected that there will be further raise due to the higher proportion of elderly in the western societies. In this context cost-of-illness studies can significantly contribute to a better understanding of the drivers and problems which lead to the increasing costs in heart failure. The aim of this study was to perform a systematic review of published cost-of-illness studies related to heart failure to highlight the increasing cost impact of heart failure. METHODS: A systematic review was conducted from 2004 to 2016 to identify cost-of-illness studies related to heart failure, searching PubMed (Medline), Cochrane, Science Direct (Embase), Scopus and CRD York Database. RESULTS: Of the total of 16 studies identified, 11 studies reported prevalence-based estimates, 2 studies focused on incidence-based data and 3 articles presented both types of cost data. A large variation concerning cost components and estimates can be noted. Only three studies estimated indirect costs. Most of the included studies have shown that the costs for hospital admission are the most expensive cost element. Estimates for annual prevalence-based costs for heart failure patients range from $868 for South Korea to $25,532 for Germany. The lifetime costs for heart failure patients have been estimated to $126.819 per patient. CONCLUSIONS: Our review highlights the considerable and growing economic burden of heart failure on the health care systems. The cost-of-illness studies included in this review show large variations in methodology used and the cost results vary consequently. High quality data from cost-of-illness studies with a robust methodology applied can inform policy makers about the major cost drivers of heart failure and can be used as the basis of further economic evaluations. PMID- 29716541 TI - Onchocerca - infected cattle produce strong antibody responses to excretory secretory proteins released from adult male Onchocerca ochengi worms. AB - BACKGROUND: The front line molecules from filarial worms and other nematodes or helminthes are their Excretory-Secretory (ES) products. Their interaction with the host cells, proteins and immune system accounts for the skin and eye pathology or hyposensitivity observed in human onchocerciasis. ES products and adult worms' crude extracts from Onchocerca ochengi, a filarial nematode that infects the African zebu cattle, were utilized in the present study as a model for studying Onchocerca volvulus that causes river blindness in man. METHODS: The ES products were generated from adult male and female worms in vitro and analyzed with poly acrylamide gel electrophoresis (PAGE) and enzyme-linked immunosorbent assay (ELISA) using sera from Onchocerca-infected cattle and humans. The cattle sera were collected from a herd that had been exposed for six years to natural transmission of Onchocerca spp. The expressed reactivity was evaluated and differences analyzed statistically using Kruskal-Wallis rank and Chi-square tests. RESULTS: The gel electrophoretic analyses of 156 ES products from O. ochengi female and male worms and of two somatic extracts from three females and 25 males revealed differences in the protein pattern showing pronounced bands at 15, 30-50 and 75 kDa for male ES proteins and 15, 25 and 40-75 kDa for somatic extracts, respectively and less than 100 kDa for female worms. Proteins in the ES products and somatic extracts from female and male Onchocerca ochengi worms were recognized by IgG in sera from both Onchocerca-exposed cattle and humans. Bovine serum antibodies reacted more strongly with proteins in the somatic extracts than with those in the ES products. Interestingly, the reaction was higher with male ES products than with ES products from female worms, suggesting that the males which migrate from one nodule to another are more exposed to the host immune system than the females which remain encapsulated in intradermal nodules. CONCLUSIONS: This study demonstrates that O. ochengi ES products and, in particular, extracts from male filariae may represent a good source of immunogenic proteins and potential vaccine candidates. PMID- 29716542 TI - In-depth comparative analysis of malaria parasite genomes reveals protein-coding genes linked to human disease in Plasmodium falciparum genome. AB - BACKGROUND: Plasmodium falciparum is the most virulent malaria parasite capable of parasitizing human erythrocytes. The identification of genes related to this capability can enhance our understanding of the molecular mechanisms underlying human malaria and lead to the development of new therapeutic strategies for malaria control. With the availability of several malaria parasite genome sequences, performing computational analysis is now a practical strategy to identify genes contributing to this disease. RESULTS: Here, we developed and used a virtual genome method to assign 33,314 genes from three human malaria parasites, namely, P. falciparum, P. knowlesi and P. vivax, and three rodent malaria parasites, namely, P. berghei, P. chabaudi and P. yoelii, to 4605 clusters. Each cluster consisted of genes whose protein sequences were significantly similar and was considered as a virtual gene. Comparing the enriched values of all clusters in human malaria parasites with those in rodent malaria parasites revealed 115 P. falciparum genes putatively responsible for parasitizing human erythrocytes. These genes are mainly located in the chromosome internal regions and participate in many biological processes, including membrane protein trafficking and thiamine biosynthesis. Meanwhile, 289 P. berghei genes were included in the rodent parasite-enriched clusters. Most are located in subtelomeric regions and encode erythrocyte surface proteins. Comparing cluster values in P. falciparum with those in P. vivax and P. knowlesi revealed 493 candidate genes linked to virulence. Some of them encode proteins present on the erythrocyte surface and participate in cytoadhesion, virulence factor trafficking, or erythrocyte invasion, but many genes with unknown function were also identified. Cerebral malaria is characterized by accumulation of infected erythrocytes at trophozoite stage in brain microvascular. To discover cerebral malaria-related genes, fast Fourier transformation (FFT) was introduced to extract genes highly transcribed at the trophozoite stage. Finally, 55 candidate genes were identified. Considering that parasite-infected erythrocyte surface protein 2 (PIESP2) contains gap-junction-related Neuromodulin_N domain and that anti-PIESP2 might provide protection against malaria, we chose PIESP2 for further experimental study. CONCLUSIONS: Our analysis revealed a limited number of genes linked to human disease in P. falciparum genome. These genes could be interesting targets for further functional characterization. PMID- 29716543 TI - Characteristics of patients with missing information on stage: a population-based study of patients diagnosed with colon, lung or breast cancer in England in 2013. AB - BACKGROUND: Stage is a key predictor of cancer survival. Complete cancer staging is vital for understanding outcomes at population level and monitoring the efficacy of early diagnosis initiatives. Cancer registries usually collect details of the disease extent but staging information may be missing because a stage was never assigned to a patient or because it was not included in cancer registration records. Missing stage information introduce methodological difficulties for analysis and interpretation of results. We describe the associations between missing stage and socio-demographic and clinical characteristics of patients diagnosed with colon, lung or breast cancer in England in 2013. We assess how these associations change when completeness is high, and administrative issues are assumed to be minimal. We estimate the amount of avoidable missing stage data if high levels of completeness reached by some Clinical Commissioning Groups (CCGs), were achieved nationally. METHODS: Individual cancer records were retrieved from the National Cancer Registration and linked to the Routes to Diagnosis and Hospital Episode Statistics datasets to obtain additional clinical information. We used multivariable beta binomial regression models to estimate the strength of the association between socio demographic and clinical characteristics of patients and missing stage and to derive the amount of avoidable missing stage. RESULTS: Multivariable modelling showed that old age was associated with missing stage irrespective of the cancer site and independent of comorbidity score, short-term mortality and patient characteristics. This remained true for patients in the CCGs with high completeness. Applying the results from these CCGs to the whole cohort showed that approximately 70% of missing stage information was potentially avoidable. CONCLUSIONS: Missing stage was more frequent in older patients, including those residing in CCGs with high completeness. This disadvantage for older patients was not explained fully by the presence of comorbidity. A substantial gain in completeness could have been achieved if administrative practices were improved to the level of the highest performing areas. Reasons for missing stage information should be carefully assessed before any study, and potential distortions introduced by how missing stage is handled should be considered in order to draw the most correct inference from available statistics. PMID- 29716544 TI - NLRP3 promotes tumor growth and metastasis in human oral squamous cell carcinoma. AB - BACKGROUND: Inflammasomes are reported to be abnormally expressed and activated in several malignancies and play important roles in tumor development. The present study was designed to investigate the expression and function of the NLR family pyrin domain containing protein 3 (NLRP3) inflammasome in oral squamous cell carcinoma (OSCC). METHODS: NLRP3 expression in OSCC cell lines and the normal human immortalized oral epithelial cells (HIOEC) was determined by real time PCR and western blot. Immunohistochemistry was used to examine the expression of NLRP3 and IL-1beta in the paraffin-embedded OSCC tissues. The proliferation of OSCC cells was detected by the 3-(4,5-dimethylthiazol- 2-yl)-2,5 diphenyl tetrazolium bromide (MTT) assay and cell colony formation ability of the OSCC cells was also evaluated. Tumor cell migration or invasion was measured by the transwell assay and related protein markers were determined by western blot. A mouse xenograft model was established to investigate the OSCC tumor growth in vivo. RESULTS: Significant higher expression of NLRP3 was observed in the OSCC cells. Obvious expression of NLRP3 and IL-1beta was found in the paraffin embedded OSCC tissues, and the NLRP3 expression levels were correlated with the tumor size, lymphonode metastatic status and IL-1beta expression. Downregulating NLRP3 expression markedly reduced the cleavage of caspase-1 and production of IL 1beta in OSCC cells. NLRP3 knockdown also inhibited the proliferation, migration and invasion of OSCC cells. Further investigation indicated that expressions of E cadherin and vimentin in OSCC cells were increased, while N-cadherin expression was decreased after NLRP3 knockdown. Downregulating NLRP3 expression in OSCC cells significantly reduced the tumor growth in vivo. CONCLUSIONS: Our data suggested that the increased expression of NLRP3 in OSCC was associated with tumor growth and metastasis. NLRP3 may be considered as a potential target for OSCC therapy. PMID- 29716545 TI - Management and control of communicable diseases in schools and other child care settings: systematic review on the incubation period and period of infectiousness. AB - BACKGROUND: Information on the incubation period and period of infectiousness or shedding of infectious pathogens is critical for management and control of communicable diseases in schools and other childcare settings. METHODS: We performed a systematic literature review (Pubmed and Embase) to identify and critically appraise all relevant published articles using incubation, infectiousness or shedding, and exclusion period as parameters for the search. No language, time, geographical or study design restrictions were applied. RESULTS: A total of 112 articles met the eligibility criteria. A relatively large number were retrieved for gastrointestinal diseases and influenza or respiratory syncytial virus, but there were few or no studies for other diseases. Although a considerable number of publications reported the incubation and shedding periods, there was less evidence concerning the period of infectiousness. On average, five days of exclusion is considered for measles, mumps, rubella, varicella and pertussis. For other diseases, such as most cases of meningococcal disease, hepatitis A and influenza exclusion is considered as long as severe symptoms persist. However, these results are based on a diverse range of study characteristics, including age, treatment, vaccination, underlying diseases, diagnostic tools, viral load, study design and definitions, making statistical analysis difficult. CONCLUSIONS: Despite inconsistent definitions for key variables and the diversity of studies reviewed, published data provide sufficient quantitative estimates to inform decision making in schools and other childcare settings. The results can be used as a reference when deciding about the exclusion of a child with a communicable disease that both prevents exposure and avoids unnecessary absenteeism. PMID- 29716546 TI - Staining of E-selectin ligands on paraffin-embedded sections of tumor tissue. AB - BACKGROUND: The E-selectin ligands expressed by cancer cells mediate adhesion of circulating cancer cells to endothelial cells, as well as within tissue microenvironments important for tumor progression and metastasis. The identification of E-selectin ligands within cancer tissue could yield new biomarkers for patient stratification and aid in identifying novel therapeutic targets. The determinants of selectin ligands consist of sialylated tetrasaccharides, the sialyl Lewis X and A (sLeX and sLeA), displayed on protein or lipid scaffolds. Standardized procedures for immunohistochemistry make use of the antibodies against sLeX and/or sLeA. However, antibody binding does not define E-selectin binding activity. METHODS: In this study, we developed an immunohistochemical staining technique, using E-selectin-human Ig Fc chimera (E Ig) to characterize the expression and localization of E-selectin binding sites on paraffin-embedded sections of different cancer tissue. RESULTS: E-Ig successfully stained cancer cells with high specificity. The E-Ig staining show high reactivity scores in colon and lung adenocarcinoma and moderate reactivity in triple negative breast cancer. Compared with reactivity of antibody against sLeX/A, the E-Ig staining presented higher specificity to cancer tissue with better defined borders and less background. CONCLUSIONS: The E-Ig staining technique allows the qualitative and semi-quantitative analysis of E-selectin binding activity on cancer cells. The development of accurate techniques for detection of selectin ligands may contribute to better diagnostic and better understanding of the molecular basis of tumor progression and metastasis. PMID- 29716547 TI - Transcriptional analysis of liver from chickens with fast (meat bird), moderate (F1 layer x meat bird cross) and low (layer bird) growth potential. AB - BACKGROUND: Divergent selection for meat and egg production in poultry has resulted in strains of birds differing widely in traits related to these products. Modern strains of meat birds can reach live weights of 2 kg in 35 d, while layer strains are now capable of producing more than 300 eggs per annum but grow slowly. In this study, RNA-Seq was used to investigate hepatic gene expression between three groups of birds with large differences in growth potential; meat bird, layer strain as well as an F1 layer x meat bird. The objective was to identify differentially expressed (DE) genes between all three strains to elucidate biological factors underpinning variations in growth performance. RESULTS: RNA-Seq analysis was carried out on total RNA extracted from the liver of meat bird (n = 6), F1 layer x meat bird cross (n = 6) and layer strain (n = 6), males. Differential expression of genes were considered significant at P < 0.05, and a false discovery rate of < 0.05, with any fold change considered. In total, 6278 genes were found to be DE with 5832 DE between meat birds and layers (19%), 2935 DE between meat birds and the cross (9.6%) and 493 DE between the cross and layers (1.6%). Comparisons between the three groups identified 155 significant DE genes. Gene ontology (GO) enrichment and Kyoto Encyclopaedia of Genes and Genomes (KEGG) pathway analysis of the 155 DE genes showed the FoxO signalling pathway was most enriched (P = 0.001), including genes related to cell cycle regulation and insulin signalling. Significant GO terms included 'positive regulation of glucose import' and 'cellular response to oxidative stress', which is also consistent with FoxOs regulation of glucose metabolism. There were high correlations between FoxO pathway genes and bodyweight, as well as genes related to glycolysis and bodyweight. CONCLUSIONS: This study revealed large transcriptome differences between meat and layer birds. There was significant evidence implicating the FoxO signalling pathway (via cell cycle regulation and altered metabolism) as an active driver of growth variations in chicken. Functional analysis of the FoxO genes is required to understand how they regulate growth and egg production. PMID- 29716548 TI - A genome-wide assessment of conserved SNP alleles reveals a panel of regulatory SNPs relevant to the peripheral nerve. AB - BACKGROUND: Identifying functional non-coding variation is critical for defining the genetic contributions to human disease. While single-nucleotide polymorphisms (SNPs) within cis-acting transcriptional regulatory elements have been implicated in disease pathogenesis, not all cell types have been assessed and functional validations have been limited. In particular, the cells of the peripheral nervous system have been excluded from genome-wide efforts to link non-coding SNPs to altered gene function. Addressing this gap is essential for defining the genetic architecture of diseases that affect the peripheral nerve. We developed a computational pipeline to identify SNPs that affect regulatory function (rSNPs) and evaluated our predictions on a set of 144 regions in Schwann cells, motor neurons, and muscle cells. RESULTS: We identified 28 regions that display regulatory activity in at least one cell type and 13 SNPs that affect regulatory function. We then tailored our pipeline to one peripheral nerve cell type by incorporating SOX10 ChIP-Seq data; SOX10 is essential for Schwann cells. We prioritized 22 putative SOX10 response elements harboring a SNP and rapidly validated two rSNPs. We then selected one of these elements for further characterization to assess the biological relevance of our approach. Deletion of the element from the genome of cultured Schwann cells-followed by differential gene expression studies-revealed Tubb2b as a candidate target gene. Studying the enhancer in developing mouse embryos revealed activity in SOX10-positive cells including the dorsal root ganglia and melanoblasts. CONCLUSIONS: Our efforts provide insight into the utility of employing strict conservation for rSNP discovery. This strategy, combined with functional analyses, can yield candidate target genes. In support of this, our efforts suggest that investigating the role of Tubb2b in SOX10-positive cells may reveal novel biology within these cell populations. PMID- 29716549 TI - LYL1 gene amplification predicts poor survival of patients with uterine corpus endometrial carcinoma: analysis of the Cancer genome atlas data. AB - BACKGROUND: Somatic amplifications of the LYL1 gene are relatively common occurrences in patients who develop uterine corpus endometrial carcinoma (UCEC) as opposed to other cancers. This study was undertaken to determine whether such genetic alterations affect survival outcomes of UCEC. METHODS: In 370 patients with UCEC, we analysed clinicopathologic characteristics and corresponding genomic data from The Cancer Genome Atlas database. Patients were stratified according to LYL1 gene status, grouped as amplification or non-amplification. Heightened levels of cancer-related genes expressed in concert with LYL1 amplification were similarly investigated through differentially expressed gene and gene set enrichment analyses. Factors associated with survival outcomes were also identified. RESULTS: Somatic LYL1 gene amplification was observed in 22 patients (5.9%) with UCEC. Patients displaying amplification (vs. non amplification) were significantly older at the time of diagnosis and more often were marked by non-endometrioid, high-grade, or advanced disease. In survival analysis, the amplification subset showed poorer progression-free survival (PFS) and overall survival (OS) rates (3-year PFS: 34.4% vs. 79.9%, P = 0.031; 5-year OS: 25.1% vs. 84.9%, P = 0.014). However, multivariate analyses adjusted for tumor histologic type, grade, and stage did not confirm LYL1 gene amplification as an independent prognostic factor for either PFS or OS. Nevertheless, MAPK, WNT, and cell cycle pathways were significantly enriched by LYL1 gene amplification (P < 0.001, P = 0.002, and P = 0.004, respectively). CONCLUSIONS: Despite not being identified as an independent prognostic factor in UCEC, LYL1 gene amplification is associated with other poor prognostic factors and correlated with upregulation of cancer-related pathways. PMID- 29716550 TI - Smokers' interest in a lung cancer screening programme: a national survey in England. AB - BACKGROUND: Following the recommendation of lung cancer screening in the US, screening committees in several European countries are reviewing the evidence for implementing national programmes. However, inadequate participation from high risk groups poses a potential barrier to its effectiveness. The present study examined interest in a national lung cancer screening programme and modifiable attitudinal factors that may affect participation by smokers. METHODS: A population-based survey of English adults (n = 1464; aged 50-70 years) investigated screening intentions in different invitation scenarios, beliefs about lung cancer, early detection and treatment, worry about lung cancer risk, and stigma. Data on smoking status and perceived chances of quitting were also collected, but eligibility for lung screening in the event of a national programme was unknown. RESULTS: Intentions to be screened were high in all three invitation scenarios for both current (>= 89%) and former (>= 94%) smokers. However, smokers were less likely to agree that early-stage survival is good (43% vs. 53%; OR: 0.64, 0.46-0.88) or be willing to have surgery for an early stage, screen-detected cancer (84% vs. 94%; OR: 0.38, 0.21-0.68), compared with former smokers. Willingness to have surgery was positively associated with screening intentions; with absolute differences of 25% and 29%. Worry about lung cancer risk was also most common among smokers (48%), and one fifth of respondents thought screening smokers was a waste of NHS money. CONCLUSIONS: A national lung cancer screening programme would be well-received in principle. To improve smokers' participation, care should be taken to communicate the survival benefits of early-stage diagnosis, address concerns about surgery, and minimise anxiety and stigma related to lung cancer risk. PMID- 29716551 TI - Sociodemographic and physical predictors of non-participation in community based physical checkup among older neighbors: a case-control study from the Kyoto Kameoka longitudinal study, Japan. AB - BACKGROUND: It is difficult to obtain detailed information on non-participants in physical and health examination checkups in community-based epidemiological studies. We investigated the characteristics of non-participants in a physical and health examination checkup for older adults in a nested study from the Japanese Kyoto-Kameoka Longitudinal Study. METHODS: We approached a total of 4831 people aged >=65 years in 10 randomly selected intervention regions. Participants responded to a mail-based population survey on needs in the sphere of daily life to encourage participation in a free face-to-face physical checkup examination; 1463 participants (706 men, 757 women) participated in the physical checkup. A multiple logistic regression model was performed to investigate the adjusted odds ratios (aOR) of non-participation based on sociodemographic status apart from psychological and physiological frailty as assessed by the validated Kihon Checklist. RESULTS: There was a significant, inverse relationship between non participation and frequently spending time alone among individuals who lived with someone or other family structure (aOR = 0.53, standard error [SE] 0.08 in men, aOR = 0.66, SE 0.09 in women). Very elderly (over 80 years old) women, poorer health consciousness and current smoking in both sexes and poor self-rated health in men, were significantly related to higher non-participation rates. In both sexes, individuals who did not participate in community activities were significantly more likely to be non-participants than individuals who did (aOR = 1.94, SE 0.23 in men, aOR = 3.29, SE 0.39 in women). Having low IADL and physical functioning scores were also associated with higher rates of non-participation. CONCLUSION: Health consciousness and lack of community activity participation were predictors of non-participation in a physical checkup examination among older adults. In addition, lower IADL and physical functioning/strength were also predictors of non-participation. On the contrary, older inhabitants living with someone tended to participate in the physical checkup examination for social interchange when they were frequently alone in the household. This study suggests the importance of considering aging especially for women and poor sociodemographic background and physical frailty for both sexes so that older people can access health programs without difficulty. TRIAL REGISTRATION: UMIN000008105 . Registered 26 April 2012. Retrospectively registered. PMID- 29716552 TI - The validity of proxy-based data on loneliness in suicide research: a case control psychological autopsy study in rural China. AB - BACKGROUND: There is a lack of evidence for the role of loneliness on suicide using psychological autopsy method, and the validity of proxy informants' reports on loneliness is not well established. This study aimed to investigate the validity of proxy respondent reports on loneliness, and the reliability and validity of the University of California Los Angeles Loneliness Scale-6 (ULS-6) as used in psychological autopsy method with rural elderly people in China. METHODS: Two hundred forty-two suicide cases and 242 normal community controls were selected, and the psychological autopsy method was utilized to collect information. Data from proxy respondents of the living controls were compared with data reported by the targets (gold standards). RESULTS: Subject-proxy concordance for ULS-6 was fair (ICC = 0.447) in the living controls. The suicide cases were more likely to have a higher score of ULS-6 than the living controls. Additionally, our data supported that ULS-6 had adequate psychometric properties in both suicide and control groups: factor analyses yielded one-factor component solution; Cronbach's alpha (both > 0.90) demonstrated excellent internal consistency; the Spearman correlation analysis indicated that the ULS-6 score was positively correlated with depression; and negatively correlated with QOL and social support. CONCLUSIONS: Results support proxy-based data on loneliness in research of suicide in older adults in rural China, and the ULS-6 is a psychometrically sound instrument for measuring loneliness in psychological autopsy studies. PMID- 29716553 TI - Protocol for a cluster-randomised controlled trial evaluating the impact of a preschool-based capacity building intervention on intimate partner violence and substance misuse in Sri Lanka. AB - BACKGROUND: Past research has identified links between intimate partner violence (IPV) and alcohol misuse and poverty in Sri Lanka. Services that address substance misuse are amongst the few interventions shown to reduce IPV in settings similar to Sri Lanka. This paper describes the protocol for a study examining the impact of a preschool-based capacity building intervention on the prevalence of IPV and substance misuse in parents with children attending preschools, including uptake of available government services. METHODS: The study is a cluster randomised controlled trial. Government-managed preschools (n = 34) in Galle and Colombo municipalities will be randomly assigned to an intervention (n = 17) or control group (n = 17). Parents with children attending these preschools will be recruited to participate. The study intervention will build the capacity of selected community volunteers (parents) and preschool teachers in the provision of information and support to families affected by IPV and substance misuse. This intervention is directed at improving uptake, access and coordination of existing services. Data will be collected from all parents, and teachers in the intervention group, pre-intervention and 10 months post intervention. The primary outcome for this study is experience of IPV amongst mothers of preschool-attending children. Secondary outcomes are substance misuse amongst fathers, measured via the locally adapted Alcohol Use Disorders Identification Test and Drug Abuse Screening Test; and awareness and uptake of services for these issues measured through locally-relevant tools. Demographic information and satisfaction with the intervention will also be assessed. DISCUSSION: By intervening through preschools we aim to support high-risk families early enough to arrest the cycle of violence that results in children themselves becoming victims and perpetrators of such violence. The innovative project design will reach the most vulnerable sections of the community and will provide a sustainable and feasible strategy for scale-up of the intervention. TRIAL REGISTRATION: This study is registered with the Sri Lankan Clinical Trials Registry (2017/038) and has been submitted to ClinicalTrials.gov (U.S National Institutes of Health) under the title "Randomized control trial: preschool-based training and support programs to reduce intimate partner violence (IPV) by addressing alcohol and drug misuse in young families in Sri Lanka"; Registration number: NCT03341455 ; Registration date: 14 November 2017. PMID- 29716554 TI - Clinically significant association of elevated expression of nuclear factor E2 related factor 2 expression with higher glucose uptake and progression of upper urinary tract cancer. AB - BACKGROUND: There is growing evidence that the transcription factor nuclear factor E2-related factor 2 (Nrf2) is the major participant in regulating antioxidants and pathways for detoxifying reactive oxygen species (ROS), as well as having a vital role in tumor proliferation, invasion, and chemoresistance. It was also recently reported that Nrf2 supports cell proliferation by promoting metabolic activity. Thus, Nrf2 is involved in progression of cancer. Upper urinary tract urothelial carcinoma (UTUC) is a biologically aggressive tumor with high rates of recurrence and progression, resulting in a poor prognosis. However, the role of Nrf2 in UTUC is largely unknown. METHODS: In order to study the role of Nrf2 in UTUC from the metabolic perspective, we retrospectively assessed Nrf2 expression in the surgical specimen and the preoperative maximum standard glucose uptake (SUVmax) on [18F]fluorodeoxy-glucose positron emission tomography (18F-FDG PET) of 107 patients with UTUC who underwent radical nephroureterectomy. RESULTS: Increased expression of Nrf2 in the primary lesion was correlated with less differentiated histology, local invasion, and lymph node metastasis, and was also an independent indicator of shorter overall survival according to multivariate analysis. Furthermore, increased expression of Nrf2 was associated with higher preoperative SUVmax by the primary tumor on 18F-FDG-PET, while Nrf2 expression and SUVmax were also significantly correlated in the metastatic lymph nodes. Among the 18 patients with lymph node metastasis at nephroureterectomy who underwent retroperitoneal lymph node dissection and received adjuvant chemotherapy, the patients with higher Nrf2 expression in the primary tumor had worse recurrence-free survival. CONCLUSIONS: These results suggest that constitutive activation of Nrf2 might be linked with tumor aerobic glycolysis and progression of UTUC, indicating that Nrf2 signaling in the tumor microenvironment promotes progression of UTUC. PMID- 29716555 TI - Efficacy and safety outcomes of robotic radical hysterectomy in Chinese older women with cervical cancer compared with laparoscopic radical hysterectomy. AB - BACKGROUND: Recently, as a complex integrating a number of modern high-tech means, robotic surgery system is a well-deserved revolutionary tool in globally minimally invasive surgical field. For the first time in China, the objective of this study was to evaluate the efficacy and safety outcomes of robotic radical hysterectomy (RRH) in Chinese older women with cervical cancer compared with laparoscopic radical hysterectomy (LRH). METHODS: In this prospective, randomized and double-blinded study, 60 Chinese older women with cervical cancer were evenly divided to accept the RRH or LRH. Follow-up period lasted for 24 months. RESULTS: Median age for the entire cohort was 65 (range: 61-69) years. There was no difference in International Federation of Gynecology and Obstetrics (FIGO) stages and cell types between two groups (p > 0.05 for all). Uterine size, tumor size, vaginal length and numbers of left and right pelvic lymph nodes did not differ between two groups (p > 0.05 for all). No difference was observed in numbers of left and right lymph node metastasis (p > 0.05 for all). All patients had negative margins without conversion to laparotomy. There were significantly less postoperative complications in the RRH group than in the LRH group (p < 0.05). Shorter indwelling time of bladder and drain catheters was observed in the RRH group than in the LRH group (p < 0.05 for all). Length of postoperative hospital stay in the RRH group was significantly shorter compared with that in the LRH group (p < 0.05). Patients in two groups similarly experienced the recurrence and death (p > 0.05 for all). CONCLUSIONS: This study demonstrated that RRH provided additional benefits for Chinese older women with cervical cancer because of less complications and faster recovery compared with LRH. Meanwhile, this study supported an equivalence of surgical qualities and survival outcomes of RRH to LRH. Robotics-assisted surgical method is effective, safe and feasible for Chinese older women with cervical cancer. PMID- 29716556 TI - Vaccination hesitancy in the antenatal period: a cross-sectional survey. AB - BACKGROUND: Recent reports of childhood vaccination coverage in Australia have shown steadily improving vaccination coverage and narrowing differences between highest and lowest coverage regions, yet the NSW North Coast consistently has the lowest coverage rates nationally. Better understanding of parents' vaccination attitudes and actions within this region may guide strategies to improve uptake. The antenatal period is when many parents explore and consolidate vaccination attitudes and so is pivotal for study. METHODS: Women attending public antenatal clinics at six NSW North Coast hospitals completed a 10-min cross-sectional survey capturing stage of decision-making and decisional-conflict as well as vaccination hesitancy, attitudes, intentions and actions. Unscored responses were analysed for individual items. Decisional conflict subscales were scored using published algorithms. For consented children, immunisation status was assessed at 8 months using the Australian Immunisation Register. For Likert scale items, odds ratios and Fisher's exact, chi-squared and Chasson's tests assessed differences between subgroups. Wilcoxon rank-sum tests assessed differences between subgroups for items on scales of 0-to-10 and decisional conflict sub-scale scores. RESULTS: First-time mothers were 3 times more likely than others (OR = 3.40, 95% CI 1.34 8.60) to identify as unsure, somewhat or very hesitant. Most respondents (92.2%) wanted their new baby to receive all recommended vaccinations. Many had high or moderate levels of concern about vaccine side effects (25.4%), safety (23.6%) and effectiveness (23.1%). Increased hesitancy was associated with decreased confidence in the schedule (p < 0.001), decreased trust in child's doctor (p < 0.0001), decreased perceived protection from disease (p < 0.05) and increased decisional conflict on all measured subscales (p < 0.0001). First-time mothers had higher decisional conflict on values clarity, support and uncertainty sub scales. By 8 months of age, 83.2% of infants were fully vaccinated. Those with none or a few minor concerns were over 8 times more likely than others to vaccinate on schedule (OR = 8.7, 1.3-56.7). CONCLUSIONS: Importantly this study provides further strong justification to talk with women about vaccination during pregnancy and particularly to ensure that first-time mothers are offered assistance in making these important decisions, where indicated. Further research should focus on optimising the timing, content and delivery style of perinatal interventions. PMID- 29716557 TI - Complex patterns of response to oral hygiene instructions: longitudinal evaluation of periodontal patients. AB - BACKGROUND: Oral hygiene instruction is an intervention widely practiced but increased knowledge about oral health does not necessarily dramatically impact oral disease prevalence in populations. We aimed to measure plaque and bleeding in periodontal patients over time to determine patterns of patient response to oral hygiene instructions. METHODS: Longitudinal plaque and bleeding index data were evaluated in 227 periodontal patients to determine the impact of oral hygiene instructions. Over multiple visits, we determined relative plaque accumulation and gingival bleeding for each patient. Subsequently, we grouped them in three types of oral hygiene status in response to initial instructions, using the longitudinal data over the period they were treated and followed for their periodontal needs. These patterns of oral hygiene based on the plaque and gingival bleeding indexes were evaluated based on age, sex, ethnic background, interleukin 1 alpha and beta genotypes, diabetes status, smoking habits, and other concomitant diseases. Chi-square and Fisher's exact tests were used to determine if any differences between these variables were statistically significant with alpha set at 0.05. RESULTS: Three patterns in response to oral hygiene instructions emerged. Plaque and gingival bleeding indexes improved, worsened, or fluctuated over time in the periodontal patients studied. Out of all the confounders considered, only ethnic background showed statistically significant differences. White individuals more often than other ethnic groups fluctuated in regards to oral hygiene quality after instructions. CONCLUSIONS: There are different responses to professional oral hygiene instructions. These responses may be related to ethnicity. PMID- 29716558 TI - Single-stage laparoscopic surgery for bilateral organ tumors using a transumbilical approach with a zigzag incision: a report of two cases. AB - BACKGROUND: Reduced port laparoscopic surgery (RPLS) is comparable to conventional multiport laparoscopic surgery and has the potential to provide improved cosmesis and decreased pain; as such, it satisfies a growing demand for less invasive surgical procedures. Moreover, a zigzag incision of the umbilicus results in a less visible scar in plastic surgery. Here we report a series of two cases with bilateral organ tumors treated by single-stage RPLS using a combination of a transumbilical approach and a zigzag incision. CASE PRESENTATION: Case 1: A 63-year-old man was diagnosed with right renal cell carcinoma (RCC) (clear cell carcinoma, pT1a, venous invasion (-)) and a splenic tumor (cavernous hemangioma). Case 2: An 84-year-old woman was diagnosed with concurrent left RCC (clear cell carcinoma, pT1b, 65 * 65 mm, venous invasion (+)) and ascending colon cancer (adenocarcinoma pT3 with no nodal involvement (0/48)). The perioperative course was uneventful in both cases. However, an additional incision was required in Case 2 for specimen excision. Therefore, the scars were more obvious in Case 2 than in Case 1. CONCLUSIONS: Although more cases are required to evaluate the superiority of this technique, this novel procedure could be considered for patients with bilateral lesions. PMID- 29716559 TI - Health behaviour changes in partners of women with recent gestational diabetes: a phase IIa trial. AB - BACKGROUND: We recently demonstrated that a gestational diabetes history in mothers is associated with higher postpartum incident diabetes not only in mothers but also in fathers. In the present study, we examined changes in health behaviours and cardiometabolic profiles in both mothers and partners who participated in a diabetes prevention program within 5 years of a gestational diabetes pregnancy. METHODS: Couples were enrolled into a 13-week program that included 5 half-day group sessions and web/telephone-based support between sessions. It was designed in consultation with patients and previously studied in mothers. We computed mean changes from baseline (95% CI) for physical activity, eating, and sleep measures, and cardiometabolic parameters (fasting and 2-h post glucose load plasma glucose, BMI, blood pressure) in both partners and mothers. RESULTS: Among 59 couples enrolled, 45 partners (76%) and 47 mothers (80%) completed final evaluations. Baseline cardiometabolic measures averaged within normal limits. Similar to mothers, partners increased physical activity (+ 1645 steps/day, 95%CI 730, 2561; accelerometer assessed moderate-to-vigorous physical activity + 36.4 min/week, 95% CI 1.4, 71.4) and sleep duration (+ 0.5 h/night, 95% CI 0.1, 0.9) and reduced the sodium-to-potassium ratio of food intake (- 0.09 95% CI -0.19, - 0.001). No conclusive changes were observed in glucose measures or insulin resistance; in analyses combining mothers and partners, systolic blood pressure decreased (- 2.7 mmHg, 95% CI -4.4, - 1.0). CONCLUSIONS: Partners and mothers demonstrated improved physical activity, sleep, and dietary quality. Baseline cardiometabolic profiles averaged at normal values and there were no changes in glucose or insulin resistance; some blood pressure impact was observed. While strategies need to be developed to attract participants at higher cardiometabolic risk, this study demonstrates that partners of women within 5 years of a gestational diabetes diagnosis can be recruited and do achieve health behaviour change. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02343354 (date of registration: January 22, 2015). PMID- 29716560 TI - Prevalence and stabilizing trends in overweight and obesity among children and adolescents in China, 2011-2015. AB - BACKGROUND: The prevalence of childhood overweight and obesity in developed countries appears to be plateauing. The purpose of this study was to provide the most recent data on the prevalence and trends in overweight and obesity among Chinese children and adolescents from 2011 to 2015. METHODS: We used data collected in the China Health and Nutrition Survey (CHNS) and China Nutritional Transition Cohort Study (CNTCS). We used two waves of the survey in 12 provinces conducted in 2011 (aged 7-18 years; n = 1458) and 2015 (aged 7-18 years; n = 1084) to perform a trend analysis. We used data collected in 15 provinces (aged 7 18 years; n = 1617) to estimate the prevalence of overweight and obesity among Chinese children and adolescents in 2015. RESULTS: In 2015, based on the Working Group for Obesity in China (WGOC) criteria, the prevalence of overweight and obesity were 14.0% (95% CI, 11.6-16.3) and 10.5% (95% CI, 8.4-12.6) in boys, and 9.7% (95% CI, 7.7-11.8) and 7.1% (95% CI, 5.2-8.9) in girls, respectively. The increase in BMI z-scores from 2011 to 2015 was statistically significant among adolescents (p = 0.0083), but not among children. No significant changes were observed in prevalence of overweight and obesity between 2011 and 2015, excepting adolescents aged 12-18 years (p = 0.0086). CONCLUSIONS: Since 2011, overweight has remained stable, and obesity has stabilized in children, though not in adolescents. Although levels of childhood overweight and obesity in China are not high compared to other developed countries, they remain concerning enough that effective policies and interventions need to be sustained and intensified for lowering rates of childhood overweight and obesity. PMID- 29716561 TI - Oral health knowledge, attitudes and care practices of people with diabetes: a systematic review. AB - BACKGROUND: People with uncontrolled diabetes are at greater risk for several oral health problems, particularly periodontal (gum) disease. Periodontal disease also impacts diabetes control. Good oral hygiene and regular dental visits are recommended to prevent and manage oral health problems. Several studies have been conducted to assess the oral health knowledge, attitudes, and practices of people with diabetes yet a review of these findings has not yet been undertaken. The aim of this systematic review was to synthesize current evidence on the knowledge, attitudes and practices of people with diabetes in relation to their oral health care. METHODS: A systematic search of all literature was carried out in five databases using key search terms. The inclusion criteria were: 1) published in the English language; 2) from 2000 to November, 2017; 3) conducted on persons with any type of diabetes and of all ages; 4) explored at least one study outcome (knowledge or attitude or practices toward oral health care); and 5) used quantitative methods of data collection. No restrictions were placed on the quality and setting of the study. RESULTS: A total of 28 studies met the inclusion criteria. The studies included a total of 27,894 people with diabetes and were conducted in 14 countries. The review found that people with diabetes have inadequate oral health knowledge, poor oral health attitudes, and fewer dental visits. They rarely receive oral health education and dental referrals from their care providers. Provision of oral health education by diabetes care providers and referral to dentists when required, was associated with improved oral health behaviours among patients. CONCLUSIONS: Overall, people with diabetes have limited oral health knowledge and poor oral health behaviours. It is therefore essential to educate patients about their increased risk for oral health problems, motivate them for good oral health behaviours and facilitate access to dental care. PMID- 29716562 TI - Heavy ion mutagenesis combined with triclosan screening provides a new strategy for improving the arachidonic acid yield in Mortierella alpina. AB - BACKGROUND: Arachidonic acid (ARA), which is a omega-6 polyunsaturated fatty acid, has a wide range of biological activities and is an essential component of cellular membranes in some human tissues. Mortierella alpina is the best strain for industrial production of ARA. To increase its yield of arachidonic acid, heavy ion beam irradiation mutagenesis of Mortierella alpina was carried out in combination with triclosan and octyl gallate treatment. RESULTS: The obtained mutant strain F-23 ultimately achieved an ARA yield of 5.26 g L- 1, which is 3.24 times higher than that of the wild-type strain. In addition, quantitative real time PCR confirmed that the expression levels of fatty acid synthase (FAS), Delta5-desaturase, Delta6-desaturase, and Delta9-desaturase were all significantly up-regulated in the mutant F-23 strain, especially Delta6- and Delta9-desaturase, which were up-regulated 3- and 2-fold, respectively. CONCLUSIONS: This study confirmed a feasible mutagenesis breeding strategy for improving ARA production and provided a mutant of Mortierella alpina with high ARA yield. PMID- 29716563 TI - Standardised high dose versus low dose cranberry Proanthocyanidin extracts for the prevention of recurrent urinary tract infection in healthy women [PACCANN]: a double blind randomised controlled trial protocol. AB - BACKGROUND: Urinary tract infections (UTIs) are amongst the most common bacterial infections affecting women. Although antibiotics are the treatment of choice for UTI, cranberry derived products have been used for many years to prevent UTIs, with limited evidence as to their efficacy. Our objective is to assess the efficacy of a cranberry extract capsule standardized in A-type linkage proanthocyanidins (PACs) for the prevention of recurrent urinary tract infection. METHODS: We will perform a 1:1 randomized, controlled, double blind clinical trial in women aged 18 years or more who present >=2 UTIs in 6 months or >= 3 UTIs in 12 months. One hundred and forty-eight women will be recruited and randomized in two groups to either receive an optimal dose of cranberry extract quantified and standardized in PACs (2 * 18.5 mg PACs per day) or a control dose (2 * 1 mg PACs per day). The primary outcome for the trial is the mean number of new symptomatic UTIs in women during a 6-month intervention period. Secondary outcomes are: (1) To evaluate the mean number of new symptomatic UTIs with pyuria as demonstrated by a positive leucocyte esterase test; (2) To detect the mean number of new symptomatic culture-confirmed UTIs; (3) To quantify urinary PACs metabolites in women who take a daily dose of 37 mg PACs per day compared to women who take a daily dose of 2 mg per day for 6 months; (4) To characterize women who present recurrent UTI based on known risk factors for recurrent UTI; (5) To describe the side effects of daily intake of cranberry extract containing 37 mg PACs compared to 2 mg PACs. This report provides comprehensive methodological data for this randomized controlled trial. DISCUSSION: The results of this trial will inform urologists, gynaecologists, family physicians and other healthcare professionals caring for healthy women with recurrent UTI, as to the benefits of daily use of an optimal dose of cranberry extract for the prevention of recurrent UTI. TRIAL REGISTRATION: Clinicaltrials.gov, identifier: NCT02572895 October 8th 2015. PMID- 29716564 TI - Assessment of the quality of patient-oriented information over internet on testicular cancer. AB - BACKGROUND: This study aimed to assess the quality and readability of patient education information available on the internet on testicular cancer. METHODS: Internet searches were performed using the keywords 'testicular cancer', 'testicular tumour', 'testicular tumor', 'testicular malignancy', 'germ cell tumour' and 'germ cell tumor' using Google, Yahoo! And Bing search engines with default settings. The first 50 web links appeared in each search engine were evaluated for their readability by using the validated Flesch Reading Ease Score (FRES) while accessibility, usability and reliability were assessed using the LIDA tool. The quality was assessed using DISCERN instrument. Non-parametric tests were used for statistical analysis. RESULTS: Overall, 900 websites were assessed and 62 websites were included in the analysis. Twenty two (22) websites (35.5%) were certified by Health on the Net Foundation code of conduct (HON code). The majority (n = 57, 91.9%) were non-governmental websites. The median FRES score was 51.6 (range: 28.1-74.1), the overall median LIDA score was 115 (range: 81-147); accessibility 55 (range: 46-61), reliability 22 (range: 8-45) and usability 38.5 (range: 21-50), while the median DISCERN score was 43.5 (range: 16-69). The DISCERN score was significantly associated with the overall LIDA score and usability and reliability components of the LIDA score (p < 0.001). However, no significant associations were observed between readability and accessibility. A significant correlation was noted between usability and reliability components of the LIDA score (Spearman's rho: 0.789, p < 0.001). CONCLUSION: In this study, the readability, reliability and quality scores of most websites were found to be suboptimal and hence, there is potential for improvement. As the internet is expanding rapidly as a readily available source of information to the public, it is essential to implement steps to ensure that highest quality information is provided without any commercial motivation or bias. PMID- 29716565 TI - Flu vaccination among patients with diabetes: motives, perceptions, trust, and risk culture - a qualitative survey. AB - BACKGROUND: Vaccination against seasonal influenza (SIV) is recommended for patients with diabetes, but their vaccination coverage is unsatisfactory in France and elsewhere. This qualitative survey of people with diabetes sought to explore 1) the extent to which SIV-related behaviour is more or less automatic; 2) reasons they choose/reject SIV; 3) their trust/distrust in authorities, science, and medicine. METHODS: We conducted semi-structured in-depth interviews of 19 adults with diabetes in 2014. We recruited them through physicians or patient associations and implemented an analysis of thematic content. RESULTS: Eight patients were vaccinated against flu in the preceding flu season and 11 were not. SIV uptake and refusal were stable over time and justified by multiple arguments. Coupons for free vaccines and regular doctor visits contributed to the habit of vaccination. Vaccination decisions were frequently anchored in past experiences of influenza and its vaccine. Patients often justified non vaccination with attitudes of trivialisation/relativisation of influenza associated risks and the perception that these can be controlled by means other than vaccination (e.g., through the avoidance of exposure). Some misbeliefs (e.g., SIV causes influenza) and doubts about SIV effectiveness and safety also existed. Several patients reported increased mistrust of SIV since the A/H1N1 pandemic in 2009. Patients trusted their doctors strongly regardless of their SIV behaviour, but unvaccinated patients had little trust in the government and pharmaceutical companies. Some discordances were found between perceptions and behaviour (e.g., remaining vaccinated despite doubts about SIV effectiveness or remaining unvaccinated despite feelings of vulnerability towards influenza complication), suggesting the existence of some vaccine hesitancy among patients. CONCLUSION: This study among patients with diabetes suggest that SIV uptake is stable, thanks to a favourable environment. Nonetheless, SIV refusal is also stable over time. Unvaccinated patients used multiple arguments to justify SIV refusal, including compensatory health beliefs. Physicians should take every opportunity to recommend SIV. The necessary individualised patient education regarding SIV requires better physician training in patients priorities. While almost all patients strongly trust their doctors, unvaccinated patients distrust distal stakeholders: it is absolutely essential to restore trust in them and to develop new more effective influenza vaccines. PMID- 29716567 TI - The value of program science to optimize knowledge brokering on infectious diseases for public health. AB - BACKGROUND: Knowledge translation (KT) and related terms have variously been defined as process and as products. In this paper we contribute to debates on effective KT, specifically knowledge brokering, by describing an adaptation of Program Science that aligns with the real-world of public health activities. We describe an adaptation of the Program Science framework to our knowledge translation and brokering planning and projects at the National Collaborating Centre for Infectious Diseases. The systematic approach allows for layering of knowledge year to year and translating knowledge from one infectious disease content area to another. Using a recent forum on syphilis outbreaks as an example, we also demonstrate the value of using Program Science to shape the design and delivery of the knowledge brokering event. CONCLUSION: The use of scientific knowledge to improve public health program design, implementation and evaluation forms the basis for the program science framework. Providing the right public health information to the right audience at the right time can foster long term outcomes of networks and new partnerships which can potentially improve delivery of public health services. PMID- 29716566 TI - Active aging - resilience and external support as modifiers of the disablement outcome: AGNES cohort study protocol. AB - BACKGROUND: Population aging increases the need for knowledge on positive aspects of aging, and contributions of older people to their own wellbeing and that of others. We defined active aging as an individual's striving for elements of wellbeing with activities as per their goals, abilities and opportunities. This study examines associations of health, health behaviors, health literacy and functional abilities, environmental and social support with active aging and wellbeing. We will develop and validate assessment methods for physical activity and physical resilience suitable for research on older people, and examine their associations with active aging and wellbeing. We will examine cohort effects on functional phenotypes underlying active aging and disability. METHODS: For this population-based study, we plan to recruit 1000 participants aged 75, 80 or 85 years living in central Finland, by drawing personal details from the population register. Participants are interviewed on active aging, wellbeing, disability, environmental and social support, mobility, health behavior and health literacy. Physical activity and heart rate are monitored for 7 days with wearable sensors. Functional tests include hearing, vision, muscle strength, reaction time, exercise tolerance, mobility, and cognitive performance. Clinical examination by a nurse and physician includes an electrocardiogram, tests of blood pressure, orthostatic regulation, arterial stiffness, and lung function, as well as a review of chronic and acute conditions and prescribed medications. C-reactive protein, small blood count, cholesterol and vitamin D are analyzed from blood samples. Associations of factors potentially underlying active aging and wellbeing will be studied using multivariate methods. Cohort effects will be studied by comparing test results of physical and cognitive functioning with results of a cohort examined in 1989-90. CONCLUSIONS: The current study will renew research on positive gerontology through the novel approach to active aging and by suggesting new biomarkers of resilience and active aging. Therefore, high interdisciplinary impact is expected. This cross-sectional study will not provide knowledge on temporal order of events or causality, but an innovative cross sectional dataset provides opportunities for emergence of novel creative hypotheses and theories. PMID- 29716569 TI - Delays to treatment initiation is associated with tuberculosis treatment outcomes among patients on directly observed treatment short course in Southwest Ethiopia: a follow-up study. AB - BACKGROUND: Despite reported long delays to initiate anti-TB treatment and poor outcomes in different parts of Ethiopia and elsewhere, evidences on association between the delay and treatment outcomes are scanty. METHODS: A follow up study among 735 new TB cases registered at health facilities in districts of southwest Ethiopia was conducted from January 2015 to June 2016. Patients reported days elapsed between onset of illness and treatment commencement of 30 days cutoff was considered to ascertain exposure. Thus, those elapsed beyond 30 days to initiate anti-TB treatment since onset of illness were exposed and otherwise non-exposed. The cases were followed until earliest outcome was observed. Treatment outcomes was ascertained as per the World Health Organization standard definitions and dichotomized into 'successful' when cured or treatment completed and 'unsuccessful' when lost to follow-up or died or treatment failure. Bivariate and multiple log-binomial models were fitted to identify predictors of unsuccessful outcomes. RESULTS: The overall treatment success among the treatment cohort was 89.7% (88.4% vs. 94.2%, p = 0.01 respectively among those initiated treatment beyond and within of 30 days of onset of illness. Higher risk of unsuccessful outcome was predicted by treatment initiation beyond 30 days of onset [Adjusted Relative Risk (ARR) = 1.92, 95%CI:1.30, 2.81], HIV co-infection (ARR = 2.18, 95%CI:1.47, 3.25) and received treatment at hospital (ARR = 3.73, 95%CI:2.23, 6.25). On the other hand, lower risk of unsuccessful outcome was predicted by weight gain (ARR = 0.40, 95%CI:0.19, 0.83) and sputum smear negative conversion (ARR = 0.17,95% CI:0.09, 0.33) at the end of second month treatment. CONCLUSION: Higher risk of unsuccessful outcome is associated with prolonged days elapsed between onset of illness and treatment commencement. Hence, promotion of early care seeking, improving diagnostic and case holding efficiencies of health facilities and TB/HIV collaborative interventions can reduce risk of unsuccessful outcome. PMID- 29716568 TI - MERS transmission and risk factors: a systematic review. AB - BACKGROUND: Since Middle East respiratory syndrome (MERS) infection was first reported in 2012, many studies have analysed its transmissibility and severity. However, the methodology and results of these studies have varied, and there has been no systematic review of MERS. This study reviews the characteristics and associated risk factors of MERS. METHOD: We searched international (PubMed, ScienceDirect, Cochrane) and Korean databases (DBpia, KISS) for English- or Korean-language articles using the terms "MERS" and "Middle East respiratory syndrome". Only human studies with > 20 participants were analysed to exclude studies with low representation. Epidemiologic studies with information on transmissibility and severity of MERS as well as studies containing MERS risk factors were included. RESULT: A total of 59 studies were included. Most studies from Saudi Arabia reported higher mortality (22-69.2%) than those from South Korea (20.4%). While the R0 value in Saudi Arabia was < 1 in all but one study, in South Korea, the R0 value was 2.5-8.09 in the early stage and decreased to < 1 in the later stage. The incubation period was 4.5-5.2 days in Saudi Arabia and 6 7.8 days in South Korea. Duration from onset was 4-10 days to confirmation, 2.9 5.3 days to hospitalization, 11-17 days to death, and 14-20 days to discharge. Older age and concomitant disease were the most common factors related to MERS infection, severity, and mortality. CONCLUSION: The transmissibility and severity of MERS differed by outbreak region and patient characteristics. Further studies assessing the risk of MERS should consider these factors. PMID- 29716570 TI - Insomnia as an independent predictor of suicide attempts: a nationwide population based retrospective cohort study. AB - BACKGROUND: Numerous studies have verified that insomnia is associated with suicidal ideation, suicide attempts, and death by suicide. Limited population based cohort studies have been conducted to examine the association. The present study aimed to analyze whether insomnia increases the risk of suicide attempts and verify the effects of insomnia on suicide risk. METHODS: This study is a cohort study using 2000-2013 hospitalization data from the National Health Insurance Research Database (NHIRD) to track the rate of suicide attempts among insomnia patients aged 15 years or older. In addition, a 1:2 pairing based on sex, age, and date of hospitalization was conducted to identify the reference cohort (patients without insomnia). Cox proportional hazard model was used to assess the effects of insomnia on suicide risk. RESULTS: The total number of hospitalized patients aged 15 years or older was 479,967 between 2000 and 2013 (159,989 patients with insomnia and 319,978 patients without insomnia). After adjusting for confounders, suicide risk in insomnia patients was 3.533-fold that of patients without insomnia (adjusted hazard ratio [HR] = 3.533, 95% confidence interval [CI] = 3.059-4.080, P < 0.001). Suicide risk in low-income patients was 1.434-fold (adjusted HR = 1.434, 95% CI = 1.184-1.736, P < 0.001) that of non-low income patients. Suicide risk in patients with drug dependence and with mental disorders was 1.592-fold (adjusted HR = 1.592, 95% CI = 1.220-2.077, P < 0.001) and 4.483-fold (adjusted HR = 4.483, 95% CI = 3.934-5.109, P < 0.001) that of patients without drug dependence and without mental disorders, respectively. In the female population, suicide risk in insomnia patients was 4.186-fold (adjusted HR = 4.186, 95% CI = 3.429-5.111, P < 0.001) that of patients without insomnia. Among patients aged 25-44 years, suicide risk in insomnia patients was 5.546-fold (adjusted HR = 5.546, 95% CI = 4.236-7.262, P < 0.001) that of patients without insomnia. Furthermore, the suicide risk of insomnia patients with mental disorders was 18.322-fold that of patients without insomnia and mental disorders (P < 0.001). CONCLUSION: Insomnia, low income, drug dependence, and mental disorders are independent risk factors for suicide attempts. Female patients and those aged 25-44 years are at high risk of suicide due to insomnia. Insomnia, mental disorders, and low income exhibit a synergistic effect on suicide attempts. Clinicians should pay attention to mental status and income level of insomnia patients. PMID- 29716571 TI - Development of an intervention delivered by mobile phone aimed at decreasing unintended pregnancy among young people in three lower middle income countries. AB - BACKGROUND: Unintended pregnancies can result in poorer health outcomes for women, children and families. Young people in low and middle income countries are at particular risk of unintended pregnancies and could benefit from innovative contraceptive interventions. There is growing evidence that interventions delivered by mobile phone can be effective in improving a range of health behaviours. This paper describes the development of a contraceptive behavioural intervention delivered by mobile phone for young people in Tajikistan, Bolivia and Palestine, where unmet need for contraception is high among this group. METHODS: Guided by Intervention Mapping, the following steps contributed to the development of the interventions: (1) needs assessment; (2) specifying behavioural change to result from the intervention; (3) selecting behaviour change methods to include in the intervention; (4) producing and refining the intervention content. RESULTS: The results of the needs assessment produced similar interventions across the countries. The interventions consist of short daily messages delivered over 4 months (delivered by text messaging in Palestine and mobile phone application instant messages in Bolivia and Tajikistan). The messages provide information about contraception, target attitudes that are barriers to contraceptive uptake and support young people in feeling that they can influence their reproductive health. The interventions each contain the same ten behaviour change methods, adapted for delivery by mobile phone. CONCLUSIONS: The development resulted in a well-specified, theory-based intervention, tailored to each country. It is feasible to develop an intervention delivered by mobile phone for young people in resource-limited settings. PMID- 29716572 TI - The Association among Emotions and Food Choices in First-Year College Students Using mobile-Ecological Momentary Assessments. AB - BACKGROUND: Studies have examined the associations between emotions and overeating but have only rarely considered associations between emotions and specific food choices. The purpose of this secondary data analysis was to use mobile ecological momentary assessments (mEMAs) to examine associations between emotions and food choices among first-year college students living in residence halls. METHODS: Using an intensive repeated-measures design, mEMAs were used to assess concurrent emotions and food choices in a racially/ethnically diverse sample of first-year college students (n = 663). Emotions were categorized as negative (sad, stressed, tired), positive (happy, energized, relaxed), and apathetic (bored, meh). Assessments were completed multiple times per day on four quasi-randomly selected days (three random weekdays and one random weekend day) during a 7-day period using random prompt times. Generalized estimating equations (GEE) were used to examine between- and within-person associations of emotional status with a variety of healthy and unhealthy food choices (sweets, salty snacks/fried foods, fruits/vegetables, pizza/fast food, sandwiches/wraps, meats/proteins, pasta/rice, cereals), adjusting for gender, day of week, and time of day, accounting for within-person dependencies among repeated measurements of eating behavior. RESULTS: At the between-person level, participants who reported positive emotions more frequently compared to others consumed meats/proteins more often (OR = 1.8; 99% CI = 1.2, 2.8). At the within-person level, on occasions when any negative emotion was reported (versus no negative emotion reported) participants were more likely to consume meats/proteins (OR = 1.5, 99% CI = 1.0, 2.1); on occasions when any positive emotion was reported as compared to occasions with no positive emotions, participants were more likely to consume sweets (OR = 1.7, 99% CI = 1.1, 2.6), but less likely to consume pizza/fast food (OR = 0.6, 99% CI = 0.4, 1.0). CONCLUSIONS: Negative and positive emotions were significantly associated with food choices. mEMA methodology provides a unique opportunity to examine these associations within and between people, providing insights for individual and population-level interventions. These findings can be used to guide future longitudinal studies and to develop and test interventions that encourage healthy food choices among first-year college students and ultimately reduce the risk of weight gain. PMID- 29716573 TI - Health-related quality of life in paediatric arterial hypertension: a cross sectional study. AB - BACKGROUND: The prevalence of paediatric hypertension is increasing worldwide, especially due to the childhood obesity epidemic, and is an important public health concern. While the Health-Related Quality of Life (HRQoL) was already shown to be impaired in the adult hypertensive population, a scarcity of data still exists on HRQoL in paediatric hypertensive patients. Our purpose was thus to assess the HRQoL of children and adolescents with arterial hypertension, using self- and proxy-reports, and to determine the correlations between child and parent questionnaire scores. METHODS: The Paediatric Quality of Life InventoryTM 4.0 Generic Core Scales were administered via post to children and adolescents, aged 5-18 years, with primary or secondary arterial hypertension and parents as proxy-reports. Patients were recruited from a paediatric nephrology unit in a tertiary hospital, using an out-patient clinic visit registry. Healthy school children and adolescents from a local primary school, aged 6 to 15 years, and their parents formed the control group. HRQoL group comparisons were calculated with independent samples t-test and child-parent correlations with the Pearson's r correlation coefficient. RESULTS: In total we recruited 139 patient and 199 control group participants as self- and proxy-reports. Scores from self- as well as proxy-reports indicated a significantly lower overall HRQoL in the paediatric hypertensive population (95% CI for mean score difference: - 11.02, - 2.86 for self- and - 10.28, - 2.67 for proxy-reports; p = .001). In self-reports, lower physical (95% CI: -13.95, - 4.89; p = <.001), emotional (95% CI: -12.96, - 2.38; p = .005), school (95% CI: -11.30, - 0.42; p = .035), and psychosocial functioning scores were observed (95% CI: -10.34, - 1.89; p = .005). Parent proxy reports were lower in physical (95% CI: -14.31, - 5.39; p = <.001), emotional (95% CI: -12.39, - 2.60; p = .003) and psychosocial scores (95% CI: -9.36, - 1.34; p = .009). Pearson's r values ranged between 0.62 to 0.79 in patient and 0.56 to 0.80 in control sample (p < .001). Interestingly, hypertensive children reported lower social functioning scores than hypertensive adolescents (p < .001). CONCLUSIONS: This cross-sectional study gives insight into the detrimental impact of hypertension on children's and adolescents HRQoL, which may inform public health experts. Furthermore, it shows that clinicians should aim to improve patients' physical and psychosocial well-being throughout their development. PMID- 29716574 TI - How to define core entrustable professional activities for entry into residency? PMID- 29716575 TI - Terminalia chebula extract prevents scopolamine-induced amnesia via cholinergic modulation and anti-oxidative effects in mice. AB - BACKGROUND: Terminalia chebula Retz. (Combretaceae) is a traditional herbal medicine that is widely used in the treatment of diabetes, immunodeficiency diseases, and stomach ulcer in Asia. However, the anti-amnesic effect of T. chebula has not yet been investigated. The present study was designed to determine whether T. chebula extract (TCE) alleviates amnesia induced by scopolamine in mice. We also investigated possible mechanisms associated with cholinergic system and anti-oxidant effects. METHODS: TCE (100 or 200 mg/kg) was orally administered to mice for fourteen days (days 1-14), and scopolamine was intraperitoneally injected to induce memory impairment for seven days (days 8 14). Learning and memory status were evaluated using the Morris water maze. Hippocampal levels of acetylcholine (ACh), acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) were measured ex vivo. Levels of reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA) in the hippocampus were also examined. RESULTS: In the Morris water maze task, TCE treatment reversed scopolamine-induced learning and memory deficits in acquisition and retention. TCE reduced hippocampal AChE activities and increased ChAT and ACh levels in the scopolamine-induced model. Moreover, TCE treatment suppressed scopolamine-induced oxidative damage by ameliorating the increased levels of ROS, NO, and MDA. CONCLUSION: These findings suggest that TCE exerts potent anti amnesic effects via cholinergic modulation and anti-oxidant activity, thus providing evidence for its potential as a cognitive enhancer for amnesia. PMID- 29716576 TI - Protocol: a multi-level intervention program to reduce stress in 9-1-1 telecommunicators. AB - BACKGROUND: Nationwide, emergency response systems depend on 9-1-1 telecommunicators to prioritize, triage, and dispatch assistance to those in distress. 9-1-1 call center telecommunicators (TCs) are challenged by acute and chronic workplace stressors: tense interactions with citizen callers in crisis; overtime; shift-work; ever-changing technologies; and negative work culture, including co-worker conflict. This workforce is also subject to routine exposures to secondary traumatization while handling calls involving emergency situations and while making time urgent, high stake decisions over the phone. Our study aims to test the effectiveness of a multi-part intervention to reduce stress in 9-1-1 TCs through an online mindfulness training and a toolkit containing workplace stressor reduction resources. METHODS/DESIGN: The study employs a randomized controlled trial design with three data collection points. The multi-part intervention includes an individual-level online mindfulness training and a call center-level organizational stress reduction toolkit. 160 TCs will be recruited from 9-1-1 call centers, complete a baseline survey at enrollment, and are randomly assigned to an intervention or a control group. Intervention group participants will start a 7-week online mindfulness training developed in-house and tailored to 9-1-1 TCs and their call center environment; control participants will be "waitlisted" and start the training after the study period ends. Following the intervention group's completion of the mindfulness training, all participants complete a second survey. Next, the online toolkit with call-center wide stress reduction resources is made available to managers of all participating call centers. After 3 months, a third survey will be completed by all participants. The primary outcome is 9-1-1 TCs' self-reported symptoms of stress at three time points as measured by the C-SOSI (Calgary Symptoms of Stress Inventory). Secondary outcomes will include: perceptions of social work environment (measured by metrics of social support and network conflict); mindfulness; and perceptions of social work environment and mindfulness as mediators of stress reduction. DISCUSSION: This study will evaluate the effectiveness of an online mindfulness training and call center-wide stress reduction toolkit in reducing self-reported stress in 9-1-1 TCs. The results of this study will add to the growing body of research on worksite stress reduction programs. TRIAL REGISTRATION: ClinicalTrials.gov Registration Number: NCT02961621 Registered on November 7, 2016 (retrospectively registered). PMID- 29716577 TI - Is adolescent body mass index and waist circumference associated with the food environments surrounding schools and homes? A longitudinal analysis. AB - BACKGROUND: There has been considerable interest in the role of access to unhealthy food options as a determinant of weight status. There is conflict across the literature as to the existence of such an association, partly due to the dominance of cross-sectional study designs and inconsistent definitions of the food environment. The aim of our study is to use longitudinal data to examine if features of the food environment are associated to measures of adolescent weight status. METHODS: Data were collected from secondary schools in Leeds (UK) and included measurements at school years 7 (ages 11/12), 9 (13/14), and 11 (15/16). Outcome variables, for weight status, were standardised body mass index and standardised waist circumference. Explanatory variables included the number of fast food outlets, supermarkets and 'other retail outlets' located within a 1 km radius of an individual's home or school, and estimated travel route between these locations (with a 500 m buffer). Multi-level models were fit to analyse the association (adjusted for confounders) between the explanatory and outcome variables. We also examined changes in our outcome variables between each time period. RESULTS: We found few associations between the food environment and measures of adolescent weight status. Where significant associations were detected, they mainly demonstrated a positive association between the number of amenities and weight status (although effect sizes were small). Examining changes in weight status between time periods produced mainly non-significant or inconsistent associations. CONCLUSIONS: Our study found little consistent evidence of an association between features of the food environment and adolescent weight status. It suggests that policy efforts focusing on the food environment may have a limited effect at tackling the high prevalence of obesity if not supported by additional strategies. PMID- 29716578 TI - Selected indicators and determinants of women's health in the vicinity of a copper mine development in northwestern Zambia. AB - BACKGROUND: Large projects in the extractive industry sector can affect people's health and wellbeing. In low- and middle-income countries (LMICs), women's health is of particular concern in such contexts due to potential educational and economic disadvantages, vulnerability to transactional sex and unsafe sex practices. At the same time, community health interventions and development initiatives present opportunities for women's and maternal health. METHODS: Within the frame of the health impact assessment (HIA) of the Trident copper mining project in Zambia, two health surveys were conducted (baseline in 2011 and follow-up in 2015) in order to monitor health and health-related indicators. Emphasis was placed on women residing in the mining area and, for comparison, in settings not impacted by the project. RESULTS: All measured indicators improved over time, regardless of whether communities were affected by the project or not. Additionally, the percentage of mothers giving birth in a health facility, the percentage of women who acknowledge that HIV cannot be transmitted by witchcraft or other supernatural means and the percentage of women having ever tested for HIV showed a significant increase in the impacted sites but not in the comparison communities. In 2015, better health, behavioural and knowledge outcomes in women were associated with employment by the project (or a sub-contractor thereof), migration background, increased wealth and higher educational attainment. CONCLUSIONS: Our study reveals that natural resource development projects can positively impact women's health, particularly if health risks are adequately anticipated and managed. Hence, the conduct of a comprehensive HIA should be a requirement at the feasibility stage of any large infrastructure project, particularly in LMICs. Continued monitoring of health outcomes and wider determinants of health after the initial assessment is crucial to judge the project's influence on health and for reducing inequalities over time. PMID- 29716579 TI - Laterally spreading tumour of the distal stomach: a case report. AB - BACKGROUND: Laterally spreading tumours (LSTs) are superficial neoplasms that usually extend laterally along the intra-luminal wall of the gastrointestinal tract. Recently, the incidence of LSTs in the colorectal mucosa has greatly increased. However, LSTs in the stomach are exceedingly rare and have never been previously reported. CASE PRESENTATION: Here, we report a 69-year-old male with epigastric pain and a gastric LST 6 cm in diameter located in the distal stomach and grossly extended into the duodenal bulb. The stomach lesion was initially diagnosed as high-grade intraepithelial neoplasia, while the duodenal lesion was diagnosed as a tubulovillous adenoma. A therapeutic strategy of endoscopic submucosal dissection and distal gastrectomy was applied. The surgeries and postoperative course were uneventful, and the patient remained asymptomatic 1 year after surgery. CONCLUSIONS: This is a clinically significant case, as it provides detailed information regarding laterally spreading early gastric cancer and emphasizes the diagnostic and therapeutic approaches for early gastric cancerous lesions. PMID- 29716580 TI - Cost-effectiveness of the mobile application TCApp combined with face-to-face CBT treatment compared to face-to-face CBT treatment alone for patients with an eating disorder: study protocol of a multi-centre randomised controlled trial. AB - BACKGROUND: The clinical utility of the existing apps for people with eating disorders (EDs) is not clear. The TCApp has been specifically developed for people with EDs, is based on the principles of Cognitive Behavioural Treatment (CBT) and allows a bidirectional link between the patient and the therapist. The objectives of the study are, first, to assess the clinical efficacy of a combined intervention for Eating Disorders (EDs) that includes an online intervention through the TCApp plus standard face-to-face CBT in comparison to standard face to-face CBT alone, and second, to examine the cost-effectiveness of the TCApp and identify potential predicting, moderating and mediating variables that promote or hinder the implementation of the TCApp in ED units in Spain. METHODS: The study methodology is that of a randomised controlled trial combining qualitative and quantitative methods, with a 6-month follow-up. Approximately 250 patients over 12 years old with a diagnosis of an ED from several ED units in Spain will be randomised to one of two different conditions. Participants, their caregivers, healthcare professionals and technical staff involved in the development and maintenance of the application will be assessed at baseline (T0), post intervention (T1) and at 6 months follow-up (T2). Primary outcome measures will include ED symptomatology while secondary measures will include general psychopathology and quality of life for patients, quality of life and caregiving experience for family caregivers and adoption-related variables for all participants involved, such as perceived usability, user's satisfaction and technology acceptance. For the cost-effectiveness analysis, we will assess quality-adjusted life years (QALYs); total societal cost will be estimated using costs to patients and the health plan, and other related costs. DISCUSSION: The study will provide an important advance in the treatment of EDs; in the long term, it is expected to improve the quality of patient care and the treatment efficacy and to reduce waiting lists as well as direct and indirect costs associated with the treatment of EDs in Spain. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03197519 ; registration date: June 23, 2017. PMID- 29716581 TI - Remediating lapses in professionalism among undergraduate pre-clinical medical students in an Asian Institution: a multimodal approach. AB - BACKGROUND: Fostering personal identity formation and professional development among undergraduate medical students is challenging. Based on situated learning, experiential learning and role-modelling frameworks, a six-week course was developed to remediate lapses in professionalism among undergraduate medical students. This study aims to explore the students' perceptions of their personal identity formation and professional development following completion of the course. METHODS: This qualitative study, adopting a phenomenological design, uses the participants' reflective diaries as primary data sources. In the pilot course, field work, role-model shadowing and discussions with resource personnel were conducted. A total of 14 students were asked to provide written self reflections. Consistent, multi-source feedback was provided throughout the course. A thematic analysis was conducted to identify the key processes of personal and professional development among the students during remediation. RESULTS: Three main themes were revealed. First, students highlighted the strength of small group activities in helping them 'internalise the essential concepts'. Second, the role-model shadowing supported their understanding of 'what kind of medical doctors they would become'. Third, the field work allowed them to identify 'what the "noble values" are and how to implement them in daily practice'. CONCLUSION: By implementing multimodal activities, the course has high potential in supporting personal identity formation and professional development among undergraduate pre-clinical medical students, as well as remediating their lapses in professionalism. However, there are challenges in implementing the model among a larger student population and in documenting the long-term impact of the course. PMID- 29716582 TI - Effects of summer internship and follow-up distance mentoring programs on middle and high school student perceptions and interest in health careers. AB - BACKGROUND: Minorities are underrepresented in health professions and efforts to recruit minority students into health careers are considered a way to reduce health disparities. There is little research about the effectiveness of these programs, other than satisfaction. This study aimed to measure program effects on student understanding of and interest in health careers. METHODS: Students took a career interest inventory, completed a scale measuring their self-reported understanding and interest in health careers, and wrote essays about health careers before and after completing a 1 week on campus internship on health careers and after a 9 month follow up distance mentoring program where they continued to interact with university faculty by videoconference about career options. Changes in inventory, scale, and essay scores were analyzed for changes over time using Wilcoxon and Mann-Whitney tests. RESULTS: Inventory scores were unchanged over time, but scale and essay scores trended upward significantly post internship and mentoring. CONCLUSION: Health career education and mentoring programs can positively affect student knowledge of health careers and their attitudes about them. The study's methods extend measures of program impact beyond satisfaction. PMID- 29716583 TI - Immunization with one Theileria parva strain results in similar level of CTL strain-specificity and protection compared to immunization with the three component Muguga cocktail in MHC-matched animals. AB - BACKGROUND: The tick-borne protozoan parasite Theileria parva causes a usually fatal cattle disease known as East Coast fever in sub-Saharan Africa, with devastating consequences for poor small-holder farmers. Immunity to T. parva, believed to be mediated by a cytotoxic T lymphocyte (CTL) response, is induced following natural infection and after vaccination with a live vaccine, known as the Infection and Treatment Method (ITM). The most commonly used version of ITM is a combination of parasites derived from three isolates (Muguga, Kiambu 5 and Serengeti-transformed), known as the "Muguga cocktail". The use of a vaccine comprising several strains is believed to be required to induce a broad immune response effective against field challenge. In this study we investigated whether immunization with the Muguga cocktail induces a broader CTL response than immunization with a single strain (Muguga). RESULTS: Four MHC haplotype-matched pairs of cattle were immunized with either the trivalent Muguga cocktail or the single Muguga strain. CTL specificity was assessed on a panel of five different strains, and clonal responses to these strains were also assessed in one of the MHC-matched pairs. We did not find evidence for a broader CTL response in animals immunized with the Muguga cocktail compared to those immunized with the Muguga strain alone, in either the bulk or clonal CTL analyses. This was supported by an in vivo trial in which all vaccinated animals survived challenge with a lethal dose of the Muguga cocktail vaccine stabilate. CONCLUSION: We did not observe any substantial differences in the immunity generated from animals immunized with either Muguga alone or the Muguga cocktail in the animals tested here, corroborating earlier results showing limited antigenic diversity in the Muguga cocktail. These results may warrant further field studies using single T. parva strains as future vaccine candidates. PMID- 29716584 TI - Clinicians' attitude towards a placebo-controlled randomised clinical trial investigating the effect of neuraminidase inhibitors in adults hospitalised with influenza. AB - BACKGROUND: The value of neuraminidase inhibitors (NAIs) in reducing severe clinical outcomes from influenza is debated. A clinical trial to generate better evidence is desirable. However, it is unknown whether UK clinicians would support a placebo-controlled trial. A survey was conducted to determine the attitude of clinicians towards a clinical trial and their current practice in managing adults admitted to hospital with suspected influenza. METHODS: Senior clinicians (n = 50) across the UK actively involved in the care of patients hospitalised with severe respiratory infections and/or respiratory infection research were invited to participate in an on-line survey. Participants were asked their opinion on the evidence for benefit of NAIs in influenza, their current practice in relation to: a) testing for influenza; b) treating empirically with NAIs; and c) when influenza infection is virolologically confirmed, prescribing NAIs. RESULTS: Thirty-five (70%) of 50 clinicians completed the survey. Respondents were drawn mainly from infectious diseases, intensive care and respiratory medicine. Only 11 (31%) of 35 respondents agreed that NAIs are effective at reducing influenza mortality; 14 (40%) disagreed, 10 (28.6%) neither agreed nor disagreed. When managing adults admitted to non-ICU wards with a respiratory infection during an influenza season, 15 (51.7%) clinicians indicated they would usually perform a test for influenza in greater than 60% of patients but only 9 (31%) would treat empirically with NAIs in greater than 60% of patients. Few clinicians would either test or empirically treat patients presenting with other (non-respiratory infection related) diagnoses. If influenza infection is confirmed, 17 (64.5%) clinicians would prescribe NAIs in greater than 80% of patients with a respiratory infection treated on non-ICU wards Thirty-one (89%) clinicians agreed that a placebo-controlled clinical trial should be conducted and 29 (85%) would participate in such a trial. CONCLUSIONS: There is strong support from UK clinicians for a placebo-controlled trial of NAI treatment in adults hospitalised with suspected influenza. Current variation in medical opinion and clinical practice demonstrates collective equipoise, supporting ethical justification for a trial. Low use of NAIs in the UK suggests randomisation of treatment would not substantially divert patients towards placebo. PMID- 29716586 TI - Access to health care for uninsured Latina immigrants in South Carolina. AB - BACKGROUND: South Carolina is considered a "new destination" state for Latino immigrants. Language barriers, transportation difficulties, low socioeconomic status, inflexible work schedules, different cultural norms, and anxiety and fear related to the current anti-immigrant political climate all negatively impact Latino immigrants' frequency of contact with the health care system, and consequently they suffer poor health outcomes. The study objective was to explore uninsured Latina immigrant women's access to health care and alternative treatment strategies in coastal South Carolina. METHODS: The study design was a qualitative interview design. Thirty women participated in semi-structured interviews in community sites. Thematic analysis identified salient categories of topics across interview participants. RESULTS: The themes were organized into four primary categories including: 1) Barriers and Facilitators to Healthcare, 2) Health Behaviors and Coping Mechanisms, 3) Disease Management Strategies, and 4) Cultural Factors. Participants demonstrated determination for accessing care but reported that their primary health care access barriers included the high cost of services, lack of health insurance, family and work responsibilities, and language barriers. Coping mechanisms included activating their social networks, visiting family and friends and assisting one another with navigating life challenges. CONCLUSION: Participants overcame obstacles to obtain healthcare for themselves and their family members despite the multiple barriers presented. Social networks were leveraged to protect against some of the negative effects of financial barriers to health care access. PMID- 29716585 TI - Clinical trial registration and reporting: a survey of academic organizations in the United States. AB - BACKGROUND: Many clinical trials conducted by academic organizations are not published, or are not published completely. Following the US Food and Drug Administration Amendments Act of 2007, "The Final Rule" (compliance date April 18, 2017) and a National Institutes of Health policy clarified and expanded trial registration and results reporting requirements. We sought to identify policies, procedures, and resources to support trial registration and reporting at academic organizations. METHODS: We conducted an online survey from November 21, 2016 to March 1, 2017, before organizations were expected to comply with The Final Rule. We included active Protocol Registration and Results System (PRS) accounts classified by ClinicalTrials.gov as a "University/Organization" in the USA. PRS administrators manage information on ClinicalTrials.gov. We invited one PRS administrator to complete the survey for each organization account, which was the unit of analysis. RESULTS: Eligible organization accounts (N = 783) included 47,701 records (e.g., studies) in August 2016. Participating organizations (366/783; 47%) included 40,351/47,701 (85%) records. Compared with other organizations, Clinical and Translational Science Award (CTSA) holders, cancer centers, and large organizations were more likely to participate. A minority of accounts have a registration (156/366; 43%) or results reporting policy (129/366; 35%). Of those with policies, 15/156 (11%) and 49/156 (35%) reported that trials must be registered before institutional review board approval is granted or before beginning enrollment, respectively. Few organizations use computer software to monitor compliance (68/366; 19%). One organization had penalized an investigator for non-compliance. Among the 287/366 (78%) accounts reporting that they allocate staff to fulfill ClinicalTrials.gov registration and reporting requirements, the median number of full-time equivalent staff is 0.08 (interquartile range = 0.02-0.25). Because of non-response and social desirability, this could be a "best case" scenario. CONCLUSIONS: Before the compliance date for The Final Rule, some academic organizations had policies and resources that facilitate clinical trial registration and reporting. Most organizations appear to be unprepared to meet the new requirements. Organizations could enact the following: adopt policies that require trial registration and reporting, allocate resources (e.g., staff, software) to support registration and reporting, and ensure there are consequences for investigators who do not follow standards for clinical research. PMID- 29716587 TI - Inclination towards research and the pursuit of a research career among medical students: an international cohort study. AB - BACKGROUND: Involvement of clinicians in biomedical research is imperative for the future of healthcare. Several factors influence clinicians' inclination towards research: the medical school experience, exposure to research article reading and writing, and knowledge of research. This cohort study follows up medical students at time of graduation to explore changes in their inclination towards research and pursuing a research career compared to their inclination at time of entry into medical school. METHODS: Students from medical schools in six different countries were enrolled in their first year of school and followed-up upon graduation in their final year. Students answered the same self-administered questionnaire at both time points. Changes in inclination towards research and pursuing a research career were assessed. Factors correlated with these changes were analysed. RESULTS: Of the 777 medical students who responded to the study questionnaire at entry into medical school, 332 (42.7%) completed the follow-up survey. Among these 332 students, there was no significant increase in inclination towards research or pursuing a research career over the course of their medical schooling. Students from a United States based school, in contrast to those from schools other countries, were more likely to report having research role models to guide them (51.5% vs. 0%-26.4%) and to have published in a peer reviewed journal (75.7% vs. 8.9%-45%). Absence of a role model was significantly associated with a decrease in inclination towards research, while an increased desire to learn more about statistics was significantly associated with an increase in inclination towards pursuing a research career. CONCLUSION: Most medical students did not experience changes in their inclination towards research or pursuing a research career over the course of their medical schooling. Factors that increased their inclination to undertaking research or pursuing a research career were availability of a good role model, and a good knowledge of both the research process and the analytical tools required. PMID- 29716588 TI - Prostaglandin E2 involvement in mammalian female fertility: ovulation, fertilization, embryo development and early implantation. AB - BACKGROUND: Infertility in mammalian females has been a challenge in reproductive medicine. The causes of female infertility include anovulation, ovulated oocyte defects, abnormal fertilization, and insufficient luteal support for embryo development, as well as early implantation. Ovulation induction, in vitro fertilization and luteal support regimens have been performed for decades to increase fertility rates. The identification of proteins and biochemical factors involved in female reproduction is essential to further increase female fertility rates. Evidence has shown that prostaglandins (PGs) might be involved in the female reproductive process, mainly ovulation, fertilization, and implantation. However, only a few studies on individual PGs in female reproduction have been done so far. This review aimed to identify the pivotal role of prostaglandin E2 (PGE2), a predominant PG, in female reproduction to improve fertility, specifically ovulation, fertilization, embryo development and early implantation. RESULTS: Prostaglandin E2 (PGE2) was shown to play a relevant role in the ovulatory cascade, including meiotic maturation, cumulus expansion and follicle rupture, through inducing ovulatory genes, such as Areg, Ereg, Has2 and Tnfaip6, as well as increasing intracellular cAMP levels. PGE2 reduces extracellular matrix viscosity and thereby optimizes the conditions for sperm penetration. PGE2 reduces the phagocytic activity of polymorphonuclear neutrophils (PMNs) against sperm. In the presence of PGE2, sperm function and binding capacity to oocytes are enhanced. PGE2 maintains luteal function for embryo development and early implantation. In addition, it induces chemokine expression for trophoblast apposition and adhesion to the decidua for implantation. CONCLUSION: It has been shown that PGE2 positively affects different stages of female fertility. Therefore, PGE2 should be taken into consideration when optimizing reproduction in infertile females. We suggest that in clinical practice, the administration of non-steroidal anti-inflammatory drugs, which are PGE2 synthesis inhibitors, should be reasonable and limited in infertile women. Additionally, assessments of PGE2 protein and receptor expression levels should be taken into consideration. PMID- 29716589 TI - A systematic review of the psychometric properties of the cross-cultural translations and adaptations of the Multidimensional Perceived Social Support Scale (MSPSS). AB - BACKGROUND: Social support (SS) has been identified as an essential buffer to stressful life events. Consequently, there has been a surge in the evaluation of SS as a wellbeing indicator. The Multidimensional Perceived Social Support Scale (MSPSS) has evolved as one of the most extensively translated and validated social support outcome measures. Due to linguistic and cultural differences, there is need to test the psychometrics of the adapted versions. However, there is a paucity of systematic evidence of the psychometrics of adapted and translated versions of the MSPSS across settings. OBJECTIVES: To understand the psychometric properties of the MSPSS for non-English speaking populations by conducting a systematic review of studies that examine the psychometric properties of non-English versions of the MSPSS. METHODS: We searched Africa-Wide Information, CINAHL, Medline and PsycINFO, for articles published in English on the translation and or validation of the MSPSS. Methodological quality and quality of psychometric properties of the retrieved translations were assessed using the COSMIN checklist and a validated quality assessment criterion, respectively. The two assessments were combined to produce the best level of evidence per language/translation. RESULTS: Seventy articles evaluating the MSPSS in 22 languages were retrieved. Most translations [16/22] were not rigorously translated (only solitary backward-forward translations were performed, reconciliation was poorly described, or were not pretested). There was poor evidence for structural validity, as confirmatory factor analysis was performed in only nine studies. Internal consistency was reported in all studies. Most attained a Cronbach's alpha of at least 0.70 against a backdrop of fair methodological quality. There was poor evidence for construct validity. CONCLUSION: There is limited evidence supporting the psychometric robustness of the translated versions of the MSPSS, and given the variability, the individual psychometrics of a translation must be considered prior to use. Responsiveness, measurement error and cut-off values should also be assessed to increase the clinical utility and psychometric robustness of the translated versions of the MSPSS. TRIAL REGISTRATION: PROSPERO - CRD42016052394. PMID- 29716590 TI - In vitro effects of aqueous extract from Maytenus senegalensis (Lam.) Exell stem bark on egg hatching, larval migration and adult worms of Haemonchus contortus. AB - BACKGROUND: Maytenus senegalensis is a common shrub which is scattered in tropical Africa. Different parts of this plant have been reported to be useful in traditional medicine against gastrointestinal disorders and intestinal worms. This study evaluated the anthelmintic activity of the aqueous stem bark extract of M. senegalensis using egg hatch assay (EHA), larval migration inhibition assay (LMIA) and adult worms' motility inhibition assay (AMIA). RESULTS: On EHA, the extract concentrations tested resulted in a significant (p < 0.01) inhibition of egg hatching in concentration-dependent manner and ranged between 31.86% at 75 MUg.mL- 1 to 54.92% at 2400 MUg.mL- 1 after a 48 h post-exposure with eggs. For the LMI assays, the aqueous extract of M. senegalensis showed a significant (p < 0.05) inhibition of larval migration in a concentration-dependent manner. The highest concentration used (2400 MUg.mL- 1) showed a 37.77% inhibition. The use of polyvinyl polypyrrolidone (PVPP) indicated that tannins and flavonoids were partly involved in the effect since the larval migration was inhibited by 15.5%, but other biochemical compounds were also implicated. On AMIA, M. senegalensis was associated with a reduced worm motility after a 24 h post exposure compared to phosphate buffered saline as control (p < 0.05). By this time 66.66% of the worms' were found immotile or dead in the wells containing plant extract at 2400 MUg.mL- 1. The Phytochemical analysis of aqueous extract of M. senegalensis by HPLC-ESI-MSn detected the presence of proanthocyanidins (20%) and flavonoids (> 50%). CONCLUSIONS: These in vitro results suggest the presence of some anthelmintic properties in M. senegalensis extract, which is traditionally used by small farmers in west and central Africa. These effects may be due to the flavonoids and proanthocyanidins present in the extract and need to be studied under in vivo conditions. PMID- 29716591 TI - The primary stability of different implants for intra-articular calcaneal fractures: an in vitro study. AB - BACKGROUND: Calcaneal fractures account for around 2% of all fractures and most of them are intra-articular fractures. Many implants have been used in the fixation of calcaneal fractures, but their biomechanical stability has not yet been well investigated. The aim of this study was to compare the primary stability of four fixations of calcaneal fracture. METHODS: Eight cadaveric calcaneus samples were used to simulate the Sanders' types III fracture pattern and fixed through four different implants, namely, K-wires, cannulated screws (CS), absorbable screws (AS), and plate-screw system (PSS). Each specimen was then placed into a custom-made jig and was loaded through a material testing machine to simulate the physiological condition. The primary stability was measured in the vertical direction as the stiffness and anterior-posterior direction as the calcaneocuboid force. One-way analysis of variance was used for data analysis. RESULTS: The results showed the highest stiffness of 634 (383-891; SD 226) N/mm in the intact model. It was significantly higher than the models fixed with K-wires, CS or PSS. There was no significant difference in vertical stiffness between fractures fixed with AS and the intact model or other fixed models. The intact model showed the lowest calcaneocuboid force of 153 (120-218; SD 39) N, while the fractures fixed with AS showed the greatest force of 242 (146 398; SD 84) N. The significance was only detected between these two models. CONCLUSIONS: The global stiffness was similar when the calcaneal fractures were fixed by K-wires, CS and PSS. The stability of the AS fixation differed along both the vertical and anterior-posterior directions, and was greatly influenced by the bone quality. AS for fracture fixation should be designed with greater strength and pull-out resistance. PMID- 29716593 TI - RNA-Seq profiling of circular RNAs in human laryngeal squamous cell carcinomas. AB - Abnormal expression of non-coding circular RNAs (circRNAs) have been reported in many types of tumors. circRNA have been suggested to be an ideal candidate biomarker for diagnostic and therapeutic implications in cancers. The aim of this study was to assess the circRNA expression profile of laryngeal squamous cell carcinomas (LSCC). The biopsy samples from patients with LSCC were obtained intra operatively. The circRNA expression was performed using secondary sequencing. Among 10 patients with LSCC, 2 were well differentiated, 3 were moderately differentiated and 5 were adjunctive samples with normal and LSCC tissues. A total of 21,444 distinct circRNA candidates were detected. Among them, we defined the statistical criteria for selecting aberrant-expressed circRNA using a q-value of < 0.001 with a fold change of > 2.0 or < 0.5. A total of 29 circRNA were upregulated and 19 circRNA were downregulated significantly in the LSCC tissues. The intersection of these dysregulated circRNAs of normal-well differentiated set and normal-moderately differentiated set was then assessed to narrow the upregulated and downregulated circRNAs down to 18 and 5 respectively. Furthermore, an association of the circRNA-miRNA-mRNA was investigated, showing that 20 dysregulated circRNA successfully predicted an interaction with several cancer-related miRNAs. Finally, a further KEGG analysis showed that PPAR, Axon guidance, Wnt and Cell cycle signaling pathway were key putative pathways in the process of LSCC. hsa_circ:chr20:31876585-31,897,648 was found to be able to differentiate most of LSCC from the matching normal tissues. This observational study demonstrated dysregulation of circRNA in LSCC, which may have an impact on development of potential biomarkers in this disease. Validation of down regulation of hsa_circ:chr20:31876585-31,897,648 in LSCC compared to each adjunctive tissue by Q-RT-PCR, indicating that hsa_circ:chr20:31876585-31,897,648 may be a novel promising tumor suppresser in LSCC. PMID- 29716594 TI - The involvement of Canadian physicians in promoting and providing unproven and unapproved stem cell interventions. AB - BACKGROUND: Direct to consumer offerings of unproven stem cell interventions (SCIs) is a pressing scientific and policy issue. According to media reports, providers of SCIs have emerged in Canada. This study provides the first systematic scan of Canadian providers and associated trends and claims. METHODS: The study sample consisted of 15 websites retrieved from a GoogleTM keyword search. The websites were assessed by a rater using a peer-reviewed coding frame that queried treatment location, stem cell offerings, treatment claims, supporting evidence, and legal and regulatory compliance. A second rater reviewed a subset of the websites for purposes of inter-rater reliability. Disagreements between raters were resolved by consensus. Data collected by the raters was analyzed in SPSS. RESULTS: Physicians are the dominant treatment providers in Canada. Providers operate in urban and semi-urban areas in the most populous provinces. SCIs provided are mainly autologous adult stem cells for multiple conditions including musculoskeletal disorders, spinal cord injury (SCI) and diabetes. Efficacy and benefits of treatment are prominently and positively portrayed, while risks are not mentioned or portrayed as trivial. Regulatory concerns are not discussed. CONCLUSIONS: The involvement of physicians in promoting and providing unproven and unapproved SCIs raises significant ethical, legal and regulatory concerns. Treatment claims and trends appear to contravene applicable professional standards, statutory obligations, and consumer protection laws. While the number of providers observed is still marginal, urgent and proactive regulatory response is needed to prevent proliferation of a potentially exploitative and harmful market for unproven SCIs in Canada. PMID- 29716595 TI - Factorial structure of the locomotor disability scale in a sample of adults with mobility impairments in Bangladesh. AB - BACKGROUND: Disability does not only depend on individuals' health conditions but also the contextual factors in which individuals live. Therefore, disability measurement scales need to be developed or adapted to the context. Bangladesh lacks any locally developed or validated scales to measure disabilities in adults with mobility impairment. We developed a new Locomotor Disability Scale (LDS) in a previous qualitative study. The present study developed a shorter version of the scale and explored its factorial structure. METHODS: We administered the LDS to 316 adults with mobility impairments, selected from outpatient and community based settings of a rehabilitation centre in Bangladesh. We did exploratory factor analysis (EFA) to determine a shorter version of the LDS and explore its factorial structure. RESULTS: We retained 19 items from the original LDS following evaluation of response rate, floor/ceiling effects, inter-item correlations, and factor loadings in EFA. The Eigenvalues greater than one rule and the Scree test suggested a two-factor model of measuring locomotor disability (LD) in adults with mobility impairment. These two factors are 'mobility activity limitations' and 'functional activity limitations'. We named the higher order factor as 'locomotor disability'. This two-factor model explained over 68% of the total variance among the LD indicators. The reproduced correlation matrix indicated a good model fit with 14% non-redundant residuals with absolute values > 0.05. However, the Chi-square test indicated poor model fit (p < .001). The Bartlett's test of Sphericity confirmed patterned relationships amongst the LD indicators (p < .001). The Kaiser-Meyer-Olkin Measure (KMO) of sampling adequacy was .94 and the individual diagonal elements in the anti-correlation matrix were > .91. Among the retained 19 items, there was no correlation coefficient > .9 or a large number of correlation coefficients < .3. The communalities were high: between .495 and .882 with a mean of 0.684. As an evidence of convergent validity, we had all loadings above .5, except one. As an evidence of discriminant validity, we had no strong (> .3) cross loadings and the correlation between the two factors was .657. The 'mobility activity limitations' and 'functional activity limitations' sub-scales demonstrated excellent internal consistency (Cronbach's alpha were .954 and .937, respectively). CONCLUSIONS: The 19-item LDS was found to be a reliable and valid scale to measure the latent constructs mobility activity limitations and functional activity limitations among adults with mobility impairments in outpatient and community-based settings in Bangladesh. PMID- 29716592 TI - Pollution and respiratory disease: can diet or supplements help? A review. AB - Pollution is known to cause and exacerbate a number of chronic respiratory diseases. The World Health Organisation has placed air pollution as the world's largest environmental health risk factor. There has been recent publicity about the role for diet and anti-oxidants in mitigating the effects of pollution, and this review assesses the evidence for alterations in diet, including vitamin supplementation in abrogating the effects of pollution on asthma and other chronic respiratory diseases. We found evidence to suggest that carotenoids, vitamin D and vitamin E help protect against pollution damage which can trigger asthma, COPD and lung cancer initiation. Vitamin C, curcumin, choline and omega-3 fatty acids may also play a role. The Mediterranean diet appears to be of benefit in patients with airways disease and there appears to be a beneficial effect in smokers however there is no direct evidence regarding protecting against air pollution. More studies investigating the effects of nutrition on rapidly rising air pollution are urgently required. However it is very difficult to design such studies due to the confounding factors of diet, obesity, co-morbid illness, medication and environmental exposure. PMID- 29716596 TI - Assessment of static posturography and pedobarography for the detection of unilateral forelimb lameness in ponies. AB - BACKGROUND: Static posturography and pedobarography are based on the detection of postural imbalance and, consequently, the pressure redistribution between limbs in lame subjects. These techniques have proven to be useful for the detection of lameness in humans and dogs. The main objective of this study was to test the suitability of static posturography and pedobarography in diagnosing lameness in ponies. A pressure platform was used to obtain postural data (statokinesiograms, mean X and Y, length, LFS ratio, and mean velocity) from 10 sound ponies and 7 ponies with unilateral forelimb lameness. Static pedobarographic data (pressure distribution, mean pressure, and peak pressure) were also collected and compared with force plate data (peak vertical force and vertical impulse) obtained from the same animals at the walk. RESULTS: Significant differences were seen between lame and sound ponies for almost all evaluated parameters. With this sample size, differences between lame and sound limbs/groups were detected with a statistical power of 90%, except for mean X and Y. CONCLUSIONS: Static posturography and pedobarography provide a complementary approach for lameness detection in equids. PMID- 29716597 TI - Hepatitis E virus infection in Turkey: a systematic review. AB - Hepatitis E virus (HEV), a non-enveloped single stranded RNA virus causes sporadic cases of hepatitis or outbreaks. The disease is generally self-limited although it may cause fulminant hepatitis in pregnant women, elderly, those with underlying chronic hepatitis, immunosuppressed, and transplant recipients. It is transmitted through fecal-oral route and zoonotic transmission. Hepatitis is a main health care problem in Turkey; HBV and HCV prevalences are 4 and 1% respectively. Hepatitis D represents another considerable hepatitis etiology with a prevalence of 5-27%. The information about HEV is not clear. In this systematic review, we aimed to analyze HEV studies reported from Turkey, to determine the current situation of the disease in the country, to delineate the limits of the studies and to determine the future study areas. The prevalence of HEV ranged from 0 to 12.4%. Children had lower prevalence than the adults. The prevalence was determined as 7-8% in pregnant women, 13% in chronic HBV patients, 54% in chronic HCV patients, 13.9-20.6% in patients with chronic renal failure, and ~ 35% in agriculture workers. Among individuals immigrating form Turkey to Europe, HEV seroprevalence was found 10.3% in Italy and 33.4% in the Netherlands. HEV prevalence seems high in certain risk groups. Although previous studies suggest that Turkey is among the endemic countries of HEV, there are some pitfalls for the analysis of data: the studies are not powered enough to represent the whole population; they did not include immunosuppressed patients and solid organ recipients; and the prevalence of non-A non-B hepatitis was not determined. PMID- 29716598 TI - Localized instance fusion of MRI data of Alzheimer's disease for classification based on instance transfer ensemble learning. AB - BACKGROUND: Diagnosis of Alzheimer's disease (AD) is very important, and MRI is an effective imaging mode of Alzheimer's disease. There are many existing studies on the diagnosis of Alzheimer's disease based on MRI data. However, there are no studies on the transfer learning between different datasets (including different subjects), thereby improving the sample size of target dataset indirectly. METHODS: Therefore, a new framework method is proposed in this paper to solve this problem. First, gravity transfer is used to transfer the source domain data closer to the target data set. Secondly, the best deviation between the transferred source domain samples and the target domain samples is searched by instance transfer learning algorithm (ITL) based on wrapper mode, thereby obtaining optimal transferred domain samples. Finally, the optimal transferred domain samples and the target domain training samples are combined for classification. If the source data and the target data have different features, a feature growing algorithm is proposed to solve this problem. RESULTS: The experimental results show that the proposed method is effective regardless of different kernel functions, different number of samples and different parameters. Besides, the transferred source domain samples by ITL algorithm can enlarge the target domain training samples and assist to improve the classification accuracy significantly. CONCLUSIONS: Therefore, the study can enlarge the samples of AD by instance transfer learning, thereby being helpful for the small sample problems of AD. Since the proposed algorithm is a framework algorithm, the study is heuristics to the relevant researchers. PMID- 29716599 TI - Proprioceptive impairments in high fall risk older adults: the effect of mechanical calf vibration on postural balance. AB - BACKGROUND: Impairments in proprioceptive mechanism with aging has been observed and associated with fall risk. The purpose of the current study was to assess proprioceptive deficits among high fall risk individuals in comparison with healthy participants, when postural performance was disturbed using low-frequency mechanical gastrocnemius vibratory stimulation. METHODS: Three groups of participants were recruited: healthy young (n = 10; age = 23 +/- 2 years), healthy elders (n = 10; age = 73 +/- 3 years), and high fall risk elders (n = 10; age = 84 +/- 9 years). Eyes-open and eyes-closed upright standing balance performance was measured with no vibration, and 30 and 40 Hz vibration of both calves. Vibration-induced changes in balance behaviors, compared to baseline (no vibratory stimulation) were compared between three groups using multivariable repeated measures analysis of variance models. RESULTS: Overall, similar results were observed for two vibration frequencies. However, changes in body sway due to vibration were more obvious within the eyes-closed condition, and in the medial lateral direction. Within the eyes-closed condition high fall risk participants showed 83% less vibration-induced change in medial-lateral body sway, and 58% less sway velocity, when compared to healthy participants (p < 0.001; effect size = 0.45-0.64). CONCLUSIONS: The observed differences in vibration effects on balance performance may be explained by reduced sensitivity in peripheral nervous system among older adults with impaired balance. PMID- 29716600 TI - Validating an algorithm to identify metastatic gastric cancer in the absence of routinely collected TNM staging data. AB - BACKGROUND: Accurate TNM stage information is essential for cancer health services research, but is often impractical and expensive to collect at the population-level. We evaluated algorithms using administrative healthcare data to identify patients with metastatic gastric cancer. METHODS: A population-based cohort of gastric cancer patients diagnosed between 2005 and 2007 identified from the Ontario Cancer Registry were linked to routinely collected healthcare data. Reference standard data identifying metastatic disease were obtained from a province-wide chart review, according to the Collaborative Staging method. Algorithms to identify metastatic gastric cancer were created using administrative healthcare data from hospitalization, emergency department, and physician billing records. Time frames of data collection in the peri-diagnosis period, and the diagnosis codes used to identify metastatic disease were varied. Algorithm sensitivity, specificity, and accuracy were evaluated. RESULTS: Of 2366 gastric cancer patients, included within the chart review, 54.3% had metastatic disease. Algorithm sensitivity ranged from 50.0- 90%, specificity ranged from 27.6 - 92.5%, and accuracy from 61.5 - 73.4%. Sensitivity and specificity were maximized when the most conservative list of diagnosis codes from hospitalization and outpatient records in the six months prior to and the six months following diagnosis were included. CONCLUSION: Algorithms identifying metastatic gastric cancer can be used for research purposes using administrative healthcare data, although they are imperfect measures. The properties of these algorithms may be generalizable to other high fatality cancers and other healthcare systems. This study provides further support for the collection of population-based, TNM stage data. PMID- 29716601 TI - Osteoarthritis of the temporomandibular joint in the Eastern Atlantic harbour seal (Phoca vitulina vitulina) from the German North Sea: a study of the lesions seen in dry bone. AB - BACKGROUND: Pathological changes and resulting functional impairment of the temporomandibular joint (TMJ) can substantially affect physical condition, morbidity, and mortality of wildlife species. Analysis of TMJ disorders is therefore of interest for the characterization of the health status of populations of wild mammals. This paper, for the first time, analyses the prevalence of TMJ osteoarthritis (TMJ-OA) and the spectrum of osteoarthritic bone lesions of the TMJ in the Eastern Atlantic harbour seal (Phoca vitulina vitulina), applying a standardized scoring system. Dry skulls of 1872 individuals from the German North Sea, collected between 1961 and 1994, were examined for lesions consistent with a diagnosis of TMJ-OA. Of the skulls, 913 (48.8%) were from male, 959 (51.2%) from female seals, with age at death ranging from 2 weeks to 25 years. Possible associations of TMJ-OA with dental or periodontal disorders were also analysed. RESULTS: Lesions consistent with TMJ-OA were found in 963 (53.9%) of the 1787 juvenile/subadult (5 weeks to 5 years of age) and adult (> 5 years) specimens, the condition mostly (95.0% of affected individuals) occurring in a bilateral fashion. Males were affected more frequently than females (p < 0.001), while lesion severity tended to be higher in females (p < 0.05). Severity of TMJ-OA lesions was positively correlated with age (p < 0.001). Lesion severity was also weakly positively correlated with the number of fractured teeth (p < 0.05) and of intravitally lost teeth (p < 0.01), when controlling for age at death as a confounder. CONCLUSIONS: TMJ-OA is a common disorder in the Eastern Atlantic harbour seal. The more pronounced severity of the lesions in females compared to males is basically attributed to the higher average age of the female subsample. The causes underlying the high prevalence of TMJ-OA in the studied assemblage remain unknown. Most of the specimens (75.3%) analysed in the present study were found dead during the first phocine distemper virus epizootic in 1988. Therefore, it is assumed that, contrary to other museum collections, only little overrepresentation of pathological skeletal conditions is present in this death sample compared with the population from which it originated. PMID- 29716602 TI - Lower plasma trans-4-hydroxyproline and methionine sulfoxide levels are associated with insulin dysregulation in horses. AB - BACKGROUND: Insulin dysregulation in horses is a metabolic condition defined by high insulin concentrations in the blood and peripheral insulin resistance. This hyperinsulinemia is often associated with severe damage in the hooves, resulting in laminitis. However, we currently lack detailed information regarding the potential involvement of particular metabolic pathways in pathophysiological causes and consequences of equine insulin dysregulation. This study aimed to assess the dynamic metabolic responses given to an oral glucose test (OGT) in insulin-sensitive and insulin-dysregulated horses by a targeted metabolomics approach to identify novel metabolites associated with insulin dysregulation. RESULTS: Oral glucose testing triggered alterations in serum insulin (26.28 +/- 4.20 vs. 422.84 +/- 88.86 MUIU/mL, p < 0.001) and plasma glucose concentrations (5.00 +/- 0.08 vs. 9.43 +/- 0.44 mmol/L, p < 0.001) comparing basal and stimulated conditions after 180 min. Metabolome analyses indicated OGT-induced changes in short-chain acylcarnitines (6.00 +/- 0.53 vs. 3.99 +/- 0.23 MUmol/L, p < 0.001), long-chain acylcarnitines (0.13 +/- 0.004 vs. 0.11 +/- 0.002 MUmol/L, p < 0.001) and amino acids (2.18 +/- 0.11 vs. 1.87 +/- 0.08 MUmol/L, p < 0.05). Kynurenine concentrations increased (2.88 +/- 0.18 vs. 3.50 +/- 0.19 MUmol/L, p < 0.01), whereas spermidine concentrations decreased during OGT (0.09 +/- 0.004 vs. 0.08 +/- 0.002 MUmol/L, p < 0.01), indicating proinflammatory conditions after oral glucose load. Insulin dysregulation was associated with lower concentrations of trans-4-hydroxyproline (4.41 +/- 0.29 vs. 6.37 +/- 0.71 MUmol/L, p < 0.05) and methionine sulfoxide (0.40 +/- 0.06 vs. 0.87 +/- 0.13 MUmol/L, p < 0.01; mean +/- SEM in insulin-dysregulated vs. insulin-sensitive basal samples, respectively), two metabolites which are related to antioxidant defense mechanisms. CONCLUSION: Oral glucose application during OGT resulted in profound metabolic and proinflammatory changes in horses. Furthermore, insulin dysregulation was predicted in basal samples (without OGT) by pathways associated with trans-4 hydroxyproline and methionine sulfoxide, suggesting that oxidative stress and oxidant-antioxidant disequilibrium are contributing factors to insulin dysregulation. The present findings provide new hypotheses for future research to better understand the underlying pathophysiology of insulin dysregulation in horses. PMID- 29716603 TI - Study on the equity of medical services utilization for elderly enrolled in different basic social medical insurance systems in an underdeveloped city of Southwest China. AB - BACKGROUND: The equity of medical services utilization for elderly individuals enrolled in different basic social medical insurance systems holds significant meaning for social harmony against a background of demographic aging and a growing wealth gap in China. This study is to explore the equity of the three medical insurance systems in southwest China with the aim of providing recommendations for relevant policy. METHODS: A total of 9600 elderly people insured through basic social medical insurance were selected and interviewed with a questionnaire. This study used a binary logistic regression model to investigate the effect of household income for medical services utilization and adopted a concentration index to measure the inequity of medical services utilization among elderly participants enrolled in different medical insurance categories. RESULTS: Outpatient services utilization was almost identical in the different insurance systems (78.5%, 77.7% and 78.6%). There were no statistically significant differences according to income level in the Urban Employee Basic Medical Insurance (UEBMI) and Urban Resident Basic Medical Insurance (URBMI) programs, but in the New Cooperative Medical Scheme (NCMS), higher-income groups tended to utilize more services. The corresponding concentration index (CI) values were 0.0162, 0.0173 and 0.0179 respectively. The NCMS showed a lower hospitalization rate than UEBMI and URBMI (17.7% vs 24.2% and 24.9%). The higher income group utilized hospitalization more, regardless of the insurance system. The corresponding CI values were 0.0817, 0.0605 and 0.0319 respectively. CONCLUSION: The equity of medical services utilization for elderly exist in all three health insurance systems, in particular, the inequities in utilization of hospitalization were more severe than outpatient services. UEBMI and URBMI were better than NCMS in the equity of outpatient services. Although NCMS was more equitable than URBMI and UEBMI in terms of hospitalization, this was based on "overall low utilization of hospitalization regardless of income levels" in NCMS compared with URBMI and UEBMI. The disparities of the three basic social medical insurance systems should be eliminated. For low-income residents, specific insurance policies including reducing deductible, covering more medical service and increasing reimbursement ratio could be considered. PMID- 29716604 TI - The impact of Aloe vera and licorice extracts on selected mechanisms of humoral and cell-mediated immunity in pigeons experimentally infected with PPMV-1. AB - BACKGROUND: The aim of the study was to evaluate the impact of herbal extracts on selected immunity mechanisms in clinically healthy pigeons and pigeons inoculated with the pigeon paramyxovirus type 1 (PPMV-1). For the first 7 days post inoculation (dpi), an aqueous solution of Aloe vera or licorice extract was administered daily at 300 or 500 mg/kg body weight (BW). The birds were euthanized at 4, 7 and 14 dpi, and spleen samples were collected during necropsy. Mononuclear cells were isolated from spleen samples and divided into two parts: one part was used to determine the percentage of IgM+ B cells in a flow cytometric analysis, and the other was used to evaluate the expression of genes encoding IFN-gamma and surface receptors on CD3+, CD4+ and CD8+ T cells. RESULTS: The expression of the IFN-gamma gene increased in all birds inoculated with PPMV 1 and receiving both herbal extracts. The expression of the CD3 gene was lowest at 14 dpi in healthy birds and at 7 dpi in inoculated pigeons. The expression of the CD4 gene was higher in uninoculated pigeons receiving both herbal extracts than in the control group throughout nearly the entire experiment with a peak at 7 dpi. A reverse trend was observed in pigeons inoculated with PPMV-1 and receiving both herbal extracts. In uninoculated birds, increased expression of the CD8 gene was noted in the pigeons receiving a lower dose of the Aloe vera extract and both doses of licorice extracts. No significant differences in the expression of this gene were found between inoculated pigeons receiving both herbal extracts. The percentage of IgM+ B cells did not differ between any of the evaluated groups. CONCLUSIONS: This results indicate that Aloe vera and licorice extracts have immunomodulatory properties and can be used successfully to prevent viral diseases, enhance immunity and as supplementary treatment for viral diseases in pigeons. PMID- 29716606 TI - The impact of orthopaedic research evidence on health financing in Australia. AB - BACKGROUND: In Australia, approval by the Medical Services Advisory Committee (MSAC) is an important step in the implementation of new health technologies. The MSAC considers health technology assessments (HTA) when submitting a recommendation to the Minister of Health on a new technology's suitability for public funding. Despite being such a critical tool in formulating policy, there has been little scrutiny on the impact of limited evidence on the performance of a national HTA agency's mandate. We aim to determine the proportion of HTAs of orthopaedic technologies prepared for the MSAC that were supported by higher levels of evidence for effectiveness, and whether this affected the MSAC's ability to conclude on efficacy. We also investigated whether the availability of higher level evidence affected the performance of cost-effectiveness analyses. METHODS: We performed a cohort study of all HTAs prepared for the MSAC from 1998 to 2017 with regards to new technologies in orthopaedic surgery. RESULTS: We identified seven HTAs encompassing nine orthopaedic technologies for inclusion. Higher levels of evidence were available for assessing the technology's effectiveness in six out of the nine technologies. The results did not show a statistically significant relationship between the availability of higher level evidence and MSAC's ability to make a clear conclusion on the assessment of effectiveness (P = 0.5). The proportion of HTAs where a cost-effectiveness analysis was performed was significantly higher (P < 0.05) when higher levels of evidence were available for the assessment of effectiveness. CONCLUSIONS: The results indicate that there is a paucity of high quality evidence in the formulation of health policy with regards to the implementation of new orthopaedic technologies in the public healthcare system. This represents an opportunity for strong leadership from surgeons to help develop the tools needed for effective clinical decision-making. PMID- 29716605 TI - Integration of the work-related online aftercare intervention 'GSA-online plus' (healthy and without stress at the workplace) into clinical practice: study protocol for an implementation study. AB - BACKGROUND: In a previous RCT we established the efficacy of the psychodynamic online aftercare programme 'GSA-Online' ('Health Training Stress Management at the Workplace') for rehabilitants with work-related stress facing return to work after long-term sickness absence. The purpose of this trial is to implement it into routine care. METHODS/DESIGN: The study is performed in rehabilitation clinics with patients of different medical indications (psychosomatic, orthopedic and cardiological diseases). Rehabilitants get access to the study platform during inpatient medical rehabilitation. 'GSA-Online plus' integrates exploratory and motivational videos on the web application to familiarize potential participants and motivate them to follow through with it. In the 12-week writing intervention, patients write weekly online diary entries, answered by anonymous online therapists within 24 h. Primary outcome measures are the recommendation rate of 'GSA-Online plus' and participation rates of the rehabilitants. As secondary outcomes, psychological symptoms, overall satisfaction, helpfulness of the therapeutic feedback and utilization of 'GSA-Online plus' will be analysed exploratory along with the course of weekly ratings of well-being and work ability. DISCUSSION: Meanwhile many clinical trials and meta-analysis prove that internet-based interventions are effective. This study will add insights on the dissemination and implementation of efficacious, evidence-based online treatments into medical practice. We expect a successful implementation of 'GSA-Online plus' in the clinical routine of the rehabilitation clinics. The focus of evaluation is on acceptance of the programme, both by the physicians in charge and the patients. In the future 'GSA-Online plus' could be implemented as a routine aftercare programme for rehabilitation inpatients with occupational stress. TRIAL REGISTRATION: The trial was retrospectively registered on 6th January 2017 at ClinicalTrials.gov (Trial Registration number: ClinicalTrials Gov ID NCT03019718 ). PMID- 29716607 TI - Internal migration of physicians who graduated in Brazil between 1980 and 2014. AB - BACKGROUND: The internal migration of physicians from one place to another in the same country can unbalance the supply and distribution of these professionals in national health systems. In addition to economic, social and demographic issues, there are individual and professional factors associated with a physician's decision to migrate. In Brazil, there is an ongoing debate as to whether opening medicine programmes in the interior of the country can induce physicians to stay in these locations. This article examines the migration of physicians in Brazil based on the location of the medical schools from which they graduated. METHODS: A cross-sectional design based on secondary data of 275,801 physicians registered in the Regional Councils of Medicine (Conselhos Regionais de Medicina-CRMs) who graduated between 1980 and 2014. The evaluated outcome was migration, which was defined as moving away from the state where they completed the medicine programme to another state where they currently work or live. RESULTS: 57.3% of the physicians in the study migrated. The probability of migration ratio was greater in small grouped municipalities and lower in state capitals. 93.4% of the physicians who trained in schools located in cities with less than 100,000 inhabitants migrated. Fewer women (54.2%) migrated than men (60.0%). More than half of the physicians who graduated between 1980 and 2014 are in federative units different from the unit in which they graduated. Individual factors, such as age, gender, time of graduation and specialty, vary between the physicians who did or did not migrate. CONCLUSIONS: The probability of migration ratio was greater in small municipalities of the Southeast region and strong in the states of Tocantins, Acre and Santa Catarina. New studies are recommended to deepen understanding of the factors related to the internal migration and non-migration of physicians to improve human resource for health policies. PMID- 29716609 TI - Can task-shifting work at scale?: Comparing clinical knowledge of non-physician clinicians to physicians in Nigeria. AB - BACKGROUND: In contexts with severe physician shortages, the World Health Organization advocates task shifting to cadres with shorter training. To investigate the effects of task shifting at scale in primary health care, we assessed the clinical knowledge of non-physician clinicians versus physicians working in public primary care facilities in Nigeria. METHODS: We assessed 4138 health workers using clinical vignettes of hypothetical patients suffering from illnesses commonly seen in primary care. Facility-level fixed effects models were used to compare health worker knowledge of (i) consultation guidelines, (ii) diagnostic accuracy and (iii) treatment guidelines. RESULTS: Unadjusted averages of overall health worker knowledge were low across all types of worker except medical officers. After adjustment for potential confounding, the differences across all three measures between cadres became small or statistically insignificant. CONCLUSION: Non-physician clinicians can provide the same quality of primary care, for a set of common illnesses, as Medical Officers with similar personal characteristics, but clinical skills across cadres need strengthening. PMID- 29716608 TI - Comparison of the virulence of three H3N2 canine influenza virus isolates from Korea and China in mouse and Guinea pig models. AB - BACKGROUND: Avian-origin H3N2 canine influenza virus (CIV) has been the most common subtype in Korea and China since 2007. Here, we compared the pathogenicity and transmissibility of three H3N2 CIV strains [Chinese CIV (JS/10), Korean CIV (KR/07), and Korean recombinant CIV between the classic H3N2 CIV and the pandemic H1N1 virus (MV/12)] in BALB/c mouse and guinea pig models. The pandemic H1N1 (CA/09) strain served as the control. RESULTS: BALB/c mice infected with H1N1 had high mortality and obvious body weight loss, whereas no overt disease symptoms were observed in mice inoculated with H3N2 CIV strains. The viral titers were higher in the group MV/12 than those in groups JS/10 and KR/07, while the mice infected with JS/10 showed higher viral titers in all tissues (except for the lung) than the mice infected with KR/07. The data obtained in guinea pigs also demonstrated that group MV/12 presented the highest loads in most of the tissues, followed by group JS/10 and KR/07. Also, direct contact transmissions of all the three CIV strains could be observed in guinea pigs, and for the inoculated and the contact groups, the viral titer of group MV/12 and KR/07 was higher than that of group JS/10 in nasal swabs. These findings indicated that the matrix (M) gene obtained from the pandemic H1N1 may enhance viral replication of classic H3N2 CIV; JS/10 has stronger viral replication ability in tissues as compared to KR/07, whereas KR/07 infected guinea pigs have more viral shedding than JS/10 infected guinea pigs. CONCLUSIONS: There exists a discrepancy in pathobiology among CIV isolates. Reverse genetics regarding the genomes of CIV isolates will be helpful to further explain the virus characteristics. PMID- 29716610 TI - Service provision in the wake of a new funding model for community pharmacy. AB - BACKGROUND: Recently, New Zealand has taken a system wide approach providing the biggest reform to New Zealand community pharmacy for 70 years with the aim of providing more clinically orientated patient centred services through a new funding model. The aim of this study was to understand the types of services offered in New Zealand community pharmacies since introduction of the new funding model, what the barriers are to providing these services. METHOD: A survey of all community pharmacies were undertaken between August, 2014 and February, 2015. Basic descriptive statistics were completed and group comparisons were made using the chi squared test with significance set at p < 0.05. RESULTS: 528 responses were received. Education and advice on prescription and non-prescription medicines were the two top listed services provided. There were no significant differences in service provision between rural and metro based pharmacies. Many pharmacies were considering introducing new patient centred services. Four of the top ten frequently provided services have no public funding attached. Costs and staff availability are the most common barriers to undertake services, more predominantly in patient centred services. CONCLUSION: This study was the first to provide an evaluation of service provision in response to a new funding model for New Zealand Community Pharmacies. A broad range of services are being undertaken in New Zealand community pharmacies including patient-centred services. A number of barriers to service provision were identified. This study provides a baseline for the current levels of service provision upon which future studies can compare to and evaluate any changes in service provision with differing funding models going forward. PMID- 29716611 TI - Evaluation of self-educational training methods to learn laparoscopic skills - a randomized controlled trial. AB - BACKGROUND: Evaluation of two different self-educational methods (video assisted learning versus video assisted learning plus a nodal point operation primer) on learning laparoscopic suturing and intracorporal knotting. METHODS: Randomized controlled trial at the laparoscopic surgical training center, University of Tubingen with 45 surgical novices first year medical students being pretested for dexterity. After self-educational training for 90 min with either method (Group A: video assisted learning, Group B: video assisted learning plus a nodal point operation primer) participants had to perform five laparoscopic intracorporal knots. Assessed were number of knots completed (maximum of five knots counted, knot integrity, technical proficiency and knotting time per knot. Primary outcome measure is a composed knot score combining knot integrity, technical proficiency and knotting time. RESULTS: Group B (n = 23) achieved a significantly higher composed knot score than Group A (n = 22) (53.3 +/- 8.4 versus 46.5 +/- 13.6 points respectively, p = 0.016). Median knotting time per completed knot was significantly different between Group B and Group A (308 s [100-1221] versus 394 s [138-1397] respectively, p = 0.001). Concerning number of completed knots there was a trend towards more knots achieved in Group B (4.2 +/- 1.2 versus 3.55 +/- 1.4 respectively, p = 0.075) . CONCLUSIONS: The use of a nodal point operation primer highlighting essential key steps of a procedure augment the success of learning laparoscopic skills as suturing and intracorporal knotting. (UIN researchregistry3866, March 22, 2018). PMID- 29716612 TI - Vascular adhesion protein-1 is actively involved in the development of inflammatory lesions in rat models of multiple sclerosis. AB - BACKGROUND: Vascular adhesion protein-1 (VAP-1) is an inflammation-inducible endothelial cell molecule and primary amine oxidase that mediates leukocyte entry to sites of inflammation. However, there is limited knowledge of the inflammation related expression of VAP-1 in the central nervous system (CNS). Therefore, we investigated the expression of VAP-1 within the CNS vasculature in two focal rat models of experimental autoimmune encephalomyelitis (EAE) mimicking multiple sclerosis (MS). METHODS: EAE was induced either with Bacillus Calmette-Guerin, resulting in a delayed-type hypersensitivity-like pathogenesis (fDTH-EAE), or with myelin oligodendrocyte glycoprotein (fMOG-EAE). A subgroup of fMOG-EAE rats were treated daily with a selective VAP-1 inhibitor (LJP1586; 5 mg/kg). On 3 and 14 days after lesion activation, rat brains were assessed using magnetic resonance imaging (MRI), and ex vivo autoradiography was conducted to evaluate the binding of Gallium-68-labelled VAP-1 ligand. Histology and immunohistochemistry (OX-42, VAP-1, intercellular adhesion protein-1 [ICAM-1], P selectin) supported the ex vivo autoradiography. RESULTS: EAE lesions showed MRI detectable signal changes and binding of the VAP-1-targeting radiotracer in both rat models. Some of the VAP-1 positive vessels showed morphological features typical for high endothelial-like venules at sites of inflammation. Inhibition of VAP-1 activity with small molecule inhibitor, LJP1586, decreased lymphocyte density in the acute inflammatory phase of fMOG-EAE lesions (day 3, P = 0.026 vs. untreated), but not in the remission phase (day 14, P = 0.70 vs. untreated), and had no effect on the amount of OX-42-positive cells in either phase. LJP1586 treatment reduced VAP-1 and ICAM-1 expression in the acute inflammatory phase, whereas P-selectin remained not detectable at all studied stages of the disease. CONCLUSIONS: Our results revealed that VAP-1 is expressed and functionally active in vasculature within the induced focal EAE lesions during the acute phase of inflammation and remains expressed after the acute inflammation has subsided. The study indicates that VAP-1 is actively involved in the development of inflammatory CNS lesions. During this process, the endothelial cell lesion related vasculature seem to undergo a structural transformation from regular flat walled endothelium to HEV-like endothelium. PMID- 29716613 TI - Task shifting in health service delivery from a decision and policy makers' perspective: a case of Uganda. AB - BACKGROUND: Documented evidence shows that task shifting has been practiced in Uganda to bridge the gaps in the health workers' numbers since 1918. The objectives of this study were to provide a synthesis of the available evidence on task shifting in Uganda; to establish levels of understanding, perceptions on task shifting and acceptability from the decision and policy makers' perspective; and to provide recommendations on the implications of task shifting for the health of the population in Ugandan and human resource management policy. METHODS: This was a qualitative study. Data collection involved review of published and unpublished literature, key informant interviews and group discussion for stakeholders in policy and decision making positions. Data was analyzed by thematic content analysis (ethical clearance number: SS 2444). RESULTS: Task shifting was implemented with minimal compliance to the WHO recommendations and guidelines. Uganda does not have a national policy and guidelines on task shifting. Task shifting was unacceptable to majority of policy and decision makers mainly because less-skilled health workers were perceived to be incompetent due to cases of failed minor surgery, inappropriate medicine use, overwork, and inadequate support supervision. CONCLUSIONS: Task shifting has been implemented in Uganda for a long time without policy guidance and regulation. Policy makers were not in support of task shifting because it was perceived to put patients at risk of drug abuse, development of drug resistance, and surgical complications. Evidence showed the presence of unemployed higher-skilled health workers in Uganda. They could not be absorbed into public service because of the low wage bill and lack of political commitment to do so. Less-skilled health workers were remarked to be incompetent and already overworked; yet, the support supervision and continuous medical education systems were not well resourced and effective. Hiring the existing unemployed higher-skilled health workers, fully implementing the human resource motivation and retention strategy, and enforcing the bonding policy for Government-sponsored graduates were recommended. PMID- 29716615 TI - Correction to a posterior versus anterior debridement in combination with bone graft and internal fixation for lumbar and thoracic tuberculosis. AB - In the original publication of this article (1) was an incorrect funding number published. The correct version can be found below. PMID- 29716614 TI - Lewy body-like alpha-synuclein inclusions trigger reactive microgliosis prior to nigral degeneration. AB - BACKGROUND: Converging evidence suggests a role for microglia-mediated neuroinflammation in Parkinson's disease (PD). Animal models of PD can serve as a platform to investigate the role of neuroinflammation in degeneration in PD. However, due to features of the previously available PD models, interpretations of the role of neuroinflammation as a contributor to or a consequence of neurodegeneration have remained elusive. In the present study, we investigated the temporal relationship of neuroinflammation in a model of synucleinopathy following intrastriatal injection of pre-formed alpha-synuclein fibrils (alpha syn PFFS). METHODS: Male Fischer 344 rats (N = 114) received unilateral intrastriatal injections of alpha-syn PFFs, PBS, or rat serum albumin with cohorts euthanized at monthly intervals up to 6 months. Quantification of dopamine neurons, total neurons, phosphorylated alpha-syn (pS129) aggregates, major histocompatibility complex-II (MHC-II) antigen-presenting microglia, and ionized calcium-binding adaptor molecule-1 (Iba-1) immunoreactive microglial soma size was performed in the substantia nigra. In addition, the cortex and striatum were also examined for the presence of pS129 aggregates and MHC-II antigen presenting microglia to compare the temporal patterns of pSyn accumulation and reactive microgliosis. RESULTS: Intrastriatal injection of alpha-syn PFFs to rats resulted in widespread accumulation of phosphorylated alpha-syn inclusions in several areas that innervate the striatum followed by significant loss (~ 35%) of substantia nigra pars compacta dopamine neurons within 5-6 months. The peak magnitudes of alpha-syn inclusion formation, MHC-II expression, and reactive microglial morphology were all observed in the SN 2 months following injection and 3 months prior to nigral dopamine neuron loss. Surprisingly, MHC-II immunoreactivity in alpha-syn PFF injected rats was relatively limited during the later interval of degeneration. Moreover, we observed a significant correlation between substantia nigra pSyn inclusion load and number of microglia expressing MHC-II. In addition, we observed a similar relationship between alpha-syn inclusion load and number of microglia expressing MHC-II in cortical regions, but not in the striatum. CONCLUSIONS: Our results demonstrate that increases in microglia displaying a reactive morphology and MHC-II expression occur in the substantia nigra in close association with peak numbers of pSyn inclusions, months prior to nigral dopamine neuron degeneration, and suggest that reactive microglia may contribute to vulnerability of SNc neurons to degeneration. The rat alpha-syn PFF model provides an opportunity to examine the innate immune response to accumulation of pathological alpha-syn in the context of normal levels of endogenous alpha-syn and provides insight into the earliest neuroinflammatory events in PD. PMID- 29716616 TI - Stability of the HTLV-1 glycoprotein 46 (gp46) gene in an endemic region of the Brazilian Amazon and the presence of a significant mutation (N93D) in symptomatic patients. AB - BACKGROUND: The human T-lymphotropic virus type 1 (HTLV-1) affects 2-5 million people worldwide, and is associated with a number of degenerative and infectious diseases. The Envelope glycoproteins (gp) are highly conserved among the different HTLV-1 isolates, although nucleotide substitutions in the region that codifies these proteins may influence both the infectivity and the replication of the virus. The gp46 gene has functional domains which have been associated with the inhibition of the formation of the syncytium, cell-cell transmission, and the production of antibodies. The present study investigated the genetic stability of the gp46 gene of HTLV-1 in an endemic region of Brazilian Amazonia. METHODS: Index case (IC - a sample of a given family group) carriers of HTLV-1 were investigated in the metropolitan region of Belem (Para, Brazil) between January 2010 (registered retrospectively) and December 2015. The sequences that codify the gp46 were amplified by PCR, purified and sequenced (MF084788-MF084825). The gene was characterized using bioinformatics and Bayesian Inference. RESULTS: The 40 patients analyzed had a mean age of 45.2 years and 70% presented some type of symptom, with a predominance of pain and sensitivity, dysautonomia, and motor disorders. All patients presented the aA (Transcontinental Cosmopolitan) genotype, with an extremely low mutation rate, which is characteristic of the codifying region (aA - 1.83 * 10-4 mutations per site per year). The gp46 gene had a nucleotide diversity of between 0.00% and 2.0%. Amino acid mutations were present in 66.6% of the samples of individuals with signs/symptoms or diseases associated with HTLV-1 (p = 0.0091). Of the three most frequent mutations, the previously undescribed N93D mutant was invariably associated with symptomatic cases. CONCLUSIONS: The aA HTLV-1 subtype is predominant in the metropolitan region of Belem and presented a high degree of genetic stability in the codifying region. The rare N93D amino acid mutation may be associated with the clinical manifestations of this viral infection. IMPORTANCE: Little is known of the phylogeny of HTLV-1 in the endemic region of Brazilian Amazonia, and few complete gene sequences are available for the gp46 glycoprotein from the local population. The nucleotide sequences of the viral gp46 gene recorded in the present study confirmed the genetic stability of the region, and pointed to a homogeneous viral group, with local geographic characteristics. Further research will be necessary to more fully understand the molecular diversity of this protein, given the potential of this codifying region as a model for an effective HTLV-1 vaccine. The identification of a rare mutation (N93D), present only in symptomatic patients, should also be investigated further as a potential clinical marker. TRIAL REGISTRATION: ISRCTN 12345678, registered 28 September 2014. PMID- 29716617 TI - Focal dose escalation for prostate cancer using 68Ga-HBED-CC PSMA PET/CT and MRI: a planning study based on histology reference. AB - BACKGROUND: Focal radiation therapy has gained of interest in treatment of patients with primary prostate cancer (PCa). The question of how to define the intraprostatic boost volume is still open. Previous studies showed that multiparametric MRI (mpMRI) or PSMA PET alone could be used for boost volume definition. However, other studies proposed that the combined usage of both has the highest sensitivity in detection of intraprostatic lesions. The aim of this study was to demonstrate the feasibility and to evaluate the tumour control probability (TCP) and normal tissue complication probability (NTCP) of radiation therapy dose painting using 68Ga-HBED-CC PSMA PET/CT, mpMRI or the combination of both in primary PCa. METHODS: Ten patients underwent PSMA PET/CT and mpMRI followed by prostatectomy. Three gross tumour volumes (GTVs) were created based on PET (GTV-PET), mpMRI (GTV-MRI) and the union of both (GTV-union). Two plans were generated for each GTV. Plan95 consisted of whole-prostate IMRT to 77 Gy in 35 fractions and a simultaneous boost to 95 Gy (Plan95PET/Plan95MRI/Plan95union). Plan80 consisted of whole-prostate IMRT to 76 Gy in 38 fractions and a simultaneous boost to 80 Gy (Plan80PET/Plan80MRI/Plan80union). TCPs were calculated for GTV-histo (TCP-histo), which was delineated based on PCa distribution in co-registered histology slices. NTCPs were assessed for bladder and rectum. RESULTS: Dose constraints of published protocols were reached in every treatment plan. Mean TCP-histo were 99.7% (range: 97%-100%) and 75.5% (range: 33%-95%) for Plan95union and Plan80union, respectively. Plan95union had significantly higher TCP-histo values than Plan95MRI (p = 0.008) and Plan95PET (p = 0.008). Plan80union had significantly higher TCP-histo values than Plan80MRI (p = 0.012), but not than Plan80PET (p = 0.472). Plan95MRI had significantly lower NTCP-rectum than Plan95union (p = 0.012). No significant differences in NTCP rectum and NTCP-bladder were observed for all other plans (p > 0.05). CONCLUSIONS: IMRT dose escalation on GTVs based on mpMRI, PSMA PET/CT and the combination of both was feasible. Boosting GTV-union resulted in significantly higher TCP-histo with no or minimal increase of NTCPs compared to the other plans. PMID- 29716618 TI - FOCS: a novel method for analyzing enhancer and gene activity patterns infers an extensive enhancer-promoter map. AB - Recent sequencing technologies enable joint quantification of promoters and their enhancer regions, allowing inference of enhancer-promoter links. We show that current enhancer-promoter inference methods produce a high rate of false positive links. We introduce FOCS, a new inference method, and by benchmarking against ChIA-PET, HiChIP, and eQTL data show that it results in lower false discovery rates and at the same time higher inference power. By applying FOCS to 2630 samples taken from ENCODE, Roadmap Epigenomics, FANTOM5, and a new compendium of GRO-seq samples, we provide extensive enhancer-promotor maps ( http://acgt.cs.tau.ac.il/focs ). We illustrate the usability of our maps for deriving biological hypotheses. PMID- 29716619 TI - The impact of blood type O on mortality of severe trauma patients: a retrospective observational study. AB - BACKGROUND: Recent studies have implicated the differences in the ABO blood system as a potential risk for various diseases, including hemostatic disorders and hemorrhage. In this study, we evaluated the impact of the difference in the ABO blood type on mortality in patients with severe trauma. METHODS: A retrospective observational study was conducted in two tertiary emergency critical care medical centers in Japan. Patients with trauma with an Injury Severity Score (ISS) > 15 were included. The association between the different blood types (type O versus other blood types) and the outcomes of all-cause mortality, cause-specific mortalities (exsanguination, traumatic brain injury, and others), ventilator-free days (VFD), and total transfusion volume were evaluated using univariate and multivariate competing-risk regression models. Moreover, the impact of blood type O on the outcomes was assessed using regression coefficients in the multivariate analysis adjusted for age, ISS, and the Revised Trauma Score (RTS). RESULTS: A total of 901 patients were included in this study. The study population was divided based on the ABO blood type: type O, 284 (32%); type A, 285 (32%); type B, 209 (23%); and type AB, 123 (13%). Blood type O was associated with high mortality (28% in patients with blood type O versus 11% in patients with other blood types; p < 0.001). Moreover, this association was observed in a multivariate model (adjusted odds ratio = 2.86, 95% confidence interval 1.84-4.46; p < 0.001). The impact of blood type O on all cause in-hospital mortality was comparable to 12 increases in the ISS, 1.5 decreases in the RTS, and 26 increases in age. Furthermore, blood type O was significantly associated with higher cause-specific mortalities and shorter VFD compared with the other blood types; however, a significant difference was not observed in the transfusion volume between the two groups. CONCLUSIONS: Blood type O was significantly associated with high mortality in severe trauma patients and might have a great impact on outcomes. Further studies elucidating the mechanism underlying this association are warranted to develop the appropriate intervention. PMID- 29716620 TI - Postprandial increase in serum CA125 as a surrogate biomarker for early diagnosis of ovarian cancer. AB - BACKGROUND: CA125 is a prevalently used serum biomarker for detecting ovarian cancer over the last three decades. However, it has a significant deficiency in screening for early-stage cancer. With the purpose of exploring an effective approach to improve its performance in early diagnosis, we investigated the postprandial fluctuation pattern of cancer-derived CA125 and the underlying mechanism. METHODS: In two medical centers, 551 patients sonographically diagnosed with ovarian (adnexal) cysts (< 5 cm in diameter) were enrolled and divided into five disease groups (pelvic inflammatory cysts, retention cysts, endometrioma, benign/borderline cystadenoma and malignant cysts). The subtle differences in 1-h postprandial serum CA125 increases were compared between disease groups. A support vector machine (SVM)-based algorithm was used for refining the performance of CA125 postprandial increment. Ovarian cancer xenograft animal and cancer cell models were used to recapitulate the clinical findings and reveal the molecular basis of postprandial blood glucose and insulin in invoking the synthesis/secretion/re-absorption of CA125. RESULTS: Patients with ovarian cancer presented the highest postprandial increment 13.3 +/- 0.7% (mean +/- standard deviation) among the five disease groups. Using a CA125 increment >= 10% criterion, the sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) reached 83.3, 96.3, 61.1 and 98.8%, respectively, for early-stage ovarian cancer. This performance was further improved by the SVM-based CA125-increment algorithm, which exhibited 91.7% sensitivity, 99.2% specificity, 89.2% PPV and 99.4% NPV. Both modalities manifested diagnostic advantages over the traditional CA125 test (75.0% sensitivity, 25.4% specificity, 6.6% PPV and 93.6% NPV at the cut-off of 35 U/mL). Regarding the molecular basis, the postprandial blood glucose and insulin invoked overexpression of Mucin 16 (encoding CA125) were demonstrated in animal and cancer cell models, which were mediated by the PI3K-Akt pathway. Nevertheless, a Mesothelin-based CA125 re-absorption behavior was noted in the treated cancer cells, which contributed to the over-drop following the postprandial peak of serum CA125. CONCLUSIONS: Cancer-derived serum CA125 possesses a unique and distinctive postprandial pattern, that distinguishes it from the common CA125 elevation in a benign disease condition. The dynamic measurement/assessment strategy can achieve a discriminatory power superior to that of a static test. PMID- 29716621 TI - Pathology of natural Francisella tularensis subsp. holarctica infection in two yellow-necked mice (Apodemus flavicollis). AB - BACKGROUND: Tularemia is a zoonosis caused by the bacterium Francisella tularensis. It has a wide host range, which includes mammals, birds and invertebrates. F. tularensis has often been isolated from various species of small rodents, but the pathology in naturally infected wild rodent species has rarely been reported. CASE PRESENTATION: Herein, we describe the pathology of tularemia in two naturally infected wild yellow-necked mice (Apodemus flavicollis). To visualize F. tularensis subsp. holarctica, indirect immunofluorescence and immunohistochemistry were applied on tissue sections. Real time polymerase chain reaction detected the bacterium in samples from liver and spleen in both mice. The only finding at necropsy was splenomegaly in one of the mice. Histological examination revealed necrotic foci in the liver associated with mild inflammation in both mice. Immunohistochemistry and indirect immunofluorescence showed bacteria disseminated in many organs, in the cytoplasm of macrophages, and intravascularly. CONCLUSIONS: The two yellow-necked mice died of an acute disease caused by tularemic infection disseminated to many organs. Further investigations of naturally infected small rodents are important to better understand the variability in pathological presentation caused by infection by F. tularensis subsp. holarctica, as well to elucidate the importance of small rodents as transmitters and/or reservoirs. PMID- 29716622 TI - A novel small molecule inhibitor of MDM2-p53 (APG-115) enhances radiosensitivity of gastric adenocarcinoma. AB - BACKGROUND: Gastric cancer is the leading cause of cancer related death worldwide. Radiation alone or combined with chemotherapy plays important role in locally advanced and metastatic gastric adenocarcinoma. MDM2-p53 interaction and downstream signaling affect cellular response to DNA damage which leads to cell cycle arrest and apoptosis. Therefore, restoring p53 function by inhibiting its interaction with MDM2 is a promising therapeutic strategy for cancer. APG-115 is a novel small molecule inhibitor which blocks the interaction of MDM2 and p53. In this study, we investigated that the radiosensitivity of APG-115 in gastric adenocarcinoma in vitro and in vivo. METHODS: The role of APG-115 in six gastric cancer cells viability in vitro was determined by CCK-8 assay. The expression level of MDM2, p21, PUMA and BAX in AGS and MKN45 cell lines was measured via real-time PCR (RT-PCR). The function of treatment groups on cell cycle and cell apoptosis were detected through Flow Cytometry assay. Clonogenic assays were used to measure the radiosensitivity of APG-115 in p53 wild type gastric cancer cell lines. Western blot was conducted to detect the protein expressions of mdm2-p53 signal pathway. Xenograft models in nude mice were established to explore the radiosensitivity role of APG-115 in gastric cancer cells in vivo. RESULTS: We found that radiosensitization by APG-115 occurred in p53 wild-type gastric cancer cells. Increasing apoptosis and cell cycle arrest was observed after administration of APG-115 and radiation. Radiosensitivity of APG-115 was mainly dependent on MDM2-p53 signal pathway. In vivo, APG-115 combined with radiation decreased xenograft tumor growth much more significantly than either single treatment. Moreover, the number of proliferating cells (Ki-67) significantly decreased in combination group compared with single treatment group. CONCLUSIONS: In summary, we found that combination of MDM2-p53 inhibitor (APG-115) and radiotherapy can enhance antitumor effect both in vitro and in vivo. This is the first report on radiosensitivity of APG-115 which shed light on clinical trial of the combination therapy of radiation with APG-115 in gastric adenocarcinoma. PMID- 29716623 TI - miR-221 stimulates breast cancer cells and cancer-associated fibroblasts (CAFs) through selective interference with the A20/c-Rel/CTGF signaling. AB - BACKGROUND: MicroRNA (miRNAs) are non-coding small RNA molecules that regulate gene expression by inhibiting the translation of target mRNAs. Among several dysregulated miRNAs in human cancer, the up-regulation of miR-221 has been associated with development of a variety of hematologic and solid malignancies. In this study, we investigated the involvement of miR-221 in breast cancer. METHODS: TaqMan microRNA assay was used to detect the miR-221 levels in normal cells and in MDA-MB 231 and SkBr3 breast cancer cells as well as in main players of the tumor microenvironment, namely cancer-associated fibroblasts (CAFs). miR 221 mimic sequence and locked nucleic acid (LNA)-i-miR-221 construct were used to induce or inhibit, respectively, the miR-221 expression in cells used. Quantitative PCR and western blotting analysis were performed to evaluate the levels of the miR-221 target gene A20 (TNFAIP3), as well as the member of the NF kB complex namely c-Rel and the connective tissue growth factor (CTGF). Chromatin immunoprecipitation (ChIP) assay was performed to ascertain the recruitment of c Rel to the CTFG promoter. Finally, the cell growth and migration in the presence of LNA-i-miR-221 or silencing c-Rel and CTGF by specific short hairpin were assessed by cell count, colony formation and boyden chambers assays. Statistical analysis was performed by ANOVA. RESULTS: We first demonstrated that LNA-i-miR 221 inhibits both endogenous and ectopic expression of miR-221 in our experimental models. Next, we found that the A20 down-regulation, as well as the up-regulation of c-Rel induced by miR-221 were no longer evident using LNA-i-miR 221. Moreover, we established that the miR-221 dependent recruitment of c-Rel to the NF-kB binding site located within the CTGF promoter region is prevented by using LNA-i-miR-221. Furthermore, we determined that the up-regulation of CTGF mRNA and protein levels by miR-221 is no longer evident using LNA-i-miR221 and silencing c-Rel. Finally, we assessed that cell growth and migration induced by miR-221 in MDA-MB 231 and SkBr3 breast cancer cells as well as in CAFs are abolished by LNAi-miR-221 and silencing c-Rel or CTGF. CONCLUSIONS: Overall, these data provide novel insights into the stimulatory action of miR-221 in breast cancer cells and CAFs, suggesting that its inhibition may be considered toward targeted therapeutic approaches in breast cancer patients. PMID- 29716624 TI - Reconstruction of a replication-competent ancestral murine endogenous retrovirus L. AB - BACKGROUND: About 10% of the mouse genome is composed of endogenous retroviruses (ERVs) that represent a molecular fossil record of past retroviral infections. One such retrovirus, murine ERV-L (MuERV-L) is an env-deficient ERV that has undergone episodic proliferation, with the most recent amplification occurring ~ 2 million years ago. MuERV-L related sequences have been co-opted by mice for antiretroviral defense, and possibly as promoters for some genes that regulate totipotency in early mouse embryos. However, MuERV-L sequences present in modern mouse genomes have not been observed to replicate. RESULTS: Here, we describe the reconstruction of an ancestral MuERV-L (ancML) sequence through paleovirological analyses of MuERV-L elements in the modern mouse genome. The resulting MuERV-L (ancML) sequence was synthesized and a reporter gene embedded. The reconstructed MuERV-L (ancML) could replicate in a manner that is dependent on reverse transcription and generated de novo integrants. Notably, MuERV-L (ancML) exhibited a narrow host range. Interferon-alpha could reduce MuERV-L (ancML) replication, suggesting the existence of interferon-inducible genes that could inhibit MuERV-L replication. While mouse APOBEC3 was able to restrict the replication of MuERV-L (ancML), inspection of endogenous MuERV-L sequences suggested that the impact of APOBEC3 mediated hypermutation on MuERV-L has been minimal. CONCLUSION: The reconstruction of an ancestral MuERV-L sequence highlights the potential for the retroviral fossil record to illuminate ancient events and enable studies of the impact of retroviral elements on animal evolution. PMID- 29716625 TI - 6% Hydroxyethyl starch (HES 130/0.4) diminishes glycocalyx degradation and decreases vascular permeability during systemic and pulmonary inflammation in mice. AB - BACKGROUND: Increased vascular permeability is a pathophysiological hallmark of sepsis and results in increased transcapillary leakage of plasma fluid, hypovolemia, and interstitial edema formation. 6% hydroxyethyl starch (HES 130/0.4) is commonly used to treat hypovolemia to maintain adequate organ perfusion and oxygen delivery. The present study was designed to investigate the effects of 6% HES 130/0.4 on glycocalyx integrity and vascular permeability in lipopolysaccharide (LPS)-induced pulmonary inflammation and systemic inflammation in mice. METHODS: 6% HES 130/0.4 or a balanced electrolyte solution (20 ml/kg) was administered intravenously 1 h after cecal ligation and puncture (CLP) or LPS inhalation. Sham-treated animals receiving 6% HES 130/0.4 or the electrolyte solution served as controls. The thickness of the endovascular glycocalyx was visualized by intravital microscopy in lung (LPS inhalation model) or cremaster muscle (CLP model). Syndecan-1, hyaluronic acid, and heparanase levels were measured in blood samples. Vascular permeability in the lungs, liver, kidney, and brain was measured by Evans blue extravasation. RESULTS: Both CLP induction and LPS inhalation resulted in increased vascular permeability in the lung, liver, kidney, and brain. 6% HES 130/0.4 infusion led to significantly reduced plasma levels of syndecan-1, heparanase, and hyaluronic acid, which was accompanied by a preservation of the glycocalyx thickness in postcapillary venules of the cremaster (0.78 +/- 0.09 MUm vs. 1.39 +/- 0.10 MUm) and lung capillaries (0.81 +/ 0.09 MUm vs. 1.49 +/- 0.12 MUm). CONCLUSIONS: These data suggest that 6% HES 130/0.4 exerts protective effects on glycocalyx integrity and attenuates the increase of vascular permeability during systemic inflammation. PMID- 29716626 TI - Injury in kite buggying: the role of the 'out-of-buggy experience'. AB - BACKGROUND: The purpose of this descriptive, epidemiological study is to classify injury patterns and determine dynamics of injuries, possible causes and preventive measures. METHODS: A questionnaire was filled in by 127 kite buggying enthusiasts in 17 countries. Injuries were classified by type and anatomical site. Incident causes were analysed using the Haddon matrix. RESULTS: Injuries classified as moderate or severe (AIS score >= 2) were sustained by 26% of kite buggy enthusiasts. The most common incident dynamic (61.8%) was the OBE (an acronym for 'out-of-buggy experience'). Causal factors were largely equipment related (42.3%), with remaining incidents being equally attributable to environmental and human factors. While upper and lower limbs were equally involved in incidents, the most frequently affected anatomical site was the shoulder (23%). CONCLUSION: Kite buggying can be considered a sport with the potential for serious injury. Injury prevention in this sport needs to be approached from several angles and should include the development and adoption of automatic release systems and shoulder guards, the establishment of formal training programs covering the subject of meteorology and the establishment of secure, designated kite buggying areas. Findings from this study are important for two reasons. First, they demonstrate the significance of understanding specific sports when considering health and safety, and second, the study provides specific data for the fast growing extreme sport of kite buggying. PMID- 29716627 TI - MicroRNA-424/503 cluster members regulate bovine granulosa cell proliferation and cell cycle progression by targeting SMAD7 gene through activin signalling pathway. AB - BACKGROUND: The granulosa cells are indispensable for follicular development and its function is orchestrated by several genes, which in turn posttranscriptionally regulated by microRNAs (miRNA). In our previous study, the miRRNA-424/503 cluster was found to be highly abundant in bovine granulosa cells (bGCs) of preovulatory dominant follicle compared to subordinate counterpart at day 19 of the bovine estrous cycle. Other study also indicated the involvement of miR-424/503 cluster in tumour cell resistance to apoptosis suggesting this miRNA cluster may involve in cell survival. However, the role of miR-424/503 cluster in granulosa cell function remains elusive Therefore, this study aimed to investigate the role of miRNA-424/503 cluster in bGCs function using microRNA gain- and loss-of-function approaches. RESULTS: The role of miR-424/503 cluster members in granulosa cell function was investigated by overexpressing or inhibiting its activity in vitro cultured granulosa cells using miR-424/503 mimic or inhibitor, respectively. Luciferase reporter assay showed that SMAD7 and ACVR2A are the direct targets of the miRNA-424/503 cluster members. In line with this, overexpression of miRNA-424/503 cluster members using its mimic and inhibition of its activity by its inhibitor reduced and increased, respectively the expression of SMAD7 and ACVR2A. Furthermore, flow cytometric analysis indicated that overexpression of miRNA-424/503 cluster members enhanced bGCs proliferation by promoting G1- to S- phase cell cycle transition. Modulation of miRNA-424/503 cluster members tended to increase phosphorylation of SMAD2/3 in the Activin signalling pathway. Moreover, sequence specific knockdown of SMAD7, the target gene of miRNA-424/503 cluster members, using small interfering RNA also revealed similar phenotypic and molecular alterations observed when miRNA 424/503 cluster members were overexpressed. Similarly, to get more insight about the role of miRNA-424/503 cluster members in activin signalling pathway, granulosa cells were treated with activin A. Activin A treatment increased cell proliferation and downregulation of both miRNA-424/503 members and its target gene, indicated the presence of negative feedback loop between activin A and the expression of miRNA-424/503. CONCLUSION: This study suggests that the miRNA 424/503 cluster members are involved in regulating bovine granulosa cell proliferation and cell cycle progression. Further, miRNA-424/503 cluster members target the SMAD7 and ACVR2A genes which are involved in the activin signalling pathway. PMID- 29716629 TI - Vibrational spectroscopy: a promising approach to discriminate neurodegenerative disorders. AB - Neurodegenerative diseases are a growing burden in modern society, thus crucially calling for the development of accurate diagnostic strategies. These diseases are currently incurable, a fact which has been attributed to their late diagnosis, after brain damage has already become widespread. An earlier and improved diagnosis is necessary for the enrolment of patients into clinical trials and can pave the way for the development of therapeutic tactics. Novel analytical techniques, such as mass spectrometry and vibrational spectroscopy, have been able to successfully detect and characterise neurodegenerative disorders. It is critical to globally support and make use of innovative basic research and techniques, which could ultimately lead to the creation of a cost-effective diagnostic test. Minimally invasive samples, such as biological fluids, have also been shown to reveal information for these diseases; utilising them could simplify sample collection/analysis and be more preferable to patients. PMID- 29716628 TI - Nanog interaction with the androgen receptor signaling axis induce ovarian cancer stem cell regulation: studies based on the CRISPR/Cas9 system. AB - BACKGROUND: Ovarian cancer stem cells (OCSCs) contribute to the poor prognosis of ovarian cancer. Involvement of the androgen receptor (AR) in the malignant behaviors of other tumors has been reported. However, whether AR associates with Nanog (a stem cell marker) and participates in OCSC functions remain unclear. In this study, we investigated the interaction of Nanog with AR and examined whether this interaction induced stem-like properties in ovarian cancer cells. METHODS: AR and Nanog expression in ovarian tumors was evaluated. Using the CRISPR/Cas9 system, we constructed a Nanog green fluorescent protein (GFP) marker cell model to investigate the expression and co-localization of Nanog and AR. Then, we examined the effect of androgen on the Nanog promoter in ovarian cancer cell lines (A2780 and SKOV3). After androgen or anti-androgen treatment, cell proliferation, migration, sphere formation, colony formation and tumorigenesis were assessed in vitro and in vivo. RESULTS: Both AR and Nanog expression were obviously high in ovarian tumors. Our results showed that Nanog expression was correlated with AR expression. The androgen 5alpha-dihydrotestosterone (DHT) activated Nanog promoter transcription. Meanwhile, Nanog GFP-positive cells treated with DHT exhibited higher levels of proliferation, migration, sphere formation and colony formation. We also observed that the tumorigenesis of Nanog GFP-positive cells was significantly higher than that of the GFP-negative cells. Xenografts of Nanog GFP-positive cells showed significant differences when treated with androgen or anti-androgen drugs in vivo. CONCLUSIONS: The interaction of Nanog with the AR signaling axis might induce or contribute to OCSC regulation. In addition, androgen might promote stemness characteristics in ovarian cancer cells by activating the Nanog promoter. This finding merits further study because it may provide a new understanding of OCSC regulation from a hormone perspective and lead to the reevaluation of stem cell therapy for ovarian cancer. PMID- 29716630 TI - Serum miR-22 as potential non-invasive predictor of poor clinical outcome in newly diagnosed, uniformly treated patients with diffuse large B-cell lymphoma: an explorative pilot study. AB - BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous group of tumors, with aggressive clinical course that renders prognostication and choice of treatment strategy difficult. Chemo-immunotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP) is the current first-line treatment. MicroRNAs (miRNAs) are under investigation as novel diagnostic and prognostic biomarkers in several malignancies, including malignant lymphomas. While tissue miRNAs in DLBCL patients have been extensively studied as biomarkers, only few reports to date have evaluated the role of circulating/serum miRNAs as potential prognostic factors. Here circulating/serum miRNAs, including miR-22, were investigated as potential non-invasive biomarkers, with the aim of a better prognostic stratification of DLBCL patients. METHODS: MiRNAs were selected by global expression profile of serum miRNAs of DLBCL patients, The Cancer Genome Atlas (TCGA) analysis and literature research. Serum and tissues miRNA expression profile in de novo DLBCL patients, consecutively enrolled for this study, were detected by quantitative real-time polymerase chain reaction. Relative expression was calculated using the comparative Ct method. Statistical significance was determined using the Mann-Whitney rank sum and Fisher's exact test. Survival analysis was conducted through the use of Kaplan-Meier method. Spearman's Rho was applied to study the correlation between miRNA distributions and days to first relapse. Experimentally validated miRNA-target interactions were assessed by miRTarBase database. Negative miRNA-mRNA correlation was evaluated in TCGA DLBCL dataset. Pathway analysis was performed by the functional annotation clustering DAVID tool. RESULTS: We showed a significant modulation of serum miR-22 after R CHOP treatment compared with basal values but no difference between baseline serum miRNAs values of DLBCL patients and healthy controls. High expression level of serum miR-22 in DLBCL at diagnosis (n = 36) is associated with a worse PFS and is independent of the currently used clinical prognostic index. Integrative and pathways analysis of miR-22 identified target genes involved in different important pathways such as p53 signaling. CONCLUSIONS: Our data suggest that miR 22 is of potential interest as non-invasive biomarker to predict clinical outcome in DLBCL patients. Characterization of miR-22 pathways can pave the way to the development of targeted therapy approaches for specific subgroups of DLBCL patients. PMID- 29716631 TI - NHERF1 and tumor microenvironment: a new scene in invasive breast carcinoma. AB - BACKGROUND: Tumor microenvironment (TME) includes many factors such as tumor associated inflammatory cells, vessels, and lymphocytes, as well as different signaling molecules and extracellular matrix components. These aspects can be de regulated and consequently lead to a worsening of cancer progression. In recent years an association between the scaffolding protein Na+/H+ exchanger regulatory factor 1 (NHERF1) and tumor microenvironment changes in breast cancer (BC) has been reported. METHODS: Subcellular NHERF1 localization, vascular endothelial growth factor (VEGF), its receptor VEGFR1, hypoxia inducible factor 1 alpha (HIF 1alpha), TWIST1 expression and microvessel density (MVD) in 183 invasive BCs were evaluated, using immunohistochemistry on tissue microarrays (TMA). Immunofluorescence was employed to explore protein interactions. RESULTS: Cytoplasmic NHERF1(cNHERF1) expression was directly related to cytoplasmic VEGF and VEGFR1 expression (p = 0.001 and p = 0.027 respectively), and inversely to nuclear HIF-1alpha (p = 0.021) and TWIST1 (p = 0.001). Further, immunofluorescence revealed an involvement of tumor cells with NHERF1 positive staining in neo-vascular formation, suggesting a "mosaic" structure development of these neo-vessels. Survival analyses showed that loss of nuclear TWIST1 (nTWIST1) expression was related to a decrease of disease free survival (DFS) (p < 0.001), while nTWIST1-/mNHERF1+ presented an increased DFS with respect to nTWIST1+/mNHERF1- phenotype (p < 0.001). Subsequently, the analyses of nTWIST1+/cNHERF1+ phenotype selected a subgroup of patients with a worse DFS compared to nTWIST1-/cNHERF1- patients (p = 0.004). CONCLUSION: Resulting data suggested a dynamic relation between NHERF1 and TME markers, and confirmed both the oncosuppressor role of membranous NHERF1 expression and the oncogene activity of cytoplasmic NHERF1. PMID- 29716632 TI - Multi-cellular human bronchial models exposed to diesel exhaust particles: assessment of inflammation, oxidative stress and macrophage polarization. AB - BACKGROUND: Diesel exhaust particles (DEP) are a major component of outdoor air pollution. DEP mediated pulmonary effects are plausibly linked to inflammatory and oxidative stress response in which macrophages (MQ), epithelial cells and their cell-cell interaction plays a crucial role. Therefore, in this study we aimed at studying the cellular crosstalk between airway epithelial cells with MQ and MQ polarization following exposure to aerosolized DEP by assessing inflammation, oxidative stress, and MQ polarization response markers. METHOD: Lung mucosa models including primary bronchial epithelial cells (PBEC) cultured at air-liquid interface (ALI) were co-cultured without (PBEC-ALI) and with MQ (PBEC-ALI/MQ). Cells were exposed to 12.7 MUg/cm2 aerosolized DEP using XposeALI(r). Control (sham) models were exposed to clean air. Cell viability was assessed. CXCL8 and IL-6 were measured in the basal medium by ELISA. The mRNA expression of inflammatory markers (CXCL8, IL6, TNFalpha), oxidative stress (NFKB, HMOX1, GPx) and MQ polarization markers (IL10, IL4, IL13, MRC1, MRC2 RETNLA, IL12 andIL23) were measured by qRT-PCR. The surface/mRNA expression of TLR2/TLR4 was detected by FACS and qRT-PCR. RESULTS: In PBEC-ALI exposure to DEP significantly increased the secretion of CXCL8, mRNA expression of inflammatory markers (CXCL8, TNFalpha) and oxidative stress markers (NFKB, HMOX1, GPx). However, mRNA expressions of these markers (CXCL8, IL6, NFKB, and HMOX1) were reduced in PBEC-ALI/MQ models after DEP exposure. TLR2 and TLR4 mRNA expression increased after DEP exposure in PBEC-ALI. The surface expression of TLR2 and TLR4 on PBEC was significantly reduced in sham-exposed PBEC-ALI/MQ compared to PBEC ALI. After DEP exposure surface expression of TLR2 was increased on PBEC of PBEC ALI/MQ, while TLR4 was decreased in both models. DEP exposure resulted in similar expression pattern of TLR2/TLR4 on MQ as in PBEC. In PBEC-ALI/MQ, DEP exposure increased the mRNA expression of anti-inflammatory M2 macrophage markers (IL10, IL4, IL13, MRC1, MRC2). CONCLUSION: The cellular interaction of PBEC with MQ in response to DEP plays a pivotal role for MQ phenotypic alteration towards M2 subtypes, thereby promoting an efficient resolution of the inflammation. Furthermore, this study highlighted the fact that cell-cell interaction using multicellular ALI-models combined with an in vivo-like inhalation exposure system is critical in better mimicking the airway physiology compared with traditional cell culture systems. PMID- 29716633 TI - Targeting FLT3 in acute myeloid leukemia using ligand-based chimeric antigen receptor-engineered T cells. AB - BACKGROUND: Chimeric antigen receptor-engineered T (CAR-T) cells have extraordinary effect in treating lymphoblastic leukemia. However, treatment of acute myeloid leukemia (AML) using CAR-T cells remains limited to date. Leukemogenesis always relates with the abnormalities of cytogenetics, and nearly one third of AML patients have activating mutations in Fms-like tyrosine kinase 3 (FLT3) which reminded poor prognosis. Considering the FLT3 expressed in AML patients' blast cells, it may be a new candidate target for CAR-T therapy to treat FLT3+ AML, especially patients harboring FLT3-ITD mutation. METHODS: The FLT3L CAR-T using FLT3 ligand as recognizing domain was constructed. The specific cytotoxicity against FLT3+ leukemia cell lines, primary AML cells, and normal hematopoietic progenitor stem cells (HPSCs) in vitro were evaluated. In addition, FLT3+ AML mouse model was used to assess the effect of FLT3L CAR-T therapy in vivo. RESULTS: FLT3L CAR-T cells could specifically kill FLT3+ leukemia cell lines and AML patients' bone marrow mononuclear cells in vitro (with or without FLT3 mutation) and have more potent cytotoxicity to FLT3-ITD cells. In a human FLT3+ AML xenograft mouse model, FLT3L CAR-T cells could significantly prolong the survival of mice. Furthermore, it was found that FLT3L CAR-T cells could activate the FLT3/ERK signaling pathway of FLT3+ leukemia cells with wild-type FLT3; meanwhile, it had no inhibitory effects on the colony formation of CD34+ stem cells derived from normal human umbilical cord blood. CONCLUSIONS: The ligand-based FLT3L CAR-T cells could be a promising strategy for FLT3+ AML treatment, especially those carried FLT3 mutation. PMID- 29716634 TI - Successful fertility following optimized perfusion and cryopreservation of whole ovary and allotransplantation in a premature ovarian insufficiency rat model. AB - BACKGROUND: Fertility preservation by whole ovary cryopreservation and transplantation (WOCP&TP) with vascular anastomosis requires successful cryopreservation. In this study, we investigated the possibility of restoring ovarian function and natural fertility after WOCP&TP in a premature ovarian insufficiency (POI) rat model. The influence of cryopreservation on the offspring of rats following WOCP&TP was also explored. METHOD: Rats aged 8-10 weeks were used as donors and recipients for allotransplantation. Fifteen rat whole ovaries were divided into three groups: the optimized group, the conventional group, and the fresh group. Different perfusion modes were used before cryopreservation and after thawing. Whole ovaries were observed by morphologic analysis, immunohistochemical staining, and transferase-mediated deoxyuridine triphosphate nick end-labeling assay. Ovarian function and fertility after WOCP&TP were then observed in 25 cyclophosphamide-induced POI rats for 8 months. Ovarian function was assessed by vaginal smears and blood hormone levels. Fertility restoration was quantified as the live birth rate after mating. The filial generation of rats was mated at 8-10 weeks of age. Offspring were observed for birth defect. RESULTS: Histological evaluation demonstrated intact morphology of follicles in all groups, with 77.6% of the total number of follicles identified as intact in the optimized group. The apoptotic rates of ovarian cells in the optimized group were significantly lower than that in the conventional group. Of the 20 live POI rats, 14 (70%) began to recover ovarian function after 2 weeks of transplantation, with normal hormone levels achieved 4 weeks after transplantation. Four of 14 rats were pregnant and delivered live offspring. One rat had a second pregnancy and delivered a second litter of live offspring. When the offspring matured, they were mated, and second and third generations of rats were born. All offspring had no abnormalities in appearance. CONCLUSIONS: High rates of restoration of ovarian function and natural fertility with multiple generations of offspring were obtained following WOCP&TP in a cyclophosphamide induced POI rat model by utilizing optimized perfusion. Cryopreservation did not affect the viability of successive generations. PMID- 29716636 TI - Video-assisted Thoracoscopic Surgery (VATS) with mini-thoracotomy for the management of pulmonary hydatid cysts. AB - BACKGROUND: Hydatid cyst is an endemic infectious disease. Various modalities have been provided to approach hydatosis. This article reports a 20-years experience of a new minimally invasive technique for the management of solitary pulmonary hydatid cysts using video-assisted thoracoscopic surgery (VATS) with mini-thoracotomy. METHODS: We reviewed the medical records of patients who underwent unilateral or bilateral single pulmonary hydatid cyst excision using VATS with mini-thoracotomy. All patients were managed by the same surgeon over the period from January 1996 till January 2015. RESULTS: The study involved 120 patients aged between 11 and 74 years (median age = 30 years). The overall number of conducted surgeries was 130 (10 patients needed two surgeries). No deaths were reported during or after surgery. No recurrences were seen in the follow-up period that ranged between 10 and 30 months. Three patients (2.3% out of the 130 surgeries) developed post-operative complications: one patient had prolonged air leak and two patients developed empyema. CONCLUSION: VATS with mini-thoracotomy is an effective and safe option for managing intact or ruptured solitary pulmonary hydatid cysts. Further studies in controlled prospective design are needed to compare this approach to other modalities of management. PMID- 29716637 TI - Is intravenously administered, subdissociative-dose KETAmine non-inferior to MORPHine for prehospital analgesia (the KETAMORPH study): study protocol for a randomized controlled trial. AB - BACKGROUND: Acute pain is a common condition among prehospital patients and prompt management is pivotal. Opioids are the most frequently analgesics used in the prehospital setting. However, opioids are highly addictive, and some patients may develop opioid dependence, even when they are exposed to brief opioid treatments. Therefore, alternative non-opioid analgesia should be developed to manage pain in the prehospital setting. Used at subdissociative doses, ketamine, a noncompetitive N-methyl-D-aspartate and glutamate receptor antagonist, provides analgesic effects accompanied by preservation of protective airway reflexes. In this context, we will carry out a randomized controlled, open-label, multicenter trial to compare a subdissociative dose of ketamine to morphine to provide pain relief in the prehospital setting, in patients with traumatic and non-traumatic pain. METHODS/DESIGN: This will be a multicenter, single-blind, randomized controlled trial. Consecutive adults will be enrolled in the prehospital setting if they experience moderate to severe, acute, non-traumatic and traumatic pain, defined as a numeric rating scale score greater or equal to 5. Patients will be randomized to receive ketamine or morphine by intravenous push. The primary outcome will be the between-group difference in mean change in numeric rating scale pain scores measured from the time before administration of the study medication to 30 min later. DISCUSSION: This upcoming randomized clinical trial was design to assess the efficacy and safety of ketamine, an alternative non opiate analgesia, to manage non-traumatic and traumatic pain in the prehospital setting. We aim to provide evidence to change prescribing practices to reduce exposition to opioids and the subsequent risk of addiction. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT03236805 . Registered on 2 August 2017. PMID- 29716635 TI - CLIP-related methodologies and their application to retrovirology. AB - Virtually every step of HIV-1 replication and numerous cellular antiviral defense mechanisms are regulated by the binding of a viral or cellular RNA-binding protein (RBP) to distinct sequence or structural elements on HIV-1 RNAs. Until recently, these protein-RNA interactions were studied largely by in vitro binding assays complemented with genetics approaches. However, these methods are highly limited in the identification of the relevant targets of RBPs in physiologically relevant settings. Development of crosslinking-immunoprecipitation sequencing (CLIP) methodology has revolutionized the analysis of protein-nucleic acid complexes. CLIP combines immunoprecipitation of covalently crosslinked protein RNA complexes with high-throughput sequencing, providing a global account of RNA sequences bound by a RBP of interest in cells (or virions) at near-nucleotide resolution. Numerous variants of the CLIP protocol have recently been developed, some with major improvements over the original. Herein, we briefly review these methodologies and give examples of how CLIP has been successfully applied to retrovirology research. PMID- 29716638 TI - Liver transplantation for very severe hepatopulmonary syndrome due to vitamin A induced chronic liver disease in a patient with Shwachman-Diamond syndrome. AB - Vitamin A intoxication is a rare cause of liver disease, but the risk increases in patients with underlying liver dysfunction. We present a patient with Shwachman-Diamond Syndrome who developed liver fibrosis, portal hypertension and very severe hepatopulmonary syndrome as a consequence of chronic vitamin A intoxication. She underwent successful liver transplantation with complete resolution of the pulmonary shunting. PMID- 29716639 TI - Educational interventions to improve people's understanding of key concepts in assessing the effects of health interventions: a systematic review. AB - BACKGROUND: Health information is readily accessible but is of variable quality. General knowledge about how to assess whether claims about health interventions are trustworthy is not common, so people's health decisions can be ill-informed, unnecessarily costly and even unsafe. This review aims to identify and evaluate studies of educational interventions designed to improve people's understanding of key concepts for evaluating claims about the effects of health interventions. METHODS/DESIGN: We searched multiple electronic databases and sources of grey literature. Inclusion criteria included all study types that included a comparison, any participants (except health professionals or health professional students) and educational interventions aimed at improving people's understanding of one or more of the key concepts considered necessary for assessing health intervention claims. Knowledge and/or understanding of concepts or skills relevant to evaluating health information were our primary outcome measures. Secondary outcomes included behaviour, confidence, attitude and satisfaction with the educational interventions. Two authors independently screened search results, assessed study eligibility and risk of bias and extracted data. Results were summarised using descriptive synthesis. RESULTS: Among 24 eligible studies, 14 were randomised trials and 10 used other study designs. There was heterogeneity across study participants, settings and educational intervention type, content and delivery. The risk of bias was high in at least one domain for all randomised studies. Most studies measured outcomes immediately after the educational intervention, with few measuring later. In most of the comparisons, measures of knowledge and skills were better among those who had received educational interventions than among controls, and some of these differences were statistically significant. The effects on secondary outcomes were inconsistent. CONCLUSIONS: Educational interventions to improve people's understanding of key concepts for evaluating health intervention claims can improve people's knowledge and skills, at least in the short term. Effects on confidence, attitude and behaviour are uncertain. Many of the studies were at moderate or greater risk of bias. Improvements in study quality, consistency of outcome measures and measures of longer-term effects are needed to improve confidence in estimates of the effects of educational interventions to improve people's understanding of key concepts for evaluating health intervention claims. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016033103. PMID- 29716640 TI - Tranexamic Acid versus Placebo to Prevent Blood Transfusion during Radical Cystectomy for Bladder Cancer (TACT): Study Protocol for a Randomized Controlled Trial. AB - BACKGROUND: Radical cystectomy for bladder cancer is associated with a high risk of needing red blood cell transfusion. Tranexamic acid reduces blood loss during cardiac and orthopedic surgery, but no study has yet evaluated tranexamic acid use during cystectomy. METHODS: A randomized, double-blind (surgeon-, anesthesiologist-, patient-, data-monitor-blinded), placebo-controlled trial of tranexamic acid during cystectomy was initiated in June 2013. Prior to incision, the intervention arm participants receive a 10 mg/kg loading dose of intravenously administered tranexamic acid, followed by a 5 mg/kg/h maintenance infusion. In the control arm, the patient receives an identical volume of normal saline that is indistinguishable from the intervention. The primary outcome is any blood transfusion from the start of surgery up to 30 days post operative. There are no strict criteria to mandate the transfusion of blood products. The decision to transfuse is entirely at the discretion of the treating physicians who are blinded to patient allocation. Physicians are allowed to utilize all resources to make transfusion decisions, including serum hemoglobin concentration and vital signs. To date, 147 patients of a planned 354 have been randomized to the study. DISCUSSION: This protocol reviews pertinent data relating to blood transfusion during radical cystectomy, highlighting the need to identify methods for reducing blood loss and preventing transfusion in patients receiving radical cystectomy. It explains the clinical rationale for using tranexamic acid to reduce blood loss during cystectomy, and outlines the study methods of our ongoing randomized controlled trial. TRIAL REGISTRATIONS: Canadian Institute for Health Research (CIHR) Protocol: MOP-342559; ClinicalTrials.gov, ID: NCT01869413. Registered on 5 June 2013. PMID- 29716642 TI - A triplex quantitative real-time PCR assay for differential detection of human adenovirus serotypes 2, 3 and 7. AB - BACKGROUND: Human adenovirus (HAdV) serotypes 2, 3 and 7 are more prevalent than other serotypes and have been associated with severe pneumonia in pediatric children. Molecular typing of HAdV is not routinely performed in clinical diagnostic laboratories as it is time-consuming and labor-intensive. METHODS: In the present study, we developed a triplex quantitative real-time PCR assay (tq PCR) in a single closed tube for differential detection and quantitative analysis of HAdV serotypes 2, 3 and 7. The sensitivity, specificity, reproducibility and clinical performance of tq-PCR were evaluated. RESULTS: The analytical sensitivity of the tq-PCR was 100 copies/reaction for each of HAdV serotypes 2, 3 and 7, and no cross-reaction with other common respiratory viruses or HAdV serotypes 1,4,5,6,31,55 and 57 was observed. The coefficients of variation (CV) of intra-assay and inter-assay were between 0.6% to 3.6%. Of 138 previously defined HAdV-positive nasopharyngeal aspirates samples tested, the detection agreement between tq-PCR and nested PCR was 96.38% (133/138). CONCLUSION: The proposed tq-PCR assay is a sensitive, specific and reproducible method and has the potential for clinical use in the rapid and differential detection and quantitation of HAdV serotypes 2, 3 and 7. PMID- 29716641 TI - Real-time PCR applications for diagnosis of leishmaniasis. AB - Leishmaniasis is a vector-borne disease caused by many Leishmania species, which can infect both humans and other mammals. Leishmaniasis is a complex disease, with heterogeneous clinical manifestations ranging from asymptomatic infections to lesions at cutaneous sites (cutaneous leishmaniasis), mucosal sites (mucocutaneous leishmaniasis) or in visceral organs (visceral leishmaniasis), depending on the species and host characteristics. Often, symptoms are inconclusive and leishmaniasis can be confused with other co-endemic diseases. Moreover, co-infections (mainly with HIV in humans) can produce atypical clinical presentations. A correct diagnosis is crucial to apply the appropriate treatment and the use of molecular techniques in diagnosis of leishmaniasis has become increasingly relevant due to their remarkable sensitivity, specificity and possible application to a variety of clinical samples. Among them, real-time PCR (qPCR)-based approaches have become increasingly popular in the last years not only for detection and quantification of Leishmania species but also for species identification. However, despite qPCR-based methods having proven to be very effective in the diagnosis of leishmaniasis, a standardized method does not exist. This review summarizes the qPCR-based methods in the diagnosis of leishmaniasis focusing on the recent developments and applications in this field. PMID- 29716643 TI - TDP-43 pathology in anterior temporal pole cortex in aging and Alzheimer's disease. AB - TDP-43 pathology was investigated in the anterior temporal pole cortex (ATPC) and orbital frontal cortex (OFC), regions often degenerated in frontotemporal lobar degenerations (FTLD), in aging and Alzheimer's disease (AD). Diagnosis of dementia in the 1160 autopsied participants from 3 studies of community-dwelling elders was based on clinical evaluation and cognitive performance tests which were used to create summary measures of the five cognitive domains. Neuronal and glial TDP-43 cytoplasmic inclusions were quantitated in 8 brain regions by immunohistochemistry, and used in ANOVA and regression analyses. TDP-43 pathology was present in 547 (49.4%) participants in whom ATPC (41.9%) was the most frequently involved neocortical region and in 15.5% of these cases, ATPC was the only neocortical area with TDP-43 pathology suggesting not only that ATPC is involved early by TDP-43 but that ATPC may represent an intermediate stage between mesial temporal lobe involvement by TDP-43 and the last stage with involvement of other neocortical areas. To better study this intermediary neocortical stage, and to integrate with other staging schemes, our previous 3 stage distribution of TDP-43 pathology was revised to a 5 stage distribution scheme with stage 1 showing involvement of the amygdala only; stage 2 showed extension to hippocampus and/or entorhinal cortex; stage 3 showed extension to the ATPC; stage 4 - showed extension to the midtemporal cortex and/or OFC and finally in stage 5, there was extension to the midfrontal cortex. Clinically, cases in stages 2 to 5 had impaired episodic memory, however, stage 3 was distinct from stage 2 since stage 3 cases had significantly increased odds of dementia. The proportion of cases with hippocampal sclerosis increased progressively across the stages with stage 5 showing the largest proportion of hippocampal sclerosis cases. Stage 5 cases differed from other stages by having impairment of semantic memory and perceptual speed, in addition to episodic memory impairment. These data suggest that of the regions studied, TDP-43 pathology in the ATPC is an important early neocortical stage of TDP-43 progression in aging and AD while extension of TDP-43 pathology to the midfrontal cortex is a late stage associated with more severe and global cognitive impairment. PMID- 29716644 TI - Equine strongyle communities are constrained by horse sex and species dipersal fecundity trade-off. AB - BACKGROUND: Equine strongyles are a major health issue. Large strongyles can cause death of horses while cyathostomins (small strongyles) have shown increased resistance to anthelmintics worldwide. Description of strongyle communities have accumulated but little is known about the diversity of these communities and underpinning environmental factors. METHODS: Strongyles were recovered after ivermectin treatment from 48 horses located in six premises in Poland. Correlation between previously published species fecundity and the observed relative abundance and prevalence were estimated. Significance of horse sex was determined at the species level (prevalence, relative abundance) and at the community level (species richness and dissimilarity between communities). RESULTS: Strongyle species fell into two groups, contrasted by their prevalence and relative abundance. Six to nine horses were necessary to sample at least 90% of strongyle community diversity, providing a minimal cut-off to implement sampling trial in the field. Strongyle communities entertained a network of mostly positive interactions and species co-occurrence was found more often than expected by chance. In addition, species fecundity and prevalence were negatively correlated (Pearson's r = -0.71), suggesting functional trade-offs between species dispersal abilities and fecundity. This functional trade-off may underpin species coexistence. Horse sex was also a significant constraint shaping strongyle communities. Indeed, mares generally displayed more similar strongyle communities than stallions (P = 0.003) and Cylicostephanus calicatus was more abundant in stallions suggesting sex-specific interactions (P = 0.006). CONCLUSIONS: While niche partitioning is likely to explain some of the positive interactions between equine strongyle species, coexistence may also result from a functional trade-off between dispersal ability and fecundity. There is significant evidence that horse sex drives strongylid community structure, which may require differential control strategies between mares and stallions. PMID- 29716645 TI - Effects of habitat suitability for vectors, environmental factors and host characteristics on the spatial distribution of the diversity and prevalence of haemosporidians in waterbirds from three Brazilian wetlands. AB - BACKGROUND: Wetlands are ecosystems in which vectors of avian haemosporidians live and reproduce and where waterbirds join to breed in colonies. Brazil has wetlands at different latitudes, which enables testing the influence of the ecological factors on the prevalence and diversity of haemosporidians. We identified avian haemosporidians in waterbird species in three wetlands and investigated the effects of vector habitat suitability, landscape and host characteristics on the diversity and prevalence of these parasites. METHODS: We created a map with the probability of occurrence of avian haemosporidian vectors using maximum-entropy modelling based on references addressing species known to be vectors of haemosporidians in birds in Brazil. We determined the prevalence and diversity index of haemosporidians in the great egret (Ardea alba) (n = 129) and roseate spoonbill (Platalea ajaja) (n = 180) and compared the findings to data for the wood stork (Mycteria americana) (n = 199). RESULTS: We report the first record of Plasmodium in the family Threskiornithidae: four lineages in the roseate spoonbill, which also presented one lineage of Haemoproteus. In the family Ardeidae, we found three Plasmodium lineages in the great egret. The similar habitat suitability for vectors found in three wetlands explains the pattern of haemosporidian diversity determined for great egret and wood stork populations. Comparisons of haemosporidian diversity within each waterbird species and between regions showed a higher level in the central-western roseate spoonbill population than in the northern population (P = 0.021). Removing the host effect, we discussed the results obtained in terms of characteristics of the Pantanal region. Comparisons of Plasmodium spp. prevalence among waterbird species within the same wetland showed higher level in roseate spoonbill (74%) than those found in the great egret (21%) and wood stork (11%). Excluding the environmental effect, we interpreted result focusing host characteristics that favour infection: time required for nestlings to be covered by feathers and migratory behaviour. CONCLUSIONS: The map of habitat suitability showed that wetlands located in a 30 degrees latitudinal range offer similar conditions for avian vectors species and diversity of haemosporidians. The lineages described in waterbirds were previously identified in birds of prey as Plasmodium paranucleophilum. PMID- 29716646 TI - Evaluation of in vitro culture systems for the maintenance of microfilariae and infective larvae of Loa loa. AB - BACKGROUND: Suitable and scalable in vitro culture conditions for parasite maintenance are needed to foster drug research for loiasis, one of the neglected tropical diseases which has attracted only limited attention over recent years, despite having important public health impacts. The present work aims to develop adequate in vitro culture systems for drug screening against both microfilariae (mf) and infective third-stage larvae (L3) of Loa loa. METHODS: In vitro culture conditions were evaluated by varying three basic culture media: Roswell Park Memorial Institute (RPMI-1640), Dulbecco's modified Eagle's medium (DMEM) and Iscove's modified Dulbecco's medium (IMDM); four sera/proteins: newborn calf serum (NCS), foetal bovine serum (FBS), bovine serum albumin (BSA) and the lipid enriched BSA (AlbuMax(r) II, ALB); and co-culture with the Monkey Kidney Epithelial Cell line (LLC-MK2) as a feeder layer. The various culture systems were tested on both mf and L3, using survival (% motile), motility (T90 = mean duration (days) at which at least 90% of parasites were fully active) and moulting rates of L3 as the major criteria. The general linear model regression analysis was performed to assess the contribution of each variable on the viability of Loa loa L3 and microfilarie. All statistical tests were performed at 95% confidence interval. RESULTS: Of the three different media tested, DMEM and IMDM were the most suitable sustaining the maintenance of both L. loa L3 and mf. IMDM alone could sustain L3 for more than 5 days (T90 = 6.5 +/- 1.1 day). Serum supplements and LLC-MK2 co-cultures significantly improved the survival of parasites in DMEM and IMDM. In co-cultures with LLC-MK2 cells, L. loa mf were maintained in each of the three basic media (T90 of 16.4-19.5 days) without any serum supplement. The most effective culture systems promoting significant moulting rate of L3 into L4 (at least 25%) with substantial maintenance time were: DMEM + BSA, DMEM + NCS, DMEM-AlbuMax(r)II, DMEM + FBS all in co-culture with LLC-MK2, and IMDM + BSA (1.5%), DMEM + FBS (10%) and DMEM + NCS (5%) without feeder cells. DMEM + 1% BSA in co-culture scored the highest moulting rate of 57 of 81 (70.37%). The factors that promoted L. loa mf viability included feeder cells (beta = 0.490), both IMDM (beta = 0.256) and DMEM (beta = 0.198) media and the protein supplements NCS (beta = 0.052) and FBS (beta = 0.022); while for L. loa L3, in addition to feeder cells (beta = 0.259) and both IMDM (beta = 0.401) and DMEM (beta = 0.385) media, the protein supplements BSA (beta = 0.029) were found important in maintaining the worm motility. CONCLUSIONS: The findings from this work display a range of culture requirements for the maintenance of Loa loa stages, which are suitable for developing an effective platform for drug screening. PMID- 29716647 TI - Seroprevalence of Borrelia burgdorferi in Belgian forestry workers and associated risk factors. AB - BACKGROUND: As forest is the preferred environment for ticks, forestry workers are exposed to tick bites and tick-borne diseases. We assessed the seroprevalence of anti-Borrelia burgdorferi (Bb) antibodies and investigated, using an integrated landscape approach, the individual and environmental factors associated with the seroprevalence of Bb in Belgian forestry workers, a high-risk group in Belgium. METHODS: A group of 310 Belgian forest workers was examined to assess the seroprevalence of anti-Borrelia IgG antibodies. Using principal component analysis and binary logistic regression, the joint effects of individual characteristics and environmental characteristics were examined. RESULTS: Sixty-seven of the 310 workers were seropositive for Lyme disease (LD), leading to a seroprevalence of 21.6%. The seroprevalence was higher among forest workers visiting forests more frequently (P = 0.003) or who reported over 100 tick bites (P-value < 0.001). The intensity of tick bites and the use of protection measures against tick bites have a positive impact on LD seroprevalence while the quantity of shadow from trees at ground level had a negative one. CONCLUSIONS: This study showed that forest workers are a population at risk for LD and, by extension, at risk for various tick-borne diseases. In addition to the role of the environment, our results also showed the importance of considering exposure when predicting the risk of infection by Bb. PMID- 29716648 TI - Genomic and biologic comparisons of cyprinid herpesvirus 3 strains. AB - Cyprinid herpesvirus 3 (CyHV-3) is the archetypal fish alloherpesvirus and the etiologic agent of a lethal disease in common and koi carp. To date, the genome sequences of only four CyHV-3 isolates have been published, but no comparisons of the biologic properties of these strains have been reported. We have sequenced the genomes of a further seven strains from various geographical sources, and have compared their growth in vitro and virulence in vivo. The major findings were: (i) the existence of the two genetic lineages previously described as European and Asian was confirmed, but inconsistencies between the geographic origin and genotype of some strains were revealed; (ii) potential inter-lineage recombination was detected in one strain, which also suggested the existence of a third, as yet unidentified lineage; (iii) analysis of genetic disruptions led to the identification of non-essential genes and their potential role in virulence; (iv) comparison of the in vitro and in vivo properties of strains belonging to the two lineages revealed that inter-lineage polymorphisms do not contribute to the differences in viral fitness observed; and (v) a negative correlation was observed among strains between viral growth in vitro and virulence in vivo. This study illustrates the importance of coupling genomic and biologic comparisons of viral strains in order to enhance understanding of viral evolution and pathogenesis. PMID- 29716649 TI - Preexisting radiological interstitial lung abnormalities are a risk factor for severe radiation pneumonitis in patients with small-cell lung cancer after thoracic radiation therapy. AB - BACKGROUND: Previous studies reported that patients with preexisting radiological interstitial lung abnormalities (ILAs) were more susceptible to developing radiation pneumonitis (RP) after thoracic radiation therapy (TRT). The present study aimed to evaluate the incidence and predictors of RP after TRT in patients with small-cell lung cancer (SCLC) with or without preexisting radiological ILAs. METHODS: A total of 95 consecutive patients with SCLC between January 2015 and December 2015, who were treated with thoracic intensity-modulated radiation therapy at Shanghai Pulmonary Hospital,Tongji University School of Medicine, were analyzed. The diagnosis of ILAs was reviewed by two experienced thoracic radiologists based on the pretreatment high-resolution computed tomography imaging, such as honeycombing, subpleural reticular opacities, ground-glass opacity, and traction bronchiectasis. Univariate and multivariate analyses were used to assess the correlation of clinical factors, preexisting radiological ILAs, and dose-volume histogram-based dosimetric parameters with RP. RESULTS: Fifteen (15.8%) patients had preexisting radiological ILAs. The incidence of >= grade 2 and 3 RP at 1 year was 27.1% and 12.7% in the entire cohort, respectively. Preexisting radiological ILAs were associated with an increased risk of >=grade 2 RP (50.0% in ILAs + vs 23.3% in ILAs-, P = 0.017) and >= grade 3 RP (35.8% in ILAs + vs 8.9% in ILAs-, P = 0.005) at 1 year. Preexisting radiological ILAs and smoking history (>=40 pack-years of smoking) were significant predictors of >=grade 3 RP in multivariate analysis (P = 0.023 and 0.012, respectively). CONCLUSIONS: Preexisting radiological ILAs and smoking history (>=40 pack-years of smoking) are associated with an increased risk of >=grade 3 RP after TRT in patients with SCLC. PMID- 29716650 TI - Humans as holobionts: implications for prevention and therapy. AB - The human gut microbiota is increasingly recognized for its important or even decisive role in health. As it becomes clear that microbiota and host mutually affect and depend on each other in an intimate relationship, a holistic view of the gut microbiota-host association imposes itself. Ideally, a stable state of equilibrium, homeostasis, is maintained and serves health, but signs are that perturbation of this equilibrium beyond the limits of resilience can propel the system into an alternative stable state, a pre-disease state, more susceptible to the development of chronic diseases. The microbiota-host equilibrium of a large and growing proportion of individuals in Western society may represent such a pre disease state and explain the explosive development of chronic diseases such as inflammatory bowel disease, obesity, and other inflammatory diseases. These diseases themselves represent other alternative stable states again and are therefore hard to cure. The holistic view of the microbiota-host association where feedback loops between microbiota and host are thought to maintain the system in a stable state-be it a healthy, pre-disease, or disease state-implies that integrated approaches, addressing host processes and microbiota, should be used to treat or prevent (pre-)disease. PMID- 29716651 TI - Overexpressed HDAC8 in cervical cancer cells shows functional redundancy of tubulin deacetylation with HDAC6. AB - BACKGROUND: Histone deacetylases (HDACs) are involved in epigenetic gene regulation via deacetylation of acetylated lysine residues of both histone and non-histone proteins. Among the 18 HDACs identified in humans, HDAC8, a class I HDAC, is best understood structurally and enzymatically. However, its precise subcellular location, function in normal cellular physiology, its protein partners and substrates still remain elusive. METHODS: The subcellular localization of HDAC8 was studied using immunofluorescence and confocal imaging. The binding parterns were identified employing immunoprecipitation (IP) followed by MALDI-TOF analysis and confirmed using in-silico protein-protein interaction studies, HPLC-based in vitro deacetylation assay, intrinsic fluorescence spectrophotometric analysis, Circular dichroism (CD) and Surface Plasmon Resonance (SPR). Functional characterization of the binding was carried out using immunoblot and knockdown by siRNA. Using one way ANOVA statistical significance (n = 3) was determined. RESULTS: Here, we show that HDAC8 and its phosphorylated form (pHDAC8) localized predominantly in the cytoplasm in cancerous, HeLa, and non-cancerous (normal), HEK293T, cells, although nucleolar localization was observed in HeLa cells. The study identified Alpha tubulin as a novel interacting partner of HDAC8. Further, the results indicated binding and deacetylation of tubulin at ac-lys40 by HDAC8. Knockdown of HDAC8 by siRNA, inhibition of HDAC8 and/or HDAC6 by PCI-34051 and tubastatin respectively, cell-migration, cell morphology and cell cycle analysis clearly explained HDAC8 as tubulin deacetylase in HeLa cells and HDAC6 in HEK 293 T cells. CONCLUSIONS: HDAC8 shows functional redundancy with HDAC6 when overexpressed in cervical cancer cells, HeLa, and deacetylaes ac-lys40 of alpha tubulin leading to cervical cancer proliferation and progression. PMID- 29716652 TI - alpha-Synuclein fibril-induced paradoxical structural and functional defects in hippocampal neurons. AB - Neuronal inclusions composed of alpha-synuclein (alpha-syn) characterize Parkinson's Disease (PD) and Dementia with Lewy bodies (DLB). Cognitive dysfunction defines DLB, and up to 80% of PD patients develop dementia. alpha-Syn inclusions are abundant in the hippocampus, yet functional consequences are unclear. To determine if pathologic alpha-syn causes neuronal defects, we induced endogenous alpha-syn to form inclusions resembling those found in diseased brains by treating hippocampal neurons with alpha-syn fibrils. At seven days after adding fibrils, alpha-syn inclusions are abundant in axons, but there is no cell death at this time point, allowing us to assess for potential alterations in neuronal function that are not caused by neuron death. We found that exposure of neurons to fibrils caused a significant reduction in mushroom spine densities, adding to the growing body of literature showing that altered spine morphology is a major pathologic phenotype in synucleinopathies. The reduction in spine densities occurred only in wild type neurons and not in neurons from alpha-syn knockout mice, suggesting that the changes in spine morphology result from fibril induced corruption of endogenously expressed alpha-syn. Paradoxically, reduced postsynaptic spine density was accompanied by increased frequency of miniature excitatory postsynaptic currents (EPSCs) and presynaptic docked vesicles, suggesting enhanced presynaptic function. Action-potential dependent activity was unchanged, suggesting compensatory mechanisms responding to synaptic defects. Although activity at the level of the synapse was unchanged, neurons exposed to alpha-syn fibrils, showed reduced frequency and amplitudes of spontaneous Ca2+ transients. These findings open areas of research to determine the mechanisms that alter neuronal function in brain regions critical for cognition at time points before neuron death. PMID- 29716653 TI - Esophageal pulmonary fistula - a rare complication of radiation therapy: a case report. AB - BACKGROUND: Esophageal respiratory fistulae are abnormal communications between the esophagus and the respiratory system. They are either congenital or acquired. Most acquired esophageal respiratory fistulae are of the esophageal tracheal and esophageal bronchial type and are caused by infections or malignant neoplasms, whereas esophageal pulmonary fistulae are rare. CASE PRESENTATION: We report a case of a 72-year-old Caucasian man with squamous cell carcinoma of the lung presenting with abrupt-onset dyspnea during localized mediastinal radiotherapy. His laboratory test results suggested major respiratory infection. A chest x-ray revealed left apical lung radiopacity along with excavated lesions, consistent with secondary tumor infection. No clinical improvement was observed despite antibiotic treatment. A contrast-enhanced computed tomographic scan of the chest confirmed persistent lung infection with unfavorable progression and air in the mediastinum; the latter suggested a fistula from the upper third of the esophagus to the upper left pulmonary lobe. Videofluoroscopy confirmed the diagnosis of an acquired esophageal pulmonary fistula. The patient underwent endoscopy, and an esophageal self-expandable metallic stent was deployed. CONCLUSIONS: Esophageal pulmonary fistulae must be suspected whenever patients undergoing local mediastinal radiotherapy present with acute pulmonary complications, particularly pneumonia resistant to antibiotic treatment. Esophageal pulmonary fistulae are diagnosed by means of radiological imaging. Because esophageal respiratory fistulae are acute life-threatening conditions, prompt treatment with an endoscopically placed covered stent proves vital. PMID- 29716654 TI - Psychological health is associated with knee pain and physical function in patients with knee osteoarthritis: an exploratory cross-sectional study. AB - BACKGROUND: Depressive symptoms are a major comorbidity in older adults with knee osteoarthritis (OA). However, the type of activity-induced knee pain associated with depression has not been examined. Furthermore, there is conflicting evidence regarding the association between depression and performance-based physical function. This study aimed to examine (i) the association between depressive symptoms and knee pain intensity, particularly task-specific knee pain during daily living, and (ii) the association between depressive symptoms and performance-based physical function, while considering other potential risk factors, including bilateral knee pain and ambulatory physical activity. METHODS: Patients in orthopaedic clinics (n = 95; age, 61-91 years; 67.4% female) who were diagnosed with radiographic knee OA (Kellgren/Lawrence [K/L] grade >= 1) underwent evaluation of psychological health using the Geriatric Depression Scale (GDS). Knee pain and physical function were assessed using the Japanese Knee Osteoarthritis Measure (JKOM), 10-m walk, timed up and go (TUG), and five repetition chair stand tests. RESULTS: Ordinal logistic regression analysis showed that depression, defined as a GDS score >= 5 points, was significantly associated with a worse score on the JKOM pain-subcategory and a higher level of task-specific knee pain intensity during daily living, after being adjusted for age, sex, body mass index (BMI), K/L grade, and ambulatory physical activity. Furthermore, depression was significantly associated with a slower gait velocity and a longer TUG time, after adjusting for age, sex, BMI, K/L grade, presence of bilateral knee pain, and ambulatory physical activity. CONCLUSIONS: These findings indicate that depression may be associated with increased knee pain intensity during daily living in a non-task-specific manner and is associated with functional limitation in patients with knee OA, even after controlling for covariates, including bilateral knee pain and ambulatory physical activity. PMID- 29716655 TI - A double-blind placebo-controlled cross-over clinical trial of DONepezil In Posterior cortical atrophy due to underlying Alzheimer's Disease: DONIPAD study. AB - BACKGROUND: The study investigated whether donepezil exerts symptomatic benefit in patients with posterior cortical atrophy (PCA), an atypical variant of Alzheimer's disease. METHODS: A single-centre, double-blind, placebo-controlled, cross-over clinical trial was performed to assess the efficacy of donepezil in patients with PCA. Each patient received either donepezil (5 mg once daily in the first 6 weeks and 10 mg once daily in the second 6 weeks) or placebo for 12 weeks. After a 2-week washout period, each patient received the other treatment arm during the following 12 weeks followed by another 2-week washout period. The primary outcome was the Mini-Mental State Examination (MMSE) at 12 weeks. Secondary outcome measures were five neuropsychological tests reflecting parieto occipital function. Intention-to-treat analysis was used. For each outcome measure, carry-over effects were first assessed. If present, then analysis was restricted to the first 12-week period. Otherwise, the standard approach to the analysis of a 2 * 2 cross-over trial was used. RESULTS: Eighteen patients (13 females) were recruited (mean age 61.6 years). There was a protocol violation in one patient, who subsequently withdrew from the study due to gastrointestinal side effects. There was statistically significant (p < 0.05) evidence of a carry over effect on MMSE. Therefore, the analysis of treatment effect on MMSE was restricted to the first 12-week period. Treatment effect at 6 weeks was statistically significant (difference = 2.5 in favour of donepezil, 95% CI 0.1 to 5.0, p < 0.05). Treatment effect at 12 weeks was close, but not statistically significant (difference = 2.0 in favour of donepezil, 95% CI -0.1 to 4.5, p > 0.05). There were no statistically significant treatment effects on any of the five neuropsychological tests, except for digit span at 12 weeks (higher by 0.5 digits in favour of placebo, 95% CI 0.1 to 0.9). Gastrointestinal side effects occurred most frequently, affecting 13/18 subjects (72%), and were the cause of study discontinuation in one subject. Nightmares and vivid dreams occurred in 8/18 subjects (44%), and were statistically more frequent during treatment with donepezil. CONCLUSIONS: In this small study, there was no statistically significant treatment effect of donepezil on the primary outcome measure (MMSE score at 12 weeks) in PCA patients, who appear to be particularly susceptible to the development of nightmares and vivid dreams when treated. TRIAL REGISTRATION: Trial registration: Current Controlled Trials ISRCTN22636071 . Retrospectively registered 19 May 2010. PMID- 29716656 TI - Large inter- and intra-case variability of first generation tau PET ligand binding in neurodegenerative dementias. AB - Imaging of pathological tau with positron emission tomography (PET) has the potential to allow early diagnosis of the dementias and monitoring of disease progression, including assessment of therapeutic interventions, in vivo. The first generation of tau PET tracers, including the carbazole flortaucipir and the 2-arylquinolines of the THK series, are now used in clinical research; however, concerns have been raised about off-target binding and low sensitivity.With the aim to determine the nature of tau pathology depicted by structurally distinct tau ligands we carried out a microscopic neuropathological evaluation in post mortem human brain tissue of cases with primary and secondary tauopathies. Carbazole and 2-arylquinoline binding was only observed in cases with Alzheimer's disease and one case with frontotemporal dementia and parkinsonism linked to chromosome 17 exhibiting a R406W MAPT mutation. In end stage Alzheimer's disease cases, fluorescent imaging with the carbazole T726 and the 2-arylquinoline THK 5117 revealed high inter- and intra-case variability of tracer binding, and this was corroborated by quantitative phosphorimaging with the PET tracer [18F]THK 5117. Microscopic analysis of the pathological inclusions revealed that the fluorescent tracers preferentially bind to premature tau aggregates. Whilst T726 binding was limited to neuronal tau, THK-5117 additionally depicted neuritic tau. Neither tracer depicted tau in pre-symptomatic disease.Our results highlight limitations of the first generation of tau PET tracers, in particular lack of correlation between pathological tau load and tracer binding, limited sensitivity to tau in early disease, and high variability in tracer binding between and within cases. Concerns remain that these limitations may also affect the next generation tracers as they target the same high affinity binding site. Therefore, it is crucial to assess inter- and intra-subject correlation of tracer binding with pathological tau load in post-mortem tissue studies, and to rigorously assess novel tau PET tracers before translation into clinical studies. PMID- 29716657 TI - Comparison of McMaster and FECPAKG2 methods for counting nematode eggs in the faeces of alpacas. AB - This study aimed to compare the FECPAKG2 and the McMaster techniques for counting of gastrointestinal nematode eggs in the faeces of alpacas using two floatation solutions (saturated sodium chloride and sucrose solutions). Faecal eggs counts from both techniques were compared using the Lin's concordance correlation coefficient and Bland and Altman statistics. Results showed moderate to good agreement between the two methods, with better agreement achieved when saturated sugar is used as a floatation fluid, particularly when faecal egg counts are less than 1000 eggs per gram of faeces. To the best of our knowledge this is the first study to assess agreement of measurements between McMaster and FECPAKG2 methods for estimating faecal eggs in South American camelids. PMID- 29716658 TI - A case report of spontaneous abortion caused by Brucella melitensis biovar 3. AB - BACKGROUND: Brucellosis is a worldwide zoonotic disease caused by Brucella spp. Brucella invades the body through the skin mucosa, digestive tract, and respiratory tract. However, only a few studies on human spontaneous abortion attributable to Brucella have been reported. In this work, the patient living in Shanxi Province in China who had suffered a spontaneous abortion was underwent pathogen detection and Brucella melitensis biovar 3 was identified. CASE PRESENTATION: The patient in this study was 22 years old. On July 16, 2015, she was admitted to Shanxi Grand Hospital, Shanxi Province, China because of one day of vaginal bleeding and three days of abdominal distension accompanied by fever after five months of amenorrhea. A serum tube agglutination test for brucellosis and blood culture were positive. At the time of discharge, she was prescribed oral doxycycline (100 mg/dose, twice a day) and rifampicin (600 mg/dose, once daily) for 6 weeks as recommended by the World Health Organization (WHO). No recurrence was observed during the six months of follow-up after the cessation of antibiotic treatment. CONCLUSIONS: This is the first reported case of miscarriage resulting from Brucella melitensis biovar 3 isolated from a pregnant woman who was infected through unpasteurized milk in China. Brucellosis infection was overlooked in the Maternity Hospital because of physician unawareness. Early recognition and prompt treatment of brucellosis infection are crucial for a successful outcome in pregnancy. PMID- 29716659 TI - The reporting of a Bacillus anthracis B-clade strain in South Africa after more than 20 years. AB - OBJECTIVES: Anthrax is a disease with an age old history in Africa caused by the Gram-positive endospore forming soil bacterium Bacillus anthracis. Epizootics of wild ungulates occur annually in the enzootic region of Pafuri, Kruger National Park (KNP) in the Limpopo Province of South Africa. Rigorous routine surveillance and diagnostics in KNP, has not revealed these rare isolates since the 1990s, despite unabated annual outbreaks. In 2011 a cheetah was diagnosed as anthrax positive from a private game reserve in Limpopo Province and reported to State Veterinary Services for further investigation. Isolation, molecular diagnostics, whole genome sequencing and comparative genomics were carried out for B. anthracis KC2011. RESULTS: Bacteriological and molecular diagnostics confirmed the isolate as B. anthracis. Subsequent typing and whole genome single nucleotide polymorphisms analysis indicated it clustered alongside B. anthracis SA A0091 in the B.Br.010 SNP branch. Unlike B. anthracis KrugerB strain, KC2011 strain has unique SNPs and represents a new branch in the B-clade. The isolation and genotypic characterisation of KC2011 demonstrates a gap in the reporting of anthrax outbreaks in the greater Limpopo province area. The identification of vulnerable and susceptible cheetah mortalities due to this strain has implications for conservation measures and disease control. PMID- 29716660 TI - A blended psychosocial support program for partners of patients with amyotrophic lateral sclerosis and progressive muscular atrophy: protocol of a randomized controlled trial. AB - BACKGROUND: Informal caregivers of patients with Amyotrophic Lateral Sclerosis (ALS) or Progressive Muscular Atrophy (PMA) face stressful demands due to severe impairments and prospect of early death of the patients they care for. Caregivers often experience feelings of psychological distress and caregiver burden, but supportive interventions are lacking. The objective of this study is to investigate the effectiveness of a psychosocial support program aimed at enhancing feelings of control over caregiving tasks and reducing psychological distress. This support program is based on an existing program for adult partners of people with cancer and is adapted to meet the needs of ALS caregivers. METHODS: This study is a randomized controlled trial using a wait-list control design. One hundred and forty caregiver-patient dyads, recruited from a nationwide database and through the website of the Dutch ALS Center, will be either randomized to a support program or a wait-list control group. The blended intervention is based on Acceptance and Commitment Therapy and consists of 1 face to-face contact, 6 online guided modules and 1 telephone contact. The intervention can be worked through in 8 weeks. The effectiveness and the participants' satisfaction with the intervention will be evaluated using a mixed method design. Caregivers and patients will be asked to fill in questionnaires on 4 occasions during the study: baseline, 3 months, 6 months and 9 months. The main study outcome is the psychological distress of the caregiver assessed with the Hospital Anxiety and Depression Scale. Secondary outcomes are caregiver burden, caregiver quality of life, quality of life of the patient and psychological distress of the patient. Group differences in primary and secondary outcomes at 6 months will be compared with linear mixed model analysis. In a subgroup of caregivers we will explore experiences with the support program through semi structured interviews. Usage of the online modules will be logged. DISCUSSION: The study will provide insights into the effectiveness of a blended psychosocial support program on psychological distress of caregivers of patients with ALS or PMA, as well as into indirect relations with patients' wellbeing. TRIAL REGISTRATION: Netherlands Trial Registry NTR5734 , registered 28 March 2016. PMID- 29716661 TI - Detection of ascaridoid nematode parasites in the important marine food-fish Conger myriaster (Brevoort) (Anguilliformes: Congridae) from the Zhoushan Fishery, China. AB - BACKGROUND: The whitespotted conger Conger myriaster (Brevoort) (Anguilliformes: Congridae) is an extremely marketable food fish, commonly consumed as sashimi or sushi in some Asian countries (i.e. Japan, Korea and China). Conger myriaster is also suspected as being an extremely important source of human anisakidosis. However, there is currently very little information on the levels of infection with ascaridoid nematode parasites in this economically important marine fish. The aims of the present study are to determine the species composition, prevalence and mean intensity of ascaridoid parasites of C. myriaster caught in the Zhoushan Fishery. RESULTS: A total of 1142 third-stage ascaridoid larvae were isolated from 204 C. myriaster. The overall prevalence of infection was 100% (mean intensity 5.6). Nine species of such larvae were accurately identified using integrative taxonomic techniques involving both morphological and genetic data; these included Anisakis pegreffii, A. typica and A. simplex (sensu stricto) * A. pegreffii, Hysterothylacium fabri, H. aduncum, H. sinense, H. amoyense, H. zhoushanense and Raphidascaris lophii. Although high levels of infection and species richness were revealed in C. myriaster, most of the ascaridoid parasites (1135 individuals) were collected from the body cavity and visceral organs of the fish and only seven individuals of A. pegreffii were found in the musculature. CONCLUSIONS: This study represents the first report C. myriaster from the Zhoushan Fishery being heavily infected with third-stage ascaridoid larvae. Among the ascaridoid larvae parasitic in this fish, an important etiological agent of human anisakidosis, A. pegreffii (L3), represents the predominant species. The genus Hysterothylacium has the highest species richness, with H. fabri (L3) being the most prevalent species. This high level of infection of A. pegreffii (L3) in C. myriaster suggests a high risk of anisakidosis or associated allergies for people consuming raw or poorly cooked fish originating from this marine area. These findings provide important basic information on the occurrence and infection parameters of ascaridoid nematodes in this economically important marine fish. They also have significant implications for the prevention and control of human anisakidosis when conger eels from the Zhoushan Fishery are consumed. PMID- 29716662 TI - Nitric oxide balances osteoblast and adipocyte lineage differentiation via the JNK/MAPK signaling pathway in periodontal ligament stem cells. AB - BACKGROUND: Critical tissues that undergo regeneration in periodontal tissue are of mesenchymal origin; thus, investigating the regulatory mechanisms underlying the fate of periodontal ligament stem cells could be beneficial for application in periodontal tissue regeneration. Nitric oxide (NO) regulates many biological processes in developing embryos and adult stem cells. The present study was designed to investigate the effects of NO on the function of human periodontal ligament stem cells (PDLSCs) as well as to elucidate the underlying molecular mechanisms. METHODS: Immunofluorescent staining and flow cytometry were used for stem cell identification. Western blot, reverse transcription polymerase chain reaction (RT-PCR), immunofluorescent staining, and flow cytometry were used to examine the expression of NO-synthesizing enzymes. The proliferative capacity of PDLSCs was determined by EdU assays. The osteogenic potential of PDLSCs was tested using alkaline phosphatase (ALP) staining, Alizarin Red staining, and calcium concentration detection. Oil Red O staining was used to analyze the adipogenic ability. Western blot, RT-PCR, and staining were used to examine the signaling pathway. RESULTS: Human PDLSCs expressed both inducible NO synthase (iNOS) and endothelial NO synthase (eNOS) and produced NO. Blocking the generation of NO with the NOS inhibitor L-NG-monomethyl arginine (L-NMMA) had no influence on PDLSC proliferation and apoptosis but significantly attenuated the osteogenic differentiation capacity and stimulated the adipogenic differentiation capacity of PDLSCs. Increasing the physiological level of NO with NO donor sodium nitroprusside (SNP) significantly promoted the osteogenic differentiation capacity but reduced the adipogenic differentiation capacity of PDLSCs. NO balances the osteoblast and adipocyte lineage differentiation in periodontal ligament stem cells via the c-Jun N-terminal kinase (JNK)/mitogen-activated protein kinase (MAPK) signaling pathway. CONCLUSIONS: NO is essential for maintaining the balance between osteoblasts and adipocytes in PDLSCs via the JNK/MAPK signaling pathway. NO balances osteoblast and adipocyte lineage differentiation via JNK/MAPK signaling pathway. PMID- 29716663 TI - Organization or Community-Based Outbreak? Responding to Cases of Meningitis Under Epidemiologic Uncertainty. AB - Six cases of serogroup C invasive meningococcal disease were identified in Treviso district, Veneto region, Italy between December 13 and 15, 2007. The afflicted patients were found to have attended the same Latin-dance clubs on the same nights, and chemoprophylaxis was provided to potentially exposed individuals. Despite these efforts, 2 cases caused by the same meningococcal strain subsequently occurred in the same area, without any apparent epidemiological correlation to the initial cases. This may have resulted from a failure to neutralize the meningococcal carrier/s. The root cause analysis method applied to public health emergency preparedness was used to analyze the response to this critical incident. The root cause analysis revealed a need to develop regional guidelines for the classification and management of a meningococcal outbreak and for developing risk-communication strategies that include the identification of appropriate channels of communication for differing segments of the population. (Disaster Med Public Health Preparedness. 2018;page 1 of 4). PMID- 29716664 TI - Effects of Callistemon citrinus aqueous extract on prepatent and patent infections with Schistosoma mansoni in experimentally infected mice. AB - Schistosomiasis is a chronic debilitating parasitic disease that causes hepatic damage and is known to be endemic in developing countries. Recent control strategies for schistosomiasis depend exclusively on chemotherapeutic agents, specifically praziquantel. Unfortunately, praziquantel has low efficacy in the early phase of infection, and resistance to treatment is increasingly reported. The aim of this work was to find an alternative treatment by assessing the in vivo activity of aqueous extract of Callistemon citrinus against Schistosoma mansoni in both prepatent and patent phases in experimentally infected mice. The study was conducted on 80 male BALB/c albino mice divided into eight groups. Callistemon was administered at a dose of 200 mg/kg on days 14 and 45 post infection as a single therapy and in combination with praziquantel. Porto mesenteric worm burden, hepatic and intestinal egg counts, hepatic granuloma number and diameter, and oogram pattern were assessed to evaluate the anti schistosomal properties of C. citrinus. Liver enzymes and total bilirubin were tested to assess hepatoprotective effects. Results revealed that the use of C. citrinus was associated with a significant decrease in worm burden and tissue egg load together with an increased percentage of dead eggs. In addition, there was a significant reduction in granuloma formation. Callistemon also led to a significant improvement in liver function. The best results were obtained when C. citrinus was given in the prepatent phase of infection and when combined with praziquantel. Although the effects of C. citrinus are considered to be promising, further studies using different extracts, active ingredients and doses are needed. PMID- 29716665 TI - Cognitive remediation in large systems of psychiatric care. AB - : IntroductionWith the increasing enthusiasm to provide cognitive remediation (CR) as an evidence-based practice, questions arise as to what is involved in implementing CR in a large system of care. This article describes the first statewide implementation of CR in the USA, with the goal of documenting the implementation issues that care providers are likely to face when bringing CR services to their patients. METHODS: In 2014, the New York State Office of Mental Health set up a Cognitive Health Service that could be implemented throughout the state-operated system of care. This service was intended to broadly address cognitive health, to assure that the cognitive deficits commonly associated with psychiatric illnesses are recognized and addressed, and that cognitive health is embedded in the vocabulary of wellness. It involved creating a mechanism to train staff to recognize how cognitive health could be prioritized in treatment planning as well as implementing CR in state-operated adult outpatient psychiatry clinics. RESULTS: By 2017, CR was available at clinics serving people with serious mental illness in 13 of 16 adult Psychiatric Centers, located in rural and urban settings throughout New York state. The embedded quality assurance program evaluation tools indicated that CR was acceptable, sustainable, and effective. CONCLUSIONS: Cognitive remediation can be feasibly implemented in large systems of care that provide a multilevel system of supports, a training program that educates broadly about cognitive health and specifically about the delivery of CR, and embedded, ongoing program evaluation that is linked to staff supervision. PMID- 29716666 TI - Lessons Learnt From Exercise Celestial Navigation: The Application of a Geographic Information System to Inform Legionnaires' Disease Control Activity. AB - Geographic information systems (GIS) have emerged in the past few decades as a technology capable of assisting in the control of infectious disease outbreaks. A Legionnaires' disease cluster investigation in May 2016 in Sydney, New South Wales (NSW), Australia, demonstrated the importance of using GIS to identify at risk water sources in real-time for field investigation to help control any immediate environmental health risk, as well as the need for more staff trained in the use of this technology. Sydney Local Health District Public Health Unit (PHU) subsequently ran an exercise (based on this investigation) with 11 staff members from 4 PHUs across Sydney to further test staff capability to use GIS across NSW. At least 80% of exercise participants reported that the scenario progression was realistic, assigned tasks were clear, and sufficient data were provided to complete tasks. The exercise highlighted the multitude of geocoding applications and need for inter-operability of systems, as well as the need for trained staff with specific expertise in spatial analysis to help assist in outbreak control activity across NSW. Evaluation data demonstrated the need for a common GIS, regular education and training, and guidelines to support the collaborative use of GIS for infectious disease epidemiology in NSW. (Disaster Med Public Health Preparedness. 2018;page 1 of 3). PMID- 29716667 TI - Can Flanders resist the measles outbreak? Assessing vaccination coverage in different age groups among Flemish residents. AB - The Belgian strategic plan to eliminate measles contains several vaccination strategies including routine immunisation programmes and catch-up campaigns. A new expanded programme on immunisation-based survey (2016) assessed the uptake of the recommended measles-mumps-rubella (MMR) vaccine in three different cohorts: toddlers, adolescents and parents of toddlers. A two-stage cluster sampling technique was used to select 875 toddlers (age 18-24 months) and 1250 adolescents (born in 2000) from 107 municipalities in Flanders. After consent of the parent(s), 746 (85.2%) families of toddlers and 1012 (81.0%) families of adolescents were interviewed at home. Measles vaccination coverage was high at 18 24 months (96.2%) and 81.5% were vaccinated at recommended age. Toddlers who had two siblings or a non-working mother or changed vaccinator were more at risk for not being vaccinated. Coverage of the teenager dose reached 93.5% and was lower in adolescents with educational underachievement or whose mother was part-time working or with a non-Belgian background. Only 56.0% of mothers and 48.3% of fathers remembered having received at least one measles-containing vaccine. Although measles vaccination coverage in toddlers meets the required standards for elimination, administration of the teenager dose of MMR vaccine and parent compliance to the recent measles catch-up campaign in Flanders leave room for improvement. PMID- 29716669 TI - The Health Sector Response to the 2015 Earthquake in Nepal. AB - In April 2015, Nepal experienced an earthquake of a magnitude of 7.6 on the Richter scale that resulted in deaths, morbidities, and infrastructure damage. In the post-earthquake period, 4 different workshops and a national "Lessons Learnt" conference were organized to assess the adequacy of the preparedness and response of the health sector. This article summarizes the main conclusions of these discussions relating to leadership, timely search and rescue, referral operations, medical relief to response activities, awareness campaigns, and support from the national and international levels, and epidemiological surveillance. The earthquake response was channeled through rapid response teams that spanned from the community level to the central level via a cluster coordination approach. Overall, the health sector's response was concluded to be largely satisfactory because it focused not only on emergency medical care, but also on the resumption of basic health services and preventive health care (eg, hygiene, risk communication) equally. Post-disaster disease outbreak did not occur because effective surveillance and outbreak monitoring was one of the priority actions. However, services related to birthing centers, neonatal services, and vaccinations were impeded in some rural areas. Some weaknesses in planning, coordination, and management were also noted. The lessons learned can provide the impetus to strengthen future preparedness and response mechanisms. (Disaster Med Public Health Preparedness. 2018;12:543-547). PMID- 29716668 TI - A person-centered approach to the assessment of early life stress: Associations with the volume of stress-sensitive brain regions in early adolescence. AB - Researchers are becoming increasingly interested in linking specific forms of early life stress (ELS) to specific neurobiological markers, including alterations in the morphology of stress-sensitive brain regions. We used a person centered, multi-informant approach to investigate the associations of specific constellations of ELS with hippocampal and amygdala volume in a community sample of 211 9- to 13-year-old early adolescents. Further, we compared this approach to a cumulative risk model of ELS, in which ELS was quantified by the total number of stressors reported. Using latent class analysis, we identified three classes of ELS (labeled typical/low, family instability, and direct victimization) that were distinguished by experiences of family instability and victimization. Adolescents in the direct victimization class had significantly smaller hippocampal volume than did adolescents in the typical/low class; ELS classes were not significantly associated with amygdala volume. The cumulative risk model of ELS had a poorer fit than did the person-centered model; moreover, cumulative ELS was not significantly associated with hippocampal or amygdala volume. Our results underscore the utility of taking a person-centered approach to identify alterations in stress-sensitive brain regions based on constellations of ELS, and suggest victimization is specifically associated with hippocampal hypotrophy observed in early adolescence. PMID- 29716670 TI - Baclofen in the treatment of alcohol dependence with or without liver disease: multisite, randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: There are no available medications for the management of alcohol dependence for patients with alcoholic liver disease (ALD).AimsTo conduct a multisite, double blind, placebo-controlled, randomised clinical trial of baclofen in the treatment of alcohol dependence, with or without liver disease (trial registration: ClinicalTrials.gov, NCT01711125). METHOD: Patients (n = 104) were randomised to placebo, baclofen 30 mg/day or 75 mg/day for 12 weeks. Primary outcomes included survival time to lapse (any drinking), relapse (>=5 drinks per day in men and >=4 in women), and the composite outcome of drinks per drinking day, number of heavy drinking days, and percentage days abstinent. RESULTS: There was a significant effect of baclofen (composite groups) on time to lapse (chi2 = 6.44, P<0.05, Cohen's d = 0.56) and relapse (chi2 = 4.62, P<0.05, d = 0.52). A significant treatment effect of baclofen was observed for percentage days abstinent (placebo 43%, baclofen 30 mg 69%, baclofen 75 mg 65%; P<0.05). There was one serious adverse event (overdose) directly related to medication (75 mg). CONCLUSIONS: Baclofen may be an effective treatment option for patients with ALD. However, given the profile of adverse events, the role for this medication might be best limited to specialist services.Declaration of interestNone. PMID- 29716671 TI - Risk factors associated with seropositivity to California serogroup viruses in humans and pet dogs, Quebec, Canada. AB - Jamestown Canyon and snowshoe hare viruses are two emerging human pathogens associated with cases of neuroinvasive disease in North America. This study aimed to identify environmental and individual risk factors for seropositivity to these arboviruses in humans and pet dogs from Quebec, Canada, 2012-2014. In humans, areas with moderate densities of white-tailed deer (Odocoileus virginianus) were associated with higher odds of seropositivity compared with areas with low densities of white-tailed deer (OR 2.50, P = 0.009) and odds of seropositivity were higher in males than in females (OR 2.03, P = 0.016). Among humans reporting more than 10 mosquito bites weekly, the odds of being seropositive were 4.44 times higher (P = 0.004) for people living in hardwood forested areas. Exposure to areas with coniferous forests was identified as the main environmental risk factor for seroconversion in dogs (OR 2.39, P = 0.04). These findings may help target further public health research, diagnostic and surveillance efforts in Canada. PMID- 29716672 TI - MiR-185 inhibits cell proliferation and invasion of non-small cell lung cancer by targeting KLF7. AB - MicroRNAs are short endogenous non-coding RNAs, which can frequently emerge as regulators in many cancer types. It wasdemonstrated in the research that miR-185 expression levels were remarkably down-regulated in NSCLC tissues than in adjacent normal tissues. Lower miR-185 expression levels were definitely associated with lymph node metastasis. Functional assays showed that up-regulated miR-185 expression in NSCLC cells could inhibit the cell propagation, cell colony formation and incursion capacities in vitro. Furthermore, it was researched that miR-185 could suppress the epithelial-mesenchymal transition (EMT) process with the way of down-regulating E-cadherin expression and upregulating N-cadherin expression. Bioinformatics analysis and luciferase reporter gene assays revealed that Kruppel-like factor 7 (KLF7) acted as straightforward target of miR-185. Overexpression of miR-185 reduced the expression of KLF7 in NSCLC cells. Up regulated KLF7 partly rescued the inhibiting effects induced by miR-185 on cell proliferation and invasion of NSCLC. Additionally, it was confirmed that miR-185 expression suppressed tumor growth using a tumor xenograft model in vivo. Thus, it was concluded that miR-185 may serve as a potential target of NSCLC treatment. PMID- 29716673 TI - Overexpression of miR-1283 inhibits cell proliferation and invasion of glioma cells by targeting ATF4. AB - It is well known that activating transcription factor 4 (ATF4) expression is closely associated with progression of many cancers. And we found that miR-1283 could directly target the ATF4. However, the precise mechanisms of miR-1283 in glioma have not been well clarified. Our study aimed to explore the interaction between ATF4 and miR-1283 in glioma. In this study, we found that the level of miR-1283 was dramatically decreased in glioma tissues and cell lines, and the expression of ATF4 was significantly increased. And the low level of miR-1283 was closely associated with high expression of ATF4 in glioma tissues. Moreover, introduction of miR-1283 significantly inhibited proliferation and invasion of glioma cells. However, knockdown of miR-1283 promoted the proliferation and invasion in glioma cells. Bioinformatics analysis predicted that the ATF4 was a potential target gene of miR-1283. Luciferase reporter assay demonstrated that miR-1283 could directly target ATF4. In addition, knockdown of ATF4 had the similar effects with miR-1283 overexpression on glioma cells. Up-regulation of ATF4 in glioma cells partially reversed the inhibitory effects of miR-1283 mimic. Overexpression of miR1283 inhibited cell proliferation and invasion of glioma cells by directly down-regulating ATF4 expression. PMID- 29716674 TI - MicroRNA-411 inhibits cervical cancer progression by directly targeting STAT3. AB - Cervical cancer is the third most common gynecological cancer and the fourth leading cause of cancer-related deaths inwomen around the world. Substantial evidence has proved that microRNA (miRNA) expression is disordered in many malignant tumors. The dysregulation of miRNAs has been suggested to be involved in the tumorigenesis and tumor development of cervical cancer. Therefore, identification of miRNAs and their biological roles and targets involved in tumor pathology would provide valuable insight into the diagnosis and treatment of patients with cervical cancer. MiRNA-411 (miR-411) has been reported to play an important role in several types of human cancer. However, the expression level, role and underlying molecular mechanisms of miR-411 in cervical cancer remain unclear. Therefore, the objective of this study is to investigate the expression pattern and clinical significance of miR-411 in cervical cancer, and to evaluate its role and underlying mechanisms in this disease. In this study, we confirmed that the expression of miR-411 was significantly downregulated in both cervical cancer tissues and cell lines. Low expression of miR-411 was associated with tumor size, FIGO stage, lymph node metastasis and distant metastasis. Additionally, miR-411 overexpression inhibited cell proliferation and invasion in cervical cancer. Furthermore, a signal transducer and activator of transcription 3 (STAT3) was identified as a direct target of miR-411 in this disease. In clinical samples, miR-411 expression levels were inversely correlated with STAT3, which was significantly upregulated in cervical cancer. Restored STAT3 expression abolished the tumor-suppressing effects of miR-411 overexpression on the proliferation and invasion of cervical cancer cells. In conclusion, our data demonstrated that miR-411 inhibited cervical cancer progression by directly targeting STAT3 and may represent a novel potential therapeutic target and prognostic marker for patients with this disease. PMID- 29716676 TI - High prevalence of metabolic syndrome in antisynthetase syndrome. AB - OBJECTIVES: A high frequency of metabolic syndrome (MetS) has been recently described in different idiopathic inflammatory myopathies, but not in antisynthetase syndrome (ASS). Therefore, the aim of the present study was to determine the prevalence of MetS in ASS and also its possible association with cardiovascular the risk factors and ASS-related disease characteristics. METHODS: A cross-sectional single centre study of 42 consecutive ASS patients was conducted from 2012 to 2015 and compared to 84 healthy individuals matched for gender, age, ethnicity and body mass index-matched (control group). MetS was defined according to the 2009 Join Interim Statement. Clinical and laboratory data were assessed according to a standardised protocol. RESULTS: ASS patients had a median age of 41.1 years with a predominance of female gender and white race. ASS patients had a higher frequency of MetS (42.9% vs. 13.1%; p<0.001) as well as of insulin resistance than controls. Moreover, ASS patients had higher resistin, lower leptin and similar adiponectin levels in serum than controls. Further analysis of ASS patients with (n=18) and without (n=24) MetS revealed that older age at disease onset (48.7 vs. 35.4 years; p<0.001) was identified in those with the syndrome but were similar regarding disease duration, disease status, treatment, insulin resistance and serum adipocytokine levels. CONCLUSIONS: The prevalence of MetS was high in ASS patients that also had serum resistin and low leptin levels. As also identified in other idiopathic inflammatory myopathies, MetS in ASS is more prevalent in older patients. PMID- 29716677 TI - One year in review 2018: pathogenesis of rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease that primarily affects joints. The several mechanisms involved in the development of the disease are not completely understood. It has been proposed that different environmental factors, such as cigarette smoking, occupational and atmospheric agents act as trigger stimuli for the development of RA in genetically predisposed individuals, leading to synovial hyperplasia and bone destruction. The initial disease stage of RA is associated with alteration of innate and adaptive immune system with consequent production of autoantibodies, targeting various molecules including modified self-epitopes. In the following stages of the disease, both the innate (e.g. dendritic cells, macrophages and neutrophils) and adaptive immune cells (e.g. B and T lymphocytes) contribute to the amplification and perpetuation of the chronic inflammatory state. The recognition of key cells, mediators and mechanisms implicated in the pathogenesis of RA could provide the basis for the development of new and precise disease-modifying anti rheumatic drugs. Therefore, we reviewed the literature of the last year in order to find the new insights in RA pathogenesis. PMID- 29716678 TI - Sympathetic Nerve Injury in Thyroid Cancer. AB - The double innervation of the thyroid comes from the sympathetic and parasympathetic nervous system. Injury rates during surgery are at 30% but can be minimized by upwardly preparing the thyroid vessels at the level of thyroid capsule. Several factors have been accused of increasing the risk of injury including age and tumor size. Our aim was to investigate of there is indeed any possible correlations between these factors and a possible increase in injury rates following thyroidectomy. Seven studies were included in the meta-analysis. Statistical correlation was observed for a positive relationship between injury of the sympathetic nerve and thyroid malignancy surgery (p 2 = 74%) No statistical correlations were observed for a negative or positive relationship between injury of the sympathetic nerve and tumor size. There was also no statistically significant value observed for the correlation of the patients' age with the risk of sympathetic nerve injury (p = 0.388). Lack of significant correlation reported could be due to the small number of studies and great heterogeneity between them. PMID- 29716679 TI - Dose Dependent Prophylactic Efficacy of 6-Chlorotacrine in Soman-Poisoned Mice. AB - AIM: The influence of the dose on the ability of promising newly prepared reversible inhibitor of acetylcholinesterase (6-chlorotacrine) to increase the resistance of mice against soman and the efficacy of antidotal treatment of soman poisoned mice was evaluated. METHODS: The evaluation of the effect of pharmacological pretreatment is based on the identification of changes of soman induced toxicity that was evaluated by the assessment of its LD50 value and its 95% confidence limit using probit-logarithmical analysis of death occurring within 24 hrs after administration of soman. RESULTS: The dose of 6-chlorotacrine significantly influences the prophylactic efficacy of 6-chlorotacrine. Its highest dose was only able to significantly protect mice against acute toxicity of soman and increase the efficacy of antidotal treatment (atropine in combination with the oxime HI-6) of soman-poisoned mice. In addition, the highest dose of 6-chlorotacrine was significantly more effective to protect mice from soman poisoning than its lowest dose. CONCLUSION: These findings demonstrate the important influence of the dose of 6-chlorotacine on its prophylactic efficacy in the case of pharmacological pretreatment of soman poisoning in mice. PMID- 29716680 TI - Prevalence of Fibromyalgia Syndrome and Its Correlations with Arrhythmia in Patients with Palpitations. AB - OBJECTIVE: It is aimed to determine the prevalence of fibromyalgia syndrome (FMS) and its correlations with arrhythmia in patients with palpitations. MATERIAL AND METHODS: Sixty-two patients who underwent electrophysiological study (EPS) due to palpitation complaints in Cardiology department and 40 healthy controls were included in the study. The precise diagnosis of arrhythmia was established using EPS. All participants were screened for FMS using American College of Rheumatology 2010 Fibromyalgia diagnostic criteria. Clinical assessments included measurement of severity of pain, fatigue and morning fatigue with visual analog scale (VAS), functional status with Fibromyalgia Impact Questionnaire (FIQ), and anxiety/depression with Hospital Anxiety and Depression Scale (HAD). RESULTS: FMS was diagnosed in 22 of the 62 patients (36%), and 4 of the 40 healthy controls (10%) (p 0.05). EPS+ patients with FMS had higher fatigue levels, HAD and FIQ scores than EPS- patients, although statistically insignificant. HV durations were statistically longer in the EPS- subgroup (p < 0.05) but other EPS data were similar. CONCLUSION: FMS frequency and HAD anxiety scores were found to be higher in patients with palpitation complaints. However, we found no association between arrhythmia, EPS parameters and FMS. In our clinical practice we should keep in mind to carry out assessments in terms of FMS in patients with palpitation. PMID- 29716681 TI - Treatment of Multifocal Multisystem BRAF Positive Langerhans Cell Histiocytosis with Cladribine, Surgery and Allogenic Stem Cell Transplantation. AB - Langerhans cell histiocytosis (LCH) is a very rare disease in adults and as well a very rare cause of sellar expansion. The clinical presentation can be heterogeneous, from a single bone lesion to potentially fatal, widespread disease. We describe the difficulties with the diagnosis and treatment of LCH as well as successful treatment with cladribine chemotherapy and allogeneic stem cell transplantation. PMID- 29716682 TI - A Large Laryngeal Mucocele Causing Progressive upper Airway Obstruction and Cervical Swelling. AB - Laryngocele (LC) is an uncommon clinical entity, occasionally associated with fatal complications. If its neck becomes obstructed, mucous accumulates and then a laryngeal mucocele (LMC) is formed. Reports of LMCs are rare in the literature. A fluid-filled combined LMC in a 48 year-old Greek construction worker with presenting symptoms of cervical swelling and dysphonia is described. The male patient was surgically treated via an external approach. A LC rarely becomes symptomatic and infection unusually occurs. Magnetic resonance imaging depicts in detail the size, extension and structure of the neck mass and remains the diagnostic gold standard, providing superior soft-tissue discrimination, in cases of a concurrent laryngeal tumor. Histopathological examination confirms diagnosis, since there is always a high index of suspicion for malignancy. Established guidelines regarding surgical treatment of a LC do not exist. Although during the last two decades micro laryngoscopy with CO2 laser has gained popularity for the treatment of an internal LC, the external approach still remains the method of choice in cases of a combined LMC. PMID- 29716683 TI - Severe Self-Inflicted Acute Ocular Siderosis Caused by an Iron Tablet in the Conjunctival Fornix. AB - We present the case of a female patient who grinded a ferrous sulfate tablet and placed it at the conjunctival fornix of her left eye. She rapidly developed severe ocular siderosis, with profoundly decreased visual acuity, corneal opacities, cataract, retinal degeneration and ultimately phthisis bulbi. To our knowledge, this is the first report on the consequences of application of an iron tablet on the conjunctiva. PMID- 29716684 TI - Giant Metastatic Liver Tumor of Unknown Primary Origin: Thoracic Autopsy Solves the Mystery. AB - A 59-year-old male patient was hospitalized in the Internal Medicine Department for investigation of hepatic metastases from an unknown primary neoplasm. During the hospitalization the patient died from acute myocardial infarction. The autopsy revealed a 8.2 kilograms (kg) liver that was diffusely infiltrated by whitish metastatic masses. No other tumor was detected, apart from a 2.5 centimeters (cm) pulmonary nodule next to the right intermediate bronchus that was histologically compatible with small cell lung cancer (SCLC). Despite the fact that hepatic metastases from SCLCs are common, diffuse metastatic hepatomegaly from a malignant pulmonary nodule are rarely seen. Given that the most common cause of malignancy-related death is lung cancer, early diagnosis and appropriate management of pulmonary nodules is of paramount importance. PMID- 29716685 TI - SGLT-2 Inhibitors: Are They a Promising Treatment Option in T2DM Patients with NAFLD? AB - Sodium glucose co-transporter type 2 inhibitors (SGLT-2 inhibitors) are a class of antidiabetics, recently approved for the treatment of patients with T2DM. They feature cardioprotective and renoprotective action, while they exert beneficial effects on metabolic parameters. Non-alcoholic fatty liver disease (NAFLD) is a frequent co-morbidity in diabetic patients. Its prevalence reaches up to 70%. Since there is no specific treatment approved for NAFLD, both experimental and clinical studies have been recently conducted highlighting the efficacy and safety of SGLT-2 inhibitors mainly in animal models and secondarily in patients with T2DM and NAFLD. This class of antidiabetics seems very attractive, improving both glycemic control and liver function tests, while inhibiting NAFLD progression. However, further investigation is required to establish them as a first-line treatment option in T2DM patients with NAFLD, after thorough assessment of their efficacy and safety in clinical practice. PMID- 29716686 TI - Deja-vu-How Not to Make the Same Mistake Twice. PMID- 29716687 TI - The Use of Tobacco, E-Cigarettes, and Methods to Quit Smoking in Germany. AB - BACKGROUND: Current data on tobacco use are a necessary prerequisite for the study of the implementation of tobacco control measures in the general population. The German Study on Tobacco Use (Deutsche Befragung zum Rauchverhalten, DEBRA) provides previously lacking data on key indicators of smoking behavior and on the consumption of new products such as e-cigarettes. The continual acquisition and accumulation of data permits the analysis of trends and precise statistical evaluation. METHODS: Data were obtained by repeated face-to face interviews, at 2-month intervals, of representative samples of approximately 2000 persons across Germany aged 14 years and above. For this article, data from 12 273 persons that were acquired in 6 waves of the survey (June/July 2016 to April/May 2017) were aggregated and weighted. RESULTS: The one-year prevalence of current tobacco consumption was 28.3% (95% confidence interval: [27.5; 29.1]) in the overall survey population and 11.9% [8.9; 14.9] among persons under age 18. Higher tobacco consumption was correlated with lower educational attainment and lower income. 28.1% of the smokers had tried to quit smoking in the past year; the most commonly used method of quitting was e-cigarettes (9.1%). Brief physician advice or pharmacotherapy for smoking cessation were tried by 6.1% and 7.0%, respectively. 1.9% of the overall survey population but only 0.3% of persons who had never smoked were current consumers of e-cigarettes. CONCLUSION: Tobacco consumption is very high in Germany compared to other countries in Western and Northern Europe, and its distribution across the population is markedly uneven, with a heavy influence of socioeconomic status. PMID- 29716688 TI - Chest Pain Due to Pacemaker Lead Perforation. PMID- 29716689 TI - E-Cigarettes and the Use of Conventional Cigarettes. AB - BACKGROUND: In 2015, 12.1% of 12- to 17-year-olds in Germany had reportedly already tried e-cigarette smoking at least once. We carried out a study of the "gateway" hypothesis, according to which the use of e-cigarettes can motivate adolescents to start smoking conventional cigarettes. METHODS: During the 2015/2016 school year, 2186 tenth-graders in the German states of Lower Saxony and Schleswig-Holstein who had never smoked conventional cigarettes before took part in a survey over a 6-month period (mean age 15.5 years, standard deviation 0.65; 53.6% female). RESULTS: 14.3% of the survey population (313 adolescents) said at the start of the survey period that they had already tried e-cigarettes at least once. By the end of the survey period, 12.3% (268) of those who had never smoked before had begun to experiment with conventional cigarettes. The risk of beginning such experimentation was 2.2 times higher among e-cigarette users. This association remained (relative risk = 2.18 [1.65; 2.83]) after statistical control for age, sex, state, immigrant background, type of school, socioeconomic status, various personality traits (sensation-seeking, impulsivity, anxiety, hopelessness, extraversion, agreeableness, conscientiousness, neuroticism, openness), and the use of alcohol, cannabis, and other illicit drugs. Further analysis revealed that the association between the use of e cigarettes and the onset of conventional cigarette smoking was stronger among adolescents with low sensation-seeking scores and without any experience of alcohol intoxication. CONCLUSION: Among adolescents who have never smoked, experimentation with conventional cigarettes is more common in those who have used e-cigarettes. This effect seems to be stronger among adolescents who, in general, have a lower risk of starting to smoke. The 6-month observation period of this study is too short to allow any inference regarding a connection between e-cigarette use and the development of tobacco dependence. PMID- 29716691 TI - Para-Articular Cysts in a 64-Year-Old Man. PMID- 29716690 TI - Heart in the Wrong Place: Cardiac Herniation after Pulmonectomy. PMID- 29716692 TI - Manifestation of a Congenital Disorder. PMID- 29716693 TI - In Reply. PMID- 29716694 TI - Adding ivabradine to beta-blockers in chronic heart failure: Do not rest without lowering the resting heart rate sufficiently. PMID- 29716695 TI - Substrate ablation for post-infarct and Brugada storm: Triggering the calm. PMID- 29716696 TI - Evaluation of serum 25-hydroxyvitamin D levels in calcific rheumatic mitral stenosis- A cross sectional study. AB - BACKGROUND AND AIM OF THE STUDY: Rheumatic mitral stenosis (RMS) is an autoimmune, progressive destructive valve disease occurring as a sequele of streptococcal infection. Epidemiological studies support an association of vitamin D deficiency with initial susceptibility and severity of autoimmune diseases. The aim of the present study was to assess serum level of 25 hydroxyvitamin D in subjects of RMS and assess if any correlation exists with serum levels of vitamin D and severity of disease along with calcification assessed semi-quantitatively by echocardiography by applying Wilkins score. METHOD: Fifty five patients of RMS without any calcification of the valves (Group A) assessed by echocardiography along with fifty five patients of RMS with mild to moderately calcified valves (Group B, Wilkins calcium score 1 or 2) and 55 patients with severely calcified valves (Group C, Wilkins calcium score 3 or 4) were enrolled for the study. All subjects underwent clinical, echocardiographic, and biochemical evaluation. The total Wilkins score, Wilkins calcium score along with serum level of 25 hydroxyvitamin D was evaluated in all the patients. RESULTS: The median serum level of 25 hydroxyvitamin D was significantly lower in Group B (20.4ng/ml, p<0.001) and group C (11.4ng/ml, p<0.001) compared to Group A patients (27.9ng/ml). Similarly serum level of 25 hydroxyvitamin D in Group C patients were significantly less than Group B patients (p<0.001). A significant inverse correlation was identified between serum level of 25 hydroxyvitamin D and total Wilkins score (r=-0.65, p<0.001) as well as Wilkins calcium score (r=-0.69, p<0.001). But no correlation was identified between 25 hydroxyvitamin D levels and other echocardiographic parameters of RMS. CONCLUSION: Our study showed a significantly lower level of 25 hydroxyvitamin D in subjects of RMS with severely damaged and calcified valves as compared to those with less severely damaged non calcified valves and it correlated with both Wilkins score and Wilkins calcification score. Thus a link may exist between vitamin D deficiency (an immunomodulator) and severity of autoimmune injury on the valves. PMID- 29716697 TI - Incidence, predictors, clinical profile, management and outcome of patients with isolated left main coronary artery ostial disease. AB - OBJECTIVES: Isolated left main coronary artery (LMCA) ostial disease is a rare variant of LMCA disease. Earlier studies on this disease are limited by small number of patients enrolled. The aim of the present study was to analyze the incidence, risk factors, clinical profile and long term outcome of patients with isolated LMCA ostial disease. METHODS: 15,553 patients who underwent coronary angiogram in a single tertiary care cardiac hospital were analyzed for LMCA disease. 351(2.2%) patients were found to have significant LMCA disease out of which 28(0.18%) had isolated LMCA ostial disease. These 28 patients were compared with 323 non-ostial and non-isolated LMCA disease patients. RESULTS: The mean age of isolated LMCA ostial disease group was significantly less than the other group (p=0.009). Females were more affected than males (p=0.008). They also had low incidence of coronary risk factors (especially dyslipidemia, p=0.04). They tend to present more with stable angina and less with myocardial infarction. They had higher ejection fraction and normal regional wall motion (p=0.04). There was no mortality difference between two groups at the end of 1 year (p=0.234). CONCLUSION: In one of the largest studies done in these patients, we found that isolated LMCA ostial disease is more common in middle aged females with few coronary risk factors. These patients also had a better ejection fraction and normal regional wall motion compared to patients with non-ostial and non-isolated LMCA disease. The clinical and angiographic profile of these patients suggests that they may represent a distinct clinical entity. PMID- 29716698 TI - Estimating the prevalence of elevated plasma neutrophil gelatinase associated lipocalin level in patients with acute coronary syndromes and its association with outcomes. AB - OBJECTIVES: The principal objective of this study was to estimate the plasma levels of neutrophil gelatinase associated lipocalin (NGAL) in a cohort of patients with acute coronary syndromes (ACS) across their entire spectrum, and to correlate them with outcomes. METHODS: 87 patients with acute coronary syndromes were included in the study. Apart from the routine work up and management, all patients underwent determination of plasma NGAL and serum high sensitivity C reactive protein (HSCRP) levels at admission. The patients were followed up through the hospital stay as well as for one month after discharge for clinical outcomes, and echocardiographic parameters of left ventricular function. Plasma NGAL was studied for its predictive power for various defined outcomes. RESULTS: Plasma NGAL levels were detectably elevated in 67% of patients with ACS without any significant proportion with renal dysfunction, sepsis or overt infection. Plasma NGAL was the strongest independent predictor of all cause hospital mortality in Cox regression multivariate analysis with an odds ratio of 8.353, p=0.0237. Plasma NGAL did not correlate with HSCRP, or severity of coronary artery disease (CAD). CONCLUSION: This is a small study that shows that plasma NGAL in patients admitted with ACS can predict hospital mortality and forms the basis for consideration of this molecule as a possible new risk marker in ACS meriting further and more extensive investigation. PMID- 29716699 TI - Assessment of periodontitis and its role in viridans streptococcal bacteremia and infective endocarditis. AB - OBJECTIVES: To evaluate the role of periodontitis in viridans group streptococci (VGS) bacteremia and infective endocarditis (IE). METHODS: A total of 200 subjects including two groups. Group A- 34 subjects undergoing tooth extraction with periodontitis, 46 subjects undergoing tooth extraction without periodontitis and 40 healthy controls. Group B: 40 confirmed cases of IE (17 with and 23 without periodontitis) and 40 healthy controls. Subgingival plaque and blood samples were obtained and processed by standard procedures. RESULTS: A total of 53 blood samples (66.25%) yielded positive cultures after tooth extraction. The relationship between the presence of periodontitis and a positive blood culture was significantly higher (p=0.05) for tooth extraction cases with periodontitis (79.40%) than tooth extraction cases without periodontitis (56.50%). Periodontitis was observed in 42.5% of IE cases. Out of the 40 patients of IE, the blood samples yielded 40 different isolates, majority were viridans streptococci 15 (37.5%) and staphylococci nine (22.5%). No statistically significant difference was observed between the subgingival plaque and blood isolates of periodontitis in both the groups, indicating similarity of biotypes of viridans streptococci isolated from the blood and the subgingival plaque. Similarity was also observed between the antibiogram profiles of viridans streptococci from both the groups. CONCLUSIONS: Periodontitis enhances viridans streptococcal bacteremia and may be a potential risk factor for IE. PMID- 29716700 TI - Prognostic value of blood count parameters in patients with acute coronary syndrome. AB - BACKGROUND: Recent studies have shown that complete blood count (CBC) parameters can effectively predict long-term mortality and re-infarction rates in acute coronary syndrome (ACS). However, the role of these parameters in predicting short term mortality has not been studied extensively. The main objective of this study was to determine whether CBC parameters can predict 30-days mortality and the incidence of major adverse cardiac event (MACE) in ACS patients. METHODOLOGY: A total of 297 patients with ACS were recruited in this prospective study. The relationship of baseline white blood cell (WBC) to mean platelet volume ratio (WMR) with MACE and mortality was assessed during a 30-days follow up. The patients were divided into two groups: Group A [WMR<1000] and Group B [WMR>1000]. Multivariate COX regression was performed to calculate hazard ratios (HR). RESULTS: WMR had the highest area under receiver operating characteristics curve and highest discriminative ability amongst all CBC parameters in predicting mortality. Patients in Group B had a higher mortality rate (p<0.001) than patients in Group A. WBC count (p=0.02), platelet count (p=0.04), WMR (p=0.008), platelet to lymphocyte ratio (p<0.001) and neutrophil to lymphocyte ratio (p=0.03) were significantly higher in the MACE-positive group as compared to MACE negative. In multivariate cox regression analysis, WMR>1000 (HR=2.9, 95% confidence interval 1.3-6.5, p=0.01) was found to be strongest biochemical marker in predicting mortality. CONCLUSION: WMR is an easily accessible and an inexpensive indicator, which may be used as a prognostic marker in patients with ACS. PMID- 29716702 TI - Heart rate manipulation in dilated cardiomyopathy: Assessing the role of Ivabradine. AB - BACKGROUND: Heart rate (HR) reduction is of benefit in chronic heart failure (HF). The effect of heart rate reduction using Ivabradine on various echocardiographic parameters in dilated cardiomyopathy has been less investigated. METHODS: Of 187 patients with HF (DCM, NYHA II-IV, baseline HR>70/min), 125 patients were randomized to standard therapy (beta blockers, ACEI, diuretics, n=62) or add-on Ivabradine (titrated to maximum 7.5mg BD, n=63). Beta-blockers were titrated in both the groups. RESULTS: At 3 months both groups had improvement in NYHA class, 6min walk test, Minnesota Living With Heart Failure (MLWHF) scores and fall in BNP, however the magnitude of change was greater in Ivabradine group. Those on Ivabradine also had lower LV volumes, higher LVEF (28.8+/-3.6 vs 27.2+/-0.5, p=0.01) and more favorable LV global strain (11+/-1.7vs 12.2+/-1.1, p=<0.001), MPI (0.72+/-0.1 vs 0.6+/-0.1, p=<0.001), LV mass (115.2+/-30 vs 131.4+/-35, p=0.007), LV wall stress (219.8+/ 46 vs 238+/-54) and calculated LV work (366+/-101 vs 401+/-102, p=0.05). The benefit of Ivabradine was sustained at 6 months follow up. The % change in HR was significantly higher in Ivabradine group (-32.2% vs -19.3%, p=0.001) with no difference in blood pressure. Resting HR<70/min was achieved in 96.8% vs 27.9%, respectively in the two groups. CONCLUSION: Addition of Ivabradine to standard therapy in patients with DCM and symptomatic HF and targeting a heart rate<70/min improves symptoms, quality of life and various echocardiographic parameters. PMID- 29716701 TI - Differences in symptoms and presentation delay times in myocardial infarction patients with and without diabetes: A cross-sectional study in Pakistan. AB - OBJECTIVE: A short pre-hospital delay, from the onset of symptoms to rapid initiation of reperfusion therapy, is a crucial factor in determining prognosis of myocardial infarction (MI). The purpose of this study was to evaluate symptoms and presentation delay times in MI patients with and without diabetes. METHODS: This cross-sectional study was conducted in 3 tertiary care hospitals of Pakistan over a period of 6 months. The study sample consisted of 280 consenting individuals diagnosed with ST-elevation MI (STEMI) or Non-ST elevation MI (NSTEMI), out of which 130 were diabetic and 150 were non-diabetic. Data was collected using a standardized questionnaire, investigating MI symptoms along with causes and duration of pre-hospital delay within 72hours of admission. RESULTS: No significant difference was found in the intensity of chest pain between diabetics and non-diabetics. Atypical symptoms of MI such as anxiety (p<0.001), cold sweats (p=0.034) and epigastric pain (p=0.017) were more frequently reported in diabetics. MI patients with diabetes had a significantly longer presentation delay time with 75% of the patients presenting after elapse of 3h. Only a few patients reported to the hospital within an hour of onset of symptoms (n=23, 8.2%), out of which majority were non-diabetics (n=18). A majority of patients (n=146, 52%) in both groups did not use emergency medical services. CONCLUSION: This study provides an incentive for further research, aiming to reduce pre hospital delay along with investigating the effectiveness of emergency medical services. PMID- 29716703 TI - An information, education and communication module to reduce dietary salt intake and blood pressure among tea garden workers of Assam. AB - OBJECTIVE: High salt diet increases blood pressure. Tea garden workers (TGW) of Assam, India have high (60.8%) prevalence of hypertension (HTN), which may be due to consumption of extra salt (salt as side dish) and salted tea at work place and home. The present study evaluated an information, education and communication (IEC) module to reduce salt intake and blood pressure among TGW. METHODS: Two tea gardens (usual care and intervention) were selected at random covering a total population of 13,458. The IEC module consisting of poster display, leaflets, health rally, documentary show, individual and group discussion was introduced in the intervention garden targeting study participants, health care providers, key stake holders, school children and teachers. IEC intervention was continued for one year. Participants from usual care and intervention were followed at three monthly intervals and BP and other information were compared after one year. RESULTS: A total of 393 study participants (Non intervention: 194; intervention: 199) were included. After one year of follow up, consumption of extra salt was reduced significantly in the intervention participants (66.3 vs. 45.5%, p=0.000). Intention to treat analysis revealed significant reduction in systolic [-6.4 ( 8.6 to -4.2)] and diastolic [-6.9 (-8.1 to -5.7)] blood pressure after one year. Prevalence of HTN was reduced significantly (52.5 vs. 40.0%, p=0.02) among them. CONCLUSIONS: Our IEC module created awareness about risk of hypertension associated with high salt intake and could reduce dietary salt intake and BP. PMID- 29716704 TI - Clinical - microbiological characterization and risk factors of mortality in infective endocarditis from a tertiary care academic hospital in Southern India. AB - AIMS: To dissect the clinical-microbiological profile of Infective endocarditis (IE) population and to determine the risk factors for IE related mortality. METHODS: A cohort study was conducted using relevant data from clinical records of patients (>=12years) with definite/possible IE from December 2007 to December 2013 and was analyzed using appropriate statistical tests. RESULTS: In the cohort of 139 IE patients, mean age was 47.9+/-15.8years, with male preponderance (68.3%). Rheumatic heart disease was the commonest (30.9%) underlying cardiac lesion followed by mitral valve prolapse with mitral regurgitation (23.7%), degenerative valvular disease (23%), congenital heart disease (15.8%) and prosthetic valves (3.6%). Vegetations were detected in 94.2% cases. Blood cultures were positive in 69.8% cases, commonest organism isolated was alpha - hemolytic streptococci (30.9%) followed by Enterococcus (12.9%) and methicillin sensitive Staphylococcus aureus (10.8%). Complications observed were congestive cardiac failure (31.2%), acute kidney injury (25.9%), stroke (21.6%), septic shock (16.5%), embolic phenomenon non-stroke (8.6%), atrial fibrillation (5%) and ring abscess (2.9%). Mortality rate was 17.3%. Congestive cardiac failure, increase in the peak leucocyte count and stroke were the independent predictors of mortality. CONCLUSIONS: This study reiterates the persistent dominance of rheumatic heart disease in the population studied and alpha - hemolytic Streptococci as the commonest responsible microorganism. PMID- 29716705 TI - Evaluation for airway obstruction in adult patients with stable ischemic heart disease. AB - BACKGROUND: Ischemic heart disease (IHD) and chronic airway disease (COPD and Asthma) are major epidemics accounting for significant mortality and morbidity. The combination presents many diagnostic challenges. Clinical symptoms and signs frequently overlap. There is a need for airway evaluation in these patients to plan appropriate management. METHODS: Consecutive stable IHD patients attending the cardiology OPD in a tertiary care centre were interviewed for collecting basic demographic information, brief medical, occupational, personal history and risk factors for coronary artery disease and airway disease, modified medical research centre (MMRC) grade for dyspnea, quality of life-St. George respiratory questionnaire (SGRQ), spirometry and six-min walk tests. Patients with chronic airway obstruction were treated as per guidelines and were followed up at 3rd month with spirometry, six-minute walk test and SGRQ. RESULTS: One hundred fourteen consecutive patients with stable cardiac disease were included (Males 88, Females-26). Mean age was 58.89+/-12.24years, 53.50% were smokers, 31.56% were alcoholics, 40.35% diabetics, 47.36% hypertensive. Twenty five patients had airway obstruction on spirometry (COPD-13 and Asthma-12) and none were on treatment. Thirty-one patients had cough and 48 patients had dyspnea. Patients with abnormal spirometry had higher symptoms, lower exercise tolerance and quality of life. Treatment with appropriate respiratory medications resulted in increase in lung function, quality of life and exercise tolerance at 3rd month. CONCLUSION: Chronic respiratory disease in patients with stable IHD is frequent but often missed due to overlap of symptoms. Spirometry is a simple tool to recognize the underlying pulmonary condition and patients respond favorably with appropriate treatment. PMID- 29716706 TI - Systolic aortic regurgitation in rheumatic carditis: Mechanistic insight by Doppler echocardiography. AB - BACKGROUND: Aortic regurgitation (AR) usually occurs in diastole in presence of an incompetent aortic valve. Systolic AR is a rare phenomenon occurring in patients with reduced left ventricular systolic pressure and atrial fibrillation or premature ventricular contractions. Its occurrence is a Doppler peculiarity and adds to the hemodynamic burden. AIM: Rheumatic carditis is often characterised by acute or subacute severe mitral regurgitation (MR) due to flail anterior mitral leaflet and elongated chords. In patients with acute or subacute MR, developed left ventricular systolic pressure may fall in mid and late systole due to reduced afterload and end-systolic volume and may be lower than the aortic systolic pressure, causing flow reversal in aorta and systolic AR. MATERIAL AND METHODS: 17 patients with acute rheumatic fever were studied in the echocardiography lab during the period 2005-2015. Five patients had severe MR of which two had no AR and hence were excluded from the study. Three young male patients (age 8-24 years) who met modified Jones' criteria for rheumatic fever with mitral and aortic valve involvement were studied for the presence of systolic AR. RESULTS: In presence of acute or subacute severe MR, flail anterior mitral valve and heart failure, all three showed both diastolic and late systolic AR by continuous-wave and color Doppler echocardiography. CONCLUSION: Systolic AR is a unique hemodynamic phenomenon in patients with acute rheumatic carditis involving both mitral and aortic valves and occurs in presence of severe MR. PMID- 29716707 TI - Balloon embedded stenting: A novel technique for percutaneous coronary intervention of bifurcation lesions, experience in Indian population. AB - BACKGROUND: Bifurcation lesions account for 15-20% of interventions carried out in a catheterization laboratory. Several techniques have been described for treating bifurcation lesions of which culotte and T-stenting and protrusion(TAP) are commonly used. Both these techniques involve recrossing the struts of primary stent, failing which the flow in second branch which can be impaired and lead to catastrophic events. In this study, we describe a novel balloon embedded stenting technique which can be incorporated with traditional culotte or TAP technique and facilitates conversion to bail out crush in case of such an event. METHODS AND RESULTS: 28 patients who were treated with balloon embedded stenting for bifurcation lesions were included in the study. Angiographic and procedural success were achieved in all the patients. Primary stent could not be recrossed in 1 patient, who was successfully converted to bail out crush using the technique. There were no complications during the procedure. Mean fluoroscopy time and contrast volume was similar to that of conventional culotte and TAP. CONCLUSION: The present study suggests that incorporation of balloon embedded stenting into traditional culotte or TAP technique is achievable and can facilitate conversion to bail out crush when required. PMID- 29716708 TI - The effect of percutaneous coronary revascularization on plasma N-terminal pro-B type natriuretic peptide levels in stable coronary artery disease. AB - BACKGROUND: This study was conducted to assess the effect of percutaneous coronary revascularization (PCR) on plasma NT-proBNP concentration in patients with chronic stable angina (CSA). METHODS: This prospective open label interventional study included 22 patients with moderate to severe CSA, normal left ventricular (LV) systolic functions and critical (>90%) proximal stenosis in one of the three major epicardial coronary arteries. After stabilization of medications for 8 weeks, resting supine plasma NT-proBNP levels were measured and patients underwent PCR of the involved vessels. Eight weeks later, with medications unaltered; plasma NT-proBNP levels were repeated and compared with the baseline levels. LV systolic and diastolic functions were assessed before and after PCR. RESULTS: The mean age of the patients was 61.27+/-8.87years. Out of 22 patients, 20 were male and 2 were female. PCR was performed on left anterior descending coronary artery (LAD) in 12 patients and in a non-LAD vessel in 10 patients. After 8 weeks of successful PCR, there was a significant overall reduction in mean plasma NT-proBNP levels (from 244.36+/-218.99 to 168.68+/ 161.61pg/mL, p=0.016). The patients who underwent PCR of LAD demonstrated significantly reduced NT-pro-BNP levels after PCR (p=0.009). In the non-LAD group, NT-proBNP levels also decreased, albeit insignificantly (p=0.432). Reduction in NT-proBNP was independent of change in LV systolic functions. CONCLUSION: Successful PCR, by relieving myocardial ischemia, significantly reduced plasma NT-proBNP levels in majority of the patients with chronic stable angina secondary to critical epicardial coronary artery stenosis. PMID- 29716709 TI - Management of electrical storm of unstable ventricular tachycardia in post myocardial infarction patients: A single centre experience. AB - OBJECTIVE: This is a case series of consecutive patients with past myocardial infarction presenting with Electrical Storm (ES) of unstable ventricular tachycardia (VT) treated by a protocol directed algorithm. METHODS: Management protocol involved treatment of reversible causes, ventilatory & hemodynamic support, administration of antiarrhythmic drugs (AAD) & maximally tolerated doses of beta-blockers, stellate ganglionectomy and Radiofrequency ablation (RFA) guided by Electro Anatomic Mapping (EAM). Patients were followed up periodically with review of device data logs. RESULTS: There were 12 patients (mean age=61.38+/-6.48years & mean LVEF=31.92+/-4.23%). Presentation was recurrent ICD shocks (n=5) or VT (n=7). All were mechanically ventilated. Reversible causes were identified in 4 patients and appropriately addressed. Totally 8 patients underwent endocardial substrate modification by EAM & RFA. Endocardial LV Voltage mapping demonstrated a mean scar area of 70.04+/-17.63 sq.cm (27.04+/-6.20% of mapped area). The electrograms targeted for ablation included late potentials, fractionated electrograms, double potentials and channels within the scar. Two patients had stellate ganglionectomy in addition. Ten patients (83.3%) survived to discharge, all of whom are alive at a follow up of 30.12+/-19months free of ES. VT free survival at end of follow up was 80%. No patient had hospitalization related to VT. Single episode of VT recurrence was seen in 2 patients at 7 months and 1year of follow up respectively. CONCLUSION: In post myocardial infarction patients presenting with ES and unstable VT, a protocol driven approach involving substrate modification targeting abnormal electrograms improves outcomes. PMID- 29716710 TI - Catheter ablation for electrical storm in Brugada syndrome: Results of substrate based ablation. AB - BACKGROUND: Brugada syndrome (BrS) is known to cause malignant ventricular arrhythmia (VA) and sudden cardiac death (SCD). Patients with implantable cardioverter defibrillator (ICD) may experience recurrent shocks from ICD. Recent reports indicate that radiofrequency ablation (RFA) in BrS is feasible, and effective. Catheter ablation of premature ventricular complexes (PVCs) triggering VA and substrate modification of right ventricular outflow tract (RVOT) has been described. METHODS AND RESULTS: Five patients (4 males, age-23 to 32 years) with BrS and electrical storm (ES) despite being on isoprenaline infusion and cilostazol (phosphodiestrase-3 inhibitor) underwent 3 dimensional electroanatomic mapping and RFA. Ventricular fibrillation was easily inducible in two patients. Voltage map of right ventricle was created in sinus rhythm in all patients. Substrate modification of RVOT was performed endocardially in one patient, both endocardial and epicardial in three and only epicardially in one patient. Brugada pattern gradually resolved over one week in all patients post procedure. These patients completed follow up of median 40 months (1.5-70). One patient had inappropriate shock due to atrial fibrillation, one had an episode of VF and appropriate shock 24 months after the RFA. The remaining four patients had no device therapy or VA in device log on follow up. CONCLUSION: Abnormal myocardial substrate is observed in RVOT among patients with BrS. Substrate modification in these patients may abolish Brugada pattern on the ECG and prevents spontaneous VAs on long term follow up. PMID- 29716711 TI - Cardiac magnetic resonance imaging, myocardial scar and coronary flow pattern in anomalous origin of left coronary artery from the pulmonary artery. AB - BACKGROUND: Anomalous origin of left coronary artery from pulmonary artery (ALCAPA) is a very rare congenital heart defect characterized by myocardial ischemia and ultimately scaring. The scar burden will determine eventual recovery of left ventricular function after corrective surgery. MATERIAL METHOD: All patients with proven diagnosis of ALCAPA and who underwent treatment at present centre were included. Detail echocardiography and cardiac magnetic resonance imaging (CMR) (delayed Gadolinium enhancement) was performed before and after surgery. RESULTS: There were 4 patients (3 females, age group 3 months to 3 yr, follow up 6 months to 20 months.) There was no peri operative mortality. All patients had significant improvement in symptom class and LVEF (increase of more than 10%) when evaluated at last follow up. Three patients had pre operative CMR and 3 post operative CMR. All patients had improvement in post operative LVEF, but >50% was observed only in one patient who had less than half thickness delayed gadolinium enhancement. The right coronary flow pattern were unique to disease. The left coronary flow pattern were had significant variation and could predict extent of scared myocardium. CONCLUSION: Ischemia in ALCAPA can lead to myocardial scarring even in early infancy. The recovery in left ventricular function is a closely related to scar burden. Coronary flow patterns are unique and give useful insight into disease process and natural history. PMID- 29716712 TI - Contemporary outcomes of percutaneous closure of patent ductus arteriosus in adolescents and adults. AB - BACKGROUND: Catheter based treatment has gained wide acceptance for management of patent ductus arteriosus (PDA) ever since its introduction. Percutaneous closure in adults can be challenging because of anatomical factors including large sizes, associated pulmonary arterial hypertension (PAH) and co-morbidities. This study aimed to provide comprehensive contemporary data on the safety and efficacy of percutaneous device closure of PDA in adult and adolescent population at a large referral center. METHODS: This single-center retrospective analysis included 70 patients (33 adolescents and 37 adults) who underwent successful percutaneous device closure of PDA between January 2011 and February 2017.Baseline patient demographics, clinical characteristics, procedural and device related variables, and immediate outcomes during hospital stay were recorded. Patients were followed up for residual shunt and complications. RESULTS: Of 70 PDA device closure cases, 71.4% were females; the mean age was 23 years (range:10-58years). Devices used were 4-Cook's detachable coils, 64-occluders (ADO-I and II, Lifetech, Cardi-O Fix), 1-vascular plug and 1-ventricular septal occluder device. Device success was achieved in all including those with very large PDAs. At 24-h post-procedure, the success rate of transcatheter intervention was 95.7%. At 6-months follow up, complete closure was observed in all (mean follow up duration-531days). In patients with severe PAH, significant immediate and sustained reduction of the mean pulmonary pressure was observed(77mmHg to 33mmHg;P=0.014). No procedure related complications including death, device embolization and stenosis of aorta or pulmonary artery occurred. CONCLUSIONS: In contemporary practice, percutaneous device closure is an effective and safe treatment option for adolescent and adult PDA patients. PMID- 29716713 TI - Are objective measures of tricuspid annular motion and velocity used as frequently as recommended by current guidelines? A pilot study. AB - In this retrospective study 420 echocardiograms from a single center were reviewed showing that TAPSE was acquired in 66% while TA TDI s' signals were recorded in 98% of all echocardiograms. Based on these results greater efforts are required to standardize acquisition and reporting of objective measurements of RV function. PMID- 29716714 TI - Evaluation of a polymorphism in MYBPC3 in patients with anthracycline induced cardiotoxicity. AB - Cardiotoxicity is the most serious side effect of anthracyclines (doxorubicin, daunorubicin or epirubicin). The incidence of anthracycline induced late cardiac toxicity (AIC) that is overt clinically is 3-5% in the Indian population. Polymorphism in intron 32 (deletion of 25bp) of MYBPC3 has been shown to be present exclusively in Asians and more so in South India (3-8%). The frequency of the polymorphism is significantly higher (13%) in patients with cardiomyopathy in India. Fifteen patients were identified to have cardiac dysfunction following treatment for malignant lymphoma with doxorubicin containing regimens. Peripheral blood DNA from control, amplified by polymerase chain reaction yielded a 467bp fragment while in the presence of the 25bp deletion only a 442bp fragment was detected. To confirm the presence or absence of the polymorphism, amplified DNA was restricted using Bgl1 in all samples. Bgl1 restricted amplified DNA only if the 25bp deletion was absent. A 467 base pair band was observed in all the 15 samples, which suggested the absence of polymorphism in MYBPC3. In a sample of DNA from a patient with a deletion in exon 33 (confirmed by sequencing) a 442bp fragment was detected. Amplified DNA from this patient was not restricted with Bgl1. Wild type MYBPC3 when amplified gave a distinct restriction banding pattern consisting of two bands of 401bp and 66bp. Amplified DNA from all peripheral blood samples restricted with Bgl1 suggesting the absence of the polymorphism. In this preliminary report, MYBPC3 does not seem to play a role in anthracycline induced cardiotoxicity. PMID- 29716715 TI - Utility of ankle-brachial index in screening for peripheral arterial disease in rural India: A cross-sectional study and review of literature. AB - BACKGROUND: Peripheral arterial disease (PAD) is an underdiagnosed illness often affecting the elderly population. Ankle brachial index (ABI) is a good diagnostic tool for PAD in outpatient practice, but remains underused. MATERIALS AND METHODS: Patients were recruited from an outpatient medical camp in rural India, and assessed for symptoms and pre-existing risk factors. Measured ABI<=0.9 was considered abnormal and considered PAD. RESULTS: Out of 100 patients recruited, PAD was diagnosed in 57 patients. Associated risk factors were like age >55years (67%), hypertension (66%), smoking (69%) and diabetes mellitus (35%) were common. CONCLUSION: PAD is a very common and underdiagnosed illness in rural India. A simple tool like ABI can help diagnosis in underserved areas. PMID- 29716716 TI - Takotsubo cardiomyopathy and acute coronary syndromes: Are they always mutually exclusive? PMID- 29716717 TI - Role of optical coherence tomography guided percutaneous coronary intervention to assess stent malapposition in de-novo coronary lesions. PMID- 29716718 TI - Types of Dual LAD-Nomenclature confusion!!! PMID- 29716719 TI - Glaucoma Adherence-From Theriac to the Future. PMID- 29716720 TI - Clinical experience with patients with spasmodic dysphonia and primary Meige syndrome. AB - INTRODUCTION: Meige syndrome (MS) is part of the group of segmental cranial dystonias, which affect more than two cranial muscle groups. Specifically, blepharospasm is associated with another cranial dystonia (oromandibular, cervical or laryngeal). The aim of this paper was to report our experience in patients with spasmodic dysphonia (SD) associated with primary MS. MATERIAL AND METHODS: A retrospective study involving 8 patients between May 2010 and June 2015. Variables recorded were: age, sex, associated dystonia, electromyographic pattern in laryngeal muscles and treatment given. Outcomes after treatment were assessed using GRBAS(i) scale and VHI-30 questionnaire, always provided by the same examiner. RESULTS: Fifty-six patients with MS were treated in the Neurology Department. Eight patients of 56 were diagnosed with SD (prevalence of 14%). All of our patients had adductor SD. The median age was 71years. All the patients were treated with intralaryngeal botulinum toxin under electromyographic control. Clinically relevant improvements were found after treatment on both the GRBAS(i) scale and the VHI-30 questionnaire. CONCLUSION: In the study of SD, we should always rule out an association with MS. From the point of view of otorhinolaryngology, the joint use of the GRBAS(i) scale and the VHI-30 questionnaire are useful, reliable and efficient methods for assessing progress and response to treatment. Laryngeal infiltration under electromyographic control with botulinum toxin is the therapeutic alternative that provides better results. The management of SD associated with MS does not differ from isolated SD. PMID- 29716721 TI - Diagnostic performance of a streamlined 18F-choline PET-CT protocol for the detection of prostate carcinoma recurrence in combination with appropriate-use criteria. AB - AIM: To evaluate the efficacy of single time-point half-body (skull base to thighs) fluorine-18 choline positron emission tomography-computed tomography (PET CT) compared to a triple-phase acquisition protocol in the detection of prostate carcinoma recurrence. MATERIALS AND METHODS: Consecutive choline PET-CT studies performed at a single tertiary referral centre in patients with biochemical recurrence of prostate carcinoma between September 2012 and March 2017 were reviewed retrospectively. The indication for the study, imaging protocol used, imaging findings, whether management was influenced by the PET-CT, and subsequent patient outcome were recorded. RESULTS: Ninety-one examinations were performed during the study period; 42 were carried out using a triple-phase protocol (dynamic pelvic imaging for 20 minutes after tracer injection, half-body acquisition at 60 minutes and delayed pelvic scan at 90 minutes) between 2012 and August 2015. Subsequently following interim review of diagnostic performance, a streamlined protocol and appropriate-use criteria were introduced. Forty-nine examinations were carried out using the single-phase protocol between 2015 and 2017. Twenty-nine (69%) of the triple-phase studies were positive for recurrence compared to 38 (78%) of the single-phase studies. Only one patient who had a single-phase study would have benefited from a dynamic acquisition, they have required no further treatment or imaging and are currently under prostate specific antigen (PSA) surveillance. CONCLUSION: Choline PET-CT remains a useful tool for the detection of prostate recurrence when used in combination with appropriate-use criteria. Removal of dynamic and delayed acquisition phases reduces study time without adversely affecting accuracy. Benefits include shorter imaging time which improves patient comfort, reduced cost, and improved scanner efficiency. PMID- 29716722 TI - Multi-view stereo in the operating room allows prediction of healing complications in a patient-specific model of reconstructive surgery. AB - Excessive mechanical stress leads to wound healing complications following reconstructive surgery. However, this knowledge is not easily applicable in clinical scenarios due to the difficulty in measuring stress contours during complex tissue rearrangement procedures. Computational tools have been proposed as an alternative to address this need, but obtaining patient specific geometries with an affordable and flexible setup has remained a challenge. Here we present a methodology to determine the stress contours from a reconstructive procedure on a patient-specific finite element model based on multi-view stereo (MVS). MVS is a noninvasive technology that allows reconstruction of 3D geometries using a standard digital camera, making it ideal for the operating room. Finite element analysis can then be used on the patient-specific geometry to perform a virtual surgery and predict regions at risk of complications. We applied our approach to the case of a 7-year-old patient who was treated to correct a cranial contour deformity and resect two large areas of scalp scarring. The simulation showed several zones of high stress, particularly near the suture lines at the distal ends of the flaps. The patient did show delayed healing and partial flap tip necrosis at one of such predicted regions at the 30-day follow up visit. Our results further establish the application of computational tools in individualized medical scenarios to advance preoperative planing and anticipate regions of concern immediately after surgery. PMID- 29716723 TI - Experimental evaluation of current and novel approximations of articular surfaces of the ankle joint. AB - Kinematics and flexibility properties of both natural and replaced ankle joints are affected by the geometry of the articulating surfaces. Recent studies proposed an original saddle-shaped, skewed, truncated cone with laterally oriented apex, as tibiotalar contact surfaces for ankle prosthesis. The goal of this study was to compare in vitro this novel design with traditional cylindrical or medially centered conic geometries in terms of their ability to replicate the natural ankle joint mechanics. Ten lower limb cadaver specimens underwent a validated process of custom design for the replacement of the natural ankle joint. The process included medical imaging, 3D modeling and printing of implantable sets of artificial articular surfaces based on these three geometries. Kinematics and flexibility of the overall ankle complex, along with the separate ankle and subtalar joints, were measured under cyclic loading. In the neutral and in maximum plantarflexion positions, the range of motion under torques in the three anatomical planes of the three custom artificial surfaces was not significantly different from that of the natural surfaces. In maximum dorsiflexion the difference was significant for all three artificial surfaces at the ankle complex, and only for the cylindrical and medially centered conic geometries at the tibiotalar joint. Natural joint flexibility was restored by the artificial surfaces nearly in all positions. The present study provides experimental support for designing articular surfaces matching the specific morphology of the ankle to be replace, and lays the foundations of the overall process for designing and manufacturing patient-specific total ankle replacements. PMID- 29716724 TI - Responsible use of advanced imaging technology. How well are risks and benefits of radiation recognised? PMID- 29716725 TI - Staphylococcus aureus colonization in an institutionalized elderly population long-term care facilities in the Bay of Cadiz area, Spain: prevalence and associated risk factors. AB - BACKGROUND AND OBJECTIVE: Staphylococcus aureus is a health problem behind a great variety of infections. The objective of the study was to establish the prevalence and risk factors of S. aureus carriers in community nursing homes in Cadiz. PATIENTS AND METHOD: A cross study from September 2016 to May 2017. POPULATION: All residents institutionalized in the largest long-term care facilities centers in Cadiz. The main variable was being a S. aureus carrier (sensitive and resistant to methicillin, MSSA and MRSA). The independent variables were age, sex, comorbidity, functional status, antibiotic therapy and hospitalization in the last three months. Bivariate analysis with logistic regression was conducted. RESULTS: Prevalence of colonization: MSSA 17,4% and MRSA 3.8%. Use of beta-lactams was significantly related to a MSSA and MRSA carrier status using multivariate logistic regression OR = 3.3 and OR = 3.8. CONCLUSIONS: There is a low prevalence of S. aureus carriers in the study population. Use of beta-lactams before the study was significantly associated with being a carrier colonized by MSSA y MRSA. Primary care prescriptions are a key in controlling pathogenic multiresistant strains. PMID- 29716726 TI - Clinical judicial syndrome: The impact of judicial proceedings on physician. AB - Complaints of alleged malpractice are a concern for doctors, however the impact these complaints have on them receives little attention. We present a systematic review of the scientific literature by searching the MEDLINE database, without no time limit, of manuscripts on doctors' reaction to a malpractice claim, carried out in Spanish, English and French. Their methodological quality was evaluated, and the results were analysed. The search identified a total of 18 articles, mostly without empirical sample analysis, which described the clinical judicial syndrome construct, its symptomatology, prevalence, etiopathogenesis and issues of prevention and approach. The literature on this subject is very scarce and has poor empirical foundation. However, the available data underscored the relevance of the impact that these complaints have on doctors and highlight the need to establish preventive measures and approaches to the so-called clinical judicial syndrome. PMID- 29716729 TI - Prognostic impact of lymphadenectomy on outcomes of sublobar resection for stage IA non-small cell lung cancer <=2 cm. AB - OBJECTIVE: To investigate the prognostic impact of lymph node (LN) dissection on sublobar resection for stage IA non-small cell lung cancer (NSCLC) tumors <=2 cm. METHODS: All patients who underwent sublobar resection for stage IA NSCLC tumors <=2 cm were identified from the Surveillance, Epidemiology and End Results database. Patients were classified into no-LN dissection and LN dissection groups, and the latter was subclassified by the extent of LN dissection (1-3 regional LNs or >=4 regional LNs). These groups were compared in terms of lung cancer-specific survival (LCSS) and overall survival (OS) rates. Propensity score matched comparative analysis and a Cox regression model were used. RESULTS: A total of 3269 patients met our criteria, including 1459 (44.6%) who underwent no LN dissection, 891 (27.3%) who underwent dissection of 1 to 3 regional LNs, 919 (28.1%) who underwent dissection of >=4 regional LNs. Compared with no LN dissection, LN dissection was associated with more favorable LCSS and OS rates in patients who underwent sublobar resection for stage IA tumors <=2 cm. More extensive regional LN dissection (>=4 regional LNs) was associated with better LCSS and OS rates compared with less extensive regional LN dissection (1 to 3 regional LNs). A multivariable analysis of our patient population revealed independent associations of no LN dissection and less extensive regional LN dissection with poorer LCSS and OS rates compared with overall LN dissection and more extensive regional LN dissection, respectively. CONCLUSIONS: This propensity score-matched analysis reveals an association of LN dissection, particularly more extensive regional LN dissection (>=4 regional LNs), with better survival rates in patients who undergo sublobar resection for stage IA NSCLC tumors <=2 cm. PMID- 29716728 TI - p63 Silencing induces reprogramming of cardiac fibroblasts into cardiomyocyte like cells. AB - OBJECTIVE: Reprogramming of fibroblasts into induced cardiomyocytes represents a potential new therapy for heart failure. We hypothesized that inactivation of p63, a p53 gene family member, may help overcome human cell resistance to reprogramming. METHODS: p63 Knockout (-/-) and knockdown murine embryonic fibroblasts (MEFs), p63-/- adult murine cardiac fibroblasts, and human cardiac fibroblasts were assessed for cardiomyocyte-specific feature changes, with or without treatment by the cardiac transcription factors Hand2-Myocardin (HM). RESULTS: Flow cytometry revealed that a significantly greater number of p63-/- MEFs expressed the cardiac-specific marker cardiac troponin T (cTnT) in culture compared with wild-type (WT) cells (38% +/- 11% vs 0.9% +/- 0.9%, P < .05). HM treatment of p63-/- MEFs increased cTnT expression to 74% +/- 3% of cells but did not induce cTnT expression in wild-type murine embryonic fibroblasts. shRNA mediated p63 knockdown likewise yielded a 20-fold increase in cTnT microRNA expression compared with untreated MEFs. Adult murine cardiac fibroblasts demonstrated a 200-fold increase in cTnT gene expression after inducible p63 knockout and expressed sarcomeric alpha-actinin as well as cTnT. These p63-/- adult cardiac fibroblasts exhibited calcium transients and electrically stimulated contractions when co-cultured with neonatal rat cardiomyocytes and treated with HM. Increased expression of cTnT and other marker genes was also observed in p63 knockdown human cardiac fibroblasts procured from patients undergoing procedures for heart failure. CONCLUSIONS: Downregulation of p63 facilitates direct cardiac cellular reprogramming and may help overcome the resistance of human cells to reprogramming. PMID- 29716730 TI - Abracadabra I, II...HeartMate 3? PMID- 29716731 TI - Symptoms versus testing: How should we follow-up achalasia after myotomy? PMID- 29716732 TI - Different Nuss procedures and risk management for pectus excavatum after surgery for congenital heart disease. AB - PURPOSE: In Nuss procedure for pectus excavatum (PE) after surgery for congenital heart disease (CHD), retrosternal adhesion may increase the risk of cardiac injury. This study aimed to explore different Nuss procedures and their implications for reducing the incidence of serious complications and improving surgical safety. METHODS: We retrospectively reviewed 49 cases (29 male and 20 female) of Nuss procedures for PE after surgery for CHD that were performed between April 2003 and December 2016. The median age was 5.8 years (range, 3.0 17.9), and the median Haller index was 4.6 (3.2-17.7). All patients were evaluated on their cardiac function and severity of PE by echocardiography and computed tomography scan, respectively. Three surgical procedures were used. Perioperative conditions were analyzed, including CHD type, interval between two operations, blood loss, operation time, hospital stay, complications, and postoperative results. RESULTS: All 49 cases were completed successfully. Fourteen cases (28.6%) involved the standard three-incision thoracoscopic Nuss procedure, 30 cases (61.2%) involved the Nuss procedure assisted by a median sternum incision, and 5 cases (10.2%) involved the Nuss procedure with sternal suspension. The median interval between the CHD surgery and Nuss procedure was 4.0 years (0.5-12.0). The median blood loss was 2.0 mL (1.0-150.0 mL). The median operation time was 45.0 min (27.0-230.0), and the median hospital stay was 6.0 days (5.0-9.0). Three patients (6.1%) experienced severe surgical complications: 2 experienced a rupture of the right atrium and 1 had pericardial injury. Patients were followed up for 7-120 months after surgery. The postoperative results were excellent in 46 cases (93.9%) and good in 3 (6.1%). Twenty-four of the 49 patients have had their bars removed. The median time for bar removal was 36.0 months (24.0-47.0). The outcome after bar removal surgery was excellent in 20 cases and good in 4. CONCLUSIONS: Patients may develop PE or worsening of preexisting PE after open heart surgery for CHD. Surgery for PE can still be performed by the standard Nuss technique without increasing the risk of cardiac injury for the patients that have had interventional cardiology procedures for CHD previously. However, the risk of cardiac injury during the Nuss procedure dramatically increases due to retrosternal adhesions that develop after open heart surgery for CHD. In our experience, the Nuss procedure is safe and feasible after open heart surgery for CHD when performed by an experienced pectus surgeon using an individualized surgical plan for each patient. TYPE OF STUDY: Retrospective study. LEVEL OF EVIDENCE: Level IV. PMID- 29716733 TI - Acute adrenal crisis and mortality in adrenal insufficiency: Still a concern in 2018! AB - Despite established replacement therapy, mortality in patients suffering from chronic adrenal insufficiency is increasing. This may be partly explained by the fact that lack of adrenal stress hormones impairs the body's capacity to deal adequately with stress situations, resulting in life-threatening adrenal crises. Since many such situations are of rapid onset, concepts that allow for quick response to emergencies are particularly important. Optimal education for patients and relatives, improved awareness on the part of health professionals and the development of new easy-to-use drugs for acute therapy are of prime importance. PMID- 29716734 TI - The difficulties of pseudo-Cushing's syndrome (or "non-neoplastic hypercortisolism"). AB - Pseudo-Cushing's syndrome covers different pathological conditions responsible for mild-to-moderate ACTH-dependent hypercortisolism, related not to an ACTH secreting tumor but rather to CRH and/or AVP hypothalamic secretion through activation of various neural pathways, in patients generally displaying excess central adiposity. It is better termed "non-neoplastic hypercortisolism" (NNH). The main conditions implicated in NNH comprise: neuropsychiatric disorder, alcohol abuse, insulin-resistant obesity, polycystic ovary syndrome, and end stage kidney disease. Glucocorticoid resistance is one differential diagnosis, as are some cases of primary adrenal disease with incompletely suppressed ACTH. Differentiating between NNH and mild-to-moderate Cushing's disease can be a real challenge. Clinical analysis, based on thorough history taking and screening for catabolic signs is essential; useful explorations include midnight serum or salivary cortisol and Dex/CRH and ddAVP stimulation response. Pituitary MRI suffers from limitations regarding both sensitivity and specificity, while bilateral inferior petrosal sinus sampling cannot distinguish between pituitary ACTH secretion by a tumor or by normal cells stimulated by endogenous CRH. Definitive diagnosis of functional etiology requires demonstrating that treatment of the underlying condition restores normal secretion of ACTH and cortisol, but this is not always possible. Lingering diagnostic uncertainty has to be accepted in certain patients, who will have to be followed up for some time before diagnosis can be considered more or less definitive. PMID- 29716735 TI - Determination of transformation products of unsymmetrical dimethylhydrazine in water using vacuum-assisted headspace solid-phase microextraction. AB - A new, sensitive and simple method based on vacuum-assisted headspace solid-phase microextraction (Vac-HSSPME) followed by gas chromatography-mass-spectrometry (GC MS), is proposed for the quantification of rocket fuel unsymmetrical dimethylhydrazine (UDMH) transformation products in water samples. The target transformation products were: pyrazine, 1-methyl-1H-pyrazole, N nitrosodimethylamine, N,N-dimethylformamide, 1-methyl-1N-1,2,4-triazole, 1-methyl imidazole and 1H-pyrazole. For these analytes and within shorter sampling times, Vac-HSSPME yielded detection limits (0.5-100 ng L-1) 3-10 times lower than those reported for regular HSSPME. Vac-HSSPME sampling for 30 min at 50 degrees C yielded the best combination of analyte responses and their standard deviations (<15%). 1-Formyl-2,2-dimethylhydrazine and formamide were discarded because of the poor precision and accuracy when using Vac-HSSPME. The recoveries for the rest of the analytes ranged between 80 and 119%. The modified Mininert valve and Thermogreen septum could be used for automated extraction as it ensured stable analyte signals even after long waiting times (>24 h). Finally, multiple Vac HSSME proved to be an efficient tool for controlling the matrix effect and quantifying UDMH transformation products. PMID- 29716736 TI - Recyclable aqueous two-phase system based on two pH-responsive copolymers and its application to porcine circovirus type 2 Cap protein purification. AB - Aqueous two-phase system (ATPS) has great potential in industrial applications of bio-separations and bio-reactions. However, its large-scale application is limited by recovery difficulty of phase systems. In this paper, a recyclable ATPS was prepared by two pH-responsive copolymers (PADB4.99 and PMDM7.08) and applied for purification of porcine circovirus type 2 Cap protein fermentation broth (PCV2 Cap protein). Phase separation mechanism was studied by using low-field nuclear magnetic resonance (LF-NMR). The results showed that relatively desirable ATPS were formed successfully when two copolymer concentrations were 4%-6% (w/w) with pH 7.5-8.6. The main parameters, such as copolymer concentration, temperature, pH, type and concentration of salts, were investigated. The results demonstrated that the best ATPS consisted of 4% (w/w) PADB4.99 and 6% (w/w) PMDM7.08, the optimal partition coefficient (K) and extraction recovery (ER) of PCV2 cap protein were 0.25 and 94.2% in the presence of 50 mM Li2SO4, 3.53 and 93.4% in the presence of 40 mM KCl, respectively, at 30 degrees C, pH 8.1. The maximum purity of PCV2 Cap protein was 88.4%. In addition, the two phase-forming copolymers could be recycled by adjusting solution pH to their isoelectric points (pI), with recoveries of over 97.5%. PMID- 29716737 TI - Development and optimization of a plunger assisted solvent extraction method for polycyclic aromatic hydrocarbons sampled onto multi-channel silicone rubber traps. AB - A plunger assisted solvent extraction (PASE) method for multi-channel silicone rubber trap samplers was developed and evaluated as an alternative to direct thermal desorption for the monitoring of polycyclic aromatic hydrocarbons (PAHs). The proposed extraction method was simple, fast (a total of 2 min for extraction), and used a small volume of solvent (a total of 2 mL from two sequential 1 mL extractions). The PASE method presented an advantage over thermal desorption in that samples could be re-analyzed, as only a portion of the extract was injected. Additionally, this approach is cost effective and can be applied in laboratories which do not have thermal desorption systems, hence allowing for the more widespread use of the polydimethylsiloxane samplers which can be employed as denuders in the monitoring of gas and particle partitioning of air pollutants. The method was validated over a wide concentration range (0.005-10 ng MUL-1) and the limits of detection ranged from 13.6 ng m-3 for naphthalene to 227.1 ng m-3 for indeno[1,2,3-cd]pyrene. Overall extraction efficiencies of the target PAHs were good (from 76% for naphthalene to 99% for phenanthrene) with relative standard deviations below 6%. The PASE method was successfully applied to the analysis of domestic fire air emission samples taken at 10 and 20 min after ignition, using a sampling flow rate of 500 mL min-1 for 10 min in each case. The samples were found to contain primarily naphthalene (maximum concentration of 9.5 MUg m-3, 10 min after ignition), as well as fluorene, anthracene, phenanthrene, fluoranthene and pyrene. PMID- 29716738 TI - Neuropsychological consequences of childhood medulloblastoma and possible interventions: A review. AB - BACKGROUND: Children who have been treated for a medulloblastoma often suffer long-term cognitive impairments that often negatively affect their academic performance and quality of life. In this article, we will review the neuropsychological consequences of childhood medulloblastoma and discuss the risk factors known to influence the presence and severity of these cognitive impairments and possible interventions to improve their quality of life. METHODS: This narrative review was based on electronic searches of PubMed to identify all relevant studies. RESULTS: Although many types of cognitive impairments often emerge during a child's subsequent development, the core cognitive domains that are most often affected in children treated for a medulloblastoma are processing speed, attention and working memory. The emergence and magnitude of these deficits varies greatly among patients. They are influenced by demographic (age at diagnosis, parental education), medical and treatment-related factors (perioperative complications, including posterior fossa syndrome, radiation therapy dose, etc.), and the quality of interventions such as school adaptations provided to the child or rehabilitation programs that focus on cognitive skills, behavior and psychosocial functioning. CONCLUSION: These patients require specialized and coordinated multidisciplinary rehabilitation follow-up that provides timely and adapted assessments and culminates in personalized intervention goals being set with the patient and the family. Follow-up should be continued until referral to adult services. PMID- 29716739 TI - Converging endometrial and ovarian tumorigenesis in Lynch syndrome: Shared origin of synchronous carcinomas. AB - OBJECTIVE: The diagnosis of carcinoma in both the uterus and the ovary simultaneously is not uncommon and raises the question of synchronous primaries vs. metastatic disease. Targeted sequencing of sporadic synchronous endometrial and ovarian carcinomas has shown that such tumors are clonally related and thus represent metastatic disease from one site to the other. Our purpose was to investigate whether or not the same applies to Lynch syndrome (LS), in which synchronous cancers of the gynecological tract are twice as frequent as in sporadic cases, reflecting inherited defects in DNA mismatch repair (MMR). METHODS: MMR gene mutation carriers with endometrial or ovarian carcinoma or endometrial hyperplasia were identified from a nationwide registry. Endometrial (n = 35) and ovarian carcinomas (n = 23), including 13 synchronous carcinoma pairs, were collected as well as endometrial hyperplasias (n = 56) and normal endometria (n = 99) from a surveillance program over two decades. All samples were studied for MMR status, ARID1A and L1CAM protein expression and tumor suppressor gene promoter methylation, and synchronous carcinomas additionally for somatic mutation profiles of 578 cancer-relevant genes. RESULTS: Synchronous carcinomas were molecularly concordant in all cases. Prior or concurrent complex (but not simple) endometrial hyperplasias showed a high degree of concordance with endometrial or ovarian carcinoma as the endpoint lesion. CONCLUSIONS: Our investigation suggests shared origins for synchronous endometrial and ovarian carcinomas in LS, in analogy to sporadic cases. The similar degrees of concordance between complex hyperplasias and endometrial vs. ovarian carcinoma highlight converging pathways for endometrial and ovarian tumorigenesis overall. PMID- 29716740 TI - Chemical interaction of glycero-phosphate dimethacrylate (GPDM) with hydroxyapatite and dentin. AB - OBJECTIVES: Although the functional monomer glycero-phosphate dimethacrylate (GPDM) has since long been used in several dental adhesives and more recently in self-adhesive composite cements and restoratives, its mechanism of chemical adhesion to hydroxyapatite (HAp) is still unknown. We therefore investigated the chemical interaction of GPDM with HAp using diverse chemical analyzers and ultra structurally characterized the interface of a GPDM-based primer formulation with dentin. METHODS: HAp particles were added to a GPDM solution for various periods, upon which they were thoroughly washed with ethanol and water prior to being air dried. As control, 10-methacryloyloxydecyl dihydrogen phosphate (MDP) was used. The molecular interaction of GPDM with HAp was analyzed using X-ray diffraction (XRD) and solid-state nuclear magnetic resonance (NMR) spectroscopy. Crystal formation upon application of GPDM onto dentin was analyzed using thin-film XRD (TF-XRD). Its hydrophobicity was measured using contact-angle measurement. The interaction of GPDM with dentin was characterized using transmission electron microscopy (TEM). RESULTS: XRD revealed the deposition of dicalcium phosphate dihydrate (DCPD: CaHPO4.2H2O) on HAp after 24h. NMR confirmed the adsorption of GPDM onto HAp. However, GPDM was easily removed after washing with water, unlike MDP that remained adhered to HAp. Dentin treated with GPDM appeared more hydrophilic compared to dentin treated with MDP. TEM disclosed exposed collagen in the hybrid layer produced by the GPDM-based primer formulation. SIGNIFICANCE: Although GPDM adsorbed to HAp, it did not form a stable calcium salt. The bond between GPDM and HAp was weak, unlike the strong bond formed by MDP to HAp. Due to its high hydrophilicity, GPDM might be an adequate monomer for an etch-and rinse adhesive, but appears less appropriate for a 'mild' self-etch adhesive that besides micro-retention ionically interacts with HAp, or for a self-adhesive restorative material. PMID- 29716741 TI - Lessons in Lateralisation from the Insects. AB - The behavioural lateralisation of a species is thought to be influenced by social organisation. However, recent studies of insect species with different social structures suggest that traits showing both population-level and individual-level lateralisation can be found in single species. This has broad implications for our understanding of how lateralisation and handedness evolves. PMID- 29716742 TI - Climate Velocity Can Inform Conservation in a Warming World. AB - Climate change is shifting the ranges of species. Simple predictive metrics of range shifts such as climate velocity, that do not require extensive knowledge or data on individual species, could help to guide conservation. We review research on climate velocity, describing the theory underpinning the concept and its assumptions. We highlight how climate velocity has already been applied in conservation-related research, including climate residence time, climate refugia, endemism, historic and projected range shifts, exposure to climate change, and climate connectivity. Finally, we discuss ways to enhance the use of climate velocity in conservation through tailoring it to be more biologically meaningful, informing design of protected areas, conserving ocean biodiversity in 3D, and informing conservation actions. PMID- 29716743 TI - FOXO3a Reverses the Cisplatin Resistance in Ovarian Cancer. AB - OBJECTIVE: Ovarian cancer is one of the most serious disease in female reproductive system. Platinum is the first-line drug for the treatment of ovarian cancer, while the resistance of platinum drug in clinical hindered the relief ovarian cancer. Our previous study found that decreased FOXO3a might be a poor prognosis in human ovarian cancer. In this research, we study whether FOXO3a was involved in the mechanism of platinum drug resistance. METHODS: The CCK-8 and FACS analysis were used to monitor the survival of ovarian cancer, and the FOXO3a expression was detected by western-blot. RESULTS: We found that FOXO3a expression upregulated significantly in A2780 compared with A2780/DDP cells with the treatment of platinum. Moreover, overexpression of FOXO3a in ovarian cancer inversed the platinum resistance in ovarian cancer. CONCLUSION: These observations reminded that the role of FOXO3a might be one of the critical mechanisms in developing platinum drug resistance in ovarian cancer. PMID- 29716744 TI - Why Do Sex Chromosomes Stop Recombining? AB - It is commonly assumed that sex chromosomes evolve recombination suppression because selection favours linkage between sex-determining and sexually antagonistic genes. However, although the role of sexual antagonism during sex chromosome evolution has attained strong support from theory, experimental and observational evidence is rare or equivocal. Here, we highlight alternative, often neglected, hypotheses for recombination suppression on sex chromosomes, which invoke meiotic drive, heterozygote advantage, and genetic drift, respectively. We contrast the hypotheses, the situations when they are likely to be of importance, and outline why it is surprisingly difficult to test them. Lastly, we discuss future research directions (including modelling, population genomics, comparative approaches, and experiments) to disentangle the different hypotheses of sex chromosome evolution. PMID- 29716746 TI - The Benzodiazepine Binding Sites of GABAA Receptors. AB - Everyday activity is based on a subtle equilibrium of excitatory and inhibitory neuronal systems. The most prominent players in neuronal inhibition are synaptic and extrasynaptic GABAA receptors. Benzodiazepines are popular drugs that act as positive allosteric modulators of a subset of these receptors. Benzodiazepines have sedative, hypnotic, muscle-relaxant, and anticonvulsive effects, and are of outstandingly low overdose risk. The discovery of a large number of subtypes of GABAA receptors has raised hopes for a clear separation of this spectrum of actions. We discuss here how far this separation has been achieved, and outline recent progress towards the discovery of novel ligands for canonical and non canonical binding sites. PMID- 29716745 TI - Replicability and Prediction: Lessons and Challenges from GWAS. AB - Since the publication of the Wellcome Trust Case Control Consortium (WTCCC) landmark study a decade ago, genome-wide association studies (GWAS) have led to the discovery of thousands of risk variants involved in disease etiology. This success story has two angles that are often overlooked. First, GWAS findings are highly replicable. This is an unprecedented phenomenon in complex trait genetics, and indeed in many areas of science, which in past decades have been plagued by false positives. At a time of increasing concerns about the lack of reproducibility, we examine the biological and methodological reasons that account for the replicability of GWAS and identify the challenges ahead. In contrast to the exemplary success of disease gene discovery, at present GWAS findings are not useful for predicting phenotypes. We close with an overview of the prospects for individualized prediction of disease risk and its foreseeable impact in clinical practice. PMID- 29716748 TI - Re: re: Gillies temporal incision: an alternative approach to biopsy of the superficial temporal artery. PMID- 29716747 TI - Mechanisms of the effect of magnesium salts in preeclampsia. AB - Preeclampsia is a heterogeneous pregnancy-specific syndrome associated with abnormal trophoblast invasion and endothelial dysfunction. Magnesium (Mg2+) level may be normal or decreased in women with preeclampsia. However, the use of Mg2+ salts, such as Mg2+ sulphate, are useful in reducing the pathophysiological consequences of preeclampsia with severe features and eclampsia. Although the mechanism of action of this Mg2+ salt is not well understood, the available evidence suggests a beneficial effect of Mg2+ for the mother and foetus. The mechanisms include a lower level of soluble fms-like tyrosine kinase 1 and endoglin, blockage of brain N-methyl-D-aspartate receptors, decreased inflammation mediators, activation of nitric oxide synthases, blockage of arginases, and reduced free radicals level. The maintenance of Mg2+ homeostasis in pregnancy is crucial for an appropriate pregnancy progression. Oral Mg2+ salts can be used for this purpose which could result in mitigating the deleterious consequences of this syndrome to the mother, foetus, and newborn. PMID- 29716749 TI - New technique for endoscopically-assisted particulate graft reconstruction of the mandible. AB - The reconstruction of mandibular defects using particulate grafts is a proven technique that restores the osseous anatomy effectively. Secondary osseous reconstruction can be accomplished with endoscopic assistance and reduced-access incisions if an intermediate spacer is placed during resection. Two patients required reconstruction after resection of mandibular ameloblastomas. We used a modified protocol that involved the implantation of a graft of particulate corticocancellous bone after removal of the spacer, and prepared the recipient site under endoscopic guidance with small extraoral incisions. The grafts healed uneventfully and matured into ossicles suitable for the placement of osseointegrated implants. PMID- 29716750 TI - Re: Gillies temporal incision: an alternative approach to biopsy of the superficial temporal artery. PMID- 29716751 TI - Predicted extinction of unique genetic diversity in marine forests of Cystoseira spp. AB - Climate change is inducing shifts in species ranges across the globe. These can affect the genetic pools of species, including loss of genetic variability and evolutionary potential. In particular, geographically enclosed ecosystems, like the Mediterranean Sea, have a higher risk of suffering species loss and genetic erosion due to barriers to further range shifts and to dispersal. In this study, we address these questions for three habitat-forming seaweed species, Cystoseira tamariscifolia, C. amentacea and C. compressa, throughout their entire ranges in the Atlantic and Mediterranean regions. We aim to 1) describe their population genetic structure and diversity, 2) model the present and predict the future distribution and 3) assess the consequences of predicted future range shifts for their population genetic structure, according to two contrasting future climate change scenarios. A net loss of suitable areas was predicted in both climatic scenarios across the range of distribution of the three species. This loss was particularly severe for C. amentacea in the Mediterranean Sea (less 90% in the most extreme climatic scenario), suggesting that the species could become potentially at extinction risk. For all species, genetic data showed very differentiated populations, indicating low inter-population connectivity, and high and distinct genetic diversity in areas that were predicted to become lost, causing erosion of unique evolutionary lineages. Our results indicated that the Mediterranean Sea is the most threatened region, where future suitable Cystoseira habitats will become more limited. This is likely to have wider ecosystem impacts as there is a lack of species with the same ecological niche and functional role in the Mediterranean. The projected accelerated loss of already fragmented and disturbed populations and the long-term genetic effects highlight the urge for local scale management strategies that sustain the capacity of these habitat forming species to persist despite climatic impacts while waiting for global emission reductions. PMID- 29716752 TI - Cirrhotic cardiomyopathy. PMID- 29716753 TI - Anal and rectal function after intensity-modulated prostate radiotherapy with endorectal balloon. AB - BACKGROUND AND PURPOSE: Late anorectal toxicity influences quality of life after external beam radiotherapy (EBRT) for prostate cancer. A daily inserted endorectal balloon (ERB) during EBRT aims to reduce anorectal toxicity. Our goal is to objectify anorectal function over time after prostate intensity-modulated radiotherapy (IMRT) with ERB. MATERIAL AND METHODS: Sixty men, irradiated with IMRT and an ERB, underwent barostat measurements and anorectal manometry prior to EBRT and 6 months, one year and 2 years after radiotherapy. Primary outcome measures were rectal distensibility and rectal sensibility in response to stepwise isobaric distensions and anal pressures. RESULTS: Forty-eight men completed all measurements. EBRT reduced maximal rectal capacity 2 years after EBRT (250 +/- 10 mL vs. 211 +/- 10 mL; p < 0.001), area under the pressure-volume curve (2878 +/- 270 mL mmHg vs. 2521 +/- 305 mL mmHg; p = 0.043) and rectal compliance (NS). Sensory pressure thresholds for first sense and first urge (both p < 0.01) increased. Anal maximum pressure diminished after IMRT (p = 0.006). CONCLUSIONS: Rectal capacity and sensory function are increasingly affected over time after radiotherapy. There is an indication that these reductions are affected less with IMRT + ERB compared to conventional radiation techniques. PMID- 29716754 TI - [Use of a medical discharge sheet for medication reconciliation in an internal medicine department: Assessment of general practitioners' opinion]. AB - BACKGROUND: Medication reconciliation (MR) is a systematic and comprehensive review of all medication a patient is taking. In this study, a discharge medication sheet (DMS) is given to patients upon discharge: it contains discharge prescription and any changes made to admission prescription with justifications. The aim of this study is to explore general practitioners' (GP) perceptions of this DMS in order to suggest improvements. METHODS: In this prospective observational study, individual semi-directed interviews were conducted with GPs who received a DMS following the hospitalization of one of their patients. Answers were grouped by topic and subjected to descriptive analysis. RESULTS: Between October 2015 and July 2016, 33 DMS were completed. Among the 33 GPs, 16 had seen their patients with their DMS and agreed to be interviewed. The DMS was very appreciated and improved care pathway. However, this study highlights transmission difficulties for this sheet, attributed in particular to a lack of information of practitioners and patients and to the paper format, which appears to be inadequate. The main suggested improvement is real-time transmission of the DMS via email. CONCLUSION: Practitioners' opinion is in favor of the use of a DMS. Certain specific points need to be improved, such as better information of practitioners and patients, and transmission of the DMS via a secure email system. PMID- 29716755 TI - Description of human AAA by cytokine and immune cell aberrations compared to risk factor matched controls. AB - BACKGROUND: The pathogenesis driving the formation of abdominal aortic aneurysms continues to be poorly understood. Therefore, we systemically define the cytokine and circulating immune cell environment observed in human abdominal aortic aneurysm compared with risk-factor matched controls. METHODS: From 2015 to 2017, a total of 274 patients donated blood to the Indiana University Center for Aortic Disease. Absolute concentrations of circulating cytokines were determined, using enzyme-linked immunosorbent assays while the expression of circulating immune cell phenotypes were assayed via flow cytometric analysis. RESULTS: Human abdominal aortic aneurysm is characterized by a significant depletion of the antigen-specific, CD4+ Tr1 regulatory lymphocyte that corresponds to an upregulation of the antigen-specific, inflammatory Th17 cell. We found no differences in the incidence of Treg, B10, and myeloid-derived suppressor regulatory cells. Similarly, no disparities were noted in the following inflammatory cytokines: IL-1beta, C-reactive protein, tumor necrosis factor alpha, interferon gamma, and IL-23. However, significant upregulation of the inflammatory cytokines osteopontin, IL-6, and IL-17 were noted. Additionally, no changes were observed in the regulatory cytokines IL-2, IL-4, IL-13, TNF stimulated gene 6 protein, and prostaglandin E2, but we did observe a significant decrease in the essential regulatory cytokine IL-10. CONCLUSION: In this investigation, we systematically characterize the abdominal aortic aneurysm immune environment and present preliminary evidence that faulty immune regulation may also contribute to aneurysm formation and growth. PMID- 29716757 TI - Eculizumab as a treatment for atypical hemolytic syndrome secondary to carfilzomib. PMID- 29716756 TI - Coronary microvascular dysfunction in patients with stable coronary artery disease: The CE-MARC 2 coronary physiology sub-study. AB - BACKGROUND: In patients with angina undergoing invasive management, no obstructive coronary artery disease (NOCAD) is a common finding, and angina may persist following percutaneous coronary intervention (PCI). Coronary microvascular dysfunction may be relevant. We aimed to assess the proportion of patients presenting with suspected CAD who had coronary microvascular dysfunction. METHODS: Clinical Evaluation of Magnetic Resonance Imaging in Coronary Heart Disease 2 (CE-MARC 2) was a prospective multicenter randomised controlled trial of functional imaging versus guideline-based management in patients with suspected CAD. Invasive coronary angiography was protocol-directed. Fractional flow reserve (FFR) and parameters of microvascular function (coronary flow reserve (CFR), index of microcirculatory resistance (IMR), resistance reserve ratio (RRR)) were measured in major epicardial coronary arteries with >=40-<=90% diameter stenosis. An FFR value <=0.80 indicated the presence of obstructive CAD. RESULTS: 267/1202 (22.2%) patients underwent angiography and 81 (30%) patients had FFR measured. 63 (78%) of these patients had microvascular function assessed in 85 arteries (mean age 58.5 +/- 8.2 years; 47 (75%) male). 25/63 (40%) patients had NOCAD, and of these, 17 (68%) had an abnormality >=1 parameter of microvascular function (abnormal IMR (>=25), abnormal CFR (<2.0), and abnormal RRR (<2.0) occurred in 10 (40%), 12 (48%), and 11 (44%), respectively). 38/63 (60%) patients had obstructive epicardial CAD. Of these patients, 15/38 (39%), 20/38 (53%), and 12/38 (32%) had an abnormal IMR, CFR and RRR, respectively. CONCLUSIONS: Coronary microvascular dysfunction is common in patients with angina. Invasive assessment of microvascular function may be informative and relevant for decision-making in patients with both NOCAD and obstructive epicardial CAD. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01664858. PMID- 29716758 TI - Distal renal tubular acidosis in two children with acquired hypothyroidism. AB - Two cases of children diagnosed with renal tubular acidosis (RTA) associated with autoimmune hypothyroidism are presented. Case 1 developed an intestinal ileus at the age of five in the context of a respiratory problem. The tests performed confirmed metabolic acidosis, hyperchloraemia, hypokalaemia and nephrocalcinosis. Case 2 was diagnosed with hypothyroidism at the age of 11, and with RTA two years later. In both patients, the diagnosis of RTA was verified when decreased maximum urinary pCO2 was found. In case 2, a proximal bicarbonate leak (type 3 RTA) was also confirmed. This was the first case to be published on the topic. The causes of RTA in patients with hypothyroidism are reviewed. The deleterious effect on the kidneys may be due to the absence of thyroid hormone and/or autoantibodies in the cases of autoimmune hypothyroidism. PMID- 29716759 TI - Effect of total solid content and pretreatment on the production of lactic acid from mixed culture dark fermentation of food waste. AB - Food waste landfilling causes environmental degradation, and this work assesses a sustainable food valorization technique. In this study, food waste is converted into lactic acid in a batch assembly by dark fermentation without pH control and without the addition of external inoculum at 37 degrees C. The effect of total solid (TS), enzymatic and aeration pretreatment was investigated on liquid products concentration and product yield. The maximum possible TS content was 34% of enzymatic pretreated waste, and showed the highest lactic acid concentration of 52 g/L, with a lactic acid selectivity of 0.6 glactic/gtotalacids. The results indicated that aeration pretreatment does not significantly improve product concentration or yield. Non-pretreated waste in a 29% TS system showed a lactic acid concentration of 31 g/L. The results showed that enzymatic pretreated waste at TS of 34% results in the highest production of lactic acid. PMID- 29716761 TI - Understanding the implications of current health trends on the aroma of wet and dry cured meat products. AB - Meat product aroma is affected by various meat processing factors. In this review the main biochemical reactions involved in the development of meat product aroma (wet, dry cured and fermented) are fully described. Moreover, the different techniques used for key aroma elucidation in meat products are defined. The aroma compounds present in wet, dry cured and fermented meat products (sausage and whole piece) have been summarized. The mechanisms of aroma formation during the manufacture of cooked and dry/fermented meat products are described. In wet meat products the main reactions described are lipid degradation (oxidative reactions), Maillard reactions, Strecker degradation, and thiamine degradation while in dry meat products are; lipid degradation (oxidative reactions), thiamine degradation, microbial carbohydrate fermentation and microbial metabolism including complex interactions among them such as the amino acid degradation produced by lipid oxidation products. Finally, the effect of current health trends such as salt, fat and nitrifying content reduction on the development of meat product aroma is explained. PMID- 29716760 TI - The role of meat in foodborne disease: Is there a coming revolution in risk assessment and management? AB - Meat has featured prominently as a source of foodborne disease and a public health concern. For about the past 20 years the risk management paradigm has dominated international thinking about food safety. Control through the supply chain is supported by risk management concepts, as the public health risk at the point of consumption becomes the accepted outcome based measure. Foodborne pathogens can be detected at several points in the supply chain and determining the source of where these pathogens arise and how they behave throughout meat production and processing are important parts of risk based approaches. Recent improvements in molecular and genetic based technologies and data analysis for investigating source attribution and pathogen behaviour have enabled greater insights into how foodborne outbreaks occur and where controls can be implemented. These new approaches will improve our understanding of the role of meat in foodborne disease and are expected to have a significant impact on our understanding in the coming years. PMID- 29716762 TI - Plasma zinc in institutionalized elderly individuals: Relation with immune and cardiometabolic biomarkers. AB - Changes in zinc metabolism caused by aging and the institutionalization process may contribute to zinc deficiency in elderly individuals. Hypozincemia results in changes in glycemic, lipid, and inflammatory profiles. The aim of this study was to evaluate plasma zinc concentrations and their relationships with sociodemographic, dietary, inflammatory, and cardiometabolic biomarkers in institutionalized elderly individuals. A cross-sectional study was carried out including 255 elderly adults living in nursing homes. The associations between plasma zinc and dietary zinc intake, sociodemographic indicators, and glycemic, lipid, and inflammatory biomarkers were evaluated. Independent variables were analyzed according to quartiles of plasma zinc concentrations (Q1: <71.1 MUg/dL; Q2: 71.1-83.3 MUg/dL; Q3: <83.3-93.7 MUg/dL; Q4: >93.7 MUg/dL). The relationship between plasma zinc concentrations and predictor variables was also tested. In Q1, higher concentrations of the following variables were observed, compared with those in other quartiles: total cholesterol and low-density lipoprotein cholesterol (LDL-c; Q1 > Q2, Q3, Q4; all p <0.001); triglycerides (Q1 > Q3, Q4; all p < 0.001); interleukin (IL)-6 (Q1 > Q3, Q4; p = 0.024 and p = 0.010, respectively); tumor necrosis factor (TNF)-alpha (Q1 > Q3, p = 0.003). A significant reduction in plasma zinc concentrations was observed with increasing age-adjusted institutionalization time (Delta = - 0.10; 95% confidence interval [CI]: -0.18 to -0.01). The concentrations of total cholesterol (Delta = - 0.19; 95% CI: -0.23 to -0.15), LDL-c (Delta = - 0.19; 95% CI: -0.23 to -0.15), triglycerides (Delta = - 0.11; 95% CI: -0.16 to -0.06), IL-6 (Delta = - 1.41; 95% CI: -2.64 to -0.18), and TNF-alpha (Delta = - 1.04; 95% CI: -1.71 to -0.36) were also significantly increased. In conclusion, decreased plasma zinc concentrations were associated with longer institutionalization time and worse lipid and inflammatory profiles in elderly institutionalized individuals. PMID- 29716763 TI - Expanding Eligibility for the Ross Procedure: A Reasonable Proposition? AB - BACKGROUND: Although the Ross procedure offers potential benefits in young adults, technical complexity represents a significant limitation. Therefore, the safety of expanding its use in more complex settings is uncertain. The aim of this study was to compare early outcomes of standard isolated Ross procedures vs expanding elgibility to higher-risk clinical settings. METHODS: From 2011 to 2016, 261 patients (46 +/- 12 years) underwent Ross procedures in 2 centres. Patients were divided into 2 groups: standard Ross (n = 166) and expanded eligibility Ross (n = 95). Inclusion criteria for the expanded eligibility group were previous cardiac surgery, acute aortic valve endocarditis, severely impaired left ventricular (LV) function and patients undergoing concomitant procedures. All data were prospectively collected and are 100% complete. RESULTS: Hospital mortality was 0% in the standard group (0/166) vs 2% in the expanded eligibility group (2/95) (P = 0.13). Sixteen patients (10%) developed acute renal injury in the standard group vs 13 (14%) patients in the expanded eligibility group (P = 0.31). There were no postoperative myocardial infarctions, no neurological events, and no infectious complications. Median intensive care unit (ICU) stay in the standard group was 2 vs 3 days in the expanded eligibility group (P = 0.004), whereas median hospital stay was 6 vs 7 days, respectively (range: 3-19 days) (P < 0.001). CONCLUSION: Aside from longer ICU and hospital lengths of stay after the Ross procedure in higher-risk clinical scenarios, perioperative mortality and morbidity is similar to standard Ross procedures. Expanding the use of the Ross operation in young adults is a safe alternative in centres of expertise. PMID- 29716764 TI - Significantly higher frequencies of hemoglobin, iron, vitamin B12, and folic acid deficiencies and of hyperhomocysteinemia in patients with Behcet's disease. AB - BACKGROUND/PURPOSE: Behcet's disease (BD) patients may have one or more hematinic deficiencies. This study evaluated whether there were significantly higher frequencies of hemoglobin, iron, vitamin B12, and folic acid deficiencies and of hyperhomocysteinemia in BD patients. METHODS: The blood hemoglobin, iron, vitamin B12, folic acid, and homocysteine concentrations in 63 BD patients were measured and compared with the corresponding levels in 126 age- and sex-matched healthy control subjects. RESULTS: We found that 30.2%, 34.9%, 6.3%, 6.3%, and 14.3% of 63 BD patients had hemoglobin, iron, vitamin B12, and folic acid deficiencies and hyperhomocysteinemia, respectively. Both 63 BD and 19 major-typed RAS/BD patients had significantly higher frequencies of hemoglobin, iron, vitamin B12, and folic acid deficiencies and of hyperhomocysteinemia than 126 healthy control subjects (all P-values < 0.05). Moreover, 44 minor-typed RAS/BD patients had significantly higher frequencies of hemoglobin and iron deficiencies than 126 healthy control subjects (both P-values < 0.001). Of the 19 anemic BD patients, one had pernicious anemia, one had macrocytic anemia, 12 had normocytic anemia, four had iron deficiency anemia, and one had thalassemia trait-induced anemia. CONCLUSION: There are significantly higher frequencies of hemoglobin, iron, vitamin B12, and folic acid deficiencies and of hyperhomocysteinemia in BD patients. The normocytic anemia is the most common type of anemia in our 63 BD patients. We suggest that supplementations of vitamin BC capsules plus deficient vitamin B12 and/or folic acid may reduce the abnormally high serum homocysteine level to a relatively lower level in BD patients with hyperhomocysteinemia. PMID- 29716765 TI - A short synthesis of Dronedarone. AB - A modification of the Nenitzescu reaction was used to obtain Dronedarone from quinonimine 20 and 1,3-diketone 14 (R = CH2CH2CH2NBu2) in a two-stage process in almost 55% overall yield. Our results represent significant improvement over other state-of-the-art methods as no extra steps for the decoration of the benzofuran core are required. PMID- 29716766 TI - Activating transcription factor 3 promotes intestinal epithelial cell apoptosis in Crohn's disease. AB - Intestinal epithelial cell (IEC) apoptosis plays a vital role in the pathogenesis of Crohn's disease (CD), which is an inflammatory bowel disease (IBD). Activating transcription factor 3 (ATF3) modulates apoptosis under stress via regulating the p53 pathway. However, the expression and function of ATF3 in CD are unclear. In the present study, ATF3, p53, and p53 target gene Bax expression increased in CD patients; a mouse 2, 4, 6-trinitrobenzenesulfonic acid (TNBS)-induced CD model; and a TNF-alpha-treated HT29 cell colitis model. ATF3 knockdown effectively decreased TNF-alpha-induced p53 and Bax expression, as well as inhibited the apoptosis of HT29 cells. Additionally, ATF3 enhanced the stability and transcription activity of p53 via interacting with p53. In summary, these data indicated that ATF3 might promote IEC apoptosis in CD via up-regulating the stability and transcription activity of p53, implying a novel molecular target for CD therapy. PMID- 29716767 TI - Radiobiology of Acute Rectal Toxicity. PMID- 29716769 TI - The Cobalt/Chromium Ratio Provides Similar Diagnostic Value to a Low Cobalt Threshold in Predicting Adverse Local Tissue Reactions in Patients With Metal-on Metal Hip Arthroplasty. AB - BACKGROUND: A higher cobalt/chromium (Co/Cr) ratio is thought to be associated with corrosion of the trunnion and increased adverse local tissue reaction (ALTR) risk in patients treated with metal-on-metal (MoM) hip arthroplasty. The main aim of this study was to investigate the diagnostic value of Co/Cr ratio in identifying ALTR in patients treated with MoM hip resurfacing arthroplasty and total hip arthroplasty (THA). METHODS: A total of 310 unilateral patients were included. All patients received a metal artifact reduction sequence magnetic resonance imaging to detect ALTR. Blood Co and Cr levels were measured. RESULTS: MoM THA patients had a higher Co/Cr ratio than MoM hip resurfacing arthroplasty patients (1.7, interquartile range 1.2-3.1 vs 0.9, interquartile range 0.7-1.3, P < .001). The continuous Co/Cr ratio, continuous Co, and Co >= 7 ppb were predictive of ALTR when tested in receiver-operating characteristic analyses. The most sensitive and specific cutoffs were found to be 1.4 for Co/Cr ratio (sensitivity = 80.0%; specificity = 48.7%) and 2.4 ppb for Co (sensitivity = 77.8%; specificity = 46.2%). In multivariate analysis, continuous Co, Co >= 7 ppb, and the receiver-operating characteristic analysis-generated cutoffs were associated with ALTR prevalence. CONCLUSION: Blood metal ions are strong, but not perfect, predictors of ALTR in patients with MoM hip arthroplasty. Higher Co/Cr ratios are associated with increased risk for ALTR in MoM THA. However, blood Co levels alone are as good a predictor of ALTR as the Co/Cr ratio. The most ALTR sensitive cutoffs are lower than previously reported in the literature. PMID- 29716768 TI - Why Do Disordered and Structured Proteins Behave Differently in Phase Separation? AB - Intracellular membraneless organelles and their myriad cellular functions have garnered tremendous recent interest. It is becoming well accepted that they form via liquid-liquid phase separation (LLPS) of protein mixtures (often including RNA), where the organelles correspond to a protein-rich droplet phase coexisting with a protein-poor bulk phase. The major protein components contain disordered regions and often also RNA-binding domains, and the disordered fragments on their own easily undergo LLPS. By contrast, LLPS for structured proteins has been observed infrequently. The contrasting phase behaviors can be explained by modeling disordered and structured proteins, respectively, as polymers and colloids. These physical models also provide a better understanding of the regulation of droplet formation by cellular signals and its dysregulation leading to diseases. PMID- 29716770 TI - Letter to the Editor on "Correlation of the Caprini Score and Venous Thromboembolism Incidence Following Primary Total Joint Arthroplasty-Results of a Single-Institution Protocol". PMID- 29716771 TI - Estimating the annual attack rate of seasonal influenza among unvaccinated individuals: A systematic review and meta-analysis. AB - INTRODUCTION: Seasonal influenza affects millions of people globally each year, causing significant morbidity and mortality. However, there remains substantial uncertainty about the attack rate (incidence) of influenza, particularly in unvaccinated individuals. METHODS: We undertook a systematic review of vaccine randomised controlled trials (RCTs) that reported on laboratory-confirmed seasonal influenza in the placebo arm. We calculated the influenza attack rate from included studies as the number of laboratory-confirmed positive seasonal influenza cases in the placebo arm divided by the total number of subjects in this arm. A random effects meta-analysis was conducted to estimate the influenza attack rate among unvaccinated individuals (both symptomatic only as well as symptomatic and asymptomatic combined). RESULTS: We included 32 RCTs that had a total of 13,329 participants. The pooled estimates for symptomatic influenza were 12.7% (95%CI 8.5%, 18.6%) for children (<18 years), 4.4% (95%CI 3.0%, 6.3%) for adults, and 7.2% (95%CI 4.3%, 12.0%) for older people (65 years and above). The pooled estimates for symptomatic and asymptomatic influenza combined for all influenza were 22.5% (95%CI 9.0%, 46.0%) for children and 10.7% (95%CI 4.5%, 23.2%) for adults. Only one study was identified for symptomatic and asymptomatic combined in older people which had a rate of 8.8% (95%CI 7.0%, 10.8%). There was substantial heterogeneity between studies. CONCLUSION: Overall, we found that approximately 1 in 5 unvaccinated children and 1 in 10 unvaccinated adults were estimated to be infected by seasonal influenza annually, with rates of symptomatic influenza roughly half of these estimates. Our findings help to establish the background risk of seasonal influenza infection in unvaccinated individuals. PMID- 29716772 TI - An audit of the reliability of influenza vaccination and medical information extracted from eHealth records in general practice. AB - To evaluate the reliability of information in general practice (GP) electronic health records (EHRs), 2100 adult patients were randomly selected for interview regarding the presence of specific medical conditions and recent influenza vaccination. Agreement between self-report and data extracted from EHRs was compared using Cohen's kappa coefficient (k) and interpreted in accordance with Altman's Kappa Benchmarking criteria; 377 (18%) patients declined participation, and 608 (29%) could not be contacted. Of 1115 (53%) remaining, 856 (77%) were active patients (>=3 visits to the GP practice in the last two years) who provided complete information for analysis. Although a higher proportion of patients self-reported being vaccinated or having a medical condition compared to the EHR (50.7% vs 36.9%, and 39.4% vs 30.3%, respectively), there was "good" agreement between self-report and EHR for both vaccination status (kappa = 0.67) and medical conditions (kappa = 0.66). These findings suggest EHR may be useful for public health surveillance. PMID- 29716773 TI - Hepatitis B vaccination coverage among adults aged >=18 years traveling to a country of high or intermediate endemicity, United States, 2015. AB - BACKGROUND: Persons from the United States who travel to developing countries are at substantial risk for hepatitis B virus (HBV) infection. Hepatitis B vaccine has been recommended for adults at increased risk for infection, including travelers to high or intermediate hepatitis B endemic countries. PURPOSE: To assess hepatitis B vaccination coverage among adults >=18 years traveling to a country of high or intermediate endemicity from the United States. METHODS: Data from the 2015 National Health Interview Survey (NHIS) were analyzed to determine hepatitis B vaccination coverage (>=1 dose) and series completion (>=3 doses) among persons aged >=18 years who reported traveling to a country of high or intermediate hepatitis B endemicity. Multivariable logistic regression and predictive marginal analyses were conducted to identify factors independently associated with hepatitis B vaccination. RESULTS: In 2015, hepatitis B vaccination coverage (>=1 dose) among adults aged >=18 years who reported traveling to high or intermediate hepatitis B endemic countries was 38.6%, significantly higher compared with 25.9% among non-travelers. Series completion (>=3 doses) was 31.7% and 21.2%, respectively (P < 0.05). On multivariable analysis among all respondents, travel status was significantly associated with hepatitis B vaccination coverage and series completion. Other characteristics independently associated with vaccination (>=1 dose, and >=3 doses) among travelers included age, race/ethnicity, educational level, duration of US residence, number of physician contacts in the past year, status of ever being tested for HIV, and healthcare personnel status. CONCLUSIONS: Although travel to a country of high or intermediate hepatitis B endemicity was associated with higher likelihood of hepatitis B vaccination, hepatitis B vaccination coverage was low among adult travelers to these areas. Healthcare providers should ask their patients about travel plans and recommend and offer travel related vaccinations to their patients or refer them to alternate sites for vaccination. PMID- 29716774 TI - Dengue vaccination during pregnancy - An overview of clinical trials data. AB - BACKGROUND: The live, attenuated, tetravalent dengue vaccine (CYD-TDV) is licensed in several endemic countries and contraindicated during pregnancy. Inadvertent vaccination during pregnancy may occur during clinical trials that include women of childbearing age. The potential risk associated with dengue vaccination in pregnancy remains unknown. We describe pregnancy outcomes following inadvertent dengue vaccination in pregnancy from CYD-TDV trial data. METHODS: Data were collected from trials conducted as part of the CYD-TDV clinical development. Women who received CYD-TDV or placebo during the pre specified pregnancy risk window (from 30 days before the date of their last menstrual period to end of pregnancy) were considered as exposed; pregnancies occurring in non-risk periods during the trials were considered to be non exposed. Pregnancy losses were defined as abortion (spontaneous or unspecified), death in utero, and stillbirth. RESULTS: 615 pregnancies were reported from 19 CYD-TDV trials: 404 in the CYD-TDV arm, and 211 in the placebo arm. Exposure could not be determined for 7 pregnancies (5, CYD-TDV; 2, placebo). In the CYD TDV arm, 58 pregnancies were considered as exposed. Most of these (n = 47, 81%) had healthy live births; 6 (10.3%) had pregnancy losses; 3 underwent elective termination and 2 had unknown outcome. In the placebo group, 30 pregnancies were considered exposed. Most of these (n = 25, 83%) had healthy births; 4 (13.3%) had pregnancy losses; and 1 had elective termination. Among non-exposed pregnancies, most resulted in healthy live births; 23/341 (6.7%) in the CYD-TDV group and 17/179 (9.5%) in the placebo group had pregnancy losses. Most reported pregnancy losses were in women considered high-risk for adverse pregnancy outcome, primarily due to young age. CONCLUSION: In the small dataset assessed, no evidence of increased adverse pregnancy outcomes has been identified from inadvertent immunization of women in early pregnancy with CYD-TDV compared with the control group. PMID- 29716775 TI - Population-level factors predicting variation in influenza vaccine uptake among adults and young children in England, 2015/16 and 2016/17. AB - England's influenza vaccination programme targets persons with clinical risk factors, pregnant women, those aged 65 years and older and children. Low vaccine uptake amongst primary school children was previously found to be significantly associated with increasing deprivation, Black or Minority Ethnic (BME) and certain religions. It is unknown whether these population predictors are associated with vaccine uptake in other groups. GP level data for target groups during the 2015/16 and 2016/17 seasons were linearly regressed against various factors to determine potential predictors associated with variation in uptake. Adjusted uptake for 2-4 year olds during both seasons was more than 11% lower in the most deprived decile and more than 3% lower in 34%+ BME populations compared to the least deprived and non-BME populations. Pregnant women in deprived areas had significantly lower vaccine uptake than in non-deprived areas. Patients 16-64 years old at risk showed no significant variation in uptake by deprivation, whereas patients 65 years and older had more than 3% higher vaccine uptake in the least deprived populations than the most deprived populations. Areas with the highest Muslim and BME populations had a significantly higher vaccine uptake among patients ages 16 to under 65 years old in a clinical risk group than non Muslim and non-BME populations during both seasons. Population-factors have different effects on vaccine uptake for the various target groups. These findings support segmenting public health activities to improve vaccine uptake and reduce inequalities. PMID- 29716776 TI - Estimating effectiveness of HPV vaccination against HPV infection from post vaccination data in the absence of baseline data. AB - BACKGROUND: HPV vaccination programs have been introduced in large parts of the world, but monitoring of effectiveness is not routinely performed. Many countries introduced vaccination programs without establishing the baseline of HPV prevalences. We developed and validated methods to estimate protective effectiveness (PE) of vaccination from the post-vaccination data alone using references, which are invariant under HPV vaccination. METHODS: Type-specific HPV prevalence data for 15-39 year-old women were collected from the pre- and post vaccination era in a region in southern Sweden. In a region in middle Sweden, where no baseline data had been collected, only post-vaccination data was collected. The age-specific baseline prevalence of vaccine HPV types (vtHPV, HPV 6, 11, 16, 18) were reconstructed as Beta distributions from post-vaccination data by applying the reference odds ratios between the target HPV type and non vaccine-type HPV (nvtHPV) prevalences. Older non-vaccinated age cohorts and the southern Sweden region were used as the references. The methods for baseline reconstructions were validated by computing the Bhattacharyya coefficient (BC), a measure for divergence, between reconstructed and actual observed prevalences for vaccine HPV types in Southern Sweden, and in addition, for non-vaccine types in both regions. The PE estimates among 18-21 year-old women were validated by comparing the PE estimates that were based on the reconstructed baseline prevalences against the PE estimates based on the actual baseline prevalences. RESULTS: In Southern Sweden the PEs against vtHPV were 52.2% (95% CI: 44.9-58.5) using the reconstructed baseline and 49.6% (43.2-55.5) using the actual baseline, with high BC 82.7% between the reconstructed and actual baseline. In the middle Sweden region where baseline data was missing, the PE was estimated at 40.5% (31.6-48.5). CONCLUSIONS: Protective effectiveness of HPV vaccination can be estimated from post-vaccination data alone via reconstructing the baseline using non-vaccine HPV type data. PMID- 29716777 TI - Attitudes, believes, determinants and organisational barriers behind the low seasonal influenza vaccination uptake in healthcare workers - A cross-sectional survey. AB - BACKGROUND: Seasonal influenza threatens hospitalised patients and residents of nursing homes annually. Due to age and chronic disease their protection following immunisation is diminished. Additional immunisation of direct contacts and in particular healthcare workers (HCWs) has proven added value. As vaccination coverage in HCWs remains low, we aimed to gain insight in the factors behind the demotivation for influenza vaccination. METHODS: Attitudes and believes towards influenza vaccination and socio-demographic and professional determinants were surveyed in 5141 Belgian HCWs from 13 hospitals and 14 nursing homes. Additionally, influenza campaign coordinators of the participating healthcare institutions were interviewed about the factors of success/failure in their campaigns. RESULTS: The mean vaccination coverage registered by the participating healthcare institutions was 40.4% in the hospitals and 45.3% in the nursing homes. Overall, up to 90% of HCWs found it important not to infect their patients. However, only 20% of non-vaccinated HCWs considered influenza vaccination a duty to not harm their patients. Up to 40% of unvaccinated staff believed they could get influenza after vaccination and that vaccination weakens their immune system. Also, only about 20% of unvaccinated staff thought to have a high chance of getting influenza. Reasons for unvaccinated staff to get vaccinated in the future are self-protection and protection of family members. Factors that positively influenced vaccination coverage are encouragement by supervisors (OR, hospitals: 7.1, p < 0.001; nursing homes: 7.5, p < 0.001) and well-organized vaccination campaigns with on-site vaccination. Factors that negatively affected vaccination coverage are misconceptions about influenza and its vaccine (OR, range 0.1-0.7, p < 0.001 for most misconceptions) and underestimation of the risk of contracting influenza by patients or HCWs (OR of perceived susceptibility, range 2.1-5.1, p < 0.001 for most factors). CONCLUSION: There is a need for guidance for the organization of seasonal influenza campaigns, in which education, communication and easy accessible vaccination are promoted. PMID- 29716778 TI - Fatal accidental inhalation of brake cleaner aerosols. AB - Brake cleaner liquid is commonly used for cleaning of engines and motor parts. The commercially available products usually contain mainly volatile organic compounds. As a consequence brake cleaner evaporates fast and almost completely from the cleaned surface. This case report presents a fatal accidental inhalation of brake cleaner liquid aerosols due to the attempted cleaning of a boat engine. A 16year old boy was found lifeless in the engine compartment of a boat engine. In close proximity to the body, the police found cleanings wipes soaked with brake cleaner as well as a pump spray bottle filled with brake cleaner. Essentially the autopsy revealed a cerebral oedema with encephalomalacia, no coagulated blood as well as increased blood and tissue fluid content of the lung. Toxicological analysis revealed brake cleaner fluid in the lung, gastric content and heart blood. PMID- 29716779 TI - Effect of maternal metabolism on fetal supply: Glucose, non-esterified fatty acids and beta-hydroxybutyrate concentrations in canine maternal serum and fetal fluids at term pregnancy. AB - The progressive adaptations in carbohydrate and lipid metabolism during canine pregnancy are reflected in the concentrations of glucose, non-esterified fatty acids (NEFA) and beta-hydroxybutyrate (BHB). The levels of these metabolites in the bitch likely affect fetal concentrations and the composition of amniotic and allantoic fluids (AMF and ALF, respectively). We studied 31 canine parturitions (Cesarean sections) and found that glucose, NEFA and BHB concentrations were significantly higher in maternal serum than in AMF or ALF. Glucose levels in maternal serum, AMF and ALF were closely related (R2 >= 0.821, P < 0.0001) as well as serum and AMF BHB levels (R2 = 0.661, P < 0.0001). In maternal serum, increases in NEFA were associated with increased BHB, and both were negatively related to glucose (P <= 0.010). To estimate the effect of the metabolic burden of pregnancy, we evaluated these variables in relation to the dam's body weight and to the ratio of litter weight to the dam's body weight (LW/BW). Maternal serum glucose was not influenced by LW/BW, but it was lower in small than in large/giant bitches. Small breed dogs and those with >10% LW/BW had significantly higher serum NEFA and BHB concentrations. Glucose in AMF and ALF was independent of LW/BW (P >= 0.399). AMF NEFA was lower and BHB higher, if LW/BW was >10% (P <= 0.048). In conclusion, the extent of the metabolic load of pregnancy in bitches depends on breed size and on the ratio of litter weight to dam's body weight. Maternal concentrations of glucose, BHB and NEFA determine the concentrations of these metabolites in fetal fluids. PMID- 29716780 TI - Highly potent activity of isopulegol-derived substituted octahydro-2H-chromen-4 ols against influenza A and B viruses. AB - A set of (-)-isopulegol derived octahydro-2H-chromen-4-ols was synthesized and evaluated in vitro for antiviral activity against panel of reference influenza virus strains differing in subtype, origin (human or avian) and drug resistance. Compound (4R)-11a produced via one-pot synthesis by interaction between (-) isopulegol and acetone was found to exhibit an outstanding activity against a number of H1N1 and H2N2 influenza virus strains with selectivity index more than 1500. (4R)-11a was shown to be most potent at early stages of viral cycle. Good correlation between anti-viral activity and calculated binding energy to hemagglutinin TBHQ active site was demonstrated. PMID- 29716781 TI - Harnessing biosynthesis and quantitative NMR for late stage functionalization of lead molecules: Application to the M1 positive allosteric modulator (PAM) program. AB - A facile method for late stage diversification of lead molecules for the M1 PAM program using biosynthesis is described. Liver microsomes from several species are screened to identify a high turnover system. Subsequent incubations using less than 1 mg of substrate generate nanomole quantities of drug metabolites that are purified, characterized by microcryoprobe NMR spectroscopy, and quantified to known concentrations to enable rapid biology testing. The late-stage diversification of lead compounds provides rapid SAR feedback to the medicinal chemistry design cycle. PMID- 29716782 TI - An evaluation of the Movement ABC-2 Test for use in Italy: A comparison of data from Italy and the UK. AB - BACKGROUND: The standardized test within the Movement Assessment Battery for Children-2nd edition (MABC-2) is used worldwide to assess motor problems in children. Ideally, any country using a test developed in another country should produce national norms to ensure that it functions effectively in the new context. AIM: The first objective of this study was to explore the differences in motor performance between Italian and British children. The second was to examine the structural validity of the test for the Italian sample. METHOD: A total of 718 Italian (IT) and 765 British (UK) children, aged 3-10 years, were individually tested on the age-appropriate items of the MABC-2 Test. RESULTS: Developmental trends emerged on every task and differences between IT and UK children were obtained on 11 of 27 task comparisons. Interactions between age and country indicated that differences were not consistently in favor of one culture. Confirmatory factor analysis generally supported the proposed structure of the MABC-2 Test. CONCLUSION: Although the differences between the IT and the UK children were relatively few, those that did emerge emphasize the need for population specific norms and suggest that cultural diversity in motor experiences should be considered when evaluating motor abilities in children. PMID- 29716783 TI - Ultrawide-Field OCT to Investigate Relationships between Myopic Macular Retinoschisis and Posterior Staphyloma. AB - PURPOSE: To investigate the relationships between myopic macular retinoschisis (MRS) and posterior staphylomas and to reveal the characteristics of other retinal lesions associated with MRS. DESIGN: Retrospective, observational case series. PARTICIPANTS: Seven hundred twenty-nine eyes of 420 patients with high myopia, which was defined as myopic refractive error of more than -8.0 diopters or an axial length longer than 26.5 mm. METHODS: Highly myopic eyes were examined by ultrawide-field (UWF) swept-source (SS) OCT with scan width of up to 23 mm and scan depth of 5 mm. The OCT features of MRS and posterior staphylomas and their spatial relationship were examined in UWF SS OCT images. MAIN OUTCOME MEASURES: Associations between MRS and staphylomas. RESULTS: In 729 eyes with mean axial length of 30.2+/-2.1 mm, posterior staphyloma was detected in 482 eyes (66.1%) and MRS was detected in 136 eyes (18.7%). All 136 eyes with an MRS showed outer retinoschisis, and 40 eyes (29.4%) also showed inner retinoschisis. Posterior staphyloma was detected significantly more frequently in eyes with MRS (117/136 [86.0%]) than in eyes without MRS (365/593 [61.6%]; P < 0.001). In all eyes with both staphyloma and outer retinoschisis, the area of the outer retinoschisis was restricted to the area within the staphyloma. In 1 of the 19 eyes with outer retinoschisis but without staphyloma, the outer retinoschisis extended beyond the range of the scanned fundus area. Among the 40 eyes with inner retinoschisis, the inner retinoschisis was located within the region of the outer retinoschisis in 39 eyes (97.5%). In all eyes with inner retinoschisis, retinal lesions causing an inward-directed tractional force were found within the area of the inner retinoschisis. CONCLUSIONS: In highly myopic eyes, the sites of the MRS and staphylomas were spatially related to each other. Posterior-directed force in association with staphylomas, and an inward-directed force resulting from epiretinal membranes or vitreoretinal attachments, may act as causative factors for MRS. However, the exact mechanisms related to the development of an MRS are probably diverse and complex. PMID- 29716784 TI - Emixustat Hydrochloride for Geographic Atrophy Secondary to Age-Related Macular Degeneration: A Randomized Clinical Trial. AB - PURPOSE: To determine whether emixustat hydrochloride (emixustat) reduces the rate of enlargement of geographic atrophy (GA) compared with placebo in subjects with age-related macular degeneration (AMD) and to evaluate the safety and tolerability of emixustat over 24 months of treatment. DESIGN: Multicenter, randomized, double-masked, placebo-controlled, phase 2b/3 clinical trial. PARTICIPANTS: Patients with GA secondary to AMD, a visual acuity score of at least 35 letters, and GA with a total area of 1.25 to 18 mm2 were enrolled. METHODS: Subjects were randomized (1:1:1:1) to emixustat 2.5 mg, 5 mg, 10 mg, or placebo, administered orally once daily for 24 months. Visits included screening, baseline, and months 1, 2, 3, 6, 9, 12, 15, 18, 21, 24, and 25. MAIN OUTCOME MEASURES: The primary efficacy end point was the mean annual growth rate of total GA area in the study eye, as measured by a central reading center using fundus autofluorescence (FAF) images. The change from baseline in normal luminance best corrected visual acuity (NL-BCVA) was a secondary efficacy end point. RESULTS: Of 508 randomized subjects, 320 completed the study. Demographics and baseline characteristics were comparable between treatment groups. On average, GA lesions in the study eye grew at a similar rate in each group (emixustat: 1.69 to 1.84 mm2/year; placebo: 1.69 mm2/year; P >= 0.81). Changes in NL-BCVA were also comparable between groups. Subjects with a larger low luminance deficit (LLD) at baseline (>=20 letters) demonstrated a more rapid growth of GA over 24 months. No relationship was observed between the risk-allele status of the AMD-associated single-nucleotide polymorphisms tested and the growth rate of GA. The most common adverse events in emixustat-treated subjects were delayed dark adaptation (55%), chromatopsia (18%), visual impairment (15%), and erythropsia (15%). CONCLUSIONS: Emixustat did not reduce the growth rate of GA in AMD. The most common adverse events were ocular in nature and likely related to the drug's mechanism of action. Data gained from this study over a 2-year period add to the understanding of the natural history of GA and the baseline characteristics affecting the growth rate of GA. PMID- 29716785 TI - Hyperopic Trend after Cataract Surgery in Eyes with Fuchs' Endothelial Corneal Dystrophy. PMID- 29716787 TI - Management of Acute Retinal Ischemia: Follow the Guidelines! AB - Acute retinal arterial ischemia, including vascular transient monocular vision loss (TMVL) and branch (BRAO) and central retinal arterial occlusions (CRAO), are ocular and systemic emergencies requiring immediate diagnosis and treatment. Guidelines recommend the combination of urgent brain magnetic resonance imaging with diffusion-weighted imaging, vascular imaging, and clinical assessment to identify TMVL, BRAO, and CRAO patients at highest risk for recurrent stroke, facilitating early preventive treatments to reduce the risk of subsequent stroke and cardiovascular events. Because the risk of stroke is maximum within the first few days after the onset of visual loss, prompt diagnosis and triage are mandatory. Eye care professionals must make a rapid and accurate diagnosis and recognize the need for timely expert intervention by immediately referring patients with acute retinal arterial ischemia to specialized stroke centers without attempting to perform any further testing themselves. The development of local networks prompting collaboration among optometrists, ophthalmologists, and stroke neurologists should facilitate such evaluations, whether in a rapid-access transient ischemic attack clinic, in an emergency department-observation unit, or with hospitalization, depending on local resources. PMID- 29716788 TI - Aquaporin-4 and Myelin Oligodendrocyte Glycoprotein Autoantibody Status Predict Outcome of Recurrent Optic Neuritis. AB - PURPOSE: To determine the aquaporin-4 and myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG) serostatus and visual outcomes in patients with recurrent optic neuritis (rON) initially seeking treatment. DESIGN: Cross sectional cohort study. PARTICIPANTS: The study identified patients by searching the Mayo Clinic computerized central diagnostic index (January 2000-March 2017). The 246 eligible patients fulfilled the following criteria: (1) initially seeking treatment for at least 2 consecutive episodes of optic neuritis (ON) and (2) serum available for testing. METHODS: Serum was tested for aquaporin-4 IgG and MOG IgG1 using an in-house validated flow cytometric assay using live HEK293 cells transfected with M1 aquaporin-4 or full-length MOG. MAIN OUTCOMES MEASURES: Aquaporin-4 IgG and MOG IgG1 serostatus, clinical characteristics, and visual outcomes. RESULTS: Among 246 patients with rON at presentation, glial autoantibodies were detected in 32% (aquaporin-4 IgG, 19%; MOG IgG1, 13%); 186 patients had rON only and 60 patients had rON with subsequent additional inflammatory demyelinating attacks (rON-plus group). The rON-only cohort comprised the following: double seronegative (idiopathic), 110 patients (59%); MOG IgG1 positive, 27 patients (15%; 4 with chronic relapsing inflammatory optic neuropathy); multiple sclerosis (MS), 25 patients (13%); and aquaporin-4 IgG positive, 24 patients (13%). The rON-plus cohort comprised the following: aquaporin-4 IgG positive, 23 patients (38%); MS, 22 patients (37%); double seronegative, 11 patients (18%); and MOG IgG1 positive, 4 patients (7%). The annualized relapse rate for the rON-only group was 1.2 for MOG IgG1-positive patients, 0.7 for double-seronegative patients, 0.6 for aquaporin-4 IgG-positive patients, and 0.4 for MS patients (P = 0.005). The median visual acuity (VA) of patients with the worst rON-only attack at nadir were hand movements in aquaporin 4 IgG-positive patients, between counting fingers and hand movements in MOG IgG1 positive patients, 20/800 in idiopathic patients, and 20/100 in MS patients (P = 0.02). The median VA at last follow-up for affected eyes of the rON-only cohort were counting fingers for aquaporin-4 IgG-positive patients, 20/40 for idiopathic patients, 20/25 for MS patients and MOG IgG1-positive patients (P = 0.006). At 5 years after ON onset, 59% of aquaporin-4 IgG-positive patients, 22% of idiopathic patients, 12% of MOG IgG1-positive patients, and 8% of MS patients were estimated to have severe visual loss. CONCLUSIONS: Glial autoantibodies (MOG IgG1 or aquaporin-4 IgG) are found in one third of all patients with rON. Aquaporin-4 IgG seropositivity predicts a worse visual outcome than MOG IgG1 seropositivity, double seronegativity, or MS diagnosis. Myelin oligodendrocyte glycoprotein IgG1 is associated with a greater relapse rate but better visual outcomes. PMID- 29716789 TI - Comparison of HIV Status Between Transgender Women and Men Who Have Sex with Men: A Meta-Analysis. AB - As key population groups in HIV infection, transgender women (TGW) share the same oral and anal sexual practices with men who have sex with men (MSM). However, the differences in HIV rates between the two groups are still unclear. In our study, relevant publications were electronically searched in three databases. After excluding irrelevant studies based on review of the title, abstract, and full text, a total of 24 studies, including 37,521 cases, were identified. There were no significant differences between TGW and MSM regarding HIV status and condom use. However, TGW had a higher proportion of high-risk behaviors, including exchanges of sex, forced sex, receptive intercourse, and sex work experience. Moreover, most curable sexually transmitted diseases were more prevalent in the TGW group compared to MSM. Although TGW showed a higher proportion of high-risk behavior and sexually transmitted disease incidence, their HIV incidence was the same as that for MSM. PMID- 29716786 TI - Systemic and Ocular Determinants of Peripapillary Retinal Nerve Fiber Layer Thickness Measurements in the European Eye Epidemiology (E3) Population. AB - PURPOSE: To investigate systemic and ocular determinants of peripapillary retinal nerve fiber layer thickness (pRNFLT) in the European population. DESIGN: Cross sectional meta-analysis. PARTICIPANTS: A total of 16 084 European adults from 8 cohort studies (mean age range, 56.9+/-12.3-82.1+/-4.2 years) of the European Eye Epidemiology (E3) consortium. METHODS: We examined associations with pRNFLT measured by spectral-domain OCT in each study using multivariable linear regression and pooled results using random effects meta-analysis. MAIN OUTCOME MEASURES: Determinants of pRNFLT. RESULTS: Mean pRNFLT ranged from 86.8+/-21.4 MUm in the Rotterdam Study I to 104.7+/-12.5 MUm in the Rotterdam Study III. We found the following factors to be associated with reduced pRNFLT: Older age (beta = -0.38 MUm/year; 95% confidence interval [CI], -0.57 to -0.18), higher intraocular pressure (IOP) (beta = -0.36 MUm/mmHg; 95% CI, -0.56 to -0.15), visual impairment (beta = -5.50 MUm; 95% CI, -9.37 to -1.64), and history of systemic hypertension (beta = -0.54 MUm; 95% CI, -1.01 to -0.07) and stroke (beta = -1.94 MUm; 95% CI, -3.17 to -0.72). A suggestive, albeit nonsignificant, association was observed for dementia (beta = -3.11 MUm; 95% CI, -6.22 to 0.01). Higher pRNFLT was associated with more hyperopic spherical equivalent (beta = 1.39 MUm/diopter; 95% CI, 1.19-1.59) and smoking (beta = 1.53 MUm; 95% CI, 1.00 2.06 for current smokers compared with never-smokers). CONCLUSIONS: In addition to previously described determinants such as age and refraction, we found that systemic vascular and neurovascular diseases were associated with reduced pRNFLT. These may be of clinical relevance, especially in glaucoma monitoring of patients with newly occurring vascular comorbidities. PMID- 29716790 TI - Neuronal Regulation of eIF2alpha Function in Health and Neurological Disorders. AB - A key site of translation control is the phosphorylation of the eukaryotic translation initiation factor 2alpha (eIF2alpha), which reduces the rate of GDP to GTP exchange by eIF2B, leading to altered translation. The extent of eIF2alpha phosphorylation within neurons can alter synaptic plasticity. Phosphorylation of eIF2alpha is triggered by four stress-responsive kinases, and as such eIF2alpha is often phosphorylated during neurological perturbations or disease. Moreover, in some cases decreasing eIF2alpha phosphorylation mitigates neurodegeneration, suggesting that this could be a therapeutic target. Mutations in the gamma subunit of eIF2, the guanine exchange factor eIF2B, an eIF2alpha phosphatase, or in two eIF2alpha kinases can cause disease in humans, demonstrating the importance of proper regulation of eIF2alpha phosphorylation for health. PMID- 29716791 TI - Predictors of 30-day readmission following pancreatic surgery: A retrospective review. AB - BACKGROUND: Pancreatectomies have been identified as procedures with an increased risk of readmission. In surgical patients, readmissions within 30 days of discharge are usually procedure-related. We sought to determine predictors of 30 day readmission following pancreatic resections in a large healthcare system. METHODS: We retrospectively collected information from the records of 383 patients who underwent pancreatic resections from 2004-2013. To find the predictors of readmission in the 30 days after discharge, we performed a univariate screen of possible variables using the Fisher's exact test for categorical variables and the Mann-Whitney U test for continuous variables. Multivariate analysis was used to determine the independent factors. RESULTS: Fifty-eight (15.1%) patients were readmitted within 30 days of discharge. Of the patients readmitted, the most common diagnoses at readmission were sepsis (17.2%), and dehydration (8.6%). Multivariate logistic regression found that the development of intra-abdominal fluid collections (OR = 5.32, P < 0.0001), new thromboembolic events (OR = 4.08, P = 0.016), and pre-operative BMI (OR = 1.06, P = 0.040) were independent risk factors of readmission within 30 days of discharge. CONCLUSION: Our data demonstrate that factors predictive of 30-day readmission are a combination of patient characteristics and the development of post-operative complications. Targeted interventions may be used to reduce the risk of readmission. PMID- 29716792 TI - Remembering Pathogen Dose: Long-Term Adaptation in Innate Immunity. AB - Recent investigations reveal memory-like adaptive responses of the innate immune system to sequential pathogen challenge. Of note, opposing effects that include both sensitization ('training') and desensitization ('tolerance') have been reported. While hitherto the nature of the pathogen was thought to be of prime importance, we propose that pathogen dose plays a key role in determining these opposing effects. Within this concept, training and tolerance of innate immune cells emerge as adaptive responses to increasing pathogen load. Furthermore, environmental stressors significantly impact the pathogen-induced responses of these innate immune cells. Therefore, we hypothesize that pathogens, like other stressors, provoke hormetic responses of the affected cells. This concept could explain the tight interplay of dose-related effects of pathogens and other stressors in infectious diseases. PMID- 29716793 TI - The Intestinal Epithelium: Central Coordinator of Mucosal Immunity. AB - The gastrointestinal (GI) tract represents a unique challenge to the mammalian immune system. It must tolerate the presence of the luminal microbiota and thus not respond to their products, but still protect the intestinal mucosa from potentially harmful dietary antigens and invading pathogens. The intestinal epithelium, composed of a single layer of cells, is crucial for preserving gut homeostasis and acts both as a physical barrier and as a coordinating hub for immune defense and crosstalk between bacteria and immune cells. We highlight here recent findings regarding communication between microbes and intestinal epithelial cells (IECs), as well as the immune mechanisms employed by distinct IEC subsets to promote homeostasis, emphasizing the central and active role that these cells play in host enteric defense. PMID- 29716794 TI - Proliferative glomerulonephritis with monoclonal immunoglobulin G deposits is associated with high rate of early recurrence in the allograft. AB - The characteristics of allograft proliferative glomerulonephritis with monoclonal immunoglobulin G deposits (PGNMID) are not well defined. To better characterize this disease we retrospectively identified 26 patients with allograft PGNMID, including 16 followed with early protocol biopsies. PGNMID was found to be a recurrent disease in most (89%) patients. A diagnostic biopsy was done for proteinuria and/or increased creatinine in most patients. Median time from transplant to diagnostic biopsy was 5.5 months, with detection within three to four months post-transplant in 86% of patients. Mesangial proliferative glomerulonephritis was the most common pattern on the diagnostic biopsy with 89% of cases showing immunoglobulin G3 subtype restriction. A detectable serum paraprotein was present in 20% of patients. During a mean follow up of 87 months from implantation, 11 of 25 patients lost their allograft largely due to PGNMID within a mean of 36 months from diagnosis. Median graft survival was 92 months. Independent predictors of graft loss were a higher degree of peak proteinuria and longer time from implantation to diagnosis. Sixteen patients were treated with immunosuppressive therapy which resulted in over 50% reduction in proteinuria in 60%, and improvement of glomerular pathology in nine of 13 patients. However, 44% of responders subsequently relapsed. Thus, PGNMID has a high recurrence rate in renal allografts occurring early with detection enhanced by protocol biopsies. Graft outcome is guarded as nearly half of patients lose their graft within three years from diagnosis. Hence, there is a need for better treatment strategies for this disease. PMID- 29716795 TI - Metformin prevents the development of severe chronic kidney disease and its associated mineral and bone disorder. AB - Chronic kidney disease (CKD) causes dysregulation of mineral metabolism, vascular calcification and renal osteodystrophy, an entity called 'CKD-Mineral and Bone Disorder' (CKD-MBD). Here we determine whether metformin, an anti-diabetic drug, exerts favorable effects on progressive, severe CKD and concomitant mineral metabolism disturbances. Rats with CKD-MBD, induced by a 0.25% adenine diet for eight weeks, were treated with 200 mg/kg/day metformin or vehicle from one week after CKD induction onward. Severe, stable CKD along with marked hyperphosphatemia and hypocalcemia developed in these rats which led to arterial calcification and high bone turnover disease. Metformin protected from development toward severe CKD. Metformin-treated rats did not develop hyperphosphatemia or hypocalcemia and this prevented the development of vascular calcification and inhibited the progression toward high bone turnover disease. Kidneys of the metformin group showed significantly less cellular infiltration, fibrosis and inflammation. To study a possible direct effect of metformin on the development of vascular calcification, independent of its effect on renal function, metformin (200 mg/kg/day) or vehicle was dosed for ten weeks to rats with warfarin-induced vascular calcification. The drug did not reduce aorta or small vessel calcification in this animal model. Thus, metformin protected against the development of severe CKD and preserved calcium phosphorus homeostasis. As a result of its beneficial impact on renal function, associated comorbidities such as vascular calcification and high bone turnover disease were also prevented. PMID- 29716796 TI - Protein carbamylation exacerbates vascular calcification. AB - Protein carbamylation is a posttranslational modification that can occur non enzymatically in the presence of high concentrations of urea. Although carbamylation is recognized as a prognostic biomarker, the contribution of protein carbamylation to organ dysfunction remains uncertain. Because vascular calcification is common under carbamylation-prone situations, we investigated the effects of carbamylation on this pathologic condition. Protein carbamylation exacerbated the calcification of human vascular smooth muscle cells (hVSMCs) by suppressing the expression of ectonucleotide pyrophosphate/phosphodiesterase 1 (ENPP1), a key enzyme in the generation of pyrophosphate, which is a potent inhibitor of ectopic calcification. Several mitochondrial proteins were carbamylated, although ENPP1 itself was not identified as a carbamylated protein. Rather, protein carbamylation reduced mitochondrial membrane potential and exaggerated mitochondria-derived oxidative stress, which down-regulated ENPP1. The effects of carbamylation on ectopic calcification were abolished in hVSMCs by ENPP1 knockdown, in mitochondrial-DNA-depleted hVSMCs, and in hVSMCs treated with a mitochondria-targeted superoxide scavenger. We also evaluated the carbamylation effects using ex vivo and in vivo models. The tunica media of a patient with end stage renal disease was carbamylated. Thus, our findings have uncovered a previously unrecognized aspect of uremia-related vascular pathology. PMID- 29716797 TI - Chronic pancreatitis and resectable synchronous pancreatic carcinoma: A survival analysis. AB - BACKGROUND/OBJECTIVES: Chronic pancreatitis (CP) is a risk factor for pancreatic cancer (PDAC). CP and PDAC are characterized by an abundance of desmoplastic tissue. The effect of this pancreatic desmoplastic tissue on PDAC is poorly understood. In literature, negative and positive effects on the natural course of PDAC have been discussed. The present analysis aims to assess the impact of CP on patients with resectable synchronous PDAC regarding short- and long-term survival. METHODS: All patients who underwent pancreatic resection at our institution from January 2005 to January 2014 were retrospectively evaluated. Definition of CP was based on clinical and radiological aspects and histological confirmation as used previously. We identified patients with CP, CP and PDAC, and PDAC without CP and compared perioperative course and survival. Statistical analysis was performed by chi-square, Kruskal-Wallis/Mann-Whitney-U and Breslow survival analysis. P-values <0.05 were defined as statistically significant. RESULTS: 159 patients met our inclusion criteria for CP. 49 of them (30.8%) had synchronous PDAC. 145 patients had PDAC without a history of CP. There was a more advanced nodal involvement in PDAC patients with CP. Perioperative outcome and long-term survival of PDAC patients with and without CP did not differ significantly. CONCLUSION: In a large clinical series CP had no impact on survival of patients with PDAC after resection with curative intent. PMID- 29716798 TI - Identification of risk factors for failure in patients with skin and soft tissue infections. AB - PURPOSE: The purpose was to determine significant predictors of treatment failure of skin and soft tissue infections (SSTI) in the inpatient and outpatient setting. METHODS: A retrospective chart review of patients treated between January 1, 2005 to July 1, 2016 with ICD-9 or ICD-10 code of cellulitis or abscess. The primary outcome was failure defined as an additional prescription or subsequent hospital admission within 30 days of treatment. Risk factors for failure were identified through multivariate logistic regression. RESULTS: A total of 541 patients were included. Seventeen percent failed treatment. In the outpatient group, 24% failed treatment compared to 9% for inpatients. Overweight/obesity (body mass index (BMI) > 25 kg/m2) was identified in 80%, with 15% having a BMI >40 kg/m2. BMI, heart failure, and outpatient treatment were determined to be significant predictors of failure. The unit odds ratio for failure with BMI was 1.04 (95% [Cl] = 1.01 to 1.1, p = 0.0042). Heart failure increased odds by 2.48 (95% [Cl] = 1.3 to 4.7, p = 0.0056). Outpatients were more likely to fail with an odds ratio of 3.36. CONCLUSION: Patients with an elevated BMI and heart failure were found to have increased odds of failure with treatment for SSTIs. However, inpatients had considerably less risk of failure than outpatients. These risk factors are important to note when making the decision whether to admit a patient who presents with SSTI in the emergency department. Thoughtful strategies are needed with this at-risk population to prevent subsequent admission. PMID- 29716799 TI - Emergency and critical care applications for contrast-enhanced ultrasound. AB - INTRODUCTION: Contrast-enhanced ultrasound (CEUS) using intravascular microbubbles has potential to revolutionize point-of-care ultrasonography by expanding the use of ultrasonography into clinical scenarios previously reserved for computed tomography (CT), magnetic resonance imaging, or angiography. METHODS: We performed a literature search and report clinical experience to provide an introduction to CEUS and describe its current applications for point of-care indications. RESULTS: The uses of CEUS include several applications highly relevant for emergency medicine, such as solid-organ injuries, actively bleeding hematomas, or abdominal aortic aneurysms. Compared with CT as the preeminent advanced imaging modality in the emergency department, CEUS is low cost, radiation sparing, repeatable, and readily available. It does not require sedation, preprocedural laboratory assessment, or transportation to the radiology suite. CONCLUSIONS: CEUS is a promising imaging technique for point-of-care applications in pediatric and adult patients and can be applied for patients with allergy to CT contrast medium or with impaired renal function. More high-quality CEUS research focusing on accuracy, patient safety, health care costs, and throughput times is needed to validate its use in emergency and critical care settings. PMID- 29716800 TI - The size of the study population: Correspondance related "Measurement of blood lactate, D-dimer, and activated prothrombin time improves prediction of in hospital mortality in adults blunt trauma". PMID- 29716801 TI - Eruptive xanthoma in the setting of hypertriglyceridemia and pancreatitis. AB - BACKGROUND: Undifferentiated dermatologic complaints are often encountered in the emergency department. While a patient's exposures, risk factors, and comorbidities may help guide emergency department evaluation, the accurate diagnosis of dermatologic findings is critical to allowing rapid identification and treatment of disease. CASE: In this vignette we discuss a case of eruptive xanthoma in a 33-year-old male with diabetic ketoacidosis and pancreatitis. DISCUSSION: Dermatologic complaints pose a unique challenge to the emergency physician. Many dermatologic findings are benign; however, some may represent underlying serious disease even in young, otherwise healthy appearing patients. Eruptive xanthomas are cutaneous lesions often indicating severe hypertriglyceridemia and uncontrolled diabetes. Likely presentations and risk factors for eruptive xanthomas will be discussed as well as ED evaluation and management. PMID- 29716802 TI - Perforated duodenal ulcers after Roux-Y Gastric Bypass. AB - Even though the incidence of complicated peptic ulcer disease (PUD) has decreased in the last decades, it remains a condition with a significant mortality. Whilst diagnosis and treatment of PUD in morbidly obese patients can be challenging, patients with excluded segments - such as after Roux-Y Gastric Bypass (RYGB) - present an even greater problem, as the subsequent altered anatomy impedes the common modalities used for diagnostic and therapeutic measures. We report the cases of two patients after RYGB with perforated duodenal ulcers in the intention to highlight problems regarding diagnosis and treatment. Patients with perforation after RYGB usually present without signs of hollow organ perforation in clinical examination but also in computed tomography scans. Diagnostic laparoscopy was performed to address the discrepancy between pain and non diagnostic examinations. An aggressive approach in case of unexplained symptoms in these patients is not only justified but mandatory. PMID- 29716803 TI - Pericallosal aneurysm coiling with a "hubbed" 167 cm 0.013" headway duo via a transradial approach. AB - Cerebral aneurysms in patients with extreme proximal tortuosity may contraindicate endovascular therapy as a result of both the approach and an inability to navigate a coil-compatible microcatheter into the aneurysm due to microcatheter length. We present a 72 year-old male with multiple medical comorbidities admitted with a grade 3, ruptured pericallosal aneurysm. Aortoiliac disease contraindicated a transfemoral approach and thus a 6 French 105 cm guide catheter was advanced through a 6 French short radial sheath into a bovine left common carotid artery. After straightening proximal access anatomy with an Amplatz wire to allow advancement of the guide catheter into the internal carotid artery, a 167 cm 0.013 in. headway duo was advanced through a 5 French Sofia through the guide catheter and "hubbed" to enter the aneurysm. The aneurysm was then successfully coil embolized with 4 Target Ultrasoft coils. This case illustrates the utility of a 167 cm microcatheter for coil embolization of a pericallosal aneurysm with significant proximal tortuosity via a transradial approach. Despite its 0.013 in. inner diameter and length, common Target coils were compatible and deployed without incident. PMID- 29716804 TI - Root cause analysis of diagnostic and surgical failures in the treatment of suspected Cushing's disease. AB - Cushing's disease (CD) is a condition characterized by excess glucocorticoid from an ACTH pituitary adenoma. Identifying surgical candidates represents a major diagnostic challenge. We performed a root cause analysis (RCA) of treatment failures for patients with suspected CD. The present study aims to categorize failures in treatment. Medical records were reviewed from 2008 to 2017 for all patients treated surgically for suspected CD. Demographics, past medical history, endocrine outcomes, imaging findings, laboratory studies and clinical features were collected. Eighty-five patients were identified with pre-operative suspicion for CD. Thirty-four (40.0%) had undergone prior surgery confirming ACTH adenoma, leaving 51 (60.0%) for analysis. The average length of follow-up was 18.3 +/- 24.1 months, 42 (82.4%) patients had postoperative biochemical remission of hypercortisolism. Forty-three (84.3%) had histologically confirmed CD, two (3.9%) were diagnosed with extracranial ACTH-secreting tumors, four (7.8%) had no obvious tumor upon intraoperative exploration, one (1.9%) had suspected pituitary ACTH hyperplasia, and one (1.9%) had no identifiable pathologic tissue despite apparent gross tumor observed during surgery. Thirty-four (66.7%) patients had remission following surgery alone, four (7.8%) after reoperation, and four (7.81%) after radiosurgery. One patient (1.9%) was found to have an ectopic source of ACTH, and one (1.9%) had immunohistochemically confirmed adrenal tumors. On RCA, we identified six categories of treatment failures. CD is a diagnostic challenge that can be difficult to distinguish from other forms of hypercortisolism. Surgical efficacy can be improved with more accurate patient selection, and perhaps with improved imaging methods. PMID- 29716805 TI - Predictors of clinical outcomes among patients with brain abscess in Thailand. AB - Although brain abscess is a fatal neurological infection, the studies in Thailand are quite limited and outdate. This study aims to identify predictors of mortality among patients with brain abscess in Thailand. Patients with a diagnosis of brain abscess admitted to Songklanagarind Hospital, a referral tertiary care hospital in southern Thailand, between 2002 and 2017 were enrolled into this retrospective case control study. Demographic data, neurological status, clinical presentations, predisposing factors, microbiological profiles, neuroimaging findings, treatments, and outcomes were collected from electronic medical records. Predictors of death outcome were analyzed by univariate and multivariate logistic regression analysis. Among eighty-one patients enrolled into the study, forty-seven patients (58.0%) were male and 34 patients (42.0%) were female. The overall mean age (+/-SD) was 47.68 (+/-16.92) years old. The major predisposing factors of brain abscess were an immunocompromised state (42.0%) and the extension of a paracranial infections (24.7%). The common clinical presentations included headache (61.7%), fever (50.6%), and hemiplegia (34.6%). Eleven patients (13.6%) were dead at hospital discharge. The independent factor associated with death outcome identified by multivariate analysis was confusion (odds ratio 7.67, 95% CI 1.95-30.14; p = 0.003). In summary, the current study shows that an immunocompromised state is a significant predisposing factor of brain abscess. The independent factor associated with death outcome was confusion which was correlated with septic encephalopathy. PMID- 29716806 TI - Dual origin of the right vertebral artery from the right common carotid and aberrant right subclavian arteries. AB - This report describes a case of duplicated origin of the right vertebral artery incidentally found in a young patient. Computed tomographic angiography and digital subtraction angiography showed a dominant branch derived from the right common carotid artery and an accessory branch that derived from the right subclavian artery, which aberrantly originated from the far left aortic arch, and adjoined the dominant branch at the C5 level. We discuss angiographic findings, clinical implications and embryological basis for this rare anomaly. PMID- 29716807 TI - Endoport-assisted surgical evacuation of a deep-seated cerebral abscess. AB - Conventional surgical treatment for cerebral abscesses includes craniotomy or stereotactic aspiration. Deep-seated, large abscesses pose a challenge to neurosurgeons, due to the risk of injury to the cortex and white matter tracts secondary to the brain retraction necessary to access the lesion. The endoport is a tubular conduit that can be employed for minimally invasive approaches to deep seated intracranial lesions, and it may reduce the length of dural opening, size of corticotomy, and retraction-related injury. In this technical note, we present the first report of an adult with a deep cerebral abscess which was successfully treated with endoport-assisted surgical evacuation. The endoport has been shown to be useful for the treatment of other intracranial pathologies, and we believe that this technology may be employed for the evacuation of appropriately selected cerebral abscesses. PMID- 29716808 TI - Immediate improvement of intraoperative monitoring signals following CSF release for cervical spine stenosis: Case report. AB - Cervical spondylotic myelopathy (CSM) is a degenerative pathology characterized by partial or complete conduction block on intraoperative neuromonitoring. We describe a case treated using osseoligamentous decompression and durotomy for cerebrospinal fluid (CSF) release. Intraoperative monitoring demonstrated immediate signal improvement with CSF release, suggesting that clinical improvement in CSM may result from resolution of CSF flow anomalies. PMID- 29716809 TI - Successful transcatheter aortic valve replacement in an oversized 800 mm2 annulus and bicuspid aortic valve. AB - The current iterations of balloon-expandable transcatheter aortic valve replacement (TAVR) valves consist of a maximum size of 29 mm, corresponding to maximum annulus area of 680 mm2. However, a number of patients who qualify for TAVR based on surgical risk may have anatomical features outside the FDA-approved descriptions. The technique of overexpansion of TAVR valves during deployment allows for more patients to be treated successfully. This particular case demonstrates that overexpansion is safe and efficacious in a very large annulus of >800 mm2. Careful planning and consideration of aortic root calcification is helpful for technique of overexpansion and, ultimately, the technique may increase the number of patients eligible for TAVR. PMID- 29716810 TI - Long term follow-up of total arterial versus conventional and hybrid myocardial revascularization: A propensity score matched analysis. AB - PURPOSE: To evaluate the impact of the revascularization technique (by means of conventional, total arterial or hybrid myocardial revascularization) in patients with multivessel coronary artery disease. METHODS: A propensity-score analysis of patients undergoing myocardial revascularization from 1998 to 2012 was performed based on the surgical technique utilized, either total arterial (Group1, G1,n degrees = 89), conventional CABG(LIMA on LAD plus veins, Group2, G2,n degrees = 89), or hybrid revascularization (LIMA on LAD plus PTCA on non-LAD vessels, Group3, G3, n degrees = 89). Primary end-points were overall survival and cardiac-related death while secondary composite end-point was survival freedom from major adverse cardiac and cerebrovascular events (MACCEs) defined as myocardial infarction, cardiac death, stroke and repeated target vessel revascularization. RESULTS: Study population was mostly affected by double vessels disease (G1 = 2.35 vs G2 = 2.3 vs G3 = 2.4, p = 0.14) with a preserved LV function(G1 = 48% vs G2 = 49% vs G3 = 50%, p = 0.12). Hospital mortality was 0% in all groups. At a mean follow-up of 6 +/- 2 years overall survival was significantly better in patients receiving total arterial myocardial revascularization (G1 = 90.4 +/- 3.5% vs G2 = 82.3 +/- 4.2% vs G3 = 82.1 +/- 5.9%, p = 0.049) as well as freedom from MACCEs (G1 = 95.2 +/- 2.4% vs G2 = 86.5 +/- 4% vs G3 = 68 +/- 6.9%, p = 0.001) while survival free from cardiac-related death was similar(G1 = 97.7 +/- 1.6% vs G2 = 95.1 +/- 2.4% vs G3 = 89.5 +/- 5.4%, p = 0.08). Conversely, at 10 years follow-up only freedom from MACCEs was significantly better in patients of Group 1(G1 = 78.9 +/- 8.6% vs G2 = 72.4 +/- 5.7% vs G3 = 52 +/- 8.7%, p < 0.001). CONCLUSIONS: Total arterial revascularization provides improved outcomes at mid and long term follow-up compared with conventional or hybrid revascularization. The latter technique is particularly associated with a significantly higher incidence of late myocardial infarction and repeat revascularization. PMID- 29716812 TI - First report of the isolation of blaIMI-1-producing colistin-heteroresistant Enterobacter cloacae in Japan, September 2016. AB - The isolation of a carbapenem-resistant Enterobacter cloacae strain harboring the IMI-1 variant of blaIMI-1 carbapenemase points to the worldwide emergence of multidrug resistant bacteria as a potential source of health care infections. In this report, we describe the first isolation of E. cloacae with blaIMI-1 carbapenemase isolated from a Japanese patient in September 2016. The isolate was resistant to carbapenems, levofloxacin, and aminoglycosides, and heteroresistant to colistin but sensitive to fourth-generation cephalosporins. All microbiology laboratories worldwide should be made aware of these blaIMI-1-producing subtypes with unusual antibiotic susceptibility profiles. PMID- 29716811 TI - Neuropeptide oxytocin enhances MU opioid receptor signaling as a positive allosteric modulator. AB - Oxytocin (OT) is a 9-amine neuropeptide that plays an essential role in mammalian labor, lactation, maternal bonding, and social affiliation. OT has been reported to exert an analgesic effect in both humans and animals, and the results of certain animal experiments have shown that the analgesic effect of OT is partially blocked by opioid receptor antagonists. To investigate the relationship between OT and MU opioid receptor (MOR), we evaluated how OT affects MOR in vitro by performing an electrical impedance-based receptor biosensor assay (CellKeyTM assay), an intracellular cAMP assay, and a competitive receptor-binding analysis by using cells stably expressing human MOR and OT receptor. In both the CellKeyTM assay and the intracellular cAMP assay, OT alone exerted no direct agonistic effect on human MOR, but treatment with 10-6 M OT markedly enhanced the MOR signaling induced by 10-6 M endomorphin-1, beta-endorphin, morphine, fentanyl, and DAMGO. Moreover, in the competitive receptor-binding assay, 10-6 M OT did not alter the affinity of endomorphin-1 or morphine for MOR. These results suggest that OT could function as a positive allosteric modulator that regulates the efficacy of MOR signaling, and thus OT might represent a previously unrecognized candidate analgesic agent. PMID- 29716813 TI - Video-EEG during tilt-table testing is an invaluable aid for understanding syncope. PMID- 29716814 TI - Commentary to 'Laparoscopic inguinal hernia repair by modified peritoneal leaflet closure: Description and initial results in children'. PMID- 29716815 TI - Effect of traffic legislation on road traffic deaths in Ningbo, China. AB - PURPOSE: Road safety is a major public health concern in China. However, the effectiveness of traffic laws in China is not known. We investigated the effect of traffic legislation on traffic deaths using data in Ningbo, China. METHODS: We obtained traffic fatality data from 2002 to 2014 from the Ningbo Municipal Center for Disease Control and Prevention. An interrupted time series was used to look for change points in fatalities over time. We first used multiple change-point analysis to identify whether change points existed. Then, we checked if the identified change points corresponded to major changes in traffic legislation. Finally, we used a generalized additive model to examine the magnitude of those changes on fatalities. RESULTS: A total of 12,412 traffic fatalities occurred in the study period. We detected two change points in traffic fatalities, which corresponded to the road safety law in 2004 and the Criminal Law Amendment criminalizing risky driving in 2011. The fatalities showed an 18.9% reduction (relative risk = 0.81, 95% confidence interval, 0.74-0.89) after the first change point and a further 19.2% reduction (relative risk = 0.80, 95% confidence interval, 0.74-0.89) after the second change point. CONCLUSIONS: Traffic legislation might improve road safety by spurring behavioral changes that reduce traffic deaths in China. These laws may provide a sound model for other similar countries. PMID- 29716816 TI - Patient-specific pre-contouring of osteosynthesis plates for mandibular reconstruction: Using a three-dimensional key printed solution. AB - PURPOSE: In mandibular reconstructive surgery, the osteosynthesis plates require contouring according to the patients' individual anatomical situation. These plates are frequently contoured around a three-dimensional (3D) printed model. However, the translation to the actual patient can introduce inaccuracies and unwanted rotations in the condyles and mandibular ramus, due to malpositioning of the pre-contoured plate. MATERIALS AND METHODS: This article describes an easy access method for exact translation of the pre-contoured plate to the patient's mandible. This is done by using 3D printed guides that allow pre-drilling of screw holes in both the contour model and the patients' mandible. The accuracy of the Key Printed Solution was analysed by comparing the anatomical landmarks on both the 3D planned and post-operative models. RESULTS: The method was applied to 4 cases. All landmarks were identified on both the 3D planning and post-operative computed tomographic data. This showed an average deviation of 1.0 mm between planning and the post-operative result. The inter-observer variation was 0.6 mm (intra-class correlation, 0.75). CONCLUSION: This article presents an easy-to-use method for pre-bending the osteosynthesis plate and subsequent accurate translation of the intended contour with corresponding screw hole locations. The method was proved to be accurate and time-efficient. PMID- 29716817 TI - All-in-one surgical guide: A new method for cranial vault resection and reconstruction. AB - INTRODUCTION: Great precision is required for craniofacial surgery, and computer aided design (CAD) methods may be used to plan surgery before it is performed. In this study, three-dimensional (3D)-printed cutting guides are used to match computer models with surgical procedures. We describe a novel method of computer aided surgery for autologous cranioplasty that includes a new strategy for generating and using cutting guides. These guides may be used not only for osteotomies, but also for many other steps in the surgical procedure. MATERIALS AND METHODS: Preoperatively, anatomical data were imported into a CAD package and used for virtual surgical planning (VSP). Cutting guides were designed after considering how to integrate all the surgical steps. Models of the microplates and micro-screws were also made. Surgical guides were exported and printed, and preoperative simulations using a replica of the patient's skull established the sequence of steps. The accuracy of the procedure was evaluated postoperatively using computed tomography (CT) scans. RESULTS: In every patient examined, the all in-one surgical-guide system was able to automate the many steps in the procedure and dramatically decreased the duration of surgery. The experimental guide enhanced every phase of surgery, including excising the lesion, and harvesting, positioning, and fixing the graft. In each step, precision was enhanced and the outcome corresponded with the VSP. CONCLUSIONS: The few previous reports on cutting guides used in cranioplasty generally describe the use of separate guides for dismantling and reconstruction. The ability to perform more surgical sequences using a single tool can improve surgical accuracy. Clearly there is no single perfect surgical guide; however, effective surgical-design strategies should be used to build the best approach to each procedure. PMID- 29716818 TI - Evaluation of nerve growth factor (NGF) treated mesenchymal stem cells for recovery in neurotmesis model of peripheral nerve injury. AB - BACKGROUND: Peripheral nerve damages are a relatively common type of the nervous system injuries. Although peripheral nerves show some capacity of regeneration after injury, the extent of regeneration is not remarkable. The present study aimed to evaluate the effect of NGF treated mesenchymal stem cells on regeneration of transected sciatic nerve. MATERIALS AND METHODS: In this experimental study, forty-two male Wistar.rats (180-200 g) were randomly divided into 6 groups (n = 7) including control, Membrane + Cell (Mem + Cell), NGF group, NGF + Cell group, NGF + Mem group and NGF + Mem + Cell group. Regeneration of sciatic nerve was evaluated using behavioral analysis, electrophysiological assessment and histological examination. RESULTS: The rats in the NGF + Mem + Cell group showed significant decrease in sciatic functional index (SFI) and hot water paw immersion test during the 2nd to 8th weeks after surgery. (p < 0.001). At 8 weeks after surgery, electrophysiological findings showed that amplitude increased and latency decreased significantly in NGF + Mem + Cell group (p < 0.001). Measured histological parameters showed that number of nerve fibers, number of vessels and percent of vessel area also increased significantly in NGF + Mem + Cell group (p < 0.05). CONCLUSION: The present study showed that NGF in accompany with mesenchymal stem cells improved electrophysiological and histological indices. PMID- 29716819 TI - A Randomized Trial Comparing Metered Dose Inhalers and Breath Actuated Nebulizers. AB - BACKGROUND: Despite little evidence for its effectiveness, the breath-actuated nebulizer (BAN) is the default albuterol delivery method in our pediatric emergency department. OBJECTIVE: We compared the clinical efficacy of BAN and the metered-dose inhaler (MDI) in treating subjects patients 2 to 17 years of age who presented with mild to moderate asthma exacerbations. METHODS: This is a randomized, nonblinded, noninferiority study conducted at a single pediatric tertiary care emergency department. Subjects presenting with a Pediatric Asthma Score ranging from 5 to 11 received albuterol by BAN or MDI via standard weight based and symptom severity dosing protocols. Aerosolized ipratropium (via BAN) and intravenous magnesium sulfate were given when clinically indicated. The primary outcome was patient disposition. The noninferiority margin for the primary outcome was an admission rate difference <=10%. Analyses were adjusted for confounders that were significant at p <= 0.10. RESULTS: We enrolled 890 subjects between October 2014 and April 2015. BAN and MDI groups were comparable for age, gender, and race but not for pretreatment symptom severity; 51% in the MDI group had a Pediatric Asthma Score of moderate severity (8-11) vs. 63% in the BAN group (p < 0.003). Unadjusted admission rates were 11.9% for MDI and 12.8% for BAN, for an unadjusted risk difference of -0.9% (95% confidence interval -5% to 3%). After adjusting for baseline confounder severity, the risk difference was 2% (95% confidence interval -4% to 7%), which met the criteria for noninferiority. CONCLUSIONS: Albuterol therapy by MDI is noninferior to BAN for the treatment of mild to moderate asthma exacerbations in children 2 to 17 years of age. PMID- 29716820 TI - Man with a Swollen Eye: Nonspecific Orbital Inflammation in an Adult in the Emergency Department. AB - BACKGROUND: Nonspecific orbital inflammation (NSOI) is a rare idiopathic ocular pathology characterized by unilateral, painful orbital swelling without identifiable infectious or systemic disorders, which can be complicated by optic nerve compromise. CASE REPORT: A 50-year-old man presented to the Emergency Department with recurring, progressive painless left eye swelling, decreased visual acuity, and binocular diplopia in the absence of trauma, infection, or known malignancy. His physical examination was notable for left-sided decreased visual acuity, an afferent pupillary defect, severe left eye proptosis and chemosis, and restricted extraocular movements; his dilatated funduscopic examination was notable for ipsilateral retinal folds within the macula, concerning for a disruption between the sclera and the retina. Ocular examination of the right eye was unremarkable. Laboratory data were unrevealing. Gadolinium enhanced magnetic resonance imaging showed marked thickening of the left extraocular muscles associated with proptosis, dense inflammatory infiltration of the orbital fat, and characteristics consistent with perineuritis. The patient was diagnosed with NSOI with optic neuritis and admitted for systemic steroid therapy; he was discharged on hospital day 2 after receiving high-dose intravenous (i.v.) methylprednisolone with significant improvement. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: NSOI is a rare and idiopathic ocular emergency, with clinical mimicry resembling a broad spectrum of systemic diseases such as malignancy, autoimmune diseases, endocrine disorders, and infection. Initial work-up for new-onset ocular proptosis should include comprehensive laboratory testing and gadolinium-enhanced magnetic resonance imaging. Timely evaluation by an ophthalmologist is crucial to assess for optic nerve involvement. Signs of optic nerve compromise include decreased visual acuity, afferent pupillary defect, or decreased color saturation. Patients with optic nerve compromise require admission for aggressive anti-inflammatory therapy with i.v. steroids in an attempt to reduce risk of long-term visual sequelae. Our case demonstrates a severe presentation of this disorder and exhibits remarkable visual recovery after 48 h of systemic i.v. steroid treatment. PMID- 29716821 TI - Artery of Percheron Stroke. AB - BACKGROUND: Coma is not a common symptom of stroke. CASE REPORT: We present a patient with a stroke to the artery of Percheron, which infarcted the bilateral paramedian thalami and resulted in coma. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Identifying strokes in comatose patients is important for therapeutic management. The bilateral thalami are involved in maintaining consciousness. The artery of Percheron is an anatomic variant in the posterior circulation whereby the bilateral paramedian thalami are perfused by it solely. This is an atypical stroke syndrome that emergency physicians need to be able to identify. PMID- 29716822 TI - Congestive Heart Failure as a Differential Diagnosis of Cholangitis. PMID- 29716823 TI - Apical Hypertrophic Cardiomyopathy: A Concerning Electrocardiogram in the Emergency Department. AB - BACKGROUND: Apical hypertrophic cardiomyopathy is a rare, complex phenotypic variant of the classically taught hypertrophic cardiomyopathy. It is highly variable in its pathophysiology as well as its clinical course, spanning the spectrum from a healthy asymptomatic lifestyle to sudden cardiac death and severe diastolic dysfunction. The hallmark electrocardiographic findings of unusually large T-wave inversions, in conjunction with the most common presenting symptom being chest pain, makes this disease entity concerning in the emergency department (ED) setting. CASE REPORT: A 61-year-old man with a history of hypertension presented to the ED with chest pain. His electrocardiogram exhibited a biphasic T wave in lead V2 with ST depressions in leads V3-V6 with deep symmetrical T-wave inversions in these leads as well. His troponin was negative and the patient was taken for cardiac catheterization. Catheterization revealed no coronary artery disease; however, it revealed a "spade like" filling pattern of the left ventricle, suggestive of an apical variant of hypertrophic cardiomyopathy. Subsequent cardiac magnetic resonance imaging confirmed the diagnosis of apical hypertrophic cardiomyopathy and the patient was started on a beta-blocker and discharged with cardiology follow-up. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Electrocardiographic interpretation is a critical skill of the emergency physician. Awareness of the syndrome and its specific electrocardiogram findings may help facilitate further testing that will aid in timely diagnosis and interventions. PMID- 29716824 TI - Middle Aged Woman with Dyspnea. PMID- 29716825 TI - Giant coronary ectasia and athlete's heart mimicking an acute coronary syndrome. PMID- 29716826 TI - Making the hidden seen: A narrative analysis of the experiences of Assumption of Care at birth. AB - BACKGROUND: Being involved in any child protection system is complex and multifaceted and none more so than in non-voluntary Assumption of Care which occurs in New South Wales when, for child protection concerns, the Department of Family and Community Services removes a newborn baby from her/his mother. OBJECTIVE: This research studied childbearing women's and professionals' experiences of Assumption of Care at birth to increase understanding of individual participants' stories, how they made sense of meanings and how these experiences framed their lives. METHOD: A narrative inquiry framework guided interviews with four groups: childbearing women, midwives, social workers and Family and Community Services case managers. Holistic form was used for reading, interpreting and analysing the narratives. FINDINGS: This research found unwanted emotional (isolation, shame, guilt, loss, disenfranchised grief) and physical consequences (depression, substance abuse complications) for women experiencing an Assumption of Care at the time of birth. There were also conflicting ethical and moral positions for the professionals involved. The use/abuse of power, concealment of facts and disenfranchised grief were identified as intertwined plots that caused or increased tensions. DISCUSSION: Both the women and the professionals felt pressure from trying to achieve competing and overlapping roles. The unwanted effects of Assumption of Care are exacerbated by the current child protection and maternity care systems. CONCLUSION: To address the tensions raised in this study, we suggest a two-fold change to maternity care for women at risk of an Assumption of Care: a therapeutic justice model of maternity care and continuity of midwifery care with a dedicated midwife. Introducing these changes could increase women's and children's safety and wellbeing. PMID- 29716827 TI - Vascular Access: Clinical Practice Guidelines of the European Society for Vascular Surgery. PMID- 29716828 TI - Eluate testing with monospecific antisera unmasks multiple immunoglobulin classes and identifies frequent IgA involvement in severe autoimmune hemolytic anemia. PMID- 29716829 TI - Checkpoints and beyond - Immunotherapy in colorectal cancer. AB - Immunotherapy is the latest revolution in cancer therapy. It continues to show impressive results in malignancies like melanoma and others. At least so far, effects are modest in colorectal cancer (CRC) and only a subset of patients benefits from already approved checkpoint inhibitors. In this review, we discuss major hurdles of immunotherapy like the immunosuppressive niche and low immunogenicity of CRC next to current achievements of checkpoint inhibitors, interleukin treatment and adoptive cell transfer (dendritic cells/cytokine induced killer cells, tumor infiltrating lymphocytes, chimeric antigen receptor cells, T cell receptor transfer) in pre-clinical models and clinical trials. We intensively examine approaches to overcome low immunogenicity by combination of different therapies and address future strategies of therapy as well as the need of predictive factors in this emerging field of precision medicine. PMID- 29716830 TI - Pediatric donation after circulatory determination of death (pDCD): A narrative review. AB - Pediatric donation after circulatory death (pDCD) is an established pathway for organ donation. It remains, however, a relatively rare event worldwide, and most clinicians outside of the pediatric intensive care unit (PICU) are unfamiliar with it. The goal of this review is to introduce the processes and concepts of pDCD. While most children die in circumstances that would not allow pDCD, many children that die after withdrawal of life sustaining therapy (WLST) may be eligible for donation of some organs. The potential benefits of this practice to patients on the wait list are well known, but donation can also be an opportunity to honor a patient's or family's desire to altruistically improve the lives of others. Offering the possibility of donation requires careful attention to ethical principles to ensure that conflicts of interest are avoided and that the family is free to make an independent, fully informed decision. Doing so allows families and decision makers the autonomy to decide if donation is something they wish to incorporate into end-of-life care. PMID- 29716831 TI - In vivo MR in the drug pipeline. AB - The application of in vivo magnetic resonance (MR) in drug development has several requirements that differ significantly from most applications primarily because the biopharmaceutical industry must develop new safe and effective drugs more quickly and at lower cost in a highly regulated environment. In vivo MR is recognized as a useful method to provide biomarkers for target engagement, treatment response, safety and mechanism of action that can be translated between animal and clinical studies. Thus, it has the potential to help identify drugs that are more likely to be safe and effective earlier in the process of drug development, which may help reduce the time and money required to get new drugs to patients with an unmet medical need. A brief introduction of how novel drugs are discovered and developed, what drives the biopharmaceutical industry's interest in using biomarkers and what it takes to use MR as a biomarker to support drug development, including regulatory concerns, provides context for understanding what makes the application of in vivo MR in drug development different from most others. Exploration of three programs (trebananib, ZD6126 and axitinib) using dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) in the development of antivascular agents provides insight into how in vivo MR biomarkers impact drug discovery and development and the limitations of biomarkers. PMID- 29716832 TI - Early prognostic factors for acute encephalopathy with reduced subcortical diffusion. AB - OBJECTIVE: The aim of this study was to determine the prognostic factors for acute encephalopathy with reduced diffusion (AED) during the acute phase through retrospective case evaluation. METHODS: The participants included 23 patients with AED. The diagnosis of AED was based on their clinical course and radiological findings. We divided the patients into severe and non-severe groups based on the neurodevelopmental outcome. The severe group included seven patients (median age, 21 months; range, 6-87 months) and the non-severe group included 16 patients (19 months, 9-58 months). Clinical symptoms, laboratory data and electroencephalogram (EEG) findings within 48 h from the initial seizure onset were compared between the two groups to identify neurological outcome predictors. RESULTS: The incidence of coma 12-24 h after onset, serum creatinine (Cr) levels within 2 h after onset, maximum aspartate aminotransferase (AST) levels within 24 h after onset, and the rate of electrographic seizures in EEG were significantly higher in the severe group (Coma, 80%; Cr, 0.40 mg/dl, 0.37-0.73; AST, 363 IU/L, 104-662; electrographic seizures, 80%) than the non-severe group (Coma, 0%; Cr, 0.29 mg/dL, 0.19-0.45; AST, 58.5 IU/L, 30-386; electrographic seizures, 0%). CONCLUSIONS: Coma 12-24 h after onset, elevation of Cr levels within 2 h after onset, elevation of AST levels within 24 h after onset, and non-convulsive status epileptics (NCSE) in comatose patients were early predictors of severe AED. Patients in a coma after a febrile seizure should be checked for NCSE signs in EEG to terminate NCSE without delay. PMID- 29716833 TI - Understanding Customers: The Jobs to Be Done Theory Applied in the Context of a Rural Food Pantry. AB - BACKGROUND: Food insecurity, and particularly rural food insecurity, has unique challenges associated with it. Understanding the customer or patron needs is increasingly important in resolving this national concern. The Jobs to Be Done Theory posits that when considering customers, it is beneficial to move past demographic profiling and focus on what the customer wants to accomplish by using a particular product or service. OBJECTIVE: This qualitative study aimed to determine customers' jobs to be done at a rural food pantry. In addition, it seeks to demonstrate the application of contemporary management theory to dietetics practice. DESIGN: A case study approach was used in this study. Case study data collection procedures included six male and six female food pantry patrons in Montana completing in-depth, audio-recorded interviews and surveys. Each person's interview and survey were constructed into individual case descriptions; the case descriptions were analyzed using uniform categories determined by researchers. To identify themes in the holistic case, word tables were created for each uniform category and assessed for key themes representing patrons' experiences. RESULTS: The key themes that emerged were the customer in context, customers' food relief needs, connecting with customers, and barriers to utilization. CONCLUSIONS: The application of Jobs to Be Done Theory to rural food pantry customers demonstrates that demographic segmentation does not capture the social, emotional, and functional dimensions for this sample. Investigation of customer experiences, circumstances, and obstacles is important for improving dietetics services. PMID- 29716834 TI - Primary Lung Adenocarcinoma With 68Gallium Prostate-Specific Membrane Antigen PET/CT Scan Avidity in a Patient on Surveillance After Prostatectomy. PMID- 29716835 TI - Enzyme replacement therapy with velmanase alfa (human recombinant alpha mannosidase): Novel global treatment response model and outcomes in patients with alpha-mannosidosis. AB - Alpha-mannosidosis is an ultra-rare monogenic disorder resulting from a deficiency in the lysosomal enzyme alpha-mannosidase, with a prevalence estimated to be as low as 1:1,000,000 live births. The resulting accumulation of mannose rich oligosaccharides in all tissues leads to a very heterogeneous disorder with a continuum of clinical manifestations with no distinctive phenotypes. Long-term enzyme replacement therapy (ERT) with velmanase alfa is approved in Europe for the treatment of non-neurological manifestations in patients with mild to moderate alpha-mannosidosis. The clinical heterogeneity and rarity of the disease limit the sensitivity of single parameters to detect clinically relevant treatment effects. Thus, we propose a novel multiple variable responder analysis to evaluate the efficacy of ERT for alpha-mannosidosis and present efficacy analyses for velmanase alfa using this method. Global treatment response to velmanase alfa (defined by response to >=2 domains comprising pharmacodynamic, functional, and quality of life outcomes) was applied post hoc to data from the pivotal placebo-controlled rhLAMAN-05 study and to the longer-term integrated data from all patients in the clinical development program (rhLAMAN-10). After 12 months of treatment, a global treatment response was achieved by 87% of patients receiving velmanase alfa (n = 15) compared with 30% of patients receiving placebo (n = 10). Longer-term data from all patients in the clinical program (n = 33) showed 88% of patients were global responders, including all (100%) pediatric patients (n = 19) and the majority (71%) of adult patients (n = 14). The responder analysis model demonstrates a clinically meaningful treatment effect with velmanase alfa and supports the early initiation and continued benefit of longer-term treatment of all patients with alpha-mannosidosis with this ERT. PMID- 29716836 TI - Cardiovascular and respiratory effects of two doses of fentanyl in the presence or absence of bradycardia in isoflurane-anesthetized dogs. AB - OBJECTIVE: To compare the cardiopulmonary effects of low and high doses of fentanyl before and after the correction of bradycardia in isoflurane anesthetized dogs. STUDY DESIGN: Prospective, randomized crossover trial. ANIMALS: Eight healthy male Beagle dogs weighing 11.1 +/- 1.3 kg [mean +/- standard deviation (SD)] and aged approximately 1 year. METHODS: The dogs were anesthetized with isoflurane [1.3 * minimum alveolar concentration (MAC)] on two occasions and fentanyl was administered intravenously; either low-dose fentanyl, loading dose (33 MUg kg-1) and infusion (0.2 MUg kg-1 minute-1) or a high-dose, loading dose (102 MUg kg-1) and infusion (0.8 MUg kg-1 minute-1). Cardiopulmonary variables were measured at three time points in equipotent isoflurane concentrations (1.3 MAC): before fentanyl administration (ISO), during fentanyl induced bradycardia (ISO-F) and after administration of glycopyrrolate normalized heart rate (ISO-FNHR). Data are mean +/- SD. RESULTS: Heart rate and cardiac index (CI) decreased and systemic vascular resistance index (SVRI) increased at ISO-F in both treatments. Bradycardia and vasoconstriction at ISO-F were greater in high than in low-dose fentanyl (42 +/- 7 versus 57 +/- 15 beats minute-1 and 3457 +/- 1108 versus 2528 +/- 968 dyne second cm-5 m-2), respectively. Oxygen delivery index (DO2I) decreased only during high-dose fentanyl. CI and DO2I were higher in both treatments at ISO-FNHR than at ISO-F; however, they were higher only during the high-dose fentanyl than at ISO. SVRI was higher at ISO-F than at ISO and ISO-FNHR in both treatments, and was higher at ISO-F in the high than in the low-dose treatment. CONCLUSIONS AND CLINICAL RELEVANCE: An overall improvement in cardiovascular function of dogs anesthetized with equipotent isoflurane doses (1.3 MAC) was observed after the treatment of bradycardia only with the high-dose fentanyl. PMID- 29716837 TI - Comparison of the postoperative analgesic effects of cimicoxib, buprenorphine and their combination in healthy dogs undergoing ovariohysterectomy. AB - OBJECTIVE: To determine the noninferior postoperative analgesic efficacy of cimicoxib compared to buprenorphine following elective ovariohysterectomy in healthy bitches. STUDY DESIGN: Prospective, randomized, blinded, controlled clinical trial. ANIMALS: A total of 63 healthy dogs. METHODS: To provide perioperative analgesia, cimicoxib 2 mg kg-1 (orally), buprenorphine 0.02 mg kg-1 (two doses, intramuscularly), or both drugs combined, were administered. Dogs were sedated with acepromazine and anaesthetized with propofol and isoflurane. Pain was assessed with the short form of the Glasgow Composite Pain Scale (GCPS), a pain numerical rating scale (NRS) and mechanical nociceptive thresholds (MNT), preoperatively and at 1, 2, 4, 6, 20 and 23 hours after extubation. Sedation was also scored at the same time points. A noninferiority approach was employed to determine the efficacy of cimicoxib compared to buprenorphine. Treatment groups were compared with parametric [analysis of variance (anova), t test] and nonparametric test as appropriate (Kruskal-Wallis, chi-square). RESULTS: The GCPS, pain NRS and MNT tests demonstrated noninferiority of cimicoxib compared to buprenorphine (rejection of inferiority: p < 0.001, all). Furthermore, cimicoxib provided better analgesia compared to buprenorphine alone according to the GCPS (p < 0.01) and NRS (p < 0.05), but not the MNT. Conversely, an increase in the analgesic effect when cimicoxib was combined with buprenorphine was only observed with the MNT (p < 0.01). There were no differences in rescue analgesia requirements both intra- and postoperatively between treatments. Gastrointestinal side effects were increased in dogs administered cimicoxib, whereas dogs treated with buprenorphine had higher sedation scores 1-hour postoperatively and required lower doses of propofol for the induction of anaesthesia. CONCLUSIONS AND CLINICAL RELEVANCE: Cimicoxib has noninferior postoperative analgesic efficacy compared to buprenorphine, and both drugs have comparable analgesic effects for the control of postoperative pain in bitches undergoing ovariohysterectomy. PMID- 29716838 TI - Low probability of a dilution effect for Lyme borreliosis in Belgian forests. AB - An increasing number of studies have investigated the consequences of biodiversity loss for the occurrence of vector-borne diseases such as Lyme borreliosis, the most common tick-borne disease in the northern hemisphere. As host species differ in their ability to transmit the Lyme borreliosis bacteria Borrelia burgdorferi s.l. to ticks, increased host diversity can decrease disease prevalence by increasing the proportion of dilution hosts, host species that transmit pathogens less efficiently. Previous research shows that Lyme borreliosis risk differs between forest types and suggests that a higher diversity of host species might dilute the contribution of small rodents to infect ticks with B. afzelii, a common Borrelia genospecies. However, empirical evidence for a dilution effect in Europe is largely lacking. We tested the dilution effect hypothesis in 19 Belgian forest stands of different forest types along a diversity gradient. We used empirical data and a Bayesian belief network to investigate the impact of the proportion of dilution hosts on the density of ticks infected with B. afzelii, and identified the key drivers determining the density of infected ticks, which is a measure of human infection risk. Densities of ticks and B. afzelii infection prevalence differed between forest types, but the model indicated that the density of infected ticks is hardly affected by dilution. The most important variables explaining variability in disease risk were related to the density of ticks. Combining empirical data with a model-based approach supported decision making to reduce tick-borne disease risk. We found a low probability of a dilution effect for Lyme borreliosis in a north-western European context. We emphasize that under these circumstances, Lyme borreliosis prevention should rather aim at reducing tick-human contact rate instead of attempting to increase the proportion of dilution hosts. PMID- 29716839 TI - Surgical treatment and functional outcomes of multicomponent soft tissue injuries of the wrist. AB - The aim of this study was to emphasize the importance of early surgical treatment of multicomponent soft tissue injuries of the wrist. A retrospective review was performed on 156 patients with multicomponent soft tissue injuries of the wrist who were treated between July 2007 and July 2015. All the patients included in the study were operated within the first 36hours of the injury and were hospitalized after the surgery based on the extent of their injury. The patients were evaluated in terms of age, gender, etiology, injured structures, total number of damaged structures, mean follow-up time, complications and reoperation. The results were evaluated based on tendon function, opposition, intrinsic muscles, deformities and sensation. According to these criteria, excellent results were obtained in 81.6% to 88.8% of the patients. Poor results were found in less than 4 percent of the patients. In conclusion, we believe that early surgical management of multicomponent soft tissue injuries of the wrist, a meticulous approach and regular physical therapy are required to achieve good functional outcomes. PMID- 29716840 TI - Terrorist attack in Nice - The experience of general surgeons. AB - INTRODUCTION: After the attacks in Paris, France was again struck by terrorism in the city of Nice during the night of July 14, 2016. At 22:33 in the evening, a 19 ton truck drove into the crowd of holiday celebrators. The attack resulted in 458 wounded and 86 deaths. The purpose of this study was to describe the management of patients with abdominal trauma admitted alive in our institution, in the context of a massive influx of victims. MATERIAL AND METHODS: We performed a retrospective analysis of the management of adults with abdominal trauma arising from the terrorist attack in Nice. RESULTS: Among the 182 victims admitted to our trauma center, eleven patients presented with abdominal trauma. The median age was 44 years [14-63] and the median Injury Severity Score (ISS) was 34 [9-59]. Eight patients underwent urgent surgical treatment in the operating room including six for abdominal trauma. These patients were treated according to the principles of surgical damage control, albeit without the need for temporary abdominal closure or packing. Three patients could have had their lesions managed non-operatively had they been admitted outside this surge episode, which saturated the technical means of the receiving hospital. CONCLUSION: The terrorist attack that victimized the citizens of Nice resulted in the second largest number of dead of any attack on French soil. A large number of patients were admitted to the city's only center for adult trauma care. The management of these patients posed diagnostic, therapeutic and logistical problems. Increased use of pre-hospital pelvic restraint belts may help to reduce vehicular trauma. We do not feel that non-operative management of abdominal lesions can be envisaged in the context of a mass influx of victims. We recommend surgical hemostasis for patients with secondary hemorrhagic risk from visceral trauma in the context of a massive influx of victims. PMID- 29716841 TI - [Response to pregnancy in adolescents in the last 11 years. Reasons for consulting and risk factors]. PMID- 29716842 TI - The Ideal Lipid Report: A Need for Consensus. PMID- 29716843 TI - Short trains of transcutaneous auricular vagus nerve stimulation (taVNS) have parameter-specific effects on heart rate. AB - BACKGROUND: Optimal parameters of transcutaneous auricular vagus nerve stimulation (taVNS) are still undetermined. Given the vagus nerve's role in regulating heart rate (HR), it is important to determine safety and HR effects of various taVNS parameters. OBJECTIVE: We conducted two sequential trials to systematically test the effects of various taVNS parameters on HR. METHODS: 15 healthy individuals participated in the initial two-visit, crossover exploratory trial, receiving either tragus (active) or earlobe (control) stimulation each visit. Nine stimulation blocks of varying parameters (pulse width: 100 MUs, 200 MUs, 500 MUs; frequency: 1 Hz, 10 Hz, 25 Hz) were administered each visit. HR was recorded and analyzed for stimulation-induced changes. Using similar methods and the two best parameters from trial 1 (500MUs 10 Hz and 500MUs 25 Hz), 20 healthy individuals then participated in a follow-up confirmatory study. RESULTS: Trial 1 There was no overall effect of the nine conditions on HR during stimulation. However multivariate analysis revealed two parameters that significantly decreased HR during active stimulation compared to control (500MUs 10 Hz and 500MUs 25 Hz; p < 0.01). Additionally, active taVNS significantly attenuated overall sympathetic HR rebound (post-stimulation) compared to control (p < 0.001). Trial 2-For these two conditions, active taVNS significantly decreased HR compared to control (p = 0.02), with the strongest effects at 500MUs 10 Hz (p = 0.032). CONCLUSION: These studies suggest that 60s blocks of tragus stimulation are safe, and some specific parameters modulate HR. Of the nine parameters studied, 500MUs 10 Hz induced the greatest HR effects. PMID- 29716844 TI - Genetic assessment of Staphylococcus aureus in an underreported locality: Ambulatory care clinic. AB - BACKGROUND: Staphylococcus aureus has strong association with anthropogenic environments. This association has not been well supported by use of genetic tools. The aim of this study was to phylogenetically relate numerous isolates from three environments - NCBI samples from hospitals, a community, and a previously unexplored healthcare environment: an ambulatory care clinic (ACC). METHODS: This study incorporated hospital samples from NCBI, a community database from the University of Central Florida (UCF), and newly added samples taken from employees of an ambulatory care clinic located at UCF. Samples were collected from nasal swabs of employees, and positive samples were cultured, extracted, and sequenced at seven MLST loci and one virulence locus (spa). MLST sequences were used in eBURST and TCS population structure analyses and all sequences were incorporated into a phylogenetic reconstruction of relationships. RESULTS: A total of 185 samples were incorporated in this study (15 NCBI sequences from hospital infections, 29 from the ACC, and 141 from the community). In both phylogenetic and population genetics analyses, samples proved to be panmixic, with samples not segregating monophyletically based on sample origin. CONCLUSION: Samples isolated from ambulatory care clinics are not significantly differentiated from either community or hospital samples at the representative loci chosen. These results strengthen previous conclusions that S. aureus may exhibit high genetic similarity across anthropogenic environments. PMID- 29716845 TI - Push versus pull gastrostomy in cancer patients: A single center retrospective analysis of complications and technical success rates. AB - PURPOSE: To compare the technical success and complication rates of push versus pull gastrostomy tubes in cancer patients, and to examine their dependence on operator experience. MATERIALS AND METHODS: A retrospective review was performed of 304 cancer patients (170 men, 134 women; mean age 60.3+/-12.6 [SD], range: 19 102 years) referred for primary gastrostomy tube placement, 88 (29%) of whom had a previously unsuccessful attempt at percutaneous endoscopic gastrostomy (PEG) placement. Analyzed variables included method of insertion (push versus pull), indication for gastrostomy, technical success, operator experience, and procedure related complications within 30 days of placement. RESULTS: Gastrostomy tubes were placed for feeding in 189 patients and palliative decompression in 115 patients. Technical success was 91%: 78% after endoscopy had previously been unsuccessful and 97% when excluding failures associated with prior endoscopy. In the first 30 days, there were 29 minor complications (17.2%) associated with push gastrostomies, and only 8 minor complications (7.5%) with pull gastrostomies (P<0.05). There was no significant difference in major complications (push gastrostomy 5.3%, pull gastrostomy 5.6%). For decompressive gastrostomy tubes, the pull technique resulted in lower rates of both minor and major complications. There was no difference in complications or technical success rates for more versus less experienced operators. CONCLUSION: Pull gastrostomy tube placement had a lower rate of complications than push gastrostomy tube placement, especially when the indication was decompression. The technical success rate was high, even after a failed attempt at endoscopic placement. Both the rates of success and complications were independent of operator experience. PMID- 29716846 TI - Transcatheter embolization for the management of traumatic coronary venous injury. PMID- 29716848 TI - Worsening of the Cardiovascular Profile in a Developing Country: The Greater Beirut Area Cardiovascular Cohort. AB - BACKGROUND: Lebanon has no established governmental noncommunicable diseases surveillance and monitoring system to permit reporting on noncommunicable diseases rates. The last World Health Organization-supported surveillance report showed worrying trends in cardiovascular disease (CVD) risk factors. OBJECTIVES: A cardiovascular cohort was established to permit CVD outcomes studies in an urban sample in the Lebanese capital and the study in hand presents the baseline CVD risk factors of this cohort. METHODS: A cross-sectional study was carried out including 501 Lebanese adults (64.3% women) from the Greater Beirut area using random multistage probability sampling. Interviews, physical exams, and blood withdrawal were conducted to collect information on demographic and lifestyle factors, body mass index, blood pressure, fasting blood glucose, blood lipids, as well as history of coronary artery diseases, hypertension, diabetes mellitus type 2, dyslipidemia, and stroke. Means with SD for continuous variables and frequencies and percentages for categorical variables are reported. RESULTS: The prevalence CVD risk factors including obesity, smoking, diabetes mellitus type 2, hypertension, and dyslipidemia prevalence in the Greater Beirut area was higher than that reported for the general population. Important sex and age differences were also observed, whereby older participants and women had higher rates of obesity, diabetes mellitus type 2, and dyslipidemia and younger participants and men were engaged more in cigarette smoking and alcohol consumption. Interestingly, water pipe smoking was similarly prevalent among genders. CONCLUSIONS: The overall prevalence of CVD risk factors in this urban population is higher than reported in the 2010 World Health Organization Stepwise Approach to Surveillance report on the Lebanese population, indicating that the urban population in the capital carries a higher burden of CVD risk. In addition, sex and age difference rates of CVD risk factors highlight the need for tailored public health measures to tackle the sex- and age-based CVD risk factors. PMID- 29716849 TI - Enhanced UV protection of ketoconazole using Hyptis suaveolens micro emulsion. AB - Ketoconazole is photolabile antifungal drug. Photochemical reactions may decrease its therapeutic effect or induce toxic compounds. The aim of this study was to prepare ketoconazole loaded microemulsion containing H. suaveolens oil with antifungal and antioxidant powers in order to obtain effective antifungal formulation. The release study, antifungal activity and photostability test, were then evaluated. The results showed that optimized Hyptis suaveolens microemulsion for ketoconazole loading was selected through construction of pseudo-ternary phase diagrams. It consisted of 12.5% H. suaveolens oil, 12.5% capryol, 25% tween 80, 25% ethanol and 25% water. Mean globule size was 153 nm, as analyzed by photon correlation spectroscopy. Ketoconazole-loaded Hyptis suaveolens microemulsion and Hyptis suaveolens microemulsion had antifungal activity against Candida albican, Microsporum gypseum and Trichophyton mentagrophyte, showing inhibition zone ranged from 28-37 mm and 23-32 mm, respectively. Ketoconazole was released from Hyptis suaveolens microemulsion more than 90% within 5 days. In the results of photostability test, ketoconazole-loaded Hyptis suaveolens microemulsion gave significantly higher remaining ketoconazole than ketoconazole solution. This study demonstrated that Hyptis suaveolens microemulsion could be used to improve the photoprotection of photolabile drug. PMID- 29716847 TI - Implementation Research to Address the United States Health Disadvantage: Report of a National Heart, Lung, and Blood Institute Workshop. AB - Four decades ago, U.S. life expectancy was within the same range as other high income peer countries. However, during the past decades, the United States has fared worse in many key health domains resulting in shorter life expectancy and poorer health-a health disadvantage. The National Heart, Lung, and Blood Institute convened a panel of national and international health experts and stakeholders for a Think Tank meeting to explore the U.S. health disadvantage and to seek specific recommendations for implementation research opportunities for heart, lung, blood, and sleep disorders. Recommendations for National Heart, Lung, and Blood Institute consideration were made in several areas including understanding the drivers of the disadvantage, identifying potential solutions, creating strategic partnerships with common goals, and finally enhancing and fostering a research workforce for implementation research. Key recommendations included exploring why the United States is doing better for health indicators in a few areas compared with peer countries; targeting populations across the entire socioeconomic spectrum with interventions at all levels in order to prevent missing a substantial proportion of the disadvantage; assuring partnership have high-level goals that can create systemic change through collective impact; and finally, increasing opportunities for implementation research training to meet the current needs. Connecting with the research community at large and building on ongoing research efforts will be an important strategy. Broad partnerships and collaboration across the social, political, economic, and private sectors and all civil society will be critical-not only for implementation research but also for implementing the findings to have the desired population impact. Developing the relevant knowledge to tackle the U.S. health disadvantage is the necessary first step to improve U.S. health outcomes. PMID- 29716850 TI - Methylphenidate-induced hepatotoxicity in rats and its reduction by buspirone. AB - Methylphenidate is commonly use for the treatment of attention deficit hyperactivity disorder (ADHD), but its long term use was found to produce hepatic necrosis in mice. Purpose of this study was to investigate that co-administration of buspirone (drug which attenuates methylphenidate induced sensitization) may attenuate methylphenidate-induced hepatotoxic effects and to determine the effect of challenge dose of haloperidol (D2 antagonist that blocks the effects of methylphenidate in case of intoxication) on SGPT and SGOT levels in methylphenidate treated rats. Estimation of SGPT and SGOT were performed using kit method. Prolong oral administration of methylphenidate at a dose of 2.0 mg/kg/day, buspirone at a dose of 10 mg/kg/day, their co-administration and challenge dose of haloperidol (1 mg/kg i.p.) in rats increased SGPT concentration and decreased SGOT concentration, effect is more pronounced in methylphenidate treated rats and potentiate with administration of haloperidol challenge dose. In conclusion our analysis showed that methylphenidate and challenge dose of haloperidol is associated with elevation of SGPT in rats, which is attenuate in co-administration of methylphenidate buspirone treated rats. To quantify the risk of methylphenidate-induced hepatic injury and role of buspirone to reduce the injury further pharmacoepidemiological investigations are required. PMID- 29716851 TI - Effect of pioglitazone on vasopressor responses to adrenergic agonists and angiotensin II in diabetic and non-diabetic spontaneously hypertensive rats. AB - Pioglitazone, peroxisome proliferator-activated receptor (PPAR-gamma) agonist, is a therapeutic drug for diabetes. Present study investigated the interaction between PPAR-gamma and alpha adrenoceptors in modulating vasopressor responses to Angiotensin II (Ang II) and adrenergic agonists, in diabetic & non-diabetic Spontaneously Hypertensive Rats (SHRs). Diabetes was induced with an i.p injection of streptozotocin (40 mg/kg) in two groups (STZ-CON, STZ-PIO), whereas two groups remained non diabetic (ND-CO, ND-PIO). One diabetic and non-diabetic group received Pioglitazone (10mg/kg) orally for 21 days. On day 28, the animals were anaesthetized with sodium pentobarbitone (60mg/kg) and prepared for measurement of systemic haemodynamics. Basal mean arterial pressure of STZ-CON was higher than ND-CON, whereas following pioglitazone treatment, MAP was lower compared to respective controls. MAP responses to i.v administration of NA, PE, ME and ANG II were significantly lower in diabetic SHRs: STZ-CON vs ND-CON (35%). Pioglitazone significantly decreased responses to NA, PE, ME and ANG II in ND-PIO versus ND-CON by 63%. Responses to NA and ANG II were significantly attenuated in STZ-PIO vs. ND-PIO (40%). PPAR-gamma regulates systemic hemodynamic in diabetic model and cross-talk relationship exists between PPAR-gamma and alpha1 adrenoceptors, ANG II in systemic vasculature of SHRs. PMID- 29716852 TI - Immunomodulatory activity and chemical characterization of fixed oils obtained from different parts of Oxytropis glabra DC. AB - Oxytropis glabra DC. is a plant with enormous therapeutic vitality. In the present study a comparison of lipophilic profiling of different parts of O. glabra has been carried out by using gas chromatography-mass spectrometry. A total of 32 compounds have been identified from this plant, amongst which 31 have been identified for the first time. These compounds have been further confirmed from their Van den Dool and Kratz (I) Indices. Out of these 32 compounds, 18 have been identified from flower (80.94%), 15 from fruit (85.36%), 11 from leaves (66.35%) and 11 from root (45.96%). The major class of metabolite identified from different parts is fatty acid. Hydrocarbons have also been detected in flower and fruit but not in root and leaves. The extracts were screened for their immunomodulatory activity on whole blood cells. The root oil was found to be moderately active (IC50 32.3 MUg/mL). At present only limited data is available on the phytochemical composition of O. glabra. PMID- 29716853 TI - Fermentation of Aristolochia debilis by six different medicinal fungi and identification of aristolochic acid derivates in their products by HPLC-ESI-TOF MS. AB - To analyze the content change of the nephrotoxic substances, aristolochic acid derivates (AAs) in the roots of Aristolochia debilis and the products generated from the solid-state fermentation of six different medicinal fungi by HPLC-ESI TOF-MS, the chromatographic separation was carried out on C18 column at 30 degrees C with the DAD detector. The elution was performed using the mobile phase of acetonitrile (A) and 0.2% acetic acid (B). Several new peaks were found in the scale of 0-20 min elution of HPLC diagram in the fermentation products. The ESI MS detection (negative ion mode) was carried out by post-column flow splitting method following the automatic injection. Seven AAs in the fermentation products and A. debilis were deduced, which were recognized as AAIa or IIIa (1), AAVIa (2), AAIVa, Va, VIIa or VIIIa (3); AAII (4); AAIII (5); AAI (6); AAIV or VII (7). The areas of almost all these seven components existing originally in the corresponding crude drug decreased after the fermentation process, suggesting that fermentation is an effective way of lowering the nephrotoxicity induced by AAs in Chinese medicines similar with A. debilis. In addition, Optimized HPLC-MS method is helpful to AAs content identification. PMID- 29716854 TI - A study of the interaction between H. pylori mice passage strains and gastric epithelial cells. AB - Helicobacter pylori (H. pylori) infections are very serious health problem that are further worsened by increasing/developing resistance to the current antibiotics. Therefore, new therapeutic agents are needed for H. pylori eradication. Use of a CD46 derived peptide (P3) as bactericidal agent against H. pylori has shown high activity rate in vivo and this study examines the changes in H. pylori features in response to effect of P3 treatment.AGS cells were infected with H. pylori wild type strain 67:21 and its mice passage strains (P3 treated and untreated strains) and further examined using immunoblotting assay, FACS and Urease activity analysis. Comparatively we found increased level of Urease alpha subunit A (UreA) and alkyl hydroperoxide reductase C (AhpC) proteins for P3 treated strain of H. pylori than its wild type or untreated strain after infection of AGS cells. Conclusion These results suggest that there might be a high rate of adherence to host cells for the P3 treated passage strain than untreated or wild type strain. Our findings also indicate that either adhesins are being changed or H. pylori interaction to the host cells is affected after P3 treatment. PMID- 29716855 TI - Effect of black seed oil supplementation on selected immunological, hematological and Iron status parameters in ribavirin treated female albino rats. AB - Ribavirin has been found to enhance the anti HCV potential of pegylated interferon and sovaldi. However its use was associated with impact on the hemopoietic system and iron status. The hemopoietic toxicity, sometimes forced patients to reduce the dosage or to discontinue treatment in rare occasions. The main purpose of the present study was to assess the potential of black seed oil, a known potent antioxidant, to ameliorate the negative impact of ribavirin on hematological indices, iron status and natural immunity in rats. Twenty four female albino rats were equally divided into four groups as follows: Group1, served as negative control and received an oral dose of (0.5 ml) saline. Group 2, served as positive control and were given 30 mg/kg/day doses of Ribavirin for / 5 days/ week for 4 weeks. Group 3, which were orally fed a 1ml/kg/ of black seed oil for 5 day/week for 4 weeks. Group 4, which were orally given the above mentioned doses of black seed oil plus ribavirin / 5 days/ week for 4 weeks. The results demonstrated that treatment with ribavirin induced significant decrease in absolute neutrophils count, RBCs count, haemoglobin concentrations (Hb), Packed Cell Volume percentage (PCV%) and liver total iron binding capacity (TIBC). On the other hand, it induced significant increases in serum and liver iron, liver ferritin, transferring saturation % compared to control group. Black seed oil treatment increase absolute neutrophil count and restored RBCs count, Hb concentration and PCV percentage to normal control level. It also significantly reduced serum iron and liver total iron in animals treated ribavirin. Black seed oil supplementation also enhanced serum IgM and IgG concentrations in ribavirin treated rats. In conclusion, black seed oil had the potential to ameliorate the negative effect of ribavirin on the hemopoietic system offering better chances for completion of HCV treatment course with full dose. It also has proven to have the ability to reduce serum and liver iron load and enhance natural IgM and IgG levels. PMID- 29716856 TI - Effect of Punica granatum, Citrus limon and their combinations on the plasma Gonadotropins in female rabbits. AB - Fruits produce revitalizing effects, hence the impact of Punica granatum, Citrus limon and their combinations have been investigated on the plasma levels of gonadotropin, testosterone and sexual development capacity in female rabbits. Ninety female rabbits were randomly assigned into nine groups, each comprising of ten animals. One group was given saline and designated as control. Three groups were given P. granatum 2mL /kg, 5mL/kg, 8mL/kg, other three groups received C. limon 0.2mL/kg, 0.4mL/kg, 0.6mL/kg respectively, remaining groups received C. limon and P. granatum in combination i.e. 0.4mL/kg C. limon + 5mL/kg P. granatum and 0.2mL/kg C. limon + 8mL/kg P. granatum. Juices were administered once daily by mouth from day 0 of pups delivered to postnatal day15. Blood samples were gathered from ear vein at day11 and day15. There was significant increase in follicle stimulating hormone by P. granatum at 5 and 8mL/kg on day 11 and 15, by C. limon at 0.4 and 0.6mL/kg on day11, 0.4mL/kg at day15, by combination doses of C. limon and P. granatum 0.4 +5mL/kg at day 11, 0.4+5 mL/kg and 0.2 + 8mL/kg at day15. There was also significant increase in luteinizing hormone by P. granatum at 2, 5 and 8mL/kg and by C. limon 0.4mL/kg at day11. There was highly significant increase on day 11 in LH at combination doses of C. limon and P. granatum 0.4 + 5mL/kg. There was significant increase in testosterone level by P. granatum at 2, 5 and 8mL/kg on day 11 and 5mL/kg on day15 and highly significant increase at 2 and 8mL/kg. C. limon caused significant increase in testosterone at 0.4 mL/kg on day11, 0.2 and 0.6mL/kg on day 15 and highly significant increase at 0.4mL/kg on day15. Whereas combinations doses of C. limon and P. granatum at 0.4+5mL/kg caused highly significant increase in testosterone level as compare to control. Results of present study revealed increase in plasma gonadotropin and testosterone levels showing increase in sexual capacity of female rabbits which could be mainly accounted for high vitamin C and flavonoids contents of these juices. PMID- 29716857 TI - Development of a rapid resolution HPLC method for the quantitative determination of sitagliptin in Human plasma. AB - A new high performance liquid chromatography (HPLC) method for the quantitative determination of sitagliptin in human plasma was developed and validated for pharmacokinetics study. The plasma was spiked with the internal standard (Salbutamol, IS), extracted with trichloro acetic acid. The extracted analyte was injected into a Symmetry(r) ODS C18 column (250mm*4.5mm, 5m) and the flourometric detector was operated at 267nm for excitation and 575nm for emission. The mobile phase consisting of Potassium dihydrogen phosphate buffer pH (4.9)-Acetonitrile Methanol (30:50:20 v/v) at flow rate of 1.0mL/min. The method showed high specificity. Calibration curves of the peak area ratio of each analyte/IS versus sitagliptin concentration were linear in the range of 0.122-31.25MUg/mL (r>0.989) for plasma and 0.012-25ug/ml for QC solution(r>0.995). The lower limit of quantification (LLOQ) was 0.122MUg/mL in plasma and 0.012 in QC solution. The intraday and interday coefficient of variation was lower than 10%. The accuracy (relative recovery) at three levels was 100.95%, 101.03% and 97.79% respectively. The extraction recovery was 97.6%, 92.2% and 91.96% at the concentrations of 6.25, 25 and 100MUg/mL, respectively. Short term and long term, freeze thaw stability of standard solutions and plasma samples were satisfactory. The optimized HPLC method was validated and proved to be specific, robust and accurate for determination of Sitagliptin in human plasma. PMID- 29716858 TI - Assessment of potential interaction between simvastatin and clarithromycin in healthy adult male subjects. AB - Cardiac patients with weak immune system are susceptible to bacterial infections. Their prescriptions frequently contain simvastatin and clarithromycin together. The objective of present project was to assess the potential interaction between simvastatin and clarithromycin by evaluating the clarithromycin effects on the pharmacokinetics of simvastatin in healthy adult male subjects. The study design comprised of two phases, used at interval of one week. In first phase simvastatin 20 mg alone was administered to each volunteer. In second phase, co administration of simvastatin 20 mg with clarithromycin 250 mg was made under similar specified conditions. Blood samples were collected at specified time intervals. Simvastatin plasma concentrations were analyzed through High Performance Liquid Chromatography with UV detector at 238 nm wavelength. Using one compartment open model, MW/PHARM version 3.02 software program was used by F. Rombut for pharmacokinetic parameters calculation. Clarithromycin co-treatment resulted in 2.3 fold increase in maximum plasma concentration Cmax (from 2.47+/ 0.34 ng.mL-1 to 5.66+/-1.18 ng.mL-1; p<0.05) and 3.9 fold increase in area under time versus concentration curve from 0 to 10 hours AUC0-10 (from 15.10+/-3.73 ng.hr.mL-1 to 58.49+/-15.73 ng.hr.mL-1; p<0.05) of simvastatin. These results suggest that co-prescription of simvastatin and clarithromycin should be avoided to minimize the adverse events resulting from high simvastatin concentration, without sacrificing therapeutic worth of simvastatin. PMID- 29716859 TI - Impact of blood lead level on haemoglobin and intelligence among school children living near lead based industries. AB - Blood lead level and its impact on haemoglobin and intelligence among school children near lead based industries, and to supplement them with a nutritious food for its effect, were studied. Blood was withdrawn from 120 children (9-12 years) and lead was estimated by Lead Care Analyzer Kit and haemoglobin by auto analyser. Culture Fair Non-verbal Test was used to assess the Intelligence Quotient. After pre-test, the experimental group (n = 60) were given nutritional supplementation for 3 months and education on hygiene measures, while the control group (n = 60) did not receive them. Food supplementation and education significantly decreased the lead level in the experimental group (8.8+/-0.5 to 6.9+/-0.4, MUg/dL, mean +/- SE) but not in the control group. The intelligence score improved in the experimental group but not in the control group. A negative correlation was observed between the lead level and intelligence. No improvement was observed in the haemoglobin. This study shows that the blood lead level in children near lead based industries is high and is negatively correlated with intelligence. Supplementation of nutritious food and education on hygiene measures have decreased the lead level and increased the intelligence score. PMID- 29716860 TI - In vivo evaluation of antihyperlipidemic, antihyperglycemic and hepatoprotective effects of Vernonia anthelmintica seeds in diet model. AB - Anti-hyperglycemic, anti-hyperlipidemic and hepatoprotective effects of Vernonia anthelmintica seeds were evaluated in diet rat model. The study included forty eight Sprague Dawley rats of either sex with eight animals in each group. Except for control the disease control, standard and treatment groups were treated with high-fat high-sugar diet for 8 weeks. After confirmation of hyperlipidemia and hyperglycemia, the standard group received atorvastatin (2.1 mg.kg-1), treatment groups received hexane extract, ethanol extract and water decoction of Vernonia anthelmintica seeds (300mg.kg-1) for next 30 days. Disease control and control were given normal saline in volume equivalent to other groups. High-fat high sugar diet was continued in all groups except control for 30 day period. Lipid profile, liver function tests and fasting blood sugar were analyzed in fasting blood samples. Cardiac risk parameters were calculated and results were analyzed by one way ANOVA using SPSS. All three tested extracts showed significant decrease in fasting blood glucose, LDL-C, triglycerides, VLDL-C and cardiac risk parameters as compared to disease control. However, HDL-C and cholesterol levels in treatment groups were found to be significantly increased compared to disease control. Furthermore, treatment groups showed significantly decreased AST and ALP levels compared to disease control. Hexane extract, ethanol extracts and water decoction of Vernonia anthelmintica seeds exhibited potential anti-hyperglycemic, anti-hyperlipidemic effects with favorable hepatic profile. However, further studies should be designed to strengthen these findings on mechanistic ground. PMID- 29716861 TI - Multidrug resistance reversal activity of extract and a rare dimeric naphthoquinone from Diospyros lotus. AB - A dimeric naphthoquinone namely dihydrodyspyrole R (1) was purified once more from Diospyros lotus. Dihydrodyspyrole R and chloroform fractions were evaluated for their effects on the reversion of multidrug resistance (MDR). The compounds (1) and extract exhibited promising MDR reversing effect in a dose-dependent manner against mouse T-lymphoma cell line. Molecular docking of compound 1 revealed the correlation between in-silico with in-vitro results. The molecular docking results showed that compound 1 is bind closely where co-crystal ligand of P-gp is present. But usually, computational investigation predicts that, if a compound gives lesser score then compound will exhibit good activity. Hence, the docking scores of compound 1 are the near to the Rhodamine. It is conclude that there are certain important structural features of compound 1which are responsible for the inhibiting potency of P-gp from mice. The computational Petra/Osiris/Molinspiration (POM) analysis confirms the possibility of use of compound 1 without side effect or less toxicity risks. PMID- 29716862 TI - Synthesis, characterization and SAR of novel Bezimidazole derivatives as Nematicidal agents. AB - Six novel analogues were prepared by reacting benzimidazole molecules (BM and CMB) propiophenone and benzoyl chlorides respectively. The structures of newly synthesized compounds were determined with the help of spectroscopic techniques. The compounds were subjected to in-vitro screening for their activity against nematodes. It was observed that the benzimidazole (BM) derivatives possessed more nematicidal activity as compared to that of cyanomethyl-benzimidazole (CMB) for Meloidogyne incognita. Among them, the propiophenone substituted benzimidazole derivative B3 was found to be the most active compound and can be further studied as lead molecule for development of anthelmintic drugs. PMID- 29716863 TI - Analysis of the main constituents of Changshu tablet and its spasmolysis effect against contraction induced by acetylcholine in the rat-isolated intestinal smooth muscle. AB - The Changshu tablet (CST), one kind of Chinese patent medicine with astringent to the intestine and relieving diarrhea, was made by the root of Rose odorata Sweet var. gigantean (Coll.et Hemsl.) Rehd.et Wils. Although CST has a long history of clinical application, but the research of its chemical composition is less. So the objective of this study was to investigate the main constituents and preliminarily research its effect of the contraction of isolated intestine in vitro. The contents of total polyphenols (126.23mg/g) and total triterpenoids (132.75mg/g) in CST were determined by ultraviolet spectrophotometry. Procyanidin B3, epigallo catechin, catechin, epicatechin, (-)-fisetinidol-(4alpha, 8)-(-) catechin, (4alpha, 8)-(-)-fisetinidol-(-)-epicatechins and (+)-guibourtinidol (4beta, 8)-epicatechin were identified and determined by high performance liquid chromatography and their contents were distributed from 0.04mg/g to 1.46 mg/g. CST showed significant inhibitory effect against acetylcholine-induced contraction on the rat-isolated intestinal smooth muscle with a dose-dependent manner from 0.06 to 0.6mg/mL. The maxim inhibition rates of CST on duodenum, jejunum, ileum and colon were 65.70+/-3.47%, 79.74+/-1.27%, 58.90+/-1.87% and 45.75+/-2.21% respectively. These results indicated that CST has a spasmolytic role in gastrointestinal motility which was probably mediated through inhibition of muscarinic receptors. All these findings promote the improvement of the quality control standard of CST and provide pharmacological foundation for clinical application of CST in gastrointestinal tract. PMID- 29716864 TI - Phytochemical analysis, phytotoxic and insecticidal activities of medicinally important Periploca hydaspidis. AB - The present study investigates the phyto-chemical analysis, phytotoxic activity and insecticidal activity of the stem and root tissues of medicinally important Periploca hydaspidis. All the extracted samples exhibited the phytotoxic activity. The data confirmed that water was the best solvent to extract the phytotoxic compounds from stem and root tissues. Roots extracted with different solvents exhibited better phytotoxic potential than samples obtained from the stem tissues. Samples extracted in methanol and water from both stems and roots tissues were active against the subject insects while hexane, ethyl acetate and butanol extracted samples in both parts exhibited no insecticidal activity. Water extracted samples of the stem and root exhibited better insecticidal activity compared with methanol extracted samples. Tribolium castaneum and Rhizopertha dominica were more sensitive in both the cases than Callosobruchus maculates. The plant contained alkaloids, flavonoids, carbohydrate, proteins and saponins. PMID- 29716865 TI - The increasing of catalase activity in dimethylbenz-alpha-anthracene (DMBA) induced rat treated by Hibiscus sabdariffa L extract. AB - The objective of the present study was to characterize the activity and expression of catalase enzymes in Hibiscus sabdariffa L (rosella) extract treated rat induced by dimethylbenz-alpha-anthracene (DMBA) and to evaluate the relationship between the catalase activity and histopathological characteristics of liver organ. The 25 animals were divided randomly into 5 groups: the normal group, the negative control group, and treated groups, which treated by rosella extract with variation of dose of 10, 50 and 100mg/kgBW/day for 35 days. On day36 the animals were given with DMBA in dose of 75 mg/kgBW single dose. After one week, the animals were sacrificed and the catalase activity was measured from liver homogenate by the decomposition of H2O2 and followed directly by the decrease in absorbance at 240 nm. The expression of catalase gene was observed using RT-PCR. The results showed that treatment of rosella extract increases the activity of catalase, significantly (P<0.05). The increasing of catalase activity was found in dose dependent manner. The catalase gene expression was also found to increase in rosella extract treated groups. The histopathological observation of liver organ was found normal. Rosella extract increase the catalase activity and expression of catalase antioxidant gene. It was concluded that rosella extract increase activity and gene expression of catalase in vivo. PMID- 29716866 TI - Synthesis of some new 2-[4-(2-furoyl)-1-piperazinyl]-N-aryl/aralkyl acetamides as potent antibacterial agents. AB - In this work, a new series of 2-[4-(2-furoyl)-1-piperazinyl]-N-aryl/aralkyl acetamides has been synthesized and evaluated for their antibacterial potential. The synthesis was initiated by the reaction of different aryl/aralkyl amines (1a u) with 2-bromoacetylbromide (2) to obtain N-aryl/aralkyl-2-bromoacetamides (3a u). Equimolar quantities of different N-aryl/aralkyl-2-bromoacetamides (3a-u) and 2-furoyl-1-piperazine (4) was allowed to react in acetonitrile and in the presence of K2CO3, to form 2-[4-(2-furoyl)-1-piperazinyl]-N-aryl/aralkyl acetamides (5a-u). The structural elucidation was done by EI-MS, IR and 1H-NMR techniques of all the synthesized compounds. All of the synthesized molecules were active against various Gram positive and Gram negative bacterial strains. Among them 5o and 5c showed very excellent MIC values. The cytotoxicity of the molecules was also checked to find their utility as possible therapeutic agents, where 5c (0.51%) and 5g (1.32%) are found to be least toxic in the series. PMID- 29716867 TI - Quantitative determination of mogroside V in rat plasma by LC-MS/MS and its application to a pharmacokinetic study. AB - Mogroside V is the most abundant (approximately 0.50%) cucurbitane-type triterpene glycoside in Siraitia grosvenorii and exhibits significant antitussive, expectorant, anti-carcinogenic, and anti-inflammatory effects. A sensitive, robust and selective liquid chromatography tandem with mass spectrometry (LC-MS/MS) was developed and validated for the determination and pharmacokinetic investigation of mogroside V in rat plasma. Samples were prepared through an one-step deproteinization procedure with 250 uL of methanol to a 75-uL plasma sample. Plasma samples were effectively separated on a Shiseido Capcell Pak UG120 C18 column (2.0 * 50mm, 3.0um) using a mobile phase consisting of methanol: water (60:40, v/v) with an isocratic elution program. The running time for each sample was 7.0 min and the elution times of mogroside V and IS were 2.0 and 4.8 min, respectively. The detection relied on a triple-quadrupole tandem with mass spectrometer equipped with negative-ion electrospray ionization interface by selected-reaction monitoring (SRM) of the transitions at m/z 1285.6 > 1123.7 for mogroside V and m/z 1089.6 -> 649.6 for IS. The calibration curve was linear over the range of 96.0-96000ng/mL with a limit of quantitation (LOQ) of 96.0ng/mL. Intra-day and inter-day precisions were both <10.1%. Mean recovery and matrix effect of mogroside V in plasma were in the range of 91.3-95.7% and 98.2-105.0%, respectively. This method was successfully applied in the pharmacokinetic study of mogroside V after intravenous or intraperitoneal administration of 1.12mg/kg mogroside V in rats. PMID- 29716868 TI - Phycochemical and pharmacological studies on Ulva fasciata Delile. AB - Phycochemical and pharmacological studies were carried out on Ulva fasciata Delile. The ash content was found as 20.4812 % dry weight, moisture content 14.5514 %, total fat content as 0.1878% and 0.49341 %. Total carbohydrate was found as 54.5301-54.2246% dry weight, phenolic content as 0.022%, flavonoids found to be 0.0313% and tannins were 0.00003 %. Ulva fasicata showed central analgesic activity and significant anti-inflammatory activity at the dose of 400 mg/kg bw. PMID- 29716869 TI - Delivery of risperidone from gels across porcine skin in vitro and in vivo in rabbits. AB - The purpose of this study was to develop and evaluate a transdermal delivery system for RIS using hydrogels. First, the effects of different concentrations of hydroxypropyl methylcellulose and Carbomer 934 (CBR) on RIS permeation were investigated in porcine skin. The optimized formulation was chosen as the base gel to screen for penetration enhancers. The pharmacokinetics of the optimized RIS formulation was then studied in vitro in rabbits. A formulation with 0.5% CBR showed the highest RIS permeation and was selected as the base gel. RIS permeation was further increased by incorporation of Azone, lauryl alcohol, or menthol, and the enhancing effects of the three were dose-dependent. When each enhancer combined with propylene glycol (PG) a synergistic effect was found. A combination of 6% menthol and 6% PG exhibited highest RIS in vitro penetration rate and showed a high efficiency in vivo, with a relative bioavailability of 131.53% compared with intragastric administration. These findings showed that 1% RIS in 0.5% CBR, containing a combination of 6% menthol and 6% PG, can deliver doses of RIS that are therapeutically relevant for treating patients with schizophrenia. PMID- 29716870 TI - Role of Leptin and dyslipidemia in chronic kidney disease. AB - Chronic kidney disease (CKD) patients are at an increased risk of cardiovascular complications and plasma leptin level is elevated in cardio renal syndrome. We wanted to explore leptin levels in patients with different stages of CKD and find its association with risk of cardiovascular disease. This cross-sectional study was conducted in Nephrology Department of Jinnah Post Graduate Medical Centre (JPMC) from January 2014 to September 2014. Group I comprised of controls (GFR=116+/-8.3, n = 44) acquired from general population, CKD patients were grouped as II, III and IV respectively with GFR; 85.77+/-9.9 (n = 42), 53.84+/ 9.9 (n=42) and 20.22+/-8.4 (n = 42).CKD patients with any inflammatory disease, Diabetes Mellitus and on steroid therapy were excluded. Serum leptin, lipid profile and C reactive proteins (CRP) were measured. Leptin and CRP levels increased significantly with progression of CKD. High density lipoproteins (HDL) to low density lipoproteins (LDL) ratio was significantly high in control as compared to CKD groups (p<0.001). A positive correlation of leptin was observed with CRP and HDL/LDL ratio (r= 0.994,p<0.001 and r=-0.403 p<0.001) respectively. Hyperleptinemia observed with progression of CKD contributed to pathogenesis of cardiovascular disease by decreasing HDL/LDL ratio. PMID- 29716871 TI - Therapeutic effect evaluation of reteplase on acute pulmonary embolism. AB - Thrombolysis is the main therapeutic method of acute pulmonary embolism (APE). In order to investigate the efficacy of reteplase on APE and the changes of cytokines in the progression of APE, 72 patients with APE were randomized into reteplase group and urokinase group which received reteplase thrombolysis and urokinase thrombolysis, respectively. The clinical symptoms, blood pressure, heart rate (HR), blood gas index and cytokines of patients were observed before and after therapy for assessing the thrombolysis effect of each group; blood level of high sensitive C-reactive protein (hs-CRP), TNF-alpha, IL-1beta, IL-6 and IL-10 was detected at 0h, 2h, 6h, 12h and 24h after thrombolysis. After treatment, the clinical symptoms of both groups were alleviated obviously; PaO2, PaCO2, blood pressure and HR in both groups were significantly improved than those before treatment (p<0.001), and reteplase group showed a more obvious improvement than urokinase group (p<0.001). Since 6h after therapy, the content of hs-CRP, IL-1beta and IL-6 in patients of reteplase group declined significantly (p<0.05 or 0.01). In conclusion, therapeutic effect of reteplase is better than urokinase, hs-CRP, IL-1beta and IL-6 can be used to monitor the thrombolysis efficacy of APE patients. PMID- 29716872 TI - Measuring central percentiles of blood pressure levels among adults in Pakistan: A case study of Rawalpindi. AB - The prevalence pattern of hypertension (HTN) in developing countries is different from that in the developed countries. In Pakistan, the percentage of hypertensive patients has been growing since last two decades. Various factors might have contributed to this rising trend like, age, body mass index (BMI), lack of physical activity, family history of HTN and smoking etc. In this study, we examine prevalence of HTN in Rawalpindi district of Pakistan using the Eighth Joint National Committee (JNC 8) criteria, with the aim to measure central percentiles of blood pressure (BP) depending on different stated factors. For this purpose, quantile regression is used. A cross-sectional study including 2000 volunteer adults was designed. The data were obtained about systolic BP (SBP), diastolic BP (DBP), gender, age, weight height, family history of HTN, physical activity, presence of any kidney disease and diabetic status etc. Quantile regression was used to estimate the central percentiles of SBP and DBP. The present study concludes that the central percentiles of BP reflect alarming situation as half of the adults fall into either pre-hypertensive or hypertensive category and thus, some special awareness program about HTN should frequently be organized. PMID- 29716873 TI - Extraction of biomedical compounds from the wood of Pterocarpus macarocarpus Kurz heartwood. AB - Some wood can be used as traditional Chinese medicine. The medicinal value of wood is associated with its extractives. Pterocarpus macarocarpus Kurz heartwood is a kind of top valuable reddish hardwood in making furniture and handicrafts, but the research about medicine value of this wood is not enough. In order to investigate the high value biomedical compounds in Pterocarpus macarocarpus Kurz heartwood, the woody extractives were obtained by Soxhlet extraction and ultrasonic extraction with benzene-ethanol (1:2, v/v) solvent simultaneously and were analyzed by Gas Chromatography-Mass Spectrometer (GC-MS). Combining with the results of the two extraction methods, 44 compounds can be identified in total. Amony these identified compounds, there were 5 flavonoids, 15 terpenes and 3 steroidal compounds. The representative biomedical compositions were homopterocarpin, medicarpin, (-)-pterocarpin, formononetin, beta-eudesmol, stigmasterol, linoleic acid and so on, which indicated that the extractives from Pterocarpus macarocarpus Kurz heartwood have huge potential in biomedicine. This research provides scientific basis for further comprehensive utilization of Pterocarpus macarocarpus Kurz heartwood as Chinese medicine. PMID- 29716874 TI - Antagonistic behaviour of organic compounds from Bacillus species and Brevundimonas specie. AB - Bacterial strains, Bacillus cereus Lb (KF011486), Brevundimonas sp. A2 (JX996070), Bacillus cereus AZS and Bacillus sp. 11A, isolated from soil sample, were checked for their antimicrobial property against Bacillus as test organism. The bactericidal effect of the antagonistic strains against test organism was found to be at 1280, 1280, 40 and 160 arbitrary units (AU/ml), respectively. The Crude Antimicrobial Compound (CAC) had a bactericidal effect on target cell by degeneration of its cell wall. The chemical analysis of TLC purified extract of intracellular and extracellular antimicrobial compound produced by Bacillus cereus Lb by GC-MS analysis revealed the presence of organic compounds such as acetic acid and certain volatile organic substances such as, toluene, 2-butanone, etc., with antimicrobial property. N-acetylmuramoyl-L-alanine amidase is a cell wall hydrolysing enzyme and involved in cell wall degeneration of the target cells. These volatile organic compounds help this enzyme by decreasing the pH of the environment hence maximizing the amidase activity which possesses maximum activity at pH range of 5.5-6.5. PMID- 29716875 TI - Potential impact of Panax ginseng against ethanol induced hyperlipidemia and cardiac damage in rats. AB - The objective of the current work was to explore the possible hypolipidemic and therapeutic impacts of Panax ginseng against cardiac damage in response to ethanol ingestion in male and female rats. 10% ethanol was ingested (2ml/Kg) to both male and female rats daily for fourteen days. The results showed that ingestion of ginseng (150mg/Kg) daily for six weeks to male and female rats intoxicated with ethanol, two weeks after ethanol ingestion, successfully modulated the alterations in the serum lipid profiles, namely, triglycerides (TGs), total cholesterol (TCh), low density lipoprotein (LDL-C) and high density lipoprotein (HDL-C), in male and female rats exposed to ethanol versus untreated intoxicated ones. The plant also pronouncedly attenuated the increases in serum cardiac damage biomarkers, namely lactate dehydrogenase (LDH) and creatine phosphokinase (CPK) compared with ethanol intoxicated untreated rats. In conclusion, this study showed that Panax ginseng has a beneficial impact against ethanol induced hyperlipidemia as a risk element for cardiovascular illness. PMID- 29716876 TI - Screening and characterization of selected drugs having antibacterial potential. AB - Due to ever increasing antibiotic resistance offered by pathogenic bacterial strains and side effects of synthetic antibiotics, thereof, there is a need to explore the effective phytochemicals from natural resources. In order to help overcoming the problem of effective natural drug and the side effects posed by the use of the synthetic drugs, five different plants namely Thymus vulgaris, Lavandula angustifolia, Rosmarinus officinalis, Cymbopogon citratus and Achillea millefolium were selected to study their antibacterial potential. Antibacterial activity and minimum inhibitory concentration (MIC) checked against the selected bacterial strains. As compared to other test plants, ethanolic extract of Rosmarinus officinalis leaves showed the most promising inhibitory effect i.e: inhibition zone (18.17+/- 0.44mm) against Klebsiella pneumoniae and the lowest inhibition (15.5+/-0.29mm) against Pseudomonas aeruginosa and Escherichia coli (p<0.05). The MIC values were recorded in the range of 1 to 20mg/ml. Screening of the selected extracts for the test plants additionally indicate some unique variations. Results were further confirmed through TLC for alkaloids and terpenoids (15% sulphuric acid and Dragedroff's reagent) in ethanolic extract. Characterization of Rosmarinus officinalis of ethanolic extract was carried out using column chromatography. The appearance of orange crystals may indicate the presence of alkaloidal bioactive compounds which need to be further investigated. The tested plants may have a potential for fighting against some infectious diseases caused by selected human pathogenic bacterial strains. This knowledge may incite a gateway to effective drug search and so on. PMID- 29716877 TI - Reoirt: Insight into the lipophilicity of selected monosubstituted chalcones. AB - This study represents our attempt to understand how the antimicrobial activity of chalcones is modulated by their lipophilicity. To achieve this overall objective, a library of monosubstituted chalcones was targeted after careful consideration of the stereo electronic properties of the substituents appended in each of its constituent members. The lipophilicities of these derivatives were determined experimentally as well as by means of different validated computational programs. The theoretical determination was necessitated by the long-winded and time consuming experimental protocols involved. It was gratifying to note the good correlation between these determinations which indicated the suitability of using such theoretical descriptors not only for assessing the lipophilicity of putative lead molecules but also for evaluating their biological activity. Standard disc diffusion technique employed against gram positive & negative bacteria as well as fungi revealed some preliminary information about the antimicrobial activity of these analogues. PMID- 29716878 TI - Report: Phytochemical screening and antimicrobial activities of red silk cotton tree (Bombax ceiba L.). AB - The present study was conducted to investigate the phytochemical screening and antimicrobial activities of stem bark of Bombax ceiba L. The methanol extract was subjected to qualitative phytochemical screening using standard procedures. The results indicated the presence of alkaloids, tannins, glycosides, reducing sugar, saponins, phlobatanins and terpenoids. The antimicrobial activity was measured by disc diffusion method. Data revealed that Pseudomonas aeruginosa was inhibited by both methanol and ethanol extracts at the concentration of 2mg disc-1 {21.8mm (68.12%) and 21.3mm (66.56%)}. Similarly, methanol extract reduced the growth of Bacillus subtilis by 17.1mm (74.34%) at the concentration of 1 mg disc-1. However, ethanol extract showed a good activity of 18mm (121.6%) and 20.6mm (112.5%) against Xanthomonas maltophilia at concentrations of 1 and 2 mg disc-1, respectively. Aqueous extract showed 16 mm (53.33% Z.I) against Escherichia coli at 2 mg disc-1. Klebsiella pneumoniae was found resistant to all of the three extracts, while the growth of Candida albicans was inhibited by methanol through 16.5 mm (58.92% Z.I) at 1 mg disc-1. The above study concluded the medicinal potential of B. ceiba. PMID- 29716879 TI - Report: Comparison of qualitative, quantitative analysis and antioxidant potential between wild and cultivated Borago officinalis leaves from palestine. AB - Borago officinalis plant is an important plant of high medicinal and nutritional values. This study designed to evaluate antioxidant activity, screen the existence of phytogenic chemical compounds and to determine the total flavonoid and phenol contents of wild and cultivated Borago officinalis. Total flavonoid contents of the wild and cultivated Borago officinalis were determined by using rutin reference standard method and total phenols determined by using Folin Ciocalteu's method while antioxidant activity evaluated by using 2, 2-diphenyl-1 picryl-hydrazyl-hydrate assay. Phytochemical analyses indicated the presence of carbohydrate, phenols, flavonoids, phytosteroids tannins and volatile oil. The total flavonoid content of the methanolic extract from the wild borage plant was 22.4mg RU/g this value was reduced to 13.1mg RU/g for the cultivated methanolic extract as well as the total phenols contents was dropped from 5.21mg GA/g to 2.37mg GA/g methanolic extracts. Total tannins content of the wild growing borage plant was 13.7mg GA/g methanolic extract. This value was higher in the cultivated borage with 21.33mg GA/g methanolic extract. The wild leaves extract had IC50 =6.3MUg/mL for wild leaves extract was closer to IC50 value of Trolox (standard reference with high antioxidant activity), while the cultivated leaves extract had higher IC50= 8.7MUg/mL which mean lower antioxidant activity than the wild growing one. The data of this study showed that the extracts of Borago officinalis possess antioxidant and free radical scavenging activities. Variation was clear between wild and cultivated species, these findings propose that such plant extract could have a wide range of applications in both food and pharmaceutical industries. Therefore, more research is necessary to investigate different cultural practices on the efficiency of borage plant. PMID- 29716880 TI - Report: An ex vivo up-take of levamisole molecules by cestode (Monezia expensa) of goat (Capra hirsa) and its detection through RP-HPLC. AB - Detection of various molecules of drugs remained a prime issue especially in tissues of animals, humans and in their target parasites. The cestode/tapeworms pose a dilemma because of their weird body composition and uptake pattern of nutrients and medicines especially through absorption by tegument. We selected levamisole; thought to be potent antiparasitic/ani-cestodal drug. The uptake of levamisole (LEV) through cestodeal tissues is studied through HPCL in this paper. High performance liquid chromatography technique has been utilized to know the uptake of levamisole in tissues of cestodes of Goat (Monezia expensa) in small ruminants. The drug was exposed to M. expensa by in vitro till its death or a parasite ceases its movement. The tissue/ part of proglattids of the M. expensa were homogenized with some modifications and levamisole extraction was performed with liquid phase extraction method. The evaporation of solvent was done and the residual cestodal tissues were cleaned by solid phase. After the solid phase extraction method, the recovery of drug, detection and quantification of levamisole from cestodal tissues was determined through Reverse Phase Column High Performance Liquid Chromatography (RP-HPLC). Levamisole (LEV) molecules assay was obtained on a C18 reverse-phase (20um, 6mm x 150mm) column at flow rate of 1ml/min using acetonitrile and ammonium acetate as mobile phase and UV detection was done at 254nm. The development of method of Levamisole (LEV) detection from cestodal tissues by HPLC in vitro samples has been demonstrated first time in Pakistan, which can provide the solution of parasitic control and provide in sight in to the uptake of anti cestodal drugs either against human or livestock parasites. PMID- 29716881 TI - Mini Review: Chronic obstructive pulmonary disease, its new drug treatments and strategies: A review. AB - COPD is a complicated disease. Current available treatments are just for symptomatic relief and they cannot reverse the damages to lungs tissues due to alveolar destruction in COPD. Research is being conducted to evaluate new treatments and strategies to find specific treatments to minimize the symptoms of COPD. A new mixture of herbal medicine i.e AKL1 has emerged and thought to cure COPD symptoms especially cough related quality of life of COPD patients. Although, the results have showed no significant difference as compared to placebo but researchers recommend further evaluation in a large population (COPD Patients) group. Another medicine Roflumilast, a phosphodiesterase 4 inhibitor, was also found to be effective to treat COPD under specific recommendations with further research needed. Finally another medicine Indacaterol, a novel, once daily (o.d) inhaled long-acting beta2-agonist proved to be effective clinically to treat COPD related broncho-constriction and also increasing the COPD patient's compliance by reducing the number of doses as compared to other conventional inhaled bronchodilators such as Albuterol. PMID- 29716882 TI - Vacuolization in Myeloid and Erythroid Precursors in a child with Menkes Disease. PMID- 29716884 TI - Comment on "An Online Intervention Comparing a Very Low-Carbohydrate Ketogenic Diet and Lifestyle Recommendations Versus a Plate Method Diet in Overweight Individuals With Type 2 Diabetes: A Randomized Controlled Trial". PMID- 29716885 TI - An Assistive Technology System that Provides Personalized Dressing Support for People Living with Dementia: Capability Study. AB - BACKGROUND: Individuals living with advancing stages of dementia (persons with dementia, PWDs) or other cognitive disorders do not have the luxury of remembering how to perform basic day-to-day activities, which in turn makes them increasingly dependent on the assistance of caregivers. Dressing is one of the most common and stressful activities provided by caregivers because of its complexity and privacy challenges posed during the process. OBJECTIVE: In preparation for in-home trials with PWDs, the aim of this study was to develop and evaluate a prototype intelligent system, the DRESS prototype, to assess its ability to provide automated assistance with dressing that can afford independence and privacy to individual PWDs and potentially provide additional freedom to their caregivers (family members and professionals). METHODS: This laboratory study evaluated the DRESS prototype's capacity to detect dressing events. These events were engaged in by 11 healthy participants simulating common correct and incorrect dressing scenarios. The events ranged from donning a shirt and pants inside out or backwards to partial dressing-typical issues that challenge a PWD and their caregivers. RESULTS: A set of expected detections for correct dressing was prepared via video analysis of all participants' dressing behaviors. In the initial phases of donning either shirts or pants, the DRESS prototype missed only 4 out of 388 expected detections. The prototype's ability to recognize other missing detections varied across conditions. There were also some unexpected detections such as detection of the inside of a shirt as it was being put on. Throughout the study, detection of dressing events was adversely affected by the relatively smaller effective size of the markers at greater distances. Although the DRESS prototype incorrectly identified 10 of 22 cases for shirts, the prototype preformed significantly better for pants, incorrectly identifying only 5 of 22 cases. Further analyses identified opportunities to improve the DRESS prototype's reliability, including increasing the size of markers, minimizing garment folding or occlusions, and optimal positioning of participants with respect to the DRESS prototype. CONCLUSIONS: This study demonstrates the ability to detect clothing orientation and position and infer current state of dressing using a combination of sensors, intelligent software, and barcode tracking. With improvements identified by this study, the DRESS prototype has the potential to provide a viable option to provide automated dressing support to assist PWDs in maintaining their independence and privacy, while potentially providing their caregivers with the much-needed respite. PMID- 29716886 TI - Authors' Reply: Comment on "An Online Intervention Comparing a Very Low Carbohydrate Ketogenic Diet and Lifestyle Recommendations Versus a Plate Method Diet in Overweight Individuals With Type 2 Diabetes: A Randomized Controlled Trial". PMID- 29716887 TI - Are EBV-related and EBV-unrelated Hodgkin lymphomas different with regard to susceptibility to checkpoint blockade? AB - Epstein-Barr virus (EBV)-related and EBV-unrelated classical Hodgkin lymphomas (cHLs) are morphologically and phenotypically indistinguishable. However, the tumor microenvironment of EBV-related cHLs contains higher numbers of macrophages and higher expression levels of PD-L1 than that of EBV-unrelated cHLs. Moreover, viral oncoprotein LMP1 may sustain an immunosuppressive microenvironment by inducing/enhancing production of immunosuppressive cytokines and the expression of PD-1. The presence of enhanced immunosuppressive features in EBV-related cHL should make EBV-related cHL patients more susceptible to checkpoint blockade. PMID- 29716883 TI - Factors Determining the Success and Failure of eHealth Interventions: Systematic Review of the Literature. AB - BACKGROUND: eHealth has an enormous potential to improve healthcare cost, effectiveness, and quality of care. However, there seems to be a gap between the foreseen benefits of research and clinical reality. OBJECTIVE: Our objective was to systematically review the factors influencing the outcome of eHealth interventions in terms of success and failure. METHODS: We searched the PubMed database for original peer-reviewed studies on implemented eHealth tools that reported on the factors for the success or failure, or both, of the intervention. We conducted the systematic review by following the patient, intervention, comparison, and outcome framework, with 2 of the authors independently reviewing the abstract and full text of the articles. We collected data using standardized forms that reflected the categorization model used in the qualitative analysis of the outcomes reported in the included articles. RESULTS: Among the 903 identified articles, a total of 221 studies complied with the inclusion criteria. The studies were heterogeneous by country, type of eHealth intervention, method of implementation, and reporting perspectives. The article frequency analysis did not show a significant discrepancy between the number of reports on failure (392/844, 46.5%) and on success (452/844, 53.6%). The qualitative analysis identified 27 categories that represented the factors for success or failure of eHealth interventions. A quantitative analysis of the results revealed the category quality of healthcare (n=55) as the most mentioned as contributing to the success of eHealth interventions, and the category costs (n=42) as the most mentioned as contributing to failure. For the category with the highest unique article frequency, workflow (n=51), we conducted a full-text review. The analysis of the 23 articles that met the inclusion criteria identified 6 barriers related to workflow: workload (n=12), role definition (n=7), undermining of face-to-face communication (n=6), workflow disruption (n=6), alignment with clinical processes (n=2), and staff turnover (n=1). CONCLUSIONS: The reviewed literature suggested that, to increase the likelihood of success of eHealth interventions, future research must ensure a positive impact in the quality of care, with particular attention given to improved diagnosis, clinical management, and patient-centered care. There is a critical need to perform in-depth studies of the workflow(s) that the intervention will support and to perceive the clinical processes involved. PMID- 29716889 TI - GP who sexually assaulted patient who thought she was having a heart attack is jailed for 15 months. PMID- 29716890 TI - The BMJ Awards 2018: UK Research Paper of the Year. PMID- 29716891 TI - Doctors for Choice: five minutes with . . . Hayley Webb. PMID- 29716888 TI - Predicting Mortality in African Americans With Type 2 Diabetes Mellitus: Soluble Urokinase Plasminogen Activator Receptor, Coronary Artery Calcium, and High Sensitivity C-Reactive Protein. AB - BACKGROUND: Type 2 diabetes mellitus is a major risk factor for cardiovascular disease; however, outcomes in individual patients vary. Soluble urokinase plasminogen activator receptor (suPAR) is a bone marrow-derived signaling molecule associated with adverse cardiovascular and renal outcomes in many populations. We characterized the determinants of suPAR in African Americans with type 2 diabetes mellitus and assessed whether levels were useful for predicting mortality beyond clinical characteristics, coronary artery calcium (CAC), and high-sensitivity C-reactive protein (hs-CRP). METHODS AND RESULTS: We measured plasma suPAR levels in 500 African Americans with type 2 diabetes mellitus enrolled in the African American-Diabetes Heart Study. We used Kaplan-Meier curves and Cox proportional hazards models adjusting for clinical characteristics, CAC, and hs-CRP to examine the association between suPAR and all cause mortality. Last, we report the change in C-statistics comparing the additive values of suPAR, hs-CRP, and CAC to clinical models for prediction of mortality. The suPAR levels were independently associated with female sex, smoking, insulin use, decreased kidney function, albuminuria, and CAC. After a median 6.8-year follow-up, a total of 68 deaths (13.6%) were recorded. In a model incorporating suPAR, CAC, and hs-CRP, only suPAR was significantly associated with mortality (hazard ratio 2.66, 95% confidence interval 1.63-4.34). Addition of suPAR to a baseline clinical model significantly improved the C-statistic for all-cause death (Delta0.05, 95% confidence interval 0.01-0.10), whereas addition of CAC or hs-CRP did not. CONCLUSIONS: In African Americans with type 2 diabetes mellitus, suPAR was strongly associated with mortality and improved risk discrimination metrics beyond traditional risk factors, CAC and hs-CRP. Studies addressing the clinical usefulness of measuring suPAR concentrations are warranted. PMID- 29716892 TI - Human Proislet Peptide Promotes Pancreatic Progenitor Cells to Ameliorate Diabetes Through FOXO1/Menin-Mediated Epigenetic Regulation. AB - We investigated how human proislet peptide (HIP) regulates differentiation of human fetus-derived pancreatic progenitor cells (HFPPCs) and explored the potential link between HIP signaling and the menin pathway, which is key to regulating pancreatic islet differentiation. The data show that HIP promoted expression of proislet transcription factors (TFs), including PDX-1, MAFA, and NKX6.1, as well as other maturation markers of beta-cells, such as insulin, GLUT2, KIR6.2, SUR1, and VDCC. Moreover, HIP increased insulin content and promoted the ability of HFPPCs to normalize blood glucose in diabetic mice. HIP inhibited the TF FOXO1 by increasing AKT-mediated phosphorylation. HIP-induced repression of FOXO1 suppressed menin expression, leading to reducing menin binding to the promoter of the three key proislet TFs, decreasing recruitment of H3K9 methyltransferase SUV39H1, and thus reducing repressive H3K9me3 at the promoter. These coordinated actions lead to increased expression of the proislet TFs, resulting in induction of HFPPC differentiation. Consistently, constitutive activation of FOXO1 blocks HIP-induced transcription of these TFs. Together, these studies unravel the crucial role of the HIP/AKT/FOXO/menin axis in epigenetically controlling expression of proislet TFs, regulating the differentiation of HFPPCs, and normalizing blood glucose in diabetic mice. PMID- 29716893 TI - Complement C5 but not C3 is expendable for tissue factor activation by cofactor independent antiphospholipid antibodies. AB - The complement and coagulation cascades interact at multiple levels in thrombosis and inflammatory diseases. In venous thrombosis, complement factor 3 (C3) is crucial for platelet and tissue factor (TF) procoagulant activation dependent on protein disulfide isomerase (PDI). Furthermore, C5 selectively contributes to the exposure of leukocyte procoagulant phosphatidylserine (PS), which is a prerequisite for rapid activation of monocyte TF and fibrin formation in thrombosis. Here, we show that monoclonal cofactor-independent antiphospholipid antibodies (aPLs) rapidly activate TF on myelomonocytic cells. TF activation is blocked by PDI inhibitor and an anti-TF antibody interfering with PDI binding to TF, and requires C3 but unexpectedly not C5. Other prothrombotic, complement fixing antibodies, for example, antithymocyte globulin, typically induce TF activation dependent on C5b-7-mediated PS exposure on the outer membrane of monocytes. We show that aPLs directly induce procoagulant PS exposure independent of C5. Accordingly, mice deficient in C3, but not mice deficient in C5, are protected from in vivo thrombus formation induced by cofactor-independent aPLs. Only immunoglobulin G (IgG) fractions with cofactor-independent anticardiolipin reactivity from patients with antiphospholipid syndrome (APS) induce complement independent monocyte PS exposure and PDI-dependent TF activation. Neither a human monoclonal aPL directed against beta2-glycoprotein I (beta2GPI) nor patient IgG with selective reactivity to beta2GPI rapidly activated monocyte TF. These results indicate that inhibitors of PDI and TF, but not necessarily clinically available drugs targeting C5, have therapeutic benefit in preventing thrombosis associated with APS caused by pathogenic aPLs primarily reactive with lipid, independent of beta2GPI. PMID- 29716896 TI - Gates Foundation challenges researchers to create universal flu vaccine with $12m offer. PMID- 29716894 TI - Hamartoma-like lesions in the mouse retina: an animal model of Pten hamartoma tumour syndrome. AB - PTEN hamartoma tumour syndrome (PHTS) is a heterogeneous group of rare, autosomal dominant disorders associated with PTEN germline mutations. PHTS patients routinely develop hamartomas, which are benign tissue overgrowths comprised of disorganized 'normal' cells. Efforts to generate PHTS animal models have been largely unsuccessful due to the early lethality of homozygous germline mutations in Pten, together with the lack of hamartoma formation in most conditional mutants generated to date. We report herein a novel PHTS mouse model that reproducibly forms hamartoma-like lesions in the central retina by postnatal day 21. Specifically, we generated a Pten conditional knockout (cKO) using a retinal specific Pax6::Cre driver that leads to a nearly complete deletion of Pten in the peripheral retina but produces a mosaic of 'wild-type' and Pten cKO cells centrally. Structural defects were only observed in the mosaic central retina, including in Muller glia and in the outer and inner limiting membranes, suggesting that defective mechanical integrity partly underlies the hamartoma like pathology. Finally, we used this newly developed model to test whether rapamycin, an mTOR inhibitor that is currently the only PHTS therapy, can block hamartoma growth. When administered in the early postnatal period, prior to hamartoma formation, rapamycin reduces hamartoma size, but also induces new morphological abnormalities in the Pten cKO retinal periphery. In contrast, administration of rapamycin after hamartoma initiation fails to reduce lesion size. We have thus generated and used an animal model of retinal PHTS to show that, although current therapies can reduce hamartoma formation, they might also induce new retinal dysmorphologies.This article has an associated First Person interview with the first author of the paper. PMID- 29716895 TI - Metabolic Syndrome and Neurocognition Among Diverse Middle-Aged and Older Hispanics/Latinos: HCHS/SOL Results. AB - OBJECTIVE: Hispanics/Latinos have the highest risks for metabolic syndrome (MetS) in the U.S. and are also at increased risk for Alzheimer disease. In this study, we examined associations among neurocognitive function, MetS, and inflammation among diverse middle-aged and older Hispanics/Latinos. RESEARCH DESIGN AND METHODS: Cross-sectional data (2008-2011) from the Hispanic Community Health Study/Study of Latinos (HCHS/SOL) were analyzed to examine associations between neurocognition and MetS among diverse Hispanics/Latinos (N = 9,136; aged 45-74 years). RESULTS: MetS status was associated with lower global neurocognition, mental status, verbal learning and memory, verbal fluency, and executive function. Age significantly modified the associations between MetS and learning and memory measures. Significant associations between MetS and neurocognition were observed among middle-aged Hispanics/Latinos, and all associations remained robust to additional covariates adjustment. CONCLUSIONS: We found that MetS was associated with lower neurocognitive function, particularly in midlife. Our findings support and extend current hypotheses that midlife may be a particularly vulnerable developmental period for unhealthy neurocognitive aging. PMID- 29716898 TI - Load-Dependent Changes in Left Ventricular Structure and Function in a Pathophysiologically Relevant Murine Model of Reversible Heart Failure. AB - BACKGROUND: To better understand reverse left ventricular (LV) remodeling, we developed a murine model wherein mice develop LV remodeling after transverse aortic constriction (TAC) and a small apical myocardial infarct (MI) and undergo reverse LV remodeling after removal of the aortic band. METHODS AND RESULTS: Mice studied were subjected to sham (n=6) surgery or TAC+MI (n=12). Two weeks post TAC+MI, 1 group underwent debanding (referred to as heart failure debanding [HF DB] mice; n=6), whereas the aortic band remained in a second group (heart failure [HF] group; n=6). LV remodeling was evaluated by 2D echocardiography at 1 day, 2 weeks and 6 weeks post-TAC+MI. The hearts were analyzed by transcriptional profiling at 4 and 6 weeks and histologically at 6 weeks. Debanding normalized LV volumes, LV mass, and cardiac myocyte hypertrophy at 6 weeks in HF-DB mice, with no difference in myofibrillar collagen in the HF and HF-DB mice. LV ejection fraction and radial strain improved after debanding; however, both remained decreased in the HF-DB mice relative to sham and were not different from HF mice at 6 weeks. Hemodynamic unloading in the HF-DB mice was accompanied by a 35% normalization of the HF genes at 2 weeks and 80% of the HF genes at 4 weeks. CONCLUSIONS: Hemodynamic unloading of a pathophysiologically relevant mouse model of HF results in normalization of LV structure, incomplete recovery of LV function, and incomplete reversal of the HF transcriptional program. The HF-DB mouse model may provide novel insights into mechanisms of reverse LV remodeling. PMID- 29716900 TI - Alfie Evans and Charlie Gard-should the law change? PMID- 29716897 TI - Prospective Randomized Biomarker Study of Metformin and Lifestyle Intervention for Prevention in Obese Women at Increased Risk for Endometrial Cancer. AB - Obesity increases risk of endometrial cancer through dysregulation of estrogen and insulin signaling. The primary aim of this study was to evaluate the impact of metformin or lifestyle intervention on endometrial proliferation in postmenopausal obese women. Secondary aims included evaluating obesity-related biomarkers and adverse events experienced. Obese, postmenopausal women with prediabetes were randomized into four groups for a 16-week intervention using a 2 (metformin 1700 mg/day vs. placebo) * 2 (lifestyle intervention vs. no lifestyle intervention) factorial design. Pre- and postintervention endometrial proliferation, anthropometrics, body composition, and serum biomarkers (sex hormones, sex hormone binding globulin, IGF-I, adiponectin, omentin, insulin, glucose, and others) were assessed. Data were analyzed with linear regression models and false-discovery rate correction. Of 576 women approached for the study, 52 attended initial screening, 29 were eligible and randomized, and 26 completed the study. Lifestyle intervention resulted in significant loss of weight (-4.23 kg, P = 0.006) and total fat mass (-3.23 kg, P < 0.001). Participants receiving metformin lost 3.43 kg of weight (P = 0.023), but this was not statistically significant after multiple comparisons adjustment controlling false-discovery rate to 10%. Endometrial proliferation was low at baseline (mean 7.1%) and remained unchanged by 16 weeks, but included substantial variability. Metformin and lifestyle intervention produced minor changes to serum biomarkers. Lifestyle intervention produced the most significant changes in weight and body composition. While it is known that obese postmenopausal women are at increased risk for endometrial cancer, improved biomarkers are needed to stratify risk and test prevention strategies, particularly at the endometrial tissue level. Cancer Prev Res; 11(8); 477-90. (c)2018 AACR. PMID- 29716899 TI - Risk Factor Burden, Heart Failure, and Survival in Women of Different Ethnic Groups: Insights From the Women's Health Initiative. AB - BACKGROUND: The higher risk of heart failure (HF) in African-American and Hispanic women compared with white women is related to the higher burden of risk factors (RFs) in minorities. However, it is unclear if there are differences in the association between the number of RFs for HF and the risk of development of HF and death within racial/ethnic groups. METHODS AND RESULTS: In the WHI (Women's Health Initiative; 1993-2010), African-American (n=11 996), white (n=18 479), and Hispanic (n=5096) women with 1, 2, or 3+ baseline RFs were compared with women with 0 RF within their respective racial/ethnic groups to assess risk of developing HF or all-cause mortality before and after HF, using survival analyses. After adjusting for age, socioeconomic status, and hormone therapy, the subdistribution hazard ratio (95% confidence interval) of developing HF increased as number of RFs increased (P<0.0001, interaction of race/ethnicity and RF number P=0.18)-African-Americans 1 RF: 1.80 (1.01-3.20), 2 RFs: 3.19 (1.84-5.54), 3+ RFs: 7.31 (4.26-12.56); Whites 1 RF: 1.27 (1.04-1.54), 2 RFs: 1.95 (1.60-2.36), 3+ RFs: 4.07 (3.36-4.93); Hispanics 1 RF: 1.72 (0.68-4.34), 2 RFs: 3.87 (1.60 9.37), 3+ RFs: 8.80 (3.62-21.42). Risk of death before developing HF increased with subsequent RFs (P<0.0001) but differed by racial/ethnic group (interaction P=0.001). The number of RFs was not associated with the risk of death after developing HF in any group (P=0.25; interaction P=0.48). CONCLUSIONS: Among diverse racial/ethnic groups, an increase in the number of baseline RFs was associated with higher risk of HF and death before HF but was not associated with death after HF. Early RF prevention may reduce the burden of HF across multiple racial/ethnic groups. PMID- 29716902 TI - Clinical Pearls. PMID- 29716901 TI - Celebrating May-and Nursing! PMID- 29716903 TI - Effects of an Integrative Nursing Intervention on Pain in Critically Ill Patients: A Pilot Clinical Trial. AB - BACKGROUND: Pain, a persistent problem in critically ill patients, adversely affects outcomes. Despite recommendations, no evidence-based nonpharmacological approaches for pain treatment in critically ill patients have been developed. OBJECTIVES: To investigate the effects of a multimodal integrative intervention on the incidence of pain and on secondary outcomes: intensity of pain, hemodynamic indices (systolic and mean arterial pressure, heart rate), anxiety, fear, relaxation, optimism, and sleep quality. METHODS: A randomized, controlled, double-blinded repeated-measures trial with predetermined eligibility criteria was conducted. The intervention included relaxation, guided imagery, moderate pressure massage, and listening to music. The primary outcome was incidence of pain (score on Critical Care Pain Observation Tool > 2). Other outcomes included pain ratings, hemodynamic measurements, self-reported psychological outcomes, and quality of sleep. Repeated-measures models with adjustments (baseline levels, confounders) were used. RESULTS: Among the 60 randomized critically ill adults in the sample, the intervention group experienced significant decreases in the incidence (P = .003) and ratings of pain (P < .001). Adjusted models revealed a significant trend for lower incidence (P = .002) and ratings (P < .001) of pain, systolic arterial pressure (P < .001), anxiety (P = .01), and improved quality of sleep (P = .02). CONCLUSION: A multimodal integrative intervention may be effective in decreasing pain and improving pain-related outcomes in critically ill patients. PMID- 29716904 TI - Identifying Barriers to Nurse-Facilitated Patient Mobility in the Intensive Care Unit. AB - BACKGROUND: Nurse-facilitated mobility of patients in the intensive care unit can improve outcomes. However, a gap exists between research findings and their implementation as part of routine clinical practice. Such a gap is often attributed, in part, to the barrier of lack of time. The Translating Evidence Into Practice model provides a framework for research implementation, including recommendations for identifying barriers to implementation via direct observation of clinical care. OBJECTIVES: To report on design, implementation, and outcomes of an approach to identify and understand lack of time as a barrier to nurse facilitated mobility in the intensive care unit. METHODS: An interprofessional team designed the observational process and evaluated the resulting data by using qualitative content analysis. RESULTS: During three 4-hour observations of 2 nurses and 1 nursing technician, 194 distinct tasks were performed (ie, events). A total of 4 categories of nurses' work were identified: patient care (47% of observation time), provider communication (25%), documentation (18%), and down time (10%). In addition, 3 types of potential mobility events were identified: in bed, edge of bed, and out of bed. The 194 observed events included 34 instances (18%) of potential mobility events that could be implemented: in bed (53%), edge of bed (6%), and out of bed (41%). CONCLUSIONS: Nurses have limited time for additional clinical activities but may miss potentially important opportunities for facilitating patient mobility during existing patient care. The proposed method is feasible and helpful in empirically investigating barriers to nurse facilitated patient mobility in the intensive care unit. PMID- 29716905 TI - Mobilization Therapy in the Pediatric Intensive Care Unit: A Multidisciplinary Quality Improvement Initiative. AB - BACKGROUND: Mobilization is safe and associated with improved outcomes in critically ill adults, but little is known about mobilization of critically ill children. OBJECTIVE: To implement a standardized mobilization therapy protocol in a pediatric intensive care unit and improve mobilization of patients. METHODS: A goal-directed mobilization protocol was instituted as a quality improvement project in a 20-bed cardiac and medical-surgical pediatric intensive care unit within an academic tertiary care center. The mobilization goal was based on age and severity of illness. Data on severity of illness, ordered activity limitations, baseline functioning, mobilization level, complications of mobilization, and mobilization barriers were collected. Goal mobilization was defined as a ratio of mobilization level to severity of illness of 1 or greater. RESULTS: In 9 months, 567 patient encounters were analyzed, 294 (52%) of which achieved goal mobilization. The mean ratio of mobilization level to severity of illness improved slightly but nonsignificantly. Encounters that met mobilization goals were in younger (P = .04) and more ill (P < .001) patients and were less likely to have barriers (P < .001) than encounters not meeting the goals. Complication rate was 2.5%, with no difference between groups (P = .18). No serious adverse events occurred. CONCLUSIONS: A multidisciplinary, multiprofessional, goal-directed mobilization protocol achieved goal mobilization in more than 50% of patients in this pediatric intensive care unit. Undermobilized patients were older, less ill, and more likely to have mobilization barriers at the patient and provider level. PMID- 29716906 TI - No Time for Early Mobility? PMID- 29716910 TI - Noninvasive Blood Pressure Monitoring and Prediction of Fluid Responsiveness to Passive Leg Raising. AB - BACKGROUND: Intravenous fluid boluses are administered to patients in shock to improve tissue hypoperfusion. However, fluid boluses result in clinically significant stroke volume increases in only about 50% of patients. Hemodynamic responses to passive leg raising measured with invasive and minimally invasive methods are accurate predictors of fluid responsiveness. However, few studies have used noninvasive blood pressure measurement to evaluate responses to passive leg raising. OBJECTIVE: To determine if passive leg raising-induced increases in pulse pressure or systolic blood pressure can be used to predict clinically significant increases in stroke volume index in healthy volunteers. METHODS: In a repeated-measures study, hemodynamic measurements were obtained in 30 healthy volunteers before, during, and after passive leg raising. Each participant underwent the procedure twice. RESULTS: In the first test, 20 participants (69%) were responders (stroke volume index increased by >= 15%); 9 (31%) were nonresponders. In the second test, 15 participants (50%) were responders and 15 (50%) were nonresponders. A passive leg raising-induced increase in pulse pressure of 9% or more predicted a 15% increase in stroke volume index (sensitivity, 50%; specificity, 44%). There was no association between passive leg raising-induced changes in systolic blood pressure and fluid responsiveness. CONCLUSION: A passive leg raising-induced change in stroke volume index measured by bioreactance differentiated fluid responders and nonresponders. Pulse pressure and systolic blood pressure measured by oscillometric noninvasive blood pressure monitoring were not sensitive or specific predictors of fluid responsiveness in healthy volunteers. PMID- 29716911 TI - Early Warning Score Communication Bundle: A Pilot Study. AB - BACKGROUND: Unplanned admissions of patients to intensive care units from medical surgical units often result from failure to recognize clinical deterioration. The early warning score is a clinical decision support tool for nurse surveillance but must be communicated to nurses and implemented appropriately. A communication process including collaboration with experienced intensive care unit nurses may reduce unplanned transfers. OBJECTIVE: To determine the impact of an early warning score communication bundle on medical-surgical transfers to the intensive care unit, rapid response team calls, and morbidity of patients upon intensive care unit transfer. METHODS: After an early warning score was electronically embedded into medical records, a communication bundle including notification of and telephone collaboration between medical-surgical and intensive care unit nurses was implemented. Data were collected 3 months before and 21 months after implementation. RESULTS: Rapid response team calls increased nonsignificantly during the study period (from 6.47 to 8.29 per 1000 patient-days). Rapid response team calls for patients with early warning scores greater than 4 declined (from 2.04 to 1.77 per 1000 patient-days). Intensive care unit admissions of patients after rapid response team calls significantly declined (P = .03), as did admissions of patients with early warning scores greater than 4 (P = .01), suggesting that earlier intervention for patient deterioration occurred. Documented reassessment response time declined significantly to 28 minutes (P = .002). CONCLUSION: Electronic surveillance and collaboration with experienced intensive care unit nurses may improve care, control costs, and save lives. Critical care nurses have a role in coaching and guiding less experienced nurses. PMID- 29716913 TI - The Value of Lead aVR: A Frequently Neglected Lead. PMID- 29716912 TI - Effect of Dynamic Light Application on Cognitive Performance and Well-being of Intensive Care Nurses. AB - BACKGROUND: Exposure to bright light has alerting effects. In nurses, alertness may be decreased because of shift work and high work pressure, potentially reducing work performance and increasing the risk for medical errors. OBJECTIVES: To determine whether high-intensity dynamic light improves cognitive performance, self-reported depressive signs and symptoms, fatigue, alertness, and well-being in intensive care unit nurses. METHODS: In a single-center crossover study in an intensive care unit of a teaching hospital in the Netherlands, 10 registered nurses were randomly divided into 2 groups. Each group worked alternately for 3 to 4 days in patients' rooms with dynamic light and 3 to 4 days in control lighting settings. High-intensity dynamic light was administered through ceiling mounted fluorescent tubes that delivered bluish white light up to 1700 lux during the daytime, versus 300 lux in control settings. Cognitive performance, self reported depressive signs and symptoms, fatigue, and well-being before and after each period were assessed by using validated cognitive tests and questionnaires. RESULTS: Cognitive performance, self-reported depressive signs and symptoms, and fatigue did not differ significantly between the 2 light settings. Scores of subjective well-being were significantly lower after a period of working in dynamic light. CONCLUSIONS: Daytime lighting conditions did not affect intensive care unit nurses' cognitive performance, perceived depressive signs and symptoms, or fatigue. Perceived quality of life, predominantly in the psychological and environmental domains, was lower for nurses working in dynamic light. PMID- 29716909 TI - Survival of Patients With Severe Acute Respiratory Distress Syndrome Treated Without Extracorporeal Membrane Oxygenation. AB - BACKGROUND: Case series have reported favorable outcomes with extracorporeal membrane oxygenation (ECMO) in patients with severe acute respiratory distress syndrome. However, those patients were generally young, with few comorbid conditions. OBJECTIVE: To characterize the clinical features and survival rates of patients with severe acute respiratory distress syndrome who met criteria for ECMO but were managed without it. METHODS: Patients who met the study criteria were identified prospectively. Inclusion criteria for ECMO included severe hypoxemia, uncompensated hypercapnia, or elevated end-inspiratory plateau pressures despite low tidal volume ventilation. Predicted survival rates with ECMO were calculated using the Respiratory ECMO Survival Prediction score. RESULTS: Of the 46 patients who met the criteria for severe acute respiratory distress syndrome and ECMO consideration, 5 received ECMO and 16 patients had at least 1 contraindication to it. The remaining 25 patients met ECMO criteria but did not receive the treatment. The patients' mean age was 53.5 (SD, 14.3) years; 84% had at least 1 major comorbid condition. The median predicted survival rate with ECMO was 57%. The actual hospital discharge survival rate without ECMO was 56%. CONCLUSIONS: The general medical intensive care patient population with severe acute respiratory distress syndrome is older and sicker than patients reported in prior case series in which patients were treated with ECMO. In this study, the survival rate without ECMO was similar to predicted survival rates with ECMO. PMID- 29716914 TI - 2018 National Teaching Institute Research Abstracts. PMID- 29716908 TI - Critical Care Nurses' Experiences With Spiritual Care: The SPIRIT Study. AB - BACKGROUND: Little is known about the effect of chaplains on critical care nurses who are caring for critically ill patients and their families. OBJECTIVE: To understand nurses' experiences when they make a referral to the Spiritual Care Department for a patient or the family of a patient who is dying or deceased. Specific aims were to explore spiritual care's effect on nurses and how nurses understand the role of spiritual care in practice. METHODS: A qualitative descriptive study using in-person, semistructured interviews in a 21-bed medical surgical intensive care unit in a teaching hospital. Purposeful sampling identified nurses who had at least 5 years of experience and had cared for at least 5 patients who died on their shift and at least 5 patients for whom they initiated a spiritual care referral. Interviews were digitally recorded and anonymized; conventional content analysis was used to analyze transcripts. Three investigators independently coded 5 transcripts and developed the preliminary coding list. As analysis proceeded, investigators organized codes into categories and themes. RESULTS: A total of 25 nurses were interviewed. The central theme that emerged was presence, described through 3 main categories: the value of having chaplains present in the intensive care unit and their role, nurses' experiences working with chaplains, and nurses' experiences providing spiritual care. CONCLUSION: Nurses considered spiritual care essential to holistic care and valued the support chaplains provide to patients, families, and staff in today's spiritually diverse society. PMID- 29716907 TI - Early Blood Transfusions in Sepsis: Unchanged Survival and Increased Costs. AB - BACKGROUND: Early red blood cell transfusions are a common treatment for adults hospitalized for sepsis without shock. However, their utility and association with mortality and costs have not been well studied. OBJECTIVES: To examine early transfusion rates for patients with sepsis treated outside intensive care units, and to find a correlation between transfusion rates and survival rates and costs. METHODS: Data were obtained from hospital members of the Premier Healthcare Alliance that admitted at least 50 adults with sepsis between January 1, 2006, and December 31, 2010. Early transfusion rates at each hospital were calculated as the observed incidence of allogeneic red blood cells administered by hospital day 2. A multivariable logistic regression model was constructed to estimate the expected or risk-adjusted transfusion rates, mortality rates, and costs. RESULTS: A total of 256 396 adults were hospitalized with sepsis without major bleeding or surgery at 364 US hospitals. Approximately 84% of all patients admitted with sepsis, without vasopressor therapy, were treated outside the intensive care unit (by day 2). The mean institutional early transfusion rate was 6.9%. After risk standardization, the median (interquartile range) transfusion rate was 6.7% (5.8% 7.6%), mortality rate was 15.5% (13.1%-18.1%), and costs were $13 333 ($11 939 $14 986). Early transfusion rates were not correlated with mortality but were modestly positively correlated with costs (Spearman rho = 0.157; P = .003). CONCLUSIONS: Early transfusion rates during hospitalization for sepsis without shock varied widely across the hospitals. Transfusion rates were associated with increased costs but not with mortality rates. PMID- 29716917 TI - Rocketing smoking rates across Africa stoke TB and HIV fears. PMID- 29716916 TI - Reducing overtreatment of prostate cancer by radical prostatectomy in Eastern Ontario: a population-based cohort study. AB - BACKGROUND: Canadian guidelines recommend against population-based screening for prostate cancer because of the risk of overdiagnosis and overtreatment. We sought to assess whether a higher proportion of patients receiving surgery had clinically significant cancer over time. METHODS: All hospitals in Eastern Ontario that perform prostatectomy participate in a Prostate Cancer Community of Practice, which prospectively maintains a database for the region. Using these data, we conducted a retrospective cohort study that included all patients who underwent prostatectomy from 2009 to 2015 in the region. We examined trends in biopsy findings, clinical stage, prostate-specific antigen level and Gleason score. We then determined whether the proportion of patients with clinically significant cancer (Gleason score >= 7 or stage pT3) increased over time. RESULTS: During the study period, 1897 patients underwent prostatectomy in Eastern Ontario (mean 271 surgeries/yr). The proportion of patients who were determined to have National Comprehensive Cancer Network intermediate or high risk disease increased from 46.7% in 2009 to 90.2% in 2015. The proportion of men with clinically significant cancer on prostatectomy increased from 59.7% in 2009 to 93.1% in 2015. Adjusted analyses suggested that the proportion of patients with clinically significant cancer increased by 5% per year during the study period. INTERPRETATION: There has been a change in the tumour characteristics of patients who undergo prostatectomy in Eastern Ontario. In recent years, almost all patients have had clinically significant cancer, which suggests that overtreatment of prostate cancer has decreased. PMID- 29716915 TI - PSMD5 Inactivation Promotes 26S Proteasome Assembly during Colorectal Tumor Progression. AB - Protein degradation by the ubiquitin-proteasome system (UPS) is central to protein homeostasis and cell survival. The active 26S proteasome is a large protease complex consisting of a catalytic 20S subunit and 19S regulatory particles. Cancer cells are exposed to considerable protein overload due to high metabolic rates, reprogrammed energy metabolism, and aneuploidy. Here we report a mechanism that facilitates the assembly of active 26S proteasomes in malignant cells. Upon tumorigenic transformation of the gut epithelium, 26S proteasome assembly was significantly enhanced, but levels of individual subunits were not changed. This enhanced assembly of 26S proteasomes increased further with tumor progression and was observed specifically in transformed cells, but not in other rapidly dividing cells. Moreover, expression of PSMD5, an inhibitor of proteasome assembly, was reduced in intestinal tumors and silenced with tumor progression. Reexpression of PSMD5 in tumor cells caused decreased 26S assembly and accumulation of polyubiquitinated proteins. These results suggest that inhibition of cancer-associated proteasome assembly may provide a novel therapeutic strategy to selectively kill cancer cells.Significance: Enhanced cancer-associated proteasome assembly is a major stress response that allows tumors to adapt to and to withstand protein overload.Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3458/F1.large.jpg Cancer Res; 78(13); 3458-68. (c)2018 AACR. PMID- 29716926 TI - Studying the Effects of Nonindicated Medications on Cancer: Etiologic versus Action-Focused Analysis of Epidemiologic Data. AB - The study of nonindicated medications on cancer outcomes is challenged by potential time-related biases. The literature has strongly advocated for treating the exposure as time-varying and summarizing the outcomes through a dose-response model (an etiologic-focused analysis). An alternative is to refashion the data to resemble a hypothetical randomized trial of drug use (an action-focused analysis). To our knowledge, their relative treatment of time-related bias and aspects of interpretation have not been compared. In this commentary, using the study of metformin use on colorectal cancer risk by Bradley and colleagues (2018) as motivation, we compare the etiologic versus action-focused analysis of epidemiologic data. We examine their treatment of immortal person-time, time varying confounding, selection bias, and the biological and clinical relevance of their results. In doing so, we aim to establish areas of common ground and points of departure that can guide future observational studies of medications on cancer risk, recurrence, and survival. Cancer Epidemiol Biomarkers Prev; 27(5); 520-4. (c)2018 AACRSee related article by Bradley et al., p. 525. PMID- 29716921 TI - A Multi-center Phase I Trial of Ipilimumab in Patients with Myelodysplastic Syndromes following Hypomethylating Agent Failure. AB - Purpose: After failure of hypomethylating agents (HMA), patients with myelodysplastic syndromes (MDS) have dismal survival and no approved treatment options.Patients and Methods: We conducted a phase 1b investigator-initiated trial of ipilimumab in patients with higher risk MDS who have failed HMAs. Patients received monotherapy at two dose levels (DL; 3 and 10 mg/kg) with an induction followed by a maintenance phase. Toxicities and responses were evaluated with CTCAE.4 and IWG-2006 criteria, respectively. We also performed immunologic assays and T-cell receptor sequencing on serial samples.Results: Twenty-nine patients from 7 centers were enrolled. In the initial DL1 (3 mg), 3 of 6 patients experienced grade 2-4 immune-related adverse events (IRAE) that were reversible with drug discontinuation and/or systemic steroids. In DL2, 4 of 5 patients experienced grade 2 or higher IRAE; thus, DL1 (3 mg/kg) was expanded with no grade 2-4 IRAEs reported in 18 additional patients. Best responses included marrow complete response (mCR) in one patient (3.4%). Prolonged stable disease (PSD) for >=46 weeks occurred in 7 patients (24% of entire cohort and 29% of those treated with 3 mg/kg dose), including 3 patients with more than a year of SD. Five patients underwent allografting without excessive toxicity. Median survival for the group was 294 days (95% CI, 240-671+). Patients who achieved PSD or mCR had significantly higher frequency of T cells expressing ICOS (inducible T cell co-stimulator).Conclusions: Our findings suggest that ipilimumab dosed at 3 mg/kg in patients with MDS after HMA failure is safe but has limited efficacy as a monotherapy. Increased frequency of ICOS-expressing T cells might predict clinical benefit. Clin Cancer Res; 24(15); 3519-27. (c)2018 AACR. PMID- 29716919 TI - Abemaciclib, a Selective CDK4/6 Inhibitor, Enhances the Radiosensitivity of Non Small Cell Lung Cancer In Vitro and In Vivo. AB - Purpose: To characterize the ionizing radiation (IR) enhancing effects and underlying mechanisms of the CDK4/6 inhibitor abemaciclib in non-small cell lung cancer (NSCLC) cells in vitro and in vivoExperimental Design: IR enhancement by abemaciclib in a variety of NSCLC cell lines was assessed by in vitro clonogenic assay, flow cytometry, and target inhibition verified by immunoblotting. IR induced DNA damage repair was evaluated by gammaH2AX analysis. Global metabolic alterations by abemaciclib and IR combination were evaluated by LC/MS mass spectrometry and YSI bioanalyzer. Effects of abemaciclib and IR combination in vivo were studied by xenograft tumor regrowth delay, xenograft lysate immunoblotting, and tissue section immunohistochemistry.Results: Abemaciclib enhanced the radiosensitivity of NSCLC cells independent of RAS or EGFR status. Enhancement of radiosensitivity was lost in cell lines deficient for functional p53 and RB protein. After IR, abemaciclib treatment inhibited DNA damage repair as measured by gammaH2AX. Mechanistically, abemaciclib inhibited RB phosphorylation, leading to cell-cycle arrest. It also inhibited mTOR signaling and reduced intracellular amino acid pools, causing nutrient stress. In vivo, abemaciclib, when administered in an adjuvant setting for the second week after fractionated IR, further inhibited vasculogenesis and tumor regrowth, with sustained inhibition of RB/E2F activity, mTOR pathway, and HIF-1 expression. In summary, our study signifies inhibiting the CDK4/6 pathway by abemaciclib in combination with IR as a promising therapeutic strategy to treat NSCLC.Conclusions: Abemaciclib in combination with IR enhances NSCLC radiosensitivity in preclinical models, potentially providing a novel biomarker driven combination therapeutic strategy for patients with NSCLC. Clin Cancer Res; 24(16); 3994-4005. (c)2018 AACR. PMID- 29716918 TI - The IGF2/IR/IGF1R Pathway in Tumor Cells and Myofibroblasts Mediates Resistance to EGFR Inhibition in Cholangiocarcinoma. AB - Purpose: Cholangiocarcinoma (CCA) is a desmoplastic tumor of the biliary tree in which epidermal growth factor receptor (EGFR) is overexpressed and contributes to cancer progression. Although EGFR has been envisaged as a target for therapy, treatment with tyrosine kinase inhibitors (TKI) such as erlotinib did not provide therapeutic benefit in patients with CCA, emphasizing the need to investigate resistance mechanisms against EGFR inhibition.Experimental Design: Resistant CCA cells to EGFR inhibition were obtained upon long-time exposure of cells with erlotinib. Cell signaling, viability, migration, and spheroid growth were determined in vitro, and tumor growth was evaluated in CCA xenograft models.Results: Erlotinib-resistant CCA cells displayed metastasis-associated signatures that correlated with a marked change in cell plasticity associated with an epithelial-mesenchymal transition (EMT) and a cancer stem cell (CSC)-like phenotype. Resistant cells exhibited an upregulation of insulin receptor (IR) and insulin-like growth factor (IGF) 1 receptor (IGF1R), along with an increase in IGF2 expression. IR/IGF1R inhibition reduced EMT and CSC-like traits in resistant cells. In vivo, tumors developed from resistant CCA cells were larger and exhibited a more prominent stromal compartment, enriched in cancer-associated fibroblasts (CAF). Pharmacological coinhibition of EGFR and IR/IGF1R reduced tumor growth and stromal compartment in resistant tumors. Modeling of CCA-CAF crosstalk showed that IGF2 expressed by fibroblasts boosted IR/IGF1R signaling in resistant cells. Furthermore, IR/IGF1R signaling positively regulated fibroblast proliferation and activation.Conclusions: To escape EGFR-TKI treatment, CCA tumor cells develop an adaptive mechanism by undergoing an IR/IGF1R-dependent phenotypic switch, involving a contribution of stromal cells. Clin Cancer Res; 24(17); 4282-96. (c)2018 AACR. PMID- 29716925 TI - Catchment Areas and Community Outreach and Engagement: The New Mandate for NCI Designated Cancer Centers. PMID- 29716923 TI - Interferon Gamma Messenger RNA Signature in Tumor Biopsies Predicts Outcomes in Patients with Non-Small Cell Lung Carcinoma or Urothelial Cancer Treated with Durvalumab. AB - Purpose: To identify a predictive biomarker for durvalumab, an anti-programmed death ligand 1 (PD-L1) mAb.Experimental Design: RNA sequencing of 97 advanced stage non-small cell lung carcinoma (NSCLC) biopsies from a nonrandomized phase Ib/II clinical trial (1108/NCT01693562) were profiled to identify a predictive signature; 62 locally advanced or metastatic urothelial cancer tumors from the same study were profiled to confirm predictive utility of the signature. Thirty NSCLC patients provided pre- and posttreatment tumors for messenger RNA (mRNA) analysis. NSCLC with >=25% tumor cells and urothelial cancer with >=25% tumor or immune cells stained for PD-L1 at any intensity were scored PD-L1 positive (PD L1+). Kaplan-Meier and Cox proportional hazards analyses were used to adjust for gender, age, prior therapies, histology, ECOG status, liver metastasis, and smoking. Tumor mutation burden (TMB) was calculated using data from The Cancer Genome Atlas (TCGA).Results: In the NSCLC discovery set, a four-gene IFNgamma positive (IFNgamma+) signature comprising IFNgamma, CD274, LAG3, and CXCL9 was associated with higher overall response rates, longer median progression-free survival, and overall survival compared with signature-low patients. IFNgamma+ signature NSCLC patients had improved survival regardless of IHC PD-L1 status. These associations were replicated in a urothelial cancer cohort. The IFNgamma+ signature was induced 2-fold (P = 0.003) by durvalumab after 8 weeks of therapy in patients with NSCLC, and baseline signature was associated with TMB but not survival in TCGA data.Conclusions: The IFNgamma+ mRNA signature may assist in identifying patients with improved outcomes with durvalumab, independent of PD-L1 assessed by IHC. Clin Cancer Res; 24(16); 3857-66. (c)2018 AACR. PMID- 29716929 TI - Collagen Alignment and Recurrence of DCIS-Letter. PMID- 29716927 TI - A Cohort Study of Metformin and Colorectal Cancer Risk among Patients with Diabetes Mellitus. AB - Background: Several epidemiologic studies have reported strong inverse associations between metformin use and risk of colorectal cancer, although time related biases, such as immortal time bias, may in part explain these findings. We reexamined this association using methods to minimize these biases.Methods: A cohort study was conducted among 47,351 members of Kaiser Permanente Northern California with diabetes and no history of cancer or metformin use. Follow-up for incident colorectal cancer occurred from January 1, 1997, until June 30, 2012. Cox regression was used to calculate HRs and 95% confidence intervals (CIs) for colorectal cancer risk associated with metformin use (ever use, total duration, recency of use, and cumulative dose).Results: No association was observed between ever use of metformin and colorectal cancer risk (HR, 0.90; 95% CI, 0.76-1.07) and there was no consistent pattern of decreasing risk with increasing total duration, dose, or recency of use. However, long-term use (>=5.0 years) appeared to be associated with reduced risk of colorectal cancer in the full population (HR, 0.78; 95% CI, 0.60-1.02), among current users (HR, 0.78; 95% CI, 0.59-1.04), and in men (HR, 0.65; 95% CI, 0.45-0.94) but not in women. Higher cumulative doses of metformin were associated with reduced risk. In initial users of sulfonylureas, switching to or adding metformin was also associated with decreased colorectal cancer risk.Conclusions: Our findings showed an inverse association between long-term use of metformin and colorectal cancer risk. Findings, especially the risk reduction among men, need to be confirmed in large, well-conducted studies.Impact: If our findings are confirmed, metformin may have a role in the chemoprevention of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 27(5); 525-30. (c)2018 AACRSee related commentary by Jackson and Garcia Albeniz, p. 520. PMID- 29716930 TI - Periodontal Disease and Incident Cancer-Letter. PMID- 29716920 TI - CD20-TCB with Obinutuzumab Pretreatment as Next-Generation Treatment of Hematologic Malignancies. AB - Purpose: Despite promising clinical activity, T-cell-engaging therapies including T-cell bispecific antibodies (TCB) are associated with severe side effects requiring the use of step-up-dosing (SUD) regimens to mitigate safety. Here, we present a next-generation CD20-targeting TCB (CD20-TCB) with significantly higher potency and a novel approach enabling safer administration of such potent drug.Experimental Design: We developed CD20-TCB based on the 2:1 TCB molecular format and characterized its activity preclinically. We also applied a single administration of obinutuzumab (Gazyva pretreatment, Gpt; Genentech/Roche) prior to the first infusion of CD20-TCB as a way to safely administer such a potent drug.Results: CD20-TCB is associated with a long half-life and high potency enabled by high-avidity bivalent binding to CD20 and head-to-tail orientation of B- and T-cell-binding domains in a 2:1 molecular format. CD20-TCB displays considerably higher potency than other CD20-TCB antibodies in clinical development and is efficacious on tumor cells expressing low levels of CD20. CD20 TCB also displays potent activity in primary tumor samples with low effector:target ratios. In vivo, CD20-TCB regresses established tumors of aggressive lymphoma models. Gpt enables profound B-cell depletion in peripheral blood and secondary lymphoid organs and reduces T-cell activation and cytokine release in the peripheral blood, thus increasing the safety of CD20-TCB administration. Gpt is more efficacious and safer than SUD.Conclusions: CD20-TCB and Gpt represent a potent and safer approach for treatment of lymphoma patients and are currently being evaluated in phase I, multicenter study in patients with relapsed/refractory non-Hodgkin lymphoma (NCT03075696). Clin Cancer Res; 24(19); 4785-97. (c)2018 AACR See related commentary by Prakash and Diefenbach, p. 4631. PMID- 29716934 TI - Getting to the Right Place at the Right Time: Another Piece of the STEMI Puzzle. PMID- 29716932 TI - Correction: Gene Copy Number Estimation from Targeted Next-Generation Sequencing of Prostate Cancer Biopsies: Analytic Validation and Clinical Qualification. PMID- 29716933 TI - Taking the Reins on Systems of Care for ST-Segment-Elevation Myocardial Infarction Patients: A Report From the American Heart Association Mission: Lifeline Program. AB - BACKGROUND: Early success with regionalization of ST-segment-elevation myocardial infarction (STEMI) care has led many states to adopt statewide prehospital STEMI hospital destination policies, allowing emergency medical services to bypass non percutaneous coronary intervention-capable hospitals. The association between adoption of these policies and patterns of care among STEMI patients is unknown. METHODS AND RESULTS: Using data from January 1, 2013, to December 31, 2014, from the National Cardiovascular Data Registry and Acute Coronary Treatment and Intervention Outcomes Network Registry, 6 states with bypass policies (cases included Delaware, Iowa, Maryland, North Carolina, Pennsylvania, and Massachusetts) were matched to 6 states without bypass policies (controls included South Carolina, Minnesota, Virginia, Texas, New York, and Connecticut) a priori on region, hospital density, and percent state participation in the registry. Using the matched sample, logistic regression models were adjusted for patient- and state-level characteristics. Outcomes were receipt of reperfusion and receipt of timely percutaneous coronary intervention. Our study cohort included 19 287 patients at 379 sites across 12 states. Patients from states with hospital destination policies were similar in age, sex, and comorbidities to patients from states without such policies. After adjustment for patient- and state-level characteristics, 57.9% (95% confidence intervals, 53.2%-62.5%) of patients living in states with hospital destination policies when compared with 47.5% (95% confidence intervals, 43.4%-51.7%) living in states without hospital destination policies received primary percutaneous coronary intervention within their relevant guideline-recommended time from first medical contact. CONCLUSIONS: Statewide adoption of STEMI hospital destination policies allowing emergency medical services to bypass non-percutaneous coronary intervention capable facilities is associated with significantly faster treatment times for patients with STEMI. PMID- 29716939 TI - Oncogenic Mutants of MEK1: A Trilogy Unfolds. AB - It has generally been assumed that MEK mutants function similarly to one another and respond in the same manner to targeted drugs. Gao and colleagues challenge this assumption and report that MEK1 mutants fall into three unique phenotypic classes with respect to RAF dependency. A new class of MEK1 mutants is shown here to be RAF-independent, resistant to allosteric MEK inhibitors, and yet sensitive to treatment with a new ATP-competitive MEK inhibitor. Cancer Discov; 8(5); 534 6. (c)2018 AACRSee related article by Gao et al., p. 648. PMID- 29716928 TI - Dairy Consumption in Adolescence and Early Adulthood and Risk of Breast Cancer. AB - Background: Carcinogenic exposure in early life may be critical for subsequent breast cancer risk. Dairy consumption was examined during adolescence and early adulthood in relation to incident breast cancer in the Nurses' Health Study II cohort.Methods: For the analyses of early adulthood dairy consumption, we included 90,503 premenopausal women ages 27 to 44 years in 1991 who reported dairy consumption using a validated food-frequency questionnaire. From 1991 to 2013, 3,191 invasive breast cancer cases were identified. In 1998, 44,264 women recalled adolescent dairy consumption. This subgroup of women was followed up from 1998 to 2013; 1,318 invasive breast cancer cases were identified. Multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox proportional hazard regression.Results: Adolescent and early adulthood total dairy consumption was not associated with overall breast cancer risk (each serving/day during adolescence, total dairy HR = 1.02, 95% CI, 0.97-1.07; for early adulthood total dairy HR = 1.01, 95% CI, 0.97-1.04), as were intakes of calcium, vitamin D, and lactose. Adolescent consumption of total and high-fat dairy was associated with higher risk of estrogen and progesterone receptor negative (each serving/day: total dairy HR = 1.11, 95% CI, 1.00-1.24; high-fat dairy HR = 1.17, 95% CI, 1.04-1.31). However, higher adolescent high-fat dairy consumption was associated with lower risk of estrogen and progesterone receptor positive tumors (each serving/day HR = 0.91, 95% CI, 0.86 0.97).Conclusions: Our results suggest no overall association between dairy consumption during adolescence or early adulthood and breast cancer risk, but the findings may differ by hormone receptor status of tumors.Impact: Dairy consumption in adolescence or early adulthood may not be a significant predictor of breast cancer incidence. Cancer Epidemiol Biomarkers Prev; 27(5); 575-84. (c)2018 AACR. PMID- 29716938 TI - Dual MAPK/CDK Targeting in Melanoma: New Approaches, New Challenges. AB - Dual MAPK and CDK4/6 targeting is an emerging strategy in melanoma, but toxicity and acquired resistance are limitations. In this issue, two groups (Teh and colleagues and Romano and colleagues) show that therapeutic resistance mechanisms converge on the PI3K pathway, and inhibition of this pathway's mediators can overcome this resistance. Cancer Discov; 8(5); 532-3. (c)2018 AACRSee related article by Romano et al., p. 556See related article by Teh et al., p. 568. PMID- 29716941 TI - Increased Reticulon 3 (RTN3) Leads to Obesity and Hypertriglyceridemia by Interacting With Heat Shock Protein Family A (Hsp70) Member 5 (HSPA5). AB - BACKGROUND: Reticulon 3 (RTN3) is an endoplasmic reticulum protein that has previously been shown to play a role in neurodegenerative diseases, but little is known about its role in lipid metabolism. METHODS: Obese patients (n=149), hypertriglyceridemic patients (n=343), and healthy control subjects (n=84) were enrolled to assess their levels of RTN3. To explore the pathophysiological roles of RTN3 in the control of lipid metabolism, we used transgenic mice overexpressing the wild-type human RTN3 gene, the RTN3-null transgenic mouse model, and multiple Caenorhabditis legans strains for molecular characterization. The underlying mechanisms were studied with 3T3L1 cell cultures in vitro. RESULTS: We report that overexpressed RTN3 in mice induces obesity and higher accumulation of triglycerides. Increased RTN3 expression is also found in patients with obesity and hypertriglyceridemia. We reveal that RTN3 plays critical roles in regulating the biosynthesis and storage of triglycerides and in controlling lipid droplet expansion. Mechanistically, RTN3 regulates these events through its interactions with heat shock protein family A (Hsp70) member 5, and this enhanced interaction increases sterol regulatory element-binding protein 1c and AMP-activated kinase activity. CONCLUSIONS: This study provides evidence for a role of RTN3 in inducing obesity and triglyceride accumulation and suggests that inhibiting the expression of RTN3 in fat tissue may be a novel therapeutic approach to treat obesity and hypertriglyceridemia. PMID- 29716940 TI - Residual Inflammatory Risk on Treatment With PCSK9 Inhibition and Statin Therapy. AB - BACKGROUND: The combination of statin therapy and PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition markedly lowers low-density lipoprotein cholesterol (LDL-C) and reduces cardiovascular event rates. Whether residual inflammatory risk as measured by on-treatment high sensitivity C-reactive protein (hsCRP) remains an important clinical issue in such patients is uncertain. METHODS: We evaluated residual inflammatory risk among 9738 patients participating in the SPIRE-1 and SPIRE-2 cardiovascular outcomes trials (Studies of PCSK9 Inhibition and the Reduction in Vascular Events), who were receiving both statin therapy and bococizumab, according to on-treatment levels of hsCRP (hsCRPOT) and LDL-COT measured 14 weeks after drug initiation. The primary end point was nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina requiring urgent revascularization, or cardiovascular death. RESULTS: At 14 weeks, the mean percentage change in LDL-C among statin-treated patients who additionally received bococizumab was -60.5% (95% confidence interval [CI], -61.2 to -59.8; P<0.001; median change, -65.4%) as compared to 6.6% (95% CI, -1.0 to 14.1; P=0.09; median change, 0.0%) for hsCRP. Incidence rates for future cardiovascular events for patients treated with both statin therapy and bococizumab according to hsCRPOT <1, 1 to 3, and >3 mg/L were 1.96, 2.50, and 3.59 events per 100 person-years, respectively, corresponding to multivariable adjusted hazard ratios of 1.0, 1.16 (95% CI, 0.81-1.66), and 1.62 (95% CI, 1.14-2.30) (P-trend=0.001) after adjustment for traditional cardiovascular risk factors and LDL-COT. Comparable adjusted hazard ratios for LDL-COT (<30, 30-50, >50 mg/dL) were 1.0, 0.87, and 1.21, respectively (P trend=0.16). Relative risk reductions with bococizumab were similar across hsCRPOT groups (P-interaction=0.87). CONCLUSIONS: In this post hoc analysis of the SPIRE trials of bococizumab in a stable outpatient population, evidence of residual inflammatory risk persisted among patients treated with both statin therapy and proprotein convertase subtilisin-kexin type 9 inhibition. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT01975376, NCT01975389. PMID- 29716922 TI - MEIS1 and MEIS2 Expression and Prostate Cancer Progression: A Role For HOXB13 Binding Partners in Metastatic Disease. AB - Purpose: Germline mutations within the MEIS-interaction domain of HOXB13 have implicated a critical function for MEIS-HOX interactions in prostate cancer etiology and progression. The functional and predictive role of changes in MEIS expression within prostate tumor progression, however, remain largely unexplored.Experimental Design: Here we utilize RNA expression datasets, annotated tissue microarrays, and cell-based functional assays to investigate the role of MEIS1 and MEIS2 in prostate cancer and metastatic progression.Results: These analyses demonstrate a stepwise decrease in the expression of both MEIS1 and MEIS2 from benign epithelia, to primary tumor, to metastatic tissues. Positive expression of MEIS proteins in primary tumors, however, is associated with a lower hazard of clinical metastasis (HR = 0.28) after multivariable analysis. Pathway and gene set enrichment analyses identified MEIS-associated networks involved in cMYC signaling, cellular proliferation, motility, and local tumor environment. Depletion of MEIS1 and MEIS2 resulted in increased tumor growth over time in vivo, and decreased MEIS expression in both patient-derived tumors and MEIS-depleted cell lines was associated with increased expression of the protumorigenic genes cMYC and CD142, and decreased expression of AXIN2, FN1, ROCK1, SERPINE2, SNAI2, and TGFbeta2.Conclusions: These data implicate a functional role for MEIS proteins in regulating cancer progression, and support a hypothesis whereby tumor expression of MEIS1 and MEIS2 expression confers a more indolent prostate cancer phenotype, with a decreased propensity for metastatic progression. Clin Cancer Res; 24(15); 3668-80. (c)2018 AACR. PMID- 29716944 TI - Nitric oxide-mediated intersegmental modulation of cycle frequency in the crayfish swimmeret system. AB - Crayfish swimmerets are paired appendages located on the ventral side of each abdominal segment that show rhythmic beating during forward swimming produced by central pattern generators in most abdominal segments. For animals with multiple body segments and limbs, intersegmental coordination of central pattern generators in each segment is crucial for the production of effective movements. Here we develop a novel pharmacological approach to analyse intersegmental modulation of swimmeret rhythm by selectively elevating nitric oxide levels and reducing them with pharmacological agents, in specific ganglia. Bath application of L-arginine, the substrate NO synthesis, increased the cyclical spike responses of the power-stroke motor neurons. By contrast the NOS inhibitor, L-NAME decreased them. To determine the role of the different local centres in producing and controlling the swimmeret rhythm, these two drugs were applied locally to two separate ganglia following bath application of carbachol. Results revealed that there was both ascending and descending intersegmental modulation of cycle frequency of the swimmeret rhythm in the abdominal ganglia and that synchrony of cyclical activity between segments of segments was maintained. We also found that there were gradients in the strength effectiveness in modulation, that ascending modulation of the swimmeret rhythm was stronger than descending modulation. PMID- 29716945 TI - Fish learn collectively, but groups with differing personalities are slower to decide and more likely to split. AB - We tested zebrafish shoals to examine whether groups exhibit collective spatial learning and whether this relates to the personality of group members. To do this we trained shoals to associate a collective spatial decision with a reward and tested whether shoals could reorient to the learned location from a new starting point. There were strong indications of collective learning and collective reorienting, most likely by memorising distal cues, but these processes were unrelated to personality differences within shoals. However, there was evidence that group decisions require agreement between differing personalities. Notably, shoals with more boldness variation were more likely to split during training trials and took longer to reach a collective decision. Thus cognitive tasks, such as learning and cue memorisation, may be exhibited collectively, but the ability to reach collective decisions is affected by the personality composition of the group. A likely outcome of the splitting of groups with very disparate personalities is the formation of groups with members more similar in their personality. PMID- 29716943 TI - Hepatic glucose metabolic responses to digestible dietary carbohydrates in two isogenic lines of rainbow trout. AB - Rainbow trout (Oncorhynchus mykiss) was recognized as a typical 'glucose intolerant' fish and poor dietary carbohydrate user. Our first objective was to test the effect of dietary carbohydrates themselves (without modification of dietary protein intake) on hepatic glucose gene expression (taking into account the paralogs). The second aim was to research if two isogenic trout lines had different responses to carbohydrate intake, showing one with a better use dietary carbohydrates. Thus, we used two isogenic lines of rainbow trout (named A32h and AB1h) fed with either a high carbohydrate diet or a low carbohydrate diet for 12 weeks. We analysed the zootechnical parameters, the plasma metabolites, the hepatic glucose metabolism at the molecular level and the hormonal-nutrient sensing pathway. Globally, dietary carbohydrate intake was associated with hyperglycaemia and down regulation of the energy sensor Ampk, but also with atypical regulation of glycolysis and gluconeogenesis in the liver. Indeed, the first steps of glycolysis and gluconeogenesis catalysed by the glucokinase and the phospenolpyruvate carboxykinase are regulated at the molecular level by dietary carbohydrates as expected (i.e. induction of the glycolytic gck and repression of the gluconeogenic pck); by contrast, and surprisingly, for two other key glycolytic enzymes (phosphofructokinase enzyme - pfkl and pyruvate kinase - pk) some of the paralogs (pfklb and pklr) are inhibited by carbohydrates whereas some of the genes coding gluconeogenic enzymes (the glucose-6-phosphatase enzyme g6pcb1b and g6pcb2a gene and the fructose1-6 biphosphatase paralog fbp1a) are induced. On the other hand, some differences for the zootechnical parameters and metabolic genes were also found between the two isogenic lines, confirming the existence of genetic polymorphisms for nutritional regulation of intermediary metabolism in rainbow trout. In conclusion, our study determines some new and unexpected molecular regulations of the glucose metabolism in rainbow trout which may partly lead to the poor utilization of dietary carbohydrates and it underlines the existence of differences in molecular regulation of glucose metabolism between two isogenic lines which provides arguments for future selection of rainbow trout. PMID- 29716951 TI - Correction: Ormeloxifene Suppresses Desmoplasia and Enhances Sensitivity of Gemcitabine in Pancreatic Cancer. PMID- 29716952 TI - Correction: SlicerDMRI: Open Source Diffusion MRI Software for Brain Cancer Research. PMID- 29716948 TI - Tension-loaded bone marrow stromal cells potentiate the paracrine osteogenic signaling of co-cultured vascular endothelial cells. AB - Co-culture of bone marrow stromal cells (BMSCs) and vascular endothelial cells (VECs) is a promising strategy for better osteogenesis and pre-vascularization in bone tissue engineering. Recent reports have shown that mechanical stretching further promotes osteogenesis in BMSC/VEC co-culture systems, but the underlying mechanism of this process remains unclear. In this study, noncontact co-cultures of rat primary BMSCs and VECs were employed to interrogate paracrine cell-to-cell communications in response to tension. Exposure of VECs to 6% tension for 48 h elicited neither ALP activity nor mRNA expression of OCN and OPN in BMSCs incubated in a shared culture medium. Instead, BMSCs subjected to tension induced robust VEGF release, and its conditioned medium enhanced the proliferation and tubular formation of VECs with a concurrent increase in BMP-2 and IGF-1 production. Conditioned medium from activated VECs in turn promoted expression of osteogenic genes in BMSCs, followed by an increase in matrix mineralization. The addition of VEGF-R inhibitor Tivozanib to these systems abrogated the tension induced paracrine effects on VECs and subsequently impaired BMSC osteogenesis. These results clearly demonstrate that the response of BMSCs to tension potentiates paracrine osteogenic signaling from VECs; this positive feedback loop is initiated by VEGF release. PMID- 29716953 TI - Correction: Comparative Cistromics Reveals Genomic Cross-talk between FOXA1 and ERalpha in Tamoxifen-Associated Endometrial Carcinomas. PMID- 29716949 TI - Motor Proteins. AB - SUMMARYMyosin motors power movements on actin filaments, whereas dynein and kinesin motors power movements on microtubules. The mechanisms of these motor proteins differ, but, in all cases, ATP hydrolysis and subsequent release of the hydrolysis products drives a cycle of interactions with the track (either an actin filament or a microtubule), resulting in force generation and directed movement. PMID- 29716946 TI - Cell-autonomous role of GFRalpha1 in the development of olfactory bulb GABAergic interneurons. AB - GFRalpha1, a receptor for glial cell line-derived neurotrophic factor (GDNF), is critical for the development of the main olfactory system. The olfactory bulb (OB) of Gfra1 knockout mice shows significant reductions in the number of olfactory sensory neurons, mitral and tufted cells, as well as all major classes of OB GABAergic interneurons. However, the latter do not express significant levels of GFRalpha1, leaving the mechanism of action of GFRalpha1 in OB interneuron development unexplained. Here we report that GFRalpha1 is highly expressed in the precursor cells that give rise to all major classes of OB interneurons, but is downregulated as these neurons mature. Conditional ablation of GFRalpha1 in embryonic GABAergic cells recapitulated the cell losses observed in global Gfra1 knockouts at birth. GFRalpha1 was also required for the sustained generation and allocation of OB interneurons in adulthood. Conditional loss of GFRalpha1 altered the migratory behaviour of neuroblasts along the rostral migratory stream (RMS) as well as RMS glial tunnel formation. Together, these data indicate that GFRalpha1 functions cell-autonomously in subpopulations of OB interneuron precursors to regulate their generation and allocation in the mammalian OB. PMID- 29716947 TI - Embryonic bone morphogenetic protein and nodal induce invasion in melanocytes and melanoma cells. AB - Despite recent progress in melanoma therapy via inhibition of activated oncogenes or immune stimulation, most stage IV melanoma patients still have limited survival times. Existing therapeutic approaches eventually fail to prevent further invasion and metastasis, which is driven by a morphological process termed epithelial-mesenchymal transition (EMT). We previously demonstrated that inhibition of EMT in melanoma cells via antagonizing the bone morphogenetic protein (BMP)-pathway abrogated EMT and neural crest migration of melanoma cells in chick embryos. Here, we show that BMP-2 is highly expressed in invasive melanoma cells and is elevated in the serum of stage IV melanoma patients compared to stage IB-IIC patients and healthy controls. Highly BMP-2-expressing melanoma cells display enhanced invasion in the rhombencephalon of the chick embryo. In addition to driving neural crest migration in the zebrafish embryo, the agonists BMP-2, BMP-7 and nodal induce EMT/invasion in radial growth phase melanoma cells and in human melanocytes in skin reconstructs. Blocking either BMP or nodal signaling by antagonists (noggin, lefty), or the Alk4/5/7-receptor inhibitor SB431542, decreases EMT and invasion of melanoma cells in human epidermal skin reconstructs. Together, our data suggest that inhibition of EMT inducing pathways in melanoma might be a therapeutic approach to attenuate melanoma cell invasiveness. PMID- 29716942 TI - Mechanosensitive Gene Regulation by Myocardin-Related Transcription Factors Is Required for Cardiomyocyte Integrity in Load-Induced Ventricular Hypertrophy. AB - BACKGROUND: Hypertrophic cardiomyocyte growth and dysfunction accompany various forms of heart disease. The mechanisms responsible for transcriptional changes that affect cardiac physiology and the transition to heart failure are not well understood. The intercalated disc (ID) is a specialized intercellular junction coupling cardiomyocyte force transmission and propagation of electrical activity. The ID is gaining attention as a mechanosensitive signaling hub and hotspot for causative mutations in cardiomyopathy. METHODS: Transmission electron microscopy, confocal microscopy, and single-molecule localization microscopy were used to examine changes in ID structure and protein localization in the murine and human heart. We conducted detailed cardiac functional assessment and transcriptional profiling of mice lacking myocardin-related transcription factor (MRTF)-A and MRTF-B specifically in adult cardiomyocytes to evaluate the role of mechanosensitive regulation of gene expression in load-induced ventricular remodeling. RESULTS: We found that MRTFs localize to IDs in the healthy human heart and accumulate in the nucleus in heart failure. Although mice lacking MRTFs in adult cardiomyocytes display normal cardiac physiology at baseline, pressure overload leads to rapid heart failure characterized by sarcomere disarray, ID disintegration, chamber dilation and wall thinning, cardiac functional decline, and partially penetrant acute lethality. Transcriptional profiling reveals a program of actin cytoskeleton and cardiomyocyte adhesion genes driven by MRTFs during pressure overload. Indeed, conspicuous remodeling of gap junctions at IDs identified by single-molecule localization microscopy may partially stem from a reduction in Mapre1 expression, which we show is a direct mechanosensitive MRTF target. CONCLUSIONS: Our study describes a novel paradigm in which MRTFs control an acute mechanosensitive signaling circuit that coordinates cross-talk between the actin and microtubule cytoskeleton and maintains ID integrity and cardiomyocyte homeostasis in heart disease. PMID- 29716954 TI - Nmnat mitigates sensory dysfunction in a Drosophila model of paclitaxel-induced peripheral neuropathy. AB - Chemotherapy-induced peripheral neuropathy (CIPN) is the major dose-limiting side effect of many commonly used chemotherapeutic agents, including paclitaxel. Currently, there are no neuroprotective or effective symptomatic treatments for CIPN. Lack of understanding of the in vivo mechanisms of CIPN has greatly impeded the identification of therapeutic targets. Here, we optimized a model of paclitaxel-induced peripheral neuropathy using Drosophila larvae that recapitulates aspects of chemotherapy-induced sensory dysfunction. We showed that nociceptive sensitivity is associated with disrupted organization of microtubule associated MAP1B/Futsch and aberrant stabilization of peripheral sensory dendrites. These findings establish a robust and amenable model for studying peripheral mechanisms of CIPN. Using this model, we uncovered a critical role for nicotinamide mononucleotide adenylyltransferase (Nmnat) in maintaining the integrity and function of peripheral sensory neurons and uncovered Nmnat's therapeutic potential against diverse sensory symptoms of CIPN. PMID- 29716955 TI - Evolutionary Pathways for the Generation of New Self-Incompatibility Haplotypes in a Nonself-Recognition System. AB - Self-incompatibility (SI) is a genetically based recognition system that functions to prevent self-fertilization and mating among related plants. An enduring puzzle in SI is how the high diversity observed in nature arises and is maintained. Based on the underlying recognition mechanism, SI can be classified into two main groups: self-recognition (SR) and nonself-recognition (NSR). Most work has focused on diversification within SR systems despite expected differences between the two groups in the evolutionary pathways and outcomes of diversification. Here, we use a deterministic population genetic model and stochastic simulations to investigate how novel S-haplotypes evolve in a gametophytic NSR [SRNase/S Locus F-box (SLF)] SI system. For this model, the pathways for diversification involve either the maintenance or breakdown of SI and can vary in the order of mutations of the female (SRNase) and male (SLF) components. We show analytically that diversification can occur with high inbreeding depression and self-pollination, but this varies with evolutionary pathway and level of completeness (which determines the number of potential mating partners in the population), and, in general, is more likely for lower haplotype number. The conditions for diversification are broader in stochastic simulations of finite population size. However, the number of haplotypes observed under high inbreeding and moderate-to-high self-pollination is less than that commonly observed in nature. Diversification was observed through pathways that maintain SI as well as through self-compatible intermediates. Yet the lifespan of diversified haplotypes was sensitive to their level of completeness. By examining diversification in a NSR SI system, this model extends our understanding of the evolution and maintenance of haplotype diversity observed in a recognition system common in flowering plants. PMID- 29716958 TI - Provider Perspectives on Partnering With Parents of Hospitalized Children to Improve Safety. AB - BACKGROUND AND OBJECTIVES: There is increasing emphasis on the importance of patient and family engagement for improving patient safety. Our purpose in this study was to understand health care team perspectives on parent-provider safety partnerships for hospitalized US children to complement a parallel study of parent perspectives. METHODS: Our research team, including a family advisor, conducted semistructured interviews and focus groups of a purposive sample of 20 inpatient pediatric providers (nurses, patient care technicians, physicians) in an acute-care pediatric unit at a US urban tertiary hospital. We used a constant comparison technique and qualitative thematic content analysis. RESULTS: Themes emerged from providers on facilitators, barriers, and role negotiation and/or balancing interpersonal interactions in parent-provider safety partnership. Facilitators included the following: (1) mutual respect of roles, (2) parent advocacy and rule-following, and (3) provider quality care, empathetic adaptability, and transparent communication of expectations. Barriers included the following: (1) lack of respect, (2) differences in parent versus provider risk perception and parent lack of availability, and (3) provider medical errors and inconsistent communication, lack of engagement skills and time, and fear of overwhelming information. Providers described themes related to balancing parent advocacy with clinician's expertise, a provider's personal response to challenges to the professional role, and parents balancing relationship building with escalating safety concerns. CONCLUSIONS: To keep children safe in the hospital, providers balance perceived challenges to their personal and professional roles continuously in interpersonal interactions, paralleling parent concerns about role ambiguity and trust. Understanding these shared barriers to and facilitators of parent-provider safety partnerships can inform system design, parent education, and professional training. PMID- 29716968 TI - Case 1: Concurrent Upper Respiratory Tract Infection and Vulvar Ulcers in a Teenage Girl. PMID- 29716969 TI - Case 2: Sore Throat and Dysphagia in a 6-year-old Boy. PMID- 29716964 TI - Nuclear Receptor CAR Suppresses GADD45B-p38 MAPK Signaling to Promote Phenobarbital-induced Proliferation in Mouse Liver. AB - Phenobarbital, a nongenotoxic hepatocarcinogen, induces hepatic proliferation and promotes development of hepatocellular carcinoma (HCC) in rodents. Nuclear receptor constitutive active/androstane receptor (NR1I3/CAR) regulates the induction and promotion activities of phenobarbital. Here, it is demonstrated that phenobarbital treatment results in dephosphorylation of a tumor suppressor p38 MAPK in the liver of C57BL/6 and C3H/HeNCrlBR mice. The molecular mechanism entails CAR binding and inhibition of the growth arrest and DNA-damage-inducible 45 beta (GADD45B)-MAPK kinase 6 (MKK6) scaffold to repress phosphorylation of p38 MAPK. Phenobarbital-induced hepatocyte proliferation, as determined by BrdUrd incorporation, was significantly reduced in both male and female livers of GADD45B knockout (KO) mice compared with the wild-type mice. The phenobarbital induced proliferation continued until 48 hours after phenobarbital injection in only the C57BL/6 males, but neither in males of GADD45B KO mice nor in females of C57BL/6 and GADD45B KO mice. Thus, these data reveal nuclear receptor CAR interacts with GADD45B to repress p38 MAPK signaling and elicit hepatocyte proliferation in male mice.Implications: This GADD45B-regulated male-predominant proliferation can be expanded as a phenobarbital promotion signal of HCC development in future studies.Visual Overview: http://mcr.aacrjournals.org/content/molcanres/16/8/1309/F1.large.jpg Mol Cancer Res; 16(8); 1309-18. (c)2018 AACR. PMID- 29716960 TI - Abnormal liver phosphatidylcholine synthesis revealed in patients with acute respiratory distress syndrome. AB - Acute respiratory distress syndrome (ARDS) is associated with a severe pro inflammatory response; although decreased plasma cholesterol concentration has been linked to systemic inflammation, any association of phospholipid metabolic pathways with ARDS has not been characterized. Plasma phosphatidylcholine (PC), the major phospholipid of circulating lipoproteins, is synthesized in human liver by two biologically diverse pathways: the cytidine diphosphocholine (CDP):choline and phosphatidylethanolamine N-methyltransferase (PEMT) pathways. Here, we used ESI-MS/MS both to characterize plasma PC compositions and to quantify metabolic fluxes of both pathways using stable isotopes in patients with severe ARDS and in healthy controls. Direct incorporation of methyl-D9-choline estimated CDP:choline pathway flux, while PEMT flux was determined from incorporations of one and two methyl-D3 groups derived from methyl-D9-choline. The results of MS/MS analysis showed significant alterations in plasma PC composition in patients with ARDS versus healthy controls. In particular, the increased overall methyl-D9-PC enrichment and, most importantly, the much lower methyl-D3-PC and methyl-D6-PC enrichments suggest increased flux through the CDP:choline pathway and reduced flux through the PEMT pathway in ARDS. To our knowledge, this study is the first to demonstrate significant plasma PC molecular compositional changes combined with associated alterations in the dynamics of PC synthetic pathways in patients with ARDS. PMID- 29716965 TI - Pediatric Vision Screening. PMID- 29716967 TI - Bordetella pertussis (Pertussis). PMID- 29716970 TI - Case 3: Persistent Respiratory Distress in a Teenager Treated for Severe Asthma Exacerbation. PMID- 29716971 TI - Case 4: Muscle Rigidity in a 5-year-old Boy. PMID- 29716966 TI - Screening for Poverty and Poverty-Related Social Determinants of Health. PMID- 29716977 TI - Visual Diagnosis: Newborn Girl with Congenital Unilateral Eye Opacity. PMID- 29716963 TI - Plk1 Inhibition Enhances the Efficacy of BET Epigenetic Reader Blockade in Castration-Resistant Prostate Cancer. AB - Polo-like kinase 1 (Plk1), a crucial regulator of cell-cycle progression, is overexpressed in multiple types of cancers and has been proven to be a potent and promising target for cancer treatment. In case of prostate cancer, we once showed that antineoplastic activity of Plk1 inhibitor is largely due to inhibition of androgen receptor (AR) signaling. However, we also discovered that Plk1 inhibition causes activation of the beta-catenin pathway and increased expression of c-MYC, eventually resulting in resistance to Plk1 inhibition. JQ1, a selective small-molecule inhibitor targeting the amino-terminal bromodomains of BRD4, has been shown to dramatically inhibit c-MYC expression and AR signaling, exhibiting antiproliferative effects in a range of cancers. Because c-MYC and AR signaling are essential for prostate cancer initiation and progression, we aim to test whether targeting Plk1 and BRD4 at the same time is an effective approach to treat prostate cancer. Herein, we show that a combination of Plk1 inhibitor GSK461364A and BRD4 inhibitor JQ1 had a strong synergistic effect on castration resistant prostate cancer (CRPC) cell lines, as well as in CRPC xenograft tumors. Mechanistically, the synergistic effect is likely due to two reasons: (i) Plk1 inhibition results in the accumulation of beta-catenin in the nucleus, thus elevation of c-MYC expression, whereas JQ1 treatment directly suppresses c-MYC transcription; (ii) Plk1 and BRD4 dual inhibition acts synergistically in inhibition of AR signaling. Mol Cancer Ther; 17(7); 1554-65. (c)2018 AACR. PMID- 29716961 TI - Whole Genome Sequence and Comparative Genomics Analysis of Multi-drug Resistant Environmental Staphylococcus epidermidis ST59. AB - Staphylococcus epidermidis is a major opportunistic pathogen primarily recovered from device-associated healthcare associated infections (DA-HAIs). Although S. epidermidis and other coagulase-negative staphylococci (CoNS) are less virulent than Staphylococcus aureus, these bacteria are an important reservoir of antimicrobial resistance genes and resistance-associated mobile genetic elements that can be transferred between staphylococcal species. We report a whole genome sequence of a multidrug resistant S. epidermidis (strain G6_2) representing multilocus sequence type (ST) 59 and isolated from an environmental sampling of a hotel room in London, UK. The genome of S. epidermidis G6_2 comprises of a 2408357 bp chromosome and six plasmids, with an average G+C content of 32%. The strain displayed a multi-drug resistance phenotype which was associated with carriage of 7 antibiotic resistance genes (blaZ, mecA, msrA, mphC, fosB, aacA aphD, tetK) as well as resistance-conferring mutations in fusA and ileS Antibiotic resistance genes were located on plasmids and chromosome. Comparative genomic analysis revealed that antibiotic resistance gene composition found in G6_2 was partly preserved across the ST59 lineage. PMID- 29716974 TI - Mastoiditis. PMID- 29716973 TI - Case 6: Seizures and Low Cerebrospinal Fluid Glucose in a 4-day-old Boy. PMID- 29716976 TI - Visual Diagnosis: Visual Impairment, Polydactyly, and Obesity: Red Flags in a Child. PMID- 29716962 TI - Bruno-3 regulates sarcomere component expression and contributes to muscle phenotypes of myotonic dystrophy type 1. AB - Steinert disease, or myotonic dystrophy type 1 (DM1), is a multisystemic disorder caused by toxic noncoding CUG repeat transcripts, leading to altered levels of two RNA binding factors, MBNL1 and CELF1. The contribution of CELF1 to DM1 phenotypes is controversial. Here, we show that the Drosophila CELF1 family member, Bru-3, contributes to pathogenic muscle defects observed in a Drosophila model of DM1. Bru-3 displays predominantly cytoplasmic expression in muscles and its muscle-specific overexpression causes a range of phenotypes also observed in the fly DM1 model, including affected motility, fiber splitting, reduced myofiber length and altered myoblast fusion. Interestingly, comparative genome-wide transcriptomic analyses revealed that Bru-3 negatively regulates levels of mRNAs encoding a set of sarcomere components, including Actn transcripts. Conversely, it acts as a positive regulator of Actn translation. As CELF1 displays predominantly cytoplasmic expression in differentiating C2C12 myotubes and binds to Actn mRNA, we hypothesize that it might exert analogous functions in vertebrate muscles. Altogether, we propose that cytoplasmic Bru-3 contributes to DM1 pathogenesis in a Drosophila model by regulating sarcomeric transcripts and protein levels. PMID- 29716956 TI - Cell-free formation and interactome analysis of caveolae. AB - Caveolae have been linked to the regulation of signaling pathways in eukaryotic cells through direct interactions with caveolins. Here, we describe a cell-free system based on Leishmania tarentolae (Lt) extracts for the biogenesis of caveolae and show its use for single-molecule interaction studies. Insertion of expressed caveolin-1 (CAV1) into Lt membranes was analogous to that of caveolin in native membranes. Electron tomography showed that caveolins generate domains of precise size and curvature. Cell-free caveolae were used in quantitative assays to test the interaction of membrane-inserted caveolin with signaling proteins and to determine the stoichiometry of interactions. Binding of membrane inserted CAV1 to several proposed binding partners, including endothelial nitric oxide synthase, was negligible, but a small number of proteins, including TRAF2, interacted with CAV1 in a phosphorylation-(CAV1Y14)-stimulated manner. In cells subjected to oxidative stress, phosphorylated CAV1 recruited TRAF2 to the early endosome forming a novel signaling platform. These findings lead to a novel model for cellular stress signaling by CAV1. PMID- 29716978 TI - THERAPY OF ENDOCRINE DISEASE: Growth hormone replacement therapy in adults: 30 years of personal clinical experience. AB - The acute metabolic actions of purified human growth hormone (GH) were first documented in adult hypopituitary patients more than 50 years ago, and placebo controlled long-term GH trials in GH-deficient adults (GHDA) surfaced in 1989 with the availability of biosynthetic human GH. Untreated GHDA is associated with excess morbidity and mortality from cardiovascular disease and the phenotype includes fatigue, reduced aerobic exercise capacity, abdominal obesity, reduced lean body mass, osteopenia and elevated levels of circulating cardiovascular biomarkers. Several of these features reverse and normalize with GH replacement. It remains controversial whether quality of life, assessed by questionnaires, improves. The known side effects are fluid retention and insulin resistance, which are reversible and dose dependent. The dose requirement declines markedly with age and is higher in women. Continuation of GH replacement into adulthood in patients with childhood-onset disease is indicated, if the diagnosis is reconfirmed. GH treatment of frail elderly subjects without documented pituitary disease remains unwarranted. Observational data show that mortality in GH replaced patients is reduced compared to untreated patients. Even though this reduced mortality could be due to selection bias, GH replacement in GHDA has proven beneficial and safe. PMID- 29716972 TI - Case 5: Abdominal Distention, Poor Growth, and Motor Delay in a 1-year-old Girl. PMID- 29716979 TI - HEADS4: Social Media Screening in Adolescent Primary Care. PMID- 29716975 TI - Brain Abscess. PMID- 29716959 TI - The phospholipase A2 activity of peroxiredoxin 6. AB - Peroxiredoxin 6 (Prdx6) is a Ca2+-independent intracellular phospholipase A2 (called aiPLA2) that is localized to cytosol, lysosomes, and lysosomal-related organelles. Activity is minimal at cytosolic pH but is increased significantly with enzyme phosphorylation, at acidic pH, and in the presence of oxidized phospholipid substrate; maximal activity with phosphorylated aiPLA2 is ~2 umol/min/mg protein. Prdx6 is a "moonlighting" protein that also expresses glutathione peroxidase and lysophosphatidylcholine acyl transferase activities. The catalytic site for aiPLA2 activity is an S32-H26-D140 triad; S32-H26 is also the phospholipid binding site. Activity is inhibited by a serine "protease" inhibitor (diethyl p-nitrophenyl phosphate), an analog of the PLA2 transition state [1-hexadecyl-3-(trifluoroethyl)-sn-glycero-2-phosphomethanol (MJ33)], and by two naturally occurring proteins (surfactant protein A and p67phox), but not by bromoenol lactone. aiPLA2 activity has important physiological roles in the turnover (synthesis and degradation) of lung surfactant phospholipids, in the repair of peroxidized cell membranes, and in the activation of NADPH oxidase type 2 (NOX2). The enzyme has been implicated in acute lung injury, carcinogenesis, neurodegenerative diseases, diabetes, male infertility, and sundry other conditions, although its specific roles have not been well defined. Protein mutations and animal models are now available to further investigate the roles of Prdx6-aiPLA2 activity in normal and pathological physiology. PMID- 29716980 TI - The Biomarker S100B and Mild Traumatic Brain Injury: A Meta-analysis. AB - CONTEXT: The usefulness of S100B has been noted as a biomarker in the management of mild traumatic brain injury (mTBI) in adults. However, S100B efficacy as a biomarker in children has previously been relatively unclear. OBJECTIVE: A meta analysis is conducted to assess the prognostic value of S100B in predicting intracerebral lesions in children after mTBI. DATA SOURCES: Medline, Embase, the Cochrane Central Register of Controlled Trials (CENTRAL), Web of Science, Scopus, and Google Scholar. STUDY SELECTION: Studies including children suffering mTBI who underwent S100B measurement and computed tomography (CT) scans were included. DATA EXTRACTION: Of 1030 articles screened, 8 studies met the inclusion criteria. RESULTS: The overall pooled sensitivity and specificity were 100% (95% confidence interval [CI]: 98%-100%) and 34% (95% CI: 30%-38%), respectively. A second analysis was based on the collection of 373 individual data points from 4 studies. Sensitivity and specificity results, obtained from reference ranges in children with a sampling time <3 hours posttrauma, were 97% (95% CI: 84.2%-99.9%) and 37.5% (95% CI: 28.8%-46.8%), respectively. Only 1 child had a low S100B level and a positive CT scan result without clinically important traumatic brain injury. LIMITATIONS: Only patients undergoing both a CT scan and S100B testing were selected for evaluation. CONCLUSIONS: S100B serum analysis as a part of the clinical routine could significantly reduce the number of CT scans performed on children with mTBI. Sampling should take place within 3 hours of trauma. Cutoff levels should be based on pediatric reference ranges. PMID- 29716981 TI - Literature Highlights: Impactful Papers Published Elsewhere: Article Recommendations from Our Deputy and Senior Editors. PMID- 29716957 TI - Lifespan analysis of brain development, gene expression and behavioral phenotypes in the Ts1Cje, Ts65Dn and Dp(16)1/Yey mouse models of Down syndrome. AB - Down syndrome (DS) results from triplication of human chromosome 21. Neuropathological hallmarks of DS include atypical central nervous system development that manifests prenatally and extends throughout life. As a result, individuals with DS exhibit cognitive and motor deficits, and have delays in achieving developmental milestones. To determine whether different mouse models of DS recapitulate the human prenatal and postnatal phenotypes, here, we directly compared brain histogenesis, gene expression and behavior over the lifespan of three cytogenetically distinct mouse models of DS: Ts1Cje, Ts65Dn and Dp(16)1/Yey. Histological data indicated that Ts65Dn mice were the most consistently affected with respect to somatic growth, neurogenesis and brain morphogenesis. Embryonic and adult gene expression results showed that Ts1Cje and Ts65Dn brains had considerably more differentially expressed (DEX) genes compared with Dp(16)1/Yey mice, despite the larger number of triplicated genes in the latter model. In addition, DEX genes showed little overlap in identity and chromosomal distribution in the three models, leading to dissimilarities in affected functional pathways. Perinatal and adult behavioral testing also highlighted differences among the models in their abilities to achieve various developmental milestones and perform hippocampal- and motor-based tasks. Interestingly, Dp(16)1/Yey mice showed no abnormalities in prenatal brain phenotypes, yet they manifested behavioral deficits starting at postnatal day 15 that continued through adulthood. In contrast, Ts1Cje mice showed mildly abnormal embryonic brain phenotypes, but only select behavioral deficits as neonates and adults. Altogether, our data showed widespread and unexpected fundamental differences in behavioral, gene expression and brain development phenotypes between these three mouse models. Our findings illustrate unique limitations of each model when studying aspects of brain development and function in DS. This work helps to inform model selection in future studies investigating how observed neurodevelopmental abnormalities arise, how they contribute to cognitive impairment, and when testing therapeutic molecules to ameliorate the intellectual disability associated with DS.This article has an associated First Person interview with the first author of the paper. PMID- 29716982 TI - Hallmarks of T-cell Exit from Quiescence. AB - The appropriate activation of the adaptive immune system relies upon the reprogramming of naive T cells into specialized effector T cells that can combat pathogens and tumors. Naive T cells are actively maintained in a state of hyporesponsiveness termed quiescence, which is characterized by small cell size, low proliferative rate, and low basal metabolism. Engagement of antigen and costimulatory receptors drives T cells to exit quiescence to promote subsequent clonal expansion and functional differentiation. The exit from quiescence, which precedes activation-induced proliferation, is associated with extensive remodeling of cellular morphology and metabolism. Here, we define and discuss the implications of the six key features of the exit of naive T cells from quiescence: (i) cell-cycle entry, (ii) cell growth, (iii) autocrine or paracrine interleukin-2 signaling, (iv) anabolic metabolism, (v) nutrient uptake, and (vi) remodeling of mitochondrial function. Ultimately, understanding how naive T cells meet each of these requirements for quiescence exit will allow for the tuning of T-cell responses to treat infectious diseases, autoimmunity, and cancer. Cancer Immunol Res; 6(5); 502-8. (c)2018 AACR. PMID- 29716984 TI - Simultaneous Discovery of Cell-Free DNA and the Nucleosome Ladder. PMID- 29716987 TI - Click Chemistry-mediated Biotinylation Reveals a Function for the Protease BACE1 in Modulating the Neuronal Surface Glycoproteome. AB - The cell surface proteome is dynamic and has fundamental roles in cell signaling. Many surface membrane proteins are proteolytically released into a cell's secretome, where they can have additional functions in cell-cell-communication. Yet, it remains challenging to determine the surface proteome and to compare it to the cell secretome, under serum-containing cell culture conditions. Here, we set up and evaluated the 'surface-spanning protein enrichment with click sugars' (SUSPECS) method for cell surface membrane glycoprotein biotinylation, enrichment and label-free quantitative mass spectrometry. SUSPECS is based on click chemistry-mediated labeling of glycoproteins, is compatible with labeling of living cells and can be combined with secretome analyses in the same experiment. Immunofluorescence-based confocal microscopy demonstrated that SUSPECS selectively labeled cell surface proteins. Nearly 700 transmembrane glycoproteins were consistently identified at the surface of primary neurons. To demonstrate the utility of SUSPECS, we applied it to the protease BACE1, which is a key drug target in Alzheimer's disease. Pharmacological BACE1-inhibition selectively remodeled the neuronal surface glycoproteome, resulting in up to 7-fold increased abundance of the BACE1 substrates APP, APLP1, SEZ6, SEZ6L, CNTN2, and CHL1, whereas other substrates were not or only mildly affected. Interestingly, protein changes at the cell surface only partly correlated with changes in the secretome. Several altered proteins were validated by immunoblots in neurons and mouse brains. Apparent nonsubstrates, such as TSPAN6, were also increased, indicating that BACE1-inhibition may lead to unexpected secondary effects. In summary, SUSPECS is broadly useful for determination of the surface glycoproteome and its correlation with the secretome. PMID- 29716986 TI - Credentialing Individual Samples for Proteogenomic Analysis. AB - An integrated analysis of DNA, RNA and protein, so called proteogenomic studies, has the potential to greatly increase our understanding of both normal physiology and disease development. However, such studies are challenged by a lack of a systematic approach to credential individual samples resulting in the introduction of noise into the system that limits the ability to identify important biological signals. Indeed, a recent proteogenomic CPTAC study identified 26% of samples as unsatisfactory, resulting in a marked increase in cost and loss of information content. Based on a large-scale analysis of RNA-seq and proteomic data generated by reverse phase protein arrays (RPPA) and by mass spectrometry, we propose a protein-mRNA correlation-based (PMC) score as a robust metric to credential single samples for integrated proteogenomic studies. Samples with high PMC scores have significantly higher protein-mRNA correlation, total protein content and tumor purity. Our results highlight the importance of credentialing individual samples prior to proteogenomic analysis. PMID- 29716983 TI - Phylogeny of the Genus Drosophila. AB - Understanding phylogenetic relationships among taxa is key to designing and implementing comparative analyses. The genus Drosophila, which contains over 1600 species, is one of the most important model systems in the biological sciences. For over a century, one species in this group, Drosophila melanogaster, has been key to studies of animal development and genetics, genome organization and evolution, and human disease. As whole-genome sequencing becomes more cost effective, there is increasing interest in other members of this morphologically, ecologically, and behaviorally diverse genus. Phylogenetic relationships within Drosophila are complicated, and the goal of this paper is to provide a review of the recent taxonomic changes and phylogenetic relationships in this genus to aid in further comparative studies. PMID- 29716994 TI - Folding and binding pathways of BH3-only proteins are encoded within their intrinsically disordered sequence, not templated by partner proteins. AB - Intrinsically disordered regions are present in one-third of eukaryotic proteins and are overrepresented in cellular processes such as signaling, suggesting that intrinsically disordered proteins (IDPs) may have a functional advantage over folded proteins. Upon interacting with a partner macromolecule, a subset of IDPs can fold and bind to form a well-defined three-dimensional conformation. For example, disordered BH3-only proteins bind promiscuously to a large number of homologous BCL-2 family proteins, where they fold to a helical structure in a groove on the BCL-2-like protein surface. As two protein chains are involved in the folding reaction, and the structure is only formed in the presence of the partner macromolecule, this raises the question of where the folding information is encoded. Here, we examine these coupled folding and binding reactions to determine which component determines the folding and binding pathway. Using Phi value analysis to compare transition state interactions between the disordered BH3-only proteins PUMA and BID and the folded BCL-2-like proteins A1 and MCL-1, we found that, even though the BH3-only protein is disordered in isolation and requires a stabilizing partner to fold, its folding and binding pathway is encoded in the IDP itself; the reaction is not templated by the folded partner. We suggest that, by encoding both its transition state and level of residual structure, an IDP can evolve a specific kinetic profile, which could be a crucial functional advantage of disorder. PMID- 29716988 TI - Structures of N-Glycans of Bothrops Venoms Revealed as Molecular Signatures that Contribute to Venom Phenotype in Viperid Snakes. AB - The complexity of snake venoms has long been investigated to explore a myriad of biologically active proteins and peptides that are used for immobilizing or killing prey, and are responsible for the pathological effects observed on envenomation. Glycosylation is the main post-translational modification (PTM) of viperid venoms but currently there is little understanding of how protein glycosylation impacts the variation of venom proteomes. We have previously reported that Bothrops venom glycoproteomes contain a core of components that markedly define their composition and parallel their phylogenetic classification. Here we extend those observations to eight Bothrops species evaluating the N glycomes by LC-MS as assigned cartoon structures and detailing those structures separately as methylated analogs using ion-trap mass spectrometry (MSn). Following ion disassembly through multiple steps provided sequence and linkage isomeric details that characterized 52 unique compositions in Bothrops venoms. These occurred as 60 structures, of which 26 were identified in the venoms of the Jararaca Complex (B. alcatraz, B. insularis, and B. jararaca), 20 in B. erythromelas, B. jararacussu, B. moojeni and B. neuwiedi venoms, and 22 in B. cotiara venom. Further, quantitative analysis of these N-glycans showed variable relative abundances in the venoms. For the first time a comprehensive set of N glycan structures present in snake venoms are defined. Despite the fact that glycosylation is not template-defined, the N-glycomes of these venoms mirror the phylogeny cladograms of South American bothropoid snakes reported in studies on morphological, molecular data and feeding habits, exhibiting distinct molecular signatures for each venom. Considering the complexity of N-glycan moieties generally found in glycoproteins, characterized by different degrees of branching, isomer structures, and variable abundances, our findings point to these factors as another level of complexity in Bothrops venoms, features that could dramatically contribute to their distinct biological activities. PMID- 29716989 TI - Life of PPi: Soluble PPases and H+-PPase Act Cooperatively to Keep Pyrophosphate Levels in Check. PMID- 29716992 TI - Phosphatidic Acid Counteracts S-RNase Signaling in Pollen by Stabilizing the Actin Cytoskeleton. AB - S-RNase is the female determinant of self-incompatibility (SI) in pear (Pyrus bretschneideri). After translocation to the pollen tube, S-RNase degrades rRNA and induces pollen tube death in an S-haplotype-specific manner. In this study, we found that the actin cytoskeleton is a target of P. bretschneideri S-RNase (PbrS-RNase) and uncovered a mechanism that involves phosphatidic acid (PA) and protects the pollen tube from PbrS-RNase cytotoxicity. PbrS-RNase interacts directly with PbrActin1 in an S-haplotype-independent manner, causing the actin cytoskeleton to depolymerize and promoting programmed cell death in the self incompatible pollen tube. Pro-156 of PbrS-RNase is essential for the PbrS-RNase PbrActin1 interaction, and the actin cytoskeleton-depolymerizing function of PbrS RNase does not require its RNase activity. PbrS-RNase cytotoxicity enhances the expression of phospholipase D (PbrPLDdelta1), resulting in increased PA levels in the incompatible pollen tube. PbrPLDdelta1-derived PA initially prevents depolymerization of the actin cytoskeleton elicited by PbrS-RNase and delays the SI signaling that leads to pollen tube death. This work provides insights into the orchestration of the S-RNase-based SI response, in which increased PA levels initially play a protective role in incompatible pollen, until sustained PbrS RNase activity reaches the point of no return and pollen tube growth ceases. PMID- 29717001 TI - Corrigendum: Detecting differential copy number variation between groups of samples. PMID- 29717002 TI - Corrigendum: Evolutionary expansion of DNA hypomethylation in the mammalian germline genome. PMID- 29716999 TI - The histone methyltransferase SETD2 is required for expression of acrosin-binding protein 1 and protamines and essential for spermiogenesis in mice. AB - Spermatogenesis is precisely controlled by complex gene expression programs and involves epigenetic reprogramming, including histone modification and DNA methylation. SET domain-containing 2 (SETD2) is the predominant histone methyltransferase catalyzing the trimethylation of histone H3 lysine 36 (H3K36me3) and plays key roles in embryonic stem cell differentiation and somatic cell development. However, its role in male germ cell development remains elusive. Here, we demonstrate an essential role of Setd2 for spermiogenesis, the final stage of spermatogenesis. Using RNA-seq, we found that, in postnatal mouse testes, Setd2 mRNA levels dramatically increase in 14-day-old mice. Using a germ cell-specific Setd2 knockout mouse model, we also found that targeted Setd2 knockout in germ cells causes aberrant spermiogenesis with acrosomal malformation before step 8 of the round-spermatid stage, resulting in complete infertility. Furthermore, we noted that the Setd2 deficiency results in complete loss of H3K36me3 and significantly decreases expression of thousands of genes, including those encoding acrosin-binding protein 1 (Acrbp1) and protamines, required for spermatogenesis. Our findings thus reveal a previously unappreciated role of the SETD2-dependent H3K36me3 modification in spermiogenesis and provide clues to the molecular mechanisms in epigenetic disorders underlying male infertility. PMID- 29716995 TI - Structural determinants in a glucose-containing lipopolysaccharide from Mycobacterium tuberculosis critical for inducing a subset of protective T cells. AB - Mycobacteria synthesize intracellular, 6-O-methylglucose-containing lipopolysaccharides (mGLPs) proposed to modulate bacterial fatty acid metabolism. Recently, it has been shown that Mycobacterium tuberculosis mGLP specifically induces a specific subset of protective gamma9delta2 T cells. Mild base treatment, which removes all the base-labile groups, reduces the specific activity of mGLP required for induction of these T cells, suggesting that acylation of the saccharide moieties is required for gamma9delta2 T-cell activation. On the basis of this premise, we used analytical LC/MS and NMR methods to identify and locate the acyl functions on the mGLP saccharides. We found that mGLP is heterogeneous with respect to acyl functions and contains acetyl, isobutyryl, succinyl, and octanoyl groups and that all acylations in mGLP, except for succinyl and octanoyl residues, reside on the glucosyl residues immediately following the terminal 3-O-methylglucose. Our analyses also indicated that the octanoyl residue resides at position 2 of an internal glucose toward the reducing end. LC/MS analysis of the residual product obtained by digesting the mGLP with pancreatic alpha-amylase revealed that the product is an oligosaccharide terminated by alpha-(1->4)-linked 6-O-methyl-d-glucosyl residues. This oligosaccharide retained none of the acyl groups, except for the octanoyl group, and was unable to induce protective gamma9delta2 T cells. This observation confirmed that mGLP induces gamma9delta2 T cells and indicated that the acylated glucosyl residues at the nonreducing terminus of mGLP are required for this activity. PMID- 29716990 TI - The m6A Reader ECT2 Controls Trichome Morphology by Affecting mRNA Stability in Arabidopsis. AB - The epitranscriptomic mark N6-methyladenosine (m6A) can be written, read, and erased via the action of a complex network of proteins. m6A binding proteins read m6A marks and transduce their downstream regulatory effects by altering RNA metabolic processes. The characterization of m6A readers is an essential prerequisite for understanding the roles of m6A in plants, but the identities of m6A readers have been unclear. Here, we characterized the YTH-domain family protein ECT2 as an Arabidopsis thaliana m6A reader whose m6A binding function is required for normal trichome morphology. We developed the formaldehyde cross linking and immunoprecipitation method to identify ECT2-RNA interaction sites at the transcriptome-wide level. This analysis demonstrated that ECT2 binding sites are strongly enriched in the 3' untranslated regions (3' UTRs) of target genes and led to the identification of a plant-specific m6A motif. Sequencing analysis suggested that ECT2 plays dual roles in regulating 3' UTR processing in the nucleus and facilitating mRNA stability in the cytoplasm. Disruption of ECT2 accelerated the degradation of three ECT2 binding transcripts related to trichome morphogenesis, thereby affecting trichome branching. The results shed light on the underlying mechanisms of the roles of m6A in RNA metabolism, as well as plant development and physiology. PMID- 29717003 TI - Corrigendum: A systematic comparison reveals substantial differences in chromosomal versus episomal encoding of enhancer activity. PMID- 29716996 TI - Calcium-dependent phosphorylation of Plasmodium falciparum serine repeat antigen 5 triggers merozoite egress. AB - The human malaria parasite Plasmodium falciparum proliferates in red blood cells following repeated cycles of invasion, multiplication, and egress. P. falciparum serine repeat antigen 5 (PfSERA5), a putative serine protease, plays an important role in merozoite egress. However, regulation of its activity leading to merozoite egress is poorly understood. In this study, we show that PfSERA5 undergoes phosphorylation prior to merozoite egress. Immunoprecipitation of parasite lysates using anti-PfSERA5 serum followed by MS analysis identified calcium-dependent protein kinase 1 (PfCDPK1) as an interacting kinase. Association of PfSERA5 with PfCDPK1 was corroborated by co-sedimentation, co immunoprecipitation, and co-immunolocalization analyses. Interestingly, PfCDPK1 phosphorylated PfSERA5 in vitro in the presence of Ca2+ and enhanced its proteolytic activity. A PfCDPK1 inhibitor, purfalcamine, blocked the phosphorylation and activation of PfSERA5 both in vitroas well as in schizonts, which, in turn, blocked merozoite egress. Together, these results suggest that phosphorylation of PfSERA5 by PfCDPK1 following a rise in cytosolic Ca2+ levels activates its proteolytic activity to trigger merozoite egress. PMID- 29717004 TI - Galectins at a glance. AB - Galectins are carbohydrate-binding proteins that are involved in many physiological functions, such as inflammation, immune responses, cell migration, autophagy and signalling. They are also linked to diseases such as fibrosis, cancer and heart disease. How such a small family of only 15 members can have such widespread effects remains a conundrum. In this Cell Science at a Glance article, we summarise recent literature on the many cellular activities that have been ascribed to galectins. As shown on the accompanying poster, these include carbohydrate-independent interactions with cytosolic or nuclear targets and carbohydrate-dependent interactions with extracellular glycoconjugates. We discuss how these intra- and extracellular activities might be linked and point out the importance of unravelling molecular mechanisms of galectin function to gain a true understanding of their contributions to the physiology of the cell. We close with a short outlook on the organismal functions of galectins and a perspective on the major challenges in the field. PMID- 29716991 TI - The AWPM-19 Family Protein OsPM1 Mediates Abscisic Acid Influx and Drought Response in Rice. AB - Abscisic acid (ABA) regulates plant stress responses and development. However, how the ABA signal is transmitted in response to stresses remains largely unclear, especially in monocots. In this study, we found that rice (Oryza sativa) OsPM1 (PLASMA MEMBRANE PROTEIN1), encoded by a gene of AWPM-19 like family, mediates ABA influx through the plasma membrane. OsPM1 is predominantly expressed in vascular tissues, guard cells, and mature embryos. Phenotypic analysis of overexpression, RNA interference (RNAi), and knockout (KO) lines showed that OsPM1 is involved in drought responses and seed germination regulation. 3H-(+/ )ABA transport activity and fluorescence resonance energy transfer assays both demonstrated that OsPM1 facilitates ABA uptake into cells. The physiological isomer of ABA, (+)-ABA, is the preferred substrate of OsPM1. Higher ABA accumulation and faster stomatal closure in response to ABA treatment were observed in the overexpression lines compared with the wild-type control. Many ABA-responsive genes were upregulated more in the OsPM1-overexpression lines but less in the RNAi lines compared with wild-type plants. Further investigation revealed that OsPM1 expression is regulated by the AREB/ABF family transcription factor OsbZIP46. Our results thus revealed that OsPM1 is an ABA influx carrier that plays an important role in drought responses. PMID- 29716993 TI - Danger-Associated Peptides Close Stomata by OST1-Independent Activation of Anion Channels in Guard Cells. AB - The plant elicitor peptides (Peps), a family of damage/danger-associated molecular patterns (DAMPs), are perceived by two receptors, PEPR1 and PEPR2, and contribute to plant defense against pathogen attack and abiotic stress. Here, we show that the Peps-PEPR signaling pathway functions in stomatal immunity by activating guard cell anion channels in Arabidopsis thaliana The mutant plants lacking both PEPR1 and PEPR2 (pepr1 pepr2) displayed enhanced bacterial growth after being sprayed with Pseudomonas syringae pv tomato (Pst) DC3000, but not after pathogen infiltration into leaves, implicating PEPR function in stomatal immunity. Indeed, synthetic Arabidopsis Peps (AtPeps) effectively induced stomatal closure in wild-type but not pepr1 pepr2 mutant leaves, suggesting that the AtPeps-PEPR signaling pathway triggers stomatal closure. Consistent with this finding, patch-clamp recording revealed AtPep1-induced activation of anion channels in the guard cells of wild-type but not pepr1 pepr2 mutant plants. We further identified two guard cell-expressed anion channels, SLOW ANION CHANNEL1 (SLAC1) and its homolog SLAH3, as functionally overlapping components responsible for AtPep1-induced stomatal closure. The slac1 slah3 double mutant, but not slac1 or slah3 single mutants, failed to respond to AtPep1 in stomatal closure assays. Interestingly, disruption of OPEN STOMATA1 (OST1), an essential gene for abscisic acid-triggered stomatal closure, did not affect the AtPep1-induced anion channel activity and stomatal response. Together, these results illustrate a DAMP triggered signaling pathway that, unlike the flagellin22-FLAGELLIN-SENSITIVE2 pathway, triggers stomata immunity through an OST1-independent mechanism. PMID- 29716998 TI - Limonene dehydrogenase hydroxylates the allylic methyl group of cyclic monoterpenes in the anaerobic terpene degradation by Castellaniella defragrans. AB - The enzymatic functionalization of hydrocarbons is a central step in the global carbon cycle initiating the mineralization of methane, isoprenes, and monoterpenes, the most abundant biologically produced hydrocarbons. Also, terpene modifying enzymes have found many applications in the energy-economic biotechnological production of fine chemicals. Here, we describe a limonene dehydrogenase that was purified from the facultatively anaerobic betaproteobacterium Castellaniella defragrans 65Phen grown on monoterpenes under denitrifying conditions in the absence of molecular oxygen. The purified limonene:ferrocenium oxidoreductase activity hydroxylated the methyl group of limonene (1-methyl-4-(1-methylethenyl)-cyclohex-1-ene) yielding perillyl alcohol ([4-(prop-1-en-2-yl)cyclohex-1-en-1-yl]methanol). The enzyme had a DTT:perillyl alcohol oxidoreductase activity yielding limonene. Mass spectrometry and molecular size determinations revealed a heterodimeric enzyme comprising CtmA and CtmB. Recently, the two proteins had been identified by transposon mutagenesis and proteomics as part of the cyclic terpene metabolism (ctm) in C. defragrans and are annotated as FAD-dependent oxidoreductases of the protein domain family phytoene dehydrogenases and related proteins (COG1233). CtmAB is the first heterodimeric enzyme in this protein superfamily. Flavins in the purified CtmAB are oxidized by ferrocenium and are reduced by limonene. Heterologous expression of CtmA, CtmB, and CtmAB in Escherichia coli demonstrated that limonene dehydrogenase activity required both subunits, each carrying a flavin cofactor. Native CtmAB oxidized a wide range of monocyclic monoterpenes containing the allylic methyl group motif (1-methyl-cyclohex-1-ene). In conclusion, we have identified CtmAB as a hydroxylating limonene dehydrogenase and the first heteromer in a family of FAD-dependent dehydrogenases acting on allylic methylene or methyl CH-bonds. We suggest placing in Enzyme Nomenclature as new entry EC 1.17.99.8. PMID- 29717005 TI - Correction: Wash exhibits context-dependent phenotypes and, along with the WASH regulatory complex, regulates Drosophila oogenesis (doi:10.1242/211573). PMID- 29716997 TI - Long noncoding RNA Hoxb3os is dysregulated in autosomal dominant polycystic kidney disease and regulates mTOR signaling. AB - Autosomal dominant polycystic kidney disease (ADPKD) is a debilitating disease that is characterized by the accumulation of numerous fluid-filled cysts in the kidney. ADPKD is primarily caused by mutations in two genes, PKD1 and PKD2 Long noncoding RNAs (lncRNA), defined by a length >200 nucleotides and absence of a long ORF, have recently emerged as epigenetic regulators of development and disease; however, their involvement in PKD has not been explored previously. Here, we performed deep RNA-Seq to identify lncRNAs that are dysregulated in two orthologous mouse models of ADPKD (kidney-specific Pkd1 and Pkd2 mutant mice). We identified a kidney-specific, evolutionarily conserved lncRNA called Hoxb3os that was down-regulated in cystic kidneys from Pkd1 and Pkd2 mutant mice. The human ortholog HOXB3-AS1 was down-regulated in cystic kidneys from ADPKD patients. Hoxb3os was highly expressed in renal tubules in adult WT mice, whereas its expression was lost in the cyst epithelium of mutant mice. To investigate the function of Hoxb3os, we utilized CRISPR/Cas9 to knock out its expression in mIMCD3 cells. Deletion of Hoxb3os resulted in increased phosphorylation of mTOR and its downstream targets, including p70 S6 kinase, ribosomal protein S6, and the translation repressor 4E-BP1. Consistent with activation of mTORC1 signaling, Hoxb3os mutant cells displayed increased mitochondrial respiration. The Hoxb3os mutant phenotype was partially rescued upon re-expression of Hoxb3os in knockout cells. These findings identify Hoxb3os as a novel lncRNA that is down-regulated in ADPKD and regulates mTOR signaling and mitochondrial respiration. PMID- 29717000 TI - Two distinct domains of the glucagon-like peptide-1 receptor control peptide mediated biased agonism. AB - G protein-coupled receptors (GPCRs) can be differentially activated by ligands to generate multiple and distinct downstream signaling profiles, a phenomenon termed biased agonism. The glucagon-like peptide-1 receptor (GLP-1R) is a class B GPCR and a key drug target for managing metabolic disorders; however, its peptide agonists display biased signaling that affects their relative efficacies. In this study, we combined mutagenesis experiments and mapping of surface mutations onto recently described GLP-1R structures, which revealed two major domains in the GLP 1/GLP-1R/Gs protein active structure that are differentially important for both receptor quiescence and ligand-specific initiation and propagation of biased agonism. Changes to the conformation of transmembrane helix (TM) 5 and TM 6 and reordering of extracellular loop 2 were essential for the propagation of signaling linked to cAMP formation and intracellular calcium mobilization, whereas ordering and packing of residues in TMs 1 and 7 were critical for extracellular signal-regulated kinase 1/2 (pERK) activity. On the basis of these findings, we propose a model of distinct peptide-receptor interactions that selectively control how these different signaling pathways are engaged. This work provides important structural insight into class B GPCR activation and biased agonism. PMID- 29717014 TI - Erratum for May and Silhavy, "The Escherichia coli Phospholipase PldA Regulates Outer Membrane Homeostasis via Lipid Signaling". PMID- 29717007 TI - Selective Packaging in Murine Coronavirus Promotes Virulence by Limiting Type I Interferon Responses. AB - Selective packaging is a mechanism used by multiple virus families to specifically incorporate genomic RNA (gRNA) into virions and exclude other types of RNA. Lineage A betacoronaviruses incorporate a 95-bp stem-loop structure, the packaging signal (PS), into the nsp15 locus of ORF1b that is both necessary and sufficient for the packaging of RNAs. However, unlike other viral PSs, where mutations generally resulted in viral replication defects, mutation of the coronavirus (CoV) PS results in large increases in subgenomic RNA packaging with minimal effects on gRNA packaging in vitro and on viral titers. Here, we show that selective packaging is also required for viral evasion of the innate immune response and optimal pathogenicity. We engineered two distinct PS mutants in two different strains of murine hepatitis virus (MHV) that packaged increased levels of subgenomic RNAs, negative-sense genomic RNA, and even cellular RNAs. All PS mutant viruses replicated normally in vitro but caused dramatically reduced lethality and weight loss in vivo PS mutant virus infection of bone marrow derived macrophages resulted in increased interferon (IFN) production, indicating that the innate immune system limited the replication and/or pathogenesis of PS mutant viruses in vivo PS mutant viruses remained attenuated in MAVS-/- and Toll like receptor 7-knockout (TLR7-/-) mice, two well-known RNA sensors for CoVs, but virulence was restored in interferon alpha/beta receptor-knockout (IFNAR-/-) mice or in MAVS-/- mice treated with IFNAR-blocking antibodies. Together, these data indicate that coronaviruses promote virulence by utilizing selective packaging to avoid innate immune detection.IMPORTANCE Coronaviruses (CoVs) produce many types of RNA molecules during their replication cycle, including both positive- and negative-sense genomic and subgenomic RNAs. Despite this, coronaviruses selectively package only positive-sense genomic RNA into their virions. Why CoVs selectively package their genomic RNA is not clear, as disruption of the packaging signal in MHV, which leads to loss of selective packaging, does not affect genomic RNA packaging or virus replication in cultured cells. This contrasts with other viruses, where disruption of selective packaging generally leads to altered replication. Here, we demonstrate that in the absence of selective packaging, the virulence of MHV was significantly reduced. Importantly, virulence was restored in the absence of interferon signaling, indicating that selective packaging is a mechanism used by CoVs to escape innate immune detection. PMID- 29717013 TI - Quorum Sensing Extracellular Death Peptides Enhance the Endoribonucleolytic Activities of Mycobacterium tuberculosis MazF Toxins. AB - mazEF is a toxin-antitoxin module located on chromosomes of most bacteria. MazF toxins are endoribonucleases antagonized by MazE antitoxins. Previously, we characterized several quorum sensing peptides called "extracellular death factors" (EDFs). When secreted from bacterial cultures, EDFs induce interspecies cell death. EDFs also enhance the endoribonucleolytic activity of Escherichia coli MazF. Mycobacterium tuberculosis carries several mazEF modules. Among them, the endoribonucleolytic activities of MazF proteins mt-1, mt-3, and mt-6 were identified. MazF-mt6 and MazF-mt-3 cleave M. tuberculosis rRNAs. Here we report the in vitro effects of EDFs on the endoribonucleolytic activities of M. tuberculosis MazFs. Escherichia coli EDF (EcEDF) and the three Pseudomonas aeruginosa EDFs (PaEDFs) individually enhance the endoribonucleolytic activities of MazF-mt6 and MazF-mt3 and overcome the inhibitory effect of MazE-mt3 or MazE mt6 on the endoribonucleolytic activities of the respective toxins. We propose that these EDFs can serve as a basis for a novel class of antibiotics against M. tuberculosisIMPORTANCEMycobacterium tuberculosis is one of the leading causes of death from infectious disease. M. tuberculosis is highly drug resistant, and drug delivery to the infected site is very difficult. In previous studies, we showed that extracellular death factors (EDFs) can work as quorum sensing molecules which participate in interspecies bacterial cell death. In this study, we demonstrated the role of different EDFs in the endoribonucleolytic activities of M. tuberculosis MazFs. Escherichia coli EDF (EcEDF) and the three Pseudomonas aeruginosa EDFs (PaEDFs) individually enhance the endoribonucleolytic activities of MazF-mt6 and MazF-mt3. The current report provides a basis for the use of the EDF peptides EcEDF and PaEDF as novel antibiotics against M. tuberculosis. PMID- 29717006 TI - Conductive Particles Enable Syntrophic Acetate Oxidation between Geobacter and Methanosarcina from Coastal Sediments. AB - Coastal sediments are rich in conductive particles, possibly affecting microbial processes for which acetate is a central intermediate. In the methanogenic zone, acetate is consumed by methanogens and/or syntrophic acetate-oxidizing (SAO) consortia. SAO consortia live under extreme thermodynamic pressure, and their survival depends on successful partnership. Here, we demonstrate that conductive particles enable the partnership between SAO bacteria (i.e., Geobacter spp.) and methanogens (Methanosarcina spp.) from the coastal sediments of the Bothnian Bay of the Baltic Sea. Baltic methanogenic sediments were rich in conductive minerals, had an apparent isotopic fractionation characteristic of CO2-reductive methanogenesis, and were inhabited by Geobacter and Methanosarcina As long as conductive particles were delivered, Geobacter and Methanosarcina persisted, whereas exclusion of conductive particles led to the extinction of Geobacter Baltic Geobacter did not establish a direct electric contact with Methanosarcina, necessitating conductive particles as electrical conduits. Within SAO consortia, Geobacter was an efficient [13C]acetate utilizer, accounting for 82% of the assimilation and 27% of the breakdown of acetate. Geobacter benefits from the association with the methanogen, because in the absence of an electron acceptor it can use Methanosarcina as a terminal electron sink. Consequently, inhibition of methanogenesis constrained the SAO activity of Geobacter as well. A potential benefit for Methanosarcina partnering with Geobacter is that together they competitively exclude acetoclastic methanogens like Methanothrix from an environment rich in conductive particles. Conductive particle-mediated SAO could explain the abundance of acetate oxidizers like Geobacter in the methanogenic zone of sediments where no electron acceptors other than CO2 are available.IMPORTANCE Acetate-oxidizing bacteria are known to thrive in mutualistic consortia in which H2 or formate is shuttled to a methane-producing Archaea partner. Here, we discovered that such bacteria could instead transfer electrons via conductive minerals. Mineral SAO (syntrophic acetate oxidation) could be a vital pathway for CO2-reductive methanogenesis in the environment, especially in sediments rich in conductive minerals. Mineral-facilitated SAO is therefore of potential importance for both iron and methane cycles in sediments and soils. Additionally, our observations imply that agricultural runoff or amendments with conductive chars could trigger a significant increase in methane emissions. PMID- 29717009 TI - An Attenuated CRISPR-Cas System in Enterococcus faecalis Permits DNA Acquisition. AB - Antibiotic-resistant bacteria are critical public health concerns. Among the prime causative factors for the spread of antibiotic resistance is horizontal gene transfer (HGT). A useful model organism for investigating the relationship between HGT and antibiotic resistance is the opportunistic pathogen Enterococcus faecalis, since the species possesses highly conjugative plasmids that readily disseminate antibiotic resistance genes and virulence factors in nature. Unlike many commensal E. faecalis strains, the genomes of multidrug-resistant (MDR) E. faecalis clinical isolates are enriched for mobile genetic elements (MGEs) and lack clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR-associated protein (Cas) genome defense systems. CRISPR-Cas systems cleave foreign DNA in a programmable, sequence-specific manner and are disadvantageous for MGE-derived genome expansion. An unexplored facet of CRISPR biology in E. faecalis is that MGEs that are targeted by native CRISPR-Cas systems can be maintained transiently. Here, we investigate the basis for this "CRISPR tolerance." We observe that E. faecalis can maintain self-targeting constructs that direct Cas9 to cleave the chromosome, but at a fitness cost. Interestingly, DNA repair genes were not upregulated during self-targeting, but integrated prophages were strongly induced. We determined that low cas9 expression contributes to this transient nonlethality and used this knowledge to develop a robust CRISPR-assisted genome-editing scheme. Our results suggest that E. faecalis has maximized the potential for DNA acquisition by attenuating its CRISPR machinery, thereby facilitating the acquisition of potentially beneficial MGEs that may otherwise be restricted by genome defense.IMPORTANCE CRISPR-Cas has provided a powerful toolkit to manipulate bacteria, resulting in improved genetic manipulations and novel antimicrobials. These powerful applications rely on the premise that CRISPR-Cas chromosome targeting, which leads to double-stranded DNA breaks, is lethal. In this study, we show that chromosomal CRISPR targeting in Enterococcus faecalis is transiently nonlethal. We uncover novel phenotypes associated with this "CRISPR tolerance" and, after determining its genetic basis, develop a genome-editing platform in E. faecalis with negligible off-target effects. Our findings reveal a novel strategy exploited by a bacterial pathogen to cope with CRISPR-induced conflicts to more readily accept DNA, and our robust CRISPR editing platform will help simplify genetic modifications in this organism. PMID- 29717010 TI - Signature Arsenic Detoxification Pathways in Halomonas sp. Strain GFAJ-1. AB - Since the original report that Halomonas sp. strain GFAJ-1 was capable of using arsenic instead of phosphorus to sustain growth, additional studies have been conducted, and GFAJ-1 is now considered a highly arsenic-resistant but phosphorus dependent bacterium. However, the mechanisms supporting the extreme arsenic resistance of the GFAJ-1 strain remain unknown. In this study, we show that GFAJ 1 has multiple distinct arsenic resistance mechanisms. It lacks the genes to reduce arsenate, which is the essential step in the well-characterized resistance mechanism of arsenate reduction coupled to arsenite extrusion. Instead, GFAJ-1 has two arsenic resistance operons, arsH1-acr3-2-arsH2 and mfs1-mfs2-gapdh, enabling tolerance to high levels of arsenate. mfs2 and gapdh encode proteins homologous to Pseudomonas aeruginosa ArsJ and glyceraldehyde-3-phosphate dehydrogenase (GAPDH), respectively, which constitute the equivalent of an As(V) efflux system to catalyze the transformation of inorganic arsenate to pentavalent organoarsenical 1-arseno-3-phosphoglycerate and its subsequent extrusion. Surprisingly, the arsH1-acr3-2-arsH2 operon seems to consist of typical arsenite resistance genes, but this operon is sufficient to confer both arsenite and arsenate resistance on Escherichia coli AW3110 even in the absence of arsenate reductase, suggesting a novel pathway of arsenic detoxification. The simultaneous occurrence of these two unusual detoxification mechanisms enables the adaptation of strain GFAJ-1 to the particularly arsenic-rich environment of Mono Lake.IMPORTANCEHalomonas sp. strain GFAJ-1 was previously reported to use arsenic as a substitute for phosphorus to sustain life under phosphate-limited conditions. Although this claim was later undermined by several groups, how GFAJ 1 can thrive in environments with high arsenic concentrations remains unclear. Here, we determined that this ability can be attributed to the possession of two arsenic detoxification operons, arsH1-acr3-2-arsH2 and mfs1-mfs2-gapdhmfs2 and gapdh encode proteins homologous to ArsJ and GAPDH in Pseudomonas aeruginosa; these proteins create an arsenate efflux pathway to reduce cellular arsenate accumulation. Interestingly, the combination of acr3-2 with either arsH gene was sufficient to confer resistance to both arsenite and arsenate in E. coli AW3110, even in the absence of arsenate reductase, suggesting a new strategy for bacterial arsenic detoxification. This study concludes that the survival of GFAJ 1 in high arsenic concentrations is attributable to the cooccurrence of these two unusual arsenic detoxification mechanisms. PMID- 29717015 TI - Regulation of Flagellum Biosynthesis in Response to Cell Envelope Stress in Salmonella enterica Serovar Typhimurium. AB - Flagellum-driven motility of Salmonella enterica serovar Typhimurium facilitates host colonization. However, the large extracellular flagellum is also a prime target for the immune system. As consequence, expression of flagella is bistable within a population of Salmonella, resulting in flagellated and nonflagellated subpopulations. This allows the bacteria to maximize fitness in hostile environments. The degenerate EAL domain protein RflP (formerly YdiV) is responsible for the bistable expression of flagella by directing the flagellar master regulatory complex FlhD4C2 with respect to proteolytic degradation. Information concerning the environmental cues controlling expression of rflP and thus about the bistable flagellar biosynthesis remains ambiguous. Here, we demonstrated that RflP responds to cell envelope stress and alterations of outer membrane integrity. Lipopolysaccharide (LPS) truncation mutants of Salmonella Typhimurium exhibited increasing motility defects due to downregulation of flagellar gene expression. Transposon mutagenesis and genetic profiling revealed that sigma24 (RpoE) and Rcs phosphorelay-dependent cell envelope stress response systems sense modifications of the lipopolysaccaride, low pH, and activity of the complement system. This subsequently results in activation of RflP expression and degradation of FlhD4C2 via ClpXP. We speculate that the presence of diverse hostile environments inside the host might result in cell envelope damage and would thus trigger the repression of resource-costly and immunogenic flagellum biosynthesis via activation of the cell envelope stress response.IMPORTANCE Pathogenic bacteria such as Salmonella Typhimurium sense and adapt to a multitude of changing and stressful environments during host infection. At the initial stage of gastrointestinal colonization, Salmonella uses flagellum-mediated motility to reach preferred sites of infection. However, the flagellum also constitutes a prime target for the host's immune response. Accordingly, the pathogen needs to determine the spatiotemporal stage of infection and control flagellar biosynthesis in a robust manner. We found that Salmonella uses signals from cell envelope stress-sensing systems to turn off production of flagella. We speculate that downregulation of flagellum synthesis after cell envelope damage in hostile environments aids survival of Salmonella during late stages of infection and provides a means to escape recognition by the immune system. PMID- 29717018 TI - Medicago Plants Control Nodulation by Regulating Proteolysis of the Receptor-Like Kinase DMI2. AB - Plants use receptor-like kinases to monitor environmental changes and transduce signals into plant cells. The Medicago truncatula (hereafter Mtruncatula) DOES NOT MAKE INFECTIONS2 (DMI2) protein functions as a coreceptor of rhizobial signals to initiate nodule development and rhizobial infection during nitrogen fixing symbiosis, but the mechanisms regulating DMI2 protein level and folding are still unknown. Here, we report that DMI2 protein abundance changes during nitrogen-fixing symbiosis. DMI2 accumulates in the nodules and is induced by rhizobia treatment through a posttranscriptional process. However, DMI2 induction is independent of the perception of Nod factor, a group of lipochitooligosaccharides secreted by rhizobia. The stability of the DMI2 protein is controlled by the proteasome pathway: in rhizobia-free environments, DMI2 is degraded by the proteasome, but during rhizobial infection, DMI2 is protected from the proteasome, resulting in protein accumulation. Furthermore, proteasome inhibitor-promoted accumulation of DMI2 protein in Medicago roots induces the expression of two early nodulation marker genes, supporting the hypothesis that DMI2 accumulation activates downstream symbiosis signaling. The extracellular region of DMI2 contains two malectin-like domains (MLDs) and a leucine-rich repeat. When conserved amino acids in the MLDs are mutated, DMI2 fails to restore nodule development in dmi2 mutants, and point-mutated MLD proteins are degraded constitutively, suggesting that the MLD may be vital for the accumulation of DMI2. Our findings suggest that legumes control nodule development through modulating the protein level of DMI2, revealing a layer of regulation in the interaction between plants and rhizobia in nitrogen-fixing symbiosis. PMID- 29717011 TI - Statins Suppress Ebola Virus Infectivity by Interfering with Glycoprotein Processing. AB - Ebola virus (EBOV) infection is a major public health concern due to high fatality rates and limited effective treatments. Statins, widely used cholesterol lowering drugs, have pleiotropic mechanisms of action and were suggested as potential adjunct therapy for Ebola virus disease (EVD) during the 2013-2016 outbreak in West Africa. Here, we evaluated the antiviral effects of statin (lovastatin) on EBOV infection in vitro Statin treatment decreased infectious EBOV production in primary human monocyte-derived macrophages and in the hepatic cell line Huh7. Statin treatment did not interfere with viral entry, but the viral particles released from treated cells showed reduced infectivity due to inhibition of viral glycoprotein processing, as evidenced by decreased ratios of the mature glycoprotein form to precursor form. Statin-induced inhibition of infectious virus production and glycoprotein processing was reversed by exogenous mevalonate, the rate-limiting product of the cholesterol biosynthesis pathway, but not by low-density lipoprotein. Finally, statin-treated cells produced EBOV particles devoid of the surface glycoproteins required for virus infectivity. Our findings demonstrate that statin treatment inhibits EBOV infection and suggest that the efficacy of statin treatment should be evaluated in appropriate animal models of EVD.IMPORTANCE Treatments targeting Ebola virus disease (EVD) are experimental, expensive, and scarce. Statins are inexpensive generic drugs that have been used for many years for the treatment of hypercholesterolemia and have a favorable safety profile. Here, we show the antiviral effects of statins on infectious Ebola virus (EBOV) production. Our study reveals a novel molecular mechanism in which statin regulates EBOV particle infectivity by preventing glycoprotein processing and incorporation into virus particles. Additionally, statins have anti-inflammatory and immunomodulatory effects. Since inflammation and dysregulation of the immune system are characteristic features of EVD, statins could be explored as part of EVD therapeutics. PMID- 29717008 TI - Hacking the Cell: Network Intrusion and Exploitation by Adenovirus E1A. AB - As obligate intracellular parasites, viruses are dependent on their infected hosts for survival. Consequently, viruses are under enormous selective pressure to utilize available cellular components and processes to their own advantage. As most, if not all, cellular activities are regulated at some level via protein interactions, host protein interaction networks are particularly vulnerable to viral exploitation. Indeed, viral proteins frequently target highly connected "hub" proteins to "hack" the cellular network, defining the molecular basis for viral control over the host. This widespread and successful strategy of network intrusion and exploitation has evolved convergently among numerous genetically distinct viruses as a result of the endless evolutionary arms race between pathogens and hosts. Here we examine the means by which a particularly well connected viral hub protein, human adenovirus E1A, compromises and exploits the vulnerabilities of eukaryotic protein interaction networks. Importantly, these interactions identify critical regulatory hubs in the human proteome and help define the molecular basis of their function. PMID- 29717025 TI - The type IV pilus assembly motor PilB is a robust hexameric ATPase with complex kinetics. AB - The bacterial type IV pilus (T4P) is a versatile nanomachine that functions in pathogenesis, biofilm formation, motility, and horizontal gene transfer. T4P assembly is powered by the motor ATPase PilB which is proposed to hydrolyze ATP by a symmetrical rotary mechanism. This mechanism, which is deduced from the structure of PilB, is untested. Here, we report the first kinetic studies of the PilB ATPase, supporting co-ordination among the protomers of this hexameric enzyme. Analysis of the genome sequence of Chloracidobacterium thermophilum identified a pilB gene whose protein we then heterologously expressed. This PilB formed a hexamer in solution and exhibited highly robust ATPase activity. It displays complex steady-state kinetics with an incline followed by a decline over an ATP concentration range of physiological relevance. The incline is multiphasic and the decline signifies substrate inhibition. These observations suggest that variations in intracellular ATP concentrations may regulate T4P assembly and T4P mediated functions in vivo in accordance with the physiological state of bacteria with unanticipated complexity. We also identified a mutant pilB gene in the genomic DNA of C. thermophilum from an enrichment culture. The mutant PilB variant, which is significantly less active, exhibited similar inhibition of its ATPase activity by high concentrations of ATP. Our findings here with the PilB ATPase from C. thermophilum provide the first line of biochemical evidence for the co-ordination among PilB protomers consistent with the symmetrical rotary model of catalysis based on structural studies. PMID- 29717022 TI - Epigenetic reprogramming during spermatogenesis and male factor infertility. AB - Infertility is an often devastating diagnosis encountered by around one in six couples who are trying to conceive. Moving away from the long-held belief that infertility is primarily a female issue, it is now recognised that half, if not more, of these cases may be due to male factors. Recent evidence has suggested that epigenetic abnormalities in chromatin dynamics, DNA methylation or sperm borne RNAs may contribute to male infertility. In light of advances in deep sequencing technologies, researchers have been able to increase the coverage and depth of sequencing results, which in turn has allowed more comprehensive analyses of spermatozoa chromatin dynamics and methylomes and enabled the discovery of new subsets of sperm RNAs. This review examines the most current literature related to epigenetic processes in the male germline and the associations of aberrant modifications with fertility and development. PMID- 29717012 TI - The Impact of ExoS on Pseudomonas aeruginosa Internalization by Epithelial Cells Is Independent of fleQ and Correlates with Bistability of Type Three Secretion System Gene Expression. AB - Pseudomonas aeruginosa is internalized into multiple types of epithelial cell in vitro and in vivo and yet is often regarded as an exclusively extracellular pathogen. Paradoxically, ExoS, a type three secretion system (T3SS) effector, has antiphagocytic activities but is required for intracellular survival of P. aeruginosa and its occupation of bleb niches in epithelial cells. Here, we addressed mechanisms for this dichotomy using invasive (ExoS-expressing) P. aeruginosa and corresponding effector-null isogenic T3SS mutants, effector-null mutants of cytotoxic P. aeruginosa with and without ExoS transformation, antibiotic exclusion assays, and imaging using a T3SS-GFP reporter. Except for effector-null PA103, all strains were internalized while encoding ExoS. Intracellular bacteria showed T3SS activation that continued in replicating daughter cells. Correcting the fleQ mutation in effector-null PA103 promoted internalization by >10-fold with or without ExoS. Conversely, mutating fleQ in PAO1 reduced internalization by >10-fold, also with or without ExoS. Effector null PA103 remained less well internalized than PAO1 matched for fleQ status, but only with ExoS expression, suggesting additional differences between these strains. Quantifying T3SS activation using GFP fluorescence and quantitative reverse transcription-PCR (qRT-PCR) showed that T3SS expression was hyperinducible for strain PA103DeltaexoUT versus other isolates and was unrelated to fleQ status. These findings support the principle that P. aeruginosa is not exclusively an extracellular pathogen, with internalization influenced by the relative proportions of T3SS-positive and T3SS-negative bacteria in the population during host cell interaction. These data also challenge current thinking about T3SS effector delivery into host cells and suggest that T3SS bistability is an important consideration in studying P. aeruginosa pathogenesis.IMPORTANCEP. aeruginosa is often referred to as an extracellular pathogen, despite its demonstrated capacity to invade and survive within host cells. Fueling the confusion, P. aeruginosa encodes T3SS effectors with anti internalization activity that, paradoxically, play critical roles in intracellular survival. Here, we sought to address why ExoS does not prevent internalization of the P. aeruginosa strains that natively encode it. Results showed that ExoS exerted unusually strong anti-internalization activity under conditions of expression in the effector-null background of strain PA103, often used to study T3SS effector activity. Inhibition of internalization was associated with T3SS hyperinducibility and ExoS delivery. PA103 fleQ mutation, preventing flagellar assembly, further reduced internalization but did so independently of ExoS. The results revealed intracellular T3SS expression by all strains and suggested that T3SS bistability influences P. aeruginosa internalization. These findings reconcile controversies in the literature surrounding P. aeruginosa internalization and support the principle that P. aeruginosa is not exclusively an extracellular pathogen. PMID- 29717023 TI - The functional principle of eukaryotic molybdenum insertases. AB - The molybdenum cofactor (Moco) is a redox-active prosthetic group found in the active site of Moco-dependent enzymes, which are vitally important for life. Moco biosynthesis involves several enzymes that catalyze the subsequent conversion of GTP into cyclic pyranopterin monophosphate (cPMP), molybdopterin (MPT), adenylated MPT (MPT-AMP), and finally Moco. While the underlying principles of cPMP, MPT, and MPT-AMP formation are well understood, the molybdenum insertase (Mo-insertase)-catalyzed final Moco maturation step is not. In the present study, we analyzed high-resolution X-ray datasets of the plant Mo-insertase Cnx1E that revealed two molybdate-binding sites within the active site, hence improving the current view on Cnx1E functionality. The presence of molybdate anions in either of these sites is tied to a distinctive backbone conformation, which we suggest to be essential for Mo-insertase molybdate selectivity and insertion efficiency. PMID- 29717017 TI - The MicroRNA390/TRANS-ACTING SHORT INTERFERING RNA3 Module Mediates Lateral Root Growth under Salt Stress via the Auxin Pathway. AB - Salt-induced developmental plasticity in a plant root system strongly depends on auxin signaling. However, the molecular events underlying this process are poorly understood. MicroRNA390 (miR390), trans-actin small interfering RNAs (tasiRNAs), and AUXIN RESPONSE FACTORs (ARFs) form a regulatory module involved in controlling lateral root (LR) growth. Here, we found that miR390 expression was strongly induced by exposure to salt during LR formation in poplar (Populus spp.) plants. miR390 overexpression stimulated LR development and increased salt tolerance, whereas miR390 knockdown caused by a short tandem target mimic repressed LR growth and compromised salt resistance. ARF3.1, ARF3.2, and ARF4 expression was inhibited significantly by the presence of salt, and transcript abundance was decreased dramatically in the miR390-overexpressing line but increased in the miR390-knockdown line. Constitutive expression of ARF4m harboring mutated trans-acting small interfering ARF-binding sites removed the salt resistance of the miR390 overexpressors. miR390 positively regulated auxin signaling in LRs subjected to salt, but ARF4 inhibited auxin signaling. Salinity stabilized the poplar Aux/IAA repressor INDOLE-3-ACETIC ACID17.1, and overexpression of an auxin/salt-resistant form of this repressor suppressed LR growth in miR390-overexpressing and ARF4-RNA interfering lines in the presence of salt. Thus, the miR390/TAS3/ARFs module is a key regulator, via modulating the auxin pathway, of LR growth in poplar subjected to salt stress. PMID- 29717016 TI - SUN2 Modulates HIV-1 Infection and Latency through Association with Lamin A/C To Maintain the Repressive Chromatin. AB - The postintegrational latency of HIV-1 is characterized by reversible silencing of long terminal repeat (LTR)-driven transcription of the HIV genome. It is known that the formation of repressive chromatin at the 5'-LTR of HIV-1 proviral DNA impedes viral transcription by blocking the recruitment of positive transcription factors. How the repressive chromatin is formed and modulated during HIV-1 infection remains elusive. Elucidation of which chromatin reassembly factor mediates the reorganization of chromatin is likely to facilitate the understanding of the host's modulation of HIV-1 transcription and latency. Here we revealed that "Sad1 and UNC84 domain containing 2" (SUN2), an inner nuclear membrane protein, maintained the repressive chromatin and inhibited HIV LTR driven transcription of proviral DNA through an association with lamin A/C. Specifically, lamin A/C tethered SUN2 to the nucleosomes 1 and 2 of the HIV-1 5' LTR to block the initiation and elongation of HIV-1 transcription. SUN2 knockdown converted chromatin to an active form and thus enhanced the phosphorylation of RNA polymerase II and its recruitment to the 5'-LTR HIV-1 proviral DNA, leading to reactivation of HIV-1 from latency. Conversely, the exogenous factors such as tumor necrosis factor alpha (TNF-alpha) induced reactivation, and the replication of HIV-1 led to the disassociation between SUN2 and lamin A/C, suggesting that disruption of the association between SUN2 and lamin A/C to convert the repressive chromatin to the active form might be a prerequisite for the initiation of HIV-1 transcription and replication. Together, our findings indicate that SUN2 is a novel chromatin reassembly factor that helps to maintain chromatin in a repressive state and consequently inhibits HIV-1 transcription.IMPORTANCE Despite the successful use of scores of antiretroviral drugs, HIV latency poses a major impediment to virus eradication. Elucidation of the mechanism of latency facilitates the discovery of new therapeutic strategies. It has been known that the formation of repressive chromatin at the 5'-LTR of HIV 1 proviral DNA impedes viral transcription and maintains viral latency, but how the repressive chromatin is formed and modulated during HIV-1 infection remains elusive. In this study, we performed in-depth virological and cell biological studies and discovered that an inner nuclear membrane protein, SUN2, is a novel chromatin reassembly factor that maintains repressive chromatin and thus modulates HIV-1 transcription and latency: therefore, targeting SUN2 may lead to new strategies for HIV cure. PMID- 29717024 TI - A phosphatidic acid-binding protein is important for lipid homeostasis and adaptation to anaerobic biofilm conditions in Pseudomonas aeruginosa. AB - A quantitative Pseudomonas aeruginosa proteomics approach revealed increased abundance of the so-far uncharacterized protein PA3911 in anaerobic biofilms grown under conditions of the cystic fibrosis lung. Physiological relevance of ORF PA3911 was demonstrated, inter alia, using phenotype microarray experiments. The mutant strain showed increased susceptibility in the presence of antimicrobials (minocycline, nafcillin, oxacillin, chloramphenicol and thiamphenicol), enhanced twitching motility and significantly impaired biofilm formation. PA3911 is a soluble, cytoplasmic protein in P. aeruginosa In protein lipid overlay experiments, purified PA3911 bound specifically to phosphatidic acid (PA), the central hub of phospholipid metabolism. Structure-guided site directed mutagenesis was used to explore the proposed ligand-binding cavity of PA3911. Protein variants of Leu56, Leu58, Val69 and Leu114 were shown to impair PA interaction. A comparative shotgun lipidomics approach demonstrated a multifaceted response of P. aeruginosa to anaerobic conditions at the lipid head group and fatty acid level. Lipid homeostasis in the PA3911 mutant strain was imbalanced with respect to lysophosphatidylcholine, phosphatidylcholine and diacylglycerol under anaerobic and/or aerobic conditions. The impact of the newly identified PA-binding protein on lipid homeostasis and the related macroscopic phenotypes of P. aeruginosa are discussed. PMID- 29717021 TI - Cytokinin Targets Auxin Transport to Promote Shoot Branching. AB - Cytokinin promotes shoot branching by activating axillary buds, but its mechanism of action in Arabidopsis (Arabidopsis thaliana) in this process is unclear. We have shown previously that a hextuple mutant lacking a clade of type-A Arabidopsis Response Regulators (ARRs) known to act in cytokinin signaling has reduced shoot branching compared with the wild type. Since these proteins typically act as negative regulators of cytokinin signaling, this is an unexpected result. To explore this paradox more deeply, we characterized the effects of loss of function of the type-B ARR, ARR1, which positively regulates cytokinin-induced gene expression. The arr1 mutant has increased branching, consistent with a role antagonistic to the type-A ARRs but in apparent conflict with the known positive role for cytokinin in bud activation. We show that the arr branching phenotypes correlate with increases in stem auxin transport and steady-state levels of the auxin export proteins PIN3 and PIN7 on the plasma membrane of xylem-associated cells in the main stem. Cytokinin treatment results in an increased accumulation of PIN3, PIN7, and the closely related PIN4 within several hours, and loss of PIN3, PIN4, and PIN7 can partially rescue the arr1 branching phenotype. This suggests that there are multiple signaling pathways for cytokinin in bud outgrowth; one of these pathways regulates PIN proteins in shoots, independently of the canonical signaling function of the ARR genes tested here. A hypothesis consistent with the arr shoot phenotypes is that feedback control of biosynthesis leads to altered cytokinin accumulation, driving cytokinin signaling via this pathway. PMID- 29717027 TI - Clinical utility of decarboxylation prothrombin combined with alpha-fetoprotein for diagnosing primary hepatocellular carcinoma. AB - We conducted a comprehensive analysis to evaluate clinical utility of decarboxylation prothrombin combined with alpha-fetoprotein (AFP) for diagnosing primary hepatocellular carcinoma (HCC). Systematical searches were performed in PubMed, Web of Science, China National Knowledge Internet, and Wangfang databases. The bivariate random-effect model was used to calculate the pooled sensitivity, specificity, positive likelihood ratio (PLR), negative likelihood, diagnostic odds ratio (DOR), and summary area under the curve (AUC). Fourteen studies were included in the meta-analysis. For decarboxylation prothrombin, the overall pooled parameters are as follows: sensitivity: 79% (95% confidence interval (CI): 74-84%), specificity: 91% (95%CI: 87-93%), PLR: 8.42 (95%CI: 5.79 12.23), negative likelihood ratio (NLR): 0.23 (95%CI: 0.17-0.30), DOR: 37.09 (95%CI: 21.37-64.36), summary AUC: 0.92 (95%CI: 0.89-0.94); for combined diagnostic, the overall pooled parameters were as follows: sensitivity: 91% (95%CI: 85-95%), specificity: 83% (95%CI: 74-89%), PLR: 5.26 (95%CI: 3.53-7.83), NLR: 0.11 (95%CI: 0.07-0.18), DOR: 47.14 (95%CI: 30.09-73.85), summary AUC: 0.94 (95%CI: 0.91-0.95). The serum decarboxylation prothrombin showed a relatively higher diagnostic specificity for primary HCC and decarboxylation prothrombin combined with AFP exhibited can improve sensitivity for HCC than any of the biomarkers alone. PMID- 29717028 TI - Long non-coding RNA AK096174 promotes cell proliferation and invasion in gastric cancer by regulating WDR66 expression. AB - Gastric cancer (GC) is one of the major causes of cancer deaths worldwide; however, the mechanism of carcinogenesis is complex and poorly understood. Long non-coding RNA (lncRNA) has been reported to be involved in the development of multiple cancers. Here, we identified a novel lncRNA, AK096174, which was up regulated and associated with tumorigenesis, tumor size, metastasis, and poor prognosis in GC. Our data showed that AK096174 was highly expressed in the GC tissues and cell lines (SGC-7901, AGS, BGC-823, MGC-803), and patients with higher AK096174 expression had a poorer prognosis and shorter overall survival (OS). AK096174 knockdown inhibited the proliferation, migration, and invasiveness in SGC-7901 and BGC-823 cells, whereas AK096174 overexpression had the promoting effects. Furthermore, mechanistic investigation showed that AK096174 positively correlated with the expression of WD repeat-containing protein 66 (WDR66) gene at the translational level. Knockdown of WRD66 attenuated the positive impact of AK096174 in GC cells. The findings of the present study establish a function for AK096174 in GC progression and suggest it may serve as a potential target for GC therapy in the future. PMID- 29717020 TI - OsMADS6 Controls Flower Development by Activating Rice FACTOR OF DNA METHYLATION LIKE1. AB - OsMADS6, an ancient AGAMOUS-LIKE6 (AGL6)-like gene, has essential functions in specifying floral organ and meristem identity in rice (Oryza sativa). However, how AGL6 genes control flower development remains largely unknown. In this study, we report that OsMADS6 directly targets FACTOR OF DNA METHYLATION LIKE 1 (OsFDML1), a rice homolog of the SUPPRESSOR OF GENE SILENCING3-like gene FACTOR OF DNA METHYLATION 1 (FDM1) from Arabidopsis (Arabidopsis thaliana). Arabidopsis FDM1 is involved in RNA-directed DNA methylation and OsFDML1 regulates flower development. The expression of OsFDML1 overlaps with that of OsMADS6 in the palea primordia and the ovule, and OsMADS6 directly promotes OsFDML1 expression through binding to regions containing putative CArG motifs within the OsFDML1 promoter during rice spikelet development. Consistent with the phenotypes of osmads6 mutants, the osfdml1 mutants showed floral defects, including altered palea identity with lemma-like shape containing no marginal region of palea, increased numbers of stigmas and fused carpels, and meristem indeterminacy. Moreover, transgenic plants overexpressing OsFDML1 displayed floral defects, such as abnormal paleae. Phylogenetic analysis showed that OsFDML1 homologs exist only in terrestrial plants. In addition, protein-protein interaction assays showed that OsFDML1 interacts with its close paralog OsFDML2, similar to the activity of OsFDML1 homologs in Arabidopsis. These results provide insight into how the ancient AGL6 gene regulates floral development. PMID- 29717026 TI - Steroid receptor coactivator-1 interacts with NF-kappaB to increase VEGFC levels in human thyroid cancer. AB - Thyroid cancer is the most common endocrine cancer, and has a high incidence of lymphatic metastasis. Vascular endothelial growth factor C (VEGFC) is essential for development of lymphatic vessels and lymphatic metastases during carcinogenesis. Steroid receptor coactivator-1 (SRC-1) interacts with nuclear receptors and transcription factors to promote tumor proliferation and metastasis. However, the correlation between SRC-1 and VEGFC levels in the lymphatic metastases of thyroid cancer remains unclear. We analyzed 20-paired specimens of thyroid cancer tissue and normal thyroid tissue and found increased levels of SRC-1 and VEGFC proteins in 13/20 and 15/20 thyroid cancer specimens, respectively, when compared with those levels in specimens of normal thyroid tissue. A high level of SRC-1 expression was positively correlated with VEGFC and lymphatic endothelial cell marker LYVE-1 expression. Papillary thyroid carcinoma cell line TPC-1 displayed high levels of SRC-1 and VEGFC expression and was selected for stable knockdown of SRC-1 in vitro Inhibition of SRC-1 significantly reduced the VEGFC levels in TPC-1 cells. We found that SRC-1 binds to transcription factor NF-kB (p50/p65), and that this coactivation complex directly promoted VEGFC transcription, which could be abrogated by SRC-1 knockdown. Up regulated NF-kB signaling was also confirmed in thyroid cancer tissues. In vivo studies showed that SRC-1 knockdown restricted tumor growth, reduced the numbers of LYVE-1-positive lymphatic vessels, and decreased the levels of VEGFC in tumor tissues. These results suggest a tumorigenic role for SRC-1 in thyroid cancer via its ability to regulate VEGFC expression. PMID- 29717019 TI - FLOURY SHRUNKEN ENDOSPERM1 Connects Phospholipid Metabolism and Amyloplast Development in Rice. AB - Starch synthesized and stored in amyloplasts serves as the major energy storage molecule in cereal endosperm. To elucidate the molecular mechanisms underlying amyloplast development and starch synthesis, we isolated a series of floury endosperm mutants in rice (Oryza sativa). We identified the rice mutant floury shrunken endosperm1 (fse1), which exhibited obvious defects in the development of compound starch grains, decreased starch content, and altered starch physicochemical features. Map-based cloning showed that FSE1 encodes a phospholipase-like protein homologous to phosphatidic acid-preferring phospholipase A1FSE1 was expressed ubiquitously with abundant levels observed in developing seeds and roots. FSE1 was localized to both the cytosol and intracellular membranes. Lipid profiling indicated that total extra-plastidic lipids and phosphatidic acid were increased in fse1 plants, suggesting that FSE1 may exhibit in vivo phospholipase A1 activity on phosphatidylcholine, phosphatidylinositol, phosphatidyl-Ser, phosphatidylethanolamine, and, in particular, phosphatidic acid. Additionally, the total galactolipid content in developing fse1 endosperm was significantly reduced, which may cause abnormal amyloplast development. Our results identify FSE1 as a phospholipase-like protein that controls the synthesis of galactolipids in rice endosperm and provide a novel connection between lipid metabolism and starch synthesis in rice grains during endosperm development. PMID- 29717029 TI - A comprehensive evaluation for polymorphisms in let-7 family in cancer risk and prognosis: a system review and meta-analysis. AB - miRNA polymorphisms had potential to be biomarkers for cancer susceptibility and prognosis. The mature miRNA-let-7 family was considered as the most important miRNA for the cancer incidence and progression. Recently, the promising let-7 miRNAs were reported to be associated with various cancers, but the results were inconsistent. We performed a first-reported systematic review with a meta analysis for the association of let-7 family single nucleotide polymorphisms (SNPs) with cancer risk/prognosis. Ten studies were included with a total of 3878 cancer cases and 4725 controls for the risk study and 1665 cancer patients for the prognosis study in this meta-analysis. In the risk study, the let-7i rs10877887 and let-7a-1/let-7f-1/let-7d rs13293512 were shown no significant association for the overall cancer risk. In the stratified analysis, the rs10877887 variant genotype was significantly associated with a decreased cancer risk in head and neck cancer (TC compared with TT: P=0.017; odds ratio (OR) = 0.81; TC + CC compared with TT: P=0.020; OR = 0.82). In the prognosis study, the let-7i rs10877887 SNP was shown to be associated with a higher risk for cancer prognosis in the dominate model (P=0.004; hazard ratio (HR) = 1.32). The other two SNPs (let-7a-1 rs10739971 and let-7a-2 rs629367) were not found to be associated with cancer survival. None of the let-7 family polymorphisms had potential to be biomarkers for cancer susceptibility but let-7i rs10877887 SNP had potential to be predicting markers for cancer prognosis. In the future, large sample studies are still needed to verify our findings. PMID- 29717034 TI - Magnetic Resonance Imaging of Bilateral Hands Is More Optimal Than MRI of Unilateral Hands for Rheumatoid Arthritis. AB - OBJECTIVE: To explore the advantages of magnetic resonance imaging (MRI) of bilateral hands in rheumatoid arthritis (RA). METHODS: Consecutive patients with active RA were recruited for clinical assessments, radiographs, and MRI of bilateral hands. Bilateral hands were scanned simultaneously on 3.0 T whole-body MRI system and were scored on synovitis, osteitis, and bone erosion according to the RA MRI scoring (RAMRIS) system. RESULTS: Among 120 patients included, wrist bones and metacarpophalangeal joint (MCPJ) 2 proximal showed bone erosion in early RA. The second to fifth metacarpal bases and the second to fourth MCPJ distal showed more bone erosion in mid-stage or late-stage RA. When MRI of dominant unilateral hand was analyzed, MRI synovitis and osteitis in 5% of wrists and 3 MRI features in 5-14% of MCPJ were misdiagnosed (McNemar test, all p < 0.05). There were 46% wrist synovitis, 29-52% MCPJ2-5 synovitis, 45% wrist osteitis, and 20%-34% MCPJ2-5 osteitis not detected by joint tenderness and/or swelling. When the clinically more severe hand was selected for MRI of unilateral hand according to physical examination, MRI synovitis in 5% of wrists and 3 MRI features in 7-15% of MCPJ were misdiagnosed (all p < 0.05). Scatter plots and linear regression analyses were used to illustrate RAMRIS between dominant or selected hand (Y values) and nondominant or nonselected hand (X values). All linear models were markedly different from a Y = X linear model, indicating the dominant or clinically more severe hand could not represent the contralateral hand to evaluate RAMRIS. CONCLUSION: MRI of bilateral hands is more optimal than MRI of the unilateral hand in RA. PMID- 29717036 TI - PGA*BSA: A Measure of Psoriasis Severity Tested in Patients with Active Psoriatic Arthritis and Treated with Certolizumab Pegol. AB - OBJECTIVE: The product of physician's global assessment and body surface area (PGA*BSA) to assess psoriasis severity has previously been investigated in patients with psoriasis, with the aim of assessing PGA*BSA as an alternative to the time-consuming Psoriasis Area and Severity Index (PASI). Here, we investigate PGA*BSA as an alternative to PASI in patients with psoriatic arthritis (PsA). METHODS: Analyses used data from the double-blind, placebo-controlled, RAPID-PsA trial (NCT01087788) that investigated the efficacy of certolizumab pegol (CZP) in patients with PsA. Outcomes assessed whether the PGA*BSA and PASI results were comparable, and whether these outcomes correlated with one another or with the Dermatology Life Quality Index (DLQI). RESULTS: For CZP-treated patients, both PGA*BSA and PASI demonstrated similar sensitivities to treatment between baseline and Week 24, with mean improvements of 77.4% and 69.0%, respectively. Similar improvements were also seen with placebo (PGA*BSA: 3.2%, PASI: 6.1%). Achievement of 75% response criterion in PGA*BSA and PASI was attained by similar proportions of patients with CZP (PGA*BSA75: 59.0%, PASI75: 61.4%) and placebo (PGA * BSA75: 15.1%, PASI75: 15.1%). Cross tabulations showed high concordance between achievement of response outcomes in PGA*BSA and PASI (79.6-95.2%). Spearman correlations revealed strong correlations between PGA*BSA and PASI at baseline (r = 0.78; n = 225) and percentage improvement to Week 24 (r = 0.85; n = 186). Both outcomes were only moderately correlated with DLQI (r = 0.41-0.50; n = 179-249). CONCLUSION: PGA*BSA is sensitive to changes in skin manifestations in patients with PsA treated with CZP. Further, PGA*BSA correlates strongly with PASI, and achievement of 75% improvement was similar for PGA*BSA and PASI. PMID- 29717033 TI - An Outsourced Health-enhancing Physical Activity Program for People with Rheumatoid Arthritis: Study of the Maintenance Phase. AB - OBJECTIVE: To describe changes of health-enhancing physical activity (HEPA), health perception, and functioning during the second year of a 2-year support program, determine aspects of adherence and response, and describe perceptions of the program. METHODS: Out of 220 individuals with rheumatoid arthritis (RA), 177 participated in the followup. Group support, strength training, and moderate intensity aerobic activity were encouraged. Data collection included HEPA, perceived health, functioning, and perceptions of the program. Participants with unchanged/improved general health perception and at least 2 of aerobic capacity, grip strength, or timed standing were considered responders. RESULTS: Current and maintained HEPA decreased from 82% to 75% (p = 0.0141) and from 41% to 27% (p < 0.0001) during the second year. Minor declines in quality of life and activity limitation occurred (p = 0.0395 and 0.0038, respectively), while outcome expectations for benefits of physical activity increased (p = 0.0010 and 0.0186) and waist circumference tapered off (p = 0.0070). Strength training was performed on average 41 and 35 times among responders (n = 54) and nonresponders (n = 105), respectively (p = 0.2708); HEPA 194 and 171 days, respectively (p = 0.0828); and support group meetings 12 and 10 times, respectively (p = 0.0943). Strength training, aerobic activity, and short text message reminders were perceived as most valuable; step registration and the self-monitoring walk tests were less appreciated. CONCLUSION: About one-fourth of the originally sedentary individuals with RA sustained their new HEPA behaviors after 2 years and most improvements of health and functioning were sustained. Structured use of behavior change techniques and a second year to support maintenance with a reduced program might help patients with RA to sustain HEPA behavior. PMID- 29717037 TI - The Effect of Biologic and Targeted Synthetic Drugs on Work- and Productivity related Outcomes for Patients with Psoriatic Arthritis: A Systematic Review. AB - OBJECTIVE: To systematically review the effects of biologic therapies for psoriatic arthritis [secukinumab, ustekinumab, adalimumab, etanercept, certolizumab pegol (CZP), apremilast, golimumab (GOL), or infliximab (IFX)] on work productivity. METHODS: A systematic review of Medline, EMBASE, CENTRAL, and ClinicalTrials.gov was conducted to identify randomized controlled trials reporting on work productivity outcomes at the end of the placebo-controlled double-blind period. RESULTS: There were 7959 records identified. Full text of 377 records was further assessed for eligibility, of which 5 trials were included. All included trials were assessed with the Cochrane Risk of Bias Tool, and 4 out of 5 were judged to be of low risk of bias in most domains. Improvements in self-assessed work productivity were observed in 5 trials (IFX, GOL, CZP, ustekinumab, and apremilast), ranging from a mean difference of -0.9 to -1.8 on a 1-10 scale of self-assessed work productivity (negative change represents improvement), although statistical significance of the results was not reported for CZP and apremilast. Treatment with CZP resulted in a statistically significant reduction in absenteeism (200 mg) and presenteeism (200 and 400 mg). IFX and GOL reported a nonsignificant reduction of absenteeism. The Work Productivity Survey, the Work Limitations Questionnaire, and visual analog scales were used to measure work productivity. CONCLUSION: Treatment with IFX, GOL, CZP, ustekinumab, and apremilast resulted in improvements in self-reported work productivity. A pooled analysis was not possible because of the clinical heterogeneity of the trials and variability in outcome reporting. PMID- 29717035 TI - Predictors of Flare Following Etanercept Withdrawal in Patients with Rheumatoid Factor-negative Juvenile Idiopathic Arthritis Who Reached Remission while Taking Medication. AB - OBJECTIVE: To evaluate the rate of flare after etanercept (ETN) withdrawal in patients with juvenile idiopathic arthritis (JIA) who attained clinical remission while taking medication, and to identify predictors of flare. METHODS: Patients were included with oligo- (oJIA) and rheumatoid factor-negative polyarticular JIA (pJIA) who received a first course of ETN for at least 18 months, maintained clinically inactive disease (CID) for at least 6 months during treatment, and were followed for 12 months after ETN withdrawal. Demographic and clinical features were collected at onset, at baseline (initiation of ETN), and at time of disease flare. RESULTS: After ETN withdrawal, 66 of the 110 patients enrolled (60%) flared with arthritis (of whom 7 flared with concurrent anterior uveitis; none with uveitis alone). The median time to flare was 4.3 months (interquartile range 2.5-6.4) with no evident differences between oJIA and pJIA. The number and type of joints involved at baseline and characteristics of ETN treatment/discontinuation were not associated with flare. Patients who flared were more frequently males (p = 0.034), positive for antinuclear antibody (ANA; p = 0.047), and had higher values of C-reactive protein (CRP; p = 0.012) at baseline. These variables remained significantly associated with flare in a multivariate logistic analysis, a model accounting for only 14% of the variability of the occurrence of the flare. CONCLUSION: Our results show that a significant proportion of patients with JIA who maintain CID for at least 6 months experience a relapse after ETN withdrawal. Male sex, presence of ANA, and elevated CRP at baseline were associated with higher risk of flare. PMID- 29717032 TI - Responsiveness of Single versus Composite Measures of Pain in Knee Osteoarthritis. AB - OBJECTIVE: In rheumatoid arthritis, composite outcomes constructed from a combination of outcome measures are widely used to enhance responsiveness (sensitivity to change) and comprehensively summarize response. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain is the primary outcome measure in many osteoarthritis (OA) trials. Information from other outcomes, such as rescue medication use and other WOMAC subscales, could be added to create composite outcomes, but the sensitivity of such a composite has not been tested. METHODS: We used data from a completed trial of tanezumab for knee OA (NCT00733902). The WOMAC questionnaire and rescue medication use were measured at several timepoints, up to 16 weeks. Pain and rescue medication outcomes were standardized and combined into 3 composite outcomes through principal components analysis to produce 1 score (composite outcome) and their responsiveness was compared to WOMAC pain, the standard. We pooled all treatment doses of tanezumab into 1 treatment group, for simplicity, and compared this to the control group (placebo). RESULTS: The composite outcomes showed modestly, but not statistically significantly greater responsiveness when compared to WOMAC pain alone. Adding information on rescue medication to the composite improved responsiveness. While improvements in sensitivity were modest, the required sample sizes for trials using composites was 20-40% less than trials using WOMAC pain alone. CONCLUSION: Combining information from related but distinct outcomes considered relevant to a particular treatment improved responsiveness, could reduce sample size requirements in OA trials, and might offer a way to better detect treatment efficacy in OA trials. PMID- 29717030 TI - Lack of association between miR-218 rs11134527 A>G and Kawasaki disease susceptibility. AB - Kawasaki disease (KD) is a type of disease that includes the development of a fever that lasts at least 5 days and involves the clinical manifestation of multicellular vasculitis. KD has become one of the most common pediatric cardiovascular diseases. Previous studies have reported that miR-218 rs11134527 A>G is associated with susceptibility to various cancer risks. However, there is a lack of evidence regarding the relationship between this polymorphism and KD risk. The present study explored the correlation between the miR-218 rs11134527 A>G polymorphism and the risk of KD. We recruited 532 patients with KD and 623 controls to genotype the miR-218 rs11134527 A>G polymorphism with a TaqMan allelic discrimination assay. Our results illustrated that the miR-218 rs11134527 A>G polymorphism was not associated with KD risk. In an analysis stratified by age, sex, and coronary artery lesions, we found only that the risk of KD was significantly decreased for children older than 5 years (GG vs. AA/AG: adjusted OR = 0.26, 95% CI = 0.07-0.94, P=0.041). The present study demonstrated that the miR-218 rs1113452 A>G polymorphism may have an age-related relationship with KD susceptibility that has not previously been revealed. PMID- 29717031 TI - Piperine functions as a tumor suppressor for human ovarian tumor growth via activation of JNK/p38 MAPK-mediated intrinsic apoptotic pathway. AB - Piperine, a kind of natural alkaloid found in the fruit of black (Piper nigrum Linn) and long (Piper longum Linn), has shown antitumor activities toward various cancer cell lines. However, the antitumor effects of Piperine on ovarian cancer and the underlying mechanism are not fully elucidated. Our result showed that Piperine reduced the cell viability of A2780 cells in a concentration and time dependent manner, but has not any effect on normal ovarian cells. Flow cytometric analysis revealed that Piperine suppressed cells proliferation via induction of apoptosis, which was followed by release of mitochondrial cytochrome c to cytosol, activation of caspase-3 and -9, as well as cleaved PARP. Moreover, Western blot results confirmed that Piperine (8, 16, and 20 MUM) decreased phosphorylation of JNK and p38 MAPK in A2780 cells. In addition, caspase-3 inhibitor (Z-DEVD-FMK), caspase-9 inhibitor (Z-LEDH-FMK), JNK-inhibitor (SP600125), or p38 MAPK inhibitor (SB203580) could abate the apoptosis induced by Piperine (20 MUM) treatment, while caspase-8 inhibitor (Z-IETD- FMK) exhibited no inhibitory effect on the induction of apoptosis in A2780 cells. These results provide the first evidence for the anticancer potential of Piperine in ovarian cancer cells, partially via JNK/p38 MAPK-mediated intrinsic apoptotic pathway. PMID- 29717044 TI - ChIP-Quantitative Polymerase Chain Reaction (ChIP-qPCR). AB - It is critical to determine if the ChIP actually enriched the DNA sequences that are associated with the target protein. If there are known genomic binding sites, primers can be designed for quantitative PCR (qPCR) to determine if the known sites are specifically enriched by immunoprecipitation. If there are no known sites but candidate target genes are available, one can consider designing qPCR primers along the length of potential regulatory regions such as promoters and conserved noncoding sequences within intergenic and genic regions. If candidate target genes or potential sites are not available, ChIP-chip or ChIP-seq should be considered instead. Because real-time PCR can be performed in either a 96- or 384-well format in a minimal reaction volume and primers can be synthesized with minimal cost, ChIP-qPCR is an attractive strategy to interrogate target genes and potential regulatory regions across a large number of experimental conditions and different cell types. PMID- 29717045 TI - ChIP-chip. AB - ChIP-chip can be used to analyze protein-DNA interactions in a region-wide and genome-wide manner. DNA microarrays contain PCR products or oligonucleotide probes that are designed to represent genomic sequences. Identification of genomic sites that interact with a specific protein is based on competitive hybridization of the ChIP-enriched DNA and the input DNA to DNA microarrays. The ChIP-chip protocol can be divided into two main sections: Amplification of ChIP DNA and hybridization of ChIP DNA to arrays. A large amount of DNA is required to hybridize to DNA arrays, and hybridization to a set of multiple commercial arrays that represent the entire human genome requires two rounds of PCR amplifications. The relative hybridization intensity of ChIP DNA and that of the input DNA is used to determine whether the probe sequence is a potential site of protein-DNA interaction. Resolution of actual genomic sites bound by the protein is dependent on the size of the chromatin and on the genomic distance between the probes on the array. As with expression profiling using gene chips, ChIP-chip experiments require multiple replicates for reliable statistical measure of protein-DNA interactions. PMID- 29717042 TI - Support for the value 5/2 for the spin glass lower critical dimension at zero magnetic field. AB - We study numerically various properties of the free energy barriers in the Edwards-Anderson model of spin glasses in the low-temperature region in both three and four spatial dimensions. In particular, we investigated the dependence of height of free energy barriers on system size and on the distance between the initial and final states (i.e., the overlap distance). A related quantity is the distribution of large local fluctuations of the overlap in large 3D samples at equilibrium. Our results for both quantities (barriers and large deviations) are in agreement with the prediction obtained in the framework of mean-field theory. In addition, our result supports [Formula: see text] as the lower critical dimension of the model. PMID- 29717039 TI - Plant acclimation to long-term high nitrogen deposition in an N-rich tropical forest. AB - Anthropogenic nitrogen (N) deposition has accelerated terrestrial N cycling at regional and global scales, causing nutrient imbalance in many natural and seminatural ecosystems. How added N affects ecosystems where N is already abundant, and how plants acclimate to chronic N deposition in such circumstances, remains poorly understood. Here, we conducted an experiment employing a decade of N additions to examine ecosystem responses and plant acclimation to added N in an N-rich tropical forest. We found that N additions accelerated soil acidification and reduced biologically available cations (especially Ca and Mg) in soils, but plants maintained foliar nutrient supply at least in part by increasing transpiration while decreasing soil water leaching below the rooting zone. We suggest a hypothesis that cation-deficient plants can adjust to elevated N deposition by increasing transpiration and thereby maintaining nutrient balance. This result suggests that long-term elevated N deposition can alter hydrological cycling in N-rich forest ecosystems. PMID- 29717038 TI - Lipidomic profiling reveals soluble epoxide hydrolase as a therapeutic target of obesity-induced colonic inflammation. AB - Obesity is associated with enhanced colonic inflammation, which is a major risk factor for colorectal cancer. Considering the obesity epidemic in Western countries, it is important to identify novel therapeutic targets for obesity induced colonic inflammation, to develop targeted strategies for prevention. Eicosanoids are endogenous lipid signaling molecules involved in regulating inflammation and immune responses. Using an LC-MS/MS-based lipidomics approach, we find that obesity-induced colonic inflammation is associated with increased expression of soluble epoxide hydrolase (sEH) and its eicosanoid metabolites, termed fatty acid diols, in colon tissue. Furthermore, we find that pharmacological inhibition or genetic ablation of sEH reduces colonic concentrations of fatty acid diols, attenuates obesity-induced colonic inflammation, and decreases obesity-induced activation of Wnt signaling in mice. Together, these results support that sEH could be a novel therapeutic target for obesity-induced colonic inflammation and associated diseases. PMID- 29717043 TI - Roughness-dependent tribology effects on discontinuous shear thickening. AB - Surface roughness affects many properties of colloids, from depletion and capillary interactions to their dispersibility and use as emulsion stabilizers. It also impacts particle-particle frictional contacts, which have recently emerged as being responsible for the discontinuous shear thickening (DST) of dense suspensions. Tribological properties of these contacts have been rarely experimentally accessed, especially for nonspherical particles. Here, we systematically tackle the effect of nanoscale surface roughness by producing a library of all-silica, raspberry-like colloids and linking their rheology to their tribology. Rougher surfaces lead to a significant anticipation of DST onset, in terms of both shear rate and solid loading. Strikingly, they also eliminate continuous thickening. DST is here due to the interlocking of asperities, which we have identified as "stick-slip" frictional contacts by measuring the sliding of the same particles via lateral force microscopy (LFM). Direct measurements of particle-particle friction therefore highlight the value of an engineering-tribology approach to tuning the thickening of suspensions. PMID- 29717046 TI - ChIP-seq. AB - Owing to its digital nature, ChIP-seq has become the standard method for genome wide ChIP analysis. Using next-generation sequencing platforms (notably the Illumina Genome Analyzer), millions of short sequence reads can be obtained. The densities of recovered ChIP sequence reads along the genome are used to determine the binding sites of the protein. Although a relatively small amount of ChIP DNA is required for ChIP-seq, the current sequencing platforms still require amplification of the ChIP DNA by ligation-mediated PCR (LM-PCR). This protocol, which involves linker ligation followed by size selection, is the standard ChIP seq protocol using an Illumina Genome Analyzer. The size-selected ChIP DNA is amplified by LM-PCR and size-selected for the second time. The purified ChIP DNA is then loaded into the Genome Analyzer. The ChIP DNA can also be processed in parallel for ChIP-chip results. PMID- 29717052 TI - Hot Start Polymerase Chain Reaction (PCR). AB - The purpose of hot start polymerase chain reaction (PCR) is to optimize the yield of the desired amplified product in PCRs and, simultaneously, to suppress nonspecific amplification and formation of primer dimers. This is achieved by withholding an essential component of the PCR-the DNA polymerase, or the primers, for example-until the reaction mixture has been heated to a temperature that inhibits hybridization of primers to one another or to nonspecific regions of the template. PMID- 29717053 TI - Touchdown Polymerase Chain Reaction (PCR). AB - "Touchdown polymerase chain reaction (PCR)" is a method to decrease off-target priming and hence to increase the specificity of PCRs. In touchdown PCR the temperature selected for the annealing step is initially set 5 degrees C-10 degrees C higher than the calculated Tm of the primers. Annealing under conditions of high stringency favors the formation of perfect primer-template hybrids. In subsequent cycles, the annealing temperature is gradually decreased by a small amount so that by the end of the PCR, the annealing temperature is 2 degrees C-5 degrees C below the calculated Tm of the primers. By then, the target sequence will have undergone several cycles of geometric amplification and therefore becomes the dominant product of the PCR. To minimize mispriming during the early stages of the PCR, touchdown PCR should always be performed in conjunction with a hot start protocol. The use of touchdown PCR is essential when the sequence of the primer might not match that of the target-for example, if the sequence of the primer has been deduced from amino acid sequences, when the template DNA may contain several closely related targets, or when the target DNA is of a different species from that used to design the primers. PMID- 29717047 TI - Isolation of DNA from Mouse Tails without Extraction by Organic Solvents. AB - This protocol describes a variation of a simple method for isolation of DNA from mouse tails that does not require extraction with phenol:chloroform. This variant is useful when processing very large numbers of samples. PMID- 29717048 TI - Mouse Embryo Cryopreservation by Slow Freezing. AB - This embryo cryopreservation protocol is used by The Jackson Laboratory and several other repositories around the world. This protocol has clearly withstood the test of time; >2 million embryos from thousands of strains have been cryopreserved using this method. It requires a controlled-rate freezer, but is simple, effective, and can be applied to cryopreserve embryos from the two-cell to the blastocyst stage. Thawing requires neither special media nor equipment because the insemination straw contains all of the needed elements, making this very useful for distributing cryopreserved embryos. Embryo survival rates of greater than 90% can be expected when this method is used, making it reliable and enabling staff with prior embryo-handling experience to become proficient quickly. PMID- 29717049 TI - Mouse Embryo Cryopreservation by Rapid Cooling. AB - Embryo cryopreservation has been used to archive mouse strains. Protocols have evolved over this time and now vary considerably in terms of cryoprotectant solution, cooling and warming rates, methods to add and remove cryoprotectant, container or carrier type, volume of cryoprotectant, the stage of preimplantation development, and the use of additional treatments such as blastocyst puncture and microinjection. The rapid cooling methods use concentrated solutions of cryoprotectants to reduce the water content of the cell before cooling commences, thus preventing the formation of ice crystals. Embryos are equilibrated with the cryoprotectants, loaded into a carrier, and then rapidly cooled (e.g., by being plunged directly into LN2 or onto a surface cooled in LN2). The rapid cooling methods eliminate the need for controlled-rate freezers and seeding procedures. However, they are much more sensitive to minor variations when performing the steps. The rapid-cooling protocol described here is suitable for use with plastic insemination straws. Because it uses relatively large volumes, it is less technically demanding than some other methods that use minivolume devices. PMID- 29717050 TI - Mouse Embryo Cryopreservation by High-Osmolality Vitrification. AB - In conventional vitrification methods, the embryos are vitrified under considerable supercooling (i.e., under nonequilibrium conditions). This protocol is a refinement of newer equilibrium vitrification methods. The equilibrium vitrification solution contains a high concentration of cryoprotectants that increase its osmolality and allows vitrified embryos to survive not only during storage in liquid nitrogen (LN2) at -196 degrees C but also during temporary holding at -80 degrees C (for at least 5 mo). This high-osmolality vitrification (HOV) method is as simple as conventional vitrification and provides essentially the same high postwarming survival rate. It has several advantages over conventional vitrification: (1) Cryopreserved embryos are less likely to be damaged during handling for warming; (2) samples can be temporarily evacuated to a -80 degrees C freezer and can be successfully recovered after 5 mo at -80 degrees C; (3) samples can be arranged and sorted at -80 degrees C; and (4) vitrified embryos can be transported using dry ice. Also included here is an alternative protocol that describes the use of straws instead of cryotubes. PMID- 29717051 TI - The Basic Polymerase Chain Reaction (PCR). AB - This protocol describes the reagents and procedures required to amplify a segment of double-stranded DNA in a chain reaction catalyzed by a thermostable DNA polymerase. It is the foundation for all subsequent variations of the polymerase chain reaction (PCR). PMID- 29717054 TI - Making Weak Antigens Strong: Modifying Antigens by Dinitrophenol or Arsynyl Coupling. AB - Many compounds on their own do not have all of the properties needed to induce a strong antibody response. However, small changes in the structure of an antigen can often greatly alter the immunogenicity of a compound. Common methods for doing so include the addition of small modifying groups such as dinitrophenol or arsenate to the molecules. These techniques either alter regions of the immunogen to provide better sites for T-cell binding or expose new epitopes for B-cell binding. The techniques are rapid and easy, and have been used extensively as a general procedure to increase the chances of raising antisera, particularly against well-conserved antigens. PMID- 29717041 TI - Reversible photoswitching of encapsulated azobenzenes in water. AB - Efficient molecular switching in confined spaces is critical for the successful development of artificial molecular machines. However, molecular switching events often entail large structural changes and therefore require conformational freedom, which is typically limited under confinement conditions. Here, we investigated the behavior of azobenzene-the key building block of light controlled molecular machines-in a confined environment that is flexible and can adapt its shape to that of the bound guest. To this end, we encapsulated several structurally diverse azobenzenes within the cavity of a flexible, water-soluble coordination cage, and investigated their light-responsive behavior. Using UV/Vis absorption spectroscopy and a combination of NMR methods, we showed that each of the encapsulated azobenzenes exhibited distinct switching properties. An azobenzene forming a 1:1 host-guest inclusion complex could be efficiently photoisomerized in a reversible fashion. In contrast, successful switching in inclusion complexes incorporating two azobenzene guests was dependent on the availability of free cages in the system, and it involved reversible trafficking of azobenzene between the cages. In the absence of extra cages, photoswitching was either suppressed or it involved expulsion of azobenzene from the cage and consequently its precipitation from the solution. This finding was utilized to develop an information storage medium in which messages could be written and erased in a reversible fashion using light. PMID- 29717056 TI - Chromatin Immunoprecipitation (ChIP) Analysis of Protein-DNA Interactions. AB - Here we describe chromatin immunoprecipitation (ChIP), a molecular approach that uses formaldehyde cross-linking to investigate genome structure and function. This approach allows us to determine the distribution of histone modifications (e.g., acetylation, methylation), the deposition of histone variants (H2AZ, H3.3, etc.), and the location of sequence-specific and general transcription factors. We introduce well-established ChIP-based methods that allow analysis of protein DNA interactions in living cells. PMID- 29717055 TI - Making Weak Antigens Strong: Modifying Protein Antigens by Denaturation. AB - Many molecules can be made more immunogenic by denaturation. This treatment will change the structure of many compounds, particularly proteins, and expose new epitopes. In addition, heating will often cause protein antigens to aggregate, and, because aggregated antigens are often more immunogenic, this can increase the antibody response. Either heating alone or heating with sodium dodecyl sulfate (SDS) is the usual treatment. Injecting denatured antigens will be more likely to produce an antibody response against epitopes that are not found on the native antigen. If antibodies against totally denatured proteins are desired, the SDS-heat treatment is normally best. These treatments will generate antibodies that should be particularly good for immunoblots, for screening bacterial expression libraries, and for immunoprecipitation of proteins synthesized during in vitro translations. PMID- 29717040 TI - Comparative genomics of the nonlegume Parasponia reveals insights into evolution of nitrogen-fixing rhizobium symbioses. AB - Nodules harboring nitrogen-fixing rhizobia are a well-known trait of legumes, but nodules also occur in other plant lineages, with rhizobia or the actinomycete Frankia as microsymbiont. It is generally assumed that nodulation evolved independently multiple times. However, molecular-genetic support for this hypothesis is lacking, as the genetic changes underlying nodule evolution remain elusive. We conducted genetic and comparative genomics studies by using Parasponia species (Cannabaceae), the only nonlegumes that can establish nitrogen fixing nodules with rhizobium. Intergeneric crosses between Parasponia andersonii and its nonnodulating relative Trema tomentosa demonstrated that nodule organogenesis, but not intracellular infection, is a dominant genetic trait. Comparative transcriptomics of P. andersonii and the legume Medicago truncatula revealed utilization of at least 290 orthologous symbiosis genes in nodules. Among these are key genes that, in legumes, are essential for nodulation, including NODULE INCEPTION (NIN) and RHIZOBIUM-DIRECTED POLAR GROWTH (RPG). Comparative analysis of genomes from three Parasponia species and related nonnodulating plant species show evidence of parallel loss in nonnodulating species of putative orthologs of NIN, RPG, and NOD FACTOR PERCEPTION Parallel loss of these symbiosis genes indicates that these nonnodulating lineages lost the potential to nodulate. Taken together, our results challenge the view that nodulation evolved in parallel and raises the possibility that nodulation originated ~100 Mya in a common ancestor of all nodulating plant species, but was subsequently lost in many descendant lineages. This will have profound implications for translational approaches aimed at engineering nitrogen-fixing nodules in crop plants. PMID- 29717057 TI - To be or not to be... secreted as exosomes, a balance finely tuned by the mechanisms of biogenesis. AB - The release of extracellular vesicles such as exosomes provides an attractive intercellular communication pathway. Exosomes are 30- to 150-nm membrane vesicles that are generated in endosomal compartment and act as intercellular mediators in both physiological and pathological context. Despite the growing interest in exosome functions, the mechanisms responsible for their biogenesis and secretion are still not completely understood. Knowledge about these mechanisms is important because they control the composition, and hence the function and secretion, of exosomes. Exosomes are produced as intraluminal vesicles in extremely dynamic endosomal organelles, which undergo various maturation processes in order to form multivesicular endosomes. Notably, the function of multivesicular endosomes is balanced between exosome secretion and lysosomal degradation. In the present review, we present and discuss each intracellular trafficking pathway that has been reported or proposed as regulating exosome biogenesis, with a particular focus on the importance of endosomal dynamics in sorting out cargo proteins to exosomes and to the secretion of multivesicular endosomes. An overall picture reveals several key mechanisms, which mainly act at the crossroads of endosomal pathways as regulatory checkpoints of exosome biogenesis. PMID- 29717058 TI - Exosomes and cardiovascular cell-cell communication. AB - Exosomes have become an important player in intercellular signaling. These lipid microvesicles can stably transfer miRNA, protein, and other molecules between cells and circulate throughout the body. Exosomes are released by almost all cell types and are present in most if not all biological fluids. The biologically active cargo carried by exosomes can alter the phenotype of recipient cells. Exosomes increasingly are recognized as having an important role in the progression and treatment of cardiac disease states. Injured cardiac cells can release exosomes with important pathological effects on surrounding tissue, in addition to effecting other organs. But of equal interest is the possible benefit(s) conferred by exosomes released from stem cells for use in treatment and possible repair of cardiac damage. PMID- 29717059 TI - Fed-EXosome: extracellular vesicles and cell-cell communication in metabolic regulation. AB - Extracellular vesicles (EVs) have emerged as a novel messaging system of the organism, mediating cell-cell and interorgan communication. Through their content of proteins and nucleic acids, as well as membrane proteins and lipid species, EVs can interact with and modulate the function of their target cells. The regulation of whole-body metabolism requires cross-talk between key metabolic tissues including adipose tissue (AT), the liver and skeletal muscle. Furthermore, the regulation of nutrient/energy allocation during pregnancy requires co-ordinated communication between the foetus and metabolic organs of the mother. A growing body of evidence is suggesting that EVs play a role in communication between and within key metabolic organs, both physiologically during metabolic homoeostasis but also contributing to pathophysiology during metabolic dysregulation observed in metabolic diseases such as obesity and diabetes. As obesity and its associated metabolic complications are reaching epidemic proportions, characterization of EV-mediated communication between key metabolic tissues may offer important insights into the regulation of metabolic functions during disease and offer global therapeutic opportunities. Here, we focus on the role of EVs in metabolic regulation and, in particular, EV-mediated cross-talk between cells of the AT. PMID- 29717060 TI - Cell-cell communication via ciliary extracellular vesicles: clues from model systems. AB - In this short review, we will focus on the uniqueness of ciliary extracellular vesicles (EVs). In particular, we will review what has been learned regarding EVs produced by cilia of model organisms. Model systems including Chlamydomonas, Caenorhabditis elegans, and mouse revealed the fundamental biology of cilia and flagella and provide a paradigm to understand the roles of cilia and flagella in human development, health, and disease. Likewise, we propose that general principles learned from model systems regarding ciliary EV biogenesis and functions may provide a framework to explore the roles of ciliary EVs in human development, health, and disease. PMID- 29717061 TI - The interaction between IKKalpha and LC3 promotes type I interferon production through the TLR9-containing LAPosome. AB - Toll-like receptor 9 (TLR9) recognizes DNA in endosomes and activates distinct signaling pathways to stimulate the production of proinflammatory cytokines and type I interferons (IFNs). The assembly of signaling platforms on microtubule associated proteins 1A/1B-light chain 3 (LC3)-decorated endosomal vesicles is required to transduce TLR9 signals that stimulate the production of IFN but not interleukin-12 p40 (IL-12p40). LC3-associated phagocytosis (LAP), a form of noncanonical autophagy, is critical for the activation of interferon regulatory factor 7 (IRF7) and for IFN synthesis. We showed that after the stimulation of TLR9 by CpG oligonucleotides, the autophagy protein LC3 and the kinase IKKalpha were recruited to endosomes that contained TLR9. The recruitment of IKKalpha and LC3 to such signaling endosomes was not stimulated by catalysts of classical autophagosome formation but involved LAP formation, which required ATG5 but not FIP200. In addition, we found that the LC3-IKKalpha complex further associated with both TRAF3 and IRF7. We identified three putative LC3-interacting regions (LIRs) in IKKalpha, and mutagenesis suggested that two of these were critical for direct binding to LC3. Moreover, mutation of the same LIR sequences failed to rescue type I IFN production in IKKalpha-deficient dendritic cells upon reconstitution. Together, these data suggest a direct link between LAP formation and IKKalpha recruitment downstream of TLR9 activation that is necessary to facilitate type I IFN production. PMID- 29717062 TI - VEGF-neuropilin-2 signaling promotes stem-like traits in breast cancer cells by TAZ-mediated repression of the Rac GAP beta2-chimaerin. AB - The role of vascular endothelial growth factor (VEGF) signaling in cancer is not only well known in the context of angiogenesis but also important in the functional regulation of tumor cells. Autocrine VEGF signaling mediated by its co receptors called neuropilins (NRPs) appears to be essential for sustaining the proliferation and survival of cancer stem cells (CSCs), which are implicated in mediating tumor growth, progression, and drug resistance. Therefore, understanding the mechanisms involved in VEGF-mediated support of CSCs is critical to successfully treating cancer patients. The expression of the Hippo effector TAZ is associated with breast CSCs and confers stem cell-like properties. We found that VEGF-NRP2 signaling contributed to the activation of TAZ in various breast cancer cells, which mediated a positive feedback loop that promoted mammosphere formation. VEGF-NRP2 signaling activated the GTPase Rac1, which inhibited the Hippo kinase LATS, thus leading to TAZ activity. In a complex with the transcription factor TEAD, TAZ then bound and repressed the promoter of the gene encoding the Rac GTPase-activating protein (Rac GAP) beta2-chimaerin. By activating GTP hydrolysis, Rac GAPs effectively turn off Rac signaling; hence, the TAZ-mediated repression of beta2-chimaerin resulted in sustained Rac1 activity in CSCs. Depletion of beta2-chimaerin in non-CSCs increased Rac1 activity, TAZ abundance, and mammosphere formation. Analysis of a breast cancer patient database revealed an inverse correlation between beta2-chimaerin and TAZ expression in tumors. Our findings highlight an unexpected role for beta2 chimaerin in a feed-forward loop of TAZ activation and the acquisition of CSC properties. PMID- 29717063 TI - Nuclear PTEN enhances the maturation of a microRNA regulon to limit MyD88 dependent susceptibility to sepsis. AB - Sepsis-induced organ damage is caused by systemic inflammatory response syndrome (SIRS), which results in substantial comorbidities. Therefore, it is of medical importance to identify molecular brakes that can be exploited to dampen inflammation and prevent the development of SIRS. We investigated the role of phosphatase and tensin homolog (PTEN) in suppressing SIRS, increasing microbial clearance, and preventing lung damage. Septic patients and mice with sepsis exhibited increased PTEN expression in leukocytes. Myeloid-specific Pten deletion in an animal model of sepsis increased bacterial loads and cytokine production, which depended on enhanced myeloid differentiation primary response gene 88 (MyD88) abundance and resulted in mortality. PTEN-mediated induction of the microRNAs (miRNAs) miR125b and miR203b reduced the abundance of MyD88. Loss- and gain-of-function assays demonstrated that PTEN induced miRNA production by associating with and facilitating the nuclear localization of Drosha-Dgcr8, part of the miRNA-processing complex. Reconstitution of PTEN-deficient mouse embryonic fibroblasts with a mutant form of PTEN that does not localize to the nucleus resulted in retention of Drosha-Dgcr8 in the cytoplasm and impaired production of mature miRNAs. Thus, we identified a regulatory pathway involving nuclear PTEN mediated miRNA generation that limits the production of MyD88 and thereby limits sepsis-associated mortality. PMID- 29717065 TI - Imagination and Intersection. PMID- 29717066 TI - Interprofessional Collaborative Practice: How Could Dentistry Participate? AB - There is a remarkable phenomenon occurring among health professionals: the development of ongoing, routine collaboration, both in educating the next generation of providers and in delivering care. These new approaches, commonly referred to as interprofessional education and interprofessional collaborative practice, have been introduced into academic health settings and delivery systems throughout the U.S. and the rest of the world; however, the full integration of dentistry in health care teams remains unrealized. In academic settings, dentistry has found ways to collaborate with the other health professions, but most practicing dentists still find themselves on the margins of new models of care delivery. This article provides a perspective on the history and context of the evolution of collaborative approaches to health care and proposes ways in which dentistry can participate more fully in the future. PMID- 29717064 TI - Glycerol monolaurate induces filopodia formation by disrupting the association between LAT and SLP-76 microclusters. AB - Glycerol monolaurate (GML) is a monoglyceride with potent antimicrobial properties that suppresses T cell receptor (TCR)-induced signaling and T cell effector function. Actin rearrangement is needed for the interaction of T cells with antigen-presenting cells and for migration to sites of infection. Because of the critical role actin rearrangement plays in T cell effector function, we analyzed the effect of GML on the rearrangement of the actin cytoskeleton after TCR activation. We found that GML-treated human T cells were less adherent than untreated T cells and did not form actin ring structures but instead developed numerous inappropriate actin-mediated filopodia. The formation of these filopodia was not due to disruption of TCR-proximal regulators of actin or microtubule polymerization. Instead, total internal reflection fluorescence microscopy demonstrated mislocalization of actin nucleation protein Arp2 microclusters, but not those containing the adaptor proteins SLP-76 and WASp, or the actin nucleation protein ARPC3, which are necessary for TCR-induced actin rearrangement. Additionally, SLP-76 microclusters colocalized with WASp and WAVE microclusters but not with LAT. Together, our data suggest that GML alters actin cytoskeletal rearrangements and identify diverse functions for GML as a T cell suppressive agent. PMID- 29717067 TI - Developing Interprofessional Education at One U.S. Dental School: Establishing a Baseline and Moving Forward. AB - Dental schools across the U.S. are in the process of incorporating interprofessional education (IPE) into their curricula. At Louisiana State University Health Sciences Center-New Orleans (LSUHSC), the process of educating competent students fully prepared to maximize patient outcomes through interprofessional care is under way. The aim of this study was to establish baseline data on three years of LSU dental students' perceptions of IPE prior to and as a new two-year IPE curriculum was being introduced. A survey was conducted of dental students in all four years from 2015 to 2017 using the Student Perceptions of Interprofessional Clinical Education-Revised instrument, version 2 (SPICE-R2). In 2015, 120 students participated in the survey for a response rate of 46%, followed by 160 students in 2016 (62%) and 170 in 2017 (67%). The results showed that the first-year students in 2017 had a higher total SPICE-R2 mean score than the first-year students in 2015 and 2016; the difference was statistically significant. Even though the 2017 first-year students had only received an orientation to the curriculum at the time they completed the survey, this change in attitude suggests the new focus on IPE was already having an effect on students. There were no statistically significant differences between mean scores for the three cohorts of second-, third-, and fourth-year students, none of whom had experienced the new IPE curriculum. Data from this study will serve as a baseline from which to evaluate the impact of the new IPE curriculum that is now required of all first- and second-year dental students. Through continued IPE exposure in the curriculum and ongoing faculty development, further improvements in students' attitudes toward IPE can be anticipated. PMID- 29717068 TI - Nursing and Dental Students' Reflections on Interprofessional Practice After a Service-Learning Experience in Appalachia. AB - Nowhere is the discrepancy between good and poor oral health status more pronounced in the U.S. than in the Appalachian region, where there is a high incidence of dental problems related to non-flouridated water, limited access to care, and tooth loss. To address these disparities, in 2016 University at Buffalo dental and nurse practitioner faculty members led a group of dental and nursing students on a two-day service-learning experience in rural Tennessee. The aim of this study was to assess the dental and nursing students' reflections on this interprofessional service-learning experience in Appalachia. After the program, all 36 students who took part in it were invited to complete a survey with open ended questions about the experience and their attitudes about interprofessional practice. Of the students, 34 (94.4%) returned the surveys, and 23 completed all the questions. Thematic analysis was used to code and analyze the student comments, which were then organized into themes. Five themes emerged: facilitating care through teamwork, gaining mutual respect, gaining confidence, understanding dental role in overall health, and relieving suffering. The overarching pattern was the link among all the themes: that everyone has a part to play in ensuring that patients get the best care. The themes and overarching pattern corresponded to the Interprofessional Education Collaboration (IPEC) competencies and the overall goal of delivering patient-centered care to a population that is underserved. These findings suggest that exposure to patients who lack dental care and have severe oral health problems can impact developing nursing and dental professionals in ways that can increase their appreciation of interprofessional practice and their future willingness to provide care in underserved settings. PMID- 29717069 TI - Interprofessional Education Perceptions of Dental Assisting and Radiologic Technology Students Following a Live Patient Experience. AB - Health professions students are often unaware of other health care providers' roles or professional expertise due to most education taking place within their single profession. This pattern may be even more prevalent for baccalaureate and associate degree programs since most interprofessional education (IPE) occurs in predoctoral programs and, when IPE is incorporated into allied health professions education, it often utilizes simulation instead of live patient experiences. The aim of this study was to determine if radiologic technology and dental assisting students' perceptions changed regarding interprofessional practice and teamwork after an IPE activity with actual patients. The participants were students in the University of Southern Indiana (USI) radiologic technology and dental assisting programs. This mixed-methods pilot study conducted in 2017 collected quantitative and qualitative data from pre and post surveys, the researchers' observations of student interactions during live patient assessment and acquisition of panoramic images, and large-group discussion. Twenty-five of the 26 students who participated in the IPE program completed both pre and post surveys, for a 96% response rate. The results showed significant differences in the participants' perceptions from the pre to post surveys on a wide variety of survey items. Most notable were the positive changes in perceptions related to trust in judgment of others within their profession (p=0.001), relationships with other professions (p=0.002), and thinking highly of other professions (p=0.002). Overall, this study found that incorporating the IPE activity with a live patient into these radiologic technology and dental assisting programs improved the students' perceptions of other allied health professionals. Future research should include more participants to increase sample size and add quantitative data collection. PMID- 29717070 TI - Effect on Dental Hygiene Students of a Substance Use Simulation Conducted with Nursing Students. AB - Dental professionals have an opportunity to screen for substance use, provide targeted feedback based on patients' oral health, provide patient education, and refer for further assessment as needed. The aim of this study was to assess the impact on dental hygiene students of an interprofessional Screening, Brief Intervention, and Referral to Treatment (SBIRT) educational intervention with standardized patients as a tool for initiating discussions on alcohol and drug use with patients. Starting in 2015, dental hygiene students in two classes at the University of Pittsburgh participated with nursing students in one and a half hours of didactic instruction followed within a ten-week period by SBIRT simulation scenarios utilizing standardized patients, with subsequent debriefing of students by faculty. Students' attitudes were assessed before and after the didactic session and immediately after the SBIRT simulation, using the Alcohol and Alcohol Problems Perceptions Questionnaire and the Drug and Drug Problems Perceptions Questionnaire. All 67 dental hygiene students in the program at the time participated in the educational intervention and surveys. The results showed significant positive changes in role security, defined as the acceptance of SBIRT delivery as part of their role identity as dental hygienists, following the intervention. This study found that the IPE intervention with dental hygiene and nursing students improved the dental hygiene students' attitudes through using SBIRT. PMID- 29717071 TI - Implementation of Recommended Tobacco Cessation Systems in Dental Practices: A Qualitative Exploration in Northeastern North Carolina. AB - Every year, cigarettes and other tobacco products cause nearly one in five deaths in the U.S., but many smokers report not being advised to quit by their health care providers. Dentists have an important role to play in tobacco cessation, but more research is needed about the extent of and barriers to implementation in dental practices. The aims of this study were to assess the extent to which dental practices in northeastern North Carolina were implementing the recommended U.S. Public Health Service (PHS) Clinical Practice Guideline, to understand policies about smoking in dental practice settings, and to identify barriers to implementation of recommended systems. In the 252 telephone area code, which covers northeastern North Carolina, 75 general dentists were identified from the American Dental Association website and purposely selected for geographic, gender, race, and practice size diversity from the sampling frame. The 11 dentists who agreed to participate (seven male, four female) took part in 15 minute semi-structured interviews by phone in January-March 2017. The interview transcripts were thematically coded for adherence to the PHS guideline. The results showed that full implementation of the guideline and the 5As was limited, although asking, advising, and assessing about tobacco use was consistently present in these dental practices. Other recommendations, particularly designation of a staff member as coordinator, were not implemented. In terms of barriers, interviewees reported very limited past or present training for themselves or their staff members. This study found meaningful levels of adherence to the tobacco cessation guideline in this area with high smoking prevalence; but the results suggest room for improvement in training through both dental curricula and continuing education. PMID- 29717072 TI - Assessing Dental Students' Readiness to Treat Populations That Are Underserved: A Scoping Review. AB - In North America, all dental schools have adopted some form of community-based dental education (CBDE) or service-learning, but little is known about the areas being researched and reported in published studies. The aim of this study was to conduct a scoping review to determine what areas of research had been conducted to determine the effects of CBDE on dental students' readiness to treat populations that are underserved. A systematic search of articles published in English or French since 2000 was performed on July 29, 2015, and combined quantitative and qualitative synthesis of data was conducted. Of the 32 studies evaluated, 23 (72%) were quantitative, seven (22%) were qualitative, and two were multi-method. The majority (66%) used self-report methods, most frequently surveys. Participants in 50% of the studies were fourth-year dental students; the others assessed third- and fourth-year (13%), first- and second-year (6%), and first-year (13%) students. Dentists were the participants in three studies (9%), with dentists and students in one study (3%). Either the types of populations receiving care were unspecified or four or more groups were pooled together in 25 studies (78%), while two focused on children, one on rural populations, one on elderly populations, two on persons with special health care needs, and one on low-income populations. The study areas were wide-ranging, but generally fell into three categories: student performance (37.5%), teaching approaches and evaluation methods (37.5%), and perceptions of CBDE (25%). This review identified many research gaps for determining whether students are prepared to treat populations that are underserved. The disparate nature of CBDE research demonstrates a compelling argument for determining elements that define student readiness to care for patients who are underserved and for research that includes the voices of patients, curriculum development, and more comprehensive and rigorous evaluation methodologies. PMID- 29717074 TI - Comparing Practice Management Courses in Canadian Dental Schools. AB - Practice management has become an increasingly important aspect of dental education over the years in order to better prepare students for the reality of practice. The aim of this study was to quantify and describe practice management courses taught at the ten Canadian dental schools in order to identify common approaches, compare hours, determine types of instructors, and assess the relationship between courses' learning objectives and the Association of Canadian Faculties of Dentistry (ACFD) competencies and Bloom's cognitive levels. The academic deans at these ten schools were surveyed in 2016; all ten schools responded for a 100% response rate. The authors also gathered syllabi and descriptions of the courses and analyzed them for themes. The results showed a total of 22 practice management courses in the ten Canadian dental schools. The courses provided 27 to 109 hours of teaching and were mostly taught in the third and fourth years and by dentists on three main topics: ethics, human resource management, and running a private practice. The courses were correlated to the ACFD competencies related to ethics, professionalism, application of basic principles of business practices, and effective interpersonal communication. Most of the courses' learning objectives addressed comprehension and knowledge in Bloom's cognitive levels of learning. These results can help to guide discussions on how practice management courses can be developed, improved, and refined to meet the challenges of preparing students for dental practice. PMID- 29717073 TI - Assessing the Medical Emergency Preparedness of Dental Faculty, Residents, and Practicing Periodontists: An Exploratory Study. AB - With the increased number of elderly and medically compromised individuals receiving dental care and the presence of systemic comorbidities and associated treatment modalities in this patient population, it is imperative that dentists be prepared to manage a variety of medical emergencies. The aim of this study was to assess the knowledge of and preparedness to manage common medical emergencies of cohorts of practicing periodontists, specialty residents, and faculty members, both for comparative purposes and as an aid to refining a dental school's standardized case scenarios. The study, conducted in 2017, was designed for four groups of randomly selected participants with at least 20 in each group; the actual number of voluntary participants was 28 private practice periodontists, 22 residents in specialty programs, 21 specialist faculty members, and 24 general practice faculty members. Participants were asked to evaluate ten clinical emergency cases and identify the diagnosis and indicated intervention for each. Groups were also evaluated for differences among correct responses for each case. Overall, there were no statistically significant differences for number of correct diagnoses or interventions among the four groups. However, several cases had varying degrees of incorrect diagnoses and management across all groups. Participants who had recently graduated or were still in school were able to treat cases appropriately more often than the other participants. Further refinement of cases to assess provider preparedness to correctly diagnose and manage medical emergencies is needed, specifically establishing case-specific features and addressing areas of potential confusion before the cases are used for educational purposes. PMID- 29717075 TI - Timing of Case-Based Discussions and Educational Outcomes for Dental Students. AB - The aim of this study was to determine if the timing of a case-based discussion affected dental students' assessment scores. The study specifically investigated whether the timing of a 60-minute case-based discussion before or after a 90 minute lecture affected students' performance on a quiz on topics in pediatric dentistry. In addition, students' preferences for the timing of the case discussion and confidence in the material with different timings were assessed in a survey. In a crossover design, all 52 second-year students in fall 2016 at one U.S. dental school participated in a case-based discussion either before or after lectures on stainless steel crowns and pulp therapy, compared to a control unit on space maintenance with no case-based discussion. The students took quizzes and responded to questionnaires a week after the lectures. A total of 45 (87%) of the 52 students consented to have their scores used. The results showed that the students performed better on the quiz when participating in a case-based discussion after the lecture compared to the discussion before the lecture (after mean=6.1+/-0.8 vs. before mean=5.5+/-1.3). The students' control quiz mean following a lecture with no associated case discussion was 6.3+/-0.8. Students also expressed more confidence when the case was held after the lecture (12.7 vs. 11.6, p=0.02) and preferred the case after (p=0.01). This study found that higher quiz and confidence scores resulted when a case discussion was held after (vs. before) a lecture. When dental educators consider adding a case discussion to a lecture format as a method of increasing students' active learning, these results suggest that having the case discussion after the lecture may be more effective for learners new to the material. PMID- 29717076 TI - What Matters from Admissions? Identifying Success and Risk Among Canadian Dental Students. AB - The aims of this study were to determine whether different student profiles would emerge in terms of high and low GPA performance in each year of dental school and to investigate the utility of preadmissions variables in predicting performance and performance stability throughout each year of dental school. Data from 11 graduating cohorts (2004-14) at the Schulich School of Medicine & Dentistry, University of Western Ontario, Canada, were collected and analyzed using bivariate correlations, latent profile analysis, and hierarchical generalized linear models (HGLMs). The data analyzed were for 616 students in total (332 males and 284 females). Four models were developed to predict adequate and poor performance throughout each of four dental school years. An additional model was developed to predict student performance stability across time. Two separate student profiles reflecting high and low GPA performance across each year of dental school were identified, and scores on cognitive preadmissions variables differentially predicted the probability of grouping into high and low performance profiles. Students with higher pre-dental GPAs and DAT chemistry were most likely to remain stable in a high-performance group across each year of dental school. Overall, the findings suggest that selection committees should consider pre-dental GPA and DAT chemistry scores as important tools for predicting dental school performance and stability across time. This research is important in determining how to better predict success and failure in various areas of preclinical dentistry courses and to provide low-performing students with adequate academic assistance. PMID- 29717078 TI - Privileged incorporation of selenium as selenocysteine in Lactobacillus reuteri proteins demonstrated by selenium-specific imaging and proteomics. PMID- 29717080 TI - Correction: PRIMA-1Met/APR-246 Displays High Antitumor Activity in Multiple Myeloma by Induction of p73 and Noxa. PMID- 29717083 TI - Erratum. PMID- 29717082 TI - Aetna and 68Ga-DOTATATE: A Sequel to "The Injustice of Being Judged by the Errors of Others". PMID- 29717084 TI - Fifty Years Ago in JNM. PMID- 29717086 TI - SNMMI Leadership Update: A Strong SNMMI. PMID- 29717085 TI - RADAR Develops New Generation of Dosimetry Phantoms. PMID- 29717089 TI - NRC Advisory Committee on Medical Uses of Isotopes Spring Meeting. PMID- 29717090 TI - Reclassifying Diagnostic Radiopharmaceuticals. PMID- 29717091 TI - Wessels to Be Recognized with Loevinger-Berman Award. PMID- 29717092 TI - Controlled Joint Inflammation but Still No Remission? It's Time to Attend to Depressive Symptoms. PMID- 29717093 TI - Assessing Barriers to Therapeutic Regimens for Young People with Juvenile Idiopathic Arthritis. PMID- 29717094 TI - Coexisting Gout and Chondrocalcinosis on Hand Radiograph. PMID- 29717095 TI - Causative Pathogens, Antibiotic Susceptibility, and Characteristics of Patients with Bacterial Septic Arthritis over Time. PMID- 29717096 TI - LACC1 Gene Defects in Familial Form of Juvenile Arthritis. PMID- 29717097 TI - 30-Day Morbidity and Mortality Rates in Elderly Subjects Following Surgical Tracheostomy. AB - BACKGROUND: Tracheostomy is considered to be effective in the respiratory support of mechanically ventilated patients. We studied a single-center experience of surgical tracheostomy in mechanically ventilated patients to describe the demographics, risk factors, and outcomes of early (<= 14 d after ventilation) versus late surgical tracheostomy (>= 15 d after ventilation). METHODS: In this retrospective study, we collected demographic data, medical history, timing of surgical tracheostomy in relation to ventilation day, blood test results, preoperative surgical assessment (subjective impression of neck length, difficulty in neck extension, presence of a goiter), intraoperative complications (bleeding > 100 mL, difficulties in cannula insertion), and postoperative morbidities (bleeding, wound infection, fever, inadvertent de-cannulation, and 30 d postoperative mortality rate) of subjects who underwent surgical tracheostomy in a secondary medical center during 2010-2015. Morbidity and mortality rates were compared between the early versus late surgical tracheostomy groups. RESULTS: Three hundred eleven subjects underwent surgical tracheostomy and met the eligibility criteria. Most of subjects were elderly, with a mean age of 82 y (range 62.5-88 y). There were 22 (7%) subjects in the early surgical tracheostomy group and 289 (93%) subjects in the late surgical tracheostomy group. Late surgical tracheostomy subjects were significantly older compared to early surgical tracheostomy subjects (median age 82 y vs 74 y, P = .001). With regard to intraoperative complications, no appreciable differences were observed between the groups. Timing of surgical tracheostomy was not associated with greater morbidity rates, nor was timing associated with higher postoperative complication rates. Those who survived 30 d were younger than those who died (median 81 vs 83 years, hazard ratio = 1.03). CONCLUSION: In elderly subjects, late surgical tracheostomy was not associated with increased 30-d morbidity or mortality rates. Comorbid conditions and subject age had a greater association with 30-d mortality rate than surgical tracheostomy timing. PMID- 29717098 TI - Effect of Transcutaneous Electrode Temperature on Accuracy and Precision of Carbon Dioxide and Oxygen Measurements in the Preterm Infants. AB - BACKGROUND: High electrode temperature during transcutaneous monitoring is associated with skin burns in extremely premature infants. We evaluated the accuracy and precision of CO2 and O2 measurements using lower transcutaneous electrode temperatures below 42 degrees C. METHODS: We enrolled 20 neonates. Two transcutaneous monitors were placed simultaneously on each neonate, with one electrode maintained at 42 degrees C and the other randomized to temperatures of 38, 39, 40, 41, and 42 degrees C. Arterial blood was collected twice at each temperature. RESULTS: At the time of arterial blood sampling, values for transcutaneously measured partial pressure of CO2 (PtcCO2 ) were not significantly different among test temperatures. There was no evidence of skin burning at any temperature. For PtcCO2 , Bland-Altman analyses of all test temperatures versus 42 degrees C showed good precision and low bias. Transcutaneously measured partial pressure of O2 (PtcO2 ) values trended arterial values but had large negative bias. CONCLUSION: Transcutaneous electrode temperatures as low as 38 degrees C allow an assessment of PtcCO2 as accurate as that with electrodes at 42 degrees C. PMID- 29717099 TI - Results of a Pulmonologist Survey Regarding Knowledge and Practices With Inhalation Devices for COPD. AB - BACKGROUND: COPD guidelines advise on inhaled medication use, yet no advice is offered on when to use and which type of patient could benefit from a specific delivery device. We investigated pulmonologists' perception of their knowledge and practices with delivery devices for COPD management. METHODS: An online survey was designed by a steering committee of American Thoracic Society clinicians and scientists and conducted by a national market research firm between January 7 and 29, 2016. RESULTS: Two hundred and five respondents completed the survey. Nearly 80% of the respondents believed that they were very knowledgeable in COPD management and the use of medications; 68% believed that they were knowledgeable about preventing exacerbations. Ninety-eight percent of the respondents stated that they were at least somewhat knowledgeable about devices. Many respondents (70%) stated that small-volume nebulizers were more effective than dry powder inhalers and pressurized metered-dose inhalers in the management of COPD exacerbations, and 63% believed that these were more effective in severe COPD (modified Medical Research Council dyspnea scale grade 4). Only 54% of the respondents discussed device options with their patients. Physician screening for physical or cognitive impairments that could impact device choices was 53% and 16%, respectively. Seventy percent of the respondents discussed device use, whereas 9% discussed cleaning and storage during a patient's first visit. Few respondents were very knowledgeable in teaching patients how to use devices (43%) and, specifically, how to use (32%) or clean and/or maintain (20%) small-volume nebulizers. CONCLUSIONS: Most respondents were confident in their knowledge about treating COPD. Fewer respondents were confident about the use and maintenance of inhalation devices, and most respondents desired to learn more about inhalation devices. PMID- 29717100 TI - Science and Culture: Animal cognition research offers outreach opportunity. PMID- 29717101 TI - Inner Workings: A new crop of landers and rovers seeks to answer key questions about Venus-and, by extension, Earth. PMID- 29717103 TI - Angina Pectoris in Young Male due to Agenesis of Left Circumflex Artery. AB - BACKGROUND This case study demonstrated that although highly symptomatic, agenesis of the left circumflex artery was a benign finding. Anomalies of the coronary arteries were found to be the cause of sudden death in a young individual. Left circumflex anomalies were not associated with major cardiac events. CASE REPORT A 20-year-old male was admitted due to syncope preceded by chest pain. His electrocardiogram (ECG) showed global ST segment elevation as well as biphasic T waves in anterior precordial leads. Troponin T values were normal. Echocardiography was normal. Computerized axial tomography (CAT) scan showed agenesis of the circumflex artery with a super-dominant right coronary artery. Myocardial scintigraphy showed no perfusion defects. Exercise test did not present any arrhythmias. Tilt table test displayed stable blood pressure and pulse response. A reveal recorder registered no malignant arrhythmias. A coronary angiography confirmed the finding of the CAT scan and showed no collateral vessel development. CONCLUSIONS This case demonstrated that agenesis left circumflex artery although presenting with severe symptoms, such as chest pain, is a benign finding. Chest pain was not correlated to perfusion defects in this case. Although the patient experienced loss of consciousness, there was no objective support for cardiac origin as no malignant arrhythmias were found. PMID- 29717104 TI - Overexpression of Kin of IRRE-Like Protein 1 (KIRREL) in Gastric Cancer and Its Clinical Prognostic Significance. AB - BACKGROUND The aim of this study was to examine the expression level of IRRE-like protein 1 (KIRREL) in gastric cancer (GC) and to explore its prognostic significance. MATERIAL AND METHODS Bioinformatics methods were used to predict the differential expression levels of KIRREL mRNA in GC and normal gastric tissues by mining cancer-related databases (TCGA and Oncomine). Immunohistochemistry was done to verify the KIRREL protein expression levels in 71 cases of GC tissues combined with matched normal tissues. The relationship between clinicopathologic parameters and KIRREL differential expression levels in GC was investigated by the chi-square test. Kaplan-Meier univariate and Cox multivariate survival analyses were performed to explore the prognostic significance of KIRREL expression in GC patients. RESULTS TCGA and GEO data analyses showed that KIRREL mRNA expression level was remarkably higher in GC than that in normal gastric tissues (both P<0.05). KIRREL mRNA levels were dramatically increased from stage I to stage IV (P=0.037). Immunohistochemical results showed that the high positive rate of KIRREL staining in GC was 61.97% (44/71). Moreover, GC patients with KIRREL mRNA or protein high levels had significantly shorter overall survival times than those with KIRREL mRNA or low protein levels (All P<0.05). Additionally, Cox multivariate survival analysis revealed that KIRREL differential expression levels (low vs. high) were the only independent parameter predicting the prognosis of GC patients (P=0.000). CONCLUSIONS KIRREL was overexpressed in GC and the overexpression of KIRREL could serve as an independent predictor of poor prognosis in GC patients. PMID- 29717105 TI - Long noncoding RNA DANCR promotes colorectal cancer proliferation and metastasis via miR-577 sponging. AB - Long non-coding RNAs (lncRNAs) play key roles in various malignant tumors, including colorectal cancer (CRC). Long non-coding RNA differentiation antagonizing non-protein coding RNA (DANCR) is overexpressed in CRC patients, but whether it affects CRC proliferation and metastasis via regulation of heat shock protein 27 (HSP27) remains unclear. In the present study, we found that DANCR was highly expressed and correlated with proliferation and metastasis in CRC. In addition, we demonstrated that DANCR and HSP27 were both targets of microRNA-577 (miR-577) and shared the same binding site. Furthermore, we revealed that DANCR promoted HSP27 expression and its mediation of proliferation/metastasis via miR 577 sponging. Finally, using an in vivo study, we confirmed that overexpression of DANCR promoted CRC tumor growth and liver metastasis. The present study demonstrated the function of DANCR in CRC and might provide a new target in the treatment of CRC. PMID- 29717106 TI - Role of clusterin/progranulin in toluene diisocyanate-induced occupational asthma. AB - Toluene diisocyanate (TDI) exposure induces oxidative stress and epithelial cell derived inflammation, which affect the pathogenesis of TDI-induced occupational asthma (TDI-OA). Recent studies suggested a role for clusterin (CLU) and progranulin (PGRN) in oxidative stress-mediated airway inflammation. To evaluate CLU and PGRN involvement in airway inflammation in TDI-OA, we measured their serum levels in patients with TDI-OA, asymptomatic exposed controls (AECs), and unexposed healthy normal controls (NCs). Serum CLU and PGRN levels were significantly lower in the TDI-OA group than in the AEC and NC groups (P < 0.05). The sensitivity and specificity for predicting the TDI-OA phenotype were 72.4% and 53.4% when either CLU or PGRN levels were below the cutoff values (<=125 MUg/mL and <=68.4 ng/mL, respectively). If both parameters were below the cutoff levels, the sensitivity and specificity were 58.6% and 89.8%, respectively. To investigate CLU and PGRN function, we evaluated their production by human airway epithelial cells (HAECs) in response to TDI exposure and co-culturing with neutrophils. TDI-human serum albumin stimulation induced significant CLU/PGRN release from HAECs in a dose-dependent manner, which positively correlated with IL-8 and folliculin levels. Co-culturing with neutrophils significantly decreased CLU/PGRN production by HAECs. Intracellular ROS production in epithelial cells co cultured with neutrophils tended to increase initially, but the ROS production decreased gradually at a higher ratio of neutrophils. Our results suggest that CLU and PGRN may be involved in TDI-OA pathogenesis by protecting against TDI induced oxidative stress-mediated inflammation. The combined CLU/PGRN serum level may be used as a potential serological marker for identifying patients with TDI OA among TDI-exposed workers. PMID- 29717107 TI - Exendin-4 ameliorates high glucose-induced fibrosis by inhibiting the secretion of miR-192 from injured renal tubular epithelial cells. AB - Extracellular vesicles (EVs), which contain microRNA (miRNA), constitute a novel means of cell communication that may contribute to the inevitable expansion of renal fibrosis during diabetic kidney disease (DKD). Exendin-4 is effective for treating DKD through its action on GLP1R. However, the effect of exendin-4 on EV miRNA expression and renal cell communication during the development of DKD remains unknown. In this study, we found that EVs derived from HK-2 cells pre treated with exendin-4 and high glucose (Ex-HG), which were taken up by normal HK 2 cells, resulted in decreased levels of FN and Col-I compared with EVs from HK-2 cells pre-treated with HG alone. Furthermore, we found that pretreatment with HG and exendin-4 may have contributed to a decrease in miR-192 in both HK-2 cells and EVs in a p53-dependent manner. Finally, we demonstrated that the amelioration of renal fibrosis by exendin-4 occurred through a miR-192-GLP1R pathway, indicating a new pathway by which exendin-4 regulates GLP1R. The results of this study suggest that exendin-4 inhibits the transfer of EV miR-192 from HG-induced renal tubular epithelial cells to normal cells, thus inhibiting GLP1R downregulation and protecting renal cells. This study reports a new mechanism by which exendin-4 exerts a protective effect against DKD. PMID- 29717108 TI - The AFF-1 exoplasmic fusogen is required for endocytic scission and seamless tube elongation. AB - Many membranes must merge during cellular trafficking, but fusion and fission events initiating at exoplasmic (non-cytosolic) membrane surfaces are not well understood. Here we show that the C. elegans cell-cell fusogen anchor-cell fusion failure 1 (AFF-1) is required for membrane trafficking events during development of a seamless unicellular tube. EGF-Ras-ERK signaling upregulates AFF-1 expression in the excretory duct tube to promote tube auto-fusion and subsequent lumen elongation. AFF-1 is required for scission of basal endocytic compartments and for apically directed exocytosis to extend the apical membrane. Lumen elongation also requires the transcytosis factor Rab11, but occurs independently of dynamin and clathrin. These results support a transcytosis model of seamless tube lumen growth and show that cell-cell fusogens also can play roles in intracellular membrane trafficking events. PMID- 29717109 TI - Substitution of D701N in the PB2 protein could enhance the viral replication and pathogenicity of Eurasian avian-like H1N1 swine influenza viruses. AB - Eurasian avian-like H1N1 (EA H1N1) swine influenza viruses (SIVs) have become predominant in pig populations in China and have recently been reported to have the most potential to raise the next pandemic in humans. The mutation D701N in the PB2 protein, which accounts for 31% of H1N1 SIVs, has previously been shown to contribute to the adaptation of the highly pathogenic H5N1 or H7N7 avian influenza viruses in mammals. However, little is known of the effects of this substitution on the EA H1N1 viruses. Herein, we investigated the contributions of 701N in the PB2 protein to an EA H1N1 SIV (A/Hunan/42443/2015(H1N1), HuN EA H1N1), which had 701D in the PB2 protein. Our results found that viral polymerase activity, viral replication, and pathogenicity in mice were indeed enhanced due to the introduction of 701N into the PB2 protein, and the increased viral growth was partly mediated by the host factor importin-alpha7. Thus, substantial attention should be paid to the D701N mutation in pig populations. PMID- 29717110 TI - IL-21 drives expansion and plasma cell differentiation of autoreactive CD11chiT bet+ B cells in SLE. AB - Although the aetiology of systemic lupus erythematosus (SLE) is unclear, dysregulated B cell responses have been implicated. Here we show that an unusual CD11chiT-bet+ B cell subset, with a unique expression profile including chemokine receptors consistent with migration to target tissues, is expanded in SLE patients, present in nephrotic kidney, enriched for autoreactive specificities and correlates with defined clinical manifestations. IL-21 can potently induce CD11chiT-bet+ B cells and promote the differentiation of these cells into Ig secreting autoreactive plasma cells. While murine studies have identified a role for T-bet-expressing B cells in autoimmunity, this study describes and exemplifies the importance of CD11chiT-bet+ B cells in human SLE. PMID- 29717111 TI - Low doses of LPS exacerbate the inflammatory response and trigger death on TLR3 primed human monocytes. AB - TLR sensing of pathogens triggers monocyte activation to initiate the host innate immune response to infection. Monocytes can dynamically adapt to different TLR agonists inducing different patterns of inflammatory response, and the sequence of exposure to TLRs can dramatically modulate cell activation. Understanding the interactions between TLR signalling that lead to synergy, priming and tolerance to TLR agonists may help explain how prior infections and inflammatory conditioning can regulate the innate immune response to subsequent infections. Our goal was to investigate the role of MyD88-independent/dependent TLR priming on modulating the monocyte response to LPS exposure. We stimulated human blood monocytes with agonists for TLR4 (LPS), TLR3 (poly(I:C)) and TLR7/8 (R848) and subsequently challenged them to low doses of endotoxin. The different TLR agonists promoted distinct inflammatory signatures in monocytes. Upon subsequent LPS challenge, LPS- and R848-primed monocytes did not enhance the previous response, whereas poly(I:C)-primed monocytes exhibited a significant inflammatory response concomitant with a sharp reduction on cell viability. Our results show that TLR3-primed monocytes are prompted to cell death by apoptosis in the presence of low endotoxin levels, concurrent with the production of high levels of TNFalpha and IL6. Of note, blocking of TNFR I/II in those monocytes did reduce TNFalpha production but did not abrogate cell death. Instead, direct signalling through TLR4 was responsible of such effect. Collectively, our study provides new insights on the effects of cross-priming and synergism between TLR3 and TLR4, identifying the selective induction of apoptosis as a strategy for TLR-mediated host innate response. PMID- 29717112 TI - Gastrin stimulates pancreatic cancer cell directional migration by activating the Galpha12/13-RhoA-ROCK signaling pathway. AB - The mechanism by which gastrin promotes pancreatic cancer cell metastasis is unclear. The process of directing polarized cancer cells toward the extracellular matrix is principally required for invasion and distant metastasis; however, whether gastrin can induce this process and its underlying mechanism remain to be elucidated. In this study, we found that gastrin-induced phosphorylation of paxillin at tyrosine 31/118 and RhoA activation as well as promoted the metastasis of PANC-1 cancer cells. Depletion of Galpha12 and Galpha13 inhibited the phosphorylation of paxillin and downstream activation of GTP-RhoA, blocked the formation and aggregation of focal adhesions and facilitated polarization of actin filaments induced by gastrin. Suppression of RhoA and ROCK also exhibited identical results. Selective inhibition of the CCKBR-Galpha12/13-RhoA-ROCK signaling pathway blocked the reoriented localization of the Golgi apparatus at the leading edge of migrated cancer cells. YM022 and Y-27632 significantly suppressed hepatic metastasis of orthotic pancreatic tumors induced by gastrin in vivo. Collectively, we demonstrate that gastrin promotes Golgi reorientation and directional polarization of pancreatic cancer cells by activation of paxillin via the CCKBR-Galpha12/13-RhoA-ROCK signal pathway. PMID- 29717113 TI - CCL4 enhances preosteoclast migration and its receptor CCR5 downregulation by RANKL promotes osteoclastogenesis. AB - Chemokine CCL4 (MIP-1beta) is released from osteoblast cells to restore the homeostasis of hematopoietic stem cells during the activation of bone marrow. In this study, we investigated the function of CCL4 and its receptor CCR5 during osteoclastogenesis. CCL4 promoted the migration and viability of preosteoclast cells. However, CCL4 had no direct effect on the receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclast differentiation in mouse preosteoclast cells. In addition, CCR5 expression was rapidly reduced by RANKL treatment, which was recovered by IFN-gamma during osteoclastogenesis. CCR5 downregulation by RANKL was mediated by MEK and JNK in preosteoclast cells and promoted osteoclastogenesis. These results suggest that CCL4 can enhance the recruitment of preosteoclasts to bone in the early stage, and the reduction of CCR5 promotes osteoclastogenesis when RANKL is prevalent. PMID- 29717114 TI - Frizzled-8 integrates Wnt-11 and transforming growth factor-beta signaling in prostate cancer. AB - Wnt-11 promotes cancer cell migration and invasion independently of beta-catenin but the receptors involved remain unknown. Here, we provide evidence that FZD8 is a major Wnt-11 receptor in prostate cancer that integrates Wnt-11 and TGF-beta signals to promote EMT. FZD8 mRNA is upregulated in multiple prostate cancer datasets and in metastatic cancer cell lines in vitro and in vivo. Analysis of patient samples reveals increased levels of FZD8 in cancer, correlating with Wnt 11. FZD8 co-localizes and co-immunoprecipitates with Wnt-11 and potentiates Wnt 11 activation of ATF2-dependent transcription. FZD8 silencing reduces prostate cancer cell migration, invasion, three-dimensional (3D) organotypic cell growth, expression of EMT-related genes, and TGF-beta/Smad-dependent signaling. Mechanistically, FZD8 forms a TGF-beta-regulated complex with TGF-beta receptors that is mediated by the extracellular domains of FZD8 and TGFBR1. Targeting FZD8 may therefore inhibit aberrant activation of both Wnt and TGF-beta signals in prostate cancer. PMID- 29717115 TI - Non-canonical activation of DAPK2 by AMPK constitutes a new pathway linking metabolic stress to autophagy. AB - Autophagy is an intracellular degradation process essential for adaptation to metabolic stress. DAPK2 is a calmodulin-regulated protein kinase, which has been implicated in autophagy regulation, though the mechanism is unclear. Here, we show that the central metabolic sensor, AMPK, phosphorylates DAPK2 at a critical site in the protein structure, between the catalytic and the calmodulin-binding domains. This phosphorylation activates DAPK2 by functionally mimicking calmodulin binding and mitigating an inhibitory autophosphorylation, providing a novel, alternative mechanism for DAPK2 activation during metabolic stress. In addition, we show that DAPK2 phosphorylates the core autophagic machinery protein, Beclin-1, leading to dissociation of its inhibitor, Bcl-XL. Importantly, phosphorylation of DAPK2 by AMPK enhances DAPK2's ability to phosphorylate Beclin 1, and depletion of DAPK2 reduces autophagy in response to AMPK activation. Our study reveals a unique calmodulin-independent mechanism for DAPK2 activation, critical to its function as a novel downstream effector of AMPK in autophagy. PMID- 29717116 TI - Contrast-enhanced ultrasound measurement of pancreatic blood flow dynamics predicts type 1 diabetes progression in preclinical models. AB - In type 1 diabetes (T1D), immune-cell infiltration into the islets of Langerhans (insulitis) and beta-cell decline occurs many years before diabetes clinically presents. Non-invasively detecting insulitis and beta-cell decline would allow the diagnosis of eventual diabetes, and provide a means to monitor therapeutic intervention. However, there is a lack of validated clinical approaches for specifically and non-invasively imaging disease progression leading to T1D. Islets have a denser microvasculature that reorganizes during diabetes. Here we apply contrast-enhanced ultrasound measurements of pancreatic blood-flow dynamics to non-invasively and predictively assess disease progression in T1D pre-clinical models. STZ-treated mice, NOD mice, and adoptive-transfer mice demonstrate altered islet blood-flow dynamics prior to diabetes onset, consistent with islet microvasculature reorganization. These assessments predict both time to diabetes onset and future responders to antiCD4-mediated disease prevention. Thus contrast enhanced ultrasound measurements of pancreas blood-flow dynamics may provide a clinically deployable predictive marker for disease progression in pre symptomatic T1D and therapeutic reversal. PMID- 29717117 TI - N-glycosylation of mouse TRAIL-R restrains TRAIL-induced apoptosis. AB - The sensitivity of cells to death receptor-induced apoptosis is commonly controlled by multiple checkpoints in order to limit induction of excessive or unnecessary death. Although cytotoxic in various cancer cells, tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) does not trigger apoptosis in most non-transformed cells. The molecular nature of the checkpoints that normally protect the cells from TRAIL-induced death are not fully understood. Endoplasmic reticulum (ER) stress has been reported to switch the sensitivity of human cells to the cytotoxic effect of TRAIL, suggesting that this cellular state perturbs some of these protective mechanisms. We found that tunicamycin (TU), but no other ER stress inducers, sensitized mouse fibroblasts and hippocampal neuronal cells to TRAIL-induced apoptosis. Importantly, the sensitization was specific to TRAIL and not caused by differences in ER stress induction. Instead, it relied on the inhibition of N-glycosylation of the mouse TRAIL receptor (mTRAIL-R). Inhibition of N-glycosylation did not alter cell surface expression of mTRAIL-R but enhanced its ability to bind TRAIL, and facilitated mTRAIL-R oligomerization, which resulted in enhanced death-inducing signaling complex (DISC) formation and caspase-8 activation. Remarkably, reconstitution of mTRAIL-R deficient cells with a version of mTRAIL-R mutated for the three N-glycosylation sites identified in its ectodomain confirmed higher sensitivity to TRAIL-induced apoptosis. Together, our results demonstrate that inhibition of N-glycosylation of mTRAIL-R, and not ER stress induction, sensitizes mouse cells to TRAIL-induced apoptosis. We therefore reveal a new mechanism restraining TRAIL cytotoxicity in mouse cells. PMID- 29717118 TI - Distinct mutational signatures characterize concurrent loss of polymerase proofreading and mismatch repair. AB - Fidelity of DNA replication is maintained using polymerase proofreading and the mismatch repair pathway. Tumors with loss of function of either mechanism have elevated mutation rates with characteristic mutational signatures. Here we report that tumors with concurrent loss of both polymerase proofreading and mismatch repair function have mutational patterns that are not a simple sum of the signatures of the individual alterations, but correspond to distinct, previously unexplained signatures: COSMIC database signatures 14 and 20. We then demonstrate that in all five cases in which the chronological order of events could be determined, polymerase epsilon proofreading alterations precede the defect in mismatch repair. Overall, we illustrate that multiple distinct mutational signatures can result from different combinations of a smaller number of mutational processes (of either damage or repair), which can influence the interpretation and discovery of mutational signatures. PMID- 29717120 TI - Flexible and ultra-lightweight polymer membrane lasers. AB - Organic semiconductors enable the fabrication of a range of lightweight and mechanically flexible optoelectronic devices. Most organic semiconductor lasers, however, have remained rigid until now, predominantly due to the need for a support substrate. Here, we use a simple fabrication process to make membrane based, substrate-less and extremely thin (<500 nm) organic distributed feedback lasers that offer ultralow-weight (m/A<0.5 gm-2) and excellent mechanical flexibility. We show operation of the lasers as free-standing membranes and transfer them onto other substrates, e.g. a banknote, where the unique lasing spectrum is readily read out and used as security feature. The pump thresholds and emission intensity of our membrane lasers are well within the permissible exposures for ocular safety and we demonstrate integration on contact lenses as wearable security tags. PMID- 29717119 TI - Dkk3 dependent transcriptional regulation controls age related skeletal muscle atrophy. AB - Age-related muscle atrophy (sarcopenia) is the leading cause for disability in aged population, but the underlying molecular mechanisms are poorly understood. Here we identify a novel role for the secreted glycoprotein Dickkopf 3 (Dkk3) in sarcopenia. Forced expression of Dkk3 in muscles in young mice leads to muscle atrophy. Conversely, reducing its expression in old muscles restores both muscle size and function. Dkk3 induces nuclear import of beta-catenin and enhances its interaction with FoxO3, which in turn activates the transcription of E3 ubiquitin ligase Fbxo32 and Trim63, driving muscle atrophy. These findings suggest that Dkk3 may be used as diagnostic marker and as therapeutic target for age-related muscle atrophy, and reveal a distinct transcriptional control of Fbxo32 and Trim63. PMID- 29717121 TI - Validating the concept of mutational signatures with isogenic cell models. AB - The diversity of somatic mutations in human cancers can be decomposed into individual mutational signatures, patterns of mutagenesis that arise because of DNA damage and DNA repair processes that have occurred in cells as they evolved towards malignancy. Correlations between mutational signatures and environmental exposures, enzymatic activities and genetic defects have been described, but human cancers are not ideal experimental systems-the exposures to different mutational processes in a patient's lifetime are uncontrolled and any relationships observed can only be described as an association. Here, we demonstrate the proof-of-principle that it is possible to recreate cancer mutational signatures in vitro using CRISPR-Cas9-based gene-editing experiments in an isogenic human-cell system. We provide experimental and algorithmic methods to discover mutational signatures generated under highly experimentally controlled conditions. Our in vitro findings strikingly recapitulate in vivo observations of cancer data, fundamentally validating the concept of (particularly) endogenously-arising mutational signatures. PMID- 29717122 TI - Therapeutic potential of a phospholipase D1 inhibitory peptide fused with a cell penetrating peptide as a novel anti-asthmatic drug in a Der f 2-induced airway inflammation model. AB - Asthma is a chronic lung disease that causes airflow obstruction due to airway inflammation. However, its therapeutics remain inadequate. We previously reported that phospholipase D1 (PLD1) is a key enzyme involved in the production of pro inflammatory cytokines in airway inflammation induced by the house dust mite allergen Dermatophagoides farinae 2 (Der f 2). We also revealed that PLD1 is specifically inactivated by AP180 (assembly protein, 180 kDa) and identified the PLD1-specific binding motif (TVTSP) of AP180. Therefore, the aims of this study were to develop a novel anti-asthmatic agent that could suppress airway inflammation by inhibiting PLD1 and examine its acute and chronic toxicity. We designed TAT-TVTSP, a PLD1-inhibitory peptide fused with a cell-penetrating peptide (CPP) delivery system. TAT-TVTSP was efficiently delivered to bronchial epithelial cells and significantly reduced Der f 2-induced PLD activation and Interleukin 13 (IL-13) production. Intranasally administered TAT-TVTSP was also efficiently transferred to airway tissues and ameliorated airway inflammation in a Der f 2-induced allergic asthma mouse model. Moreover, we investigated the safety of TAT-TVTSP as a therapeutic agent through single- and repeated-dose toxicity studies in a mouse model. Taken together, these results indicated that a PLD1-inhibitory peptide fused with a cell-penetrating peptide may be useful for treating allergic inflammatory asthma induced by house dust mites (HDMs). PMID- 29717123 TI - Sulfenate anions as organocatalysts for benzylic chloromethyl coupling polymerization via C=C bond formation. AB - Organocatalytic polymerization reactions have a number of advantages over their metal-catalyzed counterparts, including environmental friendliness, ease of catalyst synthesis and storage, and alternative reaction pathways. Here we introduce an organocatalytic polymerization method called benzylic chloromethyl coupling polymerization (BCCP). BCCP is catalyzed by organocatalysts not previously employed in polymerization processes (sulfenate anions), which are generated from bench-stable sulfoxide precatalysts. The sulfenate anion promotes an umpolung polycondensation via step-growth propagation cycles involving sulfoxide intermediates. BCCP represents an example of an organocatalyst that links monomers by C=C double bond formation and offers transition metal-free access to a wide variety of polymers that cannot be synthesized by traditional precursor routes. PMID- 29717125 TI - Catalytic condensation for the formation of polycyclic heteroaromatic compounds. AB - The conservation of our global element resources is a challenge of the utmost urgency. Since aliphatic and aromatic alcohols are accessible from abundant indigestible kinds of biomass, first and foremost lignocellulose, the development of novel chemical reactions converting alcohols into important classes of compounds is a particularly attractive carbon conservation and CO2-emission reduction strategy. Herein, we report the catalytic condensation of phenols and aminophenols or aminoalcohols. The overall reaction of this synthesis concept proceeds via three steps: hydrogenation, dehydrogenative condensation and dehydrogenation. Reusable catalysts recently developed in our laboratory mediate these reactions highly efficient. The scope of the concept is exemplarily demonstrated by the synthesis of carbazoles, quinolines and acridines, the structural motifs of which figure prominently in many important natural products, drugs and materials. PMID- 29717124 TI - Magnetic nanochain integrated microfluidic biochips. AB - Microfluidic biochips hold great potential for liquid analysis in biomedical research and clinical diagnosis. However, the lack of integrated on-chip liquid mixing, bioseparation and signal transduction presents a major challenge in achieving rapid, ultrasensitive bioanalysis in simple microfluidic configurations. Here we report magnetic nanochain integrated microfluidic chip built upon the synergistic functions of the nanochains as nanoscale stir bars for rapid liquid mixing and as capturing agents for specific bioseparation. The use of magnetic nanochains enables a simple planar design of the microchip consisting of flat channels free of common built-in components, such as liquid mixers and surface-anchored sensing elements. The microfluidic assay, using surface-enhanced Raman scattering nanoprobes for signal transduction, allows for streamlined parallel analysis of multiple specimens with greatly improved assay kinetics and delivers ultrasensitive identification and quantification of a panel of cancer protein biomarkers and bacterial species in 1 MUl of body fluids within 8 min. PMID- 29717126 TI - Architecture of the U6 snRNP reveals specific recognition of 3'-end processed U6 snRNA. AB - The spliceosome removes introns from precursor messenger RNA (pre-mRNA) to produce mature mRNA. Prior to catalysis, spliceosomes are assembled de novo onto pre-mRNA substrates. During this assembly process, U6 small nuclear RNA (snRNA) undergoes extensive structural remodeling. The early stages of this remodeling process are chaperoned by U6 snRNP proteins Prp24 and the Lsm2-8 heteroheptameric ring. We now report a structure of the U6 snRNP from Saccharomyces cerevisiae. The structure reveals protein-protein contacts that position Lsm2-8 in close proximity to the chaperone "active site" of Prp24. The structure also shows how the Lsm2-8 ring specifically recognizes U6 snRNA that has been post transcriptionally modified at its 3' end, thereby elucidating the mechanism by which U6 snRNPs selectively recruit 3' end-processed U6 snRNA into spliceosomes. Additionally, the structure reveals unanticipated homology between the C-terminal regions of Lsm8 and the cytoplasmic Lsm1 protein involved in mRNA decay. PMID- 29717127 TI - Starting geometry creation and design method for freeform optics. AB - We describe a method for designing freeform optics based on the aberration theory of freeform surfaces that guides the development of a taxonomy of starting-point geometries with an emphasis on manufacturability. An unconventional approach to the optimization of these starting designs wherein the rotationally invariant 3rd order aberrations are left uncorrected prior to unobscuring the system is shown to be effective. The optimal starting-point geometry is created for an F/3, 200 mm aperture-class three-mirror imager and is fully optimized using a novel step by-step method over a 4 * 4 degree field-of-view to exemplify the design method. We then optimize an alternative starting-point geometry that is common in the literature but was quantified here as a sub-optimal candidate for optimization with freeform surfaces. A comparison of the optimized geometries shows the performance of the optimal geometry is at least 16* better, which underscores the importance of the geometry when designing freeform optics. PMID- 29717128 TI - Author Correction: Rice auxin influx carrier OsAUX1 facilitates root hair elongation in response to low external phosphate. AB - The original version of this Article omitted the following from the Acknowledgements:'We also thank DBT-CREST BT/HRD/03/01/2002.'This has been corrected in both the PDF and HTML versions of the Article. PMID- 29717129 TI - GATA4 regulates angiogenesis and persistence of inflammation in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by abnormal inflammation, angiogenesis, and cartilage destruction. In RA, neoangiogenesis is an early and crucial event to promote the formation of pannus, causing further inflammatory cell infiltration. The transcription factor GATA4 is a critical regulator of cardiac differentiation-specific gene expression. We find that a higher level of GATA4 exists in synovium of rheumatoid arthritis (RA) patients, but the function of GATA4 in RA remains unclear. In the present study, IL-1beta induces inflammation in fibroblast-like synoviocytes (FLS) MH7A, which is accompanied with the increased expression of GATA4 and VEGF production. Through application of GATA4 loss-of-function assays, we confirm the requirement of GATA4 expression for inflammation induced by IL-1beta in FLS. In addition, we demonstrate for the first time that GATA4 plays key roles in regulating VEGF secretion from RA FLS to promote cellular proliferation, induce cell migration, and angiogenic tube formation of endothelial cells. GATA4 induces the angiogenic factors VEGFA and VEGFC, by directly binding to the promoter and enhancing transcription. The knockdown of GATA4 attenuates the development of collagen induced arthritis (CIA) and prevents RA-augmented angiogenesis in vivo, which are accompanied with decreased VEGF level. These results reveal a previously unrecognized function for GATA4 as a regulator of RA angiogenesis and we provide experimental data validating the therapeutic target of GATA4 in RA mice. PMID- 29717130 TI - High frequency neural spiking and auditory signaling by ultrafast red-shifted optogenetics. AB - Optogenetics revolutionizes basic research in neuroscience and cell biology and bears potential for medical applications. We develop mutants leading to a unifying concept for the construction of various channelrhodopsins with fast closing kinetics. Due to different absorption maxima these channelrhodopsins allow fast neural photoactivation over the whole range of the visible spectrum. We focus our functional analysis on the fast-switching, red light-activated Chrimson variants, because red light has lower light scattering and marginal phototoxicity in tissues. We show paradigmatically for neurons of the cerebral cortex and the auditory nerve that the fast Chrimson mutants enable neural stimulation with firing frequencies of several hundred Hz. They drive spiking at high rates and temporal fidelity with low thresholds for stimulus intensity and duration. Optical cochlear implants restore auditory nerve activity in deaf mice. This demonstrates that the mutants facilitate neuroscience research and future medical applications such as hearing restoration. PMID- 29717131 TI - Avian hepatitis E virus infection of duck, goose, and rabbit in northwest China. PMID- 29717132 TI - Potential role of CBX7 in regulating pluripotency of adult human pluripotent-like olfactory stem cells in stroke model. AB - The adult olfactory mucosa, a highly regenerative tissue with unique life-long neurogenesis ability, is thought to harbor a naive yet tightly controlled stem cell population. It will provide unique benefits in various stem cell-based therapies, such as stroke treatment. Here, we identified a subpopulation of adult pluripotent-like olfactory stem cells (APOSCs), which were modulated by an epigenetic repressor of CBX7. APOSCs form a floating sphere, express pluripotency markers Nanog, Oct-4, Sox-2, and SSEA-4 and show alkaline phosphatase activity. In addition, APOSCs display self-renewal and a pluripotent potential to differentiate into all three germ layers. Moreover, APOSCs coexpress pluripotency markers with CBX7. Within their natural niche, APOSCs from CBX7+/+ mice responded promptly to either spontaneous or injury-induced tissue regeneration. However, APOSCs from CBX7-/- mice manifested an impaired self-renewal and differentiation potential. Similarly, in vitro-cultivated CBX7-/- APOSCs underwent premature senescence, whereas CBX7+/+ APOSCs still actively divided, indicating that CBX7 is required for the self-renewal of APOSCs. Intracerebral implantation of APOSCs improved the stroke-mediated neurological dysfunction in rodents. These findings indicate that CBX7 plays a critical role in the regenerative properties of APOSCs and indicate the safety and feasibility of implantation of autologous APOSCs in stroke treatment. PMID- 29717133 TI - Kinesin light chain-4 depletion induces apoptosis of radioresistant cancer cells by mitochondrial dysfunction via calcium ion influx. AB - Kinesins act as molecular microtubule-dependent motor proteins and have various important cellular functions related to cell division, intracellular transport, and membrane trafficking. However, the function of kinesin light chain 4 (KLC4) in cancer, especially radioresistance, has not been previously described. Thus, we investigated KLC4 function in lung cancer cells and radioresistant R-H460 cells by analyzing alterations in radiosensitivity after gene knockdown with siRNA and by evaluating cellular phenotypes and xenograft tumor growth. KLC4 was upregulated in human lung cancer cell lines. Moreover, in paired clinical specimens of lung cancer patients, KLC4 expression was significantly higher in tumor tissues than in paired adjacent normal tissues. Fluorescence-activated cell sorting (FACS) analysis showed that apoptosis rates and cleaved poly (ADP-ribose) polymerase (PARP) and cleaved caspase-3 levels in KLC4-knockdown lung cancer cells were significantly increased compared with those in control cells. Colony formation decreased as the radiation dose increased in KLC4-knockdown lung cancer cells, demonstrating an essential role for KLC4 in radioresistance. Importantly, KLC4 silencing suppressed tumor growth in an in vivo xenograft model, accompanied by increased apoptosis. Finally, KLC4-knockdown cells exhibited impaired mitochondrial respiration, increased mitochondrial reactive oxygen species production, and enhanced mitochondrial calcium uptake, resulting in mitochondrial dysfunction. Thus, KLC4 as a kinesin superfamily-targeted therapy may represent a novel, effective anticancer strategy, particularly for patients showing radioresistance. PMID- 29717134 TI - G3BP1 promotes tumor progression and metastasis through IL-6/G3BP1/STAT3 signaling axis in renal cell carcinomas. AB - The chronic inflammatory microenvironment within or surrounding the primary renal cell carcinoma (RCC) site promotes oncogenic transformation as well as contributes to the development of metastasis. G3BP stress granule assembly factor 1 (G3BP1) was found to be involved in the regulation of multiple cellular functions. However, its functions in RCC have not been previously explored. Here, we first showed that the expression of G3BP1 is elevated in human RCC and correlates with RCC progression. In cultured RCC cells, knockdown of G3BP1 results in inhibition of tumor cell proliferation, migration, and invasion, consistently with the alteration of epithelial-mesenchymal transition (EMT) and cell proliferative markers, including Cadherins, Vimentin, Snail, Slug, c-Myc, and cyclin D1. Remarkably, knockdown of G3BP1 dramatically impaired the signaling connection of pro-inflammatory cytokine IL-6 stimulation and downstream STAT3 activation in RCC, thus eventually contributing to the disruption of IL-6 elicited RCC migration and metastasis. In addition, in vivo orthotopic tumor xenografts results confirmed that knockdown of G3BP1 suppressed RCC tumor growth and metastasis in mice. Collectively, our findings support the notion that G3BP1 promotes tumor progression and metastasis through IL-6/G3BP1/STAT3 signaling axis in RCC. PMID- 29717135 TI - Substrate-bound outward-open structure of a Na+-coupled sialic acid symporter reveals a new Na+ site. AB - Many pathogenic bacteria utilise sialic acids as an energy source or use them as an external coating to evade immune detection. As such, bacteria that colonise sialylated environments deploy specific transporters to mediate import of scavenged sialic acids. Here, we report a substrate-bound 1.95 A resolution structure and subsequent characterisation of SiaT, a sialic acid transporter from Proteus mirabilis. SiaT is a secondary active transporter of the sodium solute symporter (SSS) family, which use Na+ gradients to drive the uptake of extracellular substrates. SiaT adopts the LeuT-fold and is in an outward-open conformation in complex with the sialic acid N-acetylneuraminic acid and two Na+ ions. One Na+ binds to the conserved Na2 site, while the second Na+ binds to a new position, termed Na3, which is conserved in many SSS family members. Functional and molecular dynamics studies validate the substrate-binding site and demonstrate that both Na+ sites regulate N-acetylneuraminic acid transport. PMID- 29717136 TI - Ancient DNA study reveals HLA susceptibility locus for leprosy in medieval Europeans. AB - Leprosy, a chronic infectious disease caused by Mycobacterium leprae (M. leprae), was very common in Europe till the 16th century. Here, we perform an ancient DNA study on medieval skeletons from Denmark that show lesions specific for lepromatous leprosy (LL). First, we test the remains for M. leprae DNA to confirm the infection status of the individuals and to assess the bacterial diversity. We assemble 10 complete M. leprae genomes that all differ from each other. Second, we evaluate whether the human leukocyte antigen allele DRB1*15:01, a strong LL susceptibility factor in modern populations, also predisposed medieval Europeans to the disease. The comparison of genotype data from 69 M. leprae DNA-positive LL cases with those from contemporary and medieval controls reveals a statistically significant association in both instances. In addition, we observe that DRB1*15:01 co-occurs with DQB1*06:02 on a haplotype that is a strong risk factor for inflammatory diseases today. PMID- 29717137 TI - Publisher Correction: Chloroquine modulates antitumor immune response by resetting tumor-associated macrophages toward M1 phenotype. AB - In the originally published version of this Article, images in Fig. 5n were inadvertently replaced with duplicates of images in Fig. 5o during the production process. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 29717138 TI - Topologically guided tuning of Zr-MOF pore structures for highly selective separation of C6 alkane isomers. AB - As an alternative technology to energy intensive distillations, adsorptive separation by porous solids offers lower energy cost and higher efficiency. Herein we report a topology-directed design and synthesis of a series of Zr-based metal-organic frameworks with optimized pore structure for efficient separation of C6 alkane isomers, a critical step in the petroleum refining process to produce gasoline with high octane rating. Zr6O4(OH)4(bptc)3 adsorbs a large amount of n-hexane but excluding branched isomers. The n-hexane uptake is ~70% higher than that of a benchmark adsorbent, zeolite-5A. A derivative structure, Zr6O4(OH)8(H2O)4(abtc)2, is capable of discriminating all three C6 isomers and yielding a high separation factor for 3-methylpentane over 2,3-dimethylbutane. This property is critical for producing gasoline with further improved quality. Multicomponent breakthrough experiments provide a quantitative measure of the capability of these materials for separation of C6 alkane isomers. A detailed structural analysis reveals the unique topology, connectivity and relationship of these compounds. PMID- 29717140 TI - Author Correction: Structural determinants and functional consequences of protein affinity for membrane rafts. AB - In the originally published version of this Article, financial support was not fully acknowledged. The PDF and HTML versions of the Article have now been corrected to include support from National Institute of General Medical Sciences, National Institutes of Health grant R01GM124072. PMID- 29717139 TI - Gas and seismicity within the Istanbul seismic gap. AB - Understanding micro-seismicity is a critical question for earthquake hazard assessment. Since the devastating earthquakes of Izmit and Duzce in 1999, the seismicity along the submerged section of North Anatolian Fault within the Sea of Marmara (comprising the "Istanbul seismic gap") has been extensively studied in order to infer its mechanical behaviour (creeping vs locked). So far, the seismicity has been interpreted only in terms of being tectonic-driven, although the Main Marmara Fault (MMF) is known to strike across multiple hydrocarbon gas sources. Here, we show that a large number of the aftershocks that followed the M 5.1 earthquake of July, 25th 2011 in the western Sea of Marmara, occurred within a zone of gas overpressuring in the 1.5-5 km depth range, from where pressurized gas is expected to migrate along the MMF, up to the surface sediment layers. Hence, gas-related processes should also be considered for a complete interpretation of the micro-seismicity (~M < 3) within the Istanbul offshore domain. PMID- 29717141 TI - The topological requirements for robust perfect adaptation in networks of any size. AB - Robustness, and the ability to function and thrive amid changing and unfavorable environments, is a fundamental requirement for living systems. Until now it has been an open question how large and complex biological networks can exhibit robust behaviors, such as perfect adaptation to a variable stimulus, since complexity is generally associated with fragility. Here we report that all networks that exhibit robust perfect adaptation (RPA) to a persistent change in stimulus are decomposable into well-defined modules, of which there exist two distinct classes. These two modular classes represent a topological basis for all RPA-capable networks, and generate the full set of topological realizations of the internal model principle for RPA in complex, self-organizing, evolvable bionetworks. This unexpected result supports the notion that evolutionary processes are empowered by simple and scalable modular design principles that promote robust performance no matter how large or complex the underlying networks become. PMID- 29717142 TI - Author Correction: Lack of acclimatization to chronic hypoxia in humans in the Antarctica. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29717143 TI - In vivo Dynamic Phase-Contrast X-ray Imaging using a Compact Light Source. AB - We describe the first dynamic and the first in vivo X-ray imaging studies successfully performed at a laser-undulator-based compact synchrotron light source. The X-ray properties of this source enable time-sequence propagation based X-ray phase-contrast imaging. We focus here on non-invasive imaging for respiratory treatment development and physiological understanding. In small animals, we capture the regional delivery of respiratory treatment, and two measures of respiratory health that can reveal the effectiveness of a treatment; lung motion and mucociliary clearance. The results demonstrate the ability of this set-up to perform laboratory-based dynamic imaging, specifically in small animal models, and with the possibility of longitudinal studies. PMID- 29717144 TI - The extent of wind-mediated dispersal of small metazoans, focusing nematodes. AB - Wind-mediated transport is an important mechanism in the dispersal of small metazoans. Yet, concrete dispersal rates have hardly been examined. Here we present the results of an one-year field experiment investigating the composition and dispersal rates of aeroplankton. To gain insights into the dynamics of dispersal at the species level, we focused on nematodes, worldwide the most common metazoan taxon. Among the six taxa collected in this study (nematodes, rotifers, collembolans, tardigrades, mites, and thrips), nematodes had the highest dispersal rates (up to >3000 individuals m-2 in 4 weeks, 27 species identified) and represented >44% of aeroplankton. Only living nematodes, and no propagules, were dispersed. All taxa had a higher dispersal potential in environments linked to the source habitat, evidenced by the much higher deposition of organisms in funnels placed on the ground than on the rooftop of a ten-story building. Nematodes under conditions of high humidity and wind speed had the highest dispersal rates, while increasing temperatures and dryness had a significantly positive impact on the wind drift of mites and thrips. The results indicated that wind dispersal over long distances is possible. The notable organismal input by wind dispersal may contribute to biodiversity and ecosystem functions. PMID- 29717145 TI - Sequence investigation of 34 forensic autosomal STRs with massively parallel sequencing. AB - STRs vary not only in the length of the repeat units and the number of repeats but also in the region with which they conform to an incremental repeat pattern. Massively parallel sequencing (MPS) offers new possibilities in the analysis of STRs since they can simultaneously sequence multiple targets in a single reaction and capture potential internal sequence variations. Here, we sequenced 34 STRs applied in the forensic community of China with a custom-designed panel. MPS performance were evaluated from sequencing reads analysis, concordance study and sensitivity testing. High coverage sequencing data were obtained to determine the constitute ratios and heterozygous balance. No actual inconsistent genotypes were observed between capillary electrophoresis (CE) and MPS, demonstrating the reliability of the panel and the MPS technology. With the sequencing data from the 200 investigated individuals, 346 and 418 alleles were obtained via CE and MPS technologies at the 34 STRs, indicating MPS technology provides higher discrimination than CE detection. The whole study demonstrated that STR genotyping with the custom panel and MPS technology has the potential not only to reveal length and sequence variations but also to satisfy the demands of high throughput and high multiplexing with acceptable sensitivity. PMID- 29717146 TI - Genome-wide Analysis of Large-scale Longitudinal Outcomes using Penalization GALLOP algorithm. AB - Genome-wide association studies (GWAS) with longitudinal phenotypes provide opportunities to identify genetic variations associated with changes in human traits over time. Mixed models are used to correct for the correlated nature of longitudinal data. GWA studies are notorious for their computational challenges, which are considerable when mixed models for thousands of individuals are fitted to millions of SNPs. We present a new algorithm that speeds up a genome-wide analysis of longitudinal data by several orders of magnitude. It solves the equivalent penalized least squares problem efficiently, computing variances in an initial step. Factorizations and transformations are used to avoid inversion of large matrices. Because the system of equations is bordered, we can re-use components, which can be precomputed for the mixed model without a SNP. Two SNP effects (main and its interaction with time) are obtained. Our method completes the analysis a thousand times faster than the R package lme4, providing an almost identical solution for the coefficients and p-values. We provide an R implementation of our algorithm. PMID- 29717147 TI - Direct observation of multiple conformational states in Cytochrome P450 oxidoreductase and their modulation by membrane environment and ionic strength. AB - Cytochrome P450 oxidoreductase (POR) is the primary electron donor in eukaryotic cytochrome P450 (CYP) containing systems. A wealth of ensemble biophysical studies of Cytochrome P450 oxidoreductase (POR) has reported a binary model of the conformational equilibrium directing its catalytic efficiency and biomolecular recognition. In this study, full length POR from the crop plant Sorghum bicolor was site-specifically labeled with Cy3 (donor) and Cy5 (acceptor) fluorophores and reconstituted in nanodiscs. Our single molecule fluorescence resonance energy transfer (smFRET) burst analyses of POR allowed the direct observation and quantification of at least three dominant conformational sub populations, their distribution and occupancies. Moreover, the state occupancies were remodeled significantly by ionic strength and the nature of reconstitution environment, i.e. phospholipid bilayers (nanodiscs) composed of different lipid head group charges vs. detergent micelles. The existence of conformational heterogeneity in POR may mediate selective activation of multiple downstream electron acceptors and association in complexes in the ER membrane. PMID- 29717149 TI - Author Correction: Exosomes secreted by human adipose mesenchymal stem cells promote scarless cutaneous repair by regulating extracellular matrix remodelling. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29717148 TI - Molecular Epidemiology of the HIV Epidemic in Three German Metropolitan Regions - Cologne/Bonn, Munich and Hannover, 1999-2016. AB - Using HIV sequence data to characterize clusters of HIV transmission may provide insight into the epidemic. Phylogenetic and network analyses were performed to infer putative relationships between HIV-1 partial pol sequences from 2,774 individuals receiving care in three German regions between 1999-2016. The regions have in common that they host some of the largest annual festivals in Europe (Carnival and Oktoberfest). Putative links with sequences (n = 150,396) from the Los Alamos HIV Sequence database were evaluated. A total of 595/2,774 (21.4%) sequences linked with at least one other sequence, forming 184 transmission clusters. Clustering individuals were significantly more likely to be younger, male, and report sex with men as their main risk factor (p < 0.001 each). Most clusters (77.2%) consisted exclusively of men; 41 (28.9%) of these included men reporting sex with women. Thirty-two clusters (17.4%) contained sequences from more than one region; clustering men were significantly more likely to be in a position bridging regional HIV epidemics than clustering women (p = 0.027). We found 236 clusters linking 547 sequences from our sample with sequences from the Los Alamos database (n = 1407; 31% from other German centres). These results highlight the pitfalls of focusing HIV prevention efforts on specific risk groups or specific locales. PMID- 29717150 TI - Clinical and Molecular Epidemiology of Human Parainfluenza Viruses 1-4 in Children from Viet Nam. AB - HPIVs are serologically and genetically grouped into four species that account for up to 10% of all hospitalizations due to acute respiratory infection in children under the age of five. Genetic and epidemiological data for the four HPIVs derived from two pediatric cohorts in Viet Nam are presented. Respiratory samples were screened for HPIV1-4 by real-time PCR. Demographic and clinical data of patients infected with different HPIV were compared. We used a hemi-nested PCR approach to generate viral genome sequences from HPIV-positive samples and conducted a comprehensive phylogenetic analysis. In total, 170 samples tested positive for HPIV. HPIV3 was most commonly detected in our cohort and 80 co detections of HPIV with other respiratory viruses were found. Phylogenetic analyses suggest local endemic circulation as well as punctuated introductions of new HPIV lineages. Viral gene flow analysis revealed that Viet Nam is a net importer of viral genetic diversity. Epidemiological analyses imply similar disease severity for all HPIV species. HPIV sequences from Viet Nam formed local clusters and were interspersed with sequences from diverse geographic regions. Combined, this new knowledge will help to investigate global HPIV circulation patterns in more detail and ultimately define more suitable vaccine strains. PMID- 29717151 TI - Dehydration prompts increased activity and blood feeding by mosquitoes. AB - Current insights into the mosquito dehydration response rely on studies that examine specific responses but ultimately fail to provide an encompassing view of mosquito biology. Here, we examined underlying changes in the biology of mosquitoes associated with dehydration. Specifically, we show that dehydration increases blood feeding in the northern house mosquito, Culex pipiens, which was the result of both higher activity and a greater tendency to land on a host. Similar observations were noted for Aedes aegypti and Anopheles quadrimaculatus. RNA-seq and metabolome analyses in C. pipiens following dehydration revealed that factors associated with carbohydrate metabolism are altered, specifically the breakdown of trehalose. Suppression of trehalose breakdown in C. pipiens by RNA interference reduced phenotypes associated with lower hydration levels. Lastly, mesocosm studies for C. pipiens confirmed that dehydrated mosquitoes were more likely to host feed under ecologically relevant conditions. Disease modeling indicates dehydration bouts will likely enhance viral transmission. This dehydration-induced increase in blood feeding is therefore likely to occur regularly and intensify during periods when availability of water is low. PMID- 29717152 TI - Chicken Interferon-induced Protein with Tetratricopeptide Repeats 5 Antagonizes Replication of RNA Viruses. AB - The intracellular actions of interferon (IFN)-regulated proteins, including IFN induced proteins with tetratricopeptide repeats (IFITs), attribute a major component of the protective antiviral host defense. Here we applied genomics approaches to annotate the chicken IFIT locus and currently identified a single IFIT (chIFIT5) gene. The profound transcriptional level of this effector of innate immunity was mapped within its unique cis-acting elements. This highly virus- and IFN-responsive chIFIT5 protein interacted with negative sense viral RNA structures that carried a triphosphate group on its 5' terminus (ppp-RNA). This interaction reduced the replication of RNA viruses in lentivirus-mediated IFIT5-stable chicken fibroblasts whereas CRISPR/Cas9-edited chIFIT5 gene knockout fibroblasts supported the replication of RNA viruses. Finally, we generated mosaic transgenic chicken embryos stably expressing chIFIT5 protein or knocked down for endogenous chIFIT5 gene. Replication kinetics of RNA viruses in these transgenic chicken embryos demonstrated the antiviral potential of chIFIT5 in ovo. Taken together, these findings propose that IFIT5 specifically antagonize RNA viruses by sequestering viral nucleic acids in chickens, which are unique in innate immune sensing and responses to viruses of both poultry and human health significance. PMID- 29717153 TI - Cystatin F involvement in adenosine A2A receptor-mediated neuroinflammation in BV2 microglial cells. AB - Our previous studies have shown adenosine A2A R activation markedly promotes the expression of cystatin F (CF) and exacerbates the white matter lesions induced by hypoxic brain injuries. Thus, we hypothesized that CF was probably involved in neuroinflammation of activated microglia induced by A2A R activation. We transfected the BV2 cells with a CF shRNA vector and examined the production of pro-inflammatory cytokines in hypoxic-BV2 cells in which A2A R was activated or inactivated to confirm this hypothesis. Additionally, we also investigated the probable signaling pathways involved in modulation of A2A R activation on CF expression in hypoxia-activated BV2 cells. Activation of A2A R promoted CF expression, which was significantly increased after the low glucose and hypoxia treatments in BV2 cells. CF gene knockdown markedly inhibited the increase in the expression of pro-inflammatory cytokines induced by A2A R activation in hypoxic BV2 cells. Furthermore, the increased expression of the CF induced by A2A R activation was remarkably inhibited in hypoxic-BV2 cells administrated with the PKA inhibitor H-89 and the PKC inhibitor staurosporine. Hence, these results indicate that hypoxia BV2 cells highly express CF, which is involved in A2A R activation-mediated neuroinflammation via the PKA/CREB and PKC/CREB or ERK1/2 signaling pathways. PMID- 29717154 TI - Dietary, environmental, and genetic risk factors of Extensive Macular Atrophy with Pseudodrusen, a severe bilateral macular atrophy of middle-aged patients. AB - EMAP (Extensive Macular Atrophy with Pseudodrusen) is a maculopathy we recently described that shares pseudodrusen and geographic atrophy with Age-related Macular Disease (AMD). EMAP differs from AMD by an earlier age of onset (50-55 years) and a characteristic natural history comprising a night blindness followed by a severe visual loss. In a prospective case-control study, ten referral centers included 115 EMAP (70 women, 45 men) patients and 345 matched controls to appraise dietary, environmental, and genetic risk factors. The incidence of EMAP (mean 2.95/1.106) was lower in Provence-Cote d'Azur with a Mediterranean diet (1.9/1.106), and higher in regions with intensive farming or industrialized activities (5 to 20/1.106). EMAP patients reported toxic exposure during professional activities (OR 2.29). The frequencies of common AMD complement factor risk alleles were comparable in EMAP. By contrast, only one EMAP patient had a rare AMD variant. This study suggests that EMAP could be a neurodegenerative disorder caused by lifelong toxic exposure and that it is associated with a chronic inflammation and abnormal complement pathway regulation. This leads to diffuse subretinal deposits with rod dysfunction and cone apoptosis around the age of 50 with characteristic extensive macular atrophy and paving stones in the far peripheral retina. PMID- 29717155 TI - Survey of Antithrombotic Treatment in Rural Patients (>60 years) with Atrial Fibrillation in East China. AB - The prevalence and antithrombotic treatment of atrial fibrillation (AF) in Chinese rural population is not well known. The aim of this study was to investigate the extent to which antithrombotic treatment was prescribed for rural AF patients >60 years. We identified 828 AF patients from 36734 rural residents >60 years in Shanghai China. Our data indicated the overall prevalence rate of AF was 2.3% in rural population >60 years in East China and 38.9% of AF patients underwent antithrombotic therapy, including warfarin (5.9%), aspirin (29.6%), clopidogrel (2.9%) and aspirin combined with clopidogrel (0.5%). Of enrolled subjects, 98.4% had CHA2DS2-VASc score >=1, 72.0% had HAS-BLED score <3 and 59.2% had CHA2DS2-VASc score >=2 with HAS-BLED score <3. Missing early detection (34.9%), delay in seeking treatment for asymptomatic AF (25.5%) and doctors's incomplete inform of AF-related risk of stroke to patients (21.7%) were three dominant causes for failing anticoagulant usage. In conclusion, most AF patients were with a high risk of thrombosis and a low risk of bleeding in China, but a large majority of them failed to take anticoagulants mainly for missing an early screening of AF and lack of awareness on AF for both patients and primary care physicians. PMID- 29717156 TI - High Basolateral Glucose Increases Sodium-Glucose Cotransporter 2 and Reduces Sirtuin-1 in Renal Tubules through Glucose Transporter-2 Detection. AB - Under diabetic conditions, sodium-glucose cotransporter 2 (SGLT2) for glucose uptake in proximal tubules (PTs) increases, whereas NAD+-dependent protein deacetylase silent mating type information regulation 2 homolog 1 (Sirtuin-1; SIRT1) for PT survival decreases. Therefore, we hypothesized that increased glucose influx by SGLT2 reduces SIRT1 expression. To test this hypothesis, db/db mice with diabetes and high-glucose (HG)-cultured porcine PT LLC-PK1 cells in a two-chamber system were treated with the SGLT2 inhibitor canagliflozin. We also examined SIRT1 and SGLT2 expression in human kidney biopsies. In db/db mice, SGLT2 expression increased with concomitant decreases in SIRT1, but was inhibited by canagliflozin. For determination of the polarity of SGLT2 and SIRT1 expression, LLC-PK1 cells were seeded into Transwell chambers (pore size, 0.4 um; Becton Dickinson, Oxford, UK). HG medium was added to either or to both of the upper and lower chambers, which corresponded to the apical and basolateral sides of the cells, respectively. In this system, the lower chamber with HG showed increased SGLT2 and decreased SIRT1 expression. Canagliflozin reversed HG-induced SIRT1 downregulation. Gene silencing and inhibitors for glucose transporter 2 (GLUT2) blocked HG-induced SGLT2 expression upregulation. Gene silencing for the hepatic nuclear factor-1alpha (HNF-1alpha), whose nuclear translocation was enhanced by HG, blocked HG-induced SGLT2 expression upregulation. Similarly, gene silencing for importin-alpha1, a chaperone protein bound to GLUT2, blocked HG induced HNF-1alpha nuclear translocation and SGLT2 expression upregulation. In human kidney, SIRT1 immunostaining was negatively correlated with SGLT2 immunostaining. Thus, under diabetic conditions, SIRT1 expression in PTs was downregulated by an increase in SGLT2 expression, which was stimulated by basolateral HG through activation of the GLUT2/importin-alpha1/HNF-1alpha pathway. PMID- 29717157 TI - Effective in vivo treatment of acute lung injury with helical, amphipathic peptoid mimics of pulmonary surfactant proteins. AB - Acute lung injury (ALI) leads to progressive loss of breathing capacity and hypoxemia, as well as pulmonary surfactant dysfunction. ALI's pathogenesis and management are complex, and it is a significant cause of morbidity and mortality worldwide. Exogenous surfactant therapy, even for research purposes, is impractical for adults because of the high cost of current surfactant preparations. Prior in vitro work has shown that poly-N-substituted glycines (peptoids), in a biomimetic lipid mixture, emulate key biophysical activities of lung surfactant proteins B and C at the air-water interface. Here we report good in vivo efficacy of a peptoid-based surfactant, compared with extracted animal surfactant and a synthetic lipid formulation, in a rat model of lavage-induced ALI. Adult rats were subjected to whole-lung lavage followed by administration of surfactant formulations and monitoring of outcomes. Treatment with a surfactant protein C mimic formulation improved blood oxygenation, blood pH, shunt fraction, and peak inspiratory pressure to a greater degree than surfactant protein B mimic or combined formulations. All peptoid-enhanced treatment groups showed improved outcomes compared to synthetic lipids alone, and some formulations improved outcomes to a similar extent as animal-derived surfactant. Robust biophysical mimics of natural surfactant proteins may enable new medical research in ALI treatment. PMID- 29717158 TI - Genomic analysis and immune response in a murine mastitis model of vB_EcoM-UFV13, a potential biocontrol agent for use in dairy cows. AB - Bovine mastitis remains the main cause of economic losses for dairy farmers. Mammary pathogenic Escherichia coli (MPEC) is related to an acute mastitis and its treatment is still based on the use of antibiotics. In the era of antimicrobial resistance (AMR), bacterial viruses (bacteriophages) present as an efficient treatment or prophylactic option. However, this makes it essential that its genetic structure, stability and interaction with the host immune system be thoroughly characterized. The present study analyzed a novel, broad host-range anti-mastitis agent, the T4virus vB_EcoM-UFV13 in genomic terms, and its activity against a MPEC strain in an experimental E. coli-induced mastitis mouse model. 4,975 Single Nucleotide Polymorphisms (SNPs) were assigned between vB_EcoM-UFV13 and E. coli phage T4 genomes with high impact on coding sequences (CDS) (37.60%) for virion proteins. Phylogenetic trees and genome analysis supported a recent infection mix between vB_EcoM-UFV13 and Shigella phage Shfl2. After a viral stability evaluation (e.g pH and temperature), intramammary administration (MOI 10) resulted in a 10-fold reduction in bacterial load. Furthermore, pro inflammatory cytokines, such as IL-6 and TNF-alpha, were observed after viral treatment. This work brings the whole characterization and immune response to vB_EcoM-UFV13, a biocontrol candidate for bovine mastitis. PMID- 29717159 TI - Neural and behavioural correlates of repeated social defeat. AB - Dominance hierarchies are common across the animal kingdom and have important consequences for reproduction and survival. Animals of lower social status cope with repeated social defeat using proactive and reactive behaviours. However, there remains a paucity of information on how an individual's coping behaviours changes over time or what neural mechanisms are involved. We used a resident intruder paradigm in the African cichlid fish Astatotilapia burtoni to investigate the neural correlates of these two opposing behaviour groups. Fish initially used both proactive and reactive behaviours, but had a dramatic increase in use of proactive behaviours during the third interaction, and this was followed by cessation of proactive behaviours and exclusive use of reactive coping. By quantifying neural activation in socially-relevant brain regions, we identify a subset of brain nuclei, including those homologous to the mammalian amygdala, showing higher activation in fish displaying proactive but not reactive behaviours. Fish displaying reactive behaviours had greater neural activation in the superior raphe, suggesting a possible conserved function during social defeat across vertebrates. These data provide the first evidence on the involvement of specific brain regions underlying proactive and reactive coping in fishes, indicating that these nuclei have conserved functions during social defeat across taxa. PMID- 29717161 TI - Weighted Multi-marker Genetic Risk Scores for Incident Coronary Heart Disease among Individuals of African, Latino and East-Asian Ancestry. AB - We examined the clinical utility of two multi-locus genetic risk scores (GRSs) previously validated in Europeans among persons of African (AFR; n = 2,089), Latino (LAT; n = 4,349) and East-Asian (EA; n = 4,804) ancestry. We used data from the GERA cohort (30-79 years old, 68 to 73% female). We utilized two GRSs with 12 and 51 SNPs, respectively, and the Framingham Risk Score (FRS) to estimate 10-year CHD risk. After a median 8.7 years of follow-up, 450 incident CHD events were documented (95 in AFR, 316 in LAT and 39 EA, respectively). In a model adjusting for principal components and risk factors, tertile 3 vs. tertile 1 of GRS_12 was associated with 1.86 (95% CI, 1.15-3.01), 1.52 (95% CI, 1.02 2.25) and 1.19 (95% CI, 0.77-1.83) increased hazard of CHD in AFR, LAT and EA, respectively. Inclusion of the GRSs in models containing the FRS did not increase the C-statistic but resulted in net overall reclassification of 10% of AFR, 7% LAT and EA and in reclassification of 13% of AFR and EA as well as 10% LAT in the intermediate FRS risk subset. Our results support the usefulness of incorporating genetic information into risk assessment for primary prevention among minority subjects in the U.S. PMID- 29717160 TI - Transcriptional Profiling of Somatostatin Interneurons in the Spinal Dorsal Horn. AB - The spinal dorsal horn (SDH) is comprised of distinct neuronal populations that process different somatosensory modalities. Somatostatin (SST)-expressing interneurons in the SDH have been implicated specifically in mediating mechanical pain. Identifying the transcriptomic profile of SST neurons could elucidate the unique genetic features of this population and enable selective analgesic targeting. To that end, we combined the Isolation of Nuclei Tagged in Specific Cell Types (INTACT) method and Fluorescence Activated Nuclei Sorting (FANS) to capture tagged SST nuclei in the SDH of adult male mice. Using RNA-sequencing (RNA-seq), we uncovered more than 13,000 genes. Differential gene expression analysis revealed more than 900 genes with at least 2-fold enrichment. In addition to many known dorsal horn genes, we identified and validated several novel transcripts from pharmacologically tractable functional classes: Carbonic Anhydrase 12 (Car12), Phosphodiesterase 11 A (Pde11a), and Protease-Activated Receptor 3 (F2rl2). In situ hybridization of these novel genes showed differential expression patterns in the SDH, demonstrating the presence of transcriptionally distinct subpopulations within the SST population. Overall, our findings provide new insights into the gene repertoire of SST dorsal horn neurons and reveal several novel targets for pharmacological modulation of this pain mediating population and treatment of pathological pain. PMID- 29717162 TI - Growth differentiation factor 15 ameliorates nonalcoholic steatohepatitis and related metabolic disorders in mice. AB - Growth differentiation factor 15 (GDF15) is an endocrine hormone belonging to the TGFbeta superfamily member. GDF15 administration or GDF15 overexpression has been reported to have anti-obesity and anti-diabetic effects. Although non-alcoholic fatty liver disease (NAFLD)/non-alcoholic steatohepatitis (NASH) is frequently associated with obesity and insulin resistance, the functional role of endogenous GDF15 and therapeutic effect of GDF15 overexpression in NASH and related metabolic deterioration have not been evaluated. Here, we found that GDF15 expression was increased in the livers of NASH animal models and human subjects with NASH. Elevated expression of GDF15 was due to diet-induced hepatic endoplasmic reticulum (ER) stress. Gdf15-knockout mice exhibited aggravated NASH phenotypes such as increased steatosis, hepatic inflammation, fibrosis, liver injury, and metabolic deterioration. Furthermore, GDF15 directly suppressed expression of fibrosis-related genes and osteopontin (OPN), contributing factors for NASH-related fibrosis, in hepatic stellate cells in vitro and in the liver of mice in vivo. Finally, we found that GDF15-transgenic mice showed attenuation of NASH phenotypes and metabolic deterioration. Therefore, our results suggest that induction of endogenous GDF15 is a compensatory mechanism to protect against the progression of NASH and that GDF15 could be an attractive therapeutic candidate for treatment of NASH and NASH-related metabolic deterioration. PMID- 29717163 TI - In-patient outcomes of Hematopoietic Stem Cell Transplantation in Patients with Immune Mediated Inflammatory Diseases: A Nationwide Study. AB - The impact of underlying immune-mediated inflammatory diseases (IMID) in patients undergoing hematopoietic stem cell transplant (HSCT) is unclear. Hematopoietic cell transplantation co-morbidity index (HCT-CI) is gaining acceptance as a reliable clinical method to score pre-transplant co-morbidities. Higher HCT-CI from a co-morbid IMID implies higher NRM. However, HCT-CI integrates many IMIDs with different pathogenesis and treatment together which may lead to spurious results. We performed a cross-sectional study using Nationwide Inpatient Sample dataset from 1998 to 2011 to compare the outcomes of HSCT in patients with different co-morbid IMIDs with patients without any co-morbid IMIDs. In both our multivariate and stringent matched-pair analysis, ulcerative colitis (UC) was associated with increased mortality while rheumatoid arthritis and psoriasis were associated with lower mortality as compared to no IMID group. Furthermore, in allogeneic HSCT subgroup, UC was associated with higher mortality and psoriasis was associated with lower mortality. In conclusion, we found that depending on the type of HSCT, each IMID has a different impact on outcomes of HSCT. Furthermore, UC patients had increased mortality if they had primary sclerosing cholangitis and had a higher risk of opportunistic infections like tuberculosis and cytomegalovirus suggesting the need for increased vigilance in this cohort. PMID- 29717164 TI - Comparative analyses of whole-genome protein sequences from multiple organisms. AB - Phylogenies based on entire genomes are a powerful tool for reconstructing the Tree of Life. Several methods have been proposed, most of which employ an alignment-free strategy. Average sequence similarity methods are different than most other whole-genome methods, because they are based on local alignments. However, previous average similarity methods fail to reconstruct a correct phylogeny when compared against other whole-genome trees. In this study, we developed a novel average sequence similarity method. Our method correctly reconstructs the phylogenetic tree of in silico evolved E. coli proteomes. We applied the method to reconstruct a whole-proteome phylogeny of 1,087 species from all three domains of life, Bacteria, Archaea, and Eucarya. Our tree was automatically reconstructed without any human decisions, such as the selection of organisms. The tree exhibits a concentric circle-like structure, indicating that all the organisms have similar total branch lengths from their common ancestor. Branching patterns of the members of each phylum of Bacteria and Archaea are largely consistent with previous reports. The topologies are largely consistent with those reconstructed by other methods. These results strongly suggest that this approach has sufficient taxonomic resolution and reliability to infer phylogeny, from phylum to strain, of a wide range of organisms. PMID- 29717165 TI - Variations of Prevalence and Incidence of Atrial Fibrillation and Oral Anticoagulation Rate According to Different Analysis Approaches. AB - The reported incidence and prevalence of atrial fibrillation (AF) has been inconsistent across published studies. Using the National Health Insurance Service database of Korea, the prevalence and incidence of AF, and oral anticoagulation (OAC) use of AF patients were explored according to three different approaches; 'formal approach', considering individual AF diagnosis and mortality; 'limited diagnosis approach', using upper 5 main diagnosis; and 'medical use approach', using the number of medical use AF population by year without considering individual AF history and mortality. The AF prevalence progressively increased by 2.46-fold from 0.50% in 2004 to 1.54% in 2015 when using a 'formal approach' (p for trend <0.001). The overall prevalence was 1.09% and 0.97% when using a 'formal approach' and 'limited diagnosis approaches', respectively. Overall prevalence decreased to 0.52% with a 'medical use approach'. The trend of annual AF incidence was stable when using a 'formal approach', but increased by 15% when using a 'medical use approach'. OAC rate in 2015 was 2.1 times higher when using a 'medical use approach' compared to using a 'formal approach' (40.3% vs. 19.1%, p < 0.001). Given the wide variability in prevalence and incidence figures with different analysis approaches, careful attention to the analysis methodology is needed. PMID- 29717166 TI - Comparative Proteomics Reveal the Association between SPANX Proteins and Clinical Outcomes of Artificial Insemination with Donor Sperm. AB - Semen analysis is used for diagnosing male infertility and evaluating male fertility for more than a century. However, the semen analysis simply represents the population characteristics of sperm. It is not a comprehensive assessment of the male reproductive potential. In this study, 20 semen samples from human sperm bank with distinctive artificial insemination with donor sperm (AID) clinical outcomes were collected and analyzed using a two-dimensional differential in-gel electrophoresis (2D-DIGE); 45 differentially expressed protein spots were obtained, and 26 proteins were identified. Most differentially expressed proteins were related to sperm motility, energy consumption, and structure. These identified proteins included several sperm proteins associated with the nucleus on the X chromosome (SPANX) proteins. This prospective study aimed to investigate the association between the expression levels of SPANX proteins and the AID clinical outcomes. The proteins identified in this study provided a reference for the molecular mechanism of sperm fertility and revealed a predictive value of the SPANX proteins. PMID- 29717167 TI - Understanding the element segregation and phase separation in the Ce-substituted Nd-(Fe,Co)-B based alloys. AB - Ce substituted Nd2Fe14B (2:14:1)-type permanent magnets have shown increasing potential in the applications due to their high properties/cost ratio. However, the element segregation and phase separation in the Ce substituted magnets have not been fully understood yet. In this work, (Nd1-xCex)25Fe40Co20Al4B11 alloys with high coercivities were prepared by copper mold casting. Based on detailed microstructure and composition analysis, the segregation of rare earth (RE) elements was observed in the as-cast alloys. Nd element prefers to enter into the 2:14:1 phase and the Ce element enter into the 1:2 phase. The existence of the 1:2 phase can promote the element segregation. The alloy shows an abnormal increase of coercivity from 641 kA/m for x = 0.2 to 863 kA/m for x = 0.3. This increase could be attributed to the phase separation of the 2:14:1 phase, which has been confirmed by the microstructural characterization. The present data provides useful information for exploring Ce-containing Nd-Fe-B magnets. PMID- 29717168 TI - Allosteric modulation of the farnesoid X receptor by a small molecule. AB - The bile acid activated transcription factor farnesoid X receptor (FXR) regulates numerous metabolic processes and is a rising target for the treatment of hepatic and metabolic disorders. FXR agonists have revealed efficacy in treating non alcoholic steatohepatitis (NASH), diabetes and dyslipidemia. Here we characterize imatinib as first-in-class allosteric FXR modulator and report the development of an optimized descendant that markedly promotes agonist induced FXR activation in a reporter gene assay and FXR target gene expression in HepG2 cells. Differential effects of imatinib on agonist-induced bile salt export protein and small heterodimer partner expression suggest that allosteric FXR modulation could open a new avenue to gene-selective FXR modulators. PMID- 29717170 TI - Structural Evolution of Hydrothermally Derived Reduced Graphene Oxide. AB - Hydrothermal reduction is a promising approach for graphene oxide (GO) reduction since it is environmentally friendly, simple, and cost effective. We present a detailed study of structural changes occurring in graphene oxide during the reduction process. The correlations between the interlayer spacing, chemical states, work functions, surface morphology, level of disorders, the number of layers, and processing time are elucidated. The results reveal that GO flakes remain in the early stage of the reduction process and that they are fully reduced after a 4-h hydrothermal treatment. With an increase in the reduction time, the resulting product, i.e., reduced graphene oxide, has a low oxygen content, small interlayer spacing, and crumbled and wrinkled structures. We are convinced that these properties can be tuned to a desired level for various applications. PMID- 29717169 TI - UNG-1 and APN-1 are the major enzymes to efficiently repair 5-hydroxymethyluracil DNA lesions in C. elegans. AB - In Caenorhabditis elegans, two DNA glycosylases, UNG-1 and NTH-1, and two AP endonucleases, APN-1 and EXO-3, have been characterized from the base-excision repair (BER) pathway that repairs oxidatively modified DNA bases. UNG-1 removes uracil, while NTH-1 can remove 5-hydroxymethyluracil (5-hmU), an oxidation product of thymine, as well as other lesions. Both APN-1 and EXO-3 can incise AP sites and remove 3'-blocking lesions at DNA single strand breaks, and only APN-1 possesses 3'- to 5'-exonulease and nucleotide incision repair activities. We used C. elegans mutants to study the role of the BER pathway in processing 5-hmU. We observe that ung-1 mutants exhibited a decrease in brood size and lifespan, and an elevated level of germ cell apoptosis when challenged with 5-hmU. These phenotypes were exacerbated by RNAi downregulation of apn-1 in the ung-1 mutant. The nth-1 or exo-3 mutants displayed wild type phenotypes towards 5-hmU. We show that partially purified UNG-1 can act on 5-hmU lesion in vitro. We propose that UNG-1 removes 5-hmU incorporated into the genome and the resulting AP site is cleaved by APN-1 or EXO-3. In the absence of UNG-1, the 5-hmU is removed by NTH-1 creating a genotoxic 3'-blocking lesion that requires the action of APN-1. PMID- 29717172 TI - Generation and annihilation time of magnetic droplet solitons. AB - Magnetic droplet solitons were first predicted to occur in materials with uniaxial magnetic anisotropy due to a long-range attractive interaction between elementary magnetic excitations, magnons. A non-equilibrium magnon population provided by a spin-polarized current in nanocontacts enables their creation and there is now clear experimental evidence for their formation, including direct images obtained with scanning x-ray transmission microscopy. Interest in magnetic droplets is associated with their unique magnetic dynamics that can lead to new types of high frequency nanometer scale oscillators of interest for information processing, including in neuromorphic computing. However, there are no direct measurements of the time required to nucleate droplet solitons or their lifetime experiments to date only probe their steady-state characteristics, their response to dc spin-currents. Here we determine the timescales for droplet annihilation and generation using current pulses. Annihilation occurs in a few nanoseconds while generation can take several nanoseconds to a microsecond depending on the pulse amplitude. Micromagnetic simulations show that there is an incubation time for droplet generation that depends sensitively on the initial magnetic state of the nanocontact. An understanding of these processes is essential to utilizing the unique characteristics of magnetic droplet solitons oscillators, including their high frequency, tunable and hysteretic response. PMID- 29717171 TI - Elevated expression of human bHLH factor ATOH7 accelerates cell cycle progression of progenitors and enhances production of avian retinal ganglion cells. AB - The production of vertebrate retinal projection neurons, retinal ganglion cells (RGCs), is regulated by cell-intrinsic determinants and cell-to-cell signaling events. The basic-helix-loop-helix (bHLH) protein Atoh7 is a key neurogenic transcription factor required for RGC development. Here, we investigate whether manipulating human ATOH7 expression among uncommitted progenitors can promote RGC fate specification and thus be used as a strategy to enhance RGC genesis. Using the chicken retina as a model, we show that cell autonomous expression of ATOH7 is sufficient to induce precocious RGC formation and expansion of the neurogenic territory. ATOH7 overexpression among neurogenic progenitors significantly enhances RGC production at the expense of reducing the progenitor pool. Furthermore, forced expression of ATOH7 leads to a minor increase of cone photoreceptors. We provide evidence that elevating ATOH7 levels accelerates cell cycle progression from S to M phase and promotes cell cycle exit. We also show that ATOH7-induced ectopic RGCs often exhibit aberrant axonal projection patterns and are correlated with increased cell death during the period of retinotectal connections. These results demonstrate the high potency of human ATOH7 in promoting early retinogenesis and specifying the RGC differentiation program, thus providing insight for manipulating RGC production from stem cell-derived retinal organoids. PMID- 29717173 TI - Optically Tunable Gratings Based on Coherent Population Oscillation. AB - We theoretically study the optically tunable gratings based on a L-type atomic medium using coherent population oscillations from the angle of reflection and transmission of the probe field. Adopting a standing-wave driving field, the refractive index of the medium as well as the absorption are periodically modified. Consequently, the Bragg scattering causes the effective reflection. We show that different intensities of the control field lead to three types of reflection profile which actually correspond to different absorption/amplification features of the medium. We present a detailed analyses about the influence of amplification on the reflection profile as well. The coherent population oscillation is robust to the dephasing effect, and such induced gratings could have promising applications in nonlinear optics and all optical information processing. PMID- 29717175 TI - A randomized, double-blind, placebo-controlled trial on the efficacy of ginger in the prevention of abdominal distention in post cesarean section patients. AB - The objective of the study was to evaluate the efficacy of ginger in the prevention of abdominal distention in post cesarean section patients. A randomized, double-blind, placebo controlled trial was conducted. One hundred and seventy-eight post cesarean section patients were either randomized to the study group receiving oral ginger capsules or to the placebo group receiving oral placebo capsules. The average age of the studied women was 32.3 years. The incidence of postoperative abdominal distention was not different between the ginger and the placebo groups (20.2% vs 29.2%, p = 0.328). The efficacy to relieve abdominal distention was superior in the ginger group than the placebo group (91% vs 65.2%, p < 0.001). With regards to quality of life, the number of patients who had the ability to eat was higher in the ginger group than in the placebo group (59.6% vs 43.8%, p = 0.035). There were no significant differences in time to first flatus, maternal satisfaction, and side effects. Ginger does not decrease the incidence of post cesarean section abdominal distention. But, ginger is more effective than the placebo in relieving the severity of abdominal distention on the fourth day after operation and improving the ability to eat. PMID- 29717174 TI - Cell Cycle Regulation by Alternative Polyadenylation of CCND1. AB - Global shortening of 3'UTRs by alternative polyadenylation (APA) has been observed in cancer cells. However, the role of APA in cancer remains unknown. CCND1 is a proto-oncogene that regulates progression through the G1-S phase of the cell cycle; moreover, it has been observed to be switching to proximal APA sites in cancer cells. To investigate the biological function of the APA of CCND1, we edited the weak poly(A) signal (PAS) of the proximal APA site to a canonical PAS using the CRISPR/Cas9 method, which can force the cells to use a proximal APA site. Cell cycle profiling and proliferation assays revealed that the proximal APA sites of CCND1 accelerated the cell cycle and promoted cell proliferation, but UTR-APA and CR-APA act via different molecular mechanisms. These results indicate that PAS editing with CRISPR/Cas9 provides a good method by which to study the biological function of APA. PMID- 29717176 TI - Recent climate warming drives ecological change in a remote high-Arctic lake. AB - The high Arctic is the fastest warming region on Earth, evidenced by extreme near surface temperature increase in non-summer seasons, recent rapid sea ice decline and permafrost melting since the early 1990's. Understanding the impact of climate change on the sensitive Arctic ecosystem to climate change has so far been hampered by the lack of time-constrained, high-resolution records and by implicit climate data analyses. Here, we show evidence of sharp growth in freshwater green algae as well as distinct diatom assemblage changes since ~1995, retrieved from a high-Arctic (80 degrees N) lake sediment record on Barentsoya (Svalbard). The proxy record approaches an annual to biennial resolution. Combining remote sensing and in-situ climate data, we show that this ecological change is concurrent with, and is likely driven by, the atmospheric warming and a sharp decrease in the length of the sea ice covered period in the region, and throughout the Arctic. Moreover, this research demonstrates the value of palaeoclimate records in pristine environments for supporting and extending instrumental records. Our results reinforce and extend observations from other sites that the high Arctic has already undergone rapid ecological changes in response to on-going climate change, and will continue to do so in the future. PMID- 29717177 TI - CNOT6 regulates a novel pattern of mRNA deadenylation during oocyte meiotic maturation. AB - In many cell types, the length of the poly(A) tail of an mRNA is closely linked to its fate - a long tail is associated with active translation, a short tail with silencing and degradation. During mammalian oocyte development, two contrasting patterns of polyadenylation have been identified. Some mRNAs carry a long poly(A) tail during the growth stage and are actively translated, then become deadenylated and down-regulated during the subsequent stage, termed meiotic maturation. Other mRNAs carry a short tail poly(A) tail and are translationally repressed during growth, and their poly(A) tail lengthens and they become translationally activated during maturation. As well, a program of elimination of this 'maternal' mRNA is initiated during oocyte maturation. Here we describe a third pattern of polyadenylation: mRNAs are deadenylated in growing oocytes, become polyadenylated during early maturation and then deadenylated during late maturation. We show that the deadenylase, CNOT6, is present in cortical foci of oocytes and regulates deadenylation of these mRNAs, and that PUF binding elements (PBEs) regulate deadenylation in mature oocytes. Unexpectedly, maintaining a long poly(A) tail neither enhances translation nor inhibits degradation of these mRNAs. Our findings implicate multiple machineries, more complex than previously thought, in regulating mRNA activity in oocytes. PMID- 29717178 TI - Volatile diterpene emission by two Mediterranean Cistaceae shrubs. AB - Mediterranean vegetation emits a wide range of biogenic volatile organic compounds (BVOCs) among which isoprenoids present quantitatively the most important compound class. Here, we investigated the isoprenoid emission from two Mediterranean Cistaceae shrubs, Halimium halimifolium and Cistus ladanifer, under controlled and natural conditions, respectively. For the first time, diurnal emission patterns of the diterpene kaurene were detected in real-time by Proton Transfer-Reaction-Time-of-Flight-Mass-Spectrometer. Kaurene emissions were strongly variable among H. halimifolium plants, ranging from 0.01 +/- 0.003 to 0.06 +/- 0.01 nmol m-2 s-1 in low and high emitting individuals, respectively. They were in the same order of magnitude as monoterpene (0.01 +/- 0.01 to 0.11 +/ 0.04 nmol m-2 s-1) and sesquiterpene (0.01 +/- 0.01 to 0.52 nmol m-2 s-1) emission rates. Comparable range and variability was found for C. ladanifer under natural conditions. Labelling with 13C-pyruvate suggested that emitted kaurene was not derived from de novo biosynthesis. The high kaurene content in leaves, the weak relationship with ecophysiological parameters and the tendency of higher emissions with increasing temperatures in the field indicate an emission from storage pools. This study highlights significant emissions of kaurene from two Mediterranean shrub species, indicating that the release of diterpenes into the atmosphere should probably deserve more attention in the future. PMID- 29717179 TI - Transplantation of human microbiota into conventional mice durably reshapes the gut microbiota. AB - Human microbiota-associated (HMA) mice are an important model to study the relationship between liver diseases and intestinal microbiota. We describe a new method to humanize conventional mice based on bowel cleansing with polyethylene glycol followed by fecal microbiota transplantation (FMT) from a human donor. Four successive bowel cleansings were sufficient to empty the intestine and decrease the microbiota by 90%. We then compared four different strategies based on the frequency of FMT over four weeks: (1) twice a week; (2) once a week; (3) two FMTs; (4) one FMT. We were able to transfer human bacteria to mice, irrespective of the strategy used. We detected human bacteria after four weeks, even if only one FMT was performed, but there was a shift of the microbiota over time. FMT twice a week for four weeks was too frequent and perturbed the stability of the newly formed ecosystem. FMT once a week appears to be the best compromise as it allowed engraftment of Faecalibacterium, and a higher diversity of bacteria belonging to the Bacteroidales order. Our easy to establish HMA mouse model could be used as an alternative to classical HMA mice to study the relationship between the liver and the microbiota. PMID- 29717180 TI - Zinc use efficiency is enhanced in wheat through nanofertilization. AB - Ferti-fortification of wheat with zinc, an essential micronutrient is one of the strategies for combating 'hidden hunger' in a large proportion of people all over the world. During fertilization, application of large quantities of micronutrients often results in nutrient wastage and subsequent environmental pollution. Here, we report zinc complexed chitosan nanoparticles (Zn-CNP) for ferti-fortification of durum wheat in field-scale experiments. The efficacy of Zn CNP was assessed vis-a-vis conventionally applied ZnSO4 (0.2%; 400 mgL-1 zinc) in two durum wheat genotypes (MACS 3125, an indigenous high yielding genotype and UC 1114, a genotype containing the Gpc-B1gene). The observed grain zinc enrichment using Zn-CNP nanocarrier (~36%) and conventional ZnSO4 (~50%) were comparable, despite 10 folds less zinc (40 mgL-1) used in the former. Nanofertilizer application increased grain zinc content without affecting grain yield, protein content, spikelets per spike, thousand kernel weight, etc. Grain zinc enrichment observed in the four-year field trials on plots with varying soil zinc content was consistent, proving the utility of Zn-CNP as a novel nanofertilizer which enhanced fertilizer use efficiency. Our work describes a new paradigm in micronutrient fortification, viz. 'use nanofertilizers at the right place, right time and in right doses'. PMID- 29717182 TI - Publisher Correction: Spiral Form of the Human Cochlea Results from Spatial Constraints. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29717181 TI - Increased experimental conditions and marker densities identified more genetic loci associated with southern and northern leaf blight resistance in maize. AB - Southern leaf blight (SLB) and northern leaf blight (NLB) are the two major foliar diseases limiting maize production worldwide. Upon previous study with the nested association mapping (NAM) population, which consist of 5,000 recombinant inbred lines from 25 parents crossed with B73, we expanded the phenotyping environments from the United States (US) to China, and increased the marker densities from 1106 to 7386 SNPs for linkage mapping, and from 1.6 to 28.5 million markers for association mapping. We identified 49 SLB and 48 NLB resistance-related unique QTLs in linkage mapping, and multiple loci in association mapping with candidate genes involved in known plant disease resistance pathways. Furthermore, an independent natural population with 282 diversified inbred lines were sequenced for four candidate genes selected based on their biological functions. Three of them demonstrated significant associations with disease resistance. These findings provided valuable resources for further implementations to develop varieties with superior resistance for NLB and SLB. PMID- 29717183 TI - Predicting drug resistance related to ABC transporters using unsupervised Consensus Self-Organizing Maps. AB - ATP binding cassette (ABC) transporters play a pivotal role in drug elimination, particularly on several types of cancer in which these proteins are overexpressed. Due to their promiscuous ligand recognition, building computational models for substrate classification is quite challenging. This study evaluates the use of modified Self-Organizing Maps (SOM) for predicting drug resistance associated with P-gp, MPR1 and BCRP activity. Herein, we present a novel multi-labelled unsupervised classification model which combines a new clustering algorithm with SOM. It significantly improves the accuracy of substrates classification, catching up with traditional supervised machine learning algorithms. Results can be applied to predict the pharmacological profile of new drug candidates during the drug development process. PMID- 29717184 TI - Strong contributions of local background climate to the cooling effect of urban green vegetation. AB - Utilization of urban green vegetation (UGV) has been recognized as a promising option to mitigate urban heat island (UHI) effect. While we still lack understanding of the contributions of local background climate to the cooling effect of UGV. Here we proposed and employed a cooling effect framework and selected eight typical cities located in Temperate Monsoon Climate (TMC) and Mediterranean Climate (MC) demonstrate that local climate condition largely affects the cooling effect of UGV. Specifically, we found increasing (artificial) rainfall and irrigation contribute to improving the cooling intensity of grassland in both climates, particularly in the hot-dry environment. The cities with high relative humidity would restrict the cooling effect of UGV. Increasing wind speed would significantly enhance the tree-covered while weakening the grass covered UGVs' cooling effect in MC cities. We also identified that, in order to achieve the most effective cooling with the smallest sized tree-covered UGV, the area of trees in both climate zones' cities should generally be planned around 0.5 ha. The method and results enhance understanding of the cooling effect of UGVs on larger (climate) scales and provide important insights for UGV planning and management. PMID- 29717185 TI - Author Correction: Two large deletions extending beyond either end of the RHD gene and their red cell phenotypes. AB - The authors of the above paper noticed an error in publication. In Results section, under sub-section RHD genetic variations, the deletion nomenclature for Sample 1 was incorrectly given as [NC_000001.11(NG_007494.1):c.(1-15149_1 15153)_(148+3154_148+3158)del]. PMID- 29717186 TI - Novel NEXMIF pathogenic variant in a boy with severe autistic features, intellectual disability, and epilepsy, and his mildly affected mother. AB - Intellectual disability (ID) and autism spectrum disorders are complex neurodevelopmental disorders occurring among all ethnic and socioeconomic groups. Pathogenic variants in the neurite extension and migration factor (NEXMIF) gene (formerly named KIAA2022) on the X chromosome are responsible for ID, autistic behavior, epilepsy, or dysmorphic features in males. Most affected females described had a milder phenotype or were asymptomatic obligate carriers. We report here for the first time mother-to-son transmission of a novel NEXMIF truncating variant without X-inactivation skewing in the blood. Truncating gene variant leads to symptomatic mother to severely affected son transmission. Our findings emphasize that NEXMIF sequencing should be strongly considered in patients with unexplained autism spectrum disorder, ID, and epilepsy, irrespective of gender. Such testing could increase our knowledge of the pathogenicity of NEXMIF variants and improve genetic counseling. PMID- 29717188 TI - Author Correction: Angular flux creep contributions in YBa2Cu3O7-delta nanocomposites from electrical transport measurements. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29717187 TI - Rest-related consolidation protects the fine detail of new memories. AB - Newly encoded memories are labile and consolidate over time. The importance of sleep in memory consolidation has been well known for almost a decade. However, recent research has shown that awake quiescence, too, can support consolidation: people remember more new memories if they quietly rest after encoding than if they engage in a task. It is not yet known how exactly this rest-related consolidation benefits new memories, and whether it affects the fine detail of new memories. Using a sensitive picture recognition task, we show that awake quiescence aids the fine detail of new memories. Young adults were significantly better at discriminating recently encoded target pictures from similar lure pictures when the initial encoding of target pictures had been followed immediately by 10 minutes of awake quiescence than an unrelated perceptual task. This novel finding indicates that, in addition to influencing how much we remember, our behavioural state during wakeful consolidation determines, at least in part, the level of fine detail of our new memories. Thus, our results suggest that rest-related consolidation protects the fine detail of new memories, allowing us to retain detailed memories. PMID- 29717189 TI - Subclassification of diabetes based on quantitative traits. PMID- 29717190 TI - Rethinking progression of CKD as a process of punctuated equilibrium. PMID- 29717191 TI - Cellular recording devices imprint the history of the cell. PMID- 29717192 TI - Local structure of molten AuGa2 under pressure: Evidence for coordination change and planetary implications. AB - In situ x-ray diffraction measurements and inverse Monte Carlo simulations of pair distribution functions were used to characterize the local structure of molten AuGa2 up to 16 GPa and 940 K. Our results document systematic changes in liquid structure due to a combination of bond compression and coordination increase. Empirical potential structure refinement shows the first-neighbor coordination of Ga around Au and of Au around Ga to increase from about 8 to 10 and 4 to 5, respectively between 0 and 16 GPa, and the inferred changes in liquid structure can explain the observed melting-point depression of AuGa2 up to 5 GPa. As intermetallic AuGa2 is an analogue for metallic SiO2 at much higher pressures, our results imply that structural changes documented for non-metallic silicate melts below 100 GPa are followed by additional coordination changes in the metallic state at pressures in the 0.2-1 TPa range achieved inside large planets. PMID- 29717193 TI - Author Correction: Mental workload and neural efficiency quantified in the prefrontal cortex using fNIRS. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29717194 TI - Author Correction: Recurrent acquisition of cytosine methyltransferases into eukaryotic retrotransposons. AB - The original version of this Article contained an error in the spelling of the author Hongfei Li, which was incorrectly given as Fei Hong. This has now been corrected in both the PDF and HTML versions of the Article. PMID- 29717195 TI - Author Correction: MiRNA-29c regulates the expression of inflammatory cytokines in diabetic nephropathy by targeting tristetraprolin. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29717196 TI - EEG Analytics for Early Detection of Autism Spectrum Disorder: A data-driven approach. AB - Autism spectrum disorder (ASD) is a complex and heterogeneous disorder, diagnosed on the basis of behavioral symptoms during the second year of life or later. Finding scalable biomarkers for early detection is challenging because of the variability in presentation of the disorder and the need for simple measurements that could be implemented routinely during well-baby checkups. EEG is a relatively easy-to-use, low cost brain measurement tool that is being increasingly explored as a potential clinical tool for monitoring atypical brain development. EEG measurements were collected from 99 infants with an older sibling diagnosed with ASD, and 89 low risk controls, beginning at 3 months of age and continuing until 36 months of age. Nonlinear features were computed from EEG signals and used as input to statistical learning methods. Prediction of the clinical diagnostic outcome of ASD or not ASD was highly accurate when using EEG measurements from as early as 3 months of age. Specificity, sensitivity and PPV were high, exceeding 95% at some ages. Prediction of ADOS calibrated severity scores for all infants in the study using only EEG data taken as early as 3 months of age was strongly correlated with the actual measured scores. This suggests that useful digital biomarkers might be extracted from EEG measurements. PMID- 29717197 TI - Effects of NGM282, an FGF19 variant, on colonic transit and bowel function in functional constipation: a randomized phase 2 trial. AB - OBJECTIVE: NGM282 is an analog of fibroblast growth factor 19 (FGF19), a potent inhibitor of bile acid (BA) synthesis in animals and humans. In phase 2 trials in type 2 diabetes and primary biliary cholangitis, NGM282 was associated with dose related abdominal cramping and diarrhea. We aimed to examine effects of NGM282 on colonic transit, stool frequency and consistency, hepatic BA synthesis (fasting serum C4), fecal fat, and BA in functional constipation (FC). METHODS: Two-dose NGM282 (1 and 6 mg, subcutaneously daily), parallel-group, randomized, placebo controlled, 14-day study in patients with FC (Rome III criteria) and baseline colonic transit 24 h geometric center (GC) <3.0. We explored treatment interaction with SNPs in genes KLB, FGFR4, and TGR5 (GPBAR1). STATISTICAL ANALYSIS: overall ANCOVA at alpha = 0.025 (baseline as covariate where available), with three pairwise comparisons among the three groups (alpha = 0.008). RESULTS: Overall, NGM282 altered bowel function (number of bowel movements, looser stool form, and increased ease of passage) and significantly accelerated gastric and colonic transit. Dose-related effects were seen with GC 24 h, but not with gastric emptying (GE) and GC 48 h. There were no differences in fecal fat or weight, but there was reduced fecal total BA excretion with NGM282. The most common adverse events were increased appetite (n = 0 with placebo, 2 with 1 mg, 9 with 6 mg), injection site reaction (n = 2 placebo, 4 with 1 mg, 8 with 6 mg), and diarrhea (n = 1 with 1 mg and 4 with 6 mg NGM282). There was treatment interaction with KLB SNP, with greater increase in colonic transit in participants with the minor A allele (p = 0.056). CONCLUSION: NGM282 significantly impacts GE and colonic transit, consistent with the observed clinical symptoms. The specific mechanism of prokinetic activity requires further research. PMID- 29717198 TI - Anti-Rhizopus activity of tanzawaic acids produced by the hot spring-derived fungus Penicillium sp. BF-0005. AB - A silkworm infection assay with the pathogenic fungus Rhizopus oryzae was established. Microbial culture broths were screened for anti-Rhizopus antibiotics using this assay. A new compound, tanzawaic acid R was isolated along with known and structurally related tanzawaic acids and arohynapene A from the culture broth of the hot spring-derived fungus Penicillium sp. BF-0005. The structure of tanzawaic acid R was elucidated by various spectroscopic data including 1D and 2D nuclear magnetic resonance spectroscopy. Tanzawaic acids A, B, C, and R and arohynapene A exhibited antifungal activity against R. oryzae. Tanzawaic acids A and B dose-dependently exerted therapeutic effects in the silkworm infection assay with R. oryzae. PMID- 29717199 TI - Antibacterial anthraquinone derivatives isolated from a mangrove-derived endophytic fungus Aspergillus nidulans by ethanol stress strategy. AB - Three new natural products, including a new anthraquinone derivative isoversicolorin C (1), a new xanthone analog isosecosterigmatocystin (2), and a new amino acid derivative, glulisine A (3), along with six related metabolites (4 9) were isolated from the culture broth and mycelia extracts of the mangrove derived endophytic fungus Aspergillus nidulans MA-143 under 0.1% ethanol stress. Their structures were elucidated by detailed analysis of their NMR spectra, ECD spectrum, and X-ray crystallographic experiments. Compounds 1 and 4 showed potent antibacterial activity against some of the tested microbes. PMID- 29717200 TI - Chemerin suppresses hepatocellular carcinoma metastasis through CMKLR1-PTEN-Akt axis. AB - BACKGROUND: Chemerin, a known chemoattractant, participates in multiple biological events. However, its role in cancer remains largely unknown. METHODS: Chemerin expression was evaluated by real-time PCR, western blot and immunohistochemistry. Forced expression, RNAi, immunoprecipitation, etc. were used in function and mechanism study. Mouse models of extrahepatic and intrahepatic metastasis were employed to evaluate the therapeutic potential of chemerin. RESULTS: Chemerin expression was significantly downregulated in hepatocellular carcinoma, and associated with poor prognosis of HCC patients. Forced expression of chemerin inhibited in vitro migration, invasion and in vivo metastasis of HCC cells. Administration of chemerin effectively suppressed extrahepatic and intrahepatic metastases of HCC cells, resulting in prolonged survival of tumour-bearing nude mice. Chemerin upregulated expression and phosphatase activity of PTEN by interfering with PTEN-CMKLR1 interaction, leading to weakened ubiquitination of PTEN and decreased p-Akt (Ser473) level, which was responsible for suppressed migration, invasion and metastasis of HCC cells. Positive correlation between chemerin and PTEN, and reverse correlation between chemerin and p-Akt (Ser473) were also observed in HCC clinical samples and intrahepatic mouse model in vivo. CONCLUSIONS: Our study has revealed the suppressive role and therapeutic potential of chemerin in HCC metastasis, providing both a prognostic marker and drug candidate for HCC. PMID- 29717201 TI - Facile Tumor Spheroids Formation in Large Quantity with Controllable Size and High Uniformity. AB - A facile method for generation of tumor spheroids in large quantity with controllable size and high uniformity is presented. HCT-116 cells are used as a model cell line. Individual tumor cells are sparsely seeded onto petri-dishes. After a few days of growth, separated cellular islets are formed and then detached by dispase while maintaining their sheet shape. These detached cell sheets are transferred to dispase-doped media under orbital shaking conditions. Assisted by the shear flow under shaking and inhibition of cell-to-extracellular matrix junctions by dispase, the cell sheets curl up and eventually tumor spheroids are formed. The average size of the spheroids can be controlled by tuning the cell sheet culturing period and spheroid shaking period. The uniformity can be controlled by a set of sieves which were home-made using stainless steel meshes. Since this method is based on simple petri-dish cell culturing and shaking, it is rather facile for forming tumor spheroids with no theoretical quantity limit. This method has been used to form HeLa, A431 and U87 MG tumor spheroids and application of the formed tumor spheroids in drug screening is also demonstrated. The viability, 3D structure, and necrosis of the spheroids are characterized. PMID- 29717202 TI - Double domain polyethylenimine-based nanoparticles for integrin receptor mediated delivery of plasmid DNA. AB - The objective of the present study is to conjugate L-thyroxine PEI derivative onto another PEI to compensate the amine content of the whole structure which has been utilized for the ligand conjugation. Since alphavbeta3 integrin receptors are over-expressed on cancer cells and there is binding site for L-thyroxine on these receptors, PEI conjugation by L-thyroxine along with restoring the PEI amine content might be an efficient strategy for targeted delivery using polymeric nanoparticles. The results demonstrated the ability of the PEI conjugate in the formation of nanoparticles with the size of around 210 nm with higher buffering capacity. The conjugated PEI derivative increased the transfection efficiency in the cell lines over-expressing integrin by up to two folds higher than unmodified PEI, whereas in the cell lines lacking the integrin receptors there was no ligand conjugation-associated difference in gene transfer ability. The specificity of transfection demonstrated the delivery of plasmid DNA through integrin receptors. Also, the results of in vivo imaging of the polyplexes revealed that 99mTc-labeled PEI/plasmid DNA complexes accumulated in kidney and bladder 4 h post injection. Therefore, this PEI derivative could be considered as an efficient targeted delivery system for plasmid DNA. PMID- 29717204 TI - Synaptic nibbling. PMID- 29717203 TI - Multiple-Brain Connectivity During Third Party Punishment: an EEG Hyperscanning Study. AB - Compassion is a particular form of empathic reaction to harm that befalls others and is accompanied by a desire to alleviate their suffering. This altruistic behavior is often manifested through altruistic punishment, wherein individuals penalize a deprecated human's actions, even if they are directed toward strangers. By adopting a dual approach, we provide empirical evidence that compassion is a multifaceted prosocial behavior and can predict altruistic punishment. In particular, in this multiple-brain connectivity study in an EEG hyperscanning setting, compassion was examined during real-time social interactions in a third-party punishment (TPP) experiment. We observed that specific connectivity patterns were linked to behavioral and psychological intra- and interpersonal factors. Thus, our results suggest that an ecological approach based on simultaneous dual-scanning and multiple-brain connectivity is suitable for analyzing complex social phenomena. PMID- 29717205 TI - Pathways to contextual control. PMID- 29717206 TI - Inferring a nonlinear biochemical network model from a heterogeneous single-cell time course data. AB - Mathematical modeling and analysis of biochemical reaction networks are key routines in computational systems biology and biophysics; however, it remains difficult to choose the most valid model. Here, we propose a computational framework for data-driven and systematic inference of a nonlinear biochemical network model. The framework is based on the expectation-maximization algorithm combined with particle smoother and sparse regularization techniques. In this method, a "redundant" model consisting of an excessive number of nodes and regulatory paths is iteratively updated by eliminating unnecessary paths, resulting in an inference of the most likely model. Using artificial single-cell time-course data showing heterogeneous oscillatory behaviors, we demonstrated that this algorithm successfully inferred the true network without any prior knowledge of network topology or parameter values. Furthermore, we showed that both the regulatory paths among nodes and the optimal number of nodes in the network could be systematically determined. The method presented in this study provides a general framework for inferring a nonlinear biochemical network model from heterogeneous single-cell time-course data. PMID- 29717207 TI - Improved strategy for the curation and classification of kinases, with broad applicability to other eukaryotic protein groups. AB - Despite the substantial amount of genomic and transcriptomic data available for a wide range of eukaryotic organisms, most genomes are still in a draft state and can have inaccurate gene predictions. To gain a sound understanding of the biology of an organism, it is crucial that inferred protein sequences are accurately identified and annotated. However, this can be challenging to achieve, particularly for organisms such as parasitic worms (helminths), as most gene prediction approaches do not account for substantial phylogenetic divergence from model organisms, such as Caenorhabditis elegans and Drosophila melanogaster, whose genomes are well-curated. In this paper, we describe a bioinformatic strategy for the curation of gene families and subsequent annotation of encoded proteins. This strategy relies on pairwise gene curation between at least two closely related species using genomic and transcriptomic data sets, and is built on recent work on kinase complements of parasitic worms. Here, we discuss salient technical aspects of this strategy and its implications for the curation of protein families more generally. PMID- 29717208 TI - High prevalence of diabetes among migrants in the United Arab Emirates using a cross-sectional survey. AB - In 2011, the United Arab Emirates (UAE) had the 10th highest diabetes prevalence globally, but this was based on data that excluded migrants who comprise 80% of the population. This study assessed diabetes prevalence across the UAE population. A random sample of migrants was recruited from the visa renewal centers. Data were collected using interviews, anthropometric measurements and fasting blood for glucose, lipids and genetic analyses. 2724 adults completed the questionnaires and blood tests. Of these, 81% were males, 65% were <=40 years old and 3% were above 60 years. Diabetes, based on self-report or fasting plasma glucose >=7.0 mmol/l, showed a crude prevalence of 15.5%, of whom 64.2% were newly diagnosed. Overall age- and sex-adjusted diabetes prevalence, according to the world mid-year population of 2013, was 19.1%. The highest prevalence was in Asians (16.4%) and non-Emirati Arabs (15.2%) and lowest in Africans and Europeans (11.9%). It increased with age: 6.3% in 18-30 years and 39.7% in 51 to 60 years. Lower education, obesity, positive family history, hypertension, dyslipidemia, snoring, and low HDL levels, all showed significant associations with diabetes. The high diabetes prevalence among migrants in the UAE, 64% of which was undiagnosed, necessitates urgent diabetes prevention and control programs for the entire UAE population. PMID- 29717209 TI - Therapeutic Delivery Specifications Identified Through Compartmental Analysis of a Mesenchymal Stromal Cell-Immune Reaction. AB - Despite widespread preclinical success, mesenchymal stromal cell (MSC) therapy has not reached consistent pivotal clinical endpoints in primary indications of autoinflammatory diseases. Numerous studies aim to uncover specific mechanisms of action towards better control of therapy using in vitro immunomodulation assays. However, many of these immunomodulation assays are imperfectly designed to accurately recapitulate microenvironment conditions where MSCs act. To increase our understanding of MSC efficacy, we herein conduct a systems level microenvironment approach to define compartmental features that can influence the delivery of MSCs' immunomodulatory effect in vitro in a more quantitative manner than ever before. Using this approach, we notably uncover an improved MSC quantification method with predictive cross-study applicability and unveil the key importance of system volume, time exposure to MSCs, and cross-communication between MSC and T cell populations to realize full therapeutic effect. The application of these compartmental analysis can improve our understanding of MSC mechanism(s) of action and further lead to administration methods that deliver MSCs within a compartment for predictable potency. PMID- 29717211 TI - Up-regulation of microRNA-203 in influenza A virus infection inhibits viral replication by targeting DR1. AB - MicroRNAs (miRNAs) are small noncoding RNA molecules that play important roles in various biological processes. Much evidence shows that miRNAs are closely associated with numerous virus infections; however, involvement of cellular miRNAs in influenza A virus (IAV) infection is unclear. Here, we found that expression of miR-203 was up-regulated markedly via two different mechanisms during IAV infection. First, we examined the effects of type I interferon induced by IAV on direct activation of miR-203 expression. Next, we showed that DNA demethylation within the miR-203 promoter region in A549 cells induced its up regulation, and that expression of DNA methyltransferase 1 was down-regulated following H5N1 virus infection. Ectopic expression of miR-203 in turn inhibited H5N1 virus replication by targeting down-regulator of transcription 1 (DR1), which was identified as a novel target of miR-203. Silencing DR1 in miR-203 knockout cells using a specific siRNA inhibited replication of the H5N1 virus, an effect similar to that of miR-203. In summary, the data show that host cell expression of miR-203 is up-regulated upon IAV infection, which increases antiviral responses by suppressing a novel target gene, DR1. Thus, we have identified a novel mechanism underlying the relationship between miR-203 and IAV infection. PMID- 29717210 TI - Exploring intrinsically disordered proteins in Chlamydomonas reinhardtii. AB - The content of intrinsically disordered protein (IDP) is related to organism complexity, evolution, and regulation. In the Plantae, despite their high complexity, experimental investigation of IDP content is lacking. We identified by mass spectrometry 682 heat-resistant proteins from the green alga, Chlamydomonas reinhardtii. Using a phosphoproteome database, we found that 331 of these proteins are targets of phosphorylation. We analyzed the flexibility propensity of the heat-resistant proteins and their specific features as well as those of predicted IDPs from the same organism. Their mean percentage of disorder was about 20%. Most of the IDPs (~70%) were addressed to other compartments than mitochondrion and chloroplast. Their amino acid composition was biased compared to other classic IDPs. Their molecular functions were diverse; the predominant ones were nucleic acid binding and unfolded protein binding and the less abundant one was catalytic activity. The most represented proteins were ribosomal proteins, proteins associated to flagella, chaperones and histones. We also found CP12, the only experimental IDP from C. reinhardtii that is referenced in disordered protein database. This is the first experimental investigation of IDPs in C. reinhardtii that also combines in silico analysis. PMID- 29717212 TI - Band transition and topological interface modes in 1D elastic phononic crystals. AB - In this report, we design a one-dimensional elastic phononic crystal (PC) comprised of an Aluminum beam with periodically arranged cross-sections to study the inversion of bulk bands due to the change of topological phases. As the geometric parameters of the unit cell varies, the second bulk band closes and reopens forming a topological transition point. This phenomenon is confirmed for both longitudinal waves and bending waves. By constructing a structural system formed by two PCs with different topological phases, for the first time, we experimentally demonstrate the existence of interface mode within the bulk band gap as a result of topological transition for both longitudinal and bending modes in elastic systems, although for bending modes, additional conditions have to be met in order to have the interface mode due to the dispersive nature of the bending waves in uniform media compared to the longitudinal waves. PMID- 29717214 TI - Nanoimmunotherapy targeting CD40-TRAF6 signalling to reduce atherosclerosis. PMID- 29717213 TI - Metabolic systems analysis of LPS induced endothelial dysfunction applied to sepsis patient stratification. AB - Endothelial dysfunction contributes to sepsis outcome. Metabolic phenotypes associated with endothelial dysfunction are not well characterised in part due to difficulties in assessing endothelial metabolism in situ. Here, we describe the construction of iEC2812, a genome scale metabolic reconstruction of endothelial cells and its application to describe metabolic changes that occur following endothelial dysfunction. Metabolic gene expression analysis of three endothelial subtypes using iEC2812 suggested their similar metabolism in culture. To mimic endothelial dysfunction, an in vitro sepsis endothelial cell culture model was established and the metabotypes associated with increased endothelial permeability and glycocalyx loss after inflammatory stimuli were quantitatively defined through metabolomics. These data and transcriptomic data were then used to parametrize iEC2812 and investigate the metabotypes of endothelial dysfunction. Glycan production and increased fatty acid metabolism accompany increased glycocalyx shedding and endothelial permeability after inflammatory stimulation. iEC2812 was then used to analyse sepsis patient plasma metabolome profiles and predict changes to endothelial derived biomarkers. These analyses revealed increased changes in glycan metabolism in sepsis non-survivors corresponding to metabolism of endothelial dysfunction in culture. The results show concordance between endothelial health and sepsis survival in particular between endothelial cell metabolism and the plasma metabolome in patients with sepsis. PMID- 29717215 TI - DNAp: A Pipeline for DNA-seq Data Analysis. AB - Next-generation sequencing is empowering genetic disease research. However, it also brings significant challenges for efficient and effective sequencing data analysis. We built a pipeline, called DNAp, for analyzing whole exome sequencing (WES) and whole genome sequencing (WGS) data, to detect mutations from disease samples. The pipeline is containerized, convenient to use and can run under any system, since it is a fully automatic process in Docker container form. It is also open, and can be easily customized with user intervention points, such as for updating reference files and different software or versions. The pipeline has been tested with both human and mouse sequencing datasets, and it has generated mutations results, comparable to published results from these datasets, and reproducible across heterogeneous hardware platforms. The pipeline DNAp, funded by the US Food and Drug Administration (FDA), was developed for analyzing DNA sequencing data of FDA. Here we make DNAp an open source, with the software and documentation available to the public at http://bioinformatics.astate.edu/dna pipeline/ . PMID- 29717216 TI - Scandium doping brings speed improvement in Sb2Te alloy for phase change random access memory application. AB - Phase change random access memory (PCRAM) has gained much attention as a candidate for nonvolatile memory application. To develop PCRAM materials with better properties, especially to draw closer to dynamic random access memory (DRAM), the key challenge is to research new high-speed phase change materials. Here, Scandium (Sc) has been found it is helpful to get high-speed and good stability after doping in Sb2Te alloy. Sc0.1Sb2Te based PCRAM cell can achieve reversible switching by applying even 6 ns voltage pulse experimentally. And, Sc doping not only promotes amorphous stability but also improves the endurance ability comparing with pure Sb2Te alloy. Moreover, according to DFT calculations, strong Sc-Te bonds lead to the rigidity of Sc centered octahedrons, which may act as crystallization precursors in recrystallization process to boost the set speed. PMID- 29717218 TI - Ganetespib targets multiple levels of the receptor tyrosine kinase signaling cascade and preferentially inhibits ErbB2-overexpressing breast cancer cells. AB - Although ErbB2-targeted therapeutics have significantly improved ErbB2+ breast cancer patient outcomes, therapeutic resistance remains a significant challenge. Therefore, the development of novel ErbB2-targeting strategies is necessary. Importantly, ErbB2 is a sensitive client protein of heat shock protein 90 (HSP90), which regulates client protein folding, maturation, and stabilization. HSP90 inhibition provides an alternative therapeutic strategy for ErbB2-targeted degradation. In particular, ganetespib, a novel HSP90 inhibitor, is a promising agent for ErbB2+ cancers. Nevertheless, the anti-cancer efficacy and clinical application of ganetespib for ErbB2+ breast cancer is largely unknown. In our study, we examined the anti-cancer effects of ganetespib on ErbB2+ BT474 and SKBR3 breast cancer cells, and isogenic paired cancer cell lines with lentivirus mediated ErbB2 overexpression. Ganetespib potently inhibited cell proliferation, cell cycle progression, survival, and activation/phosphorylation of ErbB2 and key downstream effectors in ErbB2+ breast cancer cells. Moreover, ganetespib decreased the total protein levels of HSP90 client proteins and reduced ErbB2 protein half-life. ErbB2-overexpressing cancer cells were also more sensitive to ganetespib-mediated growth inhibition than parental cells. Ganetespib also strikingly potentiated the inhibitory effects of lapatinib in BT474 and SKBR3 cells. Ultimately, our results support the application of ganetespib-mediated HSP90 inhibition as a promising therapeutic strategy for ErbB2+ breast cancer. PMID- 29717217 TI - Progression of Post-Traumatic Osteoarthritis in rat meniscectomy models: Comprehensive monitoring using MRI. AB - Knee injury often triggers post-traumatic osteoarthritis (PTOA) that affects articular cartilage (AC), subchondral bone, meniscus and the synovial membrane. The available treatments for PTOA are largely ineffective due to late diagnosis past the "treatment window". This study aimed to develop a detailed understanding of the time line of the progression of PTOA in murine models through longitudinal observation of the femorotibial joint from the onset of the disease to the advanced stage. Quantitative magnetic resonance microimaging (uMRI) and histology were used to evaluate PTOA-associated changes in the knee joints of rats subjected to knee meniscectomy. Systematic longitudinal changes in the articular cartilage thickness, cartilage T2 and the T2 of epiphysis within medial condyles of the tibia were all found to be associated with the development of PTOA in the animals. The following pathogenesis cascade was found to precede advanced PTOA: meniscal injury -> AC swelling -> subchondral bone remodelling -> proteoglycan depletion -> free water influx -> cartilage erosion. Importantly, the imaging protocol used was entirely MRI-based. This protocol is potentially suitable for whole-knee longitudinal, non-invasive assessment of the development of OA. The results of this work will inform the improvement of the imaging methods for early diagnosis of PTOA. PMID- 29717219 TI - Proteomic differences between focal and diffuse traumatic brain injury in human brain tissue. AB - The early molecular response to severe traumatic brain injury (TBI) was evaluated using biopsies of structurally normal-appearing cortex, obtained at location for intracranial pressure (ICP) monitoring, from 16 severe TBI patients. Mass spectrometry (MS; label free and stable isotope dimethyl labeling) quantitation proteomics showed a strikingly different molecular pattern in TBI in comparison to cortical biopsies from 11 idiopathic normal pressure hydrocephalus patients. Diffuse TBI showed increased expression of peptides related to neurodegeneration (Tau and Fascin, p < 0.05), reduced expression related to antioxidant defense (Glutathione S-transferase Mu 3, Peroxiredoxin-6, Thioredoxin-dependent peroxide reductase; p < 0.05) and increased expression of potential biomarkers (e.g. Neurogranin, Fatty acid-binding protein, heart p < 0.05) compared to focal TBI. Proteomics of human brain biopsies displayed considerable molecular heterogeneity among the different TBI subtypes with consequences for the pathophysiology and development of targeted treatments for TBI. PMID- 29717220 TI - Conserved and novel responses to cytokinin treatments during flower and fruit development in Brassica napus and Arabidopsis thaliana. AB - Hormones are an important component in the regulatory networks guiding plant development. Cytokinins are involved in different physiological and developmental processes in plants. In the model plant Arabidopsis thaliana, cytokinin application during gynoecium development produces conspicuous phenotypes. On the other hand, Brassica napus, also known as canola, is a crop plant belonging to the Brassicaceae family, as A. thaliana. This makes B. napus a good candidate to study whether the cytokinin responses observed in A. thaliana are conserved in the same plant family. Here, we observed that cytokinin treatment in B. napus affects different traits of flower and fruit development. It increases ovule and seed number, affects stamen filament elongation and anther maturation, and causes a conspicuous overgrowth of tissue in petals and gynoecia. Furthermore, cytokinin recovers replum development in both wild type B. napus and in the A. thaliana rpl ntt double mutant, in which no replum is visible. These results indicate both conserved and novel responses to cytokinin in B. napus. Moreover, in this species, some cytokinin-induced phenotypes are inherited to the next, untreated generation, suggesting that cytokinins may trigger epigenetic modifications. PMID- 29717221 TI - Publisher Correction: Periodic and transient motions of large woodpeckers. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29717222 TI - Paraneoplastic limbic encephalitis associated with lung cancer. AB - Paraneoplastic limbic encephalitis (PLE) is a rare autoimmune neurological syndrome observed in lung cancer patients. We retrospectively investigated the clinical characteristics, treatment responses, and prognoses in 16 PLE patients who were subsequently diagnosed with lung cancer. Fifteen patients initially presented with disturbance of consciousness, 13 with disorientation, and 12 with seizures. Thirteen patients had autoantibodies, including eight with gamma aminobutyric acid B receptor (GABABR) antibodies and eight with Hu antibodies. PET-CT revealed lung neoplasms in 13 patients, nine of whom exhibited abnormal metabolic activity in the temporal lobe and hippocampus. Fifteen cases were confirmed as limited-stage small cell lung cancer and one as stage IV large cell neuroendocrine carcinoma. Eleven patients received immunomodulatory therapy, and four showed neurological improvement, who all had antibodies against GABABR. Fifteen patients received chemotherapy, of which 14 maintained or improved their PLE status. The overall cancer response rate was 75%, and two-year overall survival was 74.7%. Our results suggest patients with GABAB encephalitis might respond better to immunotherapy than the classical PLE patients with anti-Hu antibodies. Anti-cancer treatment could further improve neurological symptoms. Lung cancer patients with PLE, especially those in limited stage, might have better outcome due to earlier diagnosis and prompt anti-cancer treatment. PMID- 29717223 TI - Effect of the sodium-glucose cotransporter 2 inhibitor luseogliflozin on pancreatic beta cell mass in db/db mice of different ages. AB - To examine the effects of luseogliflozin, a sodium-glucose cotransporter 2 inhibitor, on pancreatic beta cell mass in db/db mice of different ages. db/db mice aged 6, 10, 14 and 24 weeks old were fed either standard chow (control group) or standard chow containing 0.01% luseogliflozin (luseo group). After 4 weeks, immunohistochemistry and gene expression tests were conducted. In 6-week old db/db mice, immunohistochemistry revealed a significant increase in beta cell mass in the luseo group compared with the control group after 4 weeks of treatment. Gene expression profiling of isolated islets showed upregulation Mafa, Pdx1, Ki67 and Ccnd2 in the luseo group. Beta cell mass decreased with age in db/db mice in the control group. Beta cell mass in the luseo group significantly increased compared with the control group regardless of age, although beta cell mass in the 28-week-old luseo group (4 weeks of treatment in 24-week-old db/db mice) was significantly lower than in the 10-week-old luseo group (4 weeks of treatment in 6-week-old db/db mice). Luseogliflozin preserved beta cell mass in db/db mice. The protective effect was more evident in the earlier phase of diabetes. PMID- 29717224 TI - An Optical Method for the In-Vivo Characterization of the Biomechanical Response of the Right Ventricle. AB - The intraoperative in-vivo mechanical function of the left ventricle has been studied thoroughly using echocardiography in the past. However, due to technical and anatomical issues, the ultrasound technology cannot easily be focused on the right side of the heart during open-heart surgery, and the function of the right ventricle during the intervention remains largely unexplored. We used optical imaging and digital image correlation for the characterization of the right ventricle motion and deformation during open-heart surgery. This work is a pilot study focusing on one patient only with the aim of establishing the framework for long term research. These experiments show that optical imaging and the analysis of the images can be used to obtain similar parameters, and partly at higher accuracy, for describing the mechanical functioning of the heart as the ultrasound technology. This work describes the optical imaging based method to characterize the mechanical response of the heart in-vivo, and offers new insight into the mechanical function of the right ventricle. PMID- 29717227 TI - Children passively allow other's rule violations in cooperative situations. AB - Recent studies in developmental psychology have revealed the developmental origins of cooperation. Although such studies regard cooperation as a pro-social behavior, studies on adults have found a negative aspect: cooperation sometimes promotes unethical behavior. Adults also exhibit altruistic cheating, even though their cheating might not actually benefit them. However, the development of negative aspects of cooperation remains unclear. Our study examined whether 7 year-old children engage in negative aspects of cooperation from two aspects using a peeking paradigm. Specifically, Experiment 1 examined children's negative aspects of cooperation from the perspective of collaboration and Experiment 2 examined altruistic behavior. Results of Experiment 1 revealed that children kept the cheating of a collaborative partner secret even though they did not actively cheat themselves. In Experiment 2, children also kept the partner's cheating secret even when violations did not provide any reward to themselves, if the predefined reward was high. In contrast, children did not keep the cheating secret if the predefined reward was low. Overall, our findings suggest that even 7-year-olds tend to act as if cooperating is more important than following rules that are compatible and exhibit negative aspects of cooperation. PMID- 29717225 TI - Experimental Zika Virus Infection in the Pregnant Common Marmoset Induces Spontaneous Fetal Loss and Neurodevelopmental Abnormalities. AB - During its most recent outbreak across the Americas, Zika virus (ZIKV) was surprisingly shown to cause fetal loss and congenital malformations in acutely and chronically infected pregnant women. However, understanding the underlying pathogenesis of ZIKV congenital disease has been hampered by a lack of relevant in vivo experimental models. Here we present a candidate New World monkey model of ZIKV infection in pregnant marmosets that faithfully recapitulates human disease. ZIKV inoculation at the human-equivalent of early gestation caused an asymptomatic seroconversion, induction of type I/II interferon-associated genes and proinflammatory cytokines, and persistent viremia and viruria. Spontaneous pregnancy loss was observed 16-18 days post-infection, with extensive active placental viral replication and fetal neurocellular disorganization similar to that seen in humans. These findings underscore the key role of the placenta as a conduit for fetal infection, and demonstrate the utility of marmosets as a highly relevant model for studying congenital ZIKV disease and pregnancy loss. PMID- 29717228 TI - Accurate estimation of a phase diagram from a single STM image. AB - We propose a new approach to constructing a phase diagram using the effective Hamiltonian derived only from a single real-space image produced by scanning tunneling microscopy (STM). Currently, there have been two main methods to construct phase diagrams in material science: ab initio calculations and CALPHAD with thermodynamic information obtained by experiments and/or theoretical calculations. Although the two methods have successfully revealed a number of unsettled phase diagrams, their results sometimes contradicted when it is difficult to construct an appropriate Hamiltonian that captures the characteristics of materials, e.g., for a system consisting of multiple-scale objects whose interactions are essential to the system's characteristics. Meanwhile, the advantage of our approach over existing methods is that it can directly and uniquely determine the effective Hamiltonian without any thermodynamic information. The validity of our approach is demonstrated through an Mg-Zn-Y long-period stacking-ordered structure, which is a challenging system for existing methods, leading to contradictory results. Our result successfully reproduces the ordering tendency seen in STM images that previous theoretical study failed to reproduce and clarifies its previously unknown phase diagram. Thus, our approach can be used to clear up contradictions shown by existing methods. PMID- 29717226 TI - Aldosterone Impairs Mitochondrial Function in Human Cardiac Fibroblasts via A Kinase Anchor Protein 12. AB - Aldosterone (Aldo) contributes to mitochondrial dysfunction and cardiac oxidative stress. Using a proteomic approach, A-kinase anchor protein (AKAP)-12 has been identified as a down-regulated protein by Aldo in human cardiac fibroblasts. We aim to characterize whether AKAP-12 down-regulation could be a deleterious mechanism which induces mitochondrial dysfunction and oxidative stress in cardiac cells. Aldo down-regulated AKAP-12 via its mineralocorticoid receptor, increased oxidative stress and induced mitochondrial dysfunction characterized by decreased mitochondrial-DNA and Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1alpha) expressions in human cardiac fibroblasts. CRISPR/Cas9-mediated knock-down of AKAP-12 produced similar deleterious effects in human cardiac fibroblasts. CRISPR/Cas9-mediated activation of AKAP-12 blunted Aldo effects on mitochondrial dysfunction and oxidative stress in human cardiac fibroblasts. In Aldo-salt-treated rats, cardiac AKAP-12, mitochondrial-DNA and PGC-1alpha expressions were decreased and paralleled increased oxidative stress. In myocardial biopsies from patients with aortic stenosis (AS, n = 26), AKAP-12, mitochondrial-DNA and PGC-1alpha expressions were decreased as compared to Controls (n = 13). Circulating Aldo levels inversely correlated with cardiac AKAP 12. PGC-1alpha positively associated with AKAP-12 and with mitochondrial-DNA. Aldo decreased AKAP-12 expression, impairing mitochondrial biogenesis and increasing cardiac oxidative stress. AKAP-12 down-regulation triggered by Aldo may represent an important event in the development of mitochondrial dysfunction and cardiac oxidative stress. PMID- 29717231 TI - EpiTOFing ageing. PMID- 29717232 TI - Global time-size distribution of volcanic eruptions on Earth. AB - Volcanic eruptions differ enormously in their size and impacts, ranging from quiet lava flow effusions along the volcano flanks to colossal events with the potential to affect our entire civilization. Knowledge of the time and size distribution of volcanic eruptions is of obvious relevance for understanding the dynamics and behavior of the Earth system, as well as for defining global volcanic risk. From the analysis of recent global databases of volcanic eruptions extending back to more than 2 million years, I show here that the return times of eruptions with similar magnitude follow an exponential distribution. The associated relative frequency of eruptions with different magnitude displays a power law, scale-invariant distribution over at least six orders of magnitude. These results suggest that similar mechanisms subtend to explosive eruptions from small to colossal, raising concerns on the theoretical possibility to predict the magnitude and impact of impending volcanic eruptions. PMID- 29717235 TI - Fibre aids fight against nasty gut infection. PMID- 29717236 TI - More whiplash weather in store for California. PMID- 29717230 TI - Therapeutic developments in pancreatic cancer: current and future perspectives. AB - The overall 5-year survival for pancreatic cancer has changed little over the past few decades, and pancreatic cancer is predicted to be the second leading cause of cancer-related mortality in the next decade in Western countries. The past few years, however, have seen improvements in first-line and second-line palliative therapies and considerable progress in increasing survival with adjuvant treatment. The use of biomarkers to help define treatment and the potential of neoadjuvant therapies also offer opportunities to improve outcomes. This Review brings together information on achievements to date, what is working currently and where successes are likely to be achieved in the future. Furthermore, we address the questions of how we should approach the development of pancreatic cancer treatments, including those for patients with metastatic, locally advanced and borderline resectable pancreatic cancer, as well as for patients with resected tumours. In addition to embracing newer strategies comprising genomics, stromal therapies and immunotherapies, conventional approaches using chemotherapy and radiotherapy still offer considerable prospects for greater traction and synergy with evolving concepts. PMID- 29717229 TI - Dietary divergence is associated with increased intra-specific competition in a marine predator. AB - Optimal foraging theory predicts that when food is plentiful all individuals should take a small range of preferred prey types, but as competition increases less preferred prey will be included in the diet. This dietary switching may not be uniform among individuals, which produces discrete dietary clusters. We tested this hypothesis for gentoo penguins at Bird Island, South Georgia, using stable isotope analysis and biologging. Competition, in the form of the density of foraging dives, increased markedly from incubation to chick-rearing owing to increased foraging effort. Birds responded behaviourally by exploiting a greater portion of the available foraging radius and increasing dive depths. Dietary niche width doubled and two discrete dietary clusters appeared; one comprising birds that consumed mostly krill and another that ate a greater proportion of demersal fish. There were no differences in morphology between the dietary classes, but birds in the fish class had a tendency to dive deeper, which suggests a behavioural basis for specialization. Our findings are consistent with the hypothesis that intra-specific competition expands the population's dietary niche width and drives divergence in diets among individuals. PMID- 29717237 TI - Kids beat elite runners in fitness tests. PMID- 29717240 TI - Early stick insect was a master of disguise. PMID- 29717238 TI - Arctic ice carries heavy freight of plastic. PMID- 29717241 TI - Billion-star map of Milky Way set to transform astronomy. PMID- 29717243 TI - Abandoned fort holds clues to mass slaughter. PMID- 29717245 TI - Souped-up T cells home in on cancer. PMID- 29717246 TI - Measuring the Milky Way's mind-boggling mass. PMID- 29717239 TI - Mars quakes set to reveal tantalizing clues to planet's early years. PMID- 29717234 TI - Effect of in-situ aged and fresh biochar on soil hydraulic conditions and microbial C use under drought conditions. AB - Biochar (BC) amendments may be suitable to increase the ecosystems resistance to drought due to their positive effects on soil water retention and availability. We investigated the effect of BC in situ ageing on water availability and microbial parameters of a grassland soil. We used soil containing 13C labeled BC and determined its water holding capacity, microbial biomass and activity during a 3 months incubation under optimum and drought conditions. Our incubation experiment comprised three treatments: soil without BC (Control), soil containing aged BC (BCaged) and soil containing fresh BC (BCfresh), under optimum soil water (pF 1.8) and drought conditions (pF 3.5). Under optimum water as well as drought conditions, soils containing BC showed higher soil organic carbon (SOC) mineralization as compared to control soil. Moreover, BC effects on the soil water regime increase upon in situ aging. Native SOC mineralization increased most for soils containing BCaged. The BCaged led to improved C use under drought as compared to the other treatments. We conclude that BC addition to soils can ameliorate their water regime, especially under drought conditions. This beneficial effect of BC increases upon its aging, which also improved native substrate availability. PMID- 29717242 TI - Giving at-risk children pre-emptive antibiotics reduces deaths. PMID- 29717244 TI - Physicists in Earth's remotest corners race to reproduce 'cosmic dawn' signal. PMID- 29717248 TI - Helium discovered in the tail of an exoplanet. PMID- 29717254 TI - To treat pain, study people in all their complexity. PMID- 29717257 TI - Real-world illness requires medical multitasking. PMID- 29717252 TI - Unconventional lifestyle found in island bird. PMID- 29717259 TI - Surprising safety outcomes of urate-lowering therapy. PMID- 29717250 TI - Protein and gel combined to make hyperexpandable crystals. PMID- 29717253 TI - Brazil's lawmakers renew push to weaken environmental rules. PMID- 29717249 TI - Evolutionary insights from an ancient bird. PMID- 29717256 TI - Scientists downsize bold plan to make human genome from scratch. PMID- 29717260 TI - A modified gene trap approach for improved high-throughput cancer drug discovery. AB - While advances in laboratory automation has dramatically increased throughout of compound screening efforts, development of robust cell-based assays in relevant disease models remain resource-intensive and time-consuming, presenting a bottleneck to drug discovery campaigns. To address this issue, we present a modified gene trap approach to efficiently generate pathway-specific reporters that result in a robust "on" signal when the pathway of interest is inhibited. In this proof-of-concept study, we used vemurafenib and trametinib to identify traps that specifically detect inhibition of the mitogen-activated protein kinase (MAPK) pathway in a model of BRAFV600E driven human malignant melanoma. We demonstrate that insertion of our trap into particular loci results in remarkably specific detection of MAPK pathway inhibitors over compounds targeting any other pathway or cellular function. The accuracy of our approach was highlighted in a pilot screen of ~6000 compounds where 40 actives were detected, including 18 MEK, 10 RAF, and 3 ERK inhibitors along with a few compounds representing previously under-characterized inhibitors of the MAPK pathway. One such compound, bafetinib, a second generation BCR/ABL inhibitor, reduced phosphorylation of ERK and when combined with trametinib, both in vitro and in vivo, reduced growth of vemurafenib resistant melanoma cells. While piloted in a model of BRAF-driven melanoma, our results set the stage for using this approach to rapidly generate reporters against any transcriptionally active pathway across a wide variety of disease-relevant cell-based models to expedite drug discovery efforts. PMID- 29717261 TI - Antagonizing CD105 enhances radiation sensitivity in prostate cancer. AB - Radiation therapy is the primary intervention for nearly half of the patients with localized advanced prostate cancer and standard of care for recurrent disease following surgery. The development of radiation-resistant disease is an obstacle for nearly 30-50% of patients undergoing radiotherapy. A better understanding of mechanisms that lead to radiation resistance could aid in the development of sensitizing agents to improve outcome. Here we identified a radiation-resistance pathway mediated by CD105, downstream of BMP and TGF-beta signaling. Antagonizing CD105-dependent BMP signaling with a partially humanized monoclonal antibody, TRC105, resulted in a significant reduction in clonogenicity when combined with irradiation. In trying to better understand the mechanism for the radio-sensitization, we found that radiation-induced CD105/BMP signaling was sufficient and necessary for the upregulation of sirtuin 1 (SIRT1) in contributing to p53 stabilization and PGC-1alpha activation. Combining TRC105 with irradiation delayed DNA damage repair compared to irradiation alone. However, in the absence of p53 function, combining TRC105 and radiation resulted in no reduction in clonogenicity compared to radiation alone, despite similar reduction of DNA damage repair observed in p53-intact cells. This suggested DNA damage repair was not the sole determinant of CD105 radio-resistance. As cancer cells undergo an energy deficit following irradiation, due to the demands of DNA and organelle repair, we examined SIRT1's role on p53 and PGC-1alpha with respect to glycolysis and mitochondrial biogenesis, respectively. Consequently, blocking the CD105-SIRT1 axis was found to deplete the ATP stores of irradiated cells and cause G2 cell cycle arrest. Xenograft models supported these findings that combining TRC105 with irradiation significantly reduces tumor size over irradiation alone (p value = 10-9). We identified a novel synthetic lethality strategy of combining radiation and CD105 targeting to address the DNA repair and metabolic addiction induced by irradiation in p53-functional prostate cancers. PMID- 29717262 TI - Glycosylation controls cooperative PECAM-VEGFR2-beta3 integrin functions at the endothelial surface for tumor angiogenesis. AB - Most of the angiogenesis inhibitors clinically used in cancer treatment target the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) pathway. However, the current strategies for treating angiogenesis have limited efficacy. The issue of how to treat angiogenesis and endothelial dysfunction in cancer remains a matter of substantial debate. Here we demonstrate a glycosylation dependent regulatory mechanism for tumor angiogenesis. St6gal1-/- mice, lacking the alpha2,6-sialylation enzyme, were shown to exhibit impaired tumor angiogenesis through enhanced endothelial apoptosis. In a previous study, St6gal1 /- endothelial cells exhibited a reduction in the cell surface residency of platelet endothelial cell adhesion molecule (PECAM). In this study, we found that cooperative functionality of PECAM-VEGFR2-integrin beta3 was disturbed in St6gal1 /- mice. First, cell surface PECAM-VEGFR2 complexes were lost, and both VEGFR2 internalization and the VEGFR-dependent signaling pathway were enhanced. Second, enhanced anoikis was observed, suggesting that the absence of alpha2,6-sialic acid leads to dysregulated integrin signaling. Notably, ectopic expression of PECAM increased cell surface integrin-beta3, indicating that the reduction of cell surface integrin-beta3 involves loss-of-endothelial PECAM. The results suggest that the cell surface stability of these glycoproteins is significantly reduced by the lack of alpha2,6-sialic acid, leading to abnormal signal transduction. The present findings highlight that alpha2,6-sialylation is critically involved in endothelial survival by controlling the cell surface stability and signal transduction of angiogenic molecules, and could be a novel target for anti-angiogenesis therapy. PMID- 29717258 TI - Robustness of cortical and subcortical processing in the presence of natural masking sounds. AB - Processing of ethologically relevant stimuli could be interfered by non-relevant stimuli. Animals have behavioral adaptations to reduce signal interference. It is largely unexplored whether the behavioral adaptations facilitate neuronal processing of relevant stimuli. Here, we characterize behavioral adaptations in the presence of biotic noise in the echolocating bat Carollia perspicillata and we show that the behavioral adaptations could facilitate neuronal processing of biosonar information. According to the echolocation behavior, bats need to extract their own signals in the presence of vocalizations from conspecifics. With playback experiments, we demonstrate that C. perspicillata increases the sensory acquisition rate by emitting groups of echolocation calls when flying in noisy environments. Our neurophysiological results from the auditory midbrain and cortex show that the high sensory acquisition rate does not vastly increase neuronal suppression and that the response to an echolocation sequence is partially preserved in the presence of biosonar signals from conspecifics. PMID- 29717263 TI - DNA methyltransferase 3A isoform b contributes to repressing E-cadherin through cooperation of DNA methylation and H3K27/H3K9 methylation in EMT-related metastasis of gastric cancer. AB - DNA methyltransferase 3A (DNMT3A) has been recognised as a key element of epigenetic regulation in normal development, and the aberrant regulation of DNMT3A is implicated in multiple types of cancers, especially haematological malignancies. However, its clinical significance and detailed functional role in solid tumours remain unknown, although abnormal expression has gained widespread attention in these cancers. Here, we show that DNMT3A isoform b (DNMT3Ab), a member of the DNMT3A isoform family, is critical for directing epithelial mesenchymal transition (EMT)-associated metastasis in gastric cancer (GC). DNMT3Ab is positively linked to tumour-node-metastasis (TNM) stage, lymph node metastasis and poor prognosis in GC patients. Overexpression of DNMT3Ab promotes GC cell migration and invasion as well as EMT through repression of E-cadherin. Meanwhile, DNMT3Ab promotes lung metastasis of GC in vivo. Mechanistic studies indicate that DNMT3Ab mediates the epigenetic inaction of the E-cadherin gene via DNA hypermethylation and histone modifications of H3K9me2 and H3K27me3. Depletion of DNMT3Ab effectively restores the expression of E-cadherin and reverses TGF beta-induced EMT by reducing DNA methylation, H3K9me2 and H3K27me3 levels at the E-cadherin promoter. Importantly, DNMT3Ab cooperated with H3K9me2 and H3K27me3 contributes to the transcriptional regulation of E-cadherin in a Snail-dependent manner. Further, gene expression profiling analysis indicates that multiple metastasis-associated genes and oncogenic signalling pathways are regulated in response to DNMT3Ab overexpression. These results identify DNMT3Ab as a crucial regulator of metastasis-related genes in GC. Targeting the DNMT3Ab/Snail/E cadherin axis may provide a promising therapeutic strategy in the treatment of metastatic GC with high DNMT3Ab expression. PMID- 29717233 TI - Diverse developmental pathways of intestinal intraepithelial lymphocytes. AB - The intestinal epithelial barrier is patrolled by resident intraepithelial lymphocytes (IELs) that are involved in host defence against pathogens, wound repair and homeostatic interactions with the epithelium, microbiota and nutrients. Intestinal IELs are one of the largest populations of lymphocytes in the body and comprise several distinct subsets, the identity and lineage relationships of which have long remained elusive. Here, we review advances in unravelling the complexity of intestinal IEL populations, which comprise conventional alphabeta T cell receptor (TCRalphabeta)+ subsets, unconventional TCRalphabeta+ and TCRgammadelta+ subsets, group 1 innate lymphoid cells (ILC1s) and ILC1-like cells. Although these intestinal IEL lineages have partially overlapping effector programmes and recognition properties, they have strikingly different developmental pathways. We suggest that evolutionary pressure has driven the recurrent generation of cytolytic effector lymphocytes to protect the intestinal epithelial layer, but they may also precipitate intestinal inflammatory disorders, such as coeliac disease. PMID- 29717268 TI - Adrenomedullary function, obesity and permissive influences of catecholamines on body mass in patients with chromaffin cell tumours. AB - BACKGROUND: Obesity-associated activation of sympathetic nervous outflow is well documented, whereas involvement of dysregulated adrenomedullary hormonal function in obesity is less clear. This study assessed relationships of sympathoadrenal function with indices of obesity and influences of circulating catecholamines on body mass. METHODS: Anthropometric and clinical data along with plasma and 24-h urine samples were collected from 590 volunteers and 1368 patients tested for phaeochromocytoma and paraganglioma (PPGL), among whom tumours were diagnosed in 210 individuals. RESULTS: Among patients tested for PPGL, those with tumours less often had a body mass index (BMI) above 30 kg/m2 (12 vs. 31%) and more often a BMI under 25 kg/m2 (56 vs. 32%) than those without tumours (P < 0.0001). Urinary outputs of catecholamines in patients with PPGL were negatively related to BMI (r = -0.175, P = 0.0133). Post-operative weight gain (P < 0.0001) after resection of PPGL was positively related to presurgical tumoural catecholamine output (r = 0.257, P = 0.0101). Higher BMI in men and women and percent body fat in women of the volunteer group were associated with lower plasma concentrations and urinary outputs of adrenaline and metanephrine, the former indicating obesity-related reduced adrenaline secretion and the latter obesity-related reduced adrenomedullary adrenaline stores. Daytime activity was associated with substantial increases in urinary adrenaline and noradrenaline excretion, with blunted responses in obese subjects. CONCLUSIONS: The findings in patients with PPGL support an influence of high circulating catecholamines on body weight. Additional associations of adrenomedullary dysfunction with obesity raise the possibility of a permissive influence of the adrenal medulla on the regulation of body weight. PMID- 29717269 TI - Multiple genetic variations confer risks for obesity and type 2 diabetes mellitus in arab descendants from UAE. AB - BACKGROUND: The United Arab Emirates (UAE) is one of the countries most threatened with obesity. Here we investigated associations between hundreds of single-nucleotide polymorphisms (SNPs) and the following obesity indicators: body mass index (BMI), waist circumference (WC), and height. We also investigated the associations between obesity-related genes with type 2 diabetes mellitus (T2DM). METHODS: We tested 87, 58, and 586 SNPs in a previous genome-wide significance level for associations with BMI (n = 880), WC (n = 455), and height (n = 897), respectively. For each trait, we used normally transformed Z scores and tested them with SNPs using linear regression models that incorporated age and gender as covariates. The weighted polygenic risk scores for significant SNPs for each trait were tested with the corresponding Z scores using linear regression models with the same covariates. We further tested 145 obesity loci with T2DM (464 cases, 415 controls) using a logistic regression model including age, gender, and BMI Z scores as covariates. RESULTS: The Mean BMI was 29.39 kg/m2, and mean WC was 103.66 cm. Hypertension and dyslipidemia were common obesity comorbidities (>60%). The best associations for BMI was in FTO, LOC284260 and USP37, and for WC in RFX7 and MYEOV. For height, the best association was in NSD1 followed by MFAP2 and seven other loci. The polygenic scores revealed stronger associations for each trait than individual SNPs; although they could only explain <1% of the traits' Z scores variations. For T2DM, the strongest associations were with the TCF7L2 and MC4R loci (P < 0.01, OR ~1.70), with novel associations detected with KCNK3 and RARB. CONCLUSIONS: In this first study of Arab descendants, we confirmed several known obesity (FTO, USP37, and RFX7), height (NSD1, MFAP2), and T2DM (TCF7L2, MC4R) associations; and report novel associations, like KCNK3 and RARB for T2DM. PMID- 29717266 TI - Is weight associated with severity of acute respiratory illness? AB - BACKGROUND/OBJECTIVES: Obesity was an independent risk factor for severe disease in hospitalized adults during the 2009 pandemic H1N1 influenza season. Few studies have investigated the association between weight and severity of acute respiratory illnesses in children or in adults seeking care in the emergency department (ED) during other winter respiratory seasons. SUBJECTS/METHODS: We prospectively and systematically enrolled patients >=2 years of age who presented to the ED or inpatient setting in a single geographic region with fever/acute respiratory illness over four consecutive winter respiratory seasons (2010-2014). We collected demography, height and weight, and high risk co-morbid conditions. Multivariable logistic regression was used for prediction of hospital admission (primary outcome), length of stay and supplemental oxygen requirement among those hospitalized, and antibiotic prescription (secondary outcomes). RESULTS: We enrolled 3560 patients (N = 749 children, 2811 adults), 1405 (39%) with normal weight, 860 (24%) with overweight, and 1295 (36%) with obesity. Following multivariable logistic regression, very young or very old age (p < 0.001) and high-risk conditions (p < 0.001) predicted hospitalization. Risk of hospitalization was decreased for adults with overweight [aOR 0.8 (95% CI 0.6 1.0)], class 1 obesity [aOR 0.7 (95% CI 0.5-1.0)], and class 2 obesity [aOR 0.6 (95% CI 0.4-0.8)] compared to normal-weight. Class 3 obesity was associated with supplemental oxygen requirement in adults [aOR 1.6 (95% CI 1.1-2.5)]. No association was seen in children. CONCLUSION: Overweight and obesity were not associated with increased risk of hospitalization during winter respiratory seasons in children or adults. PMID- 29717264 TI - Epigenetic silencing of miR-483-3p promotes acquired gefitinib resistance and EMT in EGFR-mutant NSCLC by targeting integrin beta3. AB - All lung cancers patients with epidermal growth factor receptor (EGFR) mutation inevitably develop acquired resistance to EGFR tyrosine kinase inhibitors (TKI). In up to 30% of cases, the mechanism underlying acquired resistance remains unknown. MicroRNAs (miRNAs) is a group of small non-coding RNAs commonly dysregulated in human cancers and have been implicated in therapy resistance. The aim of this study was to understand the roles of novel miRNAs in acquired EGFR TKI resistance in EGFR-mutant non-small cell lung cancer (NSCLC). Here, we reported the evidence of miR-483-3p silencing and epithelial-to-mesenchymal transition (EMT) phenotype in both in vitro and in vivo EGFR-mutant NSCLC models with acquired resistance to gefitinib. In those tumor models, forced expression of miR-483-3p efficiently increased sensitivity of gefitinib-resistant lung cancer cells to gefitinib by inhibiting proliferation and promoting apoptosis. Moreover, miR-483-3p reversed EMT and inhibited migration, invasion, and metastasis of gefitinib-resistant lung cancer cells. Mechanistically, miR-483-3p directly targeted integrin beta3, and thus repressed downstream FAK/Erk signaling pathway. Furthermore, the silencing of miR-483-3p in gefitinib-resistant lung cancer cells was due to hypermethylation of its own promoter. Taken together, our data identify miR-483-3p as a promising target for combination therapy to overcome acquired EGFR TKI resistance in EGFR-mutant NSCLC. PMID- 29717270 TI - Biological and psychological mediators of the relationships between fat mass, fat free mass and energy intake. AB - BACKGROUND: While recent studies in humans indicate that fat-free mass (FFM) is closely associated with energy intake (EI) when in energy balance, associations between fat mass (FM) and EI are inconsistent. OBJECTIVES: The present study used a cross-sectional design to examine the indirect and direct effects of FFM, FM and resting metabolic rate (RMR) on EI in individuals at or close to energy balance. METHODS: Data for 242 individuals (114 males; 128 females; BMI = 25.7 +/ 4.9 kg/m2) were collated from the non-intervention baseline conditions of five studies employing common measures of body composition (air-displacement plethysmography), RMR (indirect calorimetry) and psychometric measures of eating behaviours (Dutch Eating Behaviour Questionnaire). Daily EI (weighed dietary records) and energy expenditure (flex heart rate) were measured for 6-7 days. Sub analyses were conducted in 71 individuals who had additional measures of body composition (dual-energy X-ray absorptiometry) and fasting glucose, insulin and leptin. RESULTS: After adjusting for age, sex and study, linear regression and mediation analyses indicated that the effect of FFM on EI was mediated by RMR (P < 0.05). FM also independently predicted EI, with path analysis indicating a positive indirect association (mediated by RMR; P < 0.05), and a stronger direct negative association (P < 0.05). Leptin, insulin and insulin resistance failed to predict EI, but cognitive restraint was a determinant of EI and partially mediated the association between FM and EI (P < 0.05). CONCLUSIONS: While the association between FFM and EI was mediated by RMR, FM influenced EI via two separate and opposing pathways; an indirect 'excitatory' effect (again, mediated by RMR), and a stronger direct 'inhibitory' effect. Psychological factors such as cognitive restraint remain robust predictors of EI when considered alongside physiological determinants of EI, and indeed, have the potential to play a mediating role in the overall expression of EI. PMID- 29717265 TI - Identification of a MET-eIF4G1 translational regulation axis that controls HIF 1alpha levels under hypoxia. AB - Poor oxygenation is a common hallmark of solid cancers that strongly associates with aggressive tumor progression and treatment resistance. While a hypoxia inducible factor 1alpha (HIF-1alpha)-associated transcriptional overexpression of the hepatocyte growth factor (HGF) receptor tyrosine kinase (RTK) MET has been previously documented, any regulation of the HIF-1alpha system through MET downstream signaling in hypoxic tumors has not been yet described. By using MET driven in vitro as well as ex vivo tumor organotypic fresh tissue models we report that MET targeting results in depletion of HIF-1alpha and its various downstream targets. Mechanistically, we provide evidence that MET regulates HIF 1alpha levels through a protein translation mechanism that relies on phosphorylation modulation of the eukaryotic initiation factor 4G1 (eIF4G1) on serine 1232 (Ser-1232). Targeted phosphoproteomics data demonstrate a significant drop in eIF4G1 Ser-1232 phosphorylation following MET targeting, which is linked to an increased affinity between eIF4G1 and eIF4E. Since phosphorylation of eIF4G1 on Ser-1232 is largely mediated through mitogen-activated protein kinase (MAPK), we show that expression of a constitutively active K-RAS variant is sufficient to abrogate the inhibitory effect of MET targeting on the HIF-1alpha pathway with subsequent resistance of tumor cells to MET targeting under hypoxic conditions. Analysis of The Cancer Genome Atlas data demonstrates frequent co expression of MET, HIF-1alpha and eIF4G1 in various solid tumors and its impact on disease-free survival of non-small cell lung cancer patients. Clinical relevance of the MET-eIF4G1-HIF-1alpha pathway is further supported by a co occurrence of their expression in common tumor regions of individual lung cancer patients. PMID- 29717271 TI - Physical activity and inactivity trajectories associated with body composition in pre-schoolers. AB - BACKGROUND/OBJECTIVES: Early childhood is characterised by rapid development and is a critical period for the establishment of activity behaviours. We aim to examine how physical activity (PA) and sedentary behaviour (SB) track during the first 5 years of life, and to investigate associations between trajectories and body composition at 5 years of age. SUBJECTS/METHODS: A total of 438 participants (50% male) wore an Actical accelerometer for 5 days at at least two of 1, 2, 3.5 and 5 years of age. Spearman correlation coefficients examined PA tracking from age 1 to 5 and trajectories of PA and SB were estimated using discrete mixture modelling. Regression models tested associations between both PA and SB trajectories and body composition measures. RESULTS: Tracking coefficients for PA ranged from r = 0.31-0.51 across the ages, with similar tracking observed for sedentary behaviour (r = 0.21-0.39). Four distinct trajectory patterns were identified separately for PA and SB: consistently low, consistently high, increasing and decreasing. BMI and waist circumference were not significantly associated with PA trajectories, but those in the consistently high activity group had significantly lower % body fat (95% CI) at age 5 (14.3%; 13.5, 15.2) than those in the consistently low (16.8%; 15.6, 18.2) or increasing (15.7%; 14.7, 16.7) groups (P = 0.017). Sedentary behaviour trajectories were not associated with any of the anthropometric measures at age 5 (P > 0.05). CONCLUSIONS: Physical activity and sedentary behaviour tracking is broadly similar from infancy to early childhood. Children with consistently higher levels of physical activity have reduced body fat at 5 years of age, although differences are relatively small. PMID- 29717267 TI - Maternal smoking during pregnancy and offspring overweight: is there a dose response relationship? An individual patient data meta-analysis. AB - BACKGROUND/OBJECTIVES: A number of meta-analyses suggest an association between any maternal smoking in pregnancy and offspring overweight obesity. Whether there is a dose-response relationship across number of cigarettes and whether this differs by sex remains unclear. SUBJECT/METHODS: Studies reporting number of cigarettes smoked during pregnancy and offspring BMI published up to May 2015 were searched. An individual patient data meta-analysis of association between the number of cigarettes smoked during pregnancy and offspring overweight (defined according to the International Obesity Task Force reference) was computed using a generalized additive mixed model with non-linear effects and adjustment for confounders (maternal weight status, breastfeeding, and maternal education) and stratification for sex. RESULTS: Of 26 identified studies, 16 authors provided data on a total of 238,340 mother-child-pairs. A linear positive association was observed between the number of cigarettes smoked and offspring overweight for up to 15 cigarettes per day with an OR increase per cigarette of 1.03, 95% CI = [1.02-1.03]. The OR flattened with higher cigarette use. Associations were similar in males and females. Sensitivity analyses supported these results. CONCLUSIONS: A linear dose-response relationship of maternal smoking was observed in the range of 1-15 cigarettes per day equally in boys and girls with no further risk increase for doses above 15 cigarettes. PMID- 29717273 TI - Identification of an episignature of human colorectal cancer associated with obesity by genome-wide DNA methylation analysis. AB - BACKGROUND: Obesity was established as a relevant modifiable risk factor in the onset and progression of colorectal cancer (CRC). This relationship could be mediated by an epigenetic regulation. OBJECTIVES: The current work aimed to explore the effects of excess body weight on the DNA methylation profile of CRC using a genome-wide DNA methylation approach and to identify an epigenetic signature of obesity-related CRC. METHODS: Fifty-six CRC-diagnosed patients (50 years) were included in the study and categorized according to their body mass index (BMI) as non-obese (BMI <= 25 kg/m2) or overweight/obese (BMI > 25 kg/m2). Data from Infinium 450k array-based methylomes of 28 CRC tumor samples were coupled with information on BMI categories. Additionally, DNA methylation results were validated in 28 CRC tumor samples. RESULTS: The analysis revealed statistically significant differences at 299 CpG sites, and they were mostly characterized as changes towards CpG hypermethylation occurring in the obese group. The 152 identified genes were involved in inflammatory and metabolic functional processes. Among these genes, novel genes were identified as epigenetically regulated in CRC depending on adiposity. ZNF397OS and ZNF543 represented the top scoring associated events that were further validated in an independent cohort and exhibited strong correlation with BMI and excellent and statistically significant efficiency in the discrimination of obese from non obese CRC patients (area under the curve >0.80; p < 0.05). CONCLUSIONS: The present study identifies a potential epigenome mark of obesity-related CRC that could be useful for precision medicine in the management of this disease taking into account adiposity as a relevant risk factor. PMID- 29717277 TI - Dechlorane Plus increases adipogenesis in 3T3-L1 and human primary preadipocytes independent of peroxisome proliferator-activated receptor gamma transcriptional activity. AB - BACKGROUND/OBJECTIVES: Polybrominated diphenyl ethers (PBDEs) are chemicals that were added to consumer products to reduce flammability but were deemed toxic and bioaccumulative and were phased out of commerce. Flame retardants (FRs) such as Dechlorane Plus (DP) were introduced as replacements. DP is being produced in high volumes and is detected in the environment, human milk, and human serum. Although human exposure to DP is evident, little is known about its potential effects on human health. We and others have shown that some FRs are potential obesogens, i.e., promote adipogenesis. However, the effects of DP on adipogenesis are not known. METHODS: Murine 3T3-L1 and human primary subcutaneous (Sc) and omental (Om) preadipocytes were differentiated in the presence of DP (0.001-10 uM) and adipogenic effects were measured. Further, the ability of DP to activate the adipogenic transcription factor peroxisome proliferator-activated receptor gamma (PPARgamma) was also assessed. RESULTS: We show that treatment of murine preadipocytes with DP significantly (p < 0.05) increased lipid accumulation (2.5 fold) and the mRNA expression of adipogenic markers: fatty acid binding protein 4 (Fabp4), lipoprotein lipase (Lpl), perilipin (Plin), adipsin, and adiponectin. DP also significantly (p < 0.05) increased the protein levels of selected mature adipocyte markers. We further show using luciferase reporter assays that DP increased PPARgamma transcriptional activity by threefold (p < 0.05). When the PPARgamma agonist was replaced by DP in the human preadipocyte differentiation cocktail, DP significantly (p < 0.05) increased the mRNA levels of adipogenic markers, PPARgamma, FABP4, and PLIN in human Sc as well as Om cultures. Finally, PPARgamma antagonist studies revealed that DP-mediated upregulation of adipogenic markers Fabp4 and Lpl did not occur via PPARgamma activation. CONCLUSION: The current study shows that DP can induce adipogenesis of murine and human preadipocytes. We show that, although DP can directly activate PPARgamma, its adipogenic effects may be mediated via other pathways. PMID- 29717280 TI - Prevalence of Sepsis and Possible Severe Bacterial Infection among Neonates in Nepal. AB - Nepal lacks adequate data on the prevalence of sepsis and Possible Severe Bacterial Infection (PSBI) among neonates. Thus, this systematic review was designed to estimate the prevalence of neonatal sepsis and PSBI status in Nepal. We searched PubMed and Nepal Journal Online for relevant studies on PSBI and neonatal sepsis published from 2006 to 2016. The eligibility criteria included those studies done in Nepal, evaluating the prevalence of PSBI/neonatal sepsis with denominators as the population at risk that is either total live births or total cases evaluated. Altogether, four studies met the review criteria, out of which three were hospital-based and one community-based. There is a vast difference in prevalence rate between hospital-based (2-4%) and community-based (9%) studies. Two studies used haematological scoring system and blood culture to base their diagnosis; one used signs and symptoms for PSBI while the other did not mention the diagnostic criteria. This systematic review suggests that though neonatal sepsis poses a big problem, it lacks a significant number of related studies. There is a need to conduct a nationwide survey on the prevalence of sepsis and PSBI among neonates, which will help to develop health policy. PMID- 29717278 TI - Role of obesity in the release of extracellular nucleosomes in acute pancreatitis: a clinical and experimental study. AB - BACKGROUND/OBJECTIVES: A high body mass index increases the risk of severe pancreatitis and associated mortality. Our aims were: (1) To determine whether obesity affects the release of extracellular nucleosomes in patients with pancreatitis; (2) To determine whether pancreatic ascites confers lipotoxicity and triggers the release of extracellular nucleosomes in lean and obese rats. METHODS: DNA and nucleosomes were determined in plasma from patients with mild or moderately severe acute pancreatitis either with normal or high body mass index (BMI). Lipids from pancreatic ascites from lean and obese rats were analyzed and the associated toxicity measured in vitro in RAW 264.7 macrophages. The inflammatory response, extracellular DNA and nucleosomes were determined in lean or obese rats with pancreatitis after peritoneal lavage. RESULTS: Nucleosome levels in plasma from obese patients with mild pancreatitis were higher than in normal BMI patients; these levels markedly increased in obese patients with moderately severe pancreatitis vs. those with normal BMI. Ascites from obese rats exhibited high levels of palmitic, oleic, stearic, and arachidonic acids. Necrosis and histone 4 citrullination-marker of extracellular traps-increased in macrophages incubated with ascites from obese rats but not with ascites from lean rats. Peritoneal lavage abrogated the increase in DNA and nucleosomes in plasma from lean or obese rats with pancreatitis. It prevented fat necrosis and induction of HIF-related genes in lung. CONCLUSIONS: Extracellular nucleosomes are intensely released in obese patients with acute pancreatitis. Pancreatitis associated ascitic fluid triggers the release of extracellular nucleosomes in rats with severe pancreatitis. PMID- 29717272 TI - Total volume versus bouts: prospective relationship of physical activity and sedentary time with cardiometabolic risk in children. AB - BACKGROUND/OBJECTIVES: Examine the prospective relationship of total volume versus bouts of sedentary behaviour (SB) and moderate-to-vigorous physical activity (MVPA) with cardiometabolic risk in children. In addition, the moderating effects of weight status and MVPA were explored. SUBJECTS/METHODS: Longitudinal study including 454 primary school children (mean age 10.3 years). Total volume and bouts (i.e. >=10 min consecutive minutes) of MVPA and SB were assessed by accelerometry in Nov 2009/Jan 2010 (T1) and Aug/Oct 2010 (T2). Triglycerides, total cholesterol/HDL cholesterol ratio (TC:HDLC ratio), homoeostatic model assessment of insulin resistance, systolic blood pressure and waist circumference were assessed at T2 (Sept/Oct 2010) and combined in a composite cardiometabolic risk score. Associations of total time and uninterrupted MVPA and SB were examined using multilevel mixed linear models, with or without mutual adjustments between MVPA and SB. The moderating effects of weight status and MVPA (for SB only) were examined by adding interaction terms. RESULTS: Children engaged daily in about 60 min of total MVPA and 0-15 min/week in MVPA bouts. Mean total sedentary time was around 7 h/day with over 3 h/day accumulated in bouts. Higher mean levels of MVPA were significantly associated with a lower waist circumference, triglycerides, insulin resistance, TC:HDLC ratio and composite cardiometabolic risk, with non-significant associations for uninterrupted MVPA. Associations with sedentary time were much smaller and inconsistent: higher total sedentary time was associated with higher insulin resistance; after adjusting for MVPA, higher mean total and bouts of sedentary time were associated with lower waist circumference, and sedentary bouts with lower composite cardiometabolic risk. CONCLUSIONS: Children accumulated MVPA intermittently and rarely in bouts, and about half their total sedentary time in bouts. Total MVPA is important for lowering cardiometabolic risk in children, whereas both total and uninterrupted sedentary time seem of less importance. PMID- 29717276 TI - Ectopic fat obesity presents the greatest risk for incident type 2 diabetes: a population-based longitudinal study. AB - OBJECTIVES: Obesity is a risk factor for type 2 diabetes mellitus. Among obesity, visceral fat obesity, and ectopic fat obesity, it has been unclear which has the greatest effect on incident diabetes. METHODS: In this historical cohort study of 8430 men and 7034 women, we investigated the effect of obesity phenotypes on incident diabetes. Obesity, visceral fat obesity, and ectopic fat obesity were defined as body mass index >=25 kg/m2, waist circumference >=90 cm in men or >=80 cm in women, and having fatty liver diagnosed by abdominal ultrasonography, respectively. We divided the participants into eight groups according to the presence or absence of the three obesity phenotypes. RESULTS: During the median 5.8 years follow-up for men and 5.1 years follow-up for women, 286 men and 87 women developed diabetes. Compared to the non-obese group, the hazard ratios (HRs) of incident diabetes in the only-obesity, only-visceral fat obesity, only ectopic fat obesity groups, and with all-three types of obesity group were 1.85 (95%CI 1.06-3.26, p = 0.05) in men and 1.79 (0.24-13.21, p = 0.60) in women, 3.41 (2.51-4.64, p < 0.001) in men and 2.30 (0.87-6.05, p = 0.12) in women, 4.74 (1.91 11.70, p < 0.001) in men and 13.99 (7.23-27.09, p < 0.001) in women and 10.5 (8.02-13.8, p < 0.001) in men and 30.0 (18.0-50.0, p < 0.001) in women. Moreover, the risk of incident diabetes of the groups with ectopic fat obesity were almost higher than that of the four groups without ectopic fat obesity. CONCLUSION: Ectopic fat obesity presented the greatest risk of incident type 2 diabetes. PMID- 29717285 TI - Anxiety Level of Patients Undergoing Oral Surgical Procedures. AB - BACKGROUND: Evidences on dental anxiety scale are essential in dental practice for better service delivery. The main objective of this study was to determine the anxiety level of patients undergoing oral surgical procedures and explore its associated factors. METHODS: This was a cross sectional study enrolling 142 patients. Semi structured questionnaire based on Corah's dental anxiety scale was prepared and administered to gather information. Descriptive statistics, chi- square test and independent t- test were used to analyze the data. RESULTS: Sixty nine percent were feeling relaxed in waiting area. Nine patients (6.3%) were afraid of persons in white attire. About 17% reported that they were afraid of sound of dental apparatus. Many participant (81%) expected better outcomes of their dental procedures. When waiting for their procedure at the waiting area, about 50% stated to sense restlessness. Nearly 56% felt unease while waiting at dental chair. Nearly 70 % of cases had less than 7 dental anxiety scale score indicating low anxiety to dental procedures, 23.2% showed moderate anxiety with score of 7 to 9 and 7% showed high anxiety by scoring 10 or more out of score of 15.Average dental anxiety scale scores did not vary as per age differences. The anxiety scores for both sexes were alike. CONCLUSIONS: Even though anxiety level was low among the cases undergoing oral surgical procedure, being in waiting area and dental chair raises their apprehension. PMID- 29717274 TI - Detecting epistasis within chromatin regulatory circuitry reveals CAND2 as a novel susceptibility gene for obesity. AB - BACKGROUND: Genome-wide association studies have identified many susceptibility loci for obesity. However, missing heritability problem is still challenging and ignorance of genetic interactions is believed to be an important cause. Current methods for detecting interactions usually do not consider regulatory elements in non-coding regions. Interaction analyses within chromatin regulatory circuitry may identify new susceptibility loci. METHODS: We developed a pipeline named interaction analyses within chromatin regulatory circuitry (IACRC), to identify genetic interactions impacting body mass index (BMI). Potential interacting SNP pairs were obtained based on Hi-C datasets, PreSTIGE (Predicting Specific Tissue Interactions of Genes and Enhancers) algorithm, and super enhancer regions. SNP * SNP analyses were next performed in three GWAS datasets, including 2286 unrelated Caucasians from Kansas City, 3062 healthy Caucasians from the Gene Environment Association Studies initiative, and 3164 Hispanic subjects from the Women's Health Initiative. RESULTS: A total of 16,643,227 SNP * SNP analyses were performed. Meta-analyses showed that two SNP pairs, rs6808450-rs9813534 (combined P = 2.39 * 10-9) and rs6808450-rs3773306 (combined P = 2.89 * 10-9) were associated with BMI after multiple testing corrections. Single-SNP analyses did not detect significant association signals for these three SNPs. In obesity relevant cells, rs6808450 is located in intergenic enhancers, while rs9813534 and rs3773306 are located in the region of strong transcription regions of CAND2 and RPL32, respectively. The expression of CAND2 was significantly downregulated after the differentiation of human Simpson-Golabi-Behmel syndrome (SGBS) preadipocyte cells (P = 0.0241). Functional validation in the International Mouse Phenotyping Consortium database showed that CAND2 was associated with increased lean body mass and decreased total body fat amount. CONCLUSIONS: Detecting epistasis within chromatin regulatory circuitry identified CAND2 as a novel obesity susceptibility gene. We hope IACRC could facilitate the interaction analyses for complex diseases and offer new insights into solving the missing heritability problem. PMID- 29717275 TI - Selective insulin resistance with differential expressions of IRS-1 and IRS-2 in human NAFLD livers. AB - BACKGROUND/OBJECTIVE: Insulin signals, via the regulation of key enzyme expression, both suppress gluconeogenesis and enhance lipid synthesis in the liver. Animal studies have revealed insulin signaling favoring gluconeogenesis suppression to be selectively impaired in steatotic livers. However, whether, and if so how, such selective insulin resistance occurs in human steatotic livers remains unknown. Our aim was to investigate selective insulin resistance in human livers with non-alcoholic fatty liver disease (NAFLD). SUBJECTS/METHODS: We examined mRNA expressions of key molecules for insulin signaling, gluconeogenesis and lipogenesis in human liver biopsy samples obtained from 51 non-diabetic subjects: 9 healthy controls and 42 NAFLD patients, and analyzed associations of these molecules with each other and with detailed pathological and clinical biochemistry data. RESULTS: In NAFLD patients, insulin receptor substrate (IRS)-2 expression was decreased, while those of key enzymes for gluconeogenesis were increased. These alterations of IRS-2 and gluconeogenesis enzymes were induced both in simple steatosis (SS) and non-alcoholic steatohepatitis (NASH), while these expression levels did not differ between SS and NASH. Furthermore, alterations in the expressions of IRS-2 and gluconeogenesis enzymes showed strong negative correlations and were concurrently induced in the early histological stage of NAFLD. In contrast, fatty acid synthase (FAS) expression was not decreased in NAFLD, despite IRS-2 downregulation, but correlated strongly with IRS-1 expression. Furthermore, no histological scores were associated with these molecules. Thus, IRS-1 signaling, which is not impaired in NAFLD, appears to modulate FAS expression. CONCLUSION: These analyses revealed that selective insulin resistance is present in human NAFLD livers and occurs in its early phases. The effect of insulin, during the IRS step, on gene expressions for lipogenesis and gluconeogenesis are apparently distinct and preferential downregulation of IRS-2 may contribute to selective resistance to the suppressive effects of insulin on gluconeogenesis. PMID- 29717282 TI - Clinical Evaluation of Maxillary Anterior Teeth in Relation to Golden Proportion, Red Proportion and Golden Percentage. AB - BACKGROUND: Golden proportion, recurrent esthetic dental proportion and golden percentage are the widely accepted tools to measure perceived mesiodistal width of maxillary anterior teeth. Our study was aimed to identify appropriate tool among the above mentioned proportion to measure perceived mesiodistal width. METHODS: A cross-sectional observational study was conducted in National Academy of Medical Sciences, Bir Hospital, Nepalese Army Institute of Medical Sciences and Patan Academy of Health Sciences between March 2014 to March 2015.Sixty-three respondents were recruited in the study by the convenient sampling technique. Photographs of the maxillary anterior teeth were taken using digital single reflex camera with macrolens. Data analysis was done using SPSS version 17.0 and paired sample t- test was performed. RESULTS: In our study the golden proportion was 14.28% between central and lateral incisor and 12.69% between canine and lateral incisor. Therefore, golden proportion in our scenario doesn't exist. Recurrent esthetic dental proportion in female Aryans was 71 and 71 on left side and 71and 75 on right side. Golden percentage of respondents was near to values 11, 15, 22, 22, 15, and 12 %. CONCLUSIONS: Golden percentage is an appropriate anterior tooth proportion which may serve as a guideline for the restoration of anterior tooth. RED proportion is applicable only in Mongoloid female population. PMID- 29717281 TI - Review of Pre-Analytical Errors in Oral Glucose Tolerance Testing in a Tertiary Care Hospital. AB - BACKGROUND: The pre-pre-analytical and pre-analytical phases form a major chunk of the errors in a laboratory. The process has taken into consideration a very common procedure which is the oral glucose tolerance test to identify the pre-pre analytical errors. Quality indicators provide evidence of quality, support accountability and help in the decision making of laboratory personnel. The aim of this research is to evaluate pre-analytical performance of the oral glucose tolerance test procedure. METHODS: An observational study that was conducted overa period of three months, in the phlebotomy and accessioning unit of our laboratory using questionnaire that examined the pre-pre-analytical errors through a scoring system. The pre-analytical phase was analyzed for each sample collected as per seven quality indicators. RESULTS: About 25% of the population gave wrong answer with regard to the question that tested the knowledge of patient preparation. The appropriateness of test result QI-1 had the most error. Although QI-5 for sample collection had a low error rate, it is a very important indicator as any wrongly collected sample can alter the test result. CONCLUSIONS: Evaluating the pre-analytical and pre-pre-analytical phase is essential and must be conducted routinely on a yearly basis to identify errors and take corrective action and to facilitate their gradual introduction into routine practice. PMID- 29717284 TI - Antibiotic Susceptibility Pattern of Gram-negative Isolates of Lower Respiratory Tract Infection. AB - BACKGROUND: Lower respiratory tract infection is a common cause of morbidity and mortality worldwide. A cross-sectional study was carried out with an objective to study the antibiogram of Gram-negative isolates of patients with lower respiratory tract infection visiting Kathmandu Model Hospital. METHODS: A total of 274 specimens including sputum, endotracheal aspirates, suction tips were cultured as per standard microbiological technique. Antibiotic susceptibility and detection of Extended-spectrum beta- lactamases (ESBLs) were performed following Clinical Laboratory Standard Institute (CLSI 2014) guidelines. RESULTS: Respiratory pathogens were recovered from 24.6% (n=65) cases. Klebsiella pneumoniae (40%) was the commonest isolates. The highest prevalence of multidrug resistance (69.23%) was observed in Acinetobacter calcoaceticus baumannii complex. Extended-spectrum beta- lactamases were detected in Escherichia coli (n=4), Klebsiella pneumoniae (n=4) and Acinetobacter calcoaceticus baumannii complex (n=1). CONCLUSIONS: High prevalence of multidrug-resistance and extended- spectrum beta- lactamase producers were observed in respiratory isolates. For effective management of lower respiratory tract infections, an ultimate and detailed microbiological diagnosis and susceptibility testing is required. PMID- 29717279 TI - Temporal relationship between hyperuricemia and obesity, and its association with future risk of type 2 diabetes. AB - BACKGROUND/OBJECTIVES: Although hyperuricemia and obesity are significantly correlated, their temporal relationship and whether this relationship is associated with future risk of diabetes are largely unknown. This study examined temporal relationship between hyperuricemia and obesity, and its association with future risk of type 2 diabetes. SUBJECTS/METHODS: This study examined two longitudinal cohorts totally including 17,044 subjects from China with an average of 6.0 years follow-up. Measurements of body mass index (BMI), waist circumference (WC), percentage of body fat and fasting serum uric acid were obtained at two time points. Cross-lagged panel and mediation analysis were used to examine the temporal relationship between hyperuricemia and obesity, and the association of this temporal relationship with follow-up diabetes. RESULTS: In combined data of the two cohorts, the cross-lagged path coefficient (beta1 = 0.121; 95% confidence interval (CI): 0.108-0.135) from baseline uric acid to the follow-up BMI was significantly greater than the path coefficient (beta2 = 0.055, 95% CI: 0.038-0.072) from baseline BMI to the follow-up uric acid (P = 8.14e-10 for the difference between beta1 and beta2) with adjustment for covariates. The separate cross-lagged path models of uric acid with WC and percentage of body fat showed temporal patterns similar to that noted for uric acid with BMI. Further, the path coefficient (beta1) from baseline uric acid to follow-up BMI in the group with diabetes was significantly greater than without diabetes (P = 0.003 for the difference of beta1s in the two groups). BMI partially mediated the association of uric acid with risk of diabetes, and the percentage of mediated association was estimated at 20.3% (95% CI: 15.7-24.8%). Results of these analyses in the combined data were consistent with those in the two cohorts, respectively. CONCLUSIONS: These findings indicated that increased uric acid levels probably associated with obesity and type 2 diabetes, and more definite research is needed to define any role for uric acid in relation to these diseases. PMID- 29717286 TI - Quality of Life of Peri and Postmenopausal Women attending Outpatient Department of Obstretics and Gynecology of A Tertiary Care Hospital. AB - BACKGROUND: Many women experience menopausal symptoms during menopausal transition and postmenopausal years. This natural phenomenon often results in various psychological, somatic and urinary symptoms which impair the overall quality of life of women. This study aimed to access the quality of life of women during perimenopausal and early postmenopausal years attending outpatient department of OBGYN at Kathmandu Medical College Teaching Hospital. METHODS: A descriptive cross-sectional study of 240 perimenopausal women of aged 45-60 years attending gynaecological outpatient clinic was carried out between 15th January to 13th April 2017. Data were collected using Women Health Questionnaire, containing 37 questions by interview technique and analyzed using chi-square test to assess the association between sociodemographic information and the quality of life. RESULTS: The median age of onset of menopause was 50 years and 50.8% of respondents were having good quality of life. Sociodemographic variables such as age of women, marital status, educational level, last menstrual period and regular menstrual period were statistically significant with the quality of life of peri and postmenopausal women. CONCLUSIONS: Menopausal symptoms are common but due to lack of awareness, they do not seek medical advice. Hence priority lies on generating awareness among women about menopause and menopausal symptoms and establishment of dedicated elderly clinic to help these women live a healthy and comfortable life. PMID- 29717283 TI - Utility of Ischemia Modified Albumin as an Early Marker for Diagnosis of Acute Coronary Syndrome. AB - BACKGROUND: The diagnosis of acute coronary syndrome remains challenging, as cardiac troponins and creatine kinase-MB do not detect myocardial ischemia. Ischemia modified albumin is biomarker positive within 6-10 minutes following ischemic onset, where oxygen free radicals leads to reduction in binding capacity of human serum albumin to transitional metal-cobalt. The objective of this study was to compare ischemia modified albumin between acute coronary syndrome patients and healthy controls, and evaluate diagnostic performance of ischemia modified albumin compared to cardiac troponins, creatine kinase-MB and electrocardiogram in acute coronary syndrome patients. METHODS: Fifty ACS patients and 50 healthy controls were enrolled in this cross-sectional study. Ischemia modified albumin was measured after addition of known amount of cobalt to human serum albumin, followed by spectrophotometric determination of unbound cobalt fraction at 470 nm using dithiothreitol as coloring agent. Independent student t-test and One-way ANOVA to compare differences of mean between groups; diagnostic sensitivity and specificity of ischemia modified albumin was determined by receiver operating characteristic curve; McNemar-test was used to assess diagnostic performance of entire test parameters, when used alone and in combinations. RESULTS: Ischemia modified albumin was significantly higher in acute coronary syndrome patients compared to controls (0.823+/-0.191 vs 0.410+/-0.081)(p<0.001). Receiver operating characteristic curve derived optimal cut-off of 0.475 Absorbance unit had sensitivity and specificity of 92% and 82% respectively (area under curve- 0.96). However, no significant differences in mean ischemia modified albumin values between three categories of acute coronary syndrome were seen. Sensitivity of ischemia modified albumin assay (92%) was significantly higher compared to electrocardiogram (72%), cardiac troponin I (18%), and creatine kinase-MB(42%). CONCLUSIONS: Ischemia modified albumin is elevated in acute coronary syndrome patients with better diagnostic performance compared to electrocardiogram, cardiac troponin I, and creatine kinase-MB for early diagnosis, however, with limited ability to discriminate between ST-elevation myocardial infarction, non ST-elevation myocardial infarction and unstable angina. PMID- 29717287 TI - Universal Access to Essential Medicines: An Evaluation of Nepal's Free Health Care Scheme. AB - BACKGROUND: Access to medicine for the poor is recognized to be difficult task and one of the major challenges in achieving universal health coverage, particularly in low-and- middle income countries. In order to ensure the availability of essential medicines free of cost in public health facilities, Nepal has also commenced Free Health Care Services (FHCS). So, this study aims to evaluate availability, expiry, and stock-out duration of essential medicines at front line service providers in Nepal. METHODS: Cross-sectional survey was conducted 28 public health facilities, 7 district warehouses, and 14 private pharmacies in 7 districts of Nepal. The survey was conducted during the March and April 2014. Survey tools recommended by the WHO operational package for assessing, monitoring and evaluating country pharmaceutical situations was used with slight modification as per Nepal's situation. RESULTS: The availability of medicine was found to be 92.44% in this study. The percentage of expired medicines in district warehouse was found to be 8.40. The average stock-out duration in district warehouse was 0.324 days. CONCLUSIONS: Although the availability of essential medicines at peripheral health facilities was found to be satisfactory with lesser proportion of expired medicines, a strong monitoring and evaluation of expired and stock medicines are desirable to maintain and improve the access to essential medicines. PMID- 29717289 TI - Nurse's Awareness on Ethico-legal Aspects of Nursing Profession. AB - BACKGROUND: Nursing practice amicably includes practical efficacy and ethics. Now a days legal and ethical problems associated with client care are arising day by day. Therefore, nurses should have adequate understanding of basic legal concepts and issues relevant to nursing profession in order to protect the rights of the clients and the nurses. METHODS: A cross sectional descriptive design was adopted for the study. 142 nurses were included by using purposive sampling technique. Data was collected with self-administered structured questionnaire. Descriptive statistics was used to reveal demographic information. Kruskal Wallis and Mann Whitney test were used to find out association of selected demographic variables and ethico legal aspects of nursing. RESULTS: Majority of participants were belonging to 20-29 years of age. More than half nurses had complete bachelor's degree and had less than 10 year's experiences. Majority of participants reported that they did not encounter any legal issues in their professional life till date. Similarly, majority of participants had average level knowledge and equate level of practice. Years of experiences and education level did not affect in knowledge level and existing practice related to ethico legal aspect of nursing. There was no significant relationship between level of knowledge and existing practice. CONCLUSIONS: Nurses have average knowledge and practice on ethico legal aspects. There is positive relationship between knowledge and practice though it is not statistically significant. PMID- 29717294 TI - Bullying Behavior and Psychosocial Health - A Cross-sectional Study among School Students of Pyuthan Municipality. AB - BACKGROUND: Bullying remains as pervasive phenomenon affecting children worldwide. Bullying in school has long been a matter of concern as wide range of adjustment problems including poor mental health and violent behavior in school are associated with it. The present study examined the prevalence of bullying behavior (bullies, victims and bully-victims) and their association with depression and psychosomatic symptoms. METHODS: A cross-sectional descriptive study was carried out among 8th, 9th and 10th grade students of Pyuthan Municipality, Mid-Western Nepal. A total of 405 students responded to the structured self-administered questionnaire. Data was collected from randomly selected public and private schools. Descriptive and inferential statistics were used for analysis. RESULTS: The result of this study showed higher prevalence of bully (55.8%) among students of Relatively Advantaged Janajati whereas victims (64.86%) belonged to Disadvantaged Janajatis. Students who bully were found more in grade 8 and 10 whilst the students of grade 9 were more victims. Bullying behavior prevailed more in private schools than in public schools. CONCLUSIONS: The overall prevalence of bullying behavior (either bully or victim) is 69.14%. The finding bolsters an association between bullying behavior and depression, psychosomatic symptoms and school type. Higher prevalence of bullying behavior suggested by this study portends the alarming consequences among school students. Bullying needs to be addressed fleetly. Effective interventions that reduce bullying practice in school is essential. PMID- 29717293 TI - Percutaneous Renal Biopsy: Comparison of Blind and Real-time Ultrasound Guided Technique. AB - BACKGROUND: Percutaneous renal biopsy is performed for diagnosis and prediction of prognosis of renal diseases. Adequacy of tissue and clinically significant bleeding are the main issues of the procedure. We aimed to compare these issues in renal biopsy by blind and real time ultrasound guided technique. METHODS: It was a cross sectional, randomized study conducted between June 2016 to December 2016. In blind technique, marking for biopsy was done by ultrasound. Two attempts were performed for all and more if tissue was inadequate. Patients kept in bed rest for 24 hours, observed for post procedure hematuria and ultrasound done at 6 hours and 24 hours to diagnose perinephric hematoma. RESULTS: Total 75 biopsies (blind = 37 and Ultrasound -guided = 38) were evaluated. Blind and Ultrasound guided technique had significant difference of number of attempt (mean+/-SD) 2.4+/-0.6 and 2.1+/-0.3 (p<0.01) respectively with no difference of number of glomeruli in light microscopy. Bleeding complications were macroscopic hematuria (11(30%)vs15(40%)) and perinephric hematoma ( 5(13.5%)vs3(7.9%)) in blind and Ultrasound-guided technique respectively with no significant difference. Those patients who developed perinephric hematoma was observed in all at 6 hours. CONCLUSIONS: Ultrasound-guided technique of percutaneous renal biopsy is superior with fewer attempts and equivalent in adequacy of tissue and bleeding complication than blind technique. PMID- 29717288 TI - Effects of Adding Intrathecal Dexmedetomidine to Hyperbaric Bupivacaine for Saddle Spinal Block in Adults Undergoing Peri-anal Surgeries. AB - BACKGROUND: Saddle spinal block is the first choice anesthetic technique for adults undergoing peri-anal surgeries. It prevents unnecessary high levels of analgesia and sympathetic block. However, it may not provide prolonged analgesia. This study aims to investigate analgesic effects of dexmedetomidine when added to hyperbaric bupivacaine in saddle spinal block. METHODS: Fifty otherwise healthy adults scheduled for uncomplicated peri-anal surgery were randomly allocated into two equal groups in this double-blinded study. Group A received hyperbaric bupivacaine five milligrams; group B received hyperbaric bupivacaine five milligrams plus dexmedetomidine five micrograms intrathecally. Patients remained seated for ten minutes. Time to first analgesic request by patients was the primary end point. Onset and extent of sensory block, and, magnitude and duration of motor block were assessed. Post-operative analgesic consumption and side effects were studied for 24 hours. Student's t-test for quantitative variables and Chi-square test for categorical variables were used for statistical analysis. RESULTS: Patients in group B had a significantly prolonged duration of analgesia (group B, 501 +/- 306 minutes; group A, 284 +/- 58 minutes) and significantly reduced analgesic requirement than patients in group A. Sensory block in first sacral dermatome appeared significantly earlier in group B. Peak sensory block, magnitude of motor block, and side effects were not significantly different between groups A and B. CONCLUSIONS: Dexmedetomidine as an intrathecal adjuvant to hyperbaric bupivacaine in saddle spinal block prolongs duration of analgesia and decreases analgesic requirement with no added side effects. PMID- 29717290 TI - Anxiety, Depression and Post-Traumatic Stress Disorder after Earthquake. AB - BACKGROUND: Prevalence of anxiety, depression and post traumatic stress disorder is high after earthquake. The aim of the study is to study the prevalence and comorbidity of commonly occurring psychological symptoms in people exposed to Nepal mega earthquake in 2015 after a year of the event. METHODS: A community based, cross sectional, descriptive study was carried out in Bhumlichaur area of Gorkha district, Nepal after around 14 months of the first major earthquake. We used self-reporting questionnaire 20, Post-traumatic stress disorder 8 and hospital anxiety and depression scale to screen for presence of symptoms of anxiety and depression or post-traumatic stress disorder in this population. The risk of having these disorders according to different socio-demographic variable was assessed by calculating odds ratio. All calculations were done using predictive and analytical software (PASW) version 16.0. RESULTS: A total of 198 participants were included in the final data analysis. The mean age of study participants was 35.13 years (SD=18.04). Borderline anxiety symptoms were found in 104 (52.5%) while significant anxiety symptoms were found in 40 (20%) of respondents. Borderline depressive symptoms were seen in 40 (20%) while significant depressive symptoms were seen in 16 (8%) of subjects. Around 27% (n= 53) of respondents were classified as having post-traumatic stress disorder. CONCLUSIONS: The prevalence of anxiety and depressive symptoms and post-traumatic stress disorder seems to be high even after one year in people exposed to earthquake. PMID- 29717291 TI - Evaluation of Pain Following the Use of Scalpel versus Diathermy for Skin Incision in Ear, Nose, Throat and Head and Neck Surgeries. AB - BACKGROUND: Many studies have shown the benefits of diathermy over scalpel for making skin incisions in terms of post operative pain and post operative analgesics requirement. The objective of the study is to compare the pain following incision by scalpel and diathermy for skin in ENT surgery. METHODS: We conducted a prospective, randomized study and compared early post operative pain and analgesics requirement in patients undergoing ENT and Head and Neck surgery in Department of ENT at Kathmandu Medical College from September 2016 to August 2017. The statistical analysis was done using MS Excel and SPSS software. RESULTS: Out of 65 participants, 31 were allocated in scalpel group and 30 were allocated in diathermy group. The mean VAS score was significantly greater in scalpel group as compared to diathermy group in post operative 12, 24 and 48 hours (P<0.05). The mean ketorolac requirement was significantly more in scalpel group than in diathermy group in post operative 24 hours. CONCLUSIONS: The early post operative pain is less in ENT-Head and Neck surgery patients with skin incision by diathermy as compared to the patients with skin incision by scalpel. PMID- 29717299 TI - Anorectal Gastrointestinal Stromal Tumour: A Case Treated with Radical Surgery. AB - Gastrointestinal Stromal Tumour involving rectum and anal canal is an extremely rare entity. This is a case report of a 47 years lady presented with fresh rectal bleed associated with rectal pain and foul smelling rectal mucus discharge. On rectal examination, she had a firm mass palpable about 1.5 cm from anal verge. Considering the size of the tumour and its close proximity with cervix and involvement of levator muscles, extralevator abdominal perineal excision of rectum was undertaken with good recovery after surgery. It was followed by imatinib therapy. PMID- 29717300 TI - An Unusual Case of Acute Abdomen: Ovarian Vein Thrombosis. AB - Ovarian vein thrombosis is one of the rare causes for acute abdomen. Occult presentation of this disease may lead to diagnostic dilemma. A sixteen years female who was operated as a case of ectopic pregnancy was finally diagnosed as having ovarian vein thrombosis. She was successfully treated with anticoagulant. PMID- 29717296 TI - Profile of Caesarean Section in Mid-Western Regional Hospital in Nepal. AB - BACKGROUND: Rising rate of caesarean section since few decades has been a global public health issue.This study is aimed to determine the rate of caesarean section plus examine the indications and complications of caesarean section. METHODS: A retrospective cross-sectional study was conducted using secondary data sources at Mid-Western Regional Hospital in Surkhet, Nepal. Data were collected from patients'records ofthe hospital dating from 16 July 2016 to 15 July 2017. All patients who had delivered their baby by caesarean section were included in this study. Data were analyzed by help of SPSS version 21.Ethical approval was obtained from the hospital authority prior to the study. RESULTS: During the study, out of total 3,694 deliveries, 695 (18.8%) were caesarean section. Most of the caesarean section were emergency than elective (83.0% vs 17.0%). Among all women who underwent caesarean section, majority were from 37 to 42 weeks pregnancy (88.5%), age group between 20 and 24 (42.9%) and multiparous (53.5%).Fetal distress (20.1%) was most common among all major indications of caesarean section.Maternal complications due to caesarean section was low (3.7%). Among all complications, Post-partum hemorrhage (30.5%) was the major maternal complication of caesarean section. Most of newborn babies had APGAR score six or more at one minute (94.5%) and five minutes (97.9%). CONCLUSIONS: In our study, caesarean section rate was 18.8%, which is higher than WHO recommendation (10 - 15%). Main indication for caesarean section was fetal distress. Maternal and fetal complications were low. PMID- 29717292 TI - Outbreak Investigation Following the 2015 Earthquake Disaster in Nepal. AB - BACKGROUND: Infectious disease outbreaks following natural disasters are reported in literature. Outbreaks were documented following natural disasters in many countries including Haiti. Such possibility following 2015 Nepal earthquake was a public health concern. Risk factors needed evaluation by post-disaster outbreak investigation. Hence, present study was undertaken to investigate potentials for such outbreak and to generate evidence for public health intervention. METHODS: The study was conducted between April - May, 2015, with the cooperation of National Public Health Laboratory, Epidemiology and Disease Control Division, Nepal Health Research Council and the Chinese team. Rapid Response Teams visited earthquake affected districts and collected samples for analysis. Syndromic surveillance approach was followed. Samples were collected from syndromic patients under supervision. Those sick prior to earthquake or receiving treatment were excluded. Blood, stool and throat swab samples, as indicated, were collected. Drinking water and food samples including captured live mosquitoes from inhabited areas were obtained for study with the help of EDCD. Laboratory analysis was performed at the NPHL. RESULTS: Total samples were 360 (114 biological, 246 environmental). Salmonella spp. was detected in two and Varicella zoster in one blood sample. Influenza B virus was detected in one throat swab. Rota virus was detected in two, Shigella dysenteriae in one and Salmonella spp. in one stool sample. No pathogen detected in water or food samples. Mosquitoes tested negative for dengue virus. CONCLUSIONS: Post-earthquake outbreak investigated in disaster phase-2. Diarrheal, enteric fever pathogens and Influenza B virus were detected. Environmental samples tested negative for pathogens. Vigilance is necessary for other risk factors. PMID- 29717298 TI - Abortion: Still Unfinished Agenda in Nepal. AB - Unsafe abortion is affecting a lot, in health, socio-economic and health care cost of many countries. Despite invention of simple technology and scientifically approved safe abortion methods, women and girls are still using unsafe abortion practices. Since 2002, Nepal has achieved remarkable progress in developing policies, guidelines, task shifting, training human resources and increasing access to services. However, more than half of abortion in Nepal are performed clandestinely by untrained or unapproved providers or induced by pregnant woman herself. Knowledge on legalization and availability of safe abortion service among women is still very poor. Stigma on abortion still persists among community people, service providers, managers, and policy makers. Access to safe abortion, especially in remote and rural areas, is still far behind as compared to their peers from urban areas. The existing law is not revised in the spirit of current Constitution of Nepal and rights-based approach. The existence of abortion stigma and the shifting of the government structure from unitary system to federalism in absence of a complete clarity on how the safe abortion service gets integrated into the local government structure might create challenge to sustain existing developments. There is, therefore, a need for all stakeholders to make a lot of efforts and allocate adequate resources to sustain current achievements and ensure improvements in creating a supportive social environment for women and girls so that they will be able to make informed decisions and access to safe abortion service in any circumstances. PMID- 29717297 TI - Comparison of Stage and Lymph Node Ratio in Young and Older Patients with Colorectal Cancer Operated in a Tertiary Hospital in Nepal. AB - BACKGROUND: Colorectal cancer is being diagnosed more frequently in the young and it presents in an advanced stage. In TNM staging, stage depends on tumor size and number of positive nodes, which depend on location of tumor as well as the extent of dissection.The lymph node ratio is regarded as a more reliable marker for prognosis. In this study, we compare epidemiology of colorectal cancer in the young (<40 years) and older patients as well as the LNR. METHODS: Patients with colorectal cancer operated at the Tribhuvan University Teaching Hospital, Kathmandu, Nepal for a period of 4 years (2012 - 2016) were included in the study. Patients were grouped into young (? 40 years) and older (> 40 years) and clinic-pathological data such as site of lesion, clinical stage, and lymph node ratio were compared. RESULTS: Of the 95 patients of colorectal cancer, 25 patients were of age ? 40 years (26%) and they had a higher median stage at diagnosis. In patients above 40 years, it was diagnosed at a relatively earlier stage. The mean number of positive nodes was 11.64 in younger patients whereas it was 18.34in those more than 40 years of age,but younger patients had higher lymph node ratio than elderly (0.31 vs 0.13) (P-value ? 0.005). CONCLUSIONS: Young patients with colorectal cancer tend to have more advanced disease. The lymph node metastasis and lymph node ratio tend to be higher in young patients. PMID- 29717295 TI - Risk Factors for Postoperative Complications after Percutaneous Nephrolithotomy. AB - BACKGROUND: To identify the perioperative factors associated with complications after percutaneous nephrolithotomy by classification of complications according to the modified Clavien scoring system and evaluation of the minor and major complications related to the procedure. METHODS: A prospective study of all the percutaneous nephrolithotomy performed by standard technique within 1.5 years at Bir Hospital was made. Possible demographic, preoperative and intraoperative variables were included in the study and patients were followed up postoperatively for any complications. All complications were classified according to modified Clavien scoring system and analyzed to identify the prognostic variables. RESULTS: Two hundred and forty six percutaneous nephrolithotomy done within the study period were analyzed. Although 41.06 % of the study population developed complications, only 9.35 % had major complications. Age, body mass index, gender, clinical presentation, history of previous surgery and ASA score did not correlate with complications. Diabetes was the only comorbidity associated (p = 0.0482). Preoperatively estimated stone burden (p = 0.0023), number of calyces involved by the stones (p = 0.0002), and presence of staghorn calculi were significantly associated with development of postoperative complications. Multiple tracts were required (p = 0.0151) and operative time was longer (p < 0001) in the patients who developed complications. CONCLUSIONS: Percutaneous nephrolithotomy has lesser complications. Diabetic patients are more prone to develop complications. Larger stone burden, involvement of multiple calyces by stones and staghorn calculi are associated with need of multiple tracts and longer operative time, thus predisposing to higher incidence of complications. PMID- 29717301 TI - Historical Development of Health Research Ethics in Nepal. AB - Health research in Nepal initiated with a survey in malaria in 1952. The first regulatory body for health research was Nepal Medical Research Committee formed under Ministry of Health. Ethical Review Body is the first ethical review structure. Nepal Health Research Council is now an independent body to regulate health research in Nepal. Development of research ethics in Nepal is clearly evident with the development of ethical guidelines; functioning of Ethical Review Board; expansion of institutional review committees and initiation of online submission system. However, monitoring compliance with research ethics could be a challenge for the Nepal Health Research Council. PMID- 29717303 TI - Surgical Education. AB - NA. PMID- 29717305 TI - In situ semi-quantitative assessment of single-cell viability by resonance Raman spectroscopy. AB - Currently, studies are increasingly focusing on the cytotoxic effects of anticancer drugs. Such investigations urgently warrant the assessment of single cell viability. Here, we developed a novel method for quantifying single-cell viability with high selectivity by resonance Raman scattering. We report on this powerful tool that will allow researchers to study cellular metabolism at the level of a single cell. PMID- 29717302 TI - Can the Therapeutically-rational Exchange (T-REX) of Glucose-6-phosphate Dehydrogenase Deficient Red Blood Cells Reduce Plasmodium falciparum Malaria Morbidity and Mortality? AB - NA. PMID- 29717306 TI - Combined effect of hydrogen bonding interactions and freezing of rotameric equilibrium on the enhancement of photostability. AB - The photophysics and photostability of 12,13-dihydro-5H-indolo[3,2-c]acridine (IA), a rigid bifunctional indole derivative with proton donor/acceptor functionalities, can be drastically changed by the environment. The formation of hydrogen bonds with alcohols leads to a significant decrease of the triplet formation efficiency and an increase of photostability. The photodegradation yield was found to be about two hundred times lower in methanol and 1-propanol than in n-hexane or acetonitrile. A similar effect has been reported for two indole-naphthyridines, molecules that can exist in syn and anti rotameric forms. We demonstrate that IA, which can exist only in the syn form, is more photostable in alcohols than similar, but non-rigid molecules. This additional photostability enhancement is due to the elimination of a slower channel of excited state deactivation in alcohol complexes, S0 <- S1 internal conversion. The dominant, faster channel of S1 depopulation is the excited state double proton transfer, manifested by the presence of low energy tautomeric fluorescence. PMID- 29717304 TI - Effect of diets with goat milk fat supplemented with exercise on anxiety and oxidative stress in the brains of adult rats. AB - The objective of this study is to evaluate the effects of a diet with goat milk fat supplemented with physical training on markers of oxidative stress in the brain and anxiety behavior in rats. Adult male rats were randomly divided into six groups (n = 10 per group): control sedentary (CON) and exercised (CON-EX) groups, goat milk fat sedentary (GM) and exercised (GM-EX) groups, goat milk fat enriched with CLA sedentary (GM-CLA) and exercised (GM-CLA-EX) groups. The exercised groups were submitted to treadmill running during four weeks. Anxiety parameters were evaluated with the open field (OF) and elevated plus maze (EPM) tests. Malondialdehyde (MDA) and glutathione (GSH) levels were measured in the brain. Compared to the CON and GM groups, the GM-CLA group (p < 0.05), in which the animals were treated with goat milk fat with an increased CLA content, showed higher rearing. All exercised animals presented an increase in grooming when compared to sedentary animals. The number of entries in the open arms and time spent in the open arms was higher in sedentary groups (p < 0.05). MDA levels in the brain were lower in the GM group when compared to those in the CON group (p < 0.05). MDA increased in exercised animals (p < 0.05). GM and GM-CLA groups showed a significant elevation in the GSH levels in the brain. Goat milk fat, however, showed a potential effect on the reduction of oxidative stress, which was associated with a reduction in anxiety behavior. However, this beneficial effect was reversed when exercise was involved. PMID- 29717312 TI - Chemical tools for the generation and detection of singlet oxygen. AB - Growing evidence indicates intermediacy of singlet dioxygen (1O2) in a variety of pathophysiological processes. 1O2 has also found great utility of destructive actions for clinical and environmental applications. However, many details of the molecular mechanisms mediated by 1O2 remain insufficiently understood. Efforts to elucidate the 1O2 chemistry have been hampered by the lack of chemical tools capable of generation and detection of 1O2. In this review, I summarize the recent advances in the development of the chemical tools of 1O2. This article focuses on two topics. The first part introduces chemical methods for ground state generation of 1O2. Designs of the molecular carriers of 1O2 are also explained. The second part discloses molecular probes of 1O2. The probes are categorized into three groups, depending on signaling modalities: absorption based probes, photoluminescent probes, and chemiluminescent probes. Focus is on the molecular design to maximize the signaling actions. Disadvantages of using the probes are also discussed to motivate the future research. I hope that this review will serve as helpful guidance to the exploitation and development of the chemical tools of 1O2. PMID- 29717307 TI - Highly enantioselective synthesis of trifluoromethyl cyclopropanes by using Ru(ii)-Pheox catalysts. AB - An asymmetric synthesis of various trifluoromethyl cyclopropanes from olefins, such as vinyl ferrocene, vinyl ethers, vinyl amines, vinyl carbamates and dienes, was achieved by using Ru(ii)-Pheox catalysts. This catalytic system can function at a low catalyst loading (3 mol%) compared with those reported previously, and the desired cyclopropane products are obtained in high yields with excellent diastereoselectivity (up to >99 : 1) and enantioselectivity (up to 97% ee). PMID- 29717310 TI - Stereodynamic insight into the thermal history effects on poly(vinyl chloride) calorimetric sub-glass and glass transitions as a fragile glass model. AB - The dynamic thermal history impact of poly(vinyl chloride) (PVC) has been explored for a wide range of pre-cooling rates, from 1 to 30 degrees C min-1. A first macroscopic insight into the dynamic thermal history influence has been highlighted through a decrease in the apparent activation energy (Eapp) in the first stage of the glass transition. The overall glass transition Eapp surface was successfully modeled in a polynomial fashion regarding the pre-cooling range. Raman scattering was used to associate the Eapp variations along the glass transition conversion with the stereochemistry evolution during the polymeric relaxation. Herein, the selection of atactic PVC as the polymer model permits us to monitor the glassy polymer segment stereodynamics during the heating ramp through the C-Cl stretching. The intermolecular H-Cl dipole interactions, as well as intramolecular conformational reorganizations among syndiotactic, isotactic and heterotactic polymer sequences, have been associated with non-cooperative and cooperative motions, i.e. the beta- and alpha-process, respectively. The fruitful comparison of the two extreme values of the pre-cooling rates permits us to propose a thermokinetic scenario that explains the occurrence, intensity, and inter-dependence of beta- and alpha-processes in the glassy state and during the glass transition. This scenario could potentially be generalized to all the other polymeric glass-formers. PMID- 29717319 TI - Two-step electrodeposition to fabricate the p-n heterojunction of a Cu2O/BiVO4 photoanode for the enhancement of photoelectrochemical water splitting. AB - A Cu2O/BiVO4 p-n heterojunction based photoanode in photoelectrochemical (PEC) water splitting is fabricated by a two-step electrodeposition method on an FTO substrate followed by annealing treatment. The structures and properties of the samples are characterized by XRD, FESEM, HRTEM, XPS and UV-visible spectra. The photoelectrochemical activity of the photoanode in water oxidation has been investigated and measured in a three electrode quartz cell system; the obtained maximum photocurrent density of 1.72 mA cm-2 at 1.23 V vs. RHE is 4.5 times higher than that of pristine BiVO4 thin films (~0.38 mA cm-2). The heterojunction based photoanode also exhibits a tremendous cathodic shift of the onset potential (~420 mV) and enhancement in the IPCE value by more than 4-fold. The enhanced photoelectrochemical properties of the Cu2O/BiVO4 photoelectrode are attributed to the efficient separation of the photoexcited electron-hole pairs caused by the inner electronic field (IEF) of the p-n heterojunction. PMID- 29717309 TI - Revealing the linear relationship between electrical, thermal, mechanical and structural properties of carbon nanocoils. AB - The special helical morphologies and polycrystalline-amorphous internal structures differ carbon nanocoils (CNCs) from carbon nanotubes or carbon nanofibers, but bring difficulties in illuminating the correlations between physical and structural properties. In this paper, we measure the electrical conductivity (sigma), thermal diffusivity (alpha) and Young's modulus (E) of single CNCs at the same time, using a transient electrothermal technique and an electromechanical vibration technique. Based on the statistical results of 8 single CNC samples, a linear correlation between the three parameters is uncovered, expressed as sigma = 0.052(alpha - 2.5) * 104 S m-1, E = (-10.38sigma + 14.04) GPa and E = (-0.59alpha + 16.08) GPa, where the unit of alpha is 10-7 m2 s-1. Concise proportional relations between the three parameters and average graphite grain size (ld) are deduced, expressed as sigma = Ald(C1 - T)-1, alpha = Bld(C2 + T)-1 and E = -Dld + E0. The proportional relation between physical parameters and ld demonstrates the confinement originated from the nano-grain system. PMID- 29717313 TI - Chemically initiated liquid-like behavior and fabrication of periodic wavy Cu/CuAu nanocables with enhanced catalytic properties. AB - Solid crystalline materials have long range order in their atomic arrangement while liquids have short range order, and the transition between them is usually caused by heat and/or pressure. Herein, we report the finding that chemical processes may play a similar role as heat and initiate liquid-like behavior of crystalline nanomaterials at a temperature far below their melting points. When the straight Cu/CuAu crystalline nanocables are dispersed in organic amine at 80 degrees C under ambient conditions, the continuous oxidation of Cu atoms on the surface and diffusion of Cu atoms from the core to the surface would break up the long-range ordered arrangement of atoms and lead to the transformation of an anisotropic crystal into an isotropic liquid-like state, which resulted in the evolution of the straight morphology of the nanocables into periodic wavy structures following the Rayleigh instability. It was also demonstrated that periodic wavy Cu@CuAu nanocables exhibit much better catalytic activity than straight Cu@CuAu nanocables towards the reduction of p-nitrophenol into p aminophenol by NaBH4. Our results not only provide new insights into the transition between a solid crystal and a liquid-like state at the nanoscale, but also facilitate the development of new strategies for the synthesis of functional nanomaterials. PMID- 29717314 TI - Solvent effects for vertical absorption and emission processes in solution using a self-consistent state specific method based on constrained equilibrium thermodynamics. AB - A self-consistent state specific (SS) method in the framework of TDDFT is presented to account for solvent effects on absorption and emission processes for molecules in solution. In these processes, the initial state is an equilibrium state, while the polarization of the solvent is in nonequilibrium with the electron density of the solute in the final state. Nonequilibrium solvation free energy is calculated based on a novel nonequilibrium solvation model with constrained equilibrium manipulation. The bulk solvent effects are considered using the polarizable continuum method (PCM), where the solvent-solute interaction is described with a reaction field. Molecular orbitals and orbital energies in the presence of the reaction field corresponding to the excited state are employed and the response of the solvent is not included in the TDDFT calculations. A self-consistent procedure is designed to obtain the excited state reaction field. The equations based on this new nonequilibrium solvation model in the framework of the self-consistent SS-PCM/TDDFT method for calculation of vertical absorption and emission energies are presented and implemented in the Q Chem package. Vertical absorption and emission energies for several small molecules in solution using the newly developed code are calculated and compared with available experimental data and the results of other theoretical studies. Solvent shifts of absorption and emission energies are reasonably reproduced with this approach. The new model is a promising approach to study nonequilibrium absorption and emission processes in solution. PMID- 29717326 TI - Enhanced hydrogen photogeneration by bulk g-C3N4 through a simple and efficient oxidation route. AB - The search for new environment-friendly visible-light absorbing catalysts is an urgent task. g-C3N4 has excellent photocatalytic properties and the possibility of developing cost-effective routes to make this material a viable alternative to the currently used catalysts is required. In this work, we show that a simple chemical oxidation process of g-C3N4 with nitric acid allowed significantly enhancing the hydrogen photogeneration from aqueous triethanolamine, under simulated solar light. An 8-fold improvement of the H2 production, with respect to the pristine sample, was achieved by properly controlling the physical chemical parameters of the oxidation process, reaching a value of about 4000 MUmol g-1 h-1, which is one of the highest hydrogen production rates for bulk g C3N4. Such high levels of photocatalytic activity result from the combination of improved surface area and changes in the electronic structure induced by the oxidation process. PMID- 29717316 TI - Theoretical design and investigation of 1,8-naphthalimide-based two-photon fluorescent probes for detecting cytochrome P450 1A with separated fluorescence signal. AB - As a type of enzyme with a terminal oxygen, the CYP1A subfamily possesses the ability to catalyze the reactions of many environmental toxins, endogenous substrates and clinical drugs. The development of efficient methods for the rapid and real-time detection of CYP1A enzyme activity in complex biological systems is of considerable significance for identifying potential abnormalities in these cancer-related enzymes. With this goal, we firstly provided a series of 1,8 naphthalimide-based two-photon fluorescent chromophores with large two-photon absorption (TPA) cross-sections (500-7000 GM) and remarkable changes in fluorescence spectra upon recognizing the CYP1A enzyme from its theoretical aspect. Moreover, we have thoroughly studied the effects of cyclic acceptor (dichlorobenzene and benzothiadiazole) and donor (fluorene and carbazole) groups on the one-photon absorption (OPA), TPA, and fluorescence properties of CYP1A enzyme probes and the corresponding reaction products. The connection of a heterocycle as the donor group to a 1,8-naphthalimide-based molecule to form a D pi-A-pi-D-type electronic structure can effectively cause red shifts in the absorption and emission wavelengths to facilitate bioimaging in the near infrared (NIR) region, which is attributed to the lower transition energy, larger transition dipole moment and amount of transferred charge. Docking analysis suggests that the two-photon fluorescent probes NCMN-3 and NCMN-5 that were designed will guarantee and achieve excellent selectivity for the CYP1A enzyme. PMID- 29717317 TI - High temperature hydrothermal synthesis of rare-earth titanates: synthesis and structure of RE5Ti4O15(OH) (RE = La, Er), Sm3TiO5(OH)3, RE5Ti2O11(OH) (RE = Tm Lu) and Ce2Ti4O11. AB - Reactions of rare-earth oxides with TiO2 were performed in high temperature (650 700 degrees C) hydrothermal fluids. Two different mineralizer fluids were examined, 20 M KOH and 30 M CsF, and their respective products analyzed. When concentrated KOH fluids were used, single crystals of a variety of new OH- containing species were isolated and structurally characterized: RE5Ti4O15(OH) (RE = La, Er) I, Sm3TiO5(OH)3II and RE5Ti2O11(OH) (RE = Tm-Lu) III. La5Ti4O15(OH) I crystallizes in the orthorhombic space group Pnnm with unit cell dimensions of a = 30.5152(12) A, b = 5.5832(2) A, c = 7.7590(3) A and V = 1321.92(9) A3, Z = 4. Sm3TiO5(OH)3II crystallizes in the monoclinic space group P21/m with unit cell parameters of a = 5.6066(2) A, b = 10.4622(4) A, c = 6.1258(2) A and beta = 104.7390(10) degrees , V = 347.50(2) A3, Z = 2. Lu5Ti2O11(OH) III crystallizes in the monoclinic space group C2/m with unit cell dimensions of a = 12.1252(9) A, b = 5.8243(4) A, c = 7.0407(5) A, beta = 106.939(3) degrees and V = 475.65(6) A3, Z = 2. When concentrated fluoride solutions are used, mostly RE2Ti2O7 type compounds were isolated in either cubic or monoclinic phases. In the case of cerium, Ce2Ti4O11IV was isolated that crystallizes in the monoclinic space group C2/c with unit cell parameters of a = 13.6875(7) A, b = 5.0955(3) A, c = 12.8592(7) A, beta = 108.964(2) degrees and V = 848.18(8) A3, Z = 4. The synthesis, structural characterization, and supporting characterization are reported for all compounds. The work highlights the complementary nature of hydroxide and fluoride fluids in studying the reactivity of refractory oxides. PMID- 29717318 TI - Precursor control over the self-assembly of [2]catenanes via hydrazone condensation in water. AB - By means of hydrazone condensation, a series of homo-[2]catenanes were self assembled in high yields in water. The properties of the precursors have a great impact on the self-assembly pathway, as well as the stability and co conformations of the products. PMID- 29717315 TI - Rippling of graphitic surfaces: a comparison between few-layer graphene and HOPG. AB - The surface structure of Few-Layer Graphene (FLG) epitaxially grown on the C-face of SiC has been investigated by TM-AFM in ambient air and upon interaction with dilute aqueous solutions of bio-organic molecules (l-methionine and dimethyl sulfoxide, DMSO). Before interaction with molecular solutions, we observe nicely ordered, three-fold oriented rippled domains, with a 4.7 +/- 0.2 nm periodicity (small periodicity, SP) and a peak-to-valley distance in the range 0.1-0.2 nm. Upon mild interaction with the molecular solution, the ripple periodicity "relaxes" to 6.2 +/- 0.2 nm (large periodicity, LP), while the peak-to-valley height increases to 0.2-0.3 nm. When additional energy is transferred to the system through sonication in solution, graphene planes are peeled off, as shown by quantitative analysis of Raman spectroscopy and X-ray photoelectron spectroscopy which indicate a neat reduction of thickness. Upon exfoliation rippled domains are no longer observed. In comparative experiments on cleaved HOPG, we could not observe ripples on pristine samples in ambient air, while LP ripples develop upon interaction with the molecular solutions. Recent literature on similar systems is not univocal regarding the interpretation of rippling. The ensemble of our comparative observations on FLG and HOPG can be hardly rationalized solely on the basis of the surface assembly of molecules, either organic molecules coming from the solution or adventitious species. We propose to consider rippling as the manifestation of the free-energy minimization of quasi 2D layers, eventually affected by factors such as interplanar stacking, and interactions with molecules and/or with the AFM tip. PMID- 29717311 TI - Outstanding Reviewers for Analyst in 2017. PMID- 29717328 TI - Bilateral painful foot masses. Bilateral hypertrophy of extensor digitorum brevis (EDB). PMID- 29717327 TI - Content and quality of workplace guidelines developed to prevent mental health problems: results from a systematic review. AB - Objectives A wide range of guidelines have been developed to prevent work-related mental health problems (MHP), but little is known about the quality of such guidelines. We systematically reviewed the content and quality of workplace guidelines aiming to prevent, detect, and/or manage work-related MHP. Methods We conducted systematic online and database searches (MEDLINE; Web of Science; PsychNET; occupational safety and health databases) to identify guidelines. Eligibility criteria included guidelines recommending primary, secondary, or tertiary preventive interventions to be implemented at the workplace by employers, employees or organizational staff. A minimum of minimum three independent reviewers assessed the quality of guidelines using the Guidelines for Research and Evaluation (AGREE II). Guidelines rated >=65% with regards to domain I, II, and III were considered to be of good developmental quality. Results Seventeen guidelines were quality assessed. Guidelines mainly targeted employers: eight guidelines recommended primary preventive interventions (eg, reduction of psychosocial hazards by risk management procedures), three recommended tertiary (eg, stay at work or return to work procedures for management), and six recommended a combination of primary, secondary and tertiary interventions (eg, facilitate return to work by increasing mental health literacy of all staff and coordination of sick-listed employees). Four guidelines had developed recommendations of good quality, but the evidence of two guidelines was outdated and studies documenting the effect of implementation were not yet available. Conclusions Few guidelines have been developed with sufficient rigor to help employers prevent or manage work-related MHP and evidence of their effectiveness remains scarce. PMID- 29717308 TI - Rylene annulated phthalocyanine: a fully conjugated block for the construction of a supramolecular two-dimensional framework. AB - A rylene annulated phthalocyanine (ZnPcPDI4) was designed and synthesized. Single crystal X-ray diffraction analyses unambiguously confirmed the giant molecule quasi-planar "four leaf clover" skeleton with a 27 A diameter and a two dimensional cage-like supramolecular structure. The fully conjugated characteristics endowed it with significant Q-band red-shifts to the near infrared region of 785 nm, and a largely degenerated LUMO level. PMID- 29717329 TI - Reply to the letter to the editor. PMID- 29717320 TI - An anionic eta2-naphthalene complex of titanium supported by a tripodal [O3C] ligand and its reactions with dinitrogen, anthracene and THF. AB - We report the synthesis and characterization of a dianionic titanium naphthalene complex supported by a tripodal triaryloxidemethyl ligand, which is a rare example of an eta2-coordinated arene complex of low-valent early transition metals. The eta2-naphthalene ligand is readily displaced by N2 and anthracene along with the release of free naphthalene, resulting in the formation of the end on N2 bridging dititanium complex and the anthracene complex, respectively. The naphthalene complex undergoes C-O bond cleavage of THF to produce a 1-oxa-2 titanacyclohexane. PMID- 29717331 TI - Ectomycorrhizal Communities Associated with the Legume Acacia spirorbis Growing on Contrasted Edaphic Constraints in New Caledonia. AB - This study aims to characterize the ectomycorrhizal (ECM) communities associated with Acacia spirorbis, a legume tree widely spread in New Caledonia that spontaneously grows on contrasted edaphic constraints, i.e. calcareous, ferralitic and volcano-sedimentary soils. Soil geochemical parameters and diversity of ECM communities were assessed in 12 sites representative of the three mains categories of soils. The ectomycorrhizal status of Acacia spirorbis was confirmed in all studied soils, with a fungal community dominated at 92% by Basidiomycota, mostly represented by/tomentella-thelephora (27.6%), /boletus (15.8%), /sebacina (10.5%), /russula-lactarius (10.5%) and /pisolithus scleroderma (7.9%) lineages. The diversity and the proportion of the ECM lineages were similar for the ferralitic and volcano-sedimentary soils but significantly different for the calcareous soils. These differences in the distribution of the ECM communities were statistically correlated with pH, Ca, P and Al in the calcareous soils and with Co in the ferralitic soils. Altogether, these data suggest a high capacity of A. spirorbis to form ECM symbioses with a large spectrum of fungi regardless the soil categories with contrasted edaphic parameters. PMID- 29717338 TI - Trends in Rhinoplasty Research: A 20-Year Bibliometric Analysis. AB - BACKGROUND: Rhinoplasty is a popular aesthetic and reconstructive surgical procedure. It is one of the top five surgical cosmetic procedures performed worldwide. OBJECTIVES: To evaluate global trends in rhinoplasty research spanning 20 years between 1994 and 2013. METHODS: The top 15 plastic surgery and otolaryngology journals containing rhinoplasty research were determined using impact factors (IF). A database of rhinoplasty articles from 1994 to 2013 was created to include the following classifications: IF, authors' geographic location, study design, level of evidence (LOE), and pertinence to aesthetic or reconstructive rhinoplasty. Productivity index and productivity share were calculated for each region. RESULTS: A total of 1244 rhinoplasty articles were included in the database. The mean IF among the 15 journals increased from 0.75 in 1994 to 1.90 in 2013 (p < 0.001). The majority of rhinoplasty publications were clinical in study design (91.0%) and were predominantly of weaker LOE (level IV: 42.4%; level V: 33.2%). The USA led in proportion of total rhinoplasty publications by volume and productivity index (37.9%, 41.2%), followed by Asia (29.1%, 28.2%) and Western Europe (18.8%, 18.2%). The majority of articles published were classified as aesthetic (60.4%), whereas 30.6% were reconstructive; there was a significant increase in the proportion of aesthetic rhinoplasty articles published per year (p = 0.009). CONCLUSIONS: The USA has consistently been the most productive country in rhinoplasty research. However, its lead has diminished over the last 20 years. The trend in rhinoplasty research appears to be toward aesthetic rather than reconstructive topics. Attention should be given to producing stronger LOE studies. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29717330 TI - Use of ultraviolet-visible spectrophotometry associated with artificial neural networks as an alternative for determining the water quality index. AB - The water quality index (WQI) is an important tool for water resource management and planning. However, it has major disadvantages: the generation of chemical waste, is costly, and time-consuming. In order to overcome these drawbacks, we propose to simplify this index determination by replacing traditional analytical methods with ultraviolet-visible (UV-Vis) spectrophotometry associated with artificial neural network (ANN). A total of 100 water samples were collected from two rivers located in Assis, SP, Brazil and calculated the WQI by the conventional method. UV-Vis spectral analyses between 190 and 800 nm were also performed for each sample followed by principal component analysis (PCA) aiming to reduce the number of variables. The scores of the principal components were used as input to calibrate a three-layer feed-forward neural network. Output layer was defined by the WQI values. The modeling efforts showed that the optimal ANN architecture was 19-16-1, trainlm as training function, root-mean-square error (RMSE) 0.5813, determination coefficient between observed and predicted values (R2) of 0.9857 (p < 0.0001), and mean absolute percentage error (MAPE) of 0.57% +/- 0.51%. The implications of this work's results open up the possibility to use a portable UV-Vis spectrophotometer connected to a computer to predict the WQI in places where there is no required infrastructure to determine the WQI by the conventional method as well as to monitor water body's in real time. PMID- 29717339 TI - Inverted Nipple Treatment and Poliglecaprone Spacer. AB - INTRODUCTION: Nipple inversion is defined as a non-projectile nipple. It is a frequent pathologic condition, in which the whole nipple, or a portion of its, is buried inward towards the lactiferous duct and lies below the plane of the areola. Numerous strategies have been described to correct nipple inversion. All the procedures have the purpose to give a good shape to the nipple, preserving its function and sensitivity, when it is possible. To avoid recurrences and to obtain good aesthetic results, we present a modified percutaneous technique. METHOD: We performed a retrospective study between 2011 and 2016 and included all the cases of inverted nipples treated in our department. Our modified percutaneous technique consists of a minimal incision supported by a percutaneous suture as a temporary spacer to fill the defect caused by releasing the fibro ductal bands. RESULTS: A total of 41 cases of inverted nipples were corrected in 32 patients. After 1 year of follow-up, no recurrence was observed and all nipples maintained complete eversion. There was only one case of partial unilateral necrosis in a patient who underwent tumorectomy and radiotherapy. All patients were satisfied with the aesthetic outcomes. CONCLUSION: This is a simple, safe and cheap technique that should be considered as a reliable method for long-term correction of nipple inversion. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29717335 TI - A novel radiographic scoring system for growth abnormalities and structural change in children with juvenile idiopathic arthritis of the hip. AB - BACKGROUND: Approximately 20-50% of children with juvenile idiopathic arthritis (JIA) have hip involvement within 6 years of diagnosis. Scoring systems for hip related radiographic changes are lacking. OBJECTIVE: To examine precision of potential radiographic variables and to suggest a scoring system. MATERIALS AND METHODS: We reviewed a set of 75 pelvic radiographs from 75 children with JIA hip involvement across two European centres. We assessed findings of (1) destructive change and (2) growth abnormality, according to a pre-defined scoring system. All radiographs were scored independently by two sets of radiologists. One set scored the radiographs a second time. We used kappa statistics to rate inter- and intra observer variability. RESULTS: Assessment of erosions of the femoral head, femoral neck and the acetabulum showed moderate to good agreement for the same reader (kappa of 0.5-0.8). The inter-reader agreement was, however, low (kappa of 0.1-0.3). There was moderate to high agreement for the assessment of femoral head flattening (kappa of 0.6-0.7 for the same reader, 0.3-0.7 between readers). Joint space narrowing showed moderate to high agreement both within and between observers (kappa of 0.4-0.8). Femoral neck length and width measurements, the centrum-collum-diaphysis angle, and trochanteric-femoral head lengths were relatively precise, with 95% limits of agreement within 10-15% of the observer average. CONCLUSION: Several radiographic variables of destructive and growth abnormalities in children with hip JIA have reasonable reproducibility. We suggest that future studies on clinical validity focus on assessing only reproducible radiographic variables. PMID- 29717340 TI - Successful Balloon-Assisted Hepatic Tract Embolization Using the Pull-Through Technique to Remove a Malpositioned Chest Tube Penetrating the Liver and into the Right Ventricle. AB - Intra-abdominal injury is an uncommon complication of chest tube insertion. A 66 year-old man had empyema and underwent chest tube insertion for drainage. Massive hemorrhage occurred; the postprocedural radiograph showed the malpositioned chest tube in the mediastinum. Computed tomography scan showed that the tube's tip penetrated through the liver capsule and passed through the hepatic vein to the right ventricle. Hepatic tract embolization with coiling was performed during chest tube removal under a controlled condition with the hepatic tract occluded by a balloon catheter. The balloon catheter was placed from the right jugular vein using the pull-through technique, establishing a through-and-through guidewire. This is the first report of successful removal of a chest tube malpositioned in the hepatic vein by balloon-assisted hepatic tract embolization without complication. PMID- 29717332 TI - Clinical utility of FDG-PET in amyotrophic lateral sclerosis and Huntington's disease. AB - AIM: To evaluate the incremental value of FDG-PET over clinical tests in: (i) diagnosis of amyotrophic lateral sclerosis (ALS); (ii) picking early signs of neurodegeneration in patients with a genetic risk of Huntington's disease (HD); and detecting metabolic changes related to cognitive impairment in (iii) ALS and (iv) HD patients. METHODS: Four comprehensive literature searches were conducted using the PICO model to extract evidence from relevant studies. An expert panel then voted using the Delphi method on these four diagnostic scenarios. RESULTS: The availability of evidence was good for FDG-PET utility to support the diagnosis of ALS, poor for identifying presymptomatic subjects carrying HD mutation who will convert to HD, and lacking for identifying cognitive-related metabolic changes in both ALS and HD. After the Delphi consensual procedure, the panel did not support the clinical use of FDG-PET for any of the four scenarios. CONCLUSION: Relative to other neurodegenerative diseases, the clinical use of FDG PET in ALS and HD is still in its infancy. Once validated by disease-control studies, FDG-PET might represent a potentially useful biomarker for ALS diagnosis. FDG-PET is presently not justified as a routine investigation to predict conversion to HD, nor to detect evidence of brain dysfunction justifying cognitive decline in ALS and HD. PMID- 29717341 TI - Strontium ranelate-induced anti-adipocytic effects are involved in negative regulation of autophagy in rat bone marrow mesenchymal stem cells. AB - PURPOSES: Strontium ranelate (SrRN) is a novel and effective anti-osteoporotic drug used to promote bone formation and restrain bone resorption. However, studies of the effects and mechanism of SrRN on adipocytic differentiation from bone marrow mesenchymal stem cells (BMMSCs) remain limited. METHODS: The cytoactivity of BMMSCs was analyzed by CCK-8 and annexin V-FITC/PI kit. Then the differentiation efficiency was analyzed by Oil Red O staining and western blotting. The level of autophagy was evaluated by immunofluorescence and western blotting. The autophagy inhibitor chloroquine and the selective Akt antagonist API-2 were used to study the relationship between autophagy regulation and adipocytic differentiation. Finally variations in beta-catenin protein levels were also analyzed by western blotting, as were proteins related with autophagy and differentiation signaling pathways. RESULTS: SrRN had no influence on the vatility of BMMSCs (bone marrow mesenchymal stem cells) and exhibited anti adipocytic effects in dose-dependent manner. At the early stage of adipocytic differentiation, autophagy level significantly increased and SrRN inhibited the variation tendency. Then we detected the PPAR-gamma and beta-catenin variation when applied with autophagy inhibitor CQ (chloroquine) and the same way, after Akt selective inhibitor applied in the test, the effect of SrRN was compromised. At last, we detected the increased phosphorylation of Akt-related pathway at 1.00 mM concentration of SrRN in comparison with the adipocytic induction. CONCLUSIONS: SrRN could disturb the process of adipocytic differentiation of BMMSCs and interfere with the variation tendency of autophagy level after adipocytic induction in Akt-dependent manners. PMID- 29717334 TI - The role of striatal dopamine D2/3 receptors in cognitive performance in drug free patients with schizophrenia. AB - OBJECTIVE: A considerable body of research links cognitive function to dopaminergic transmission in the prefrontal cortex, but less is known about cognition in relation to striatal dopamine D2/3 receptors in unmedicated patients with psychosis. METHODS: We investigated this association by obtaining PET recordings with the high-affinity D2/3 antagonist ligand [18F] fallypride in 15 medication-free patients with schizophrenia and 11 healthy controls. On the day of PET scanning, we undertook comprehensive neuropsychological testing and assessment of psychopathology using the Positive and Negative Syndrome Scale (PANSS). RESULTS: The patients' performance in cognitive tests was significantly impaired in almost all domains. Irrespective of medication history, the mean [18F] fallypride binding potential (BPND) in the patient group tended to be globally 5-10% higher than that of the control group, but without reaching significance in any brain region. There were significant positive correlations between individual patient performance in the Trail Making Test (TMT(A) and TMT(B)) and Digit-Symbol-Substitution-Test with regional [18F] fallypride BPND, which remained significant after Bonferroni correction for the TMT(A) in caudate nucleus (CN) and for the TMT(B) in CN and putamen. No such correlations were evident in the control group. DISCUSSION: The association between better cognitive performance and greater BPND in schizophrenia patients may imply that relatively lower receptor occupancy by endogenous dopamine favors better sparing of cognitive function. Absence of comparable correlations in healthy controls could indicate a greater involvement of signaling at dopamine D2/3 receptors in certain cognitive functions in schizophrenia patients than in healthy controls. PMID- 29717336 TI - Global burden of hypoglycaemia-related mortality in 109 countries, from 2000 to 2014: an analysis of death certificates. AB - AIMS/HYPOTHESIS: In the context of increasing prevalence of diabetes in elderly people with multimorbidity, intensive glucose control may increase the risk of severe hypoglycaemia, potentially leading to death. While rising trends of severe hypoglycaemia rates have been reported in some European, North American and Asian countries, the global burden of hypoglycaemia-related mortality is unknown. We aimed to investigate global differences and trends of hypoglycaemia-related mortality. METHODS: We used the WHO mortality database to extract information on death certificates reporting hypoglycaemia or diabetes as the underlying cause of death, and the United Nations demographic database to obtain data on mid-year population estimates from 2000 to 2014. We calculated crude and age-standardised proportions (defined as number of hypoglycaemia-related deaths divided by total number of deaths from diabetes [i.e. the sum of hypoglycaemia- and diabetes related deaths]) and rates (hypoglycaemia-related deaths divided by mid-year population) of hypoglycaemia-related mortality and compared estimates across countries and over time. RESULTS: Data for proportions were extracted from 109 countries (31 had data from all years analysed [2000-2014] available). Combining all countries, the age-standardised proportion of hypoglycaemia-related deaths was 4.49 (95% CI 4.44, 4.55) per 1000 total diabetes deaths. Compared with the overall mean, most Central American, South American and (mainly) Caribbean countries reported higher proportions (five more age-standardised hypoglycaemia related deaths per 1000 total diabetes deaths in Chile, six in Uruguay, 11 in Belize and 22 in Aruba), as well as Japan (11 more age-standardised hypoglycaemia related deaths per 1000 total diabetes deaths). In comparison, lower proportions were noted in most European countries, the USA, Canada, New Zealand and Australia. For countries with data available for all years analysed, trend analysis showed a 60% increase in hypoglycaemia-related deaths until 2010 and stable trends onwards. Rising trends were most evident for Argentina, Brazil, Chile, the USA and Japan. Data for rates were available for 105 countries (30 had data for all years analysed [2000-2014] available). Combining all countries, the age-standardised hypoglycaemia-related death rate was 0.79 (95% CI 0.77, 0.80) per 1 million person-years. Most Central American, South American and Caribbean countries similarly reported higher rates of hypoglycaemia-related death, whilst virtually all European countries, the USA, Canada, Japan, New Zealand and Australia reported lower rates compared with the overall mean. Age-standardised rates were very low for most countries (lower than five per 1 million person years in 89.5% of countries), resulting in small absolute differences among countries. As noted with the proportions analysis, trend analysis showed an overall 60% increase in hypoglycaemia-related deaths until 2010 and stable rate trends onwards; rising rates were particularly evident for Brazil, Chile and the USA. CONCLUSIONS/INTERPRETATION: Most countries in South America, Central America and the Caribbean showed the highest proportions of diabetes-related deaths attributable to hypoglycaemia and the highest rates of hypoglycaemia-related deaths. Between 2000 and 2014, rising trends were observed in Brazil, Chile and the USA for both rates and proportions of hypoglycaemia-related death, and in Argentina and Japan for proportions only. Further studies are required to unravel the contribution of clinical and socioeconomic factors, difference in diabetes prevalence and heterogeneity of death certification in determining lower rates and proportions of hypoglycaemia-related deaths in high-income countries in Europe, North America and Asia. DATA AVAILABILITY: Data used for these analyses are available at https://doi.org/10.17632/ndp52fbz8r.1. PMID- 29717342 TI - A novel approach for toluene gas treatment using a downflow hanging sponge reactor. AB - A novel gas-scrubbing bioreactor based on a downflow hanging sponge (DHS) reactor was developed as a new volatile organic compound (VOC) treatment system. In this study, the effects of varying the space velocity and gas/liquid ratio were investigated to assess the effectiveness of using toluene gas as a model VOC. Under optimal conditions, the toluene removal rate was greater than 80%, and the maximum elimination capacity was observed at approximately 13 g-C m-3 h-1. The DHS reactor demonstrated slight pressure loss (20 Pa) and a high concentration of suspended solids (up to 30,000 mg/L-sponge). Cloning analysis of the 16S rRNA and functional genes of toluene degradation pathways (tmoA, todC, tbmD, xylA, and bssA) revealed that the clones belonging to the toluene-degrading bacterium Pseudomonas putida constituted the predominant species detected at the bottom of the DHS reactor. The toluene-degrading bacteria Pseudoxanthomonas spadix and Pseudomonas sp. were also detected by tmoA- and todC-targeted cloning analyses, respectively. These results demonstrate the potential for the industrial application of this novel DHS reactor for toluene gas treatment. PMID- 29717337 TI - Exercise training decreases pancreatic fat content and improves beta cell function regardless of baseline glucose tolerance: a randomised controlled trial. AB - AIMS/HYPOTHESIS: Pancreatic fat accumulation may contribute to the development of beta cell dysfunction. Exercise training improves whole-body insulin sensitivity, but its effects on pancreatic fat content and beta cell dysfunction are unclear. The aim of this parallel-group randomised controlled trial was to evaluate the effects of exercise training on pancreatic fat and beta cell function in healthy and prediabetic or type 2 diabetic participants and to test whether the responses were similar regardless of baseline glucose tolerance. METHODS: Using newspaper announcements, a total of 97 sedentary 40-55-year-old individuals were assessed for eligibility. Prediabetes (impaired fasting glucose and/or impaired glucose tolerance) and type 2 diabetes were defined by ADA criteria. Of the screened candidates, 28 healthy men and 26 prediabetic or type 2 diabetic men and women met the inclusion criteria and were randomised into 2-week-long sprint interval or moderate-intensity continuous training programmes in a 1:1 allocation ratio using random permuted blocks. The primary outcome was pancreatic fat, which was measured by magnetic resonance spectroscopy. As secondary outcomes, beta cell function was studied using variables derived from OGTT, and whole-body insulin sensitivity and pancreatic fatty acid and glucose uptake were measured using positron emission tomography. The measurements were carried out at the Turku PET Centre, Finland. The analyses were based on an intention-to-treat principle. Given the nature of the intervention, blinding was not applicable. RESULTS: At baseline, the group of prediabetic or type 2 diabetic men had a higher pancreatic fat content and impaired beta cell function compared with the healthy men, while glucose and fatty acid uptake into the pancreas was similar. Exercise training decreased pancreatic fat similarly in healthy (from 4.4% [3.0%, 6.1%] to 3.6% [2.4%, 5.2%] [mean, 95% CI]) and prediabetic or type 2 diabetic men (from 8.7% [6.0%, 11.9%] to 6.7% [4.4%, 9.6%]; p = 0.036 for time effect) without any changes in pancreatic substrate uptake (p >= 0.31 for time effect in both insulin stimulated glucose and fasting state fatty acid uptake). In prediabetic or type 2 diabetic men and women, both exercise modes similarly improved variables describing beta cell function. CONCLUSIONS/INTERPRETATION: Two weeks of exercise training improves beta cell function in prediabetic or type 2 diabetic individuals and decreases pancreatic fat regardless of baseline glucose tolerance. This study shows that short-term training efficiently reduces ectopic fat within the pancreas, and exercise training may therefore reduce the risk of type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT01344928 FUNDING: This study was funded by the Emil Aaltonen Foundation, the European Foundation for the Study of Diabetes, the Finnish Diabetes Foundation, the Orion Research Foundation, the Academy of Finland (grants 251399, 256470, 281440, and 283319), the Ministry of Education of the State of Finland, the Paavo Nurmi Foundation, the Novo Nordisk Foundation, the Finnish Cultural Foundation, the Hospital District of Southwest Finland, the Turku University Foundation, and the Finnish Medical Foundation. PMID- 29717333 TI - 68Ga-PSMA-617 PET/CT: a promising new technique for predicting risk stratification and metastatic risk of prostate cancer patients. AB - PURPOSE: The purpose of this study was to investigate the performance of 68Ga PSMA-617 PET/CT in predicting risk stratification and metastatic risk of prostate cancer. METHODS: Fifty newly diagnosed patients with prostate cancer as confirmed by needle biopsy were continuously included, 40 in a train set and ten in a test set. 68Ga-PSMA-617 PET/CT and clinical data of all patients were retrospectively analyzed. Semi-quantitative analysis of PET images provided maximum standardized uptake (SUVmax) of primary prostate cancer and volumetric parameters including intraprostatic PSMA-derived tumor volume (iPSMA-TV) and intraprostatic total lesion PSMA (iTL-PSMA). According to prostate cancer risk stratification criteria of the NCCN Guideline, all patients were simplified into a low-intermediate risk group or a high-risk group. The semi-quantitative parameters of 68Ga-PSMA-617 PET/CT were used to establish a univariate logistic regression model for high risk prostate cancer and its metastatic risk, and to evaluate the diagnostic efficacy of the predictive model. RESULTS: In the train set, 30/40 (75%) patients had high-risk prostate cancer and 10/40 (25%) patients had low-to-moderate-risk prostate cancer; in the test set, 8/10 (80%) patients had high-risk prostate cancer while 2/10 (20%) had low-intermediate risk prostate cancer. The univariate logistic regression model established with SUVmax, iPSMA-TV and iTL-PSMA could all effectively predict high-risk prostate cancer; the AUC of ROC were 0.843, 0.802 and 0.900, respectively. Based on the test set, the sensitivity and specificity of each model were 87.5% and 50% for SUVmax, 62.5% and 100% for iPSMA TV, and 87.5% and 100% for iTL-PSMA, respectively. The iPSMA-TV and iTL-PSMA based predictive model could predict the metastatic risk of prostate cancer, the AUC of ROC was 0.863 and 0.848, respectively, but the SUVmax-based prediction model could not predict metastatic risk. CONCLUSIONS: Semi-quantitative analysis indexes of 68Ga-PSMA-617 PET/CT imaging can be used as "imaging biomarkers" to predict risk stratification and metastatic risk of prostate cancer. PMID- 29717343 TI - Identification of the Achilles heels of the laurel wilt pathogen and its beetle vector. AB - Ambrosia beetles harbor fungal symbionts that serve as food sources for larvae and adults. These beetles lay their eggs along tunnels in xylem sapwood, which is the substrate for fungal growth. Symbiotic fungi of the genus Raffaelea found in invasive and indigenous ambrosia beetles include the highly virulent plant pathogen Raffaelea lauricola affecting members of the Lauraceae family. R. lauricola is responsible for the deaths of > 500 million trees since 2005. Infection by as few as 100 spores can kill a healthy tree within months. Our data show that R. lauricola is cold-adapted with optimal growth between 16 and 26 degrees C, with little to no growth at temperatures >= 30 degrees C. The fungus is halophilic and shows a dramatic decrease in growth at pH >= 6.8. Fungicide resistance profiling revealed sensitivity of R. lauricola to prochloraz, dichlorofluanid, most conazoles, dithiocarbamates, and zineb (zinc fungicide), whereas the related species Raffaelea arxii showed more limited fungicide sensitivity. Entomopathogenic fungi potentially useful for beetle control were generally highly resistant to most fungicides tested. Coupling pH decreased the concentration for 95% inhibition of fungal growth (IC95) of the most potent R. lauricola fungicides by 3-4-fold. Use of avocado bark plug insect bioassays revealed that commercially available Beauveria bassiana can be used as a biological control agent capable of effectively killing the beetle vectors. These data provide simple and practical recommendations to specifically target R. lauricola while having minimal effects on other symbiotic and entomopathogenic fungi, the latter of which can be used to manage the beetle vectors. PMID- 29717347 TI - Splenic Cysts: A Strong Indication for a Minimally Invasive Partial Splenectomy. Could the Splenic Hilar Vasculature Type Hold a Defining Role? AB - BACKGROUND: The aim of the study is to assess the impact of the splenic hilar vasculature configuration on the amount of remnant splenic parenchyma volume after partial splenectomy for splenic cysts. METHODS: The data of all patients receiving a splenectomy for a splenic cyst from 2002 to 2016 at the Center of General Surgery and Liver Transplantation of Fundeni Clinical Institute were retrospectively reviewed. The size and location in the splenic parenchyma of the cyst and the splenic hilar vasculature type were assessed for each patient with a splenectomy. RESULTS: Thirty-one patients with non-parasitic and 32 patients with hydatid cysts were recorded. In cases of centrally located cysts, a total splenectomy was performed for the majority of cases, while in peripheral cysts a spleen-preserving surgery was feasible for most of the patients (p = 0.001). The size of the cyst was significantly higher in the group of patients with a total splenectomy, compared with the group with a partial splenectomy (p = 0.003). In the subgroup with a distributed arterial pattern, preservation of more than 50% of the initial parenchyma was achieved in a significantly higher proportion of patients, compared with the subgroup of patients with a magistral pattern (p = 0.012). CONCLUSION: Besides cyst size or peripheral location in the splenic parenchyma, the vascular pattern is also considered another decisive factor that associates with successful conservative or minimally invasive approach. PMID- 29717348 TI - Authors' Reply: Enhanced Recovery After Surgery for Low and Middle-Income Countries. PMID- 29717344 TI - Radical Gastrectomy After Chemotherapy May Prolong Survival in Stage IV Gastric Cancer: A Korean Multi-institutional Analysis. AB - ABASTRACT: BACKGROUND: Despite the development of newer treatments, the prognosis for patients with stage IV gastric cancer remains grave. This study evaluated the efficacy of gastrectomy following response to chemotherapy in patients with stage IV gastric cancer. METHODS: A total of 419 patients who were diagnosed with stage IV gastric cancer were identified from the multi-institutional Catholic Gastric Cancer Study Group database. The patients were divided into four groups: 212 were in the chemotherapy only (CTx) group, 124 were in the chemotherapy after palliative gastrectomy (G-CTx) group, 23 were in the radical gastrectomy after chemotherapy (CTx-G) group, and 60 were in the best supportive care group. To compensate for the effects of chemotherapy, cases of chemotherapy responsive were analyzed separately. To identify factors affecting survival rates, cure rates for surgery in the surgery group were analyzed. RESULTS: The 3-year survival rate of the CTx-G group was significantly higher than that of the CTx group (42.8 vs. 12.0%, p = 0.001). Moreover, the CTx-G group's 3-year survival rate was greater than that of the G-CTx group (42.8 vs. 37.1%, p = 0.207). Chemotherapy-responsive patients in the CTx-G group had a better 3-year survival rate than those in the G CTx group (46.1 vs. 18.4%, respectively, p = 0.011). In the surgery group, R0 resection led to a significantly better 3-year survival rate than palliative gastrectomy (61.1 vs. 16.2%, p = 0.003). CONCLUSIONS: Adjuvant surgery might improve the survival rate of patients with stage IV gastric cancer, particularly in R0 resection cases. PMID- 29717351 TI - Capsule endoscopy vs. colonoscopy vs. histopathology in colorectal cancer screening: matched analyses of polyp size, morphology, and location estimates. AB - PURPOSE: Colon capsule endoscopy (CCE) is considered a potential alternative to optical colonoscopy (OC) for colorectal cancer screening. However, the accuracy of CCE in polyp size and morphology estimation is unknown. METHODS: A fully paired study was performed (2015-2016), where 255 participants from the Danish national screening program had CCE, OC, and histopathology (HP) of all detected polyps. We developed a new algorithm to match CCE and OC polyps, based on objective measures of similarity between polyps. We performed paired comparisons of size, morphology and location of CCE, and OC- and HP-matched polyps. We used cross-validation to develop a model able to predict HP polyp size, based on CCE. RESULTS: CCE overestimated size assessed by HP (by 4.3 mm; 95%CI 3.3-5.2 mm) and OC (by 2.7 mm; 95%CI 1.4-3.9 mm). Polyps were more likely to being assessed as "pedunculated" and less likely to being assessed as "flat" in CCE, compared to OC (p < 0.0001). Our model could predict HP polyp size >= 6 mm, solely using CCE assessed size, location, and morphology as model inputs, with a sensitivity = 0.93 (95%CI 0.66-1.00) and specificity = 0.50 (95%CI 0.32-0.68). CONCLUSIONS: If CCE is to be used as a screening test, it is essential: (1) to translate CCE polyp estimations into histopathologic polyp sizes and (2) to consider that, compared to OC, CCE has a higher tendency to assess polyps as pedunculated and a lower tendency to assess them as flat. TRIAL REGISTRATION: Clinicaltrials.gov No. NCT02303756. PMID- 29717345 TI - VATS Partial Pleurectomy Versus VATS Pleural Abrasion: Significant Reduction in Pneumothorax Recurrence Rates After Pleurectomy. AB - INTRODUCTION: Surgical treatment of primary spontaneous pneumothorax (PSP) usually consists of bullectomy and any form of pleurodesis to reduce risk of disease recurrence. Whether pleurectomy is superior to pleural abrasion is still a matter of debate with recurrence rates especially high when performed with a video-assisted thoracoscopic (VATS) approach. Aim of this study was to compare the efficacy of the two methods in prevention of recurrence of pneumothorax in a minimally invasive setting. MATERIALS AND METHODS: Between 01/2005 and 12/2015, 107 patients younger than 40 years with PSP underwent VATS bullectomy and either partial pleurectomy or pleural abrasion. Medical records of patients were reviewed retrospectively. RESULTS: Pleural abrasion was performed in 34/107 patients, 73/107 patients underwent partial pleurectomy. There were no statistically significant differences in age, sex, body mass index or smoking history at time of surgery. There was no significant difference in major postoperative complications (p = 0.3022). Nine (8.4%) patients had a recurrence of pneumothorax during follow-up. Incidence of recurrence in those undergoing pleural abrasion was significantly higher than those undergoing apical pleurectomy (8/34 vs. 1/73, p < 0.001). Surgical technique was the only factor associated with a recurrence of PSP after surgical intervention. DISCUSSION: In our analysis, a VATS partial pleurectomy proved to be effective for prevention of recurrent PSP. Recurrence rates were low despite a minimally invasive approach and significantly lower than in the pleural abrasion group. According to these findings, VATS pleurectomy might be considered as the primary choice for surgical pleurodesis in patients with PSP. PMID- 29717346 TI - Health-Related Quality of Life After Surgery for Small Intestinal Neuroendocrine Tumours. AB - BACKGROUND: Overall survival for patients with small intestinal neuroendocrine tumours (siNETs) is long, even with metastatic disease, making quality of life issues relevant. The impact of surgery on quality of life is not known. We investigated determinants of health-related quality of life in patients who had undergone surgery for a siNET. METHODS: Patients operated for a siNET between 1998 and 2016 at Skane University Hospital (Lund, Sweden), who were alive in February 2017, were sent two questionnaires constructed by the European Organisation for Research and Treatment of Cancer (EORTC QLQ-C30, EORTC QLQ GINET21). Global quality of life, physical function, disease-related worries, diarrhoea and endocrine symptoms were evaluated with linear and logistic regression in relation to patient-, tumour- and treatment-related factors. Statistical analysis was performed using STATA 11(r). RESULTS: One hundred patients (84%) completed the questionnaires. Women had worse global quality of life (p = 0.019), more disease-related worries (p < 0.001) and endocrine symptoms (p = 0.017) than men. Older age was associated with more disease-related worries (p = 0.007), but fewer endocrine symptoms (p = 0.034). Non-symptomatic tumour versus symptomatic tumour (p = 0.002), and treatment with somatostatin analogues versus no treatment (p = 0.040) were associated with less diarrhoea. Small versus large bowel resection was associated with better global quality of life (p = 0.036) and physical function (p = 0.035). CONCLUSIONS: Male gender, younger age, treatment with somatostatin analogues, non-symptomatic tumour, and small intestinal surgery rather than large bowel surgery were associated with better quality of life. PMID- 29717356 TI - Mesenchymal stem cells seeded onto tissue-engineered osteoinductive scaffolds enhance the healing process of critical-sized radial bone defects in rat. AB - Long bone defects comprise one of the most prevalent clinical problems worldwide and the current bone grafting materials have major limitations to repair them. Although tremendous efforts have been made to repair critical-sized long bone defects in animal models, designing an optimal bone tissue-engineered substitute remains one of the main challenges. Hence, this study aims to closely mimic a natural bone healing process by a tissue-engineered construct including osteoinductive materials pre-seeded with bone marrow-derived mesenchymal stem cells (BMSCs). Bioactive glass (BG) was incorporated into the gelatin/nano hydroxyapatite (G/nHAp) scaffold (conventional one) to improve the bone regeneration process via its osteoinductivity and angiogenic activity. The fabricated G/nHAp and gelatin/nano-hydroxyapatite/bioactive glass (G/nHAp/BG) scaffolds were characterized by X-ray diffraction (XRD) and scanning electron microscopy (SEM) and analyzed for porosity and degradation rate. The osteogenic capability of fabricated scaffolds with or without BMSCs was then evaluated in vitro and in vivo. Critical-sized radial bone defects in rats were randomly filled with cell-free and BMSC-seeded scaffolds, autograft and a group left empty without any treatment. In vitro analysis showed that the G/nHAp/BG scaffold significantly increased the expression level of osteogenic and angiogenic markers in comparison to the G/nHAp-treated and control groups (P < 0.05). Moreover, the defects treated with the BMSC-seeded scaffolds showed superior bone formation and structural properties compared to the cell-free scaffolds 4 and 12 weeks post surgery. The radiological and histomorphological properties of defects treated by BMSC-seeded scaffolds, especially the BMSC-seeded G/nHAp/BG scaffold, were comparable to those of the autograft group. It is concluded that the combination of osteoconductive materials (i.e., nHAp) with the bioactive ones such as bioactive glass can effectively accelerate the bone regeneration process. In addition, our results demonstrated that the BMSCs have the potential to drastically increase the bone regeneration ability of osteoinductive scaffolds. PMID- 29717354 TI - Assessment of trace elements in terminal tap water of Hunan Province, South China, and the potential health risks. AB - A total of 116 terminal tap water (TTW) samples from Xiangjiang, Zijiang, Yuanjiang, and Lishui river basins of Hunan province were collected and concentrations of As, Cd, Cr, Pb, Mn, Zn, Fe, Al, and Cu were determined using inductively coupled plasma mass spectrometry. The results showed that 10% of the water samples exceeded the limit level of Cd established by World Health Organization (WHO) of 0.003 mg L-1. Three percent of the samples had Fe level and 1% had As level above the WHO limits of 0.3 and 0.01 mg L-1, respectively. Multivariate statistic approach (cluster analysis and principal component analysis) results revealed that anthropogenic activities and pipeline corrosion were major sources of TTW contamination in Hunan province. The individual and total hazard quotient values estimated by deterministic and probabilistic approaches were both less than 1. However, the mean cancer risk values of Cd were 2.2 * 10-4 and 1.4 * 10-4 for Xiangjiang and Yuanjiang river basin, respectively, both greater than 10-4. The 95th percentile value of cancer risk for Cr was slightly greater than 10-4 in Xiangjiang river basins. Long-term exposure to Cd and Cr through tap water consumption poses moderate carcinogenic health risks to the local residents. PMID- 29717350 TI - Pediatric intracranial aneurysms: changes from previous studies. AB - PURPOSE: To develop a better understanding of pediatric intracranial aneurysms (PIAs). METHODS: All PIAs treated in our center from January 2012 to April 2017 were retrospectively included. Clinical data, treatment summaries, and follow-up outcomes were retrieved and analyzed. RESULTS: A total of 66 PIAs were found in 64 patients with a mean age of 11.4 +/- 5.7 years, 68.8% of whom were male. The most common symptoms were seizure (n = 7, 63.6%) for the 0-5 age group and headache (n = 38, 71.7%) for the 6-18 age group. Fifty-one PIAs (77.3%) were located in the anterior circulation, with the middle cerebral artery (MCA) being the most common site (n = 28, 42.4%). Fifteen patients (23.4%) had PIAs that were pseudoaneurysms, and nine of them (60%) had a combined history of head trauma. Thirty-five patients (54.7%) had distal arterial aneurysms, and 21 of them (60%) presented with seizure. During a mean follow-up time of 1.6 +/- 1.2 years, 79.7% of patients (n = 51) had favorable outcomes, 5 patients (7.8%) died, and the remaining 8 patients (12.5%) had unfavorable outcomes with severe neurological deficits. CONCLUSION: Apart from characteristics consistent with previous studies, several new findings regarding PIAs were reported, including a difference in the most common symptoms in different age groups, the MCA as the predominant location of PIAs, the high ratio of pseudoaneurysms and their head trauma etiology, and the incidence of distal arterial aneurysms and their relationship with the risk of seizures. PMID- 29717353 TI - Bioaccumulation of nickel in tomato plants: risks to human health and agro environmental impacts. AB - Anthropogenic activities such as agriculture, industry, and mining have contributed significantly to the accumulation of heavy metals in the soil, which in turn cause problems to human health and to the environment. The present work aims to study the effects of nickel (Ni) on the development of tomato plants, the risks to human health associated to the consumption of contaminated tomatoes, and the consequences to the environment. The experiment was carried out in greenhouse environment for a period of 120 days, and the plants were cultivated in soils with four different concentrations of Ni: 0, 35, 70, and 105 mg kg-1. The concentration of nickel in each part (root, stem, leaf, and fruit) of the tomato plant was measured at four different stages of the cycle: 30, 60, 90, and 120 days, by inductively coupled plasma optical emission spectrometer (ICP-OES). At the end of the cycle, the concentration of certain macro- and micronutrients was also determined and related to the corresponding Ni concentration in the soil. The distribution of Ni in the parts of the plant was analyzed from the bioaccumulation factor temporal behavior. Nickel concentrations found in the fruit were too low to pose a risk to human health. As a result of this research, it was verified that soils with nickel concentrations close to 70 mg kg-1, which is the limit established by the CONAMA resolution (420/2009), may actually represent an optimum concentration value for the development of tomato plants. It also increases productivity per plant and reduces the use of resources such as water and agricultural inputs. PMID- 29717349 TI - The release of cytochrome c and the regulation of the programmed cell death progress in the endosperm of winter wheat (Triticum aestivum L.) under waterlogging. AB - It has been shown in mammalian systems that the mitochondria can play a key role in the regulation of apoptosis by releasing intermembrane proteins (such as cytochrome c) into the cytosol. Cytochrome c released from the mitochondria to the cytoplasm activates proteolytic enzyme cascades, leading to specific nuclear DNA degradation and cell death. This pathway is considered to be one of the important regulatory mechanisms of apoptosis. Previous studies have shown that endosperm cell development in wheat undergoes specialized programmed cell death (PCD) and that waterlogging stress accelerates the PCD process; however, little is known regarding the associated molecular mechanism. In this study, changes in mitochondrial structure, the release of cytochrome c, and gene expression were studied in the endosperm cells of the wheat (Triticum aestivum L.) cultivar "huamai 8" during PCD under different waterlogging durations. The results showed that waterlogging aggravated the degradation of mitochondrial structure, increased the mitochondrial permeability transition (MPT), and decreased mitochondrial transmembrane potential (DeltaPsim), resulting in the advancement of the endosperm PCD process. In situ localization and western blotting of cytochrome c indicated that with the development of the endosperm cell, cytochrome c was gradually released from the mitochondria to the cytoplasm, and waterlogging stress led to an advancement and increase in the release of cytochrome c. In addition, waterlogging stress resulted in the increased expression of the voltage-dependent anion channel (VDAC) and adenine nucleotide translocator (ANT), suggesting that the mitochondrial permeability transition pore (MPTP) may be involved in endosperm PCD under waterlogging stress. The MPTP inhibitor cyclosporine A effectively suppressed cell death and cytochrome c release during wheat endosperm PCD. Our results indicate that the mitochondria play important roles in the PCD of endosperm cells and that the increase in mitochondrial damage and corresponding release of cytochrome c may be one of the major causes of endosperm PCD advancement under waterlogging. PMID- 29717357 TI - Fullerene-based anodic stripping voltammetry for simultaneous determination of Hg(II), Cu(II), Pb(II) and Cd(II) in foodstuff. AB - Various carbon nanomaterials for use in anodic stripping voltammetric analysis of Hg(II), Cu(II), Pb(II) and Cd(II) are screened. Graphene, carbon nanotubes, carbon nanofibers and fullerene (C60), dispersed in chitosan (Chit) aqueous solution, are used to modify a glassy carbon electrode (GCE). The fullerene chitosan modified GCE (C60-Chit/GCE) displays superior performance in terms of simultaneous determination of the above ions. The electrodes and materials are characterized by electrochemical impedance spectroscopy, cyclic voltammetry, scanning electron microscopy, Raman spectroscopy, X-ray diffraction and X-ray photoelectron spectroscopy. The excellent performance of C60-Chit/GCE is attributed to the good electrical conductivity, large surface area, strong adsorption affinity and unique crystalline structure of C60. Using differential pulse anodic stripping voltammetry, the assay has the following features for Hg(II), Cu(II), Pb(II) and Cd(II), respectively: (a) Peak voltages of +0.14, 0.11, -0.58 and - 0.82 V (vs SCE); (b) linear ranges extending from 0.01-6.0 MUM, 0.05-6.0 MUM, 0.005-6.0 MUM and 0.5-9.0 MUM; and (c), detection limits (3sigma method) of 3 nM (0.6 ppb), 14 nM (0.9 ppb), 1 nM (0.2 ppb) and 21 nM (2.4 ppb). Moreover, the modified GCE is well reproducible and suitable for long-term usage. The method was successfully applied to the simultaneous determination of these ions in spiked foodstuff. Graphical abstract Compared with graphene, carbon nanotubes and carbon nanofibers, an electrode modified with fullerene in chitosan electrode displays superior performance for the simultaneous anodic stripping voltammetric detection of Hg(II), Cu(II), Pb(II) and Cd(II). PMID- 29717352 TI - 17alpha-Ethinylestradiol and 17beta-estradiol removal from a secondary urban wastewater using an RBC treatment system. AB - The presence of micropollutants that include endocrine-disrupting compounds (EDC) in aquatic environments is currently one of the most relevant aspects of water quality due to their adverse effects on aquatic organisms and human health. From the several categories of EDC, 17beta-estradiol (E2) is a natural hormone, which is prevalent in vertebrates, associated with the female reproductive system and maintenance of the sexual characters. 17alpha-Ethinylestradiol (EE2) is a synthetic hormone produced from the natural hormone E2 and is an essential component of oral contraceptives. These compounds are susceptible to bioconcentration and have high potential to bioaccumulation. Wastewater treatment plants are the main point source of E2 and EE2 into aquatic environments, but conventional wastewater treatment systems are not specifically designed for steroid removal. To overcome this problem, biological tertiary treatment may be a solution for the removal of emergent pollutants such as E2 and EE2. The main purpose of the present study is to provide a solution based on the optimization of a rotating biological contactor system to remove estrogens, specifically E2 and EE2, and to quantify their removal efficiency on different matrices, namely real wastewater and different synthetic wastewaters. All assays presented viable removal efficiencies for compound E2 with values always above 50%; real wastewater yielded the highest removal efficiencies. EE2 removal had better removal efficiencies with synthetic wastewater as feed solution, with removals above 15%, whereas the removal efficiency with real wastewater was inexistent. PMID- 29717358 TI - Survival after radical prostatectomy or radiotherapy for locally advanced (cT3) prostate cancer. AB - PURPOSE: No prospective data examined the effect of radical prostatectomy (RP) vs. external beam radiotherapy (EBRT) in locally advanced prostate cancer (PCa). We aimed to compare survival outcomes of RP and EBRT in patients harboring cT3N0 1 PCa. METHODS: Within the SEER database (2004-2014), we identified 5500 cT3N0-1 PCa patients. Cumulative incidence plots and competing-risks regression models (CRRs) tested cancer-specific mortality (CSM) and other cause of mortality (OCM) according to treatment type. The multivariable relationship between baseline prostate-specific antigen (PSA) values and 10-year CSM after either RP or EBRT was graphically depicted using the LOESS smoothing method. Sensitivity analyses were performed in cT3N0-only patients, after OCM propensity score matching, and through landmark analyses. RESULTS: Ten-year CSM and OCM rates were significantly higher after EBRT (15.8 and 28.2%) than RP (8.1 and 10.4%) (all p < 0.0001). In multivariable CRRs, RP yielded lower CSM [hazard ratio (HR): 0.64] than EBRT. Significantly lower 10-year CSM rate was recorded after RP vs. EBRT through the entire range of baseline PSA values. The same results were recorded in cT3N0 subgroup, as well as after OCM propensity score matching. Finally, landmark analyses at 6, 12, 24, and 36 months rejected the effect of favorable survival bias after RP. CONCLUSIONS: CSM was significantly lower after RP than EBRT in cT3N0-1 PCa. A lower CSM was recorded throughout the entire range of baseline PSA and even in cT3N0 subgroup, as well as after OCM propensity score matching and landmark analyses. PMID- 29717355 TI - The function of TRP channels in neutrophil granulocytes. AB - Neutrophil granulocytes are exposed to widely varying microenvironmental conditions when pursuing their physiological or pathophysiological functions such as fighting invading bacteria or infiltrating cancer tissue. Examples for harsh environmental challenges include among others mechanical shear stress during the recruitment from the vasculature or the hypoxic and acidotic conditions within the tumor microenvironment. Chemokine gradients, reactive oxygen species, pressure, matrix elasticity, and temperature can be added to the list of potential challenges. Transient receptor potential (TRP) channels serve as cellular sensors since they respond to many of the abovementioned environmental stimuli. The present review investigates the role of TRP channels in neutrophil granulocytes and their role in regulating and adapting neutrophil function to microenvironmental cues. Following a brief description of neutrophil functions, we provide an overview of the electrophysiological characterization of neutrophilic ion channels. We then summarize the function of individual TRP channels in neutrophil granulocytes with a focus on TRPC6 and TRPM2 channels. We close the review by discussing the impact of the tumor microenvironment of pancreatic ductal adenocarcinoma (PDAC) on neutrophil granulocytes. Since neutrophil infiltration into PDAC tissue contributes to disease progression, we propose neutrophilic TRP channel blockade as a potential therapeutic option. PMID- 29717359 TI - Serious complications after button battery ingestion in children. AB - : Serious and fatal complications after button battery ingestion are increasing worldwide. The aim of this study is to describe serious complications after battery ingestion in children in the Netherlands.All pediatric gastroenterologists in the Netherlands performing upper endoscopies were asked to report all serious complications after battery ingestion in children (0-18 years) between 2008 and 2016 retrospectively.Sixteen serious complications were reported: death after massive bleeding through esophageal-aortal fistula (n = 1), esophageal-tracheal fistula (n = 5), stenosis after (suspected) perforation and mediastinitis (n = 5), (suspected) perforation and mediastinitis (n = 3), vocal cord paralysis (n = 1), and required reintubation for dyspnea and stridor (n = 1). The median time interval between ingestion and presentation was 5 (IQR 2-258) h. All children were <= 5 (median 1.4; IQR 0.9-2.1) years. Vomiting (31.3%), swallowing/feeding problems (31.3%), and fever (31.3%) were the most common presenting symptoms; however, 18.8% of the patients were asymptomatic (n = 1 missing). All batteries were button batteries (75% >= 20 mm; 18.8% < 20 mm; n = 1 missing). The batteries were removed by esophagogastroduodenoscopy (50%) and rigid endoscopy (37.5%) or surgically (12.5%). CONCLUSION: Sixteen serious complications occurred after small and large button batteries ingestion between 2008 and 2016 in both symptomatic and asymptomatic children in the Netherlands. Therefore, immediate intervention after (suspected) button battery ingestion is required. What is Known: * Button battery ingestion may result in serious and fatal complications. * Serious and fatal complications after button battery ingestion are increasing worldwide. What is New: * Sixteen serious complications after button battery ingestion occurred during 2008-2016 in children in the Netherlands. * Serious complications were also caused by small batteries (< 20 mm) in the Netherlands and also occurred in asymptomatic Dutch children. PMID- 29717360 TI - Electrochemiluminescence based competitive immunoassay for Sudan I by using gold functionalized graphitic carbon nitride and Au/Cu alloy nanoflowers. AB - A flower-like Au/Cu alloy nanocomposite (Au/Cu NFs) was synthesized and used in an electrochemiluminescence (ECL) based method for sensitive determination of the dye Sudan I. The Au-g-C3N4 nanosheets as an ECL emitter were prepared by electrostatic adsorption between gold nanoparticles and g-C3N4. They form a film on a glassy carbon electrode (GCE) and then can be connected with Sudan I antigen via gold-nitrogen bond and amidation reactions. The Au/Cu NFs combined with Sudan I antibody also via the Au-N bond and was introduced into the modified GCE by specific recognition between the antibody and the antigen. The overlap between emission spectra of the Au-g-C3N4 nanosheets and absorption spectra of Au/Cu NFs enabled the appearance of ECL resonance energy transfer process. That is, when the Sudan I analyte not present, the ECL was weakened due to absorption by the gray Au/Cu NFs on applying voltages from -1.7 V to 0 V. Conversely, the Au/Cu NFs on the GCE are reduced due to the competition for the antibody between the analyte and the antigen. A strong green ECL emission was obtained. The ECL response is linear in the 0.5 pg mL-1 to 100 ng mL-1 Sudan I concentration range, and the detection limit is 0.17 pg mL-1. Graphical abstract An Au/Cu alloy flower like nanocomposite (Au/Cu NFs) is firstly synthesized as an acceptor to constitute an electrochemiluminescence-resonance energy transfer (ECL-RET) system for sensitive measurement of Sudan I, while Au nanoparticles (Au NPs) functionalized graphitic carbon nitride (g-C3N4) acted as a donor. PMID- 29717361 TI - Non-interventional study to collect data for the application of lidocaine gel 2% during scaling and root planing and professional mechanical plaque removal. AB - OBJECTIVES: Evaluation of the safety and efficacy of a topical lidocaine gel 2% (LG) during scaling and root planing (SRP) and professional mechanical plaque removal (PMPR). MATERIALS AND METHODS: The anesthetic effects as well as unwanted effects of LG prior to or during SRP and PMPR were evaluated in an observational, non-randomized, non-interventional study design. A total of 385 treatments were recorded in 68 study centers all over Germany. Rating of the anesthetic effect of LG by treating personnel and patients using a four-item verbal rating scale (VRS), tolerability, safety (adverse effects), and need for additional local injection anesthesia (ALI). RESULTS: In SRP as well as in PMPR, application of LG allowed a sufficiently pain-free therapy in more than 90% of the patients as stated on the VRS (SRP: 97.8%, PMPR: 93.75%). Overall, ALI was needed in only 4.23% of the patients treated (SRP: 5.3%, PMPR: 2.62%). One adverse effect occurred within the observation. CONCLUSIONS: Application of LG may offer a safe and effective way to achieve pain-free therapy in periodontal patients. CLINICAL RELEVANCE: Patient compliance is key to the success of periodontal maintenance therapy. Effective and safe pain control during various kinds of periodontal therapy might increase patient compliance and therefore contribute to the long term treatment success, among other factors. With regard to the patients observed in this study, 47% had previously received periodontal maintenance therapy and were therefore familiar with the treatment and the associated pain. PMID- 29717362 TI - Microbial accumulation on different suture materials following oral surgery: a randomized controlled study. AB - BACKGROUND: The aim of the study was to compare bacterial accumulation on different suture materials following oral surgery. METHODS: Patients scheduled for implant or periodontal surgery were included in the study. Upon flap closure, four different sutures were placed in a randomized sequence-silk, coated polyglactin, nylon, and polyester. Ten days following surgery, the sutures were removed and incubated in aerobic as well as anaerobic conditions for 7 days and colony-forming units (CFUs) were calculated. Association between bacterial accumulation and periodontal diagnosis, type of surgery, and antibiotic treatment were also tested. RESULTS: All sutures in all patients were found to contain bacteria. Overall, nylon sutures showed significantly lower CFU levels compared to silk, coated polyglactin, and polyester sutures. The type of surgery (implant vs. periodontal surgery) did not significantly influence bacterial accumulation. Also, periodontal diagnosis had little impact on CFU counts. Interestingly, post surgical antibiotic treatment also had only a minor effect on bacterial accumulation on the various sutures. DISCUSSION: The results indicate that the monofilamentous nylon sutures showed less microbial accumulation than the other tested materials that were all braided. This effect may be due to material qualities as well as suture macrostructure. Type of surgery, periodontal diagnosis, and antibiotic consumption have little effect on bacterial accumulation of sutures. CLINICAL RELEVANCE: The study provides the microbial profile of commonly used sutures and may assist in suture selection during clinical procedures. PMID- 29717363 TI - Oromandibular dystonia screening questionnaire for differential diagnosis. AB - OBJECTIVES: Oromandibular dystonia, which is characterized by stereotypic, task specific, or sustained contractions of masticatory and/or lingual muscles, is frequently misdiagnosed as temporomandibular disorders or psychogenic disease. Diagnostic delay in oromandibular dystonia is not acceptable; thus, a screening tool that can distinguish this condition from a temporomandibular disorder may be helpful for medical professionals unfamiliar with involuntary movements or temporomandibular disorders. MATERIALS AND METHODS: A questionnaire that included questions on the clinical features of oromandibular dystonia, such as stereotypy, task-specificity, sensory tricks, and morning benefit, and included questions to rule out temporomandibular disorders (total point range 0-40) was administered to 553 patients suspected to have involuntary movements. RESULTS: Based on a careful examination and the differential diagnosis, the patients were divided into four groups: oromandibular dystonia (n = 385), oral dyskinesia (n = 84), psychogenic (functional) movement disorder (n = 50), and temporomandibular disorders (n = 34). The questionnaire had a high level of internal consistency as measured by the Cronbach's alpha (0.91), and item-total correlation was significant (p < 0.001). The test-retest reliability on two separate occasions showed a significant correlation (p < 0.001). Mean total scores of the questionnaire significantly differed among oromandibular dystonia (32.0), temporomandibular disorders (10.4; one-way analysis of variance, p < 0.001), oral dyskinesia (21.0; p < 0.001), and psychogenic (functional) movement disorder (13.7; p < 0.001). CONCLUSIONS: Findings of this study suggest that the present questionnaire is a simple diagnostic tool that is useful for tentative differentiation of oromandibular dystonia from temporomandibular disorders. CLINICAL RELEVANCE: This screening tool can be used to distinguish oromandibular dystonia from temporomandibular disorders. PMID- 29717364 TI - Acute promyelocytic leukemia cell adhesion to vascular endothelium is reduced by heparins. AB - Adhesion of acute promyelocytic leukemia (APL) cells to endothelial cells (EC) is among the mechanisms of the APL-associated coagulopathy, responsible for early hemorrhagic deaths in affected patients. We compared the effects of dalteparin and enoxaparin, two low-molecular-weight heparins (LMWH), and unfractionated heparin (UFH), on APL NB4 adhesion to micro- (HMEC-1) and macro-vascular EC (HUVEC), in resting and interleukin-1beta (IL-1beta)-stimulated conditions. The heparin effect on EC adhesion molecule (ICAM-1, VCAM-1, E-selectin) expression was also assessed. In HMEC-1, dalteparin inhibited IL1beta-induced NB4 adhesion by 80%, enoxaparin by 52%, and UFH by 44%. Similar results were obtained in HUVEC. This was associated with a significant decrease of VCAM-1 and ICAM-1 expression. In conclusion, we show that LMWH significantly counteract APL cell adhesion to the vessel wall, by modulating EC adhesion molecule expression. This property of heparins may represent one approach for hampering excess clotting activation and microthrombi deposition in APL. PMID- 29717365 TI - The WHO diagnostic criteria for polycythemia vera-role of red cell mass versus hemoglobin/hematocrit level and morphology. AB - Regarding diagnosis of polycythemia vera (PV), discussion persists about hemoglobin (Hb) and/or hematocrit (Hct) threshold values as surrogate markers for red cell mass (RCM) and the diagnostic impact of bone marrow (BM) morphology. We performed a retrospective study on 290 patients with PV (151 males, 139 females; median age 65 years) presenting with characteristic BM features (initial biopsies, centralized evaluation) and endogenous erythroid colony (EEC) formations. This cohort included (1) a group of 229 patients when following the 2008 versus 256 patients diagnosed according to the 2016 World Health Organization (WHO) guidelines, all presented with increased RCM; (2) masked PV patients with low Hb (n = 143)/Hct (n = 45) recruited from the 2008 WHO cohort; (3) a cohort of 17 PV patients with elevated diagnostic Hb/Hct levels but low RCM; and (4) nine PV patients with increased RCM, opposing low Hb/Hct values. All patients were treated according to current PV guidelines (phlebotomies 87%, hydroxyurea 79%, and acetylsalicylic acid 87%). Applying the 2016 WHO criteria significantly increased concordance between RCM and Hb values compared with the 2008 WHO criteria (90 vs. 43% in males and 83 vs. 64% in females). Further analysis of the WHO 2016 PV cohort revealed that increased RCM is associated with increased Hb/Hct (93.8/94.6%). Our study supports and extends the diagnostic impact of the 2016 revised WHO classification for PV by highlighting the importance of characteristic BM findings and implies that Hb/Hct threshold values may be used as surrogate markers for RCM measurements. PMID- 29717366 TI - A portion of expanded granular lymphocytes cause pure white cell aplasia? PMID- 29717367 TI - Allogeneic stem cell transplantation recipients requiring intensive care: time is of the essence. AB - The benefit of early admission of allogeneic stem cell transplantation (SCT) recipients to the intensive care unit (ICU) as soon as they develop organ injury is unknown. We performed a retrospective study on 92 patients admitted to the ICU to determine the impact of time from organ injury to ICU admission on outcome. The number of organ injuries prior to ICU admission was associated with an increased in-hospital mortality (OR 1.7, 95% CI 1-2.7, p = 0.04). Time between first organ injury and ICU admission was also associated with an increased in hospital survival (OR 1.4, 95% CI 1.1-1.8, p = 0.02). A score combining these two covariates-the number of organ injuries/day (sum of days spent with each individual organ injury)-further improved the prediction of hospital survival. Patients with more organ injuries/day had significantly higher in-hospital mortality rate even after adjustment for refractory acute GVHD and the SOFA (OR 1.3, 95% CI 1-1.7, p = 0.02). Early ICU admission of allogeneic SCT recipients to the ICU as soon as they develop organ injury is associated with decreased in hospital mortality. PMID- 29717369 TI - Molecular identification of Trichodina compacta Van As and Basson, 1989 (Ciliophora: Peritrichia) from cultured Oreochromis niloticus in Egypt and its impact on immune responses and tissue pathology. AB - Trichodinids are peritrichous ciliated protozoa that affect both wild and cultured fishes. Several Trichodina species have low host specificity and are morphologically distinct, facilitating their identification based primarily on the presence of adhesive discs and the number of attached denticles. A trichodinid species named Trichodina compacta was first reported by Van As and Basson (1989) (Protozoa: Ciliophora: Peritrichia). However, in trichodinid infestations, morphological characteristics are insufficient for identifying the infesting species. Therefore, molecular and phylogenetic analyses are considered to be promising and useful tools for identifying the infesting species. This study aimed to achieve the molecular identification of a trichodinid infestation in Nile tilapia and to construct the phylogenetic relationships between the identified species and other peritrichous parasites. Moreover, we also aimed to study the pathological and immunological impacts of trichodinids on fry tissue to improve our understanding of the immune responses of teleost fish to trichodinae parasitic infestations and develop a better control method. Here, we used molecular techniques to identify the isolated trichodina species as T. compacta and demonstrated that Trichodina infestation in Nile tilapia is associated with remarkable immunogenic and inflammatory responses (increased il-1beta expression and decreased il-8 and tgf-beta expression). These findings improve our understanding of the responses of teleost fish to trichodinid parasite infestation and will be helpful for the development of novel control strategies that reverse the inflammatory and immunogenic alterations that occur in infested fish. PMID- 29717368 TI - Hybrid cardiac imaging using PET/MRI: a joint position statement by the European Society of Cardiovascular Radiology (ESCR) and the European Association of Nuclear Medicine (EANM). AB - : Positron emission tomography (PET) and magnetic resonance imaging (MRI) have both been used for decades in cardiovascular imaging. Since 2010, hybrid PET/MRI using sequential and integrated scanner platforms has been available, with hybrid cardiac PET/MR imaging protocols increasingly incorporated into clinical workflows. Given the range of complementary information provided by each method, the use of hybrid PET/MRI may be justified and beneficial in particular clinical settings for the evaluation of different disease entities. In the present joint position statement, we critically review the role and value of integrated PET/MRI in cardiovascular imaging, provide a technical overview of cardiac PET/MRI and practical advice related to the cardiac PET/MRI workflow, identify cardiovascular applications that can potentially benefit from hybrid PET/MRI, and describe the needs for future development and research. In order to encourage its wide dissemination, this article is freely accessible on the European Radiology and European Journal of Hybrid Imaging web sites. KEY POINTS: * Studies and case reports indicate that PET/MRI is a feasible and robust technology. * Promising fields of application include a variety of cardiac conditions. * Larger studies are required to demonstrate its incremental and cost-effective value. * The translation of novel radiopharmaceuticals and MR-sequences will provide exciting new opportunities. PMID- 29717370 TI - Chemical composition and assessment of larvicidal and repellent capacity of 14 Lamiaceae essential oils against Aedes albopictus. AB - In the current laboratory study, 14 essential oils (EOs) derived from 12 Lamiaceae plant species and their major components were screened for their larvicidal and repellent properties against Aedes albopictus, an invasive mosquito species of great medical importance. The results of toxicity bioassays revealed that the EOs from Thymus vulgaris, Ocimum basilicum, Origanum dictamnus, Origanum majorana, and Origanum vulgare, as well as their major components (terpenes), namely thymol, carvacrol, p-cymene, and gamma-terpinene exerted the highest larvicidal effect. Essential oils from Mellisa officinalis, Origanum dictamus, Mentha spicata (chem. piperitenone epoxide), Origanum majorana, and Satureja thymbra were the most potent repellents, with the last two assigned as the best ones. Among the terpenes tested, piperitenone epoxide, carvacrol, thymol, and piperitenone provided the highest level of protection against Ae. albopictus adults. Chemical analysis revealed the presence of a high number of terpenes in the EOs, while in most cases, the biological action of the tested EOs and their major components was in consistency. The most effective EOs and terpenes that were identified through the current laboratory bioassays could be used as alternative agents to control larvae and repel adults of Ae. albopictus. PMID- 29717371 TI - Visceral leishmaniasis from a non-endemic Himalayan region of Nepal. AB - Visceral leishmaniasis (VL) is endemic to the southern plains of Nepal. Here, we report the first case of VL from a non-endemic Himalayan region of Nepal. The patient presented with a history of high-grade fever, splenomegaly, and anemia but had not traveled to a VL-endemic region. Visceral leishmaniasis was diagnosed following microscopic detection of the Leishmania species amastigote in a bone marrow aspirate, positive result for the rK39 test, and further validation by nested polymerase chain reaction (PCR). The patient was treated with 5 mg/kg liposomal amphotericin B and was clinically improved upon discharge. Our result suggests that VL is expanding towards non-endemic regions of Nepal, and it should therefore be considered that VL surveillance systems be strengthened, particularly for non-program districts and VL be included as a differential diagnosis in febrile illnesses. PMID- 29717372 TI - Combined repeat laparoscopy and transanal endolumenal repair (hybrid approach) in the early management of postoperative colorectal anastomotic leaks: technique and outcomes. AB - BACKGROUND: Few clear recommendations exist for the management of colorectal anastomotic leaks, often based on surgeon preferences or institutional protocols. The primary goal was to evaluate the feasibility and safety of the combined laparoscopic and transanal (hybrid) approach to treat postoperative colorectal anastomotic leaks. The secondary goals included comparison of outcomes following early (< 5 days after initial resection) versus late (>= 5 days) detection of leaks. MATERIALS AND METHODS: Sixteen hemodynamically stable patients, with anastomotic dehiscence < 50% of the circumference after laparoscopic anterior resection underwent repeat laparoscopy (lavage/drainage) and transanal endolumenal repair (7 low (< 5 cm from the anal verge) with an ordinary anoscope and 9 high (>= 5 cm from the anal verge) with a transanal endoscopic operations (TEO(r)) platform). RESULTS: The median delay to detection and management was 4.5 days. The procedure was feasible in 13/16 patients (3 patients required conversion to laparotomy). Primary healing of the anastomosis was obtained in 14 patients (13 with the combined procedure, one after conversion). Two patients (1 early, 1 late) sustained persistent purulent discharge via their drain, but the repair healed secondarily. All patients requiring conversion to laparotomy (n = 3) or sustaining intra-operative complications (n = 3) were in the delayed group. No patients required further intervention or died. Protective stomas, created either at index surgery (n = 7) or at re-operation (n = 9), were closed in 14/16 patients within 6 months and no anastomotic sinus, persistent or recurrent fistula, was noted at 1-year follow-up. LIMITATIONS: This is a single-center study consisting of small sample size. CONCLUSIONS: Combined repeat laparoscopy and transanal endolumenal repair is feasible and safe, potentially reducing postoperative morbidity associated with repeat laparotomy and anastomotic leaks. Early detection and re-intervention are fundamental to success. Currently missing from the International Study Group of Rectal Cancer recommendations, laparoscopy and endolumenal repair could be added as a therapeutic option in Grade B. PMID- 29717373 TI - Transpapillary endopancreatic surgery: decompression of duct system and comparison of greenlight laser with monopolar electrosurgical device in ex vivo and in vivo animal models. AB - BACKGROUND: Endopancreatic surgery (EPS) is an experimental minimally invasive technique for resection of pancreatic tissue from inside the pancreatic duct, accessed via the duodenum and papilla. It is proposed as an alternative to duodenum-preserving pancreatic head resection in benign diseases such as chronic pancreatitis (CP). This study evaluated the use of EPS for resection of pancreatic duct stenoses. Moreover, greenlight laser (GLL) and monopolar electrosurgical device (MES) were compared as resection tools for EPS. METHODS: The suitability of EPS for resection of stenoses was evaluated in ex vivo bovine pancreas (n = 8). Artificially created stenoses in the pancreatic head were accessed via the duodenal papilla and resected from inside the organ with MES through a rigid endoscope. Furthermore, standardized pancreatic resections were performed in an in vivo porcine model using either GLL (n = 18) or MES (n = 18) to compare blood loss, operating time, and complications. Thermal damage to the surrounding tissue was assessed using a standardized histological classification. RESULTS: Stenosis resection by EPS was feasible in 8/8 bovine pancreases, with a procedure time of 17 (12-24) min. No perforation of the organ occurred. Resection by GLL was associated with reduced blood loss [median 1.7 (interquartile range 0.6-2.6) ml vs. 5.1 (3.8-13.2) ml; p < 0.01] and shorter operating time [109 (81 127) s vs. 390 (337-555) s; p < 0.01] compared with MES. The zone of thermal tissue damage was more extensive when using GLL than with MES [4.12 (3.48-4.89) mm vs. 1.33 (1.09-1.48) mm; p < 0.01]. CONCLUSION: Transduodenal-transpapillary EPS can be used to resect stenoses and decompress the pancreatic duct system. Both GLL and MES are feasible resection methods for EPS. However, GLL showed better hemostatic characteristics than MES in an in vivo porcine model. Safety measures such as temperature control and image-guided navigation should be employed to monitor the resection and tissue heating. PMID- 29717374 TI - All in: expansion of the acquisition of data for outcomes and procedure transfer (ADOPT) program to an entire SAGES annual meeting hands-on hernia course. AB - BACKGROUND: Continuing professional development (CPD) for the surgeon has been challenging because of a lack of standardized approaches of hands-on courses, resulting in poor post-course outcomes. To remedy this situation, SAGES has introduced the ADOPT program, implementing a standardized, long-term mentoring program as part of its hernia hands-on course. Previous work evaluating the pilot program showed increased adoption of learned procedures as well as increased confidence of the mentored surgeons. This manuscript describes the impact of such a program when it is instituted across an entire hands-on course. METHODS: Following collection of pre-course benchmark data, all participants in the 2016 SAGES hands-on hernia course underwent structured, learner-focused instruction during the cadaveric lab. All faculty had completed a standardized teaching course in the Lapco TT format. Subsequently, course participants were enrolled in a year-long program involving longitudinal mentorship, webinars, conference calls, and coaching. Information about participant demographics, training, experience, self-reported case volumes, and confidence levels related to procedures were collected via survey 3 months prior to 9 months after the course. RESULTS: Twenty surgeons participated in the SAGES ADOPT 2016 hands-on hernia program. Of these, seventeen completed pre-course questionnaires (85%), ten completed the 3-month questionnaire (50%), and four completed the 9-month questionnaire (20%). Nine of ten respondents of the 3-month survey (90%) reported changes in their practice. In the 9-month survey, significant increases in the annualized procedural volumes were reported for open primary ventral hernia repair, open components separation, and mesh insertion for ventral hernia repair (p < 0.001). CONCLUSIONS: The expansion of the ADOPT program to an entire hands on hernia course is both feasible and beneficial, with evidence of Kirkpatrick Levels 1-4a training effectiveness. This expanded success suggests that it is a useful blueprint for the CPD of surgeons wishing to learn new techniques and procedures for their patients. PMID- 29717375 TI - Cerebellar atrophy is common among mitochondrial disorders. PMID- 29717376 TI - Development and validation of an HPLC-MS/MS method for the determination of arginine-vasopressin receptor blocker conivaptan in human plasma and rat liver microsomes: application to a metabolic stability study. AB - PURPOSE: To develop and validate a bio-analytical HPLC-MS/MS method for the determination of conivaptan (CVA) an arginine-vasopressin receptor blocker in human plasma and in rat liver microsomes (RLMs). METHODS: Analytes were separated on a reversed phase C18 column (50 mm * 2.1 mm, 1.8 MUm). The mobile phase was a mixture of acetonitrile and 10 mM ammonium formate (40:60 v/v, pH 4.0) and was pumped isocratically for 4 min at a flow rate of 0.2 ml/min. Multiple reaction monitoring in positive ionization mode was used for the assay. RESULTS: The method yielded a linear calibration plot (r 2 = 0.9977 and 0.9998) over 5-500 ng/ml with a limit of detection at 1.52 and 0.88 ng/ml for human plasma and RLMs, respectively. The reproducibility of detection of CVA in human plasma and RLMs was found to be in an acceptable range. CONCLUSION: The method developed in this study is applicable for accurately quantifying CVA in human plasma and rat liver microsomal samples. The optimized procedure was applied to study of metabolic stability of CVA. Conivaptan concentration rapidly decreased in the first 2 min of RLMs incubation and the conversion reached a plateau for the remainder of the incubation period. The in vitro half-life (t1/2) was estimated at 11.51 min and the intrinsic clearance (CLin) was 13.8 +/- 0.48 ml/min/kg. PMID- 29717377 TI - A Systematic Review of Sleep, Hypertension, and Cardiovascular Risk in Children and Adolescents. AB - PURPOSE OF REVIEW: Many of the risk factors for heart disease have recently been shown to develop during childhood such as left ventricular hypertrophy and fibrous plaque lesions. As risk for cardiovascular disease in children and adolescents has risen, sleep duration has decreased, and inadequate sleep in children and adolescents has been found to be associated with cardiovascular disease risk. The aims of this manuscript are to provide an updated systematic review of the literature assessing sleep, hypertension, and cardiovascular risk and evaluate the strength of the evidence based on the available research. RECENT FINDINGS: A systematic review was conducted using six databases from January 1, 2015 through March 9, 2018. We sought studies which looked at the relationship between sleep duration, sleep timing, or sleep quality and outcome variables of hypertension, inflammation, obesity, glucose or insulin, and lipids in children and adolescents. We found 24 studies which met our criteria. Nine studies included hypertension as an outcome variable; fifteen included obesity; thirteen included glucose or insulin; eight included lipids; and three included measures of inflammation. The existing literature on sleep and cardiovascular disease in children and adolescents is limited and relatively weak. Only one RCT was identified, and the overwhelming majority of studies had a high risk of bias. The strongest evidence of an association with sleep is with obesity, hypertension, and insulin sensitivity. Further research using more standardized methods and objective measures is needed to determine if a causal relationship truly exists between sleep and cardiovascular risk. PMID- 29717378 TI - Risk factors for clinical ketosis and association with milk production and reproduction variables in dairy cows in a hot environment. AB - The aims of the present study were to investigate (1) the risk factors that influence the occurrence of clinical ketosis (CK; blood beta-hydroxybutyrate > 3.0 mmol/L) and (2) to determine the influence of subclinical ketosis (SCK; 1.2 <= beta-hydroxybutyrate <= 2.9 mmol/L) and CK on reproductive performance and milk yield in high-yielding Holstein cows in a hot environment. Cows (n = 345) were blood sampled from 6 to 15 days postpartum for beta-hydroxybutyrate (BHB) determination with a hand-held meter. Cows calving in spring had 3.7 increased odds of having CK (20.7% incidence) than cows calving in summer (3.9% incidence) and autumn (9.4% incidence). Temperature-humidity index < 83 was associated with 1.6 times higher risk for CK compared with cows calving in warmer days. First service conception rate was 12 and 16 percentage point higher (P < 0.05) in nonketotic cows compared with cows with SCK and CK, respectively. Actual 305-day milk yields for healthy, SCK, and CK cows were 9991 +/- 1411, 10,123 +/- 1442, and 10,386 +/- 1435 kg (mean +/- SD), respectively, with no difference (P > 0.05) between groups. In conclusion, this study documented that ketosis was seasonal with lower incidence of this metabolic disease during hot seasons and with increased ambient temperature at calving. Also, 305-day milk yield of Holstein cows was not related to blood BHB content early in lactation in this hot environment. However, elevated circulating BHB was negatively associated with conception rate at first service and fetal losses. PMID- 29717379 TI - Regional geochemical baseline concentration of potentially toxic trace metals in the mineralized Lom Basin, East Cameroon: a tool for contamination assessment. AB - The distribution of trace metals in active stream sediments from the mineralized Lom Basin has been evaluated. Fifty-five bottom sediments were collected and the mineralogical composition of six pulverized samples determined by XRD. The fine fraction (< 150 um) was subjected to total digestion (HClO4 + HF + HCl) and analyzed for trace metals using a combination of ICP-MS and AAS analytical methods. Results show that the mineralogy of stream sediments is dominated by quartz (39-86%), phyllosilicates (0-45%) and feldspars (0-27%). Mean concentrations of the analyzed metals are low (e.g. As = 99.40 ug/kg, Zn = 573.24 ug/kg, V = 963.14 ug/kg and Cr = 763.93 ug/kg). Iron and Mn have significant average concentrations of 28.325 and 442 mg/kg, respectively. Background and threshold values of the trace metals were computed statistically to determine geochemical anomalies of geologic or anthropogenic origin, particularly mining activity. Factor analysis, applied on normalized data, identified three associations: Ni-Cr-V-Co-As-Se-pH, Cu-Zn-Hg-Pb-Cd-Sc and Fe-Mn. The first association is controlled by source geology and the neutral pH, the second by sulphide mineralization and the last by chemical weathering of ferromagnesian minerals. Spatial analysis reveals similar distribution trends for Co-Cr-V-Ni and Cu-Zn-Pb-Sc reflecting the lithology and sulphide mineralization in the basin. Relatively high levels of As were concordant with reported gold occurrences in the area while Fe and Mn distribution are consistent with their source from the Fe-bearing metamorphic rocks. These findings provide baseline geochemical values for common and parallel geological domains in the eastern region of Cameroon. Although this study shows that the stream sediments are not polluted, the evaluation of metal composition in environmental samples from abandoned and active mine sites for comparison and environmental health risk assessment is highly recommended. PMID- 29717381 TI - Parental Support and Youth Occupational Attainment: Help or Hindrance? AB - Although several concerns surround the transition to adulthood and youth increasingly rely on parental support, our knowledge about the implications of parental support for youth development and transition to adulthood is limited. This study fills this gap by conceptualizing development within a life course perspective that links social inequality and early life course transitions. It draws on a subsample of youth observed between age 18 and 28 from the Transition to Adulthood supplement of the Panel Study of Income Dynamics 2005-2015 (N = 7,542; 53% female, 51.3% white). Mixed-effects models reveal that the more direct financial transfers youth receive, the higher their occupational status. Yet, indirect financial support parents offer through co-residence shows the opposite pattern. Among youth receiving monetary transfers, college graduates have particularly high occupational status; however, among youth living with their parents, college graduates have the lowest occupational status. Although different types of parental support may equally act as safety nets, their divergent implications for youths' occupational attainment raise concerns about the reproduction and possible intensification of inequality during this developmental stage. PMID- 29717380 TI - Selective vs. Global Renal Denervation: a Case for Less Is More. AB - PURPOSE OF REVIEW: Review the renal nerve anatomy and physiology basics and explore the concept of global vs. selective renal denervation (RDN) to uncover some of the fundamental limitations of non-targeted renal nerve ablation and the potential superiority of selective RDN. RECENT FINDINGS: Recent trials testing the efficacy of RDN showed mixed results. Initial investigations targeted global RDN as a therapeutic goal. The repeat observation of heterogeneous response to RDN including non-responders with lack of a BP reduction, or even more unsettling, BP elevations after RDN has raised concern for the detrimental effects of unselective global RDN. Subsequent studies have suggested the presence of a heterogeneous fiber population and the potential utility of renal nerve stimulation to identify sympatho-stimulatory fibers or "hot spots." The recognition that RDN can produce heterogeneous afferent sympathetic effects both change therapeutic goals and revitalize the potential of therapeutic RDN to provide significant clinical benefits. Renal nerve stimulation has emerged as potential tool to identify sympatho-stimulatory fibers, avoid sympatho-inhibitory fibers, and thus guide selective RDN. PMID- 29717382 TI - Iron metabolism in critically ill patients developing anemia of inflammation: a case control study. AB - BACKGROUND: Anemia occurring as a result of inflammatory processes (anemia of inflammation, AI) has a high prevalence in critically ill patients. Knowledge on changes in iron metabolism during the course of AI is limited, hampering the development of strategies to counteract AI. This case control study aimed to investigate iron metabolism during the development of AI in critically ill patients. METHODS: Iron metabolism in 30 patients who developed AI during ICU stay was compared with 30 septic patients with a high Hb and 30 non-septic patients with a high Hb. Patients were matched on age and sex. Longitudinally collected plasma samples were analyzed for levels of parameters of iron metabolism. A linear mixed model was used to assess the predictive values of the parameters. RESULTS: In patients with AI, levels of iron, transferrin and transferrin saturation showed an early decrease compared to controls with a high Hb, already prior to the development of anemia. Ferritin, hepcidin and IL-6 levels were increased in AI compared to controls. During AI development, erythroferrone decreased. Differences in iron metabolism between groups were not influenced by APACHE IV score. CONCLUSIONS: The results show that in critically ill patients with AI, iron metabolism is already altered prior to the development of anemia. Levels of iron regulators in AI differ from septic controls with a high Hb, irrespective of disease severity. AI is characterized by high levels of hepcidin, ferritin and IL-6 and low levels of iron, transferrin and erythroferrone. PMID- 29717383 TI - [18F]DPA-714 PET imaging shows immunomodulatory effect of intravenous administration of bone marrow stromal cells after transient focal ischemia. AB - BACKGROUND: The potential application of bone marrow stromal cell (BMSC) therapy in stroke has been anticipated due to its immunomodulatory effects. Recently, positron emission tomography (PET) with [18F]DPA-714, a translocator protein (TSPO) ligand, has become available for use as a neural inflammatory indicator. We aimed to evaluate the effects of BMSC administration after transient middle cerebral artery occlusion (MCAO) using [18F]DPA-714 PET. The BMSCs or vehicle were administered intravenously to rat MCAO models at 3 h after the insult. Neurological deficits, body weight, infarct volume, and histology were analyzed. [18F]DPA-714 PET was performed 3 and 10 days after MCAO. RESULTS: Rats had severe neurological deficits and body weight loss after MCAO. Cell administration ameliorated these effects as well as the infarct volume. Although weight loss occurred in the spleen and thymus, cell administration suppressed it. In both vehicle and BMSC groups, [18F]DPA-714 PET showed a high standardized uptake value (SUV) around the ischemic area 3 days after MCAO. Although SUV was increased further 10 days after MCAO in both groups, the increase was inhibited in the BMSC group, significantly. Histological analysis showed that an inflammatory reaction occurred in the lymphoid organs and brain after MCAO, which was suppressed in the BMSC group. CONCLUSIONS: The present results suggest that BMSC therapy could be effective in ischemic stroke due to modulation of systemic inflammatory responses. The [18F]DPA-714 PET/CT system can accurately demonstrate brain inflammation and evaluate the BMSC therapeutic effect in an imaging context. It has great potential for clinical application. PMID- 29717384 TI - The Complement Alternative Pathway and Preeclampsia. AB - PURPOSE OF REVIEW: Significant and intricate immune adaptations are essential for the establishment and maintenance of normal pregnancy. Preeclampsia is a morbid, potentially life-threatening disease for both mother and neonate that occurs uniquely in pregnancy, at least in part, due to maternal immune maladaptation. We aim to review the literature that focuses on case reports, diagnostic approaches, and treatment strategies for disorders of the complement alternative pathway (CAP) as related to preeclampsia. RECENT FINDINGS: There is evidence of complement dysregulation in preeclampsia and HELLP syndrome, similar to that observed in a few rare types of thrombotic microangiopathies. Complement dysregulation may be identified with functional laboratory testing as well as genetic testing. Increased utilization of a standardized diagnostic approach to establish whether persistent and/or severe cases of preeclampsia and HELLP syndrome are complement-mediated may lead to development of future treatment strategies, such as complement-targeted therapy. PMID- 29717385 TI - Determination of gamma camera calibration factors for quantitation of therapeutic radioisotopes. AB - BACKGROUND: Camera calibration, which translates reconstructed count map into absolute activity map, is a prerequisite procedure for quantitative SPECT imaging. Both planar and tomographic scans using different phantom geometries have been proposed for the determination of the camera calibration factor (CF). However, there is no consensus on which approach is the best. The aim of this study is to evaluate all these calibration methods, compare their performance, and propose a practical and accurate calibration method for SPECT quantitation of therapeutic radioisotopes. Twenty-one phantom experiments (Siemens Symbia SPECT/CT) and 12 Monte Carlo simulations (GATE v6.1) using three therapy isotopes (131I, 177Lu, and 188Re) have been performed. The following phantom geometries were used: (1) planar scans of point source in air (PS), (2) tomographic scans of insert(s) filled with activity placed in non-radioactive water (HS + CB), (3) tomographic scans of hot insert(s) in radioactive water (HS + WB), and (4) tomographic scans of cylinders uniformly filled with activity (HC). Tomographic data were reconstructed using OSEM with CT-based attenuation correction and triple energy window (TEW) scatter correction, and CF was determined using total counts in the reconstructed image, while for planar scans, the photopeak counts, corrected for scatter and background with TEW, were used. Additionally, for simulated data, CF obtained from primary photons only was analyzed. RESULTS: For phantom experiments, CF obtained from PS and HS + WB agreed to within 6% (below 3% if experiments performed on the same day are considered). However, CF from HS + CB exceeded those from PS by 4-12%. Similar trend was found in simulation studies. Analysis of CFs from primary photons helped us to understand this discrepancy. It was due to underestimation of scatter by the TEW method, further enhanced by attenuation correction. This effect becomes less important when the source is distributed over the entire phantom volume (HS + WB and HC). CONCLUSIONS: Camera CF could be determined using planar scans of a point source, provided that the scatter and background contributions are removed, for example using the clinically available TEW method. This approach is simple and yet provides CF with sufficient accuracy (~ 5%) to be used in clinics for radiotracer quantification. PMID- 29717386 TI - Low-level laser irradiation induces a transcriptional myotube-like profile in C2C12 myoblasts. AB - Low-level laser irradiation (LLLI) has been used as a non-invasive method to improve muscular regeneration capability. However, the molecular mechanisms by which LLLI exerts these effects remain largely unknown. Here, we described global gene expression profiling analysis in C2C12 myoblasts after LLLI that identified 514 differentially expressed genes (DEG). Gene ontology and pathway analysis of the DEG revealed transcripts among categories related to cell cycle, ribosome biogenesis, response to stress, cell migration, and cell proliferation. We further intersected the DEG in C2C12 myoblasts after LLLI with publicly available transcriptomes data from myogenic differentiation studies (myoblasts vs myotube) to identify transcripts with potential effects on myogenesis. This analysis revealed 42 DEG between myoblasts and myotube that intersect with altered genes in myoblasts after LLLI. Next, we performed a hierarchical cluster analysis with this set of shared transcripts that showed that LLLI myoblasts have a myotube like profile, clustering away from the myoblast profile. The myotube-like transcriptional profile of LLLI myoblasts was further confirmed globally considering all the transcripts detected in C2C12 myoblasts after LLLI, by bi dimensional clustering with myotubes transcriptional profiles, and by the comparison with 154 gene sets derived from previous published in vitro omics data. In conclusion, we demonstrate for the first time that LLLI regulates a set of mRNAs that control myoblast proliferation and differentiation into myotubes. Importantly, this set of mRNAs revealed a myotube-like transcriptional profile in LLLI myoblasts and provide new insights to the understanding of the molecular mechanisms underlying the effects of LLLI on skeletal muscle cells. PMID- 29717387 TI - beta4GalT1 Mediates PPARgamma N-Glycosylation to Attenuate Microglia Inflammatory Activation. AB - The inflammatory activation of microglia has double-edged effects in central nervous system (CNS) diseases. The ligand-activated transcriptional factor peroxisome proliferator-activated receptor gamma (PPARgamma) inhibits the inflammatory response. beta-1,4-Galactosyltransferase Iota (beta1, 4GalT1) mediates N-glycosylation. In this study, the N-glycosylation of PPARgamma, as well as two N-linked glycosylation sites in its DNA binding domain (DBD), was identified. Disruption of both sites by site-directed mutagenesis completely abrogated the N-glycosylation of PPARgamma. PPAR wild-type (WT) transfection inhibited the inflammatory activation of microglia, while the anti-inflammatory function of unglycosylated PPARgamma was down-regulated. In addition, beta1, 4GalT1 was shown to interact with PPARgamma and to mediate PPARgamma glycosylation. beta1, 4GalT1 promoted PPARgamma's anti-transcription and anti inflammatory functions. Collectively, our findings define that beta-1, 4GalT1 mediated PPARgamma glycosylation to attenuate the inflammatory activation of microglia, which has implications for potential therapies for CNS inflammatory diseases. PMID- 29717389 TI - Calibration and validation of toxicokinetic-toxicodynamic models for three neonicotinoids and some aquatic macroinvertebrates. AB - Exposure patterns in ecotoxicological experiments often do not match the exposure profiles for which a risk assessment needs to be performed. This limitation can be overcome by using toxicokinetic-toxicodynamic (TKTD) models for the prediction of effects under time-variable exposure. For the use of TKTD models in the environmental risk assessment of chemicals, it is required to calibrate and validate the model for specific compound-species combinations. In this study, the survival of macroinvertebrates after exposure to the neonicotinoid insecticide was modelled using TKTD models from the General Unified Threshold models of Survival (GUTS) framework. The models were calibrated on existing survival data from acute or chronic tests under static exposure regime. Validation experiments were performed for two sets of species-compound combinations: one set focussed on multiple species sensitivity to a single compound: imidacloprid, and the other set on the effects of multiple compounds for a single species, i.e., the three neonicotinoid compounds imidacloprid, thiacloprid and thiamethoxam, on the survival of the mayfly Cloeon dipterum. The calibrated models were used to predict survival over time, including uncertainty ranges, for the different time variable exposure profiles used in the validation experiments. From the comparison between observed and predicted survival, it appeared that the accuracy of the model predictions was acceptable for four of five tested species in the multiple species data set. For compounds such as neonicotinoids, which are known to have the potential to show increased toxicity under prolonged exposure, the calibration and validation of TKTD models for survival needs to be performed ideally by considering calibration data from both acute and chronic tests. PMID- 29717390 TI - Long-term benefits and risks of parathyroid hormone treatment in compliant osteoporotic patients. A Danish national register based cohort study. AB - PURPOSE: Medical treatment of osteoporosis should preferably be both effective and have minimal side effects. The aim of the present study was to examine long term benefits and risks of parathyroid hormone (PTH) treatment in compliant patients. METHODS: This is a nationwide retrospective cohort study based on national registers in which we identified 1739 patients treated with PTH (2003 2010) (index cases) for at least 18 months and with a medication possession rate of > 0.8. For comparison, patients treated with bisphosphonate (BP) (n = 13,131) and anti-osteoporotic treatment-naive controls (n = 12,721) were selected. Incidence of fractures, drug consumption, and comorbidity were compared between the three cohorts. Mean follow-up of the PTH-treated patients was 4.3 years (range 1.8-8.7 years). RESULTS: Before initiation of treatment, PTH patients had a significantly higher Charlson comorbidity index score and more osteoporotic fractures than both BP patients and controls. No difference was detected in the incidence of fractures during PTH treatment or years after between PTH patients and BP patients. No significant difference in the use of drugs was seen between PTH and BP patients, except for PPI intake which was higher in PTH patients. No significant increases were found in the incidence of cancers or other ICD-10 diagnoses among PTH-treated patients in comparison with both BP and controls. CONCLUSION: Overall, PTH treatment is effective and safe. Following PTH treatment in compliant patients, neither fracture incidence nor drug consumption differed between PTH-treated and BP-treated patients, despite the fact that PTH-treated patients had more severe osteoporosis. No increased incidence of malignant diseases or other diseases was detected. PMID- 29717388 TI - Dimerization of AT2 and Mas Receptors in Control of Blood Pressure. AB - PURPOSE OF REVIEW: Angiotensin type 2 receptor (AT2R) and receptor Mas (MasR) are part of the "protective arm" of the renin angiotensin system. Gene and pharmacological manipulation studies reveal that AT2R and MasR are involved in natriuretic, vasodilatory, and anti-inflammatory responses and in lowering blood pressure in various animal models under normal and pathological conditions such as salt-sensitive hypertension, obesity, and diabetes. The scope of this review is to discuss co-localization and heterodimerization as potential molecular mechanisms of AT2R- and MasR-mediated functions including antihypertensive activities. RECENT FINDINGS: Accumulating evidences show that AT2R and MasR are co-localized, make a heterodimer, and are functionally interdependent in producing their physiological responses. Moreover, ang-(1-7) preferably may be an AT1R-biased agonist while acting as a MasR agonist. The physical interactions of AT2R and MasR appear to be an important mechanism by which these receptors are involved in blood pressure regulation and antihypertensive activity. Whether heteromers of these receptors influence affinity or efficacy of endogenous or synthetic agonists remains a question to be considered. PMID- 29717391 TI - Parental Restriction of Movie Viewing Prospectively Predicts Adolescent Alcohol and Marijuana Initiation: Implications for Media Literacy Programs. AB - Youth are heavy consumers of media, and exposure to mature media content is associated with initiation and progression of substance use. Parental restriction of such content has been shown to be an effective mechanism to reduce negative consequences attributed to exposure to mature media content. This study assessed the influence of parental restriction of movie watching across Motion Picture Association of America rating categories on subsequent alcohol and marijuana initiation at 1- and 2-year follow-up. Using data from a longitudinal study of adolescent substance use (N = 1023), we used logistic regression analyses to determine the odds of alcohol and marijuana initiation across movie rating categories, within R-rated restriction categories in particular, and based on changes in parental restriction of movies over time. All analyses controlled for important parental, personality, and behavioral correlates of adolescent substance use. Results suggest that restriction of R-rated movies is protective of both alcohol and marijuana initiation. Important differences among parental restriction of R-rated movie categories emerged such that being allowed to watch them with adult supervision was protective of substance use, while those who reported watching R-rated films despite parental restrictions were at heightened risk for alcohol initiation. Changes in parental movie restrictions were not predictive of substance use initiation over the subsequent year. Implications of these findings for media literacy program prevention strategies are discussed. PMID- 29717392 TI - Arterial Distensibility, Physical Activity, and the Metabolic Syndrome. AB - PURPOSE OF REVIEW: Metabolic syndrome (MetS), a cluster of risk factors including central obesity, metabolic abnormalities, and arterial hypertension, is a well known determinant of arterial wall remodeling and stiffening. The mechanisms whereby MetS promotes arterial stiffening include increased sympathetic activity with the associated fast heart rate, enhanced activity of the renin-angiotensin aldosterone system, increased production of inflammatory cytokines and reactive oxygen species, and reduction of nitric oxide availability. These adverse effects can explain why aerobic physical activity can retard the age-related decline in arterial elasticity in subjects with MetS. RECENT FINDINGS: A large number of studies have shown that in patients with MetS, exercise can reduce body weight and blood pressure and improve the metabolic profile. In addition, regular exercise training can counterbalance the detrimental effects of MetS by reducing sympathetic activity and improving endothelial function with a beneficial effect on arterial elasticity. Indeed, the majority of published data have shown a favorable effect of aerobic exercise on pulse wave velocity, augmentation index, central blood pressure, and small artery compliance. Special attention should be paid by clinicians to people with MetS in whom the adverse effect of metabolic disturbances on arterial structure and function can be offset by a program of physical training. PMID- 29717394 TI - Editorial to themed issue: Recent advances in cardiovascular pharmacokinetic pharmacodynamic modeling and simulation. PMID- 29717393 TI - Hypertension in Developing Countries: A Major Challenge for the Future. AB - PURPOSE OF REVIEW: Outline recent epidemiologic data regarding hypertension in developing countries, distinguish differences from developed countries, and identify challenges in management and future perspectives. RECENT FINDINGS: Increased sugar intake, air and noise pollution, and low birth weight are emerging hypertension risk factors. The major challenges in management are difficulties in accurate diagnosis of hypertension and adequate blood pressure control. In contrast to developed countries, hypertension prevalence rates are on the rise in developing countries with no improvement in awareness or control rates. The increasing burden of hypertension is largely attributable to behavioral factors, urbanization, unhealthy diet, obesity, social stress, and inactivity. Health authorities, medical societies, and drug industry can collaborate to improve hypertension control through education programs, public awareness campaigns, legislation to limit salt intake, encourage generic drugs, development and dissemination of national guidelines, and involving nurses and pharmacists in hypertension management. More epidemiologic data are needed in the future to identify reasons behind increased prevalence and poor blood pressure control and examine trends in prevalence, awareness, treatment, and control. National programs for better hypertension control based on local culture, economic characteristics, and available resources in the population are needed. The role of new tools for hypertension management should be tested in developing world. PMID- 29717397 TI - Correction to: Secretomes reveal several novel proteins as well as TGF-beta1 as the top upstream regulator of metastatic process in breast cancer. AB - In the original publication of the article, Acknowledgement section was missed out and Table 1 was published incompletely. The Acknowledgment and complete table 1 are given in this correction. The original article has been corrected. PMID- 29717395 TI - Biocommunication between Plants and Pollinating Insects through Fluorescence of Pollen and Anthers. AB - Flowering plants attract pollinators via various stimuli such as odor, color, and shape. Factors determining the foraging behavior of pollinators remain a major theme in ecological and evolutionary research, although the floral traits and cognitive ability of pollinators have been investigated for centuries. Here we show that the autofluorescence emitted from pollen and anthers under UV irradiation may act as another attractant for flower-visiting insects. We have identified fluorescent compounds from pollen and anthers of five plant species as hydroxycinnamoyl derivatives. The fluorescent compounds are also shown to quench UV energy and exhibit antioxidant activity, indicating a function as protectants of pollen genes from UV-induced damage. A two-choice assay using honeybees in the field demonstrated that they perceived the blue fluorescence emitted from the fluorescent compounds and were attracted to it. This result suggested that the fluorescence from pollen and anthers serves as a visual cue to attract pollinators under sunlight. PMID- 29717396 TI - Acute fibrinous and organizing pneumonia as initial presentation of primary Sjogren's syndrome: a case report and literature review. AB - Acute fibrinous and organizing pneumonia (AFOP) is a new histopathological pattern of acute lung injury first described by Beasley et al. in 2002. Hallmarks of pathological findings are characterized by the presence of intra-alveolar fibrin in the form of fibrin "balls" within the alveolar spaces and organizing pneumonia with a patchy distribution. Patients with AFOP may have an acute or subacute clinical presentation. Although the pathogenesis of AFOP is not fully elucidated, it may be associated with autoimmune diseases. Reported herein is a patient diagnosed of acute AFOP associated with primary Sjogren's syndrome. The patient's condition promptly improved after treatment with corticosteroid. PMID- 29717398 TI - Successful limb salvage through staged bypass combined with free gracilis muscle transfer for critical limb ischemia with osteomyelitis after failed endovascular therapy. AB - BACKGROUND: Critical limb ischemia with osteomyelitis is so difficult to treat that even appropriate revascularization and wound therapy cannot achieve limb salvage because of uncontrollable infection. It is still difficult to judge the possibility of limb salvage before revascularization. CASE PRESENTATION: A 73 year-old male complained of a small ulcer on his left toe, which was treated with multiple endovascular therapy. After failed endovascular therapy, he suffered extensive tissue loss with tibial osteomyelitis. We carried out staged surgery that was composed of dual bypass to the sural artery and posterior tibial artery. After intensive debridement and wound care, insertion of a subsequent free gracilis muscle flap to cover the exposed tibial bone was performed, achieving functional limb salvage. CONCLUSION: Even in the threatened limb with extensive tissue loss and osteomyelitis, intensive and multidisciplinary treatment with staged revascularization, muscle transfer, and appropriate wound care achieved functional limb salvage. PMID- 29717399 TI - Synthesis, Spectra, and Theoretical Investigations of 1,3,5-Triazines Compounds as Ultraviolet Rays Absorber Based on Time-Dependent Density Functional Calculations and three-Dimensional Quantitative Structure-Property Relationship. AB - A series of 1,3,5-triazines were synthesized and their UV absorption properties were tested. The computational chemistry methods were used to construct quantitative structure-property relationship (QSPR), which was used to computer aided design of new 1,3,5-triazines ultraviolet rays absorber compounds. The experimental UV absorption data are in good agreement with those predicted data using the Time-dependent density functional theory (TD-DFT) [B3LYP/6-311 + G(d,p)]. A suitable forecasting model (R > 0.8, P < 0.0001) was revealed. Predictive three-dimensional quantitative structure-property relationship (3D QSPR) model was established using multifit molecular alignment rule of Sybyl program, which conclusion is consistent with the TD-DFT calculation. The exceptional photostability mechanism of such ultraviolet rays absorber compounds was studied and confirmed as principally banked upon their ability to undergo excited-state deactivation via an ultrafast excited-state proton transfer (ESIPT). The intramolecular hydrogen bond (IMHB) of 1,3,5-triazines compounds is the basis for the excited state proton transfer, which was explored by IR spectroscopy, UV spectra, structural and energetic aspects of different conformers and frontier molecular orbitals analysis. PMID- 29717400 TI - Crizotinib-induced simultaneous multiple cardiac toxicities. AB - Crizotinib is a receptor tyrosine kinase inhibitor that has several targets, including c-ros oncogene 1 and the MET proto-oncogene. Considering its known cardiac toxicity, bradycardia is often investigated following treatment with crizotinib. Our patients had bradycardia, QT prolongation, ventricular rhythm, ventricular fibrillation, and pericarditis simultaneously. The cardiotoxicity of crizotinib can sometimes be simultaneous; thus, intensive observation is needed. PMID- 29717401 TI - Modelling mortality and discharge of hospitalized stroke patients using a phase type recovery model. AB - We model the length of in-patient hospital stays due to stroke and the mode of discharge using a phase-type stroke recovery model. The model allows for three different types of stroke: haemorrhagic (the most severe, caused by ruptured blood vessels that cause brain bleeding), cerebral infarction (less severe, caused by blood clots) and transient ischemic attack or TIA (the least severe, a mini-stroke caused by a temporary blood clot). A four-phase recovery process is used, where the initial phase depends on the type of stroke, and transition from one phase to the next depends on the age of the patient. There are three differing modes of absorption for this phase-type model: from a typical recovery phase, a patient may die (mode 1), be transferred to a nursing home (mode 2) or be discharged to the individual's usual residence (mode 3). The first recovery phase is characterized by a very high rate of mortality and very low rates of discharge by the other two modes. The next two recovery phases have progressively lower mortality rates and higher mode 2 and 3 discharge rates. The fourth recovery phase is visited only by those who experience a very mild TIA, and they are discharged to home after a short stay. The novelty of our approach to phase representation is two-fold: first, it aligns the phases with labelled diagnosis states, representing stages of illness severity; second, the model allows us to obtain expressions for Key Performance Indicators that are of use to healthcare professionals. This allows us to use a backward estimation process where we leverage the fact that we know the phase of admission (the diagnosis), but not which phases are subsequently entered or when this happens; this strategy improves both computational efficiency and accuracy. The model has clear practical value as it yields length of stay distributions by age and type of stroke, which are useful in resource planning. Also, inclusion of the three modes of discharge permits analyses of outcomes. PMID- 29717402 TI - Assessing the Effect of Recent Incarceration in Prison on HIV Care Retention and Viral Suppression in Two States. AB - The prevalence of HIV among people in correctional facilities remains much higher than that of the general population. Numerous studies have demonstrated the effectiveness and acceptability of HIV treatment for individuals incarcerated in US prisons and jails. However, the period following incarceration is characterized by significant disruptions in HIV care. These disruptions include failure to link in a timely manner (or at all) to community care post-release, as well as not being retained in care after linking. We used a retrospective, propensity-matched cohort design to compare retention in care between HIV positive individuals recently released from prison (releasees) who linked to care in Ryan White HIV/AIDS Program (RWHAP) clinics and RWHAP patients without a recent incarceration history (community controls). We also performed analyses comparing viral load suppression of those retained in both groups. This study shows that even for those who do successfully link to care after prison, they are 24 to 29 percentage points less likely to be retained in care than those already in community care. However, we found that for those who did retain in care, there was no disparity in rates of viral suppression. These findings provide valuable insight regarding how best to address challenges associated with ensuring that HIV-positive individuals leaving prison successfully move through the HIV care continuum to become virally suppressed. PMID- 29717404 TI - Invited Response Letter: "Gastrointestinal Stromal Tumor After Laparoscopic Sleeve Gastrectomy: Be Awake Before, During, and After a Bariatric Procedure". PMID- 29717403 TI - The Role of Apolipoprotein E and Ethanol Exposure in Age-Related Changes in Choline Acetyltransferase and Brain-Derived Neurotrophic Factor Expression in the Mouse Hippocampus. AB - Disruption of apolipoprotein E (APOE) is responsible for age-dependent neurodegeneration and cognitive impairment. Elderly individuals are more sensitive than young individuals to the effects of ethanol (EtOH), particularly those affecting cognition. We investigated the role of APOE deficiency and EtOH exposure on age-dependent alterations in choline acetyltransferase (ChAT) and brain-derived neurotrophic factor (BDNF) mRNA and protein expression in the mouse hippocampus. Three-month-old (young) and 12-month-old (aged) ApoE-knockout (ApoE KO) and wild-type (WT) mice were treated with saline or 2 g/kg EtOH, and the bilateral hippocampus was collected after 60 min for real-time PCR and western blotting analyses. ChAT (P < 0.01) and BDNF (P < 0.01) expression were significantly decreased in both young and aged saline- and EtOH-treated ApoE-KO mice versus young and aged saline- and EtOH-treated WT mice. Aged saline- and EtOH-treated ApoE-KO mice exhibited greater differences in ChAT and BDNF expression (P < 0.01) than young saline- and EtOH-treated ApoE-KO mice. Aged EtOH treated WT mice also exhibited larger decreases in BDNF expression (P < 0.01)-but not in ChAT expression-than young EtOH-treated WT mice. EtOH decreased ChAT and BDNF expression in both young (P < 0.01) and aged (P < 0.01) ApoE-KO mice versus EtOH-free ApoE-KO mice of the same age. EtOH also decreased BDNF expression in aged (P < 0.01) WT mice versus EtOH-free aged WT mice. In summary, these results suggest that APOE deficiency and EtOH exposure cause age-dependent decreases in ChAT and BDNF in the hippocampus. Importantly, the decreases in ChAT and BDNF were greater in aged EtOH-treated mice, particularly those lacking APOE, raising the possibility that APOE-deficient individuals who consume alcohol may be at greater risk of memory deficit. PMID- 29717405 TI - Risk of GERD-Related Disorders in Obese Patients on PPI Therapy: a Population Analysis. AB - BACKGROUND: Increasing prevalence of obesity has shown an associated increase in gastroesophageal reflux disease (GERD)-related diseases. Proton pump inhibitor (PPI) therapy has been demonstrated to reduce the incidence of such diseases. The study's aim was to analyze the Clinical Practice Research Datalink (CPRD) to determine factors that increase the propensity of obese patients on PPIs to develop Barrett's esophagus (BE) and esophageal carcinoma. METHOD: A case-control population study was carried out, including patients from the CPRD. Clinicopathological factors were extracted for each patient alongside clinical endpoints of GERD, BE, and esophageal carcinoma. Multivariate analysis was utilized to identify factors that increase the propensity to develop BE and esophageal carcinoma. Statistical significance was p < 0.050. RESULTS: One hundred sixty five thousand nine hundred twenty nine obese patients on PPI treatment were identified up until July 2017. Median follow-up time was 119.0 months (range 11.3-1397.9 months). In patients with GERD, the following were associated with increased BE risk: age >= 60 years (OR = 1.197; p = 0.039), male (OR = 2.209; p < 0.001), H2 antagonists (OR = 1.377; p < 0.001), D2 antagonists (OR = 1.241; p = 0.008), and hiatus hernias (OR = 6.772; p = 0.017). The following were associated with increased risk of esophageal carcinoma: age (OR = 2.831; p = 0.031), male sex (OR = 3.954; p = 0.003), and hiatus hernias (OR = 12.170; p < 0.001). Only D2 antagonists (OR = 2.588; p = 0.002) were associated with increased risk of developing esophageal carcinoma in BE patients. CONCLUSIONS: In obese patients on PPI therapy for reflux, higher BMIs were not associated with increased risk of BE or esophageal carcinoma. Males, older patients, and those with hiatus hernias are at increased risk of developing BE and carcinoma. Failure of PPI monotherapy is predictive of future metaplasia and dysplasia. PMID- 29717406 TI - Effect of Sleeve Gastrectomy on Platelet Counts and Mean Platelet Volumes. AB - BACKGROUND: Obesity is a chronic metabolic disorder associated with cardiovascular disease, characterized by a chronic proinflammatory and prothrombotic state. The size and hemostatic potential of circulating platelets (PLTs) differ, with larger PLTs containing more granules and producing greater amounts of vasoactive and prothrombotic factors. This study aimed to investigate the effect of laparoscopic sleeve gastrectomy (LSG) on PLT count and mean platelet volume (MPV) in morbidly obese patients. METHODS: Two hundred five patients (females, n = 143; males, n = 62) who attended monitoring visits in the period prior to LSG and for 6 months after surgery were included in this study. Routine physical examination findings and laboratory parameters recorded preoperatively were compared with the same parameters in the postoperative 6th month. RESULTS: The mean age of the patients was 37.36 +/- 10.93 years. The mean preoperative body mass index (BMI) of the patients was 47.65 kg/m2, whereas the mean postoperative BMI at 6 months was 31.49 kg/m2. Prior to LSG, the mean PLT count was 314.16 +/- 76.40 * 109/L. At the postoperative 6th month, the mean PLT count was significantly reduced (263.17 +/- 65.67 * 109/L, p < 0.001). In the preoperative period, the MPV was 10.12 +/- 0.88 fL. In the postoperative period, it was significantly increased (10.41 +/- 1.23 fL, p > 0.001). Both preoperatively and postoperatively, PLT counts were significantly higher in females than in males. After LSG, the MPV increased in both females and males. CONCLUSIONS: The results demonstrated that PLT counts decreased and MPV levels increased significantly after LSG and that the decrease in PLT counts was independent of changes in BMI. PMID- 29717407 TI - Simultaneous determination of dynamic cardiac metabolism and function using PET/MRI. AB - BACKGROUND: Cardiac metabolic changes in heart disease precede overt contractile dysfunction. However, metabolism and function are not typically assessed together in clinical practice. The purpose of this study was to develop a cardiac positron emission tomography/magnetic resonance (PET/MR) stress test to assess the dynamic relationship between contractile function and metabolism in a preclinical model. METHODS: Following an overnight fast, healthy pigs (45-50 kg) were anesthetized and mechanically ventilated. 18F-fluorodeoxyglucose (18F-FDG) solution was administered intravenously at a constant rate of 0.01 mL/s for 60 minutes. A cardiac PET/MR stress test was performed using normoxic gas (FIO2 = .209) and hypoxic gas (FIO2 = .12). Simultaneous cardiac imaging was performed on an integrated 3T PET/MR scanner. RESULTS: Hypoxic stress induced a significant increase in heart rate, cardiac output, left ventricular (LV) ejection fraction (EF), and peak torsion. There was a significant decline in arterial SpO2, LV end diastolic and end-systolic volumes in hypoxia. Increased LV systolic function was coupled with an increase in myocardial FDG uptake (Ki) during hypoxic stress. CONCLUSION: PET/MR with continuous FDG infusion captures dynamic changes in both cardiac metabolism and contractile function. This technique warrants evaluation in human cardiac disease for assessment of subtle functional and metabolic abnormalities. PMID- 29717408 TI - Detoxification of Organosolv-Pretreated Pine Prehydrolysates with Anion Resin and Cysteine for Butanol Fermentation. AB - Bioconversion of lignocellulose to biofuels suffers from the degradation compounds formed during pretreatment and acid hydrolysis. In order to achieve an efficient biomass to biofuel conversion, detoxification is often required before enzymatic hydrolysis and microbial fermentation. Prehydrolysates from ethanol organosolv-pretreated pine wood were used as substrates in butanol fermentation in this study. Six detoxification approaches were studied and compared, including overliming, anion exchange resin, nonionic resin, laccase, activated carbon, and cysteine. It was observed that detoxification by anion exchange resin was the most effective method. The final butanol yield after anion exchange resin treatment was comparable to the control group, but the fermentation was delayed for 72 h. The addition of Ca(OH)2 was found to alleviate this delay and improve the fermentation efficiency. The combination of Ca(OH)2 and anion exchange resin resulted in completion of fermentation within 72 h and acetone-butanol-ethanol (ABE) production of 11.11 g/L, corresponding to a yield of 0.21 g/g sugar. The cysteine detoxification also resulted in good detoxification performance, but promoted fermentation towards acid production (8.90 g/L). The effect of salt on ABE fermentation was assessed and the possible role of Ca(OH)2 was to remove the salts in the prehydrolysates by precipitation. PMID- 29717409 TI - Synthesis of a Fucosylated Trisaccharide Via Transglycosylation by alpha-L Fucosidase from Thermotoga maritima. AB - Fucosylated oligosaccharides, such as 2'-fucosyllactose in human milk, have important biological functions such as prebiotics and preventing infection. In this work, the effect of an acceptor substrate (lactose) and the donor substrate 4-nitrophenyl-alpha-L-fucopyranoside (pNP-Fuc) on the synthesis of a fucosylated trisaccharide was studied in a transglycosylation reaction using alpha-L fucosidase from Thermotoga maritima. Conducting a matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS), it was demonstrated that synthesized oligosaccharide corresponded to a fucosylated trisaccharide, and high-performance liquid chromatography (HPLC) of the hydrolyzed compound confirmed it was fucosyllactose. As the concentration of the acceptor substrate increased, the concentration and synthesis rate of the fucosylated trisaccharide also increased, and the highest concentration obtained was 0.883 mM (25.2% yield) when using the higher initial lactose concentration (584 mM). Furthermore, the lower donor/acceptor ratio had the highest synthesis, so at the molar ratio of 0.001, a concentration of 0.286 mM was obtained (32.5% yield). PMID- 29717410 TI - Acetaminophen or Tylenol? A Retrospective Analysis of Medication Digital Communication Practices. PMID- 29717411 TI - Treat the Patient, Not the Pain: Using a Multidimensional Assessment Tool to Facilitate Patient-Centered Chronic Pain Care. PMID- 29717412 TI - Visual recognition of mirrored letters and the right hemisphere advantage for mirror-invariant object recognition. AB - Unlike most objects, letter recognition is closely tied to orientation and mirroring, which in some cases (e.g., b and d), defines letter identity altogether. We combined a divided field paradigm with a negative priming procedure to examine the relationship between mirror generalization, its suppression during letter recognition, and language-related visual processing in the left hemisphere. In our main experiment, observers performed a centrally viewed letter-recognition task, followed by an object-recognition task performed in either the right or the left visual hemifield. The results show clear evidence of inhibition of mirror generalization for objects viewed in either hemifield but a right hemisphere advantage for visual recognition of mirrored and repeated objects. Our findings are consistent with an opponent relationship between symmetry-related visual processing in the right hemisphere and neurally recycled mechanisms in the left hemisphere used for visual processing of written language stimuli. PMID- 29717414 TI - Primary central sleep apnea and anesthesia: a retrospective case series. AB - PURPOSE: Primary (idiopathic) central sleep apnea (PCSA) is a rare central sleep related breathing disorder characterized by increased chemoreceptor sensitivity to partial pressure of carbon dioxide, which manifests as hyperventilation followed by apnea during non-rapid eye movement sleep. The purpose of this retrospective study was to describe the postoperative course of patients who had PCSA and underwent procedures requiring anesthetic management. METHODS: Patients who received a diagnosis of PCSA at our institution and required procedural anesthesia between 1 January 2010 and 1 June 2016 underwent a comprehensive review of their health records with a focus on identifying respiratory complications. RESULTS: Ten patients (nine males, one female) underwent 47 procedures requiring anesthetic management: 20 (43%) under general anesthesia, 25 (53%) with monitored anesthetic care, and two (4%) with regional anesthesia. Procedures were complicated by second-degree heart block in one patient and pneumonia in another two (one had Ivor-Lewis esophagectomy and the other bronchoscopy to evaluate worsening lung infiltration). Hypoxemia (oxyhemoglobin saturation < 90% for three minutes) developed in three patients during anesthesia recovery. One was possibly due to PCSA-a 73-yr-old male with alcoholic cirrhosis who was moderately sedated and hypoxemic after orthopedic surgery; his oxygenation improved with an adaptive servoventilator positive airway pressure device and supplemental oxygen. His underlying medical condition or level of sedation may have contributed to hypoxemia. The other patients became hypoxemic after bronchoscopy. No other cases were complicated by postoperative respiratory compromise. CONCLUSIONS: No major adverse outcomes were related to PCSA postoperatively. Nevertheless, continuation of home positive airway pressure therapy during anesthesia recovery was useful in one patient who had cirrhosis and postoperative hypoxemia. PMID- 29717415 TI - Esophageal Metastases from Breast Carcinoma: a Rare Delayed Metastases After 15 Years. PMID- 29717413 TI - Spinal Cord Injury Scarring and Inflammation: Therapies Targeting Glial and Inflammatory Responses. AB - Deficits in neuronal function are a hallmark of spinal cord injury (SCI) and therapeutic efforts are often focused on central nervous system (CNS) axon regeneration. However, secondary injury responses by astrocytes, microglia, pericytes, endothelial cells, Schwann cells, fibroblasts, meningeal cells, and other glia not only potentiate SCI damage but also facilitate endogenous repair. Due to their profound impact on the progression of SCI, glial cells and modification of the glial scar are focuses of SCI therapeutic research. Within and around the glial scar, cells deposit extracellular matrix (ECM) proteins that affect axon growth such as chondroitin sulfate proteoglycans (CSPGs), laminin, collagen, and fibronectin. This dense deposition of material, i.e., the fibrotic scar, is another barrier to endogenous repair and is a target of SCI therapies. Infiltrating neutrophils and monocytes are recruited to the injury site through glial chemokine and cytokine release and subsequent upregulation of chemotactic cellular adhesion molecules and selectins on endothelial cells. These peripheral immune cells, along with endogenous microglia, drive a robust inflammatory response to injury with heterogeneous reparative and pathological properties and are targeted for therapeutic modification. Here, we review the role of glial and inflammatory cells after SCI and the therapeutic strategies that aim to replace, dampen, or alter their activity to modulate SCI scarring and inflammation and improve injury outcomes. PMID- 29717416 TI - Lowbush cranberry acts through DAF-16/FOXO signaling to promote increased lifespan and axon branching in aging posterior touch receptor neurons. AB - Medicinal berries are appreciated for their health benefits, in traditional ecological knowledge and nutrition science. Determining the cellular mechanisms underlying the effects of berry supplementation may contribute to our understanding of aging. Here, we report that lowbush cranberry (Vaccinium vitis idaea) treatment causes marked nuclear localization of the central aging-related transcription factor DAF-16/FOXO in aged Caenorhabditis elegans. Further, functional DAF-16 is required for the lifespan extension, improved mechanosensation, and posterior touch receptor neuron morphological changes induced by lowbush cranberry treatments. DAF-16 is not observed in nuceli nor required for lifespan extension in lifespan-extending Alaskan blueberry treatments and, while DAF-16 is not visibly induced into the nucleus in lifespan extending Alaskan chaga treatments, it is required for chaga-induced lifespan extension. These findings underscore the importance of DAF-16 in the aging of whole organisms and touch receptor neurons and also, importantly, indicate that this critical pathway is not always activated upon consumption of functional foods that impact aging. PMID- 29717418 TI - Transition from tube feeding to oral feeding: experience in a tertiary care paediatric cardiology unit. AB - BACKGROUND: Home enteral tube feeding (HETF) is imperative for many infants and children with congenital heart disease (CHD). Tube weaning (TW) facilitates the progression from tube feeding to oral diet. There is limited literature on TW practices, protocols and success for children with CHD that have been tube fed. AIMS: The objective of this study is to assess the process of weaning HETF in a tertiary referral centre for paediatric CHD. Specifically, we aimed to assess the duration of HETF, duration of TW and the interventions involved. METHODS: We retrospectively reviewed the medical and dietetic records of all infants and children that were successfully weaned off HETF over a 12-month period from January 2015 to December 2015. RESULTS: There were 30 children included in the study, 9 boys and 21 girls. The diagnoses included 15 septal defects, 8 univentricular diagnosis and other diagnoses in 7 children. The median age at initiation of enteral tube feeding was 45 days (range 2-169). The median duration to wean from enteral tube feeding was 52 days (range 2-359). Number of dietetic consults required for successful TW varied among patients, median 5 (range 2-23). The number of days required for successful TW was associated with age and duration on HETF. Dietetic interventions included discontinuation of nutrient dense feeds, altering feed schedule and reduction of feed volume. CONCLUSIONS: Weaning HETF is possible in the outpatient setting. Early and frequent dietetic intervention is recommended to ensure prompt discontinuation of HETF when appropriate. PMID- 29717419 TI - Multivariate Analysis of Increase in Life Span of Caenorhabditis elegans Through Intestinal Colonization by Indigenous Probiotic Strains. AB - The present study aimed to analyze the colonization potential of indigenous probiotic strains and to assess their effects on physiology of Caenorhabditis elegans. The protective effect of probiotics was evaluated in terms of increase in life span of the worm through colonization in the intestine. A total of 15 probiotic cultures were evaluated for their effect on mean life span, pharyngeal pumping, and normal reproduction behavior in the worms. The chemotactic behavior in terms of binary choice index was also evaluated. The adherence and colonization of the intestine of the worm by probiotics were monitored at different time intervals by enumerating the microbial population and fluorescent microscopic observations. The survival analysis-based Kaplan-Meier method indicated that the probiotic cultures increased the survival probability as compared to control strain E. coli OP50. There was no effect of feeding probiotics on physiological responses of the worm such as pharyngeal pumping and reproduction. The principal component analysis (PCA) of the results indicated Lactobacillus plantarum K90 and L. paracasei CD4 as potential probiotics with binary choice index of 0.8 as food preference of C. elegans. The strains exhibit higher adherence and colonization in the gut of worms and increased the life span by 5 days as compared to control E. coli OP50. In conclusion, feeding with probiotic cultures is effective in extending the lifespan of C. elegans; however, the colonization ability differs among the strains. PMID- 29717420 TI - Gene Cloning, Expression, and Antifungal Activities of Permatin from Naked Oat (Avena nuda). AB - Thaumatin-like proteins (TLPs) are the products of a large, highly complex gene family involved in host defense. TLPs also belong to the pathogenesis-related family 5 (PR-5) of plant defense proteins. Most TLPs exhibit potential antifungal activities, and their accumulation in the plant is related to many physiological processes. In this study, a gene encoding TLP named permatin with an open reading frame of 678 bp encoding a protein of 225 amino acids with a calculated molecular mass of 23.5 kDa was cloned from naked oat leaves. Phylogenetic analysis revealed that permatin shares high homology with a number of other TLPs among diverse taxa. Model of structure by homology modeling showed that permatin consists of an acidic cleft region consistent with most TLPs. Recombinant NusA-permatin was overexpressed in Escherichia coli strain BL21 and purified by Heparin column combined with Sephacryl S-200 column. The protein exhibited antifungal activity to Fusarium oxysporum (half maximal inhibitory concentration, IC50 = 21.42 MUM). Morphological observation showed that NusA-permatin can induce mycelium deformation of F. oxysporum, the cell membrane is blurred, and the diaphragm is not obvious. NusA-permatin also causes membrane permeabilization and reactive oxygen species accumulation in the mycelium of F. oxysporum. Permatin may play an important role in the disease resistance responses of plants against pathogen attacks through its antifungal activity. PMID- 29717417 TI - Hydrogen sulfide ameliorates aging-associated changes in the kidney. AB - Aging is associated with replacement of normal kidney parenchyma by fibrosis. Because hydrogen sulfide (H2S) ameliorates kidney fibrosis in disease models, we examined its status in the aging kidney. In the first study, we examined kidney cortical H2S metabolism and signaling pathways related to synthesis of proteins including matrix proteins in young and old male C57BL/6 mice. In old mice, increase in renal cortical content of matrix protein involved in fibrosis was associated with decreased H2S generation and AMPK activity, and activation of insulin receptor (IR)/IRS-2-Akt-mTORC1-mRNA translation signaling axis that can lead to increase in protein synthesis. In the second study, we randomized 18-19 month-old male C57BL/6 mice to receive 30 MUmol/L sodium hydrosulfide (NaHS) in drinking water vs. water alone (control) for 5 months. Administration of NaHS increased plasma free sulfide levels. NaHS inhibited the increase in kidney cortical content of matrix proteins involved in fibrosis and ameliorated glomerulosclerosis. NaHS restored AMPK activity and inhibited activation of IR/IRS-2-Akt-mTORC1-mRNA translation axis. NaHS inhibited age-related increase in kidney cortical content of p21, IL-1beta, and IL-6, components of the senescence associated secretory phenotype. NaHS abolished increase in urinary albumin excretion seen in control mice and reduced serum cystatin C levels suggesting improved glomerular clearance function. We conclude that aging-induced changes in the kidney are associated with H2S deficiency. Administration of H2S ameliorates aging-induced kidney changes probably by inhibiting signaling pathways leading to matrix protein synthesis. PMID- 29717421 TI - Treatment Intensity Differences After Early-Stage Breast Cancer (ESBC) Diagnosis Depending on Participation in a Screening Program. AB - BACKGROUND: While population mammographic screening identifies early-stage breast cancers (ESBCs; ductal carcinoma in situ [DCIS] and invasive disease stages 1 3A), commentaries suggest that harms from overdiagnosis and overtreatment may outweigh the benefits. Apparent benefits to patients with screen-detected cancers may be due to selection bias from exclusion of interval cancers (ICs). Treatment intensity is rarely discussed, with an assumption that all ESBCs are treated similarly. We hypothesized that women diagnosed while in a screening program would receive less-intense treatment than those never or not recently screened (NRS). METHODS: This was a retrospective analysis of all women aged 50-69 years managed for ESBC (invasive or DCIS) during the period 2007-2013 within a single service, comparing treatment according to screening status. Data on demographics, detection, pathology, and treatment were derived from hospital, cancer registry, and screening service records. RESULTS: Overall, 622 patients were active screeners (AS) at diagnosis (569 screen-detected and 53 ICs) and 169 patients were NRS. AS cancers were smaller (17 mm vs. 26 mm, p < 0.0001), less likely to involve nodes (26% vs. 48%, p < 0.0001), and lower grade. For invasive cancer, NRS patients were more likely to be recommended for mastectomies [35% vs. 16%; risk ratio(RR) 2.2, p < 0.0001], axillary dissection (43% vs. 19%; RR 2.3, p < 0.0001), adjuvant chemotherapy (65% vs. 37%; RR 1.7, p < 0.0001), and postmastectomy radiotherapy (58% vs. 39%; RR 1.5, p = 0.04). CONCLUSION: Participants in population screening diagnosed with ESBC receive substantially less-intense treatment than non-participants. Differences persist when potential overdiagnosis is taken into account; these differences should be factored into debates around mammographic screening. PMID- 29717422 TI - Management of Mucinous Appendiceal Tumors. PMID- 29717423 TI - Clinical Role of Programmed Cell Death-1 Expression in Patients with Non-muscle invasive Bladder Cancer Recurring After Initial Bacillus Calmette-Guerin Therapy. AB - BACKGROUND: The programmed cell death-1 (PD-1) pathway has been suggested to play an important role in tumor immune escape. We evaluated changes in PD-1 expression before and after Bacillus Calmette-Guerin (BCG) therapy and its prognostic significance in non-muscle-invasive bladder cancer (NMIBC) patients. METHODS: We examined 78 paired tissue samples of NMIBC in tumors just before BCG therapy and BCG-relapsing tumors, defined as recurrence after achieving disease-free status by initial BCG instillations for 6 months. We counted PD-1-positive cells, and PD 1 expression was defined as high when the number of PD-1-positive cells was more than 18 under *200 magnification. RESULTS: The median number of PD-1-positive cells in tumors just before BCG therapy was 3.5, significantly lower than that in BCG-relapsing tumors (17.0, p < 0.001). High PD-1 expression was observed in 20 tumors just before BCG therapy (25.6%) and 36 BCG-relapsing tumors (46.2%). Fifty two cases (66.6%) showed an increase in the number of PD-1-positive cells in BCG relapsing tumors. High PD-1 expression in BCG-relapsing tumors was independently associated with subsequent tumor recurrence (p = 0.011) and stage progression (p = 0.033). The 5-year recurrence-free and progression-free survival rates were 40.7 and 74.1% in patients with high PD-1 expression in BCG-relapsing tumors, significantly lower than those in their counterparts (72.9 and 94.1%, respectively). CONCLUSIONS: PD-1 was induced by BCG therapy, and its expression in BCG-relapsing tumors may be an important indicator for predicting worse clinical outcomes in NMIBC patients treated with BCG therapy. PMID- 29717425 TI - Removal of pharmaceutically active compounds from synthetic and real aqueous mixtures and simultaneous disinfection by supported TiO2/UV-A, H2O2/UV-A, and TiO2/H2O2/UV-A processes. AB - Pharmaceutically active compounds are carried into aquatic bodies along with domestic sewage, industrial and agricultural wastewater discharges. Psychotropic drugs, which can be toxic to the biota, have been detected in natural waters in different parts of the world. Conventional water treatments, such as activated sludge, do not properly remove these recalcitrant substances, so the development of processes able to eliminate these compounds becomes very important. Advanced oxidation processes are considered clean technologies, capable of achieving high rates of organic compounds degradation, and can be an efficient alternative to conventional treatments. In this study, the degradation of alprazolam, clonazepam, diazepam, lorazepam, and carbamazepine was evaluated through TiO2/UV A, H2O2/UV-A, and TiO2/H2O2/UV-A, using sunlight and artificial irradiation. While using TiO2 in suspension, best results were found at [TiO2] = 0.1 g L-1. H2O2/UV-A displayed better results under acidic conditions, achieving from 60 to 80% of removal. When WWTP was used, degradation decreased around 50% for both processes, TiO2/UV-A and H2O2/UV-A, indicating a strong matrix effect. The combination of both processes was shown to be an adequate approach, since removal increased up to 90%. H2O2/UV-A was used for disinfecting the aqueous matrices, while mineralization was obtained by TiO2-photocatalysis. PMID- 29717426 TI - Tropospheric ozone enhancement during post-harvest crop-residue fires at two downwind sites of the Indo-Gangetic Plain. AB - In the present study, surface ozone (O3), nitrogen oxides (NOx), and carbon monoxide (CO) levels were measured at two sites downwind of fire active region in the Indo-Gangetic Plain (IGP): Agra (27.16 degrees N, 78.08 degrees E) and Delhi (28.37 degrees N, 77.12 degrees E) to study the impact of post-harvest crop-residue fires. The study period was classified into two groups: Pre-harvest period and Post-harvest period. During the post-harvest period, an enhancement of 17.3 and 31.7 ppb in hourly averaged O3 mixing ratios was observed at Agra and Delhi, respectively, under similar meteorological conditions. The rate of change of O3 was also higher in the post-harvest period by 56.2% in Agra and 39.5% in Delhi. Relatively higher O3 episodic days were observed in the post-harvest period. Fire hotspots detected by Moderate Resolution Imaging Spectroradiometer (MODIS) along with backward air-mass trajectory analysis suggested that the enhanced O3 and CO levels at the study sites during the post-harvest period could be attributed to crop-residue burning over the North-West IGP (NW-IGP). Satellite observations of surface CO mixing ratios and tropospheric formaldehyde (HCHO) column also showed higher levels during the post-harvest period. Graphical abstract. PMID- 29717427 TI - Design of Ag/ and Pt/TiO2-SiO2 nanomaterials for the photocatalytic degradation of phenol under solar irradiation. AB - The design of hybrid mesoporous TiO2-SiO2 (TS1) materials decorated with Ag and Pt nanoparticles was performed. The photocatalytic degradation of phenol under artificial solar irradiation was studied and the activity and selectivity of the intermediate products were verified. TiO2-SiO2 was prepared by sol-gel method while Ag- and Pt-based photocatalysts (TS1-Ag and TS1-Pt) were prepared by photodeposition of the noble metals on TS1. Two series of photocatalysts were prepared varying Ag and Pt contents (0.5 and 1.0 wt%). An increase in the photocatalytic activity up to two and five times higher than TS1 was found on TS1 Ag-1.0 and TS1-Pt-1.0, respectively. Changes in the intermediate products were detected on Ag- and Pt-based photocatalysts with an increase in the catechol formation up to 3.3 and 6.6 times higher than that observed on TS1, respectively. A two-parallel reaction mechanism for the hydroquinone and catechol formation is proposed. A linear correlation between the photocatalytic activity and the surface concentration of noble metals was found indicating that the electron affinity of noble metals is the driven force for both the increase in the photoactivity and for the remarkable changes in the selectivity of products. PMID- 29717428 TI - Prenatal exposure to perfluorooctanoic acid induces nerve growth factor expression in cerebral cortex cells of mouse offspring. AB - Previous studies have showed perfluorooctanoic acid (PFOA) inducing cytotoxicity in an organ. In addition, epidemiological data show that high level of PFOA in cord blood of a pregnant woman is detected. Therefore, we extrapolate that circulating PFOA may affect organogenesis in offspring, such as the brain. In this study, intrauterine exposure to PFOA in mice was used to characterize the potential impacts of prenatal PFOA exposure on cerebral cortex cells of postnatal 21 (PND21) offspring. In an ex vivo cell model, PND21-based cortex cells were exposed to PFOA or/and nerve growth factor (NGF)-specific inhibitor before further biochemical assays. As results, biochemical data showed increased trends of liver metabolic enzymes in sera of PFOA-treated PND21 mice. Interestingly, PFOA-treated PND21 mice resulted in increased levels of NGF in sera and cortex cells. In addition, PFOA-exposed cerebral cortex cells induced NGF and proliferating cell nuclear antigen (PCNA) expressions, while exposure to PFOA/NGF specific inhibitor downregulated expressions of NGF and PCNA. In addition, Nissl labeled, NGF-positive cells, and NGF protein expression in cortex cells of PFOA treated PND21 mice were upregulated, respectively. Further, immunoblotting assays showed that intracephalic poly (ADP-ribose) polymerase (PARP) and p42/44 mitogen activated protein kinase (MAPK) proliferation-regulated protein levels were elevated in PFOA-treated cortex cells. Taken together, our current findings indicate that the prenatal PFOA exposure may induce proliferation of cerebral cortex cells in PND21 mice through promoting intracephalic NGF expression in the cortex. PMID- 29717429 TI - Effect of compost tea containing phosphogypsum on potato plant growth and protection against Fusarium solani infection. AB - Three composts made of industrial wastes were prepared by mixing olive oil mill waste water (OMW), olive pomace, coffee grounds, and phosphogypsum (0, 10, and 30%). Potato plants (Solanum tuberosum) cultivated in a greenhouse were used to screen compost tea suppressive ability. All compost tea treatments inhibited Fusarium solani growth and improved plant growth and response to F. solani infection. The antagonistic effects of the different treatments were associated with a marked increase of the antioxidant enzymes and PR (pathogenesis related) protein expression and a decrease of disease severity. These results also showed that plant growth and disease suppression were improved by application of phosphogypsum-supplemented compost teas (A10 and A30). This enhancement can be attributed to the influence of phosphogypsum on nutrient elements and microbial diversity in the resulting compost teas. PMID- 29717430 TI - Biochemical and life cycle effects of triclosan chronic toxicity to earthworm Eisenia fetida. AB - The study aimed at determining the response of adult Eisenia fetida earthworms to chronic exposure to triclosan (TCS) (10-750 mg kg-1) in soil. TCS life cycle toxicity was evaluated by the means of survival, growth rate, and reproduction assessment. Biochemical responses including changes in the activity of antioxidative enzymes (catalase, superoxide dismutase, and glutathione reductase) and concentration of malondialdehyde (MDA) were determined. Significant reduction in the earthworm survival was observed only if the exposure to TCS was longer than 4 weeks. TCS reduced the growth rate of E. fetida; the weight of the fastest growing control individuals exceeded that for the slowest growing by factor of 2.56. Reproduction was the most sensitive life cycle parameter and was affected at the very low levels of TCS in the soil. The results showed that chronic exposure to TCS levels in the soil induced a significant increase in the activity of antioxidative enzymes and MDA concentration. Present study revealed that an integrated approach combining biochemical and life cycle endpoints would provide a more comprehensive assessment of the ecological effects of chronic TCS exposure on earthworms. PMID- 29717432 TI - Classifying dysmorphic syndromes by using artificial neural network based hierarchical decision tree. AB - Dysmorphic syndromes have different facial malformations. These malformations are significant to an early diagnosis of dysmorphic syndromes and contain distinctive information for face recognition. In this study we define the certain features of each syndrome by considering facial malformations and classify Fragile X, Hurler, Prader Willi, Down, Wolf Hirschhorn syndromes and healthy groups automatically. The reference points are marked on the face images and ratios between the points' distances are taken into consideration as features. We suggest a neural network based hierarchical decision tree structure in order to classify the syndrome types. We also implement k-nearest neighbor (k-NN) and artificial neural network (ANN) classifiers to compare classification accuracy with our hierarchical decision tree. The classification accuracy is 50, 73 and 86.7% with k-NN, ANN and hierarchical decision tree methods, respectively. Then, the same images are shown to a clinical expert who achieve a recognition rate of 46.7%. We develop an efficient system to recognize different syndrome types automatically in a simple, non-invasive imaging data, which is independent from the patient's age, sex and race at high accuracy. The promising results indicate that our method can be used for pre-diagnosis of the dysmorphic syndromes by clinical experts. PMID- 29717431 TI - Status, sources, and risk assessment of polycyclic aromatic hydrocarbons in urban soils of Xi'an, China. AB - To identify status, source of polycyclic aromatic hydrocarbons (PAHs) in urban soils and to assess soil environmental quality in Xi'an City, China, total 45 soil samples were collected from surface layer (0-10 cm) in different functional areas. Total concentrations of 16 US EPA priority PAHs ranged from 149.9 to 5770 MUg kg-1, with a mean of 1246 MUg kg-1. High molecular weight (HMW) PAHs accounted for the majority (42.4-72.2%) of the total PAHs in the urban soils, and phenanthrene (Phe), fluorene (Flo), pyrene (Pyr), benzo(b)fluoranthene (BbF), and chrysene (Chr) were the major compounds. Concentrations of PAHs varied among different functional areas. High level of PAHs was particularly apparent in industrial zones and city road overpass, while low level was recorded in scenic spots and campus. The integration of isomer ratios, principal component analysis (PCA), and positive matrix factor (PMF) indicated that the sources of PAHs in Xi'an urban soils were mainly derived from vehicle emissions and coal combustion. Based on incremental lifetime cancer risks (ILCR) model, the urban soils from the three functional areas (industrial zone, urban road, and city road overpass) posed potential cancer risk, and the cancer risks of direct ingestion for children were apparently higher than that for adolescence and for adult, respectively. Therefore, attention should be paid to the health risk for children exposed to PAHs in the urban soils. PMID- 29717433 TI - Protective Effect of Ganoderma Triterpenoids on Cadmium-Induced Testicular Toxicity in Chickens. AB - Studies have shown that cadmium can cause chicken testicular damage, but a protective effect of Ganoderma triterpenoids on cadmium-induced testicular damage in chickens has not yet been reported. The present study was designed to research the protective effect of Ganoderma triterpenoids on cadmium-induced testicular damage in chicken. Eighty healthy 7-day-old Hyline egg laying chickens were randomly divided into four groups with 20 in each group. The control group was fed with normal full-fodder, the model group was fed with normal full-fodder with 140 mg/kg of CdCl2, the Ganoderma triterpenoid treatment group was fed with a full-fodder diet containing 140 mg/kg of CdCl2 and 0.5 mL of Ganoderma triterpenoid solution (20 mg/mL), and the Ganoderma triterpenoid group was fed normal full-fodder and 0.5 mL of Ganoderma triterpenoid solution (20 mg/mL) gavage. The chickens were euthanized at 20, 40, and 60 days, respectively, and the testes were harvested. The changes of cadmium contents, the antioxidant enzymes (superoxide dismutase (SOD), glutathione peroxidase (GSH-Px)), peroxide (malondialdehyde (MDA)), inflammatory factors (interleukin (IL)-1beta, IL-6, and tumor necrosis factor alpha (TNF-alpha)), and apoptosis-related proteins (Bax, Bcl-2, and Caspase-3) were detected. The pathological sections of the testes were made at the same time. The results suggested that Ganoderma triterpenoids could reduce the accumulation of cadmium in testis tissue; reduce the content of IL 1beta, IL-6, and TNF-alpha in cadmium poisoning testis; significantly increase the activity of SOD and GSH-Px; decrease the content of MDA; regulate the expression of Bax, Caspase-3, and Bcl-2; and reduce the damage of testicular tissue. The results showed that Ganoderma triterpenoids have a protective effect on cadmium-induced testicular injury in chicken. PMID- 29717434 TI - Entering the Pantheon of 21st Century Molecular Biology Tools: A Perspective on Digital PCR. AB - After several decades of relatively modest use, in the last several years digital PCR (dPCR) has grown to become the new gold standard for nucleic acid quantification. This coincides with the commercial availability of scalable, affordable, and reproducible droplet-based dPCR platforms in the past five years and has led to its rapid dissemination into diverse research fields and testing applications. Among these, it has been adopted most vigorously into clinical oncology where it is beginning to be used for plasma genotyping in cancer patients undergoing treatment. Additionally, innovation across the scientific community has extended the benefits of reaction partitioning beyond DNA and RNA quantification alone, and demonstrated its usefulness in evaluating DNA size and integrity, the physical linkage of colocalized markers, levels of enzyme activity and specific cation concentrations in a sample, and more. As dPCR technology gains in popularity and breadth, its power and simplicity can often be taken for granted; thus, the reader is reminded that due diligence must be exercised in order to make claims not only of precision but also of accuracy in their measurements. PMID- 29717435 TI - Basic Concepts and Validation of Digital PCR Measurements. AB - Use of digital polymerase chain reaction (dPCR) technology is rapidly growing and diversifying into a range of areas in life science. The release of dPCR commercial systems has facilitated access, leading to recognition of the potential advantages compared to previous quantitative PCR technologies, and the scope for novel applications. The capability of dPCR to deliver unprecedented levels of precision, accuracy, and resolution in quantification of nucleic acids has triggered a strong interest by academia and the life sciences industry in use of this technology as a molecular diagnostic tool. However, the performance of dPCR, as for a "classical" PCR assay, essentially still relies on enzyme-based amplification of nucleic acid using specific reagents and instrumentation. This chapter describes basic concepts, key properties, and important factors to consider for the verification and validation of dPCR measurements. PMID- 29717436 TI - Fundamentals of Counting Statistics in Digital PCR: I Just Measured Two Target Copies-What Does It Mean? AB - Current commercially available digital PCR (dPCR) systems and assays are capable of detecting individual target molecules with considerable reliability. As tests are developed and validated for use on clinical samples, the need to understand and develop robust statistical analysis routines increases. This chapter covers the fundamental processes and limitations of detecting and reporting on single molecule detection. We cover the basics of quantification of targets and sources of imprecision. We describe the basic test concepts: sensitivity, specificity, limit of blank, limit of detection, and limit of quantification in the context of dPCR. We provide basic guidelines how to determine those, how to choose and interpret the operating point, and what factors may influence overall test performance in practice. PMID- 29717437 TI - Control Materials and Digital PCR Methods for Evaluation of Circulating Cell-Free DNA Extractions from Plasma. AB - Cell-free DNA is an accessible source of genetic material found naturally in plasma that could be used in many diagnostic applications. Translation of cfDNA analysis methods from research laboratories into the clinic would benefit from controls for monitoring the efficiency of patient sample purification and for quality control of the whole workflow from extraction through to analysis. Here we describe two types of control materials that can be "spiked" into plasma samples to monitor and evaluate different aspects of the workflow. The first control material is an internal control that enables evaluation of extraction efficiency, fragment size bias, and sample inhibition. The second control material serves as a parallel quality control material for measurement of specific genetic targets such as tumor mutations. PMID- 29717438 TI - Multiplex Droplet Digital PCR Protocols for Quantification of GM Maize Events. AB - The standard-curve based simplex quantitative polymerase chain reaction (qPCR) has been the gold standard for DNA target quantification for more than a decade. The large and growing number of individual analyses needed to test for genetically modified organisms (GMOs) is reducing the cost-effectiveness of qPCR. Droplet digital PCR (ddPCR) enables absolute quantification without standard curves, avoids the amplification efficiency bias observed with qPCR, allows more accurate estimations at low target copy numbers and, in combination with multiplexing, significantly improves cost efficiency. Here we describe two protocols for multiplex quantification of GM maize events: (1) nondiscriminating, with multiplex quantification of targets as a group (12 GM maize lines) and (2) discriminating, with multiplex quantification of individual targets (events). The first enables the quantification of twelve European Union authorized GM maize events as a group with only two assays, but does not permit determination of the individual events present. The second protocol enables the quantification of four individual targets (three GM events and one endogene) in a single reaction. Both protocols can be modified for quantification of any other DNA target. PMID- 29717439 TI - Using Droplet Digital PCR to Detect Coinfection of Human Herpesviruses 6A and 6B (HHV-6A and HHV-6B) in Clinical Samples. AB - Droplet digitalTM polymerase chain reaction (ddPCRTM) is a unique digital PCR technique that allows for absolute quantification of nucleic acid samples. This technique operates on the basis of amplification within water-oil emulsion droplets and can detect very small quantities of target molecules, yielding extremely precise data. Here, we describe in detail a ddPCR procedure for multiplexed detection of two clinically relevant herpesviruses, HHV-6A and HHV 6B. PMID- 29717440 TI - Biomarkers in Cerebrospinal Fluid: Analysis of Cell-Free Circulating Mitochondrial DNA by Digital PCR. AB - Cerebrospinal fluid (CSF) contains molecules directly linked with brain function because it permeates brain tissue. The analysis of protein biomarkers in CSF is currently recommended for the diagnosis of neurodegenerative disorders, but the clinical sensitivity and specificity are still being investigated. A major drawback is that most of the currently used biomarkers of neurodegenerative diseases are proteins that are found at very low concentrations in CSF and need to be measured by immunoassays that provide relative values, which sometimes are difficult to reproduce between laboratories. In contrast, the recent availability of digital PCR platforms allows the absolute quantification of nucleic acids at single-molecule resolution, but their presence in CSF has not been characterized. CSF contains cell-free mitochondrial DNA (mtDNA) and changes in the concentration of this nucleic acid are linked to neurodegeneration. Here we describe a method to measure the concentration of cell-free circulating mtDNA directly in unpurified CSF using droplet digital PCR with either hydrolysis probes or fluorescent DNA-binding dye methods. This protocol allows the detection and absolute quantification of mtDNA content in the CSF with high analytical sensitivity, specificity, and accuracy. PMID- 29717441 TI - Testing of General and Human-Associated Fecal Contamination in Waters. AB - qPCR has become increasingly popular for microbial water quality testing because it is faster, more specific, and more flexible than culture-based methods. However, qPCR method limitations such as quantification bias introduced by reliance on standards and susceptibility to PCR inhibitors are major obstacles for implementation in water testing. This is because water testing requires accurate quantification of rare targets and because environmental waters often contain PCR inhibitors. Digital PCR offers the opportunity to maintain qPCR's advantages over culture-based methods while ameliorating two of qPCR's major limitations: the necessity to run standard curves and high susceptibility to inhibition. Here we describe a complete method for simultaneous testing for a general microbial water quality indicator (Enterococcus spp.) and a human associated fecal marker in environmental waters. The complete method includes water sampling and filtration to capture bacteria, DNA extraction from bacteria captured on the filter, and droplet digital PCR to quantify the genetic markers from bacteria indicative of general and human-associated fecal contamination. PMID- 29717442 TI - Analyzing Copy Number Variation with Droplet Digital PCR. AB - Many genomic segments vary in copy number among individuals of the same species, or between cancer and normal cells within the same person. Correctly measuring this copy number variation is critical for studying its genetic properties, its distribution in populations and its relationship to phenotypes. Droplet digital PCR (ddPCR) enables accurate measurement of copy number by partitioning a PCR reaction into thousands of nanoliter-scale droplets, so that a genomic sequence of interest-whose presence or absence in a droplet is determined by end-point fluorescence-can be digitally counted. Here, we describe how we analyze copy number variants using ddPCR and review the design of effective assays, the performance of ddPCR with those assays, the optimization of reactions, and the interpretation of data. PMID- 29717443 TI - Assessing HER2 Amplification in Plasma cfDNA. AB - Digital PCR (dPCR) is a highly accurate method to determine DNA concentration. In dPCR, DNA is portioned into many discrete single entities, and these are analyzed individually for the presence or absence of a target molecule of interest. Here we describe how digital PCR can be employed to determine the presence of oncogenic amplification through noninvasive analysis of circulating free DNA (cfDNA), and exemplify this approach by developing a plasma circulating free DNA dPCR assay for HER2 copy number. PMID- 29717444 TI - Detection and Quantification of Mosaic Genomic DNA Variation in Primary Somatic Tissues Using ddPCR: Analysis of Mosaic Transposable-Element Insertions, Copy Number Variants, and Single-Nucleotide Variants. AB - Here, we describe approaches using droplet digital polymerase chain reaction (ddPCR) to validate and quantify somatic mosaic events contributed by transposable-element insertions, copy-number variants, and single-nucleotide variants. In the ddPCR assay, sample or template DNA is partitioned into tens of thousands of individual droplets such that when DNA input is low, the vast majority of droplets contains no more than one copy of template DNA. PCR takes place in each individual droplet and produces a fluorescent readout to indicate the presence or absence of the target of interest allowing for the accurate "counting" of the number of copies present in the sample. The number of partitions is large enough to assay somatic mosaic events with frequencies down to less than 1%. PMID- 29717446 TI - Detection of Cancer DNA in Early Stage and Metastatic Breast Cancer Patients. AB - Breast cancer is the leading cause of cancer in women and the second leading cause of cancer-related death. There are many subtypes of breast cancer, which can be identified through the process of molecular and genetic profiling. While the current standard of care utilizes tumor tissue biopsy to subclassify breast cancer, plasma tumor DNA (ptDNA) can be detected through droplet digital PCR (ddPCR) of plasma obtained from a simple blood draw. Tissue biopsy is not only more invasive but because tumors exhibit heterogeneity it can be less accurate. Blood collects DNA shed from normal and cancerous cells alike, thus ddPCR of plasma offers a broader picture of a cancer's genetic makeup. This chapter summarizes how patients with breast cancer can be screened for specific cancerous mutations in both tissue and plasma through the use of ddPCR. PMID- 29717445 TI - Monitoring of Response and Resistance in Plasma of EGFR-Mutant Lung Cancer Using Droplet Digital PCR. AB - The identification of oncogenic driver mutations has led to the rapid rise of genotype-directed treatments. However, genetic analysis of tumors remains cumbersome and a morbid experience for patients. Noninvasive assessment of tumor genotype, so-called "liquid biopsy," such as plasma genotyping represents a potentially transformative tool. Here we describe a genotyping protocol of cell free plasma DNA (cfDNA) using Droplet DigitalTM PCR (ddPCRTM). ddPCR emulsifies DNA into ~20,000 droplets in which PCR is performed to endpoint in each droplet for both mutant and wild-type DNA. Droplets are run through a modified flow cytometer where mutant and wild-type DNA emit different colored signals. The count of these signals upon Poisson distribution analysis allows sensitive quantification of allelic prevalence. PMID- 29717447 TI - Droplet Digital PCR for Minimal Residual Disease Detection in Mature Lymphoproliferative Disorders. AB - Minimal residual disease (MRD) detection has a powerful prognostic relevance for response evaluation and prediction of relapse in hematological malignancies. Real time quantitative PCR (qPCR) has become the settled and standardized method for MRD assessment in lymphoid disorders. However, qPCR is a relative quantification approach, since it requires a reference standard curve. Droplet digitalTM PCR (ddPCRTM) allows a reliable absolute tumor burden quantification withdrawing the need for preparing, for each experiment, a tumor-specific standard curve. We have recently shown that ddPCR has a good concordance with qPCR and could be a feasible and reliable tool for MRD monitoring in mature lymphoproliferative disorders. In this chapter we describe the experimental workflow, from the detection of the clonal molecular marker to the MRD monitoring by ddPCR, in patients affected by multiple myeloma, mantle cell lymphoma and follicular lymphoma. However, standardization programs among different laboratories are needed in order to ensure the reliability and reproducibility of ddPCR-based MRD results. PMID- 29717448 TI - Quantitation of JAK2 V617F Allele Burden by Using the QuantStudioTM 3D Digital PCR System. AB - The JAK2 V617F mutation is highly prevalent in patients with myeloproliferative neoplasms (MPN). Furthermore, it has been shown that its allelic burden correlates with hematologic characteristics, drug response, and clinical endpoints in MPN patients. Digital PCR is an emerging technology for sensitive mutation detection and quantitation, based on dilution and high-grade partitioning of a sample. Here, we describe the use of the nanofluidic chip-based QuantStudioTM 3D Digital PCR System for quantitation of the JAK2 V617F mutation. PMID- 29717449 TI - Novel Multiplexing Strategies for Quantification of Rare Alleles Using ddPCR. AB - Droplet digital PCR (ddPCR) has come to be regarded as the gold standard for the ultrasensitive detection and absolute quantification of closely related DNA sequences within complex mixtures. Most ddPCR assays to date, however, rely on sets of hydrolysis probes conjugated with dyes having different emission spectra to allow independent counting of rare mutant and wild-type alleles. Here, we describe a set of novel strategies that leverage the simultaneous detection and quantification of both mutant and wild-type alleles with a single hydrolysis probe. Variants of these strategies empower multiplexing and a more cost effective approach for concurrent screening of multiple genetic variants. PMID- 29717450 TI - Identification and Use of Personalized Genomic Markers for Monitoring Circulating Tumor DNA. AB - Digital PCR techniques are ideally suited for accurately quantifying trace amounts of target DNA sequences, such as tumor-derived mutant DNA that is present in the blood circulation of patients with cancer. Here, we describe an approach marrying low-coverage whole-genome sequencing of tumor tissues, to enumerate chromosomal rearrangement breakpoints, together with droplet digital PCR (ddPCR) based personalized rearrangement assays to cost-effectively monitor circulating tumor DNA levels at multiple time-points during the clinical course. The method is generally applicable to essentially any cancer patient, as all cancers harbor unstable genomes, and may have uses for measuring minimal residual disease, response to therapy, and early detection of metastasis. PMID- 29717451 TI - Single Color Multiplexed ddPCR Copy Number Measurements and Single Nucleotide Variant Genotyping. AB - Droplet digital PCR (ddPCR) allows for accurate quantification of genetic events such as copy number variation and single nucleotide variants. Probe-based assays represent the current "gold-standard" for detection and quantification of these genetic events. Here, we introduce a cost-effective single color ddPCR assay that allows for single genome resolution quantification of copy number and single nucleotide variation. PMID- 29717452 TI - A Universal Droplet Digital PCR Approach for Monitoring of Graft Health After Transplantation Using a Preselected SNP Set. AB - Transplanted organs release cell-free DNA into the bloodstream of the recipient. This graft-derived cell-free DNA (GcfDNA) is a sensitive biomarker for organ health, since higher GcfDNA levels are indicative of increased cell-death in the graft. This protocol describes a method to measure relative GcfDNA concentrations by ddPCR assays. The method uses a set of preselected SNP assays from which the informative SNPs for each recipient-donor combination are selected in a straightforward two-step procedure that requires only one blood draw. Sampling of donor tissue and separate genotyping is not required, rendering the technique applicable also to patients, whose transplantation was not recent. In these patients there will be mostly no access to donor DNA anymore. PMID- 29717453 TI - Detection and Quantification of HDR and NHEJ Induced by Genome Editing at Endogenous Gene Loci Using Droplet Digital PCR. AB - Genome editing holds great promise for experimental biology and potential clinical use. To successfully utilize genome editing, it is critical to sensitively detect and quantify its outcomes: homology-directed repair (HDR) and nonhomologous end joining (NHEJ). This has been difficult at endogenous gene loci and instead is frequently done using artificial reporter systems. Here, we describe a droplet digital PCR (ddPCR)-based method to simultaneously measure HDR and NHEJ at endogenous gene loci. This highly sensitive and quantitative method may significantly contribute to a better understanding of DNA repair mechanisms underlying genome editing and to the improvement of genome editing technology by allowing for efficient and systematic testing of many genome editing conditions in parallel. PMID- 29717454 TI - DNA Methylation Analysis Using Droplet Digital PCR. AB - Droplet digital (ddPCR) is a recent advance in PCR technology that enables the precise detection and absolute quantification of nucleic acid target sequences and that has a range of applications for both research and clinical diagnostic studies. Here, we discuss the parameters important in the design and performance of ddPCR for the detection and quantification of methylated DNA. We provide explicit instructions for conducting methylation specific ddPCR (aka MethyLight ddPCR). We also present an example that demonstrates the sensitivity and precision of the method for detecting methylated DNA in the promoter region of mir342/EVL, a potential DNA methylation biomarker for colon cancer risk. Common technical problems and troubleshooting for conducting successful MethyLight ddPCR assays are also discussed. PMID- 29717456 TI - Using Droplet Digital PCR to Analyze Allele-Specific RNA Expression. AB - Genome-wide association studies have discovered thousands of common alleles that associate with human phenotypes and disease. Many of these variants are in non protein-coding (regulatory) regions and are believed to affect phenotypes by modifying gene expression. In any organism with a diploid genome, such as humans, measuring the expression of each allele of a gene provides a well-controlled way to identify allelic influences on that gene's expression. Here, we describe a protocol for precisely measuring the allele-specific expression of individual genes. This method targets the nucleotide differences between the two alleles of a gene within an individual and measures the "allelic skew," the extent to which one allele is expressed more than the other. We cover the design of effective assays, the optimization of reactions, and the interpretation of the resulting data. PMID- 29717455 TI - Simultaneous Quantification of Multiple Alternatively Spliced mRNA Transcripts Using Droplet Digital PCR. AB - Currently there is no sensitive, precise, and reproducible method to quantitate alternative splicing of mRNA transcripts. Droplet digitalTM PCR (ddPCRTM) analysis allows for accurate digital counting for quantification of gene expression. Human telomerase reverse transcriptase (hTERT) is one of the essential components required for telomerase activity and for the maintenance of telomeres. Several alternatively spliced forms of hTERT mRNA in human primary and tumor cells have been reported in the literature. Using one pair of primers and two probes for hTERT, four alternatively spliced forms of hTERT (alpha-/beta+, alpha+/beta- single deletions, alpha-/beta- double deletion, and nondeletion alpha+/beta+) were accurately quantified through a novel analysis method via data collected from a single ddPCR reaction. In this chapter, we describe this ddPCR method that enables direct quantitative comparison of four alternatively spliced forms of the hTERT messenger RNA without the need for internal standards or multiple pairs of primers specific for each variant, eliminating the technical variation due to differential PCR amplification efficiency for different amplicons and the challenges of quantification using standard curves. This simple and straightforward method should have general utility for quantifying alternatively spliced gene transcripts. PMID- 29717457 TI - Very Low Abundance Single-Cell Transcript Quantification with 5-Plex ddPCRTM Assays. AB - Gene expression studies have provided one of the most accessible windows for understanding the molecular basis of cell and tissue phenotypes and how these change in response to stimuli. Current PCR-based and next generation sequencing methods offer great versatility in allowing the focused study of the roles of small numbers of genes or comprehensive profiling of the entire transcriptome of a sample at one time. Marrying of these approaches to various cell sorting technologies has recently enabled the profiling of expression in single cells, thereby increasing the resolution and sensitivity and strengthening the inferences from observed expression levels and changes. This chapter presents a quick and efficient 1-day workflow for sorting single cells with a small laboratory cell-sorter followed by an ultrahigh sensitivity, multiplexed digital PCR method for quantitative tracking of changes in 5-10 genes per single cell. PMID- 29717458 TI - Quantification of Circulating MicroRNAs by Droplet Digital PCR. AB - MicroRNAs (miRNAs) are released in the blood as cell-free molecules either linked to Ago proteins and LDL or enveloped inside exosomes and microvescicles. The amount of specific circulating microRNAs has been discovered to change accordingly to a disease state and to be potentially used as a disease biomarker. Sensitive and accurate methods for circulating microRNA quantification using probe-based or dye-based digital PCR technology have been developed. With a digital PCR system it is possible to obtain the absolute quantification of specific miRNAs, bypassing several issues related to low abundance targets and miRNA normalization. This chapter addresses the workflow and methods for miRNA assessment in biological fluids using EvaGreen-based droplet digital PCR as well as how to analyze and interpret results. PMID- 29717459 TI - Droplet Digital PCR for Absolute Quantification of Extracellular MicroRNAs in Plasma and Serum: Quantification of the Cancer Biomarker hsa-miR-141. AB - Droplet-based digital PCR provides high-precision, absolute quantification of nucleic acid target sequences with wide-ranging applications for both research and clinical diagnostic applications. Droplet-based digital PCR enables absolute quantification by counting nucleic acid molecules encapsulated in discrete, volumetrically defined water-in-oil droplet partitions. The current available systems overcome the previous lack of scalable and practical technologies for digital PCR implementation. Extracellular microRNAs in biofluids (plasma, serum, urine, cerebrospinal fluid, etc.) are promising noninvasive biomarkers in multiple diseases and different clinical settings (e.g., diagnosis, early diagnosis, prediction of recurrence, and prognosis). Here we describe a protocol that enables highly precise and reproducible absolute quantification of extracellular microRNAs using droplet digital PCR. PMID- 29717460 TI - Droplet DigitalTM PCR Next-Generation Sequencing Library QC Assay. AB - Digital PCR is a valuable tool to quantify next-generation sequencing (NGS) libraries precisely and accurately. Accurately quantifying NGS libraries enable accurate loading of the libraries on to the sequencer and thus improve sequencing performance by reducing under and overloading error. Accurate quantification also benefits users by enabling uniform loading of indexed/barcoded libraries which in turn greatly improves sequencing uniformity of the indexed/barcoded samples. The advantages gained by employing the Droplet Digital PCR (ddPCRTM) library QC assay includes the precise and accurate quantification in addition to size quality assessment, enabling users to QC their sequencing libraries with confidence. PMID- 29717461 TI - Phasing DNA Markers Using Digital PCR. AB - Besides quantifying the absolute number of copies of known DNA targets, digital PCR can also be used to assess whether two nonpolymorphic gene sequences or two heterozygous markers reside on the same DNA molecule (i.e., are physically linked). Some useful linkage applications include: phasing variants to define a haplotype; genotyping of inversions; determining the presence of multimarker pathogenic bacteria in a metagenomic sample; and assessing DNA integrity. This chapter describes an efficient and cost-effective method for analyzing linkage of any two genetic sequences up to at least 200 Kb apart, including phasing of heterozygous markers such as that which occur abundantly in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. PMID- 29717462 TI - ddTRAP: A Method for Sensitive and Precise Quantification of Telomerase Activity. AB - Telomerase is a cellular RNA template-dependent reverse transcriptase that adds telomere repeats to the 3' ends of chromosomes. Telomerase is expressed almost universally in tumor cells (>85%) to maintain telomere length, thus providing the ability of tumor cells to avoid senescence and to have unlimited replication ability, one of the key hallmarks of cancer. ddTRAP (droplet digital Telomere Repeat Amplification Protocol) is a two-step assay with whole cell lysates that utilizes a telomerase-mediated primer extension followed by droplet digital PCR (ddPCR) detection of extended products. The adoptation of the TRAP assay to ddPCR has resulted in improved throughput, increased sensitivity and better repeatability of the TRAP assay. The protocol described below details our procedures for ddTRAP. PMID- 29717463 TI - Highly Efficient and Reliable DNA Aptamer Selection Using the Partitioning Capabilities of ddPCR: The Hi-Fi SELEX Method. AB - In addition to its growing use in detecting and quantifying genes and larger genomic events, the partitioning used in digital PCR can serve as a powerful tool for high-fidelity amplification of synthetic combinatorial libraries of single stranded DNA. Sequence-diverse libraries of this type are used as a basis for selecting tight-binding aptamers against a specific target. Here we provide a detailed description of the Hi-Fi SELEX protocol for rapid and efficient DNA aptamer selection. As part of that methodology, we describe how Hi-Fi SELEX gains advantages over other aptamer selection methods in part through the use of the massive partitioning capability of digital PCR. PMID- 29717464 TI - Alteration in skeletal muscle mass in women with subclinical hypercortisolism. AB - PURPOSE: Despite the well-known deleterious effects of cortisol on skeletal muscle, whether subtle cortisol excess in subclinical hypercortisolism (SH) affects skeletal muscle mass is unknown. Our objective was to understand the effects of the cortisol level on skeletal muscle mass in patients with SH. METHODS: We compared skeletal muscle mass and fat mass (FM) between 21 patients with SH (12 women and 9 men) and 224 controls (67 women and 157 men) with nonfunctioning adrenal incidentaloma (NFAI). Medical records were reviewed, and we measured body composition parameters using bioelectrical impedance analysis and serum cortisol levels after the overnight 1-mg dexamethasone suppression test (DST). RESULTS: After adjusting for confounding factors, 1-mg DST levels were inversely correlated with appendicular skeletal muscle mass (ASM) (gamma = 0.245, P = 0.040), lower limb ASM (gamma = -0.244, P = 0.040), and appendicular skeletal muscle index (ASMI; height-adjusted ASM) (gamma = -0.229, P = 0.048) in all women, but not men. ASM and ASMI were significantly lower by 6.2% (P = 0.033) and 5.9% (P = 0.046), respectively, in women with SH compared with those with NFAI, but not men. Conversely, FM and percent fat mass were similar between the two groups. Compared with women with NFAI, among those with SH, lower limb, but not upper limb, ASM was lower by 6.8% (P = 0.020). CONCLUSIONS: This study showed that women with SH had lower skeletal muscle mass, especially of the lower limb, and suggested that subtle cortisol excess also has adverse effects on skeletal muscle metabolism. PMID- 29717465 TI - Animal Models in Forensic Science Research: Justified Use or Ethical Exploitation? AB - A moral dilemma exists in biomedical research relating to the use of animal or human tissue when conducting scientific research. In human ethics, researchers need to justify why the use of humans is necessary should suitable models exist. Conversely, in animal ethics, a researcher must justify why research cannot be carried out on suitable alternatives. In the case of medical procedures or therapeutics testing, the use of animal models is often justified. However, in forensic research, the justification may be less evident, particularly when research involves the infliction of trauma on living animals. To determine how the forensic science community is dealing with this dilemma, a review of literature within major forensic science journals was conducted. The frequency and trends of the use of animals in forensic science research was investigated for the period 1 January 2012-31 December 2016. The review revealed 204 original articles utilizing 5050 animals in various forms as analogues for human tissue. The most common specimens utilized were various species of rats (35.3%), pigs (29.3%), mice (17.7%), and rabbits (8.2%) although different specimens were favored in different study themes. The majority of studies (58%) were conducted on post-mortem specimens. It is, however, evident that more needs to be done to uphold the basic ethical principles of reduction, refinement and replacement in the use of animals for research purposes. PMID- 29717466 TI - Balancing for an Effective Communication in Organizations. AB - Communication is an essential part of all activities of organizations. However, it is affected by technology. Today, email and social media are popular methods of communication in organizations. Each of the listed methods has advantages and disadvantages which will be discussed in this letter which tries to drive the attention of organizations to the need for a standard and balanced approach toward communication. PMID- 29717467 TI - Research Ethics: Researchers Consider How Best to Prevent Misconduct in Research in Malaysian Higher Learning Institutions Through Ethics Education. AB - The purpose of this study is to encourage and highlight discussion on how to improve the teaching of research ethics in institutions of higher education in Malaysia. Drawing on semi-structured interviews with 21 academics in a research intensive university in Malaysia, interviewees agreed on the importance of emphasizing the subject of research ethics among students, as well as academics or researchers. This study reveals that participants felt that there is an urgent need to improve the current awareness and knowledge of issues related to misconduct in research among students and academics. The results of this study indicate a need for better teaching on the subject of research ethics in order to prevent misconduct in research. Finally, it concludes with suggestions that there should be a clear definition of research misconduct, to include consequences when engaging in misconduct; a separate research ethics syllabus for pure and social sciences should be conducted; research ethics should be implemented as a core subject, and there should be an early intervention and continuous learning of research ethics, with an emphasis on ethics training. PMID- 29717468 TI - It is the Quality of the Review that Matters. PMID- 29717469 TI - The Distinction Between Curative and Assistive Technology. AB - Disability activists have sometimes claimed their disability has actually increased their well-being. Some even say they would reject a cure to keep these gains. Yet, these same activists often simultaneously propose improvements to the quality and accessibility of assistive technology. However, for any argument favoring assistive over curative technology (or vice versa) to work, there must be a coherent distinction between the two. This line is already vague and will become even less clear with the emergence of novel technologies. This paper asks and tries to answer the question: what is it about the paradigmatic examples of curative and assistive technologies that make them paradigmatic and how can these defining features help us clarify the hard cases? This analysis will begin with an argument that, while the common views of this distinction adequately explain the paradigmatic cases, they fail to accurately pick out the relevant features of those technologies that make them paradigmatic and to provide adequate guidance for parsing the hard cases. Instead, it will be claimed that these categories of curative or assistive technologies are defined by the role the technologies play in establishing a person's relational narrative identity as a member of one of two social groups: disabled people or non-disabled people. PMID- 29717470 TI - ATM Card Cloning and Ethical Considerations. AB - With the advent of modern technology, the way society handles and performs monetary transactions has changed tremendously. The world is moving swiftly towards the digital arena. The use of Automated Teller Machine (ATM) cards (credit and debit) has led to a "cash-less society" and has fostered digital payments and purchases. In addition to this, the trust and reliance of the society upon these small pieces of plastic, having numbers engraved upon them, has increased immensely over the last two decades. In the past few years, the number of ATM fraud cases has increased exponentially. With the money of the people shifting towards the digital platform, ATM skimming has become a problem that has eventually led to a global outcry. The present review discusses the serious repercussions of ATM card cloning and the associated privacy, ethical and legal concerns. The preventive measures which need to be taken and adopted by the government authorities to mitigate the problem have also been discussed. PMID- 29717471 TI - A common source of attention for auditory and visual tracking. AB - Tasks that require tracking visual information reveal the severe limitations of our capacity to attend to multiple objects that vary in time and space. Although these limitations have been extensively characterized in the visual domain, very little is known about tracking information in other sensory domains. Does tracking auditory information exhibit characteristics similar to those of tracking visual information, and to what extent do these two tracking tasks draw on the same attention resources? We addressed these questions by asking participants to perform either single or dual tracking tasks from the same (visual-visual) or different (visual-auditory) perceptual modalities, with the difficulty of the tracking tasks being manipulated across trials. The results revealed that performing two concurrent tracking tasks, whether they were in the same or different modalities, affected tracking performance as compared to performing each task alone (concurrence costs). Moreover, increasing task difficulty also led to increased costs in both the single-task and dual-task conditions (load-dependent costs). The comparison of concurrence costs between visual-visual and visual-auditory dual-task performance revealed slightly greater interference when two visual tracking tasks were paired. Interestingly, however, increasing task difficulty led to equivalent costs for visual-visual and visual auditory pairings. We concluded that visual and auditory tracking draw largely, though not exclusively, on common central attentional resources. PMID- 29717472 TI - Feature integration in basic detection and localization tasks: Insights from the attentional orienting literature. AB - Once presumed to be intimately related, feature integration and the consequences of attentional orienting are now often studied separately. Yet the paradigms used to study each can be highly similar; participants respond to a stimulus, which is then followed by a second stimulus, matching or mismatching the first on some feature(s). Given the similarities between the methods, it seems likely that these fields each could gain insights regarding their own work by looking at the other. Here we note a peculiarity of feature integration research: It relies on paradigms that require or encourage participants to identify the nonspatial features of a stimulus in order to make the correct response. This leaves open the question of whether feature integration effects can be found in tasks that do not require stimulus identity (e.g., color or shape) processing. To answer this question, we reviewed attentional orienting studies that manipulated whether stimulus identity repeated but that required only detection or localization responses, irrespective of stimulus identity. With one exception, feature integration effects were absent from those experiments. Furthermore, we attempted to replicate the exception and found no feature integration effects. Our review shows that detection and localization paradigms are particularly useful for studying the consequences of attentional orienting in the absence of integration effects, and that these same tasks provide a baseline to understand the sources of feature integration effects with only slightly variations in the basic task. PMID- 29717473 TI - Comparison of quick recovery outcome of inhalable doxorubicin and cisplatin in lung cancer patients: a randomized, double-blind, single-center trial. AB - : Systematic chemotherapy has required high time span for recovery in cancer patients, serious toxic effects, and increased the time of cancer-free survival of patient but decreased the overall survival time of patients irrespective of diseased condition(s). To compare the quick recovery of inhalable doxorubicin and cisplatin in the lung cancer patients. A total of 240 patients with non-small cell lung cancer (NSCLC) patients were randomly divided into two groups of 120 each. Patients had inhaled 25 mg/m2 doxorubicin (DON group) or 10 mg/m2 cisplatin (CPN group) once in a day for 21 days. Volume, diameter, type, and a number of lung nodes, pulmonary function, and 21-day lung cancer risk assessment were evaluated. One-way ANOVA following Bonferroni multiple comparison tests was performed at 95% of confidence level. DON and CPN both groups had shrunken the lung cancer nodule, decreased solid nodules and non-solid nodules, and increased partially solid nodules. The DON group (5.88 +/- 3.98%) had strongly decreased nodule size than the CPN group (4.15 +/- 2.92%; p < 0.0001, q = 3.721). The incidence of nodular size reduction was 9.47 +/- 1.13% higher for doxorubicin than cisplatin. The CPN group had 36.53 +/- 0.66% and the DON group had 34.65 +/- 0.7% lung cancer risk assessment after 21 days (p < 0.0001, q = 3.785). Inhalable doxorubicin might be an effective therapy in NSCLC patients with acceptable hematologic and non-hematologic toxic effects. TRIAL REGISTRY: researchregistry3382, dated 28 December 2014 ( www.researchregistry.com ). PMID- 29717474 TI - Magnetic nanoparticle formulation for targeted delivery of chemotherapeutic irinotecan to lungs. AB - Lung cancer is the single largest cause of cancer related deaths in the world. Current treatments include surgery, radiation therapy, chemotherapy using cytotoxic drugs, and monoclonal antibodies. Such treatments have limited efficacy due to diverse nature of lung cells involved and lack of tissue penetration. Cytotoxic drugs, while potent, have the enormous drawback of limited entry into the lung selectively, thus causing collateral damage to other tissues. To overcome these shortcomings, we report here the development of new magnetic irinotecan containing nanoparticles (NPs), which target the lung over other tissues by over 5-fold. Selective targeting of lungs is achieved by deliberately incorporating a facilitated transport mechanism into the NPs. The iron containing NPs can be further exploited to retain the drug into the lung for maximum efficacy using an external magnet. This irinotecan nanoformulation can be used as mono therapy or combination therapy and offers a cost-effective and efficacious therapy for lung cancers. PMID- 29717475 TI - Antibacterial, anti-inflammatory, and bone-regenerative dual-drug-loaded calcium phosphate nanocarriers-in vitro and in vivo studies. AB - A dual local drug delivery system (DDS) composed of calcium phosphate bioceramic nanocarriers aimed at treating the antibacterial, anti-inflammatory, and bone regenerative aspects of periodontitis has been developed. Calcium-deficient hydroxyapatite (CDHA, Ca/P = 1.61) and tricalcium phosphate (beta-TCP) were prepared by microwave-accelerated wet chemical synthesis method. The phase purity of the nanocarriers was confirmed by x-ray diffraction (XRD) and Fourier transform infrared spectroscopy (FT-IR), while the transmission electron microscopy (TEM) confirmed their nanosized morphology. CDHA was selected as carrier for the antibiotic (tetracycline) while TCP was chosen as the anti inflammatory drug (ibuprofen) carrier. Combined drug release profile was studied in vitro from CDHA/TCP (CTP) system and compared with a HA/TCP (BCP) biphasic system. The tetracycline and ibuprofen release rate was 71 and 23% from CTP system as compared to 63 and 20% from BCP system. CTP system also showed a more controlled drug release profile compared to BCP system. Modeling of drug release kinetics from CTP system indicated that the release follows Higuchi model with a non-typical Fickian diffusion profile. In vitro biological studies showed the CTP system to be biocompatible with significant antibacterial and anti-inflammatory activity. In vivo implantation studies on rat cranial defects showed greater bone healing and new bone formation in the drug-loaded CTP system compared to control (no carrier) at the end of 12 weeks. The in vitro and in vivo results suggest that the combined drug delivery platform can provide a comprehensive management for all bone infections requiring multi-drug therapy. PMID- 29717476 TI - Physiologically Based Pharmacokinetic Modeling for Olaparib Dosing Recommendations: Bridging Formulations, Drug Interactions, and Patient Populations. AB - We report physiologically based pharmacokinetic-modeling analyses to determine olaparib (tablet or capsule) drug-drug interactions (DDIs). Verified DDI simulations provided dose recommendations for olaparib coadministration with clinically relevant CYP3A4 modulators to eliminate potential risk to patient safety or olaparib efficacy. When olaparib is given with strong/moderate CYP3A inhibitors, the dose should be reduced to 100/150 mg b.i.d. (tablet), and 150/200 mg b.i.d. (capsule). Olaparib administration is not recommended with strong/moderate CYP3A inducers. No dose reductions are required with weak CYP3A inhibitors/inducers. Olaparib was shown to be a weak inhibitor of CYP3A (1.6-fold increase in exposure of a sensitive CYP3A probe) and to have no effect on P glycoprotein or UGT1A1 substrates. Finally, this model was used to simulate exposure in scenarios where clinical data of olaparib are lacking, such as severe renal or hepatic impairment populations, and provided initial dosing recommendations in pediatric patients. PMID- 29717477 TI - Smartphones Democratize Advanced Biomedical Instruments and Foster Innovation. AB - From microscopy to diagnostics and monitoring of vital parameters, scientists, engineers, and educators have been making use of smartphones and smartphone components in various innovative ways, helping to democratize advanced measurement instruments used in research and education. PMID- 29717478 TI - Monotherapy Is Good Enough for Patients With Mild-to-Moderate Alzheimer's Disease: A Network Meta-Analysis of 76 Randomized Controlled Trials. AB - Memantine and the acetylcholinesterase inhibitors (AChEIs) are two classes of drugs that are used to treat patients with Alzheimer's disease (AD). We conducted a network meta-analysis of randomized controlled trials to compare the treatment effectiveness of monotherapy or combination therapy A total of 23,707 AD patients in 76 randomized trials were identified. In patients with mild-to-moderate AD, monotherapy with donepezil, galantamine, or rivastigmine were superior to placebo in enhancing cognitive functions and activities of daily living, whereas monotherapy with donepezil or memantine were superior to placebo in improving behavioral symptoms. However, combination therapy with AChEIs and memantine did not show additional benefit than monotherapy. In patients with moderate-to-severe AD, neither monotherapy nor combination therapy were superior to placebo in any domain measurement. Combination therapy with memantine and AChEIs is confirmed to have no additional benefits over monotherapy. PMID- 29717479 TI - Improving socio-emotional health for pupils in early secondary education with Pyramid: A school-based, early intervention model. AB - BACKGROUND: Policymakers are focusing increased attention on the role of schools to promote and support children's mental health, and evidence-based models of good practice are in demand. Pyramid Club is a school-based, socio-emotional intervention, demonstrably effective with primary-aged pupils. AIMS: This study extends previous Pyramid Club evaluations by examining effectiveness with pupils in early secondary education; service users' perceptions and experiences were investigated to increase understanding of Pyramid's impact, thus supporting enhanced practice. SAMPLE: Participants (n = 126) comprised selected pupils, aged 11-14 (52 males; 74 females), who completed the 10 week programme (Pyramid group) and a non-intervention comparison group. Club leaders (n = 23) were trained, Pyramid volunteers. METHODS: A mixed-methods design was implemented. The Strengths and Difficulties Questionnaire (SDQ), informant-rated version (Goodman, 1997, J Child Psychol Psychiat, 38, 581) and self-report version (Goodman, Meltzer, & Bailey, 1998, Europ Child Adolesc Psychiatry, 7, 125), was used to measure socio-emotional well-being: pre-club (baseline assessment), post-test (within 2 weeks of programme completion), and at 12-month follow-up (informant rated version only). Focus groups were conducted separately with Pyramid pupils and Club leaders. RESULTS: Findings from informants and self-reports identified significant improvements for the Pyramid group in total difficulties and on pertinent SDQ subscales (e.g., emotional symptoms and peer relationship problems) at post-test. Improvements were sustained at 12-month follow-up. Comparison pupils demonstrated minimal change over time. Thematic analysis of qualitative data supported the quantitative findings and provided valuable insights into the Pyramid Club experience. CONCLUSIONS: Findings contribute to evidence-based, preventative models for the early adolescent population and support the social validity of Pyramid Club. PMID- 29717480 TI - Genetic features of multicentric/multifocal intramucosal gastric carcinoma. AB - Chronic gastritis caused by Helicobacter pylori (H. pylori) infection could lead to the development of gastric cancer. The finding that multiple gastric cancers can develop synchronously and/or metachronously suggests the development of field cancerization in chronically inflamed, H. pylori-infected gastric mucosa. The genetic basis of multiple tumorigenesis in the inflamed stomach, however, is not well understood. In this study, we analyzed the microsatellite instability (MSI) status and copy number aberrations (CNAs) of 41 multiple intramucosal early gastric cancers that synchronously or metachronously developed in 19 patients with H. pylori infection. Among the 41 intramucosal gastric carcinomas, 9 (22%) exhibited MSI, and the remaining 32 (78%) exhibited the microsatellite stable (MSS) phenotype. Metachronous multiple intramucosal gastric carcinoma exhibit inter-tumor heterogeneity by individually acquiring genetic aberrations. All synchronous multiple intramucosal gastric carcinoma pairs shared a common MSI/MSS profile, and CNA analysis revealed that synchronous multiple intramucosal gastric carcinoma pairs with the MSS phenotype shared common aberrations of representative tumor-suppressor genes, including focal deletion of APC, TP53, CDKN2A, and CDKN2B. Multiregional CNA analysis revealed that heterogeneous gene amplifications/deletions, including PDL1 amplification, evolved under the presence of shared "trunk" genetic alterations in a subpopulation of individual intramucosal gastric carcinomas. These data suggest that multiple gastric carcinomas develop in a multicentric/multifocal manner exhibiting features of inter- and intra-tumor heterogeneity in H. pylori-infected gastric mucosa, whereas synchronous multiple intramucosal gastric carcinomas could share partially common genetic alterations, possibly via common oncogenic pathways. PMID- 29717481 TI - mRNA expression of IFN-lambdas in the gingival tissue of patients with chronic or aggressive periodontitis: A polymerase chain reaction study. AB - BACKGROUND: Several studies have proven the existence of herpesviruses in periodontal pockets of patients with chronic or aggressive periodontitis. Recently discovered interferon lambda (IFN-lambda) has antiviral properties and is induced by herpesviruses. The present study was a quantitative analysis of messenger RNA (mRNA) expression of IFN-lambdas (IFN-lambda1, IFN-lambda2, IFN lambda3) in the gingival tissues of patients with chronic or aggressive periodontitis. METHODS: A total of 90 participants (50 men and 40 women; age range 19-50 years, mean age 31.50 +/- 7.8) were categorized into three groups: healthy participants, patients with chronic periodontitis, and patients with aggressive periodontitis. mRNA expression of IFN-lambdas in gingival tissues was estimated using reverse transcriptase polymerase chain reaction and was correlated with clinical parameters such as gingival index (GI), probing pocket depth (PPD), and clinical attachment level (CAL). RESULTS: mRNA of IFN-lambda1, IFN-lambda2, and IFN-lambda3 was expressed in gingival tissues of healthy participants and in patients with chronic or aggressive periodontitis. The highest level of IFN-lambda1 was observed in patients with aggressive periodontitis (3.049 +/- 9.793), whereas IFN-lambda2 (4.322 +/- 11.310) and IFN lambda3 (11.932 +/- 27.479) were highest in patients with chronic periodontitis. The difference in mRNA expression of IFN-lambda1 (P = 0.008) and IFN-lambda3 (P = 0.043) among three groups was statistically significant CONCLUSION: Increased quantity of IFN-lambdas in patients with chronic and patients with aggressive periodontitis suggests a role in periodontitis. Variation in the expression of IFN-lambda1 and IFN-lambda3 in patients with periodontitis needs to be further evaluated. The mRNA expression of antiviral IFN-lambdas in gingival tissues might enhance our understanding related to viral pathogenesis of periodontal diseases. PMID- 29717482 TI - The blood utilization calculator, a target-based electronic decision support algorithm, increases the use of single-unit transfusions in a large academic medical center. AB - BACKGROUND: Electronic decision support has been used to reduce use of red blood cell (RBC) transfusion. With the goal of reducing transfusions, we modified our RBC orders to default to 1 unit. Next, we created a target-based algorithm, the blood utilization calculator or BUC, to calculate a dose in units, based on initial hemoglobin or hematocrit and weight. STUDY DESIGN AND METHODS: RBC orders defaulted to 1 unit in March 2016 and the BUC was implemented in July 2016. This gave three periods to compare old orders (before intervention), new orders (1 unit default), and the BUC period. A hospital dashboard that tracks blood product orders was queried to determine changes in single-unit transfusions between periods. Changes in transfusions were compared by analysis of variance. Acceptance of the BUC dosage recommendation was studied in both medical-based and surgical-based specialties. RESULTS: The number of single-unit transfusions showed significant increases after each of the two interventions studied from 247 +/- 19 before interventions to 358 +/- 19 and then to 445 +/- 141-unit transfusions/month (p < 0.0001). The ratio of 1-unit to 2-unit transfusions increased from 0.72 to 1.67 (p < 0.0001) and we observed a 19% overall reduction in units transfused. The BUC recommendation was accepted in 49% of orders. CONCLUSIONS: One-unit default orders and implementation of the BUC resulted in a significant increase in the use of single-unit transfusions. Improvement in the rate of acceptance of the BUC recommendation should further increase the use of single-unit transfusions. PMID- 29717483 TI - Neurocognitive functioning over the course of trauma-focused psychotherapy for PTSD: Changes in verbal memory and executive functioning. AB - OBJECTIVES: Individuals with post-traumatic stress disorder (PTSD) have neurocognitive deficits in verbal memory and executive functioning. In this study, we examined whether memory and executive functioning changed over the course of treatment and which clinical variables were associated with change. DESIGN: Neuropsychological assessments were administered at baseline and endpoint of a randomized controlled trial as secondary outcome. METHODS: Trauma survivors (n = 88) diagnosed with PTSD received trauma-focused psychotherapy within a 17 week randomized controlled trial. Neuropsychological tests were the California Verbal Learning Test, Rivermead Behavioural Memory Test, Stroop Color Word Test, and Trail Making Test. RESULTS: Significant, small- to medium-sized improvements in verbal memory, information processing speed, and executive functioning were found after trauma-focused psychotherapy (Cohen's d 0.16-0.68). Greater PTSD symptom decrease was significantly related to better post-treatment neurocognitive performance (all p < .005). Patients with comorbid depression improved more than patients with PTSD alone on interference tasks (p < .01). No differences emerged between treatment conditions and between patients on serotonergic antidepressants and those who were not. CONCLUSIONS: This study suggests that neurocognitive deficits in PTSD can improve over the course of trauma-focused psychotherapy and are therefore at least partly reversible. Improvements over treatment are in line with previous neuropsychological and neuroimaging studies and effect sizes exceed those of practice effects. Future research should determine whether these changes translate into improved functioning in the daily lives of the patients. PRACTITIONER POINTS: Patients with PTSD have difficulties performing verbal memory tasks (e.g., remembering a grocery list, recall of a story) and executive functioning tasks (e.g., shifting attention between two tasks, ignoring irrelevant information to complete a task). Verbal memory, information processing speed, and executive functioning significantly improved in patients with post-traumatic stress disorder over the course of trauma-focused psychotherapy. Improvements were equal in size for two different trauma-focused psychotherapies (Eye movement desensitization and reprocessing therapy and brief eclectic psychotherapy for PTSD). Medium-sized effects were found for recall of a story, whereas effects in other aspects of verbal memory, information processing speed, and executive functioning were small sized. No causal attributions can be made because we could not include a control group without treatment for ethical reasons. Findings may be more reflective of patients who completed treatment than patients who prematurely dropped out as completers were overrepresented in our sample. PMID- 29717484 TI - Microbiologic effect of two topical anti-infective treatments on ligature-induced peri-implantitis: A pilot study in dogs. AB - BACKGROUND: The aim of this split-mouth design pilot study in dogs was to assess microbiologic effects of two topical anti-infective treatment protocols on dental implants subjected to ligature-induced peri-implantitis, without use of systemic antibiotics. METHODS: Eight adult Beagle dogs each received four dental implants in contralateral, edentulated, mandibular jaw quadrants. After 8 weeks, silk ligatures were installed, to be removed after another 8 weeks. After 6 additional weeks, induced peri-implantitis lesions were subjected to either antimicrobial photodynamic therapy (aPDT) or a topical tetracycline (TTC) hydrochloride (50 mg/mL) solution. Microbiologic samples were collected from the deepest proximal peri-implantitis site in each jaw quadrant before and after treatment. The samples were analyzed using DNA-DNA hybridization checkerboard technique. RESULTS: Peri-implantitis induction successfully produced lesions with microbiologic characteristics similar to those found in humans. Overall results showed effective bacterial count reductions for both protocols. aPDT demonstrated major reductions of the red complex, but no statistical differences between groups were observed when adjusted for multiple comparisons. CONCLUSION: aPDT and TTC successfully decontaminated infected implant surfaces. Implant decontamination with aPDT appears to be a viable alternative to TTC in the management of peri-implantitis infection. PMID- 29717485 TI - Prospective metabolomics study identifies potential novel blood metabolites associated with pancreatic cancer risk. AB - Using a metabolomics approach, we systematically searched for circulating metabolite biomarkers for pancreatic cancer risk in a case-control study nested within two prospective Shanghai cohorts. Included in our study were 226 incident pancreatic cancer cases and their individually-matched controls. Untargeted mass spectrometry platforms were used to measure metabolites in blood samples collected prior to cancer diagnosis. Conditional logistic regression was performed to assess the associations of metabolites with pancreatic cancer risk. We identified 10 metabolites associated with pancreatic cancer, after accounting for multiple comparisons (the Benjamini-Hochberg false discovery rate <0.05). The majority of the identified metabolites were glycerophospholipids (ORs per SD increase: 0.44-2.32; p values: 7.2 * 10-4 to 1.0 * 10-6 ), six of which were associated with decreased risk and one with increased risk. Additionally, levels of coumarin (OR = 1.96, p = 3.7 * 10-6 ) and picolinic acid (OR = 2.53, p = 5.0 * 10-5 ) were positively associated with pancreatic cancer risk, while tetracosanoic acid was inversely associated with risk (OR = 0.48, p = 7.16 * 10-7 ). Four metabolites remained statistically significant after mutual adjustment. Our study provides novel evidence that the dysregulation of glycerophospholipids may play an important role in pancreatic cancer development. PMID- 29717486 TI - Heightened risk of ischemic stroke after recent herpes zoster ophthalmicus. PMID- 29717487 TI - Rab37 in lung cancer mediates exocytosis of soluble ST2 and thus skews macrophages toward tumor-suppressing phenotype. AB - Interplay between cancer epithelial cells and the surrounding immune cells shape the tumor microenvironment to promote cancer progression. Tumor-associated macrophages are well recognized for their roles in cancer progression. Accumulating evidence also indicates implication of Rab small GTPase-mediated exocytosis in tumorigenesis. However, the mechanism for Rab-mediated exocytosis in regulation of macrophage polarization is not clear. We have previously identified Rab37 as a metastasis suppressor in lung cancer. In our study, we identified a novel Rab37 trafficking cargo soluble ST2 (sST2), which skewed macrophage polarization toward anti-tumoral M1-like phenotype in vitro. We further demonstrated that Rab37-mediated sST2 secretion significantly increased the ratio of M1 vs. M2 in xenografts and thus reduced tumor growth. Moreover, lung cancer patients with low Rab37, low sST2 and low ratio of M1 vs. M2 macrophages expression profile correlated with worse overall survival examined by Kaplan-Meier survival analysis. Multivariate Cox regression analysis showed that this Rab37-sST2-M1/M2 expression profile predicted poor prognosis. Our findings reveal a novel regulation of cancerous Rab37 in microenvironmental macrophages polarization, which preferentially shifts to anti-tumoral phenotype and thereby suppresses lung tumor growth. PMID- 29717488 TI - Clonazepam add-on therapy for refractory epilepsy in adults and children. AB - BACKGROUND: Epilepsy affects about 50 million people worldwide, nearly a quarter of whom have drug-refractory epilepsy. People with drug-refractory epilepsy have increased risks of premature death, injuries, psychosocial dysfunction, and a reduced quality of life. OBJECTIVES: To assess the efficacy and tolerability of clonazepam when used as an add-on therapy for adults and children with refractory focal onset or generalised onset epileptic seizures, when compared with placebo or another antiepileptic agent. SEARCH METHODS: We searched the following databases on 14 September 2017: Cochrane Epilepsy Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Register of Studies Online (CRSO), MEDLINE (Ovid 1946 to 14 September 2017), ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform (ICTRP). SELECTION CRITERIA: Double-blind randomised controlled studies of add-on clonazepam in people with refractory focal or generalised onset seizures, with a minimum treatment period of eight weeks. The studies could be of parallel or cross-over design. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, extracted relevant data, and assessed trial quality. We contacted study authors for additional information. MAIN RESULTS: No double-blind randomised controlled trials met the inclusion criteria. AUTHORS' CONCLUSIONS: There is no evidence from double-blind randomised controlled trials for or against the use of clonazepam as an add-on therapy for adults and children with refractory focal or generalised onset epileptic seizures. PMID- 29717489 TI - Influence of a cancer diagnosis on changes in fruit and vegetable consumption according to cancer site, stage at diagnosis and socioeconomic factors: Results from the large E3N-EPIC study. AB - Many studies have demonstrated that lifestyle factors, including diet, may influence cancer survival. The number of cancer survivors is increasing worldwide and little is known about long-term diet changes in people who had cancer. We studied 53,981 women from the prospective E3N-EPIC cohort study with available dietary data in 1993 and 2005, among whom 4,619 had a cancer diagnosis inbetween (including n = 2,699 breast cancers). We evaluated the potential impact of a cancer diagnosis (comparing women with cancer to women with no cancer) on changes in FV consumption using multivariable linear regression models considering cancer site, stage at diagnosis and socioeconomic factors. Compared to women with no cancer, a statistically significant increase in FV consumption (beta=+2.65%, [1.22-4.09]) was observed in women who had cancer, and this association appeared to be driven by breast cancer exclusively. The increase in FV consumption was larger in women who had an advanced stage of breast cancer (stages II-IV) (beta=+7.23%, [3.92-10.5]) than in women with stages 0-I (beta=+2.03%, [-0.20 to 4.26]). Women with no partner and no children were those having the highest increase in FV consumption (beta=+18.71%, [6.51-30.91]). These changes were only observed in specific SE groups. When considering adherence to guidelines, the proportion of women who consumed less than 7.5 portions a day in 1993 and more in 2005 was greater in women with advanced breast cancer. More research is now needed to understand how the inequities we observed impact the long-term health after cancer. PMID- 29717490 TI - When is a proxy not a proxy? The foibles of studying non-image forming light. PMID- 29717491 TI - Corrigendum for Ann. N.Y. Acad. Sci. 2018. 1413: 143-153. PMID- 29717492 TI - Corrigendum for Ann. N.Y. Acad. Sci. 2018. 1413: 163-169. PMID- 29717493 TI - miR-1 is increased in pulmonary hypertension and downregulates Kv1.5 channels in rat pulmonary arteries. AB - KEY POINTS: The expression of miR-1 is increased in lungs from the Hyp/Su5416 PAH rat model. Pulmonary artery smooth muscle cells from this animal model are more depolarized and show decreased expression and activity of voltage-dependent potassium channel (Kv)1.5. miR-1 directly targets Kv1.5 channels, reduces Kv1.5 activity and induces membrane depolarization. Antagomir-1 prevents Kv1.5 channel downregulation and the depolarization induced by hypoxia/Su5416 exposition. ABSTRACT: Impairment of the voltage-dependent potassium channel (Kv) plays a central role in the development of cardiovascular diseases, including pulmonary arterial hypertension (PAH). MicroRNAs are non-coding RNAs that regulate gene expression by binding to the 3'-untranslated region region of specific mRNAs. The present study aimed to analyse the effects of miR-1 on Kv channel function in pulmonary arteries (PA). Kv channel activity was studied in PA from healthy animals transfected with miR-1 or scrambled-miR. Kv currents were studied using the whole-cell configuration of the patch clamp technique. The characterization of the Kv1.5 currents was performed with the selective inhibitor DPO-1. miR-1 expression was increased and Kv1.5 channels were decreased in lungs from a rat model of PAH induced by hypoxia and Su5416. miR-1 transfection increased cell capacitance, reduced Kv1.5 currents and induced membrane depolarization in isolated pulmonary artery smooth muscle cells. A luciferase reporter assay indicated that KCNA5, which encodes Kv1.5 channels, is a direct target gene of miR-1. Incubation of PA with Su5416 and hypoxia (3% O2 ) increased miR-1 and induced a decline in Kv1.5 currents, which was prevented by antagomiR-1. In conclusion, these data indicate that miR-1 induces pulmonary artery smooth muscle cell hypertrophy and reduces the activity and expression of Kv channels, suggesting a pathophysiological role in PAH. PMID- 29717495 TI - Editorial. PMID- 29717494 TI - Periodontitis and prevalence of elevated aminotransferases in the Hispanic Community Health Study/Study of Latinos. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) prevalence is greater among Hispanics/Latinos than other racial/ethnic groups and prevalence is further reported to vary among Hispanic/Latino background groups. Experimental animal and human studies demonstrate associations between periodontitis and NAFLD, not yet reported among Hispanics/Latinos. This study examined periodontitis as a novel risk factor that may contribute to the burden of NAFLD among Hispanics/Latinos. METHODS: Data came from 11,914 participants of the Hispanic Community Health Study/Study of Latinos. Periodontitis was defined as the extent (none, < 30%, >=30%) of periodontal sites with clinical attachment level (CAL) of >=3 mm or probing pocket depth (PD) of >=4 mm. Elevated serum transaminases indicative of suspected NAFLD were defined as having alanine aminotransferase levels (ALT) > 40 IU/L or aspartate aminotransferase (AST) > 37 IU/L for men and ALT > 31 IU/L or AST > 31 IU/L for women. Survey-logistic regression models estimated prevalence odds ratios (POR) and 95% confidence intervals (CI) for the association between periodontitis and suspected NAFLD. RESULTS: The overall age-standardized percentage of study participants with < 30% of sites with CAL >=3 mm or PD >=4 mm was 53.5% and 58.6%, respectively, while participants with >=30% sites with CAL >=3 mm or PD >=4 mm comprised 16% and 5.72%, respectively. The overall age standardized prevalence (95% CI) of suspected NAFLD was 18.1% (17.1-19.0). For the entire cohort, we observed a dose-response (i.e. graded) association between PD >=4 mm and the prevalence odds of suspected NAFLD, whereby participants with < 30% affected had a crude POR = 1.19 (95% CI: 1.03, 1.38) while participants with >=30% affected had a crude POR = 1.39 (95% CI: 1.02, 1.90). These crude estimates were attenuated toward the null and rendered non-significant upon covariate adjustment. No differences were found by Hispanic/Latino background group. CONCLUSION: Previously reported associations between periodontitis and NAFLD were marginal to null in this study of a diverse group of Hispanics/Latinos. PMID- 29717496 TI - Evidence for paternal kin bias in the social affiliation of adult female blue monkeys. AB - If animals increase inclusive fitness by cooperating with relatives, nepotism should involve maternal and paternal kin equally, all else being equal. Evidence of a behavioral bias toward paternal half-siblings in primates is both limited and mixed, with most positive reports from papionins. To expand knowledge of paternal kin recognition, particularly in cercopithecine monkeys, we examined evidence for paternal kin bias in wild blue monkeys (Cercopithecus mitis), a species living mostly in one-male groups. Seasonal breeding and the amount of male reproductive skew in blue monkeys suggests that opportunities to distinguish paternal kin are plentiful, and their social system would make such discrimination beneficial. We compared spatial association and social contact (grooming and contact-sitting) of 20 adult females with at least one paternal half-sibling and at least one non-relative that were present at the same time. We used two data sets, one in which social partners were other parous females, the other in which they were juveniles. Data came from a 7-year period. When interacting with other adult females, subjects groomed and sat in contact with paternal half-siblings significantly more than with known non-kin, and there was a similar trend for spatial association. We detected no paternal kin bias in interactions with juvenile partners. Kin-biased affiliative contact with adult female partners did not appear to be based on age proximity, measured by birth cohort. The study species' social system suggests phenotype matching as the most likely alternative mechanism, though we could not test it directly. Across both behaviors, there was no significant relationship between the number of matrilineal kin a subject had and the degree to which she preferred paternal half siblings over non-kin as affiliative partners. These findings contribute to a comparative understanding of paternal kin recognition in primates. PMID- 29717497 TI - Negativity bias in infants' expectations about agents' dispositions. AB - This study investigated 6- and 10-month-old infants' abilities to infer others' preferences based on social interactions using looking time and choice measures. Infants were randomly assigned to either a helping/neutral or hindering/neutral condition. Those in the helping/neutral condition were first familiarized with a helping event, in which an agent helped a circle climb a hill, and a neutral event, in which another agent followed the same path as the helping agent but had no interaction with the circle. During the test phase, the circle approached either the helper or the neutral agent. In the hindering/neutral condition, the infants were familiarized with a hindering event, in which an agent hindered the circle from reaching the top of the hill, and a neutral event, in which another agent followed the same path as the hindering agent but had no interaction with the circle. During the test phase, the circle approached either the hinderer or the neutral agent. For the looking-time measure, infants in the hindering/neutral condition looked reliably longer at the approach-hinderer than at the approach neutral agent event, whereas those in the helping/neutral condition looked for equal amounts of time at both test events. These results suggest that the infants expected the circle to avoid the hinderer but did not expect it to approach the helper. In the choice task, infants chose the helper more often than the neutral agent and the neutral agent more often than the hinderer, suggesting an ability to generate their own preferences for a particular agent based on the valence of helping and hindering actions. This research demonstrates infants' sensitivity to the moral valence of agents' social interactions, which may serve as a foundation for advanced socio-moral reasoning. Statement of contribution What is already known on this subject? Research on infants' ability in social evaluation has established that even preverbal infants can distinguish between positive and negative social interactions. Infants as young as 6 months of age can distinguish between helping and hindering actions and can generate their own preference towards helpful agents. What does this study add? The present study sheds light on infants' ability to infer a third-party's preference, which is a more challenging task for the infants than generating their own preference. Specifically, 6- and 10-month-old infants could infer others' preference for the neutral agent over the hinderer. Such results demonstrate infants' sensitivity to the moral valence of agents' social interactions and provide an evidence of negativity bias in social evaluation. PMID- 29717498 TI - Infrared thermal imaging: Positive and negative emotions modify the skin temperatures of monkey and ape faces. AB - Facial thermography has enabled researchers to noninvasively and continuously measure the changes of a range of emotional states in humans. The present work used this novel technology to study the effect of positive and negative emotions in nonhuman primates by focusing on four facial areas (the peri-orbital area, the nose bridge, the nose tip, and the upper lip). Monkeys and apes were examined for positive emotions (during interactions with toys and during tickling) and for negative emotions (during food delay and teasing). For the combined toy and tickling condition, the results indicated a drop in the nose tip temperature and a tendency of an increase in the peri-orbital temperature. For the combined food delay and teasing condition, the results also revealed a rise in the upper lip temperature of the subjects. These different effects on the facial temperatures in monkeys and apes most likely reflect distinctive physiological reactions of a primordial primate emotion system. We conclude that facial thermal imaging represents a promising physiologically grounded technology to noninvasively and continuously obtain reliable data on emotional states in nonhuman primates, which may help modernize research on emotions in nonhuman primates and enhance our understanding of the evolution of human emotions. PMID- 29717499 TI - Meeting report from the Prostate Cancer Foundation PSMA-directed radionuclide scientific working group. AB - INTRODUCTION: The Prostate Cancer Foundation (PCF) convened a PSMA-Directed Radionuclide Scientific Working Group on November 14, 2017, at Weill Cornell Medicine, New York, NY. METHODS: The meeting was attended by 35 global investigators with expertise in prostate cancer biology, radionuclide therapy, molecular imaging, prostate-specific membrane antigen (PSMA)-targeted agents, drug development, and prostate cancer clinical trials. The goal of this meeting was to discuss the potential for using PSMA-targeted radionuclide agents for the treatment of advanced prostate cancer and to define the studies and clinical trials necessary for validating and optimizing the use of these agents. RESULTS: Several major topic areas were discussed including the overview of PSMA biology, lessons and applications of PSMA-targeted PET imaging, the nuances of designing PSMA-targeted radionuclide agents, clinical experiences with PSMA-targeted radionuclides, PCF-funded projects to accelerate PSMA-targeted radionuclide therapy, and barriers to the use of radionuclide treatments in widespread clinical practice. DISCUSSION: This article reviews the major topics discussed at the meeting with the goal of promoting research that will validate and optimize the use of PSMA-targeted radionuclide therapies for the treatment of advanced prostate cancer. PMID- 29717500 TI - Evaluation of a pictorial method to obtain subject-specific inertial properties in equine limb segments. AB - Data describing segmental masses and moments of inertia (MOI) of limb segments are required for inverse dynamic calculations. In horses, these values are usually calculated using regression equations that have been developed from a limited number of horses representing a small number of breeds. The objective of the present study was to evaluate the performance of a scaling method and a pictorial method for estimating of the values of segmental masses, lengths, and MOI in the equine limb segments by comparing their output with the standard technique involving direct measurements. Limbs of 30 horses of various breeds and sizes were disarticulated post mortem. Segmental masses, lengths, and MOI were determined using a standard method based on weighing the segments, measuring their length with calipers, and estimating the MOI from the rotational frequency of a trifilar pendulum. The scaling method used a jack-knifing procedure to avoid the need for two data sets. The pictorial method was based on digitization of two orthogonal photographs to determine segmental volumes, which were combined with published values for average segment densities to determine the inertial parameters. Scaling method and pictorial method provided comparable estimation of segmental messes and lengths, but the scaling method performed better in estimating segmental MOI. The scaling method worked well enough in the majority of horses but there were a few horses in which it was less effective. The pictorial method sometimes showed a bias correctable by regression equations but it may not warrant the additional effort unless for specific cases. PMID- 29717501 TI - Sensory evoked cortical potentials of the lower urinary tract in healthy men. AB - AIMS: To assess the afferent innervation of various locations in the male lower urinary tract (LUT) using sensory evoked cortical potentials (SEPs). METHODS: Twelve healthy men (mean age: 29.6 +/- 7.2 years, mean height: 1.8 +/- 0.1 m) underwent repetitive slow (0.5 Hz/1 ms) and fast (3 Hz/0.2 ms) electrical stimulations of bladder (dome/trigone) and urethral (proximal/membranous/distal) locations with simultaneous cortical SEP recording (Cz-Fz). Latencies (ms) and peak-to-peak amplitudes (MUV) for SEP components P1, N1, and P2 were analyzed. Tibial SEPs were assessed as methodological control. The reproducibility was investigated from between visits and inter-rater assessments using Bland-Altman plots. Statistical tests comprised analysis of variance (ANOVA), linear regressions, and paired t-tests. Values are given as mean +/- standard deviation. RESULTS: Typical LUTSEPs with P1, N1, and P2 components were successfully detected (100% responder rate) for slow but less successfully for fast stimulation. The slow stimulation provided reproducible LUTSEPs with position specific N1 latencies: dome 125.6 +/- 21.3 ms, trigone 122.9 +/- 20.5 ms, proximal- 116.1 +/- 21.4 ms, membraneous- 118.8 +/- 29.3 ms, and distal urethra 108.8 +/- 17.8 ms. Despite good inter-rater agreement, latency variability between and within subjects was higher for LUTSEPs than for tibial SEPs. N1 latencies became shorter (P < 0.01) with increasing subject age for bladder dome and distal urethra stimulation. CONCLUSIONS: LUTSEPs can be successfully obtained for different LUT locations in men using slow electrical stimulation. Location specific differences in N1 latencies may indicate different local afferent innervation. Larger variability of LUTSEPs versus tibial SEPs may be related to the more challenging approach and afferent fibre access within the LUT. Further studies optimizing measurement and analysis approach are required. PMID- 29717502 TI - Statin use, high cholesterol and prostate cancer progression; results from HCaP NC. AB - BACKGROUND: Statin use is associated with lower advanced prostate cancer risk and reduced prostate cancer-specific mortality, but prior studies were conducted mainly in white men. We examined the effect of statin use on risk of prostate cancer progression in a population-based, minority-enriched cohort. METHODS: We used data from prostate cancer cases (45% African American) diagnosed between 2004 and 2007 who participated in the Health Care Access and Prostate Cancer Treatment in North Carolina cohort (HCaP-NC). We abstracted statin use at diagnosis. Men reported if they had ever been diagnosed with high cholesterol. Multivariable Cox proportional hazards analysis was used to examine associations between statin use and risk of prostate cancer progression (biochemical recurrence or secondary treatment), overall and by race. In secondary analysis, we examined the association between high cholesterol and risk of progression, overall, and by statin use. RESULTS: Of 669 men, 244 (36%) were statin users at diagnosis. During 3.8 years median follow-up, 138 men experienced prostate cancer progression. There was no association between statin use and risk of progression, either overall (HR 1.03; 95%CI 0.72-1.46) or stratified by race. High cholesterol was inversely associated with risk of progression, particularly among statin users (HR 0.43; 95%CI 0.20-0.94; p-interaction = 0.22) and in men with higher perceived access to care (HR 0.57; 95%CI 0.36-0.90; p-interaction = 0.03). Study limitations included a relatively small sample size, short follow-up, and lack of data regarding post diagnosis statin use. CONCLUSIONS: Statin use at diagnosis was not associated with prostate cancer progression in the population-based, minority-enriched HCaP-NC. Greater healthcare engagement, including actively controlling serum cholesterol, may be linked to better prostate cancer-specific outcomes. PMID- 29717503 TI - Will cesarean section increase the risk of interstitial cystitis/painful bladder syndrome? AB - AIMS: A high number of patients with interstitial cystitis/painful bladder syndrome (IC/PBS) have a history of pelvic surgeries, and cesarean section is one of the most common pelvic surgeries in women. This study aimed to investigate if cesarean section increases the risk of IC/PBS. METHODS: Women who exclusively gave birth through cesarean section or vaginal delivery were identified from a nationwide database between 2002 and 2013. All were followed up during the study period to detect the event of IC/PBS. The IC/PBS hazard ratio (HR) in the cesarean cohort was compared with the vaginal delivery cohort with and without matching for confounding factors. RESULTS: The unmatched group included 22 158 cesarean deliveries and 40 214 vaginal deliveries. The IC/PBS HR in the cesarean cohort compared with that in the vaginal delivery cohort was 1.370 (95% confidence interval [CI], 0.903-2.079; P = 0.139). In the matched group, 8368 women were matched in each cesarean and vaginal delivery cohort using propensity scores for age and comorbidities. The IC/PBS HR was 0.725 (95%CI, 0.358-1.471; P = 0.373). Both HRs in these two groups were not significantly different. The incidence density of IC/PBS in delivered women, non-delivery women, and the general female population were not significantly different either (0.310, 0.255, and 0.292 per 1000 person-years, respectively; P = 0.549). CONCLUSIONS: The risk of IC/PBS was not different between cesarean and vaginal delivery after controlling the confounding factors in this cohort study. Cesarean section has no causal effect on IC/BPS. Furthermore, delivery was not a risk factor for IC/PBS. PMID- 29717504 TI - Resources for nurturing childcare practices in urban and rural settings: Findings from the Colombia 2010 Demographic and Health Survey. AB - BACKGROUND: The health and development potential of young children is dependent on nurturing care (NC) provided by primary caregivers. NC encompasses attention to nutrition; symptom management; early learning, attachment, and socialization; and security and safety. Despite the importance of NC to child health and development, the measurement and study of NC are neglected. This has become a point of major concern in the public health field in low- and middle-income countries (LMICs) such as Colombia where many families are hard pressed for childcare resources. The aims of this study were therefore to (a) create age specific NC summary indexes (0-5, 6-11, and 12-23 months) suitable for research in LMICs and (2) examine the relationship of NC to maternal resources. METHODS: 2010 Colombia Demographic and Health Survey data were obtained from mothers and their children ages 0-5 months (n = 1,357); 6-11 months (n = 1,623); and 12-23 months (n = 3,006). Age-specific NC indexes were created including information on child feeding, immunization, hygiene, response to illness symptoms, and psychosocial care. Independent variables included mother's education level and household assets, and enrolment in a government child development programme. Regression analyses with NC as the outcome variable were conducted with urban and rural subsamples in the 3 age groups. RESULTS: Among rural children, NC was significantly higher with greater household assets, maternal decision latitude, and development programme participation, with variation by child age. Among urban children, higher maternal education and white-collar occupation also predicted higher NC, with some variation by age. CONCLUSION: It is feasible to measure age specific NC in survey research, and NC is related to maternal resources. Age and urban-rural differences in how NC is related to social factors are observed. The findings support the importance of subgroup analysis in the study of NC in LMICs such as Colombia. PMID- 29717506 TI - Width proportion of the urethral plate to the glans can serve as an appraisal index of the urethral plate in hypospadias repair. AB - OBJECTIVES: To find a new appropriate evaluation for urethral plate quality in hypospadias repair, with particular interest in the width proportion of the urethral plate to the glans, serving as an appraisal index. METHODS: Data were prospectively collected from prepubertal boys who underwent primary tubularized incised plate hypospadias repair between January 2014 and April 2016 in one center. Intrinsic parameters of the penis (meatal location, glans width, urethral plate width and curvature degree) were measured during the operation. Urethroplasty complications were recorded during follow up. The correlation between width proportion of the urethral plate to the glans and urethroplasty complications was analyzed. RESULTS: Primary tubularized incised plate repair was carried out in 442 patients (mean age 2.8 years, range 0.5-12 years). At mean follow up of 26 months (range 12-38 months), urethroplasty complications occurred in 59 (13.3%) patients. The width proportion of the urethral plate to the glans was weakly correlated to both the glans width and meatal location. The width proportion of the urethral plate to the glans ranged from 0.18 to 0.73, with a mean of 0.39. The cut-off value of width proportion of the urethral plate to the glans was determined to be 0.36 by the receiver operating characteristic curve. Urethroplasty complications occurred in 17 out of 254 patients (6.7%) with width proportion of the urethral plate to the glans >0.36, and 42 out of 188 patients (22.3%) with width proportion of the urethral plate to the glans <=0.36. The width proportion of the urethral plate to the glans <=0.36 showed an increased odds of 4.819-fold (95% confidence interval 2.548-9.112, P < 0.001) risk of urethroplasty complications compared with width proportion of the urethral plate to the glans >0.36. Midshaft and proximal meatal location also increased the risk of urethroplasty complications. CONCLUSIONS: The present study highlights the value of the width proportion of the urethral plate to the glans for objectivity and accuracy in urethral plate evaluation, which in turn serves as an independent factor influencing outcomes in tubularized incised plate repair. PMID- 29717505 TI - Diagnostic accuracy of whole slide imaging for cutaneous, soft tissue, and melanoma sentinel lymph node biopsies with and without immunohistochemistry. AB - BACKGROUND: Diagnostic accuracy with whole slide imaging (WSI) for complex inpatient and outpatient dermatopathology cases with immunohistochemistry (IHC) is unknown. METHODS: WSI (Leica Aperio AT2 Digital Pathology scanner, N = 151 cases) was performed for Emory inpatient and outpatient skin (N = 105), soft tissue (N = 30), and melanoma sentinel lymph node biopsies (N = 16) collected between 2000 and 2016. Resultant images were uploaded to an online cloud storage system for review by 2 board-certified dermatopathologists (reviewers 1 and 2) with greater than 5 years of dermatopathology experience and 1 dermatopathology fellow (reviewer 3). RESULTS: Reviewers 1 (diagnostic accuracy = 97%) and 2 (diagnostic accuracy = 95%) demonstrated high diagnostic accuracy with WSI. Diagnostic accuracy was greater than 90% for inpatient biopsies, melanocytic lesions, melanoma sentinel lymph node biopsies, and cases with immunohistochemistry, but was slightly lower for soft tissue cases (reviewer 1 = 89%; reviewer 2 = 89%). The dermatopathology fellow (reviewer 3) demonstrated lower diagnostic accuracy (84%). CONCLUSIONS: Diagnostic accuracy with WSI for skin, soft tissue, and melanoma sentinel lymph node biopsies with and without immunohistochemistry was greater than 95% for 2 reviewers with greater than 5 years of dermatopathology experience. Professional experience signing out dermatopathology cases may impact diagnostic accuracy with WSI. PMID- 29717507 TI - Microhabitat utilization by fork-marked dwarf lemurs (Phaner spp.) and needle clawed galagos (Euoticus spp.) in primary and secondary forests. AB - Needle-clawed galagos (Euoticus spp.) and fork-marked dwarf lemurs (Phaner spp.) are specialist gummivores inhabiting the forests of Cameroon and Madagascar, respectively. They share a suite of adaptations related to their foraging behavior, but are distantly related. I compared structural characteristics of the natural vegetation in which these strepsirrhines occurred using 10 m * 10 m (100 m2 ) quadrats established in forest areas selected on the grounds of observations of animals during nocturnal surveys. I established a total of 27 quadrats (13 in Madagascar and 14 in Cameroon). In each quadrat, trees potentially used by the animals (i.e., with a circumference at breast height >=10 cm) were assessed for diameter at breast height (DBH), total height, and maximum crown diameter (MCD) as well as tree density. The nature of the bark, and presence of exudates and flowers were also assessed, together with habitat characteristics such as percentage canopy cover and herbaceous cover. Primary and secondary forest types studied in Madagascar showed significant differences in DBH, MCD, and tree density, whereas only tree density was significantly different for the two forest types in Cameroon. Most of the trees in the quadrats had rough bark, but few had either exudates or flowers. Both Phaner and Euoticus show some degree of plasticity in their use of both primary and secondary forests, although they specialize in habitats with tall, large diameter trees. They can adjust to using trees in human modified habitats. Both taxa can survive in areas where a reasonably continuous canopy is not lacking. PMID- 29717508 TI - Time series analysis of fMRI data: Spatial modelling and Bayesian computation. AB - Time series analysis of fMRI data is an important area of medical statistics for neuroimaging data. Spatial models and Bayesian approaches for inference in such models have advantages over more traditional mass univariate approaches; however, a major challenge for such analyses is the required computation. As a result, the neuroimaging community has embraced approximate Bayesian inference based on mean field variational Bayes (VB) approximations. These approximations are implemented in standard software packages such as the popular statistical parametric mapping software. While computationally efficient, the quality of VB approximations remains unclear even though they are commonly used in the analysis of neuroimaging data. For reliable statistical inference, it is important that these approximations be accurate and that users understand the scenarios under which they may not be accurate. We consider this issue for a particular model that includes spatially varying coefficients. To examine the accuracy of the VB approximation, we derive Hamiltonian Monte Carlo (HMC) for this model and conduct simulation studies to compare its performance with VB in terms of estimation accuracy, posterior variability, the spatial smoothness of estimated images, and computation time. As expected, we find that the computation time required for VB is considerably less than that for HMC. In settings involving a high or moderate signal-to-noise ratio (SNR), we find that the 2 approaches produce very similar results suggesting that the VB approximation is useful in this setting. On the other hand, when one considers a low SNR, substantial differences are found, suggesting that the approximation may not be accurate in such cases and we demonstrate that VB produces Bayes estimators with larger mean squared error. A comparison of the 2 computational approaches in an application examining the hemodynamic response to face perception in addition to a comparison with the traditional mass univariate approach in this application is also considered. Overall, our work clarifies the usefulness of VB for the spatiotemporal analysis of fMRI data, while also pointing out the limitation of VB when the SNR is low and the utility of HMC in this case. PMID- 29717509 TI - Impact of delirium on patients hospitalized for myocardial infarction: A propensity score analysis of the National Inpatient Sample. AB - BACKGROUND: Delirium is associated with worse outcomes in critically ill patients. In the subset of patients with myocardial infarction (MI), the impact on clinical outcomes of delirium is not as well elucidated. HYPOTHESIS: Delirium is associated with increased mortality in patients hospitalized for MI. METHODS: The study used data from the National Inpatient Sample 2012 to 2014, Healthcare Cost and Utilization Project. We included discharges associated with the primary diagnosis of MI using the relevant International Classification of Diseases, Ninth Revision, Clinical Modification codes. The outcome was inpatient mortality between the delirium group and propensity score-matched controls without delirium. RESULTS: The study included 1 330 020 weighted discharges with MI as the principal diagnosis. Within this cohort, 18 685 discharges (1.4%) had delirium. Delirium was associated with older age, lower rates of percutaneous coronary intervention, and increased comorbid conditions. The delirium group had higher mortality (10.5% vs 2.6%, P < 0.001). Propensity score-matching analysis showed increased mortality in the delirium group (10.5% vs 7.6%, relative risk: 1.39 [95% confidence interval: 1.2-1.6, P < 0.001) using nearest neighbor 1:1 matching. CONCLUSIONS: In individuals with MI, delirium was associated with increased inpatient mortality. PMID- 29717510 TI - Long-term urodynamic follow-up after external sphincterotomy in patients with spinal cord injury. AB - AIMS: External sphincterotomy (ES) is a therapeutic option for male spinal cord injury patients with detrusor sphincter dyssynergia. However, some patients need to change their voiding management after ES. One of the potential causes of failure is reportedly detrusor dysfunction, but long-term urodynamic follow-up data after ES is limited. In the present study, we reviewed the urodynamic data before and after ES and analyzed it for possible causes of ES failure. METHODS: A total of 37 patients who were followed up at our center for at least 5 years after ES were included. Mean follow-up period was 16.5 years. Urodynamic assessment was routinely performed every 2 or 3 years after ES, and the data were reviewed and analyzed. RESULTS: Of the 37 patients, 27 are still managed with reflex voiding to a condom catheter (success group), while 10 needed to change their bladder management. Mean maximum bladder pressure (MBP) was preserved at a low level after ES. However, after ES, there was a gradual increase over time in both the mean bladder volume at first neurogenic detrusor overactivity (NDO) and the percentage of patients without NDO. The mean preoperative MBP in the success group was significantly higher than that in the failure group. CONCLUSIONS: MBP is maintained at a low level over 20 years after ES. However, NDO gradually decreases over time, which might be one of the reasons for failure after ES. In addition, low preoperative MBP would be a poor prognostic factor for ES. PMID- 29717511 TI - Refined nomogram incorporating standing cough test improves prediction of male transobturator sling success. AB - AIMS: To develop a decision aid in predicting sling success, incorporating the Male Stress Incontinence Grading Scale (MSIGS) into existing treatment algorithms. METHODS: We reviewed men undergoing first-time transobturator sling for stress urinary incontinence (SUI) from 2007 to 2016 at our institution. Patient demographics, reported pads per day (PPD), and Standing Cough Test (SCT) results graded 0-4, according to MSIGS, were assessed. Treatment failure was defined as subsequent need for >1 PPD or further procedures. Parameters associated with failure were included in multivariable logistic models, compared by area under the receiver-operating characteristic curves. A nomogram was generated from the model with greatest AUC and internally validated. RESULTS: Overall 203 men (median age 67 years, IQR 63-72) were evaluated with median follow-up of 45 months (IQR 11-75 months). A total of 185 men (91%) were status post radical prostatectomy and 29 (14%) had pelvic radiation history. Median PPD and SCT grade were both two. Eighty men (39%) failed treatment (use of >=1 PPD or subsequent anti-incontinence procedures) at a median of 9 months. History of radiation (P = 0.03), increasing MSIGS (P < 0.0001) and increasing preoperative PPD (P < 0.0001) were associated with failure on univariate analysis. In a multivariable model with AUC 0.81, MSIGS, and PPD remained associated (P = 0.002 and <0.0001 respectively, and radiation history P = 0.06), and was superior to models incorporating PPD and radiation alone (AUC 0.77, P = 0.02), PPD alone (AUC 0.76, P = 0.02), and a cutpoint of >2 PPD alone (AUC 0.71, P = 0.0001). CONCLUSIONS: MSIGS adds prognostic value to PPD in assessing success of transobturator sling for treatment of SUI. PMID- 29717512 TI - Impact of ultra-thin struts on restenosis after chronic total occlusion recanalization: Insights from the randomized PRISON IV trial. AB - OBJECTIVES: The PRISON-IV trial showed inferior outcome in patients with chronic total occlusions (CTOs) treated with the ultrathin-struts (60 MUm for stent diameter <=3 mm, 81MUm >3 mm) hybrid-sirolimus eluting stents (SES) compared with everolimus eluting stents (EES, 81 MUm). The aim of this study is to investigate if the use of smaller stents (<=3 mm) was responsible for the inferior outcome reported in the trial. METHODS: In the PRISON-IV trial 330 patients with CTO lesion were randomized 1:1 to receive either hybrid-SES or EES. The hybrid-SES failed to reach the non-inferiority primary endpoint of in-segment late lumen loss (LLL) at 9-month angiographic follow-up. In this sub-analysis, we divided the population according to the different size of stents implanted in those receiving only stents with diameter <=3 mm (Group-A, 178 patients), only stents >3 mm (Group-B, 59 patients), and those receiving stents of both sizes (Group-C, 93 patients). RESULTS: Baseline and procedural characteristics were comparable in the three groups. At angiographic follow-up, most of the adverse outcomes occurred in Group A, with higher incidence of binary restenosis in the Hybrid-SES versus EES (10.3% vs 1.3%, P = 0.03) and augmented in-stent diameter stenosis (26.04 +/- 18.59% vs 21.24 +/- 12.84, P = 0.06). Similarly, optical coherence tomography (OCT), which was performed in 60 patients at follow-up, documented a mild trend toward lower values of minimum in stent area in Hybrid-SES arm of Group A (4.4 +/- 1.02mm2 vs 5.0 +/- 1.28mm2, respectively, P = 0.16). CONCLUSIONS: The present analysis suggests that the inferior performance of the ultra-thin hybrid-SES in CTO-PCI is particularly pronounced when smaller stent (<=3 mm diameter) are adopted, if compared with EES. PMID- 29717513 TI - Dynamic optical coherence tomography of histamine induced wheals. AB - BACKGROUND: Dynamic optical coherence tomography (D-OCT) is a noninvasive imaging technique providing images of the skin and detecting movement in the tissue ie, measuring blood flow. The "attenuation coefficient" describes light absorption and scattering abilities of the tissue, while the dynamic signal provides a quantitative measure of the blood flow. AIM: The study objective is to describe the dynamic changes of the skin and skin vessels during histamine release using D OCT. METHODS: Healthy volunteers had local histamine injections in the skin and D OCT-scans performed at 2-minute intervals to detect changes in blood flow, attenuation and clinical symptoms. RESULTS: 9/10 participants showed clinical wheals. An increase in blood flow was shown at all depths (P < .001 at 2 minutes). The highest relative increase was seen at 300 MUm. The signal at 500 MUm decreased to insignificant values and remained low after 4 minutes. A decrease in visualization depth of up to 32.7% as well as a significant increase in the attenuation coefficient was shown (P < .001 at 12 minutes for both tests). CONCLUSION: Dynamic optical coherence tomography is able to reliably identify changes in blood flow of histamine induced wheals. Dermal oedema reduces visualization depth and increases the attenuation coefficient. PMID- 29717514 TI - Direct Electrical Neurostimulation with Organic Pigment Photocapacitors. AB - An efficient nanoscale semiconducting optoelectronic system is reported, which is optimized for neuronal stimulation: the organic electrolytic photocapacitor. The devices comprise a thin (80 nm) trilayer of metal and p-n semiconducting organic nanocrystals. When illuminated in physiological solution, these metal semiconductor devices charge up, transducing light pulses into localized displacement currents that are strong enough to electrically stimulate neurons with safe light intensities. The devices are freestanding, requiring no wiring or external bias, and are stable in physiological conditions. The semiconductor layers are made using ubiquitous and nontoxic commercial pigments via simple and scalable deposition techniques. It is described how, in physiological media, photovoltage and charging behavior depend on device geometry. To test cell viability and capability of neural stimulation, photostimulation of primary neurons cultured for three weeks on photocapacitor films is shown. Finally, the efficacy of the device is demonstrated by achieving direct optoelectronic stimulation of light-insensitive retinas, proving the potential of this device platform for retinal implant technologies and for stimulation of electrogenic tissues in general. These results substantiate the conclusion that these devices are the first non-Si optoelectronic platform capable of sufficiently large photovoltages and displacement currents to enable true capacitive stimulation of excitable cells. PMID- 29717515 TI - Parallel chromatography and in situ scattering to interrogate competing protein aggregation pathways. AB - Protein aggregation can follow different pathways, and these can result in different net aggregation rates and kinetic profiles. alpha-chymotypsinogen A (aCgn) was used as a model system to quantitatively and qualitatively assess an approach that combines ex situ size-exclusion chromatography (SEC) with in situ laser scattering (LS) to monitor aggregation vs. time. Aggregation was monitored for a series of temperatures and initial dimer (ID) levels for starting conditions that were primarily (> 97%) monomer, and under initial-rate conditions (limited to low monomer conversion-less than 20% monomer mass loss), as these conditions are of most to interest to many pharmaceutical and biotechnology applications. SEC results show that modest decreases of ID levels can greatly reduce monomer loss rates, but do not affect the effective activation energy for aggregation. The normalized aggregation rates determined from LS were typically ~ 1 order of magnitude higher than the corresponding rates from SEC. Furthermore, LS signals vs. time became variable and highly nonlinear with decreasing ID level, temperature, and/or total protein concentration. Temperature-cycling LS experiments showed this corresponded to conditions where dimer/oligomer "seeding" was suppressed, and high levels of reversible oligomers ("prenuclei") were formed prior to "nucleation" and growth of stable aggregates. In those conditions, aggregation rates inferred from LS and SEC are greatly different, as the techniques monitor different stages of the aggregation process. Overall, the results illustrate an approach for interrogating non-native protein aggregation pathways, and potential pitfalls if one relies on a single method to monitor aggregation-this holds more generally than the particular methods here. PMID- 29717516 TI - Effects of concentrate-to-forage ratios and 2-methylbutyrate supplementation on ruminal fermentation, bacteria abundance and urinary excretion of purine derivatives in Chinese Simmental steers. AB - This study evaluated the effects of dietary concentrate levels and 2 methylbutyrate (2MB) supplementation on performance, ruminal fermentation, bacteria abundance, microbial enzyme activity and urinary excretion of purine derivatives (PD) in steers. Eight ruminally cannulated Simmental steers (12 months of age; 389 +/- 3.7 kg of body weight) were used in a replicated 4 * 4 Latin square design with a 2 * 2 factorial arrangement. Moderate-concentrate (400 g/kg diet [MC]) or high-concentrate (600 g/kg diet [HC]) diets were fed with or without 2MB (0 g/day [2MB-] or 15.0 g/day [2MB+]). Dry matter intake and average daily gain increased, but feed conversion ratio decreased with the HC diet or 2MB supplementation. Ruminal pH decreased, but total volatile fatty acid increased with the HC diet or 2MB supplementation. Molar proportion of acetate and acetate to-propionate ratio decreased with the HC diet, but increased with 2MB supplementation. Propionate molar proportion and ruminal NH3 -N content increased with the HC diet, but decreased with 2MB supplementation. Neutral detergent fibre degradability decreased with the HC diet, but increased with 2MB supplementation. Crude protein degradability increased with the HC diet or 2MB supplementation. Abundance of Ruminococcus albus, Ruminococcus flavefaciens, Fibrobacter succinogenes and Bufyrivibrio fibrisolvens as well as activities of carboxymethyl cellulase, cellobiase, xylanase and pectinase decreased with the HC diet, but increased with 2MB supplementation. However, abundance of Prevotella ruminicola and Ruminobacter amylophilus as well as activities of alpha-amylase and protease increased with the HC diet or 2MB supplementation. Total PD excretion also increased with the HC diet or 2MB supplementation. The results suggested that growth performance, ruminal fermentation, CP degradability and total PD excretion increased with increasing dietary concentrate level from 40% to 60% or 2MB supplementation. The observed diet * 2MB interaction indicated that supplementation of 2MB was more efficacious for improving growth performance, ruminal fermentation and total PD excretion with promoted ruminal bacteria abundance and enzyme activity in the MC diet than in the HC diet. PMID- 29717517 TI - LncRNA HOTAIR promotes renal interstitial fibrosis by regulating Notch1 pathway via the modulation of miR-124. AB - OBJECTIVE: To understand the mechanism of long non-coding RNA (LncRNA) HOTAIR on renal interstitial fibrosis (RIF) by regulating Notch1 pathway via the modulation of miR-124. METHODS: Unilateral ureteral occlusion (UUO) was used to construct the RIF rat model. And HK-2 cells induced by TGF-beta1 were used for the in vitro experiment, which were divided into five groups: Vehicle, TGF-beta1, si-HOTAIR + TGF-beta1, miR-124 inhibitor + TGF-beta1, and si-HOTAIR+miR-124 inhibitor + TGF beta1 groups. Quantitative real-time PCR (qRT-PCR) and Western blot were performed to detect the expression of HOTAIR, miR-124, Notch1- and EMT-related proteins. RESULTS: Significant elevated HOTAIR and reduced miR-124 were presented in UUO rats and TGF-beta1-induced HK-2 cells in a time-dependent manner, with the increased Jagged1 (JAG1), Notch1, NICD, alpha-SMA and FN, as well as the decreased E-cadherin (all P < 0.05). Compared with the TGF-beta1 group, cells in the si-HOTAIR + TGF-beta1 group were remarkably declined in cell proliferation and the protein expressions of JAG1, Notch1, NICD, alpha-SMA, and FN, but dramatically higher in E-cadherin expression (all P < 0.05). However, in comparison with the si-HOTAIR + TGF-beta1 group, cells in the si-HOTAIR+miR-124 inhibitor + TGF-beta1 group were apparently improved in proliferation and the protein expression of JAG1, Notch1, NICD, alpha-SMA, and FN, but substantially reduced in the level of E-cadherin protein (all P < 0.05). CONCLUSION: Silencing lncRNA HOTAIR can up-regulate miR-124 to block Notch1 pathway, and thereby alleviating EMT and RIF, indicating HOTAIR as a potential target for RIF treatment. PMID- 29717518 TI - Evaluation of the Accuracy of Conventional and Digital Impression Techniques for Implant Restorations. AB - PURPOSE: The increased use of CAD systems can generate doubt about the accuracy of digital impressions for angulated implants. The aim of this study was to evaluate the accuracy of different impression techniques, two conventional and one digital, for implants with and without angulation. MATERIALS AND METHODS: We used a polyurethane cast that simulates the human maxilla according to ASTM F1839, and 6 tapered implants were installed with external hexagonal connections to simulate tooth positions 17, 15, 12, 23, 25, and 27. Implants 17 and 23 were placed with 15 degrees of mesial angulation and distal angulation, respectively. Mini cone abutments were installed on these implants with a metal strap 1 mm in height. Conventional and digital impression procedures were performed on the maxillary master cast, and the implants were separated into 6 groups based on the technique used and measurement type: G1 - control, G2 - digital impression, G3 - conventional impression with an open tray, G4 - conventional impression with a closed tray, G5 - conventional impression with an open tray and a digital impression, and G6 - conventional impression with a closed tray and a digital impression. A statistical analysis was performed using two-way repeated measures ANOVA to compare the groups, and a Kruskal-Wallis test was conducted to analyze the accuracy of the techniques. RESULTS: No significant difference in the accuracy of the techniques was observed between the groups. Therefore, no differences were found among the conventional impression and the combination of conventional and digital impressions, and the angulation of the implants did not affect the accuracy of the techniques. CONCLUSIONS: All of the techniques exhibited trueness and had acceptable precision. The variation of the angle of the implants did not affect the accuracy of the techniques. PMID- 29717520 TI - Alterations in hypothalamic synaptophysin and death markers may be associated with vasopressin impairment in sepsis survivor rats. AB - The impairment in arginine vasopressin (AVP) secretion during sepsis is described in clinical and experimental studies and has been associated with oxidative stress, apoptosis, and diminished activation of hypothalamic neurons. Few studies have, however, assessed these abnormalities in sepsis survivors. Here we performed two sets of experiments on Wistar rats that had been subjected to sepsis by cecal ligation and puncture (CLP) or nonmanipulated (naive) as control. In the first set, tissues and blood were collected from survivor rats 10 days after CLP to quantify hypothalamic Bcl-2, cleaved caspase- 3 and synaptophysin content, and bacterial load. In the second set, survivor rats were submitted to an acute osmotic stimulus (hypertonic saline), and after 30 minutes the water intake and AVP secretion were analyzed. The sepsis-surviving rats did not show bacterial load in tissues, but their hypothalamic synaptophysin and Bcl-2 levels were decreased, and the cleaved caspase- 3 level was increased when compared with the control group. However, AVP secretion was significantly attenuated in the CLP survivor animals submitted to an acute osmotic stimulus. These results suggest that the persistent AVP impairment in sepsis survivor animals may be due to a hypothalamic dysfunction associated with a synaptic deficit and decreased anti apoptotic protein expression. This article is protected by copyright. All rights reserved. PMID- 29717519 TI - Antidiarrheal effect of bioactivity-guided fractions and bioactive components of pomegranate (Punica granatum L.) peels. AB - BACKGROUND: Pomegranate peels have been widely used to treat diarrhea in China. The antidiarrheal activities of aqueous extracts of pomegranate peels have been evaluated. However, there have not been any bioactivity-guided fractionation studies on the antidiarrheal effect to identify the bioactive components of the extract. METHODS: Bioactivity-guided fractionation of an aqueous extract of pomegranate peels was performed using different solvents of increasing polarity, generating fractions dissolved in ethyl acetate, n-butyl alcohol, and the residual fraction. The principal chemical composition of the active fraction was analyzed by HPLC/ESI-MS. KEY RESULTS: Fecal frequencies revealed that only the ethyl acetate fraction possessed significant antidiarrheal activity. Furthermore, administration of the ethyl acetate fraction at 100, 200, and 400 mg/kg significantly reduced gastrointestinal transit in charcoal meal tests in mice. It also significantly inhibited castor oil-induced enteropooling compared to control animals. Histopathological analysis revealed that small intestine lesions of mice treated with the ethyl acetate fraction were alleviated compared to those in mice treated with castor oil. The ethyl acetate fraction was found to be composed mainly of punicalagin, corilagin, and ellagic acid, and a combination of these compounds could mediate the antidiarrheal activities. CONCLUSION AND INFERENCES: Our study describes the protective effects of pomegranate peels against castor oil-induced diarrhea. The findings showed that the ethyl acetate fraction was the active fraction of pomegranate peels, of which punicalagin, corilagin, and ellagic acid were responsible for the antidiarrheal effect of aqueous extracts. PMID- 29717521 TI - Evolution of interspecies unilateral incompatibility in the relatives of Arabidopsis thaliana. AB - The evolutionary concurrence of intraspecies self-incompatibility (SI) and explosive angiosperm radiation in the Cretaceous have led to the hypothesis that SI was one of the predominant drivers of rapid speciation in angiosperms. Interspecies unilateral incompatibility (UI) usually occurs when pollen from a self-compatible (SC) species is rejected by the pistils of a SI species, while the reciprocal pollination is compatible (UC). Although this SI * SC type UI is most prevalent and viewed as a prezygotic isolation barrier to promote incipient speciation of angiosperms, comparative evidence to support such a role is lacking. We show that SI * SI type UI in SI species pairs is also common in the well-characterized accessions representing the four major lineages of the Arabidopsis genus and is developmentally regulated. This allowed us to reveal a strong correlation between UI strength and species divergence in these representative accessions. In addition, analyses of a SC accession and the pseudo self-compatible (psc) spontaneous mutant of Arabidopsis lyrata indicate that UI shares, at least, common pollen rejection pathway with SI. Furthermore, genetic and genomic analyses of SI * SI type UI in A. lyrata * A. arenosa species pair showed that two major-effect quantitative trait loci are the stigma and pollen side determinant of UI, respectively, which could be involved in heterospecies pollen discrimination. By revealing a close link between UI and SI pathway, particularly between UI and species divergence in these representative accessions, our findings establish a connection between SI and speciation. Thus, the pre-existence of SI system would have facilitated the evolution of UI and accordingly promote speciation. PMID- 29717522 TI - Brain morphologic changes in early stages of psychosis: Implications for clinical application and early intervention. AB - To date, a large number of magnetic resonance imaging (MRI) studies have been conducted in schizophrenia, which generally demonstrate gray matter reduction, predominantly in the frontal and temporo-limbic regions, as well as gross brain abnormalities (e.g., a deviated sulcogyral pattern). Although the causes as well as timing and course of these findings remain elusive, these morphologic changes (especially gross brain abnormalities and medial temporal lobe atrophy) are likely present at illness onset, possibly reflecting early neurodevelopmental abnormalities. In addition, longitudinal MRI studies suggest that patients with schizophrenia and related psychoses also have progressive gray matter reduction during the transition period from prodrome to overt psychosis, as well as initial periods after psychosis onset, while such changes may become almost stable in the chronic stage. These active brain changes during the early phases seem to be relevant to the development of clinical symptoms in a region-specific manner (e.g., superior temporal gyrus atrophy and positive psychotic symptoms), but may be at least partly ameliorated by antipsychotic medication. Recently, increasing evidence from MRI findings in individuals at risk for developing psychosis has suggested that those who subsequently develop psychosis have baseline brain changes, which could be at least partly predictive of later transition into psychosis. In this article, we selectively review previous MRI findings during the course of psychosis and also refer to the possible clinical applicability of these neuroimaging research findings, especially in the diagnosis of schizophrenia and early intervention for psychosis. PMID- 29717523 TI - Influence of the Crystal Structure of Titanium Oxide on the Catalytic Activity of Rh/TiO2 in Steam Reforming of Propane at Low Temperature. AB - Solid oxide fuel cells (SOFCs) with liquefied petroleum gas (LPG) reduce CO2 emissions due to their high-energy-conversion efficiency. Although SOFCs can convert LPG directly, coking occurs easily by decomposition of hydrocarbons, including C-C bonds on the electrode of fuel cell stacks. It is therefore necessary to develop an active steam pre-reforming catalyst that eliminates the hydrocarbons at low temperature, in which waste heat of SOFCs is used. Herein, we show that the crystal structure of the TiO2 that anchors Rh particles is crucial for catalytic activity of Rh/TiO2 catalysts for propane pre-reforming. Our experimental results revealed that strong metal support interaction (SMSI) induced during H2 pre-reduction were optimized over Rh/TiO2 with a rutile structure; this catalyst catalyzed the reaction much more effectively than conventional Rh/gamma-Al2 O3 . In contrast, the SMSI was too strong for Rh/TiO2 with an anatase structure, and the surface of the Rh particles was therefore covered mostly with partially reduced TiO2 . The result was very low activity. PMID- 29717524 TI - Oscillatory EEG signatures of postponed somatosensory decisions. AB - In recent electroencephalography (EEG) studies, the vibrotactile frequency comparison task has been used to study oscillatory signatures of perceptual decision making in humans, revealing a choice-selective modulation of premotor upper beta band power shortly before decisions were reported. Importantly, these studies focused on decisions that were (1) indicated immediately after stimulus presentation, and (2) for which a direct motor mapping was provided. Here, we investigated whether the putative beta band choice signal also extends to postponed decisions, and how such a decision signal might be influenced by a response mapping that is dissociated from a specific motor command. We recorded EEG data in two separate experiments, both employing the vibrotactile frequency comparison task with delayed decision reports. In the first experiment, delayed choices were associated with a fixed motor mapping, whereas in the second experiment, choices were mapped onto a color code concealing a specific motor response until the end of the delay phase. In between stimulus presentations, as well as after the second stimulus, prefrontal beta band power indexed stimulus information held in working memory. Beta band power also encoded choices during the response delay, notably, in different cortical areas depending on the provided response mapping. In particular, when decisions were associated with a specific motor mapping, choices were represented in premotor cortices, whereas the color mapping resulted in a choice-selective modulation of beta band power in parietal cortices. Together, our findings imply that how a choice is expressed (i.e., the decision consequence) determines where in the cortical sensorimotor hierarchy an according decision signal is processed. PMID- 29717525 TI - A single-center audit of the indications and clinical impact of prolonged ambulatory small intestinal manometry. AB - BACKGROUND: Small bowel manometry is a diagnostic test available only in a few specialized referral centers. Its exact place in the management of refractory symptoms is controversial. METHODS: The records of all patients who underwent 24 hour ambulatory duodenojejunal manometry over a 6-year period were retrospectively reviewed. We studied the clinical indications for small bowel manometry, and reviewed the impact of manometric findings on the clinical outcome. One hundred and forty-six studies were performed in 137 patients (46M, 91F) with a mean age of 44.9 +/- 15.7 years. Mean follow-up duration was 15.1 +/- 22.6 months. Appropriate endoscopic, radiological and gastric scintigraphy studies were performed in all patients prior to small bowel manometry. Criteria for abnormal motor activity were based on Bharucha's classification. KEY RESULTS: The indications for small bowel manometry were chronic abdominal pain (n = 43), slow-transit constipation (n = 17), refractory gastroparesis (n = 16), chronic diarrhea (n = 7), recurrent episodes of subocclusion (n = 16), postsurgical evaluation (n = 36), suspicion of gut involvement in systemic disease (n = 9), and unexplained nausea (n = 2). The most common finding was a normal 24-hour ambulatory small bowel manometry (n = 113). Thirty-three studies yielded abnormal findings which included extrinsic neuropathy (n = 6), intrinsic neuropathy (n = 18), intestinal myopathy (n = 2), and subocclusion (n = 7). Ambulatory small bowel manometry excluded a generalized motility disorder in 77% and had a significant impact on the subsequent clinical course in 23%. CONCLUSIONS & INFERENCES: Ambulatory small bowel manometry is a useful and safe diagnostic tool to complement traditional investigative modalities in patients with severe unexplained abdominal symptoms. PMID- 29717527 TI - Cultural adaptation of cognitive stimulation therapy (CST) for Chinese people with dementia: multicentre pilot study. AB - OBJECTIVE: Ageing of the Chinese population will drive a continued surge in dementia prevalence. Empirically tested non-pharmacological interventions developed in western cultures may be implemented in Chinese. Cognitive Stimulation Therapy (CST) that originated in the UK has proven benefits on cognition and quality of life in people with dementia. We investigated the feasibility and cultural appropriateness of CST in Hong Kong Chinese (CST-HK). METHODS: Mixed methods research was conducted following the formative method for adapting psychotherapy. A culturally adapted CST-HK, developed involving multidisciplinary stakeholders, was tested in a pilot multicentre study in people with mild dementia (n = 30) receiving community or residential care. Changes in cognition and quality of life were measured. Opinions from family caregivers and group facilitators (n = 25) were collected through focus groups and in-depth interviews for understanding the appropriateness of CST-HK. Feasibility was explored. RESULTS: After receiving CST-HK, 54% of participants achieved outcome of no cognitive deterioration, and 23% showed clinically meaningful improvement. Family caregivers and group facilitators expressed good acceptance of CST, with a low attrition (13%) and high attendance rate of CST-HK sessions (92%). Key cultural issues identified are (i) less active opinion sharing in group discussions due to conservatism/cautiousness and (ii) preference of practical activities with reward/recognition over pure discussion due to pragmatism. CONCLUSIONS: The CST-HK is feasible and culturally appropriate in Hong Kong Chinese. Further amendments can be made to ensure language use and enjoyment, with potential implications on effectiveness. We have provided a systematically developed, culturally adapted protocol for larger-scale implementation and research in Chinese populations. Copyright (c) 2017 John Wiley & Sons, Ltd. PMID- 29717526 TI - Nephronophthisis: A review of genotype-phenotype correlation. AB - Nephronophthisis is an autosomal recessive cystic kidney disease and one of the most common genetic disorders causing end-stage renal disease in children. Nephronophthisis is a genetically heterogenous disorder with more than 25 identified genes. In 10%-20% of cases, there are additional features of a ciliopathy syndrome, such as retinal defects, liver fibrosis, skeletal abnormalities, and brain developmental disorders. This review provides an update of the recent advances in the clinical features and related gene mutations of nephronophthisis, and novel approaches for therapy in nephronophthisis patients may be needed. PMID- 29717528 TI - The Prevalence and Risk Factors for Chronic Kidney Disease in Primary Health Care in the Southern Region of New Zealand. AB - BACKGROUND: While the prevalence of end stage kidney disease in New Zealand (NZ) is well defined, the prevalence of CKD in NZ is unknown. AIM: To estimate the prevalence of and risk factors for CKD in the southern region of New Zealand METHODS: A retrospective electronic health record cohort study using data from the Southern Primary Care register covering 94% of the population. Patients, 20 years or older were identified and linked to laboratory results for serum creatinine and urinary albumin excretion. Chronic kidney disease was defined as an estimated glomerular filtration rate of less than 60ml/min/1.73m2 (G3-5) or the presence of albuminuria of greater than 3mg/mmol (A2-3). Diabetes was identified from a national virtual diabetes database. From this, we estimated the prevalence of CKD by age, gender, ethnicity, deprivation and the presence of diabetes mellitus. RESULTS: Of a total adult population of 211,980, 159,799 had a serum creatinine checked and 27,905 had an estimate of albuminuria. The estimated prevalence of CKD was 11.8%. 6.3% of total population had CKD stage G3a, 2.4% G3b, 0.8% G4, 0.2% G5, 1.8% A2 albuminuria and 0.3% A3 albuminuria. Increasing age, female sex, ethnic group, social deprivation and diabetes mellitus were associated with an increased risk of CKD. 11,351 patients had a diagnosis of diabetes mellitus and were almost universally tested (99.3%) for CKD. The presence of albuminuria was strongly correlated with ethnic group, male sex and living in a deprived area. LIMITATIONS: Retrospective electronic health record study with associated selection and testing bias. CONCLUSION: CKD prevalence in this region appears to be similar to other reported populations. The majority of those at risk for CKD were tested for reduced eGFR. The presence of albuminuria, an integral component of CKD diagnostic criteria, was under utilised in the non diabetic population. PMID- 29717529 TI - Estimation of vocational aptitudes using functional brain networks. AB - The success of human life in modern society is highly dependent on occupation. Therefore, it is very important for people to identify and develop a career plan that best suits their aptitude. Traditional test batteries for vocational aptitudes are not oriented to measure developmental changes in job suitability because repeated measurements can introduce bias as the content of the test batteries is learned. In this study, we attempted to objectively assess vocational aptitudes by measuring functional brain networks and identified functional brain networks that intrinsically represented vocational aptitudes for 19 job divisions in a General Aptitude Test Battery. In addition, we derived classifiers based on these networks to predict the aptitudes of our test participants for each job division. Our results suggest that the measurement of brain function can indeed yield an objective evaluation of vocational aptitudes; this technique will enable a person to follow changes in one's job suitability with additional training or learning, paving a new way to advise people on career development. PMID- 29717530 TI - Utility of immunohistochemistry for mismatch repair proteins on colorectal polyps in the familial cancer clinic. AB - BACKGROUND: Immunohistochemistry for loss of expression of one or more of the mismatch repair proteins is performed on colorectal cancer tissue as a screening test for Lynch syndrome; however, its role in pre-malignant polyps remains controversial. AIM: To determine the effectiveness of mismatch repair immunohistochemistry performed on pre-malignant colorectal polyps in identifying Lynch syndrome, focusing on clinical utility and value. METHODS: A retrospective audit was conducted of mismatch repair immunohistochemistry performed on non malignant polyps in patients who attended the Family Cancer Clinic at the Royal Melbourne Hospital. Two hundred and six patient records over a 10-year period (2006-2016) were reviewed. Personal and family history data were collected, including genetic testing results. RESULTS: Of the 57 patients who underwent polyp testing, the family histories comprised Amsterdam II Criteria (12.3%), Lynch syndrome-associated malignancies (42.1%), Lynch syndrome-associated malignancies and polyps (35.1%) and polyps only (8.8%); 10.5% of patients had no significant family history. Normal expression of the mismatch repair proteins was observed in 94.7% of patients; loss of expression was observed in three individuals with concordant germline variants in two patients (one PMS2 variant of unknown significance and one MSH6 mutation). Additional genetic testing in 21 patients with normal immunohistochemistry did not identify any additional Lynch syndrome cases. CONCLUSION: The clinical utility of mismatch repair immunohistochemistry on polyp tissue was low. No additional cases of Lynch syndrome were identified, and a large proportion of patients proceeded to germline testing despite normal polyp immunohistochemistry. We suggest there is no value in this approach. PMID- 29717531 TI - Stress predictors in two Asian dental schools with an integrated curriculum and traditional curriculum. AB - INTRODUCTION: This study explored stress predictors and the role of instructional methods and institutional differences in perceived stress levels amongst students at two Asian dental schools. MATERIALS AND METHODS: An anonymous questionnaire was distributed to undergraduate dental students at Tokyo Medical and Dental University (TMDU), Japan and the University of Medicine and Pharmacy (UMP), Hochiminh City, Vietnam in 2016. Data concerning the students' demographic information and grades, and responses to the Perceived Stress Scale (PSS) and Dental Environment Stress questionnaire (DES) were collected. The questionnaires were prepared in English and translated into Japanese and Vietnamese following a forward-backward translation process. RESULTS: Altogether 684 students answered the questionnaire with a response rate of 97% for TMDU and 89% for UMP. The mean DES score of UMP students was significantly higher than TMDU (P < .001). TMDU students with dentistry as their first programme choice had significantly lower PSS and DES scores in several categories than other TMDU students, whilst UMP clinical students reported higher stress scores in several areas than UMP preclinical students. CONCLUSION: Having dentistry as their first choice of educational programme was a significant stress predictor for Japanese students whilst the clinical practicum was a significant stress predictor for Vietnamese students. Previous academic performance was not a significant stress predictor for students at either dental school. Dental students of an integrated, active learning curriculum reported lower stress levels than students of a traditional, discipline-based curriculum. PMID- 29717532 TI - The urgent need for more research on how to treat recurrent focal and segmental glomerulosclerosis. PMID- 29717533 TI - A Long Cycle Life, Self-Healing Zinc-Iodine Flow Battery with High Power Density. AB - A zinc-iodine flow battery (ZIFB) with long cycle life, high energy, high power density, and self-healing behavior is prepared. The long cycle life was achieved by employing a low-cost porous polyolefin membrane and stable electrolytes. The pores in the membrane can be filled with a solution containing I3- that can react with zinc dendrite. Therefore, by consuming zinc dendrite, the battery can self recover from micro-short-circuiting resulting from overcharging. By using KI, ZnBr2 , and KCl as electrolytes and a high ion-conductivity porous membrane, a very high power density can be achieved. As a result, a ZIFB exhibits an energy efficiency (EE) of 82 % at 80 mA cm-2 , which is 8 times higher than the currently reported ZIFBs. Furthermore, a stack with an output of 700 W was assembled and continuously run for more than 300 cycles. We believe this ZIFB can lead the way to development of new-generation, high-performance flow batteries. PMID- 29717534 TI - So, what are longitudinal community placements? PMID- 29717535 TI - Structural basis for nucleotide recognition by the ectoenzyme CD203c. AB - : The ecto-nucleotide pyrophosphatase/phosphodiesterase (NPP) enzyme family modulates purinergic signaling by degrading extracellular nucleotides. CD203c (NPP3, ENPP3) regulates the inflammatory response of basophils via ATP hydrolysis and is a marker for allergen sensitivity on the surface of these cells. Multiple other roles and substrates have also been proposed for this protein. In order to gain insight into its molecular functions, we determined the crystal structure of human NPP3 as well as its complex with an ATP analog. The enzyme exhibits little preference for nucleobase type, and forms specific contacts with the alpha and beta phosphate groups of its ligands. Dimerization of the protein does not affect its catalytic activity. These findings expand our understanding of substrate recognition within the NPP family. DATABASE: Structural data are available in the Protein Data Bank under the accession numbers 6C01 (human NPP3) and 6C02 (human NPP3 T205A N594S with AMPCPP). PMID- 29717536 TI - Generation of High-Molecular-Weight Polymers with Diverse Substituents: An Unusual Metal-Free Synthesis of Poly(aminoborane)s. AB - A new concept has been introduced for the preparation of high-molecular-weight poly(aminoborane)s with diverse substituents on the nitrogen atom. Whereas previous methods were oxidative and relied largely on catalytic dehydrocoupling, the new process is based on an uncatalysed polymerisation reaction promoted by amine-aminoborane exchange, and should give access to previously inaccessible polymers. PMID- 29717537 TI - Crosstalk between phosphorylation and O-GlcNAcylation: friend or foe. AB - A wide variety of protein post-translational modifications (PTMs) decorate cellular proteins, regulating their structure, interactions and ultimately their function. The density of co-occurring PTMs on proteins can be very high, where multiple PTMs can positively or negatively influence each other's actions, termed PTM crosstalk. In this review, we highlight recent progress in the area of PTM crosstalk, whereby we focus on crosstalk between protein phosphorylation and O GlcNAcylation. These two PTMs largely target identical (i.e., Ser and Thr) amino acids in proteins. Phosphorylation/O-GlcNAcylation crosstalk comes in many flavors, for instance by competition for the same site/residue (reciprocal crosstalk), as well as by modifications influencing each other in proximity or even distal on the protein sequence. PTM crosstalk is observed on the writers of these modifications (i.e., kinases and O-GlcNAc transferase), on the erasers (i.e., phosphatases and O-GlcNAcase), and on the readers and the substrates. We describe examples of all these different flavors of crosstalk, and additionally the methods that are emerging to better investigate in particular phosphorylation/O-GlcNAcylation crosstalk. PMID- 29717538 TI - Curcuminoids combined with gefitinib mediated apoptosis and autophagy of human oral cancer SAS cells in vitro and reduced tumor of SAS cell xenograft mice in vivo. AB - Gefitinib has been used for cancer patients and curcumin (CUR), demethoxycurcumin (DMC), or bisdemethoxycurcumin (BDMC) also shown to induce cancer cell apoptosis. However, no report shows the combination of gefitinib with, CUR, DMC, or BDMC induce cell apoptosis and autophagy in human oral cancer cells. In this study, we investigated the effects of gefitinib with or without CUR, DMC, or BDMC co treatment on the cell viability, apoptotic cell death, autophagy, mitochondria membrane potential (MMP), and caspase-3 activities by flow cytometry assay and autophagy by acridine orange (AO) staining in human oral cancer SAS cells. Results indicated that gefitinib co-treated with CUR, DMC, or BDMC decreased total viable cell number through the induction of cell apoptosis and autophagy and decreased the levels of MMP and increased caspase-3 activities in SAS cells. Western blotting indicated that gefitinib combined with CUR, DMC, or BDMC led to decrease Bcl-2 protein expression which is an antiapoptotic protein and to increase ATG5, Beclin 1, p62/SQSTM1, and LC3 expression that associated with cell autophagy in SAS cells. Gefitinib combined with CUR and DMC led to significantly reduce the tumor weights and volumes in SAS cell xenograft nude mice but did not affect the total body weights. Based on those observations, we suggest that the combination of gefitinib with CUR, DMC, and BDMC can be a potential anticancer agent for human oral cancer in future. PMID- 29717539 TI - fMRI connectivity of expressive language in young children and adolescents. AB - Studies of language representation in development have shown a bilateral distributed pattern of activation that becomes increasingly left-lateralized and focal from young childhood to adulthood. However, the level by which canonical and extra-canonical regions, including subcortical and cerebellar regions, contribute to language during development has not been well-characterized. In this study, we employed fMRI connectivity analyses (fcMRI) to characterize the distributed network supporting expressive language in a group of young children (age 4-6) and adolescents (age 16-18). We conducted an fcMRI analysis using seed to-voxel and seed-to-ROI (region of interest) strategies to investigate interactions of left pars triangularis with other brain areas. The analyses showed significant interhemispheric connectivity in young children, with a minimal connectivity of the left pars triangularis to subcortical and cerebellar regions. In contrast, adolescents showed significant connectivity between the left IFG seed and left perisylvian cortex, left caudate and putamen, and regions of the right cerebellum. Importantly, fcMRI analyses indicated significant differences between groups at 3 anatomical clusters, including left IFG, left supramarginal gyrus, and right cerebellar crura, suggesting a role in the functional development of language. PMID- 29717540 TI - BrainMap VBM: An environment for structural meta-analysis. AB - The BrainMap database is a community resource that curates peer-reviewed, coordinate-based human neuroimaging literature. By pairing the results of neuroimaging studies with their relevant meta-data, BrainMap facilitates coordinate-based meta-analysis (CBMA) of the neuroimaging literature en masse or at the level of experimental paradigm, clinical disease, or anatomic location. Initially dedicated to the functional, task-activation literature, BrainMap is now expanding to include voxel-based morphometry (VBM) studies in a separate sector, titled: BrainMap VBM. VBM is a whole-brain, voxel-wise method that measures significant structural differences between or within groups which are reported as standardized, peak x-y-z coordinates. Here we describe BrainMap VBM, including the meta-data structure, current data volume, and automated reverse inference functions (region-to-disease profile) of this new community resource. CBMA offers a robust methodology for retaining true-positive and excluding false positive findings across studies in the VBM literature. As with BrainMap's functional database, BrainMap VBM may be synthesized en masse or at the level of clinical disease or anatomic location. As a use-case scenario for BrainMap VBM, we illustrate a trans-diagnostic data-mining procedure wherein we explore the underlying network structure of 2,002 experiments representing over 53,000 subjects through independent components analysis (ICA). To reduce data-redundancy effects inherent to any database, we demonstrate two data-filtering approaches that proved helpful to ICA. Finally, we apply hierarchical clustering analysis (HCA) to measure network- and disease-specificity. This procedure distinguished psychiatric from neurological diseases. We invite the neuroscientific community to further exploit BrainMap VBM with other modeling approaches. PMID- 29717541 TI - Simultaneous Stabilization of LiNi0.76 Mn0.14 Co0.10 O2 Cathode and Lithium Metal Anode by Lithium Bis(oxalato)borate as Additive. AB - The long-term cycling performance, rate capability, and voltage stability of lithium (Li) metal batteries with LiNi0.76 Mn0.14 Co0.10 O2 (NMC76) cathodes is greatly enhanced by lithium bis(oxalato)borate (LiBOB) additive in the LiPF6 based electrolyte. With 2 % LiBOB in the electrolyte, a Li?NMC76 cell is able to achieve a high capacity retention of 96.8 % after 200 cycles at C/3 rate (1 C=200 mA g-1 ), which is the best result reported for a Ni-rich NMC cathode coupled with Li metal anode. The significantly enhanced electrochemical performance can be ascribed to the stabilization of both the NMC76 cathode/electrolyte and Li metal-anode/electrolyte interfaces. The LiBOB-containing electrolyte not only facilitates the formation of a more compact solid-electrolyte interphase on the Li metal surface, it also forms a enhanced cathode electrolyte interface layer, which efficiently prevents the corrosion of the cathode interface and mitigates the formation of the disordered rock-salt phase after cycling. The fundamental findings of this work highlight the importance of recognizing the dual effects of electrolyte additives in simultaneously stabilizing both cathode and anode interfaces, so as to enhance the long-term cycle life of high-energy-density battery systems. PMID- 29717542 TI - Mid-infrared spectral microimaging of inflammatory skin lesions. AB - Skin is one of the most important organs of the human body because of its characteristics and functions. There are many alterations, either pathological or physiological, that can disturb its functioning. However, at present all methods used to investigate skin diseases, non-invasive or invasive, are based on clinical examinations by physicians. Thus, diagnosis, prognosis and therapeutic management rely on the expertise of the practitioner, the quality of the method and the accessibility of distinctive morphological characteristics of each lesion. To overcome the high sensitivity of these parameters, techniques based on more objective criteria must be explored. Vibrational spectroscopy has become as a key technique for tissue analysis in the biomedical research field. Based on a non-destructive light/matter interaction, this tool provides information about specific molecular structure and composition of the analyzed sample, thus relating to its precise physiopathological state and permitting to distinguish lesional from normal tissues. This label-free optical method can be performed directly on the paraffin-embedded tissue sections without chemical dewaxing. In this study, the potential of the infrared microspectroscopy, combined with data classification methods was demonstrated, to characterize at the tissular level different types of inflammatory skin lesions, and this independently from conventional histopathology. PMID- 29717543 TI - Gold/silver/gold trilayer films on nanostructured polycarbonate substrates for direct and label-free nanoplasmonic biosensing. AB - Ultrasmooth gold/silver/gold trilayer nanostructured plasmonic sensors were obtained using commercial Blu-ray optical discs as nanoslits-based flexible polymer substrates. A thin gold film was used as an adhesion and nucleation layer to improve the chemical stability and reduce the surface roughness of the overlying silver film, without increasing ohmic plasmon losses. The structures were physically and optically characterized and compared with nanostructures of single gold layer. Ultrasmooth and chemically stable trilayer nanostructures with a surface roughness <0.5 nm were obtained following a simple and reproducible fabrication process. They showed a figure of merit (FOM) value up to 69.2 RIU-1 which is significantly higher (more than 95%) than the gold monolayer counterpart. Their potential for biosensing was demonstrated by employing the trilayer sensor for the direct and refractometric (label-free) detection of C reactive protein (CRP) biomarker in undiluted urine achieving a Limit of Detection (LOD) in the pM order. PMID- 29717544 TI - Impact of paranasal sinus invasion on advanced nasopharyngeal carcinoma treated with intensity-modulated radiation therapy: the validity of advanced T stage of AJCC/UICC eighth edition staging system. AB - The aim of this study was to clarify the prognostic role of paranasal sinus invasion in advanced NPC patients. Data of patients (n = 295) with advanced NPC (T3/T4N0-3 M0) treated with intensity-modulated radiation therapy were retrospectively analyzed. Staging was according to the AJCC/UICC eighth edition staging system. Overall survival (OS), local recurrence-free survival (LRFS), distant metastasis-free survival (DMFS), and disease-free survival (DFS) were calculated, and differences were compared between patients with and without paranasal sinus invasion. Multivariate analysis was used to identify the independent predictors of different survival parameters. Paranasal sinus invasion was present in 126 of 295 (42.7%) patients. Sphenoid, ethmoid, maxillary, and frontal sinus involvements were present in 123 of 295 (41.7%), 95 of 295 (32.2%), 45 of 295 (15.3%), and 0 of 295 (0%), respectively. All survival parameters were significantly better in patients without paranasal sinus invasion. When paranasal sinus invasion was reclassified as T4 instead of T3, all survival rates, other than LRFS (P = 0.156), were significantly better in the new T3 patients, and differences in all survival parameters remained nonsignificant between T3 with paranasal sinus invasion and T4 without paranasal sinus invasion patients (all P > 0.05). In multivariate analysis, paranasal sinus invasion was found to be an independent negative prognostic factor for OS, DFS, and DMFS (P = 0.016, P = 0.004, and P = 0.006, respectively), but not for LRFS (P = 0.068). Paranasal sinus invasion has prognostic value in advanced NPC. It may be reasonable to classify paranasal sinus invasion as T4 stage. PMID- 29717545 TI - Very low asthma death incidence among Finnish children from 1999 to 2015. AB - BACKGROUND: The most recent reports concerning asthma fatalities in Finnish children are from 1998. Since that time, asthma care has improved and asthma related hospitalizations have decreased. Yet, it is unknown whether pediatric asthma deaths have similarly decreased. OBJECTIVE: To investigate the epidemiology of asthma deaths in the Finnish pediatric population from 1999 onward and to describe the details of fatal asthma exacerbations. METHODS: We obtained copies of the death certificates from Statistics Finland of all Finnish children aged 0-19 years who died from asthma between 1999 and 2015. After analyzing the death certificates, the medical records of those with possible asthma death were evaluated in detail to confirm the diagnosis. Incidence rates (IR) of asthma deaths were estimated per 1 000 000 person-years by dividing the number of asthma deaths by the total number of person-years. RESULTS: Between 1999-2015, there were 6845 deaths among 0-19 year-old children, of which 21 were possible asthma deaths. Based on patient records and pathological findings, we identified four convincing asthma deaths: aged 7 months, 1 year, 2.5 years, and 19 years. None had known allergies or regularly used inhaled corticosteroids. No pre-school or school-aged children died from asthma in Finland between 1999 and 2015. The cumulative incidence of pediatric asthma deaths was 0.19 per million person-years. CONCLUSION: Four Finnish children died from asthma between 1999 and 2015. This corresponds to a total incidence of 0.19 per million person-years. No pre-school or school-aged children died from asthma in Finland during the study period. PMID- 29717547 TI - Kinetic Estimated Glomerular Filtration Rate as a Predictor of Successful Continuous Renal Replacement Therapy Discontinuation. AB - AIM: No standardised criteria for continuous renal replacement therapy (CRRT) discontinuation have been established so far. Kinetic estimated glomerular filtration rate (eGFR) is a newly developed estimation method based on dynamic changes of serum creatinine expected to reflect the true GFR. This study aimed to evaluate the predictive role of kinetic eGFR for CRRT discontinuation. METHODS: A retrospective single-centre cohort study was conducted. Acute kidney injury (AKI) patients who received CRRT between May 2015 and April 2016 were enrolled. Successful CRRT discontinuation was defined as neither resuming CRRT for the next 48 h nor receiving intermittent haemodialysis 7 days from the CRRT discontinuation. Clinical factors associated with CRRT discontinuation were evaluated by receiver operating characteristic (ROC) curve analysis. RESULTS: Of 52 AKI patients treated with CRRT, 38 could discontinue CRRT while 14 could not. Urine volume, regular and kinetic eGFR of days 0 (day of CRRT discontinuation) and 1 were all good predictive parameters (area under the ROC curve (AUC) > 0.7). Kinetic eGFR of day 1 showed the AUC of 0.87 [95% confidence interval 0.73 0.94]). Combining kinetic eGFR of day 1 and urine volume of day 0 gave a high AUC of 0.93 [95% confidence interval 0.82-0.97]. The combination was significantly greater than urine volume of day 0 (P = 0.008). CONCLUSION: This study evaluated kinetic eGFR as a predictive parameter for CRRT discontinuation. Kinetic eGFR combined with urine volume was a better predictor for CRRT discontinuation. Evaluation of kinetic eGFR utility in other clinical settings will be necessary. PMID- 29717548 TI - Expression and Activation of Horseradish Peroxidase-Protein A/G Fusion Protein in Silkworm Larvae for Diagnostic Purposes. AB - Recombinant protein production can create artificial proteins with desired functions by introducing genetic modifications to the target proteins. Horseradish peroxidase (HRP) has been used extensively as a reporter enzyme in biotechnological applications; however, recombinant production of HRP has not been very successful, hampering the utilization of HRP with genetic modifications. A fusion protein comprising an antibody binding protein and HRP will be an ideal bio-probe for high-quality HRP-based diagnostic systems. A HRP protein A/G fusion protein (HRP-pAG) is designed and its production in silkworm (Bombyx mori) is evaluated for the first time. HRP-pAG is expressed in a soluble apo form, and is activated successfully by incubating with hemin. The activated HRP-pAG is used directly for ELISA experiments and retains its activity over 20 days at 4 degrees C. Moreover, HRP-pAG is modified with biotin by the microbial transglutaminase (MTG) reaction. The biotinylated HRP-pAG is conjugated with streptavidin to form a HRP-pAG multimer and the multimeric HRP-pAG produced higher signals in the ELISA system than monomeric HRP-pAG. The successful production of recombinant HRP in silkworm will contribute to creating novel HRP based bioconjugates as well as further functionalization of HRP by applying enzymatic post-translational modifications. PMID- 29717546 TI - The Dorsal Column Lesion Model of Spinal Cord Injury and Its Use in Deciphering the Neuron-Intrinsic Injury Response. AB - The neuron-intrinsic response to axonal injury differs markedly between neurons of the peripheral and central nervous system. Following a peripheral lesion, a robust axonal growth program is initiated, whereas neurons of the central nervous system do not mount an effective regenerative response. Increasing the neuron intrinsic regenerative response would therefore be one way to promote axonal regeneration in the injured central nervous system. The large-diameter sensory neurons located in the dorsal root ganglia are pseudo-unipolar neurons that project one axon branch into the spinal cord, and, via the dorsal column to the brain stem, and a peripheral process to the muscles and skin. Dorsal root ganglion neurons are ideally suited to study the neuron-intrinsic injury response because they exhibit a successful growth response following peripheral axotomy, while they fail to do so after a lesion of the central branch in the dorsal column. The dorsal column injury model allows the neuron-intrinsic regeneration response to be studied in the context of a spinal cord injury. Here we will discuss the advantages and disadvantages of this model. We describe the surgical methods used to implement a lesion of the ascending fibers, the anatomy of the sensory afferent pathways and anatomical, electrophysiological, and behavioral techniques to quantify regeneration and functional recovery. Subsequently we review the results of experimental interventions in the dorsal column lesion model, with an emphasis on the molecular mechanisms that govern the neuron intrinsic injury response and manipulations of these after central axotomy. Finally, we highlight a number of recent advances that will have an impact on the design of future studies in this spinal cord injury model, including the continued development of adeno-associated viral vectors likely to improve the genetic manipulation of dorsal root ganglion neurons and the use of tissue clearing techniques enabling 3D reconstruction of regenerating axon tracts. (c) 2018 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 00: 000-000, 2018. PMID- 29717549 TI - Antibody expression stability in CHO clonally derived cell lines and their subclones: Role of methylation in phenotypic and epigenetic heterogeneity. AB - Routine CHO cell line development practices involve a lengthy process of iteratively screening clonally derived cell lines to identify a single line suitable for IND filing and clinical manufacture. Paramount in this process is development of a stable production cell line having consistent growth, productivity and product quality for the entire generational length of the manufacturing process. Scale-down stability models used to screen clones for consistency are time consuming and often a rate-limiting step in clone selection. To investigate CHEF1 production stability in CHO cells we analyzed genotypic and phenotypic attributes of monoclonal primary clones and their respective subclones over time in standard antibody production models. The main finding of this work indicates that monoclonal cell lines derived from single cell progenitors grow into populations of cells with varied phenotypic heterogeneity, as revealed in their subclones, from either stable or unstable cell lines. Investigation of the subclones demonstrates that clonally derived cell lines grow out into populations with variable phenotypes and genotypes, even if the primary clone shows consistency in both over many generations in a stability study. Phenotypic and genotypic heterogeneity mostly did not correlate, but growth and productivity appear driven in part by cytosine methylation heterogeneity in both primary and secondary clones. This work presents evidence that epigenetic analysis may be useful for early detection of stability traits, but emphasizes the continued importance of rigorous cell line stability screening to identify primary clones that have consistent phenotypic characteristics, especially growth and productivity, throughout the in vitro lifecycle of the cells. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:635-649, 2018. PMID- 29717550 TI - An integrated course based on two dimensional-electrophoresis and mass spectrometry analysis to teach proteomic techniques for undergraduate students. AB - Here, we developed an integrated course based on two dimensional-electrophoresis and spectrometry mass (2DE-MS) technique for undergraduate students to help them learn proteomic techniques. The soluble proteins in wild type and gene knockout bacteria were separated by 2DE and the differently expressed proteins were identified by MS analysis. The proteomic data was finally confirmed by RT-PCR detection. The separated experiments of 2DE, MS, RNA isolation, RT-PCR, as well as essential bioinformatic analysis, were integrated into a one-week course, which provided students an opportunity to systematically understand the proteomic techniques and their applications in current scientific research. (c) 2018 by The International Union of Biochemistry and Molecular Biology, 46:354-360, 2018. PMID- 29717551 TI - How to calculate thermostability of enzymes using a simple approach. AB - Determination of thermostability of enzymes is of prime importance for their successful industrial applications and, yet, the published data has often been incompletely analyzed to assess the suitability of enzymes. It is possible to determine meaningful thermostability parameters from the routinely acquired data through a straightforward method that is not only more informative but also provides a means to compare thermostability of enzymes from different sources. Here, we describe a simple, effective, and economical way to determine enzyme thermostability. In our opinion, including this method in Biochemistry and Molecular Biology curricula will encourage students to include thermostability analysis in their future work, leading to a more meaningful approach to evaluate and compare enzymes. Furthermore, as the method requires minimum specialized equipment, the analysis will be particularly suitable for labs that cannot afford expensive setup. (c) 2018 by The International Union of Biochemistry and Molecular Biology, 46:398-402, 2018. PMID- 29717552 TI - Impact of a cystic fibrosis transmembrane conductance regulator (CFTR) modulator on high-dose ibuprofen therapy in pediatric cystic fibrosis patients. AB - BACKGROUND: This study was undertaken to determine if a clinically relevant drug drug interaction occurred between ibuprofen and lumacaftor/ivacaftor. METHODS: Peak ibuprofen plasma concentrations were measured prior to and after lumacaftor/ivacaftor initiation. A Wilcoxon signed rank sum test was used to compare the values. RESULTS: Nine patients were included in the final analysis. Peak ibuprofen plasma concentrations decreased an average of 36.4 mcg/mL after initiation of lumacaftor/ivacaftor with a relative reduction of 41.7%. The average peak plasma concentration was 84.2 mcg/mL (SD = 10.9) prior to lumacaftor/ivacaftor initiation and 47.9 mcg/mL (SD = 16.4) following initiation (P = 0.0039). Peak concentrations occurred at an average of 100 min (SD = 30) and 107 min (SD = 40) prior to and following lumacaftor/ivacaftor initiation, respectively. CONCLUSIONS: We suggest a clinically relevant drug-drug interaction exists between ibuprofen and lumacaftor/ivacaftor. Lumacaftor may cause subtherapeutic ibuprofen plasma concentrations due to the induction of CYP enzymes and increased metabolism of ibuprofen. Based on this analysis, we have modified our use of ibuprofen in several patients after evaluation of this drug drug interaction. PMID- 29717553 TI - Faster-X evolution of gene expression is driven by recessive adaptive cis regulatory variation in Drosophila. AB - The hemizygosity of the X (Z) chromosome fully exposes the fitness effects of mutations on that chromosome and has evolutionary consequences on the relative rates of evolution of X and autosomes. Specifically, several population genetics models predict increased rates of evolution in X-linked loci relative to autosomal loci. This prediction of faster-X evolution has been evaluated and confirmed for both protein coding sequences and gene expression. In the case of faster-X evolution for gene expression divergence, it is often assumed that variation in 5' noncoding sequences is associated with variation in transcript abundance between species but a formal, genomewide test of this hypothesis is still missing. Here, I use whole genome sequence data in Drosophila yakuba and D. santomea to evaluate this hypothesis and report positive correlations between sequence divergence at 5' noncoding sequences and gene expression divergence. I also examine polymorphism and divergence in 9,279 noncoding sequences located at the 5' end of annotated genes and detected multiple signals of positive selection. Notably, I used the traditional synonymous sites as neutral reference to test for adaptive evolution, but I also used bases 8-30 of introns <65 bp, which have been proposed to be a better neutral choice. X-linked genes with high degree of male-biased expression show the most extreme adaptive pattern at 5' noncoding regions, in agreement with faster-X evolution for gene expression divergence and a higher incidence of positively selected recessive mutations. PMID- 29717554 TI - Modification of Immobead 150 support for protein immobilization: Effects on the properties of immobilized Aspergillus oryzae beta-galactosidase. AB - We studied the modification of Immobead 150 support by either introducing aldehyde groups using glutaraldehyde (Immobead-Glu) or carboxyl groups through acid solution (Immobead-Ac) for enzyme immobilization by covalent attachment or ion exchange, respectively. These two types of immobilization were compared with the use of epoxy groups that are now provided on a commercial support. We used Aspergillus oryzae beta-galactosidase (Gal) as a model protein, immobilizing it on unmodified (epoxy groups, Immobead-Epx) and modified supports. Immobilization yield and efficiency were tested as a function of protein loading (10-500 mg g-1 support). Gal was efficiently immobilized on the Immobeads with an immobilization efficiency higher than 75% for almost all supports and protein loads. Immobilization yields significantly decreased when protein loadings were higher than 100 mg g-1 support. Gal immobilized on Immobead-Glu and Immobead-Ac retained approximately 60% of its initial activity after 90 days of storage at 4 degrees C. The three immobilized Gal derivatives presented higher half-lifes than the soluble enzyme, where the half-lifes were twice higher than the free Gal at 73 degrees C. All the preparations were moderately operationally stable when tested in lactose solution, whey permeate, cheese whey, and skim milk, and retained approximately 50% of their initial activity after 20 cycles of hydrolyzing lactose solution. The modification of the support with glutaraldehyde provided the most stable derivative during cycling in cheese whey hydrolysis. Our results suggest that the Immobead 150 is a promising support for Gal immobilization. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:934-943, 2018. PMID- 29717555 TI - A generalized purification step for viral particles using mannitol flocculation. AB - Vaccine manufacturing has conventionally been performed by the developed world using traditional unit operations like filtration and chromatography. There is currently a shift in the manufacturing of vaccines to the less developed world, requiring unit operations that reduce costs, increase recovery, and are amenable to continuous manufacturing. This work demonstrates that mannitol can be used as a flocculant for an enveloped and nonenveloped virus and can purify the virus from protein contaminants after microfiltration. The recovery of the virus ranges from 58 to 96% depending on virus, the filter pore size, and the starting concentration of the virus. Protein removal of 80% was achieved for the small nonenveloped virus using a 0.1 um filter because proteins were not flocculated with the virus and flowed through the filter. It is hypothesized that mannitol dehydrates the viral surface by controlling the water structure surrounding the virus. Without the ability to become compact, as occurs with proteins, the virus aggregates in the presence of osmolytes and proteins do not. Osmolyte flocculation is a scalable process using high flux microfilters. It has been applied to both an enveloped and nonenveloped virus, making this process friendly to a variety of vaccine and gene therapy products. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:1027-1035, 2018. PMID- 29717557 TI - New Editor-in-Chief of Transboundary and Emerging Diseases. PMID- 29717556 TI - Heart failure and sudden cardiac death in heritable thoracic aortic disease caused by pathogenic variants in the SMAD3 gene. AB - BACKGROUND: Predominant cardiovascular manifestations in the spectrum of Heritable Thoracic Aortic Disease include by default aortic root aneurysms- and dissections, which may be associated with aortic valve disease. Mitral- and tricuspid valve prolapse are other commonly recognized features. Myocardial disease, characterized by heart failure and/or malignant arrhythmias has been reported in humans and in animal models harboring pathogenic variants in the Fibrillin1 gene. METHODS: Description of clinical history of three cases from one family in Ghent (Belgium) and one family in St. Louis (US). RESULTS: We report on three cases from two families presenting end-stage heart failure (in two) and lethal arrhythmias associated with moderate left ventricular dilatation (in one). All three cases harbor a pathogenic variant in the SMAD3 gene, known to cause aneurysm osteoarthritis syndrome, Loeys-Dietz syndrome type 3 or isolated Heritable Thoracic Aortic Disease. CONCLUSIONS: These unusual presentations warrant awareness for myocardial disease in patients harboring pathogenic variants in genes causing Heritable Thoracic Aortic Disease and indicate the need for prospective studies in larger cohorts. PMID- 29717559 TI - Commentary on 'Complete mesocolic excision (CME) in right sided colon cancer does not increase severe short term postoperative adverse events'. PMID- 29717562 TI - Corrigendum. PMID- 29717560 TI - Could Blockchain technology add value to surgical outcomes research? PMID- 29717564 TI - Commentary on 'Short- and long-term clinical and patient-reported outcomes following laparoscopic ventral mesh rectopexy using biological mesh for pelvic organ prolapse: a prospective cohort study of 224 consecutive patients'. PMID- 29717566 TI - Estimating the age of Hb G-Coushatta [beta22(B4)Glu->Ala] mutation by haplotypes of beta-globin gene cluster in Denizli, Turkey. AB - BACKGROUND: Hb G-Coushatta variant was reported from various populations' parts of the world such as Thai, Korea, Algeria, Thailand, China, Japan and Turkey. In our study, we aimed to discuss the possible historical relationships of the Hb G Coushatta mutation with the possible migration routes of the world. For this purpose, associated haplotypes were determined using polymorphic loci in the beta globin gene cluster of hemoglobin G-Coushatta and normal populations in Denizli, Turkey. METHODS: We performed statistical analysis such as haplotype analysis, Hardy-Weinberg equilibrium, measurement of genetic diversity and population differentiation parameters, analysis of molecular variance using F-statistics, historical-demographic analyses, mismatch distribution analysis of both populations and applied the test statistics in Arlequin ver. 3.5 software program. RESULTS: The diversity of haplotypes has been shown to indicate different genetic origins for two populations. However, AMOVA results, molecular diversity parameters and population demographic expansion times showed that the Hb G-Coushatta mutation develops on the normal population gene pool. Our estimated tau values showed the average time since the demographic expansion for normal and Hb G-Coushatta populations ranged from approximately 42,000 to 38,000 ybp, respectively. CONCLUSION: Our data suggest that Hb G-Coushatta population originate in normal population in Denizli, Turkey. These results support the hypothesis that the multiple origin of Hb G-Coushatta and indicate that mutation may have been triggered the formation of new variants on beta globin haplotypes. PMID- 29717567 TI - Risk of Brain Tumor Induction from Pediatric Head CT Procedures: A Systematic Literature Review. AB - Head computed tomography (CT) is instrumental for managing patients of all ages. However, its low dose radiation may pose a low but non-zero risk of tumor induction in pediatric patients. Here, we present a systematic literature review on the estimated incidence of brain tumor induction from head CT exams performed on children and adolescents. MEDLINE was searched using an electronic protocol and bibliographic searches to identify articles related to CT, cancer, and epidemiology or risk assessment. Sixteen studies that predicted or measured head CT-related neoplasm incidence or mortality were identified and reviewed. Epidemiological studies consistently cited increased tumor incidence in pediatric patients (ages 0-18) exposed to head CTs. Excess relative risk of new brain tumor averaged 1.29 (95% confidence interval, 0.66-1.93) for pediatric patients exposed to one or more head CTs. Tumor incidence increased with number of pediatric head CTs in a dose-dependent manner, with measurable excess incidence even after a single scan. Converging evidence from epidemiological studies supported a small excess risk of brain tumor incidence after even a single CT exam in pediatric patients. However, refined epidemiological methods are needed to control for confounding variables that may contribute to reverse causation, such as patients with pre-existing cancer or cancer susceptibility. CT remains an invaluable technology that should be utilized so long as there is clinical indication for the study and the radiation dose is as small as reasonably achievable. PMID- 29717568 TI - Mitochondrial 10398A>G NADH-Dehydrogenase Subunit 3 of Complex I Is Frequently Altered in Intra-Axial Brain Tumors in Malaysia. AB - BACKGROUND: Mitochondria are major cellular sources of reactive oxygen species (ROS) generation which can induce mitochondrial DNA damage and lead to carcinogenesis. The mitochondrial 10398A>G alteration in NADH-dehydrogenase subunit 3 (ND3) can severely impair complex I, a key component of ROS production in the mitochondrial electron transport chain. Alteration in ND3 10398A>G has been reported to be linked with diverse neurodegenerative disorders and cancers. The aim of this study was to find out the association of mitochondrial ND3 10398A>G alteration in brain tumor of Malaysian patients. METHODS: Brain tumor tissues and corresponding blood specimens were obtained from 45 patients. The ND3 10398A>G alteration at target codon 114 was detected using the PCR-RFLP analysis and later was confirmed by DNA sequencing. RESULTS: Twenty-six (57.8%) patients showed ND3 10398A>G mutation in their tumor specimens, in which 26.9% of these mutations were heterozygous mutations. ND3 10398A>G mutation was not significantly correlated with age, gender, and histological tumor grade, however was found more frequently in intra-axial than in extra-axial tumors (62.5% vs. 46.2%, p<0.01). CONCLUSION: For the first time, we have been able to describe the occurrence of ND3 10398A>G mutations in a Malaysian brain tumor population. It can be concluded that mitochondrial ND3 10398A>G alteration is frequently present in brain tumors among Malaysian population and it shows an impact on the intra axial tumors. PMID- 29717569 TI - Intermediate Pilomyxoid Astrocytoma in the Cerebellum of a 5-Year-Old Boy. AB - Intermediate pilomyxoid tumors (IPTs) were defined by the presence of some features typical of pilomyxoid astrocytoma (PMA) in combination with features that could be considered more consistent with pilocytic astrocytoma (PA). PMA is rare in the cerebellum. And, IPT in the cerebellum is rarer than PMA. To our knowledge, only 2 reports have described IPT in the cerebellum. A 5-year-old boy had nausea and vomiting. Computed tomography revealed a large, round, low-density tumor in the cerebellar vermis area. On enhanced magnetic resonance imaging (MRI), the tumor showed inhomogeneous diffuse enhancement; the central portion showed homogenous enhancement, while the peripheral portion showed inhomogeneous enhancement. The patient underwent a midline suboccipital craniotomy, and gross total resection was performed. The tumor was gray-colored, rubbery hard, and severely hemorrhagic with a clear boundary. On pathologic examination, the combined features of both PA and PMA were retrospectively indicative of an IPT. The patient was symptom-free for 18 months, with no evidence of tumor recurrence on MRI. More observation and further studies on PMA and IPT are required to determine the most appropriate treatment for these tumors. PMID- 29717570 TI - Extensive Pituitary Apoplexy after Chemotherapy in a Patient with Metastatic Breast Cancer. AB - Surgery, anticoagulation therapy, pregnancy, and hormone treatments, such as bromocriptine, are well-characterized precipitating factors for pituitary apoplexy. However, whether cytotoxic chemotherapy for systemic cancer could cause pituitary apoplexy has not been investigated. Here, we present a case of a 41 year-old woman who developed a severe headache with decreased visual acuity after intravenous cytotoxic chemotherapy to treat metastatic breast cancer. Preoperative neuroimaging revealed pituitary adenoma with necrosis. Operative findings and pathologic examination concluded extensive necrosis with a small intratumoral hemorrhage in a pre-existing pituitary adenoma. We reviewed two additional previously published cases of pituitary apoplexy after systemic chemotherapy and suggest that cytotoxic chemotherapy may induce pituitary apoplexy. PMID- 29717571 TI - Cochlear Damage Caused by the Striking Noise of Titanium Head Golf Driver. AB - Objectives: To investigate how mouse cochleae are affected by the striking noise of titanium head golf driver. Methods: Thirty-two BALB/c mice (20-22 g) with normal hearing were used. The impact acoustic stimulus generated by the striking of titanium golf driver head was centered around 4.5 kHz with 120.5 dB sound pressure level. The recorded impact noise was provided to mice in two ways with the same exposure time of 288 seconds: 1,440 repetitions and an impact duration of 0.2 seconds for 2 hours (repetitive noise) or serially connected impact noise for 288 seconds (continuous noise). Auditory brainstem responses were measured at baseline, day 7, and day 14 after exposure. The mice were then sacrificed for histology. Results: Both groups showed statistically significant threshold shifts immediately after noise exposure. Mice in the continuous exposure group, except for those exposed to 32 kHz noise, recovered from threshold shifts 1-2 weeks after noise exposure. However, in the repetitive exposure group, threshold shifts remained for 2 weeks after exposure. The repetitive exposure group had greater hair cell damage than did the continuous exposure group. Structural changes in the stria vascularis were observed in the repetitive exposure group. Conclusion: Overexposure to impact noise caused by hitting of titanium head golf driver may be hazardous to the cochlea, and repetitive exposure may induce greater damage than continuous exposure. PMID- 29717572 TI - Corrigendum: Misplacement of images in a table including the structure of the cerebral cortex. AB - [This corrects the article on p. 32 in vol. 13.]. PMID- 29717573 TI - A four year epidemiological and chemotherapy survey of babesiosis and theileriosis, and tick vectors in sheep, cattle and goats in Dehgolan, Iran AB - Babesia and Theileria are two protozoa belonging to the phylum Apicomplexa, which result in babesiosis and theileriosis in different hosts, cause considerable problems in domestic animals and as a consequence economic losses. These two diseases are transmitted by ticks. This survey was carried out due to the lack of studies and information regarding tick vectors and Theileria and Babesia species in the Dehgolan area of Iran, which is a center of agriculture and animal holding industry. This study was conducted during a four-year period, between 2012 and 2016. Infection with Theileria and Babesia was observed throughout the year while in contrast to cattle and sheep, infection with Babesia in goats was not observed between December and February. Infection with Babesia and Theileria reached the highest peak in July and this was more considerable for Theileria in cattle and sheep with a prevalence of 37-47% and 46-79%, respectively. The infection rate in goats for both diseases was 20%. The results in this study showed that Imidocarb Diproprionate and Buparvaquone are effective treatments for Babesia and Theileria, respectively. In this survey, the ticks of Rhipicephalus spp. and Hyalomma anatolicum had the highest infection rate with Babesia and Theileria, respectively. Considering the significant relationship between the prevalence of Theileria and Babesia with tick infection in this study and other studies, more studies on climate changes and tick vector prevalence are necessary. PMID- 29717574 TI - Efficacy and tolerability of artesunate-amodiaquine versus artemether lumefantrine in the treatment of uncomplicated Plasmodium falciparum malaria at two sentinel sites across Cote d'Ivore AB - Malaria remains a major public health problem in Cote d'Ivoire. The aim of this study is to compare the efficacy and tolerability of artesunate-amodiaquine (ASAQ) versus artemether-lumefantrine (AL) for the treatment of uncomplicated malaria, at two malaria surveillance sites in Cote d'Ivoire. The World Health Organization 2003 protocol was used for this multicenter open randomized clinical trial with a 42-day follow-up. We recruited 240 patients (120 per arm), of whom 114 (ASAQ group) and 112 (AL group) were fully followed-up. According to intention-to-treatstatistical analysis, PCR-corrected cure rates for ASAQ and AL treatments were 95.8% and 92.5% on day 28, and 95% and 92.5% on day 42, respectively. Based on per-protocol statistical analysis, ASAQ and AL treatment rates reached 100% and 99.1%, respectively, on day 28 and remained the same on day 42. Overall, both drugs were well-tolerated at the clinical and biological level. This study shows that ASAQ and AL are still effective and well-tolerated. Accordingly, they can continue being used to treat uncomplicated malaria in Cote d'Ivoire. However, monitoring of their efficacy should remain a priority for health authorities. PMID- 29717575 TI - The in vitro effect of Ferula asafoetida and Allium sativum extracts on Strongylus spp. AB - The high incidence of equine gastrointestinal worms and their increased resistance against anthelmintics has encouraged research into the effectiveness of rational phytotherapy. This study investigates the in vitro anti-parasitic effects of extracts of Ferula asafoetida and Allium sativum, two native plants that are widespread in Iran on Strongylus spp. larvae. Faecal samples were collected from horses, examined by routine parasitology methods and positive samples were used for future examination. After incubation, the third-stage larvae were harvested by the Baermann technique.A hydroalcoholic extract from the plants was used for the antiparasitic study, while tap water was used for controls. Trials for each concentration and control group were performed in three replicates. The results showed that that during the first day of exposure, the hydroalcoholic extract of F. asafoetida at concentration of 10, 50 and 100 mg/ml killed over the 90% of the larvae, and A. sativum extract at concentration of 50 and 100 mg/ml killed over the 95% of larvae (p<0.05). The results obtained from the bioassay showed that two plant extracts have a larvicidal effect on theStrongylus spp. larval stages compared with the control group. PMID- 29717576 TI - Helminth parasites of stone marten (Martes foina) in central Portugal AB - The stone marten (Martes foina) is one of the most common species of marten in Europe. Due to increased urbanization and forest degradation, it is now often found in urban habitats, which increased the possibility of parasites transmission between wildlife-domestic animals and humans. Our preliminary study of this mustelid in Portugal, aimed to assess prevalence of helminths. Six helminth parasites were found (Crenosoma vulpis,Angiostrongylus sp., Toxocara sp., Toxascaris leonina, Ancylostomatidae and Strongyloides sp.). To our knowledge, this is the first report of Toxascaris leonina in this host species. PMID- 29717577 TI - Cryptosporidiosis in a fire skink (Lepidothyris fernandi) and molecular identification of infecting species AB - Cryptosporidiosis is an infectious protozoan disease that affects a wide range of animals including reptiles. This is the first report of cryptosporidiosis in a fire skink (Lepidothyris fernandi), an insectivorous reptile commonly found in tropical West Africa. Faecal sample was collected from a fire skink at necropsy for the detection of parasites by faecal sedimentation method, Ziehl-Neelsen (ZN) acid-fast staining, Nested Polymerase Chain Reaction (PCR) and Nucleotide sequencing. Sections of the intestines were also processed for histopathology. Light microscopy revealed the presence of Ophidascarids sp. eggs and Cryptosporidium oocysts. Amplification of the 18S rRNA gene and nucleotide sequencing confirmed Cryptosporidium varanii as the infecting species. Histopathology revealed cellular infiltration and disruption of the epithelial cells along the brush border characteristic of intestinal inflammation. PMID- 29717578 TI - Expression on hypoxia-inducible factor-1alpha in human tegumentary leishmaniosis caused by Leishmania braziliensis AB - Several immune markers have been studied in controlling American tegumentary leishmaniosis based on mouse models. However, there is a lack of studies regarding human tegumentary leishmaniosis caused by Leishmania braziliensis. In this study, hypoxia-inducible factor-1alpha was found to be an important effector element in the localized control of human cutaneous and mucocutaneous lesions. PMID- 29717579 TI - [Arrhythmia heartbeats classification based on neighborhood preserving embedding algorithm]. AB - Arrhythmia is a kind of common cardiac electrical activity abnormalities. Heartbeats classification based on electrocardiogram(ECG) is of great significance for clinical diagnosis of arrhythmia. This paper proposes a feature extraction method based on manifold learning, neighborhood preserving embedding(NPE) algorithm, to achieve the automatic classification of arrhythmia heartbeats. With classification system, we obtained low dimensional manifold structure features of high dimensional ECG signals by NPE algorithm, then we inputted the feature vectors into support vector machine(SVM) classifier for heartbeats diagnosis. Based on MIT-BIH arrhythmia database, we clustered 14 classes of arrhythmia heartbeats in the experiment, which yielded a high overall classification accuracy of 98.51%. Experimental result showed that the proposed method was an effective classification method for arrhythmia heartbeats. PMID- 29717580 TI - [Three-dimensional tooth model reconstruction based on fusion of dental computed tomography images and laser-scanned images]. AB - Complete three-dimensional(3D) tooth model provides essential information to assist orthodontists for diagnosis and treatment planning. Currently, 3D tooth model is mainly obtained by segmentation and reconstruction from dental computed tomography(CT) images. However, the accuracy of 3D tooth model reconstructed from dental CT images is low and not applicable for invisalign design. And another serious problem also occurs, i.e. frequentative dental CT scan during different intervals of orthodontic treatment often leads to radiation to the patients. Hence, this paper proposed a method to reconstruct tooth model based on fusion of dental CT images and laser-scanned images. A complete3 D tooth model was reconstructed with the registration and fusion between the root reconstructed from dental CT images and the crown reconstructed from laser-scanned images. The crown of the complete 3D tooth model reconstructed with the proposed method has higher accuracy. Moreover, in order to reconstruct complete 3D tooth model of each orthodontic treatment interval, only one pre-treatment CT scan is needed and in the orthodontic treatment process only the laser-scan is required. Therefore, radiation to the patients can be reduced significantly. PMID- 29717581 TI - [Plaque region segmentation of intracoronary optical cohenrence tomography images based on kernel graph cuts]. AB - The segmentation of the intracoronary optical coherence tomography(OCT) images is the basis of the plaque recognition, and it is important to the following plaque feature analysis, vulnerable plaque recognition and further coronary disease aided diagnosis. This paper proposes an algorithm about multi region plaque segmentation based on kernel graph cuts model that realizes accurate segmentation of fibrous, calcium and lipid pool plaques in coronary OCT image, while boundary information has been well reserved. We segmented 20 coronary images with typical plaques in our experiment, and compared the plaque regions segmented by this algorithm to the plaque regions obtained by doctor's manual segmentation. The results showed that our algorithm is accurate to segment the plaque regions. This work has demonstrated that it can be used for reducing doctors' working time on segmenting plaque significantly, reduce subjectivity and differences between different doctors, assist clinician's diagnosis and treatment of coronary artery disease. PMID- 29717582 TI - [Simulation research on magnetoacoustic effect and thermoacoustic effect of pulsed magnetic excitation]. AB - According to the coupling relationship of electromagnetic field and acoustic field when electromagnetic field irradiates low conductivity objects, we carried out a study on the magnetoacoustic effect and thermoacoustic effect in pulsed magnetic excitation. In this paper, we provide the pressure wave equation in pulsed magnetic excitation based on the theory of electromagnetic field and acoustic wave propagation. A 2-dimensional coil carrying current and a circular thin sheet model were constructed to simulate the physical imaging environment. The transient electromagnetic field was simulated using finite element method. Numerical studies were conducted to simulate the pressures excited by magnetoacoustic effect and thermoacoustic effect according to the result of electromagnetic simulation. It was shown that the thermoacoustic effect played a leading role in the low conductivity objects on the microsecond Gauss pulsed magnetic excitation, and thermoacoustic effect and magnetoacoustic effect coexisted on the microsecond Gauss pulsed magnetic field and 0.2 T static magnetic field excitation. This study lays the foundation for the further application of magnetoacoustic tomography with magnetic induction and magnetically mediated thermoacoustic imaging. PMID- 29717583 TI - [Simulation research of respiratory monitoring with magnetic detection electrical impedance tomography]. AB - In order to explore the feasibility of applying magnetic detection electrical impedance tomography(MDEIT) on respiratory monitoring, aiming at the forward problem of magnetic detection electrical impedance tomography, we calculated the electric potential and current density distribution inside the imaging object by using the finite element method. We then got magnetic induction intensity outside the object at the end of exhaling and inhaling according to Biot-Savart's law. The results showed that the magnetic induction intensity at the end of inhaling was 8.875%,less than that at the end of exhaling. By the simulation results, we could understand the difference of magnetic induction intensity value surrounding the lung at the end of exhaling and inhaling due to the change of lung volume and electrical conductivity distribution better. Our research laid the foundation for the late image reconstruction and clinical disease detection. PMID- 29717584 TI - [Study on the effect of artificial cartilage with different elastic modulus on the mechanical environment of the chondrocyte in defect cartilage repaired area]. AB - A solid-liquid two-phase finite element model of articular cartilage and a microscopic finite element model of chondrocytes were established using the finite element software COMSOL in this study. The purpose of the study is to investigate the mechanics environment and the liquid flow field of the host cartilage chondrocytes in each layer by multi-scale method, under physiological load, with the different elastic modulus of artificial cartilage to repair cartilage defect. The simulation results showed that the uniform elastic modulus of artificial cartilage had different influences on the microenvironment of different layer chondrocytes. With the increase of the elastic modulus of artificial cartilage, the stress of the shallow surface layer and the intermediate layer chondrocytes increased and the stress of deep layer chondrocytes decreased. The flow field direction of the middle layer and the bottom layer of cartilage can also be changed by artificial cartilage implantation, as well as the ways of nourishment supply of the middle layer and underlying chondrocytes change.A barrier to underlying chondrocytes nutrition supply may be caused by this, thus resulting in the uncertainty of the repair results. With cross-scale finite element model simulation analysis of chondrocytes, we can quantitatively evaluate the mechanical environment of chondrocytes in each layer of the host cartilage. It is helpful to assess the clinical effect of cartilage defect reparation more accurately. PMID- 29717585 TI - [Effect of muscle biofidelity on thoracic impact biomechanical response of a six year-old child using finite element method]. AB - Finite element(FE) model of thorax with high biofidelity is one of the most important methods to investigate thoracic injury mechanism because of the absence of pediatric cadaver experiments. Based on the validated thorax finite element model, the FE models with equivalent muscles and real geometric muscles were developed respectively, and the effect of muscle biofidelity on thoracic injury was analyzed with reconstructing pediatric cadaver thorax impact experiments. The simulation results showed that the thoracic impact force, the maximum displacement and the maximum von-Mises stress of FE models with equivalent muscles were slightly greater than those from FE models with real geometric muscles, and the maximum principal strains of heart and lung were a little lower. And the correlation coefficient between cadaver corridor and FE model with real muscles was also greater than that between cadaver corridor and FE model with equivalent muscles. As a conclusion, the FE models with real geometric muscles can accurately reflect the biomechanical response of thorax during the impact. PMID- 29717586 TI - [Research on the mechanical differences of machinable lithium disilicate all ceramic crowns]. AB - Due to the superior pigment and high flexural strength, machinable lithium disilicate ceramics can be used as a monolithic crown or veneering porcelains on the zirconia core to form the all-ceramic crowns by sintering or bonding procedures. This paper reports the research on the differences in stress distributions amongst these three types of all-ceramic crowns under typical loading conditions. Three-dimensional numerical models of the restored crown based on the first mandibular molar were developed. The vertical concentrated load and 8-point uniformly distributed load were applied, respectively. The maximum stress and stress distribution were resulted from finite element evaluation. It was found that the maximum tensile stress in 3 types of restored crowns subjected to the concentrate load was less than the flexural strength of IPS e.max. The stress distributions in the sintered and bonded double layered crowns were basically identical, and different from the monolithic crown. The stress magnitude in veneer porcelain of the bonded crown was greater than that in the sintered crown. The use of IPS e.max computer aided design monolithic crown as molar restorations should be careful to avoid high stress as the cyclic stress is a concern of fatigue which may influence the longevity of the restored crown. The bonded double layer crowns bear greater risks of veneer chipping compared with the sintered crowns. The conclusions of this study provide helpful guidelines in clinical applications for preparation of computer aided design/computer aided manufacture lithium disilicate all-ceramic restorations. PMID- 29717587 TI - [Research on ground reaction forces and utilized coefficient of friction of turning gait]. AB - Utilized coefficient of friction(UCOF), which is calculated with ground reaction forces(GRF), is an effective factor to predict the possibility of slip. For researching the UCOF values of different turning strategies and then predicting the possibility of slip, this study selected 10 healthy young men to perform straight walking and 60 degrees and 90 degrees turning using two turning strategies(step turning and spin turning). ATMI force plate was used to collect the data of GRF,and then the UCOF values of different walking conditions were calculated. The study showed that difference of the medial-lateral force in different walking conditions was great; the slip possibility of turning was significantly greater than that of straight walking. For spin turn, turning angle had no significant effect on peak UCOF values. For step turn, the propulsive force decreased with the increase of turning angle, which caused a result that the peak UCOF values of 60 degrees turn were significantly greater than that for 90 degrees turn. This suggests that turning angle had little effect on possibility of slip of spin turning but great effect on that of step turning, and the greater angle led smaller possibility of slip. PMID- 29717589 TI - [A new method for calculating pulse oxygen saturation]. AB - Real-time updates of metrical data can not generally be realized in the commonly used methods for calculating the pulse wave of blood oxygen saturation. Based on the hardware platform of pulse wave signal from NJL5501 R, and high linear correlation of the red laser and infrared light collected in pulse wave signal measurement, an approach to determine the value of the blood oxygen saturation is proposed in the present paper by establishing the linear regression model of the red laser and infrared light. The effect of the sampling number of pulse wave signal in calculation on the characteristic parameters of pulse wave is also analyzed. The experimental results showed that the approach could guarantee the measuring accuracy and realize the fast updates of blood oxygen saturation data. This paper provides an effective method for real-time and accurate monitoring of pulse blood oxygen saturation in human body. PMID- 29717588 TI - [Structure design of a new video laryngoscope image sensor]. AB - In order to overcome the influence of stray light and impurity on the image of video laryngoscope, we designed an optical structure by using Trace Pro, a simulation software, to imitate optical path status. Images are captured by CMOS sensor which has the size of 4.5 mm*18 mm and the pixel size is 1.75 MUm*1.75 MUm. The sensor is placed in the elbow of the laryngoscope, and the elbow has the size of 9 mm*10 mm. As a result, the video laryngoscope could meet the requirements, including wide viewing angle(80 degrees ), short focal length(2.8 mm), long working distance(10 cm), and least impurity. In the test, the image was clear and there was no facula or impurity in the condition of required illumination,and thus stray light and image impurity were eliminated and the image quality was improved. PMID- 29717590 TI - [Assessment of laparoscopic training based on eye tracker and electroencephalograph]. AB - The aim of this study is to evaluate the effect of laparoscopic simulation training with different attention. Attention was appraised using the sample entropy and theta/beta value, which were calculated according to electroencephalograph(EEG) signal collected with Brain Link. The effect of laparoscopic simulation training was evaluated using the completion time, error number and fixation number, which were calculated according to eye movement signal collected with Tobii eye tracker. Twenty volunteers were recruited in this study. Those with the sample entropy lower than0.77 were classified into group A and those higher than 0.77 into group B. The results showed that the sample entropy of group A was lower than that of group B, and fluctuations of A were more steady. However, the sample entropy of group B showed steady fluctuations in the first five trainings, and then demonstrated relatively dramatic fluctuates in the later five trainings. Compared with that of group B, the theta/beta value of group A was smaller and shows steady fluctuations. Group A has a shorter completion time, less errors and faster decrease of fixation number. Therefore, this study reached the following conclusion that the attention of the trainees would affect the training effect. Members in group A, who had a higher attention were more efficient and faster training. For those in group B, although their training skills have been improved, they needed a longer time to reach a plateau. PMID- 29717591 TI - [Visualized detection for mycobacterium tuberculosis using loop-mediated isothermal amplification assay]. AB - In this study, loop-mediated isothermal amplification(LAMP) assay in conjunction with calcein for visualized detection of Mycobacterium tuberculosis(MTB) was established. Firstly, four LAMP primers were designed according to the region of 16 S r DNA sequences of MTB. Secondly, clinical sputum samples were collected,decontaminated and their DNA was extracted. Thirdly, standard MTB strains were used to evaluate the specificity and sensitivity of LAMP. At the same time, electrophoresis was used for products detection and calcein was used for visualized verification. At last, Chi-squared test function in SPSS 17.0 software was used for consistency evaluation of LAMP assay as compared with the gold standard(culture method). Results showed that there was no nonspecific amplification appeared in the specificity assay and the detection limit was 10 copies/tube in the sensitivity assay. In addition, visualized method by calcein had a comparable sensitivity with that of electrophoresis method. After evaluation of clinical practicability, the sensitivity of LAMP was calculated as 94.74% and the specificity was 90%, respectively. And Chi-squared test showed that LAMP and culture method had no statistic difference, and the two methods were in good consistency(P>0.05). In conclusion, LAMP assay introduced in our study has the characteristics of high efficiency and visualized detection so that this technique has great application prospects in the resource-limited environment, such as work field and primary care hospitals. PMID- 29717593 TI - [Study of vascularization of hydroxyapatite/tricalcium phosphate biomaterials implanted in mice during osteoinduction]. AB - This study aims to explore the vascularization of hydroxyapatite/tricalcium phosphate(HA/TCP)biomaterials implanted in mice during osteoinduction. The HA/TCP biomaterials were implanted in muscle of mice, and2, 4, 6, 8, 10 and 12 weeks after the implantation, the materials were harvested to prepare serial sections and hematoxylineosin(HE) staining. The process of vascularization was dynamically described, and the area percentage of neovascularization was quantitatively analyzed. The results showed that neovascularization formation was a continuous and dynamic process. The neovascularization appeared largely in the first two weeks, with a rising trend in week 4,reached peak in week 6, and gradually reduced in week 8. The results provide ideas for improving the success rate of bone tissue engineering, and indicate the mechanism of osteoinduction. PMID- 29717592 TI - [Experimental study on inhibitory effect of zoledronic acid on the action style of the osteoclast]. AB - This study is to investigate the inhibitory effect of different concentrations of zoledronic acid on the activity of osteoclasts, to obtain characteristics on inhibitory effect and to find the lowest effective concentration of zoledronic acid. Marrow cells of C57 mice(6 weeks) were cultured in vitro. Osteoclasts were induced by single nuclear cells. According to the concentration of zoledronic acid, we set up the experimental group with five different concentrations, i.e. 1*10-8 mol/L, 1*10-7 mol/L, 1*10-6 mol/L, 1*10-5 mol/L, and 1*10-4 mol/L. The control group did not contain any bisphosphonate. By tartrate resistant acid phosphatase staining, the number of multinuclear cells, cells through the filter and bone resorption lacune were counted. Five days after the cultivation, the number of multinuclear cells in the experimental group decreased with the increase of concentration of zoledronic acid. Inhibition on the formation of osteoclasts in vitro was effective at 1*10-6 mol/L. At the concentration of 1*10 5 mol/L, the effect of inhibition on migration of osteoclast and bone resorption was more obvious. The effect was further enhanced at concentration of 1*10-4 mol/L. However, the concentration and inhibition curves were gradually mild. The inhibitory effect on different concentrations of zoledronic acid on the activity of osteoclasts was different. The inhibition effect was obvious at 1*10-6 mol/L. We should pay attention to administrate appropriate concentration of zoledronic acid in the clinical applications. PMID- 29717594 TI - [Effect of lung ischemia-reperfusion injury on the expressions of transient receptor potential vanilloid 1 in lung and brainstem of rats]. AB - This study aims to investigate the effect of lung ischemia reperfusion injury(LIRI) on expression of transient receptor potential vanilloid 1(TRPV1) in the lung and brainstem of rats. Sixteen adult male Sprague Dawley rats weighing 250-320 g were randomly divided into Sham group and ischemia reperfusion group(IR group). Before ischemia,0.5 hour and 4 hours after the reperfusion, respectively, arterial partial pressure of oxygen(PaO2) and arterial-alveolar oxygen pressure gradient(A-a DO2) were recorded and calculated, respectively. Left lung tissues and the brainstems were obtained at the end of the experiment. Lung tissue malondialdehyde(MDA), myeloperoxidase(MPO) activities, calcitonin gene related peptide(CGRP) and substance P(SP) levels were assessed. The m RNA and protein expressions of TRPV1 in the lung and brainstem were measured by q RT-PCR and Western blot. Compared with in the Sham group, rats in the IR group had a poorer blood gas exchange(P<0.05) and the MPO activity and MDA level of lung tissues in the IR group were significantly higher than those in the Sham group(P<0.05). CGRP level in the IR group increased remarkably(P<0.05),while SP level did not differ statistically between the two groups(P>0.05). The m RNA and protein expressions of TRPV1 in the lung tissue were upregulated in the IR group(P<0.05), but there were no differences of those in the brainstem between the two groups(P>0.05). The results suggest that LIRI could upregulate the expressions of TRPV1 and evoke CGRP release in the lung. PMID- 29717595 TI - [An improved algorithm for electrohysterogram envelope extraction]. AB - Extraction uterine contraction signal from abdominal uterine electromyogram(EMG) signal is considered as the most promising method to replace the traditional tocodynamometer(TOCO) for detecting uterine contractions activity. The traditional root mean square(RMS) algorithm has only some limited values in canceling the impulsive noise. In our study, an improved algorithm for uterine EMG envelope extraction was proposed to overcome the problem. Firstly, in our experiment, zero-crossing detection method was used to separate the burst of uterine electrical activity from the raw uterine EMG signal. After processing the separated signals by employing two filtering windows which have different width, we used the traditional RMS algorithm to extract uterus EMG envelope. To assess the performance of the algorithm, the improved algorithm was compared with two existing intensity of uterine electromyogram(IEMG) extraction algorithms. The results showed that the improved algorithm was better than the traditional ones in eliminating impulsive noise present in the uterine EMG signal. The measurement sensitivity and positive predictive value(PPV) of the improved algorithm were 0.952 and 0.922, respectively, which were not only significantly higher than the corresponding values(0.859 and 0.847) of the first comparison algorithm, but also higher than the values(0.928 and 0.877) of the second comparison algorithm. Thus the new method is reliable and effective. PMID- 29717596 TI - [Study of attention deficit/hyperactivity disorder classification based on convolutional neural networks]. AB - Attention deficit/hyperactivity disorder(ADHD) is a behavioral disorder syndrome found mainly in school-age population. At present, the diagnosis of ADHD mainly depends on the subjective methods, leading to the high rate of misdiagnosis and missed-diagnosis. To solve these problems, we proposed an algorithm for classifying ADHD objectively based on convolutional neural network. At first, preprocessing steps, including skull stripping, Gaussian kernel smoothing, et al., were applied to brain magnetic resonance imaging(MRI). Then, coarse segmentation was used for selecting the right caudate nucleus, left precuneus, and left superior frontal gyrus region. Finally, a 3 level convolutional neural network was used for classification. Experimental results showed that the proposed algorithm was capable of classifying ADHD and normal groups effectively, the classification accuracies obtained by the right caudate nucleus and the left precuneus brain regions were greater than the highest classification accuracy(62.52%) in the ADHD-200 competition, and among 3 brain regions in ADHD and the normal groups, the classification accuracy from the right caudate nucleus was the highest. It is well concluded that the method for classification of ADHD and normal groups proposed in this paper utilizing the coarse segmentation and deep learning is a useful method for the purpose. The classification accuracy of the proposed method is high, and the calculation is simple. And the method is able to extract the unobvious image features better, and can overcome the shortcomings of traditional methods of MRI brain area segmentation, which are time-consuming and highly complicate. The method provides an objective diagnosis approach for ADHD. PMID- 29717597 TI - [Online brain-computer interface system based on independent component analysis]. AB - In the research of non-invasive brain-computer interface(BCI), independent component analysis(ICA) has been considered as a promising method of electroencephalogram(EEG) preprocessing and feature enhancement. However, there have been few investigations and implements about online ICA-BCI system up till now.This paper reports the investigation of the ICA-based motor imagery BCI(MIBCI) system, combining the characteristics of unsupervised learning of ICA and event-related desynchronization(ERD) related to motor imagery. We constructed a simple and practical method of ICA spatial filter calculation and discriminate criterion of three-type motor imageries in the study. To validate the online performance of proposed algorithms, an ICA-MIBCI experimental system was fully established based on Neuro Scan EEG amplifier and VC++ platform. Four subjects participated in the experiment of MIBCI testing and two of them took part in the online experiment. The average classification accuracies of the three-type motor imageries reached 89.78% and 89.89% in the offline and online testing, respectively. The experimental results showed that the proposed algorithm produced high classification accuracy and required less time consumption, which would have a prospect of cross platform application. PMID- 29717598 TI - [Cell data clustering method in flow cytometry based on kernel principal component analysis]. AB - The process of multi-parametric flow cytometry data analysis is complicate and time-consuming,which requires well-trained professionals to operate on. To overcome this limitation, a method for multi-parameter flow cytometry data processing based on kernel principal component analysis(KPCA) was proposed in this paper. The dimensionality of the data was reduced by nonlinear transform. After the new characteristic variables were obtained,automatical clustering can be achieved using improved K-means algorithm. Experimental data of peripheral blood lymphocyte were processed using the principal component analysis(PCA)-based method and KPCA-based method and then the influence of different feature parameter selections was explored. The results indicate that the KPCA can be successfully applied in the multi-parameter flow cytometry data analysis for efficient and accurate cell clustering, which can improve the efficiency of flow cytometry in clinical diagnosis analysis. PMID- 29717599 TI - [Investigation of the glucose dynamics with an approach of refined composite multi-scale entropy analysis]. AB - The study on complexity of glucose fluctuation not only helps us understand the regulation of the glucose homeostasis system but also brings us a new insight of the research methodology on glucose regulation. In the experiments, we analyzed the complexity of the temporal structure of the 72 hours continuous glucose time series from a group of 93 subjects with type II diabetes mellitus using the multi scale entropy method. We adapted the most recently improved refined composite multi-scale entropy(RCMSE) algorithm which could overcome the shortcomings on the 72 hours short time series analysis. We then quantified and compared the complexity of continuous glucose time series between groups with type II diabetes mellitus with different mean absolute glycemic excursion(MAGE) and glycated hemoglobin(Hb A1c). The results implied that the complexity of glucose time series decreased on lower MAGE group compared to high MAGE group, and the entropy on scale 1 to 6 which corresponded to 5 to 30 min had significant differences between these two groups; the complexity of glucose time series decreased with the increasing Hb A1 c level but the entropy had no statistical difference among groups at different scales. Therefore, RCMSE provided us with a new prospect to analyze the glucose time series and it was proved that less complexity of glucose dynamics could indicate the impaired gluco-regulation function from the MAGE point of view or Hb A1 c for patients, and the glucose complexity had the potential to become a new biomarker to reflect the fluctuation of the glucose time series. PMID- 29717600 TI - [A signature based on relative gene expression orderings for lung cancer diagnosis]. AB - Traditional classifiers, such as support vector machine and Bayesian classifier, require data normalization for removing experimental batch effects, which limit their applications at the individual level. In this paper,we aim to build a classifier to distinguish lung cancer and non-cancer lung tissues(pneumonia and normal lung tissues).We identified gene pairs as signatures to build a classifier based on the within-sample relative expression orderings of gene pairs in a particular type of tissues(cancer or non-cancer). Using multiple independent datasets as the training data,including a total of 197 lung cancer cases and 189 non-cancer cases, we identified three gene pairs. Classifying a sample by the majority voting rule, the average accuracy reached 95.34% in the training data. Using multiple independent validation datasets, including a total of 251 lung cancer samples and 141 non-cancer samples without data normalization, the average accuracy was as high as 96.78%. The rank-based signature is robust against experimental batch effects and can be used to diagnose lung cancer using samples measured by different laboratories at the individual level. PMID- 29717601 TI - [Recognition study of double strand DNA with hairpin oligopolyamide]. AB - Selective recognition of double strands DNA(ds DNA) has been a research hot spot in molecular biology and biomedicine for a couple decades. Based on the selective interaction between natural nucleic acid/synthetic molecular ligands and ds DNA, gene diagnosis, gene therapy and gene editing would be realized. Hairpin oligopolyamide is a molecular ligand with excellent cellular permeability and nucleases-resistance which can target ds DNA sequence with high affinity and specificity at minor groove. This paper reviews the binding properties and biomedical applications of hairpin oligopolyamide targeting ds DNA, which provide references for further design and application of hairpin oligopolyamide. PMID- 29717602 TI - [Research progress of disrupted brain connectivity in mild cognitive impairment:findings from graph theoretical studies of whole brain networks]. AB - Mild cognitive impairment(MCI) is a clinical transition state between age-related cognitive decline and dementia. Researchers can use neuroimaging and neurophysiological techniques to obtain structural and functional information about the human brain. Using this information researchers can construct the brain network based on complex network theory. The literature on graph theory shows that the large-scale brain network of MCI patient exhibits small-world property, which ranges intermediately between Alzheimer's disease and that in the normal control group. But brain connectivity of MCI patients presents topologically structural disorder. The disorder is significantly correlated to the cognitive functions. This article reviews the recent findings on brain connectivity of MCI patients from the perspective of multimodal data. Specifically, the article focuses on the graph theory evidences of the whole brain structural and functional and the joint covariance network disorders. At last, the article shows the limitations and future research directions in this field. PMID- 29717603 TI - [A review of progress of real-time tumor tracking radiotherapy technology based on dynamic multi-leaf collimator]. AB - While radiation treatment to patients with tumors in thorax and abdomen is being performed, further improvement of radiation accuracy is restricted by the tumor intra-fractional motion due to respiration. Real-time tumor tracking radiation is an optimal solution to tumor intra-fractional motion. A review of the progress of real-time dynamic multi-leaf collimator(DMLC) tracking is provided in the present review, including DMLC tracking method, time lag of DMLC tracking system, and dosimetric verification. PMID- 29717604 TI - [Design and research progress of zero profile cervical Interbody cage]. AB - Zero profile cervical interbody cage is an improvement of traditional fusion products and necessary supplement of emerging artificial intervertebral disc products. When applied in Anterior Cervical Decompression Fusion(ACDF), zero profile cervical interbody cage can preserve the advantages of traditional fusion and reduce the incidence of postoperative complications. Moreover, zero profile cervical interbody cage can be applied under the tabu symptoms of Artificial Cervical Disc Replacement(ACDR). This article summarizes zero profile interbody cage products that are commonly recognized and widely used in clinical practice in recent years, and reviews the progress of structure design and material research of zero profile cervical interbody cage products. Based on the latest clinical demands and research progress, this paper also discusses the future development directions of zero profile interbody cage. PMID- 29717605 TI - [Present status and prospects of injectable hydrogels for treatment of myocardial infarction]. AB - Survivors from myocardial infarction(MI) eventually develop heart failure due to the post-infarct ventricular remodeling which could not be suppressed by existing treatments. Currently, coronary heart disease has become the major cause of heart failure instead of rheumatic heart disease in China. For this reason, seeking effective treatment to prevent post-infarct ventricular remodeling is urgent. Intramyocardial injection of hydrogels as a new strategy for MI treatment has made great progress recently. This review discusses the principle, present status,mechanisms and prospects of injectable hydrogel therapies for MI. PMID- 29717606 TI - Cities' Role in Mitigating United States Food System Greenhouse Gas Emissions. AB - Current trends of urbanization, population growth, and economic development have made cities a focal point for mitigating global greenhouse gas (GHG) emissions. The substantial contribution of food consumption to climate change necessitates urban action to reduce the carbon intensity of the food system. While food system GHG mitigation strategies often focus on production, we argue that urban influence dominates this sector's emissions and that consumers in cities must be the primary drivers of mitigation. We quantify life cycle GHG emissions of the United States food system through data collected from literature and government sources producing an estimated total of 3800 kg CO2e/capita in 2010, with cities directly influencing approximately two-thirds of food sector GHG emissions. We then assess the potential for cities to reduce emissions through selected measures; examples include up-scaling urban agriculture and home delivery of grocery options, which each may achieve emissions reductions on the order of 0.4 and ~1% of this total, respectively. Meanwhile, changes in waste management practices and reduction of postdistribution food waste by 50% reduce total food sector emissions by 5 and 11%, respectively. Consideration of the scale of benefits achievable through policy goals can enable cities to formulate strategies that will assist in achieving deep long-term GHG emissions targets. PMID- 29717608 TI - Correction to Understanding Mechanisms of Synergy between Acidification and Ultrasound Treatments for Activated Sludge Dewatering: From Bench to Pilot-Scale Investigation. PMID- 29717607 TI - Enantioselective Halolactonization Reactions using BINOL-Derived Bifunctional Catalysts: Methodology, Diversification, and Applications. AB - A general protocol is described for inducing enantioselective halolactonizations of unsaturated carboxylic acids using novel bifunctional organic catalysts derived from a chiral binaphthalene scaffold. Bromo- and iodolactonization reactions of diversely substituted, unsaturated carboxylic acids proceed with high degrees of enantioselectivity, regioselectivity, and diastereoselectivity. Notably, these BINOL-derived catalysts are the first to induce the bromo- and iodolactonizations of 5-alkyl-4( Z)-olefinic acids via 5- exo mode cyclizations to give lactones in which new carbon-halogen bonds are created at a stereogenic center with high diastereo- and enantioselectivities. Iodolactonizations of 6 substituted-5( Z)-olefinic acids also occur via 6- exo cyclizations to provide delta-lactones with excellent enantioselectivities. Several notable applications of this halolactonization methodology were developed for desymmetrization, kinetic resolution, and epoxidation of Z-alkenes. The utility of these reactions is demonstrated by their application to a synthesis of precursors of the F-ring subunit of kibdelone C and to the shortest catalytic, enantioselective synthesis of (+)-disparlure reported to date. PMID- 29717609 TI - Spontaneous Assembly of Rotaxanes from a Primary Amine, Crown Ether and Electrophile. AB - We report the synthesis of crown ether-ammonium, amide and amine [2]rotaxanes via transition state stabilization of axle-forming reactions. In contrast to the two step "clipping" and "capping" strategies generally used for rotaxane synthesis, here the components assemble into the interlocked molecule in a single, reagent less, step under kinetic control. The crown ether accelerates the reaction of the axle-forming components through the cavity to give the threaded product in a form of metal-free active template synthesis. Rotaxane formation can proceed through the stabilization of different transition states featuring 5-coordinate (e.g., SN2) or 4-coordinate (e.g., acylation, Michael addition) carbon. Examples prepared using the approach include crown-ether-peptide rotaxanes and switchable molecular shuttles. PMID- 29717610 TI - Correction to Dinuclear PhotoCORMs: Dioxygen-Assisted Carbon Monoxide Uncaging from Long-Wavelength-Absorbing Metal-Metal-Bonded Carbonyl Complexes. PMID- 29717611 TI - Oxy-Alkylation of Allylamines with Unactivated Alkyl Bromides and CO2 via Visible Light-Driven Palladium Catalysis. AB - A selective oxy-alkylation of allylamines with unactivated alkyl bromides and CO2 via visible-light-driven palladium catalysis is reported. The commercially available Pd(PPh3)4 is used as the sole catalyst in this three-component reaction. A variety of tertiary, secondary, and primary alkyl bromides undergo reactions to generate important 2-oxazolidinones in high yields and selectivity. The mild reaction conditions, easy scalability, and facile derivatization of products provide great potential for application in organic synthesis and pharmaceutical chemistry. PMID- 29717612 TI - Reorganization of Hydration Water of DPPC Multilamellar Vesicles Induced by l Cysteine Interaction. AB - The aim of this study is to analyze the consequences of water redistribution on the structure and stability of phospholipid bilayers induced by cysteine (Cys). This interaction is studied with 1,2-dipalmitoyl- sn-glycero-3 phosphatidylcholine (DPPC) multilamellar vesicles in gel (30 degrees C) and liquid crystalline (50 degrees C) state; experimental studies were performed by means of Fourier transform infrared (FTIR) spectroscopy, Raman spectroscopy, and differential scanning calorimetry (DSC). The polar head sites of the lipid molecules to which water can bind are identified by competition with compounds that form hydrogen bonds, such as Cys. FTIR spectroscopy results revealed that there is a Cys interaction with the phospholipid head groups in the gel and liquid crystalline phases. Raman spectra were measured in the gel state. They were dominated by vibrations of the fatty acyl chains, with superposition of a few bands from the head group, and clearly showed that the S-H stretching band of Cys shifted to lower frequencies with a decrease in its force constant. DSC disclosed an overview of the behavior of the multilamellar vesicles in the working temperature range (30-50 degrees C) and showed how the increase of the molar ratios modified the environment of the polar head and the hydrocarbon chains. A loss of the pretransition ( TP) and an increase in the temperature of main transition ( Tm) with increasing Cys/DPPC molar ratio were observed. PMID- 29717613 TI - Electrochemical Synthesis of Bisindolylmethanes from Indoles and Ethers. AB - An electrochemical bisindolylation of ethers was developed. Carried out under ambient conditions and in the absence of any chemical oxidants, this reaction exhibits a broad substrate scope and good functional group compatibility. PMID- 29717614 TI - I2-Mediated Oxidative C-N and N-S Bond Formation in Water: A Metal-Free Synthesis of 4,5-Disubstituted/N-Fused 3-Amino-1,2,4-triazoles and 3-Substituted 5-Amino 1,2,4-thiadiazoles. AB - An environmentally benign and convenient strategy for the synthesis of 4,5 disubstituted/N-fused 3-amino-1,2,4-triazoles and 3-substituted 5-amino-1,2,4 thiadiazoles from isothiocyanates has been developed. This metal-free method involves I2-mediated oxidative C-N and N-S bond formations in water. Furthermore, this facile protocol exhibited excellent substrate tolerance in good to high yields and scalable fashion. PMID- 29717615 TI - HIV-1-Induced miR-146a Attenuates Monocyte Migration by Targeting CCL5 in Human Primary Macrophages. AB - MicroRNAs (miRNAs) are widely involved in immune regulation during virus infection. Several studies showed that the expression of miR-146a was increased in human immunodeficiency virus type I (HIV-1)-infected cells, but the definitive function of miR-146a in HIV-1 infection remains obscure. The production of chemokine (C-C motif) ligand 5 (CCL5) in macrophages has been reported to play an important role in HIV/AIDS-associated pathogenesis. In this study, we examined the effects of miR-146a on CCL5 regulation in HIV-1-infected macrophages. Gain and loss of function studies showed that CCL5 might be one of the miR-146a targets, as miR-146a mimic reduced, while miR-146a inhibitor increased CCL5 production in HIV-1-infected macrophages. In addition, we demonstrated that miR 146a reduced CCL5-induced monocyte migration. Our study provided evidence that miR-146a targets CCL5 3' untranslated regions, downregulates its release from macrophages, and affects monocyte migration consequently. These findings drew a novel layer of posttranscriptional control of the chemokine CCL5 by miR-146a during HIV infection, which might contribute to HIV pathogenesis. PMID- 29717616 TI - Neighborhood Environment and Disparities in Health Care Access Among Urban Medicare Beneficiaries With Diabetes: A Retrospective Cohort Study. AB - Older adults' health is sensitive to variations in neighborhood environment, yet few studies have examined how neighborhood factors influence their health care access. This study examined whether neighborhood environmental factors help to explain racial and socioeconomic disparities in health care access and outcomes among urban older adults with diabetes. Data from 123 233 diabetic Medicare beneficiaries aged 65 years and older in New York City were geocoded to measures of neighborhood walkability, public transit access, and primary care supply. In 2008, 6.4% had no office-based "evaluation and management" (E&M) visits. Multilevel logistic regression indicated that this group had greater odds of preventable hospitalization in 2009 (odds ratio = 1.31; 95% confidence interval: 1.22-1.40). Nonwhites and low-income individuals had greater odds of a lapse in E&M visits and of preventable hospitalization. Neighborhood factors did not help to explain these disparities. Further research is needed on the mechanisms underlying these disparities and older adults' ability to navigate health care. Even in an insured population living in a provider-dense city, targeted interventions may be needed to overcome barriers to chronic illness care for older adults in the community. PMID- 29717617 TI - Selegiline Nanoformulation in Attenuation of Oxidative Stress and Upregulation of Dopamine in the Brain for the Treatment of Parkinson's Disease. AB - Objective of this study was to determine whether the prepared nanoemulsion would be able to deliver selegiline to the brain by intranasal route, improving its bioavailability. Antioxidant activity, pharmacokinetic parameters, and dopamine concentration were determined. Oxidative stress models, which had Parkinson's disease-like symptoms, were used to evaluate the antioxidant activity of nanoemulsion loaded with selegiline in vivo. The antioxidant activity was evaluated by 1,1-diphenyl-2-picryl-hydrazyl (DPPH) assay and reducing power assay, which showed high scavenging efficiency for selegiline nanoemulsion compared to pure selegiline. Biochemical estimation results showed that the levels of antioxidant enzymes, including glutathione and superoxide dismutase, were increased, whereas the levels of thiobarbituric acid-reactive substances were decreased in intranasally administered selegiline nanoemulsion-treated group when compared with haloperidol-induced Parkinson's disease group (control). Moreover, selegiline nanoemulsion was found to be successful in decreasing the dopamine loss, indicating that nanoemulsion is a potential approach for intranasal delivery of selegiline to decrease the damage due to free radicals, thus avoiding consequent biochemical alterations that arise during Parkinson's disease. Brain:blood ratio of 2.207 > 0.093 of selegiline-loaded nanoemulsion (intranasally administered) > selegiline solution (administered intravenously), respectively, at 0.5 hours showed direct nose-to-brain delivery of drug bypassing blood-brain barrier. Selegiline-loaded nanoemulsion administered intranasally showed significantly high dopamine concentration (16.61 +/- 3.06 ng/mL) compared to haloperidol-treated rats (8.59 +/- 1.00 ng/mL) (p < 0.05). In this way, intranasal delivery of selegiline nanoemulsion might play an important role in the better management of Parkinson's disease. PMID- 29717618 TI - Glucocorticoid Signaling Enhances Expression of Glucose-Sensing Molecules in Immature Pancreatic Beta-Like Cells Derived from Murine Embryonic Stem Cells In Vitro. AB - Pluripotent stem cells may serve as an alternative source of beta-like cells for replacement therapy of type 1 diabetes; however, the beta-like cells generated in many differentiation protocols are immature. The maturation of endogenous beta cells involves an increase in insulin expression starting in late gestation and a gradual acquisition of the abilities to sense glucose and secrete insulin by week 2 after birth in mice; however, what molecules regulate these maturation processes are incompletely known. In this study, we aim to identify small molecules that affect immature beta cells. A cell-based assay, using pancreatic beta-like cells derived from murine embryonic stem (ES) cells harboring a transgene containing an insulin 1-promoter driven enhanced green fluorescent protein reporter, was used to screen a compound library (NIH Clinical Collection 003). Cortisone, a glucocorticoid, was among five positive hit compounds. Quantitative reverse transcription-polymerase chain reaction analysis revealed that glucocorticoids enhance the gene expression of not only insulin 1 but also glucose transporter-2 (Glut2; Slc2a2) and glucokinase (Gck), two molecules important for glucose sensing. Mifepristone, a pharmacological inhibitor of glucocorticoid receptor (GR) signaling, reduced the effects of glucocorticoids on Glut2 and Gck expression. The effects of glucocorticoids on ES-derived cells were further validated in immature primary islets. Isolated islets from 1-week-old mice had an increased Glut2 and Gck expression in response to a 4-day treatment of exogenous hydrocortisone in vitro. Gene deletion of GR in beta cells using rat insulin 2 promoter-driven Cre crossed with GRflox/flox mice resulted in a reduced gene expression of Glut2, but not Gck, and an abrogation of insulin secretion when islets were incubated in 0.5 mM d-glucose and stimulated by 17 mM d-glucose in vitro. These results demonstrate that glucocorticoids positively regulate glucose sensors in immature murine beta-like cells. PMID- 29717619 TI - Aligned Nanofibrillar Scaffolds for Controlled Delivery of Modified mRNA. AB - RNA-based vector delivery is a promising gene therapy approach. Recent advances in chemical modification of mRNA structure to form modified mRNA (mmRNA or cmRNA or modRNA) have substantially improved their stability and translational efficiency within cells. However, mmRNA conventionally delivered in solution can be taken up nonspecifically or become cleared away prematurely, which markedly limits the potential benefit of mmRNA therapy. To address this limitation, we developed mmRNA-incorporated nanofibrillar scaffolds that could target spatially localized delivery and temporally controlled release of the mmRNA both in vitro and in vivo. To establish the efficacy of mmRNA therapy, mmRNA encoding reporter proteins such as green fluorescence protein or firefly luciferase (Fluc) was loaded into aligned nanofibrillar collagen scaffolds. The mmRNA was released from mmRNA-loaded scaffolds in a transient and temporally controlled manner and induced transfection of human fibroblasts in a dose-dependent manner. In vitro transfection was further verified using mmRNA encoding the angiogenic growth factor, hepatocyte growth factor (HGF). Finally, scaffold-based delivery of HGF mmRNA to the site of surgically induced muscle injury in mice resulted in significantly higher vascular regeneration after 14 days, compared to implantation of Fluc mmRNA-releasing scaffolds. After transfection with Fluc mmRNA-releasing scaffold in vivo, Fluc activity was detectable and localized to the muscle region, based on noninvasive bioluminescence imaging. Scaffold-based local mmRNA delivery as an off-the-shelf form of gene therapy has broad translatability for treating a wide range of diseases or injuries. PMID- 29717620 TI - Age-Related Differences in Diagnostic Accuracy of Plasma Glial Fibrillary Acidic Protein and Tau for Identifying Acute Intracranial Trauma on Computed Tomography: A TRACK-TBI Study. AB - Plasma tau and glial fibrillary acidic protein (GFAP) are promising biomarkers for identifying traumatic brain injury (TBI) patients with intracranial trauma on computed tomography (CT). Accuracy in older adults with mild TBI (mTBI), the fastest growing TBI population, is unknown. Our aim was to assess for age-related differences in diagnostic accuracy of plasma tau and GFAP for identifying intracranial trauma on CT. Samples from 169 patients (age <40 years [n = 79], age 40-59 years [n = 60], age 60 years+ [n = 30]), a subset of patients from the Transforming Research and Clinical Knowledge in TBI (TRACK-TBI) Pilot study who presented with mTBI (Glasgow Coma Scale score of 13-15), received head CT, and consented to blood draw within 24 h of injury, were assayed for hyperphosphorylated-tau (P-tau), total-tau (T-tau; both via amplification-linked enhanced immunoassay using multi-arrayed fiberoptics), and GFAP (via sandwich enzyme-linked immunosorbent assay). P-tau, T-tau, P-tau:T-tau ratio, and GFAP concentration were significantly associated with CT findings. Overall, discriminative ability declined with increasing age for all assays, but this decline was only statistically significant for GFAP (area under the receiver operating characteristic curve [AUC]: old 0.73 [reference group; ref] vs. young 0.93 [p = 0.037] or middle-aged 0.92 [p = 0.0497]). P-tau concentration consistently showed the highest diagnostic accuracy across all age-groups (AUC: old 0.84 [ref] vs. young 0.95 [p = 0.274] or middle-aged 0.93 [p = 0.367]). Comparison of models including P-tau alone versus P-tau plus GFAP revealed significant added value of GFAP. In conclusion, the GFAP assay was less accurate for identifying intracranial trauma on CT among older versus younger mTBI patients. Mechanisms of this age-related difference, including role of assay methodology, specific TBI neuroanatomy, pre-existing conditions, and anti thrombotic use, warrant further study. PMID- 29717622 TI - A cross-sectional study of family caregiver burden and psychological distress linked to frailty and functional dependency of a relative with advanced dementia. AB - Psychological health of caregivers of people with dementia is a major public concern. This study sought to determine the relationship between caregiver burden, psychological distress, frailty and functional dependency of a relative with advanced dementia. Persons with dementia and their caregivers (102 dyads) participated in this Portuguese community based cross-sectional study. Data were collected using the Clinical Dementia Rating Scale, a sociodemographic questionnaire, the Zarit Burden Interview, the Brief Symptoms Inventory and the Edmonton Frail Scale. Alzheimer's disease was the most common type of dementia among the recipients of care, who showed moderate (42.2%) to severe (52.9%) dementia. Among them 35.3% exhibited moderate and 45.1% severe frailty. Family caregivers reported moderate (76.5%) to severe burden (18.6%). Psychological distress was very high among family caregivers. Results show that people with dementia exhibited moderate (35.3%) or severe frailty (45.1%) and that a severe frailty was found in people with moderate dementia. A one-way ANOVA was conducted between the Global Severity Index and some sociodemographic variables. ANOVA reached p < .01 for employment status of the caregiver, assistance and professional support, and psychiatric history; and p = 0.01 for caregiver age and years of caregiving. Although caregivers reported benefit from the supportive approach offered by the multidisciplinary home care team, high levels of distress and associated burden were found, which might decrease their capacity to care for the person with dementia and their own health and well-being. PMID- 29717621 TI - Online insomnia treatment and the reduction of anxiety symptoms as a secondary outcome in a randomised controlled trial: The role of cognitive-behavioural factors. AB - OBJECTIVE:: Insomnia and anxiety commonly co-occur, yet the mechanisms underlying this remain unclear. The current paper describes the impact of an Internet-based intervention for insomnia on anxiety, and explores the influence of two cognitive behavioural constructs - dysfunctional beliefs about sleep and sleep-threat monitoring. METHODS:: A large-scale, 9-week, two-arm randomised controlled trial ( N = 1149) of community-dwelling Australian adults with insomnia and elevated yet subclinical depression symptoms was conducted, comparing a cognitive behavioural therapy-based online intervention for insomnia (Sleep Healthy Using The Internet) with an attention-matched online control intervention (HealthWatch). Symptoms of anxiety were assessed at pretest, posttest, and 6 month follow-up. Dysfunctional beliefs about sleep and sleep threat monitoring were assessed only at pretest. RESULTS:: Sleep Healthy Using The Internet led to a greater reduction in anxiety symptoms at both posttest ( t724.27 = -6.77, p < 0.001) and at 6-month follow-up ( t700.67 = -4.27, p < 0.001) than HealthWatch. At posttest and follow-up, this effect was found to moderated by sleep-threat monitoring ( t713.69 = -2.39, p < 0.05 and t694.77 = -2.98, p < 0.01 respectively) but not by dysfunctional beliefs about sleep at either posttest or follow-up ( t717.53 = -0.61, p = 0.55 and t683.79 = 0.22, p = 0.83 respectively). Participants in the Sleep Healthy Using The Internet condition with higher levels of sleep-threat monitoring showed a greater reduction in anxiety than those with lower levels from pretest to posttest, ( t724.27 = -6.77, p < 0.001) and through to 6-month follow-up ( t700.67 = -4.27, p < 0.001). This result remained after controlling for baseline anxiety levels. CONCLUSION:: The findings suggest that online cognitive behavioral therapy interventions for insomnia are beneficial for reducing anxiety regardless of people's beliefs about their sleep and insomnia, and this is particularly the case for those with high sleep-threat monitoring. This study also provides further evidence for cognitive models of insomnia. PMID- 29717623 TI - Aortic Sca-1+ Progenitor Cells Arise from the Somitic Mesoderm Lineage in Mice. AB - Sca-1+ progenitor cells in the adult mouse aorta are known to generate vascular smooth muscle cells (VSMCs), but their embryological origins and temporal abundance are not known. Using tamoxifen-inducible Myf5-CreER mice, we demonstrate that Sca-1+ adult aortic cells arise from the somitic mesoderm beginning at E8.5 and continue throughout somitogenesis. Myf5 lineage-derived Sca 1+ cells greatly expand in situ, starting at 4 weeks of age, and become a major source of aortic Sca-1+ cells by 6 weeks of age. Myf5-derived adult aortic cells are capable of forming multicellular sphere-like structures in vitro and express the pluripotency marker Sox2. Exposure to transforming growth factor-beta3 induces these spheres to differentiate into calponin-expressing VSMCs. Pulse chase experiments using tamoxifen-inducible Sox2-CreERT2 mice at 8 weeks of age demonstrate that ~35% of all adult aortic Sca-1+ cells are derived from Sox2+ cells. The present study demonstrates that aortic Sca-1+ progenitor cells are derived from the somitic mesoderm formed at the earliest stages of somitogenesis and from Sox2-expressing progenitors in adult mice. PMID- 29717624 TI - Chondrogenic Differentiation Processes in Human Bone-Marrow Aspirates Seeded in Three-Dimensional-Woven Poly(E-Caprolactone) Scaffolds Enhanced by Recombinant Adeno-Associated Virus-Mediated SOX9 Gene Transfer. AB - Combining gene therapy approaches with tissue engineering procedures is an active area of translational research for the effective treatment of articular cartilage lesions, especially to target chondrogenic progenitor cells such as those derived from the bone marrow. This study evaluated the effect of genetically modifying concentrated human mesenchymal stem cells from bone marrow to induce chondrogenesis by recombinant adeno-associated virus (rAAV) vector gene transfer of the sex-determining region Y-type high-mobility group box 9 (SOX9) factor upon seeding in three-dimensional-woven poly(E-caprolactone; PCL) scaffolds that provide mechanical properties mimicking those of native articular cartilage. Prolonged, effective SOX9 expression was reported in the constructs for at least 21 days, the longest time point evaluated, leading to enhanced metabolic and chondrogenic activities relative to the control conditions (reporter lacZ gene transfer or absence of vector treatment) but without affecting the proliferative activities in the samples. The application of the rAAV SOX9 vector also prevented undesirable hypertrophic and terminal differentiation in the seeded concentrates. As bone marrow is readily accessible during surgery, such findings reveal the therapeutic potential of providing rAAV-modified marrow concentrates within three dimensional-woven PCL scaffolds for repair of focal cartilage lesions. PMID- 29717627 TI - Use of an anionic surfactant for the sorption of a binary mixture of antibiotics from aqueous solutions. AB - Amoxicillin (AMX) and ampicillin (AMP) are two representative beta-lactam antibiotics that have been used extensively in human and veterinary medicine and have gained increasing attention due to their continual introduction to the environment which would pose serious ecological risk. The present work investigates the feasibility of the removal of AMX and AMP antibiotics produced by SAIDAL, antibiotical company from aqueous solutions. To this end, a novel separation technique based on an aqueous surfactant extraction has been developed for the treatment of a complex medium consisting of a mixture of antibiotics amoxicillin and ampicillin using an anionic surfactant namely Sodium Dodecyl Sulphate (SDS). The efficiency of the applied treatment was evaluated by HPLC analysis. The main parameters influencing the process have been investigated such as: contact time, agitation speed, temperature, pH, initial effluents concentration and surfactant concentration. The results obtained confirm the proposed technique. Thus, a removal rate of 59.76% of ampicillin and 72.73% of amoxicillin was achieved under optimum conditions (contact time of 40 min, agitation speed of 350 rpm, temperature of 40 degrees C, pH 4, initial antibiotics concentration of 20 and 10 mg/L of SDS). The thermodynamic parameters obtained (DeltaGAMX = 2.6 kcal/mol, DeltaGAMP = -2.37 kcal/mol, DeltaHAMX = 4.51 kcal/mol, DeltaHAMP = 5.47 kcal/mol K, DeltaSAMX = 24.28 kcal/mol K and DeltaSAMP = 26.75 kcal/mol K) showed that the process is feasible, spontaneous and endothermic. PMID- 29717626 TI - The Moderating Effect of the Ankyrin Repeat and Kinase Domain Containing One Gene on the Association of Family Environment with Longitudinal Executive Function following Traumatic Brain Injury in Early Childhood: A Preliminary Study. AB - This study examined whether the ankyrin repeat and kinase domain containing 1 gene (ANKK1) C/T single-nucleotide polymorphism (SNP) rs1800497 moderated the association of family environment with long-term executive function (EF) following traumatic injury in early childhood. Caregivers of children with traumatic brain injury (TBI) and children with orthopedic injury completed the Behavior Rating Inventory of Executive Function (BRIEF) at post-injury visits. DNA was collected to identify the rs1800497 genotype in the ANKK1 gene. General linear models examined gene-environment interactions as moderators of the effects of TBI on EF at two times post-injury (12 months and 7 years). At 12 months post injury, analyses revealed a significant three-way interaction of genotype with level of permissive parenting and injury type. Post hoc analyses showed genetic effects were more pronounced for children with TBI from more positive family environments, such that children with TBI who were carriers of the risk allele (T allele) had significantly poorer EF compared with non-carriers only when they were from more advantaged environments. At 7 years post-injury, analyses revealed a significant two-way interaction of genotype with level of authoritarian parenting. Post hoc analyses found that carriers of the risk allele had significantly poorer EF compared with non-carriers only when they were from more advantaged environments. These results suggest a gene-environment interaction involving the ANKK1 gene as a predictor of EF in a pediatric injury population. The findings highlight the importance of considering environmental influences in future genetic studies on recovery following TBI and other traumatic injuries in childhood. PMID- 29717625 TI - Remote Changes in Cortical Excitability after Experimental Traumatic Brain Injury and Functional Reorganization. AB - Although cognitive and behavioral deficits are well known to occur following traumatic brain injury (TBI), motor deficits that occur even after mild trauma are far less known, yet are equally persistent. This study was aimed at making progress toward determining how the brain reorganizes in response to TBI. We used the adult rat controlled cortical impact injury model to study the ipsilesional forelimb map evoked by electrical stimulation of the affected limb, as well as the contralesional forelimb map evoked by stimulation of the unaffected limb, both before injury and at 1, 2, 3, and 4 weeks after using functional magnetic resonance imaging (fMRI). End-point c-FOS immunohistochemistry data following 1 h of constant stimulation of the unaffected limb were acquired in the same rats to avoid any potential confounds due to altered cerebrovascular coupling. Single and paired-pulse sensory evoked potential (SEP) data were recorded from skull electrodes over the contralesional cortex in a parallel series of rats before injury, at 3 days, and at 1, 2, 3, and 4 weeks after injury in order to determine whether alterations in cortical excitability accompanied reorganization of the cortical map. The results show a transient trans-hemispheric shift in the ipsilesional cortical map as indicated by fMRI, remote contralesional increases in cortical excitability that occur in spatially similar regions to altered fMRI activity and greater c-FOS activation, and reduced or absent ipsilesional cortical activity chronically. The contralesional changes also were indicated by reduced SEP latency within 3 days after injury, but not by blood oxygenation level-dependent fMRI until much later. Detailed interrogation of cortical excitability using paired-pulse electrophysiology showed that the contralesional cortex undergoes both an early and a late post-injury period of hyper excitability in response to injury, interspersed by a period of relatively normal activity. From these data, we postulate a cross-hemispheric mechanism by which remote cortex excitability inhibits ipsilesional activation by rebalanced cortical excitation-inhibition. PMID- 29717628 TI - Adipose-derived stem-cell-implanted poly(epsilon-caprolactone)/chitosan scaffold improves bladder regeneration in a rat model. AB - AIM: The study investigated the feasibility of seeding adipose-derived stem cells (ASCs) onto a poly(epsilon-caprolactone)/chitosan (PCL/CS) scaffold for bladder reconstruction using a rat model of bladder augmentation. MATERIALS & METHODS: In the experimental group, the autologous ASCs were seeded onto the PCL/CS scaffold for bladder augmentation. An unseeded scaffold was used for bladder augmentation as control group. The sham group was also set. RESULT: 8 weeks after implantation, more densely smooth muscles were detected in the experimental group with a larger bladder capacity and more intensive blood vessels. Immunofluorescence staining demonstrated that some of the smooth muscle cells were transdifferentiated from the ASCs. CONCLUSION: Our findings indicated that ASC-seeded PCL/CS may be a potential scaffold for bladder tissue engineering. PMID- 29717629 TI - A Comparative Study of the Effects of Nigella sativa Oil Gel and Aloe Vera Gel on Wound Healing in Diabetic Rats. AB - Clinicians and wound care nurses in Indonesia usually use Nigella sativa oil (NSO) gel and aloe vera (AV) gel to treat diabetic ulcers. However, there are no studies directly comparing the effects of NSO and AV gels on wound healing, so it is unknown which of these 2 plants is better at promoting wound healing in diabetic ulcers. If the comparative efficacy between these 2 gels was known, it would be important evidence favoring the clinical use of one or the other product in Indonesia. The aim of this study was to investigate and compare the effectiveness of NSO and AV gels on wound healing in a rat model of diabetic ulcers. This experimental study involved 3 groups: NSO gel, AV gel, and controls. Our study showed that from day 5 onward, necrotic tissue and inflammation decreased in the AV gel group compared with the other groups. The wound areas on days 6 ( P = .020) and 7 ( P = .021) were significantly smaller in the AV gel group than in the NSO gel group. Reepithelialization was also better in the AV gel group than in the other groups. This is the first study to compare the effects of AV and NSO gels on wound healing in diabetic ulcers. Our study indicates that the AV gel is better than the NSO gel. Therefore, it is recommended that clinicians and wound care nurses use AV gel instead of NSO gel for the topical treatment of diabetic ulcers. PMID- 29717630 TI - Knowledge and causal attributions for mental disorders in HIV-positive children and adolescents: results from rural and urban Uganda. AB - Increasing availability of antiretroviral treatment (ART) has led HIV to be considered a chronic disease, shifting attention to focus on quality of life including mental wellbeing. We investigated knowledge and causal attributions for mental disorders in HIV-positive children and adolescents in rural and urban Uganda. This qualitative study was nested in an epidemiological mental health study among HIV-positive children and adolescents aged 5-17 years in rural and urban Uganda. In-depth interviews were conducted with caregivers of HIV-positive children (5-11 years) and adolescents (12-17 years) in HIV care. Interviews were audio recorded with permission from participants and written consent and assent sought before study procedures. Thirty eight participants (19 caregivers, 19 children/adolescents) were interviewed. Age range of caregivers was 28-69 years; majority were female (17). Caregivers had little knowledge on mental disorders ;only 3 related the vignette to a mental problem and attributed it to: improper upbringing, violence, poverty and bereavement. Five adolescents identified vignettes as portraying mental disorders caused by: ill-health of parents, bereavement, child abuse, discrimination, HIV and poverty. Caregivers are not knowledgeable about behavioural and emotional challenges in HIV-positive children/adolescents. Mental health literacy programmes at HIV care clinics are essential to enhance treatment-seeking for mental health. PMID- 29717631 TI - Hypoxia and Reactive Oxygen Species as Modulators of Endoplasmic Reticulum and Golgi Homeostasis. AB - SIGNIFICANCE: Eukaryotic cells execute various functions in subcellular compartments or organelles for which cellular redox homeostasis is of importance. Apart from mitochondria, hypoxia and stress-mediated formation of reactive oxygen species (ROS) were shown to modulate endoplasmic reticulum (ER) and Golgi apparatus (GA) functions. Recent Advances: Research during the last decade has improved our understanding of disulfide bond formation, protein glycosylation and secretion, as well as pH and redox homeostasis in the ER and GA. Thus, oxygen (O2) itself, NADPH oxidase (NOX) formed ROS, and pH changes appear to be of importance and indicate the intricate balance of intercompartmental communication. CRITICAL ISSUES: Although the interplay between hypoxia, ER stress, and Golgi function is evident, the existence of more than 20 protein disulfide isomerase family members and the relative mild phenotypes of, for example, endoplasmic reticulum oxidoreductin 1 (ERO1)- and NOX4-knockout mice clearly suggest the existence of redundant and alternative pathways, which remain largely elusive. FUTURE DIRECTIONS: The identification of these pathways and the key players involved in intercompartmental communication needs suitable animal models, genome-wide association, as well as proteomic studies in humans. The results of those studies will be beneficial for the understanding of the etiology of diseases such as type 2 diabetes, Alzheimer's disease, and cancer, which are associated with ROS, protein aggregation, and glycosylation defects. PMID- 29717632 TI - Ribbon-wise customized lingual appliance and orthodontic anchor screw for the treatment of skeletal high-angle maxillary protrusion without bowing effect. AB - This case report demonstrates the treatment of a skeletal Class II high-angle adult patient with bimaxillary protrusion, angle Class I occlusion, and crowded anterior teeth. A ribbon-wise arch wire and a customized lingual appliance with anterior vertical slots were used to achieve proper torque control of the maxillary anterior teeth. An orthodontic anchor screw and a palatal bar were used for vertical control to avoid increasing the Frankfort-mandibular plane angle (FMA) by maxillary molar extrusion. Through the combined use of the ribbon-wise customized lingual appliance, palatal bar, and orthodontic anchor screw, vertical control and an excellent treatment result were achieved without the vertical and horizontal bowing effects peculiar to conventional lingual treatment. PMID- 29717634 TI - Notch Signaling Enhances Stemness by Regulating Metabolic Pathways Through Modifying p53, NF-kappaB, and HIF-1alpha. AB - Human adipose-derived mesenchymal stromal cells (hASCs) are attractive for regenerative medicine, but their limited in vitro life span limits their therapeutic applicability. Recent data demonstrate that hypoxia may benefit the ex vivo culture of stem cells. Such cells exhibit a high level of glycolytic metabolism under hypoxic conditions. However, the physiological role of glycolytic activation and its underlying regulatory mechanism are incompletely understood. We have shown that when activated under conditions of 5% O2, Notch signaling dramatically increases the rate of glycolysis, improves proliferation efficiency, prevents senescence, and maintains the multipotency of hASCs. In the present study, we found that activated Notch1 enhanced nuclear p65 levels, resulting in an increase in glucose metabolism through the upregulation of glycolytic factors, including GLUT3. Notch signaling was also involved in glucose metabolism through p53 inactivation. We also found that NF-kappaB signaling was regulated by p53. These data suggest that Notch-HES1 signaling enhances the glycolytic pathway through p53 and NF-kappaB. Our data also revealed that activated Notch1 markedly increased the transcriptional activity of hypoxia inducible factor 1 (HIF-1). Knockdown of HIF-1alpha significantly attenuated glycolysis induced by activated Notch1, indicating that the glycolysis pathway is regulated by the coordination of Notch signaling and HIF. Overall, our observations provide new regulatory mechanisms for the glycolysis by Notch signaling to maintain the stemness of hASCs. PMID- 29717635 TI - Sexual and gender minority health in medical curricula in new England: a pilot study of medical student comfort, competence and perception of curricula. AB - BACKGROUND: Sexual and gender minority (SGM) individuals experience high rates of harassment and discrimination when seeking healthcare, which contributes to substantial healthcare disparities. Improving physician training about gender identity, sexual orientation, and the healthcare needs of SGM patients has been identified as a critical strategy for mitigating these disparities. In 2014, the Association of American Medical Colleges (AAMC) published medical education competencies to guide undergraduate medical education on SGM topics. OBJECTIVE: Conduct pilot study to investigate medical student comfort and competence about SGM health competencies outlined by the AAMC and evaluate curricular coverage of SGM topics. DESIGN: Six-hundred and fifty-eight students at New England allopathic medical schools (response rate 21.2%) completed an anonymous, online survey evaluating self-reported comfort and competence regarding SGM health competencies, and coverage of SGM health in the medical curriculum. RESULTS: 92.7% of students felt somewhat or very comfortable treating sexual minorities; 68.4% felt comfortable treating gender minorities. Most respondents felt not competent or somewhat not competent with medical treatment of gender minority patients (76.7%) and patients with a difference of sex development (81%). At seven schools, more than 50% of students indicated that the curriculum neither adequately covers SGM-specific topics nor adequately prepares students to serve SGM patients. CONCLUSIONS: The prevalence of self-reported comfort is greater than that of self-reported competence serving SGM patients in a convenience sample of New England allopathic medical students. The majority of participants reported insufficient curricular preparation to achieve the competencies necessary to care for SGM patients. This multi-institution pilot study provides preliminary evidence that further curriculum development may be needed to enable medical students to achieve core competencies in SGM health, as defined by AAMC. Further mixed methods research is necessary to substantiate and expand upon the findings of this pilot study. This pilot study also demonstrates the importance of creating specific evaluation tools to assess medical student achievement of competencies established by the AAMC. PMID- 29717636 TI - Importance of cardiovascular examination in patients with multiple lentigines: two cases of LEOPARD syndrome with hypertrophic cardiomyopathy. AB - Introduction LEOPARD syndrome is a rare genetic disorder characterised by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonary stenosis, abnormal genitalia, retardation of growth and sensorineural deafness. Clinical manifestations are often mild, which may result in difficult and late diagnosis. Cardiac involvement may have a significant impact on the prognosis, however, appearance of severe abnormalities such as hypertrophic cardiomyopathy usually precedes the occurrence of multiple lentigines and may be asymptomatic. Case presentation We report two cases of LEOPARD syndrome with hypertrophic cardiomyopathy in a 10-year-old girl and an 18-year-old boy. In both cases, multiple lentigines, ocular hypertelorism and growth retardation were present. The first patient was followed up at the paediatric cardiology clinic due to the risk of progression of septal hypertrophy and pressure gradient across the left ventricular outflow tract, the second patient underwent surgery for a moderate obstruction of the left ventricular outflow tract with uncomplicated post-operative follow-up. Conclusion In both presented patients, hypertrophic cardiomyopathy was clinically silent and the murmur over the precordium was the sole cardiac abnormality revealed during routine visit. A detailed cardiologic examination should be considered in the patients with suspicion of LEOPARD syndrome since the ventricular hypertrophy is thought to precede the occurrence of lentigines and progress over time. PMID- 29717637 TI - Validation of a radioimmunoassay of serum trypsin-like immunoreactivity in ferrets. AB - Measurement of serum trypsin-like immunoreactivity (TLI) is used to assess exocrine pancreatic function in dogs and cats. Ferrets ( Mustela putorius furo) serve as valuable animal models for human diseases such as cystic fibrosis and other pulmonary diseases, and may be a useful model of other diseases including pancreatitis. We developed and analytically validated a competitive radioimmunoassay (RIA) for measurement of TLI in ferret serum by determination of analytical sensitivity, assay linearity, accuracy of spiking recovery, precision, and reproducibility. Analytical sensitivity of the assay was 0.55 MUg/L. Observed to-expected (O/E) ratio for dilutional parallelism was 90.2-127.9% (mean: 108.1 +/- 11.9%). The O/E ratio for spiking recovery was 94.5-113.0% (mean: 103.9 +/- 7.2%). The intra- and inter-assay coefficients of variation (CVs) were 2.7-5.7% and 3.5-8.2%, respectively. The reference interval (RI) for serum TLI derived from 31 healthy ferrets was 28-115 MUg/L; the 90% confidence interval for the lower and upper limits of the RI were 10.0-32.1 MUg/L and 103-126 MUg/L, respectively. This TLI RIA is analytically sensitive, sufficiently linear, accurate, precise, and reproducible for the measurement of TLI in ferret serum samples. PMID- 29717638 TI - Fatal bromethalin intoxication in 3 cats and 2 dogs with minimal or no histologic central nervous system spongiform change. AB - Use of the neurotoxic rodenticide bromethalin has steadily increased since 2011, resulting in an increased incidence of bromethalin intoxications in pets. Presumptive diagnosis of bromethalin toxicosis relies on history of possible rodenticide exposure coupled with compatible neurologic signs or sudden death, and postmortem examination findings that eliminate other causes of death. Diagnosis is confirmed by detecting the metabolite desmethylbromethalin (DMB) in tissues. In experimental models, spongiform change in white matter of the central nervous system (CNS) is the hallmark histologic feature of bromethalin poisoning. We describe fatal bromethalin intoxication in 3 cats and 2 dogs with equivocal or no CNS white matter spongiform change, illustrating that the lesions described in models can be absent in clinical cases of bromethalin intoxication. Cases with history and clinical signs compatible with bromethalin intoxication warrant tissue analysis for DMB even when CNS lesions are not evident. PMID- 29717640 TI - Differentiation of Brachyspira spp. isolated from laying hens using PCR-based methods and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - Avian intestinal spirochetosis (AIS), an important but neglected disease in laying hens, is caused by Brachyspira pilosicoli, B. intermedia, and B. alvinipulli. Poultry are also frequently colonized by putatively nonpathogenic species such as B. murdochii and B. innocens. We evaluated the differentiation of Brachyspira species by 3 methods: sequencing of the reduced nicotinamide adenine dinucleotide (NADH) oxidase gene ( nox), matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), and a new multiplex (m)PCR targeting genes such as the tryptophanase A gene ( tnaA) and the p-aminobenzoyl-glutamate hydrolase subunit B gene ( abgB). Sequencing of 414 bp of the nox PCR amplification products generated from 41 pure cultures of avian Brachyspira isolates allowed presumptive species identification in 33 isolates with at least 99% identity in basic local alignment search tool analysis, including B. pilosicoli, B. intermedia, B. murdochii, B. innocens, and " B. pulli". MALDI-TOF MS analysis was found to be a reliable tool for differentiation after extension of the manufacturer's database. In the mPCR, all isolates identified as B. pilosicoli and B. intermedia were positive for abgB and tnaA, respectively. The mPCR might be very useful in detecting Brachyspira species in mixed cultures including not only nonpathogenic species, such as B. innocens, but also one of the AIS pathogens. We found that MALDI-TOF MS analysis combined with the mPCR targeting tnaA and abgB was suitable for the identification of avian isolates of B. pilosicoli and B. intermedia, 2 important agents of AIS. PMID- 29717639 TI - Streptococcus equi subspecies zooepidemicus septicemia in alpacas: three cases and review of the literature. AB - Streptococcus equi subspecies zooepidemicus septicemia of alpacas and llamas, also called alpaca fever, is characterized clinically by fever, depression, recumbency, and death, and pathologically by polyserositis. Although a few natural and experimental cases of the disease have been reported, very little information about the pathology of spontaneous cases has been published. We present a detailed gross and microscopic description of 3 spontaneous cases of alpaca fever and review the literature on this condition. Typical of spontaneous and experimental infections with S. equi ssp. zooepidemicus, the 3 animals had disseminated fibrinosuppurative polyserositis with vascular thrombosis and intralesional gram-positive cocci. In addition, 2 of the animals had severe fibrinosuppurative pneumonia, endocarditis, and myocardial necrosis; the third animal had transmural pleocellular enteritis with prominent lymphangitis. The enteric lymphangitis observed in the latter suggests that dissemination of S. equi ssp. zooepidemicus occurred through lymphatic circulation and that, at least in this animal, the portal of entry of infection was the alimentary system. PMID- 29717641 TI - Eastern equine encephalitis in puppies in Michigan and New York states. AB - Eastern equine encephalitis virus (EEEV) is classified as a select agent and is capable of causing mortality in humans and a number of veterinary species. Herein, we describe 3 cases of EEE in puppies in Michigan and New York. Two puppies were euthanized following an acute history of seizures and obtundation. A littermate of one of these puppies died 2 wk earlier following a history of anorexia and fever. All 3 puppies lacked significant gross anatomic lesions at autopsy and tested negative for rabies virus. In all 3 puppies, histologic examination revealed necrotizing, neutrophilic, lymphoplasmacytic meningoencephalitis with strong positive immunohistochemical labeling for EEEV antigen in neurons and glial cells. The diagnosis of EEE was confirmed by PCR in one puppy and by plaque reduction neutralization testing in the other 2 dogs. EEE is rare in dogs, and has only been reported in puppies. The initial clinical signs of EEE in puppies are typically nonspecific, including anorexia, fever, and diarrhea, but rapidly progress to severe neurologic disease characterized by seizures and recumbency. Although rare, EEE should be considered as a differential diagnosis for neurologic disease in puppies, especially after more common diseases, such as canine distemper, rabies, and toxoplasmosis have been ruled out. PMID- 29717642 TI - Adiaspiromycosis in a wild European rabbit, and a review of the literature. AB - Adiaspiromycosis is a mycotic infection caused by thermally dimorphic fungi classified as Emmonsia parva and E. crescens (formerly Chrysosporium spp.) until recently, when new classifications were proposed. We document the pathologic findings in a severe case of adiaspiromycosis, with lymph node involvement, in a wild European rabbit ( Oryctolagus cuniculus). The rabbit exhibited granulomatous pneumonia with tracheobronchial lymph node enlargement. Histopathologically, the lung was expanded by myriad, densely cellular, heterophilic and granulomatous foci, surrounding bi- to trilaminar adiaspores. Adiaspore density was considered to be similar in all lung lobes. In the left caudal lung lobe, 80 adiaspores were counted in a 50-mm2 area using digital image analysis. The mean and median adiaspore diameters were 240 +/- 52 MUm and 255 MUm, respectively. Tracheobronchial lymph nodes exhibited moderate numbers of similar adiaspores. PCR amplification of DNA extracted from microdissected adiaspores failed to identify Emmonsia spp.-specific DNA. These data suggest that adiaspiromycosis may result in severe granulomatous pneumonia in wild European rabbits. Although confirmation of the etiologic agent by PCR using DNA extracted from formalin fixed tissue is not always successful, digital image analysis can be used to aid accurate assessment of adiaspore density and morphology. PMID- 29717644 TI - Surveiller l'observance des medicaments : les consequences pour les patients et les dispensateurs de soins. AB - La non-observance des medicaments est un enjeu mondial primordial qui peut etre responsable de resultats cliniques indesirables chez les patients et accroitre les couts pour le systeme de sante. Un processus facilitant la transmission d'avis de non-observance violerait-il l'autonomie individuelle ou les attentes en matiere de confidentialite? En revanche, les patients qui ne prennent pas leurs medicaments se rendent peut-etre a risque sans le savoir et sans que les prescripteurs en soient informes et puissent intervenir. Avec l'avenement des methodes electroniques de surveillance de l'observance des medicaments, un nouveau niveau de complexite s'ajoute a ce dilemme ethique. Les auteurs presentent deux scenarios observes en clinique, qui refletent des situations courantes au sein du systeme de sante canadien. PMID- 29717645 TI - Medication adherence monitoring: implications for patients and providers. AB - Non-adherence to medication is a key worldwide issue and can lead to adverse patient outcomes and increased health system costs. Would a process facilitating notification of non-adherence infringe upon the autonomy of individuals or breach expectations of privacy? In contrast, patients who are not taking their medication could unknowingly be putting themselves at risk and all the while prescribers are unaware and without the opportunity to intervene. With the advent of electronic methods of medication adherence monitoring, this ethical dilemma now involves a new layer of complexity. We present two scenarios encountered in clinical practice that reflect issues occurring regularly in the Canadian healthcare system. PMID- 29717643 TI - National Institute of Neurological Disorders and Stroke and Department of Defense Sport-Related Concussion Common Data Elements Version 1.0 Recommendations. AB - Through a partnership with the National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health, and Department of Defense, the development of Sport-Related Concussion (SRC) Common Data Elements (CDEs) was initiated. The aim of this collaboration was to increase the efficiency and effectiveness of clinical research studies and clinical treatment outcomes, increase data quality, facilitate data sharing across studies, reduce study start up time, more effectively aggregate information into metadata results, and educate new clinical investigators. The SRC CDE Working Group consisted of 32 worldwide experts in concussion from varied fields of related expertise divided into three Subgroups: Acute (<72 h post-concussion), Subacute (3 days-3 months post-concussion) and Persistent/Chronic (>3 months post-concussion). To develop CDEs, the Subgroups reviewed various domains, then selected from, refined, and added to existing CDEs, case report forms and field-tested data elements from national registries and funded research studies. Recommendations were posted to the NINDS CDE Website for Public Review from February 2017 to April 2017. Following an internal Working Group review of recommendations, along with consideration of comments received from the Public Review period, the first iteration (Version 1.0) of the NINDS SRC CDEs was completed in June 2017. The recommendations include Core and Supplemental-Highly Recommended CDEs for cognitive data elements and symptom checklists, as well as other outcomes and end points (e.g., vestibular, oculomotor, balance, anxiety, depression), and sample case report forms (e.g., injury reporting, demographics, concussion history) for domains typically included in clinical research studies. The NINDS SRC CDEs and supporting documents are publicly available on the NINDS CDE website www.commondataelements.ninds.nih.gov . Widespread use of CDEs by researchers and clinicians will facilitate consistent SRC clinical research and trial design, data sharing, and metadata retrospective analysis. PMID- 29717646 TI - Enhancing health leadership performance using neurotherapy. AB - The discovery of neuroplasticity means the brain can change, functionally, in response to the environment and to learning. While individuals can develop harmful patterns of brain activity in response to stressors, they can also learn to modify or control neurological conditions associated with specific behaviors. Neurotherapy is one way of changing brain functioning to modify troubling conditions which can impair leadership performance, through responding to feedback on their own brain activity, and enhancing optimal leadership functioning through learning to maximize such cognitive strengths as mental efficiency, focus, creativity, perseverance, and executive functioning. The present article outlines the application of the concept of optimal performance training to organizational leadership in a healthcare context, by describing approaches to neurotherapy and illustrating their application through a case study of a health leader learning to overcome the neurological and emotional sequelae of workplace stress and trauma. PMID- 29717647 TI - A three-step model of stress management for health leaders. AB - The current healthcare system is often as highly stressful environment for patients, their families, and for the employees of the system. Health leaders also experience stress, which can have profound repercussions if not well managed. This article describes the impact of stress on the brain and nervous system functioning of health leaders, then, drawing on evidence from the literature, presents a three-step model for managing stress at the individual, team/organizational, and system levels. PMID- 29717648 TI - Neuroleadership: Themes and limitations of an emerging interdisciplinary field. AB - The relationship between brain and behaviour has perplexed philosophers and scientists since the time of the ancient Greeks. Recent technological advances have allowed neuroscience to flourish, alongside growing romanticism that reductionist studies will allow us to understand complex interpersonal behaviours. Organizational cognitive neuroscience and neuroleadership are newly established interdisciplinary fields that use neuroscientific techniques to answer questions about behaviours within organizations. Neuroleadership aims to discover screening tools for good leaders, to improve leadership skills, and to identify unconscious factors affecting behaviour in hopes of improving management and leadership practices. Although proponents of neuroleadership are optimistic, if we know anything about the functions of the human brain and our interpersonal behaviours, it is that they are exquisitely complex and context dependant. Here, we briefly discuss the major themes emerging in the new field of neuroleadership and the limitations and potential consequences of applying findings from the field prematurely and with blind optimism. PMID- 29717649 TI - A neuroscience-based approach to changing organizational behaviour. AB - The greatest challenge in healthcare management is not identifying what changes are needed but actually changing behaviour on a long-term basis. Traditional approaches to organizational change are doomed to fail because they focus almost entirely on raising awareness. But countless studies show that the mere intention to change is not sufficient to reshape behaviour. In this article, we propose a new approach to organizational change informed by the principles of neuroleadership. The framework is called PHS: Priorities, Habits, Systems. The steps are as follows: (1) priorities: inform people about what changes are desired, (2) habits: teach people new habits, (3) systems: implement organizational systems to support and sustain new habits over the long term. By building solutions informed by the science of how the brain actually works, we believe organizations can bridge the intention behaviour gap and create lasting behaviour change. PMID- 29717650 TI - The shadows in healthcare leadership. AB - This article outlines personality traits such as psychopathy, narcissism, Machiavellianism, and sadism which, when elevated in health leaders, may have negative effects upon teams, the organizations they work for, and ultimately the public. The implications of such traits for specific core health leadership competency domains are explored as well as potential mitigation approaches to minimize and possibly redirect such personality traits. PMID- 29717651 TI - Efficacy and safety of first-line sunitinib in Chinese patients with metastatic renal cell carcinoma. AB - AIM: We report the first prospective study of sunitinib for metastatic renal cell carcinoma (mRCC) in China. METHODS: Chinese mRCC patients received first-line sunitinib 50 mg daily (4/2 regimen). Overall survival (OS), progression-free survival (PFS), objective response rate and safety were assessed. Potential efficacy biomarkers were explored in post hoc analyses. RESULTS: Median PFS was 61.7 weeks; median OS was 133.4 weeks; objective response rate was 31.1%. Most frequent adverse events (AEs) were: hand-foot syndrome (63.8%), decreased white blood cell count (52.4%), fatigue (51.4%) and decreased platelet count (51.4%). AEs were identified that predicted longer PFS and OS. CONCLUSION: Sunitinib showed efficacy and manageable AE profile in treatment-naive Chinese mRCC patients. Larger prospective studies are required to confirm identified AEs as predictors of efficacy. PMID- 29717652 TI - Training in Goal-Oriented Attention Self-Regulation Improves Executive Functioning in Veterans with Chronic Traumatic Brain Injury. AB - Deficits in executive control functions are some of the most common and disabling consequences of both military and civilian brain injury. However, effective interventions are scant. The goal of this study was to assess whether cognitive rehabilitation training that was successfully applied in chronic civilian brain injury would be effective for military veterans with traumatic brain injury (TBI). In a prior study, participants with chronic acquired brain injury significantly improved after training in Goal-Oriented Attentional Self Regulation (GOALS) on measures of attention/executive function, functional task performance, and goal-directed control over neural processing on functional magnetic resonance imaging. The objective of this study was to assess effects of GOALS training in veterans with chronic TBI. A total of 33 veterans with chronic TBI and executive difficulties in their daily life completed either 5 weeks of manualized GOALS training or Brain-Health Education (BHE) matched by time and intensity. Evaluator-blinded assessments at baseline and post-training included neuropsychological and complex functional task performance and self-report measures of emotional regulation. After GOALS, but not BHE training, participants significantly improved from baseline on primary outcome measures of Overall Complex Attention/Executive Function composite neuropsychological performance score (F = 7.10, p = 0.01; partial eta2 = 0.19), and on overall complex functional task performance (Goal Processing Scale Overall Performance; F = 6.92, p = 0.01, partial eta2 = 0.20). Additionally, post-GOALS participants indicated significant improvement on emotional regulation self-report measures (Profile of Mood States Confusion Score; F = 6.05, p = 0.02, partialeta2 = 0.20). Training in attentional self-regulation applied to participant-defined goals may improve cognitive functioning in veterans with chronic TBI. Attention regulation training may not only impact executive control functioning in real-world complex tasks, but also may improve emotional regulation and functioning. Implications for treatment of veterans with TBI are discussed. PMID- 29717653 TI - Double Carina: A Novel Tracheo-Bronchial Anomaly Found During a Pediatric Airway Evaluation. AB - OBJECTIVES: To present a novel pediatric airway anomaly encountered on direct laryngoscopy and bronchoscopy, further characterized with computed tomography imaging of the chest. STUDY DESIGN: Case report and literature review. METHODS: Review of the clinical presentation, operative findings, and imaging findings of an infant who presented with respiratory distress in the setting of multiple congenital abnormalities. A brief literature review supplements the case presentation. RESULTS: While multiple tracheobronchial anomalies have long been reported, this is the first report of a double or false carina: a system of symmetric paired upper and lower bronchi connected by a central conduit. Operative evaluation was limited given the narrow lumen, and postoperative imaging aided in further characterization of the pediatric airway. CONCLUSIONS: This is the first report of a novel tracheobronchial anomaly presenting as a double carina. Tracheobronchial anomalies are diverse and should be considered when performing operative airway evaluations. Imaging can be a helpful adjunct with anatomic characterization. PMID- 29717655 TI - Hypoxia-Inducible Factor-1alpha (HIF-1alpha) Expression on Endothelial Cells in Juvenile Nasopharyngeal Angiofibroma: A Review of 70 cases and Tissue Microarray Analysis. AB - OBJECTIVE: To examine the expression of hypoxia-inducible factor-1alpha (HIF 1alpha) and its related molecules (cellular repressor of E1A-stimulated genes [CREG], osteopontin [OPN], proto-oncogene tyrosine-protein kinase Src [c-Src], and vascular endothelial growth factor [VEGF]) in juvenile nasopharyngeal angiofibroma (JNA) and explore the correlation between clinical prognosis and HIF 1alpha expression. METHODS: The study performed a retrospective review of the clinical records of patients with JNA treated between 2003 and 2007. Specimens were analyzed by immunohistochemistry for HIF-1alpha, CREG, OPN, c-Src, and VEGF expression, and microvessel density (MVD) was assessed by tissue microarray. The correlation between expression levels and clinicopathological features including age, tumor stage, intraoperative blood loss, and recurrence was analyzed. RESULTS: HIF-1alpha, CREG, OPN, c-Src, and VEGF were upregulated in endothelial cells (ECs) of patients with JNA, and strong correlations in the expression of these molecules were observed. HIF-1alpha expression was higher in young patients ( P = .032) and in recurrent cases ( P = .01). Survival analysis showed that low HIF-1alpha levels in ECs predicted longer time to recurrence (log rank test P = .006). Receiver operating characteristic curve analysis showed that HIF-1alpha was a prognostic factor for recurrence (area under the curve = 0.690, P = .019). No correlation was found between the expression of molecules and Radkowski stage or intraoperative blood loss. CONCLUSION: In cases of JNA treated surgically, HIF 1alpha expression in ECs is a useful prognostic factor for tumor recurrence. PMID- 29717656 TI - Delayed Recovery in Pediatric Sudden Sensorineural Hearing Loss Predicted via Magnetic Resonance Imaging. AB - OBJECTIVES: To evaluate the potential origins via magnetic resonance imaging and the relevant hearing recovery course of pediatric sudden sensorineural hearing loss. METHODS: We retrospectively analyzed data of 25 pediatric patients from our center with sudden sensorineural hearing loss from January 2011 to December 2016. All individuals were closely followed up at baseline and 1 and 6 months. RESULTS: Magnetic resonance imaging identified presumed causes in 9 cases, 5 of which showed intralabyrinthine hyperintensity, suggesting presumptive intralabyrinthine hemorrhage. The remaining 20 patients showed no hyperintensity. Restoration of hearing and speech discrimination abilities were noted in these 25 children at 6 months versus the initial levels (74.2 +/- 22.6 vs 93.5 +/- 20.5 dB, p = .000, and 45.8 +/- 36.0 vs. 18.3 +/- 22.1%, p = .004, respectively). The prognosis of the individuals with intralabyrinthine hemorrhage were superior in terms of frequency and hearing threshold at 6 months compared with that of the no hemorrhage participants. Word recognition scores improved in either studied group. CONCLUSION: The potential recovery of hearing in children raises concerns about very early surgical intervention within the first 6 months. Rational imaging and sequential audiometric evaluation to monitor the progression of recovery may be beneficial. PMID- 29717659 TI - Comprehensive Review of Nutritional Components for Occupational Health Nurses Part 1. AB - This article, the first in a two-part series, reviews and examines the components of clinical nutrition. In Part 1, the authors introduce the concept of nutrition and the role it plays in supporting healthy employees, current guidelines, and recommendations for determining healthy eating and the nutritional component of carbohydrates. In Part 2, the components of fats, proteins, vitamins, minerals, and water, and a resource guide are provided for the occupational health nurse to assist in the implementation of employee education in the area of healthy nutrition. The intent of the articles is to acquaint and inform occupational health nurses on the current guidelines for healthy eating so they can better appraise their employee population, thus creating a healthier workforce. The information provided is not all-inclusive on the topics discussed, but provides a foundation to understand the requirements for a healthier workforce. PMID- 29717658 TI - Concurrent Inguinal Hernia Repair in Patients Undergoing Minimally Invasive Radical Prostatectomy: A National Surgical Quality Improvement Program Study. AB - OBJECTIVE: To compare perioperative 30-day outcomes between minimally invasive radical prostatectomy (MIRP) with and without concurrent inguinal hernia repair (IHR) using a national database. METHODS: The National Surgical Quality Improvement Program database was queried for MIRP from 2012 to 2015. Concurrent IHR was identified using relevant Current Procedural Terminology codes. Primary outcomes were overall complications, reoperations, unplanned readmissions, and mortality within 30 days of MIRP. Secondary outcomes included operative time (OT), length of stay (LOS), prolonged length of stay (PLOS, >2 days), and discharged to continued care (DCC). Multivariable logistic regression was performed to identify the association between concurrent IHR and outcomes. RESULTS: A total of 18,065 patients were included; 375 (2.1%) had concurrent IHR. The unadjusted comparison showed no significant difference in overall complication, reoperation, unplanned readmission, or mortality rates between MIRP+IHR and MIRP only groups. OT was longer in the MIRP+IHR group (229 vs 195 minutes, p < 0.001) but no differences were found in LOS, PLOS, or DCC rates. Multivariable logistic regression showed concurrent IHR was not associated with increased odds of overall complication (odds ratio [OR] = 0.83, 95% confidence interval [CI] = 0.49-1.40, p = 0.479), reoperation (OR = 0.57, 95% CI = 0.14 2.30, p = 0.426), unplanned readmission (OR = 0.92, 95% CI = 0.51-1.64, p = 0.771), PLOS (OR = 1.19, 95% CI = 0.86-1.63, p = 0.297), or DCC (OR = 1.94, 95% CI = 0.70-5.34, p = 0.202). CONCLUSIONS: Concurrent IHR with MIRP was associated with longer OT, but there were no increased 30-day adverse outcomes within the National Surgical Quality Improvement Program (NSQIP) database. These data support the safety of performing concurrent IHR at the time of MIRP and it should be considered to spare men an additional procedure. PMID- 29717661 TI - CD4+ T Cell Activation During the Newborn Period: Barriers Against and Pathways Toward Th1 Immunity. AB - During the period of transition from intrauterine to extrauterine life, the neonatal immune system must learn to rapidly identify pathogens while balancing pro-inflammatory, antimicrobial responses with immune regulation that allows for resolution of inflammation and limits responses to commensal organisms and benign environmental antigens. However, the naive immune system of neonates is presented with several barriers that limit robust proinflammatory immune responses. Specifically, epigenetic modifications to neonatal naive CD4+ T cells, heightened neonatal regulatory T cell frequency and function, and limitations in the co stimulatory potential of neonatal antigen presenting cells restrict development of CD4+ T cells with a T-helper 1 type functional profile. This restriction likely contributes to the increased risk of severe infection observed during early life. New research, however, suggests that neonates are capable of utilizing unique compensatory mechanisms to circumvent these restrictions and generate T-helper 1 type immunity under some circumstances. Understanding how to manipulate the immune responses of young infants to optimize development of T helper 1 type immunity is key to the development of immune-based treatments and prevention strategies for severe infections in this vulnerable population. PMID- 29717657 TI - Bone Marrow CD133+ Stem Cells Ameliorate Visual Dysfunction in Streptozotocin induced Diabetic Mice with Early Diabetic Retinopathy. AB - Diabetic retinopathy (DR), one of the leading causes of vision loss worldwide, is characterized by neurovascular disorders. Emerging evidence has demonstrated retinal neurodegeneration in the early pathogenesis of DR, and no treatment has been developed to prevent the early neurodegenerative changes that precede detectable microvascular disorders. Bone marrow CD133+ stem cells with revascularization properties exhibit neuroregenerative potential. However, whether CD133+ cells can ameliorate the neurodegeneration at the early stage of DR remains unclear. In this study, mouse bone marrow CD133+ stem cells were immunomagnetically isolated and analyzed for the phenotypic characteristics, capacity for neural differentiation, and gene expression of neurotrophic factors. After being labeled with enhanced green fluorescent protein, CD133+ cells were intravitreally transplanted into streptozotocin (STZ)-induced diabetic mice to assess the outcomes of visual function and retina structure and the mechanism underlying the therapeutic effect. We found that CD133+ cells co-expressed typical hematopoietic/endothelial stem/progenitor phenotypes, could differentiate to neural lineage cells, and expressed genes of robust neurotrophic factors in vitro. Functional analysis demonstrated that the transplantation of CD133+ cells prevented visual dysfunction for 56 days. Histological analysis confirmed such a functional improvement and showed that transplanted CD133+ cells survived, migrated into the inner retina (IR) over time and preserved IR degeneration, including retina ganglion cells (RGCs) and rod-on bipolar cells. In addition, a subset of transplanted CD133+ cells in the ganglion cell layer differentiated to express RGC markers in STZ-induced diabetic retina. Moreover, transplanted CD133+ cells expressed brain-derived neurotrophic factors (BDNFs) in vivo and increased the BDNF level in STZ-induced diabetic retina to support the survival of retinal cells. Based on these findings, we suggest that transplantation of bone marrow CD133+ stem cells represents a novel approach to ameliorate visual dysfunction and the underlying IR neurodegeneration at the early stage of DR. PMID- 29717662 TI - The Role of Bruton's Tyrosine Kinase in Immune Cell Signaling and Systemic Autoimmunity. AB - Bruton's tyrosine kinase (BTK) is an intracellular signaling molecule first identified as the molecule affected in X-linked agammaglobulinemia (XLA) patients, who almost completely lack peripheral B cells and serum immunoglobulins. BTK is crucial for B cell development and various B cell functions, including cytokine and natural antibody production. Importantly, it is also expressed in numerous other cells, including monocytes, macrophages, granulocytes, dendritic cells, and osteoclasts. A few rare cases of autoimmune disease in XLA patients have been described. Interestingly, increased BTK protein expression in patients with systemic autoimmune disease appears to be correlated with autoantibody production. In addition, BTK may promote autoimmunity as an important driver of an imbalance in B-T cell interaction. Because of this overwhelming evidence of a pathogenic role of BTK in autoimmunity, several clinical trials in rheumatoid arthritis and systemic lupus erythematosus patients with BTK inhibitors are currently running. Here, we review BTK function in different signaling pathways and in different cell lineages, focusing on the growing body of literature indicating a critical role for BTK in autoimmunity. We also discuss BTK and the promising results of BTK inhibition in animal models of autoimmune disease. PMID- 29717663 TI - RUNX3-Mediated Immune Cell Development and Maturation. AB - The transcription factor RUNX3 is a prominent regulator of multiple hematopoietic cell lineages. Gene loss of function studies demonstrated the unique and essential roles of this master regulator in differentiated lymphoid and myeloid cells. As a complementary approach, RUNX3 was upregulated in various leukocyte subsets to probe the instructive role of this 'multilineage'-specific transcription factor. In this report, we overview the immunomodulatory functions of RUNX3 within the hematopoietic compartment to gain insight into the consequences of Runx3 deletion or overexpression in committed immune cells. Genetic studies revealed the essential role of RUNX3 in Langerhans cell development. Moreover, this transcription factor is necessary for the differentiation and maintenance of the cytotoxic CD8+ T cells. In addition, T helper, natural killer, and B cells are also influenced by RUNX3. Importantly, the ectopic expression of Runx3 enhances the immunogenicity of cytotoxic T cells and pluripotent stem-cell-derived dendritic cells, suggesting that this protein can be applied in cell-based immunotherapies. PMID- 29717664 TI - Lipids and Surfactants: The Inside Story of Lipid-Based Drug Delivery Systems. AB - In the bioavailability enhancement of poorly aqueous soluble drugs, self emulsifying/microemulsifying drug delivery systems (SEDDS/SMEDDS) are isotropic mixtures of oils, surfactants, solvents, and cosolvents/surfactants that have gained immense popularity because of their self-emulsification ability. This characteristic relies on some critical parameters such as surfactant concentration, oil-to-surfactant ratio, polarity of the emulsion, droplet size and charge, which are acquired from an amalgamation of appropriate excipients. The fabrication of this combination is of utmost importance for formulation scientists. Hence, to explore the potential of such a delivery system, standardized guidelines for excipients must be developed to address bioavailability issues. In the present review, we summarize the approaches to selecting the most suitable lipid(s)-based drug delivery system, including characterization, especially for oral delivery, of both physicochemical and biopharmaceutical aspects and properties of assorted excipients as well as the related patent reports. PMID- 29717665 TI - Mannosylated Constructs as a Platform for Cell-Specific Delivery of Bioactive Agents. AB - Dictating the transport of drug carriers and augmenting the drug concentration at the desired anatomical site with high selectivity are worthwhile pursuits of current pharmaceutical research. Such approaches to drug targeting have been classified into passive and active strategies. As discussed in this article, active targeting promises greater selectivity because it exploits the incorporation of appropriate ligands, which are recognized by the target cells. Ligands, such as folate, peptides, transferrin, antibodies and their fragments, sugar, and sugar-mimetics, etc., with affinity to the molecules typical to or enriched in target tissues, have been investigated in this context. Mannose receptors (MRs) are abundantly expressed on a variety of cells, such as antigen presenting cells, dendritic cells, and macrophages. Mannose receptors have lectin recognition domains that exhibit a high binding affinity for mannose. As a result, specific recognition of mannose-functionalized constructs has extensively been explored in the cell-specific targeting of drugs, vaccines, and other bioactive agents. This review outlines and discusses the key aspects of synthesis of mannosylated constructs, their mode of cellular uptake and application to targeted delivery of bioactive agents. PMID- 29717666 TI - In Vitro Evaluation of the Antiviral Activity of Some Mushrooms from Turkey. AB - Despite considerable recent work to reveal different features of mushrooms species, the few studies of antiviral activities are inadequate and therefore further studies are required. Morchella conica, M. esculenta, Terfezia boudieri, Pleurotus ostreatus, Tricholoma anatolicum, Fomes fomentarius, Laetiporus sulphureus, Phellinus igniarius, Porodaedalea pini, and Pyrofomes demidoffii from Turkey were investigated to reveal their in vitro cytotoxic and anti-herpes simplex virus 1 (HSV-1) activities. The crude methanol extracts (MEs) and aqueous extracts (AEs) of fungal species and acyclovir (ACV) were used. Various dilutions were used to assess the cytotoxic effects of fungal species (50-0.10 mg/mL) and ACV (500-0.98 MUg/mL) on uninfected Vero cells. Maximum nontoxic concentrations were determined for all extracts and ACV by comparing the optical densities of their cell controls. The concentration providing 50% protection against the cytopathic effect caused by the virus, extracts, and ACV (EC50) was calculated, and the half-maximal cytotoxic concentration (CC50) and the selectivity index (SI) were determined, the latter as the ratio of CC50 to EC50. While the AEs of F. fomentarius (EC50, 11.22 mg/mL; SI > 4.46), Ph. igniarius (EC50, 9.71 mg/mL; SI > 5.15), and P. pini (EC50, 7.16 mg/mL; SI > 6.98) showed considerable antiherpetic activity, MEs and AEs of the other fungal species did not showed any effects. The EC50 and SI of ACV were determined as 0.20 MUg/mL and 3085, respectively. The results demonstrate that F. fomentarius, Ph. igniarius, and P. pini have important anti-HSV-1 activity. PMID- 29717667 TI - Hepatoprotective Effect of Auricularia delicata (Agaricomycetes) from India in Rats: Biochemical and Histopathological Studies and Antimicrobial Activity. AB - Auricularia delicata, an edible mushroom, has been used as a traditional medicine in Manipur, India, for various gastrointestinal and liver ailments. This study evaluates the antioxidant, antimicrobial, and hepatoprotective potential of A. delicata. A. delicata fruiting bodies were extracted with hexane, chloroform, ethyl acetate, and methanol. All these extracts were examined for in vitro antioxidant activity. To study antimicrobial activity, minimum inhibitory concentrations (milligrams per milliliter) were determined through the use of the broth dilution method. In vivo hepatoprotective activity against acetaminophen induced hepatic injury in rats was investigated by evaluating serum biochemistry, antioxidant enzymes, and histopathology. With regard to antioxidant activity, 21 and 48 MUg/mL were the lowest half-maximal effective concentrations, obtained for the methanol and ethyl acetate fractions, respectively. In the antimicrobial study, the ethyl acetate fraction showed the lowest inhibition of Bacillus subtilis, Enterococcus feacium, Streptococcus aureus, B. cereus, and Escherichia coli, with minimum inhibitory concentrations of 0.03, 0.015, 0.03, 0.11, and 0.5 mg/mL, respectively. Further, in in vivo studies, elevated levels of biochemical markers were significantly returned to near normal values; this was supported by histopathological changes. Thus A. delicata showed antimicrobial, antioxidant, and protective roles in induced hepatic injury. Phytochemical analysis using high performance liquid chromatography revealed the presence of chlorogenic acid in the extracts. Its protective property might be due to the presence of a mitochondrial-targeted antioxidant effect of chlorogenic acid. The antimicrobial activity accounts for its use against diarrhea. Hence, A. delicata could be one of the best sources for natural gastrointestinal and hepatoprotective medicines in the future. PMID- 29717668 TI - ITS1/5.8S/ITS2, a Good Marker for Initial Classification of Shiitake Culinary Medicinal Lentinus edodes (Agaricomycetes) Strains in China. AB - China is home to rich wild and cultivated strains of Lentinus edodes, an important edible and medicinal mushroom. Artificial selection of L. edodes has a long history, and the widely cultivated strains belong to populations different from those of most wild strains. Internal transcribed spacer (ITS) regions have been used as good markers to identify L. edodes populations. But because ITS regions exhibit incomplete concerted evolution, the use of an ITS to identify L. edodes populations has been questioned. The objective of this study was to determine whether the ITS region is suitable for identifying L. edodes populations and which populations the widely cultivated strains and the most wild strains belong to by investigating intraindividual and differential ITS polymorphisms between 44 cultivars and 44 wild strains of L. edodes in China. Intraindividual ITS polymorphism is common in L. edodes strains, and most strains possessed 2 different ITS sequences, which came from their heterokaryons. The genetic polymorphisms of ITS1, 5.8S, and ITS2 in L. edodes strains are distinct. All strains were divided into one 5.8S type (5.8S-A), 2 ITS1 types (ITS1-A and ITS1-B), and 2 ITS2 types (ITS2-A and ITS2-B), which were subdivided into 2 branches (ITS2-A1 and ITS2-A2; ITS2-B1 and ITS2-B2). ITS1/5.8S/ITS2 could be used as a good marker in preliminary classification of L. edodes strains in China. It not only exhibited classified information of ITS1, 5.8S, and ITS2 for each strain at the same time, it also indicated whether the strain was heterozygous. The 44 cultivated strains were mainly the A/A/A1 type, and the 44 wild strains were mainly the A/A/A2 and other mixed types. PMID- 29717669 TI - Novel Kombucha Beverage from Lingzhi or Reishi Medicinal Mushroom, Ganoderma lucidum, with Antibacterial and Antioxidant Effects. AB - Kombucha is a nonalcoholic beverage traditionally made by fermenting black tea using a combination of yeast and acetic acid bacteria (AAB) cultures. Ganoderma lucidum hot water extract (HWE) was used-to our knowledge for the first time-to prepare a novel, health-promoting kombucha product. During the 11-day fermentation, pH, total acidity, and the numbers of yeasts and AAB were monitored. It was found that sweetened G. lucidum HWE was a good medium for yeast and AAB growth. The desired acidity for the beverage was reached on the second day (3 g/L) of the fermentation process; the maximum established acidity was 22.8 +/- 0.42 g/L. Fourier transform infrared analysis revealed that the vacuum-dried beverage is a mixture of various compounds such as polysaccharides, phenols, proteins, and lipids. Total phenolic content of the liquid sample was 4.91 +/- 0.2338 mg gallic acid equivalents/g, whereas the vacuum-dried sample had a smaller amount of phenolics (2.107 +/- 0.228 mg gallic acid equivalents/g). Established half-maximal effective concentrations for DPPH scavenging activity and reducing power were 22.8 +/- 0.17 and 10.61 +/- 0.34 mg/mL, respectively. The antibacterial testing revealed that activity does not originate solely from synthesized acetic acid. The liquid G. lucidum beverage was the most effective against the tested bacteria, with the lowest minimum inhibitory concentration (0.04 mg/mL) against Staphylococcus epidermidis and Rhodococcus equi, and a minimum bactericidal concentration (0.16 mg/mL) against Bacillus spizizenii, B. cereus, and R. equi. The vacuum-dried sample was less effective, with the lowest minimum bactericidal concentration against the Gram-positive bacteria R. equi (1.875 mg/mL) and against the Gram-negative bacteria Proteus hauseri (30 mg/mL). PMID- 29717670 TI - Effects of Cooking and In Vitro Digestion on Antioxidant Properties and Cytotoxicity of the Culinary-Medicinal Mushroom Pleurotus ostreatoroseus (Agaricomycetes). AB - In this study we evaluated the antioxidant capacity, antimicrobial activity, and cytotoxicity of an aqueous extract of the Pleurotus ostreatoroseus mushroom, which was cooked. Fresh basidiocarps were heated and steamed at 100 degrees C and the resulting aqueous extract was assessed before and after in vitro digestion. Cooking reduced the amounts of phenolic compounds in the extract. The antioxidant activity of the extract was evaluated through the use of 4 methods. The lowest half-maximal effective concentration (EC50) against ABTS radicals was 0.057 +/- 0.002 mg/mL for the uncooked basidiocarp extract. Cooking and the digestive process led to decreased activity (P > 0.05) against ABTS and DPPH radicals. A significant increase in chelating activity (P > 0.05) occurred after the basidiocarps were cooked (EC50 = 0.279 +/- 0.007 mg/mL). The reducing power did not significantly change among the different extracts. The uncooked basidiocarp extract was cytotoxic to Vero cells. After cooking and subsequent in vitro digestion, the cytotoxicity of the extracts decreased (P < 0.05). Bacillus subtilis, Staphylococcus aureus, and Candida albicans were sensitive to the fresh mushroom extract. The data showed that after being cooked and digested, the P. ostreatoroseus mushroom maintains antioxidant activity and has a low cytotoxic effect. PMID- 29717671 TI - Improvement of Nutritional and Bioactive Compound Production by Lion's Mane Medicinal Mushroom, Hericium erinaceus (Agaricomycetes), by Spraying Growth Regulators. AB - Hericium erinaceus is a popular culinary and medicinal mushroom in China because of its broad beneficial effects. In this study we evaluated the effects of stimulation with 7 growth regulators at 5 different concentrations on improving the production of nutritional and bioactive compounds by H. erinaceus. Results showed that among all the tested regulators, gibberellic acid (GA) increased protein content (165%), free amino acids (100%), polysaccharides (108%), and polyphenols (26%). Spraying nephthyl acetic acid increased polysaccharides and triterpenoids to 4.37 and 17.27 g/100 g, respectively. Spraying chitosan significantly increased polyphenols by 42%. The addition of triacontanol, indole acetic acid, and 2,4-dichlorophenoxyacetic acid improved the production of proteins, free amino acids, polysaccharides, and polyphenols, but not to the extent that GA did. These results indicate that adding certain growth regulators can effectively improve the production of nutritional and bioactive compounds in H. erinaceus. PMID- 29717672 TI - Antiatherogenic Potential of Extracts from the Gray Oyster Medicinal Mushroom, Pleurotus pulmonarius (Agaricomycetes), In Vitro. AB - This study evaluates the in vitro inhibition of angiotensin-converting enzyme (ACE) and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA) by Pleurotus pulmonarius extracts. The protective effect on the endothelial membrane against oxidative stress through the protection of nitric oxide bioavailability, as well as inhibition of endocan expression, was evaluated using human aortic endothelial cells (HAECs). Crude cold aqueous extract exhibited the most potent inhibitory activities against ACE and HMG-CoA reductase, with 61.79% and 44.30% inhibition, respectively. It also protected the bioavailability of NO released by HAECs, with 84.88% cell viability. The crude hot water extract was the most potent in inhibiting endocan expression, with 18.61% inhibition. PMID- 29717673 TI - Bioavailability of Compounds Susceptible to Enzymatic Oxidation Enhances Growth of Shiitake Medicinal Mushroom (Lentinus edodes) in Solid-State Fermentation with Vineyard Prunings. AB - Grapes are widely produced in northwestern Mexico, generating many wood trimmings (vineyard prunings) that have no further local use. This makes vineyard prunings a very attractive alternative for the cultivation of white-rot medicinal mushrooms such as Lentinus edodes. This type of wood can also offer a model for the evaluation of oxidative enzyme production during the fermentation process. We tested the effect of wood from vineyard prunings on the vegetative growth of and production of ligninolytic enzymes in L. edodes in solid-state fermentation and with wheat straw as the control substrate. The specific growth rate of the fungus was 2-fold higher on vineyard pruning culture (MUM = 0.95 day-1) than on wheat straw culture (MUM = 0.47 day-1). Laccase-specific production was 4 times higher in the vineyard prunings culture than on wheat straw (0.34 and 0.08 mU . mg protein-1 . ppm CO2-1, respectively), and manganese peroxidase production was 3.7 times higher on wheat straw culture than on vineyard prunings (2.21 and 0.60 mU . mg protein-1 . ppm CO2-1, respectively). To explain accurately these differences in growth and ligninolytic enzyme activity, methanol extracts were obtained from each substrate and characterized. Resveratrol and catechins were the main compounds identified in vineyard prunings, whereas epigallocatechin was the only one detected in wheat straw. Compounds susceptible to enzymatic oxidation are more bioavailable in vineyard prunings than in wheat straw, and thus the highest L. edodes growth rate is associated with the presence of these compounds. PMID- 29717674 TI - The 9th International Medicinal Mushrooms Conference (IMMC9), September 24-28, 2017, Palermo, Italy. PMID- 29717675 TI - Quantitative Ultrasound Using Texture Analysis of Myofascial Pain Syndrome in the Trapezius. AB - Objective-The objective of this study is to assess the discriminative ability of textural analyses to assist in the differentiation of the myofascial trigger point (MTrP) region from normal regions of skeletal muscle. Also, to measure the ability to reliably differentiate between three clinically relevant groups: healthy asymptomatic, latent MTrPs, and active MTrP. Methods-18 and 19 patients were identified with having active and latent MTrPs in the trapezius muscle, respectively. We included 24 healthy volunteers. Images were obtained by research personnel, who were blinded with respect to the clinical status of the study participant. Histograms provided first-order parameters associated with image grayscale. Haralick, Galloway, and histogram-related features were used in texture analysis. Blob analysis was conducted on the regions of interest (ROIs). Principal component analysis (PCA) was performed followed by multivariate analysis of variance (MANOVA) to determine the statistical significance of the features. Results-92 texture features were analyzed for factorability using Bartlett's test of sphericity, which was significant. The Kaiser-Meyer-Olkin measure of sampling adequacy was 0.94. PCA demonstrated rotated eigenvalues of the first eight components (each comprised of multiple texture features) explained 94.92% of the cumulative variance in the ultrasound image characteristics. The 24 features identified by PCA were included in the MANOVA as dependent variables, and the presence of a latent or active MTrP or healthy muscle were independent variables. Conclusion-Texture analysis techniques can discriminate between the three clinically relevant groups. PMID- 29717676 TI - Lung and Heart Sounds Analysis: State-of-the-Art and Future Trends. AB - Lung sounds, which include all sounds that are produced during the mechanism of respiration, may be classified into normal breath sounds and adventitious sounds. Normal breath sounds occur when no respiratory problems exist, whereas adventitious lung sounds (wheeze, rhonchi, crackle, etc.) are usually associated with certain pulmonary pathologies. Heart and lung sounds that are heard using a stethoscope are the result of mechanical interactions that indicate operation of cardiac and respiratory systems, respectively. In this article, we review the research conducted during the last six years on lung and heart sounds, instrumentation and data sources (sensors and databases), technological advances, and perspectives in processing and data analysis. Our review suggests that chronic obstructive pulmonary disease (COPD) and asthma are the most common respiratory diseases reported on in the literature; related diseases that are less analyzed include chronic bronchitis, idiopathic pulmonary fibrosis, congestive heart failure, and parenchymal pathology. Some new findings regarding the methodologies associated with advances in the electronic stethoscope have been presented for the auscultatory heart sound signaling process, including analysis and clarification of resulting sounds to create a diagnosis based on a quantifiable medical assessment. The availability of automatic interpretation of high precision of heart and lung sounds opens interesting possibilities for cardiovascular diagnosis as well as potential for intelligent diagnosis of heart and lung diseases. PMID- 29717677 TI - Facilitating Earlier Diagnosis of Cardiovascular Disease through Point-of-Care Biosensors: A Review. AB - Cardiovascular disease (CVD) accounts for 30% of all global deaths and is predicted to dominate in the coming years, despite vast improvements in medical technology. Current clinical methods of assessing an individual's cardiovascular health include blood tests to monitor relevant biomarker levels as well as varying imaging modalities such as electrocardiograms, computed tomography, and angiograms to assess vasculature. As informative as these tools are, they each require lengthy scheduling, preparation, and highly trained personnel to interpret the results before any information is accessible to patients, often leading to delayed treatment, which can be fatal. A point-of-care (POC) sensor platform is thus paramount in rapid and early diagnosis of CVD. Among the many POC detection platforms, including established optical and mechanical methods, electrochemical-based detection mechanisms have become increasingly desirable because of their superior sensitivity, low cost, and label-free detection. Specifically, electrochemical impedance spectroscopy (EIS) has demonstrated remarkable abilities in low-level (femtomolar) detection of several clinically useful biomarkers and has been reported in CVD diagnostic applications. In this review, we provide an in-depth overview of prevalent CVD diseases and clinically relevant proteomic biomarkers for assessing them. Subsequently, we discuss the ongoing development of POC sensors for CVD, highlighting the current clinical gold standard, potential alternative modalities, and electrochemical methodologies previously successful in quantifying specific biomarkers approved by the Food and Drug Administration (FDA). A discussion of EIS highlighting the attributes and capabilities of novel analysis algorithms is included to showcase the possibility of simultaneous dual-marker detection. PMID- 29717678 TI - Communicating Gastrointestinal Symptoms: The Patient's Challenge. AB - Gastrointestinal (GI) disorders present with signs that are objective and symptoms that are subjective, evaluable only if an individual can recognize, characterize, describe, and communicate them to a healthcare professional (HCP). The aim of this study was to quantify the extent to which healthcare seekers perceive difficulties in communicating their GI symptoms to HCPs. Interviews were conducted in two settings where individuals were expected to acknowledge experiencing GI symptoms: a tertiary-care, ambulatory GI clinic and the digestive health medication area of a large retail pharmacy. A 13-item questionnaire was designed to identify subjects' perceptions of the component stages of a symptom communication process. Surveys were completed by 100 participants, 50 from the clinic and 50 from the pharmacy. Most participants reported that it was difficult to know if their symptom descriptions had been understood (clinic: 68%; pharmacy: 86%), that difficulty in describing symptoms hampered access to healthcare (clinic: 82%; pharmacy: 76%), and that use of different descriptors (e.g., icons) would facilitate symptom reporting (clinic: 90%; pharmacy: 98%). Apart from difficulties in selecting a standard term and in providing a specific description for their symptoms, perceived barriers to communicating symptoms did not differ between the clinic and pharmacy settings. Most individuals with GI symptoms perceive difficulty in communicating their symptoms to healthcare professionals. Improved access and improved GI healthcare require new, patient-centered tools for symptom communication. These may be pictogram- or icon-based tools rather than traditional verbal descriptors. PMID- 29717679 TI - Review: Assessing fish welfare in research and aquaculture, with a focus on European directives. AB - The number of farmed fish in the world has increased considerably. Aquaculture is a growing industry that will in the future provide a large portion of fishery products. Moreover, in recent years, the number of teleost fish used as animal models for scientific research in both biomedical and ecological fields has increased. Therefore, it is increasingly important to implement measures designed to enhance the welfare of these animals. Currently, a number of European rules exist as requirements for the establishment, care and accommodation of fish maintained for human purposes. As far as (teleost) fish are concerned, the fact that the number of extant species is much greater than that of all other vertebrates must be considered. Of further importance is that each species has its own specific physical and chemical requirements. These factors make it difficult to provide generalized recommendations or requirements for all fish species. An adequate knowledge is required of the physiology and ecology of each species bred. This paper integrates and discusses, in a single synthesis, the current issues related to fish welfare, considering that teleosts are target species for both aquaculture and experimental models in biological and biomedical research. We first focus on the practical aspects, which must be considered when assessing fish welfare in both research and aquaculture contexts. Next, we address husbandry and the care of fish housed in research laboratories and aquaculture facilities in relation to their physiological and behavioural requirements, as well as in reference to the suggestions provided by European regulations. Finally, to evaluate precisely which parameters described by Directive 2010/63/EU are reported in scientific papers, we analysed 82 articles published by European researchers in 2014 and 2015. This review found that there is a general lack of information related to the optimal environmental conditions that should be provided for the range of species covered by this directive. PMID- 29717680 TI - Intergenerational and early life influences on the well-being of Australian Aboriginal and Torres Strait Islander children: overview and selected findings from Footprints in Time, the Longitudinal Study of Indigenous Children. AB - Footprints in Time: The Longitudinal Study of Indigenous Children (LSIC) is a national study of 1759 Australian Aboriginal and Torres Strait Islander children living across urban, regional and remote areas of Australia. The study is in its 11th wave of annual data collection, having collected extensive data on topics including birth and early life influences, parental health and well-being, identity, cultural engagement, language use, housing, racism, school engagement and academic achievement, and social and emotional well-being. The current paper reviews a selection of major findings from Footprints in Time relating to the developmental origins of health and disease for Australian Aboriginal and Torres Strait Islander peoples. Opportunities for new researchers to conduct further research utilizing the LSIC data set are also presented. PMID- 29717681 TI - Relative contributions of recommended food environment policies to improve population nutrition: results from a Delphi study with international food policy experts. AB - OBJECTIVE: To determine weightings for the relative contributions of nineteen widely recommended good practice food environment policies to improve population nutrition, based on evidence of effectiveness and expert ratings, to facilitate benchmarking of the implementation of food environment policies globally. DESIGN: A two-round Delphi study was performed in 2015, whereby international food policy experts (n Round1 27, n Round2 21) compared effectiveness of all possible pairs of policy domains and good practice policies within domains to improve population nutrition according to the Saaty scale (1 to 9). Weightings for each domain and policy were derived from expert ratings based on the Analytic Hierarchy Process method. SETTING: International. SUBJECTS: Food policy experts. RESULTS: Out of the seven policy domains, Food Prices and Food Promotion received the highest weightings for impact on improving population nutrition, while Food Trade received the lowest weighting. Among the nineteen specific policies, taxing unhealthy foods (3.8 (0.7)), healthy food provision in schools (2.8 (0.4)) and minimizing taxes on healthy foods (2.6 (0.4)) were given the highest weightings, while nutrient declarations on packaged foods (1.2 (0.2)) and healthy food policies in private-sector workplaces (1.0 (0.2)) received the lowest weightings (mean (95 % CI)). CONCLUSIONS: Expert-derived weightings on the relative contributions of recommended food environment policies to improve population nutrition will facilitate monitoring and benchmarking the implementation of these policies by governments among countries globally. Additional weightings for contributions of policies to reducing nutrition inequalities and improving consumer and child rights could be developed in the future. PMID- 29717682 TI - Review: Abnormalities of the bull - occurrence, diagnosis and treatment of abnormalities of the bull, including structural soundness. AB - Selecting bulls for reproductive soundness requires that the bull be structurally sound, free of abnormalities that impair his ability to produce adequate numbers of motile, morphologically normal spermatozoa, and be able to successfully complete coitus. This review discusses the diagnosis and etiology of abnormalities of the penis, prepuce as well as common musculoskeletal conditions that prevent normal pasture breeding soundness. A review of testicular and thermoregulation addresses the potential impact of musculoskeletal disorders on normal sperm production. PMID- 29717683 TI - Progress of negative symptoms over the initial 5 years of a first episode of psychosis - CORRIGENDUM. PMID- 29717684 TI - Prevalence of vitamin D deficiency in adult patients admitted to a psychiatric hospital. AB - : Aims and methodVitamin D deficiency is increasing in the general population, and is linked with physical and mental illness. However, evidence on its prevalence in people with mental illness is limited. This study investigated vitamin D deficiency in 104 adult patients admitted to a psychiatric hospital in the UK. RESULTS: Forty-nine per cent were vitamin D deficient (serum 25(OH)D 50 nmol/L). There were no statistically significant differences in mean serum vitamin D between different subgroups of mental illness.Clinical implicationsVitamin D deficiency is highly prevalent among individuals with severe mental illness admitted to hospital. Assessment and treatment of vitamin D deficiency should be considered in in-patients to protect musculoskeletal health. Further epidemiological and intervention studies are needed to investigate the role of vitamin D in the pathophysiology of mental disorders.Declaration of interestNone. PMID- 29717685 TI - A Bibliometric Profile of Disaster Medicine Research from 2008 to 2017: A Scientometric Analysis. AB - ABSTRACTThis study analyzed and assessed publication trends in articles on "disaster medicine," using scientometric analysis. Data were obtained from the Web of Science Core Collection (WoSCC) of Thomson Reuters on March 27, 2017. A total of 564 publications on disaster medicine were identified. There was a mild increase in the number of articles on disaster medicine from 2008 (n=55) to 2016 (n=83). Disaster Medicine and Public Health Preparedness published the most articles, the majority of articles were published in the United States, and the leading institute was Tohoku University. F. Della Corte, M. D. Christian, and P. L. Ingrassia were the top authors on the topic, and the field of public health generated the most publications. Terms analysis indicated that emergency medicine, public health, disaster preparedness, natural disasters, medicine, and management were the research hotspots, whereas Hurricane Katrina, mechanical ventilation, occupational medicine, intensive care, and European journals represented the frontiers of disaster medicine research. Overall, our analysis revealed that disaster medicine studies are closely related to other medical fields and provides researchers and policy-makers in this area with new insight into the hotspots and dynamic directions. (Disaster Med Public Health Preparedness. 2018;page 1 of 8). PMID- 29717686 TI - Supplementing sow diets with palm oil during late gestation and lactation: effects on milk production, sow hormonal profiles and growth and development of her offspring. AB - The supplementing of sow diets with lipids during pregnancy and lactation has been shown to reduce sow condition loss and improve piglet performance. The aim of this study was to determine the effects of supplemental palm oil (PO) on sow performance, plasma metabolites and hormones, milk profiles and pre-weaning piglet development. A commercial sow ration (C) or an experimental diet supplemented with 10% extra energy in the form of PO, were provided from day 90 of gestation until weaning (24 to 28 days postpartum) in two groups of eight multiparous sows. Gestation length of PO sows increased by 1 day (P<0.05). Maternal BW changes were similar throughout the trial, but loss of backfat during lactation was reduced in PO animals (C: -3.6+/-0.8 mm; PO: -0.1+/-0.8 mm; P<0.01). Milk fat was increased by PO supplementation (C day 3: 8.0+/-0.3% fat; PO day 3: 9.1+/-0.3% fat; C day 7: 7.8+/-0.5% fat; PO day 7: 9.9+/-0.5% fat; P<0.05) and hence milk energy yield of PO sows was also elevated (P<0.05). The proportion of saturated fatty acids was greater in colostrum from PO sows (C: 29.19+/-0.31 g/100 g of fat; PO: 30.77+/-0.36 g/100 g of fat; P<0.01). Blood samples taken on 105 days of gestation, within 24 h of farrowing, day 7 of lactation and at weaning (28+/-3 days post-farrowing) showed there were no differences in plasma concentrations of triacylglycerol, non-esterified fatty acids, insulin or IGF-1 throughout the trial. However, circulating plasma concentrations of both glucose and leptin were elevated during lactation in PO sows (P<0.05 and P<0.005, respectively) and thyroxine was greater at weaning in PO sows (P<0.05). Piglet weight and body composition were similar at birth, as were piglet growth rates throughout the pre-weaning period. A period of 7 days after birth, C piglets contained more body fat, as indicated by their lower fat free mass per kg (C: 66.4+/-0.8 arbitrary units/kg; PO: 69.7+/-0.8 arbitrary unit/kg; P<0.01), but by day 14 of life this situation was reversed (C: 65.8+/ 0.6 arbitrary units/kg; PO: 63.6+/-0.6 arbitrary units/kg; P<0.05). Following weaning, PO sows exhibited an increased ratio of male to female offspring at their subsequent farrowing (C: 1.0+/-0.3; PO: 2.2+/-0.2; P<0.05). We conclude that supplementation of sow diets with PO during late gestation and lactation appears to increase sow milk fat content and hence energy supply to piglets. Furthermore, elevated glucose concentrations in the sow during lactation may be suggestive of impaired glucose homoeostasis. PMID- 29717688 TI - Review: Semen handling, time of insemination and insemination technique in cattle. AB - In cattle artificial insemination plays not only a vital role in the successful establishment of pregnancy, which is a prerequisite for initiation of the subsequent lactation, but also in accelerating genetic improvement and facilitating the distribution of semen from genetically elite sires. The latter has been greatly facilitated by the ability to successfully cryopreserve semen. The objective of an insemination is to ensure that there is an adequate reservoir of competent, capacitated, motile sperm in the caudal region of the oviductal isthmus, the site of the main sperm reservoir in the cow, at the time of ovulation to ensure fertilisation. Handling of semen, particularly the 0.25 ml straw, is critically important. Thawed semen needs to be protected from cold and heat shocks and inseminated within 6 to 8 min of thawing. Uterine horn insemination give a modest improvement in conceptions rates particularly in situations where conception rates are low following uterine body inseminations. Most of the studies that evaluated heterospermic insemination were conducted on fresh semen only, and many lacked adequate replication. Consequently, it is difficult to deduce if there are real benefits from using heterospermic semen. While the interval from oestrous onset to time of ovulation would appear to be similar for cows and heifers at about 28 h there is huge variation (standard deviations of 5 to 6 h) around this average. While best conception rates are achieved when cows are inseminated from mid oestrus to a few hours after the onset of oestrus, this is difficult to achieve in practice. There is emerging evidence that having one insemination time, when all cows requiring insemination in the herd on that day are inseminated, does not compromise fertility provided insemination technique is good and the semen used is of high fertility. PMID- 29717687 TI - Dietary patterns and the risk of metabolic syndrome in Chinese adults: a population-based cross-sectional study. AB - OBJECTIVE: Data on dietary patterns in relation to the risk of metabolic syndrome (MetS) in a middle-aged Chinese population are sparse. The present study was performed to determine the major dietary patterns among a population aged 45-59 years and to evaluate their associations with MetS risk in China. DESIGN: Cross sectional examination of the association between dietary patterns and MetS. Face to-face interviews were used to assess dietary intake using a validated semi quantitative FFQ. OR and 95 % CI for MetS were calculated across quartiles of dietary pattern scores using multivariate logistic regression analysis models. SETTING: City of Linyi, Shandong Province, China. SUBJECTS: Adults (n 1918) aged 45-59 years. RESULTS: Three major dietary patterns were identified: traditional Chinese, animal food and high-energy. After adjustment for potential confounders, individuals in the highest quartile of the traditional Chinese pattern had a reduced risk of MetS relative to the lowest quartile (OR=0.72, 95 % CI 0.596, 0.952; P<0.05). Compared with those in the lowest quartile, individuals in the highest quartile of the animal food pattern had a greater risk of MetS (OR=1.28; 95 % CI 1.103, 1.697; P<0.05). No significant association was observed between the high-energy pattern and risk of MetS. CONCLUSIONS: These findings indicate that the traditional Chinese pattern was associated with a reduced risk, while the animal food pattern was associated with increased risk of MetS. Given the cross-sectional nature of our study, further prospective studies are warranted to confirm these findings. PMID- 29717689 TI - Advancing our diagnostic tools and treatment options for delirium. AB - Delirium is one of the most prevalent and disabling conditions impacting older adults in hospitals and long-term care settings. The estimates of frequency of delirium in hospitals and nursing homes among older adults range widely, yet it is safe to assume that perhaps as many as 25-30% of elderly individuals in hospitals experience an episode of delirium, often undetected unless a regular screening process is implemented. Until the past couple of decades, actual research into delirium had been sparse and done little to inform clinical practice. Engel and Romano (1959) published a classic review nearly 60 years ago, which served for decades as the foundational article for understanding delirium. In recent years, however, our understanding of delirium has increased dramatically, from the basic neuropathological underpinnings through screening and diagnosis to treatment. In this issue of International Psychogeriatrics, five papers are published, which further expand our knowledge of delirium. The papers cover a range of topics including the frequency of delirium in a primary care setting, outcomes predicted by various diagnostic systems, cognitive function measures as they relate to delirium motor subtypes, screening for delirium using a standardized drug screen, and the effectiveness of multimodal interventions for preventing delirium in older hip fracture patients. What are the take home lessons from these studies? PMID- 29717690 TI - Sociodemographic and geographical inequalities in under- and overnutrition among children and mothers in Bangladesh: a spatial modelling approach to a nationally representative survey. AB - OBJECTIVE: To investigate the sociodemographic and geographical variation in under- and overnutrition prevalence among children and mothers. DESIGN: Data from the 2014 Bangladesh Demographic and Health Survey were analysed. Stunting and wasting for children and BMI<18.5 kg/m2 for mothers were considered as undernutrition; overweight was considered as overnutrition for both children and mothers. We estimated the prevalence and performed simple logistic regression analyses to assess the associations between outcome variables and predictors. Bayesian spatial models were applied to estimate region-level prevalence to identify the regions (districts) prone to under- and overnutrition.Settings/SubjectsChildren aged<5 years and their mothers aged 15-49 years in Bangladesh. RESULTS: A significant difference (P<0.001) was observed in both under- and overnutrition prevalence between poor and rich. A notable regional variation was also observed in under- and overnutrition prevalence. Stunting prevalence ranged from 20.3 % in Jessore to 56.2 % in Sunamgonj, wasting from 10.6 % in Dhaka to 19.2 % in Bhola, and overweight from 0.8 % in Shariatpur to 2.6 % in Dhaka. Of the sixty-four districts, twelve had prevalence of stunting and thirty-two districts had prevalence of wasting higher than the WHO critical threshold levels. Similarly, fifty-three districts had prevalence of maternal underweight higher than the national level. In contrast, the prevalence of overweight was comparatively high in the industrially equipped metropolitan districts. CONCLUSIONS: Observed sociodemographic and geographical inequalities imply slow progress in the overall improvement of both under- and overnutrition. Therefore, effective intervention programmes and policies need to be designed urgently targeting the grass-roots level of such regions. PMID- 29717692 TI - Corrigendum: Death and gastrointestinal bleeding complicate encephalomyelitis in mice with delayed appearance of CNS IgM after intranasal alphavirus infection. PMID- 29717694 TI - Vaccines, trust and European public health. PMID- 29717693 TI - Vaccine hesitancy in the French population in 2016, and its association with vaccine uptake and perceived vaccine risk-benefit balance. AB - BackgroundVaccine hesitancy (VH) is prominent in France. Objectives: This study aimed to estimate the prevalence and socio-demographic correlates of VH in sub groups of the French population and to investigate the association of VH with both vaccine uptake and perceived risk-benefit balance (RBB) for four vaccines. Methods: During the 2016 Health Barometer - a national cross-sectional telephone survey in a representative sample of the French population - parents of 1-15 year old children, parents of 11-15 year-old girls and elderly people aged 65-75 years were asked about VH (using three questions adapted from the World Health Organization definition), vaccine uptake and perceived RBB for measles and hepatitis B (children's parents), human papillomavirus (girls' parents) and seasonal influenza (elderly people) vaccines. Results: A total of 3,938 parents including 959 girls' parents - and 2,418 elderly people were interviewed. VH prevalence estimates were 46% (95% confidence interval (CI): 44-48) among parents, 48% (95%CI: 45-51) among girls' parents and 35% (95% CI: 33-36) among elderly people, with higher estimates associated with high education level, children's age (10-15 years), and, for the elderly, poor perception of health status. VH was associated with uncertainty about and/or an unfavourable perception of vaccines' RBB for the four vaccines and with lower self-reported vaccine uptake, except for human papillomavirus vaccine in girls. Results were confirmed by multivariable analysis. Conclusion: Further research is needed to study the association between VH and vaccine uptake for other vaccines, and to design and validate measurement tools to monitor VH over time. PMID- 29717695 TI - A modified chain binomial model to analyse the ongoing measles epidemic in Greece, July 2017 to February 2018. AB - Greece is currently experiencing a large measles outbreak, in the context of multiple similar outbreaks across Europe. We devised and applied a modified chain binomial epidemic model, requiring very simple data, to estimate the transmission parameters of this outbreak. Model results indicate sustained measles transmission among the Greek Roma population, necessitating a targeted mass vaccination campaign to halt further spread of the epidemic. Our model may be useful for other countries facing similar measles outbreaks. PMID- 29717696 TI - Extension of French vaccination mandates: from the recommendation of the Steering Committee of the Citizen Consultation on Vaccination to the law. AB - On 4 December 2017, French parliamentarians passed a law extending the vaccination mandates for children up to 2 years of age from three vaccinations (against diphtheria, tetanus and poliomyelitis) to 11 by adding vaccinations against pertussis, Haemophilus influenza b (Hib), hepatitis B, pneumococcal diseases, meningococcal C diseases, measles, mumps and rubella. This vote follows a recommendation made by the Steering Committee of the Citizen Consultation on Vaccination that took place in 2016. The law applies to all children born after 1 January 2018. Parents who do not fulfil the mandate will not be fined but non vaccinated children will not be admitted to any collective child services such as nurseries or schools. No exemption other than for medical reasons will be considered. Here we describe the historical background of this evolution and its main epidemiological, sociological and policy drivers. They mainly refer to insufficient vaccine coverage, persistence of a preventable burden for some diseases and growing vaccine hesitancy in the French population. We also discuss some of the challenges and conditions of success. PMID- 29717691 TI - Probability of major depression diagnostic classification using semi-structured versus fully structured diagnostic interviews. AB - BACKGROUND: Different diagnostic interviews are used as reference standards for major depression classification in research. Semi-structured interviews involve clinical judgement, whereas fully structured interviews are completely scripted. The Mini International Neuropsychiatric Interview (MINI), a brief fully structured interview, is also sometimes used. It is not known whether interview method is associated with probability of major depression classification.AimsTo evaluate the association between interview method and odds of major depression classification, controlling for depressive symptom scores and participant characteristics. METHOD: Data collected for an individual participant data meta analysis of Patient Health Questionnaire-9 (PHQ-9) diagnostic accuracy were analysed and binomial generalised linear mixed models were fit. RESULTS: A total of 17 158 participants (2287 with major depression) from 57 primary studies were analysed. Among fully structured interviews, odds of major depression were higher for the MINI compared with the Composite International Diagnostic Interview (CIDI) (odds ratio (OR) = 2.10; 95% CI = 1.15-3.87). Compared with semi structured interviews, fully structured interviews (MINI excluded) were non significantly more likely to classify participants with low-level depressive symptoms (PHQ-9 scores <=6) as having major depression (OR = 3.13; 95% CI = 0.98 10.00), similarly likely for moderate-level symptoms (PHQ-9 scores 7-15) (OR = 0.96; 95% CI = 0.56-1.66) and significantly less likely for high-level symptoms (PHQ-9 scores >=16) (OR = 0.50; 95% CI = 0.26-0.97). CONCLUSIONS: The MINI may identify more people as depressed than the CIDI, and semi-structured and fully structured interviews may not be interchangeable methods, but these results should be replicated.Declaration of interestDrs Jette and Patten declare that they received a grant, outside the submitted work, from the Hotchkiss Brain Institute, which was jointly funded by the Institute and Pfizer. Pfizer was the original sponsor of the development of the PHQ-9, which is now in the public domain. Dr Chan is a steering committee member or consultant of Astra Zeneca, Bayer, Lilly, MSD and Pfizer. She has received sponsorships and honorarium for giving lectures and providing consultancy and her affiliated institution has received research grants from these companies. Dr Hegerl declares that within the past 3 years, he was an advisory board member for Lundbeck, Servier and Otsuka Pharma; a consultant for Bayer Pharma; and a speaker for Medice Arzneimittel, Novartis, and Roche Pharma, all outside the submitted work. Dr Inagaki declares that he has received grants from Novartis Pharma, lecture fees from Pfizer, Mochida, Shionogi, Sumitomo Dainippon Pharma, Daiichi-Sankyo, Meiji Seika and Takeda, and royalties from Nippon Hyoron Sha, Nanzando, Seiwa Shoten, Igaku-shoin and Technomics, all outside of the submitted work. Dr Yamada reports personal fees from Meiji Seika Pharma Co., Ltd., MSD K.K., Asahi Kasei Pharma Corporation, Seishin Shobo, Seiwa Shoten Co., Ltd., Igaku-shoin Ltd., Chugai Igakusha and Sentan Igakusha, all outside the submitted work. All other authors declare no competing interests. No funder had any role in the design and conduct of the study; collection, management, analysis and interpretation of the data; preparation, review or approval of the manuscript; and decision to submit the manuscript for publication. PMID- 29717698 TI - Life in vaccine science - a conversation with Stanley Plotkin at the 4th Conference on Vaccines in Dubrovnik, Croatia, September 2017. PMID- 29717697 TI - Adverse events following immunisation with a meningococcal serogroup B vaccine: report from post-marketing surveillance, Germany, 2013 to 2016. AB - Background and aimIn January 2013, a novel vaccine against Neisseria meningitidis serogroup B, the multicomponent meningococcal serogroup B vaccine (4CMenB), was approved by the European Medicines Agency. We aimed to evaluate the safety profile of this vaccine. Methods: All adverse events following immunisation (AEFI) reported from Germany since the vaccine's launch in Germany in November 2013 through December 2016 were reviewed and analysed. Results: Through December 2016, a total of 664 individual case safety reports (ICSR) notifying 1,960 AEFI were received. A majority of vaccinees for whom AEFI were reported were children 2 to 11 years of age (n = 280; 42.2%) followed by infants and toddlers aged 28 days to 23 months (n = 170; 25.6%). General disorders and administration site conditions was the System Organ Class (SOC) with the majority of AEFI (n = 977; 49.8%), followed by nervous system disorders (n = 249; 12.7%), and skin and subcutaneous tissue disorders (n = 191; 9.7%). Screening of patient records for immune-mediated and neurological diseases did not raise any safety signal in terms of an increased proportional reporting ratio (PRR). Conclusions: The safety profile described in the Summary of Product Characteristics, in general, is confirmed by data from spontaneous reporting. No safety concerns were identified. PMID- 29717699 TI - Self-Management education for adults with poorly controlled epILEpsy [SMILE (UK)]: a randomised controlled trial. AB - BACKGROUND: Epilepsy is a common neurological condition resulting in recurrent seizures. Research evidence in long-term conditions suggests that patients benefit from self-management education and that this may improve quality of life (QoL). Epilepsy self-management education has yet to be tested in a UK setting. OBJECTIVES: To determine the effectiveness and cost-effectiveness of Self Management education for people with poorly controlled epILEpsy [SMILE (UK)]. DESIGN: A parallel pragmatic randomised controlled trial. SETTING: Participants were recruited from eight hospitals in London and south-east England. PARTICIPANTS: Adults aged >= 16 years with epilepsy and two or more epileptic seizures in the past year, who were currently being prescribed antiepileptic drugs. INTERVENTION: A 2-day group self-management course alongside treatment as usual (TAU). The control group received TAU. MAIN OUTCOME MEASURES: The primary outcome is QoL in people with epilepsy at 12-month follow-up using the Quality Of Life In Epilepsy 31-P (QOLIE-31-P) scale. Other outcomes were seizure control, impact of epilepsy, medication adverse effects, psychological distress, perceived stigma, self-mastery and medication adherence. Cost-effectiveness analyses and a process evaluation were undertaken. RANDOMISATION: A 1 : 1 ratio between trial arms using fixed block sizes of two. BLINDING: Participants were not blinded to their group allocation because of the nature of the study. Researchers involved in data collection and analysis remained blinded throughout. RESULTS: The trial completed successfully. A total of 404 participants were enrolled in the study [SMILE (UK), n = 205; TAU, n = 199] with 331 completing the final follow-up at 12 months [SMILE (UK), n = 163; TAU, n = 168]. In the intervention group, 61.5% completed all sessions of the course. No adverse events were found to be related to the intervention. At baseline, participants had a mean age of 41.7 years [standard deviation (SD) 14.1 years], and had epilepsy for a median of 18 years. The mean QOLIE-31-P score for the whole group at baseline was 66.0 out of 100.0 (SD 14.2). Clinically relevant levels of anxiety symptoms were reported in 53.6% of the group and depression symptoms in 28.0%. The results following an intention to-treat analysis showed no change in any measures at the 12-month follow-up [QOLIE-31-P: SMILE (UK) mean: 67.4, SD 13.5; TAU mean: 69.5, SD 14.8]. The cost effectiveness study showed that SMILE (UK) was possibly cost-effective but was also associated with lower QoL. The process evaluation with 20 participants revealed that a group course increased confidence by sharing with others and improved self-management behaviours. CONCLUSIONS: For people with epilepsy and persistent seizures, a 2-day self-management education course is cost-saving, but does not improve QoL after 12-months or reduce anxiety or depression symptoms. A psychological intervention may help with anxiety and depression. Interviewed participants reported attending a group course increased their confidence and helped them improve their self-management. FUTURE WORK: More research is needed on self-management courses, with psychological components and integration with routine monitoring. TRIAL REGISTRATION: Current Controlled Trials ISRCTN57937389. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 21. See the NIHR Journals Library website for further project information. PMID- 29717700 TI - [Establishing a screening programme in Denmark for foetal and neonatal alloimmune thrombocytopenia]. AB - Foetal and neonatal alloimmune thrombocytopenia (FNAIT) can cause cerebral haemorrhage in newborns. FNAIT occurs in women, who do not have the thrombocyte type human platelet antigen (HPA)-1a and are carrying an HPA-1a positive foetus. Maternal antibodies can cause thrombocytopenia in the foetus or newborn. Antenatal screening for FNAIT can easily be integrated in the already existing national screening programme for rhesus immunisation. Prophylactic treatment with immunoglobulines for pregnancies at risk can prevent neonatal complications. We argue, that the WHO criteria for a screening programme for FNAIT are met. PMID- 29717701 TI - [Severe hypoglycaemia due to insulinoma after gastric bypass surgery]. AB - Postprandial hypoglycaemia with endogenous hyper-insulinaemia is relatively common after gastric bypass (GB) surgery. However, alternative aetiologies of hypoglycaemia should be kept in mind. We report a case of severe hypo-glycaemia in a patient who had previously undergone GB surgery for morbid obesity. Hypoglycaemic episodes differed from typical GB-related hypoglycaemia by occurring during fasting periods. Examination revealed insulinoma, and nine months after resection the patient remained symptom free. PMID- 29717702 TI - [Germ line mutations causing paediatric cancer predisposition syndromes are common in children and adolescents with cancer]. AB - Germ line mutations causing paediatric cancer predisposition syndromes (PCPSs) are more common than previously anticipated and are now recognised as a significant contributor to the incidence of childhood cancer. Advances in and increased clinical application of next-generation sequencing technologies have led to a rise in paediatric patients undergoing whole genome sequencing (WGS). This review focuses on the potential syndromes/diagnoses, which WGS may reveal in patients with childhood cancers, and highlights the clinical and psychosocial impact of PCPSs. PMID- 29717703 TI - [Telepsychiatry provides new opportunities for the prevention and treatment of mental health disorders]. AB - Digital technologies in mental healthcare are envisioned to offer easier, faster and more cost-effective access to mental healthcare. The scope for integrating digital technology into mental healthcare is vast: video conferencing, developing novel treatments using interactive software, mobile applications, and sensor technologies. We outline technology-based interventions, which are relevant to clinical practice, and present the evidence base for using digital technology as well as emerging challenges for their implementation in clinical practice. PMID- 29717704 TI - [Functional neurological symptoms and the positive diagnostic process]. AB - Functional neurological symptoms are common in neurology and general medical practice. Functional neurological symptoms refer to neurological symptoms, which are not explained by a defined disease. The most common are functional weakness and non-epileptic seizures. Psychiatric models have dominated the classification, aetiology and treatment, limiting the neurologist's role to making the diagnosis by excluding disease and pronouncing the symptoms to be psychogenic. In this review, we outline the possibility of a positive diagnostic process, which can be the first step of treatment. PMID- 29717705 TI - [Handling of hypermetabolism in major burn injuries]. AB - Multitrauma, critical illness and major burn injuries give rise to a stress response with a consequential increase in resting energy expenditure. Especially for burn trauma patients, this stress response is severe and prolonged and may cause a reduced lean muscle mass, loss of peripheral fatty tissue, hyperglycaemia and stress-induced diabetes. This review provides an overview of current strategies to attenuate the hypermetabolic stress response in order to improve the clinical outcome for these patients. PMID- 29717707 TI - Electrode-size dependent thresholds in subretinal neuroprosthetic stimulation. AB - OBJECTIVE: Retinal prostheses have shown promising results in restoring some visual perception to blind patients but successful identification of objects of different size remains a challenge. Here we investigated electrode-size specific stimulation thresholds and their variability for subretinal electrical stimulation. Our findings indicate the range of charge densities required to achieve identification of small objects and the object-size-specific scaling of stimulation threshold. APPROACH: Using biphasic voltage-limited current stimuli provided by a light-sensitive microchip, we determined threshold charge densities for stimulation with variable electrode sizes. The stimulated activation of the retinal network was identified by recording the spiking of retinal ganglion cells in photoreceptor-degenerated mouse rd10 retinas. Stimulation thresholds were determined for cells with saturating stimulus response relationships (SRRs) but not for cells characterized by monotonically increasing or decreasing SRRs. MAIN RESULTS: Stimulation thresholds estimated in rd10 retinas ranged between 100-900 uC cm-2 for stimulation with small electrodes (30 um diameter). Threshold charge density decreased with increasing electrode size and plateaued at 20 uC cm-2 for an electrode diameter larger than 300 um. This trend of decreasing threshold down to a plateau value was confirmed in wild-type mouse retina suggesting an underlying physiological source. SIGNIFICANCE: Our results suggest the following guidelines for retinal prosthetics employing biphasic current pulses. The encoding of small objects may be achieved through the activation of a confined set of different retinal ganglion cells, with individual stimulation thresholds spanning a wide range of charge densities. The encoding of increasing object sizes may be achieved by decreasing stimulation charge density. PMID- 29717706 TI - Impact of specific training in anaphylaxis of the Triage nursing staff in a Tertiary Hospital's Paediatric Emergency Department. AB - BACKGROUND: After a diagnosis of anaphylaxis, patients receive action management plans to prevent and treat new episodes, including attending the Emergency Departments (ED) for control or further treatment. In a previous study, we observed that more than half of the children with anaphylaxis were incorrectly prioritized in our Paediatrics Emergency Unit (PEU), delaying their treatment. In conjunction with our PEU staff we designed a basic educational intervention (BEI) to try to solve this problem. We analyzed the effect of this intervention in the effective triage of the subsequent children diagnosed with anaphylaxis. METHODS: Our BEI consisted of a formative lecture given to the PEU triage nurses and the design of a Reference Card highlighting anaphylaxis symptoms and risk factors. We included 138 children with medical diagnosis of anaphylaxis and assessed modifications in their triage priority level and waiting times for physician (WT) after our intervention. According to the EI implementation date, 69 children were diagnosed before (G1) and 69 after (G2). Clinical data were compared to assess the severity of the episodes. RESULTS: There were no differences between groups. The WT diminished (from 8 to 1 minute [p: 0.03]), and the number of correctly identified patients increased (36.2% [G1] and 72.2% [G2][p= 0.0001]) after the BEI. CONCLUSIONS: Our BEI has been effective, improving the identification and priorization of children with anaphylaxis and reducing their WT. We need to pay attention to the functioning of our patients' reference ED and establish interdisciplinary measures that allow optimizing anaphylaxis' management. PMID- 29717708 TI - The precision of the symmetry in Z-ring placement in Escherichia coli is hampered at critical temperatures. AB - Cell division in Escherichia coli is morphologically symmetric due to, among other things, the ability of these cells to place the Z-ring at midcell. Studies have reported that, at sub-optimal temperatures, this symmetry decreases at the single-cell level, but the causes remain unclear. Using fluorescence microscopy, we observe FtsZ-GFP and DAPI-stained nucleoids to assess the robustness of the symmetry of Z-ring formation and positioning in individual cells under sub optimal and critical temperatures. We find the Z-ring formation and positioning to be robust at sub-optimal temperatures, as the Z-ring's mean width, density and displacement from midcell maintain similar levels of correlation to one another as at optimal temperatures. However, at critical temperatures, the Z-ring displacement from midcell is greatly increased. We present evidence showing that this is due to enhanced distance between the replicated nucleoids and, thus, reduced Z-ring density, which explains the weaker precision in setting a morphologically symmetric division site. This also occurs in rich media and is cumulative, i.e. combining richer media and critically high temperatures enhances the asymmetries in division, which is evidence that the causes are biophysical. To further support this, we show that the effects are reversible, i.e. shifting cells from optimal to critical, and then to optimal again, reduces and then enhances the symmetry in Z-ring positioning, respectively, as the width and density of the Z-ring return to normal values. Overall, our findings show that the Z-ring positioning in E. coli is a robust biophysical process under sub optimal temperatures, and that critical temperatures cause significant asymmetries in division. PMID- 29717709 TI - Structural rearrangements occurring upon cofactor binding in the Mycobacterium smegmatis beta-ketoacyl-acyl carrier protein reductase MabA. AB - In mycobacteria, the ketoacyl-acyl carrier protein (ACP) reductase MabA (designated FabG in other bacteria) catalyzes the NADPH-dependent reduction of beta-ketoacyl-ACP substrates to beta-hydroxyacyl-ACP products. This first reductive step in the fatty-acid biosynthesis elongation cycle is essential for bacteria, which makes MabA/FabG an interesting drug target. To date, however, very few molecules targeting FabG have been discovered and MabA remains the only enzyme of the mycobacterial type II fatty-acid synthase that lacks specific inhibitors. Despite the existence of several MabA/FabG crystal structures, the structural rearrangement that occurs upon cofactor binding is still not fully understood. Therefore, unlocking this knowledge gap could help in the design of new inhibitors. Here, high-resolution crystal structures of MabA from Mycobacterium smegmatis in its apo, NADP+-bound and NADPH-bound forms are reported. Comparison of these crystal structures reveals the structural reorganization of the lid region covering the active site of the enzyme. The crystal structure of the apo form revealed numerous residues that trigger steric hindrance to the binding of NADPH and substrate. Upon NADPH binding, these residues are pushed away from the active site, allowing the enzyme to adopt an open conformation. The transition from an NADPH-bound to an NADP+-bound form is likely to facilitate release of the product. These results may be useful for subsequent rational drug design and/or for in silico drug-screening approaches targeting MabA/FabG. PMID- 29717710 TI - Bacteroides thetaiotaomicron generates diverse alpha-mannosidase activities through subtle evolution of a distal substrate-binding motif. AB - A dominant human gut microbe, the well studied symbiont Bacteroides thetaiotaomicron (Bt), is a glyco-specialist that harbors a large repertoire of genes devoted to carbohydrate processing. Despite strong similarities among them, many of the encoded enzymes have evolved distinct substrate specificities, and through the clustering of cognate genes within operons termed polysaccharide utilization loci (PULs) enable the fulfilment of complex biological roles. Structural analyses of two glycoside hydrolase family 92 alpha-mannosidases, BT3130 and BT3965, together with mechanistically relevant complexes at 1.8-2.5 A resolution reveal conservation of the global enzyme fold and core catalytic apparatus despite different linkage specificities. Structure comparison shows that Bt differentiates the activity of these enzymes through evolution of a highly variable substrate-binding region immediately adjacent to the active site. These observations unveil a genetic/biochemical mechanism through which polysaccharide-processing bacteria can evolve new and specific biochemical activities from otherwise highly similar gene products. PMID- 29717711 TI - Determination of Patterson group symmetry from sparse multi-crystal data sets in the presence of an indexing ambiguity. AB - Combining X-ray diffraction data from multiple samples requires determination of the symmetry and resolution of any indexing ambiguity. For the partial data sets typical of in situ room-temperature experiments, determination of the correct symmetry is often not straightforward. The potential for indexing ambiguity in polar space groups is also an issue, although methods to resolve this are available if the true symmetry is known. Here, a method is presented to simultaneously resolve the determination of the Patterson symmetry and the indexing ambiguity for partial data sets. PMID- 29717713 TI - Crystal structure of pyrrolizidine alkaloid N-oxygenase from the grasshopper Zonocerus variegatus. AB - The high-resolution crystal structure of the flavin-dependent monooxygenase (FMO) from the African locust Zonocerus variegatus is presented and the kinetics of structure-based protein variants are discussed. Z. variegatus expresses three flavin-dependent monooxygenase (ZvFMO) isoforms which contribute to a counterstrategy against pyrrolizidine alkaloids (PAs). PAs are protoxic compounds produced by some angiosperm lineages as a chemical defence against herbivores. N Oxygenation of PAs and the accumulation of PA N-oxides within their haemolymph result in two evolutionary advantages for these insects: (i) they circumvent the defence mechanism of their food plants and (ii) they can use PA N-oxides to protect themselves against predators, which cannot cope with the toxic PAs. Despite a high degree of sequence identity and a similar substrate spectrum, the three ZvFMO isoforms differ greatly in enzyme activity. Here, the crystal structure of the Z. variegatus PA N-oxygenase (ZvPNO), the most active ZvFMO isoform, is reported at 1.6 A resolution together with kinetic studies of a second isoform, ZvFMOa. This is the first available crystal structure of an FMO from class B (of six different FMO subclasses, A-F) within the family of flavin dependent monooxygenases that originates from a more highly developed organism than yeast. Despite the differences in sequence between family members, their overall structure is very similar. This indicates the need for high conservation of the three-dimensional structure for this type of reaction throughout all kingdoms of life. Nevertheless, this structure provides the closest relative to the human enzyme that is currently available for modelling studies. Of note, the crystal structure of ZvPNO reveals a unique dimeric arrangement as well as small conformational changes within the active site that have not been observed before. A newly observed kink within helix alpha8 close to the substrate-binding path might indicate a potential mechanism for product release. The data show that even single amino-acid exchanges in the substrate-entry path, rather than the binding site, have a significant impact on the specific enzyme activity of the isoforms. PMID- 29717712 TI - Microfocus diffraction from different regions of a protein crystal: structural variations and unit-cell polymorphism. AB - Real macromolecular crystals can be non-ideal in a myriad of ways. This often creates challenges for structure determination, while also offering opportunities for greater insight into the crystalline state and the dynamic behavior of macromolecules. To evaluate whether different parts of a single crystal of a dynamic protein, EutL, might be informative about crystal and protein polymorphism, a microfocus X-ray synchrotron beam was used to collect a series of 18 separate data sets from non-overlapping regions of the same crystal specimen. A principal component analysis (PCA) approach was employed to compare the structure factors and unit cells across the data sets, and it was found that the 18 data sets separated into two distinct groups, with large R values (in the 40% range) and significant unit-cell variations between the members of the two groups. This categorization mapped the different data-set types to distinct regions of the crystal specimen. Atomic models of EutL were then refined against two different data sets obtained by separately merging data from the two distinct groups. A comparison of the two resulting models revealed minor but discernable differences in certain segments of the protein structure, and regions of higher deviation were found to correlate with regions where larger dynamic motions were predicted to occur by normal-mode molecular-dynamics simulations. The findings emphasize that large spatially dependent variations may be present across individual macromolecular crystals. This information can be uncovered by simultaneous analysis of multiple partial data sets and can be exploited to reveal new insights about protein dynamics, while also improving the accuracy of the structure-factor data ultimately obtained in X-ray diffraction experiments. PMID- 29717714 TI - Multi-position data collection and dynamic beam sizing: recent improvements to the automatic data-collection algorithms on MASSIF-1. AB - Macromolecular crystallography is now a mature and widely used technique that is essential in the understanding of biology and medicine. Increases in computing power combined with robotics have not only enabled large numbers of samples to be screened and characterized but have also enabled better decisions to be taken on data collection itself. This led to the development of MASSIF-1 at the ESRF, the first beamline in the world to run fully automatically while making intelligent decisions taking user requirements into account. Since opening in late 2014, the beamline has processed over 42 000 samples. Improvements have been made to the speed of the sample-handling robotics and error management within the software routines. The workflows initially put into place, while highly innovative at the time, have been expanded to include increased complexity and additional intelligence using the information gathered during characterization; this includes adapting the beam diameter dynamically to match the diffraction volume within the crystal. Complex multi-position and multi-crystal data collections have now also been integrated into the selection of experiments available. This has led to increased data quality and throughput, allowing even the most challenging samples to be treated automatically. PMID- 29717715 TI - KAMO: towards automated data processing for microcrystals. AB - In protein microcrystallography, radiation damage often hampers complete and high resolution data collection from a single crystal, even under cryogenic conditions. One promising solution is to collect small wedges of data (5-10 degrees ) separately from multiple crystals. The data from these crystals can then be merged into a complete reflection-intensity set. However, data processing of multiple small-wedge data sets is challenging. Here, a new open-source data processing pipeline, KAMO, which utilizes existing programs, including the XDS and CCP4 packages, has been developed to automate whole data-processing tasks in the case of multiple small-wedge data sets. Firstly, KAMO processes individual data sets and collates those indexed with equivalent unit-cell parameters. The space group is then chosen and any indexing ambiguity is resolved. Finally, clustering is performed, followed by merging with outlier rejections, and a report is subsequently created. Using synthetic and several real-world data sets collected from hundreds of crystals, it was demonstrated that merged structure factor amplitudes can be obtained in a largely automated manner using KAMO, which greatly facilitated the structure analyses of challenging targets that only produced microcrystals. PMID- 29717716 TI - Domain swap in the C-terminal ubiquitin-like domain of human doublecortin. AB - Doublecortin, a microtubule-associated protein that is only produced during neurogenesis, cooperatively binds to microtubules and stimulates microtubule polymerization and cross-linking by unknown mechanisms. A domain swap is observed in the crystal structure of the C-terminal domain of doublecortin. As determined by analytical ultracentrifugation, an open conformation is also present in solution. At higher concentrations, higher-order oligomers of the domain are formed. The domain swap and additional interfaces observed in the crystal lattice can explain the formation of doublecortin tetramers or multimers, in line with the analytical ultracentrifugation data. Taken together, the domain swap offers a mechanism for the observed cooperative binding of doublecortin to microtubules. Doublecortin-induced cross-linking of microtubules can be explained by the same mechanism. The effect of several mutations leading to lissencephaly and double cortex syndrome can be traced to the domain swap and the proposed self association of doublecortin. PMID- 29717717 TI - Structural insight into industrially relevant glucoamylases: flexible positions of starch-binding domains. AB - Glucoamylases are one of the most important classes of enzymes in the industrial degradation of starch biomass. They consist of a catalytic domain and a carbohydrate-binding domain (CBM), with the latter being important for the interaction with the polymeric substrate. Whereas the catalytic mechanisms and structures of the individual domains are well known, the spatial arrangement of the domains with respect to each other and its influence on activity are not fully understood. Here, the structures of three industrially used fungal glucoamylases, two of which are full length, have been crystallized and determined. It is shown for the first time that the relative orientation between the CBM and the catalytic domain is flexible, as they can adopt different orientations independently of ligand binding, suggesting a role as an anchor to increase the contact time and the relative concentration of substrate near the active site. The flexibility in the orientations of the two domains presented a considerable challenge for the crystallization of the enzymes. PMID- 29717718 TI - Density and electron density of aqueous cryoprotectant solutions at cryogenic temperatures for optimized cryoprotection and diffraction contrast. AB - The glass-phase densities at T = 77 K of aqueous solutions of the common cryoprotective agents (CPAs) methanol, ethanol, 2-propanol, glycerol, 2-methyl 2,4-pentanediol (MPD), ethylene glycol, polyethylene glycol 200 and polypropylene glycol 425 were measured as a function of CPA concentration. Individual drops with volumes as small as ~65 pl were rapidly cooled to achieve the glass phase, and their densities at T = 77 K were determined by cryoflotation. These densities were used to determine the glass-phase electron density of each solution and its volume thermal contraction between room temperature and 77 K. When combined with data for the critical cooling rates required to achieve the glass phase versus CPA concentration, these yield alternative measures of cryoprotectant effectiveness. These reference data will aid in minimizing sample stresses and mechanical damage in cryocrystallography, in cryogenic temperature X-ray imaging and in vitrification-based cryopreservation protocols, and in maximizing electron density contrast between cryoprotectant solutions and biomolecules in cryogenic temperature small-angle X-ray scattering experiments and cryo-electron microscopy. PMID- 29717719 TI - Orthorhombic lysozyme crystallization at acidic pH values driven by phosphate binding. AB - The structure of orthorhombic lysozyme has been obtained at 298 K and pH 4.5 using sodium chloride as the precipitant and in the presence of sodium phosphate at a concentration as low as 5 mM. Crystals belonging to space group P212121 (unit-cell parameters a = 30, b = 56, c = 73 A, alpha = beta = gamma = 90.00 degrees ) diffracted to a resolution higher than 1 A, and the high quality of these crystals permitted the identification of a phosphate ion bound to Arg14 and His15. The binding of this ion produces long-range conformational changes affecting the loop containing Ser60-Asn74. The negatively charged phosphate ion shields the electrostatic repulsion of the positively charged arginine and histidine residues, resulting in higher stability of the phosphate-bound lysozyme. Additionally, a low-humidity orthorhombic variant was obtained at pH 4.5, and comparison with those previously obtained at pH 6.5 and 9.5 shows a 1.5 A displacement of the fifth alpha-helix towards the active-site cavity, which might be relevant to protein function. Since lysozyme is broadly used as a model protein in studies related to protein crystallization and amyloid formation, these results indicate that the interaction of some anions must be considered when analysing experiments performed at acidic pH values. PMID- 29717720 TI - Ouabain Attenuates Sepsis-Induced Immunosuppression in Mice by Activation and Anti-Apoptosis of T Cells. AB - BACKGROUND Sepsis is known to trigger impaired T cell function, which relates to immunosuppression, contributing to refractory infection and high mortality. The mechanisms of T cell recovery remain to be elucidated, and novel and effective therapeutics for sepsis are needed. Ouabain, a small molecule of cardiac glycosides, can reverse immunoparalysis in many settings. MATERIAL AND METHODS Our study was designed to determine if ouabain can relieve sepsis by modulating T cell response and related pathways. The "two-hit" model of sepsis was applied, established by intraperitoneally LPS injection 3 days after cecal ligation puncture (CLP-LPS). Ouabain was administered to mice intravenously (0.1 mg/kg) after in vivo LPS stimulation every day for 4 days. The survival rate of mice, level of serum cytokines, percentage of activated T cells, apoptosis of T cells, and possibly related genes were assessed. RESULTS The results suggest that ouabain administration after establishment of the CLP-LPS model improved survival rates, elevated pro-inflammatory cytokines, and decreased anti-inflammatory cytokines in serum. More activated T cells and fewer apoptotic T cells were detected in the spleens after treatment with ouabain. Such changes might correlate with the genes of Bcl-2, PUMA, IRAK-M, and SOCS1. CONCLUSIONS Taken together, our data show ouabain is a T cell mediator during sepsis recovery. PMID- 29717721 TI - Precision Medicine: the Future of Critical Care. AB - NA. PMID- 29717722 TI - 1,2,4,5-Benzenetetracarboxylic acid: a versatile hydrogen bonding template for controlling the regioselective topochemical synthesis of head-to-tail photodimers from stilbazole derivatives. AB - The crystal engineering of hydrogen bonded organic assemblies based on 1,2,4,5 benzenetetracarboxylic acid (H4bta) and stilbazole derivatives (1-10) is exploited to provide regio-controlled [2 + 2] photocycloadditions in the solid state. Single crystal X-ray diffraction analyses have revealed that all the arrays are built-up from the self-assembly of the (H2bta)2- dianion with two stilbazolium cations via O-HO- and N+-HO- charge-assisted H-bonding synthons: (4 Hstilbazolium+)2(H2bta2-). The dianion displays an interesting diversity of H bonding motifs. Such structural flexibility allowed us to obtain four structure types defined by the preferential formation of intramolecular or intermolecular hydrogen bonds between carboxylate-carboxylic groups. In these ionic assemblies two predominant structural H-bonding patterns were observed. The first pattern is characterised by the formation of intramolecular H-bonds in the dianion, leading to discrete assemblies based on ternary arrays. The second hydrogen pattern consists of 2-D hydrogen networks built-up from the self-assembly of anions via intermolecular H-bonds that are linked to the cations. Two additional examples, in which the dianion is self-assembled in two types of ribbons, were also observed. Another supramolecular feature predominant in all these arrays is the stacking of the cations in a head-to-tail fashion, which is controlled via cation pi interactions. These arrays are photoactive in the solid state upon UV irradiation leading to the regioselective synthesis of rctt-cyclobutane head-to tail-isomers in high to quantitative yield. In this work, the template tolerance either to steric or electronic effects by changing the number or positions of the supramolecular interactions exerted by distinctive functional groups was also explored. In addition, assemblies bearing 2-chloro (7 and 8) and 3-chloro-4 stilbazole (1 and 9) crystallize in two different crystalline forms, leading to novel examples of supramolecular isomers with similar solid state reactivity. PMID- 29717724 TI - Minimising conformational bias in fluoroprolines through vicinal difluorination. AB - Monofluorination at the proline 4-position results in conformational effects, which is exploited for a range of applications. However, this conformational distortion is a hindrance when the natural proline conformation is important. Here we introduce (3S,4R)-3,4-difluoroproline, in which the individual fluorine atoms instil opposite conformational effects, as a suitable probe for fluorine NMR studies. PMID- 29717723 TI - Direct surface-enhanced Raman scattering (SERS) spectroscopy of nucleic acids: from fundamental studies to real-life applications. AB - Plasmonic optical biosensors for the analysis of nucleic acids have drawn a great deal of interest in nanomedicine because of their capability to overcome major limitations of conventional methods. Within this realm, surface-enhanced Raman scattering (SERS)-based sensing is progressively emerging as a powerful analytical tool beyond the basic grounds of academia to viable commercial products. SERS benefits from the synergistic combination between the intrinsic structural specificity and experimental flexibility of Raman spectroscopy, the extremely high sensitivity provided by plasmonic nanomaterials, and the tremendous advances in nanofabrication techniques and spectroscopic instrumentation. SERS application to nucleic acids analysis has been largely restricted to indirect sensing approaches, where a SERS reporter and oligonucleotide ligands are typically combined onto the nanomaterials to enable extrinsic detection of the target sequences. On the other hand, the acquisition of the intrinsic SERS vibrational fingerprint of nucleic acids (direct sensing) has traditionally suffered from major limitations. However, recent years have witnessed a burst of interest in this area, largely driven by the efforts to address key reproducibility and sensitivity issues. In this tutorial review, we summarize and discuss the most recent cutting-edge research in the field of direct SERS sensing of nucleic acids by coherently organising the diverse data reported in the literature in a structurally logical fashion. PMID- 29717725 TI - A triple modality BSA-coated dendritic nanoplatform for NIR imaging, enhanced tumor penetration and anticancer therapy. AB - Functional theranostic systems for drug delivery capable of concurrent near infrared (NIR) fluorescence imaging, active tumor targeting and anticancer therapies are desired for concise cancer diagnosis and treatment. Dendrimers with controllable size and surface functionalities are good candidates for such platforms. However, integration of active targeting ligands and imaging agents separately on the surface or encapsulation of the imaging agents in the inner core of the dendrimers will result in a more complex composition or reduced drug loading efficiency. Herein, we reported a PAMAM-based theranostic system, with a simple integrin-specific imaging ligand prepared from two motifs. One motif is a NIR carbocyanine fluorescent dye (Cyp) for precise in vivo monitoring of the system and identification of tumor or cancer cells, and the other is a novel tumor-penetrating cyclic peptide (CRGDKGPDC, abbreviated iRGD). BSA was non covalently bonded with Cyp to reduce NIR agent fluorescence-quenching aggregates and enhance imaging signals. The chemotherapy effect of these dendritic systems was achieved by encapsulating paclitaxel into the hydrophobic interior of the dendrimers. In vitro and in vivo targeting and penetrating studies revealed that a significantly high amount of the dendritic systems was endocytosed by HepG2 cells and enhanced accumulation and penetration at tumor sites. Our safety evaluation showed that masking of cationic-end groups of PAMAM to neutral or anionic groups has resulted in decreased or even zero-toxicity. The preliminary antitumor efficacy of the dendritic system was evaluated. In vitro and in vivo studies confirmed that paclitaxel-encapsulated functionalized PAMAM can efficiently kill HepG2 cancer cells. In conclusion, our functionalized theranostic dendritic system could be a promising nanocarrier to effectively deliver drugs to deep tumor regions for anticancer therapy. PMID- 29717726 TI - New insights into re-entrant melting of microgel particles by polymer-induced aggregation experiments. AB - While microgels are in general described as soft particles, polystyrene (PS) microgels can be synthesized in a way that cross-link density has only a minor influence on their physical properties. Even though the particles swell in a good solvent, the imparted slight softness still allows a mapping on hard sphere behaviour for a large range of cross-link densities [Schneider et al., Soft Matter, 2017, 13, 445]. Nevertheless, the hard sphere analogy breaks down as soon as polymer chains are added to these systems. Quantitative differences between PS microgels and true hard sphere systems appear and the differences between stronger and weaker cross-linked PS microgels can be observed. To gain deeper insights into the origin of these deviations from true hard sphere behaviour, this work is addressed to a systematic study of the colloid-polymer interactions in PS microgel-polymer mixtures. We investigated the aggregation behaviour (namely aggregation concentration and cluster structure) as a function of colloid size, cross-link density and colloid-polymer size ratio in very dilute colloidal suspensions. Our results show that the interplay of cross-link density and polymer size is a key parameter for the strength of the colloid-polymer interactions. Furthermore, the centre-to-centre distance of the colloidal particles in the formed clusters decreases if the cross-link density is decreased, allowing for a higher packing density. This may also explain the unusually high fluid packing fractions observed in the re-entry region of the phase diagram of PS microgel-free PS polymer mixtures. PMID- 29717727 TI - An antimicrobial bicyclic peptide from chemical space against multidrug resistant Gram-negative bacteria. AB - We used the concept of chemical space to explore a virtual library of bicyclic peptides formed by double thioether cyclization of a precursor linear peptide, and identified an antimicrobial bicyclic peptide (AMBP) with remarkable activity against several MDR strains of Acinetobacter baumannii and Pseudomonas aeruginosa. PMID- 29717728 TI - Reinforcement of polymeric nanoassemblies for ultra-high drug loadings, modulation of stiffness and release kinetics, and sustained therapeutic efficacy. AB - The optimization of current polymeric nanoparticle therapies is restricted by low drug loadings and limited tunability of core properties. To overcome these shortcomings, a novel self-association approach is utilized to fabricate a dual loaded poly(1,2-glycerol carbonate)-graft-succinic acid-paclitaxel (PGC-PTX) conjugate nanoparticle (NP) in which the physical entrapment of free paclitaxel (PTX) affords unprecedented ultra-high drug loadings >100 wt%, modulation of mechanical stiffness, and tunable release kinetics. Despite high incorporation of free PTX (up to 50 wt%), the dual-loaded PGC-PTX nanocarriers (i.e., PGC-PTX + PTX NPs) exhibit controlled and sustained drug release over 15 days, without burst release effects. Importantly, optimization of drug/material efficiency concomitantly affords improved in vitro efficacy. In vivo, PGC-PTX + PTX NPs are safely administered at doses exceeding the median lethal dose of standard PTX, while a single high dose significantly extends survival relative to weekly PTX administrations in a murine model of peritoneal carcinomatosis. PMID- 29717730 TI - Outstanding Reviewers for Nanoscale in 2017. PMID- 29717729 TI - What drives the H-abstraction reaction in bio-mimetic oxoiron-bTAML complexes? A computational investigation. AB - Monomeric iron-oxo units have been confirmed as intermediates involved in the C-H bond activation in various metallo-enzymes. Biomimetic oxoiron complexes of the biuret modified tetra-amido macrocyclic ligand (bTAML) have been demonstrated to oxidize a wide variety of unactivated C-H bonds. In the current work, density functional theory (DFT) has been employed to investigate the hydrogen abstraction (HAT) reactivity differences across a series of bTAML complexes. The cause for the differences in the HAT energy barriers has been found to be the relative changes in the energy of the frontier molecular orbitals (FMOs) induced by electronic perturbation. PMID- 29717731 TI - Static second hyperpolarizability of inverse sandwich compounds (M1-C5H5-M2) of alkali (M1 = Li, Na, K) and alkaline earth metals (M2 = Be, Mg, Ca). AB - In the investigated inverse sandwich complexes, charge transfer from alkali metal (M1) led to aromatically stabilized Cp ring, which prevented further charge transfer from the alkaline earth metal (M2). This electron push effect resulted in diffusion of electron density from the outermost "ns" subshell of alkaline earth metal. The alkaline earth metal is weakly bound to the alkali metal-C5H5 complex. The vertical ionization energy of the chosen M1-Cp-M2 complexes was smaller than that of the corresponding alkaline earth metals. Large second hyperpolarizability (106-108 a.u.) was obtained for the studied molecules. The correction due to the basis set superposition error (BSSE) in the calculated second hyperpolarizability was found to be small for larger systems, while it was rather significant for small systems. The MP4SDQ and CCSD results were in fair agreement, which indicates the necessity of higher order electron correlation treatment in the accurate description of second hyperpolarizability. Calculated dynamic second hyperpolarizabilities at 1064 nm were found to increase considerably for most of the chosen metal complexes. PMID- 29717732 TI - Recent progress in the tailored growth of two-dimensional hexagonal boron nitride via chemical vapour deposition. AB - Recent years have witnessed many advances in two-dimensional (2D) hexagonal boron nitride (h-BN) materials in both fundamental research and practical applications. This has ultimately been inspired by the unique electrical and optical properties, as well as the excellent thermal and chemical stability of h-BN. However, controllable and scalable preparation of 2D h-BN materials has been challenging. Very recently, the chemical vapour deposition (CVD) technique has shown great promise for achieving high-quality h-BN samples with excellent layer number selectivity and large-area uniformity, considerably contributing to the latest advancements of 2D material research. In this tutorial review, we provide a systematic summary of the state-of-the-art in the tailored production of 2D h BN on various substrates by virtue of CVD routes. PMID- 29717733 TI - Thresholds of photolysis of O2 and of formation of O3 from O2 dispersed in solid neon. AB - Irradiation of O2 dispersed in solid Ne with ultraviolet light produced infrared absorption lines of O3 and emission lines from atomic O (1D2 -> 3P1,2), molecular O2 (A' 3Deltau -> X 3Sigmag) and radical OH (A 2Sigma+ -> X 2PiI) in the visible and near-ultraviolet regions. The threshold wavelength for the formation of O3 was determined to be 200 +/- 4 nm, corresponding to energy 6.20 +/- 0.12 eV, which is hence the threshold for dissociation of O2. The thresholds of emission from excited O (1D2), O2 (A' 3Deltau) and OH (A 2Sigma+) were all observed to be 200 +/- 4 nm, the same as for the formation of O3 in this photochemical system. The results indicate that, once O3 was generated, it was readily photolyzed to produce the long-lived atom O (1D2). Further reactions of O (1D2) with O3 produced excited O2 (A' 3Deltau); reaction with water yielded radical OH (A 2Sigma+). These results enhance our understanding of the evolution of the transformation of oxygen and open a window for the understanding of complicated processes in the solid phase. PMID- 29717734 TI - Asymmetric twins in boron rich boron carbide. AB - Twin boundaries (TBs) play an essential role in enhancing the mechanical, electronic and transport properties of polycrystalline materials. However, the mechanisms are not well understood. In particular, we considered that they may play an important role in boron rich boron carbide (BvrBC), which exhibits promising properties such as low density, super hardness, high abrasion resistance, and excellent neutron absorption. Here, we apply first-principles based simulations to identify the atomic structures of TBs in BvrBC and their roles for the inelastic response to applied stresses. In addition to symmetric TBs in BvrBC, we identified a new type of asymmetric twin that constitutes the phase boundaries between boron rich boron carbide (B13C2) and BvrBC (B14C). The predicted mechanical response of these asymmetric twins indicates a significant reduction of the ideal shear strength compared to single crystals B13C2 and B14C, suggesting that the asymmetric twins facilitate the disintegration of icosahedral clusters under applied stress, which in turn leads to amorphous band formation and brittle failure. These results provide a mechanistic basis towards understating the roles of TBs in BvrBC and related superhard ceramics. PMID- 29717735 TI - Gelation of patchy ligand shell nanoparticles decorated by liquid-crystalline ligands: computer simulation study. AB - We consider the coarse-grained modelling of patchy ligand shell nanoparticles with liquid crystalline ligands. The cases of two, three, four and six symmetrically arranged patches of ligands are discussed, as well as the cases of their equatorial and icosahedral arrangement. A solution of decorated nanoparticles is considered within a slit-like pore with solid walls and the interior filled by a polar solvent. The ligands form physical cross-links between the nanoparticles due to strong liquid crystalline interaction, turning the solution into a gel-like structure. Gelation is carried out repeatedly starting each time from a freshly equilibrated dispersed state of nanoparticles. The gelation dynamics and the range of network characteristics of the gel are examined, depending on the type of patchy decoration and on the solution density. Emphasis is given to the theoretical prediction of the type of decoration and the solution density most suitable for producing a uniformly cross-linked and highly elastic gel structure. PMID- 29717736 TI - Maximum in density heterogeneities of active swimmers. AB - Suspensions of unicellular microswimmers such as flagellated bacteria or motile algae can exhibit spontaneous density heterogeneities at large enough concentrations. We introduce a novel model for biological microswimmers that creates the flow field of the corresponding microswimmers, and takes into account the shape anisotropy of the swimmer's body and stroke-averaged flagella. By employing multiparticle collision dynamics, we directly couple the swimmer's dynamics to the fluid's. We characterize the nonequilibrium phase diagram, as the filling fraction and Peclet number are varied, and find density heterogeneities in the distribution of both pullers and pushers, due to hydrodynamic instabilities. We find a maximum degree of clustering at intermediate filling fractions and at large Peclet numbers resulting from a competition of hydrodynamic and steric interactions between the swimmers. We develop an analytical theory that supports these results. This maximum might represent an optimum for the microorganisms' colonization of their environment. PMID- 29717741 TI - An ultra-broadband perovskite-PbS quantum dot sensitized carbon nanotube photodetector. AB - Organic-inorganic perovskites have been hailed as promising candidates for optoelectronic and photovoltaic devices, but their operation remains limited to the visible spectrum. Here, we combine single-wall carbon nanotubes, PbS quantum dots and a perovskite to synthesize hybrid devices suitable for operation in both the visible and near-infrared. The photodetectors thus fabricated show responsivities as high as 0.5 A W-1 and 0.35 A W-1 at 500 nm and at 1300 nm, respectively, with an applied bias of 1 V. Moreover, the incorporation of nanotubes within the perovskite matrix facilitates the carrier extraction, resulting in response time under 250 MUs, a gain-bandwidth product of 0.1 MHz and detectivities of 1.4 * 1011 Jones and 0.9 * 1011 Jones at 500 nm and at 1300 nm, respectively. This unique approach opens new pathways for the development of low cost, high-speed and broadband perovskite-based optoelectronic devices for large scale manufacturing. PMID- 29717739 TI - Suppression of T24 human bladder cancer cells by ROS from locally delivered hematoporphyrin-containing polyurethane films. AB - Systemic injection of a photosensitizer is a general method in photodynamic therapy, but it has complications due to the unintended systemic distribution and remnants of photosensitizers. This study focused on the possibility of suppressing luminal proliferative cells by excessive reactive oxygen species from locally delivered photosensitizer with biocompatible polyurethane, instead of the systemic injection method. We used human bladder cancer cells, hematoporphyrin as the photosensitizer, and polyurethane film as the photosensitizer-delivering container. The light source was a self-made LED (510 nm, 5 mW cm-2) system. The cancer cells were cultured on different doses of hematoporphyrin-containing polyurethane film and irradiated with LED for 15 minutes and 30 minutes each. After irradiating with LED and incubating for 24 hours, cell viability analysis, cell cycle analysis, apoptosis assay, intracellular and extracellular ROS generation study and western blot were performed. The cancer cell suppression effects of different concentrations of the locally delivered hematoporphyrin with PDT were compared. Apoptosis dominant cancer cell suppressions were shown to be hematoporphyrin dose-dependent. However, after irradiation, intracellular ROS amounts were similar in all the groups having different doses of hematoporphyrin, but these values were definitely higher than those in the control group. Excessive extracellular ROS from the intended, locally delivered photosensitizer for photodynamic treatment application had an inhibitory effect on luminal proliferative cancer cells. This method can be another possibility for PDT application on contactable or attachable lesions. PMID- 29717743 TI - Inhibition of drug-induced seizure development in both zebrafish and mouse models by a synthetic nanoreceptor. AB - A synthetic nanoreceptor, cucurbit[7]uril (CB[7]), fully encapsulated pentylenetetrazol (PTZ), a seizure-inducing model drug. As a consequence of the encapsulation, the development of PTZ induced convulsion behaviors in both larval zebrafish and mouse models were dramatically alleviated, suggesting that CB[7] holds great neuroprotection potential against neurotoxic drugs for clinical applications. PMID- 29717744 TI - Chemoselective epoxidation of cholesterol derivatives on a surface-designed molecularly imprinted Ru-porphyrin catalyst. AB - A new molecularly imprinted Ru-porphyrin complex catalyst on a SiO2 support was designed, prepared, and characterized in a step-by-step manner for the C5[double bond, length as m-dash]C6 epoxidation of cholesterol derivatives. High chemoselectivity for the C5[double bond, length as m-dash]C6 epoxidation of cholesterol derivatives without protecting the 3-position OH group and other oxidizable functional groups was achieved on the molecularly imprinted catalyst. PMID- 29717745 TI - Photocatalysis and self-catalyzed photobleaching with covalently-linked chromophore-quencher conjugates built around BOPHY. AB - Two Chromophore-Quencher Conjugates (CQCs) have been synthesized by covalent attachment of the anti-oxidant dibutylated-hydroxytoluene (BHT) to a pyrrole-BF2 chromophore (BOPHY) in an effort to protect the latter against photofading. In fluid solution, light-induced intramolecular charge transfer is favoured in polar solvents and helps to inhibit photo-bleaching of the chromophore. The rate of photo-fading, which scales with the number of BHT residues, is zero-order in polar solvents but shows a linear dependence on the number of absorbed photons. The zero-order rate constant shows an inverse correlation with the fluorescence quantum yield measured in the same solvent. Photo-bleaching in benzonitrile involves autocatalysis while reaction in cyclohexane shows an unexpected stoichiometry. NMR spectroscopy indicates initial damage takes place at the BHT unit and allows identification of a reactive hydroperoxide as being the primary product. In the presence of an adventitious substrate, this hydroperoxide is a photocatalyst for amide formation under mild conditions. PMID- 29717746 TI - PDA-assisted formation of ordered intermetallic CoPt3 catalysts with enhanced oxygen reduction activity and stability. AB - Structurally ordered intermetallic alloys with definite composition and distinct structure show great potential as electro-catalysts for the oxygen reduction reaction (ORR). However, their fabrication with small particle size remains a challenge since grain growth caused by high temperature annealing is unavoidable for the formation of the ordered phase. Here we propose an effective space confined strategy to prepare an intermetallic alloy with small size (CoPt3/C-S) through annealing of the disordered Pt-Co alloy coated with polydopamine (PDA). The CoPt3/C-S intermetallic catalyst exhibits over 7-fold higher ORR activity and comparable stability compared to large intermetallic nanoparticles (CoPt3/C-L) prepared by direct heat-treatment without PDA. The superior ORR performance of the CoPt3/C-S catalyst can be attributed to the abundant active sites and unsaturated coordinated bonds caused by its special electronic structure, as proved by XPS and XAS tests. This work not only proposes a feasible synthesis route for small intermetallic nanoparticles but also provides a valid strategy to improve the ORR performance of ordered intermetallic catalysts. PMID- 29717747 TI - Unique homo-heterojunction synergistic system consisting of stacked BiOCl nanoplate/Zn-Cr layered double hydroxide nanosheets promoting photocatalytic conversion of CO2 into solar fuels. AB - A unique homo-heterojunction synergistic system consisting of stacked BiOCl nanoplate/Zn-Cr layered double hydroxide (Zn-Cr LDH) nanosheets was rationally constructed via a simple electrostatic interaction between them. The purposeful spatial isolation of the holes in the crystal facet-based BiOCl homojunction from the BiOCl/Zn-Cr LDH heterojunction interface significantly increased the survivability of the electrons crossing therein. The optimized loading of Zn-Cr LDH in the system is the prerequisite for the enhanced photoconversion efficiency of CO2. PMID- 29717748 TI - The alpha-hydroxyphosphonate-phosphate rearrangement of a noncyclic substrate - some new observations. AB - Racemic ethyl hydrogen (1-hydroxy-2-methylsulfanyl-1-phenylethyl)phosphonate was resolved with (R)-1-phenylethylamine. The (R)-configuration of the (-)-enantiomer was determined by chemical correlation. Esterification of the (-)-enantiomer with a substituted diazomethane derived from 3-hydroxy-1,3,5(10)-estratrien-17-one delivered two epimeric phosphonates separated by HPLC. Methylation with methyl fluorosulfate at the sulfur atom and treatment with a strong base induced an alpha-hydroxyphosphonate-phosphate rearrangement with formation of dimethyl sulphide and two enantiomerically pure enol phosphates. Their oily nature interfered with a single crystal X-ray structure analysis to determine the stereochemistry at the phosphorus atom. PMID- 29717749 TI - A unique self-assembly-driven probe for sensing a lipid bilayer: ratiometric probing of vesicle to micelle transition. AB - An amphiphilic pyrene-terpyridine (Pytpy) probe forms novel, fluorescent nanoaggregates in phospholipid membranes. This unique membrane-driven self assembly of Pytpy shows large Stokes shifts and long-lived fluorescent states and efficiently reports on vesicle-micelle transition through ratiometric changes. Strikingly, Pytpy can even distinguish between bilayer-like domains and more dynamic micelle-like 'rim' phases that co-exist in mixed assemblies (bicelles). PMID- 29717750 TI - Synchronization of self-propelled soft pendulums. AB - We investigated self-propelled motions of thin filaments atop water, where we focused on understanding pendulum-type oscillations and synchronization. The filaments were produced from a commercial adhesive (consisting mainly of nitrocellulose and acetone), and exhibited deformable motions. One end of each filament was held on the edge of a quadrangular water chamber while the other was left free. Acetone and other organic molecules from the nitrocellulose filament develop on the water surface and decrease the surface tension. The difference in the surface tension around the filament becomes the driving force of the self propelled motions. When a single filament was placed in the water chamber, a pendulum-type oscillation in the deformation of the filament was observed. When two filaments were placed in parallel in the chamber, in-phase, out-of-phase, and no-synchronization motions were observed. It was found that the class of motions depends on the distance between the two fixed points of the filaments. Mathematical modeling and numerical simulations were also used in order to further understand the dynamics of the surface active molecules and the filament motions. We propose a mathematical model equation and reproduce various behaviors exhibited by soft self-propelled matters through numerical simulation. PMID- 29717751 TI - How does the total charge and isomerism influence the Ru-NO ammine complexes? AB - Nitric oxide plays an important role in several physiological processes. This study investigates model ruthenium ammine coordination compounds to control NO bioavailability: cis-[RuCl(NO)(NH3)4]+ (1+), cis-[RuCl(NO)(NH3)4]2+ (12+), cis [RuCl(NO)(NH3)4]3+ (13+), trans-[RuCl(NO)(NH3)4]+ (2+), trans-[RuCl(NO)(NH3)4]2+ (22+), trans-[RuCl(NO)(NH3)4]3+ (23+), [Ru(NO)(NH3)5]+ (3+), [Ru(NO)(NH3)5]2+ (32+), and [Ru(NO)(NH3)5]3+ (33+). We employed natural population analysis (NPA) atomic charges (qNPA) and the LUMO to identify the main reduction sites in the complexes 1, 2 and 3. For example, in the transformations 12+ -> 1+, 22+ -> 2+, and 33+ -> 32+, the main reduction site was a NO pi* orbital, which accounted for the lower electron density of the Ru-NO bond critical point (BCP) in 1+, 2+, and 32+ than 12+, 22+, and 33+, respectively, as shown by the quantum theory of atoms in molecules (QTAIM). The QTAIM method indicated that the electron density was larger in Ru-NO BCP due to the Cl negative cis- and trans-influence in 12+ and 22+, respectively, as compared with the NH3 influence in 33+. Compared to trans Cl-Ru-NO in 22+, the interacting quantum atoms method demonstrated that cis-Cl-Ru NO in 12+ displayed (i) a larger repulsive electrostatic energy, which agreed with qNPA, and (ii) a less negative exchange-correlation energy between Ru and the NO nitrogen atom, which agreed with topological analyses performed by the QTAIM method. Thus, the combination of topological and energy decomposition analyses allowed the mechanism behind the Ru-NO bond to be revealed regarding the influence of the total charge and the relative position of the ligands. PMID- 29717754 TI - Editorial: Involving Primary Care Health Professionals in Geriatric Assessment. PMID- 29717753 TI - Editorial: Dysphagia, Dementia and Frailty. PMID- 29717755 TI - Mediterranean Diet, Food Consumption and Risk of Late-Life Depression: The Mugello Study. AB - OBJECTIVES: To investigate eating habits and adherence to Mediterranean Diet (MD) in relation to the risk of depression in a cohort of nonagenarians enrolled within the Mugello Study, an epidemiological study aimed at investigating both clinically relevant geriatric items and various health issues, including those related to nutritional status. DESIGN: Cross-sectional study. SETTING: Homes and nursing homes in the Mugello area, Florence, Italy. PARTICIPANTS: Subjects aged 90-99 years [N=388 (271F; 117M) mean age: 92.7+/-3.1]. MEASUREMENTS: All subjects were evaluated through questionnaires and instrumental examinations. Adherence to MD was assessed through the Mediterranean Diet Score. A shorter version of the Geriatric Depression Scale (GDS) was used to detect the possible presence of depressive symptoms. In addition, cognitive and functional status was assessed using the Mini-Mental State Examination, the Clock Drawing Test, as well as the Basic and Instrumental Activities of Daily Living test. RESULTS: Depressed subjects (DS) (GDS score>=5, 43.8%) were older, females and widows, than non depressed subjects (NDS). DS reported a slightly but not statistically significant lower MD score than NDS (33.9+/-3.9 vs. 34.6+/-3.3, p=0.149). Subjects who reported to consume a greater amount of olive oil and fruit were associated with a lower risk of depression (OR=0.35, 95%CI=0.20-0.59, p<0.001 and OR=0.46, 95%CI=0.26-0.84, p=0.011, respectively) after adjustment for many possible confounders. Similar results were obtained for women, while no statistically significant differences emerged for men. CONCLUSION: Our results support the hypothesis that a diet rich in olive oil and fruit, characteristics of MD, may protect against the development of depressive symptoms in older age. PMID- 29717756 TI - Dietary Behaviors among Young and Older Adults in Brazil. AB - OBJECTIVES: To describe healthy and unhealthy dietary behaviors among young and older Brazilian adults. DESIGN: Cross-sectional study based on secondary data from the Brazilian National Health Survey 2013/2014, conducted by the Brazilian Institute of Geography and Statistics (IBGE). SETTINGS: Brazil. PARTICIPANTS: 59,402 Brazilian adults (18 years or over), representative of the whole community dwelling Brazilian adult population. MEASUREMENTS: Frequency of regular (5 days/week or more) consumption of food considered of a healthy diet (fruit, vegetables, greens, cooked vegetables, beans, milk, chicken, fish) and unhealthy diet (red meat, soda and sweets, meal replacement for fast food and high salt consumption) was investigated. Differences among young adults (18-39 years), middle-aged adults (40-59 years) and older adults (60+ years) were assessed through 95% confidence intervals and logistic regression models with contrast function, considering the complexity of the sample and the sample weight of the research. RESULTS: Less than half of the population reported consuming fruit regularly (41.3%, 95% CI = 40.5 - 42.2) and only one quarter reported consuming vegetables regularly (25.4%, 95% CI = 24.7 - 26.1). Regular consumption of soft drinks was cited by 26.6% (95% CI = 25.5 - 27.6) for men and 20.6% (95% CI = 19.8 - 21.4) for women. Young adults presented, in general, lower frequency of regular consumption of healthy food and higher frequency of unhealthy food when compared to middle-aged and the older adults. CONCLUSION: Current dietary behaviors adopted by the Brazilian population is characterized by a high prevalence of inadequate food intake, mainly among young adults calling the attention to the necessity for age-specific public health interventions. PMID- 29717757 TI - The Role of Nutritional Status in Elderly Patients with Heart Failure. AB - Evidence indicates that malnutrition very frequently co-occurs with chronic heart failure (HF) and leads to a range of negative consequences. Studies show associations between malnutrition and wound healing disorders, an increased rate of postoperative complications, and mortality. In addition, considering the increasing age of patients with HF, a specific approach to their treatment is required. Guidelines proposed by the European Society of Cardiology (ESC) for treating acute and chronic HF refer to the need to monitor and prevent malnutrition in HF patients. However, the guidelines feature no strict nutritional recommendations for HF patients, who are at high nutritional risk as a group, nor do they offer any such recommendations for the poor nutritional status subgroup, for which high morbidity and mortality rates have been observed. In the context of multidisciplinary healthcare, recommended by the ESC and proven by research to offer multifaceted benefits, nutritional status should be systematically assessed in HF patients. Malnutrition has become a challenge within healthcare systems and day-to-day clinical practice, especially in developed countries, where it affects the course of disease and patients' prognosis. PMID- 29717758 TI - The Association of Inflammation with Food Intake in Older Hospitalized Patients. AB - OBJECTIVES: An acute inflammatory process may play a role in inhibiting appetite and food intake particularly in acutely ill older individuals. However, there is a lack of knowledge on the effect of inflammation on food intake in humans. In this study, we sought to investigate the association of C-reactive protein (CRP), as an inflammatory marker, with food intake in acutely ill older hospitalized patients. DESIGN AND SETTING: This cross-sectional study investigated older participants who were consecutively admitted to a geriatric acute care ward. Food intake during previous week was measured according to the Nutritional Risk Screening (NRS-2002) and patients were grouped into two categories as intake >=75% and <75% of requirements. Disease severity and mobility were measured based on the NRS-2002 and Mini Nutritional Assessment Short Form (MNA-SF), respectively. Serum CRP was analyzed according to standard procedures. RESULTS: Of 177 older participants (mean age 83.1 +/- 6.5 y, BMI range of 14.7-43.6 kg/m2; 116 females), 67 (38.0%) had moderate to severe inflammation (CRP>3.0 mg/dl). In addition, 109 (62.0%) patients had intake <75% of requirements during previous week, in which 34 (31.0%) and 54 (50.0%) demonstrated mild and moderate to severe inflammation, respectively. Furthermore, there were significant differences in CRP levels between intake >=75% and <75% of requirements (P<0.001). In a logistic regression analysis, CRP level (odds ratio; OR, 1.14; P=0.006), disease severity (OR, 2.94; P=0.022), mobility (OR, 0.44; P=0.005) and BMI (OR, 0.89; P=0.003) were the major independent predictors of low food intake. CONCLUSION: Our findings confirm a close association between food intake and inflammation in older hospitalized patients. In addition, CRP level and disease severity together were the most important independent predictors associated with food intake in these patients. PMID- 29717759 TI - Age-Related 12-Year Changes in Dietary Diversity and Food Intakes among Community Dwelling Japanese Aged 40 to 79 Years. AB - OBJECTIVES: This study describes trends in dietary diversity and food intake over 12 years according to age at first participation in the study. DESIGN: Prospective cohort study. SETTING: The National Institute for Longevity Sciences Longitudinal Study of Aging, a community-based study. PARTICIPANTS: Participants included 922 men and 879 women who participated in the first study-wave (age, 40 79 years) and also participated in at least one study-wave from the second to seventh study-wave. Study-waves were conducted biennially. MEASUREMENTS: Dietary intake was calculated from 3-day dietary records with photographs. Dietary diversity was determined using the Quantitative Index for Dietary Diversity based on food intake. A mixed-effects model was used to estimate linear changes in dietary diversity and food intake over 12 years according to age at first study wave. RESULTS: Mean (standard deviation (SD)) follow-up time and number of study wave visits were 9.5 (3.7) years and 5.4 (1.8), respectively. Mean (SD, range) dietary diversity score was 0.86 (0.06, 0.52-0.96) in men and 0.88 (0.04, 0.66 0.96) in women, respectively. Fixed effects for interactions of age and time with dietary diversity score were statistically significant (p<0.05). The slope of dietary diversity among men aged 40 to 55 years increased (40-year-old slope = 0.00093/year, p<0.01; 55-year-old slope = 0.00035/year, p=0.04), with a decreasing trend started at 65 years old, although this trend was not significant (65-year-old slope = -0.00003/year, p=0.88; 79-year-old slope = -0.00057/year, p=0.21). The slope of dietary diversity among women aged 40 to 44 years increased (40-year-old slope = 0.00053/year, p=0.02; 44-year-old slope = 0.00038/year, p=0.04), whereas the slope of dietary diversity among women aged 63 to 79 years decreased (63-year-old slope = -0.00033/year, p=0.03; 79-year-old slope = 0.00092/year, p<0.001). Fruit, milk and dairy intake decreased in men around their 60s; milk and dairy intake decreased in women around their 50s; and beans and fruit intake decreased in women from their 70s. CONCLUSION: Twelve-year longitudinal data showed dietary diversity declined in women in their 60s. In terms of food intake, fruit, milk and dairy intake decreased in both sexes in their 50s and 60s; such declines would lower dietary diversity. PMID- 29717760 TI - Relation of Disease with Standardized Phase Angle among Older Patients. AB - BACKGROUND: A low phase angle (PA) has been associated with negative outcome in specific diseases. However, many patients suffer from several co-morbidities. This study aims at identifying the impact of the type and the severity of diseases on PA in a retrospective cohort study of older people. METHODS: We included all people >=65 years who underwent a PA measurement (Nutriguard(r)) between 1990 and 2011 at the Geneva University Hospitals. PA was standardized for gender, age and body mass index according to German reference values. Co morbidities were reported in form of the Cumulative Illness Rating Scale which considers 14 different organs/systems (disease categories), each rated from 0 (healthy) to 4 (severe illness) (severity grades). The association between the diseases categories and standardized PA was evaluated by a multivariate linear regression. For each significant disease category, we performed univariate regression models. The adjusted R2 was used to identify the best predictors of standardized PA. We considered that the severity grade affected standardized PA if there was a progressive decrease in the regression coefficients. RESULTS: We included 1181 people (37% women). The multivariate regression model showed that the disease categories explain 17% of the variance of standardized PA. Many disease categories affect standardized PA and the ones best associated with standardized PA were the hematopoietic and vascular (R2 7.4%), the musculo skeletal (R2 5.5%) and the respiratory (R2 4.0%) diseases. The regression coefficients in the univariate linear regression model decreased progressively with higher severity grades in respiratory (-0.15, -0.27, -0.55, -0.67) and musculo-skeletal diseases (-0.09, -0.46, -0.85, -0.86). CONCLUSIONS: Many different diseases affect standardized PA. The higher the severity grade in musculo-skeletal and respiratory diseases, the lower is the standardized PA. PMID- 29717761 TI - Selenium Concentrations and Mortality among Community-Dwelling Older Adults: Results from IlSIRENTE Study. AB - BACKGROUND: Selenium has a wide range of pleiotropic effects, influencing redox homeostasis, thyroid hormone metabolism, and protecting from oxidative stress and inflammation. Serum selenium levels are reduced in the older population. OBJECTIVES: to investigate the association of serum selenium levels with all cause mortality in a sample of community-dwelling older adults. DESIGN AND SETTING: Data are from the 'Invecchiamento e Longevita nel Sirente' (Aging and Longevity in the Sirente geographic area, ilSIRENTE) study, a prospective cohort study that collected information on individuals aged 80 years and older living in an Italian mountain community (n=347). The main outcome was risk of death after ten years of follow-up. PARTICIPANTS AND MEASUREMENTS: Participants were classified according to the median value of selenium (105.3 MUg/L) in two groups: high selenium and low selenium. RESULTS: A total of 248 deaths occurred during a 10-year follow-up. In the unadjusted model, low levels of selenium was associated with increased mortality (HR, 0.66; 95% CI 0.51-0.85). After adjusting for potential confounders the relationship remained significant (HR, 0.71; 95% CI 0.54-0.92). CONCLUSIONS: Low serum levels of selenium are associated with reduced survival in elderly, independently of age and other clinical and functional variables. PMID- 29717762 TI - Adherence to the Mediterranean Diet and the Risk of Frailty in Old People: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Frailty is a common geriatric syndrome in old people. It remains controversial whether Mediterranean diet could prevent old people from developing into frailty. The aim of this study is to summarize the relevant studies and assess the effectiveness of adherence to Mediterranean diet on frailty in old people. METHOD: A systematic search of MEDLINE, EMBASE and Cochrane Central Register of Controlled Trials was conducted to identify all relevant studies up to Oct 2017. We included studies regarding the associations between adherence to Mediterranean diet and risk of frailty among elders. A meta-analysis was performed to explore the effects of Mediterranean diet on frailty. RESULTS: Six studies matched the inclusion criteria, of which five were prospective and one was cross-sectional. A total of 10,210 participants from the five prospective cohort studies were included to perform the meta-analyses. In comparison with lowest adherence to Mediterranean diet, elders with highest adherence to Mediterranean diet were significantly associated with lower risk of frailty in the future (RR= 0.56, 95% CI=0.36-0.89, p=0.015). Furthermore, the pooled estimates from four studies performed among participants in western countries (European and North American) showed that higher adherence to Mediterranean diet was associated with a 52% reduced risk of frailty (RR= 0.48, 95% CI=0.32-0.72, p<0.001). However, one study showed no association between Mediterranean diet and frailty among Asian elders (RR=1.06, 95% CI=0.83-1.36, p=0.638). CONCLUSION: A higher adherence to Mediterranean diet is associated with a lower risk of frailty in old people. Meanwhile, the benefits may be more obvious among elders from western countries. PMID- 29717763 TI - Influence of Dietary Patterns and Inflammatory Markers on Atherosclerosis Using Ankle Brachial Index as a Surrogate. AB - OBJECTIVE: To examine the influence of various dietary patterns on ankle-brachial index (ABI) as a surrogate of atherosclerosis, taking into account serum levels of C-reactive protein (CRP) and factors that predispose to inflammation and/or endothelial damage (homocysteine) or may be protective (tryptophan, vitamin D), as well as age, gender, and lifestyle risk factors. DESIGN: Cross sectional analysis. SETTING: Cohort of 4000 men and women aged 65 years living in the community in Hong Kong SAR China. MEASUREMENTS: Interviewer administered questionnaire that includes dietary intake estimation by the food frequency records (from which various dietary patterns can be characterized), socioeconomic status, smoking habit, alcohol consumption, physical activity. Clinical measurements include body weight and height, and ankle-brachial index using hand held Doppler machine. Laboratory measurements include assays of serum 25 hydroxyvitamin D, CRP, homocysteine, and tryptophan using LC/MC methods. RESULT: Compared with the lowest quintile of vitamin D level, higher quintile was associated with lower prevalence of ABI <0.9 in women only after multiple adjustments of covariates. In men the low score group of the vegetables-fruits dietary pattern was associated with increased odds of having ABI<0.9 after adjusting for all covariates (OR=16.51 (95% CI: 2.21, 123.26)). Similar findings apply to the low score group in the MIND (Mediterranean-DASH Intervention for Neurodegenerative Delay Diet) pattern (OR=2.6 (95% CI: 1.24, 5.42)). In women, ABI<0.9 was associated with low Dietary Quality Index (DQI) score (OR=2.05 (95% CI: 1.22, 3.43)), and low score group of snacks-drinks-milk products dietary pattern (OR=3.07 (95% CI: 1.05, 9.04)). No association was observed for the Mediterranean Dietary Pattern (MDS), Dietary Approaches to Stop Hypertension (DASH), Okinawan and "meat-fish" dietary patterns in either men or women. CONCLUSION: We conclude that any dietary patterns emphasizing fruit and vegetable intake are associated with better vascular health using ABI as an indicator. PMID- 29717764 TI - Status of Geriatrics in 22 Countries. AB - OBJECTIVES: The aim of this article is to describe the current status of geriatrics and position of geriatricians in 22 countries of three continents, and to portray their attitudes towards and resources allocated to geriatrics. METHODS: An electronic survey was delivered to a convenience sample of 22 geriatricians in leading positions of their countries. RESULTS: The time required in post graduation specialist training to become a geriatrician varied from one year (subspecialty in the USA) to six years (independent specialty in Belgium). The number in the population aged 80+ per geriatrician varied from 450 (Austria) to 25,000 (Turkey). Of respondents, 55% reported that geriatrics is not a popular specialty in their country. Acute geriatric wards, rehabilitation and outpatient clinics were the most common working places for geriatricians. Nearly half of the respondents had an opinion that older patients who were acutely ill, were receiving subacute rehabilitation or had dementia should be cared for by geriatricians whereas half of the respondents would place geriatricians also in charge of nursing home and orthogeriatric patients. The biggest problems affecting older people's clinical care in their countries were: lack of geriatric knowledge, lack of geriatricians, and attitudes towards older people. Half of respondents thought that older people's health promotion and comprehensive geriatric assessment were not well implemented in their countries, although a majority felt that they could promote good geriatric care in their present position as a geriatrician. CONCLUSION: The position of geriatric, geriatricians' training and contents of work has wide international variety. PMID- 29717765 TI - Bromodomain-containing protein 4 is critical for the antiproliferative and pro apoptotic effects of gambogic acid in anaplastic thyroid cancer. AB - Gambogic acid (GA) has been widely used as an anticancer drug for different tumors, including thyroid cancer. However, the potential function and molecular mechanisms of GA in anaplastic thyroid cancer (ATC) has not been illustrated thus far. The aim of the present study was to demonstrate the antitumor effects of GA on ATC cells and investigate its underlying molecular mechanisms. The results revealed that GA significantly decreased the viability and proliferation, as well as induced cell apoptosis in ATC cell lines. Next, it was demonstrated that GA decreased the expression of bromodomain-containing protein 4 (BRD4), which has been reported to function as an oncogene in various types of cancer. BRD4 expression was significantly higher in ATC tissues compared with that in adjacent normal thyroid tissues. In addition, BRD4 silencing significantly repressed the cell viability and proliferation, and increased the cell apoptotic rate in vitro, while it also delayed the tumor growth in vivo. Notably, ectopic BRD4 expression significantly weakened the biological effects of GA on ATC cells in vitro and in vivo, which suggested that GA served its anticancer functions partially via downregulating BRD4. In conclusion, BRD4, functioning as an oncogene in ATC, is important for the antiproliferative and pro-apoptotic effects of GA. PMID- 29717766 TI - Bu-Shen-Ning-Xin decoction suppresses osteoclastogenesis by modulating RANKL/OPG imbalance in the CD4+ T lymphocytes of ovariectomized mice. AB - Postmenopausal osteoporosis (PMO) has been recognized as an inflammatory condition. CD4+ T cells serve a key role in the interaction between bone metabolism and the immune system. Bu-Shen-Ning-Xin decoction (BSNXD), a traditional Chinese medicine, has been ultilized as a remedy for PMO. In the present study, the aim was to investigate the immune modulatory effects of BSNXD on CD4+ T cells, receptor activation of nuclear factor kappaB ligand (RANKL)/osteoprotegerin (OPG) imbalance, skeletal parameters and osteoclastogenesis. Ovariectomized (OVX) mice were treated with a series of concentrations of BSNXD and then autopsied. The bone phenotype was analyzed by micro computed tomography. CD4+ T cells were isolated and their percentage was measured using flow cytometry (FCM). RANKL and OPG expression by the CD4+ T cells at the transcriptional and translational levels were quantified by reverse transcription-quantitative polymerase chain reaction, ELISA and FCM. CD4+ T cells were cultured with blood serum derived from BSNXD-treated OVX mice (BSNXD-derived serum) and the apoptosis rate was quantified by FCM. CD4+ T cells were co cultured with bone marrow-derived macrophages and exposed to BSNXD-derived serum to whether CD4+ T cells are involved in BSNXD-modulated osteoclastogenesis and the results were quantified via tartrate-resistant acid phosphatase staining. The results revealed that BSNXD ameliorated OVX-induced bone loss, prevented the expansion of CD4+ T cells and restored the RANKL/OPG imbalance in the CD4+ T cells of OVX mice. In vitro, BSNXD-derived serum promoted the apoptosis of CD4+ T cells. The co-culture system demonstrated that CD4+ T cells from OVX mice increase osteoclastogenesis, while this effect was suppressed by BSNXD administration. The findings of the study collectively suggest that BSNXD exerts an immunoprotective effect on the bone phenotype of OVX mice by ameliorating RANKL/OPG imbalance in CD4+ T cells and attenuating osteoclastogenesis. PMID- 29717767 TI - Bisphosfonate matrix metalloproteinase inhibitors for the treatment of periodontitis: An in vitro study. AB - Periodontitis is an inflammatory disease caused by anaerobic bacteria, including Porphyromonas gingivalis. Lipopolysaccharide (LPS)-stimulated persistent inflammation is responsible for an increase in matrix metalloproteinase (MMP) expression, resulting in periodontal tissue destruction. The aim of the present study was to investigate synthesized bisphosphonic MMP inhibitors, in an in vitro model consisting of human gingival fibroblasts exposed to LPS, and to compare the biological responses to those induced by zoledronate (ZA), a commercial bisphosphonate. MTT and lactate dehydrogenase (LDH) assays were used to measure cell viability and cytotoxicity, respectively. ELISA was performed to evaluate prostaglandin E2 (PGE2), interleukin (IL)6 and collagen secretion, while western blotting was used to analyze MMP expression. No effect on viability and low cytotoxicity were observed following treatment with bisphosphonate compounds. In the present study, treatment with compound 1 did not increase the release of PGE2 and IL6. Increased levels of collagen I secretion were reported when compound 3 and ZA were administered. An increase of MMP8 was observed following ZA treatment, while a decrease of MMP9 and MMP14 following treatment with compounds 1, 2 and ZA were reported. The performance of compound 1 was optimal in terms of cell viability. Compound 1 also did not induce inflammation, and had the ability to counteract LPS-induced increases in MMP expression. These data suggested that compound 1 was the most suitable treatment to progress to an in vivo animal study, with the aim to confirm its use for the treatment of periodontitis. PMID- 29717768 TI - Breviscapine ameliorates CCl4-induced liver injury in mice through inhibiting inflammatory apoptotic response and ROS generation. AB - Acute liver injury is characterized by fibrosis, inflammation and apoptosis, leading to liver failure, cirrhosis or cancer and affecting the clinical outcome in the long term. However, no effective therapeutic strategy is currently available. Breviscapine, a mixture of flavonoid glycosides, has been reported to have multiple biological functions. The present study aimed to investigate the effects of breviscapine on acute liver injury induced by CCl4 in mice. C57BL/6 mice were subjected to intraperitoneal injection with CCl4 for 8 weeks with or without breviscapine (15 or 30 mg/kg). Mice treated with CCl4 developed acute liver injury, as evidenced by histological analysis, Masson trichrome and Sirius Red staining, accompanied with elevated levels of alanine aminotransferase and aspartate aminotransferase. Furthermore, increases in pro-inflammatory cytokines, chemokines and apoptotic factors, including caspase-3 and poly(ADP ribose) polymerase-2 (PARP-2), were observed. Breviscapine treatment significantly and dose-dependently reduced collagen deposition and the fibrotic area. Inflammatory cytokines were downregulated by breviscapine through inactivating Toll-like receptor 4/nuclear factor-kappaB signaling pathways. In addition, co administration of breviscapine with CCl4 decreased the apoptotic response by enhancing B-cell lymphoma-2 (Bcl-2) levels, while reducing Bcl-2-associated X protein, apoptotic protease activating factor 1, caspase-3 and PARP activity. Furthermore, CCl4-induced oxidative stress was blocked by breviscapine through improving anti-oxidants and impeding mitogen-activated protein kinase pathways. The present study highlighted that breviscapine exhibited liver-protective effects against acute hepatic injury induced by CCl4 via suppressing inflammation and apoptosis. PMID- 29717769 TI - Prognostic significance of microsatellite instability-associated pathways and genes in gastric cancer. AB - The aim of the present study was to reveal the potential molecular mechanisms of microsatellite instability (MSI) on the prognosis of gastric cancer (GC). The investigation was performed based on an RNAseq expression profiling dataset downloaded from The Cancer Genome Atlas, including 64 high-level MSI (MSI-H) GC samples, 44 low-level MSI (MSI-L) GC samples and 187 stable microsatellite (MSI S) GC samples. Differentially expressed genes (DEGs) were identified between the MSI-H, MSI-L and MSI-S samples. Pathway enrichment analysis was performed for the identified DEGs and the pathway deviation scores of the significant enrichment pathways were calculated. A Multi-Layer Perceptron (MLP) classifier, based on the different pathways associated with the MSI statuses was constructed for predicting the outcome of patients with GC, which was validated in another independent dataset. A total of 190 DEGs were selected between the MSI-H, MSI-L and MSI-S samples. The MLP classifier was established based on the deviation scores of 10 significant pathways, among which antigen processing and presentation, and inflammatory bowel disease pathways were significantly enriched with HLA-DRB5, HLA-DMA, HLA-DQA1 and HLA-DRA; the measles, toxoplasmosis and herpes simplex infection pathways were significantly enriched with Janus kinase 2 (JAK2), caspase-8 (CASP8) and Fas. The classifier performed well on an independent validation set with 100 GC samples. Taken together, the results indicated that MSI status may affect GC prognosis, partly through the antigen processing and presentation, inflammatory bowel disease, measles, toxoplasmosis and herpes simplex infection pathways. HLA-DRB5, HLA-DMA, HLA-DQA1, HLA-DRA, JAK2, CASP8 and Fas may be predictive factors for prognosis in GC. PMID- 29717770 TI - Stanozolol administration combined with exercise leads to decreased telomerase activity possibly associated with liver aging. AB - Anabolic agents are doping substances which are commonly used in sports. Stanozolol, a 17alpha-alkylated derivative of testosterone, has a widespread use among athletes and bodybuilders. Several medical and behavioral adverse effects are associated with anabolic androgenic steroids (AAS) abuse, while the liver remains the most well recognized target organ. In the present study, the hepatic effects of stanozolol administration in rats at high doses resembling those used for doping purposes were investigated, in the presence or absence of exercise. Stanozolol and its metabolites, 16-beta-hydroxystanozolol and 3' hydroxystanozolol, were detected in rat livers using liquid chromatography-mass spectrometry (LC-MS). Telomerase activity, which is involved in cellular aging and tumorigenesis, was detected by examining telomerase reverse transcriptase (TERT) and phosphatase and tensin homolog (PTEN) expression levels in the livers of stanozolol-treated rats. Stanozolol induced telomerase activity at the molecular level in the liver tissue of rats and exercise reversed this induction, reflecting possible premature liver tissue aging. PTEN gene expression in the rat livers was practically unaffected either by exercise or by stanozolol administration. PMID- 29717771 TI - Identification and antioxidant activity of synthetic peptides from phycobiliproteins of Pyropia yezoensis. AB - The objective of the present study was to identify peptides, based on active components of the red algae seaweed Pyropia yezoensis, able to inhibit the generation of reactive oxygen species (ROS), which is associated with aging and oxidative activities. Phycobilin, specific to red algae, covalently binds with water-soluble proteins. There are three types of pigment bound proteins, known as phycobiliproteins (PBPs): Phycoerythrin (PE), phycocyanin (PC) and allophycocyanin (APC). In the present study, PBPs reported previously to have antioxidant activities in P. yezoensis were identified and, based on these data, several peptides were synthesized (PBP 1-13) and their inhibition of ROS generation was examined. The existence of PBPs of each type, PE, PC and APC, was established in P. yezoensis and all were analyzed. In addition, PBP 1-2 and 7-9 peptides from PE were synthesized and showed antioxidant activities in HepG2 cells. In HepG2 cells, treatment with PBP2 reduced hydrogen peroxide-mediated oxidative stress and restored the expression of superoxide dismutase (SOD). Furthermore, phosphorylated nuclear factor erythroid-derived 2-like 2 (Nrf2) was elevated by PBP2 treatment. Overall, these results suggested that Nrf2-SOD pathways may be involved in the PBP2-mediated antioxidant effects. Therefore, from the investigations of P. yezoensis, several candidate peptides were identified with promising antioxidant and, potentially, anti-aging properties. PMID- 29717772 TI - Connexin 43 reduces susceptibility to sympathetic atrial fibrillation. AB - Atrial fibrillation (AF) is the most common arrhythmia reported in clinical practice. Connexin 43 (Cx43) is a member of the connexin protein family, which serves important roles in signal transduction in vivo. The aim of the present study was to investigate the role of Cx43 in the induction and maintenance of atrial fibrillation by using an animal model of sympathomimetic atrial fibrillation. Cx43 was successfully knocked down in the myocardium with gene specific small interfering (si)RNA via lentiviral infection. A total of 25 dogs were randomly and evenly divided into five groups: Normal (N), rapid atrial pacing (RAP), isoproterenol (ISO) + RAP, RAP + Cx43 siRNA and ISO + RAP + Cx43 siRNA. The mRNA and protein levels, as well as the distribution of Cx43 on the cell membrane, were gradually decreased in each group compared with the N group following treatment (P<0.05). The induction rate of the atrial effective refractory period was not significantly affected in the RAP and RAP + Cx43 siRNA groups, whereas it was significantly reduced in the ISO + RAP and ISO + RAP + Cx43 siRNA groups compared with the N group (P<0.05). The induction rate of AF was gradually increased in the RAP + Cx43 siRNA, ISO + RAP and ISO + RAP + Cx43 siRNA groups compared with the N group (P<0.05). The expression of nerve growth factor (NGF) and tyrosine hydroxylase (TH) was gradually increased in the ISO + RAP and ISO + RAP + Cx43 siRNA groups compared with their respective controls (RAP and RAP + Cx43 siRNA groups, respectively). However, no significant difference in the levels of NGF and TH was observed between the RAP, RAP + Cx43 siRNA, ISO + RAP and ISO + RAP + Cx43 siRNA groups. The mitochondrial morphology in each group was notably altered compared with the N group. The mitochondrial reactive oxygen species production and apoptotic index were gradually increased in each group compared with the N group (P<0.05). The results of the present study suggest that Cx43 reduces susceptibility to AF. Downregulation of Cx43 mediates the induction and maintenance of sympathetic AF. PMID- 29717773 TI - Cucurbitacin B inhibits tumor angiogenesis by triggering the mitochondrial signaling pathway in endothelial cells. AB - Cucurbitacin B (CuB), the active component of a traditional Chinese herbal medicine, Pedicellus Melo, has been shown to exhibit antitumor and anti inflammation effects, but its role in tumor angiogenesis, the key step involved in tumor growth and metastasis, and the involved molecular mechanism are unknown. Tumor angiogenesis is one of the hallmarks of the development in malignant neoplasias and metastasis. Effective targeting of tumor angiogenesis is a key area of interest for cancer therapy. Here, we demonstrated that CuB significantly inhibited human umbilical vascular endothelial cell (HUVEC) proliferation, migration, tubulogenesis in vitro, and blocked angiogenesis in chick embryo chorioallantoic membrane (CAM) assay in vivo. Furthermore, CuB induced HUVEC apoptosis and may induce apoptosis by triggering the mitochondrial apoptotic pathway. Finally, we found that CuB inhibiting angiogenesis was associated with inhibition of the activity of vascular endothelial growth factor receptor 2 (VEGFR2). Our investigations suggested that CuB was a potential drug candidate for angiogenesis related diseases. PMID- 29717774 TI - Physcion 8-O-beta-glucopyranoside extracted from Polygonum cuspidatum exhibits anti-proliferative and anti-inflammatory effects on MH7A rheumatoid arthritis derived fibroblast-like synoviocytes through the TGF-beta/MAPK pathway. AB - The present study aimed to investigate the anti-arthritic effect of physcion 8-O beta-glucopyranoside (POGD) and its possible mechanisms. The anti-proliferative effects of POGD on MH7A cells were detected using a CCK-8 assay, and the release of pro-inflammatory cytokines, interleukin (IL)-1beta, IL-6, IL-8, IL-12 and IL 17A, were determined by ELISA. A type II collagen-induced arthritis (CIA) rat model was established to evaluate the anti-arthritic effect of POGD in vivo. The paw volumes, arthritis indices and serum levels of tumor necrosis factor (TNF) alpha, IL-1beta, IL-6, IL-8, IL-17A were determined by ELISA. The mRNA expression levels of matrix metalloproteinase (MMP)-2, MMP-3, MMP-9, vascular endothelial growth factor and cyclooxygenase-2 were determined by reverse transcription quantitative polymerase chain reaction analysis, and the expression levels of transforming growth factor (TGF)-beta1, small mothers against decapentaplegic (Smad)4, Smad7, c-Jun N-terminal kinase (JNK), phosphorylated (p-)JNK, p-P38, P38, p-extracellular signal-regulated kinase (ERK)1/2, ERK1/2, nuclear factor (NF)-kappaB p65 in the nucleus (N), cytosolic NF-kappaB p65 (C), and inhibitor of NF-kappaB (IkappaB) were determined by western blot analysis. The results indicated that POGD significantly inhibited MH7A cell growth. POGD markedly inhibited paw swelling and the arthritis indices of the CIA rats, and POGD may also inhibit the release of pro-inflammatory cytokines. Furthermore, POGD downregulated the expression levels of TGF-beta1, Smad4, NF-kappaB p65 (N), p38, p-p38, p-ERK1/2, JNK, p-JNK, TGF-beta1, Smad4, p-JNK, JNK, p-P38, P38, p-ERK1/2, ERK1/2 and NF-kappaB p65 (N), and upregulated the Smad7, NF-kappaB p65 (C) and IkappaB in TNF-alpha induced MH7A cells. In conclusion, the results suggested that POGD is a promising potential anti-inflammatory drug, and that POGD may decrease the expression of pro-inflammatory cytokines and mediators via inhibiting the TGF-beta/NF-kappaB/mitogen-activated protein kinase pathways. PMID- 29717776 TI - Proximal optimization technique, proximal rewiring, side-branch dilation and paired balloon inflation to minimize metal carina in inadequate jailing. PMID- 29717777 TI - Syncope and right-sided heart failure due to right ventricular outflow tract obstruction by giant sinus of Valsalva aneurysm. PMID- 29717775 TI - Xanthatin inhibits corneal neovascularization by inhibiting the VEGFR2-mediated STAT3/PI3K/Akt signaling pathway. AB - Alkali burn is one of the main causes of corneal injury. The inflammation and neovascularization caused by alkali burns aggravate corneal damage, resulting in loss of vision. The aim of the present study was to evaluate the efficacy of xanthatin in the treatment of alkali burn-induced inflammation and neovascularization. A CCK-8 assay was used to detect the effects of different concentrations of xanthatin on the proliferation of human umbilical vein endothelial cells (HUVECs). The effects of xanthatin on the migration of HUVECs and the ability of lumen formation were examined using a scratch test and lumen formation assay, respectively. A total of 60 Sprague-Dawley rats were randomly divided into two groups to establish a corneal alkali burn model, and were treated with PBS and xanthatin eye drops four times a day. A slit lamp microscope recorded changes of the cornea at 0, 4, 7, 10 and 14 days, and the inflammatory indices of the cornea and the neovascular area were evaluated. The expression levels of vascular endothelial growth factor (VEGF) and pigment epithelium derived factor (PEDF) in the cornea under different treatment conditions were detected using immunofluorescence and western blot analysis. In order to investigate the mechanism of xanthatin on the inhibition of inflammation and neovascularization, HUVECs were treated with xanthatin and PBS following VEGF treatment. The subcellular localization of signal transducer and activator of transcription 3 (STAT3) was detected using immunofluorescence. The expression levels of VEGF receptor 2 (VEGFR2), STAT3, phosphoinositide 3-kinase (PI3K) and Akt were detected using western blot analysis. The results revealed that xanthatin inhibited the proliferation of HUVECs in a concentration-dependent manner. The migration ability and lumen-forming ability of the HUVECs were also inhibited by xanthatin. Slit lamp microscopy showed that the inflammatory index and the area of neovascularization in the xanthatin-treated group were significantly reduced, compared with those in the PBS treatment group. The xanthatin treatment group exhibited a lower protein expression level of VEGF and increased protein expression level of PEDF, compared with the PBS treatment group. In the VEGF-treated HUVECs, xanthatin significantly decreased the expression levels of p-VEGFR2, phosphorylated (p-)STAT3, p-PI3K and p-Akt. In conclusion, the present study confirmed that xanthatin inhibited corneal neovascularization and inflammation in the alkali burn model, elucidating the underlying mechanisms involved in its protective effects. Therefore, xanthatin may be a novel drug for the treatment of corneal alkali burn. PMID- 29717778 TI - A stealing syndrome after an iliaco-mesenteric bypass graft. PMID- 29717779 TI - Personality and atrioventricular nodal reentrant tachycardia, beyond the topic. PMID- 29717780 TI - Exercise dose in clinical practice: Right is better than more. PMID- 29717781 TI - Exercise dose in clinical practice: Should safety limits be set? PMID- 29717782 TI - Targeting an epicardial-endocardial breakthrough in a case with an intractable common atrial flutter using ultra-high-resolution three-dimensional mapping. AB - The recent development of high-density high-spatial resolution three-dimensional mapping has provided detailed information for understanding complicated atrial activation patterns at a level not previously possible. Using this technology, we report a case with recurrent common atrial flutter, demonstrating the presence of a bridging epicardial fiber that traveled across the previous cavotricuspid isthmus ablation lesion with apparent epicardial-endocardial breakthrough (EEB) sites located on both sides of the ablation line. The entrainment study indicated that the EEB site, located adjacent to the coronary sinus ostium, was part of the recurrent circuit and a focal ablation targeting that site terminated the tachycardia. PMID- 29717783 TI - Magnetic Binary Silicide Nanostructures. AB - In spite of numerous advantageous properties of silicides, magnetic properties are not among them. Here, the magnetic properties of epitaxial binary silicide nanostructures are discussed. The vast majority of binary transition-metal silicides lack ferromagnetic order in their bulk-size crystals. Silicides based on rare-earth metals are usually weak ferromagnets or antiferromagnets, yet both groups tend to exhibit increased magnetic ordering in low-dimensional nanostructures, in particular at low temperatures. The origin of this surprising phenomenon lies in undercoordinated atoms at the nanostructure extremities, such as 2D (surfaces/interfaces), 1D (edges), and 0D (corners) boundaries. Uncompensated superspins of edge atoms increase the nanostructure magnetic shape anisotropy to the extent where it prevails over its magnetocrystalline counterpart, thus providing a plausible route toward the design of a magnetic response from nanostructure arrays in Si-based devices, such as bit-patterned magnetic recording media and spin injectors. PMID- 29717784 TI - Intracellular rupture, exocytosis and actin interaction of endocytic vacuoles in pancreatic acinar cells: initiating events in acute pancreatitis. AB - KEY POINTS: Giant trypsin-containing endocytic vacuoles are formed in pancreatic acinar cells stimulated with inducers of acute pancreatitis. F-actin envelops endocytic vacuoles and regulates their properties. Endocytic vacuoles can rupture and release their content into the cytosol of acinar cells. Endocytic vacuoles can fuse with the plasma membrane of acinar cells and exocytose their content. ABSTRACT: Intrapancreatic activation of trypsinogen is an early event in and hallmark of the development of acute pancreatitis. Endocytic vacuoles, which form by disconnection and transport of large post-exocytic structures, are the only resolvable sites of the trypsin activity in live pancreatic acinar cells. In the present study, we characterized the dynamics of endocytic vacuole formation induced by physiological and pathophysiological stimuli and visualized a prominent actin coat that completely or partially surrounded endocytic vacuoles. An inducer of acute pancreatitis taurolithocholic acid 3-sulphate and supramaximal concentrations of cholecystokinin triggered the formation of giant (more than 2.5 MUm in diameter) endocytic vacuoles. We discovered and characterized the intracellular rupture of endocytic vacuoles and the fusion of endocytic vacuoles with basal and apical regions of the plasma membrane. Experiments with specific protease inhibitors suggest that the rupture of endocytic vacuoles is probably not induced by trypsin or cathepsin B. Perivacuolar filamentous actin (observed on the surface of ~30% of endocytic vacuoles) may play a stabilizing role by preventing rupture of the vacuoles and fusion of the vacuoles with the plasma membrane. The rupture and fusion of endocytic vacuoles allow trypsin to escape the confinement of a membrane-limited organelle, gain access to intracellular and extracellular targets, and initiate autodigestion of the pancreas, comprising a crucial pathophysiological event. PMID- 29717785 TI - Concentrated Sunlight for Materials Synthesis and Diagnostics. AB - Herein, the use of highly concentrated sunlight for materials science research is reviewed. Specific research directions include: (1) the generation of inorganic nanostructures, some of which had eluded experimental realization with conventional synthetic processes, and (2) elucidating the processes governing the degradation of organic and perovskite-based photovoltaic materials and devices, along with accelerated assessment of their stability. Both approaches employ solar concentrators capable of producing flux densities exceeding those of terrestrial solar radiation by up to three orders of magnitude, and are geared toward either creating extensive ultrahot reactor conditions conducive to the rapid, safe synthesis of unusual nanomaterials or judiciously interrogating photovoltaic devices. PMID- 29717786 TI - A Theoretical Outlook on the Stereoselectivity Origins of Isoselective Zirconocene Propylene Polymerization Catalysts. AB - The first three insertion steps of propylene for isoselective metallocenes from the one-carbon-bridged cyclopentadienyl-fluorenyl {Cp/Flu} and silicon-bridged ansa-bis(indenyl) {SBI} families were computed by using a theoretical method implementing the B3PW91 functional in combination with solvent corrections incorporated with the Solvation Model based on Density (SMD) continuum model. For C1 -symmetric {Cp/Flu}-type metallocenes, two mechanisms of stereocontrol were validated theoretically: more facile and more stereoselective chain "stationary" insertion (or site epimerization backskip) and less stereoselective alternating mechanisms. For the C2 -symmetric {SBI}-type system, the computation results were in complete agreement with the sole operating chain migratory insertion mechanism. The thermochemical data obtained through the study were used to predict microstructures of polypropylenes by using three-parameter and one parameter statistical models for the two metallocene systems, respectively. The calculated meso/rac pentad distributions were found to be in good agreement with those determined experimentally for isotactic polypropylene samples obtained at different polymerization temperatures. PMID- 29717787 TI - Isotropic morphometry and multicomponent T1 rho mapping of human knee articular cartilage in vivo at 3T. AB - BACKGROUND: The progressive loss of hyaline articular cartilage due to osteoarthritis (OA) changes the functional and biochemical properties of cartilage. Measuring the T1 rho along with the morphological assessment can potentially be used as noninvasive biomarkers in detecting early-stage OA. To correlate the biochemical and morphological data, submillimeter isotropic resolution for both studies is required. PURPOSE: To implement a high spatial resolution 3D-isotropic-MRI sequence for simultaneous assessment of morphological and biexponential T1 rho relaxometry of human knee cartilage in vivo. STUDY TYPE: Prospective. POPULATION: Ten healthy volunteers with no known inflammation, trauma, or pain in the knee. FIELD STRENGTH/SEQUENCE: Standard FLASH sequence and customized Turbo-FLASH sequence to acquire 3D-isotropic-T1 rho-weighted images on a 3T MRI scanner. ASSESSMENT: The mean volume and thickness along with mono- and biexponential T1 rho relaxations were assessed in the articular cartilage of 10 healthy volunteers. STATISTICAL TESTS: Nonparametric rank-sum tests. Bland-Altman analysis and coefficient of variation. RESULTS: The mean monoexponential T1 rho relaxation was 40.7 +/- 4.8 msec, while the long and short components were 58.2 +/- 3.9 msec and 6.5 +/- 0.6 msec, respectively. The mean fractions of long and short T1 rho relaxation components were 63.7 +/- 5.9% and 36.3 +/- 5.9%, respectively. Statistically significant (P <= 0.03) differences were observed in the monoexponential and long components between some of the regions of interest (ROIs). No gender differences between biexponential components were observed (P > 0.05). Mean cartilage volume and thickness were 25.9 +/- 6.4 cm3 and 2.2 +/- 0.7 mm, respectively. Cartilage volume (P = 0.01) and thickness (P = 0.03) were significantly higher in male than female participants across all ROIs. Bland Altman analysis showed agreement between two morphological methods with limits of agreement between -1000 mm3 and +1100 mm3 for volume, and -0.78 mm and +0.46 mm for thickness, respectively. DATA CONCLUSION: Simultaneous assessment of morphological and multicomponent T1 rho relaxation of knee joint with 0.7 * 0.7 * 0.7 mm isotropic spatial resolution is demonstrated in vivo. Comparison with a standard method showed that the proposed technique is suitable for assessing the volume and thickness of articular cartilage. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;48:1707-1716. PMID- 29717788 TI - Assessment of liver ischemia reperfusion injury in mice using hepatic T2 mapping: Comparison with histopathology. AB - BACKGROUND: Liver ischemia reperfusion injury (IRI) occurs during liver surgery or transplantation resulting in an inflammatory response, tissue damage, and functional impairment of the organ. PURPOSE: To assess the feasibility of T2 mapping for noninvasive quantification of liver edema after partial liver IRI in mice. STUDY TYPE: Prospective, experimental study. ANIMAL MODEL: Partial liver IRI was induced in C57BL/6-mice by transient clamping of the left lateral and median liver lobes for 35 (n = 8), 45 (n = 6), 60 (n = 17), or 90 minutes (n = 5). For comparison, healthy C57BL/6-mice were examined as controls (n = 9). FIELD STRENGTH/SEQUENCE: Functional liver MRI was performed on a 7T scanner using a respiratory-triggered multiecho spin-echo sequence. ASSESSMENT: Healthy control mice and mice with partial liver IRI on day 1 after surgery, and additionally on day 7 in a subgroup with 60 minutes IRI (n = 8) were examined. Maps of T2 relaxation time of liver tissue were used to assess distribution, severity of tissue edema (mean T2 time), and the percentage of edematous liver tissue. STATISTICAL TEST: One-way analysis of variance (ANOVA) with Tukey's honest significant difference (HSD), paired t-tests, Pearson's test for correlation of MRI parameters with levels of liver enzymes, and histopathology, receiver operating characteristic (ROC) analysis. RESULTS: Significant tissue edema induced by liver IRI as compared to the control group was detected by increased mean T2 times in groups with 60 minutes (P < 0.001) and 90 minutes IRI (P < 0.001). The percentage of edematous liver tissue significantly increased with longer ischemia times (controls 3.4 +/- 0.4%, 35 minutes 5.3 +/- 0.6%, 45 minutes 23.3 +/- 7.6%, 60 minutes 39.7 +/- 3.6%, 90 minutes 51.3 +/- 4.5%). Mean T2 times and the percentage of edematous liver tissue significantly correlated with elevation of liver enzymes (P < 0.001), histological evidence of liver injury (r = 0.80 and r = 0.82, P < 0.001), and neutrophil infiltration (r = 0.70 and r = 0.74, P < 0.001). In the subgroup with follow-up, the severity (P < 0.01) and extent of liver edema decreased significantly over time (P < 0.01). DATA CONCLUSION: T2 mapping allows quantification and follow-up of liver injury in mice. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1586-1594. PMID- 29717789 TI - Response to: Can patch test sensitization with gold sodium thiosulfate be ruled out?-A case report. PMID- 29717790 TI - Use of diffusion kurtosis imaging and quantitative dynamic contrast-enhanced MRI for the differentiation of breast tumors. AB - BACKGROUND: Breast MRI is a sensitive imaging technique to assess breast cancer but its effectiveness still remains to be improved. PURPOSE: To evaluate the diagnostic performance of diffusion-weighted imaging (DWI), diffusion kurtosis imaging (DKI), and quantitative dynamic contrast-enhanced (DCE)-MRI in differentiating malignant from benign breast lesions independently or jointly and to explore whether correlations exist among these parameters. STUDY TYPE: Retrospective. POPULATION: In all, 106 patients with breast lesions (47 malignant, 59 benign). SEQUENCE: DKI sequence with seven b values and quantitative DCE sequence on 3.0T MRI. ASSESSMENT: Diffusion parameters (mean diffusivity [MD], mean diffusivity [MK], and apparent diffusion coefficient [ADC]) from DKI and DWI and perfusion parameters from DCE (Ktrans , kep , ve , and vp ) were calculated by two experienced radiologists after postprocessing. Disagreement between the two observers was resolved by consensus. STATISTICAL TESTS: The parameters in benign and malignant lesions were compared by Student's t-test. The diagnostic performances of DKI and quantitative DCE, either alone or in combination, were evaluated by receiver operating characteristic (ROC) analysis. The Spearman correlation test was used to evaluate correlations among the diffusion parameters and perfusion parameters. RESULTS: MK, MD, ADC, Ktrans , and kep values were significantly different between breast cancer and benign lesions (P < 0.05). MK from DKI demonstrated the highest AUC of 0.849, which is significantly higher than ADC derived from conventional DWI (z = 3.345, P = 0.0008). The specificity of DCE-MRI-derived parameters was improved when combining diffusion parameters, such as ADC and MK. The highest diagnostic specificity (93.2%) was obtained when kep and ADC were combined. kep was correlated moderately positively with MK (r = 0.516) and moderately negatively with MD (r = -0.527). Ktrans was weakly positively correlated with MK with an r of 0.398 and weakly negatively correlated with MD with an r of -0.450. DATA CONCLUSION: DKI is more valuable than conventional DWI in distinguishing between benign and malignant breast lesions. DKI exhibits promise as a quantitative technique to augment quantitative DCE-MRI. Diffusion parameters derived from DKI were statistically correlated with perfusion parameters from quantitative DCE MRI. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1358-1366. PMID- 29717791 TI - Perceived organizational support-burnout-satisfaction relationship in workers with disabilities: The moderation of family support. AB - Our study tests the perceived organizational support-burnout-satisfaction relationship based on stressor-strain-outcome model of stress (Koeske & Koeske, ) and on the conservation of resources theory (Hobfoll, ) in workers with disabilities employed in ordinary or competitive jobs (open labor market), analyzing the relationship between perceived organizational support, family support, job satisfaction and burnout. We use a sample of 246 workers with physical, motor, sensory and psychological disabilities working in ordinary jobs. To test our proposed model we used a regression-based path analysis using PROCESS software, which is a computational tool for estimating and probing interactions and the conditional indirect effects of moderated mediation models. We find that the positive relationship between organizational support and job satisfaction was partially mediated by the levels of cynicism and the relationship between burnout and job satisfaction was moderated by family support. Employees with low support from family had identical job satisfaction with high burnout or low burnout, but employees with high support from family when they had high burnout had lower job satisfaction than when they had low burnout, indicating that the support outside work could have a negative effect in workers' life. Practical implications and future research are discussed and proposed. PMID- 29717792 TI - Systematic review on the characterization of chronic traumatic encephalopathy by MRI and MRS. AB - BACKGROUND: Chronic traumatic encephalopathy (CTE) is a neurodegenerative disease that is found in people who have suffered from chronic traumatic brain injury (TBI). Up to now, diagnosis of CTE could only be made based on postmortem histopathological examinations. The application of MR techniques might offer a promising possibility for in vivo diagnoses. PURPOSE/HYPOTHESIS: To provide a critical systematic review of the characterization of chronic TBI and CTE by considering the range of MR techniques. STUDY TYPE: This was a systematic review for which the electronic databases PubMed and Embase were searched using the terms ("chronic traumatic encephalopathy" OR "punch drunk syndrome" OR "chronic traumatic brain injury" OR "dementia pugilistica" OR "chronic head trauma") AND ("magnetic resonance imaging" OR mri OR imaging OR mrs OR "magnetic resonance spectroscopy" OR spectroscopy). POPULATION/SUBJECTS/PHANTOM/SPECIMEN/ANIMAL MODEL: Of the 432 studies identified by the database search, 25 were included in this review. FIELD STRENGTH/SEQUENCE: Diffusion, structural, and functional MRI sequences and MR spectroscopy were evaluated at 1.5T or 3T and at 11.74T for the ex vivo studies. ASSESSMENT: Data were extracted by two reviewers independently. Specific inclusion and exclusion criteria like the study design, publication type, and applied MR techniques were used to select studies for review. STATISTICAL TESTS: Results of the original research articles were stated in this review as significant if P <= 0.05. RESULTS: Of the included articles, two were ex vivo studies focusing on the coregistration of histology and MRI. All other studies were based on in vivo data. DATA CONCLUSION: The included studies varied considerably regarding study setup, MR techniques, and results. Nevertheless, this work aims to establish links between the studies and discusses the results and limitations associated with the characterization of chronic TBI and CTE based on MR. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;00:000-000. PMID- 29717794 TI - Are treatment results for eating disorders affected by ADHD symptoms? A one-year follow-up of adult females. AB - OBJECTIVE: To explore the influence of self-reported Attention Deficit Hyperactivity Disorder (ADHD) symptoms on recovery rate at 1-year follow-up in an unselected group of patients in a specialized eating disorder (ED) clinic. METHODS: Four hundred forty-three adult females with an ED were assessed with the ADHD Self-Report Scale for Adults (ASRS-screener), and for demographic variables and ED symptoms. Recovery was registered at 1-year follow-up. RESULTS: A high degree of ADHD symptoms at baseline was predictive for nonrecovery of ED at 1 year follow-up in patients with loss of control over eating, bingeing, or purging. The presence of inattentive ADHD symptoms was stronger associated with nonrecovery than hyperactive/impulsive symptoms. CONCLUSIONS: A high degree of ADHD symptoms may have a negative impact on recovery in ED. Screening/diagnostic evaluation of ADHD in all loss of control over eating/bingeing/purging ED patients and studies of the effect of implementing ADHD-treatment strategies in this patient group are recommended. PMID- 29717795 TI - Bronchiectasis: Yet another systemic disease? PMID- 29717793 TI - Drug-induced dysphoria is enhanced following prolonged cocaine abstinence and dynamically tracked by nucleus accumbens neurons. AB - Negative reinforcement models postulate that addicts use drugs to alleviate negative affective states (e.g. dysphoria) associated with withdrawal. In a pre clinical model, rats exhibit negative affect to a normally rewarding tastant when it predicts impending, but delayed cocaine, and nucleus accumbens (NAc) neurons dynamically track this state. Here, we examined the effects of short versus prolonged experimenter-imposed cocaine abstinence on negative affect, cocaine seeking and self-administration. Rats were given 14 saccharin-cocaine sessions; NAc activity and affective responses to the taste (i.e. taste reactivity) were measured during sessions 1 and 14. Next, following 1 or 30 days of abstinence, taste reactivity and cell firing were recorded in a three-phase test session: (1) intraoral saccharin infusions, (2) extinction and (3) cocaine self administration. Results showed that 30 days of abstinence led to a significant enhancement of aversive responses to the cocaine-paired tastant, accompanied by a dramatic decline in NAc phasic activity during tastant infusion. While extinction behavior did not differ across groups, NAc phasic firing reemerged during drug seeking. Further, when drug was again readily available, greater aversion to the drug-paired tastant before and after abstinence was associated with increased self-administration following prolonged (30-day) abstinence in rats classified as high (not low) aversive. Collectively, these findings show that drug-induced dysphoria is enhanced following prolonged cocaine abstinence and that NAc neural signaling is dynamic, dampening when negative affect is at its highest (phase 1), but transitioning back 'online' during subsequent drug seeking and taking (phases 2 and 3). PMID- 29717796 TI - Galaninergic intramural nerve and tissue reaction to antral ulcerations. AB - BACKGROUND: Well-developed galaninergic gastric intramural nerve system is known to regulate multiple stomach functions in physiological and pathological conditions. Stomach ulcer, a disorder commonly occurring in humans and animals, is accompanied by inflammatory reaction. Inflammation can cause intramural neurons to change their neurochemical profile. Galanin and its receptors are involved in inflammation of many organs, however, their direct participation in stomach reaction to ulcer is not known. Therefore, the aim of the study was to investigate adaptive changes in the chemical coding of galaninergic intramural neurons and mRNA expression encoding Gal, GalR1, GalR2, GalR3 receptors in the region of the porcine stomach directly adjacent to the ulcer location. METHODS: The experiment was performed on 24 pigs, divided into control and experimental groups. In 12 experimental animals, stomach antrum ulcers were experimentally induced by submucosal injection of acetic acid solution. Stomach wall directly adjacent to the ulcer was examined by: (1) double immunohistochemistry-to verify the changes in the number of galaninergic neurons (submucosal, myenteric) and fibers; (2) real-time PCR to verify changes in mRNA expression encoding galanin, GalR1, GalR2, GalR3 receptors. KEY RESULTS: In the experimental animals, the number of Gal-immunoreactive submucosal perikarya was increased, while the number of galaninergic myenteric neurons and fibers (in all the stomach wall layers) remained unchanged. The expression of mRNA encoding all galanin receptors was increased. CONCLUSIONS & INTERFERENCES: The results obtained unveiled the participation of galanin and galanin receptors in the stomach tissue response to antral ulcerations. PMID- 29717797 TI - Tropical Medicine & International Health. PMID- 29717798 TI - Programmable Hydrogel Ionic Circuits for Biologically Matched Electronic Interfaces. AB - The increased need for wearable and implantable medical devices has driven the demand for electronics that interface with living systems. Current bioelectronic systems have not fully resolved mismatches between engineered circuits and biological systems, including the resulting pain and damage to biological tissues. Here, salt/poly(ethylene glycol) (PEG) aqueous two-phase systems are utilized to generate programmable hydrogel ionic circuits. High-conductivity salt solution patterns are stably encapsulated within PEG hydrogel matrices using salt/PEG phase separation, which route ionic current with high resolution and enable localized delivery of electrical stimulation. This strategy allows designer electronics that match biological systems, including transparency, stretchability, complete aqueous-based connective interface, distribution of ionic electrical signals between engineered and biological systems, and avoidance of tissue damage from electrical stimulation. The potential of such systems is demonstrated by generating light-emitting diode (LED)-based displays, skin mounted electronics, and stimulators that deliver localized current to in vitro neuron cultures and muscles in vivo with reduced adverse effects. Such electronic platforms may form the basis of future biointegrated electronic systems. PMID- 29717799 TI - Information, education, and health behaviors: Evidence from the MMR vaccine autism controversy. AB - In the wake of strong, although later refuted, claims of a link between autism and the measles-mumps-rubella (MMR) vaccine, I examine whether fewer parents immunized or delayed vaccinations for their children and if there was a differential response by mother's education level. Using various controls and a differencing strategy that compares in MMR take-up with other vaccines, I find that the MMR-autism controversy led to a decline in the immediate years and that there were negative spillovers onto other vaccines. I also find evidence that more highly educated mothers responded more strongly to the controversy either by not immunizing their children altogether or, to a lesser degree, delaying vaccination. Moreover, the educational gap was greater in states where there was greater media attention devoted to the controversy. This is consistent with the health allocative efficiency hypothesis whereby part of the education gradient in health outcomes is due to more-educated individuals absorbing and responding to health information more quickly. However, unlike in the United Kingdom, where previous studies find that the gap was eliminated after the link was refuted, the evidence for the United States suggests that the educational gap persisted. PMID- 29717800 TI - Influence of variability in assessment of Breslow thickness, mitotic rate and ulceration among US pathologists interpreting invasive melanoma, for the purpose of AJCC staging. AB - BACKGROUND: Melanoma staging has depended on depth of invasion (Breslow thickness, BT), mitotic rate (MR) and ulceration. In anticipation of the AJCC's eighth edition, variability in pathologists' assessment of these factors and consequently in tumor staging was assessed. METHODS: One-hundred and fifteen cases of invasive melanoma, established by a consensus panel, were assessed by 187 pathologists. Variation was studied in BT, the detection of mitotic figures, and ulceration. The sources of this variation and its effect on tumor staging are considered. RESULTS: On average, participant assessments closely approached consensus BT. Greater variation was identified in the classification of mitogenicity, which (like ulceration) upstages a T1 melanoma from T1a to T1b in the seventh but not eighth edition. In cases with a T1a diagnosis by the consensus panel, 15.6% of participants identified one or more mitotic figures (indicative of a false positive); and in cases diagnosed asT1b by the consensus panel, 32.0% of participants failed to find mitotic figures (false negative). CONCLUSION: Variability in the staging of T1 melanoma among pathologists when using the AJCC seventh edition criteria is closely related to the detection of mitotic figures, with BT playing a less prominent role. Decreased variability is expected after implementation of the eighth edition. PMID- 29717801 TI - Prevalence of and factors associated with successful aging in Brazilian older adults: Frailty in Brazilian older people Study (FIBRA RJ). AB - AIM: We aimed to estimate the factors associated with the biomedical dimension of successful aging (SA) and its prevalence in older Brazilian individuals. The conceptual framework for this approach relies on the considerable variation in the biophysiological effects of aging and the need to understand the factors that influence this process. METHODS: Data from a total of 845 older adults were analyzed. SA operationalization included the following criteria: good physical and cognitive performance, absence of disabilities, and good health conditions. Descriptive analyses were used to estimate the prevalence of SA, and the factors associated with SA were assessed using multivariate logistic regressions. RESULTS: The overall prevalence of SA was 25%, and the associated factors were the absence of (OR 10.5, 95% CI 5.2-21.1) or fewer than two physical morbidities (OR,3.5, 95% CI 2.1-5.9), body mass index in the overweight range (OR 1.8, 95% CI 1.02-3.3), absence of depression (OR ,2.1, 95% CI 1.07 = 4.1), high levels of physical activity (OR 1.88, 95% CI 1.14-3.2), high levels of social participation (OR 2.07, 95% CI 1.16-3.4) and younger age (65-74 years, OR 4.27, 95% CI 1.79 10.1; 75-84 years, OR 2.7, 95% CI 1.18-6.41). CONCLUSIONS: A small proportion of older adults met the criteria defining successful aging. Despite the great impact of biological determinants, modifiable social and lifestyle factors predicted successful aging in this population, suggesting that health promotion targeting behavioral changes might lead to tangible benefits for health and well-being in old age. Geriatr Gerontol Int 2018; 18: 1280-1285. PMID- 29717803 TI - Ultrathin Wall (1 nm) and Superlong Pt Nanotubes with Enhanced Oxygen Reduction Reaction Performance. AB - The synthesis of Pt nanotubes catalysts remains a substantial challenge, especially for those with both sub-nanometer wall thickness and micrometer-scale length characteristics. Combining techniques of insulin fibril template with Pd nanowire template, numerous Pt nanotubes with diameter of 5.5 nm, tube-length of several micrometers, and ultrathin wall thickness of 1 nm are assembled. These tubular catalysts with both open ends deliver electrochemical active surface area (ECSA) of 91.43 m2 gpt-1 which results from multiple Pt atoms exposed on the inner and outer surfaces that doubled Pt atoms can participate in catalytic reactions, further with enhanced electrocatalytic performance for oxygen reduction reaction (ORR). The ultrafine Pt nanotubes represent a class of hollow nanostructure with increased Pt-utilization and large ECSA, which is regarded as a type of cost-effective catalysts for ORR. PMID- 29717804 TI - Three-dimensional printed polycaprolactone-microcrystalline cellulose scaffolds. AB - Microcrystalline cellulose (MCC) is proposed in this study as an additive in polycaprolactone (PCL) matrices to obtain three-dimensional (3D) printed scaffolds with improved mechanical and biological properties. Improving the mechanical behavior and the biological performance of polycaprolactone-based scaffolds allows to increase the potential of these structures for bone tissue engineering. Different groups of samples were evaluated in order to analyze the effect of the additive in the properties of the PCL matrix. The concentrations of MCC in the groups of samples were 0, 2, 5, and 10% (w/w). These combinations were subjected to a thermogravimetric analysis in order to evaluate the influence of the additive in the thermal properties of the composites. 3D printed scaffolds were manufactured with a commercial 3D printer based on fused deposition modelling. The operation conditions have been established in order to obtain scaffolds with a 0/90 degrees pattern with pore sizes between 450 and 500 um and porosity values between 50 and 60%. The mechanical properties of these structures were measured in the compression and flexural modes. The scaffolds containing 2 and 5% MCC have higher flexural and compression elastic modulus, although those containing 10% do not show this reinforcement effect. On the other hand, the proliferation of sheep bone marrow cells on the proposed scaffolds was evaluated over 8 days. The results show that the proliferation is significantly better (p < 0.05) on the group of samples containing 2% MCC. Therefore, these scaffolds (PCL:MCC 98:2) have suitable properties to be further evaluated for bone tissue engineering applications. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. PMID- 29717802 TI - The effect of enriched environment across ages: A study of anhedonia and BDNF gene induction. AB - Enriched environment treatment (EET) is a potential intervention for depression by inducing brain-derived neurotrophic factor (BDNF). However, its age dependency remains unclear. We recently found that EET during early-life development (ED) was effective in increasing exploratory activity and anti-despair behavior, particularly in promoter IV-driven BDNF deficient mice (KIV), with the largest BDNF protein induction in the hippocampus and frontal cortex. Here, we further determined age dependency of EET effects on anhedonia and promoter-specific BDNF transcription, by using the sucrose preference test and qRT-PCR. Wild-type (WT) and KIV mice received 2 months of EET during ED, young-adulthood and old adulthood (0-2, 2-4 and 12-14 months, respectively). All KIV groups showed reduced sucrose preference, which EET equally reversed regardless of age. EET increased hippocampal BDNF mRNA levels for all ages and genotypes, but increased frontal cortex BDNF mRNA levels only in ED KIV and old WT mice. Transcription by promoters I and IV was age-dependent in the hippocampus of WT mice: more effective induction of exon IV or I during ED or old-adulthood, respectively. Transcription by almost all 9 promoters was age-specific in the frontal cortex, mostly observed in ED KIV mice. After discontinuance of EET, the EET effects on anti-anhedonia and BDNF transcription in both regions persisted only in ED KIV mice. These results suggested that EET was equally effective in reversing anhedonia and inducing hippocampal BDNF transcription, but was more effective during ED in inducing frontal cortex BDNF transcription and for lasting anti anhedonic and BDNF effects particularly in promoter IV-BDNF deficiency. PMID- 29717805 TI - The Insertion Mechanism of a Living Cell Determined by the Stress Segmentation Effect of the Cell Membrane during the Tip-Cell Interaction. AB - Atomic force microscopy probes are proved to be powerful tools to measure and manipulate the individual cell, providing potential applications for the controlled drug/protein delivery. However, the measured insertion efficiency varies dramatically from 20 to 80%, in some cases, the nanotip can never penetrate the cell membrane no matter how much force is applied to it. Thus, the insertion mechanism of a living cell during the tip-cell interaction must be thoroughly investigated before this technology comes into practical applications. In this work, a multistructural cell model is established to study the tip membrane interaction. The simulation results show that the stress of the cell membrane can be divided into two stages by the stress segmentation point S. After point S, the stress of the cell membrane increases slightly and most of the indentation force is allocated to the cytoskeleton. This phenomenon is called "stress segmentation effect of the cell membrane," which confirms the hypothesis based on the experimental studies. Moreover, according to the experimental and numerical studies, the hypothesis of the stress segmentation effect also explains the reason that modifying the cell membrane or using the manmade sharpened nanotip can increase the insertion efficiency. PMID- 29717806 TI - Dynamic Sessile-Droplet Habitats for Controllable Cultivation of Bacterial Biofilm. AB - Bacterial biofilms play essential roles in biogeochemical cycling, degradation of environmental pollutants, infection diseases, and maintenance of host health. The lack of quantitative methods for growing and characterizing biofilms remains a major challenge in understanding biofilm development. In this study, a dynamic sessile-droplet habitat is introduced, a simple method which cultivates biofilms on micropatterns with diameters of tens to hundreds of micrometers in a microfluidic channel. Nanoliter plugs are utilized, spaced by immiscible carrier oil to initiate and support the growth of an array of biofilms, anchored on and spatially confined to the micropatterns arranged on the bottom surface of the microchannel, while planktonic or dispersal cells are flushed away by shear force of aqueous plugs. The performance of the aforementioned method of cultivating biofilms is demonstrated by Pseudomonas aeruginosa PAO1 and its derived mutants, and quantitative antimicrobial susceptibility testing of PAO1 biofilms. This method could significantly eliminate corner effects, avoid microchannel clogging, and constrain the growth of biofilms for long-term observations. The controllable sessile droplet-based biofilm cultivation presented in this study should shed light on more quantitative and long-term studies of biofilms, and open new avenues for investigation of biofilm attachment, growth, expansion, and eradication. PMID- 29717807 TI - Flexible Cationic Nanoparticles with Photosensitizer Cores for Multifunctional Biomedical Applications. AB - One challenge for multimodal therapy is to develop appropriate multifunctional agents to meet the requirements of potential applications. Photodynamic therapy (PDT) is proven to be an effective way to treat cancers. Diverse polycations, such as ethylenediamine-functionalized poly(glycidyl methacrylate) (PGED) with plentiful primary amines, secondary amines, and hydroxyl groups, demonstrate good gene transfection performances. Herein, a series of multifunctional cationic nanoparticles (PRP) consisting of photosensitizer cores and PGED shells are readily developed through simple dopamine-involving processes for versatile bioapplications. A series of experiments demonstrates that PRP nanoparticles are able to effectively mediate gene delivery in different cell lines. PRP nanoparticles are further validated to possess remarkable capability of combined PDT and gene therapy for complementary tumor treatment. In addition, because of their high dispersities in biological matrix, the PRP nanoparticles can also be used for in vitro and in vivo imaging with minimal aggregation-caused quenching. Therefore, such flexible nanoplatforms with photosensitizer cores and polycationic shells are very promising for multimodal tumor therapy with high efficacy. PMID- 29717808 TI - How should procalcitonin and C-reactive protein levels be interpreted in haemodialysis patients? AB - BACKGROUND: Procalcitonin (PCT) and C-reactive protein (CRP) are used most widely in the diagnosis/treatment of bacterial infections. These are not infection specific and may also show increases in other inflammation-causing cases. AIM: To establish a new cut-off value for PCT and CRP to eliminate confusion in the diagnosis and treatment of bacterial infections in haemodialysis (HD) patients. METHODS: A total of 1110 patients, 802 with undocumented infection and 308 with documented infection, was included in the study. RESULTS: A total of 802 patients with undocumented infection had a mean CRP value of 12.2 +/- 9.6 mg/dL and a mean PCT value of 0.51 +/- 0.96 ng/mL and the 308 patients with documented infection had a mean CRP value of 125.9 +/- 83.3 mg/dL and a mean PCT value of 13.9 +/- 26.9 ng/mL at the time of admittance. In HD patients, the cut-off values for CRP was determined as 19.15 mg/dL and for PCT as 0.685 ng/mL in the presence of infection. The use of these two parameters in combination (CRP >=19.15 mg/dL and PCT >= 0.685 ng/mL) was found to have 95% positive predictive value (PPV) and 93% negative predictive value (NPV) for the diagnosis of infectious diseases in HD patients. When CRP >=100 mg/dL and PCT >=5 ng/mL, this was found to have 100% PPV and 94% NPV for the diagnosis of sepsis in HD patients. CONCLUSION: We specified PCT and CRP cut-off values with high PPV and NPV for revealing the presence of bacterial infection and sepsis in HD patients. PMID- 29717809 TI - Hydrodynamically Formed Uniform Thick Coatings on Microspheres. AB - Forming uniform thick coatings on microspheres remains a significant challenge in various surface modification and drug delivery applications. In this work, a hydrodynamic method is demonstrated for centering microspheres in droplets with sizes ranging from tens to hundreds of micrometers. The core microspheres stay at the center of the droplets due to the hydrodynamic pressure generated in the surrounding liquid shells, despite the significant density difference between the core microsphere and the liquid shell. Therefore, by using polymerizable liquids that can be solidified thermally or by illumination as the shell layer, core shell particles with gas, liquid, or solid cores can be surrounded with uniform coatings using the present method. PMID- 29717810 TI - Ferroelectric Localized Field-Enhanced ZnO Nanosheet Ultraviolet Photodetector with High Sensitivity and Low Dark Current. AB - Zinc oxide (ZnO) nanosheets have demonstrated outstanding electrical and optical properties, which are well suited for ultraviolet (UV) photodetectors. However, they have a high density of intrinsically unfilled traps, and it is difficult to achieve p-type doping, leading to the poor performance for low light level switching ratio and a high dark current that limit practical applications in UV photodetection. Here, UV photodetectors based on ZnO nanosheets are demonstrated, whose performance is significantly improved by using a ferroelectric localized field. Specifically, the photodetectors have achieved a responsivity of up to 3.8 * 105 A W-1 , a detectivity of 4.4 * 1015 Jones, and a photocurrent gain up to 1.24 * 106 . These device figures of merit are far beyond those of traditional ZnO ultraviolet photodetectors. In addition, the devices' initial dark current can be easily restored after continuous photocurrent measurement by using a positive gate voltage pulse. This study establishes a new approach to produce high-sensitivity and low-dark-current ultraviolet photodetectors and presents a crucial step for further practical applications. PMID- 29717811 TI - Shape Memory Alloy (SMA)-Based Microscale Actuators with 60% Deformation Rate and 1.6 kHz Actuation Speed. AB - Shape memory alloys (SMAs) are widely utilized as an actuation source in microscale devices, since they have a simple actuation mechanism and high-power density. However, they have limitations in terms of strain range and actuation speed. High-speed microscale SMA actuators are developed having diamond-shaped frame structures with a diameter of 25 um. These structures allow for a large elongation range compared with bulk SMA materials, with the aid of spring-like behavior under tensile deformation. These actuators are validated in terms of their applicability as an artificial muscle in microscale by investigating their behavior under mechanical deformation and changes in thermal conditions. The shape memory effect is triggered by delivering thermal energy with a laser. The fast heating and cooling phenomenon caused by the scale effect allows high-speed actuation up to 1600 Hz. It is expected that the proposed actuators will contribute to the development of soft robots and biomedical devices. PMID- 29717812 TI - Mineral-Templated 3D Graphene Architectures for Energy-Efficient Electrodes. AB - 3D graphene networks have shown extraordinary promise for high-performance electrochemical devices. Herein, the chemical vapor deposition synthesis of a highly porous 3D graphene foam (3D-GF) using naturally abundant calcined Iceland crystal as the template is reported. Intriguingly, the Iceland crystal transforms to CaO monolith with evenly distributed micro/meso/macropores through the releasing of CO2 at high temperature. Meanwhile, the hierarchical structure of the calcined template could be easily tuned under different calcination conditions. By precisely inheriting fine structure from the templates, the as prepared 3D-GF possesses a tunable hierarchical porosity and low density. Thus, the hierarchical pores offer space for guest hybridization and provide an efficient pathway for ion/charge transport in typical energy conversion/storage systems. The 3D-GF skeleton electrode hybridized with Ni(OH)2 /Co(OH)2 through an optimal electrodeposition condition exhibits a high specific capacitance of 2922.2 F g-1 at a scan rate of 10 mV s-1 , and 2138.4 F g-1 at a discharge current density of 3.1 A g-1 . The hybrid 3D-GF symmetry supercapacitor shows a high energy density of 83.0 Wh kg-1 at a power density of 1011.3 W kg-1 and 31.4 Wh kg-1 at a high power density of 18 845.2 W kg-1 . The facile fabrication process enables the mass production of hierarchical porous 3D-GF for high performance supercapacitors. PMID- 29717813 TI - Atomic Insights into Phase Evolution in Ternary Transition-Metal Dichalcogenides Nanostructures. AB - Phase engineering through chemical modification can significantly alter the properties of transition-metal dichalcogenides, and allow the design of many novel electronic, photonic, and optoelectronics devices. The atomic-scale mechanism underlying such phase engineering is still intensively investigated but elusive. Here, advanced electron microscopy, combined with density functional theory calculations, is used to understand the phase evolution (hexagonal 2H >monoclinic T'->orthorhombic Td ) in chemical vapor deposition grown Mo1-x W x Te2 nanostructures. Atomic-resolution imaging and electron diffraction indicate that Mo1-x W x Te2 nanostructures have two phases: the pure monoclinic phase in low W-concentrated (0 < x <= 10 at.%) samples, and the dual phase of the monoclinic and orthorhombic in high W-concentrated (10 < x < 90 at.%) samples. Such phase coexistence exists with coherent interfaces, mediated by a newly uncovered orthorhombic phase Td '. Td ', preserves the centrosymmetry of T' and provides the possible phase transition path for T'->Td with low energy state. This work enriches the atomic-scale understanding of phase evolution and coexistence in multinary compounds, and paves the way for device applications of new transition-metal dichalcogenides phases and heterostructures. PMID- 29717814 TI - Prospects for management of whitefly using plant semiochemicals, compared with related pests. AB - Whitefly (Hemiptera: Sternorrhyncha: Aleyrodidae) pests, including the tobacco whitefly, Bemisia tabaci, and the greenhouse whitefly, Trialeurodes vaporariorum, are important economically in agriculture. Whiteflies are controlled mainly by synthetic insecticides but resistance to these is evolving rapidly. A semiochemical-based management strategy could provide an alternative to the use of insecticides, by exploiting natural volatile signalling processes to manipulate insect behaviour. Whitefly behaviour is affected by differences in plant odour blends. Selected compounds have been suggested as putative semiochemicals, but in only a few studies have potential volatiles been characterized by electrophysiology or olfactometry. Application of antennal preparation methods from closely related families, the aphids (Hemiptera: Aphididae) and psyllids (Hemiptera: Psyllidae), may help to facilitate whitefly electroantennography. Behavioural bioassays are essential to identify the repellent or attractant effect of each semiochemical. The relevance of semiochemicals in whitefly management needs to be evaluated in the respective cultivation system. Although the value of semiochemicals against whiteflies has not been demonstrated in the field, there is an emerging range of possible field applications and some promising prospects. Overall, the olfactory system of whiteflies needs to be elucidated in more detail. (c) 2018 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry. PMID- 29717815 TI - beta-lactam resistance: The role of low molecular weight penicillin binding proteins, beta-lactamases and ld-transpeptidases in bacteria associated with respiratory tract infections. AB - Disruption of peptidoglycan (PG) biosynthesis in the bacterial cell wall by beta lactam antibiotics has transformed therapeutic options for bacterial infections. These antibiotics target the transpeptidase domains in penicillin binding proteins (PBPs), which can be classified into high and low molecular weight (LMW) counterparts. While the essentiality of the former has been extensively demonstrated, the physiological roles of LMW PBPs remain poorly understood. Herein, we review the function of LMW PBPs, beta-lactamases and ld transpeptidases (Ldts) in pathogens associated with respiratory tract infections. More specifically, we explore their roles in mediating beta-lactam resistance. Using a comparative genomics approach, we identified a high degree of genetic redundancy for LMW PBPs which retain the motifs, SxxN, SxN and KTG required for catalytic activity. Differences in domain architecture suggest distinct physiological roles, possibly related to bacterial cell cycle and/or adaptation to various environmental conditions. Many of the LMW PBPs play an important role in beta-lactam resistance either through mutation or variation in abundance. In all of the bacterial genomes assessed, at least one beta-lactamase homologue is present, suggesting that enzymatic degradation of beta-lactams is a highly conserved resistance mechanism. Furthermore, the presence of Ldt homologues in the majority of species surveyed suggests that alternative PG crosslinking may further mediate beta-lactam drug resistance. A deeper understanding of the interplay between these different mechanisms of beta-lactam resistance will provide a framework for new therapeutics, which are urgently required given the rapid emergence of antimicrobial resistance. (c) 2018 IUBMB Life, 70(9):855-868, 2018. PMID- 29717816 TI - High-Contrast SEM Imaging of Supported Few-Layer Graphene for Differentiating Distinct Layers and Resolving Fine Features: There is Plenty of Room at the Bottom. AB - For supported graphene, reliable differentiation and clear visualization of distinct graphene layers and fine features such as wrinkles are essential for revealing the structure-property relationships for graphene and graphene-based devices. Scanning electron microscopy (SEM) has been frequently used for this purpose where high-quality image contrast is critical. However, it is surprising that the effect of key imaging parameters on the image contrast has been seriously undermined by the graphene community. Here, superior image contrast of secondary electron (SE) images for few-layer graphene supported on SiC and SiO2 /Si is realized through simultaneously tuning two key parameters-acceleration voltage (Vacc ) and working distance (WD). The overlooked role of WD in characterizing graphene is highlighted and clearly demonstrated. A unified model of Vacc and WD dependence of three types of SE collected by the standard side attached Everhart-Thornley (E-T) SE detector is conceptually developed for mechanistically understanding the improved mass thickness contrast for supported few-layer graphene. The findings reported here will have important implications for effective characterizations of atomically thick 2D materials and devices. PMID- 29717817 TI - A multilayer scaffold design with spatial arrangement of cells to modulate esophageal tissue growth. AB - Esophageal diseases may require resectioning of the damaged portion. The current standard of care requires the replacement of the esophagus with the stomach or the intestine. Such procedures have high rates of mortality and morbidity; therefore, the use of alternative conduits is needed. A tissue engineering approach that allows for the regeneration of esophageal tissues would have significant clinical application. A cell-seeded synthetic scaffold could replace the resected part of the esophagus and elicit tissue regrowth. In order to ideally recreate a functioning esophagus, its two crucial tissue layers should be induced: an epithelium on the luminal surface and a muscle layer on the exterior surface. To create a bioengineered esophagus with both tissue layers, a multilayer (ML) tubular scaffold design was considered. Luminal and exterior layers were electrospun with broad pore size to promote penetration and proliferation of mesenchymal stem cells on the lumen and smooth muscle cells on the external. These two layers would be separated by a thin layer with substantially narrower pore size intended to act as a barrier for the two cell types. This ML scaffold design was achieved via electrospinning by tuning the solution and the process parameters. Analysis of the scaffold demonstrated that this tuning enabled the production of three integrated layers with distinguishable microstructures and good mechanical integrity. In vitro validation was conducted on the separated unilayer components of the ML scaffold. The resultant proof-of-concept ML scaffold design could possibly support the spatial arrangement of cells needed to promote esophageal tissue regeneration. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. PMID- 29717818 TI - Anisotropic Strain Relaxation of Graphene by Corrugation on Copper Crystal Surfaces. AB - Corrugation is a ubiquitous phenomenon for graphene grown on metal substrates by chemical vapor deposition, which greatly affects the electrical, mechanical, and chemical properties. Recent years have witnessed great progress in controlled growth of large graphene single crystals; however, the issue of surface roughness is far from being addressed. Here, the corrugation at the interface of copper (Cu) and graphene, including Cu step bunches (CuSB) and graphene wrinkles, are investigated and ascribed to the anisotropic strain relaxation. It is found that the corrugation is strongly dependent on Cu crystallographic orientations, specifically, the packed density and anisotropic atomic configuration. Dense Cu step bunches are prone to form on loose packed faces due to the instability of surface dynamics. On an anisotropic Cu crystal surface, Cu step bunches and graphene wrinkles are formed in two perpendicular directions to release the anisotropic interfacial stress, as revealed by morphology imaging and vibrational analysis. Cu(111) is a suitable crystal face for growth of ultraflat graphene with roughness as low as 0.20 nm. It is believed the findings will contribute to clarifying the interplay between graphene and Cu crystal faces, and reducing surface roughness of graphene by engineering the crystallographic orientation of Cu substrates. PMID- 29717819 TI - Recent Advances in the Development of Antimicrobial Nanoparticles for Combating Resistant Pathogens. AB - The rapid growth of harmful pathogens and their multidrug-resistance poses a severe challenge for health professionals and for the development of new healthcare products. Various strategies are exploited for the development of effective antimicrobial agents, and nanoparticles are a particularly promising class of materials in this respect. This review summarizes recent advances in antimicrobial metallic, polymeric, and lipid-based nanoparticles such as liposomes, solid lipid nanoparticles, and nanostructured lipid carriers. The latter materials in particular are engineered for antimicrobial agent delivery and act by encapsulation, receptor-based binding, and disruption of microbial adherence to cellular substrates. Potential strategies for the design of multifunctional antimicrobial nanocarriers, combining material chemistry and biological interface science, are also discussed. PMID- 29717820 TI - Mobile Intensive Care Unit: A case management team dedicated to early psychosis in France. AB - AIM: To present the activities of a Mobile Intensive Care Unit in France. METHODS: We summarize participant recruitment as well as the diagnostic procedures and therapeutic interventions offered to individuals with an at-risk mental state or first-episode psychosis (FEP). RESULTS: Since its inception in 2010, 266 individuals from 16 to 30 years old living in an area of 120 000 citizens have been recruited by the Mobile Intensive Care Unit. Patients are evaluated by clinical and neuropsychological assessments, and therapeutic interventions include medication, individual case management and both individual and group cognitive behavioural therapy. Diagnostic assessments are also provided for the patients outside of our geographic area. CONCLUSIONS: The Mobile Intensive Care Unit is a functional unit enabling young adults with a high-risk mental state or FEP to receive high standard of care and mobile management over 2 years, aimed at diminishing the risk of transition to chronic disease and decreasing functional impairment. PMID- 29717821 TI - About Chemical Strategies to Fabricate Cell-Instructive Biointerfaces with Static and Dynamic Complexity. AB - Properly functioning cell-instructive biointerfaces are critical for healthy integration of biomedical devices in the body and serve as decisive tools for the advancement of our understanding of fundamental cell biological phenomena. Studies are reviewed that use covalent chemistries to fabricate cell-instructive biointerfaces. These types of biointerfaces typically result in a static presentation of predefined cell-instructive cues. Chemically defined, but dynamic cell-instructive biointerfaces introduce spatiotemporal control over cell instructive cues and present another type of biointerface, which promises a more biomimetic way to guide cell behavior. Therefore, strategies that offer control over the lateral sorting of ligands, the availability and molecular structure of bioactive ligands, and strategies that offer the ability to induce physical, chemical and mechanical changes in situ are reviewed. Specific attention is paid to state-of-the-art studies on dynamic, cell-instructive 3D materials. Future work is expected to further deepen our understanding of molecular and cellular biological processes investigating cell-type specific responses and the translational steps toward targeted in vivo applications. PMID- 29717822 TI - Soft and Moldable Mg-Doped Liquid Metal for Conformable Skin Tumor Photothermal Therapy. AB - As a class of emerging multifunctional soft materials, gallium-based liquid metal (LM) amalgams, metal/nonmetal particles dispersed in an LM environment, suggest a combination of intriguing properties. In this article, Mg particles in gallium indium alloy for making new conceptual biomedical materials, which can adapt to any irregular skin surface, are introduced, and superior photothermal effect with a 61.5% photothermal conversion (PTC) increase with respect to that of the LM is realized. The formation of a new intermetallic phase Mg2 Ga5 and adjustable surface roughness, which guarantees a rapid temperature increase when illuminated by laser, are found to be responsible for the photothermal effect enhancement. The obtained soft metallic mixtures also possess excellent thermal conductivity, favorable formability, together with benign biocompatibility. The potential use of the currently produced LM mixtures for conformable photothermal therapy (PTT) of skin tumors, which is hard to precisely heat otherwise via conventional ways, is explored. The soft Mg-GaIn mixtures can adapt to irregular tumor shapes to achieve conformable and minimal invasive tumor treatment. In vivo experiments on skin-tumor-bearing mice show obvious tumor growth suppression and life span extension after PTT treatment. As a novel functional PTC material, the Mg-GaIn mixtures exhibit promising potentials in the coming clinical cancer theranostics. PMID- 29717823 TI - Thermoreversible Hyaluronic Acid-PNIPAAm Hydrogel Systems for 3D Stem Cell Culture. AB - Human pluripotent stem cells (hPSCs) offer considerable potential for biomedical applications including drug screening and cell replacement therapies. Clinical translation of hPSCs requires large quantities of high quality cells, so scalable methods for cell culture are needed. However, current methods are limited by scalability, the use of animal-derived components, and/or low expansion rates. A thermoresponsive 3D hydrogel for scalable hPSC expansion and differentiation into several defined lineages is recently reported. This system would benefit from increased control over material properties to further tune hPSC behavior, and here a scalable 3D biomaterial with the capacity to tune both the chemical and the mechanical properties is demonstrated to promote hPSC expansion under defined conditions. This 3D biomaterial, comprised of hyaluronic acid and poly(N isopropolyacrylamide), has thermoresponsive properties that readily enable mixing with cells at low temperatures, physical encapsulation within the hydrogel upon elevation at 37 degrees C, and cell recovery upon cooling and reliquefaction. After optimization, the resulting biomaterial supports hPSC expansion over long cell culture periods while maintaining cell pluripotency. The capacity to modulate the mechanical and chemical properties of the hydrogel provides a new avenue to expand hPSCs for future therapeutic application. PMID- 29717824 TI - Molecularly Engineered Biolubricants for Articular Cartilage. AB - Lubrication within articular joints plays a crucial role in daily life, providing an extremely low coefficient of friction and preventing wear at the surface of the articular cartilage. Natural biomacromolecules responsible for lubrication are part of the synovial fluid and their degradation is associated with the onset of degenerative diseases, such as osteoarthritis (OA). The current absence of effective treatments for OA has captured the attention of chemists and material scientists over the last two decades, triggering the development of partially or fully synthetic biolubricants aimed to reduce friction within the joints and restore cartilage functions. Although there is still a long way to go before synthetic replacements of natural biolubricants can be applied clinically, this review highlights those formulations that meet the fundamental requirements for being efficient lubricants for articular cartilage. PMID- 29717825 TI - Treatment of Nonarteritic Acute Central Retinal Artery Occlusion. AB - Central retinal artery occlusion (CRAO) is an event most often caused by an embolus originating in the ipsilateral carotid artery, aortic arch, or heart. CRAO may result from partial or complete occlusion of the central retinal artery (CRA), which acts as the primary blood supply to the inner neurosensory retina, and typically results in profound vision loss and permanent visual disability. No consensus has emerged regarding the optimal treatment of CRAO. All proposed treatments are of questionable efficacy and many have uncertain risk profiles. In certain circumstances, thrombolysis may be attempted as a treatment option; however, the evidence to support broad use of thrombolytics in the treatment of acute CRAO remains elusive. It is known that the risk factors that predispose to other cardiovascular and cerebrovascular events are often present in CRAO. Accordingly, identification of patients at highest risk of stroke and secondary prevention of ischemic events remains the primary focus of management. This review offers a summary of the clinical presentation, diagnosis, and prognosis of CRAO, with an emphasis on treatment options. PMID- 29717826 TI - [Animal models of male genital tract chlamydia infection: An update]. AB - Chlamydia trachomatis infection is one of the most prevalent sexually transmitted diseases in males and studies on its pathogenic and immunologic mechanisms are rather limited. Animal models play an important role in studying the pathogenesis, course and treatment of human diseases, and those of male genital tract chlamydial infection are relatively few and not well developed. This article focuses on the chlamydia species, animal species, infection route, infected organ, and infection process of chlamydia, as well as its impact on reproduction, aiming to provide some help for further studies of male genital tract chlamydial infection. PMID- 29717827 TI - [Immediate and delayed intracavernous injection of bone marrow mesenchymal stem cells to improve erectile function in rats with cavernous nerve injury]. AB - Objective: To explore the effects of immediate and delayed intracavernous injection of bone marrow mesenchymal stem cells (BM-MSCs) on neurogenic erectile dysfunction (NED) induced by bilateral cavernous nerve injury in Sprague-Dawley (SD) rats. METHODS: BM-MSCs isolated from male SD rats were cultured and identified. Twenty-eight 8-week-old male SD rats were randomly divided into four groups, sham operation, NED model control, BM-MSCs immediate, and BM-MSCs delayed, and NED models were established in the latter three groups by crushing the bilateral cavernous nerves. The rats in the sham operation and model control groups were injected intracavernously with placebo while those in the latter two with BM-MSCs immediately or 2 weeks after modeling. At 12 weeks after operation, the penile function of the rats was assessed according to the penile intracavernous pressure (ICP), mean arterial pressure (MAP), and ICP/MAP ratio obtained from different groups of rats. Then, all the animals were sacrificed and the penile cavernosal tissue collected for histological analysis. RESULTS: At 12 weeks after modeling, both ICP and ICP/MAP were significantly increased in the BM MSCs immediate and delayed groups as compared with those in the model control (P <0.05), and so were the ratio of smooth muscle to collagen (P <0.05) and the smooth muscle content in the corpus cavernosum (P <0.05), and the number of neurofilament (NF)-positive nerve fibers (P <0.05) and the expression of neuronal nitric oxide synthase (nNOS) in the dorsal nerves of the midshaft penis (P <0.05). CONCLUSIONS: Intracavernous injection of BM-MSCs can improve erectile function in rats with bilateral cavernous nerve injury by elevating the smooth muscle-collagen ratio and smooth muscle content in the corpus cavernosum and thus preventing its fibrosis as well as by increasing the number of NF-positive nerve fibers and expression of nNOS in the penile dorsal nerves. PMID- 29717828 TI - [Role of mast cells in experimental autoimmune prostatitis in rats]. AB - Objective: To investigate the role of mast cells in chronic prostatitis / chronic pelvic pain syndrome (CP/CPPS). METHODS: Forty-five male SD rats were equally randomized into a control, an experimental autoimmune prostatitis (EAP) model, and an intervention group. The EAP model was made in the latter two groups by subcutaneous injection of mixed suspension of complete Freund's adjuvant and prostate tissue, while the controls were treated subcutaneously with 0.9% sodium chloride. Tactile allodynia was quantified in the pelvic region of the control and EAP animals using Von-Frey filaments at 5, 10, 20, 30 and 40 days. After successful establishment of the EAP model, the rats of the intervention group were injected intraperitonieally with cromolyn sodium for 10 days, and meanwhile tactile allodynia was detected in the rats of the intervention and EAP model groups every other day. Then the prostates of the rats were harvested for HE and toluidine blue staining and measurement of the expression of mast cell tryptase by immunohistochemistry and Western blot. RESULTS: Von-Frey assessment showed a more severe pelvic pain in the EAP model than in the control rats, but milder in the intervention group than in the EAP models. HE staining revealed infiltration of lymphocytes and neutrophils in the prostate and congestion surrounding the gland in the EAP model rats, but none in the controls. However, both the infiltration and congestion were significantly alleviated in the intervention group. Toluidine blue staining shown that. Compared with the control group, the total count of mast cells and the number degranulated mast cells were markedly increased in the EAP models (P <0.01) but decreased in the intervention group (P <0.05). Both immunohistochemistry and Western blot manifested that the expression of tryptase in the mast cells was remarkably upregulated in the EAP (both P <0.01) but down-regulated in the intervention group (P <0.05 and P <0.01). CONCLUSIONS: Both the total count of mast cells and the number of degranulated mast cells are significantly increased in the prostate of EAP rats. Mast cells are one of the most important mediators of type III prostatitis-induced chronic pelvic pain, which can be used as a target for the intervention and treatment of type III prostatitis. PMID- 29717829 TI - [Expressions of ERK and p-ERK in advanced prostate cancer]. AB - Objective: To investigate the expressions of extracellular signal-regulated kinase (ERK) and p-ERK in benign and malignant prostate tissues, and whether it can be used as a marker for the prognosis of advanced prostate cancer (PCa). METHODS: Using immunohistochemical Envision, we detected the expressions of ERK1/2 and p-ERK1/2 in 20 cases of benign prostatic hyperplasia (BPH) and 40 cases of advanced PCa and analyzed their correlation with PCa metastasis, Gleason score, PSA level, and prognosis. RESULTS: The expression of ERK1/2 was remarkably higher in the advanced PCa than in the BPH cases (82.5% vs 55%, P<0.05), which was not associated with cancer metastasis, Gleason score, PSA level, or survival time of the patients with advanced PCa, and so was that of p-ERK1/2 (75.0% vs 35%, P<0.05), which was not associated with the Gleason score or PSA level of the PCa patients, either. The expression rates of p-ERK in the metastasis, non metastasis, survival >5 yr, and survival <= 5 yr groups were 61.9%, 89.5%, 57.9%, and 90.5%, respectively, with statistically significant differences among these groups (P<0.05). CONCLUSIONS: ERK1/2 and p-ERK1/2 proteins are highly expressed in advanced PCa and p-ERK1/2 is associated with the metastasis and prognosis of advanced PCa. PMID- 29717830 TI - [Expressions of glutathione S-transferase P1 and 4- hydroxynonenal and the progression of prostate cancer]. AB - Objective: To investigate the expressions of glutathione S-transferase (GSTP1) and tetra-hydroxynonenal (4-HNE) in prostate cancer (PCa) and their clinical significance. METHODS: We determined the expressions of GSTP1 and 4-HNE in 40 patients with PCa and another 42 with benign prostatic hyperplasia (BPH) by immunohistochemistry and analyzed their relationship with Gleason grades. RESULTS: The expression rate of GSTP1 was 92.9% in the BPH tissue, and those in the highly, moderately, and lowly differentiated PCa tissues were 58.3%, 20.0%, and 16.7%, respectively, significantly higher in the BPH than in the PCa group (P <0.01). However, the positive rate of 4-HNE was only 5.0% in the BPH tissue, markedly lower than 91.6%, 100.0%, and 100.0% in the highly, moderately, and lowly differentiated PCa tissues (P <0.01). There was a negative correlation between the expression of GSTP1 and that of 4-HNE in the PCa tissue (r = -2.73, P <0.01). CONCLUSIONS: Expression deletion of GSTP1 and high expression of 4-HNE may play an important role in the progression of prostate cancer. PMID- 29717831 TI - [Saw palmetto fruit extract improves LUTS in type IIIA prostatitis patients]. AB - Objective: To assess the clinical efficacy of the saw palmetto fruit extract (SPFE) in the treatment of lower urinary tract symptoms (LUTS) in patients with type IIIA prostatitis. METHODS: This retrospective study included 54 cases of type IIIA prostatitis treated in the Outpatient Department of our hospital from January to December 2015. The patients were aged 35.06 +/- 5.85 years, with a mean disease course of 3.8 +/- 2.1 years, and all received oral medication of SPFE Capsules at the dose of 320 mg qd for 12 weeks. We assessed the therapeutic effects by comparing the NIH-chronic prostatitis symptom indexes (NIH-CPSI), voiding diary, International Prostate Symptom Scores (IPSS), and results of urodynamic examination before and after treatment. RESULTS: Compared with the baseline, both NIH-CPSI and IPSS were significantly decreased after medication (27.61 +/- 3.76 vs 18.6 +/- 5.34, P <0.01; 20.44 +/- 4.51 vs 10.96+/-4.62, P <0.01), and urodynamic examination and voiding diary showed dramatic post medication improvement in the average urinary flow rate ([8.05+/-1.42] vs [12.05+/-2.60] ml/s, P <0.01 ), maximum urinary flow rate ([14.22+/-1.74] vs [21.32+/-4.51] ml/s, P <0.01), residual urine volume ([46.15+/-16.57] vs [14.55+/ 10.21] ml, P <0.01), maximum urethral closure pressure ([76.52+/-3.53] vs [65.32+/-4.75] cm H2O, P <0.01), mean urinary volume ([124.63+/-40.55] vs [285.93+/-58.68] ml, P <0.01), urination frequency (16.96+/-4.17 vs 8.96+/-2.50, P <0.01), and nocturia frequency (8.94+/-3.23 vs 3.15+/-1.90, P <0.01). No apparent adverse reactions were observed in any of the patients. CONCLUSIONS: SPFE Capsules can safely and effectively improve LUTS and thus the quality of life of patients with type IIIA prostatitis. PMID- 29717832 TI - [Frenulum identification positioning with a disposable suture device in circumcision to prevent postoperative penile frenulum malposition]. AB - Objective: To investigate the effect of the frenulum identification positioning method with a disposable suture device in circumcision for the prevention of postoperative penile frenulum malposition. METHODS: Totally 212 patients with phimosis or redundant prepuce underwent circumcision from March 2015 to September 2016, including 109 cases of conventional circumcision (the control group) and 103 cases treated by frenulum identification positioning with a disposable suture device (the observation group). We observed the postoperative position of the penile frenulum and median raphe and compared the deviation angles of the frenulum between the two groups of patients. RESULTS: The median of penile frenulum deviation angle (interquartile range) was 0 (3.56) in the observation group, significantly smaller than 12.41 (19.59) in the control (P <0.001, P = 0.000). And the rate of frenulum deviation was remarkably lower in the former (8.74% [9/103]) than in the latter group (66.06% [72/109]) (P <0.01). CONCLUSIONS: Circumcision using the frenulum identification positioning method with a disposable suture device can effectively avoid postoperative penile frenulum malposition. With the advantages of safety and easy operation, it deserves clinical application and popularization. PMID- 29717833 TI - [Laparoscopic percutaneous extraperitoneal closure does not affect vas deferens orientation or testicular volume and perfusion]. AB - Objective: To investigate the influence of single-port laparoscopic percutaneous extraperitoneal closure (LPEC) on the orientation of the vas deferens and the volume and perfusion of the testis in pediatric patients undergoing inguinal hernia repair. METHODS: A total of 92 consecutively enrolled boys diagnosed with unilateral inguinal hernia underwent single-port LPEC between June 2013 and June 2014. The orientation of the vas deferens and the testicular volume and perfusion of the patients were ultrasonographically assessed preoperatively and at 1 and 6 months after surgery. RESULTS: All the surgical procedures were performed successfully without conversion or serious perioperative complications. Ultrasonography showed no angulation or distortion of the vas deferens on the surgical side during a six-month follow-up period. Similarly, no obvious changes were observed in the testicular volume or perfusion. CONCLUSIONS: Single-port LPEC is safe and effective in the treatment of pediatric inguinal hernia and does not affect the orientation of the vas deferens or testicular volume and perfusion. PMID- 29717834 TI - [Hepatitis B virus infection increases the incidence of immune infertility in males]. AB - Objective: To investigate the relationship between hepatitis B virus (HBV) infection and the incidence of male immune infertility. METHODS: Based on the levels of serum HBsAg, 3 124 infertile men were classified into an HBV-positive and an HBV-negative group and, according to the results of IBT tests, those with immune infertility were further divided into an HBV-positive and an HBV-negative group. Statistical analyses were made on the incidence rate of immune infertility and seminal parameters in the immune infertility patients of the HBV-positive and HBV-negative groups, the correlation of the number of HBV DNA copies in the serum with that in the seminal plasma of the HBV-positive patients, the association of the numbers of HBV DNA copies in the serum and seminal plasma with semen parameters, and the relationship of the number of HBV DNA copies in the seminal plasma with the incidence of immune infertility. Sperm concentration and the percentage of progressively motile sperm (PMS) were measured by computer-aided sperm analysis, sperm morphology determined by Diff-Quik staining, the level of HBsAg detected by ELISA, and the numbers of HBV DNA copies in the serum and seminal plasma calculated by RT-PCR. RESULTS: The incidence rate of immune infertility was significantly higher in the HBV-positive than in the HBV-negative group (20.3 vs 3.3%, chi2 = 187.5, P <0.01), and the percentage of morphologically normal sperm (MNS) was markedly lower in the HBV-positive than in the HBV-negative infertility patients ([3.9 +/- 1.7] vs [6.3 +/- 2.2]%, P <0.05), but no statistically significant differences were observed between the two groups of infertile males in the semen volume, sperm concentration, or PMS (P >0.05). The number of HBV DNA copies in the serum was positively correlated with that in the seminal plasma (rs = 0.86, P <0.01) while both the number of HBV DNA copies in the serum and that in the seminal plasma were negatively correlated with PMS (r = -0.233 and -0.465, P <0.01) and MNS (r = -0.250 and -0.508, P <0.01). The incidence rate of immune infertility showed no statistically significant differences among the groups with different numbers of HBV DNA copies in the seminal plasma (P >0.05). CONCLUSIONS: HBV infection can increase the incidence rate of immune infertility in men and is correlated with the low quality of sperm. PMID- 29717835 TI - [Prevalence of erectile dysfunction in men with pre-diabetes: An investigation in Lanzhou]. AB - Objective: To investigate the prevalence of erectile dysfunction (ED) in men with pre-diabetes. METHODS: This study included 500 men with impaired fasting glycaemia (IFG), 500 with impaired glucose tolerance (IGT), and another 500 with normal blood glucose (NBG), all from Lanzhou. We conducted a questionnaire investigation among the subjects using the International Index of Erectile Dysfunction 5 (IIEF-5). RESULTS: The prevalence rates of ED in the IFG, IGT, and NBG groups were 14.8%, 29.2%, and 33.2%, respectively. After controlling for age, nationality, occupation, education, income, obesity, and blood pressure, the incidence rate was markedly higher in the IFG and IGT than in the NBG group (29.2% and 33.2% vs 14.8%, P <0.05), but showed no statistically significant difference between the IFG and IGT groups (P >0.05). CONCLUSIONS: The prevalence of ED is higher in men with pre-diabetes than in those with normal blood glucose in Lanzhou. PMID- 29717836 TI - [Risk factors for different types of hypospadias]. AB - Objective: To explore the risk factors for different types of hypospadias. METHODS: According to the 1?1 ratio, we included hypospadias children in the case group and those without urinary abnormality as controls, all from the Third Affiliated Hospital of Zhengzhou University between October 2015 to October 2016. Using univariate and multivariate logistic regression analyses, we investigated the risk factors for hypospadias as well as for four different types of the disease. RESULTS: Among the 440 subjects, the risk factors for hypospadias included preterm birth, fetal growth restriction, rural residence of the mother, pregnancy age <20 or >35 years, primipara, maternal smoking (including passive smoking), oral progesterone, cold or fever during pregnancy, and exposure to high temperature in early pregnancy, while the protective factors included protein supplement in early pregnancy. The pregnancy age <20 or >35 years was the main risk factor for type I hypospadias; preterm birth, fetal growth restriction, rural residence of the mother, primipara, and maternal smoking (including passive smoking) during pregnancy were the risk factors for type II; preterm birth, fetal growth restriction, rural residence of the mother, and exposure to high temperature in early pregnancy were those for type III; and exposure to high temperature in early pregnancy and oral progesterone during pregnancy were those for type IV. CONCLUSIONS: The risk factors for hypospadias vary for different types, and therefore hypospadias-related clinical studies should be conducted and preventive measures should be taken accordingly. However, a larger sample size is needed to get more scientific and reliable results concerning the risk factors for different types of hypospadias. PMID- 29717837 TI - [Efficacy and safety of Wanfeile in the treatment of erectile dysfunction: Report of 100 cases and review of the literature]. AB - Objective: To investigate the clinical effect and safety of Wanfeile in the treatment of erectile dysfunction (ED). METHODS: Totally 100 ED patients received oral Wanfeile at 100 mg, once every 3 days, for a course of 3 months. We compared the IIEF-5 scores of the patients before and after medication and among the patients with different degrees of ED. We evaluated the total clinical effectiveness of Wanfeile and analyzed adverse reactions. RESULTS: The total effectiveness rate of Wanfeile was 95.6%. All the patients showed significant improvement in the IIEF-5 scores after treatment as compared with the baseline (P <0.05). Adverse reactions were observed in 5 cases (5.50%), all mild and transient. CONCLUSIONS: Wanfeile is safe and efficacious for the treatment of ED. PMID- 29717838 TI - [Zinner syndrome:A case report and review of the literature]. AB - Objective: To explore the clinical diagnosis and treatment of seminal vesicle cyst (SVC) associated with ipsilateral renal agenesis (Zinner syndrome) in order to promote the understanding of the disease. METHODS: We retrospectively analyzed the clinical data about 1 case ofZinner syndrome diagnosed and treated in our hospital and reviewed the literature related to this disease in domestic and foreign authoritative databases. RESULTS: The patient was a 23-year-old male, diagnosed with Zinner syndrome, treated bytransrectal aspiration of SVC, and discharged from hospital 3 days postoperatively. Follow-upat 6 months after discharge found that the patient no longer felt perineal discomfort in the endstage of urination, but transrectal ultrasonography of the prostate revealedthe samevolume of fluid in the left seminal vesicles as before,which indicated recurrence. CONCLUSIONS: SVC associated with ipsilateral renal agenesis can be considered asZinner syndrome. Transrectal aspiration of SVCcan relieve the local symptoms of the patient but relapse may easilyoccur. Therefore it is not recommended as the first-choice treatment of the disease. PMID- 29717839 TI - [Oral Testosterone Undecanoate Capsules combined with Qilin Pills for late-onset hypogonadism in males]. AB - Objective: To investigate the clinical effects of oral Testosterone Undecanoate Capsules (TUC) combined with Qilin Pills (QLP) on late-onset hypogonadism (LOH) in men. METHODS: Sixty-three LOH patients meeting the inclusion criteria were randomly divided into a control group (aged [48.4 +/- 6.2] yr, n = 32) and an experimental group (aged [47.2 +/- 5.6] yr, n = 31) to be treated with oral TUC (80 mg, qd) and TUC + QLP (6g, tid), respectively, both for 3 months. Comparisons were made between the two groups of patients in the IIEF-5 scores, total testosterone (TT) levels, and scores in the Aging Males' Symptoms (AMS) scale before and after treatment. RESULTS: After treatment, the patients of the experimental group, as compared with the controls, showed a significantly increased IIEF-5 score (21.7 +/- 5.8 vs 15.9 +/- 4.7, P <0.05) and TT level ([16.7 +/- 2.2] vs [13.1 +/- 2.8] nmol/L, P <0.05), but a decreased AMS score (20.7 +/- 5.7 vs 31.3+/-6.5, P <0.05). CONCLUSIONS: TUC combined with Qilin Pills has a better effect and a lower rate of adverse reactions than TUC used alone in the treatment of late-onset hypogonadism in males. PMID- 29717840 TI - [Transrectal ultrasound conductance-guided administration of traditional Chinese medicine for histological prostatitis in men with small-size BPH and LUTS after TURP]. AB - Objective: To investigate the effects of transrectal ultrasound conductance (TRUSC)-guided administration of traditional Chinese medicine on histological prostatitis in men with small-size BPH and low urinary tract symptoms (LUTS) after transurethral resection of the prostate (TURP). METHODS: This study included 167 BPH patients without surgical contraindications. We randomized the patients into an experimental group (n = 84) and a control group (n = 83), with no statistically significant differences between the two groups in age, prostate volume, International Prostate Symptom Score (IPSS), and quality of life (QoL) (P >0.05). The patients of the experimental group received TRUSC-guided administration of traditional Chinese medicine, qd, for 7 days before TURP, while those of the control group underwent TURP only. After treatment, we compared the results of postoperative pathological examination of the prostate tissue, the histological grade of inflammation, IPSS, and QoL scores between the two groups of patients. RESULTS: In the experimental group, there were 12 cases of non inflammation (14.3%), 43 cases of mild inflammation (51.2%), 28 cases of moderate inflammation (33.3%), and 1 case of severe inflammation (1.2%), as compared with 8 cases of non-inflammation (9.6%), 28 cases of mild inflammation (33.7%), 45 cases of moderate inflammation (51.8%), and 2 cases of severe inflammation (2.4%) in the control group (P <0.05). Compared with the baseline, both the experimental and control groups showed significant improvement at 4 weeks after surgery in IPSS (22.20+/-4.14 vs 4.26+/-2.64 and 23.05+/-4.11 vs 7.02+/-4.15, P <0.05) and QoL scores (4.33+/-0.83 vs 1.25+/-1.64 and 4.25+/-0.91 vs 2.05+/-1.95, P <0.05). CONCLUSIONS: TRUSC-guided administration of traditional Chinese medicine can significantly alleviate histological inflammation and improve QoL in men with small-size BPH and LUTS after TURP. PMID- 29717841 TI - [Triple acupuncture at the Qugu acupoint as an adjunctive therapy for type-III chronic prostatitis: Analysis of short- and long-term clinical effects]. AB - Objective: To investigate the short- and long-term effects of triple acupuncture at the Qugu acupoint as an adjunctive therapy on type-III chronic prostatitis / chronic pelvic pain syndrome (CP/CPPS). METHODS: We equally randomized 90 CP/CPPS patients into a control and a treatment group, both treated with Levofloxacin Mesylate Tablets (0.5 g, tid) + Terazosin Hydrochloride Capsules (2 mg qd) for 4 weeks, while the latter group by triple acupuncture at the Qugu acupoint as an adjunctive therapy twice a week at the same time. Then, we followed up all the patients for 4 weeks, recorded the cases, time and rate of recurrence, obtained the scores in National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI), quality of life (QoL) and Zung Depression Scale (ZDS), and compared them between the two groups of patients. RESULTS: Compared with the controls, the patients of the treatment group showed significantly decreased NIH-CPSI scores in pain (8.6 +/- 2.12 vs 6.2 +/- 2.25, P <0.05), micturition (5.8 +/- 1.22 vs 3.1 +/ 1.10, P <0.05), and QoL (6.0 +/- 1.33 vs 3.4 +/- 1.71, P <0.05) and ZDS score as well (43.9 +/- 4.53 vs 33.6 +/- 3.20, P <0.01). The recurrence rate was markedly lower while the recurrence time remarkably longer in the treatment than in the control group (15.56 vs 35.56% and [20.0 +/- 2.72] vs [12.5 +/- 3.47] d, P <0.05). CONCLUSIONS: As an adjunctive therapy, triple acupuncture at the Qugu acupoint can evidently ameliorate the clinical symptoms, enhance the curative effect of antibacterials, reduce the recurrence rate, and prolong the recurrence time in the treatment of CP/CPPS. PMID- 29717842 TI - [Differentiation of pluripotent stem cells into male germ cells: An update]. AB - Pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have the potential of differentiating into all types of adult cells. Today, mature functional sperm can be derived from mouse PSCs in vitro, and meanwhile primordial germ cells (PGCs) and meiotic prophase sperm cells can be generated from human ESCs/iPSCs (hESCs/hiPSCs). It is proposed that non-genetic azoospermia might be cured if functional sperm could be obtained from human PSCs (hPSCs) in vitro. It is also possible that healthy functional sperm could be derived from the patient with genetic factor-induced azoospermia by combining iPSCs and gene editing technology. IPSC-derived functional sperm have a higher clinical value for the avoidance of the sperm source and the issue of medical ethics. This article summarizes recent advances in the differentiation of PSCs into male germ cells in vitro, aiming to provide some reference for the treatment of male infertility with PSCs. PMID- 29717843 TI - [Outer dense fiber 2 and sperm function: Progress in studies]. AB - Oligoasthenozoospermia, teratozoospermia or low sperm motility is the main cause of male infertility. Low sperm motility can be induced by abnormalities of the sperm tail structure and sperm function. The outer dense fiber protein 2 (ODF2) is a protein fiber maintaining cytoskeleton, as a major component of the mammalian sperm tail and centrosome, and its abnormality is closely related to asthenospermia. Recent studies indicate that ODF2 includes many proteins of the same name and homologous splices located in the sperm centrosomes and spindles of cleaved-embryos, necessary for animal ciliogenesis and associated with sperm capacitation. The features of ODF2 indicate that it is not a single-structural protein. This paper reviews the known functions of ODF2, paving a ground for further studies of the relationship between the ODF2 protein and fertilization. PMID- 29717844 TI - Disseminating research information through Facebook and Twitter (DRIFT): presenting an evidence-based framework. AB - BACKGROUND: The social media platform Facebook boasts of having more than 1,284 million daily active users globally. A large proportion of adults use the internet to seek health-related information. AIM: To critically analyse the use of social media to engage parents of children with attention deficit hyperactivity disorder (ADHD) with the findings of clinical research. DISCUSSION: Observation and qualitative content analysis combined with Facebook Audience Insights were used to evaluate the levels of engagement and interaction with different types of research information. More than 1,100 people from 41 nations engaged with the group. Sharing information through a range of Facebook functions was found to successfully achieve engagement and reach this demographic nationally and internationally. CONCLUSION: Lay research users are eager to engage and understand clinical research. Social media platforms are an appropriate way to disseminate research. IMPLICATIONS FOR PRACTICE: This paper presents a much-needed evidence-based framework that nursing and health researchers can use for effective communication. PMID- 29717845 TI - Assessment and management of older patients with delirium in acute settings. AB - This article aims to assist nurses and nursing students to consider the presentation of delirium in older patients and the resulting assessment and nursing interventions required. It considers the three types of delirium: hyperactive, hypoactive and mixed. It also discusses potential causes of delirium. Older patients are at increased risk of delirium due to factors such as cognitive impairment, co-morbidities and acute illness. Nurses should be confident in the use of the 4AT score to assess patients with delirium. Use of the mnemonic PINCH ME is suggested to guide management of delirious patients in acute settings. Families of patients with delirium have emotional and other care needs and there are several ways in which nurses can meet them. PMID- 29717846 TI - Recognizing and managing emerging infectious diseases in the emergency department [digest]. AB - With population shifts, increased travel, and climate change, the spread of emerging and re-emerging infections is increasing. Although encountering a patient with an emerging infection on any given emergency department shift is unlikely, missing a diagnosis could have profound consequences for the patient, healthcare workers, and the patient's close contacts. This review provides a framework to evaluate, diagnose, and treat a returning traveler with suspected Middle East respiratory syndrome, chikungunya virus, or Zika virus-3 recently emerged infections. All may present with nonspecific viral-like symptoms and are easily missed if an appropriate travel history is not obtained. A high level of vigilance and proper disposition will enable the emergency clinician to effectively diagnose, manage, and contain these diseases. [Points & Pearls is a digest of Emergency Medicine Practice.]. PMID- 29717847 TI - [Advances in Salmonella pathogenicity island 2 type III secretion system - A review]. AB - Salmonella is a Gram-negative facultative intracellular pathogen that can infect vast array of hosts andcause a series of diseases, sometimes even life threatening systemic diseases. As an indispensable virulencedeterminant associated with the systemic infections, Salmonella pathogenicity island 2 (SPI2) encodes type IIIsecretion system 2 (T3SS2) which is induced after invasion, and the T3SS2 secreted effectors are essential forSalmonella to survive and replicate inside various cell types. In recent years, this issue remains the focus ofpathogenic research. This review focuses on the aspects of gene characterization of SPI2, regulation of SPI2 geneexpression, the structure and assembly of T3SS2, the T3SS2 effectors and some vaccine candidates associated withT3SS2 to present the current understanding of Salmonella T3SS2. PMID- 29717848 TI - [Genomics basis of Arthrobacter spp. environmental adaptability- A review]. AB - Arthrobacter species are found ecologically diverse and can survive in various environments. Many strainsof these species have metabolic versatility and can degrade many environmental pollutants. Arthrobacter species arethought to play important roles in catabolism of environmental pollutants in nature. In recent years, the genomes ofmany Arthrobacter strains have been sequenced, which provides comprehensive information to clarify the molecularmechanisms related to environmental adaptability of Arthrobacter species. These genomics findings revealed severalfeatures that are commonly observed in Arthrobacter strains allowing for survival under stressful conditions. Theseinclude an array of genes associated with sigma factors and responses to oxidative, osmotic, starvation andtemperature stresses. The genomics basis of their environmental adaptability are reviewed, which is expected toprovide useful information for applying Arthrobacter strains in pollution remediation and shed some light on otherbacterial environmental adaptability researches. PMID- 29717849 TI - Seasonal and spatial variation of Deuteromycetes population in polluted cost of Kiaochow Bay. AB - Objective: To reveal the relationship between Deuteromycetes community and the environmental inKiaochow Bay of the Yellow Sea. Methods: Using recorded pollution survey, we used molecular methods to study seasonal and spatial variation of Deuteromycetes community diversity in different polluted waters of Kiaochow Bay of the Yellow Sea, China. Results: Denaturing gradient gel electrophoresis fingerprints varied obviously among different sites of similar level of pollution. Moreover, sequence analysis of recovered dominant bands exhibited the existence of plenty of uncultivable fungi, among which Penicillium was the dominant genus. Furthermore, in heavily polluted estuary, there were abundant animal pathogens such as amoeba and Pythium as well as Deuteromycetes.These discoveries demonstrate that the Deuteromycetes community structure is closely related to marine environment, and are indicative of different level of marine contamination. Conclusion: The relationship between Deuteromycetes community and different level of pollution and seasons varied were closely related. PMID- 29717850 TI - [Nitrogen removal characteristics of mixed aerobic denitrification bacteria under in-situ biological inoculation]. AB - Objective: We studied the influences of water pressure and temperature on denitrification, and detected its nitrogen removal characteristics for providing evidence to remediate the micro-polluted reservoir source water. Methods: Mixed oligotrophic aerobic denitrification bacteria was obtained through enrichment, domestication, andscreening processes, which was isolated from sediment in the source water reservoir; and the nitrogen removalcharacteristics was detected by an in-situ biological inoculation experiment (DO at 3-8 mg/L). Results: Nitrate of the hard flask system (with water pressure influence) was removed completely, however, at 0.5, 5 m water layer, the nitrate removal rate of the soft flask reached 90.66%, 100%, other layers reached 99.61%, 80.55%, 67.01%, 64.73%. No nitrite accumulated. Because of bacteria death, ammonia had a slight increase. At the end of the experiment, in the 0.5, 5.0, 7.5, 10.0, 12.5 and 15.0 m water layer, the total nitrogen removal rates of hard flask reached 50.11%, 61.49%, 56.24%, 44.50%, 36.80% and 38.73%, however, that of soft system reached 33.47%, 60.61%, 43.98%, 36.28%, 27.52% and 28.57%. OD600 and pH first rose and then dropped. The mixed bacteria had prominent nitrogen removal ability between 11 degrees C and 30 degrees C. Conclusion: The mixed bacteria have a strong adaptability to temperature and the water pressure has a disadvantage to the nitrogen removal. PMID- 29717851 TI - [Diversity of cultivable yeast in Qilu Lake in winter]. AB - Objective: To investigate yeasts diversity in Qilu Lake and analyze the influence of environmental factorson yeast diversity. Methods: Yeasts were isolated by in situ cultivation and analyzed for the D1/D2 domain of large subunit (26S) ribosomal DNA and morphological characterization. We analyzed yeast species richness and species distribution in the Qilu Lake. Results: In total 321 isolated yeasts were identified to 14 genera and 27 species. Rhodosporidium kratochvilovae and Aureobasidium pullulans were the dominating species in the lake, representing 29.6% and 16.8% of the total strains, respectively. Principal component analysis (PCA) showed that the total phosphorus was an important environmental factor affecting the distribution of Rhodosporidium and the pH affected Cryptococcus yeasts distribution. Conclusion: There was a high diversity of yeasts community in the Qilu Lake.Keywords: Qilu Lake, yeast, diversity, environmental factors. PMID- 29717852 TI - [Diversity of endophytic bacteria isolated from Huperzia serrata]. AB - Objective: To explore the diversity of species and biological activities of the endophytes from Huperziaserrata that is a wild medicinal plant under state protection (category ii), and to discover and collect endophytic bacteria from medicinal plants. Methods: Huperzia serrata samples were collected from Sichuan and Fujian Provinces. Culture-dependent method was used to obtain endophytes from the surface-sterilized plant samples. The diversity of the isolates was analyzed according to the 16S rRNA gene sequences information. Jaccard index, Shannon wiener Index, Simpson Index and Pielou Index were calculated. Then six screening models were followed to study the physiological activities of the isolates, based on which we evaluated the diversity of biological activities ofthe endophytes from Huperzia serrata and their potential medicinal value. Results: A total of 356 endophytic bacteria were purified from Huperzia serrata, and the analysis results of their 16S rRNA gene sequences showed that they affiliated to 41 genera of 26 families in the phyla Actinobacteria, Firmicutes and Proteobacteria. The numbers and biodiversity indexes of endophytes from the aboveground part and belowground part of Huperzia serrata were approximately equivalent. Among them 11 potential novel species belonged to the genera Amycolatopsis, Angustibacter, Arthrobacter, Curtobacterium, Frondihabitans, Glaciihabitans, Jatrophihabitans, Luteimicrobium, Massilia, Naumannella and Tardiphaga, and 1 novel genus of the family Dermacoccaceae was discovered. The screening for anti-microbial results from these 356 isolates were as follows: the activity rates of against Enterococcus faecalis, Klebsiella pneumonia, Mycobacterium smegmatis and Xanthomonas campestris were 9.0%, 1.4%, 2.2% and 0.8% respectively. Of them 4.5% exhibited activities on the screening model of statins-like antihyperlipidemics showing inhibition of Sporobolomyces salmonicolor SS04; 8.6% of them had the activities of against HIV-1. In total, the fermentation broths from 74 strains exhibited activities on at least one screening model, the positive rate among the isolates was 20.8%. Conclusion: This study demonstrated that the endophytic bacteria from Huperzia serrata were of great significant bio-diversity and antibiotic diversity, therefore, they could be an ideal microbial resource for further discovery of new natural products. PMID- 29717854 TI - [Effects of antibiotics on the transfer frequency of SXT/R391 element of Vibrio alginolyticus]. AB - Objective: We studied the effects of nalidixic acid, norfloxacin and kanamycin on the transfer frequency of SXT/R391 element ICEValA056-1 in Vibrio alginolyticus. Methods: The circular ICEValA056-1 in V. alginolyticus A056 was detected by PCR. Conjugation experiments were conducted between V. alginolyticus A056 and Escherichia coli VB111 to explore the frequency variation of the integrating conjugative elements transfer after donor strain A056 was cultured in Luria Broth containing nalidixic acid or norfloxacin or kanamycin in different concentrations for 15 min or 30 min. Results: Circular ICEValA056-1 was detected in V. alginolyticus A056, indicating that ICEValA056-1 had the potential to transfer. Treatment with 40 MUg/mL nalidixic acid for 30 min increased the transfer frequency of ICEValA056-1 to19.59 folds. Treatment with 50 MUg/mL norfloxacin for 15 min increased the transfer frequency of ICEValA056-1 to 31.25 folds. The transfer frequency of ICEValA056-1 had no significant changes under treatment with different concentrations of kanamycin for 30 min. Conclusion: This study indicates that some antibiotics can obviously increase the transfer frequency of ICEValA056-1, and that antibiotics abuse and arbitrarily discharge might intensify dissemination of integrating conjugative elements from V. alginolyticus to other bacteria. PMID- 29717853 TI - [Disruption of leucyl aminopeptidase gene affects phenotypes and second metabolite production of Saccharopolyspora spinosa]. AB - Objective: In order to investigate effects of leucyl aminopeptidase on mycelia morphology, growth rate, spinosad yield and protein expression in Saccharopolyspora spinosa by disrupting its encoding gene pepA and analyzing the characteristics of engineered S. spinosa. Methods: The pepA gene of S. spinosa was amplified based on the conserved sequence and cloned into Escherichia coli Streptomyces shuttle vector pOJ260 to generate pOJ260- pepA, which was transformed into S. spinosa by conjugation. Mycelium observation, SDS-PAGE and HPLC were used to analyze the engineered strain. Results: Mycelia in S. sp DeltapepA displayed a much higher degree of fragmentation and fewer branches compared to that of parental strain. Meanwhile, the growth rate of S. sp DeltapepA was retarded and its biomass was reduced. Shake-flask fermentation demonstrated that spinosad yield increased by 122% in S. sp-DeltapepA strain compared to that of parental strain. SDS-PAGE analysis showed that protein expression profile of the engineered strain significantly changed. Conclusion: The pepA gene negatively regulates the biosynthesis of spinosad and disruption of pepA gene could affect the mycelial morphology and growth of S. spinosa. PMID- 29717855 TI - [Phosphorus dissolving capability, glucose dehydrogenase gene expression and activity of two phosphate solubilizing bacteria]. AB - Objective: To identify the function of glucose dehydrogenase (GDH) and gene expression level in theprocess of solubilizing phosphorus. Methods: Phosphate solubilizing bacteria (PSB) were isolated and purified by soluble phosphorus circle method, and identified by Vitek 2 system and 16S rRNA sequence. The phosphate solubilization capacity and GDH activity of PSB were determined. GDH genes were cloned by PCR and the relative expression level of both genes under different conditions were determined by real-time quantitative PCR. Results: Two PSB were identified as Pseudomonas sp. and Enterobacter sp. and the highest phosphorus solubilizing capability was 558 MUg/mL for the former and 478 MUg/mL for the latter. GDH genes of the two bacteria were cloned and the fragments were 2007 bp and 2066 bp. Different GDH activity and GDH gene expression were cultivated under the condition of different phosphorus sources and pH value. GDH gene expression of strain wj1 was higher than the other under high phosphorus, and the result was opposite under phosphorus stress. However, GDH gene expression of strain wj3 was lower in all phosphorus levels. The expression of GDH gene and the change of the enzyme activity were not obviously related with phosphorus solubilizing capability for strain wj3. Conclusion: There were different characteristics of GDH activity and GDH gene expression in two isolated strains that have different phosphate solubilizing mechanisms. PMID- 29717856 TI - [Phylogenetic and diversity analysis of Acidithiobacillus spp. based on 16S rRNA and RubisCO genes homologues]. AB - Objective: The purpose of the study was to reveal geographic region-related Acidithiobacillus spp. distribution and allopatric speciation. Phylogenetic and diversity analysis was done to expand our knowledge on microbial phylogeography, diversity-maintaining mechanisms and molecular biogeography. Methods: We amplified 16S rRNA gene and RubisCO genes to construct corresponding phylogenetic trees based on the sequence homology and analyzed genetic diversity of Acidithiobacillus spp.. Results: Thirty-five strains were isolated from three different regions in China (Yunnan, Hubei, Xinjiang). The whole isolates were classified into five groups. Four strains were identified as A. ferrivorans, six as A. ferridurans, YNTR4-15 Leptspirillum ferrooxidans and HBDY3-31 as Leptospirillum ferrodiazotrophum. The remaining strains were identified as A. ferrooxidans. Analysis of cbbL and cbbM genes sequences of representative 26 strains indicated that cbbL gene of 19 were two copies (cbbL1 and cbbL2) and 7 possessed only cbbL1. cbbM gene was single copy. In nucleotide-based trees, cbbL1 gene sequences of strains were separated into three sequence types, and the cbbL2 was similar to cbbL1 with three types. Codon bias of RubisCO genes was not obvious in Acidithiobacillus spp.. Conclusion: Strains isolated from three different regions in China indicated a great genetic diversity in Acidithiobacillus spp. and their 16S rRNA/RubisCO genes sequence was of significant difference. Phylogenetic tree based on 16S rRNA genes and RubisCO genes was different in Acidithiobacillus spp.. PMID- 29717857 TI - [Detection of CRSPR-Cas system in Streptococcus thermophiles]. AB - Objective: We aimed to detect the CRSPR-Cas system of six Streptococcus thermophilus. Methods: Bioinformatics method was used to predict CRSPR-Cas system of nine S. thermophilus that published in National Center for Biotechnology Information. Four primers were designed according to the flanking sequences of standard strains and the CRISPR-Cas system of six S. thermophilus have been detected by PCR method. Results: S. thermophilus S4 had a Cas9 gene, others all had Cas9 gene, Cas10 gene and Cas9* gene. In addition, 79 and KLDS3.0207 still had Cas3 gene. Conclusion: Signature genes amplification of CRSPR-Cas system could predict the type of CRSPR-Cas system in unsequenced strains, these findings will help establish the foundation for the study of CRSPR-Cas system in lactic acid bacteria. PMID- 29717858 TI - [Diversity and cytotoxic activity of endophytic bacteria isolated from Sonneratia apetala of Maowei Sea]. AB - Objective: The purpose of this study was to study the distribution, diversity and cytotoxic activity ofendophytic bacteria of Sonneratia apetala collected from Maowei Sea, Qinzhou city. Methods: The 16S rRNA gene sequencing and MTT were used to explore the diversity and cytotoxic activity of endophytic bacteria isolated from different organs and tissues of Sonneratia apetala. Results: Total of 38 isolates were obtained. The result of diversity analysis showed that these isolates could be phylogenetically classified into 21 genera and 12 families, based on their 16S rRNA gene sequencing. Of them 5 were potential new genera or new genus. Five strains (R74, R71, S92, S85 and S84) had cytotoxic activity against human liver carcinoma Hep G2 cell line. Conclusion: Endophytic bacteria of Sonneratia apetala are genetically diverse and most of them have abundant new bioactivities. PMID- 29717859 TI - [Molecular cloning, expression and characterization of lysine decarboxylase gene of endophytic fungus Shiraia sp. Slf14 from Huperzia serrata]. AB - Objective: Huperzine A (HupA) was approved as a drug for the treatment of Alzheimer's disease. The HupA biosynthetic pathway was started from lysine decarboxylase (LDC), which catalyzes lysine to cadaverine. In this study, we cloned and expressed an LDC gene from a HupA-producing endophytic fungus, and tested LDC activities. Methods: An endophytic fungus Shiraia sp. Slf14 from Huperzia serrata was used. LDC gene was obtained by RT-PCR, and cloned into pET 22b(+) and pET-32a(+) vectors to construct recombinant plasmids pET- 22b-LDC and pET-32a-LDC. These two recombinant plasmids were transformed into E. coli BL21, cultured for 8 h at 24 degrees C, 200 r/min with 1*10-3 mol/L IPTG into medium to express the LDC proteins, respectively. LDC proteins werepurified by Ni2+ affinity chromatography. Catalytic activities were measured by Thin Layer Chromatography. At last, the physicochemical properties and structures of these two LDCs were obtained by bioinformatics software. Results: LDC and Trx-LDC were expressed in E. coli BL21 successfully. SDS-PAGE analysis shows that the molecularweight of LDC and Trx-LDC were 24.4 kDa and 42.7 kDa respectively, which are consistent with bioinformaticsanalysis. In addition, TLC analysis reveals that both LDC and Trx-LDC had catalytic abilities. Conclusion: This work can provide fundamental data for enriching LDC molecular information and reveal the HupA biosynthetic pathway in endophytic fungi. PMID- 29717860 TI - [Difference of community structure among culturable bacteria in different glacial samples on Chongce Ice Cap]. AB - Objective: We studied the difference of bacterial community composition among glacial snow, morainedeposits and glacial soil on Chongce Ice Cap of West Kunlun Mountains. Methods: Based on traditional culturedependent and 16S rRNA sequence analysis, we analyzed the community structure of bacteria on the level of genus and phylum. Results: Results show that glacial bacteria were composed of Firmicutes, Proteobacteria, Actinobacteria and Bacteroidetes on the phylum level. Glacial snow was dominated by Proteobacteria, whereas glacial soil andmoraine deposits were dominated by Actinobacteria. On the genus level, glacial soil was dominated by Arthrobacter, while glacial snow was dominated by Methylobacterium, Modestobacter, Hymenobacter, Brevundimonas and Bacillus. Bacterial composition was similar between glacial soil and moraine deposits, but different from glacial snow. Skermanella may be unique on Chongce Ice Cap. Conclusion: Our study indicated the vulnerability of bacterial diversity in glacial snow with glacial retreat, and the importance of bacterial resources preservation on glacial snow environments. PMID- 29717861 TI - [Screening and biodiversity of endophytic and rhizosphere bacteria containing ACC deaminase from halophyte Limonium sinense (Girard) Kuntze]. AB - Objective: We isolated and screened endophytic and rhizosphere bacteria with 1 aminocyclopropane-1-carboxylic acid (ACC) deaminase from halophyte Limonium sinense (Girard) Kuntze collected from Jiangsu coastal area and investigated their diversity and plant growth promoting potential. Methods: Strains were obtained from inner tissues and rhizosphere soils using pure culture cultivation method and identified by 16S rRNA gene sequencing and phylogenetic analysis. Their potential plant growth promoting index of nitrogen fixation, phosphate solubilization, indoleacetic acid (IAA) production and NaCl tolerance ability were evaluated. Results: Eighteen strains with ACC deaminase were obtained and 13 of them exhibited more than 20 nmol alpha-KA/(mg Pr.h) ACC deaminase activity. Nine isolates produced IAA, 11 had nitrogen fixation ability and 7 of them had phosphate solubilization ability. Most of the isolates could grow under 0%-13% NaCl. The results of 16S rRNA sequencing showed that these strains belonged to seven genera, with Arthrobacter as the most predominant genus. Among them, strain KLBMP 5180 was found to be a potential novel species of the genus Arthrobacter. Conclusion: The halophyte plants Limonium sinense (Girard) Kuntze located in the area of coastal shoal contain a variety of symbiotic bacteria with ACC deaminase as well as the source of novel species. Some of them had good research prospect in the future. PMID- 29717862 TI - MOF-Templated N-Doped Carbon-Coated CoSe2 Nanorods Supported on Porous CNT Microspheres with Excellent Sodium-Ion Storage and Electrocatalytic Properties. AB - Three-dimensional (3D) porous microspheres composed of CoSe2@N-doped carbon nanorod-deposited carbon nanotube (CNT) building blocks (CoSe2@NC-NR/CNT) can be successfully synthesized using CNT/Co-based metal-organic framework (ZIF-67) porous microspheres as a precursor. This strategy involves the homogeneous coating of ZIF-67 polyhedrons onto porous CNT microspheres prepared by spray pyrolysis and further selenization of the composites under an Ar/H2 atmosphere. During the selenization process, the ZIF-67 polyhedrons on the CNT backbone are transformed into N-doped carbon-coated CoSe2 nanorods by a directional recrystallization process, resulting in a homogeneous deposition of CoSe2@NC nanorods on the porous CNT microspheres. Such a unique structure of CoSe2@NC NR/CNT microspheres facilitates the transport of ions, electrons, and mass and provides a conductive pathway for electrons during electrochemical reactions. Correspondingly, the composite exhibits a superior dual functionality as both an electrocatalyst for the hydrogen evolution reaction (HER) and an electrode for sodium-ion batteries (SIBs). The CoSe2@NC-NR/CNT microspheres exhibit a small Tafel slope (49.8 mV dec-1) and a superior stability for HER. Furthermore, the composite delivers a high discharge capacity of 555 mA h g-1 after 100 cycles at a current density of 0.2 A g-1 and a good rate capability for SIBs. PMID- 29717864 TI - Quasi-Solid-State Sodium-Ion Full Battery with High-Power/Energy Densities. AB - Developing a high-performance, low-cost, and safer rechargeable battery is a primary challenge in next-generation electrochemical energy storage. In this work, a quasi-solid-state (QSS) sodium-ion full battery (SIFB) is designed and fabricated. Hard carbon cloth derived from cotton cloth and Na3V2(PO4)2O2F (NVPOF) are employed as the anode and the cathode, respectively, and a sodium ion conducting gel-polymer membrane is used as both the QSS electrolyte and separator, accomplishing the high energy and power densities in the QSS sodium ion batteries. The energy density can reach 460 W h kg-1 according to the mass of the cathode materials. Moreover, the fabricated QSS SIFB also exhibits an excellent rate performance (e.g., about 78.1 mA h g-1 specific capacity at 10 C) and a superior cycle performance (e.g., ~90% capacity retention after 500 cycles at 10 C). These results show that the developed QSS SIFB is a hopeful candidate for large-scale energy storage. PMID- 29717863 TI - Bexarotene Binds to the Amyloid Precursor Protein Transmembrane Domain, Alters Its alpha-Helical Conformation, and Inhibits gamma-Secretase Nonselectively in Liposomes. AB - Bexarotene is a pleiotropic molecule that has been proposed as an amyloid-beta (Abeta)-lowering drug for the treatment of Alzheimer's disease (AD). It acts by upregulation of an apolipoprotein E (apoE)-mediated Abeta clearance mechanism. However, whether bexarotene induces removal of Abeta plaques in mouse models of AD has been controversial. Here, we show by NMR and CD spectroscopy that bexarotene directly interacts with and stabilizes the transmembrane domain alpha helix of the amyloid precursor protein (APP) in a region where cholesterol binds. This effect is not mediated by changes in membrane lipid packing, as bexarotene does not share with cholesterol the property of inducing phospholipid condensation. Bexarotene inhibited the intramembrane cleavage by gamma-secretase of the APP C-terminal fragment C99 to release Abeta in cell-free assays of the reconstituted enzyme in liposomes, but not in cells, and only at very high micromolar concentrations. Surprisingly, in vitro, bexarotene also inhibited the cleavage of Notch1, another major gamma-secretase substrate, demonstrating that its inhibition of gamma-secretase is not substrate specific and not mediated by acting via the cholesterol binding site of C99. Our data suggest that bexarotene is a pleiotropic molecule that interfere with Abeta metabolism through multiple mechanisms. PMID- 29717866 TI - Aggregation-Induced Emission-Active Near-Infrared Fluorescent Organic Nanoparticles for Noninvasive Long-Term Monitoring of Tumor Growth. AB - Effective long-term monitoring of tumor growth is significant for the evaluation of cancer therapy. Aggregation-induced emission-active near-infrared (NIR) fluorescent organic nanoparticles (TPFE-Rho dots) are designed and synthesized for long-term in vitro cell tracking and in vivo monitoring of tumor growth. TPFE Rho dots display the advantages of NIR fluorescent emission, large Stokes shift (~180 nm), good biocompatibility, and high photostability. In vitro cell tracing studies demonstrate that TPFE-Rho dots can track SK-Hep-1 cells over 11 generations. In vivo optical imaging results confirm that TPFE-Rho dots can monitor tumor growth for more than 19 days in a real-time manner. This work indicates that TPFE-Rho dots could act as NIR fluorescent nanoprobes for real time long-term in situ in vivo monitoring of tumor growth. PMID- 29717865 TI - Confined Molybdenum Phosphide in P-Doped Porous Carbon as Efficient Electrocatalysts for Hydrogen Evolution. AB - Highly efficient electrocatalysts for hydrogen evolution reactions (HER) are crucial for electrochemical water splitting, where high-cost and low-abundance Pt based materials are the benchmark catalysts for HER. Herein, we report the fabrication of MoP nanoparticles confined in P-doped porous carbon (MoP@PC) via a metal-organic framework-assisted route for the first time. Remarkably, due to the synergistic effects of MoP nanocrystals, P dopant, and porous carbon, the resulting MoP@PC composite exhibits superior HER catalytic activity with an onset overpotential of 97 mV, a Tafel slope of 59.3 mV dec-1, and good long-term durability, which compares to those of most reported MoP-based HER catalysts. Most importantly, the work opens a new route in the development of high performance nonprecious HER electrocatalysts derived from MOFs. PMID- 29717867 TI - Time-Dependent Liquid Transport on a Biomimetic Topological Surface. AB - Liquid drops impacting on a solid surface is a familiar phenomenon. On rainy days, it is quite important for leaves to drain off impacting raindrops. Water can bounce off or flow down a water-repellent leaf easily, but with difficulty on a hydrophilic leaf. Here, we show an interesting phenomenon in which impacting drops on the hydrophilic pitcher rim of Nepenthes alata can spread outward to prohibit water filling the pitcher tank. We mimic the peristome surface through a designed 3D printing and replicating way and report a time-dependently switchable liquid transport based on biomimetic topological structures, where surface curvature can work synergistically with the surface microtextures to manipulate the switchable spreading performance. Motived by this strange behavior, we construct a large-scaled peristome-mimetic surface in a 3D profile, demonstrating the ability to reduce the need to mop or to squeegee drops that form during the drop impacting process on pipes or other curved surfaces in food processing, moisture transfer, heat management, etc. PMID- 29717868 TI - Gradiently Polymerized Solid Electrolyte Meets with Micro-/Nanostructured Cathode Array. AB - The poor contact between the solid-state electrolyte and cathode materials leads to a high interfacial resistance, severely limiting the rate capability of solid Li metal batteries. Herein, an integrative battery design is introduced with a gradiently polymerized solid electrolyte (GPSE), a microchannel current collector array, and nanosized cathode particles. An in situ formed GPSE encapsulates cathode nanoparticles in the microchannel with ductile inclusions to lower the interfacial impedance, and the stiff surface layer of GPSE toward anode suppresses the Li dendrite growth. The Li metal batteries based on GPSE and the Li-free hydrogenated V2O5 (V2O5-H) cathode exhibit an outstanding high rate response of up to 5 C (the capacity ratio of 5 C/1 C is 90.3%) and an ultralow capacity fade rate of 0.07% per cycle over 300 cycles. The other Li-containing cathodes such as LiFePO4 and LiNi0.5Mn0.3Co0.2O2 can also operate effectively at the rates of 5 and 2 C, respectively. Such an ingenious design may provide new insights into other solid metal batteries through an interfacial engineering manipulation at the micro- and nanolevel. PMID- 29717869 TI - B-H Bond Activation by an Amidinate-Stabilized Amidosilylene: Non-Innocent Amidinate Ligand. AB - The activation of B-H and B-Cl bonds in boranes by base-stabilized low-valent silicon compounds is described. The reaction of the amidinato amidosilylene borane adduct [L{Ar(Me3Si)N}SiBH3] [1; L = PhC(N tBu)2, and Ar = 2,6- iPr2C6H3] with MeOTf in toluene at room temperature formed [L{Ar(Me3Si)N}SiBH2OTf] (2). [LSiN(SiMe3)Ar] in compound 2 then underwent a B-H bond activation with BH2OTf in refluxing toluene to afford the B-H bond activation product [LB(H)Si(H)(OTf){N(SiMe3)Ar}] (3). On the other hand, when compound 2 was reacted with 4-dimethylaminopyridine in refluxing toluene, another B-H bond activation product [(MU-kappa1:kappa1-L)B(H)(DMAP)Si(H){N(Ar)SiMe3}]OTf (4) was afforded. Mechanistic studies show that "(MU-kappa1:kappa1-L)B(H)(OTf)Si(H){N(Ar)SiMe3}" (2A) is the key intermediate in the reactions mentioned above. The formation of 2A is further evidenced by the activation of the B-Cl bond in PhBCl2 by the amidinato silicon(I) dimer [LSi:]2 to form the B-Cl bond activation product [(MU kappa1:kappa1-L)B(Cl)(Ph)Si(Cl)]2 (6). Compounds 2-4 and 6 were characterized by nuclear magnetic resonance spectroscopy and X-ray crystallography. PMID- 29717870 TI - Reliable and Performant Identification of Low-Energy Conformers in the Gas Phase and Water. AB - Prediction of compound properties from structure via quantitative structure activity relationship and machine-learning approaches is an important computational chemistry task in small-molecule drug research. Though many such properties are dependent on three-dimensional structures or even conformer ensembles, the majority of models are based on descriptors derived from two dimensional structures. Here we present results from a thorough benchmark study of force field, semiempirical, and density functional methods for the calculation of conformer energies in the gas phase and water solvation as a foundation for the correct identification of relevant low-energy conformers. We find that the tight-binding ansatz GFN-xTB shows the lowest error metrics and highest correlation to the benchmark PBE0-D3(BJ)/def2-TZVP in the gas phase for the computationally fast methods and that in solvent OPLS3 becomes comparable in performance. MMFF94, AM1, and DFTB+ perform worse, whereas the performance optimized but far more expensive functional PBEh-3c yields energies almost perfectly correlated to the benchmark and should be used whenever affordable. On the basis of our findings, we have implemented a reliable and fast protocol for the identification of low-energy conformers of drug-like molecules in water that can be used for the quantification of strain energy and entropy contributions to target binding as well as for the derivation of conformer-ensemble-dependent molecular descriptors. PMID- 29717872 TI - Rapid Access to Thiolactone Derivatives through Radical-Mediated Acyl Thiol-Ene and Acyl Thiol-Yne Cyclization. AB - A new synthetic approach to thiolactones that employs an efficient acyl thiol-ene (ATE) or acyl thiol-yne (ATY) cyclization to convert unsaturated thiocarboxylic acid derivatives into thiolactones under very mild conditions is described. The high overall yields, fast kinetics, high diastereoselectivity, excellent regiocontrol, and broad substrate scope of these reaction processes render this a very useful approach for diversity-oriented synthesis and drug discovery efforts. A detailed computational rationale is provided for the observed regiocontrol. PMID- 29717871 TI - VUV Photoionization Study of the Formation of the Simplest Polycyclic Aromatic Hydrocarbon: Naphthalene (C10H8). AB - The formation of the simplest polycyclic aromatic hydrocarbon (PAH), naphthalene (C10H8), was explored in a high-temperature chemical reactor under combustion like conditions in the phenyl (C6H5)-vinylacetylene (C4H4) system. The products were probed utilizing tunable vacuum ultraviolet light by scanning the photoionization efficiency (PIE) curve at a mass-to-charge m/ z = 128 (C10H8+) of molecules entrained in a molecular beam. The data fitting with PIE reference curves of naphthalene, 4-phenylvinylacetylene (C6H5CCC2H3), and trans-1 phenylvinylacetylene (C6H5CHCHCCH) indicates that the isomers were generated with branching ratios of 43.5+/-9.0 : 6.5+/-1.0 : 50.0+/-10.0%. Kinetics simulations agree nicely with the experimental findings with naphthalene synthesized via the hydrogen abstraction-vinylacetylene addition (HAVA) pathway and through hydrogen assisted isomerization of phenylvinylacetylenes. The HAVA route to naphthalene at elevated temperatures represents an alternative pathway to the hydrogen abstraction-acetylene addition (HACA) forming naphthalene in flames and circumstellar envelopes, whereas in cold molecular clouds, HAVA synthesizes naphthalene via a barrierless bimolecular route. PMID- 29717873 TI - Pepluanols C-D, Two Diterpenoids with Two Skeletons from Euphorbia peplus. AB - Pepluanols C and D (1 and 2), featuring unprecedented 5/5/10 with out,out [7.2.1]bicylcododecane core and 6/6/7/3 fused-ring skeletons, respectively, were isolated from Euphorbia peplus. Their chemical structures and absolute configurations were determined by a series of extensive spectroscopic methods, and X-ray diffraction analysis. In addition, pepluanols C and D showed 31.6 +/- 8.3% and 30.5 +/- 2.8% peak current inhibition on the Kv1.3 potassium channel at 30 MUM. PMID- 29717874 TI - High Electron Mobility and Insights into Temperature-Dependent Scattering Mechanisms in InAsSb Nanowires. AB - InAsSb nanowires are promising elements for thermoelectric devices, infrared photodetectors, high-speed transistors, as well as thermophotovoltaic cells. By changing the Sb alloy fraction the mid-infrared bandgap energy and thermal conductivity may be tuned for specific device applications. Using both terahertz and Raman noncontact probes, we show that Sb alloying increases the electron mobility in the nanowires by over a factor of 3 from InAs to InAs0.65Sb0.35. We also extract the temperature-dependent electron mobility via both terahertz and Raman spectroscopy, and we report the highest electron mobilities for InAs0.65Sb0.35 nanowires to date, exceeding 16,000 cm2 V-1 s-1 at 10 K. PMID- 29717876 TI - Asymmetric Epoxidation of 1,4-Naphthoquinones Catalyzed by Guanidine-Urea Bifunctional Organocatalyst. AB - An enantioselective nucleophilic epoxidation of 2-substituted 1,4-naphthoquinones in the presence of a newly developed guanidine-bisurea bifunctional organocatalyst with tert-butyl hydroperoxide (TBHP) as an oxidant is presented. 1,4-Naphthoquinones bearing substituents at C6, C7, and C2 were available for the reaction, and the corresponding epoxides were obtained with 88:12-95:5 er in 71 98% yields. DFT calculations indicated that substituents at C2 and C6 in the terminal Ar group of the catalyst 9k play a key role in controlling the stereochemical outcome. PMID- 29717875 TI - A Single Mutation Traps a Half-Sites Reactive Enzyme in Midstream, Explaining Asymmetry in Hydride Transfer. AB - In Escherichia coli thymidylate synthase (EcTS), rate-determining hydride transfer from the cofactor 5,10-methylene-5,6,7,8-tetrahydrofolate to the intermediate 5-methylene-2'-deoxyuridine 5'-monophosphate occurs by hydrogen tunneling, requiring precise alignment of reactants and a closed binding cavity, sealed by the C-terminal carboxyl group. Mutations that destabilize the closed conformation of the binding cavity allow small molecules such as beta mercaptoethanol (beta-ME) to enter the active site and compete with hydride for addition to the 5-methylene group of the intermediate. The C-terminal deletion mutant of EcTS produced the beta-ME adduct in proportions that varied dramatically with cofactor concentration, from 50% at low cofactor concentrations to 0% at saturating cofactor conditions, suggesting communication between active sites. We report the 2.4 A X-ray structure of the C-terminal deletion mutant of E. coli TS in complex with a substrate and a cofactor analogue, CB3717. The structure is asymmetric, with reactants aligned in a manner consistent with hydride transfer in only one active site. In the second site, CB3717 has shifted to a site where the normal cofactor would be unlikely to form 5-methylene-2' deoxyuridine 5'-monophosphate, consistent with no formation of the beta-ME adduct. The structure shows how the binding of the cofactor at one site triggers hydride transfer and borrows needed stabilization from substrate binding at the second site. It indicates pathways through the dimer interface that contribute to allostery relevant to half-sites reactivity. PMID- 29717877 TI - Dynamics of the Optically Directed Assembly and Disassembly of Gold Nanoplatelet Arrays. AB - The tremendous progress in nanoscience now allows the creation of static nanostructured materials for a broad range of applications. A further goal is to achieve dynamic and reconfigurable nanostructures. One approach involves nanoparticle-based optical matter, but so far, studies have only considered spherical constituents. A nontrivial issue is that nanoparticles with other shapes are expected to have different local electromagnetic field distributions and interactions with neighbors in optical-matter arrays. Therefore, one would expect their dynamics to be different as well. This paper reports the directed assembly of ordered arrays of gold nanoplatelets in optical line traps, demonstrating the reconfigurability of the array by altering the phase gradient via holographic-beam shaping. The weaker gradient forces and resultant slower motion of the nanoplatelets, as compared with plasmonic (Ag and Au) nanospheres, allow the precise study of their assembly and disassembly dynamics. Both temporal and spatial correlations are detected between particles separated by distances of hundreds of nanometers to several microns. Electrodynamics simulations reveal the presence of multipolar plasmon modes that induce short-range (near-field) and longer-range electrodynamic (e.g., optical binding) interactions. These interactions and the interferences between mutipolar plamon modes cause both the strong correlations and the nonuniform dynamics observed. Our study demonstrates new opportunities for the generation of complex addressable optical matter and the creation of novel active optical technology. PMID- 29717878 TI - Electrostatically Driven Guest Binding in a Self-Assembled Porous Network at the Liquid/Solid Interface. AB - We present here the construction of a self-assembled two-dimensional (2D) porous monolayer bearing a highly polar 2D space to study guest co-adsorption through electrostatic interactions at the liquid/solid interface. For this purpose, a dehydrobenzo[12]annulene (DBA) derivative, DBA-TeEG, having tetraethylene glycol (TeEG) groups at the end of the three alternating alkoxy chains connected by p phenylene linkers was synthesized. As a reference host molecule, DBA-C10, having nonpolar C10 alkyl chains at three alternating terminals, was employed. As guest molecules, hexagonal phenylene-ethynylene macrocycles (PEMs) attached by triethylene glycol (TEG) ester and hexyl ester groups, PEM-TEG and PEM-C6, respectively, at each vertex of the macrocyclic periphery were used. Scanning tunneling microscopy observations at the 1,2,4-trichlorobenzene/highly oriented pyrolytic graphite interface revealed that PEM-TEG was immobilized in the pores formed by DBA-TeEG at higher probability because of electrostatic interactions such as dipole-dipole and hydrogen bonding interactions between oligoether units of the host and guest, in comparison to PEM-C6 with nonpolar groups. These observations are discussed based on molecular mechanics simulations to investigate the role of the polar functional groups. When a nonpolar host matrix formed by DBA-C10 was used, however, only phase separation and preferential adsorption were observed; virtually no host-guest complexation was discernible. This is ascribed to the strong affinity between the guest molecules which form by themselves densely packed van der Waals networks on the surface. PMID- 29717879 TI - ABM Clinical Protocol #12: Transitioning the Breastfeeding Preterm Infant from the Neonatal Intensive Care Unit to Home, Revised 2018. AB - A central goal of the Academy of Breastfeeding Medicine is the development of clinical protocols, free from commercial interest or influence, for managing common medical problems that may impact breastfeeding success. These protocols serve only as guidelines for the care of breastfeeding mothers and infants and do not delineate an exclusive course of treatment or serve as standards of medical care. Variations in treatment may be appropriate according to the needs of an individual patient. PMID- 29717880 TI - Most Good, Least Harm: Isoform-Specific Targeting of ROCK in Pulmonary Fibrosis. PMID- 29717881 TI - Mindfulness in Corporate America: Is the Trojan Horse Ethical? PMID- 29717882 TI - Gratitude and Recognition in a Hospital Setting: Addressing Provider Well-Being and Patient Outcomes. PMID- 29717883 TI - Drugging homologous recombination: back to the future. PMID- 29717884 TI - A new ionone derivative from the leaves of Picrasma quassioides. AB - Nigakialcohol A (1), as unusual cyclization ionone derivative, together with eight known ones (2-9), were isolated from the leaves of Picrasma quassioides (D. Don) Benn (Simaroubaceae). Their structures were elucidated by extensive spectroscopic analyses and comparison with literature data. Compound 2 showed a weak inhibitory effect on NO production at non-cytotoxic concentration (100 MUM) with inhibitory rate of 59%, and thus it should be regarded as potential anti inflammatory agents. PMID- 29717885 TI - Time-restricted feeding of a high-fat diet in male C57BL/6 mice reduces adiposity but does not protect against increased systemic inflammation. AB - Time-restricted feeding (TRF) limits the duration of food availability without altering diet composition and can combat obesity in humans and mice. For this study we evaluated the effect of timing of food access during a TRF protocol on weight gain, adiposity, and inflammation. Young male C57BL/6 mice were placed on a high-fat (HF) diet (45% fat) for 8 weeks. Food access was unrestricted (HF) or restricted to 6 h per day, either for the first half (HF-early) or the second half (HF-late) of the active phase to resemble a window of time for food consumption early or late in the day in a human population. Weight, obesity associated parameters, and inflammation were measured. TRF reduced weight gain over the 8-week period in mice consuming the same high-fat diet. Consistent with decreased weight gain in the TRF groups, body fat percentage, liver triglycerides, and plasma leptin and cholesterol levels were reduced. Adipose tissue inflammation, measured by CD11b+F4/80+ macrophage infiltration, was reduced in both TRF groups, but systemic tumor necrosis factor-alpha was increased in all groups consuming the high-fat diet. The HF-late group gained more weight than the HF-early group and had increased insulin resistance, while the HF-early group was protected. Therefore, a TRF protocol is beneficial for weight management when a high-fat diet is consumed, with food consumption earlier in the day showing greater health benefits. However, increased inflammatory markers in the TRF groups suggest that diet components can still increase inflammation even in the absence of overt obesity. PMID- 29717886 TI - Robotic oesophago-gastric cancer surgery. PMID- 29717887 TI - Robotics in oral and maxillofacial surgery. PMID- 29717888 TI - Robotics in urology. PMID- 29717890 TI - An extra set of hands. PMID- 29717889 TI - Robotics in trauma and orthopaedics. PMID- 29717891 TI - Robotics in neurosurgery. PMID- 29717892 TI - A short history of robotic surgery. PMID- 29717894 TI - Amputees at High Altitude: The Potentially Sticky Issue of Thrombophilia. PMID- 29717893 TI - Robotics in HPB surgery. PMID- 29717895 TI - Effects of Phytoestrogens on Depressive Symptoms in Climacteric Women: A Meta Analysis of Randomized Controlled Trials. PMID- 29717896 TI - The importance of food, nutrition and physical activity in cancer prevention: an interview with Dr Kate Allen. AB - Kate Allen speaks to Roshaine Wijayatunga, Managing Commissioning Editor. Dr Kate Allen works as an Executive Director in Science and Public Affairs at World Cancer Research Fund International ( http://wcrf.org ), an NGO and leading authority in the field of cancer prevention through diet, weight and physical activity. Kate is responsible for the organization's scientific, policy and conference programs in the areas of food, nutrition, physical activity and weight management. An important aspect of her role is helping to create collaborative relationships and activities across the WCRF national charities (in Europe, America and Asia) in these areas, as well as maintaining and creating external partnerships. Previously, Kate worked at the Institute of Cancer Research, where she set up an award-winning Interactive Education Unit to develop learning materials for scientists, healthcare professionals, students, patients and the general public. Before that she worked at Medi Cine International, a medical education agency, where she developed educational materials across all media, mainly for specialist physician audiences. Kate has a PhD in neuroscience, carried out at the Institute of Neurology and the National Hospital for Neurology and Neurosurgery at Queen Square, London and the Royal College of Surgeons of England. The Third Expert Report that Kate mentions in the interview, featuring the updated World Cancer Research Fund Cancer Prevention Recommendations is launched 24 May 2018. For more information see http://wcrf.org . PMID- 29717897 TI - Neutrophil-mediated T-Cell Suppression in Influenza: Novel Finding Raising Additional Questions. PMID- 29717898 TI - Informed consent comprehension among vulnerable populations in Ecuador: video delivered vs. in-person standard method. AB - The informed consent comprehension process is key to engaging potential research subject participation. The aim of this study is to compare informed consent comprehension between two methods: standard and video-delivered. We compared the in-person and video-delivered informed consent process in the Familias Unidas intervention. We evaluated comprehension using a 7-item true/false questionnaire. There were a total of 152 participants in the control group and 87 in the experimental. General characteristics were similar between both groups (p > 0.05). First-attempt informed consent comprehension was higher in the intervention group but was not statistically significant (80% and 78% respectively p = 0.44). A video-delivered informed consent process did not differ from the standard method of informed consent in a low educational and socioeconomic environment. PMID- 29717899 TI - Challenges and Patterns of Seeking Primary Health Care in Slums of Karachi: A Disaster Lurking in Urban Shadows. AB - This study aimed to evaluate the challenges and patterns of seeking primary health care services in slums of Karachi, where about 60% of the population lives in various informal settlements. We surveyed 8 largest slums of the metropolitan, and analyzed the data both descriptively and inferentially to evaluate the factors associated with health care seeking behavior. Significantly positive association of quality health care seeking behavior and various socioeconomic indicators were found. In addition, substantial insights about the conditions of slum dwellers and health challenges of the population, such as low immunization and low vaccinations, among others, were reported. Thus, the role of policymakers is emphasized to strategize for the inclusion of these people in national health plans and to develop health infrastructure near these communities. Furthermore, there is a strong need to increase awareness of the population about hygiene practices, importance of immunization, and importance of utilizing appropriate health care services. PMID- 29717900 TI - The effect of brief intermittent stair climbing on glycemic control in people with type 2 diabetes: a pilot study. AB - We examined the effect of brief intermittent stair climbing exercise on glycemic control using continuous glucose monitoring in people with type 2 diabetes (n = 7, 5 men; 2 women; age, 21-70 years). The protocol involved three 60-s bouts of vigorously ascending and slowly descending a flight of stairs. Mean 24-h blood glucose was unchanged after an acute session (p = 0.43) and following 18 sessions over 6 weeks (p = 0.13). The protocol was well tolerated by participants but seemingly insufficient to alter glycemic control. PMID- 29717901 TI - Faking Good: An Investigation of Social Desirability and Defensiveness in an Inpatient Sample With Personality Disorder Traits. AB - Accurate interpretations of psychological assessments rely heavily on forthright reporting. However, researchers and practitioners recognize that examinees can easily invalidate their test results by underreporting symptoms or overstating positive attributes. Rogers (2008) delineated two distinct but related forms of positive impression management (PIM): defensiveness (denying symptoms and psychological impairment) and social desirability (putting forth an exaggeratedly positive image). Although these two have often been combined in past research, this study sought to investigate each separately via a mixed within- and between subjects simulation design. Simulation scenarios included a special rehabilitation program for the defensiveness (DF) condition and a competitive job for social desirability (SD). The study used the Personality Inventory for DSM-5 (PID-5; Krueger, Derringer, Markon, Watson, & Skodol, 2012) and recruited 106 inpatients from a psychiatric hospital. As expected, inpatients with prominent personality traits substantially suppressed them under both PIM conditions. Having shown the susceptibility of the PID-5 to intentional distortion, two empirically derived and conceptually based validity scales were next developed to address this important concern. Pending further validation, they might contribute to screening PIM presentations, thus promoting the PID-5's clinical utility. Continued research is needed across multiscale inventories for differentiating PIM presentations. PMID- 29717902 TI - Disparities in Nursing Home Use and Quality Among African American, Hispanic, and White Medicare Residents With Alzheimer's Disease and Related Dementias. AB - OBJECTIVE: This article examines differences in nursing home use and quality among Medicare beneficiaries, in both Medicare Advantage and fee-for-service, newly admitted to nursing homes with Alzheimer's disease and related dementias (ADRD). METHOD: Retrospective, national, population-based study of Medicare residents newly admitted to nursing homes with ADRD by race and ethnic group. Our analytic sample included 1,302,099 nursing home residents-268,181 with a diagnosis of ADRD-in 13,532 nursing homes from 2014. RESULTS: We found that a larger share of Hispanic Medicare residents that are admitted to nursing homes have ADRD compared with African American and White beneficiaries. Both Hispanics and African Americans with ADRD received care in segregated nursing homes with fewer resources and lower quality of care compared with White residents. DISCUSSION: These results have implications for targeted efforts to achieve health care equity and quality improvement efforts among nursing homes that serve minority patients. PMID- 29717903 TI - Bactericidal Effect of Various Laser Irradiation Systems on Enterococcus faecalis Biofilms in Dentinal Tubules: A Confocal Laser Scanning Microscopy Study. AB - OBJECTIVE: The aim of this study was to compare the bactericidal effect of various laser irradiation systems on Enterococcus faecalis biofilms in dentinal tubules by using a novel dentin infection model and confocal laser scanning microscopy (CLSM). BACKGROUND DATA: Laser-activated irrigations have been proposed as an adjuvant to conventional protocols of root canal treatment to enhance the smear layer removal, which is a promising protocol for root canal disinfection. MATERIALS AND METHODS: E. faecalis were centrifuged into the dentinal tubules, cultured for 3 weeks, and then received 1- and 3-min treatments as follows: (A) 5.25% sodium hypochlorite (NaOCl) irrigation, (B) Nd:YAG laser irradiation, (C) diode laser irradiation, (D) Nd:YAP laser irradiation, (E) Er,Cr:YSGG laser-activated NaOCl irrigation, and (F) Er:YAG laser-activated NaOCl irrigation. Bacterial reductions were assessed by CLSM using a LIVE/DEAD(r) bacterial viability stain method. RESULTS: For each group, the bacterial reduction increased as the treatment time increased (p < 0.05). The Er,Cr:YSGG and Er:YAG laser significantly enhanced the bactericidal effect of NaOCl (p < 0.05). Under the conditions of the same treatment time, bacterial reductions were presented in the descending order of Er:YAG + NaOCl, Er,Cr:YSGG + NaOCl > Nd:YAP > Nd:YAG, diode > NaOCl. CONCLUSIONS: Under the conditions of present study, treatments of Er:YAG + NaOCl and Er,Cr:YSGG + NaOCl presented the strongest bactericidal effect among the tested protocols and are potential protocols for root canal disinfection. PMID- 29717904 TI - Time Well Spent. PMID- 29717905 TI - Genetic and Environmental Influences on the Associations Between Uric Acid Levels and Metabolic Syndrome Over Time. AB - BACKGROUND: The longitudinal associations between serum uric acid (UA) levels and metabolic syndrome (MetS) and its components, as well as the shared genetic and environmental correlations between these traits, were evaluated. PARTICIPANTS AND METHODS: In a total of 1803 participants (675 men and 1128 women; 695 monozygotic twin individuals, 159 dizygotic twin individuals, and 949 non-twin family members; 44.3 +/- 12.8 years old) and 321 monozygotic twin pairs with data on UA levels and MetS components at baseline and follow-up, mixed linear model, conditional logistic regression, and bivariate variance component analysis were conducted. RESULTS: After 3.7 +/- 1.4 years, the incident and persistent prevalence of MetS were 5.3% and 11.6%, respectively. UA was positively associated with the concurrent and future number of MetS criteria, blood pressure (BP), and triglyceride (TG) levels, whereas an inverse association was observed between UA and future high-density lipoprotein cholesterol (HDL-C) levels after adjusting for twin and household effects, demographics, health behaviors at baseline, and other confounders according to outcome variables. In the adjusted bivariate analysis, UA had genetic and environmental correlations with the concurrent and future number of MetS criteria, and had genetic correlations with concurrent BP and TG levels and future diastolic BP and HDL-C levels. In the adjusted co-twin control analysis, twins with a higher UA level were more likely to have concurrent MetS [odds ratio (95% confidence interval) 1.59 (1.00-2.53)], high blood glucose levels [1.84 (1.06-3.17)], future MetS [2.35 (1.19-4.64)], and high TG levels [1.52 (1.03-2.24)] than co-twins with a lower UA level. CONCLUSION: Genetic and environmental factors affect the concurrent and longitudinal associations between UA and MetS as well as some of its components. PMID- 29717906 TI - Relationship of Selected Adipokines with Markers of Vascular Damage in Patients with Type 2 Diabetes. AB - BACKGROUND: In this study we compared levels of selected adipokines between patients with type 2 diabetes (T2D) and healthy individuals and we determined their relationship with early vascular damage markers. METHODS: Seventy-seven subjects: 56 patients with T2D (34 men and 22 women) and 21 healthy controls (8 men and 13 women) were examined in this cross-sectional study. Selected adipokines [adiponectin, adipocyte fatty acid-binding protein (A-FABP), fibroblast growth factor 21 (FGF-21), C1q/TNF-related protein 9 (CTRP-9), and allograft inflammatory factor-1 (AIF-1)] with possible cardiovascular impact were measured in all participants. To identify markers of vascular damage von Willebrand factor (vWF), plasminogen activator inhibitor-1 (PAI-1) and arterial stiffness parameters were examined in all the subjects. RESULTS: When compared with healthy controls, T2D had significantly higher levels of A-FABP [50.0 (38.1 68.6) vs. 28.6 (23.6-32.9) ng/mL, P < 0.0001] and lower levels of adiponectin [5.9 (4.3-9.0) vs. 11.3 (8.7-14.8) MUg/mL, P < 0.0001]. Differences in other adipokines were not statistically significant. Adiponectin level correlated negatively with vWF levels (rho = -0.29, P < 0.05) and PAI-1 (rho = -0.36, P < 0.05) and A-FABP positively with vWF (rho = 0.61, P < 0.05) and PAI-1 (rho = 0.47, P < 0.05) and augmentation index (rho = 0.26, P < 0.05). Multivariate regression analysis showed independent association between A-FABP and vWF (b = 0.24, P < 0.05). CONCLUSIONS: Patients with T2D have significantly higher levels of A-FABP and lower levels of adiponectin. These adipokines correlate with indicators of vascular damage and could contribute to cardiovascular risk in patients with T2D. A-FABP may participate in direct endothelium damage. PMID- 29717907 TI - Cephalosporin Plus Metronidazole for Surgical Prophylaxis. PMID- 29717908 TI - Comparison of GreenLight Laser Photoselective Vaporization and Thulium Laser Enucleation for Nonmuscle Invasive Bladder Cancer. AB - OBJECTIVE: To evaluate the safety and efficacy of GreenLight laser vaporization and thulium laser enucleation for nonmuscle invasive bladder cancer (NMIBC). PATIENTS AND METHODS: A total of 150 patients of NMIBC who underwent either GreenLight laser vaporization (Group A, n = 78) or thulium laser enucleation (Group B, n = 72) were analyzed, respectively. The preoperative, intraoperative, and postoperative clinical data were recorded and compared in the two groups. RESULTS: All patients were successfully treated with GreenLight laser vaporization or thulium laser enucleation. No significant difference was observed in operation time, catheterization time, and postoperative hospital stay time between them. No complications such as obturator nerve reflex, bladder perforation, overhydration, or intraoperative or postoperative bleeding occurred in all patients. The patients were followed up for 12 months; during the period the recurrence rate was 10.26% (8/78) and 9.72% (7/72), respectively, between Groups A and B. CONCLUSIONS: Both GreenLight laser vaporization and thulium laser enucleation are effective and safe treatments for patients with NMIBC. Long-term clinical trials are necessary to increase the current scientific evidence base. PMID- 29717909 TI - A Technique of Cone-Beam Computerized Tomography Superimposition in Implant Dentistry. PMID- 29717910 TI - Treating ADHD With Suggestion: Neurofeedback and Placebo Therapeutics. AB - OBJECTIVE: We propose that clinicians can use suggestion to help treat conditions such as ADHD. METHODS: We use EEG neurofeedback as a case study, alongside evidence from a recent pilot experiment utilizing a sham MRI scanner to highlight the therapeutic potential of suggestion-based treatments. RESULTS: The medical literature demonstrates that many practitioners already prescribe treatments that hardly outperform placebo comparators. Moreover, the sham MRI experiment showed that, even with full disclosure of the procedure, suggestion alone can reduce the symptomatology of ADHD. CONCLUSION: Non-deceptive suggestion-based treatments, especially those drawing on accessories from neuroscience, may offer a safe complement and potential alternative to current standard of care for individuals with ADHD. PMID- 29717911 TI - Epidemiology of Trauma-Related Infections among a Combat Casualty Cohort after Initial Hospitalization: The Trauma Infectious Disease Outcomes Study. AB - BACKGROUND: The Trauma Infectious Disease Outcomes Study (TIDOS) cohort follows military personnel with deployment-related injuries in order to evaluate short- and long-term infectious complications. High rates of infectious complications have been observed in more than 30% of injured patients during initial hospitalization. We present data on infectious complications related to combat trauma after the initial period of hospitalization. PATIENTS AND METHODS: Data related to patient care for military personnel injured during combat operations between June 2009 and May 2012 were collected. Follow-up data were captured from interviews with enrolled participants and review of electronic medical records. RESULTS: Among 1,006 patients enrolled in the TIDOS cohort with follow-up data, 357 (35%) were diagnosed with one or more infection during their initial hospitalization, of whom 160 (45%) developed a trauma-related infection during follow-up (4.2 infections per 10,000 person-days). Patients with three or more infections during the initial hospitalization had a significantly higher rate of infections during the follow-up period compared with those with only one inpatient infection (incidence rate: 6.6 versus 3.1 per 10,000 days; p < 0.0001). There were 657 enrollees who did not have an infection during initial hospitalization, of whom 158 (24%) developed one during follow-up (incidence rate: 1.6 per 10,000 days). Overall, 318 (32%) enrolled patients developed an infection after hospital discharge (562 unique infections) with skin and soft tissue infections being predominant (66%) followed by osteomyelitis (16%). Sustaining an amputation or open fracture, having an inpatient infection, and use of anti-pseudomonal penicillin (>=7 d) were independently associated with risk of an extremity wound infection during follow-up, whereas shorter hospitalization (15-30 d) was associated with a reduced risk. CONCLUSIONS: Combat-injured patients have a high burden of infectious complications that continue long after the initial period of hospitalization with soft-tissue and osteomyelitis being predominant. Further research on the long-term impact and outcomes of combat associated infection is needed. PMID- 29717912 TI - USPSTF Testicular Examination Nomination-Self-Examinations and Examinations in a Clinical Setting. AB - In 2004, the U.S. Preventive Services Task Force (USPSTF) published a Grade D recommendation for both testicular self-examination (TSE) and clinical evaluation to screen for testicular cancer in asymptomatic males. This review committee reaffirmed these recommendations in 2009 and again in 2011 (Testicular Cancer: Screening Release Date: April 2011. Final Update Summary: Testicular Cancer: Screening. U.S. Preventive Services Task Force. September 2016). The 2011 USPSTF review found no significant evidence that would warrant a change from the last full review in 2004. We believe that the USPSTF erred in its assessments. As acknowledged in the task force report, testicular cancer is not believed to be preventable, and treatment of early detected testicular cancer is generally associated with very favorable outcomes; it is our belief therefore that every encouragement should be given to early detection. We are therefore requesting that the USPSTF review the D rating for testicular examination, both in a clinical setting and as self-examination. We are requesting this, as recent studies and public health warrant a change in grade. The new studies build on earlier studies that support the benefits of regular screening by individuals and their physicians. Further, and equally important, we believe that the current grade and attendant information confuses men and boys about the importance of self-care and wellness and continues to inadvertently reinforce negative cultural attitudes. We believe that adjusting the rating to a Grade B is both warranted and necessary. PMID- 29717913 TI - Ethnic Drinking Culture, Acculturation, and Enculturation in Relation to Alcohol Drinking Behavior Among Marriage-Based Male Immigrants in Taiwan. AB - Drinking behavior among immigrants could be influenced by drinking-related cultural norms in their country of origin and host country. This study examined the association of ethnic drinking culture, acculturation, and enculturation with alcohol drinking among male immigrants in Taiwan. This cross-sectional survey recruited 188 male immigrants. Ethnic drinking culture was divided into dry and wet according to per capita alcohol consumption and abstinent rate in the countries of origin in reference to that in Taiwan. A scale, Bidimensional Acculturation Scale for Marriage-Based Immigrants, was developed to measure acculturation (adaptation to the host culture) and enculturation (maintenance of the original culture). Drinking patterns (abstinent, low-risk drinking, and hazardous drinking) were determined by scores on the Alcohol Use Disorder Identification Test. There was a significant interaction between ethnic drinking culture and enculturation/acculturation on drinking patterns. Multinomial logistic regression models identified that for those from dry ethnic drinking cultures, a high level of acculturation was associated with increased low-risk drinking, while a high level of enculturation was associated with decreased low risk drinking. For those from wet ethnic drinking cultures, a low level of acculturation and high level of enculturation were associated with increased hazardous drinking. High family socioeconomic status was associated with increased drinking, while perceived insufficient family income was positively associated with hazardous use. To prevent hazardous use of alcohol, health education should be targeted at immigrant men who drink, especially among those who have economic problems, are from wet ethnic drinking cultures, and demonstrate low adaptation to the host culture. PMID- 29717914 TI - Added prognostic value of FDG-PET/CT in relapsing multiple myeloma patients. PMID- 29717915 TI - HrpS Is a Global Regulator on Type III Secretion System (T3SS) and Non-T3SS Genes in Pseudomonas savastanoi pv. phaseolicola. AB - The type III secretion system (T3SS) is the main machinery for Pseudomonas savastanoi and other gram-negative bacteria to invade plant cells. HrpR and HrpS form a hetero-hexamer, which activates the expression of HrpL, which induces all T3SS genes by binding to a 'hrp box' in promoters. However, the individual molecular mechanism of HrpR or HrpS has not been fully understood. Through chromatin immunoprecipitation coupled to high-throughput DNA sequencing, we found that HrpR, HrpS, and HrpL had four, 47, and 31 targets on the genome, respectively. HrpS directly bound to the promoter regions of a group of T3SS genes and non-T3SS genes. HrpS independently regulated these genes in a hrpL deletion strain. Additionally, a HrpS-binding motif (GTGCCAAA) was identified, which was verified by electrophoretic mobility shift assay and lux-reporter assay. HrpS also regulated motility and biofilm formation in P. savastanoi. The present study strongly suggests that HrpS alone can work as a global regulator on both T3SS and non-T3SS genes in P. savastanoi. [Formula: see text] Copyright (c) 2018 The Author(s). This is an open-access article distributed under the CC BY-NC ND 4.0 International license . PMID- 29717916 TI - Risk Factors Associated With the Development of Acquired Airway Disease After Congenital Heart Surgery: A Retrospective Cohort Study. AB - OBJECTIVE: In this single-center, retrospective review, we sought to determine the risk factors associated with the development of severe acquired airway disease (AAD; vocal cord paralysis [VCP] or subglottic stenosis [SGS]) in pediatric patients who had undergone surgery for congenital heart disease (CHD) with cardiopulmonary bypass. All patients who required surgical treatment for CHD using cardiopulmonary bypass at our institution between 2010 and 2015 were reviewed. We defined severe AAD as either clinically significant VCP, SGS, or both, requiring consultation with the otolaryngology (ENT) service for evaluation. The disease was classified as severe because it led to difficulty with intubation or failure to wean mechanical ventilation. This airway disease was not present or was clinically insignificant prior to congenital heart surgery. RESULTS: Over a 5-year period (August 2010 to December 2015), 1395 patients were evaluated. Of these, 25 (1.8%) had significant AAD. Age was the only statistically significant independent predictor of AAD ( P < .001). Those with AAD were younger-3 versus 8 months-and had longer intubation time: 5 (2-18) versus 2 days (1-5). Of those who developed AAD, most (22/25) required some form of additional surgical procedure for its evaluation or management. Only 3 of the 25 patients with severe AAD required tracheostomy. CONCLUSIONS: Children who undergo congenital heart surgery with cardiopulmonary bypass are at risk for developing AAD, most often because of SGS or VCP. AAD can lead to failed extubation in the postoperative setting as well as difficult intubation during subsequent anesthetics. Although it often requires surgical treatment, it responds well to therapy and rarely requires tracheostomy. PMID- 29717917 TI - Higher versus Lower Dose of Cefotetan or Cefoxitin for Surgical Prophylaxis in Patients Weighing One Hundred Twenty Kilograms or More. AB - BACKGROUND: Clinical practice guidelines recommend a 2-g dose of cefotetan and cefoxitin for surgical prophylaxis. Pharmacokinetic data suggest benefit from higher cefotetan and cefoxitin dosing in obese patients. However, clinical studies examining higher dosing strategies in this at-risk population are lacking. The purpose of this study was to determine whether 3 g of cefotetan or cefoxitin administered pre-operatively for patients who weigh 120 kg or more is associated with a lower proportion of surgical site infection (SSI) compared with 2 g. PATIENTS AND METHODS: Medical records of patients weighing 120 kg or more who had received cefotetan or cefoxitin (2 or 3 g) as surgical prophylaxis for intra-abdominal procedures between July 2012 and August 2015 were reviewed for the development of an SSI (primary outcome), study drug-related adverse events, and re-admissions attributed to SSIs (secondary outcomes). Relative risk calculations were performed for analysis of the primary and secondary outcomes. RESULTS: One-hundred seventy-five procedures in 169 patients were included in the study. Cefotetan was used in 81% (141/175) of procedures. Three grams of cefotetan or cefoxitin was used in 20% (35/175) of procedures. The median body mass index (BMI) in both dosing groups was 42 kg/m2 and patients who received 3 g more often weighed more than 130 kg (relative risk [RR] 1.36, 1.01-1.76; p = 0.04). Surgical site infections occurred in 20.7% within the 2-g group and 22.9% in the 3-g group (RR 1.10, 0.55-2.20; p = 0.78). There was no difference in the number of study drug-related adverse effects in the 3-g compared with the 2-g group. Thirty-day re-admissions because of SSI also did not differ between the 2 g and 3-g groups (7.9% vs. 17.1%, respectively; p = 0.11). CONCLUSION: This small retrospective study did not find a difference in SSI rates between 3-g and 2-g surgical prophylaxis dosing for patients 120 kg or more with a median BMI >40 kg/m2. PMID- 29717918 TI - Drug and Alcohol-Related Crime Among University Students. AB - The aim of the article is to determine the approximate prevalence of drug and alcohol-related crime among university students in seven universities in the United Kingdom and to assess whether there are differences between substance users who offend and substance users who do not offend. In total, 7,855 students submitted a questionnaire. The results of the study show that 10% of students who used drugs and about the same percentage who used alcohol had committed substance related crimes in the current academic year. The most prolific offenders in relation to both drug and alcohol-related offending were males, those who frequently went out to socialise, frequent users of nightclubs off campus, and those in poor physical or mental health. The article proposes that preventative interventions should be used to address alcohol and drug-related crime and its consequences. PMID- 29717919 TI - Optimization of the nitrification process of wastewater resulting from cassava starch production. AB - The present study has the objective of optimizing operational conditions of an aerated reactor applied to the removal of ammoniacal nitrogen from wastewater resulting from the production of cassava starch. An aerated reactor with a usable volume of 4 L and aeration control by rotameter was used. The airflow and cycle time parameters were controlled and their effects on the removal of ammoniacal nitrogen and the conversion to nitrate were evaluated. The highest ammoniacal nitrogen removal, of 96.62%, occurred under conditions of 24 h and 0.15 L min-1 Lreactor-1. The highest nitrate conversion, of 24.81%, occurred under conditions of 40.92 h and 0.15 L min-1 Lreactor-1. The remaining value of ammoniacal nitrogen was converted primarily into nitrite, energy, hydrogen and water. The optimal operational values of the aerated reactor are 29.25 h and 0.22 L min-1 Lreactor-1. The mathematical models representative of the process satisfactorily describe ammoniacal nitrogen removal efficiency and nitrate conversion, presenting errors of 2.87% and 3.70%, respectively. PMID- 29717920 TI - Retrospective Study on Laser Treatment of Oral Vascular Lesions Using the "Leopard Technique": The Multiple Spot Irradiation Technique with a Single-Pulsed Wave. AB - OBJECTIVE: This study aimed to retrospectively evaluate the efficacy and safety of laser treatment of oral vascular lesions using the multiple spot irradiation technique with a single-pulsed wave. BACKGROUND DATA: In laser therapy for vascular lesions, heat accumulation induced by excessive irradiation can cause adverse events postoperatively, including ulcer formation, resultant scarring, and severe pain. To prevent heat accumulation and side effects, we have applied a multiple pulsed spot irradiation technique, the so-called "leopard technique" (LT) to oral vascular lesions. This approach was originally proposed for laser treatment of nevi. It can avoid thermal concentration at the same spot and spare the epithelium, which promotes smooth healing. The goal of the study was to evaluate this procedure and treatment outcomes. PATIENTS AND METHODS: The subjects were 46 patients with 47 oral vascular lesions treated with the LT using a Nd:YAG laser (1064 nm), including 24 thick lesions treated using a combination of the LT and intralesional photocoagulation. RESULTS: All treatment outcomes were satisfactory without serious complications such as deep ulcer formation, scarring, bleeding, or severe swelling. CONCLUSIONS: Laser therapy with the LT is a promising less-invasive treatment for oral vascular lesions. PMID- 29717921 TI - Perceptions of Pediatric Residents Regarding Counseling About Use of Social Networking Sites. AB - Increasing use of social networking sites (SNS) among youth prompted professional organizations to urge pediatricians to promote healthy media use. Electronic questionnaires were distributed to 76 pediatric residents at one academic center measuring attitudes, practices, and familiarity with SNS. Of 43 respondents (response rate = 57%), most reported personal SNS use (98%) and familiarity with SNS used by youth (72%), and 88% agreed that pediatricians should provide counseling on SNS use. Only 5% felt they had adequate training on SNS use in children, and just 26% felt comfortable advising families. Residents were less likely to discuss SNS use than general media use (19% vs 56%, P = .007). Media counseling was correlated with SNS counseling ( r = .38, P = .01). Pediatric residents recognize the importance of guiding families on SNS use, yet do not routinely provide counseling despite high levels of personal SNS use and familiarity. Focused training is necessary for pediatricians to prioritize practical guidance. PMID- 29717922 TI - Clinical and Radiographic Evaluation of Short Implants Placed in the Posterior Mandible: A 1-Year Pilot Split-Mouth Study. AB - In many cases, due to anatomical limitations, the placement of regular-length implants cannot be facilitated without the performance of advanced surgical procedures. However, these are associated with morbidity, prolonged treatment time, and costs. To overcome such disadvantages, short implants were introduced. The aim of this prospective pilot split-mouth study was to compare the clinical outcome between short implants (7 mm) and regular-length (>=10 mm) implants placed in the posterior mandible after 1 year of prosthetic delivery. Ten patients received 4 implants in the posterior mandible. Two short implants were placed in one side and 2 regular-length implants were placed contralaterally. These were restored by means of splinted screw-retained metal-ceramic crowns. Marginal bone loss (MBL) and soft-tissue parameters were compared. No implant failed. Both types of implants showed success rates of 90% and survival rates of 100%. From prosthetic delivery to 1 year post-loading a bone gain of +0.29 mm for short implants and +0.19 mm for regular-length implants was present without showing any statistically significant differences in MBL between the 2 implant types ( P > .05). Bleeding on probing, clinical attachment level, probing depth, and crown-to-implant ratio did not show any statistically significant differences between the 2 implant lengths ( P > .05). One case of chipping occurred in the regular-length implant group, leading to a prosthetic survival rate of 95%. Short implants showed a prosthetic survival rate of 100%. After 1 year, short implants showed comparable clinical outcomes to that of regular-length implants, making them a viable treatment option in the posterior mandible. PMID- 29717923 TI - Epigenetic Control of CXCL10: Regulating the Counterregulator in Idiopathic Pulmonary Fibrosis. PMID- 29717924 TI - Prevalence and Burden Related to Genital Warts in India. AB - The prevalence of genital warts (GW) and self-reported human papillomavirus (HPV) as well as disease-related psychosocial impact among male and female patients aged 18-60 years in India were assessed. GW prevalence was estimated using a 2 week daily log of patients examined from June 7-September 22, 2011 by 200 participating physicians in 6 regions of India. Psychosocial impact was estimated using one-time, self-administered surveys, including HPV Impact Profile (HIP), Cuestionario Especifico para Condiloma Acuminado ([Spanish] CECA; "Specific questionnaire for Condylomata Acuminata") and EuroQol-5 Dimension survey. T-tests or Mann-Whitney U-tests were used for continuous comparisons and Chi-square or Fisher exact tests were applied for categorical comparisons. Overall GW prevalence in India was estimated at 1.07% (95% confidence interval = 0.97-1.17) and was higher among men than women. Regional prevalence ranged from high in Delhi (2.17%) to low in Bangalore (0.40%). Patients aged 25-29 years had the highest GW prevalence (1.42%). GW patients were most often newly diagnosed (74.07%). Among those with existing GW, 56.24% were recurrent, and 43.76% were resistant. According to total HIP scores, 55.4% of male GW patients and 20.0% of those without GW reported moderate psychological impact (p < 0.0001). HIP scores among women revealed that patients with abnormal Papanicolaou (Pap) test results (34.3%), precancerous lesions (46.2%), external GW (48.0%), and those without HPV related disease (18.5%) reported moderate psychological impact (p = 0.0089) (Psychosocial impact results are reported in the Supplementary Data ). Estimated national GW prevalence, diagnosis, and treatment costs in India were higher for men than for women. GW in men and HPV infection in women had a negative psychosocial impact on well-being and health-related quality of life (HRQoL) scores, especially among women diagnosed with GW and precancerous lesions compared to those with other selected HPV-related diseases. Despite its limitations, this study provides an estimation of GW data in India not previously available. PMID- 29717925 TI - Understanding Conceptualizations of Pregnancy and Planning for Pregnancy Among Adolescent Girls and Young Women in Harare, Zimbabwe. AB - Zimbabwe has one of the highest rates of maternal mortality, yet little is understood about adolescent girls' and young women's perspectives on pregnancy or planning for pregnancy. The research study took an emic approach to understand and describe how adolescent girls and young women (14-24 years) in Harare, Zimbabwe, conceptualize pregnancy and planning for pregnancy and how these conceptualizations inform pregnancy decisions. Semi-structured, in-depth, qualitative interviews were conducted with adolescent girls and young women ( N = 48) and data were analyzed thematically using NVivo 10. Pregnancy was conceptualized across nine themes: carrying a child and oneself, growing a family, motherhood, the best time for pregnancy, pregnancy decision makers, who is responsible for the pregnancy, pregnancy burden, pregnancy dangers, and increase in social status with pregnancy. Planning for pregnancy was conceptualized during the prepregnancy, pregnancy, and postpregnancy phases. Findings emphasize considering sociocultural views concerning pregnancy and including social networks in maternal health efforts. PMID- 29717926 TI - Association of Dietary Intakes of Total Polyphenol and Its Subclasses with the Risk of Metabolic Syndrome: Tehran Lipid and Glucose Study. AB - BACKGROUND: The purpose of the present study was to investigate the longitudinal association of total polyphenol and its main four subclasses intake with metabolic syndrome (MetS) and its components. METHODS: The present prospective study was conducted on 1265 Tehranian adults, aged 19-74 years. Usual dietary intake was evaluated using a validated food-frequency questionnaire. MetS was defined using NCEP ATP III guidelines. Intakes of total polyphenol and its four main subclasses, including flavonoids, phenolic acids, stilbenes, and lignans, were estimated using Phenol-Explorer database. RESULTS: Median (interquartile range [IQR]) of total polyphenol intake and its subclasses, including flavonoids, phenolic acids, lignans, and stilbenes, was 1422 (967-2137), 69.5 (45.5-99.8), 75.7 (52.2-115), 3.8 (1.9-6.9), and 0.2 (0.1-0.5) mg/day, respectively. After adjustment for confounding factors, participants in the highest tertile of flavonoid intake had 31% lower risk of developing MetS (odds ratio [OR] 0.69; 95% CI 0.48-0.98) and 36% lower risk of hypertriglyceridemia (OR 0.64; 95% CI 0.48 0.99) during 6 years of follow-up. Total polyphenol intake and other subclasses of polyphenol were not associated with MetS and its components. CONCLUSION: Higher intake of flavonoids was inversely associated with risk of developing MetS and hypertriglyceridemia in a Tehranian population. PMID- 29717927 TI - Food Intake and Eating Behavior After Bariatric Surgery. AB - Obesity is an escalating global chronic disease. Bariatric surgery is a very efficacious treatment for obesity and its comorbidities. Alterations to gastrointestinal anatomy during bariatric surgery result in neurological and physiological changes affecting hypothalamic signaling, gut hormones, bile acids, and gut microbiota, which coalesce to exert a profound influence on eating behavior. A thorough understanding of the mechanisms underlying eating behavior is essential in the management of patients after bariatric surgery. Studies investigating candidate mechanisms have expanded dramatically in the last decade. Herein we review the proposed mechanisms governing changes in eating behavior, food intake, and body weight after bariatric surgery. Additive or synergistic effects of both conditioned and unconditioned factors likely account for the complete picture of changes in eating behavior. Considered application of strategies designed to support the underlying principles governing changes in eating behavior holds promise as a means of optimizing responses to surgery and long-term outcomes. PMID- 29717930 TI - Myoediting: Toward Prevention of Muscular Dystrophy by Therapeutic Genome Editing. AB - Muscular dystrophies represent a large group of genetic disorders that significantly impair quality of life and often progress to premature death. There is no effective treatment for these debilitating diseases. Most therapies, developed to date, focus on alleviating the symptoms or targeting the secondary effects, while the underlying gene mutation is still present in the human genome. The discovery and application of programmable nucleases for site-specific DNA double-stranded breaks provides a powerful tool for precise genome engineering. In particular, the CRISPR/Cas system has revolutionized the genome editing field and is providing a new path for disease treatment by targeting the disease causing genetic mutations. In this review, we provide a historical overview of genome-editing technologies, summarize the most recent advances, and discuss potential strategies and challenges for permanently correcting genetic mutations that cause muscular dystrophies. PMID- 29717928 TI - Impact of the Autonomic Nervous System on the Skeleton. AB - It is from the discovery of leptin and the central nervous system as a regulator of bone remodeling that the presence of autonomic nerves within the skeleton transitioned from a mere histological observation to the mechanism whereby neurons of the central nervous system communicate with cells of the bone microenvironment and regulate bone homeostasis. This shift in paradigm sparked new preclinical and clinical investigations aimed at defining the contribution of sympathetic, parasympathetic, and sensory nerves to the process of bone development, bone mass accrual, bone remodeling, and cancer metastasis. The aim of this article is to review the data that led to the current understanding of the interactions between the autonomic and skeletal systems and to present a critical appraisal of the literature, bringing forth a schema that can put into physiological and clinical context the main genetic and pharmacological observations pointing to the existence of an autonomic control of skeletal homeostasis. The different types of nerves found in the skeleton, their functional interactions with bone cells, their impact on bone development, bone mass accrual and remodeling, and the possible clinical or pathophysiological relevance of these findings are discussed. PMID- 29717929 TI - Specialized Proresolving Mediators in Innate and Adaptive Immune Responses in Airway Diseases. AB - Airborne pathogens and environmental stimuli evoke immune responses in the lung. It is critical to health that these responses be controlled to prevent tissue damage and the compromise of organ function. Resolution of inflammation is a dynamic process that is coordinated by biochemical and cellular mechanisms. Recently, specialized proresolving mediators (SPMs) have been identified in resolution exudates. These molecules orchestrate anti-inflammatory and proresolving actions that are cell type specific. In this review, we highlight SPM biosynthesis, the influence of SPMs on the innate and adaptive immune responses in the lung, as well as recent insights from SPMs on inflammatory disease pathophysiology. Uncovering these mediators and cellular mechanisms for resolution is providing new windows into physiology and disease pathogenesis. PMID- 29717931 TI - (Re)generating Human Beta Cells: Status, Pitfalls, and Perspectives. AB - Diabetes mellitus results from disturbed glucose homeostasis due to an absolute (type 1) or relative (type 2) deficiency of insulin, a peptide hormone almost exclusively produced by the beta cells of the endocrine pancreas in a tightly regulated manner. Current therapy only delays disease progression through insulin injection and/or oral medications that increase insulin secretion or sensitivity, decrease hepatic glucose production, or promote glucosuria. These drugs have turned diabetes into a chronic disease as they do not solve the underlying beta cell defects or entirely prevent the long-term complications of hyperglycemia. Beta cell replacement through islet transplantation is a more physiological therapeutic alternative but is severely hampered by donor shortage and immune rejection. A curative strategy should combine newer approaches to immunomodulation with beta cell replacement. Success of this approach depends on the development of practical methods for generating beta cells, either in vitro or in situ through beta cell replication or beta cell differentiation. This review provides an overview of human beta cell generation. PMID- 29717933 TI - The KEAP1-NRF2 System: a Thiol-Based Sensor-Effector Apparatus for Maintaining Redox Homeostasis. AB - The Kelch-like ECH-associated protein 1-NF-E2-related factor 2 (KEAP1-NRF2) system forms the major node of cellular and organismal defense against oxidative and electrophilic stresses of both exogenous and endogenous origins. KEAP1 acts as a cysteine thiol-rich sensor of redox insults, whereas NRF2 is a transcription factor that robustly transduces chemical signals to regulate a battery of cytoprotective genes. KEAP1 represses NRF2 activity under quiescent conditions, whereas NRF2 is liberated from KEAP1-mediated repression on exposure to stresses. The rapid inducibility of a response based on a derepression mechanism is an important feature of the KEAP1-NRF2 system. Recent studies have unveiled the complexities of the functional contributions of the KEAP1-NRF2 system and defined its broader involvement in biological processes, including cell proliferation and differentiation, as well as cytoprotection. In this review, we describe historical milestones in the initial characterization of the KEAP1-NRF2 system and provide a comprehensive overview of the molecular mechanisms governing the functions of KEAP1 and NRF2, as well as their roles in physiology and pathology. We also refer to the clinical significance of the KEAP1-NRF2 system as an important prophylactic and therapeutic target for various diseases, particularly aging-related disorders. We believe that controlled harnessing of the KEAP1-NRF2 system is a key to healthy aging and well-being in humans. PMID- 29717935 TI - Expression of soluble epoxide hydrolase in renal tubular epithelial cells regulates macrophage infiltration and polarization in IgA nephropathy. AB - Tubulointerstitial inflammatory cell infiltration and activation contribute to kidney inflammation and fibrosis. Epoxyeicosatrienoic acids (EETs), which are rapidly metabolized to dihydroxyeicosatrienoic acids by the soluble epoxide hydrolase (sEH), have multiple biological functions, including vasodilation, anti inflammatory action, and others. Inhibition of sEH has been demonstrated to attenuate inflammation in many renal disease models. However, the relationship between sEH expression and macrophage polarization in the kidney remains unknown. In this study, we investigated the relationships between the level of sEH and clinical and pathological parameters in IgA nephropathy. The level of sEH expression positively correlated with proteinuria and infiltration of macrophages. sEH-positive tubules were found to be surrounded by macrophages. Furthermore, we found that incubation of immortalized human proximal tubular HK-2 cells with total urinary protein and overexpression of sEH promoted inflammatory factor production, which was associated with M1 polarization. We also exposed RAW264.7 mouse leukemic monocytes/macrophages to different HK-2 cell culture media conditioned by incubation with various substances affecting sEH amount or activity. We found that the upregulation of sEH promoted M1 polarization. However, pharmacological inhibition of sEH and supplementation with EETs reversed the conditioning effects of urinary proteins by inhibiting M1 polarization through the NF-kappaB pathway and stimulating M2 polarization through the phosphatidylinositol 3-kinase pathway. These data suggest that inhibition of sEH could be a new strategy to prevent the progression of inflammation and to attenuate renal tubulointerstitial fibrosis. PMID- 29717937 TI - Deletion or pharmacological blockade of TLR4 confers protection against cyclophosphamide-induced mouse cystitis. AB - Interstitial Cystitis/Bladder Pain Syndrome (IC/BPS) is a chronic inflammatory disease without consistently effective treatment. We investigate the role of toll like receptor 4 (TLR4) on voiding dysfunction and inflammation in the cyclophosphamide (CYP)-induced mouse cystitis. Male C57BL/6 [wild-type, (WT)] and/or TLR4 knockout (TLR4-/-) mice were treated with an injection of CYP (300 mg/kg, 24 h) or saline (10 ml/kg). The pharmacological blockade of the TLR4 by resatorvid (10 mg/kg) was also performed 1 h prior CYP-injection in WT mice. Urodynamic profiles were assessed by voiding stain on filter paper and filling cystometry. Contractile responses to carbachol were measured in isolated bladders. In CYP-exposed WT mice, mRNA for TLR4, myeloid differentiation primary response 88, and TIR-domain-containing adapter-inducing interferon-beta increased by 45%, 72%, and 38%, respectively ( P < 0.05). In free-moving mice, CYP-exposed mice exhibited a higher number of urinary spots and smaller urinary volumes. Increases of micturition frequency and nonvoiding contractions, concomitant with decreases of intercontraction intervals and capacity, were observed in the filling cystometry of WT mice ( P < 0.05). Carbachol-induced bladder contractions were significantly reduced in the CYP group, which was paralleled by reduced mRNA for M2 and M3 muscarinic receptors. These functional and molecular alterations induced by CYP were prevented in TLR4-/- and resatorvid-treated mice. Additionally, the increased levels of inflammatory markers induced by CYP exposure, myeloperoxidase activity, interleukin-6, and tumor necrosis factor alpha were significantly reduced by resatorvid treatment. Our findings reveal a central role for the TLR4 signaling pathway in initiating CYP-induced bladder dysfunction and inflammation and thus emphasize that TLR4 receptor blockade may have clinical value for IC/BPS treatment. PMID- 29717936 TI - Different effects of global osteopontin and macrophage osteopontin in glomerular injury. AB - Osteopontin (OPN) is a pro-and anti-inflammatory molecule that simultaneously attenuates oxidative stress. Both inflammation and oxidative stress play a role in the pathogenesis of glomerulonephritis and in the progression of kidney injury. Importantly, OPN is highly induced in nephritic kidneys. To characterize further the role of OPN in kidney injury we used OPN-/- mice in antiglomerular basement membrane reactive serum-induced immune (NTS) nephritis, an inflammatory and progressive model of kidney disease. Normal wild-type (WT) and OPN-/- mice did not show histological differences. However, nephritic kidneys from OPN-/- mice showed severe damage compared with WT mice. Glomerular proliferation, necrotizing lesions, crescent formation, and tubulointerstitial injury were significantly higher in OPN-/- mice. Macrophage infiltration was increased in the glomeruli and interstitium in OPN-/- mice, with higher expression of IL-6, CCL2, and chemokine CXCL1. In addition, collagen (Col) I, Col III, and Col IV deposition were increased in kidneys from OPN-/- mice. Elevated expression of the reactive oxygen species-generating enzyme Nox4 and blunted expression of Nrf2, a molecule that inhibits reactive oxygen species and inflammatory pathways, was observed in nephritic kidneys from OPN-/- mice. Notably, CD11b diphteria toxin receptor mice with NTS nephritis selectively depleted of macrophages and reconstituted with OPN-/- macrophages showed less kidney injury compared with mice receiving WT macrophages. These findings suggest that in global OPN-/- mice there is increased inflammation and redox imbalance that mediate kidney damage. However, absence of macrophage OPN is protective, indicating that macrophage OPN plays a role in the induction and progression of kidney injury in NTS nephritis. PMID- 29717938 TI - Comparison of folate-conjugated rapamycin versus unconjugated rapamycin in an orthologous mouse model of polycystic kidney disease. AB - Autosomal-dominant polycystic kidney disease (ADPKD) is a very common genetic disease leading to renal failure. Numerous aberrantly regulated signaling pathways have been identified as promising molecular drug targets for ADPKD therapy. In rodent models, many small-molecule drugs against such targets have proven effective in reducing renal cyst growth. For example, mammalian target of rapamycin (mTOR) inhibition with rapamycin greatly ameliorates renal cystic disease in several rodent models. However, clinical trials with mTOR inhibitors were disappointing largely due to the intolerable extrarenal side effects during long-term treatment with these drugs. Most other potential drug targets in ADPKD are also widely expressed in extrarenal tissues, which makes it likely that untargeted therapies with small-molecule inhibitors against such targets will lead to systemic adverse effects during the necessary long-term treatment of years and decades in ADPKD patients. To overcome this problem, we previously demonstrated that folate-conjugated rapamycin (FC-rapa) targets polycystic kidneys due to the high expression of the folate receptor (FRalpha) and that treatment of a nonortholgous PKD mouse model leads to inhibition of renal cyst growth. Here we show, in a head-to-head comparison with unconjugated rapamycin, that FCrapa inhibits renal cyst growth, mTOR activation, cell cycling, and fibrosis in an orthologous Pkd1 mouse model. Both unconjugated rapamycin and FC rapa are similarly effective on polycystic kidneys in this model. However, FC rapa lacks the extrarenal effects of unconjugated rapamycin, in particular immunosuppressive effects. We conclude that folate-conjugation is a promising avenue for increasing the tissue specificity of small-molecule compounds to facilitate very long-term treatment in ADPKD. PMID- 29717934 TI - Understanding Leishmania parasites through proteomics and implications for the clinic. AB - INTRODUCTION: Leishmania spp. are causative agents of leishmaniasis, a broad spectrum neglected vector-borne disease. Genomic and transcriptional studies are not capable of solving intricate biological mysteries, leading to the emergence of proteomics, which can provide insights into the field of parasite biology and its interactions with the host. Areas covered: The combination of genomics and informatics with high throughput proteomics may improve our understanding of parasite biology and pathogenesis. This review analyses the roles of diverse proteomic technologies that facilitate our understanding of global protein profiles and definition of parasite development, survival, virulence and drug resistance mechanisms for disease intervention. Additionally, recent innovations in proteomics have provided insights concerning the drawbacks associated with conventional chemotherapeutic approaches and Leishmania biology, host-parasite interactions and the development of new therapeutic approaches. Expert commentary: With progressive breakthroughs in the foreseeable future, proteome profiles could provide target molecules for vaccine development and therapeutic intervention. Furthermore, proteomics, in combination with genomics and informatics, could facilitate the elimination of several diseases. Taken together, this review provides an outlook on developments in Leishmania proteomics and their clinical implications. PMID- 29717940 TI - Clinical and Body Compositional Factors Associated with Metabolic Syndrome in Obese Koreans: A Cross-Sectional Study. AB - BACKGROUND: Obesity and metabolic syndrome (MetS) are increasing rapidly worldwide, but metabolically healthy population exists. Thus, this study evaluated the proportion of obesity and MetS and investigated clinical and body compositional factors associated with MetS in obese Koreans. METHODS: This cross sectional observational study enrolled subjects from the Korea National Health and Nutrition Examination Survey (n = 15,408). Obesity was defined by body mass index (BMI) cutoff points of 25 and 27.5 kg/m2. Clinical and laboratory parameters were compared by MetS presence and factors associated with insulin resistance or MetS in obese subjects were evaluated by multivariate or logistic regression analyses. RESULTS: The proportion of obesity was 29.7% at a BMI cutoff point of 25 kg/m2 and 10.4% at 27.5 kg/m2. The proportion of MetS was greater in obese population and increased with higher obesity cutoff point, where men were more prevalent than women. The subjects with MetS showed higher age, glycated hemoglobin, insulin resistance, liver enzymes, and ferritin compared with metabolically healthy population in both obese genders. Factors associated with insulin level or presence of MetS were high trunk fat percentage, trunk-to-limb fat ratio, and trunk-to-leg fat ratio, but low limb fat percentage and leg fat percentage. Among body composition indices, trunk-to-limb fat ratio and trunk-to leg fat ratio showed significantly high odds ratios for MetS in both obese genders regardless of BMI cutoff points. CONCLUSIONS: MetS in obese population concurrently increased with higher obesity cutoff point. Higher age, insulin resistance, liver enzymes, ferritin, and higher proportion of truncal fat mass-to limb or leg fat mass significantly contribute to MetS, where trunk-to-limb fat ratio and trunk-to-leg fat ratio could be helpful in identifying and preventing MetS in the obese Korean population. PMID- 29717941 TI - Understanding and diagnosing the potential for bias when using machine learning methods with doubly robust causal estimators. AB - Data-adaptive methods have been proposed to estimate nuisance parameters when using doubly robust semiparametric methods for estimating marginal causal effects. However, in the presence of near practical positivity violations, these methods can produce a separation of the two exposure groups in terms of propensity score densities which can lead to biased estimates of the treatment effect. To motivate the problem, we evaluated the Targeted Minimum Loss-based Estimation procedure using a simulation scenario to estimate the average treatment effect. We highlight the divergence in estimates obtained when using parametric and data-adaptive methods to estimate the propensity score. We then adapted an existing diagnostic tool based on a bootstrap resampling of the subjects and simulation of the outcome data in order to show that the estimation using data-adaptive methods for the propensity score in this study may lead to large bias and poor coverage. The adapted bootstrap procedure is able to identify this instability and can be used as a diagnostic tool. PMID- 29717939 TI - Are general practitioners characteristics associated with the quality of type 2 diabetes care in general practice? Results from the Norwegian ROSA4 study from 2014. AB - OBJECTIVE: To explore the associations between general practitioners (GPs) characteristics such as gender, specialist status, country of birth and country of graduation and the quality of care for patients with type 2 diabetes (T2DM). DESIGN: Cross-sectional survey. SETTING AND SUBJECTS: The 277 GPs provided care for 10082 patients with T2DM in Norway in 2014. The GPs characteristics were self reported: 55% were male, 68% were specialists in General Practice, 82% born in Norway and 87% had graduated in Western Europe. Of patients, 81% were born in Norway and 8% in South Asia. Data regarding diabetes care were obtained from electronic medical records and manually verified. MAIN OUTCOME MEASURES: Performance of recommended screening procedures, prescribed medication and level of HbA1c, blood pressure and LDL-cholesterol stratified according to GPs characteristics, adjusted for patient and GP characteristics. RESULT: Female GPs, specialists, GPs born in Norway and GPs who graduated in Western Europe performed recommended procedures more frequently than their counterparts. Specialists achieved lower mean HbA1c (7.14% vs. 7.25%, p < 0.01), a larger proportion of their patients achieved good glycaemic control (HbA1c = 6.0%-7.0%) (49.1% vs. 44.4%, p = 0.018) and lower mean systolic blood pressure (133.0 mmHg vs. 134.7 mmHg, p < 0.01) compared with non-specialists. GPs who graduated in Western Europe achieved lower diastolic blood pressure than their counterparts (76.6 mmHg vs. 77.8 mmHg, p < 0.01). CONCLUSION: Several quality indicators for type 2 diabetes care were better if the GPs were specialists in General Practice. Key Points Research on associations between General Practitioners (GPs) characteristics and quality of care for patients with type 2 diabetes is limited. Specialists in General Practice performed recommended procedures more frequently, achieved better HbA1c and blood pressure levels than non-specialists. GPs who graduated in Western Europe performed screening procedures more frequently and achieved lower diastolic blood pressure compared with their counterparts. There were few significant differences in the quality of care between GP groups according to their gender and country of birth. PMID- 29717942 TI - Median bias reduction in random-effects meta-analysis and meta-regression. AB - The reduction of the mean or median bias of the maximum likelihood estimator in regular parametric models can be achieved through the additive adjustment of the score equations. In this paper, we derive the adjusted score equations for median bias reduction in random-effects meta-analysis and meta-regression models and derive efficient estimation algorithms. The median bias-reducing adjusted score functions are found to be the derivatives of a penalised likelihood. The penalised likelihood is used to form a penalised likelihood ratio statistic which has known limiting distribution and can be used for carrying out hypothesis tests or for constructing confidence intervals for either the fixed-effect parameters or the variance component. Simulation studies and real data applications are used to assess the performance of estimation and inference based on the median bias reducing penalised likelihood and compare it to recently proposed alternatives. The results provide evidence on the effectiveness of median bias reduction in improving estimation and likelihood-based inference. PMID- 29717943 TI - Cox regression analysis with missing covariates via nonparametric multiple imputation. AB - We consider the situation of estimating Cox regression in which some covariates are subject to missing, and there exists additional information (including observed event time, censoring indicator and fully observed covariates) which may be predictive of the missing covariates. We propose to use two working regression models: one for predicting the missing covariates and the other for predicting the missing probabilities. For each missing covariate observation, these two working models are used to define a nearest neighbor imputing set. This set is then used to non-parametrically impute covariate values for the missing observation. Upon the completion of imputation, Cox regression is performed on the multiply imputed datasets to estimate the regression coefficients. In a simulation study, we compare the nonparametric multiple imputation approach with the augmented inverse probability weighted (AIPW) method, which directly incorporates the two working models into estimation of Cox regression, and the predictive mean matching imputation (PMM) method. We show that all approaches can reduce bias due to non-ignorable missing mechanism. The proposed nonparametric imputation method is robust to mis-specification of either one of the two working models and robust to mis-specification of the link function of the two working models. In contrast, the PMM method is sensitive to misspecification of the covariates included in imputation. The AIPW method is sensitive to the selection probability. We apply the approaches to a breast cancer dataset from Surveillance, Epidemiology and End Results (SEER) Program. PMID- 29717944 TI - Use of state sequence analysis for care pathway analysis: The example of multiple sclerosis. AB - The concept of care pathways is increasingly being used to enhance the quality of care and to optimize the use of resources for health care. We here propose an innovative method in epidemiology that is derived from social sciences: state sequence analysis (SSA). This method takes into account the chronology of care consumption and allows for identification of specific patterns. A process for using SSA in the health area is proposed and discussed. The main steps are: data coding, measurement of dissimilarities between sequences (focusing on optimal matching methods and the choice of related costs), and application of a clustering method to obtain a typology of sequence patterns. As an example of its use in the health area, SSA was employed to analyse care pathways of a random sample of patients with multiple sclerosis. This sample has been selected from the main French healthcare database covering the period 2007 to 2013 ( n = 1 000). A five-cluster typology was obtained which allowed distinction of care consumption groups. Overall, about half of the patients had low care consumption, about one quarter had medium to high consumption, and another quarter had high consumption. We conclude that state sequence analysis is an innovative and flexible methodology that is worth considering in health care research. PMID- 29717945 TI - Bayesian sample size re-estimation using power priors. AB - The sample size of a randomized controlled trial is typically chosen in order for frequentist operational characteristics to be retained. For normally distributed outcomes, an assumption for the variance needs to be made which is usually based on limited prior information. Especially in the case of small populations, the prior information might consist of only one small pilot study. A Bayesian approach formalizes the aggregation of prior information on the variance with newly collected data. The uncertainty surrounding prior estimates can be appropriately modelled by means of prior distributions. Furthermore, within the Bayesian paradigm, quantities such as the probability of a conclusive trial are directly calculated. However, if the postulated prior is not in accordance with the true variance, such calculations are not trustworthy. In this work we adapt previously suggested methodology to facilitate sample size re-estimation. In addition, we suggest the employment of power priors in order for operational characteristics to be controlled. PMID- 29717946 TI - Immediate effects of talus-stabilizing taping on balance and gait parameters in patients with chronic stroke: a cross-sectional study. AB - BACKGROUND: Talus-stabilizing taping (TST) may improve ankle range of motion and gait performance by providing a posterior-inferior talar glide in a closed-chain dorsiflexion position. OBJECTIVES: This study aimed to investigate the immediate effects of TST on balance and gait parameters in patients with chronic stroke. METHODS: Twenty post-stroke patients participated in this study. Each participant performed tests under three conditions (TST, barefoot, and conventional ankle foot orthosis [AFO]), in random order. Before testing, the patients walked for 10 min under the three conditions, followed by a 5 min rest period. The outcome measures were static balance ability (SBA), timed up-and-go (TUG) test results, and gait parameters evaluated using a 6-m-long gait mat. One-way repeated measures analysis of variance was used to determine the difference in balance and gait parameters under the three conditions. RESULTS: SBA more significantly improved in the TST condition than in the barefoot condition. SBA more significantly improved in the conventional AFO condition than in the barefoot condition. The TUG test results more significantly improved in the TST condition than in the conventional AFO and barefoot conditions. Walking speed, cadence, and affected side and unaffected side step and stride lengths more significantly improved in the TST condition than in the conventional AFO and barefoot conditions. CONCLUSIONS: This study used a cross-sectional method and demonstrated that TST improves SBA, TUG, gait speed, cadence, step length, and stride length in patients with chronic stroke. PMID- 29717947 TI - In this issue - Patient risks are ignored at organisation level. PMID- 29717948 TI - The effect of a birth place decision support tool on women's decision making and information gathering behaviours during pregnancy: MyBirthplace Study Protocol. AB - BACKGROUND: The recent Maternity Review for England highlighted the need for more choice for women with more accessible information to support decisions. This study assesses the effect of an unique Decision Support Tool (DST) called MyBirthplace on decision making and information gathering behaviours of pregnant women regarding birth place choice. The study seeks to understand women's views and opinions about using the DST and their feelings about how well the DST supports them to make a decision. METHODS: A mixed method sequential exploratory design will be utilised to meet the above aim. This three phase study will involve a proposed sample of 169 women from a large maternity hospital in the United Kingdom. Phase one will be a questionnaire survey with women pre and post access to the DST, which is given to them by their midwife at the initial appointment. The questionnaire will look at baseline data, knowledge level and decision making using the Stages of Decision making scale (SDMS). A follow up questionnaire at 28 weeks (phase 2) will review the SDMS to enable the usefulness of Mybirthplace to be evaluated and to seek women's opinion on various aspects of MyBirthplace. The proposed sample size was determined by a power calculation based on changes attributed to the DST as measured by the SDMS. Phase three involves qualitative interviews with a minimum of 10 purposely chosen women at approximately 36 weeks gestation, and is followed by collating data on where the women actually give birth. DISCUSSION: This study is the first study to assess the effect of a DST in supporting women's choice of place of birth. It will add to current DST literature. It is also one of very few studies to utilise the stages of decision making scale with DST in pregnancy and thus will build on the existing literature; whilst broaching key concepts highlighted in the National Maternity Review. PMID- 29717949 TI - Managing health IT risks: reflections and recommendations. AB - Health information technology (IT) offers exciting opportunities for providing novel services to patients, and for improving the quality and safety of care. However, the introduction of IT can lead to unintended consequences, and create opportunities for failure, which can have significant effects on patient safety. In this paper I argue that many health IT patient safety risks are probably quite predictable, but are often not considered at the time. This puts patients at risk, and it threatens the successful adoption of health IT. I recommend that healthcare providers focus on strengthening their processes for organisational learning, promote proactive risk management strategies, and make risk management decisions transparent and explicit. PMID- 29717950 TI - Telemedicine: Is it really worth it? A perspective from evidence and experience. AB - BACKGROUND: Although the formal evidence base is equivocal, practical experience suggests that implementations of technology that support telemedicine initiatives can result in improved patient outcomes, better patient and carer experience and reduced expenditure. OBJECTIVE: To answer the questions "Is an investment in telemedicine worth it?" and "How do I make a telemedicine implementation work?" METHODS: Summary of systematic review evidence and an illustrative case study. Discussion of implications for industry and policy. RESULTS: Realisation of telemedicine benefits is much less to do with the technology itself and much more around the context of the implementing organisation and its ability to implement. CONCLUSION: We recommend that local organisations consider deployment of telemedicine initiatives but with a greater awareness of the growing body of implementation best practice. We also recommend, for the NHS, that the centre takes a greater role in the collation and dissemination of best practice to support successful implementations of telemedicine and other health informatics initiatives. PMID- 29717951 TI - Completeness and accuracy of anthropometric measurements in electronic medical records for children attending primary care. AB - BACKGROUND: Electronic medical records (EMRs) from primary care may be a feasible source of height and weight data. However the use of EMRs in research has been impeded by lack of standardization of EMRs systems, data access and concerns about the quality of the data. OBJECTIVES: The study objectives were to determine the data completeness and accuracy of child heights and weights collected in primary care EMRs, and to identify factors associated with these data quality attributes. METHODS: A cross-sectional study examining height and weight data for children <19 years from EMRs through the Electronic Medical Records Administrative data Linked Database (EMRALD), a network of family practices across the province of Ontario. Body mass index z-scores were calculated using the WHO Growth Standards and Reference. RESULTS: A total of 54,964 children were identified from EMRALD. Overall, 93% had at least 1 complete set of growth measurements to calculate a BMI z-score. 66.2% of all primary care visits had complete BMI z-score data. After stratifying by visit type 89.9% of well-child visits and 33.9% of sick visits had complete BMI z-score data; incomplete BMI z score was mainly due to missing height measurements. Only 2.7% of BMI z-score data were excluded due to implausible values. CONCLUSIONS: Data completeness at well-child visits and overall data accuracy were greater than 90%. EMRs may be a valid source of data to provide estimates of obesity in children who attend primary care. PMID- 29717952 TI - Towards understanding healthcare professionals' adoption and use of technologies in clinical practice: Using Qmethodology and models of technology acceptance. AB - BACKGROUND: Technologies have globally been recognised to improve productivity across different areas of practice including healthcare. This has been achieved due to the expansion of computers and other forms of information technologies. Despite this advancement, there has also been the growing challenge of the adoption and use of these technologies within practice and especially in healthcare. The evolution of information technologies and more specifically e health within the healthcare practice has its own barriers and facilitators. METHODOLOGY: This paper describes a pilot study to explore these factors that influence information and technology adoption and use by health professionals in the clinical area in Sub-Saharan Africa. We report on the use of Q-methodology and the models of technology acceptance used in combination for the first time. The methodology used for this study aims to explore the subjectivity of healthcare professionals and present their shared views (factors) on their adoption and use of e-health within clinical practice. PMID- 29717953 TI - Robot Assisted Surgical Ward Rounds: Virtually Always There. AB - BACKGROUND: While an explosion in technological sophistication has revolutionized surgery within the operating theatre, delivery of surgical ward based care has seen little innovation. Use of telepresence allowing off-site clinicians communicate with patients has been largely restricted to outpatient settings or use of complex, expensive, static devices. We designed a prospective study to ascertain feasibility and face validity of a remotely controlled mobile audiovisual drone (LUCY) to access inpatients. This device is, uniquely, lightweight, freely mobile and emulates 'human' interaction by swiveling and adjusting height to patients' eye-level. METHODS: Robot-assisted ward rounds(RASWR) were conducted over 3 months. A remotely located consultant surgeon communicated with patients/bedside teams via encrypted audiovisual telepresence robot (DoubleRoboticstm, California USA). Likert-scale satisfaction questionnaires, incorporating free-text sections for mixed-methods data collection, were disseminated to patient and staff volunteers following RASWRs. The same cohort completed a linked questionnaire following conventional (gold standard) rounds, acting as control group. Data were paired, and non-parametric analysis performed. RESULTS: RASWRs are feasible (>90% completed without technical difficulty). The RASWR(n=52 observations) demonstrated face validity with strong correlations (r>0.7; Spearman, p-value <0.05) between robotic and conventional ward rounds among patients and staff on core themes, including dignity/confidentiality/communication/satisfaction with management plan. Patients (96.08%, n=25) agreed RASWR were a satisfactory alternative when consultant physical presence was not possible. There was acceptance of nursing/NCHD cohort (100% (n=11) willing to regularly partake in RASWR). CONCLUSION: RASWRs receive high levels of patient and staff acceptance, and offer a valid alternative to conventional ward rounds when a consultant cannot be physically present. PMID- 29717954 TI - Learning Health Systems: The research community awareness challenge. PMID- 29717955 TI - Computerised medical record systems that guide and protect - reflections on the Bawa-Garba case. AB - Lawrence Weed proposed we develop computerised, problem orientated medical records that guide and teach. The Bawa-Garba case outcomes might have been different if care had been supported by computerised medical record (CMR) systems. CMR systems can reduce prescribing errors and could be develop to flag gaps in supervision. However, CMR systems are not a panacea and need to be fit for purpose. Our informatics perspective on this case is to call for widespread use of CMR systems - designed to guide and protect. PMID- 29717956 TI - Smiles, turnout, candidates, and the winning of district seats. AB - Research has shown that a candidate's appearance affects the support he or she receives in elections. We extend this research in this article in three ways. First, we examine this relationship further in a non-Western context using 2015 local elections in Japan. Next, we show that this positive relationship is more complicated depending on the characteristics of the election under consideration. Specifically, we distinguished election contests by levels of turnout and found that despite a positive relationship between turnout and the extent to which smiling increases a candidate's support levels, the marginal increase in support declined as turnout increased and, in fact, became negative when some high turnout threshold was crossed. Finally, we show that the number of candidates competing in an election is negatively related to the impact of a candidate smiling, confirming research conducted by the Dartmouth Group. PMID- 29717957 TI - Subduing attitude polarization? AB - Researchers have sought to understand the effects of like-minded versus contrary news exposure on attitude polarization, which can be a threat to democracy. The online news environment offers opportunities for exposure to both types of news, albeit unequally. This study tests the effects of exposure to heterogeneous partisan news bundles (both like-minded and contrary news) on attitude polarization. Because media exposure can lead to bias, attitude polarization is tested as a direct and indirect effect via hostile media perceptions. Data in this study are from a between-subjects experimental design about the issue of assisted suicide. Results indicate that even though the effect of the partisan news bundle on hostile media perceptions is significant, both direct and indirect effects on attitude polarization are null. PMID- 29717958 TI - Social cues and ideology. AB - Research shows that individuals with liberal and conservative ideological orientations display different value positions concerning the acceptance of social change and inequality. Research also links the expression of different values to a number of biological factors, including heredity. In light of these biological influences, I investigate whether differences in social values associated with liberal and conservative ideologies reflect alternative strategies to maximize returns from social interactions. Using an American sample of Democrats and Republicans, I test whether information about shared and unshared social values in the form of implicit social attitudes have a disproportionate effect on the willingness of Democrats and Republicans to trust an anonymous social partner. I find evidence that knowledge of shared values significantly increases levels of trust among Democrats but not Republicans. I further find that knowledge of unshared values significantly decreases trust among Republicans but not Democrats. These findings are consistent with studies indicating that differences in ideological orientation are linked to differences in cognition and decision-making. PMID- 29717959 TI - What do we know about suicide bombing? AB - In this article, the present status of our knowledge about the phenomenon of "suicide" bombing or "martyrdom" operations is identified. A review of many studies located at different levels of analysis is conducted, followed by an analysis and evaluation of the state of the research at each level. In addition, an exploration of the evolution in the characteristics of this tactic and the differences, if any, between subnational and transnational acts is undertaken. The conclusion identifies what we know and what may be appropriate for future research and public policy initiatives. PMID- 29717960 TI - Handedness and the neurocognitive foundations of public attitudes about international laws and norms. AB - Whether Geneva Conventions (GC) rights should apply to terrorists is a contentious question that has received little attention in public opinion research. Both personality and contextual factors may be important. We queried participants' support for applying the GC to alleged terrorists, but first we measured participants' authoritarianism and presented them with a scenario concerning an alleged terrorist. We manipulated whether (1) the scenario contained examples of GC rights and (2) the alleged terrorist's religious affiliation was Muslim or non-Muslim. Support for applying the GC to alleged terrorists was high and unaffected by providing examples of GC provisions, but it was negatively related to authoritarianism. Support was reduced by priming with a Muslim terrorist, but only among participants exhibiting a behavioral marker for limited interhemispheric interaction - consistent-handedness. Consistent-handers in our sample expressed greater authoritarianism, suggesting that limited interhemispheric interaction promotes greater authoritarianism, which decreases support for applying the GC to alleged terrorists. PMID- 29717961 TI - Breast cancer screening. AB - Cass R. Sunstein's 2016 book The Ethics of Influence: Government in the Age of Behavioral Science provides an extremely informative introduction to the science and ethics of the exercise of "influence" over others. As a longtime physician employed in both the public and private sectors, I now recognize that most of my formal training has been in the hard sciences, with little, if any, training in the appropriate influence of the decision-making processes of my patients and/or other health care professionals in institutional settings. Breast cancer screening is an excellent example of the conflicts of modern medicine, highlighting our collective inability to effectively "nudge" others in the pursuit of health and/or organizational effectiveness and efficiency. Using the framework of Sunstein's ethical values of welfare, autonomy, dignity, and self government, I discuss many of the conflicting issues in a nationwide breast cancer screening program and the effects of these issues on client nudging to determine whether mammography screening is ethical. PMID- 29717962 TI - The problem of obesity and dietary nudges. AB - From a psychological perspective, Cass R. Sunstein's 2016 book The Ethics of Influence is an insightful examination of the ethics of using social and cognitive psychological principles to influence behavior and decision-making. The United States has been experiencing what can only be described as an obesity epidemic. Scientists know that this epidemic has been brought about in part by the prevailing choice architecture, which influences what we eat, how much we eat, and how little we exercise. From a public health perspective, the policy issue centers on how a democracy can employ a combination of bans, mandates, and nudges to reshape our dietary habits to combat obesity. In this article, I will address how policymakers must nudge and change the existing psychological and physical choice architecture to combat obesity. The obesity epidemic cannot be won solely by increasing taxes, mandates, and bans on certain food items as that infringes on the personal liberty, welfare, autonomy, and dignity of citizens. PMID- 29717963 TI - Nudging toward a stable retirement. AB - The classical economics perspective is that public policy should be used to allow, not hinder, economic freedom. In some cases it may be possible for government to gently nudge individuals to change their behavior without hindering freedom. One example is a change from the default on pension program enrollment forms from "not contribute" to "contribute." This is generally viewed as a good nudge that gets people to do what the majority of people view as generally the correct behavior. However, a choice to contribute to a pension fund is not always in the individual's best interest - thus, it is a nudge, not a mandate. To maintain personal liberty, individuals should be fully informed about the consequences of their choice and the motives of the political authority. Saving for retirement is a complex issue, and pension contribution decisions are often made with little foresight or information. Pension contribution nudges may not always be freedom preserving because of complexity and unintended consequences. The benefits, risks, and limitations of default contribution pension nudges are discussed. PMID- 29717964 TI - An introduction to "nudge science". AB - Let's begin by addressing the most obvious question: given the vast number of books published on political science every year, why would the Association for Politics and the Life Sciences (APLS) and its journal Politics and the Life Sciences expend time, energy, and resources publishing a multiple-author analysis of a series of books that contain little (if anything) about the life sciences, Darwin, or evolution? The answer is that Cass R. Sunstein's recent research on "nudge science" provides an excellent opportunity for APLS to expand its commitment to interdisciplinarity, especially its long-standing interest in behavioral economics. Sunstein, a prolific author, has written many books and scholarly articles defending "libertarian paternalism." Libertarian critics have long argued that the conjunction of "libertarian" and "paternalism" is oxymoronic and that the "liberty principle" or the "principle of autonomy" excludes paternalistic intervention on behalf of rational, competent adults. Over the years, with varying degrees of success, Sunstein has addressed many, if not most, lines of criticism emanating from the political left and right. Like many scholars, his views have evolved over time based on that criticism. This introductory essay will focus on some of the more enduring elements of the conceptual framework and issues that underlie nudge science in the larger context of behavioral economics, including choice architecture, political bans and mandates, political nudges, ethics, and paternalistic intervention. PMID- 29717965 TI - Issues with choice architecture, environmental ethics, and globalization. AB - Cass R. Sunstein's book The Ethics of Influence appears to have three ideological features notable for purposes of this essay. The book emphasizes choice architecture (and related notions such as nudges and defaults), which should be ethically scrutinized to guard against ethical abuses and to assist us in ethically desirable uses of scientific psychology and behavioral economics. (1) This particular book focuses more on scrutinizing nation-state government than on corporate activities. (2) This book focuses more on domestically directed governmental action than on externally directed governmental action. (3) This book focuses more on certain developed liberal democracies than on the more comprehensive global situation. Sunstein is especially interested in environmental issues, particularly energy policy, global warming, and climate change. This essay argues that Sunstein's conceptual scheme can be fruitfully expanded to progress toward a normative environmental ethics that can be integrated with the insights of global political economy. PMID- 29717966 TI - Cass R. Sunstein's "nudge science". PMID- 29717968 TI - Amylibacter lutimaris sp. nov., isolated from sea-tidal flat sediment. AB - A Gram-stain-negative, aerobic bacterial strain, designated strain m18T, was isolated from a sea-tidal flat in South Korea. Cells were non-motile short rods showing oxidase and catalase activities. Growth of m18T was observed at 10-40 degrees C (optimum, 30 degrees C), pH 5.5-10.0 (optimum, pH 7.0) and 0.5-7.0 % (w/v) NaCl (optimum, 3.0 %). The major respiratory quinone was ubiquinone-10 and the major fatty acids of were summed feature 8 (comprising C18 : 1omega7c/C18 : 1omega6c) and C16 : 0. The G+C content of the genomic DNA was 56.7 mol%. Phosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, an unidentified phospholipid, an unidentified aminolipid and four unidentified lipids were detected in m18T. The results of phylogenetic analysis based on 16S rRNA gene sequences indicated that m18T formed a tight phyletic lineage with the members of the genus Amylibacter. Strain m18T was most closely related to Amylibactercionae H-12T, Amylibacter ulvae 6Alg 255T and Amylibacter marinus 2-3T with 98.9, 96.1 and 95.5 % 16S rRNA gene sequence similarities, respectively. The DNA-DNA hybridization value between m18T and the type strain of A. cionae was 43.6+/-3.4 %. On the basis of phenotypic, chemotaxonomic and molecular properties, m18T represents a novel species of the genus Amylibacter, for which the name Amylibacterlutimaris sp. nov. is proposed. The type strain is m18T (KACC 19229T=JCM 32051T). PMID- 29717932 TI - Gestational Hypoxia and Developmental Plasticity. AB - Hypoxia is one of the most common and severe challenges to the maintenance of homeostasis. Oxygen sensing is a property of all tissues, and the response to hypoxia is multidimensional involving complicated intracellular networks concerned with the transduction of hypoxia-induced responses. Of all the stresses to which the fetus and newborn infant are subjected, perhaps the most important and clinically relevant is that of hypoxia. Hypoxia during gestation impacts both the mother and fetal development through interactions with an individual's genetic traits acquired over multiple generations by natural selection and changes in gene expression patterns by altering the epigenetic code. Changes in the epigenome determine "genomic plasticity," i.e., the ability of genes to be differentially expressed according to environmental cues. The genomic plasticity defined by epigenomic mechanisms including DNA methylation, histone modifications, and noncoding RNAs during development is the mechanistic substrate for phenotypic programming that determines physiological response and risk for healthy or deleterious outcomes. This review explores the impact of gestational hypoxia on maternal health and fetal development, and epigenetic mechanisms of developmental plasticity with emphasis on the uteroplacental circulation, heart development, cerebral circulation, pulmonary development, and the hypothalamic pituitary-adrenal axis and adipose tissue. The complex molecular and epigenetic interactions that may impact an individual's physiology and developmental programming of health and disease later in life are discussed. PMID- 29717970 TI - Role of biofilm morphology, matrix content and surface hydrophobicity in the biofilm-forming capacity of various Candida species. AB - The present study aimed to evaluate the role of biofilm morphology, matrix content and surface hydrophobicity in the biofilm-forming capacity of Candida albicans and non-albicans Candida (NAC) spp. Biofilm formation was determined by microtitre plate assay and bright-field and scanning electron microscopy. The matrix carbohydrates, proteins and e-DNA were quantified by phenol-sulfuric acid, bicinchoninic acid and UV spectroscopy, respectively. Specific glycosyl residues were detected by dot blot. The cell-surface hydrophobicity was determined by hydrocarbon adhesion assay. Candida tropicalis was found to exhibit the highest adherence to polystyrene. It formed dense biofilms with extensive pseudohyphae and hyphal elements, high hydrophobicity and the greatest amount of matrix carbohydrates, proteins and e-DNA. C. albicans displayed higher adherence and a complex biofilm morphology with larger aggregates than Candida parapsilosis and Candida krusei, but had lower matrix content and hydrophobicity. Thus, the combinatorial effect of increased filamentation, maximum matrix content and high hydrophobicity contributes to the enhanced biofilm-forming capacity of C. tropicalis. PMID- 29717969 TI - Performance of OMNIgene*SPUTUM (DNA Genotek) and cetylpyridinium chloride for sputum storage prior to mycobacterial culture. AB - PURPOSE: The aim was to assess the performance of both cetylpyridinium chloride (CPC) and OMNIgene*SPUTUM (OMNI) reagents for the maintenance of Mycobacterium tuberculosis viability in sputum prior to recovery by culture. METHODOLOGY: Using 312 sputa, we evaluated the performance of the two reagents using culture on Lowenstein-Jensen medium after sputum storage in CPC or OMNI for up to 28 days. In addition, the viability of M. tuberculosis isolates stored in both reagents was assessed. RESULTS: The contamination rates for freshly processed samples and those stored in CPC were not statistically different, while the contamination rate for OMNI was significantly lower than that for fresh sputa (P=0.026 for 8 days and P=0.002 for 28 days of storage). The culture positivity for fresh sputa (81.7 %) was similar to that for samples stored in CPC, regardless of the storage time (89.8 % for CPC-8 and 73.0 % for CPC-28). For OMNI-preserved samples, the culture positivity was similar after 8 days of storage (84.2 %), but decreased significantly after 28 days (42.7 %; P<0.0001) compared to fresh sputa, CPC-8, CPC-28 and OMNI-8. There was a significant loss of viability for the H37Rv strain when it was stored in OMNI at room temperature beyond 8 days compared to CPC, but storage at 37 degrees C decreased recovery from both CPC- and OMNI-stored suspensions. CONCLUSION: Culture from sputum stored for 8 days at room temperature in OMNI or CPC gave comparable culture positivity rates to culture from fresh sputum, but after 28 days of storage the performance of OMNI decreased significantly compared to CPC. PMID- 29717971 TI - Notification that new names of prokaryotes, new combinations and new taxonomic opinions have appeared in volume 68, part 2, of the IJSEM. PMID- 29717972 TI - Contribution of efflux to colistin heteroresistance in a multidrug resistant Acinetobacter baumannii clinical isolate. AB - PURPOSE: The mechanisms underlying colistin heteroresistance in Acinetobacter baumannii are not fully understood. Here, we investigated the role of efflux in colistin-heteroresistant populations of a multidrug-resistant (MDR) A. baumannii clinical isolate. METHODOLOGY: Three colistin-resistant A. baumannii strain variants isolated from the same clinical sample were studied for the presence of heteroresistance to colistin by drug susceptibility testing, genotyping and drug resistance target mutation analysis. The existence of active efflux was studied by synergism assays with efflux inhibitors, real-time efflux activity measurements and analysis of the mRNA transcriptional levels of selected efflux pump genes in response to colistin. RESULTS: All of the strain variants belong to the ST218, clonal complex 92, international clonal lineage II. Different colistin susceptibility levels were observed among the three strain variants, indicating that colistin-heteroresistant subpopulations were being selected upon exposure to colistin. No mutations were found in the genes lpxACD and pmrAB, which are associated with colistin resistance. The results showed the existence of synergistic interactions between efflux inhibitors and colistin and ethidium bromide. Real-time efflux assays demonstrated that the three strain variants had increased efflux activity that could be inhibited in the presence of the inhibitors. The efflux pump genes adeB, adeJ, adeG, craA, amvA, abeS and abeM were found to be overexpressed in the strain variants in response to colistin exposure. CONCLUSION: This study shows that efflux activity contributes to colistin heteroresistance in an MDR A. baumannii clinical isolate. The use of efflux inhibitors as adjuvants of the therapy can resensitize A. baumannii to colistin and prevent the emergence of drug resistance. PMID- 29717973 TI - Isolation and characterization of Streptococcus respiraculi sp. nov. from Marmota himalayana (Himalayan marmot) respiratory tract. AB - Two bacterial strains were individually isolated from Marmota himalayana respiratory tracts; the animals were from the Tibet-Qinghai Plateau, PR China. The isolates were Gram-stain-positive, catalase-negative, coccus-shaped, chain forming organisms. Analysis of 16S rRNA gene sequences indicated that the type strain HTS25T shared 98.0, 97.4, 97.2 and 97.1 % similarity with Streptococcus cuniculi, Streptococcus acidominimus, Streptococcus marmotae and Streptococcus himalayensis respectively. Sequence analysis of the sodA and rpoB genes indicated that HTS25T was closely related to S. marmotae (similarities of 94.7 and 91.4 % respectively). Analysis of groEL sequences showed interspecies similarity of 84.8 % between HTS25T and S. himalayensis. A whole-genome phylogenetic tree reconstructed from 81 core genes from the genomes of 17 members of the genus Streptococcus was used to validate that HTS25T forms a distinct subline from other recognized species of the genus Streptococcus. DNA-DNA hybridization of HTS25T showed a maximum estimated DNA reassociation value of 32.1 % to Streptococcus cuniculi CCUG 65085T. On the basis of the results of phenotypic and phylogenetic analyses, we propose that the two isolates be classified as representing a novel species of the genus Streptococcus, named Streptococcus respiraculi sp. nov. The type strain is HTS25T (=DSM 101998T=CGMCC 1.15531T). The genome of Streptococcus respiraculi sp. nov. strain HTS25T (2 067 971 bp) contains 2001 genes with an average DNA G+C content of 42.7 mol%. PMID- 29717974 TI - Surveillance of antimicrobial resistance in Neisseria meningitidis strains isolated from invasive cases in Brazil from 2009 to 2016. AB - PURPOSE: To describe the antimicrobial resistance profile of Neisseria meningitidis isolates causing invasive disease in Brazil from 2009 to 2016. METHODOLOGY: Among 3548 N. meningitidis isolates received, 2888 (81.4 %) were analysed for antimicrobial resistance using the broth microdilution technique, as recommended by the Clinical and Laboratory Standards Institute. Isolates were tested for ciprofloxacin, chloramphenicol, ceftriaxone, penicillin G, ampicillin and rifampin. RESULTS: All the isolates tested were susceptible to ceftriaxone, while 953 (33.0 %), 1307 (45.3 %) and 2 (0.07 %) isolates were penicillin G-, ampicillin- and rifampin-intermediate, respectively. Resistance to rifampin, ciprofloxacin and chloramphenicol was shown by three isolates (0.1 %), two isolates (0.07 %) and one (0.03 %) isolate, respectively. Although no isolates were resistant to penicillin G in the period of 2009-2016, our results show an upward trend in minimum inhibitory concentrations (MICs) for this drug as of 2010 (P<0.001). There was no significant difference between different gender and age groups of patients for reduced susceptibility to penicillin G. There was a higher frequency of isolates with reduced susceptibility to penicillin G in the South and Southeast regions (P<0.001). This reduced susceptibility was also associated with serotype 19 inside serogroup B (P<0.001). CONCLUSION: Despite the decrease in susceptibility to penicillin G and ampicillin observed from 2010, the overall resistance of N. meningitidis isolates to the antimicrobials tested remained uncommon and sporadic, confirming their efficacy for chemoprophylaxis or treatment of invasive meningococcal disease (IMD) in Brazil. Continued surveillance of N. meningitidis antimicrobial susceptibility profiles is important in order to monitor variations in resistance either geographically, over time or in association with emergent clones. PMID- 29717975 TI - Prevalence of Total and Untreated Dental Caries Among Youth: United States, 2015 2016. AB - Dental caries is the most common chronic disease among youth aged 6-19 years. Untreated caries can cause pain and infections. Monitoring prevalence of untreated and total caries (untreated and treated) is key to preventing and controlling oral diseases. This report presents the prevalence of total and untreated caries in primary or permanent teeth among youth aged 2-19 years for 2015-2016, and trends from 2011-2012 through 2015-2016. PMID- 29717976 TI - Declines in Births to Females Aged 10-14 in the United States, 2000-2016. AB - The birth rate for teen mothers aged 15-19 declined 57% from 2000 through 2016. During this time, the rate for young adolescent mothers aged 10-14 also declined. Childbearing by very young mothers is a matter of public concern because of the elevated health risks for these mothers and their infants and the socioeconomic consequences. This report describes recent trends and variations in births to young mothers aged 10-14 by race and Hispanic origin and state. PMID- 29717977 TI - A study of novel bilateral thermal capsulotomy with focused ultrasound for treatment-refractory obsessive-compulsive disorder: 2-year follow-up. AB - BACKGROUND: Recently, a new thermal lesioning approach using magnetic-resonance guided focused ultrasound (MRgFUS) was introduced for the treatment of neurologic disorders. However, only 2 studies have used this approach for treatment refractory obsessive-compulsive disorder (OCD), and follow-up was short-term. We investigated the efficacy and safety of bilateral thermal lesioning of the anterior limb of the internal capsule using MRgFUS in patients with treatment refractory OCD and followed them for 2 years. METHODS: Eleven patients with treatment-refractory OCD were included in the study. Clinical outcomes were evaluated using the Yale-Brown Obsessive Compulsive Scale, the Clinical Global Impression scale (including improvement and severity), the Hamilton Rating Scale for Depression (HAM-D) and the Hamilton Rating Scale for Anxiety (HAM-A) at 1 week and 1, 3, 6, 12 and 24 months following MRgFUS. Neuropsychological functioning, Global Assessment of Functioning and adverse events were also assessed. RESULTS: After MRgFUS, Yale-Brown Obsessive Compulsive Scale scores decreased significantly across the 24-month follow-up period (mean +/- standard deviation, 34.4 +/- 2.3 at baseline v. 21.3 +/- 6.2 at 24 months, p < 0.001). Scores on the Hamilton rating scales for depression and anxiety also significantly decreased from baseline to 24 months (HAM-D, 19.0 +/- 5.3 v. 7.6 +/ 5.3, p < 0.001; HAM-A, 22.4 +/- 5.9 v. 7.9 +/- 3.9, p < 0.001). Global Assessment of Functioning scores improved significantly (35.8 +/- 4.9 at baseline v. 56.0 +/- 10.3 at 24 months, p < 0.001) and Memory Quotient significantly improved, but other neuropsychological functions were unchanged. The side effects of MRgFUS included headache and vestibular symptoms, but these were mild and transient. LIMITATIONS: The main limitations of this study were the small sample size and the open-label design. CONCLUSION: Bilateral thermal lesioning of the anterior limb of the internal capsule using MRgFUS may improve obsessive compulsive, depressive and anxiety symptoms in patients with treatment-refractory OCD, without serious adverse effects. PMID- 29717978 TI - Self-sampling kits to increase HIV testing among black Africans in the UK: the HAUS mixed-methods study. AB - BACKGROUND: Timely diagnosis of human immunodeficiency virus (HIV) enables access to antiretroviral treatment, which reduces mortality, morbidity and further transmission in people living with HIV. In the UK, late diagnosis among black African people persists. Novel methods to enhance HIV testing in this population are needed. OBJECTIVES: To develop a self-sampling kit (SSK) intervention to increase HIV testing among black Africans, using existing community and health care settings (stage 1) and to assess the feasibility for a Phase III evaluation (stage 2). DESIGN: A two-stage, mixed-methods design. Stage 1 involved a systematic literature review, focus groups and interviews with key stakeholders and black Africans. Data obtained provided the theoretical base for intervention development and operationalisation. Stage 2 was a prospective, non-randomised study of a provider-initiated, HIV SSK distribution intervention targeted at black Africans. The intervention was assessed for cost-effectiveness. A process evaluation explored feasibility, acceptability and fidelity. SETTING: Twelve general practices and three community settings in London. MAIN OUTCOME MEASURE: HIV SSK return rate. RESULTS: Stage 1 - the systematic review revealed support for HIV SSKs, but with scant evidence on their use and clinical effectiveness among black Africans. Although the qualitative findings supported SSK distribution in settings already used by black Africans, concerns were raised about the complexity of the SSK and the acceptability of targeting. These findings were used to develop a theoretically informed intervention. Stage 2 - of the 349 eligible people approached, 125 (35.8%) agreed to participate. Data from 119 were included in the analysis; 54.5% (65/119) of those who took a kit returned a sample; 83.1% of tests returned were HIV negative; and 16.9% were not processed, because of insufficient samples. Process evaluation showed the time pressures of the research process to be a significant barrier to feasibility. Other major barriers were difficulties with the SSK itself and ethnic targeting in general practice settings. The convenience and privacy associated with the SSK were described as beneficial aspects, and those who used the kit mostly found the intervention to be acceptable. Research governance delays prevented implementation in Glasgow. LIMITATIONS: Owing to the study failing to recruit adequate numbers (the intended sample was 1200 participants), we were unable to evaluate the clinical effectiveness of SSKs in increasing HIV testing in black African people. No samples were reactive, so we were unable to assess pathways to confirmatory testing and linkage to care. CONCLUSIONS: Our findings indicate that, although aspects of the intervention were acceptable, ethnic targeting and the SSK itself were problematic, and scale-up of the intervention to a Phase III trial was not feasible. The preliminary economic model suggests that, for the acceptance rate and test return seen in the trial, the SSK is potentially a cost effective way to identify new infections of HIV. FUTURE WORK: Sexual and public health services are increasingly utilising self-sampling technologies. However, alternative, user-friendly SSKs that meet user and provider preferences and UK regulatory requirements are needed, and additional research is required to understand clinical effectiveness and cost-effectiveness for black African communities. STUDY REGISTRATION: This study is registered as PROSPERO CRD42014010698 and Integrated Research Application System project identification 184223. FUNDING: The National Institute for Health Research Health Technology Assessment programme and the BHA for Equality in Health and Social Care. PMID- 29717979 TI - Boosting ATM activity alleviates aging and extends lifespan in a mouse model of progeria. AB - DNA damage accumulates with age (Lombard et al., 2005). However, whether and how robust DNA repair machinery promotes longevity is elusive. Here, we demonstrate that ATM-centered DNA damage response (DDR) progressively declines with senescence and age, while low dose of chloroquine (CQ) activates ATM, promotes DNA damage clearance, rescues age-related metabolic shift, and prolongs replicative lifespan. Molecularly, ATM phosphorylates SIRT6 deacetylase and thus prevents MDM2-mediated ubiquitination and proteasomal degradation. Extra copies of Sirt6 extend lifespan in Atm-/- mice, with restored metabolic homeostasis. Moreover, the treatment with CQ remarkably extends lifespan of Caenorhabditis elegans, but not the ATM-1 mutants. In a progeria mouse model with low DNA repair capacity, long-term administration of CQ ameliorates premature aging features and extends lifespan. Thus, our data highlights a pro-longevity role of ATM, for the first time establishing direct causal links between robust DNA repair machinery and longevity, and providing therapeutic strategy for progeria and age-related metabolic diseases. PMID- 29717980 TI - 5-HT2a receptor in mPFC influences context-guided reconsolidation of object memory in perirhinal cortex. AB - Context-dependent memories may guide adaptive behavior relaying in previous experience while updating stored information through reconsolidation. Retrieval can be triggered by partial and shared cues. When the cue is presented, the most relevant memory should be updated. In a contextual version of the object recognition task, we examined the effect of medial PFC (mPFC) serotonin 2a receptor (5-HT2aR) blockade during retrieval in reconsolidation of competing objects memories. We found that mPFC 5-HT2aR controls retrieval and reconsolidation of object memories in the perirhinal cortex (PRH), but not in the dorsal hippocampus in rats. Also, reconsolidation of objects memories in PRH required a functional interaction between the ventral hippocampus and the mPFC. Our results indicate that in the presence of conflicting information at retrieval, mPFC 5-HT2aR may facilitate top-down context-guided control over PRH to control the behavioral response and object memory reconsolidation. PMID- 29717981 TI - Electron cryo-microscopy structure of the canonical TRPC4 ion channel. AB - Canonical transient receptor channels (TRPC) are non-selective cation channels. They are involved in receptor-operated Ca2+ signaling and have been proposed to act as store-operated channels (SOC). Their malfunction is related to cardiomyopathies and their modulation by small molecules has been shown to be effective against renal cancer cells. The molecular mechanism underlying the complex activation and regulation is poorly understood. Here, we report the electron cryo-microscopy structure of zebrafish TRPC4 in its unliganded (apo), closed state at an overall resolution of 3.6 A. The structure reveals the molecular architecture of the cation conducting pore, including the selectivity filter and lower gate. The cytoplasmic domain contains two key hubs that have been shown to interact with modulating proteins. Structural comparisons with other TRP channels give novel insights into the general architecture and domain organization of this superfamily of channels and help to understand their function and pharmacology. PMID- 29717982 TI - [Bovine dilated cardiomyopathy: Almost forgotten but still present]. AB - INTRODUCTION: Numerous cases of bovine dilatative cardiomyopathy (BDCMP) were registered in the nineteen-eighties, but the prevalence decreased steadily thanks to classical selection measures, i.e. excluding putative carrier animals from breeding. The cases described here show that the recessively inherited disease is still present in the Swiss cattle population. By use of a direct gene test developed a few years ago, a clinical tentative diagnosis can be confirmed. Since the end of the year 2016, carriers are officially labelled as such in Switzerland. Currently, about 2% of the insemination sires of the Holstein, Red Holstein and Swiss Fleckvieh breeds carry the causative mutation in the OPA3 gene. A combination of increased awareness of the disease and use of the gene test should allow for complete elimination of the disease from the Swiss cattle population. PMID- 29717983 TI - Whole-heart 4D flow cardiac magnetic resonance in healthy dogs. AB - INTRODUCTION: In cardiac magnetic resonance imaging (CMR), accurate flow measurements rely on perpendicular plane-alignment with flow direction. For 2D phase contrast (PC) cardiac magnetic resonance measurements, planes have to be defined during the examination of the heart, which is time consuming and error prone. Collection of flow information of the entire volume of the heart by a 4D flow CMR postpones plane alignment to post-processing. Sampling of such a large amount of data requires acceleration of data acquisition with techniques such as SENSitivity Encoding (k-t SENSE) or Broad-use Linear Acquisition Speed-up Technique (k-t BLAST). Objectives of the study were to compare 4D flow CMR, accelerated with two different acceleration methods with the established 2D PC CMR based on assessment of stroke volume at all four cardiac valves. The values of stroke volume acquired with the 4D flow CMR SENSE did not differ significantly when compared to the 2D PC CMR SENSE at the left side of the heart (aortic and mitral valve). Significant differences between the techniques were seen at the pulmonic and tricuspid valves. Acceleration with k-t BLAST revealed significantly lower values of stroke volume at all cardiac valves, except at the mitral valve. PMID- 29717984 TI - Effect of tranexamic acid on intra- and postoperative haemorrhage in dogs with surgically treated hemoperitoneum. AB - INTRODUCTION: Tranexamic acid (TXA) is an antifibrinolytic drug that is used for uncontrolled bleeding of various origin. This retrospective study investigated the effect of tranexamic acid administration on bleeding tendency in dogs with surgically managed hemoperitoneum. Thirty dogs were treated with (TXA group) and 25 dogs without (CTR group) tranexamic acid prior to surgery. Various parameters (decrease in haematocrit, number of transfusions, shock index and changes in abdominal fluid accumulation) were used for characterization of bleeding tendency and compared between groups. Groups were similar at presentation and prior to surgery. None of the dogs undergoing rotational thromboelastography analysis showed hyperfibrinolysis prior to surgery. Overall transfusion and erythrocyte transfusion requirements as well as bleeding tendency, hospitalisation time and hospital discharge rate were similar between groups. Dogs of the TXA group received significantly more intraoperative plasma transfusions (P=0.013) and showed a higher systolic and mean arterial blood pressure (P=0.002 and 0.050) and lower shock index (P=0.028) with less dogs being in shock (P=0.012) at 24h. In summary, in this study population of dogs with surgically managed spontaneous hemoperitoneum dogs treated with tranexamic acid received more plasma transfusions intraoperatively and showed a lower shock index 24h after presentation. In dogs with surgically treated hemoabdomen tranexamic acid administration prior to surgery does not reduce red blood cell transfusion requirements or postoperative bleeding tendency. PMID- 29717985 TI - [Calcitriol induced hypercalcemia in a hunting dog with a disseminated Paecilomyces variotii infection]. AB - INTRODUCTION: A 5-year old hunting dog was presented with reduced appetite, weight loss and polyuria/polydipsia. Hematology and clinical chemistry revealed anemia, leukocytosis, increased liver enzymes, hypoalbuminemia and hypercalcemia. The cytological, pathohistological and microbiological examination identified a disseminated infection with the saprophytic mould fungus Paecilomyces variotii in the biopsies of the spleen and a lymph node. Determination of vitamin D metabolites confirmed a calcitriol induced hypercalcemia. PMID- 29717986 TI - Aortic dissecting aneurysm associated with systemic arterial hypertension in a cat. AB - INTRODUCTION: Aortic dissection is characterized by a tear in the aortic wall resulting in blood from the aortic lumen penetrating into the media, which causes dissection. When aortic dissection does not cause rupture, it provokes localized dilation of the aorta or aneurism, also called dissecting aortic aneurism (DAA). This case report describes a DAA in a cat associated with systemic arterial hypertension (SAHT). A 10-year-old male Domestic shorthair cat was presented for cardiac evaluation. Anamnestic clinical complaints were a syncope associated with paraparesis and weak femoral pules. Cardiomegaly had been found radiographically, and cardiogenic arterial thromboembolism had been suspected. Upon presentation physical abnormalities were tachycardia and a heart murmur. Measurement of systolic systemic arterial blood pressure (SABP) revealed severe SAHT. Echocardiographic images showed severe DAA, and marked aortic valve insufficiency. Palliative antihypertensive treatment resulted in fast clinical improvement and significant decrease in blood pressure. Four months later, acute severe respiratory distress due to cardiogenic pulmonary edema led to the cat's euthanasia. In human medicine, DAA is a well-reported complication of SAHT. This is the second case of DAA with congestive heart failure reported in a hypertensive cat. PMID- 29717988 TI - [Alzheimer disease - A 21st century epidemic]. PMID- 29717987 TI - [Regulation of e-cigarette sale and use in Iceland]. PMID- 29717989 TI - [Screening for tuberculosis before TNFalpha treatment in routine rheumatic care in Iceland. Result from the nationwide ICEBIO registry]. AB - INTRODUCTION: Treatment with TNFalpha inhibitors (TNFalphai) greatly increases the risk of reactivation of tuberculosis in rheumatic patients. Therefore, it is recommended to screen patients for tuberculosis before initiating TNFalphai treatment. Iceland has a low prevalence of tuberculosis and BCG vaccination is not routine praxis. The purpose of this study was to review the results from TB screening in routine praxis and to analyze whether changes in the screening process are to be recommended. MATERIAL AND METHODS: All patients with RA, PsA and AS who were registered in ICEBIO (1999-2014) due to TNFalphai treatment were included. Data collection consisted of age, sex, start date of TNFalphai treatment and results from a tuberculin skin test (TST) and chest x-ray. The data were then crosschecked with the Berkill registry, a nationwide database for TB. RESULTS: 756 individuals (58% female, mean-age of 54 years) were included. TST was negative in 614 cases (81%), 41 positive (5.4%), 9 false positives (1.2%) and 92 were missing (12%). 119 patients were registered in Berkill whereof 72 had a history of positive TST and 55 had been vaccinated, while 14 patients had been diagnosed with tuberculo-sis (where of 7 had negative TST on screening). Three patients were diagnosed with tuberculosis after the TNFi treatment. CONCLUSION: These results illustrate the importance of tuberculosis screening before initiating TNFalphai treatment. Improvement in registration of TST results is necessary and whether interferon gamma release assays (IGRA) should be added to the screening process remains to be discussed. PMID- 29717990 TI - [MINOCA in Iceland. Acute coronary syndrome in patients with normal or nonobstructive coronary arteries]. AB - INTRODUCTION: The classical pathophysiological process underlying acute coronary syndromes has been considered to be plaque rup-ture followed by platelet activation and aggregation and subsequent thrombus formation leading to myocardial ischemia and infarction. A substantial number of patients with acute coronary syndromes appear to have normal or near normal (<50% stenosis) coronary arteries on angiography. Recently, this clinical entity has been coined MINOCA (Myocardial Infarction with Non-Obstructive Coronary Arteries). The purpose of this paper is to describe the proportion of MINOCA among ACS patients in Iceland. MATERIAL AND METHODS: We performed a retrospective analysis of all admissions for acute coronary syndromes at Landspitali University Hospital, the single coronary catheterization facility in Iceland, during a five year period between 2012 and 2016. All patients admitted for STEMI or NSTEMI that turned out to have normal or near normal coronary arteries were consecutively included in the study. For each patient the diagnosis was re-evaluated according to further assessments using a diagnostic algorithm specially constructed for this study. RESULTS: During the five year study period 1708 patients were studied with coronary angiography during first hospitalization for STEMI or NSTEMI. Among these, 225 (13.2%) had normal or non-obstructive coronary arteries with less than 50% luminal narrowing. The final diagnosis of these patients were plaque erosion / rupture in 72 indi viduals (32%), myocarditis in 33 (14.7%), takotsubo cardiomyopathy in 28 (12.4%), type II myocardial infarction in 30 (13.3%), vasospastic angina in 31 (13.8%) and other or undetermined cause in 31 (13.8%) patients. CONCLUSION: The proportion of MINOCA in Iceland is 13.2% of patients admitted for acute coronary syndromes. Plaque erosion / rupture was considered a likely cause in one third of patients with other causes beeing evenly distributed with approximately half that frequency. Identification of the underlying cause of MINOCA would become more accurate with a consistent use of cardiac magnetic resonance imaging in these patients as it provided a definitive diagnosis in all of those -studied. PMID- 29717991 TI - Survival to amputation in pre-antibiotic era: a case study from a Longobard necropolis (6th-8th centuries AD). AB - The Longobard necropolis of Povegliano Veronese dates from the 6th to the 8th centuries AD. Among the 164 tombs excavated, the skeleton of an older male shows a well-healed amputated right forearm. The orientation of the forearm fracture suggests an angled cut by a single blow. Reasons why a forearm might be amputated include combat, medical intervention, and judicial punishment. As with other amputation cases reported in literature, this one exhibits both healing and osteoblastic response. We argue that the forelimb stump morphology suggests the use of a prosthesis. Moreover, dental modification of RI2 shows considerable wear and smoothing of the occlusal surface, which points to dental use in attaching the prosthesis to the limb. Other indications of how this individual adjusted to his amputated condition includes a slight change in the orientation of the right glenoid fossa surface, and thinning of right humeral cortical bone. This is a remarkable example in which an older male survived the loss of a forelimb in pre antibiotic era. We link archaeological remains found in the tomb (buckle and knife) with the biological evidence to show how a combined bioarchaeological approach can provide a clearer interpretation of the life history of an individual. PMID- 29717992 TI - Gender balance in the scientific production of the Atapuerca archaeological and palaeontological research project. PMID- 29717993 TI - Crystal structure of the mouse innate immunity factor bacterial permeability increasing family member A1. AB - Bacterial permeability-increasing family member A1 (BPIFA1) is an innate immunity factor and one of the most abundantly secreted proteins in the upper airways. BPIFA1 is multifunctional, with antimicrobial, surfactant and lipopolysaccharide binding activities, as well as established roles in lung hydration. Here, the 2.5 A resolution crystal structure of BPIFA1 from Mus musculus (mBPIFA1) is presented and compared with those of human BPIFA1 (hBPIFA1) and structural homologs. Structural distinctions between mBPIFA1 and hBPIFA1 suggest potential differences in biological function, including the regulation of a key pulmonary ion channel. PMID- 29717994 TI - A cryoprotectant induces conformational change in glyceraldehyde-3-phosphate dehydrogenase. AB - Glyceraldehyde-3-phosphate dehydrogenase (GAPDH), a glycolytic enzyme, catalyses the conversion of D-glyceraldehyde 3-phosphate to 1,3-bisphosphoglycerate. While mammalian and yeast GAPDHs are multifunctional proteins that have additional functions beyond those involved in glycolysis, including reactions related to nuclear RNA transport, DNA replication/repair, membrane fusion and cellular apoptosis, Escherichia coli GAPDH (ecGAPDH) has only been reported to function in glycolysis. The S-loop of GAPDH is required for interaction with its cofactor and with other proteins. In this study, the three-dimensional crystal structure of GAPDH treated with trehalose is reported at 2.0 A resolution. Trehalose was used as a cryoprotectant for the GAPDH crystals. The structure of trehalose-bound ecGAPDH was compared with the structures of both NAD+-free and NAD+-bound ecGAPDH. At the S-loop, the bound trehalose in the GAPDH structure induces a 2.4 degrees rotation compared with the NAD+-free ecGAPDH structure and a 3.1 degrees rotation compared with the NAD+-bound ecGAPDH structure. PMID- 29717996 TI - Crystal structures of human CK2alpha2 in new crystal forms arising from a subtle difference in salt concentration. AB - The catalytic subunits of protein kinase CK2 are classified into two subtypes: CK2alpha1 and CK2alpha2. CK2alpha1 is an attractive drug-discovery target for various diseases such as cancers and nephritis. CK2alpha2 is defined as an off target of CK2alpha1 and is a potential target in the development of male contraceptive drugs. High-resolution crystal structures of both isozymes are likely to provide crucial clues for the design of selective inhibitors of CK2alpha1 and/or CK2alpha2. To date, several crystal structures of CK2alpha1 have been solved at high resolutions of beyond 1.5 A. However, crystal structures of CK2alpha2 have barely achieved a low resolution of around 3 A because of the formation of needle-shaped crystals. In this study, new crystal forms were exploited and one provided a crystal structure of CK2alpha2 at 1.89 A resolution. This result, together with the structure of CK2alpha1, will assist in the development of highly selective inhibitors for both isozymes. PMID- 29717995 TI - The putative siderophore-interacting protein from Vibrio anguillarum: protein production, analysis, crystallization and X-ray crystallographic studies. AB - Siderophore-interacting proteins (SIPs) play an important role in iron acquisition in many bacteria. SIPs release iron from the internalized ferric siderophore complex by reducing ferric iron to ferrous iron, but how the iron is reduced is not well understood. Here, a sip gene was identified in the genome of Vibrio anguillarum 775. To further understand the catalytic mechanism of the protein, the SIP was overexpressed in Escherichia coli Rosetta (DE3) cells, purified and crystallized for X-ray diffraction analysis. The crystal diffracted to 1.113 A resolution and belonged to space group P21, with unit-cell parameters a = 64.63, b = 58.47, c = 70.65 A, beta = 114.19 degrees . PMID- 29717997 TI - Crystal structure of chorismate mutase from Burkholderia thailandensis. AB - Burkholderia thailandensis is often used as a model for more virulent members of this genus of proteobacteria that are highly antibiotic-resistant and are potential agents of biological warfare that are infective by inhalation. As part of ongoing efforts to identify potential targets for the development of rational therapeutics, the structures of enzymes that are absent in humans, including that of chorismate mutase from B. thailandensis, have been determined by the Seattle Structural Genomics Center for Infectious Disease. The high-resolution structure of chorismate mutase from B. thailandensis was determined in the monoclinic space group P21 with three homodimers per asymmetric unit. The overall structure of each protomer has the prototypical AroQgamma topology and shares conserved binding-cavity residues with other chorismate mutases, including those with which it has no appreciable sequence identity. PMID- 29717998 TI - In situ proteolysis of an N-terminal His tag with thrombin improves the diffraction quality of human aldo-keto reductase 1C3 crystals. AB - Human aldo-keto reductase 1C3 (AKR1C3) stereospecifically reduces steroids and prostaglandins and is involved in the biotransformation of xenobiotics. Its role in various cancers makes it a potential therapeutic target for the development of inhibitors. Recombinant AKR1C3 with a thrombin-cleavable N-terminal His6 tag was expressed from a pET-28(+) vector for structural studies of enzyme-inhibitor complexes. A modified in situ proteolysis approach was applied to specifically remove the His tag by thrombin cleavage during crystallization screening trials. This improved the morphology and diffraction quality of the crystals and allowed the acquisition of high-resolution diffraction data and structure solution. This approach may be generally applicable to other proteins expressed using the pET 28(+) vector. PMID- 29717999 TI - Improved protein-crystal identification by using 2,2,2-trichloroethanol as a fluorescence enhancer. AB - The identification of initial lead conditions for successful protein crystallization is crucial for structural studies using X-ray crystallography. In order to reduce the number of false-negative conditions, an emerging number of fluorescence-based methods have been developed which allow more efficient identification of protein crystals and help to distinguish them from salt crystals. Detection of the native tryptophan fluorescence of protein crystals is one of the most widely used methods. However, this method can fail owing to the properties of the crystallized protein or the chemical composition of the crystallization trials. Here, a simple, fast and cost-efficient method employing 2,2,2-trichloroethanol (TCE) has been developed. It can be performed with a standard UV-light microscope and can be applied to cases in which detection of native tryptophan fluorescence fails. In four test cases this method had no effect on the diffraction properties of the crystals and no structural changes were observed. Further evidence is provided that TCE can be added to crystallization trials during their preparation, making this method compatible with high-throughput approaches. PMID- 29718000 TI - Structure of the tandem PX-PH domains of Bem3 from Saccharomyces cerevisiae. AB - The structure of the tandem lipid-binding PX and pleckstrin-homology (PH) domains of the Cdc42 GTPase-activating protein Bem3 from Saccharomyces cerevisiae (strain S288c) has been determined to a resolution of 2.2 A (Rwork = 21.1%, Rfree = 23.4%). It shows that the domains adopt a relative orientation that enables them to simultaneously bind to a membrane and suggests possible cooperativity in membrane binding. PMID- 29718001 TI - The CD163 long-range scavenger receptor cysteine-rich repeat: expression, purification and X-ray crystallographic characterization. AB - Scavenger receptors (SRs) play critical roles in various physiological and pathological pathways. One of them, CD163, is a multifunctional endocytic receptor and is characterized by a long-range scavenger receptor cysteine-rich (SRCR) repeat. However, the structural and functional details of this long-range SRCR repeat have not yet been elucidated. In this study, the CD163 long-range SRCR repeat was expressed in Drosophila Schneider 2 cells. The recombinant protein was homogeneous after purification by metal-affinity, cation-exchange and size-exclusion chromatography. Single crystals were obtained using 20% PEG 4000, 0.15 M potassium sodium tartrate tetrahydrate pH 8.5 and diffracted to 3.30 A resolution. As the first view of a long-range SRCR repeat, this work lays the structural basis for a deep understanding of SRs and their multiple functions. PMID- 29718002 TI - Vertebral Artery Dissection Masquerading as Concussion in an Adolescent. AB - OBJECTIVE: Educate providers about the clinical presentation and consequences of delaying diagnosis of traumatic vertebral artery dissection with thromboembolic ischemic strokes in the pediatric population. Vertebral artery dissection is often difficult to diagnose and can be a potentially devastating cause of ischemic stroke. METHODS: Review of the chart, peer review/discussion, and imaging interpretation. RESULTS: A 16-year-old boy was admitted with confusion after a head and neck trauma was sustained while wrestling. (Glasgow Coma Scale=15, NIHSS = 0). Investigations including computed tomography (CT) head and cervical spine were normal. He then developed severe nausea, vomiting, dizziness, and headaches and was admitted for symptoms of concussion. Ten hours later, patient declined (hypertensive and unresponsive) and was noted to have decerebrate posturing. After emergent intubation, he was transferred to the pediatric intensive care unit. Repeat CT head showed an acute left cerebellar infarct with associated cerebellar edema resulting in effacement of the fourth ventricle/basilar cisterns and acute hydrocephalus. The CT angiography and magnetic resonance imaging of brain confirmed arterial dissection and near occlusion of the left vertebral artery at the C2 level. Extensive infarct was seen in the left cerebellum, brainstem, and right cerebellum. During a prolonged hospital stay, the family opted to continue care, and he was transferred to an inpatient rehabilitation facility because of limited brainstem activity, being nonverbal, and not demonstrating purposeful spontaneous movements. CONCLUSIONS: Detailed history and thorough neurological examination in conjunction with appropriate imaging are necessary to distinguish between brainstem/cerebellar ischemia from vertebral artery dissection and concussion. PMID- 29718003 TI - Brown adipose tissue and lipid metabolism. AB - PURPOSE OF REVIEW: This article explores how the interplay between lipid metabolism and thermogenic adipose tissues enables proper physiological adaptation to cold environments in rodents and humans. RECENT FINDINGS: Cold exposure triggers systemic changes in lipid metabolism, which increases fatty acid delivery to brown adipose tissue (BAT) by various routes. Next to fatty acids generated intracellularly by de-novo lipogenesis or by lipolysis at lipid droplets, brown adipocytes utilize fatty acids released by white adipose tissue (WAT) for adaptive thermogenesis. WAT-derived fatty acids are internalized directly by BAT, or indirectly after hepatic conversion to very low-density lipoproteins and acylcarnitines. In the postprandial state, chylomicrons hydrolyzed by lipoprotein lipase - activated specifically in thermogenic adipocytes - are the predominant fatty acid source. Cholesterol-enriched chylomicron remnants and HDL generated by intravascular lipolysis in BAT are cleared more rapidly by the liver, explaining the antiatherogenic effects of BAT activation. Notably, increased cholesterol flux and elevated hepatic synthesis of bile acids under cold exposure further promote BAT-dependent thermogenesis. SUMMARY: Although pathways providing fatty acids for activated BAT have been identified, more research is needed to understand the integration of lipid metabolism in BAT, WAT and liver, and to determine the relevance of BAT for human energy metabolism. PMID- 29718004 TI - Update on diagnosis and management of congenital adrenal hyperplasia due to 21 hydroxylase deficiency. AB - PURPOSE OF REVIEW: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is a relatively common inherited disorder of cortisol biosynthesis that can be fatal if untreated. RECENT FINDINGS: The basic biochemistry and genetics of CAH have been known for decades but continue to be refined by the discoveries of an alternative 'backdoor' metabolic pathway for adrenal androgen synthesis and the secretion of 11-hydroxy and 11-keto analogs of known androgens, by the elucidation of hundreds of new mutations, and by the application of high throughput sequencing techniques to noninvasive prenatal diagnosis. Although hydrocortisone is a mainstay of treatment, overtreatment may have adverse effects on growth, risk of obesity, and cardiovascular disease; conversely, undertreatment may increase risk of testicular adrenal rest tumors in affected men. SUMMARY: Refinements to screening techniques may improve the positive predictive value of newborn screening programs. Alternative dosing forms of hydrocortisone and additional therapeutic modalities are under study. Although surgical treatment of virilized female genitalia is widely accepted by families and patients, it is not without complications or controversy, and some families choose to defer it. PMID- 29718006 TI - Where do we stand in the field of neonatal jaundice? Commentary on the 2017 J. Donald Ostrow Trieste Yellow Retreat. PMID- 29718005 TI - Novel sequences, structural variations and gene presence variations of Asian cultivated rice. AB - Genomic diversity within a species genome is the genetic basis of its phenotypic diversity essential for its adaptation to environments. The big picture of the total genetic diversity within Asian cultivated rice has been uncovered since the sequencing of 3,000 rice genomes, including the SNP data publicly available in the SNP-Seek database. Here we report other aspects of the genetic diversity, including rice sequences assembled from over 3,000 accessions but absent in the Nipponbare reference genome, structural variations (SVs) and gene presence/absence variations (PAVs) in 453 accessions with sequencing depth over 20x. Using either SVs or gene PAVs, we were able to reconstruct the population structure of O. sativa, which was consistent with previous result based on SNPs. Moreover, we demonstrated the usefulness of the new data sets by successfully detecting the strong association of the "Green Revolution gene", sd1, with plant height. Our data provide a more comprehensive view of the genetic diversity within rice, as well as additional genomic resources for research in rice breeding and plant biology. PMID- 29718007 TI - Upregulation of cholesterol 24-hydroxylase following hypoxia-ischemia in neonatal mouse brain. AB - BackgroundMaintenance of cholesterol homeostasis is crucial for brain development. Brain cholesterol relies on de novo synthesis and is cleared primarily by conversion to 24S-hydroxycholesterol (24S-HC) with brain-specific cholesterol 24-hydroxylase (CYP46A1). We aimed to investigate the impact of hypoxia-ischemia (HI) on brain cholesterol metabolism in the neonatal mice.MethodsPostnatal day 9 C57BL/6 pups were subjected to HI using the Vannucci model. CYP46A1 expression was assessed with western blotting and its cellular localization was determined using immunofluorescence staining. The amount of brain cholesterol, 24S-HC in the cortex and in the serum, was measured with enzyme-linked immunosorbent assay (ELISA).ResultsThere was a transient cholesterol loss at 6 h after HI. CYP46A1 was significantly upregulated at 6 and 24 h following HI with a concomitant increase of 24S-HC in the ipsilateral cortex and in the serum. The serum levels of 24S-HC correlated with those in the brain, as well as with necrotic and apoptotic cell death evaluated by the expression of spectrin breakdown products and cleaved caspase-3 at 6 and 24 h after HI.ConclusionEnhanced cholesterol turnover by activation of CYP46A1 represents disrupted brain cholesterol homeostasis early after neonatal HI. 24S-HC might be a novel blood biomarker for severity of hypoxic-ischemic encephalopathy with potential clinical application. PMID- 29718008 TI - Correlation between Lung and Joint Involvement in Patients with Rheumatoid Arthritis and Interstitial Lung Disease: A Cross-Sectional Study. AB - Background: Rheumatoid arthritis (RA) can affect the lungs in different manners, with interstitial lung disease (ILD) as the most serious manifestation. Although lung and joint compromise could be thought to evolve in parallel, there are data suggesting the opposite. In this study, we evaluated the relationship between lung and joint involvement in RA ILD. Methods: An observational cross-sectional study of RA ILD patients evaluated from January 2015 to February 2017. Joint disease assessment included number of tender and swollen joints, patient's global assessment of disease activity, erythrocyte sedimentation rate (ESR) or C reactive protein, and disease activity score (DAS28). Lung disease assessment included forced vital capacity, diffusion capacity (DLCO), and Goh high resolution computed tomography (HRCT) score for total extent, ground glass, and reticular pattern. We studied the correlation between both components of the disease. Results: We included 46 patients, 14 (30.4%) men, with a mean (SD) of the age of 59.9 years (11.89). 12 (26.09) patients were in remission or had low disease activity measured with DAS28. The HRCT showed usual interstitial pneumonia (UIP) pattern in 10 (21.7%), possible UIP in 18 (39.1%), and inconsistent with UIP in 18 (39.1%). We found a good correlation between the ESR and the ground glass score in the HRCT (r = 0.39; p = 0.03). However, we found no correlation between lung function tests or HRCT scores and the other components of the DAS28. Conclusions: We only found a good correlation between ESR and ground glass score. It is possible that different pathways of the immune response mediate damage in lungs and joints. PMID- 29718009 TI - Pulmonary Vasoreactivity and Phenotypes in Pulmonary Arterial Hypertension Associated to Connective Tissue Diseases. AB - Background: Pulmonary arterial hypertension (PAH) is a fatal complication in patients with connective tissue disease (CTD). Objective: The objective of the study was to study the prognostic value of the acute pulmonary vasoreactivity test with inhaled iloprost and its association with clinical deterioration in a tertiary care academic medical center. Methods: We conducted a prospective study of patients with CTD and the diagnosis of PAH established by right heart catheterization. Patients were classified into classic responders, partial responders, and non-responders. The association of the pulmonary response and clinical deterioration was analyzed. Results: We enrolled 25 patients (mean age of 47 +/- 13.4 years); 88% were female. The most frequent rheumatologic diagnosis was systemic lupus erythematosus, in 16 (64%) patients. Seventy-two percent of patients were classified as non-responders, and 28% were partial responders. Patients with a partial response had lower right atrial pressure values (5.1 +/- 3.1 vs. 8.5 +/- 3.2, p = 0.01) and greater systolic pulmonary arterial pressure (87.6 +/- 8.1 vs. 72.4 +/- 16.2, p = 0.02), compared with non-responders. Non responders had a tendency for a shorter time to clinical deterioration than partial responders (17.8 vs. 41.1 months, p = 0.052). Conclusions: Patients with a partial response to the acute pulmonary vasodilator test with inhaled iloprost had a longer clinical deterioration-free period than non-responders. PMID- 29718010 TI - Phenotypic Variability in a Mexican Mestizo Family with Retinal Vasculopathy with Cerebral Leukodystrophy and TREX1 Mutation p.V235Gfs*6. AB - Background: Retinal vasculopathy with cerebral leukodystrophy (RVCL) is an adult onset, autosomal dominant disease involving microvessels of the brain and eye resulting in central nervous system degeneration with visual disturbances, stroke, motor impairment, and cognitive decline. Frameshift mutations at the C terminus of TREX1 gene are the molecular cause of this disorder. Objectives: The objective of this study is to present the different clinical manifestations of RVCL in three-related patients and to investigate the presence of TREX1 mutation in the extended genealogy. Methods: Multidisciplinary testing was performed in three related patients. Based on their family history, the study was extended to 34 relatives from the same small community. Neurological evaluation, sequencing of TREX1, and presymptomatic diagnosis were offered to all participants. Results: The patients exhibited the heterozygous TREX1 mutation p.V235Gfs*6, but with phenotypic variability. In addition, 15 relatives were identified as pre-manifest mutation carriers. The remaining participants did not carry the mutation. Conclusions: This is the figrst report of a large Mexican genealogy with RVCL, where the same TREX1 mutation causes a variation in organ involvement and clinical progression. The early identification and follow-up of individuals at risk may help provide insights into the basis for this variability in presentation. PMID- 29718011 TI - Association of Intron-2 Variable Numbers of an 86-bp Tandem Repeat-Polymorphisms of Interleukin-1 Receptor Antagonist Gene and Idiopathic Recurrent Spontaneous Abortion. AB - Background: It has been proposed that abnormal modulation of inflammatory response is involved in the physiopathology of idiopathic recurrent spontaneous abortion (iRSA). Factors that may participate in this process include the genetic background such as carrying specific polymorphisms of genes with functional effects. Objective: The objective is to study the association between iRSA and the frequency of intron-2 variable number tandem repeat-polymorphisms of interleukin-1 receptor antagonist gene (IL1RN). Methods: We conducted a case control study including 108 women with iRSA and 103 controls. Five allelic variants of IL1RN were determined by polymerase chain reaction (PCR) product length analysis. Results: The most frequent IL1RN allele in this population was IL1RN*1, which was present in 78% of cases and 94% of controls, and allele IL1RN*2, in 45 (20.8%) cases and 12 (5.8%) controls. Allele IL1RN*2 was significantly associated with iRSA (odds ratio = 4.28, 95% confidence interval 2.2-8.4; p = 0.000). Conclusion: Carrying allele IL1RN*2 had a strong association with iRSA in Mexican women. This polymorphism codifies for a low-function protein, which may allow for increased activity of IL-1 pro-inflammatory axis in iRSA. PMID- 29718013 TI - Ketamine for Treatment-Resistant Depression: a New Advocate. AB - Current alternatives for the treatment of major depressive disorder lack efficacy and have a delayed onset of action. Recently, the glutamatergic neurotransmission system has been noted to play an important role in the pathophysiology of this disorder. Ever since the first report of the antidepressant effects of the N methyl-D-aspartate receptor antagonist, ketamine, research has been redirected to novel therapeutic targets. With this rapidly growing evidence of a fast-acting antidepressant such as ketamine, as well as its efficacy in treatment-resistant cases of depression, off-label use has become popular in certain settings. In this article, the clinical antidepressant properties of ketamine in relation to the glutamate hypothesis of depression are discussed, to highlight the breakthrough of these findings in the development of novel therapeutic strategies and provide a clearer view of its benefits and potential harms. PMID- 29718012 TI - Schwann Cell Precursor Transplant in a Rat Spinal Cord Injury Model. AB - Background: Differentiation of mesenchymal stem cells into Schwann cell precursors could reverse established lesions and sequelae of medullary transection. Objective: The objective of this study was to study the clinical response of mesenchymal stem cell transplantation with Schwann precursor cell transplantation in a rat spinal cord injury model, using motor function and histopathologic studies. Materials and Methods: A total of 28 Sprague-Dawley rats were randomly divided among four groups (n = 7 in each): sham group, control group, mesenchymal stem cell transplant group, and Schwann cell precursor transplant group. The surgical procedure was a laminectomy with transection of the spinal cord at the T11 level in the transplant groups and the injury control group. After 1 week, the transplant groups received stem cells directly in the injury site. Hind limb motor function was assessed using the locomotive scale of Basso, Beattie, and Bresnahan. 1 month after transplantation, all specimens were sacrificed to make a histopathologic description of sections taken from the site of injury and where stem cells were transplanted. Mean scores of mobility were compared using analysis of variance (ANOVA) of one factor with 95% reliability between groups and ANOVA of repetitive measures to evaluate evolution in the same group. Results: We observed that the control group had statistically greater mobility than the other groups (p < 0.0001) and that the group with spinal injury without treatment had the lowest mean mobility. The mobility score values from the Schwann cell precursor group were statistically higher than the group treated with mesenchymal stem cells (p < 0.0001). Conclusion: Schwann precursor cells had a greater effect on locomotive function than mesenchymal stem cells. PMID- 29718014 TI - Linear terra firma-forme dermatosis of the midline back. AB - Terra firma-forme dermatosis (TFFD) is a benign and likely underdiagnosed disorder with relatively few reports in the literature. A 46-year-old woman presented to our clinic with a 3-year history of linear TFFD extending from the upper sacrum to the midline upper back. It initially was thought to be acanthosis nigricans or lichen simplex chronicus, and a topical steroid cream was applied without success. The lesion ultimately was removed by rubbing with isopropyl alcohol, which confirmed a diagnosis of TFFD. Due to its ability to mimic other skin diseases, TFFD should be considered when patients present with hyperkeratotic hyperpigmented lesions. PMID- 29718015 TI - Postherpetic isotopic responses with 3 simultaneously occurring reactions following herpes zoster. AB - Inflammatory, infectious, and neoplastic processes can all occur in prior areas of herpes infection (postherpetic isotopic response [PHIR]). Postzoster granulomatous dermatitis is among the most frequently encountered PHIR, but the exact pathogenesis has not been fully elucidated. Rarely, multiple diseases manifest concurrently in a PHIR. We report a case of cutaneous chronic lymphocytic leukemia (CLL) with an associated granulomatous dermatitis and medium vessel vasculitis occurring simultaneously at the site of prior herpes zoster. Clinicians and dermatopathologists should be aware of the multiplicity of postzoster isotopic responses and should consider the possibility of multiple diseases manifesting in the same clinical lesion in this setting. PMID- 29718016 TI - Diffuse cutaneous breast cancer metastases resembling subcutaneous nodules with no surface changes. AB - Cutaneous metastases typically occur in only a small minority of breast cancer patients. Clinical appearance can vary, but lesions often present as isolated dermal nodules with superficial discoloration or a change in texture on the chest ipsilateral to the primary breast malignancy. We report the case of a woman with metastatic adenocarcinoma of the breast presenting with diffuse cutaneous nodules with no surface changes. The nodules were almost undetectable clinically and had minimal elevation, making them difficult to detect, especially without palpation. A punch biopsy showed positive cytokeratin immunostaining consistent with the markers for the primary breast cancer. A review of the literature on cutaneous metastases from breast adenocarcinomas also is provided. PMID- 29718017 TI - Invasive penile squamous cell carcinoma. AB - Invasive penile squamous cell carcinoma (PSCC) is a rare malignancy with considerable morbidity and mortality. Because a delayed or incorrect diagnosis can have a devastating outcome, physicians should maintain a high index of clinical suspicion for PSCC in patients presenting with penile lesions, particularly in young or middle-aged patients in whom presentation of PSCC is uncommon. We report the case of a 27-year-old circumcised man who presented with invasive PSCC following a diagnosis of condyloma 8 years prior. The patient underwent robotic laparoscopic bilateral pelvis and inguinal lymph node dissection and re-excision of the primary PSCC, with one of 15 superficial right inguinal lymph nodes testing positive for squamous cell carcinoma. Given the patient's single-node positivity as well as the risks associated with chemotherapy with respect to his concurrent medical conditions, close follow-up with repeat imaging was planned following surgery. This case highlights the importance of biopsy in any lesion recalcitrant to conventional treatment modalities regardless of age. Early detection and treatment of PSCC can prevent organ dysfunction, loss of organ, or even death. PMID- 29718018 TI - Do psoriasis patients engage in vigorous physical activity? AB - Psoriasis is associated with cardiovascular risk factors and myocardial infarction, but regular physical activity is known to decrease the risk of coronary heart disease. We performed a systematic review of PubMed articles indexed for MEDLINE as well as articles in the Embase database and Cochrane Library using the search terms psoriasis and physical activity to determine the likelihood of psoriasis patients to engage in vigorous physical activity. A total of 353 nonduplicate articles were identified, and of 4 relevant studies, one provided sufficient data and was included in our review. Results from our review indicate that individuals with psoriasis are less likely to participate in vigorous physical activity compared to individuals without psoriasis. Further research is necessary to clarify this relationship. PMID- 29718019 TI - Deepithelialized flaps and grafts: applications in dermatologic surgery. AB - Deepithelialized flaps and grafts have been widely used by reconstructive surgeons in a diverse array of surgical specialties and have more recently made an appearance in dermatologic surgery. These techniques may be advantageous in their enabling of contour preservation of deep defects, reconstructions in areas of high mechanical tension, single-stage repairs, auricle reconstruction requiring tissue transfer, and reconstruction requiring free margins in areas with a paucity of local soft tissue. This article provides a review of the literature on deepithelialized flaps and grafts. We also highlight the use of these techniques in the field of dermatology and encourage appropriate application of deepithelialized flaps and grafts in dermatologic surgery. PMID- 29718020 TI - Concurrent anticytokine biologics for the management of severe hidradenitis suppurativa: are they safe and effective? PMID- 29718021 TI - Bullous eruption in 2 brothers. PMID- 29718022 TI - Asymptomatic subcutaneous nodule on the cheek. PMID- 29718023 TI - Let there be light: update on coding for photodynamic therapy and lasers. PMID- 29718025 TI - Digital strategies for dermatology patient education. PMID- 29718024 TI - What's eating you? Ixodes tick and related diseases, part 1: life cycle, local reactions, and lyme disease. AB - The Ixodes tick is an important arthropod vector in the transmission of human disease. This 3-part review highlights the biology of the Ixodes tick and manifestations of related diseases. Part 1 addresses the Ixodes tick biology and life cycle; local reactions; and Lyme disease, the most prevalent of associated diseases. Part 2 will address human granulocytic anaplasmosis, babesiosis, Powassan virus infection, Borrelia miyamotoi disease, tick-borne encephalitis, and tick paralysis. Part 3 will address coinfection with multiple pathogens as well as methods of tick-bite prevention and tick removal. PMID- 29718026 TI - Pushing the limits: developing a new standard of care for psoriasis. PMID- 29718027 TI - Emerging therapies in psoriasis: a systematic review. AB - Many new biologics are being studied for use in psoriasis. In this review, we evaluate and summarize findings about emerging biologic therapies for psoriasis. We reviewed published data from phase 2 and 3 clinical trials of 2 IL-17 inhibitors (ixekizumab and brodalumab); 3 IL-23 inhibitors (guselkumab, tildrakizumab, and risankizumab); and 1 tumor necrosis factor (TNF) inhibitor (certolizumab pegol). Janus kinase inhibitors were not included in our review, as they currently are not approved by the US Food and Drug Administration (FDA) and there are no plans to further develop this class for treatment of psoriasis. Overall, the clinical improvement provided by and the safety profiles of these agents are promising; they may be equal to or more efficacious than available therapeutic options for treating the symptoms of psoriasis. Long-term studies are still needed, however, to further establish safety and efficacy profiles for these biologic agents. PMID- 29718028 TI - Current guidelines for psoriasis treatment: a work in progress. AB - Psoriasis is a complex chronic autoimmune skin disease with multiple comorbidities that can have a considerable impact on quality of life (QoL). As therapeutic options evolve, physicians should look to treatment guidelines and consensus statements to keep their practice and management of psoriasis patients current with worldwide standards. This article reviews the most up-to-date general guidelines available for the management of psoriasis. PMID- 29718029 TI - Violaceous plaques and papulonodules on the umbilicus. PMID- 29718030 TI - Brown-black papulonodules on the arm. PMID- 29718031 TI - A recalcitrant case of toxic epidermal necrolysis. AB - We describe a case that was initially diagnosed and treated as toxic epidermal necrolysis (TEN) by an outside hospital. After failure to improve on high-dose steroids and intravenous (IV) immunoglobulin, the patient was transferred to our hospital where he was subsequently diagnosed with a disseminated herpes simplex virus (HSV) infection. The patient recovered after 21 days of antiviral therapy. We review key physical examination findings that will help the clinician diagnose a viral etiology in the setting of an acute blistering eruption with mucosal involvement. PMID- 29718032 TI - Revealing the principal attributes of protein adsorption on block copolymer surfaces with direct experimental evidence at the single protein level. AB - Understanding protein adsorption onto polymer surfaces is of great importance in designing biomaterials, improving bioanalytical devices, and controlling biofouling, to name a few examples. Although steady research efforts have been advancing this field, our knowledge of this ubiquitous and complex phenomenon is still limited. In this study, we elucidate competitive protein adsorption behaviors sequentially occurring onto nanoscale block copolymer (BCP) surfaces via combined experimental and computer simulation approaches. The model systems chosen for our investigation are immunoglobulin G and fibrinogen introduced in different orders into the self-assembled nanodomains of poly(styrene)-block poly(methylmethacrylate). We unambiguously reveal the adsorption, desorption, and replacement events of the same protein molecules via single protein tracking with atomic force microscopy. We then ascertain adsorption-related behaviors such as lateral mobility and self-association of proteins. We provide the much-needed, direct experimental proof of sequential adsorption events at the biomolecular level, which was virtually nonexistent before. We determine key protein adsorption pathways and dominant tendencies of sequential protein adsorption. We also reveal preadsorbed surface-associated behaviors in sequential adsorption, distinct from situations involving initially empty surfaces. We perform Monte Carlo simulations to further substantiate our experimental outcomes. Our endeavors in this study may facilitate a well-guided mechanistic understanding of protein-polymer interactions by providing definite experimental evidence of competitive, sequential adsorption at the nanoscale. Increasingly, biomaterial and biomedical applications rely on systems of multicomponent proteins and chemically intricate, nanoscale polymer surfaces. Hence, our findings can also be beneficial for the development of next-generation nanobiomaterials and nanobiosensors exploiting self-assembled BCP nanodomain surfaces. PMID- 29718033 TI - Center-iodized graphene as an advanced anode material to significantly boost the performance of lithium-ion batteries. AB - Iodine edge-doped graphene can improve the capacity and stability of lithium-ion batteries (LIBs). Our theoretical calculations indicate that center-iodization can further significantly enhance the anode catalytic process. To experimentally prove the theoretical prediction, iodine-doped graphene materials were prepared by one-pot hydrothermal and ball-milling approaches to realize different doping sites. Results show that the center-iodinated graphene (CIG) anode exhibits a remarkably high reversible capacity (1121 mA h g-1 after 180 cycles at 0.5 A g 1), long-cycle life (0.01% decay per cycle over 300 cycles at 1 A g-1) and high rate capacity (374 mA h g-1 after 800 cycles at 8 A g-1), which greatly improves the performance of the edge-iodinated graphene anode and these results are in good agreement with the theoretical analysis. More importantly, the CIG anode also delivers a high-rate capacity and excellent cycling stability (279 mA h g-1 after 500 cycles at 10 A g-1) in full-cells. Both the theoretical analysis and experimental investigation reveal the enhancement mechanism, in which the center iodization increases the surface charge for fast electron transfer rate, improves the conductivity for charge transport and rationalizes the pore structure for enhanced mass transport and ion insertion/desertion, thus resulting in a high rate capacity and long cycle life. This work not only discloses the critical role of catalytic sites including both amounts and site positions but also offers great potential for high-power rechargeable LIB applications. PMID- 29718034 TI - Efficient Co-N/PC@CNT bifunctional electrocatalytic materials for oxygen reduction and oxygen evolution reactions based on metal-organic frameworks. AB - Cobalt-based, nitrogen-doped porous carbon materials with in situ grown carbon nanotubes (CNTs) were synthesized by the facile carbonization of porous 3D Bio MOF-11 [Co2(ad)2(CH3COO)2].2DMF.0.5H2O (ad = adenine). Co-N/PC@CNT-Ts inherit the octahedral shape from the precursor, and have a porous structure with in situ grown CNTs catalyzed by Co particles. Co-N/PC@CNT-T materials have excellent activities as bifunctional electrocatalysts for oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) in 0.1 M KOH electrolyte. Among the Co N/PC@CNT-Ts, Co-N/PC@CNT-700 has the highest electrocatalytic activity. For ORR, Co-N/PC@CNT-700 has a higher onset potential of 0.92 V vs. reversible hydrogen electrode (RHE), high stability and methanol tolerance, which are even better than that of Pt/C. For OER, it has a low potential of 1.63 V at a current density of 10 mA cm-2. In addition, Co-N/PC@CNT-700 affords a low reversible overvoltage (bifunctional performance parameter) of 0.862 V between ORR and OER compared to the current advancing bifunctional catalysts. The superb bifunctional activity can be attributed to uniform CoNx active sites embedded in graphitized carbon, unique in situ grown CNT structure and ordered mesoporous structure. The synergistic effect enlarged the contact surface, exposed more active centers and provided many pathways, thereby boosting the electrocatalytic performance. In conclusion, this study provides a novel avenue for the application of stable transition metal-based, nitrogen-doped carbon materials as extremely efficient electrocatalysts for ORR and OER. PMID- 29718035 TI - A densely packed Sb2O3 nanosheet-graphene aerogel toward advanced sodium-ion batteries. AB - As a promising anodic material for rechargeable batteries, Sb2O3 has drawn increasing attention due to its high theoretical capacity and abundant natural deposits. However, poor cyclability and rate performance of Sb2O3 derived from a large volume change during insertion/desertion reactions as well as a sluggish kinetic process restrict its practical application. Herein, we report a facile amorphous-to-crystalline strategy to synthesize a densely packed Sb2O3 nanosheet graphene aerogel as a novel anode for sodium ion batteries (SIBs). This Sb2O3/graphene composite displays a reversible capacity as high as 657.9 mA h g-1 even after 100 cycles at 0.1 A g-1, along with an excellent rate capacity of 356.8 mA h g-1 at 5.0 A g-1. The superior electrochemical performance is attributed to the synergistic effects of densely packed Sb2O3 nanosheets and graphene aerogel, which serves as both a robust support and stable buffer layer to maintain the structural stability of the nanocomposite, and enhances the electrode kinetics of electrolyte diffusion and electron transfer simultaneously. Hence, this densely-packed two-dimensional Sb2O3 nanosheet-graphene aerogel can be a promising anode material for rechargeable SIBs due to its facile synthesis process and outstanding electrochemical performance. PMID- 29718037 TI - Studies on the interactions of 5-R-3-(2-pyridyl)-1,2,4-triazines with arynes: inverse demand aza-Diels-Alder reaction versus aryne-mediated domino process. AB - The interactions between substituted 5-R-3-(pyridyl-2)-1,2,4-triazines with in situ generated substituted aryne intermediates have been studied. The reaction afforded either inverse demand (ID) aza-Diels-Alder products or 1,2,4-triazine ring rearrangement (domino) products as major ones depending on the nature of both the substituents at the C5 position of the 1,2,4-triazine core or in the aryne moiety. The structures of the key products were confirmed based on X-ray data. Based on the density functional theoretical (DFT) studies of the Diels Alder transition state geometries, the influence of the nature of arynes on the direction of the 1,2,4-triazine transformation has been proposed. PMID- 29718038 TI - Up in the air: oxygen tolerance in controlled/living radical polymerisation. AB - The requirement for deoxygenation in controlled/living radical polymerisation (CLRP) places significant limitations on its widespread implementation by necessitating the use of large reaction volumes, sealed reaction vessels as well as requiring access to specialised equipment such as a glove box and/or inert gas source. As a result, in recent years there has been intense interest in developing strategies for overcoming the effects of oxygen inhibition in CLRP and therefore remove the necessity for deoxygenation. In this review, we highlight several strategies for achieving oxygen tolerant CLRP including: "polymerising through" oxygen, enzyme mediated deoxygenation and the continuous regeneration of a redox-active catalyst. In order to provide further clarity to the field, we also establish some basic parameters for evaluating the degree of "oxygen tolerance" that can be achieved using a given oxygen scrubbing strategy. Finally, we propose some applications that could most benefit from the implementation of oxygen tolerant CLRP and provide a perspective on the future direction of this field. PMID- 29718039 TI - Selectively arranged single-wire based nanosensor array systems for gas monitoring. AB - Gas nanosensors, comprised of arrays of nanoelectrodes with finger-widths of ~100 nm developed by electron beam lithography and aerosol assisted chemical vapor deposited non-functionalized and Pt-functionalized tungsten oxide nanowires (<100 nm) subsequently integrated across the pairs of electrodes via the dielectrophoresis method, are developed in this work. The functionality of these devices is validated towards various concentrations of NO2 and C2H5OH. The results demonstrate reproducible and consistent responses with better sensitivity and partial selectivity for the non-functionalized systems to NO2, as opposed to the Pt-functionalized systems, which display better sensing properties towards C2H5OH with a loss of response to NO2. These results are explained on the basis of the additional chemical and electronic interactions at the Pt/tungsten oxide interface, which increase the pre-adsorption of oxygen species and make the functionalized surface rather more sensitive to C2H5OH than to NO2, in contrast to the non-functionalized surface. PMID- 29718044 TI - Screening and multiple detection of cancer exosomes using an SERS-based method. AB - As a kind of most important cancer biomarker, exosomes are getting more frequently investigated in cancer diagnosis. In this study, we proposed an SERS based method for the screening and simultaneous multiple detection of exosomes using magnetic substrates and SERS probes. Specifically, the capturing substrates are achieved using gold shell magnetic nanobeads modified by aptamers, which can capture most kinds of exosomes by recognizing the generic surface protein CD63. Moreover, the SERS probes are made of gold nanoparticles decorated with a Raman reporter and a specific aptamer for targeting exosomes. Further, for the simultaneous detection of multiple kinds of exosomes, three kinds of SERS probes were designed using different SERS reporters. While detecting specific kinds of exosomes, the capturing substrates were mixed with these three kinds of SERS probes. When the target exosome is present, an apta-immunocomplex can be formed among the target exosomes, the substrate, and the corresponding kind of SERS probes, and the other non-specific SERS probes remain in the suspension. Hence, an SERS signal with a decreased intensity will be detected in the supernatant, indicating the presence of the target exosomes. Finally, this detection method has also been successfully employed for the detection of exosomes in real blood samples; this proves that the proposed SERS-based method is a promising tool for clinical cancer screening based on exosomes. PMID- 29718045 TI - Network-controlled unique reactivities of carbonyl groups in hollow and microporous organic polymer. AB - Hollow and microporous organic network bearing alkynone moieties was prepared via carbonylative Sonogashira coupling. The carbonyl groups in the network showed unusual chemical reactivities, compared with those of a model alkynone compound. The observed differences between the reactivities of alkynones in the molecule and in the network were analyzed based on the "network effect". PMID- 29718046 TI - Dandelion-like Co3O4 mesoporous nanostructures supported by a Cu foam for efficient oxygen evolution and lithium storage. AB - Novel dandelion-like Co3O4 mesoporous nanostructures, supported by a Cu foam, are prepared by a combination of hydrothermal synthesis and annealing. The resulting Co3O4@Cu foam exhibits superior oxygen evolution (Tafel slope = 42.8 mV dec-1) and lithium storage (capacity = 882 mA h g-1@2C after 100 cycles, 1C = 890 mA g 1) properties, which highlight its great promise in the fields of energy storage and conversion. PMID- 29718049 TI - In vitro selection of electrochemical peptide probes using bioorthogonal tRNA for influenza virus detection. AB - An electrosensitive peptide probe has been developed from an in vitro selection technique using biorthogonal tRNA prepared with an electroreactive non-natural amino acid, 3,4-ethylenedioxythiophene-conjugated aminophenylalanine. The selected probe quantitatively detected the influenza virus based on a signal "turn-on" mechanism. The developed strategy could be used to develop electrochemical biosensors toward a variety of targets. PMID- 29718050 TI - Single particle states of colloidal particles in 2D periodic potentials. AB - Colloidal particles when subjected to a periodic array of potential wells are observed to adopt discrete stable configurations depending on the particle size/array wavelength ratio. Experimentally, the configuration states are determined for singlets, doublets and triplets of identical spheres in a periodic array of traps. The energy landscape of a single spherical particle is obtained by considering the refraction of the incident light as it passes throughout the particle. Then, the energy of a dumbbell is determined as the superposition of two singlets. The energy of a triplet is calculated as the superposition of a dumbbell and a single particle. As it is shown here, this direct method predicts accurately the stable particle configurations as observed in the experiments. The method can be generalized to obtain the potential energy of an n-particle aggregate, using as building blocks the energies of singlets and doublets. PMID- 29718051 TI - On the measurement of intermolecular heteronuclear cross relaxation rates in ionic liquids. AB - The HOESY (Heteronuclear Overhauser Effect SpectroscopY) NMR experiment is commonly used to study interactions and structuring in ionic liquids (ILs) via the measurement of the cross relaxation rate sigma between two spins. In the intermolecular case, sigma is proportional to r-n, where r is the internuclear distance and n can vary between 1 and 6 depending on the frequency of the nuclei and their dynamics, thus sigma can potentially provide detailed information on the liquid phase structure. However, in HOESY studies of ILs only relative values for sigma are typically reported, making comparisons between different samples difficult. Herein we discuss the quantitative measurement of intermolecular cross relaxation rates based on the normalisation of HOESY signal intensities to the nuclear Boltzmann polarisation, demonstrated for 7Li-1H spin pairs in a lithium containing pyrrolidinum-based ionic liquid electrolyte. We also use a simple model based on diffusing hard spheres for interpreting these quantities in terms of a distance of closest approach. PMID- 29718053 TI - Photo-thermal reactions of ethanol over Ag/TiO2 catalysts. The role of silver plasmon resonance in the reaction kinetics. AB - Photo-thermal catalytic reactions of ethanol over Ag/TiO2 were conducted in order to probe into the role of plasmonic resonance response in the reaction kinetics. In the 300-500 K temperature domain the increase in reaction rate is found to be mainly due to changes in the activation energy while above this temperature range the increase was due to the pre-exponential factor. These results might be linked to the role of plasmonic Ag particles in polarising the reaction intermediates and therefore increasing the reaction products at temperatures up to about 500 K. PMID- 29718054 TI - Restructuring of poly(2-ethyl-2-oxazoline)/tannic acid multilayers into fibers. AB - H-Bonded, pH-responsive poly(2-ethyl-2-oxazoline) (PEOX) and tannic acid (TA) multilayers were prepared by layer-by-layer deposition. Free-floating PEOX/TA multilayers were shown to restructure in a pH3 phosphate buffer solution to H bonded, pH-responsive PEOX/TA fibers. This restructuring was also evident during the growth of multilayers thicker than 15 bilayers (BL). The growth profile of 30 BL-thick films showed a significant decrease in the film thickness from 118 nm to 85 nm between 15 BL and 20 BL, after which the growth trend was regained with some small fluctuations. This decrease was associated with the detachment of film patches from the top surface of the film. The rinse solutions consisted of fibrous aggregates, which were formed by the restructuring of the detached multilayer patches. These fibers were characterized by TGA, XPS, FTIR and SEM measurements which showed that the fibers consisted of H-bonded PEOX and TA molecules. As such, the fibers were pH-responsive and disintegrated at pH > 8.5. Scanning electron microscopy images indicated that the fibers might have been formed by the curling of planar LbL film patches and the dried fibers looked like collapsed hollow tubes on solid substrates. These results contribute to our understanding of the stability of LbL films in various chemical conditions and the ways to modify the morphology of self-assembled structures. pH-responsive fibrous aggregates are important in a variety of biomedical applications, from controlled release to sensors. PMID- 29718056 TI - Rotation of a floating hydrophobic disk: influence of line tension. AB - The rotation of a sub-millimeter size disk over a water bath is reported. The origin of the rotation arises from the transfer of angular momentum from a plane wave diffracted by an asymmetrical picture printed on the disk. Because of its hydrophobic character, the viscous friction contribution to the rotational motion of the object floating on the air/liquid interface is weak. From the driving optical torque and the steady-state rotation, we measure the contribution of the line tension in the femto-Newton range. PMID- 29718058 TI - A three-dimensional transient mixed hybrid finite element model for superabsorbent polymers with strain-dependent permeability. AB - A hydrogel is a cross-linked polymer network with water as solvent. Industrially widely used superabsorbent polymers (SAP) are partially neutralized sodium polyacrylate hydrogels. The extremely large degree of swelling is one of the most distinctive characteristics of such hydrogels, as the volume increase can be about 30 times its original volume when exposed to physiological solution. The large deformation resulting from the swelling demands careful numerical treatment. In this work, we present a biphasic continuum-level swelling model using the mixed hybrid finite element method (MHFEM) in three dimensions. The hydraulic permeability is highly dependent on the swelling ratio, resulting in values that are orders of magnitude apart from each other. The property of the local mass conservation of MHFEM contributes to a more accurate calculation of the deformation as the permeability across the swelling gel in a transient state is highly non-uniform. We show that the proposed model is able to simulate the free swelling of a random-shaped gel and the squeezing of fluid out of a swollen gel. Finally, we make use of the proposed numerical model to study the onset of surface instability in transient swelling. PMID- 29718059 TI - Interaction between amino-functionalized inorganic nanoshells and acid autocatalytic reactions. AB - Amino-functionalized inorganic silica nanoshells with a diameter of 511 +/- 57 nm are efficiently used as hydrogen ion binders with a base dissociation constant of (1.2 +/- 0.1) * 10-4. The hydrogen removal has been shown to produce reaction diffusion fronts of constant propagation velocity in the autocatalytic chlorite tetrathionate reaction when it is run in thin planar slices of nanoshell containing agarose gel to exclude all convection related effects. By controlling the exact amount of amino-functionalized hollow nanospheres in the gel matrix it is possible to finely tune the propagation velocity of the chemical front in the 0.1-10 cm h-1 range. Remarkably, this can be achieved with very low amino functionalized hollow inorganic nanosphere loadings between 0.1-0.01 (m V-1)%. The front width has also been determined experimentally, which increases by a factor of two with one magnitude decrease in the front velocity. PMID- 29718060 TI - Platinum nanoparticles: a non-toxic, effective and thermally stable alternative plasmonic material for cancer therapy and bioengineering. AB - Absorption of near infrared (NIR) light by metallic nanoparticles can cause extreme heating and is of interest for instance in cancer treatment since NIR light has a relatively large penetration depth into biological tissue. Here, we quantify the extraordinary thermoplasmonic properties of platinum nanoparticles and demonstrate their efficiency in photothermal cancer therapy. Although platinum nanoparticles are extensively used for catalysis, they are much overlooked in a biological context. Via direct measurements based on a biological matrix we show that individual irradiated platinum nanoparticles with diameters of 50-70 nm can easily reach surface temperatures up to 900 K. In contrast to gold nanoshells, which are often used for photothermal purposes, we demonstrate that the platinum particles remain stable at these extreme temperatures. The experiments are paralleled by finite element modeling confirming the experimental results and establishing a theoretical understanding of the particles' thermoplasmonic properties. At extreme temperatures it is likely that a vapor layer will form around the plasmonic particle, and we show this scenario to be consistent with direct measurements and simulations. Viability studies demonstrate that platinum nanoparticles themselves are non-toxic at therapeutically relevant concentrations, however, upon laser irradiation we show that they efficiently kill human cancer cells. Therefore, platinum nanoparticles are highly promising candidates for thermoplasmonic applications in the life sciences, in nano-medicine, and for bio-medical engineering. PMID- 29718061 TI - Nanoparticle adsorption dynamics at fluid interfaces. AB - Understanding the dynamic adsorption of nanoparticles (NPs) at fluid interfaces is important for stabilizing emulsions and for the preparation of 2D NP-based materials. Here we show that the Ward-Tordai equations commonly employed to describe the dynamics of surfactant adsorption at a fluid interface combined with a Frumkin adsorption isotherm can be employed to model the diffusion-limited adsorption of NPs onto a fluid interface. In contrast to surfactants, an additional wetting equation of state (EOS) must be incorporated to characterize the dynamic interfacial tension during the adsorption of NPs to the oil-water interface. Our results show agreement between the model and experiments with NP area fractions <0.3. Slower dynamics are observed at larger area fractions, which are speculated to arise from polydispersity or re-organization at the interface. We show the model can be extended to the competitive adsorption between the NPs and a surface active species. PMID- 29718062 TI - Iowa Gambling Task Performance in Parkinson Disease Patients with Impulse Control Disorders. AB - Objective: A subgroup of patients with Parkinson disease (PD) develops impulse control disorders (ICD) associated with their dopamine replacement therapy. Patients and their families may be reluctant to report ICD symptoms or unaware these symptoms are related to PD medication, which can make detecting an ICD difficult for clinicians. Ideally, a behavioral measure that is sensitive to ICD could be employed to ensure that patients with these behaviors are identified and treated. The Iowa Gambling Task (IGT), a standardized decision-making task, has proven sensitive in other populations with impulse control problems. We hypothesized that the IGT would differentiate between PD patients with and without ICD. Methods: We compared IGT performance and disease variables in 24 PD patients with ICD and 24 PD patients without ICD. Patient groups were matched in terms of age, sex, and duration of PD. Results: There were no significant differences in IGT scores between PD groups. IGT performance declined with increasing age, but the majority of patients performed within normal limits based on published age- and education-corrected normative data. Conclusions: The IGT did not distinguish between PD patients with and without ICD. Increasing age negatively impacted performance in both groups. Other studies have found that IGT performance may decline in normal aging. Our results suggest that the IGT lacks the sensitivity and specificity needed to differentiate between age-related deficits and disruption in frontal-subcortical circuits underlying ICD associated with PD medications. Therefore, the IGT is not an appropriate behavioral measure for ICD in PD patients. PMID- 29718063 TI - The protective effects of HGF against apoptosis in vascular endothelial cells caused by peripheral vascular injury. AB - Closed vascular injuries have danger of developing critical tissue ischemia with a high risk of amputation and limb loss. However, limited effective strategies exist at present. In this study, we investigate the role of hepatocyte growth factor (HGF) on apoptosis of vascular endothelial cells (VECs). First, apoptosis of VECs was induced by hypoxia treatment with or without HGF. Annexin V-7AAD apoptosis assay revealed that HGF overexpression significantly reduced VEC apoptosis. Then a closed peripheral vascular injury animal model was created by balloon catheter in female New Zealand rabbit. The VECs overexpressing HGF were injected into balloon injury rabbit. TUNEL and caspase 3 staining assays revealed that balloon catheter-treated artery showed severe intimal hyperplasia, with a 70% apoptosis rate (P < 0.05, vs. sham group), while HGF-overexpressing group showed a significant reduction of apoptosis. Furthermore, the expressions of Fas/FasL and their downstream apoptosis-related proteins were significantly decreased in HGF-overexpressing group when compared with those in balloon injury group as detected by western blot analysis. All these data indicated that HGF exhibited anti-apoptotic effects during VEC apoptosis, which might be mediated by the inhibition of Fas/FasL pathway. Our study provides a theoretic basis for the application of HGF in the gene therapy of closed peripheral vascular injury. PMID- 29718064 TI - Cardiorespiratory fitness and risk of dementia: a prospective population-based cohort study. AB - Dementia is considered to be one of the major public health problems in light of the ageing population. Little is known about directly measured cardiorespiratory fitness as measured by maximal oxygen uptake and the risk of dementia. Our aim was to examine the relationship of cardiorespiratory fitness, as indicated by maximal oxygen uptake, with subsequent incidence of dementia. This was a population-based cohort study with an average follow-up of 22 (range 0.22-29.8) years from eastern Finland. About 2,031 men with a mean age of 52.8 years of age and no history of dementia or pulmonary disease at baseline participated in the study. Among these men, 208 cases of dementia occurred. Maximal oxygen uptake (ml/kg/min) was measured during exercise testing at baseline. One standard deviation increase in VO2max was associated with a 20% decrease in dementia. Cardiorespiratory fitness was inversely related to the risk of dementia. Men with low cardiorespiratory fitness (VO2max < 23.7 ml/kg/min, lowest quintile) had a 1.92-fold (1.24-2.967, P = 0.003), risk of dementia as compared with men who had high cardiorespiratory fitness (VO2max >36.5 ml/kg/min, highest quintile) after adjusting for age and examination years. In a multivariate model, low cardiorespiratory fitness was associated with a 1.95-fold (1.24-3.05, P = 0.003) risk of dementia. Our findings show that low cardiorespiratory fitness was associated with an increased risk of dementia. PMID- 29718065 TI - Use of Multiple Data Sources for Surveillance of Work-Related Chronic Low-Back Pain and Disc-Related Sciatica in a French Region. AB - Objectives: To compare the data of the French workers' compensation system (WCS) and three surveillance networks, and to determine the possibility of identifying the industry sectors most in need of programs for prevention of low-back pain (LBP). Methods: This study compared four databases and two types of indicators in a west central region of France: * surveillance of musculoskeletal symptoms in the working population [LBP and disc-related sciatica (DRS) indicators; Cosali study] * surveillance of uncompensated work-related diseases (LBP and DRS indicators) * surveillance of lumbar disc surgery (LDS) in the general population (DRS indicator) * French WCS (disc herniation with radiculopathy caused by vibration or handling of materials; DRS indicator) People aged 20-59 were studied. The prevention index (PI) was used to rank industry sectors according to the number of cases and the prevalence/incidence rate. Results: Construction and manufacturing were the first sectors in terms of PI for men in all databases and indicators. Moreover, transport and agriculture were not consistently highlighted. For women, manufacturing was the leading sector (except for the LDS study: health sector), followed by the health sector. Specific epidemiologic surveillance networks (LDS and Cosali studies) provided ranking of the greatest number of sectors out of the 17 classified. For DRS indicators, the LDS study classified 13 sectors for both genders, and for LBP indicators, the Cosali study ranked 8 and 7 sectors in men and women, respectively. Conclusions: The results showed the complementarity of the four surveillance programs. A multi-component surveillance system allowed detection of industry sectors most in need of prevention programs. PMID- 29718066 TI - A Psychometric Approach to Theory-Based Behavior Change Intervention Development: Example From the Colorado Meaning-Activity Project. AB - Background: There has been a notable disconnect between theories of behavior change and behavior change interventions. Because few interventions are both explicitly and adequately theory-based, investigators cannot assess the impact of theory on intervention effectiveness. Theory-based interventions, designed to deliberately engage the theory's proposed mechanisms of change, are needed to adequately test theories. Thus, systematic approaches to theory-based intervention development are needed. Purpose: This article will introduce and discuss the psychometric method of developing theory-based interventions. Methods: The psychometric approach to intervention development utilizes basic psychometric principles at each step of the intervention development process in order to build a theoretically driven intervention to, subsequently, be tested in process (mechanism) and outcome studies. Five stages of intervention development are presented as follows: (i) Choice of theory; (ii) Identification and characterization of key concepts and expected relations; (iii) Intervention construction; (iv) Initial testing and revision; and (v) Empirical testing of the intervention. Results: Examples of this approach from the Colorado Meaning Activity Project (COMAP) are presented. Based on self-determination theory integrated with meaning or purpose, and utilizing a motivational interviewing approach, the COMAP intervention is individually based with an initial interview followed by smart phone-delivered interventions for increasing daily activity. Conclusions: The psychometric approach to intervention development is one method to ensure careful consideration of theory in all steps of intervention development. This structured approach supports developing a research culture that endorses deliberate and systematic operationalization of theory into behavior change intervention from the outset of intervention development. PMID- 29718068 TI - Introducing a New ASJ Video Series: Open Access Publishing in Plastic Surgery. PMID- 29718067 TI - Quantification of Carbon Nanotubes by Raman Analysis. AB - The increasing prevalence of carbon nanotubes (CNTs) in manufacturing and research environments, together with the potential exposure risks, necessitates development of reliable and accurate monitoring methods for these materials. We examined quantification of CNTs by two distinct methods based on Raman spectroscopy. First, as measured by the Raman peak intensity of aqueous CNT suspensions, and second, by Raman mapping of air filter surfaces onto which CNTs were collected as aerosols or applied as small-area (0.05 cm2) deposits. Correlation (R2 = 0.97) between CNT concentration and Raman scattering intensity for suspensions in cuvettes was found over a concentration range from about 2 to 10 ug/ml, but measurement variance precludes practical determination of a calibration curve. Raman mapping of aerosol sample filter surfaces shows correlation with CNT mass when the surface density is relatively high (R2 = 0.83 and 0.95 above about 5 ug total mass on filter), while heterogeneity of CNT deposition makes obtaining representative maps of lower density samples difficult. This difficulty can be mitigated by increasing the area mapped relative to the total sample area, improving both precision and the limit of detection (LOD). For small-area deposits, detection of low masses relevant to occupational monitoring can be achieved, with an estimated LOD of about 50 ng. PMID- 29718069 TI - Bovine Allergens in a Ruminant Clinic and Dairy Barns: Exposure Levels, Determinants, and Variability. AB - Background: Dairy farmers may develop specific sensitization and allergic airway diseases due to bovine allergens. However, dose-response relationships are lacking, and as yet little is known on bovine allergen exposure levels. Objective: To investigate bovine allergen exposure levels in a ruminant clinic and dairy barns, and to assess exposure determinants and variability of exposure. Methods: Samples were collected using active and passive airborne dust measurements in a ruminant clinic and several dairy barns. Bovine allergen levels were determined by sandwich enzyme-linked immunosorbent assay. Linear mixed models were applied to explore the association between bovine allergen exposure levels and potential exposure determinants. Day-to-day within-worker and between worker exposure variability was determined, as well as how exposure determinants affect exposure variability. Results: Bovine allergens were measureable in all samples. Personal bovine allergen exposure levels in the ruminant clinic ranged from 0.10 to 24.8 ug/m3, geometric mean (GM) 1.34 ug/m3. Exposure levels varied dependent on job titles. Personal exposure levels in dairy barns ranged from 0.10 to 46.8 ug/m3, GM 1.47 ug/m3. Type of bedding materials in the barns appeared to be a significant determinant of bovine allergen levels. Compost bedding, particularly, increased allergen levels. Milking by robot was the most important determinant explaining between-worker exposure variability, while bedding was important as well. Bovine allergen levels in stationary measurements were somewhat lower than personal measurements (GM ratio 0.47). Bovine allergens could be readily detected in electrostatic dust-fall collector measurements. Conclusion: This study provides insight in bovine allergen exposure levels and their determinants, which is a first step to investigate dose-response relationships between sensitization/allergy associated with exposure to bovine allergen levels in future studies. PMID- 29718070 TI - Accelerated Cognitive Ageing in Epilepsy: A Neuropsychological Evaluation of Cognitive Deterioration. AB - Objective: Shed light on cognitive deterioration in Accelerated Cognitive Ageing (ACA) in epilepsy from a neuropsychological point of view in order to improve clinical diagnostics. Methods: We compared the IQ-profile including GAI, OPIE IV premorbid IQ and deterioration-scores of 21 epilepsy patients with ACA with 21 matched epilepsy patients without ACA (Epilepsy Controls) and 16 age- and education-matched Healthy Controls. Memory was also evaluated. Results: Premorbid IQs were equal in all groups. Deterioration was apparent in the ACA-group in the WAIS-IV FSIQ and PRI, whereas no deterioration was found in the two control groups. PSI was impaired in both epilepsy groups, though with more impairment seen in the ACA-group. The VCI remained unimpaired. The FSIQ-GAI discrepancy was equal in both patient groups and significantly larger than in the Healthy Controls. WMS-IV memory indices were of average level in all groups. Memory impairment in ACA was not statistically different from the Epilepsy Controls. 85.7% of ACA-patients could be correctly classified through factors DET_FSIQ and PSI. Conclusions: Cognitive deterioration in ACA is characterized by an average drop of 19 IQ-points in FSIQ and PRI. Verbal abilities remain unimpaired. Impairments in fluid functions compromise cognitive abilities in epilepsy, but only partially contribute to cognitive deterioration in ACA. PSI proved to have some diagnostic value in differentiating epilepsy patients from healthy controls, but fails to differentiate between ACA and Epilepsy Controls. A comparison made between OPIE-IV equations and obtained IQs leads to a significant better detection of cognitive deterioration in epilepsy than the use of GAI-FSIQ discrepancies alone. PMID- 29718071 TI - Two case reports of zoledronic acid-induced uveitis. AB - Zoledronic acid (zoledronate) is a bisphosphonate used predominantly as a second line treatment for post-menopausal osteoporosis. Its administration is associated with an acute phase reaction. Here, we present two cases of anterior uveitis following initial administration of zoledronate. In the first case, an 80-year old lady presented with right eye pain and decreased visual acuity 24-hours post infusion. Uveitis was diagnosed and sub-conjunctival injection of corticosteroids was required. In the second case, a 78-year-old lady presented with right eye pain, vomiting and decreased acuity 24-hours after infusion. She was treated with topical steroids and required cataract surgery to normalise visual acuity. Patients prescribed zoledronate should be warned of the risk of ocular side effects and asked to report promptly for treatment if they develop a red, painful eye or blurred vision. PMID- 29718073 TI - CNS response to osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFR-TKI sensitising mutation (EGFRm)-positive advanced non-small cell lung cancer (NSCLC): Data from the FLAURA study. PMID- 29718074 TI - Accuracy of death certification of dementia in population-based samples of older people: analysis over time. AB - Background: death certification data are routinely collected in most developed countries. Coded causes of death are a readily accessible source and have the potential advantage of providing complete follow-up, but with limitations. Objective: to investigate the reliability of using death certificates for surveillance of dementia, the time trend of recording dementia on death certificates and predictive factors of recording of dementia. Subjects: individuals aged 65 and over in six areas across England and Wales were randomly selected for the Medical Research Council Cognitive Function and Ageing Study (CFAS) and CFAS II with mortality follow-up. Methods: prevalence of dementia recorded on death certificates were calculated by year. Reporting of dementia on death certificates compared with the study diagnosis of dementia, with sensitivity, specificity and Cohen's kappa were estimated. Multivariable logistic regression models explored the impact of potential factors on the reporting of dementia on the death certificate. Results: the overall unadjusted prevalence of dementia on death certificates rose from 5.3% to 25.9% over the last 26 years. Dementia reported on death certificates was poor with sensitivity 21.0% in earlier cohort CFAS, but it had increased to 45.2% in CFAS II. Dementia was more likely to be recorded on death certificates in individuals with severe dementia, or those living in an institution, yet less likely reported if individuals died in hospital. Conclusion: recording dementia on death certificate has improved significantly in the England and Wales. However, such information is still an underestimate and should be used alongside epidemiological estimations. PMID- 29718075 TI - Neuropsychology in the Integrated MS Care Setting. AB - The goal of this paper is to describe the role of the neuropsychologist in a Multiple Sclerosis clinic setting. A brief overview of the pathophysiology and neuropsychological deficits in MS is presented. Practical details regarding relations with the neurology team, and the neuropsychologist's focus on assessment are described. Recommendations regarding necessary training and skills, as well as typical clinical practice routines are described. The neuropsychologist's communication with internal and external providers and family members in order to assist implementation of recommendations is described. PMID- 29718076 TI - Clinical Neuropsychology in Integrated Rehabilitation Care Teams. AB - Neuropsychologists have been an integral part of rehabilitation-oriented integrated care teams for some time and they provide care that is complimentary to other specialties, such as rehabilitation psychologists. Neuropsychologists are more likely than other specialties to offer objective cognitive data that includes consideration of emotional and behavioral features when assessing patients who have known or suspected brain injury or illness. Objective cognitive data is then often used for treatment and discharge planning as well as anticipating safety issues and impairment of functional skills. Unlike a consultative model, neuropsychologists in rehabilitation must work as part of a team of rehabilitation professionals and understand the contributions each specialty offers patients. This paper will highlight a number of issues pertaining to the practice of neuropsychology in rehabilitation settings including: (i) essential skills and duties, (ii) reimbursement, (iii) practice specifics, (iv) types of recommendations, (v) communication issues, (vi) impact of neuropsychological services, (vii) role satisfaction; (viii) advice for early career neuropsychologists, and (ix) a sample report. PMID- 29718072 TI - Putting primary metabolism into perspective to obtain better fruits. AB - Background: One of the key goals of fruit biology is to understand the factors that influence fruit growth and quality, ultimately with a view to manipulating them for improvement of fruit traits. Scope: Primary metabolism, which is not only essential for growth but is also a major component of fruit quality, is an obvious target for improvement. However, metabolism is a moving target that undergoes marked changes throughout fruit growth and ripening. Conclusions: Agricultural practice and breeding have successfully improved fruit metabolic traits, but both face the complexity of the interplay between development, metabolism and the environment. Thus, more fundamental knowledge is needed to identify further strategies for the manipulation of fruit metabolism. Nearly two decades of post-genomics approaches involving transcriptomics, proteomics and/or metabolomics have generated a lot of information about the behaviour of fruit metabolic networks. Today, the emergence of modelling tools is providing the opportunity to turn this information into a mechanistic understanding of fruits, and ultimately to design better fruits. Since high-quality data are a key requirement in modelling, a range of must-have parameters and variables is proposed. PMID- 29718077 TI - The Role of Neuropsychology on Organ Transplant Teams. AB - Neuropsychological evaluations have been a required component of heart transplant workups at the University of Minnesota Medical Center since 1989. Since end stage kidney, liver, pancreas, and lung disease commonly effects cognition, our service now regularly consults on those transplant teams as well. This article details the role of neuropsychology in a large transplant center, outlining the requisite training and skills needed to serve these patient populations. While transplant is restricted to major medical centers, patients with end stage organ failure are plentiful and can benefit from neuropsychological expertise, providing a substantial source of clinical expansion and research study for our profession. PMID- 29718078 TI - Neuropsychology in a Memory Disorder Clinic. AB - The rationale for and factors related to embedding a neuropsychologist in the midst of a neurology-based memory disorder clinic are discussed. Common conditions encountered are briefly reviewed, along with an evaluation aimed at assisting with differential diagnosis. Advice for neuropsychologists is offered in terms of creating and refining a working model in a neurology clinic and strategies to improve communication and effectiveness are presented. PMID- 29718079 TI - The Integrated Care Team Approach of the Department of Veterans Affairs (VA): Geriatric Primary Care. AB - Historically, integrated mental and behavioral healthcare in the Department of Veterans Affairs (VA) commenced with initiatives in geriatrics. Innovation and system-wide expansion has occurred over decades and culminated in a unified vision for training and practice in the VA medical home model: Patient Aligned Care Team or PACT approach. In one VA hospital, the integration of neuropsychological services in geriatric primary care is pivotal and increases access for patients, as well as contributing to timely and effective care on an interprofessional team. The development and innovative use of an algorithm to identify problems with cognition, health literacy, and mental and behavioral health has been pragmatic and provides useful information for collaborative treatment planning in GeriPACT, VA geriatric primary care. Use of the algorithm also assists with decision-making regarding brief versus comprehensive neuropsychological assessment in the primary care setting. The model presented here was developed by supervising neuropsychologists as part of a postdoctoral residency program in geropsychology. However, postdoctoral residency programs in neuropsychology, as well as neuropsychological clinics, can also use this model to integrate neuropsychological assessment and interventions in geriatric primary care settings. PMID- 29718080 TI - The Role of a Neuropsychologist on a Movement Disorders Deep Brain Stimulation Team. AB - The term movement disorders is misleading in the implication that the symptoms are limited to motor problems. Most movement disorders include a variety of neurobehavioral and neurocognitive symptoms that require neuropsychological expertise. The goal of this paper is to provide a rationale and practical roadmap for neuropsychologists' involvement in a Movement Disorders team with a specific focus on pre-operative deep brain stimulation (DBS) evaluations. Pragmatic recommendations regarding requisite skills, clinical practice, recommendations, communication, and benefits are outlined. PMID- 29718082 TI - Integration of Neuropsychological Services in a VA HIV Primary Care Clinic. AB - The Department of Veteran Affairs (VA) is the largest health care provider for individuals with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS), with >28,000 Veterans with HIV/AIDS enrolled in care. Advances in medical treatment have improved the life-limiting effects of the disease, though many chronic symptoms persist. Comprehensive care is critical to manage the diverse constellation of symptoms. However, many patients face challenges to receiving optimal care due to limited resources, mistrust of health care providers, and/or co-occurring medical, psychiatric, and substance use disorders. The VA is a leader in developing integrated models of care to address these barriers. The inclusion of subspecialty mental health and substance abuse treatment in HIV care has been implemented across many VAs, with evidence of improved patient outcomes. However, neuropsychology has not traditionally been included, despite the fact that cognitive dysfunction represents one of the most ubiquitous complications of HIV/AIDS. Cognitive impairment is associated with myriad negative outcomes including medication non-adherence, reduced quality of life, and increased mortality. We contend that neuropsychologists are uniquely equipped to contribute to the comprehensive care of patients with HIV/AIDS. Neuropsychologists understand the range of factors that can impact cognition and have the requisite knowledge and skills to assess and treat cognitive dysfunction. Although we focus on HIV/AIDS, neuropsychologists often play critical roles in the provision of care for other infectious diseases (e.g., hepatitis C). PMID- 29718081 TI - Neuropsychological Practice in the Oncology Setting. AB - Oncology has experienced positive shifts in survival curves for many cancers largely due to the development of earlier diagnostics and better therapeutics. This has increased the visibility and need for survivorship services, including clinical neuropsychology. Patients with cancer frequently experience cognitive dysfunction related to the presence of cancer itself and treatment neurotoxicity. These cognitive difficulties can profoundly impact patient functioning and autonomy with accompanying declines in quality of life. Clinical neuropsychologists are uniquely positioned to evaluate the cognitive and affective sequelae of cancer and treatment and provide interventions and recommendations that can benefit well-being and potentially alter the disease course. Despite increasing recognition of the importance of neuropsychological issues to cancer survivorship, many neuropsychologists have limited training and guidance regarding navigating and implementing services within the oncology setting. This article provides the basic rationale for neuropsychological practice and research activities in oncology, as well as the experience of the Section of Neuropsychology at The University of Texas MD Anderson Cancer Center. PMID- 29718083 TI - Neuropsychology Within a Tertiary Care Epilepsy Center. AB - Epilepsy is a prevalent condition characterized by variations in its clinical presentation, etiology, and amenability to treatment. Through history, neuropsychologists have played a significant role in performing research studies on changes in language, memory, and executive functioning in patients with epilepsy, including those undergoing surgical treatment for medically refractory seizures. These studies provided a foundation for establishing neuropsychologists as critical members of interdisciplinary clinical teams specializing in evaluation and treatment of epilepsy. This article describes a number of elements of specialized neuropsychological practice that have evolved over the years within a tertiary care epilepsy center. Through diagnostic interview and objective testing, the neuropsychologist is able to provide a more complete and objective understanding of a patient's cognitive and behavioral functioning than what is obtained by other clinicians through brief office visits. While assessment of cognition, mood, and behavior is the most commonly provided service to patients with epilepsy from all age groups, there are many instances when neuropsychologists in surgical settings are called to perform more specialized procedures, including the intracarotid amytal (Wada) procedure, electrocortical stimulation mapping of language eloquent brain regions, and functional brain imaging procedures. While working as a neuropsychologist on an interdisciplinary epilepsy care team requires specialized knowledge and clinical training, it is extremely satisfying due to the diversity of the patient population and the particular challenges resulting from the often unique manner that cognition and behavior can be affected in patients with epilepsy across the lifespan. PMID- 29718084 TI - Integration of Neuropsychology in Primary Care. AB - The field of neuropsychology is making inroads in primary care as the importance of cognition in physical health is increasingly acknowledged. With neuropsychology primary care integration, patients receive a range of cognitive assessments (e.g., screens, brief neuropsychological assessments, treatment recommendations through provider-to-neuropsychologist consultations) based on a stepped model of care which can more efficiently diagnose cognitive disorders/problems and assist with treatment. Two case studies are described to illuminate this process. Information is provided to illustrate how neuropsychology integration was introduced in two primary care clinics at a community-based hospital system. PMID- 29718085 TI - Role of Computerized Screening in Healthcare Teams: Why Computerized Testing is Not the Death of Neuropsychology. PMID- 29718086 TI - Introduction to the Special Issue on Neuropsychology Practices in Integrated Care Teams. AB - This special issue on neuropsychology practices in integrated healthcare teams demonstrates how neuropsychologists have transformed their practices in an evolving healthcare landscape. These contributions are an overview of the many ways in which neuropsychologists function in integrated care teams. The experiences of integrated neuropsychologists serve as a model for those seeking new practice opportunities by providing highly practical, clinically relevant information. Included in this volume are articles on education and reimbursement issues, information about clinical practices that address diagnostic issues, prognostics and clinical management, as well as surgical treatment planning and outcome prediction. Authors highlight the value of their services, their contribution to improving team and patient communication, as well as the biopsychosocial understanding of the patient. Several unexpected challenges are detailed among the pearls and pitfalls of these practices. PMID- 29718087 TI - Physical Properties of Silicone Gel Breast Implants. AB - Background: Surgical applications using breast implants are individualized operations to fill and shape the breast. Physical properties beyond shape, size, and surface texture are important considerations during implant selection. Objective: Compare form stability, gel material properties, and shell thickness of textured shaped, textured round, and smooth round breast implants from 4 manufacturers: Allergan, Mentor, Sientra, and Establishment Labs through bench testing. Methods: Using a mandrel height gauge, form stability was measured by retention of dimensions on device movement from a horizontal to vertical supported orientation. Dynamic response of gel material (gel cohesivity, resistance to gel deformation, energy absorption) was measured using a synchronized target laser following application of graded negative pressure. Shell thickness was measured using digital thickness gauge calipers. Results: Form stability, gel material properties, and shell thickness differed across breast implants. Of textured shaped devices, Allergan Natrelle 410 exhibited greater form stability than Mentor MemoryShape and Sientra Shaped implants. Allergan Inspira round implants containing TruForm 3 gel had greater form stability, higher gel cohesivity, greater resistance to gel deformation, and lower energy absorption than those containing TruForm 2 gel and in turn, implants containing TruForm 1 gel. Shell thickness was greater for textured versus smooth devices, and differed across styles. Conclusions: Gel cohesivity, resistance to gel deformation, and energy absorption are directly related to form stability, which in turn determines shape retention. These characteristics provide information to aid surgeons choosing an implant based on surgical application, patient tissue characteristics, and desired outcome. PMID- 29718088 TI - Editorial: Synthesizing the Evidence on Prisoner Health-Taking Stock and Moving Forward. PMID- 29718089 TI - Bevacizumab+chemotherapy versus chemotherapy alone in elderly patients with untreated metastatic colorectal cancer: a randomized phase II trial-PRODIGE 20 study results. PMID- 29718090 TI - An Audit of Repeat Testing at an Academic Medical Center: Consistency of Order Patterns With Recommendations and Potential Cost Savings. AB - Objectives: To evaluate the prevalence of potentially unnecessary repeat testing (PURT) and the associated economic burden for an inpatient population at a large academic medical facility. Methods: We evaluated all inpatient test orders during 2016 for PURT by comparing the intertest times to published recommendations. Potential cost savings were estimated using the Centers for Medicare & Medicaid Services maximum allowable reimbursement rate. We evaluated result positivity as a determinant of PURT through logistic regression. Results: Of the evaluated 4,242 repeated target tests, 1,849 (44%) were identified as PURT, representing an estimated cost-savings opportunity of $37,376. Collectively, the association of result positivity and PURT was statistically significant (relative risk, 1.2; 95% confidence interval, 1.1-1.3; P < .001). Conclusions: PURT contributes to unnecessary health care costs. We found that a small percentage of providers account for the majority of PURT, and PURT is positively associated with result positivity. PMID- 29718091 TI - The Five Es of Efficient Engagement: Attaining Esprit de Corps. PMID- 29718093 TI - Commentary on: Efficacy and Safety of ATX-101 by Treatment Session: Pooled Analysis of Data From the Phase 3 REFINE Trials. PMID- 29718092 TI - Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2 negative advanced breast cancer. AB - Background: The phase III MONALEESA-2 study demonstrated significantly prolonged progression-free survival (PFS) and a manageable toxicity profile for first-line ribociclib plus letrozole versus placebo plus letrozole in patients with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2 ) advanced breast cancer. Here, we report updated efficacy and safety data, together with exploratory biomarker analyses, from the MONALEESA-2 study. Patients and methods: A total of 668 postmenopausal women with HR+, HER2- recurrent/metastatic breast cancer were randomized (1 : 1; stratified by presence/absence of liver and/or lung metastases) to ribociclib (600 mg/day; 3 weeks-on/1-week-off; 28-day treatment cycles) plus letrozole (2.5 mg/day; continuous) or placebo plus letrozole. The primary end point was locally assessed PFS. The key secondary end point was overall survival (OS). Other secondary end points included overall response rate (ORR) and safety. Biomarker analysis was an exploratory end point. Results: At the time of the second interim analysis, the median duration of follow-up was 26.4 months. Median PFS was 25.3 months [95% confidence interval (CI) 23.0-30.3] for ribociclib plus letrozole and 16.0 months (95% CI 13.4-18.2) for placebo plus letrozole (hazard ratio 0.568; 95% CI 0.457 0.704; log-rank P = 9.63 * 10-8). Ribociclib treatment benefit was maintained irrespective of PIK3CA or TP53 mutation status, total Rb, Ki67, or p16 protein expression, and CDKN2A, CCND1, or ESR1 mRNA levels. Ribociclib benefit was more pronounced in patients with wild-type versus altered receptor tyrosine kinase genes. OS data remain immature, with 116 deaths observed; 50 in the ribociclib arm and 66 in the placebo arm (hazard ratio 0.746; 95% CI 0.517-1.078). The ORR was 42.5% versus 28.7% for all patients treated with ribociclib plus letrozole versus placebo plus letrozole, respectively, and 54.5% versus 38.8%, respectively, for patients with measurable disease. Safety results, after a further 11.1 months of follow-up, were comparable with those reported at the first analysis, with no new or unexpected toxicities observed, and no evidence of cumulative toxicity. Conclusions: The improved efficacy outcomes and manageable tolerability observed with first-line ribociclib plus letrozole are maintained with longer follow-up, relative to letrozole monotherapy. Clinical trials number: NCT01958021. PMID- 29718094 TI - Yes, Size Does Matter! PMID- 29718095 TI - Neoadjuvant rectal score as individual-level surrogate for disease-free survival in rectal cancer in the CAO/ARO/AIO-04 randomized phase III trial. AB - Background: Surrogate end points in rectal cancer after preoperative chemoradiation are lacking as their statistical validation poses major challenges, including confirmation based on large phase III trials. We examined the prognostic role and individual-level surrogacy of neoadjuvant rectal (NAR) score that incorporates weighted cT, ypT and ypN categories for disease-free survival (DFS) in 1191 patients with rectal carcinoma treated within the CAO/ARO/AIO-04 phase III trial. Patients and methods: Cox regression models adjusted for treatment arm, resection status, and NAR score were used in multivariable analysis. The four Prentice criteria (PC1-4) were used to assess individual-level surrogacy of NAR for DFS. Results: After a median follow-up of 50 months, the addition of oxaliplatin to fluorouracil-based chemoradiotherapy (CRT) significantly improved 3-year DFS [75.9% (95% confidence interval [CI] 72.30% to 79.50%) versus 71.3% (95% CI 67.60% to 74.90%); P = 0.034; PC 1) and resulted in a shift toward lower NAR groups (P = 0.034, PC 2) compared with fluorouracil-only CRT. The 3-year DFS was 91.7% (95% CI 88.2% to 95.2%), 81.8% (95% CI 78.4% to 85.1%), and 58.1% (95% CI 52.4% to 63.9%) for low, intermediate, and high NAR score, respectively (P < 0.001; PC 3). NAR score remained an independent prognostic factor for DFS [low versus high NAR: hazard ratio (HR) 4.670; 95% CI 3.106-7.020; P < 0.001; low versus intermediate NAR: HR 1.971; 95% CI 1.303-2.98; P = 0.001] in multivariable analysis. Notwithstanding the inherent methodological difficulty in interpretation of PC 4 to establish surrogacy, the treatment effect on DFS was captured by NAR, supporting satisfaction of individual-level PC 4. Conclusion: Our study validates the prognostic role and individual-level surrogacy of NAR score for DFS within a large randomized phase III trial. NAR score could help oncologists to speed up response-adapted therapeutic decision, and further large phase III trial data sets should aim to confirm trial-level surrogacy. PMID- 29718096 TI - GapRepairer: a server to model a structural gap and validate it using topological analysis. AB - Motivation: Over 25% of protein structures possess unresolved fragments. On the other hand, approximately 6% of protein chains have non-trivial topology (and form knots, slipknots, lassos and links). As the topology is fundamental for the proper function of proteins, modeling of topologically correct structures is decisive in various fields, including biophysics, biotechnology and molecular biology. However, none of the currently existing tools take into account the topology of the model and those which could be modified to include topology, demand experience in bioinformatics, protein topology and knot theory. Results: In this work, we present the GapRepairer-the server that fills the gap in the spectrum of structure modeling methods. Its easy and intuitive interface offers the power of Modeller homology modeling to many non-experts in the field. This server determines the topology of templates and predicted structures. Such information when possible is used by the server to suggest the best model, or it can be used by the user to score models or to design artificially (dis)entangled structures. Availability and implementation: GapRepairer server along with tutorials, usage notes, movies and the database of already repaired structures is available at http://gaprepairer.cent.uw.edu.pl. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29718097 TI - RBind: computational network method to predict RNA binding sites. AB - Motivation: Non-coding RNA molecules play essential roles by interacting with other molecules to perform various biological functions. However, it is difficult to determine RNA structures due to their flexibility. At present, the number of experimentally solved RNA-ligand and RNA-protein structures is still insufficient. Therefore, binding sites prediction of non-coding RNA is required to understand their functions. Results: Current RNA binding site prediction algorithms produce many false positive nucleotides that are distance away from the binding sites. Here, we present a network approach, RBind, to predict the RNA binding sites. We benchmarked RBind in RNA-ligand and RNA-protein datasets. The average accuracy of 0.82 in RNA-ligand and 0.63 in RNA-protein testing showed that this network strategy has a reliable accuracy for binding sites prediction. Availability and implementation: The codes and datasets are available at https://zhaolab.com.cn/RBind. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29718099 TI - Variability of High-Sensitivity Troponin T Concentrations in Emergency Settings: Impact for the Diagnosis of Myocardial Infarction. AB - Objectives: To assess biological variation of troponin T in emergency settings and establish limits for interpretation of serial results. Methods: We studied 6,557 consecutive patients with troponin measurements. A stable reference subset was selected to estimate biological variation and threshold limits. Results: The first troponin level was elevated in 32% of patients, and 2,490 had a second troponin level with a myocardial infarction (MI) prevalence of 16.2%. In the stable reference group with at least one abnormal value, the 99th percentile of the absolute delta between the first two samples was 16 ng/L. For MI diagnosis, the area under the receiver operating characteristic curve was 0.85 (confidence interval [CI], 0.83-0.87) for the first troponin level and 0.94 (CI, 0.93-0.95) for the absolute delta. Conclusions: An absolute delta of 16 ng/L has good specificity in the emergency setting. This threshold is valid for any sex, age, and sampling interval between 3 and 24 hours and is higher than published limits found in healthy outpatients. PMID- 29718101 TI - [WITHDRAWN AS DUPLICATE] A historical perspective on some "new" discoveries on spermatogenesis from the laboratory of Enrico Sertoli in 1878. PMID- 29718100 TI - TMCrys: predict propensity of success for transmembrane protein crystallization. AB - Motivation: Transmembrane proteins (TMPs) are crucial in the life of the cells. As they have special properties, their structure is hard to determine--the PDB database consists of 2% TMPs, despite the fact that they are predicted to make up to 25% of the human proteome. Crystallization prediction methods were developed to aid the target selection for structure determination, however, there is a need for a TMP specific service. Results: Here, we present TMCrys, a crystallization prediction method that surpasses existing prediction methods in performance thanks to its specialization for TMPs. We expect TMCrys to improve target selection of TMPs. Availability and implementation: https://github.com/brgenzim/tmcrys. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29718098 TI - Current knowledge on the acute regulation of steroidogenesis. AB - How rapid induction of steroid hormone biosynthesis occurs in response to trophic hormone stimulation of steroidogenic cells has been a subject of intensive investigation for approximately six decades. A key observation made very early was that acute regulation of steroid biosynthesis required swift and timely synthesis of a new protein whose role appeared to be involved in the delivery of the substrate for all steroid hormones, cholesterol, from the outer to the inner mitochondrial membrane where the process of steroidogenesis begins. It was quickly learned that this transfer of cholesterol to the inner mitochondrial membrane was the regulated and rate-limiting step in steroidogenesis. Following this observation, the quest for this putative regulator protein(s) began in earnest in the late 1950s. This review provides a history of this quest, the candidate proteins that arose over the years and facts surrounding their rise or decline. Only two have persisted-translocator protein (TSPO) and the steroidogenic acute regulatory protein (StAR). We present a detailed summary of the work that has been published for each of these two proteins, the specific data that has appeared in support of their role in cholesterol transport and steroidogenesis, and the ensuing observations that have arisen in recent years that have refuted the role of TSPO in this process. We believe that the only viable candidate that has been shown to be indispensable is the StAR protein. Lastly, we provide our view on what may be the most important questions concerning the acute regulation of steroidogenesis that need to be asked in future. PMID- 29718102 TI - MetaboDiff: an R package for differential metabolomic analysis. AB - Summary: Comparative metabolomics comes of age through commercial vendors offering metabolomics for translational researchers outside the mass spectrometry field. The MetaboDiff packages aims to provide a low-level entry to differential metabolomic analysis with R by starting off with the table of metabolite measurements. As a key functionality, MetaboDiffs offers the exploration of sample traits in a data-derived metabolic correlation network. Availability and implementation: The MetaboDiff R package is platform-independent, available at http://github.com/andreasmock/MetaboDiff/ and released under the MIT licence. The package documentation comprises a step-by-step markdown tutorial. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29718103 TI - A powerful approach reveals numerous expression quantitative trait haplotypes in multiple tissues. AB - Motivation: Recently many studies showed single nucleotide polymorphisms (SNPs) affect gene expression and contribute to development of complex traits/diseases in a tissue context-dependent manner. However, little is known about haplotype's influence on gene expression and complex traits, which reflects the interaction effect between SNPs. Results: In the present study, we firstly proposed a regulatory region guided eQTL haplotype association analysis approach, and then systematically investigate the expression quantitative trait loci (eQTL) haplotypes in 20 different tissues by the approach. The approach has a powerful design of reducing computational burden by the utilization of regulatory predictions for candidate SNP selection and multiple testing corrections on non independent haplotypes. The application results in multiple tissues showed that haplotype-based eQTLs not only increased the number of eQTL genes in a tissue specific manner, but were also enriched in loci that associated with complex traits in a tissue-matched manner. In addition, we found that tag SNPs of eQTL haplotypes from whole blood were selectively enriched in certain combination of regulatory elements (e.g. promoters and enhancers) according to predicted chromatin states. In summary, this eQTL haplotype detection approach, together with the application results, shed insights into synergistic effect of sequence variants on gene expression and their susceptibility to complex diseases. Availability and implementation: The executable application 'eHaplo' is implemented in Java and is publicly available at http://grass.cgs.hku.hk/limx/ehaplo/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29718104 TI - Exact Bayesian inference for phylogenetic birth-death models. AB - Motivation: Inferring the rates of change of a population from a reconstructed phylogeny of genetic sequences is a central problem in macro-evolutionary biology, epidemiology and many other disciplines. A popular solution involves estimating the parameters of a birth-death process (BDP), which links the shape of the phylogeny to its birth and death rates. Modern BDP estimators rely on random Markov chain Monte Carlo (MCMC) sampling to infer these rates. Such methods, while powerful and scalable, cannot be guaranteed to converge, leading to results that may be hard to replicate or difficult to validate. Results: We present a conceptually and computationally different parametric BDP inference approach using flexible and easy to implement Snyder filter (SF) algorithms. This method is deterministic so its results are provable, guaranteed and reproducible. We validate the SF on constant rate BDPs and find that it solves BDP likelihoods known to produce robust estimates. We then examine more complex BDPs with time varying rates. Our estimates compare well with a recently developed parametric MCMC inference method. Lastly, we perform model selection on an empirical Agamid species phylogeny, obtaining results consistent with the literature. The SF makes no approximations, beyond those required for parameter quantization and numerical integration and directly computes the posterior distribution of model parameters. It is a promising alternative inference algorithm that may serve either as a standalone Bayesian estimator or as a useful diagnostic reference for validating more involved MCMC strategies. Availability and implementation: The Snyder filter is implemented in Matlab and the time-varying BDP models are simulated in R. The source code and data are freely available at https://github.com/kpzoo/snyder birth-death-code. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29718105 TI - Corrigendum to: Does Telomere Length Indicate Biological, Physical, and Cognitive Health Among Older Adults? Evidence from the Health and Retirement Study. PMID- 29718106 TI - Quantification of biases in predictions of protein stability changes upon mutations. AB - Motivation: Bioinformatics tools that predict protein stability changes upon point mutations have made a lot of progress in the last decades and have become accurate and fast enough to make computational mutagenesis experiments feasible, even on a proteome scale. Despite these achievements, they still suffer from important issues that must be solved to allow further improving their performances and utilizing them to deepen our insights into protein folding and stability mechanisms. One of these problems is their bias toward the learning datasets which, being dominated by destabilizing mutations, causes predictions to be better for destabilizing than for stabilizing mutations. Results: We thoroughly analyzed the biases in the prediction of folding free energy changes upon point mutations (DeltaDeltaG0) and proposed some unbiased solutions. We started by constructing a dataset Ssym of experimentally measured DeltaDeltaG0s with an equal number of stabilizing and destabilizing mutations, by collecting mutations for which the structure of both the wild-type and mutant protein is available. On this balanced dataset, we assessed the performances of 15 widely used DeltaDeltaG0 predictors. After the astonishing observation that almost all these methods are strongly biased toward destabilizing mutations, especially those that use black-box machine learning, we proposed an elegant way to solve the bias issue by imposing physical symmetries under inverse mutations on the model structure, which we implemented in PoPMuSiCsym. This new predictor constitutes an efficient trade-off between accuracy and absence of biases. Some final considerations and suggestions for further improvement of the predictors are discussed. Supplementary information: Supplementary data are available at Bioinformatics online. Note: The article 10.1093/bioinformatics/bty340/, published alongside this paper, also addresses the problem of biases in protein stability change predictions. PMID- 29718107 TI - The intervention effect of aspirin on a lipopolysaccharide-induced preeclampsia like mouse model by inhibiting the nuclear factor-kappaB pathway. AB - Preeclampsia is a severe pregnancy-related disorder, and patients usually present with high circulating inflammatory factor levels and excessive activation of the nuclear factor-kappaB (NF-kappaB) pathway. Administration of aspirin (ASP) is effective for preventing preeclampsia, and thus, we propose that ASP might affect placental function by regulating the NF-kappaB pathway. Systemic lipopolysaccharide (LPS) (20 MUg/kg) was used to induce preeclampsia-like pregnant mouse model, and low-dose ASP (15.2 mg/kg) was administrated. Here, we report significantly increased circulatory expression levels of the proinflammatory cytokines tumor necrosis factor-alpha, interleukin-6, and soluble Fms-related tyrosine kinase-1 in LPS-treated pregnant mice, accompanied by kidney and placental dysfunction. Low-dose ASP treatment significantly reversed the preeclampsia-like phenotype, lowering hypertension, decreasing proteinuria, and ameliorating fetal growth retardation. Moreover, the excessive activation of NF kappaB signaling in mice placentae induced by LPS was significantly reduced by ASP. In JEG-3 cells, LPS activated the NF-kappaB signaling pathway by upregulating the expression of cyclooxygenase-2 (COX-2) and related inflammatory factors, whereas the invasion ability of JEG-3 cells was weakened. However, ASP administration impeded NF-kappaB signaling activation, downregulated COX-2 and inflammatory factor expression, and rescued trophoblast invasion. This study provides new evidence that low-dose ASP is beneficial for preeclampsia prevention by inhibiting NF-kappaB and its downstream signaling pathways in trophoblast cells. PMID- 29718108 TI - The anti-epileptic drug lamotrigine inhibits the CYP17A1 lyase reaction in vitro. AB - The potential endocrine disrupting effects of the commonly prescribed anti epileptic drug lamotrigine (LAM) were investigated using the H295R steroidogenic in vitro assay and computational chemistry methods. The H295R cells were exposed to different concentrations of LAM, and a multi-steroid LC-MS/MS method was applied to quantify the amount of secreted steroid hormones. LAM affected several steroid hormones in the steroidogenesis at therapeutic concentrations. All progestagens as well as 11-deoxycorticosterone and corticosterone increased 100 200% with increasing concentrations of LAM suggesting a selective inhibitory effect of LAM on CYP17A1, in particular on the lyase reaction. Recombinant CYP17A1 assay confirmed the competitive inhibition of LAM toward the enzyme with IC50 values of 619 and 764 MUM for the lyase and the hydroxylase reaction, respectively. Levels of androstenedione and testosterone decreased at LAM concentrations above the therapeutic concentration range. The ability of LAM to bind to CYP17A1, CYP19A1, and CYP21A2 was investigated using docking and molecular dynamics simulations. This in silico study showed that LAM was able to bind directly to the heme iron in the active site of CYP17A1, but not CYP21A2, thus supporting the results of the in vitro studies. The molecular dynamics simulations also suggested binding of LAM to the heme iron in the CYP19A1 active site. No inhibition of the aromatase enzyme was, however, observed in the H295R assay. This could be due to a sequential effect within the steroidogenesis caused by the inhibition of CYP17A1, which reduced the amounts of androgens available for CYP19A1. PMID- 29718109 TI - Evolution of gonadotropin signaling on gonad development: insights from gene knockout studies in zebrafish. AB - Gonadal development is precisely regulated by the two gonadotropins luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Much progress on understanding the functions of LH and FSH signaling on gonad development has been achieved in the past decades, mostly from studies in mammals, especially genetic studies in both mouse and human. The functions of both LH and FSH signaling in nonmammalian species are still largely unknown. In recent years, using zebrafish, a teleost phylogenetically distant from mammals, we and others have genetically analyzed the functions of gonadotropins and their receptors through gene knockout studies. In this review, we will summarize the pertinent findings and discuss how the actions of gonadotropin signaling on gonad development have evolved during evolution from fish to mammals. PMID- 29718110 TI - Tracking the Epigenetic Clock Across the Human Life Course: A Meta-analysis of Longitudinal Cohort Data. AB - Background: Epigenetic clocks based on DNA methylation yield high correlations with chronological age in cross-sectional data. Due to a paucity of longitudinal data, it is not known how Deltaage (epigenetic age - chronological age) changes over time or if it remains constant from childhood to old age. Here, we investigate this using longitudinal DNA methylation data from five datasets, covering most of the human life course. Methods: Two measures of the epigenetic clock (Hannum and Horvath) are used to calculate Deltaage in the following cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) offspring (n = 986, total age-range 7-19 years, 2 waves), ALSPAC mothers (n = 982, 16-60 years, 2 waves), InCHIANTI (n = 460, 21-100 years, 2 waves), SATSA (n = 373, 48-99 years, 5 waves), Lothian Birth Cohort 1936 (n = 1,054, 70-76 years, 3 waves), and Lothian Birth Cohort 1921 (n = 476, 79-90 years, 3 waves). Linear mixed models were used to track longitudinal change in Deltaage within each cohort. Results: For both epigenetic age measures, Deltaage showed a declining trend in almost all of the cohorts. The correlation between Deltaage across waves ranged from 0.22 to 0.82 for Horvath and 0.25 to 0.71 for Hannum, with stronger associations in samples collected closer in time. Conclusions: Epigenetic age increases at a slower rate than chronological age across the life course, especially in the oldest population. Some of the effect is likely driven by survival bias, where healthy individuals are those maintained within a longitudinal study, although other factors like the age distribution of the underlying training population may also have influenced this trend. PMID- 29718111 TI - GenomicScores: seamless access to genomewide position-specific scores from R and Bioconductor. AB - Summary: Genomewide position-specific scores, such as those estimating conservation, constraint, fitness or mutation tolerance, are ubiquitous in current genome analyses. The diversity of sources and formats of these scores, as well as their size, increase the burden to use them. We present GenomicScores, a Bioconductor package that provides efficient storage and seamless access of genomewide position-specific scores from R, facilitating their use in genome analysis workflows. Availability and implementation: GenomicScores is implemented in R and available at https://bioconductor.org/packages/GenomicScores under the open source 'Artistic-2.0' license. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29718112 TI - High precision in protein contact prediction using fully convolutional neural networks and minimal sequence features. AB - Motivation: In addition to substitution frequency data from protein sequence alignments, many state-of-the-art methods for contact prediction rely on additional sources of information, or features, of protein sequences in order to predict residue-residue contacts, such as solvent accessibility, predicted secondary structure, and scores from other contact prediction methods. It is unclear how much of this information is needed to achieve state-of-the-art results. Here, we show that using deep neural network models, simple alignment statistics contain sufficient information to achieve state-of-the-art precision. Our prediction method, DeepCov, uses fully convolutional neural networks operating on amino-acid pair frequency or covariance data derived directly from sequence alignments, without using global statistical methods such as sparse inverse covariance or pseudolikelihood estimation. Results: Comparisons against CCMpred and MetaPSICOV2 show that using pairwise covariance data calculated from raw alignments as input allows us to match or exceed the performance of both of these methods. Almost all of the achieved precision is obtained when considering relatively local windows (around 15 residues) around any member of a given residue pairing; larger window sizes have comparable performance. Assessment on a set of shallow sequence alignments (fewer than 160 effective sequences) indicates that the new method is substantially more precise than CCMpred and MetaPSICOV2 in this regime, suggesting that improved precision is attainable on smaller sequence families. Overall, the performance of DeepCov is competitive with the state of the art, and our results demonstrate that global models, which employ features from all parts of the input alignment when predicting individual contacts, are not strictly needed in order to attain precise contact predictions. Availability and implementation: DeepCov is freely available at https://github.com/psipred/DeepCov. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29718113 TI - Prediction of lncRNA-disease associations based on inductive matrix completion. AB - Motivation: Accumulating evidences indicate that long non-coding RNAs (lncRNAs) play pivotal roles in various biological processes. Mutations and dysregulations of lncRNAs are implicated in miscellaneous human diseases. Predicting lncRNA disease associations is beneficial to disease diagnosis as well as treatment. Although many computational methods have been developed, precisely identifying lncRNA-disease associations, especially for novel lncRNAs, remains challenging. Results: In this study, we propose a method (named SIMCLDA) for predicting potential lncRNA-disease associations based on inductive matrix completion. We compute Gaussian interaction profile kernel of lncRNAs from known lncRNA-disease interactions and functional similarity of diseases based on disease-gene and gene gene onotology associations. Then, we extract primary feature vectors from Gaussian interaction profile kernel of lncRNAs and functional similarity of diseases by principal component analysis, respectively. For a new lncRNA, we calculate the interaction profile according to the interaction profiles of its neighbors. At last, we complete the association matrix based on the inductive matrix completion framework using the primary feature vectors from the constructed feature matrices. Computational results show that SIMCLDA can effectively predict lncRNA-disease associations with higher accuracy compared with previous methods. Furthermore, case studies show that SIMCLDA can effectively predict candidate lncRNAs for renal cancer, gastric cancer and prostate cancer. Availability and implementation: https://github.com//bioinfomaticsCSU/SIMCLDA. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29718114 TI - MiRGOFS: a GO-based functional similarity measurement for miRNAs, with applications to the prediction of miRNA subcellular localization and miRNA disease association. AB - Motivation: Benefiting from high-throughput experimental technologies, whole genome analysis of microRNAs (miRNAs) has been more and more common to uncover important regulatory roles of miRNAs and identify miRNA biomarkers for disease diagnosis. As a complementary information to the high-throughput experimental data, domain knowledge like the Gene Ontology and KEGG pathway is usually used to guide gene function analysis. However, functional annotation for miRNAs is scarce in the public databases. Till now, only a few methods have been proposed for measuring the functional similarity between miRNAs based on public annotation data, and these methods cover a very limited number of miRNAs, which are not applicable to large-scale miRNA analysis. Results: In this paper, we propose a new method to measure the functional similarity for miRNAs, called miRGOFS, which has two notable features: (i) it adopts a new GO semantic similarity metric which considers both common ancestors and descendants of GO terms; (i) it computes similarity between GO sets in an asymmetric manner, and weights each GO term by its statistical significance. The miRGOFS-based predictor achieves an F1 of 61.2% on a benchmark dataset of miRNA localization, and AUC values of 87.7 and 81.1% on two benchmark sets of miRNA-disease association, respectively. Compared with the existing functional similarity measurements of miRNAs, miRGOFS has the advantages of higher accuracy and larger coverage of human miRNAs (over 1000 miRNAs). Availability and implementation: http://www.csbio.sjtu.edu.cn/bioinf/MiRGOFS/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29718116 TI - Interleukin 6 knock-out Inhibits aging-related Accumulation of p53 in the Mouse Myocardium. AB - Interleukin 6 (IL6) and p53 are linked by mutual regulatory mechanisms and are both upregulated in aging. The aim of this study was to evaluate the effects of aging and IL-6 on expression of p53 in the mouse heart. Male C57BL6/J wild-type (WT) and IL6 knock-out (IL6KO) mice at the age of 4-5 months (young adult) and 24 30 months (old) were used. Myocardial expression of proteins: p53, p21, Mdm2, and phospho-Akt/Akt was estimated using western blotting and expression of p53 and p21 mRNA using real-time-PCR. Expression of p53 protein was lower in IL6KO than in WT hearts. Aging caused significant upregulation of p53 protein level, however it was significantly higher in old WT than in old IL6KO hearts (p<0.05). Similar p53 mRNA levels in all groups implied IL6 influence on age-related proteasomal degradation of p53. Localization of p53 mainly in the extranuclear compartment and lack of p21 upregulation in aged hearts may suggest quenched transcriptional activity of p53 despite increased abundance of p53. We conclude that lack of IL6 attenuates expression of p53 protein in the hearts of young mice and diminishes its accumulation with aging by post-transcriptional mechanisms, however this is not related to altered phenotype of aging heart. PMID- 29718115 TI - Efficient flexible backbone protein-protein docking for challenging targets. AB - Motivation: Binding-induced conformational changes challenge current computational docking algorithms by exponentially increasing the conformational space to be explored. To restrict this search to relevant space, some computational docking algorithms exploit the inherent flexibility of the protein monomers to simulate conformational selection from pre-generated ensembles. As the ensemble size expands with increased flexibility, these methods struggle with efficiency and high false positive rates. Results: Here, we develop and benchmark RosettaDock 4.0, which efficiently samples large conformational ensembles of flexible proteins and docks them using a novel, six-dimensional, coarse-grained score function. A strong discriminative ability allows an eight-fold higher enrichment of near-native candidate structures in the coarse-grained phase compared to RosettaDock 3.2. It adaptively samples 100 conformations each of the ligand and the receptor backbone while increasing computational time by only 20 80%. In local docking of a benchmark set of 88 proteins of varying degrees of flexibility, the expected success rate (defined as cases with >=50% chance of achieving 3 near-native structures in the 5 top-ranked ones) for blind predictions after resampling is 77% for rigid complexes, 49% for moderately flexible complexes and 31% for highly flexible complexes. These success rates on flexible complexes are a substantial step forward from all existing methods. Additionally, for highly flexible proteins, we demonstrate that when a suitable conformer generation method exists, the method successfully docks the complex. Availability and implementation: As a part of the Rosetta software suite, RosettaDock 4.0 is available at https://www.rosettacommons.org to all non commercial users for free and to commercial users for a fee. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29718117 TI - Capturing intra-tumor genetic heterogeneity by de novo mutation profiling of circulating cell-free tumor DNA: a proof-of-principle. PMID- 29718118 TI - D3NER: biomedical named entity recognition using CRF-biLSTM improved with fine tuned embeddings of various linguistic information. AB - Motivation: Recognition of biomedical named entities in the textual literature is a highly challenging research topic with great interest, playing as the prerequisite for extracting huge amount of high-valued biomedical knowledge deposited in unstructured text and transforming them into well-structured formats. Long Short-Term Memory (LSTM) networks have recently been employed in various biomedical named entity recognition (NER) models with great success. They, however, often did not take advantages of all useful linguistic information and still have many aspects to be further improved for better performance. Results: We propose D3NER, a novel biomedical named entity recognition (NER) model using conditional random fields and bidirectional long short-term memory improved with fine-tuned embeddings of various linguistic information. D3NER is thoroughly compared with seven very recent state-of-the-art NER models, of which two are even joint models with named entity normalization (NEN), which was proven to bring performance improvements to NER. Experimental results on benchmark datasets, i.e. the BioCreative V Chemical Disease Relation (BC5 CDR), the NCBI Disease and the FSU-PRGE gene/protein corpus, demonstrate the out-performance and stability of D3NER over all compared models for chemical, gene/protein NER and over all models (without NEN jointed, as D3NER) for disease NER, in almost all cases. On the BC5 CDR corpus, D3NER achieves F1 of 93.14 and 84.68% for the chemical and disease NER, respectively; while on the NCBI Disease corpus, its F1 for the disease NER is 84.41%. Its F1 for the gene/protein NER on FSU-PRGE is 87.62%. Availability and implementation: Data and source code are available at: https://github.com/aidantee/D3NER. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29718119 TI - Frailty Quantified by the "Valencia Score" as a Potential Predictor of Lifespan in Mice. AB - The development of frailty scores suitable for mice and which resemble those used in the clinical scenario is of great importance to understand human frailty. The aim of the study was to determine an individual frailty score for each mouse at different ages and analyze the association between the frailty score and its lifespan. For this purpose, the "Valencia Score" for frailty was used. Thus, a longitudinal study in mice was performed analyzing weight loss, running time and speed, grip strength and motor coordination at the late-adult, mature and old ages (40, 56 and 80 weeks old, respectively). These parameters are equivalent to unintentional weight loss, poor endurance, slowness, weakness, and low activity level, respectively, in humans. A cut-off point was used to identify frail mice for each criterion. All the measurements were also performed on chronologically adult prematurely aging mice. The results show that by using the "Valencia Score" for frailty a prematurely aged phenotype can be identified even during the adulthood of animals. This opens up the possibility of carrying out preventive long-term interventions. Moreover, the individual frailty score of a given mouse at the late-adult, mature and old ages is shown to be a relevant predictor of its lifespan. PMID- 29718120 TI - Mapping unmet supportive care needs, quality-of-life perceptions and current symptoms in cancer survivors across the Asia-Pacific region: results from the International STEP Study. PMID- 29718121 TI - Corrigendum to: miR-30c-5p regulates macrophage-mediated inflammation and pro atherosclerosis pathways. PMID- 29718122 TI - Asymptomatic or Mild Febrile Cases of Madariaga: The Base of the Iceberg? PMID- 29718123 TI - The Effects of Graded Levels of Calorie Restriction: XIII. Global Metabolomics Screen Reveals Graded Changes in Circulating Amino Acids, Vitamins, and Bile Acids in the Plasma of C57BL/6 Mice. AB - Calorie restriction (CR) remains the most robust intervention to extend life span and improve health span. Using a global mass spectrometry-based metabolomics approach, we identified metabolites that were significantly differentially expressed in the plasma of C57BL/6 mice, fed graded levels of calorie restriction (10% CR, 20% CR, 30% CR, and 40% CR) compared with mice fed ad libitum for 12 hours a day. The differential expression of metabolites increased with the severity of CR. Pathway analysis revealed that graded CR had an impact on vitamin E and vitamin B levels, branched chain amino acids, aromatic amino acids, and fatty acid pathways. The majority of amino acids correlated positively with fat free mass and visceral fat mass, indicating a strong relationship with body composition and vitamin E metabolites correlated with stomach and colon size, which may allude to the beneficial effects of investing in gastrointestinal organs with CR. In addition, metabolites that showed a graded effect, such as the sphinganines, carnitines, and bile acids, match our previous study on liver, which suggests not only that CR remodels the metabolome in a way that promotes energy efficiency, but also that some changes are conserved across tissues. PMID- 29718124 TI - Gut Dysbiosis Associated With Hepatitis C Virus Infection. AB - Background: Little is known about the effect of hepatitis C virus (HCV) infection on gut microbiota and the relationship between alteration of gut microbiota and chronic hepatitis C (CHC) progression. We performed a comparative study of gut microbiota composition between CHC patients and healthy individuals. Methods: Fecal samples from 166 CHC patients were compared with those from 23 healthy individuals; the gut microbiota community was analyzed using 16S ribosomal RNA gene sequencing. CHC patients were diagnosed with persistently normal serum alanine aminotransferase without evidence of liver cirrhosis (LC) (PNALT, n = 18), chronic hepatitis (CH, n = 84), LC (n = 40), and hepatocellular carcinoma in LC (n = 24). Results: Compared with healthy individuals, bacterial diversity was lower in persons with HCV infection, with a decrease in the order Clostridiales and an increase in Streptococcus and Lactobacillus. Microbiota dysbiosis already appeared in the PNALT stage with the transient increase in Bacteroides and Enterobacteriaceae. Predicted metagenomics of microbial communities showed an increase in the urease gene mainly encoded by viridans streptococci during CHC progression, consistent with a significantly higher fecal pH in CH and LC patients than in healthy individuals or those in the PNALT stage. Conclusions: HCV infection is associated with gut dysbiosis, even in patients with mild liver disease. Additionally, overgrowth of viridans streptococci can account for hyperammonemia in CH and LC. Further studies would help to propose a novel treatment strategy because the gut microbiome can be therapeutically altered, potentially reducing the complications of chronic liver disease. PMID- 29718125 TI - Biodegradable coronary scaffolds: their future and clinical and technological challenges. AB - Angioplasty and stenting are standard treatment options for both stabile occlusive coronary artery disease and acute myocardial infarctions. Over the last years, several biodegradable stent systems have entered pre-clinical and clinical evaluation and into clinical practice. A strong supporting scaffold is necessary after angioplasty to prevent elastic recoil of the vessel but in the long term a permanent metallic stent will only impair normal physiology of the artery wall. Thus, the main advantage of a resorbable system is the potential for better vessel recovery and function in the long term. The new stent systems differ from traditional stents in size and biological responses and questions have risen regarding their mechanical strength and increased risk of stent thrombosis. Here, we present current treatment options with biodegradable scaffolds, discuss further key areas for improvements and review novel technological advances in the context of all up-to-date clinical trial information. New material choices are also covered as well as special considerations for pre-clinical testing. PMID- 29718126 TI - Relapse pathway of glioblastoma revealed by single-cell molecular analysis. AB - Glioblastoma multiforme (GBM) remains an incurable brain tumor. The highly malignant behavior of GBM may, in part, be attributed to its intraclonal genetic and phenotypic diversity (subclonal evolution). Identifying the molecular pathways driving GBM relapse may provide novel, actionable targets for personalized diagnosis, characterization of prognosis and improvement of precision therapy. We screened single-cell transcriptomes, namely RNA-seq data of primary and relapsed GBM tumors from a patient, to define the molecular profile of relapse. Characterization of hundreds of individual tumor cells identified three mutated genes within single cells, involved in the RAS/GEF GTP-dependent signaling pathway. The identified molecular pathway was further verified by meta analysis of RNA-seq data from more than 3000 patients. This study showed that single-cell molecular analysis overcomes the inherent heterogeneity of bulk tumors with respect to defining tumor subclonal evolution relevant to GBM relapse. PMID- 29718127 TI - Madariaga Virus: Identification of a Lineage III Strain in a Venezuelan Child With Acute Undifferentiated Febrile Illness, in the Setting of a Possible Equine Epizootic. AB - We report identification of Madariaga virus (MADV) in plasma and urine samples from a child with acute undifferentiated febrile illness in Venezuela. Our data document the occurrence of milder MADV infections (ie, without encephalitis), with a symptom complex that resembles that seen with other arboviral infections, including dengue and zika. PMID- 29718128 TI - Advanced Glycation End Products Are Associated With Physical Activity and Physical Functioning in the Older Population. AB - Background: Decline in physical activity and functioning is commonly observed in the older population and might be associated with biomarkers such as advanced glycation end products (AGEs). AGEs contribute to age-related decline in the function of cells and tissues in normal aging and have been found to be associated with motor function decline. The aim of this study is to investigate the association between the levels of AGEs, as assessed by skin autofluorescence, and the amount of physical activity and loss of physical functioning in older participants. Methods: Cross-sectional data of 5,624 participants aged 65 years and older from the LifeLines Cohort Study were used. Linear regression analyses were utilized to study the associations between skin autofluorescence/AGE levels (AGE Reader), the number of physically active days (SQUASH), and physical functioning (RAND-36). A logistic regression analysis was used to study the associations between AGE levels and the compliance with the Dutch physical activity guidelines (SQUASH). Results: A statistical significant association between AGE levels and the number of physically active days (beta = -0.21, 95% confidence interval: -0.35 to -0.07, p = .004), physical functioning (beta = 1.60, 95% confidence interval: -2.64 to -0.54, p = .003), and compliance with the Dutch physical activity guidelines (odds ratio = 0.76, 95% confidence interval: 0.62 to 0.94, p = .010) was revealed. Conclusions: This study indicates that high AGE levels may be a contributing factor as well as a biomarker for lower levels of physical activity and functioning in the older population. PMID- 29718129 TI - Giardia/Cryptosporidium QUIK CHEK Assay Is More Specific Than Quantitative Polymerase Chain Reaction for Rapid Point-of-care Diagnosis of Cryptosporidiosis in Infants in Bangladesh. AB - Background: Cryptosporidium is a major cause of childhood diarrhea. Current modes of cryptosporidiosis diagnosis involve procedures that are costly and require both a well-equipped laboratory and technical expertise. Therefore, a cost effective, user-friendly, and rapid method for point-of-care detection of Cryptosporidium is desirable. Methods: A total of 832 diarrheal stool specimens collected from 200 children aged <2 years were tested by Giardia/Cryptosporidium QUIK CHEK, enzyme-linked immunosorbent assay (ELISA), and quantitative polymerase chain reaction (qPCR) to compare the performance of the individual techniques. We also tested for the presence of other diarrheal pathogens in qPCR-positive samples with a TaqMan Array Card (TAC) to assess whether Cryptosporidium was the sole causative agent for the diarrheal episodes. Results: Of 832 samples, 4.4% were found positive for Cryptosporidium by QUIK CHEK, 3.6% by ELISA, and 8.8% by qPCR. Using TAC-attributed Cryptosporidium diarrhea as the gold standard, the sensitivities of QUIK CHEK, ELISA, and qPCR were 92.3%, 71.8%, and 100%, respectively; the specificities were 97.1%, 94.3%, and 0%, respectively. Analysis of the qPCR-positive and QUIK CHEK-negative samples by TAC identified other enteropathogens as more likely than Cryptosporidium to be the causative agents of diarrhea. Conclusions: QUIK CHEK was more sensitive and specific than ELISA. While qPCR detected Cryptosporidium in more samples than QUIK CHEK, most of these were instances of qPCR detecting small quantities of Cryptosporidium DNA in a diarrheal episode caused by another enteropathogen. We concluded that QUIK CHEK was comparable in sensitivity and superior in specificity to qPCR for the diagnosis of Cryptosporidium diarrhea. PMID- 29718130 TI - AbDb: antibody structure database-a database of PDB-derived antibody structures. AB - Database URL: www.bioinf.org.uk/abs/abdb/. PMID- 29718132 TI - ImagePy: an open-source, Python-based and platform-independent software package for bioimage analysis. AB - Summary: This note presents the design of a scalable software package named ImagePy for analysing biological images. Our contribution is concentrated on facilitating extensibility and interoperability of the software through decoupling the data model from the user interface. Especially with assistance from the Python ecosystem, this software framework makes modern computer algorithms easier to be applied in bioimage analysis. Availability and implementation: ImagePy is free and open source software, with documentation and code available at https://github.com/Image-Py/imagepy under the BSD license. It has been tested on the Windows, Mac and Linux operating systems. PMID- 29718131 TI - Retraining speech production and fluency in non-fluent/agrammatic primary progressive aphasia. AB - The non-fluent/agrammatic variant of primary progressive aphasia (nfvPPA) presents with a gradual decline in grammar and motor speech resulting from selective degeneration of speech-language regions in the brain. There has been considerable progress in identifying treatment approaches to remediate language deficits in other primary progressive aphasia variants; however, interventions for the core deficits in nfvPPA have yet to be systematically investigated. Further, the neural mechanisms that support behavioural restitution in the context of neurodegeneration are not well understood. We examined the immediate and long-term benefits of video implemented script training for aphasia (VISTA) in 10 individuals with nfvPPA. The treatment approach involved repeated rehearsal of individualized scripts via structured treatment with a clinician as well as intensive home practice with an audiovisual model using 'speech entrainment'. We evaluated accuracy of script production as well as overall intelligibility and grammaticality for trained and untrained scripts. These measures and standardized test scores were collected at post-treatment and 3-, 6-, and 12-month follow-up visits. Treatment resulted in significant improvement in production of correct, intelligible scripted words for trained topics, a reduction in grammatical errors for trained topics, and an overall increase in intelligibility for trained as well as untrained topics at post-treatment. Follow-up testing revealed maintenance of gains for trained scripts up to 1 year post-treatment on the primary outcome measure. Performance on untrained scripts and standardized tests remained relatively stable during the follow-up period, indicating that treatment helped to stabilize speech and language despite disease progression. To identify neural predictors of responsiveness to intervention, we examined treatment effect sizes relative to grey matter volumes in regions of interest derived from a previously identified speech production network. Regions of significant atrophy within this network included bilateral inferior frontal cortices and supplementary motor area as well as left striatum. Volumes in a left middle/inferior temporal region of interest were significantly correlated with the magnitude of treatment effects. This region, which was relatively spared anatomically in nfvPPA patients, has been implicated in syntactic production as well as visuo-motor facilitation of speech. This is the first group study to document the benefits of behavioural intervention that targets both linguistic and motoric deficits in nfvPPA. Findings indicate that behavioural intervention may result in lasting and generalized improvement of communicative function in individuals with neurodegenerative disease and that the integrity of spared regions within the speech-language network may be an important predictor of treatment response. PMID- 29718133 TI - Patterns and Perceived Benefits of Utilizing Seven Major Complementary Health Approaches in U.S. Older Adults. AB - Objectives: To examine patterns and perceived benefits of seven major complementary health approaches (CHA) among older adults in the United States. Methods: Data from the 2012 National Health Interview Survey (NHIS), which represents non-institutionalized adults aged 65 or older (n = 7,116 unweighted), were used. We elicited seven most common CHA used in older adults, which are acupuncture, herbal therapies, chiropractic, massage, meditation, Tai Chi, and yoga. Survey participants were asked to self-report perceived benefits (eg, maintaining health and stress reduction) in their CHA used. We estimated prevalence and perceived benefits of CHA use. We also investigated socio demographic and clinical factors associated with the use of any of these seven CHA. Results: Overall, 29.2% of older adults used any of seven CHA in the past year. Most commonly used CHA included herbal therapies (18.1%), chiropractic (8.4%), and massage (5.7%). More than 60% of older CHA users reported that CHA were important for maintaining health and well-being. Other perceived benefits included improving overall health and feeling better (52.3%), giving a better sense of control over health (27.4%), and making it easier to cope with health problems (24.7%). Older adults with higher education and income levels, >=2 chronic conditions, and functional limitations had greater odds of using CHA (p < .01, respectively). Conclusion: A substantial number of older CHA users reported CHA-related benefits. CHA may play a crucial role in improving health status among older adults. At the population level, further research on the effects of CHA use on bio-psycho-social outcomes is needed to promote healthy aging in older adults. PMID- 29718134 TI - The Gut-Liver Axis in Hepatitis C Virus Infection: A Path Towards Altering the Natural History of Fibrosis Progression? PMID- 29718135 TI - The era of cardiovascular epigenetics: histone deacetylases and vascular inflammation. PMID- 29718136 TI - Molecular Insights to Withaferin-A induced Senescence: Bioinformatics and Experimental Evidence to the Role of NF-kappa B and CARF. AB - Withaferin-A (Wi-A) has been shown to possess anticancer activity. Molecular mechanism(s) of its action have not been fully resolved. We recruited low dose of Wi-A that caused slow growth arrest in cancer cells, and was relatively safe for normal cells. Consistently, we detected nuclear translocation of NFkappaB and activation of p38MAPK selectively in cancer cells. Bioinformatics analyses revealed that Wi-A did not disrupt IKK/IKKbeta-Nemo complex that regulates NFkappaB activity. However, it caused moderate change in the conformation of IKKbeta-Nemo interacting domain. Experimental data revealed increased level of phosphorylated IkappaBalpha in Wi-A treated cells, suggesting an activation of IKK complex that was supported by nuclear translocation of NFkappaB. Molecular docking analysis showed that Wi-A did not disrupt, however decreased the stability of the NFkappaB-DNA complex. It was supported by downregulation of DNA binding and transcriptional activities of NFkappaB. Further analysis revealed that Wi-A caused upregulation of CARF (Collaborator of ARF) demonstrating an activation of DNA damage oxidative stress response in both cancer and normal cells. In line with this, upregulation of p21WAF1, p16INK4A, hypophoshorylated pRB and induction of senescence was observed demonstrating that Wi-A-induced senescence is mediated by multiple pathways in which CARF-mediated DNA damage and oxidative stress play a major role. PMID- 29718137 TI - Anthracycline cardiotoxicity: looking for new therapeutic approaches targeting cell senescence? PMID- 29718138 TI - Disparities and Determinants of Cancer Treatment in Elderly Americans Living With Human Immunodeficiency Virus/AIDS. AB - Background: Previous studies suggest that human immunodeficiency virus (HIV) infected cancer patients are less likely to receive cancer treatment. The extent to which this disparity affects the growing population of elderly individuals is unknown and factors that mediate these treatment differences have not been explored. Methods: We studied 930359 Americans aged 66-99 years who were diagnosed with 10 common cancers. Surveillance, Epidemiology, and End Results Medicare claims from 1991 to 2011 were used to determine HIV status and receipt of cancer treatment in 6 months following diagnosis. Mediation analysis was conducted to estimate the direct effect of HIV, and indirect effect through cancer stage at diagnosis and comorbidities, on cancer treatment. Results: HIV infected individuals (n = 687) were less likely to receive cancer treatment (70% vs 75% HIV uninfected; P < .01). This difference was larger in individuals aged 66-70 years, among whom only 65% were treated (vs 81% in HIV uninfected; P < .01), and time from cancer diagnosis to treatment was longer (median, 42.5 vs 36 days in HIV uninfected; P < .01). Accounting for potential confounders, HIV infected individuals aged 66-70 years remained 20% less likely to receive cancer treatment (hazard ratio, 0.81 [95% confidence interval, .71-.92]). Seventy-five percent of this total effect was due to HIV itself, with a nonsignificant 24% mediated by cancer stage and comorbidities. Conclusions: Lowest cancer treatment rates were seen in the younger subset of HIV-infected individuals, who would likely benefit most from treatment in terms of life expectancy. PMID- 29718139 TI - Ion channels in EEG: isolating channel dysfunction in NMDA receptor antibody encephalitis. AB - See Roberts and Breakspear (doi:10.1093/brain/awy136) for a scientific commentary on this article.Neurological and psychiatric practice frequently lack diagnostic probes that can assess mechanisms of neuronal communication non-invasively in humans. In N-methyl-d-aspartate (NMDA) receptor antibody encephalitis, functional molecular assays are particularly important given the presence of NMDA antibodies in healthy populations, the multifarious symptomology and the lack of radiological signs. Recent advances in biophysical modelling techniques suggest that inferring cellular-level properties of neural circuits from macroscopic measures of brain activity is possible. Here, we estimated receptor function from EEG in patients with NMDA receptor antibody encephalitis (n = 29) as well as from encephalopathic and neurological patient controls (n = 36). We show that the autoimmune patients exhibit distinct fronto-parietal network changes from which ion channel estimates can be obtained using a microcircuit model. Specifically, a dynamic causal model of EEG data applied to spontaneous brain responses identifies a selective deficit in signalling at NMDA receptors in patients with NMDA receptor antibody encephalitis but not at other ionotropic receptors. Moreover, though these changes are observed across brain regions, these effects predominate at the NMDA receptors of excitatory neurons rather than at inhibitory interneurons. Given that EEG is a ubiquitously available clinical method, our findings suggest a unique re-purposing of EEG data as an assay of brain network dysfunction at the molecular level. PMID- 29718140 TI - Characterization of Poly(MAA-co-EDMA) Monolithic Column for High Performance Liquid Chromatography: Scanning Electron Microscopy, Thermodynamic Parameters and Linear Solvation Energy Relationship Methodology. AB - A poly(Methacrylate-co-Ethyleneglycol dimethacrylate) monolithic column was prepared in situ for high performance liquid chromatography and characterized utilizing scanning electron microscopy, thermodynamic parameters and linear solvation energy relationship methodology. The results revealed that there were many microglobules forming the larger cluster in poly(Methacrylate-co Ethyleneglycol dimethacrylate) monolith prepared under the selected preparation conditions, which composed continuously aligned macroporous channels through the monolith skeleton. The poly(Methacrylate-co-Ethyleneglycol dimethacrylate) monolithic column had a good permeability, a high mechanical stability. The interaction model for each probe molecule on the poly(Methacrylate-co Ethyleneglycol dimethacrylate) monolithic column was invariable within the studied temperature range due to an excellent linear relationship between lnk and 1/T for each probe molecule. The chromatographic retention for each probe molecule on the poly(Methacrylate-co-Ethyleneglycol dimethacrylate) monolithic column was an enthalpy-driven process due to |?H degrees | > |T?S degrees | and ?G degrees <0. The main interaction forces of the poly(Methacrylate-co Ethyleneglycol dimethacrylate) monolith with probe molecules contain hydrogen bonding interaction, hydrophobic interaction and dipole-dipole interaction. However, the contribution of each interaction was in the order of hydrogen bonding acidity > hydrophobic interactions > dipole-dipole interaction > hydrogen bonding basicity. In addition, the poly(Methacrylate-co-Ethyleneglycol dimethacrylate)monolithic column is suitable for the separation of both nonpolar and polar compounds. PMID- 29718142 TI - hts-nim: scripting high-performance genomic analyses. AB - Motivation: Extracting biological insight from genomic data inevitably requires custom software. In many cases, this is accomplished with scripting languages, owing to their accessibility and brevity. Unfortunately, the ease of scripting languages typically comes at a substantial performance cost that is especially acute with the scale of modern genomics datasets. Results: We present hts-nim, a high-performance library written in the Nim programming language that provides a simple, scripting-like syntax without sacrificing performance. Availability and implementation: hts-nim is available at https://github.com/brentp/hts-nim and the example tools are at https://github.com/brentp/hts-nim-tools both under the MIT license. PMID- 29718141 TI - PVCbase: an integrated web resource for the PVC bacterial proteomes. AB - Interest in the Planctomycetes-Verrucomicrobia-Chlamydiae (PVC) bacterial superphylum is growing within the microbiology community. These organisms do not have a specialized web resource that gathers in silico predictions in an integrated fashion. Hence, we are providing the PVC community with PVCbase, a specialized web resource that gathers in silico predictions in an integrated fashion. PVCbase integrates protein function annotations obtained through sequence analysis and tertiary structure prediction for 39 representative PVC proteomes (PVCdb), a protein feature visualizer (Foundation) and a custom BLAST webserver (PVCBlast) that allows to retrieve the annotation of a hit directly from the DataTables. We display results from various predictors, encompassing most functional aspects, allowing users to have a more comprehensive overview of protein identities. Additionally, we illustrate how the application of PVCdb can be used to address biological questions from raw data. PVCbase is freely accessible at: www.pvcbacteria.org/pvcbase. PMID- 29718143 TI - The Association Between Empirical Antibiotic Treatment and Mortality in Severe Infections Caused by Carbapenem-resistant Gram-negative Bacteria: A Prospective Study. AB - Background: Empirical colistin should be avoided. We aimed to evaluate the association between covering empirical antibiotics (EAT) and mortality for infections caused by carbapenem-resistant gram-negative bacteria (CRGNB). Methods: This was a secondary analysis of a randomized controlled trial, including adults with bloodstream infections, pneumonia, or urosepsis caused by CRGNB. All patients received EAT followed by covering targeted therapy. The exposure variable was covering EAT in the first 48 hours. The outcome was 28-day mortality. We adjusted the analyses by multivariable regression analysis and propensity score matching. Results: The study included 406 inpatients with severe CRGNB infections, mostly Acinetobacter baumannii (312/406 [77%]). Covering EAT was given to 209 (51.5%) patients, mostly colistin (n = 200). Patients receiving noncovering EAT were older, more frequently unconscious and dependent, carrying catheters, and mechanically ventilated with pneumonia. Mortality was 84 of 197 (42.6%) with noncovering vs 96 of 209 (45.9%) with covering EAT (P = .504). Covering EAT was not associated with survival in the adjusted analysis; rather, there was a weak association with mortality (odds ratio [OR], 1.37; 95% confidence interval [CI], 1.02-1.84). Results were similar for colistin monotherapy and colistin-carbapenem combination EAT. In the propensity score matched cohort (n = 338) covering antibiotics were not significantly associated with mortality (OR, 1.42; 95% CI, .91-2.22). Similar results were obtained in an analysis of 14-day mortality. Conclusions: Empirical use of colistin before pathogen identification, with or without a carbapenem, was not associated with survival following severe infections caused by CRGNBs, mainly A. baumannii. PMID- 29718145 TI - Corrigendum to: 'Impact of thoracic endovascular aortic repair on radial strain in an ex vivo porcine model' [Eur J Cardiothorac Surg 2017;51(4):783--789]. PMID- 29718144 TI - Genomic Surveillance Reveals Diversity of Multidrug-Resistant Organism Colonization and Infection: A Prospective Cohort Study in Liver Transplant Recipients. AB - Background: Multidrug-resistant organisms (MDROs) are an important cause of morbidity and mortality after solid organ transplantation. We aimed to characterize MDRO colonization dynamics and infection in liver transplant (LT) recipients through innovative use of active surveillance and whole-genome sequencing (WGS). Methods: We prospectively enrolled consecutive adult patients undergoing LT from March 2014 to March 2016. Fecal samples were collected at multiple timepoints from time of enrollment to 12 months posttransplant. Samples were screened for carbapenem-resistant Enterobacteriaceae (CRE), Enterobacteriaceae resistant to third-generation cephalosporins (Ceph-RE), and vancomycin-resistant enterococci. We performed WGS of CRE and selected Ceph-RE isolates. We also collected clinical data including demographics, transplant characteristics, and infection data. Results: We collected 998 stool samples and 119 rectal swabs from 128 patients. MDRO colonization was detected in 86 (67%) patients at least once and was significantly associated with subsequent MDRO infection (0 vs 19.8%, P = .002). Child-Turcotte-Pugh score at LT and duration of post-LT hospitalization were independent predictors of both MDRO colonization and infection. Temporal dynamics differed between MDROs with respect to onset of colonization, clearance, and infections. We detected an unexpected diversity of CRE colonizing isolates and previously unrecognized transmission that spanned Ceph-RE and CRE phenotypes, as well as a cluster of mcr-1-producing isolates. Conclusions: Active surveillance and WGS showed that MDRO colonization is a highly dynamic and complex process after LT. Understanding that complexity is crucial for informing decisions regarding MDRO infection control, use of therapeutic decolonization, and empiric treatment regimens. PMID- 29718146 TI - Echocardiographic-fluoroscopic fusion imaging for transcatheter mitral valve repair guidance. AB - The echocardiographic-fluoroscopic fusion imaging is a new imaging system which has recently become available, with the proposal to facilitate catheters and device navigation during catheter-based structural heart disease interventions. Several reports have described the early developments and the first clinical experiences, but literature focusing on the practical applications of fusion imaging technology to mitral valve transcatheter interventions, and on its potential advantages and current limitations, is still limited. In this review, we, therefore, describe the role of this novel imaging system during Mitraclip, Cardioband, and paravalvular leak closure interventions. The technical principles and the fluoroscopic anatomy of the interatrial septum and mitral valve are also described. PMID- 29718147 TI - Evaluating the severity of aortic stenosis: a re-look at our current 'gold standard' measurements. PMID- 29718148 TI - Transcatheter aortic valve implantation: current status and future perspectives. AB - In the 16 years since the first pioneering procedure, transcatheter aortic valve implantation (TAVI) has come of age and become a routine strategy for aortic valve replacement, increasingly performed under conscious sedation via transfemoral access. Simplification of the procedure, accumulation of clinical experience, and improvements in valve design and delivery systems have led to a dramatic reduction in complication rates. These advances have allowed transition to lower risk populations, and outcome data from the PARTNER 2A and SURTAVI trials have established a clear evidence base for use in intermediate risk patients. Ongoing studies with an expanding portfolio of devices seem destined to expand indications for TAVI towards lower risk, younger and asymptomatic populations. In this article, we outline recent advances, new devices and current guidelines informing the use of TAVI, and describe remaining uncertainties that need to be addressed. PMID- 29718149 TI - A common co-morbidity modulates disease expression and treatment efficacy in inherited cardiac sodium channelopathy. AB - Aims: Management of patients with inherited cardiac ion channelopathy is hindered by variability in disease severity and sudden cardiac death (SCD) risk. Here, we investigated the modulatory role of hypertrophy on arrhythmia and SCD risk in sodium channelopathy. Methods and results: Follow-up data was collected from 164 individuals positive for the SCN5A-1795insD founder mutation and 247 mutation negative relatives. A total of 38 (obligate) mutation-positive patients died suddenly or suffered life-threatening ventricular arrhythmia. Of these, 18 were aged >40 years, a high proportion of which had a clinical diagnosis of hypertension and/or cardiac hypertrophy. While pacemaker implantation was highly protective in preventing bradycardia-related SCD in young mutation-positive patients, seven of them aged >40 experienced life-threatening arrhythmic events despite pacemaker treatment. Of these, six had a diagnosis of hypertension/hypertrophy, pointing to a modulatory role of this co-morbidity. Induction of hypertrophy in adult mice carrying the homologous mutation (Scn5a1798insD/+) caused SCD and excessive conduction disturbances, confirming a modulatory effect of hypertrophy in the setting of the mutation. The deleterious effects of the interaction between hypertrophy and the mutation were prevented by genetically impairing the pro-hypertrophic response and by pharmacological inhibition of the enhanced late sodium current associated with the mutation. Conclusion: This study provides the first evidence for a modulatory effect of co existing cardiac hypertrophy on arrhythmia risk and treatment efficacy in inherited sodium channelopathy. Our findings emphasize the need for continued assessment and rigorous treatment of this co-morbidity in SCN5A mutation-positive individuals. PMID- 29718150 TI - Photothermal treatment with EGFRmAb-AuNPs induces apoptosis in hypopharyngeal carcinoma cells via PI3K/AKT/mTOR and DNA damage response pathways. AB - Hypopharyngeal carcinoma (HC) is one of the most malignant tumors in the upper aerodigestive tract. Currently, there are no effective treatments for HC. Gold nanoparticles (AuNPs) are a promising tool that can be used for plasmonic photothermal therapy (PPTT), which refers to the use of electromagnetic radiation, most often in near infrared (NIR) region, for the treatment of various medical conditions including cancer. AuNPs have been proved to be a promising tool for NIR spectroscopy-mediated photothermal therapies. In this study, we chemically conjugated AuNPs with a monoclonal antibody (mAb) targeting the epidermal growth factor receptor (EGFR), a cell-surface receptor that is overexpressed in many cancers. We then assessed the effect of NIR photothermal treatment with the EGFRmAb-AuNPs in FaDu HC cells. Our data showed that nanoparticle conjugation with the EGFRmAb improved the specific targeting towards FaDu cells and reduced cytotoxicity towards normal (293 T) cells which do not overexpress the EGFR. A significant amount of our EGFRmAb-conjugated AuNPs could enter the nucleus. Moreover, the expression levels of double strand DNA break repair proteins, including p-ATR, p-CHK1, and p-CHK2 were increased following AuNPs treatment, indicating the presence of DNA damage. These findings suggest that the AuNPs can potentially disrupt genome integrity and induce apoptosis. In addition, EGFRmAb-AuNPs+NIR could induce FaDu cell apoptosis, accompanied by the inhibition of the PI3K/AKT/mTOR pathway and stimulation of DNA damage response. Based on these data, PPTT using the EGFRmAb-AuNPs could be a new promising treatment for HC. PMID- 29718152 TI - Confounding is not the only bias influencing associations of adiposity with cardiovascular disease. PMID- 29718153 TI - Corrigendum: Comparing and Combining Topiramate and Aripiprazole on Alcohol Related Outcomes in a Human Laboratory Study. PMID- 29718151 TI - The impact of confounding on the associations of different adiposity measures with the incidence of cardiovascular disease: a cohort study of 296 535 adults of white European descent. AB - Aims: The data regarding the associations of body mass index (BMI) with cardiovascular (CVD) risk, especially for those at the low categories of BMI, are conflicting. The aim of our study was to examine the associations of body composition (assessed by five different measures) with incident CVD outcomes in healthy individuals. Methods and results: A total of 296 535 participants (57.8% women) of white European descent without CVD at baseline from the UK biobank were included. Exposures were five different measures of adiposity. Fatal and non fatal CVD events were the primary outcome. Low BMI (<=18.5 kg m-2) was associated with higher incidence of CVD and the lowest CVD risk was exhibited at BMI of 22 23 kg m-2 beyond, which the risk of CVD increased. This J-shaped association attenuated substantially in subgroup analyses, when we excluded participants with comorbidities. In contrast, the associations for the remaining adiposity measures were more linear; 1 SD increase in waist circumference was associated with a hazard ratio of 1.16 [95% confidence interval (CI) 1.13-1.19] for women and 1.10 (95% CI 1.08-1.13) for men with similar magnitude of associations for 1 SD increase in waist-to-hip ratio, waist-to-height ratio, and percentage body fat mass. Conclusion: Increasing adiposity has a detrimental association with CVD health in middle-aged men and women. The association of BMI with CVD appears more susceptible to confounding due to pre-existing comorbidities when compared with other adiposity measures. Any public misconception of a potential 'protective' effect of fat on CVD risk should be challenged. Take home figureThe obesity paradox is mainly due to the effect of confounding on BMI and disappears on other adiposity measures. PMID- 29718154 TI - Early extubation is associated with improved early outcome after extracardiac total cavopulmonary connection independently of duration of cardiopulmonary bypass. AB - OBJECTIVES: Strict patient selection, short cardiopulmonary bypass (CPB) time and short mechanical ventilation are well-recognized aspects of optimizing the postoperative course after total cavopulmonary connection. In this study, we evaluated the influence of our early postoperative extubation strategy in our population of Fontan patients over the past 2 decades. METHODS: Early postoperative course was evaluated retrospectively in 211 consecutive patients, who were selected for total cavopulmonary connection in our institution between 1995 and 2015. We analysed postoperative haemodynamic parameters and early outcome after surgery (mortality and length of hospital stay) according to preoperative patient characteristics, duration of CPB and duration of mechanical ventilation. To investigate the influence of mechanical ventilation, the cohort was subdivided into a 'fast-track' extubation group (<=6 h ventilation, n = 59) and a prolonged ventilation group (>6 h ventilation, n = 152). RESULTS: In the entire cohort, duration of CPB did not correlate with duration of mechanical ventilation (P = 0.1), and it did not differ between both groups (P = 0.3). Patients in the fast-track group showed significantly better haemodynamics with higher mean arterial pressure and lower mean pulmonary artery pressure at 6, 24 and 48 h postoperatively when compared with the prolonged ventilation group (P = 0.02-0.001). In multivariable analysis, longer mechanical ventilation, but not duration of CPB, was independently associated with length of hospital stay. CONCLUSIONS: Early weaning from mechanical ventilation correlates with improved early Fontan haemodynamics, whereas early outcome is unrelated to duration of CPB. This indicates that early extubation may represent a principal strategy for improving early results after total cavopulmonary connection. PMID- 29718156 TI - The right time-dependent statistics: this is the moment. PMID- 29718155 TI - Robotic resection of Stage III lung cancer: an international retrospective study. AB - OBJECTIVES: Minimally invasive surgery is accepted for early-stage lung cancer, but its role in locally advanced disease is controversial, especially using a robotic platform. The aim of this retrospective study was to assess the safety and effectiveness of robot-assisted resection in patients with Stage IIIA non small-cell lung cancer (NSCLC) or carcinoid tumours in the series as a whole and in different subgroups according to adjuvant treatment. METHODS: This was a retrospective multicentre study of consecutive patients with clinically evident or occult N2 disease (210 NSCLC and 13 carcinoid) who, in 2007-2016, underwent robot-assisted resection at 7 high-volume centres. Perioperative outcomes, recurrences and overall survival were assessed. RESULTS: N2 disease was diagnosed preoperatively in 72 (32%) patients and intraoperatively in 151 (68%) patients. Surgical margins were negative in 98.4% of cases with available data. Thirty-four (15.2%) patients received neoadjuvant treatment, 140 (63%) patients received postoperative treatment, and 49 (22%) patients underwent surgery only. There were 22 (9.9%) conversions to thoracotomy, 23 (10.3%) had serious (Grades III-IV) postoperative morbidity and the mean hospital stay was 5.3 days. Complications and outcomes did not differ significantly between treatment groups. Of the 34 patients who were given neoadjuvant chemotherapy, all had R0 resection, 5 (15%) patients required conversion but none required conversion because of bleeding and 4 (12%) patients had Grade III or IV postoperative complications. After a median of 18 (interquartile range 8-33) months, 3-year overall survival in NSCLC patients was 61.2% and 60.3% (P = 0.6) of patients in the subgroup were given induction treatment. However, overall survival was significantly better (P = 0.012) in NSCLC patients with <=2 positive nodes (vs >2). Nineteen (8.5%) patients developed local recurrence. CONCLUSIONS: Robot-assisted lobectomy is safe and effective in patients with Stage III NSCLC or carcinoid tumours with low conversions and complications. Among patients with NSCLC, including those who were given induction chemotherapy, survival was similar to that reported for open surgery. PMID- 29718157 TI - Fatty acids are the best fuel for overloaded hearts. PMID- 29718158 TI - Management of left main disease: an update. AB - A severe narrowing of the left main coronary artery (LMCA), usually due to atherosclerosis, jeopardizes a large area of myocardium and increases the risk of major adverse cardiac events. Management strategies for LMCA disease include coronary artery bypass grafting (CABG) and percutaneous coronary intervention (PCI). In general, PCI offers more rapid recovery and a lower early adverse event rate, whereas CABG offers a more durable procedure. The largest of six LMCA trials comparing PCI with CABG recently reported that in patients with site reported low or intermediate anatomical complexity PCI was non-inferior to CABG with respect to the composite of death, stroke, or myocardial infarction at 3 years. This result was obtained on a background of contemporary PCI standards, including safer and more effective stents, intravascular imaging and physiology assessment. This review updates on the current management of LMCA disease, with an emphasis on clinical data and procedural knowledge supporting the use of PCI in a growing proportion of patients. PMID- 29718159 TI - Mitral regurgitation: anatomy is destiny. AB - Mitral regurgitation (MR) occurs when any of the valve and ventricular mitral apparatus components are disturbed. As MR progresses, left ventricular remodelling occurs, ultimately causing heart failure when the enlarging left ventricle (LV) loses its conical shape and becomes globular. Heart failure and lethal ventricular arrhythmias may develop if the left ventricular end-systolic volume index exceeds 55 ml/m2. These adverse changes persist despite satisfactory correction of the annular component of MR. Our goal was to describe this process and summarize evolving interventions that reduce the volume of the left ventricle and rebuild its elliptical shape. This 'valve/ventricle' approach addresses the spherical ventricular culprit and offsets the limits of treating MR by correcting only its annular component. PMID- 29718160 TI - Safety and feasibility of robotic-assisted Ivor-Lewis esophagectomy. AB - Esophagectomy is associated with substantial morbidity. Robotic surgery allows complex resections to be performed with potential benefits over conventional techniques. We applied this technology to transthoracic esophagectomy to assess safety, feasibility, and reliability of this technology. A retrospective cohort study of all patients undergoing robotic-assisted Ivor-Lewis esophagectomy (RAIL) from 2009 to 2014 was conducted. Clinicopathologic factors and surgical outcomes were recorded and compared. All statistical tests were two-sided and a P-value of <0.05 was considered statistically significant. We identified 147 patients with an average age 66 +/- 10 years. Neoadjuvant therapy was administered to 114 (77.6%) patients, and all patients underwent a R0 resection. The mean operating room (OR) time was 415 +/- 84.6 minutes with a median estimated blood loss (EBL) of 150 (25-600) mL. Mean intensive care unit (ICU) stay was 2.00 +/- 4.5 days, median length of hospitalization (LOH) was 9 (4-38) days, and readmissions within 90 days were low at 8 (5.5%). OR time decreased from 471 minutes to 389 minutes after 20 cases and a further decrease to mean of 346 minutes was observed after 120 cases. Complications occurred in 37 patients (25.2%). There were 4 anastomotic (2.7%) leaks. Thirty and 90-day mortality was 0.68% and 1.4%, respectively. This represents to our knowledge the largest series of robotic esophagectomies. RAIL is a safe surgical technique that provides an alternative to standard minimally invasive and open techniques. In our series, there was no increased risk of LOH, complications, or death and re-admission rates were low despite earlier discharge. PMID- 29718161 TI - Outcome of long benign esophageal strictures undergoing endoscopictherapy: a tertiary center experience. AB - Complex benign esophageal strictures are defined by length (>=2 cm), small diameter, and stricture angulation or tortuosity. The long-term course of complex esophageal strictures based on length is currently unclear. We suspect that the esophageal stricture length might impact the effectiveness of endoscopic dilation therapy. We performed a retrospective study of all benign esophageal strictures of 2 cm or longer treated at a single center between July 1, 2010, and May 31, 2014. Primary outcomes were changed in dysphagia score at the end of follow-up compared to first dilation at our facility and the need for gastrostomy placement or esophagectomy during follow-up. Data were stratified into four subgroups according to stricture length 20-29, 30-49, 50-99, and 100 mm or longer. Eighty seven patients (mean age 66 years, 54% women) were followed over a median of 40 months. Patients underwent a median of 6 dilations, averaging 0.3 dilations per month. Median dysphagia score remained unchanged at 2; 37 (43%) patients reported resolution or improved dysphagia and 50 (57%) patients reported no improvement or worsened dysphagia. Gastrostomy placement or esophagectomy was needed for 23 (26%) and 3 (3%) patients, respectively. Median degree of dysphagia at the end of follow-up did not differ between the four stricture length subgroups, yet no patient had improvement in the 100 mm or longer subgroup. More than half of patients with long benign esophageal strictures had unchanged dysphagia or developed worse dysphagia during follow-up. Long-term outcomes did not differ between different stricture lengths: . PMID- 29718162 TI - lncFunTK: a toolkit for functional annotation of long noncoding RNAs. AB - Motivation: Thousands of long noncoding RNAs (lncRNAs) were newly identified from high throughput RNA-seq data. Functional annotation and prioritization of these lncRNAs for further experimental validation as well as the functional investigation is the bottleneck step for many noncoding RNA studies. Results: Here we describe lncFunTK that can run either as standard application or webserver for this purpose. It integrates high throughput sequencing data (i.e. ChIP-seq, CLIP-seq and RNA-seq) to construct the regulatory network associated with lncRNAs. Through the network, it calculates the Functional Information Score (FIS) of each individual lncRNA for prioritizing and inferring its functions through Gene Ontology (GO) terms of neighboring genes. In addition, it also provides utility scripts to support the input data preprocessing and the parameter optimizing. We further demonstrate that lncFunTK can be widely used in various biological systems for lncRNA prioritization and functional annotation. Availability and implementation: The lncFunTK standalone version is an open source package and freely available at http://sunlab.cpy.cuhk.edu.hk/lncfuntk under the MIT license. A webserver implementation is also available at http://sunlab.cpy.cuhk.edu.hk/lncfuntk/runlncfuntk.html. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29718163 TI - Profiling of 3696 Nuclear Receptor-Coregulator Interactions: A Resource for Biological and Clinical Discovery. AB - Nuclear receptors (NRs) are ligand-inducible transcription factors that play critical roles in metazoan development, reproduction, and physiology and therefore are implicated in a broad range of pathologies. The transcriptional activity of NRs critically depends on their interaction(s) with transcriptional coregulator proteins, including coactivators and corepressors. Short leucine-rich peptide motifs in these proteins (LxxLL in coactivators and LxxxIxxxL in corepressors) are essential and sufficient for NR binding. With 350 different coregulator proteins identified to date and with many coregulators containing multiple interaction motifs, an enormous combinatorial potential is present for selective NR-mediated gene regulation. However, NR-coregulator interactions have often been determined experimentally on a one-to-one basis across diverse experimental conditions. In addition, NR-coregulator interactions are difficult to predict because the molecular determinants that govern specificity are not well established. Therefore, many biologically and clinically relevant NR coregulator interactions may remain to be discovered. Here, we present a comprehensive overview of 3696 NR-coregulator interactions by systematically characterizing the binding of 24 nuclear receptors with 154 coregulator peptides. We identified unique ligand-dependent NR-coregulator interaction profiles for each NR, confirming many well-established NR-coregulator interactions. Hierarchical clustering based on the NR-coregulator interaction profiles largely recapitulates the classification of NR subfamilies based on the primary amino acid sequences of the ligand-binding domains, indicating that amino acid sequence is an important, although not the only, molecular determinant in directing and fine-tuning NR-coregulator interactions. This NR-coregulator peptide interactome provides an open data resource for future biological and clinical discovery as well as NR-based drug design. PMID- 29718164 TI - Aortic valve repair techniques: state of the art. PMID- 29718166 TI - "Peering" Into Our Endocrinology Future. PMID- 29718165 TI - Bisphenol A and Phthalates Modulate Peritoneal Macrophage Function in Female Mice Involving SYMD2-H3K36 Dimethylation. AB - Ample evidence suggests that environmental and occupational exposure to bisphenol A (BPA) and phthalate, two chemicals widely used in the plastics industry, disturbs homeostasis of innate immunity and causes inflammatory diseases. However, the underlying molecular mechanisms of these toxicants in the regulation of macrophage inflammatory functions remain poorly understood. In this study, we addressed the effect of chronic exposure to BPA or phthalate at levels relevant to human exposure, either in vitro or in vivo, on the inflammatory reprograming of peritoneal macrophages. Our studies revealed that BPA and phthalates adversely affected expression levels of the proinflammatory cytokines and mediators in response to lipopolysaccharide stimulation. Exposure to these toxicants also affected gene expression of scavenger receptors and phagocytic capacity of peritoneal macrophages. Our studies revealed that the epigenetic inhibitors differentially modulated target gene expression in these cells. Further analysis revealed that certain histone modification enzymes were aberrantly expressed in response to BPA or phthalate exposure, leading to alteration in the levels of H3K36 acetylation and dimethylation, two chromatin modifications that are critical for transcriptional efficacy and accuracy. Our results further revealed that silencing of H3K36-specific methyltransferase Smyd2 expression or inhibition of SMYD2 enzymatic activity attenuated H3K36 dimethylation and enhanced interleukin-6 and tumor necrosis factor-alpha expression but dampened the phagocytic capacity of peritoneal macrophages. In summary, our results indicate that peritoneal macrophages are vulnerable to BPA or phthalate at levels relevant to human exposure. These environmental toxicants affect phenotypic programming of macrophages via epigenetic mechanisms involving SMYD2-mediated H3K36 modification. PMID- 29718167 TI - Strategies to Increase Human Immunodeficiency Virus Testing Among Men to Reach UNAIDS 90-90-90 Targets. PMID- 29718168 TI - Differences in initiation and discontinuation of preventive medications and use of non-pharmacological interventions after acute coronary syndrome among migrants and Danish-born. AB - Aims: The aim of this article is to assess initiation and discontinuation of preventive medication and use of non-pharmacological prevention interventions after acute coronary syndrome (ACS) among migrants to Denmark compared to the local-born Danish population, taking differences in comorbidity and sociodemographic factors into account. Methods and results: In this large cohort study, we selected the population (n = 33 199) from nationwide registers and followed each individual among migrants and Danish-born 180 days after ACS. We identified the initiation and discontinuation of medications and the initiation and number of contacts for non-pharmacological interventions in the Register of Medicinal Products Statistics and the National Patient Register, and adjusted for comorbidity and sociodemographic factors. Non-Western migrants had lower relative risks for initiating adenosine diphosphate receptor (ADP)- and angiotensin converting enzyme (ACE)-inhibitors (0.93, CI: 0.90; 0.96, and 0.91, CI: 0.87; 0.96) and patient education (0.95, CI: 0.92; 0.98). Further, non-Western migrants had higher hazard ratios for discontinuing medications (statins: 1.64, CI: 1.45; 1.86, ADP-inhibitors: 1.72, CI: 1.50; 1.97, beta-blockers: 1.52, CI: 1.40; 1.64, and ACE-inhibitors: 1.72, CI: 1.46; 2.02), and fewer contacts for physical exercise and patient education (P < 0.001 and P = 0.011). Conclusion: We identified differences between non-Western migrants and Danish-born in initiation and discontinuation of preventive medications and use of non-pharmacological interventions after ACS. These differences could not be explained by differences in comorbidity or sociodemographic factors. PMID- 29718169 TI - Small septal vessel occlusion results in big damage: ventricular septal dissection and rupture. PMID- 29718170 TI - BlockFeST: Bayesian calculation of region-specific FST to detect local adaptation. AB - Summary: The fixation index FST can be used to identify non-neutrally evolving loci from genome-scale SNP data across two or more populations. Recent years have seen the development of sophisticated approaches to estimate FST based on Markov Chain Monte-Carlo simulations. Here, we present a vectorized R implementation of an extension of the widely used BayeScan software for codominant markers, adding the option to group individual SNPs into pre-defined blocks. A typical application of this new approach is the identification of genomic regions, genes, or gene sets containing SNPs that evolved under directional selection. Availability and implementation: The R implementation of our method, which builds on the powerful population genetics and genomics software PopGenome, is available freely from CRAN. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29718171 TI - Improved management of acute kidney injury in primary care using e-alerts and an educational outreach programme. AB - Purpose: Acute kidney injury (AKI) detected in primary care is associated with increased morbidity and mortality. AKI electronic alerts (e-alerts) and educational programmes have recently been implemented but their contribution to improve AKI care is unknown. This project aimed to improve response to AKI detected in primary care and used a factorial design to evaluate the impact of the UK National Health Service (NHS) AKI e-alert and AKI educational outreach sessions on time to response to primary care AKI stages 2 and 3 between April and August 2016. Methods: A total of 46 primary care practices were randomized into four groups. A 2 * 2 factorial design exposed each group to different combinations of two interventions. The primary outcome was 'time to repeat test' or hospitalization following AKI e-alert for stages 2 and 3. Yates algorithm was used to evaluate the impact of each intervention. Time to response and mortality pre- and post-intervention were analysed using Mann-Whitney U test and chi-square test respectively. The factorial design included two interventions: an AKI educational outreach programme and the NHS AKI e-alerts. Results: 1807 (0.8%) primary care blood tests demonstrated AKI 1-3 (78.3% stage 1, 14.8% stage 2, 6.9% stage 3). There were 391 stage 2 and 3 events from 251 patients. E-alerts demonstrated a reduction in mean response time (-29 hours). Educational outreach had a smaller effect (-3 hours). Median response time to AKI 2 and 3 pre- and post-interventions was 27 hours versus 16 hours respectively (P = 0.037). Stage 2 and 3 event-related 30-day all-cause mortality decreased following the interventions (15.6% versus 3.9% P = 0.036). Conclusion: AKI e-alerts in primary care hasten response to AKI 2 and 3 and reduce all-cause mortality. Educational outreach sessions further improve response time. PMID- 29718172 TI - Organohalide respiratory chains: composition, topology and key enzymes. AB - The utilization of halogenated organic compounds as terminal electron acceptors separates the phylogenetically diverse organohalide-respiring bacteria from other respiratory anaerobes that predominantly use nitrate, fumarate, sulfate or oxidized metals. Organohalide respiration is unique in recruiting a cobamide containing iron-sulfur protein, the extracellular membrane-bound reductive dehalogenase, as terminal reductase in the electron transfer chain. In recent years substantial contributions have been made to the understanding of how electron transfer paths couple mechanistically to chemiosmosis in the organohalide-respiring bacteria. The structural analysis of a respiratory and a non-respiratory reductive dehalogenase revealed the intramolecular electron transfer via two cubane iron-sulfur clusters to the cobamide at the active site. Based on whether quinones are involved, two types of intermolecular electron transfer chains have been identified, which differ in their composition and mode of proton translocation. Indeed, various respiratory chain architectures have been unraveled and evidence for different putative coupling mechanisms presented. The identification of a multienzyme respiratory complex that combines uptake hydrogenase, a complex iron-sulfur molybdoenzyme and a reductive dehalogenase in Dehalococcoides mccartyi strain CBDB1 has raised new questions regarding the mode of energy conservation in these enigmatic microbes. In this mini-review, we highlight these findings and provide an outlook on potential future developments. PMID- 29718173 TI - ERRATUM FOR "Serotonin Receptor 1A (HTR1A), a Novel Regulator of GnRH Neuronal Migration in Chick Embryo". PMID- 29718174 TI - How structured yeast multicellular communities live, age and die? AB - Yeasts, like other microorganisms, create numerous types of multicellular communities, which differ in their complexity, cell differentiation and in the occupation of different niches. Some of the communities, such as colonies and some types of biofilms, develop by division and subsequent differentiation of cells growing on semisolid or solid surfaces to which they are attached or which they can penetrate. Aggregation of individual cells is important for formation of other community types, such as multicellular flocs, which sediment to the bottom or float to the surface of liquid cultures forming flor biofilms, organized at the border between liquid and air under specific circumstances. These examples together with the existence of more obscure communities, such as stalks, demonstrate that multicellularity is widespread in yeast. Despite this fact, identification of mechanisms and regulations involved in complex multicellular behavior still remains one of the challenges of microbiology. Here, we briefly discuss metabolic differences between particular yeast communities as well as the presence and functions of various differentiated cells and provide examples of the ability of these cells to develop different ways to cope with stress during community development and aging. PMID- 29718175 TI - Lipotoxicty in yeast: a focus on plasma membrane signalling and membrane contact sites. AB - Lipotoxicity is a pathophysiological process triggered by lipid overload. In metazoans, lipotoxicity is characterised by the ectopic deposition of lipids on organs other than adipose tissue. This leads to organ dysfunction, cell death, and is intimately linked to lipid-associated diseases such as cardiac dysfunction, atherosclerosis, stroke, hepatosteatosis, cancer and the metabolic syndrome. The molecules involved in eliciting lipotoxicity include FAs and their acyl-CoA derivatives, triacylglycerol (TG), diacylglycerol (DG), ceramides, acyl carnitines and phospholipids. However, the cellular transport of toxic lipids through membrane contact sites (MCS) and vesicular mechanisms as well as lipid metabolism that progress lipotoxicity to the onset of disease are not entirely understood. Yeast has proven a useful model organism to study the molecular mechanisms of lipotoxicity. Recently, the Rim101 pathway, which senses alkaline pH and the lipid status at the plasmamembrane, has been connected to lipotoxicity. In this review article, we summarise recent research advances on the Rim101 pathway and MCS in the context of lipotoxicity in yeast and present a perspective for future research directions. PMID- 29718177 TI - JRmGRN: joint reconstruction of multiple gene regulatory networks with common hub genes using data from multiple tissues or conditions. AB - Motivation: Joint reconstruction of multiple gene regulatory networks (GRNs) using gene expression data from multiple tissues/conditions is very important for understanding common and tissue/condition-specific regulation. However, there are currently no computational models and methods available for directly constructing such multiple GRNs that not only share some common hub genes but also possess tissue/condition-specific regulatory edges. Results: In this paper, we proposed a new graphic Gaussian model for joint reconstruction of multiple gene regulatory networks (JRmGRN), which highlighted hub genes, using gene expression data from several tissues/conditions. Under the framework of Gaussian graphical model, JRmGRN method constructs the GRNs through maximizing a penalized log likelihood function. We formulated it as a convex optimization problem, and then solved it with an alternating direction method of multipliers (ADMM) algorithm. The performance of JRmGRN was first evaluated with synthetic data and the results showed that JRmGRN outperformed several other methods for reconstruction of GRNs. We also applied our method to real Arabidopsis thaliana RNA-seq data from two light regime conditions in comparison with other methods, and both common hub genes and some conditions-specific hub genes were identified with higher accuracy and precision. Availability and implementation: JRmGRN is available as a R program from: https://github.com/wenpingd. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29718176 TI - Chronic biofilm-based infections: skewing of the immune response. AB - Many of the deadliest bacterial diseases that plague humanity in the modern age are caused by bacterial biofilms that produce chronic infections. However, most of our knowledge of the host immune response comes from the study of planktonic pathogens. While there are similarities in the host response to planktonic and biofilm bacteria, specific immune responses toward biofilms have not been well studied; the only apparent difference is the inability to clear the bacteria allowing the biofilm infection to become chronic. In some cases, the biofilms skew T-cell response toward a balance that allows a stalemate between the host and the pathogen, in which the infection can become persistent. In this minireview, we will summarize well-known examples of this phenomena as well as some emerging studies that may indicate that this situation is much more common than initially thought. PMID- 29718178 TI - Results of aortic valve repair using decellularized bovine pericardium in congenital surgery. AB - OBJECTIVES: The search for an optimal patch material for aortic valve reconstruction (AVR) is an ongoing challenge. In this study, we report our experience of AVR using decellularized bovine pericardial patch material in congenital heart surgery. METHODS: Data of 40 consecutive patients who underwent AVR using the CardioCel(r) patch (Admedus Regen Pty Ltd, Perth, WA, Australia) between February 2014 and August 2016 were retrospectively reviewed. The median age of the patients at operation was 9 (2-34) years, and 18 patients were younger than 7 years. Twenty-six patients initially presented with aortic valve insufficiency (AI) and 14 with stenosis. Clinical and echocardiographic data were available until August 2017 for a median postoperative follow-up (FU) of 22 (6 42) months. RESULTS: Nine of 40 (23%) patients experienced an event during FU (death: n = 1, 2.5%; reoperation: n = 8, 20%). Overall, the probability of freedom from reoperation or death was 97 +/- 3%, 76 +/- 9% and 57 +/- 12% at 12, 24 and 36 months of FU, respectively. Reason for reoperation was stenosis in 3 (37.5%) patients, insufficiency in 4 (50%) patients and 1 (12.5%) patient was diagnosed with aortic valve endocarditis. Of the remaining 31 patients, 2 patients are scheduled for reoperation (aortic valve stenosis: n = 1 and AI: n = 1) and 9 patients exhibit worsening of aortic valve function with moderate AI. Freedom from developing combined end point [death/reoperation/moderate degree of aortic valve dysfunction (aortic valve stenosis, AI)] after AVR was 92 +/- 5%, 55 +/- 9% and 28 +/- 9% at 12, 24 and 36 months, respectively. CONCLUSIONS: AVR using decellularized bovine pericardial patch material in patients with congenital aortic valve disease show unsatisfactory results within the first 3 years of FU. PMID- 29718179 TI - Influence of uvrA, recJ and recN gene mutations on nucleoid reorganization in UV treated Escherichia coli cells. AB - Exposure to ultraviolet (UV) radiation blocks DNA replication and arrests cellular division in Escherichia coli. Restoration of chromosome replication involves nucleoid reorganization, which involves the participation of the recombination-catalyzing proteins RecA, RecO, RecR and RecN. In this work, we evaluated the influence of recN, uvrA and recJ gene mutations on post-irradiation nucleoid reorganization. We used isogenic E. coli strains that are defective for these genes to study post-irradiation kinetics of the nucleoid shape fractions using fluorescence microscopy. The results showed that in the wild-type strain, post-irradiation nucleoid reorganization occurs, which restores the nucleoid shape fractions in the cells to those observed prior to irradiation. First, the nucleoid condenses into the central area of the irradiated cell. Second, the nucleoid disperses along the cell. Third, the cell enters the chromosome replicative phase and cytokinesis. Escherichia coli cells with a recN mutation did not exhibit increased nucleoid condensation, but chromosome replication and cytokinesis occurred. In the uvrA and recJ strains, the condensation step was delayed compared to the wild-type strain, and chromosome replication and cytokinesis did not occur. The results are discussed with an emphasis on the functions of RecN, UvrA and RecJ in nucleoid reorganization in UV-irradiated E. coli cells. PMID- 29718180 TI - Deciphering the genome and secondary metabolome of the plant pathogen Fusarium culmorum. AB - Fusarium culmorum is one of the most important fungal plant pathogens that causes diseases on a wide diversity of cereal and non-cereal crops. We report herein for the first time the genome sequence of F. culmorum strain PV and its associated secondary metabolome that plays a role in the interaction with other microorganisms and contributes to its pathogenicity on plants. The genome revealed the presence of two terpene synthases, trichodiene and longiborneol synthase, which generate an array of volatile terpenes. Furthermore, we identified two gene clusters, deoxynivalenol and zearalenone, which encode for the production of mycotoxins. Linking the production of mycotoxins with in vitro bioassays, we found high virulence of F. culmorum PV on maize, barley and wheat. By using ultra-performance liquid chromatography-mass spectrometry, we confirmed several compounds important for the behaviour and lifestyle of F. culmorum. This research sets the basis for future studies in microbe-plant interactions. PMID- 29718181 TI - The role of bacteria in pine wilt disease: insights from microbiome analysis. AB - Pine Wilt Disease (PWD) has a significant impact on Eurasia pine forests. The microbiome of the nematode (the primary cause of the disease), its insect vector, and the host tree may be relevant for the disease mechanism. The aim of this study was to characterize these microbiomes, from three PWD-affected areas in Portugal, using Denaturing Gradient Gel Electrophoresis, 16S rRNA gene pyrosequencing, and a functional inference-based approach (PICRUSt). The bacterial community structure of the nematode was significantly different from the infected trees but closely related to the insect vector, supporting the hypothesis that the nematode microbiome might be in part inherited from the insect. Sampling location influenced mostly the tree microbiome (P < 0.05). Genes related both with plant growth promotion and phytopathogenicity were predicted for the tree microbiome. Xenobiotic degradation functions were predicted in the nematode and insect microbiomes. Phytotoxin biosynthesis was also predicted for the nematode microbiome, supporting the theory of a direct contribution of the microbiome to tree-wilting. This is the first study that simultaneously characterized the nematode, tree and insect-vector microbiomes from the same affected areas, and overall the results support the hypothesis that the PWD microbiome plays an important role in the disease's development. PMID- 29718183 TI - Historical links between toxinology and immunology. AB - Research on bacterial toxins is closely linked to the birth of immunology. Our understanding of the interaction of bacterial protein toxins with immune cells has helped to decipher immunopathology, develop preventive and curative treatments for infections, and propose anti-cancer immunotherapies. The link started when Behring and Kitasato demonstrated that serotherapy was effective against 'the strangling angel', namely diphtheria, and its dreadful toxin discovered by Roux and Yersin. The antitoxin treatment helped to save thousands of children. Glenny demonstrated the efficacy of the secondary immune response compared to the primary one. Ramon described anatoxins that allowed the elaboration of effective vaccines and discovered the use of adjuvant to boost the antibody response. Similar approaches were later made for the tetanus toxin. Studying antitoxin antibodies Ehrlich demonstrated, for the first time, the transfer of immunity from mother to newborns. In 1989 Marrack and Kappler coined the concept of 'superantigens' to characterize protein toxins that induce T lymphocyte proliferation, and cytokine release by both T-lymphocytes and antigen presenting cells. More recently, immunotoxins have been designed to kill cancer cells targeted by either specific antibodies or cytokines. Finally, the action of IgE antibodies against toxins may explain their persistence through evolution despite their side effect in allergy. PMID- 29718182 TI - Fluorescent Mycobacterium tuberculosis reporters: illuminating host-pathogen interactions. AB - The pathogenesis of Mycobacterium tuberculosis (Mtb) is intrinsically linked to its intimate and enduring interaction with its host, and understanding Mtb-host interactions at a molecular level is critical to attempts to decrease the significant burden of tuberculosis disease. The marked heterogeneity that exists in lesion progression and outcome during Mtb infection necessitates the development of methods that enable in situ analyses of Mtb biology and host response within the spatial context of tissue structure. Fluorescent reporter Mtb strains have thus come to the forefront as an approach with broad utility for the study of the Mtb-host interface, enabling visualization of the bacteria during infection, and contributing to the discovery of several facets such as non uniformity in microenvironments and Mtb physiology in vivo, and their relation to the host immune response or therapeutic intervention. We review here the different types of fluorescent reporters and ways in which they have been utilized in Mtb studies, and expand on how they may further be exploited in combination with novel imaging and other methodologies to illuminate key aspects of Mtb-host interactions. PMID- 29718184 TI - The pyrin inflammasome: from sensing RhoA GTPases-inhibiting toxins to triggering autoinflammatory syndromes. AB - Numerous pathogens including Clostridium difficile and Yersinia pestis have evolved toxins or effectors targeting GTPases from the RhoA subfamily (RhoA/B/C) to inhibit or hijack the host cytoskeleton dynamics. The resulting impairment of RhoA GTPases activity is sensed by the host via an innate immune complex termed the pyrin inflammasome in which caspase-1 is activated. The cascade leading to activation of the pyrin inflammasome has been recently uncovered. In this review, following a brief presentation of RhoA GTPases-modulating toxins, we present the pyrin inflammasome and its regulatory mechanisms. Furthermore, we discuss how some pathogens have developed strategies to escape detection by the pyrin inflammasome. Finally, we present five monogenic autoinflammatory diseases associated with pyrin inflammasome deregulation. The molecular insights provided by the study of these diseases and the corresponding mutations on pyrin inflammasome regulation and activation are presented. PMID- 29718185 TI - Structure-based working model of SecDF, a proton-driven bacterial protein translocation factor. AB - The bacterial membrane protein SecDF enhances protein translocation across the membrane driven by the complex of SecA ATPase and SecYEG. Many newly synthesized proteins in the cytoplasm are programmed to be translocated to the periplasm via the narrow channel that is formed in the center of SecYEG. During the protein translocation process, SecDF is proposed to undergo repeated conformational transitions to pull out the precursor protein from the SecYEG channel into the periplasm. Once SecDF captures the precursor protein on the periplasmic surface, SecDF can complete protein translocation even if SecA function is inactivated by ATP depletion, implying that SecDF is a protein-translocation motor that works independent of SecA. Structural and functional analyses of SecDF in 2011 suggested that SecDF utilizes the proton gradient and interacts with precursor protein in the flexible periplasmic region. The crystal structures of SecDF in different states at more than 3A resolution were reported in 2017 and 2018, which further improved our understanding of the dynamic molecular mechanisms of SecDF. This review summarizes recent structural studies of SecDF. PMID- 29718186 TI - Identification and characterization of the Komagataella phaffii mating pheromone genes. AB - The methylotrophic yeast Komagataella phaffii (Pichia pastoris) is a haploid yeast that is able to form diploid cells by mating once nitrogen becomes limiting. Activation of the mating response requires the secretion of a- and alpha-factor pheromones, which bind to G-protein coupled receptors on cells of opposite mating type. In K. phaffii, the genes coding for the alpha-factor (MFalpha), the pheromone surface receptors and the conserved a-factor biogenesis pathway have been annotated previously. Initial homology-based search failed to identify potential a-factor genes (MFA). By using transcriptome data of heterothallic strains under mating conditions, we found two K. phaffiia-factor genes. Deletion of both MFA genes prevented mating of a-type cells. MFA single mutants were still able to mate and activate the mating response pathway in alpha type cells. A reporter assay was used to confirm the biological activity of synthetic a- and alpha-factor peptides. The identification of the a-factor genes enabled the first characterization of the role and regulation of the mating pheromone genes and the response of K. phaffii to synthetic pheromones and will help to gain a better understanding of the mating behavior of K. phaffii. PMID- 29718188 TI - Emotional salience of the image component facilitates recall of the text of cigarette warning labels. AB - Background: Graphic warning labels (GWLs) on cigarette packages, that combine textual warnings with emotionally salient images depicting the adverse health consequences of smoking, have been adopted in most European countries. In the US, the courts deemed the evidence justifying the inclusion of emotionally salient images in GWLs insufficient and put the implementation on hold. We conducted a controlled experimental study examining the effect of emotional salience of GWL's images on the recall of their text component. Methods: Seventy-three non treatment-seeking daily smokers received cigarette packs carrying GWLs for a period of 4 weeks. Participants were randomly assigned to receive packs with GWLs previously rated as eliciting high or low level of emotional reaction (ER). The two conditions differed in respect to images but used the same textual warning statements. Participants' recognition of GWL images and statements were tested separately at baseline and again after the 4-week repetitive exposure. Results: Textual warning statements were recognized more accurately when paired with high ER images than when paired with low ER images, both at baseline and after daily exposure to GWLs over a 4-week period. Conclusion: The results suggest that emotional salience of GWLs facilitates cognitive processing of the textual warnings, resulting in better remembering of the information about the health hazards of smoking. Thus, high emotional salience of the pictorial component of GWLs is essential for their overall effectiveness. PMID- 29718189 TI - Risk factors for persisting measles susceptibility: a case-control study among unvaccinated orthodox Protestants. AB - Background: Measles is an infectious disease providing lifelong immunity. Epidemics periodically occur among unvaccinated orthodox Protestants in the Netherlands. During the 2013/2014 epidemic, 17% of the reported patients was over 14 years old. Apparently, they did not catch measles during the previous 1999/2000 epidemic and remained susceptible. We wanted to identify risk factors for this so-called persisting measles susceptibility, and thus risk factors for acquiring measles at older age with increased risk of complications. Methods: A case-control study was performed among unvaccinated orthodox Protestants born between 1988 and 1998; cases had measles in 2013/2014, controls during or before 1999/2000. Associations between demographic, geographical and religion-related determinants and persisting measles susceptibility were determined using univariate and multivariable logistic regression. Analyses were stratified in two age-groups: infants/toddlers and primary school-aged children during the 1999/2000 measles epidemic. Results: In total, 204 cases and 563 controls were included. Risk factors for persisting measles susceptibility for infants/toddlers in 1999/2000 were belonging to a moderately conservative church, absence of older siblings and residency outside low vaccination coverage (LVC)-municipalities. Risk factors for primary school-aged children were residency outside LVC municipalities and attendance of non-orthodox Protestant primary school. Conclusion: Unvaccinated orthodox Protestant adolescents and adults who resided outside the LVC-municipalities, did not attend an orthodox Protestant primary school, had no older siblings and belonged to a moderately conservative church were at risk for persisting measles susceptibility and, thus, for acquiring measles at older age with increased risk of complications. For this subgroup of orthodox Protestants targeted information on vaccination is recommended. PMID- 29718190 TI - Metabolic engineering of Escherichia coli for the production of isoprenoids. AB - Metabolic engineering is the practice of using directed genetic manipulations to rewire cellular metabolism primarily with the aim to transform the organism into a single-celled chemical factory. Using biological processes, we can produce more complex chemicals in a more sustainable way. This is particularly important for chemicals which are hard to synthesize using traditional chemistry. However, cells have evolved for growth and must be engineered to produce a single chemical at commercially viable levels. This review focuses on the strategies used to rewire cellular metabolism to produce chemicals using isoprenoid production in Escherichia coli as an example that illustrates many of the challenges faced in metabolic engineering. PMID- 29718187 TI - Mutations in COA7 cause spinocerebellar ataxia with axonal neuropathy. AB - Several genes related to mitochondrial functions have been identified as causative genes of neuropathy or ataxia. Cytochrome c oxidase assembly factor 7 (COA7) may have a role in assembling mitochondrial respiratory chain complexes that function in oxidative phosphorylation. Here we identified four unrelated patients with recessive mutations in COA7 among a Japanese case series of 1396 patients with Charcot-Marie-Tooth disease (CMT) or other inherited peripheral neuropathies, including complex forms of CMT. We also found that all four patients had characteristic neurological features of peripheral neuropathy and ataxia with cerebellar atrophy, and some patients showed leukoencephalopathy or spinal cord atrophy on MRI scans. Validated mutations were located at highly conserved residues among different species and segregated with the disease in each family. Nerve conduction studies showed axonal sensorimotor neuropathy. Sural nerve biopsies showed chronic axonal degeneration with a marked loss of large and medium myelinated fibres. An immunohistochemical assay with an anti COA7 antibody in the sural nerve from the control patient showed the positive expression of COA7 in the cytoplasm of Schwann cells. We also observed mildly elevated serum creatine kinase levels in all patients and the presence of a few ragged-red fibres and some cytochrome c oxidase-negative fibres in a muscle biopsy obtained from one patient, which was suggestive of subclinical mitochondrial myopathy. Mitochondrial respiratory chain enzyme assay in skin fibroblasts from the three patients showed a definitive decrease in complex I or complex IV. Immunocytochemical analysis of subcellular localization in HeLa cells indicated that mutant COA7 proteins as well as wild-type COA7 were localized in mitochondria, which suggests that mutant COA7 does not affect the mitochondrial recruitment and may affect the stability or localization of COA7 interaction partners in the mitochondria. In addition, Drosophila COA7 (dCOA7) knockdown models showed rough eye phenotype, reduced lifespan, impaired locomotive ability and shortened synaptic branches of motor neurons. Our results suggest that loss of-function COA7 mutation is responsible for the phenotype of the presented patients, and this new entity of disease would be referred to as spinocerebellar ataxia with axonal neuropathy type 3. PMID- 29718191 TI - MetaCompare: a computational pipeline for prioritizing environmental resistome risk. AB - The spread of antibiotic resistance is a growing public health concern. While numerous studies have highlighted the importance of environmental sources and pathways of the spread of antibiotic resistance, a systematic means of comparing and prioritizing risks represented by various environmental compartments is lacking. Here, we introduce MetaCompare, a publicly available tool for ranking 'resistome risk', which we define as the potential for antibiotic resistance genes (ARGs) to be associated with mobile genetic elements (MGEs) and mobilize to pathogens based on metagenomic data. A computational pipeline was developed in which each ARG is evaluated based on relative abundance, mobility, and presence within a pathogen. This is determined through the assembly of shotgun sequencing data and analysis of contigs containing ARGs to determine if they contain sequence similarity to MGEs or human pathogens. Based on the assembled metagenomes, samples are projected into a 3-dimensionalhazard space and assigned resistome risk scores. To validate, we tested previously published metagenomic data derived from distinct aquatic environments. Based on unsupervised machine learning, the test samples clustered in the hazard space in a manner consistent with their origin. The derived scores produced a well-resolved ascending resistome risk ranking of: wastewater treatment plant effluent, dairy lagoon, and hospital sewage. PMID- 29718192 TI - ERRATUM FOR "Sodium Deficiency Regulates Rat Adrenal Zona Glomerulosa Gene Expression". PMID- 29718193 TI - Transcriptional Profiling of Age-Associated Gene Expression Changes in Human Circulatory CD1c+ Myeloid Dendritic Cell Subset. AB - Immune dysfunction is a hallmark of aging and is thought to be responsible for the age-associated diseases. Dendritic cells(DCs) of the immune system function as initiators and regulators of the immune responses. Recent studies have highlighted the division of labor between various DC subsets. CD1c+ DC subset has emerged as a major inducer of CD4 T cell response. There is a scarcity of information regarding the age-associated changes in the functions of DC subsets in the elderly. Here we investigated the changes in transcriptional profile of CD1c+ DC subset from healthy aged and young individuals using RNA-sequencing. Our results suggest that majority of the genes in DCs are upregulated with age. Glucose transport, GPCR and potassium channel genes are all upregulated in DCs from aged as compared to young indicating an enhanced activation state of DCs from aged individuals. The expression of histones, SNORA, SNORDs and lnc RNAs is also substantially upregulated in the DCs from aged. In contrast, the antigen presenting and energy generating pathways are downregulated. In summary, DCs from aged subjects display an activated state coupled with reduced antigen presentation which may be responsible for age-associate immune dysfunction. PMID- 29718194 TI - What are we measuring? Refocusing on some fundamentals in the age of desktop bibliometrics. AB - The central challenge in bibliometrics is finding the best ways to represent complex constructs like 'quality,' 'impact' or 'excellence' using quantitative methods. The marketplace for bibliometric data and services has evolved rapidly and users now face quite unprecedented choice when it comes to the range of data now available: from traditional citation-based indicators to reader ratings and Wikipedia mentions. Choice and ease of access have democratised bibliometrics and this is a tool now available to everyone. The era of 'desktop bibliometrics' should be welcomed: it promises greater transparency and the opportunity for experimentation in a field that has frankly become a little jaded. The downside is that we are in danger of chasing numbers for numbers' sake, with little understanding of what they mean. There is a looming crisis in construct validity, fuelled by supply side choice and user-side impatience, and this has significant implications for all stakeholders in the research evaluation space. PMID- 29718195 TI - Impact of Intervention to Improve Nursing Home Resident-Staff Interactions and Engagement. AB - Background and Objectives: For nursing home residents, positive interactions with staff and engagement in daily life contribute meaningfully to quality of life. We sought to improve these aspects of person-centered care in an opportunistic snowball sample of six Veterans Health Administration nursing homes (e.g., Community Living Centers-CLCs) using an intervention that targeted staff behavior change, focusing on improving interactions between residents and staff and thereby ultimately aiming to improve resident engagement. Research Design and Methods: We grounded this mixed-methods study in the Capability, Opportunity, Motivation, Behavior (COM-B) model of behavior change. We implemented the intervention by (a) using a set of evidence-based practices for implementing quality improvement and (b) combining primarily CLC-based staff facilitation with some researcher-led facilitation. Validated resident and staff surveys and structured observations collected pre and post intervention, as well as semi structured staff interviews conducted post intervention, helped assess intervention success. Results: Sixty-two CLC residents and 308 staff members responded to the surveys. Researchers conducted 1,490 discrete observations. Intervention implementation was associated with increased staff communication with residents during the provision of direct care and decreased negative staff interactions with residents. In the 66 interviews, staff consistently credited the intervention with helping them (a) develop awareness of the importance of identifying opportunities for engagement and (b) act to improve the quality of interactions between residents and staff. Discussion and Implications: The intervention proved feasible and influenced staff to make simple enhancements to their behaviors that improved resident-staff interactions and staff-assessed resident engagement. PMID- 29718196 TI - Role of protein phosphomannosylation in the Candida tropicalis-macrophage interaction. AB - Candida tropicalis is an opportunistic fungal pathogen responsible for mucosal and systemic infections. The cell wall is the initial contact point between a fungal cell and the host immune system, and mannoproteins are important components that play key roles when interacting with host cells. In Candida albicans, mannans are modified by mannosyl-phosphate moieties, named phosphomannans, which can work as molecular scaffolds to synthesize beta1,2 mannooligosaccharides, and MNN4 is a positive regulator of the phosphomannosylation pathway. Here, we showed that C. tropicalis also displays phosphomannans on the cell surface, but the amount of this cell wall component varies depending on the fungal strain. We also identified a functional ortholog of CaMNN4 in C. tropicalis. Disruption of this gene caused depletion of phosphomannan content. The C. tropicalis mnn4Delta did not show defects in the ability to stimulate cytokine production by human mononuclear cells but displayed virulence attenuation in an insect model of candidiasis. When the mnn4Delta macrophage interaction was analyzed, results showed that presence of cell wall phosphomannan was critical for C. tropicalis phagocytosis. Finally, our results strongly suggest a differential role for phosphomannans during phagocytosis of C. albicans and C. tropicalis. PMID- 29718198 TI - Corrigendum: Letter to the Editor: Individualized FSH dosing improves safety and reduces iatrogenic poor response while maintaining live-birth rates. PMID- 29718197 TI - [PIN+]ing down the mechanism of prion appearance. AB - Prions are conformationally flexible proteins capable of adopting a native state and a spectrum of alternative states associated with a change in the function of the protein. These alternative states are prone to assemble into amyloid aggregates, which provide a structure for self-replication and transmission of the underlying conformer and thereby the emergence of a new phenotype. Amyloid appearance is a rare event in vivo, regulated by both the aggregation propensity of prion proteins and their cellular environment. How these forces normally intersect to suppress amyloid appearance and the ways in which these restrictions can be bypassed to create protein-only phenotypes remain poorly understood. The most widely studied and perhaps most experimentally tractable system to explore the mechanisms regulating amyloid appearance is the [PIN+] prion of Saccharomyces cerevisiae. [PIN+] is required for the appearance of the amyloid state for both native yeast proteins and for human proteins expressed in yeast. These observations suggest that [PIN+] facilitates the bypass of amyloid regulatory mechanisms by other proteins in vivo. Several models of prion appearance are compatible with current observations, highlighting the complexity of the process and the questions that must be resolved to gain greater insight into the mechanisms regulating these events. PMID- 29718199 TI - Boutiques: a flexible framework to integrate command-line applications in computing platforms. AB - We present Boutiques, a system to automatically publish, integrate, and execute command-line applications across computational platforms. Boutiques applications are installed through software containers described in a rich and flexible JSON language. A set of core tools facilitates the construction, validation, import, execution, and publishing of applications. Boutiques is currently supported by several distinct virtual research platforms, and it has been used to describe dozens of applications in the neuroinformatics domain. We expect Boutiques to improve the quality of application integration in computational platforms, to reduce redundancy of effort, to contribute to computational reproducibility, and to foster Open Science. PMID- 29718200 TI - Dynamic Patterns of Spontaneous Ongoing Activity in the Visual Cortex of Anesthetized and Awake Monkeys are Different. AB - Ongoing internal cortical activity plays a major role in perception and behavior both in animals and humans. Previously we have shown that spontaneous patterns resembling orientation-maps appear over large cortical areas in the primary visual-cortex of anesthetized cats. However, it remains unknown 1) whether spontaneous-activity in the primate also displays similar patterns and 2) whether a significant difference exists between cortical ongoing-activity in the anesthetized and awake primate. We explored these questions by combining voltage sensitive-dye imaging with multiunit and local-field-potential recordings. Spontaneously emerging orientation and ocular-dominance maps, spanning up to 6 * 6 mm2, were readily observed in anesthetized but not in awake monkeys. Nevertheless, spontaneous correlated-activity involving orientation-domains was observed in awake monkeys. Under both anesthetized and awake conditions, spontaneous correlated-activity coincided with traveling waves. We found that spontaneous activity resembling orientation-maps in awake animals spans smaller cortical areas in each instance, but over time it appears across all of V1. Furthermore, in the awake monkey, our results suggest that the synaptic strength had been completely reorganized including connections between dissimilar elements of the functional architecture. These findings lend support to the notion that ongoing-activity has many more fast switching representations playing an important role in cortical function and behavior. PMID- 29718201 TI - PERK inhibition delays neurodegeneration and improves motor function in a mouse model of Marinesco-Sjogren syndrome. AB - Marinesco-Sjogren syndrome (MSS) is a rare, early onset, autosomal recessive multisystem disorder characterized by cerebellar ataxia, cataracts and myopathy. Most MSS cases are caused by loss-of-function mutations in the gene encoding SIL1, a nucleotide exchange factor for the molecular chaperone BiP which is essential for correct protein folding in the endoplasmic reticulum. Woozy mice carrying a spontaneous Sil1 mutation recapitulate key pathological features of MSS, including cerebellar atrophy with degeneration of Purkinje cells and progressive myopathy. Because the PERK branch of the unfolded protein response is activated in degenerating neurons of woozy mice, and inhibiting PERK-mediated translational attenuation has shown protective effects in protein-misfolding neurodegenerative disease models, we tested the therapeutic efficacy of GSK2606414, a potent inhibitor of PERK. Mice were chronically treated with GSK2606414 starting from a presymptomatic stage, and the effects were evaluated on biochemical, histopathological and clinical readouts. GSK2606414 delayed Purkinje cell degeneration and the onset of motor deficits, prolonging the asymptomatic phase of the disease; it also reduced the skeletal muscle abnormalities and improved motor performance during the symptomatic phase. The protein but not the mRNA level of ORP150, a nucleotide exchange factor which can substitute for SIL1, was increased in the cerebellum of GSK2606414-treated woozy mice, suggesting that translational recovery promoted the synthesis of this alternative BiP co-factor. Targeting PERK signaling may have beneficial disease modifying effects in carriers of SIL1 mutations. PMID- 29718203 TI - The use of gamification in the teaching of disease epidemics and pandemics. AB - With the launch of the teaching excellence framework, teaching in higher education (HE) is under greater scrutiny than ever before. Didactic lecture delivery is still a core element of many HE programmes but there is now a greater expectation for academics to incorporate alternative approaches into their practice to increase student engagement. These approaches may include a large array of techniques from group activities, problem-based learning, practical experience and mock scenarios to newly emerging approaches such as flipped learning practices and the use of gamification. These participatory forms of learning encourage students to become more absorbed within a topic that may otherwise be seen as rather 'dry' and reduce students engagement with, and therefore retention of, material. Here we use participatory-based teaching approaches in microbiology as an example to illustrate to University undergraduate students the potentially devastating effects that a disease can have on a population. The 'threat' that diseases may pose and the manner in which they may spread and/or evolve can be challenging to communicate, especially in relation to the timescales associated with these factors in the case of an epidemic or pandemic. PMID- 29718202 TI - The global catalogue of microorganisms 10K type strain sequencing project: closing the genomic gaps for the validly published prokaryotic and fungi species. AB - Genomic information is essential for taxonomic, phylogenetic, and functional studies to comprehensively decipher the characteristics of microorganisms, to explore microbiomes through metagenomics, and to answer fundamental questions of nature and human life. However, large gaps remain in the available genomic sequencing information published for bacterial and archaeal species, and the gaps are even larger for fungal type strains. The Global Catalogue of Microorganisms (GCM) leads an internationally coordinated effort to sequence type strains and close gaps in the genomic maps of microorganisms. Hence, the GCM aims to promote research by deep-mining genomic data. PMID- 29718204 TI - A mutation-led search for novel functional domains in MeCP2. AB - Most missense mutations causing Rett syndrome (RTT) affect domains of MeCP2 that have been shown to either bind methylated DNA or interact with a transcriptional co-repressor complex. Several mutations, however, including the C-terminal truncations that account for ~10% of cases, fall outside these characterized domains. We studied the molecular consequences of four of these 'non-canonical' mutations in cultured neurons and mice to see if they reveal additional essential domains without affecting known properties of MeCP2. The results show that the mutations partially or strongly deplete the protein and also in some cases interfere with co-repressor recruitment. These mutations therefore impact the activity of known functional domains and do not invoke new molecular causes of RTT. The finding that a stable C-terminal truncation does not compromise MeCP2 function raises the possibility that small molecules which stabilize these mutant proteins may be of therapeutic value. PMID- 29718205 TI - Innovative assembly strategy contributes to understanding the evolution and conservation genetics of the endangered Solenodon paradoxus from the island of Hispaniola. AB - Solenodons are insectivores that live in Hispaniola and Cuba. They form an isolated branch in the tree of placental mammals that are highly divergent from other eulipothyplan insectivores The history, unique biology, and adaptations of these enigmatic venomous species could be illuminated by the availability of genome data. However, a whole genome assembly for solenodons has not been previously performed, partially due to the difficulty in obtaining samples from the field. Island isolation and reduced numbers have likely resulted in high homozygosity within the Hispaniolan solenodon (Solenodon paradoxus). Thus, we tested the performance of several assembly strategies on the genome of this genetically impoverished species. The string graph-based assembly strategy seemed a better choice compared to the conventional de Bruijn graph approach due to the high levels of homozygosity, which is often a hallmark of endemic or endangered species. A consensus reference genome was assembled from sequences of 5 individuals from the southern subspecies (S. p. woodi). In addition, we obtained an additional sequence from 1 sample of the northern subspecies (S. p. paradoxus). The resulting genome assemblies were compared to each other and annotated for genes, with an emphasis on venom genes, repeats, variable microsatellite loci, and other genomic variants. Phylogenetic positioning and selection signatures were inferred based on 4,416 single-copy orthologs from 10 other mammals. We estimated that solenodons diverged from other extant mammals 73.6 million years ago. Patterns of single-nucleotide polymorphism variation allowed us to infer population demography, which supported a subspecies split within the Hispaniolan solenodon at least 300 thousand years ago. PMID- 29718207 TI - Determinants of the efficacy of natural selection on coding and noncoding variability in two passerine species. PMID- 29718208 TI - The Novel Evolution of the Sperm Whale Genome. PMID- 29718209 TI - Highlight: Big Surprises from the World's Smallest Fish. PMID- 29718210 TI - Long-term trends of use of health service among heart failure patients. AB - Aims: We aimed to identify subgroups in the patient population with different trajectories of long-term readmission rates. The study also aimed to assess common causes and their sequences of readmissions for each subgroup. Methods and results: Patients with a primary diagnosis of heart failure (HF) in the period 2008-09 were identified using nationally representative primary care data linked to national hospital data, which contain information on 10.5 million patients. Heart failure patients were followed up for 5 years. Group-based trajectory models and sequence analysis were applied. The model categorised the HF population (n = 9466) into five subgroups: low-impact (66.9%); two intermediate ones (27.4%); chronic high-impact (2.3%) with steady high annual readmission rates; and short-term high-impact (3.4%) with rapid decline in readmission rates. The groups were defined by their trends of yearly number of readmissions. The all cause 5-year mortality was highest in the short-term high-impact group (n = 185, 72.8%), followed by Group 2 (intermediate users) (n = 744, 58.8%), low-impact (n = 4244, 56.9%), chronic high-impact (n = 88, 37.6%), and Group 1 (intermediate users) (n = 401, 30.3%) (P < 0.01). Compared with low-impact users, high-impact users were associated with higher mortality, bereavement episodes, and more out of-hours general practitioner visits. The chronic high-impact users had distinct sequences of causes of emergency admissions most often consisting of chest infection, ischaemic heart disease, and cardio-pulmonary signs and/or symptoms. Conclusion: Chronic high-impact users constitute a small proportion of total patients, but they have increasingly high use of healthcare services. Short-term high-impact users represent largely end of life patients. They require prompt involvement of the palliative care team to reduce unnecessary readmissions to hospital. PMID- 29718206 TI - Facioscapulohumeral dystrophy: activating an early embryonic transcriptional program in human skeletal muscle. AB - Facioscapulohumeral dystrophy (FSHD) is the third most prevalent muscular dystrophy. A progressive disease, it presents clinically as weakness and wasting of the face, shoulder and upper arm muscles, with later involvement of the trunk and lower extremities. FSHD develops through complex genetic and epigenetic events that converge on a common mechanism of toxicity with mis-expression of the transcription factor double homeobox 4 (DUX4). There is currently no treatment available for FSHD. However, the consensus that ectopic DUX4 expression in skeletal muscle is the root cause of FSHD pathophysiology has allowed research efforts to turn toward cultivating a deeper understanding of DUX4 biology and the pathways that underlie FSHD muscle pathology, and to translational studies aimed at developing targeted therapeutics using ever more sophisticated cell and animal based models of FSHD. This review summarizes recent advances in our understanding of FSHD, including the regulation and activity of DUX4 in its normal developmental roles as well as its pathological contexts. We highlight how these advances raise new questions and challenges for the field as it moves into the next decade of FSHD research. PMID- 29718212 TI - RE: "MODELING RISK-FACTOR TRAJECTORIES WHEN MEASUREMENT TOOLS CHANGE SEQUENTIALLY DURING FOLLOW-UP IN COHORT STUDIES: APPLICATION TO DIETARY HABITS IN PRODROMAL DEMENTIA". PMID- 29718211 TI - Failure to Recover Major Events of Gene Flux in Real Biological Data Due to Method Misapplication. AB - In prokaryotes, known mechanisms of lateral gene transfer (transformation, transduction, conjugation, and gene transfer agents) generate new combinations of genes among chromosomes during evolution. In eukaryotes, whose host lineage is descended from archaea, lateral gene transfer from organelles to the nucleus occurs at endosymbiotic events. Recent genome analyses studying gene distributions have uncovered evidence for sporadic, discontinuous events of gene transfer from bacteria to archaea during evolution. Other studies have used traditional models designed to investigate gene family size evolution (Count) to support claims that gene transfer to archaea was continuous during evolution, rather than involving occasional periodic mass gene influx events. Here, we show that the methodology used in analyses favoring continuous gene transfers to archaea was misapplied in other studies and does not recover known events of single simultaneous origin for many genes followed by differential loss in real data: plastid genomes. Using the same software and the same settings, we reanalyzed presence/absence pattern data for proteins encoded in plastid genomes and for eukaryotic protein families acquired from plastids. Contrary to expectations under a plastid origin model, we found that the methodology employed inferred that gene acquisitions occurred uniformly across the plant tree. Sometimes as many as nine different acquisitions by plastid DNA were inferred for the same protein family. That is, the methodology that recovered gradual and continuous lateral gene transfer among lineages for archaea obtains the same result for plastids, even though it is known that massive gains followed by gradual differential loss is the true evolutionary process that generated plastid gene distribution data. Our findings caution against the use of models designed to study gene family size evolution for investigating gene transfer processes, especially when transfers involving more than one gene per event are possible. PMID- 29718214 TI - Correction: A Multilevel Bidirectional Linkage Model in Enhancing Continuity of Psychiatric Care. PMID- 29718213 TI - The Scientific Filesystem. AB - Background: Here, we present the Scientific Filesystem (SCIF), an organizational format that supports exposure of executables and metadata for discoverability of scientific applications. The format includes a known filesystem structure, a definition for a set of environment variables describing it, and functions for generation of the variables and interaction with the libraries, metadata, and executables located within. SCIF makes it easy to expose metadata, multiple environments, installation steps, files, and entry points to render scientific applications consistent, modular, and discoverable. A SCIF can be installed on a traditional host or in a container technology such as Docker or Singularity. We start by reviewing the background and rationale for the SCIF, followed by an overview of the specification and the different levels of internal modules ("apps") that the organizational format affords. Finally, we demonstrate that SCIF is useful by implementing and discussing several use cases that improve user interaction and understanding of scientific applications. SCIF is released along with a client and integration in the Singularity 2.4 software to quickly install and interact with SCIF. When used inside of a reproducible container, a SCIF is a recipe for reproducibility and introspection of the functions and users that it serves. Results: We use SCIF to evaluate container software, provide metrics, serve scientific workflows, and execute a primary function under different contexts. To encourage collaboration and sharing of applications, we developed tools along with an open source, version-controlled, tested, and programmatically accessible web infrastructure. SCIF and associated resources are available at https://sci-f.github.io. The ease of using SCIF, especially in the context of containers, offers promise for scientists' work to be self-documenting and programatically parseable for maximum reproducibility. SCIF opens up an abstraction from underlying programming languages and packaging logic to work with scientific applications, opening up new opportunities for scientific software development. PMID- 29718215 TI - Large inserts for big data: artificial chromosomes in the genomic era. AB - The exponential increase in available microbial genome sequences coupled with predictive bioinformatic tools is underscoring the genetic capacity of bacteria to produce an unexpected large number of specialized bioactive compounds. Since most of the biosynthetic gene clusters (BGCs) present in microbial genomes are cryptic, i.e. not expressed under laboratory conditions, a variety of cloning systems and vectors have been devised to harbor DNA fragments large enough to carry entire BGCs and to allow their transfer in suitable heterologous hosts. This minireview provides an overview of the vectors and approaches that have been developed for cloning large BGCs, and successful examples of heterologous expression. PMID- 29718216 TI - Is the Pharmacokinetic Profile of a First Anti-TNF Predictive of the Clinical Outcome and Pharmacokinetics of a Second Anti-TNF? AB - Aim: The aim of this study was to evaluate prospectively the clinical outcomes and pharmacokinetics of a second anti-TNF according to the pharmacokinetics of the first anti-TNF in patients with inflammatory bowel disease (IBD). Methods: In patients in loss of response (LOR) to a first optimized anti-TNF and switched to a second anti-TNF, pharmacokinetics of anti-TNF were measured at the switch time, 30 weeks later, at the time of LOR, or at the end of the study (102 weeks). Results: At the switch time, patients (n = 59) belonged to 4 groups according to the pharmacokinetics of the first anti-TNF: group 1 (n = 18), therapeutic trough levels; group 2 (n = 13) undetectable trough levels with antibodies against anti TNF; group 3 (n = 13) without antibodies against anti-TNF; and group 4 (n = 15) subtherapeutic trough levels. After switching, the failure rates at week 30 and during the follow-up were as follows, respectively: in group 1 with therapeutic levels, 50% and 78%, despite therapeutic levels of the second anti-TNF in 83% of cases; in group 2 with undetectable levels and antibodies, 15% and 69% with undetectable levels of the second anti-TNF and antibodies in 85% of cases; in group 3 with undetectable levels without antibodies, 0% and 31% with therapeutic levels in 77% of cases; in group 4 with subtherapeutic levels, 13% and 33% with therapeutic levels in 73% of cases. Clinical remission rates were significantly lower (P <= 0.05) in groups 1 and 2 with therapeutic or undetectable levels with antibodies than in the 2 other groups. Conclusion: In the case of LOR with therapeutic levels of the first anti-TNF or undetectable levels with antibodies, the switch to a second anti-TNF results in pharmacokinetic profile similar to the first one and again in LOR in most of the patients. PMID- 29718218 TI - Current Landscape of Telemedicine Practice in Inflammatory Bowel Disease. AB - Inflammatory bowel disease (IBD), comprised of Crohn's disease and ulcerative colitis, affects 1.6 million people in the United States. Although effective medical treatments exist to treat the disease, outcomes are still suboptimal. The reasons for poor outcomes vary but include nonadherence to therapy, inadequate monitoring of patients, limited access to IBD specialty care, concurrent psychiatric disease, limited patient knowledge of the disease and treatments, and patient provider discordance. Telemedicine is a candidate intervention that can be used to improve patient outcomes through more frequent monitoring, patient self-management, delivery of education (patient and provider), and to increase access to multidisciplinary IBD care. Telemedicine includes remote monitoring, telehealth, teleconsultation, and teleconferencing.Telemedicine systems have been used in patients with IBD with widespread patient acceptance of the technology. However, early clinical trials demonstrated high attrition rates among intervention patients. In general, use of telemedicine systems have been associated with improved quality of life, improved patient knowledge, and decreased utilization of health care resources. Early studies evaluating telehealth visits report high patient satisfaction, decreased indirect costs to patients, and no decrease in quality of care delivered.Due to widespread access to computers and smart phones among patients, telemedicine will continue to expand in the care of patients with IBD. To optimize use and effectiveness of telemedicine, barriers for use including concerns over increased liability, need for informed consent, licensure restrictions to providing interstate telehealth visits, and cybersecurity need to be addressed. PMID- 29718217 TI - Detection of genome-edited cells by oligoribonucleotide interference-PCR. AB - Genome editing by engineered sequence-specific nucleases, such as the clustered regularly interspaced short palindromic repeats (CRISPR) system is widely used for analysis of gene functions. Several techniques have been developed for detection of genome-edited cells, but simple, cost-effective, and positive detection methods remain limited. Recently, we developed oligoribonucleotide (ORN) interference-PCR (ORNi-PCR), in which hybridization of an ORN with a complementary DNA sequence inhibits amplification across the sequence. Here, we investigated whether ORNi-PCR can be used to detect genome-edited cells. First, we showed that ORNs that hybridize to a CRISPR target site in the THYN1 locus inhibited amplification across the target site, but no longer inhibited amplification after the target site was edited, resulting in mismatches. Importantly, ORNi-PCR could distinguish even single-nucleotide differences. These features of ORNi-PCR enabled detection of genome-edited cells by positive PCR amplification. In addition, ORNi-PCR was successful in discriminating genome edited cells from wild-type cells, and multiplex ORNi-PCR simultaneously detected indel mutations at multiple loci. However, endpoint ORNi-PCR may not be able to distinguish between mono- and bi-allelic mutations, which may limit its utility. Taken together, these results demonstrate the potential utility of ORNi-PCR for the screening of genome-edited cells. PMID- 29718219 TI - Xenobiotic Nuclear Receptor Signaling Determines Molecular Pathogenesis of Progressive Familial Intrahepatic Cholestasis. AB - Progressive familial intrahepatic cholestasis (PFIC) is a genetically heterogeneous disorder of bile flow disruption due to abnormal canalicular transport or impaired bile acid (BA) metabolism, causing excess BA accumulation and liver failure. We previously reported an intrahepatic cholestasis mouse model based on loss of function of both farnesoid X receptor (FXR; NR1H4) and a small heterodimer partner (SHP; NR0B2) [double knockout (DKO)], which has strong similarities to human PFIC5. We compared the pathogenesis of DKO livers with that of another intrahepatic cholestasis model, Bsep-/-, which represents human PFIC2. Both models exhibit severe hepatomegaly and hepatic BA accumulation, but DKO showed greater circulating BA and liver injury, and Bsep-/- had milder phenotypes. Molecular profiling of BAs uncovered specific enrichment of cholic acid (CA)-derived BAs in DKO livers but chenodeoxycholate-derived BAs in Bsep-/- livers. Transcriptomic and proteomic analysis revealed specific activation of CA synthesis and alternative basolateral BA transport in DKO but increased chenodeoxycholic acid synthesis and canalicular transport in Bsep-/-. The constitutive androstane receptor (CAR)/pregnane X receptor (PXR)-CYP2B/CYP2C axis is activated in DKO livers but not in other cholestasis models. Loss of this axis in Fxr:Shp:Car:Pxr quadruple knockouts blocked Cyp2b/Cyp2c gene induction, impaired bilirubin conjugation/elimination, and increased liver injury. Differential CYP2B expression in DKO and Bsep-/- was recapitulated in human PFIC5 and PFIC2 livers. In conclusion, loss of FXR/SHP results in distinct molecular pathogenesis and CAR/PXR activation, which promotes Cyp2b/Cyp2c gene transcription and bilirubin clearance. CAR/PXR activation was not observed in Bsep-/- mice or PFIC2 patients. These findings provide a deeper understanding of the heterogeneity of intrahepatic cholestasis. PMID- 29718220 TI - Outcomes of Endoscopic Therapy for Luminal Strictures in Crohn's Disease. AB - Backgrounds: We sought to describe the outcomes of endoscopic therapy of luminal strictures in patients with Crohn's disease (CD) at a large tertiary referral center. Methods: All patients who had undergone endoscopic dilation of CD strictures between January 1, 1990 and November 30, 2013 were identified. Demographics, disease characteristics including medication use and history of surgeries, details of endoscopic procedures, and long-term outcomes were analyzed. A successful procedure was defined as ability of the endoscope to pass through the stricture after dilation or effacement of the dilating balloon under fluoroscopy. Kaplan-Meier and Cox proportional hazards analysis were used. Results: For this study 286 index procedures for CD-related stricture dilation were performed in 273 patients (53.8% women) with median age of 45.9 years (range, 14.9-92.2). The most common stricture locations were ileocolonic anastomosis (36.4%) and colon (13.9%). One hundred fourteen (41.8%) patients had a second dilation. The cumulative probability of need for a second dilation following the index procedure was 33.6% at 1 year (95% CI, 25.9%-38.7%), 53.9% at 3 years (45.9%-61.2%), and 60.2% at 5 years (51.4%-67.5%). Six adverse events occurred after the first procedure: 4 perforations, 1 patient with bleeding, and 1 patient with abdominal pain requiring hospitalization. A total of 82 (30%) patients required surgery for their stricture. Conclusions: In a large cohort, endoscopic stricture dilation in CD was safe and effective. About 33% of patients required a second dilation at 1 year after the initial dilation; younger age and smaller inner diameter of the index stricture predicted need for a second dilation. 10.1093/ibd/izy049_video1izy049.video15794820307001. PMID- 29718221 TI - Salivary Function and Oral Health Problems in Crohn's Disease Patients. AB - Background: In Crohn's disease (CD) patients, many oral complaints have been reported. The aim of this study was to determine whether salivary function is contributing to reduced oral health in CD. Oral and dental complaints in patients were explored. The prevalence of xerostomia in conjunction with salivary flow rates and biochemical saliva composition was studied. Methods: The Xerostomia Inventory score (XI-score), the salivary flow rates, the concentrations of salivary amylase and mucin 5B, and the type of oral and dental complaints were evaluated. These outcomes were stratified by disease activity, using the Harvey Bradshaw Index (HBI) and the Inflammatory Bowel Disease Questionnaire (IBDQ-9). Results: Fifty-three CD patients in a Dutch tertiary referral hospital were included. Of the patients evaluated, 9.4% had hyposalivation under resting conditions, and 28.3% had hyposalivation under chewing stimulated conditions. Saliva secretion rates were not correlated to XI-scores. Median XI-score was 25 (11-45). XI-scores were correlated to the IBDQ scores (r = -0.352, P = 0.010). Salivary mucin 5B was correlated to disease activity (r = 0.295, P = 0.04). Regarding the number of oral complaints, a correlation with disease activity (HBI r = 0.349, P = 0.011) and experienced xerostomia (r = -0.554, P = 0.000) was observed. Oral and dental problems like oral ulcers (37.7%) and cavities (46%) occurred more frequently in CD patients, especially when compared with a non-IBD population. Conclusions: Oral and dental complaints are common in CD patients. Xerostomia is correlated with disease activity-associated quality of life and with the number of oral and dental complaints. Changes in salivary function may contribute to reduced oral health in CD patients. 10.1093/ibd/izy017_video1izy017.video15776803023001. PMID- 29718222 TI - Genetic Variation Affects C-Reactive Protein Elevations in Crohn's Disease. AB - Background: C-reactive protein (CRP) is a serum marker that is used to measure disease activity in Crohn's disease (CD). However, a subset of CD patients have normal CRP during flares. In rheumatoid arthritis and lupus, genetic variants can restrict CRP elevations during flares. This study sought to determine if common CRP genetic variants affect CRP values during active CD. Methods: Subjects with CD who participated in the Partners HealthCare BioBank were genotyped for 5 common CRP genetic variants (rs2794520, rs3122012, rs3093077, rs2808635, and rs1800947). Medical records were reviewed to determine disease activity and the highest CRP value during active CD. CRP values during active infection or malignancy at the time of the test were excluded. CRP values were compared by genotype using the Mann-Whitney test. Results: The study included 199 subjects with active CD (21 to 86 years of age). Subjects with the rs2794520 TT genotype had a lower CRP than subjects with the CC genotype (58.3 mg/L vs 28.4 mg/L, P = 0.008). Subjects with the rs1800947 CG genotype had a lower CRP than those with the CC genotype (54.3 mg/L vs 22.4 mg/L, P < 0.0001); 41.6% of TT subjects had a normal CRP compared with 24.1% of CT subjects and 16.5% of CC subjects (P = 0.041). Conclusions: This study demonstrates that rs2794520 and rs1800947 are associated with a restriction of CRP elevations during active CD. While CRP is typically a reliable biomarker in CD, there is a subset of CD patients with a genetically determined restriction of CRP in whom other disease markers should be utilized. PMID- 29718223 TI - Outcomes of Treatment for Latent Tuberculosis Infection in Patients With Inflammatory Bowel Disease Receiving Biologic Therapy. AB - Background: Treatment for latent tuberculosis infection (LTBI) is of particular concern in patients with inflammatory bowel disease (IBD) initiating biologic therapies to prevent tuberculosis (TB) reactivation. This study aimed to evaluate the effectiveness of LTBI treatment in IBD patients receiving biologic therapy. Methods: There was a retrospective review of all IBD patients diagnosed with LTBI following a tuberculin skin test (TST) and/or interferon gamma release assay (IGRA) and who received biologic therapy between 2002 and 2016. The primary outcome was tuberculosis reactivation after completion of LTBI treatment. Results: Three-hundred twenty-nine IBD patients were identified, and 35 (27 Crohn's disease; 8 ulcerative colitis) met the study inclusion criteria. The mean age was 38.3 years, and 68.6% were male. The most common LTBI treatment regimen was isoniazid (INH) for 9 months (74%). Biologic therapies used were infliximab (40%), adalimumab (29%), vedolizumab (20%), and certolizumab pegol (11%). Combination therapy with an immunomodulator was administered in 57% of cases. The median time from initiation of LTBI treatment to biologics was 43 days. The mean duration of follow-up was 2.9 years. The estimated median annual risk of TB reactivation without treatment was 0.52% by a prediction formula. Only 1 patient taking adalimumab monotherapy developed reactivation of TB several years after completing 6 months of isoniazid therapy. The estimated TB reactivation rate was 0.98 cases per 100 patient-years of follow-up in our cohort. Conclusions: Treatment for LTBI in patients with IBD treated with biologics is effective but does not eliminate the risk of reactivation. 10.1093/ibd/izy133_video1izy133.video15776720675001. PMID- 29718224 TI - The Association of Diet and Exercise With Body Composition in Pediatric Crohn's Disease. AB - Background: In pediatric Crohn's disease, fat mass improves over time with treatment, but lean mass deficits persist. This observational study of the associations of physical activity and dietary intake with lean mass and muscle strength in children with Crohn's disease was ancillary to a previously reported randomized clinical trial of an intervention to improve bone health. Methods: In this study, 138 participants were followed at baseline and at 6, 12, and 24 months with evaluation of lean and fat mass using DXA, muscle strength (peak torque), Crohn's characteristics, dietary intake, time in moderate to vigorous physical activity (MVPA), and serum insulin-like growth factor-1 (IGF-1) and tumor necrosis factor-alpha (TNF-alpha). Race- and sex-specific Z-scores for leg lean mass and whole body fat mass were generated. Quasi least square regression evaluated determinants of changes in body composition and muscle strength. Results: Leg lean mass and muscle strength were positively associated with time in MVPA (P < 0.05) and negatively associated with increasing clinical disease activity (P < 0.05). Both leg lean mass and strength were positively associated with IGF-1 Z-score (P <= 0.03) but negatively associated with serum TNF-alpha (P <= 0.04). Neither lean mass nor muscle strength was associated with caloric or protein intake. Conclusions: Persistence of lean mass deficits was related to ongoing Crohn's disease activity but improved with greater time spent in moderate to vigorous physical activity. Future trials are needed to evaluate the efficacy of physical activity in improving lean mass in pediatric Crohn's disease. PMID- 29718225 TI - Clinical Use of Patency Capsule: A Comprehensive Review of the Literature. AB - The patency capsule is a radiopaque, dissolvable diagnostic tool, similar in shape and size to small bowel capsule endoscopes. It was developed to offer a simple, safe, efficient, and accurate evaluation of small bowel functional patency. Although unable to provide direct visual information regarding the presence and location of strictures, masses, or luminal narrowing of the small bowel, a successful patency test minimizes the risk of retention and allows the safe administration of a capsule endoscope. However, its use entails a low risk of potentially harmful adverse events, which in their majority are indolent and resolve spontaneously. Abdominal pain and symptomatic retention are accountable for the majority of reported adverse events, whereas a limited number of reports describe life-threatening complications, namely intestinal obstruction, perforation, and intestinal ischemia. Computed tomography is the modality of choice for the identification of the exact position of an impacted patency capsule, whilst the use of plain abdominal radiographs should be avoided for the evaluation of the patency capsule position, as they provide false information. Hereby, we present a comprehensive review of the available literature regarding the characteristics, indications, clinical use, effectiveness, and adverse events of the patency capsule.10.1093/ibd/izy152_video1izy152.video15777752348001. PMID- 29718226 TI - Genetic Markers Predict Primary Nonresponse and Durable Response to Anti-Tumor Necrosis Factor Therapy in Ulcerative Colitis. AB - Background: Despite a high nonresponse rate, predictors of response to anti-tumor necrosis factor (anti-TNF) therapy in ulcerative colitis (UC) remain limited. We aim to determine clinical and genetic predictors of primary nonresponse (PNR) and durable response (DR) to anti-TNF therapy in a large prospective UC cohort. Methods: Using the Illumina Immunochip, candidate polymorphisms associated with clinical outcomes of PNR and DR were separately evaluated and combined into weighted genetic risk scores. Combined genetic and clinical multivariable models for PNR and DR were compared with clinical predictive models using area under the receiver operating characteristic (AUROC) curves. Models were internally (DR) or externally (PNR) validated. Multivariable logistic regression was utilized to assess the association of genetic risk scores with infliximab levels and antibodies. Results: Of 231 patients, 28 (12%) experienced PNR and 120 (52%) experienced DR. There was no significant difference in clinical features between primary nonresponders and responders. Eight alleles were associated with PNR. A combined clinical-genetic model (AUROC, 0.87) more accurately predicted PNR compared with a clinical-only model (AUROC, 0.57; P < 0.0001). In an external cohort of 131 patients, increasing tertiles of PNR genetic risk score correlated with increased risk of PNR (P = 0.052). Twelve candidate loci were associated with DR. Genetic risk score quartiles for DR demonstrated a strong dose-response relationship in predicting treatment duration. Genetic risk scores for PNR and DR were not associated with infliximab levels or antibody formation. Conclusion: Genetic polymorphisms enhance prediction of PNR and DR to anti-TNF therapy in patients with UC. PMID- 29718228 TI - Revealing the Puzzle of Nonadherence in IBD-Assembling the Pieces. AB - Background: Adherence is generally associated with improved treatment outcomes in inflammatory bowel disease (IBD) patients. Different components of the patient profile have an impact on patient adherence. Capturing nonadherent patients by identifying modifiable risk factors in daily practice still remains a challenge. The objective of this study was to identify modifiable and nonmodifiable risk factors for nonadherence in IBD patients. Methods: Patients filled out questionnaires including demographic, clinical, and socioeconomic information and accessibility to gastrointestinal services. Psychological features were assessed using the Sense of Coherence, Hospital Anxiety and Depression Scale, IBD-Self Efficacy, and Brief Illness Perception (BIPQ) questionnaires. Adherence to treatment was evaluated using the Morisky score. Results: The study included 311 patients: 62.4% females, median age 34.78 years, 70.4% Crohn's disease (CD). Multivariate analysis was done in 3 sections: demographic and disease characteristics, communication with medical staff, and psychological aspects; all included sex and disease type. Ulcerative colitis (UC) patients were less adherent (odds ratio [OR], 1.792; OR, 1.915; OR, 1.748; respectively). Females were less adherent in 2 sections (OR, 1.841; OR, 1.751; respectively). Employment (OR, 2.449), low score in on the BIPQ-understanding of disease (OR, 0.881), and poor communication with the gastroenterologist (OR, 1.798) were also predictors of low adherence. Conclusions: Nonmodifiable characteristics such as female sex and UC are associated with low adherence. Good communication with the treating physician and understanding the disease are modifiable factors associated with high adherence. Early intervention might improve patients' adherence. PMID- 29718229 TI - Complex life cycle, broad host range and adaptation strategy of the intranuclear Paramecium symbiont Preeria caryophila comb. nov. AB - Holospora and related bacteria are a group of obligate Paramecium symbionts. Characteristic features are their infectivity, the presence of two distinct morphotypes, and usually a strict specialization for a single Paramecium species as host and for a nuclear compartment (either somatic or generative nucleus) for reproduction. Holospora caryophila steps out of line, naturally occurring in Paramecium biaurelia and Paramecium caudatum. This study addresses the phylogenetic relationship among H. caryophila and other Holospora species based on 16S rRNA gene sequence comparison analyzing the type strain and seven new macronuclear symbionts. Key aspects of Holospora physiology such as infectivity, symbiosis establishment and host range were determined by comprehensive infection assays. Detailed morphological investigations and sequence-based phylogeny confirmed a high similarity between the type strain of H. caryophila and the novel strains. Surprisingly, they are only distantly related to other Holospora species suggesting that they belong to a new genus within the family Holosporaceae, here described as Preeria caryophila comb. nov. Adding to this phylogenetic distance, we also observed a much broader host range, comprising at least eleven Paramecium species. As these potential host species exhibit substantial differences in frequency of sexual processes, P. caryophila demonstrates which adaptations are crucial for macronuclear symbionts facing regular destruction of their habitat. PMID- 29718230 TI - Planning for minimally invasive aortic valve replacement: key steps for patient assessment. AB - Minimally invasive aortic valve replacement (MIAVR) has proved to be a safe approach for the treatment of aortic valve stenosis and/or insufficiency and is associated with a number of additional benefits for patients. This includes reduced blood loss, reduced transfusion requirements, reduced length of hospital stay and improved aesthetic appearance. As all types of minimally invasive surgery rely on optimizing exposure within a more limited field of view, a thorough preoperative assessment of patients is important to identify and address potential exposure problems. MIAVR through an upper hemisternotomy is considered feasible in almost every patient, but various clinical conditions or anatomical variations can complicate the procedure and may impact on the postoperative outcome. MIAVR through an anterior right thoracotomy requires suitable anatomy, and this should be evaluated preoperatively through a computed tomography or magnetic resonance imaging scan. In this review, we aimed to present an overview of the current literature and to reflect on our personal experiences with MIAVR techniques. This should provide an aid-especially to surgeons wanting to start or have little experience with MIAVR-for a structured preoperative patient assessment and planning to increase the chance of a safe procedure with a good outcome. PMID- 29718231 TI - Introduction: minimally invasive aortic valve surgery supplement. PMID- 29718232 TI - Knowledge transfer and quality control in minimally invasive aortic valve replacement. AB - Cardiac surgery has adapted to new demands and the development of new technologies has become a necessity. With this in mind, the interest in minimally invasive aortic valve replacement has grown tremendously. It is evident that the learning curve is an important consideration in the adoption of new technologies and has an impact on outcomes while it is being navigated. In this review, we discuss the process of knowledge transfer and quality control in the setting of minimally invasive aortic valve replacement. PMID- 29718233 TI - Minimally invasive aortic valve replacement techniques using endoscopic surgery: 'must dos' and 'preferences'. AB - Aortic valve replacement via a full sternotomy remains the gold standard for aortic stenosis treatment; however, minimally invasive techniques have grown in popularity and continue to evolve. A recent evolution of minimally invasive aortic valve replacement is endoscopic surgical aortic valve replacement: a miniaturized surgical approach under video guidance. To ensure a safe and reproducible procedure, we have developed 'must dos' and 'preferences' for endoscopic surgical aortic valve replacement. These include specific endoscopic surgical skills to avoid severe adverse events or an emergency conversion to a full sternotomy. PMID- 29718234 TI - Technical points for aortic valve replacement through right anterior minithoracotomy. AB - After 8 years of practice and over 400 operated patients, we present a technique of minimally invasive aortic valve replacement that can be used by all surgeons on many patients. The access to the aorta is via the 2nd or 3rd right anterior intercostal space. Cardiopulmonary bypass is provided using the femoral artery and vein. The aorta is clamped directly. One shot of Custodiol (EUSA Pharma, Limonest, France) is the most commonly used cardioplegia. Aortic valve replacement is performed in the regular way. To reduce the aortic cross-clamping time, sutureless or rapid-deployment valves, as well as the Cor-Knot (LSI Solutions, Inc., Victor, NY, USA) automatic knotting system, are excellent options. Right anterior minithoracotomy for aortic valve replacement is safe and reproducible. PMID- 29718235 TI - Outcomes of minimally invasive aortic valve replacement surgery. AB - Minimally invasive aortic valve replacement has been used for more than 20 years, but its uptake has been limited. The volumes have increased steadily over the last 10 years, but it is still not regarded as a mainstream procedure. The issue, to some extent, is due to the lack of perceived evidence that minimal access incisions confer any benefit other than cosmetic appearance. In this article, the current literature on minimally invasive aortic valve replacement is reviewed, and it is concluded that benefits are demonstrable, particularly in higher risk, comorbid settings. PMID- 29718236 TI - Universal evolutionary selection for high dimensional silent patterns of information hidden in the redundancy of viral genetic code. AB - Motivation: Understanding how viruses co-evolve with their hosts and adapt various genomic level strategies in order to ensure their fitness may have essential implications in unveiling the secrets of viral evolution, and in developing new vaccines and therapeutic approaches. Here, based on a novel genomic analysis of 2625 different viruses and 439 corresponding host organisms, we provide evidence of universal evolutionary selection for high dimensional 'silent' patterns of information hidden in the redundancy of viral genetic code. Results: Our model suggests that long substrings of nucleotides in the coding regions of viruses from all classes, often also repeat in the corresponding viral hosts from all domains of life. Selection for these substrings cannot be explained only by such phenomena as codon usage bias, horizontal gene transfer and the encoded proteins. Genes encoding structural proteins responsible for building the core of the viral particles were found to include more host repeating substrings, and these substrings tend to appear in the middle parts of the viral coding regions. In addition, in human viruses these substrings tend to be enriched with motives related to transcription factors and RNA binding proteins. The host-repeating substrings are possibly related to the evolutionary pressure on the viruses to effectively interact with host's intracellular factors and to efficiently escape from the host's immune system. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29718237 TI - Inflammatory Bowel Disease Care: What to Do When There Is a Breach of Contract between the Patient and Physician? AB - Care for patients is generally delivered under the context of an unwritten contract with few clauses, among them being that the physician will educate the patient about treatment options and recommend the treatment that they believe will be most likely to help the patient and that the patient will do their best to follow the agreed upon treatment plan. As the treatments for inflammatory bowel disease have become more complex, the demands placed on patients to complete pretreatment screening, monitoring, and health maintenance activities have also increased. Physicians caring for these patients face challenging decisions when patients do not adhere to the recommended protocol. This commentary discusses potential implications of different approaches to this clinical dilemma. PMID- 29718238 TI - Transection of the Nasal Base Muscles for the Correction of Plunging Tip: An Outcome Analysis. AB - Background: The plunging-tip deformity has been attributed to the combined actions of nasal base muscles. However, there are no quantitative data in the literature to discuss the effect of muscle transections on the clinical outcome. Objectives: This study was designed to assess the actions of the nasal tip, nasal base, and upper lip in patients with plunging-tip deformity and to compare their preoperative and postoperative activities following multiple myotomies. Methods: Patients were treated for nasal base animation deformity by the transection of the depressor septi nasalis, myrtiformis, nasalis, and levator labii superior alaeque nasi muscles. The profile views of preoperative and 12 months postoperative photographs were selected for measurements. Rest and smile images were overlaid to achieve alignment, and movements were measured with reference to the Frankfurt horizontal plane. Results: Twenty-seven (27) patients were included in the study. Movements of the nasal tip and nasal base were significantly reduced postoperatively. The upper lip shortened significantly in smile poses postoperatively compared with preoperative measurements. The change in the tip angle during animation significantly decreased in the postoperative measurements. Conclusions: Movements of the nasal tip and the alar base contributed significantly to the hyperdynamic nasal tip deformity. Transection of the nasal base muscles is an effective treatment method with a weaker recovery of the muscle function in the long term. Dynamic upper lip shortening is an unexpected finding following surgery and should be investigated further. Level of Evidence 4: PMID- 29718240 TI - Freeze-all: 51% live births in first cycle. PMID- 29718239 TI - Neural Crest Transplantation Reveals Key Roles in the Evolution of Cavefish Development. AB - Evolutionary changes in Astyanax mexicanus cavefish with respect to conspecific surface fish, including the regression of eyes, loss of pigmentation, and modification of the cranial skeleton, involve derivatives of the neural crest. However, the role of neural crest cells in cavefish evolution and development is poorly understood. One of the reasons is that experimental methods for neural crest analysis are not well developed in the Astyanax system. Here we describe neural crest transplantation between Astyanax surface fish and cavefish embryos. We found differences in the migration of cranial neural crest cells transplanted from the surface fish anterior hindbrain to the same region of surface fish or cavefish hosts. Cranial neural crest cells migrated extensively throughout the head, and to a lesser extent the trunk, in surface fish hosts but their migration was mostly restricted to the anterior and dorsal head regions in cavefish hosts. Cranial neural crest cells derived from the surface fish transplants invaded the degenerating eyes of cavefish hosts, resulting in increased eye size and suggesting that cavefish neural crest cells are defective in forming optic derivatives. We found that melanophores were formed in albino cavefish from grafts of surface fish trunk neural crest cells, showing that the cavefish tissue environment is conducive for pigment cell development, and implicating intrinsic changes in cavefish neural crest cells in loss of body pigmentation. It is concluded that changes in neural crest cells play key roles in the evolution of cavefish development. PMID- 29718241 TI - Cost-Effectiveness of Different Strategies for the Treatment of Moderate-to Severe Ulcerative Colitis. AB - Background: Knowledge regarding the economic outcomes of anti-tumour necrosis factor-alpha (anti-TNFalpha) and oral Janus kinase inhibitor (JAKi) therapies for the treatment of ulcerative colitis (UC) is limited. We conducted this analysis to assess the economic outcomes of anti-TNFalpha, antiadhesion molecule inhibitors (anti-AMi), and oral JAKi therapies for the treatment of UC from the perspectives of the United Kingdom (UK) and China, which are the representatives of high-income and middle-income regions, respectively. Methods: A Markov model based economic analysis was performed by incorporating effectiveness and utility data obtained from the literature and costs based on publicly available reports. The UK and Chinese health care perspectives were adopted to evaluate different intervention treatment sequences, including 14 treatment sequences consisting of conventional therapy, tofacitinib, adalimumab, vedolizumab, golimumab, and infliximab. The participants were the patients with moderate-to-severe UC eligible for anti-TNFalpha, anti-Ami, and JAKi treatment. Cost, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER) were reported. Results: Compared to other alternatives comprising adalimumab, golimumab, and infliximab, the use of a treatment sequence comprising tofacitinib and vedolizumab always had better health outcomes. The most cost-effective options in the UK included the sequences comprising tofacitinib and vedolizumab, and the most cost-effective treatment option in China was tofacitinib. There were uncertainties surrounding the results, the key drivers of which being the utility values, effectiveness of conventional therapy, and relative efficacy of the active treatments. Conclusions: The treatment with tofacitinib and vedolizumab for moderate-to-severe UC is likely to be the most favorable cost-effective option in the high-income UK, and tofacitinib is the most cost-effective option in the middle-income China. PMID- 29718242 TI - Daptomycin selects for genetic and phenotypic adaptations leading to antibiotic tolerance in MRSA. AB - Objectives: Daptomycin non-susceptibility in Staphylococcus aureus can emerge via the accumulation of single or multiple mutations, each resulting in a slight increase in the daptomycin MIC. The daptomycin-non-susceptible phenotype may include other features such as daptomycin tolerance. This study identifies S. aureus genomic regions that frequently develop mutations following prolonged daptomycin exposure but have not been previously associated with daptomycin non susceptibility. Methods: Sequence variations in the same eight loci independently observed following 28 day parallel serial passages of S. aureus J01 in daptomycin were introduced in isolation into S. aureus J01. MICs were determined by microbroth dilution. Daptomycin killing and tolerance were determined by kill curve analysis. Results: Single mutations in snoF, hmp1, sspA, rimP, hepT, rsh, map1 and amaP had only a modest impact on the daptomycin MIC (<=2-fold). In contrast, individual mutation in several of these regions resulted in pronounced changes to daptomycin tolerance. Conclusions: This study demonstrates that less characterized mutations in S. aureus following daptomycin exposure do not result in significant daptomycin susceptibility changes, but rather allow for enhanced survival characteristics during treatment. This sheds new light on genetic adaptations that may play a role in persistent infection. Further studies are needed to elucidate the prevalence of these mutations in clinical isolates. PMID- 29718243 TI - The Impact of Age at Time of Ileal Pouch Anal Anastomosis on Short and Long-Term Outcomes in Adults. AB - Background: There is limited knowledge on ileal pouch anal anastomosis (IPAA) function when performed on patients older than age 50 years. The aim of this study was to determine if surgery on those older than age 50 years impacts short term complications or long-term function. Methods: A retrospective review of all patients undergoing IPAA for chronic ulcerative colitis at a single tertiary referral center between 2002 and 2013 was conducted. Short-term postoperative complications and long-term function and quality of life were analyzed according to age at pouch formation (age >50 vs age <=50 years). Results: A total of 911 patients who underwent IPAA (542 male) were included, with 178 patients (20%) age >50 years and 733 (80%) <=50 years. Patients >50 years had higher American Society of Anesthesiology score (ASA) scores and increased rates of obesity and dysplasia or cancer at the time of colectomy, and were less often on steroids (all P < 0.01). Over a median follow-up of 5 years, older patients reported increased daytime incontinence (60% vs 37%, P < 0.01) and pad usage (34% vs 11%, P < 0.01) at up to 1.5 years post-IPAA, after which time the groups became similar. Other functional outcomes, including pouch failure and quality of life, were similar between the 2 groups across the follow-up periods. Conclusion: Performing an IPAA on carefully selected patients older than age 50 years has minor, transient differences in pouch function compared with patients younger than age 50 years. Assuming appropriate patient selection, IPAA should continue to be offered to older patients without increased risk of compromised function or of pouch failure. PMID- 29718244 TI - Burden of Ulcerative Colitis on Functioning and Well-being: A Systematic Literature Review of the SF-36(r) Health Survey. AB - Background and Aims: This review is the first to evaluate the burden of ulcerative colitis [UC] on patients' quality of life by synthesizing data from studies comparing scores from the SF-36(r) Health Survey, a generic measure assessing eight quality-of-life domains, between UC patients and matched reference samples. Methods: A systematic review of the published literature identified articles reporting SF-36 domains or physical and mental component summary scores [PCS, MCS] from UC and reference samples. Burden of disease for each SF-36 domain was then summarized across studies by comparing weighted mean differences in scores between patient and reference samples with minimally important difference thresholds. Results: Thirty articles met pre-specified inclusion criteria. SF-36 scores were extracted from five samples of patients with active disease, 11 samples with a mixture of disease activity, five samples of patients in clinical remission, and 13 samples of patients following proctocolectomy with ileostomy or ileal pouch-anal anastomosis, along with respective reference samples. Clinically meaningful burden was observed in samples with active or mixed disease activity [deficits: PCS = 5.6, MCS = 5.5] on all SF-36 domains except Physical Functioning. No burden was observed in samples in remission or post-surgical patients [deficits: PCS = 0.8, MCS = 0.4] except for the General Health perception domain. Conclusions: Patients with active UC experience a clinically meaningful burden of disease across most aspects of quality of life. Patients with inactive UC exhibit negligible disease burden and are comparable to the general population on most quality-of-life outcomes. Thus, treatments which effectively induce and maintain remission may restore physical and mental health status. PMID- 29718245 TI - Systematic Review and Meta-Analysis: Preoperative Vedolizumab Treatment and Postoperative Complications in Patients with Inflammatory Bowel Disease. AB - Background and Aims: The impact of vedolizumab, a gut-selective monoclonal antibody, on postoperative outcomes is unclear. This study aimed to assess the impact of preoperative vedolizumab treatment on the rate of postoperative complications in patients with inflammatory bowel disease [IBD] undergoing abdominal surgery. Methods: A systematic search of multiple electronic databases from inception until May 2017 identified studies reporting rates of postoperative complications in vedolizumab-treated IBD patients compared to no biologic exposure or anti-tumor necrosis factor (anti-TNF) treated IBD patients. Outcomes of interest included postoperative infectious complications and overall postoperative complications. Pooled risk ratios and 95% confidence intervals were estimated using the random-effects model. Results: Five studies comprising 307 vedolizumab-treated IBD patients, 490 anti-TNF-treated IBD patients and 535 IBD patients not exposed to preoperative biologic therapy were included. The risk of postoperative infectious complications (risk ratio [RR] 0.99, 95% confidence interval [CI] 0.37-2.65) and overall postoperative complications [RR 1.00, 95% CI 0.46-2.15] were not significantly different between vedolizumab-treated patients and those who received no preoperative biologic therapy. In addition, the risk of postoperative infectious complications [RR 0.99, 95% CI 0.34-2.90] and overall postoperative complications [RR 0.92, 95% CI 0.44-1.92] were not significantly different between vedolizumab-treated vs anti-TNF-treated patients. Conclusions: Preoperative vedolizumab treatment in IBD patients does not appear to be associated with an increased risk of postoperative infectious or overall postoperative complications compared to either preoperative anti-TNF therapy or no biologic therapy. Future prospective studies which include perioperative drug level monitoring are needed to confirm these findings. PMID- 29718246 TI - Covariate-adjusted heatmaps for visualizing biological data via correlation decomposition. AB - Motivation: Heatmap is a popular visualization technique in biology and related fields. In this study, we extend heatmaps within the framework of matrix visualization (MV) by incorporating a covariate adjustment process through the estimation of conditional correlations. MV can explore the embedded information structure of high-dimensional large-scale datasets effectively without dimension reduction. The benefit of the proposed covariate-adjusted heatmap is in the exploration of conditional association structures among the subjects or variables that cannot be done with conventional MV. Results: For adjustment of a discrete covariate, the conditional correlation is estimated by the within and between analysis. This procedure decomposes a correlation matrix into the within- and between-component matrices. The contribution of the covariate effects can then be assessed through the relative structure of the between-component to the original correlation matrix while the within-component acts as a residual. When a covariate is of continuous nature, the conditional correlation is equivalent to the partial correlation under the assumption of a joint normal distribution. A test is then employed to identify the variable pairs which possess the most significant differences at varying levels of correlation before and after a covariate adjustment. In addition, a z-score significance map is constructed to visualize these results. A simulation and three biological datasets are employed to illustrate the power and versatility of our proposed method. Availability and implementation: GAP is available to readers and is free to non-commercial applications. The installation instructions, the user's manual, and the detailed tutorials can be found at http://gap.stat.sinica.edu.tw/Software/GAP. Supplementary information: Supplementary Data are available at Bioinformatics online. PMID- 29718248 TI - Antibacterial activity and mechanism of action of analogues derived from the antimicrobial peptide mBjAMP1 isolated from Branchiostoma japonicum. AB - Objectives: The worldwide increase in antibiotic-resistant bacteria is a growing threat to public health. Antimicrobial peptides (AMPs) are potentially effective alternatives to conventional antibiotics. We therefore tested analogues of the AMP mBjAMP1 from Branchiostoma japonicum, which we produced by adding and/or replacing amino acids to increase antimicrobial activity against Gram-negative bacteria. Methods: We compared the antimicrobial activities of mBjAMP1 analogues against Gram-negative bacteria reference strains and 52 strains of Klebsiella pneumoniae isolated from patients. Antibiofilm activity and cytotoxicity were evaluated, and the mechanisms of action were then studied. Results: Analogue peptides exhibited greater antimicrobial and antibiofilm activities than mBjAMP1. In particular, the analogue IARR-Anal10 displayed not only the greatest antimicrobial and antibiofilm activities, but also no toxicity against human red blood cells or other mammalian cells. IARR-Anal10 had little or no effect on bacterial outer membrane permeability, membrane polarization or membrane integrity. Instead, it appears IARR-Anal10 binds bacterial DNA, as evidenced in DNA gel retardation assays. Thus, IARR-Anal10 likely kills bacteria through an intracellular mechanism. We also confirmed that IARR-Anal10 suppresses the virulence of K. pneumoniae to a degree similar to tigecycline, used to treat carbapenem-resistant Enterobacteriaceae infections. Notably, IARR-Anal10 did not induce development of resistance by K. pneumoniae, though both meropenem and tigecycline did so within a short time. Conclusions: These results suggest that IARR-Anal10 is a promising agent for treating infections caused by bacteria resistant to tigecycline and meropenem. PMID- 29718249 TI - Perceived Neighborhood Safety, Social Cohesion, and Psychological Health of Older Adults. PMID- 29718247 TI - Emerging resistance mutations in PI-naive patients failing an atazanavir-based regimen (ANRS multicentre observational study). AB - Background: Atazanavir is a PI widely used as a third agent in combination ART. We aimed to determine the prevalence and the patterns of resistance in PI-naive patients failing on an atazanavir-based regimen. Methods: We analysed patients failing on an atazanavir-containing regimen used as a first line of PI therapy. We compared the sequences of reverse transcriptase and protease before the introduction of atazanavir and at failure [two consecutive viral loads (VLs) >50 copies/mL]. Resistance was defined according to the 2014 Agence Nationale de Recherche sur le SIDA et les Hepatites Virales (ANRS) algorithm. Results: Among the 113 patients, atazanavir was used in the first regimen in 71 (62.8%) patients and in the first line of a PI-based regimen in 42 (37.2%). Atazanavir was boosted with ritonavir in 95 (84.1%) patients and combined with tenofovir/emtricitabine or lamivudine (n = 81) and abacavir/lamivudine or emtricitabine (n = 22). At failure, median VL was 3.05 log10 copies/mL and the median CD4+ T cell count was 436 cells/mm3. The median time on atazanavir was 21.2 months. At failure, viruses were considered resistant to atazanavir in four patients (3.5%) with the selection of the following major atazanavir-associated mutations: I50L (n = 1), I84V (n = 2) and N88S (n = 1). Other emergent PI mutations were L10V, G16E, K20I/R, L33F, M36I/L, M46I/L, G48V, F53L, I54L, D60E, I62V, A71T/V, V82I/T, L90M and I93L/M. Emergent NRTI substitutions were detected in 21 patients: M41L (n = 2), D67N (n = 3), K70R (n = 1), L74I/V (n = 3), M184V/I (n = 16), L210W (n = 1), T215Y/F (n = 3) and K219Q/E (n = 2). Conclusions: Resistance to atazanavir is rare in patients failing the first line of an atazanavir-based regimen according to the ANRS. Emergent NRTI resistance-associated mutations were reported in 18% of patients. PMID- 29718250 TI - Proximal first: a beneficial strategy for no-touch saphenous vein graft. AB - In the mid-1990s, a novel saphenous vein harvesting technique, in which the vein is harvested with its surrounding tissue without manual distention, was introduced. This no-touch technique provides an excellent long-term patency; however, graft twisting and kinking should be given attention. To fully bring out the benefit of the no-touch method while reducing the risk of twisting and kinking, we have modified the anastomosis strategy. Our simple modified strategy involved a proximal anastomosis prior to the distal anastomosis. This strategy was successfully used in 16 patients. PMID- 29718251 TI - Major complications of minimally invasive Ivor Lewis oesophagectomy using the purse string-stapled anastomotic technique in 215 patients with oesophageal carcinoma. AB - OBJECTIVES: The purse string-stapled anastomotic technique is a method for minimally invasive oesophagectomy with intrathoracic anastomosis, in which a purse string is hand sewn without the necessity of specialized devices, such as OrVil and Endo-Stitch. Since this technique was first reported by our surgical team in 2012, several measures in the operation have been refined. Furthermore, there are very few literature reports on the major complications of minimally invasive oesophagectomy with this technique. This article studies the major complications of minimally invasive Ivor Lewis oesophagectomy with this technique and explores methods for prevention and treatment. METHODS: Clinical data of 215 patients with oesophageal cancer who underwent thoracoscopic laparoscopic oesophagectomy with intrathoracic anastomosis from October 2011 to December 2015 were analysed. No patients received preoperative radiotherapy and chemotherapy. During the operation, the purse string was simply hand sewn before it was tightened and tied, and anastomosis was performed using a circular stapler. RESULTS: Six (2.79%) patients developed anastomotic leakage, and all of them were treated conservatively. Three (1.40%) patients experienced postoperative haemorrhage; of them, 2 were cured with conservative treatment. The remaining patient was cured by endoscopic management using titanium clips. Thirty-nine (18.14%) patients experienced postoperative pulmonary complications. One (1.47%) patient died due to pulmonary infection with respiratory failure although he had received mechanical ventilator support after tracheotomy. Five (2.33%) patients developed chyle leakage and 5 (2.33%) patients developed recurrent laryngeal nerve injuries. CONCLUSIONS: The incidence of major complications is acceptable for thoracoscopic laparoscopic oesophagectomy with intrathoracic anastomosis using this purse string-stapled anastomotic technique, which is feasible and safe to perform. Some measures designed in the operation will be conducive to reduce the incidence of major complications. PMID- 29718252 TI - Mitochondria, Temperature, and the Pace of Life. AB - Life history strategies, physiological traits, and behavior are thought to covary along a "pace of life" axis, with organisms at the fast end of this continuum having higher fecundity, shorter lifespan, and more rapid development, growth, and metabolic rates. Countergradient variation represents a special case of pace of life variation, in which high-latitude organisms occupy the fast end of the continuum relative to low-latitude conspecifics when compared at a common temperature. Here, we use Atlantic killifish (Fundulus heteroclitus) to explore the role of mitochondrial properties as a mechanism underlying countergradient variation, and thus variation in the pace of life. This species is found along the Atlantic coast of North America, through a steep latitudinal thermal gradient. The northern subspecies has faster development, more rapid growth, higher routine metabolic rate, and higher activity than the southern subspecies when compared at a common temperature. The northern subspecies also has greater mitochondrial respiratory capacity in the liver, although these differences are not evident in other tissues. The increased respiratory capacity of liver mitochondria in northern fish is associated with increases in the activity of multiple electron transport complexes, which largely reflects an increase in the amount of inner mitochondrial membrane per mitochondrion in the northern fish. There are also differences in the lipid composition of liver mitochondrial membranes, including differences in cardiolipin species, which could also influence respiratory capacity. These data suggest that variation in mitochondrial properties could, at least in part, underlie variation in the pace of life in Atlantic killifish. PMID- 29718254 TI - Effects of intermittent feeding of tylosin phosphate during the finishing period on feedlot performance, carcass characteristics, antimicrobial resistance, and incidence and severity of liver abscesses in steers. AB - Liver abscesses (LA) are a source of economic loss for feedlot cattle feedlots, and the 2017 veterinary feed directive has restricted further use of tylosin phosphate to prevention and control of LA. Our objective was to evaluate effects of intermittent tylosin phosphate feeding on incidence and severity of LA in feedlot cattle and presence of total antimicrobial-resistant Enterococcus spp. Steers (n = 312, 411.4 +/- 6.71 kg) were blocked by initial BW and randomly assigned to a treatment group. Treatments included a negative control group (no tylosin phosphate throughout the finishing period), a positive control group (tylosin phosphate fed continuously throughout the finishing period), and a group that received tylosin phosphate off-label by feeding the drug on a repeated intermittent basis (1 wk on, 2 wk off). Steers were housed in 24 soil-surfaced pens with 13 steers per pen. Body weights of cattle were obtained every 28 d and at the end of 119 d the steers were weighed and harvested at a commercial abattoir. Fecal samples were collected on days 0, 21, and 118 to characterize antimicrobial-resistant Enterococcus spp. Total LA percentage was greater (P = 0.012) for the no tylosin phosphate treatment compared with the other treatments, but did not differ between the continuous tylosin phosphate treatment and the intermittently fed tylosin phosphate treatment (P = 0.716). No difference was observed among treatments for ADG (P = 0.21), DMI (P = 0.28), or G:F (P = 0.75). Marbling score was lower (P = 0.022) for tylosin phosphate treatment when compared with both intermittent treatment and continuous tylosin phosphate treatment. Enterococcus spp. bacterial counts did not differ by treatment group over time (P > 0.05); however, there was a strong period effect for macrolide resistance among all groups (P < 0.01), suggesting an important environmental component as cattle were first placed in pens and then progressed through the feeding period. We conclude that feeding tylosin phosphate intermittently during the finishing phase decreases the total percentage of LA and maintains feedlot performance and carcass characteristics to the same extent as feeding tylosin phosphate throughout the finishing phase; furthermore, we hypothesize that enteric antimicrobial resistance is a result of longer term antibiotic usage in a particular environment rather than a direct short-term result of the treatment during any given feeding period. PMID- 29718255 TI - Mitochondrial DNA Is a Pro-Inflammatory Damage-Associated Molecular Pattern Released During Active IBD. AB - Background: Due to common evolutionary origins, mitochondrial DNA (mtDNA) shares many similarities with immunogenic bacterial DNA. MtDNA is recognized as a pro inflammatory damage-associated molecular pattern (DAMP) with a pathogenic role in several inflammatory diseases. We hypothesised that mtDNA is released during active disease, serving as a key pro-inflammatory factor in inflammatory bowel disease (IBD). Methods: Between 2014 and 2015, we collected plasma separated within 2 hours of sampling from 97 prospectively recruited IBD patients (67 ulcerative colitis [UC] and 30 Crohn's disease [CD]) and 40 non-IBD controls. We measured circulating mtDNA using quantitative polymerase chain reaction (amplifying mitochondria COXIII/ND2 genes) and also in mouse colitis induced by dextran sulfate-sodium (DSS). We used a mass spectometry approach to detect free plasma mitochondrial formylated peptides. Furthermore, we examined for mitochondrial damage using electron microscopy (EM) and TLR9 expression, the target for mtDNA, in human intestinal IBD mucosa. Results: Plasma mtDNA levels were increased in UC and CD (both P < 0.0001) compared with non-IBD controls. These levels were significantly correlated to blood (C-reactive protein, albumin, white cell count), clinical and endoscopic markers of severity, and disease activity. In active UC, we identified 5 mitochondrial formylated peptides (the most abundant being fMMYALF with known chemoattractant function) in plasma. We observed mitochondrial damage in inflamed UC mucosa and significantly higher fecal MtDNA levels (vs non-IBD controls [P < 0.0001]), which supports gut mucosal mitochondrial DAMP release as the primary source. In parallel, plasma mtDNA levels increased during induction of acute DSS colitis and were associated with more severe colitis (P < 0.05). In active IBD, TLR9+ lamina propria inflammatory cells were significantly higher in UC and CD compared with controls (P < 0.05). Conclusions: We present the first evidence to show that mtDNA is released during active IBD. MtDNA is a potential mechanistic biomarker, and our data point to mtDNA-TLR9 as a therapeutic target in IBD. 10.1093/ibd/izy095_videoizy095.video5776747659001. PMID- 29718256 TI - DSCAM Mutation Impairs Motor Cortex Network Dynamic and Voluntary Motor Functions. AB - While it is well known that netrin-1 and its receptors UNC5 and UNC40 family members are involved in the normal establishment of the motor cortex and its corticospinal tract, less is known about its other receptor Down syndrome cell adherence molecule (DSCAM). DSCAM is expressed in the developing motor cortex, regulates axonal outgrowth of cortical neurons, and its mutation impairs the dendritic arborization of cortical neurons, thus suggesting that it might be involved in the normal development and functioning of the motor cortex. In comparison to WT littermates, DSCAM2J mutant mice slipped and misplaced their paw while walking on the rungs of a horizontal ladder, and exhibited more difficulties in stepping over an obstacle while walking at slow speed. Anterograde tracing showed a normal pyramidal decussation and corticospinal projection, but a more dorsal distribution of their axonal terminals in the spinal gray matter. Intracortical microstimulations showed a reduced corticospinal and intracortical efficacy, whereas stimulations of the pyramidal tract revealed a normal spinal efficacy and excitability of corticospinal tract axons, thus arguing for a dysfunctional cortical development. Our study reveals impairment of the network dynamics within the motor cortex, reducing corticospinal drive and impairing voluntary locomotor functions upon DSCAM2J mutation. PMID- 29718257 TI - The role of epidemiology in firearm violence prevention: a Policy Brief. PMID- 29718253 TI - Adverse effects of statin therapy: perception vs. the evidence - focus on glucose homeostasis, cognitive, renal and hepatic function, haemorrhagic stroke and cataract. AB - Aims: To objectively appraise evidence for possible adverse effects of long-term statin therapy on glucose homeostasis, cognitive, renal and hepatic function, and risk for haemorrhagic stroke or cataract. Methods and results: A literature search covering 2000-2017 was performed. The Panel critically appraised the data and agreed by consensus on the categorization of reported adverse effects. Randomized controlled trials (RCTs) and genetic studies show that statin therapy is associated with a modest increase in the risk of new-onset diabetes mellitus (about one per thousand patient-years), generally defined by laboratory findings (glycated haemoglobin >=6.5); this risk is significantly higher in the metabolic syndrome or prediabetes. Statin treatment does not adversely affect cognitive function, even at very low levels of low-density lipoprotein cholesterol and is not associated with clinically significant deterioration of renal function, or development of cataract. Transient increases in liver enzymes occur in 0.5-2% of patients taking statins but are not clinically relevant; idiosyncratic liver injury due to statins is very rare and causality difficult to prove. The evidence base does not support an increased risk of haemorrhagic stroke in individuals without cerebrovascular disease; a small increase in risk was suggested by the Stroke Prevention by Aggressive Reduction of Cholesterol Levels study in subjects with prior stroke but has not been confirmed in the substantive evidence base of RCTs, cohort studies and case-control studies. Conclusion: Long-term statin treatment is remarkably safe with a low risk of clinically relevant adverse effects as defined above; statin-associated muscle symptoms were discussed in a previous Consensus Statement. Importantly, the established cardiovascular benefits of statin therapy far outweigh the risk of adverse effects. PMID- 29718258 TI - The benefits of health information exchange: an updated systematic review. AB - Objective: Widespread health information exchange (HIE) is a national objective motivated by the promise of improved care and a reduction in costs. Previous reviews have found little rigorous evidence that HIE positively affects these anticipated benefits. However, early studies of HIE were methodologically limited. The purpose of the current study is to review the recent literature on the impact of HIE. Methods: We used the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines to conduct our systematic review. PubMed and Scopus databases were used to identify empirical articles that evaluated HIE in the context of a health care outcome. Results: Our search strategy identified 24 articles that included 63 individual analyses. The majority of the studies were from the United States representing 9 states; and about 40% of the included analyses occurred in a handful of HIEs from the state of New York. Seven of the 24 studies used designs suitable for causal inference and all reported some beneficial effect from HIE; none reported adverse effects. Conclusions: The current systematic review found that studies with more rigorous designs all reported benefits from HIE. Such benefits include fewer duplicated procedures, reduced imaging, lower costs, and improved patient safety. We also found that studies evaluating community HIEs were more likely to find benefits than studies that evaluated enterprise HIEs or vendor-mediated exchanges. Overall, these finding bode well for the HIEs ability to deliver on anticipated improvements in care delivery and reduction in costs. PMID- 29718259 TI - Asymptomatic hyperCKemia During Infliximab Therapy in Patients With Inflammatory Bowel Disease. PMID- 29718260 TI - Asymptomatic hyperCKemia During Infliximab Therapy in Patients With Inflammatory Bowel Disease. AB - Background: Both muscle-related complaints and elevated serum creatine kinase (CK) levels have been reported in patients with inflammatory bowel disease (IBD) treated with infliximab (IFX), mainly as case reports. The aim of this study was to investigate the effect of IFX therapy on serum CK levels in a cohort of Greek IBD patients. Methods: Demographic, clinical (including muscle complaints), and laboratory data of consecutive IBD patients undergoing IFX treatment and a matched control group of IBD patients without any use of biological treatment were retrospectively analyzed. In both groups, patients having at least 3 CK measurements, with at least 10 days' interval among them, were included. Results: The IFX-treated IBD patient group included 82 individuals (75.6% Crohn's Disease [CD]; mean age, 44.7 +/- 13.3 years; 60.9% men; median [interquartile range {IQR}] duration of IFX treatment, 27 [12-84] months). Eighty-two patients without treatment with any biological agent formed the control group (62.2% CD; mean age, 50.4 +/- 16.4 years; 59.8% men). Twenty-five IFX-treated patients (30.5%) had elevated mean serum CK levels (>180 U/L), compared with 9 (11%) in the control group (P = 0.0003). The median CK value in the IFX group (123.5 U/L; IQR, 91 190.75) was significantly higher than that of the control group (81 U/L; IQR, 57 112.75; P < 0.0001). In the logistic regression analysis, the presence of hyperCKemia was independently correlated with the use of IFX (odds ratio, 4.03; IQR, 1.64-9.90; P = 0.002). No patient with hyperCKemia in both groups reported any persistent symptom of myopathy. Conclusions: More than 30% of IBD patients on IFX present asymptomatic persistent and treatment-related hyperCKemia. Further relevant prospective investigation is needed. 10.1093/ibd/izy088_video1izy088.video15778459427001. PMID- 29718261 TI - Mice lacking all of the Skint family genes. AB - gammadeltaT cells develop in the thymus and play important roles in protection against infection and tumor development, but the mechanisms by which the thymic microenvironment supports gammadeltaT cell differentiation remain largely unclear. Skint1, a B7-related protein expressed in thymic epithelial cells, was shown to be essential for the development of mouse Vgamma5Vdelta1 gammadeltaT cells. The Skint family in mouse consists of 11 members, Skint1-11. Here we generated mutant mice lacking the entire genomic region that contains all of the Skint genes. These mice exhibited a marked reduction of Vgamma5Vdelta1 gammadeltaT cells in the thymus and skin, but surprisingly, had normal development of other gammadeltaT cell subsets and leukocytes including alphabetaT, B and myeloid cells. This phenotype is essentially identical to that of Skint1-deficient mice. These results indicate that the Skint family exerts an exclusive function in regulating the development of Vgamma5Vdelta1 gammadeltaT cells and is dispensable for development of other leukocytes. PMID- 29718263 TI - Ask not what your technician can do for you-ask what you can do for your technician. AB - Historically, the vital roles played by technicians in Higher Education (HE) have had little recognition. Job opportunities are often overlooked by those who have no working knowledge of such organisations and poorly defined career pathways mean that it may not be a first choice for well-qualified, ambitious individuals. With just over a third of all HE technicians in the UK expected to retire in the next 10 to 15 years fundamental changes are needed, both to attract large numbers of people into vacant roles and to retain current technical staff. National initiatives, founded and driven by charitable and professional bodies, are currently working to address the issues of technicians within HE. Organisations have been urged to take action or face potential recruitment difficulties and skills gaps over the coming years. In light of these national campaigns, institutions across the UK are beginning to develop proper structured career pathways, provide professional development and improve recognition for the work of their technical workforce. Whilst these are encouraging signs, only time will tell if enough has been done to raise both the profile and appeal of a technical career in HE. PMID- 29718262 TI - Ketamine Effects on EEG during Therapy of Treatment-Resistant Generalized Anxiety and Social Anxiety. AB - Background: Ketamine is swiftly effective in a range of neurotic disorders that are resistant to conventional antidepressant and anxiolytic drugs. The neural basis for its therapeutic action is unknown. Here we report the effects of ketamine on the EEG of patients with treatment-resistant generalized anxiety and social anxiety disorders. Methods: Twelve patients with refractory DSM-IV generalized anxiety disorder and/or social anxiety disorder provided EEG during 10 minutes of relaxation before and 2 hours after receiving double-blind drug administration. Three ascending ketamine dose levels (0.25, 0.5, and 1 mg/kg) and midazolam (0.01 mg/kg) were given at 1-week intervals to each patient, with the midazolam counterbalanced in dosing position across patients. Anxiety was assessed pre- and postdose with the Fear Questionnaire and HAM-A. Results: Ketamine dose-dependently improved Fear Questionnaire but not HAM-A scores, decreased EEG power most at low (delta) frequency, and increased it most at high (gamma) frequency. Only the decrease in medium-low (theta) frequency at right frontal sites predicted the effect of ketamine on the Fear Questionnaire. Ketamine produced no improvement in Higuchi's fractal dimension at any dose or systematic changes in frontal alpha asymmetry. Conclusions: Ketamine may achieve its effects on treatment-resistant generalized anxiety disorder and social anxiety disorder through related mechanisms to the common reduction by conventional anxiolytic drugs in right frontal theta. However, in the current study midazolam did not have such an effect, and it remains to be determined whether, unlike conventional anxiolytics, ketamine changes right frontal theta when it is effective in treatment-resistant depression. PMID- 29718264 TI - A hypothesis explaining why so many pathogen virulence proteins are moonlighting proteins. AB - Moonlighting or multitasking proteins refer to those proteins with two or more functions performed by a single polypeptide chain. Proteins that belong to key ancestral functions and metabolic pathways such as primary metabolism typically exhibit moonlighting phenomenon. We have collected 698 moonlighting proteins in MultitaskProtDB-II database. A survey shows that 25% of the proteins of the database correspond to moonlighting functions related to pathogens virulence activity. Why is the canonical function of these virulence proteins mainly from ancestral key biological functions (especially of primary metabolism)? Our hypothesis is that these proteins present a high conservation between the pathogen protein and the host counterparts. Therefore, the host immune system will not elicit protective antibodies against pathogen proteins. The fact of sharing epitopes with host proteins (known as epitope mimicry) might be the cause of autoimmune diseases. Although many pathogen proteins can be antigenic, only a few of them would elicit a protective immune response. This would also explain the lack of successful vaccines based in these conserved moonlighting proteins. PMID- 29718265 TI - Effectiveness of a brief psycho-oncology training program for general nurses: a preliminary study. AB - Many nurses are not confident in management of psychological distress in cancer patients. We developed a brief psycho-oncology training program for general nurses, and explored the usefulness of the program preliminary. Seventy-two nurses in 17 designated cancer hospitals received a 4-h program comprising an e learning lecture on assessment and management of normal psychological responses to cancer and an onsite workshop, including a role-play exercise and group work. Primary outcomes were changes in self-reported confidence, knowledge and attitudes toward caring for patients with normal psychological response between pre-training and post-training. All outcomes, excepting several aspects of attitude, were significantly improved after training (P < 0.05). Intervention acceptability was good as no participants dropped out and all participants considered the program useful in clinical practice. Further consideration is required to clarify whether the cancer care provided by nurses who received psycho-oncology training is effective to ameliorate psychological distress in cancer patients. PMID- 29718266 TI - Donor aortic dissection in a heart transplantation recipient. AB - Aortic dissection after orthotopic heart transplantation is a rare condition, and a limited number of reports have been published in the literature. Herein, we report a case of Type A aortic dissection 16 years after heart transplantation. PMID- 29718267 TI - Integrated vaccine screening system: using cellular functional capacity in vitro to assess genuine vaccine protectiveness in ruminants. AB - Experimental trials in the natural host are essential for development and screening of effective vaccines. For chronic diseases of livestock such as paratuberculosis, these can be lengthy and costly in nature. An alternative is to screen vaccines in vitro; however, previous studies have found that vaccine success in vitro in existing screening assays does not translate to in vivo efficacy. To overcome these issues, we have developed a system that combines both in vivo and in vitro aspects. We hypothesise that the effectiveness of vaccine induced immune responses mounted in vivo could be gauged by assessing the ability of immune cells to 'control' an in vitro infection. Monocytes from Merino wethers (n = 45) were infected with Mycobacterium avium subspecies paratuberculosis (MAP) in vitro, cultured with autologous lymphocytes and remaining viable intracellular MAP was quantified. Cells from MAP exposed sheep had a higher capacity to kill intracellular MAP compared to non-exposed controls (P = 0.002). Importantly, cells from MAP exposed uninfected sheep had a greater capacity to kill intracellular MAP compared to vaccinated animals that were infected (ineffective vaccination), indicating that this in vitro assay has the potential to gauge actual protectiveness, or lack thereof, of a vaccine. PMID- 29718268 TI - Health conditions, functional status and health care utilization in adults with cerebral palsy. AB - Aim: Health conditions in children with cerebral palsy (CP) are well described, yet health is less defined with advancing age. We examined health conditions, functional status and health care utilization in adults with CP across age groups. Methods: We collected cross-sectional data on health conditions, functional status and utilization from the medical records of adults with CP across a large university-affiliated primary care network using the Rochester Health Status Survey IV (RHSS-IV), a 58-item validated survey. Data from the National Health and Nutrition Examination Survey and National Health Interview Survey provided prevalence estimates for the general population as comparison. Results: Compared to the general population, adults with CP had higher rates of seizure disorder, obesity and asthma across all ages. Adults with CP under 30 years of age had higher rates of hypertension (16.7 versus 5.6%; P = 0.04), urinary incontinence (41.7 versus 10.5%; P < 0.001) and depression (16.7 versus 6.9%; P = 0.07). Conversely, there were lower rates of alcohol misuse, tobacco/nicotine and sexually transmitted illnesses. Independence with all activities of daily living decreased from 37.5% at 18-29 years of age to 22.5% in those 60 and over. Seizure disorders, urinary incontinence and gastroesophageal reflux disease were all independently associated with lower functional status. As expected, health care utilization increased with advancing age. Conclusions: Adults with CP should be monitored for conditions occurring at higher prevalence in CP, as well as common conditions occurring with advancing age. Age-related functional decline should be anticipated, especially with coexisting seizure disorders and urinary incontinence. PMID- 29718269 TI - Evolution Under Dietary Restriction Decouples Survival From Fecundity in Drosophila melanogaster Females. AB - One of the key tenets of life-history theory is that reproduction and survival are linked and that they trade-off with each other. When dietary resources are limited, reduced reproduction with a concomitant increase in survival is commonly observed. It is often hypothesized that this dietary restriction effect results from strategically reduced investment in reproduction in favor of somatic maintenance to survive starvation periods until resources become plentiful again. We used experimental evolution to test this "waiting-for-the-good-times" hypothesis, which predicts that selection under sustained dietary restriction will favor increased investment in reproduction at the cost of survival because "good-times" never come. We assayed fecundity and survival of female Drosophila melanogaster fruit flies that had evolved for 50 generations on three different diets varying in protein content-low (classic dietary restriction diet), standard, and high-in a full-factorial design. High-diet females evolved overall increased fecundity but showed reduced survival on low and standard diets. Low diet females evolved reduced survival on low diet without corresponding increase in reproduction. In general, there was little correspondence between the evolution of survival and fecundity across all dietary regimes. Our results contradict the hypothesis that resource reallocation between fecundity and somatic maintenance underpins life span extension under dietary restriction. PMID- 29718270 TI - Protein adhesins as vaccine antigens for Group A Streptococcus. AB - Group A Streptococcus (GAS) is a globally important human pathogen that causes a broad spectrum of disease ranging from mild superficial infections to severe invasive diseases with high morbidity and mortality. Currently, there is no vaccine available for human use. GAS produces a vast array of virulence factors including multiple adhesin molecules. These mediate binding of the bacteria to host tissues and are essential in the initial phases of infection. Prophylactic vaccination with adhesins is a promising vaccine strategy and many GAS adhesins are currently in development as vaccine candidates. The most advanced candidates, having entered clinical trials, are based on the M protein, while components of the pilus and a number of fibronectin-binding proteins are in pre-clinical development. Adhesin-based vaccines aim to induce protective immunity via two main mechanisms: neutralisation where adhesin-specific antibodies block the ability of the adhesin to bind to host tissue and opsonisation in which adhesin specific antibodies tag the GAS bacteria for phagocytosis. This review summarises our current knowledge of GAS adhesins and their structural features in the context of vaccine development. PMID- 29718272 TI - Handling Artificially Terminated Events in Electropenetrography Data. AB - Electropenetrography a.k.a. electrical penetration graph or EPG is a rigorous technique for studying arthropod behavior. Essentially, the arthropod and host are part of an electrical circuit that generates patterns of voltage (waveforms), whose biological meanings are defined by correlation with histology and behavior. EPG is used for studying stylet probing behavior of hemipterans, and blood feeding arthropods. These results are applied to understanding pesticide action, host plant resistance, and vector-pathogen-host interactions. At the end of all recordings, the arthropod begins a behavior that ends because the scientist stopped recording. An argument for keeping this event in the data has been made based on the assumption that the insect is adapting to laboratory conditions. In this adaptation process, the expected durations of ingestion behaviors will increase as the insect adapts. We show that this assumption can cause problems in data analysis and interpretation of the data. If the assumption is false, then there are more options for analyzing the data. Deleting artificially terminated events can be advantageous, but the best approach needs to consider the biology of the arthropod and align with research objectives. PMID- 29718273 TI - FGF23 Regulates Wnt/beta-Catenin Signaling-Mediated Osteoarthritis in Mice Overexpressing High-Molecular-Weight FGF2. AB - Although humans with X-linked hypophosphatemia (XLH) and the Hyp mouse, a murine homolog of XLH, are known to develop degenerative joint disease, the exact mechanism that drives the osteoarthritis (OA) phenotype remains unclear. Mice that overexpress high-molecular-weight fibroblast growth factor (FGF) 2 isoforms (HMWTg mice) phenocopy both XLH and Hyp, including OA with increased FGF23 production in bone and serum. Because HMWTg cartilage also has increased FGF23 and there is cross-talk between FGF23-Wnt/beta-catenin signaling, the purpose of this study was to determine if OA observed in HMWTg mice is due to FGF23-mediated canonical Wnt signaling in chondrocytes, given that both pathways are implicated in OA pathogenesis. HMWTg OA joints had decreased Dkk1, Sost, and Lrp6 expression with increased Wnt5a, Wnt7b, Lrp5, Axin2, phospho-GSK3beta, Lef1, and nuclear beta-catenin, as indicated by immunohistochemistry or quantitative PCR analysis. Chondrocytes from HMWTg mice had enhanced alcian blue and alkaline phosphatase staining as well as increased FGF23, Adamts5, Il-1beta, Wnt7b, Wnt16, and Wisp1 gene expression and phospho-GSK3beta protein expression as indicated by Western blot, compared with chondrocytes of vector control and chondrocytes from mice overexpressing the low-molecular-weight isoform, which were protected from OA. Canonical Wnt inhibitor treatment rescued some of those parameters in HMWTg chondrocytes, seemingly delaying the initially accelerated chondrogenic differentiation. FGF23 neutralizing antibody treatment was able to partly ameliorate OA abnormalities in subchondral bone and reduce degradative/hypertrophic chondrogenic marker expression in HMWTg joints in vivo. These results demonstrate that osteoarthropathy of HMWTg is at least partially due to FGF23-modulated Wnt/beta-catenin signaling in chondrocytes. PMID- 29718275 TI - Quantitative imaging and spectroscopic technologies for microbiology. AB - Light microscopy has enabled the observation of the structure and organisation of biofilms. Typically, the contrast in an image obtained from light microscopy is given by the time-averaged intensity that is effective in visualising the overall structure. Technological advancements in light microscopy have led to the creation of techniques that not only provide a static intensity image of the biofilm, but also enable one to quantify various dynamic physicochemical properties of biomolecules in microbial biofilms. Such light microscopy-based techniques can be grouped into two main classes, those that are based on luminescence and those that are based on scattering. Here, we review the fundamentals and applications of luminescence and scattering-based techniques, specifically, fluorescence lifetime imaging, Forster resonance energy transfer, fluorescence correlation spectroscopy, fluorescence recovery after photobleaching, single-particle tracking, transient state imaging, and Brillouin and Raman microscopy. These techniques provide information about the abundance, interactions and mobility of various molecules in the biofilms and also properties of the local microenvironment at optical resolution. Further, one could use any of these techniques to probe the real-time changes in these physical parameters upon the addition of external agents or at different stages during the growth of biofilms. PMID- 29718274 TI - Clinical usefulness of 2-deoxy-2-[18F] fluoro-d-glucose-positron emission tomography/computed tomography for assessing early oral squamous cell carcinoma (cT1-2N0M0). AB - Background: Positron emission tomography with 2-deoxy-2-[18F] fluoro-d-glucose integrated with computed tomography (FDG-PET/CT) is a useful method to evaluate patients with oral squamous cell carcinoma (OSCC). However, the prognostic significance of FDG-PET/CT for assessing early OSCC remains unclear. Methods: Pretreatment FDG-PET/CT of 205 consecutive patients (125 men, 80 women, mean age 59.7 year old) with early OSCC (cT1-2N0M0) between June 2010 and December 2014 were retrospectively analyzed. FDG avidity in primary lesions was assessed by visual interpretation. Thereafter, maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV) and total lesion glycolysis (TLG) were measured in primary lesions. The relationship between each parameter and recurrence free survival (RFS) was assessed using the log-rank test. The performance of FDG PET/CT for diagnosing metastatic lesions and synchronous cancer was also assessed. Results: During the follow-up period (mean 32.9 months), 43 patients developed recurrences (21.0%). Patients with visually positive FDG uptake in primary lesions showed significantly shorter RFS than the others (63.0 months vs. 52.9 months, P = 0.005). In those patients, greater SUVmax, MTV, and TLG did not significantly predict shorter RFS. The sensitivity and specificity of FDG-PET/CT for cervical nodal metastases detection were 32.3% and 77.6%, respectively. FDG PET/CT detected eight synchronous cancers (3.9%) and overlooked six synchronous cancers (2.9%). Conclusions: Although its utility for detecting cervical nodal metastases and synchronous cancers is limited, FDG-PET/CT is a potentially prognostic indicator in early OSCC. PMID- 29718271 TI - Cholesterol and fatty acids grease the wheels of Mycobacterium tuberculosis pathogenesis. AB - Tuberculosis is a distinctive disease in which the causative agent, Mycobacterium tuberculosis, can persist in humans for decades by avoiding clearance from host immunity. During infection, M. tuberculosis maintains viability by extracting and utilizing essential nutrients from the host, and this is a prerequisite for all of the pathogenic activities that are deployed by the bacterium. In particular, M. tuberculosis preferentially acquires and metabolizes host-derived lipids (fatty acids and cholesterol), and the bacterium utilizes these substrates to cause and maintain disease. In this review, we discuss our current understanding of lipid utilization by M. tuberculosis, and we describe how these pathways promote pathogenesis to fuel metabolic processes in the bacillus. Finally, we highlight weaknesses in these pathways that potentially can be targeted for drug discovery. PMID- 29718276 TI - The expanding horizon of alkyl quinolone signalling and communication in polycellular interactomes. AB - Population dynamics within natural ecosystems is underpinned by microbial diversity and the heterogeneity of host-microbe and microbe-microbe interactions. Small molecule signals that intersperse between species have been shown to govern many virulence-related processes in established and emerging pathogens. Understanding the capacity of microbes to decode diverse languages and adapt to the presence of 'non-self' cells will provide an important new direction to the understanding of the 'polycellular' interactome. Alkyl quinolones (AQs) have been described in the ESKAPE pathogen Pseudomonas aeruginosa, the primary agent associated with mortality in patients with cystic fibrosis and the third most prevalent nosocomial pathogen worldwide. The role of these molecules in governing the physiology and virulence of P. aeruginosa and other pathogens has received considerable attention, while a role in interspecies and interkingdom communication has recently emerged. Herein we discuss recent advances in our understanding of AQ signalling and communication in the context of microbe microbe and microbe-host interactions. The integrated knowledge from these systems-based investigations will facilitate the development of new therapeutics based on the AQ framework that serves to disarm the pathogenesis of P. aeruginosa and competing pathogens. PMID- 29718277 TI - Cohort Profile: The Taiwan Maternal and Infant Cohort Study (TMICS) of phthalate exposure and health risk assessment. PMID- 29718279 TI - Corrigendum to: Smooth muscle cell fate and plasticity in atherosclerosis. PMID- 29718278 TI - The Impact of Combination Therapy on Infliximab Levels and Antibodies in Children and Young Adults With Inflammatory Bowel Disease. AB - Goal: The aim of this study was to evaluate the effect of combination therapy with methotrexate or 6-mercaptopurine on infliximab levels (IFXL) and antibodies to infliximab (ATI). Background: Infliximab (IFX) is a highly effective therapy for inflammatory bowel disease (IBD). Unfortunately, 25%-50% of patients will lose response to IFX. Loss of response is correlated with low IFXL and ATI formation which accelerates drug clearance. Combination therapy is thought to decrease ATI formation. Methods: We performed a cross-sectional analysis of 223 pediatric and young adult patients with IBD on IFX. IFXL and ATI were measured and compared between subjects on current combination therapy, prior combination therapy, and IFX monotherapy. Results: Eighty-four (37.7%) patients were on combination therapy and 139 (62.3%) were on IFX monotherapy. Within the current monotherapy group, 112 (80.6%) had previously been on combination therapy, while 27 (19.4%) had never been on a concomitant immunomodulator. Patients currently on combination therapy had a higher IFXL (17.00 +/- 1.33 MUg/mL) than those currently on IFX monotherapy (13.18 +/- 1.26 MUg/mL), P < 0.01. IFXL was lowest in patients who had never been on combination therapy (11.53 +/- 2.05 MUg/mL) and highest in patients currently on combination therapy (17.00 +/- 1.33 MUg/mL). Patients currently on combination therapy had a lower rate of detectable ATI (9.5%) compared with those on monotherapy (20.0%) in multivariate analysis (odds ratio [OR]: 0.3; 95% confidence interval (CI), 0.1-0.7, P < 0.01). Conclusions: Current or prior combination therapy is associated with higher IFXL and lower rates of ATI formation. PMID- 29718280 TI - Early Communication Development of Children with Auditory Brainstem Implants. AB - The auditory brainstem implant (ABI) is an auditory sensory device that is surgically placed on the cochlear nucleus of the brainstem for individuals who are deaf but unable to benefit from a cochlear implant (CI) due to anatomical abnormalities of the cochlea and/or eighth nerve, specific disease processes, or temporal bone fractures. In the United States, the Food and Drug Administration has authorized a Phase I clinical trial to determine safety and feasibility of the ABI in up to 10 eligible young children who are deaf and either derived no benefit from the CI or were anatomically unable to receive a CI. In this paper, we describe the study protocol and the children who have enrolled in the study thus far. In addition, we report the scores on speech perception, speech production, and language (spoken and signed) for five children with 1-3 years of assessment post-ABI activation. To date, the results indicate that spoken communication skills are slow to develop and that visual communication remains essential for post-ABI intervention. PMID- 29718282 TI - Suspected Driving Under the Influence Case Involving Mitragynine. AB - Mitragynine is a novel psychoactive substance (NPS) that has emerged as a designer opioid being distributed on the street. Mitragynine, also known as kratom, has dose-dependent pharmacological effects and possesses both stimulant like and sedative effects due to dual-binding of alpha-adrenergic and MU-opioid receptors. This herbal remedy readily available online has caused adverse effects including tachycardia, agitation, tremors, hallucination and death; however, this is the first reported suspected driving under the influence case involving mitragynine. Additional testing outside of the normal routine protocol for suspected impaired driving cases was performed based on the admission of kratom use from the suspect to the drug recognition expert (DRE) officer. Based on the evaluation, the DRE officer concluded that the driver was under the influence of a central nervous system stimulant and cannabis. An alkaline drug screen identified mitragynine in a 37-year-old female driver who was suspected of driving under the influence after nearly striking an oncoming vehicle. A blood amphetamine concentration was quantified at 0.052 mg/L and mitragynine and citalopram were reported qualitatively. The goal of this case study is to provide demographic history, adverse effects and a DRE evaluation in a driver known to have abused mitragynine. PMID- 29718281 TI - Comprehensive Endocrine-Metabolic Evaluation of Patients With Alstrom Syndrome Compared With BMI-Matched Controls. AB - Background: Alstrom syndrome (AS), a monogenic form of obesity, is caused by recessive mutations in the centrosome- and basal body-associated gene ALMS1. AS is characterized by retinal dystrophy, sensory hearing loss, cardiomyopathy, childhood obesity, and metabolic derangements. Objective: We sought to characterize the endocrine and metabolic features of AS while accounting for obesity as a confounder by comparing patients with AS to body mass index (BMI) matched controls. Methods: We evaluated 38 patients with AS (age 2 to 38 years) who were matched with 76 controls (age 2 to 48 years) by age, sex, race, and BMI. Fasting biochemistries, mixed meal test (MMT), indirect calorimetry, dual-energy X-ray absorptiometry, and MRI/magnetic resonance spectroscopy were performed. Results: Frequent abnormalities in AS included 76% obesity, 37% type 2 diabetes mellitus (T2DM), 29% hypothyroidism (one-third central, two-thirds primary), 3% central adrenal insufficiency, 57% adult hypogonadism (one-third central, two thirds primary), and 25% female hyperandrogenism. Patients with AS and controls had similar BMI z scores, body fat, waist circumference, abdominal visceral fat, muscle fat, resting energy expenditure (adjusted for lean mass), free fatty acids, glucagon, prolactin, ACTH, and cortisol. Compared with controls, patients with AS were shorter and had lower IGF-1 concentrations (Ps <= 0.001). Patients with AS had significantly greater fasting and MMT insulin resistance indices, higher MMT glucose, insulin, and C-peptide values, higher HbA1c, and higher prevalence of T2DM (Ps < 0.001). Patients with AS had significantly higher triglycerides, lower high-density lipoprotein cholesterol, and a 10-fold greater prevalence of metabolic syndrome (Ps < 0.001). Patients with AS demonstrated significantly greater liver triglyceride accumulation and higher transaminases (P < 0.001). Conclusion: Severe insulin resistance and T2DM are the hallmarks of AS. However, patients with AS may present with multiple other endocrinopathies affecting growth and development. PMID- 29718283 TI - Drug-Resistance and Population Structure of Plasmodium falciparum Across the Democratic Republic of Congo Using High-Throughput Molecular Inversion Probes. AB - A better understanding of the drivers of the spread of malaria parasites and drug resistance across space and time is needed. These drivers can be elucidated using genetic tools. Here, a novel molecular inversion probe (MIP) panel targeting all major drug-resistance mutations and a set of microsatellites was used to genotype Plasmodium falciparum infections of 552 children from the 2013-2014 Demographic and Health Survey conducted in the Democratic Republic of the Congo (DRC). Microsatellite-based analysis of population structure suggests that parasites within the DRC form a homogeneous population. In contrast, sulfadoxine-resistance markers in dihydropteroate synthase show marked spatial structure with ongoing spread of double and triple mutants compared with 2007. These findings suggest that parasites in the DRC remain panmictic despite rapidly spreading antimalarial resistance mutations. Moreover, highly multiplexed targeted sequencing using MIPs emerges as a cost-effective method for elucidating pathogen genetics in complex infections in large cohorts. PMID- 29718284 TI - Scented Sugar Baits Enhance Detection of St. Louis Encephalitis and West Nile Viruses in Mosquitoes in Suburban California. AB - Scented sugar baits deployed in California deserts detected early West Nile virus (WNV) transmission by mosquitoes, representing a potential improvement to conventional arbovirus surveillance that relies heavily on infection rates in mosquito pools. In this study, we expanded deployment of scented sugar baits into suburban Sacramento and Yolo (2015, 2016) and Riverside Counties (2016), California. The goal of the study was to determine whether scented sugar baits detect WNV and St. Louis encephalitis virus (SLEV) concurrent with mosquito infections in trapped pools in areas of high human density. Between 8 and 10% of sugar baits were WNV RNA positive in both study years across the three counties. In Riverside County, where SLEV re-emerged in 2015, 1% of sugar baits were SLEV positive in 2016. Rates of sugar bait positives were at least 100 times higher than infection rates in trapped mosquitoes in the same districts. The prevalence of sugar bait positives varied temporally and did not coincide with infections in mosquitoes collected at the same sites each week. WNV RNA positive sugar baits were detected up to 2 wk before and after concurrent surveillance detected infection in mosquito pools at the same sites. Sugar baits also detected WNV in Riverside County at locations where no WNV activity was detected in mosquito pools. Sugar baits generated between 0.8 and 1.2 WNV positives per $1,000 and can be more economical than carbon dioxide baited traps that produce 0.8 positives per $1,000. These results indicate that the sugar bait approach enhances conventional arbovirus surveillance in mosquitoes in suburban California. PMID- 29718285 TI - Associations Between the Small Hive Beetle and the Yeast Kodamaea ohmeri Throughout the Host Life Cycle. AB - The small hive beetle, Aethina tumida Murray (Coleoptera: Nitidulidae), is a pest of colonies of social bees, including the honeybee Apis mellifera L. (Hymenoptera: Apidae). We investigated A. tumida oviposition behavior and development and found that it laid eggs in clutches that ranged in size (3-75 eggs per clutch) and that when fed on hive products in laboratory culture (27 degrees C; RH 65%; 12:12 (L:D) h) it completed three larval instars before pupation. The yeast Kodamaea ohmeri (Etchells & Bell) Y. Yamada, T. Suzuki, M. Matsuda & K. Mikata (Ascomycota: Saccharomycotina) is associated with A. tumida, but the exact nature of this relationship is unknown. We examined the association in host eggs, larvae, pupae, and adults to establish its extent and potential specificity and determined the likely mechanism of vertical transmission. K. ohmeri was detected in egg mucilage and on host cuticle and from internal preparations of A. tumida at every stage of development. Based on colony forming unit (CFU) counts, the K. ohmeri densities varied significantly between developmental stages; the highest internal density was recorded in third instar larvae. Presence of K. ohmeri within adult A. tumida was not affected by contamination of the cuticle by the yeast during the larval and pupal stages nor by the mated status of the adult. This deepened understanding of A. tumida ovipositional behavior and larval development along with a better understanding of the relationship between K. ohmeri and its host is important for the development of management strategies for this important pest. PMID- 29718286 TI - Triennial Reproduction Symposium: Looking back and moving forward-how reproductive physiology has evolved. PMID- 29718287 TI - Harnessing the Perioperative Period to Improve Long-term Cancer Outcomes. PMID- 29718288 TI - The pathogenesis of lysosomal storage disorders: beyond the engorgement of lysosomes to abnormal development and neuroinflammation. AB - There is growing evidence that the complex clinical manifestations of lysosomal storage diseases (LSDs) are not fully explained by the engorgement of the endosomal-autophagic-lysosomal system. In this review, we explore current knowledge of common pathogenetic mechanisms responsible for the early onset of tissue abnormalities of two LSDs, Mucopolysaccharidosis type II (MPSII) and Niemann-Pick type C (NPC) diseases. In particular, perturbations of the homeostasis of glycosaminoglycans (GAGs) and cholesterol (Chol) in MPSII and NPC diseases, respectively, affect key biological processes, including morphogen signaling. Both GAGs and Chol finely regulate the release, reception and tissue distribution of Shh. Hence, not surprisingly, developmental processes depending on correct Shh signaling have been found altered in both diseases. Besides abnormal signaling, exaggerated activation of microglia and impairment of autophagy and mitophagy occur in both diseases, largely before the appearance of typical pathological signs. PMID- 29718289 TI - "The Neurosis That Has Possessed Us": Political Repression in the Cold War Medical Profession. AB - Political repression played a central role in shaping the political complexion of the American medical profession, the policies it advocated, and those allowed to function comfortably in it. Previous work on the impact of McCarthyism and medicine focuses heavily on the mid-century failure of national health insurance (NHI) and medical reform organizations that suffered from McCarthyist attacks. The focus is national and birds-eye but says less about the impact on the day-to day life of physicians caught in a McCarthyist web; and how exactly the machinery of political repression within the medical profession worked on the ground. This study shifts orientation by using the abrupt dismissal of three Los Angeles physicians from their jobs as a starting point for exploring these dynamics. I argue that the rise of the medical profession and the repressive state at mid century, frequently studied apart, worked hand-in-hand, with institutions from each playing symbiotic and mutually reinforcing roles. I also explore tactics of resistance - rhetorical and organizational - to medical repression by physicians who came under attack. PMID- 29718290 TI - A Longitudinal Study of Commonly Used Admissions Measures and Disenrollment from Medical School and Graduate Medical Education Probation or Termination from Training. AB - Introduction: This is an empirical study to better understand commonly used medical school admission measures and disenrollment decisions during undergraduate medical education as well as graduate medical education (GME) probation or termination decisions. Materials and Methods: Based on the data of USUHS medical students matriculating between 1998 and 2011 (N = 2,460), we compared medical school graduates and those disenrolled from medical school on MCAT scores, undergraduate BCPM (Biology, Chemistry, Physics, Math) GPA, and undergraduate overall GPA. We also reported more specific reasons for disenrollment decisions. Next, we compared the students who were referred to the student promotion committee (SPC) with other students on these measures. Moving onto GME, we compared trainees who were put on probation or terminated from training with those who were not on MCAT and undergraduate GPA measures. In addition, we examined the association between being referred to the SPC and GME probation or termination. Results: There were 2,347 graduates and 113 disenrolled students from medical school (4.8%). For the disenrolled students, 43 (38.7%) students were disenrolled for exclusively (or primarily) non-academic reasons, and 68 (61.3%) were disenrolled for exclusively (or primarily) academic reasons. The t-tests showed statistically significant differences on the MCAT score of the first attempt (t(2,449) = 7.22, P < 0.01, Cohen's d = 0.70), average MCAT score (t(2,449) = 4.22, P < 0.01, Cohen's d = 0.41), and highest MCAT score (t(2,449) = 3.51, P < 0.01, Cohen's d = 0.34). Logistic regression model selection also revealed that the best predictor for disenrollment was the first MCAT score (exp(b) = 0.83, 95% CI = (0.78, 0.88)). No significant differences on these measures were found from the group comparisons on SPC and GME probation or termination. There was no significant association between SPC appearance and GME probation or termination. Conclusions: Academic difficulties, especially in the basic sciences, appear to be the most common factor for disenrollment from medical school. These students also had lower MCAT scores, particularly on the first attempt. The MCAT performance indicators and undergraduate GPA were consistently lower, but not statistically significant, for those who appeared before SPC or were put on probation or terminated from training during GME. PMID- 29718291 TI - Molecular Testing for Group A Streptococcal Pharyngitis: To Test or Not To Test, That Is the Question. PMID- 29718292 TI - Editorial to the thematic issue climate change and microbiology. PMID- 29718293 TI - Health Effects of the Relocation of Patients With Dementia: A Scoping Review to Inform Medical and Policy Decision-Making. AB - Background and Objectives: Research into the relocation (including international relocation) of people with dementia is increasingly important due to the aging population and latest developments in the international politics (including globalization and concerns over international migration). There is need for an overview of the health effects of relocation to facilitate and inform decision- and policy-making regarding these relocations. The aim of this literature review was to provide insight into the physical, psychological, and social consequences of varied types of relocations of older adults suffering from dementia. Research Design and Methods: A scoping literature review with a systematic search was performed in PubMed, Web of Science, PsychInfo, JSTOR, and ScienceDirect. The articles dealing with subject of relocation of older adults from 1994 to 2017 were included and analyzed. Methodological quality assessment was performed for all articles. Results: Final list included 13 articles. The effects of relocation were discussed in terms of mortality and morbidity. In most studies, the health effects of the relocation of older adults suffering from dementia were negative. A decline in physical, mental, behavioral, and functional well-being was reported. The most recurring effect was a higher level of stress, which is more problematic for patients with dementia. In general, unless it is carefully planned, it is best to avoid changing lives of people with dementia and it is recommended to actively work to reduce their exposure to stress. Discussion and Implications: The outcomes of the study suggest definite evidence for the negative effects of relocation of the older adults. This research aims to be used as the support of the legal and medical decisions of relocation of patients with dementia. PMID- 29718294 TI - Formation of correlated chromatin domains at nanoscale dynamic resolution during transcription. AB - Intrinsic dynamics of chromatin contribute to gene regulation. How chromatin mobility responds to genomic processes, and whether this response relies on coordinated chromatin movement is still unclear. Here, we introduce an approach called Dense Flow reConstruction and Correlation (DFCC), to quantify correlation of chromatin motion with sub-pixel sensitivity at the level of the whole nucleus. DFCC reconstructs dense global flow fields of fluorescent images acquired in real time. We applied our approach to analyze stochastic movements of DNA and histones, based on direction and magnitude at different time lags in human cells. We observe long-range correlations extending over several MUm between coherently moving regions over the entire nucleus. Spatial correlation of global chromatin dynamics was reduced by inhibiting elongation by RNA polymerase II, and abolished in quiescent cells. Furthermore, quantification of spatial smoothness over time intervals up to 30 s points to clear-cut boundaries between distinct regions, while smooth transitions in small (<1 MUm) neighborhoods dominate for short time intervals. Rough transitions between regions of coherent motion indicate directed squeezing or stretching of chromatin boundaries, suggestive of changes in local concentrations of actors regulating gene expression. The DFCC approach hence allows characterizing stochastically forming domains of nuclear activity. PMID- 29718296 TI - Epidemiology and Outcomes of Hospitalizations With Invasive Aspergillosis in the United States, 2009-2013. AB - Background: Though invasive aspergillosis (IA) complicates care of up to 13% of patients with immunocompromise, little is known about its morbidity and mortality burden in the United States. Methods: We analyzed the Health Care Utilization Project's data from the Agency for Healthcare Research and Quality for 2009-2013. Among subjects with high-risk conditions for IA, IA was identified via International Classification of Diseases, Ninth Revision, Clinical Modification codes 117.3, 117.9, and 484.6. We compared characteristics and outcomes between those with (IA) and without IA (non-IA). Using propensity score matching, we calculated the IA-associated excess mortality and 30-day readmission rates, length of stay, and costs. Results: Of the 66634683 discharged patients meeting study inclusion criteria, 154888 (0.2%) had a diagnosis of IA. The most common high-risk conditions were major surgery (50.1%) in the non-IA and critical illness (41.0%) in the IA group. After propensity score matching, both mortality (odds ratio, 1.43; 95% confidence interval, 1.36-1.51) and 30-day readmission (1.39; 1.34-1.45) rates were higher in the IA group. IA was associated with 6.0 (95% confidence interval, 5.7-6.4) excess days in the hospital and $15542 ($13869 $17215) in excess costs per hospitalization. Conclusions: Although rare even among high-risk groups, IA is associated with increased hospital mortality and 30 day readmission rates, excess duration of hospitalization, and costs. Given nearly 40000 annual admissions for IA in the United States, the aggregate IA attributable excess costs may reach $600 million annually. PMID- 29718295 TI - Genetic and enzymatic characterization of 3-O-sulfotransferase SNPs associated with Plasmodium falciparum parasitaemia. AB - The HS3ST3A1/B1 genes encode two homologous 3-O-sulfotransferases involved in the late modification step during heparan sulfate (HS) biosynthesis. In addition to the single nucleotide polymorphisms (SNPs) rs28470223 (C > T) in the promoter region of both HS3ST3A1 and rs62636623 (Gly/Arg) in the stem region of HS3ST3B1, three missense mutations (rs62056073, rs61729712 and rs9906590) located within the catalytic sulfotransferase domain of 3-OST-B1 are linked and associated to Plasmodium falciparum parasitaemia. To ascertain the functional effects of these SNP associations, we investigated the regulatory effect of rs28470223 and characterized the enzymatic activity of the missense SNP rs61729712 (Ser279Asn) localized at proximity of the substrate binding cleft. The SNP rs28470223 results in decreased promoter activity of HS3ST3A1 in K562 cells, suggesting a reduced in vivo transcription activity of the target gene. A comparative kinetic analysis of wt HS3ST3B1 and the Ser269Asn variant (rs61729712) using a HS-derived oligosaccharide substrate reveals a slightly higher catalytic activity for the SNP variant. These genetic and enzymatic studies suggest that genetic variations in enzymes responsible of HS 3-O-sulfation can modulate their promoter and enzymatic activities and may influence P. falciparum parasitaemia. PMID- 29718297 TI - The Effect of Supraphysiological Estradiol on Pregnancy Outcomes Differs Between Women With PCOS and Ovulatory Women. AB - Context: Supraphysiological estradiol exposure after ovarian stimulation may disrupt embryo implantation after fresh embryo transfer. Women with polycystic ovary syndrome (PCOS), who usually overrespond to ovarian stimulation, have a better live birth rate after frozen embryo transfer (FET) than after fresh embryo transfer; however, ovulatory women do not. Objective: To evaluate whether the discrepancy in live birth rate after fresh embryo transfer vs FET between these two populations is due to the variation in ovarian response (i.e., peak estradiol level or oocyte number). Design, Setting, Patients, Intervention(s), and Main Outcome Measure(s): This was a secondary analysis of data from two multicenter randomized trials with similar study designs. A total of 1508 women with PCOS and 2157 ovulatory women were randomly assigned to undergo fresh or FET. The primary outcome was live birth. Results: Compared with fresh embryo transfer, FET resulted in a higher live birth rate (51.9% vs 40.7%; OR, 1.57; 95% CI, 1.22 to 2.03) in PCOS women with peak estradiol level >3000pg/mL but not in those with estradiol level <=3000 pg/mL. In women with PCOS who have >=16 oocytes, FET yielded a higher live birth rate (54.8% vs 42.1%; OR, 1.67; 95% CI, 1.20 to 2.31), but this was not seen in those with <16 oocytes. In ovulatory women, pregnancy outcomes were similar after fresh embryo transfer and FET in all subgroups. Conclusions: Supraphysiological estradiol after ovarian stimulation may adversely affect pregnancy outcomes in women with PCOS but not in ovulatory women. PMID- 29718298 TI - Genomic Structure and Tissue Expression of the NK-Lysin Gene Family in Bison. AB - Antimicrobial peptides (AMPs) are a class of natural peptides with varying numbers of amino acids. They are principal components of innate immunity in vertebrates, encoding natural antibiotics and providing a protective response against a broad range of microbes including those responsible for tuberculosis, an important disease in bison. NK-lysins are AMPs that have been described in various organisms and are coded by a single gene in several mammalian species, including human. Recently, we described a family of 4 NK-lysin genes in cattle. Here, we examined NK-lysin genes in bison and identified 4 bison paralogs (NK1, NK2A, NK2B, and NK2C), although the current bison genome assembly annotates only 2 (NK1 and NK2). Sequence and phylogenetic analysis support the triplication of NK2 prior to the most recent common ancestor of bison and cattle. Comparative mapping of bison and cattle paralogs indicates that the NK-lysin family is located on bison chromosome 11 with well-conserved synteny of flanking genes relative to cattle. The 3 bison NK-lysin2 genes share high sequence similarity with each other. RNA-seq analysis demonstrates that NK2A, NK2B, and NK2C are expressed primarily in the lung, whereas NK1 is expressed at low levels in all tissues studied. This tissue expression pattern differs from that previously reported for cattle, suggesting some divergence in function since the evolutionary separation of the 2 species. PMID- 29718299 TI - Improving Quality in the Care of Patients with Inflammatory Bowel Diseases. AB - Efforts to improve healthcare quality were firmly established before the Institute of Medicine (IOM) historic 2000 and 2001 reports, To Err is Human Building a Safer Health System and Crossing the Quality Chasm: A New Health System for the 21st Century Despite the long-standing healthcare quality improvement (QI) efforts that date back to the turn of the 20th century, the IOM reports significantly advanced the awareness of healthcare quality deficits and the resulting risk to patients from those gaps in care. Studies immediately following the IOM reports emphasized and verified the presence of detrimental care gaps and highlighted a myriad of contributing factors. Studies focused specifically on the inflammatory bowel diseases (IBD), Crohn's disease and ulcerative colitis , demonstrated suboptimal patient outcomes stemming from, in part, system and provider variation. In the years that have followed, research studies have shown the persistence of suboptimal outcomes in IBD despite an awareness of key drivers for poor care quality and concerted efforts in advancing QI initiatives. In 2017, IBD advocacy groups and provider networks have demonstrated progress in furthering both pediatric and adult IBD outcomes through the use of QI methods and tools including collaborative learning networks. A significant amount of work lies ahead, however, to build upon these advances and improve IBD outcomes further. This article reviews the history of quality initiatives in healthcare, identifies ongoing gaps in IBD care with a review of current IBD improvement efforts taking place, and identifies several targets for improving IBD care quality moving forward into the 21st century. PMID- 29718300 TI - Myeloperoxidase Associates With Degenerative Remodeling and Rupture of the Saccular Intracranial Aneurysm Wall. AB - Rupture of a saccular intracranial aneurysm (sIA) is often fatal. Thus, early detection of rupture-prone sIAs is vital. Myeloperoxidase (MPO), derived mainly from neutrophils, associates with sIA rupture, and therefore its role in sIA pathogenesis warrants further studies. We analyzed MPO and its association with other histological markers in 36 (16 unruptured and 20 ruptured) sIA samples by immunohistochemistry. MPO was present in all studied sIAs, and its expression associated with wall inflammatory cell infiltrations (r = 0.50, 0.63, and 0.75, all p <= 0.002), degenerative remodeling (p = 0.002) and rupture (p = 0.003). MPO associated strongly with the presence of organized luminal thrombi (p < 0.001), which also stained positive for MPO. Polymorphonuclear MPO+ cells were detected in the sIA walls, indicating neutrophils as MPO-source. MPO correlated strongly with accumulation of oxidized lipids (r = 0.67, p < 0.001) and loss of smooth muscle cells (r = -0.68, p < 0.001), suggesting that MPO is a relevant source of oxidative stress leading to cell death in the sIA wall. Furthermore, MPO associated with erythrocyte fragmentation (r = 0.74, p < 0.001) and iron deposition (p = 0.041), 2 outcomes known to amplify MPO-dependent oxidative stress. Taken together, these results suggest that MPO associates with degenerative remodeling predisposing to sIA wall rupture and may serve as a biomarker of a rupture-prone sIA wall. PMID- 29718301 TI - Calcium Signals in the Plant Nucleus: Origin and Function. AB - The universality of calcium as an intracellular messenger depends on the dynamics of its spatial and temporal release from calcium stores. Accumulating evidence over the past two decades supports an essential role for nuclear calcium signalling in the transduction of specific stimuli into cellular responses. This review focusses on mechanisms underpinning changes in nuclear calcium concentrations and discusses what is known so far, about the origin of the nuclear calcium signals identified, primarily in the context of microbial symbioses and abiotic stresses. PMID- 29718302 TI - Caution Needed: Molecular Diagnosis of Pediatric Group A Streptococcal Pharyngitis. AB - Among throat swabs processed in the microbiology laboratory as back-up for negative rapid antigen detection test results, we found a significant increase in the proportion that tested positive for group A streptococci after changing from throat culture to a molecular test.For group A streptococcus testing, our hospital laboratory replaced throat cultures with a stand-alone molecular diagnostic test that takes no more than 1 hour to perform. The prevalence of positive laboratory test results increased significantly (P < .0001) after the change to molecular testing, probably because of the extreme sensitivity of the molecular test. PMID- 29718304 TI - Reply to Kojima and Klausner. PMID- 29718303 TI - The KDM4A/KDM4C/NF-kappaB and WDR5 epigenetic cascade regulates the activation of B cells. AB - T follicular helper (Tfh) cell-derived signals promote activation and proliferation of antigen-primed B cells. It remains unclear whether epigenetic regulation is involved in the B cell responses to Tfh cell-derived signals. Here, we demonstrate that Tfh cell-mimicking signals induce the expression of histone demethylases KDM4A and KDM4C, and the concomitant global down-regulation of their substrates, H3K9me3/me2, in B cells. Depletion of KDM4A and KDM4C potentiates B cell activation and proliferation in response to Tfh cell-derived signals. ChIP seq and de novo motif analysis reveals NF-kappaB p65 as a binding partner of KDM4A and KDM4C. Their co-targeting to Wdr5, a MLL complex member promoting H3K4 methylation, up-regulates cell cycle inhibitors Cdkn2c and Cdkn3. Thus, Tfh cell derived signals trigger KDM4A/KDM4C - WDR5 - Cdkn2c/Cdkn3 cascade in vitro, an epigenetic mechanism regulating proper proliferation of activated B cells. This pathway is dysregulated in B cells from systemic lupus erythematosus patients and may represent a pathological link. PMID- 29718305 TI - Invasive Epithelial Ovarian Cancer Survival by Histotype and Disease Stage. AB - Background: The understanding of ovarian cancer pathogenesis has recently shifted to recognize distinct changes in how ovarian cancer histotypes are defined. Using the 2014 World Health Organization (WHO) diagnostic guidelines, we classified ovarian cancer histotypes in Surveillance, Epidemiology, and End Results (SEER) cancer registry data and examined survival patterns by histotype and disease stage. Methods: We extracted data on 28 118 incident epithelial ovarian cancer cases diagnosed in 2004-2014 from SEER and defined histotype using the 2014 WHO guidelines (high-grade serous, low-grade serous, endometrioid, clear cell, mucinous, carcinosarcoma, and malignant Brenner tumors). By histotype and disease stage, we estimated Kaplan-Meier survival curves and calculated age-adjusted overall and cause-specific survival estimates. Cox proportional hazards regression models were used to estimate histotype-specific hazard ratios (HRs) and 95% confidence intervals (CIs) by disease stage while adjusting for age at diagnosis, region, race/ethnicity, and receipt of surgery. Results: Within two years after diagnosis, localized/regional-stage carcinosarcoma and distant-stage mucinous, clear cell, and carcinosarcoma had a higher risk of mortality compared with high-grade serous, with the most pronounced association for localized/regional carcinosarcoma (>1-2-year time period: HR = 3.81, 95% CI = 2.74 to 5.30) and distant-stage mucinous (0-1-year time period: HR = 3.87, 95% CI = 3.45 to 4.34). In the time period more than four to 10 years after diagnosis, hazard ratios for all histotypes relative to high-grade serous, irrespective of disease stage, were less than 1.00. Cumulatively, both localized/regional and distant-stage low-grade serous and endometrioid carcinomas had the most favorable outcomes. Conclusions: Our large study, which is representative of the United States population and incorporates the most current knowledge of ovarian cancer pathogenesis, highlights the need to recognize ovarian cancer as a set of distinct diseases and not a single entity. Only then will we be able to effectively target the unique features of each histotype to reduce ovarian cancer mortality. PMID- 29718306 TI - Corrigendum to 'A comparison of early redo surgery rates in Mosaic porcine and Perimount bovine pericardial valves' [Eur J Cardiothorac Surg 2018; doi:10.1093/ejcts/ezy113]. PMID- 29718307 TI - Ecological Expansion and Extinction in the Late Ediacaran: Weighing the Evidence for Environmental and Biotic Drivers. AB - The Ediacara Biota, Earth's earliest communities of complex, macroscopic, multicellular organisms, appeared during the late Ediacaran Period, just prior to the Cambrian Explosion. Ediacara fossil assemblages consist of exceptionally preserved soft-bodied forms of enigmatic morphology and affinity which nonetheless represent a critical stepping-stone in the evolution of complex animal ecosystems. The Ediacara Biota has historically been divided into three successive Assemblages-the Avalon, the White Sea, and the Nama. Although the oldest (Avalon) Assemblage documents the initial appearance of several groups of Ediacara taxa, the two younger (White Sea and Nama) Assemblages record a particularly striking suite of ecological innovations, including the appearance of diverse Ediacara body plans-in tandem with the rise of bilaterian animals-as well as the emergence of novel ecological strategies such as movement, sexual reproduction, biomineralization, and the development of dense, heterogeneous benthic communities. Many of these ecological innovations appear to be linked to adaptations to heterogeneous substrates and shallow and energetic marine settings. In spite of these innovations, the majority of Ediacara taxa disappear by the end of the Ediacaran, with interpretations for this disappearance historically ranging from the closing of preservational windows to environmentally or biotically mediated extinction. However, in spite of the unresolved affinity and eventual extinction of individual Ediacara taxa, these distinctive ecological strategies persist across the Ediacaran-Cambrian boundary and are characteristic of younger animal-dominated communities of the Phanerozoic. The late Ediacaran emergence of these strategies may, therefore, have facilitated subsequent radiations of the Cambrian. In this light, the Ediacaran and Cambrian Periods, although traditionally envisioned as separate worlds, are likely to have been part of an ecological and evolutionary continuum. PMID- 29718308 TI - Endoscopic and Histologic Features of Immune Checkpoint Inhibitor-Related Colitis. AB - Background: Diarrhea and colitis are the second most common immune checkpoint inhibitor (ICPI)-induced adverse events. However, a comprehensive characterization of the endoscopic and histologic features of ICPI-induced diarrhea and colitis is lacking. Therefore, we aimed to describe endoscopic and histologic features of ICPI-induced gastrointestinal toxicities and to assess their association with patients' clinical characteristics and outcomes. Methods: We retrospectively reviewed records of 53 patients with ICPI-related diarrhea/colitis between 2011 and 2017. We collected data on demographics, diarrhea/colitis grade, treatment, and endoscopic and histologic findings. Long term follow-up included repeat endoscopy findings, diarrhea recurrence, and overall survival. We compared groups by treatment, endoscopic and histologic findings, and constructed Kaplan-Meier survival curves. Results: Most patients had grade 2 or higher diarrhea (87%) and colitis (60%). Thirty-one patients were successfully treated with corticosteroids, and 22 additionally required infliximab. On endoscopy, 21 (40%) patients had ulcerations and 22 (42%) had nonulcerative inflammation. Patients with ulcerations had more steroid-refractory disease (P = 0.044) and high-grade diarrhea (P = 0.033). Histology showed mostly acute (23%) or chronic (60%) inflammation. During mean follow-up duration of 18.9 months, 19 (36%) developed recurrent diarrhea. Most patients had persistent endoscopic (8/13, 62%) and histologic (9/11, 82%) inflammation. Patients with higher-grade adverse events had improved survival. Higher-grade colitis was associated with endoscopic inflammation (P = 0.039), but grade of diarrhea was not associated with endoscopic inflammation or grade of colitis. Conclusion: 10.1093/ibd/izy104_video1izy104.video15808053084001. PMID- 29718309 TI - Real-Time Shear Wave Ultrasound Elastography Differentiates Fibrotic from Inflammatory Strictures in Patients with Crohn's Disease. AB - Background and aim: The distinction of intestinal fibrosis from inflammation in Crohn's disease (CD) associated strictures has important therapeutic implications. Ultrasound elastography is useful in evaluating the degree of fibrosis in liver, but there is little evidence whether it can assess fibrosis in the bowel. We determined whether shear-wave elastography (SWE), a novel modification of elastography, quantifying tissue stiffness, could differentiate between inflammatory and fibrotic components in strictures of patients with CD. Methods: Consecutive CD patients with ileal/ileocolonic strictures who underwent SWE within 1 week to surgical resection were enrolled. The SWE value of the stenotic bowel wall was compared to the grade and severity of fibrosis and inflammation, respectively, in the resected bowel specimen. Results: Thirty-five patients were enrolled. The mean SWE value of stenotic bowel wall was significantly higher in severe fibrosis (23.0 +/- 6.3 Kpa) than that in moderate (17.4 +/- 3.8 Kpa) and mild fibrosis (14.4 +/- 2.1 Kpa)(P = 0.008). Using 22.55 KPa as the cutoff value in discriminating between mild/moderate and severe fibrosis, the sensitivity and specificity was 69.6 % and 91.7% with an area under the curve (AUC) of 0.822 (P = 0.002). However, no significant difference regarding mean SWE existed among different grades of inflammation. The sensitivity and specificity of bowel vascularization score on conventional ultrasound in differentiating severe inflammation from mild/moderate was 87.5 % and 57.9% with AUC of 0.811 (P = 0.002). Combining SWE and conventional ultrasound (bowel vascularization score), we propose a bowel ultrasound classification of intestinal strictures. A moderate agreement between ultrasound and pathological classification was observed (kappa = 0.536, P<0.001). Conclusions: This pilot study suggests that SWE is feasible and accurate in detecting intestinal fibrosis in patients with CD. After validation, combing SWE and bowel vascularization on conventional ultrasound might be applied to guide a management strategy in CD patients through defining the type of intestinal stricture. 10.1093/ibd/izy115_video1izy115.video15777734754001. PMID- 29718310 TI - Clinical Features and Outcomes of Children with Culture-Negative Septic Arthritis. AB - Background: Septic arthritis is a serious infection, but the results of blood and joint fluid cultures are often negative in children. We describe here the clinical features and management of culture-negative septic arthritis in children at our hospital and their outcomes. Methods: We performed a retrospective review of a cohort of children with septic arthritis who were hospitalized at Children's Hospital of Philadelphia between January 2002 and December 2014. Culture-negative septic arthritis was defined as a joint white blood cell count of >50000/MUL with associated symptoms, a clinical diagnosis of septic arthritis, and a negative culture result. Children with pretreatment, an intensive case unit admission, Lyme arthritis, immunodeficiency, or surgical hardware were excluded. Treatment failure included a change in antibiotics, surgery, and/or reevaluation because of a lack of improvement/worsening. Results: We identified 157 children with septic arthritis. The patients with concurrent osteomyelitis (n = 28) had higher inflammatory marker levels at presentation, had a longer duration of symptoms (median, 4.5 vs 3 days, respectively; P < .001), and more often had bacteremia (46.4% vs 6.2%, respectively; P < .001). Among children with septic arthritis without associated osteomyelitis, 69% (89 of 129) had negative culture results. These children had lower C-reactive protein levels (median, 4.0 vs 7.3 mg/dL, respectively; P = .001) and erythrocyte sedimentation rates (median, 39 vs 51 mm/hour, respectively; P = .01) at admission and less often had foot/ankle involvement (P = .02). Among the children with culture-negative septic arthritis, the inpatient treatment failure rate was 9.1%, and treatment failure was more common in boys than in girls (17.1% vs 3.8%, respectively; P = .03). We found no association between treatment failure and empiric antibiotics or patient age. No outpatient treatment failures occurred during the 6-month follow-up period, although 17% of the children discharged with a peripherally inserted central catheter line experienced complications, including 3 with bacteremia. Conclusions: The majority of septic arthritis infections at our institution were culture negative. Among patients with culture-negative infection, empiric antibiotics failed for 9% and necessitated a change in therapy. More sensitive diagnostic testing should be implemented to elucidate the causes of culture negative septic arthritis in children. PMID- 29718311 TI - School Functioning in Adolescents With Inflammatory Bowel Diseases: An Examination of Disease and Demographic Correlates. AB - Background: Symptoms of inflammatory bowel diseases (IBD) can interfere with optimal psychosocial functioning of adolescents, including school functioning. School functioning can be broadly conceptualized as involving attendance, academic performance, and participation in academic and extracurricular activities. However, previous research has largely examined the impact of IBD on school attendance. The present study aimed to describe school attendance, performance, and participation in a sample of adolescents with IBD and to examine demographic and disease-related correlates of poorer school functioning. Methods: One-hundred sixty-one adolescent-parent dyads (M [SD] adolescent age = 14.5 [1.9] years, 43% female) completed questionnaires assessing demographics, school attendance, performance, and participation. Clinical disease activity was rated by physicians at the time of study enrollment. Results: Difficulties with school attendance were reported, with nearly three-quarters of participants reporting school absences due to visits with doctors or hospitalizations and just under half of the sample reporting general school absences and missing school due to not feeling well. In bivariate analyses, older age was associated with poorer school performance and participation, whereas greater disease activity was associated with poorer school attendance. In regression analyses, greater disease activity and older age emerged as the most salient predictors of poorer school attendance. Older age also emerged as the most salient predictor of school performance and participation. Conclusions: Demographic factors and age in particular were more consistent predictors of school functioning than disease factors. Special attention to older youth and those with active disease may be important to ensure optimal school functioning. PMID- 29718312 TI - Differences in silencing of mismatched targets by sliced versus diced siRNAs. AB - It has been reported that the two major types of RNA interference triggers, the classical Dicer-generated small RNAs (siRNAs), which function with all members of the Argonaute (Ago) protein family in mammals, and the Ago2-sliced small RNAs (sli-siRNAs), which function solely through Ago2, have similar potency in target cleavage and repression. Here, we show that sli-siRNAs are generally more potent than siRNAs in silencing mismatched targets. This phenomenon is usually more apparent in targets that have mismatched nucleotides in the 3' supplementary region than in targets with mismatches in the seed region. We demonstrate that Ago2 slicer activity is a major factor contributing to the greater silencing efficiency of sli-siRNA against mismatched targets and that participation of non slicing Agos in silencing mismatched siRNA targets may dilute the slicing ability of Ago2. The difference in length of the mature guide RNA used in sli-RISCs and si-RISCs may also contribute to the observed difference in knockdown efficiency. Our data suggest that a sli-siRNA guide strand is likely to have substantially stronger off-target effects than a guide strand with the same sequence in a classical siRNA and that Dicer and non-slicing Agos may play pivotal roles in controlling siRNA target specificity. PMID- 29718313 TI - UNRES server for physics-based coarse-grained simulations and prediction of protein structure, dynamics and thermodynamics. AB - A server implementation of the UNRES package (http://www.unres.pl) for coarse grained simulations of protein structures with the physics-based UNRES model, coined a name UNRES server, is presented. In contrast to most of the protein coarse-grained models, owing to its physics-based origin, the UNRES force field can be used in simulations, including those aimed at protein-structure prediction, without ancillary information from structural databases; however, the implementation includes the possibility of using restraints. Local energy minimization, canonical molecular dynamics simulations, replica exchange and multiplexed replica exchange molecular dynamics simulations can be run with the current UNRES server; the latter are suitable for protein-structure prediction. The user-supplied input includes protein sequence and, optionally, restraints from secondary-structure prediction or small x-ray scattering data, and simulation type and parameters which are selected or typed in. Oligomeric proteins, as well as those containing D-amino-acid residues and disulfide links can be treated. The output is displayed graphically (minimized structures, trajectories, final models, analysis of trajectory/ensembles); however, all output files can be downloaded by the user. The UNRES server can be freely accessed at http://unres-server.chem.ug.edu.pl. PMID- 29718314 TI - Simulation Modeling of Cancer Clinical Trials: Application to Omitting Radiotherapy in Low-risk Breast Cancer. AB - Background: We used two models to simulate a proposed noninferiority trial of radiotherapy (RT) omission in low-risk invasive breast cancer to illustrate how modeling could be used to predict the trial's outcomes, inform trial design, and contribute to practice debates. Methods: The proposed trial was a prospective randomized trial of no-RT vs RT in women age 40 to 74 years undergoing lumpectomy and endocrine therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative, stage I breast cancer with an Oncotype DX score of 18 or lower. The primary endpoint was recurrence-free interval (RFI), including locoregional recurrence, distant recurrence, and breast cancer death. Noninferiority required the two-sided 90% confidence interval of the RFI hazard ratio (HR) for no-RT vs RT to be entirely below 1.7. Model inputs included published data. The trial was simulated 1000 times, and results were summarized as percent concluding noninferiority and mean (standard deviation) of hazard ratios for Model GE and Model M, respectively. Results: Noninferiority was demonstrated in 18.0% and 3.7% for the two models. The respective means (SD) of the RFI hazard ratios were 1.8 (0.7) and 2.4 (0.9); most were locoregional recurrences. The mean five-year RFI rates for no-RT vs RT (SD) were 92.7% (2.9%) vs 95.5% (2.2%) and 88.4% (2.0%) vs 94.5% (1.6%). Both models showed little or no difference in breast cancer-specific or overall survival. Alternative definitions of low risk based on combinations of age and grade produced similar results. Conclusions: The proposed trial was unlikely to show noninferiority of omitting radiotherapy even using alternative definitions of low-risk, as the endpoint included local recurrence. Future trials regarding radiotherapy should address absolute reduction in recurrence and impact of type of recurrence on the patient. PMID- 29718315 TI - Metal artifact reduction by filter-based dual-energy cone-beam computed tomography on a bench-top micro-CBCT system: concept and demonstration. AB - We evaluated two dual-energy cone-beam computed tomography (DE-CBCT) methodologies for a bench-top micro-CBCT system to reduce metal artifacts on reconstructed images. Two filter-based DE-CBCT methodologies were tested: (i) alternative spectral switching and (ii) simultaneous beam splitting. We employed filters of 0.6-mm-thick tin and 0.1-mm-thick tungsten to generate high- and low energy spectra from 120 kVp X-rays, respectively. The spectral switching method was imitated by two half scans with different filters (pseudo-switching). Filters were placed and between the X-ray tube and a phantom ('1-u,' '2-u'), a phantom and a flat panel detector ('1-d,' '2-d'), and compared with (iii) two half scans at 80 and 140 kVp [pseudo-(80,140)]. For the splitting method, two half-width filters were aligned along a rotating axis. Projections were separated into halves and merged with corresponding areas of opposed projections after one full rotation. A solid 30-mm-diameter acrylic phantom and an acrylic phantom with four 5-mm-diameter titanium rods were used. DE images were generated by weighted summation of the high- and low-energy images. The blending factor was changed from 0 to +5 in increments of 0.01. Relative errors (REs) of the linear attenuation coefficients of the two phantoms and the contrast-to-noise ratios (CNRs) between the titanium and acrylic regions were compared. All methods showed zero REs except for the method (2-d). CNRs for pseudo-switching with upstream placement were 1.4-fold larger than CNRs for the pseudo-(80,140) method. CNRs for the downstream placements were small. It was concluded that the pseudo-switching method with upstream placement is appropriate for reducing metal artifacts. PMID- 29718316 TI - PhytoNet: comparative co-expression network analyses across phytoplankton and land plants. AB - Phytoplankton consists of autotrophic, photosynthesizing microorganisms that are a crucial component of freshwater and ocean ecosystems. However, despite being the major primary producers of organic compounds, accounting for half of the photosynthetic activity worldwide and serving as the entry point to the food chain, functions of most of the genes of the model phytoplankton organisms remain unknown. To remedy this, we have gathered publicly available expression data for one chlorophyte, one rhodophyte, one haptophyte, two heterokonts and four cyanobacteria and integrated it into our PlaNet (Plant Networks) database, which now allows mining gene expression profiles and identification of co-expressed genes of 19 species. We exemplify how the co-expressed gene networks can be used to reveal functionally related genes and how the comparative features of PhytoNet allow detection of conserved transcriptional programs between cyanobacteria, green algae, and land plants. Additionally, we illustrate how the database allows detection of duplicated transcriptional programs within an organism, as exemplified by two putative DNA repair programs within Chlamydomonas reinhardtii. PhytoNet is available from www.gene2function.de. PMID- 29718317 TI - MeShClust: an intelligent tool for clustering DNA sequences. AB - Sequence clustering is a fundamental step in analyzing DNA sequences. Widely-used software tools for sequence clustering utilize greedy approaches that are not guaranteed to produce the best results. These tools are sensitive to one parameter that determines the similarity among sequences in a cluster. Often times, a biologist may not know the exact sequence similarity. Therefore, clusters produced by these tools do not likely match the real clusters comprising the data if the provided parameter is inaccurate. To overcome this limitation, we adapted the mean shift algorithm, an unsupervised machine-learning algorithm, which has been used successfully thousands of times in fields such as image processing and computer vision. The theory behind the mean shift algorithm, unlike the greedy approaches, guarantees convergence to the modes, e.g. cluster centers. Here we describe the first application of the mean shift algorithm to clustering DNA sequences. MeShClust is one of few applications of the mean shift algorithm in bioinformatics. Further, we applied supervised machine learning to predict the identity score produced by global alignment using alignment-free methods. We demonstrate MeShClust's ability to cluster DNA sequences with high accuracy even when the sequence similarity parameter provided by the user is not very accurate. PMID- 29718318 TI - A rare cause of pericardial effusion due to intracardiac cement embolism. PMID- 29718319 TI - Characterization of the Nile Grass Rat as a Unique Model for Type 2 Diabetic Polyneuropathy. AB - Type 2 diabetes (T2D) has reached pandemic proportions worldwide. Almost half of T2D patients suffer from polyneuropathy that can present as paresthesia, hyperalgesia, allodynia, or hypoesthesia. Therapeutic treatment options are largely incomplete, suggesting new avenues of research are needed. Herein, we introduce the African Nile Grass rat (NGR), which develops T2D solely by diet manipulation, as a novel T2D polyneuropathy model. The purpose of this study was to first characterize T2D-induced polyneuropathy in the NGRs before highlighting their strength as a potential prediabetic model of T2D. NGRs with long-term T2D exhibit hallmark features of polyneuropathy such as decreased motor nerve conduction velocity, intraepidermal denervation, and hyposensitivity to noxious mechanical and thermal stimulation. At the dorsal root ganglia, T2D neurons have altered sodium channel expression, specifically increased Nav1.7 and Nav1.9, and their surrounding satellite glial cells express glial fibrillary acidic protein. Now that these T2D NGRs have been characterized and shown to have a similar presentation to human and other animal models of T2D, the strength of this diet induced model can be exploited. The prediabetic changes can be observed over their long progression to develop T2D which may allow for a therapeutic window to prevent T2D before permanent damage occurs. PMID- 29718320 TI - A survey on the knowledge, attitudes and practices of physicians towards pharmacovigilance in Jordanian health centres. AB - Background: Knowledge, attitudes and practices of health care professionals towards pharmacovigilance are strongly associated with reporting adverse drug reactions, as proven by a number of studies. This study aims to evaluate the levels of knowledge, attitudes and practices towards pharmacovigilance among physicians working at health centres of the Jordanian Ministry of Health. Methods: This took the form of a cross-sectional survey. Questionnaires were distributed by the researcher and research assistant to the physicians. Twenty primary and comprehensive health centres were covered. Results: The study included 106 physicians. Poor knowledge and practices were observed (mean knowledge score of 1.5+/-1.2 out of five, and mean practice score of 5.5+/-1.8 out of 15), while a high level of positive attitudes was observed (mean attitude score of 9.3+/-1.3 out of 10). Half of the physicians were aware that monitoring adverse drug reactions in Jordan is carried out by the Jordan Pharmacovigilance Centre. The majority of physicians (95.2%) mentioned that they rarely or never used the adverse drug reactions reporting form in Jordan. Conclusions: It is clear that there is a need to initiate educational activities and intervention programmes to raise the awareness of health care providers in Jordan regarding pharmacovigilance. PMID- 29718322 TI - CoNekT: an open-source framework for comparative genomic and transcriptomic network analyses. AB - The recent accumulation of gene expression data in the form of RNA sequencing creates unprecedented opportunities to study gene regulation and function. Furthermore, comparative analysis of the expression data from multiple species can elucidate which functional gene modules are conserved across species, allowing the study of the evolution of these modules. However, performing such comparative analyses on raw data is not feasible for many biologists. Here, we present CoNekT (Co-expression Network Toolkit), an open source web server, that contains user-friendly tools and interactive visualizations for comparative analyses of gene expression data and co-expression networks. These tools allow analysis and cross-species comparison of (i) gene expression profiles; (ii) co expression networks; (iii) co-expressed clusters involved in specific biological processes; (iv) tissue-specific gene expression; and (v) expression profiles of gene families. To demonstrate these features, we constructed CoNekT-Plants for green alga, seed plants and flowering plants (Picea abies, Chlamydomonas reinhardtii, Vitis vinifera, Arabidopsis thaliana, Oryza sativa, Zea mays and Solanum lycopersicum) and thus provide a web-tool with the broadest available collection of plant phyla. CoNekT-Plants is freely available from http://conekt.plant.tools, while the CoNekT source code and documentation can be found at https://github.molgen.mpg.de/proost/CoNekT/. PMID- 29718321 TI - Telomere sequence content can be used to determine ALT activity in tumours. AB - The replicative immortality of human cancer cells is achieved by activation of a telomere maintenance mechanism (TMM). To achieve this, cancer cells utilise either the enzyme telomerase, or the Alternative Lengthening of Telomeres (ALT) pathway. These distinct molecular pathways are incompletely understood with respect to activation and propagation, as well as their associations with clinical outcomes. We have identified significant differences in the telomere repeat composition of tumours that use ALT compared to tumours that do not. We then employed a machine learning approach to stratify tumours according to telomere repeat content with an accuracy of 91.6%. Importantly, this classification approach is applicable across all tumour types. Analysis of pathway mutations that were under-represented in ALT tumours, across 1,075 tumour samples, revealed that the autophagy, cell cycle control of chromosomal replication, and transcriptional regulatory network in embryonic stem cells pathways are involved in the survival of ALT tumours. Overall, our approach demonstrates that telomere sequence content can be used to stratify ALT activity in cancers, and begin to define the molecular pathways involved in ALT activation. PMID- 29718323 TI - PRMT5-mediated arginine methylation of TDP1 for the repair of topoisomerase I covalent complexes. AB - Human tyrosyl-DNA phosphodiesterases (TDP) hydrolyze the phosphodiester bond between DNA and the catalytic tyrosine of Top1 to excise topoisomerase I cleavage complexes (Top1cc) that are trapped by camptothecin (CPT) and by genotoxic DNA alterations. Here we show that the protein arginine methyltransferase PRMT5 enhances the repair of Top1cc by direct binding to TDP1 and arginine dimethylation of TDP1 at residues R361 and R586. Top1-induced replication mediated DNA damage induces TDP1 arginine methylation, enhancing its 3'- phosphodiesterase activity. TDP1 arginine methylation also increases XRCC1 association with TDP1 in response to CPT, and the recruitment of XRCC1 to Top1cc DNA damage foci. PRMT5 knockdown cells exhibit defective TDP1 activity with marked elevation in replication-coupled CPT-induced DNA damage and lethality. Finally, methylation of R361 and R586 stimulate TDP1 repair function and promote cell survival in response to CPT. Together, our findings provide evidence for the importance of PRMT5 for the post-translational regulation of TDP1 and repair of Top1cc. PMID- 29718324 TI - Activation of LANCL2 by BT-11 Ameliorates IBD by Supporting Regulatory T Cell Stability Through Immunometabolic Mechanisms. AB - Background: Inflammatory bowel disease (IBD) afflicts 5 million people and is increasing in prevalence. There is an unmet clinical need for safer and effective treatments for IBD. The BT-11 is a small molecule oral therapeutic that ameliorates IBD by targeting lanthionine synthetase C-like 2 (LANCL2) and has a benign safety profile in rats. Methods: Mdr1a-/-, dextran sodium sulphate , and adoptive transfer mouse models of colitis were employed to validate therapeutic efficacy and characterize the mechanisms of therapeutic efficacy of BT-11. In vitro cultures of CD4+ T cell differentiation and human peripheral blood mononuclear cells from Crohn's disease patients were used to determine its potential for human translation. Results: BT-11 reduces inflammation in multiple mouse models of IBD. Oral treatment with BT-11 increases the numbers of lamina propria regulatory T cells (Tregs) in a LANCL2-dependent manner. In vitro, BT-11 increases the differentiation in Treg phenotypes, the upregulation of genes implicated in Treg cell stability, and conditions Treg cells to elicit greater suppressive actions. These immunoregulatory effects are intertwined with the ability of BT-11 to regulate late stage glycolysis and tricarboxylic acid cycle. Immunometabolic mechanistic findings translate into human peripheral blood mononuclear cells from healthy individuals and Crohn's disease patients. Conclusions: BT-11 is a safe, efficacious oral therapeutic for IBD with a human translatable mechanism of action that involves activation of LANCL2, immunometabolic modulation of CD4+ T cell subsets leading to stable regulatory phenotypes in the colonic LP. PMID- 29718326 TI - Mumps: A Pain in the Neck. PMID- 29718325 TI - High throughput discovery of protein variants using proteomics informed by transcriptomics. AB - Proteomics informed by transcriptomics (PIT), in which proteomic MS/MS spectra are searched against open reading frames derived from de novo assembled transcripts, can reveal previously unknown translated genomic elements (TGEs). However, determining which TGEs are truly novel, which are variants of known proteins, and which are simply artefacts of poor sequence assembly, is challenging. We have designed and implemented an automated solution that classifies putative TGEs by comparing to reference proteome sequences. This allows large-scale identification of sequence polymorphisms, splice isoforms and novel TGEs supported by presence or absence of variant-specific peptide evidence. Unlike previously reported methods, ours does not require a catalogue of known variants, making it more applicable to non-model organisms. The method was validated on human PIT data, then applied to Mus musculus, Pteropus alecto and Aedes aegypti. Novel discoveries included 60 human protein isoforms, 32 392 polymorphisms in P. alecto, and TGEs with non-methionine start sites including tyrosine. PMID- 29718327 TI - Association Between Serum Infliximab Trough Concentrations During Maintenance Therapy and Biochemical, Endoscopic, and Histologic Remission in Crohn's Disease. AB - Background and aim: Objective and more rigorous therapeutic outcomes are emerging as novel targets in Crohn's disease (CD). We investigated the association between maintenance serum infliximab trough concentrations and biochemical, endoscopic, or histologic remission in CD. Methods: This retrospective multicenter study involved consecutive CD patients treated with infliximab who had a serum C reactive protein (CRP) measured within 1 week or endoscopic evaluation within 12 weeks of therapeutic drug monitoring between January 2010 and June 2016. Biochemical remission was defined as a normal CRP (<=5 mg/L). Endoscopic remission was defined as absence of any mucosal break (ulceration or erosion) or for patients with an ileocolonic resection, a Rutgeerts score of <=i1. Histologic remission was defined as absence of active inflammation. Results: Seventy-one CRP levels and 96 colonoscopies from 110 CD patients were evaluated. Based on ROC analyses, infliximab concentration thresholds of 2.2, 9.7, and 9.8 MUg/mL were found to be related with biochemical, endoscopic, and histologic remission, respectively. Multiple logistic regression analyses identified infliximab concentration >=2.2 (OR 6.4; 95% CI, 1.5-27.1; P = 0.011), >=9.7 (OR 3.6; 95% CI, 1.4-9; P = 0.006) and >=9.8 MUg/mL (OR 3.2; 95% CI, 1.3-7.9; P = 0.011) as variables independently associated with biochemical, endoscopic, and histologic remission, respectively. Conclusions: This study showed that higher maintenance infliximab trough concentrations are associated with more favorable rates of biochemical, endoscopic, or histologic remission in CD patients and that infliximab concentrations may differ based on the treatment goal. PMID- 29718328 TI - Endocrinology-It Takes All of Us. PMID- 29718329 TI - Antimicrobial susceptibility and ribotypes of Clostridium difficile isolates from a Phase 2 clinical trial of ridinilazole (SMT19969) and vancomycin. AB - Objectives: We evaluated the antimicrobial susceptibility and ribotypes of Clostridium difficile isolates from participants in a Phase 2 study of ridinilazole, a novel targeted-spectrum agent for treatment of C. difficile infection. Methods: Participants received ridinilazole (200 mg twice daily) or vancomycin (125 mg four times daily) for 10 days (ClinicalTrials.gov: NCT02092935). The MICs of ridinilazole and comparators for C. difficile isolates from stool samples were determined by agar dilution. Toxin gene profiling was performed by multiplex PCR and ribotype identification by capillary electrophoresis. Results: Eighty-nine isolates were recovered from 88/100 participants (one participant had two strains at baseline). The median colony count (cfu/g stool) was 1.9 * 104 (range: 2.5 * 102-7.0 * 106). Twelve participants (three received ridinilazole and nine received vancomycin) experienced recurrence, confirmed by immunoassays for free toxin in stool samples. The ribotype of eight out of nine isolates obtained at recurrence matched those of the initial isolates. All isolates, including those obtained at recurrence, were susceptible to ridinilazole within the expected range [median (range) MIC: 0.12 (0.06-0.5) mg/L]. The median (range) vancomycin MIC was 1 (0.5 4.0) mg/L. At baseline, 13.6% and 13.3% of samples in the ridinilazole and vancomycin groups were positive for VRE, increasing to 23.7% and 29.7% by day 40, respectively. Common ribotypes included 014-20 (14 isolates), 027 (13), 106 (7), 002 (7), 078-126 (4), 001 (4), 087 (3) and 198 (3). Toxin gene profiling of nearly all baseline isolates (98.9%) revealed a binary toxin gene (cdtA/cdtB) prevalence of 35%. Conclusions: Ridinilazole potently inhibited recovered C. difficile isolates. Recurrence was not associated with altered susceptibility. PMID- 29718330 TI - DynaMut: predicting the impact of mutations on protein conformation, flexibility and stability. AB - Proteins are highly dynamic molecules, whose function is intrinsically linked to their molecular motions. Despite the pivotal role of protein dynamics, their computational simulation cost has led to most structure-based approaches for assessing the impact of mutations on protein structure and function relying upon static structures. Here we present DynaMut, a web server implementing two distinct, well established normal mode approaches, which can be used to analyze and visualize protein dynamics by sampling conformations and assess the impact of mutations on protein dynamics and stability resulting from vibrational entropy changes. DynaMut integrates our graph-based signatures along with normal mode dynamics to generate a consensus prediction of the impact of a mutation on protein stability. We demonstrate our approach outperforms alternative approaches to predict the effects of mutations on protein stability and flexibility (P-value < 0.001), achieving a correlation of up to 0.70 on blind tests. DynaMut also provides a comprehensive suite for protein motion and flexibility analysis and visualization via a freely available, user friendly web server at http://biosig.unimelb.edu.au/dynamut/. PMID- 29718331 TI - The Uba4 domain interplay is mediated via a thioester that is critical for tRNA thiolation through Urm1 thiocarboxylation. AB - Eukaryotic ubiquitin-like proteins (UBLs) have evolved from prokaryotic sulfur carrier proteins (SCPs). Ubiquitin related modifier 1 (Urm1) shares biochemical and structural features of UBLs and SCPs and is essential for 2-thiolation of cytoplasmic tRNA. This chemical modification of wobble uridine is highly conserved amongst species and is achieved via Urm1 thiocarboxylation by the non canonical ubiquitin activating 4 enzyme (Uba4), which contains an E1- and a Rhodanese (RHD) domain. While the RHD catalyzes the last step in Urm1 thiocarboxylate formation, the previous steps in Urm1 activation and the interplay between the two domains have remained elusive. To define the underlying mechanism, we established an Urm1 in vitro thiocarboxylation assay, which combined with structure-function and chemical profiling analyses revealed a critical thioester linkage between Urm1 and Uba4 residue Cys225. This linkage is indispensable for the Urm1 intramolecular transfer between the two domains of Uba4 and it is thus, essential for tRNA thiolation in vivo. These findings contribute to a deeper understanding of UBL evolution. PMID- 29718332 TI - Endoscopic Endonasal Transmaxillary Transsphenoidal Approach for Excision of a Superior Orbital Fissure-Cavernous Sinus Meningioma: 2-Dimensional Operative Video. AB - We present a 43-old-male who suffered from a slowly progressive loss of vision in the left eye. Magnetic resonance (MR) imaging revealed a well-circumscribed contrast-enhancing lesion in the region of the anterior cavernous sinus and superior orbital fissure that extended into the optic canal. A schwannoma or meningioma was suspected. A transcranial surgery performed at another institution was not successful in removing the tumor and further deterioration of vision occurred. After resection of the left middle turbinate, the sphenoid and maxillary sinus were opened. The bulging of the tumor was seen at the lateral wall of the sphenoid sinus. After bony decompression of the optic canal, the dura was opened. A meningioma was exposed that arose in between the dural layers of the cavernous sinus. A nice dissection plane was found and the tumor was circumferentially dissected and finally totally removed. There were no complications such as double vision or visual field deficit. MR imaging confirmed a total tumor resection. The visual acuity normalized within a few days. MR imaging obtained 3 yr after surgery shows no recurrence. PMID- 29718333 TI - Neural Response After a Single ECT Session During Retrieval of Emotional Self Referent Words in Depression: A Randomized, Sham-Controlled fMRI Study. AB - Background: Negative neurocognitive bias is a core feature of depression that is reversed by antidepressant drug treatment. However, it is unclear whether modulation of neurocognitive bias is a common mechanism of distinct biological treatments. This randomized controlled functional magnetic resonance imaging study explored the effects of a single electroconvulsive therapy session on self referent emotional processing. Methods: Twenty-nine patients with treatment resistant major depressive disorder were randomized to one active or sham electroconvulsive therapy session at the beginning of their electroconvulsive therapy course in a double-blind, between-groups design. The following day, patients were given a self-referential emotional word categorization test and a free recall test. This was followed by an incidental word recognition task during whole-brain functional magnetic resonance imaging at 3T. Mood was assessed at baseline, on the functional magnetic resonance imaging day, and after 6 electroconvulsive therapy sessions. Data were complete and analyzed for 25 patients (electroconvulsive therapy: n = 14, sham: n = 11). The functional magnetic resonance imaging data were analyzed using the FMRIB Software Library randomize algorithm, and the Threshold-Free Cluster Enhancement method was used to identify significant clusters (corrected at P < .05). Results: A single electroconvulsive therapy session had no effect on hippocampal activity during retrieval of emotional words. However, electroconvulsive therapy reduced the retrieval-specific neural response for positive words in the left frontopolar cortex. This effect occurred in the absence of differences between groups in behavioral performance or mood symptoms. Conclusions: The observed effect of electroconvulsive therapy on prefrontal response may reflect early facilitation of memory for positive self-referent information, which could contribute to improvements in depressive symptoms including feelings of self-worth with repeated treatments. PMID- 29718334 TI - Low-Dose Levothyroxine Reduces Intrahepatic Lipid Content in Patients With Type 2 Diabetes Mellitus and NAFLD. AB - Context: Nonalcoholic fatty liver disease (NAFLD) is highly prevalent in patients with type 2 diabetes mellitus (T2DM) and associated with significant morbidity and mortality. Thyroid hormone (TH) increases beta-oxidation of fatty acids and decreases intrahepatic lipid content (IHLC) in rodents with NAFLD. Objective: We investigated the possibility of low intrahepatic TH concentration in NAFLD and studied the effect of TH treatment in humans. Design/Setting: This was a phase 2b single-arm study in six hospitals in Singapore. Intrahepatic thyroid hormone concentrations were measured in rats with induced NAFLD. Patients: Euthyroid patients with T2DM and steatosis measured by ultrasonography. Intervention: Levothyroxine was titrated to reach a thyroid-stimulating hormone level of 0.34 to 1.70 mIU/L before a 16-week maintenance phase. Main Outcome Measures: The primary outcome measure was change in IHLC measured by proton magnetic resonance spectroscopy after treatment. Results: Twenty male patients were included in the per-protocol analysis [mean +/- SD: age, 47.8 +/- 7.8 years; body mass index (BMI), 30.9 +/- 4.4 kg/m2; baseline IHLC, 13% +/- 4%]. After treatment, IHLC was decreased 12% (+/-SEM, 26%) relative to baseline (absolute change, -2%; 95% CI, 3 to 0; P = 0.046). Small decreases in BMI (P = 0.044), visceral adipose tissue volume (P = 0.047), and subcutaneous adipose tissue volume (P = 0.045) were observed. No significant changes in glucose regulation or lipid profile occurred. Conclusion: This study demonstrated the efficacy and safety of low-dose TH therapy for NAFLD in men. TH or TH analogs may be beneficial for this condition. PMID- 29718335 TI - Negative effect of vitamin D on kidney function: a Mendelian randomization study. AB - Background: The kidney plays a central role in the regulation of vitamin D metabolism. It is not clear, however, whether vitamin D influences kidney function. Previous studies have reported conflicting results, which may have been influenced by reverse causation and residual confounding. We conducted a Mendelian randomization (MR) study to obtain unconfounded estimates of the association between genetically instrumented vitamin D metabolites and estimated glomerular filtration rate (eGFR) as well as the urinary albumin:creatinine ratio (UACR). Methods: We performed a two-sample MR study based on three single nucleotide variants associated with 25(OH)D levels: rs2282679, rs10741657 and rs12785878, related to the genes GC, CYP2R1 and DHCR7, respectively. Estimates of the allele-dependent effects on serum 25(OH)D and eGFR/UACR were obtained from summary statistics of published genome-wide association meta-analyses. Additionally, we performed a one-sample MR analysis for both 25(OH)D and 1,25(OH)2 D using individual-level data from six cohorts. Results: The combined MR estimate supported a negative causal effect of log transformed 25(OH)D on log transformed eGFR (beta = -0.013, P = 0.003). The analysis of individual-level data confirmed the main findings and also revealed a significant association of 1,25(OH)2 D on eGFR (beta = -0.094, P = 0.008). These results show that a 10% increase in serum 25(OH)D levels causes a 0.3% decrease in eGFR. There was no effect of 25(OH)D on UACR (beta = 0.032, P = 0.265). Conclusion: Our study suggests that circulating vitamin D metabolite levels are negatively associated with eGFR. Further studies are needed to elucidate the underlying mechanisms. PMID- 29718336 TI - A clinical decision support system algorithm for intravenous to oral antibiotic switch therapy: validity, clinical relevance and usefulness in a three-step evaluation study. AB - Objectives: To evaluate a clinical decision support system (CDSS) based on consensus-based intravenous to oral switch criteria, which identifies intravenous to oral switch candidates. Methods: A three-step evaluation study of a stand alone CDSS with electronic health record interoperability was performed at the Erasmus University Medical Centre in the Netherlands. During the first step, we performed a technical validation. During the second step, we determined the sensitivity, specificity, negative predictive value and positive predictive value in a retrospective cohort of all hospitalized adult patients starting at least one therapeutic antibacterial drug between 1 and 16 May 2013. ICU, paediatric and psychiatric wards were excluded. During the last step the clinical relevance and usefulness was prospectively assessed by reports to infectious disease specialists. An alert was considered clinically relevant if antibiotics could be discontinued or switched to oral therapy at the time of the alert. Results: During the first step, one technical error was found. The second step yielded a positive predictive value of 76.6% and a negative predictive value of 99.1%. The third step showed that alerts were clinically relevant in 53.5% of patients. For 43.4% it had already been decided to discontinue or switch the intravenous antibiotics by the treating physician. In 10.1%, the alert resulted in advice to change antibiotic policy and was considered useful. Conclusions: This prospective cohort study shows that the alerts were clinically relevant in >50% (n = 449) and useful in 10% (n = 85). The CDSS needs to be evaluated in hospitals with varying activity of infectious disease consultancy services as this probably influences usefulness. PMID- 29718337 TI - Quadruplexes in 'Dicty': crystal structure of a four-quartet G-quadruplex formed by G-rich motif found in the Dictyostelium discoideum genome. AB - Guanine-rich DNA has the potential to fold into non-canonical G-quadruplex (G4) structures. Analysis of the genome of the social amoeba Dictyostelium discoideum indicates a low number of sequences with G4-forming potential (249-1055). Therefore, D. discoideum is a perfect model organism to investigate the relationship between the presence of G4s and their biological functions. As a first step in this investigation, we crystallized the dGGGGGAGGGGTACAGGGGTACAGGGG sequence from the putative promoter region of two divergent genes in D. discoideum. According to the crystal structure, this sequence folds into a four quartet intramolecular antiparallel G4 with two lateral and one diagonal loops. The G-quadruplex core is further stabilized by a G-C Watson-Crick base pair and a A-T-A triad and displays high thermal stability (Tm > 90 degrees C at 100 mM KCl). Biophysical characterization of the native sequence and loop mutants suggests that the DNA adopts the same structure in solution and in crystalline form, and that loop interactions are important for the G4 stability but not for its folding. Four-tetrad G4 structures are sparse. Thus, our work advances understanding of the structural diversity of G-quadruplexes and yields coordinates for in silico drug screening programs and G4 predictive tools. PMID- 29718338 TI - BCseq: accurate single cell RNA-seq quantification with bias correction. AB - With rapid technical advances, single cell RNA-seq (scRNA-seq) has been used to detect cell subtypes exhibiting distinct gene expression profiles and to trace cell transitions in development and disease. However, the potential of scRNA-seq for new discoveries is constrained by the robustness of subsequent data analysis. Here we propose a robust model, BCseq (bias-corrected sequencing analysis), to accurately quantify gene expression from scRNA-seq. BCseq corrects inherent bias of scRNA-seq in a data-adaptive manner and effectively removes technical noise. BCseq rescues dropouts through weighted consideration of similar cells. Cells with higher sequencing depths contribute more to the quantification nonlinearly. Furthermore, BCseq assigns a quality score for the expression of each gene in each cell, providing users an objective measure to select genes for downstream analysis. In comparison to existing scRNA-seq methods, BCseq demonstrates increased robustness in detection of differentially expressed (DE) genes and cell subtype classification. PMID- 29718340 TI - Cell size and morphological properties of yeast Saccharomyces cerevisiae in relation to growth temperature. AB - Cell volume is an important parameter for modelling cellular processes. Temperature-induced variability of cellular size, volume, intracellular granularity, a fraction of budding cells of yeast Saccharomyces cerevisiae CEN.PK 113-7D (in anaerobic glucose unlimited batch cultures) were measured by flow cytometry and matched with the performance of the biomass growth (maximal specific growth rate (MUmax), specific rate of glucose consumption, the rate of maintenance, biomass yield on glucose). The critical diameter of single cells was 7.94 MUm and it is invariant at growth temperatures above 18.5 degrees C. Below 18.5 degrees C, it exponentially increases up to 10.2 MUm. The size of the bud linearly depends on MUmax, and it is between 50% at 5 degrees C and 90% at 31 degrees C of the averaged single cell. The intracellular granularity (side scatter channel (SSC)-index) negatively depends on MUmax. There are two temperature regions (5-31 degrees C vs. 33-40 degrees C) where the relationship between SSC-index and various cellular parameters differ significantly. In supraoptimal temperature range (33-40 degrees C), cells are less granulated perhaps due to a higher rate of the maintenance. There is temperature dependent passage through the checkpoints in the cell cycle which influences the MUmax. The results point to the existence of two different morphological states of yeasts in these different temperature regions. PMID- 29718339 TI - High-resolution mapping of DNA polymerase fidelity using nucleotide imbalances and next-generation sequencing. AB - DNA polymerase fidelity is affected by both intrinsic properties and environmental conditions. Current strategies for measuring DNA polymerase error rate in vitro are constrained by low error subtype sensitivity, poor scalability, and lack of flexibility in types of sequence contexts that can be tested. We have developed the Magnification via Nucleotide Imbalance Fidelity (MagNIFi) assay, a scalable next-generation sequencing assay that uses a biased deoxynucleotide pool to quantitatively shift error rates into a range where errors are frequent and hence measurement is robust, while still allowing for accurate mapping to error rates under typical conditions. This assay is compatible with a wide range of fidelity-modulating conditions, and enables high-throughput analysis of sequence context effects on base substitution and single nucleotide deletion fidelity using a built-in template library. We validate this assay by comparing to previously established fidelity metrics, and use it to investigate neighboring sequence-mediated effects on fidelity for several DNA polymerases. Through these demonstrations, we establish the MagNIFi assay for robust, high-throughput analysis of DNA polymerase fidelity. PMID- 29718341 TI - Anti-TNF Therapy Induces CD4+ T-Cell Production of IL-22 and Promotes Epithelial Repairs in Patients With Crohn's Disease. AB - Background: Anti-tumor necrosis factor (TNF) therapy appears to be effective in the treatment of Crohn's disease (CD), a chronic inflammatory disease of the gastrointestinal tract. However, the mechanisms involved are not completely understood. Methods: Fifty-seven active CD patients were enrolled, and cytokine profiles in colonic biopsies of patients with active CD receiving anti-TNF monoclonal antibody (mAb) (infliximab [IFX]) treatment were determined using quantitative real-time polymerase chain reaction (qRT-PCR). Colonic biopsies of active CD patients and healthy donors were cultured with IFX in vitro, and cytokine profiles were measured by qRT-PCR. Peripheral blood (PB)-CD4+ T cells were stimulated with anti-CD3 and anti-CD28 mAbs in the presence of human immunoglobin (HIg), IFX, recombinant human TNF-alpha converting enzyme (rhTACE), and aryl hydrocarbon receptor (AhR) inhibitor (CH-223191), respectively, to determine interleukin (IL)-22 expression by CD4+ T cells. Caco2 cells were also utilized to study their potential role in modulating epithelial cell barrier repairs in vitro. Results: IFX therapy markedly upregulated IL-22 mRNA expression in the gut mucosa of CD patients. In vitro treatment with IFX greatly promoted CD CD4+ T cells to express IL-22, which was inhibited by rhTACE, indicating that reverse signaling through binding to membrane-bound TNF mediates anti-TNF-induced IL-22 expression of CD CD4+ T cells. However, blockade of AhR markedly inhibited anti-TNF-induced IL-22+CD4+ T (Th22) cell differentiation in CD patients. Moreover, treatment with IL-22 induced intestinal epithelial cell expression of tight junction proteins (eg, claudin1 and ZO-1) and facilitated transepithelial resistance, indicating that IL-22 protects intestinal mucosa from inflammation via maintenance of epithelial barrier integrity. Conclusions: Our results uncover a novel mechanism whereby anti-TNF therapy upregulates IL-22 production in CD patients through promoting Th22 cell differentiation and contributes to intestinal epithelial barrier repairs. PMID- 29718342 TI - Increased Systemic Inflammation and Gut Permeability Among Women With Treated HIV Infection in Rural Uganda. AB - In a cohort of human immunodeficiency virus (HIV)-infected individuals and age- and sex-matched HIV-uninfected comparators, we assessed soluble CD14 (sCD14), sCD163, interleukin 6, intestinal fatty acid binding protein (IFAPB), and high sensitivity C-reactive protein (hs-CRP) levels. The median age was 51 years. Among HIV-positive individuals, the median antiretroviral therapy (ART) duration was 7 years, the median CD4+ T-cell count was 433 cells/MUL, and 86% had an undetectable viral load. Although HIV-positive individuals had higher sCD14, IFABP, and hs-CRP levels, we found evidence of interaction by sex, such that HIV positive women had greater differences from HIV-negative women, compared with differences between HIV-positive men and HIV-negative men. In models restricted to HIV-positive individuals, women had higher levels of all 5 biomarkers than men. PMID- 29718343 TI - Dermatological Manifestations in Pediatric Patients with Inflammatory Bowel Diseases on Anti-TNF Therapy. AB - Background: Anti-tumor necrosis factor (anti-TNF) therapies are effective treatments for inflammatory bowel diseases (IBD). However, infections, psoriasis, and eczema are potential manifestations. Descriptions of these are limited. Our aim was to characterize these skin manifestations in children with IBD on anti TNF therapy. Methods: Our study is a retrospective review of IBD patients ranging in age from 6 to 18 years who were treated with anti-TNFs from 2010-2015. Data collected included demographics, clinical information, anti-TNF therapy used, and whether patients developed skin manifestations and their type of complication, clinical interventions, and outcomes. Results: Of the 409 patients analyzed, 47 (11.4%) developed dermatologic manifestations (39 CD, 8 UC/IC). Among these 47 patients, there were 72 manifestations of infections (28/72; 38.9%), psoriasis (33/72; 45.8%), and eczema (10/72; 13.9%). There was no significant difference between patients with CD and UC/IC in the type of manifestation. Children on infliximab experienced an increased risk of psoriasis than those on adalimumab (P = 0.05). A greater percentage of female patients developed a skin manifestation (28/47; 60%). The majority of patients with a skin manifestation were able to continue the current anti-TNF regimen. Amongst the patients that developed psoriasis, 60% did not require change in anti-TNF therapy. Conclusions: This is the largest study analyzing anti-TNF related skin manifestations in a pediatric IBD cohort. Psoriasiform lesions were the most prevalent dermatological manifestation, and females experienced more reactions than males. Most patients were able to continue their anti-TNF therapy. However, if a change was required, it was most likely among those who developed psoriasis and required either a dose or interval change, different anti-TNF medication, or a medication class change. PMID- 29718344 TI - Association of plexiform neurofibroma volume changes and development of clinical morbidities in neurofibromatosis 1. AB - Background: Plexiform neurofibromas (PN) in neurofibromatosis 1 (NF1) can cause substantial morbidities. Clinical trials targeting PN have recently described decreases in PN volumes. However, no previous study has assessed the association between changes in PN volumes and PN-related morbidities. Our objective was to assess if increasing PN volume in NF1 is associated with increasing PN-related morbidity. Methods: This is a retrospective review of patients enrolled on the NCI NF1 natural history study with >=7 years of data available. Morbidities including pain, motor dysfunction, vision loss, and PN-related surgery were assessed at time of baseline PN MRI with volumetric analysis and time of MRI with maximum PN volume. Results: Forty-one patients (median age at baseline 8 y) with 57 PN were included. At baseline, 40 PN had at least 1 PN-associated morbidity. During the observation period, 27 PN required increasing pain medication, and these PN grew faster per year (median difference 8.3%; 95% CI: 2.4, 13.8%) than those PN which did not. PN resulting in motor impairment at baseline (n = 11) had larger volumes compared with those that did not (median difference 461 mL; 95% CI: 66.9, 820). Conclusions: Many NF1 PN were associated with clinically significant morbidity at baseline, highlighting the need for longitudinal morbidity evaluations starting at an early age to capture changes in PN associated morbidities. Prospective evaluation of standardized patient reported and functional outcomes in clinical trials are ongoing and may allow further characterization of the association of PN volume increase or decrease and clinical changes. PMID- 29718347 TI - Peter Libby MD and CANTOS. PMID- 29718346 TI - Two years of bicalutamide monotherapy in patients with biochemical relapse after radical prostatectomy. AB - Background: Salvage treatments for biochemical relapse (BCR) after radical prostatectomy (RP) have several problems in terms of indications or adverse events. We studied the possibility of 2 years of bicalutamide monotherapy for BCR after RP. Methods: Patients who showed BCR (prostate-specific antigen (PSA) >= 0.2 ng/ml) after RP were recruited. Protocol treatment was planned as 2 years of bicalutamide (80 mg/day) followed by observation. Protocol treatment failure was defined as PSA re-elevation of >=0.2 ng/ml, clinical progression, any other treatments, or discontinuation or restart of bicalutamide. Primary endpoint of this study is time to protocol treatment failure from initiation of bicalutamide. Results: A total of 91 patients were registered between 2003 and 2009. Median age and PSA at initiating bicalutamide were 68 (range, 55-78) years and 0.32 (range, 0.19-7.91) ng/ml. Twenty-four (26.4%) patients could not complete 2 years of bicalutamide mainly due to progression of disease. Of the 91 patients, 2- and 5 year protocol treatment failure-free survivals were 74.6% and 33.0%, with a median follow-up of 76 (range, 11-118) months. Median time from initiating bicalutamide to treatment failure was 43 (95% confidence interval, 33-47) months. High-risk status at RP and time to BCR after RP < 6 months were significant predictors of second BCR. Conclusions: Two years of bicalutamide monotherapy should not be recommended as standard management for BCR after RP, but might be feasible for selected patients who do not have high-risk status at RP and short time to BCR. PMID- 29718345 TI - PI3K activation in neural stem cells drives tumorigenesis which can be ameliorated by targeting the cAMP response element binding protein. AB - Background: Hyperactivation of phosphoinositide 3-kinase (PI3K) signaling is common in cancers, but the precise role of the pathway in glioma biology remains to be determined. Some understanding of PI3K signaling mechanisms in brain cancer comes from studies on neural stem/progenitor cells (NSPCs), where signals transmitted via the PI3K pathway cooperate with other intracellular pathways and downstream transcription factors to regulate critical cell functions. Methods: To investigate the role of the PI3K pathway in glioma initiation and development, we generated a mouse model targeting the inducible expression of a PIK3CAH1047A oncogenic mutant and deletion of the PI3K negative regulator, phosphatase and tensin homolog (PTEN), to NSPCs. Results: Expression of a Pik3caH1047A was sufficient to generate tumors with oligodendroglial features, but simultaneous loss of PTEN was required for the development of invasive, high-grade glioma. Pik3caH1047A-PTEN mutant NSPCs exhibited enhanced neurosphere formation which correlated with increased Wnt signaling, while loss of cAMP response element binding protein (CREB) in Pik3caH1047A-Pten mutant tumors led to longer symptom free survival in mice. Conclusion: Taken together, our findings present a novel mouse model for glioma demonstrating that the PI3K pathway is important for initiation of tumorigenesis and that disruption of downstream CREB signaling attenuates tumor expansion. PMID- 29718348 TI - Diet and Nutrition after the PURE study. PMID- 29718349 TI - Sarcomere Gene Mutation correction. PMID- 29718350 TI - Ferrara VI. PMID- 29718351 TI - Joseph C. Wu. PMID- 29718352 TI - A new cardiology position in Bern, Switzerland. PMID- 29718353 TI - Refining cardiovascular risk: anthropometric measures, potassium, high altitude exposure, and cancer therapy. PMID- 29718354 TI - Effectiveness of a WHO Safe Childbirth Checklist Coaching-based intervention on the availability of Essential Birth Supplies in Uttar Pradesh, India. AB - Objective: Evaluate the impact of a World Health Organization Safe Childbirth Checklist coaching-based intervention (BetterBirth Program) on availability and procurement of essential childbirth-related supplies. Design: Matched pair, cluster-randomized controlled trial. Setting: Uttar Pradesh, India. Participants: 120 government-sector health facilities (60 interventions, 60 controls). Supply availability surveys were conducted quarterly in all sites. Coaches collected supply procurement sources from intervention sites. Interventions: Coaching targeting implementation of Checklist with data feedback and action planning. Main Outcome Measures: Mean supply availability by study arm; change in procurement sources for intervention sites. Results: At baseline, 6 and 12 months, the intervention sites had a mean of 20.9 (95% confidence interval (CI): 20.2-21.5); 22.4 (95% CI: 21.8-22.9) and 22.1 (95% CI:21.4-22.8) items, respectively. Control sites had 20.8 (95% CI: 20.3-21.3); 20.9 (95% CI: 20.3 21.5) and 21.7 (95% CI: 20.8-22.6) items at the same time-points. There was a small but statistically significant higher availability in intervention sites at 6 months (difference-in-difference (DID) = 1.43, P < 0.001), which was not seen by 12 months (DID = 0.37, P = 0.53). Greater difference between intervention and control sites starting in the bottom quartile of supply availability was seen at 6 months (DID = 4.0, P = 0.0002), with no significant difference by 12 months (DID = 1.5, P = 0.154). No change was seen in procurement sources with ~5% procured by patients with some rates as high as 29% (oxytocin). Conclusions: Implementation of the BetterBirth Program, incorporating supply availability, resulted in modest improvements with catch-up by control facilities by 12 months. Supply-chain coaching may be most beneficial in sites starting with lower supply availability. Efforts are needed to reduce reliance on patient-funding for some critical medications. Trial Registration: ClinicalTrials.gov #NCT02148952; Universal Trial Number: U1111-1131-5647. PMID- 29718356 TI - CMV Disease in IBD: Comparison of Diagnostic Tests and Correlation with Disease Outcome. AB - Background: Significance of cytomegalovirus (CMV) in inflammatory bowel disease (IBD) is unclear due to pathobiology, numerous CMV tests, and disparate treatment outcomes. Methods: Retrospective chart review was done on patients with positive qualitative CMV tissue polymerase chain reaction (PCR) from 2005-2013 at a tertiary referral hospital. Frequency of PCR+, hematoxylin and eosin staining(HE)+, histopathology and immunohistochemistry (IHC)+ was assessed. IHC was assessed on a sample of PCR- tissues. Surgery rates were correlated with CMV testing and treatment. Results: PCR was done on 310 samples from 180 patients. Thirty-seven samples were PCR+ (51.4% PCR+ only, 35.1% IHC/PCR+, 13.5% HE/IHC/PCR+). The H&E frequently failed to detect CMV identified on extensive IHC. Of 13 PCR- samples tested with IHC, 100% were negative. Twenty-five patients were CMV+ (40% PCR+, 40% IHC/PCR+, 20% HE/IHC/PCR+). Surgery rates increased with number of positive tests: 60% in IHC/PCR+ and 80% in HE/IHC/PCR+, compared to 26.8% in PCR- or PCR+ (P = 0.03, P = 0.02, respectively). There were 20/25 PCR+ patients who received CMV treatment. Surgery occurred in 80% of HE+ patients despite treatment and 100% of IHC+ patients without treatment. Conclusions: Rates of CMV+ testing and surgical risk varied by test modality. PCR+ results were most frequent but alone did not detect clinically significant CMV. HE+ testing was least frequent and associated with highest surgical rate, despite treatment. CMV treatment may benefit IHC+ patients most, supporting immunostaining as optimal diagnostic test for clinically significant CMV in IBD. In PCR+ samples, HE frequently did not detect CMV identified on extensive IHC. In PCR- samples, data suggest IHC is likely negative. Consider using qualitative PCR to guide extensive immunostaining. PMID- 29718355 TI - MetExplore: collaborative edition and exploration of metabolic networks. AB - Metabolism of an organism is composed of hundreds to thousands of interconnected biochemical reactions responding to environmental or genetic constraints. This metabolic network provides a rich knowledge to contextualize omics data and to elaborate hypotheses on metabolic modulations. Nevertheless, performing this kind of integrative analysis is challenging for end users with not sufficiently advanced computer skills since it requires the use of various tools and web servers. MetExplore offers an all-in-one online solution composed of interactive tools for metabolic network curation, network exploration and omics data analysis. In particular, it is possible to curate and annotate metabolic networks in a collaborative environment. The network exploration is also facilitated in MetExplore by a system of interactive tables connected to a powerful network visualization module. Finally, the contextualization of metabolic elements in the network and the calculation of over-representation statistics make it possible to interpret any kind of omics data. MetExplore is a sustainable project maintained since 2010 freely available at https://metexplore.toulouse.inra.fr/metexplore2/. PMID- 29718357 TI - Examining risk perceptions among daily smokers naive to reduced nicotine content cigarettes. AB - Introduction: The U.S. Food and Drug Administration (FDA) has stated its interest in reducing the addictiveness of combustible cigarettes by lowering their nicotine content. Delineating risk perceptions of reduced nicotine content (RNC) cigarettes prior to federal regulation may inform the content of future educational campaigns accompanying this policy. Methods: 500 non-treatment seeking, daily smokers naive to RNC cigarettes (63.0% male, 51.6% non-White, mean [SD] cigarettes per day = 15.69 [7.58], age = 43.44 [11.46]) completed a 10-item RNC cigarette risk perception questionnaire at baseline in two, unrelated experimental studies. We used multinomial logistic regression models to identify demographic (e.g., gender) and smoking-related (e.g., nicotine dependence) correlates of RNC cigarette risk perceptions. Results: While the majority of participants did not misperceive RNC cigarettes as less harmful than regular or high nicotine cigarettes, a large portion of the sample held misperceptions about RNC cigarettes' addictiveness (56.4%) and cessation aid potential (63.4%). More than 20% of the sample reported being unsure about RNC-related risks, especially tar content (51.8%). Non-White smokers were 2.5 to 3 times more likely to be incorrect about multiple RNC cigarette risks (p's = .002 - .006). Conclusions: If the FDA mandates a reduced nicotine content standard for cigarettes, educational campaigns will be needed to correct misperceptions about RNC cigarettes' addictiveness and potential to aid cessation as well as inform consumers about their safety risks. Campaigns tailored toward non-White smokers may also be needed to correct misperceptions of RNC cigarette risks held by this subgroup. Implications: The FDA has stated its interest in reducing cigarettes' addictiveness by lowering their nicotine content, enabling smokers to quit. Our findings suggest that most smokers who have not used RNC cigarettes do not perceive these products as less addictive or as cessation tools, stressing a need for future educational campaigns to correct these misperceptions. Campaigns are also needed to educate uninformed smokers about RNC cigarettes, and should consider targeting messages toward subgroups likely to hold misperceptions about the risks and benefits of using these products (e.g., non-White smokers). PMID- 29718358 TI - Identification of Key Bacteria Involved in the Induction of Incident Bacterial Vaginosis: A Prospective Study. AB - Background: The sequence of events preceding incident bacterial vaginosis (iBV) is unclear. Methods: African American women who have sex with women, who had no Amsel criteria and Nugent scores of 0-3, were followed for 90 days to detect iBV (defined as a Nugent score of 7-10 on at least 2-3 consecutive days), using self collected vaginal swab specimens. For women with iBV (cases) and women maintaining normal vaginal flora (healthy women), 16S ribosomal RNA gene sequencing targeting V4 was performed. Longitudinal vaginal microbiome data were analyzed. Results: Of 204 women screened, 42 enrolled; of these, 45% developed iBV. Sequencing was performed on 448 specimens from 14 cases and 8 healthy women. Among healthy women, Lactobacillus crispatus dominated the vaginal microbiota in 75%. In contrast, prior to iBV, the vaginal microbiota in 79% of cases was dominated by Lactobacillus iners and/or Lactobacillus jensenii/Lactobacillus gasseri. The mean relative abundance of Prevotella bivia, Gardnerella vaginalis, Atopobium vaginae, and Megasphaera type I became significantly higher in cases 4 days before (P. bivia), 3 days before (G. vaginalis), and on the day of (A. vaginae and Megasphaera type I) iBV onset. The mean relative abundance of Sneathia sanguinegens, Finegoldia magna, BV-associated bacteria 1-3, and L. iners was not significantly different between groups before onset of iBV. Conclusion: G. vaginalis, P. bivia, A. vaginae, and Megasphaera type I may play significant roles in iBV. PMID- 29718359 TI - How Cervical Reconstruction Surgery Affects Global Spinal Alignment. AB - BACKGROUND: There have been no reports describing how cervical reconstruction surgery affects global spinal alignment (GSA). OBJECTIVE: To elucidate the effects of cervical reconstruction for GSA through a retrospective multicenter study. METHODS: Seventy-eight patients who underwent cervical reconstruction surgery for cervical kyphosis were divided into a Head-balanced group (n = 42) and a Trunk-balanced group (n = 36) according to the values of the C7 plumb line (PL). We also divided the patients into a cervical sagittal balanced group (CSB group, n = 18) and a cervical sagittal imbalanced group (CSI group, n = 60) based on the C2 PL-C7 PL distance. Various sagittal Cobb angles and the sagittal vertical axes were measured before and after surgery. RESULTS: Cervical alignment was improved to achieve occiput-trunk concordance (the distance between the center of gravity [COG] PL, which is considered the virtual gravity line of the entire body, and C7 PL < 30 mm) despite the location of COG PL and C7PL. A subsequent significant change in thoracolumbar alignment was observed in Head balanced and CSI groups. However, no such significant change was observed in Trunk-balanced and CSB groups. We observed 1 case of transient and 1 case of residual neurological worsening. CONCLUSION: The primary goal of cervical reconstruction surgery is to achieve occiput-trunk concordance. Once it is achieved, subsequent thoracolumbar alignment changes occur as needed to harmonize GSA. Cervical reconstruction can restore both cervical deformity and GSA. However, surgeons must consider the risks and benefits in such challenging cases. PMID- 29718360 TI - Metabolomic profiling to improve glomerular filtration rate estimation: a proof of-concept study. AB - Background: Estimation of glomerular filtration rate (GFR) using estimated glomerular filtration rate creatinine (eGFRcr) is central to clinical practice but has limitations. We tested the hypothesis that serum metabolomic profiling can identify novel markers that in combination can provide more accurate GFR estimates. Methods: We performed a cross-sectional study of 200 African American Study of Kidney Disease and Hypertension (AASK) and 265 Multi-Ethnic Study of Atherosclerosis (MESA) participants with measured GFR (mGFR). Untargeted gas chromatography/dual mass spectrometry- and liquid chromatography/dual mass spectrometry-based quantification was followed by the development of targeted assays for 15 metabolites. On the log scale, GFR was estimated from single- and multiple-metabolite panels and compared with eGFR using the Chronic Kidney Disease Epidemiology equations with creatinine and/or cystatin C using established metrics, including the proportion of errors >30% of mGFR (1-P30), before and after bias correction. Results: Of untargeted metabolites in the AASK and MESA, 283 of 780 (36%) and 387 of 1447 (27%), respectively, were significantly correlated (P <= 0.001) with mGFR. A targeted metabolite panel eGFR developed in the AASK and validated in the MESA was more accurate (1-P30 3.7 and 1.9%, respectively) than eGFRcr [11.2 and 18.5%, respectively (P < 0.001 for both)] and estimating GFR using cystatin C (eGFRcys) [10.6% (P = 0.02) and 9.1% (P < 0.05), respectively] but was not consistently better than eGFR using both creatinine and cystatin C [3.7% (P > 0.05) and 9.1% (P < 0.05), respectively]. A panel excluding creatinine and demographics still performed well [1-P30 6.4% (P = 0.11) and 3.4% (P < 0.001) in the AASK and MESA] versus eGFRcr. Conclusions: Multimetabolite panels can enable accurate GFR estimation. Metabolomic equations, preferably excluding creatinine and demographic characteristics, should be tested for robustness and generalizability as a potential confirmatory test when eGFRcr is unreliable. PMID- 29718361 TI - Alcohol Metabolism in the Progression of Human Nonalcoholic Steatohepatitis. AB - Alcohol metabolism is a well-characterized biological process that is dominated by the alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH) families. Nonalcoholic steatohepatitis (NASH) is the advanced inflammatory stage of nonalcoholic fatty liver disease (NAFLD) and is known to alter the metabolism and disposition of numerous drugs. The purpose of this study was to investigate the alterations in alcohol metabolism processes in response to human NASH progression. Expression and function of ADHs, ALDHs, and catalase were examined in normal, steatosis, NASH (fatty) and NASH (not fatty) human liver samples. ALDH4A1 mRNA was significantly decreased in both NASH groups, while no significant changes were observed in the mRNA levels of other alcohol-related enzymes. The protein levels of ADH1A, ADH1B, and ADH4 were each decreased in the NASH groups, which was consistent with a decreased overall ADH activity. The protein level of ALDH2 was significantly increased in both NASH groups, while ALDH1A1 and ALDH1B1 were only decreased in NASH (fatty) samples. ALDH activity represented by oxidation of acetaldehyde was decreased in the NASH (fatty) group. The protein level of catalase was decreased in both NASH groups, though activity was unchanged. Furthermore, the significant accumulation of 4-hydroxynonenal protein adduct in NASH indicated significant oxidative stress and a potential reduction in ALDH activity. Collectively, ADH and ALDH expression and function are profoundly altered in the progression of NASH, which may have a notable impact on ADH- and ALDH-associated cellular metabolism processes and lead to significant alterations in drug metabolism mediated by these enzymes. PMID- 29718362 TI - Origins and History of Laboratory Insect Stocks in a Multispecies Insect Production Facility, With the Proposal of Standardized Nomenclature and Designation of Formal Standard Names. AB - Laboratory insect colonies are an essential part of experimental insect science. Formalized naming of laboratory stocks is standard practice in model organisms such as mice and fruit flies, but crucial details such as colony origin and standard names are often lacking in nonmodel systems. For institutions involved in rearing multiple nonmodel species, effective monitoring requires standardized naming and nomenclature, from establishment to production, distribution, and publication. Insect rearing has been the cornerstone of the Insect Production and Quarantine Laboratories (IPQL) at the Great Lakes Forestry Centre for over 70 yr, but the histories of the insect colonies in this facility have not been adequately documented and formal, standardized names do not exist. We propose a standardized naming framework that we applied to the eight species reared at the IPQL to rectify these deficiencies. We also present the origin and history of each colony, essential information that is challenging to obtain post hoc. We suggest that other research institutions consider developing similar standards, so they can accurately document, communicate, and track laboratory insect their within the facilities and through the scientific literature. PMID- 29718363 TI - Efficacy and safety comparison of nabpaclitaxel plus S-1 and gemcitabine plus S-1 as first-line chemotherapy for metastatic pancreatic cancer. AB - Objective: To compare efficacy and safety of nabpaclitaxel plus S-1 (AS) with gemcitabine plus S-1 (GS) as first-line treatment for metastatic pancreatic cancer. Methods: We conducted a retrospective cohort, single-institution analysis by reviewing medical records of 38 patients who received either AS (nabpaclitaxel 125 mg/m2 on Days 1, 8 and S-1 80 mg/m2 on Days 1 to 14) or GS (gemcitabine 1000 mg/m2 on Days 1, 8 and S-1 80 mg/m2 on Days 1 to 14) chemotherapy. Results: AS was associated with a prolonged median time to progression (TTP; 7.1 months, 95% CI, 4.5-9.7 vs. 3.6 months, 95% CI, 1.8-5.4; P value = 0.022) and improved median overall survival (OS; 10.2 months, 95% CI, 9.1-11.3 vs. 6 months, 95% CI, 4.2 7.8; P value <0.001) compared with GS. In cox proportional hazards model, treatment regimen was the only variable to be significantly associated with improvements in both TTP and OS. Subgroup analyses based on HER2 expression showed that AS seemed to have better outcome of OS in HER2 positive patients (HR = 0.168; 95% CI, 0.022-1.27; P value = 0.084). Hematological adverse events were commonly seen in both group (12.5% and 22.7%, GS and AS group, Grade 3 or 4; P value = 0.675) while AS got increased risk of sensory neuropathy (6 of 22 patients in AS, 27.3% vs. 0 of 16 patients in GS, all grade; P value = 0.03). Conclusions: AS could be an effective treatment regimen for metastatic pancreatic cancer under surveillance of toxicity. PMID- 29718364 TI - The DYW Domains of Pentatricopeptide Repeat RNA Editing Factors Contribute to Discriminate Target and Non-Target Editing Sites. AB - In land plant organelles, many transcripts are modified by cytidine to uridine RNA editing. Target cytidines are specifically recognized by nuclear-encoded pentatricopeptide repeat (PPR) proteins via their sequence-specific RNA-binding motifs. In the moss Physcomitrella patens, all PPR editing factors have C terminal E and DYW domains. To examine the contribution of E and DYW domains in RNA editing, we performed a complementation assay using mutated PpPPR_56 and PpPPR_71, which are responsible for mitochondrial editing sites. This assay showed that both E and DYW domains are required for RNA editing at the target sites, and that the conserved zinc-binding signature and the terminal triplet of the DYW domain are essential for editing. In addition, DYW domain-swapping experiments demonstrated that DYW domains are functionally different between PpPPR_56 and other mitochondrial PPR editing factors, and that residues 37-42 of the DYW domain are involved in site-specific editing. Our results suggest that PPR-DYW proteins specifically recognize their target editing sites via PPR motifs and the DYW domain. PMID- 29718365 TI - High and low estimated glomerular filtration rates are associated with adverse outcomes in patients undergoing surgery for gastrointestinal malignancies. AB - Background: Abnormally high estimated glomerular filtration rates (eGFRs) are associated with endothelial dysfunction and frailty. Previous studies have shown that low eGFR is associated with increased morbidity, but few reports address high eGFR. The purpose of this study is to evaluate the association of high eGFR with surgical outcomes in patients undergoing surgery for gastrointestinal malignancies. Methods: We identified patients who underwent elective surgery for gastrointestinal malignancies from 2005 to 2015 in the American College of Surgeons National Surgical Quality Improvement Program database. We evaluated associations of eGFR with surgical outcomes by Cox or logistic models with restricted cubic spline functions, adjusting for case mix variables (i.e. age, gender, race and diabetes). Results: The median eGFR is 83 (interquartile range 67-96) mL/min/1.73 m2. Thirty-day mortality was 1.9% (2555/136 896). There is a U shaped relationship between eGFR and 30-day mortality. The adjusted hazard ratios (95% confidence intervals) for eGFRs of 30, 60, 105 and 120 mL/min/1.73 m2 (versus 90 mL/min/1.73 m2) are 1.73 (1.52-1.97), 1.00 (0.89-1.11), 1.42 (1.31 1.55) and 2.20 (1.79-2.70), respectively. Similar associations are shown for other surgical outcomes, including return to the operating room and postoperative pneumonia. Subgroup analyses show that eGFRs both higher and lower than the respective medians are consistently associated with a higher risk of adverse outcomes across age, gender and race. Conclusions: High and low eGFRs are associated with more adverse surgical outcomes in patients undergoing surgery for gastrointestinal malignancies. The eGFR associated with the lowest postoperative risk is approximately at the median eGFR of a given population. PMID- 29718367 TI - Increased Oxidative Stress Exacerbates alpha-Synuclein Aggregation In Vivo. AB - Increasing evidence suggests a relationship between oxidative stress and alpha synuclein aggregation, the primary pathological hallmark of Parkinson disease (PD). However, a direct causal relationship has not yet been established in vivo in mouse models of PD. Superoxide dismutase 2 (SOD2) is rate limiting in the antioxidant machinery of the mitochondria and even its partial deficiency elevates oxidative stress in mice. Therefore, in order to investigate a possible interaction between oxidative stress and alpha-synuclein aggregation in vivo, a transgenic model of PD with haplodeficiency for SOD2 was generated on the basis of the well-characterized murine (Thy-1)-h[A30P]-alpha-synuclein transgenic line. In comparison with littermate controls with full SOD2 capacity, alpha-synuclein transgenic mice with partial SOD2 deficiency exhibited a significantly more advanced stage of synucleinopathy at 16 months, as demonstrated by higher median PK-PET blot scores (p < 0.01) and a greater amount of truncated alpha-synuclein in the insoluble fraction of homogenized brains (p < 0.05). These results show that compromising the capacity to scavenge free radicals can exacerbate alpha synuclein aggregation, indicating that elevated levels of oxidative stress could modulate the progression of PD. PMID- 29718366 TI - Intratumoral heterogeneity of oxygen metabolism and neovascularization uncovers 2 survival-relevant subgroups of IDH1 wild-type glioblastoma. AB - Background: The intratumoral heterogeneity of oxygen metabolism in combination with variable patterns of neovascularization (NV) as well as reprogramming of energy metabolism affects the landscape of tumor microenvironments (TMEs) in glioblastoma. Knowledge of the hypoxic and perivascular niches within the TME is essential for understanding treatment failure. Methods: Fifty-two patients with untreated glioblastoma (isocitrate dehydrogenase 1 wild type [IDH1wt]) were examined with a physiological MRI protocol including a multiparametric quantitative blood oxygen level dependent (qBOLD) approach and vascular architecture mapping (VAM). Imaging biomarker information about oxygen metabolism (mitochondrial oxygen tension) and neovascularization (microvascular density and type) were fused for classification of 6 different TMEs: necrosis, hypoxia with/without neovascularization, oxidative phosphorylation (OxPhos), and glycolysis with/without neovascularization. Association of the different TME volume fractions with progression-free survival (PFS) was assessed using Kaplan Meier analysis and Cox proportional hazards models. Results: A common spatial structure of TMEs was detected: central necrosis surrounded by tumor hypoxia (with defective and functional neovasculature) and different TMEs with a predominance of OxPhos and glycolysis for energy production, respectively. The percentage of the different TMEs on the total tumor volume uncovered 2 clearly different subtypes of glioblastoma IDH1wt: a glycolytic dominated phenotype with predominantly functional neovasculature and a necrotic/hypoxic dominated phenotype with approximately 50% of defective neovasculature. Patients with a necrotic/hypoxic dominated phenotype showed significantly shorter PFS (P = 0.035). Conclusions: Our non-invasive mapping approach allows for classification of the TME and detection of tumor-supportive niches in glioblastoma which may be helpful for both clinical patient management and research. PMID- 29718368 TI - Commentary: Trends in the National Resident Matching Program (NRMP) Data for Graduating US Medical Students Matching in Neurosurgery. PMID- 29718369 TI - Medical practice variation: public reporting a first necessary step to spark change. AB - From previous work, we know that medical practice varies widely, and that unwarranted variation signals low value for patients and society. We also know that public reporting helps to create awareness of the need for quality improvement. Despite the availability of rich data, most Western countries have no routine surveillance of the geographic distribution of utilization, costs, and outcomes of healthcare, including trends in variation over time. This paper highlights the role of transparent public reporting as a necessary first step to spark change and reduce unwarranted variation. Two recent examples of public reporting are presented to illustrate possible ways to reduce unwarranted variation and improve care. We conclude by introducing the Value Improvement Cycle, which underscores that reporting is only a necessary first step, and suggests a path toward developing a multi-stakeholder approach to change. PMID- 29718370 TI - Pediatric Inflammatory Bowel Diseases: Should We Be Looking for Kidney Abnormalities? AB - Background: Kidney disease has been reported in adults with inflammatory bowel disease (IBD) and is regarded an extraintestinal manifestation or more rarely a side effect of the medical treatment. Methods: In this cross-sectional study we describe the extent of kidney pathology in a cohort of 56 children with IBD. Blood and urine samples were analyzed for markers of kidney disease and ultrasonography was performed to evaluate pole-to-pole kidney length. Results: We found that 25% of the patients had either previously reported kidney disease or ultrasonographic signs of chronic kidney disease. The median kidney size compared with normal children was significantly reduced. In a multivariate linear mixed model, small kidneys significantly correlated with the use of infliximab, whereas the use of enteral nutritional therapy was associated with larger kidneys. Conclusion: Children with IBD are at risk of chronic kidney disease, and the risk seems to be increased with the severity of the disease. PMID- 29718371 TI - Metabolic syndrome and its components in southern Kazakhstan: a cross-sectional study. AB - Background: The study aimed to assess the prevalence of metabolic syndrome (MetS) and its components in southern Kazakhstan. Methods: A total of 965 adults, ages 20-74 y, participated in a cross-sectional study. MetS was defined using National Education Cholesterol Education Program Adult Treatment Panel III (NCEP), American Heart Association/National Heart, Lung and Blood Institute (AHA) and International Diabetes Federation (IDF) criteria. Social variations in the prevalence of components of MetS were assessed using Poisson regression. Results: Among women, the prevalence of MetS was 17.9% (95% confidence interval [CI] 14.7 21.1), 25.8% (95% CI 22.5-29.1) and 21.8% (95% CI 18.5-25.2) for the NCEP, AHA and IDF criteria, respectively (European standard population). The corresponding data for men were 15.3% (95% CI 10.7-19.9), 26.6% (95% CI 21.2-32.9) and 23.9% (95% CI 18.6-29.2). Abdominal obesity was the most prevalent component of MetS among women (74.3%), followed by hyperglycaemia (26.5%) and diastolic hypertension (25.5%), while for men the three most common components were abdominal obesity (70.7%), systolic hypertension (44.4%) and diastolic hypertension (40.0%). Secondary education was associated with a higher prevalence of abdominal obesity in both men (1.3 [95% CI 1.0-1.6]) and women (1.2 [95% CI 1.1-1.4]). Unmarried men were less likely to be obese (odds ratio 0.5 [95% CI 0.3 0.9]). Conclusions: The distribution of components of MetS in southern Kazakhstan is different from other parts of the European World Health Organization region and varies across genders. PMID- 29718373 TI - POSTER VIEWING I: DERMATOLOGY| 0.44 Paraneoplastic vasculitis in occult lung malignancy. PMID- 29718372 TI - Defining the impact of melanopsin missense polymorphisms using in vivo functional rescue. AB - Melanopsin (OPN4) is an opsin photopigment expressed within intrinsically photosensitive retinal ganglion cells (ipRGCs) that mediate non-image forming (NIF) responses to light. Two single nucleotide polymorphisms (SNPs) in human melanopsin (hOPN4), Pro10Leu and Thr394Ile, have recently been associated with abnormal NIF responses to light, including Seasonal Affective Disorder. It has been suggested these behavioural changes are due to altered melanopsin signalling. However, there is currently no direct evidence to support this. Here we have used ipRGC-specific delivery of hOPN4 wildtype (WT), Pro10Leu or Thr394Ile adeno-associated viruses (AAV) to determine the functional consequences of hOPN4 SNPs on melanopsin-driven light responses and associated behaviours. Immunohistochemistry confirmed hOPN4 AAVs exclusively transduced mouse ipRGCs. Behavioural phenotyping performed before and after AAV injection demonstrated that both hOPN4 Pro10Leu and Thr394Ile could functionally rescue pupillary light responses and circadian photoentrainment in Opn4-/-mice, with no differences in NIF behaviours detected for animals expressing either SNP compared to hOPN4 WT. Multi-electrode array recordings revealed that ipRGCs expressing hOPN4 Thr394Ile exhibit melanopsin-driven light responses with significantly attenuated response amplitude, decreased sensitivity and faster offset kinetics compared to hOPN4 WT. IpRGCs expressing hOpn4 Pro10Leu also showed reduced response amplitude. Collectively these data suggest Thr394Ile and Pro10Leu may be functionally significant SNPs, which result in altered melanopsin signalling. To our knowledge, this study provides the first direct evidence for the effects of hOPN4 polymorphisms on melanopsin-driven light responses and NIF behaviours in vivo, providing further insight into the role of these SNPs in melanopsin function and human physiology. PMID- 29718374 TI - Epidemiology of hypocomplementaemic urticarial vasculitis (anti-C1q vasculitis). AB - Objectives: The aim was to describe the clinical characteristics and epidemiology of hypocomplementaemic urticarial vasculitis (HUV; anti-C1q vasculitis) in two geographically defined areas of Sweden. Methods: In the health-care districts surrounding Skane University Hospital (mean population 950 560) and Linkoping University Hospital (mean population 428 503), all incident cases of HUV residing within the study areas at the onset of disease were identified during the years 2000-15. The diagnosis of HUV was confirmed by review of medical records. Only patients meeting the proposed diagnostic HUV criteria and/or the 2012 Chapel Hill consensus definitions in combination with an ever-positive anti-C1q antibody test were included. Results: Sixteen patients (14 females) were identified during the study period. The median (interquartile range) age at diagnosis was 51 (40.7 56.7) years. Median (interquartile range) time of follow-up from diagnosis to 31 December 2015, or death, was 94 (46.5-136.2) months. The most frequent manifestations at diagnosis were urticaria (100%), arthritis (88%), followed by biopsy-proven glomerulonephritis (19%), episcleritis/scleritis (19%) and recurrent abdominal pain (13%). The annual incidence rate per million inhabitants was estimated as 0.7 (95% CI: 0.4, 1.1). Sixty-three per cent suffered from pulmonary disease at the last follow-up. Two patients died during the follow-up period. One patient underwent lung transplantation, and two patients proceeded to end-stage renal disease. The point prevalence on 31 December 2015 was 9.5/million (95% CI: 4.5, 14.5). Conclusion: Hypocomplementaemic urticarial vasculitis constitutes a rare, but not always benign condition. Renal and lung manifestations were severe in some cases, highlighting the need for careful screening and monitoring of this potentially serious condition. PMID- 29718376 TI - Assessment of Ablative Fractional CO2 Laser and Er:YAG Laser to Treat Hypertrophic Scars in a Red Duroc Pig Model. AB - Hypertrophic scarring is a fibroproliferative process that occurs following a third-degree dermal burn injury, producing significant morbidity due to persistent pain, itching, cosmetic disfigurement, and loss of function due to contractures. Ablative fractional lasers have emerged clinically as a fundamental or standard therapeutic modality for hypertrophic burn scars. Yet the examination of their histopathological and biochemical mechanisms of tissue remodeling and comparison among different laser types has been lacking. In addition, deficiency of a relevant animal model limits our ability to gain a better understanding of hypertrophic scar pathophysiology. To evaluate the effect of ablative fractional lasers on hypertrophic third-degree burn scars, we have developed an in vivo Red Duroc porcine model. Third-degree burn wounds were created on the backs of animals, and burn scars were allowed to develop for 70 days before treatment. Scars received treatment with either CO2 or erbium: yttrium aluminum garnet (YAG) ablative fractional lasers. Here, we describe the effect of both lasers on hypertrophic third-degree burn scars in Red Duroc pigs. In this report, we found that Er:YAG has improved outcomes versus fractional CO2. Molecular changes noted in the areas of dermal remodeling indicated that matrix metalloproteinase 2, matrix metalloproteinase 9, and Decorin may play a role in this dermal remodeling and account for the enhanced effect of the Er:YAG laser. We have demonstrated that ablative fractional laser treatment of burn scars can lead to favorable clinical, histological, and molecular changes. This study provides support that hypertrophic third-degree burn scars can be modified by fractional laser treatment. PMID- 29718375 TI - Influence of Na+ and Mg2+ ions on RNA structures studied with molecular dynamics simulations. AB - The structure of ribonucleic acid (RNA) polymers is strongly dependent on the presence of, in particular Mg2+ cations to stabilize structural features. Only in high-resolution X-ray crystallography structures can ions be identified reliably. Here, we perform molecular dynamics simulations of 24 RNA structures with varying ion concentrations. Twelve of the structures were helical and the others complex folded. The aim of the study is to predict ion positions but also to evaluate the impact of different types of ions (Na+ or Mg2+) and the ionic strength on structural stability and variations of RNA. As a general conclusion Mg2+ is found to conserve the experimental structure better than Na+ and, where experimental ion positions are available, they can be reproduced with reasonable accuracy. If a large surplus of ions is present the added electrostatic screening makes prediction of binding-sites less reproducible. Distinct differences in ion binding between helical and complex folded structures are found. The strength of binding (DeltaG? for breaking RNA atom-ion interactions) is found to differ between roughly 10 and 26 kJ/mol for the different RNA atoms. Differences in stability between helical and complex folded structures and of the influence of metal ions on either are discussed. PMID- 29718377 TI - Automatic recognition of self-acknowledged limitations in clinical research literature. AB - Objective: To automatically recognize self-acknowledged limitations in clinical research publications to support efforts in improving research transparency. Methods: To develop our recognition methods, we used a set of 8431 sentences from 1197 PubMed Central articles. A subset of these sentences was manually annotated for training/testing, and inter-annotator agreement was calculated. We cast the recognition problem as a binary classification task, in which we determine whether a given sentence from a publication discusses self-acknowledged limitations or not. We experimented with three methods: a rule-based approach based on document structure, supervised machine learning, and a semi-supervised method that uses self-training to expand the training set in order to improve classification performance. The machine learning algorithms used were logistic regression (LR) and support vector machines (SVM). Results: Annotators had good agreement in labeling limitation sentences (Krippendorff's alpha = 0.781). Of the three methods used, the rule-based method yielded the best performance with 91.5% accuracy (95% CI [90.1-92.9]), while self-training with SVM led to a small improvement over fully supervised learning (89.9%, 95% CI [88.4-91.4] vs 89.6%, 95% CI [88.1-91.1]). Conclusions: The approach presented can be incorporated into the workflows of stakeholders focusing on research transparency to improve reporting of limitations in clinical studies. PMID- 29718378 TI - Evaluation of Total and IgA-Specific Antibody Targeting Epstein-Barr Virus Glycoprotein 350 and Nasopharyngeal Carcinoma Risk. AB - Background: We previously reported that higher levels of antibody targeting Epstein-Barr virus (EBV) glycoprotein350 (gp350), an EBV vaccine candidate, were protective against nasopharyngeal carcinoma (NPC) in genetically high-risk families from Taiwan. The current study attempted to extend this association to a general population cohort. Methods: We compared total and IgA-specific gp350 antibody levels in 35 incident NPC cases and 81 disease-free controls from the Cancer Screening Program in Taiwan (23943 individuals recruited 1991-1992). Luciferase immunoprecipitation assays quantified gp350 antibody. Results: Total EBVgp350 antibody levels were not higher in individuals who remained disease free compared to those who developed NPC (P = .11). This lack of a protective gp350 association persisted for cases diagnosed >=5 years (odds ratio [OR] = 1.05; P = .91) and <5 years (OR = 1.85; P = .40) after blood draw. IgA-specific gp350 antibody levels were higher in cases than controls (OR = 7.03; P = .001). This increased risk was most pronounced for cases diagnosed <5 years after blood draw (OR = 11.7; P = .004). Conclusion: Unlike our prior findings in those with a strong family history of NPC, total gp350 antibody levels were not protective against NPC development in this general population setting. PMID- 29718379 TI - Seven years post-Fukushima: overcoming the resident-specialist gap. PMID- 29718381 TI - Relapsing polychondritis: a diagnosis not to be missed. PMID- 29718380 TI - High Levels of Copy Number Variation of Ampliconic Genes across Major Human Y Haplogroups. AB - Because of its highly repetitive nature, the human male-specific Y chromosome remains understudied. It is important to investigate variation on the Y chromosome to understand its evolution and contribution to phenotypic variation, including infertility. Approximately 20% of the human Y chromosome consists of ampliconic regions which include nine multi-copy gene families. These gene families are expressed exclusively in testes and usually implicated in spermatogenesis. Here, to gain a better understanding of the role of the Y chromosome in human evolution and in determining sexually dimorphic traits, we studied ampliconic gene copy number variation in 100 males representing ten major Y haplogroups world-wide. Copy number was estimated with droplet digital PCR. In contrast to low nucleotide diversity observed on the Y in previous studies, here we show that ampliconic gene copy number diversity is very high. A total of 98 copy-number-based haplotypes were observed among 100 individuals, and haplotypes were sometimes shared by males from very different haplogroups, suggesting homoplasies. The resulting haplotypes did not cluster according to major Y haplogroups. Overall, only two gene families (RBMY and TSPY) showed significant differences in copy number among major Y haplogroups, and the haplogroup of a male could not be predicted based on his ampliconic gene copy numbers. Finally, we did not find significant correlations either between copy number variation and individual's height, or between the former and facial masculinity/femininity. Our results suggest rapid evolution of ampliconic gene copy numbers on the human Y, and we discuss its causes. PMID- 29718382 TI - Mid-borderline leprosy masquerading as an overlap syndrome. PMID- 29718383 TI - Levosimendan versus placebo in cardiac surgery: a systematic review and meta analysis. AB - The aim of this meta-analysis was to review all published randomized clinical trials comparing levosimendan versus placebo in patients undergoing cardiac surgery. PubMed, EMBASE and the Cochrane library database of clinical trials were searched for prospective randomized clinical trials investigating the perioperative use of levosimendan versus placebo in patients undergoing adult cardiac surgery from 1 May 2000 to 10 April 2017. Binary outcomes from individual studies were analysed to compute individual and pooled risk ratios (RRs) with pertinent 95% confidence intervals (CIs). Fourteen randomized clinical trials with a total of 2243 patients were included in this review. Overall meta-analysis results demonstrated that levosimendan was associated with a significant reduction in 30-day mortality (RR = 0.71, 95% CI = 0.53-0.95; P = 0.023). Subgroup analysis showed that this benefit was confined to the moderate and low ejection fraction studies (RR = 0.44, 95% CI = 0.27-0.70; P < 0.001), whereas no benefit was observed in the preserved ejection fraction studies (RR = 1.06, 95% CI = 0.72-1.56; P = 0.78). Levosimendan also reduced the risk of renal replacement therapy (RR = 0.66, 95% CI = 0.47-0.92; P = 0.015) and low cardiac output (RR = 0.40, 95% CI = 0.22-0.73; P = 0.003). No significant differences were detected, between the levosimendan group and the placebo group, in terms of risk of myocardial injury (RR = 0.90, 95% CI = 0.69-1.17; P = 0.44), intensive care unit stay (weighted mean differences = -0.57, 95% CI = -1.15 to 0.01; P = 0.055) and the use of ventricular assist device (RR = 0.42, 95% CI = 0.07-2.63; P = 0.35). In conclusion, levosimendan was associated with a reduced risk of mortality, renal replacement therapy and low cardiac output syndrome in patients undergoing cardiac surgery. PMID- 29718385 TI - Evaluation of the Efficacy, Safety, and Tolerability of BI 409306, a Novel Phosphodiesterase 9 Inhibitor, in Cognitive Impairment in Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled, Phase II Trial. AB - Background: Patients with cognitive impairment associated with schizophrenia may benefit from treatments targeting dysfunctional glutamatergic neurotransmission. BI 409306, a potent and selective phosphodiesterase 9 inhibitor, was assessed in patients with schizophrenia using a learn-and-confirm adaptive trial design. Methods: This double-blind, parallel-group trial randomized patients 2:1:1:1:1 to once-daily placebo or BI 409306 (10, 25, 50, or 100 mg) for 12 weeks. Stage 1 (learn) assessed change from baseline in Cambridge Neuropsychological Test Automated Battery (CANTAB) scores (week 12) to identify >=1 meaningful endpoints for stage 2 (confirm). If no domains showed efficacy, change from baseline in Measurements and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery (MCCB) composite scores (week 12) was the primary endpoint. The key secondary endpoint was change from baseline in Schizophrenia Cognition Rating Scale (SCoRS) total score. Safety was monitored. Results: Five hundred eighteen patients were randomized. In stage 1, CANTAB did not differentiate between BI 409306 and placebo (n = 120), so the primary endpoint of change from baseline in MCCB composite score was analyzed in 450 patients in stage 2. There was no significant difference between BI 409306 (1.2 2.8) and placebo (2.5) in MCCB composite score change. BI 409306 did not significantly improve change from baseline in SCoRS total score (-3.1 to -2.0) vs placebo (-2.5). Adverse events were dose-dependent, increasing from 33.3% (10 mg) to 53.5% (100 mg), vs 36.4% for placebo. Conclusion: The primary endpoint of cognitive function improvement was not met. BI 409306 was well-tolerated, with an acceptable safety profile. PMID- 29718384 TI - Neural substrates for moral judgments of psychological versus physical harm. AB - While we may think about harm as primarily being about physical injury, harm can also take the form of negative psychological impact. Using functional magnetic resonance imaging, we examined the extent to which moral judgments of physical and psychological harms are processed similarly, focusing on brain regions implicated in mental state reasoning or theory of mind, a key cognitive process for moral judgment. First, univariate analyses reveal item-specific features that lead to greater recruitment of theory of mind regions for psychological harm versus physical harm. Second, multivariate pattern analyses reveal sensitivity to the psychological/physical distinction in two regions implicated in theory of mind: the right temporoparietal junction and the precuneus. Third, we find no reliable differences between neurotypical adults and adults with autism spectrum disorder with regard to neural activity related to theory of mind during moral evaluations of psychological and physical harm. Altogether, these results reveal neural sensitivity to the distinction between psychological harm and physical harm. PMID- 29718387 TI - Investigating predictors of cognitive decline using machine learning. AB - Objectives: Genetic risks for cognitive decline are not modifiable; however their relative importance compared to modifiable factors is unclear. We used machine learning to evaluate modifiable and genetic risk factors for Alzheimer's disease(AD), to predict cognitive decline. Methods: Health and Retirement Study participants, aged 65-90, with DNA and >2 cognitive evaluations, were included (n=7,142). Predictors included age, body mass index, gender, education, APOE epsilon4, CVD, hypertension, diabetes, stroke, neighborhood socio-economic status(NSES), and AD risk genes. Latent class trajectory analyses of cognitive scores determined the form and number of classes. Random Forests (RF) classification investigated predictors of cognitive trajectories. Performance metrics (accuracy, sensitivity and specificity) were reported. Results: Three classes were identified. Discriminating highest from lowest classes produced the best RF performance: accuracy=78%(1.0%), sensitivity=75%(1.0%) and specificity=81%(1.0%). Top ranked predictors were education, age, gender, stroke, NSES, and diabetes, APOE epsilon4 carrier status and BMI. When discriminating high from medium classes, top predictors were education, age, gender, stroke, diabetes, NSES and BMI. When discriminating medium from the low classes, education, NSES, age, diabetes and stroke were top predictors. Discussion: The combination of latent trajectories and RF classification techniques suggested that non-genetic factors contribute more to cognitive decline than genetic factors. Education was the most relevant predictor for discrimination. PMID- 29718388 TI - The use of Hypofractionated Radiosurgery for the Treatment of Intracranial Lesions Unsuitable for Single-Fraction Radiosurgery. AB - Stereotactic radiosurgery (SRS) is commonly used in the treatment of brain metastases, benign tumors, and arteriovenous malformations (AVM). Single-fraction radiosurgery, though ubiquitous, is limited by lesion size and location. In these cases, hypofractionated radiosurgery (hfSRS) offers comparable efficacy and toxicity. We review the recent literature concerning hfSRS in the treatment of brain metastases, benign tumors, and AVMs that are poorly suited for single fraction SRS. Published retrospective analyses suggest that local control rates for brain metastases and benign tumors, as well as the rates of AVM obliteration, following hfSRS treatment are comparable to those reported for single-fraction SRS. Additionally, the toxicities from hypofractionated treatment appear comparable to those seen with single-fractioned SRS to small lesions. PMID- 29718386 TI - StpA and Hha stimulate pausing by RNA polymerase by promoting DNA-DNA bridging of H-NS filaments. AB - In enterobacteria, AT-rich horizontally acquired genes, including virulence genes, are silenced through the actions of at least three nucleoid-associated proteins (NAPs): H-NS, StpA and Hha. These proteins form gene-silencing nucleoprotein filaments through direct DNA binding by H-NS and StpA homodimers or heterodimers. Both linear and bridged filaments, in which NAPs bind one or two DNA segments, respectively, have been observed. Hha can interact with H-NS or StpA filaments, but itself lacks a DNA-binding domain. Filaments composed of H-NS alone can inhibit transcription initiation and, in the bridged conformation, slow elongating RNA polymerase (RNAP) by promoting backtracking at pause sites. How the other NAPs modulate these effects of H-NS is unknown, despite evidence that they help regulate subsets of silenced genes in vivo (e.g. in pathogenicity islands). Here we report that Hha and StpA greatly enhance H-NS-stimulated pausing by RNAP at 20 degrees C. StpA:H-NS or StpA-only filaments also stimulate pausing at 37 degrees C, a temperature at which Hha:H-NS or H-NS-only filaments have much less effect. In addition, we report that both Hha and StpA greatly stimulate DNA-DNA bridging by H-NS filaments. Together, these observations indicate that Hha and StpA can affect H-NS-mediated gene regulation by stimulating bridging of H-NS/DNA filaments. PMID- 29718389 TI - An update on PUG-REST: RESTful interface for programmatic access to PubChem. AB - PubChem (https://pubchem.ncbi.nlm.nih.gov) is one of the largest open chemical information resources available. It currently receives millions of unique users per month on average, serving as a key resource for many research fields such as cheminformatics, chemical biology, medicinal chemistry, and drug discovery. PubChem provides multiple programmatic access routes to its data and services. One of them is PUG-REST, a Representational State Transfer (REST)-like web service interface to PubChem. On average, PUG-REST receives more than a million requests per day from tens of thousands of unique users. The present paper provides an update on PUG-REST since our previous paper published in 2015. This includes access to new kinds of data (e.g. concise bioactivity data, table of contents headings, etc.), full implementation of synchronous fast structure search, support for assay data retrieval using accession identifiers in response to the deprecation of NCBI's GI numbers, data exchange between PUG-REST and NCBI's E-Utilities through the List Gateway, implementation of dynamic traffic control through throttling, and enhanced usage policies. In addition, example Perl scripts are provided, which the user can easily modify, run, or translate into another scripting language. PMID- 29718390 TI - Greater Early Bactericidal Activity at Higher Rifampicin Doses Revealed by Modeling and Clinical Trial Simulations. AB - Background: The currently recommended rifampicin dose (10 mg/kg) for treating tuberculosis is suboptimal. The PanACEA HIGHRIF1 trial evaluated the pharmacokinetics and early bactericidal activity of rifampicin doses of up to 40 mg/kg. Conventional statistical analyses revealed no significant exposure response relationship. Our objectives were to explore the exposure-response relationship for high-dose rifampicin by using pharmacokinetic-pharmacodynamic modeling and to predict the early bactericidal activity of 50 mg/kg rifampicin. Methods: Data included time to Mycobacterium tuberculosis positivity of liquid cultures of sputum specimens from 83 patients with tuberculosis who were treated with 10 mg/kg rifampicin (n = 8; reference arm) or 20, 25, 30, 35, or 40 mg/kg rifampicin (n = 15/arm) for 7 days. We used a semimechanistic time-to-event approach to model the time-to-positivity data. Rifampicin exposure and baseline time to culture positivity were explored as covariates. Results: The baseline time to culture positivity was a significant covariate on the predicted initial bacterial load, and rifampicin exposure was a significant covariate on the bacterial kill rate in sputum resulting in increased early bactericidal activity. The 90% prediction interval for the predicted median day 7 increase in time to positivity for 50 mg/kg rifampicin was 7.25-10.3 days. Conclusions: A significant exposure-response relationship was found between rifampicin exposure and early bactericidal activity. Clinical trial simulations showed greater early bactericidal activity for 50 mg/kg rifampicin. Clinical Trials Registration: NCT01392911. PMID- 29718392 TI - Patient Information: To Share or Not to Share? AB - This commentary considers the General Medical Council's new guidance, Confidentiality: Good Practice in Handling Patient Information, which came into effect in April 2017. The commentary highlights some of the changes from the previous guidance and argues that, while some areas could have been developed further, the new guidelines are in general more detailed and user-friendly than previously, and will therefore be of benefit to practitioners. The commentary also highlights further developments on the horizon, such as new data protection legislation. PMID- 29718391 TI - Serologic Reactivity Reflects Clinical Expression of Ulcerative Colitis in Children. AB - Background: In contrast to pediatric Crohn's disease (CD), little is known in pediatric ulcerative colitis (UC) about the relationship between disease phenotype and serologic reactivity to microbial and other antigens. Aim: The aim of this study was to examine disease phenotype and serology in a well characterized inception cohort of children newly diagnosed with UC during the PROTECT Study (Predicting Response to Standardized Pediatric Colitis Therapy). Methods: Patients were recruited from 29 participating centers. Demographic, clinical, laboratory, and serologic (pANCA, ASCA IgA/IgG, Anti-CBir1, and Anti OmpC) data were obtained from children 4-17 years old with UC. Results: Sixty five percent of the patients had positive serology for pANCA, with 62% less than 12 years old and 66% 12 years old or older. Perinuclear anti-neutrophil cytoplasmic antibodies did not correspond to a specific phenotype though pANCA >=100, found in 19%, was strongly associated with pancolitis (P = 0.003). Anti CBir1 was positive in 19% and more common in younger children with 32% less than 12 years old as compared with 14% 12 years old or older (P < 0.001). No association was found in any age group between pANCA and Anti-CBir1. Relative rectal sparing was more common in +CBir1, 16% versus 7% (P = 0.02). Calprotectin was lower in Anti-CBir1+ (Median [IQR] 1495 mcg/g [973-3333] vs 2648 mcg/g [1343 4038]; P = 0.04). Vitamin D 25-OH sufficiency was associated with Anti-CBir1+ (P = 0.0009). Conclusions: The frequency of pANCA in children was consistent with adult observations. High titer pANCA was associated with more extensive disease, supporting the idea that the magnitude of immune reactivity may reflect disease severity. Anti-CBir1+ was more common in younger ages, suggesting host-microbial interactions may differ by patient age. PMID- 29718394 TI - Generation of orthogonal Fab-based trispecific antibody formats. AB - The clinical success of monoclonal antibodies to treat diseases across nearly every therapeutic area has spurred advances in bispecific antibody technology with the goal of cost-effectively combining various therapies or providing novel mechanisms for disease intervention. Many novel bispecific antibodies are now in clinical development or the late pre-clinical setting. A new horizon exists for novel molecular entities with the ability to bind three or more antigens. Here we describe the production and characterization of novel trispecific antibody-like proteins denoted 'OrthoTsAbs' that self-assemble through the application of engineered antibody domain interfaces. PMID- 29718393 TI - Risk of HPV-16/18 Infections and Associated Cervical Abnormalities in Women Seropositive for Naturally Acquired Antibodies: Pooled Analysis Based on Control Arms of Two Large Clinical Trials. AB - Background: Studies on the role of antibodies produced after infection with human papillomavirus 18 (HPV-18) and subsequent protection from HPV-18 infection have been conflicting, mainly due to inadequate sample size. Methods: We pooled data from the control arms of the Costa Rica Vaccine Trial and the PATRICIA trial. Using Poisson regression we compared the risk of newly detected 1-time HPV-18 infection, HPV-18 1-year persistent infection (12MPI), and HPV-18-associated atypical squamous cells of undetermined significance or greater (ASC-US+) lesions between HPV-18 seropositive and seronegative women. Results: High HPV-18 antibodies at enrollment was associated with reduced subsequent HPV-18 detection (P trend = 0.001; relative rate [RR] = 0.69; 95% confidence interval [CI], 0.47 1.01 for the third quartile; RR = 0.63; 95% CI, 0.43-0.94 for the fourth quartile, compared to seronegative). The risk of 12MPI showed a decreasing trend with increasing antibodies (P trend = 0.06; RR = 0.72; 95% CI, 0.29-1.77; RR = 0.42; 95% CI, 0.13-1.32 for the third and fourth quartiles, respectively). Lastly, we observed a significant decreased risk of HPV-18 ASC-US+ with increasing antibody (P trend = 0.01; RR = 0.46; 95% CI, 0.21-0.97 for the fourth quartile). We also observed a significant decreased risk of HPV-16 infection, 12MPI, and ASC-US+ with increasing HPV-16 antibody level. Conclusions: High HPV 18 naturally acquired antibodies were associated with partial protection from future HPV-18 infections and associated lesions. Clinical Trials Registration: NCT00128661 and NCT001226810. PMID- 29718395 TI - Distinct growth phenology but similar daily stem dynamics in three co-occurring broadleaved tree species. AB - Dendrometers offer a useful tool for long-term, high-resolution monitoring of tree responses to environmental fluctuations and climate change. Here, we analyze a 4-year dendrometer dataset (2014-17) on European beech (Fagus sylvatica L.), common hornbeam (Carpinus betulus L.) and pedunculate oak (Quercus robur L.), co occuring in a mixed broadleaved forest in northeastern Germany. In our analyses, we focus both on seasonal growth dynamics as well as on the environmental forcing of daily stem-size variations. Over the study period with contrasting weather conditions, we observed species- and year-specific differences in growth phenology (i.e., growth onset, cessation and duration). Oak was characterized by early growth onset and long growth duration in all years as compared with beech and hornbeam. The analysis on the environmental forcing of daily stem dynamics revealed, however, highly similar responses for the studied species, with current day vapor pressure deficit and sunshine duration negatively, and relative humidity and precipitation positively affecting stem size. When considering lagged effects, environmental conditions often oppositely affected stem-size changes. No consistent seasonality in environmental responses was detected, though specific weather conditions were found to affect temporal patterns in individual years. We suggest that the high similarity in environmental forcing observed between tree species can be explained by daily stem-size changes mainly reflecting tree water status rather than tree growth. Our results stress that correcting dendrometer series for reversible stem hydrological changes is of utmost importance to better quantify tree growth from dendrometers in future. PMID- 29718396 TI - Potential Benefit of Intra-operative Administration of Ketorolac on Breast Cancer Recurrence According to the Patient's Body Mass Index. AB - Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) are currently used in some countries as analgesics in primary cancer surgery. Retrospective studies suggest that NSAIDs could reduce breast cancer recurrences. Because NSAIDs also act on biological mechanisms present in patients with increased adiposity, we aimed at assessing whether the intra-operative administration of ketorolac or diclofenac would be associated with a reduction of recurrence in patients with elevated body mass index (BMI). Methods: We considered two institutional retrospective series of 827 and 1007 patients evaluating the administration of ketorolac (n = 529 with, n = 298 without) or diclofenac (n = 787 with, n = 220 without). The BMI subgroups were defined as less than 25 kg/m2 (lean) and 25 or more kg/m2 (overweight and obese). Cumulative incidence estimation of distant metastases as well as Fine-Gray and Dixon-Simon models was used. These analyses were adjusted for clinico-pathological variables. All statistical tests were two sided. Results: The administration of ketorolac was statistically significantly associated with decreased incidence of distant recurrences (adjusted hazard ratio [aHR]= 0.59, 95% confidence interval [CI] = 0.37 to 0.96, P = .03). In particular, the association was evident in the high-body mass index (BMI) group of patients (aHR = 0.55, 95% CI = 0.31 to 0.96, P = .04). The administration of diclofenac was not statistically significantly associated with decreased incidence of distant recurrences, either in the global population or in the BMI subgroups. Conclusions: These results show that the intra-operative administration of ketorolac, but not diclofenac, is statistically significantly associated with a reduction of distant recurrences in patients with increased BMI. Altogether, this study points to a potentially important repositioning of ketorolac in the intra-operative treatment of patients with elevated BMI that, if prospectively validated, might be as impactful as and cheaper than adjuvant systemic anticancer therapies. PMID- 29718397 TI - Improving RNA nearest neighbor parameters for helices by going beyond the two state model. AB - RNA folding free energy change nearest neighbor parameters are widely used to predict folding stabilities of secondary structures. They were determined by linear regression to datasets of optical melting experiments on small model systems. Traditionally, the optical melting experiments are analyzed assuming a two-state model, i.e. a structure is either complete or denatured. Experimental evidence, however, shows that structures exist in an ensemble of conformations. Partition functions calculated with existing nearest neighbor parameters predict that secondary structures can be partially denatured, which also directly conflicts with the two-state model. Here, a new approach for determining RNA nearest neighbor parameters is presented. Available optical melting data for 34 Watson-Crick helices were fit directly to a partition function model that allows an ensemble of conformations. Fitting parameters were the enthalpy and entropy changes for helix initiation, terminal AU pairs, stacks of Watson-Crick pairs and disordered internal loops. The resulting set of nearest neighbor parameters shows a 38.5% improvement in the sum of residuals in fitting the experimental melting curves compared to the current literature set. PMID- 29718398 TI - Targetable Gene Fusions Associate With the IDH Wild-Type Astrocytic Lineage in Adult Gliomas. AB - Gene fusions involving oncogenes have been reported in gliomas and may serve as novel therapeutic targets. Using RNA-sequencing, we interrogated a large cohort of gliomas to assess for the incidence of targetable genetic fusions. Gliomas (n = 390) were profiled using the ArcherDx FusionPlex Assay. Fifty-two gene targets were analyzed and fusions with preserved kinase domains were investigated. Overall, 36 gliomas (9%) harbored a total of 37 potentially targetable fusions, the majority of which were found in astrocytomas (n = 34). Within this lineage 11% (25/235) of glioblastomas, 12% (5/42) of anaplastic astrocytomas, 8% (2/25) of grade II astrocytomas, and 33% (2/6) of pilocytic astrocytoma harbored targetable fusions. Fusions were significantly more frequent in IDH wild-type tumors (12%, n = 31/261) relative to IDH mutants (4%; n = 4/109) (p = 0.011). No fusions were seen in oligodendrogliomas. The most frequently observed therapeutically targetable fusions were in FGFR (n = 12), MET (n = 11), and NTRK (n = 8). Several additional novel fusions that have not been previously described in gliomas were identified including EGFR:VWC2 and FGFR3:NBR1. In summary, targetable gene fusions are enriched in IDH wild-type high-grade astrocytic tumors, which will influence enrollment in and interpretation of clinical trials of glioma patients. PMID- 29718399 TI - A CRISPR/molecular beacon hybrid system for live-cell genomic imaging. AB - The clustered regularly interspersed short palindromic repeat (CRISPR) gene editing system has been repurposed for live-cell genomic imaging, but existing approaches rely on fluorescent protein reporters, making sensitive and continuous imaging difficult. Here, we present a fluorophore-based live-cell genomic imaging system that consists of a nuclease-deactivated mutant of the Cas9 protein (dCas9), a molecular beacon (MB), and an engineered single-guide RNA (sgRNA) harboring a unique MB target sequence (sgRNA-MTS), termed CRISPR/MB. Specifically, dCas9 and sgRNA-MTS are first co-expressed to target a specific locus in cells, followed by delivery of MBs that can then hybridize to MTS to illuminate the target locus. We demonstrated the feasibility of this approach for quantifying genomic loci, for monitoring chromatin dynamics, and for dual-color imaging when using two orthogonal MB/MTS pairs. With flexibility in selecting different combinations of fluorophore/quencher pairs and MB/MTS sequences, our CRISPR/MB hybrid system could be a promising platform for investigating chromatin activities. PMID- 29718400 TI - Defining quality assurance and quality control measures in connection with ovarian tissue cryopreservation and transplantation: a call to action. AB - Freezing of ovarian tissue for fertility preservation has been gaining ground as a valid method in recent years. More than 100 children have been born from this procedure worldwide. As a result, many fertility clinics are now implementing this method. However, the practical procedures that need to be mastered to successfully implement the freezing of ovarian tissue are different in many aspects from those normally used in fertility clinics and are not well defined. Furthermore, success is difficult to measure since patients usually do not return for transplantation until several years after freezing, which puts extra emphasis of good quality control and quality assurance measures to secure a transplantation of tissue with surviving follicles that can sustain fertility. The present paper describes the procedures and a checklist implemented in Denmark in order to secure a successful clinical service. To standardize and implement uniform measures for this new method, we suggest a consensus conference to collectively agree on the best technical and clinical practice. PMID- 29718401 TI - Inter- and Intra-Specific Differentiation of Trichogramma (Hymenoptera: Trichogrammatidae) Species Using PCR-RFLP Targeting COI. AB - The identification of Trichogramma (Hymenoptera: Trichogrammatidae) species is problematic due to their small size and lack of distinct morphological characters. In this study, we combined morphological characters of the male genitalia and molecular methods using the mitochondrial cytochrome oxidase I (COI) gene as a molecular marker to identify eight species from 16 geographic populations: T. evanescens Westwood, T. cacoeciae Marchal, T. ostriniae Pang et Chen, T. chilonis Ishii, T. japonicum Ashmead, T. brassicae Bezdenko, T. bilingensis He et Pang, and T. dendrolimi Matsumura. We developed a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method targeting the mitochondrial COI to distinguish the eight Trichogramma species using three restriction enzymes. We further analyzed 109 COI fragments from 18 Trichogramma species and found that the PCR-RFLP method could distinguish both intra- and inter-specific genetic variation among most of the species using four additional restriction enzymes. PMID- 29718402 TI - Every breath you take: how does air pollution affect the international traveller? PMID- 29718403 TI - A cluster of Zika virus infection among travellers returning to China from Samoa: a case tracing study. AB - Background: A febrile man, who returned to China after a 9-day travel in Fiji and Samoa, was detected to be infected with Zika virus (ZIKV) at the port by Shenzhen Entry-Exit Inspection and Quarantine Bureau on 14 February 2016. Methods: The patient and his 32 travelling companions were traced for ZIKV infection. A standardised questionnaire was used to obtain the information on demographics, clinical manifestations and exposure history. Their samples were tested for ZIKV by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR). The positive samples were subjected to viral culture and genome sequencing. Findings: Four of the 33 travellers were confirmed to be infected by ZIKV through qRT-PCR and viral culture, with an overall infection rate of 12%. Interestingly, one case (Patient 3) where high viremia levels were tested 4 days prior to symptoms. In addition, a 7-year-old girl was identified to have ZIKV infection on 17 February, but never had any manifestation. ZIKV was isolated from the four imported cases. Phylogenetic analysis based on whole genome sequences revealed that these isolates were similar to each other and close to the strain causing the French Polynesia outbreak in 2013. Interpretation: The travellers should be informed of the high risk for ZIKV infection during their stay in areas with active transmission and measures to prevent mosquito bites. PMID- 29718404 TI - Telemedicine for health issues while abroad: interest and willingness to pay among travellers prior to departure. AB - Background: Telemedicine is emerging as a useful tool to provide expert medical advice to individuals facing health issues while travelling in remote areas. Before embarking on the development of a telemedicine system, we conducted a survey to assess the needs and expectations of travellers for such a service, and evaluate opinions about the importance of various travel criteria that may determine the contract of such insurance. Objectives: (i) To assess whether a telemedicine service is considered useful by travellers, (ii) to investigate which telecommunication medium is preferred, (iii) to determine which subgroup of travellers would be most interested in this service and (iv) to estimate the amount of money travellers would be willing to pay for a telemedicine service. Methods: Travellers coming to our clinic for pre-travel advice were given a questionnaire to be filled in before consultation. The questionnaire focused on demographics, travel details, health status, interest and willingness to pay for a telemedicine service. Results: Among 307 returned questionnaires, 59% of travellers were interested in a telemedicine service. Email was the preferred communication medium for 63%, mobile phone for 46% and video calls for 31% individuals (multiple answers). Travellers aged >=60 years and those with an immunocompromising condition tended to be more interested in telemedicine (respectively OR = 1.65; 95% CI: 0.75-3.62 and OR = 3.56; 95% CI: 0.41-30.95). The 99% of travellers were willing to pay for such a service. Median price was 50 USD (IQR: 30-50 USD). There was no correlation between travel duration and amount to be paid. Conclusion: Among individuals consulting for pre-travel advice at a specialized clinic, there is considerable interest in telemedicine, particularly among older and immunocompromised travellers. Based on these data, a pilot system using email communication to help travellers confronted with health issues while abroad was developed and implemented in our travel clinic. PMID- 29718406 TI - Vascular endothelial growth factor backfiltration in the glomerulus: an intriguing mechanism. PMID- 29718405 TI - Structure and hydrodynamics of a DNA G-quadruplex with a cytosine bulge. AB - The identification of four-stranded G-quadruplexes (G4s) has highlighted the fact that DNA has additional spatial organisations at its disposal other than double stranded helices. Recently, it became clear that the formation of G4s is not limited to the traditional G3+NL1G3+NL2G3+NL3G3+ sequence motif. Instead, the G3 triplets can be interrupted by deoxythymidylate (DNA) or uridylate (RNA) where the base forms a bulge that loops out from the G-quadruplex core. Here, we report the first high-resolution X-ray structure of a unique unimolecular DNA G4 with a cytosine bulge. The G4 forms a dimer that is stacked via its 5'-tetrads. Analytical ultracentrifugation, static light scattering and small angle X-ray scattering confirmed that the G4 adapts a predominantly dimeric structure in solution. We provide a comprehensive comparison of previously published G4 structures containing bulges and report a special gamma torsion angle range preferentially populated by the G4 core guanylates adjacent to bulges. Since the penalty for introducing bulges appears to be negligible, it should be possible to functionalize G4s by introducing artificial or modified nucleotides at such positions. The presence of the bulge alters the surface of the DNA, providing an opportunity to develop drugs that can specifically target individual G4s. PMID- 29718407 TI - Design and implementation of a standardized framework to generate and evaluate patient-level prediction models using observational healthcare data. AB - Objective: To develop a conceptual prediction model framework containing standardized steps and describe the corresponding open-source software developed to consistently implement the framework across computational environments and observational healthcare databases to enable model sharing and reproducibility. Methods: Based on existing best practices we propose a 5 step standardized framework for: (1) transparently defining the problem; (2) selecting suitable datasets; (3) constructing variables from the observational data; (4) learning the predictive model; and (5) validating the model performance. We implemented this framework as open-source software utilizing the Observational Medical Outcomes Partnership Common Data Model to enable convenient sharing of models and reproduction of model evaluation across multiple observational datasets. The software implementation contains default covariates and classifiers but the framework enables customization and extension. Results: As a proof-of-concept, demonstrating the transparency and ease of model dissemination using the software, we developed prediction models for 21 different outcomes within a target population of people suffering from depression across 4 observational databases. All 84 models are available in an accessible online repository to be implemented by anyone with access to an observational database in the Common Data Model format. Conclusions: The proof-of-concept study illustrates the framework's ability to develop reproducible models that can be readily shared and offers the potential to perform extensive external validation of models, and improve their likelihood of clinical uptake. In future work the framework will be applied to perform an "all-by-all" prediction analysis to assess the observational data prediction domain across numerous target populations, outcomes and time, and risk settings. PMID- 29718409 TI - The Puzzle of HIV Neutral and Selective Evolution. AB - HIV is one of the fastest evolving organisms known. It evolves about 1 million times faster than its host, humans. Because HIV establishes chronic infections, with continuous evolution, its divergence within a single infected human surpasses the divergence of the entire humanoid history. Yet, it is still the same virus, infecting the same cell types and using the same replication machinery year after year. Hence, one would think that most mutations that HIV accumulates are neutral. But the picture is more complicated than that. HIV evolution is also a clear example of strong positive selection, that is, mutants have a survival advantage. How do these facts come together? PMID- 29718408 TI - Ancient Nuclear Receptor VDR With New Functions: Microbiome and Inflammation. AB - The biological functions of 1alpha,25-dihydroxyvitamin D3 are regulated by nuclear receptor vitamin D receptor (VDR). The expression level of VDR is high in intestine. VDR is an essential regulator of intestinal cell proliferation, barrier function, and immunity. Vitamin D/VDR plays a protective role in inflammatory bowel diseases (IBDs), both ulcerative colitis and Crohn's disease. Emerging evidence demonstrates low VDR expression and dysfunction of vitamin D/VDR signaling in patients with IBD. Here, we summarize the progress made in vitamin D/VDR signaling in genetic regulation, immunity, and the microbiome in IBD. We cover the mechanisms of intestinal VDR in regulating inflammation through inhibiting the NF-KB pathway and activating autophagy. Recent studies suggest that the association of VDR single nucleotide polymorphisms with immune and intestinal pathology may be sex dependent. We emphasize the tissue specificity of VDR and its sex- and time-dependent effects. Furthermore, we discuss potential clinical application and future direction of vitamin D/VDR in preventing and treating IBD. PMID- 29718410 TI - The multifaceted presentation of chronic recurrent multifocal osteomyelitis: a series of 486 cases from the Eurofever international registry. PMID- 29718411 TI - BUSCA: an integrative web server to predict subcellular localization of proteins. AB - Here, we present BUSCA (http://busca.biocomp.unibo.it), a novel web server that integrates different computational tools for predicting protein subcellular localization. BUSCA combines methods for identifying signal and transit peptides (DeepSig and TPpred3), GPI-anchors (PredGPI) and transmembrane domains (ENSEMBLE3.0 and BetAware) with tools for discriminating subcellular localization of both globular and membrane proteins (BaCelLo, MemLoci and SChloro). Outcomes from the different tools are processed and integrated for annotating subcellular localization of both eukaryotic and bacterial protein sequences. We benchmark BUSCA against protein targets derived from recent CAFA experiments and other specific data sets, reporting performance at the state-of-the-art. BUSCA scores better than all other evaluated methods on 2732 targets from CAFA2, with a F1 value equal to 0.49 and among the best methods when predicting targets from CAFA3. We propose BUSCA as an integrated and accurate resource for the annotation of protein subcellular localization. PMID- 29718414 TI - A Simple 1-Day Colon Capsule Endoscopy Procedure Demonstrated to be a Highly Acceptable Monitoring Tool for Ulcerative Colitis. AB - Background: Second-generation colon capsule endoscopy (CCE-2) has been reported as a potential tool for monitoring ulcerative colitis (UC). However, its excretion rate is still unsatisfactory, and the bowel preparation regimen is not well tolerated. Furthermore, a standard bowel preparation regimen validated for UC has not been established. The aim of this study was to develop a simple 1-day CCE-2 procedure while evaluating its excretion rate and acceptability in UC. Factors associated with the colonic transit time and acceptability of CCE-2 were evaluated. Methods: Thirty-three patients were prospectively evaluated. Five hundred milliliters of hypertonic polyethylene glycol solution, followed by 250 mL of water, was ingested 2.5 hours before, then 1, 3, and 6 hours after capsule ingestion until its excretion, with castor oil added to the second ingestion. Mayo endoscopic subscore (MES) and Ulcerative Colitis Endoscopic Index of Severity (UCEIS) were graded, and their correlations with fecal calprotectin (FC) were assessed. A questionnaire comparing CCE-2 with previous colonoscopy (CS) was conducted. Results: The excretion rate was 93.9% (31/33). The acceptability of CCE-2 was superior to CS (CCE-2 42.4% vs CS 27.3%). The median colonic transit time was 119 minutes and showed a positive correlation with MES (P = 0.010), UCEIS (P = 0.010), and FC (P = 0.041). CCE-2 was not favored by patients whose colonic transit times were longer. Conclusions: A novel bowel preparation regimen of CCE-2 was well tolerated, with a high excretion rate, by UC patients. Patients with active disease required longer colonic transit time, which may have resulted in the lower acceptability of CCE-2. PMID- 29718415 TI - Experience with Continuous Infusion Vancomycin Dosing in a Large Pediatric Hospital. AB - Background: There is a paucity of data on dosing of continuous infusion of vancomycin (CIV) in pediatric patients, despite it being an attractive treatment option for limiting escalating doses of intermittent infusion of vancomycin. The purpose of this study was to determine the total daily dose of CIV required to attain therapeutic serum vancomycin concentrations (SVCs) in pediatric patients according to age (>=31 days to <2 years, 2 to <8 years, and 8 to <18 years). Methods: We retrospectively evaluated patients who were transitioned from intermittent infusion of vancomycin to CIV between January 2013 and December 2016. Demographic data, vancomycin data (indication, dosing, steady-state SVCs, and time to reach goal SVC), and adverse-effect data (infusion reactions and serum creatinine level) were collected. Results: Of the 240 patients included, 76 had a goal SVC of 10 to 15 ug/mL and 164 had a goal of 15 to 20 ug/mL. The dose of CIV required to reach an SVC of 10 to 15 ug/mL in the youngest age group was 48.4 mg/kg per day versus 45.6 and 39.4 mg/kg per day in the older age groups (P < .005). The 2 younger age groups of patients with a goal SVC of 15 to 20 ug/mL required 50.2 and 50.6 mg/kg per day, respectively, whereas patients aged >=8 years required 44.7 mg/kg per day (P = .008). One patient experienced renal injury, and 1 experienced renal failure. Conclusions: CIV is an effective method for attaining a therapeutic SVC in pediatric patients. Patients <8 years of age require higher dosing than older pediatric patients to reach the goal SVCs of 10 to 15 and 15 to 20 ug/mL. PMID- 29718413 TI - Understanding Molecular Evolution and Development of the Organ of Corti Can Provide Clues for Hearing Restoration. AB - The mammalian hearing organ is a stereotyped cellular assembly with orderly innervation: two types of spiral ganglion neurons (SGNs) innervate two types of differentially distributed hair cells (HCs). HCs and SGNs evolved from single neurosensory cells through gene multiplication and diversification. Independent regulation of HCs and neuronal differentiation through expression of basic helix loop-helix transcription factors (bHLH TFs: Atoh1, Neurog1, Neurod1) led to the evolution of vestibular HC assembly and their unique type of innervation. In ancestral mammals, a vestibular organ was transformed into the organ of Corti (OC) containing a single row of inner HC (IHC), three rows of outer HCs (OHCs), several unique supporting cell types, and a peculiar innervation distribution. Restoring the OC following long-term hearing loss is complicated by the fact that the entire organ is replaced by a flat epithelium and requires reconstructing the organ from uniform undifferentiated cell types, recapitulating both evolution and development. Finding the right sequence of gene activation during development that is useful for regeneration could benefit from an understanding of the OC evolution. Toward this end, we report on Foxg1 and Lmx1a mutants that radically alter the OC cell assembly and its innervation when mutated and may have driven the evolutionary reorganization of the basilar papilla into an OC in ancestral Therapsids. Furthermore, genetically manipulating the level of bHLH TFs changes HC type and distribution and allows inference how transformation of HCs might have happened evolutionarily. We report on how bHLH TFs regulate OHC/IHC and how misexpression (Atoh1-Cre; Atoh1f/kiNeurog1) alters HC fate and supporting cell development. Using mice with altered HC types and distribution, we demonstrate innervation changes driven by HC patterning. Using these insights, we speculate on necessary steps needed to convert a random mixture of post-mitotic precursors into the orderly OC through spatially and temporally regulated critical bHLH genes in the context of other TFs to restore normal innervation patterns. PMID- 29718412 TI - T7 RNA polymerase non-specifically transcribes and induces disassembly of DNA nanostructures. AB - The use of proteins that bind and catalyze reactions with DNA alongside DNA nanostructures has broadened the functionality of DNA devices. DNA binding proteins have been used to specifically pattern and tune structural properties of DNA nanostructures and polymerases have been employed to directly and indirectly drive structural changes in DNA structures and devices. Despite these advances, undesired and poorly understood interactions between DNA nanostructures and proteins that bind DNA continue to negatively affect the performance and stability of DNA devices used in conjunction with enzymes. A better understanding of these undesired interactions will enable the construction of robust DNA nanostructure-enzyme hybrid systems. Here, we investigate the undesired disassembly of DNA nanotubes in the presence of viral RNA polymerases (RNAPs) under conditions used for in vitro transcription. We show that nanotubes and individual nanotube monomers (tiles) are non-specifically transcribed by T7 RNAP, and that RNA transcripts produced during non-specific transcription disassemble the nanotubes. Disassembly requires a single-stranded overhang on the nanotube tiles where transcripts can bind and initiate disassembly through strand displacement, suggesting that single-stranded domains on other DNA nanostructures could cause unexpected interactions in the presence of viral RNA polymerases. PMID- 29718416 TI - Drivers of Variability in 90-Day Cost for Elective Anterior Cervical Discectomy and Fusion for Cervical Degenerative Disease. AB - BACKGROUND: Value-based episode of care reimbursement models is being investigated to curb unsustainable health care costs. Any variation in the cost of index spine surgery can affect the payment bundling during the 90-d global period. OBJECTIVE: To determine the drivers of variability in cost for patients undergoing elective anterior cervical discectomy and fusion (ACDF) for degenerative cervical spine disease. METHODS: Four hundred forty-five patients undergoing elective ACDF for cervical spine degenerative diagnoses were included in the study. The direct 90-d cost was derived as sum of cost of surgery, cost associated with postdischarge utilization. Multiple variable linear regression models were built for total 90-d cost. RESULTS: The mean 90-d direct cost was $17685 +/- $5731. In a multiple variable linear regression model, the length of surgery, number of levels involved, length of hospital stay, preoperative history of anticoagulation medication, health-care resource utilization including number of imaging, any complications and readmission encounter were the significant contributor to the 90-d cost. The model performance as measured by R2 was 0.616. CONCLUSION: There was considerable variation in total 90-d cost for elective ACDF surgery. Our model can explain about 62% of these variations in 90-d cost. The episode of care reimbursement models needs to take into account these variations and be inclusive of the factors that drive the variation in cost to develop a sustainable payment model. The generalized applicability should take in to account the differences in patient population, surgeons' and institution-specific differences. PMID- 29718418 TI - The Effectiveness of Dry Needling and Exercise Therapy in Patients with Dizziness Caused By Cervical Myofascial Pain Syndrome; Prospective Randomized Clinical Study. AB - Objective: The aim of this study is to compare the effectiveness of dry needling therapy combined with exercise and exercise treatment alone for alleviating the dizziness caused by cervical myofascial pain syndrome. Design: This was a prospective randomized clinical study that included 61 women who had dizziness and myofascial trigger points on the neck muscles. The patients were randomized into a dry needling + exercise group (N = 31) and an exercise only group (N = 30). Results: The mean age of the patients (+/-SD) was 38.4 +/- 8.3 years. The intragroup comparisons of the severity of neck pain, algometric measurement, number of dizziness attacks per week, severity of the dizziness, fall index, and the Dizziness Handicap Inventory were improved in both groups at the first and fourth months (P < 0.05). The intergroup comparisons of the severity of neck pain, algometric measurement, number of dizziness attacks per week, the severity of the dizziness, and the Dizziness Handicap Inventory were more improved in the dry needling + exercise group at the first or fourth month compared with their inital assessments (P < 0.05). There was no diffence in fall index scores between the groups (P > 0.05). Conclusions: Both dry needling + exercise therapy and exercise therapy alone were effective in treating dizziness caused by cervical myofascial pain syndrome. However, dry needling + exercise treatment was superior to exercise treatment alone. PMID- 29718419 TI - Introducing structure-switching functionality into small-molecule-binding aptamers via nuclease-directed truncation. AB - We report a broadly applicable enzyme digestion strategy for introducing structure-switching functionality into small-molecule-binding aptamers. This procedure is based on our discovery that exonuclease III (Exo III) digestion of aptamers is greatly inhibited by target binding. As a demonstration, we perform Exo III digestion of a pre-folded three-way-junction (TWJ)-structured cocaine binding aptamer and a stem-loop-structured ATP-binding aptamer. In the absence of target, Exo III catalyzes 3'-to-5' digestion of both aptamers to form short, single-stranded products. Upon addition of target, Exo III digestion is halted four bases prior to the target-binding domain, forming a major target-bound aptamer digestion product. We demonstrated that target-binding is crucial for Exo III inhibition. We then determine that the resulting digestion products of both aptamers exhibit a target-induced structure-switching functionality that is absent in the parent aptamer, while still retaining high target-binding affinity. We confirm that these truncated aptamers have this functionality by using an exonuclease I-based digestion assay and further evaluate this characteristic in an electrochemical aptamer-based cocaine sensor and a fluorophore-quencher ATP assay. We believe our Exo III-digestion method should be applicable for the generation of structure-switching aptamers from other TWJ- or stem-loop containing small-molecule-binding aptamers, greatly simplifying the generation of functionalized sensor elements for folding-based aptasensors. PMID- 29718417 TI - Regional conformational flexibility couples substrate specificity and scissile phosphate diester selectivity in human flap endonuclease 1. AB - Human flap endonuclease-1 (hFEN1) catalyzes the divalent metal ion-dependent removal of single-stranded DNA protrusions known as flaps during DNA replication and repair. Substrate selectivity involves passage of the 5'-terminus/flap through the arch and recognition of a single nucleotide 3'-flap by the alpha2 alpha3 loop. Using NMR spectroscopy, we show that the solution conformation of free and DNA-bound hFEN1 are consistent with crystal structures; however, parts of the arch region and alpha2-alpha3 loop are disordered without substrate. Disorder within the arch explains how 5'-flaps can pass under it. NMR and single molecule FRET data show a shift in the conformational ensemble in the arch and loop region upon addition of DNA. Furthermore, the addition of divalent metal ions to the active site of the hFEN1-DNA substrate complex demonstrates that active site changes are propagated via DNA-mediated allostery to regions key to substrate differentiation. The hFEN1-DNA complex also shows evidence of millisecond timescale motions in the arch region that may be required for DNA to enter the active site. Thus, hFEN1 regional conformational flexibility spanning a range of dynamic timescales is crucial to reach the catalytically relevant ensemble. PMID- 29718422 TI - Aetiology and management of acute kidney injury in multiple myeloma. PMID- 29718423 TI - Efflux pump inhibitor CCCP to rescue colistin susceptibility in mcr-1 plasmid mediated colistin-resistant strains and Gram-negative bacteria. AB - Objectives: Efflux in bacteria is a ubiquitous mechanism associated with resistance to antimicrobials agents. Efflux pump inhibitors (EPIs) have been developed to inhibit efflux mechanisms and could be a good alternative to reverse colistin resistance, but only CCCP has shown good activity. The aim of our study was to identify CCCP activity in a collection of 93 Gram-negative bacteria with known and unknown colistin resistance mechanisms including isolates with mcr-1 plasmid-mediated colistin resistance. Methods: Colistin MIC was evaluated with and without CCCP and the fold decrease of colistin MIC was calculated for each strain. In order to evaluate the effect of this combination, a time-kill study was performed on five strains carrying different colistin resistance mechanisms. Results: Overall, CCCP was able to reverse colistin resistance for all strains tested. The effect of CCCP was significantly greater on intrinsically colistin resistant bacteria (i.e. Proteus spp., Serratia marcescens, Morganella morganii and Providencia spp.) than on other Enterobacteriaceae (P < 0.0001). The same was true for bacteria with a heteroresistance mechanism compared to bacteria with other colistin resistance mechanisms (P < 0.0001). A time-kill study showed the combination was bacteriostatic on strains tested. Conclusions: These results suggest an efflux mechanism, especially on intrinsically resistant bacteria and Enterobacter spp., but further analysis is needed to identify the molecular support of this mechanism. EPIs could be an alternative for restoring colistin activity in Gram-negative bacteria. Further work is necessary to identify new EPIs that could be used in humans. PMID- 29718421 TI - Tofacitinib is associated with attainment of the minimally important reduction in axial magnetic resonance imaging inflammation in ankylosing spondylitis patients. AB - Objectives: Minimally important changes (MICs) for SPondyloArthritis Research Consortium of Canada (SPARCC) MRI scores are ?2.5 for SI joint and ?5 for spine. This post hoc analysis assessed achievement of MIC in SPARCC scores in biologic naive patients with AS treated with tofacitinib or placebo, and correlation with clinical responses. Methods: Adult AS patients in a 12-week phase 2 study (n = 207) were randomized 1: 1: 1: 1 to tofacitinib 2, 5 or 10 mg twice daily (BID) or placebo. MIC in SPARCC SI joint and spine scores were assessed for patients with available MRI data (N = 164; 79%). Clinical endpoints at week 12, including Assessment of SpondyloArthritis international Society 20% improvement (ASAS20), were compared between patients achieving/not achieving MIC. Results: A greater proportion of patients achieved MIC with tofacitinib 2, 5 and 10 mg BID vs placebo for SI joint (28.6, 38.6, 29.6 vs 11.8%) and spine scores (29.3, 36.4, 40.9 vs 11.8%). Generally, a greater proportion of patients treated with tofacitinib 2, 5 and 10 mg BID or placebo, respectively, who achieved MIC for SI joint and spine scores achieved ASAS20 (SI joint: 75.0, 88.2, 69.2, 75.0%; spine: 91.7, 85.7, 72.2, 75.0%) vs patients who did not achieve MIC (SI joint: 51.7, 84.0, 58.1, 48.3%; spine: 46.4, 85.7, 53.8, 48.3%). Numerically greater responses were seen in those patients achieving vs not achieving MIC across a range of other efficacy assessments. Conclusion: Approximately one-third of tofacitinib treated AS patients experienced clinically meaningful reductions in spinal MRI inflammation at week 12. Patients achieving MIC for MRI inflammation had greater clinical response. PMID- 29718424 TI - psRNATarget: a plant small RNA target analysis server (2017 release). AB - Plant regulatory small RNAs (sRNAs), which include most microRNAs (miRNAs) and a subset of small interfering RNAs (siRNAs), such as the phased siRNAs (phasiRNAs), play important roles in regulating gene expression. Although generated from genetically distinct biogenesis pathways, these regulatory sRNAs share the same mechanisms for post-translational gene silencing and translational inhibition. psRNATarget was developed to identify plant sRNA targets by (i) analyzing complementary matching between the sRNA sequence and target mRNA sequence using a predefined scoring schema and (ii) by evaluating target site accessibility. This update enhances its analytical performance by developing a new scoring schema that is capable of discovering miRNA-mRNA interactions at higher 'recall rates' without significantly increasing total prediction output. The scoring procedure is customizable for the users to search both canonical and non-canonical targets. This update also enables transmitting and analyzing 'big' data empowered by (a) the implementation of multi-threading chunked file uploading, which can be paused and resumed, using HTML5 APIs and (b) the allocation of significantly more computing nodes to its back-end Linux cluster. The updated psRNATarget server has clear, compelling and user-friendly interfaces that enhance user experiences and present data clearly and concisely. The psRNATarget is freely available at http://plantgrn.noble.org/psRNATarget/. PMID- 29718425 TI - Incisional Hernia After Minimally Invasive Lateral Retroperitoneal Surgery: Case Series and Review of the Literature. AB - BACKGROUND: Minimally invasive lateral retroperitoneal (lateral-MIS) approaches to the spine involve traversing the lateral abdominal wall musculature and fascia. Incisional hernia is an uncommon approach-related complication. OBJECTIVE: To review the incidence, treatment, and preventative measures of incisional hernia after lateral-MIS approaches. METHODS: This is a retrospective review of cases performed by a single surgeon from 2011 to 2016. All patients who underwent lateral-MIS approaches at this institution were included. Patients with a postoperative diagnosis of lateral hernia on physical exam and corroborating advanced imaging findings were included in this study. Cases of flank bulge due to peripheral nerve injury were excluded. RESULTS: Three-hundred three patients underwent lateral-MIS approaches to the spine. Three (1%) patients with incisional hernia were identified. Two patients presented with a clinically symptomatic incisional hernia, while 1 patient was diagnosed incidentally after a routine abdominal magnetic resonance imaging for an unrelated reason. No patients suffered bowel entrapment or strangulation. CONCLUSION: Incisional hernia after lateral-MIS approaches is rare. Patients with incisional hernias may be susceptible to bowel incarceration and ischemia, though the incidence of this is probably low. Meticulous closure of the fascia is critical to avoiding this complication. PMID- 29718420 TI - Long-term effect of a practice-based intervention (HAPPY AUDIT) aimed at reducing antibiotic prescribing in patients with respiratory tract infections. AB - Objectives: Few studies have evaluated the long-term effects of educational interventions on antibiotic prescription and the results are controversial. This study was aimed at assessing the effect of a multifaceted practice-based intervention carried out 6 years earlier on current antibiotic prescription for respiratory tract infections (RTIs). Methods: The 210 general practitioners (GPs) who completed the first two registrations in 2008 and 2009 were invited to participate in a third registration. The intervention held before the second registration consisted of discussion about the first registration of results, appropriate use of antibiotics for RTIs, patient brochures, a workshop and the provision of rapid tests. As in the previous registrations, GPs were instructed to complete a template for all the patients with RTIs during 15 working days in 2015. A new group of GPs from the same areas was also invited to participate and acted as controls. A multilevel logistic regression analysis was performed considering the prescription of antibiotics as the dependent variable. Results: A total of 121 GPs included in the 2009 intervention (57.6%) and 117 control GPs registered 22 247 RTIs. On adjustment for covariables, compared with the antibiotic prescription observed just after the intervention, GPs assigned to intervention prescribed slightly more antibiotics 6 years later albeit without statistically significant differences (OR 1.08, 95% CI 0.89-1.31, P = 0.46), while GPs in the control group prescribed significantly more antibiotics (OR 2.74, 95% CI 2.09-3.59, P < 0.001). Conclusions: This study shows that a single multifaceted intervention continues to reduce antibiotic prescribing 6 years later. PMID- 29718427 TI - iPath3.0: interactive pathways explorer v3. AB - iPath3.0 (http://pathways.embl.de) is a web-application for the visualization and analysis of cellular pathways. It is freely available and open to everyone. Currently it is based on four KEGG global maps, which summarize up to 158 traditional KEGG pathway maps, 192 KEGG modules and other metabolic elements into one connected and manually curated metabolic network. Users can fully customize these networks and interactively explore them through its redesigned, fast and lightweight interface, which highlights general metabolic trends in multi-omics data. It also offers navigation at various levels of details to help users further investigate those trends and ultimately uncover novel biological insights. Support for multiple experimental conditions and time-series datasets, tools for generation of customization data, programmatic access, and a free user accounts system were introduced in this version to further streamline its workflow. PMID- 29718426 TI - geno2pheno[ngs-freq]: a genotypic interpretation system for identifying viral drug resistance using next-generation sequencing data. AB - Identifying resistance to antiretroviral drugs is crucial for ensuring the successful treatment of patients infected with viruses such as human immunodeficiency virus (HIV) or hepatitis C virus (HCV). In contrast to Sanger sequencing, next-generation sequencing (NGS) can detect resistance mutations in minority populations. Thus, genotypic resistance testing based on NGS data can offer novel, treatment-relevant insights. Since existing web services for analyzing resistance in NGS samples are subject to long processing times and follow strictly rules-based approaches, we developed geno2pheno[ngs-freq], a web service for rapidly identifying drug resistance in HIV-1 and HCV samples. By relying on frequency files that provide the read counts of nucleotides or codons along a viral genome, the time-intensive step of processing raw NGS data is eliminated. Once a frequency file has been uploaded, consensus sequences are generated for a set of user-defined prevalence cutoffs, such that the constructed sequences contain only those nucleotides whose codon prevalence exceeds a given cutoff. After locally aligning the sequences to a set of references, resistance is predicted using the well-established approaches of geno2pheno[resistance] and geno2pheno[hcv]. geno2pheno[ngs-freq] can assist clinical decision making by enabling users to explore resistance in viral populations with different abundances and is freely available at http://ngs.geno2pheno.org. PMID- 29718428 TI - Photo-control of the mitotic kinesin Eg5 using a novel photochromic inhibitor composed of a spiropyran derivative. AB - In this study, we synthesized a novel photochromic inhibitor of the mitotic kinesin Eg5, which is composed of the photochromic compound spiropyran to photo control the function of Eg5. The compound (S)-2, 3-dispiropyran propionic acid (DSPPA) exhibits reversible spiropyran-merocyanine photo-isomerization upon irradiation with visible or ultra-violet light. DSPPA induced reversible changes in the inhibitory effect on Eg5 ATPase and motor activities, which correlates with the spiropyran-merocyanine photo-isomerization. Microtubule-dependent ATPase activity was significantly more inhibited by the spiropyran isomer of DSPPA than by the merocyanine isomer. Additionally, an in vitro motility assay revealed that the microtubule gliding velocity was reduced more by the spiropyran isomer than by the merocyanine isomer. This indicates that the spiropyran derivative may be useful in regulating the function of the mitotic kinesin. PMID- 29718429 TI - Behavioral and neural correlates of parenting self-evaluation in mothers of young children. AB - In this study, we utilized a novel fMRI paradigm to examine the behavioral and neural correlates of parenting self-evaluation in a sample of mothers with at least one child under the age of 4 (N = 37). Prior self-report, behavioral and observational research document the implications of parenting self-evaluations for parent well-being and caregiving behavior; however, relatively little is known about the neural circuitry underlying these self-referential processes and to what extent they are influenced by caregiving experience. Although neuroimaging paradigms indexing other aspects of parental function exist, this is the first to use functional neuroimaging to study parenting self-evaluation in a controlled laboratory setting. We found parenting self-evaluations elicited significantly greater activity across most cortical midline structures, including the medial prefrontal cortex compared to control evaluations; these findings converge with previous work on the neural underpinning of general trait self evaluation. Notable differences by parity were observed in exploratory analyses: specifically, primiparous mothers endorsed a higher number of developmentally supportive traits, exhibited faster reaction times, and showed a greater difference in mPFC activity when making self-evaluations of developmentally supportive traits than of developmentally unsupportive traits, compared to multiparous mothers. Implications of these findings and study limitations are discussed. PMID- 29718431 TI - Stabilization of cell-cell junctions by active vitamin D ameliorates uraemia induced loss of human endothelial barrier function. AB - Background: Uraemia induces endothelial cell (EC) injury and impaired repair capacity, for which the underlying mechanism remains unclear. Active vitamin D (VD) may promote endothelial repair, however, the mechanism that mediates the effects of VD in chronic kidney disease are poorly understood. Thus, we investigated uraemia-induced endothelial damage and the protection against such damage by active VD. Methods: We applied electric cell-substrate impedance sensing (ECIS) to study real-time responses of human ECs exposed to pooled uraemic and non-uraemic plasma with or without the addition of active VD. The effects of indoxyl sulphate and p-cresol were tested in non-uraemic plasma. Structural changes for vascular endothelial (VE)-cadherin and F-actin were assessed by immunostaining and quantified. Results: The exposure of ECs to uraemic media significantly decreased endothelial barrier function after 24 h. Cell migration after electrical wounding and recovery of the barrier after thrombin-induced loss of integrity were significantly impaired in uraemic-medium stimulated cells and cells exposed to indoxyl sulphate and p-cresol. This effect on ECIS was dependent on loss of cell-cell interaction. Mechanistically, we found that EC, exposed to uraemic media, displayed disrupted VE-cadherin interactions and F-actin reorganization. VD supplementation rescued both endothelial barrier function and cell-cell interactions in ECs exposed to uraemic media. These events were associated with an increment of VE-cadherin at intercellular junctions. Conclusions: Our data demonstrate a potentially clinically relevant mechanism for uraemia-induced endothelial damage. Furthermore, active VD rescued the uraemic medium-induced loss of cell-cell adhesion, revealing a novel role of active VD in preservation of endothelial integrity during uraemia. PMID- 29718432 TI - Impact of H3.3 K27M Mutation on Prognosis and Survival of Grade IV Spinal Cord Glioma on the Basis of New 2016 World Health Organization Classification of the Central Nervous System. AB - BACKGROUND: Spinal cord glioma grade IV is a rare, diffuse midline glioma. H3 K27M-mutant was classified in a different entity in the 2016 World Health Organization (WHO) classification recently. No reports about prognosis of spinal cord glioma grade IV are available yet. OBJECTIVE: To analyze the prognostic factors for spinal cord glioma grade IV. METHODS: Twenty-five patients with spinal cord glioma of grade IV who underwent surgery in a single institute were selected. All grade IV spinal cord glioma histologically confirmed as glioblastoma or "diffuse midline glioma with H3 K27M-mutant" by the 2016 WHO classification of the central nervous system were included. Basic demographics, treatment modalities, and pathological tumor molecular profiles were investigated for prognosis. RESULTS: Mean age was 39.1 yr; male to female ratio was 18 : 7. Tumor was located in thoracic cord (53.3%), cervical cord (40%), and lumbar area (6.7%). Median overall survival was 37.1 mo; median disease-free survival was 18.5 mo. Treatment modality showed no statistical difference. Only K27M profile showed significant prognostic value, 20 patients (80%) showed K27M mutation positive, K27M mutation patients showed longer overall survival (40.07 mo) than K27M negative patients (11.63 mo, P < .0001), and disease-free survival (20.85 vs 8.72 mo, P = .0241). CONCLUSION: This study is the first and largest report of the prognosis of primary spinal cord grade IV glioma using the new WHO classification. This study reported survival analysis and prognostic factors, and revealed that H3.3 K27M mutation is not a major poor prognostic factor. Further studies to explore K27M mutations needed for risk stratification and therapy optimization. PMID- 29718433 TI - Mosquito repellents for the traveller: does picaridin provide longer protection than DEET? AB - Background: This review examines the published laboratory and field tests where the repellents DEET and picaridin have been compared for their efficacy as repellents against mosquitoes. The review is limited to an assessment of whether the duration of protection afforded by picaridin is similar to or better than DEET. Method: Identification and analysis of laboratory and field-based trials published in peer-reviewed journals that compared DEET to picaridin efficacy. Results: Only eight field studies and three laboratory studies met the review criteria for inclusion and most were considered to be of high risk of bias and of lower quality when judged against evidence-based principles. Overall, the studies showed little potential difference between DEET and picaridin applied at the same dosage, with some evidence pointing to a superior persistence for picaridin. Conclusion: Applied dosage is one important variable in determining the persistence of a repellent experienced by users but the maximum concentration in current picaridin formulation is <30%w/v. Therefore, where only 30% DEET or lower concentrations are available, then on current evidence, it is reasonable to offer DEET or picaridin as a first choice. Where >50% DEET products are available then the protection time advantage associated with these formulations reasonably can be invoked to consider them as first choice repellents. PMID- 29718434 TI - Recent and historical trends in the epidemiology of Japanese encephalitis and its implication for risk assessment in travellers. AB - Japanese encephalitis is a major disease in many countries in Asia often visited by both leisure and non-leisure travellers. Although reported cases of Japanese apoptosis (JE) in travellers are relatively few, there are indications that both the number of cases might be underreported and that changes in the epidemiological situation in these parts of Asia may increase the risk, especially non-leisure travellers. Although JE mainly is considered a rural disease urban cases are seen the large economic growth and urbanization of previously rural areas in many for JE high-endemic areas may further add to the risk for JE, especially for business travellers, when visiting newly established peri-urban areas. This review will address these dynamic and unpredictable risks for JE and discuss its possible implications for the traveller. PMID- 29718430 TI - Post-ruminal branched-chain amino acid supplementation and intravenous lipopolysaccharide infusion alter blood metabolites, rumen fermentation, and nitrogen balance of beef steers. AB - Steers exposed to an endotoxin may require additional branched-chain AA (BCAA) to support an increase in synthesis of immune proteins. This study evaluated effects of bacterial lipopolysaccharide (LPS) and BCAA supplementation on blood metabolites and N balance of 20 ruminally-cannulated steers (177 +/- 4.2 kg BW). The experiment was a randomized block design, with 14-d adaptation to metabolism stalls and diet (DM fed = 1.5% BW) and 6-d collection. Treatments were a 2 * 2 factorial of LPS (0 vs. 1.0 to 1.5 MUg/kg BW; -LPS vs. +LPS) and BCAA (0 vs. 35 g/d; -BCAA vs. +BCAA). The LPS in 100 mL sterile saline was infused (1 mL/min via i.v. catheter) on day 15. The BCAA in an essential AA solution were abomasally infused (900 mL/d) three times daily in equal portions beginning on day 7. Blood, rumen fluid, and rectal temperature were collected on day 15 at h 0, 2, 4, 8, 12, and 24 after LPS infusion. Feces and urine were collected from day 16 to 20. Rectal temperatures were greater for +LPS vs. -LPS steers at 4 h and lower at 8 h after LPS infusion (LPS * h, P < 0.01). Serum cortisol and plasma urea N were greater for +LPS than -LPS steers at 2 (cortisol only), 4, 8, 12, and 24 h after LPS infusion (LPS * h, P < 0.01). Serum cortisol was greater for +BCAA than -BCAA steers at 12 h after LPS infusion (BCAA * h, P < 0.05). Serum glucose was greater for +LPS than -LPS steers at 2 h after LPS infusion (LPS * h, P < 0.01). Plasma Ile, Leu, and Val were lower, and plasma His was greater in +LPS than -LPS steers (LPS, P < 0.05). Plasma Lys, Met, Thr, and Trp of +LPS steers were lower than LPS steers at 4 (Thr only), 8 (Lys and Trp only), 12, and 24 h after infusion (LPS * h, P < 0.05). Plasma Ile, Leu, and Val were greater (BCAA, P < 0.01), and Met, His, Phe, Thr, and Trp were lower for +BCAA than -BCAA steers at 0 and 24 h after LPS infusion (BCAA * h, P <= 0.05). Steers receiving +LPS had lower rumen pH at 8 h, greater total VFA at 8 h, and lower rumen NH3 at 24 h after LPS infusion compared with -LPS steers (LPS * h, P <= 0.04). Total tract passage rates, DM, OM, NDF, ADF, and N intake, fecal N, digested N, and retained N were lower (P < 0.05) for +LPS than -LPS steers. Total N supply (dietary plus infused) and fecal N were greater (P < 0.05) for +BCAA vs. -BCAA steers. The absence of LPS * BCAA interactions (P >= 0.20) for N balance indicated that post-ruminal supplementation of BCAA did not alleviate the negative effects of endotoxin on N utilization by growing steers. PMID- 29718435 TI - Japanese encephalitis: the vectors, ecology and potential for expansion. AB - Background: Japanese encephalitis (JE) is a viral disease predominantly located in South East Asia and commonly associated with transmission between amplifying hosts, such as pigs, and the mosquito Culex tritaeniorhynchus, where human infection represents a dead end in the life cycle of the virus. The expansion of JE beyond an Asiatic confine is dependent on a multitude of complex factors that stem back to genetic subtype variation. A complex interplay of the genetic variation and vector competencies combine with variables such as geography, climate change and urbanization. Methods: Our understanding of JE is still at an early stage with long-term longitudinal vector surveillance necessary to better understand the dynamics of JE transmission and to characterize the role of potential secondary vectors such as Cx. pipiens and Cx. bitaeniorhynchus. The authors review the vectors indicated in transmission and the ecological, genetic and anthropological factors that affect the disease's range and epidemiology. Conclusion: Monitoring for the presence of JE virus in mosquitoes in general can be used to estimate levels of potential JE exposure, intensity of viral activity and genetic variation of JEV throughout surveyed areas. Increased surveillance and diagnosis of viral encephalitis caused by genotype 5 JE virus is required in particular, with the expansion in epidemiology and disease prevalence in new geographic areas an issue of great concern. Additional studies that measure the impact of vectors (e.g. bionomics and vector competence) in the transmission of JEV and that incorporate environmental factors (e.g. weekly rainfall) are needed to define the roles of Culex species in the viral pathogenesis during outbreak and non-outbreak years. PMID- 29718436 TI - Non-pharmacotherapeutic interventions in travellers diarrhoea (TD). AB - Background: This is a review of some of the non-pharmacotherapeutic interventions in travellers diarrhoea (TD) looking particularly at the role of pre and probiotics, the evidence behind water purification and the impact of advice given and its adherence by travellers. Method: A systematic review of the research completed under section using the listed key words and searched using the databases of Google Scholar, Journal of Travel Medicine, QxMD, ReadCube and The Knowledge Network. Results and conclusions: Travellers' diarrhoea and use of pre/probiotics: There is no significant evidence to suggest the benefit of using pre or probiotics to prevent or treat TD. A new second generation of B-GOS prebiotics shows some potential in preventing the incidence and symptoms of TD but lack high levels of graded evidence. Recent reports from the biotics industry suggest that a review of the above issues is being addressed and in the future more robust studies may be completed. The evidence behind water purification and diarrhoeal disease: Evidence suggests there is no direct correlation that water purification has an impact on diarrhoeal disease, although some studies underline the value of water purification. The use of bottled water is questioned as being unreliable due to the inconsistencies of microbiological safety. With new water purification products and methods being introduced a benefit could be found for publishing effectiveness against pathogen groups to improve comparison. Are travellers given good sanitary advice and do they follow it? The advice given to travellers by non-clinical sources is unregulated and not a statutory obligation of a reservation to travel. Within the clinical sector the advice provided and the outcomes of advice provision do not correlate with a reduction in TD as a variance can occur by travellers' changes and behaviours towards the advice given. Following recommended advice and consuming higher risks foods do not correspond directly with levels of reported TD, suggesting attitudes and practices deviate away from this advice when travelling. PMID- 29718437 TI - Antibiotic resistance in travellers' diarrhoeal disease, an external perspective. AB - Background: There are many recommendations on the use of antibiotics for prophylaxis and treatment of travellers' diarrhoea (TD). As pharmacists with a special interest in antimicrobial stewardship, we examine and offer our perspective on advice that is recommended to travellers in terms of prevention, treatment and management of TD with a focus on antibiotic use and resistance. Methods: Publications on TD were identified through PubMed, Google Scholar and Cochrane Library databases searches using search terms 'travellers diarrhoea', 'travellers diarrhoea', 'travellers' diarrhoea' 'guidelines', 'expert opinion', 'expert reviews', 'South Asia' and 'South East Asia' (S and SE Asia), 'antibiotics', 'resistance genes', 'travel advice', 'pharmacists', 'guidelines', 'prevention' and 'treatment'. References of articles were also screened for additional relevant studies. Results: Whilst most guidelines and expert reviews were in agreement with the restricted use of antibiotics unless there was a clinical need, the literature review identified gaps in research into behaviours of travellers regarding non-compliance with the pre-travel advice provided and the need for in depth training and education for all healthcare professionals in providing 'tailored' advice for travellers going to high-risk destinations. Conclusions: Travellers should be made aware of the problems of antimicrobial resistance in their destination and home countries and offered alternative forms of prophylaxis for TD. Strategies for prevention of TD, other than the use of antibiotics, also need to be emphasized. All healthcare professionals involved in giving advice about TD should be familiar with the epidemiology of the condition as this will inform responsible behaviours, risk assessment and management strategies in different geographical areas. PMID- 29718438 TI - Asian travel: from the rare to the difficult. PMID- 29718439 TI - Cholera: under diagnosis and differentiation from other diarrhoeal diseases. AB - Background: Globally 1.4 billion people are at risk from cholera in countries where the disease is endemic, with an estimated 2.8 million cases annually. The disease is significantly under reported due to economic, social and political disincentives as well as poor laboratory resources and epidemiological surveillance in those regions. In addition, identification of cholera from other diarrhoeal causes is often difficult due to shared pathology and symptoms with few reported cases in travellers from Northern Europe. Methods: A search of PubMed and Ovid Medline for publications on cholera diagnosis from 2010 through 2017 was conducted. Search terms included were cholera, Rapid Diagnostic Test (RDT), multiplex PCR and diagnosis of diarrhoea. Studies were included if they are published in English, French or Spanish. Results: An increase of RDT study publications for diarrhoeal disease and attempted test validations were seen over the publication period. RDTs were noted as having varied selectivity and specificity, as well as associated costs and local resource requirements that can prohibit their use. Conclusions: Despite opportunities to employ RDTs with high selectivity and specificity in epidemic areas, or in remote locations without access to health services, such tests are limited to surveillance use. This may represent a missed opportunity to discover the true global presence of Vibrio cholerae and its role in all cause diarrhoeal disease in underdeveloped countries and in travellers to those areas. The wider applicability of RDTs may also represent an opportunity in the wider management of traveller's diarrhoea. PMID- 29718440 TI - Low Dose of Bisphenol A Modulates Ovarian Cancer Gene Expression Profile and Promotes Epithelial to Mesenchymal Transition Via Canonical Wnt Pathway. AB - The xenoestrogen bisphenol A (BPA) is a synthetic endocrine disrupting chemical, having the potential to increase the risk of hormone-dependent ovarian cancer. Thus, a deeper understanding of the molecular and cellular mechanisms is urgently required in the novel cell models of ovarian cancer which express estrogen receptors. To understand the possible mechanisms underlying the effects of BPA, human ovarian adenocarcinoma SKOV3 cells were exposed to BPA (10 or 100 nM) or 0.1% DMSO for 24 h, and then global gene expression profile was determined by high-throughput RNA sequencing. Also, enrichment analysis was carried out to find out relevant functions and pathways within which differentially expressed genes were significantly enriched. Transcriptomic analysis revealed 94 differential expression genes. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses indicated that these genes related to tumorigenesis and metastasis. Further studies were carried out to validate the results of functional annotation, which indicated that BPA (10 and 100 nM) increased migration and invasion as well as induced epithelial to mesenchymal transitions in SKOV3 and A2780 cells. Accordingly, environmentally relevant-dose BPA activated the canonical Wnt signaling pathway. Our study first comprehensively analyzed the possible mechanisms underlying the effects of BPA on ovarian cancer. Environmentally relevant doses of BPA modulated the gene expression profile, promoted epithelial to mesenchymal transition progress via canonical Wnt signaling pathway of ovarian cancer. PMID- 29718442 TI - The Rise of Zebrafish as a Model for Toxicology. PMID- 29718441 TI - Prevalence and molecular characteristics of DNA mismatch repair protein-deficient sebaceous neoplasms and keratoacanthomas in a Japanese hospital-based population. AB - Background: Muir-Torre syndrome (MTS) is currently considered as a clinical variant of Lynch syndrome (LS). The clinical significance of the screening of patients with MTS-associated cutaneous tumors for the identification of LS has not yet been established. In addition, the prevalence and molecular characteristics of mismatch repair (MMR) protein deficiency in such tumors has scarcely been investigated in the Japanese population. Methods: Immunohistochemistry (IHC) for MMR proteins (MLH1, MSH2, MSH6 and PMS2) was performed in formalin-fixed paraffin-embedded sections prepared from 16 sebaceous neoplasms (SNs) resected from 13 patients and 32 keratoacanthomas (KAs) resected from 31 patients at our institution between January 2005 and March 2014. Tumors showing MMR protein loss were further subjected to genetic analysis for detecting the presence of germline and/or somatic alterations of the MMR genes to identify the precise molecular mechanisms underlying the protein loss. Results: Among the 16 SNs resected from 13 patients, eight SNs resected from five patients (38.5%) showed loss of expression of MMR proteins (MLH1/PMS2 loss, one patient; MSH2/MSH6 loss, four patients). Genetic analyses showed a pathogenic germline MSH2 mutation in one patient, somatic hypermethylation of the MLH1 promoter region in one patient, and somatic alterations of MSH2 without detectable germline mutations of MSH2 in three patients. None of the KAs examined in the study showed any loss of MMR protein expression. Conclusions: The efficacy of routine screening of cutaneous neoplasms known to be associated with MTS by IHC for MMR proteins to identify LS may be fairly limited. MMR protein loss as determined by IHC in SNs is not always diagnostic of LS, and appears, in most cases, to be a result of somatic inactivation of the MMR genes. PMID- 29718443 TI - Efficacy of In Vivo Electroporation on the Delivery of Molecular Agents into Aphid (Hemiptera: Aphididae) Ovarioles. AB - While the wealth of genomic data presently available is increasing rapidly, the advancement of functional genomics technologies for the large majority of these organisms has lagged behind. The Clustered Regularly Interspaced Palindromic Repeats (CRISPR)/Cas9 system is an emerging gene-editing technology derived from a bacterial adaptive immune system that has proven highly effective in multiple model systems. Here, the CRISPR/Cas9 system was delivered into the ovarioles of the pea aphid, Acyrthosiphon pisum (Harris) (Hemiptera, Aphididae), with a new delivery method utilizing in vivo electroporation. To validate gene-editing, a target sequence within the marker tor pigment gene was chosen, and gene-editing was predicted to result in white pigmentation in the offspring of treated adult aphids. Adult aphids (10-d old) were injected with the tor single guide RNA and Cas9 complex and subsequently subjected to electroporation. Adult aphids were given 4 d to produce viviparous offspring. After offspring developed for 6 d, DNA was extracted and sequenced to validate if CRISPR/Cas9-directed gene editing occurred. A survival rate over 70% was found in treated adult aphids. A distinct white pigmentation was found in 2.5% of aphids; however, gene-editing within the target sequence was not found in any of the individuals screened. Presence of white aphids without gene-editing suggests other mechanisms may have influenced pigmentation. High survival rates in experimental treatments demonstrate the robustness of this new technique, and further refinement of this technique may prove it as an effective functional genomics tool for viviparous insects and/or gene editing at a somatic level. PMID- 29718444 TI - Photobiology of vitamins. AB - This review explores contemporary ideas about the relationship between light exposure and vitamin biology. Nutritional biochemistry has long recognized the relationship between vitamins A and D and light exposure, but in recent years other vitamins have also been implicated in photoresponsive biological mechanisms that influence health, well-being, and even evolutionary processes. Interactions between light and vitamins can modify genotype-phenotype relationships across the life cycle, providing a basis for interesting new explanations relevant to wide aspects of human biology. This review examines both well-established and emerging ideas about vitamin photobiology in the context of the following: (1) light responsiveness of vitamin D (photosynthesized in skin), vitamin A (linked to vision), and vitamin B3 (needed to repair genomic damage); (2) vulnerability of folate and vitamins B1, B2, B12, and D to ultraviolet (UV) light (all potentially degraded); (3) protective/filtering actions of carotenoids and vitamins C and E, which act as antioxidants and/or natural sunscreens, against UV light; (4) role of folate, carotenoids, and vitamins A, B3, C, D, and E in UV-related genomic regulation, maintenance, and repair; (5) role of folate and vitamins A, B2, B12, and D in a range of light-signaling and light-transduction pathways; and (6) links between folate and vitamin D and the evolution of UV light-adaptive phenotypes. PMID- 29718445 TI - New educational video helps South Asian rheumatoid arthritis patients manage condition and understand treatment pathway. PMID- 29718446 TI - Letter: Results of Surgery for Low-Grade Brain Arteriovenous Malformation Resection by Early Career Neurosurgeons: An Observational Study. PMID- 29718448 TI - Perspectives on Ovarian Cancer From SEER: Today and Tomorrow. PMID- 29718447 TI - Posterior Summarization in Bayesian Phylogenetics Using Tracer 1.7. AB - Bayesian inference of phylogeny using Markov chain Monte Carlo (MCMC) plays a central role in understanding evolutionary history from molecular sequence data. Visualizing and analyzing the MCMC-generated samples from the posterior distribution is a key step in any non-trivial Bayesian inference. We present the software package Tracer (version 1.7) for visualizing and analyzing the MCMC trace files generated through Bayesian phylogenetic inference. Tracer provides kernel density estimation, multivariate visualization, demographic trajectory reconstruction, conditional posterior distribution summary, and more. Tracer is open-source and available at http://beast.community/tracer. PMID- 29718449 TI - Cross-Site Reliability of Human Induced Pluripotent stem cell-derived Cardiomyocyte Based Safety Assays Using Microelectrode Arrays: Results from a Blinded CiPA Pilot Study. AB - Recent in vitro cardiac safety studies demonstrate the ability of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to detect electrophysiologic effects of drugs. However, variability contributed by unique approaches, procedures, cell lines, and reagents across laboratories makes comparisons of results difficult, leading to uncertainty about the role of hiPSC CMs in defining proarrhythmic risk in drug discovery and regulatory submissions. A blinded pilot study was conducted to evaluate the electrophysiologic effects of 8 well-characterized drugs on 4 cardiomyocyte lines using a standardized protocol across 3 microelectrode array platforms (18 individual studies). Drugs were selected to define assay sensitivity of prominent repolarizing currents (E-4031 for IKr, JNJ303 for IKs) and depolarizing currents (nifedipine for ICaL, mexiletine for INa) as well as drugs affecting multichannel block (flecainide, moxifloxacin, quinidine, and ranolazine). Inclusion criteria for final analysis was based on demonstrated sensitivity to IKr block (20% prolongation with E-4031) and L-type calcium current block (20% shortening with nifedipine). Despite differences in baseline characteristics across cardiomyocyte lines, multiple sites, and instrument platforms, 10 of 18 studies demonstrated adequate sensitivity to IKr block with E-4031 and ICaL block with nifedipine for inclusion in the final analysis. Concentration-dependent effects on repolarization were observed with this qualified data set consistent with known ionic mechanisms of single and multichannel blocking drugs. hiPSC-CMs can detect repolarization effects elicited by single and multichannel blocking drugs after defining pharmacologic sensitivity to IKr and ICaL block, supporting further validation efforts using hiPSC-CMs for cardiac safety studies. PMID- 29718450 TI - Real-time Interobserver Agreement in Bowel Ultrasonography for Diagnostic Assessment in Patients With Crohn's Disease: An International Multicenter Study. AB - Background: The unavailability of standardized parameters in bowel ultrasonography (US) commonly used in Crohn's disease (CD) and the shortage of skilled ultrasonographers are 2 limiting factors in the use of this imaging modality around the world. The aim of this study is to evaluate interobserver agreement among experienced sonographers in the evaluation of bowel US parameters in order to improve standardization in imaging reporting and interpretation. Methods: Fifteen patients with an established diagnosis of CD underwent blinded bowel US performed by 6 experienced sonographers. Prior to the evaluation, the sonographers and clinical and radiological IBD experts met to formally define the US parameters. Interobserver agreement was tested with the Quatto method (s). Results: All operators agreed on the presence/absence of CD lesions and distinguished absence of/mild activity or moderate/severe lesions in all patients. S values were moderate for bowel wall thickness (s = 0.48, P = n.s.), bowel wall pattern (s = 0.41, P = n.s.), vascularization (s = 0.52, P = n.s.), and presence of lymphnodes (s = 0.61, P = n.s.). Agreement was substantial for lesion location (s = 0.68, P = n.s.), fistula (s = 0.74, P = n.s.), phlegmon (s = 0.78, P = 0.04), and was almost perfect for abscess (s = 0.95, P = 0.02). Poor agreement was observed for mesenteric adipose tissue alteration, lesion extent, stenosis, and prestenotic dilation. Conclusions: In this study, the majority of the US parameters used in CD showed moderate/substantial agreement. The development of shared US imaging interpretation patterns among sonographers will lead to improved comparability of US results among centers and facilitate the development of multicenter studies and the spread of bowel US training, thereby allowing a wider adoption of this useful technique. PMID- 29718451 TI - MOLEonline: a web-based tool for analyzing channels, tunnels and pores (2018 update). AB - MOLEonline is an interactive, web-based application for the detection and characterization of channels (pores and tunnels) within biomacromolecular structures. The updated version of MOLEonline overcomes limitations of the previous version by incorporating the recently developed LiteMol Viewer visualization engine and providing a simple, fully interactive user experience. The application enables two modes of calculation: one is dedicated to the analysis of channels while the other was specifically designed for transmembrane pores. As the application can use both PDB and mmCIF formats, it can be leveraged to analyze a wide spectrum of biomacromolecular structures, e.g. stemming from NMR, X-ray and cryo-EM techniques. The tool is interconnected with other bioinformatics tools (e.g., PDBe, CSA, ChannelsDB, OPM, UniProt) to help both setup and the analysis of acquired results. MOLEonline provides unprecedented analytics for the detection and structural characterization of channels, as well as information about their numerous physicochemical features. Here we present the application of MOLEonline for structural analyses of alpha-hemolysin and transient receptor potential mucolipin 1 (TRMP1) pores. The MOLEonline application is freely available via the Internet at https://mole.upol.cz. PMID- 29718452 TI - Accuracy of Activity Trackers in Parkinson Disease: Should We Prescribe Them? AB - Background: Wearable, consumer-grade activity trackers have become widely available as a means of monitoring physical activity in the form of step counts. However, step counts may not be accurate in persons with Parkinson disease (PD) due to atypical gait characteristics. Objective: This study aimed to investigate the accuracy of 4 consumer-grade activity trackers in individuals with PD while ambulating during continuous and discontinuous walking tasks. Design: This study used a cross-sectional design. Methods: Thirty-three persons with PD (Hoehn & Yahr stages 1-3) donned 4 models of activity trackers on the less affected side of their bodies. Participants performed 2 continuous walking tasks (2-minute walk tests at comfortable and fast speeds) and 2 discontinuous walking tasks (a simulated household course and an obstacle negotiation course) in an outpatient setting. Bland-Altman plots and intraclass correlation coefficients [ICC(2,1)] were computed as a measure of agreement between actual steps taken (reference standard: video recording) and steps recorded by each tracker. Results: The accuracy of the activity trackers varied widely, with ICCs ranging from -0.03 to 0.98. Overall, the most accurate device across all tasks was the Fitbit Zip, and the least accurate was the Jawbone Up Move during the simulated household course. All activity trackers were more accurate for continuous walking tasks compared with discontinuous walking tasks. Waist-mounted devices were more accurate than wrist-mounted devices with continuous tasks. Bland-Altman plots revealed that all activity trackers underestimated step counts. Limitations: All walking tasks were measured over relatively short distances. Conclusions: In persons with mild-to moderate PD, waist-worn activity trackers may be prescribed to monitor bouts of continuous walking with reasonable accuracy; however, activity trackers have little utility in monitoring discontinuous walking common in household settings. PMID- 29718453 TI - Molecular Landscape of ERBB2/ERBB3 Mutated Colorectal Cancer. AB - Background: Despite growing therapeutic relevance of ERBB2 amplifications in colorectal cancer (CRC), little is known about ERBB2/ERBB3 mutations. We aimed to characterize these subsets of CRC. Methods: We performed a retrospective analysis of 419 CRC patients from MD Anderson (MDACC) and 619 patients from the Nurses' Health Study (NHS)/Health Professionals Follow-Up Study (HPFS) with tissue sequencing, clinicopathologic, mutational, and consensus molecular subtype (CMS) profiles of ERBB2/ERBB3 mutant patients. A third cohort of 1623 CRC patients with ctDNA assays characterized the ctDNA profile of ERBB2 mutants. All statistical tests were two-sided. Results: ERBB2 mutations occurred in 4.1% (95% confidence interval [CI] = 2.4% to 6.4%), 5.8% (95% CI = 4.1% to 8.0%), and 5.1% (95% CI = 4.0% to 6.2%) of MDACC, NHS/HPFS, and ctDNA patients, respectively. ERBB3 mutations occurred in 5.7% (95% CI = 3.7% to 8.4%, 95% CI = 4.0% to 7.8%) of patients in both tissue cohorts. Age, stage, and tumor location were not associated with either mutation. Microsatellite instability (MSI) was associated with ERBB2 (odds ratio [OR] = 5.98, 95% CI = 2.47 to 14.49, P < .001; OR = 5.13, 95% CI = 2.38 to 11.05, P < .001) and ERBB3 mutations (OR = 3.48, 95% CI = 1.51 to 8.02, P = .002; OR = 3.40, 95% CI = 1.05 to 10.96, P = .03) in both tissue cohorts. Neither gene was associated with TP53, APC, KRAS, NRAS, or BRAF mutations in tissue. However, PIK3CA mutations were strongly associated with ERBB2 mutations in all three cohorts (OR = 3.68, 95% CI = 1.83 to 7.41, P = .001; OR = 2.25, 95% CI = 1.11 to 4.58, P = .02; OR = 2.11, 95% CI = 1.25 to 3.58, P = .004) and ERBB3 mutations in the MDACC cohort (OR = 13.26, 95% CI = 5.27 to 33.33, P < .001). ERBB2 (P = 0.08) and ERBB3 (P = .008) mutations were associated with CMS1 subtype. ERBB2 (hazard ratio [HR] = 1.82, 95% CI = 1.23 to 4.03, P = .009), but not ERBB3 (HR = 0.88, 95% CI = 0.45 to 1.73, P = .73), mutations were associated with worse overall survival. Conclusions: MSI and PIK3CA mutations are associated with ERBB2/ERBB3 mutations. Co-occurring PIK3CA mutations may represent a second hit to oncogenic signaling that needs consideration when targeting ERBB2/ERBB3. PMID- 29718454 TI - Neutral Theory in Cancer Cell Population Genetics. AB - Kimura's neutral theory provides the whole theoretical basis of the behavior of mutations in a Wright-Fisher population. We here discuss how it can be applied to a cancer cell population, in which there is an increasing interest in genetic variation within a tumor. We explain a couple of fundamental differences between cancer cell populations and asexual organismal populations. Once these differences are taken into account, a number of powerful theoretical tools developed for a Wright-Fisher population could be readily contribute to our deeper understanding of the evolutionary dynamics of cancer cell population. PMID- 29718455 TI - Cortisol, Testosterone, and Prospective Risk for War-zone Stress-Evoked Depression. AB - Introduction: The major challenges of efforts to reveal biological risk factors and biomarkers of depression include the complexity of underlying systems, interactions with other systems, and contextual factors governing their expression. Altered endocrine function is believed to be a central contributor to depressive illness, but across studies, evidence for a link between endocrine markers and depression has been mixed, inconclusive, or conditional in nature. In the present study, we evaluated basal testosterone (T), cortisol (C), and CO2 inhalation-stress-reactivity measures of these hormones (TR, CR) as pre deployment moderators of the later impact of war-zone stressors on depression symptoms in-theater. Materials and Methods: At pre-deployment, U.S. soldiers (N = 120) completed demographic, clinical and hormone measures, and during deployment, they completed monthly, web-based assessments of war-zone stressors and depression symptoms (N = 533 observations). Mixed effects models estimated the effects of the pre-deployment hormone profiles in moderating war-zone stressors' impact on in-theater depression. Models also tested whether hormonally linked risk for later stress-evoked depression depends on pre-existing depression. Results: Controlling for pre-deployment depression, high T was protective; whereas TR had depressogenic effects that were amplified by pre-deployment depression. Further, high C was protective, but heightened CR was depressogenic, but only among those with elevated pre-deployment depression. Conclusions: Findings highlight the importance of examining basal and reactivity measures of endocrine function, and use of prospective, longitudinal models to test hypothesized causal pathways associated with depression vulnerability in the war zone. Results also suggest that pre-existing depression and cortisol may work in tandem to increase vulnerability for later stress-evoked depression in the war zone. PMID- 29718456 TI - Risk of Motor Vehicle Accidents Related to Sleepiness at the Wheel: A Systematic Review and Meta-Analysis. PMID- 29718457 TI - The phage T4 MotA transcription factor contains a novel DNA binding motif that specifically recognizes modified DNA. AB - During infection, bacteriophage T4 produces the MotA transcription factor that redirects the host RNA polymerase to the expression of T4 middle genes. The C terminal 'double-wing' domain of MotA binds specifically to the MotA box motif of middle T4 promoters. We report the crystal structure of this complex, which reveals a new mode of protein-DNA interaction. The domain binds DNA mostly via interactions with the DNA backbone, but the binding is enhanced in the specific cognate structure by additional interactions with the MotA box motif in both the major and minor grooves. The linker connecting the two MotA domains plays a key role in stabilizing the complex via minor groove interactions. The structure is consistent with our previous model derived from chemical cleavage experiments using the entire transcription complex. alpha- and beta-d-glucosyl-5 hydroxymethyl-deoxycytosine replace cytosine in T4 DNA, and docking simulations indicate that a cavity in the cognate structure can accommodate the modified cytosine. Binding studies confirm that the modification significantly enhances the binding affinity of MotA for the DNA. Consequently, our work reveals how a DNA modification can extend the uniqueness of small DNA motifs to facilitate the specificity of protein-DNA interactions. PMID- 29718459 TI - Divergent phenological and leaf gas exchange strategies of two competing tree species drive contrasting responses to drought at their altitudinal boundary. AB - In Mediterranean mountains, Pinus sylvestris L. is expected to be displaced under a warming climate by more drought-tolerant species such as the sub-Mediterranean Quercus pyrenaica Willd. Understanding how environmental factors drive tree physiology and phenology is, therefore, essential to assess the effect of changing climatic conditions on the performance of these species and, ultimately, their distribution. We compared the cambial and leaf phenology and leaf gas exchange of Q. pyrenaica and P. sylvestris at their altitudinal boundary in Central Spain and assessed the environmental variables involved. Results indicate that P. sylvestris cambial phenology was more sensitive to weather conditions (temperature at the onset and water deficit at the end of the growing season) than Q. pyrenaica. On the other hand, Q. pyrenaica cambial and leaf phenology were synchronized and driven by photoperiod and temperatures. Pinus sylvestris showed lower photosynthetic nitrogen-use efficiency and higher intrinsic water use efficiency than Q. pyrenaica as a result of a tighter stomatal control in response to summer dry conditions, despite its less negative midday leaf water potentials. These phenological and leaf gas exchange responses evidence a stronger sensitivity to drought of P. sylvestris than that of Q. pyrenaica, which may therefore hold a competitive advantage over P. sylvestris under the predicted increase in recurrence and intensity of drought events. On the other hand, both species could benefit from warmer springs through an advanced phenology, although this effect could be limited in Q. pyrenaica if it maintains a photoperiod control over the onset of xylogenesis. PMID- 29718458 TI - Bi-lung transplantation in anti-synthetase syndrome with life-threatening interstitial lung disease. PMID- 29718460 TI - Age Moderates Smokers' Subjective Response to Very Low Nicotine Content Cigarettes: Evidence from a Randomized Controlled Trial. AB - Introduction: Reducing the level of nicotine in cigarettes is a regulatory strategy that has the potential to greatly improve public health. If nicotine levels are reduced in all commercially available cigarettes, current smokers might find it easier to quit and young people might be less likely to become dependent. However, it is not yet known whether age moderates subjective or behavioral responses to low-nicotine cigarettes. Methods: Recently, a large, multisite randomized clinical trial was conducted to compare the effects of cigarettes differing in nicotine content (either usual brand or research cigarettes containing 15.8, 5.2, 2.4, 1.3, or 0.4 mg nicotine/g tobacco) across six weeks of exposure. In this secondary analysis, we tested whether age moderated smokers' subjective (measures of psychological reward, smoking satisfaction) and behavioral (cigarettes smoked per day, smoking topography, and nicotine exposure) responses to cigarettes varying in nicotine content after two and six weeks of use, while controlling for baseline dependence and demographic factors. Results: Results indicated that younger adults (age 18-24) who smoked cigarettes with 2.4-0.4 mg/g nicotine reported significantly less smoking satisfaction and psychological reward, and smoked fewer cigarettes per day, than older adults (25+ years) after two weeks of use. No differences in topography were observed at either time point. After six weeks of use, differences had diminished on all measures. Conclusions: The reduced positive effects of reduced nicotine content cigarettes in young adults suggests that this regulatory policy may reduce smoking reinforcement in this vulnerable population. Implications: As the FDA considers reducing the level of nicotine in cigarettes to make them less addictive, understanding the potential impact of this policy on young people is of crucial importance. We found that young adults had significantly lower positive subjective effects to VLNC cigarettes and smoked fewer VLNC cigarettes than older adults after two weeks of use, indicating that this policy may reduce smoking reinforcement more quickly in young adults. These data add to the growing body of evidence on the potential for this policy to positively impact public health. PMID- 29718461 TI - Dissecting the role of MADS-box genes in monocot floral development and diversity. AB - Many monocot plants have high social and economic value. These include grasses such as rice (Oryza sativa), wheat (Triticum aestivum), and barley (Hordeum vulgare), which produce soft commodities for many food and beverage industries, and ornamental flowers such ase lily (Lilium longiflorum) and orchid (Oncidium Gower Ramsey), which represent an important component of international flower markets. There is constant pressure to improve the development and diversity of these species, with a significant emphasis on flower development, and this is particularly relevant considering the impact of changing environments on reproduction and thus yield. MADS-box proteins are a family of transcription factors that contain a conserved 60 amino acid MADS-box motif. In plants, attention has been devoted to characterization of this family due to their roles in inflorescence and flower development, which holds promise for the modification of floral architecture for plant breeding. This has been explored in diverse angiosperms, but particularly the dicot model Arabidopsis thaliana. The focus of this review is on the less well characterized roles of the MADS-box proteins in monocot flower development and how changes in MADS-box proteins throughout evolution may have contributed to creating a diverse range of flowers. Examining these changes within the monocots can identify the importance of certain genes and pinpoint those which might be useful in future crop improvement and breeding strategies. PMID- 29718462 TI - Heat-stress priming and alternative splicing-linked memory. PMID- 29718464 TI - Oli2go: an automated multiplex oligonucleotide design tool. AB - The success of widely used oligonucleotide-based experiments, ranging from PCR to microarray, strongly depends on an accurate design. The design process involves a number of steps, which use specific parameters to produce high quality oligonucleotides. Oli2go is an efficient, user friendly, fully automated multiplex oligonucleotide design tool, which performs primer and different hybridization probe designs as well as specificity and cross dimer checks in a single run. The main improvement to existing oligonucleotide design web-tools is that oli2go combines multiple steps in an all-in-one solution, where other web applications only accomplish parts of the whole design workflow. Especially, the oli2go specificity check is not only performed against a single species (e.g. mouse), but against bacteria, viruses, fungi, invertebrates, plants, protozoa, archaea and sequences from whole genome shotgun sequence projects and environmental samples, at once. This allows the design of highly specific oligonucleotides in multiplex applications, which is further assured by performing dimer checks not only on the primers themselves, but in an all-against all fashion. The software is freely accessible to all users at http://oli2go.ait.ac.at/. PMID- 29718467 TI - Erratum. PMID- 29718465 TI - Proteinase-3 and myeloperoxidase serotype in relation to demographic factors and geographic distribution in anti-neutrophil cytoplasmic antibody-associated glomerulonephritis. AB - Background: In anti-neutrophil cytoplasmic antibody (ANCA)-associated glomerulonephritis, antigen specificity varies between myeloperoxidase (MPO) and proteinase 3 (PR3). This has been reported to vary in relation to age, gender, geography and extrarenal manifestations. However, studies are difficult to compare as criteria for inclusion vary. The aim of this study was to investigate the relationship between ANCA serotype, latitude, ultraviolet (UV) radiation levels, age, gender and renal function at diagnosis in a large study with uniform inclusion criteria. Methods: Patients with biopsy-proven ANCA-associated glomerulonephritis were identified from regional or nationwide registries in 14 centres in Norway, Sweden, the UK, the Czech Republic, Croatia, Italy and the USA during the period 2000-13. UV radiation levels for 2000-13 in Europe were obtained from the Swedish Meteorological and Hydrological Institute. Results: A total of 1408 patients (45.2% PR3-ANCA) were included in the study. In univariable analysis, PR3-ANCA was significantly associated with male gender {odds ratio [OR] 2.12 [95% confidence interval (CI) 1.71-2.62]}, younger age [OR per year 0.97 (95% CI 0.96-0.98)] and higher glomerular filtration rate [OR per mL/min 1.01 (95% CI 1.01-1.02); P < 0.001] at diagnosis but not with latitude or UV radiation. In multivariable logistic regression analysis, latitude and UV radiation also became significant, with higher odds for PR3-ANCA positivity at northern latitudes/lower UV radiation levels. However, the latitudinal difference in MPO:PR3 ratio is smaller than differences previously reported concerning microscopic polyangiitis and granulomatosis with polyangiitis. Conclusions: The ratio between PR3-ANCA and MPO-ANCA varies in glomerulonephritis with respect to age, gender, renal function and geographic latitude/UV radiation levels. PMID- 29718466 TI - Genome-wide mapping of the RNA targets of the Pseudomonas aeruginosa riboregulatory protein RsmN. AB - Pseudomonads typically carry multiple non-identical alleles of the post transcriptional regulator rsmA. In Pseudomonas aeruginosa, RsmN is notable in that its structural rearrangement confers distinct and overlapping functions with RsmA. However, little is known about the specificities of RsmN for its target RNAs and overall impact on the biology of this pathogen. We purified and mapped 503 transcripts directly bound by RsmN in P. aeruginosa. About 200 of the mRNAs identified encode proteins of demonstrated function including some determining acute and chronic virulence traits. For example, RsmN reduces biofilm development both directly and indirectly via multiple pathways, involving control of Pel exopolysaccharide biosynthesis and c-di-GMP levels. The RsmN targets identified are also shared with RsmA, although deletion of rsmN generally results in less pronounced phenotypes than those observed for DeltarsmA or DeltarsmArsmNind mutants, probably as a consequence of different binding affinities. Targets newly identified for the Rsm system include the small non-coding RNA CrcZ involved in carbon catabolite repression, for which differential binding of RsmN and RsmA to specific CrcZ regions is demonstrated. The results presented here provide new insights into the intricacy of riboregulatory networks involving multiple but distinct RsmA homologues. PMID- 29718463 TI - Engineering altered protein-DNA recognition specificity. AB - Protein engineering is used to generate novel protein folds and assemblages, to impart new properties and functions onto existing proteins, and to enhance our understanding of principles that govern protein structure. While such approaches can be employed to reprogram protein-protein interactions, modifying protein-DNA interactions is more difficult. This may be related to the structural features of protein-DNA interfaces, which display more charged groups, directional hydrogen bonds, ordered solvent molecules and counterions than comparable protein interfaces. Nevertheless, progress has been made in the redesign of protein-DNA specificity, much of it driven by the development of engineered enzymes for genome modification. Here, we summarize the creation of novel DNA specificities for zinc finger proteins, meganucleases, TAL effectors, recombinases and restriction endonucleases. The ease of re-engineering each system is related both to the modularity of the protein and the extent to which the proteins have evolved to be capable of readily modifying their recognition specificities in response to natural selection. The development of engineered DNA binding proteins that display an ideal combination of activity, specificity, deliverability, and outcomes is not a fully solved problem, however each of the current platforms offers unique advantages, offset by behaviors and properties requiring further study and development. PMID- 29718468 TI - RNApdbee 2.0: multifunctional tool for RNA structure annotation. AB - In the field of RNA structural biology and bioinformatics, an access to correctly annotated RNA structure is of crucial importance, especially in the secondary and 3D structure predictions. RNApdbee webserver, introduced in 2014, primarily aimed to address the problem of RNA secondary structure extraction from the PDB files. Its new version, RNApdbee 2.0, is a highly advanced multifunctional tool for RNA structure annotation, revealing the relationship between RNA secondary and 3D structure given in the PDB or PDBx/mmCIF format. The upgraded version incorporates new algorithms for recognition and classification of high-ordered pseudoknots in large RNA structures. It allows analysis of isolated base pairs impact on RNA structure. It can visualize RNA secondary structures-including that of quadruplexes-with depiction of non-canonical interactions. It also annotates motifs to ease identification of stems, loops and single-stranded fragments in the input RNA structure. RNApdbee 2.0 is implemented as a publicly available webserver with an intuitive interface and can be freely accessed at http://rnapdbee.cs.put.poznan.pl/. PMID- 29718469 TI - Pre-dialysis fluid status, pre-dialysis systolic blood pressure and outcome in prevalent haemodialysis patients: results of an international cohort study on behalf of the MONDO initiative. AB - Background: Pre-dialysis fluid overload (FO) associates with mortality and causes elevated pre-dialysis systolic blood pressure (pre-SBP). However, low pre-SBP is associated with increased mortality in haemodialysis patients. The objective of this study was to investigate the interaction between pre-dialysis fluid status (FS) and pre-SBP in association with mortality. Methods: We included all patients from the international Monitoring Dialysis Outcome Initiative (MONDO) database with a pre-dialysis multifrequency bioimpedance spectroscopy measurement in the year 2011. We used all parameters available during a 90-day baseline period. All cause mortality was recorded during 1-year follow-up. Associations with outcome were assessed with Cox models and a smoothing spline Cox analysis. Results: We included 8883 patients. In patients with pre-dialysis FO (>+1.1 to +2.5 L), pre SBP <110 mmHg was associated with an increased risk of death {hazard ratio (HR) 1.52 [95% confidence interval (CI) 1.06-2.17]}. An increased risk of death was also associated with pre-dialysis fluid depletion (FD; <-1.1 L) combined with a pre-SBP <140 mmHg. In normovolemic (NV) patients, low pre-SBP <110 mmHg was associated with better survival [HR 0.46 (95% CI 0.23-0.91)]. Also, post-dialysis FD associated with a survival benefit. Results were similar when inflammation was present. Only high ultrafiltration rate could not explain the higher mortality rates observed. Conclusion: The relation between pre-SBP and outcome is dependent on pre-dialysis FS. Low pre-SBP appears to be disadvantageous in patients with FO or FD, but not in NV patients. Post-dialysis FD was found to associate with improved survival. Therefore, we suggest interpreting pre-SBP levels in the context of FS and not as an isolated marker. PMID- 29718470 TI - Evidence for policy and practice. PMID- 29718471 TI - Microarteriovenous Malformations-Value of Indocyanine Green Fluorescence and Nuances of Surgical Excision: 2-Dimensional Operative Video. AB - MicroAVMs (microarteriovenous malformation) are arteriovenous shunts with a nidus smaller than 1 centimeter.1 They are typically diagnosed after hemorrhage. When the nidus is very small, diagnosis can be challenging even on catheter angiography and careful examination of the arterial and capillary phases is required to identify the early shunt. Because of the very small size, identification and localization of the actual AV shunt can be problematic during surgical exploration. Advances in frameless stereotactic neuronavigation and the introduction of intraoperative indocyanine green (ICG) fluorescein provide useful adjuncts in the surgical treatment of these relatively uncommon lesions. In this video, we present 2 cases which document the value of intraoperative ICG fluorescein as well as some of the surgical pitfalls in the treatment of these lesions. PMID- 29718473 TI - Ovarian cancer incidence rates in the world from the Cancer Incidence in Five Continents XI. PMID- 29718472 TI - Sociodemographic and Clinical Correlates of Physical Therapy Utilization in Adults With Symptomatic Knee Osteoarthritis. AB - Background: Physical therapy is essential for conservative management of symptomatic knee osteoarthritis (OA). However, physical therapy utilization data are limited for knee OA. Objective: The purpose of this study is to identify correlates of physical therapy utilization among adults with symptomatic knee OA. Design: The design consisted of secondary analysis using baseline data from a randomized controlled trial of 350 adults with physician-diagnosed symptomatic knee OA. Methods: Patients completed baseline surveys regarding demographics, pain, function, medical history, and prior physical therapy utilization for symptomatic knee OA. Multivariable logistic regression identified correlates of physical therapy utilization, with models adjusted for body mass index and age. Interactions of race and sex with all other characteristics were evaluated. Results: One hundred and eighty-one patients (52%) reported prior physical therapy utilization. Factors independently associated with increased odds of physical therapy utilization were female sex (odds ratio [OR] = 3.06, 95% CI = 1.58-5.93), bachelor degree or higher degree (OR = 2.44, 95% CI = 1.15-5.16), prior knee injury (OR = 1.86, 95% CI = 1.08-3.19), and duration of knee OA symptoms (OR = 2.16, 95% CI = 1.09-4.29 for >5-10 years; OR = 2.11, 95% CI = 1.10 4.04 for >10 years). Whites who had received a joint injection were >3 times as likely to have utilized physical therapy (OR = 3.69, 95% CI = 1.94-7.01); this relationship did not exist for non-whites who had received joint injections. Limitations: A sample enrolled in an exercise study may limit generalizability. Self-report of physical therapy may misclassify utilization. It cannot be determined whether lack of utilization resulted from lack of referral or from patients choosing not to attend physical therapy. Conclusion: Physical therapy is underutilized to manage symptomatic knee OA. Women and those with a bachelor degree or higher degree, prior knee injury, and longer duration of knee OA symptoms were more likely to have used therapy previously. Differences by race in the link between joint injection and physical therapy utilization may reflect a reduced likelihood of referral and decreased use of health interventions for symptomatic knee OA among non-whites, or both. PMID- 29718474 TI - Aluminum effects on photosynthesis, reactive oxygen species and methylglyoxal detoxification in two Citrus species differing in aluminum tolerance. AB - Citrus are mainly grown in low pH soils with high active aluminum (Al). 'Xuegan' (Citrus sinensis (L.) Osbeck) and 'Shatian pummelo' (Citrus grandis (L.) Osbeck) seedlings were fertilized for 18 weeks with nutrient solution containing either 0 mM (control) or 1 mM (Al toxicity) AlCl3.6H2O. Aluminum induced decreases of biomass, leaf photosynthesis, relative water content and total soluble protein levels, and increases of methylglyoxal levels only occurred in C. grandis roots and leaves. Besides, the Al-induced decreases of pigments and alterations of chlorophyll a fluorescence transients and fluorescence parameters were greater in C. grandis leaves than those in C. sinensis leaves. Aluminum-treated C. grandis had higher stem and leaf Al levels and similar root Al levels relative to Al treated C. sinensis, but lower Al distribution in roots and Al uptake per plant. Aluminum toxicity decreased nitrogen, phosphorus, potassium, calcium, magnesium and sulfur uptake per plant in C. grandis and C. sinensis seedlings, with the exception of Al-treated C. sinensis seedlings exhibiting increased sulfur uptake per plant and unaltered magnesium uptake per plant. Under Al-stress, macroelement uptake per plant was higher in C. sinensis than that in C. grandis. Aluminum toxicity decreased the ratios of reduced glutathione/(reduced + oxidized glutathione) and of ascorbate/(ascorbate + dehydroascorbate) only in C. grandis roots and leaves. The activities of most antioxidant enzymes, sulfur metabolism related enzymes and glyoxalases and the levels of S-containing compounds were higher in Al-treated C. sinensis roots and leaves than those in Al-treated C. grandis ones. Thus, C. sinensis displayed higher Al tolerance than C. grandis did. The higher Al tolerance of C. sinensis might involve: (i) more Al accumulation in roots and less transport of Al from roots to shoots; (ii) efficient maintenance of nutrient homeostasis; and (iii) efficient maintenance of redox homeostasis via detoxification systems of reactive oxygen species and methylglyoxal. PMID- 29718475 TI - How to Think - Not Feel - about Tobacco Harm Reduction. AB - Introduction: The debate over tobacco harm reduction (THR) has divided the tobacco control community into two camps, one expressing serious reservations about THR while the other believes that reduced-risk products like e-cigarettes will disrupt the cigarette market. The often emotional debate would benefit from dispassionate data-based evaluation of evidence. Methods: After briefly discussing harm reduction in public health and specifically in tobacco control, this paper identifies major issues concerning e-cigarettes and reviews relevant evidence. Issues include: e-cigarettes' risks compared to cigarette smoking; the effect of vaping on youth smoking; vaping's impact on adult smoking cessation; the net long-term public health implications of vaping; and differences in views on policy issues. The intent is to provide a broad overview of issues and evidence, directing readers to more detailed reviews of specific issues. Findings: Principal findings include the following: (i) While longitudinal studies suggest that vaping increases never-smoking young people's odds of trying smoking, national survey data indicate that adolescents' 30-day smoking prevalence decreased at an unprecedented rate precisely while vaping increased. Use of all other tobacco products also declined. (ii) Recent population-level studies add evidence that vaping is increasing adult smoking cessation. (iii) Vaping is likely to make a positive contribution to public health. Conclusions: THR can be a complement to, not a substitute for, evidenced-based tobacco control interventions. Tobacco control professionals need to focus on objective assessment of and discussion about the potential costs and benefits of THR. Implications: Participants on both sides of the divisive THR debate need to examine the complicated issues and evidence more objectively. That entails considering both the potential benefits and costs associated with reduced-risk products like e-cigarettes. Further, it requires examining different kinds of evidence when considering specific issues. For example, those concerned by longitudinal study findings that vaping increases students' trial of cigarettes should consider US national survey evidence that youth smoking has decreased at an unprecedented rate. A review of the major issues suggests that the potential of vaping to assist adult smokers to quit outweighs the potential negatives. PMID- 29718476 TI - Erratum. PMID- 29718477 TI - Committing to Breastfeeding in Social Work. AB - This article addresses the importance of breastfeeding for the social work profession. Because breastfeeding is a critical component of maternal and child health, persistent racial and socioeconomic breastfeeding inequality is a social justice issue in need of social work commitment. Even while breastfeeding rates have been increasing in the United States there are some groups of mothers who initiate breastfeeding less frequently or have trouble with sustaining breastfeeding for recommended lengths. These mothers and their babies thus miss out on the ample benefits of this nurturing interaction. Using social work's unique disciplinary perspective and commitment to social justice, the authors place essential understanding of breastfeeding health benefits within the core values of the National Association of Social Work ethical code. The practice context for early breastfeeding intervention with mothers and families is discussed with acknowledgment of the maternal-child health focus at the root of the profession. Recognition of the potential of contemporary social work to advance breastfeeding equity through practice, scholarship, and action positions breastfeeding support activities as integral to meeting the grand challenges of the social work profession. PMID- 29718478 TI - Developmental Exposure to a Mixture of 23 Chemicals Associated With Unconventional Oil and Gas Operations Alters the Immune System of Mice. AB - Chemicals used in unconventional oil and gas (UOG) operations have the potential to cause adverse biological effects, but this has not been thoroughly evaluated. A notable knowledge gap is their impact on development and function of the immune system. Herein, we report an investigation of whether developmental exposure to a mixture of chemicals associated with UOG operations affects the development and function of the immune system. We used a previously characterized mixture of 23 chemicals associated with UOG, and which was demonstrated to affect reproductive and developmental endpoints in mice. C57Bl/6 mice were maintained throughout pregnancy and during lactation on water containing two concentrations of this 23 chemical mixture, and the immune system of male and female adult offspring was assessed. We comprehensively examined the cellularity of primary and secondary immune organs, and used three different disease models to probe potential immune effects: house dust mite-induced allergic airway disease, influenza A virus infection, and experimental autoimmune encephalomyelitis (EAE). In all three disease models, developmental exposure altered frequencies of certain T cell sub populations in female, but not male, offspring. Additionally, in the EAE model disease onset occurred earlier and was more severe in females. Our findings indicate that developmental exposure to this mixture had persistent immunological effects that differed by sex, and exacerbated responses in an experimental model of autoimmune encephalitis. These observations suggest that developmental exposure to complex mixtures of water contaminants, such as those derived from UOG operations, could contribute to immune dysregulation and disease later in life. PMID- 29718480 TI - Sleep duration in the United States: a letter to the editor commenting on the recent publication by M. Basner and D. Dinges. PMID- 29718479 TI - Complex repeat structure promotes hyper-amplification and amplicon evolution through rolling-circle replication. AB - Inverted repeats (IRs) are abundant in genomes and frequently serve as substrates for chromosomal aberrations, including gene amplification. In the early stage of amplification, repeated cycles of chromosome breakage and rearrangement, called breakage-fusion-bridge (BFB), generate a large inverted structure, which evolves into highly-amplified, complex end products. However, it remains to be determined how IRs mediate chromosome rearrangements and promote subsequent hyper amplification and amplicon evolutions. To dissect the complex processes, we constructed repetitive structures in a yeast chromosome and selected amplified cells using genetic markers with limited expression. The genomic architecture was associated with replication stress and produced extra-/intra-chromosomal amplification. Genetic analysis revealed structure-specific endonucleases, Mus81 and Rad27, and post-replication DNA repair protein, Rad18, suppress the amplification processes. Following BFB cycles, the intra-chromosomal products undergo intensive rearrangements, such as frequent inversions and deletions, indicative of rolling-circle replication. This study presents an integrated view linking BFB cycles to hyper-amplification driven by rolling-circle replication. PMID- 29718482 TI - Abridged Life Tables for Cephalonomia stephanoderis and Prorops nasuta (Hymenoptera: Bethylidae) Parasitoids of Hypothenemus hampei (Coleoptera: Curculionidae: Scolytinae) Reared on Artificial Diet. AB - Biological aspects and demographic parameters of Cephalonomia stephanoderis Betrem (Hymenoptera: Bethylidae) and Prorops nasuta Waterston (Hymenoptera: Bethylidae) parasitoids of the coffee berry borer (CBB), Hypothenemus hampei (Ferrari) (Coleoptera: Curculionidae: Scolytinae) were investigated using diet reared CBB hosts. Developmental time from eggs to adults, oviposition, and postoviposition period were comparable for both parasitoids. However, P. nasuta had a considerably longer preoviposition and longevity period averaging 17.3 and 63.1 d, respectively. The reproductive rate for C. stephanoderis was 46.1 daughters per female with a mean generation time of 47.4 d, whereas P. nasuta had a reproductive rate of 18.3 daughters per female in a mean time of 58.6 d. Oviposition behavior was also different with C. stephanoderis typically ovipositing on CBB prepupae and pupae, while P. nasuta preferred prepupae and second-instar CBB larvae. An abridged cohort life table for both parasitoids was constructed for growth rates estimations. PMID- 29718481 TI - The fractured landscape of RNA-seq alignment: the default in our STARs. AB - Many tools are available for RNA-seq alignment and expression quantification, with comparative value being hard to establish. Benchmarking assessments often highlight methods' good performance, but are focused on either model data or fail to explain variation in performance. This leaves us to ask, what is the most meaningful way to assess different alignment choices? And importantly, where is there room for progress? In this work, we explore the answers to these two questions by performing an exhaustive assessment of the STAR aligner. We assess STAR's performance across a range of alignment parameters using common metrics, and then on biologically focused tasks. We find technical metrics such as fraction mapping or expression profile correlation to be uninformative, capturing properties unlikely to have any role in biological discovery. Surprisingly, we find that changes in alignment parameters within a wide range have little impact on both technical and biological performance. Yet, when performance finally does break, it happens in difficult regions, such as X-Y paralogs and MHC genes. We believe improved reporting by developers will help establish where results are likely to be robust or fragile, providing a better baseline to establish where methodological progress can still occur. PMID- 29718484 TI - Corrigendum to: "A General Approach to Test for Interaction Among Mixtures of Insecticidal Proteins Which Target Different Orders of Insect Pests". PMID- 29718483 TI - The Complete Mitochondrial Genome of the Longhorn Beetle Dorysthenes paradoxus (Coleoptera: Cerambycidae: Prionini) and the Implication for the Phylogenetic Relationships of the Cerambycidae Species. AB - The longhorn beetle Dorysthenes paradoxus (Faldermann, 1833) (Coleoptera: Cerambycidae) is not only a serious agricultural pest but also a traditionally edible insect in China. However, no genetic information on this species has been acquired. In the present study, we report the mitochondrial genome (mitogenome) of Do. paradoxus, as the first complete mitogenome of Prioninae. The circular mitogenome of 15,922 bp encodes 13 protein-coding genes (PCGs), 22 transfer RNAs (tRNAs), and two ribosomal RNAs (rRNAs), and it contains an A+T-rich region. This mitogenome exhibits the lowest A+T content (71.13%) but harbors the largest AT skew (0.116) among the completely sequenced Cerambycidae species. Eleven of the 13 PCGs have a typical ATN start codon, whereas COI and ND1 are tentatively designated by AAT and TTG, respectively. Only 4 of the 13 PCGs harbor a complete termination codon, and the remaining 9 possess incomplete termination codons (T or TA). Apart from tRNASer(AGN), the other 21 tRNAs can fold into a typical clover-leaf secondary structures. The Do. paradoxus A+T-rich region contains two poly-T stretches and a tandem repeat that comprises two 47-bp-long copies. Both Bayesian inference and Maximum likelihood analyses confirmed the subfamily ranks of Cerambycidae ([Prioninae + Cerambycinae] + Lamiinae) and the close relationship between Philinae and Prioninae/Cerambycinae. However, the data did not support the monophyly of Prioninae and Cerambycinae. The mitogenome presented here provides basic genetic information for this economically important species. PMID- 29718485 TI - Molecular Characterization and Expression of Vitellogenin and Vitellogenin Receptor of Thitarodes pui (Lepidoptera: Hepialidae), an Insect on the Tibetan Plateau. AB - Vitellogenin (Vg) and vitellogenin receptor (VgR) play important roles in the vitellogenesis of insects. In this study, we cloned and characterized the two corresponding genes (TpVg and TpVgR) in an economically important insect, Thitarodes pui (Lepidoptera: Hepialidae), from the Tibetan plateau. The full length of TpVg is 5566 bp with a 5373 bp open reading frame (ORF) encoding 1,790 amino acids. Sequence alignment revealed that TpVg has three conserved domains: a Vitellogenin_N domain, a DUF1943 domain, and a von Willebrand factor type D domain (VWD). The full length of TpVgR is 5732 bp, with a 5397 bp ORF encoding 1798 amino acids. BLASTP showed that TpVgR belongs to the low-density lipoprotein receptor (LDLR) gene superfamily. Structural analysis revealed that TpVgR has a group of four structural domains: a ligand-binding domain (LBD), an epidermal growth factor (EGF)-precursor homology domain, a transmembrane (TM) domain, and a cytoplasmic domain. In addition, TpVgR has four cysteine-rich LDL repeats in the first ligand-binding site and seven in the second. Quantitative real-time polymerase chain reaction analysis revealed that the expression levels of TpVg and TpVgR are much higher in later pupa than in either the larval or adult stage, implying that the synthesis and uptake of Vg in T. pui occurs in the later pupal stage. These results will help us to understand the molecular mechanism of the reproductive capacity and will provide new insight into the mass rearing and utilization of T. pui. PMID- 29718486 TI - Identification and Characterization of C-type Lectins in Ostrinia furnacalis (Lepidoptera: Pyralidae). AB - C-type lectins (CTLs) are a large family of calcium-dependent carbohydrate binding proteins. They function primarily in cell adhesion and immunity by recognizing various glycoconjugates. We identified 14 transcripts encoding proteins with one or two CTL domains from the transcriptome from Asian corn borer, Ostrinia furnacalis (Guenee; Lepidoptera: Pyralidae). Among them, five (OfCTL-S1 through S5) only contain one CTL domain, the remaining nine (OfIML-1 through 9) have two tandem CTL domains. Five CTL-Ss and six OfIMLs have a signal peptide are likely extracellular while another two OfIMLs might be cytoplasmic. Phylogenetic analysis indicated that OfCTL-Ss had 1:1 orthologs in Lepidoptera, Diptera, Coleoptera and Hymenoptera species, but OfIMLs only clustered with immulectins (IMLs) from Lepidopteran. Structural modeling revealed that the 22 CTL domains adopt a similar double-loop fold consisting of beta-sheets and alpha helices. The key residues for calcium-dependent or independent binding of specific carbohydrates by CTL domains were predicted with homology modeling. Expression profiles assay showed distinct expression pattern of 14 CTLs: the expression and induction were related to the developmental stages and infected microorganisms. Overall, our work including the gene identification, sequence alignment, phylogenetic analysis, structural modeling, and expression profile assay would provide a valuable basis for the further functional studies of O. furnacalis CTLs. PMID- 29718487 TI - Influence of Supplemental Protein on the Life Expectancy and Reproduction of the Chinese Citrus Fruit Fly, Bactrocera minax (Enderlein) (Tetradacus minax) (Diptera: Tephritidae). AB - Bactrocera minax (Enderlein) (Diptera: Tephritidae) is a major citrus pest in China, whose artificial rearing technology of the adult is not well documented to date. In this study, we tried to determine if supplementing proteins to the adult diet could result in the enhancement of some fitness parameters of B. minax. Four feeds with varying protein source were provided as F0 (water), F1 (sucrose), F2 (sucrose + yeast), and F3 (sucrose + peptone). F0 and F1 being the control, F2 and F3 were protein food types. The results showed that adults fed by F2 and F3 lived longer with 40.1 d and 32.8 d, respectively, had reduced death rates (death peaks were delayed for 5.6 d and 4.1 d, respectively), increased mating frequencies (8.1 and 5.3 per females, 4.7 and 7.3 per males, respectively), and longer mating durations (with 42 d and 34 d). In addition, females recorded an increased adult ovary development, more egg load (with 94.8 and 77.3 brood eggs per ovary) and to greater oviposition rates of 63.2 eggs/female and 19.3 eggs/female. Based on our results, protein supplements enhanced B. minax survival, mating, and fecundity. This study does not only provide basic knowledge to implement artificial rearing of B. minax, but also deepens our understanding on its physiology that could be used to enhance the management of the pest. PMID- 29718489 TI - Taxonomy of Aulacochilus (Coleoptera: Erotylidae: Erotylinae) From China, with a Key Based on Adult Characters. AB - The history of taxonomy of Aulacochilus from China was reviewed. A key based on adult characters to separate the Chinese species of this genus is presented. A map of the collecting sites in China is given. One new species, Aulacochilus xingtaiensis sp. nov., from China is described and illustrated. PMID- 29718488 TI - The Complete Mitochondrial Genome of Coptotermes 'suzhouensis' (syn. Coptotermes formosanus) (Isoptera: Rhinotermitidae) and Molecular Phylogeny Analysis. AB - Coptotermes suzhouensis (Isoptera: Rhinotermitidae) is a significant subterranean termite pest of wooden structures and is widely distributed in southeastern China. The complete mitochondrial DNA sequence of C. suzhouensis was analyzed in this study. The mitogenome was a circular molecule of 15,764 bp in length, which contained 13 protein-coding genes (PCGs), 22 transfer RNA genes, two ribosomal RNA genes, and an A+T-rich region with a gene arrangement typical of Isoptera mitogenomes. All PCGs were initiated by ATN codons and terminated by complete termination codons (TAA), except COX2, ND5, and Cytb, which ended with an incomplete termination codon T. All tRNAs displayed a typical clover-leaf structure, except for tRNASer(AGN), which did not contain the stem-loop structure in the DHU arm. The A+T content (69.23%) of the A+T-rich region (949 bp) was higher than that of the entire mitogenome (65.60%), and two different sets of repeat units (A+B) were distributed in this region. Comparison of complete mitogenome sequences with those of Coptotermes formosanus indicated that the two taxa have very high genetic similarity. Forty-one representative termite species were used to construct phylogenetic trees by maximum likelihood, maximum parsimony, and Bayesian inference methods. The phylogenetic analyses also strongly supported (BPP, MLBP, and MPBP = 100%) that all C. suzhouensis and C. formosanus samples gathered into one clade with genetic distances between 0.000 and 0.002. This study provides molecular evidence for a more robust phylogenetic position of C. suzhouensis and inferrs that C. suzhouensis was the synonymy of C. formosanus. PMID- 29718490 TI - Patterns of Tarnished Plant Bug (Hemiptera: Miridae) Resistance to Pyrethroid Insecticides in the Lower Mississippi Delta for 2008-2015: Linkage to Pyrethroid Use and Cotton Insect Management. AB - Populations of tarnished plant bug, Lygus lineolaris (Palisot de Beauvois) (Hemiptera: Miridae), from the Lower Mississippi Delta regions of Arkansas, Louisiana, and Mississippi were evaluated from 2008 through 2015 for susceptibility to pyrethroid insecticides using a diagnostic-dose assay with permethrin. Resulting data add to the compilation of pyrethroid susceptibility data carefully tracked in this pest since 1994 and provide continuing evidence of high frequencies of pyrethroid resistance in field populations of the tarnished plant bug. Resistance levels are variable, and some populations remain susceptible suggesting practical value in the continued use of the diagnostic dose assays prior to pyrethroid treatments. Recent studies with dose-response models suggest that levels of pyrethroid resistance in some populations may still be evolving, with some populations requiring higher doses to reach levels of control comparable to those observed 10 yr ago. Concerns for frequent use of multiple classes of insecticides and possible selection for tarnished plant bugs with metabolic resistance mechanisms capable of detoxifying available insecticide chemistries warrant continued efforts to manage resistance in this important crop pest. Associations among measured pyrethroid resistance levels, published data on annual use of pyrethroid insecticides, and annual estimates of cotton insect losses and control costs were explored and summarized for the 8 yr of this investigation. Mortality of tarnished plant bugs at the diagnostic-dose of permethrin was negatively correlated with kilograms of pyrethroids applied per acre of harvested cropland. PMID- 29718491 TI - De novo Synthesis of Chemical Defenses in an Aposematic Moth. AB - Many animals protect themselves from predation with chemicals, both self-made or sequestered from their diet. The potential drivers of the diversity of these chemicals have been long studied, but our knowledge of these chemicals and their acquisition mode is heavily based on specialist herbivores that sequester their defenses. The wood tiger moth (Arctia plantaginis, Linnaeus, 1758) is a well studied aposematic species, but the nature of its chemical defenses has not been fully described . Here, we report the presence of two methoxypyrazines, 2-sec butyl-3-methoxypyrazine and 2-isobutyl-3-methoxypyrazine, in the moths' defensive secretions. By raising larvae on an artificial diet, we confirm, for the first time, that their defensive compounds are produced de novo rather than sequestered from their diet. Pyrazines are known for their defensive function in invertebrates due to their distinctive odor, inducing aversion and facilitating predator learning. While their synthesis has been suspected, it has never previously been experimentally confirmed. Our results highlight the importance of considering de novo synthesis, in addition to sequestration, when studying the defensive capabilities of insects and other invertebrates. PMID- 29718492 TI - Ovipositional Preferences of Two Squash Bug Species, Anasa tristis and Anasa armigera (Heteroptera: Coreidae), for Different Cultivars and Species of Cucurbitaceae. AB - The ovipositional preferences of two squash bug species, Anasa tristis (DeGeer) (Heteroptera: Coreidae) and Anasa armigera Say (Heteroptera: Coreidae), were evaluated in paired choice tests of different species and cultivars of plants in the family Cucurbitaceae. Females of A. tristis preferred to oviposit on the cultivar from which they were reared over three other cultivars of the same species. However, females did not show any ovipositional preference for different cultivars when they had no previous exposure to either cultivar. Females of A. tristis were equally likely to oviposit on Cucurbita pepo, Cucurbita maxima, and Cucurbita moschata but were significantly more likely to oviposit on C. pepo than on cucumber and watermelon. Females of A. armigera were equally likely to oviposit on C. pepo or cucumber, regardless of the species they were reared on. When A. armigera was reared on C. pepo, females were more likely to oviposit on C. maxima than on cucumber and less likely to oviposit on C. moschata than on cucumber. PMID- 29718494 TI - Mature Larval Dispersal and Adult Emergence of the Economically Significant Pest, Scirtothrips aurantii Faure (Thysanoptera: Thripidae), in Commercial Citrus. AB - Scirtothrips aurantii Faure (Thysanoptera: Thripidae) is a major pest of citrus fruit in subtropical southern Africa. Population monitoring is an important aspect of S. aurantii control, but additional information is required on its phenology. Dispersal of mature larvae onto the soil surface from the tree canopy, and emergence of adults, were assessed using dispersal/emergence (D/E) traps in an untreated citrus orchard in South Africa. Overall, 90.7% of adult Thysanoptera emerging from soil / leaf litter beneath the citrus trees were S. aurantii, of which 35.7% were males, and 64.3% were females. Female S. aurantii having survived winter as adults oviposited on the early spring flush. This resulted in the first population peak of larvae dropping to the ground to pupate and adults emerging in spring, September to early October, as the first vegetative flush of the citrus-growing season hardened, and fruit was set as blossoming ended. Initial infestation of young fruit occurred after a build-up of larval numbers on the soft citrus flush late July to early August. The second generation larval and adult peak occurred late November to early December, whether there was new flush or not, as young fruit could support the S. aurantii population. A third peak occurred mid-December to late January, depending on year. Thus, there were three generations of S. aurantii during the period of citrus fruit susceptibility to thrips damage (September-January). After the autumn flush in April, another peak of larvae and adults occurred before the population declined to a minimum from May to July. PMID- 29718493 TI - Comparison of Life Table Parameters and Digestive Physiology of Rhyzopertha dominica (Coleoptera: Bostrichidae) Fed on Various Barley Cultivars. AB - In this study, the effect of 20 barley cultivars were evaluated on the life table parameters and digestive enzymatic activity of the lesser grain borer, Rhyzopertha dominica (F.) (Coleoptera: Bostrichidae) under laboratory conditions (28 +/- 1 degrees C, 60 +/- 5% RH, and a photoperiod of 16:8 (L:D) h). Among barley cultivars tested developmental time of R. dominica immature stages was longest on cultivar Bahman (61.00) and shortest on Mahoor (46.60 d). The lowest realized fecundities were recorded for insects reared on cultivar Bahman (217.60); and the highest ones were observed for insects reared on Sahra (348.05 eggs/female). The net reproductive rate (R0) was significantly affected by various barley cultivars being lowest on cultivar Bahman (53.98) and highest on Mahoor (146.79 offspring/female). Records for intrinsic rates of increase (rm) were lowest on cultivar Dasht (0.043) and the highest on Mahoor (0.066 day-1). The highest levels of amylolytic and proteolytic activity were recorded on cultivars Mahoor and EBYT-92-10, respectively. By contrast, the insects reared on cultivars Dasht had the lowest levels of alpha-amylase and general protease activity. Correlation analyses showed that high correlations existed between the immature period, adult longevity, fecundity, and life table parameters on one side and protein content and particle size index on the other. The results of our experiments showed that cultivar Mahoor was a relatively susceptible and cultivars Bahman and Dasht were relatively resistant to R. dominica which could be useful in the development of IPM programs for this pest in store. PMID- 29718495 TI - Rapid Divergence of Wing Volatile Profiles Between Subspecies of the Butterfly Pieris rapae (Lepidoptera: Pieridae). AB - Complex signaling traits such as pheromone profiles can play an important role in the early stages of reproductive isolation between populations. These signals can diverge along multiple trait axes, and signal receivers are often sensitive to subtle differences in signal properties. In the Lepidoptera, prior research has highlighted that natural selection can drive rapid chemical signal divergence, for instance via mate recognition to maintain species boundaries. Much less is known about the occurrence of such changes for predominantly sexually selected chemical signals, such as those released by many male lepidopterans. We evaluated the divergence in male and female wing volatile profiles between two recently isolated subspecies of the pierid butterfly Pieris rapae Linnaeus (Lepidoptera: Pieridae): P. rapae rapae and P. rapae crucivora. In laboratory settings, these subspecies exhibit strong premating isolation, with females rejecting males of the opposite subspecies despite the fact that males direct equivalent courtship effort toward females of either subspecies. Using gas chromatography-mass spectrometry, we analyzed the volatile chemical profiles of individual males and females of each subspecies. We find that males of each subspecies differ in their wing volatile profiles, including quantitative differences in a male sex pheromone, ferrulactone. In contrast, female wing volatiles profiles have diverged significantly less. These sex-specific patterns suggest that male chemical profiles may play a role in the observed premating isolation between these two subspecies, providing support for future investigations of sexually selected chemical traits in population divergence. PMID- 29718496 TI - Clear Resin Casting of Arthropods of Medical Importance for Use in Educational and Outreach Activities. AB - Arthropod-related morbidity and mortality represent a major threat to human and animal health. An important component of reducing vector-borne diseases and injuries is training the next generation of medical entomologists and educating the public in proper identification of arthropods of medical importance. One challenge of student training and public outreach is achieving a safe mounting technique that allows observation of morphological characteristics, while minimizing damage to specimens that are often difficult to replace. Although resin-embedded specimens are available from commercial retailers, there is a need for a published protocol that allows entomologists to economically create high quality resin-embedded arthropods for use in teaching and outreach activities. We developed a detailed protocol using readily obtained equipment and supplies for creating resin-embedded arthropods of many species for use in teaching and outreach activities. PMID- 29718497 TI - Best Host Age of Anastrepha obliqua (Diptera: Tephritidae) for Multiplication of Four Native Parasitoids from the Americas. AB - The success of the mass rearing of parasitoids is directly related to host quality, and it requires selecting the best biological host age to ensure the optimal performance of the parasitoids released into the field. The larval development of the parasitoids Utetes anastrephae (Viereck) (Hymenoptera: Braconidae) and Odontosema anastrephae Borgmeier (Hymenoptera: Eucoilidae) and the pupal development of the parasitoids Coptera haywardi (Ogloblin) (Hymenoptera: Diapriidae) and Dirhinus sp. (Hymenoptera: Chalcididae) on the native host Anastrepha obliqua (Macquart) (Diptera: Tephritidae) in different larvae and pupae ages were investigated under laboratory conditions. Not all parasitoid species developed with the same efficiency in immature individuals of A. obliqua; U. anastrephae and C. haywardi showed the higher parasitism rates. The emergence and parasitism of U. anastrephae were equal using larvae from 5 to 8 d, while C. haywardi reared in 1- to 8-d-old pupae showed higher averages of parasitism. These results suggest that native parasitoids can be used to strengthen the implementation of biological control projects against A. obliqua, a pest of economic importance in South America. PMID- 29718498 TI - A Laboratory Study on the Modeling of Temperature-Dependent Development and Antioxidant System of Chilo suppressalis (Lepidoptera: Crambidae). AB - The developmental rates of Chilo suppressalis (Walker; Lepidoptera: Crambidae) were investigated at different constant temperatures of 11, 18, 22, 24, 26, 30, 32, 34, and 36 degrees C to find out temperature thresholds, thermal requirements and larval antioxidant responses. The time to complete immature stages separately reduced by raising the rearing temperature except for eggs which showed no significant differences at 30-34 degrees C. Data analysis by traditional and Ikemoto-Takai linear models determined Tmin of 10.0 and 9.92 degrees C as well as thermal constants of 840.34 and 848.0 DD for the overall immature stages. The models including Analytis, Briere-2, Lactin-2, and Sharpe-Schoolfield-Ikemoto (SSI) calculated Tmin values of 9.15, 9.57, 10.0, and 11.37 degrees C for overall immature stages while Tfast was found to be 33.8, 33.3, 33.7, and 33.0 degrees C, respectively. Tmax was calculated as 35.12, 34.66, 34.56, 36.84, 34.11, and 35.15 degrees C for Analytis, Briere-2, Lactin-2, SSI, Logan-6, and Logan-10. Topt using SSI was calculated as 24.42 degrees C for total developmental time. The larvae exposure to 34 degrees C in the short-term period demonstrated the highest activities of catalase, peroxidase, and superoxide dismutase compared to control (24 degrees C). Activities of ascorbate peroxidase and glucose-6-phosphate hydrogenase also increased at 34 degrees C in the short-term period for all preparations. The larvae exposed to 34 degrees C in short-term period showed the highest amounts of Malondialdehyde and oxidized and reduced thiols (RSSR/RSH) ratio compared to control. These results may be useful to explain potentially ecological performance of C. suppressalis as the major pest of rice in Iran. PMID- 29718499 TI - Lethal and Sublethal Effects of Clothianidin on the Development and Reproduction of Bemisia tabaci (Hemiptera: Aleyrodidae) MED and MEAM1. AB - The Bemisia tabaci (Gennadius) cryptic species complex includes important crop pests, and among them, the cryptic species Mediterranean (MED) and Middle East Asia Minor 1 (MEAM1) cause substantial crop losses in China. The second generation neonicotinoid clothianidin acts as an agonist of the nicotinic acetylcholine receptor in the insect nervous system and has both stomach and contact activity. In this study, the toxicity of clothianidin and five other insecticides to MED and MEAM1 was examined. The sublethal effects of clothianidin on the development and reproduction of MED and MEAM1 were also investigated. Among the six insecticides tested, clothianidin showed toxicities to both MED and MEAM1 adults with LC50 values of 5.23 and 5.18 mg/liter, respectively. The sublethal effects of clothianidin were assessed by treating MED and MEAM1 adults with the LC25 of 1.58 and 1.13 mg/liter, respectively. The LC25 treatments accelerated the development of the F1 generation but reduced survival and fecundity of both species. Our results indicate that clothianidin could be useful for the management of B. tabaci MED and MEAM1. PMID- 29718500 TI - Larval Age and Nutrition Affect the Susceptibility of Culex quinquefasciatus (Diptera: Culicidae) to Temephos. AB - Larval age and nutrition significantly affected the insect's physiology. These influences are important when rearing a population of vectors that is used to monitor the resistance level, in which standardized conditions are crucial for a more harmonized result. Little information has been reported on the effects of larval age and nutrition on the susceptibility of insects to insecticides, and therefore, we studied the effects on the susceptibility of Culex quinquefasciatus Say's (Diptera: Culicidae) larvae to temephos by comparing the median lethal concentration (LC50) after 24 hr between the second and fourth instar larvae and between the larvae that fed on protein-based and carbohydrate-based larval diets. The susceptibility of the larvae was significantly affected by the larval diets, as the larvae that fed on protein-based beef food and milk food demonstrated significantly higher LC50 value compared with the larvae that fed on carbohydrate based food: lab food and yeast food. The larval diet interacted significantly with the larval age: while the second instar larvae were susceptible to temephos when supplied with carbohydrate-based food, the second and fourth instar larvae had no significant effect when supplied with protein-based diets, implying that a protein-rich environment may cause the mosquito to be less susceptible to temephos. This study suggested the importance of standardizing nutrition when rearing a vector population in order to obtain more harmonized dosage-response results in an insecticide resistance monitoring program. Future research could focus on the biochemical mechanism between the nutrition and the enzymatic activities of the vector. PMID- 29718501 TI - Morphological and Genetic Analysis of Four Color Morphs of Bean Leaf Beetle. AB - Bean leaf beetle (BLB), Cerotoma trifurcata (Forster; Coleoptera: Chrysomelidae), exhibits considerable color variation but little is known about the underlying genetic structure and gene flow among color phenotypes. Genetic and morphological variation among four color phenotypes-green with spots (G+S), green without spots (G-S), red with spots (R+S) and red without spots (R-S)-were analyzed using amplified fragment length polymorphisms (AFLP) and morphometrics, respectively. AFLP generated 175 markers that showed >=80% polymorphism. Analysis of molecular variance (AMOVA) indicated that genetic variation was greatest within phenotypes (82.6-84.0%); gene flow among the four phenotypes was relatively high (Nm = 3.82). The dendrogram and STRUCTURE analysis indicated some population divergence of G-S from the other phenotypes. Morphological parameters were similar among phenotypes except that R+S showed significant differences in weight and body length. Canonical variables 1 and 2, based on average morphometric characters, accounted for 98% of the total variation; some divergence was indicated between G+S and R+S from each other and from the G-S/R-S BLB color morphs. The pattern of genetic variation indicated potential divergence of G-S and G+S from each other and from R-S and R+S. Although these results indicate that the four different color morphs are not genetically or reproductively isolated, there is some genetic differentiation/structure and morphological dissimilarity suggesting weak/incomplete isolation. PMID- 29718502 TI - Use of Body-Mounted Cameras to Enhance Data Collection: An Evaluation of Two Arthropod Sampling Techniques. AB - A study was conducted that compared the effectiveness of a sweepnet versus a vacuum suction device for collecting arthropods in cotton. The study differs from previous research in that body-mounted action cameras (B-MACs) were used to record the activity of the person conducting the arthropod collections. The videos produced by the B-MACs were then analyzed with behavioral event recording software to quantify various aspects of the sampling process. The sampler's speed and the number of sampling sweeps or vacuum suctions taken over a fixed distance (12.2 m) of cotton were two of the more significant sampling characteristics quantified for each method. The arthropod counts obtained, combined with the analyses of the videos, enabled us to estimate arthropod sampling efficiency for each technique based on fixed distance, time, and sample unit measurements. Data revealed that the vacuuming was the most precise method for collecting arthropods in the relatively small cotton research plots. However, data also indicates that the sweepnet method would be more efficient for collecting most of the cotton dwelling arthropod taxa, especially if the sampler could continuously sweep for at least 1 min or >=80 m (e.g., in larger research plots). The B-MACs are inexpensive and non-cumbersome, the video images generated are outstanding, and they can be archived to provide permanent documentation of a research project. The methods described here could be useful for other types of field-based research to enhance data collection efficiency. PMID- 29718503 TI - The Complete Mitochondrial Genome of the Plant Bug Lygus pratensis Linnaeus (Hemiptera: Miridae). AB - Lygus pratensis is a phytophagous pest responsible for yield losses in Bt alfalfa and other economic crops in Northwestern China. To better characterize Miridae at the genomic level, the complete mitochondrial (mt) genome of L. pratensis was sequenced and analyzed in this study. The mt genome was amplified via the polymerase chain reaction to generate overlapping fragments. These fragments were then sequenced, spliced, and analyzed to include the examination of nucleotide composition, codon usage, compositional biases, protein-coding genes (PCGs), and RNA secondary structures. Phylogenetic relationships between L. pratensis and other species in different Heteroptera families were also examined. The mt genome was found to be a typical circular genome with a length of 16,591 bp and a total AT content of 75.1%, encoded for 13 PCGs, 22 transfer RNAs (tRNAs), 2 ribosomal RNAs (lrRNA and srRNA), and a noncoding control region. The nucleotide composition of the entire mt genome was heavily biased toward A and T. All of the tRNAs were predicted to have classic clover leaf structures, but three of the tRNAs (tRNAAsn, tRNAHis, tRNAHis) were missing the TPsiC loop. The control region (2,017 bp), which was found to be located between 12S and tRNAIle, contained three tandem repeat elements. Phylogenetic analyses showed that L. pratensis is closely related to the other three examined Lygus bugs, and that it is a sister group to Apolygus and Adelphocoris. This study confirms the usability of the mt genome in phylogenesis studies pertaining to the Lygus genus, within Miridae. PMID- 29718504 TI - Proteomic-Based Approach to the Proteins Involved in 1-Deoxynojirimycin Accumulation in Silkworm Bombyx mori (Lepidoptera: Bombycidae). AB - 1-Deoxynojirimycin (DNJ) is the most abundant poly-hydroxylated alkaloid in the latex of mulberry leaves and it protects mulberry from insect predation. However, silkworms can survive the poisoning effect of DNJ and accumulate DNJ by consumption of the mulberry leaves. In order to determine the molecular mechanism of DNJ accumulation in silkworm, comparative proteomic analysis was employed to evaluate protein expression in two groups of silkworm bodies (the third instar silkworm bodies had the maximum content of DNJ throughout life, and the newly hatched silkworm bodies had no DNJ). Our results indicated some differentially expressed proteins in the third instar silkworm involved in material metabolism, energy metabolism, oxidation-reduction, detoxification, immune, and transport regulation may correspond to the accumulation of DNJ. Furthermore, the expression levels of five selected differentially expressed protein-encoding genes namely heat shock cognate protein (Hsp 70), glutathione S-transferase sigma 1 (GST), serine protease precursor (Ser), hemolymph protein (30K), and thiol peroxiredoxin (TPx) were investigated by quantitative real-time PCR and the accumulation of DNJ was measured by HPLC. Correlation analysis showed that the expression levels of Hsp70 and Ser were negatively correlated to DNJ accumulation with weak correlation, while 30K, GST, and TPx genes had positive correlation with DNJ accumulation. The findings suggested that these three proteins were probably important in the physiological process of DNJ accumulation in silkworm. PMID- 29718505 TI - Ovicidal and Larvicidal Effects of Garlic and Asafoetida Essential Oils Against West Nile Virus Vectors. AB - We examined the chemical composition of garlic and asafoetida essential oils and their individual and combined toxicity against larvae of Culex pipiens Linnaeus and Culex restuans Theobald (Diptera: Culicidae). The effect of the two essential oils on egg hatch was also examined. Ten and 12 compounds, respectively, were identified in garlic and asafoetida essential oils. Allyl disulfide (49.13%) and diallyl trisulfide (31.08%) were the most abundant compounds in garlic essential oil accounting for 80.2% of the total oil. In contrast, (E)-sec-butyl propenyl disulfide (30.03%), (Z)-sec-butyl propenyl disulfide (24.32%), and disulfide, methyl 1-(methylthio)propyl (21.87%) were the most abundant compounds in asafoetida essential oil. Allyl disulfide accounted for 7.38% of the total oil in asafoetida essential oil and was one of only three compounds found in both oils. For both mosquito species, garlic essential oil was more toxic than asafoetida essential oil with Cx. restuans (LC50: garlic = 2.7 ppm; asafoetida = 10.1 ppm) being more sensitive than Cx. pipiens (LC50: garlic = 7.5 ppm; asafoetida = 13.5 ppm). When combined, the two essential oils had antagonistic effects. The majority of Culex egg rafts exposed to garlic (73.1%) or asafoetida (55.8%) essential oils failed to hatch and larvae of the few that did hatch mostly died as first instars. Allyl disulfide exhibited strong ovicidal and larvicidal activity suggesting its important contribution to the overall toxicity of the two essential oils. Thus, garlic and asafoetida essential oils are potent mosquito ovicides and larvicides but if used jointly, they could undermine vector control programs. PMID- 29718506 TI - Complete Mitochondrial Genome of Dinorhynchus dybowskyi (Hemiptera: Pentatomidae: Asopinae) and Phylogenetic Analysis of Pentatomomorpha Species. AB - Dinorhynchus dybowskyi (Hemiptera: Pentatomidae: Asopinae) is used as a biological control agent against various insect pests for its predatory. In the present study, the complete mitochondrial genome (mitogenome) of the species was sequenced using the next-generation sequencing technology. The results showed that the mitogenome is 15,952 bp long, including 13 protein-coding genes (PCGs), 22 transfer RNAs (tRNAs), two ribosomal RNAs (rRNAs), and a control region. Furthermore, the gene order and orientation of this mitogenome are identical to those of most heteropterans. There are 21 intergenic spacers (of length 1-28 bp) and 13 overlapping regions (of length 1-23 bp) throughout the genome. The control region is 1,291 bp long. The start codon of the PCGs is ATN, except cox1 (TTG), and stop codon is TAA, except nad1 (TAG). The 22 tRNAs exhibit a typical cloverleaf secondary structure, except trnS1, which lacks a dihydrouridine (DHU) arm and trnV, where the DHU arm forms a simple loop. The analyses based on nucleotide sequences of the 13 PCGs by Bayesian Inference and maximum likelihood methods. The results support the monophyly of five superfamilies Aradoidea, Pentatomoidea, Pyrrhocoroidea, Lygaeoidea, and Coreoidea. Within Pentatomoidea, the relationship observed is as follows: (Plataspidae + Urostylididae) + (Pentatomidae + (Acanthosomatidae + (Cydnidae + (Scutelleridae + (Dinidoridae + Tessaratomidae))))), and D. dybowskyi was placed in Pentatomidae and close to Eurydema gebleri. PMID- 29718507 TI - Hemocyte Morphology and Cellular Immune Response in Termite (Reticulitermes speratus). AB - Because termites (Reticulitermes speratus) are very small, it is difficult to conduct experiments involving pathogen injection and hemocyte collection. Therefore, to observe hemocyte-mediated immune responses against foreign substances, in vitro hemocyte culture is essential. After collecting about 3 MUl of hemolymph, hemocytes were cultured for 7 d, during which the cells maintained full function. Four types of hemocyte were identified, namely, granulocytes, plasmatocytes, oenocytoids, and prohemocytes, among which granulocytes are the main immune hemocytes that fight invasion by foreign substances. Most hemocytes were alive and/or functioning after 7 d of culture, but then either died or lost function. PMID- 29718508 TI - Expression Characterization and Localization of the foraging Gene in the Chinese Bee, Apis cerana cerana (Hymenoptera: Apidae). AB - In social insects, the foraging gene (for) regulates insect age- and task-based foraging behaviors. We studied the expression and localization of the for gene (Acfor) in Apis cerana cerana workers to explore whether the differential regulation of this gene is associated with the behaviors of nurses and foragers. The expression profiles of Acfor in different tissues and at different ages were examined using real-time quantitative reverse transcription polymerase chain reaction. Cellular localization in the brain was detected using in situ hybridization. Acfor transcripts in different ages workers showed that Acfor expression was detected in all the heads of 1- to 30-d-old worker bees. Acfor expression reached a peak at 25 d of age, and then declined with increasing age. The results showed that Acfor gene expression in five tissues was respectively significantly higher in foragers than in nurses. In nurses, the relative expression of Acfor was the highest in the antennae. There was a highly significant difference in expression between antennae, legs, and the other three tissues. In foragers, Acfor expression was the highest in the thorax, which was significantly different from all other tissues. In situ hybridization showed that Acfor was highly expressed in the lamina of the optic lobes, in a central column of Kenyon cells in the mushroom bodies of the brain of workers, and in the antennal lobes. This suggested that Acfor expression affects age-related foraging behavior in Apis cerana cerana, and that it may be related to flight activity. PMID- 29718509 TI - Evolution of Darwin's Peloric Gloxinia (Sinningia speciosa) Is Caused by a Null Mutation in a Pleiotropic TCP Gene. AB - Unlike most crops, which were domesticated through long periods of selection by ancient humans, horticultural plants were primarily domesticated through intentional selection over short time periods. The molecular mechanisms underlying the origin and spread of novel traits in the domestication process have remained largely unexplored in horticultural plants. Gloxinia (Sinningia speciosa), whose attractive peloric flowers influenced the thoughts of Darwin, have been cultivated since the early 19th century, but its origin and genetic basis are currently unknown. By employing multiple experimental approaches including genetic analysis, genotype-phenotype associations, gene expression analysis, and functional interrogations, we showed that a single gene encoding a TCP protein, SsCYC, controls both floral orientation and zygomorphy in gloxinia. We revealed that a causal mutation responsible for the development of peloric gloxinia lies in a 10-bp deletion in the coding sequence of SsCYC. By combining genetic inference and literature searches, we have traced the putative ancestor and reconstructed the domestication path of the peloric gloxinia, in which a 10 bp deletion in SsCYC under selection triggered its evolution from the wild progenitor. The results presented here suggest that a simple genetic change in a pleiotropic gene can promote the elaboration of floral organs under intensive selection pressure. PMID- 29718510 TI - ProTox-II: a webserver for the prediction of toxicity of chemicals. AB - Advancement in the field of computational research has made it possible for the in silico methods to offer significant benefits to both regulatory needs and requirements for risk assessments, and pharmaceutical industry to assess the safety profile of a chemical. Here, we present ProTox-II that incorporates molecular similarity, pharmacophores, fragment propensities and machine-learning models for the prediction of various toxicity endpoints; such as acute toxicity, hepatotoxicity, cytotoxicity, carcinogenicity, mutagenicity, immunotoxicity, adverse outcomes pathways (Tox21) and toxicity targets. The predictive models are built on data from both in vitro assays (e.g. Tox21 assays, Ames bacterial mutation assays, hepG2 cytotoxicity assays, Immunotoxicity assays) and in vivo cases (e.g. carcinogenicity, hepatotoxicity). The models have been validated on independent external sets and have shown strong performance. ProTox-II provides a freely available webserver for in silico toxicity prediction for toxicologists, regulatory agencies, computational and medicinal chemists, and all users without login at http://tox.charite.de/protox_II. The webserver takes a two-dimensional chemical structure as an input and reports the possible toxicity profile of the chemical for 33 models with confidence scores, and an overall toxicity radar chart along with three most similar compounds with known acute toxicity. PMID- 29718511 TI - Relationship between diet, the gut microbiota, and brain function. AB - The human intestinal microbiota, comprising trillions of microorganisms, exerts a substantial effect on the host. The microbiota plays essential roles in the function and development of several physiological processes, including those in the brain. A disruption in the microbial composition of the gut has been associated with many metabolic, inflammatory, neurodevelopmental, and neurodegenerative disorders. Nutrition is one of several key factors that shape the microbial composition during infancy and throughout life, thereby affecting brain structure and function. This review examines the effect of the gut microbiota on brain function. The ability of external factors, such as diet, to influence the microbial composition implies a certain vulnerability of the gut microbiota. However, it also offers a potential therapeutic strategy for ameliorating symptoms of mental and physical disorders. Therefore, this review examines the potential effect of nutritional components on gut microbial composition and brain function. PMID- 29718513 TI - Leadership and Communication Competencies in Nursing: What Are We Missing? PMID- 29718512 TI - Why Social Workers Should Care about Changes to Title IX under Trump. PMID- 29718514 TI - Statistical Power in Nursing Education Research. AB - Nursing researchers have been encouraged for decades to address the validity of their statistical conclusions in part by accumulating evidence from studies that are capable of correctly identifying relationships between variables when those relationships are truly present. However, it has been noted that only a fraction of nursing studies appear to have undertaken power analyses to help mitigate the risk of Type II statistical conclusion errors. This Methodology Corner article reviews some of the major aspects of power analysis procedures and reiterates recommendations that researchers who plan to use inferential statistical analyses also conduct a power analysis to guide decision making about target sample sizes to increase the validity of study findings. [J Nurs Educ. 2018;57(5):262-264.]. PMID- 29718515 TI - Optimizing NCLEX-RN Pass Rate Performance Using an Educational Microsystems Improvement Approach. AB - BACKGROUND: Improvement methods were applied to optimize NCLEX-RN first-attempt pass rates in an Accelerated Bachelor of Science in Nursing (ABSN) program. METHOD: An improvement team was formed comprising nursing faculty, a student, faculty leading a course in the ABSN program involved in preparing students for NCLEX-RN, and a faculty expert in improvement science. Two Plan-Do-Study-Act (PDSA) cycles aimed at increasing practice and mastery were conducted. Effects were assessed using inferential statistics and statistical process control analyses. RESULTS: One hundred eighty-four ABSN students participated over two semesters. Average practice questions per student per semester increased from 1,000 questions at baseline to 2,130 questions (p < .01) postintervention, average practice examinations from 2.9 to 3.2 (p < .05), and average practice test mastery from 6.8 to 7.2 on an 8-point scale (p < .05). First-attempt NCLEX RN pass rates increased from 76.7% to 86.2% (p < .05). CONCLUSION: ABSN NCLEX-RN performance improved subsequent to this microsystem-based improvement effort. [J Nurs Educ. 2018;57(5):265-274.]. PMID- 29718516 TI - After the Medication Error: Recent Nursing Graduates' Reflections on Adequacy of Education. AB - BACKGROUND: The purpose of this study was to better understand individual- and system-level factors surrounding making a medication error from the perspective of recent Bachelor of Science in Nursing graduates. METHOD: Online survey mixed methods items included perceptions of adequacy of preparatory nursing education, contributory variables, emotional responses, and treatment by employer following the error. RESULTS: Of the 168 respondents, 55% had made a medication error. Errors resulted from inexperience, rushing, technology, staffing, and patient acuity. Twenty-four percent did not report their errors. Key themes for improving education included more practice in varied clinical areas, intensive pharmacological preparation, practical instruction in functioning within the health care environment, and coping after making medication errors. CONCLUSION: Errors generally caused emotional distress in the error maker. Overall, perceived treatment after the error reflected supportive environments, where nurses were generally treated with respect, fair treatment, and understanding. Opportunities for nursing education include second victim awareness and reinforcing professional practice standards. [J Nurs Educ. 2018;57(5):275-280.]. PMID- 29718517 TI - Nursing Students' Perceptions of Participatory Action Research. AB - BACKGROUND: This article evaluates the experience of students engaged in a participatory action research project. METHOD: Nursing students were assigned to research activities addressing poverty and social inclusion in the lives of individuals with mental health issues. Focus group interviews were held with 25 students, representing 58.1% of eligible students. RESULTS: Themes and subthemes were categorized from the transcripts, with two overarching themes emerging: (a) aspects that worked well, and (b) aspects that could be improved. The range of activities students engaged in while assigned to the project and students' perceptions, both positive and negative, about their overall exposure to participatory action research are identified and discussed. CONCLUSION: Findings in the literature with regard to perceived benefits and limitations of participatory action research projects involving students are supported by those found in this study. Based on the findings of this study, curriculum development for an interdisciplinary graduate-level course is in process. [J Nurs Educ. 2018;57(5):282-286.]. PMID- 29718518 TI - Nursing Students' Perceptions of Safety and Communication Issues in the Clinical Setting. AB - BACKGROUND: The purpose of this study is to describe nursing students' perceptions of safety issues and communication in clinical settings. METHOD: A descriptive study of nursing students' perceptions of safety and communication in clinical settings was conducted at a state university in the northeastern United States. Study participants consisted of 196 junior- and senior-level undergraduate nursing students in a baccalaureate program. RESULTS: One third of the students reported thinking that mistakes are held against them. In addition, they reported fear of communicating an error and fear of asking questions if something does not seem right. The majority reported they never encountered a near-miss event and would not report an error that and not harm the patient. Students also responded that actual errors and near misses are not consistently reported. CONCLUSION: Findings indicate educators have an opportunity to enhance nursing curricula with strategies to foster and embrace a culture of safety. [J Nurs Educ. 2018;57(5):287-290.]. PMID- 29718519 TI - Collaborative Testing: An Effective Invitational Strategy for High-Stakes Testing in Nursing. AB - BACKGROUND: A collaborative testing intervention was designed as an application of the invitational education model in an undergraduate nursing course. The purpose of this study was to evaluate the effect of collaborative testing on examination scores and knowledge retention of course content and to evaluate students' feelings about the collaborative testing process. METHOD: A quasi experimental design was used to evaluate the effect of collaborative testing on examination scores and knowledge retention among undergraduate nursing students in a public health course (N = 106). A descriptive survey was used to evaluate students' perceptions of the collaborative testing intervention. RESULTS: Collaborative testing increased examination scores and facilitated knowledge retention. Students' perceptions of the intervention were positive. CONCLUSION: Invitational strategies, such as collaborative testing, may result in measurably better outcomes, such as better examination scores and improved knowledge retention. Rigor does not need to be a barrier to invitational learning and, in fact, it may be complemented and enhanced by it. [J Nurs Educ. 2018;57(5):291 295.]. PMID- 29718520 TI - Type D Personality as a Predictor of Resilience Among Nursing Students. AB - BACKGROUND: Understanding the factors that influence resilience is especially important in the context of emotionally demanding work environments in health care. The aim of this study is to examine the associations between Type D personality and resilience among nursing students. METHOD: A correlational study design was used, and 150 baccalaureate nursing students participated. The Type D personality subscale, sense of coherence questionnaire, and Baruth protective factors inventory were used. Linear regression analysis and Student's t tests were used. RESULTS: The negative affectivity subscale of the Type D scale was a significant predictor for resilience and sense of coherence. Students with high levels of Type D characteristics had significantly lower levels of resilience and sense of coherence. CONCLUSION: It would be beneficial to include specific interventions for decreasing negative affectivity and promoting stress coping skills training in the training programs in nursing school curricula. [J Nurs Educ. 2018;57(5):296-299.]. PMID- 29718521 TI - Associate Degree in Nursing-to-Bachelor of Science in Nursing Graduates' Education and Their Perceived Ability to Keep Patients Safe. AB - BACKGROUND: Associate Degree in Nursing (ADN)-to-Bachelor of Science in Nursing (BSN) programs are designed to advance the ADN-prepared RNs' clinical reasoning and analytical skills. However, little is known about exactly how their BSN education may improve their clinical practice, specifically in the area of patient safety. METHOD: During semi-structured one-to-one interviews, ADN-to-BSN graduates were asked about their educational process and the perceived affect their education made on their ability to keep patients safe. Content analysis were used to identify emerging themes and categories. RESULTS: Three themes emerged from the data: (a) an unaltered approach to keeping patients safe, (b) experience as an ADN matters, and (c) BSN degree as a stepping stone. CONCLUSION: The call to increase the number of BSN-prepared nurses at the bedside is supported in the evidence and noteworthy of pursuit. However, as ADN-to-BSN programs increase in numbers to meet this demand, the outcomes of graduates need to be considered. [J Nurs Educ. 2018;57(5):300-303.]. PMID- 29718522 TI - Using a Web-Based e-Visit Simulation to Educate Nurse Practitioner Students. AB - BACKGROUND: The purpose of this pilot study was to develop and implement a Web based, e-Visit simulation experience for nurse practitioner students and evaluate student satisfaction and perceived learning. METHOD: The convenience sample consisted of 26 senior-level Master of Science in Nursing students in the Pediatric Nurse Practitioner and Adult-Gerontology Nurse Practitioner programs. A Likert survey was used for evaluation that measured items from 1 (strongly disagree) to 5 (strongly agree). RESULTS: Students reported that the simulation cases closely resembled real-world patients (97%; M = 4.42, SD = 0.69), providing them with a better understanding of complaints commonly addressed via telehealth services (96%; M = 4.46, SD = 0.57). Accuracy of diagnosis and treatment on first attempt was 95%. CONCLUSION: A Web-based, e-Visit simulation can be a useful learning experience for nurse practitioner students with knowledge gained that is transferable to real clinical situations. [J Nurs Educ. 2018;57(5):304-307.]. PMID- 29718523 TI - Cost-Effective Virtual Clinical Site Visits for Nurse Practitioner Students. AB - BACKGROUND: Clinical site visits (CSVs) are critical to assess the progress of nurse practitioner (NP) students. To overcome the challenges of effectively assessing long-distance students while maintaining a reasonable faculty workload, faculty implemented a project using FaceTime(r) to conduct online CSVs to assess NP student progress. FaceTime is a videoconferencing program available on Apple(r) devices. METHOD: Site visits were conducted by school of nursing faculty with real-time observation of the NP student-patient encounter. Afterward, faculty then completed the student, site, and preceptor evaluations. Faculty, preceptors, and students were surveyed regarding ease of use and acceptability of the iPad(r) visits. RESULTS: FaceTime CSVs provided faculty with the information needed to fill out the required evaluation forms of the student, preceptor, and site, and the iPad visits were easy to use and acceptable to all stakeholders. CONCLUSION: Using FaceTime for CSVs saved faculty travel time and used fewer program resources. [J Nurs Educ. 2018;57(5):308-311.]. PMID- 29718524 TI - Advocacy and Awareness: Integrating LGBTQ Health Education Into the Prelicensure Curriculum. AB - BACKGROUND: An identified gap in the curriculum related to lesbian, gay, bisexual, transgender, and queer (LGBTQ) health needs prompted nursing faculty to implement a collaborative educational offering. LGBTQ individuals experience significant health disparities, compared with heterosexual counterparts. Enhancing established LGBTQ population-specific training to highlight health disparities and awareness of special health care needs was piloted with two clinical groups of senior baccalaureate nursing students (N = 16). METHOD: Didactic, simulated, and panel discussion related to LGBTQ terminology, current health standards of care, and the importance of advocacy was provided by campus advocates, experienced health care providers, and a student panel identifying as LGBTQ. Health specific learning outcomes were established and evaluated. RESULTS: Posteducation, anonymous surveys, and journaling were completed. Survey respondents (n = 13) reported increased awareness and understanding of health disparities specific to the LGBTQ population. CONCLUSION: LGBTQ-specific health education has been implemented as a permanent curriculum change. [J Nurs Educ. 2018;57(5):312-314.]. PMID- 29718526 TI - Using Storyboarding Pedagogy to Promote Learning in a Distance Education Program. PMID- 29718525 TI - Poetry: An Innovative Teaching Strategy for Exploring Empathy With Beginning Nursing Students. AB - BACKGROUND: Empathy is a professional value difficult to teach and challenging for beginning nursing students to grasp. This article describes how a poem was integrated in a seminar to engage students in exploring empathy and its relevance to their forming professional identities. METHOD: Preseminar, nursing students (N = 8) read a book chapter about thinking empathetically. In seminar, they read an assigned poem and, using guiding questions, discussed it in small and large groups. Postseminar, students wrote self-reflections about their most important learning of the week. RESULTS: Through in-seminar discussions and postseminar reflections, students crafted new meanings of empathy, contemplated new insights, and integrated them into their imagined professional identities. In written self reflections, six of eight students indicated the seminar was their most important learning of the week. CONCLUSION: Poetry is an engaging platform that makes accessible to beginning students the values of the profession that are difficult to articulate and grasp. [J Nurs Educ. 2018;57(5):315-318.]. PMID- 29718527 TI - Fun With Pharmacology: Winning Students Over With Kahoot! Game-Based Learning. PMID- 29718528 TI - Established and potential echocardiographic markers of embolism and their therapeutic implications in patients with ischemic stroke. AB - Cardiogenic strokes comprised 11% of all strokes and 25% of ischemic strokes. An accurate identification of the cause of stroke is necessary in order to prepare an adequate preventive strategy. In this review the confirmed and potential causes of embolic strokes are presented, which can be detected in echocardiography in the context of present treatment guidelines and gaps in evidence. There remains a need for further studies assessing the meaning of potential cardiac sources of embolism and establishment of rules for optimal medical prevention (antiplatelet therapy [APT] vs. oral anticoagulation [OAC]) and interventional procedures to reduce the incidence of ischemic strokes. Currently available data does not provide definitive evidence on the comparative benefits of OAC vs. APT in patients with cryptogenic stroke or embolic stroke of undetermined source. There is a lack of antithrombotic treatment scheme in the time between stroke and the completed diagnosis of potential sources of thromboembolism. PMID- 29718529 TI - Impact of left atrial appendage closure on cardiac functional and structural remodeling: A Difference-in-Difference analysis of propensity score matched samples. AB - BACKGROUND: Although the safety and efficacy of left atrial appendage (LAA) closure (LAAC) in nonvalvular atrial fibrillation (NVAF) patients have been well documented in randomized controlled trials and real-world experience, there are limited data in the literature about the impact of LAAC on cardiac remodeling. The aim of the study was to examine the impact of LAAC on cardiac functional and structural remodeling in NVAF patients. METHOD: s: Between March 2014 and November 2016, 47 NVAF patients who underwent LAAC were included in this study (LAAC group). A control group (non-LAAC group) was formed from 141 NVAF patients without LAAC using propensity score matching. The Difference-in-Difference analysis was used to evaluate the difference in cardiac remodeling between the two groups at baseline and follow-up evaluations. RESULTS: The LAAC group had a larger increase in left atrial dimension (LAD), volume (LAV) and volume index (LAVI) than the non-LAAC group (+3.9 mm, p = 0.001; +9.7 mL, p = 0.006 and +5.9 mL/m2, p = 0.011, respectively). Besides, a significant increase in E and E/e' ratio was also observed in the LAAC group (+14.6 cm/s, p = 0.002 and +2.3, p = 0.028, respectively). Compared with the non-LAAC group, left ventricular ejection fraction and fractional shortening decreased in LAAC patients, but were statistically insignificant (-3.5%, p = 0.109 and -2.0%, p = 0.167, respectively). CONCLUSIONS: There were significant increases in LA size and LV filling pressure among NVAF patients after LAAC. These impacts of LAAC on cardiac functional and structural remodeling may have some clinical implications that need to be addressed in future studies. PMID- 29718530 TI - Effect of LCZ696, a dual angiotensin receptor neprilysin inhibitor, on isoproterenol-induced cardiac hypertrophy, fibrosis, and hemodynamic change in rats. AB - BACKGROUND: Recent clinical studies have shown that treatment with LCZ696, a complex containing the angiotensin receptor blocker valsartan and neprilysin inhibitor sacubitril, improves the prognosis of heart failure patients with a reduced ejection fraction. This study evaluated whether LCZ696 affects left ventricular hypertrophy, fibrosis, and hemodynamics in isoproterenol (ISO) treated rats compared with valsartan alone. METHODS: Male Wistar rats received subcutaneous saline (n = 10), subcutaneous ISO (2.4 mg/kg/day; n = 10), subcutaneous ISO + oral LCZ696 (60 mg/kg/day; n = 20) (ISO-LCZ), or subcutaneous ISO + oral valsartan (30 mg/kg/day; n = 20) (ISO-VAL) for 7 days. RESULTS: LCZ696 and valsartan did not significantly reduce the increased heart weight/body weight ratio in rats treated with ISO. Echocardiography showed that the deceleration time shortened by ISO was restored by LCZ696 but not valsartan alone (p = 0.01 vs. the ISO group). Histological analysis showed that cardiac interstitial fibrosis increased by ISO was decreased significantly by LCZ696 but not valsartan alone (control: 0.10 +/- 0.14%; ISO: 0.41 +/- 0.32%; ISO-LCZ: 0.19 +/- 0.23% [p < 0.01 vs. the ISO group]; ISO-VAL: 0.34 +/- 0.23% [p = 0.34 vs. the ISO group]). Quantitative PCR showed that mRNA expression of Tgfb1, Col1a1, Ccl2, and Anp increased by ISO was significantly attenuated by LCZ696 but not valsartan alone (p < 0.05 vs. the ISO group). CONCLUSIONS: LCZ696 improves cardiac fibrosis, but not hypertrophy, caused by continuous exposure to ISO in rats. PMID- 29718531 TI - Loss of AMIGO2 causes dramatic damage to cardiac preservation after ischemic injury. AB - BACKGROUND: Recent studies have identified amphoterin-induced gene and open reading frame (AMIGO) 2. The role of AMIGO2 in tumour research is well-studied, but its role in ischemic heart diseases is seldom reported. In the present study, the role of AMIGO2 in myocardial infarction is under investigation for the first time. METHODS: For in vitro studies, cardiomyocytes (CMs) and endothelial cells (ECs) were isolated from both AMIGO2 knockout (KO) and WT mice. The apoptosis of CMs was tested after 48 h of ischemic stimulation. A proliferation test was implemented after 7 days of normoxic incubation and tube formation on ECs. For in vivo studies, the MI model was built in mice hearts. Echocardiographic evaluation was performed at 3 days and 28 days post-MI, while the hemodynamics test was performed at 28 days post-MI. The histological results of the apoptosis, proliferation, angiogenesis and infarct zone assessments were determined using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labelling (TUNEL) assay, Ki67 staining, alpha-SMA/CD31 immunostain and the Masson-Trichrome method, respectively. The expression changes of the Akt pathway and related proteins were confirmed using both quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. RESULTS: The present results demonstrated that AMIGO2 deficiency caused more CMs suffering apoptosis, lower proliferation and less angiogenesis in vitro and in vivo. Weaker cardiac function and larger scar formation were detected in AMIGO2 KO mice, and increased expression of active caspase-3 and decreased expression of PDK1, p-Akt, Bcl-2/Bax and VEGF occurred. CONCLUSIONS: Herein the findings indicate that AMIGO2 deficiency plays an attenuated cardio-protective role in ischemic heart disease via inactivation of the PDK1/Pten/Akt pathway. PMID- 29718532 TI - The subcutaneous implantable cardioverter-defibrillator: A tertiary center experience. AB - BACKGROUND: The aim of the study was to evaluate subcutaneous implantable cardioverter-defibrillator (S-ICD) patients with regard to underlying etiology, peri-procedural outcome, appropriate/inappropriate shocks, and complications during follow-up. METHODS: All patients who underwent S-ICD implantation from February 2013 to March 2017 at an academic hospital in Vienna were included. Medical records were examined and follow-up interrogations of devices were conducted. RESULTS: A total of 79 S-ICD patients (58.2% males) with a mean age of 44.5 +/- 17.2 years were followed for a mean duration of 12.8 +/- 13.7 months. A majority of patients (58.2%) had S-ICD for primary prevention of sudden cardiac death. The most common of the 16 underlying etiologies were ischemic cardiomyopathy, non-ischemic cardiomyopathy, and idiopathic ventricular fibrillation. The lead was implanted to the left sternal border in 96.2% of cases, between muscular layers in 72.2%. Mean implant time was 45 min, 3 patients were induced, and all patients except one were programmed to two zones. Six (7.6%) patients experienced at least one appropriate therapy for ventricular arrhythmias and the time to first event ranged from 1 to 52 months. Seven patients experienced inappropriate shocks due to T-wave oversensing, atrial tachycardia with rapid atrioventricular conduction, external electromagnetic interference, and/or baseline oversensing due to lead movement. Four patients underwent revision for lead repositioning (n = 1), loose device suture (n = 1), and infection (n = 2). CONCLUSIONS: While S-ICDs are a feasible and effective treatment, issues remain with inappropriate shock and infection. PMID- 29718533 TI - Monotherapy of aspirin or warfarin for prevention of ischemic stroke in low-risk atrial fibrillation: A Easter Asian population-based study. AB - BACKGROUND: This study aimed to investigate the effectiveness of monotherapy aspirin and warfarin for stroke prevention in low-risk atrial fibrillation (AF) by using a population-based cohort study in Taiwan. METHODS: A newly diagnosed low-risk AF patient cohort were identified by using National Health Insurance Research Database (NHIRD) in Taiwan in 2008. The study cohort was observed with a follow-up of 2 years to examine the onset of ischemic stroke (IS) (to 2010). The longitudinal data were analyzed by using generalized estimation equations (GEE). RESULTS: A total of 8,065 newly-diagnosed low-risk AF patients were identified in 2008. 7.4% were prescribed with aspirin and 4.6% were prescribed with warfarin. The GEE results showed that low-risk AF patients with hypertension who received warfarin were associated with a statistically significant 58.4% reduction of IS risk (OR = 0.416, p = 0.024, 95% CI 0.194-0.891). Additionally, low-risk AF patients with hyperlipidemia who received warfarin were associated with a 69.3% reduction of IS risk (OR = 0.307, p = 0.044, 95% CI 0.097-0.969). CONCLUSIONS: Warfarin is suggested to be prescribed in preventing ischemic stroke for low stroke-risk atrial fibrillation patients with hypertension and hyperlipidemia. PMID- 29718534 TI - Restricting branched-chain amino acids: an approach to improve metabolic health. PMID- 29718536 TI - Usefulness of simultaneous screening for HIV-specific and HCV-specific antibodies and HBsAg by a capillary-based multiplex rapid diagnostic test to strengthen linkage-to-care in sub-Saharan patients attending sexually transmitted infection clinic. AB - Adult outpatients attending the main sexually transmitted infection clinic of Bangui, Central African Republic, were prospectively subjected to a multiplex rapid diagnostic test for human immunodeficiency virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV). In group I (n = 208) of patients already followed for HIV, 6 (2.9%) were unexpectedly negative, thus corresponding to false positive for HIV by the national HIV algorithm; hepatitis B surface antigen and HCV positivities were high (18.7% and 4.3%, respectively). In group II (n = 71) of patients with unknown HIV status, at least 1 chronic viral disease was diagnosed in 26 (36.6%) patients, including 5 (7.1%) HIV, 17 (23.9%) HBV, and 3 (4.2%) HCV infections. PMID- 29718535 TI - Vigilant attention to threat, sleep patterns, and anxiety in peripubertal youth. AB - BACKGROUND: Vigilant attention to threat is commonly observed in anxiety, undergoes developmental changes in early adolescence, and has been proposed to interfere with sleep initiation and maintenance. We present one of the first studies to use objective measures to examine associations between vigilant attention to threat and difficulties initiating and maintaining sleep in an early adolescent anxious sample. We also explore the moderating role of development (age, puberty) and sex. METHODS: Participants were 66 peripubertal youth (ages 9 14) with a primary anxiety disorder and 24 healthy control subjects. A dot-probe task was used to assess attentional bias to fearful relative to neutral face stimuli. Eye-tracking indexed selective attentional bias to threat, and reaction time bias indexed action readiness to threat. Sleep was assessed via actigraphy (e.g. sleep onset delay, wake after sleep onset, etc.), parent report (Children's Sleep Habits Questionnaire), and child report (Sleep Self-Report). The Pediatric Anxiety Rating Scale assessed anxiety severity. RESULTS: Eye-tracking initial threat fixation bias (beta = .33, p = .001) and threat dwell time bias (beta = .22, p = .041) were positively associated with sleep onset latency. Reaction time bias was positively associated with wake after sleep onset (beta = .24, p = .026) and parent-reported sleep disturbance (beta = .25, p = .019). Anxiety (severity, diagnosis) was not associated with these outcomes. Sex (beta = -.32, p = .036) moderated the relation between initial threat fixation bias and sleep onset latency, with a positive association for males (p = .005), but not for females (p = .289). Age and pubertal status did not moderate effects. CONCLUSIONS: Vigilant attention to threat is related to longer sleep onset and reduced sleep maintenance. These associations are not stronger in early adolescents with anxiety. Implications for early intervention or prevention that targets vigilant attention to threat to impact sleep disturbance, and vice versa, are discussed. PMID- 29718537 TI - Resolution of HBV infection occurs sooner than recovery of renal disease in adult serum HBsAg-negative HBV-associated glomerulonephritis. AB - Most cases of hepatitis B virus-associated glomerulonephritis (HBV-GN) occur in children and present with serum HBsAg positivity. Few studies have investigated adult patients with HBV-GN who are serum HBsAg-negative. This study aimed to determine the clinical and pathological features of adult patients with HBV-GN who are serum hepatitis B surface antigen (HBsAg)-negative. Clinical, pathologic, and laboratory findings were collected and analyzed in a cohort of 27 adult patients with HBV-GN who were serum HBsAg-negative upon diagnosis. The study population included mostly men of middle age (40-59 years). Clinically, patients presented with nephrotic syndrome. Serum immunoglobulin G levels were low, whereas serum immunoglobulin M, immunoglobulin A, complement C3 (C3), and complement C4 (C4) levels as well as liver and renal function tests were normal in most or all patients. Among the 27 patients, 21 tested positive for HBV antibodies. Membranous nephropathy was the dominant pathological form on kidney biopsy. In addition, only a few patients showed a "full house" staining pattern and renal immune deposit of complement C1q (C1q). Serum HBsAg-negative HBV-GN may represent a late stage of HBV infection. We recommend routine testing for HBV markers on renal biopsy in regions where HBV is prevalent, even when tests for serum HBV markers are negative. PMID- 29718538 TI - Age-specific seroprevalence of dengue infection in Hong Kong. AB - A newly developed dengue virus vaccine (chimeric yellow fever virus-tetravalent dengue vaccine [CYD-TDV]) has recently been licensed for clinical use. The World Health Organization recommends vaccination for populations with seroprevalence of at least 70% to maximize public health impact. This study aimed to delineate the seroprevalence of dengue infection in Hong Kong. A total of 105 972 serum samples submitted for clinical testing during the period 2013-2015 were age-stratified and sex-stratified. For each year of collection, 25 samples were randomly selected from each age-sex group. Altogether, 2100 samples were tested for the dengue immunoglobulin G (IgG) antibody using a non-type-specific ELISA kit. The overall dengue IgG-positive rate was 4.6% and showed no significant change over the 3 years. The positive rate was not associated with sex, but a steep rise in seroprevalence for persons above 65 years (32.7%) was observed. The low dengue seroprevalence in Hong Kong does not support implementation of a national immunization program. Majority of the population in Hong Kong are susceptible to dengue infection, and a substantial proportion of persons older than 65 years could acquire secondary infection and are prone to develop severe dengue. PMID- 29718539 TI - Long-term community change through multiple rapid transitions in a desert rodent community. AB - While studies increasingly document long-term change in community composition, whether long-term change occurs gradually or via rapid reorganization events remains unclear. We used Latent Dirichlet Allocation (LDA) and a change-point model to examine the long-term dynamics of a desert rodent community undergoing compositional change over a 38-yr span. Our approach detected three rapid reorganization events, where changes in the relative abundances of dominant and rare species occurred, and a separate period of increased variance in the structure of the community. These events coincided with time periods, possibly related to climate events, where the total abundance of rodents was extremely low. There are a variety of processes that could link low abundance events with a higher probability of rapid ecological transitions, including higher importance of stochastic processes (i.e., competitive interactions or priority effects) and the removal of structuring effects of competitive dominants or incumbent species. Continued study of the dynamics of community change will provide important information not only on the processes structuring communities, but will also provide guidance for forecasting how communities will undergo change in the future. PMID- 29718540 TI - Obesity, gestational diabetes and macrosomia are associated with increasing rates of early-term induction of labour at The Canberra Hospital. AB - BACKGROUND: Early-term delivery is an important cause of short-term neonatal morbidity and associated high healthcare costs, with possible additional long term developmental ramifications. As a form of 'iatrogenic' delivery, induction of labour (IOL) is a potentially modifiable contributor to this burden. AIMS: To determine patterns of, and primary indication for, early-term IOL, as well as temporal trends in this primary indication and differences from other modes of delivery with respect to maternal factors and maternal/neonatal outcomes. MATERIALS AND METHODS: The Canberra Hospital births database (2012-2016) was queried; patients who underwent IOL were included in the analysis. RESULTS: Total deliveries and the proportion of early-term IOL procedures rose markedly over the time period. Gestational diabetes mellitus (GDM) was the most frequent and an increasing main indication for IOL. GDM was associated with significantly higher body mass index, an increased proportion of obesity, and a greater incidence of labour complications related to macrosomia. Birthweight of neonates of diabetic mothers was significantly higher, which was associated with decreased rates of admission to the special care nursery/neonatal intensive care unit (SCN/NICU) compared to all other babies. GDM increased relative risk of early-term IOL in obese women by 1.8 times. CONCLUSIONS: The burden of GDM and early-term IOL have increased at The Canberra Hospital although adverse short-term neonatal outcomes have not, possibly suggesting appropriate management of these patients. Nonetheless, effort should be made to identify patients who can safely continue pregnancy to full term, given the higher proportion of SCN/NICU admissions among early-term neonates. PMID- 29718541 TI - Differential cell surface recruitment of the superoxide-producing NADPH oxidases Nox1, Nox2 and Nox5: The role of the small GTPase Sar1. AB - Transmembrane glycoproteins, synthesized at the endoplasmic reticulum (ER), generally reach the Golgi apparatus in COPII-coated vesicles en route to the cell surface. Here, we show that the bona fide nonglycoprotein Nox5, a transmembrane superoxide-producing NADPH oxidase, is transported to the cell surface in a manner resistant to co-expression of Sar1 (H79G), a GTP-fixed mutant of the small GTPase Sar1, which blocks COPII vesicle fission from the ER. In contrast, Sar1 (H79G) effectively inhibits ER-to-Golgi transport of glycoproteins including the Nox5-related oxidase Nox2. The trafficking of Nox2, but not that of Nox5, is highly sensitive to over-expression of syntaxin 5 (Stx5), a t-SNARE required for COPII ER-to-Golgi transport. Thus, Nox2 and Nox5 mainly traffic via the Sar1/Stx5 dependent and -independent pathways, respectively. Both participate in Nox1 trafficking, as Nox1 advances to the cell surface in two differentially N glycosylated forms, one complex and one high mannose, in a Sar1/Stx5-dependent and -independent manner, respectively. Nox2 and Nox5 also can use both pathways: a glycosylation-defective mutant Nox2 is weakly recruited to the plasma membrane in a less Sar1-dependent manner; N-glycosylated Nox5 mutants reach the cell surface in part as the complex form Sar1-dependently, albeit mainly as the high mannose form in a Sar1-independent manner. PMID- 29718543 TI - Scanning SQUID View of Oxide Interfaces. AB - The emergence of states of matter in low-dimensional systems is one of the most intriguing topics in condensed matter physics. Interfaces between nonmagnetic, insulating oxides are found to give rise to surprising behaviors, such as metallic conductivity, superconductivity, and magnetism. Sensitive, noninvasive local characterization tools are essential for understanding the electronic and magnetic behavior of these systems. Here, the scanning superconducting quantum interference device (SQUID) technique for local magnetic imaging is described and its contribution to the field of oxide interfaces is reviewed. PMID- 29718542 TI - High-Efficiency PbS Quantum-Dot Solar Cells with Greatly Simplified Fabrication Processing via "Solvent-Curing". AB - PbS quantum-dot (QD) solar cells are promising candidates for low-cost solution processed photovoltaics. However, the device fabrication usually requires ten more times film deposition and rinsing steps, which is not ideal for scalable manufacturing. Here, a greatly simplified deposition processing is demonstrated by replacing methanol with acetonitrile (ACN) as the rinsing solvent. It is discovered that ACN can effectively "cure" the film cracks generated from the volume loss during the solid-state ligand-exchange process, which enables the deposition of thick and dense films with much fewer deposition steps. Meanwhile, due to the aprotic nature of ACN, fewer trap states can be introduced during the rinsing process. As a result, with only three deposition steps for the active layer, a CPVT-certified 11.21% power conversion efficiency is obtained, which is the highest efficiency ever reported for PbS QD solar cells employing a solid state ligand-exchange process. More importantly, the simple film-deposition processing provides an opportunity for the future application of QDs in low-cost printing of optoelectronic devices. PMID- 29718544 TI - High-Level Ab Initio Calculations of Intermolecular Interactions: Heavy Main Group Element pi-Interactions. AB - This work reports high-level ab initio calculations and a detailed analysis on the nature of intermolecular interactions of heavy main-group element compounds and pi systems. For this purpose we have chosen a set of benchmark molecules of the form MR3 , in which M=As, Sb, or Bi, and R=CH3 , OCH3 , or Cl. Several methods for the description of weak intermolecular interactions are benchmarked including DFT-D, DFT-SAPT, MP2, and high-level coupled cluster methods in the DLPNO-CCSD(T) approximation. Using local energy decomposition (LED) and an analysis of the electron density, details of the nature of this interaction are unraveled. The results yield insight into the nature of dispersion and donor acceptor interactions in this type of system, including systematic trends in the periodic table, and also provide a benchmark for dispersion interactions in heavy main-group element compounds. PMID- 29718545 TI - Studies of advanced glycation end products and oxidation biomarkers for type 2 diabetes. AB - Advanced glycation end products (AGEs) are formed upon nonenzymatic reactions of sugars or their metabolites with proteins and other cellular constituents. Many AGEs are long lived. Recent findings suggest that AGEs may predict diabetes and its complications and thus may warrant further study. The objective of this study was to assess the validity of our experimental procedures for measuring AGEs in stored blood sample and to conduct a pilot study for developing AGE biomarkers for diabetes and/or age-related changes of glucose metabolism. We conducted a reliability study of the samples and methods using liquid chromatography-tandem mass spectrometry (LC-MS)/MS assays for 10 AGEs (including methylglyoxal-derived hydroimidazolone (MG-H1), glucosepane (GSP) and two oxidation measures, in stored repository blood samples from the Nurses' Health Study and the Health Professionals Follow-up Study. We also analyzed data relating blood GSP levels to type 2 diabetes status in a case-control study (25 cases and 15 controls). Among the AGEs, GSP, and MG-H1 showed the highest reliability across the various measures: reliability in duplicate samples and stability with delayed processing and storage over 1-2 year period. Furthermore, plasma GSP was associated with older age (P = 0.04) and type 2 diabetes status (age-adjusted P = 0.0475). Our findings suggest that analysis of these AGEs may be developed as biomarkers for diabetes and/or age-related changes of glucose metabolism. (c) 2018 BioFactors, 44(3):281-288, 2018. PMID- 29718546 TI - Improvement of liver stiffness measurement, acoustic radiation force impulse measurements, and noninvasive fibrosis markers after direct-acting antivirals for hepatitis C virus G4 recurrence post living donor liver transplantation: Egyptian cohort. AB - Progression of recurrent hepatitis C is accelerated in liver transplant (LT) recipients. Direct-acting antivirals (DAAs) have recently emerged as a promising therapeutic regimen for the treatment of hepatitis C virus infection. Rates of sustained virological response (SVR) have drastically improved since the introduction of DAAs. The aim is to elucidate the changes in liver stiffness measurement (LSM) by transient elastography (TE) as well as acoustic radiation force impulse (ARFI) elastography and fibrosis scores after DAA treatment in LT recipients with hepatitis C virus recurrence. A single-center, prospective study including 58 LT recipients with hepatitis C recurrence who received different sofosbuvir-based treatment regimens. Transient elastography and ARFI elastography values were recorded as well as fibrosis 4 score (FIB-4) and aspartate aminotransferase-to-platelet ratio index were calculated at baseline and SVR at week 24 (SVR24). The outcome was improvement in LSM and at least a 20% decrease in LSM at SVR24 compared with baseline. The sustained virological response was 98.1%. There was improvement of platelet counts, alanine aminotransferase, and aspartate aminotransferase, which in turn caused improvement in fibrosis scores at SVR24. LSM by TE and ARFI elastography decreased from the baseline median value of 6.3 kPa (interquartile range [IQR]; 4.6 to 8.8 kPa) and 1.28 m/s (IQR; 1.07 to 1.53 m/s) to an SVR24 median value of 6.2 kPa (IQR; 4.85 to 8.9 kPa) and 1.12 (IQR; 0.97 to 1.30 m/s), respectively. Logistic regression analysis showed that baseline viral load was the only significant predictor of improvement in LS after DAA therapy at SVR24. Sofosbuvir-based treatment resulted in an early improvement in parameters of liver fibrosis in post-LT patients with hepatitis C recurrence. PMID- 29718547 TI - Can we assess severity of Guillain-Barre syndrome using absolute monocyte count? AB - INTRODUCTION: Guillain-Barre syndrome (GBS) is an inflammatory demyelinating autoimmune disease, associated with blood-nerve barrier breakdown, inflammatory cells infiltration, and cytokine leakage in the peripheral nervous system. Currently, it has been revealed that monocytes play key roles in the inflammatory response. Therefore, we aimed to assess the correlation between monocyte count and GBS in this study. METHODS: Retrospective study was conducted in 114 patients with GBS and 120 age- and gender-matched individuals. RESULTS: Absolute monocyte count in patients with GBS was higher than that in healthy controls (0.61 +/- 0.24 vs 0.41 +/- 0.10; P < .001). Interestingly, monocyte count had significant positive correlations with CRP, ESR, and disease severity of GBS (r = .244, P = .009; r = .269, P = .004; r = .322, P < .001). A cutoff value of 0.515 for monocyte count was observed in patients with GBS (areas under the curve = 0.808, 95% confidence interval = 0.749-0.868, P < .001). Meanwhile, absolute monocyte count was independently associated with GBS in logistic regression analysis (odds ratio = 2.291, 95% confidence interval = 3.557-27.493, P < .001). CONCLUSION: Our findings demonstrated that elevated monocyte count is independently associated with GBS patients, and suggested monocyte count is positively associated with disease severity of GBS. PMID- 29718548 TI - Heterologous Biosynthesis of Fungal Indole Sesquiterpene Sespendole. AB - Indole sesquiterpene sespendole, which has been isolated from the filamentous fungus Pseudobotrytis terrestris FKA-25, is a specific inhibitor of lipid droplet synthesis in mouse macrophages. The biosynthetic pathway that involves genes encoding six enzymes (spdEMBQHJ) was elucidated through heterologous expression of spd genes in Aspergillus oryzae, biotransformation experiments, and in vitro enzymatic reactions with a recombinant protein, thereby revealing the mechanism underlying the characteristic modification on the indole ring, catalyzed by a set of prenyltransferase (SpdE)/cytochrome P450 (SpdJ) enzymes. Functional analysis of the homologous genes encoding these enzymes involved in the biosynthesis of lolitrem allowed a biosynthetic pathway for the bicyclic ring skeleton fused to the indole ring to be proposed. PMID- 29718549 TI - Are Australian smokers with mental illness receiving adequate smoking cessation and harm reduction information? AB - Provision of smoking cessation support in the form of advice and information is central to increasing quit rates, including among people with mental illness (MI), who have 3-5 times higher odds of smoking than those without MI. This study investigated the extent and perceived utility of quit smoking advice and information available to Australian smokers with MI through face-to-face, semi structured, in-depth interviews with 29 current smokers with MI. Qualitative analysis identified four major sources of quit smoking advice and information: (i) mental health practitioners; (ii) Quitline; (iii) social networks; and (iv) Internet and media. All identified sources, including formal sources (mental health practitioners and Quitline), were perceived as providing inadequate information about quitting smoking, particularly regarding optimal usage of nicotine replacement therapy (NRT). Social networks emerged as a substantial source of quit smoking advice and information, especially for nontraditional methods such as vaping. Participants showed high interest in receiving support from peer-led smoking cessation groups. A minority of participants reported that they had received quit smoking information from Internet and media; this was largely restricted to negative reports about e-cigarettes and short advertisements for nicotine replacement therapy. Our findings suggest that more can be done to provide smokers with MI with practical smoking cessation advice and support. Comprehensive information resources tailored for smokers with MI should be developed and disseminated via multiple pathways. We also recommend a number of policy and practice reforms to promote smoking cessation among those with MI. PMID- 29718550 TI - Combining Whispering-Gallery Mode Optical Biosensors with Microfluidics for Real Time Detection of Protein Secretion from Living Cells in Complex Media. AB - The noninvasive monitoring of protein secretion of cells responding to drug treatment is an effective and essential tool in latest drug development and for cytotoxicity assays. In this work, a surface functionalization method is demonstrated for specific detection of protein released from cells and a platform that integrates highly sensitive optical devices, called whispering-gallery mode biosensors, with precise microfluidics control to achieve label-free and real time detection. Cell biomarker release is measured in real time and with nanomolar sensitivity. The surface functionalization method allows for antibodies to be immobilized on the surface for specific detection, while the microfluidics system enables detection in a continuous flow with a negligible compromise between sensitivity and flow control over stabilization and mixing. Cytochrome c detection is used to illustrate the merits of the system. Jurkat cells are treated with the toxin staurosporine to trigger cell apoptosis and cytochrome c released into the cell culture medium is monitored via the newly invented optical microfluidic platform. PMID- 29718551 TI - Late-Stage Functionalization of Arylacetic Acids by Photoredox-Catalyzed Decarboxylative Carbon-Heteroatom Bond Formation. AB - The rapid transformation of pharmaceuticals and agrochemicals enables access to unexplored chemical space and thus has accelerated the discovery of novel bioactive molecules. Because arylacetic acids are regarded as key structures in bioactive compounds, new transformations of these structures could contribute to drug/agrochemical discovery and chemical biology. This work reports carbon nitrogen and carbon-oxygen bond formation through the photoredox-catalyzed decarboxylation of arylacetic acids. The reaction shows good functional group compatibility without pre-activation of the nitrogen- or oxygen-based coupling partners. Under similar reaction conditions, carbon-chlorine bond formation was also feasible. This efficient derivatization of arylacetic acids makes it possible to synthesize pharmaceutical analogues and bioconjugates of pharmaceuticals and natural products. PMID- 29718552 TI - Manganese-Catalyzed Dehydrogenative Alkylation or alpha-Olefination of Alkyl Substituted N-Heteroarenes with Alcohols. AB - Catalysis with earth-abundant transition metals is an option to help save our rare noble-metal resources and is especially interesting when novel reactivity or selectivity patterns are observed. We report here on a novel reaction, namely the dehydrogenative alkylation or alpha-olefination of alkyl-substituted N heteroarenes with alcohols. Manganese complexes developed in our laboratory catalyze the reaction with high efficiency whereas iron and cobalt complexes stabilized by the same ligands are essentially inactive. Hydrogen is liberated during the reaction, and bromine and iodine functional groups as well as olefins are tolerated. A variety of alkyl-substituted N-heteroarenes can be functionalized, and benzylic and aliphatic alcohols undergo the reaction. PMID- 29718553 TI - Nanoscale Chemical Imaging of Zeolites Using Atom Probe Tomography. AB - Understanding structure-composition-property relationships in zeolite-based materials is critical to engineering improved solid catalysts. However, this can be difficult to realize as even single zeolite crystals can exhibit heterogeneities spanning several orders of magnitude, with consequences for, for example, reactivity, diffusion as well as stability. Great progress has been made in characterizing these porous solids using tomographic techniques, though each method has an ultimate spatial resolution limitation. Atom probe tomography (APT) is the only technique so far capable of producing 3D compositional reconstructions with sub-nanometer-scale resolution, and has only recently been applied to zeolite-based catalysts. Herein, we discuss the use of APT to study zeolites, including the critical aspects of sample preparation, data collection, assignment of mass spectral peaks including the predominant CO peak, the limitations of spatial resolution for the recovery of crystallographic information, and proper data analysis. All sections are illustrated with examples from recent literature, as well as previously unpublished data and analyses to demonstrate practical strategies to overcome potential pitfalls in applying APT to zeolites, thereby highlighting new insights gained from the APT method. PMID- 29718554 TI - Corrigendum. PMID- 29718555 TI - Treatment with broadly neutralizing influenza antibodies reduces severity of secondary pneumococcal pneumonia in mice. AB - Secondary bacterial pneumonia is a frequent complication of influenza, associated with high morbidity and mortality. We hypothesized that treatment with neutralizing influenza A antibody AT10_002 protects against severe secondary pneumococcal infection in a mouse model of influenza A infection. Influenza A (H3N2) virus-infected male C57Bl6 mice were treated intravenously with either AT10_002 or a control 2 days postinfection. Seven days later, both groups were infected with Streptococcus pneumoniae and killed 18 hours later. Mice receiving AT10_002 showed less loss of bodyweight compared with controls (+1% vs -12%, P < .001), lower viral loads in bronchoalveolar lavage fluids (BALFs) (7 vs 194 RNA copies per uL; P < .001), and reduced bacterial outgrowth in lung homogenates (3.3 * 101 vs 2.5 * 105 colony-forming units per mg; P < .001). The treatment group showed lower pulmonary wet weights, lower cell counts, and lower protein levels in BALF compared with controls. Treatment with AT10_002 was associated with lower levels of tumor necrosis factor-alpha, interleukin (IL)-6, cytokine induced neutrophil chemoattractant (KC), and interferon-gamma in BALF and lower IL-6 and KC in lung homogenates. Treatment with anti-influenza antibody AT10_002 is associated with reduced weight loss, viral load, bacterial outgrowth, and lung injury in a murine model of secondary pneumococcal pneumonia following influenza infection. PMID- 29718556 TI - Football training improves metabolic and cardiovascular health status in 55- to 70-year-old women and men with prediabetes. AB - We examined the effects of 16 weeks of football training and dietary advice on blood glucose control and health status in 55- to 70-year-old women and men with prediabetes. Fifty participants with prediabetes (age; 61 +/- 6 years, BMI; 29.6 +/- 4.7; VO2max 22.3 +/- 5.7 mL.min-1 .kg-1 ) were randomized into a football and dietary advice group (F+D; n = 27) and a dietary advice group (D; n = 23). F+D performed football training (twice weekly 30- to 60-minutes sessions) and received dietary advice, while D only received dietary advice. An oral glucose tolerance test (OGTT) was completed pre and post the 16-week period. Body composition, blood pressure, and maximal oxygen uptake (VO2max ) were additionally measured. Both groups demonstrated a decrement (P < .05) in fasting blood glucose (-0.4 +/- 0.5 mmol.L-1 ) and lowered blood glucose throughout OGTT. F+D displayed lower values than D (P < .05) after 60 minutes (9.0 +/- 2.7 vs 10.6 +/- 2.9 mmol.L-1 ) and 120 minutes (5.7 +/- 1.6 vs 7.5 +/- 2.4 mmol.L-1 ). VO2max increased by 14% in F+D, with a higher (P < .05) change score than in D (2%). Mean arterial pressure declined more (P < .05) in F+D than in D (-8 +/- 9 vs -4 +/- 11 mm Hg). Fat loss was greater (P < .05) in F+D than in D (-3.4 +/- 2.8 vs 1.2 +/- 2.0 kg), and the increase in lean body mass was also greater (P < .05) in F+D than in D (0.7 +/- 1.5 vs -0.3 +/- 1.6 kg). In conclusion, football training combined with dietary advice has broad-spectrum effects on metabolic and cardiovascular health profile with greater overall effects than professional dietary advice per se for 55- to 70-year-old women and men with prediabetes. PMID- 29718557 TI - Fiprole insecticide resistance of Laodelphax striatellus: electrophysiological and molecular docking characterization of A2'N RDL GABA receptors. AB - BACKGROUND: Phenylpyrazole (fiprole) insecticides, including ethiprole, fipronil and flufiprole with excellent activity on rice planthoppers, are very important in Asia but resistance has developed after decades of use. The molecular mechanism of fipronil- but not ethiprole-resistance has been previously studied in rice planthoppers. In our laboratory, a small brown planthopper Laodelphax striatellus strain with ethiprole-resistance was cultured and the molecular mechanisms of ethiprole resistance and of cross-resistance among fiprole insecticides were investigated. RESULTS: Ethiprole-resistant L. striatellus has >5000-fold resistance compared to the susceptible strain, and exhibits around 200 fold cross-resistance with fipronil and flufiprole. RDL genes were isolated from susceptible and ethiprole-resistant L. striatellus and expressed in Xenopus oocytes. Electrophysiological studies showed fiprole insecticides inhibited gamma aminobutyric acid (GABA)-induced current with IC50 = 0.1-1.4 MUM to LsRDL-S homomers. In LsRDL-R with A2'N mutation, only 1-13% inhibition was observed on treatment with 10 MUM ethiprole, fipronil or flufiprole. Homology models indicate A2'N mutation allows crosslinking hydrogen bonding between Asn sidechains at the 2' position around the channel pore, blocking insecticides from interacting near this position. In contrast, insecticides showed favorable binding near A2' in wild-type L. striatellus. CONCLUSION: Cross-resistance is increasing for fiprole insecticides in L. striatellus and management strategies are necessary to minimize resistance. (c) 2018 Society of Chemical Industry. PMID- 29718558 TI - Simple staging system for osteosarcoma performs equivalently to the AJCC and MSTS systems. AB - Both the American Joint Committee on Cancer (AJCC) and Musculoskeletal Tumor Society (MSTS) staging systems for skeletal sarcomas have major weaknesses. A revised staging system for osteosarcoma (the Vanderbilt system) was developed based on exploratory analyses of the relative prognostic impacts of histologic grade, tumor size, local tumor extension, and specific anatomic sites of metastasis using case records from the National Cancer Database (N = 4,285). AJCC, MSTS, and Vanderbilt staging schemes were then compared using a separate, population-based cancer registry (the Surveillance, Epidemiology, and End Results database; N = 2,246) as a validation dataset. Predictive accuracy for 5-year sarcoma-specific survival was evaluated by comparing areas under receiver operating characteristic curves generated from logistic regression. Three different concordance indices and Bayesian information criteria were also calculated for model comparisons. The Vanderbilt staging system showed comparable predictive accuracy for 5-year disease-specific survival (65%) compared to the AJCC (67%) and MSTS (67%) staging systems. Most cross-comparisons of model concordance were not significantly different either. Bayesian information criterion was lowest for the MSTS staging system. Substaging osteosarcoma by current anatomical criteria is ineffectual. A simplified staging system based only on histologic grade and the presence of distant metastasis to any anatomic site performs similarly to the current AJCC and MSTS staging systems by multiple statistical criteria and is proposed for clinical and pathological staging of osteosarcomas of the non-pelvic appendicular and non-spinal axial skeleton. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2802-2808, 2018. PMID- 29718559 TI - Feasibility of early discharge following vaginal hysterectomy with a bipolar electrocoagulation device. AB - OBJECTIVE: To evaluate the safety and efficacy of vaginal hysterectomy for benign conditions (excluding prolapse) using the BiClamp (Erbe Elektromedizin, Tubingen, Germany) bipolar electrocoagulation system. METHODS: The present study was a prospective audit of a consecutive case series of patients who underwent vaginal hysterectomy for benign conditions, performed using the BiClamp between March 1, 2015, and June 30, 2016, at Norfolk and Norwich University Hospital, Norwich, UK. Surgeries performed for benign conditions were eligible, excluding prolapse; severe endometriosis with pelvic adhesions was an exclusion criterion. Patient demographics and past history were recorded, along with intraoperative findings and adverse events. Follow-up data were obtained via telephone interviews 24 hours after surgery and a nurse-led postoperative clinic 8 weeks postoperatively. RESULTS: The series included 75 patients; 32 (43%) were discharged on the same day as surgery and 70 (93%) within 23 hours. There were two patients who experienced vault hematomas and remained admitted for more than 24 hours. There was one intraoperative bladder injury that was repaired vaginally. No delayed adverse events occurred within 8 weeks. No patient required patient-controlled analgesia or an epidural injection for postoperative analgesia. CONCLUSION: Patients experienced low postoperative pain following BiClamp treatment and 93% were was discharged within 23 hours. PMID- 29718560 TI - Relativistic Effects on Donor-Acceptor Interactions in Coinage Metal Carbonyl Complexes [TM(CO)n ]+ (TM=Cu, Ag, Au; n=1, 2). AB - DFT calculations at the BP86+D3(BJ)/TZ2P level, with and without relativistic contributions, using the ZORA approximation have been carried out for the coinage metal carbonyl complexes [TM(CO)]+ and [TM(CO)2 ]+ with TM=Cu, Ag, Au. The nature of the metal-CO interactions and the relativistic effects on the different energy terms were analyzed with the EDA-NOCV method. The three terms Pauli repulsion, Coulomb attraction, and orbital interactions become stronger when relativistic effects are accounted for; the strengthening exhibits the order DeltaEPauli >DeltaEelstat >DeltaEorb . The largest change in the calculated energy terms is, as expected, found for gold, followed by silver and copper. The relativistic contributions on the Cu+ -CO interactions are significant and thus, relativistic effects should not be neglected in quantum chemical calculations in copper compounds. Breakdown of the orbital term into individual contributions shows that the relativistic effect in [TM(CO)]+ is for the TM+ <-CO sigma-donation stronger than for TM+ ->CO pi-backdonation, except for TM=Cu. The trend in the dicarbonyls [TM(CO)2 ]+ has the order (+,+) sigma-donation > pi-backdonation > (+,-) sigma donation. The bonding analysis reveals that there is a sizeable contribution from TM+ ->CO sigma-backdonation in all carbonyl complexes that further stabilizes the metal-carbonyl bonds. In [Au(CO)2 ]+ it becomes even larger than the (+,-) OC >TM+ <-CO sigma-donation. The trends of the various orbital interactions and the effect of relativity on their strength can be understood when the valence orbitals of the metals and CO are considered. PMID- 29718561 TI - Zinc deficiency tolerance in maize is associated with the up-regulation of Zn transporter genes and antioxidant activities. AB - Zinc (Zn) is an essential micronutrient for the growth and development of plants. However, Zn deficiency is a common abiotic stress causing yield loss in crop plants. This study elucidates the mechanisms of Zn deficiency tolerance in maize through physiological and molecular techniques. Maize lines tolerant (PAC) and sensitive (DAC) to Zn deficiency were examined physiologically and by atomic absorption spectrometry (AAS). Proteins, H2 O2 , SOD, POD, membrane permeability and gene expression (using real-time PCR) of roots and shoots of both maize lines were assessed. Zn deficiency had no significant effect on root parameters compared with control plants in PAC and DAC but showed a substantial reduction in shoot parameters in DAC. AAS showed a significant decrease in Zn concentrations in both roots and shoots of DAC but not PAC under Zn deficiency, implying that Zn deficiency tolerance mechanisms exist in PAC. Consistently, total protein and membrane permeability were significantly reduced in DAC but not PAC in both roots and shoots under Zn deficiency in comparison with Zn-sufficient plants. Real-time PCR showed that expression of ZmZIP1, ZmZIP4 and ZmIRT1 transporter genes significantly increased in roots of PAC, but not in DAC due to Zn deficiency compared with controls. The H2 O2 concentration dramatically increased in roots of DAC but not PAC. Moreover, tolerant PAC showed a significant increase in POD and SOD activity due to Zn deficiency, suggesting that POD- and SOD-mediated antioxidant defence might provide tolerance, at least in part, under Zn deficiency in PAC. This study provides an essential background for improving Zn biofortification of maize. PMID- 29718562 TI - Solidarity as a national health care strategy. AB - The Trump Administration's recent attempts to repeal the Affordable Care Act have reignited long-running debates surrounding the nature of justice in health care provision, the extent of our obligations to others, and the most effective ways of funding and delivering quality health care. In this article, I respond to arguments that individualist systems of health care provision deliver higher quality health care and promote liberty more effectively than the cooperative, solidaristic approaches that characterize health care provision in most wealthy countries apart from the United States. I argue that these claims are mistaken and suggest one way of rejecting the implied criticisms of solidaristic practices in health care provision they represent. This defence of solidarity is phrased in terms of the advantages solidaristic approaches to health care provision have over individualist alternatives in promoting certain important personal liberties, and delivering high-quality, affordable health care. PMID- 29718563 TI - First pathological report of a de novo CD5-positive diffuse large B-cell lymphoma patient presenting with Guillain-Barre syndrome-like neuropathy due to neurolymphomatosis. AB - Peripheral neuropathy occurs in approximately 5% of the patients with lymphoma. Two major causes of peripheral neuropathy associated with lymphoma are neurolymphomatosis and paraneoplastic neuropathy such as demyelinating neuropathy. The differential diagnosis between neurolymphomatosis and demyelinating neuropathy is difficult, because electrophysiological findings suggestive of demyelination are frequently observed even in patients with neurolymphomatosis. Here, we report a patient with de novo CD5-positive diffuse large B-cell lymphoma (DLBCL) who presented with Guillain-Barre syndrome (GBS) like neuropathy. Demyelination due to paraneoplastic neuropathy was clinically suspected. However, autopsy demonstrated that the cause of the neuropathy was neurolymphomatosis. Clinical courses of neurolymphomatosis vary and neurolymphomatosis cases presenting with GBS-like neuropathy are reported. In addition, DLBCL is the most frequent histological type of malignant lymphoma that develops neurolymphomatosis. Furthermore, "CD5-positive" DLBCL may tend to develop neurolymphomatosis. If a patient with "CD5-positive" DLBCL develops peripheral neuropathy, neurolymphomatosis should be considered and imaging studies performed and, if possible, nerve tissue biopsy, regardless of clinical symptoms of the neuropathy. To our knowledge, this is the first report of a patient with de novo CD5-positive DLBCL with neurolymphomatosis who presented with GBS-like neuropathy. PMID- 29718564 TI - Decision complacency and conservation planning. PMID- 29718565 TI - Kidney offer acceptance at programs undergoing a Systems Improvement Agreement. AB - In the United States, the Centers for Medicare and Medicaid Services (CMS) use Systems Improvement Agreements (SIAs) to require transplant programs repeatedly flagged for poor-performance to improve performance or lose CMS funding for transplants. We identified 14 kidney transplant (KT) programs with SIAs and 28 KT programs without SIAs matched on waitlist volume and characterized kidney acceptance using SRTR data from 12/2006-3/2015. We used difference-in-differences linear regression models to identify changes in acceptance associated with an SIA independent of program variation and trends prior to the SIA. SIA programs accepted 26.9% and 22.1% of offers pre- and post-SIA, while non-SIA programs accepted 33.9% and 44.4% of offers in matched time periods. After adjustment for donor characteristics, time-varying waitlist volume, and secular trends, SIAs were associated with a 5.9 percentage-point (22%) decrease in kidney acceptance (95% CI: -10.9 to -0.8, P = .03). The decrease in acceptance post-SIA was more pronounced for KDPI 0-40 kidneys (12.3 percentage-point decrease, P = .007); reductions in acceptance of higher KDPI kidneys occurred pre-SIA. Programs undergoing SIAs substantially reduced acceptance of kidney offers for waitlisted candidates. Attempts to improve posttransplant outcomes might have the unintended consequence of reducing access to transplantation as programs adopt more restrictive organ selection practices. PMID- 29718566 TI - 'I-as-We' - Powerful boundaries within the field of mental health coproduction. AB - To date, there is little research on personal crisis experiences of mental health professionals. The aim of this study was to explore some of the reasons for why self-disclosure is so difficult and how these difficulties may prevent productive forms of coproduction. These questions are addressed both from a psychiatrist's autoethnographic account and from the perspective of a peer worker who works in various coproductive relationships. It is shown that mental health professionals often revert to an "I-as-we", speaking of themselves as a collective and thereby reifying the boundaries between 'vulnerable users' and 'invulnerable professionals'. Ethnographic examples are given, of how these boundaries are produced by a continuous, often invisible, and powerful category work. It is discussed how the dichotomous logic of these boundaries can cause people on both sides to feel reduced to a representation of a certain species, which can take on an existential dimension. Ways out are identified for mental health professionals to self-reflexively engage with their own crisis experience in coproductive and other relationships. PMID- 29718567 TI - Usefulness of dual-phase cone-beam computed tomography during arteriography and automated tumour-feeder detection software in transarterial embolization for obscure arterial bleeding in the abdomen. AB - We report the usefulness of dual-phase cone-beam computed tomography during angiography (CBCTA) and automated tumour-feeder detection software (AFD) in transarterial embolization (TAE) for three consecutive cases of obscure arterial bleeding in the abdomen. Two patients presented with lower gastrointestinal bleeding and one showed bleeding into the pancreatic pseudocyst. Superior mesenteric or common hepatic angiography did not demonstrate extravasation, but dual-phase CBCTA and AFD could identify extravasation and an access route to the bleeding point. TAE with gelatin sponge particles and a microcoil was successfully performed under AFD guidance in all patients without any complication, and haemostasis could be achieved. PMID- 29718568 TI - An Exceptionally Efficient Co-Co2 P@N, P-Codoped Carbon Hybrid Catalyst for Visible Light-Driven CO2 -to-CO Conversion. AB - Artificial photosynthesis has attracted wide attention, particularly the development of efficient solar light-driven methods to reduce CO2 to form energy rich carbon-based products. Because CO2 reduction is an uphill process with a large energy barrier, suitable catalysts are necessary to achieve this transformation. In addition, CO2 adsorption on a catalyst and proton transfer to CO2 are two important factors for the conversion reaction, and catalysts with high surface area and more active sites are required to improve the efficiency of CO2 reduction. Here, a visible light-driven system for CO2 -to-CO conversion is reported, which consists of a heterogeneous hybrid catalyst of Co and Co2 P nanoparticles embedded in carbon nanolayers codoped with N and P (Co-Co2 P@NPC) and a homogeneous RuII -based complex photosensitizer. The average generation rate of CO of the system was up to 35 000 MUmol h-1 g-1 with selectivity of 79.1 % in 3 h. Linear CO production at an exceptionally high rate of 63 000 MUmol h-1 g-1 was observed in the first hour of reaction. Inspired by this highly active catalyst, Co@NC and Co2 P@NPC materials were also synthesized and their structure, morphology, and catalytic properties for CO2 photoreduction were explored. The results showed that the nanoparticle size, partially adsorbed H2 O molecules on the catalyst surface, and the hybrid nature of the systems influenced their photocatalytic CO2 reduction performance. PMID- 29718569 TI - GRP78-targeted in-silico virtual screening of novel anticancer agents. AB - Overexpression of GRP78 in a variety of cancers such as glioblastoma, leukemia, lung, prostate, breast, gastric, and colon makes it a prime target for anticancer drug development. Present study reports GRP78-based design of novel anticancer agents using in-silico methods. As a first step toward the work, the interactions between GRP78 and 15 known ligands were modeled by docking simulation. The docked complex, GRP78-13, superior to other compounds with respect to its experimental activity and energy descriptors, was deduced into a structure-based pharmacophore. This hypothesis was applied as a screening filter to Asinex and Chemdiv databases. Finally, 23 hits were tested in vitro. Among these, VH1019 and VH1011 induced a concentration-dependent strong broad antiproliferative effect in glioma (U87-MG), breast cancer (MCF-7), and prostate cancer (DU-145) cell lines as compared to nontumorigenic control, neonatal foreskin fibroblast (HFF-1). These compounds showed preferential growth inhibition of cancer cells over normal cells. The acetohydrazide derivative VH1019 was identified as a potential new chemotype for GRP78 inhibitors with an IC50 of 12.7 MUM in MCF-7. PMID- 29718570 TI - What a drag: necrotic platelets induce remote neutrophil thrombi following ischemic gut injury. PMID- 29718571 TI - Corrigendum. PMID- 29718572 TI - A Carbapenem-Based Off-On Fluorescent Probe for Specific Detection of Metallo beta-Lactamase Activities. AB - Metallo-beta-lactamase is one of the major clinical threats because this beta lactam-hydrolyzing enzyme confers significant resistance to most beta-lactam antibiotics, including carbapenems, among bacterial pathogens. Reported herein is a novel fluorogenic sensor for the specific detection of metallo-beta-lactamase activities. This carbapenem-based reagent exhibits excellent selectivity to metallo-beta-lactamase over other serine-beta-lactamases, including serine carbapenemases. The usefulness of this probe was further demonstrated in the rapid identification of metallo-beta-lactamase-expressing pathogenic bacteria. PMID- 29718573 TI - Metal-Free Nitrogen Fixation at Boron. AB - No metal needed: Boron does the job! The activation of the inert dinitrogen molecule has fascinated chemists for ages. In a ground-breaking study Braunschweig and co-workers have now demonstrated that N2 activation can be achieved with the aid of the p-block element boron-a reactivity previously restricted to transition metals. PMID- 29718574 TI - Optimising motivation and reducing burnout for radiation oncology trainees: A framework using self-determination theory. AB - Radiation oncology trainees in Australia and New Zealand have relatively high levels of emotional exhaustion and depersonalisation which are core components of burnout. The stresses of a demanding clinical load, studying for exams as well as family commitments are all contributing factors. Self-Deter mination Theory (SDT) provides a framework for optimising motivation which may be intrinsic or extrinsic. The three core components of SDT are competence, relatedness and autonomy. These factors should be addressed at a college level, Institutional and a personal level if the best outcomes are to be achieved. An environment that supports the individual's experience of competency, relatedness and autonomy will foster motivation and work engagement which in turn will improve performance, energy, resilience and creativity and reduce levels of burnout. PMID- 29718575 TI - Roles of the genomic sequence surrounding the stem-loop structure in the junction region including the 3' terminus of open reading frame 1 in hepatitis E virus replication. AB - Hepatitis E virus (HEV), a member of the family Hepeviridae, causes both acute and chronic viral hepatitis. We have previously demonstrated that the stem-loop structure in the junction region (JR) of HEV genome plays a critical role in HEV replication. However, the function of the sequence bordering the JR, including the 3' terminus of open reading frame (ORF1), in HEV replication is unknown. In this study, a panel of HEV Renilla luciferase (Rluc) replicons containing various deletions at 5' or 3' termini of the JR was constructed to determine the effect of the deletions on HEV replication in Huh7 human liver cells. We showed that even a single nucleotide deletion at the 5' terminus of the JR abolished HEV replication, whereas deletions at the 3' terminus of the JR also decreased virus replication efficiency. Furthermore, we also constructed firefly luciferase and Rluc dual-reporter HEV replicons containing the 3' terminal ORF1 of various lengths and the JR inserted upstream of the Rluc reporter. A higher level of HEV replication was observed in cells transfected with replicons containing the 3' terminal ORF1 than that of the JR only replicon. We also showed that the ORF3 noncoding sequence along with the JR promoted a higher level of translation activity than that promoted by JR and the ORF2 noncoding sequence. PMID- 29718576 TI - Trimethyl Orthoacetate and Ethylene Glycol Mono-Vinyl Ether as Enolate Surrogates in Enantioselective Iridium-Catalyzed Allylation. AB - Trimethyl orthoacetate and ethylene glycol mono-vinyl ether are employed in iridium-catalyzed enantioselective allylation reactions. The method documented enables their convenient use as surrogates for silyl ketene acetals and silyl enol ethers to prepare gamma,delta-unsaturated esters and protected aldehydes with excellent enantioselectivity. The utility of this novel method has been demonstrated by its implementation in a formal enantioselective synthesis of the meroterpenoid (+)-conicol. PMID- 29718577 TI - Engineering Bulk, Layered, Multicomponent Nanostructures with High Energy Density. AB - The precise control of individual components in multicomponent nanostructures is crucial to realizing their fascinating functionalities for applications in electronics, energy-conversion devices, and biotechnologies. However, this control remains particularly challenging for bulk, multicomponent nanomaterials because the desired structures of the constitute components often conflict. Herein, a strategy is reported for simultaneously controlling the structural properties of the constituent components in bulk multicomponent nanostructures through layered structural design. The power of this approach is illustrated by generating the desired structures of each constituent in a bulk multicomponent nanomaterial (SmCo + FeCo)/NdFeB, which cannot be attained with existing methods. The resulting nanostructure exhibits a record high energy density (31 MGOe) for this class of bulk nanocomposites composed of both hard and soft magnetic materials, with the soft magnetic fraction exceeding 20 wt%. It is anticipated that other properties beyond magnetism, such as the thermoelectric and mechanical properties, can also be tuned by engineering such layered architectures. PMID- 29718578 TI - Learning from failure in healthcare: Dynamic panel evidence of a physician shock effect. AB - Procedural failures of physicians or teams in interventional healthcare may positively or negatively predict subsequent patient outcomes. We identify this effect by applying (non)linear dynamic panel methods to data from the Belgian transcatheter aorta valve implantation registry containing information on the first 860 transcatheter aorta valve implantation procedures in Belgium. We find that a previous death of a patient positively and significantly predicts subsequent survival of the succeeding patient. We find that these learning from failure effects are not long-lived and that learning from failure is transmitted across adverse events. PMID- 29718579 TI - A simulation approach for power calculation in large cohort studies based on multistate models. AB - Realistic power calculations for large cohort studies and nested case control studies are essential for successfully answering important and complex research questions in epidemiology and clinical medicine. For this, we provide a methodical framework for general realistic power calculations via simulations that we put into practice by means of an R-based template. We consider staggered recruitment and individual hazard rates, competing risks, interaction effects, and the misclassification of covariates. The study cohort is assembled with respect to given age-, gender-, and community distributions. Nested case-control analyses with a varying number of controls enable comparisons of power with a full cohort analysis. Time-to-event generation under competing risks, including delayed study-entry times, is realized on the basis of a six-state Markov model. Incidence rates, prevalence of risk factors and prefixed hazard ratios allow for the assignment of age-dependent transition rates given in the form of Cox models. These provide the basis for a central simulation-algorithm, which is used for the generation of sample paths of the underlying time-inhomogeneous Markov processes. With the inclusion of frailty terms into the Cox models the Markov property is specifically biased. An "individual Markov process given frailty" creates some unobserved heterogeneity between individuals. Different left-truncation- and right-censoring patterns call for the use of Cox models for data analysis. p values are recorded over repeated simulation runs to allow for the desired power calculations. For illustration, we consider scenarios with a "testing" character as well as realistic scenarios. This enables the validation of a correct implementation of theoretical concepts and concrete sample size recommendations against an actual epidemiological background, here given with possible substudy designs within the German National Cohort. PMID- 29718581 TI - Anesthesia and SICD implantation-When less (invasive) may be more. PMID- 29718580 TI - Community/public health nursing faculty's knowledge, skills and attitudes of the Quad Council Competencies for Public Health Nurses. AB - : A multisite collaborative team of community/public health nursing (C/PHN) faculty surveyed baccalaureate nursing faculty to explore their knowledge, skills, attitudes, and application of the Quad Council Competencies for Public Health Nurses (QCC-PHN). OBJECTIVES: (1) Evaluate the knowledge, skills, and attitudes of the 2011 QCC-PHN by academic C/PHN faculty; (2) Evaluate the application of 2011 QCC-PHN by C/PHN faculty in the clinical practicum for undergraduate baccalaureate C/PHN students; and (3) Determine if a significant difference existed in the knowledge for each domain. DESIGN: A mixed methods descriptive research design was used to answer three specific hypotheses related to the study objectives. A convenience sample of 143 faculty teaching C/PHN in baccalaureate schools of nursing completed an online survey. MEASUREMENTS: ANOVA was used to determine the difference between knowledge, skills, attitudes, and application of nursing faculty regarding the QCC-PHN based on years of nursing experience, C/PHN experience, and nursing specialty preparation. Participants' qualitative comments for each domain were analyzed for themes. RESULTS: C/PHN nursing faculty are described and differences in knowledge, skills, and attitudes delineated. A statistically significant difference was found in skills based on years of experience in C/PHN and in the application of the competencies based on nursing specialty preparation. Variations in knowledge of the QCC-PHN are identified. CONCLUSIONS: Ten recommendations are proposed for key skill sets and necessary preparation for faculty to effectively teach C/PHN in baccalaureate schools of nursing. PMID- 29718582 TI - Rotavirus and norovirus in children with severe diarrhea in Burkina Faso before rotavirus vaccine introduction. AB - Burkina Faso introduced rotavirus vaccine (RotaTeq) to the national immunization program in November 2013. This study describes the detection rates, clinical profiles, and molecular epidemiology of rotavirus and norovirus (NoV) infections among children <5 years hospitalized (n = 154) because of acute diarrhea in Ouagadougou, Burkina Faso, from December 2012 to November 2013, just before the start of vaccination. Overall, 44% and 23% of fecal samples were positive for rotavirus and NoV, respectively, most of them detected during the cold dry season (December-March). The predominant G/P combinations were G12P[8] (47%) and G6P[6] (30%). G2P[4] (n = 3), G12P[6] (n = 3), and G6P[8] (n = 1) were also detected. Nearly all (94%) successfully genotyped NoV strains belonged to genotype GII.4. The predominance of rotavirus and NoV was noteworthy in the age group <=6 months, with 67% rotavirus and 22% NoV, respectively. Vomiting was significantly more common among rotavirus-infected children. To conclude, this study shows high detection rates of both rotavirus and NoV in children with severe diarrhea in Burkina Faso just before the introduction of rotavirus group A vaccination. The results can be used for estimating the impact of rotavirus group A vaccination, which started in the end of 2013. Furthermore, this study shows that the G6P[6] rotavirus strains emerging in Burkina Faso in 2010 is now established as a regionally important genotype. PMID- 29718583 TI - Targeted gene disruption by use of CRISPR/Cas9 ribonucleoprotein complexes in the water flea Daphnia pulex. AB - The microcrustacean Daphnia pulex is an important model for environmental, ecological, evolutionary and developmental genomics because its adaptive life history displays plasticity in response to environmental changes. Even though the whole-genome sequence is available and omics data have actively accumulated for this species, the available tools for analyzing gene function have thus far been limited to RNAi (RNA interference) and TALEN (the transcription activator-like effector nuclease) systems. The development of the CRISPR/Cas9 (clustered regularly interspaced short palindromic repeats/CRISPR-associated 9) system is thus expected to further increase the genetic tractability of D. pulex and to advance the understanding of this species. In this study, we developed a genome editing system for D. pulex using CRISPR/Cas9 ribonucleoprotein complexes (Cas9 RNPs). We first assembled a CRISPR single-guide RNA (sgRNA) specific to the Distal-less gene (Dll), which encodes a homeodomain transcription factor essential for distal limb development in invertebrates and vertebrates. Then, we injected Cas9 RNPs into eggs and evaluated its activity in vivo by a T7 endonuclease I assay. Injected embryos showed defective formation of the second antenna and disordered development of appendages, and indel mutations were detected in Dll loci, indicating that this technique successfully knocked out the target gene. PMID- 29718584 TI - Eosin Y as a Direct Hydrogen-Atom Transfer Photocatalyst for the Functionalization of C-H Bonds. AB - Eosin Y, a well-known economical alternative to metal catalysts in visible-light driven single-electron transfer-based organic transformations, can behave as an effective direct hydrogen-atom transfer catalyst for C-H activation. Using the alkylation of C-H bonds with electron-deficient alkenes as a model study revealed an extremely broad substrate scope, enabling easy access to a variety of important synthons. This eosin Y-based photocatalytic hydrogen-atom transfer strategy is promising for diverse functionalization of a wide range of native C-H bonds in a green and sustainable manner. PMID- 29718585 TI - Insight into How Telomeric G-Quadruplexes Enhance the Peroxidase Activity of Cellular Hemin. AB - The toxic oxidative damage of G-quadruplexes (G4), linked to neurodegenerative diseases, may arise from their ability to bind and oxidatively activate cellular hemin. However, there have been no precise studies on how telomeric G4 enhances the low intrinsic peroxidase activity of hemin. Herein, a label-free and nanopore based strategy was developed to explore the enhancement mechanism of peroxidase activity of hemin induced by telomeric G4 (d(TTAGGG)n ). The nanopore-based strategy demonstrated that there were simultaneously two different binding modes of telomere G4 to hemin. At the single-molecule level, it was found that the hybrid structural telomeric G4 directly binds to hemin (the affinity constant (Ka )~106 m-1 ) to form a tight complex, and some of them underwent a topological change to a parallel structure with an enhancement of Ka to approximately 107 m 1 . Through detailed analysis of the topology and peroxidase activity and molecular modeling investigations, the parallel telomere G4/hemin DNAzyme structure was proven to be preferable for high peroxidase activity. Upon strong pi-pi stacking, the parallel structural telomere G4 supplied a key axial ligand to the hemin iron, which accelerated the intermediate compound formation with H2 O2 in the catalytic cycle. Our studies developed a label-free and single-molecule strategy to fundamentally understand the catalytic activity and mechanism of telomeric DNAzyme, which provides some support for utilizing the toxic, oxidative damage property in cellular oxidative disease and anticancer therapeutics. PMID- 29718586 TI - Measurement of rivaroxaban concentrations demonstrates lack of clinical utility of a PT, dPT and APTT test in estimating levels. AB - INTRODUCTION: Rivaroxaban concentrations were measured in 127 inpatient samples using an HPLC-MS/MS assay. METHODS: We compared this measurement with a calibrated anti-Xa assay and performed PT, aPTT and dilute PT tests to assess the value of clot-based assays in clinical decision-making. RESULTS: The correlation between the anti-Xa assay and the HPLC-MS/MS at therapeutic concentrations was strong (R2 = 0.98). The PT, RecombiPlasTin 2G, and aPTT, Actin FS, showed a linear dose-response but poor correlation (R2 = 0.32 and 0.44, respectively) and at dilutions of 1 in 150 to 1 in 750 the dilute PT assay also showed poor correlation with rivaroxaban concentrations measured by specific assays. A normal PT or aPTT alone did not identify a likely safe rivaroxaban concentration to allow surgery or invasive procedures, but the combination of normal PT and aPTT identified a group of patients with rivaroxaban levels less than 90 ng/mL. Combined normal PT and aPTT had specificity and sensitivity of 0.97 (95% CI 0.92 0.99) and 0.37 (95% CI 0.1-0.74) for a rivaroxaban concentration < 32 ng/mL. CONCLUSIONS: The PT and aPTT show poor correlation with rivaroxaban levels measured by calibrated anti-Xa and HPLC-MS/MS assays. A normal combined PT and APTT identified low rivaroxaban levels with high specificity but lacked sensitivity. The dPT assay at several dilutions could not be used to quantify rivaroxaban in clinical samples. The utility of these PT, aPTT and dilute PT assays in a clinical setting is very limited, and results generated must be interpreted with caution. PMID- 29718587 TI - Self-Assembly of Diblock Molecular Polymer Brushes in the Spherical Confinement of Nanoemulsion Droplets. AB - Understanding the self-assembly behavior of polymers of various topologies is key to a reliable design of functional polymer materials. Self-assembly under confinement conditions emerges as a versatile avenue to design polymer particles with complex internal morphologies while simultaneously facilitating scale-up. However, only linear block copolymers have been studied to date, despite the increasing control over macromolecule composition and architecture available. This study extends the investigation of polymer self-assembly in confinement from regular diblock copolymers to diblock molecular polymer brushes (MPBs). Block type MPBs with polystyrene (PS) and polylactide (PLA) compartments of different sizes are incorporated into surfactant-stabilized oil-in-water (chloroform/water) emulsions. The increasing confinement in the nanoemulsion droplets during solvent evaporation directs the MPBs to form solid nano/microparticles. Microscopy studies reveal an intricate internal particle structure, including interpenetrating networks and axially stacked lamellae of PS and PLA, depending on the PS/PLA ratio of the brushes. PMID- 29718588 TI - Community attitudes to emergency research without prospective informed consent: A survey of the general population. AB - OBJECTIVE: To give voice to the general public's views of prospective and retrospective (deferred) consent in the emergency research setting. METHODS: A cross-sectional, stratified population-based, telephone survey was conducted in April to July 2016. A questionnaire consisting of standardised health and demographic details, and seven specifically designed, and pilot-tested questions, five closed and two open text, based on literature review and previous surveys in the field was used. Quantitative and qualitative techniques were used in the data analysis. This was a centrally coordinated national telephone survey in Australia, the 2016 National Social Survey, coordinated by Central Queensland University. Data for 1217 adult (18+ years) participants were included in the analysis, with a response rate of 26%. The sample demographics were broadly representative of the Australian population. RESULTS: The majority of respondents were supportive of research in emergency circumstances without prospective informed consent. However, the type of research and level of risk influence its acceptability. Common themes in qualitative analysis included the critical or life-threatening nature of the illness being researched, and the potential harms and benefits of participation. CONCLUSIONS: This research provided the first opportunity for the community to contribute to discourse about prospective and retrospective (deferred) consent in the emergency research setting in Australia. Further work is needed to determine community expectations of how this process can be optimised and implemented, and to identify potential situations where this may not be acceptable. PMID- 29718589 TI - Comorbid inner ear disorders in 50 patients with congenital nystagmus. PMID- 29718590 TI - "One-for-All" Strategy in Fast Energy Storage: Production of Pillared MOF Nanorod Templated Positive/Negative Electrodes for the Application of High-Performance Hybrid Supercapacitor. AB - Currently, metal-organic frameworks (MOFs) are intensively studied as active materials for electrochemical energy storage applications due to their tunable structure and exceptional porosities. Among them, water stable pillared MOFs with dual ligands have been reported to exhibit high supercapacitor (SC) performance. Herein, the "One-for-All" strategy is applied to synthesize both positive and negative electrodes of a hybrid SC (HSC) from a single pillared MOF. Specifically, Ni-DMOF-TM ([Ni(TMBDC)(DABCO)0.5 ], TMBDC: 2,3,5,6-tetramethyl-1,4 benzenedicarboxylic acid, DABCO: 1,4-diazabicyclo[2.2.2]-octane) nanorods are directly grown on carbon fiber paper (CFP) (denoted as CFP@TM-nanorods) with the help of triethylamine and function as the positive electrode of HSC under alkaline electrolyte. Meanwhile, calcinated N-doped hierarchical porous carbon nanorods (CFP@TM-NPCs) are produced and utilized as the negative counter electrode from a one-step heat treatment of CFP@TM-nanorods. After assembling these two electrodes together to make a hybrid device, the TM-nanorods//TM-NPCs exhibit a wide voltage window of 1.5 V with a high sloping discharge plateau between 1-1.2 V, indicating its great potential for practical applications. This as-described "One-for-All" strategy is widely applicable and highly reproducible in producing MOF-based electrode materials for HSC applications, which shortens the gap between experimental synthesis and practical application of MOFs in fast energy storage. PMID- 29718591 TI - Glomerular crescents are associated with worse graft outcome in allograft IgA nephropathy. AB - The prognosis of patients with allograft IgA nephropathy (IgAN) requires further investigation. We performed a bicenter retrospective cohort study on kidney transplant recipients diagnosed with IgAN in allograft biopsy. Recipients without allograft IgAN but with known IgAN before transplantation were included as the control group. We investigated the associations between clinicopathological characteristics, including allograft crescents, and the risk of death-censored graft failure. In total, 1256 IgAN patients in both pre- and posttransplant stages were included. Among them, 559 were diagnosed with allograft IgAN, which was a time-dependent risk factor for worse prognosis (adjusted hazard ratio = 5.009 [3.610-6.951]; P < .001) during a median of 8.1 years of follow-up. Of the patients with allograft IgAN, 88 (15.9%) had glomerular crescents, including 40 patients (7.2%) with >10% crescent formation in the total biopsied glomeruli. The presence of glomerular crescents in IgAN was associated with a worse graft prognosis, and the association was still valid with the C scores of the current Oxford classification. In conclusion, allograft IgAN is a time-dependent event and is associated with worse graft outcomes. The pathological characteristics of allograft, particularly the degree of glomerular crescent formation, may represent important risk factors for a poor prognosis. PMID- 29718593 TI - Primary pulmonary meningioma presenting as a micro solid nodule: A rare case report. AB - An ectopic meningioma, such as a primary pulmonary meningioma (PPM), is a rare type of tumor that primarily originates outside of the central nervous system. A 65-year-old female patient underwent a thoracoscopic lung wedge resection of the right lower lobe for a micro solid nodule detected via computed tomography. The histologic result revealed a PPM. PPMs manifested with micro solid nodules are a very rare occurrence in clinical practice. Increased awareness of the clinical and pathological characteristics of this rare disease can assist thoracic surgical teams to apply adequate management. PMID- 29718592 TI - Epinephrine augments posttetanic potentiation in mouse skeletal muscle with and without myosin phosphorylation. AB - Sympathetic tone may influence force potentiation, that is, the stimulation induced increase in skeletal muscle mechanical function associated with myosin phosphorylation, although the mechanism for this effect remains unknown. The purpose of this study was to examine the influence of epinephrine on concentric twitch force potentiation of wild-type and skeletal myosin light-chain kinase devoid mouse muscle (skMLCK-/- ). To this end, concentric twitch force was assessed before and after a potentiating stimulus (PS) to determine the peak and the duration of potentiation in the absence (-EPI) and presence (+EPI) of 1 MUmol/L epinephrine in both genotypes. Twitch force of wild-type and skMLCK-/- muscles was increased by up to 31 and 35% and 18 and 23% in the -EPI and EPI conditions, respectively (all data n = 8, P < 0.05). In wild-type muscles, the PS increased RLC phosphorylation from 0.14 +/- 0.05 (rest) to 0.66 +/- 0.08 mol phos mol RLC; by 480 sec RLC phosphorylation had returned to baseline (all data n = 4 each time point, P < 0.05). Neither resting nor peak levels of RLC phosphorylation were altered by +EPI, although the duration of RLC phosphorylation was prolonged. In skMLCK-/- muscles, RLC phosphorylation was not elevated above constituent levels by stimulation in either the -EPI or +EPI condition. Thus, given the similarity in potentiation responses between genotypes our data suggest that the influence of epinephrine on potentiation was independent of skMLCK catalyzed phosphorylation of the RLC, although the clinical significance of this pathway for skeletal muscle function remains to be identified. PMID- 29718594 TI - Pharmacodynamic and pharmacokinetic studies and prostatic tissue distribution of fosfomycin tromethamine in bacterial prostatitis or normal rats. AB - In this study, we assessed the therapeutic effects of fosfomycin tromethamine (FT) in a bacterial prostatitis (BP) rat model. The BP model was induced by Escherichia coli and was demonstrated after 7 days microbiologically and histologically. Then, 25 BP rats selected were randomly divided into five treatment groups: model group, positive group, FT-3 day group, FT-7 day group and FT-14 day group. Ventral lobes of prostate from all animals were removed, and the serum samples were collected at the end of the experiments. Microbiological cultures and histological findings of the prostate samples demonstrated reduced bacterial growth and improved inflammatory responses in FT-treatment groups compared with the model group, indicating that FT against prostatic infection induced by E. coli showed good antibacterial effects. Moreover, plasma pharmacokinetics and prostatic distribution of fosfomycin were studied and compared in BP and normal rats. The concentrations of fosfomycin in samples were analysed by liquid chromatography-tandem mass spectrometry. There were no differences in plasma pharmacokinetic parameters between two groups. But significantly higher penetration of fosfomycin into prostatic tissues was found in BP rats. We therefore suggested that FT had a good therapeutic effect on BP and it might be used in curing masculine reproductive system diseases. PMID- 29718595 TI - Distinguishing Between Borderline Personality Disorder and Bipolar Disorder. PMID- 29718596 TI - Dr Gonzalez-Pinto and Colleagues Reply. PMID- 29718597 TI - No Changes in Gray Matter Density or Cortical Thickness in Late-Life Minor Depression. PMID- 29718598 TI - Does a Meta-Analysis of Sleep Deprivation Studies Demonstrate Efficacy? PMID- 29718599 TI - Drs Boland and Gehrman Reply. PMID- 29718600 TI - Relative Efficacy and Acceptability of Antidepressant Drugs in Adults With Major Depressive Disorder: Commentary on a Network Meta-Analysis. AB - A large number of antidepressant drugs are available across the world. All have been compared against placebo, and many have been compared with some but not all other antidepressants. There is therefore little information about a hierarchy of the efficacy and acceptability of these drugs. About 9 years ago, a network meta analysis attempted to rank the efficacy and acceptability of 12 newer antidepressant drugs in adults with major depressive disorder. Very recently, this network meta-analysis was updated to include 21 antidepressant drugs, most of which were introduced during the 1980s and afterward. The present article explains what meta-analysis and network meta-analysis do, summarizes the important findings of the 21-antidepressant network meta-analysis, and offers comments on the findings. In general, it appears that antidepressant drugs are associated with clinically significant superiority over placebo with regard to response and remission rates; that almost all antidepressants do not differ from placebo with regard to all-cause discontinuation; that escitalopram, mirtazapine, amitriptyline, venlafaxine, and paroxetine are associated with better response rates than certain other antidepressants; that reboxetine, trazodone, and fluoxetine are associated with poorer response rates than certain other antidepressants; that agomelatine, escitalopram, and vortioxetine are associated with lower all-cause discontinuation than certain other antidepressants; and that clomipramine, reboxetine, and duloxetine are associated with higher all-cause discontinuation than certain other antidepressants. Whereas this conclusion is necessarily subjective, escitalopram could be a first choice in the balance of efficacy and acceptability, and reboxetine, the last choice. The strengths and limitations of the network meta-analysis are examined, and some comments on the findings are offered. PMID- 29718601 TI - Diagnosing Bipolar Disorder in Pediatric Patients. AB - As many as 2 million youths in the US alone could have bipolar disorder. In this CME brief report, get up-to-date on common presentations of pediatric bipolar disorder, DSM-5 diagnostic criteria, and structured interviews and screening tools that can help you detect manic symptomatology. PMID- 29718602 TI - Treating Bipolar Disorder in Adolescents. AB - How do you select among treatments for bipolar disorder in adolescents? Check out this brief report activity to explore the efficacy and safety of lithium, anticonvulsants, and atypical antipsychotics in the treatment of adolescent bipolar disorder. Plus, receive guidance for monitoring for common adverse effects, such as weight gain and fatigue. PMID- 29718603 TI - Non-technical skills required to recognise and escalate patient deterioration in acute hospital settings. AB - Recognising patient deterioration is a vital nursing role. Observation based on vital signs and early warning scores are mandatory for all adult patients in acute hospital care and are the first steps in identifying deterioration. However, they rely on users' understanding of the significance of the results they find and their ability to escalate to senior colleagues if necessary. This article examines the non-technical skills nurses require to recognise and escalate patient deterioration. Itexplores and analyses the literature on this topic and suggests there is a need for greater focus on situational awareness in nurse training and in healthcare in general, as this is linked to improved patient safety. PMID- 29718604 TI - HEALTHCARE CHANGES CAN CREATE A LEADERSHIP "CHASM". PMID- 29718605 TI - PROVIDER AGREEMENTS WITH HEALTH PLANS AND SEPARATE TAX IDS. PMID- 29718606 TI - SAVE TIME AND MONEY ON PAYMENT PROCESSING WITH A HEALTHCARE IMAGE LOCKBOX. PMID- 29718607 TI - IS MARIJUANA MEDICINE? PMID- 29718608 TI - NO EASY FIX. PMID- 29718609 TI - THE GOOD NEWS/ BAD NEWS ABOUT TENNESSEE'S OPIOID EPIDEMIC. PMID- 29718610 TI - PAIN RELIEF DOESN'T ALWAYS COME IN A PILL. PMID- 29718611 TI - DRUG-RELATED DEATHS: THE MEDICAL EXAMINER PERSPECTIVE. PMID- 29718612 TI - Another Strategy in the Opioid Battle. PMID- 29718613 TI - OUR "COTTAGE INDUSTRY": ALAS, I KNEW IT WELL! PMID- 29718614 TI - REVITALIZATION IN THE UPPER CUMBERLAND. PMID- 29718615 TI - Homemade Cookies Make a Comeback. PMID- 29718616 TI - A Study of Workplace Violence: What Nurses Need to Know to Take Action. PMID- 29718617 TI - Lead with Ethics. PMID- 29718618 TI - Mentoring a Bond of Trust. PMID- 29718619 TI - Advancing the Practice of Nursing in the Upper Cumberland: Celebrating the Past, Present, and Future PMID- 29718620 TI - Health Idea Gets Second Chance. PMID- 29718621 TI - Transforming Nursing Education: Next Steps at Belmont. PMID- 29718622 TI - Essential Virtues in Nursing. PMID- 29718623 TI - Lara's Law: Make Tennessee Roads Safer Now. PMID- 29718624 TI - Healing the Gap Post-Election: A Call to Action. PMID- 29718625 TI - Reflection on the Scope of Practice Task Force. PMID- 29718626 TI - And Now for the Rest of the Story. PMID- 29718627 TI - Nursing and Ethical Commitments. PMID- 29718628 TI - Fostering a Healthy Workforce: Cultivating Civility in Nursing. PMID- 29718629 TI - A Guide to Writing: Time, Commitment, and Preparation. PMID- 29718630 TI - PAC MENTALITY: EMPOWERING THE VOICES OF TEXAS NURSES. PMID- 29718631 TI - WORKPLACE VIOLENCE: INCREASED FOCUS ON SAFETY IN HEALTH CARE SETTINGS. PMID- 29718632 TI - HEALTH IT: Texas Nurses Evaluate Usage/Usability. PMID- 29718633 TI - PREVENTING PATIENT HARM: Achieving a Culture of Safety in 2016. PMID- 29718634 TI - UNFINISHED CARE: RESEARCHER DELVES INTO IMPACT OF NURSE STAFFING CONUNDRUM. PMID- 29718635 TI - BRIDGE TO RECOVERY: TPAPN STRIVES TO RETURN NURSES TO SAFE PRACTICE. PMID- 29718636 TI - COMMUNICATION SKILLS FOR PATIENT SAFETY: Speak So Your Message Can Be Heard. PMID- 29718640 TI - SOMEONE TO LEAN ON: TPAPN Advocates Give Back to Nurses in Recovery. PMID- 29718641 TI - BOARD OF NURSING FACES SUNSET: WHAT DOES THAT MEAN FOR YOU? PMID- 29718642 TI - HEALTHY COMMUNITIES START WITH NURSES. PMID- 29718643 TI - FATIGUE: A NURSE'S RESPONSIBILITY TO SELF & PATIENTS. PMID- 29718644 TI - DELIVERING YOUR MESSAGE POWERFULLY. PMID- 29718645 TI - CULTURAL HUMILITY: SEEKING TO UNDERSTAND ANOTHER'S PERSPECTIVE. PMID- 29718646 TI - PRACTICING WITH RESPECT: STORY OF LEE. PMID- 29718647 TI - GENDER TRANSITION: ONE NURSE'S STORY. PMID- 29718648 TI - SO YOU WANT TO BE AN APPROVED PROVIDER? PMID- 29718649 TI - Synthetic drug intoxication in children: recognition and management in the emergency department [digest]. AB - When children and adolescents present to the emergency department with agitation or mental status changes, intoxication from synthetic drug use should be in the differential diagnosis. Identifying the responsible compound(s) may be difficult, so asking the patient broad questions and utilizing appropriate diagnostic studies, when indicated, will aid in making the diagnosis and help identify more serious complications. This issue discusses the challenges presented by the changing chemical formulations of synthetic cannabinoids, cathinones, and phenethylamines; outlines common presentations of intoxication from these substances; and summarizes best practices for evaluating and managing patients who present with intoxication after consumption of these synthetic drugs of abuse. [Points & Pearls is a digest of Pediatric Emergency Medicine Practice.]. PMID- 29718650 TI - Metal TiO2 Nanotube Layers for the Treatment of Dental Implant Infections. AB - Titanium oxide nanotube layers with silver and zinc nanoparticles are attracting increasing attention in the design of bone and dental implants due to their antimicrobial potential and their ability to control host cell adhesion, growth, and differentiation. However, recent reports indicate that the etiology of dental infections is more complex than has been previously considered. Therefore, the antimicrobial potential of dental implants should be evaluated against at least several different microorganisms cooperating in human mouth colonization. In this study, Ag and Zn nanoparticles incorporated into titanium oxide nanotubular layers were studied with regard to how they affect Candida albicans, Candida parapsilosis, and Streptococcus mutans. Layers of titanium oxide nanotubes with an average diameter of 110 nm were fabricated by electrochemical anodization, annealed at 650 degrees C, and modified with approx. 5 wt % Ag or Zn nanoparticles. The surfaces were examined with the scanning electron microscopy energy dispersive X-ray analysis, scanning transmission electron microscopy, and X-ray photoelectron spectroscopy techniques and subjected to evaluation of microbial-killing and microbial adhesion-inhibiting potency. In a 1.5 h long adhesion test, the samples were found more effective toward yeast strains than toward S. mutans. In a release-killing test, the microorganisms were almost completely eliminated by the samples, either within 3 h of contact (for S. mutans) or 24 h of contact (for both yeast strains). Although further improvement is advisable, it seems that Ag and Zn nanoparticles incorporated into TiO2 nanotubular surfaces provide a powerful tool for reducing the incidence of bone implant infections. Their high bidirectional activity (against both Candida species and S. mutans) makes the layers tested particularly promising for the design of dental implants. PMID- 29718651 TI - One-Dimensional Cu2- xSe Nanorods as the Cathode Material for High-Performance Aluminum-Ion Battery. AB - In this work, nonstoichiometric Cu2- xSe fabricated by a facile water evaporation process is used as high-performance Al-ion battery cathode materials. Cu2- xSe electrodes show high reversible capacity and excellent cycling stability, even at a high current density of 200 mA g-1, the specific charge capacity in the initial cycle is 241 mA h g-1 and maintains 100 mA h g-1 after 100 cycles with a Coulombic efficiency of 96.1%, showing good capacity retention. The prominent kinetics of Cu2- xSe electrodes is also revealed by the GITT, which is attributed to the ultrahigh electronic conductivity of the Cu2- xSe material. Most importantly, an extensive research is dedicated to investigating the detailed intercalation and de-intercalation of relatively large chloroaluminate anions into the cubic Cu2- xSe, which is conducive to better understand the reaction mechanism of the Al/Cu2- xSe battery. PMID- 29718652 TI - TiO2-MnO x-Pt Hybrid Multiheterojunction Film Photocatalyst with Enhanced Photocatalytic CO2-Reduction Activity. AB - Photocatalytic CO2 conversion into solar fuels has an alluring prospect. However, the rapid recombination of photogenerated electron-hole pairs for TiO2-based photocatalyst hinders its wide application. To alleviate this bottleneck, a ternary hybrid TiO2-MnO x-Pt composite is excogitated. Taking advantage of the surface junction between {001} and {101} facets, MnO x nanosheets and Pt nanoparticles are selectively deposited on each facet by a facile photodeposition method. This design accomplishes the formation of two heterojunctions: p-n junction between MnO x and TiO2 {001} facet and metal-semiconductor junction between Pt and TiO2 {101} facet. Both of them, together with the surface heterojunction between {001} and {101} facets, are contributive to the spatial separation of the photogenerated electron-hole pairs. Thanks to their cooperative and synergistic effect, the as-prepared composite photocatalyst exhibits a promoted yield of CH4 and CH3OH, which is over threefold of pristine TiO2 nanosheets films. The conjecture of the mechanism that selective formation of multijunction structure maximizes the separation and transfer efficiency of photogenerated charge carriers is proved by the photoelectrochemical analysis. This work not only successfully achieves an efficient multijunction photocatalyst by ingenious design but also provides insight into the mechanism of the performance enhancement. PMID- 29718653 TI - Silk Sponges Ornamented with a Placenta-Derived Extracellular Matrix Augment Full Thickness Cutaneous Wound Healing by Stimulating Neovascularization and Cellular Migration. AB - Regeneration of full-thickness wounds without scar formation is a multifaceted process, which depends on in situ dynamic interactions between the tissue engineered skin substitutes and a newly formed reparative tissue. However, the majority of the tissue-engineered skin substitutes used so far in full-thickness wound healing cannot mimic the natural extracellular matrix (ECM) complexity and thus are incapable of providing a suitable niche for endogenous tissue repair. Herein, we demonstrated a simple approach to fabricate porous hybrid ECM sponges (HEMS) using a placental ECM and silk fibroin for full-thickness wound healing. HEMS with retained cytokines/growth factors provided a noncytotoxic environment in vitro for human foreskin fibroblasts (HFFs), human epidermal keratinocytes (HEKs), and human amniotic membrane-derived stem cells to adhere, infiltrate, and proliferate. Interestingly, HEMS-conditioned media accelerated the migration of HFFs and HEKs owing to the presence of cytokines/growth factors. Also, the ex vivo chick chorioallantoic membrane assay of HEMS demonstrated its excellent vascularization potential by inducing and supporting blood vessels. Additionally, HEMS when subcutaneously implanted demonstrated no severe immune response to the host. Furthermore, HEMS implanted in full-thickness wounds in a rat model showed augmented healing progression with well-organized epidermal-dermal junctions via pronounced angiogenesis, accelerated migration of HFFs/HEKs, enhanced granulation tissue formation, and early re-epithelialization. Taken together, these findings show that porous HEMS ornamented with cytokines/growth factors having superior physicomechanical properties may be an appropriate skin substitute for full thickness cutaneous wounds. PMID- 29718654 TI - How Transparent Oxides Gain Some Color: Discovery of a CeNiO3 Reduced Bandgap Phase As an Absorber for Photovoltaics. AB - In this work, we describe the formation of a reduced bandgap CeNiO3 phase, which, to our knowledge, has not been previously reported, and we show how it is utilized as an absorber layer in a photovoltaic cell. The CeNiO3 phase is prepared by a combinatorial materials science approach, where a library containing a continuous compositional spread of Ce xNi1- xO y is formed by pulsed laser deposition (PLD); a method that has not been used in the past to form Ce-Ni O materials. The library displays a reduced bandgap throughout, calculated to be 1.48-1.77 eV, compared to the starting materials, CeO2 and NiO, which each have a bandgap of ~3.3 eV. The materials library is further analyzed by X-ray diffraction to determine a new crystalline phase. By searching and comparing to the Materials Project database, the reduced bandgap CeNiO3 phase is realized. The CeNiO3 reduced bandgap phase is implemented as the absorber layer in a solar cell and photovoltages up to 550 mV are achieved. The solar cells are also measured by surface photovoltage spectroscopy, which shows that the source of the photovoltaic activity is the reduced bandgap CeNiO3 phase, making it a viable material for solar energy. PMID- 29718655 TI - Fabrication of Multiple-Layered Hydrogel Scaffolds with Elaborate Structure and Good Mechanical Properties via 3D Printing and Ionic Reinforcement. AB - A major challenge in three-dimensional (3D) printing of hydrogels is the fabrication of stable constructs with high precision and good mechanical properties and biocompatibility. Existing methods typically feature complicated reinforcement steps or use potentially toxic components, such as photocuring polymers and crosslinking reagents. In this study, we used a thermally sensitive hydrogel, hydroxybutyl chitosan (HBC), for 3D-printing applications. For the first time, we demonstrated that this modified polysaccharide is affected by the specific ion effect. As the salt concentration was increased and stronger kosmotropic anions were used, the lower critical solution temperature of the HBC decreased and the storage modulus was improved, indicating a more hydrophobic structure and stronger molecular chain interactions. On the basis of the thermosensitivity and the ion effects of HBC, a 25-layered hydrogel scaffold with strong mechanical properties and an elaborate structure was prepared via a 3D printing method and one-step ionic post-treatment. In particular, the scaffold treated with 10% NaCl solution exhibited a tunable elastic modulus of 73.2 kPa to 40 MPa and excellent elastic recovery, as well as biodegradability and cytocompatibility, suggesting the potential for its applications to cartilage tissue repair. By simply controlling the temperature and salt concentrations, this novel approach provides a convenient and green route to improving the structural accuracy and regulating the properties of 3D-printed hydrogel constructs. PMID- 29718657 TI - Probing Exciton Complexes and Charge Distribution in Inkslab-Like WSe2 Homojunction. AB - By virtue of the layer-dependent band structure and valley-selected optical/electronic properties, atomically layered transition-metal dichalcogenides (TMDs) exhibit great potentials such as in valleytronics and quantum devices, and have captured significant attentions. Precise control of the optical and electrical properties of TMDs is always the pursuing goal for real applications, and constructing advanced structures that allow playing with more degrees of freedom may hold the key. Here, we introduce a triangular inkslab-like WSe2 homojunction with a monolayer in the inner surrounded by a multilayer frame. Benefit from this interesting structure, the photoluminescence (PL) peaks redshift up to 50 meV and the charge density increases about 6 times from the center to the edge region of the inner monolayer. We demonstrated that the Se deficient multilayer frame offers the excessive free electrons for the generation of the electron density gradient inside the monolayer, which also results in the spatial variation and distribution gradient of a series of exciton complexes. Furthermore, we observed the strong rectifying characteristic and clear photovoltaic response across the homojunction through measuring and mapping the photocurrent of the devices. Our result provides another route for efficient modulation of the exciton-complex emissions of TMDs, which is exceptionally desirable for the "layer- and charge-engineered" photonic and optoelectronic devices. PMID- 29718656 TI - Small Molecule Inhibitors of Metabolic Enzymes Repurposed as a New Class of Anthelmintics. AB - The enormous prevalence of infections caused by parasitic nematodes worldwide, coupled to the rapid emergence of their resistance to commonly used anthelmintic drugs, presents an urgent need for the discovery of new drugs. Herein, we have identified several classes of small molecules with broad spectrum activity against these pathogens. Previously, we reported the identification of carnitine palmitoyltransferases (CPTs) as a representative class of enzymes as potential targets for metabolic chokepoint intervention that was elucidated from a combination of chemogenomic screening and experimental testing in nematodes. Expanding on these previous findings, we have discovered that several chemical classes of known small molecule inhibitors of mammalian CPTs have potent activity as anthelmintics. Cross-clade efficacy against a broad spectrum of adult parasitic nematodes was demonstrated for multiple compounds from different series. Several analogs of these initial hit compounds were designed and synthesized. The compounds we report represent a good starting point for further lead identification and optimization for development of new anthelmintic drugs with broad spectrum activity and a novel mechanism of action. PMID- 29718658 TI - The Design and Characterization of Multifunctional Aptamer Nanopore Sensors. AB - Aptamer-modified nanomaterials provide a simple, yet powerful sensing platform when combined with resistive pulse sensing technologies. Aptamers adopt a more stable tertiary structure in the presence of a target analyte, which results in a change in charge density and velocity of the carrier particle. In practice the tertiary structure is specific for each aptamer and target, and the strength of the signal varies with different applications and experimental conditions. Resistive pulse sensors (RPS) have single particle resolution, allowing for the detailed characterization of the sample. Measuring the velocity of aptamer modified nanomaterials as they traverse the RPS provides information on their charge state and densities. To help understand how the aptamer structure and charge density effects the sensitivity of aptamer-RPS assays, here we study two metal binding aptamers. This creates a sensor for mercury and lead ions that is capable of being run in a range of electrolyte concentrations, equivalent to river to seawater conditions. The observed results are in excellent agreement with our proposed model. Building on this we combine two aptamers together in an attempt to form a dual sensing strand of DNA for the simultaneous detection of two metal ions. We show experimental and theoretical responses for the aptamer which creates layers of differing charge densities around the nanomaterial. The density and diameter of these zones effects both the viability and sensitivity of the assay. While this approach allows the interrogation of the DNA structure, the data also highlight the limitations and considerations for future assays. PMID- 29718659 TI - Bacteria-Carried Iron Oxide Nanoparticles for Treatment of Anemia. AB - The efficiency of maghemite nanoparticles for the treatment of anemia was sensibly higher when nanoparticles were incorporated onto the probiotic bacterium Lactobacillus fermentum (MNP-bacteria) than when administrated as uncoated nanoparticles (MNP). Plasma iron and hemoglobin, intestine expression of divalent metal transporter 1 (DMT1) and duodenal Cytochrome b (DcytB), as well as hepatic expression of the hormone hepcidin were fully restored to healthy levels after administration of MNP-bacteria but not of MNP. A magnetic study on biodistribution and biodegradation showed accumulation of maghemite nanoparticles in intestine lumen when MNP-bacteria were administrated. In contrast, MNP barely reached intestine. In vivo MRI studies suggested the internalization of MNP bacteria into enterocytes, which did not occur with MNP. Transmission electronic microscopy confirmed this internalization. The collective analysis of results point out that L. fermentum is an excellent carrier to overcome the stomach medium and drive maghemite nanoparticles to intestine, where iron absorption occurs. Due the probiotic ability to adhere to the gut wall, MNP-bacteria internalize into the enterocyte, where maghemite nanoparticles are delivered, providing an adequate iron level into enterocyte. This paper advances a new route for effective iron absorption in the treatment of anemia. PMID- 29718660 TI - Coordination Properties of GdDO3A-Based Model Compounds of Bioresponsive MRI Contrast Agents. AB - We report a detailed characterization of the thermodynamic stability and dissociation kinetics of Gd3+ complexes with DO3A derivatives containing a (methylethylcarbamoylmethylamino)acetic acid (L1), (methylpropylcarbamoylmethylamino)acetic acid (L2), 2-dimethylamino- N ethylacetamide (L3), or 2-dimethylamino- N-propylacetamide (L4) group attached to the fourth nitrogen atom of the macrocyclic unit. These ligands are model systems of Ca2+- and Zn2+-responsive contrast agents (CA) for application in magnetic resonance imaging (MRI). The results of the potentiometric studies ( I = 0.15 M NaCl) provide stability constants with log KGdL values in the range 13.9-14.8. The complex speciation in solution was found to be quite complicated due to the formation of protonated species at low pH, hydroxido complexes at high pH, and stable dinuclear complexes in the case of L1,2. At neutral pH significant fractions of the complexes are protonated at the amine group of the amide side chain (log KGdL*H = 7.2-8.1). These ligands form rather weak complexes with Mg2+ and Ca2+ but very stable complexes with Cu2+ (log KCuL = 20.4-22.3) and Zn2+ (log KZnL = 15.5-17.6). Structural studies using a combination of 1H NMR and luminescence spectroscopy show that the amide group of the ligand is coordinated to the metal ion at pH ~8.5, while protonation of the amine group provokes the decoordination of the amide O atom and a concomitant increase in the hydration number and proton relaxivity. The dissociation of the complexes occurs mainly through a rather efficient proton-assisted pathway, which results in kinetic inertness comparable to that of nonmacrocyclic ligands such as DTPA rather than DOTA-like complexes. PMID- 29718663 TI - A Phenotypic Cell-Binding Screen Identifies a Novel Compound Targeting Triple Negative Breast Cancer. AB - We describe a "phenotypic cell-binding screen" by which therapeutic candidate targeting cancer cells of a particular phenotype can be isolated without knowledge of drug targets. Chemical library beads are incubated with cancer cells of the phenotype of interest in the presence of cancer cells lacking the phenotype of interest, and then the beads bound to only cancer cells of the phenotype of interest are selected as hits. We have applied this screening strategy in discovering a novel compound (LC129-8) targeting triple-negative breast cancer (TNBC). LC129-8 displayed highly specific binding to TNBC in cancer cell lines and patient-derived tumor tissues. LC129-8 exerted anti-TNBC activity by inducing apoptosis, inhibiting proliferation, reversing epithelial-mesenchymal transition, downregulating cancer stem cell activity and blocking in vivo tumor growth. PMID- 29718662 TI - High Spatial Resolution Imaging of Mouse Pancreatic Islets Using Nanospray Desorption Electrospray Ionization Mass Spectrometry. AB - Nanospray Desorption Electrospray Ionization mass spectrometry imaging (nano-DESI MSI) enables ambient imaging of biological samples with high sensitivity and minimal sample pretreatment. Recently, we developed an approach for constant distance mode MSI using shear force microscopy to precisely control the distance between the sample and the nano-DESI probe. Herein, we demonstrate the power of this approach for robust imaging of pancreatic islets with high spatial resolution of ~11 MUm. Pancreatic islets are difficult to characterize using traditional mass spectrometry approaches due to their small size (~100 MUm) and molecular heterogeneity. Nano-DESI MSI was used to examine the spatial localization of several lipid classes including phosphatidylcholine (PC), phosphatidylethanolamine (PE), sphingomyelin (SM), phosphatidylinositol (PI), and phosphatidylserine (PS) along with fatty acids and their metabolites (e.g., prostaglandins) in the individual islets and surrounding tissue. Several lipids were found to be substantially enhanced in the islets indicating these lipids may be involved in insulin secretion. Remarkably different distributions were observed for several pairs of Lyso PC (LPC) and PC species differing only by one double bond, such as LPC 18:1 vs LPC 18:0, PC 32:1 vs PC 32:0, and PC 34:2 vs PC 34:1. These findings indicate that minor variations in the fatty acid chain length and saturation have a pronounced effect on the localization of PC and LPC species in pancreatic islets. Interestingly, oxidized PC species observed experimentally were found to be specifically localized to pancreatic islets. These PCs are potential biomarkers for reactive oxygen species in the islets, which could be harmful to pancreatic beta cells. The experimental approach presented in this study will provide valuable information on the heterogeneity of individual pancreatic islets, which is difficult to assess using bulk characterization techniques. PMID- 29718661 TI - The Fifth Domain in the G-Quadruplex-Forming Sequence of the Human NEIL3 Promoter Locks DNA Folding in Response to Oxidative Damage. AB - DNA oxidation is an inevitable and usually detrimental process, but the cell is capable of reversing this state because the cell possesses a highly developed set of DNA repair machineries, including the DNA glycosylase NEIL3 that is encoded by the NEIL3 gene. In this work, the G-rich promoter region of the human NEIL3 gene was shown to fold into a dynamic G-quadruplex (G4) structure under nearly physiological conditions using spectroscopic techniques (e.g., nuclear magnetic resonance, circular dichroism, fluorescence, and ultraviolet-visible) and DNA polymerase stop assays. The presence of 8-oxo-7,8-dihydroguanine (OG) modified the properties of the NEIL3 G4 and entailed the recruitment of the fifth domain to function as a "spare tire", in which an undamaged fifth G-track is swapped for the damaged section of the G4. The polymerase stop assay findings also revealed that owing to its dynamic polymorphism, the NEIL3 G4 is more readily bypassed by DNA polymerase I (Klenow fragment) than well-known oncogene G4s are. This study identifies the NEIL3 promoter possessing a G-rich element that can adopt a G4 fold, and when OG is incorporated, the sequence can lock into a more stable G4 fold via recruitment of the fifth track of Gs. PMID- 29718664 TI - Recent Progress in Polymer Research to Tackle Infections and Antimicrobial Resistance. AB - Global health is increasingly being threatened by the rapid emergence of drug resistant microbes. The ability of these microbes to form biofilms has further exacerbated the scenario leading to notorious infections that are almost impossible to treat. For addressing this clinical threat, various antimicrobial polymers, polymer-based antimicrobial hydrogels and polymer-coated antimicrobial surfaces have been developed in the recent past. This review aims to discuss such polymer-based antimicrobial strategies with a focus on their current advancement in the field. Antimicrobial polymers, whose designs are inspired from antimicrobial peptides (AMPs), are described with an emphasis on structure activity analysis. Additionally, antibiofilm activity and in vivo efficacy are delineated to elucidate the real potential of these antimicrobial polymers as possible therapeutics. Antimicrobial hydrogels, prepared from either inherently antimicrobial polymers or biocide-loaded into polymer-derived hydrogel matrix, are elaborated followed by various strategies to engineer polymer-coated antimicrobial surfaces. In the end, the current challenges are accentuated along with future directions for further expansion of the field toward tackling infections and antimicrobial resistance. PMID- 29718665 TI - Emerging Approaches for the Identification of Protein Targets of Small Molecules A Practitioners' Perspective. AB - Small-molecule (SM) leads in the early drug discovery pipeline are progressed primarily based on potency against the intended target(s) and selectivity against a very narrow slice of the proteome. So, why is there a tendency to wait until SMs are matured before probing for a deeper mechanistic understanding? For one, there is a concern about the interpretation of complex -omic data outputs and the resources needed to test these hypotheses. However, with recent advances in broad endpoint profiling assays that have companion reference databases and refined technology integration strategies, we argue that data complexity can translate into meaningful decision-making. This same strategy can also prioritize phenotypic screening hits to increase the likelihood of accessing unprecedented target space. In this Perspective. we will highlight a cohesive process that supports SM hit prosecution, providing a data-driven rationale and a suite of methods for direct identification of SM targets driving relevant biological end points. PMID- 29718666 TI - The Role of Dopant Ions on Charge Injection and Transport in Electrochemically Doped Quantum Dot Films. AB - Control over the charge density is very important for implementation of colloidal semiconductor nanocrystals into various optoelectronic applications. A promising approach to dope nanocrystal assemblies is charge injection by electrochemistry, in which the charge compensating electrolyte ions can be regarded as external dopant ions. To gain insight into the doping mechanism and the role of the external dopant ions, we investigate charge injection in ZnO nanocrystal assemblies for a large series of charge compensating electrolyte ions with spectroelectrochemical and electrochemical transistor measurements. We show that charge injection is limited by the diffusion of cations in the nanocrystal films as their diffusion coefficient are found to be ~7 orders of magnitude lower than those of electrons. We further show that the rate of charge injection depends strongly on the cation size and cation concentration. Strikingly, the onset of electron injection varies up to 0.4 V, depending on the size of the electrolyte cation. For the small ions Li+ and Na+ the onset is at significantly less negative potentials. For larger ions (K+, quaternary ammonium ions) the onset is always at the same, more negative potential, suggesting that intercalation may take place for Li+ and Na+. Finally, we show that the nature of the charge compensating cation does not affect the source-drain electronic conductivity and mobility, indicating that shallow donor levels from intercalating ions fully hybridize with the quantum confined energy levels and that the reorganization energy due to intercalating ions does not strongly affect electron transport in these nanocrystal assemblies. PMID- 29718667 TI - Transmembrane NADH Oxidation with Tetracyanoquinodimethane. AB - The design of efficient schemes for nicotinamide adenine dinucleotide (NAD) regeneration is essential for the development of enzymatic biotechnological processes in order to sustain continuous production. In line with our motivation for the encapsulation of redox cascades in liposomes to serve as microbioreactors, we developed a straightforward strategy for the interfacial oxidation of entrapped NADH by ferricyanide as an external electron acceptor. Instead of the commonly applied enzymatic regeneration methods, we employed a hydrophobic redox shuttle embedded in the liposome bilayer. Tetracyanoquinodimethane (TCNQ) mediated electron transfer across the membrane and thus allowed us to shortcut and emulate part of the electron transfer chain functionality without the involvement of membrane proteins. To describe the experimental system, we developed a mathematical model which allowed for the determination of rate constants and exhibited handy predictive utility. PMID- 29718668 TI - Discovery of Potent and Selective Periphery-Restricted Quinazoline Inhibitors of the Cyclic Nucleotide Phosphodiesterase PDE1. AB - We disclose the discovery and X-ray cocrystal data of potent, selective quinazoline inhibitors of PDE1. Inhibitor ( S)-3 readily attains free plasma concentrations above PDE1 IC50 values and has restricted brain access. The racemic compound 3 inhibits >75% of PDE hydrolytic activity in soluble samples of human myocardium, consistent with heightened PDE1 activity in this tissue. These compounds represent promising new tools to probe the value of PDE1 inhibition in the treatment of cardiovascular disease. PMID- 29718670 TI - Evaluation of NCI-7 Cell Line Panel as a Reference Material for Clinical Proteomics. AB - Reference materials are vital to benchmarking the reproducibility of clinical tests and essential for monitoring laboratory performance for clinical proteomics. The reference material utilized for mass spectrometric analysis of the human proteome would ideally contain enough proteins to be suitably representative of the human proteome, as well as exhibit a stable protein composition in different batches of sample regeneration. Previously, The Clinical Proteomic Tumor Analysis Consortium (CPTAC) utilized a PDX-derived comparative reference (CompRef) materials for the longitudinal assessment of proteomic performance; however, inherent drawbacks of PDX-derived material, including extended time needed to grow tumors and high level of expertise needed, have resulted in efforts to identify a new source of CompRef material. In this study, we examined the utility of using a panel of seven cancer cell lines, NCI-7 Cell Line Panel, as a reference material for mass spectrometric analysis of human proteome. Our results showed that not only is the NCI-7 material suitable for benchmarking laboratory sample preparation methods, but also NCI-7 sample generation is highly reproducible at both the global and phosphoprotein levels. In addition, the predicted genomic and experimental coverage of the NCI-7 proteome suggests the NCI-7 material may also have applications as a universal standard proteomic reference. PMID- 29718669 TI - Smart Air-Water Interfaces with Arylazopyrazole Surfactants and Their Role in Photoresponsive Aqueous Foam. AB - A new light-switchable azo-surfactant arylazopyrazole tetraethylene glycol carboxylic acid (AAP-E4) was used as a molecular building block to functionalize macroscopic foams. AAP-E4 was studied in the bulk solution with UV/vis spectroscopy and at the interface with sum-frequency generation (SFG) as well as tensiometry. Additional foaming experiments were performed with a dynamic foam analyzer to study the role of AAP-E4 surfactants at the ubiquitous air-water interface as well as within macroscopic foam. In the bulk, it is possible to switch the AAP-E4 surfactant reversibly from trans to cis configurations and vice versa using 380 nm UV and 520 nm green light, respectively. At the interface, we demonstrate the excellent switching ability of AAP-E4 surfactants and a substantial modification of the surface tension. In addition, we show that the response of the interface is strongly influenced by lateral electrostatic interactions, which can be tuned by the charging state of AAP-E4. Consequently, the electrostatic disjoining pressure and thus the foam stability are highly dependent on the bulk pH and the charging state of the interface. For that reason, we have studied both the surface net charge (SFG) and the surface excess (tensiometry) as important parameters that determine foam stability in this system and show that neutral pH conditions lead to the optimal compromise between switching ability, surface excess, and surface charging. Measurements on the foam stability demonstrated that foams under irradiation with green light are more stable than foams irradiated with UV light. PMID- 29718671 TI - Adsorption of Sodium Dodecyl Sulfate at Water-Dodecane Interface in Relation to the Oil in Water Emulsion Properties. AB - The control of the behavior of oil in water emulsions requires deeper investigations on the adsorption properties of the emulsion stabilizers at the interfaces, which are fundamental to explain the (de)stabilization mechanisms. In this work, we present an extensive study on oil-in-water emulsions stabilized by sodium dodecyl sulfate (SDS) below its critical micellar concentration. Dynamic tensiometry, dilational rheology, and electrical conductivity measurements are used to investigate the adsorption properties at the droplet interface, whereas the aging of the respective emulsions was investigated by monitoring the macroscopic thickness of the emulsion layer, by microimaging and dynamic light scattering (DLS) analysis, to get information on the drop size distribution. In addition, the droplet coalescence is investigated by a microscopy setup. The results of this multitechnique study allow deriving a coherent scenario where the adsorption properties of this ionic surfactant relate to those of the emulsion, such as, for example, the prevention of droplet coalescence and the presence of other mechanisms, such as Ostwald ripening, responsible for the emulsion aging. PMID- 29718672 TI - Evaluation of Anti-LGR5 Antibodies by ImmunoPET for Imaging Colorectal Tumors and Development of Antibody-Drug Conjugates. AB - Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) is highly expressed in colorectal tumors and marks colon cancer stem cells that drive tumor growth and metastasis. Recently, we showed that LGR5 is a promising target for antibody-drug conjugate (ADC) therapy. However, it is important to identify LGR5 positive tumors that would respond to ADC treatment. Prior to drug conjugation, we evaluated two different anti-LGR5 monoclonal antibodies (mAbs), 8F2 and 9G5, using 89Zr-immunoPET to select the optimal mAb for ADC development and tumor imaging. Binding, specificity, and internalization were compared, and mAbs were prescreened as ADC candidates against colon cancer cells using secondary ADCs. Both mAbs demonstrated strong, specific binding in 293T-LGR5 cells but not 293T vector cells. In DLD-1 colorectal cancer cells, which express high levels of LGR5, the mAbs rapidly internalized into lysosomes and promoted ADC-induced cytotoxicity, with 8F2 exhibiting slightly higher potency. No binding was detected in DLD-1-shLGR5 (LGR5 knockdown) cells. 89Zr-DFO-LGR5 mAbs were generated and shown to retain high affinity and LGR5-dependent uptake in vitro. PET/CT imaging of DLD-1 tumors was performed 5 days postinjection of 89Zr-DFO LGR5 mAbs, and findings were consistent with biodistribution data, which showed significantly higher tumor uptake (%ID/g) for 89Zr-DFO-8F2 (17.9 +/- 2.2) compared to 89Zr-DFO-9G5 (5.5 +/- 1.2) and 89Zr-DFO-IgG (3.8 +/- 1.0). No significant uptake was observed in DLD-1-shLGR5 tumors. This study identifies 8F2 as the optimal candidate for ADC development and provides initial evidence that 89Zr-DFO-LGR5 mAbs may be utilized to stratify tumors which would respond best to LGR5-targeted ADC therapy. PMID- 29718674 TI - Enantioselective Total Synthesis of Natural Isoflavans: Asymmetric Transfer Hydrogenation/Deoxygenation of Isoflavanones with Dynamic Kinetic Resolution. AB - A concise and highly enantioselective synthesis of structurally diverse isoflavans from a single chromone is described. The key transformation is a single-step conversion of racemic isoflavanones into virtually enantiopure isoflavans by domino asymmetric transfer hydrogenation/deoxygenation with dynamic kinetic resolution. PMID- 29718673 TI - Particulate Coatings via Evaporation-Induced Self-Assembly of Polydisperse Colloidal Lignin on Solid Interfaces. AB - Polydisperse smooth and spherical biocolloidal particles were suspended in aqueous media and allowed to consolidate via evaporation-induced self-assembly. The stratification of the particles at the solid-air interface was markedly influenced, but not monotonically, by the drying rate. Cross-sectional imaging via electron microscopy indicated a structured coating morphology that was distinctive from that obtained by using particles with a mono- or bimodal distribution. Segregation patterns were found to derive from the interplay of particle diffusion, interparticle forces, and settling dynamics. Supporting our experimental findings, computer simulations showed an optimal drying rate for achieving maximum segregation. Overall, stratified coatings comprising nano- and microparticles derived from lignin are expected to open opportunities for multifunctional structures that can be designed and predicted on the basis of experimental Peclet numbers and computational order. PMID- 29718675 TI - Stagnation Point of Surface Flow during Drop Evaporation. AB - Capillary flow and Marangoni flow influence flow patterns of an evaporating liquid drop. While it is obvious that Marangoni stress on the drop surface affects the surface flow direction, we found that capillary flow also has an impact. The numerical results of this study showed a stagnation point near the contact line, which was further explained by the lubrication theory. The stagnation point is produced by the competing effects of Marangoni flow and capillary flow and emerges when the contact angle is small because the divergence of the capillary flow near the contact line increases as the contact angle decreases. The radial position of the stagnation point from the numerical results ( rnumerical ~ 0.995) agreed with the experimentally observed stagnation point ( rexperimental > 0.992). PMID- 29718676 TI - The Virus Bioresistor: Wiring Virus Particles for the Direct, Label-Free Detection of Target Proteins. AB - The virus bioresistor (VBR) is a chemiresistor that directly transfers information from virus particles to an electrical circuit. Specifically, the VBR enables the label-free detection of a target protein that is recognized and bound by filamentous M13 virus particles, each with dimensions of 6 nm ( w) * 1 MUm ( l), entrained in an ultrathin (~250 nm) composite virus-polymer resistor. Signal produced by the specific binding of virus to target molecules is monitored using the electrical impedance of the VBR: The VBR presents a complex impedance that is modeled by an equivalent circuit containing just three circuit elements: a solution resistance ( Rsoln), a channel resistance ( RVBR), and an interfacial capacitance ( CVBR). The value of RVBR, measured across 5 orders of magnitude in frequency, is increased by the specific recognition and binding of a target protein to the virus particles in the resistor, producing a signal Delta RVBR. The VBR concept is demonstrated using a model system in which human serum albumin (HSA, 66 kDa) is detected in a phosphate buffer solution. The VBR cleanly discriminates between a change in the electrical resistance of the buffer, measured by Rsoln, and selective binding of HSA to virus particles, measured by RVBR. The Delta RVBR induced by HSA binding is as high as 200 Omega, contributing to low sensor-to-sensor coefficients-of-variation (<15%) across the entire calibration curve for HSA from 7.5 nM to 900 nM. The response time for the VBR is 3-30 s. PMID- 29718677 TI - Substrate-Independent Surface Energy Tuning via Siloxane Treatment for Printed Electronics. AB - Digital printing enables solution processing of functional materials and opens a new route to fabricate low-cost electronic devices. One crucial parameter that affects the wettability of inks for all printing techniques is the surface free energy (SFE) of the substrate. Siloxanes, with their huge variety of side chains and their ability to form self-assembled monolayers, offer exhaustive control of the substrate SFE from hydrophilic to hydrophobic. Thus, siloxane treatment is a suitable approach to adjust the substrate conditions to the desired ink, instead of optimizing the ink to an arbitrary substrate. In this work, the influence of different fluorinated and nonfluorinated siloxanes on the SFE of different substrates, such as polymers, glasses, and metals, are examined. By mixing several siloxanes, we demonstrate the fine tuning of the surface energy. The polar and dispersive components of the SFE are determined by the Owens-Wendt Rabel-Kaelble (OWRK) method. Furthermore, the impact of the siloxanes and therefore the SFE on the pinning of droplets and wet films are assessed via dynamic contact angle measurements. SFE-optimized substrates enable tailoring the resolution of inkjet printed silver structures. A nanoparticulate silver ink was used for printing single drops, lines, and source-drain electrodes for transistors. These were examined in terms of diameter, edge quality, and functionality. We show that by adjusting the SFE of an arbitrary substrate, the printed resolution is substantially increased by minimizing the printed drop size by up to 70%. PMID- 29718678 TI - KB343, a Cyclic Tris-guanidine Alkaloid from Palauan Zoantharian Epizoanthus illoricatus. AB - A new tris-guanidine alkaloid, KB343 (1), was isolated from the aqueous extract of a Palauan zoantharian, Epizoanthus illoricatus. The structure of 1 was determined on the basis of spectral analyses of 1 and its derivatives. The absolute configuration for 1 was determined upon comparison of the CD spectrum of 1 to those obtained from density functional theory calculations. The structure of 1 is highly unusual, as three guanidine groups are present in one ring system. PMID- 29718679 TI - The Danger of Relying on Database Spectra. AB - With the availability of easy-to-use commercial instrumentation for infrared (IR) and Raman spectroscopy, the number of users is growing very fast. Even in labs in which no personnel with experience in spectroscopy is around, spectra can be recorded and analyzed. However, for an inexperienced person it is virtually impossible to check whether a spectrum is plausible. In this Note, it is demonstrated that even comparing an experimental spectrum with data from a database may lead to significant errors. The vibrational spectrum of dimethyl sulfoxide (DMSO) is presented as an example. PMID- 29718680 TI - Evolution of Frying Oil Quality Using Fourier Transform Near-Infrared (FT-NIR) Spectroscopy. AB - This study assesses the capacity of a Fourier transform near-infrared (FT-NIR) spectrometer operating in the range 4500-12 000 cm-1 (833.33-2222.22 nm) to provide quantitative predictions for the parameters of acidity (AV), p-anisidine (pAV), total polar materials (TPM), peroxide value (PV), and oxidative stability index (OSI). 562 samples of frying oil were analyzed from 14 distinct types of oil. The calibrations obtained accounted for 96%, 95%, 99%, 92%, and 91% of the AV, pAV, TPM, PV, and OSI variations in the study set and the similarity between the standard error of laboratory (RMSEP) values and the reference method errors (RMSEL), enabling the authors to conclude that NIR technology has the capacity to replace traditional methods in thermo-oxidative degradation studies in frying oils. PMID- 29718681 TI - Analysis of Rare Earth Elements in Uranium Using Handheld Laser-Induced Breakdown Spectroscopy (HH LIBS). AB - A portable handheld laser-induced breakdown spectroscopy (HH LIBS) instrument was evaluated as a rapid method to qualitatively analyze rare earth elements in a uranium oxide matrix. This research is motivated by the need for development of a method to perform rapid, at-line chemical analysis in a nuclear facility, particularly to provide a rapid first pass analysis to determine if additional actions or measurements are warranted. This will result in the minimization of handling and transport of radiological and nuclear material and subsequent exposure to their associated hazards. In this work, rare earth elements (Eu, Nd, and Yb) were quantitatively spiked into a uranium oxide powder and analyzed by the HH LIBS instrumentation. This method demonstrates the ability to rapidly identify elemental constituents in sub-percent levels in a uranium matrix. Preliminary limits of detection (LODs) were determined with values on the order of hundredths of a percent. Validity of this methodology was explored by employing a National Institute of Standards and Technology (NIST) standard reference materials (SRM) 610 and 612 (Trace Elements in Glass). It was determined that the HH LIBS method was able to clearly discern the rare earths elements of interest in the glass or uranium matrices. PMID- 29718682 TI - Optical Properties of Oilfield Wastewater and its Application in Measuring Oil Content. AB - Optical properties of oilfield wastewater play an important role in the on-line measurement of oil content. As an important parameter of optical properties, absorption coefficient is usually obtained by indirectly modeling transmittance spectra. In this work, transmittance spectra of oilfield wastewater in the wavelength range of 190-900 nm at normal incidence were measured by TU-1900 double beam ultraviolet visible spectrophotometer. The absorption coefficient of oilfield wastewater was obtained by a double thickness method, and the relationship between the oil content in oilfield wastewater and its absorption coefficient was studied. The results show that the transmittance spectra of oilfield wastewater decrease with the increase of oil content. The oil content of oilfield wastewater is found to correlate negatively with its transmittance. The oil content of oilfield wastewater and its absorption coefficient have a good fitting effect at 234 nm, and the fitting error of three order polynomial fitting is minimal, with a range of 0.02-5.39%, and the fitting accuracy is 0.9940. PMID- 29718683 TI - Determination of Elemental Content in Solder Mask Samples Used in Printed Circuit Boards Using Different Spectroanalytical Techniques. AB - Solder masks are essential materials used in the manufacture of printed circuit boards (PCB). This material protects PCBs against several types of damage and performance failure. In this study, the capabilities of laser-induced breakdown spectroscopy (LIBS) were investigated for the direct analysis of solder masks typically commercialized for homemade PCB production, and inductively coupled plasma-optical emission spectrometry (ICP-OES) was used to obtain a chemical profile for the target analytes Al, As, Ba, Cd, Co, Cr, Cu, Fe, Hg, Mg, Mn, Ni, Pb, Sb, Sn, and Zn. Inductively coupled plasma-mass spectrometry (ICP-MS) was also employed for the determination of potentially toxic elements, such as As, Cd, Cr, Pb, and Hg. In addition to the qualitative information that may be useful for obtaining the spectral profile related to the raw materials present in solder masks formulations, LIBS was also applied for major elements (Al, Ba, Cu, Fe, Mg, and Zn) determination, but due to the low sensitivity, the obtained results were only semi-quantitative for Ba. Regarding Cd, Cr, Hg, and Pb, the samples analyzed were following the restriction of hazardous substances (RoHS) directive of the European Union. PMID- 29718684 TI - Factors Associated With Psychological Readiness to Return to Sport After Anterior Cruciate Ligament Reconstruction Surgery. AB - BACKGROUND: Anterior cruciate ligament (ACL) injury has a significant psychological effect, and a negative psychological state is a commonly cited reason for a reduction or cessation of sports participation after ACL reconstruction (ACLR) surgery. PURPOSE: To identify factors that contribute to an athlete's psychological readiness to return to sport (RTS) after ACLR. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A cohort of 635 athletes (389 male, 246 female) who underwent ACLR and had been cleared to RTS completed the Anterior Cruciate Ligament-Return to Sport After Injury (ACL-RSI) scale at an average 12 months (range, 11-24 months) after surgery. Demographics (age, sex), sporting outcomes (preinjury frequency), surgical timing (injury to surgery interval), clinical factors (laxity), functional measures (single-limb hop symmetry), and symptoms of pain and function (International Knee Documentation Committee subjective) were also taken, and univariate and multiple regression models were used to determine the association between these and the psychological readiness of the athlete to RTS (ACL-RSI scores). Data for the entire cohort were initially analyzed; then, patients were grouped according to whether they had returned to competitive sport, and the analysis repeated for each group (return/nonreturn). RESULTS: Univariate analysis for the entire group showed that all of the following had a positive effect on psychological readiness: male sex (beta = 5.8; 95% CI, 2-10), younger age (beta = -0.2; 95% CI, -0.4 to 0.01), a shorter interval between injury and surgery (beta = -0.1; 95% CI, -0.1 to -0.02), a higher frequency of preinjury sport participation (beta = 5.4; 95% CI, 2-9), greater limb symmetry (beta = 0.5; 95% CI, 0.3-0.6), and higher subjective knee scores (beta = 1.3; 95% CI, 1.1-1.4). In the multivariate model, subjective knee scores and age significantly accounted for 37% of the variance in psychological readiness ( r2 = 0.37, P < .0001). The only difference between the groups who had and had not returned to sport was that female sex was a significant contributor for the nonreturn group. CONCLUSION: Self-reported symptoms and function were most associated with psychological readiness to RTS after ACLR surgery. Male patients who participated frequently in sport before ACL injury had higher psychological readiness. Conversely, female patients had a more negative outlook and may therefore benefit more from interventions designed to facilitate a smooth transition back to sport. PMID- 29718685 TI - Vector competence of certain Culex and Aedes mosquitoes for the Chittoor virus, the Indian variant of the Batai virus. AB - Chittoor virus (CHITV), a mosquito-borne bunyavirus (Orthobunyavirus: Bunyaviridae) isolated in India, has been found to be antigenically close to the Batai virus (BATV), which has a wide distribution across Asia, Europe, and Africa. The latter virus causes influenza-like illness in humans and mild illness in sheep and goats. BATV has been involved in genetic reassortment with other bunyaviruses, generating novel genome combinations and causing severe clinical manifestations including hemorrhagic fever. Conversely, CHITV has never been associated with any major outbreaks in India, although neutralizing antibodies have been detected in humans and domestic animals. Repeated isolations and seroprevalence have prompted us to determine the vector competence of three important mosquito species, viz., Culex quinquefasciatus, Culex tritaeniorhynchus, and Aedes aegypti, for CHITV. The three mosquito species replicated CHITV to titers of 6.3, 5.0, and 5.2 log10 TCID50/mL, respectively, and maintained the virus for substantial periods. Both of the Culex species demonstrated vector competence, while A. aegypti did not. Horizontal transmission to infant mice was also demonstrated by both Culex species. Active circulation of the virus and the availability of both susceptible hosts and competent vector mosquitoes pose a serious threat to public health should there be a reassortment. PMID- 29718686 TI - The assessment of adherence to infection control in oral radiology using newly developed and validated questionnaire (QICOR). AB - OBJECTIVES:: To assess the infection control in oral radiology among radiologists and dentists of diverse dentistry clinical specialties and among dentistry students. METHODS:: A Questionnaire on Infection Control in Oral Radiology was applied to 1006 dentists and 1203 dentistry students. For assessment of infection control, the scores of the questionnaire were dichotomized in high and low through the median. Simple logistic regression models were set for adherence to infection control and independent variables, estimating the crude odds ratios with the respective 95% confidence intervals. The variables with p < 0.20 in the individual analyses were tested in multiple logistic regression models, remaining in the final model the variables with p <= 0.05. RESULTS:: Individual and adjusted association analysis showed that female dentists have 1.41 ([95% CI: 1.08-1.84)] more adherence odds to infection control when compared with males (p < 0.05). There was no significant association in regarding age, time of education in dentistry, an undergraduate degree from a public or private school, and work in public and/or private clinics. There were also no differences among radiologists and dentists of other clinical specialties. The students from the last year of the dental schools had 1.7 [95% CI (1.13-2.57)] more chances of less adherence to infection control (p = 0.0001). There was no significant association with respect to sex, age and public or private schools. CONCLUSIONS:: Educational procedures should be conducted in relation to infection control protocols in oral radiology, especially among male dentists, regardless clinic specialty, and among the students of the last year of the dental school. PMID- 29718687 TI - Strategies for Detecting Biological Molecules on Titan. AB - Saturn's moon Titan has all the ingredients needed to produce "life as we know it." When exposed to liquid water, organic molecules analogous to those found on Titan produce a range of biomolecules such as amino acids. Titan thus provides a natural laboratory for studying the products of prebiotic chemistry. In this work, we examine the ideal locales to search for evidence of, or progression toward, life on Titan. We determine that the best sites to identify biological molecules are deposits of impact melt on the floors of large, fresh impact craters, specifically Sinlap, Selk, and Menrva craters. We find that it is not possible to identify biomolecules on Titan through remote sensing, but rather through in situ measurements capable of identifying a wide range of biological molecules. Given the nonuniformity of impact melt exposures on the floor of a weathered impact crater, the ideal lander would be capable of precision targeting. This would allow it to identify the locations of fresh impact melt deposits, and/or sites where the melt deposits have been exposed through erosion or mass wasting. Determining the extent of prebiotic chemistry within these melt deposits would help us to understand how life could originate on a world very different from Earth. Key Words: Titan-Prebiotic chemistry-Solar system exploration-Impact processes-Volcanism. Astrobiology 18, 571-585. PMID- 29718689 TI - Comparative effects of different dietary approaches on blood pressure in hypertensive and pre-hypertensive patients: A systematic review and network meta analysis. AB - BACKGROUND: Pairwise meta-analyses have shown beneficial effects of individual dietary approaches on blood pressure but their comparative effects have not been established. OBJECTIVE: Therefore we performed a systematic review of different dietary intervention trials and estimated the aggregate blood pressure effects through network meta-analysis including hypertensive and pre-hypertensive patients. DESIGN: PubMed, Cochrane CENTRAL, and Google Scholar were searched until June 2017. The inclusion criteria were defined as follows: i) Randomized trial with a dietary approach; ii) hypertensive and pre-hypertensive adult patients; and iii) minimum intervention period of 12 weeks. In order to determine the pooled effect of each intervention relative to each of the other intervention for both diastolic and systolic blood pressure (SBP and DBP), random effects network meta-analysis was performed. RESULTS: A total of 67 trials comparing 13 dietary approaches (DASH, low-fat, moderate-carbohydrate, high-protein, low carbohydrate, Mediterranean, Palaeolithic, vegetarian, low-GI/GL, low-sodium, Nordic, Tibetan, and control) enrolling 17,230 participants were included. In the network meta-analysis, the DASH, Mediterranean, low-carbohydrate, Palaeolithic, high-protein, low-glycaemic index, low-sodium, and low-fat dietary approaches were significantly more effective in reducing SBP (-8.73 to -2.32 mmHg) and DBP ( 4.85 to -1.27 mmHg) compared to a control diet. According to the SUCRAs, the DASH diet was ranked the most effective dietary approach in reducing SBP (90%) and DBP (91%), followed by the Palaeolithic, and the low-carbohydrate diet (ranked 3rd for SBP) or the Mediterranean diet (ranked 3rd for DBP). For most comparisons, the credibility of evidence was rated very low to moderate, with the exception for the DASH vs. the low-fat dietary approach for which the quality of evidence was rated high. CONCLUSION: The present network meta-analysis suggests that the DASH dietary approach might be the most effective dietary measure to reduce blood pressure among hypertensive and pre-hypertensive patients based on high quality evidence. PMID- 29718688 TI - Evaluation and reduction of magnetic resonance imaging artefacts induced by distinct plates for osseous fixation: an in vitro study @ 3 T. AB - OBJECTIVES:: To analyze MRI artefacts induced at 3 T by bioresorbable, titanium (TI) and glass fibre reinforced composite (GFRC) plates for osseous reconstruction. METHODS:: Fixation plates including bioresorbable polymers (Inion CPS, Inion Oy, Tampere, Finland; Rapidsorb, DePuy Synthes, Umkirch, Germany; Resorb X, Gebrueder KLS Martin GmbH, Tuttlingen, Germany), GFRC (Skulle Implants Oy, Turku, Finland) and TI plates of varying thickness and design (DePuy Synthes, Umkirch, Germany) were embedded in agarose gel and a 3 T MRI was performed using a standard protocol for head and neck imaging including T1W and T2W sequences. Additionally, different artefact reduction techniques (slice encoding for metal artefact reduction & ultrashort echo time) were used and their impact on the extent of artefacts evaluated for each material. RESULTS:: All TI plates induced significantly more artefacts than resorbable plates in T1W and T2W sequences. GFRCs induced the least artefacts in both sequences. The total extent of artefacts increased with plate thickness and height. Plate thickness had no influence on the percentage of overestimation in all three dimensions. TI-induced artefacts were significantly reduced by both artefact reduction techniques. CONCLUSIONS:: Polylactide, GFRC and magnesium plates produce less susceptibility artefacts in MRI compared to TI, while the dimensions of TI plates directly influence artefact extension. Slice encoding for metal artefact reduction and ultrashort echo time significantly reduce metal artefacts at the expense of scan time or image resolution. PMID- 29718690 TI - Transcriptome analysis reveals hybridization-induced genome shock in an interspecific F1 hybrid from Camellia. AB - The combination of two divergent genomes during hybridization can result in "genome shock". Although genome shock has been reported in the hybrids of some herbaceous plants, the pattern and the principle it follows are far from understood, especially in woody plants. Here, the gene expression patterns were remodeled in the F1 hybrid from the crossing of Camellia azalea * Camellia amplexicaulis compared with the parents as revealed by RNA-seq. About 54.5% of all unigenes were differentially expressed between the F1 hybrid and at least one of the parents, including 6404 unigenes with the highest expression level in the F1 hybrid. A series of genes, related to flower development, essential for RNA directed DNA methylation and histone methylation, as well as 223 transposable elements, were enriched; and most of them exhibited a higher level of expression in the F1 hybrid. These results indicated that the genome shock induced by interspecific hybridization in Camellia could indeed result in changes of gene expression patterns, potentially through regulating DNA methylation and histone methylation which may be helpful for the maintaining of genome stability and even related to the unique phenotype of the F1 hybrid. PMID- 29718691 TI - Connection of inherent structure with nutrient profiles and bioavailability of different co-products and by-products after processing using advanced grading and vibrational molecular spectroscopy. AB - This study aims to reveal connection and implication of molecular structure with nutrient profiles, utilization and bioavailability of both conventional and new co-products from bio-energy and bio-oil processing using grading and vibrational molecular spectroscopy with chemometics including univariate and multivariate techniques. The study focused on strategies to improve the utilization of the conventional and new co-products through chemical and heat processing treatments as well as the relationship of the molecular structural changes to nutrient bioavailability. The updated methods advanced molecular spectroscopy techniques with grading NIR, Globar FTIR, ATR-FTIR and Synchrotron SRFTIRM to study feed molecular structures were reviewed. This study provides an insight and a new approach on how to use grading and vibrational molecular spectroscopy to study molecular chemistry and molecular structure and molecular nutrition interaction. PMID- 29718692 TI - Incidence of Penicillium verrucosum in Grain Samples from Oat Varieties Commonly Grown in South Dakota. AB - Ochratoxin A (OTA) can cause toxicogenic effects in humans and animals when contaminated food products are consumed. Oat ( Avena sativa), like any other cereal grain, can be contaminated with OTA when storage conditions are favorable for fungal growth and toxin production. South Dakota is among the leading oat producing states in the United States. It is therefore important to determine the frequency of occurrence of the primary OTA-producing fungal species on oat grains produced in the state. In this study, we evaluated oat grain samples from South Dakota for the incidence of Penicillium verrucosum, the major ochratoxigenic fungus in temperate regions. Kernels from 12 oat cultivars grown at multiple locations in South Dakota from 2014 to 2016 (15 location-year combinations) were plated on dichloran yeast extract sucrose glycerol agar medium. P. verrucosum was detected on 0.30, 0.19, and 0.05% of the kernels tested in 2014, 2015, and 2016, respectively. Overall, 22 of the 360 evaluated samples had kernels contaminated with P. verrucosum. The fungal incidence of the contaminated samples ranged from 1 to 16%, and the majority of those samples originated from one location. All samples from 2014 and 2015 ( n = 240), except two, had no detectable levels of OTA. The concentration of OTA was well under the maximum limit recommended by the European Union for the two samples with detectable levels of OTA. PMID- 29718693 TI - Understanding Preferences for Interventions To Reduce Microbiological Contamination in Dutch Vegetable Production. AB - Understanding growers' preferences regarding interventions to improve the microbiological safety of their produce could help to design more effective strategies for the adoption of such food safety measures by growers. The objective of this survey study was to obtain insights for the design of interventions that could stimulate growers to increase the frequency of irrigation water sampling and water testing to reduce possible microbiological contamination of their fresh produce. The results showed that price intervention, referring to making the intervention less costly by reducing the price via discounts, is the most effective strategy to change growers' intentions to increase their frequency of irrigation water testing. Moreover, a sense of urgency affects their intentions to increase the frequency of irrigation water testing. The findings of this survey support the hypothesis that, to date, safety is not perceived as a quality control issue under normal circumstances, but safety becomes an overriding attribute in a food crisis. PMID- 29718694 TI - Feasibility and agreement of stiffness measurements using gradient-echo and spin echo MR elastography sequences in unselected patients undergoing liver MRI. AB - OBJECTIVE: To evaluate the agreement of three MR elastography (MRE) sequences in patients undergoing liver MRI for clinical care. Methods: A cross-sectional retrospective study was performed with 223 patients referred for liver MRI, including 12 patients with liver iron overload. Data obtained with spin-echo (SE) and gradient-echo (GRE) MRE sequences were compared. Multiple linear regression adjusted for the presence of liver fat was also performed to assess the correlation between fat infiltration and stiffness measurements results. Agreement between two SE sequences was assessed in patients with liver iron overload. Results: We found strong correlation between the GRE sequence and two SE sequences. Spearman's correlation coefficients between the GRE, SE, and SE-EPI MRE sequences in patients with liver R2* <75Hz were 0.74, 0.81, and 0.80. GRE-MRE failed in patients with liver R2* > 75 Hz. In this subgroup, the correlation coefficient between both SE-MRE sequences was 0.97. Liver fat did not interfere with the results. CONCLUSION: In clinical setting, there is a high correlation between the GRE and SE MRE stiffness measurements, independently of the degree of liver fat infiltration measured by PDFF. A strong correlation between SE-MRE sequences is found even in patients with iron overload. Advances in knowledge: Our study addresses liver iron and fat content simultaneously to describing the technical feasibility and correlation between different MRE sequences in consecutive unselected patients refereed for liver MRI. EPI SE-MRE should be considered an optimal alternative to assess liver fibrosis in patients in whom GRE-MRE failures, such as iron-overloaded, in pediatric, elderly, or severely ill populations. PMID- 29718695 TI - A quantitative experimental phantom study on MRI image uniformity. AB - OBJECTIVES: Our goal was to assess MR image uniformity by investigating aspects influencing said uniformity via a method laid out by the National Electrical Manufacturers Association (NEMA). METHODS: Six metallic materials embedded in a glass phantom were scanned (i.e. Au, Ag, Al, Au-Ag-Pd alloy, Ti and Co-Cr alloy) as well as a reference image. Sequences included spin echo (SE) and gradient echo (GRE) scanned in three planes (i.e. axial, coronal, and sagittal). Moreover, three surface coil types (i.e. head and neck, Brain, and temporomandibular joint coils) and two image correction methods (i.e. surface coil intensity correction or SCIC, phased array uniformity enhancement or PURE) were employed to evaluate their effectiveness on image uniformity. Image uniformity was assessed using the National Electrical Manufacturers Association peak-deviation non-uniformity method. RESULTS: Results showed that temporomandibular joint coils elicited the least uniform image and brain coils outperformed head and neck coils when metallic materials were present. Additionally, when metallic materials were present, spin echo outperformed gradient echo especially for Co-Cr (particularly in the axial plane). Furthermore, both SCIC and PURE improved image uniformity compared to uncorrected images, and SCIC slightly surpassed PURE when metallic metals were present. Lastly, Co-Cr elicited the least uniform image while other metallic materials generally showed similar patterns (i.e. no significant deviation from images without metallic metals). CONCLUSIONS: Overall, a quantitative understanding of the factors influencing MR image uniformity (e.g. coil type, imaging method, metal susceptibility, and post-hoc correction method) is advantageous to optimize image quality, assists clinical interpretation, and may result in improved medical and dental care. PMID- 29718696 TI - Electrical excitability of roach ( Rutilus rutilus) ventricular myocytes: effects of extracellular K+, temperature, and pacing frequency. AB - Exercise, capture, and handling stress in fish can elevate extracellular K+ concentration ([K+]o) with potential impact on heart function in a temperature- and frequency-dependent manner. To this end, the effects of [K+]o on the excitability of ventricular myocytes of winter-acclimatized roach ( Rutilus rutilus) (4 +/- 0.5 degrees C) were examined at different test temperatures and varying pacing rates. Frequencies corresponding to in vivo heart rates at 4 degrees C (0.37 Hz), 14 degrees C (1.16 Hz), and 24 degrees C (1.96 Hz) had no significant effect on the excitability of ventricular myocytes. Acute increase of temperature from 4 to 14 degrees C did not affect excitability, but a further rise to 24 markedly decreased excitability: stimulus current and critical depolarization needed to elicit an action potential (AP) were ~25 and 14% higher, respectively, at 24 degrees C than at 4 degrees C and 14 degrees C ( P < 0.05). This depression could be due to temperature-related mismatch between inward Na+ and outward K+ currents. In contrast, an increase of [K+]o from 3 to 5.4 or 8 mM at 24 degrees C reduced the stimulus current needed to trigger AP. However, other aspects of excitability were strongly depressed by high [K+]o: maximum rate of AP upstroke and AP duration were drastically (89 and 50%, respectively) reduced at 8 mM [K+]o in comparison with 3 mM ( P < 0.05). As an extreme case, some myocytes completely failed to elicit all-or-none AP at 8 mM [K+]o at 24 degrees C. Also, amplitude and overshoot of AP were reduced by elevation of [K+]o ( P < 0.05). Although high [K+]o antagonizes the negative effects of high temperature on excitation threshold, the precipitous depression of the rate of AP upstroke and complete loss of excitability in some myocytes suggest that the combination of high temperature and high [K+]o will severely impair ventricular excitability in roach. PMID- 29718697 TI - ZnT2 is critical for lysosome acidification and biogenesis during mammary gland involution. AB - Mammary gland involution, a tightly regulated process of tissue remodeling by which a lactating mammary gland reverts to the prepregnant state, is characterized by the most profound example of regulated epithelial cell death in normal tissue. Defects in the execution of involution are associated with lactation failure and breast cancer. Initiation of mammary gland involution requires upregulation of lysosome biogenesis and acidification to activate lysosome-mediated cell death; however, specific mediators of this initial phase of involution are not well described. Zinc transporter 2 [ZnT2 ( SLC30A2)] has been implicated in lysosome biogenesis and lysosome-mediated cell death during involution; however, the direct role of ZnT2 in this process has not been elucidated. Here we showed that ZnT2-null mice had impaired alveolar regression and reduced activation of the involution marker phosphorylated Stat3, indicating insufficient initiation of mammary gland remodeling during involution. Moreover, we found that the loss of ZnT2 inhibited assembly of the proton transporter vacuolar ATPase on lysosomes, thereby decreasing lysosome abundance and size. Studies in cultured mammary epithelial cells revealed that while the involution signal TNFalpha promoted lysosome biogenesis and acidification, attenuation of ZnT2 impaired the lysosome response to this involution signal, which was not a consequence of cytoplasmic Zn accumulation. Our findings establish ZnT2 as a novel regulator of vacuolar ATPase assembly, driving lysosome biogenesis, acidification, and tissue remodeling during the initiation of mammary gland involution. PMID- 29718698 TI - Placental ischemia-stimulated T-helper 17 cells induce preeclampsia-associated cytolytic natural killer cells during pregnancy. AB - Previous studies have demonstrated that T-helper 17 (TH17) cells and cytolytic natural killer (cNK) cells are increased in women with preeclampsia. In this study we investigated the role of placental ischemia-stimulated TH17 cells in induction of cNK cells in pregnancy. We further assessed the role of TH17 cell mediated oxidative stress in facilitation of cNK cell activation in pregnancy by treating rats with the SOD mimetic tempol. CD4+/CD25- cells were isolated from reduced uterine perfusion pressure (RUPP) rats and differentiated into TH17 cells in vitro. On day 12 of gestation ( GD12), 1 * 106 placental ischemia-stimulated TH17 cells were injected into normal pregnant (NP) rats (NP + RUPP TH17 rats), and a subset of rats were treated with tempol (30 mg.kg-1.day-1) from GD12 to GD19 (NP + RUPP TH17 + tempol rats). On GD19, cNK cells, mean arterial pressure, fetal weight, and cNK cell-associated cytokines and proteins were measured. Placental cNK cells were 2.9 +/- 1, 14.9 +/- 4, and 2.8 +/- 1.0% gated in NP, NP + RUPP TH17, and NP + RUPP TH17 + tempol rats, respectively. Mean arterial pressure increased from 96 +/- 5 mmHg in NP rats to 118 +/- 2 mmHg in NP + RUPP TH17 rats and was 102 +/- 3 mmHg in NP + RUPP TH17 + tempol rats. Fetal weight was 2.37 +/- 0.04, 1.95 +/- 0.14, and 2.3 +/- 0.05 g in NP, NP + RUPP TH17, and NP + RUPP TH17 + tempol rats, respectively. Placental IFNgamma increased from 1.1 +/- 0.6 pg/mg in NP rats to 3.9 +/- 0.6 pg/mg in NP + RUPP TH17 rats. Placental perforin increased from 0.18 +/- 0.18 pg/mg in NP rats to 2.4 +/- 0.6 pg/mg in NP + RUPP TH17 rats. Placental levels of granzymes A and B followed a similar pattern. Treatment with tempol did not lower placental cNK cytokines or proteins. The results of the present study identify TH17 cells as a mediator of aberrant NK cell activation that is associated with preeclampsia. PMID- 29718699 TI - Effect of a melanocortin type 2 receptor (MC2R) antagonist on the corticosterone response to hypoxia and ACTH stimulation in the neonatal rat. AB - The adrenal stress response in the neonatal rat shifts from ACTH-independent to ACTH-dependent between postnatal days 2 (PD2) and 8 (PD8). This may be due to an increase in an endogenous, bioactive, nonimmunoreactive ligand to the melanocortin type 2 receptor (MC2R). GPS1574 is a newly described MC2R antagonist that we have shown to be effective in vitro. Further experimentation with GPS1574 would allow better insight into this seemingly ACTH-independent steroidogenic response in neonates. We evaluated the acute corticosterone response to hypoxia or ACTH injection following pretreatment with GPS1574 (32 mg/kg) or vehicle for GPS1574 in PD2, PD8, and PD15 rat pups. Pretreatment with GPS1574 decreased baseline corticosterone in PD2 pups but increased baseline corticosterone in PD8 and PD15 pups. GPS1574 did not attenuate the corticosterone response to hypoxia in PD2 pups and augmented the corticosterone response in PD8 and PD15 pups. GPS1574 augmented the corticosterone response to ACTH in PD2 and PD15 pups but had no significant impact on the response in PD8 pups. Baseline adrenal Mrap and Star mRNA increased from PD2 to PD15, whereas Mrap2 mRNA expression was low and did not change with age. The data suggest that GPS1574 is not a pure MC2R antagonist, but rather acts as a biasing agonist/antagonist. Its ability to attenuate or augment the adrenal response may depend on the ambient plasma ACTH concentration and/or developmental changes in early transduction steroidogenic pathway genes. PMID- 29718700 TI - Relationship between intermuscular adipose tissue infiltration and myostatin before and after aerobic exercise training. AB - Intermuscular adipose tissue (IMAT) is associated with impaired skeletal muscle contractile and metabolic function. Myostatin and downstream signaling proteins such as cyclin-dependent kinase 2 (CDK2) contribute to the regulation of adipose and skeletal muscle mass in cell culture and animals models, but this relationship remains incompletely understood in humans. The purpose of this study was to determine if the infiltration of IMAT was associated with skeletal muscle myostatin and downstream proteins before and after 12 wk of aerobic exercise training (AET) in healthy older women (OW; 69 +/- 2 yr), older men (OM; 74 +/- 3 yr), and young men (YM; 20 +/- 1 yr). We found that the infiltration of IMAT was correlated with myostatin and phosphorylated CDK2 at tyrosine 15 [P-CDK2(Tyr15)]. IMAT infiltration was greater in the older subjects and was associated with lower skeletal muscle function and exercise capacity. After 12 wk of AET, there was no change in body weight. Myostatin and P-CDK2(Tyr15) were both decreased after AET, and the reduction in myostatin was associated with decreased IMAT infiltration. The decrease in myostatin and IMAT occurred concomitantly with increased exercise capacity, skeletal muscle size, and function after AET. These findings demonstrate that the reduction in IMAT infiltration after AET in weight stable individuals was accompanied by improvements in skeletal muscle function and exercise capacity. Moreover, the association between myostatin and IMAT was present in the untrained state and in response to exercise training, strengthening the potential regulatory role of myostatin on IMAT. PMID- 29718701 TI - Do Selective COX-2 Inhibitors Affect Pain Control and Healing After Arthroscopic Rotator Cuff Repair? Response. PMID- 29718702 TI - Trouble With the Curve. PMID- 29718704 TI - Do Selective COX-2 Inhibitors Affect Pain Control and Healing After Arthroscopic Rotator Cuff Repair? Letter to the Editor. PMID- 29718705 TI - Influence of ex vivo perfusion on the biomolecular profile of rat lungs. AB - Despite increasing clinical adoption, biologic influences of ex vivo lung perfusion (EVLP) remain insufficiently elucidated. The aim of the current study was to investigate biomolecular changes induced by EVLP in rat lungs. EVLP was maintained for 180 min. Hyaluronan, mediators, and cells were assessed in the perfusate. Gene expression, signaling pathways, and ATP content were investigated in lung tissue. EVLP induced the release of medium-high molecular weight hyaluronan and transcription of hyaluronan synthases ( P < 0.001). Increasing concentrations of inflammatory mediators were detected in the perfusate ( P < 0.001). Perfused lungs exhibited a distinctive transcriptional signature compared with organs examined before or after surgery/procurement ( P = 0.003). Up regulated genes were involved in inflammation and its regulation, apoptosis/survival, heat shock, and oxidative stress response ( q = 0). Down regulated genes were related to lymphocyte function ( q = 0). The NF-kappaB, signal transducer and activator of transcription 3, ERK1/2, p38, Akt, and stress activated protein kinase/JNK signaling pathways were modulated by EVLP ( P < 0.05). Most of these biomolecular changes were examined and confirmed in additional experiments that were performed in lungs procured from donation after cardiocirculatory death after 180 min of warm ischemia. The current study demonstrates that EVLP broadly affects the lung biomolecular phenotype. These findings improve our comprehension of the effects exerted by the procedure and encourage additional research in preclinical models to implement therapeutic interventions.-Lonati, C., Bassani, G. A., Brambilla, D., Leonardi, P., Carlin, A., Faversani, A., Gatti, S., Valenza, F. Influence of ex vivo perfusion on the biomolecular profile of rat lungs. PMID- 29718706 TI - Myc-nick promotes efferocytosis through M2 macrophage polarization during resolution of inflammation. AB - A key event required for effective resolution of inflammation is efferocytosis, which is defined as phagocytic removal of apoptotic cells mostly by macrophages acquiring an alternatively activated phenotype (M2). c-Myc has been reported to play a role in alternative activation of human macrophages and is proposed as one of the M2 macrophage markers. We found that M2-like peritoneal macrophages from zymosan A-treated mice exhibited a marked accumulation of Myc-nick, a truncated protein generated by a Calpain-mediated proteolytic cleavage of full-length c Myc. Further, ectopic expression of Myc-nick in murine bone marrow-derived macrophages promoted the M2 polarization and, consequently, enhanced their efferocytic capability. Notably, Myc-nick-induced efferocytosis was found to be tightly associated with alpha-tubulin acetylation by K acetyltransferase 2a (Kat2a/Gcn5) activity. These findings suggest Myc-nick as a novel proresolving mediator that has a fundamental function in maintaining homeostasis under inflammatory conditions.-Zhong, X., Lee, H.-N., Kim, S. H., Park, S.-A., Kim, W., Cha, Y.-N., Surh, Y.-J. Myc-nick promotes efferocytosis through M2 macrophage polarization during resolution of inflammation. PMID- 29718707 TI - Arginase-II negatively regulates renal aquaporin-2 and water reabsorption. AB - Type-II l-arginine:ureahydrolase, arginase-II (Arg-II), is abundantly expressed in the kidney. The physiologic role played by Arg-II in the kidney remains unknown. Herein, we report that in mice that are deficient in Arg-II (Arg-II-/-), total and membrane-associated aquaporin-2 (AQP2) protein levels were significantly higher compared with wild-type (WT) controls. Water deprivation enhanced Arg-II expression, AQP2 levels, and membrane association in collecting ducts. Effects of water deprivation on AQP2 were stronger in Arg-II-/- mice than in WT mice. Accordingly, a decrease in urine volume and an increase in urine osmolality under water deprivation were more pronounced in Arg-II-/- mice than in WT mice, which correlated with a weaker increase in plasma osmolality in Arg-II-/ mice. There was no difference in vasopressin release under water deprivation conditions between either genotype of mice. Although total AQP2 and phosphorylated AQP2-S256 levels (mediated by PKA) in kidneys under water deprivation conditions were significantly higher in Arg-II-/- mice compared with WT animals, there is no difference in the ratio of AQP2-S256:AQP2. In cultured mouse collecting duct principal mCCDcl1 cells, expression of both Arg-II and AQP2 were enhanced by the vasopressin type 2 receptor agonist, desamino- d-arginine vasopressin (dDAVP). Silencing Arg-II enhanced the expression and membrane association of AQP2 by dDAVP without influencing cAMP levels. In conclusion, in vivo and in vitro experiments demonstrate that Arg-II negatively regulates AQP2 and the urine-concentrating capability in kidneys via a mechanism that is not associated with the modulation of the cAMP pathway.-Huang, J., Montani, J.-P., Verrey, F., Feraille, E., Ming, X.-F., Yang, Z. Arginase-II negatively regulates renal aquaporin-2 and water reabsorption. PMID- 29718708 TI - Plasma metabolome analysis identifies distinct human metabotypes in the postprandial state with different susceptibility to weight loss-mediated metabolic improvements. AB - Health has been defined as the capability of the organism to adapt to challenges. In this study, we tested to what extent comprehensively phenotyped individuals reveal differences in metabolic responses to a standardized mixed meal tolerance test (MMTT) and how these responses change when individuals experience moderate weight loss. Metabolome analysis was used in 70 healthy individuals. with profiling of ~300 plasma metabolites during an MMTT over 8 h. Multivariate analysis of plasma markers of fatty acid catabolism identified 2 distinct metabotype clusters (A and B). Individuals from metabotype B showed slower glucose clearance, had increased intra-abdominal adipose tissue mass and higher hepatic lipid levels when compared with individuals from metabotype A. An NMR based urine analysis revealed that these individuals also to have a less healthy dietary pattern. After a weight loss of ~5.6 kg over 12 wk, only the subjects from metabotype B showed positive changes in the glycemic response during the MMTT and in markers of metabolic diseases. Our study in healthy individuals demonstrates that more comprehensive phenotyping can reveal discrete metabotypes with different outcomes in a dietary intervention and that markers of lipid catabolism in plasma could allow early detection of the metabolic syndrome. Fiamoncini, J., Rundle, M., Gibbons, H., Thomas, E. L., Geillinger-Kastle, K., Bunzel, D., Trezzi, J.-P., Kiselova-Kaneva, Y., Wopereis, S., Wahrheit, J., Kulling, S. E., Hiller, K., Sonntag, D., Ivanova, D., van Ommen, B., Frost, G., Brennan, L., Bell, J. Daniel, H. Plasma metabolome analysis identifies distinct human metabotypes in the postprandial state with different susceptibility to weight loss-mediated metabolic improvements. PMID- 29718709 TI - Intrauterine programming mechanism for hypercholesterolemia in prenatal caffeine exposed female adult rat offspring. AB - Clinical and animal studies have indicated that hypercholesterolemia and its associated diseases have intrauterine developmental origins. Our previous studies showed that prenatal caffeine exposure (PCE) led to fetal overexposure to maternal glucocorticoids (GCs) and increased serum total cholesterol levels in adult rat offspring. This study further confirms the intrauterine programming of PCE-induced hypercholesterolemia in female adult rat offspring. Pregnant Wistar rats were intragastrically administered caffeine (30, 60, and 120 mg/kg/d) from gestational day (GD)9 to 20. Female rat offspring were euthanized at GD20 and postnatal wk 12; several adult rat offspring were additionally subjected to ice water swimming stimulation to induce chronic stress prior to death. The effects of GCs on cholesterol metabolism and epigenetic regulation were verified using the L02 cell line. The results showed that PCE induced hypercholesterolemia in adult offspring, which manifested as significantly higher levels of serum total cholesterol and LDL cholesterol (LDL-C) as well as higher ratios of LDL-C/HDL cholesterol. We further found that the cholesterol levels were increased in fetal livers but were decreased in fetal blood, accompanied by increased maternal blood cholesterol levels and reduced placental cholesterol transport. Furthermore, analysis of PCE offspring in the uterus and in a postnatal basal/chronic stress state and the results of in vitro experiments showed that hepatic cholesterol metabolism underwent GC-dependent changes and was associated with cholesterol synthase via abnormalities in 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR) histone acetylation. We concluded that, to compensate for intrauterine placentally derived decreases in fetal blood cholesterol levels, high intrauterine GC levels activated fetal hepatic CCAAT enhancer binding protein alpha signaling and down-regulated Sirtuin1 expression, which mediated the high levels of histone acetylation ( via H3K9ac and H3K14ac) and expression of HMGCR. This GC-dependent cholesterol metabolism programming effect was sustained through adulthood, leading to the occurrence of hypercholesterolemia.-Xu, D., Luo, H. W., Hu, W., Hu, S. W., Yuan, C., Wang, G. H., Zhang, L., Yu, H., Magdalou, J., Chen, L. B., Wang, H. Intrauterine programming mechanism for hypercholesterolemia in prenatal caffeine-exposed female adult rat offspring. PMID- 29718710 TI - Identification of hepatic fibroblast growth factor 21 as a mediator in 17beta estradiol-induced white adipose tissue browning. AB - Both ovarian E2 and hepatic fibroblast growth factor 21 (FGF21) are critical for energy homeostasis and white adipose tissue browning. Estrogen receptor alpha (ERalpha) is abundantly expressed in liver. However, whether FGF21 has a role in E2-induced white adipose tissue browning remains uncertain. In this study, we showed that hepatic Fgf21 expression and secretion during estrus cycle changed with the tetradian oscillatory secretion of circulation E2 in adult, female mice, with their peak expressions and secretions at the proestrus. In addition, exogenous E2 robustly stimulated liver Fgf21 expression and elevated serum FGF21 concentrations, which induced browning gene expression and reduced the tissue weight in subcutaneous white adipose in mice with ovariectomies. The inhibitor of mammalian target of rapamycin (mTOR) and of ERalpha blocked the induction effect of E2 on the expression of Fgf21 in primary hepatocytes, which revealed that E2 might stimulate FGF21 expression via the ERalpha-mTOR pathway. Furthermore, FGF21 liver-specific deficiency abolished E2-induced white adipose browning in mice with ovariectomies. This study indicates that ovarian E2 increased liver FGF21 expression directly, which in turn, functioned as an endocrine signal to influence inguinal white adipose tissue browning.-Hua, L., Zhuo, Y., Jiang, D., Li, J., Huang, X., Zhu, Y., Li, Z., Yan, L., Jin, C., Jiang, X., Che, L., Fang, Z., Lin, Y., Xu, S., Li, J., Feng, B., Wu, D. Identification of hepatic fibroblast growth factor 21 as a mediator in 17beta-estradiol-induced white adipose tissue browning. PMID- 29718711 TI - Employees High in Personal Intelligence Differ From Their Colleagues in Workplace Perceptions and Behavior. AB - Personal intelligence (PI) involves the ability to recognize, reason, and use information about personality to understand oneself and other people. Employees in two studies (Ns = 394, 482) completed the Test of Personal Intelligence (TOPI; e.g., Mayer, Panter, & Caruso, 2017a) and assessments of workplace perception and behavior. Higher PI was associated with higher perceived workplace support and lower counterproductive work behavior. These relationships continued to hold after controlling for other key variables. The results indicate the TOPI, although still in research trials, shows promise as a screening device for selecting employees and targeting individuals for training. PMID- 29718713 TI - Correction to: Abd-Elhalem et al., Bone marrow mesenchymal stem cells suppress IL 9 in adjuvant-induced arthritis. PMID- 29718712 TI - Therapy influences goal attainment following botulinum neurotoxin injection for focal spasticity in adults with neurological conditions. AB - OBJECTIVE: To determine whether therapy influenced goal attainment following botulinum toxin (BoNT-A) injection for focal spasticity in adults with neurological conditions. METHODS: A prospective observational cohort study conducted in a large metropolitan spasticity clinic on adults with focal spasticity of any origin. Participants were provided with a therapy programme, designed to maximise therapeutic outcome. The primary outcome measure was Goal Attainment Scaling. To measure adherence, participants completed a therapy recording tool each day. Goal attainment, and the rate of adherence to the therapy programme, was evaluated after 10 weeks. RESULTS: Active indications for BoNT-A treatment made up the majority of the goals (80.30%). Goals were achieved in 43/76 cases (56.60%; 95% CI = 42.40 to 69.80%). Therapy adherence was associated with significantly greater goal attainment (OR = 1.02, p = 0.03, 95% CI = 1.00 to 1.04). Greater adherence to therapy increased the odds of goal achievement for active indications but not for passive indications, suggesting a possible statistical interaction between the indication for injection and adherence to therapy (p < 0.01). CONCLUSION: Therapy adherence was associated with greater goal attainment. Active indications for BoNT-A were more reliant on adherence to prescribed therapy programmes than passive indications, although further investigation is required. PMID- 29718715 TI - Treatment outcomes among a cohort of African American buprenorphine patients: Follow-up at 12 months. AB - BACKGROUND: Although buprenorphine/naloxone (bup/nal) is well-established as a safe and effective treatment for opioid use disorders (OUDs), there are few studies reporting 12-month outcomes of patients receiving bup/nal in formerly drug-free outpatient programs. OBJECTIVES: To examine 12-month outcomes by bup/nal treatment enrollment status among a cohort of African American patients enrolled in a clinical trial. METHODS: This analysis builds upon a randomized trial of 300 opioid-dependent African American bup/nal patients in two outpatient programs in Baltimore, MD. A subset of participants (N = 133, n = 47 female) were tracked for a 12-month follow-up interview. RESULTS: The participants receiving bup/nal at 12 months had significantly fewer opioid-positive urine screens (44% v. 73%) and days of self-reported heroin use (M [SE] = 1.13 [.34] v. 7.12 [1.44]) than the out-of-bup/nal-treatment group (both ps <= .001). Similarly, those receiving bup/nal reported significantly fewer days of cocaine use (M [SE] = 0.85 [0.23] v. 2.88[0.75]) and alcohol use (M [SE] = 1.44 [0.38] v. 3.69 [1.04]; both ps<.05). There were no significant differences related to criminal activity, quality of life, and most ASI composite scores. Models adjusting for the baseline value, prior treatment experience, and assigned study condition largely confirmed these findings, except that participants in treatment had fewer days of crime and higher psychological quality of life scores compared to those out-of-treatment. CONCLUSIONS: Those receiving bup/nal at 12 months had significantly lower rates of illicit opioid use than those who were not. Approaches to improve bup/nal treatment retention and reengagement of patients with OUD are needed. PMID- 29718714 TI - Development and evaluation of a novel drug delivery: Soluplus(r)/TPGS mixed micelles loaded with piperine in vitro and in vivo. AB - BACKGROUND: Although piperine can inhibit cells of tumors, the poor water solubility restricted its clinical application. This paper aimed to develop mixed micelles based on Soluplus(r) and D-alpha-tocopherol polyethylene glycol succinate (TPGS) to improve the aqueous solubility and anti-cancer effect. METHODS: Piperine-loaded mixed micelles were prepared using a thin-film hydration method, and their physicochemical properties were characterized. The cellular uptake of the micelles was confirmed by confocal laser scanning microscopy in A549 lung cancer cells and HepG2 liver cancer cells. In addition, cytotoxicity of the piperine mixed micelles was studied in A549 lung cancer cells and HepG2 liver cancer cells. Free piperine or piperine-loaded Soluplus(r)/TPGS mixed micelles were administered at an equivalent dose of piperine at 3.2 mg/kg via a single intravenous injection in the tail vain for the pharmacokinetic study in vivo. RESULTS: The diameter of piperine-loaded Soluplus(r)/TPGS (4:1) mixed micelles was about 61.9 nm and the zeta potential -1.16 +/- 1.06 mV with 90.9% of drug encapsulation efficiency and 4.67% of drug-loading efficiency. Differential scanning calorimetry (DSC) studies confirmed that piperine is encapsulated by the Soluplus(r)/TPGS. The release results in vitro showed that the piperine-loaded Soluplus(r)/TPGS mixed micelles presented sustained release behavior compared to the free piperine. The mixed micelles exhibited better antitumor efficacy compared to free piperine and physical mixture against in A549 and HepG2 cells by MTT assay. The pharmacokinetic study revealed that the AUC of piperine-loaded mixed micelles was 2.56 times higher than that of piperine and the MRT for piperine-loaded mixed micelles was 1.2-fold higher than piperine (p < .05). CONCLUSION: The results of the study suggested that the piperine-loaded mixed micelles developed might be a potential nano-drug delivery system for cancer chemotherapy. These results demonstrated that piperine-loaded Soluplus(r)/TPGS mixed micelles are an effective strategy to deliver piperine for cancer therapy. PMID- 29718716 TI - Complex chromosomal aberrations in a fetus originating from oocytes with smooth endoplasmic reticulum (SER) aggregates. AB - : The presence of smooth endoplasmic reticulum aggregates (SERa) in the ooplasm is considered as the most severe oocyte dysmorphism due to its serious and potentially lethal outcomes in offspring. In the present case report, a couple underwent their first intracytoplasmic sperm injection (ICSI) cycle using a gonadotrophin releasing hormone (GnRH) antagonist protocol, followed by fetal ultrasound scanning and amniocentesis. SERa were observed in all oocytes retrieved. A singleton pregnancy was established. The second trimester fetal ultrasound scan revealed a female fetus with overlapping fingers in both hands, and amniocentesis was performed for the detection of chromosomal abnormalities. Comprehensive genetic analysis with the combined use of array-comparative genomic hybridization (CGH), fluoresence in situ hybridization (FISH) and conventional cytogenetics revealed a complex chromosome rearrangement (CCR) involving three break points on two chromosomes, resulting in a reciprocal translocation with a cryptic 2q31 deletion. A week following amniocentesis, there was rupture of amniotic membranes and a stillborn was delivered. This is the first case in the literature to report a CCR with concomitant 2q31 deletion resulting in a well defined and clinically recognizable contiguous gene syndrome with an abnormal phenotype in a fetus arising from a cohort of oocytes affected by SERa. It is suggested that fertilization and transfer of oocytes with SERa should be avoided, until further research establishes whether there is a causal relationship between the presence of SERa and chromosomal abnormalities in the resulting fetus. ABBREVIATIONS: SER: smooth endoplasmic reticulum; ICSI: intracytoplasmic sperm injection; GnRH: gonadotrophin releasing hormone; CGH: comparative genomic hybridization; FISH: fluoresence in situ hybridization; FSH: follicle stimulating hormone; hCG: human chorionic gonadotrophin; OHSS: ovarian hyperstimulation syndrome; IVF: in vitro fertilization; MII: metaphase II; GV: germinal vesicle; CCR: complex chromosome rearrangement. PMID- 29718717 TI - Facets of conscientiousness and objective markers of health status. AB - OBJECTIVE: To examine the association between six facets of conscientiousness (self-control, order, industriousness, traditionalism, virtue, responsibility) and objective markers of health status, including adiposity, blood markers and physical performance. DESIGN: Cross-sectional analysis of participants from the health and retirement study (N = 12,188). MAIN OUTCOME MEASURES: Adiposity (body mass index, waist circumference), blood markers (A1c, HDL cholesterol, total cholesterol, cystatin c, c-reactive protein) and physical performance (lung function, grip strength, walking speed). RESULTS: Four of the six facets of conscientiousness were associated with nearly all of the health markers: Self control, organisation, industriousness and responsibility were related to lower adiposity, healthier metabolic, cardiovascular and inflammatory markers, and better performance on physical assessments. Traditionalism and virtue had fewer associations with these objective markers. CONCLUSION: This research took a facet level approach to the association between conscientiousness and objective markers of health status. This research builds on models of conscientiousness and health to suggest that, in addition to health-risk behaviours, facets of conscientiousness are associated with more favourable biomedical markers of health status. PMID- 29718718 TI - The Family Life Impairment Scale: Factor Structure and Clinical Utility with Young Children. AB - Although it is well-established that young children experience significant psychopathology, diagnostic decisions continue to be challenging, in part due to the way impairment is understood, defined, and measured. Most existing clinical tools assess impairment in an individualized manner, whereas for many young children, impairment is more accurately conceptualized as a family-oriented, multidimensional construct, impacting various parental and family activities. Two studies were completed using the Family Life Impairment Scale (FLIS), a multidimensional parent-report measure of family and associated impairment designed for young children. In Study 1, factor analysis was used in a large (n = 945) representative sample (23-48 months of age). FLIS associations with measures of parent and child well-being were explored to investigate convergent validity. Study 2 was completed in a sample (n = 174) of young children (18-33 months of age) diagnosed with autism spectrum disorders to explore factorial consistency in a clinical sample. Study 1 yielded evidence of a four-factor solution, including parent impairment (affecting parental well-being), family impairment (affecting family activities and routines), childcare impairment (affecting challenges with childcare), and positive growth (parental learning and growth associated with the child's problem). Evidence of convergent validity was also found, as factors were differentially associated with established measures of child symptoms and parent stress. Factor structure was supported in the clinical sample. Results support both the factorial structure and clinical utility of the FLIS for use across clinical and nonclinical populations of young children. PMID- 29718719 TI - Risk Factors for High Myopia in Koreans: The Korea National Health and Nutrition Examination Survey. AB - PURPOSE: To investigate risk factors for high myopia in the general Korean population. METHODS: In this nationwide population study, the dataset of the Korea National Health and Nutrition Examination Survey 2008-2012 was analyzed. The study cohort included 11 703 participants, aged 25-49 years, who underwent neither refractive nor cataract surgery. The association between demographic, socioeconomic, behavioral, and systemic variables and high myopia was investigated. RESULTS: The mean participant age was 37.9 +/- 6.8 years, and the prevalence of high myopia <=-6.0D was 7.0 +/- 0.3% in the study population. The right eyes (-1.76 +/- 0.03 D) were more myopic than the left eyes (-1.70 +/- 0.03 D; P < 0.001). In multivariate logistic regression analysis, high myopia was associated with age (odds ratio [OR], 0.97 per 1 year-increase) and female sex (OR, 1.24). Other identified risk factors included education level >= university graduation (OR, 1.91), the presence of hypertension (OR, 1.69), and serum glucose level (OR, 1.01 per 1 mg/dL). Sunlight exposure of >=5 h/day (OR, 0.67) and serum 25-hydroxyvitamin D level (OR, 0.97 per 1 ng/mL) showed protective effect against high myopia. CONCLUSION: High myopia is associated with younger age, female sex, high education level, longer sunlight exposure, and some other systemic conditions. PMID- 29718720 TI - Mixing of low-dose cohesive drug and overcoming of pre-blending step using a new gentle-wing high-shear mixer granulator. AB - The objective of this study was to examine the influence of drug amount and mixing time on the homogeneity and content uniformity of a low-dose drug formulation during the dry mixing step using a new gentle-wing high-shear mixer. Moreover, the study investigated the influence of drug incorporation mode on the content uniformity of tablets manufactured by different methods. Albuterol sulfate was selected as a model drug and was blended with the other excipients at two different levels, 1% w/w and 5% w/w at impeller speed of 300 rpm and chopper speed of 3000 rpm for 30 min. Utilizing a 1 ml unit side-sampling thief probe, triplicate samples were taken from nine different positions in the mixer bowl at selected time points. Two methods were used for manufacturing of tablets, direct compression and wet granulation. The produced tablets were sampled at the beginning, middle, and end of the compression cycle. An analysis of variance analysis indicated the significant effect (p < .05) of drug amount on the content uniformity of the powder blend and the corresponding tablets. For 1% w/w and 5% w/w formulations, incorporation of the drug in the granulating fluid provided tablets with excellent content uniformity and very low relative standard deviation (~0.61%) during the whole tableting cycle compared to direct compression and granulation method with dry incorporation mode of the drug. Overall, gentle-wing mixer is a good candidate for mixing of low-dose cohesive drug and provides tablets with acceptable content uniformity with no need for pre blending step. PMID- 29718721 TI - Lenvatinib for the treatment of renal cell carcinoma. AB - INTRODUCTION: Renal cell carcinoma (RCC) accounts for 2-3% of all solid tumors. Expression of the receptor for the vascular endothelial growth factor (VEGF) is one of the most common features of RCC. Areas covered: Lenvatinib is a novel multi-kinase inhibitor that has been studied in several solid tumors. It has shown promising results in the treatment of RCC, especially when combined with everolimus, In this review, we summarize the available data of lenvatinib for the treatment of advanced/metastatic renal cell carcinoma. Expert opinion: Lenvatinib in combination with everolimus has provided encouraging results in both clinical and laboratory investigations showing that blocking angiogenesis and the mTOR signalling pathway could be a remarkable approach for treating RCC. As an additive to this type of approach it would be interesting in future clinical settings testing also the combination of lenvatinib and everolimus with immune therapy. PMID- 29718722 TI - Integrating Visual Mnemonics and Input Feedback With Passphrases to Improve the Usability and Security of Digital Authentication. AB - OBJECTIVE: We developed a new authentication system based on passphrases instead of passwords. Our new system incorporates a user-generated mnemonic picture displayed during login, definition tooltips, error correction to reduce typographical errors, a decoy-based input masking technique, and random passphrase generation using either a specialized wordlist or a sentence template. BACKGROUND: Passphrases exhibit a greater level of security than traditional passwords, but their wider adoption has been hindered by human factors issues. Our assertion is that the added features of our system work particularly well with passphrases and help address these shortcomings. METHOD: We conducted a study to evaluate our new system with a customized 1,450-word list and our new system with a 6-word sentence structure against the control conditions of a user created passphrase of at least 24 characters and a system-generated passphrase using a 10,326-word list. Fifty participants completed two sessions so that we could measure the usability and security of the authentication schemes. RESULTS: With the new system conditions, memorability was improved, and security was equivalent to or better than the control conditions. Usability and overall ratings also favored the new system conditions over the control conditions. CONCLUSION: Our research presents a new authentication system using innovative techniques that improve on the usability and security of existing password and passphrase authentication systems. APPLICATION: In computer security, drastic changes should never happen overnight, but we recommend that our contributions be incorporated into current authentication systems to help facilitate a transition from passwords to usable passphrases. PMID- 29718723 TI - siRNA drug development against hepatitis B virus infection. AB - INTRODUCTION: Hepatitis B virus (HBV) infection is the worldwide leading cause of liver cirrhosis and hepatocellular carcinoma. Currently available medication can suppress viral replication in the majority of patients, but clearance of the viral antigens can be achieved in only about 10%. Areas covered: RNA interference is a very attractive therapeutic option since a well-designed compound could possibly inhibit all HBV mRNA and thus synthesis of all its antigens, which could combine antiviral and immunomodulatory modes of action. The aim of the article is to provide current knowledge on possible use of small interfering RNA (siRNA) molecules in the treatment of chronic HBV infection. Expert opinion: Based on the current status of clinical trials, we should expect that within the coming five years at least one siRNA molecule will be registered for clinical use. However, most important at this stage of development will be the safety profile, improving the route of administration, selection of the optimal combination with other anti HBV drugs (nucleoside analogues, interferons) and finally selection of the optimal system introducing siRNA molecules into infected cells. Current therapeutic options for HBV, the siRNA mechanism of action, as well as preclinical and clinical studies with siRNA molecules are presented in this article. PMID- 29718724 TI - Prospective Study on Ex-PRESS Implantation Combined with Phacoemulsification in Primary Angle-Closure Glaucoma Coexisting Cataract: 3-Year Results. AB - PURPOSE: To evaluate the feasibility, efficacy, and safety of Ex-PRESS implantation combined with phacoemulsification surgery in primary angle-closure glaucoma (PACG) with cataract. MATERIALS AND METHODS: This is a prospective, nonrandomized study. A total of 34 eyes of 34 subjects were enrolled. The assessments were conducted preoperatively and postoperatively at 1 week and 1, 3, 6, 12, 18, 24, 30, and 36 months. The assessments included intraocular pressure (IOP), best-corrected visual acuity (BCVA), the number of glaucoma medications, corneal endothelial cell density (ECD), and related complications, if any. The anterior segment structure was also assessed by anterior segment optical coherence tomography based on the anterior chamber depth (ACD), angle opening distance (AOD500), and trabecular-iris angle (TIA). A complete success was defined as a controlled IOP between 5 and 21 mmHg without medications. RESULTS: The complete success rates at 12, 24, and 36 postoperative months were 91.2%, 81.7%, and 78.3%, respectively. The mean preoperative IOP was 28.43 +/- 12.93 mmHg and decreased to 15.35 +/- 4.02 mmHg at 3 years postoperatively (P < 0.001). The number of medications decreased from 2.47 +/- 1.89 at baseline to 0.28 +/- 0.76 at 3 years postoperatively (P = 0.001). BCVA was 0.83 +/- 0.58 at baseline and 0.51 +/- 0.33 at 3 years postoperatively (P = 0.008). The ACD, AOD500, and TIA significantly increased at 3 months postoperatively compared with baseline (P < 0.001). ECD at 3 months and 3 years postoperatively were both significantly lower compared with baseline (P = 0.03), but was not significantly different between 3 months and 3 years postoperatively (P = 0.07). The device-related complications identified were hypotony (5.8%), hyphema (2.9%), and iris touch (2.9%), which the incidence rates were all very low. CONCLUSIONS: Ex-PRESS implantation combined with phacoemulsification was effective for lowering IOP in PACG coexisting with cataract. The device-related complication was rare. PMID- 29718726 TI - Using Generalizability Theory to Disattenuate Correlation Coefficients for Multiple Sources of Measurement Error. AB - Over the years, research in the social sciences has been dominated by reporting of reliability coefficients that fail to account for key sources of measurement error. Use of these coefficients, in turn, to correct for measurement error can hinder scientific progress by misrepresenting true relationships among the underlying constructs being investigated. In the research reported here, we addressed these issues using generalizability theory (G-theory) in both traditional and new ways to account for the three key sources of measurement error (random-response, specific-factor, and transient) that affect scores from objectively scored measures. Results from 20 widely used measures of personality, self-concept, and socially desirable responding showed that conventional indices consistently misrepresented reliability and relationships among psychological constructs by failing to account for key sources of measurement error and correlated transient errors within occasions. The results further revealed that G theory served as an effective framework for remedying these problems. We discuss possible extensions in future research and provide code from the computer package R in an online supplement to enable readers to apply the procedures we demonstrate to their own research. PMID- 29718725 TI - Bispecific antibodies (anti-mPEG/anti-HER2) for active tumor targeting of docetaxel (DTX)-loaded mPEGylated nanocarriers to enhance the chemotherapeutic efficacy of HER2-overexpressing tumors. AB - Anti-mPEG/anti-human epidermal growth factor receptor 2 (HER2) bispecific antibodies (BsAbs) non-covalently bound to a docetaxel (DTX)-loaded mPEGylated lecithin-stabilized micellar drug delivery system (LsbMDDs) were endowed with active targetability to improve the chemotherapeutic efficacy of DTX. DTX-loaded mPEGylated LsbMDDs formulations were prepared using lecithin/DSPE-PEG(2K or 5K) nanosuspensions to hydrate the thin film, and then they were subjected to ultrasonication. Two BsAbs (anti-mPEG/anti-DNS or anti-HER2) were simply mixed with the LsbMDDs to form BsAbs-LsbMDDs formulations, respectively, referred as the DNS-LsbMDDs and HER2-LsbMDDs. Results demonstrated that the physical characteristics of the BsAbs-LsbMDDs were similar to those of the plain LsbMDDs but more slowly released DTX than that from the LsbMDDs. Results also showed that the HER2-LsbMDDs suppressed the growth of HER2-expressing MCF-7/HER2 tumors, increasing the amount taken up via an endocytosis pathway leading to high drug accumulation and longer retention in the tumor. In conclusion, the BsAbs-LsbMDDs preserved the physical properties of the LsbMDDs and actively targeted tumors with a drug cargo to enhance drug accumulation in tumors leading to greater antitumor activity against antigen-positive tumors. PMID- 29718727 TI - Which neuropsychological functions predict various processing speed components in children with and without attention-deficit/hyperactivity disorder? AB - We identified statistical predictors of four processing speed (PS) components in a sample of 151 children with and without attention-deficit/hyperactivity disorder (ADHD). Performance on perceptual speed was predicted by visual attention/short-term memory, whereas incidental learning/psychomotor speed was predicted by verbal working memory. Rapid naming was predictive of each PS component assessed, and inhibition predicted all but one task, suggesting a shared need to identify/retrieve stimuli rapidly and inhibit incorrect responding across PS components. Hence, we found both shared and unique predictors of perceptual, cognitive, and output speed, suggesting more specific terminology should be used in future research on PS in ADHD. PMID- 29718728 TI - Extra practice outside therapy sessions to maximize training opportunity during inpatient rehabilitation after traumatic brain injury. AB - OBJECTIVE: To determine if extra practice outside therapy sessions can be conducted for patients with traumatic brain injury and identify factors that influence their participation. METHODS: A purpose-designed survey was conducted on consecutive eligible patients with traumatic brain injury and their relatives on discharge from inpatient rehabilitation. RESULTS: In total, 68 of the 69 of patients who took part in the survey reported that they participated in extra practice outside therapy sessions. Also, 58% reported that they conducted extra practice more than three times a week on average and 70% reported no barriers in conducting extra practice. Patients with poor motivation, reduced executive functioning and less severe brain injury are less likely to participate in extra practice and may require more support. Relatives tended to be involved in extra practice for patients who were dependent. A wide range of barriers were identified with poor motivation and lack of confidence being the main ones. CONCLUSION: With appropriate support, extra practice outside therapy sessions is generally feasible to maximize training opportunity for patients with traumatic brain injury. Motivation, perception of being listened to, executive functioning and severity of injury are factors that influence participation in extra practice. Strategies that improve motivation, interaction and confidence are likely to enhance participation. Relatives are a useful source of support for the more dependent patients. PMID- 29718729 TI - Financial hardship after traumatic brain injury: a brief scale for family caregivers. AB - OBJECTIVE: Financial hardship is frequently posited as a significant factor influencing family health and adjustment after brain injury, though traditional methods of measurement have shown limited usefulness. The purpose of this study was to adapt and test the utility of a brief scale of financial hardship (BSFH BI) for use with family caregivers after TBI. METHODS: The researchers constructed the BSFH-BI using financial well-being items adapted from three survey instruments. The BSFH-BI questionnaire was completed by 136 family caregivers of individuals with TBIs. Scale utility was evaluated through reliability analysis, factor analysis, and correlations with a measure of life satisfaction. RESULTS: The factor analysis revealed that the BSFH-BI had a meaningful two factor structure consisting of items related to (a) meeting essential living expenses and (b) financial changes after the injury. The scale showed high internal consistency (alpha = 0.92) and moderate negative correlations with life satisfaction (rs = -0.58). CONCLUSIONS: The preliminary findings indicate that the BSFH-BI can be a reliable and valid scale for use with family caregivers after TBI. The authors recommend further study of financial hardship within models of adaptation to TBI using psychometrically validated instruments such as the BSFH-BI. PMID- 29718730 TI - Investigational drugs for hyperuricemia, an update on recent developments. AB - INTRODUCTION: The significant proportion of gout patients not reaching serum urate levels below 6.0 mg/dL and the debated pathogenicity of hyperuricemia (HU) itself motivate investigators to develop new drugs to decrease uricemia. Areas covered: This review discusses the drugs considered to be in active development from pre-clinical to phase III studies. This review covers 11 drugs in development, including a xanthine oxidase inhibitor (topiroxostat), uricosurics (verinurad, arhalofenate, UR-1102, tranilast), dual inhibitors (RLBN1001, KUX 1151), a uricase (pergsiticase), an inhibitor of hypoxanthine production (ulodesine), and drugs with yet-to-explain mechanisms of action (levotofisopam, tuna extracts). Expert opinion: Drugs well advanced in their development - particularly arhalofenate, verinurad and topiroxostat - open the prospect of patient-comorbidity-tailored HU management. Development of novel therapies provides new insight into our understanding of gout and HU, particularly potential pathogenicity. Apart from potency to decrease serum urate levels and good tolerance profiles, novel therapies will need to focus on administration modalities facilitating treatment adherence. PMID- 29718731 TI - Parental Expressed Emotion-Criticism and Neural Markers of Sustained Attention to Emotional Faces in Children. AB - There is growing evidence for the role of environmental influences on children's information-processing biases for affectively salient stimuli. The goal of this study was to extend this research by examining the relation between parental criticism (expressed emotion-criticism, or EE-Crit) and children's processing of facial displays of emotion. Specifically, we examined the relation between EE Crit and children's sensitivity in detecting facial displays of emotion. We also examined a neural marker of sustained attention, the late positive potential (LPP) event-related potential component (ERP). Participants were 87 children (ages 7-11 years; 53.3% female, 77.8% Caucasian) and their parents (ages 24-71; 90% female, 88.9% Caucasian). Parents completed the Five-Minute Speech Sample to determine levels of EE-Crit toward their child. Children completed a morphed faces task during which behavioral and ERP responses were assessed. Although there were no group differences in sensitivity in detecting facial displays of emotion, we found that children of parents exhibiting high, compared to low, EE Crit displayed less attention (smaller LPP magnitudes) to all facial displays of emotion (fearful, happy, sad). These results suggest that children of critical parents may exhibit an avoidant pattern of attention to affectively-salient interpersonal stimuli. PMID- 29718732 TI - Avacopan in the treatment of ANCA-associated vasculitis. AB - INTRODUCTION: ANCA-associated vasculitis (AAV) is a rare but potentially life threatening disease. Currently used induction treatment (cyclophosphamide or rituximab with high-dose corticosteroids) has significantly improved outcome of AAV, but is associated with high toxicity. Alternative complement pathway activation was shown to play a role in the pathogenesis of AAV, thus providing rationale for the use of avacopan, a selective inhibitor of C5a receptor, in the treatment of AAV. Areas covered: Pharmacokinetic and pharmocodynamic properties of avacopan, clinical efficacy and safety and tolerability of avacopan in so far performed clinical trials in patients with AAV are reviewed and discussed. Expert opinion: Avacopan was shown to have at least similar efficacy compared to high dose corticosteroids in patients with active AAV with renal involvement, while there were no major safety issues reported. Replacement of corticosteroids should decrease the corticosteroid-related toxicity and improve long-term outcome of patients with AAV even though this still needs to be confirmed in a larger trial. Data on long-term outcome of avacopan-treated patients are currently lacking and will be eagerly awaited. In the future, avacopan could replace corticosteroids not only in the induction phase, but also in the maintenance treatment of AAV. PMID- 29718733 TI - Development of a multimedia educational programme for first-time hearing aid users: a participatory design. AB - OBJECTIVE: To develop content for a series of interactive video tutorials (or reusable learning objects, RLOs) for first-time adult hearing aid users, to enhance knowledge of hearing aids and communication. DESIGN: RLO content was based on an electronically-delivered Delphi review, workshops, and iterative peer review and feedback using a mixed-methods participatory approach. STUDY SAMPLE: An expert panel of 33 hearing healthcare professionals, and workshops involving 32 hearing aid users and 11 audiologists. This ensured that social, emotional and practical experiences of the end-user alongside clinical validity were captured. RESULTS: Content for evidence-based, self-contained RLOs based on pedagogical principles was developed for delivery via DVD for television, PC or internet. Content was developed based on Delphi review statements about essential information that reached consensus (>=90%), visual representations of relevant concepts relating to hearing aids and communication, and iterative peer-review and feedback of content. CONCLUSIONS: This participatory approach recognises and involves key stakeholders in the design process to create content for a user friendly multimedia educational intervention, to supplement the clinical management of first-time hearing aid users. We propose participatory methodologies are used in the development of content for e-learning interventions in hearing-related research and clinical practice. PMID- 29718734 TI - Usnic acid and its derivatives for pharmaceutical use: a patent review (2000 2017). AB - INTRODUCTION: Usnic acid (UA) is a lichen-derived secondary metabolite with a unique dibenzofuran skeleton and is commonly found in lichenized fungi of the genera Usnea and Cladonia. Usnic acid has been incorporated for years in cosmetics, perfumery, and traditional medicines. It has a wide range of bioactivities, including antimicrobial, antiviral, anticancer, anti-inflammatory properties. Areas covered: This review covers patents on therapeutic activities of UA and its synthetic derivatives published during the period 2000-2017. Expert opinion: UA demonstrates excellent anticancer and antimicrobial properties. However, its application was withdrawn due to acute liver toxicity reported with chronic consumption. The broad spectrum of its biological activity indicates high the variability of UA's binding preferences. The main idea to be addressed in the future should include the synthesis of UA derivatives because these might possess increased bioactivity, bioavailability and decreased toxicity. It is noteworthy that UA derivatives possessed better antibacterial, antitubercular, and anticancer activity than the parent compound . Most importantly, UA and its analogs (to a greater extent than UA) can be useful in cancer drug treatment. They have the potential for joint application with other anticancer drugs in order to overcome drug resistance. PMID- 29718735 TI - Expression of CRBN, IKZF1, and IKZF3 does not predict lenalidomide sensitivity and mutations in the cereblon pathway are infrequent in multiple myeloma. AB - The immunomodulatory drug thalidomide, and its analogs, lenalidomide, and pomalidomide (IMiDs), have become essential components of the standard treatment for multiple myeloma (MM), and have led to significant improvement of survival in patients with this devastating disease. Cereblon (CRBN), the direct target of IMiDs, has been proposed as a predictive biomarker of response to IMiDs. Using standard immunohistochemistry in formalin-fixed paraffin embedded (FFPE) bone marrow samples of 23 patients treated with a lenalidomide-containing regimen, we found that the malignant plasma cells of all the patients stained positive for CRBN, IKZF1, and IKZF3, regardless of sensitivity to IMiDs. Moreover, we detected no mutations in CRBN, IKZF1, IKZF3, CUL4A, or IRF4, but found expanded TP53 mutated clones in two out of seven sequential samples. Thus, our data argue against the use of CRBN and its downstream targets as predictive biomarkers of IMiD response in MM and confirm clonal evolution patterns during lenalidomide resistance. PMID- 29718736 TI - Implications of high EVI1 expression in high-risk myelodysplastic syndromes. PMID- 29718737 TI - Current knowledge of microRNA-mediated regulation of drug metabolism in humans. AB - INTRODUCTION: Understanding the factors causing inter- and intra-individual differences in drug metabolism potencies is required for the practice of personalized or precision medicine, as well as for the promotion of efficient drug development. The expression of drug-metabolizing enzymes is controlled by transcriptional regulation by nuclear receptors and transcriptional factors, epigenetic regulation, such as DNA methylation and histone acetylation, and post translational modification. In addition to such regulation mechanisms, recent studies revealed that microRNAs (miRNAs), endogenous ~22-nucleotide non-coding RNAs that regulate gene expression through the translational repression and degradation of mRNAs, significantly contribute to post-transcriptional regulation of drug-metabolizing enzymes. Areas covered: This review summarizes the current knowledge regarding miRNAs-dependent regulation of drug-metabolizing enzymes and transcriptional factors and its physiological and clinical significance. We also describe recent advances in miRNA-dependent regulation research, showing that the presence of pseudogenes, single-nucleotide polymorphisms, and RNA editing affects miRNA targeting. Expert opinion: It is unwavering fact that miRNAs are critical factors causing inter- and intra-individual differences in the expression of drug metabolizing enzymes. Consideration of miRNA-dependent regulation would be a helpful tool for optimizing personalized and precision medicine. PMID- 29718738 TI - Treatment of severe, uncontrolled eosinophilic asthma: Where we are heading. AB - OBJECTIVE: We sought to highlight how our understanding of the pathophysiology of severe asthma has evolved over time and discuss the role of biomarkers in treatment advances and emerging new therapies. DATA SOURCES: Nonsystematic PubMed literature search. STUDY SELECTION: Articles were selected based on areas of relevance to the classification of asthma by endotype, with an emphasis on the evolution of current treatment guidelines for severe asthma. RESULTS: Unlike older guidelines for the treatment of severe asthma, recent updates now distinguish between asthma severity and control. Moreover, asthma classification is shifting from phenotype to endotype with the development of biomarkers used to determine the mechanism driving a patient's disease. Many cases of severe asthma are associated with type-2 inflammation with elevated eosinophil counts in the airways. In recent studies, patients with severe, uncontrolled asthma and high eosinophil counts respond to biologic therapies targeting the type-2 signaling pathway and eosinophils themselves (eg, anti-IL-5 therapy). New treatments that address the pathophysiology of asthma offer a promising alternative to control severe asthma for patients who do not respond to traditional therapies. CONCLUSION: Understanding and using new treatment guidelines that separate the concepts of asthma severity and control may help clinicians to identify patients with severe, uncontrolled asthma who may benefit from new treatment options, such as anti-IL-5 therapies. PMID- 29718740 TI - Indazole derivatives and their therapeutic applications: a patent review (2013 2017). AB - INTRODUCTION: Indazoles are heterocyclic moieties rarely found in nature. They are nitrogen containing chemical compounds composed of a pyrazole ring condensed with a benzene ring. Various indazole derivatives have been described with a wide variety of biological activities. This has aroused great interest in the development of novel indazole based therapeutic agents. Areas covered: Forty-two patents published within the last 5 years (2013-2017) describing derivatives with the indazole scaffold and their therapeutic applications were analysed. Expert opinion: The indazole scaffold is of great pharmacological importance as it forms the basic structure of a large number of compounds with potential therapeutic value. Derivatives have been found to possess promising anticancer and anti inflammatory activity and have also found application in disorders involving protein kinases (aside from cancer) and neurodegeneration. The compounds where mechanism of action is defined can afford new molecules with biological and therapeutic properties. PMID- 29718741 TI - High-throughput behavioral assay to investigate seizure sensitivity in zebrafish implicates ZFHX3 in epilepsy. AB - Epilepsy, which affects ~1% of the population, is caused by abnormal synchronous neural activity in the central nervous system (CNS). While there is a significant genetic contribution to epilepsy, the underlying causes for the majority of genetic cases remain unknown. The NIH Undiagnosed Diseases Project (UDP) utilized exome sequencing to identify genetic variants in patients affected by various conditions with undefined etiology, including epilepsy. Confirming the functional relevance of the candidate genes identified by exome sequencing in a timely manner is crucial to translating exome data into clinically useful information. To this end, we developed a high throughput version of a seizure-sensitivity assay in zebrafish (Danio rerio) to rapidly evaluate candidate genes found by exome sequencing. We developed open access software, Studying Epilepsy In Zebrafish using R (SEIZR), to efficiently analyze the data. SEIZR was validated by disrupting function of a known epilepsy gene, prickle 1. Next, using SEIZR, we analyzed a candidate gene from the UDP screen (Zinc Finger Homeobox 3, ZFHX3), and showed that reduced ZFHX3 function in zebrafish results in a significant hyperactive response to the convulsant drug pentylenetetrazol (PTZ). We find that ZFHX3 shows strong expression in the CNS during neurogenesis including in the pallium, thalamus, tegmentum, reticular formation, and medulla oblongata - all regions which have roles in motor control and coordination. Our findings in the zebrafish confirm human ZFHX3 is a strong candidate for further neurological studies. We offer SEIZR to other researchers as a tool to rapidly and efficiently analyze large behavioral data sets. PMID- 29718743 TI - A real-world, multi-site, observational study of infusion time and treatment satisfaction with rheumatoid arthritis patients treated with intravenous golimumab or infliximab. AB - OBJECTIVES: To assess real-world infusion times for golimumab (GLM-IV) and infliximab (IFX) for rheumatoid arthritis (RA) patients and factors associated with treatment satisfaction. METHODS: An observational study assessed infusion time including: clinic visit duration, RA medication preparation and infusion time, and infusion process time. Satisfaction was assessed by a modified Treatment Satisfaction Questionnaire for Medication (patient) and study-specific questionnaires (patient and clinic personnel). Comparative statistical testing for patient data utilized analysis of variance for continuous measures, and Fisher's exact or Chi-square test for categorical measures. Multivariate analysis was performed for the primary time endpoints and patient satisfaction. RESULTS: One hundred and fifty patients were enrolled from six US sites (72 GLM-IV, 78 IFX). The majority of patients were female (80.0%) and Caucasian (88.7%). GLM-IV required fewer vials per infusion (3.7) compared to IFX (4.9; p = .0001). Clinic visit duration (minutes) was shorter for GLM-IV (65.1) compared to IFX (153.1; p < .0001), as was total infusion time for RA medication (32.8 GLM-IV, 119.5 IFX; p < .0001) and infusion process times (45.8 GLM-IV, 134.1 IFX; p < .0001). Patients treated with GLM-IV reported higher satisfaction ratings with infusion time (p < .0001) and total visit time (p = .0003). Clinic personnel reported higher satisfaction with GLM-IV than IFX specific to medication preparation time, ease of mixing RA medication, frequency of patients requiring pre-medication, and infusion time. LIMITATIONS: Findings may not be representative of care delivery for all RA infusion practices or RA patients. CONCLUSIONS: Shorter overall clinic visit duration, infusion process, and RA medication infusion times were observed for GLM-IV compared to IFX. A shorter duration in infusion time was associated with higher patient and clinic personnel satisfaction ratings. PMID- 29718742 TI - An RNAi-mediated screen identifies novel targets for next-generation antiepileptic drugs based on increased expression of the homeostatic regulator pumilio. AB - Despite availability of a diverse range of anti-epileptic drugs (AEDs), only about two-thirds of epilepsy patients respond well to drug treatment. Thus, novel targets are required to catalyse the design of next-generation AEDs. Manipulation of neuron firing-rate homoeostasis, through enhancing Pumilio (Pum) activity, has been shown to be potently anticonvulsant in Drosophila. In this study, we performed a genome-wide RNAi screen in S2R + cells, using a luciferase-based dPum activity reporter and identified 1166 genes involved in dPum regulation. Of these genes, we focused on 699 genes that, on knock-down, potentiate dPum activity/expression. Of this subgroup, 101 genes are activity-dependent based on comparison with genes previously identified as activity-dependent by RNA sequencing. Functional cluster analysis shows these genes are enriched in pathways involved in DNA damage, regulation of cell cycle and proteasomal protein catabolism. To test for anticonvulsant activity, we utilised an RNA-interference approach in vivo. RNAi-mediated knockdown showed that 57/101 genes (61%) are sufficient to significantly reduce seizure duration in the characterized seizure mutant, parabss. We further show that chemical inhibitors of protein products of some of the genes targeted are similarly anticonvulsant. Finally, to establish whether the anticonvulsant activity of identified compounds results from increased dpum transcription, we performed a luciferase-based assay to monitor dpum promoter activity. Third instar larvae exposed to sodium fluoride, gemcitabine, metformin, bestatin, WP1066 or valproic acid all showed increased dpum promoter activity. Thus, this study validates Pum as a favourable target for AED design and, moreover, identifies a number of lead compounds capable of increasing the expression of this homeostatic regulator. PMID- 29718744 TI - Osteonecrosis in children with acute lymphoblastic leukemia at initial diagnosis and prior to any chemotherapy. AB - Osteonecrosis (ON) is a common and debilitating side effect of anti-leukemic treatment in children with acute lymphoblastic leukemia (ALL). However, the impact of leukemia itself on ON development remains elusive. We analyzed 76 children enrolled in the ongoing OPAL trial, who had magnetic resonance imaging (MRI) studies at diagnosis. MRI screening revealed 14 osteonecrotic lesions (5 * hips, 9 * knees) of any grade (I-III) in 7 (9.2%) patients. Six months on, the number of ON per patient increased (1 patient), remained constant (2), and decreased (2). The severity increased from grade I to II in two patients, remained constant (1), completely resolved (2), and decreased from grade III to osteoedema (1). No differences between adolescents initially presenting with/without ON were observed concerning age, pubertal stage, body mass index, leukemia characteristics, and clinical presentation. In MRI screening, a remarkable number of adolescents with ALL present with ON at diagnosis. The course of these ON remains highly unpredictable. PMID- 29718745 TI - Use of whole genome sequencing in surveillance of drug resistant tuberculosis. AB - INTRODUCTION: The threat of resistance to anti-tuberculosis drugs is of global concern. Current efforts to monitor resistance rely on phenotypic testing where cultured bacteria are exposed to critical concentrations of the drugs. Capacity for such testing is low in TB endemic countries. Drug resistance is caused by mutations in the Mycobacterium tuberculosis genome and whole genome sequencing to detect these mutations offers an alternative means of assessing resistance. Areas covered: The challenges of assessing TB drug resistance are discussed. Progress in elucidating the M. tuberculosis resistome and evidence of the accuracy of next generation sequencing for detecting resistance is reviewed. Expert Commentary: There are considerable advantages to using next generation sequencing for TB drug resistance surveillance. Accuracy is high for detecting resistance to the major first-line drugs but is currently lower for the second-line drugs due to our incomplete knowledge regarding resistance causing mutations. With the advances in sequencing technology and the opportunity to replace phenotypic drug susceptibility testing with safer and more cost effective methods it would appear that the question is when to implement. Current bottlenecks are sample extraction to allow whole genome sequencing directly from sputum and the lack of bioinformatics expertise in some TB endemic countries. PMID- 29718739 TI - Emerging therapeutic targets for treatment of leishmaniasis. AB - INTRODUCTION: Parasitic diseases that pose a threat to human life include leishmaniasis - caused by protozoan parasite Leishmania species. Existing drugs have limitations due to deleterious side effects like teratogenicity, high cost and drug resistance. This calls for the need to have an insight into therapeutic aspects of disease. Areas covered: We have identified different drug targets via. molecular, imuunological, metabolic as well as by system biology approaches. We bring these promising drug targets into light so that they can be explored to their maximum. In an effort to bridge the gaps between existing knowledge and prospects of drug discovery, we have compiled interesting studies on drug targets, thereby paving the way for establishment of better therapeutic aspects. Expert opinion: Advancements in technology shed light on many unexplored pathways. Further probing of well established pathways led to the discovery of new drug targets. This review is a comprehensive report on current and emerging drug targets, with emphasis on several metabolic targets, organellar biochemistry, salvage pathways, epigenetics, kinome and more. Identification of new targets can contribute significantly towards strengthening the pipeline for disease elimination. PMID- 29718746 TI - Japan College of Rheumatology guideline for the use of methotrexate in patients with rheumatoid arthritis. AB - Methotrexate (MTX), the anchor drug in the current treatment strategy for rheumatoid arthritis (RA), was first approved for treatment of RA in Japan in 1999 at the recommended dose of 6-8 mg/week; it was approved as first-line drug with the maximum dose of 16 mg/week in February 2011. However, more than half of Japanese patients with RA are unable to tolerate a dose of 16 mg/week of MTX. Moreover, some serious adverse events during the treatment with MTX, such as pneumocystis pneumonia (PCP) and lymphoproliferative disorders (LPD) have been observed much more frequently in Japan than in other countries. Therefore, this article, an abridged English translation summarizing the 2016 update of the Japan College of Rheumatology (JCR) guideline for the use of MTX in Japanese patients with RA, is not intended to be valid for global use; however, it is helpful for the Japanese community of rheumatology and its understanding might be useful to the global community of rheumatology. PMID- 29718747 TI - Patent portfolio management: literature review and a proposed model. AB - INTRODUCTION: Patents and patent portfolios are gaining attention in the last decades, from the called 'pro-patent era' to the recent billionaire transactions involving patent portfolios. The field is growing in importance, both theoretically and practically and despite having substantial literature on new product development portfolio management, we have not found an article relating this theory to patent portfolios. Areas covered: The paper develops a systematic literature review on patent portfolio management to organize the evolution and tendencies of patent portfolio management, highlighting distinctive features of patent portfolio management. Interview with IP manager of three life sciences companies, including a leading multinational group provided relevant information about patent portfolio management. Expert opinion: Based on the systematic literature review on portfolio management, more specifically, on new product development portfolio theory, and interview the paper proposes the paper proposes a reference model to manage patent portfolios. The model comprises four stages aligned with the three goals of the NPD portfolio management: 1 - Linking strategy of the Company's NPD Portfolio to Patent Portfolio; 2 - Balancing the portfolio in buckets; 3 - Patent Valuation (maximizing valuation); 4 - Regularly reviewing the patent portfolio. PMID- 29718748 TI - An update on the toxicological considerations for protease inhibitors used for hepatitis C infection. AB - INTRODUCTION: Hepatitis C virus protease inhibitors (PIs) are important components of many direct acting antiviral regimens. Many clinical trials and real-world studies have described the safety data for individual PIs. We aimed to review the safety of both the first and second generation PIs in patients with chronic hepatitis C (CHC). Areas covered: The unique pharmacokinetic properties of PIs partly explain their toxicities. Second generation PIs, when used without interferon and ribavirin, are well-tolerated. Use of PIs in renal impaired patients or those on dialysis appears to be safe. Decompensated cirrhosis is a contraindication for PIs use due to increased drug exposure and risk of liver decompensation. Drug-drug interactions are common and should be always monitored; some drugs should not be co-administered with PIs. In patients with co-infected hepatitis B virus, reactivation after DAA (whether PI-containing or not) is a concern. Expert opinion: Second generation PIs are key players in the current DAA era. Post-marketing surveillance is essential to monitor unknown adverse events and drug-drug interactions. Non-PI based DAA should be used in decompensated liver disease. The use of these drugs should also be explored in the paediatric population. PMID- 29718749 TI - Importance of early diagnosis and treatment in idiopathic pulmonary fibrosis. PMID- 29718750 TI - Moniliform blepharosis in lipoid proteinosis with a homozygous ECM1 gene mutation. PMID- 29718752 TI - Corrigendum. PMID- 29718751 TI - Regression Discontinuity and Randomized Controlled Trial Estimates: An Application to The Mycotic Ulcer Treatment Trials. AB - PURPOSE: We compare results from regression discontinuity (RD) analysis to primary results of a randomized controlled trial (RCT) utilizing data from two contemporaneous RCTs for treatment of fungal corneal ulcers. METHODS: Patients were enrolled in the Mycotic Ulcer Treatment Trials I and II (MUTT I & MUTT II) based on baseline visual acuity: patients with acuity <= 20/400 (logMAR 1.3) enrolled in MUTT I, and >20/400 in MUTT II. MUTT I investigated the effect of topical natamycin versus voriconazole on best spectacle-corrected visual acuity. MUTT II investigated the effect of topical voriconazole plus placebo versus topical voriconazole plus oral voriconazole. We compared the RD estimate (natamycin arm of MUTT I [N = 162] versus placebo arm of MUTT II [N = 54]) to the RCT estimate from MUTT I (topical natamycin [N = 162] versus topical voriconazole [N = 161]). RESULTS: In the RD, patients receiving natamycin had mean improvement of 4-lines of visual acuity at 3 months (logMAR -0.39, 95% CI: -0.61, -0.17) compared to topical voriconazole plus placebo, and 2-lines in the RCT (logMAR 0.18, 95% CI: -0.30, -0.05) compared to topical voriconazole. CONCLUSIONS: The RD and RCT estimates were similar, although the RD design overestimated effects compared to the RCT. PMID- 29718753 TI - Glia: from 'just glue' to essential players in complex nervous systems: a comparative view from flies to mammals. AB - In the last years, glial cells have emerged as central players in the development and function of complex nervous systems. Therefore, the concept of glial cells has evolved from simple supporting cells to essential actors. The molecular mechanisms that govern glial functions are evolutionarily conserved from Drosophila to mammals, highlighting genetic similarities between these groups, as well as the great potential of Drosophila research for the understanding of human CNS. These similarities would imply a common phylogenetic origin of glia, even though there is a controversy at this point. This review addresses the existing literature on the evolutionary origin of glia and discusses whether or not insect and mammalian glia are homologous or analogous. Besides, this manuscript summarizes the main glial functions in the CNS and underscores the evolutionarily conserved molecular mechanisms between Drosophila and mammals. Finally, I also consider the current nomenclature and classification of glial cells to highlight the need for a consensus agreement and I propose an alternative nomenclature based on function that unifies Drosophila and mammalian glial types. PMID- 29718754 TI - Impact of total body weight on acute kidney injury in patients with gram-negative bacteremia. AB - BACKGROUND: The impact of total body weight (TBW) on the development of acute kidney injury (AKI) associated with gram-negative bacteremia has not been previously evaluated. METHODS: The cohort included 323 patients >/ = 18 years old with gram-negative bacteremia (1/1/2008-8/31/2011) who received >/ = 48 hours of antibiotics. We compared the incidence of AKI in patients with a TBW 80kg with a multivariable stepwise logistic regression adjusting for age >/ = 70 years, baseline serum creatinine of > 2.0 mg/dl, and receipt of a vasopressor. AKI was defined as an increase of 0.5 mg/dL or a > 50% increase from baseline for at least two consecutive days. RESULTS: The cohort was 62% TBW 80kg. TBW >80kg patients had higher risk of AKI (24% vs. 9%, p < 0.001), which was significant in the multivariable analysis (OR 3.41, 95% CI 1.73-6.73). A baseline serum creatinine of > 2.0 mg/dl and vasopressor use were also independently associated with AKI. CONCLUSIONS: TBW >80kg was associated with the development of AKI. However, the mechanism for this association is not clear. PMID- 29718755 TI - Complement cascade on severe traumatic brain injury patients at the chronic unconscious stage: implication for pathogenesis. AB - BACKGROUND: Patients who awake from severely traumatic brain injury (TBI) may remain unconscious for many years. Although behavioral assessment and functional imaging are currently used as diagnostic tools, the molecular basis underlying chronic condition has yet to be explored. METHOD: Plasma samples were obtained at 3 time points (1, 3 and 6 months) from 18 patients with chronic disorders of consciousness who survived severe TBI, and 6 healthy volunteers. A coupled isobaric tag for relative and absolute quantitation (iTRAQ)-based proteomics approach was used to screen differentially expressed proteins (DEPs) between patients and controls. Potential molecular mechanisms were further discussed through bioinformatics analyses. RESULT: In total, 300 plasma proteins <1% false discovery rates were identified and 32 proteins were consistently altered between patients and controls. Biological pathway analysis revealed that the DEPs were predominantly involved in complement cascade. CONCLUSIONS: This study discussed potential mechanisms of complement cascade underlying chronic stage in severe TBI. PMID- 29718756 TI - Healthcare resource utilization and costs among psoriasis patients treated with biologics, overall and by disease severity. AB - AIMS: To describe healthcare resource utilization (HCRU) and costs among biologic treated psoriasis patients in the US, overall and by disease severity. MATERIALS AND METHODS: IQVIA PharMetrics Plus administrative claims data were linked with Modernizing Medicine Data Services Electronic Health Record data and used to select adult psoriasis patients between April 1, 2010 and December 31, 2014. Eligible patients were classified by disease severity (mild, moderate, severe) using a hierarchy of available clinical measures. One-year outcomes included all cause and psoriasis-related outpatient, emergency department, inpatient, and pharmacy HCRU and costs. RESULTS: This study identified 2,130 biologic-treated psoriasis patients: 282 (13%) had mild, 116 (5%) moderate, and 49 (2%) severe disease; 1,683 (79%) could not be classified. The mean age was 47.6 years; 45.4% were female. Relative to mild psoriasis patients, patients with moderate or severe disease had more median all-cause outpatient encounters (28.0 [mild] vs 32.0 [moderate], 36.0 [severe]), more median psoriasis-related outpatient encounters (6.0 [mild] vs 7.5 [moderate], 8.0 [severe]), and a higher proportion of overall claims for medications that were psoriasis-related (28% [mild] vs 37% [moderate], 34% [severe]). Relative to mild psoriasis patients, patients with moderate or severe disease had higher median all-cause total costs ($37.7k [mild] vs $42.3k [moderate], $49.3k [severe]), higher median psoriasis-related total costs ($32.7k [mild] vs $34.9k [moderate], $40.5k [severe]), higher median all cause pharmacy costs ($33.9k [mild] vs $36.5k [moderate], $36.4k [severe]), and higher median psoriasis-related pharmacy costs ($32.2k [mild] vs $33.9k [moderate], $35.6k [severe]). LIMITATIONS: The assessment of psoriasis disease severity may not have necessarily coincided with the timing of biologic use. The definition of disease severity prevented the assessment of temporality, and may have introduced selection bias. CONCLUSIONS: Biologic-treated patients with moderate or severe psoriasis cost the healthcare system more than patients with mild psoriasis, primarily driven by higher pharmacy costs and more outpatient encounters. PMID- 29718757 TI - ARL2BP, a protein linked to retinitis pigmentosa, is needed for normal photoreceptor cilia doublets and outer segment structure. AB - The outer segment (OS) of photoreceptor cells is an elaboration of a primary cilium with organized stacks of membranous disks that contain the proteins needed for phototransduction and vision. Though ciliary formation and function has been well characterized, little is known about the role of cilia in the development of photoreceptor OS. Nevertheless, progress has been made by studying mutations in ciliary proteins, which often result in malformed OSs and lead to blinding diseases. To investigate how ciliary proteins contribute to OS formation, we generated a knockout (KO) mouse model for ARL2BP, a ciliary protein linked to retinitis pigmentosa. The KO mice display an early and progressive reduction in visual response. Before photoreceptor degeneration, we observed disorganization of the photoreceptor OS, with vertically aligned disks and shortened axonemes. Interestingly, ciliary doublet microtubule (MT) structure was also impaired, displaying open B-tubule doublets, paired with loss of singlet MTs. On the basis of results from this study, we conclude that ARL2BP is necessary for photoreceptor ciliary doublet formation and axoneme elongation, which is required for OS morphogenesis and vision. PMID- 29718758 TI - JNK2 regulates vascular remodeling in pulmonary hypertension. AB - Pulmonary arterial (PA) wall modifications are key pathological features of pulmonary hypertension (PH). Although such abnormalities correlate with heightened phosphorylation of c-Jun N-terminal kinases 1/2 (JNK1/2) in a rat model of PH, the contribution of specific JNK isoforms to the pathophysiology of PH is unknown. Hence, we hypothesized that activation of either one, or both JNK isoforms regulates PA remodeling in PH. We detected increased JNK1/2 phosphorylation in the thickened vessels of PH patients' lungs compared to that in lungs of healthy individuals. JNK1/2 phosphorylation paralleled a marked reduction in MAP kinase phosphatase 1 (JNK dephosphorylator) expression in patients' lungs. Association of JNK1/2 activation with vascular modification was confirmed in the calf model of severe hypoxia-induced PH. To ascertain the role of each JNK isoform in pathophysiology of PH, wild-type (WT), JNK1 null (JNK1-/ ), and JNK2 null (JNK2-/-) mice were exposed to chronic hypoxia (10% O2 for six weeks) to develop PH. In hypoxic WT lungs, an increase in JNK1/2 phosphorylation was associated with PH-like pathology. Hallmarks of PH pathophysiology, i.e. excessive accumulation of extracellular matrix and vessel muscularization with medial wall thickening, was also detected in hypoxic JNK1-/- lungs, but not in hypoxia-exposed JNK2-/- lungs. However, hypoxia-induced increases in right ventricular systolic pressure (RVSP) and in right ventricular hypertrophy (RVH) were similar in all three genotypes. Our findings suggest that JNK2 participates in PA remodeling (but likely not in vasoconstriction) in murine hypoxic PH and that modulating JNK2 actions might quell vascular abnormalities and limit the course of PH. PMID- 29718760 TI - Uncertainties in the determination of pyrrolizidine alkaloid levels in naturally contaminated honeys and comparison of results obtained by different analytical approaches. AB - The contamination of honey with hepatotoxic pyrrolizidine alkaloids (PAs) is a well-known hazard for food safety. While management strategies and controls of the honey industry aim to reduce the PA levels, uncertainties remain with regard to the safety of regionally produced and marketed honey. In addition, a previous study showed large differences of results obtained after various periods of storage and apparent differences between the analytical results of different laboratories. Therefore, this study aimed at examining these uncertainties by monitoring the impact of storage on the PA and PA N-oxide (PANO) content of two freshly harvested honeys and on possible demixing effects caused by pollen settling. Additionally, three analytical approaches - target analysis with matrix matched calibration or standard addition and a sum parameter method - were applied for a comparative analysis of 20 honeys harvested in summer 2016. All samples originated from Schleswig-Holstein in Northern Germany where the PA plant Jacobaea vulgaris is currently observed on a massive scale. The results of the time series analyses showed that PANO levels markedly decreased within a few weeks and practically reached the LOD 16 weeks after harvest. Tertiary PAs, by contrast, remained stable and did not increase as a consequence of PANO decrease. The experiments on a putative demixing, which may result in a heterogeneous distribution of PAs/PANOs, revealed that there was no such effect during storage of up to 12 weeks. A comparison of the PA/PANO levels obtained by different analytical approaches showed that in some cases the sum parameter method yielded much higher levels than the target approaches, whereas in other cases, the target analysis with standard addition found higher levels than the other two methods. In summary, the results of this study highlight uncertainties regarding the validity and comparability of analytical results and consequently regarding health risk assessment. PMID- 29718759 TI - Increased Insulin-like Growth Factor Binding Protein-1 Phosphorylation in Decidualized Stromal Mesenchymal Cells in Human Intrauterine Growth Restriction Placentas. AB - Intrauterine growth restriction (IUGR) is often caused by placental insufficiency, which is believed to be associated with decreased delivery of oxygen and nutrients to the placental barrier. We recently reported that hypoxia and/or leucine deprivation triggered hyperphosphorylation of insulin-like growth factor binding protein-1 (IGFBP-1) in decidualized human immortalized endometrial stromal cells (HIESCs), resulting in decreased insulin-like growth factor-1 (IGF 1) bioactivity. To test the hypothesis that human IUGR is associated with increased decidual IGFBP-1 phosphorylation at discrete sites, we used IUGR and gestational age matched appropriate for gestational age (AGA) placentas ( n=5 each). We performed dual immunofluorescence immunohistochemistry (IHC) using IGFBP-1 and vimentin as decidual and mesenchymal markers, respectively. Employing a unique strategy with imaging software, we extracted signal intensity of IGFBP-1 expressed specifically from truly decidualized cells of the placenta. Relative IGFBP-1 was increased (85%; p=0.0001) and using custom phospho-site-specific antibodies, we found that IGFBP-1 phosphorylation (pSer101; +40%, p=0.0677/pSer119; +60%, p=0.0064/pSer169; +100%, p=0.0021) was markedly enhanced in IUGR. Together, our data links for the first time, increased decidual IGFBP-1 phosphorylation at discrete sites with human IUGR. These novel findings suggest that hyperphosphorylation of IGFBP-1 in decidualized stromal mesenchymal decidua basalis contributes to potentially elevated levels of phosphorylated IGFBP-1 in maternal circulation in IUGR pregnancies. PMID- 29718761 TI - Insight derived from molecular dynamics simulation into dynamics and molecular motions of cuticle-degrading serine protease Ver112. AB - Cuticle-degrading serine protease Ver112, which derived from a nematophagous fungus Lecanicillium psalliotae, has been exhibited to have high cuticle degrading and nematicidal activities. We have performed molecular dynamics (MD) simulation based on the crystal structure of Ver112 to investigate its dynamic properties and large-scale concerted motions. The results indicate that the structural core of Ver112 shows a small fluctuation amplitude, whereas the substrate binding sites, and the regions close to and opposite the substrate binding sites experience significant conformational fluctuations. The large concerted motions obtained from essential dynamics (ED) analysis of MD trajectory can lead to open or close of the substrate binding sites, which are proposed to be linked to the functional properties of Ver112, such as substrate binding, orientation, catalytic, and release. The significant motion in the loop regions that is located opposite the binding sites are considered to play an important role in modulating the dynamics of the substrate binding sites. Furthermore, the bottom of free energy landscape (FEL) of Ver112 are rugged, which is mainly caused by the fluctuations of substrate binding regions and loops located opposite the binding site. In addition, the mechanism underlying the high flexibility and catalytic activity of Ver112 was also discussed. Our simulation study complements the biochemical and structural studies, and provides insight into the dynamics-function relationship of cuticle-degrading serine protease Ver112. PMID- 29718763 TI - Detection of melamine in milk powder using MCT-based short-wave infrared hyperspectral imaging system. AB - Extensive research has been conducted on non-destructive and rapid detection of melamine in powdered foods in the last decade. While Raman and near-infrared hyperspectral imaging techniques have been successful in terms of non-destructive and rapid measurement, they have limitations with respect to measurement time and detection capability, respectively. Therefore, the objective of this study was to develop a mercury cadmium telluride (MCT)-based short-wave infrared (SWIR) hyperspectral imaging system and algorithm to detect melamine quantitatively in milk powder. The SWIR hyperspectral imaging system consisted of a custom-designed illumination system, a SWIR hyperspectral camera, a data acquisition module and a sample transfer table. SWIR hyperspectral images were obtained for melamine-milk samples with different melamine concentrations, pure melamine and pure milk powder. Analysis of variance and the partial least squares regression method over the 1000-2500 nm wavelength region were used to develop an optimal model for detection. The results showed that a melamine concentration as low as 50 ppm in melamine-milk powder samples could be detected. Thus, the MCT-based SWIR hyperspectral imaging system has the potential for quantitative and qualitative detection of adulterants in powder samples. PMID- 29718764 TI - The brain, self and society: a social-neuroscience model of predictive processing. AB - This paper presents a hypothesis about how social interactions shape and influence predictive processing in the brain. The paper integrates concepts from neuroscience and sociology where a gulf presently exists between the ways that each describe the same phenomenon - how the social world is engaged with by thinking humans. We combine the concepts of predictive processing models (also called predictive coding models in the neuroscience literature) with ideal types, typifications and social practice - concepts from the sociological literature. This generates a unified hypothetical framework integrating the social world and hypothesised brain processes. The hypothesis combines aspects of neuroscience and psychology with social theory to show how social behaviors may be "mapped" onto brain processes. It outlines a conceptual framework that connects the two disciplines and that may enable creative dialogue and potential future research. PMID- 29718762 TI - In wound repair vimentin mediates the transition of mesenchymal leader cells to a myofibroblast phenotype. AB - Following injury, mesenchymal repair cells are activated to function as leader cells that modulate wound healing. These cells have the potential to differentiate to myofibroblasts, resulting in fibrosis and scarring. The signals underlying these differing pathways are complex and incompletely understood. The ex vivo mock cataract surgery cultures are an attractive model with which to address this question. With this model we study, concurrently, the mechanisms that control mesenchymal leader cell function in injury repair within their native microenvironment and the signals that induce this same cell population to acquire a myofibroblast phenotype when these cells encounter the environment of the adjacent tissue culture platform. Here we show that on injury, the cytoskeletal protein vimentin is released into the extracellular space, binds to the cell surface of the mesenchymal leader cells located at the wound edge in the native matrix environment, and supports wound closure. In profibrotic environments, the extracellular vimentin pool also links specifically to the mesenchymal leader cells and has an essential role in signaling their fate change to a myofibroblast. These findings suggest a novel role for extracellular, cell surface-associated vimentin in mediating repair-cell function in wound repair and in transitioning these cells to a myofibroblast phenotype. PMID- 29718767 TI - Analysis of isophthalaldehyde in migration samples from polyethylene terephthalate packaging. AB - In the present work, different pre-concentration strategies were evaluated for the analysis of isophthalaldehyde in migration samples from food packaging materials. This compound is a potential migrant in several copolymers used for food packaging, and since it is considered a non-intentionally added substance, its concentration in migration samples must be determined. Derivatisation was the first sample treatment evaluated. o-(2,3,4,5,6-Pentafluorobenzyl)hydroxylamine was tested as derivatisation agent, but no satisfactory results were obtained. Then, hollow-fibre liquid-phase microextraction (HF-LPME) and solid-phase microextraction were optimised. The HF-LPME method showed the highest sensitivity, achieving an enrichment factor of 60-fold. The limit of detection of the method was 10 ng g-1, the limit of quantification was 30 ng g-1 and the relative standard deviation was 6.1%. Finally, the method was applied to migration studies to evaluate the safety in use of a poly(ethylene terephthalate) packaging material. The content of isophthalaldehyde was determined in two aqueous food simulants: 10% ethanol (v/v) and 3% acetic acid (w/v). Different migration conditions were tested. The results obtained showed a considerable rise in the concentration of isophthalaldehyde when increasing the time and temperature of the migration experiment. PMID- 29718766 TI - Multicompartment cell-based modeling of confined migration: regulation by cell intrinsic and extrinsic factors. AB - Though cell and nuclear deformability are expected to influence efficiency of confined migration, their individual and collective influence on migration efficiency remains incompletely understood. In addition to cell intrinsic properties, the relevance of cell extrinsic factors on confined migration, if any, has not been adequately explored. Here we address these questions using a statistical mechanics-based stochastic modeling approach where cell/nuclear dimensions and their deformability are explicitly taken into consideration. In addition to demonstrating the importance of cell softness in sustaining confined migration, our results suggest that dynamic tuning of cell and nuclear properties at different stages of migration is essential for maximizing migration efficiency. Our simulations also implicate confinement shape and confinement history as two important cell extrinsic regulators of cell invasiveness. Together, our findings illustrate the strength of a multicompartment model in dissecting the contributions of multiple factors that collectively influence confined cell migration. PMID- 29718765 TI - Matrix stiffness modulates infection of endothelial cells by Listeria monocytogenes via expression of cell surface vimentin. AB - Extracellular matrix stiffness (ECM) is one of the many mechanical forces acting on mammalian adherent cells and an important determinant of cellular function. While the effect of ECM stiffness on many aspects of cellular behavior has been studied previously, how ECM stiffness might mediate susceptibility of host cells to infection by bacterial pathogens is hitherto unexplored. To address this open question, we manufactured hydrogels of varying physiologically relevant stiffness and seeded human microvascular endothelial cells (HMEC-1) on them. We then infected HMEC-1 with the bacterial pathogen Listeria monocytogenes (Lm) and found that adhesion of Lm to host cells increases monotonically with increasing matrix stiffness, an effect that requires the activity of focal adhesion kinase (FAK). We identified cell surface vimentin as a candidate surface receptor mediating stiffness-dependent adhesion of Lm to HMEC-1 and found that bacterial infection of these host cells is decreased when the amount of surface vimentin is reduced. Our results provide the first evidence that ECM stiffness can mediate the susceptibility of mammalian host cells to infection by a bacterial pathogen. PMID- 29718768 TI - Contamination of wild boars' (Sus scrofa) muscles with tetracycline antibiotic from oral-delivered rabies vaccine baits. AB - Tetracycline (TC) is used as a biomarker for rabies vaccine bait intended for foxes. However, there is a high probability of intake of the vaccine by other species living in the forest ecosystem, including wild boars (Sus scrofa), and TC residues can occur in the animals' tissues. In this study, muscle samples from 144 animals were tested for the presence of TC, collected after rabies vaccine distribution. For the quantitative analysis of TC and its 4-epi form, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method was developed. The results of this study show that TC was found in 53 samples, which represents 37% of all tested animals. The concentrations were in the range 5-286 ug/kg. The preliminary results suggest that the risk exists of contamination of muscle tissue of wild boars with TC from oral-delivery rabies vaccine baits containing the antibiotic. Control should be considered of TC residues in wild boar meat for human consumption. PMID- 29718769 TI - Effect of maternal HIV status on vaccination coverage among sub-Saharan African children: A socio-ecological analysis. AB - We investigated the relationship between maternal HIV status and uptake of the full series of three doses of diphtheria-tetanus-pertussis containing vaccines (DTP3) in sub-Saharan African children. We used data obtained from demographic and health surveys conducted in sub-Saharan Africa. We conducted meta-analysis and calculated pooled odds ratios (OR) for the association between maternal HIV status and DTP3 vaccination status for each country. A total of 4,187 out of 5,537 children of women living with HIV received DTP3 (75.6%), compared to 71,290 of 113,513 (62.8%) children of HIV negative women. National DTP3 coverage among children of HIV-positive women varied between 24% and 96% while among children of HIV negative women it was between 26% and 92%. Overall pooled result showed no significant difference in DTP3 coverage between the two groups (OR = 1.05; 95% confidence interval 0.91 - 1.22), with statistically significant heterogeneity (Chi 2 = 91.63, P = 0.000, I2 = 71.6%). There was no significant association between DTP3 coverage and maternal HIV status in sub-Saharan Africa. However, DTP3 coverage for both HIV-exposed and non-exposed children were below the required target. Meta-regression revealed no significant association between DTP3 coverage and country characteristics (e.g. HIV prevalence among women, antiretroviral therapy coverage, gross domestic product per capita, human development index, adult literacy rate and sub-region). Improved prevention of mother-to-child transmission services might have contributed to some extent to the higher DTP3 vaccination coverage among the HIV-exposed children. There is also need to address barriers impeding uptake of vaccination among HIV-exposed and non-exposed children. PMID- 29718770 TI - Endothelial nitric oxide synthase genotype is associated with pulmonary hypertension severity in left heart failure patients. AB - The biological mechanisms behind the development of pulmonary hypertension in the setting of left heart failure (HF-PH), including combined pre- and post-capillary pulmonary hypertension (Cpc-PH), remains unclear. This study aimed to use candidate polymorphisms in nitric oxide synthase (NOS) genes to explore the role of NOS in HF-PH. DNA samples from 118 patients with HF-PH were genotyped for the NOS3 rs1799983 and NOS2 rs3730017 polymorphisms. A multiple regression model was used to compare hemodynamic measurements between genotype groups. Patients with the T/T genotype at rs1799983 possessed a nearly 10 mmHg increased transpulmonary gradient (TPG) compared to those with other genotypes ( P = 0.006). This finding was replicated in an independent cohort of 94 HF-PH patients ( P = 0.005). However, when tested in a cohort of 162 pre-capillary pulmonary arterial hypertension patients, no association was observed. In a combined analysis of both HF-PH cohorts, mean pulmonary artery pressure (mPAP), diastolic pulmonary gradient (DPG), and CpcPH status were also associated with rs1799983 genotype ( P = 0.005, P = 0.03, and P = 0.02, respectively). In patients with HF-PH, the NOS3 rs1799983 polymorphism is associated with TPG, and potentially mPAP and DPG as well. These findings suggest that endothelial NOS (encoded by NOS3) may be involved in the pulmonary vascular remodeling observed in Cpc-PH and warrants further study. PMID- 29718771 TI - The flower industry gets the genetic engineering blues. AB - The genetic engineering of plants over the past two decades has led to significant scientific, commercial and humanitarian successes, with more than 2.1 billion hectares cultivated worldwide. The vast majority of cultivation has been huge-scale commodity crops - corn, cotton, canola, soybean, sugar beet and alfalfa - while specialty crops such as fruits, nuts, vegetables and ornamental plants have been underrepresented. The commercialization of genetically engineered (GE) flowers has been especially neglected. Various laboratories worldwide are conducting research on various traits and flowers, the most intense interest focusing on carnation, rose, chrysanthemum and petunia, but the expense and uncertainty of government regulation is a hindrance. There are untapped economic opportunities in this sector, but for it to blossom, a regulatory climate that can spur development is critical. We need regulation that is scientifically defensible and risk-based. PMID- 29718772 TI - Occurrence of glyphosate in beer from the Latvian market. AB - A sensitive LC-MS/MS method for the determination of glyphosate in beer has been developed, validated, and applied to analyse 100 beer samples from 24 different producers and distributors in Latvia. The selected samples represented most beer brands and varieties sold in local supermarkets. Different procedures for sample preparation and chromatographic separation were compared. The final version of the method consisted of solid phase extraction, chromatographic separation on aminopropyl stationary phase, and detection using tandem mass spectrometry. The concentration of glyphosate in beer varied from below the LOD of 0.2 MUg kg-1 up to 150 MUg kg-1, higher than previously reported. Significantly higher (p < 0.01) content of glyphosate was observed in beers that did not have the country of production disclosed on the label and were sold in local supermarkets by distributors from Latvia (1.8 MUg kg-1 median concentration in locally produced beer, 6.7 MUg kg-1 in beer of undisclosed origin). PMID- 29718773 TI - High thiamine diphosphate level as a protective factor for Alzheimer's disease. AB - Objectives Thiamine diphosphate (TDP) is an indispensable coenzyme for three key enzymes in glucose metabolism. Reduced TDP levels in patients with Alzheimer's disease (AD) has been widely demonstrated and is a diagnostic biomarker for the disease. In this study, we further explored the correlation between altered TDP metabolism and AD along with other risk factors. Methods A 1:1 case-control study was employed with 90 AD patients and 90 control subjects with normal-range cognitive abilities as assayed by the Mini Mental Status Evaluation. Age (<=2 years variation), gender, and educational background were strictly matched. Levels of the main thiamine metabolites in whole blood samples, including TDP, thiamine monophosphate, and thiamine, were assayed using high-performance liquid chromatography. Apolipoprotein E genotypes, haemoglobin, and several metabolic factors (fasting glucose, uric acid, triglyceride, and total cholesterol) associated with AD were also measured. Results The odds ratio of TDP level for AD was 0.95 (with TDP level as a continuous variable) or 0.09 (with TDP level as a dichotomized variable with a cut-off value of 99.48 nmol/L). Blood TDP levels were significantly decreased in female AD patients compared to male AD patients. No correlations were identified between TDP levels and several metabolic factors (fasting glucose, uric acid, triglyceride, and total cholesterol). Conclusions TDP is a protective factor for AD and its protective efficacy may be independent of other metabolic factors. The difference of TDP levels between genders may be another possible explanation for the higher prevalence of AD in females. PMID- 29718774 TI - Tissue residue depletion of moxidectin in lambs (Ovis aries) following subcutaneous administration. AB - To date, a tissue depletion study of moxidectin (MOX) in lambs is not available. Thus, considering that lamb meat is of great commercial interest in the world, the aim of the present study was to determine the residue levels of MOX in lamb target-tissues (muscle, liver, kidney and fat) and subsequently calculate the MOX withdrawal period. For this purpose, the target-tissues were analysed by ultra high-performance liquid chromatography-tandem mass spectrometry. Method validation was performed based on Commission Decision 2002/657/EC and VICH GL49. To quantify the analyte, matrix-matched analytical curves were constructed with spiked blank tissues. The limits of detection and quantitation were 1.5 and 5 ng g-1, respectively, for all matrices. The linearity, decision limit, detection capability accuracy and inter- and intra-day precision of the method are reported. The lambs were treated with a single subcutaneous dose of 0.2 mg MOX kg 1 body weight and were slaughtered in accordance with accepted animal care protocols. Samples of target-tissues were collected on 2, 4, 7, 14, 28 and 42 days after MOX administration. During the whole study, the highest drug residue level occurred in the fat. For the other target-tissues (muscle, liver and kidney), MOX concentrations were below the maximum residue limit (MRL). Considering the MRL value of 500 ug kg-1 for MOX residues in sheep fat, our results in lambs allowed the estimation of a MOX withdrawal period of 31 days. This indicates that the withdrawal period established for MOX in adult sheep (28 days) does not apply for lambs. PMID- 29718775 TI - Multiple e-pharmacophore modelling pooled with high-throughput virtual screening, docking and molecular dynamics simulations to discover potential inhibitors of Plasmodium falciparum lactate dehydrogenase (PfLDH). AB - Development of new antimalarial drugs continues to be of huge importance because of the resistance of malarial parasite towards currently used drugs. Due to the reliance of parasite on glycolysis for energy generation, glycolytic enzymes have played important role as potential targets for the development of new drugs. Plasmodium falciparum lactate dehydrogenase (PfLDH) is a key enzyme for energy generation of malarial parasites and is considered to be a potential antimalarial target. Presently, there are nearly 15 crystal structures bound with inhibitors and substrate that are available in the protein data bank (PDB). In the present work, we attempted to consider multiple crystal structures with bound inhibitors showing affinity in the range of 1.4 * 102-1.3 * 106 nM efficacy and optimized the pharmacophore based on the energy involved in binding termed as e pharmacophore mapping. A high throughput virtual screening (HTVS) combined with molecular docking, ADME predictions and molecular dynamics simulation led to the identification of 20 potential compounds which could be further developed as novel inhibitors for PfLDH. PMID- 29718776 TI - Effect of intensive motor training with repetitive transcranial magnetic stimulation on upper limb motor function in chronic post-stroke patients with severe upper limb motor impairment. AB - Background Intensive motor training with low-frequency repetitive transcranial magnetic stimulation (rTMS) has efficacy as a therapeutic method for motor dysfunction of the affected upper limb in patients with mild to moderate stroke. However, it is not clear whether this combination therapy has the same effect in chronic post-stroke patients with severe upper limb motor impairment. Objectives The aim of this study was to test the treatment effects of intensive motor training with low-frequency rTMS in chronic post-stroke patients with severe upper limb motor impairment. Methods A convenience sample of 26 chronic post stroke patients with severe upper limb motor impairment participated in this study with the non-randomized, non-controlled clinical trial. All subjects were hospitalized to receive intensive motor training with low-frequency rTMS. During 2 weeks in which Sundays were excluded, a total of 24 sessions (2 sessions per day) of the intervention were conducted. The Fugl-Meyer Assessment (FMA) and Wolf Motor Function Test (WMFT) were used to assess motor impairment and function of the affected upper limb, respectively, before and after intervention. Paired t test was used to analyze the effects of the intervention. Results The FMA total score and WMFT log performance time significantly improved from before to after intervention (FMA: 12.6-18.0; WMFT: 3.6-3.3, p < 0.001). Conclusions The present results suggest that intensive motor training with low-frequency rTMS could improve motor impairment in chronic post-stroke patients with severe upper limb motor impairment and contribute to the expansion of the application range of this combination therapy. PMID- 29718777 TI - Effects of a 12-month task-specific balance training on the balance status of stroke survivors with and without cognitive impairments in Selected Hospitals in Nnewi, Anambra State, Nigeria. AB - BACKGROUND: Stroke results in varying levels of physical disabilities that may adversely impact balance with increased tendency to falls. This may intensify with cognitive impairments (CI), and impede functional recovery. Therefore, task specific balance training (TSBT), which presents versatile task-specific training options that matches varied individual needs, was explored as a beneficial rehabilitation regime for stroke survivors with and without CI. It was hypothesized that there will be no significant difference in the balance control measures in stroke survivors with and without CI after a 12-month TSBT. OBJECTIVE: To determine if TSBT will have comparable beneficial effects on the balance control status of sub-acute ischemic stroke survivors with CI and without CI. METHODS: One hundred of 143 available sub-acute first ever ischemic stroke survivors were recruited using convenience sampling technique in a quasi experimental study. They were later assigned into the cognitive impaired group (CIG) and non-cognitive impaired group (NCIG), respectively, based on the baseline presence or absence of CI, after screening with the mini-mental examination (MMSE) tool. With the help of four trained research assistants, TSBT was applied to each group, thrice times a week, 60 mins per session, for 12 months. Their balance was measured as Bergs Balance scores (BBS) at baseline, 4th, 8th, and 12th month intervals. Data were analyzed statistically using Kruskal Wallis test, and repeated measure ANOVA, at p < 0.05. RESULTS: There was significant improvement across time points in the balance control of CIG with large effect size of 0.69 after 12 months of TSBT. There was also significant improvement across time points in the balance control of NCIG with large effect size of 0.544 after 12 months of TSBT. There was no significant difference between the improvement in CIG and NCIG after 8th and 12th months of TSBT. CONCLUSIONS: Within the groups, a 12-month TSBT intervention significantly improved balance control, respectively, but with broader effects in the CIG than NCIG. Importantly, though between-group comparison at baseline revealed significantly impaired balance control in the CIG than NCIG, these differences were not significant at the 8th month and non-existent at the 12th month of TSBT intervention. These results underscore the robustness of TSBT to evenly address specific balance deficits of stroke survivors with and without CI within a long term rehabilitation plan as was hypothesized. PMID- 29718778 TI - Exposure assessment of non-electric ice resurfacer operators in indoor ice rinks: a pilot study. AB - Exposure of ice resurfacer operators to indoor air contaminants was measured in six indoor ice arenas. A standardized questionnaire on technical and operational features was employed and indoor airborne concentrations of carbon monoxide (CO), carbon dioxide (CO2), nitric oxide (NO), nitrogen dioxide (NO2), sulfur dioxide (SO2), and total volatile organic compounds (VOCs) were measured. Air samples were collected using a range of direct reading instruments attached to the driver's seat of the resurfacer. The range of mean exposure concentrations via positional sampling (i.e. as close as able to the operator's breathing zone) were 5.7-7.4 ppm, 694-2171 ppm, <0.5 to 0.5 ppm, and < 0.1 to 0.2 ppm, for CO, CO2, NO, and NO2, respectively. Exposure levels for SO2 and VOC were below detection. Overall, each of the measured indoor air contaminants was found to be below its respective occupational exposure limits (OEL), suggesting that the risk of hazardous exposure is low. The use of natural gas as a fuel source is believed to contribute to low contaminant concentrations. PMID- 29718779 TI - English language YouTube videos as a source of lead poisoning-related information: a cross-sectional study. AB - Exposure to lead is detrimental to children's development. YouTube is a form of social media through which people may learn about lead poisoning. The aim of this cross-sectional study was to analyze the variation in lead poisoning-related YouTube contents between different video sources. The 100 most viewed lead poisoning-related videos were manually coded, among which, 50 were consumer generated, 19 were created by health care professionals, and 31 were news. The 100 videos had a total of more than 8.9 million views, with news videos accounting for 63% of those views. The odds of mentioning what lead poisoning is, how to remove lead, and specifically mentioning the danger in ages 1-5 because of rapid growth among videos created by health care professionals were 7.28 times (Odds ratio, OR = 7.28, 95% CI, 2.09, 25.37, p = 0.002); 6.83 times (OR = 6.83, 95% CI, 2.05, 22.75, p = 0.002) and 9.14 times (OR = 9.14, CI, 2.05, 40.70, p = 0.004) that of consumer-generated videos, respectively. In this study, professional videos had more accurate information regarding lead but their videos were less likely to be viewed compared to consumer-generated videos and news videos. If professional videos about lead poisoning can attract more viewers, more people would be better informed and could possibly influence policy agendas, thereby helping communities being affected by lead exposure. PMID- 29718781 TI - Long-term treatment with atazanavir (ATV) in real life in Belgium: a retrospective observational cohort of 2264 HIV patients. AB - Objectives This 5-year follow-up study aimed to assess clinical outcomes of HIV-1 infected adults treated with atazanavir (ATV) in clinical practice in Belgium, to describe patient profiles and characteristics, as well as treatment safety. Methods A multicenter, non-interventional, non-comparative, retrospective cohort study was performed in HIV-1 positive adult patients treated with ATV between 2006 and 2012. Data were collected from 8 AIDS reference centers' databases. All analyses were on-treatment. Sub-analyses were carried out in unboosted ATV treated patients and in females. The primary endpoint was defined as the time-to treatment-discontinuation. Furthermore, virological suppression, immunological response, time to loss of virological response, reasons for ATV initiation, and discontinuation were also assessed. Results 2264 ARV-naive and ARV-experienced patients (median age: 41 years) were included. Females and non-Caucasians were broadly represented (40 and 45%, respectively). The probability to remain on treatment was 0.78 (CI: 0.76; 0.78) for the first and 0.69 (CI: 0.66; 0.71) for the second year and was similar between males and females. Overall, 771 patients (34.1%) discontinued ATV over time, the median (Q1-Q3) time to discontinuation being 0.8 (0.3-1.5) year. In unboosted ATV-treated patients, results were comparable to the overall ATV population, except for a higher rate of discontinuation-over-time (45.1%). Conclusions Clinical and safety data from this 5 year-cohort study show that the vast majority of patients remained on ATV treatment for the first and second years, overall as well as patients treated with unboosted ATV and females. PMID- 29718782 TI - Protecting workers in the home care industry: workers' experienced job demands, resource gaps, and benefits following a socially supportive intervention. AB - The Community of Practice and Safety Support (COMPASS) program is a peer-led group intervention for home care workers. In a randomized controlled trial, COMPASS significantly improved workers' professional support networks and safety and health behaviors. However, quantitative findings failed to capture workers' complex emotional, physical, and social experiences with job demands, resource limitations, and the intervention itself. Therefore, we conducted qualitative follow-up interviews with a sample of participants (n = 28) in the program. Results provided examples of unique physical and psychological demands, revealed stressful resource limitations (e.g., safety equipment access), and elucidated COMPASS's role as a valuable resource. PMID- 29718783 TI - An update on emerging drugs for the treatment of idiopathic pulmonary fibrosis. AB - INTRODUCTION: Idiopathic pulmonary fibrosis is a chronic, progressive fibrotic lung disease of unknown etiology associated with a high morbidity and mortality. The hallmark of the disease is impaired healing after alveolar epithelial injury in the setting of a genetic predisposition. Development of two new drugs has changed the landscape of the treatment of IPF but more work is needed to improve outcomes and improve survival. Areas covered: The development of two antifibrotic agents, nintedanib and pirfenidone has been an exciting landmark in the treatment of IPF. Current research efforts are focused on developing new drugs, as well as combination of new agents with currently available therapies. New molecules in development target not only the deposition of extracellular matrix, but also upstream pathways including those mediated by immunity. Expert opinion: IPF is a complex and a heterogeneous disease involving several different pathways culminating in fibrosis. Efforts are underway to develop drugs targeting the different pathways. The key to the successful treatment of IPF will require identification of better end-points for research as well as precision medicine involving the use of multidrug therapy personalized to specific patients based on endomolecular genotyping. PMID- 29718784 TI - The self-reported prevalence and disease burden of asthma in Greece. AB - OBJECTIVES: The primary objective was to estimate the self-reported prevalence of asthma in Greece. The secondary one was to assess the impact of asthma control on patients' health related Quality-of-Life (HRQoL), productivity loss, daily activities and psychological distress. METHODS: A population-based, random-digit dialing, telephone nationwide survey was conducted to recruit patients with asthma. Among the responders, 3,946 met the age criterion (>=18 years) and completed the screening questions regarding asthma. Of them, 353 subjects reported that they had been diagnosed with asthma sometime in their life and completed the survey. Data on demographic and lifestyle characteristics, asthma control, comorbidities, limitations in daily activities, psychological distress, productivity loss, as well as HRQoL, were collected through telephone interview. RESULTS: The lifetime self-reported prevalence of asthma was found to be 9.10% (95% CI:8.14%-9.94%). Sixty three percent of patients had well-controlled (WC) asthma. Asthma control was associated with gender, age, and specific comorbidities. Moreover, patients with not well-controlled (NWC) asthma were more likely to have missed work and reduced productivity during the past 12 months due to their asthma (p < 0.01). Patients with NWC asthma were more likely to declare psychological distress and limitations in their daily living activities. Patients' HRQoL with NWC asthma was significantly worse (0.65 +/- 0.24) compared to those with WC asthma (0.86 +/- 0.17, p <= 0.001). CONCLUSIONS: The results of this survey revealed the link between the asthma control and burden of disease demonstrating the need for the implementation of programs aiming at the management of chronic symptoms related to this condition. PMID- 29718785 TI - Finally, after 56 years of type 1 diabetes: a regimen that works. AB - Prior to the availability of degludec and regular human insulin inhalation powder in the type 1 diabetic patient glycemic control with subcutaneous insulin injections was difficult to obtain due to nocturnal, pre-prandial and often severe hypoglycemia as well as post-prandial hyperglycemia and hypoglycemia due to 'stacking' of insulin. A 62-year-old female with type 1 diabetes for 56 years who could not be controlled with continuous subcutaneous insulin aspart infusion obtained glycemic control without significant hypoglycemia or increased post prandial glycemic excursions utilizing degludec insulin for basal needs and technosphere before meals and between meals if needed. The availability of degludec and technosphere insulin improved the management of brittle type 1 diabetes. PMID- 29718787 TI - Application of multiwalled carbon nanotubes and its magnetite derivative for emulsified oil removal from produced water. AB - Multiwalled carbon nanotubes and their magnetite derivatives were employed as adsorbents for emulsified oil removal from produced water. The experimental parameters for maximum emulsified oil removal efficiency and effective regeneration of these adsorbents were determined. The optimum parameters in terms of adsorbent dosage, contact time, salinity, pH and temperature were 3.0 g/L, 20.0 min, 0 ppm, 7.0 and 25 degrees C for both adsorbents. Due to their low density, multiwalledcarbon nanotubes could not be successfully employed in packed bed columns. The magnetite derivative has a larger density and hence, for the removal of emulsified oil from produced water packed bed column studies were performed utilizing multiwalled carbon magnetite nanotubes. The packed bed column efficiency and behaviour were evaluated using Thomas, Clark, Yan et al. and Bohart and Adams models. The Yan model was found to best describe the column experimental data. The adsorbents were regenerated using n-hexane and reused several times for oil removal from produced water without any significant decrease in their initial adsorption capacities. PMID- 29718786 TI - Association between serum CA125 levels in preeclampsia and its severity among women in Lagos, South-West Nigeria. AB - BACKGROUND: Preeclampsia is a syndrome of unknown etiology characterized by hypertension, proteinuria, and/or organ dysfunction. CA125 is an antigenic determinant recognized by the murine monoclonal antibody OC125 quantified by radioimmunoassay. Its role in obstetrics is yet to be fully understood as most clinical trials advocating its uses are widely experimental in nature and unacknowledged. AIM: This study was done to assess the relationship between serum concentration of CA125 in normal pregnancies and those complicated with preeclampsia. METHODS: A case-control study involving 70 women diagnosed with preeclampsia and 70 healthy controls matched for age, parity, and gestational age at enrollment. Venous samples were collected from each participant after informed consent was obtained. The preeclampsia group was further subdivided into mild and severe preeclampsia and all participants were followed up till delivery with records of delivery, maternal, and neonatal outcomes obtained thereafter. Serum CA125 levels were determined by standard enzyme-linked immunosorbent assay (ELISA) method. Hypothesis testing was done using chi-square test for categorical variables, and the independent-samples t-test and ANOVA for numerical variables. All significances were reported at P < 0.05. RESULTS: The mean serum level of CA125 in women with preeclampsia was significantly greater than those with normal pregnancy (54.17 IU/mL vs. 12.49 IU/mL, P < 0.05). CA125 level also correlated positively with systolic blood pressure (r = 0.406, P < 0.05), diastolic blood pressure (r = 0.433, P < 0.05), serum uric acid levels (r = 0.407, P = 0.001), platelet levels (r = 0.341, P = 0.001), and urinary protein levels (r = 0.325, P = 0.002). The CA125 levels between the three categories of participants in the study were: normotensive control (12.49 +/- 6.62 mIU/L), mild preeclampsia (29.43 +/- 3.7 mIU/L), and severe preeclampsia (64.25 +/- 9.21 mIU/L), respectively (P = 0.023). CONCLUSION: We can infer from this study that increased maternal serum CA 125 levels are associated with the preeclampsia and its severity. However, further validation of these findings with more robust multicenter prospective and longitudinal characterization of maternal serum CA125 profiles in pregnancy should be carried out in subsequent investigations to determine its suitability as a predictive biomarker for preeclampsia in women of African descent. PMID- 29718780 TI - Isoprenoids and protein prenylation: implications in the pathogenesis and therapeutic intervention of Alzheimer's disease. AB - The mevalonate-isoprenoid-cholesterol biosynthesis pathway plays a key role in human health and disease. The importance of this pathway is underscored by the discovery that two major isoprenoids, farnesyl and geranylgeranyl pyrophosphate, are required to modify an array of proteins through a process known as protein prenylation, catalyzed by prenyltransferases. The lipophilic prenyl group facilitates the anchoring of proteins in cell membranes, mediating protein protein interactions and signal transduction. Numerous essential intracellular proteins undergo prenylation, including most members of the small GTPase superfamily as well as heterotrimeric G proteins and nuclear lamins, and are involved in regulating a plethora of cellular processes and functions. Dysregulation of isoprenoids and protein prenylation is implicated in various disorders, including cardiovascular and cerebrovascular diseases, cancers, bone diseases, infectious diseases, progeria, and neurodegenerative diseases including Alzheimer's disease (AD). Therefore, isoprenoids and/or prenyltransferases have emerged as attractive targets for developing therapeutic agents. Here, we provide a general overview of isoprenoid synthesis, the process of protein prenylation and the complexity of prenylated proteins, and pharmacological agents that regulate isoprenoids and protein prenylation. Recent findings that connect isoprenoids/protein prenylation with AD are summarized and potential applications of new prenylomic technologies for uncovering the role of prenylated proteins in the pathogenesis of AD are discussed. PMID- 29718788 TI - Vilaprisan for treating uterine fibroids. AB - INTRODUCTION: The medical strategy to antagonize myoma size and related-symptoms is to reduce estrogen and progesterone activity on myomas. This can be obtained with the GnRH agonist (GnRHa) or with compounds that antagonize progesterone stimulatory activity on myomas. Selective progesterone receptor modulators (SPRMs) bind progesterone receptor (PR), leading to both agonist and antagonist effects. The result of SPRMs's action is tissue-specific and it depends on the particular affinity and strength of each SPRM. Area covered: Ulipristal acetate (UPA) is the first SPRM registered for myoma treatment. UPA reduces heavy uterine bleeding within 7 days from the onset of treatment, whereas a longer time is required with GnRHa treatment. Vilaprisan is a novel powerful SPRM. Phase I and II studies give encouraging results on the efficacy of vilaprisan at different doses. Like other SPRMs, vilaprisan induces benign changes of endometrium (PR modulator-associated endometrial changes, PAECs). These disappear as treatment is discontinued. Unlike GnRHa treatment, neither UPA nor vilaprisan induce hypoestrogenism and associated symptoms. Phase III studies are ongoing to confirm efficacy and safety of vilaprisan in long-term treatment of symptomatic fibroids. Expert opinion: It is fundamental to underline the rapidity of action (only 3 days) in the control of myoma-related bleeding. PMID- 29718789 TI - Fertility Preservation by Endocrine Suppression of Ovarian Function Using Gonadotropin-Releasing Hormone Agonists: The End of the Controversy? PMID- 29718791 TI - Radioembolization in Advanced Hepatocellular Carcinoma. AB - The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 68-year-old man with a remote history of alcohol abuse presented with vague abdominal pain. A review of systems suggested the patient had an Eastern Cooperative Oncology Group performance status 1 (restriction of strenuous physical activity). There were no physical examination findings of note. Laboratory studies disclosed Child-Pugh A liver status (no ascites; no encephalopathy; total bilirubin, 1 mg/dL; albumin, 3.5 g/dL; and international normalized rato, 1.2). The alpha-fetoprotein was mildly elevated (19.5 ng/mL). Magnetic resonance imaging with contrast disclosed an infiltrative mass with extensive malignant right and left portal vein thrombosis ( Fig 1A ) with cavernous transformation of the portal vein. The infiltrative mass ( Fig 2A ) was biopsied, revealing hepatocellular carcinoma. No distant metastases were found on a bone scintigraphy or computerized tomography scan. Given these features, this patient was classified as Barcelona Clinic for Liver Cancer stage C. The patient was referred for management of advanced hepatocellular carcinoma. PMID- 29718790 TI - Cumulative Risk Distribution for Interval Invasive Second Breast Cancers After Negative Surveillance Mammography. AB - Purpose The aim of the current study was to characterize the risk of interval invasive second breast cancers within 5 years of primary breast cancer treatment. Methods We examined 65,084 surveillance mammograms from 18,366 women with a primary breast cancer diagnosis of unilateral ductal carcinoma in situ or stage I to III invasive breast carcinoma performed from 1996 to 2012 in the Breast Cancer Surveillance Consortium. Interval invasive breast cancer was defined as ipsilateral or contralateral cancer diagnosed within 1 year after a negative surveillance mammogram. Discrete-time survival models-adjusted for all covariates were used to estimate the probability of interval invasive cancer, given the risk factors for each surveillance round, and aggregated across rounds to estimate the 5-year cumulative probability of interval invasive cancer. Results We observed 474 surveillance-detected cancers-334 invasive and 140 ductal carcinoma in situ and 186 interval invasive cancers which yielded a cancer detection rate of 7.3 per 1,000 examinations (95% CI, 6.6 to 8.0) and an interval invasive cancer rate of 2.9 per 1,000 examinations (95% CI, 2.5 to 3.3). Median cumulative 5-year interval cancer risk was 1.4% (interquartile range, 0.8% to 2.3%; 10th to 90th percentile range, 0.5% to 3.7%), and 15% of women had >= 3% 5-year interval invasive cancer risk. Cumulative 5-year interval cancer risk was highest for women with estrogen receptor- and progesterone receptor-negative primary breast cancer (2.6%; 95% CI, 1.7% to 3.5%), interval cancer presentation at primary diagnosis (2.2%; 95% CI, 1.5% to 2.9%), and breast conservation without radiation (1.8%; 95% CI, 1.1% to 2.4%). Conclusion Risk of interval invasive second breast cancer varies across women and is influenced by characteristics that can be measured at initial diagnosis, treatment, and imaging. Risk prediction models that evaluate the risk of cancers not detected by surveillance mammography should be developed to inform discussions of tailored surveillance. PMID- 29718792 TI - A Younger Man With Localized Prostate Cancer Asks, "Which Type of Radiation Is Right for Me?" AB - The Oncology Grand Rounds series is designed to place original reports published in the Journal into clinical context. A case presentation is followed by a description of diagnostic and management challenges, a review of the relevant literature, and a summary of the authors' suggested management approaches. The goal of this series is to help readers better understand how to apply the results of key studies, including those published in Journal of Clinical Oncology, to patients seen in their own clinical practice. A 61-year-old man presents with stage II prostate cancer after a period of active surveillance. Work-up reveals T1cN0M0 carcinoma, a prostate-specific antigen (PSA) level of 4.8 ng/mL, and Grade Group II (highest Gleason 3+4) in three cores of 12 taken, at the right mid gland and right apex. The patient has been on active surveillance for the past 16 months. He was originally diagnosed after biopsy for an elevated PSA with stage I prostate cancer, T1cN0M0; PSA, 4.5 ng/mL; Grade Group 1 (Gleason 3+3) in one core of 12 taken, also at the right mid-gland. A multiparametric magnetic resonance imaging scan showed a heterogeneous peripheral zone without a dominant lesion and a calculated prostate volume of 28 mL. His medical history includes hypercholesterolemia, for which he takes atorvastatin. He is otherwise healthy and has no other significant medical or surgical history. His father had prostate cancer in his 70s and died of other causes at 89 years of age. The patient reports 2- to 3-hour urinary frequency and 0 to 1 nocturia, and has no difficulty obtaining or maintaining an erection. After meeting with his urologist, he sees a radiation oncologist. PMID- 29718793 TI - Gonadotropin-Releasing Hormone Agonists During Chemotherapy for Preservation of Ovarian Function and Fertility in Premenopausal Patients With Early Breast Cancer: A Systematic Review and Meta-Analysis of Individual Patient-Level Data. AB - Purpose The role of temporary ovarian suppression with gonadotropin-releasing hormone agonists (GnRHa) during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal women remains controversial. This systematic review and meta-analysis using individual patient-level data was conducted to better assess the efficacy and safety of this strategy in patients with early breast cancer. Methods The trials in which premenopausal women with early breast cancer were randomly assigned to receive (neo)adjuvant chemotherapy alone or with concurrent GnRHa were eligible for inclusion. Primary end points were premature ovarian insufficiency (POI) rate and post-treatment pregnancy rate. Disease-free survival and overall survival were secondary end points. Because each study represents a cluster, statistical analyses were performed using a random effects model. Results A total of 873 patients from five trials were included. POI rate was 14.1% in the GnRHa group and 30.9% in the control group (adjusted odds ratio, 0.38; 95% CI, 0.26 to 0.57; P < .001). A total of 37 (10.3%) patients had at least one post-treatment pregnancy in the GnRHa group and 20 (5.5%) in the control group (incidence rate ratio, 1.83; 95% CI, 1.06 to 3.15; P = .030). No significant differences in disease-free survival (adjusted hazard ratio, 1.01; 95% CI, 0.72 to 1.42; P = .999) and overall survival (adjusted hazard ratio, 0.67; 95% CI, 0.42 to 1.06; P = .083) were observed between groups. Conclusion Our findings provide evidence for the efficacy and safety of temporary ovarian suppression with GnRHa during chemotherapy as an available option to reduce the likelihood of chemotherapy-induced POI and potentially improve future fertility in premenopausal patients with early breast cancer. PMID- 29718795 TI - Dietary Flavanols: A Review of Select Effects on Vascular Function, Blood Pressure, and Exercise Performance. AB - An individual's diet affects numerous physiological functions and can play an important role in reducing the risk of cardiovascular disease. Epidemiological and clinical studies suggest that dietary flavanols can be an important modulator of vascular risk. Diets and plant extracts rich in flavanols have been reported to lower blood pressure, especially in prehypertensive and hypertensive individuals. Flavanols may act in part through signaling pathways that affect vascular function, nitric oxide availability, and the release of endothelial derived relaxing and constricting factors. During exercise, flavanols have been reported to modulate metabolism and respiration (e.g., maximal oxygen uptake, O2 cost of exercise, and energy expenditure), and reduce oxidative stress and inflammation, resulting in increased skeletal muscle efficiency and endurance capacity. Flavanol-induced reductions in blood pressure during exercise may decrease the work of the heart. Collectively, these effects suggest that flavanols can act as an ergogenic aid to help delay the onset of fatigue. More research is needed to better clarify the effects of flavanols on vascular function, blood pressure regulation, and exercise performance and establish safe and effective levels of intake. Flavanol-rich foods and food products can be useful components of a healthy diet and lifestyle program for those seeking to better control their blood pressure or to enhance their physical activity. Key teaching points * Epidemiological and clinical studies indicate that dietary flavanols can reduce the risk of vascular disease. * Diets and plant extracts rich in flavanols have been reported to lower blood pressure and improve exercise performance in humans. * Mechanisms by which flavanols may reduce blood pressure function include alterations in signaling pathways that affect vascular function, nitric oxide availability, and the release of endothelial-derived relaxation and constriction factors. * Mechanisms by which flavanols may enhance exercise performance include modulation of metabolism and respiration (e.g., maximal oxygen uptake, O2 cost of exercise, and energy expenditure) and reduction of oxidative stress and inflammation. These effects can result in increased skeletal muscle efficiency and endurance capacity. * Further research is needed to clarify the amount, timing, and frequency of flavanol intake for blood pressure regulation and exercise performance. PMID- 29718794 TI - Rare variants in RNF213, a susceptibility gene for moyamoya disease, are found in patients with pulmonary hypertension and aggravate hypoxia-induced pulmonary hypertension in mice. AB - Ring finger 213 ( RNF213) is a susceptibility gene for moyamoya disease (MMD), a progressive cerebrovascular disease. Recent studies suggest that RNF213 plays an important role not only in MMD, but also in extracranial vascular diseases, such as pulmonary hypertension (PH). In this study, we undertook genetic screening of RNF213 in patients with PH and performed functional analysis of an RNF213 variant using mouse models. Direct sequencing of the exons in the C-terminal region of RNF213, where MMD-associated mutations are highly clustered, and of the entire coding exons of BMPR2 and CAV1, the causative genes for PH, was performed in 27 Japanese patients with PH. Two MMD-associated rare variants (p.R4810K and p.A4399T) in RNF213 were identified in two patients, three BMPR2 mutations (p.Q92H, p.L198Rfs*4, and p.S930X) were found in three patients, whereas no CAV1 mutations were identified. To test the effect of the RNF213 variants on PH, vascular endothelial cell (EC)-specific Rnf213 mutant transgenic mice were exposed to hypoxia. Overexpression of the EC-specific Rnf213 mutant, but neither Rnf213 ablation nor EC-specific wild-type Rnf213 overexpression, aggravated the hypoxia-induced PH phenotype (high right ventricular pressure, right ventricular hypertrophy, and muscularization of pulmonary vessels). Under hypoxia, electron microscopy showed unique EC detachment in pulmonary vessels, and western blots demonstrated a significant reduction in caveolin-1 (encoded by CAV1), a key molecule involved in EC functions, in lungs of EC-specific Rnf213 mutant transgenic mice, suggestive of EC dysfunction. RNF213 appears to be a genetic risk factor for PH and could play a role in systemic vasculopathy. PMID- 29718796 TI - A narrative review of gait training after stroke and a proposal for developing a novel gait training device that provides minimal assistance. AB - BACKGROUND: Gait impairment is common in stroke survivors. Recovery of walking ability is one of the most pressing objectives in stroke rehabilitation. OBJECTIVES: Of this report are to briefly review recent progress in gait training after stroke including the use of partial body weight-supported treadmill training (PBWSTT) and robot-assisted step training (RAST), and propose a minimal assistance strategy that may overcome some of limitations of current RAST. METHODS: The literature review emphasizes a dilemma that recent randomized clinical trials did not support the use of RAST. The unsatisfactory results of current RAST clinical trials may be partially due to a lack of careful analysis of movement deficiencies and their relevance to gait training task specificity after stroke. Normal movement pattern is implied to be part of task specificity in the current RAST. Limitations of such task specificity are analyzed. RESULTS: Based on the review, we redefine an alternative set of gait training task specificity that represents a minimal assistance strategy in terms of assisted body movements and amount of assistance. Specifically, assistances are applied only to hip flexion and ankle dorsiflexion of the affected lower limb during swing phase. Furthermore, we propose a conceptual design of a novel device that may overcome limitations of current RAST in gait training after stroke. The novel device uses a pulling cable, either manually operated by a therapist or automated by a servomotor, to provide assistive forces to help hip flexion and ankle dorsiflexion of the affected lower limb during gait training. CONCLUSION: The proposed minimal assistance strategy may help to design better devices for gait or other motor training. PMID- 29718797 TI - CEP250 mutations associated with mild cone-rod dystrophy and sensorineural hearing loss in a Japanese family. AB - BACKGROUND: CEP250 encodes the C-Nap1 protein which belongs to the CEP family of proteins. C-Nap1 has been reported to be expressed in the photoreceptor cilia and is known to interact with other ciliary proteins. Mutations of CEP250 cause atypical Usher syndrome which is characterized by early-onset sensorineural hearing loss (SNHL) and a relatively mild retinitis pigmentosa. This study tested the hypothesis that the mild cone-rod dystrophy (CRD) and SNHL in a non consanguineous Japanese family was caused by CEP250 mutations. METHODS: Detailed ophthalmic and auditory examinations were performed on the proband and her family members. Whole exome sequencing (WES) was used on the DNA obtained from the proband. RESULTS: Electrophysiological analysis revealed a mild CRD in two family members. Adaptive optics (AO) imaging showed reduced cone density around the fovea. Auditory examinations showed a slight SNHL in both patients. WES of the proband identified compound heterozygous variants c.361C>T, p.R121*, and c.562C>T, p.R188* in CEP250. The variants were found to co-segregate with the disease in five members of the family. CONCLUSIONS: The variants of CEP250 are both null variants and according to American College of Medical Genetics and Genomics (ACMG) standards and guideline, these variants are classified into the very strong category (PVS1). The criteria for both alleles will be pathogenic. Our data indicate that mutations of CEP250 can cause mild CRD and SNHL in Japanese patients. Because the ophthalmological phenotypes were very mild, high resolution retinal imaging analysis, such as AO, will be helpful in diagnosing CEP250-associated disease. PMID- 29718798 TI - Cancer. PMID- 29718799 TI - I Sought It, I Reddit: Examining Health Information Engagement Behaviors among Reddit Users. AB - Given the wide use of social media, these platforms have become important channels for understanding health-related information engagement processes. Reddit is a social media platform dedicated to user-generated content and discourse around the world. However, little research exists regarding use of the platform. Guided by the diffusion of innovation theory, the purpose of this study was to analyze Reddit users' behaviors on the platform related to perceptions of information credibility, health information seeking, and behavioral enactment of information found. Data were collected via survey from Reddit users around the world (n = 389). Data suggest that although Reddit use and perceived information credibility are unrelated to acting on the information found on Reddit, users who are specifically seeking health-related information are more likely to enact the information in their lives. Implications from the findings suggest important considerations for communication scholars, media advocates, and health promotion practitioners. PMID- 29718800 TI - Corrigendum. PMID- 29718801 TI - Simultaneous analysis of coccidiostats and sulphonamides in non-target feed by HPLC-MS/MS and validation following the Commission Decision 2002/657/EC. AB - Taking into consideration the maximum level (ML) for coccidiostats included in the European Regulation 574/2011 and the fact that the presence of residues of sulphonamides in non-target feed is forbidden, the aim of this article is to present an analytical method based on HPLC-MS/MS for the identification and quantification of sulphonamides and coccidiostats in non-target feeds. The method was validated following Commission Decision 2002/657/EC, and recovery, repeatability and reproducibility were within the limits established in the Decision. For coccidiostats, the decision limit and detection capability were calculated for the different species taking into account the ML allowed in Regulation 574/2011. The applicability of the method was investigated in 50 feed samples collected from dairy farms, 50 obtained from feed mills and 10 interlaboratory feed samples. PMID- 29718803 TI - Dependence of behavioral performance on material category in an object-grasping task with monkeys. AB - Material perception is an essential part of our cognitive function that enables us to properly interact with our complex daily environment. One important aspect of material perception is its multimodal nature. When we see an object, we generally recognize its haptic properties as well as its visual properties. Consequently, one must examine behavior using real objects that are perceived both visually and haptically to fully understand the characteristics of material perception. As a first step, we examined whether there is any difference in the behavioral responses to different materials in monkeys trained to perform an object grasping task in which they saw and grasped rod-shaped real objects made of various materials. We found that the monkeys' behavior in the grasping task, which was measured based on the success rate and the pulling force, differed depending on the material category. Monkeys easily and correctly grasped objects of some materials, such as metal and glass, but failed to grasp objects of other materials. In particular, monkeys avoided grasping fur-covered objects. The differences in the behavioral responses to the material categories cannot be explained solely based on the degree of familiarity with the different materials. These results shed light on the organization of multimodal representation of materials, where their biological significance is an important factor. In addition, a monkey that avoided touching real fur-covered objects readily touched images of the same objects presented on a CRT display. This suggests that employing real objects is important when studying behaviors related to material perception. NEW & NOTEWORTHY We tested monkeys using an object-grasping task in which monkeys saw and grasped rod-shaped real objects made of various materials. We found that the monkeys' behavior differed dramatically across the material categories and that the behavioral differences could not be explained solely based on the degree of familiarity with the different materials. These results shed light on the organization of multimodal representation of materials, where the biological significance of materials is an important factor. PMID- 29718804 TI - Interspike interval analysis and spikelets in presubicular head-direction cells. AB - Head-direction (HD) neurons are thought to provide the mammalian brain with an internal sense of direction. These cells, which selectively increase their firing when the animal's head points in a specific direction, use the spike rate to encode HD with a high signal-to-noise ratio. In the present work, we analyzed spike train features of presubicular HD cells recorded juxtacellularly in passively rotated rats. We found that HD neurons could be classified into two groups on the basis of their propensity to fire spikes at short interspike intervals. "Bursty" neurons displayed distinct spike waveforms and were weakly but significantly more modulated by HD compared with "nonbursty" cells. In a subset of HD neurons, we observed the occurrence of spikelets, small-amplitude "spike-like" events, whose HD tuning was highly correlated to that of the co recorded juxtacellular spikes. Bursty and nonbursty HD cells, as well as spikelets, were also observed in freely moving animals during natural behavior. We speculate that spike bursts and spikelets might contribute to presubicular HD coding by enhancing its accuracy and transmission reliability to downstream targets. NEW & NOTEWORTHY We provide evidence that presubicular head-direction (HD) cells can be classified into two classes (bursty and nonbursty) on the basis of their propensity to fire spikes at short interspike intervals. Bursty cells displayed distinct electrophysiological properties and stronger directional tuning compared with nonbursty neurons. We also provide evidence for the occurrence of spikelets in a subset of HD cells. These electrophysiological features (spike bursts and spikelets) might contribute to the precision and robustness of the presubicular HD code. PMID- 29718802 TI - Degeneracy in the robust expression of spectral selectivity, subthreshold oscillations, and intrinsic excitability of entorhinal stellate cells. AB - Biological heterogeneities are ubiquitous and play critical roles in the emergence of physiology at multiple scales. Although neurons in layer II (LII) of the medial entorhinal cortex (MEC) express heterogeneities in channel properties, the impact of such heterogeneities on the robustness of their cellular-scale physiology has not been assessed. Here, we performed a 55-parameter stochastic search spanning nine voltage- or calcium-activated channels to assess the impact of channel heterogeneities on the concomitant emergence of 10 in vitro electrophysiological characteristics of LII stellate cells (SCs). We generated 150,000 models and found a heterogeneous subpopulation of 449 valid models to robustly match all electrophysiological signatures. We employed this heterogeneous population to demonstrate the emergence of cellular-scale degeneracy in SCs, whereby disparate parametric combinations expressing weak pairwise correlations resulted in similar models. We then assessed the impact of virtually knocking out each channel from all valid models and demonstrate that the mapping between channels and measurements was many-to-many, a critical requirement for the expression of degeneracy. Finally, we quantitatively predict that the spike-triggered average of SCs should be endowed with theta-frequency spectral selectivity and coincidence detection capabilities in the fast gamma band. We postulate this fast gamma-band coincidence detection as an instance of cellular-scale-efficient coding, whereby SC response characteristics match the dominant oscillatory signals in LII MEC. The heterogeneous population of valid SC models built here unveils the robust emergence of cellular-scale physiology despite significant channel heterogeneities, and forms an efficacious substrate for evaluating the impact of biological heterogeneities on entorhinal network function. NEW & NOTEWORTHY We assessed the impact of heterogeneities in channel properties on the robustness of cellular-scale physiology of medial entorhinal cortical stellate neurons. We demonstrate that neuronal models with disparate channel combinations were endowed with similar physiological characteristics, as a consequence of the many-to-many mapping between channel properties and the physiological characteristics that they modulate. We predict that the spike triggered average of stellate cells should be endowed with theta-frequency spectral selectivity and fast gamma-band coincidence detection capabilities. PMID- 29718806 TI - Real-time visuomotor behavior and electrophysiology recording setup for use with humans and monkeys. AB - Large-scale network dynamics in multiple visuomotor areas is of great interest in the study of eye-hand coordination in both human and monkey. To explore this, it is essential to develop a setup that allows for precise tracking of eye and hand movements. It is desirable that it is able to generate mechanical or visual perturbations of hand trajectories so that eye-hand coordination can be studied in a variety of conditions. There are simple solutions that satisfy these requirements for hand movements performed in the horizontal plane while visual stimuli and hand feedback are presented in the vertical plane. However, this spatial dissociation requires cognitive rules for eye-hand coordination different from eye-hand movements performed in the same space, as is the case in most natural conditions. Here we present an innovative solution for the precise tracking of eye and hand movements in a single reference frame. Importantly, our solution allows behavioral explorations under normal and perturbed conditions in both humans and monkeys. It is based on the integration of two noninvasive commercially available systems to achieve online control and synchronous recording of eye (EyeLink) and hand (KINARM) positions during interactive visuomotor tasks. We also present an eye calibration method compatible with different eye trackers that compensates for nonlinearities caused by the system's geometry. Our setup monitors the two effectors in real time with high spatial and temporal resolution and simultaneously outputs behavioral and neuronal data to an external data acquisition system using a common data format. NEW & NOTEWORTHY We developed a new setup for studying eye-hand coordination in humans and monkeys that monitors the two effectors in real time in a common reference frame. Our eye calibration method allows us to track gaze positions relative to visual stimuli presented in the horizontal workspace of the hand movements. This method compensates for nonlinearities caused by the system's geometry and transforms kinematics signals from the eye tracker into the same coordinate system as hand and targets. PMID- 29718805 TI - Describing complex cells in primary visual cortex: a comparison of context and multifilter LN models. AB - Receptive field (RF) models are an important tool for deciphering neural responses to sensory stimuli. The two currently popular RF models are multifilter linear-nonlinear (LN) models and context models. Models are, however, never correct, and they rely on assumptions to keep them simple enough to be interpretable. As a consequence, different models describe different stimulus response mappings, which may or may not be good approximations of real neural behavior. In the current study, we take up two tasks: 1) we introduce new ways to estimate context models with realistic nonlinearities, that is, with logistic and exponential functions, and 2) we evaluate context models and multifilter LN models in terms of how well they describe recorded data from complex cells in cat primary visual cortex. Our results, based on single-spike information and correlation coefficients, indicate that context models outperform corresponding multifilter LN models of equal complexity (measured in terms of number of parameters), with the best increase in performance being achieved by the novel context models. Consequently, our results suggest that the multifilter LN-model framework is suboptimal for describing the behavior of complex cells: the context model framework is clearly superior while still providing interpretable quantizations of neural behavior. NEW & NOTEWORTHY We used data from complex cells in primary visual cortex to estimate a wide variety of receptive field models from two frameworks that have previously not been compared with each other. The models included traditionally used multifilter linear-nonlinear models and novel variants of context models. Using mutual information and correlation coefficients as performance measures, we showed that context models are superior for describing complex cells and that the novel context models performed the best. PMID- 29718807 TI - Regulation of dynamic postural control to attend manual steadiness constraints. AB - In daily living activities, performance of spatially accurate manual movements in upright stance depends on postural stability. In the present investigation, we aimed to evaluate the effect of the required manual steadiness (task constraint) on the regulation of dynamic postural control. A single group of young participants ( n = 20) were evaluated in the performance of a dual posturo-manual task of balancing on a platform oscillating in sinusoidal translations at 0.4-Hz (low) or 1-Hz (high) frequencies while stabilizing a cylinder on a handheld tray. Manual task constraint was manipulated by comparing the conditions of keeping the cylinder stationary on its flat or round side, corresponding to low and high manual task constraints, respectively. Results showed that in the low oscillation frequency the high manual task constraint led to lower oscillation amplitudes of the head, center of mass, and tray, in addition to higher relative phase values between ankle/hip-shoulder oscillatory rotations and between center of mass/center of pressure-feet oscillations as compared with values observed in the low manual task constraint. Further analyses showed that the high manual task constraint also affected variables related to both postural (increased amplitudes of center of pressure oscillation) and manual (increased amplitude of shoulder rotations) task components in the high oscillation frequency. These results suggest that control of a dynamic posturo-manual task is modulated in distinct parameters to attend the required manual steadiness in a complex and flexible way. NEW & NOTEWORTHY We evaluated dynamic postural control on a platform oscillating in sinusoidal translations at different frequencies while performing a manual task with low or high steadiness constraints. Results showed that high manual task constraint led to modulation of metric and coordination variables associated with greater postural stability. Our findings suggest that motor control is regulated in an integrative mode at the posturo-manual task level, with reciprocal interplay between the postural and manual components. PMID- 29718809 TI - Optogenetic surface stimulation of the rat cervical spinal cord. AB - Electrical intraspinal microstimulation (ISMS) at various sites along the cervical spinal cord permits forelimb muscle activation, elicits complex limb movements and may enhance functional recovery after spinal cord injury. Here, we explore optogenetic spinal stimulation (OSS) as a less invasive and cell type specific alternative to ISMS. To map forelimb muscle activation by OSS in rats, adeno-associated viruses (AAV) carrying the blue-light sensitive ion channels channelrhodopsin-2 (ChR2) and Chronos were injected into the cervical spinal cord at different depths and volumes. Following an AAV incubation period of several weeks, OSS-induced forelimb muscle activation and movements were assessed at 16 sites along the dorsal surface of the cervical spinal cord. Three distinct movement types were observed. We find that AAV injection volume and depth can be titrated to achieve OSS-based activation of several movements. Optical stimulation of the spinal cord is thus a promising method for dissecting the function of spinal circuitry and targeting therapies following injury. NEW & NOTEWORTHY Optogenetics in the spinal cord can be used both for therapeutic treatments and to uncover basic mechanisms of spinal cord physiology. For the first time, we describe the methodology and outcomes of optogenetic surface stimulation of the rat spinal cord. Specifically, we describe the evoked responses of forelimbs and address the effects of different adeno-associated virus injection paradigms. Additionally, we are the first to report on the limitations of light penetration through the rat spinal cord. PMID- 29718808 TI - Differences in lumbar motor neuron pruning in an animal model of early onset spasticity. AB - Motor neuron (MN) development in early onset spasticity is poorly understood. For example, spastic cerebral palsy (sCP), the most common motor disability of childhood, is poorly predicted by brain imaging, yet research remains focused on the brain. By contrast, MNs, via the motor unit and neurotransmitter signaling, are the target of most therapeutic spasticity treatments and are the final common output of motor control. MN development in sCP is a critical knowledge gap, because the late embryonic and postnatal periods are not only when the supposed brain injury occurs but also are critical times for spinal cord neuromotor development. Using an animal model of early onset spasticity [ spa mouse (B6.Cg- Glrbspa/J) with a glycine (Gly) receptor mutation], we hypothesized that removal of effective glycinergic neurotransmitter inputs to MNs during development will influence MN pruning (including primary dendrites) and MN size. Spa (Glrb-/-) and wild-type (Glrb+/+) mice, ages 4-9 wk, underwent unilateral retrograde labeling of the tibialis anterior muscle MNs via peroneal nerve dip in tetramethylrhodamine. After 3 days, mice were euthanized and perfused with 4% paraformaldehyde, and the spinal cord was excised and processed for confocal imaging. Spa mice had ~61% fewer lumbar tibialis anterior MNs ( P < 0.01), disproportionately affecting larger MNs. Additionally, a ~23% reduction in tibialis anterior MN somal surface area ( P < 0.01) and a 12% increase in primary dendrites ( P = 0.046) were observed. Thus MN pruning and MN somal surface area are abnormal in early onset spasticity. Fewer and smaller MNs may contribute to the spastic phenotype. NEW & NOTEWORTHY Motor neuron (MN) development in early onset spasticity is poorly understood. In an animal model of early onset spasticity, spa mice, we found ~61% fewer lumbar tibialis anterior MNs compared with controls. This MN loss disproportionately affected larger MNs. Thus number and heterogeneity of the MN pool are decreased in spa mice, likely contributing to the spastic phenotype. PMID- 29718810 TI - Comparison of DNA Damage and Apoptosis Induced By Silver Nanoparticle-containing Dressing Materials During Wound Healing. AB - INTRODUCTION: Silver nanoparticle (AgNP)-containing dressings are used worldwide for the treatment of wounds; however, many studies have indicated that AgNPs are toxic to humans and cause cell death, primarily via apoptosis. OBJECTIVE: In this study, the investigators compare the apoptotic effects of various AgNP dressing materials, with the hypothesis that nanosilver would be less toxic than ionic silver. MATERIALS AND METHODS: For the in vivo experiments, Sprague-Dawley (SD) and streptozotocin (STZ)-induced diabetic rats were treated with 5 dressing materials: Aquacel Ag (product A, silver ion; ConvaTec, Berkshire, UK), Acticoat (product B, AgNP; Smith & Nephew, Fort Worth, TX), Medifoam Silver (product C, silver ion; Genewel Science Co Ltd, Seongnam, South Korea), PolyMem Silver (product D, AgNP; Ferris Mfg Corp, Fort Worth, TX), and Vaseline-impregnated dressing gauze (control; Unilever, London, UK). All treatments were applied 3 times per week. After 14 days of treatment, the SD and STZ rats were euthanized, and wound samples were examined for apoptosis. The analysis included immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, Western blotting, and reverse transcription polymerase chain reaction for a semiquantitative evaluation of apoptosis. RESULTS: The AgNP containing dressing materials were more cytotoxic than the silver dressings. Compared with the AgNP dressing materials, no significant levels of apoptotic factors were observed in the silver dressing-treated wounds. The TUNEL staining showed that product C-dressed wounds contained the most apoptotic cells, while some apoptotic cells were observed in product B-dressed wounds. Moreover, apoptotic gene expression was altered, including a decline in B-cell lymphoma-2 and activation of caspase-3. This was most evident in wounds treated with product C. Interestingly, apoptotic gene expression was not induced in product A-treated wounds. Finally, product D had a relatively lower silver concentration and was less toxic than products A-C. CONCLUSIONS: Dressing materials containing AgNP have an antimicrobial effect. However, the authors observed that some AgNP dressings induced DNA damage and apoptosis. Although AgNP dressings did not cause significant acute apoptotic effects, they should be examined for cytotoxic effects in chronic wounds and should be used with caution when treating chronic wounds and those with low bacteria counts. PMID- 29718811 TI - A Total Offloading Foot Brace for Treatment of Diabetic Foot Ulcers: Results From a Halted Randomized Controlled Trial. AB - INTRODUCTION: Foot offloading is the mainstay treatment for plantar diabetic foot ulcers (DFUs). OBJECTIVE: This multicenter, single-blinded, randomized controlled trial evaluates the efficacy of a total offloading foot brace for healing plantar DFUs. MATERIALS AND METHODS: Seventeen patients were randomized to standard therapy (ie, reducing stress and pressure via mechanical offloading) or offloading foot brace. Comparison of plantar pressures was performed using digital pressure sensing films. The ulcers were assessed by physical inspection and digital planimetry of photographs. RESULTS: Reductions in peak plantar pressures ranged from 67.3% to 89.4% (P = .09). Healing at weeks 12 to 15 had minimal differences (brace vs. control: 71.7% vs. 80.3%, respectively). Although not significant, earlier periods of the brace versus the control demonstrated faster wound healing in weeks 2 to 5 (36.0% vs. 6.8%, respectively) and weeks 6 to 9 (50.7% vs. 17.0%, respectively). CONCLUSIONS: The total offloading foot brace minimizes plantar pressure, allowing for early healing of DFUs, and optimizations in brace design may enhance healing of plantar DFUs. PMID- 29718812 TI - Safety and Efficacy of an Autologous Blood Clot Product in the Management of Texas 1A or 2A Neuropathic Diabetic Foot Ulcers: A Prospective, Multicenter, Open Label Pilot Study. AB - OBJECTIVE: This pilot study evaluates safety in terms of the occurrence of adverse events (AEs) as well as the efficacy in terms of complete wound healing rates of a blood clot product when applied to chronic neuropathic diabetic foot ulcers (DFUs). MATERIALS AND METHODS: Participants were chosen from patients with DFUs visiting the wound care clinic. Up to 10 mL of blood drawn from each participant was injected into the product's clotting tray. Within 12 minutes, the blood clot product was formed, applied to the single DFU of each participant, and covered with primary and secondary dressings. Patients received up to 12 blood clot product applications every 5 to 9 days for up to 12 weeks. RESULTS: Twenty patients were enrolled; 20 were analyzed in the intent-to-treat (ITT) population and 18 were in the per-protocol (PP) population. Thirty-two AEs occurred (only 2 were possibly device related). The mean AE rate for both the ITT and PP populations was 1.6. The proportion of wounds healed in the ITT and PP populations was 13 out of 20 (65%) and 13 out of 18 (72.2%), respectively. Percentage area reduction (PAR) for the ITT population at 4 and 12 weeks was 61.6% and 67.1%, respectively; the PARs for the PP population were 60.3% and 76.2% at 4 and 12 weeks, respectively. Mean times to wound healing were 59 days and 56 days in the ITT and PP populations, respectively. CONCLUSIONS: This study demonstrates that the blood clot product is safe and efficacious for treating DFUs. PMID- 29718813 TI - Efficacy of Honeydew Honey and Blossom Honey on Full-thickness Wound Healing in Mice. AB - INTRODUCTION: The wound healing properties of honey, including blossom honey, are well known; however, the effects of honeydew honey during the wound healing process have not yet been investigated and thus remain unclear. OBJECTIVE: This study compares the effects of honeydew honey with those of blossom honey. MATERIALS AND METHODS: A total of 140 mice were divided into 2 control groups, which received either a hydrocolloid dressing (HCD; n = 22) or gauze (n = 22), and 4 experimental groups: honeydew honey (n = 23), Acacia honey (n = 23), Manuka honey (n = 22), and Japanese Pharmacopoeia honey (n = 28). Two circular full thickness wounds were made and measured for 14 days. Each wound in the experimental groups was treated with 0.1 mL of honey and covered with gauze. Dressings in the control and experimental groups were changed daily. RESULTS: The wounds in all of the honey groups and the HCD group were moist by day 14, while those in the gauze group were dry. The ratio of wound area to initial wound area and the number of inflammatory cells decreased during the inflammatory phase in all honey groups. However, the honey groups exhibited reepithelialization rates of < 40%, numerous neutrophils, weak wound contraction, and impaired collagen deposition in wounds after day 11. CONCLUSIONS: These results suggest honeydew honey and blossom honey both exert anti-inflammatory effects during the inflammatory phase. However, all of the honeys examined were less effective at promoting full-thickness wound healing than the controls. Further studies are warranted. PMID- 29718814 TI - A Retrospective Cohort Study to Determine Predictive Factors for Abdominal Wound Disruption Following Colorectal Surgery. AB - Abdominal wound disruption (AWD) is a postoperative complication that increases length of hospital stay, mortality, and cost. A retrospective cohort study was conducted to identify predictors of AWD, defined in the National Surgical Quality Improvement Program User Guide as a spontaneous reopening of a previously surgically closed (midline) wound that occurs within 30 days after index elective surgery in patients undergoing colorectal surgery. Data from the American College of Surgeons National Surgical Quality Improvement Program (2006-2012) were searched, supplemented by institutional review board-approved chart review. Patients were identified using Current Procedural Terminology codes for open and laparoscopic abdominal colorectal procedures. Data were collected to predefined worksheets and entered into a statistical analysis program and included demographics; comorbidities; pre- and postoperative laboratory tests including white blood count, blood glucose, and albumin levels; date and type of procedure; wound classification; postoperative complication rate; type of access; time to disruption; surgical site infection (SSI); and use of the SSI intervention/prevention bundle. The Wilcoxon rank sum test was utilized to compare independent continuous variables between the groups, and Fisher's exact test was utilized to compare categorical variables. Variables with a P value <.2 at univariate logistic regression were included in multivariate logistic regression analysis. Time-to-event variables were compared using Cox regression analysis. Of the 690 patients included in the study, 16 (2.3%) developed an AWD. Mean age was 61.9 +/- 15.3 years and 61.3 +/- 15.0 years in AWD and non-AWD groups, respectively (P = .704). AWD occurred more frequently in men than women (75% vs. 50%; P = .040) and in patients who did compared to those who did not develop a deep incisional SSI (12.5% vs. 2%; P = .044). Preoperative albumin level was significantly lower in AWD (3.2 +/- 0.8 vs. 3.8 +/- 0.7; P = .006), as well as the proportion of post-bundle implementation (18.75% vs. 65.7%; P = .041). No significant differences were observed for any of the other variables examined. Per multivariate analysis, male gender (P = .05), absence of SSI bundle (P = .026), and hypoalbuminemia (P = .01) were independent predictors of AWD after elective colorectal resections. Time to AWD was significantly shorter in patients without SSI (P <.001). Results indicate implementation of the SSI bundle decreased AWD rates. Further prospective studies are needed to confirm these findings. PMID- 29718815 TI - Prevalence of Skin Tears in Elderly Patients: A Retrospective Chart Review of Incidence Reports in 6 Long-term Care Facilities. AB - The incidence and prevalence of skin tears in long-term care (LTC) facilities has not been well established. To ascertain the point prevalence of reported skin tears, a retrospective review of incident reports was performed in 6 LTC facilities in western Pennsylvania from November 1, 2016 through December 31, 2016. Report data, including resident age; gender; mobility limitations; skin tear location, number, and cause (if known); occurrence time (7 am to 3 pm, 3 pm to 11 pm, or 11 pm to 7 am nursing shift); and history of previous skin tears, were abstracted. All data were entered into a statistical analysis program and analyzed using descriptive statistics. Period prevalence was used to determine prevalence rate; an independent t test was used to compare the presence of skin tears between genders. Differences between location and cause of skin tears were evaluated using a multinomial test of related proportions. A test of proportions was used to evaluate skin tear occurrence time (nursing shift) differences. The overall point prevalence rate was 9% (N = 1253 residents) ranging from 6 to 28 skin tears per facility. The average age of residents with a skin tear (n = 119) was 83.5 years. The majority (111, 93%) had mobility limitations. Falls accounted for 38 skin tears (31.9%), followed by propelling in a wheelchair (18, 15.1%; X2 =7.14; P = .008). Forearm skin tears (37, 31.1%) occurred significantly more frequently than lower leg skin tears (19, 16%; P = .016). Significantly more skin tears occurred during the 7 am to 3 pm shift (47, 39.5%) and 3 pm to 11 pm shift (49, 41.2%) than during the 11 pm to 7 am shift (23, 19.3%; X2 = 5.78; P <.01). The results of this study confirm skin tears are a significant problem among elderly residents in LTC, especially because the reported rate is likely lower than the actual rate. Research to further elucidate the incidence and prevalence of skin tears and associated risk factors is needed to help develop evidence based risk assessment, classification systems, treatment guidelines, and preventive measures. PMID- 29718816 TI - A Post-marketing Surveillance Study of Chronic Wounds Treated With a Native Collagen Calcium Alginate Dressing. AB - Chronic wounds (ie, wounds that fail to progress through a normal, orderly, timely sequence of repair) continue to pose significant clinical and economic burdens. A prospective, descriptive, 3-week post-marketing surveillance study was conducted across 3 wound care centers in the United States to evaluate the effectiveness of a collagen calcium alginate dressing on chronic wounds in conjunction with standard care (SC) practices (eg, offloading, debridement, compression) to support healing. Eligible participants had to be >18 years of age, have at least 1 chronic wound, and no known sensitivity to collagen. Demographic characteristics were recorded at the screening visit on case report forms. At each visit, wound-related pain was assessed using the Visual Analog Scale along with wound characteristics including size (using digital planimetry), wound exudate (minimal, moderate, heavy), and odor (none, mild). Participants were monitored for adverse events as well as infection based on signs and symptoms in and around the local wound bed, the deeper structures, and the surrounding skin. An intention-to-treat approach was used for all analyses. If an observation was missing, the last observation carried forward principle was used. For wounds that healed, pain and exudate were set to 0 (no pain/exudate) at visit 4. Descriptive, paired t tests and the Wilcoxon signed rank test were used to analyze the data. Of the 31 participants (15 men, 16 women, mean age 66.6 years), most (13, 42%) had a diabetic foot ulcer or venous leg ulcer (10, 32%); median duration of all wounds was 148 days. Thirty (30) patients completed the study. The mean number of comorbidities was 10.6 +/- 6.3, and patients used a mean of 9.3 +/- 5.64 prescription or over-the-counter medications. For all wounds combined, mean wound area was 4.8 +/- 8.38 cm2 at baseline. At week 3, a decrease in wound area of 38.1% was noted (median: 45% +/- 42.54; P = .006); 3 wounds healed completely. The change in wound exudate level from visit 1 to visit 4 was statistically significant (P = .006). No adverse events or infections occurred. In this population, the use of etiology-appropriate SC and a collagen calcium alginate dressing resulted in a decrease in wound area after 3 weeks of care. Longer-term studies to confirm these observations and controlled clinical studies to compare the effects of this dressing to other nongauze dressing treatments are needed. PMID- 29718817 TI - A Rare Case of Cutaneous Diffuse Large B-cell Lymphoma Presenting as a Chronic "Infectious" Skin Ulcer. AB - Cutaneous diffuse large B-cell lymphoma (DLBCL) usually manifests as papules, nodules, or plaques. A rare case of a patient with a chronic skin ulcer and signs and symptoms of infection, including fever and large amounts of yellow wound exudate, is presented. Fifteen (15) months before diagnosis, a 43-year-old otherwise healthy man noted soreness without apparent cause in his upper chest and a palpable 2 cm x 2 cm focal lump. The patient developed frequent fevers, and the lump enlarged over time, producing purulent exudate. For 14 months, the patient was examined and treated at 5 hospitals, but biopsies, smears, cultures, and various types of nucleic acid testing were negative. Antibiotics to treat the suspected but nonclassified infection were ineffective. Ultimately, debridement and pathological examination of necrotic tissue from the deep sinus revealed DLBCL. The patient was provided chemotherapy, surgical debridement, and negative pressure wound therapy. Wounds started to reduce in size once chemotherapy was initiated. The wound was surgically closed with a split-skin graft, and the patient was discharged 93 days following admission to the authors' facility. This case illustrates the possibility of cutaneous DLBCL in patients with chronic skin ulcers and infectious manifestation that do not respond to antibiotic therapy. Prompt deep tissue debridement and pathological examination of deep tissue will help confirm the presence of cutaneous DLBCL and guide required chemotherapy. PMID- 29718818 TI - Use of Viable Cryopreserved Umbilical Tissue for Soft Tissue Defects in Patients With Gas Gangrene: A Case Series. AB - INTRODUCTION: Gas gangrene is a rapidly progressive bacterial infection leading to necrosis that usually develops as a result of trauma or postoperative complications. This condition requires early diagnosis with immediate surgical intervention. With a poor prognosis, a high incidence of amputation, and comorbidities such as diabetes and peripheral vascular disease, patients with gas gangrene are put at further risk for surgical complications. OBJECTIVE: This case series reports the clinical outcomes of using a commercially available viable cryopreserved umbilical tissue (vCUT) in the surgical management of 10 patients (9 males, 1 female) with acute lower extremity gas gangrene. MATERIALS AND METHODS: All 10 patients had aggressive debridement and irrigation, followed by an intraoperative application of vCUT to cover the large, complex wounds with exposed bone, tendon, and soft tissue, which was fenestrated and sutured to the surrounding skin edges. RESULTS: The average wound size following debridement was 45.9 cm2 (range, 8 cm2-105 cm2). Average percent area reduction of the wounds at 4 weeks post-vCUT application was 68.4% (range, 49%-99.5%). The average length of hospital stay was 9 days (range, 2-16 days), and postdischarge patients were treated with negative pressure wound therapy and standard of care (nonadherent dressing, dry gauze, and mild compression) until wound closure was achieved (average, 3.3 months [range, 1.25-4.5 months]). With a 1-time application of vCUT, all patients reached complete wound closure with decreased time to closure, fewer complications, and a shorter duration of hospitalization as compared with traditional inpatient management of gas gangrene (incision and drainage with staged procedures). CONCLUSIONS: The positive clinical outcomes indicate that vCUT may be an effective aid as an intraoperative application to cover wounds following aggressive debridement in the presence of gas gangrene. PMID- 29718819 TI - Understanding Diabetic Induction of Cellular Senescence: A Concise Review. AB - OBJECTIVE: This study examines the healing dynamics of in vivo porcine muscle tissue wounds hemostatically treated with a saline-coupled bipolar tissue sealer (SCBS) compared with traditional electrosurgical (ES) coagulation. MATERIALS AND METHODS: Six cutaneous incisions were created on the dorsum of 28 adult male Yorkshire swine. The underlying muscle tissue was incised with a cold scalpel then treated with either SCBS (at 170 W) or traditional ES (at Coag 45 W). Time to hemostasis was recorded. Animals were humanely euthanized at day 2 and weeks 2, 3, or 8; treated tissue was harvested for histopathological evaluation. RESULTS: After 8 weeks, the extent of wound healing was similar between SCBS and ES. Both devices controlled bleeding effectively; however, SCBS-treated wounds exhibited a greater depth of thermal effect over the first 3 weeks despite a shorter treatment time. Wounds treated with SCBS demonstrated fewer inflammatory markers at early time points but healed more slowly, with scores that lagged behind ES for collagen deposition, fibrous tissue maturity, extracellular matrix, and stage of healing. Myofiber regeneration notably increased in SCBS-treated wounds at weeks 2, 3, and 8. By the end of the 8-week recovery period, there were no significant differences in healing parameters between the 2 groups. CONCLUSIONS: Overall, both devices elicited similar progression of healing by 8 weeks. The SCBS produced a deeper thermal effect in a shorter treatment time and improved myofiber regeneration compared with ES and had an equivalent overall course of healing. PMID- 29718820 TI - Characteristics of Surgical Site Infection Following Colorectal Surgery in a Tertiary Center: Extended-spectrum beta-Lactamase-producing Bacteria Culprits in Disease. AB - INTRODUCTION: Surgical site infection (SSI) is a well-known complication of colorectal surgery associated with increased morbidity and hospital stay. Antimicrobial prophylaxis can reduce the risk of SSI by as much as 75%. Extended spectrum beta-lactamase (ESBL)-producing pathogens make the successful use of such prophylaxis a challenge and are a real threat to patient care following colorectal surgery. OBJECTIVE: The aim of this study is to report the common characteristics of SSIs after colorectal surgery and to highlight the prevalence, risk factors, and clinical relevance of ESBL infections among these patients in a tertiary center. MATERIALS AND METHODS: All patients who underwent bowel resection operation (ie, laparoscopy, laparotomy, or laparoscopic-assisted colectomy) for benign or malignant colorectal disease were identified retrospectively from the prospective database of the colorectal department in the authors' tertiary center from March 2015 to March 2016. RESULTS: There were 123 patients included in this study, of which 21% (n = 26) had a SSI. The microorganisms isolated in the surgical sites included Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, methicillin-resistant Staphylococcus aureus, Proteus mirabilis, Morganella morganii, and Enterobacter cloacae. Thirty-eight percent of the wound infections grew ESBL-producing pathogens in their wound cultures and 62% grew non-ESBL microbes. CONCLUSIONS: More than one-third of the wound infections were due to ESBL-producing pathogens, which were resistant to the antibiotic prophylaxis given. Inappropriate antibiotic usage can delay postoperative recovery. High-risk patients for ESBL colonization may benefit from preoperative screening based on an established protocol. The cost effectiveness of an ESBL screening program needs to be further studied. PMID- 29718821 TI - Synergism of Therapies After Postoperative Autograft Failure in a Patient With Melanoma of the Foot Misdiagnosed as a Pressure Ulcer. AB - INTRODUCTION: Amelanotic melanoma of the foot is a diagnostic challenge for physicians as it often appears as a benign lesion. In order to make the correct diagnosis at early stages, it is recommended to perform a biopsy of worsening lesions that are refractory to standard treatments, particularly nonhealing wounds. CASE REPORT: The authors describe the case of a 57-year-old man with amelanotic melanoma of the foot that had been treated as a pressure ulcer for 3 months. He underwent wide local excision of the melanoma and an application of skin autograft. After skin autograft failure, optimal wound bed preparation was achieved through negative pressure wound therapy and compression bandages associated with hyperbaric therapy. Complete wound healing was obtained with an epidermal fractional skin grafting system combined with compressive inelastic bandages. CONCLUSIONS: Physicians must remain highly cautious of ulcerated lesions of the foot and may consider epidermal fractional skin grafting as a valid therapeutic option in case of postsurgical wounds resulting from wide local excision of malignant melanomas. PMID- 29718822 TI - Remote Temperature Monitoring in Diabetic Foot Ulcer Detection. AB - INTRODUCTION: Diabetic foot ulcers (DFUs) are associated with increased morbidity, mortality, and resource utilization. Remote temperature monitoring (RTM) is an evidence-based and recommended component of standard preventative foot care for high-risk populations that can detect the inflammation preceding and accompanying DFUs. OBJECTIVE: This case series illustrates the use of a RTM foot mat for the early detection and prevention of DFUs in patients with a history of DFUs. MATERIALS AND METHODS: Three patients with a history of diabetes, neuropathy, and DFUs were provided a RTM foot mat and instructed in its daily use. Persistent localized temperature differences exceeding 1.75C between the left and right feet prompted the clinical staff to call the patient to collect subjective history for further triage. RESULTS: Each patient presented with persistent temperature differences exceeding 1.75C. In one case, the patient was instructed to offload, and during a subsequent clinical exam, a callus was debrided and accommodative insoles were issued, resulting in resolution of the temperature differences. In the other 2 cases, the RTM foot mat prompted communication with and examination of the patient when there was damaged tissue deep to callus, resulting in early detection and treatment of uninfected DFUs. CONCLUSIONS: The findings of this case series are consistent with literature supporting the use of RTM for high-risk patients. PMID- 29718823 TI - Wound Bed Preparation for Capsulectomy Using a Hydrosurgery System. AB - INTRODUCTION: Wound bed preparation is necessary for proper wound healing. CASE REPORT: The case of a 75-year-old man with good outcomes after using a hydrosurgery system for capsulectomy is presented. At a 2-month follow-up visit, a fistula measuring 15 cm x 10 cm was found to have developed in the patient's left scapular region after the first wide-excision surgery for soft tissue sarcoma and reconstruction of the defect using a local flap. The wound had fluid collection and a capsule that was then debrided with a hydrosurgery system. Since no infection was detected, closure with a pedicled latissimus dorsi (LD) muscle flap (15 cm x 6 cm) was performed. Due to persistent fluid collection, the LD harvest site had to be drained after discharge (18 days postoperatively); however, in the regions debrided by the hydrosurgery system, the suction drain could be removed early. CONCLUSIONS: In the case reported herein, the hydrosurgery system proved beneficial for capsulectomy. PMID- 29718824 TI - Preparation of plasmonic porous Au@AgVO3 belt-like nanocomposites with enhanced visible light photocatalytic activity. AB - This study reports a visible light-driven plasmonic photocatalyst of Au deposited AgVO3 nanocomposites prepared by a hydrothermal method, and further in situ modification of Au nanoparticles by a reducing agent of NaHSO3 in an aqueous solution at room temperature. Various characterization techniques, such as SEM, TEM, XRD, EDS, XPS, and Brunauer-Emmett-Teller, were used to reveal the morphology, composition, and related properties. The results show that belt-like AgVO3 nanoparticles with a width of ~100 nm were successfully synthesized, and Au nanoparticles with controlled sizes (5-20 nm) were well distributed on the surface of the nanobelts. The UV-vis absorption spectra indicate that the decoration of Au nanoparticles can modulate the optical properties of the nanocomposites, namely, red shift occurs with the increase of Au content. The photocatalytic activities were measured by monitoring the degradation of Rhodamine B (RhB) with the presence of photocatalysts under visible light irradiation. The photodegradation results show that AgVO3 nanobelts exhibit good visible light photocatalytic activities with a degradation efficiency of 98% in 50 min and a reaction rate constant of 0.025 min-1 towards 30 ppm RhB. With the modification of Au nanoparticles, photocatalytic activity basically increases with the molar ratio of Au to V. Among the Au@AgVO3 nanocomposites, the 3% (molar ratio) Au decorated AgVO3 nanobelts showed the highest photocatalytic activity, and the k (0.064 min-1) was almost two times higher than that of the pure AgVO3 nanobelts. This can be attributed to several factors including specific surface areas, optical properties, and the energy band structure of the composites under visible light illumination. These findings may be useful for the practical use of visible light-driven photocatalysts with enhanced photocatalytic efficiencies for environmental remediation. PMID- 29718825 TI - Non-invasive detection of the early phase of kidney injury by photoacoustic/computed tomography imaging. AB - The early diagnosis of kidney diseases, which can remarkably impair the quality of life and are costly, has encountered great difficulties. Therefore, the development of methods for early diagnosis has great clinical significance. In this study, we used an emerging technique of photoacoustic (PA) imaging, which has relatively high spatial resolution and good imaging depth. Two kinds of PA gold nanoparticle (GNP)-based bioprobes were developed based on their superior photo detectability, size controllability and biocompatibility. The kidney injury mouse model was developed by unilateral ureteral obstruction for 96 h and the release of obstruction model). Giving 3.5 and 5.5 nm bioprobes by tail vein injection, we found that the 5.5 nm probe could be detected in the bladder in the model group, but not in the control group. These results were confirmed by computed tomography imaging. Furthermore, the model group did not show changes in the blood biochemical indices (BUN and Scr) and histologic examination. The 5.5 nm GNPs were found to be the critical point for early diagnosis of kidney injury. This new method was faster and more sensitive and accurate for the detection of renal injury, compared with conventional methods, and can be used for the development of a PA GNP-based bioprobe for diagnosing renal injury. PMID- 29718826 TI - One- or Five-Alarm Fire: Do We Call Out the Fire Engines or Turn On the Sprinklers? An Overview of the Ictal-Interictal Continuum and Approaches to Understanding the Spectrum and Treatment. PMID- 29718827 TI - Definition and Classification of Periodic and Rhythmic Patterns. AB - The growing use of continuous video-EEG recording in the inpatient setting, in particular in patients with varying degrees of encephalopathy, has yielded a window to the brain with an excellent temporal resolution. This increasingly available tool has become more than an instrument to detect nonconvulsive seizures (its primary use), and clinical indications span from ischemia detection in acute brain injuries, neuroprognostication of comatose patients, to monitoring the degree of encephalopathy. In this context, abnormal findings such as periodic discharges and rhythmic delta activity were increasingly recognized; however, significant subjectivity remained in the interpretation of these findings pertaining to key features regarding their spatial involvement, prevalence of occurrence, duration, associated morphologic features, and behavior. In 2005, the American Clinical Neurophysiology Society proposed standardized definitions and classification of electroencephalographic rhythmic and periodic patterns. This was subsequently revised in 2011 and in 2012 and is now being used by centers worldwide, with the final version published in early 2013 as an official guideline of the ACNS. The resulting uniform terminology has allowed for significant advances in the understanding of the pathophysiology, epileptogenic potential, and overall clinical implication of these patterns. Investigators across multiple institutions are now able to collaborate while exploring diagnostic and therapeutic algorithms to these patterns, an effort that may soon provide definitive evidence guiding treating clinicians on the management of these patients. PMID- 29718828 TI - Lateralized Periodic Discharges: A Literature Review. AB - The purpose of this article is to provide a comprehensive review of the literature about a particular EEG pattern, lateralized periodic discharges (LPDs), or periodic lateralized epileptiform discharges (PLEDs). The review will discuss the history and terminology of LPDs and provide a detailed summary of the etiologies, pathophysiology, clinical symptoms, and imaging studies related to LPDs. Current controversies about the association of LPDs with seizures and their management will be reviewed. Finally, some unanswered questions and suggestions for future research on LPDs will be discussed. PMID- 29718829 TI - Generalized Periodic Discharges: A Topical Review. AB - Generalized periodic discharges (GPDs) are generalized discharges that recur with a relatively uniform morphology and duration. They have a quantifiable interdischarge interval. Over the past decade, our understanding of these waveforms has improved considerably. The nomenclature has changed, and etiologic references have been removed. Many disease states can cause GPDs, such as anoxia, toxic/metabolic encephalopathy, infections, nonconvulsive status epilepticus, and hypothermia. Generally, GPDs are morphologically similar regardless of etiology. Generalized periodic discharges that are associated with nonconvulsive status epilepticus are treated with antiseizure drugs, while others are not necessarily aggressively treated. Prognosis for most patients with GPDs is guarded, although this is also dependent on the underlying etiology. As our understanding of GPDs increases, it is also clear that there is much more to be learned about these waveforms. PMID- 29718830 TI - Systematic Review of Bilateral Independent Periodic Discharges Written for Topical Journal Subject on Periodic Discharges. AB - Periodic discharges (PDs) are EEG patterns that may have important clinical and prognostic implications. There are different subtypes of PDs that are delineated by their location, and each type may have different meaning regarding prognosis and clinical associations. Bilateral independent PDs are a subtype that have not been analyzed recently and remain poorly understood. In this article, we systematically review the literature to better describe bilateral independent PDs regarding underlying neuropathology, neuroimaging, and neuroexamination correlates, seizure incidence, EEG characteristics, their comparison with other PD subtypes, and prognostic meaning. PMID- 29718831 TI - Generalized and Lateralized Rhythmic Patterns. AB - The relationship between generalized and lateralized rhythmic delta activity (RDA) and seizures is more ambiguous than the relationship between periodic discharges and seizures. Although frontally predominant generalized RDA is not associated with seizures, occipitally predominant RDA may be associated with the absence of seizures. Lateralized RDA seems to be more strongly associated with the presence of seizure activity. Appropriate recognition of generalized RDA and lateralized rhythmic delta activity may be confounded by benign etiologies of RDA, such as phi rhythm, slow alpha variant, subclinical rhythmic electrographic discharges of adults, or hyperventilation-induced high-amplitude rhythmic slowing. Angelman syndrome and NMDA-receptor antibody encephalitis can also produce morphologically distinct patterns of RDA. PMID- 29718832 TI - Stimulus-Induced Rhythmic, Periodic, or Ictal Discharges (SIRPIDs). AB - Stimulus-induced rhythmic, periodic, or ictal discharges (SIRPIDs) are a relatively common phenomenon found on prolonged electroencephalogram (EEG) monitoring that captures state changes and stimulation of critically ill patients. Common causes include hypoxic injury, traumatic brain injury, and hemorrhage, as well as toxic-metabolic disturbances. Some studies have shown an association between SIRPIDs and the presence of spontaneous electrographic seizures. Although the degree to which SIRPIDs should be treated with antiepileptic medications is unknown, the rare cases of functional imaging obtained in patients with SIRPIDs have not shown an increase in cerebral blood flow to suggest an active ictal process. Stimulus-induced rhythmic, periodic, or ictal discharges may reflect dysregulation of thalamo-cortical projections into abnormal or hyperexcitable cortex. PMID- 29718833 TI - Comorbid risks of psychological disorders and gastroesophageal reflux disorder using the national health insurance service-National Sample Cohort: A STROBE compliant article. AB - This study was performed to examine the comorbidity risks between psychological disorders, such as depression, and gastroesophageal reflux disease (GERD) using nationally representative data from a National Sample Cohort of the National Health Insurance Service in Korea.The National Health Insurance Service-National Sample Cohort (NHIS-NSC) database from 2010 to 2012 was used in this study. GERD patients were defined as those diagnosed with specific tests, with screened medication, and without any other gastrointestinal diseases. Propensity score matching for age, sex, and economic status was applied to form a control cohort. Incidence rate, relative risks, Cox proportional-hazards modeling, and Kaplan Meier analysis were applied to examine the differences between the GERD and control cohorts with regard to the risk of subsequent psychological disorders.The results showed that patients in the GERD cohort (n = 9503) had significantly higher risks of psychological disorders than those without GERD (adjusted hazard ratio [HR] 1.25, 95% confidence interval [CI] 1.07-1.47, P = .006). Specifically, the risk of depressive disorder was significantly higher for patients in the GERD cohort than in the control cohort (adjusted HR 1.41, 95% CI 1.04-1.91, P = .027). Kaplan-Meier analysis showed that the estimated probability of psychological disorders was significantly higher in the GERD cohort compared with the control cohort (log-rank test, P = .007).This study suggested that GERD may be a risk factor for subsequent psychological disorders, specifically, depressive disorder. The results of this study in GERD patients compared with non-GERD patients in Korea suggested that psychological disorders and GERD may be inter-related. PMID- 29718834 TI - Association analysis of EIF4G1 and Parkinson disease in Xinjiang Uygur and Han nationality. AB - This study is to investigate whether the known mutations P.R1205H and P.A502V were pathogenic factors of Parkinson disease (PD) in Xinjiang Uygur and Han people.A case-control study with polymerase chain reaction-restriction fragment length polymorphism method was performed on 150 cases of PD and 130 cases of age, sex, and national-matched healthy controls for rs200221361 polymorphism analysis and Sanger sequencing. Specific mutations were chosen for further sequencing in a case-control study.The 3 variants located on the exon 10, and the rs200221361 was a nonsynonymous variant. The frequencies of rs200221361 genotype and allele between PD and control groups in Uygur and Han people showed no significant difference (for genotype, chi = 0.91, P > .05; for allele, chi = 0.91, P > .05). Statistical analysis showed that there were no differences in allele and genotype frequencies of rs200221361 genotype and allele between PD and control groups among the age, gender, or race (P > .05).P.Ala502Val and P.Arg1205H may not be pathogenic mutations to PD in Xinjiang Uygur and Han people. The polymorphism of the rs200221361 may have no association with the occurrence of PD in Uygur and Han people of Xinjiang. PMID- 29718835 TI - Anti-hyperlipidemia of garlic by reducing the level of total cholesterol and low density lipoprotein: A meta-analysis. AB - BACKGROUND: This study aimed to understand the impact of garlic on improving blood lipids using a meta-analysis. METHODS: A literature search of the PubMed, EMBASE, and Cochrane Library databases was performed using keywords such as "garlic" and "hypercholesterolemia," and the deadline "July 14 (th), 2017." After extracting relevant details, each selected literature was evaluated for quality according to the quality evaluation criteria of bias risk recommended by Cochrane Collaboration recommendations and heterogeneity tests were performed. Standardized mean difference (SMD) and 95% confidence interval (CI) were evaluated using R 3.12 software. The publication bias was assessed using Egger method. RESULTS: A total of 14 eligible papers published from 1981 to 2016 were included. The quality of the literatures was of moderate to high qualities. The values of TC (SMD = -1.26, 95% CI, -1.86 to -0.66), low-density lipoprotein (LDL) (SMD = -1.07, 95% CI, -1.67 to -0.47), and high-density lipoprotein (HDL) (SMD = 0.50, 95% CI, 0.06-0.94) after taking garlic in the experimental group and the control group have statistical significance, while there was no significant difference of TG in the 2 groups (SMD = -0.16, 95% CI, -0.87-0.55). However, the result of HDL was reversed when removed some of the literatures. No significant publication bias among the eligible studies with values of TC (P = .0625), LDL (P = .0770), HDL (P = .2293), and TG (P = .3436). CONCLUSION: Garlic can reduce the level of TC and LDL instead of HDL and TG, indicating the ability of anti hyperlipidemia. PMID- 29718836 TI - Gallbladder perforation in a patient with alcoholic liver cirrhosis and asymptomatic gallstones: A case report. AB - RATIONALE: Gallbladder perforation is a relatively uncommon complication of alcoholic liver cirrhosis and may happen with or without gallstones. PATIENT CONCERNS: Here we report a 52-year-old male patient who was diagnosed as gallbladder perforation with chronic liver cirrhosis and asymptomatic gallstones. The patient was admitted with acute and severe abdominal pain during weight bearing physical labor. He had a history of alcoholic liver cirrhosis but no chronic abdominal pain or gallstones. The patient presented with localized peritoneal irritation, and abdominal puncture showed non-clotting blood. A preliminary clinical diagnosis was made as hepatocellular carcinoma rupture based on imaging findings. However, this diagnosis changed to gangrenous cholecystitis with gallbladder perforation by the laparotomy examination. DIAGNOSES: He was diagnosed with gangrenous cholecystitis with gallbladder perforation. INTERVENTIONS AND OUTCOMES: The patient performed well postoperatively. LESSONS: This case suggests that gallbladder perforation should be considered as a potential cause of acute abdominal pain even without evidence of gallstones. Early examination with a laparotomy examination can help achieve a timely diagnosis. PMID- 29718837 TI - Therapeutic approach for the cesarean scar pregnancy. AB - The aim of this study was to explore the pros and cons of different treatments of cesarean scar pregnancy (CSP).We retrospectively studied 205 cases of CSP that were treated in our hospital from June 2013 to June 2014, 189 of which had surgical operation.The average age of the patients was (32.98 +/- 4.56) years. Data from those 189 cases were analyzed.Two hundred five patients from Beijing Obstetrics and Gynecology Hospital.One hundred eighty-nine cases who had operative treatment, 111 of which received curettage under hysteroscopy, 70 of which received curettage under ultrasonography, 8 of which received laparoscopic Cesarean scar resection.Management of 189 ectopic Cesarean scar pregnancy cases discussed in this article was usage of methotrexate (MTX) via the utility of uterine arterial chemotherapy embolization (UACE).All of 189 patients were cured without hysterectomy. Hysteroscopy provides a clear view for us, making it easy to identify the range of affected tissues, and clean the pregnancy tissue. Curettage under ultrasonography is relatively simple and inexpensive. Laparoscopic surgery is more suitable for exogenous CSP patients that can reduce the operation risk and prevent uterine perforation. However, laparoscopic surgery costs much more than those 2 and needs longer time of hospitalization.Treatment options should be personalized according to different situations. Minimal invasion, thorough treatment, quick recovery, low risk of hysterectomy, preserved fertility function, and improved life quality are the principles we have been pursuing for. PMID- 29718838 TI - The HindIII and PvuII polymorphisms of lipoprotein lipase (LPL) gene reduce the risk of ischemic stroke (IS): A meta-analysis. AB - BACKGROUND: Lipoprotein lipase (LPL) polymorphisms were suggested to be the risk factor for ischemic stroke (IS). However, controversial results were obtained. Our objective was to investigate the association of LPL polymorphisms at Ser447Ter, HindIII (+/-), and PvuII (+/-) with IS risk. METHODS: Literatures search were carried out on databases: PubMed, Web of science, the Cochrane database of system reviews, Chinese National Knowledge Infrastructure, and Embase. Pooled odds ratio (OR) with 95% confidence interval (CI) was calculated to detect the relationship between LPL polymorphisms and the risk of IS. RESULTS: No significant association was detected between LPL Ser447Ter and IS in allelic, dominant, or recessive models (P > .05). Significant lower frequencies of allelic and dominant models of LPL HindIII (+/-) and PvuII (+/-) in cases were detected (HindIII (+/-): allelic model: P = .0002, OR[95%CI] = 0.80 [0.71, 0.90]; dominant model: P = 0.003, OR[95%CI] = 0.80 [0.69, 0.92]; PvuII (+/-): allelic model: P < 0.0001, OR[95%CI] = 0.75[0.65-0.86]; dominant model: P = 0.02, OR[95%CI] = 0.67[0.48-0.93]). And the recessive model of PvuII (+/-) was significantly associated with the IS risk (P = .01, OR[95%CI] = .71[0.55-0.93]). Subgroup analysis stratified by ethnicity showed that the frequencies of allelic, dominant, and recessive models of HindIII (+/-), as well as dominant model of PvuII (+/-) were significant lower in Asian cases (HindIII (+/-): allelic model: P < .00001, OR[95%CI] = 0.69 [0.59, 0.79]; dominant model: P < .0001, OR[95%CI] = 0.69 [0.58, 0.83]; recessive model: P = .005, OR[95%CI] = 0.66 [0.50, 0.89]; PvuII (+/-): dominant model: P = .0008, OR[95%CI] = 0.66 [0.51-0.84]), but not in Caucasian cases (P > .05). In addition, the frequencies of allelic and recessive models of PvuII (+/-) significantly decreased in Caucasian cases (P < .05). CONCLUSION: the HindIII (+/-) and PvuII (+/-), but not the Ser447Ter might be the protective factors for IS. PMID- 29718839 TI - Evaluation of the physical activity level, nutrition quality, and depression in patients with metabolic syndrome: Comparative study. AB - Metabolic syndrome (MetS) is a complex problem that contains risk factors related with obesity, cardiovascular diseases, and type-II diabetes. The incidence of MetS is increasing every year throughout the world.The aim of this study was to evaluate and compare physical activity levels, nutrition quality, and depression status of the individuals who are diagnosed with and without MetS.International Physical Activity Questionnaire (IPAQ), Mediterranean Diet Adherence Screener (MEDAS), Beck Depression Inventory (BDI) was used. In addition, biochemical analysis and anthropometric measurements were also taken.According to IPAQ, 81.1% of the MetS group is inactive, 6.8% is active, and 5.1% is highly active, whereas 22.3% of the non-MetS group is inactive, 46.2% is active, and 31.5% is highly active. MEDAS was found to be lower in the MetS group. BDI levels were also determined high in the MetS group.Sedentary lifestyle, depression, and unhealthy nutrition habits are among the significant factors for the development of MetS. The knowledge levels of the people should be increased by developing national physical activity and nutrition guidelines. PMID- 29718840 TI - Prostatic stromal sarcoma: A case report and literature review. AB - RATIONALE: prostatic stromal sarcoma is a very rare malignant tumor that accounts for <0.1% of prostate malignancy. PATIENT CONCERNS:: we reported a 49-year-old man presented with dysuria and hematuria, whose computed tomography examination showed an enlarged prostate gland with an irregular shape. DIAGNOSES:: the diagnosis was confirmed on the basis of imaging manifestations and histopathological findings which were proved as prostatic stromal sarcoma. INTERVENTIONS: The patient underwent radical prostatectomy OUTCOMES:: his postoperative condition was good. PMID- 29718841 TI - Radiotherapy alone and with concurrent chemotherapy for nasopharyngeal carcinoma: A retrospective study. AB - We sought to evaluate clinical outcomes and toxicities of radiation therapy (RT) alone compared to RT with concurrent chemotherapy (CCT) for nasopharyngeal carcinoma (NPC) treatment.We conducted a retrospective review of consecutive patients with biopsy-proven nonmetastatic NPC who underwent RT at our institution. From May 2001 to April 2015; 62 newly diagnosed NPC patients were treated with three-dimensional conformal radiotherapy (3D-CRT) or intensity modulated radiotherapy (IMRT) with or without CCT. The patients were classified as follows: 8% stage I, 15% stage II, 32% stage III, and 45% stage IVA/IVB. A total of 76% of tumors were World Health Organization types II or III. Acute and late toxicities were graded according to the Common Terminology Criteria for Adverse Events version 3.0. Overall survival (OS), progression-free survival (PFS), locoregional progression-free survival (LRPFS), and distant metastasis free survival (DMFS) were analyzed.The median follow-up period for living patients was 53 months. The median actual delivered dose was 70 Gy with a range of 28 to 70 Gy in fraction sizes of 2 Gy. The estimated 5-year OS, PFS, LRPFS, and DMFS rates were 72.7%, 59.8%, 77.9%, and 84.2%, respectively. The use of CCT was a predictive factor of significantly better OS and PFS, whereas stage IV was a significant predictor of poor OS and PFS. The most severe acute toxicities included Grade 3 mucositis in 56% and Grade 3 dermatitis in 8%. Subset analysis revealed that Grade 2 xerostomia was significantly lower in the IMRT (23%) group than in the 3D-CRT (52%) group (P = .02).RT yielded favorable outcomes. CCT was associated with longer PFS and OS than RT alone. PMID- 29718842 TI - Eunkyosan for treatment of the common cold: A protocol for the systematic review of controlled trials. AB - INTRODUCTION: Eunkyosan (EKS) is widely used for common colds in East Asian countries. Many clinical trials assessing the efficacy and safety of EKS formula for the treatment of common colds have been reported. This review will assess the clinical evidence for and against the use of EKS formula as a treatment for common colds. METHODS AND ANALYSIS: Fourteen databases will be searched from inception until March 2018. We will include randomized controlled trials (RCTs) assessing EKS decoctions for any type of common cold. All RCTs of decoctions or modified decoctions will be included. The methodological qualities of the RCTs will be assessed using the Cochrane Collaboration tool for assessing risk of bias, while confidence in the cumulative evidence will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) instrument. ETHICS AND DISSEMINATION: This systematic review will be published in a peer-reviewed journal and will also be disseminated electronically and in print. The review will be updated to inform and guide healthcare practices.Registration number: CRD42018087694. PMID- 29718843 TI - Predicting the risk for colorectal cancer with personal characteristics and fecal immunochemical test. AB - We aimed to predict colorectal cancer (CRC) based on the demographic features and clinical correlates of personal symptoms and signs from Tianjin community-based CRC screening data.A total of 891,199 residents who were aged 60 to 74 and were screened in 2012 were enrolled. The Lasso logistic regression model was used to identify the predictors for CRC. Predictive validity was assessed by the receiver operating characteristic (ROC) curve. Bootstrapping method was also performed to validate this prediction model.CRC was best predicted by a model that included age, sex, education level, occupations, diarrhea, constipation, colon mucosa and bleeding, gallbladder disease, a stressful life event, family history of CRC, and a positive fecal immunochemical test (FIT). The area under curve (AUC) for the questionnaire with a FIT was 84% (95% CI: 82%-86%), followed by 76% (95% CI: 74% 79%) for a FIT alone, and 73% (95% CI: 71%-76%) for the questionnaire alone. With 500 bootstrap replications, the estimated optimism (<0.005) shows good discrimination in validation of prediction model.A risk prediction model for CRC based on a series of symptoms and signs related to enteric diseases in combination with a FIT was developed from first round of screening. The results of the current study are useful for increasing the awareness of high-risk subjects and for individual-risk-guided invitations or strategies to achieve mass screening for CRC. PMID- 29718844 TI - Clinical outcomes of ligation-assisted endoscopic resection for duodenal neuroendocrine tumors. AB - Duodenal carcinoid tumors, a type of neuroendocrine tumors, are relatively rare and are usually found incidentally during endoscopy. Small duodenal carcinoid tumors (<=10-20 mm), embedded in the submucosa, can be resected endoscopically because of the low risk of metastasis. The aim of this study was to assess the safety and efficacy of ligation-assisted endoscopic mucosal resection (EMR) for the treatment of small duodenal carcinoid tumors. The clinical outcomes of the endoscopic procedures were also evaluated.Between November 2008 and November 2017, a total of 15 duodenal carcinoid tumors embedded in the submucosa were resected using EMR. Two types of EMR (conventional EMR and ligation-assisted EMR) were performed according to tumor morphology (narrow-based and broad-based).The mean tumor size was 6.6 +/- 3.9 mm and the mean procedure time was 11.0 +/- 11.2 minutes. Most of the lesions (80.0%) were located in the duodenal 1st portion. Broad-based tumors were more common than narrow-based tumors (66.7% vs 33.3%). All broad-based tumors were resected successfully using ligation-assisted EMR. Although en-bloc resection and complete resection rates were higher in ligation assisted EMR than in conventional EMR ([100% vs 87.5%], and [85.7% vs 62.5%], respectively), the difference was not significant (P = .333 and P = .310, respectively). Moreover, there was no evidence of local or distant metastasis during the follow-up (26.1 +/- 20.7 months).Ligation-assisted EMR showed a higher complete resection rate than conventional EMR. Ligation-assisted EMR may be an optimal treatment option for duodenal carcinoid tumors with a broad base. PMID- 29718845 TI - Secondary pregnancy by an implant in a laparoscopic trocar site: A case report. AB - RATIONALE: For nearly 20 years, laparoscopy has been generally regarded as the gold standard for the surgical treatment of ectopic pregnancy and its application is very widespread. According to our knowledge, secondary pregnancy at the laparoscopic trocar site has not yet been reported until now. PATIENT CONCERNS: A 24-year-old Chinese female patient is reported herein. Her left fallopian tube was removed via laparoscopy due to a first ectopic pregnancy. Her postoperative blood beta-human chorionic gonadotropin (beta-hCG) was increasing with irregular vaginal bleeding. The patient was initially regarded as having an old ectopic pregnancy. DIAGNOSES: Secondary pregnancy by an implant in a laparoscopic trocar Site. INTERVENTIONS: Because of secondary pregnancy at the laparoscopic port site, laparoscopic surgery was performed again 32 days after the first operation. Approximately 1000 milliliters (mL) of free intraperitoneal hemorrhage and active bleeding of the lesion were detected. Histopathologic examination confirmed the lesion was the result of pregnancy with visible villous tissue. OUTCOMES: Her blood beta-hCG gradually declined to a normal range in 28 days after the second operation. Menstruation occurred on day 20 after the second operation, and the duration and quantity were normal. LESSONS: Although laparoscopy has many advantages, secondary pregnancy at the laparoscopic trocar port wound caused the patient enormous physical and mental pain and increased the medical costs. The etiology of secondary ectopic pregnancy at the laparoscopic puncture site was mainly an iatrogenic factor. Therefore, the procedure should be standardized to avoid its occurrence. PMID- 29718846 TI - High-risk pulmonary embolism assessed by transthoracic echocardiography: A case report. AB - RATIONALE: Acute pulmonary embolism (APE) as a life-threatening illness may present with a wide range of manifestations. APE was diagnosed using computed tomographic pulmonary angiography (CTPA); however, transthoracic echocardiography (TTE) can reveal hemodynamic status. Early thrombolysis is the most effective therapy for the treatment of massive pulmonary embolism. PATIENTS CONCERNS: Herein, we report a case of high-risk APE with a wide range of manifestations, including chest pain, dyspnea, low-blood pressure, and syncope. DIAGNOSES: A 55 year-old, previously healthy woman, complained of dyspnea and pleuritic chest pain for 40 days, along with transitory (10 minutes) episodes of syncope that had occurred 2 days previously. INTERVENTIONS: Because of the high-risk APE, the patient received intravenous thrombolytic therapy with low-dose recombinant tissue plasminogen activator (rt-PA, 50 mg over 30 minutes) and an anticoagulant (subcutaneous low-molecular-weight heparin, once every 12 hours for 5 days). OUTCOMES: Five days after thrombolysis, bedside TTE revealed RV diastolic dimension decreased to 22 mm. Color ultrasonography revealed a significant decrease in systolic and mean pulmonary artery pressure. LESSONS: TTE may provide initial suspicion of APE and may help identify patients with unstable hemodynamic status before the onset of shock. Moreover, concomitant TTE signs of decreased RV load may predict better prognosis for high-risk APE patients. PMID- 29718847 TI - Ultrasound manifestations of lobulated ovaries: Case report. AB - RATIONALE: Ultrasound features of lobulated ovaries are rarely described in the literature. Here, we report a case of pathologically proven lobulated ovaries. PATIENT CONCERNS: A 22-year-old female with irregular menstrual cycles for 9 years came to our hospital because of endless menstruation and anemia for 1 month. DIAGNOSES: Ultrasound and computed tomography revealed pelvic masses. But diagnosing or excluding neoplasms based on imaging findings was difficult. INTERVENTIONS: The patient underwent an exploratory laparotomy. Some nodules in the right adnexal region were removed, and a left ovarian biopsy was performed. OUTCOMES: Pathology results revealed nodular ovarian tissue with cortical fibrosis, but no tumor cells. LESSONS: Our case demonstrates ultrasound manifestations of lobulated ovaries and the importance of being acquainted with these features. PMID- 29718848 TI - Surgical treatment for old subaxial cervical dislocation with bilateral locked facets in a 3-year-old girl: A case report. AB - RATIONALE: This study aimed to describe the case of a 3-year-old girl with old bilateral facet dislocation on cervical vertebrae 6 and 7, who had spinal cord transection, received surgical treatment, and achieved a relative satisfactory therapeutic effect. PATIENT CONCERNS: A 3-year-old girl was urgently transferred to the hospital after a car accident. DIAGNOSES:: she was diagnosed with splenic rupture, intracranial hemorrhage, cervical dislocation, spinal transection, and Monteggia fracture of the left upper limb. INTERVENTIONS: The girl underwent emergency splenectomy and was transferred to the intensive care unit of the hospital 15 days later. One-stage anterior-posterior approach surgery (anterior discectomy, posterior laminectomy, and pedicle screw fixation) was performed when the patient stabilized after 45-day symptomatic treatment. The operation was uneventful. OUTCOMES: The reduction of lower cervical dislocation was satisfactory, with sufficient spinal cord decompression. The internal fixation position was good, and the spinal sequence was well restored. The girl was discharged 2 weeks later after the operation and followed up for 2 years. The major nerve function of both upper limbs was recovered, with no obvious retardation of the growth of immature spine. LESSONS: A satisfactory therapeutic effect was achieved for a pediatric old subaxial cervical dislocation with bilateral locked facets using anterior discectomy, posterior laminectomy, and pedicle screw fixation. The posterior pedicle screw fixation provided a good three-dimensional stability of the spine, with reduced risk and complications caused by anterior internal fixation. The growth of immature spine was not obviously affected during the 2-year follow-up. PMID- 29718849 TI - The comorbidities and risk factors in children with congenital airway anomalies: A nationwide population-based study in Taiwan. AB - The comorbidities and risk factors associated with congenital airway anomalies (CAAs) in children are undecided. This study aimed to investigate the comorbidities commonly associated with CAA and to explore the prognosis and risk factors in CAA children.This nationwide, population-based cohort study was conducted between 2000 and 2011 with children aged 0 to 5 years assigned to either a CAA group (6341 patients) that diagnosed with CAA or an age- and gender matched control group (25,159 patients) without CAA, using the Taiwan National Health Insurance Research Database (NHIRD). Descriptive, logistic regression, Kaplan-Meier, and Cox regression analyses were used for the investigation.Cleft lip/palate (adjusted odds ratio [aOR], 7.88; 95% confidence interval [CI], 6.49 9.59), chromosome (aOR, 6.85; 95% CI, 5.03-9.34), and congenital neurologic (aOR, 5.52; 95% CI, 4.45-6.87) anomalies were the comorbidities most highly associated with CAA. Of the 31,500 eligible study patients, 636 (399 in the CAA group and 237 in the control group) died during the follow-up period (6.3% vs 0.9%, P < .001). The mortality risk after adjusting for age, gender, and comorbidities elevated significantly among CAA patients (adjusted hazard ratio [aHR], 4.59; 95% CI, 3.85-5.48). The need for tracheostomy (aHR, 2.98; 95% CI, 2.15-4.15), comorbidity with congenital heart disease (CHD) (aHR, 2.52; 95% CI, 2.05-3.10), and chromosome anomaly (aHR, 2.34; 95% CI, 1.70-3.23) were the independent risk factors most greatly related to CAA mortality.This study demonstrated that CAA was most highly associated with the comorbidities as cleft lip/palate, chromosome, and congenital neurologic anomalies. The CAA children had a significantly elevated mortality risk; the need for tracheostomy, CHD, and chromosome anomaly were the most related risk factors of mortality for CAA. Further studies are warranted to clarify the involved mechanisms. PMID- 29718850 TI - Solitary rectal ulcer syndrome: A systematic review. AB - BACKGROUND: Solitary rectal ulcer (SRUS) may mislead the inflammatory bowel disease (IBD) or rectal polyps, which may reduce the actual prevalence of it. Various treatments for SRUS have been described that can be referred to therapeutic strategies such as biofeedback, enema of corticosteroid, topical therapy, and rectal mucosectomy. Nevertheless, biofeedback should be considered as the first stage of treatment, while surgical procedures have been offered for those who do not respond to conservative management and biofeedback or those who have total rectal prolapse and rectal full-thickness. METHODS: A systematic and comprehensive search will be performed using MEDLINE, PubMed, Scopus, EMBASE, AMED, the Cochrane Library, and Google Scholar. RESULTS: The results of this systematic review will be published in a peer-reviewed journal. CONCLUSION: To our knowledge, our study discusses the factors involved in the pathogenesis, clinical symptoms, diagnosis, treatment, and management of patients. This review can provide recommended strategies in a comprehensive and targeted vision for patients suffering from this syndrome. PMID- 29718851 TI - Ultrasound B-lines in the evaluation of interstitial lung disease in patients with systemic sclerosis: Cut-off point definition for the presence of significant pulmonary fibrosis. AB - The aim of this study was to establish the cut-off point of ultrasound (US) B lines number for detecting the presence of significant interstitial lung disease (ILD) in patients with systemic sclerosis (SSc) (SSc-ILD) in relation to high resolution computed tomography (HRCT) findings.Consecutive SSc-ILD patients underwent chest HRCT, lung US (LUS), pulmonary function test, and clinical assessment. Exclusion criteria were represented by the presence of a coexisting congestive heart failure and a clinical history suggestive of lung or pleural diseases. HRCT images were scored for the presence of ILD by 2 readers, in accordance with the Warrick scoring system. US assessment was performed by a US skilled rheumatologist, blinded to HRCT results and clinical data, and included the bilateral evaluation of 14 lung intercostal spaces (LIS). In each LIS, the number of B-lines was recorded and summed. To test discriminant validity, we used the receiver operating characteristic (ROC) curve analysis applying a Warrick score of 7 as external criterion for the presence of SSc-ILD.Forty patients completed the study. The US B-lines number and the Warrick score confirmed excellent correlation (Spearman rho: 0.958, P = .0001). The ROC curve analysis revealed that the presence of 10 US B-lines is the cut-off point with the greatest positive likelihood ratio (12.52) for the presence of significant SSc ILD.The detection of 10 B-lines is highly predictive for the HRCT presence of significant SSc-ILD. In SSc patients, the LUS assessment as first imaging tool may represent an effective model to improve the correct timing of chest HRCT. PMID- 29718852 TI - Treatment outcomes of the simple bone cyst: A comparative study of 2 surgical techniques using artificial bone substitutes. AB - : Simple bone cysts (SBCs) are benign lesions of unknown etiology. Because of its high relapse rate, they occasionally need a long period of treatment and restriction of activities in children and adolescent. Although various treatment modalities with variable differing outcomes have been described in the literature, no consensus has been reached regarding the standard treatment. The purpose of this study was to evaluate the outcome of a minimally invasive technique that uses a ceramic hydroxyapatite cannulated pin (HA pin) for the treatment of SBCs.Between 1998 and 2015, we have treated 75 patients with SBCs either with continuous decompression by inserting HA pins after curettage and multiple drilling (group 1, n = 39 patients) or with calcium phosphate cement (CPC) filling after curettage (group 2, n = 36 patients). These patients were retrospectively analyzed for recurrence-free survival (RFS) and factors implicated in SBC recurrence.Seventy-five patients (50 man and 25 females) with a mean age of 17.5 +/- 11.6 years and a histopathologically confirmed diagnosis of SBCs were included. The mean follow-up period was 33 +/- 25.3 months. RFS were 88% at 1 year and 81% at 5 years. Residual or progressing cysts were observed in 12 patients after the surgery and 10 of them underwent additional surgery. Recurrence rate was significantly higher in patients under the age of 10 years (P = .01), in long bone cysts (P = .01), and in active phase cysts (P = .003) (log rank test). Multivariate analysis results revealed that age less than 10 years was an independent risk factor of recurrence (P = .04). No significant difference in recurrence rate was observed between groups 1 and 2. However, the mean operating time was significantly shorter in group 1. (62.4 +/- 25.6 vs 110.5 +/- 48.4 minutes in group 2).Continuous decompression using HA pin is a less invasive surgical technique for the treatment of SBCs compared with CPC filling and has a high healing rate. The relapse rate was still high when the cysts were caused in children aged less than 10 years, located in the long bone, or remained adjacent to the epiphysis. LEVEL OF EVIDENCE: Level 3, Retrospective comparative study. PMID- 29718853 TI - Pediatric Tuina for promoting growth and development of preterm infants: A protocol for the systematic review of randomized controlled trail. AB - BACKGROUND: Preterm infants are babies born alive before 37 weeks. Many survived infants concomitant with defects of growth and development, a lifetime of disability usually as following when insufficient intervention. In early intervention of preterm infants, pediatric Tuina shows good effect in many Chinese and some English clinical trials. This systematic review is aimed to evaluate the efficacy and safety of pediatric Tuina for promoting growth and development of preterm infants. METHODS: The electronic databases of Cochrane Library, MEDLINE, EBASE, Web of Science, Springer, World Health Organization International Clinical Trials Registry Platform, China National Knowledge Infrastructure, Chinese Biomedical Literature Database, Wan-fang database, Chinese Scientific Journal Database, and other databases will be searched from establishment to April 1, 2018. All published randomized controlled trials (RCTs) about this topic will be included. Two independent researchers will operate article retrieval, screening, quality evaluation, and data analyses by Review Manager (V.5.3.5). Meta-analyses, subgroup analysis, and/or descriptive analysis will be performed based on included data conditions. RESULTS: High-quality synthesis and/or descriptive analysis of current evidence will be provided from weight increase, motor development, neuropsychological development, length of stay, days of weight recovery to birthweight, days on supplemental oxygen, daily sleep duration, and side effects. CONCLUSION: This study will provide the evidence of whether pediatric Tuina is an effective early intervention for preterm infants. ETHICS AND DISSEMINATION: There is no requirement of ethical approval and informed consent, and it will be in print or published by electronic copies. TRAIL REGISTRATION NUMBER: This systematic review protocol has been registered in the PROSPERO network (No. CRD42018090563). PMID- 29718854 TI - Neurologic manifestations in anaphylaxis due to subcutaneous allergy immunotherapy: A case report. AB - RATIONALE: Life-threatening anaphylactic shock is a rare (1 in 1 million) but documented occurrence in response to subcutaneous immunotherapy. Immediate administration of Epinephrine (Epi) is critical to save lives in these situations. The current protocol for systemic reactions in immunotherapy is for the prescribing physician to reassess the dosing and schedule as well as the risk:benefit assessment for the therapy and determine whether or not to proceed. PATIENT CONCERNS: The patient revealed concerns regarding the neurologic sequela sustained after undergoinig life-threatening anaphylactic shock. DIAGNOSIS: The patient was diagnosed with anaphylactic shock and treated appropriately. INTERVENTIONS: The patient experienced shortness of breath and was promptly administered 2 shots of 0.3mg Epi followed by a loss of consciousness (LOC) and a series of 4 consecutive seizures accompanied with LOC and urinary incontinence. Seizures as a manifestation of anaphylaxis are rare with 1 study claiming 13% of cases of anaphylaxis having LOC and only 1.5% cases with loss of bladder or bowel control. OUTCOMES: This case is one of continued subcutaneous immunotherapy after the patient had an initial systemic reaction suspicious for anaphylaxis 6 months before the life-threatening anaphylaxis, both induced by immunotherapy. In both instances, there was a significant amount of neurologic involvement. Neurologic sequela included a transient tremor and permanent deficits in vision, fine motor coordination evidenced by a change in handwriting. LESSONS: The current protocol was followed in this patient but still ended up almost ending her life. This protocol seems to be inadequate with regards to potential fatality. Even though a very small number, some patients face life-threatening adverse effects after apparently very low-risk immunotherapies. Therefore, reevaluating the treatment protocol with addition of a longer post-shot observation step and discontinuing treatment in the case of adverse events may help minimize the overall risk of any fatal outcome. PMID- 29718855 TI - Investigation on the frailty status of the elderly inpatients in Shanghai using the FRAIL (fatigue, resistance, ambulation, illness, and loss) questionnaire. AB - This study was to investigate the frailty status of inpatients older than 65 years old in Shanghai.A 6-month cross-sectional survey was conducted using FRAIL (fatigue, resistance, ambulation, illness, and loss) questionnaire. Totally 587 patients were included. The data, including demographic characteristics, constipation, urinary retention, urinary incontinence, grip strength, and muscle strength, were collected. The data of serum prealbumin, serum albumin, serum total protein, and hemoglobin were obtained from laboratory blood tests.The incidence of nonfrailty, prefrailty, and frailty was 0.249, 0.417, and 0.334, respectively. The high incidence age of frailty was 86 to 90 years old (0.342), and the high incidence age of prefrailty was 65 to 70 years old (0.282). There was significant difference in the grip strength among different degrees of frailty (P < .01). The influencing factors related to prefrailty included prealbumin, grip strength, urinary retention, constipation and education level of illiterate (P < .05). The populations with high prealbumin level, high grip strength and illiteracy population were not easy to enter the prefrailty period, while those with constipation (OR (odds ratio) = 1.867, 95% CI (confidence interval): 1.046-3.330) and urinary retention (OR = 7.007, 95% CI: 1.137-2.757) were more likely to enter the prefrailty period. Factors associated with frailty included age, prealbumin, grip strength, muscle strength, urinary incontinence, urinary retention, and constipation (P < .05). The populations with high prealbumin level, high grip strength, and high muscle strength were not easy to enter frailty period, while those with older age (OR = 1.141, 95% CI: 1.085 1.200), urinary incontinence (OR = 10.314, 95% CI: 1.950-54.548), urinary retention (OR = 3.058, 95% CI: 1.571-5.952), and constipation (OR = 3.004, 95% CI: 1.540-5.857) were easy to enter frailty period.The high incidence ages of frailty and prefrailty are 86 to 90 years old and 65 to 70 years old, respectively. Age, low education level, low grip strength, low muscle strength, low serum prealbumin, urinary retention, urinary incontinence, and constipation are the risk factors of frailty. It is recommended to include frailty as an indicator in the existing assessment to rate the disease and develop a disease observation plan. PMID- 29718856 TI - Association of Foxp3 promoter polymorphisms with susceptibility to endometrial cancer in the Chinese Han women. AB - To evaluate the association between Foxp3 gene polymorphisms (rs3761548 and rs5902434) and susceptibility to endometrial cancer (EC), we report a hospital case-control study involving 602 women, consisting of 269 patients with EC and 333 healthy controls. Genotyping was performed by polymerase chain reaction restriction fragment length polymorphism. Our results suggest that the frequency of the A allele in rs3761548 in patients with EC was significantly lower than that in healthy controls (20.3% vs 26.4%, odds ratio [OR] 0.71, 95% confidence interval [CI]: 0.54-0.93, P = .012), while the heterozygous AC genotype showed a significant protective effect on EC in codominant, dominant, and overdominant models (adjusted OR 0.64, 95% CI: 0.45-0.91, P = .039; OR 0.65, 95% CI: 0.47 0.91, P = .011; OR 0.67, 95% CI: 0.47-0.94, P = .02, respectively), and AA genotype was more frequent in patients with cervical invasion (recessive model: OR 3.55, 95% CI: 1.10-11.44, P = .046). Moreover, ATT/ATT genotype (rs5902434) was conferred a lower risk of EC in the recessive model (adjusted OR 0.58, 95% CI: 0.35-0.96, P = .031). From the data generated, we conclude that Foxp3 promoter polymorphisms are associated with susceptibility to EC in Chinese Han women. PMID- 29718857 TI - Surgical management of tumor-positive interval node in melanoma patients: An observational study. AB - The presence of interval nodes (IN) in melanoma is testified in several studies and sometimes these lymph nodes can contain metastatic disease. Currently there are no guidelines about the management of patients with tumor-positive INs.We enrolled all patients affected by melanoma who underwent sentinel lymph node biopsy (SLNB) in a single institution. All patients with tumor-positive IN underwent the lymphadenectomy of the subsequent draining lymphatic field. Prognosis of IN+-patients was compared with subjects with positive SLNB in usual field through Kaplan-Meier and multivariate Cox regression analysis.Overall 596 subjects underwent lymphoscintigraphy and one or more INs were identified in 94 (15.8%) patients. The mean number of sentinel lymph nodes (SNs) identified per patient was significantly higher in patients with INs. Macrometastasis were more common in patients with INs. Matched pair analysis testified a statistically significant better prognosis in patients with positive-INs when compared with patients with positive SNs in usual side with the same demographic and clinical characteristics. These findings were confirmed both in analysis of 10-year recurrence-free period, then in 10-years overall survival analysis.Lymphadenectomy of the lymphatic draining field beyond positive-IN testify has proved to be a safe procedure that may improve prognosis in melanoma patients with tumor-positive INs. The better prognosis of patients with tumor positive INs undergoing lymphadenectomy may be justified by the earlier treatment of lymphatic metastases. Further multicentric comparative studies are needed to evaluate possible impact of this procedure on prognosis of melanoma patients. PMID- 29718858 TI - Efficacy and safety of oral tranexamic acid in total knee arthroplasty: A systematic review and meta-analysis. AB - BACKGROUND: Tranexamic acid (TXA) is an antifibrinolytic drug widely used as a blood-sparing technique in total knee arthroplasty (TKA), and it is usually administrated by intravenous or intraarticular injection. Recently, the oral form of TXA has been applied in TKA patients. However, there is no final consensus regarding the effectiveness and safety of oral TXA. The purpose of this systematic review and meta-analysis of randomized controlled trials (RCTs) was to evaluate the efficacy and safety of oral TXA versus control for blood loss after TKA. METHODS: We searched PubMed, Embase, Medline, Web of Science, and Cochrane Library databases for relevant studies through August 2017. The mean difference (MD) of total blood loss, hemoglobin (Hb) drop, hematocrit (Hct), drain output, and risk difference (RD) of transfusion rate and thromboembolic complications in the TXA and control groups were pooled throughout the study. The outcomes were pooled by Stata 12.0. RESULTS: A total of 5 RCTs (608 patients) were included in this study. All the included studies were randomized and the quality of included studies was relatively high. The pooled results indicated that the oral TXA group had significantly less Hb drop (standardized mean difference [SMD], -0.936; 95% confidence intervals [CI], -1.118,-0.754), Hct drop (SMD, -0.693; 95% CI, -1.113, -0.274), and drain output (SMD, -0.793; 95% CI, -0.959, -0.628) than the control group. No statistically significant differences were found in transfusion rate and the incidence of thromboembolic complications between the 2 groups. Total blood loss could not be evaluated for the insufficient date. CONCLUSIONS: Our meta-analysis suggested that the administration of oral TXA provided significantly better results with respect to Hb drop, Hct drop, and drain output without increasing the transfusion rate and the risk of thromboembolic complications after TKA. Nevertheless, our current study with some limitations such as the small sample size only provided limited quality of evidence, confirmation from further meta-analysis with large-scale, well-designed RCTs is required. PMID- 29718859 TI - The do-not-resuscitate order for terminal cancer patients in mainland China: A retrospective study. AB - With the development of palliative care, a signed do-not-resuscitate (DNR) order has become increasingly popular worldwide. However, there is no legal guarantee of a signed DNR order for patients with cancer in mainland China. This study aimed to estimate the status of DNR order signing before patient death in the cancer center of a large tertiary affiliated teaching hospital in western China. Patient demographics and disease-related characteristics were also analyzed.This was a retrospective chart analysis. We screened all charts from a large-scale tertiary teaching hospital in China for patients who died of cancer from January 2010 to February 2015. Analysis included a total of 365 records. The details of DNR order forms, patient demographics, and disease-related characteristics were recorded.The DNR order signing rate was 80%. Only 2 patients signed the DNR order themselves, while the majority of DNR orders were signed by patients' surrogates. The median time for signing the DNR order was 1 day before the patients' death. Most DNR decisions were made within the last 3 days before death. The time at which DNR orders were signed was related to disease severity and the rate of disease progression.Our findings indicate that signing a DNR order for patients with terminal cancer has become common in mainland China in recent years. Decisions about a DNR order are usually made by patients' surrogates when patients are severely ill. Palliative care in mainland China still needs to be improved. PMID- 29718861 TI - Hepatic metastases from primary extremity leiomyosarcomas: Two case reports. AB - INTRODUCTION: Leiomyosarcoma is a highly malignant soft tissue sarcoma. Most leiomyosarcomas of the extremities metastasize initially to the lungs, with few metastasizing to the liver. Also, it is difficult to diagnose metastases to other regions of the lung during follow-up. CASE PRESENTATION: The first patient was a 51-year-old Japanese woman diagnosed with a leiomyosarcoma of the left distal femur. She underwent chemotherapy, followed by wide tumor excision and reconstruction using frozen autograft with total knee arthroplasty. Eleven months later, a focal lesion was observed in her right liver, despite the absence of lung metastases. Partial hepatic resection was performed, and the hepatic lesion was diagnosed a metastasis of leiomyosarcoma. Two years later, there has been no evidence of local recurrence. The second patient was a 60-year-old Japanese male diagnosed with a leiomyosarcoma of the left thigh. He underwent preoperative chemotherapy followed by wide excision. Three years later, a focal lesion was found in his medial liver, despite the absence of lung metastases. Partial hepatic resection was performed, and the hepatic lesion was diagnosed as a metastasis of leiomyosarcoma. At the latest follow-up, there has been no evidence of local recurrence. CONCLUSIONS: The lung is the most common site of metastases from leiomyosarcomas of the extremeties, because these metastases are hematogenous. Both our patients presented with metastases of the liver, despite the absence of lung metastases. Hepatic metastasis is commonly found in computed tomography (CT) scan. Periodic CT scans of the chest and abdomen are necessary in following-up patients who undergo resection of primary leiomyosarcomas of the extremities. PMID- 29718860 TI - Favorable glycemic response after pancreatoduodenectomy in both patients with pancreatic cancer and patients with non-pancreatic cancer. AB - Diabetes mellitus (DM) is prevalent in patients with pancreatic cancer and tends to improve after tumor resection. However, the glycemic response of non pancreatic cancer patients after surgery has not been examined in detail. We aimed to investigate the changes in glucose metabolism in patients with pancreatic cancer or non-pancreatic cancer after pancreatoduodenectomy (PD).We prospectively enrolled 48 patients with pancreatic cancer and 56 patients with non-pancreatic cancer, who underwent PD. Glucose metabolism was assessed with fasting glucose, glycated hemoglobin (HbA1c), plasma C-peptide and insulin, quantitative insulin check index (QUICKI), and a homeostatic model assessment of insulin resistance (HOMA-IR) and beta cell (HOMA-beta) before surgery and 6 months after surgery. Patients were divided into 2 groups: "improved" and "worsened" postoperative glycemic response, according to the changes in HbA1c and anti-diabetic medication. New-onset DM was defined as diagnosis of DM <= 2 years before PD, and cases with DM diagnosis >2 years preceding PD were described as long-standing DM.After PD, insulin resistance (IR), as measured by insulin, HOMA IR and QUICKI, improved significantly, although C-peptide and HOMA-beta decreased. At 6 months after PD, new-onset DM patients showed improved glycemic control in both pancreatic cancer patients (75%) and non-pancreatic cancer patients (63%). Multivariate analysis showed that long-standing DM was a significant predictor for worsening glucose control (odds ratio = 4.01, P = .017).Favorable glycemic control was frequently observed in both pancreatic cancer and non-pancreatic cancer after PD. PD seems to contribute improved glucose control through the decreased IR. New-onset DM showed better glycemic control than long-standing DM. PMID- 29718862 TI - High red cell distribution width at the time of ST segment elevation myocardial infarction is better at predicting diastolic than systolic left ventricular dysfunction: A single-center prospective cohort study. AB - Multiple studies have demonstrated the association of red cell distribution width (RDW) with the ultrasound parameters of both systolic and diastolic heart dysfunction. We aimed to further investigate the clinical associations of RDW in the setting of ST-elevation myocardial infarction (STEMI) and to comparatively evaluate its predictive properties regarding systolic and diastolic dysfunction.A total of 89 patients with STEMI were prospectively analyzed. RDW was obtained at the time of STEMI and compared to the parameters of systolic and diastolic dysfunction obtained by transthoracic heart ultrasound on the 5th through 7th day post-STEMI.The median RDW was 13.9%, and among other factors, RDW was significantly associated with older age (P < .001), arterial hypertension (P = .017), hyperlipoproteinemia 2, nonsmoking (P = .027), increased thrombolysis in myocardial infarction score (P = .004), and multivessel disease (P = .007). A higher RDW was observed in patients with parameters that indicated systolic and diastolic dysfunction (ejection fraction of the left ventricle < 50% [P = .009], early/late diastolic filling wave ratio [E/A] < 1 [P = .001], ratio of peak early transmitral velocity and early diastolic annular velocity [E/E'] >10 [P < .001], and combined E/A < 1 and E/E' > 10 [P < .001]). The best discriminatory properties were observed for combined E/A < 1 and E/E' > 10. RDW remained significantly associated with the aforementioned parameters in a series of multivariate regression models.Elevated RDW is significantly associated with the parameters of systolic and diastolic dysfunction even after adjusting for several confounding factors in the setting of STEMI and subsequent percutaneous coronary intervention. RDW seems to be better at discriminating patients with diastolic rather than systolic dysfunction. PMID- 29718863 TI - Endoscopic retrograde cholangiopancreatography in adult patients with biliary atresia: PROCESS-compliant case series. AB - INTRODUCTION: Biliary atresia is a progressive inflammatory disease of the bile duct that eventually results in biliary cirrhosis. It is a rare neonatal disease that mandates treatment within the first 2 years of life in order for the infant to survive. Patients usually undergo palliative Kasai portoenterostomy. Even when Kasai portoenterostomy has been performed in a timely manner, progression is still inevitable. In fact, the majority of patients require curative liver transplantation at a later stage before reaching adulthood. METHODS: Two jaundiced biliary atresia patients who have lived well beyond 20 years with their native liver after undergoing Kasai portoenterostomy and underwent endoscopic retrograde cholangiopancreatography (ERCP) were identified. The data on patients' clinical information, procedures performed, and outcomes were retrospectively collected by chart review. RESULTS: Presence of a long Roux limb and acute angulation from external adhesions along with ductal anomaly from disease itself rendered ERCP challenging, and intraoperative ERCP had to be performed in 1 patient. As enteroscopes had to be used, availability of accessory devices was limited. CONCLUSION: Management of adult biliary atresia patients with biliary obstruction with ERCP is feasible, at times, through multidisciplinary means. PMID- 29718864 TI - A retrospective cohort survey of problems related to second childbirths during the 2-child policy period in Jiangbei District of Ningbo City in China. AB - From 1979 to 2014 in China, a 1-child policy was imposed to control population growth. During 2014 to 2015, families in which 1 spouse was only 1 child were eligible to apply for planning a second child. To foresee issues affecting obstetrical departments related to the introduction of the universal 2-child policy in 2016, we retrospectively investigated the demographics and health related outcomes of second pregnancies in families applying for a second child in Jiangbei District of Ningbo City during January 17, 2014, to January 14, 2016.A retrospective cohort survey was conducted for Jiangbei District of Ningbo City from January 17, 2014, to January 14, 2016, with reference to data from 2012 to 2014.Applications for a second birth increased after implementation of the 2 child policy, from 505 in 2012 to 2013, to 1222 in 2014 to 2015. Until the end of this study (December 31, 2016), 739 women gave birth to a second child, among whom 21.38% were aged >=35 years. Rates of cesarean deliveries (59.68%) and gestational diabetes mellitus (14.21% of women) were each positively associated with the age of the mother. Among women aged >=35 years, 37.97% refused prenatal screening.Introduction of the 1-child policy encouraged more families to apply for a second child, with many women aged >=35 years, leading to higher rates of cesarean deliveries and adverse complications. A high percentage of eligible older women refused prenatal screening. Obstetric departments should adjust perinatal health management schemes to prepare for similar probable changes associated with the universal 2-child policy. PMID- 29718865 TI - Basal ganglion hematoma evacuation and clipping of middle cerebral artery aneurysm by neuroendoscopy: A case report. AB - RATIONALE: Basal ganglia hematomas resulting from the rupture of aneurysms of the distal middle cerebral artery (MCA) are extremely rare and are usually treated by craniotomy. To date, only 5 cases of MCA aneurysm have been treated using neuroendoscopy, and none of these cases involved hematomas. For the first time, we report a special case in which neuroendoscopy was used to evacuate a hematoma and clip an aneurysm at the same time. PATIENT CONCERNS: A massive basal ganglia hematoma in a 60-year-old man was evacuated using neuroendoscopy, and a distal MCA aneurysm was discovered and clipped successfully under the neuroendoscopy during the operation. DIAGNOSIS: Basal ganglia hematoma, Distal MCA aneurysm. OUTCOMES: The patient's left pupil shrunk, and his state of consciousness gradually improved after the operation. LESSONS: Our experience with this patient demonstrates that an aneurysm originating in the distal MCA and accompanied by hematoma may be treated using minimally invasive neuroendoscopy. The fact that cerebral angiography was not performed before or after this patient's first operation indicates that all basal-ganglia hematoma patients, including those with lower risks of cerebrovascular anomalies, should undergo cerebral angiography before and after surgical treatment. PMID- 29718866 TI - Tacrolimus decreases proteinuria in patients with refractory IgA nephropathy. AB - In clinical practice, some IgA nephropathy (IgAN) patients show resistance to or are unable to achieve complete remission using steroids and/or immunosuppressants. The current study aimed to assess the efficacy and safety of tacrolimus in the treatment of cases of refractory IgAN.In this retrospective observational study, 34 primary IgAN patients with refractory proteinuria received tacrolimus for at least 12 months. Complete remission, partial remission, and other clinical data were measured at 1, 3, 6, and 12 months after the initiation of treatment.After 12 months, complete remission was achieved in 20 (58.8%) patients and partial remission in 5 (14.7%) patients, yielding a total response rate of 73.5%. The mean time for response to tacrolimus for those who achieved complete remission and partial remission was 7.0 +/- 4.7 weeks. Serum creatinine (Scr), uric acid, estimated glomerular filtration rate, alanine aminotransferase, aspartate transaminase, white blood cell count, blood pressure, blood glucose, total cholesterol, and total triglyceride were stable over time. Three patients demonstrated a loss of eGFR >15 mL/min.1.73 m from baseline. Three cases of upper respiratory infection and 2 cases of urinary tract infection were observed during the study. Patients who achieved complete remission had better renal function and lower baseline proteinuria than partial remission and nonresponder patients. Crescent formation in biopsy specimens was seen more often in nonresponder patients.Tacrolimus was safe and effective at lowering proteinuria in refractory IgAN patients. Lower baseline proteinuria and better renal function were associated with a higher probability of complete remission, while crescent formation was associated with a worse prognosis. PMID- 29718867 TI - Arsenic trioxide combined with transarterial chemoembolization for unresectable primary hepatic carcinoma: A systematic review and meta-analysis. AB - BACKGROUND: Primary hepatic carcinoma (PHC) is the third commonest leading to cancer death around the world, and transarterial chemoembolization (TACE) has been proposed as the first-line therapeutic treatment for patients with unresectable PHC. This study aims to determine whether the combination of As2O3 and TACE is superior to alone TACE for achieving more clinical therapeutic efficacy, survival time, life quality and safety in patients with unresectable PHC. METHODS: A comprehensive literature search was conducted on the clinical controlled trials comparing therapeutic effects of As2O3 & TACE versus alone TACE for unresectable PHC through English databases (including PubMed, Embase, and the Cochrane Library) and Chinese databases (including China Knowledge Resource Integrated Database, Wanfang Database, Weipu Database, and Chinese Biomedical Database). The last search was in 30 August 2017. A recursive search was performed with bibliographies of relevant studies. There were no language restrictions. Primary outcomes, defined a priori, were therapeutic responses (clinical effective rate and clinical benefit rate), survival time, life quality, and adverse events of As2O3 & TACE compared with alone TACE expressed as relative risk (RR) with 95% confidence intervals (CI). RESULTS: 25 clinical controlled trials involving 1886 participants were included. We found that there were significant superiority associated with As2O3 & TACE compared with alone TACE in clinical benefit rate (RR: 1.24, 95% CI: 1.12-1.37), clinical effective rate (RR: 1.35, 95% CI: 1.17-1.55), 2-year survival rate (RR: 1.45, 95% CI: 1.20-1.75), and improving of KPS (RR: 1.31, 95% CI: 1.14-1.50). These associations were also observed in subgroups by intervened methods of As2O3 and pulmonary metastasis. Notably, the pooled relative risk of retention of sodium and water was obviously raised in patients with As2O3 & TACE therapy (RR: 16.616, 95% CI: 8.01 - 34.486). CONCLUSION: The superiority of adjuvant As2O3 therapy combined with TACE in PHC individuals will outweigh alone TACE therapy, especially in PHC populations with pulmonary metastasis. PMID- 29718868 TI - Iodixanol versus iopromide in patients with renal insufficiency undergoing coronary angiography with or without PCI. AB - BACKGROUND: The use of contrast agents during coronary angiography can result in contrast-induced nephropathy (CIN), particularly in patients with renal dysfunction. On the contrary, different contrast agents can induce different degree of changes in cardiac function. The objective of our meta-analysis was to compare the clinical safety of iso-osmolar contrast medium iodixanol to low osmolar contrast medium iopromide in patients with renal insufficiency undergoing coronary angiography with or without percutaneous coronary intervention (PCI). METHODS: We searched Medline, Embase, Cochrane Library, and reference lists to identify randomized controlled trials that compared iodixanol to iopromide with the incidence of CIN as an endpoint in renal impaired patients undergoing coronary angiography. Outcome measures were the incidence of CIN, absolute peak serum creatinine (Scr) increase from baseline and a composite of cardiovascular adverse events. RESULTS: A total of 8 trials with 3532 patients were pooled; 1759 patients received iodixanol and 1773 patients received iopromide. There was no significant difference in the incidence of CIN (summary odds ratio [OR] 0.50, 95% confidence interval [CI] 0.19-1.35, P = .17) and peak Scr increase (mean difference -0.01 mg/dL, 95% CI -0.08 to 0.05, P = .69) when iodixanol was compared with iopromide. But iodixanol was associated with a statistically significant reduction in cardiovascular adverse events when compared with iopromide (OR 0.47, 95% CI 0.30-0.73, P = .0009). CONCLUSIONS: Analysis of pooled data from 8 randomized controlled trials of iodixanol against iopromide in patients with renal insufficiency undergoing coronary angiography with or without PCI showed that iodixanol nonsignificantly reduced the incidence of CIN, but was associated with a significantly reduced risk of cardiovascular adverse events when compared with iopromide. PMID- 29718869 TI - Changes of corneal high-order aberrations after femtosecond laser-assisted in situ keratomileusis. AB - BACKGROUND: Femtosecond laser-assisted in situ keratomileusis (FS-LASIK) has gained widespread popularity as a safe, effective and predictable treatment for correcting myopia and myopic astigmatism.However, complications such as biomechanical changes, structural weakness, dry eye and induction of high-order aberrations (HOAs) have been associated with FS laser excision. The induction of HOAs has been reported to reduce quality of vision, leading to increased glare, halos, starburst and deterioration of contrast function corneal HOAs play a significant role in whole-eye aberration. Thus, it is necessary to investigate the changes of corneal high-order aberrations after FS-LASIK. METHODS: One hundred thirty-four eyes from 68 consecutive patients with myopia or myopic astigmatism were enrolled in this study. Corneal topography and visual acuity were measured preoperatively and at 1, 3, 6, and 12 months after FS-LASIK. Wavefront errors from the whole cornea, anterior cornea, and posterior cornea were measured by Pentacam. RESULTS: Corneal aberrations on the posterior surface were less affected by FS-LASIK compared with those on the anterior surface and the whole cornea. The high-order aberrations (HOAs) on the whole and anterior corneal surfaces increased significantly at 1 month after surgery (P = .000, P = .000), while HOAs on the posterior surface did not significantly change (P = 1.000). The spherical aberration on the whole corneal and anterior corneal surfaces were significantly increased at 1 and 3 months postoperatively (P = .000 and P = .000, respectively), along with the vertical coma on the whole and anterior corneal surfaces at 1 and 3 months (P = .000 and P = .000, respectively). There was no significant difference in horizontal coma or trefoil on the whole, anterior and posterior corneal surfaces after surgery compared with preoperatively (all P = 1.000). CONCLUSION: After FS-LASIK changes in corneal aberration occurred mainly on the anterior surface, which may have a significant effect on visual quality. PMID- 29718870 TI - CTLA-4 methylation regulates the pathogenesis of myasthenia gravis and the expression of related cytokines. AB - BACKGROUND: Myasthenia gravis (MG) is a progressive autoimmune disease that occurs as a result of the failure of neuromuscular transmission and is characterized by muscle weakness. There has been evidence on the correlations between the genetic predisposition of cytotoxic T lymphocyte and the antigen-4 (CTLA-4) and MG. Thus, the present study was conducted to study is designed to examine the effects of CTLA-4 methylation on the pathogenesis of MG and the expressions of related cytokines. METHODS: The CTLA-4 methylation levels in peripheral blood were quantified in 103 samples collected from MG patients and 86 samples from healthy individiuals. The expression of serum-related cytokines as well as the Treg cell ratio were examined so as to define the contributory role of CTLA-4 methylation in MG and to identify the interaction between CTLA-4 methylation and related factors, the expressions of DNA methyltransferase (DNMT)l, DNMT3A and DNMT3B, CTLA-4, AchR-Ab, Titin-Ab, RyR-Ab, IL-2, IL-10, IFN gamma, and TGF-beta, activity of P- acetylcholinesterase (AchE) and E-AchE. RESULTS: The results indicated that the incidence of CTLA-4 methylation was significantly higher in the control group when compared with the MG group, and CTLA-4 methylation was also found to be associated with the thymus status of MG patients. It was also observed from the experiment data that the expressions of DNMTl, DNMT3A, and DNMT3B, along with the expressions of AchR-Ab, Titin-Ab, RyR Ab, IL-2, IL-10, IFN-gamma and TGF-beta, and the activity of P-AchE and E-AchE were all higher in the MG group than in the control group, with a reduction of CTLA-4 expression. Another key finding from this study revealed that methylation interference can lead to the suppression in the expression of AchR-Ab, the activity of E-AchE, the expression of IL-2, IL-10, IFN-gamma, and TGF-beta and the Treg cell ratio in lymphocytes. CONCLUSION: In conclusion, the results obtained from the present study highly indicated that CTLA-4 methylation might play a role in facilitating the occurrence of MG and increasing the expressions of related cytokines through the upregulation of AchR-Ab and E-Ach. PMID- 29718871 TI - Neurological symptoms and spinal cord embolism caused by endoscopic injection sclerotherapy for esophageal varices: A case report and literature review. AB - RATIONALE: Spinal cord embolism is a rare complication of endoscopic injection sclerotherapy (EIS). PATIENT CONCERNS: We report a case of a 56-year-old man who presented neurological symptoms and spinal cord embolism caused by EIS on esophageal varices. Clinical signs and symptoms, laboratory tests, thoracic magnetic resonance imaging (MRI), and related treatment supported its diagnosis. DIAGNOSES:: spinal cord embolism. INTERVENTIONS: We stopped the hemostatic and anti-coagulation treatment, and switched to nerve nutrition, microcirculation, and hormone therapy, along with administering gastric mucosal protective agents. OUTCOMES: The all patient's signs and symptoms and signs of spinal cord embolism were all relieved within 3 months after the clinical treatment. LESSONS: We recommend that neurological symptoms after EIS in patients with esophageal varices should be considered a rare complication. Life-threatening conditions could be avoided by an accurate and timely diagnosis. PMID- 29718872 TI - Anatomical segmentectomy of the pancreatic head along the embryological fusion plane: A case series and a literature review. AB - RATIONALE: Anatomical segmentectomy of the pancreatic head along the embryological fusion plane (EFP) has been used in the treatment of benign, borderline, and low-grade malignancy neoplasms. However, few studies have reported on the outcomes of this procedure. The aim of this study was to retrospectively assess the outcomes of anatomical segmentectomy of the pancreatic head along the EFP. PATIENT CONCERNS: We experienced two patients who underwent anatomical segmentectomy of the pancreatic head along the EFP for the treatment of pancreatic cystadenoma. Case 1 was a 69-year-old man presented with upper abdominal pain that had lasted for 3 months. Case 2 was a 52-year-old man presented with upper abdominal pain that had lasted for 1 week. DIAGNOSIS: Both patients were diagnosed of pancreatic cystadenoma. INTERVENTION: Anatomical segmentectomy of the pancreatic head along the EFP was performed. OUTCOMES: Both patients successfully underwent anatomical segmentectomy of the pancreatic head along the EFP, including ventral segmentectomy and dorsal segmentectomy, and each patient recovered uneventfully. With the inclusion of these 2 cases, there are now a total of 15 cases that have been reported in the literature, including 9 cases of ventral segmentectomy and 6 cases of dorsal segmentectomy. Although pancreatic fistula occurred in 6 of these patients (40%), all of the patients recovered completely without severe complications. LESSONS: These results suggest that anatomical segmentectomy of the pancreatic head along the EFP is a safe and feasible procedure for cases of benign pancreatic disease confined to the dorsal or ventral segment of the pancreas. PMID- 29718873 TI - The imaging features of the meniscal roots on isotropic 3D MRI in young asymptomatic volunteers. AB - BACKGROUND: This study aimed to describe clearly the normal imaging features of the meniscal roots on the magnetic resonance imaging (MRI) with a 3-dimensional (3D) proton density-weighted (PDW) sequence at 3T. METHODS: A total of 60 knees of 31 young asymptomatic volunteers were examined using a 3D MRI. The insertion patterns, constitution patterns, and MR signals of the meniscal roots were recorded. RESULTS: The anterior root of the medial meniscus (ARMM), the anterior root of the lateral meniscus (ARLM), and the posterior root of the medial meniscus (PRMM) had 1 insertion site, whereas the posterior root of the lateral meniscus (PRLM) can be divided into major and minor insertion sites. The ARLM and the PRMM usually consisted of multiple fiber bundles (>=3), whereas the ARMM and the PRLM often consisted of a single fiber bundle. The ARMM and the PRLM usually appeared as hypointense, whereas the ARLM and the PRMM typically exhibited mixed signals. CONCLUSIONS: The meniscal roots can be complex and diverse, and certain characteristics of them were observed on 3D MRI. Understanding the normal imaging features of the meniscal roots is extremely beneficial for further diagnosis of root tears. PMID- 29718874 TI - Diagnosis and treatment of acute phlegmonous gastritis: A case report. AB - RATIONALE: Acute phlegmonous gastritis (PG) is a rare and often fatal condition mainly characterized by severe bacterial infection of the gastric wall. Case reports of PG over the past century average about 1 per year. Early diagnosis and immediate treatment are crucial to achieve positive outcomes. PATIENT CONCERNS: A 47-year-old man was referred to our hospital because of abdominal pain, high fever, and vomiting for 4 days, with aggravation for 24 hours. Physical examination revealed epigastric abdominal pain, rebound pain, and abdominal wall tightness. Abdominal CT showed thickening of the stomach wall with edema and gas. DIAGNOSES: On the basis of symptoms and CT imaging findings, the patient was diagnosed with acute PG. INTERVENTIONS: Antibiotic therapy and operation. OUTCOMES: The patient immediately underwent an operation after conservative treatment using antibiotics proved ineffective. The whole stomach was obviously swollen, and the anterior side and posterior wall of the stomach were nigrescent necrotic. Hence, total gastrectomy was performed followed by reconstruction (roux en-y), and pus that accumulated in the stomach wall was cultured. At postoperative broad-spectrum antibiotic coverage, the patient finally recovered. LESSONS: Acute PG is a rare infection of the gastric wall especially after antibiotic treatment. Given the fast progression of this disease, early recognition and immediate action are crucial to achieve positive outcomes. PMID- 29718875 TI - Marital status and survival in patients with rectal cancer: A population-based STROBE cohort study. AB - To examine the impact of marital status on overall survival (OS) and rectal cancer-specific survival (RCSS) for aged patients.We used the Surveillance, Epidemiology and End Results database to identify aged patients (>65 years) with early stage rectal cancer (RC) (T1-T4, N0, M0) in the United States from 2004 to 2010. Propensity score matching was conducted to avoid potential confounding factors with ratio at 1:1. We used Kaplan-Meier to compare OS and RCSS between the married patients and the unmarried, respectively. We used cox proportion hazard regressions to obtain hazard rates for OS, and proportional subdistribution hazard model was performed to calculate hazard rates for RCSS.Totally, 5196 patients were included. The married (2598 [50%]) aged patients had better crude 5-year overall survival rate (64.2% vs 57.3%, P < .001) and higher crude 5-year cancer-specific survival rate (80% vs 75.9%, P < .001) than the unmarried (2598 (50%)), respectively. In multivariate analyses, married patients had significantly lower overall death than unmarried patients (HR = 0.77, 95% CI = 0.71-0.83, P < .001), while aged married patients had no cancer specific survival benefit versus the unmarried aged patients (HR = 0.92, 95% CI = 0.81-1.04, P = .17).Among old population, married patients with early stage RC had better OS than the unmarried, while current evidence showed that marital status might have no protective effect on cancer-specific survival. PMID- 29718876 TI - Effects of slow breathing rate on heart rate variability and arterial baroreflex sensitivity in essential hypertension. AB - This study is to investigate the effects of slow breathing on heart rate variability (HRV) and arterial baroreflex sensitivity in essential hypertension.We studied 60 patients with essential hypertension and 60 healthy controls. All subjects underwent controlled breathing at 8 and 16 breaths per minute. Electrocardiogram, respiratory, and blood pressure signals were recorded simultaneously. We studied effects of slow breathing on heart rate, blood pressure and respiratory peak, high-frequency (HF) power, low-frequency (LF) power, and LF/HF ratio of HRV with traditional and corrected spectral analysis. Besides, we tested whether slow breathing was capable of modifying baroreflex sensitivity in hypertensive subjects.Slow breathing, compared with 16 breaths per minute, decreased the heart rate and blood pressure (all P < .05), and shifted respiratory peak toward left (P < .05). Compared to 16 breaths/minute, traditional spectral analysis showed increased LF power and LF/HF ratio, decreased HF power of HRV at 8 breaths per minute (P < .05). As breathing rate decreased, corrected spectral analysis showed increased HF power, decreased LF power, LF/HF ratio of HRV (P < .05). Compared to controls, resting baroreflex sensitivity decreased in hypertensive subjects. Slow breathing increased baroreflex sensitivity in hypertensive subjects (from 59.48 +/- 6.39 to 78.93 +/- 5.04 ms/mm Hg, P < .05) and controls (from 88.49 +/- 6.01 to 112.91 +/- 7.29 ms/mm Hg, P < .05).Slow breathing can increase HF power and decrease LF power and LF/HF ratio in essential hypertension. Besides, slow breathing increased baroreflex sensitivity in hypertensive subjects. These demonstrate slow breathing is indeed capable of shifting sympatho-vagal balance toward vagal activities and increasing baroreflex sensitivity, suggesting a safe, therapeutic approach for essential hypertension. PMID- 29718877 TI - Ventricular arrhythmia as an initial sign in acute Kawasaki disease: A case report. AB - RATIONALE: Coronary artery lesion is the most prominent cardiac manifestation in Kawasaki disease. However, few cases of life-threatening cardiac arrhythmia were reported in the acute phase of Kawasaki disease. PATIENT CONCERNS: A 1-year-old girl presented in the hospital with ventricular premature beats and ventricular tachycardia after 2 days of fever. DIAGNOSIS: On the fifth day of fever, the diagnosis of Kawasaki disease was achieved. INTERVENTIONS: Immunoglobulin was administered. OUTCOME: The temperature became normal and ventricular arrhythmia disappeared. LESSONS: This case suggests that Kawasaki disease has various clinical manifestations besides typical features, and it can cause life threatening cardiac arrhythmia in the acute phase with normal coronary artery and normal cardiac function. PMID- 29718878 TI - Fatal familial insomnia presenting with agrypnia excitata and very low atonia index level: A case report and literature review. AB - RATIONALE: Fatal familial insomnia (FFI) is a human prion disease that is characterized by sleep-wake cycle deterioration, loss of slow-wave sleep, and motor overactivation over the daily 24-hour period. PATIENT CONCERNS: Here, we report the case of a 57-year-old man who had an irregular sleep-wake cycle and exhibited frequent movements and vocalizations during sleep. DIAGNOSES: Video polysomnography showed disrupted sleep structure, rapid alternation between sleep stages, and an absence of sleep spindles and slow-wave sleep. Moreover, body movements persisted throughout the entire sleep period, including rapid eye movement (REM) sleep. The atonia index was very low (<0.025) during REM sleep. Genetic testing revealed a prion protein gene mutation at codon 178, and the patient was diagnosed with FFI. INTERVENTIONS: We tried to treat with amantadine, doxycycline, and immunotherapies, but the disease progressed. OUTCOMES: Sleep disturbance is the most frequent and essential symptom of FFI. LESSONS: FFI is difficult to diagnose due to the low sensitivity of diagnostic tools. Diagnoses can be further supported by better knowledge of typical polysomnographic findings. PMID- 29718879 TI - Methamphetamine consumption and life-threatening abdominal complications: A case report. AB - RATIONALE: Methamphetamine (METH) abuse is increasing rapidly all over the world and becoming a significant public health concern in China. However, abdominal complications secondary to METH abuse are usually overlooked. We describe an unusual case of gangrenous cholecystitis and small intestinal ischemia due to METH abuse. PATIENT CONCERNS: In this report, a 44-year-old male patient with abdominal pain and hematochezia has a history of crystal meth abuse. DIAGNOSIS: The patient was diagnosed as septic shock, paralytic ileus, gangrenous cholecystitis, and small intestinal ischemia due to METH abuse based on computed tomography (CT) scan, endoscopy examination, laparotomy, and pathology. INTERVENTIONS: Antishock treatment, broad-spectrum antibiotics, and exploratory laparotomy were given. OUTCOMES: The patient survived. Six months later, he tolerated oral intake and stopped using crystal METH. LESSONS: Visceral ischemia should be considered if an adult patient with a history of METH abuse is accompanied by abdominal pain and hematochezia. PMID- 29718880 TI - Various clinical features of patients with anti-Hu associated paraneoplastic neurological syndromes: An observational study. AB - To describe and analyze the clinical features and prognosis of patients with anti Hu associated paraneoplastic neurological syndromes (PNS).The symptoms, MRI findings, cerebrospinal fluid (CSF) changes, electroencephalogram (EEG) characteristics and prognoses of 9 well-diagnosed anti-Hu associated PNS patients were analyzed.The study enrolled 6 female and 3 male patients. Three patients presented with vertigo and 6 patients exhibited a depressed mood, numbness of the lower limbs, generalized pains, seizures, mental disturbances, and a temporary unilateral hand tremor on initial presentation. Three patients presented with MRI abnormalities localized in the mesial temporal lobe and the thalamus. Abnormal interictal EEG readings were observed in all 5 patients who underwent EEG study. Four patients were found lung cancer (3 during hospitalization, 1 during follow up). Seven patients were treated with immunotherapy and improved in symptoms. Three patients died during follow-up (2 with lung cancer).The clinical manifestation of anti-Hu associated PNS is diverse and multifocal. EEG may be more sensitive than MRI for early diagnosis of PNS. Long-term follow-up for patients with CT-negative anti-Hu associated PNS is necessary. PMID- 29718881 TI - Histologic transformation from adenocarcinoma to both small cell lung cancer and squamous cell carcinoma after treatment with gefitinib: A case report. AB - RATIONALE: In the past decade, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) treatment had been an important therapy for treating advanced EGFR-mutated lung cancer patients. However, a large number of these patients with EGFR-TKIs treatment always acquired resistance to these drugs in one year. The histologic transformation is an important resistance mechanism. PATIENT CONCERNS: Here we reported a 41-year-old man with EGFR-mutated lung adenocarcinoma and he showed histologic transformation to both small-cell lung cancer (SCLC) and squamous cell carcinoma (SCC) after treatment of gefitinib. DIAGNOSES: A case of EGFR-mutated lung cancer. INTERVENTIONS: Medical thoracoscopy examination was performed and the patient was diagnosed as a EGFR mutated lung adenocarcinoma. Then gefitinib was administered orally at a dose of 250 mg daily. The patient received treatment with chemotherapy (etoposide 0.1 g day 2-5 + cis-platinum 30 mg day 2-4) after acquiring resistance to gefitinib. OUTCOMES: The patient died in April 2017 that survived for 32 months from lung cancer was found for the first time. LESSONS: To the best of our knowledge, it is the first case of EGFR-mutated lung adenocarcinoma transforming to both SCLC and SCC which was treated with and responded to gefitinib. PMID- 29718882 TI - Severe hip joint motion restriction in a patient with diffuse idiopathic skeletal hyperostosis: A case report. AB - RATIONALE: Severe limitation of motion (LOM) in the spine occasionally occurs in patients with diffuse idiopathic skeletal hyperostosis (DISH). However, in extraspinal areas, significant LOM has rarely been reported. In this study, we report a patient with DISH who had severe motion restriction within both hip joints. PATIENT CONCERNS: A 57-year-old man presented with a 10-year history of LOM of bilateral hip joints. He had gait difficulty due to shortened stride length induced by LOM. Also, he had mild bilateral hip pain [numeric rating scale (NRS): 2]. DIAGNOSES: Hip joint range of motion was 60.3% of normal. The patient had bridging ossification along the anterolateral borders of 7 contiguous vertebrae (T10 to L4) without the findings of ankylosing spondylitis or degenerative disc disease. In addition, severe hyperostosis was diffusely formed around bilateral hip joints. He was diagnosed with DISH. INTERVENTIONS: No specific treatment was performed for controlling LOM of bilateral hip joints. Meloxicam 15 mg was administered to the patient for the management of mild bilateral hip pain. OUTCOMES: At 2-month follow-up visit, the degree of LOM in the bilateral hip joints was not changed. However, the patient's pain severity was reduced from NRS 2 to 1. LESSONS: We showed that DISH can cause significant motion restriction due to severe hyperostosis in the bilateral hip joints. PMID- 29718883 TI - The American Society of Anesthesiologists score influences on postoperative complications and total hospital charges after laparoscopic colorectal cancer surgery. AB - The aim of this study was to investigate the influence of American Society of Anesthesiologists (ASA) scores on postoperative complication rates and total hospital charges following laparoscopic surgery for colorectal cancer.All patients (n = 664) underwent laparoscopic colorectal cancer surgery. A group of patients with an ASA score of 1 or 2 (n = 575) and a group of patients with an ASA score of 3 (n = 89) were compared.The mean age was higher in the group of patients with an ASA score of 3 than in the group of patients with an ASA score of 1 or 2 (70 vs 67 years). The rate of ICU admission (27% vs 15%) was higher in the ASA score 3 group. The mean hospital stay (14 vs 12 days) was longer in the ASA score 3 group. Postoperative 30-day complications (38% vs 27%), 30-day mortality (2% vs 0%), and a Clavien-Dindo classification of >=3 (21% vs 11%) occurred more frequently in the ASA score 3 group. Mean total hospital charges were significantly higher in the ASA score 3 group (13,906 vs 11,575 USD). Independent risk factors that affected postoperative complications were older age [>=80 years, hazard ratio (HR) = 2.8], an ASA score of 3 (HR = 1.6), and the presence of a primary rectal tumor (HR = 1.6). Postoperative complication rates were 21.9%, 28.5%, and 38.2% in the ASA score 1, 2, and 3 groups, respectively. Total hospital charges were 14,376 USD and 10,877 USD in the groups with and without postoperative complications, respectively. Mean total hospital charges were 10,769 USD, 11,756 USD, and 13,906 USD in the ASA score 1, 2, and 3 groups, respectively.Preoperative ASA scores may be a predictor of postoperative complications and hospital costs when planning laparoscopic surgery for colorectal cancer. PMID- 29718884 TI - Epidural versus intravenous steroids application following percutaneous endoscopic lumbar discectomy. AB - Retrospectively study.The purpose of this study was to compare the effects of intraoperative epidural steroids and single dose intravenous steroids following a percutaneous endoscopic lumbar discectomy (PELD).Inflammatory irritation of dorsal root ganglia or sensory nerve roots may cause postoperative pain. Epidural steroids have been applied after a lumbar discectomy for more than 20 years. Epidural steroid application after a PELD is easier to perform and safer because the operations are under observation of the scope.We retrospectively reviewed the medical records of patients with lumbar intervertebral disc herniation who had undergone transforaminal PELD at our department. There are 60 patients in epidural steroid group, intravenous steroid group, and control group, respectively. Visual analog scores (VAS) and the Oswestry Disability Index (ODI) were collected. Successful pain control is defined as 50% or more reduction in back and leg pain (VAS scores).VAS scores (back and leg) and ODI showed a significant decrease in all groups when comparing pre- and postoperatively. Epidural steroid group had a significant improvement in successful pain control compared with the control group at 2 weeks of follow-up. VAS scores (leg) in the epidural steroid group showed a significant decrease compared with the intravenous steroids group at 1, 3, and 7 days after the surgery, but this difference had no statistical significance at 1, 6, and 12 months of follow-up. All groups did not show a significant difference in ODI at 1, 6, and 12 months follow-up.Epidural application of steroid has a better effect on controlling the postoperative pain of PELD in the short term. The epidural application of steroid did not show a tendency to cause infection. PMID- 29718885 TI - Orofacial signs and dental abnormalities in patients with Mulvihill-Smith syndrome: A literature review on this rare progeroid pathology. AB - BACKGROUND: Mulvihill-Smith syndrome is a rare sporadic condition that was first recognized in 1975. A total of 11 cases have been described in the literature. The aim of this study was to describe the orofacial signs and dental anomalies, their frequency, and the relationship between Mulvihill-Smith syndrome and other progeroid syndromes via a review of the literature. METHODS: A systematic PubMed search was performed to retrieve articles published between 1975 and the present day that described patients affected by Mulvihill-Smith syndrome. The search identified 14 articles, and data on 11 patients were extracted from the selected articles. RESULTS: A total of 7 patients (63.6%) affected by Mulvihill-Smith syndrome were described as having a typical "bird" face. Dental abnormalities, including irregular shape, enamel defects, hypodontia, and taurodontism, were described in 6 patients (54.5%). All patients (100%) had multiple pigmented nevi on the face and a lack or thinning of subcutaneous tissue around the neck and face. Three patients with Mulvihill-Smith syndrome exhibited early onset of tumors of the gastrointestinal tract, including the tongue. CONCLUSION: Mulvihill Smith syndrome is a clinically complex disease that may be caused by a single gene mutation. Numerous different tissues of the body are affected. This analysis of the orofacial signs may help clinicians to diagnose this rare pathology. PMID- 29718886 TI - Staging resection of multiple primary esophageal cancer by endoscopic submucosal dissection and esophagectomy: A case report. AB - RATIONALE: Multiple primary esophageal cancer pose great risks to patients and are always challenging to resect surgically. In order to reduce the risk of postoperative complication and meet the needs of minimally invasive and precision medicine, new treatment plans have been always developed for patients with multiple primary esophageal cancer. PATIENT CONCERNS: A 75-year-old man was admitted to our hospital for aggravated dysphagia. No significant abnormalities were identified on physical examination. DIAGNOSES: Endoscopic examination detected 3 masses in the esophagus and biopsy confirmed multiple primary esophageal cancer. INTERVENTION: The patient received a new staging treatment procedure firstly and an innovative single-position, minimally invasive Ivor Lewis esophagectomy in our hospital. OUTCOMES: This patient discharged one week after the surgery and enjoyed a good health during our follow up for 30 month. LESSONS: We believe our procedure provides a beneficial new alternative approach for patients with multiple primary esophageal cancer. PMID- 29718887 TI - Mode of initiation and clinical significance of malignant rapid ventricular arrhythmias: An observational study. AB - The purpose of this study was to explore the modes of initiation and clinical significance of malignant rapid ventricular arrhythmias (MRVAs).The surface 12 lead electrocardiogram (ECG) or sustained electrocardiomonitor graph was analyzed in 79 patients. All patients had at least 1 MRVA after being admitted to the hospital.According to the length of coupling interval of the initial premature ventricular contraction of MRVA, the modes of initiation of MRVA were divided into the following types: those initiated by premature ventricular contraction with short coupling intervals in patients with normal Q-T interval, and for which short-long-short sequences before MRVA precipitation were not observed; those initiated following short-long-short sequences, which were divided into 2 types according to the length of Q-T interval: a normal Q-T interval and a long Q-T interval. On the basis of the different modes of onset, treatments of MRVA were different.MRVAs have different modes of onset depending on the patients' underlying condition. Prompt recognition of the mode of onset is necessary to facilitate appropriate management. These findings could have important pathophysiologic and clinical implications. PMID- 29718888 TI - Placental transmogrification of the lung presenting as a peripheral solitary nodule in a male with the history of trauma: A case report. AB - RATIONALE: Placental transmogrification of the lung is a very rare lesion which was characterized by the presence of papillae resembling placental villi. Its pathogenesis still remains unclear. Some authors think that this lesion is congenital and related to hamartoma, and others advocate it is secondary change after emphysema. So far, the majority of reported cases manifested as bullous lesions, to our knowledge , only two cases presented as a solitary nodule. PATIENT CONCERNS: Herein, we report the third case presenting as a small nodule in a 49-year-old male. Chest computed tomography revealed a nodular shadow measuring 2.6 * 1.2 cm in the right lower lobe of the lung. Histologically, the tumor composed of papillary structures covered by cuboidal pneumocytes and bland clear cells and abundant capillaries in the stroma. DIAGNOSIS: The lesion was diagnosed as a placental transmogrification of the lung. INTERVENTION: The patient then underwent wedge resection in our hospital. OUTCOMES: The postoperative course was uneventful. LESSONS: The patient had a history of traffic accident half a year before the nodule was detected. This prompts placental transmogrification of the lung may at least partially represent a acquired malformation. The present case aims to raise a new suggestion for its possible nature. In our opinion, PT may simply represent a benign morphologic change rather than an independent disease. It may be encountered in both congenital and secondary lesions. PMID- 29718889 TI - Therapeutic benefits of ACTH and levetiracetam in STXBP1 encephalopathy with a de novo mutation: A case report and literature review. AB - RATIONALE: The case report aims to discuss the clinical symptoms and treatment of encephalopathy caused by a novel syntaxin- binding protein 1 (STXBP1) genetic mutation. PATIENT CONCERNS: The patient, a girl, was born at 38+4 weeks of gestation. She had frequent spasm attacks accompanied by obvious psychomotor development retardation since the neonatal period. Genetic screening identified a novel STXBP1 genetic mutation. DIAGNOSES: Early-onset epileptic encephalopathy with STXBP1 mutation. INTERVENTIONS: We adjusted the antiepileptic strategy to oral levetiracetam and topiramate, and intravenous administration of adrenocorticotropic hormone(ACTH) for 2 weeks. Subsequently, prednisone was continued, and gradually reduced and withdrawn over 3 months. OUTCOMES: The treatment was effective with complete control of the epileptic seizures and improvements in the electroencephalogram readings. However, the effects on psychomotor ability were slow and limited. A literature review of STXBP1 mutation cases in which ACTH was administered showed that complete seizure control is observed in 60% of cases, 20% are partially affected, and the remaining 20% show no effect. LESSONS: ACTH and levetiracetam had good therapeutic effects in epilepsy control in this case of de novo STXBP1 mutation. ACTH is an effective drug for early-onset epileptic encephalopathy caused by STXBP1 mutation. However, controlling epilepsy using this therapy does not alter the psychomotor development retardation caused by the STXBP1 mutation. PMID- 29718890 TI - Delayed intracranial subdural empyema following burr hole drainage: Case series and literature review. AB - RATIONALE: A subdural empyema (SDE) following burr hole drainage of a chronic subdural hematoma (CSDH) can be difficult to distinguish from a recurrence of the CSDH, especially when imaging data is limited to a computed tomography (CT) scan. PATIENTS CONCERNS: All patients underwent burr hole drainage of the CSDH at first, and the appearance of the SDE occurred within one month. DIAGNOSES: A contrast-enhanced magnetic resonance imaging (MRI) scan, with diffusion-weighted imaging (DWI), revealed both the SDE and diffuse meningitis in all patients. INTERVENTIONS: In Case 1, because the patient was very young, burr hole drainage of the SDE, rather than craniotomy, was performed. However, subsequent craniotomy was required due to recurrence of the SDE. In Cases 2 and 3, an initial craniotomy was performed without burr hole drainage. OUTCOMES: Symptoms improved for all patients, and each was discharged without any neurologic deficits or subsequent recurrence. LESSONS: Neurosurgeons should consider the possibility of infection if recurrence of CSDH occurs within 1 month following drainage of a subdural hematoma. A contrast-enhanced MRI with DWI should be performed to differentiate SDE from CSDH. In addition, surgical evacuation of the empyema via wide craniotomy is preferred to burr hole drainage. PMID- 29718891 TI - Risk factors associated with nonsteroidal anti-inflammatory drugs (NSAIDs) induced gastrointestinal bleeding resulting on people over 60 years old in Beijing. AB - Gastrointestinal (GI) bleeding is an unwanted side effect common to all chemical types of nonsteroidal anti-inflammatory drugs (NSAIDs), particularly in elderly people. However, the risk factors of GI bleeding associated with NSAIDs for elderly people remain unknown. This study aims to evaluate the risks of GI bleeding associated with NSAIDs in 4728 elderly people over 60 years old based on database from a hospital in Beijing.This retrospective hospital-based study included 4728 patients over 60 years old prescribed with NSAIDs, of which 928 patients had GI bleeding and 3800 did not have. Odds ratios (OR) for the risk of GI bleeding associated with NSAIDs were determined by logistic regression analysis. Mean Decrease Gini (MDG) involved in random forest algorithm was used to rank the associated factors with GI bleeding.In multivariate analysis, family history of GI bleeding (OR, 3.348; P = .000), history of peptic ulcers (OR, 4.068; P = .000), history of cardiovascular and cerebrovascular disease (OR, 1.476; P = .001), diabetes mellitus (OR, 1.408; P = .000), antiplatelet drugs (OR, 3.106; P = .000), Helicobacter pylori infection (OR, 1.312; P = .001), cholesterol level (OR, 0.516; P = .000), upper abdominal discomfort (OR, 3.467; P = .000), anorexia (OR, 2.038; P = .000), and NSAIDs used for 0.5 to 3 months (OR, 0.780; P = .000) were associated with GI bleeding. After ranked the MDG of each factor, the top 5 ranked factors associated with GI bleeding were melena, hematemesis, antiplatelet drugs, cholesterol level, and upper abdominal discomfort.We found that family history of GI bleeding, history of peptic ulcers, history of cardiovascular and cerebrovascular disease, diabetes mellitus, antiplatelet drugs, Helicobacter pylori infection, hypocholesterolemia, and NSAIDs used for 0.5 to 3 months were independent risk factors for GI bleeding on people over 60 years old. Meanwhile, upper abdominal discomfort might be the predictor of GI bleeding associated with NSAIDs elderly users. PMID- 29718893 TI - Long-term effectiveness of the diabetes conversation map program: A prepost education intervention study among type 2 diabetic patients in Taiwan: Erratum. PMID- 29718892 TI - Clinical application of oral meglumine diatrizoate esophagogram in screening esophageal fistula during radiotherapy for esophageal cancer. AB - INTRODUCTION: Esophageal fistula is a serious and common complication of radiotherapy for esophageal cancer. Therefore, early diagnosis and treatment is necessary. Because of side effect of barium esophagography, it cannot be used to screening esophageal fistula during radiotherapy. Meglumine diatrizoate is an ionic contrast agent, its adverse reactions were rarely seen when it was used in the body cavity. The purpose of this trial is identified the sensitivity and specificity of oral meglumine diatrizoate in an esophagogram for screening esophageal fistula during radiotherapy. METHODS/DESIGN: This trial was a prospective, multicenter, diagnostic clinical trial. A total of 105 patients with esophageal cancer will swallowed meglumine diatrizoate and underwent a radiographic examination weekly during radiotherapy, medical personnel observed the esophageal lesions to determine whether an esophageal fistula formed. If an esophageal fistula was observed, esophagofiberoscopy and/or computer tomography was used to further confirm the diagnosis. And the sensitivity and specificity of meglumine diatrizoate should be calculated for screening esophageal fistula during radiotherapy. DISCUSSION: To our knowledge, this study protocol is the first to identify the sensitivity and specificity of oral meglumine diatrizoate in an esophagogram for screening esophageal fistula during radiotherapy. If oral meglumine diatrizoate can be used to screening esophageal fistula, more patients will benefit from early detection and treatment. PMID- 29718894 TI - Transradial percutaneous coronary intervention for left main bifurcation lesions using 7.5-Fr sheathless guide catheter. AB - Recent studies have shown sheathless guide catheters (GCs) to be safe and effective during complex lesions such as bifurcations, chronic total occlusion (CTO), and/or calcified lesions. We investigated the feasibility and safety of using 7.5-Fr sheathless GC for transradial percutaneous coronary intervention (PCI) to treat left main bifurcation lesions.A total of 82 patients were consecutively enrolled from March 2013 to February 2016. They underwent transradial PCI for left main bifurcation lesions using the 7.5-Fr sheathless GC.The mean syntax score was 28.1 +/- 6.1, and the majority (n = 55, 67.1%) was intermediate scores (23~32). The unprotected LM disease was present in 67 of 82 patients (81.7%), and true bifurcation (Medina 1, 1, 1) was present in 46 of 82 patients (56.1%). The 2-stent technique was used in 62 of 82 patients (75.6%). The 2-stent technique included 31 cases (37.8%) of "Crush," 18 cases (22.0%) of "Cullote," and 13 (15.8%) cases of "T stent and modified T stent" (T stent). Immediate angiographic success rate was 100% (82/82), and procedural success rate was 97.6% (80/82). The vascular complications occurred in 3 patients (3/82, 3.7%).The use of 7.5-Fr sheathless GC is safe and allows PCI for complex bifurcation lesions located in the distal of left main to be performed transradially with a high success rate. PMID- 29718895 TI - Long-term outcomes of patients with breast cancer after nipple-sparing mastectomy/skin-sparing mastectomy followed by immediate transverse rectus abdominis musculocutaneous flap reconstruction: Comparison with conventional mastectomy in a single center study. AB - To evaluate the oncological outcomes of patients with breast cancer after nipple sparing mastectomy (NSM)/skin-sparing mastectomy (SSM), followed by immediate reconstruction, as compared to conventional mastectomy (CM).SSM/NSM has been increasingly used to treat women with breast cancer who wish to preserve the overlying breast skin, but concern exist regarding its oncological safety due to the potential for residual breast tissue. We report our experience performing SSM/NSM for breast cancer treatment compared to CM with a long follow-up period.All consecutive patients who underwent mastectomy for breast cancer at Asan Medical Center between January 1993 and December 2008 were identified by retrospective medical chart review. The patients who underwent NSM/SSM, followed by immediate breast reconstruction with a pedicled transverse rectus abdominis musculocutaneous flap (TRAM), were compared to the patients who underwent CM in terms of breast-cancer specific survival (BCSS) rate, distant metastasis-free survival (DMFS) rate, and local recurrence (LR) rate.During the study period, 6028 patients underwent mastectomy for breast cancer. Of these, 1032 and 4996 underwent NSM/SSM with TRAM and CM, respectively. Their median follow-up durations were 94.4 (range, 8.1-220.2) and 110.8 (range, 6.1-262.0) months, respectively. Their 5 year BCSS rates were 95.4% and 88.1%, respectively (log rank, P < .001). Their 5 year DMFS rates were 93.0% and 85.6%, respectively (log rank, P < .001).Relative to CM, NSM/SSM, followed by immediate breast reconstruction, may be a viable and oncologically safe surgical treatment in selected patients with breast cancer. PMID- 29718896 TI - Salmonella potsdam causing lumbar vertebral osteomyelitis: A case report. AB - RATIONALE: Salmonella osteomyelitis is an uncommon complication of salmonella infection, especially the salmonella vertebral osteomyelitis (SVO). PATIENT CONCERNS: We reported a case of a 29-year-old female who presented with serious lower back pain and severe limitation of motion for 50 days with no obvious inducements. She once had a fever up to 39.5 degrees C. Physical examination only revealed limited motion of lower back without neurological complications. The laboratory results revealed no specificity. MRI of the lumbar spine revealed a spondylodiscitis at L4-L5. She underwent anterior lateral approach debridement and percutaneous posterior instrumentation. DIAGNOSES: Tissue and abscess culture grew showed Salmonella Potsdam infection. INTERVENTIONS: With susceptibility testing guidance, the patient was treated with intravenous levofloxacin and ceftazidime for a period of 3 weeks and another 3-week oral antibiotics therapy. OUTCOMES: The patient recovered well with no neurological deficits during the follow-up time. LESSONS: SVO is really rare and it alerts us the importance to consider uncommon pathogens in the differential diagnosis in which the etiological evidences are crucial of healthy individuals. PMID- 29718897 TI - Optimal nonvitamin K antagonist oral anticoagulant therapy in a warfarin sensitive patient after left atrial appendage closure: A case report. AB - RATIONALE: Developing an optimal medication strategy poses a challenging task in fragile patients after left atrial appendage closure (LAAC). We report an optimal nonvitamin K antagonist oral anticoagulant (NOAC) therapy in a warfarin-sensitive patient after LAAC. PATIENT CONCERNS: A 77-year-old nonvalvular atrial fibrillation (NVAF) male carrying 2 warfarin-sensitive alleles experienced 2 gum bleeding with the international normalized ratio (INR) around 3. DIAGNOSES: Persistent NVAF with a history of subtotal gastrectomy and moderate renal insufficiency. INTERVENTIONS: Warfarin was discontinued and vitamin K1 was immediately administrated via intravenous infusion. LAAC was regarded as a preferable option, and rivaroxaban 15 mg daily was managed after LACC. OUTCOMES: Complete endothelialization on the surface of device was detected via transoesophageal echocardiography (TEE), and no peridevice spillage and adverse event occurred. LESSONS: A post-LAAC treatment with NOAC may be a viable regimen in patients intolerant to warfarin. PMID- 29718899 TI - Identification of Normal Blood Pressure in Different Age Group: Erratum. PMID- 29718898 TI - A novel technique of using a miniature plate in combination with tension band wiring to treat comminuted patellar fractures: Erratum. PMID- 29718900 TI - Comparison of mid-term efficacy of spastic flatfoot in ambulant children with cerebral palsy by 2 different methods: Erratum. PMID- 29718901 TI - The effects of an educational program on depression literacy and stigma among students of secondary schools in Jazan city, 2016: A cluster-randomized controlled trial study protocol. AB - BACKGROUND: Depression is a serious mental health disorder and characterized by sadness, loss of interest in activities, and decreased energy. The aim of this study is to assess the effectiveness of the school intervention program on depression literacy and stigma among students of secondary schools. DESIGN AND METHODS: A cluster randomized trial will be conducted on sample of 360 students to assess the depression literacy and stigma towards depression before and after a designed intervention educational program. The intervention consists of a package of 2 lectures, 1 video contact, and group discussion of 5 myths about depression, posters, and brochure. The target population consists of all secondary school students in Jazan, where there are 13 secondary schools will be stratified according to sex (6 schools for boys and 7 schools for girls). EXPECTED IMPACT FOR PUBLIC HEALTH: The results of the study will provide evidence of the efficacy of educational intervention programs on increasing depression literacy among students of secondary schools in Jazan City. The expected outcome of this study is to increase the depression literacy rate among high school students in the intervention group. PMID- 29718902 TI - Bovine Acellular Dermal Matrix for Levator Lengthening in Thyroid-Related Upper Eyelid Retraction. AB - BACKGROUND Eyelid retraction is the most common and often the first sign of thyroid eye disease (TED). Upper-eyelid retraction causes both functional and cosmetic problems. In order to correct the position of the upper eyelid, surgery is required. Many procedures have demonstrated good outcomes in mild and moderate cases; however, unpredictable results have been obtained in severe cases. Dryden introduced an upper-eyelid-lengthening procedure, which used scleral grafts, but outcomes were unsatisfactory. A new technique is introduced in this study as a reasonable alternative for TED-related severe upper-eyelid retraction correction. MATERIAL AND METHODS An innovative technique for levator lengthening using bovine acellular dermal matrix as a spacer graft is introduced for severe upper-eyelid retraction secondary to TED. Additionally, 2 modifications were introduced: the fibrous cords scattered on the surface of the levator aponeurosis were excised and the orbital fat pad anterior to the aponeurosis was dissected and sutured into the skin closure in a "skin-tarsus-fat-skin" fashion. RESULTS The modified levator-lengthening surgery was performed on 32 eyelids in 26 patients consisting of 21 women and 5 men (mean age, 37.8 years; age range, 19-67 years). After corrective surgery, the average upper margin reflex distance was lowered from 7.7+/-0.85 mm to 3.3+/-0.43 mm. Eighteen cases (69%) had perfect results, while 6 cases (23%) had acceptable results. CONCLUSIONS A modified levator-lengthening procedure using bovine acellular dermal matrix as a spacer graft ameliorated both the symptoms and signs of severe upper-eyelid retraction secondary to TED. This procedure is a reasonable alternative for correction of TED-related severe upper eyelid retraction. PMID- 29718903 TI - Patients' costs, socio-economic and health system aspects associated with malaria in pregnancy in an endemic area of Colombia. AB - Malaria in pregnancy threatens birth outcomes and the health of women and their newborns. This is also the case in low transmission areas, such as Colombia, where Plasmodium vivax is the dominant parasite species. Within the Colombian health system, which underwent major reforms in the 90s, malaria treatment is provided free of charge to patients. However, patients still incur costs, such as transportation and value of time lost due to the disease. We estimated such costs among 40 pregnant women with clinical malaria (30% Plasmodium falciparum, 70% Plasmodium vivax) in the municipality of Tierralta, Northern Colombia. In a cross sectional study, women were interviewed after an outpatient or inpatient laboratory confirmed malaria episode. Women were asked to report all types of cost incurred before (including prevention), during and immediately after the contact with the health facility. Median total cost was over 16US$ for an outpatient visit, rising to nearly 30US$ if other treatments were sought before reaching the health facility. Median total inpatient cost was 26US$ or 54US$ depending on whether costs incurred prior to admission were excluded or included. For both outpatients and inpatients, direct costs were largely due to transportation and indirect costs constituted the largest share of total costs. Estimated costs are likely to represent only one of the constraints that women face when seeking treatment in an area characterized, at the time of the study, by armed conflict, displacement, and high vulnerability of indigenous women, the group at highest risk of malaria. Importantly, the Colombian peace process, which culminated with the cease-fire in August 2016, may have a positive impact on achieving universal access to healthcare in conflict areas. The current study can inform malaria elimination initiatives in Colombia. PMID- 29718904 TI - Association of vitamin D with risk of type 2 diabetes: A Mendelian randomisation study in European and Chinese adults. AB - BACKGROUND: Observational studies have reported that higher plasma 25 hydroxyvitamin D (25[OH]D) concentrations are associated with lower risks of diabetes, but it is unclear if these associations are causal. The aim of this study was to test the relevance of 25(OH)D for type 2 diabetes using genetically instrumented differences in plasma 25(OH)D concentrations. METHODS AND FINDINGS: Data were available on four 25(OH)D single nucleotide polymorphisms (SNPs; n = 82,464), plasma 25(OH)D concentrations (n = 13,565), and cases with diabetes (n = 5,565) in the China Kadoorie Biobank (CKB). The effects on risk of diabetes were assessed by a genetic score using two 25(OH)D synthesis SNPs (DHCR7-rs12785878 and CYP2R1-rs10741657), with and without the addition of SNPs affecting the transport (GC/DBP-rs2282679) and catabolism (CYP24A1-rs6013897) of 25(OH)D. The CKB results were combined in a meta-analysis of 10 studies for the 2 synthesis SNPs (n = 58,312 cases) and 7 studies for all 4 SNPs (n = 32,796 cases). Mean (SD) 25(OH)D concentration was 62 (20) nmol/l in CKB, and the per allele effects of genetic scores on 25(OH)D were 2.87 (SE 0.39) for the synthesis SNPs and 3.54 (SE 0.32) for all SNPs. A 25-nmol/l higher biochemically measured 25(OH)D was associated with a 9% (95% CI: 0%-18%) lower risk of diabetes in CKB. In a meta analysis of all studies, a 25-nmol/l higher genetically instrumented 25(OH)D concentration was associated with a 14% (95% CI: 3%-23%) lower risk of diabetes (p = 0.01) using the 2 synthesis SNPs. An equivalent difference in 25(OH)D using a genetic score with 4 SNPs was not significantly associated with diabetes (odds ratio 8%, 95% CI: -1% to 16%, lower risk, p = 0.07), but had some evidence of pleiotropy. A limitation of the meta-analysis was the access only to study level rather than individual level data. CONCLUSIONS: The concordant risks of diabetes for biochemically measured and genetically instrumented differences in 25(OH)D using synthesis SNPs provide evidence for a causal effect of higher 25(OH)D for prevention of diabetes. PMID- 29718905 TI - Identification of animal behavioral strategies by inverse reinforcement learning. AB - Animals are able to reach a desired state in an environment by controlling various behavioral patterns. Identification of the behavioral strategy used for this control is important for understanding animals' decision-making and is fundamental to dissect information processing done by the nervous system. However, methods for quantifying such behavioral strategies have not been fully established. In this study, we developed an inverse reinforcement-learning (IRL) framework to identify an animal's behavioral strategy from behavioral time-series data. We applied this framework to C. elegans thermotactic behavior; after cultivation at a constant temperature with or without food, fed worms prefer, while starved worms avoid the cultivation temperature on a thermal gradient. Our IRL approach revealed that the fed worms used both the absolute temperature and its temporal derivative and that their behavior involved two strategies: directed migration (DM) and isothermal migration (IM). With DM, worms efficiently reached specific temperatures, which explains their thermotactic behavior when fed. With IM, worms moved along a constant temperature, which reflects isothermal tracking, well-observed in previous studies. In contrast to fed animals, starved worms escaped the cultivation temperature using only the absolute, but not the temporal derivative of temperature. We also investigated the neural basis underlying these strategies, by applying our method to thermosensory neuron-deficient worms. Thus, our IRL-based approach is useful in identifying animal strategies from behavioral time-series data and could be applied to a wide range of behavioral studies, including decision-making, in other organisms. PMID- 29718906 TI - Explaining the heterogeneity in average costs per HIV/AIDS patient in Nigeria: The role of supply-side and service delivery characteristics. AB - OBJECTIVE: We estimated the average annual cost per patient of ART per facility (unit cost) in Nigeria, described the variation in costs across facilities, and identified factors associated with this variation. METHODS: We used facility level data of 80 facilities in Nigeria, collected between December 2014 and May 2015. We estimated unit costs at each facility as the ratio of total costs (the sum of costs of staff, recurrent inputs and services, capital, training, laboratory tests, and antiretroviral and TB treatment drugs) divided by the annual number of patients. We applied linear regressions to estimate factors associated with ART cost per patient. RESULTS: The unit ART cost in Nigeria was $157 USD nationally and the facility-level mean was $231 USD. The study found a wide variability in unit costs across facilities. Variations in costs were explained by number of patients, level of care, task shifting (shifting tasks from doctors to less specialized staff, mainly nurses, to provide ART) and provider's competence. The study illuminated the potentially important role that management practices can play in improving the efficiency of ART services. CONCLUSIONS: Our study identifies characteristics of services associated with the most efficient implementation of ART services in Nigeria. These results will help design efficient program scale-up to deliver comprehensive HIV services in Nigeria by distinguishing features linked to lower unit costs. PMID- 29718907 TI - Emission characteristics of harmful air pollutants from cremators in Beijing, China. AB - The process of corpse cremation generates numerous harmful air pollutants, including particulate matter (PM), sulfur dioxide (SO2), nitrogen oxides (NOx), volatile organic compounds (VOCs), and heavy metals. These pollutants could have severe effects on the surrounding environment and human health. Currently, the awareness of the emission levels of harmful air pollutants from cremators and their emission characteristics is insufficient. In this study, we obtained the emission characteristics of flue gas from cremators in Beijing and determined the localized emission factors and emission levels of harmful air pollutants based on actual monitoring data from nine typical cremators. The results show that the emissions of air pollutants from the cremators that directly discharge flue gas exceed the emission standards of China and Beijing. The installation of a flue gas post-treatment system could effectively reduce gaseous pollutants and the emission levels of PM. After being equipped with a flue gas post-treatment system, the emission concentrations of PM10, PM2.5, CO, SO2 and VOCs from the cremators are reduced by 97.6, 99.2, 19.6, 85.2 and 70.7%, respectively. Moreover, the emission factors of TSP, PM10, PM2.5, CO, SO2 and VOCs are also reduced to 12.5, 9.3, 3.0, 164.1, 8.8 and 19.8 g/body. Although the emission concentration of VOCs from the cremators is not high, they are one of major sources of "odor" in the crematories and demand more attention. Benzene, a chemical that can seriously harm human health, constitutes the largest proportion (~50%) of the chemical components of VOCs in the flue gas from the cremators. PMID- 29718908 TI - Indirect questioning method reveals hidden support for female genital cutting in South Central Ethiopia. AB - Female genital cutting (FGC) has major implications for women's physical, sexual and psychological health, and eliminating the practice is a key target for public health policy-makers. To date one of the main barriers to achieving this has been an inability to infer privately-held views on FGC within communities where it is prevalent. As a sensitive (and often illegal) topic, people are anticipated to hide their true support for the practice when questioned directly. Here we use an indirect questioning method (unmatched count technique) to identify hidden support for FGC in a rural South Central Ethiopian community where the practice is common, but thought to be in decline. Employing a socio-demographic household survey of 1620 Arsi Oromo adults, which incorporated both direct and indirect direct response (unmatched count) techniques we compare directly-stated versus privately-held views in support of FGC, and individual variation in responses by age, gender and education and target female (daughters versus daughters-in-law). Both genders express low support for FGC when questioned directly, while indirect methods reveal substantially higher acceptance (of cutting both daughters and daughters-in-law). Educated adults (those who have attended school) are privately more supportive of the practice than they are prepared to admit openly to an interviewer, indicating that education may heighten secrecy rather than decrease support for FGC. Older individuals hold the strongest views in favour of FGC (particularly educated older males), but they are also more inclined to conceal their support for FGC when questioned directly. As these elders represent the most influential members of society, their hidden support for FGC may constitute a pivotal barrier to eliminating the practice in this community. Our results demonstrate the great potential for indirect questioning methods to advance knowledge and inform policy on culturally-sensitive topics like FGC; providing more reliable data and improving understanding of the "true" drivers of FGC. PMID- 29718910 TI - BRCA1 and BRCA2 tumor suppressors in neural crest cells are essential for craniofacial bone development. AB - Craniofacial abnormalities, including facial skeletal defects, comprise approximately one-third of all birth defects in humans. Since most bones in the face derive from cranial neural crest cells (CNCCs), which are multipotent stem cells, craniofacial bone disorders are largely attributed to defects in CNCCs. However, it remains unclear how the niche of CNCCs is coordinated by multiple gene regulatory networks essential for craniofacial bone development. Here we report that tumor suppressors breast cancer 1 (BRCA1) and breast cancer 2 (BRCA2) are required for craniofacial bone development in mice. Disruption of Brca1 in CNCC-derived mesenchymal cells, but not in epithelial-derived cells, resulted in craniofacial skeletal defects. Whereas osteogenic differentiation was normal, both osteogenic proliferation and survival were severely attenuated in Brca1 mutants. Brca1-deficient craniofacial skeletogenic precursors displayed increased DNA damage and enhanced cell apoptosis. Importantly, the craniofacial skeletal defects were sufficiently rescued by superimposing p53 null alleles in a neural crest-specific manner in vivo, indicating that BRCA1 deficiency induced DNA damage, cell apoptosis, and that the pathogenesis of craniofacial bone defects can be compensated by inactivation of p53. Mice lacking Brca2 in CNCCs, but not in epithelial-derived cells, also displayed abnormalities resembling the craniofacial skeletal malformations observed in Brca1 mutants. Our data shed light on the importance of BRCA1/BRCA2 function in CNCCs during craniofacial skeletal formation. PMID- 29718909 TI - Impact of smoking on stroke outcome after endovascular treatment. AB - BACKGROUND: Recent studies suggest a paradoxical association between smoking status and clinical outcome after intravenous thrombolysis (IVT). Little is known about relationship between smoking and stroke outcome after endovascular treatment (EVT). METHODS: We analyzed data of all stroke patients treated with EVT at the tertiary stroke centre of Berne between January 2005 and December 2015. Using uni- and multivariate modeling, we assessed whether smoking was independently associated with excellent clinical outcome (modified Rankin Scale (mRS) 0-1) and mortality at 3 months. In addition, we also measured the occurrence of symptomatic intracranial hemorrhage (sICH) and recanalization. RESULTS: Of 935 patients, 204 (21.8%) were smokers. They were younger (60.5 vs. 70.1 years of age, p<0.001), more often male (60.8% vs. 52.5%, p = 0.036), had less often from hypertension (56.4% vs. 69.6%, p<0.001) and were less often treated with antithrombotics (35.3% vs. 47.7%, p = 0.004) as compared to nonsmokers. In univariate analyses, smokers had higher rates of excellent clinical outcome (39.1% vs. 23.1%, p<0.001) and arterial recanalization (85.6% vs. 79.4%, p = 0.048), whereas mortality was lower (15.6% vs. 25%, p = 0.006) and frequency of sICH similar (4.4% vs. 4.1%, p = 0.86). After correcting for confounders, smoking still independently predicted excellent clinical outcome (OR 1.758, 95% CI 1.206-2.562; p<0.001). CONCLUSION: Smoking in stroke patients may be a predictor of excellent clinical outcome after EVT. However, these data must not be misinterpreted as beneficial effect of smoking due to the observational study design. In view of deleterious effects of cigarette smoking on cardiovascular health, cessation of smoking should still be strongly recommended for stroke prevention. PMID- 29718911 TI - Mental distress and perceived wealth, justice and freedom across eight countries: The invisible power of the macrosystem. AB - Health and well-being have been related to macro-level factors such as income, income inequality or socioeconomic status. With regard to the increasing burden of disease due to mental disorders worldwide, the association between the macrosystem and mental distress should be further explored, too. In this context, the subjective evaluation of the macrosystem might play an important role. In the present exploratory study, we assessed symptoms of depression, anxiety and stress as well as perceived wealth, justice and freedom in population-based surveys in Spain, France, Germany, Poland, Russia, Sweden, the United Kingdom and the United States of America (n ~ 1000 per country). The Swedish sample presented the lowest symptom ratings of depression, anxiety and stress and the highest self-rated health. The results also indicated that the subjective evaluation of the macrosystem matters in respect to mental distress. The complete model, including the control variables country, gender, age and education, and perceived wealth, justice and freedom predicted depression, anxiety and stress symptoms explained 8% of the variance of each symptom cluster. The present results encourage research to consider the macrosystem, and the subjective evaluation of macro level factors, as a relevant component in biopsychosocial models of mental distress. PMID- 29718912 TI - microRNA profiles and functions in mosquitoes. AB - Mosquitoes are incriminated as vectors for many crippling diseases, including malaria, West Nile fever, Dengue fever, and other neglected tropical diseases (NTDs). microRNAs (miRNAs) can interact with multiple target genes to elicit biological functions in the mosquitoes. However, characterization and function of individual miRNAs and their potential targets have not been fully determined to date. We conducted a systematic review of published literature following PRISMA guidelines. We summarize the information about miRNAs in mosquitoes to better understand their metabolism, development, and responses to microorganisms. Depending on the study, we found that miRNAs were dysregulated in a species-, sex , stage-, and tissue/organ-specific manner. Aberrant miRNA expressions were observed in development, metabolism, host-pathogen interactions, and insecticide resistance. Of note, many miRNAs were down-regulated upon pathogen infection. The experimental studies have expanded the identification of miRNA target from the 3' untranslated regions (UTRs) of mRNAs of mosquitoes to the 5' UTRs of mRNAs of the virus. In addition, we discuss current trends in mosquito miRNA research and offer suggestions for future studies. PMID- 29718913 TI - Fine-granularity inference and estimations to network traffic for SDN. AB - An end-to-end network traffic matrix is significantly helpful for network management and for Software Defined Networks (SDN). However, the end-to-end network traffic matrix's inferences and estimations are a challenging problem. Moreover, attaining the traffic matrix in high-speed networks for SDN is a prohibitive challenge. This paper investigates how to estimate and recover the end-to-end network traffic matrix in fine time granularity from the sampled traffic traces, which is a hard inverse problem. Different from previous methods, the fractal interpolation is used to reconstruct the finer-granularity network traffic. Then, the cubic spline interpolation method is used to obtain the smooth reconstruction values. To attain an accurate the end-to-end network traffic in fine time granularity, we perform a weighted-geometric-average process for two interpolation results that are obtained. The simulation results show that our approaches are feasible and effective. PMID- 29718914 TI - Correction: Dengue seroprevalence and force of primary infection in a representative population of urban dwelling Indonesian children. AB - [This corrects the article DOI: 10.1371/journal.pntd.0005621.]. PMID- 29718915 TI - Are Canadian-born Major League Baseball players more likely to bat left-handed? A partial test of the hockey-influence on batting hypothesis. AB - It has been suggested that Canadian-born Major League Baseball (MLB) players are more likely to bat left-handed, possibly owing to the fact that they learn to play ice hockey before baseball, and that there is no clear hand-preference when shooting with a hockey stick; approximately half of all ice hockey players shoot left. We constructed a database on active (i.e., October, 2016) MLB players from four countries/regions based on place of birth (Canada, United States of America [USA], Dominican Republic and South Asia [i.e., Japan, Taiwan and South Korea]), including information on which hand they use to bat and throw. We also extracted information on all Canadian-born MLB players, dating back to 1917. Our results confirm that the proportion of left-handed batters born in Canada is higher when compared to the other countries selected; also, since 1917, the proportion of Canadian MLB players who bat left has been consistently higher than the league average. We also compared the proportion of left-handed batters in Canada with players born in states in the USA grouped into high, average and low based on hockey participation. The proportion of MLB players born in states with a high level of hockey participation were more likely to bat left, although the differences were significant at trend level only (p < .10). Lastly, we found that while Canadians were more likely to bat left-handed, this did not correspond with a greater left-hand dominance, as determined by throwing hand. In conclusion, the present study confirms that Canadian-born MLB players are more likely to bat left handed when compared to American, Dominican Republic and South Asian-born MLB players, providing partial support for the hockey influence on batting hypothesis. PMID- 29718917 TI - Both cetaceans in the Brazilian Amazon show sustained, profound population declines over two decades. AB - Obligate river dolphins occur only in the rivers of Asia and South America, where they are increasingly subject to damaging pressures such as habitat degradation, food competition and entanglement in fishing gear as human populations expand. The Amazon basin hosts two, very different, dolphins-the boto or Amazon river dolphin (Inia geoffrensis) and the smaller tucuxi (Sotalia fluviatilis). Both species have wide geographical ranges and were once considered to be relatively abundant. Their IUCN Red List conservation status of Data Deficient (DD), due to limited information on threats, ecology, population numbers and trends, did not initially cause alarm. However, the development of dolphin hunting to provide fish bait at around the beginning of this millennium broadly coincided with the onset of a widespread perception that numbers of both species were in decline. Consequently, the need for population trend data to inform conservation advice and measures became urgent. This paper presents a 22-year time series of standardised surveys for both dolphins within the Mamiraua Reserve, Amazonas State, Brazil. Analysis of these data show that both species are in steep decline, with their populations halving every 10 years (botos) and 9 years (tucuxis) at current rates. These results are consistent with published, independent information on survival rates of botos in this area, which demonstrated a substantial drop in annual survival, commencing at around the year 2000. Mamiraua is a protected area, and is subject to fewer environmental pressures than elsewhere in the region, so there is no reason to suspect that the decline in dolphins within the Reserve is more pronounced than outside it. If South America's freshwater cetaceans are to avoid following their Asian counterparts on the path to a perilous conservation status, effective conservation measures are required immediately. Enforcement of existing fishery laws would greatly assist in achieving this. PMID- 29718916 TI - Assessing the significance of Palaeolithic engraved cortexes. A case study from the Mousterian site of Kiik-Koba, Crimea. AB - Twenty-Seven Lower and Middle Paleolithic sites from Europe and the Middle East are reported in the literature to have yielded incised stones. At eleven of these sites incisions are present on flint cortexes. Even when it is possible to demonstrate that the engravings are ancient and human made, it is often difficult to distinguish incisions resulting from functional activities such as butchery or use as a cutting board, from those produced deliberately, and even more difficult to identify the scope of the latter. In this paper we present results of the analysis of an engraved cortical flint flake found at Kiik-Koba, a key Mousterian site from Crimea, and create an interpretative framework to guide the interpretation of incised cortexes. The frame of inference that we propose allows for a reasoned evaluation of the actions playing a role in the marking process and aims at narrowing down the interpretation of the evidence. The object comes from layer IV, the same layer in which a Neanderthal child burial was unearthed, which contains a para-Micoquian industry of Kiik-Koba type dated to between c.35 and 37 cal kyr BP. The microscopic analysis and 3D reconstruction of the grooves on the cortex of this small flint flake, demonstrate that the incisions represent a deliberate engraving made by a skilled craftsman, probably with two different points. The lines are nearly perfectly framed into the cortex, testifying of well controlled motions. This is especially the case considering the small size of the object, which makes this a difficult task. The production of the engraving required excellent neuromotor and volitional control, which implies focused attention. Evaluation of the Kiik-Koba evidence in the light of the proposed interpretative framework supports the view that the engraving was made with a representational intent. PMID- 29718918 TI - Hybrid flower pollination algorithm strategies for t-way test suite generation. AB - The application of meta-heuristic algorithms for t-way testing has recently become prevalent. Consequently, many useful meta-heuristic algorithms have been developed on the basis of the implementation of t-way strategies (where t indicates the interaction strength). Mixed results have been reported in the literature to highlight the fact that no single strategy appears to be superior compared with other configurations. The hybridization of two or more algorithms can enhance the overall search capabilities, that is, by compensating the limitation of one algorithm with the strength of others. Thus, hybrid variants of the flower pollination algorithm (FPA) are proposed in the current work. Four hybrid variants of FPA are considered by combining FPA with other algorithmic components. The experimental results demonstrate that FPA hybrids overcome the problems of slow convergence in the original FPA and offers statistically superior performance compared with existing t-way strategies in terms of test suite size. PMID- 29718919 TI - Climate change impacts on marine biodiversity, fisheries and society in the Arabian Gulf. AB - Climate change-reflected in significant environmental changes such as warming, sea level rise, shifts in salinity, oxygen and other ocean conditions-is expected to impact marine organisms and associated fisheries. This study provides an assessment of the potential impacts on, and the vulnerability of, marine biodiversity and fisheries catches in the Arabian Gulf under climate change. To this end, using three separate niche modelling approaches under a 'business-as usual' climate change scenario, we projected the future habitat suitability of the Arabian Gulf (also known as the Persian Gulf) for 55 expert-identified priority species, including charismatic and non-fish species. Second, we conducted a vulnerability assessment of national economies to climate change impacts on fisheries. The modelling outputs suggested a high rate of local extinction (up to 35% of initial species richness) by 2090 relative to 2010. Spatially, projected local extinctions are highest in the southwestern part of the Gulf, off the coast of Saudi Arabia, Qatar and the United Arab Emirates (UAE). While the projected patterns provided useful indicators of potential climate change impacts on the region's diversity, the magnitude of changes in habitat suitability are more uncertain. Fisheries-specific results suggested reduced future catch potential for several countries on the western side of the Gulf, with projections differing only slightly among models. Qatar and the UAE were particularly affected, with more than a 26% drop in future fish catch potential. Integrating changes in catch potential with socio-economic indicators suggested the fisheries of Bahrain and Iran may be most vulnerable to climate change. We discuss limitations of the indicators and the methods used, as well as the implications of our overall findings for conservation and fisheries management policies in the region. PMID- 29718920 TI - Placental cord drainage in the third stage of labor: Randomized clinical trial. AB - METHODS: An open randomized clinical trial was developed at Instituto de Medicina Integral Prof. Fernando Figueira (IMIP) in Recife and at Petronila Campos Municipal Hospital in Sao Lourenco da Mata, both in Pernambuco, northeastern Brazil, including 226 low-risk pregnant women bearing a single, full-term, live fetus after delayed cord clamping, 113 randomized to placental cord drainage and 113 to a control group not submitted to this procedure. Women incapable of understanding the study objectives and those who went on to have an instrumental or cesarean delivery were excluded. RESULTS: Duration of the third stage of labor did not differ between the two groups (14.2+/-12.9 versus 13.7+/-12.1 minutes (mean +/- SD), p = 0.66). Likewise, there was no significant difference in mean blood loss (248+/-254 versus 208+/-187ml, p = 0.39) or in postpartum hematocrit levels (32.3+/-4.06 versus 32.8+/-4.25mg/dl, p = 0.21). Furthermore, no differences were found between the groups for any of the secondary outcomes (postpartum hemorrhage >500 or >1000ml, therapeutic use of oxytocin, third stage >30 or 60 minutes, digital evacuation of the uterus or curettage, symptoms of postpartum anemia and maternal satisfaction). CONCLUSION: Placental cord drainage had no effect in reducing duration or blood loss during the third stage of labor. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov: www.clinicaltrial.gov, NCT01655576. PMID- 29718921 TI - A tale of swinger insects: Signatures of past sexuality between divergent lineages of a parthenogenetic weevil revealed by ribosomal intraindividual variation. AB - Naupactus cervinus (Boheman) (Curculionidae, Naupactini) is a parthenogenetic weevil native to the Paranaense Forest which displays high levels of genetic variation. Two divergent clades were identified, one ranging in forest areas (Forest clade), and the other in open vegetation areas (Grassland clade). Both of them have individuals with high levels of heterozygosity in ribosomal sequences. Investigation of intraindividual variation in ITS1 sequences through cloning and posterior sequencing suggested that mating between both groups most likely occurred in the Paranaense Forest after a secondary contact, which led to fixed heterozygotes as a consequence of parthenogenesis. Otherwise, sexual segregation would have disrupted multilocus genotypes. Only a small number of heterozygous genotypes of all the possible combinations are found in nature. We propose the occurrence of a hybrid zone in the Paranaense Forest. The fact that it is one of the most important biodiversity hotspots of the world, together with its key role for investigating evolutionary processes, makes it worthy of conservation. This is the first genetic evidence of bisexuality in N. cervinus. PMID- 29718922 TI - Chloroplast and nuclear DNA exchanges among Begonia sect. Baryandra species (Begoniaceae) from Palawan Island, Philippines, and descriptions of five new species. AB - The Philippine island of Palawan is highly biodiverse. During fieldwork there in 2011 & 2014 we found five unknown species in the large genus Begonia. The species are similar in their rhizomatous stems, four-tepaled flowers, inferior two- or three-locular ovaries with bilamellate placentas, and are assignable to Begonia sect. Baryandra. Our observations support the recognition of these as five new species endemic to Palawan: B. elnidoensis, B. gironellae, B. quinquealata, B. tabonensis and B. tenuibracteata which are described here. The five new species were added to phylogenies based Bayesian analysis of nrDNA (ITS) and chloroplast DNA (ndhA, ndhF-rpl32, rpl32-trnL, trnC-trnD), along with 45 other allied ingroup species. A majority of the species show incongruent positions in the two phylogenies, with evidence of prevalent chloroplast capture. Models show chloroplast capture is more likely in plant populations with high levels of inbreeding following a reduction in selfing rate after hybridisation; we suggest that this is a possible explanation for the massive amount of chloroplast exchange seen in our phylogeny, as Begonia species often exist as small isolated populations and may be prone to inbreeding depression. Our data also indicate a level of nuclear genetic exchange between species. The high prevalence of hybrid events in Begonia is potentially an important factor in driving genomic change and species evolution in this mega-diverse genus. PMID- 29718923 TI - Sacrificial-layer free transfer of mammalian cells using near infrared femtosecond laser pulses. AB - Laser-induced cell transfer has been developed in recent years for the flexible and gentle printing of cells. Because of the high transfer rates and the superior cell survival rates, this technique has great potential for tissue engineering applications. However, the fact that material from an inorganic sacrificial layer, which is required for laser energy absorption, is usually transferred to the printed target structure, constitutes a major drawback of laser based cell printing. Therefore alternative approaches using deep UV laser sources and protein based acceptor films for energy absorption, have been introduced. Nevertheless, deep UV radiation can introduce DNA double strand breaks, thereby imposing the risk of carcinogenesis. Here we present a method for the laser induced transfer of hydrogels and mammalian cells, which neither requires any sacrificial material for energy absorption, nor the use of UV lasers. Instead, we focus a near infrared femtosecond (fs) laser pulse (lambda = 1030 nm, 450 fs) directly underneath a thin cell layer, suspended on top of a hydrogel reservoir, to induce a rapidly expanding cavitation bubble in the gel, which generates a jet of material, transferring cells and hydrogel from the gel/cell reservoir to an acceptor stage. By controlling laser pulse energy, well-defined cell-laden droplets can be transferred with high spatial resolution. The transferred human (SCP1) and murine (B16F1) cells show high survival rates, and good cell viability. Time laps microscopy reveals unaffected cell behavior including normal cell proliferation. PMID- 29718924 TI - Socioenvironmental factors associated with Schistosoma mansoni infection and intermediate hosts in an urban area of northeastern Brazil. AB - Schistosomiasis, which is caused by trematodes of the genus Schistosoma and by the species Schistosoma mansoni in Brazil, is transmitted primarily by Biomphalaria glabrata mollusks. Infections occur in humans and mollusks in freshwater environments contaminated with feces from infected humans. This study aimed to evaluate potential foci of schistosomiasis based on the identification of infection sites for the snails, factors that increased the human infection probability of S. mansoni infection, and the relationship of the disease with abiotic, biotic, and sociocultural factors. The study was conducted in an urban area on the northeast coast of Brazil; this location was chosen based on the following factors: the presence of B. glabrata, nearby freshwater, and the absence of sewer treatment. A parasitological analysis was performed to evaluate infections of the mollusks and residents inside the perimeter defined by the collection points. Questionnaires were applied to obtain demographic data and to identify behaviors that led to human infection. To verify the contamination of freshwater by human feces, a microbiological analysis of the water was performed at the mollusk collection points to determine the rate of contamination with fecal coliforms. A total of 10,270 B. glabrata mollusks were collected between August 2013 and August 2014, of which 8.8% were positive for S. mansoni; the prevalence ranged from 0 to 34.5% over the study period. A total of 232 coprological samples from the residents were analyzed. The S. mansoni infection prevalence rate was 16.4%, and the S. mansoni parasitic load in the infected residents was 54.9 eggs per gram of feces on average. Males were more affected by the parasite, especially in the 8-17-year-old age range. Thermotolerant coliforms were observed at the mollusk collection sites, which indicated that freshwater and sewage were in continuous contact. This contamination indicated poor sanitary conditions, as was previously observed, which could be combined with detrimental behavior due to the residents' habits. These conditions cause a predisposition for both intermediate and definitive infections of the hosts by creating a socioenvironmental scenario that is conducive to the formation and maintenance of potential schistosomiasis foci. This and similar areas deserve special attention from the government with an aim of improving sanitation services and local resident knowledge to prevent future contamination. PMID- 29718925 TI - Does the death of a child influence parental use of psychotropic medication? A follow-up register study from Finland. AB - BACKGROUND: Several studies have found that the loss of a child is associated with psychiatric health problems, yet few studies examined whether child loss influences psychotropic medication use. This study examined short- and long-term use of psychotropic medication, both before and after the death of a child, and its potential effect modifiers. METHODOLOGY/PRINCIPAL FINDINGS: A random sample of 205,456 parents, including 902 bereaved parents, were selected from a Finnish total population registry. The analyses were based on linear regressions using generalised estimation equations (GEE) and adjusted for sociodemographic factors. Annual psychotropic use was defined as having purchased prescribed psychotropic medication between 1996 and2012. Bereaved parents were followed for four years prior to and up to four years after the death of their child. An increase in the use of antidepressants and anxiolytics was found in parents following their loss. The highest percentage of use was found around one year after bereavement, followed by a steady decrease although this remained higher than the level of use among non-bereaved four years after the death. Between 20-25% of bereaved mothers and 10-15% of bereaved fathers used antidepressants or anxiolytics one year after bereavement while the corresponding number in non-bereaved was 5-10%. An increase in psychotropic medication was also found several years before the disease related loss of a child. CONCLUSIONS/SIGNIFICANCE: The use of psychotropic medication is markedly higher among parents after losing a child. Patterns of use leading up to and following the death of a child should be further examined in relation to clinical risk factors so as to identify at risk populations. MEDICAL SUBJECT HEADINGS: Bereavement, child death, psychotropic medication, death, child, register, Finland. PMID- 29718926 TI - Bioengineered intestinal muscularis complexes with long-term spontaneous and periodic contractions. AB - Although critical for studies of gut motility and intestinal regeneration, the in vitro culture of intestinal muscularis with peristaltic function remains a significant challenge. Periodic contractions of intestinal muscularis result from the coordinated activity of smooth muscle cells (SMC), the enteric nervous system (ENS), and interstitial cells of Cajal (ICC). Reproducing this activity requires the preservation of all these cells in one system. Here we report the first serum free culture methodology that consistently maintains spontaneous and periodic contractions of murine and human intestinal muscularis cells for months. In this system, SMC expressed the mature marker myosin heavy chain, and multipolar/dipolar ICC, uniaxonal/multipolar neurons and glial cells were present. Furthermore, drugs affecting neural signals, ICC or SMC altered the contractions. Combining this method with scaffolds, contracting cell sheets were formed with organized architecture. With the addition of intestinal epithelial cells, this platform enabled up to 11 types of cells from mucosa, muscularis and serosa to coexist and epithelial cells were stretched by the contracting muscularis cells. The method constitutes a powerful tool for mechanistic studies of gut motility disorders and the functional regeneration of the engineered intestine. PMID- 29718927 TI - Predictive saccades in children and adults: A combined fMRI and eye tracking study. AB - Saccades were assessed in 21 adults (age 24 years, SD = 4) and 15 children (age 11 years, SD = 1), using combined functional magnetic resonance imaging (fMRI) and eye-tracking. Subjects visually tracked a point on a horizontal line in four conditions: time and position predictable task (PRED), position predictable (pPRED), time predictable (tPRED) and visually guided saccades (SAC). Both groups in the PRED but not in pPRED, tPRED and SAC produced predictive saccades with latency below 80 ms. In task versus group comparisons, children's showed less efficient learning compared to adults for predictive saccades (adults = 48%, children = 34%, p = 0.05). In adults brain activation was found in the frontal and occipital regions in the PRED, in the intraparietal sulcus in pPRED and in the frontal eye field, posterior intraparietal sulcus and medial regions in the tPRED task. Group-task interaction was found in the supplementary eye field and visual cortex in the PRED task, and the frontal cortex including the right frontal eye field and left frontal pole, in the pPRED condition. These results indicate that, the basic visuomotor circuitry is present in both adults and children, but fine-tuning of the activation according to the task temporal and spatial demand mature late in child development. PMID- 29718928 TI - Enteral resuscitation with oral rehydration solution to reduce acute kidney injury in burn victims: Evidence from a porcine model. AB - Intravenous (IV) resuscitation of burn patients has greatly improved outcomes and become a cornerstone of modern burn care. However, the heavy fluids and vascular access required may not be feasible in austere environments, mass casualty, or delayed transport scenarios. Enteral resuscitation has been proposed for these situations; we sought to examine the effectiveness of this strategy on improving burn-induced kidney injury. Anesthetized Yorkshire swine sustaining 40% TBSA full thickness contact burns were randomized to three groups (n = 6/group): fluid deprivation, ad libitum water access, or 70 mL/kg/d Oral Rehydration Salt solution (ORS). Urine and blood were collected at baseline (BL), 6, 12, 24, 32, and 48h post-burn, at which point tissue was harvested and CT angiography performed. Although fluid consumption by ad libitum and ORS groups were matched (132+/-54mL/kg versus 120+/-24mL/kg, respectively), ORS intake increased urine output compared with water and no water (47.3+/-9.0 mL/kg versus 16.1+/-2.5 mL/kg, and 24.5+/-1.7 mL/kg respectively). Plasma creatinine peaked 6h following burn (1.67+/-0.07mg/dL) in all animals, but at 48h was comparable to BL in animals receiving water (1.23+/-0.06mg/dL) and ORS (1.30+/-0.09mg/dL), but not fluid deprived animals (1.56+/-0.05mg/dL) (P<0.05). Circulating levels of blood urea nitrogen steadily increased, but also decreased by 48h in animals receiving enteral fluids (P<0.05). Water deprivation reduced renal artery diameter (-1.4+/ 0.17mm), whereas resuscitation with water (-0.44+/-0.14 mm) or ORS maintained it (-0.63+/-0.20 mm;P< 0.02). Circulating cytokines IL-1beta, IL-6, IFNgamma, and GM CSF were moderately elevated in the fluid-deprived group. Taken together, the data suggest that enteral resuscitation with ORS rescues kidney function following burn injury. Incorporating enteral fluids may improve outcomes in resource-poor environments and possibly reduce IV fluid requirements to prevent co-morbidities associated with over-resuscitation. Studies into different volumes/types of enteral fluids are warranted. While ORS has saved many lives in cholera-associated dehydration, it should be investigated further for use in burn patients. PMID- 29718929 TI - Use of urinary 13,14, dihydro-15-keto-prostaglandin F2alpha (PGFM) concentrations to diagnose pregnancy and predict parturition in the giant panda (Ailuropoda melanolecua). AB - Pregnancy determination is difficult in the giant panda (Ailuropoda melanolecua), representing a challenge for ex situ conservation efforts. Research in other species experiencing pseudopregnancy indicates that urinary/fecal concentrations of 13,14, dihydro-15-keto-prostaglandin F2alpha (PGFM) can accurately determine pregnancy status. Our objective was to determine if urinary PGFM concentrations are associated with pregnancy status in the giant panda. Urinary PGFM concentrations were measured in female giant pandas (n = 4) throughout gestation (n = 6) and pseudopregnancy (n = 4) using a commercial enzyme immunoassay. Regardless of pregnancy status, PGFM excretion followed a predictable pattern: 1) baseline concentrations for 11-19 weeks following ovulation; 2) a modest, initial peak 14-36 days after the start of the secondary urinary progestagen rise; 3) a subsequent period of relatively low concentrations; and 4) a large, terminal peak at the end of the luteal phase. Pregnant profiles were distinguished by an earlier initial peak (P = 0.024), higher inter-peak concentrations (P < 0.001), and a larger terminal peak (P = 0.003) compared to pseudopregnancy profiles. Parturition occurred 23 to 25 days from the initial PGFM surge and within 24 hours of the start of the terminal increase. These pattern differences indicate that urinary PGFM monitoring can be used to predict pregnancy status and time parturition in the giant panda. Furthermore, this is the only species known to exhibit a significant PGFM increase during pseudopregnancy, suggesting a unique physiological mechanism for regulating the end of the luteal phase in the giant panda. PMID- 29718930 TI - Emergence of highly prevalent CA-MRSA ST93 as an occupational risk in people working on a pig farm in Australia. AB - BACKGROUND: The occurrence of livestock-associated (LA) MRSA (ST398) in pig herds has emerged as a threat to occupational safety in many parts of the world. Recently, an outbreak of skin lesions due to MRSA occurred in workers at a pig farm in regional Australia and both the humans and pigs were shown to have a high prevalence of carriage of either the human-strain ST93 or porcine strain ST398. This study closely scrutinises this outbreak to determine factors associated with MRSA carriage amongst the workers. METHODS: Information on potential risk factors was collected from employees by means of a questionnaire. The carriage status of MRSA by workers was assessed by nasal swabs processed using standard laboratory techniques with confirmed isolates subjected to sequence typing. Associations between MRSA carriage in workers and their questionnaire responses were investigated using univariable and multivariable logistic regression. RESULTS: Nasal carriage of MRSA was identified in 60% (31/52) of participants. Workers having contact with pigs had 24 times the odds of MRSA carriage compared to workers with no direct contact (OR 23.6; CI 5.2-172.8). In addition, the probability of MRSA carriage in workers was significantly (P < 0.001) associated with the number of hours in contact with pigs and each hour of contact-time per day increased the risk of MRSA carriage by 1.44 times (CI 1.14-1.96). These associations were significant (P < 0.001) for both strains, ST398 and ST93, present on this farm. Using a multivariable logistic regression model that incorporated human exposure to five different pig age groups (dry sows, farrowing, weaner, grower, and finisher) as fixed effects, a significant (P = 0.027) increased odds of MRSA carriage was found for persons working with farrowing sows compared with those who did not (OR 6.39, CI 1.23-39.36). CONCLUSIONS: This study shows that workers in close contact with pigs on a pig farm where MRSA is present had a higher risk of MRSA carriage as the number of hours of direct contact with pigs increased. Since we have detected a significant association for the human-derived CA-MRSA ST93, similar to the pig-adapted LA MRSA ST398, we consider ST93 as a potential occupational risk for piggery workers. The risk of MRSA carriage is greatest when working with the farrowing group; therefore, an emphasis is required on personal protective equipment while working in the farrowing house. The study has ramifications for the conduct of surveillance for MRSA in people exposed to pigs. PMID- 29718931 TI - The effect of automated text messaging and goal setting on pedometer adherence and physical activity in patients with diabetes: A randomized controlled trial. AB - INTRODUCTION: Activity-monitoring devices may increase activity, but their effectiveness in sedentary, diseased, and less-motivated populations is unknown. METHODS: Subjects with diabetes or pre-diabetes were given a Fitbit and randomized into three groups: Fitbit only, Fitbit with reminders, and Fitbit with both reminders and goal setting. Subjects in the reminders group were sent text message reminders to wear their Fitbit. The goal-setting group was sent a daily text message asking for a step goal. All subjects had three in-person visits (baseline, 3 and 6 months). We modelled daily steps and goal setting using linear mixed-effects models. RESULTS: 138 subjects participated with 48 in the Fitbit only, 44 in the reminders, and 46 in the goal-setting groups. Daily steps decreased for all groups during the study. Average daily steps were 7123, 6906, and 6854 for the Fitbit-only, the goal-setting, and the reminders groups, respectively. The reminders group was 17.2 percentage points more likely to wear their Fitbit than the Fitbit-only group. Setting a goal was associated with a significant increase of 791 daily steps, but setting more goals did not lead to step increases. CONCLUSION: In a population of patients with diabetes or pre diabetes, individualized reminders to wear their Fitbit and elicit personal step goals did not lead to increases in daily steps, although daily steps were higher on days when goals were set. Our intervention improved engagement and data collection, important goals for activity surveillance. This study demonstrates that new, more-effective interventions for increasing activity in patients with pre-diabetes and diabetes are needed. PMID- 29718932 TI - Cancer growth and metastasis as a metaphor of Go gaming: An Ising model approach. AB - This work aims for modeling and simulating the metastasis of cancer, via the analogy between the cancer process and the board game Go. In the game of Go, black stones that play first could correspond to a metaphor of the birth, growth, and metastasis of cancer. Moreover, playing white stones on the second turn could correspond the inhibition of cancer invasion. Mathematical modeling and algorithmic simulation of Go may therefore benefit the efforts to deploy therapies to surpass cancer illness by providing insight into the cellular growth and expansion over a tissue area. We use the Ising Hamiltonian, that models the energy exchange in interacting particles, for modeling the cancer dynamics. Parameters in the energy function refer the biochemical elements that induce cancer birth, growth, and metastasis; as well as the biochemical immune system process of defense. PMID- 29718933 TI - A20 regulates canonical wnt-signaling through an interaction with RIPK4. AB - A20 is a ubiquitin-editing enzyme that is known to regulate inflammatory signaling and cell death. However, A20 mutations are also frequently found in multiple malignancies suggesting a potential role as a tumor suppressor as well. We recently described a novel role for A20 in regulating the wnt-beta-catenin signaling pathway and suppressing colonic tumor development in mice. The underlying mechanisms for this phenomenon are unclear. To study this, we first generated A20 knockout cell lines by genome-editing techniques. Using these cells, we show that loss of A20 causes dysregulation of wnt-dependent gene expression by RNAseq. Mechanistically, A20 interacts with a proximal signaling component of the wnt-signaling pathway, receptor interacting protein kinase 4 (RIPK4), and regulation of wnt-signaling by A20 occurs through RIPK4. Finally, similar to the mechanism by which A20 regulates other members of the receptor interacting protein kinase family, A20 modifies ubiquitin chains on RIPK4 suggesting a possible molecular mechanism for A20's control over the wnt signaling pathway. PMID- 29718934 TI - R software package based statistical optimization of process components to simultaneously enhance the bacterial growth, laccase production and textile dye decolorization with cytotoxicity study. AB - The thermophilic bacterium, Bacillus licheniformis U1 is used for the optimization of bacterial growth (R1), laccase production (R2) and synthetic disperse blue DBR textile dye decolorization (R3) in the present study. Preliminary optimization has been performed by one variable at time (OVAT) approach using four media components viz., dye concentration, copper sulphate concentration, pH, and inoculum size. Based on OVAT result further statistical optimization of R1, R2 and R3 performed by Box-Behnken design (BBD) using response surface methodology (RSM) in R software with R Commander package. The total 29 experimental runs conducted in the experimental design study towards the construction of a quadratic model. The model indicated that dye concentration 110 ppm, copper sulphate 0.2 mM, pH 7.5 and inoculum size 6% v/v were found to be optimum to maximize the laccase production and bacterial growth. Whereas, maximum dye decolorization achieved in media containing dye concentration 110 ppm, copper sulphate 0.6 mM, pH 6 and inoculum size 6% v/v. R package predicted R2 of R1, R2 and R3 were 0.9917, 0.9831 and 0.9703 respectively; likened to Design-Expert (Stat-Ease) (DOE) predicted R2 of R1, R2, and R3 were 0.9893, 0.9822 and 0.8442 respectively. The values obtained by R software were more precise, reliable and reproducible, compared to the DOE model. The laccase production was 1.80 fold increased, and 2.24 fold enhancement in dye decolorization was achieved using optimized medium than initial experiments. Moreover, the laccase-treated sample demonstrated the less cytotoxic effect on L132 and MCF-7 cell lines compared to untreated sample using MTT assay. Higher cell viability and lower cytotoxicity observed in a laccase-treated sample suggest the impending application of bacterial laccase in the reduction of toxicity of dye to design rapid biodegradation process. PMID- 29718935 TI - Automatic identification of optimal marker genes for phenotypic and taxonomic groups of microorganisms. AB - Finding optimal markers for microorganisms important in the medical, agricultural, environmental or ecological fields is of great importance. Thousands of complete microbial genomes now available allow us, for the first time, to exhaustively identify marker proteins for groups of microbial organisms. In this work, we model the biological task as the well-known mathematical "hitting set" problem, solving it based on both greedy and randomized approximation algorithms. We identify unique markers for 17 phenotypic and taxonomic microbial groups, including proteins related to the nitrite reductase enzyme as markers for the non-anammox nitrifying bacteria group, and two transcription regulation proteins, nusG and yhiF, as markers for the Archaea and Escherichia/Shigella taxonomic groups, respectively. Additionally, we identify marker proteins for three subtypes of pathogenic E. coli, which previously had no known optimal markers. Practically, depending on the completeness of the database this algorithm can be used for identification of marker genes for any microbial group, these marker genes may be prime candidates for the understanding of the genetic basis of the group's phenotype or to help discover novel functions which are uniquely shared among a group of microbes. We show that our method is both theoretically and practically efficient, while establishing an upper bound on its time complexity and approximation ratio; thus, it promises to remain efficient and permit the identification of marker proteins that are specific to phenotypic or taxonomic groups, even as more and more bacterial genomes are being sequenced. PMID- 29718936 TI - Diversity and population structure of red rice germplasm in Bangladesh. AB - While the functionality and healthy food value of red rice have increased its popularity, such that market demand for it is expected to rise, most strains suffer from low grain yield. To perform diversity and population structure analyses of red rice germplasm, therefore, becomes essential for improving yields for commercial production. In this study, fifty red rice germplasm from the Bangladesh Rice Research Institute (BRRI) genebank were characterized both morphologically and genetically using fifty simple sequence repeat (SSR) markers. Overall, 162 alleles were detected by the markers with the detected allele number varying from two to seven. Additionally, 22 unique alleles were identified for use as a germplasm diagnostic tool. The highest and lowest polymorphic information content (PIC) indices were 0.75 and 0.04 found in markers RM282 and RM304, respectively, and genetic diversity was moderate, varying from 0.05 to 0.78 (average: 0.35). While phylogenetic cluster analysis of the fifteen distance based agro-morphological traits divided the germplasm into five clusters (I, II, III, IV and V), a similar SSR analysis yielded only three major groups (I, II, and III), and a model-based population structure analysis yielded four (A, B, C and D). Both principal component and neighbors joining tree analysis from the population structure method showed the tested germplasm as highly diverse in structure. Moreover, an analysis of molecular variance (AMOVA), as well as a pairwise FST analysis, both indicated significant differentiation (ranging from 0.108 to 0.207) among all pairs of populations, suggesting that all four population structure groups differed significantly. Populations A and D were the most differentiated from each other by FST. Findings from this study suggest that the diverse germplasm and polymorphic trait-linked SSR markers of red rice are suitable for the detection of economically desirable trait loci/genes for use in future molecular breeding programs. PMID- 29718937 TI - Routine activities and emotion in the life of dairy cows: Integrating body language into an affective state framework. AB - We assessed dairy cows' body postures while they were performing different stationary activities in a loose housing system and then used the variation within and between individuals to identify potential connections between specific postures and the valence and arousal dimensions of emotion. We observed 72 individuals within a single milking herd focusing on their ear, neck and tail positions while they were: feeding from individual roughage bins, being brushed by a mechanical rotating brush and queuing to enter a single automatic milking system. Cows showed different ear, neck and tail postures depending on the situation. When combined, their body posture during feeding was ears back up and neck down, with tail wags directed towards the body, during queuing their ears were mainly axial and forward, their neck below the horizontal and the tail hanging stationary, and during brushing their ears were backwards and asymmetric, the neck horizontal and the tail wagging vigorously. We then placed these findings about cow body posture during routine activities into an arousal/valence framework used in animal emotion research (dimensional model of core affect). In this way we generate a priori predictions of how the positions of the ears, neck and tail of cows may change in other situations, previously demonstrated to vary in valence and arousal. We propose that this new methodology, with its different steps of integration, could contribute to the identification and validation of behavioural (postural) indicators of how positively or negatively cows experience other activities, or situations, and how calm or aroused they are. Although developed here on dairy cattle, by focusing on relevant postures, this approach could be easily adapted to other species. PMID- 29718938 TI - Partitioning diversity in subterranean invertebrates: The epikarst fauna of Slovenia. AB - The decomposition of diversity into within site (alpha) and between site (beta) components is especially interesting in subterranean communities because of their isolated nature and limited dispersal potential The aquatic epikarst fauna, sampled from water drips in caves affords a unique opportunity to provide comparable, quantitative samples of a portion of the obligate subterranean dwelling fauna in multiple hierarchical levels. We focused on three interrelated questions-(1) what is the spatial pattern of epikarst species diversity; (2) how does species diversity partition between local, and regional components (nested and replacement); and (3) whether epikarst hotspots are subterranean hotspots in general. We analyzed the geographic pattern of species richness of 30 species of obligate subterranean copepods found in 81 drips in Slovenian caves in three karst regions-Alpine, Dinaric, and Isolated. Comparison of Chao1 and observed (Mao-tau) estimates of species richness indicated sampling in most drips was complete, but species accumulation curves indicated roughly half of the sites in the Dinaric karst had not reached an asymptote. Overall, within drip diversity accounted for three species, different drips in a cave another three, different caves in a region six species, and different regions accounted for the remaining 18 species. Sites in the Dinaric karst had much higher species richness than the other sites, which is in agreement with studies of other components of the subterranean fauna. The fauna associated with drips in Zupanova jama (jama = cave), in the east-central Dinaric karst was the richest found. While turnover explained the majority of beta-diversity, nestedness in the form of hotspot drips was important as well. A consequence is that a small number of drips largely determine cave and regional species diversity. PMID- 29718939 TI - When approximate number acuity predicts math performance: The moderating role of math anxiety. AB - Separate lines of research suggest that people who are better at estimating numerical quantities using the approximate number system (ANS) have better math performance, and that people with high levels of math anxiety have worse math performance. Only a handful of studies have examined both ANS acuity and math anxiety in the same participants and those studies report contradictory results. To address these inconsistencies, in the current study 87 undergraduate students completed assessments of ANS acuity, math anxiety, and three different measures of math. We considered moderation models to examine the interplay of ANS acuity and math anxiety on different aspects of math performance. Math anxiety and ANS acuity were both unique significant predictors of the ability to automatically recall basic number facts. ANS acuity was also a unique significant predictor of the ability to solve applied math problems, and this relation was further qualified by a significant interaction with math anxiety: the positive association between ANS acuity and applied problem solving was only present in students with high math anxiety. Our findings suggest that ANS acuity and math anxiety are differentially related to various aspects of math and should be considered together when examining their respective influences on math ability. Our findings also raise the possibility that good ANS acuity serves as a protective factor for highly math-anxious students on certain types of math assessments. PMID- 29718940 TI - Assessing the applicability of stable isotope analysis to determine the contribution of landfills to vultures' diet. AB - Human activities cause changes to occur in the environment that affect resource availability for wildlife. The increase in the human population of cities has led to a rise in the amount of waste deposited in landfills, installations that have become a new food resource for both pest and threatened species such as vultures. In this study we used stable isotope analysis (SIA) and conventional identification of food remains from Egyptian Vultures (Neophron percnopterus) to assess the applicability of SIA as a new tool for determining the composition of the diets of vultures, a group of avian scavengers that is threatened worldwide. We focused on an expanding Egyptian Vulture population in NE Iberian Peninsula to determine the part played by landfills and livestock in the diet of these species, and aimed to reduce the biases associated with conventional ways of identifying food remains. We compared proportions of diet composition obtained with isotope mixing models and conventional analysis for five main prey. The greatest agreement between the two methods was in the categories 'landfills' and 'birds' and the greatest differences between the results from the two methods were in the categories 'livestock', 'carnivores' and 'wild herbivores'. Despite uncertainty associated to SIA, our results showed that stable isotope analysis can help to distinguish between animals that rely on waste and so present enriched levels of delta 13C than those that feed on the countryside. Indeed, a high proportion of food derived from landfills (nearly 50%) was detected in some breeding pairs. Furthermore we performed GLMM analyses that showed that high values of delta 13C in Egyptian Vulture feathers (a proxy of feeding in landfills) are related with high levels of humanization of territories. This method has the potential to be applied to other threatened vulture species for which there is a lack of information regarding resources they are consuming, being especially important as the main causes of vultures decline worldwide are related to the consumption and availability of food resources. PMID- 29718941 TI - Machine learning-based diagnosis for disseminated intravascular coagulation (DIC): Development, external validation, and comparison to scoring systems. AB - The major challenge in the diagnosis of disseminated intravascular coagulation (DIC) comes from the lack of specific biomarkers, leading to developing composite scoring systems. DIC scores are simple and rapidly applicable. However, optimal fibrin-related markers and their cut-off values remain to be defined, requiring optimization for use. The aim of this study is to optimize the use of DIC-related parameters through machine learning (ML)-approach. Further, we evaluated whether this approach could provide a diagnostic value in DIC diagnosis. For this, 46 DIC related parameters were investigated for both clinical findings and laboratory results. We retrospectively reviewed 656 DIC-suspected cases at an initial order for full DIC profile and labeled their evaluation results (Set 1; DIC, n = 228; non-DIC, n = 428). Several ML algorithms were tested, and an artificial neural network (ANN) model was established via independent training and testing using 32 selected parameters. This model was externally validated from a different hospital with 217 DIC-suspected cases (Set 2; DIC, n = 80; non-DIC, n = 137). The ANN model represented higher AUC values than the three scoring systems in both set 1 (ANN 0.981; ISTH 0.945; JMHW 0.943; and JAAM 0.928) and set 2 (AUC ANN 0.968; ISTH 0.946). Additionally, the relative importance of the 32 parameters was evaluated. Most parameters had contextual importance, however, their importance in ML-approach was different from the traditional scoring system. Our study demonstrates that ML could optimize the use of clinical parameters with robustness for DIC diagnosis. We believe that this approach could play a supportive role in physicians' medical decision by integrated into electrical health record system. Further prospective validation is required to assess the clinical consequence of ML-approach and their clinical benefit. PMID- 29718942 TI - Perilimbal sclera mechanical properties: Impact on intraocular pressure in porcine eyes. AB - There is extensive knowledge on the relationship of posterior scleral biomechanics and intraocular pressure (IOP) load on glaucomatous optic neuropathy; however, the role for biomechanical influence of the perilimbal scleral tissue on the aqueous humor drainage pathway, including the distal venous outflow system, and IOP regulation is not fully understood. The purpose of this work is to study the outflow characteristics of perfused porcine eyes relative to the biomechanical properties of the perilimbal sclera, the posterior sclera and the cornea. Enucleated porcine eyes from eleven different animals were perfused with surrogate aqueous at two fixed flow rates while monitoring their IOP. After perfusion, mechanical stress-strain and relaxation tests were conducted on specimens of perilimbal sclera, posterior sclera, and cornea from the same perfused eyes. Statistical analysis of the data demonstrated a strong correlation between increased tangent modulus of the perilimbal sclera tissues and increased perfusion IOP (R2 = 0.74, p = 0.0006 at lower flow rate and R2 = 0.71, p = 0.0011 at higher flow rate). In contrast, there were no significant correlations between IOP and the tangent modulus of the other tissues (Posterior sclera: R2 = 0.17 at lower flow rate and R2 = 0.30 at higher flow rate; cornea: R2 = 0.02 at lower flow rate and R2<0.01 at higher flow rate) nor the viscoelastic properties of any tissue (R2 <= 0.08 in all cases). Additionally, the correlation occurred for IOP and not net outflow facility (R2 <= 0.12 in all cases). These results provide new evidence that IOP in perfused porcine eyes is strongly influenced by the tangent modulus, sometimes called the tissue stiffness, of the most anterior portion of the sclera, i.e. the limbus. PMID- 29718944 TI - Aboveground mechanical stimuli affect belowground plant-plant communication. AB - Plants can detect the presence of their neighbours and modify their growth behaviour accordingly. But the extent to which this neighbour detection is mediated by abiotic stressors is not well known. In this study we tested the acclimation response of Zea mays L. seedlings through belowground interactions to the presence of their siblings exposed to brief mechano stimuli. Maize seedling simultaneously shared the growth solution of touched plants or they were transferred to the growth solution of previously touched plants. We tested the growth preferences of newly germinated seedlings toward the growth solution of touched (T_solution) or untouched plants (C_solution). The primary root of the newly germinated seedlings grew significantly less towards T_solution than to C_solution. Plants transferred to T_solution allocated more biomass to shoots and less to roots. While plants that simultaneously shared their growth solution with the touched plants produced more biomass. Results show that plant responses to neighbours can be modified by aboveground abiotic stress to those neighbours and suggest that these modifications are mediated by belowground interactions. PMID- 29718943 TI - Biomonitoring of blood cholinesterases and acylpeptide hydrolase activities in rural inhabitants exposed to pesticides in the Coquimbo Region of Chile. AB - In Chile, agriculture is a relevant economic activity and is concomitant with the use of pesticides to improve the yields. Acute intoxications of agricultural workers occur with some frequency and they must be reported to the surveillance system of the Ministry of Health. However the impacts of chronic and environmental pesticide exposure have been less studied. Among pesticides frequently used in Chile for insects control are organophosphates (OP) and carbamates (CB). They are inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). In this study we determined the pattern of both biomarkers activity in three populations with different type of chronic exposure to OP/CB: environmentally exposed (EE), occupationally exposed (OE) and a reference group (RG) without exposure. Besides this, we also measured the activity of acylpeptide hydrolase (APEH), an enzyme involved in relevant functions in the central synapses that is also expressed in erythrocytes and previously reported to be highly inhibited by some OP. A baseline measurement was done in both exposure groups and then a second measurement was done during the spraying season. The RG was measured only once at any time of the year. Our results indicate that people under chronic OP/CB exposure showed an adaptive response through an increase of basal BChE activity. During the spray season only BChE activity was decreased in the EE and OE groups (p<0.05 and p<0.01, respectively) and the higher magnitude of BChE inhibition was observed in the EE group. The analysis of the frequencies of inhibition above 30% (biological tolerance limit declared by Chilean legislation) indicated that BChE was most frequently inhibited in the EE group (53% of the individuals displayed inhibition) and AChE in the OE group (55% of the individuals displayed AChE inhibition). APEH activity showed the highest frequency of inhibition in the EE group independent of its magnitude (64%). Our results demonstrate that the rural population living nearby agricultural settings displays high levels of environmental exposure. APEH activity seems to be a sensitive biomarker for acute low-level exposure and its usefulness as a routine biomarker must to be explored in future studies. Systematic biomonitoring and health outcomes studies are necessary as well as obtaining the baseline for BChE and AChE activity levels with the aim to improve environmental and occupational health policies in Chile. PMID- 29718945 TI - Under-reporting of pertussis in Ontario: A Canadian Immunization Research Network (CIRN) study using capture-recapture. AB - INTRODUCTION: Under-reporting of pertussis cases is a longstanding challenge. We estimated the true number of pertussis cases in Ontario using multiple data sources, and evaluated the completeness of each source. METHODS: We linked data from multiple sources for the period 2009 to 2015: public health reportable disease surveillance data, public health laboratory data, and health administrative data (hospitalizations, emergency department visits, and physician office visits). To estimate the total number of pertussis cases in Ontario, we used a three-source capture-recapture analysis stratified by age (infants, or aged one year and older) and adjusting for dependency between sources. We used the Bayesian Information Criterion to compare models. RESULTS: Using probable and confirmed reported cases, laboratory data, and combined hospitalizations/emergency department visits, the estimated total number of cases during the six-year period amongst infants was 924, compared with 545 unique observed cases from all sources. Using the same sources, the estimated total for those aged 1 year and older was 12,883, compared with 3,304 observed cases from all sources. Only 37% of infants and 11% for those aged 1 year and over admitted to hospital or seen in an emergency department for pertussis were reported to public health. Public health reporting sensitivity varied from 2% to 68% depending on age group and the combination of data sources included. Sensitivity of combined hospitalizations and emergency department visits varied from 37% to 49% and of laboratory data from 1% to 50%. CONCLUSIONS: All data sources contribute cases and are complementary, suggesting that the incidence of pertussis is substantially higher than suggested by routine reports. The sensitivity of different data sources varies. Better case identification is required to improve pertussis control in Ontario. PMID- 29718946 TI - The effect of handedness on spatial and motor representation of pitch patterns in pianists. AB - This study investigated the effect of handedness on pianists' abilities to adjust their keyboard performance skills to new spatial and motor mappings. Left- and right-handed pianists practiced simple melodies on a regular MIDI piano keyboard (practice) and were then asked to perform these with modified melodic contours (the same or reversed melodic contour causing a change of fingering) and on a reversed MIDI piano keyboard (test). The difference of performance duration between the practice and the test phase as well as the amount of errors played were used as test measures. Overall, a stronger effect for modified melodic contours than for the reversed keyboard was observed. Furthermore, we observed a trend of left-handed pianists to be quicker and more accurate in playing melodies when reversing their fingering with reversed contours in their left-hand performances. This suggests that handedness may influence pianists' skill to adjust to new spatial and motor mappings. PMID- 29718947 TI - How ownership rights over microorganisms affect infectious disease control and innovation: A root-cause analysis of barriers to data sharing as experienced by key stakeholders. AB - BACKGROUND: Genetic information of pathogens is an essential input for infectious disease control, public health and for research. Efficiency in preventing and responding to global outbreaks relies on timely access to such information. Still, ownership barriers stand in the way of timely sharing of genetic data from pathogens, frustrating efficient public health responses and ultimately the potential use of such resources in innovations. Under a One Health approach, stakeholders, their interests and ownership issues are manifold and need to be investigated. We interviewed key actors from governmental and non-governmental bodies to identify overlapping and conflicting interests, and the overall challenges for sharing pathogen data, to provide essential inputs to the further development of political and practical strategies for improved data sharing practices. METHODS & FINDINGS: To identify and prioritize barriers, 52 Key Opinion Leaders were interviewed. A root-cause analysis was performed to identify causal relations between barriers. Finally, barriers were mapped to the innovation cycle reflecting how they affect the range of surveillance, innovation, and sharing activities. Four main barrier categories were found: compliance to regulations, negative consequences, self-interest, and insufficient incentives for compliance. When grouped in sectors (research institutes, public health organizations, supra-national organizations and industry) stakeholders appear to have similar interests, more than when grouped in domains (human, veterinary and food). Considering the innovation process, most of barriers could be mapped to the initial stages of the innovation cycle as sampling and sequencing phases. These are stages of primary importance to outbreak control and public health response. A minority of barriers applied to later stages in the innovation cycle, which are of more importance to product development. CONCLUSION: Overall, barriers are complex and entangled, due to the diversity of causal factors and their crosscutting features. Therefore, barriers must be addressed in a comprehensive and integrated manner. Stakeholders have different interests highlighting the diversity in motivations for sharing pathogen data: prioritization of public health, basic research, economic welfare and/or innovative capacity. Broad inter-sectorial discussions should start with the alignment of these interests within sectors. The improved sharing of pathogen data, especially in upstream phases of the innovation process, will generate substantial public health benefits through increased availability of data to inform surveillance systems, as well as to allow the (re-)use of data for the development of medical countermeasures to control infectious diseases. PMID- 29718948 TI - Impact of left ventricular diastolic function and survival in patients with severe aortic stenosis undergoing transcatheter aortic valve replacement. AB - In year 2016, the American Society of Echocardiography (ASE) and the European Association of Cardiovascular Imaging (EACVI) updated Recommendations for the assessment and grading of diastolic dysfunction (DD). We aimed to assess the applicability of this DD grading method and its association with prognosis in patients with severe aortic stenosis (AS) who underwent transcatheter aortic valve implantation (TAVI). We retrospectively identified 237 consecutive patients with severe AS who underwent trans-femoral TAVI. Baseline transthoracic echocardiography was evaluated to assess pre- and post-TAVI diastolic function according to the current ASE/EACVI Recommendations. Prior to TAVI, 41 (17%) patients were diagnosed as having grade I DD, 111 (47%) patients had grade II DD, 80 (34%) had grade III DD. DD grade after TAVI decreased (p < 0.001) with 75 patients (32%) reclassified to a lower DD grade. During the median follow-up of 1,320 days, 136 (57%) patients died. In univariable Cox proportional hazards model analysis, neither pre- nor post-TAVI DD grade were associated with prognosis. However, patients with grade III DD detected before TAVI and AR>= 2 after TAVI had poorer survival (p<0.008). Patients with grade III DD detected after TAVI and AR>= 2 after TAVI had poorer prognosis (p = 0.002). TAVI improves DD grade. While poor DD grade was not associated with mortality after treatment of AS by TAVI, concomitant presence of DD and post-procedural AR carried a poor prognosis. PMID- 29718949 TI - Comparative analyses of the complete mitochondrial genomes of Dosinia clams and their phylogenetic position within Veneridae. AB - Mitochondrial genomes have proved to be a powerful tool in resolving phylogenetic relationship. In order to understand the mitogenome characteristics and phylogenetic position of the genus Dosinia, we sequenced the complete mitochondrial genomes of Dosinia altior and Dosinia troscheli (Bivalvia: Veneridae), compared them with that of Dosinia japonica and established a phylogenetic tree for Veneridae. The mitogenomes of D. altior (17,536 bp) and D. troscheli (17,229 bp) are the two smallest in Veneridae, which include 13 protein coding genes, 2 ribosomal RNA genes, 22 tRNA genes, and non-coding regions. The mitogenomes of the Dosinia species are similar in size, gene content, AT content, AT- and GC- skews, and gene arrangement. The phylogenetic relationships of family Veneridae were established based on 12 concatenated protein-coding genes using maximum likelihood and Bayesian analyses, which supported that Dosininae and Meretricinae have a closer relationship, with Tapetinae being the sister taxon. The information obtained in this study will contribute to further understanding of the molecular features of bivalve mitogenomes and the evolutionary history of the genus Dosinia. PMID- 29718950 TI - Factors associated with body mass index in children and adolescents: An international cross-sectional study. AB - BACKGROUND: The increasing prevalence of overweight and obesity in childhood has implications for their future health. There are many potential contributors to overweight and obesity in childhood. The aim was to investigate the association between postulated risk factors and body mass index (BMI) in children and adolescents. METHODS: Secondary analysis of data from a multi-centre, multi country, cross-sectional study (ISAAC Phase Three). Parents/guardians of children aged 6-7 years completed a questionnaire about their child's current height and weight, and the postulated risk factors. Adolescents aged 13-14 years reported their own height and weight and answered questions about the postulated risk factors. A general linear mixed model was used to determine the association between BMI and the postulated risk factors. Imputation was used if there were missing responses for 3 or fewer explanatory variables. RESULTS: 65,721 children (27 centres, 15 countries) and 189,282 adolescents (70 centres, 35 countries) were included in the final analyses. Many statistically significant associations were identified, although for most variables the effect sizes were small. In children birth weight (for each kg increase in birth weight the BMI increased by +0.43 kg/m2, p<0.001), television viewing (5+ hours/day +0.33 kg/m2 vs. <1 hour/day, p<0.001), fast food (>=3 times/week +0.16 kg/m2 vs. never, p<0.001) vigorous physical activity (3+ hours/week 0.071 kg/m2 vs. never, p = 0.023) and maternal smoking in the first year of life (+0.13 kg/m2, p<0.001) were associated with a higher BMI in the adjusted model. Nut consumption (>=3 times/week -0.11 kg/m2 vs. never, p = 0.002) was associated with a lower BMI. Early life exposures (antibiotics, paracetamol and breast feeding) were also associated with BMI. For adolescents statistically significant associations with BMI and were seen with maternal smoking (+0.25 kg/m2, p<0.001), television viewing (5+ hours/day +0.23 kg/m2 vs. <1 hour/day, p<0.001), fast food (>=3 times/week -0.19 kg/m2 vs. never, p<0.001), vigorous physical activity (3+ hours/week 0.047 kg/m2 vs. never, p<0.001) and nuts (>=3 times/week -0.22 kg/m2 vs. never, p<0.001). CONCLUSIONS: Although several early life exposures were associated with small differences in BMI, most effect sizes were small. Larger effect sizes were seen with current maternal smoking, television viewing (both with higher BMI) and frequent nut consumption (lower BMI) in both children and adolescents, suggesting that current behaviours are more important than early exposures. Although many variables may influence BMI in childhood, the putative factors studied are not of sufficient magnitude to support major public health interventions. PMID- 29718951 TI - The Complementary Health Approaches for Pain Survey (CHAPS): Validity testing and characteristics of a rural population with pain. AB - OBJECTIVES: Little is known about patterns and correlates of Complementary Health Approaches (CHAs) in chronic pain populations, particularly in rural, underserved communities. This article details the development and implementation of a new survey instrument designed to address this gap, the Complementary Health Approaches for Pain Survey (CHAPS). DESIGN: Following pilot-testing using pre specified criteria to assess quality and comprehension in our target population, and after feedback regarding face-validity from content experts and stakeholders, the final cross-sectional self-report survey required 10-12 minutes to complete. It contained 69 demographic, lifestyle and health-related factors, and utilized a Transtheoretical Model (TTM) underpinning to assess short- and long-term use of 12 CHAs for pain management. Twenty additional items on pain severity, feelings, clinical outcomes, and activities were assessed using the Short-Form Global Pain Scale (SF-GPS); Internal reliability was assessed using Cronbach's alpha. SETTINGS/LOCATION: Investigators conducted consecutive sampling in four West Virginia pain management and rheumatology practices. PARTICIPANTS: 301 Appalachian adult patients seeking conventional care for pain management. RESULTS: Response rates were high (88% +/- 4.1%). High quality and comprehension deemed the CHAPS an appropriate measurement tool in a rural population with pain. Missing data were unrelated to patient characteristics. Participants predominantly experienced chronic pain (93%), had five or more health conditions (56%, Mean = 5.4+/-3.1), were white (92%), female (57%), and middle-aged (Mean = 55.6 (SD = 13.6) years). Over 40% were disabled (43%) and/or obese (44%, Mean BMI = 33.4+/-31.5). Additionally, 44% used opioids, 31% used other prescription medications, and 66% used at least one CHA for pain, with 48% using CHAs for greater than 6 months. There was high internal reliability of the SF-GPS (alpha = .93) and satisfactory internal reliability for each of the five TTM stages across (all) twelve CHAs: precontemplation (0.89), contemplation (0.72), preparation (0.75), action (0.70), and maintenance (0.70). CONCLUSIONS: The CHAPS is the first comprehensive measurement tool to assess CHA use specifically for pain management. Ease of administration in a population with pain support further use in population- and clinic-based studies in similar populations. PMID- 29718952 TI - Women are less likely than men to achieve optimal glycemic control after 1 year of treatment: A multi-level analysis of a Korean primary care cohort. AB - We investigated differences in the achievement of glycemic control among newly diagnosed type-2 diabetes patients according to gender using a multi-clinic retrospective cohort study. Optimal glycemic control was defined as hemoglobin A1c (HbA1c) of less than 6.5% after 1 year of diabetes management. A generalized linear mixed model, which controlled for the fixed effects of baseline characteristics and prescribed oral hypoglycemic agent (OHA), was used to calculate the probability of achieving the target HbA1c. The study included 2,253 newly diagnosed type-2 diabetes patients who completed 1 year of diabetic management, including OHA, in the 36 participating primary clinics. Within the study population, the women had an older average age, were less likely to smoke or drink alcohol, and showed lower levels of fasting blood glucose and HbA1c at the time of diagnosis. There were no significant differences by sex in prescribed OHA or median number of visits. After 1 year of diabetes management, 38.9% of women and 40.6% of men achieved the target HbA1c-a small but significant difference. This suggests that type-2 diabetes is managed less well in women than in men. PMID- 29718953 TI - Estimating city-level travel patterns using street imagery: A case study of using Google Street View in Britain. AB - BACKGROUND: Street imagery is a promising and growing big data source providing current and historical images in more than 100 countries. Studies have reported using this data to audit road infrastructure and other built environment features. Here we explore a novel application, using Google Street View (GSV) to predict travel patterns at the city level. METHODS: We sampled 34 cities in Great Britain. In each city, we accessed 2000 GSV images from 1000 random locations. We selected archived images from time periods overlapping with the 2011 Census and the 2011-2013 Active People Survey (APS). We manually annotated the images into seven categories of road users. We developed regression models with the counts of images of road users as predictors. The outcomes included Census-reported commute shares of four modes (combined walking plus public transport, cycling, motorcycle, and car), as well as APS-reported past-month participation in walking and cycling. RESULTS: We found high correlations between GSV counts of cyclists ('GSV-cyclists') and cycle commute mode share (r = 0.92)/past-month cycling (r = 0.90). Likewise, GSV-pedestrians was moderately correlated with past-month walking for transport (r = 0.46), GSV-motorcycles was moderately correlated with commute share of motorcycles (r = 0.44), and GSV-buses was highly correlated with commute share of walking plus public transport (r = 0.81). GSV-car was not correlated with car commute mode share (r = -0.12). However, in multivariable regression models, all outcomes were predicted well, except past-month walking. The prediction performance was measured using cross-validation analyses. GSV buses and GSV-cyclists are the strongest predictors for most outcomes. CONCLUSIONS: GSV images are a promising new big data source to predict urban mobility patterns. Predictive power was the greatest for those modes that varied the most (cycle and bus). With its ability to identify mode of travel and capture street activity often excluded in routinely carried out surveys, GSV has the potential to be complementary to new and traditional data. With half the world's population covered by street imagery, and with up to 10 years historical data available in GSV, further testing across multiple settings is warranted both for cross-sectional and longitudinal assessments. PMID- 29718954 TI - Behavioural risks in male dogs with minimal lifetime exposure to gonadal hormones may complicate population-control benefits of desexing. AB - Castration of dogs is a widespread practise with clear justification in population control and knock-on benefits for animal welfare. Deleterious behavioural consequences of castration are believed to be negligible. Gonadectomy is widely recommended as part of a multi-factorial approach to prevent problems including aggression in dogs. However, the consequences of early castration on health are still being debated. The current study focused on the reported behaviour of 6,235 male dogs castrated before 520 weeks of life for reasons other than behavioural management, and calculated their percentage lifetime exposure to gonadal hormones (PLGH) as a proportion of their age at the time of being reported to the online Canine Behavioral Assessment and Research Questionnaire (C BARQ). Forty behaviors differed between entire and castrated dogs, of which 25 were associated with PLGH and 14 with age-at-castration (AAC). Only 2 behaviours, indoor urine marking and howling when left alone, were significantly more likely in dogs with longer PLGH. In contrast, longer PLGH was associated with significantly reduced reporting of 26 (mostly unwelcome) behaviours. Of these, 8 related to fearfulness and 7 to aggression. The current data suggest that dogs' tendency to show numerous behaviours can be influenced by the timing of castration. They indicate how dog behaviour matures when gonadal hormones are allowed to have their effect. The differences reported here between undesirable behaviours of castrated and intact dogs were in the range of 5.04% and 12.31%, suggesting that, for some dogs, partial or complete denial of puberty may reduce indoor urine-marking but have many other undesirable consequences. Veterinarians may use these data to discuss unwelcome consequences with owners of male dogs before castration. PMID- 29718955 TI - Active learning of cortical connectivity from two-photon imaging data. AB - Understanding how groups of neurons interact within a network is a fundamental question in system neuroscience. Instead of passively observing the ongoing activity of a network, we can typically perturb its activity, either by external sensory stimulation or directly via techniques such as two-photon optogenetics. A natural question is how to use such perturbations to identify the connectivity of the network efficiently. Here we introduce a method to infer sparse connectivity graphs from in-vivo, two-photon imaging of population activity in response to external stimuli. A novel aspect of the work is the introduction of a recommended distribution, incrementally learned from the data, to optimally refine the inferred network. Unlike existing system identification techniques, this "active learning" method automatically focuses its attention on key undiscovered areas of the network, instead of targeting global uncertainty indicators like parameter variance. We show how active learning leads to faster inference while, at the same time, provides confidence intervals for the network parameters. We present simulations on artificial small-world networks to validate the methods and apply the method to real data. Analysis of frequency of motifs recovered show that cortical networks are consistent with a small-world topology model. PMID- 29718956 TI - A reliable and validated LC-MS/MS method for the simultaneous quantification of 4 cannabinoids in 40 consumer products. AB - In the past 50 years, Cannabis sativa (C. sativa) has gone from a substance essentially prohibited worldwide to one that is gaining acceptance both culturally and legally in many countries for medicinal and recreational use. As additional jurisdictions legalize Cannabis products and the variety and complexity of these products surpass the classical dried plant material, appropriate methods for measuring the biologically active constituents is paramount to ensure safety and regulatory compliance. While there are numerous active compounds in C. sativa the primary cannabinoids of regulatory and safety concern are (-)-Delta9-tetrahydrocannabinol (THC), cannabidiol (CBD), and their respective acidic forms THCA-A and CBDA. Using the US Food and Drug Administration (FDA) bioanalytical method validation guidelines we developed a sensitive, selective, and accurate method for the simultaneous analysis CBD, CBDA, THC, and THCA-A in oils and THC & CBD in more complex matrices. This HPLC MS/MS method was simple and reliable using standard sample dilution and homogenization, an isocratic chromatographic separation, and a triple quadrupole mass spectrometer. The lower limit of quantification (LLOQ) for analytes was 0.195 ng/mL over a 0.195-50.0 ng/mL range of quantification with a coefficient of correlation of >0.99. Average intra-day and inter-day accuracies were 94.2-112.7% and 97.2-110.9%, respectively. This method was used to quantify CBD, CBDA, THC, and THCA-A in 40 commercial hemp products representing a variety of matrices including oils, plant materials, and creams/cosmetics. All products tested met the federal regulatory restrictions on THC content in Canada (<10 MUg/g) except two, with concentrations of 337 and 10.01 MUg/g. With respect to CBD, the majority of analyzed products contained low CBD levels and a CBD: CBDA ratio of <1.0. In contrast, one product contained 8,410 MUg/g CBD and a CBD: CBDA ratio of >1,000 (an oil-based product). Overall, the method proved amenable to the analysis of various commercial products including oils, creams, and plant material and may be diagnostically indicative of adulteration with non-hemp C. sativa, specialized hemp cultivars, or unique manufacturing methods. PMID- 29718958 TI - The effects of information and social conformity on opinion change. AB - Extant research shows that social pressures influence acts of political participation, such as turning out to vote. However, we know less about how conformity pressures affect one's deeply held political values and opinions. Using a discussion-based experiment, we untangle the unique and combined effects of information and social pressure on a political opinion that is highly salient, politically charged, and part of one's identity. We find that while information plays a role in changing a person's opinion, the social delivery of that information has the greatest effect. Thirty three percent of individuals in our treatment condition change their opinion due to the social delivery of information, while ten percent respond only to social pressure and ten percent respond only to information. Participants that change their opinion due to social pressure in our experiment are more conservative politically, conscientious, and neurotic than those that did not. PMID- 29718957 TI - Sulfamethoxazole - Trimethoprim represses csgD but maintains virulence genes at 30 degrees C in a clinical Escherichia coli O157:H7 isolate. AB - The high frequency of prophage insertions in the mlrA gene of clinical serotype O157:H7 isolates renders such strains deficient in csgD-dependent biofilm formation but prophage induction may restore certain mlrA properties. In this study we used transcriptomics to study the effect of high and low sulfamethoxazole-trimethoprim (SMX-TM) concentrations on prophage induction, biofilm regulation, and virulence gene expression in strain PA20 under environmental conditions following 5-hour and 12-hour exposures in broth or on agar. SMX-TM at a sub-lethal concentration induced strong RecA expression resulting in concentration- and time-dependent major transcriptional shifts with emphasis on up-regulation of genes within horizontally-transferred chromosomal regions (HTR). Neither high or low levels of SMX-TM stimulated csgD expression at either time point, but both levels resulted in slight repression. Full expression of Ler-dependent genes paralleled expression of group 1 pch homologues in the presence of high glrA. Finally, stx2 expression, which is strongly dependent on prophage induction, was enhanced at 12 hours but repressed at five hours, in spite of early SOS initiation by the high SMX-TM concentration. Our findings indicate that, similar to host conditions, exposure to environmental conditions increased the expression of virulence genes in a clinical isolate but genes involved in the protective biofilm response were repressed. PMID- 29718959 TI - GIMAP6 is required for T cell maintenance and efficient autophagy in mice. AB - The GTPases of the immunity-associated proteins (GIMAP) GTPases are a family of proteins expressed strongly in the adaptive immune system. We have previously reported that in human cells one member of this family, GIMAP6, interacts with the ATG8 family member GABARAPL2, and is recruited to autophagosomes upon starvation, suggesting a role for GIMAP6 in the autophagic process. To study this possibility and the function of GIMAP6 in the immune system, we have established a mouse line in which the Gimap6 gene can be inactivated by Cre-mediated recombination. In mice bred to carry the CD2Cre transgene such that the Gimap6 gene was deleted within the T and B cell lineages there was a 50-70% reduction in peripheral CD4+ and CD8+ T cells. Analysis of splenocyte-derived proteins from these mice indicated increased levels of MAP1LC3B, particularly the lipidated LC3 II form, and S405-phosphorylation of SQSTM1. Electron microscopic measurements of Gimap6-/- CD4+ T cells indicated an increased mitochondrial/cytoplasmic volume ratio and increased numbers of autophagosomes. These results are consistent with autophagic disruption in the cells. However, Gimap6-/- T cells were largely normal in character, could be effectively activated in vitro and supported T cell dependent antibody production. Treatment in vitro of CD4+ splenocytes from GIMAP6fl/flERT2Cre mice with 4-hydroxytamoxifen resulted in the disappearance of GIMAP6 within five days. In parallel, increased phosphorylation of SQSTM1 and TBK1 was observed. These results indicate a requirement for GIMAP6 in the maintenance of a normal peripheral adaptive immune system and a significant role for the protein in normal autophagic processes. Moreover, as GIMAP6 is expressed in a cell-selective manner, this indicates the potential existence of a cell restricted mode of autophagic regulation. PMID- 29718960 TI - Deforestation and stream warming affect body size of Amazonian fishes. AB - Declining body size has been suggested to be a universal response of organisms to rising temperatures, manifesting at all levels of organization and in a broad range of taxa. However, no study to date evaluated whether deforestation-driven warming could trigger a similar response. We studied changes in fish body size, from individuals to assemblages, in streams in Southeastern Amazonia. We first conducted sampling surveys to validate the assumption that deforestation promoted stream warming, and to test the hypothesis that warmer deforested streams had reduced fish body sizes relative to cooler forest streams. As predicted, deforested streams were up to 6 degrees C warmer and had fish 36% smaller than forest streams on average. This body size reduction could be largely explained by the responses of the four most common species, which were 43-55% smaller in deforested streams. We then conducted a laboratory experiment to test the hypothesis that stream warming as measured in the field was sufficient to cause a growth reduction in the dominant fish species in the region. Fish reared at forest stream temperatures gained mass, whereas those reared at deforested stream temperatures lost mass. Our results suggest that deforestation-driven stream warming is likely to be a relevant factor promoting observed body size reductions, although other changes in stream conditions, like reductions in organic matter inputs, can also be important. A broad scale reduction in fish body size due to warming may be occurring in streams throughout the Amazonian Arc of Deforestation, with potential implications for the conservation of Amazonian fish biodiversity and food supply for people around the Basin. PMID- 29718961 TI - The implications of community responses to intimate partner violence in Rwanda. AB - Intimate partner violence (IPV) has significant impacts on mental health. Community-focused interventions have shown promising results for addressing IPV in low-income countries, however, little is known about the implications of these interventions for women's mental wellbeing. This paper analyses data from a community-focused policy intervention in Rwanda collected in 2013-14, including focus group discussions and in-depth interviews with community members (n = 59). Our findings point to three ways in which these community members responded to IPV: (1) reconciling couples experiencing violence, (2) engaging community support through raising cases of IPV during community discussions, (3) navigating resources for women experiencing IPV, including police, social services and legal support. These community responses support women experiencing violence by helping them access available resources and by engaging in community discussions. However, assistance is largely only offered to married women and responses tend to focus exclusively on physical rather than psychological or emotional forms of violence. Drawing on Campbell and Burgess's (2012) framework for 'community mental health competence', we interrogate the potential implications of these responses for the mental wellbeing of women affected by violence. We conclude by drawing attention to the gendered nature of community responses to IPV and the potential impacts this may have for the mental health of women experiencing IPV. PMID- 29718962 TI - High molecular weight adiponectin inhibits vascular calcification in renal allograft recipients. AB - BACKGROUND: Adiponectin (ADPN) prevents the development/recurrence of cardiovascular events via its anti-atherogenic effects. However, few long-term studies have examined the changes in serum ADPN levels and arterial calcification seen in renal allograft recipients. SUBJECTS AND METHODS: The effects of the serum ADPN level on arterial calcification were examined in 51 Japanese renal allograft recipients. Abdominal aorta calcification was evaluated on computed tomography using the aortic calcification area index (ACAI). The change in the ACAI and serum high-molecular-weight (HMW)-ADPN fractions were studied over an 8 year period. The arterial expression of ADPN, ADPN receptors (AdipoR)1 and 2, and T-cadherin (cadherin-13) were also examined by immunohistochemistry. RESULTS: The change in the ACAI were grouped into quartiles and compared with the alterations in the serum levels of each ADPN fraction over an 8-year period. The change in the ACAI was much lower in the patients with highly elevated HMW-ADPN levels.Multiple regression analysis demonstrated that an advanced age at transplant and a history of cardiovascular complications were associated with an increased change in the ACAI, while higher HMW-ADPN concentrations were associated with improvements in the ACAI. Serum HDL-C level was also identified as a positive factor to increase serum HMW-ADPN level.In immunohistochemical examinations, ADPN was detected on CD31-positive arterial endothelial cells from renal allograft biopsy samples. ADPN co-localized with T-cadherin and AdipoR1, but only partially co-localized with AdipoR2. CONCLUSION: Both HMW-ADPN and HDL-C might inhibit the progression of vascular calcification by promoting ADPN binding to vascular endothelial cells via T-cadherin and AdipoR in Japanese renal allograft recipients. PMID- 29718963 TI - An ultrasonic nanobubble-mediated PNP/fludarabine suicide gene system: A new approach for the treatment of hepatocellular carcinoma. AB - OBJECTIVE: The purpose of this study is to generate an ultrasonic nanobubble (NB) mediated purine nucleoside phosphorylase (PNP)/fludarabine suicide gene system for the treatment of human hepatocellular carcinoma (HCC). METHODS: NBs were prepared from a mixture the phospholipids 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC) and 1,2-dipalmitoyl-sn-glycero-3-phosphate (DPPA), perfluoropropane gas and other materials using the high shear dispersion method. NBs treated with ultrasound irradiation functioned as a gene-transfer system, and a self-constructed suicide gene expression plasmid, pcDNA3.1(+)/PNP, treated with fludarabine functioned as a therapeutic gene. This system was used to determine the cytotoxic effects of PNP/fludarabine on HepG2 cells and SMMC7721 cells. RESULTS: 1. NBs with a small diameter (208-416 nm) and at a high concentration and fine homogeneity were prepared under the optimal method. 2. The pcDNA3.1(+)/PNP plasmid was efficiently transfected into HCC cells using ultrasonic NBs. 3. At 0.75MUg/ml fludarabine, PNP/fludarabine showed marked cytotoxic effects toward HepG2 and SMMC7721 cells. PNP/fludarabine achieved the same effect against both SMMC7721 and HepG2 cells but at a lower concentration of fludarabine for the latter. 4. Bystander effects: a 10-20% decrease in the cell survival rate was observed when only 5-10% of transfected cells were PNP positive. CONCLUSIONS: NBs constitute a non-toxic, stable and effective gene delivery platform. The PNP/fludarabine suicide gene system inhibited the growth of HCC cells, induced HCC cell apoptosis, and caused a notable bystander effect at a low fludarabine concentration. This study establishes an important new method for miniaturizing microbubbles and improving a new NB-mediated approach for gene therapy of HCC. PMID- 29718964 TI - Determinants of blood pressure control amongst hypertensive patients in Northwest Ethiopia. AB - BACKGROUND: Controlling blood pressure (BP) leads to significant reduction in cardiovascular risks and associated deaths. In Ethiopia, data is scarce about the level and determinants of optimal BP control among hypertensive patients. This study aimed to assess the prevalence and associated factors of optimal BP control among hypertensive patients attending at a district hospital. METHODS: A hospital based, cross-sectional study was conducted among 392 hypertensive patients who were on treatment and follow-up at a district hospital. A structured questionnaire adopted from WHO approach was prepared to collect the data. Medication adherence was measured by the four-item Morisky Green Levine Scale, with a score >=3 defined as "good adherence". Blood pressure was measured, and optimal BP control was 0DEFined as systolic BP < 140 mmHg and diastolic BP<90 mmHg. Both binary and multivariable logistic regressions models were fitted to identify correlates of optimal BP control. All statistical tests were two-sided and a p values <0.05 was considered for statistical significance. RESULTS: The mean age of the participants was 58 years (SD+/-13 years). Over half (53.8%) were females. Three quarters (77.3%) of the participants were adherent to their medications. The overall proportion of participants with optimally controlled BP was 42.9%.Female sex (Adjusted Odd Ratio(AOR) = 1.94, 95% CI: 1.15, 3.26), age older than 60 years (AOR = 2.95, 95% CI: 1.18, 7.40), consumption of vegetables on most days of the week (AOR = 2.16, 95% CI: 1.25, 3.73), physical activity (AOR = 4.85, 95% CI: 2.39, 9.83), and taking less than three drugs per day (AOR = 3.04, 95% CI: 1.51, 6.14) were positively associated with optimally controlled BP. Poor adherence to medications (AOR = 0.18, 95% CI: 0.09, 0.35), having asthma comorbidity (AOR = 0.33, 95% CI:0.12, 0.88) and use of top added salt on a plate (AOR = 0.20, 95% CI:0.11, 0.36) were negatively associated with optimal BP control. CONCLUSION: A higher proportion of hypertensive patients remain with un controlled BP. Modifiable risk factors including poor adherence to medications, lack of physical exercise, adding salt into meals, being on multiple medications and comorbidities were significantly and independently associated with poor BP control. Evidence-based, adherence-enhancing and healthy life style interventions should be implemented. PMID- 29718965 TI - Comparison of pain burden and psychological factors in Brazilian women living with HIV and chronic neuropathic or nociceptive pain: An exploratory study. AB - Psychological factors including pain catastrophizing and resilience associate with adjustment and quality of life in people living with chronic pain. Nevertheless, their presentation among females living with HIV and chronic pain has been poorly studied. Given that chronic pain in those living with HIV might occur due to different mechanisms (nociceptive or neuropathic), we hypothesize that the associated psychological states could also differ between these groups. We aimed to compare pain frequency and interference, psychological factors and sleep quality between females living with chronic nociceptive or neuropathic pain. Also, we explored correlations between psychological factors, pain severity and interference in females living with HIV and chronic pain. We performed a cross sectional study assessing females living with HIV and chronic pain, and compared it with a female HIV-positive, pain-free control sample in Brazil. To discriminate the most likely underlying mechanism for the chronic pain, we applied the Leeds Assessment for Neuropathic Signs and Symptoms (LANSS). Forty nine females living with HIV and chronic pain were assessed, and divided in control (n = 12), nociceptive (n = 10) and neuropathic pain (n = 27) groups. Using validated scales, their pain catastrophizing, resilience, depression, anxiety and sleep disorders were assessed between May 2014 and August 2015. Compared to controls, females living with HIV and neuropathic chronic pain had higher pain frequency (p<0.001), interference on activities (p = 0.002), interference with emotions (p<0.001), catastrophizing (p<0.001), depression (p = 0.015), and lower resilience (p = 0.011). Catastrophizing was also significantly correlated to the burden of chronic pain. The type of chronic pain in females living with HIV should raise concerns regarding significant burden in psychological states in this population (particularly neuropathic pain). Using scales such as the LANSS to identify the type of choric pain, could be of use to address relevant issues for the patients, and to propose tailored therapies. PMID- 29718966 TI - Are endemics functionally distinct? Leaf traits of native and exotic woody species in a New Zealand forest. AB - Recent studies have concluded that native and invasive species share a common set of trait relationships. However, native species in isolated regions might be functionally constrained by their unique evolutionary histories such that they follow different carbon capture strategies than introduced species. We compared leaf traits relating to resource investment, carbon return, and resource-use efficiency in 16 native (endemic) and three non-native (invasive) species in a temperate forest in Canterbury, South Island, New Zealand. Trait differences were more closely associated with leaf habit than nativity. Deciduous species (including invaders) exhibited greater maximum photosynthetic rates at similar resource costs, which resulted in greater nitrogen- and energy-use efficiencies than evergreen natives. Leaf area was the only trait that differed significantly by nativity (over two-fold larger in invaders). Invaders and deciduous natives both occupied the 'fast return' end of the leaf economics spectrum in contrast to the native evergreens which had comparatively slow return on investment. Dominant woody invaders in this forest are physiologically distinct from many New Zealand endemic species, which are overwhelmingly evergreen. It remains unclear whether these trait differences translate to an ecological divergence in plant strategy, but these results suggest that ecophysiological tradeoffs are likely constrained by biogeography. PMID- 29718967 TI - Mycobactericidal activity of bedaquiline plus rifabutin or rifampin in ex vivo whole blood cultures of healthy volunteers: A randomized controlled trial. AB - BACKGROUND: Bedaquiline, an antimycobacterial agent approved for drug-resistant tuberculosis, is metabolized by CYP3A4, an hepatic enzyme strongly induced by rifampin, an essential part of drug-sensitive tuberculosis treatment. We examined the pharmacokinetic interactions of bedaquiline plus either rifampin or rifabutin in 33 healthy volunteers. This sub-study of that trial examined the mycobactericidal activity of these drugs against intracellular Mycobacterium tuberculosis using ex vivo whole blood culture. METHODS: Subjects were randomly assigned to receive two single 400 mg doses of bedaquiline, alone, and, after a 4 week washout period, in combination with steady-state daily dosing of either rifabutin 300 mg or rifampin 600 mg. Blood samples were collected prior to dosing and at multiple time points subsequently, to measure plasma drug concentrations and bactericidal activity in ex vivo M tuberculosis-infected whole blood cultures (WBA). RESULTS: Single oral doses of bedaquiline produced readily detectable WBA ex vivo, reaching a maximal effect of -0.28 log/day, with negative values indicating bacterial killing. Plasma concentrations of 355 ng/ml were sufficient for intracellular mycobacteriostasis. Combined dosing with rifampin or rifabutin produced maximal effects of -0.91 and -0.79 log/d, respectively. However, the activity of the rifabutin combination was sustained throughout the dosing interval, thereby producing a greater cumulative or total effect. At low drug concentrations, rifabutin plus bedaquiline yielded greater mycobactericidal activity than the sum of their separate effects. Neither drug metabolites nor cellular drug accumulation could account for this observation. CONCLUSIONS: The combination of rifabutin plus bedaquiline produces sustained intracellular mycobactericidal activity that is greater than the sum of their individual effects. Further studies of the treatment-shortening potential of this combination are warranted. PMID- 29718968 TI - Acute attenuation of fatigue after sodium bicarbonate supplementation does not manifest into greater training adaptations after 10-weeks of resistance training exercise. AB - PURPOSE: In two concurrent studies, we aimed to a) confirm the acute effect of 0.3 g.kg-1 body weight (BW) sodium bicarbonate (NaHCO3) supplementation on central and peripheral mechanisms associated with explosive power (Study 1) and b) determine whether chronic NaHCO3 supplementation would improve the adaptive response of the neuromuscular system during a 10-week resistance training program (Study 2). METHODS: Eight resistance trained participants volunteered after providing written consent. The experimental design consisted of a week of baseline testing, followed by ten weeks of training with progress measures performed in Week 5. Study 1 involved neuromuscular measurements before and after the leg extension portion of a power based training session performed in Week 1. Changes in maximal torque (MVT) and rates of torque development (RTD), along with other variables derived from femoral nerve stimulation (e.g. voluntary activation, neural recruitment) were analysed to determine the extent of fatigue under NaHCO3 or placebo conditions. Changes in these same variables, coupled with functional 1-repetition maximum leg extension strength, were measured in Study 2 from baseline (Week 0) to Week 5, and again at Week 10. RESULTS AND CONCLUSION: In Study 1, we observed a decline after the leg extension task in both MVT (~ 30%) and rates of torque production (RTD) irrespective of acid-base status, however the decline in maximal RTD (RTDMAX) was nearly 20% less in the NaHCO3 condition when compared to placebo (mean difference of 294.8 +/- 133.4 Nm.s-1 (95% CI -583.1 to -6.5 Nm, p < 0.05)). The primary finding in Study 2, however, suggests that introducing NaHCO3 repeatedly during a 10-week RT program does not confer any additional benefit to the mechanisms (and subsequent adaptive processes) related to explosive power production. PMID- 29718969 TI - Is prevention better than cure? A systematic review of the effectiveness of well being interventions for military personnel adjusting to civilian life. AB - Exposure to stressful and potentially traumatic experiences is a risk for military personnel and for some this may increase susceptibility to reduced well being. The aim of this systematic review was to examine the effectiveness of interventions to promote the well-being of military personnel adjusting to civilian life. Electronic databases were searched including MEDLINE, Embase, HMIC, PsycINFO, Pilots and CINAHL. Twelve articles, all conducted in the USA, were included in the review. Articles were synthesised narratively and assessed for bias against established criteria. The studies evaluated the effectiveness of interventions for current and former military personnel. The interventions included expressive writing, anger management, cognitive training, psycho education, and techniques to promote relaxation, connection in relationships and resilience. Interventions had some significant positive effects mostly for veterans adjusting to civilian life and other family members. There was much heterogeneity in the design and the outcome measures used in the studies reviewed. The review highlights the need for future robust trials examining the effectiveness of well-being interventions in military groups with diverse characteristics; in addition qualitative research to explore a conceptualisation of well-being for this group and the acceptability of interventions which may be perceived as treatment. The results of the review will be of interest to a number of stakeholders in military, public health and mental health settings. PROSPERO Registration number: CRD42015026341. PMID- 29718970 TI - The current status of clinical trials focusing on nasopharyngeal carcinoma: A comprehensive analysis of ClinicalTrials.gov database. AB - PURPOSE: Clinical Trials have emerged as the main force in driving the development of medicine. However, little is known about the current status of clinical trials regarding nasopharyngeal carcinoma (NPC). This study aimed at providing a comprehensive landscape of NPC-related trials on the basis of ClinicalTrials.gov database. PATIENTS AND METHODS: We used the keyword "nasopharyngeal carcinoma" to search the ClinicalTrials.gov database and assessed the characteristics of these trials. RESULTS: Up to December 30, 2016, 462 eligible trials in total were identified, of which 222 (48.0%) recruited only NPC (NPC trials) and the other 240 (52.0%) recruited both NPC and other cancers (multiple cancer trials). Moreover, 47 (10.2%) were Epstein-Barr virus (EBV) related trials and 267 (57.8%) focused on metastatic/recurrent disease. Compared with NPC trials, the multiple cancer trials had a higher percentage of phase 1 (26.7% vs. 6.7%, P < 0.001) studies and more patients with metastatic/recurrent disease (72.5% vs. 41.9%, P < 0.001). Notably, non-EBV trials had more phase 2 or 3 (78.4% vs. 48.8%, P < 0.001) and interventional studies (89.5% vs. 70.7%, P = 0.002) than EBV trials. Obviously, more phase 2/3 or 3 trials were conducted in patients with non-metastatic/recurrent disease (29.4% vs. 4.9%, P < 0.001); however, metastatic/recurrent trials were more likely to be anticancer (94.6% vs. 63.6%, P < 0.001). CONCLUSIONS: The role of plasma EBV DNA in clinical trials is underestimated, and high-level randomized clinical trials should be performed for patients with metastatic/recurrent disease. PMID- 29718971 TI - Personal, social, and environmental factors associated with lifejacket wear in adults and children: A systematic literature review. AB - OBJECTIVE: Drowning claims 7% of the global burden of injury-related deaths. Lifejackets are routinely recommended as a drowning prevention strategy; however, a review of related factors regarding lifejacket wear has not previously been investigated. METHODS: This systematic review examined literature published from inception to December 2016 in English and German languages. The personal, social, and environmental factors associated with lifejacket wear among adults and children were investigated, a quantitative evaluation of the results undertaken, and gaps in the literature identified. RESULTS: Twenty studies, with sample sizes of studies ranging between 20 and 482,331, were identified. Fifty-five percent were cross-sectional studies. All studies were scored IV or V on the Australian National Health and Medical Research Council (NHMRC) grading system indicating mostly descriptive and cross-sectional levels of evidence. Factors associated with increased wear included age (mostly children), gender (mostly female), boat type (non-motorised), boat size (small boats), role modelling (children influenced by adult lifejacket wear), and activity (water-skiing, fishing). Factors not associated or inconsistent with lifejacket wear included education, household income, ethnicity, boating ability, confidence in lifejackets, waterway type, and weather and water conditions. Factors associated with reduced lifejacket wear included adults, males, discomfort, cost and accessibility, consumption of alcohol, and swimming ability. Three studies evaluated the impact of interventions. CONCLUSION: This review identified factors associated with both increased and decreased lifejacket wear. Future research should address the motivational factors associated with individuals' decisions to wear or not wear lifejackets. This, combined with further research on the evaluation of interventions designed to increase lifejacket wear, will enhance the evidence base to support future drowning prevention interventions. PMID- 29718972 TI - Structure of frequency-interacting RNA helicase from Neurospora crassa reveals high flexibility in a domain critical for circadian rhythm and RNA surveillance. AB - The FRH (frequency-interacting RNA helicase) protein is the Neurospora crassa homolog of yeast Mtr4, an essential RNA helicase that plays a central role in RNA metabolism as an activator of the nuclear RNA exosome. FRH is also a required component of the circadian clock, mediating protein interactions that result in the rhythmic repression of gene expression. Here we show that FRH unwinds RNA substrates in vitro with a kinetic profile similar to Mtr4, indicating that while FRH has acquired additional functionality, its core helicase function remains intact. In contrast with the earlier FRH structures, a new crystal form of FRH results in an ATP binding site that is undisturbed by crystal contacts and adopts a conformation consistent with nucleotide binding and hydrolysis. Strikingly, this new FRH structure adopts an arch domain conformation that is dramatically altered from previous structures. Comparison of the existing FRH structures reveals conserved hinge points that appear to facilitate arch motion. Regions in the arch have been previously shown to mediate a variety of protein-protein interactions critical for RNA surveillance and circadian clock functions. The conformational changes highlighted in the FRH structures provide a platform for investigating the relationship between arch dynamics and Mtr4/FRH function. PMID- 29718974 TI - Effect of e-liquid flavor on electronic cigarette topography and consumption behavior in a 2-week natural environment switching study. AB - Electronic Nicotine Delivery Systems (ENDS) offer an alternate means to consume nicotine in a variety of flavored aerosols. Data are needed to better understand the impact of flavors on use behavior. A natural environment observational study was conducted on experienced ENDS users to measure the effect of e-liquid flavor on topography and consumption behavior. The RIT wPUMTM monitor was used to record to record the date and time and puff topography (flow rate, volume, duration) for every puff taken by N = 34 participants over the course of two weeks. All participants used tobacco flavor for one week, and either berry or menthol flavor for one week. Results provide strong evidence that flavor affects the topography behaviors of mean puff flow rate and mean puff volume, and there is insufficient evidence to support an influence of flavor on mean puff duration and mean puff interval. There was insufficient evidence, due to the low power associated with the limited number of observation days, to establish a relationship between flavor and cumulative consumption behavior. While the results indicate that an effect may be evident, additional observation days are required to establish significance. PMID- 29718973 TI - Abrogation of transforming growth factor-beta-induced tissue fibrosis in TBRIcaCol1a2Cre transgenic mice by the second generation tyrosine kinase inhibitor SKI-606 (Bosutinib). AB - Transforming growth factor-beta (TGF-beta) plays a crucial role in the pathogenesis of Systemic Sclerosis (SSc) and other fibrotic disorders. TGF-beta mediated c-Abl and Src kinase activation induces strong profibrotic cascade signaling. The purpose of this study was to test in vivo the antifibrotic activity of Bosutinib (SKI-606), a second generation c-Abl and Src kinase inhibitor, on TGF-beta induced cutaneous and pulmonary fibrosis. For this purpose, we employed the TBRIcaCol1a2Cre transgenic mice expressing an inducible constitutively active TGF-beta receptor 1 constitutively activated by Col1a promoter-mediated Cre recombinase. The mice were treated parenterally with 2.5, 5.0 or 10.0 mg/kg/day of Bosutinib for 42 days. Skin and lungs from control and Bosutinib-treated mice (n = 6 per group) were assessed by histopathology, measurement of tissue hydroxyproline content, PCR analysis of tissue fibrosis associated gene expression, and evidence of myofibroblast activation. Mice with constitutive TGF-beta-1 signaling displayed severe cutaneous and pulmonary fibrosis. Bosutinib administration decreased collagen deposition and hydroxyproline content in the dermis and lungs in a dose-dependent manner. Bosutinib also reversed the marked increase in profibrotic and myofibroblast activation-associated gene expression. These results demonstrate that constitutive TGF-beta-1-signaling-induced cutaneous and pulmonary fibrosis were abrogated in a dose-related manner following parenteral administration of the c Abl and Src tyrosine kinase inhibitor, Bosutinib. These results indicate that Bosutinib may be a potential therapeutic agent for tissue fibrosis in SSc and other fibroproliferative disorders. PMID- 29718975 TI - Modeling the diffusion of complex innovations as a process of opinion formation through social networks. AB - Complex innovations- ideas, practices, and technologies that hold uncertain benefits for potential adopters-often vary in their ability to diffuse in different communities over time. To explain why, I develop a model of innovation adoption in which agents engage in naive (DeGroot) learning about the value of an innovation within their social networks. Using simulations on Bernoulli random graphs, I examine how adoption varies with network properties and with the distribution of initial opinions and adoption thresholds. The results show that: (i) low-density and high-asymmetry networks produce polarization in influence to adopt an innovation over time, (ii) increasing network density and asymmetry promote adoption under a variety of opinion and threshold distributions, and (iii) the optimal levels of density and asymmetry in networks depend on the distribution of thresholds: networks with high density (>0.25) and high asymmetry (>0.50) are optimal for maximizing diffusion when adoption thresholds are right skewed (i.e., barriers to adoption are low), but networks with low density (<0.01) and low asymmetry (<0.25) are optimal when thresholds are left-skewed. I draw on data from a diffusion field experiment to predict adoption over time and compare the results to observed outcomes. PMID- 29718976 TI - The use of the hypervariable P8 region of trnL(UAA) intron for identification of orchid species: Evidence from restriction site polymorphism analysis. AB - The P8 stem-loop region of the trnL intron, which is known to be hypervariable in size with multiple repeat motifs and created difficulties in alignment, is always excluded in phylogenetic as well as barcode analyses. This region was investigated for species discrimination in 98 taxa of orchids belonging to the tribe Vandeae using in silico mapping of restriction site polymorphism. The length of the P8 regions varied from 200 nucleotides in Aerides rosea to 669 nucleotides in Dendrophylax sallei. Forty two taxa had unique lengths, while as many as eight shared a common length of 521 nucleotides. Of the 35 restriction endonucleases producing digestions in the P8 regions, three, viz., AgsI, ApoI and TspDTI turned out to have recognition sites across all the 98 taxa being studied. When their restriction data were combined, 92 taxa could be discriminated leaving three taxon pairs. However, Acampe papillosa and Aeranthes arachnites despite having similar restriction sites differed in their P8 lengths. This is the first report on thorough investigation of the P8 region of trnL intron for search of species specific restriction sites and hence its use as a potential plant DNA barcode. PMID- 29718978 TI - General trust impedes perception of self-reported primary psychopathy in thin slices of social interaction. AB - Little is known about people's ability to detect subclinical psychopathy from others' quotidian social behavior, or about the correlates of variation in this ability. This study sought to address these questions using a thin slice personality judgment paradigm. We presented 108 undergraduate judges (70.4% female) with 1.5 minute video thin slices of zero-acquaintance triadic conversations among other undergraduates (targets: n = 105, 57.1% female). Judges completed self-report measures of general trust, caution, and empathy. Target individuals had completed the Levenson Self-Report Psychopathy (LSRP) scale. Judges viewed the videos in one of three conditions: complete audio, silent, or audio from which semantic content had been removed using low-pass filtering. Using a novel other-rating version of the LSRP, judges' ratings of targets' primary psychopathy levels were significantly positively associated with targets' self-reports, but only in the complete audio condition. Judge general trust and target LSRP interacted, such that judges higher in general trust made less accurate judgments with respect to targets higher in primary and total psychopathy. Results are consistent with a scenario in which psychopathic traits are maintained in human populations by negative frequency dependent selection operating through the costs of detecting psychopathy in others. PMID- 29718977 TI - Strategy intervention for the evolution of fairness. AB - The 'irrational' preference for fairness has attracted increasing attention. Although previous studies have focused on the effects of spitefulness on the evolution of fairness, they did not consider non-monotonic rejections shown in behavioral experiments. In this paper, we introduce a non-monotonic rejection in an evolutionary model of the Ultimatum Game. We propose strategy intervention to study the evolution of fairness in general structured populations. By sequentially adding five strategies into the competition between a fair strategy and a selfish strategy, we arrive at the following conclusions. First, the evolution of fairness is inhibited by altruism, but it is promoted by spitefulness. Second, the non-monotonic rejection helps fairness overcome selfishness. Particularly for group-structured populations, we analytically investigate how fairness, selfishness, altruism, and spitefulness are affected by population size, mutation, and migration in the competition among seven strategies. Our results may provide important insights into understanding the evolutionary origin of fairness. PMID- 29718980 TI - Polymorphism in merozoite surface protein-7E of Plasmodium vivax in Thailand: Natural selection related to protein secondary structure. AB - Merozoite surface protein 7 (MSP-7) is a multigene family expressed during malaria blood-stage infection. MSP-7 forms complex with MSP-1 prior to merozoite egress from erythrocytes, and could affect merozoite invasion of erythrocytes. To characterize sequence variation in the orthologue in P. vivax (PvMSP-7), a gene member encoding PvMSP-7E was analyzed among 92 Thai isolates collected from 3 major endemic areas of Thailand (Northwest: Tak, Northeast: Ubon Ratchathani, and South: Yala and Narathiwat provinces). In total, 52 distinct haplotypes were found to circulate in these areas. Although population structure based on this locus was observed between each endemic area, no genetic differentiation occurred between populations collected from different periods in the same endemic area, suggesting spatial but not temporal genetic variation. Sequence microheterogeneity in both N- and C- terminal regions was predicted to display 4 and 6 alpha-helical domains, respectively. Signals of purifying selection were observed in alpha-helices II-X, suggesting structural or functional constraint in these domains. By contrast, alpha-helix-I spanning the putative signal peptide was under positive selection, in which amino acid substitutions could alter predicted CD4+ T helper cell epitopes. The central region of PvMSP-7E comprised the 5'-trimorphic and the 3'-dimorphic subregions. Positive selection was identified in the 3' dimorphic subregion of the central domain. A consensus of intrinsically unstructured or disordered protein was predicted to encompass the entire central domain that contained a number of putative B cell epitopes and putative protein binding regions. Evidences of intragenic recombination were more common in the central region than the remainders of the gene. These results suggest that the extent of sequence variation, recombination events and selective pressures in the PvMSP-7E locus seem to be differentially affected by protein secondary structure. PMID- 29718982 TI - Correction: Detection of human bocavirus in Saudi healthy blood donors. AB - [This corrects the article DOI: 10.1371/journal.pone.0193594.]. PMID- 29718979 TI - Diet induced obesity alters muscle spindle afferent function in adult mice. AB - Populations with obesity are more likely to fall and exhibit balance instability. The reason for this is likely multifactorial, but there is some evidence that sensory function is impaired during obesity. We tested the hypothesis that muscle proprioceptor function is compromised in a mouse model of diet induced obesity. An in vitro muscle-nerve preparation was used to record muscle spindle afferent responses to physiological stretch and sinusoidal vibration. We compared the responses of C57/Bl6 male and female mice on a control diet (10% kcal fat) with those eating a high fat diet (HFD; 60% kcal fat) for 10 weeks (final age 14-15 weeks old). Following HFD feeding, adult mice of both sexes exhibited decreased muscle spindle afferent responses to muscle movement. Muscle spindle afferent firing rates during the plateau phase of stretch were significantly lower in both male and female HFD animals as were two measures of dynamic sensitivity (dynamic peak and dynamic index). Muscle spindle afferents in male mice on a HFD were also significantly less likely to entrain to vibration. Due to the importance of muscle spindle afferents to proprioception and motor control, decreased muscle spindle afferent responsiveness may contribute to balance instability during obesity. PMID- 29718981 TI - Tauroursodeoxycholic acid (TUDCA) alleviates endoplasmic reticulum stress of nuclear donor cells under serum starvation. AB - Serum starvation is a routine protocol for synchronizing nuclear donor cells to G0/G1 phase during somatic cell nuclear transfer (SCNT). However, abrupt serum deprivation can cause serious stress to the cells cultured in vitro, which might result in endoplasmic reticulum (ER) stress, chromosome damage, and finally reduce the success rate of SCNT. In the present study, the effects of tauroursodeoxycholic acid (TUDCA), an effective ER stress-relieving drug, on the nuclear donor cells under serum deprivation condition as well as following SCNT procedures were first assessed in the bovine. The results showed that TUDCA significantly reduced ER stress and cell apoptosis in those nuclear donor cells. Moreover, it significantly decreased the expression of Hdac1 and Dnmt1, and increased the level of H3K9 acetylation in nuclear donor cells compared with control group. SCNT reconstructed embryos cloned from TUDCA-treated donor cells showed significantly higher fusion, cleavage, blastocyst formation rate, total cell number in day 7 blastocysts, and lower apoptotic index than that from control group. In addition, the expression of Hdac1, Dnmt1 and Bax was significantly lower in blastocysts derived from TUDCA-treated donor cells than that from control group. In conclusion, TUDCA significantly reduced the ER stress of nuclear donor cells under serum starvation condition, and significantly improved the developmental competence of following SCNT reconstructed embryos when these TUDCA-treated cells were used as the nuclear donors. PMID- 29718984 TI - Correction: Positive cytoplasmic UCHL5 tumor expression in gastric cancer is linked to improved prognosis. AB - [This corrects the article DOI: 10.1371/journal.pone.0193125.]. PMID- 29718983 TI - Assessment of accuracy and recognition of three-dimensional computerized forensic craniofacial reconstruction. AB - Facial reconstruction is a technique that aims to reproduce the individual facial characteristics based on interpretation of the skull, with the objective of recognition leading to identification. The aim of this paper was to evaluate the accuracy and recognition level of three-dimensional (3D) computerized forensic craniofacial reconstruction (CCFR) performed in a blind test on open-source software using computed tomography (CT) data from live subjects. Four CCFRs were produced by one of the researchers, who was provided with information concerning the age, sex, and ethnic group of each subject. The CCFRs were produced using Blender(r) with 3D models obtained from the CT data and templates from the MakeHuman(r) program. The evaluation of accuracy was carried out in CloudCompare, by geometric comparison of the CCFR to the subject 3D face model (obtained from the CT data). A recognition level was performed using the Picasa(r) recognition tool with a frontal standardized photography, images of the subject CT face model and the CCFR. Soft-tissue depth and nose, ears and mouth were based on published data, observing Brazilian facial parameters. The results were presented from all the points that form the CCFR model, with an average for each comparison between 63% and 74% with a distance -2.5 <= x <= 2.5 mm from the skin surface. The average distances were 1.66 to 0.33 mm and greater distances were observed around the eyes, cheeks, mental and zygomatic regions. Two of the four CCFRs were correctly matched by the Picasa(r) tool. Free software programs are capable of producing 3D CCFRs with plausible levels of accuracy and recognition and therefore indicate their value for use in forensic applications. PMID- 29718985 TI - Correction: Modulating lysosomal function through lysosome membrane permeabilization or autophagy suppression restores sensitivity to cisplatin in refractory non-small-cell lung cancer cells. AB - [This corrects the article DOI: 10.1371/journal.pone.0184922.]. PMID- 29718987 TI - Correction: Rates and risk factors for human cutaneous anthrax in the country of Georgia: National surveillance data, 2008-2015. AB - [This corrects the article DOI: 10.1371/journal.pone.0192031.]. PMID- 29718986 TI - Self-digitization chip for single-cell genotyping of cancer-related mutations. AB - Cancer is a heterogeneous disease, and patient-level genetic assessments can guide therapy choice and impact prognosis. However, little is known about the impact of genetic variability within a tumor, intratumoral heterogeneity (ITH), on disease progression or outcome. Current approaches using bulk tumor specimens can suggest the presence of ITH, but only single-cell genetic methods have the resolution to describe the underlying clonal structures themselves. Current techniques tend to be labor and resource intensive and challenging to characterize with respect to sources of biological and technical variability. We have developed a platform using a microfluidic self-digitization chip to partition cells in stationary volumes for cell imaging and allele-specific PCR. Genotyping data from only confirmed single-cell volumes is obtained and subject to a variety of relevant quality control assessments such as allele dropout, false positive, and false negative rates. We demonstrate single-cell genotyping of the NPM1 type A mutation, an important prognostic indicator in acute myeloid leukemia, on single cells of the cell line OCI-AML3, describing a more complex zygosity distribution than would be predicted via bulk analysis. PMID- 29718988 TI - Correction: Evaluation of the fusion inhibitor P3 peptide as a potential microbicide to prevent HIV transmission in women. AB - [This corrects the article DOI: 10.1371/journal.pone.0195744.]. PMID- 29718989 TI - First evidence of SGPL1 expression in the cell membrane silencing the extracellular S1P siren in mammary epithelial cells. AB - The bioactive lipid sphingosine-1-phosphate (S1P) is a main regulator of cell survival, proliferation, motility, and platelet aggregation, and it is essential for angiogenesis and lymphocyte trafficking. In that S1P acts as a second messenger intra- and extracellularly, it might promote cancer progression. The main cause is found in the high S1P concentration in the blood, which encourage cancer cells to migrate through the endothelial barrier into the blood vessels. The irreversible degradation of S1P is solely caused by the sphingosine-1 phosphate lyase (SGPL1). SGPL1 overexpression reduces cancer cell migration and therefore silences the endogenous S1P siren, which promotes cancer cell attraction-the main reason for metastasis. Since our previous metabolomics studies revealed an increased SGPL1 activity in association with successful breast cancer cell treatment in vitro, we further investigated expression and localization of SGPL1. Expression analyses confirmed a very low SGPL1 expression in all breast cancer samples, regardless of their subtype. Additionally, we were able to prove a novel SGPL expression in the cytoplasm membrane of non tumorigenic breast cells by fusing three independent methods. The general SGPL1 downregulation and the loss of the plasma membrane expression resulted in S1P dependent stimulation of migration in the breast cancer cell lines MCF-7 and BT 20. Not only S1P stimulated migration could be repressed by overexpressing the natural SGPL1 variant not but also more general migratory activity was significantly reduced. Here, for the first time, we report on the SGPL1 plasma membrane location in human, non-malignant breast epithelial cell lines silencing the extracellular S1P siren in vitro, and thereby regulating pivotal cellular functions. Loss of this plasma membrane distribution as well as low SGPL1 expression levels could be a potential prognostic marker and a viable target for therapy. Therefore, the precise role of SGPL1 for cancer treatment should be evaluated. PMID- 29718990 TI - A multi-antigenic MVA vaccine increases efficacy of combination chemotherapy against Mycobacterium tuberculosis. AB - Despite the existence of the prophylactic Bacille Calmette-Guerin (BCG) vaccine, infection by Mycobacterium tuberculosis (Mtb) remains a major public health issue causing up to 1.8 million annual deaths worldwide. Increasing prevalence of Mtb strains resistant to antibiotics represents an urgent threat for global health that has prompted a search for alternative treatment regimens not subject to development of resistance. Immunotherapy constitutes a promising approach to improving current antibiotic treatments through engagement of the host's immune system. We designed a multi-antigenic and multiphasic vaccine, based on the Modified Vaccinia Ankara (MVA) virus, denoted MVATG18598, which expresses ten antigens classically described as representative of each of different phases of Mtb infection. In vitro analysis coupled with multiple-passage evaluation demonstrated that this vaccine is genetically stable, i.e. fit for manufacturing. Using different mouse strains, we show that MVATG18598 vaccination results in both Th1-associated T-cell responses and cytolytic activity, targeting all 10 vaccine-expressed Mtb antigens. In chronic post-exposure mouse models, MVATG18598 vaccination in combination with an antibiotic regimen decreases the bacterial burden in the lungs of infected mice, compared with chemotherapy alone, and is associated with long-lasting antigen-specific Th1-type T cell and antibody responses. In one model, co-treatment with MVATG18598 prevented relapse of the disease after treatment completion, an important clinical goal. Overall, results demonstrate the capacity of the therapeutic MVATG18598 vaccine to improve efficacy of chemotherapy against TB. These data support further development of this novel immunotherapeutic in the treatment of Mtb infections. PMID- 29718991 TI - A lipid-binding loop of botulinum neurotoxin serotypes B, DC and G is an essential feature to confer their exquisite potency. AB - The exceptional toxicity of botulinum neurotoxins (BoNTs) is mediated by high avidity binding to complex polysialogangliosides and intraluminal segments of synaptic vesicle proteins embedded in the presynaptic membrane. One peculiarity is an exposed hydrophobic loop in the toxin's cell binding domain HC, which is located between the ganglioside- and protein receptor-binding sites, and that is particularly pronounced in the serotypes BoNT/B, DC, and G sharing synaptotagmin as protein receptor. Here, we provide evidence that this HC loop is a critical component of their tripartite receptor recognition complex. Binding to nanodisc embedded receptors and toxicity were virtually abolished in BoNT mutants lacking residues at the tip of the HC loop. Surface plasmon resonance experiments revealed that only insertion of the HC loop into the lipid-bilayer compensates for the entropic penalty inflicted by the dual-receptor binding. Our results represent a new paradigm of how BoNT/B, DC, and G employ ternary interactions with a protein, ganglioside, and lipids to mediate their extraordinary neurotoxicity. PMID- 29718992 TI - Analysis of risk factors associated with hepatocellular carcinoma in black South Africans: 2000-2012. AB - OBJECTIVE: The aims of this study were to determine the prevalence of risk factors associated with hepatocellular carcinoma (HCC) in black adult South Africans and to estimate the size of the associated risks. METHODS: A case control analysis of 150 black South African patients (aged 18-75 years) with HCC who were a subset of patients recruited for the Johannesburg Cancer Case Control Study 2000 to 2012-was undertaken. The association between this tumour and hepatitis B/C virus infections, and human immunodeficiency virus (HIV) mono- and co-infections was investigated. Odds ratios (ORs) and 95% confidence intervals (CI) adjusted for age, year of diagnosis, marital status, place of birth and selected modifiable risk factors were calculated. RESULTS: HCC was significantly associated with a rural birthplace (p<0.05), being male and living in an urban area for 14 years or less. The Odds Ratio (OR) for HCC increased significantly with HBV DNA+/HBsAg+ (OR 34.5; CI:16.26-73.13), HBV DNA+/HBsAg- (OR 3.76; CI:1.79 7.92), HBV DNA level >2000 IU/ml (OR 8.55; CI:3.00-24.54) to >=200,000 (OR 16.93; CI:8.65-33.13), anti-HCV (OR 8.98; CI:3.59-22.46), HBV DNA+/HIV+ co-infection (OR 5.36; CI:2.59-11.11), but not with HBV DNA-/HIV+ (OR 0.34; CI:0.14-0.85). We did not find a synergistic interaction between HBV and HIV. Modifiable risk factors (alcohol consumption, tobacco smoking, number of sexual partners, diabetes and hormonal contraceptive use) were nonsignificant. DISCUSSION: A considerable portion of the HCC burden in Johannesburg and surrounding provinces falls on rural migrants to urban areas, most of whom are men. The HBV will continue to contribute to HCC incidence in older age-groups and in others who missed vaccination. Although we did not find an increased risk for HCC in HIV positive individuals this may change as life expectancy increases due to greater access to antiretroviral therapies, necessitating the addition of hepatitis virus screening to preventive medical care. PMID- 29718994 TI - Premna vietnamensis (Lamiaceae, Premnoideae), a distinct new species from the Central Highlands of Vietnam. AB - Premna vietnamensis, a distinct new species which is endemic to Gia Lai Province in Central Highlands of Vietnam, is described and illustrated. It is characterized by its calyx tube bearing a semi-globose fleshy appendage, which has not been reported before from all known congeneric taxa, as well as from the Lamiaceae. A phylogenetic analysis of the whole Lamiaceae based on a sampling including representatives from all 12 currently recognized subfamilies confirmed the placement of this new species within Premna of the Premnoideae. Morphologically and geographically, P. vietnamensis is most similar to P. stenobotrys, but differs significantly in many aspects. PMID- 29718995 TI - Correction: Inhibiting TGF-beta signaling preserves the function of highly activated, in vitro expanded natural killer cells in AML and colon cancer models. AB - [This corrects the article DOI: 10.1371/journal.pone.0191358.]. PMID- 29718993 TI - Large-scale functional networks connect differently for processing words and symbol strings. AB - Reconfigurations of synchronized large-scale networks are thought to be central neural mechanisms that support cognition and behavior in the human brain. Magnetoencephalography (MEG) recordings together with recent advances in network analysis now allow for sub-second snapshots of such networks. In the present study, we compared frequency-resolved functional connectivity patterns underlying reading of single words and visual recognition of symbol strings. Word reading emphasized coherence in a left-lateralized network with nodes in classical perisylvian language regions, whereas symbol processing recruited a bilateral network, including connections between frontal and parietal regions previously associated with spatial attention and visual working memory. Our results illustrate the flexible nature of functional networks, whereby processing of different form categories, written words vs. symbol strings, leads to the formation of large-scale functional networks that operate at distinct oscillatory frequencies and incorporate task-relevant regions. These results suggest that category-specific processing should be viewed not so much as a local process but as a distributed neural process implemented in signature networks. For words, increased coherence was detected particularly in the alpha (8-13 Hz) and high gamma (60-90 Hz) frequency bands, whereas increased coherence for symbol strings was observed in the high beta (21-29 Hz) and low gamma (30-45 Hz) frequency range. These findings attest to the role of coherence in specific frequency bands as a general mechanism for integrating stimulus-dependent information across brain regions. PMID- 29718997 TI - Correction: Time- and depth-wise trophic niche shifts in Antarctic benthos. AB - [This corrects the article DOI: 10.1371/journal.pone.0194796.]. PMID- 29718996 TI - Transcriptional repression by ApiAP2 factors is central to chronic toxoplasmosis. AB - Tachyzoite to bradyzoite development in Toxoplasma is marked by major changes in gene expression resulting in a parasite that expresses a new repertoire of surface antigens hidden inside a modified parasitophorous vacuole called the tissue cyst. The factors that control this important life cycle transition are not well understood. Here we describe an important transcriptional repressor mechanism controlling bradyzoite differentiation that operates in the tachyzoite stage. The ApiAP2 factor, AP2IV-4, is a nuclear factor dynamically expressed in late S phase through mitosis/cytokinesis of the tachyzoite cell cycle. Remarkably, deletion of the AP2IV-4 locus resulted in the expression of a subset of bradyzoite-specific proteins in replicating tachyzoites that included tissue cyst wall components BPK1, MCP4, CST1 and the surface antigen SRS9. In the murine animal model, the mis-timing of bradyzoite antigens in tachyzoites lacking AP2IV 4 caused a potent inflammatory monocyte immune response that effectively eliminated this parasite and prevented tissue cyst formation in mouse brain tissue. Altogether, these results indicate that suppression of bradyzoite antigens by AP2IV-4 during acute infection is required for Toxoplasma to successfully establish a chronic infection in the immune-competent host. PMID- 29718998 TI - Changes in lipid metabolism and capillary density of the skeletal muscle following low-intensity exercise training in a rat model of obesity with hyperinsulinemia. AB - Although exercise is effective in improving obesity and hyperinsulinemia, the exact influence of exercise on the capillary density of skeletal muscles remains unknown. The aim of this study was to investigate the effects of low-intensity exercise training on metabolism in obesity with hyperinsulinemia, focusing specifically on the capillary density within the skeletal muscle. Otsuka Long Evans Tokushima fatty (OLETF) rats were used as animal models of obesity with hyperinsulinemia, whereas Long-Evans Tokushima Otsuka (LETO) rats served as controls (no obesity, no hyperinsulinemia). The animals were randomly assigned to either non-exercise or exercise groups (treadmill running for 60 min/day, for 4 weeks). The exercise groups were further divided into subgroups according to training mode: single bout (60 min, daily) vs. multiple bout (three bouts of 20 min, daily). Fasting insulin levels were significantly higher in OLETF than in LETO rats. Among OLETF rats, there were no significant differences in fasting glucose levels between the exercise and the non-exercise groups, but the fasting insulin levels were significantly lower in the exercise group. Body weight and triacylglycerol levels in the liver were significantly higher in OLETF than in LETO rats; however, among OLETF rats, these levels were significantly lower in the exercise than in the non-exercise group. The capillary-to-fiber ratio of the soleus muscle was significantly higher in OLETF than in LETO rats; however, among OLETF rats, the ratio was lower in the exercise group than in the non-exercise group. No significant differences in any of the studied parameters were noted between the single-bout and multiple-bout exercise training modes among either OLETF or LETO rats. These results suggest that low-intensity exercise training improves insulin sensitivity and fatty liver. Additionally, the fact that attenuation of excessive capillarization in the skeletal muscle of OLETF rats was accompanied by improvement in increased body weight. PMID- 29719000 TI - Mineral licks as environmental reservoirs of chronic wasting disease prions. AB - Chronic wasting disease (CWD) is a fatal neurodegenerative disease of deer, elk, moose, and reindeer (cervids) caused by misfolded prion proteins. The disease has been reported across North America and recently discovered in northern Europe. Transmission of CWD in wild cervid populations can occur through environmental routes, but limited ability to detect prions in environmental samples has prevented the identification of potential transmission "hot spots". We establish widespread CWD prion contamination of mineral licks used by free-ranging cervids in an enzootic area in Wisconsin, USA. We show mineral licks can serve as reservoirs of CWD prions and thus facilitate disease transmission. Furthermore, mineral licks attract livestock and other wildlife that also obtain mineral nutrients via soil and water consumption. Exposure to CWD prions at mineral licks provides potential for cross-species transmission to wildlife, domestic animals, and humans. Managing deer use of mineral licks warrants further consideration to help control outbreaks of CWD. PMID- 29718999 TI - Glycoengineering HIV-1 Env creates 'supercharged' and 'hybrid' glycans to increase neutralizing antibody potency, breadth and saturation. AB - The extensive glycosylation of HIV-1 envelope (Env) glycoprotein leaves few glycan-free holes large enough to admit broadly neutralizing antibodies (bnAb). Consequently, most bnAbs must inevitably make some glycan contacts and avoid clashes with others. To investigate how Env glycan maturation regulates HIV sensitivity to bnAbs, we modified HIV-1 pseudovirus (PV) using various glycoengineering (GE) tools. Promoting the maturation of alpha-2,6 sialic acid (SA) glycan termini increased PV sensitivity to two bnAbs that target the V2 apex and one to the interface between Env surface gp120 and transmembrane gp41 subunits, typically by up to 30-fold. These effects were reversible by incubating PV with neuraminidase. The same bnAbs were unusually potent against PBMC-produced HIV-1, suggesting similar alpha-2,6 hypersialylated glycan termini may occur naturally. Overexpressing beta-galactosyltransferase during PV production replaced complex glycans with hybrid glycans, effectively 'thinning' trimer glycan coverage. This increased PV sensitivity to some bnAbs but ablated sensitivity to one bnAb that depends on complex glycans. Other bnAbs preferred small glycans or galactose termini. For some bnAbs, the effects of GE were strain specific, suggesting that GE had context-dependent effects on glycan clashes. GE was also able to increase the percent maximum neutralization (i.e. saturation) by some bnAbs. Indeed, some bnAb-resistant strains became highly sensitive with GE thus uncovering previously unknown bnAb breadth. As might be expected, the activities of bnAbs that recognize glycan-deficient or invariant oligomannose epitopes were largely unaffected by GE. Non-neutralizing antibodies were also unaffected by GE, suggesting that trimers remain compact. Unlike mature bnAbs, germline-reverted bnAbs avoided or were indifferent to glycans, suggesting that glycan contacts are acquired as bnAbs mature. Together, our results suggest that glycovariation can greatly impact neutralization and that knowledge of the optimal Env glycoforms recognized by bnAbs may assist rational vaccine design. PMID- 29719002 TI - Correction: Molecular detection of airborne Emergomyces africanus, a thermally dimorphic fungal pathogen, in Cape Town, South Africa. AB - [This corrects the article DOI: 10.1371/journal.pntd.0006174.]. PMID- 29719001 TI - Optimized application of the secreted Nano-luciferase reporter system using an affinity purification strategy. AB - Secreted Nano-luciferase (secNluc) is a newly engineered secreted luciferase that possesses advantages of high structural stability, long half-life, and glow-type kinetics together with high light emission intensity, and thus would become one of the most valuable tools for bioluminescence assays. However, like other secreted luciferases, secNluc has to mix with the components in the conditioned medium surrounding test cells, or in the biological samples such as blood or urine after being secreted. These components may interfere with secNluc-catalyzed bioluminescence reactions and thus limit the application of the secNluc reporter system. In this study, we first examined the effects of three factors, pH, serum and residual reagents, on secNluc-catalyzed bioluminescence reactions, finding that these factors could interfere with bioluminescence reactions and result in background signal. To resolve these problems, we applied a simple affinity purification strategy in which secNluc was fused with a FLAG-tag, and anti-FLAG magnetic beads were used to catch and transfer the fusion protein to PBST, an optimal buffer for secNluc-catalyzed bioluminescence reactions that was identified in this study. The results indicated that this strategy could not only negate the interferences from serum or residual reagents and enhance the stability of light emission but also greatly increase signal intensity through enzyme enrichment. This strategy may contribute to biomedical studies that utilize secNluc and other secreted luciferases, especially those requiring superior sensitivity, low background noise and high reproducibility. PMID- 29719003 TI - Widespread mosquito net fishing in the Barotse floodplain: Evidence from qualitative interviews. AB - BACKGROUND: The insecticide-treated mosquito net (ITN) is a crucial component of malaria control programs, and has prevented many malaria cases and deaths due to scale up. ITNs also serve effectively as fishing nets and various sources have reported use of ITNs for fishing. This article examines how widespread the practice of mosquito net fishing with ITNs is. METHODS: We conducted in-depth interviews with fishery personnel and traditional leadership from the Barotse Royal Establishment in Western Province, Zambia, to better understand the presence or absence of the use of ITNs as fishing nets. We then coded the interviews for themes through content analysis. Additionally we conducted a desk review of survey data to show trends in malaria indicators, nutritional status of the population and fish consumption. RESULTS: All those interviewed reported that ITNs are regularly used for fishing in Western Zambia and the misuse is widespread. Concurrently those interviewed reported declines in fish catches both in terms of quantity and quality leading to threatened food security in the area. In addition to unsustainable fishing practices those interviewed referenced drought and population pressure as reasons for fishery decline. Malaria indicators do not show a trend in declining malaria transmission, fish consumption has dropped dramatically and nutritional status has not improved over time. CONCLUSIONS: Despite the misuse of the ITNs for fishing all those interviewed maintained that ITN distribution should continue. Donors, control programs and scientists should realize that misuse of ITNs as fishing nets is a current problem for malaria control and potentially for food security that needs to be addressed. PMID- 29719004 TI - Data sharing in PLOS ONE: An analysis of Data Availability Statements. AB - A number of publishers and funders, including PLOS, have recently adopted policies requiring researchers to share the data underlying their results and publications. Such policies help increase the reproducibility of the published literature, as well as make a larger body of data available for reuse and re analysis. In this study, we evaluate the extent to which authors have complied with this policy by analyzing Data Availability Statements from 47,593 papers published in PLOS ONE between March 2014 (when the policy went into effect) and May 2016. Our analysis shows that compliance with the policy has increased, with a significant decline over time in papers that did not include a Data Availability Statement. However, only about 20% of statements indicate that data are deposited in a repository, which the PLOS policy states is the preferred method. More commonly, authors state that their data are in the paper itself or in the supplemental information, though it is unclear whether these data meet the level of sharing required in the PLOS policy. These findings suggest that additional review of Data Availability Statements or more stringent policies may be needed to increase data sharing. PMID- 29719005 TI - Anchoring and adjusting amidst humans: Ranging behavior of Persian leopards along the Iran-Turkmenistan borderland. AB - Understanding the space use and movement ecology of apex predators, particularly in mosaic landscapes encompassing different land-uses, is fundamental for formulating effective conservation policy. The top extant big cat in the Middle East and the Caucasus, the Persian leopard Panthera pardus saxicolor, has disappeared from most of its historic range. Its spatial ecology in the areas where it remains is almost unknown. Between September 2014 and May 2017, we collared and monitored six adult leopards (5 males and 1 female) using GPS satellite Iridium transmitters in Tandoureh National Park (355 km2) along the Iran-Turkmenistan borderland. Using auto-correlated Kernel density estimation based on a continuous-time stochastic process for relocation data, we estimated a mean home range of 103.4 +/- SE 51.8 km2 for resident males which is larger than has been observed in other studies of Asian leopards. Most predation events occurred in core areas, averaging 32.4 +/- SE 12.7 km2. Although neighboring leopards showed high spatiotemporal overlap, their hunting areas were largely exclusive. Five out of six of leopards spent some time outside the national park, among human communities. Our study suggests that a national park can play an 'anchoring' role for individuals of an apex predator that spend some time in the surrounding human-dominated landscapes. Therefore, we envisage that instead of emphasizing either land sharing or land sparing, a combined approach can secure the viability of resilient large carnivores that are able to coexist with humans in the rugged montane landscapes of west and central Asia. PMID- 29719006 TI - Blood-based cerebral biomarkers in preeclampsia: Plasma concentrations of NfL, tau, S100B and NSE during pregnancy in women who later develop preeclampsia - A nested case control study. AB - OBJECTIVE: To evaluate if concentrations of the neuronal proteins neurofilament light chain and tau are changed in women developing preeclampsia and to evaluate the ability of a combination of neurofilament light chain, tau, S100B and neuron specific enolase in identifying neurologic impairment before diagnosis of preeclampsia. METHODS: A nested case-control study within a longitudinal study cohort was performed. 469 healthy pregnant women were enrolled between 2004-2007 and plasma samples were collected at gestational weeks 10, 25, 28, 33 and 37. Plasma concentrations of tau and neurofilament light chain were analyzed in 16 women who eventually developed preeclampsia and 36 controls throughout pregnancy with single molecule array (Simoa) method and compared within and between groups. S100B and NSE had been analyzed previously in the same study population. A statistical model with receiving characteristic operation curve was constructed with the four biomarkers combined. RESULTS: Plasma concentrations of neurofilament light chain were significantly increased in women who developed preeclampsia in gestational week 33 (11.85 ng/L, IQR 7.48-39.93 vs 6.80 ng/L, IQR 5.65-11.40) and 37 (22.15 ng/L, IQR 10.93-35.30 vs 8.40 ng/L, IQR 6.40-14.30) and for tau in gestational week 37 (4.33 ng/L, IQR 3.97-12.83 vs 3.77 ng/L, IQR 1.91 5.25) in contrast to healthy controls. A combined model for preeclampsia with tau, neurofilament light chain, S100B and neuron specific enolase in gestational week 25 displayed an area under the curve of 0.77, in week 28 it was 0.75, in week 33 it was 0.89 and in week 37 it was 0.83. Median week for diagnosis of preeclampsia was at 38 weeks of gestation. CONCLUSION: Concentrations of both tau and neurofilament light chain are increased in the end of pregnancy in women developing preeclampsia in contrast to healthy pregnancies. Cerebral biomarkers might reflect cerebral involvement before onset of disease. PMID- 29719007 TI - Gear and survey efficiency of patent tongs for oyster populations on restoration reefs. AB - Surveys of restored oyster reefs need to produce accurate population estimates to assess the efficacy of restoration. Due to the complex structure of subtidal oyster reefs, one effective and efficient means to sample is by patent tongs, rather than SCUBA, dredges, or bottom cores. Restored reefs vary in relief and oyster density, either of which could affect survey efficiency. This study is the first to evaluate gear (the first full grab) and survey (which includes selecting a specific half portion of the first grab for further processing) efficiencies of hand-operated patent tongs as a function of reef height and oyster density on subtidal restoration reefs. In the Great Wicomico River, a tributary of lower Chesapeake Bay, restored reefs of high- and low-relief (25-45 cm, and 8-12 cm, respectively) were constructed throughout the river as the first large-scale oyster sanctuary reef restoration effort (sanctuary acreage > 20 ha at one site) in Chesapeake Bay. We designed a metal frame to guide a non-hydraulic mechanical patent tong repeatedly into the same plot on a restored reef until all oysters within the grab area were captured. Full capture was verified by an underwater remotely-operated vehicle. Samples (n = 19) were taken on nine different reefs, including five low- (n = 8) and four high-relief reefs (n = 11), over a two-year period. The gear efficiency of the patent tong was estimated to be 76% (+/- 5% standard error), whereas survey efficiency increased to 81% (+/- 10%) due to processing. Neither efficiency differed significantly between young-of-the-year oysters (spat) and adults, high- and low-relief reefs, or years. As this type of patent tong is a common and cost-effective tool to evaluate oyster restoration projects as well as population density on fished habitat, knowing the gear and survey efficiencies allows for accurate and precise population estimates. PMID- 29719009 TI - Skin Disease Education Foundation's 42nd Annual Hawaii Dermatology SeminarTM Scientific Abstracts. PMID- 29719010 TI - Fat Fracture: A Rare Cause of Anterior and Medial Knee Pain in a Professional Baseball Player. AB - Blunt trauma to the anterior knee typically results in a contusion or fracture of the patella. Additionally, injury to the extensor mechanism may come from a partial or full disruption of the patellar or quadriceps tendon. A professional baseball player suffered an injury to his knee after he collided with an outfield wall. Acute swelling in the suprapatellar soft tissues concealed a palpable defect, which initially was suspected to be an injury to the quadriceps tendon. Magnetic resonance imaging of the knee revealed an intact extensor mechanism; moreover, a fracture of the subcutaneous fat anterior to the quadriceps tendon was evident and diagnosed as a fat fracture. Fat fracture is a rare diagnosis, and to the best of our knowledge, this is the first reported diagnosis in a professional athlete. Conservative management including, but not limited to, range of motion exercises, hydrotherapy, and iontophoresis effectively treated the athlete's injury. PMID- 29719011 TI - Short-Term Storage of Platelet-Rich Plasma at Room Temperature Does Not Affect Growth Factor or Catabolic Cytokine Concentration. AB - The aim of this study was to provide clinical recommendations about the use of platelet-rich plasma (PRP) that was subjected to short-term storage at room temperature. We determined bioactive growth factor and cytokine concentrations as indicators of platelet and white blood cell degranulation in blood and PRP. Additionally, this study sought to validate the use of manual, direct smear analysis as an alternative to automated methods for platelet quantification in PRP. Blood was used to generate low-leukocyte PRP (Llo PRP) or high-leukocyte PRP (Lhi PRP). Blood was either processed immediately or kept at room temperature for 2 or 4 hours prior to generation of PRP, which was then held at room temperature for 0, 1, 2, or 4 hours. Subsequently, bioactive transforming growth factor beta 1 and matrix metalloproteinase-9 were measured by ELISA (enzyme-linked immunosorbent assay). Manual and automated platelet counts were performed on all blood and PRP samples. There were no differences in growth factor or cytokine concentration when blood or Llo PRP or Lhi PRP was retained at room temperature for up to 4 hours. Manual, direct smear analysis for platelet quantification was not different from the use of automated machine counting for PRP samples, but in the starting blood samples, manual platelet counts were significantly higher than those generated using automated technology. When there is a delay of up to 4 hours in the generation of PRP from blood or in the application of PRP to the patient, bioactive growth factor and cytokine concentrations remain stable in both blood and PRP. A manual direct counting method is a simple, cost-effective, and valid method to measure the contents of the PRP product being delivered to the patient. PMID- 29719008 TI - Deciphering the molecular determinants of cholinergic anthelmintic sensitivity in nematodes: When novel functional validation approaches highlight major differences between the model Caenorhabditis elegans and parasitic species. AB - Cholinergic agonists such as levamisole and pyrantel are widely used as anthelmintics to treat parasitic nematode infestations. These drugs elicit spastic paralysis by activating acetylcholine receptors (AChRs) expressed in nematode body wall muscles. In the model nematode Caenorhabditis elegans, genetic screens led to the identification of five genes encoding levamisole-sensitive AChR (L-AChR) subunits: unc-38, unc-63, unc-29, lev-1 and lev-8. These subunits form a functional L-AChR when heterologously expressed in Xenopus laevis oocytes. Here we show that the majority of parasitic species that are sensitive to levamisole lack a gene orthologous to C. elegans lev-8. This raises important questions concerning the properties of the native receptor that constitutes the target for cholinergic anthelmintics. We demonstrate that the closely related ACR 8 subunit from phylogenetically distant animal and plant parasitic nematode species functionally substitutes for LEV-8 in the C. elegans L-AChR when expressed in Xenopus oocytes. The importance of ACR-8 in parasitic nematode sensitivity to cholinergic anthelmintics is reinforced by a 'model hopping' approach in which we demonstrate the ability of ACR-8 from the hematophagous parasitic nematode Haemonchus contortus to fully restore levamisole sensitivity, and to confer high sensitivity to pyrantel, when expressed in the body wall muscle of C. elegans lev-8 null mutants. The critical role of acr-8 to in vivo drug sensitivity is substantiated by the successful demonstration of RNAi gene silencing for Hco-acr-8 which reduced the sensitivity of H. contortus larvae to levamisole. Intriguingly, the pyrantel sensitivity remained unchanged thus providing new evidence for distinct modes of action of these important anthelmintics in parasitic species versus C. elegans. More broadly, this highlights the limits of C. elegans as a predictive model to decipher cholinergic agonist targets from parasitic nematode species and provides key molecular insight to inform the discovery of next generation anthelmintic compounds. PMID- 29719012 TI - Proximal Humerus Fracture 3-D Modeling. AB - The objective of this study is to determine the reproducibility and feasibility of using 3-dimensional (3-D) computer simulation of proximal humerus fracture computed tomography (CT) scans for fracture reduction. We hypothesized that anatomic reconstruction with 3-D models would be anatomically accurate and reproducible. Preoperative CT scans of 28 patients with 3- and 4-part (AO classification 11-B1, 11-B2, 11-C1, 11-C2) proximal humerus fractures who were treated by hemiarthroplasty were converted into 3-D computer models. The displaced fractured fragments were anatomically reduced with computer simulation by 2 fellowship-trained shoulder surgeons, and measurements were made of the reconstructed proximal humerus. The measurements of the reconstructed models had very good to excellent interobserver and intraobserver reliability. The reconstructions of these humerus fractures showed interclass correlation coefficients ranging from 0.71 to 0.93 between 1 observer and from 0.82 to 0.98 between 2 different observers. The fracture reduction was judged against normal proximal humerus geometry to determine reduction accuracy. The 3-D modeling techniques used to reconstruct 3- and 4-part proximal humerus fractures were reliable and accurate. This technique of modeling and reconstructing proximal humerus fractures could be used to enhance the preoperative planning of open reduction and internal fixation or hemiarthroplasty for 3- and 4-part proximal humerus fractures. PMID- 29719013 TI - Cutaneous Lymphoma, Introduction. PMID- 29719014 TI - Mycosis fungoides-clinical and histopathologic features, differential diagnosis, and treatment. AB - Mycosis fungoides (MF) is the most common type of cutaneous lymphoma. The term MF should be used only for the classical presentation of the disease characterized by the evolution of patches, plaques, and tumors or for variants showing a similar clinical course. MF is divided into 3 clinical phases: patch, plaque, and tumor stage, and the clinical course is usually protracted over years or decades. Histopathologically, MF is characterized by an epidermotropic infiltrate of T lymphocytes that displays in most cases a helper phenotype. Cytotoxic variants are well described and do not have specific clinical, histopathological, or prognostic features. MF should be differentiated from other cutaneous epidermotropic lymphomas and from many inflammatory dermatoses with some similar clinicopathological features. The therapy of MF is planned mainly according to the stage and extent of the disease. In early phases, nonaggressive options represent the first-line strategy (eg, local corticosteroids, psoralen, and ultraviolet A [UV-A] irradiation, etc.). In patients with advanced disease, good results with potential for cure have been obtained with allogeneic stem cell transplantation, but toxicity is a serious limiting factor for this treatment. Conventional systemic chemotherapy and single-agent chemotherapy (eg, gemcitabine) give usually good results in advanced MF, but recurrences are the rule. Monoclonal antibodies directed against cluster of differentiation (CD)52 (alemtuzumab), CD30 (brentuximab vedotin), and chemokine receptor 4 (CCR4; mogamulizumab), as well as several other experimental therapies, have shown promising results and represent a valid alternative. PMID- 29719015 TI - Mycosis fungoides variants-clinicopathologic features, differential diagnosis, and treatment. AB - Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma, which typically presents with erythematous patches and plaques, histopathologically characterized by superficial infiltrates of small to mediumsized atypical epidermotropic T cells. Apart from this classic type of MF, many clinical and/or histopathologic variants have been described. Correct diagnosis of these MF variants is important, but may be difficult, because they may mimic a wide variety of inflammatory skin diseases. In this review, clinical and histopathologic characteristics of distinct variants of MF are presented, and their differential diagnosis and therapeutic options are discussed. PMID- 29719016 TI - Sezary syndrome-clinical and histopathologic features, differential diagnosis, and treatment. AB - Sezary syndrome (SS) is a rare subtype of cutaneous T-cell lymphoma marked by erythroderma, circulating neoplastic T cells, and poor prognosis. Its low incidence has made the study of its etiology, immunologic/molecular pathways, and effective treatments difficult. Because histopathology may be nonspecific in SS, microscopic findings must be correlated with the clinical presentation and the results of blood evaluation in order to make the diagnosis. Treatments that preserve, rather than compromise, the immune system are preferred. PMID- 29719017 TI - Cutaneous CD30-positive T-cell lymphoproliferative disorders-clinical and histopathologic features, differential diagnosis, and treatment. AB - Cutaneous CD30+ T-cell lymphoproliferative disorders (CD30+ LPD) are the second most common form of cutaneous T-cell lymphoma. CD30+ LPD include lymphomatoid papulosis, primary cutaneous anaplastic large-cell lymphoma, and borderline lesions. Despite expression of CD30 by the neoplastic cells as the hallmark of these disorders, they differ in their clinical presentation and histological features as well as the course, the prognosis, and consecutively in the treatment. Diagnosis of CD30+ LPD and distinction from the broad spectrum of differential diagnoses essentially depends on clinicopathologic correlation as well as the results of staging examinations. Although the histological findings indicate a high-grade lymphoma, CD30+ LPD in most cases have a favorable prognosis. Recent advances in targeted therapy have led to new therapeutic approaches to CD30+ LPDs. This review describes the clinicopathologic features of CD30+ LPDs, their differential diagnoses, the treatment, and the role of CD30 as a diagnostic marker and therapeutic target. PMID- 29719018 TI - NK/T-cell lymphoma, nasal type, gammadelta T-cell lymphoma, and CD8-positive epidermotropic T-cell lymphoma-clinical and histopathologic features, differential diagnosis, and treatment. AB - The cytotoxic lymphomas of the skin constitute a heterogeneous group of rare lymphoproliferative diseases that are derived from mature T cells and natural killer (NK) cells that express cytotoxic molecules (T-cell intracellular antigen- 1, granzyme A/B, and perforin). Although frequently characterized by an aggressive course and poor prognosis, these diseases can have variable clinical behavior. This review delivers up-to-date information about the clinical presentation, histopathologic features, differential diagnosis, and therapy of extranodal NK/T-cell lymphoma, nasal type, primary cutaneous gamma delta T-cell lymphoma, and primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma. PMID- 29719019 TI - Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder-clinical and histopathologic features, differential diagnosis, and treatment. AB - Primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder usually presents as a slow-growing and asymptomatic solitary lesion in the form of a nodule or tumor in the head and neck region. By definition, it is histologically characterized by small- to medium-sized CD4+ lymphocytes involving the dermis in a dense and either nodular or diffuse pattern. Epidermotropism should be absent or minimal. Tumor cells are accompanied by numerous reactive B cells, plasma cells, histiocytes, and eosinophils. This lymphoproliferative disorder is characterized by the expression of follicular helper T-cell markers, particularly B-cell lymphoma 6 (BCL-6), programmed cell death protein 1 (PD-1), and C-X-C motif chemokine ligand 13 (CXCL-13), while CD10 is usually negative. Molecular studies show a clonal rearrangement of T-cell receptor genes in more than 60% of cases. Management of disease includes surgical excision, radiation therapy, and steroids (topical or intralesional). Patients with this diagnosis have an excellent prognosis, with a clinical course that is invariably indolent. PMID- 29719020 TI - Primary cutaneous B-cell lymphomas- clinical and histopathologic features, differential diagnosis, and treatment. AB - Cutaneous B-cell lymphomas (CBCLs) are a heterogeneous group of diseases that can have variable presentations, prognoses, and treatments. The proper identification of a CBCL hinges on proper histopathologic and clinical evaluation. Comprising 25% to 30% of the primary cutaneous lymphomas, incident cases of CBCL are rare. Given the variable natural history of the CBCL, proper classification is critical so that patients are treated appropriately. CBCLs can be divided into 2 main groups: indolent and aggressive. Indolent CBCLs include primary cutaneous follicle center lymphoma and primary cutaneous marginal zone lymphoma. These subtypes usually do not affect a patient's lifespan but can lead to substantial symptomatology, prompting the need for treatment. The aggressive subtypes of CBCL include diffuse large B-cell lymphoma leg type and intravascular large B-cell lymphoma. These are treated as systemic lymphomas, and their prognoses are not as good. In this article, we discuss the clinical features, differential diagnoses, histopathologic features, and treatment options for each of the 4 types of CBCL. The proper categorization of these diseases can allow physicians to properly treat a patient with CBCL, including the avoidance of unnecessary therapy. PMID- 29719021 TI - Histopathologic approach to epidermotropic lymphocytic infiltrates. AB - Mycosis fungoides is the most common and therefore quintessential cutaneous lymphoma and is typically characterized by an epidermotropic infiltrate of atypical monoclonal CD4+ lymphocytes. Classical histopathologic findings include epidermotropism, lymphocytes with convoluted nuclear contours and surrounding perinuclear "halos," and papillary dermal fibrosis. Atypical lymphocytes may occasionally form Pautrier's microabscesses with tagging of lymphocytes along the basal keratinocytes. Unfortunately, a variety of benign inflammatory infiltrates, as well as other cutaneous lymphomas, may demonstrate some similar histopathologic findings. Herein, we review the wide array of epidermotropic T cell lymphomas and discuss distinguishing features between these entities. We also offer an algorithmic approach utilizing histopathologic, immunophenotypic, and molecular techniques that can be used for analyzing an epidermotropic T-cell infiltrate in order to render a specific diagnosis. PMID- 29719022 TI - Approach to dermal-based lymphoid infiltrates and proliferations. AB - The histopathological diagnosis of dermal-based lymphoid infiltrates and proliferations is often challenging due to the vast list of biologically diverse entities that archetypally or occasionally center in the mid-dermis, especially because significant overlap exists in their clinical, histopathologic, and immunophenotypic features. The differential diagnosis includes reactive infiltrates in common and rare inflammatory dermatoses, benign conditions that may mimic lymphoid neoplasms (pseudolymphomas), and true clonal proliferations arising either primarily in the skin or rarely in extracutaneous tissues with secondary cutaneous dissemination. While numerous histopathological and immunophenotypic features have been reported to support a definitive diagnosis, no single ancillary test is sufficient for their distinction. Therefore, in this review we advocate a stepped histopathological approach for dermalbased lymphoid infiltrations, employing as key elements the general lymphocytic composition (relative B- versus T-cell ratio), coupled with the predominant cytomorphology (cell size) present. Following this strategy, the relative incidence of cutaneous involvement by each disease should always be considered, as well as the notion that a definitive diagnosis must be founded on a multiparameter approach integrating all clinical, histopathologic, immunophenotypic, and-in selected cases-molecular features. PMID- 29719023 TI - Maximizing the clinical utility of descriptive lymphoid pathology reporting. AB - Dermatopathology reporting can be both exact and inexact. Exact reporting represents the use of terminology that corresponds to a disease sui generis, such as discoid lupus erythematosus or disseminated superficial porokeratosis. Inexact reporting can vary greatly amongst various practitioners-both in terms of the exact semantics used and also stylistically-and can be used habitually by pathologists as a means to provide cover for diagnostic uncertainty or inexperience. This article explores the use of descriptive (inexact) reporting as it applies to cutaneous lymphoma and its differential diagnosis. A collection of practical descriptive diagnostic categories that will be of use to both dermatologists and dermatopathologists is included. PMID- 29719024 TI - Molecular advances in cutaneous T-cell lymphoma. AB - Cutaneous T-cell lymphoma (CTCL) is a group of malignancies derived from skin homing T cells. Mycosis fungoides (MF) and Sezary syndrome (SS) are the most common CTCL variants. In recent years, the genetic landscape of SS/MF has been characterized using genome-wide nextgeneration sequencing approaches. These studies have revealed that genes subjected to oncogenic mutations take part in cell cycle regulation, chromatin modification, Janus kinase (JAK)-signal transducer and activator of transcription protein (STAT) signaling, T-cell receptor (TCR)/ nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) signaling, and microtubule associated protein kinase (MAPK) signaling, which suggests that deregulation of these cellular processes underlies lymphomagenesis. These studies provide the groundwork for functional and clinical studies that will lead to better risk assessment and more effective therapeutic approach in CTCL patients. PMID- 29719025 TI - Correlation between Excessive Daytime Sleepiness (EDS) and self-reported and objective nasal characteristics. AB - BACKGROUND: The aim of the present study was to explore the relationship between excessive daytime sleepiness (EDS), Peak Nasal Inspiratory Flow (PNIF), and patient reported symptoms from the nose. METHOLOGY: Six hundred and fifty one consecutive patients referred to a hospital on suspicion of sleep related breathing disorder (SRBD) were included in the study. Daytime sleepiness was assessed by Epworth Sleepiness Scale (EpSS). Nasal airflow was measured with Peak Nasal Inspiratory Flow (PNIF). Symptoms of sino-nasal dysfunction and diseases were graded on Visual Analogue Scales (VAS). RESULTS: EpSS score was not correlated with nasal flow as measured by PNIF or nasal obstruction - VAS scores. There were significant associations between daytime sleepiness and patient reported VAS-scores on nasal discharge, headache, coughing, general health and to some extent sneezing when age, gender, BMI and reported co-morbidity levels were adjusted for. CONCLUSION: A clinical implication of this is that patients with EDS may be evaluated and treated for sino-nasal disease, while medical and surgical measures to open the nose per se may not be effective therapeutic options. A scientific implication is that the relationship between SRBD and sino nasal disease should be further investigated. PMID- 29719026 TI - Postponing Childbearing and Fertility Preservation in Young Professional Women. AB - OBJECTIVES: To evaluate young women's awareness of ovarian reserve testing and oocyte cryopreservation (OC) and assess how testing ovarian reserve may affect the desire for fertility preservation. METHODS: Three questionnaire-based observational studies were conducted among female students/young professionals 20 years of age and older. The third survey was completed after participants were offered anti-Mullerian hormone (AMH) testing. The main outcomes measured included awareness that OC is available, interest in pursuing fertility preservation, and whether interest would change based on knowledge of declining fertility. RESULTS: The first tier of the study included a survey of a total of 337 women. The majority of female subjects were aware of OC (92.1%). Approximately 38.5% of the women responded that they would consider OC for future fertility purposes. This percentage increased to 60.3% if one was aware her fertility was declining. The second tier of the study included 42 resident/fellow physicians who were offered AMH testing. A survey was completed before and after testing was completed. Approximately 12% of participants stated that their AMH level altered their anticipated age of childbearing, whereas 24% would consider cryopreservation based on their results. The most common concern regarding OC was the cost. CONCLUSIONS: Women should be counseled regarding reproductive aging and options for fertility preservation. Offering ovarian reserve testing and making OC more affordable may increase the number of women who undergo elective OC. PMID- 29719027 TI - Comparison of Children's Menu Items at Full- and Quick-Service Restaurants. AB - OBJECTIVES: The proportion of food consumed by children from restaurants tripled during the last 4 decades and that coincided with the increased rate of obesity. Despite the presence of data linking quick-service (QS) food consumption to poor diet quality, studies comparing the nutrition content of the children's menu items at QS restaurants (QSRs) with those at full-service restaurants (FSRs) are limited. The objectives of this study were to examine the nutrition content of common children's menu items at both QSRs and FSRs and compare these data with recommendations reported by the Dietary Guidelines for Americans 2015-2020, Eighth Edition. METHODS: Using the 2014 data of the MenuStat project, 10 food items that are on both QSR and FSR children's menus were selected. Data from each restaurant category were aggregated and the overall average of the nutritional content of each individual food item was calculated and compared between the two restaurant categories. RESULTS: The average of calories, fat, carbohydrates, and added sugar of most items on the children's menu of QSRs are lower than those of FSRs. Also, most food items on children's menus of FSRs, and to a lesser extent those of QSRs, exceeded the national recommended calories and fat content per meal. CONCLUSIONS: Although some children's menu items of QSRs have less fat and fewer calories compared with those of FSRs, most menu items in both FSRs and QSRs do not meet national dietary recommendations. Healthcare professionals may expand discussions with patients to include both restaurant categories when counseling them and their families on obesity prevention. Also, educating children and families about reading the nutritional content information of children's menu items when eating out to make an informed choice can be a tool in fighting childhood obesity. PMID- 29719028 TI - On "Diagnosis of Child Maltreatment: A Family Medicine Physician's Dilemma". PMID- 29719029 TI - Engagement in an Online Cultural Competency Training. AB - OBJECTIVES: Engagement with online cultural competency training has not been well studied. We examined knowledge, attitudes, and skills differences among medical students, physicians, and other professionals in an online cultural competency education program. METHODS: A total of 1745 participants completed up to four online modules aimed at exploring stereotype, bias, diet, and religion among African American patients with hypertension. We examined knowledge, attitudes, and self-reported skills with 17 multiple-choice questions embedded in the 4 modules. Participants received comparative responses with their peers. RESULTS: Between 75% and 84% of participants knew the definition of stereotype and <50% knew the definition of bias (47% students, 36% physicians, 33% others, P < 0.001). Most responded that minorities perceive bias (98%-100%) and believe that evidence exists showing that bias affects decision making (62%-69%). Although most perceive that religious and spiritual beliefs affect reaction to illness often (78% students, 68% physicians, 79% others, P < 0.001), few would ask about religious beliefs during a typical encounter (13% students, 16% physicians, 30% others, P < 0.001). CONCLUSIONS: All of the participants struggled to define bias; however, most agreed that minorities perceive bias in the care they receive. We examined usage and interaction with the online content as a dimension of engagement. PMID- 29719030 TI - Improving Underrepresented Minority in Medicine Representation in Medical School. AB - OBJECTIVES: Despite the efforts of various leading organizations in medical education, representation of black students in US medical schools has declined since the mid-1990s. The Florida State University College of Medicine (FSUCOM) has undertaken efforts to increase black and other underrepresented minority in medicine (URMM) representation in medical school through the Bridge to Clinical Medicine Program. This program is described and analyzed by the authors. METHODS: Demographic information, Medical College Admission Test scores, undergraduate grade point average, US Medical Licensing Examination (USMLE) scores (Steps 1 and 2), residency match information, and current practice location from 2006 to 2015 were collected from the FSUCOM. Data were analyzed using SAS and linear regression analyses were performed, comparing Bridge students with the College of Medicine and national averages. RESULTS: Sixty percent of Bridge students were black, 21% were other URMM, and the remainder were non-URMM. Black Bridge students scored 7.4 points lower on their Medical College Admission Test, and other-URMM Bridge students scored 6.0 points lower (P < 0.0001) than their non URMM non-Bridge classmates. Black Bridge students also started with a grade point average that was 0.28 points lower than their non-URMM non-Bridge counterparts, but there was no statistical difference for other-URMM Bridge students. Black students, regardless of Bridge participation, were less likely to pass USMLE Step 1 when compared with non-URMM classmates (P < 0.0001). For USMLE Step 2, however, there were no significant differences in passing rates for Bridge students compared with non-Bridge students. CONCLUSIONS: The FSUCOM Bridge program has not only increased its URMM enrollment but it also has effectively doubled the number of black students in its medical college. Other universities could produce similar results using the program outlined in this article. PMID- 29719031 TI - Importance of Interdisciplinary Medical Education: A Frontline Perspective. PMID- 29719032 TI - Commentary on "Importance of Interdisciplinary Medical Education: A Frontline Perspective". PMID- 29719033 TI - A Social-Ecological Review of Cancer Disparities in Kentucky. AB - Cancer continuously ranks among the top 10 leading causes of death in the United States. The burden of cancer is particularly elevated in the Commonwealth of Kentucky and its 54-county Appalachian region, where cancer is the leading cause of death. Kentucky's high rates of cancer have been attributed to a wide range of socioeconomic, behavioral, environmental, and policy influences, resulting in numerous disparities. The present review specifically evaluates the burden of lung, colorectal, cervical, and head and neck cancers in Kentucky, along with resultant cancer control research and community outreach efforts conducted by the state's only National Cancer Institute-designated cancer center using an adapted version of McLeroy's Social-Ecological Model. Here, we categorize disparities and identify relevant intervention approaches based on their level of influence (ie, individual, community, and policy). PMID- 29719034 TI - Measuring Functional Status in Hospitalized Older Adults Through Electronic Health Record Documentation. AB - OBJECTIVES: Hospitalization-associated disability affects up to 60% of older adults; however, standardized measures of function are not routinely used and documented. We sought to determine whether nursing documentation in electronic medical records can be used to determine mobility status and associated clinical outcomes. METHODS: A retrospective study of 2383 medical patients aged 75 years and older was conducted at a large academic tertiary hospital in New York. Mobility (low, intermediate, and high) was the primary variable of interest. Short-term clinical outcomes, including length of stay (LOS), discharge disposition, and readmissions, were the primary outcome variables. RESULTS: Average age and Charlson Comorbidity Index were 84.7 (range 74-107) and 6.46, respectively; 84.5% of patients were documented to have been ambulatory before admission. More than half (52.8%) of the subjects with in-hospital mortality were in the low mobility group (27.2 vs 0.27 vs 0, P < 0.0001). Low mobility was associated with increased LOS (7.42 vs 5.69 vs 4.14, P < 0.0001), discharge to a skilled nursing facility (39.36 vs 14.67 vs 1.91, P < 0.0001), and 30-day readmission (24.40 vs 16.67 vs 10.93, P < 0.0001). After controlling for demographics, ambulatory status before admission, and Charlson Comorbidity Index, low mobility was statistically significantly associated with increased LOS, discharge to a skilled nursing facility, and 30-day readmissions. CONCLUSIONS: The use of documented nursing observation may provide a practical way to systematically identify patients at risk for poor outcomes associated with low mobility to ultimately improve outcomes of hospitalized older adults. PMID- 29719035 TI - Single-Center Retrospective Study of Risk Factors and Predictive Value of Framingham Risk Score of Patients with ST Elevation Myocardial Infarction. AB - OBJECTIVES: The objective of this study was to identify risk factors and clinical profile of the patients presenting with ST elevation myocardial infarction (STEMI). We further evaluated the utility of the Framingham Risk Score (FRS) in the accurate identification of these patients if used before their coronary event. METHODS: We evaluated the demographic, clinical, and angiographic characteristics of patients admitted with STEMI. We also calculated cardiovascular event risk using the FRS in a subset of patients without prior known coronary artery disease and diabetes mellitus. RESULTS: A total of 44 patients, predominantly men (75%) and white (80%), with a mean age of 56 +/- 10 years, were included in our analysis. Cigarette smoking was the predominant risk factor (83%) followed by hypertension (77%) and dyslipidemia (68%). The calculated FRS in a subset of patients without prior coronary artery disease or diabetes mellitus was 14.1% +/- 5.8%. Based on the FRS, 8 (36%) patients had a 10 year risk >20% and 14 (63%) patients had a 10-year risk between 10% and 20%. CONCLUSIONS: In a series of consecutive patients with STEMI, we observed that high FRS was inadequate in correct identification and risk stratification of the majority of patients who had STEMI. Our study underlines the importance of being familiar with multiple risk scores and choosing the most applicable risk score based on the patient's individual characteristics. In addition, it is important to take into consideration the nontraditional risk factors or measurement of coronary artery calcium as a part of the risk assessment algorithm. PMID- 29719036 TI - Clinical Context and Detection of the Murmur of Advanced Aortic Stenosis. AB - OBJECTIVES: Auscultation is an important clue to the presence of aortic stenosis (AS). We sought to assess the effect of symptom status, prior knowledge of diagnosis, and other patient factors on murmur detection. METHODS: Patients with moderate-to-severe AS by echocardiography at a single center between June 2015 and June 2016 were included. Five consecutive patient encounters (inpatient and outpatient) within 12 months before the echocardiogram were analyzed. RESULTS: Ninety-five patients (418 different clinician encounters) were studied. The murmur of AS was identified by only 39% of clinicians. In multivariate analysis, significant determinants of murmur detection were examination in outpatient setting (odds ratio [OR] 3.40, 95% confidence interval [CI] 1.75-6.61), known history of AS (OR 2.77, 95% CI 1.53-5.01), female sex (OR 1.97, 95% CI 1.07 3.60), and presence of symptoms (OR 1.91 95% CI 1.12-3.26). Compared with the murmur detection findings by clinicians in medicine, the findings of surgical specialty clinicians were significantly lower (OR 0.12, 95% CI 0.06-0.26, P < 0.001). CONCLUSIONS: In this real-world assessment, clinical context played an important role in the auscultation of AS murmur. The findings have important implications for the clinical diagnosis of asymptomatic advanced AS. PMID- 29719037 TI - Provider Variation in Antibiotic Prescribing and Outcomes of Respiratory Tract Infections. AB - OBJECTIVES: Inappropriate antibiotic use for respiratory tract infection (RTI) is an ongoing problem linked to the emergence of drug resistance and other adverse effects. Less is known about the prescribing practices of individual physicians or the impact of physician prescribing habits on patient outcomes. We studied the prescribing practices of providers for acute RTIs in an integrated health system, identified patient factors associated with receipt of an antibiotic and assessed the relation between providers' adjusted prescribing rates and a number of patient outcomes. METHODS: This was a retrospective analysis of adults with an RTI visit to any primary care providers across the Cleveland Clinic Health System in 2011-2012. Patients with a history of chronic obstructive pulmonary disease or immunocompromised status were excluded. Logistic regression was used to examine patient factors associated with receipt of an antibiotic. RESULTS: Of 31,416 patients with an RTI, 54.8% received an antibiotic. Patient factors associated with antibiotic prescribing included white race (odds ratio [OR] 1.35, P < 0.001), presence of fever (OR 1.66, P < 0.001), and a diagnosis of bronchitis (OR 10.98, P < 0.001) or sinusitis (OR 33.85, P < 0.001). Among 290 providers with >=10 RTI visits, adjusted antibiotic prescribing rates ranged from 0% to 100% (mean 49%). Antibiotics were prescribed more often for sinusitis (OR 33.85, P < 0.001), bronchitis (OR 10.98, P < 0.001), or pharyngitis (OR 1.76, P < 0.001) compared with upper respiratory tract infection. Patients who were prescribed antibiotics at the index visit were more likely to return for RTI within 1 year (adjusted OR 1.26, P < 0.001). Emergency department visits for respiratory complications were rare and not associated with antibiotic receipt. CONCLUSIONS: Antibiotic prescribing for RTI varies widely among physicians and cannot be explained by patient factors. Patients prescribed antibiotics for RTI were more likely to return for RTI. PMID- 29719038 TI - Reply to: Interventions to Reduce Antipsychotic Prescribing in Nursing Home Must Cross Healthcare Silos. PMID- 29719039 TI - Prognostic Effect of Changes in Physical Function Over Prior Year on Subsequent Mortality and Long-Term Nursing Home Admission. AB - OBJECTIVES: To evaluate the prognostic effect of changes in physical function at different intervals over the prior year on subsequent outcomes after accounting for present function. DESIGN: Prospective longitudinal study. SETTING: Greater New Haven, Connecticut, from March 1998 to January 2006. PARTICIPANTS: Community living persons aged 71 and older who completed an 18-month comprehensive assessment (N=658). MEASUREMENTS: Disability in 13 activities of daily living, instrumental activities of daily living, and mobility activities was assessed at the 18-month comprehensive assessment and at 12, 6, and 3 months before 18 months. Time to death and long-term nursing home admission, defined as 3 months and longer, were ascertained for up to 5 years after 18 months. RESULTS: In the bivariate models, disability at 18 months and change in disability between 18 months and each of the 3 prior time-points (12, 6, 3 months) were significantly associated with time to death. The risk of death, for example, increased by 24% for each 1-point increase in 18-month disability score (on a scale from 0 to 13) and by 22% for each 1-point change in disability score between 18 months and prior 12 months (on a scale from -13 to 13). In a set of multivariable models with and without covariates, the associations were maintained for 18-month disability but not for change in disability between 18 months and each of the 3 prior time-points. The results were comparable for time to long-term nursing home admission except that 2 of the associations were not statistically significant. CONCLUSION: When evaluating risk of adverse outcomes, such as death and long-term nursing home admission, an assessment of change in physical function at different intervals over the prior year, although a strong bivariate predictor, did not provide useful prognostic information beyond that available from current level of function. PMID- 29719040 TI - Interventions to Reduce Antipsychotic Prescribing in Nursing Homes Must Cross Healthcare Silos. PMID- 29719041 TI - Temporomandibular Joint Disorders in Older Adults. AB - OBJECTIVES: To review the literature and summarize the evidence of temporomandibualar joint (TMJ) disorders (TMDs) in older adults, focusing on clinical manifestations of TMDs in older adults, highlighting the incidence and sexual dimorphism of TMJ degeneration and the role of sex hormones in this process, and providing potential treatment options for TMD in older adults. DESIGN: Two review authors performed the literature search, study inclusion, and data extraction. PubMed, Embase, and Google scholar were searched for literature until August 2017 (Figure ). We adopted a combination of Medical Subject Headings with related free text words for the search in PubMed and optimized the search in other search engines. RESULTS: Traditionally, it was believed that TMDs predominantly affected women of childbearing age, but recent large studies in Europe and the United States have shown that the prevalence of TMD peaks after childbearing age (45-64) and then gradually decreases with age, although not much is known about the disease in older adults. CONCLUSION: Most older adults have TMJ degeneration, which affects women more than men. In most older adults, the symptoms of TMD are mild and self-limiting and can usually be treated with self management. PMID- 29719042 TI - Early endplate remodeling and skeletal muscle signaling events following rat hindlimb suspension. AB - Motor endplates naturally undergo continual morphological changes that are altered in response to changes in neuromuscular activity. This study examines the consequences of acute (6-12 hr) disuse following hindlimb suspension on rat soleus muscle endplate structural stability. We identify early changes in several key signaling events including markers of protein kinase activation, AMPK phosphorylation and autophagy markers which may play a role in endplate remodeling. Acute disuse does not change endplate fragmentation, however, it decreases both the individual fragments and the total endplate area. This decrease was accompanied by an increase in the mean fluorescence intensity from the nicotinic acetylcholine receptors which compensate the endplate area loss. Muscle disuse decreased phosphorylation of AMPK and its substrate ACC, and stimulated mTOR controlled protein synthesis pathway and stimulated autophagy. Our findings provide evidence that changes in endplate stability are accompanied by reduced AMPK phosphorylation and an increase in autophagy markers, and these changes are evident within hours of onset of skeletal muscle disuse. PMID- 29719043 TI - Impact of whole-genome duplication events on diversification rates in angiosperms. AB - PREMISE OF THE STUDY: Polyploidy or whole-genome duplication (WGD) pervades the evolutionary history of angiosperms. Despite extensive progress in our understanding of WGD, the role of these events in promoting diversification is still not well understood. We seek to clarify the possible association between WGD and diversification rates in flowering plants. METHODS: Using a previously published phylogeny spanning all land plants (31,749 tips) and WGD events inferred from analyses of the 1000 Plants (1KP) transcriptome data, we analyzed the association of WGDs and diversification rates following numerous WGD events across the angiosperms. We used a stepwise AIC approach (MEDUSA), a Bayesian mixture model approach (BAMM), and state-dependent diversification analyses (MuSSE) to investigate patterns of diversification. Sister-clade comparisons were used to investigate species richness after WGDs. KEY RESULTS: Based on the density of 1KP taxon sampling, 106 WGDs were unambiguously placed on the angiosperm phylogeny. We identified 334-530 shifts in diversification rates. We found that 61 WGD events were tightly linked to changes in diversification rates, and state-dependent diversification analyses indicated higher speciation rates for subsequent rounds of WGD. Additionally, 70 of 99 WGD events showed an increase in species richness compared to the sister clade. CONCLUSIONS: Forty-six of the 106 WGDs analyzed appear to be closely associated with upshifts in the rate of diversification in angiosperms. Shifts in diversification do not appear more likely than random within a four-node lag phase following a WGD; however, younger WGD events are more likely to be followed by an upshift in diversification than older WGD events. PMID- 29719044 TI - A reassessment of the presumed Badegoulian skull from Rond-du-Barry cave (Polignac, France), using direct AMS radiocarbon dating. PMID- 29719045 TI - Wearing the marks of violence: Unusual trauma patterning at Coyo Oriental, Northern Chile. AB - OBJECTIVES: In this article, we present analyses of traumatic injury data from the Middle Period Coyo Oriental cemetery in northern Chile. We test a series of hypotheses about the role of sex, foreign contact, ritual access, and temporal shifts, in the patterning of cranial trauma in this cemetery. METHODS: Two hundred and twenty-seven crania from Coyo Oriental were analyzed using standard bioarcheological methods to determine sex and age as well as the presence of cranial fractures. We also documented the presence of Tiwanaku goods, objects tied to warfare or hunting, camelid offerings, snuff paraphernalia, and items related to mining. RESULTS: We recorded 98 cranial fractures in the sample with 94.9% (93/98) on the anterior of the cranium. No significant differences are observed in the prevalence of trauma by sex, type of grave, or date. However, Coyo Oriental's trauma prevalence is two to three times higher than other Middle Period sites. CONCLUSION: The prevalence and location of these injuries suggest that conflict at Coyo Oriental, while of the same nature, was at a scale different to that seen elsewhere in the oases. We posit here that the development of social hierarchy, population growth, expansive social networks, and foreign contact that characterized the Middle Period may have resulted in a need for social control among the emergent elites of the region. PMID- 29719046 TI - The bigger they are the harder they fall: size-dependent vulnerability of motor neurons in amyotrophic lateral sclerosis. PMID- 29719047 TI - Echinococcus granulosus cyst fluid enhances epithelial-mesenchymal transition. AB - Cystic echinococcosis is characterized by fluid-filled hydatid cysts in the liver and lungs. The cysts are surrounded by a host fibrous layer (the pericyst) which acts to isolate the parasite from surrounding tissues. Previous studies in liver cysts have indicated that the parasite may be a stimulating fibrosis. The aim of this study was to investigate whether hydatid cyst fluid (HCF) could influence the potential for fibrosis to occur in lung tissue by stimulating epithelial to mesenchymal transition (EMT) in a human lung epithelial cell line. An adenocarcinoma-derived alveolar basal epithelial cell line (A549) was used as a model for human alveolar epithelial cells (AEC II). These were cultured in vitro with HCF (UK sheep origin). Assays to investigate cell proliferation, cell migration and expression of cytoskeletal markers showed that HCF could stimulate changes indicative of EMT, including enhanced cell proliferation and migration; increased expression of mesenchymal cytoskeletal markers (fibronectin and vimentin) accompanied by a down-regulation of an epithelial marker (E-cadherin). Molecules within hydatid cyst fluid are capable of inducing phenotypic changes in A549 cells indicating that the parasite has the potential to modify lung epithelial cells which could contribute to fibrotic reactions. PMID- 29719048 TI - Serotonin decreases the production of Th1/Th17 cytokines and elevates the frequency of regulatory CD4+ T-cell subsets in multiple sclerosis patients. AB - Excessive levels of proinflammatory cytokines in the CNS are associated with reduced serotonin (5-HT) synthesis, a neurotransmitter with diverse immune effects. In this study, we evaluated the ability of exogenous 5-HT to modulate the T-cell behavior of patients with MS, a demyelinating autoimmune disease mediated by Th1 and Th17 cytokines. Here, 5-HT attenuated, in vitro, T-cell proliferation and Th1 and Th17 cytokines production in cell cultures from MS patients. Additionally, 5-HT reduced IFN-gamma and IL-17 release by CD8+ T cells. By contrast, 5-HT increased IL-10 production by CD4+ T cells from MS patients. A more accurate analysis of these IL-10-secreting CD4+ T cells revealed that 5-HT favors the expansion of FoxP3+ CD39+ regulatory T cells (Tregs) and type 1 regulatory T cells. Notably, this neurotransmitter also elevated the frequency of Treg17 cells, a novel regulatory T-cell subset. The effect of 5-HT in upregulating CD39+ Treg and Treg17 cells was inversely correlated with the number of active brain lesions. Finally, in addition to directly reducing cytokine production by purified Th1 and Th17 cells, 5-HT enhanced in vitro Treg function. In summary, our data suggest that serotonin may play a protective role in the pathogenesis of MS. PMID- 29719049 TI - Are olfactory traits in a pair-bonded primate under sexual selection? An evaluation of sexual dimorphism in Aotus nancymaae. AB - OBJECTIVES: Sexual selection has seemingly influenced chemical communication in numerous non-human primates, although it is unclear whether it has influenced strictly pair-living and pair-bonded taxa. The physical similarities between male and female owl monkeys suggest that disruptive selection has not played a role in this taxon. However, given their nocturnality, olfactory traits may show differing patterns of sexual selection than visual traits. If sexual selection has influenced chemical communication in owl monkeys, we expect larger scent glands and greater scent-marking in females given the high degree of paternal care, as has been proposed for callitrichines. MATERIALS AND METHODS: We evaluated sex differences in the qualitative and quantitative descriptions of the subcaudal and perianal glandular regions of captive male (n = 39) and female (n = 36) owl monkeys (A. nancymaae), and in the olfactory behaviors performed within breeding pairs (n = 16). RESULTS: Males had larger areas of secretion retained in the hairs covering the subcaudal gland, and females had more and darker secretion than males covering the perianal region. Males inspected the genital region of their partners more frequently than females did, but the sexes did not differ much in other investigative and marking behaviors. DISCUSSION: The observed sex differences and variation in olfactory traits are consistent with the hypothesis that sexual selection has influenced chemical communication in owl monkeys, with males having larger subcaudal glands and spending more time investigating odors. Still, sex differences in monogamous owl monkeys were less extreme than those in other, non-monogamous, taxa. PMID- 29719050 TI - Characterization of asthma in the adolescent population. PMID- 29719051 TI - Preliminary approach for the surface electromyographical evaluation of the oral phase of swallowing. AB - Swallowing is a muscular activity that occurs both after mastication and spontaneously as a result of saliva accumulation. Spontaneous saliva swallowing occurs about every 2 minutes. Comprehension of its functional mechanisms is relevant to assess their modification in clinical situations. A standardised surface electromyographical (ssEMG) protocol for the evaluation of this muscle activity is lacking. Aims of the present study are: (i) to determine the reproducibility of a ssEMG protocol for the evaluation of the oral phase of saliva swallowing and (ii) to evaluate the activity of masseter (MM), anterior temporalis (TA), submental muscles (SM) to draw a reference model of swallowing. Standardised surface electromyographical activity of MM, TA and SM during swallowing of saliva spontaneously accumulated was recorded in 20 healthy participants. Functional indexes including symmetry (POC), recruitment (Impact), duration of activation of each couple of muscles and of the whole exercise, position, intensity of the spike were computed. Inter- and intra-appointment reliabilities were assessed and method errors calculated. Descriptive statistics, sex- and muscles-related comparisons were carried out. Standardised surface electromyographical assessment of MM, TA and SM muscles was reliable. A high inter-individual variability was found. Percentage overlapping coefficient (POC) values were close to 80% for TA and SM, higher than for MM (P < .001). Impact values ranged between 16.4% and 30.7%, and differences were found between muscles (P < .001). The global muscle activity during swallowing lasted between 1.5 and 1.8 seconds. For each couple of muscles, the duration of activation ranged between 0.7 and 1.6 seconds and muscles-related differences were found (P < .001). The spike of activation for each couple of muscle ranged between 35.7% and 44.2% of the duration. The protocol was reliable and intra-participants repeatable measures can be carried out. Due to the high inter-participants variability, further analyses are needed to draw a model of muscular activity. PMID- 29719052 TI - Effect of single-walled carbon nanotubes on cytochrome P450 activity in human liver microsomes in vitro. AB - Single-walled carbon nanotubes (SWCNTs) are made from a rolled single sheet of graphene with a diameter in the nanometer range. SWCNTs are potential carriers for drug delivery systems because antibodies or drugs can be loaded on their surface; however, their effect on the activities of cytochrome P450 (CYP) remains unclear. The aim of this study was to investigate the effect of two kinds of SWCNTs with different lengths (FH-P- and SO-SWCNTs) on human CYP activity. In addition, other nano-sized carbon materials, such as carbon black, fullerene-C60 , and fullerene-C70 were also evaluated to compare their effects on CYP activities. Ten CYP substrates (phenacetin, coumarin, bupropion, paclitaxel, tolbutamide, S-mephenytoin, dextromethorphan, chlorzoxazone, midazolam, and testosterone) were used. Testosterone 6beta-hydroxylation and midazolam 1' hydroxylation, which are catalysed by both CYP3A4 and CYP3A5 in liver microsomes, were decreased by 25% and 45%, respectively, in the presence of 0.1 mg/ml SO SWCNT. Dextromethorphan O-demethylation, which is catalysed mainly by CYP2D6, was decreased by 40% in the presence of SO-SWCNT. Other CYP activities, however, were not attenuated by SO-SWCNT. FH-P-SWCNT, carbon black, fullerene-C60 , and fullerene-C70 at 0.1 mg/ml had no effect on CYP activities. The Ki values for testosterone 6beta-hydroxylation, midazolam 1'-hydroxylation, and dextromethorphan O-demethylation in liver microsomes were 136, 34, and 56 MUg/ml, respectively. SO-SWCNT was determined to be a competitive inhibitor of CYP3A4, CYP3A5, and CYP2D6. These results suggest that the effect of SO-SWCNT differs among CYP isoforms, and that the inhibition potency depends on the physicochemical properties of the nanocarbons. PMID- 29719053 TI - IgG4 anti-infliximab in treated patients: Clinical impact and temporal evolution. AB - BACKGROUND: Infliximab (IFX) carries potential risk of immunogenicity with the production of anti-drug antibodies (ADA). ADA may belong to different isotypes and are usually measured by ELISA bridging assay. This test is not designed to detect IgG4 antibodies. The aim was to measure IgG4 anti-IFX antibodies in a cohort of IFX-treated patients and to evaluate their relationship with ADA and their clinical impact. METHODS: Anti-drug antibodies were detected using a bridging ELISA in the serum of 222 treated patients with different clinical outcomes to IFX. The same samples were analyzed for IgG4 anti-IFX antibodies using an experimental ImmunoCAP assay with reduced serum IgG4 background levels. A longitudinal evaluation was performed in a subgroup of 38 patients to define the temporal evolution of IgG4 anti-IFX. RESULTS: IgG4 anti-IFX was found in 26.6% of patients. Eighty of 222 patients were ADA+ (36%) and the majority (57/80, 71.3%) had IgG4 anti-IFX. Two IgG4-positive but ADA-negative patients were identified. IgG4 anti-IFX levels correlated with the serum levels of ADA. IgG4 anti-IFX was more common in both reactive and nonresponder patients than in tolerant/responder patients. Patients who had experienced IgE-mediated reactions displayed significantly higher IgG4 anti-IFX than IgE-negative reactive patients. The majority of patients tested positive for IgG4 anti-IFX after the first seven infusions. CONCLUSIONS: IgG4 anti-IFX is common in treated patients and a large part of ADA producing patients produce IgG4 antibodies. The IgG4 anti-IFX response does not prevent hypersensitivity reactions to IFX and correlates with the IgE anti-IFX response. PMID- 29719054 TI - Bone tissue engineering: Adult stem cells in combination with electrospun nanofibrous scaffolds. AB - Since bone tissue lesions caused by several reasons and has global outbreak without any attentions to the modernity level of the countries. In the other hands treatment of patients with this problem faced to the several limitations, in this because the future of the bone lesions treatments is related to the future of the bone tissue engineering. This review tries to cover the most suitable stem cells and materials from either natural or synthetic sources for bone tissue engineering. These understanding points would help researchers to further uncover the application of different adult stem cell sources in electrospinning scaffolds, promotion of nanofibrous composite construct design and adult stem cell type selection to enhance cell function and bone tissue engineering, and link laboratory investigations to clinical applications. PMID- 29719055 TI - Proteasome-mediated proteostasis: Novel medicinal and pharmacological strategies for diseases. AB - Proteins actively participate in a wide range of cellular physiological functions. But aggregation of proteins results in cytotoxicity, and unwanted aggregation of misfolded proteins often causes many diseases. During abnormal protein aggregation events, cells try to cope against such deleterious consequences because of the remarkable functional attempts of two distinct proteolytic mechanisms. These tightly regulative and signaling mechanisms are autophagy pathway and ubiquitin proteasome system. Proteasome complex system holds the elimination capacity of intracellular aberrant protein aggregation. Despite the considerable progress that has been achieved, which elucidates wide function and diverse roles of proteasome system, still several crucial problems remain unanswered. For example, how the complex proteasomes assembly and their interactive pathways determine the precise sense of several proteotoxic insults, which can severely affect the cell survival and homeostasis? The specific degradation of various aberrant proteins that can disturb cellular homeostasis is achieved by proper proteasome functionality, which is yet another unclear and critical challenge. Therefore, a better understanding of the various cellular signaling mechanisms composing the proteasome machinery carries broad therapeutic implications linked with proteopathies. This article signifies the urgent need, which is now crucial for us to improve our understanding of the proteasome architecture, structure, and functions that span multiple level strategies from the molecular level to the cellular level. This systematic in-depth information of proteasome may be helpful in the near future to design a new molecular framework based on intrinsic and extrinsic cellular mechanisms that drive the assembly of proteasome to induce cellular survival against proteostasis imbalance and disease conditions. PMID- 29719056 TI - Novel primary amine diazeniumdiolates-Chemical and biological characterization. AB - Hit, Lead & Candidate Discovery Diazeniumdiolates, also known as NONOates, are extensively used in biochemical, physiological, and pharmacological studies due to their ability to release nitric oxide (NO. ) and/or their congeneric nitroxyl (HNO). The purpose of this work was to synthesize a series of primary amine-based diazeniumdiolates as HNO/NO donors and to determine their efficacy as anticancer and antifungal agents in vivo. The seven compounds (3a-3g) were successfully synthesized and characterized, one of which had been previously reported in the literature (3g). Two compounds showed anti-proliferative effects against ovarian (ES2 and SKOV3) and AML monocyte-derived cancer cells (THP-1) when tested with standard MTT assays. Compounds 3a and 3g demonstrated reduced ovarian cancer cell proliferation when treated at doses from 0.033 to 1.0 mg/mL at the 24 hr time point. These compounds also exhibited moderate and selective antifungal activity against Fusarium oxysporum f.sp. lycopersici, one cause of opportunistic infections of immunocompromised patients, inhibiting the growth of the fungi at LD50 at 10 mg/mL. A third compound (3e) did not exhibit similar activities, possibly due to the alkyl chain. Our results suggest that the primary amine diazeniumdiolates may offer a versatile platform for the development of HNO/NO donors for biomedical applications. PMID- 29719057 TI - The antitumor effect of static and extremely low frequency magnetic fields against nephroblastoma and neuroblastoma. AB - Certain magnetic fields (MF) have potential therapeutic antitumor effect whereas the underlying mechanism remains undefined. In this study, a well-characterized MF was applied to two common childhood malignancies, nephroblastoma and neuroblastoma. This MF has a time-averaged total intensity of 5.1 militesla (mT), and was generated as a superimposition of a static and an extremely low frequency (ELF) MF in 50 Hertz (Hz). In nephroblastoma and neuroblastoma cell lines including G401, CHLA255, and N2a, after MF exposure of 2 h per day, the cell viability decreased significantly after 2 days. After 3 days, inhibition rates of 17-22% were achieved in these cell lines. Furthermore, the inhibition rate was positively associated with exposure time. On the other hand, when using static MF only while maintaining the same time-averaged intensity of 5.1 mT, the inhibition rate was decreased. Thus, both time and combination of ELF field were positively associated with the inhibitory effect of this MF. Exposure to the field decreased cell proliferation and induced apoptosis. Combinational use of MF together with chemotherapeutics cisplatin (DDP) was performed in both in vitro and in vivo experiments. In cell lines, combinational treatment further increased the inhibition rate compared with single use of either DDP or MF. In G401 nephroblastoma tumor model in nude mice, combination of MF and DDP resulted in significant decrease of tumor mass, and the side effect was limited in mild liver injury. MF exposure by itself did not hamper liver or kidney functions. In summary, the antitumor effect of an established MF against neuroblastoma and nephroblastoma is reported, and this field has the potential to be used in combination with DDP to achieve increased efficacy and reduce side effects in these two childhood malignancies. Bioelectromagnetics. 39:375-385, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29719059 TI - Mitral valve prolapse causes arrhythmias from the papillary muscles: A stretch of the truth or reality? PMID- 29719058 TI - Trajectories of Community Mobility Recovery After Hospitalization in Older Adults. AB - OBJECTIVES: To identify trajectories of recovery of community mobility in acutely ill older adults using the University of Alabama at Birmingham Life-Space Assessment (LSA). DESIGN: Prospective observation cohort study. SETTING: Central Alabama, Birmingham Veterans Affairs Medical Center. PARTICIPANTS: Community dwelling adults aged 65 and older hospitalized for nonsurgical medical reasons (N=173). MEASUREMENTS: We determined LSA scores for the month before and monthly for 6 months after hospitalization (composite scores ranging from 0-120, with 120 reflecting completely unrestricted mobility). RESULTS: In the month after hospitalization, 92 (53%) participants had a clinically significant decrease in life-space mobility, while 42 (24%) were unchanged, and 39 (23%) had an increase from the month preceding hospitalization. Of participants with a life-space decrease, the majority recovered their prehospitalization mobility status during 6 months of follow-up, whereas 34% did not recover. Participants whose life-space decreased were hospitalized significantly longer (P=.01) and, on average, had higher prehospital life-space scores (P=.01) than those who maintained or increased their life-space. CONCLUSION: A clinically significant loss of community mobility was common after hospitalization, but most participants recovered to prehospitalization mobility within 6 months of discharge. Research examining in-hospital and posthospitalization interventions to achieve faster recovery of community mobility is needed. PMID- 29719060 TI - Phylogenetic analysis of human G9P[8] rotavirus strains circulating in Jiangsu, China between 2010 and 2016. AB - Rotavirus A (RVA) is the leading cause of acute viral gastroenteritis in children under 5 years of age worldwide. G9P[8] is a common RVA genotype that has been persistently prevalent in Jiangsu, China. To determine the genetic diversity of G9P[8] RVAs, 7 representative G9P[8] strains collected from Suzhou Children's Hospital between 2010 and 2016 (named JS2010-JS2016) were analyzed through whole genome sequencing. All evaluated strains showed the Wa-like constellation G9-P[8] I1-R1-C1-M1-A1-N1-T1-E1-H1. Furthermore, phylogenetic analysis revealed that the VP7 genes of all strains clustered into lineage G9-III and G9-VI. With the exception of strain JS2012 (P[8]-4), the VP4 sequences of all strains belonged to the P[8]-3 lineage. Sequencing further revealed that amino acid substitutions were present in the antigenic regions of the VP7 and VP4 genes of all strains. Moreover, there were multiple substitutions in antigenic sites I and II of the nonstructural protein 4 (NSP4) genes, whereas the other NSP genes were relatively conserved. In conclusion, our phylogenetic analysis of these 7 G9P[8] strains suggests that RVA varied across regions and time. Therefore, our findings suggest that continued surveillance is necessary to explore the molecular evolutionary characteristics of RVA for better prevention and treatment of acute viral gastroenteritis. PMID- 29719061 TI - Hypermethylation of IL-10 gene is responsible for its low mRNA expression in Behcet's disease. AB - Interleukin-10 (IL-10), produced generally by monocyte, T helper type 2 (Th2), and regulatory T cells (Treg), plays a central role in controlling inflammatory responses and regulating the immune response of the IL-10 mRNA expression. It is significantly down-regulated in many autoimmune diseases such as Behcet's disease; this is mostly associated with more aggressive complications. Nevertheless, the essential molecular process for its low expression has not been completely realized. The aim of this project was attempted to estimate the gene expression, promoter methylation, and protein levels to IL-10's down-regulated expression. In this study, blood samples from 51 (4 missed) patients and 63 (2 missed) healthy controls were taken, with the mononuclear cells isolated by the Ficoll Protocol. DNA and RNA were then subsequently extracted. Promoter methylation levels were evaluated by MeDIP-qPCR. Following this, the extracted RNA was converted to cDNA using the RT-PCR method, with the expression of IL-10 later evaluated by Real-time PCR. And then, serum levels of IL-10 were measured using ELISA method. As we expected, the expression level of the IL-10 gene was seen to significantly decline in the patient group in comparison to the control. Also, the rate of promoter methylation was significantly higher in the IL-10 mRNA low expression group (patient group) compared to its high expression group (healthy group) (P < 0.001). We revealed that hypermethylation of promoter region was the principal defect for the IL-10 mRNA low expression in patients with Behcet's disease. PMID- 29719062 TI - The facial artery perforator flap for intraoral reconstruction of a mouth floor defect. AB - Facial artery perforator flaps have been recently reported by different authors for perioral, nasal alar and cheek defects, but not for intraoral reconstruction. We have extended the use of the facial artery perforator flap in a 56-year-old man with a squamous cell carcinoma of left mouth floor, who was submitted to tumor resection with marginal mandibulectomy and left supraomohyoid neck dissection. The flap was designed according to the size of the defect (5 * 3 cm), centered on the perforator to create a symmetric flap and was tunnelled intraorally by means of a 90 degrees rotation. The postoperative period was uneventful, allowing timely initiation of adjuvant radiotherapy. After 8 months, there were no signs of local recurrence or wound dehiscence, and functional outcomes were satisfactory. The main advantages of this flap in this case were the reduction in morbidity at the donor site with preservation of nerves, muscles and facial artery, and it allowed greater freedom. To the best of the authors' knowledge, this technique has not been reported before. It may constitute an important reconstructive option when dealing with similar defects, if our results are confirmed in larger series. PMID- 29719063 TI - Diabetes is not associated with increased rates of free flap failure: Analysis of outcomes in 6030 patients from the ACS-NSQIP database. AB - BACKGROUND: Diabetes affects a significant proportion of the population in the United States. Microsurgical procedures are common in this patient population, and despite many conflicting reports in the literature, there are no large studies evaluating the direct association between diabetes and outcomes, specifically failure, following free flap reconstruction. In this study, we sought to determine the impact of diabetes on postoperative outcomes following free flap reconstruction using a national multi-institutional database. METHODS: We reviewed the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database to identify patients undergoing free flap reconstruction from 2010 to 2015. Preoperative variables and outcomes were compared between diabetic and nondiabetic patients. Univariate and multivariate analyses were performed to control for confounders. RESULTS: We identified 6030 eligible patients. No significant difference in flap failure rates was observed. However, diabetic patients presented significantly higher rates of wound complications, including deep incisional surgical site infection (SSI) (OR = 1.35; P = .01) and wound dehiscence (OR = 1.17; P = .03). Diabetic patients also presented a significantly longer hospital length of stay (LOS) (beta = .62; P < .001). CONCLUSIONS: Our study evaluated the largest national cohort of free flap procedures. These results suggest that diabetes is not associated with increased rates of flap failure. However, diabetic patients are at significantly higher risk of postoperative deep incisional SSI, wound dehiscence, and longer LOS. Our findings provide the most concrete evidence to date in support of free flap reconstruction in diabetic patients, but highlight the need for heightened clinical vigilance and wound care for optimal outcomes. PMID- 29719064 TI - Remodeling our concept of chemokine receptor function: From monomers to oligomers. AB - The chemokines direct leukocyte recruitment in both homeostatic and inflammatory conditions, and are therefore critical for immune reactions. By binding to members of the class A G protein-coupled receptors, the chemokines play an essential role in numerous physiological and pathological processes. In the last quarter century, the field has accumulated much information regarding the implications of these molecules in different immune processes, as well as mechanistic insight into the signaling events activated through their binding to their receptors. Here, we will focus on chemokine receptors and how new methodological approaches have underscored the role of their conformations in chemokine functions. Advances in biophysical-based techniques show that chemokines and their receptors act in very complex networks and therefore should not be considered isolated entities. In this regard, the chemokine receptors can form homo- and heterodimers as well as oligomers at the cell surface. These findings are changing our view as to how chemokines influence cell biology, identify partners that regulate chemokine function, and open new avenues for therapeutic intervention. PMID- 29719065 TI - 'Primum non nocere' (first do no harm). Intrapartum glycaemic control and neonatal hypoglycaemia. PMID- 29719066 TI - Displacing, squeezing, and ramming: The role of nuclear lamins in leukocyte migration. PMID- 29719067 TI - Echocardiographic evaluation of cardiac dyssynchrony: Does it still matter? AB - Cardiac resynchronization therapy (CRT) is an established treatment for patients with heart failure and left ventricular systolic dysfunction. For many years, cardiac mechanical dyssynchrony assessed by echocardiography has been considered as a key evaluation to characterize CRT candidates and predict CRT response. In current guidelines, however, CRT implant indications rely only on electrical dyssynchrony. The aim of this article was to clarify whether and how the evaluation of cardiac mechanical dyssynchrony should be performed today by echocardiography. PMID- 29719068 TI - Applications of the Whittaker smoother in NMR spectroscopy. AB - The Whittaker smoother, a special case of penalized least square, is a multipurpose algorithm that has proven to be very useful in many scientific fields, including image processing, chromatography, and optical spectroscopy. It shares many similarities with the Savitzky-Golay algorithm, but it is significantly faster and easier to automate. Its use in nuclear magnetic resonance, however, is not widespread although several applications have recently been published. In this review, the mathematical background of the method and its main applications in nuclear magnetic resonance spectroscopy will be discussed. PMID- 29719069 TI - Controlling Magnetic and Optical Properties of the van der Waals Crystal CrCl3-x Brx via Mixed Halide Chemistry. AB - Magnetic van der Waals (vdW) materials are the centerpiece of atomically thin devices with spintronic and optoelectronic functions. Exploring new chemistry paths to tune their magnetic and optical properties enables significant progress in fabricating heterostructures and ultracompact devices by mechanical exfoliation. The key parameter to sustain ferromagnetism in 2D is magnetic anisotropy-a tendency of spins to align in a certain crystallographic direction known as easy-axis. In layered materials, two limits of easy-axis are in-plane (XY) and out-of-plane (Ising). Light polarization and the helicity of topological states can couple to magnetic anisotropy with promising photoluminescence or spin orbitronic functions. Here, a unique experiment is designed to control the easy axis, the magnetic transition temperature, and the optical gap simultaneously in a series of CrCl3-x Brx crystals between CrCl3 with XY and CrBr3 with Ising anisotropy. The easy-axis is controlled between the two limits by varying spin orbit coupling with the Br content in CrCl3-x Brx . The optical gap, magnetic transition temperature, and interlayer spacing are all tuned linearly with x. This is the first report of controlling exchange anisotropy in a layered crystal and the first unveiling of mixed halide chemistry as a powerful technique to produce functional materials for spintronic devices. PMID- 29719070 TI - Searching for Models Exhibiting High Circularly Polarized Luminescence: Electroactive Inherently Chiral Oligothiophenes. AB - Two new inherently chiral oligothiophenes characterized by the atropisomeric 3,3' bithianaphtene scaffold functionalized with fused ring bithiophene derivatives, namely 4H-cyclopenta[2,1-b3:4b']dithiophene (CPDT) and dithieno[3,3-b:2',3' d]pyrrole (DTP), were synthesized. The racemates were fully characterized and resolved into antipodes by enantioselective HPLC. The enantiomers were analyzed through different chiroptical techniques: electronic circular dichroism (ECD) and vibrational circular dichroism (VCD) were employed to attribute the absolute configuration (AC). Comparison of experimental and calculated VCD spectra confirmed the DFT calculated conformational characteristics. The compound functionalized with two CPDT units was oxidized with FeCl3 , and ECD and CPL of the resulting material were measured. Circularly polarized luminescence (CPL) was measured to verify if inherently chiral oligothiophenes could be promising systems for chiral photonics applications. PMID- 29719071 TI - meso-Modified Cobalamins: Synthesis, Structure, and Properties. AB - Vitamin B12 and its derivatives present excellent paradigms for bioinspired catalysis. The inherent challenges for derivatizing cobalamins, such as vitamin B12 , to incorporate them in supramolecular designs and materials, limit the range of their utility and applications. Herein, we present a synthetic approach toward derivatives of vitamin B12 possessing electron-donating and -withdrawing substituents at the meso position (C10). Spectroscopic and cyclic voltammetry studies reveal that changes in the substitution pattern on the equatorial ligand have a significant impact on the electronic and optical properties of the cobalamin. These synthetic methods, therefore, provide invaluable routes not only for covalent linking to other structures, but also for attaining a wide range of functionalities for the derivatives of vitamin B12 . PMID- 29719072 TI - Utilization of health care services in cancer patients with elevated fear of cancer recurrence. AB - BACKGROUND: Cancer patients commonly report experiencing fear of cancer recurrence (FCR), which may lead to several negative consequences. This study aimed at examining whether clinical levels of FCR are linked to a greater use of health care services. METHOD: This is a secondary analysis of a longitudinal study of 962 cancer patients on the epidemiology of cancer-related insomnia. They completed the Fear of Cancer Recurrence Inventory-Short form (FCRI-SF) and reported information on their consultations (medical, psychosocial, and complementary and alternative medicine [CAM]) and medication usage (anxiolytics/hypnotics and antidepressants) at 6 time points over an 18-month period. RESULTS: Results indicated that clinical FCR at baseline was associated with greater consultation rates of medical and psychosocial professionals and a greater usage of anxiolytics/hypnotics and antidepressants. No significant association was found between the FCR level and use of CAM services. While consultation rates of medical and CAM professionals and usage of antidepressants generally increased over time, consultation rates of psychosocial professionals and usage of anxiolytics/hypnotics tended to decrease. CONCLUSIONS: Cancer patients with clinical levels of FCR are more likely to consult health care providers and to use psychotropic medications, which may translate into significant costs for society and the patients themselves. PMID- 29719073 TI - The expression of programed death ligand-1 could be related with unfavorable prognosis in salivary duct carcinoma. AB - BACKGROUND: Salivary duct carcinoma (SDC) is a rare tumor occurring in the salivary gland. SDC is a highly aggressive tumor and its prognosis is extremely poor. Effective treatments in advanced SDC have not yet been established. Recently, immune checkpoint inhibitors have paved the way for the treatment of various malignancies. We examined the expressions of programed death ligand (PD L) 1/PD-L2 and programed death (PD-1), and the correlation of clinicopathological findings. METHODS: We examined 18 cases of SDC and conducted immunohistochemical staining using formalin-fixed paraffin-embedded full-face sections. RESULTS: The expression of PD-L1 and PD-L2 in tumor cells was observed in nine cases (50%) and 14 cases (78%), respectively. Cases with a high expression of PD-L1 and PD-L2 were found in four (22%) and seven cases (39%), respectively. The cases with a high expression of PD-L1 showed significantly shorter overall survival compared to those with low PD-L1 expression and null expression. We also examined the expression of PD-L1/PD-L2 and PD-1 of tumor-infiltrating mononuclear cells (TIMC) in stroma. The expressions of PD-L1 in tumor cells and stroma had a significant correlation. Association between the expressions of PD-L1 in tumor cells and those of PD-1 in stroma was significant. However, PD-L2 expression in the tumor had no significant correlation with expression in TIMCs. PD-L1, PD-L2 and PD-1 expressions in stroma were not associated with patient prognosis. CONCLUSIONS: High PD-L1 expression in SDC was strongly associated with unfavorable prognosis, indicating that PD-1/PD-L1 inhibitors could be effective in SDC. PMID- 29719074 TI - Peraryl Arsoles: Practical Synthesis, Electronic Structures, and Solid-State Emission Behaviors. AB - 2,3,4,5-Tetraaryl-1-phenylarsoles were synthesized by utilizing safely generated diiodophenylarsine and zirconacyclopentadienes. The obtained peraryl arsoles showed aggregation-induced emission (AIE), where intense emission was observed in the solid states (quantum yields up to 0.61), whereas the corresponding solutions were very weakly emissive. The optical and electronic properties were examined by experimental and computational methods. It was elucidated that the aryl groups at the 2,5-positions affected the frontier orbitals and the aromaticity of the arsole core. On the other hand, those at the 1,3,5-positions were perpendicular to the luminophore and effective for a restriction of aggregation-caused quenching. Because the lone pair of the arsenic atom has a sufficient coordination ability due to the low aromaticity of the arsole moiety, a gold(I) chloride complex of 1,2,3,4,5-pentaphenylarsole was synthesized. The complex formation caused a blue shift of the emission from the bare ligand. Interestingly, the complex showed luminescent mechanochromism; grinding the crystals with a blue emission (lambdaem =445 nm) gave amorphous samples with a greenish-blue emission (lambdaem =496 nm). PMID- 29719075 TI - Reductive Coupling and Loss of N2 from Magnesium Diazomethane Derivatives. AB - The reductive coupling of two diazomethanes is affected by reaction with [(NacNacMes )Mg]2 affording the species [(NacNacMes )Mg(N2 CPh2 )]2 2 and [(NacNacMes )Mg(N2 C(C6 H4 )2 )]2 3. These species containing N4 linkages readily evolve the central N2 at 50 and 75 degrees C to give the Mg-imide products [(NacNacMes )Mg(NCPh2 )]2 (4) and [(NacNacMes )Mg(NC(C6 H4 )2 )]2 (5), respectively. The mechanism for the loss of N2 was considered computationally. Compounds 2 and 3 reacted with O2 to liberate the tetrazene (Ph2 N2 )2 6 and the hydrazine ((C6 H4 )2 CN)2 7, whereas reactions with Me3 SiOSO2 CF3 or Me3 SiCl with 2 and 3 provide the related silyl imines 8 and 9, respectively. PMID- 29719076 TI - Dissecting the role of Kruppel homolog 1 in the metamorphosis and female reproduction of the cotton bollworm, Helicoverpa armigera. AB - In insects, metamorphosis and reproduction are controlled by juvenile hormone (JH) and 20-hydroxyecdysone (20E). Kruppel homolog 1 (Kr-h1), a transcription factor, is regarded as a JH-early inducible gene responsible for the repression of metamorphosis. However, the role of Kr-h1 in reproduction of holometabolic insects is relatively less understood. In this study, we studied the role of Kr h1 in larvae-pupae transition and female reproduction in the major agricultural pest Helicoverpa armigera. Two HaKr-h1 isoforms (HaKr-h1alpha and HaKr-h1beta) were identified, with HaKr-h1alpha predominant in the cotton bollworm. In larvae, HaKr-h1 was predominately expressed in the epidermis and markedly up-regulated during the moult stage, whereas in adults HaKr-h1 was mainly expressed in females and the highest transcription was detected in the ovaries. Considering the function of hormones in larval metamorphosis, we examined the modulation of gene expression in response to hormones, which showed that HaKr-h1 was significantly induced by both JH analogue (JHA) and 20E. Knockdown of HaKr-h1 in fifth-instar larvae resulted in precocious metamorphosis from larvae to pupae. Moreover, a fluorescence immunoassay coupled with heterologous expression revealed that HaKr h1 was localized in the nucleus of oocyte membrane. In female adults, depletion of HaKr-h1 severely repressed the transcription of vitellogenin, disrupted oocyte maturation and reduced the number of eggs laid, suggesting that HaKr-h1 is required for vitellogenesis and egg production in H. armigera. The present study provides insight into the roles of HaKr-h1 in JH-mediated reproduction and highlights HaKr-h1 as a target for suppression of lepidopteran pests. PMID- 29719078 TI - Functional high-intensity training: A HIT to improve insulin sensitivity in type 2 diabetes. PMID- 29719077 TI - A scoping review of studies exploring physical activity among adolescents and young adults diagnosed with cancer. AB - OBJECTIVE: Physical activity can improve health, functional capacity, and quality of life among children and adults diagnosed with cancer. Physical activity may also offer important benefits to adolescents and young adults diagnosed with cancer (AYAs). We conducted a scoping review to: determine the extent, range, and nature of published studies on physical activity among AYAs; identify knowledge gaps; and provide directions for future research. METHODS: We searched 4 electronic databases for published studies. Two authors independently scanned the titles, abstracts, and full-texts against inclusion criteria: original research with humans, published in an English-language peer-reviewed journal, >=50% of participants were diagnosed with cancer between the ages of 15 and 39 years, and included at least 1 measure of physical activity behavior. Data were extracted from studies meeting these criteria and subsequently summarized narratively. RESULTS: Our search yielded 4729 articles; 32 met inclusion criteria. These included 18 cross-sectional and 4 longitudinal studies that explored descriptive (ie, sociodemographic or medical), physical, personal/psychological, social, other health behaviors, and/or other factors as antecedents or correlates of physical activity. The remaining 10 were intervention studies that focused on changing physical activity behavior or on testing the effects of physical activity. CONCLUSIONS: We can conclude that physical activity is not well researched among AYAs. More high-quality research adopting longitudinal or intervention study designs that incorporate a range of descriptive, physical, personal/psychological, social, and environmental measures are warranted to better inform the development of behavior change interventions as well as to establish the benefits of physical activity for AYAs. PMID- 29719079 TI - Effects of ipsilateral and contralateral fatigue and muscle blood flow occlusion on the complexity of knee-extensor torque output in humans. AB - NEW FINDINGS: What is the central question of this study? We addressed the question "what role do central and peripheral fatigue mechanisms play in the fatigue-induced loss of isometric torque complexity?" What is the main finding and its importance? When the contralateral limb is fatigued, the complexity of isometric torque output is unaffected even if the blood flow to the contralateral limb is occluded, which suggests that neither central fatigue nor afferent feedback from ischaemic muscle influences the complexity of torque output in an otherwise fresh muscle. ABSTRACT: Neuromuscular fatigue reduces the temporal structure, or complexity, of torque output during muscular contractions. To determine whether the fatigue-induced loss of torque complexity could be accounted for by central or peripheral factors, nine healthy participants performed four experimental trials involving intermittent isometric contractions of the knee extensors at 50% of the maximal voluntary contraction torque. These trials involved: (i) two bouts of contractions to failure using the right leg separated by 3 min recovery (IPS); (ii) the same protocol but with cuff occlusion during the 3 min recovery (IPS-OCC); (iii) contractions of the left leg to failure, followed 1 min later by contractions of the right leg to failure (CONT); and (iv) the same protocol but with cuff occlusion applied to the left leg throughout both the recovery period and right leg contractions (CONT-OCC). Supramaximal electrical stimulation during maximal voluntary contractions was used to determine the degree of central and peripheral fatigue, whilst complexity was determined using approximate entropy (ApEn) and detrended fluctuation analysis alpha exponent (DFA alpha). Neuromuscular fatigue was consistently associated with a loss of torque complexity in all conditions [e.g. IPS bout 1, ApEn from (mean +/- SD) 0.46 +/- 0.14 to 0.12 +/- 0.06 (P < 0.001)]. In IPS-OCC, occlusion abolished the recovery from fatigue, and torque complexity remained at the values observed at task failure in the preceding bout (IPS-OCC bout 2, first minute 0.14 +/- 0.03, P < 0.001). Prior contralateral contractions, with or without blood flow occlusion, had no effect on torque complexity. PMID- 29719080 TI - Lymphovenous anastomosis and debulking procedure for treatment of combined severe lower extremity and genital lymphedema: A case report. AB - Lymphedema most commonly occurs after cancer treatment and can affect limbs and genitalia. Genital lymphedema (GL) is a rare condition and can be disabling psychologically and physically. It often occurs along with lower extremity lymphedema (LEL). Conservative and physiologic reconstructive surgery such as lymphaticovenous anastomosis (LVA) offer good treatment options for LEL. GL however remains a reconstructive dilemma. The most effective surgical therapies in advanced GL are still debulking procedures in properly selected patients. Here, we present the surgical treatment of a 51 -year-old male patient with advanced and combined genital and right lower extremity lymphedema after Hodgkin lymphom treatment in the childhood. We performed multiple LVA to the right ankle joint, distal lower leg and lateral knee and 2 months later patient reported a significant decrease of pain and pressure in affected limb while the scrotal and penis lymphedema did not show any signs of improvement at all. Four months later, 4.9 kg of excessive lymphedematous tissue from the genital area was resected and covered by split-thickness skin grafts from the unaffected left upper thigh. The postoperative course was uneventful and 3 weeks postoperatively the skin graft healed completely. Follow up at 6 months showed reasonable cosmetic and functional outcomes and the patient reported a significant improvement of quality of life. We believe that debulking procedures and LVA may be combined in advanced GL and LEL and may provide good outcomes. PMID- 29719081 TI - Asynchronous CDX2 expression and polarization of porcine trophoblast cells reflects a species-specific trophoderm lineage determination progress model. AB - Upregulation of Cdx2 expression in outer cells is a key event responsible for cell lineage segregation between the inner cell mass and the trophoderm (TE) in mouse morula-stage embryos. In TE cells, polarization can regulate Hippo and Rho associated kinase (Rho-ROCK) signaling to induce the nuclear location of YAP, which has been demonstrated to further induce the expression of Cdx2. However, we found that CDX2 expression could not be detected in the outer cells of porcine morula-stage embryos but only in some TE cells at the early blastocyst stage. The biological significance and the regulation mechanism of this species-specific CDX2 expression pattern have still not been determined. We show here that an asynchronous CDX2 expression pattern exists in porcine TE cells during the development of the blastocyst. We demonstrate that CDX2 expression in porcine TE cells depends on the nuclear localization of YAP and polarization of the embryo through Y27632 treatment. We found that the polarization process in the morula to the late blastocyst stage porcine embryos was asynchronous, which was revealed by the apical localization of phosphorylated EZRIN staining. Artificially enhancing the number of polarized blastomeres by culturing the separated blastomeres of four-cell stage porcine embryos resulted in increased CDX2-positive cell numbers. These results indicate that the mechanism of CDX2 expression regulation is conserved, but the polarization progress is not conserved between the pig and the mouse, and results in a species-specific trophoblast determination progress model. PMID- 29719082 TI - Perturbing the acetylation status of the Type IV pilus retraction motor, PilT, reduces Neisseria gonorrhoeae viability. AB - Post-translational acetylation is a common protein modification in bacteria. It was recently reported that Neisseria gonorrhoeae acetylates the Type IV pilus retraction motor, PilT. Here, we show recombinant PilT can be acetylated in vitro and acetylation does not affect PilT ultrastructure. To investigate the function of PilT acetylation, we mutated an acetylated lysine, K117, to mimic its acetylated or unacetylated forms. These mutations were not tolerated by wild-type N. gonorrhoeae, but they were tolerated by N. gonorrhoeae carrying an inducible pilE when grown without inducer. We identified additional mutations in pilT and pilU that suppress the lethality of K117 mutations. To investigate the link between PilE and PilT acetylation, we found the lack of PilE decreases PilT acetylation levels and increases the amount of PilT associated with the inner membrane. Finally, we found no difference between wild-type and mutant cells in transformation efficiency, suggesting neither mutation inhibits Type IV pilus retraction. Mutant cells, however, form microcolonies morphologically distinct from wt cells. We conclude that interfering with the acetylation status of PilTK117 greatly reduces N. gonorrhoeae viability, and mutations in pilT, pilU and pilE can overcome this lethality. We discuss the implications of these findings in the context of Type IV pilus retraction regulation. PMID- 29719083 TI - Feasibility and principal acceptability of school-based mobile communication applications to disseminate healthy lunchbox messages to parents. AB - ISSUE ADDRESSED: This study aimed to assess the feasibility and acceptability of using an existing school-based mobile communication application to deliver messages to parents on how to pack a healthy lunchbox. METHODS: A telephone survey was conducted with 196 primary school principals within the Hunter New England region of New South Wales, Australia, in 2016. RESULTS: Almost two thirds of primary schools (59%) currently use a school-based mobile communication application to communicate with parents. Most principals (91%) agreed school lunchboxes need improving, of which 80% agree it is a school's role to provide information and guidelines to parents. However, only 50% of principals reported currently providing such information. The provision of lunchbox messages to parents by a third party appeared an acceptable model of delivery by principals. Larger schools and schools in urban and lower socio-economic localities were more likely to have used a school-based mobile communication application. CONCLUSIONS: The majority of principals recognise student lunchboxes need improving. The use of school-based mobile communication applications appears to be feasible and acceptable by principals as a method of communicating lunchbox messages to parents. SO WHAT?: Use of school-based mobile communication applications may be an effective method for delivering health information at a population level. Future research should assess the potential efficacy of disseminating health interventions via this modality. PMID- 29719084 TI - Developing a novel approach to existential suffering in cancer survivorship through Socratic dialogue. PMID- 29719085 TI - THE AER2 RECEPTOR FROM VIBRIO CHOLERAE IS A DUAL PAS-HEME OXYGEN SENSOR. AB - The diarrheal pathogen Vibrio cholerae navigates complex environments using three chemosensory systems and 44-45 chemoreceptors. Chemosensory cluster II modulates chemotaxis, whereas clusters I and III have unknown functions. Ligands have been identified for only five V. cholerae chemoreceptors. Here we report that the cluster III receptor, VcAer2, binds and responds to O2 . VcAer2 is an ortholog of Pseudomonas aeruginosa Aer2 (PaAer2), but differs in that VcAer2 has two, rather than one, N-terminal PAS domain. We have determined that both PAS1 and PAS2 form homodimers and bind penta-coordinate b-type heme via an Eeta-His residue. Heme binding to PAS1 required the entire PAS core, but receptor function also required the N-terminal cap. PAS2 functioned as an O2 -sensor [Kd(O2) , 19 MUM], utilizing the same Ibeta Trp (W276) as PaAer2 to stabilize O2 . The crystal structure of PAS2-W276L was similar to that of PaAer2-PAS, but resided in an active conformation mimicking the ligand-bound state, consistent with its signal-on phenotype. PAS1 also bound O2 [Kd(O2), 12 MUM], although O2 binding was stabilized by either a Trp or Tyr residue. Moreover, PAS1 appeared to function as a signal modulator, regulating O2 -mediated signaling from PAS2, and resulting in activation of the cluster III chemosensory pathway. This article is protected by copyright. All rights reserved. PMID- 29719086 TI - Overexpression of genes associated with hypoxia in cattle adapted to Trans Himalayan region of Ladakh. AB - Ladakh is an important part of the Trans-Himalayan region located between the Kunlun mountain range in the north and the main Great Himalayas to the south in the state of Jammu and Kashmir of India. The local cattle from Leh and Ladakh region, known as "Ladakhi cattle" is a unique germplasm having an excellent adaptation potential to high altitude hypobaric stress. In the present study, an effort was made to evaluate the transcriptional pattern of hypoxia inducing factor-1 (HIF-1) and several of its regulated genes in PBMCs of local Ladakhi cattle, Holstein Frisian crosses, Jersey (exotic) maintained at high altitude region and Sahiwal (Bos indicus) and Karan Fries (cross bred) cattle maintained in tropical environment. The combined data set indicated increased expression of HIF-1 and its regulated genes viz., glucose transporter 1 (GLUT1), vascular endothelial growth factor (VEGF), and hexokinase (HK2) in high altitude cattle indicating their importance in maintaining cellular homeostasis during high altitude hypoxia. The data indicated that hypoxia associated genes accumulated under hypoxic conditions are part of an essential adaptive component for adaptation to the high altitude of the trans-Himalayan region. In contrary, higher expression of molecular chaperons' viz., HSP70 and HSP90 in tropically adapted cattle give tolerance to high ambient temperature prevalent in tropical condition. In conclusion, HIF-1 and its regulatory genes could be termed as important candidates for producing homeostatic responses to hypoxia in cattle populations reared in higher altitudes of the Trans-Himalayan region. PMID- 29719087 TI - Regulation of inward rectifier potassium current ionic channel remodeling by AT1 Calcineurin-NFAT signaling pathway in stretch-induced hypertrophic atrial myocytes. AB - Previous studies have shown that the activation of angiotensin II receptor type I (AT1 ) is attributed to cardiac remodeling stimulated by increased heart load, and that it is followed by the activation of the calcineurin-nuclear factor of activated T-cells (NFAT) signaling pathway. Additionally, AT1 has been found to be a regulator of cardiocyte ionic channel remodeling, and calcineurin-NFAT signals participate in the regulation of cardiocyte ionic channel expression. A hypothesis therefore follows that stretch stimulation may regulate cardiocyte ionic channel remodeling by activating the AT1 -calcineurin-NFAT pathway. Here, we investigated the role of the AT1 -calcineurin-NFAT pathway in the remodeling of inward rectifier potassium (Ik1 ) channel, in addition to its role in changing action potential, in stretch-induced hypertrophic atrial myocytes of neonatal rats. Our results showed that increased stretch significantly led to atrial myocytes hypertrophy; it also increased the activity of calcineurin enzymatic activity, which was subsequently attenuated by telmisartan or cyclosporine-A. The level of NFAT3 protein in nuclear extracts, the mRNA and protein expression of Kir2.1 in whole cell extracts, and the density of Ik1 were noticeably increased in stretched samples. Stretch stimulation significantly shortened the action potential duration (APD) of repolarization at the 50% and 90% level. Telmisartan, cyclosporine-A, and 11R-VIVIT attenuated stretch-induced alterations in the levels of NFAT3 , mRNA and protein expression of Kir2.1, the density of Ik1 , and the APD. Our findings suggest that the AT1 -calcineurin-NFAT signaling pathway played an important role in regulating Ik1 channel remodeling and APD change in stretch-induced hypertrophic atrial myocytes of neonatal rats. PMID- 29719089 TI - Associations between therapists' occupational burnout and their patients' depression and anxiety treatment outcomes. AB - BACKGROUND: Occupational burnout is common in mental health professionals, but its impact on patient outcomes is as yet uncertain. This study aimed to investigate associations between therapist-level burnout and patient-level treatment outcomes after psychological therapy. METHODS: We used multilevel modeling using depression (PHQ-9) and anxiety (GAD-7) outcomes data from 2,223 patients nested within 49 therapists. Therapists completed a survey including the Oldenburg Burnout Inventory (OLBI) and a job satisfaction scale (JDSS). RESULTS: After controlling for case-mix, around 5% of variability in treatment outcomes was explained by therapist effects (TE). Higher therapist OLBI-disengagement and lower JDSS scores were significantly associated with poorer treatment outcomes, explaining between 31 and 39% of the TE estimate. Higher OLBI scores were also correlated with lower job satisfaction ratings. CONCLUSIONS: Therapist burnout has a negative impact on treatment outcomes and could be the target of future preventive and remedial action. PMID- 29719088 TI - Depressive and anxious symptoms and 20-year mortality: Evidence from the Stirling County study. AB - BACKGROUND: Depression and anxiety disorders are highly comorbid, and share significant symptom overlap. Whereas depression has been consistently associated with excess mortality, the association between anxiety and mortality is less clear. Our aim was to identify constellations of anxious and depressive symptoms and examine their associations with mortality. METHOD: This study considers respondents from the 1970 (n = 1203) and 1992 (n = 1402) cohorts of the Stirling County study. Symptoms of depression and anxiety were assessed using structured at-home interviews. Vital status of participants through 2011 was determined using probabilistic linkages to the Canadian Mortality Database. RESULTS: Exploratory factor analysis yielded three correlated factors in each cohort. Items loading on each factor varied slightly between cohorts, but roughly corresponded to (1) depressive symptoms, (2) anxious symptoms, and (3) somatic symptoms. The depressive factor was associated with increased risk of mortality in both the 1970 (HR: 1.35, 95% CI: 1.12, 1.62) and 1992 (HR: 1.25, 95% CI: 1.05, 1.48) cohorts. Anxious symptoms were associated with a reduced risk of mortality in the 1992 sample (HR: 0.72; 95% CI: 0.53, 0.90). Somatic symptoms were associated with a reduced risk of mortality in the 1970 sample (HR: 0.83, 95% CI: 0.69, 0.99), but an elevated risk of mortality in the 1992 sample (HR: 1.29; 95% CI: 1.11, 1.51). CONCLUSIONS: This study provides evidence that symptoms of depression and anxiety may have differential associations with early mortality. Somatic symptoms such as upset stomach and loss of appetite may be protective against mortality, perhaps through increased use of health care services. Conversely, symptoms such as weakness and cold sweats may be indicative of failing health. PMID- 29719090 TI - Apolipoprotein C1 promotes prostate cancer cell proliferation in vitro. AB - Here, we aimed to investigate the carcinogenic effects of apolipoprotein C1 (APOC1) in prostate cancer (PCa). APOC1 expression was evaluated in PCa and normal prostate specimens, and lentivirus-mediated RNA interference was used to knockdown APOC1 in DU145 cells. The effects of APOC1 silencing on cell proliferation, cell cycle arrest, and apoptosis were assessed. APOC1 expression was much higher in PCa tissues than in normal tissues. Moreover, APOC1 silencing inhibited cell proliferation and colony formation, arrested cell cycle progression, and enhanced apoptosis in DU145 cells. Additionally, APOC1 silencing decreased survivin, phospho-Rb, and p21 levels and increased cleaved caspase-3 expression. These data supported the procarcinogenic effects of APOC1 in the pathogenesis of PCa and suggested that targeting APOC1 may have applications in the treatment of PCa. PMID- 29719091 TI - Supramolecular Copolymerization as a Strategy to Control the Stability of Self Assembled Nanofibers. AB - A major challenge in supramolecular polymerization is controlling the stability of the polymers formed, that is, controlling the rate of monomer exchange in the equilibrium between monomer and polymer. The exchange dynamics of supramolecular polymers based on benzene-1,3,5-tricarboxamide (BTA) can be regulated by copolymerizing molecules with dendronized (dBTA) and linear (nBTA) ethylene glycol-based water-soluble side chains. Whereas nBTAs form long nanofibers in water, dBTAs do not polymerize, forming instead small spherical aggregates. The copolymerization of the two BTAs results in long nanofibers. The exchange dynamics of both the BTA monomers in the copolymer are significantly slowed down in the mixed systems, leading to a more stable copolymer, while the morphology and spectroscopic signature of the copolymers are identical to that of nBTA homopolymer. This copolymerization is the supramolecular counterpart of styrene/ maleic anhydride copolymerization. PMID- 29719092 TI - Evaluation of the toxicity effects of silk fibroin on human lymphocytes and monocytes. AB - Silk fibroin nanoparticles (SFNPs) as a natural polymer have been utilized in biomedical applications such as suture, tissue engineering-based scaffolds, and drug delivery carriers. Since there is little data regarding the toxicity effects on different cells and tissues, we aimed to determine the toxicity mechanisms of SFNPs on human lymphocytes and monocytes based on reliable methods. Our results showed that SFNPs (0.5, 1, and 2 mg/mL) induced oxidative stress via increasing reactive oxygen species production, mitochondrial membrane potential (?Psi) collapse, which was correlated to cytochrome c release and Adenosine diphosphate (ADP)/Adenosine tri phosphate (ATP) ratio increase as well as lysosomal as another toxicity mechanism, which led to cytosolic release of lysosomal digestive proteases, phosphor lipases, and apoptosis signaling. Taken together, these data suggested that SFNPs toxicity was associated with mutual mitochondrial/lysosomal cross-talk and oxidative stress on human lymphocytes and monocytes with activated apoptosis signaling. PMID- 29719093 TI - Interpersonal psychotherapy for mood and behavior dysregulation: Pilot randomized trial. AB - BACKGROUND: Youth with chronic irritability and excessive reactivity, diagnosed as disruptive mood dysregulation disorder (DMDD), have social impairment in multiple settings (i.e., peers, school, and home). This paper presents a pilot randomized trial assessing the feasibility, acceptability, and preliminary efficacy of interpersonal psychotherapy (IPT) for mood and behavior dysregulation (IPT-MBD), an adapted version of IPT for depressed adolescents. IPT-MBD focuses on decreasing outbursts and irritability and improving interpersonal interactions. METHODS: Nineteen adolescents (aged 12-17) with DMDD or its research precursor, severe mood dysregulation, were randomly assigned to IPT-MBD (n = 10) or treatment-as-usual (TAU, n = 9) in a 24-week psychosocial intervention study. Assessments of mood symptoms and overall functioning were conducted by an independent evaluator, blinded to treatment, every 4 weeks. Parent and self-report irritability measures were collected every 4 weeks. RESULTS: Eighty percent of participants randomized to the IPT-MBD arm completed the study. Also, participants enrolled in the IPT-MBD arm attended >80% of therapy sessions. Parents and teens agreed that the frequency and duration of therapy were appropriate and were satisfied with IPT-MBD treatment. Clinical global impression scales for severity and improvement showed statistically greater improvement in the IPT-MBD group compared to TAU. CONCLUSIONS: In this small pilot randomized trial, IPT-MBD was feasible and acceptable to parents and teens. There was significantly more improvement in the IPT-MBD group compared to TAU. IPT-MBD holds promise as a potentially effective psychosocial intervention for clinically impaired youth with DMDD and warrants further investigation in a larger randomized trial. PMID- 29719095 TI - MicroRNA-135a alleviates oxygen-glucose deprivation and reoxygenation-induced injury in neurons through regulation of GSK-3beta/Nrf2 signaling. AB - MicroRNAs (miRNAs) have been suggested as pivotal regulators in the pathological process of cerebral ischemia and reperfusion injury. In this study, we aimed to investigate the role of miR-135a in regulating neuronal survival in cerebral ischemia and reperfusion injury using an in vitro cellular model induced by oxygen-glucose deprivation and reoxygenation (OGD/R). Our results showed that miR 135a expression was significantly decreased in neurons with OGD/R treatment. Overexpression of miR-135a significantly alleviated OGD/R-induced cell injury and oxidative stress, whereas inhibition of miR-135a showed the opposite effects. Glycogen synthase kinase-3beta (GSK-3beta) was identified as a potential target gene of miR-135a. miR-135a was found to inhibit GSK-3beta expression, but promote the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and downstream signaling. However, overexpression of GSK-3beta significantly reversed miR-135a-induced neuroprotective effect. Overall, our results suggest that miR 135a protects neurons against OGD/R-induced injury through downregulation of GSK 3beta and upregulation of Nrf2 signaling. PMID- 29719094 TI - Protective effect of retinoic acid receptor alpha on hypoxia-induced epithelial to mesenchymal transition of renal tubular epithelial cells associated with TGF beta/MMP-9 pathway. AB - Retinoic acid receptor alpha (RARalpha), a member of family of the nuclear retinoic acid receptors (RARs), plays an essential role in various chronic kidney diseases (CKD). Renal tubular epithelial to mesenchymal transition (EMT) is a common mechanism of progression of renal interstitial fibrosis (RIF). Hypoxia has been extensively considered as one of major inducers of renal tubular EMT. However, the effects of RARalpha on hypoxia-induced EMT have not yet been described so far. The aim of the present study was to explore the roles and potential mechanisms of RARalpha in hypoxia-induced EMT of renal tubular epithelial cells (RTECs). Our results showed that expression of RARalpha in RTECs subjected to hypoxia significantly was reduced, accompanied by decreased expression level of the epithelial marker E-cadherin, and increased expression levels of the mesenchymal markers alpha-smooth muscle actin (alpha-SMA) and vimentin, in accord with EMT. Meanwhile, hypoxia could cause RTECs to obviously express TGF-beta and matrix metalloproteinase-9 (MMP-9). Furthermore, using lentivirus-based delivery vectors to overexpress RARalpha in RTECs, we demonstrated that RARalpha alleviated hypoxia-induced EMT of RTECs and downregulated the expression levels of TGF-beta and MMP-9. In a word, RARalpha protects RTECs against EMT induced by hypoxia associated with TGF-beta/MMP-9 pathway. PMID- 29719096 TI - Amorphous Pure Organic Polymers for Heavy-Atom-Free Efficient Room-Temperature Phosphorescence Emission. AB - Pure organic, heavy-atom-free room-temperature phosphorescence (RTP) materials have attracted much attention and have potential applications in photoelectric and biochemical material fields owing to their rich excited state properties. They offer long luminescent lifetime, diversified design, and facile preparation. However, recent achievements of efficient phosphorescence under ambient conditions mainly focus on ordered crystal lattices or embedding into rigid matrices, which require strict growth conditions and have poor reproducibility. Herein, we developed a concise approach to give RTP with a decent quantum yield and ultralong phosphorescence lifetime in the amorphous state by radical binary copolymerization of acrylamide and different phosphors with oxygen-containing functional groups. The cross-linked hydrogen-bonding networks between the polymeric chains immobilize phosphors to suppress non-radiative transitions and provide a microenvironment to shield quenchers. PMID- 29719097 TI - Formal Nickelate(-I) Complexes Supported by Group 13 Ions. AB - Formal nickelate(-I) complexes bearing Group 13 metalloligands (M=Al and Ga) were isolated. These 17 e- complexes were synthesized by one-electron reduction of the corresponding Ni0 ->MIII precursors, and were investigated by single-crystal X ray diffraction, EPR spectroscopy, and quantum chemical calculations. Collectively, the experimental and computational data support: 1) the strengthening of the Ni-M bond upon one-electron reduction, and 2) the delocalization of the unpaired spin across the Ni and M atoms. An intriguing electronic configuration is revealed where three valence electrons occupy two sigma-type bonding interactions: Ni(3dz2 )2 ->M and sigma-(Ni-M)1 . The latter is an unusual Ni-M sigma-bonding molecular orbital that comprises primarily the Ni 4pz and M npz /ns atomic orbitals. PMID- 29719098 TI - Allogeneic hematopoietic cell transplant following crizotinib monotherapy for relapsed/refractory anaplastic large cell lymphoma. AB - Relapsed ALK-positive ALCL often is responsive to CRZ monotherapy. The subsequent role of allogeneic HCT after achieving second remission is poorly understood. We report 6 children who underwent allogeneic HCT for relapsed ALCL after CRZ. Age at transplant ranged from 10.7 to 22.6 years. Follow-up ranged from 0.9 to 4.5 years. All patients engrafted. Three of 4 patients that received a reduced toxicity conditioning regimen containing fludarabine, alemtuzumab, and low-dose irradiation showed progressive mixed chimerism. Five patients remain in remission. One patient developed isolated CNS relapse 3.6 years after HCT despite a lack of previous CNS involvement. No acute transplant-related complications were experienced. One patient developed chronic renal disease secondary to transplant-associated microangiopathy and one patient chronic GVHD secondary to DLI. Ultimately, allogeneic HCT appears safe and potentially curative after remission induction with CRZ. The role of conditioning therapy, ablative or reduced intensity, remains uncertain for patients' post-CRZ monotherapy, and further studies may be warranted. PMID- 29719099 TI - An Artificial Heme Enzyme for Cyclopropanation Reactions. AB - An artificial heme enzyme was created through self-assembly from hemin and the lactococcal multidrug resistance regulator (LmrR). The crystal structure shows the heme bound inside the hydrophobic pore of the protein, where it appears inaccessible for substrates. However, good catalytic activity and moderate enantioselectivity was observed in an abiological cyclopropanation reaction. We propose that the dynamic nature of the structure of the LmrR protein is key to the observed activity. This was supported by molecular dynamics simulations, which showed transient formation of opened conformations that allow the binding of substrates and the formation of pre-catalytic structures. PMID- 29719100 TI - Er3+ Sensitized 1530 nm to 1180 nm Second Near-Infrared Window Upconversion Nanocrystals for In Vivo Biosensing. AB - Fluorescent bioimaging in the second near-infrared window (NIR-II) can probe deep tissue with minimum auto-fluorescence and tissue scattering. However, current NIR II fluorophore-related biodetection in vivo is only focused on direct disease lesion or organ bioimaging, it is still a challenge to realize NIR-II real-time dynamic biosensing. A new type of Er3+ sensitized upconversion nanoparticles are presented with both excitation (1530 nm) and emission (1180 nm) located in the NIR-II window for in vivo biosensing. The microneedle patch sensor for in vivo inflammation dynamic detection is developed based on the ratiometric fluorescence by combining the effective NIR-II upconversion emission and H2 O2 sensing organic probes under the Fenton catalysis of Fe2+ . Owing to the large anti-Stokes shifting, low auto-fluorescence, and tissue scattering of the NIR-II upconversion luminescence, inflammation can be dynamically evaluated in vivo at very high resolution (200*200 MUm). PMID- 29719101 TI - Structure and Magnetization Dynamics of Dy-Fe and Dy-Ru Bonded Complexes. AB - We present an investigation of isostructural complexes that feature unsupported direct bonds between a formally trivalent lanthanide ion (Dy3+ ) and either a first-row (Fe) or a second-row (Ru) transition metal (TM) ion. The sterically rigid, yet not too bulky ligand PyCp22- (PyCp22- =[2,6-(CH2 C5 H3 )2 C5 H3 N]2- ) facilitates the isolation and characterization of PyCp2 Dy-FeCp(CO)2 (1; d(Dy Fe)=2.884(2) A) and PyCp2 Dy-RuCp(CO)2 (2; d(Dy-Ru)=2.9508(5) A). Computational and spectroscopic studies suggest strong TM->Dy bonding interactions. Both complexes exhibit field-induced slow magnetic relaxation with effectively identical energy barriers to magnetization reversal. However, in going from Dy-Fe to Dy-Ru bonding, we observed faster magnetic relaxation at a given temperature and larger direct and Raman coefficients, which could be due to differences in the bonding and/or spin-phonon coupling contributions to magnetic relaxation. PMID- 29719102 TI - Risk factors for hypertrophic burn scar pain, pruritus, and paresthesia development. AB - Hypertrophic scar pain, pruritus, and paresthesia symptoms are major and particular concerns for burn patients. However, because no effective and satisfactory methods exist for their alleviation, the clinical treatment for these symptoms is generally considered unsatisfactory. Therefore, their risk factors should be identified and prevented during management. We reviewed the medical records of 129 postburn hypertrophy scar patients and divided them into two groups for each of three different symptoms based on the University of North Carolina "4P" Scar Scale: patients with scar pain requiring occasional or continuous pharmacological intervention (HSc pain, n = 75) vs. patients without such scar pain (No HSc pain, n = 54); patients with scar pruritus requiring occasional or continuous pharmacological intervention (HSc pruritus, n = 63) vs. patients without such scar pruritus (No HSc pruritus, n = 66); patients with scar paresthesia that influenced the patients' daily activities (HSc paresthesia, n = 31) vs. patients without such scar paresthesia (No HSc paresthesia, n = 98). Three multivariable logistic regression models were built, respectively, to identify the risk factors for hypertrophic burn scar pain, pruritus, and paresthesia development. Multivariable analysis showed that hypertrophic burn scar pain development requiring pharmacological intervention was associated with old age (odds ratio [OR] = 1.046; 95% confidence interval [CI], 1.011-1.082, p = 0.009), high body mass index (OR = 1.242; 95%CI, 1.068-1.445, p = 0.005), 2-5-mm thick postburn hypertrophic scars (OR = 3.997; 95%CI, 1.523-10.487, p = 0.005), and 6-12-month postburn hypertrophic scars (OR = 4.686; 95%CI, 1.318-16.653, p = 0.017). Hypertrophic burn scar pruritus development requiring pharmacological intervention was associated with smoking (OR = 3.239; 95%CI, 1.380-7.603; p = 0.007), having undergone surgical operation (OR = 2.236; 95%CI, 1.001-4.998; p = 0.049), and firm scars (OR = 3.317; 95%CI, 1.237-8.894; p = 0.017). Finally, hypertrophic burn scar paresthesia development which affected the patients' daily activities was associated with age (OR = 1.038; 95%CI, 1.002-1.075; p = 0.040), fire burns (OR = 0.041; 95%CI, 0.005-0.366; p = 0.004, other burns vs. flame burns), and banding and contracture scars (OR = 4.705; 95%CI, 1.281-17.288, p = 0.020). PMID- 29719103 TI - Controlled Expansion of a Strong-Field Iron Nitride Cluster: Multi-Site Ligand Substitution as a Strategy for Activating Interstitial Nitride Nucleophilicity. AB - Multimetallic clusters have long been investigated as molecular surrogates for reactive sites on metal surfaces. In the case of the MU4 -nitrido cluster [Fe4 (MU4 -N)(CO)12 ]- , this analogy is limited owing to the electron-withdrawing effect of carbonyl ligands on the iron nitride core. Described here is the synthesis and reactivity of [Fe4 (MU4 -N)(CO)8 (CNArMes2 )4 ]- , an electron-rich analogue of [Fe4 (MU4 -N)(CO)12 ]- , where the interstitial nitride displays significant nucleophilicity. This characteristic enables rational expansion with main-group and transition-metal centers to yield unsaturated sites. The resulting clusters display surface-like reactivity through coordination-sphere-dependent atom rearrangement and metal-metal cooperativity. PMID- 29719104 TI - The Energetics of Surfactant-Templating of Zeolites. AB - Mesoporosity can be conveniently introduced into zeolites by treating them in basic surfactant solutions. The apparent activation energy involved in the formation of mesopores in USY by surfactant-templating was determined using a combination of in situ synchrotron X-ray diffraction and ex situ gas adsorption. Additionally, techniques such as pH measurement and thermogravimetry/differential thermal analysis were employed to determine OH- evolution and cetyltrimethylammonium ion (CTA+ ) uptake during the development of mesoporosity, thereby providing information about the different steps involved. The combination of both in situ and ex situ techniques has allowed determination of the apparent activation energies of the different processes involved in the mesostructuring of USY zeolites for the first time. Apparent activation energies are of the same order of magnitude (30-65 kJ mol-1 ) as those involved in the crystallization of zeolites. Hence, important mechanistic insight into the surfactant-templating method was obtained. PMID- 29719106 TI - An Inherently Chiral Au24 Framework with Double-Helical Hexagold Strands. AB - 2,3-bis(diphenylphosphino)butane enantiomers (chiraphos, L) used as chiral auxiliaries results in the preferential formation of an unprecedented Au24 framework with inherent chirality. The crystal structure of [Au24 L6 Cl4 ]2+ (1) has a square antiprism-like octagold core twinned by two helicene-like hexagold motifs, where the inherent chirality is associated with the helical arrangement. The clusters carrying (R,R)- and (S,S)- diphosphines had right- and left-handed strands, respectively. Circular dichroism spectra showed peaks in the visible to near-IR region, some of which did not coincide with absorption bands, suggesting the enantiomeric Au24 frameworks possess unique chiroptical properties. The Au24 frameworks were thermally robust, which could be attributed to the superatomic concept (18 e- system) and the steric constraint effects of the bridging ligand units. PMID- 29719105 TI - The Interhalogen Cations [Br2 F5 ]+ and [Br3 F8 ]. AB - The synthesis and characterization of unique polyhalogen cations containing MU bridging fluorine atoms are reported. The [Br2 F5 ]+ cation features a symmetric [F2 Br-MU-F-BrF2 ] bridge, whereas the [Br3 F8 ]+ contains asymmetric MU-F bridges. These fluoronium ions, obtained as [SbF6 ]- salts, were investigated using Raman and 19 F NMR spectroscopy, as well as single-crystal X-ray diffraction. Quantum chemical calculations were carried out for the gas-phase cations as well as for the solid-state compounds. Population analyses show the MU F atoms to possess the most negative partial charge within the cations. PMID- 29719107 TI - MOF-Derived Hollow CoS Decorated with CeOx Nanoparticles for Boosting Oxygen Evolution Reaction Electrocatalysis. AB - Transition-metal sulfides (TMSs) have emerged as important candidates for oxygen evolution reaction (OER) electrocatalysts. Now a hybrid nanostructure has been decorated with CeOx nanoparticles on the surface of ZIF-67-derived hollow CoS through in situ generation. Proper control of the amount of CeOx on the surface of CoS can achieve precise tuning of Co2+ /Co3+ ratio, especially for the induced defects, further boosting the OER activity. Meanwhile, the formation of protective CeOx thin layer effectively inhibits the corrosion by losing cobalt ion species from the active surface into the solution. It is thus a rare example of a hybrid hetero-structural electrocatalyst with CeOx NPs to improve the performance of the hollow TMS nanocage. PMID- 29719108 TI - Perfluoroalcohols: The Preparation and Crystal Structures of Heptafluorocyclobutanol and Hexafluorocyclobutane-1,1-diol. AB - The first X-ray crystal structure of an alpha-fluoroalcohol is reported. Heptafluorocyclobutanol was obtained in quantitative yield from hexafluorocyclobutanone by HF addition in anhydrous hydrogen fluoride. The compound was characterized by its X-ray single crystal structure. Heptafluorocyclobutanol readily undergoes hydrolysis to hexafluorocyclobutane-1,1 diol, which was also structurally characterized by X-ray diffraction. PMID- 29719109 TI - Belatacept during pregnancy in renal transplant recipients: Two case reports. AB - Impaired fertility is common among patients with chronic organ failure, including end-stage renal disease (ESRD). Women of childbearing age undergoing transplantation may experience rapid return of fertility. Pregnancy posttransplant presents numerous risks for the patient, fetus, and allograft. Maternal risks include hypertension and preeclampsia. Allograft risks include acute rejection and failure of the organ, and fetal risks include miscarriage, birth defects from immunosuppressants, premature delivery, and low birth weight. Belatacept, a selective T cell costimulation blocker, was approved for use in kidney transplant recipients in the United States in 2011. Little is known about the safety of belatacept during pregnancy in humans. We describe 2 cases of successful pregnancy and delivery with the use of belatacept-based immunosuppression. The Transplant Pregnancy Registry International (TPR) is a voluntary registry for transplant recipients who have had pregnancies or fathered a pregnancy posttransplant. To date, these 2 cases are the only known exposures to belatacept that have been reported to the TPR. PMID- 29719110 TI - Enhancing the Kinetic Stability and Lifetime of Organic Light-Emitting Diodes based on Bipolar Hosts by using Spiroconjugation. AB - We examined how to enhance the lifetime of organic light-emitting diodes (OLEDs) based on bipolar host molecules ET-HT, where ET and HT refer to electron- and hole-transporting units, respectively, by analyzing their thermodynamic and kinetic stabilities. Our DFT calculations reveal that the thermodynamic stability of ET-HT is determined by that of its anion, which is difficult to improve by chemical modifications of ET and HT. The kinetic stability of ET-HT can be enhanced by the spiroconjugation between ET and HT, which occurs when their pi frameworks are extended and have an orthogonal arrangement. Green OLED devices were fabricated by using ET-HTs with and without spiroconjugation, to find that the device with spiroconjugation has a lifetime that is approximately 6 times longer than the one without spiroconjugation. PMID- 29719111 TI - Enantiodivergent Synthesis of Allenes by Point-to-Axial Chirality Transfer. AB - An enantiodivergent method for the synthesis of multiply substituted allenes is described. Highly enantioenriched, point-chiral boronic esters were synthesized by homologation of alpha-seleno alkenyl boronic esters with lithiated carbamates and eliminated to form axially chiral allene products. By employing either oxidative or alkylative conditions, both syn and anti elimination could be achieved with complete stereospecificity. The process enables the synthesis of either M or P allenes from a single isomer of a point-chiral precursor and can be employed for the enantioselective assembly of di-, tri-, and tetrasubstituted allenes. PMID- 29719112 TI - The plant-parasitic cyst nematode effector GLAND4 is a DNA-binding protein. AB - Cyst nematodes are plant pathogens that infect a wide range of economically important crops. One parasitic mechanism employed by cyst nematodes is the production and in planta delivery of effector proteins to modify plant cells and suppress defences to favour parasitism. This study focuses on GLAND4, an effector of Heterodera glycines and H. schachtii, the soybean and sugar beet cyst nematodes, respectively. We show that GLAND4 is recognized by the plant cellular machinery and is transported to the plant nucleus, an organelle for which little is known about plant nematode effector functions. We show that GLAND4 has DNA binding ability and represses reporter gene expression in a plant transcriptional assay. One DNA fragment that binds to GLAND4 is localized in an Arabidopsis chromosomal region associated with the promoters of two lipid transfer protein genes (LTP). These LTPs have known defence functions and are down-regulated in the nematode feeding site. When expressed in Arabidopsis, the presence of GLAND4 causes the down-regulation of the two LTP genes in question, which is also associated with increased susceptibility to the plant-pathogenic bacterium Pseudomonas syringae. Furthermore, overexpression of one of the LTP genes reduces plant susceptibility to H. schachtii and P. syringae, confirming that LTP repression probably suppresses plant defences. This study makes GLAND4 one of a small subset of characterized plant nematode nuclear effectors and identifies GLAND4 as the first DNA-binding, plant-parasitic nematode effector. PMID- 29719114 TI - The genetic determinants of renal allograft rejection. PMID- 29719113 TI - A phase 1 study of eribulin mesylate (E7389), a novel microtubule-targeting chemotherapeutic agent, in children with refractory or recurrent solid tumors: A Children's Oncology Group Phase 1 Consortium study (ADVL1314). AB - BACKGROUND: Eribulin mesylate is a novel anticancer agent that inhibits microtubule growth, without effects on shortening, and promotes nonproductive tubulin aggregate formation. We performed a phase 1 trial to determine the dose limiting toxicities (DLTs), maximum tolerated or recommended phase 2 dose (MTD/RP2D), and pharmacokinetics (PK) of eribulin in children with refractory or recurrent solid (excluding central nervous system) tumors. METHODS: Eribulin was administered intravenously on days 1 and 8 in 21-day cycles. Three dose levels (1.1, 1.4, and 1.8 mg/m2 /dose) were evaluated using the rolling six design with additional patients enrolled into a PK expansion cohort at the MTD. PK samples were obtained following the day 1, cycle 1 dose. RESULTS: Twenty-three patients, ages 3-17 (median 14) years were enrolled; 20 were evaluable for toxicity. DLTs occurred in 0/6 and 1/6 subjects at the 1.1 and 1.4 mg/m2 /dose, respectively. One subject at the 1.4 mg/m2 /dose had grade 4 neutropenia and grade 3 fatigue. At the 1.8 mg/m2 /dose, 2/5 subjects experienced dose-limiting (grade 4) neutropenia. Grade 3/4 non-DLTs included lymphopenia and hypokalemia, while low grade toxicities included anorexia and nausea. No episodes of grade > 2 corrected QT interval prolongation or peripheral neuropathy were reported. Eribulin pharmacokinetic parameters were highly variable; the median elimination half-life was 39.6 (range 24.2-96.4) hr. A partial response was observed in one patient (Ewing sarcoma). CONCLUSIONS: Eribulin was well tolerated in children with refractory or recurrent solid tumors with neutropenia identified as the primary DLT. The RP2D of eribulin is 1.4 mg/m2 /dose on days 1 and 8 of a 21-day cycle. PMID- 29719115 TI - Preemptive treatment of early donor-specific antibodies with IgA- and IgM enriched intravenous human immunoglobulins in lung transplantation. AB - This retrospective study presents our 4-year experience of preemptive treatment of early anti-HLA donor specific antibodies with IgA- and IgM-enriched immunoglobulins. We compared outcomes between patients with antibodies and treatment (case patients) and patients without antibodies (control patients). Records of patients transplanted at our institution between March 2013 and November 2017 were reviewed. The treatment protocol included one single 2 g/kg immunoglobulin infusion followed by successive 0.5 g/kg infusions for a maximum of 6 months, usually combined with a single dose of anti-CD20 antibody and, in case of clinical rejection or positive crossmatch, with plasmapheresis or immunoabsorption. Among the 598 transplanted patients, 128 (21%) patients formed the case group and 452 (76%) the control group. In 116 (91%) patients who completed treatment, 106 (91%) showed no antibodies at treatment end. Fourteen (13%) patients showed antibody recurrence thereafter. In case versus control patients and at 4-year follow-up, respectively, graft survival (%) was 79 versus 81 (P = .59), freedom (%) from biopsy-confirmed rejection 57 versus 53 (P = .34), and from chronic lung allograft dysfunction 82 versus 78 (P = .83). After lung transplantation, patients with early donor-specific antibodies and treated with IgA- and IgM-enriched immunoglobulins had 4-year graft survival similar to patients without antibodies and showed high antibody clearance. PMID- 29719116 TI - A brief primer on the mediational role of BDNF in the exercise-memory link. AB - One of the most amazing aspects of the human brain is its ability to learn information and use it to change behaviour. A key neurotrophin that influences memory function is brain-derived neurotrophic factor (BDNF). This review briefly discusses the mechanistic role that BDNF may play in facilitating learning and memory. We also describe the role of exercise on this relationship. As discussed herein, BDNF may influence memory via BDNF-induced alterations in membrane receptor expression and translocation, as well as activating several pathways (PLC-y, PI3K, ERK) that act together to facilitate cellular effects that influence synaptic plasticity. Exercise may help to facilitate BDNF expression and its downstream cellular pathways from both direct and indirect mechanisms. PMID- 29719117 TI - Decreased levels of keratin 8 sensitize mice to streptozotocin-induced diabetes. AB - AIM: Diabetes is a result of an interplay between genetic, environmental and lifestyle factors. Keratin intermediate filaments are stress proteins in epithelial cells, and keratin mutations predispose to several human diseases. However, the involvement of keratins in diabetes is not well known. K8 and its partner K18 are the main beta-cell keratins, and knockout of K8 (K8-/- ) in mice causes mislocalization of glucose transporter 2, mitochondrial defects, reduced insulin content and altered systemic glucose/insulin control. We hypothesize that K8/K18 offer protection during beta-cell stress and that decreased K8 levels contribute to diabetes susceptibility. METHODS: K8-heterozygous knockout (K8+/- ) and wild-type (K8+/+ ) mice were used to evaluate the influence of keratin levels on endocrine pancreatic function and diabetes development under basal conditions and after T1D streptozotocin (STZ)-induced beta-cell stress and T2D high-fat diet (HFD). RESULTS: Murine K8+/- endocrine islets express ~50% less K8/K18 compared with K8+/+ . The decreased keratin levels have little impact on basal systemic glucose/insulin regulation, beta-cell health or insulin levels. Diabetes incidence and blood glucose levels are significantly higher in K8+/- mice after low-dose/chronic STZ treatment, and STZ causes more beta-cell damage and polyuria in K8+/- compared with K8+/+ . K8 appears upregulated 5 weeks after STZ treatment in K8+/+ islets but not in K8+/- . K8+/- mice showed no major susceptibility risk to HFD compared to K8+/+ . CONCLUSION: Partial K8 deficiency reduces beta-cell stress tolerance and aggravates diabetes development in response to STZ, while there is no major susceptibility to HFD. PMID- 29719118 TI - Cognitive Analytic Therapy for psychosis: A case series. AB - OBJECTIVES: Cognitive Analytic Therapy (CAT) is an effective psychological intervention for several different mental health conditions. However, whether it is acceptable, safe, and beneficial for people with psychosis remains unclear, as is the feasibility of providing and evaluating it within a research context. The aim of this study was to begin to address these questions and to obtain for the first time a rich and detailed understanding of the experience of receiving CAT for psychosis. DESIGN: A mixed-methods case series design. METHOD: Seven individuals who experienced non-affective psychosis received CAT. They completed assessments at the start of CAT, 16 weeks, and 28 weeks post-baseline. Qualitative interviews were completed with four individuals following completion of or withdrawal from therapy. RESULTS: Six participants attended at least four sessions of therapy and four went on to complete therapy. There were no serious adverse events, and self-reported adverse experiences were minimal. Qualitative interviews suggested CAT is acceptable and provided a way to understand and work therapeutically with psychosis. There was limited evidence of change in psychotic symptoms, but improvement in perceived recovery and personality integration was observed. CONCLUSIONS: The results suggest that CAT is a safe and acceptable intervention for psychosis. Personality integration, perceived recovery, and functioning are relevant outcomes for future evaluations of CAT for psychosis. PRACTITIONER POINTS: It is feasible to conduct research evaluating CAT for people with psychosis. Within this case series, CAT appears acceptable and safe to individuals with psychosis. Within this case series, clients reported that CAT was a positive and helpful experience. There is a mixed picture with regard to secondary outcomes, but the design and aims of this case series limit conclusion that can be drawn from this data. PMID- 29719119 TI - Thermoregulatory profile of neurodegeneration-induced dementia of the Alzheimer's type using intracerebroventricular streptozotocin in rats. AB - AIM: Here, we have extensively investigated the relationship between thermoregulation and neurodegeneration-induced dementia of the Alzheimer's type using intracerebroventricular injections of streptozotocin (icv-STZ). METHODS: Male Wistar rats were treated with bilateral injections of icv-STZ, and their thermoregulatory profiles (core body temperature, tail-skin temperature, cold and heat defence responses and thermal place preference) were evaluated. Spatial memory, locomotor activity, social interaction, brain ventricular volume, and Abeta1-42 and tau protein levels in the brain were analysed to characterize the effects of STZ on the brain and behaviour. RESULTS: In addition to deficits in spatial memory, reduced social interaction and an increased brain ventricular volume, icv-STZ rats presented a pattern of hyperthermia, as demonstrated by an increased core body temperature. Hyperthermia was due to the activation of both autonomic heat conservation and behavioural cold avoidance, as STZ-treated rats presented tail-cutaneous vasoconstriction and an altered thermal preference. They also showed a distinct cold defence response when exposed to cold. CONCLUSION: Our data bring evidence that icv-STZ in rats causes hyperthermia, with activation of both autonomic and behavioural thermoregulatory defence responses when challenged at colder temperatures, leading us to hypothesize that they are more efficient in preventing hypothermia. These data are relevant for a better understanding of neurodegenerative disease mechanisms. PMID- 29719120 TI - Hepatoblastoma in patients with molecularly proven familial adenomatous polyposis: Clinical characteristics and rationale for surveillance screening. AB - Familial adenomatous polyposis (FAP) due to APC mutation is associated with an increased risk of hepatoblastoma. All cases of hepatoblastoma in patients with FAP reported in the literature were reviewed. One hundred and nine patients were identified. Thirty-five patients (of 49 with data) were diagnosed with hepatoblastoma prior to a later diagnosis of FAP (often in association with advanced colorectal carcinoma), emphasizing a need to identify patients earlier with germline APC mutations for early colorectal carcinoma screening. Hepatoblastoma may present at birth, and screening for hepatoblastoma in infancy in families with FAP prior to APC mutation testing results may be warranted. PMID- 29719121 TI - A Focus on Macitentan in the Treatment of Pulmonary Arterial Hypertension. AB - The approval of macitentan has increased the number of pharmacological treatments of pulmonary arterial hypertension (PAH). Here, we review the effect on PAH of macitentan compared to other endothelin receptor antagonists. Drugs targeting the endothelin (ET) pathway include the selective ETA receptor antagonist ambrisentan, the ETA /ETB receptor antagonists, bosentan and macitentan, which were recently approved for PAH treatment. Macitentan exhibits higher antagonistic potency than bosentan and ambrisentan in pulmonary smooth muscle cells. Compared to ambrisentan and bosentan, macitentan has a longer duration of action, reflected by the longer half-life, as well as pharmacodynamics attributed to its active metabolite, ACT-132577. The efficacy of macitentan on PAH was investigated in the phase III SERAPHIN trial (NCT00660179). Macitentan significantly reduced morbidity and mortality. It improved the 6-min. walk distance (6MWD) among PAH patients. In the AMB-320/321-E (NCT00578786) study, ambrisentan improved exercise capacity. In the EARLY study (NCT00091715), bosentan showed improvements in 6MWD which were not statistically significant. Bosentan had an effect on PAH in patients with Eisenmenger syndrome (ES) in the BREATHE-5 study (NCT00367770), while macitentan did not improve 6MWD in these patients, but there are differences regarding study size and functional class, and that 30% of the patients treated with macitentan were already in treatment with a phosphodiesterase type 5 inhibitor. Macitentan revealed a lower risk of developing peripheral oedema and hepatotoxicity in the SERAPHIN study. In summary, macitentan has an efficiency comparable to bosentan and ambrisentan in the treatment of PAH. Patients treated with macitentan exhibited less adverse effects compared to bosentan and ambrisentan. In patients with PAH associated with ES, the trials with bosentan and macitentan do not seem comparable, and it needs to be clarified whether these drugs are effective when administered as part of a combination treatment in this condition. PMID- 29719122 TI - Boron-Based Catalysts for C-C Bond-Formation Reactions. AB - Because the construction of the C-C bond is one of the most significant reactions in organic chemistry, the development of an efficient strategy has attracted much attention throughout the synthetic community. Among various protocols to form C-C bonds, organoboron compounds are not just limited to stoichiometric reagents, but have also made great achievements as catalysts because of the easy modification of the electronic and steric impacts on the boron center. This review presents recent developments of boron-based catalysts applied in the field of C-C bond formation reactions, which are classified into four kinds on the basis of the type of boron catalyst: 1) highly Lewis acidic borane, B(C6 F5 )3 ; 2) organoboron acids, RB(OH)2 , and their ester derivatives; 3) borenium ions, (R2 BL)X; and 4) other miscellaneous kinds. PMID- 29719123 TI - Wound-induced cell proliferation during animal regeneration. AB - Many animal species are capable of replacing missing tissues that are lost upon injury or amputation through the process of regeneration. Although the extent of regeneration is variable across animals, that is, some animals can regenerate any missing cell type whereas some can only regenerate certain organs or tissues, regulated cell proliferation underlies the formation of new tissues in most systems. Notably, many species display an increase in proliferation within hours or days upon wounding. While different cell types proliferate in response to wounding in various animal taxa, comparative molecular data are beginning to point to shared wound-induced mechanisms that regulate cell division during regeneration. Here, we synthesize current insights about early molecular pathways of regeneration from diverse model and emerging systems by considering these species in their evolutionary contexts. Despite the great diversity of mechanisms underlying injury-induced cell proliferation across animals, and sometimes even in the same species, similar pathways for proliferation have been implicated in distantly related species (e.g., small diffusible molecules, signaling from apoptotic cells, growth factor signaling, mTOR and Hippo signaling, and Wnt and Bmp pathways). Studies that explicitly interrogate molecular and cellular regenerative mechanisms in understudied animal phyla will reveal the extent to which early pathways in the process of regeneration are conserved or independently evolved. This article is categorized under: Comparative Development and Evolution > Body Plan Evolution Adult Stem Cells, Tissue Renewal, and Regeneration > Regeneration Comparative Development and Evolution > Model Systems. PMID- 29719124 TI - Graphene-Oxide-Decorated Microporous Polyetheretherketone with Superior Antibacterial Capability and In Vitro Osteogenesis for Orthopedic Implant. AB - Due to its similar elastic modulus of human bones, polyetheretherketone (PEEK) has been considered as an excellent cytocompatible material. However, the bioinertness, poor osteoconduction, and weak antibacterial activity of PEEK limit its wide applications in clinics. In this study, a facile strategy is developed to prepare graphene oxide (GO) modified sulfonated polyetheretherketone (SPEEK) (GO-SPEEK) through a simple dip-coating method. After detailed characterization, it is found that the GO closely deposits on the surface of PEEK, which is attributed to the pi-pi stacking interaction between PEEK and GO. Antibacterial tests reveal that the GO-SPEEK exhibits excellent suppression toward Escherichia coli. In vitro cell attachment, growth, differentiation, alkaline phosphatase activity, quantitative real-time polymerase chain reaction analyses, and calcium mineral deposition all illustrate that the GO-SPEEK substrate can significantly accelerate the proliferation and osteogenic differentiation of osteoblast-like MG 63 cells compared with those on PEEK and SPEEK groups. These results suggest that the GO-SPEEK has an improved antibacterial activity and cytocompatibility in vitro, showing that the developed GO-SPEEK has a great potential as the bioactive implant material in bone tissue engineering. PMID- 29719125 TI - Murrayanine Attenuates Lipopolysaccharide-induced Inflammation and Protects Mice from Sepsis-Associated Organ Failure. AB - Murrayanine (MK) is the main compound isolated from Murraya Koenigii, an aromatic plant belonging to the Rutaceae family, also known as curry leaf tree. Murrayanine was reported to possess potential antioxidant, anti-mycobacterial and anti-fungal effects. However, its effect in sepsis remains unclear. This study was designed to investigate the anti-inflammatory effect of MK using both in vitro and in vivo assay. This article is protected by copyright. All rights reserved. PMID- 29719126 TI - Randomized controlled trial comparing the supraglottic airway to use of an endotracheal tube in sinonasal surgery. AB - BACKGROUND: The supraglottic airway (SGA) represents an alternative to endotracheal intubation (endotracheal tube [ETT]) in many types of ambulatory surgery. Adoption of the SGA has progressed slowly in sinonasal surgery due to concerns about airway protection. The purpose of this study was to compare quality of life measures and indices of airway protection between patients undergoing sinonasal surgery who were ventilated via an SGA or ETT. METHODS: Patients undergoing outpatient sinonasal surgery were enrolled into a randomized, single-blind study in which patients would be ventilated with either an SGA or ETT. At the first postoperative visit, a symptom severity and quality of life questionnaire was completed. Additional objective metrics were extracted from the anesthesia record. RESULTS: A total of 102 patients were enrolled; 49 assigned to the SGA group and 53 assigned to the ETT group. No significant differences in swallowing function or cough were identified. SGA patients reported more difficulty returning to a normal diet (p = 0.03) with a trend toward reduced throat pain (p = 0.07) and improved phonation (p = 0.06). No significant difference in perioperative oxygen desaturations, emesis, recovery time, or airway blood penetration were identified. CONCLUSION: While the use of the SGA results in patient diet modification postoperatively, it may also be associated with a reduction in throat pain and dysphonia. SGA use had no appreciable effect on postanesthesia recovery times, oxygen desaturations, or emesis. Use of the SGA in sinonasal surgery appears to be a safe and reliable option for airway management in selected adult patients undergoing routine ambulatory sinonasal surgery. PMID- 29719128 TI - Prediction of Mortality with A Body Shape Index in Young Asians: Comparison with Body Mass Index and Waist Circumference. AB - OBJECTIVE: This paper investigated the impact of A Body Shape Index (ABSI) on the risk of all-cause mortality compared with the impact of waist circumference (WC) and body mass index (BMI). METHODS: This paper reviewed data of 213,569 Korean adults who participated in health checkups between 2002 and 2012 at Kangbuk Samsung Hospital in Seoul, Korea. A multivariate Cox proportional hazard analysis was performed on the BMI, WC, and ABSI z score continuous variables as well as quintiles. RESULTS: During 1,168,668.7 person-years, 1,107 deaths occurred. As continuous variables, a significant positive relationship with the risk of all cause death was found only in ABSI z scores after adjustment for age, sex, current smoking, alcohol consumption, regular exercise, presence of diabetes or hypertension, and history of cardiovascular diseases. In Cox analysis of quintiles, quintile 5 of the ABSI z score showed significantly increased hazard ratios (HRs) for mortality risk (HR [95% CI] was 1.32 [1.05-1.66]), whereas the risk for all-cause mortality, on the other hand, decreased in quintiles 3 through 5 of BMI and WC compared with their first quintiles after adjusting for several confounders. CONCLUSIONS: This study showed that the predictive value of ABSI for mortality risk was strong for a sample of young Asian participants and that its usefulness was better than BMI or WC. PMID- 29719129 TI - Adult acute rhinosinusitis guidelines worldwide: similarities and disparities. AB - BACKGROUND: Acute rhinosinusitis (ARS) is a common respiratory infection that poses a major public healthcare burden with respect to antibiotic consumption and related morbidity. Position statements and national ARS guidelines have been published worldwide, aiming to define diagnostic criteria and outline treatment options. Our objective was to analyze the similarities and disparities between such guidelines. METHODS: We conducted an electronic database search for ARS guidelines using relevant keywords between January 1, 1989, through December 31, 2017. Overall, 25 guidelines from 39 countries were retrieved: 8 from 8 developed countries, and 17 from 31 developing countries. Representative guidelines from developing and developed countries from America, Europe, Africa, Asia, and Oceania were evaluated. We compared the bibliographic data, diagnostic criteria, and treatment recommendations of selected guidelines. RESULTS: In most developed countries, otorhinolaryngological societies published ARS guidelines, whereas the Ministry of Health formulated the guidelines or adopted generic guidelines prepared by an international organization in developing countries. Many similarities in the diagnostic criteria were found, such as purulent nasal discharge and nasal obstruction sensation. In contrast, maxillary culture as a diagnostic tool was mentioned in developed countries, while it was generally ignored in developing countries. The watchful waiting (WW) policy and abstaining from immediate antibiotics was unanimously adopted in developed countries, which was only partly embraced in developing countries. The recommended universal first line antibiotic therapy is amoxicillin, with or without clavulanic acid, whereas options for second-line and third-line antibiotic therapies varied. CONCLUSION: ARS guidelines from different countries have many similarities. Specific recommendations are tailored to local epidemiology and healthcare accessibility. PMID- 29719130 TI - Activation of the rat olfactory bulb by direct ventral stimulation after nerve transection. AB - BACKGROUND: The aim of this study was to demonstrate how direct electrical stimulation can activate the olfactory bulb after denervation of the olfactory nerve input. METHODS: Sprague-Dawley rats (n = 5) were anesthetized and olfactory bulbs exposed. Olfactory nerves were transected by passing a Teflon blade between the cribriform plate and ventral surface of the bulb. A cochlear implant electrode array was used to stimulate 6 different positions along the ventral surface of the olfactory bulb. Biphasic constant-current pulses were used (50 1000 MUA, 50-1000 MUs) to stimulate the bulb, and a 16-electrode paddle array was used to record localized negative field potential responses at the dorsal surface of the bulb. RESULTS: Localized negative field potentials were reliably obtained using biphasic, 500-MUA, 200-MUs pulses. A shift in stimulating position by 1 mm resulted in a significant change in the dorsal field potential. CONCLUSION: Direct stimulation of the deafferented olfactory bulb was effective in generating localized field potential responses. These findings support the potential use of direct electrical stimulation for the treatment of anosmia. PMID- 29719127 TI - Glucocorticoid receptor isoform expression in peripheral blood mononuclear leukocytes of patients with chronic rhinosinusitis. AB - BACKGROUND: In several inflammatory disorders, altered peripheral blood mononuclear leukocyte (PBML) glucocorticoid (GC) receptor isoform expression has been associated with GC resistance and disease severity. However, it is unclear if PBML GC receptor isoforms are expressed differentially and are associated with worsened disease severity in chronic rhinosinusitis (CRS). METHODS: PBMLs were isolated from control (n = 8), CRS without nasal polyps (CRSsNP) (n = 8), atopic CRS with nasal polyps (CRSwNP) (n = 8), non-atopic CRSwNP (n = 8), and allergic fungal rhinosinusitis (AFRS) (n = 8) patients. Demographics, atopic status, asthmatic status, 22-item Sino-Nasal Outcome Test (SNOT-22) scores, Lund-Kennedy nasal endoscopy scores, Lund-Mackay sinus computed tomography (CT) scores, Kennedy Osteitis scores, and GC utilization 6 months postoperatively were collected. Intracellular immunostaining was then performed for functional GC receptor alpha (GCRalpha) and nonfunctional GC receptor beta (GCRbeta), followed by flow cytometry analysis of geometric mean fluorescent intensity (MFI) and the percentage of cells expressing each GC receptor isoform. RESULTS: Compared to controls, each CRS subtype had decreased PBML GCRalpha and GCRalpha:GCRbeta MFI expression, but no difference in GCRbeta expression. Decreasing PBML GCRalpha in AFRS was associated with increasing Lund-Mackay sinus CT scores (r = -0.880, p =0.004). No significant associations were found between GC receptor isoform expression and other clinical measures. CONCLUSION: CRS patients have reduced functional PBML GCRalpha expression and decreased GCRalpha:GCRbeta compared to controls. Reductions in GCRalpha in AFRS are associated with worsening Lund Mackay sinus CT scores. The clinical implications of decreased functional GC receptor expression merits further investigation. PMID- 29719131 TI - Preparation of Cyclic Prodiginines by Mutasynthesis in Pseudomonas putida KT2440. AB - Prodiginines are a group of naturally occurring pyrrole alkaloids produced by various microorganisms and known for their broad biological activities. The production of nature-inspired cyclic prodiginines was enabled by combining organic synthesis with a mutasynthesis approach based on the GRAS (generally recognized as safe) certified host strain Pseudomonas putida KT2440. The newly prepared prodiginines exerted antimicrobial effects against relevant alternative biotechnological microbial hosts whereas P. putida itself exhibited remarkable tolerance against all tested prodiginines, thus corroborating the bacterium's exceptional suitability as a mutasynthesis host for the production of these cytotoxic secondary metabolites. Moreover, the produced cyclic prodiginines proved to be autophagy modulators in human breast cancer cells. One promising cyclic prodiginine derivative stood out, being twice as potent as prodigiosin, the most prominent member of the prodiginine family, and its synthetic derivative obatoclax mesylate. PMID- 29719132 TI - Abdominal Subcutaneous Fat: A Favorable or Nonfunctional Fat Depot for Glucose Metabolism in Chinese Adults? AB - OBJECTIVE: The objective of this study was to assess the associations of abdominal visceral and subcutaneous adipose tissue with blood glucose and beta cell function. METHODS: In this study, 11,223 participants without known diabetes were selected for this cross-sectional analysis. Visceral and subcutaneous fat area (VFA and SFA) were measured by magnetic resonance imaging. An oral glucose tolerance test was conducted, and beta-cell function was evaluated. RESULTS: Men had significantly larger VFA but smaller SFA than women. After controlling for age, linear regression showed that SFA was adversely associated with 0-minute, 30 minute, and 2-hour plasma glucose (PG) and early-, first- and second-phase disposition indices (DIs). After further adjustment for BMI and VFA, some associations of SFA with PG indices and DIs disappeared, while the other associations became significantly weaker in men (2-hour PG: 0.05 and DI2nd : 0.05) or were reversed in women (0-minute, 30-minute, and 2-hour PG: from -0.07 to -0.04; DI1st : 0.04, P < 0.05). After adjustment for age, BMI, and SFA, VFA was significantly and adversely associated with PG indices and DIs, with the largest standardized regression coefficients with 2-hour PG. CONCLUSIONS: The associations of SFA with blood glucose and beta-cell function were clinically insignificant in Chinese adults. VFA had the strongest association with 2-hour PG. PMID- 29719133 TI - Aerobic Oxidation of Xylose to Xylaric Acid in Water over Pt Catalysts. AB - Energy-efficient catalytic conversion of biomass intermediates to functional chemicals can make bio-products viable. Herein, we report an efficient and low temperature aerobic oxidation of xylose to xylaric acid, a promising bio-based chemical for the production of glutaric acid, over commercial catalysts in water. Among several heterogeneous catalysts investigated, Pt/C exhibits the best activity. Systematic variation of reaction parameters in the pH range of 2.5 to 10 suggests that the reaction is fast at higher temperatures but high C-C scission of intermediate C5 -oxidized products to low carbon carboxylic acids undermines xylaric acid selectivity. The C-C cleavage is also high in basic solution. The oxidation at neutral pH and 60 degrees C achieves the highest xylaric acid yield (64 %). O2 pressure and Pt amount have significant influence on the reactivity. Decarboxylation of short chain carboxylic acids results in formation of CO2 , causing some carbon loss; however, such decarboxylation is slow in the presence of xylose. The catalyst retained comparable activity, in terms of product selectivity, after five cycles with no sign of Pt leaching. PMID- 29719134 TI - An Intelligent Neural Stem Cell Delivery System for Neurodegenerative Diseases Treatment. AB - Transplanted stem cells constitute a new therapeutic strategy for the treatment of neurological disorders. Emerging evidence indicates that a negative microenvironment, particularly one characterized by the acute inflammation/immune response caused by physical injuries or transplanted stem cells, severely impacts the survival of transplanted stem cells. In this study, to avoid the influence of the increased inflammation following physical injuries, an intelligent, double layer, alginate hydrogel system is designed. This system fosters the matrix metalloproeinases (MMP) secreted by transplanted stem cell reactions with MMP peptide grafted on the inner layer and destroys the structure of the inner hydrogel layer during the inflammatory storm. Meanwhile, the optimum concentration of the arginine-glycine-aspartate (RGD) peptide is also immobilized to the inner hydrogels to obtain more stem cells before arriving to the outer hydrogel layer. It is found that blocking Cripto-1, which promotes embryonic stem cell differentiation to dopamine neurons, also accelerates this process in neural stem cells. More interesting is the fact that neural stem cell differentiation can be conducted in astrocyte-differentiation medium without other treatments. In addition, the system can be adjusted according to the different parameters of transplanted stem cells and can expand on the clinical application of stem cells in the treatment of this neurological disorder. PMID- 29719135 TI - Clinical trial cytology: Use of on-site evaluation of small biopsy and FNA samples for clinical trials and biomarker research studies. AB - BACKGROUND: After increased requests for biopsies for clinical trials and biomarker research, the University of Pittsburgh Medical Center created a clinical trial research service that partnered pathology, radiology, and medicine to facilitate rapid on-site evaluation (ROSE) of fine-needle aspiration (FNA) and/or core needle biopsy (CNB) samples to confirm the presence of tumor in these studies. METHODS: Clinical trial coordinators organized biopsies for patients needing tumor samples for trials, and informed the cytopathology and radiology team. ROSE was performed to confirm the presence of sufficient tumor in FNA specimens and/or touch preparations of CNB. RESULTS: A total of 79 cases from a total of 14 clinical trials were evaluated with ROSE, 77 of which (97%) were for research only. There were 53 cases (67%) from breast/ovarian cancer studies that were initiated between 2008 and 2009, whereas 26 cases (33%) included a variety of other tumors for studies that were started between 2011 and 2014. The majority required CNB samples (60 cases; 76%), 20% of which used an FNA for needle placement before obtaining CNB material and 56% of which had touch preparations of the CNB evaluated without a preceding FNA. The concordance rate for ROSE with final adequacy of the sample was 96% to 100%. CONCLUSIONS: The study institution has experienced an increase in the number of clinical trial studies requesting ROSE to confirm the presence of tumor in a variety of malignancies. Cytology laboratories can help with patient care by offering ROSE to determine the adequacy of clinical trial material to minimize the submission of unsatisfactory or nonrepresentative material. Developing a clinical research service enhances communication and the processing of novel research specimens for cancer patients. Cancer Cytopathol 2018. (c) 2018 American Cancer Society. PMID- 29719136 TI - Relations between scanning and recognition of own- and other-race faces in 6- and 9-month-old infants. AB - Infants typically see more own-race faces than other-race faces. Existing evidence shows that this difference in face race experience has profound consequences for face processing: as early as 6 months of age, infants scan own- and other-race faces differently and display superior recognition for own- relative to other-race faces. However, it is unclear whether scanning of own-race faces is related to the own-race recognition advantage in infants. To bridge this gap in the literature, the current study used eye tracking to investigate the relation between own-race face scanning and recognition in 6- and 9-month-old Asian infants (N = 82). The infants were familiarized with dynamic own- and other race faces, and then their face recognition was tested with static face images. Both age groups recognized own- but not other-race faces. Also, regardless of race, the more infants scanned the eyes of the novel versus familiar faces at test, the better their face-recognition performance. In addition, both 6- and 9 month-olds fixated significantly longer on the nose of own-race faces, and greater fixation on the nose during test trials correlated positively with individual novelty preference scores in the own- but not other-race condition. The results suggest that some aspects of the relation between recognition and scanning are independent of differential experience with face race, whereas other aspects are affected by such experience. More broadly, the findings imply that scanning and recognition may become linked during infancy at least in part through the influence of perceptual experience. PMID- 29719137 TI - Real-Time Imaging of Brain Tumor for Image-Guided Surgery. AB - The completion of surgical resection is a key prognostic factor in brain tumor treatment. This requires surgeons to identify residual tumors in theater as well as to margin the proximity of the tumor to adjacent normal tissue. Subjective assessments, such as texture palpation or visual tissue differences, are commonly used by oncology surgeons during resection to differentiate cancer lesions from normal tissue, which can potentially result in either an incomplete tumor resection, or accidental removal of normal tissue. Moreover, malignant brain tumors are even more difficult to distinguish from normal brain tissue, and resecting noncancerous tissue may create neurological defects after surgery. To optimize the resection margin in brain tumors, a variety of intraoperative guidance techniques are developed, such as neuronavigation, magnetic resonance imaging, ultrasound, Raman spectroscopy, and optical fluorescence imaging. When combined with appropriate contrast agents, optical fluorescence imaging can provide the neurosurgeon real-time image guidance to improve resection completeness and to decrease surgical complications. PMID- 29719139 TI - Establishing the minimal clinically important difference for the Questionnaire of Olfactory Disorders. AB - BACKGROUND: Olfactory-specific quality of life (QOL) can be measured using the Questionnaire of Olfactory Disorders Negative Statements (QOD-NS). Changes in the QOD-NS after treatment can be difficult to interpret since there is no standardized definition of clinically meaningful improvement. METHODS: Patients with chronic rhinosinusitis (CRS) completed the QOD-NS. Four distribution-based methods were used to calculate the minimal clinically important difference (MCID): (1) one-half standard deviation (SD); (2) standard error of the mean (SEM); (3) Cohen's effect size (d) of the smallest unit of change; and (4) minimal detectable change (MDC). We also averaged all 4 of the scores together. Finally, the likelihood of achieving a MCID after sinus surgery using these methods, as well as average QOD-NS scores, was stratified by normal vs abnormal baseline QOD-NS scores. RESULTS: Outcomes were examined on 128 patients. The mean +/- SD improvement in QOD-NS score after surgery was 4.3 +/- 11.0 for the entire cohort and 9.6 +/- 12.9 for those with abnormal baseline scores (p < 0.001). The MCID values using the different techniques were: (1) SD = 6.5; (2) SEM = 3.1; (3) d = 2.6; and (4) MDC = 8.6. The MCID score was 5.2 on average. For the total cohort analysis, the likelihood of reporting a MCID ranged from 26% to 51%, and 49% to 70% for patients reporting preoperative abnormal olfaction. CONCLUSION: Distribution-based MCID values of the QOD-NS range between 2.6 and 8.6 points, with an average of 5.2. When stratified by preoperative QOD-NS scores the majority of patients reporting abnormal preoperative QOD-NS scores achieved a MCID. PMID- 29719140 TI - Pd-Catalyzed Decarbonylative C-H Coupling of Azoles and Aromatic Esters. AB - A decarbonylative C-H coupling of azoles and aromatic esters by palladium catalysis is described. Our previously reported Ni-catalyzed C-H coupling of azoles and aromatic esters has a significant drawback regarding the substrate scope. Herein, we employ palladium catalysis instead of nickel, resulting in a broader substrate scope in terms of azoles and aromatic esters. PMID- 29719141 TI - Predictors, costs, and causes of readmission after surgery for sinonasal cancer: a national perspective. AB - BACKGROUND: Hospital readmissions are an increasingly scrutinized marker of surgical care delivery and quality. There is a paucity of information in the literature regarding the rate, risk factors, and common causes of readmission after surgery for sinonasal cancer. METHODS: We analyzed the Nationwide Readmissions Database for patients who underwent surgery for a diagnosis of sinonasal cancer between 2010 and 2014. Rates, causes, and patient-, procedure-, and hospital-level risk factors for 30-day readmission were determined. Multivariate logistic regression was used to identify predictors of 30-day readmission. RESULTS: Among the 4173 cases, the 30-day readmission rate was 11.6%, with an average cost per readmission of $18,403. The most common readmission diagnoses were wound complications (15.3%) and infections (13.4%). On multivariate regression, significant risk factors for readmission were chronic renal failure (odds ratio [OR], 2.95; 95% confidence interval [CI], 1.41-6.17), involvement of the skull base or orbit (OR, 1.67; 95% CI, 1.11-2.51), nonelective initial surgical admission (OR, 2.35; 95% CI, 1.42-3.89), and length of stay >=7 days (OR, 1.87; 95% CI, 1.14-3.05). CONCLUSION: Through the use of a large national database, we found that approximately 1 in 9 patients undergoing surgery for sinonasal cancer was readmitted within 30 days. Readmissions were most commonly associated with wound complications and infections. Factors related to procedural complexity were more important predictors of readmission than patients' demographics or comorbidities. PMID- 29719138 TI - Mannose and Mannose-6-Phosphate Receptor-Targeted Drug Delivery Systems and Their Application in Cancer Therapy. AB - In order to overcome the main disadvantages of conventional cancer therapies, which prove to be inadequate because of their lack of selectivity, the development of targeted delivery systems is one of the main focuses in anticancer research. It is repeatedly shown that decorating the surface of nanocarriers with high-affinity targeting ligands, such as peptides or small molecules, is an effective way to selectively deliver therapeutics by enhancing their specific cellular uptake via the binding between a specific receptor and the nanosystems. Nowadays, the need of finding new potential biological targets with a high endocytic efficiency as well as a low tendency to mutate is urgent and, in this context, mannose and mannose-6-phosphate receptors appear promising to target anticancer drugs to cells where their expression is upregulated. Moreover, they open the path to encouraging applications in immune-based and gene therapies as well as in theragnostic purposes. In this work, the potential of mannose- and mannose-6-phosphate-targeted delivery systems in cancer therapy is discussed, emphasizing their broad application both in direct treatments against cancer cells with conventional chemotherapeutics or by gene therapy and also their encouraging capabilities in immunotherapy and diagnostics purposes. PMID- 29719142 TI - Selective Oxidation of Lignin Model Compounds. AB - Lignin, the planet's most abundant renewable source of aromatic compounds, is difficult to degrade efficiently to welldefined aromatics. We developed a microwave-assisted catalytic Swern oxidation system using an easily prepared catalyst, MoO2 Cl2 (DMSO)2 , and DMSO as the solvent and oxidant. It demonstrated high efficiency in transforming lignin model compounds containing the units and functional groups found in native lignins. The aromatic ring substituents strongly influenced the selectivity of beta-ether phenolic dimer cleavage to generate sinapaldehyde and coniferaldehyde, monomers not usually produced by oxidative methods. Time-course studies on two key intermediates provided insight into the reaction pathway. Owing to the broad scope of this oxidation system and the insight gleaned with regard to its mechanism, this strategy could be adapted and applied in a general sense to the production of useful aromatic chemicals from phenolics and lignin. PMID- 29719143 TI - Particle Size Distributions of Oxidative Potential of Lung-Deposited Particles: Assessing Contributions from Quinones and Water-Soluble Metals. AB - Redox-active species in ambient particulate matter (PM) cause adverse health effects through the production of reactive oxygen species (ROS) in the human respiratory tract. However, respiratory deposition of these species and their relative contributions to oxidative potential (OP) have not been described. Size segregated aerosols were collected during haze and nonhaze periods using a micro orifice uniform deposit impactor sampler at an urban site in Shanghai to address this issue. Samples were analyzed for redox-active species content and PM OP. The average dithiothreitol (DTT) activity of haze samples was approximately 2.4-fold higher than that of nonhaze samples and significantly correlated with quinone and water-soluble metal concentrations. The size-specific distribution data revealed that both water-soluble OPvDTT (volume-normalized OP quantified by DTT assay) and OPmDTT (mass-normalized OP) were unimodal, peaking at 0.56-1 and 0.1-0.32 MUm, respectively, due to contributions from accumulation-mode quinones and water soluble metals. We further estimated that transition metals (mainly copper and manganese) contributed 55 +/- 13% of the DTT activity while quinones accounted for only 8 +/- 3%. Multiple-path particle dosimetry calculations estimated that OP deposition in the pulmonary region was mainly from accumulation-mode transition metals despite quinones having the highest DTT activity. This behavior is primarily attributed to the efficiency of deposition of transition metals in the pulmonary region being approximately 1.2-fold greater than that of quinones. These results reveal that accumulation-mode transition metals are significant contributors to the OP of deposited water-soluble particles in the pulmonary region of the lung. PMID- 29719144 TI - Rapid, On-Site, Ultrasensitive Melamine Quantitation Method for Protein Beverages Using Time-Resolved Fluorescence Detection Paper. AB - To ensure protein beverage safety and prevent illegal melamine use to artificially increase protein content, a rapid, on-site, ultrasensitive detection method for melamine must be developed because melamine is detrimental to human health. Herein, an ultrasensitive time-resolved fluorescence detection paper (TFDP) was developed to detect melamine in protein beverages within 15 min using a one-step sample preparation. The lower limits of detection were 0.89, 0.94, and 1.05 ng/mL, and the linear ranges were 2.67-150, 2.82-150, and 3.15-150 ng/mL (R2 > 0.982) for peanut, walnut, and coconut beverages, respectively. The recovery rates were 85.86-110.60% with a coefficient of variation <7.80% in the spiking experiment. A high specificity was observed in the interferent experiment. When detecting real protein beverage samples, the TFDP and ultraperformance liquid chromatography-tandem mass spectrometer (UPLC-MS/MS) results were consistent. This method is a promising alternative for rapid, on-site detection of melamine in beverages. PMID- 29719145 TI - Mitigating Methane: Emerging Technologies To Combat Climate Change's Second Leading Contributor. AB - Methane (CH4) is the second greatest contributor to anthropogenic climate change. Emissions have tripled since preindustrial times and continue to rise rapidly, given the fact that the key sources of food production, energy generation and waste management, are inexorably tied to population growth. Until recently, the pursuit of CH4 mitigation approaches has tended to align with opportunities for easy energy recovery through gas capture and flaring. Consequently, effective abatement has been largely restricted to confined high-concentration sources such as landfills and anaerobic digesters, which do not represent a major share of CH4's emission profile. However, in more recent years we have witnessed a quantum leap in the sophistication, diversity and affordability of CH4 mitigation technologies on the back of rapid advances in molecular analytical techniques, developments in material sciences and increasingly efficient engineering processes. Here, we present some of the latest concepts, designs and applications in CH4 mitigation, identifying a number of abatement synergies across multiple industries and sectors. We also propose novel ways to manipulate cutting-edge technology approaches for even more effective mitigation potential. The goal of this review is to stimulate the ongoing quest for and uptake of practicable CH4 mitigation options; supplementing established and proven approaches with immature yet potentially high-impact technologies. There has arguably never been, and if we do not act soon nor will there be, a better opportunity to combat climate change's second most significant greenhouse gas. PMID- 29719146 TI - The Making and Breaking of Lead-Free Double Perovskite Nanocrystals of Cesium Silver-Bismuth Halide Compositions. AB - Replacing lead in halide perovskites is of great interest due to concerns about stability and toxicity. Recently, lead free double perovskites in which the unit cell is doubled and two divalent lead cations are substituted by a combination of mono- and trivalent cations have been synthesized as bulk single crystals and as thin films. Here, we study stability and optical properties of all-inorganic cesium silver(I) bismuth(III) chloride and bromide nanocrystals with the double perovskite crystal structure. The cube-shaped nanocrystals are monodisperse in size with typical side lengths of 8 to 15 nm. The absorption spectrum of the nanocrystals presents a sharp peak, which we assign to a direct bismuth s-p transition and not to a quantum confined excitonic transition. Using this spectroscopic handle combined with high-resolution transmission electron microscopy (TEM) based elemental analysis, we conduct stoichiometric studies at the single nanocrystal level as well as decomposition assays in solution and observe that Ag+ diffusion and coalescence is one of the pathways by which this material degrades. Drying the nanocrystals leads to self-assembly into ordered nanocrystal solids, and these exhibit less degradation than nanocrystals in solution. Our results demonstrate that Cs2AgBiX6 (X = Cl, Br) nanocrystals are a useful model system to study structure-function relationships in the search for stable nontoxic halide perovskites. PMID- 29719148 TI - A Flow Adsorption Microcalorimetry-Logistic Modeling Approach for Assessing Heterogeneity of Bronsted-Type Surfaces: Application to Pyrogenic Organic Materials. AB - Biogeochemical functioning of oxides and pyrogenic organic matter ( pyOM) are greatly influenced by surface and deprotonation characteristics. We present an energetics-based, logistic modeling approach for quantifying surface homogeneity (phisurf) and surface acidity ( pK a, surf) for Bronsted-type surfaces. The phi surf, pK a, surf and associated deprotonation behavior of pyOM were quantified across feedstock (honey mesquite, HM; pine, PI; cord grass, CG) and heat treatment-temperatures (HTT; 200-650 degrees C). At HTT200, lower phisurf [HM (0.86) > PI (0.61) > CG (0.42)] and higher pK a, surf [CG (4.4) > PI (4.2) > HM (4.1)] for CG indicated higher heterogeneity and lower acidity for Bronsted-type surface moieties on grass versus wood pyOM. Surface acidity of CG increased at HTT550/650 degrees C with no effect on phisurf; while the surface heterogeneity of both wood pyOMs increased, the acidity of HM increased and that of PI decreased. Despite different HTT-induced phisurf and pK a, surf trajectories, the deprotonation range for all pyOM was pH = [Formula: see text]. Therefore, higher heterogeneity pyOMs deprotonate more readily at lower pH, over a wider range and (for similar pK a,surf and cation exchange capacity) are better cation/metal binding surfaces at pH< pK a,surf. The approach also facilitates the evaluation of surface and deprotonation characteristics for mixtures and more complex surfaces. PMID- 29719147 TI - Tuning Magnetic Soliton Phase via Dimensional Confinement in Exfoliated 2D Cr1/3NbS2 Thin Flakes. AB - Thin flakes of Cr1/3NbS2 are fabricated successfully via microexfoliation techniques. Temperature-dependent and field-dependent magnetizations of thin flakes with various thicknesses are investigated. When the thickness of the flake is around several hundred nanometers, the softening and eventual disappearance of the bulk soliton peak is accompanied by the appearance of other magnetic peaks at lower magnetic fields. The emergence and annihilation of the soliton peaks are explained and simulated theoretically by the change in spin spiral number inside the soliton lattice due to dimensional confinement. Compared to the conventional magnetic states in nanoscale materials, the stability and thickness tunability of quantified spin spirals make Cr1/3NbS2 a potential candidate for spintronics nanodevices beyond Moore's law. PMID- 29719149 TI - Ultrafast Photophysics of a Dinitrogen-Bridged Molybdenum Complex. AB - Among the many metal-dinitrogen complexes synthesized, the end-on bridging (MU2, eta1, eta1-N2) coordination mode is notoriously unreactive for nitrogen fixation. This is principally due to the large activation energy for ground-state nitrogen element bond formation and motivates exploration of the photoexcited reactivity of this coordination mode. To provide the foundation for this concept, the photophysics of a dinitrogen-bridged molybdenum complex was explored by ultrafast electronic spectroscopies. The complex absorbs light from the UV to near-IR, and the transitions are predominantly of metal-to-ligand charge transfer (MLCT) character. Five excitation wavelengths (440, 520, 610, 730, and 1150 nm) were employed to access MLCT bands, and the dynamics were probed between 430 and 1600 nm. Despite the large energy space occupied by electronic states (ca. 1.2 eV), the dynamics were independent of the excitation wavelength. In the proposed kinetic model, photoexcitation from a Mo-N?N-Mo centered ground state populates the pi*-state delocalized over two terpyridine ligands. Due to a large terpyridine-terpyridine spatial separation, electronic localization occurs within 100 fs, augmented by symmetry breaking. The subsequent interplay of internal conversion and intersystem crossing (ISC) populates the lowest 3MLCT state in 2-3 ps. Decay to the ground state occurs either directly or via a thermally activated metal-centered (3MC) trap state having two time constants (10-15 ps, 23-26 ps [298 K]; 103 ps, 612 ps [77 K]). ISC between 1MLCT and 3MLCT involves migration of energized electron density from the terpyridine pi* orbitals to the Mo-N?N-Mo core. Implication of the observed dynamics for the potential N-H bond forming reactivity are discussed. PMID- 29719150 TI - Carbonaceous Nanomaterials Have Higher Effects on Soybean Rhizosphere Prokaryotic Communities During the Reproductive Growth Phase than During Vegetative Growth. AB - Carbonaceous nanomaterials (CNMs) can affect agricultural soil prokaryotic communities, but how the effects vary with the crop growth stage is unknown. To investigate this, soybean plants were cultivated in soils amended with 0, 0.1, 100, or 1000 mg kg-1 of carbon black, multiwalled carbon nanotubes (MWCNTs), or graphene. Soil prokaryotic communities were analyzed by Illumina sequencing at day 0 and at the soybean vegetative and reproductive stages. The sequencing data were functionally annotated using the functional annotation of prokaryotic taxa (FAPROTAX) database. The prokaryotic communities were unaffected at day 0 and were altered at the plant vegetative stage only by 0.1 mg kg-1 MWCNTs. However, at the reproductive stage, when pods were filling, most treatments (except 1000 mg kg-1 MWCNTs) altered the prokaryotic community composition, including functional groups associated with C, N, and S cycling. The lower doses of CNMs, which were previously shown to be less agglomerated and thus more bioavailable in soil relative to the higher doses, were more effective toward both overall communities and individual functional groups. Taken together, prokaryotic communities in the soybean rhizosphere can be significantly phylogenetically and functionally altered in response to bioavailable CNMs, especially when soybean plants are actively directing resources to seed production. PMID- 29719151 TI - Emulsions Stabilized by Chitosan-Modified Silica Nanoparticles: pH Control of Structure-Property Relations. AB - In food-grade emulsions, particles with an appropriate surface modification can be used to replace surfactants and potentially enhance the stability of emulsions. During the life cycle of products based on such emulsions, they can be exposed to a broad range of pH conditions and hence it is crucial to understand how pH changes affect stability of emulsions stabilized by particles. Here, we report on a comprehensive study of the stability, microstructure, and macroscopic behavior of pH-controlled oil-in-water emulsions containing silica nanoparticles modified with chitosan, a food-grade polycation. We found that the modified colloidal particles used as stabilizers behave differently depending on the pH, resulting in unique emulsion structures at multiple length scales. Our findings are rationalized in terms of the different emulsion stabilization mechanisms involved, which are determined by the pH-dependent charges and interactions between the colloidal building blocks of the system. At pH 4, the silica particles are partially hydrophobized through chitosan modification, favoring their adsorption at the oil-water interface and the formation of Pickering emulsions. At pH 5.5, the particles become attractive and the emulsion is stabilized by a network of agglomerated particles formed between the droplets. Finally, chitosan aggregates form at pH 9 and these act as the emulsion stabilizers under alkaline conditions. These insights have important implications for the processing and use of particle-stabilized emulsions. On one hand, changes in pH can lead to undesired macroscopic phase separation or coalescence of oil droplets. On the other hand, the pH effect on emulsion behavior can be harnessed in industrial processing, either to tune their flow response by altering the pH between processing stages or to produce pH-responsive emulsions that enhance the functionality of the emulsified end products. PMID- 29719152 TI - Sensitive and Facile Electrochemiluminescent Immunoassay for Detecting Genetically Modified Rapeseed Based on Novel Carbon Nanoparticles. AB - A highly sensitive electrochemiluminescent (ECL) immunoassay targeting PAT/ bar protein was facilely developed for genetically modified (GM) rapeseed detection using carbon nanoparticles (CNPs) originally prepared from printer toner. In this work, CNPs linked with antibody for PAT/ bar protein were used to modify a working electrode. After an immunoreaction between the PAT/ bar protein and its antibody, the immunocomplex formed on the electrode receptor region resulted in an inhibition of electron transfer between the electrode surface and the ECL substance, thus led to a decrease of ECL response. Under the optimal conditions, the ECL responses linearly decreased as the increase of the PAT/ bar protein concentration and the GM rapeseed RF3 content in the ranges of 0.10-10 ng/mL and 0.050-1.0%, with the limits of detection of 0.050 ng/mL and 0.020% (S/N = 3). These results open a facile, sensitive, and rapid approach for the safety control of agricultural GM rape. PMID- 29719153 TI - Influence of Silica Nanoparticle Density and Flow Conditions on Sedimentation, Cell Uptake, and Cytotoxicity. AB - Careful evaluation of the toxicological response of engineered nanomaterials (ENMs) as a function of physicochemical properties can aid in the design of safe platforms for biomedical applications including drug delivery. Typically, in vitro ENM cytotoxicity assessments are performed under conventional static cell culture conditions. However, such conditions do not take into account the sedimentation rate of ENMs. Herein, we synthesized four types of similar size silica nanoparticles (SNPs) with modified surface roughness, charge, and density and characterized their cytotoxicity under static and dynamic conditions. Influence of particle density on sedimentation and diffusion velocities were studied by comparing solid dense silica nanoparticles of approximately 350 nm in diameter with hollow rattle shape particles of similar size. Surface roughness and charge had negligible impact on sedimentation and diffusion velocities. Lower cellular uptake and toxicity was observed by rattle particles and under dynamic conditions. Dosimetry of ENMs are primarily reported by particle concentration, assuming homogeneous distribution of nanoparticles in cell culture media. However, under static conditions, nanoparticles tend to sediment at a higher rate due to gravitational forces and hence increase effective doses of nanoparticles exposed to cells. By introducing shear flow to SNP suspensions, we reduced sedimentation and nonhomogeneous particle distribution. These results have implications for design of in vitro cytotoxicity assessment of ENMs and suggest that among other factors, sedimentation of nanoparticles in toxicity assessment should be carefully considered. PMID- 29719154 TI - Fano Description of Single-Hydrocarbon Fluorescence Excited by a Scanning Tunneling Microscope. AB - The detection of fluorescence with submolecular resolution enables the exploration of spatially varying photon yields and vibronic properties at the single-molecule level. By placing individual polycyclic aromatic hydrocarbon molecules into the plasmon cavity formed by the tip of a scanning tunneling microscope and a NaCl-covered Ag(111) surface, molecular light emission spectra are obtained that unravel vibrational progression. In addition, light spectra unveil a signature of the molecule even when the tunneling current is injected well separated from the molecular emitter. This signature exhibits a distance dependent Fano profile that reflects the subtle interplay between inelastic tunneling electrons, the molecular exciton and localized plasmons in at-distance as well as on-molecule fluorescence. The presented findings open the path to luminescence of a different class of molecules than investigated before and contribute to the understanding of single-molecule luminescence at surfaces in a unified picture. PMID- 29719155 TI - Oxidative Modification of Tryptophan-Containing Peptides. AB - We herein present a broadly useful method for the chemoselective modification of a wide range of tryptophan-containing peptides. Exposing a tryptophan-containing peptide to 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) resulted in a selective cyclodehydration between the peptide backbone and the indole side chain of tryptophan to form a fully conjugated indolyl-oxazole moiety. The modified peptides show a characteristic and significant emission maximum at 425 nm, thus making the method a useful strategy for fluorescence labeling. PMID- 29719156 TI - Microwave-Assisted Cross-Polarization of Nuclear Spin Ensembles from Optically Pumped Nitrogen-Vacancy Centers in Diamond. AB - The ability to optically initialize the electronic spin of the nitrogen-vacancy (NV) center in diamond has long been considered a valuable resource to enhance the polarization of neighboring nuclei, but efficient polarization transfer to spin species outside the diamond crystal has proven challenging. Here we demonstrate variable-magnetic-field, microwave-enabled cross-polarization from the NV electronic spin to protons in a model viscous fluid in contact with the diamond surface. Further, slight changes in the cross-relaxation rate as a function of the wait time between successive repetitions of the transfer protocol suggest slower molecular dynamics near the diamond surface compared to that in bulk. This observation is consistent with present models of the microscopic structure of a fluid and can be exploited to estimate the diffusion coefficient near a solid-liquid interface, of importance in colloid science. PMID- 29719157 TI - Oronasal Transfixion Suture to Prevent Uplifted Nasal Floor Deformity in Cleft Lip and Palate Patients: A 5-Year Follow-Up. AB - OBJECTIVE: In unilateral cleft lip and palate, the reconstructed nasal floor is sometimes uplifted regardless of the reconstructive method used. We used a 5-0 absorbable anchoring suture, the oronasal transfixion suture (ONT suture), to fasten the reconstructed nasal floor to the orbicularis oris muscle to prevent this deformity. This study was performed to evaluate the effects of the ONT suture. DESIGN: Blind retrospective study of photography and chart review. SETTING: Shinshu University Hospital, tertiary care, Nagano, Japan. Private practice. PATIENTS: Ninety-three consecutive patients with unilateral complete cleft lip and palate who had undergone primary nasolabial repair in our department and affiliated hospitals between 1999 and 2011 participated in this study. Finally, 45 patients were included. INTERVENTIONS: The ONT suture was put in place at the time of primary nasolabial repair. MAIN OUTCOME MEASURE: The height of the nasal floor was evaluated on submental view photographs at 5 years old. RESULTS: The ONT suture was applied in 21 patients. The height of the nasal floor on the cleft side was significantly closer to that on the noncleft side with the ONT suture than without the ONT suture ( P = .008). CONCLUSIONS: The ONT suture is effective to prevent uplifted nasal floor deformity on the cleft side// in unilateral complete cleft lip and palate at the time of primary nasolabial repair. PMID- 29719158 TI - Recent advances in drug and nutrient transport across the blood-retinal barrier. AB - INTRODUCTION: The blood-retinal barrier (BRB) is the barrier separating the blood and neural retina, and transport systems for low-weight molecules at the BRB are expected to be useful for developing drugs for the treatment of ocular neural disorders and maintaining a healthy retina. Areas covered: This review discusses blood-to-retina and retina-to-blood transport of drugs and nutrients at the BRB. In particular, P-gp (ABCB1/MDR1) has low impact on the transport of cationic drugs at the BRB, suggesting a significant role of novel organic cation transporters in influx and efflux transport of lipophilic cationic drugs between blood and the retina. The transport of pravastatin at the BRB involves transporters including organic anion transporting polypeptide 1a4 (Oatp1a4). Recent studies have shown the involvement of solute carrier transporters in the blood-to-retina transport of nutrients including riboflavin, L-ornithine, beta alanine, and L-histidine, implying that dipeptide transport at the BRB is minimal. Expert opinion: Novel organic cation transport systems and the elimination-dominant transport of pravastatin at the BRB are expected to be useful in systemic drug delivery to the neural retina without CNS side effects. The mechanism of nutrient transport at the BRB is expected to provide a new strategy for delivery of nutrient-mimetic drugs. PMID- 29719160 TI - Propolis Protects Endotoxin Induced Acute Lung and Liver Inflammation Through Attenuating Inflammatory Responses and Oxidative Stress. AB - Propolis is a natural bee product, and it has many effects, including antioxidant, anti-inflammatory, antihepatotoxic, and anticancer activity. In this study, we aimed to explore the potential in vivo anti-inflammatory, antioxidant, and antiapoptotic properties of propolis extract on lipopolysaccharide (LPS) induced inflammation in rats. Forty-two, 3- to 4-month-old male Sprague Dawley rats were used in six groups. LPS (1 mg/kg) was administered intraperitoneally to rats in inflammation, inflammation + propolis30, and inflammation+propolis90 groups. Thirty milligram/kilogram and 90 mg/kg of propolis were given orally 24 h after LPS injection. After the determination of the inflammation in lung and liver tissues by 18F-fluoro-deoxy-d-glucose-positron emission tomography (18FDG PET), samples were collected. The levels of malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), nitric oxide (NO), and DNA fragmentation were determined. The decrease of MDA levels in inflammation + propolis30 and inflammation + propolis90 groups was determined compared to the inflammation group in lung and liver tissues. The increase of SOD% inhibition in inflammation + propolis90 group was determined in liver, lung, and hemolysate compared to the inflammation group. Increased CAT activities in inflammation + propolis30 and inflammation + propolis90 groups were observed in liver tissue and hemolysate compared to inflammation group. In lung tissue, NO levels were lower in inflammation group compared to the control group, but DNA fragmentation levels were higher. 18F-FDG uptake of tissues in inflammation + propolis30 and inflammation + propolis90 groups was decreased compared to the inflammation group. In conclusion, the data of this study indicate that the propolis application may serve as a potential approach for treating inflammatory diseases through the effect of reducing inflammation and free oxygen radical production. PMID- 29719161 TI - Patient centric drug product design in modern drug delivery as an opportunity to increase safety and effectiveness. AB - INTRODUCTION: The advances in drug delivery technologies have enabled pharmaceutical scientists to deliver a drug through various administration routes and optimize the drug release and absorption. The wide range of drug delivery systems and dosage forms represent a toolbox of technology for the development of pharmaceutical drug products but might also be a source of medication errors and nonadherence. Patient centric drug product development is being suggested as an important factor to increase therapeutic outcomes. Areas covered: Patients have impaired health and potentially disabilities and they are not medical or pharmaceutical experts but are requested to manage complex therapeutic regimens. As such the application of technology should also serve to reduce complexity, build on patients' intuition and ease of use. Patients form distinct populations based on the targeted disease, disease cluster or age group with specific characteristics or therapeutic contexts. Expert opinion: Establishing a target product and patient profile is essential to guide drug product design development. Including the targeted patient populations in the process is a prerequisite to achieve patient-centric pharmaceutical drug product design. Addressing the needs early on in the product design process, will create more universal design, avoiding the necessity for multiple product presentations to cover the different patient populations. PMID- 29719159 TI - Cuscuta arvensis Beyr "Dodder": In Vivo Hepatoprotective Effects Against Acetaminophen-Induced Hepatotoxicity in Rats. AB - Cuscuta arvensis Beyr. is a parasitic plant, and commonly known as "dodder" in Europe, in the United States, and "tu si zi shu" in China. It is one of the preferred spices used in sweet and savory dishes. Also, it is used as a folk medicine for the treatment particularly of liver problems, knee pains, and physiological hepatitis, which occur notably in newborns and their mothers in the southeastern part of Turkey. The purpose of this study was to investigate the hepatoprotective effects and antioxidant activities of aqueous and methanolic extracts of C. arvensis Beyr. on acetaminophen (APAP)-induced acute hepatotoxicity in rats. The results were supported by subsequent histopathological studies. The hepatoprotective activity of both the aqueous and methanolic extracts at an oral dose of 125 and 250 mg/kg was investigated by observing the reduction levels or the activity of alkaline phosphatase, alkaline transaminase, aspartate aminotransferase, blood urine nitrogen, and total bilirubin content. In vivo antioxidant activity was determined by analyzing the serum superoxide dismutase, malondialdehyde, glutathione, and catalase levels. Chromatographic methods were used to isolate biologically active compounds from the extract, and spectroscopic methods were used for structure elucidation. Both the methanolic and aqueous extracts exerted noticable hepatoprotective and antioxidant effects supporting the folkloric usage of dodder. One of the bioactive compounds was kaempferol-3-O-rhamnoside, isolated and identified from the methanolic extract. PMID- 29719162 TI - Molecular and eco-physiological characterization of arsenic (As)-transforming Achromobacter sp. KAs 3-5T from As-contaminated groundwater of West Bengal, India. AB - Molecular and eco-physiological characterization of arsenic (As)-transforming and hydrocarbon-utilizing Achromobacter type strain KAs 3-5T has been investigated in order to gain an insight into As-geomicrobiology in the contaminated groundwater. The bacterium is isolated from As-rich groundwater of West Bengal, India. Comparative 16S rRNA gene sequence phylogenetic analysis confirmed that the strain KAs 3-5T is closely related to Achromobacter mucicolens LMG 26685T (99.17%) and Achromobacter animicus LMG 26690T (99.17%), thus affiliated to the genus Achromobacter. Strain KAs 3-5T is nonflagellated, mesophilic, facultative anaerobe, having a broad metabolic repertoire of using various sugars, sugar /fatty acids, hydrocarbons as principal carbon substrates, and O2, NO3-, NO2-, and Fe3+ as terminal electron acceptors. Growth with hydrocarbons led to cellular aggregation and adherence of the cells to the hydrocarbon particles confirmed through electron microscopic observations. The strain KAs 3-5T showed high As resistance (MIC of 5 mM for As3+, 25 mM for As5+) and reductive transformation of As5+ under aerobic conditions while utilizing both sugars and hydrocarbons. Molecular taxonomy specified a high genomic GC content (65.5 mol %), ubiquinone 8 (UQ-8) as respiratory quinone, spermidine as predominant polyamine in the bacterium. The differential presence of C12:0, C14:0 2-OH, C18:1 omega7c, and C 14:0 iso 3-OH/ C16:1 iso fatty acids, phosphatidylglycerol (PG), phosphatidylcholine (PC), two unknown phospholipid (PL1, PL2) as polar lipids, low DNA-DNA relatedness (33.0-41.0%) with the Achromobacter members, and unique metabolic capacities clearly indicated the distinct genomic and physiological properties of strain KAs 3-5T among known species of the genus Achromobacter. These findings lead to improve our understanding on metabolic flexibility of bacteria residing in As-contaminated groundwater and As-bacteria interactions within oligotrophic aquifer system. PMID- 29719163 TI - Utility analysis and calibration of QOL assessment in disease management. AB - In clinical trials, the assessment of health-related quality of life (QOL) (or patient-reported outcome [PRO] measure) has become very popular especially for clinical studies conducted for evaluating clinical benefits of patients with chronic, severe, and/or life threatening diseases. Health-related QOL information and PRO measures are useful for disease management for achieving best clinical practice. In this article, we will focus on health-related QOL assessment. The concept, design, and analysis of health-related QOL in clinical trials are reviewed. Validation of the use of health-related QOL instrument in terms of some key performance characteristics such as accuracy, reliability, sensitivity, and responsibility for assuring quality, integrity, and validity of collected QOL data are discussed. The concept of utility analysis and calibration (e.g., with respect to life events) for achieving the optimization of disease management are proposed. The change of the QOL could be translated into different life events for effective disease management. These translations could evaluate the treatment effect by more directly displaying the change of the QOL. PMID- 29719164 TI - Genetically Encoded Biosensors in Plants: Pathways to Discovery. AB - Genetically encoded biosensors that directly interact with a molecule of interest were first introduced more than 20 years ago with fusion proteins that served as fluorescent indicators for calcium ions. Since then, the technology has matured into a diverse array of biosensors that have been deployed to improve our spatiotemporal understanding of molecules whose dynamics have profound influence on plant physiology and development. In this review, we address several types of biosensors with a focus on genetically encoded calcium indicators, which are now the most diverse and advanced group of biosensors. We then consider the discoveries in plant biology made by using biosensors for calcium, pH, reactive oxygen species, redox conditions, primary metabolites, phytohormones, and nutrients. These discoveries were dependent on the engineering, characterization, and optimization required to develop a successful biosensor; they were also dependent on the methodological developments required to express, detect, and analyze the readout of such biosensors. PMID- 29719165 TI - Receptor-Like Cytoplasmic Kinases: Central Players in Plant Receptor Kinase Mediated Signaling. AB - Receptor kinases (RKs) are of paramount importance in transmembrane signaling that governs plant reproduction, growth, development, and adaptation to diverse environmental conditions. Receptor-like cytoplasmic kinases (RLCKs), which lack extracellular ligand-binding domains, have emerged as a major class of signaling proteins that regulate plant cellular activities in response to biotic/abiotic stresses and endogenous extracellular signaling molecules. By associating with immune RKs, RLCKs regulate multiple downstream signaling nodes to orchestrate a complex array of defense responses against microbial pathogens. RLCKs also associate with RKs that perceive brassinosteroids and signaling peptides to coordinate growth, pollen tube guidance, embryonic and stomatal patterning, floral organ abscission, and abiotic stress responses. The activity and stability of RLCKs are dynamically regulated not only by RKs but also by other RLCK associated proteins. Analyses of RLCK-associated components and substrates have suggested phosphorylation relays as a major mechanism underlying RK-mediated signaling. PMID- 29719166 TI - Paleobotany and Global Change: Important Lessons for Species to Biomes from Vegetation Responses to Past Global Change. AB - Human carbon use during the next century will lead to atmospheric carbon dioxide concentrations (pCO2) that have been unprecedented for the past 50-100+ million years according to fossil plant-based CO2 estimates. The paleobotanical record of plants offers key insights into vegetation responses to past global change, including suitable analogs for Earth's climatic future. Past global warming events have resulted in transient poleward migration at rates that are equivalent to the lowest climate velocities required for current taxa to keep pace with climate change. Paleobiome reconstructions suggest that the current tundra biome is the biome most threatened by global warming. The common occurrence of paleoforests at high polar latitudes when pCO2 was above 500 ppm suggests that the advance of woody shrub and tree taxa into tundra environments may be inevitable. Fossil pollen studies demonstrate the resilience of wet tropical forests to global change up to 700 ppm CO2, contrary to modeled predictions of the future. The paleobotanical record also demonstrates a high capacity for functional trait evolution as an additional strategy to migration and maintenance of a species' climate envelope in response to global change. PMID- 29719167 TI - One Hundred Ways to Invent the Sexes: Theoretical and Observed Paths to Dioecy in Plants. AB - Dioecy, the presence of male and female flowers on separate individuals, is both widespread and uncommon within flowering plants, with only a few percent of dioecious species spread across most major phylogenetic taxa. It is therefore safe to assume that dioecy evolved independently in these different groups, which allows us to ask questions regarding the molecular and developmental mechanisms underlying these independent transitions to dioecy. We start this review by examining the problem from the standpoint of a genetic engineer trying to develop dioecy, discuss various potential solutions, and compare them to models proposed in the past and based on genetic and evolutionary considerations. Next, we present recent information regarding candidate sex determinants in three species, acquired using newly established genomic approaches. Although such specific information is still scarce, it is slowly becoming apparent that various genes or pathways can be altered to evolve dioecy. PMID- 29719168 TI - Cationic control of Panx1 channel function. AB - The sequence and predicted membrane topology of pannexin1 (Panx1) places it in the family of gap junction proteins. However, rather than forming gap junction channels, Panx1 forms channels in the nonjunctional membrane. Panx1 operates in two distinct open states, depending on the mode of stimulation. The exclusively voltage-gated channel has a small conductance (<100 pS) and is highly selective for the flux of chloride ions. The Panx1 channel activated by various physiological stimuli or by increased concentrations of extracellular potassium ions has a large conductance (~500 pS, however, with multiple, long-lasting subconductance states) and is nonselectively permeable to small molecules, including ATP. To test whether the two open conformations also differ pharmacologically, the effects of di-and trivalent cations on the two Panx1 channel conformations were investigated. The rationale for this venture was that, under certain experimental conditions, ATP release from cells can be inhibited by multivalent cations, yet the literature indicates that the ATP release channel Panx1 is not affected by these ions. Consistent with previous reports, the Panx1 channel was not activated by removal of extracellular Ca2+ and the currents through the voltage-activated channel were not altered by Ca2+, Zn2+, Ba2+, or Gd3+. In contrast, the Panx1 channel activated to the large channel conformation by extracellular K+, osmotic stress, or low oxygen was inhibited by the multivalent cations in a dose-dependent way. Thus, monovalent cations activated the Panx1 channel from the closed state to the "large" conformation, while di- and trivalent cations exclusively inhibited this large channel conformation. PMID- 29719169 TI - Phagocytosis-mediated M1 activation by chitin but not by chitosan. AB - Chitin particles have been used to understand host response to chitin-containing pathogens and allergens and are known to induce a wide range of polarized macrophage activations, depending, at least in part, on particle size. Nonphagocytosable particles larger than a macrophage induce tissue repair M2 activation. In contrast, phagocytosable chitin microparticles (CMPs, 1-10 MUm diameters) induce M1 macrophages that kill intracellular microbes and damage tissues. However, chitosan (deacetylated) microparticles (de-CMPs, 1-10 um) induce poor M1 activation. Toll-like receptor 2 (TLR2) and associated coreceptors in macrophages appear to be required for the M1 activation. To understand the exact mechanism of phagocytosis-mediated M1 activation by chitin, we isolated macrophage proteins that bind to CMPs during early phagocytosis and determined that TLR1, TLR2, CD14, late endosomal/lysosomal adaptor MAPK and mechanistic target of rapamycin activator 1 (LAMTOR1), Lck/Yes novel tyrosine kinase (Lyn), and beta-actin formed phagosomal CMP-TLR2 clusters. These proteins were also detected in TLR2 phagosomal clusters in macrophages phagocytosing de-CMPs, but at relatively lower levels than in the CMP-TLR2 clusters. Importantly, CMP-TLR2 clusters further recruited myeloid differentiation primary response gene 88 (MyD88) and Toll-IL-1 receptor-containing adaptor protein (TIRAP) and phosphorylated Lyn, whereas neither the adaptors nor phosphorylated Lyn was detected in the de-CMP clusters. The results indicate that the acetyl group played an obligatory, phagocytosis-dependent role in the initiation of an integrated signal for TLR2-mediated M1 activation. PMID- 29719171 TI - Pannexin1: a multifunction and multiconductance and/or permeability membrane channel. AB - Of the three pannexins in vertebrate proteomes, pannexin1 (Panx1) is the only one well characterized, and it is generally accepted that Panx1 functions as an ATP release channel for signaling to other cells. However, the ATP permeability of the channel is only observed with certain stimuli, including low oxygen, mechanical stress, and elevated extracellular potassium ion concentration. Otherwise, the Panx1 channel is selective for chloride ions and exhibits no ATP permeability when stimulated simply by depolarization to positive potentials. A third, irreversible activation of Panx1 follows cleavage of carboxyterminal amino acids by caspase 3. The selectivity/permeability properties of the caspase cleaved channel are unclear as it reportedly has features of both channel conformations. Here we describe the biophysical properties of the channel formed by the truncation mutant Panx1Delta378, which is identical to the caspase-cleaved protein. Consistent with previous findings for the caspase-activated channel, the Panx1Delta378 channel was constitutively active. However, like the voltage-gated channel, the Panx1Delta378 channel had high chloride selectivity, lacked cation permeability, and did not mediate ATP release unless stimulated by extracellular potassium ions. Thus, the caspase-cleaved Panx1 channel should be impermeable to ATP, contrary to previous claims. PMID- 29719170 TI - VEGF-A selectively inhibits FLT1 ectodomain shedding independent of receptor activation and receptor endocytosis. AB - Ectodomain shedding and regulated intracellular proteolysis can determine the fate or function of cell surface proteins. Fms-related tyrosine kinase (FLT) or VEGF receptor 1 is a high-affinity cell surface VEGF-A receptor tyrosine kinase that is constitutively cleaved to release an NH2-terminal VEGF-A binding ectodomain that, once shed, can antagonize the effects of VEGF-A in the extracellular milieu. We evaluated the effect of VEGF-A on FLT1 cleavage in native cells and in transient and stable expression systems. We demonstrate that VEGF-A inhibits FLT1 ectodomain cleavage in a time- and dose-dependent manner, whereas VEGF-A knockdown in HEK293 cells increases ectodomain shedding. Although kinase insert domain receptor (KDR) or VEGF receptor 2, analogous to FLT1, is also subject to extracellular and intracellular cleavage, VEGF-A does not inhibit KDR cleavage. VEGF-A inhibition of FLT1 cleavage is not dependent on FLT1 tyrosine kinase activity or the intracellular FLT1 residues. N acetylleucylleucylnorleucinal (ALLN), a proteasomal inhibitor; bafilomycin A, an inhibitor of endosomal acidification; and dynasore, a dynamin inhibitor, all increase the abundance of FLT1 and the shed ectodomain, indicating that FLT1 is subject to dynamin-mediated endocytosis and susceptible to proteasomal and lysosomal degradation. VEGF-A inhibition of cleavage is not reversed by ALLN, bafilomycin A, or dynasore. However, a 30 AA deletion in the extracellular immunoglobulin 7 domain leads to enhanced cleavage of Flt1 with a significant reduction of the VEGF inhibitory effect. Our results indicate that the inhibition of FLT1 ectodomain cleavage by VEGF-A is dependent neither on receptor activation nor on internalization nor a consequence of receptor degradation and likely represents a direct inhibitory effect on receptor cleavage. PMID- 29719172 TI - Mistargeting of a truncated Na-K-2Cl cotransporter in epithelial cells. AB - We recently reported the case of a young patient with multisystem failure carrying a de novo mutation in SLC12A2, the gene encoding the Na-K-2Cl cotransporter-1 (NKCC1). Heterologous expression studies in nonepithelial cells failed to demonstrate dominant-negative effects. In this study, we examined expression of the mutant cotransporter in epithelial cells. Using Madin-Darby canine kidney (MDCK) cells grown on glass coverslips, permeabilized support, and Matrigel, we show that the fluorescently tagged mutant cotransporter is expressed in cytoplasm and at the apical membrane and affects epithelium integrity. Expression of the mutant transporter at the apical membrane also results in the mislocalization of some of the wild-type transporter to the apical membrane. This mistargeting is specific to NKCC1 as the Na+-K+-ATPase remains localized on the basolateral membrane. To assess transporter localization in vivo, we created a mouse model using CRISPR/cas9 that reproduces the 11 bp deletion in exon 22 of Slc12a2. Although the mice do not display an overt phenotype, we show that the colon and salivary gland expresses wild-type NKCC1 abundantly at the apical pole, confirming the data obtained in cultured epithelial cells. Enough cotransporter must remain, however, on the basolateral membrane to participate in saliva secretion, as no significant decrease in saliva production was observed in the mutant mice. PMID- 29719173 TI - Reversal of cisplatin resistance by microRNA-139-5p-independent RNF2 downregulation and MAPK inhibition in ovarian cancer. AB - Some microRNAs (miRs) are dysregulated in cancers, and aberrant miR expression has been reported to correlate with chemoresistance of cancer cells. Therefore, the present study aims at investigating the effects of microRNA-139-5p (miR-139 5p) on cisplatin resistance of ovarian cancer (OC) with involvement of ring finger protein 2 (RNF2) and the mitogen-activated protein kinase (MAPK) signaling pathway. OC tissues were obtained from 66 primary OC patients. The cisplatin sensitive A2780 and cisplatin-resistant A2780/DDP cell lines were collected for construction of RNF2 silencing and overexpressed plasmids. Cell vitality and apoptosis were detected by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and annexin V-FITC/propidium iodide double-staining, respectively. Next, expression of RNF2, extracellular signal-related kinase, and p38 was determined by quantitative reverse transcription-quantitative polymerase chain reaction and Western blot analysis. Finally, the volume of xenograft tumors in BALB/c nude mice was detected. RNF2 and miR-139-5p were identified to be involved in OC. In addition, MAPK activation and RNF2 were related to cisplatin resistance of OC. miR-139-5p was downregulated in cisplatin-resistant OC tissues, and miR-139-5p overexpression could inhibit cell vitality, reduce cisplatin resistance, and promote apoptosis of OC cells. Furthermore, miR-139-5p combined with MAPK inhibitors more obviously reduced cisplatin resistance of OC. Taken together, this study demonstrated that miR-139-5p overexpression combined with inactivation of the MAPK signaling pathway can reverse the cisplatin resistance of OC by suppressing RNF2. Thus, miR-139-5p overexpression might be a future therapeutic strategy for OC. PMID- 29719174 TI - Pleural Disease. PMID- 29719175 TI - Angiography with Sodium Bicarbonate and Acetylcysteine. PMID- 29719176 TI - Improving Adoption of EHRs in Psychiatric Care. PMID- 29719177 TI - Reform at Risk - Mandating Participation in Alternative Payment Plans. PMID- 29719178 TI - Questionable Admissions. PMID- 29719179 TI - Randomized Trial of Verubecestat for Mild-to-Moderate Alzheimer's Disease. AB - BACKGROUND: Alzheimer's disease is characterized by the deposition of amyloid beta (Abeta) plaques in the brain. Abeta is produced from the sequential cleavage of amyloid precursor protein by beta-site amyloid precursor protein-cleaving enzyme 1 (BACE-1) followed by gamma-secretase. Verubecestat is an oral BACE-1 inhibitor that reduces the Abeta level in the cerebrospinal fluid of patients with Alzheimer's disease. METHODS: We conducted a randomized, double-blind, placebo-controlled, 78-week trial to evaluate verubecestat at doses of 12 mg and 40 mg per day, as compared with placebo, in patients who had a clinical diagnosis of mild-to-moderate Alzheimer's disease. The coprimary outcomes were the change from baseline to week 78 in the score on the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-cog; scores range from 0 to 70, with higher scores indicating worse dementia) and in the score on the Alzheimer's Disease Cooperative Study Activities of Daily Living Inventory scale (ADCS-ADL; scores range from 0 to 78, with lower scores indicating worse function). RESULTS: A total of 1958 patients underwent randomization; 653 were randomly assigned to receive verubecestat at a dose of 12 mg per day (the 12-mg group), 652 to receive verubecestat at a dose of 40 mg per day (the 40-mg group), and 653 to receive matching placebo. The trial was terminated early for futility 50 months after onset, which was within 5 months before its scheduled completion, and after enrollment of the planned 1958 patients was complete. The estimated mean change from baseline to week 78 in the ADAS-cog score was 7.9 in the 12-mg group, 8.0 in the 40-mg group, and 7.7 in the placebo group (P=0.63 for the comparison between the 12-mg group and the placebo group and P=0.46 for the comparison between the 40-mg group and the placebo group). The estimated mean change from baseline to week 78 in the ADCS-ADL score was -8.4 in the 12-mg group, -8.2 in the 40-mg group, and -8.9 in the placebo group (P=0.49 for the comparison between the 12-mg group and the placebo group and P=0.32 for the comparison between the 40-mg group and the placebo group). Adverse events, including rash, falls and injuries, sleep disturbance, suicidal ideation, weight loss, and hair-color change, were more common in the verubecestat groups than in the placebo group. CONCLUSIONS: Verubecestat did not reduce cognitive or functional decline in patients with mild to-moderate Alzheimer's disease and was associated with treatment-related adverse events. (Funded by Merck; ClinicalTrials.gov number, NCT01739348 .). PMID- 29719180 TI - Oxybutynin for Hot Flashes Due to Androgen Deprivation in Men. PMID- 29719181 TI - History of Childhood Kidney Disease and Risk of Adult End-Stage Renal Disease. PMID- 29719182 TI - Clinical Assessment of Peripheral Arterial Disease of the Lower Limbs. PMID- 29719183 TI - Pharmacomechanical Therapy for Deep-Vein Thrombosis. PMID- 29719184 TI - Relapsing Polychondritis. PMID- 29719185 TI - Aspiration of a Chicken Bone. PMID- 29719186 TI - Care for Undocumented Immigrants - Rethinking State Flexibility in Medicaid Waivers. PMID- 29719187 TI - The Wrong Frame of Mind. PMID- 29719188 TI - Follow-up of Patients with Clear-Cell Adenocarcinoma of the Vagina and Cervix. PMID- 29719189 TI - The Best Medical Care in the World. PMID- 29719191 TI - Letter Regarding: Combined Popliteal Catheter With Single-Injection vs Continuous Infusion Saphenous Nerve Block for Foot and Ankle Surgery. PMID- 29719190 TI - Calciphylaxis. PMID- 29719192 TI - Response to "Letter Regarding: Combined Popliteal Catheter With Single-Injection vs Continuous-Infusion Saphenous Nerve Block for Foot and Ankle Surgery". PMID- 29719194 TI - Mineral constituents in Leccinum scabrum from lowland locations in the central Europe and their relation to concentration in forest topsoil. AB - Leccinum scabrum is an edible mushroom common in European regions in the northern hemisphere. Macro and trace mineral constituents such as Ag, Al, Ba, Ca, Cd, Co, Cu, Fe, K, Mg, Mn, Na, Ni, Pb, P, Rb, Sr and Zn were studied in L. scabrum and in the top soil collected from the same location underneath soil substratum. The "pseudo-total" and labile (extractable fraction of minerals) were measured to get insight into the levels, distribution between the morphological parts of fruiting bodies, potential for their bioconcentration by mushroom and evaluated for human exposure via consumption of the mushroom. The sampling sites include the Darzlubska Wilderness, Trojmiejski Landscape Park, Sobieszewo Island, Wdzydze Landscape Park and outskirts of the Ketrzyn town in Mazury from the norther part of Poland. Median values of K, Rb and P concentrations in dehydrated L. scabrum were for caps in range 27,000-44,000 mg kg-1, 90-320 mg kg-1 and 6,200-9,100 mg kg-1, and followed by Mg at 880-1,000 mg kg-1, Ca at 48-210 mg kg-1 and Al at 15 120 mg kg-1. The median concentrations of Cu, Fe, Mn and Zn in caps were in range 15-27 mg kg-1 db 38-140 mg kg-1, 5.3-27 mg kg-1 and 130-270 mg kg-1. For Ba and Sr, concentrations on the average were at ~1 mg kg-1, and almost equally distributed between the caps and stipes of the fruiting bodies. L. scabrum mushrooms were low in toxic Ag, Cd, Hg and Pb, for which the median values in dried caps from five locations were, respectively, in range 0.48-0.98 mg kg-1 (cap to stipe index, QC/S, was 2.5-4.1), 1.0-5.8 mg kg-1 (QC/S 2.9-3.8), 0.36 0.59 mg kg-1 (QC/S 1.6-2.7) and 0.20-0.91 mg kg-1 (QC/S 1.2-1.9). Substantial variations in the concentrations of the "pseudo-total" fraction (extracted by aqua regia) or labile fraction (extracted by 20% solution of nitric acid) of the elements determined in forest topsoils were noted between some of the locations examined. The elements K, P, Cd, Cu, Hg, Mn, Na, Rb and Zn can be considered as those which were bioconcentrated by L. scabrum in fruiting bodies, while the rates of accumulation varied with the sampling location. PMID- 29719195 TI - Sarcoidosis: a state of the art review from the Thoracic Society of Australia and New Zealand. AB - Sarcoidosis is a systemic disease of unknown aetiology, characterised by non caseating granulomatous inflammation. It most commonly manifests in the lungs and intrathoracic lymph nodes but can affect any organ. This summary of an educational resource provided by the Thoracic Society of Australia and New Zealand outlines the current understanding of sarcoidosis and highlights the need for further research. Our knowledge of the aetiology and immunopathogenesis of sarcoidosis remains incomplete. The enigma of sarcoidosis lies in its immunological paradox of type 1 T helper cell-dominated local inflammation co existing with T regulatory-induced peripheral anergy. Although specific aetiological agents have not been identified, mounting evidence suggests that environmental and microbial antigens may trigger sarcoidosis. Genome-wide association studies have identified candidate genes conferring susceptibility and gene expression analyses have provided insights into cytokine dysregulation leading to inflammation. Sarcoidosis remains a diagnosis of exclusion based on histological evidence of non-caseating granulomas with compatible clinical and radiological findings. In recent years, endobronchial ultrasound-guided transbronchial needle aspiration of mediastinal lymph nodes has facilitated the diagnosis, and whole body positron emission tomography scanning has improved localisation of disease. No single biomarker is adequately sensitive and specific for detecting and monitoring disease activity. Most patients do not require treatment; when indicated, corticosteroids remain the initial standard of care, despite their adverse side effect profile. Other drugs with fewer side effects may be a better long term choice (eg, methotrexate, hydroxychloroquine, azathioprine, mycophenolate), while tumour necrosis factor-alpha inhibitors are a treatment option for patients with refractory disease. PMID- 29719196 TI - Clinical Oncology Society of Australia position statement on exercise in cancer care. AB - INTRODUCTION: Clinical research has established exercise as a safe and effective intervention to counteract the adverse physical and psychological effects of cancer and its treatment. This article summarises the position of the Clinical Oncology Society of Australia (COSA) on the role of exercise in cancer care, taking into account the strengths and limitations of the evidence base. It provides guidance for all health professionals involved in the care of people with cancer about integrating exercise into routine cancer care. Main recommendations: COSA calls for: exercise to be embedded as part of standard practice in cancer care and to be viewed as an adjunct therapy that helps counteract the adverse effects of cancer and its treatment; all members of the multidisciplinary cancer team to promote physical activity and recommend that people with cancer adhere to exercise guidelines; and best practice cancer care to include referral to an accredited exercise physiologist or physiotherapist with experience in cancer care. Changes in management as a result of the guideline: COSA encourages all health professionals involved in the care of people with cancer to: discuss the role of exercise in cancer recovery; recommend their patients adhere to exercise guidelines (avoid inactivity and progress towards at least 150 minutes of moderate intensity aerobic exercise and two to three moderate intensity resistance exercise sessions each week); and refer their patients to a health professional who specialises in the prescription and delivery of exercise (ie, accredited exercise physiologist or physiotherapist with experience in cancer care). PMID- 29719197 TI - Metabolic cofactors NAD(P)H and FAD as potential indicators of cancer cell response to chemotherapy with paclitaxel. AB - Paclitaxel, a widely used antimicrotubular agent, predominantly eliminates rapidly proliferating cancer cells, while slowly proliferating and quiescent cells can survive the treatment, which is one of the main reasons for tumor recurrence and non-responsiveness to the drug. To improve the efficacy of chemotherapy, biomarkers need to be developed to enable monitoring of tumor responses. In this study we considered the auto-fluorescent metabolic cofactors NAD(P)H and FAD as possible indicators of cancer cell response to therapy with paclitaxel. It was found that, among the tested parameters (the fluorescence intensity-based redox ratio FAD/NAD(P)H, and the fluorescence lifetimes of NAD(P)H and FAD), the fluorescence lifetime of NAD(P)H is the most sensitive in tracking the drug response, and is capable of indicating heterogeneous cellular responses both in cell monolayers and in multicellular tumor spheroids. We observed that metabolic reorganization to a more oxidative state preceded the morphological manifestation of cell death and developed faster in cells that were more responsive to the drug. Our results suggest that noninvasive, label-free monitoring of the drug-induced metabolic changes by noting the NAD(P)H fluorescence lifetime is a valuable approach to characterize the responses of cancer cells to anti-cancer treatments and, therefore, to predict the effectiveness of chemotherapy. PMID- 29719198 TI - Interaction between oral squamous cell carcinoma cells and fibroblasts through TGF-beta1 mediated by podoplanin. AB - Podoplanin is upregulated in the invasive front of oral squamous cell carcinoma (OSCC). Carcinoma-associated fibroblasts (CAFs) may mediate podoplanin expression. However, the role of podoplanin in OSCC cell and fibroblast interaction remains elusive. In the present study, we found that positive podoplanin expression in OSCC cells correlated with smooth muscle actin (alpha SMA) expression in CAFs. Using CAFs and normal mucosal fibroblasts (NFs), we established indirect and direct co-culture systems mimicking the structure of OSCC. Podoplanin-overexpressing OSCC cells promoted NF activation; in direct co culture, but not in indirect co-culture, podoplanin-overexpressing OSCC cells increased fibroblast invasion via matrix metalloproteinase 2 (MMP-2), MMP-14, and alphav/beta6 integrin receptor (ITGA5/ITGB6) signaling. CAFs also induced podoplanin expression through the transforming growth factor-beta1 (TGF beta1)/Smad pathway. TGF-beta1 increased the podoplanin-dependent activation of epidermal growth factor receptor (EGFR), AKT, and extracellular signal-regulated kinase (ERK) signaling. Additionally, CAFs promoted OSCC cell invasion by upregulating MMP-2 and MMP-14 expression in both indirect and direct co-culture. Taken together, our findings indicate that podoplanin regulates the interaction between OSCC cells and CAFs via the mutual paracrine effects of TGF-beta1. PMID- 29719199 TI - Antioxidants linked with physical, cognitive and psychological frailty: Analysis of candidate biomarkers and markers derived from the MARK-AGE study. AB - Frailty among elderly people leads to an increased risk for negative health outcomes. To prevent frailty, we need a better understanding of the underlying mechanisms and early detection of individuals at risk. Both may be served by identifying candidate (bio)markers, i.e. biomarkers and markers, for the physical, cognitive, and psychological frailty domains. We used univariate (Rank ANOVA) and multivariate (elastic net) approaches on the RASIG study population (age range: 35-74 years, n = 2220) of the MARK-AGE study to study up to 331 (bio)markers between individuals with and without frailty for each domain. Biomarkers and markers identified by both approaches were studied further regarding their association with frailty using logistic regression. Univariately, we found lower levels of antioxidants, including beta-cryptoxanthin and zeaxanthin, in those who were physically, cognitively or psychologically frail. Additionally, self-reported health was worse in these three frail groups. Multivariately, we observed lower levels of beta-cryptoxanthin and zeaxanthin in the cognitively frail. Levels of these carotenoids were inversely associated with the risk of being cognitively frail after adjusting for confounders. Antioxidants and self-reported health are potential (bio)markers to detect persons at risk of becoming frail. The biomarkers identified may indicate the involvement of inflammation in frailty, especially for physical and cognitive frailty. PMID- 29719200 TI - Proteomic analysis of micro-scale bioreactors as scale-down model for a mAb producing CHO industrial fed-batch platform. AB - The pharmaceutical production of recombinant proteins, such as monoclonal antibodies, is rather complex and requires proper development work. Accordingly, it is essential to develop appropriate scale-down models, which can mimic the corresponding production scale. In this work, we investigated the impact of the bioreactor scale on intracellular micro-heterogeneities of a CHO cell line producing monoclonal antibodies in fed-batch mode, using a 10 mL micro-bioreactor (ambrTM) scale-down model and the corresponding 300 L pilot-scale bioreactor. For each scale, we measured the time evolution of the proteome, which enabled us to compare the impact of the bioreactor scale on the intracellular processes. Nearly absolute accordance between the scales was verified by data mining methods, such as hierarchical clustering and in-detail analysis on a single protein base. The time response of principal enzymes related to N-glycosylation was discussed, emphasizing major dissimilarities between the glycan fractions adorning the heavy chain and the corresponding protein abundance. The enzyme expression displayed mainly a constant profile, whereas the resulting glycan pattern changed over time. It is concluded that the enzymatic activity is influenced by the changing environmental conditions present in the fed-batch processes leading to the observed time-dependent variation. PMID- 29719201 TI - Conformational Ensemble and Biological Role of the TCTP Intrinsically Disordered Region: Influence of Calcium and Phosphorylation. AB - The translationally controlled tumor protein (TCTP) is a multifunctional protein that may interact with many other biomolecules, including itself. The experimental determinations of TCTP structure revealed a folded core domain and an intrinsically disordered region, which includes the first highly conserved TCTP signature, but whose role in the protein functions remains to be elucidated. In this work, we combined NMR experiments and MD simulations to characterize the conformational ensemble of the TCTP intrinsically disordered loop, in the presence or not of calcium ions and with or without the phosphorylation of Ser46 and Ser64. Our results show that these changes in the TCTP electrostatic conditions induce significant shifts of its conformational ensemble toward structures more or less extended in which the disordered loop is pulled away or folded against the core domain. Particularly, these conditions impact the transient contacts between the two highly conserved signatures of the protein. Moreover, both experimental and theoretical data show that the interface of the non-covalent TCTP dimerization involves its second signature which suggests that this region might be involved in protein-protein interaction. We also show that calcium hampers the formation of TCTP dimers, likely by favoring the competitive binding of the disordered loop to the dimerization interface. All together, we propose that the TCTP intrinsically disordered region is involved in remodeling the core domain surface to modulate its accessibility to its partners in response to a variety of cellular conditions. PMID- 29719202 TI - Utilizing time-frequency amplitude and phase synchrony measure to assess feedback processing in a gambling task. AB - The neurophysiological mechanisms involved in the evaluation of performance feedback have been widely studied in the ERP literature over the past twenty years, but understanding has been limited by the use of traditional time-domain amplitude analytic approaches. Gambling outcome valence has been identified as an important factor modulating event-related potential (ERP) components, most notably the feedback negativity (FN). Recent work employing time-frequency analysis has shown that processes indexed by the FN are confounded in the time domain and can be better represented as separable feedback-related processes in the theta (3-7 Hz) and delta (0-3 Hz) frequency bands. In addition to time frequency amplitude analysis, phase synchrony measures have begun to further our understanding of performance evaluation by revealing how feedback information is processed within and between various brain regions. The current study aimed to provide an integrative assessment of time-frequency amplitude, inter-trial phase synchrony, and inter-channel phase synchrony changes following monetary feedback in a gambling task. Results revealed that time-frequency amplitude activity explained separable loss and gain processes confounded in the time-domain. Furthermore, phase synchrony measures explained unique variance above and beyond amplitude measures and demonstrated enhanced functional integration between medial prefrontal and bilateral frontal, motor, and occipital regions for loss relative to gain feedback. These findings demonstrate the utility of assessing time-frequency amplitude, inter-trial phase synchrony, and inter-channel phase synchrony together to better elucidate the neurophysiology of feedback processing. PMID- 29719203 TI - The burgeoning role of cytochrome P450-mediated vitamin D metabolites against colorectal cancer. AB - The metabolites of vitamin D3 (VD3) mediated by different cytochrome P450 (CYP) enzymes, play fundamental roles in many physiological processes in relation to human health. These metabolites regulate a variety of cellular signal pathways through the direct binding of activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. Thus, the polymorphisms of VDR and VD3 metabolizing enzymes lead to differentiated efficiency of VD3 and further affect serum VD3 levels. Moreover, VDR activation is demonstrated to inhibit the growth of various cancers, including colorectal cancer. However, excessive intake of vitamin D may lead to hypercalcemia, which limits the application of vitamin D tremendously. In this review, we have summarized the advances in VD3 research, especially the metabolism map of VD3 and the molecular mechanisms of inhibiting growth and inducing differentiation in colorectal cancer mediated by VDR-associated cellular signal pathways. The relationship between VDR polymorphism and the risk of colorectal cancer is also illustrated. In particular, novel pathways of the activation of VD3 started by CYP11A1 and CYP3A4 are highlighted, which produce several noncalcemic and antiproliferative metabolites. At last, the hypothesis is put forward that further research of CYP-mediated VD3 metabolites may develop therapeutic agents for colorectal cancer without resulting in hypercalcemia. PMID- 29719204 TI - Drug-drug interactions in the treatment for alcohol use disorders: A comprehensive review. AB - Drug interactions are one of the most common causes of side effects in polypharmacy. Alcoholics are a category of patients at high risk of pharmacological interactions, due to the presence of comorbidities, the concomitant intake of several medications and the pharmacokinetic and pharmacodynamic interferences of ethanol. However, the data available on this issue are limited. These reasons often frighten clinicians when prescribing appropriate pharmacological therapies for alcohol use disorder (AUD), where less than 15% of patients receive an appropriate treatment in the most severe forms. The data available in literature regarding the relevant drug-drug interactions of the medications currently approved in United States and in some European countries for the treatment of AUD (benzodiazepines, acamprosate, baclofen, disulfiram, nalmefene, naltrexone and sodium oxybate) are reviewed here. The class of benzodiazepines and disulfiram are involved in numerous pharmacological interactions, while they are not conspicuous for acamprosate. The other drugs are relatively safe for pharmacological interactions, excluding the opioid withdrawal syndrome caused by the combination of nalmefene or naltrexone with an opiate medication. The information obtained is designed to help clinicians in understanding and managing the pharmacological interactions in AUDs, especially in patients under multi-drug treatment, in order to reduce the risk of a negative interaction and to improve the treatment outcomes. PMID- 29719205 TI - CXCR4 overexpression is correlated with poor prognosis in colorectal cancer. AB - AIMS: Colorectal cancer threatens human health due to its high mortality resulting from metastatic progression. The expression of C-X-C chemokine receptor type 4 (CXCR4) is absent or low in most healthy tissues but high in various types of tumours. In this study, we aim to determine the prognostic significance of CXCR4 in colorectal cancer. MAIN METHODS: We retrospectively examined a total of 72 tissue samples, that qRT-PCR and immunohistochemistry were performed to detect the expression of CXCR4 as well as univariate and multivariate analyses were performed to explore the overall survival. KEY FINDINGS: Our data demonstrated that CXCR4 expression was associated with lymph node metastasis (P = 0.049), histological differentiation (P = 0.01), distant metastasis (P = 0.02) and DNA mismatch repair (MMR) index (P = 0.0002). However, CXCR4 expression was not associated with age, sex, tumour diameter or depth of invasion. Furthermore, both univariate and multivariate analyses confirmed that CXCR4 was an independent factor in predicting unfavourable overall survival (hazard ratio, 0.188; 95% confidence interval, 0.038-0.757). SIGNIFICANCE: In conclusion, our findings suggest that CXCR4 might contribute to clinical tumour progression and may be a valuable prognostic biomarker in colorectal cancer treatment. PMID- 29719206 TI - Neuromast hair cells retain the capacity of regeneration during heavy metal exposure. AB - The neuromast is the morphological unit of the lateral line of fishes and is composed of a cluster of central sensory cells (hair cells) surrounded by support and mantle cells. Heavy metals exposure leads to disruption of hair cells within the neuromast. It is well known that the zebrafish has the ability to regenerate the hair cells after damage caused by toxicants. The process of regeneration depends on proliferation, differentiation and cellular migration of sensory and non-sensory progenitor cells. Therefore, our study was made in order to identify which cellular types are involved in the complex process of regeneration during heavy metals exposure. For this purpose, adult zebrafish were exposed to various heavy metals (Arsenic, cadmium and zinc) for 72h. After acute (24h) exposure, immunohistochemical localization of S100 (a specific marker for hair cells) in the neuromasts highlighted the hair cells loss. The immunoreaction for Sox2 (a specific marker for stem cells), at the same time, was observed in the support and mantle cells, after exposure to arsenic and cadmium, while only in the support cells after exposure to zinc. After chronic (72h) exposure the hair cells were regenerated, showing an immunoreaction for S100 protein. At the same exposure time to the three metals, a Sox2 immunoreaction was expressed in support and mantle cells. Our results showed for the first time the regenerative capacity of hair cells, not only after, but also during exposure to heavy metals, demonstrated by the presence of different stem cells that can diversify in hair cells. PMID- 29719209 TI - Sit4p-mediated dephosphorylation of Atp2p regulates ATP synthase activity and mitochondrial function. AB - Sit4p is a type 2A-related protein phosphatase in Saccharomyces cerevisiae involved in a wide spectrum of cellular functions, including the glucose repression of mitochondrial transcription. Here we report that Sit4p is also involved in post-translational regulation of mitochondrial proteins and identified 9 potential targets. One of these, the ATP synthase (FoF1 complex) beta subunit Atp2p, was characterized and two phosphorylation sites, T124 and T317, were identified. Expression of Atp2p-T124 or T317 phosphoresistant versions in sit4Delta cells decreased Atp2p phosphorylation confirming these as Sit4p regulated sites. Moreover, Sit4p and Atp2p interacted both physically and genetically. Mimicking phosphorylation at T124 or T317 increased Atp2p levels, resulting in higher abundance/activity of ATP synthase. Similar changes were observed in sit4Delta cells in which Atp2p is endogenously more phosphorylated. Expression of Atp2-T124 or T317 phosphomimetics also increased mitochondrial respiration and ATP levels and extended yeast lifespan. These results suggest that Sit4p-mediated dephosphorylation of Atp2p-T124/T317 downregulates Atp2p alongside with ATP synthase and mitochondrial function. Combination of transcriptional with post-translational regulation during fermentative growth may allow for a more efficient Sit4p repression of mitochondrial respiration. PMID- 29719210 TI - Cell encapsulation: Overcoming barriers in cell transplantation in diabetes and beyond. AB - Cell-based therapy is emerging as a promising strategy for treating a wide range of human diseases, such as diabetes, blood disorders, acute liver failure, spinal cord injury, and several types of cancer. Pancreatic islets, blood cells, hepatocytes, and stem cells are among the many cell types currently used for this strategy. The encapsulation of these "therapeutic" cells is under intense investigation to not only prevent immune rejection but also provide a controlled and supportive environment so they can function effectively. Some of the advanced encapsulation systems provide active agents to the cells and enable a complete retrieval of the graft in the case of an adverse body reaction. Here, we review various encapsulation strategies developed in academic and industrial settings, including the state-of-the-art technologies in advanced preclinical phases as well as those undergoing clinical trials, and assess their advantages and challenges. We also emphasize the importance of stimulus-responsive encapsulated cell systems that provide a "smart and live" therapeutic delivery to overcome barriers in cell transplantation as well as their use in patients. PMID- 29719208 TI - Functional importance of Glutamate-445 and Glutamate-99 in proton-coupled electron transfer during oxygen reduction by cytochrome bd from Escherichia coli. AB - The recent X-ray structure of the cytochrome bd respiratory oxygen reductase showed that two of the three heme components, heme d and heme b595, have glutamic acid as an axial ligand. No other native heme proteins are known to have glutamic acid axial ligands. In this work, site-directed mutagenesis is used to probe the roles of these glutamic acids, E445 and E99 in the E. coli enzyme. It is concluded that neither glutamate is a strong ligand to the heme Fe and they are not the major determinates of heme binding to the protein. Although very important, neither glutamate is absolutely essential for catalytic function. The close interactions between the three hemes in cyt bd result in highly cooperative properties. For example, mutation of E445, which is near heme d, has its greatest effects on the properties of heme b595 and heme b558. It is concluded that 1) O2 binds to the hydrophilic side of heme d and displaces E445; 2) E445 forms a salt bridge with R448 within the O2 binding pocket, and both residues play a role to stabilize oxygenated states of heme d during catalysis; 3) E445 and E99 are each protonated accompanying electron transfer to heme d and heme b595, respectively; 4) All protons used to generate water within the heme d active site come from the cytoplasm and are delivered through a channel that must include internal water molecules to assist proton transfer: [cytoplasm] -> E107 -> E99 (heme b595) -> E445 (heme d) -> oxygenated heme d. PMID- 29719211 TI - Enzyme-free isothermal target-recycled amplification combined with PAGE for direct detection of microRNA-21. AB - MicroRNA-21 (miR-21) has been regarded as a kind of potential biomarker in several types of cancers. Herein, in this study, a simple, sensitive and cost effective miR-21 approach was developed utilizing the isothermal target-recycled enzyme-free amplification strategy and polyacrylamide gel electrophoresis (PAGE). In the target-recycled enzyme-free amplification strategy, two rational designed hairpin probes (HPs, HP1 and HP2) can form into HP1-HP2 duplex in the presence of miR-21 under the isothermal condition, producing target signal in PAGE. The sensitivity and the linear range of miR-21 approach were demonstrated by the in vitro detection of miR-21, with the detection limit of 10 pM and the linear range of 50 pM to 8 nM. In particular, the contents of miR-21 in cell extractions of different cell lines were successfully detected through miR-21 approach and the relative expression was highly coincident with the results of stem-loop RT-PCR approach. In summary, the developed approach can detect miR-21 sensitively and easily. PMID- 29719207 TI - The intricate role of selenium and selenoproteins in erythropoiesis. AB - Selenium (Se) is incorporated as the 21st amino acid selenocysteine (Sec) into the growing polypeptide chain of proteins involved in redox gatekeeper functions. Erythropoiesis presents a particular problem to redox regulation as the presence of iron, heme, and unpaired globin chains lead to high levels of free radical mediated oxidative stress, which are detrimental to erythroid development and can lead to anemia. Under homeostatic conditions, bone marrow erythropoiesis produces sufficient erythrocytes to maintain homeostasis. In contrast, anemic stress induces an alternative pathway, stress erythropoiesis, which rapidly produces new erythrocytes at extramedullary sites, such as spleen, to alleviate anemia. Previous studies suggest that dietary Se protects erythrocytes from such oxidative damage and the absence of selenoproteins causes hemolysis of erythrocytes due to oxidative stress. Furthermore, Se deficiency or lack of selenoproteins severely impairs stress erythropoiesis exacerbating the anemia in rodent models and human patients. Interestingly, erythroid progenitors develop in close proximity with macrophages in structures referred to as erythroblastic islands (EBIs), where macrophage expression of selenoproteins appears to be critical for the expression of heme transporters to facilitate export of heme from macrophage stores to the developing erythroid cells. Here we review the role of Se and selenoproteins in the intrinsic development of erythroid cells in addition to their role in the development of the erythropoietic niche that supports the functional role of EBIs in erythroid expansion and maturation in the spleen during recovery from anemia. PMID- 29719212 TI - Reply to: "Response to: Positron emission tomography/computed tomography with 18F fluorocholine improve tumor staging and treatment allocation in patients with hepatocellular carcinoma". PMID- 29719213 TI - Novel role of forkhead box O 4 transcription factor in cancer: Bringing out the good or the bad. AB - Forkhead box O (FOXO) family has recently been highlighted as important transcriptional regulators associated with many diverse carcinomas. Although redundant functionality between FOXO family members with cancer is known, regulatory ability of FOXO4 for tumorigenesis and tumor metastasis is still on the way. FOXO4 significantly regulates cell cycle, resists oxidative stress, and responses to hypoxia. FOXO4 alteration is closely linked to the progression of human cancer. In this review, we introduce the regulation of FOXO4 in physiological and pathological conditions. Particularly, the pathophysiological processes and molecular pathways regulated by FOXO4 in the development and progression of cancer are also summarized. Moreover, whether FOXO4 acts as a tumor-suppressor or pro-tumoral factor in tumors and the potential directions of future FOXO4 research are discussed. The information reviewed here may assist in the experimental design and increase the potential of FOXO4 as a therapeutic target for cancer. PMID- 29719214 TI - First echinoderm trehalase from a tropical sea cucumber (Holothuria leucospilota): Molecular cloning and mRNA expression in different tissues, embryonic and larval stages, and under a starvation challenge. AB - Trehalases are a group of enzymes that catalyse the conversion of trehalose to glucose, and they are observed in most organisms. In this study, the first echinoderm trehalase, designated Hl-Tre, was identified from a tropical sea cucumber, Holothuria leucospilota. The full-length cDNA of H. leucospilota trehalase (Hl-Tre) is 2461 bp in length with an open reading frame (ORF) of 1788 bp that encodes a 595-amino-acid protein with a deduced molecular weight of 67.95 KDa. The Hl-Tre protein contains a signal peptide at the N-terminal and a functional trehalase domain, which includes the signature motifs 1 and 2. The mRNA expression of Hl-Tre was ubiquitously detected in all selected tissues, with the highest level being detected in the intestine. By in situ hybridization (ISH), the positive Hl-Tre signals were observed in the brush borders of the intestinal mucosa. In embryonic and larval stages, the transcript levels of Hl Tre decreased during embryonic development and increased after the pentactula stage. After a challenge of starvation, the intestinal Hl-Tre mRNA levels were observed to be first decreased and partially recovered thereafter. Overall, our study provided the first evidence for trehalase in echinoderms and showed that this enzyme was potentially linked to a trehalose metabolic pathway in sea cucumbers. PMID- 29719215 TI - Rewiring FadR regulon for the selective production of omega-hydroxy palmitic acid from glucose in Escherichia coli. AB - omega-Hydroxy palmitic acid (omega-HPA) is a valuable compound for an ingredient of artificially synthesized ceramides and an additive for lubricants and adhesives. Production of such a fatty acid derivative is limited by chemical catalysis, but plausible by biocatalysis. However, its low productivity issue, including formations of unsaturated fatty acid (UFA) byproducts in host cells, remains as a hurdle toward industrial biological processes. In this study, to achieve selective and high-level production of omega-HPA from glucose in Escherichia coli, FadR, a native transcriptional regulator of fatty acid metabolism, and its regulon were engineered. First, FadR was co-expressed with a thioesterase with a specificity toward palmitic acid production to enhance palmitic acid production yield, but a considerable quantity of UFAs was also produced. In order to avoid the UFA production caused by fadR overexpression, FadR regulon was rewired by i) mutating FadR consensus binding sites of fabA or fabB, ii) integrating fabZ into fabI operon, and iii) enhancing the strength of fabI promoter. This approach led to dramatic increases in both proportion (48.3 83.0%) and titer (377.8 mg/L to 675.8 mg/L) of palmitic acid, mainly due to the decrease in UFA synthesis. Introducing a fatty acid omega-hydroxylase, CYP153A35, into the engineered strain resulted in a highly selective production of omega-HPA (83.5 mg/L) accounting for 87.5% of total omega-hydroxy fatty acids. Furthermore, strategies, such as i) enhancement in CYP153A35 activity, ii) expression of a fatty acid transporter, iii) supplementation of triton X-100, and iv) separation of the omega-HPA synthetic pathway into two strains for a co-culture system, were applied and resulted in 401.0 mg/L of omega-HPA production. For such selective productions of palmitic acid and omega-HPA, the rewiring of FadR regulation in E. coli is a promising strategy to develop an industrial process with economical downstream processing. PMID- 29719216 TI - Hybrid nanoparticle-based nicotine nanovaccines: Boosting the immunological efficacy by conjugation of potent carrier proteins. AB - A series of hybrid nanoparticle-based nicotine nanovaccines (NanoNicVac) were engineered in this work by conjugating potent carrier protein candidates (Keyhole limpet hemocyanin (KLH) multimer, KLH subunit, cross-reactive material 197 (CRM197), or tetanus toxoid (TT)) for enhanced immunological efficacy. NanoNicVac with CRM197 or TT were processed by dendritic cells more efficiently than that with KLH multimer or subunit. NanoNicVac carrying CRM197 or TT exhibited a significantly higher immunogenicity against nicotine and a considerably lower immunogenicity against carrier proteins than NanoNicVac carrying KLH multimer or subunit in mice. The in vivo results revealed that NanoNicVac with CRM197 or TT resulted in lower levels of nicotine in the brain of mice after nicotine challenge. All findings suggest that an enhanced immunological efficacy of NanoNicVac can be achieved by using CRM197 or TT instead of KLH or KLH subunit as carrier proteins, making NanoNicVac a promising next-generation immunotherapeutic candidate against nicotine addiction. PMID- 29719217 TI - Effect of laser fluence, nanoparticle concentration and total energy input per cell on photoporation of cells. AB - Intracellular delivery of molecules can be increased by laser-exposure of carbon black nanoparticles to cause photoporation of the cells. Here we sought to determine effects of multiple laser exposure parameters on intracellular uptake and cell viability with the goal of determining a single unifying parameter that predicts cellular bioeffects. DU145 human prostate cancer cells in suspension with nanoparticles were exposed to near-infrared nanosecond laser pulses over a range of experimental conditions. Increased bioeffects (i.e., uptake and viability loss determined by flow cytometry) were seen when increasing laser fluence, number of pulses and nanoparticle concentration, and decreasing cell concentration. Bioeffects caused by different combinations of these four parameters were generally predicted by their cumulative energy input per cell, which served as a unifying parameter. This indicates that photoporation depends on what appears to be the cumulative effect of multiple cell-nanoparticle interactions from neighboring nanoparticles during a series of laser pulses. PMID- 29719218 TI - Formulation and optimization of pH sensitive drug releasing O/W emulsions using Albizia lebbeck L. seed polysaccharide. AB - Smart polymers, one of the class of polymers with extensive growth in the last few decades due to their wide applications in drug targeting and controlled delivery systems. With this in mind, the aim of the present study is to design and formulate smart releasing o/w emulsion by using Albizia lebbeck L. seed polysaccharide (ALPS). For this purpose, the physicochemical and drug release characteristics like emulsion capacity (EC), emulsion stability (ES), viscosity, microscopy, zeta potential, polydispersity index (PDI) and in-vitro drug release were performed. The EC and ES values were found to increase with an increased concentration of ALPS. The emulsion formulations were statistically designed by using 32 full factorial design. All the emulsions showed a shear-thinning behavior. The zeta potential and polydispersity index were found to be in the range of -35.83 mV to -19.00 mV and 0.232-1.000 respectively. Further, the percent cumulative drug release of the emulsions at 8 h was found to be in the range of 30.19-82.65%. The drug release profile exhibited zero order release kinetics. In conclusion, the ALPS can be used as a natural emulsifier and smart polymer for the preparation of pH sensitive emulsions in drug delivery systems. PMID- 29719219 TI - Deriving a clinical prediction rule to target sexual healthcare to women attending British General Practices. AB - Some women attending General Practices (GPs) are at higher risk of unintended pregnancy (RUIP) and sexually transmitted infections (STI) than others. A clinical prediction rule (CPR) may help target resources using psychosocial questions as an acceptable, effective means of assessment. The aim was to derive a CPR that discriminates women who would benefit from sexual health discussion and intervention. Participants were recruited to a cross-sectional survey from six GPs in a city in South-East England in 2016. On arrival, female patients aged 16-44 years were invited to complete a questionnaire that addressed psychosocial factors, and the following self-reported outcomes: 2+ sexual partners in the last year (2PP) and RUIP. For each sexual risk, psychosocial questions were retained from logistic regression modelling which best discriminated women at risk using the C-statistic. Sensitivity and specificity were established in consultation with GP staff. The final sample comprised N = 1238 women. 2PP was predicted by 11 questions including age, binge-drinking weekly, ever having a partner who insulted you often, current smoking, and not cohabiting (C-statistic = 0.83, sensitivity = 73% and specificity = 77%). RUIP was predicted by 5 questions including sexual debut <16 years, and emergency contraception use in the last 6 months (C-statistic = 0.70, sensitivity = 69% and specificity = 57%). 2PP was better discriminated than RUIP but neither to a clinically-useful degree. The finding that different psychosocial factors predicted each outcome has implications for prevention strategies. Further research should investigate causal links between psychosocial factors and sexual risk. PMID- 29719220 TI - Access to US primary care physicians for new patients concerned about smoking or weight. AB - Tobacco smoking and obesity are leading causes of preventable morbidity and mortality in the US, and primary care physicians are the main source of preventive care. However, it is not known whether access for new patients is affected by an expression of interest in preventive care. In a 2015 audit, we called US primary care physicians' offices to request appointment information regarding new patient physicals for simulated patients. Simulated patients were differentiated by smoking concerns (N = 907), weight concerns (N = 867), or no health concerns ("healthy" patients; N = 3561). Additionally, patient profiles varied by race/ethnicity, sex, and insurance type. We also examined whether access differed in states that expanded Medicaid under the Affordable Care Act. We found that physicians' offices were no more likely to offer appointments to patients with smoking concerns than to healthy patients (54% vs. 55%; p-value = 0.56), and patients with smoking concerns were offered fewer appointments than patients with weight concerns (54% vs. 62%, p-value < 0.01). In analyses adjusted for covariates, smoking concerns did not improve appointment offers for any patient group, and reduced Medicare patients' offers in Medicaid expansion states by 9 percentage points relative to healthy patients (95% CI: -16, -2). Health concerns did not statistically significantly affect waits-to-appointment. Our results suggest that patients with smoking concerns are no more likely to be offered new patient appointments than those with no health concerns. The greater likelihood of appointment offers for some patients with weight concerns is encouraging for obesity prevention and management. PMID- 29719221 TI - The quality of nutrition and physical activity environments of child-care centers across three states in the southern U.S. AB - This cross-sectional study assessed the quality of nutrition and physical activity environments of child-care centers in three southern states and examined differences by rural versus urban location, participation in the Child and Adult Care Food Program, and Head Start status. The sample included 354 centers that enroll children aged 2-5: 154 centers from Georgia, 103 from Kentucky, and 97 centers from Mississippi. Directors and 1-2 teachers per center completed the Environment and Policy Assessment and Observation Self-Report (EPAO-SR) tool that assesses nutrition and physical activity environments of child-care centers. The EPAO-SR items were scored to capture six nutrition domains and six physical activity domains that were averaged and then summed to create a combined nutrition and physical activity environment score (range = 0-36); higher scores indicated that centers met more best practices, which translated to higher quality environments. Overall, the centers had an average combined nutrition and physical activity environment score of 20.2 out of 36. The scores did not differ between rural and urban centers (mean = 20.3 versus 20.2, p = 0.98). Centers in the Child and Adult Care Food Program had higher combined nutrition and physical activity environment scores than non-participating centers (mean = 20.6 versus 19.1, p < 0.01). Head Start centers also had higher combined environment scores than non-Head Start centers (mean = 22.3 versus 19.6, p < 0.01). Findings highlight the vital role of federal programs in supporting healthy child-care environments. Providing technical assistance and training to centers that are not enrolled in well-regulated, federally-funded programs might help to enhance the quality of their nutrition and physical activity environments. PMID- 29719223 TI - The Transient Receptor Potential Ankyrin Type 1 Plays a Critical Role in Cortical Spreading Depression. AB - The transient receptor potential ankyrin type-1 (TRPA1) channels have been proposed as a potential target for migraine therapy. Yet the role of cortical TRPA1 channels in migraine mechanism has not been fully understood. Cortical spreading depression (CSD) is known as an underlying cause of migraine aura. The aim of this study is to investigate if cortical TRPA1 activity is required for CSD genesis and propagation. A mouse brain slice CSD model with intrinsic optical imaging was applied for TRPA1 signaling pharmacology. The results showed that the TRPA1 agonist, umbellulone, facilitated the propagation of submaximal CSD. Correspondingly, an anti-TRPA1 antibody and two selective TRPA1 antagonists, A967079 and HC-030031, prolonged the CSD latency and reduced magnitude, indicating a reduced cortical susceptibility to CSD under TRPA1 deactivation. Furthermore, the TRPA1 agonist, allyl-isothiocyanate (AITC), reversed the suppression of CSD by HC-030031, but not by A967079. Interestingly, the inhibitory action of A967079 on CSD was reversed by exogenous calcitonin-gene related peptide (CGRP). Consistent to TRPA1 deactivation, the prolonged CSD latency was observed by an anti-CGRP antibody in the mouse brain slice, which was reversed by exogenous CGRP. We conclude that cortical TRPA1 is critical in regulating cortical susceptibility to CSD, which involves CGRP. The data strongly suggest that deactivation of TRPA1 channels and blockade of CGRP would have therapeutic benefits in preventing migraine with aura. PMID- 29719222 TI - Biomarkers of exposure to stainless steel tungsten inert gas welding fumes and the effect of exposure on exhaled breath condensate. AB - The respiratory tract is the main target organ of the inhaled hexavalent chromium (Cr-VI) and nickel (Ni) contained in stainless steel (SS) welding fumes (WFs). The aim of this study was to investigate the Cr and Ni content of the exhaled breath condensate (EBC) of SS tungsten inert gas (TIG) welders, and relate their concentrations with oxidative stress and inflammatory biomarkers. EBC and urine from 100 SS TIG welders were collected pre-(T0) and post-shift (T1) on a Friday, and pre-shift (T2) on the following Monday morning. Both EBC and urinary Cr concentrations were higher at T1 (0.08 MUg/L and 0.71 MUg/g creatinine) and T0 (0.06 MUg/L and 0.74 MUg/g creatinine) than at T2 (below the limit of detection [LOD] and 0.59 MUg/g creatinine), and EBC Ni concentrations generally remained =3 months by patients participating in clinical trials of the RNS(r) System were identified. Such "AED Starts" that produced an additional >=50% reduction in patient-reported clinical seizure frequency were categorized as clinically beneficial, and the remaining as not beneficial. Electrocorticographic features recorded by the RNS(r) Neurostimulator were analyzed during three periods: 3 months before the AED Start, first month after the AED Start, and the first 3 months after the AED Start. RESULTS: The most commonly added medications were clobazam (n = 41), lacosamide (n = 96), levetiracetam (n = 31), and pregabalin (n = 25). Across all four medications, there were sufficient clinical data for 193 AED Starts to be included in the analyses, and 59 AED Starts were considered clinically beneficial. The proportion of AED Starts that qualified as clinically beneficial was higher for clobazam (53.7%) and levetiracetam (51.6%) than for lacosamide (18.8%) and pregabalin (12%). Across all AED Starts for which RNS ECoG detection settings were held constant, the clinically beneficial AED Starts were associated with a significantly greater reduction in the detection of epileptiform activity (p < 0.001) at 1 (n = 33) and 3 months (n = 30) compared with AED Starts that were not beneficial at 1 (n = 71) and 3 months (n = 60). Furthermore, there was a significant reduction in interictal spike rate and spectral power (1-125 Hz) associated with a clinically beneficial response to an AED Start at 1 (n = 32) and 3 months (n = 35) (p < 0.001). These reductions were not observed at either 1 (n = 59) or 3 months (n = 60) for AED Starts that were not clinically beneficial. CONCLUSIONS: Significant quantitative changes in ECoG data recorded by the RNS System were observed in patients who experienced an additional clinical response to a new AED. While there was variability across patients in the changes observed, the results suggest that quantitative ECoG data may provide useful information when assessing whether a patient may have a favorable clinical response to an AED. PMID- 29719279 TI - Historical trends and the long-term changes of the hydrological cycle components in a Mediterranean river basin. AB - Identifying the historical hydrometeorological trends in a river basin is necessary for understanding the dominant interactions between climate, human activities and local hydromorphological conditions. Estimating the hydrological reference conditions in a river is also crucial for estimating accurately the impacts from human water related activities and design appropriate water management schemes. In this effort, the output of a regional past climate model was used, covering the period from 1660 to 1990, in combination with a dynamic, spatially distributed, hydrologic model to estimate the past and recent trends in the main hydrologic parameters such as overland flow, water storages and evapotranspiration, in a Mediterranean river basin. The simulated past hydrologic conditions (1660-1960) were compared with the current hydrologic regime (1960 1990), to assess the magnitude of human and natural impacts on the identified hydrologic trends. The hydrological components of the recent period of 2008-2016 were also examined in relation to the impact of human activities. The estimated long-term trends of the hydrologic parameters were partially assigned to varying atmospheric forcing due to volcanic activity combined with spontaneous meteorological fluctuations. PMID- 29719280 TI - The environmental footprint of an organic peri-urban orchard network. AB - Over the past years, the implementation of urban and peri-urban orchards in cities has increased and so has the environmental awareness regarding these systems. This study applied the environmental extended multi-regional input output analysis to obtain the Environmental Footprint associated with an organic peri-urban orchard network in Spain. The total environmental impacts were calculated for seven organic peri-urban orchards identified as PUO1 to PUO7. PUO1, PUO4 and PUO6 presented the highest environmental impacts due to a higher consumption of (1) fuel, (2) plastics and (3) electricity in comparison to the other orchards. Approximately 70% of the overall impacts were indirect impacts generated in the supply chain. A more in-depth study of climate change impacts in the supply chain of the organic peri-urban orchard network revealed that the major hotspots were the sectors "extraction of crude petroleum" (29%) and "production of electricity by gas and coal" (31%) located in Spain, China and Middle East countries. The Environmental Footprint serves as a useful indicator to provide the environmental performance of an organic peri-urban orchard network and foster greener and more sustainable cities. PMID- 29719281 TI - Expression of Nrf2 Promotes Schwann Cell-Mediated Sciatic Nerve Recovery in Diabetic Peripheral Neuropathy. AB - BACKGROUND/AIMS: High glucose-induced oxidative stress and inflammatory responses play an important role in painful diabetic neuropathy by activating the TLR4/NFkappaB signal pathway. Schwann cells (SCs) are integral to peripheral nerve biology, contributing to saltatory conduction along axons, nerve and axon development, and axonal regeneration. SCs provide a microenvironment favoring vascular regeneration but their low survival ratio in hyperglycemic conditions suppress the function to promote nerve growth. Nuclear factor erythroid 2-related factor 2 (Nrf2) promotes remyelination after peripheral nerve injury. The aim of this study was to identify the role of Nrf2 in SC-mediated functional recovery after sciatic nerve injury. METHODS: We compared plasma inflammatory factors in diabetic patients (DN) with/without diabetic peripheral neuropathy (DPN) and assessed whether Nrf2 expression in SCs could repair peripheral nerve injury in a rat model. Nrf2, TLR4/NFkappaB signal pathway and apoptosis relative protein expression were detected by western blot. Apoptosis and angiogenesis were determined by immunofluorescence and tubule formation assay, respectively. Regenerated nerves were determined by transmission electron microscope. RESULTS: Higher levels of inflammatory factors and VEGF expression were found in DPN patients. Cellular experiments indicate that Nrf2 expression inhibits hyperglycemia-induced apoptosis and promotes angiogenesis by regulating the TLR4/NFkappaB signal pathway. Animal experiments show that nerve conduction velocity, myelin sheath thickness, and sciatic vasa nervorum are restored with transplantation of SCs overexpressing Nrf2. CONCLUSIONS: Taken together, the high survival ratio of SCs in a DPN rat model indicates that overexpression of Nrf2 restores nerve injury. PMID- 29719282 TI - Intravenously Delivered Allogeneic Mesenchymal Stem Cells Bidirectionally Regulate Inflammation and Induce Neurotrophic Effects in Distal Middle Cerebral Artery Occlusion Rats Within the First 7 Days After Stroke. AB - BACKGROUND/AIMS: Neurotrophic effects and immunosuppression are the main therapeutic mechanisms of mesenchymal stem cells (MSCs) in stroke treatment. Neurotrophins are produced by graft cells, host neurons, astrocytes, and even microglia/macrophages. Meanwhile, MSCs can increase inflammation if they are not sufficiently induced by pro-inflammatory cytokines. We examined whether intravenously transplanted bone marrow MSCs (BM-MSCs) increase inflammation in distal middle cerebral artery occlusion (dMCAO) rats, how long the increased inflammation effect persists for, and what the final therapeutic outcomes will be. We also tested the neurotrophic role of BM-MSCs and attempted to identify the neurotrophin-producing cells. METHODS: At 1 h after dMCAO was performed on Sprague-Dawley rats, allogeneic BM-MSCs were transplanted intravenously. The infarct volume was examined by Tetrazolium Red staining at 2 days (day 2), and the behavioral tests (cylinder test and grid walking test) were performed at 2, 4 (day 4) and 7 days (day 7) after transplantation. The concentrations of inflammation related cytokines and neurotrophins in the ischemic cortex, ipsilateral striatum, and serum, were measured using ELISA at days 2-7. The cell source of neurotrophins was observed by immunohistochemistry. RESULTS: The transplanted cells were mainly found in the infarct border zone (IBZ) of the brain. Infarct volume was reduced and behavioral outcomes were improved at 2 days after ischemia. In the striatum and circulation, BM-MSC transplantation increased inflammation at day 2 and decreased it at day 7. At days 2-7, insulin-like growth factor-1 (IGF-1) and brain-derived neurotrophic factor (BDNF) concentrations in the ischemic core of the cortex were significantly higher in the BM-MSC group than in the ischemia vehicle group. IGF-1 and BDNF were derived mainly from host microglia/macrophages in the ischemic core, and transplanted cells in the IBZ. At day 2, BM-MSC transplantation significantly increased the number of IGF-1+CD68+ and BDNF+Iba-1+ double positive cells in the ischemic core cortex. CONCLUSIONS: Although increased inflammation, BM-MSCs were still beneficial to dMCAO recovery at day 2. The immunopromoting effect of MSCs was transient and shifted to an immunosuppressive action at day 7. The neurotrophic factors IGF-1 and BDNF, which were mainly derived from transplanted BM-MSCs and host microglia/macrophages, contributed to the therapeutic effects from day 2 to day 7. PMID- 29719283 TI - Performance of Phonatory Deviation Diagrams in Synthesized Voice Analysis. AB - OBJECTIVE: To analyze the performance of a phonatory deviation diagram (PDD) in discriminating the presence and severity of voice deviation and the predominant voice quality of synthesized voices. METHOD: A speech-language pathologist performed the auditory-perceptual analysis of the synthesized voice (n = 871). The PDD distribution of voice signals was analyzed according to area, quadrant, shape, and density. RESULTS: Differences in signal distribution regarding the PDD area and quadrant were detected when differentiating the signals with and without voice deviation and with different predominant voice quality. Differences in signal distribution were found in all PDD parameters as a function of the severity of voice disorder. CONCLUSION: The PDD area and quadrant can differentiate normal voices from deviant synthesized voices. There are differences in signal distribution in PDD area and quadrant as a function of the severity of voice disorder and the predominant voice quality. However, the PDD area and quadrant do not differentiate the signals as a function of severity of voice disorder and differentiated only the breathy and rough voices from the normal and strained voices. PDD density is able to differentiate only signals with moderate and severe deviation. PDD shape shows differences between signals with different severities of voice deviation. PMID- 29719284 TI - Characterization of Helicobacter pylori-Naive Early Gastric Cancers. AB - AIM: Helicobacter pylori-naive gastric cancers(GCs) have not been well documented. We aimed to characterize early H. pylori-naive GCs. SUBJECTS AND METHODS: Of 666 patients with GC resected by endoscopic submucosal dissection, H. pylori-naive patients were extracted according to the definition: no H. pylori eradication history, negative for serum H. pylori-antibody and current H. pylori infection tests, and no gastric atrophy by pepsinogen (PG) test, endoscopy, and histology. RESULTS: It was found that 16 GCs were H. pylori-naive, and classified into undifferentiated and differentiated type adenocarcinoma. All 9 undifferentiated type GCs were pale, depressed, mucosal pure signet ring cell adenocarcinoma except one of them and 7 differentiated type GCs were classified into 3 fundic gland type GCs and 4 foveolar type GCs. All fundic gland type GCs positive for PG-1 were cardia small submucosal tumor (SMT)-like protrusions with dilated vessels on the surface. All 4 foveolar type GCs were composed of dysplastic clear cells resembling foveolar epithelium, negative for PG-1 but positive for mucin 6 (MUC6) and MUC5AC. Endoscopically, all were laterally spreading elevations with papillary or villous surface. CONCLUSIONS: H. pylori naive GCs were infrequent at 2.5%, and classified into 3 types: a small pale depression of signet ring cell adenocarcinoma, a small SMT-like protrusion of fundic gland type GC, and a large laterally spreading elevation of foveolar type GC. PMID- 29719285 TI - Myeloproliferative Neoplasms in Danish Twins. AB - OBJECTIVE: Myeloproliferative neoplasms (MPNs) are a heterogeneous group of diseases characterized by clonal hyperproliferation of immature and mature cells of the myeloid lineage. Genetic differences have been proposed to play a role in the development of MPNs. Monozygotic twin pairs with MPNs have been reported in a few case reports, but the MPN concordance pattern in twins remains unknown. METHOD: All twin pairs born in the period 1900-2010 were identified in the nationwide Danish Twin Registry. Only pairs with both twins alive on January 1, 1977, and those born thereafter were included to allow identification in the Danish National Patient Registry. RESULTS: A total of 158 twin pairs were registered with an MPN diagnosis: 36 monozygotic, 104 dizygotic, and 18 pairs with unknown zygosity. MPNs were diagnosed in both twins in 4 pairs. The probandwise concordance rates for monozygotic twin pairs were higher than for dizygotic twin pairs (15 vs. 0%; p = 0.016). CONCLUSION: An estimated concordance rate of 15% (95% CI 0.059-0.31) is modest, but given the rarity of MPNs this finding is clinically relevant and provides further support for the role of genetic predisposition in the development of MPNs. PMID- 29719286 TI - Serial Assessment of Growth Factors Associated with Liver Regeneration in Patients Operated with Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy. AB - BACKGROUND: There is limited knowledge about the mechanisms behind the unparalleled growth of the future liver remnant (FLR) linked to associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). In this study, liver regenerative markers were examined in patients subjected to ALPPS. METHODS: Ten patients with colorectal liver metastases treated with neoadjuvant chemotherapy and ALPPS were included. Plasma was sampled at 6 time points and biopsies from both liver lobes were collected at both stages of ALPPS. The levels of interleukin (IL)-6, hepatocyte growth factor (HGF), tumor necrosis factor alpha, epidermal growth factor, and vascular endothelial growth factor in plasma were measured at each time point. Expression of mRNA for markers of proliferation and apoptosis was studied in the biopsies from both liver lobes taken at both stages. RESULTS: ALPPS resulted in a peak of IL-6 after stage 1 (p = 0.004), which decreased rapidly and did not increase again after stage 2. HGF also increased after stage 1 (p = 0.048), and the HGF levels correlated significantly with the degree of growth of the FLR before stage 2 (p = 0.02, r2 = 0.47). There was a correlation between peak levels of IL-6 and HGF (p = 0.03, r2 = 0.84). CONCLUSIONS: IL-6 and HGF seem to be early mediators of hypertrophy after stage 1 in the ALPPS procedure. The peak HGF plasma level correlates with the degree of FLR growth in patients subjected to ALPPS. PMID- 29719287 TI - Downregulation of RIF1 Enhances Sensitivity to Platinum-Based Chemotherapy in Epithelial Ovarian Cancer (EOC) by Regulating Nucleotide Excision Repair (NER) Pathway. AB - BACKGROUND/AIMS: Rap1 interacting factor 1 (RIF1) was deemed to be involved in replication timing regulation and DNA damage response. However, little is known about the role of RIF1 in malignancies. Thus, this study aimed to investigate whether the expression of RIF1 is relevant to the response of epithelial ovarian cancer (EOC) patients to cisplatin chemotherapy and its underlying mechanism. METHODS: Immunohistochemistry was used for detecting the expression of RIF1 in 72 human ovarian cancer tissues followed by association analysis of RIF1 expression with patients' responses to platinum-based chemotherapy. The survival analysis of ovarian patients based on platinum chemotherapy was analyzed using online databases. RNA interference of RIF1 was carried out in OVCAR3 and A2780 cell lines, to determine the effect of lacking RIF1 expression on cellular responses to cisplatin by using MTS assay. The nucleotide excision repair (NER) capacity of these cells was assessed by using host-cell reactivation and UV sensitivity assay. Western Blot analysis was carried out to determine the effect of RIF1 on the proteins of NER and apoptosis signaling pathway by using RIF1 knockdown cells. BALB/c nude mice model was used for detection of response to cisplatin in vivo. RESULTS: RIF1 expression was significantly associated with the response of ovarian patients to platinum-based chemotherapy (P< 0.01). In cohorts from online databases, high expression of RIF1 was associated with higher mortality of EOC patients based on platinum chemotherapy (P < 0.01). RIF1 knockdown increased sensitivity to cisplatin in EOC in vitro and in vivo. Deletion of RIF1 impaired the NER activity by inhibiting the NER proteins in ovarian cancer cells. Besides, knockdown of RIF1 enhanced cisplatin-induced apoptosis. CONCLUSIONS: RIF1 plays an important role in regulating the expression of NER proteins, which in turn contributes to cellular response to cisplatin and EOC patients' response to platinum-based chemotherapy. RIF1 knockdown also promotes cisplatin-induced apoptosis. RIF1 may serve as a novel biomarker for predicting platinum-based chemosensitivity and the prognosis of EOC patients. PMID- 29719288 TI - The Hypothalamic-Pituitary-Adrenal Axis: A Brief History. AB - The hypothalamic-pituitary-adrenal (HPA) axis is central to homeostasis, stress responses, energy metabolism, and neuropsychiatric function. The history of this complex system involves discovery of the relevant glands (adrenal, pituitary, hypothalamus), hormones (cortisol, corticotropin, corticotropin-releasing hormone), and the receptors for these hormones. The adrenal and pituitary were identified by classical anatomists, but most of this history has taken place rather recently, and has involved complex chemistry, biochemistry, genetics, and clinical investigation. The integration of the HPA axis with modern neurology and psychiatry has cemented the role of endocrinology in contemporary studies of behavior. PMID- 29719289 TI - The Effect of Minimally Invasive Surfactant Therapy on Diaphragmatic Activity. AB - BACKGROUND: Minimally invasive surfactant therapy (MIST) is increasingly used to treat preterm infants with respiratory distress syndrome (RDS). However, the effect of MIST on breathing effort is poorly studied. OBJECTIVES: To describe the effect of MIST on neural breathing effort assessed with transcutaneous electromyography of the diaphragm (dEMG) in preterm infants with RDS. METHODS: Preterm infants with a gestational age < 37 weeks treated with MIST for RDS were included. dEMG measurements were done from 15 min before to 1 h after MIST. The percentage change in dEMG activity after MIST and the clinical response were analyzed. RESULTS: Twenty preterm infants (mean gestational age 29.3 [SD 2.1] weeks; mean birth weight 1,230 [SD 391] g) were included. Seventeen infants did complete the 1-h measurement. Eleven (65%) infants had a decrease in their peakdEMG activity (median change -11.8% [IQR -26.8 to 5.8, p = 0.08]) 1 h after MIST. TonicdEMG activity decreased in 12 (71%) infants, with a median reduction of 6.3% (IQR -29.2 to 9.0, p = 0.07). FiO2 showed a rapid decrease following MIST (before, 0.47 [IQR 0.38-0.84]; 1 h after, 0.25 [IQR 0.21-0.30], p < 0.001). CONCLUSION: In addition to improved oxygenation, MIST results in a decrease in neural breathing effort measured by dEMG activity in the majority of preterm infants with RDS. PMID- 29719290 TI - Identification of a Novel Keratin 9 Missense Mutation in a Chinese Family with Epidermolytic Palmoplantar Keratoderma. AB - BACKGROUND/AIMS: Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant genodermatosis. It is characterized by diffuse yellow keratoses on the palmoplantar epidermis, with an erythematous border. The keratin 9 gene (KRT9) and less frequently the keratin 1 gene (KRT1) are responsible for EPPK. This study aims to identify and analyse genetic defects responsible for EPPK in a Han Chinese pedigree. METHODS: A four-generation Han Chinese pedigree containing five individuals affected with EPPK was recruited. Exome sequencing, Sanger sequencing, and bioinformatics tools were conducted to identify the mutation in this pedigree. HaCaT cells were transfected with either wild-type or mutated KRT9. Confocal laser immunofluorescence assay, imaging processing, and statistical analysis were performed to evaluate wild-type and mutant KRT9 groups. RESULTS: A novel heterozygous c.1369C>T transition (p.Leu457Phe) in exon 6 of the KRT9 gene was identified in four patients. It co-segregated with the disorder in the family. Functional analysis showed that withdrawal of the filament network from the cell periphery and particle formation were present in about 10% of Leu457Phe-transfected HaCaT cells, while approximately 3% of cells transfected with wild-type KRT9 showed this phenotype. The particles in mutant group were larger than that in wild-type group (P-value < 0.05). CONCLUSION: The variant may be the disease-causing missense mutation and produce dominant negative effects by interrupting keratin network formation. This study indicates the pathogenic role of the KRT9 gene mutation in this pedigree with EPPK, and may be helpful in genetic counseling, prenatal diagnosis and gene-targeted therapies of EPPK. PMID- 29719291 TI - Evaluating Otherwise-Discarded Umbilical Cord Blood as a Source for a Neonate's Complete Blood Cell Count at Various Time Points. AB - BACKGROUND: Previous studies have reported the use of cord blood for admission laboratory complete blood counts (CBCs). However, no studies have investigated its stability for the first 30 min after delivery. OBJECTIVES: We quantified blood cells drawn from the umbilical vein to determine the effect of (1) the time after placental delivery, and (2) the site of blood sampling (umbilical vein on an isolated cord segment vs. umbilical vein on the placental surface). METHODS: Timed phlebotomies were drawn at 2, 10, and 30 min from (1) the umbilical vein on an isolated, double-clamped cord segment, and (2) the umbilical vein near or on the placental surface. Leukocyte count, hemoglobin, platelet count, and fibrinogen were measured on each phlebotomy sample. RESULTS: Blood drawn from the isolated umbilical cord segments had leukocyte count, hemoglobin, platelet count, and fibrinogen that remained unchanged between the phlebotomies at 2, 10, and 30 min after delivery. However, blood drawn from the umbilical vein on the placental surface had, at 30 min, a leukocyte count (p = 0.002), hemoglobin (p = 0.01), and platelet count (p = 0.001) that were statistically different from the values at 2 and 10 min after delivery. There was no difference in fibrinogen at 2, 10, or 30 min. CONCLUSIONS: If cord blood is used for a neonate's initial CBC, the blood should be drawn within 10 min of the placental delivery when it is taken from the umbilical vein on or near the placenta. If an umbilical cord segment is obtained, the phlebotomy can be delayed for up to 30 min. PMID- 29719292 TI - MEGF6 Promotes the Epithelial-to-Mesenchymal Transition via the TGFbeta/SMAD Signaling Pathway in Colorectal Cancer Metastasis. AB - BACKGROUND/AIMS: Colorectal cancer (CRC) is a malignancy that has high morbidity and mortality and is initiated from accumulative genetic events. Although much effort has been made to elucidate the genetic mechanism underlying this disease, it still remains unknown. Here, we discovered a novel role for multiple epidermal growth factor-like domains protein 6 (MEGF6) in CRC, namely, that it induces the epithelial-to-mesenchymal transition (EMT) to promote CRC metastasis via the transforming growth factor beta (TGFbeta)/SMAD signaling pathway. METHODS: RNA sequencing data from the Gene Expression Omnibus database were analyzed using R software. Based on The Cancer Genome Atlas Colon Adenocarcinoma (TCGA-COAD) cohort, the clinical significance of MEGF6 was investigated. HCT8R, HCT116, and LoVo CRC cells were transfected with small interfering RNA against MEGF6, and their proliferation and sensitivity to fluorouracil were evaluated with the MTT cell proliferation and colony formation assays. Proteins associated with cell growth were detected by western blot analysis. The apoptosis of cells was evaluated by Annexin V/propidium iodide staining, and transwell assays were performed to assess the involvement of MEGF6 in cell migration. Markers of EMT and TGFbeta/SMAD signaling were evaluated by quantitative PCR and western blotting, and the correlation between MEGF6 and these markers was assessed in the TCGA colon and renal adenocarcinoma cohort. RESULTS: The results showed that MEGF6 was upregulated in HCT8R cells. In addition, MEGF6 was significantly overexpressed in tumor tissue and predicted a poor survival in the TCGA-COAD cohort. Moreover, MEGF6 accelerated CRC cell growth and inhibited apoptosis, and promoted CRC metastasis by inducing the EMT. Finally, we found that TGFbeta/SMAD signaling triggered the expression of Slug, which regulates the MEGF6-mediated EMT. CONCLUSIONS: MEGF6 may serve as an oncogene to promote cell proliferation and inhibit apoptosis. MEGF6 can also accelerate cell migration via TGFbeta/SMAD signaling-mediated EMT. PMID- 29719293 TI - PIK3R3 Promotes Metastasis of Pancreatic Cancer via ZEB1 Induced Epithelial Mesenchymal Transition. AB - BACKGROUND/AIMS: PIK3R3 is a regulatory subunit of phosphatidylinositol 3-kinase (PI3K) which plays an essential role in the metastasis of several types of cancer. However, whether PIK3R3 can promote the metastasis of pancreatic cancer (PC) is still unclear. In this study, we characterized the role of PIK3R3 in metastasis of PC and underlying potential mechanisms. METHODS: RT-PCR, western blot, immunofluorescence (IF) and immunohistochemistry (IHC) were applied to investigate the expression of genes and proteins in different cell lines and tissues. To assess the function of PIK3R3 and related mechanisms, the cells with RNAi-mediated knockdown or overexpression were used to perform a series of in vitro and in vivo assays. RESULTS: PIK3R3 was significantly overexpressed in pancreatic cancer tissues, especially in metastatic cancer tissues, as well as in pancreatic cancer cells. Functional assays suggested that overexpression or knockdown of PIK3R3 could respectively promote or suppress the migration and invasion of PC cells in vitro and in vivo. Further mechanism related studies demonstrated that ERK1/2-ZEB1 pathway-triggered epithelial-mesenchymal transition (EMT) might be responsible for the PIK3R3-induced PC cell migration and invasion. CONCLUSION: PIK3R3 could promote the metastasis of PC by facilitating ZEB1 induced EMT, and could act as a potential therapeutic target to limit PC metastasis. PMID- 29719294 TI - Preterm Glycosuria - New Data from a Continuous Glucose Monitoring System. AB - BACKGROUND: Careful control of glucose homeostasis is essential for infants with very low birth weight (VLBW). In clinical practice, blood and urine glucose levels are monitored; however, their correlation has not been fully investigated in VLBW infants. OBJECTIVES: To evaluate the correlation between interstitial fluid glucose concentration (ISFG), glycosuria, and urine output among VLBW infants through continuous glucose monitoring (CGM). METHODS: A prospective, single-center, open cohort study enrolled 74 VLBW infants with a mean birth weight of 1,066 g. CGM (Guardian Real-Time CGM(r); Medtronic, Northridge, CA, USA) was used to measure glucose. The urine output was calculated using 4-hour intervals. Reagent strips were used for semiquantitative measurement of glycosuria. RESULTS: The CGM delivered 102,334 glucose measurements. 2,684 urine samples were checked for glycosuria, of which 92.06% remained negative. Corresponding glycemia in samples without glycosuria remained normoglycemic (median 103 mg/dL; 10-90th percentile 80-144 mg/dL). The median glucose concentrations for samples in ascending glycosuria categories 1+, 2+, 3+, and 4+ were 152, 181, 214, and 222 mg/dL, respectively. A moderate correlation between ISFG and urine output was found for categories >=1+ (rs = 0.56; 95% confidence interval 0.42-0.68; p < 0.001). The urine output was significantly lower when glycosuria was absent (p < 0.05). Polyuria was observed only in glycosuria 4+ (median urine output 9.9; interquartile range 7.4-12.2 mL/kg/h). CONCLUSIONS: The renal glucose threshold in VLBW infants is between 150 and 180 mg/dL. A negative result for glycosuria is a reliable screening test to exclude hyperglycemia. Occurrence of glycosuria >=1+ is an indication to test blood glucose. PMID- 29719295 TI - Serum Exosomal MiR-92b-5p as a Potential Biomarker for Acute Heart Failure Caused by Dilated Cardiomyopathy. AB - BACKGROUND/AIMS: MicroRNAs (miRNAs) can be used as biomarkers for cardiovascular diseases, especially for heart failure. However, there are few reports on serum exosomal miRNA biomarkers in patients with acute heart failure (AHF) due to Dilated cardiomyopathy (DCM). METHODS: We analyzed 3 different serum exosomal miRNAs (exo-miR-92b-5p, exo-miR-192-5p, and exo-miR-320a) in 43 patients with DCM AHF and 34 healthy volunteers as a control group (CG) by using exosome separation followed by a quantitative reverse-transcript PCR assay. Exosomes were identified by electron microscopy, NaNOZS-90, and western blot analyses (CD63 and Hsp70). RESULTS: Serum exo-miR-92b-5p expression was increased in DCM-AHF patients compared to the CG (Mann-Whitney U-test: P < 0.001). Exo-miR-92b-5p was positively related to age and some ultrasound data (Spearman's correlation: exo miR-92b-5p vs. age, r = 0.297, P = 0.014; exo-miR-92b-5p vs. left atrial diameter, r = 0.431, P < 0.001; exo-miR-92b-5p vs. left ventricular diastolic diameter, r = 0.419, P < 0.001; exo-miR-92b-5p vs. left ventricular systolic diameter, r = 0.446, P < 0.001). Exo-miR-92b-5p was also negatively related to other ultrasound data (Spearman's correlation: exo-miR-92b-5p vs. left ventricular fraction shortening, r = -0.497, P < 0.001; exo-miR-92b-5p vs. left ventricular ejection fraction, r = -0.482, P < 0.001). The discrimination of DCM AHF patients from the CG by exo-miR-92b-5p was demonstrated by a receiver operating characteristic curve (exo-miR-92b-5p: cutoff value = 0.0023, area under the curve = 0.808, P < 0.001, sensitivity = 62.8%, specificity = 85.3%). CONCLUSION: Serum exo-miR-92b-5p is a potential biomarker for the diagnosis of DCM-AHF. PMID- 29719296 TI - Influence of Body Mass Index on Clinical Outcome Parameters, Complication Rate and Survival after Radical Cystectomy: Evidence from a Prospective European Multicentre Study. AB - : Background/Aims/Objectives: To evaluate the influence of body mass index (BMI) on complications and oncological outcomes in patients undergoing radical cystectomy (RC). METHODS: Clinical and histopathological parameters of patients have been prospectively collected within the "PROspective MulticEnTer RadIcal Cystectomy Series 2011". BMI was categorized as normal weight (<25 kg/m2), overweight (>=25-29.9 kg/m2) and obesity (>=30 kg/m2). The association between BMI and clinical and histopathological endpoints was examined. Ordinal logistic regression models were applied to assess the influence of BMI on complication rate and survival. RESULTS: Data of 671 patients were eligible for final analysis. Of these patients, 26% (n = 175) showed obesity. No significant association of obesity on tumour stage, grade, lymph node metastasis, blood loss, type of urinary diversion and 90-day mortality rate was found. According to the American Society of Anesthesiologists score, local lymph node (NT) stage and operative case load patients with higher BMI had significantly higher probabilities of severe complications 30 days after RC (p = 0.037). The overall survival rate of obese patients was superior to normal weight patients (p = 0.019). CONCLUSIONS: There is no evidence of correlation between obesity and worse oncological outcomes after RC. While obesity should not be a parameter to exclude patients from cystectomy, surgical settings need to be aware of higher short-term complication risks and obese patients should be counselled accordingly. PMID- 29719297 TI - Predicting Sequential Cochlear Implantation Performance: A Systematic Review. AB - This systematic review of the literature reveals which pre-operative factors affect sequential cochlear implantation outcomes in adults. The findings can help health care prof-essionals provide evidence-based advice on the expected benefits from a second cochlear implant (CI). We searched PubMed, EMBASE, and the Cochrane database from November 1977 to August 26, 2017, using the terms "sequential cochlear implantation"; the most frequently cited predictors for unilateral cochlear implantation performance and other potential predictors for sequential implantation outcome; and "speech perception," "localization" as well as synonyms of all of the above. Ten studies were included. The effects of age, duration of hearing loss, time between implantations, preoperative hearing, etiology of hearing loss, hearing aid use and duration of follow-up on sequential cochlear implantation performance were studied. The literature has shown that duration of deafness, age at onset of deafness, etiology of hearing loss, and preoperative speech perception score are (inversely) related to unilateral cochlear implantation outcome in adults. One would expect that these factors would also affect sequential bilateral implantation outcome. However, the best available evidence to date shows that advanced age, a long duration of deafness, or a long interval between implantations should not be considered negative factors when considering sequential bilateral cochlear implantation. PMID- 29719298 TI - Mesenchymal Stromal Cells to Regenerate Emphysema: On the Horizon? AB - Mesenchymal stem or stromal cells (MSCs) are multipotent cells that play a pivotal role in various phases of lung development and lung homeostasis, and potentially also lung regeneration. MSCs do not only self-renew and differentiate into renew tissues, but also have anti-inflammatory and paracrine properties to reduce damage and to support tissue regeneration, constituting a promising cell based treatment strategy for the repair of damaged alveolar tissue in emphysema. This review discusses the current state of the art regarding the potential of MSCs for the treatment of emphysema. The optimism regarding this treatment strategy is supported by promising results from animal models. Still, there are considerable challenges before effective stem cell treatment can be realized in emphysema patients. It is difficult to draw definitive conclusions from the available animal studies, as different models, dosage protocols, administration routes, and sources of MSCs have been used with different measures of effectiveness. Moreover, the regrowth potential of differentiated tissues and organs differs between species. Essential questions about MSC engraftment, retention, and survival have not been sufficiently addressed in a systematic manner. Few human studies have investigated MSC treatment for chronic obstructive pulmonary disease, demonstrating short-term safety but no convincing benefits on clinical outcomes. Possible explanations for the lack of beneficial effects on clinical outcomes could be the source (bone marrow), route, dosage, frequency of administration, and delivery (lack of a bioactive scaffold). This review will provide a comprehensive overview of the (pre)clinical studies on MSC effects in emphysema and discuss the current challenges regarding the optimal use of MSCs for cell-based therapies. PMID- 29719299 TI - Experience with One-Stage Repair of Urethral Strictures Using the Augmented Anastomotic Repair Technique. AB - INTRODUCTION: We report the results of augmented anastomotic repair (AAR) in the treatment of anterior urethral strictures. MATERIAL AND METHODS: In this retrospective study, we evaluated 71 consecutive patients who had undergone AAR between June 2004 and June 2013. Medical records were reviewed to identify early postoperative complications based on the Clavien-Dindo classification (CDC). Self developed standardized questionnaires sent to the patients and referring urologists were used to collect data on late complications (>90) days. Stricture recurrence (SR) was defined as any postoperative endoscopic or open surgical intervention on the urethra. The influence of patient demographics, stricture characteristics, and operative procedure performed on the occurrence of SR was analyzed. RESULTS: Early postoperative complications were rare events (11.3%) with only one severe CDC complication. Late complications were reported in 46.5% cases. At a median follow-up of 17 months (range 3-114 months), however, 64 patients had no evidence of SR and required no further intervention, giving an overall success rate of 90.1%. Seven patients with SR had a higher body mass index, were older, and had been operated on by less experienced surgeon(s). Most SRs occurred within the first year after surgery. CONCLUSIONS: AAR was an effective and safe operative technique that allowed one-stage repair in our patients with anterior urethral strictures who needed resection of the scarred urethra and otherwise were not suitable for primary anastomosis or simple substitution urethroplasty. PMID- 29719300 TI - Unfractionated Heparin Alleviates Human Lung Endothelial Barrier Dysfunction Induced by High Mobility Group Box 1 Through Regulation of P38-GSK3beta-Snail Signaling Pathway. AB - BACKGROUND/AIMS: The high mobility group box 1 (HMGB1) has been regarded as an important inflammatory mediator. Previous studies showed the involvement of HMGB1 protein in the dysfunction of endothelial barrier function during acute lung injury. However, the molecular mechanism remains unclear. METHODS: In this study, we used recombinant human HMGB1 (rhHMGB1) and HMGB1 plasmid to treat human pulmonary microvascular endothelial cell (HPMECs). We examined endothelial permeability by measuring TEER value and HRP flux. Western blot and real-time PCR were used to examined change of endothelial-to-mesenchymal transition (EndoMT) markers and related pathways. Immunofluorescence was used to examine localization and expression of ZO-1 and VE-cadherin. SB203580.was used to block p38 pathway. Unfractionated heparin (UFH) and RAGE siRNA were also used to antagonize the effect of HMGB1. RESULTS: We showed that HMGB1 induced EndoMT with downregulation of ZO-1 and VE-cadherin at both mRNA and protein levels in HPMECs. We also demonstrated that HMGB1 upregulated endothelial permeability by measuring TEER value and HRP flux. Moreover, HMGB1 activated p38/GSK3beta/Snail signaling pathway and treatment with p38 inhibitor SB203580 abolished its biological effects. In addition, we found that UFH was able to reverse the effect of HMGB1 on EndoMT and endothelial permeability through inhibition of p38 signaling in a dose-dependent manner. We discovered that RAGE, a membrane receptor of HMGB1, transduced p38/Snail pathway to EndoMT. RAGE siRNA inhibited the effect of HMGB1 induced EndoMT in HPMECs. CONCLUSION: The present study demonstrated that HMGB1 induced EndoMT through RAGE receptor and p38/GSK3beta/Snail pathway. While UFH antagonized HMGB1 and maintained the integrity of the endothelial barrier through p38 inhibition. PMID- 29719301 TI - Retrograde Intrarenal Surgery for Symptomatic Renal Sinus Cysts: Long-Term Results and Literature Review. AB - INTRODUCTION: To report the long-term multicenter experience with retrograde intrarenal holmium-laser incision (RIR-HoLI) in the management of symptomatic renal sinus cysts (RSCs). In the literature, RIR-HoLI has been shown to be a safe and effective treatment, but there are only a few reports regarding long-term results and reproducibility of this procedure. MATERIAL AND METHODS: From June 2010 to June 2015, 14 patients with symptomatic RSCs underwent RIR-HoLI. The mean age was 52.1 +/- 11.28 years (range 28-77) and the mean cyst size was 53.2 +/- 14.23 mm (range 35-90). In all cases, contrast-enhanced computer tomography (CT) showed compression of the renal pelvis by the cyst (no malignancy). Surgical outcome was assessed in terms of symptoms improvement (measured by Visual Analogue Scale [VAS] for pain) and renal ultrasound findings at 3-6-12 months postoperatively and then yearly. CT scan was carried out at 12 months follow-up. RESULTS: RIR-HoLI was successful in all patients. The mean operative time was 47.8 +/- 13.54 min (range 30-80) and mean hospital stay was 3.5 days (range 2-5). There were 2 Clavien grade II complications (flank pain and urgency delaying discharge). After surgery, all patients -became asymptomatic (VAS score change, p = 0.0001). One patient had persistence of a small cyst (10 mm). Mean follow-up is 44 +/- 17.24 months (range 24-84); all patients remained asymptomatic, with no signs of recurrence. CONCLUSIONS: RIR-HoLI proved to be a safe and effective treatment for symptomatic RSCs. In our experience, it provided excellent long term results and was reproducible at 4 different -institutions. PMID- 29719302 TI - A Randomized Phase II Open-Label Multi-Institution Study of the Combination of Bevacizumab and Erlotinib Compared to Sorafenib in the First-Line Treatment of Patients with Advanced Hepatocellular Carcinoma. AB - OBJECTIVES: To investigate the clinical efficacy and tolerability of the combination of bevacizumab (B) and erlotinib (E) compared to sorafenib (S) as first-line treatment for patients with advanced hepatocellular carcinoma (HCC). METHODS: A total of 90 patients with advanced HCC, Child-Pugh class A-B7 cirrhosis, and no prior systemic therapy were randomly assigned (1: 1) to receive either 10 mg/kg B intravenously every 14 days and 150 mg E orally daily (n = 47) (B+E) or 400 mg S orally twice daily (n = 43). The primary endpoint was overall survival (OS). Secondary endpoints included event-free survival (EFS), objective response rate based on Response Evaluation Criteria in Solid Tumors (RECIST 1.1), time to progression, and safety and tolerability. RESULTS: The median OS was 8.55 months (95% CI: 7.00-13.9) for patients treated with B+E and 8.55 months (95% CI: 5.69-12.2) for patients receiving S. The hazard ratio (HR) for OS was 0.92 (95% CI: 0.57-1.47). The median EFS was 4.37 months (95% CI: 2.99-7.36) for patients receiving B+E and 2.76 months (95% CI: 1.84-4.80) for patients receiving S. The HR for EFS was 0.67 (95% CI: 0.42-1.07; p = 0.09), favoring B+E over S. When OS was assessed among patients who were Child-Pugh class A, the median OS was 11.4 months (95% CI: 7.5-15.7) for patients treated with B+E (n = 39) and 10.26 months (95% CI: 5.9-13.0) for patients treated with S (n = 38) (HR = 0.88; 95% CI: 0.53 1.46). CONCLUSIONS: There was no difference in efficacy between the B+E and S arms, although the safety and tolerability profile tended to favor B+E over S based on competing risk analysis. PMID- 29719304 TI - Prognostic Value of Soluble Death Receptor Ligands in Patients with Transitional Cell Carcinoma of Bladder. AB - BACKGROUND: The activation of Fas/Fas ligand (FasL) and DR4-DR5/tumor necrosis factor-related-apoptosis-inducing ligand (TRAIL) pathways in cancer cells triggers apoptosis. The objective of this study was to investigate the prognostic value of soluble FasL (sFasL) and soluble (sTRAIL) in the serum of patients with bladder cancer. METHODS: The sFasL and sTRAIL levels in the sera of patients with bladder cancer or healthy donors were determined using the enzyme-linked immunosorbent assay. Micro-culture tetrazolium viability assay and Western blot were used to analyze cell cytotoxicity and death receptors protein expression respectively. RESULTS: Whether no difference in sTRAIL levels was seen between patients and controls, the level of sFasL was higher in patients than that in healthy donors. According to, sFasL level was the highest in the serum of patients with superficial stage or low- and medium-grade cancer. Moreover, sFasL in patients with superficial noninvasive bladder tumors or low- and medium-grade cancers was higher than that in patients with invasive carcinomas and high-grade cancers. Patients with high levels of sFasL survive longer than those with low levels, probably related to the cytotoxic potential of FasL preserved in its soluble form. CONCLUSION: The data suggest that monitoring the level of sFasL and its cytotoxic activity could be a prognostic marker in the follow-up of patients with bladder cancer. PMID- 29719303 TI - Acute Obstructive Hydrocephalus due to a Giant Posterior Cerebral Artery Aneurysm in a Pediatric Patient. AB - INTRODUCTION: Intracranial aneurysms are very rare in children. Although subarachnoidal hemorrhage (SAH) is by far the most common presentation of aneurysms in the majority of the pediatric case series, it is not rare for an unruptured aneurysm to present with a mass effect. Acute hydrocephalus is a common finding following aneurysmal SAH. However, this malady may develop even in the absence of SAH but secondary to direct obstruction by a giant aneurysm. This situation is extremely rare in children, with only a few known case reports in the literature. CASE REPORT: We report the case of a 10-year-old girl who presented with signs and symptoms of acute hydrocephalus; further radiological evaluation revealed obstructive hydrocephalus and a giant posterior cerebral artery aneurysm. Following endovascular treatment of the aneurysm, hydrocephalus was completely resolved, and the patient was symptom free. CONCLUSION: Although they are very rare, giant intracranial aneurysms must be kept in mind during the differential diagnosis of pediatric acute hydrocephalus cases. Hydrocephalus may resolve spontaneously after the successful treatment of these aneurysms. PMID- 29719305 TI - The Malversations of Authorship - Current Status in Academic Community and How to Prevent It. AB - Aim: Aim of article was to evaluate knowledge and practice of authorship issues among the academic population in the medical field. Material and methods: Article has an analytical character and includes 69 academic workers (from the medical field, with the status of a regular employee of the Faculty of Medicine or a professional associate) who responded to the survey. Results: Within the total number of respondents in the study, 34.8% of them were added as coauthors, although they did not have any input in the writing process. Even 47.8% of the respondents were under psychological pressure, that they have to add their superiors to the list of authors, though they did not have any contribution at any stage of the article preparation, while 29% of the respondents had a tacit agreement about mutual adding to the author's list, and 36.2% added their superiors to the author's list, in order that the first author would get a permission to publish the article in a certain journal. Conclusion: The relationship between the author, the mentor, the data processing person, the person providing the moral support etc. must be established, and not all of them has a place in the list of authors, they should be given special places at the end of the article, a space for acknowledgments, where these people may be mentioned. The consciousness of the academic community must change for the purpose of the concrete progress of the academic community and the scientific contributions of its members. PMID- 29719306 TI - Identifying the Factors Affecting Papers' Citability in the Field of Medicine: an Evidence-based Approach Using 200 Highly and Lowly-cited Papers. AB - Introduction: Nowadays, publishing highly-cited papers is important for researchers and editors. In this evidence-based study, the factors influencing the citability of published papers in the field of medicine have been identified. Material and Methods: 200 papers indexed in Scopus (in two groups: highly-cited and lowly-cited) with 100 papers in each were studied. Needed data were manually collected with a researcher-made checklist. Data analysis was done in SPSS using descriptive and inferential statistics. Results: Variables such as journal IF, journal rank, journal subject quartile, the first/corresponding author's h-index, the number of documents produced by the first/corresponding author, SJR and SNIP had significantly positive correlation with paper citability (p< .05). Other variables, including among others, paper age, paper type, the number of references, the number of authors, indexing institute and journal kind had not any relationship with paper citability (p> .05). Conclusion: the factors affecting the citability are among indicators relating to authors, publishing journals and published papers. Determining the extent to which these factors influence the citability of a paper needs further large-scaled research. Authors and editors searching for high-citedness should consider these factors when authoring and publishing papers. PMID- 29719308 TI - Design a Fuzzy Rule-based Expert System to Aid Earlier Diagnosis of Gastric Cancer. AB - Introduction: Screening and health check-up programs are most important sanitary priorities, that should be undertaken to control dangerous diseases such as gastric cancer that affected by different factors. More than 50% of gastric cancer diagnoses are made during the advanced stage. Currently, there is no systematic approach for early diagnosis of gastric cancer. Objective: to develop a fuzzy expert system that can identify gastric cancer risk levels in individuals. Methods: This system was implemented in MATLAB software, Mamdani inference technique applied to simulate reasoning of experts in the field, a total of 67 fuzzy rules extracted as a rule-base based on medical expert's opinion. Results: 50 case scenarios were used to evaluate the system, the information of case reports is given to the system to find risk level of each case report then obtained results were compared with expert's diagnosis. Results revealed that sensitivity was 92.1% and the specificity was 83.1%. Conclusions: The results show that is possible to develop a system that can identify High risk individuals for gastric cancer. The system can lead to earlier diagnosis, this may facilitate early treatment and reduce gastric cancer mortality rate. PMID- 29719307 TI - Magnetic Resonance Imaging (MRI) and Transvaginal Ultrasonography (TVU) at Ovarian Pain Caused by Benign Ovarian Lesions. AB - Research goal: The aim of the research is to define the possibilities of TVU and the MRI in the diagnosis of the most common benign ovarian lesions which cause pelvic pain. Patients and methods: In study were included n=74 patients with pelvic pain, who were examined with TVU and then with an MRI of pelvis. Diagnostic results of all patients (n=74) divided into two groups according to the modality that was performed (TVU results n=74 and MRI results n=74 MRI ). We compared the results of TVU and MRI, and with a pathohistological finding after surgery. TVU test sensitivity and MRI test sensitivity has been made for each pathological entity in particular. The overall sensitivity test of TVU was performed for all pathological entities together. The overall sensitivity test of MRI was performed for all pathological entities together. Results: TVU demonstrated sensitivity of 83.3% for ectopic pregnancy, 83.3% for ovarian torsion, 84% for endometriotic cyst, 88.2% for hemorrhagic cysts, 58.3% for tubo ovarian abscesses, 62.5% for dermoid cysts. Overall sensitivity of TVU for all these pathological entities was 78.4%. MRI showed a sensitivity of 100% for ovarian ectopic pregnancy, 83.3% for ovarian torsion, 100% for endometriotic cyst, 100% of hemorrhagic cysts, 83.3% tubo-ovarian abscess, and 87.5% for dermoid cysts. Overall sensitivity of MRI in all of these pathological entities was 94.6%. The analysis using the chi square test shows that there is a significant difference in the sensitivity between the US and MRI in favor of greater overall MRI sensitivity in diagnosing ovarian pain caused by benign lesions. (chi2 = 14.352, df = 9, p = 0.0021). Conclusion: TVU is the first choice method for ovarian analysis due to the convenience and absence of radiation, and MRI is a very useful modality when TVU's results are confusing and unspecific. PMID- 29719309 TI - Capabilities and Advantages of Cloud Computing in the Implementation of Electronic Health Record. AB - Background: With regard to the high cost of the Electronic Health Record (EHR), in recent years the use of new technologies, in particular cloud computing, has increased. The purpose of this study was to review systematically the studies conducted in the field of cloud computing. Methods: The present study was a systematic review conducted in 2017. Search was performed in the Scopus, Web of Sciences, IEEE, Pub Med and Google Scholar databases by combination keywords. From the 431 article that selected at the first, after applying the inclusion and exclusion criteria, 27 articles were selected for surveyed. Data gathering was done by a self-made check list and was analyzed by content analysis method. Results: The finding of this study showed that cloud computing is a very widespread technology. It includes domains such as cost, security and privacy, scalability, mutual performance and interoperability, implementation platform and independence of Cloud Computing, ability to search and exploration, reducing errors and improving the quality, structure, flexibility and sharing ability. It will be effective for electronic health record. Conclusion: According to the findings of the present study, higher capabilities of cloud computing are useful in implementing EHR in a variety of contexts. It also provides wide opportunities for managers, analysts and providers of health information systems. Considering the advantages and domains of cloud computing in the establishment of HER, it is recommended to use this technology. PMID- 29719310 TI - Proposing Electronic Health Record Usability Requirements Based on Enriched ISO 9241 Metric Usability Model. AB - Introduction: System usability assessment is among the important aspects in assessing the quality of clinical information technology, especially when the end users of the system are concerned. This study aims at providing a comprehensive list of system usability. Methods: This research is a descriptive cross-sectional one conducted using Delphi technique in three phases in 2013. After experts' ideas were concluded, the final version of the questionnaire including 163 items in three phases was presented to 40 users of information systems in hospitals. The grading ranged from 0-4. Data analysis was conducted using SPSS software. Those requirements with a mean point of three or higher were finally confirmed. Results: The list of system usability requirements for electronic health record was designed and confirmed in nine areas including suitability for the task (24 items), self-descriptiveness (22 items), controllability (19 questions), conformity with user expectations (25 items), error tolerance (21 items), suitability for individualization (7 items), suitability for learning (19 items), visual clarity (18 items) and auditory presentation (8 items). Conclusion: A relatively comprehensive model including useful requirements for using EHR was presented which can increase functionality, effectiveness and users' satisfaction. Thus, it is suggested that the present model be adopted by system designers and healthcare system institutions to assess those systems. PMID- 29719311 TI - Registry Data Coordinator (RDC): a Proper Accessible Strategy for Improving Road Traffic Injury (RTI) Hospital Based Trauma Registry Systems in Developing Countries and Low Income Countries. AB - Introduction: Evidence suggested that a significant level of trauma mortality can be prevented using registry system. Aim: This study aimed to improve Kashan Hospital Based Trauma Registry System (KHBTRS) for Road Traffic Injury (RTI). Material and methods: After conducting focus group discussion absence of minimum data set (MDS) and poor data collection process (DCP) were identified as main problems for KHBTRS- RTI. Proposed MDS were surveyed by 20 experts of trauma research center of throughout the Iran. Then approved MDS applied for trauma registry system data base in form of SQL. DCP were reform from prospective data collection (review of medical record) to concurrent (through the interview) approach. Results: Most of participants for MDS approval belonged to clinical group 13(65%). 146 MDS in eighteen main categories were proposed for RTI. The maximum score for each MDS main categories were attributed to body parts injured 220 (100%) and patient vital signs 139 (99.29%) respectively. Pilot testing of KHBTRS- RTI database of 50 (50%) riders indicated fully completeness 50 (100%) for concurrent approach. It was concluded that based on experts' viewpoints MDS relating to injury nature and place of occurrence have more priority in comparisons to MDS relating to causes of injury. It may attribute to health care providers focus on clinical care and treatment. Conclusion: It was concluded that based on experts' viewpoints MDS relating to injury nature and place of occurrence have more priority in comparisons to MDS relating to RTI prevention; it may attribute to health care providers focus on clinical care and treatment. To develop injury interventions based on given data, recruitment of professionals as registry data coordinator with specific job description to collect and advocacy of injury external causes data seems imperative. PMID- 29719312 TI - Contrast Agents and Observing Patient Safety Programs in Radiology Departments in Kermanshah Province Hospitals in West of Iran. AB - Introduction: Contrast agents play an important role in increasing the efficiency of diagnostic imaging techniques in the evaluation of vascular lesions, infections and tumors. Annually more than 70 million radiology tests performed using contrast agent materials in the world. Side effects of contrast agent can belief-threaten, so that observing safety guideline prescribed a key role in the patient's health. Aim: The aim of this study was evaluation of compliance with the instructions in the use of contrast agent materials in Kermanshah province Hospitals, West in Iran. Methods: In this cross-sectional study, five centers that were active in the administration of contrast agents were studied. The data collection tool, a checklist containing 49 safety principle of contrast agent material was administered that after confirming its validity and reliability were used. Data were analyzed using SPSS16 software and findings were presented using descriptive and analytical statistics. Findings: Results showed that the average age of the participants in this study 33.66 years.54% was male. 81.8% in the Radiology department and 18.2% were working in CT scan centers. 20.5% of prescribers the contrast agent assistant radiologist, and 79.5% was radiographer, respectively. 25% of them had passed training courses dealing with the acute effects of contrast agent. There was not a guideline to identify patients at high risk for adverse events and prevention and management of adverse reactions due to the side effects prescribing of contrast material in the imaging centers. This study showed that the overall safety of contrast agents in radiology departments only 2.3% appropriate and in 97.7% moderate. Conclusion: The results showed that the Safety observance of the use of contrast agents is not acceptable in many cases. Pregnancy and lactation control, sterile techniques during catheterization in non-inject able contrast agent was not acceptable. Monitoring the patients, use safety box in case of emergency and skilled use of defibrillator; observe this safety issues was rarely taken into consideration by prescribers of inject able contrast agents. The centers survey shows that there isn't a standard guideline to identify patients at high risk and management of side effects of prescribed contrast agent. PMID- 29719313 TI - The Framework of NICU-discharge Plan System for Preterm Infants in Iran: Duties, Components and Capabilities. AB - Introduction: The development of comprehensive discharge plan system Not only, will facilitate the discharge process, increase staff and parent satisfaction, improve the care of preterm infants, also reduce the human error. Aim: to determine duties, components and capabilities of NICU discharge plan system as a multidimensional tool for facilitating the complex process of transition preterm infants to the home and support parents for post-discharge care. Method: The descriptive and qualitative study conducted in 2017. Firstly by literature review, components of framework were determined in 38 statements under 3 major themes: duties, components, and capabilities and then related questionnaire was provided. Cronbach's alpha test was used to assess the reliability of the questionnaire. The result was more than 0.82 for all statements of questionnaire. The validity of the instrument was determined based on concepts in the valid scientific texts and comments of experts. The analysis was performed using SPSS software. Result: In overall, 29 experts participated in the consensus process. In the duties section, all of the statements reach more than 50% consensus. Among statements of the components and capabilities consensus was achieved in 12 out of 17, 12 out of 16 statements respectively. Conclusion: according to survey, checkout infant readiness determined as the main duty of the system. Alarm message for special examination before discharge and parent readiness checklist considered as the most important components. The ability to send alarm message, register and log in system were the key capabilities of the discharge system. PMID- 29719314 TI - Brain Imaging Findings in Children with Headache. AB - Background: Headache is a common problem in children, but a small percentage of them have positive findings on CT scan and MRI, and considering that CT scan and MRI is costly and risks of radiation is high for children. Therefore the aim of this study is evaluating CT scans and MRI finding in children with headache. Materials and Methods: This cross-sectional study was performed on 353 children with headaches that 217 patients underwent CT and 136 patients underwent MRI. The data collected through the report sheet of CT scan and MRI and analyzed using SPSS software and chi-square test. Results: According to the study, 88.9% of MRI and 75.7% of CT scan were normal. Abnormal findings on CT scan was significantly higher in boys (12.2% vs. 9.5%) (P= 0.03) and it was determined that MRI findings was also significantly higher in boys (26.3% vs. 21.5%) (P=0.04). The most common abnormal findings on CT scan was mass (16.6%) and hematoma (16.6%) and the most common abnormal findings on MRI was cysts (26.3%). Conclusion: The results of our study showed that the majority of imaging results in patients with headache was normal or benign lesions. Therefore, imaging should be performed only in children with abnormal findings on physical examination. PMID- 29719315 TI - The Short Term Effects of Shock-Wave Therapy for Tennis Elbow: a Clinical Trial Study. AB - Background: Tennis elbow is one of the most often diagnosed pathology of the upper extremity and different treatments have been suggested for this disease, so this study was to investigate the effects of extracorporeal shock wave therapy in Tennis elbow treatment. Materials and Methods: We design a before and after clinical trial study (registry number: IRCT2012072610405N1) and investigated 40 patients with tennis elbow disease. All patients received 2000 pulses extracorporeal shock wave by piezoelectric device (WOLF Company) daily for one week. The severity of pain was the primary outcome and measured with visual analogue scale (VAS). Secondary outcome was the ability to perform daily activities using questionnaire's quick DASH (Disabilities of the Arm, Shoulder and Hand). Primary and secondary outcomes at baseline, 30 and 60 days after intervention were measured. Results: The mean age of patients was 43.80+/-8.97 years and 28 patients (70%) were female. The mean duration of disease was 6.5 +/- 7.9 month. The mean score of VAS pain score reduced from 7.25+/-1.54cm (median=7cm) before treatment to 2.76+/-2.08cm (median=2cm) at 60 days after the end of treatment (P<0.001). The Quick Dash score reduced significantly from 25.20+/-5.31 (median=25) before treatment to 8.69+/-8.32 (median=6) at 60 days after the treatment (P<0.001). Conclusion: For newly diagnosed patients with tennis elbow, extracorporeal shock wave therapy can reduce the severity of pain and improve daily activity. PMID- 29719316 TI - The Quest of Sagittal Balance Parameters and Clinical Outcome after Short Segment Spinal Fusion. AB - Introduction: Sagittal imbalance leads to muscular distress and results in low back pain. Objectives: This study scrutinize the segmental impact of short spinal fusion on spinopelvic parameters and the global patient's clinical outcome. Materials and Methods: A retrospective analysis evaluated 56-patients who underwent lumbar fusion surgery at Klinikum Dortmund, from July 2013 to February 2014. The population was allocated into two groups: (1-level group), (2-levels group). EOS imaging applied for radiological evaluation and measurements of the following spinopelvic parameters: pelvic incidence (PI), sacral slope (SS), pelvic tilt (SS), lumbar lordosis (LL), and sagittal vertical axis (SVA). The radiological measurements were implemented during the preoperative, postoperative, 3 months and 1 year follow-up visits. All patients completed clinical questionnaires. Results: Statistically, the Pearson correlation coefficient revealed in the 1-level group that the clinical parameters correlated with the PT (R=0.40), SSA (R=-0.38) and SVA (R=-0.41) (p<0.05). While clinically, the mean preoperative VAS and mean ODI improved significantly in both groups.There was also a high correspondence between LL and SS (R=0.90); this relationship persisted at the same level even after a year. For the 2-level group, the only parameter that was interrelated with clinical parameters was the SVA (R=0.49) (p<0.05). There was also a high correlation between LL and SS (R=0.88). Conclusion: Scrutiny conducted showed: Patient with one level would improve clinically in terms of pain and radiculopathy, with only small alterations in spino-pelvic parameters. Meanwhile, two-level fusions have a statistically substantial clinical improvement interrelated to re-establishment of lumbar lordosis and sagittal vertical axis. PMID- 29719317 TI - Impact of the National Population Register in Improving the Health Information System of Malignant Diseases in Kosova. AB - Introduction: Malignant diseases are serious socio-medical problem, being that they cause grave problems in terms of health, social and economic perspective to an individual, in particular, and society in general. A proper reporting and monitoring system enables adequate calculation of indicators and evidence based decision making. Aim: The study aims to examine the appearance of malignancies diagnosed and reported in Kosovo for a three years period: 2012, 2013, and 2014 by its modalities such as by the years of appearance, gender, age, and most frequent types of malignancies. Material and methods: The study is a retrospective cohort research whereas source data we used are reports of malignant diseases from National Cancer Register (NCR) in the Health Information System (HIS) at the National Institute of Public Health of Kosova (NIPHK). Results and discussions: In Kosova during years 2012, 2013 and 2014 a total of 7437 cases of malignant diseases were reported; in 2012 were 31%, in 2013 were 24.3%, and during 2014 higher number of cases were reported, 3320 or 44.6%. During the reporting period, the appearance of malignant diseases in both sexes is about equal, with a light predominance of male cases with 50.8% (or 3780 cases), while by age group were represented with the elderly, from ages 50 to 79 years with 5111 cases or 68.8% of total malignancies. Conclusion: The highest number of malignant diseases was reported during year 2014 due to better reporting through HIS and NCR. Malignancies attacked both genders equally, whereas the most common types of malignancies were: melanoma and other malignant neoplasms of the skin, malignant diseases of the respiratory and intrathoracic organs, digestive tract, breast and female genital tract. The most affected the older ones. PMID- 29719318 TI - Contemporary Aspects of Marketing in Clinical Trials Including Segments of IT and Technology Transfer. AB - Introduction: The aim of this paper is to present the marketing strategy and the application of management (marketing management) and advertising in order to increase the efficiency of innovative approach in clinical trials that include and involve the use of new technologies and transfer of technologies. Material and Methods: This paper has a descriptive character and represents a narrative review of the literature and new model implementation. Results: Marketing models are primarily used to improve the inclusion of a larger (and appropriate) number of patients, but they can be credited for the stay and monitoring of patients in the trial. Regulatory mechanisms play an important role in the application of various marketing strategies within clinical trials. The value for the patient as the most important stakeholder is defined in the field of clinical trials according to Kotler's value model for the consumer. Conclusion: In order to achieve the best results it is important to adequately examine all the elements of clinical trials and apply this knowledge in creation of a marketing plan that will be made in accordance with the legal regulations defined globally and locally. In this paper, two challenges have been highlighted for the adequate application of marketing tools in the field of clinical trials, namely: defining business elements in order to provide an adequate marketing approach for clinical trials and technology transfer and ensuring uniformity and regulatory affirmation of marketing attitudes in clinical trials in all regions in which they are carried out in accordance with ICH-GCP and valid regulations. PMID- 29719319 TI - The Most Influential Scientists in the Development of Medical Informatics (20): Robert S. Ledley (1926-2012). PMID- 29719320 TI - Plagiarism in Scientific Publishing - the Issue of Patent Holder (War Between Developed and Undeveloped Countries) - Letter to Editor. PMID- 29719321 TI - Saudi Oncology Society and Saudi Urology Association combined clinical management guidelines for renal cell carcinoma 2017. AB - In this report, we update the previously published Saudi guidelines for the evaluation and medical and surgical management of renal cell carcinoma. It is categorized according to the stage of the disease using the tumor node metastasis staging system 7th edition. The recommendations are presented with supporting evidence level. PMID- 29719322 TI - Saudi Oncology Society and Saudi Urology Association combined clinical management guidelines for urothelial cell carcinoma of the urinary bladder 2017. AB - This is an update to the previously published Saudi guidelines for the evaluation and medical/surgical management of patients diagnosed with urothelial cell carcinoma of the urinary bladder. It is categorized according to the stage of the disease using the tumor node metastasis staging system, 7th edition. The guidelines are presented with their accompanying supporting evidence level, which is based on comprehensive literature review, several internationally recognized guidelines, and the collective expertise of the guidelines committee members (authors) who were selected by the Saudi Oncology Society and Saudi Urological Association. Considerations to the local availability of drugs, technology, and expertise have been regarded. These guidelines should serve as a roadmap for the urologists, oncologists, general physicians, support groups, and health-care policymakers in the management of patients diagnosed with urothelial cell carcinoma of the urinary bladder. PMID- 29719324 TI - Increased burden on metropolitan urological services: The era of the Australian National Emergency Access Targets (NEAT or the "4-h target"). AB - Background: The National Emergency Access Targets (NEAT) was introduced in Australia in 2011 and guides the clearance of presentations within 4-h of initial presentation from the Emergency Department (ED). We aim to assess the impact of the introduction of NEAT on acute urological services at a large metropolitan center. Methods: A retrospective cohort study was performed and data were collected from electronic patient management systems. The control group was represented by ED presentations between June and September 2011, 1 year prior to the introduction of NEAT. The two study groups consisted of ED presentations between June and September 2012 and 2013, respectively. Outcome measures included time to the ureteric stent and scrotal exploration, inpatient length of stay (IPLOS), out-of-hours operating, and hospital mortality rates. Results: Across the three study periods, a total of 76,935 patients were assessed by the EDs of the health service. 225 urological inpatient episodes were included across all periods with a trend showing increasing numbers of admissions (P = 0.003). For patients admitted under the urological service: Waiting room time and ED length of stay decreased significantly (P < 0.001). Proportion of operative cases decreased insignificantly (P = 0.275). Time from emergency presentation to emergency ureteric stent remained unchanged, however, proportions of procedures performed out-of-hours showed an increasing trend (P < 0.001). A significant increase in inter-unit transfer was observed, however, median IPLOS and mortality for operative and nonoperative cases remain unchanged. Conclusions: Concerning urological admissions, the implementation of NEAT has been associated with improvement in ED key performance indicators. Such changes have been correlated with reductions in operative cases and increases in out-of-hours emergency operating. Further research is required to evaluate the direct effect of NEAT on urological patient care. PMID- 29719323 TI - Saudi Oncology Society and Saudi Urology Association combined clinical management guidelines for prostate cancer 2017. AB - This is an update to the previously published Saudi guidelines for the evaluation and medical and surgical management of patients diagnosed with prostate cancer. Prostate cancer is categorized according to the stage of the disease using the tumor node metastasis staging system 7th edition. The guidelines are presented with supporting evidence levels based on a comprehensive literature review, several internationally recognized guidelines, and the collective expertise of the guidelines committee members (authors) who were selected by the Saudi Oncology Society and Saudi Urological Association. Local factors, such as availability, logistic feasibility, and familiarity of various treatment modalities, have been taken into consideration. These guidelines should serve as a roadmap for the urologists, oncologists, general physicians, support groups, and health-care policymakers in the management of patients diagnosed with adenocarcinoma of the prostate. PMID- 29719325 TI - Incremental value of 68-gallium-prostate-specific membrane antigen positron emission tomography/computed tomography in patients with abnormal prostate specific antigen and benign transrectal ultrasound biopsy. AB - Introduction: Bladder outlet obstruction due to prostate enlargement is a common health problem in male and frequently investigated with prostate-specific antigen (PSA) and transrectal ultrasound (TRUS). TRUS-guided biopsy is critical to differentiate benign prostatic hyperplasia (BPH) or prostate cancer (PCa) even though it has been associated with false negative with reported 3%-16% incidence of PCa in BPH specimens. Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT), a targeted molecular imaging for PCa, has showed promising results in recurrence and staging. We analyzed its role in patients with abnormal PSA and benign TRUS biopsy. Material and Methods: Of 558 68Ga-PSMA PET/CT performed from July 2014 to February 2017, we found six patients with abnormal PSA (range 8.2-24.2 ng/ml, median: 13.3 ng/ml) with benign 12 cores TRUS biopsy as indication. These cases were reanalyzed in detail. Spearman's rank test was used entire correlation using SPSS version 21. Results: 68Ga-PSMA PET/CT showed mild diffuse tracer uptake in prostate in all patients with no focality and maximum standard uptake value normalized to body weight (SUVmax) range was 3.2-5.8 (median: 3.9). Two patients with PSA <10 ng/ml had normal 68Ga-PSMA PET/CT and underwent medical management. In other four patients with PSA >10 ng/ml, two showed metastatic disease in pelvic lymph node in both and in lung in one; hence, 68Ga-PSMA PET/CT changed these patients' management. Spearman's rank test showed no correlation with baseline PSA and SUVmax of prostate (rs -0.0287, P = 0.9571) while strong positive correlation was seen with baseline PSA and 68Ga-PSMA PET/CT scan positivity for extraprostatic disease (rs = 0.828, P = 0.042). Conclusions: 68Ga-PSMA whole-body PET/CT can provide useful incremental information in patient with high PSA and negative TRUS biopsy and has a potential to guide management in this subgroup of PCa patients. PMID- 29719327 TI - Role of clinical and radiological parameters in predicting the outcome of shockwave lithotripsy for ureteric stones. AB - Introduction: Shockwave-lithotripsy (SWL) provides a noninvasive and effective option for the management of ureteric calculi. Several factors may affect the success of SWL. Identification of these predictive factors will both increase the efficacy and decrease the cost. This study was designed to identify factors affecting the outcome of SWL for ureteral stones. Materials and Methods: This study was conducted from March 2012 to November 2014 in patients with solitary ureteric calculi who were managed with SWL. Data were analyzed to identify clinical and radiological factors associated with treatment outcome. Success after SWL was described as complete stone clearance or clinically insignificant residual fragments <3 mm at 3 months after SWL. Results: A total of 110 patients with ureteric calculi were divided into two groups depending on the outcome of SWL, Group A (successful - 76%) and Group B (failed - 24%). Stone size, Skin to stone distance (SSD), secondary signs of obstruction, and presence of double J (DJ) Stent, all were significantly associated with the outcome of SWL on univariate analysis. On multivariate analysis, stone size, hounsfield unit, SSD, and DJ stent were the independent factors affecting the outcome of SWL. On Receptor-Operator Characteristic curve analysis, a cutoff value of 8.2 mm for the stone size was found which best predicts a successful outcome, with a sensitivity of 54% and specificity of 96%. Conclusion: The findings of this study suggest that Stone size, SSD, the presence of DJ stent, and stone attenuation values are the significant factors that influence the outcome of SWL in patients with ureteral stones. PMID- 29719326 TI - Prospective study to evaluate the clinical outcome of intralesional interferon alpha2b in the management of Peyronie's disease. AB - Context: Interferon (IFN)-alpha2b in Peyronie's disease (PD). Aims: This study aims to evaluate clinical efficacy of the IFN-alpha2b in both subjective and objective manner for the treatment of PD and compared with previously used intralesional verapamil in terms of cost-benefit analysis. Settings and Design: Prospective study. Materials and Methods: A prospective study conducted from January 2013 to July 2016 in the Department of Urology, Government Medical College, Kota, Rajasthan, India. We included patients with identifiable Peyronie's plaque with or without pain, curvature ranging between 30 and 90 degrees. We excluded patients with a calcified plaque and the ventral location of the plaque, any infective foci over the penis, erectile dysfunction due to other etiologies and patients who had received previous intralesional therapy. Patients were evaluated by clinical history, physical examination including plaque location, size, consistency, and penile curvature. Patients received intralesional IFN-alpha2b in a dose of 3 * 106 IU. Patients completed the visual analogue pain (VAS) score for pain, and International Index of Erectile Function 5 (IIEF-5) questionnaire at first visit as well as at follow-up of 1 month and 3 months. Statistical Analysis Used: Comparisons were performed using the paired Student's t-test and Chi-square tests as appropriate. Patient's objective and subjective clinical characteristics were described as a means (standard deviation). Results: We included 86 patients in this study. Patients had a mean age of 48.6 years, mean plaque volume 256 mm3, and disease duration of 15.2 years. After 1 month of treatment, there was a significant change in plaque volume 256-60.8 mm3; P < 0.01) and penile curvature 34.8-24.6 degrees ; P < 0.01). The patients reported significant improvement in pain score VAS and IIEF 5. Conclusions: IFN-alpha2b, as minimal invasive (intralesional) options for the treatment of PD, demonstrated significant improvement in plaque volume, penile curvature with minimal complications. Patients subjectively reported significant improvement in pain on erection and sexual activities. IFN-alpha2b and verapamil had an almost similar clinical outcome, but verapamil at much lower cost. PMID- 29719328 TI - Miniaturized percutaneous nephrolithotomy versus retrograde intrarenal surgery in the treatment of renal stones with a diameter <15 mm: A 3-year open-label prospective study. AB - Aim: The aim of this study is to compare the outcomes of miniaturized percutaneous nephrolithotomy (mini-perc) and retrograde intrarenal surgery (RIRS) in management of renal stones with a diameter <15 mm. Materials and Methods: This was an open-label prospective study that included a total of 80 cases underwent mini-perc (n = 40) and RIRS (n = 40) between July 2014 and August 2017. The primary outcome objective was stone-free rate, retreatment rate, complications, hospital stay, operative time, and reduction in hemoglobin level. Data were analyzed using SPSS version 16.0 Software. Results: Overall, 80 patients were enrolled in this study. The mean age was 40.12 and 38.20 years, and the mean stone size was 1.15 and 1.30 cm in mini-perc and RIRS group, respectively. Majority of the study participants were males. Overall, mini-perc and RIRS had stone clearance rates of 100% and 95.4%, respectively. Two patients required retreatment in RIRS group. The duration of hospital stay and the rate of complication was similar in both the groups. Operative duration was more in RIRS group. Decrease in hemoglobin level was more in mini-perc group. Conclusions: Results demonstrated that both modalities were associated with high stone clearance rates with minimal complications. RIRS was associated with less reduction in hemoglobin and could be used as standard treatment modality for small renal calculi. PMID- 29719329 TI - Primary urethral carcinoma: A Surveillance, Epidemiology, and End Results data analysis identifying predictors of cancer-specific survival. AB - Objectives: Primary urethral carcinoma (PUC) is rare, accounting for <1% of genitourinary malignancies. Current knowledge regarding is founded upon tertiary care centers reporting their experiences. We aim to identify factors predictive of outcomes using a nationwide registry database. Materials and Methods: The Surveillance, Epidemiology, and End Results-18 registries database was queried for cases of PUC ranging between 2004 and 2010. To identify PUC cases, ICD-O site code C68.0 was used as a filter, hence identifying PUC with histologic subtypes including urothelial carcinoma (UC), squamous cell carcinoma (SCC), and adenocarcinoma (AC). Tumor characteristics were compared using log-rank analysis, and survival outcomes were compared using Cox proportional hazards models. Results: A total of 419 PUC cases were identified, 250 (59.7%) male and 169 (40.3%) female patients. The most common histology in men was UC (134, 53.6%), followed by SCC (87, 34.8%) and AC (29, 11.6%). The most common histology in women was AC (79, 46.7%), followed by SCC (43, 25.4%) and UC (42, 24.9%). Log rank analysis illustrated significant difference in cancer-specific survival (CSS) for T-stage, N-stage, M-stage, and stage of PUC with all histological variants combined (P < 0.001). Multivariate Cox proportional hazards model demonstrated that stage and age were significant for survival, with a risk ratio of 1.033 (95% confidence interval [CI], 1.020-1.046)/year of increased age (P < 0.001) and 3.71 (95% CI, 2.72-5.05) for patients with regional or distant spread. Conclusions: Knowledge of patient and tumor characteristics that influences survival is paramount in dictating management. The present study illustrates that age and stage are factors significantly associated with CSS in PUC. PMID- 29719330 TI - Outcome of anastomotic posterior urethroplasty with various ancillary maneuvers for post-traumatic urethral injury. Does prior urethral manipulation affect the outcome of urethroplasty? AB - Purpose: We present our success rate and complications of delayed anastomotic urethroplasty (DAU) in patients with post-traumatic posterior urethral injury. Materials and Methods: This was a retrospective study of patients aged >=17 years that underwent DAU for post-traumatic posterior urethral injury during 2010-2014. Stricture length was measured by ascending and descending urethrogram. Success of procedure was considered when the patient was free of stricture-ralated obstruction and needed no further intervention. Primary group includes patients who underwent first time delayed urethroplasty while secondary group included patients who had some sort of urethral manipulation in local hospital. Results were analyzed using unpaired t-test, Chi-square test, binary logistic regression, Kaplan-Meier curves, and log-rank test. Results: Of the 80 male patients, 73 (91.25%) patients underwent primary DAU while 7 (8.75%) patients had secondary DAU. Median age, stricture length, and follow-up were 27.0 +/- 12.7, 1.6 +/- 0.9, and 3.2 +/- 0.9, respectively. Overall, success rate was 83.75% while success rate in primary group was 89.04% and secondary group was only 28.57% (P = 0.0059). Regarding ancillary maneuvers, urethral mobilization alone was done in 29 (36.25%) patients with success rate (72.41%), corporeal body separation in 36 (45%) patients with success rate (91.66%), inferior wedge pubectomy in 13 (16.25%) with success rate (84.61%), supracrural rerouting in 1 (1.25%) with success rate (100%), and abdominoperineal approach in 1 (1.25%) with success rate of 100% (P = 0.193). Patients who had prior urethral manipulation affect the outcome of definitive anastomotic urethroplasty. Conclusion: DAU has durable success rate with less morbidity. Ancillary elaborated maneuvers are frequently needed in patients with complex and elongated post-traumatic posterior urethral defect with successful outcome. PMID- 29719331 TI - Clinical, radiological, cytological, and microbiological assessment of painful extratesticular lesions. AB - Introduction: Most of the painful extratesticular scrotal lesions are erroneously diagnosed and treated in our clinical practice. Therefore, this study was undertaken to analyze the usefulness of a combination of clinical, radiological, cytological, and microbiological assessment in establishing the accurate diagnosis of this lesion. Aim: To study the Clinical, Radiological, Cytological and Microbiological assessment of painful extra-testicular lesions and their correlation with each other in establishing the accurate diagnosis of these lesions. Objectives: The objectives of the study were to assess the diagnostic significance of clinical, radiological, cytological, and microbiological methods and their correlation in establishing the accurate diagnosis of painful extratesticular lesions. Materials and Methods: This cross-sectional study was carried out in Departments of Surgery, Radiology, Pathology, and Microbiology, University College of Medical Sciences and GTB Hospital over the period of 2 years. During this period, we were able to accommodate 75 patients in the study, who presented with pain and swelling in the scrotum and clinically found to have extratesticular swellings. Radiological assessment was done on the 1st day of visit, using Grayscale ultrasonography along with Color Doppler of these lesions. For cytological assessment, ultrasound-guided fine-needle aspiration cytology and microbiological assessment were done from the aspirate remaining after making cytology slide. Statistical Analysis: Data analysis was done using SPSS statistical software. Kappa statistics were used to find the degree of agreement or concordance between clinical, radiological, cytological, and microbiological findings. Results: Clinically 71 patients were found to have tender extratesticular swellings, whereas in four patients, these swellings were nontender on clinical examination. Radiologically, epididymitis was found in 32 patients. Only in 37 patients out of 75, a definite diagnosis could be made on cytology. The microbiological examination did not give any positive results. Conclusion: Painful extratesticular scrotal lesion often poses a diagnostic dilemma in the mind of treating physician. Clinical findings of these lesions may be corroborated through radiological, cytological, and microbiological assessment in an endeavor to arrive at a definitive diagnosis with a defined etiology. PMID- 29719332 TI - Long-term outcomes of sigmoid vaginoplasty in patients with disorder of sexual development - our experience. AB - Introduction: To report our experience with sigmoid vaginoplasty in patients with different forms of disorder of sexual development and their long-term follow-up. Materials and Methods: This is a retrospective study of patients who underwent sigmoid vaginoplasty between July 2004 and June 2015 at our center. Follow-up included a physical examination to assess vaginal length and width, cosmetic appearance of the neovagina, and occurrence of any complications. Results: The current study included eight patients with mean age 19.5 years. The mean operative time was 164 min. No significant intraoperative or immediate postoperative complications occurred. Follow-up period ranges from 21 months to 12 years with mean of 7.5 years. In all patients, the neovagina was found to have a satisfactory cosmetic appearance. Seven patients are sexually active and satisfied. Conclusion: Sigmoid vaginoplasty is safe and acceptable procedure in patients having vaginal agenesis. Sigmoid vaginoplasty has acceptable cosmetic results and complication rate. PMID- 29719333 TI - Can preoperative clinicoradiological parameters predict the difficulty during laparoscopic retroperitoneal simple nephrectomy? - A prospective study. AB - Introduction: Urologists tend to prefer retroperitoneal approach for open nephrectomy and transperitoneal route for laparoscopic nephrectomy. Urologists consider retroperitoneal laparoscopic approach difficult to learn and perform. There is a need to objectively define predictors of difficulty during laparoscopic retroperitoneal simple nephrectomy (LRSN) for the proper preoperative selection. To the best of our knowledge, this is the first study to prospectively assess the factors associated with difficulty during LRSN. Materials and Methods: All adult patients of nonfunctioning kidneys (due to benign causes) planned for simple nephrectomies from November 2014 to January 2017 were included in the study. Various clinical and radiological parameters were noted along with intraoperative difficulty parameters (difficulty score, total operative time, and estimated blood loss). Renal and perirenal parameters were assessed and noted on computed tomography scan. Difficulty scale was calculated based on the three difficulty parameters and was used to objectively categorize the patients in easy and difficult group. Results: A total of 44 patients were included in the study. There were 23 patients in Group I (Easy) and 21 patients in Group II (Difficult). Various preoperative clinical and radiological parameters were analyzed and compared between these two groups. History of pyonephrosis and presence of nephrostomy tube were the only two statistically significant factors associated with difficult cases (Group II). None of the factors were statistically significant in multivariate analysis. Conclusion: Based on the findings of our study, history of pyonephrosis and presence of nephrostomy are the most significant factors predicting difficulty during LRSN. PMID- 29719334 TI - Knowledge and attitude about sexually transmitted diseases among youth in Saudi Arabia. AB - Background: Sexually transmitted diseases (STDs) are one of the most serious diseases in the world. Our aim was to explore the knowledge and attitude about STDs among the youth. Patients and Methods: This cross-sectional survey was conducted from August 1 to August 13, 2016. Male and female youth between 18 and 25 years were invited to participate in the survey using social media open to all Internet users consisting of questions and statements about STDs, and then the data were analyzed. Results: We received 5040 responses to the survey; out of these participants 76.6% were females and 23.4% were males with a mean age 21.5 and most of them were single (85.1%). We noticed that most of the respondents selected the Internet (71.7%) as the main source of their knowledge about STDs followed by school, television, and others, respectively. In spite of, 94.08% knew that human immunodeficiency virus/AIDS is an STD, only 43.61% knew that herpes simplex virus is an STD, and only 31.03% knew that Chlamydia is an STD. A high percent (93.1%) agreed that sexual intercourse transmits STDs. Only 59.6% agreed that condom does not provide complete protection from STDs. To our surprise, only 55% considered themselves capable of protecting themselves against STDs. About 95.8% of the participants agreed that STDs should be taught in schools, while 4.2% disagreed. Conclusion: We noticed a lack of participant's knowledge regarding the types, mode of transmission, and the ways of protections from STDs and their desire to find out information about STDs. Hence, awareness programs about STDs should be started that aim at encouraging youth to follow our religion and culture. PMID- 29719335 TI - Incidence of metastasis and prostate-specific antigen levels at diagnosis in Gleason 3+4 versus 4+3 prostate cancer. AB - Aims: The aim is to assess for a difference in the incidence of metastasis (IM) and prostate-specific antigen (PSA) levels at diagnosis in patients with Gleason score (GS) 3+4 versus 4+3 prostate cancer using a large veterans affairs database. Subjects and Methods: A retrospective review of 1402 medical records from 5 VA hospitals was conducted. The study period was from 2009 to 2014. Primary endpoints were IM and PSA levels at diagnosis. A secondary endpoint was overall survival. Statistical Analysis Used: Chi-square tests for categorical variables, Student's t-test for continuous, normally distributed variables, and rank sum tests for continuous nonnormally distributed variables. Results: There were 1050 patients with GS3+4 and 352 with GS4+3. There were no differences in sociodemographic and clinical characteristics of the study population. PSA at the time of diagnosis was significantly higher in the GS4+3 patients compared to GS3+4 (18.0 vs. 11.4, respectively; P < 0.001). The IM at diagnosis was higher in the GS4+3 patients (10/352) compared to GS3+4 (9/1041) (2.8% vs. 0.9%; P = 0.005). In an adjusted model, GS4+3 was associated with higher PSA, higher IM at diagnosis. There was no difference in overall survival between the 2 groups though a 23% reduction in overall survival in the GS4+3 was noted (P = 0.53). Conclusions: Our results indicate that patients with GS4+3 prostate cancers have higher PSA levels at diagnosis. GS4+3 is associated with 3-fold increased risk of IM at diagnosis than GS3+4 though the overall incidence is low. Further research is needed to assess whether GS4+3 patients need routine staging imaging investigations at the time of diagnosis similar to patients with higher Gleason scores (GS >=8). PMID- 29719336 TI - Study of Proliferating cell nuclear antigen expression and Angiogenesis in Urothelial neoplasms: Correlation with tumor grade and stage. AB - Background: Urinary bladder carcinoma ranks ninth in worldwide cancer incidence. About 74,000 new cases were diagnosed in 2015 alone and 16,000 persons died of the disease. Since histopathology is considered gold standard for diagnosis, it is prudent to look for potential tumor proliferation and predictive markers in such a prevalent malignancy so as to alert surgical and medical oncologists for timely intervention and provide better patient-tailored therapy. Aims: This study is to analyze the role of potential biomarkers-proliferating cell nuclear antigen (PCNA) and angiogenesis using CD31 in urothelial neoplasms in relation to tumor grade and stage. Methods: Histopathology slides were prepared from transurethral resection of bladder tumor chips and assessed by three independent observers as per the WHO/International Society of Urologic Pathology criteria 2016. Representative sections were subjected to immunohistochemistry. PCNA labeling index (PCNA LI) and mean vessel density (MVD) were calculated. Statistical Analysis: Tests of analysis were applied as appropriate. A statistical P < 0.05 was considered significant. Results: Forty-nine patients were analyzed. PCNA LI increased with grade and stage. PCNA was significantly higher in noninvasive papillary urothelial carcinoma high grade (NIPUCHG) than in noninvasive papillary urothelial carcinoma low grade (NIPUCLG) and in infiltrating urothelial carcinoma as compared to NIPUCLG. MVD also increased with tumor grade and stage; however, a significant difference was observed only between infiltrating urothelial carcinoma and papillary urothelial neoplasm of low malignant potential. A cutoff value of 73% for PCNA and 49 vessels/high-power field for CD 31 showed 100% accuracy to differentiate between noninvasive papillary urothelial carcinoma high grade and NIPUCLG. No association was observed between tumor recurrence and PCNA or CD31 expression. Conclusion: PCNA and CD31 when used together are valuable markers to help classify urothelial neoplasms in limited tumor material. However, larger prospective studies are required for better prognostication. PMID- 29719337 TI - The impact of stone composition on renal function. AB - Background: Nephrolithiasis is a common condition that has various classifications according to stone composition. Stone formation can affect renal function; it can be a strong risk factor for chronic kidney disease (CKD). The main objective of this study is to explore the association between creatinine clearance and different stone compositions. Methods: This is a retrospective cohort study conducted in a tertiary center in Jeddah, Saudi Arabia, between 2005 and 2014. Renal function was assessed by the estimating glomerular filtration rate (eGFR) by the Cockcroft-Gault equation. Stone composition was determined by urinary calculi analysis with infrared spectrometry. Results: Stones of 365 patients, with a mean age of 48.2 +/- 13.6 years and a male to female ratio of 3.2:1, were analyzed. Stage 2 CKD has been documented. It involved oxalate, struvite, cystine, and uric acid stones. The worst eGFR was reported for stones containing uric acid. The eGFR was least affected with apatite stones followed by brushite stones. Conclusion: Stone disease can affect renal function. Different stone compositions show factor for renal impairment, and this should be considered in patient management. A special precaution should be considered for higher risk groups. Multidisciplinary patient care and immediate referral to a nephrologist are strongly advised. PMID- 29719338 TI - Urachal cyst with xanthogranulomatous cystitis: A rare case report. AB - An urachal cyst is a sinus remaining from the allantois during embryogenesis which is rarely manifested in adults. The urachus is an embryologic remnant which degenerates after the birth. Defective obliteration of the urachus leads to urachal abnormalities. Urachal cyst is a rare pathology in adult women, and this pathology should be considered in the differential diagnosis of acute abdomen. Xanthogranulomatous cystitis (XC) is a benign disease of unknown etiology. The clinical manifestations of these are nonspecific such as lower abdominal pain, umbilical discharge with occasional hematuria. Urachal lesions present with persistent umbilical drainage in infants and newborn. However, in 35% cases, enclosed urachal cyst or infected urachal cyst (abscess) manifests without having umbilical discharge. Computed tomography scan and magnetic resonance imaging are of little help to the identification of these preoperatively. Here, we present a rare case of urachal cyst with XC in 30-year-old female which has produced diagnostic dilemma. PMID- 29719339 TI - A case of penile strangulation after placement of metallic rings. AB - Penile strangulation following placement of metallic rings is a rare clinical entity that needs urgent attention to avoid potentially severe clinical consequences. Careful handling and occasionally a multidisciplinary approach are the keys to a successful outcome. PMID- 29719340 TI - Embolization with Onyx(r) of an arterial pseudoaneurysm with an arteriovenous fistula complicating a percutaneous nephrolithotomy: A case report and review of literature. AB - Percutaneous nephrolithotomy (PCNL) has proven very effective in the management of renal stones. However, complications are not so rare, and bleeding is one of the most worrisome; it has a reported incidence of 1%-3% and may happen during track dilatation. In addition, arterial pseudoaneurysms and/or arteriovenous fistulas (AVF) may occur. We report the case of a patient with an intrarenal pseudoaneurysm associated with an AVF, after PCNL. Superselective endovascular embolization with Onyx(r) was successfully performed, achieving exclusion of the pseudoaneurysm and AVF with preservation of the remaining vascularization of the kidney. We review the literature regarding endovascular management of kidney vascular lesions after PCNL. Selective renal embolization is a minimally invasive procedure, highly effective with a low incidence of complications. Currently, it is considered the most appropriate technique in the treatment of arterial iatrogenic complications following percutaneous renal procedures. Onyx(r) is an effective, easy to handle, and safe alternative embolic agent for these procedures. PMID- 29719341 TI - Renal cell carcinoma in renal allograft: Case series and review of literature. AB - Renal cell carcinoma (RCC) in transplanted kidneys has been reported sporadically with incidence of about 0.5%. There are currently no standard guidelines on the management of allograft RCC in renal transplant recipients. Our objective was to study effectiveness of nephron-sparing surgery (NSS) for allograft RCC. We performed a retrospective analysis of patients with RCC in renal allografts managed with NSS in our institution from January 2000 to December 2015. Patient demographics, interval between transplant and RCC diagnosis, operative parameters, perioperative complications, final pathology, and renal function were evaluated. Three females underwent successful NSS for allograft RCC. Cause of end stage renal disease was IgA nephropathy in all; mean time between renal transplant and diagnosis of RCC was 23 years. We were able to stay extraperitoneal in all the cases. In the final pathology, two had papillary and one had clear cell RCC. One patient developed pyelocutaneous fistula which was managed by stenting. Long-term functional outcomes of NSS are excellent; none of our patients is dialysis dependent. PMID- 29719343 TI - Toward International Collaboration on ICD-11 - WHO Mental Health Collaborating Center in China 2017. PMID- 29719342 TI - Organ preservation in leiomyosarcoma bladder: Case report and review of literature. AB - Leiomyosarcomas (LMSs) account for <0.1% of all bladder malignancies. Due to the infrequent occurrence of these tumors, established guidelines for management are lacking. Conventionally, radical extirpative surgery has been advocated. We present our experience with organ preservation in a young male presenting with LMS bladder. A brief review of literature supporting organ preservation in selected cases has also been presented. PMID- 29719344 TI - Meta-analysis of the Efficacy and Safety of Repetitive Transcranial Magnetic Stimulation (rTMS) in the Treatment of Depression. AB - Background: Repetitive transcranial magnetic stimulation (rTMS) is a new type of physiotherapy technology that has been widely used in the research of depression. Although many clinical trials have found that compared to the placebo interventions, rTMS has a significant effect on the improvement of depressive symptoms, the outcomes remain inconsistent due to differences in rTMS treatment frequency, parameter settings, and site for stimulation. Aims: This study systematically evaluated the safety and efficacy of rTMS combined with antidepressants for the treatment of depression in Chinese and English randomized, double-blind and sham controlled trials and explored the possible related factors affecting the efficacy and safety. Methods: We used keywords "depression" and "transcranial magnetic Stimulaton" as filters to search for the Clinical Randomized Controlled Trials (RCTs) of rTMS treatments for depression both in Chinese electronic databases: Wan fang, Wellpresi, and China Knowledge Network and in English electronic databases: PubMed, Web of Science, Embase, PsycINFO, Cochrane Library (total 8 databases) up to January 5, 2017; assessed the quality of the included studies with Cochrane risk of bias assessment tool; and according to the trial groups performed statistical analysis of the efficacy and safety presented in the included studies with RevMan5.3 software. Results: A total of 9798 articles were retrieved, and finally, 29 studies were included in this study, with a total sample size of 1659, in which the sample size of the study groups was 838, and the control group sample size was 821. After Meta analysis, we found that treatment combined rTMS with antidepressants improves depressive symptoms in patients with depression (SDM=-0.84, 95%CI=-1.19 ~ -0.48). Based on the Cochrane risk bias Assessment tool, an assessment of the bias of the included studies was conducted, one of which was assessed as having a "high risk of bias" and others as "impossible to judge". None of the included studies reported significant adverse events, and Meta-analysis showed no statistically significant differences in dropout rate between the two groups (RR=1.27, 95%CI: 0.75~2.12, Z=0.89, p=0.37). Conclusion: treatment that combined rTMS with antidepressant medication for depressive symptoms has a certain therapeutic advantage versus the placebo controls, demonstrated slight side effects, and attained good acceptability, but the differences between trials remained relatively large. Clinical trials with large sample sizes are required for further exploration of the possible related factors affecting the efficacy. PMID- 29719345 TI - Status Investigation of Outpatients Receiving Methadone Maintenance Treatment (MMT) in Shanghai from 2005 to 2016. AB - Background: Methadone maintenance treatment (MMT) is an effective measure to control drug abuse, prevent AIDS, and improve family and social functions among those with heroin addiction. Relevant surveys in recent years show that the number of outpatients receiving MMT has a downward trend. Aims: To understand variation in maintenance treatment rates and causes of withdrawal for outpatients receiving MMT in Shanghai since initiation of this program. Method: This study was a retrospective investigation, with data from the AIDS Comprehensive Prevention and Control Data Information Management System of the China AIDS Prevention and Control Center. Descriptive statistics were used to describe demographic data, treatment maintenance rate, and number of new outpatients receiving MMT in Shanghai From May 2005 to June 2016. The causes of withdrawal were summarized and analyzed. Results: From May 2005 to June 2016, there were a total of 7181 outpatients receiving MMT in Shanghai. These patients were primarily male (male to female ratio around 3:1), young adults (more than 90% of these patients were 25 to 54 years old), with junior high school education level and below (65.4%), single (total of unmarried, divorced and widowed: 63.1%), and unemployed or underemployed (81.5%). The daily dose of methadone in MMT patients showed an upward trend since 2008, and gradually declined after reaching its peak in 2013. The mean (sd) dose of methadone taken in the years studied was 56 (2.75) ml/d. The number of new outpatients increased sharply in 2007 and 2008 (more than 1500), and then decreased year by year. The number of outpatients had increased continuously from 2005 to 2011, with the peak in 2011 (3840 patients), and then decreased gradually. The maintenance rate was stable at over 80% since 2010. The main causes of withdrawal: 1) arrested due to unrelated criminal causes (19.89%), 2) sent to compulsory isolated rehabilitation center due to occasional drug use, and 3) physical reasons (disease/pregnancy/death, 11.80%). Conclusion: The maintenance rate has been kept at a relatively good level since the initiation of the MMT outpatient clinic service in Shanghai. The number of patients receiving treatment showed an increase-then-decrease trend. The main causes of patients' withdrawal were mainly related to "crime" and "relapse". In order to make MMT outpatient service better, subsequent studies need to carry out related investigations to understand the causes of these changes and patients reasons for withdrawal. PMID- 29719346 TI - The Relationship between the Lifestyle of the Elderly in Shanghai Communities and Mild Cognitive Impairment. AB - Background: Those with mild cognitive impairment (MCI) are ten times more like to develop Alzheimer's disease (AD) than the general population. MCI diagnosis and early intervention are helpful for the diagnosis and treatment of AD in its early stages, thus delaying its development and improving the quality of life for those with MCI. Aims: To analyze the relationship between the lifestyle of the elderly in Shanghai communities and mild cognitive impairment and to look for preventative lifestyle measures for the elderly with mild cognitive impairment. Methods: 1005 elderly persons were randomly selected from the community in Shanghai. Study participants were 265 people with an MCI diagnosis and 607 non MCI elderly persons. The demographic and lifestyle data of these elderly people were collected for univariate and multivariate analysis to search for statistically significant indicators. Results: The univariate analysis revealed that smoking (chi2 = 10.808, p=0.001), tea drinking (chi2 =11.74, p= 0.001), having hobbies (chi2 = 20.815, p<0.001), reading (chi2 =28.670, p= 0.001), surfing the internet (chi2 =12.623, p= 0.001), and photography (chi2 =4.470, p= 0.034) were protective factors for MCI. The binary logistic regression, a multivariate analysis, revealed that smoking, reading, and surfing the internet had statistical significance. Their OR values were 0.562 (0.358-0.883), 0.428 (0.253-0.726), and 0.238 (0.071-0.797) respectively. Thus, smoking, reading, and surfing the internet were protective factors for MCI. Conclusions: Lifestyle is associated with the onset of MCI. Good life habits and behaviors are significant in the prevention of MCI developing into Alzheimer's. PMID- 29719347 TI - CHN2 Promoter Methylation Change May Be Associated With Methamphetamine Dependence. AB - Background: Methamphetamine (MA) abuse is becoming increasingly serious in China. The mechanism of MA dependence remains unclear. CHN2 gene encodes chimeric protein-2 that regulate axonal pruning via the Rac-GTPase system and play a pivotal role in the formation of nervous circuits. Genetic studies suggest that the polymorphism of the CHN2 gene was related to substance dependence. Aims: The aim of this study was to investigate the association between the methylation of CHN2 gene promoter with MA dependence. Methods: According to SCID-I (Structured Clinical Interview for DSM-IV Axis I Disorders, SCID-I) used for investigating MA dependence, 224 male MA addicts were recruited into the case group. In addition, 109 healthy men were recruited into the control group. Blood samples were collected with the purpose of detecting the methylation levels of CHN2 gene promoter by methylight qPCR. The association between the methylation of CHN2 gene promoter with MA dependence was analyzed. Results: The mean (sd) methylation levels of CHN2 gene promoter in the case group were significantly higher than in the control group, which were 2795.55 (733.19) and 1026.73 (698.73), respectively, showing significant differences between the two groups (t=21.25, p<0.001). Pearson analysis showed no significant correlation between the methylation levels of CHN2 promoter and other factors (the age of initial MA use, the duration of MA use, combination with K powder, tobacco and alcohol). Conclusions: The abnormal methylation of CHN2 gene promoter was significantly correlated with MA dependence. PMID- 29719348 TI - Analysis of Family Functioning and Parent-Child Relationship between Adolescents with Depression and their Parents. AB - Background: Drug therapy combined with family therapy is currently the best treatment for adolescent depression. Nevertheless, family therapy requires an exploration of unresolved problems in the family system, which in practice presents certain difficulties. Previous studies have found that the perceptual differences of family function between parents and children reflect the problems in the family system. Aims: To explore the characteristics and role of family functioning and parent-child relationship between adolescents with depressive disorder and their parents. Methods: The general information and clinical data of the 93 adolescents with depression were collected. The Family Functioning Assessment Scale and Parent-child Relationship Scale were used to assess adolescents with depressive disorder and their parents. Results: a) The dimensions of family functioning in adolescents with depressive disorder were more negative in communication, emotional response, emotional involvement, roles, and overall functioning than their parents. The differences were statistically significant. Parent-child relationship dimensions: the closeness and parent-child total scores were more negative compared with the parents and the differences were statistically significant. b) All dimensions of parent-child relationship and family functioning in adolescents with depression except the time spent together were negatively correlated or significantly negatively correlated. c) The results of multivariate regression analysis showed: the characteristics of family functioning, emotional involvement, emotional response, family structure, and income of the adolescents with depressive disorder mainly affected the parent child relationship. Conclusions: There were perceptual differences in partial family functioning and parent-child relationship between adolescents with depressive disorder and their parents. Unclear roles between family members, mutual entanglement, too much or too little emotional investment, negligence of inner feelings, parental divorce, and low average monthly family income were the main factors causing adverse parent-child relationship. These perceptual differences have a relatively good predictive effect on family problems, and can be used as an important guide for exploring the family relationship in family therapy. PMID- 29719349 TI - The Application of Cognitive Remediation Therapy in The Treatment of Mental Disorders. AB - Cognitive impairment is common in patients with mental disorders. At present, one of the only effective ways to improve cognitive impairment is cognitive remediation therapy. This article reviews the application of cognitive remediation therapy in the treatment of mental disorders. PMID- 29719350 TI - A Case Report of A Patient with Treatment-Resistant Depression Successfully Treated with Repeated Intravenous Injections of A Low Dosage of Ketamine. AB - Depression is a highly prevalent and severely disabling disease. The treatment effects, intensity and onset time of antidepressants have been highlighted in many studies. Recent studies on the rapid-onset of antidepressant response focused on the effect of a single low dose of intravenous ketamine. However, there are still some problems with treatment, including safety, efficacy, ethics, dose, frequency of administration and their effect in treatment-resistant depression. In the present study, we treated one case of treatment resistant depression with repeated intravenous injections with a low dosage of ketamine. PMID- 29719351 TI - Senile Depression with Somatization Symptoms and Insomnia is Diagnosed as Multiple System Atrophy: A Case Report. AB - Patients who have senile depression with somatization symptoms are commonly encountered in clinical practice. The present case reports on a patient with senile depression who was repeatedly hospitalized and had somatic symptoms. Although the patient recovered after the first hospitalization, she suffered from a relapse one year later. As we followed up, due to the neurological findings and the response to treatment, we found that the patient is in line with the diagnoistic criteria for multiple system atrophy (MSA). The process of diagnosis and treatment of this case reminds us that clinicians need to consider differential diagnosis for refractory senile depression, especially in those patients with prominent somatization. In this case, rapid eye movement sleep behavior disorder (RBD) serves as a characteristic feature of the organic mental disorder. PMID- 29719352 TI - Comparisons of Superiority, Non-inferiority, and Equivalence Trials. AB - Efficacy of a new drug or treatment is usually established through randomized clinical trials. However, specifying hypotheses remains a challenging problem for biomedical researchers. In this survey we discuss superiority, non-inferiority, and equivalence trials. These three types of trials have different assumptions on treatment effects. We compare the assumptions underlying these trials and provide sample size formulas. PMID- 29719354 TI - The Study of White Matter Hyperintensity (WMH) and Factors Related to Geriatric Late-Onset Depression. AB - Background: Geriatric depression is one of the most common and harmful mental illnesses seen in the elderly. However, there are few studies focusing on the relationship between late-onset depression (LOD) and social and psychological factors, as well as brain structure. Aims: To explore factors related to late onset depression (LOD) in elderly patients. Methods: 24 first onset LOD patients over 60 years old (meeting ICD-10 diagnostic criteria for depression) and 23 non depressed elders were selected for inclusion into this study. Scale assessments, including Fazelasscale for white matter hyperintensity (WMH) high signal level and the MTA-scale for medial temporal lobe atrophy levels, were combined with general demography and sociology data to find factors related to LOD. Results: There was no significant difference in age (t=0.419, p=0.678), gender (X2=1.705, p=0.244), or years of education (t=1.478, p=0.146) between the two groups. However, statistical differences were shown on scores on the WMH, (X2=7.817, p=0.008), periventricular white matter hyperintensity (PWMH)(Fisher exact test: p=0.031), having or not having religious beliefs (Fisher exact test: p=0.265) and family harmony (yes or no) (Fisher exact test: p=0.253) between the LOD group and control group. The results of linear regression analysis showed that the total score for WMH, religious beliefs (with or without) and family harmony (yes or no) were associated with depressive symptomology. Conclusion: Scores on the WMH, religious beliefs and family harmony are all potentially related to LOD in elderly patients. PMID- 29719353 TI - Meta-analysis of the Efficacy and Safety of Adjunctive Rosuvastatin for Dyslipidemia in Patients with Schizophrenia. AB - Background: Metabolic syndrome in patients with schizophrenia is a major health concern. The efficacy and safety of adjunctive rosuvastatin in treating dyslipidemia were controversial. Aims: To assess the efficacy and safety of adjunctive rosuvastatin for dyslipidemia in patients with schizophrenia. Methods: We systematically searched for relevant controlled clinical trials from the following databases: PubMed, PsycINFO, Cochrane Library, China Knowledge Network, WanFang Database and Chinese Biomedical Database up to September 28, 2017. Standardized mean difference (SMD) and risk ratio (RR) along with their 95% confidence intervals (CIs) were calculated. The quality of the included studies was assessed using the Cochrane risk of bias assessment tool. The GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) system recommendation grading method was used as the reference standard. Results: Four studies (n=274) comparing rosuvastatin (n=138) and control (n=136) groups were identified and analyzed. Adjunctive rosuvastatin showed greater efficacy than control group in low density lipoprotein cholesterol (LDL-C) [4 trials, n=272, SMD: -1.31 (95%CI: 1.93, -0.70), I2=81%], total cholesterol (2 trials, n=164, SMD: -2.00 (95%CI: 2.79, -1.21); I2=76%) and triglycerides (2 trials, n=164, SMD: -1.05 (95%CI: 1.38, -0.72); I2=0%), but not in high density lipoprotein cholesterol (2 trials, n=164, SMD: 0.14 (95%CI: -0.16, 0.45); I2=0%). After removing one study without randomization for LDL-C, significance remained [3 trials, n=172, SMD:-1.07 (95%CI: -1.60, -0.53); I2=63%]. No significant group differences regarding body weight (3 trials, n=208, SMD: -0.40 (95%CI:-1.29, 0.49); I2=89%), body mass index (2 trials, n=164, SMD: -0.34 (95%CI: -1.23, 0.56); I2=87%), waist circumference (3 trials, n=208, SMD): -0.43 (95%CI: -1.31, 0.46); I2=89%), and fasting glucose (4 trials, n=272, SMD: -0.25 (95%CI: -0.65, 0.15); I2=62%) were observed. The adverse reactions and any cause discontinuation rate were similar between the groups. According to the GRADE approach, the evidence levels of main outcomes were rated as "very low" (35.3%) to "low" (64.7%). Of them, the primary outcome (LDL-C) was rated as "very low ". Conclusions: The data available on the effectiveness and safety of adjunctive rosuvastatin in treating dyslipidemia for patients with schizophrenia is insufficient to come to a definitive interpretation about its efficacy and safety. Further high quality RCTs with extended treatment duration are warranted to confirm the findings. Review registration: PROSPERO: CRD42017078230. PMID- 29719355 TI - Risk Factors of Nocturnal Enuresis in Children with Attention Deficit Hyperactivity Disorder. AB - Background: Presence of attention deficit hyperactivity disorder (ADHD) has a negative effect on the resolution of incontinence; however, there are few studies which investigated the risk factors of nocturnal enuresis (NE) in patients with ADHD. Aims: This study was conducted to investigate the prevalence of NE and its risk factors in children with ADHD. Methods: 331 children, aged 6 to 10 years, diagnosed as having ADHD were enrolled in this study. The diagnosis of ADHD was confirmed by an experienced child and adolescent psychiatrist according to DSM-IV TR. NE was defined as nighttime wetting with or without daytime incontinence, at least twice a week over a period of 3 months or longer in children 5 years old and older without anatomical abnormalities. Details on demographic data, perinatal history, medical history and developmental history were collected from parents or medical records. Results: Most of the ADHD patients with inattentional subtype (77.5%) had NE, compared to 31.7% in the hyperactive/Impulsive subtype and 22.5% in the combined subtype (p<0.001, t=42.71). Among children with enuresis, there were significantly higher rates of history of familial enuresis (26% vs. 18 %, p<0.001, t=16.9), cesarean delivery (47% vs. 33%, p=0.019, t=5.84) and history of neonatal sepsis (16% vs. 7%, p=0.018, t=5.62) than non-NE children. Moreover, patients with NE had lower birth weight than non-NE patients (2.93(0.65) vs. 3.09 (0.46), p=0.026, t=2.51). Also, low parental education was associated with increase in the rate of NE. Conclusion: Children with ADHD have a high prevalence of NE. Male sex, low education level of parents, history of neonatal sepsis, positive family history of NE, low birth weight and caesarian delivery may be risk factors for NE in ADHD children. Most ADHD patients with inattentional subtype had NE. PMID- 29719356 TI - Defects of Gamma Oscillations in Auditory Steady-State Evoked Potential of Schizophrenia. AB - Background: Patients with schizophrenia have many cognitive deficits. Gamma oscillations exist in the human brain and are closely related to neurocognition. Auditory Steady-State Responses (ASSRs) is an electroneurophysiological index that could reflect gamma oscillations. It was found that the energy evoked by 40 Hz ASSRs in schizophrenic patients was significantly lower than that in healthy subjects. However, the correlation between ASSRs phase index and clinical symptoms and neurocognitive deficits has yet to be systematically studied. The purpose of this study was to investigate the dysfunction of neural activity of gamma rhythmdys function and its association with clinical symptoms and neurocognition in patients with schizophrenia. Aims: To compare and verify the difference in energy and phase coherence of 20 Hz and 40 Hz ASSRs between schizophrenia and healthy participants, and to explore the correlation between schizophrenia ASSRs and neurocognitive deficits. Method: Auditory steady-state evoked potentials by repeated auditory stimuli in 24 patients with schizophrenia and 30 healthy controls were recorded. The Positive and Negative Syndrome Scale (PANSS) was used to assess the clinical symptoms of the patients. MATRICS Consensus Cognitive Battery (MCCB) was used for the assessment of neurocognitive function. The correlation between indices, such as ASSRs energy, phase locking factor and phase coherence, and clinical and cognitive assessment was also systematically compared between two groups. Results: Compared with the control group, the patient group had differences in cognitive domains including information processing speed (t=-2.39, p=0.021), attention/vigilance (t=-2.36, p=0.023), verbal learning (t=-3.11, p=0.003), and reasoning and problem solving (t=-2.60, p=0.012). The energy of 40 Hz ASSRs in the patient group was significantly lower than that in the control group (t=-2.291, p=0.032), and their phase locking factor and inter-trial phase coherence index were lower than control group (t=-3.017, p=0.004 and t=3.131, p=0.003), which was also significantly correlated to reasoning and problem solving function deficits. Conclusion: Patients with schizophrenia had defects in multiple cognitive domains, and their 40 Hz ASSRs energy was low. Specifically, their phase locking characteristics and phase coherence were poor, which was to some extent related to reasoning ability and thinking disorder. PMID- 29719357 TI - A Study of The Clinical Effect and Dropout Rate of Drugs Combined with Group Integrated Psychotherapy on Elderly Patients with Depression. AB - Background: Relevant studies have shown that group cognitive behavioral therapy is effective in treating patients with depressive disorder, but the dropout rate is high. The present study is aimed to explore the patterns of integrated group psychotherapy. Aims: This study investigated the clinical effects of integrated group psychotherapy for elderly patients with senile depression. Methods: One hundred elderly patients with senile depression were divided into the experiment group (n=50) and the control group (n=50) randomly. The experiment group was given regular pharmacological treatments combined with integrated group psychotherapy, while the control group was given regular pharmacological treatments combined with integrated group cognitive behavioral therapy. These two groups were assessed with the Hamilton Depression Scale (HAMD-24) and Geriatric Depression Scale (GDS-15) before the study and at two weeks, four weeks and eight weeks after the treatments. Results: According to the comparisons within these two groups, it was found that the HAMD and GDS total scores before treatments were all significantly higher than those after treatments (F=102.50, p=0.001; F=55.94, p<0.001). We found that the HAMD total scores after four weeks and eight weeks were significantly different between the two groups (F=3.82, p=0.021). The differences between two groups' GDS total scores after two weeks, four weeks and eight weeks were also significantly different (F=4.49, p=0.009). Seven cases dropped out in the experiment group, while sixteen cases dropped out in the control group. The difference of dropout rates was statistically significant (x2 =4.57, p=0.032). Conclusion: Medication treatments combined with the group integrated psychotherapy significantly improve the clinical effect for elderly patients with senile depression. The compliance is improved and the dropout rate declines. PMID- 29719358 TI - Antipsychotic Drugs and Liver Injury. AB - In October 2015, the drug-induced liver diseases group of the Chinese Society of Hepatology drafted and published the first Diagnosis and Treatment Guidelines on Drug-induced Liver Injury in China, giving suggestions on the diagnosis and treatment of drug-induced liver injury (DILI). As a psychiatrist, I have found that in clinical practice both typical and new antipsychotic drugs can induce liver injury to varying degrees. Therefore, it is necessary to quickly and accurately determine the cause of liver injury and the type and severity of injury and establish a solution. This article reviewed relevant literature including the common pathogenesis and clinical manifestations of drug-induced liver injury caused by antipsychotic drugs, laboratory tests, diagnostic criteria and classification, and clinical management strategies. This paper also includes a summary and a perspective on liver injury caused by antipsychotic drugs. PMID- 29719359 TI - "Neuro-psycho- BS": A Case Report of Rare Association with Bipolar Disorder. AB - Bechet's Disease is an inflammatory disease characterized by recurrent oral ulcers (OU), genital ulcers (GU) and uveitis which can develop a neurobehavioral syndrome, also defined as 'neuro-psycho- BS'. Depending on vascular or parenchymal lesions, the presentations could be varied. Due to sparse literature, there is no consensus on management of psychiatric illness comorbid with Bechet's disease. Bipolar disorder in Bechet's disease is extremely rare. Here, we are presenting a case of episodic exaggeration of Bipolar disorder along with Bechet's disease which imposed both clinical and management challenges. PMID- 29719361 TI - Relationship between Omnibus and Post-hoc Tests: An Investigation of performance of the F test in ANOVA. AB - Comparison of groups is a common statistical test in many biomedical and psychosocial research studies. When there are more than two groups, one first performs an omnibus test for an overall difference across the groups. If this null is rejected, one then proceeds to the next step of post-hoc pairwise group comparisons to determine sources of difference. Otherwise, one stops and declares no group difference. A common belief is that if the omnibus test is significant, there must exist at least two groups that are significantly different and vice versa. Thus, when the omnibus test is significant, but no post-hoc between-group comparison shows significant difference, one is bewildered at what is going on and wondering how to interpret the results. At the end of the spectrum, when the omnibus test is not significant, one wonders if all post-hoc tests will be non significant as well so that stopping after a nonsignificant omnibus test will not lead to any missed opportunity of finding group difference. In this report, we investigate this perplexing phenomenon and discuss how to interpret such results. PMID- 29719360 TI - Neuropsychiatric Symptoms Induced by Large Doses of Nitrous Oxide Inhalation: A Case Report. AB - Nitrous Oxide, which is also called laughing gas, now ranks as the 7th most popular drug in the world. Nitrous oxide mainly disturbs B12 metabolism and damages nerves, followed by apparent neuropsychiatric symptoms. It's beneficial to the prognosis of patients if we identify and treat their symptoms early. This case report describes a 19-year-old male who presented with auditory hallucination, persecutory delusions and unstable emotions after abuse of nitrous oxide over the course of half a year. Moreover, neurological signs such as weakness and hyperesthesia also appeared. After supplementation of vitamin B12, the neuropsychiatric symptoms improved, while the lower extremities achieved partial recovery. Therapeutically, we should pay attention to nerve repair, motivation enhancement and reinforce interventions that prevent relapse. PMID- 29719362 TI - Life-Threatening Errors With Flecainide Suspension in Children. AB - Errors with flecainide suspension in children. PMID- 29719363 TI - White House Report on Drug Prices Is a Detailed Road Map: Price-Lowering Ideas Generated, Some Already in Motion. AB - White House report on drug prices is a detailed road map. PMID- 29719364 TI - Drug and Device News. AB - Approvals, new indications, regulatory activities, and more. PMID- 29719365 TI - Pharmaceutical Approval Update. AB - Vancomycin hydrochloride for oral solution (Firvanq) for C. difficile-associated diarrhea and enterocolitis caused by S. aureus; dexamethasone intraocular suspension 9% (Dexycu) for the treatment of inflammation after eye surgery; and apalutamide (Erleada) for prostate cancer. PMID- 29719366 TI - Olaratumab (Lartruvo): An Innovative Treatment for Soft Tissue Sarcoma. AB - Olaratumab (Lartruvo): an innovative treatment for soft tissue sarcoma. PMID- 29719367 TI - Compounding Law Five Years Later: FDA Implementation Slow, Industry Criticism Significant. AB - The FDA is making progress but is still laboring to address safety concerns about compounded drugs, an issue taken up by the Drug Quality and Security Act in 2013. PMID- 29719369 TI - Sterile Compounding Needs Risk Management: Access, Reconstitution Or Preparation, and Administration. AB - Appropriate risk management strategies must be employed for compounding and administering sterile products. We review the new credentialing, regulatory, and related legal aspects of gaining and maintaining compliance for these processes. PMID- 29719368 TI - Pharmacotherapy of Gaucher Disease: Current and Future Options. AB - The clinical manifestations of Gaucher disease, a rare genetic lysosomal storage disorder, are debilitating, and the neuronopathic forms of the disease are fatal. The authors describe the current and investigational therapies for treatment. PMID- 29719370 TI - Evaluation of Physician Prescribing Patterns For Antibiotics in the Treatment of Nonnecrotizing Skin and Soft Tissue Infections. AB - Purpose: Skin and soft tissue infections (SSTIs) cause about 15 million cases of infection that result in more than 869,000 annual hospitalizations in the United States. Cellulitis accounted for 63% of all patients hospitalized with SSTIs between 2009 and 2011. The primary objective of this study was to evaluate physician adherence rates to evidence-based practice guidelines. Secondary objectives included evaluating antibiotic selection preferences and duration of therapy. The goal of the project was to generate data to inform the development of a hospital-based protocol for nonnecrotizing SSTI treatment. Methods: This study was a single-center, retrospective, electronic chart review of patients admitted to the hospital for nonnecrotizing SSTI. We reviewed charts of patients who were admitted with a diagnosis of cellulitis and abscess infection from August 2014 to August 2015. Results: Vancomycin, piperacillin/tazobactam, and clindamycin were the initial empiric antibiotics used most frequently. The adherence rates to guideline-recommended empiric antibiotic therapy and duration of treatment were about 40% and 70%, respectively. The median duration of antibiotic therapy was 12 days. Male gender and presence of purulent discharge as independent variables led to poor adherence to guideline-recommended empiric antibiotic therapy (male versus female gender, 35% versus 50.8%; P = 0.045; purulent discharge [yes versus no], 23.9% versus 60.4%; P < 0.0001). Conclusions: The results showed substantial noncompliance with guideline recommendations on empiric antibiotic selection for the treatment of nonnecrotizing SSTIs. There is a substantial opportunity for clinical pharmacist intervention in ensuring the efficient utilization of hospital resources to improve guideline compliance; promote appropriate antibiotic selection; reduce unnecessary antibiotic exposure; and reduce cost of hospitalization. PMID- 29719371 TI - P&T Committee Drug Prioritization Criteria: A Tool Developed by a Saudi Health Care System. AB - Introduction: The workflow of a P&T committee can become overwhelming and may be affected by many internal and external factors. Organization, standardization, and an enhanced systematic approach for drug evaluations are necessary to ensure that all requested drugs receive an equal and unbiased evaluation and consideration for addition based on the institution's objectives, priorities, and budget. Our aim was to create a scoring tool that would assist in systematically prioritizing drugs being requested for formulary addition and to eliminate cumbersome evaluations for drugs that clearly do not offer any additional advantage. Methods: A working group consisting of P&T committee members met with the task of creating initial screening criteria for prioritizing drugs requested for formulary addition. Members conducted independent literature searches and focused meetings to develop a scoring tool that would be piloted on drugs being requested for addition. Results: We developed a scoring tool to prioritize drugs requested for formulary addition. The tool assigns a score for each drug that allows it to be classified into one of three categories: 1) for expedited review, 2) for routine review, or 3) for rejection without the need for a full evaluation. Conclusions: We believe that this scoring tool will assist in prioritizing drugs requested for formulary addition while allowing for full consideration of the most important decision-making factors. In an era of expected U.S. Food and Drug Administration deregulation and economic constraints, P&T committees must create tools that ease their workflow and organize their priorities. PMID- 29719372 TI - American College of Cardiology. AB - Key sessions reported on findings in noncardiac surgery, pharmacological agents in the setting of acute coronary syndromes, and cardiotoxicity of cancer therapy. PMID- 29719373 TI - Research Briefs. PMID- 29719374 TI - Clinical course of thyroid function and thyroid associated-ophthalmopathy in patients with euthyroid Graves' disease. AB - Background: Euthyroid Graves' disease (EGD) is a rare condition defined as the presence of thyroid-associated ophthalmopathy (TAO) in patients with normal thyroid function. Due to the rarity of this disease, only a limited number of studies and case reports are available for further evaluation of the characteristics of the disease. The aim of this study was to examine the changes in the thyroid function, thyrotropin receptor antibodies (TRAb) and eye symptoms, and then determine whether TRAb is related to TAO in EGD patients. TRAb in this study was defined as including both thyrotropin-binding inhibitory immunoglobulin (TBII) and thyroid-stimulating immunoglobulin (TSAb). Patients and methods: Medical records of patients diagnosed with EGD were reviewed. Ophthalmologists specializing in TAO examined the eyes of all subjects. Results: Of the 58 patients diagnosed with EGD, 24.1% developed hyperthyroidism, while 3.4% developed hypothyroidism. A total of 72.4% of the 58 patients remained euthyroid throughout the entire follow-up period. At the initial presentation, TBII and TSAb were positive in 74.5% and 70.5%, respectively. Ophthalmic treatments were administered to 30 (51.7%) out of the 58 patients. A significant spontaneous improvement of the eye symptoms was found in 28 of the EGD patients who did not require eye treatments. EGD patients exhibited positive rates for both TBII and TSAb, with the number of the TRAb-positive patients gradually decreasing while the eye symptoms spontaneously improved over time. There were no correlations found between TRAb at initial presentation and the eye symptoms. Conclusion: TBII and TSAb were positive in about 70% of EGD patients at their initial visit. Thyroid functions of EGD patients who have been euthyroid for more than 6.7 years may continue to remain euthyroid in the future. PMID- 29719375 TI - Design, synthesis, and structure-activity relationships of 2-benzylidene-1 indanone derivatives as anti-inflammatory agents for treatment of acute lung injury. AB - Purpose: The purpose of this study was to design and synthesize novel 2 benzylidene-1-indanone derivatives for treatment of acute lung injury. Methods: A series of 39 novel 2-benzylidene-indanone structural derivatives were synthesized and evaluated for anti-inflammatory activity in lipopolysaccharide (LPS) stimulated murine primary macrophages. Results: Most of the obtained compounds effectively inhibited the LPS-induced expression of IL-6 and TNF-alpha. The most active compound, 8f, was found to significantly reduce LPS-induced pulmonary inflammation, as reflected by reductions in the concentration of total protein, inflammatory cell count, as well as the lung wet/dry ratio in bronchoalveolar lavage (BAL) fluid. Furthermore, 8f effectively inhibited mRNA expression of several inflammatory cytokines after LPS challenge in vitro and in vivo. Administration of 8f also blocked LPS-induced activation of the proinflammatory NF-kappaB/MAPK signaling pathway. Conclusion: The simple synthetic preparation and biological properties of these derivatives make these 2-benzylidene-indanone scaffolds promising new entities for the development of anti-inflammatory therapeutics for the treatment of acute lung injury. PMID- 29719376 TI - Theoretical overview of clinical and pharmacological aspects of the use of etelcalcetide in diabetic patients undergoing hemodialysis. AB - Etelcalcetide is the first intravenous calcimimetic agent authorized for the treatment of secondary hyperparathyroidism (sHPT) in patients undergoing hemodialysis in Europe, the US, and Japan. The relationship between sHPT and diabetes resides on complex, bidirectional effects and largely unknown homeostatic mechanisms. Although 30% or more patients with end-stage renal disease are diabetics and about the same percentage of those patients suffer from sHPT associated with hemodialysis, no data on the specificities of the use of etelcalcetide in such patients are available yet. Regarding pharmacokinetic interactions, etelcalcetide may compete with oral hypoglycemics recommended for use in patients undergoing hemodialysis and insulins detemir and degludec, causing unexpected hypocalcemia or hypoglycemia. More importantly, hypocalcemia, a common side effect of etelcalcetide, may cause decompensation of preexisting cardiac insufficiency in diabetic patients or worsen dialysis-related hypotension and lead to hypotension-related cardiac events, such as myocardial ischemia. In diabetic patients, hypocalcemia may lead to dangerous ventricular arrhythmias, as both insulin-related hypoglycemia and hemodialysis prolong QT interval. Patients with diabetes, therefore, should be strictly monitored for hypocalcemia and associated effects. Due to an altered parathormone activity in this patient group, plasma calcium should be the preferred indicator of etelcalcetide effects. Until more clinical experience with etelcalcetide is available, the clinicians should be cautious when using this calcimimetic in patients with diabetes. PMID- 29719377 TI - Attenuation of everolimus-induced cytotoxicity by a protective autophagic pathway involving ERK activation in renal cell carcinoma cells. AB - Aim: The mammalian target of rapamycin (mTOR) pathway is a critical target for cancer treatment and the mTOR inhibitor everolimus (RAD001) has been approved for treatment of renal cell carcinoma (RCC). However, the limited efficacy of RAD001 has led to the development of drug resistance. Autophagy is closely related to cell survival and death, which may be activated under RAD001 stimulation. The aim of the present study was to identify the underlying mechanisms of RAD001 resistance in RCC cells through cytoprotective autophagy involving activation of the extracellular signal-regulated kinase (ERK) pathway. Methods and results: RAD001 strongly induced autophagy of RCC cells in a dose- and time-dependent manner, as confirmed by Western blot analysis. Importantly, suppression of autophagy by the pharmacological inhibitor chloroquine effectively enhanced RAD001-induced apoptotic cytotoxicity, as demonstrated by the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and Western blot analysis, indicating a cytoprotective role for RAD001-induced autophagy. In addition, as was shown by the MTT assay, flow cytometry, and Western blot analysis, RAD001 robustly activated ERK, but not c-Jun N-terminal kinase and p38. Activation of ERK was inhibited by the pharmacological inhibitor selumetinib (AZD6244), which effectively promoted RAD001-induced cell death. Moreover, employing AZD6244 markedly attenuated RAD001-induced autophagy and enhanced RAD001-induced apoptosis, which play a central role in RAD001-induced cell death. Furthermore, RAD001-induced autophagy is regulated by ERK-mediated phosphorylation of Beclin-1 and B-cell lymphoma 2, as confirmed by Western blot analysis. Conclusion: These results suggest that RAD001-induced autophagy involves activation of the ERK, which may impair cytotoxicity of RAD001 in RCC cells. Thus, inhibition of the activation of ERK pathway-mediated autophagy may be useful to overcome chemoresistance to RAD001. PMID- 29719378 TI - Chitosan-alginate BSA-gel-capsules for local chemotherapy against drug-resistant breast cancer. AB - Background and object: Polyelectrolyte microcapsule is a promising candidate for multifunctional drug delivery system. However, the lack of reports about animal experiments have greatly slowed down their development for drug delivery. We engineered biodegradable chitosan-alginate polyelectrolyte multilayer capsule filled with bovine serum albumin gel (BSA-gel-capsule). Herein, we demonstrated their applicability for local chemotherapy, a means of treating local or regional malignancies by direct administration of anti-tumor agents to tumor sites. Method: Doxorubicin (DOX) was loaded in BSA-gel-capsules and DOX-resistant cell line (MCF-7/ADR cells) was employed for antitumor studies in vitro. The cytotoxicity, cellular uptake and distribution of DOX from BSA-gel-capsules were studied. Afterwards, MCF-7/ADR xenografts tumor model was established in nude mice. The in vivo antitumor efficacy of DOX-loaded BSA-gel-capsules by intratumor injection was then evaluated. Result: Compared with free DOX, more effective cytotoxicity against MCF-7/ADR cells after treatment with DOX-loaded BSA-gel capsules was revealed, demonstrating the positive reversal effect on drug resistance. Thereafter, the more cellular uptake and nucleus distribution of DOX from BSA-gel-capsules in MCF-7/ADR cells provided convincing explanation for the reversal effect. DOX-loaded BSA-gel-capsules displayed remarkably more antitumor efficacy than free DOX in MCF-7/ADR cell-xenografted mice. Finally, the high DOX accumulation and prolonged retention in tumor site after local administration of DOX-loaded BSA-gel-capsules was demonstrated, displaying the unique advantages of BSA-gel-capsules for local chemotherapy. Conclusion: These findings indicate that DOX-loaded BSA-gel-capsules should be considered a potential candidate for the treatment of drug-resistant breast cancer. This paper provides a feasibility for the local chemotherapy of polyelectrolyte microcapsules, which will be a big step towards their application as drug delivery vehicles. PMID- 29719379 TI - Comparison of tadalafil pharmacokinetics after administration of a new orodispersible film versus a film-coated tablet. AB - Background: An orodispersible film (ODF) of tadalafil may provide increased convenience for erectile dysfunction (ED) patients as compared to conventional tablet formulations. In this study, we aimed to compare the pharmacokinetic, safety, and tolerability profiles of a newly developed ODF formulation of tadalafil to those of a film-coated tablet (FCT) of tadalafil. Materials and methods: This study was conducted in healthy male subjects using an open-label, randomized sequence, two-period, two-formulation, single-dose, crossover design. The subjects were randomly assigned to one of two sequences of the two formulations: both the test drug (ODF) and the reference drug (FCT) contained 20 mg of tadalafil. Blood samples were collected up to 72 h after administration. Plasma concentrations of tadalafil were analyzed using liquid chromatography tandem mass spectrometry. Geometric mean ratios (GMRs) of the ODF to FCT formulations and their 90% CIs for the pharmacokinetic parameters were estimated. Safety and tolerability were assessed throughout the study. Results: Forty healthy male subjects were enrolled, and 36 of these completed the study. The GMRs (90% CIs) of the maximum plasma concentration and the area under the plasma concentration-time curve from time zero to the time of the last quantifiable concentration for tadalafil were 0.927 (0.882-0.974) and 0.972 (0.918-1.029), respectively. Both ODF and FCT formulations were well tolerated, and no clinically significant changes from the baseline were observed after dosing. Conclusion: The pharmacokinetics of the tadalafil ODF formulation did not differ significantly from those of the FCT formulation. Furthermore, the safety and tolerability profiles of the ODF formulation were comparable to those of the FCT formulation. Therefore, this tadalafil ODF formulation offers a convenient treatment option for patients with erectile dysfunction. PMID- 29719380 TI - Astragalus polysaccharides protect cardiac stem and progenitor cells by the inhibition of oxidative stress-mediated apoptosis in diabetic hearts. AB - Introduction: Diabetic cardiomyopathy is characterized by an imbalance between myocyte death and regeneration mediated by the progressive loss of cardiac stem and progenitor cells (CSPCs) by apoptosis and necrosis due to the activation of oxidative stress with diabetes. In this study, we evaluated the beneficial effect of astragalus polysaccharides (APS) therapy on the protection of CSPCs through its antioxidative capacity in diabetic hearts. Materials and methods: Streptozotocin (STZ)-induced diabetic mice and heterozygous (SOD2+/-) knockout mice were employed and administered with APS. Ventricular CSPCs were isolated for oxidative evaluation. The abundance, apoptosis and proliferation, reactive oxygen species (ROS) formation, oxidative damage, and SOD2 protein levels and activities were evaluated in ventricular CSPCs. Results: We confirmed that APS increased the CSPC abundance, reduced the apoptosis of CSPCs, and enhanced the proliferation of CSPCs in both STZ-induced diabetic mice and nondiabetic SOD2+/- mice. In addition, therapy of APS enhanced SOD2 protein levels and enzyme activities, and inhibited ROS formation and oxidative damage of CSPCs from both STZ-induced diabetic mice and nondiabetic SOD2+/- mice. Conclusion: Our findings demonstrated the positive effect of APS on the rescue of CSPC preservation in diabetes, dependent on the inhibition of oxidative stress-mediated apoptosis. PMID- 29719381 TI - Suicide in older adults: current perspectives. AB - Suicidal behavior in older adults (65 years old and over) is a major public health issue in many countries. Suicide rates increase during the life course and are as high as 48.7/100,000 among older white men in the USA. Specific health conditions and stress factors increase the complexity of the explanatory model for suicide in older adults. A PubMed literature search was performed to identify most recent and representative studies on suicide risk factors in older adults. The aim of our narrative review was to provide a critical evaluation of recent findings concerning specific risk factors for suicidal thoughts and behaviors among older people: psychiatric and neurocognitive disorders, social exclusion, bereavement, cognitive impairment, decision making and cognitive inhibition, physical illnesses, and physical and psychological pain. We also aimed to approach the problem of euthanasia or physician-assisted suicide in older adults. Our main findings emphasize the need to integrate specific stress factors, such as feelings of social disconnectedness, neurocognitive impairment or decision making, as well as chronic physical illnesses and disability in suicide models and in suicide prevention programs in older adults. Furthermore, the chronic care model should be adapted for the treatment of older people with long-term conditions in order to improve the treatment of depressive disorders and the prevention of suicidal thoughts and acts. PMID- 29719382 TI - Can cochlear implantation improve neurocognition in the aging population? AB - Introduction: The relationship between cognition and the ability to hear is well known. Due to changes in demographics, the number of people with sensorineural hearing loss and cognitive impairment is increasing. The aim of this study was to identify the impact of hearing rehabilitation via cochlear implantation on cognitive decline among the aging population. Patients and methods: This prospective study included 60 subjects aged between 50 and 84 years (mean 65.8 years, SD=8.9) with a severe to profound bilateral hearing impairment. A computer based evaluation of short- and long-term memory, processing speed, attention, working memory and inhibition was performed prior to surgery as well as 6 and 12 months after cochlear implantation. Additionally, speech perception at 65 and 80 dB (Freiburger monosyllabic speech test) as well as disease-related (Nijmegen Cochlear Implant Questionnaire) and general (WHOQOL-OLD) quality of life were assessed. Results: Six months postimplantation, speech perception, quality of life and also neurocognitive abilities significantly increased. The most remarkable improvement after 6 months was detected in executive functions such as attention (p<0.001), inhibition (p=0.025) and working memory (n-back: p=0.002; operation span task: p=0.008), followed by delayed recall (p=0.03). In contrast, long-term memory showed a significant change of performance only after 12 months (p=0.021). After 6 months, most cognitive domains remained stable, except working memory assessed by the operation span task, which significantly improved between 6 and 12 months (p<0.001). No correlation was found between cognitive results and duration of deafness, speech perception or quality of life. Conclusion: Cochlear implantation does not only lead to better speech perception and quality of life, but has also been shown to improve cognitive skills in hearing impaired adults aged 50 years or more. These effects seem to be independent of each other. PMID- 29719383 TI - Differential anti-inflammatory effects of budesonide and a p38 MAPK inhibitor AZD7624 on COPD pulmonary cells. AB - Background: The effects of anti-inflammatory drugs in COPD patients may vary between different cell types. The aim of the current study was to assess the anti inflammatory effects of the corticosteroid budesonide and a p38 MAPK inhibitor (AZD7624) on different cell types obtained from COPD patients and healthy controls. Methods: Eight healthy smokers, 16 COPD infrequent exacerbators, and 16 frequent COPD exacerbators (>=2 exacerbations in the last year) were recruited for bronchoscopy and blood sampling. The anti-inflammatory effects of budesonide and AZD7624 were assessed on cytokine release from lipopolysaccharide-stimulated alveolar macrophages and peripheral blood mononuclear cells and polyinosinic:polycytidylic acid-stimulated bronchial epithelial cells. Results: The anti-inflammatory effects of budesonide varied greatly within a patient according to the cell type studied. Bronchial epithelial cells showed the lowest sensitivity to budesonide, while peripheral blood mononuclear cells showed the greatest sensitivity. AZD7624 had a greater effect than budesonide on cytokine production from bronchial epithelial cells. Exacerbation frequency did not influence corticosteroid sensitivity. Conclusion: We observed variable corticosteroid and p38 MAPK inhibitor anti-inflammatory responses within the same individual depending on the cell type studied. These findings support the use of multiple anti-inflammatory strategies in COPD patients due to differences between cell types. PMID- 29719384 TI - Influence of deprivation on health care use, health care costs, and mortality in COPD. AB - Background and aim: Deprivation is associated with the incidence of COPD, but its independent impact on clinical outcomes is still relatively unknown. This study aimed to explore the influence of deprivation on health care use, costs, and survival. Methods: A total of 424 outpatients with COPD were assessed for deprivation across two hospitals. The English Index of Multiple Deprivation (IMD) was used to establish a deprivation score for each patient. The relationship between deprivation and 1-year health care use, costs, and mortality was examined, controlling for potential confounding variables (age, malnutrition risk, COPD severity, and smoking status). Results: IMD was significantly and independently associated with emergency hospitalization (beta-coefficient 0.022, SE 0.007; p=0.001), length of hospital stay, secondary health care costs (beta coefficient L101, SE L30; p=0.001), and mortality (HR 1.042, 95% CI 1.015-1.070; p=0.002). IMD was inversely related to participation in exercise rehabilitation (OR 0.961, 95% CI 0.930-0.994; p=0.002) and secondary care appointments. Deprivation was also significantly related to modifiable risk factors (smoking status and malnutrition risk). Conclusion: Deprivation in patients with COPD is associated with increased emergency health care use, health care costs, and mortality. Tackling deprivation is complex; however, strategies targeting high risk groups and modifiable risk factors, such as malnutrition and smoking, could reduce the clinical and economic burden. PMID- 29719385 TI - Treatment of exacerbations as a predictor of subsequent outcomes in patients with COPD. AB - Rationale: Exacerbations of COPD are managed differently, but whether treatment of one exacerbation predicts the likelihood of subsequent events is unknown. Objective: We examined whether the treatment given for exacerbations predicted subsequent outcomes. Methods: This was a post-hoc analysis of 17,135 patients with COPD from TIOtropium Safety and Performance In Respimat(r) (TIOSPIR(r)). Patients treated with tiotropium with one or more moderate to severe exacerbations on study were analyzed using descriptive statistics, logistic and Cox regression analysis, and Kaplan-Meier plots. Results: Of 8,061 patients with moderate to severe exacerbation(s), demographics were similar across patients with exacerbations treated with antibiotics and/or steroids or hospitalization. Exacerbations treated with systemic corticosteroids alone or in combination with antibiotics had the highest risk of subsequent exacerbation (HR: 1.21, P=0.0004 and HR: 1.33, P<0.0001, respectively), and a greater risk of having a hospitalized (severe) exacerbation (HR: 1.59 and 1.63, P<0.0001, respectively) or death (HR: 1.50, P=0.0059 and HR: 1.47, P=0.0002, respectively) compared with exacerbations treated with antibiotics alone. Initial hospitalization led to the highest risk of subsequent hospitalization (all-cause or COPD related [severe exacerbation], HR: 3.35 and 4.31, P<0.0001, respectively) or death (all-cause or COPD related, HR: 3.53 and 5.54, P<0.0001, respectively) versus antibiotics alone. Conclusion: These data indicate that the way exacerbations are treated initially is a useful guide to the patient's subsequent clinical course. Factors that clinicians consider when making treatment choices require further clarification. PMID- 29719386 TI - Misuse of inhalers among COPD patients in a community hospital in Taiwan. AB - Purpose: Respiratory inhalers, which directly deliver medication to the airway, are important for controlling symptoms and preventing exacerbations of chronic obstructive pulmonary disease (COPD). The inhaler misuse rate of patients with COPD in Taiwan is unclear. In this study, the inhaler techniques and patient characteristics associated with incorrect inhaler techniques among patients with COPD were evaluated. Patients and methods: This cross-sectional study enrolled 298 patients with COPD (mean age 72.10 years) who used at least one inhaler device. The following five types of inhalers were included: metered-dose inhaler (MDI) with spacer, Diskus(r), Turbuhaler(r), Respimat(r), and Breezhaler(r). The inhaler technique was evaluated step by step. Misuse of an individual inhaler was defined as an error in at least one step. The sociodemographic characteristics, vision, hearing ability, type and number of inhalers, and inhaler-related knowledge of these patients were recorded. Results: The misuse rates of the five types of inhalers ranged from 65.00% to 87.89%. The Respimat inhaler was the most likely to be assembled incorrectly. The steps that were most commonly performed incorrectly were "breathing out fully" and "holding breath". In the logistic regression analysis, poor hearing was related to misuse of the MDI with spacer (adjusted odds ratio [aOR] 9.85; 95% CI 1.40-69.30); the number of acute exacerbations was related to misuse of Breezhaler (aOR 4.07; 95% CI 1.50-11.08). Incorrect inhaler-related knowledge was significantly associated with misuse in handling the MDI with spacer (aOR 9.58; 95% CI 2.14-42.80), Respimat (aOR 5.14; 95% CI 2.07-12.76), and Breezhaler (aOR 6.98; 95% CI 1.95-25.08). Conclusion: The misuse rates were high for all five types of inhaler. Poor hearing and the number of acute exacerbations were device-specific factors related to the misuse of inhalers. Inhaler-related knowledge was significantly associated with misuse, emphasizing the importance of inhaler education. PMID- 29719388 TI - Controlled-release and preserved bioactivity of proteins from (self-assembled) core-shell double-walled microspheres [Retraction]. AB - [This retracts the article on p. 257 in vol. 7, PMID: 22287838.]. PMID- 29719387 TI - Dietary resilience in patients with severe COPD at the start of a pulmonary rehabilitation program. AB - Background: COPD may impact food-related activities, such as grocery shopping, cooking, and eating. Decreased food intake may result in an unhealthy diet, and in malnutrition, which is highly prevalent in patients with COPD. Malnutrition is known to negatively impact clinical outcome and quality of life. Aims: In this qualitative study, we aimed to explore strategies used to overcome food-related challenges, ie, dietary resilience, and whether these led to a healthy diet. Furthermore, we aimed to identify the key themes of motivation for dietary resilience in patients with severe COPD. Methods: In October 2015 to April 2016, 12 patients with severe COPD starting a pulmonary rehabilitation program were interviewed. Qualitative description and thematic analysis were performed. Results: All participants mentioned the use of strategies to overcome challenges. Key themes of motivation for dietary resilience were identified as "wanting to be as healthy as possible", "staying independent", and "promoting a sense of continuity and duty". Two out of 12 participants met the criteria for a healthy diet. Conclusion: Our study showed a variety of motivational factors and strategies reported by patients with severe COPD to overcome food-related challenges. However, the majority (n=10) of the participants did not meet the criteria for a healthy diet. The identified key themes can be used to develop education to support patients with severe COPD to improve their diet. PMID- 29719389 TI - Preparation of bioactive interferon alpha-loaded polysaccharide nanoparticles using a new approach of temperature-induced water phase/water-phase emulsion [Retraction]. AB - [This retracts the article on p. 4841 in vol. 7, PMID: 22973103.]. PMID- 29719391 TI - Combined use of fluorescence with a magnetic tracer and dilution effect upon sentinel node localization in a murine model. AB - Background: Sentinel node biopsy using radioisotope and blue dye remains a gold standard for axillary staging in breast cancer patients with low axillary burden. However, limitations in the use of radioisotopes have resulted in emergence of novel techniques. This is the first in vivo study to assess the feasibility of combining the two most common novel techniques of using a magnetic tracer and indocyanine green (ICG) fluorescence. Materials and methods: A total of 48 mice were divided into eight groups. Groups 1 and 2, the co-localization groups, received an injection of magnetic tracers (Resovist(r) and Sienna+(r), respectively) and ICG fluorescence; distilled water was used as the solvent of ICG. Groups 3 and 4, the diluted injection groups, received an injection of magnetic tracers (Resovist and Sienna+, respectively) and saline for dilution. Groups 5, 6, and 7, the control groups, received magnetic tracer (Resovist, Sienna+) and ICG alone, respectively. Fluorescent intensity assessment and iron quantification of excised popliteal lymph nodes were performed. Group 1', a co localization group, received an injection of magnetic tracers (Resovist) and ICG' fluorescence: saline was used as the solvent for ICG. Results: Lymphatic uptake of all tracers was confined to the popliteal nodes only, with co-localization confirmed in all cases and no significant difference in fluorescent intensity or iron content of ex vivo nodes between the groups (except for Group 1'). There was no impact of dilution on the iron content in the diluted Sienna+ group, but it significantly enhanced Resovist uptake (P=0.005). In addition, there was a significant difference in iron content (P=0.003) in Group 1'. Conclusion: The combination of a magnetic tracer (Resovist or Sienna+) and ICG fluorescence is feasible for sentinel node biopsy and will potentially allow for precise transcutaneous node identification, in addition to accurate intraoperative assessment. This radioisotope-free "combined technique" warrants further assessment within a clinical trial. PMID- 29719390 TI - Smart polymeric nanoparticles with pH-responsive and PEG-detachable properties for co-delivering paclitaxel and survivin siRNA to enhance antitumor outcomes. AB - Background: The co-delivery of chemotherapeutic agents and small interfering RNA (siRNA) within one cargo can enhance the anticancer outcomes through its synergistic therapeutic effects. Materials and methods: We prepared smart polymeric nanoparticles (NPs) with pH-responsive and poly(ethylene glycol) (PEG) detachable properties to systemically co-deliver paclitaxel (PTX) and siRNA against survivin gene for lung cancer therapy. The cationic polyethyleneimine block-polylactic acid (PEI-PLA) was first synthesized and characterized, with good biocompatibility. PTX was encapsulated into the hydrophobic core of the PEI PLA polymers by dialysis, and then the survivin siRNA was loaded onto the PTX loaded NPs (PEI-PLA/PTX) through electrostatic interaction between siRNA and PEI block. Finally, the negatively charged poly(ethylene glycol)-block-poly(L aspartic acid sodium salt) (PEG-PAsp) was coated onto the surface of NPs by electrostatic interaction to form final smart polymeric NPs with mean particle size of 82.4 nm and zeta potential of 4.1 mV. After uptake of NPs by tumor cells, the PEG-PAsp segments became electrically neutral owing to the lower endosome pH and consequently detached from the smart NPs. This process allowed endosomal escape of the NPs through the proton-sponge effect of the exposed PEI moiety. Results: The resulting NPs achieved drug loading of 6.04 wt% and exhibited good dispersibility within 24 h in 10% fetal bovine serum (FBS). At pH 5.5, the NPs presented better drug release and cellular uptake than at pH 7.4. The NPs with survivin siRNA effectively knocked down the expression of survivin mRNA and protein owing to enhanced cell uptake of NPs. Cell counting kit-8 (CCK-8) assay showed that the NPs presented low systemic toxicity and improved antiproliferation effect of PTX on A549 cells. Moreover, in vivo studies demonstrated that accumulated NPs in the tumor site were capable of inhibiting the tumor growth and extending the survival rate of the mice by silencing the survivin gene and delivering PTX into tumor cells simultaneously. Conclusion: These results indicate that the prepared nano-vectors could be a promising co delivery system for novel chemo/gene combination therapy. PMID- 29719392 TI - Evaluation of the potential of a simplified co-delivery system with oligodeoxynucleotides as a drug carrier for enhanced antitumor effect. AB - Background: We previously developed a simple effective system based on oligodeoxynucleotides with CGA repeating units (CGA-ODNs) for Dox and siRNA intracellular co-delivery. Methods: In the present study, the in vitro cytotoxicity, gene transfection and in vivo safety of the co-delivery system were further characterized and discussed. Results: Compared with poly(ethyleneimine) (PEI), both CGA-ODNs and the pH-sensitive targeted coating, o-carboxymethyl chitosan (CMCS)-poly(ethylene glycol) (PEG)-aspargine-glycine-arginine (NGR) (CMCS-PEG-NGR, CPN) showed no obvious cytotoxicity in 72 h. The excellent transfection capability of CPN coated Dox and siRNA co-loaded nanoparticles (CPN PDR) was confirmed by real-time PCR and Western blot analysis. It was calculated that there was no significant difference in silencing efficiency among Lipo/siRNA, CPN-modified siRNA-loaded nanoparticles (CPN-PR) and CPN-PDR. Furthermore, CPN-PDR was observed to be significantly much more toxic than Dox- and CPN-modified Dox-loaded nanoparticles (CPN-PD), implying their higher antitumor potential. Both hemolysis tests and histological assessment implied that CPN-PDR was safe for intravenous injection with nontoxicity and good biocompatibility in vitro and in vivo. Conclusion: The results indicated that CPN PDR could be a potentially promising co-delivery carrier for enhanced antitumor therapy. PMID- 29719393 TI - Biological responses to core-shell-structured Fe3O4@SiO2-NH2 nanoparticles in rats by a nuclear magnetic resonance-based metabonomic strategy. AB - Background: Core-shell-structured nanoparticles (NPs) have attracted much scientific attention due to their promising potential in biomedical fields in recent years. However, their underlying mechanisms of action and potential adverse effects following administration remain unknown. Methods: In the present study, a 1H nuclear magnetic resonance-based metabonomic strategy was applied to investigate the metabolic consequences in rats following the intravenous administration of parent NPs of core-shell-structured nanoparticles, Fe3O4@SiO2 NH2 (Fe@Si) NPs. Results: Alterations reflected in plasma and urinary metabonomes indicated that Fe@Si NPs induced metabolic perturbation in choline, ketone-body, and amino-acid metabolism besides the common metabolic disorders in tricarboxylic acid cycle, lipids, and glycogen metabolism often induced by the exogenous agents. Additionally, intestinal flora metabolism and the urea cycle were also influenced by Fe@Si NP exposure. Time-dependent biological effects revealed obvious metabolic regression, dose-dependent biological effects implied different biochemical mechanisms between low- and high-dose Fe@Si NPs, and size-dependent biological effects provided potential windows for size optimization. Conclusion: Nuclear magnetic resonance-based metabonomic analysis helps in understanding the biological mechanisms of Fe@Si NPs, provides an identifiable ground for the selection of view windows, and further serves the clinical translation of Fe@Si NP-derived and -modified bioprobes or bioagents. PMID- 29719394 TI - Preparation, characterization, in vitro and in vivo anti-tumor effect of thalidomide nanoparticles on lung cancer. AB - Introduction: Thalidomide (THA) is an angiogenesis inhibitor and an efficient inhibitor of the tumor necrosis factor-alpha (TNF-alpha). However, the clinical application of THA has been limited due to hydrophobicity of the compound. Materials and methods: To increase the water solubility of THA and in order to evaluate the anticancer abilities of this material on human lung carcinoma, methoxy poly(ethylene glycol)-poly(epsilon-caprolactone) nanoparticles loaded with THA (THA-NPs) were prepared. The synthesis of THA-NPs was carried out via a dialysis method with relative satisfactory encapsulation efficiency, loading capacity, size distribution, and zeta potential. Results: A cytotoxicity assay demonstrated that THA-NPs inhibited the growth of cells in a dose-dependent manner. The evaluation of anti-tumor activity in vivo showed that THA-NPs could inhibit tumor growth and prolong the survival rate of tumor-bearing mice. Immunohistochemical analysis indicated that THA-NPs inhibited cell proliferation (Ki-67 positive rate, 32.8%+/-4.2%, P<0.01), and resulted in a decreased rate of the tumor tissue microvessel density (3.87%+/-0.77%, P<0.01), VEGF (26.67%+/ 4.02%, P<0.01), and TNF-alpha (75.21+/-6.85 ng/mL, P<0.01). Conclusion: In general, the drug delivery system reported herein may shed light on future targeted therapy in lung cancer treatment. PMID- 29719395 TI - Amyloid-like staining property of RADA16-I nanofibers and its potential application in detecting and imaging the nanomaterial. AB - Background: Designer self-assembling peptide nanofibers (SAPNFs) as a novel kind of emerging nanomaterial have received more and more attention in the field of nanomedicine in recent years. However, a simple method to monitor and image SAPNFs is still currently absent. Methods: RADA16-I, a well-studied ionic complementary peptide was used as a model to check potential amyloid-like staining properties of SAPNFs. Thioflavin-T (ThT) and Congo red (CR) as specific dyes for amyloid-like fibrils were used to stain RADA16-I nanofibers in solution, combined with drugs or cells, or injected in vivo as hydrogels. Fluorescent spectrometry and fluorescent microscopy were used to check ThT-binding property, and polarized light microscopy was used to check CR-staining property. Results: ThT binding with the nanofibers showed enhanced and blue-shifted fluorescence, and specific apple-green birefringence could be observed after the nanofibers were stained with CR. Based on these properties we further showed that ThT binding fluorescence intensity could be used to monitor the forming and changing of nanofibers in solution, while fluorescent microscopy and polarized light microscopy could be used to image the nanofibers as material for drug delivery, 3D cell culture, and tissue regeneration. Conclusion: Our results may provide convenient and reliable tools for detecting SAPNFs, which would be helpful for understanding their self-assembling process and exploring their applications. PMID- 29719396 TI - Fe3O4@Au composite magnetic nanoparticles modified with cetuximab for targeted magneto-photothermal therapy of glioma cells. AB - Background: Thermoresponsive nanoparticles have become an attractive candidate for designing combined multimodal therapy strategies because of the onset of hyperthermia and their advantages in synergistic cancer treatment. In this paper, novel cetuximab (C225)-encapsulated core-shell Fe3O4@Au magnetic nanoparticles (Fe3O4@Au-C225 composite-targeted MNPs) were created and applied as a therapeutic nanocarrier to conduct targeted magneto-photothermal therapy against glioma cells. Methods: The core-shell Fe3O4@Au magnetic nanoparticles (MNPs) were prepared, and then C225 was further absorbed to synthesize Fe3O4@Au-C225 composite-targeted MNPs. Their morphology, mean particle size, zeta potential, optical property, magnetic property and thermal dynamic profiles were characterized. After that, the glioma-destructive effect of magnetic fluid hyperthermia (MFH) combined with near-infrared (NIR) hyperthermia mediated by Fe3O4@Au-C225 composite-targeted MNPs was evaluated through in vitro and in vivo experiments. Results: The inhibitory and apoptotic rates of Fe3O4@Au-C225 composite-targeted MNPs-mediated combined hyperthermia (MFH+NIR) group were significantly higher than other groups in vitro and the marked upregulation of caspase-3, caspase-8, and caspase-9 expression indicated excellent antitumor effect by inducing intrinsic apoptosis. Furthermore, Fe3O4@Au-C225 composite targeted MNPs-mediated combined hyperthermia (MFH+NIR) group exhibited significant tumor growth suppression compared with other groups in vivo. Conclusion: Our studies illustrated that Fe3O4@Au-C225 composite-targeted MNPs have great potential as a promising nanoplatform for human glioma therapy and could be of great value in medical use in the future. PMID- 29719397 TI - Endogenous ornithine decarboxylase/polyamine system mediated the antagonist role of insulin/PEG-CMCS preconditioning against heart ischemia/reperfusion injury in diabetes mellitus. AB - Introduction: Insulin has shown antioxidation and cytoprotective effects to decrease heart ischemia/reperfusion injury (HI/RI) in diabetes mellitus (DM), but the role of insulin/poly(ethylene glycol)-carboxymethyl chitosan (PEG-CMCS) on HI/RI in DM is not known. This research explored whether insulin/PEG-CMCS revealed a protective effect on HI/RI in DM through ornithine decarboxylase (ODC)/polyamine systems. Materials and methods: Diabetes was induced via streptozotocin (STZ) in Sprague Dawley (SD) rats, which suffered from HI via blocking the left circumflex artery for 45 minutes, followed by 2 hours of reperfusion. alpha-Difluoromethylornithine-ethylglyoxal bis (guanylhydrazone) (DFMO-EGBG) and insulin/PEG-CMCS were administered to diabetic rats to explore their roles on severity of HI/RI. Results: Insulin could be fleetly and efficiently loaded via the nanocarrier PEG-CMCS at pH =6, showing efficient loading and stable release. In addition, insulin/PEG-CMCS showed significant hypoglycemic activity in diabetic rats. On the other hand, ischemia/reperfusion obviously augmented the contents of creatine kinase (CK), lactic dehydrogenase (LDH), putrescine (Pu), myocardial infarct size, and NF-kappaB and spermidine/spermine N'-acetyltransferase (SSAT) expressions and decreased the levels of spermine (Sp), polyamine pools (PAs), heart rate (HR), coronary blood flow (CF), left ventricular developed pressure (LVDP), and ODC expression, compared with Sham. Administration of insulin and insulin/PEG-CMCS both reduced the contents of CK, LDH, Pu, myocardial infarct size, and NF-kappaB and SSAT expressions and increased the levels of Sp, PAs, HR, CF, LVDP, and ODC expression, while insulin/PEG-CMCS significantly indicated the protective results, and DFMO-EGBG showed the opposite effects. Conclusion: The research showed that insulin/PEG-CMCS could play a protective effect on HR/RI in diabetic rats via its antioxidative, antiapoptotic, and anti-inflammatory roles and modulating ODC/polyamine systems. PMID- 29719398 TI - Comparison of changes in oxygenated hemoglobin during the tree-drawing task between patients with schizophrenia and healthy controls. AB - Background: Tree-drawing test is used as a projective psychological test that expresses the abnormal internal experience in patients with schizophrenia (SZ). Despite the widely accepted view that the cognitive function is involved in characteristic tree-drawing in patients with SZ, no study has psychophysiologically examined it. The present study aimed to investigate the involvement of cognitive function during tree-drawing in patients with SZ. For that purpose, we evaluated the brain function in patients with SZ during a tree drawing task by using near-infrared spectroscopy (NIRS) and compared them with those in healthy controls. Patients and methods: The subjects were 28 healthy controls and 28 patients with SZ. Changes in the oxygenated hemoglobin ([oxy-Hb]) concentration in both the groups during the task of drawing a tree imagined freely (free-drawing task) and the task of copying an illustration of a tree (copying task) were measured by using NIRS. Results: Because of the difference between the task conditions, [oxy-Hb] levels in controls during the free-drawing task were higher than that during the copying task at the bilateral frontal pole regions and left inferior frontal region. Because of the difference between the groups, [oxy-Hb] levels at the left middle frontal region, bilateral inferior frontal regions, bilateral inferior parietal regions, and left superior temporal region during the free-drawing task in patients were lower than that in controls. Conclusion: [oxy-Hb] during the tree-drawing task in patients with SZ was lower than that in healthy controls. Our results suggest that brain dysfunction in patients with SZ might be associated with their tree-drawing. PMID- 29719399 TI - Effectiveness and safety of oral olanzapine treatment transitioned from rapid acting intramuscular olanzapine for agitation associated with schizophrenia. AB - Objective: To assess the effectiveness and safety of oral olanzapine treatment transitioned from rapid-acting intramuscular olanzapine (RAIM) in patients with acute agitation associated with schizophrenia in a real-world clinical setting. Methods: The postmarketing surveillance study with a 3-day observational period after the last RAIM administration was conducted (original study). Following this, an extended study was added for patients who received oral olanzapine after RAIM administration during the original study period, in order to additionally observe them for 7 days after initial RAIM administration. Effectiveness and safety from initial RAIM administration were evaluated using the Positive and Negative Syndrome Scale-Excited Component score and treatment-emergent adverse events (TEAEs), respectively. Results: The effectiveness and safety analysis set included a total of 521 and 522 patients, respectively. A majority of patients received 10 mg of RAIM (475/522 patients, 91.0%). The mean +/- SD total Positive and Negative Syndrome Scale-Excited Component score was 23.6+/-6.2 (n=318) at baseline (before initial RAIM administration), 17.4+/-6.8 (n=280) at 2 hours after initial administration, 16.2+/-6.8 (n=246) 2 days after final administration, 14.9+/-6.2 (n=248) 3 days after final administration, 13.8+/-5.9 (n=242) 4 days after final administration, 13.2+/-5.8 (n=221) 7 days after initial administration, and 13.4+/-6.2 (n=351) at final observation (with the last observation carried forward approach), showing that reduction in agitation seen with RAIM was sustained with oral dose of olanzapine. The most common TEAEs were dyslalia and somnolence (each event occurred in four patients), and abnormal hepatic function and constipation (occurred in three patients). One serious adverse event of sudden cardiac death occurred after transitioned to oral olanzapine with many other antipsychotic drugs. Conclusion: In the treatment of acute agitation associated with schizophrenia, RAIM could be generally transitioned to oral olanzapine without exacerbating adverse events or losing treatment effect. PMID- 29719400 TI - New horizons for multiple sclerosis therapeutics: milestones in the development of ocrelizumab. AB - Multiple Sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system, and both T and B cells are involved in its pathogenesis. The vast majority of disease-modifying drugs used for MS act on the inflammatory component of the disease and are approved for use in relapsing-remitting (RR) patients. Ocrelizumab (OCR) is the only MS drug that has been approved by the US Food and Drug Administration (FDA) not only for patients with RRMS but also for patients with primary progressive (PP) MS. OCR is a humanized anti-CD20 monoclonal antibody that can deplete the targeted B cells through antibody dependent cellular cytotoxicity. Treatment involves administration by intravenous infusion every 6 months. OCR can cause long-lasting B-cell depletion and change the pool of reconstituted B cells. Phase III clinical trials have confirmed the results of previous Phase II studies. In particular, OPERA I and II trials, which were performed in patients with RRMS, showed a reduction in the annualized relapse rate, the risk of disability progression, and the number of new/enlarging T2 lesions and enhancing lesions measured using brain magnetic resonance. The ORATORIO trial, performed in PP subjects, showed that OCR can reduce disability progression, improve performance on the timed 25-foot walk, and decrease the total volume of T2 lesions and the mean number of new or enlarging T2 lesions. The most frequent adverse events were the infusion-related reactions and infections. Infections were mostly nasopharyngitis, as well as upper respiratory and urinary tract infections. OCR gives no indication for severe or opportunistic infections. There is not a clear increased risk of malignancies. Nevertheless, it could not be excluded. Real-life registries will provide more information about the long-term safety, the risk of exposure during pregnancy, and the risk of rare adverse events. In this review, we analyze the evidence regarding the efficacy and the safety of OCR. PMID- 29719401 TI - A restrictive dose of crystalloids in patients during laparoscopic cholecystectomy is safe and cost-effective: prospective, two-arm parallel, randomized controlled trial. AB - Purpose: There are no evidence-based guidelines for volume replacement during surgical procedures such as laparoscopic cholecystectomy. However, the administration of a restrictive volume of crystalloids could be more cost effective and safe. This trial aimed to determine the effectiveness and safety of a restrictive regimen of crystalloids in patients during laparoscopic cholecystectomy by analyzing its cost-effectiveness and 1-year morbidity rate. Patients and methods: In this randomized, prospective study, patients were assigned to one of three groups based on the volume of fluid administered: the restrictive group received 1 mL/kg/hr, the low liberal group received 5 mL/kg/hr, and the high liberal group received 15 mL/kg/hr of Ringer's solution intraoperatively. There were 40 patients in each group. Each patient's hemodynamic parameters and laboratory values (arterial blood gas and lactate levels) were measured together with their consumption of crystalloids, volatile anesthetics, and analgesics. Results: Analysis of the hemodynamic and laboratory parameters revealed no signs of global hypoperfusion in any of the groups analyzed. There was no significant difference in the duration of surgery and anesthesia, but the consumption of crystalloids, volatile anesthetics, and opioids was significantly lower in the restrictive group, compared with the low and high liberal groups. Although there was no significant difference in the 1 year morbidity among the groups, heart failure was observed in one patient in the high liberal group in the early postoperative period. Conclusion: Restrictive fluid therapy during laparoscopic cholecystectomy is justified, safe, and more cost-effective than other options. PMID- 29719402 TI - Compounding medications in a rural setting: an interprofessional perspective. AB - Background: Interprofessional learning (IPL) which focuses on the pharmacist's role in specialty practices as part of a multidisciplinary health care team has not been explored. This study aimed to determine health care students' understanding of the role of the pharmacist in compounding medications to optimize health outcomes for patients in rural and remote health care services. Methods: Four workshops followed by focus group interviews were conducted with undergraduate pharmacy, medical, nursing, physiotherapy, dentistry, Aboriginal public health, and speech pathology students (n=15). After an introductory lecture, students working in multidisciplinary teams undertook to compound three products. Focus groups were held at the end of the compounding workshops to explore students' understanding and perceptions of these compounding activities. Thematic analysis was undertaken on the qualitative data obtained from the focus groups. Results: Student participants responded positively both to the opportunity to undertake a compounding exercise and being part of an interprofessional team, perceiving benefit for their future rural and remote health practice. Four major themes emerged from the qualitative analysis: improved knowledge and understanding; application to practice; interprofessional collaboration; and rural, remote, and Indigenous context. Students acknowledged that the workshops improved their understanding of the role of the pharmacist in compounding and how they, as part of a multidisciplinary team, could deliver better health outcomes for patients with special needs, especially in a rural and remote context. Conclusion: This study highlights that workshops of this nature have a role to play in developing collaborative interprofessional practice and increasing awareness of pharmaceutical services among undergraduate health students. However, further evidence is needed to assess whether positive perceptions of specialty practice IPL workshops will translate into improved patient outcomes in practice. PMID- 29719403 TI - Analysis of the third-grade curriculum for health subjects: Application of Health Education Curriculum Analysis Tool. AB - Purpose: Applying the Health Education Curriculum Analysis Tool (HECAT), the third-grade curriculum was assessed in accordance with health-related items. Methods: A multimethod research was used to investigate the student textbooks and three modules including healthy eating, physical activity, and safety. Based on purposive sampling, curriculum committees were made up of teachers, elementary school principals, members of the parents-teachers' associations, and health care experts. Results: Data obtained from the group discussion were analyzed based on the conventional content analysis approach. All modules received coverage percentages of <34%. The highest mean coverage percentage belonged to the safety module (25.59%) and the lowest to healthy eating (12.78%). Conclusion: Suggested solutions were classified based on three general themes such as clarifying and determining healthy dietary behaviors and actions, educating life skills and adopting healthy diet behaviors, and finally utilizing social norms for adopting with healthy diet patterns. PMID- 29719404 TI - Effects of interactive teaching on university students' knowledge and attitude toward reproductive health: a pilot study in Jordan. AB - Background: Youths in Jordan lack knowledge related to reproductive health (RH). Interactive teaching methods showed positive results in enhancing health awareness and adopting healthy practices among students. Objectives: The objective of this study was to examine the usefulness of interactive teaching in promoting health awareness of RH among nonmedical university students in Jordan. Methods: We employed a quasi-experimental one group pretest and posttest design for a purposive sample of 210 students (18-24 years). Knowledge and attitudes regarding RH issues were assessed using a questionnaire developed by the researchers. Results: A significant improvement in students' knowledge and attitudes toward RH was evident. Female students had higher scores on knowledge than male students in the pretest; this difference was smaller in the posttest. Also, female students had significantly more positive attitudes toward RH in pretest than males, although this difference vanished in the posttest. Study results indicated that students benefit from study intervention regardless their gender. Conclusion: Integrating RH into university's curriculum coupled with interactive learning approach is a powerful way to promote RH awareness among youths. PMID- 29719405 TI - microRNA-26a induces a mitochondrial apoptosis mediated by p53 through targeting to inhibit Mcl1 in human hepatocellular carcinoma. AB - Aim: We have previously found that microRNA-26a (miR-26a) is a potential tumor suppressor in hepatocellular carcinoma (HCC). In this study, we further explored the roles of miR-26a in HCC apoptosis. Methods: miR-26a expression levels were detected in HCC tissues by real-time PCR. Statistical analysis was performed to explore the correlation between miR-26a expression and apoptotic cells and the antiapoptotic protein levels. In vitro assays were performed to investigate the roles of miR-26a in HCC apoptosis. The immunohistochemical staining analysis, Western blot, and luciferase reporter assay were performed to evaluate the relationship between miR-26a and its potential upstream regulating and downstream target genes. The potential mechanism of the combination treatment of interferon alpha1b (IFN-alpha1b) and 5-fluorouracil (5-FU) was explored by in vitro and in vivo assays. Results: miR-26a levels were significantly associated with the number of apoptotic cells and inversely correlated with the protein levels of Bcl 2, Bcl-xL, and Mcl1 in HCC tissues. Furthermore, miR-26a was proved to induce the mitochondrial apoptosis in vitro by directly targeting to inhibit Mcl1 in HCC cells. Moreover, p53 was demonstrated to mediate miR-26a-induced apoptosis, by activating its promoter in HCC. Meanwhile, the combination treatment of IFN alpha1b and 5-FU could induce the expression of p53, which then upregulated miR 26a and downregulated Mcl1 levels, and finally promoted the apoptosis of HCC cells through a mitochondrial pathway. Conclusion: These findings highlight the important and related molecular mechanism of miR-26a in the regulation of apoptosis and implicate the potential application of combination of IFN-alpha1b and 5-FU in HCC treatment. PMID- 29719406 TI - Cardiotoxic effects of the novel approved anti-ErbB2 agents and reverse cardioprotective effects of ranolazine. AB - Purpose: Pertuzumab, a novel anti-epidermal growth factor receptor 2 humanized monoclonal antibody, and trastuzumab-emtansine (TDM1), a novel antibody-drug conjugate made up of trastuzumab covalently linked to the highly potent microtubule inhibitory agent DM1, have been recently approved by the US Food and Drug Administration for increasing the efficiency and safety of breast cancer therapy with trastuzumab. We investigated for the first time the potential cardiotoxic effects of pertuzumab and TDM1, which are not yet fully elucidated, and we tested whether ranolazine could blunt their cardiotoxicity. Methods: The cardiotoxic effects were tested in vitro on rat cardiomyoblasts, human fetal cardiomyocytes, adult-like cardiomyocytes, and in vivo on a mouse model. Results: All the treated cardiac cell lines were significantly affected by treatment with the tested drugs. Surprisingly, TDM1 showed stronger inhibitory effects on cardiac cells with respect to trastuzumab and pertuzumab by more significantly reducing the cell viability and by changing the morphology of these cells. TDM1 also affected the beating phenotype of adult-like cardiomyocytes in vitro and reduced fractional shortening and ejection fraction in vivo in a mouse model. We also found that ranolazine attenuated not only the cardiotoxic side effects of trastuzumab but also those of pertuzumab and TDM1, when used in combinatorial treatments both in vitro and in vivo, as demonstrated by the recovery of fractional shortening and ejection fraction values in mice pretreated with TDM1. Conclusion: We demonstrated that it is possible to predict the eventual cardiotoxic effects of novel approved anticancer drugs early by using in vitro and in vivo approaches, which can also be useful to screen in advance the cardioprotective agents, so as to avoid the onset of unwanted cardiotoxic side effects. PMID- 29719407 TI - Evidence from an updated meta-analysis of the prognostic impacts of postoperative radiotherapy and chemotherapy in patients with anaplastic thyroid carcinoma. AB - Background: Radiotherapy and chemotherapy are the two important postoperative management approaches for anaplastic thyroid carcinoma (ATC), and several studies have suggested that postoperative radiotherapy and chemotherapy can prolong the survival of patients with ATC. However, the results remain inconsistent. Objective: A meta-analysis was performed to address whether postoperative radiotherapy and chemotherapy could prolong the survival of patients with ATC. Methods: Relevant studies were included, and pooled hazard ratios (HRs) together with 95% confidence intervals (CIs) were calculated. Results: Ten relevant studies on factors that affect the prognosis for ATC were included in this meta analysis, evaluating a total of 1,163 patients. The pooled HR for overall survival (OS) was calculated using a random-effects model. The pooled results demonstrated that for all patients with resectable ATC, the combination of surgery and radiotherapy significantly reduced the risk of death compared with surgery alone (HR =0.51, 95% CI: 0.36-0.73, Z=3.66, P=0.0002). To investigate the prognostic impacts of chemotherapy in patients with ATC, we also calculated the pooled HR of chemotherapy for OS using a random-effects model; however, the pooled results suggested that chemotherapy did not prolong the survival of ATC patients compared with controls (HR =0.63, 95% CI: 0.33-1.21, Z=1.39, P=0.17). Conclusion: This study provided evidence that currently, for patients with ATC, postoperative radiotherapy may prolong survival; in contrast, chemotherapy did not improve long-term survival. PMID- 29719408 TI - Role of DiGeorge syndrome critical region gene 9, a long noncoding RNA, in gastric cancer. AB - Introduction: Long non-coding RNAs (lncRNAs) regulate and influence cancer cell development and tumor formation. However, the role for lncRNAs in gastric cancer has not been fully established. In this study, DGCR9, a lncRNA, was significantly upregulated in gastric cancer cell lines. Methods: The expression levels of DGCR9 in each patient between formalin-fixed, paraffin-embedded (FFPE) gastric cancer tissues and adjacent noncancer tissues (NAT) (n=102) were measured by quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The effect of DGCR9 on cellular proliferation, migration, and glucose uptake was investigated in vitro, respectively. Results: DGCR9 was shown to have increased expression in gastric cancer tissues and in gastric cancer cell lines. Further, DGCR9 was found to be associated with clinicopathological characteristics of patients with gastric cancer. In particular, DGCR9 was positively associated with lymph node invasion and tumor-node-metastasis (TNM) stage in gastric cancer patients. By in vitro functional analysis, knockdown of DGCR9 in gastric cancer cells suppressed cellular proliferation, migration, and glucose uptake. In contrast, overexpression of DGCR9 increased each of these cancer cell characteristics. Conclusions: DGCR9 was upregulated in gastric cancer tissues and was shown to accelerate cellular proliferation, migration, and glucose metabolism, all of which would promote the formation and development of gastric cancer. PMID- 29719409 TI - Prediction of tumor mutation burden in breast cancer based on the expression of ER, PR, HER-2, and Ki-67. AB - Objective: Cancer immunoediting is the process of eliminating highly immunogenic tumor cells by somatic evolution and protecting the host from tumor development in the host immune system. Frequencies of somatic mutations or tumor mutation burden (TMB) were associated with immunogenicity of breast cancer. This study aimed to predict the level of TMB in patients with breast cancer by the expression of estrogen (ER), progesterone (PR), HER-2, and Ki-67, thereby anticipating the prognosis of patients and the possible response to immunotherapy. Patients and methods: In 53 patients with breast cancer, the 453 multigenes panel based on NGS was used to determine the TMB value of breast cancer in the patient's primary tumor tissues. The predicted TMB value was divided into 4 groups: A (0-3.33), B (3.33-5.56), C (5.56-8.89), and D (>8.89), according to the quartile method, with group A as reference level. Logistic regression was used to analyze the risk ratio of each molecule type, and the prediction model was established. Survival probabilities by covariates were assessed using Kaplan-Meier estimator survival analysis and Cox's proportional hazards models. Results: In 53 patients, the TMB value measured by the NGS polygenic panel was between 0 and 14.4/Mb. TMB distribution in 53 cases of breast cancer tissue: 18 cases in A group, 22 cases in B group, 10 cases in C group, and 3 cases in D group. HER-2 expression positivity was significantly associated with TMB (HER-2 positive vs HER-2 negative, odds ratio [OR] =34.81, 95% confidence interval [CI]: 3.711-821.689, P=0.0065). Higher TMB was distributed in the patients who were Ki-67 expression positive (>14%) than those who were Ki-67 expression negative (<=14%) (OR =0.217, 95% CI: 0.054-0.806, P=0.0242). However, no significant differences of TMB were found between ER-positive group and ER negative group (OR =3.133, 95% CI: 0.124-127.687, P=0.4954) and between PR positive group and PR-negative group in terms of TMB (OR =1.702, 95% CI: 0.162 20.335, P=0.6492). The predicted model is TMB = -1.14*ER +0.53*PR +3.55*HER-2 1.53*Ki-67+ CONSTANT (INTERCEPT). Patients with low TMB had a better disease-free survival (DFS) than those with high TMB (83 vs 59 m, P=0.002). In a multivariate analysis, high TMB (>5.56) was an independent predictive factor for decreased DFS (adjusted hazard ratio [HR], 5.594; 95% CI: 1.694-18.473; P = 0.005). Conclusion: The preliminary results suggest that the level of TMB value in patients with breast cancer can be predicted based on the expression levels of ER, PR, HER-2, and Ki-67, which may indicate the prognostic and predictive value of immunotherapy in patients with breast cancer. PMID- 29719410 TI - Oncogene mutational analysis in Chinese gastrointestinal stromal tumor patients. AB - Background: Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors and exhibit a high frequency of oncogenic KIT or PDGFRA mutations. Tyrosine kinase inhibitors (TKIs) have been mainly used in the treatment of GISTs bearing KIT/PDGFRA mutations. However, other mutation profiles have been found to affect the sensitivity to and effectiveness of TKIs in the treatment of GISTs. Purpose: The aim of the present study was to describe the mutational status of multiple genes in GIST samples and to provide information for finding potential predictive markers of therapeutic targets in Chinese GIST patients. Patients and methods: MassARRAY spectrometry was used to test 40 Chinese GIST patients for 238 mutations affecting 19 oncogenes. Results: A total of 14 oncogenes with 43 mutations were detected in 38 samples, with a mutation frequency of 95%. Among these mutation samples, 26 GISTs were found for KIT or PDGFRA mutations, while 12 were KIT/PDGFRA wild-type. Approximately half of the GIST samples harbored multiple mutations. The most frequent mutations were found in KIT (62.5%), CDK4 (17.5%), NRAS (15%) and EGFR (12.5%). Other mutations included PIK3CA and AKT1 (10%), BRAF and ABL1 (7.5%), PDGFRA, ERBB2 and HRAS (5%), and AKT2, FLT3 and KRAS (2.5%). New mutated genes (CDK4, AKT2, FLT3, ERBB2, ABL1 and AKT1), a higher BRAF mutation frequency (7.5%) and new BRAF mutation sites (G464E) were found in Chinese GIST patients. Conclusion: This study demonstrated useful mutations in a small fraction of Chinese GIST, but targeted therapeutics on these potential predictive markers need to be investigated in depth especially in Oriental populations. PMID- 29719411 TI - Forodesine in the treatment of relapsed/refractory peripheral T-cell lymphoma: an evidence-based review. AB - T-cell lymphoma is a rare hematologic malignancy with an incidence rate between 10% and 20% of that of non-Hodgkin lymphomas. Patients with peripheral T-cell lymphoma (PTCL) generally have a poor prognosis when treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)/CHOP-like chemotherapy; once relapse occurs, it is mostly regarded as an incurable disease. To overcome the chemorefractoriness of PTCL, several novel agents have been developed. Since the first approval of pralatrexate, a dihydrofolate reductase inhibitor, for relapsed/refractory PTCL by the US Food and Drug Administration, several new agents, such as romidepsin (histone deacetylase inhibitor), brentuximab vedotin (antibody-drug conjugate targeting CD30), chidamide (histone deacetylase inhibitor), and mogamulizumab (anti-CC chemokine receptor 4 monoclonal antibody), have been approved as a therapeutic option for relapsed/refractory PTCL in several countries, including the US, Europe, China, and Japan. Forodesine is a novel, potent purine nucleoside phosphorylase inhibitor that is effective against T-cell malignancies. Although the clinical development of forodesine was discontinued in the US and Europe, a multicenter Phase I/II study of oral forodesine for relapsed PTCL was recently completed in Japan. The overall response rate was 24% (10 of 41 patients), which included four patients with complete response. In general, the toxicity of forodesine is manageable. As the study met the primary end point, forodesine was approved for the treatment of relapsed/refractory PTCL in Japan in March 2017, which was the first approval of forodesine in the world. As forodesine is an oral formulation, it is more convenient than other novel intravenous agents approved for PTCL. However, it is necessary to appropriately manage opportunistic infections and secondary lymphomas possibly associated with long-lasting lymphocytopenia caused by forodesine. In this manuscript, we have summarized the currently available evidence for forodesine and discussed the clinical implications for PTCL treatment. PMID- 29719412 TI - Acute effects of smoke exposure on airway and systemic inflammation in forest firefighters. AB - Introduction: The aim of this study was to assess respiratory health and airway and systemic inflammation in professional forest firefighters post firefighting. Methods: A total of 60 firefighters who participated in forest firefighting operations in Greece during 2008 were included in the study. A questionnaire consisting of symptoms and exposure, pulmonary function, atopy, bronchial hyperresponsiveness, and markers of inflammation in induced sputum, serum, and bronchoalveolar lavage (BAL) fluid was assessed. Results: A measurable eosinophilic and neutrophilic inflammation was shown to be induced in the bronchial airways after acute exposure during forest firefighting. This was associated with increased respiratory symptoms from the upper and lower respiratory tract and pulmonary function impairment. Additionally, a measurable systemic inflammatory response was demonstrated. This study showed that acute exposure during forest firefighting significantly augments the intensity of airway and systemic inflammation in relation to the baseline inflammatory background due to chronic exposure. Conclusion: The repeated acute exposures during firefighting augment the burden of chronic airway and systemic inflammation and may eventually lead to allergic sensitization of the airways and increased incidence of rhinitis and asthma after prolonged exposure. PMID- 29719413 TI - Intermittent pneumatic compression is a cost-effective method of orthopedic postsurgical venous thromboembolism prophylaxis. AB - Background: Venous thromboembolism (VTE) is a major complication after lower-limb arthroplasty that increases costs and reduces patient's quality of life. Using anticoagulants for 10-35 days following arthroplasty is the standard prophylaxis, but its cost-effectiveness after accounting for bleeding complications remains unproven. Methods: A comprehensive, clinical model of VTE was created using the incidences, clinical effects (including bleeding), and costs of VTE and prophylaxis from randomized controlled trials, meta-analyses, and large observational studies. Over 50 years, the total health care costs and clinical impact of three prophylaxis strategies, that are as follows, were compared: low molecular-weight heparin (LMWH) alone, intermittent pneumatic compression (IPC), and IPC with LMWH (IPC+LMWH). The cost per VTE event that was avoided and cost per quality-adjusted life year (QALY) gained in both the US and Australian health care settings were calculated. Results: For every 2,000 patients, the expected number of VTE and major bleeding events with LMWH were 151 and 6 in the USA and 160 and 46 in Australia, resulting in a mean of 11.3 and 9.1 QALYs per patient, respectively. IPC reduced the expected VTE events by 11 and 8 in the USA and Australia, respectively, compared to using LMWH alone. IPC reduced major bleeding events compared to LMWH, preventing 1 event in the US and 7 in Australia. IPC+LMWH only reduced VTE events. Neither intervention substantially impacted QALYs but both increased QALYs versus LMWH. IPC was cost-effective followed by IPC+LMWH. Conclusion: IPC and IPC+LMWH are cost-effective versus LMWH after lower limb arthroplasty in the USA and Australia. The choice between IPC and IPC+LMWH depends on expected bleeding risks. PMID- 29719414 TI - Cost-effectiveness comparison of cabozantinib with everolimus, axitinib, and nivolumab in the treatment of advanced renal cell carcinoma following the failure of prior therapy in England. AB - Purpose: The aim of this study was to compare the cost-effectiveness of cabozantinib with the standard of care in England in adult patients with advanced renal cell carcinoma (aRCC), following prior vascular endothelial growth factor receptor (VEGFR)-targeted therapy. Methods: We developed a partitioned-survival model with three health states to assess the cost-effectiveness of cabozantinib and its comparators. The model time horizon was 30 years. Efficacy and safety data were derived from pivotal clinical trials (METEOR: NCT01865747, CheckMate025: NCT01668784, and AXIS: NCT00678392). METEOR data were used for a direct comparison of cabozantinib and everolimus. Cabozantinib and nivolumab were compared indirectly, whereas equal efficacy for axitinib and everolimus was assumed based on a previously published expert opinion. For all efficacy endpoints, the best-fitting log-logistic or fractional polynomial curves were used to estimate outcomes. Utilities were converted from the 5-level EQ-5D version instrument applied during the METEOR study for specific health states. Reductions in utility scores due to adverse events were applied. English costs (eg, drug prices) and resource use (eg, visit to consultant) data were used. Results: The total treatment cost was estimated to be 84,136 Great British Pounds (GBP) per patient treated with cabozantinib. The health gains were 2.26 life years (LYs) and 1.78 quality-adjusted LYs (QALYs). The incremental cost effectiveness ratios (ICERs) versus axitinib and everolimus were 98,967 GBP/QALY and 137,450 GBP/QALY, respectively. Cabozantinib was less costly and more effective than nivolumab; the incremental cost was -6,742 GBP and the QALY difference was 0.18. Conclusion: Treatment with cabozantinib was more effective than treatment with axitinib or everolimus but was associated with higher total costs. When compared with nivolumab, cabozantinib represents an efficient option with nominally better efficacy and lower costs. PMID- 29719415 TI - Plasma concentrations of zonulin are elevated in obese men with fatty liver disease. AB - Purpose: Zonulin is considered as a biomarker of increased intestinal permeability. The relationship between intestinal permeability and obesity is known, and many studies have investigated the relationship between intestinal permeability and liver disease. Thus, we aimed to investigate the potential association between plasma zonulin concentrations and fatty liver in obese men. Patients and methods: A total of 140 obese men without inflammatory bowel diseases, autoimmune diseases, and severe liver diseases were included. The subjects were divided into three groups: normal, mild fatty liver, and moderate to-severe fatty liver, according to abdominal ultrasonography findings. We subdivided the subjects into two subgroups based on the amount of alcohol consumption (appropriate drinking and hazardous drinking), and subgroup analyses were performed. Results: The mean plasma zonulin concentrations (ng/mL) in the normal, mild fatty liver, and moderate-to-severe fatty liver groups were 0.618, 2.143, and 5.815, respectively (P<0.001). A multivariate multinomial logistic regression analysis revealed an odds ratio (OR) of 1.77 (P=0.015) in the moderate to-severe fatty liver group. The median plasma zonulin concentrations (ng/mL) in the appropriate drinking subgroup of the fatty liver groups were 0.002, 0.500, and 6.550, respectively (P-trend<0.001), and in the hazardous drinking subgroup were 0.002, 0.590, and 5.800, respectively (P-trend=0.001). The ORs for moderate to-severe fatty liver were 1.91 (P=0.039) in the appropriate drinking group and 1.56 (P=0.045) in the hazardous drinking group. Conclusion: Plasma zonulin concentrations were elevated among obese men. A significant association was found between zonulin concentrations and severity of fatty liver. PMID- 29719416 TI - Pain and emotion as predictive factors of interoception in fibromyalgia. AB - Introduction: This study investigated interoception in fibromyalgia (FM), a disorder characterized by chronic pain accompanied by mood deregulation. Based on observations on the relationship between somatosensory processing and pain in FM and considering the affective symptoms of this disorder, we tested in FM three dimensions of interoception: interoceptive accuracy (IA), interoceptive awareness (IAW) and interoceptive sensibility (IS). Materials and methods: Twenty-one female FM patients (Mage = 50.3) and 21 female matched controls (Mage = 46.3) completed a heartbeat tracking task as an assessment of IA, rated confidence in their responses as a measure of IAW and completed the Multidimensional Assessment of Interoceptive Awareness as a measure of IS. Furthermore, they completed self report scales that, according to a principal component analysis, targeted anxiety, emotional consciousness and pain-related affect and reactions. Results: Multiple regression analyses showed that increased pain-related affect and reactions decrease IA in FM. When the results of each group were examined separately, such effect was found only in FM patients. On its turn, IS was predicted by emotional consciousness and pain-related affect and reactions, but these effects did not differ between FM and controls. Finally, none of the variables we used predicted IAW. Discussion: Pain-related affect and reactions in FM patients can reduce their interoceptive ability. Our results help to better understand the integration between bodily signals and emotional processing in chronic pain. PMID- 29719417 TI - Pharmacotherapeutic considerations for use of cannabinoids to relieve pain in patients with malignant diseases. AB - Purpose: The aim of this review was to assess the efficacy of cannabis preparations for relieving pain in patients with malignant diseases, through a systematic review of randomized controlled trials (RCTs), which were predominantly double-blind trials that compared cannabis preparation to a placebo. Methods: An electronic search of all literature published until June 2017 was made in MEDLINE/PubMed, Embase, The Cochrane Controlled Trials Register and specific web pages devoted to cannabis. Results: Fifteen of the 18 trials demonstrated a significant analgesic effect of cannabinoids as compared to placebo. The most commonly reported adverse effects were generally well tolerated, mild to moderate. The main side effects were drowsiness, nausea, vomiting and dry mouth. There is evidence that cannabinoids are safe and modestly effective in neuropathic pain and also for relieving pain in patients with malignant diseases. The proportion of "responders" (patients who at the end of 2 weeks of treatment reported >=30% reduction in pain intensity on a scale of 0-10, which is considered to be clinically important) was 43% in comparison with placebo (21%). Conclusion: The target dose for relieving pain in patients with malignant diseases is most likely about 10 actuations per day, which is about 27 mg tetrahydrocannabinol (THC) and 25 mg cannabidiol (CBD), and the highest approved recommended dose is 12 actuations per day (32 mg THC/30 mg CBD). Further large studies of cannabinoids in homogeneous populations are required. PMID- 29719418 TI - Assessment of synchronous neural activities revealed by regional homogeneity in individuals with acute eye pain: a resting-state functional magnetic resonance imaging study. AB - Objective: Previous neuroimaging studies have demonstrated that pain-related diseases are associated with brain function and anatomical abnormalities, whereas altered synchronous neural activity in acute eye pain (EP) patients has not been investigated. The purpose of this study was to explore whether or not synchronous neural activity changes were measured with the regional homogeneity (ReHo) method in acute EP patients. Methods: A total of 20 patients (15 males and 5 females) with EP and 20 healthy controls (HCs) consisting of 15 and 5 age-, sex-, and education-matched males and females, respectively, underwent resting-state functional magnetic resonance imaging. The ReHo method was applied to assess synchronous neural activity changes. Results: Compared with HCs, acute EP patients had significantly lower ReHo values in the left precentral/postcentral gyrus (Brodmann area [BA]3/4), right precentral/postcentral gyrus (BA3/4), and left middle frontal gyrus (BA6). In contrast, higher ReHo values in acute EP patients were observed in the left superior frontal gyrus (BA11), right inferior parietal lobule (BA39/40), and left precuneus (BA7). However, no relationship was found between the mean ReHo signal values of the different areas and clinical manifestations, which included both the duration and degree of pain in EP patients. Conclusion: Our study highlighted that acute EP patients showed altered synchronous neural activities in many brain regions, including somatosensory regions. These findings might provide useful information for exploration of the neural mechanisms underlying acute EP. PMID- 29719419 TI - Emergency treatment of complicated colorectal cancer. AB - Aim: To find evidence to suggest the best approach in patients admitted as an emergency for complicated colorectal cancer. Methods: The medical records of 131 patients admitted as an emergency with an obstructing, perforated, or bleeding colorectal cancer to Noble's Hospital, Isle of Man, and the Umberto I University Hospital, Rome, were retrospectively evaluated. Patients were divided in 3 groups on the basis of the emergency treatment they received, namely 1) immediate resection, 2) damage control procedure and elective or semielective resection, and 3) no radical treatment. Demographic variables, clinical data, and treatment data were considered, and formed the basis for the comparison of groups. Primary endpoints were 90-day mortality and morbidity. Secondary endpoints were length of stay, number of lymph nodes analyzed, rate of radical R0 resections, and the number of patients who had chemoradiotherapy. Results: Forty-two patients did not have any radical treatment because the cancer was too advanced or they were too ill to tolerate an operation, 78 patients had immediate resection and 11 had damage control followed by elective resection. There was no statistically significant difference between immediate resections and 2-stage treatment in 90 day mortality and morbidity (mortality: 15.4% vs 0%; morbidity: 26.9% vs 27.3%), number of nodes retrieved (16.6+/-9.4 vs 14.9+/-5.7), and rate of R0 resections (84.6% vs 90.9%), but mortality was slightly higher in patients who underwent immediate resection. The patients who underwent staged treatment had a higher possibility of receiving a laparoscopic resection (11.5% vs 36.4%). Conclusion: The present study failed to demonstrate a clear superiority of one treatment with respect to the other, even if there is an interesting trend favoring staged resection. PMID- 29719420 TI - Transoral robotic surgery for oropharyngeal cancer: patient selection and special considerations. AB - The increasing incidence of oropharyngeal squamous cell carcinoma (OPSCC) emphasizes the importance of optimizing treatment for the disease. Historical protocol has utilized definitive radiation and invasive open procedures; these techniques expose the patient to significant risks and morbidity. Transoral robotic surgery (TORS) has emerged as a therapeutic modality with promise. Here, the literature regarding proper patient selection and other considerations for this procedure was reviewed. Multiple patient and tumor-related factors were found to be relevant for successful use of this treatment strategy. Outcomes regarding early and advanced-stage OPSCC were analyzed. Finally, the literature regarding use of TORS in three distinct patient populations, individuals with primary OPSCC, carcinoma of unknown primary and those with recurrent OPSCC, was examined. PMID- 29719421 TI - Lower-extremity amputations in people with and without diabetes in Germany, 2008 2012 - an analysis of more than 30 million inhabitants. AB - Background and purpose: Lower-extremity amputations (LEAs) in people with diabetes are associated with reduced quality of life and increased health care costs. Detailed knowledge on amputation rates (ARs) is of utmost importance for future health care and economics strategies. We conducted the present cohort study in order to estimate the incidences of LEA as well as relative and attributable risk due to diabetes and to investigate time trends for the period 2008-2012. Methods: On the basis of the administrative data from three large branches of German statutory health insurers, covering ~34 million insured people nationwide (about 40% of the German population), we estimated age-sex standardized AR (first amputation per year) in the populations with and without diabetes for any, major, and minor LEAs. Time trends were analyzed using Poisson regression. Results: A total of 108,208 individuals (diabetes: 67.3%; mean age 72.6 years) had at least one amputation. Among people with diabetes, we observed a significant reduction in major and minor ARs during 2008-2012 from 81.2 (95% CI 77.5-84.9) to 58.4 (55.0-61.7), and from 206.1 (197.3-214.8) to 177.0 (169.7 184.4) per 100,000 person-years, respectively. Among people without diabetes, the major AR decreased significantly from 14.3 (13.9-14.8) to 11.6 ([11.2-12.0], 12.0), whereas the minor AR increased from 15.8 (15.3-16.3) to 17.0 (16.5-17.5) per 100,000 person-years. The relative risk (RR) comparing the diabetic with the nondiabetic populations decreased significantly for both major and minor LEAs (4% and 5% annual reduction, respectively). Conclusion: In this large nationwide population, we still found higher major and minor ARs among people with diabetes compared with those without diabetes. However, AR and RR of major and minor LEAs in the diabetic compared with the nondiabetic population decreased significantly during the study period, confirming a positive trend that has been observed in smaller and regional studies in recent years. PMID- 29719422 TI - Antimicrobial action of chlorhexidine digluconate in self-ligating and conventional metal brackets infected with Streptococcus mutans biofilm. AB - Objectives: The objectives of this study were to assess the adherence of Streptococcus mutans biofilms grown over conventional ligature (CL) or self ligating (SL) metal brackets and their bacterial viability after 0.12% chlorhexidine (CHX) digluconate treatment. Materials and methods: The sample consisted of 48 metallic orthodontic brackets divided randomly into two groups: CL (n=24) and SL brackets (n=24). S. mutans biofilms were grown over the bracket surface (96 h) and treated with CHX (positive control) or 0.9% phosphate-buffered saline (PBS) (negative control) for 1 min each. Quantitative analysis was assessed by colony-forming units, and fluorescence microscopy was performed aiming to illustrate the outcomes. The tests were done in triplicate at three different times (n=9). Data were analyzed using ANOVA and Tukey test (P<0.05). Results: There were significant differences in brackets' biofilm formation, being CL largely colonized compared with SL, which was observed by colony-forming unit counting (P<0.05) and microcopy images. Significant reduction in the viability of S. mutans was found in both brackets treated with CHX compared to PBS (P<0.05). Conclusion: The antimicrobial activities of CHX were similar for CL and SL brackets (P>0.05). In conclusion, a lower colonization was achieved in SL brackets and S. mutans biofilms were susceptible to CHX treatment to both studied brackets. PMID- 29719423 TI - Reduction in laboratory turnaround time decreases emergency room length of stay. AB - Objective: Laboratory tests are an important contributor to treatment decisions in the emergency department (ED). Rapid turnaround of laboratory tests can optimize ED throughout by reducing the length of stay (LOS) and improving patient outcomes. Despite evidence supporting the effect of shorter turnaround time (TAT) on LOS and outcomes, there is still a lack of large retrospective studies examining these associations. Here, we evaluated the effect of a reduction in laboratory TAT on ED LOS using retrospective analysis of Electronic Health Records (EHR). Materials and methods: Retrospective analysis of ED encounters from a large, US-based, de-identified EHR database and a separate analysis of ED encounters from the EHR of an ED at a top-tier tertiary care center were performed. Additionally, an efficiency model calculating the cumulative potential LOS time savings and resulting financial opportunity due to laboratory TAT reduction was created, assuming other factors affecting LOS are constant. Results: Multivariate regression analysis of patients from the multisite study showed that a 1-minute decrease in laboratory TAT was associated with 0.50 minutes of decrease in LOS. The single-site analysis confirmed our findings from the multisite analysis that a positive correlation between laboratory TAT and ED LOS exists in the ED population as a whole, as well as across different patient acuity levels. In addition, based on the calculations from the efficiency model, for a 5-, 10- and 15-minute TAT reduction, the single-site ED can potentially admit a total of 127, 256 and 386 additional patients, respectively, annually. Conclusion: A positive correlation between laboratory TAT and ED LOS was observed in a broad patient population and across distinct acuity levels. PMID- 29719424 TI - Heart rate phenotypes and clinical correlates in a large cohort of adults without sleep apnea. AB - Background: Normal sleep is associated with typical physiological changes in both the central and autonomic nervous systems. In particular, nocturnal blood pressure dipping has emerged as a strong marker of normal sleep physiology, whereas the absence of dipping or reverse dipping has been associated with cardiovascular risk. However, nocturnal blood pressure is not measured commonly in clinical practice. Heart rate (HR) dipping in sleep may be a similar important marker and is measured routinely in at-home and in-laboratory sleep testing. Methods: We performed a retrospective cross-sectional analysis of diagnostic polysomnography in a clinically heterogeneous cohort of n=1047 adults without sleep apnea. Results: We found that almost half of the cohort showed an increased HR in stable nonrapid eye movement sleep (NREM) compared to wake, while only 13.5% showed a reduced NREM HR of at least 10% relative to wake. The strongest correlates of HR dipping were younger age and male sex, whereas the periodic limb movement index (PLMI), sleep quality, and Epworth Sleepiness Scale (ESS) scores were not correlated with HR dipping. PLMI was however significantly correlated with metrics of impaired HR variability (HRV): increased low-frequency power and reduced high-frequency power. HRV metrics were unrelated to sleep quality or the ESS value. Following the work of Vgontzas et al, we also analyzed the sub-cohort with insomnia symptoms and short objective sleep duration. Interestingly, the sleep-wake stage-specific HR values depended upon insomnia symptoms more than sleep duration. Conclusion: While our work demonstrates heterogeneity in cardiac metrics (HR and HRV), the population analysis suggests that pathological signatures of HR (nondipping and elevation) are common even in this cohort selected for the absence of sleep apnea. Future prospective work in clinical populations will further inform risk stratification and set the stage for testing interventions. PMID- 29719426 TI - Overwhelming research and clinical evidence of exercise medicine efficacy in cancer management-translation into practice is the challenge before us. PMID- 29719425 TI - The relationship between leadership style and health worker motivation, job satisfaction and teamwork in Uganda. AB - Background: Leadership is key to strengthening performance of Health Systems. Leadership styles are important organizational antecedents, especially in influencing employee's motivation, job satisfaction, and teamwork. There is limited research exploring this relationship among health workers in resource limited settings such as Uganda. The aim of this study was to examine the relationship between transformational, transactional, and laissez-faire leadership styles and motivation, job satisfaction, and teamwork of health workers in Uganda. Method: We conducted a cross-sectional study in 3 geographic regions of Uganda in November 2015, using self-administered questionnaires with 564 health workers from 228 health facilities. Data were collected on health workers' perception of leadership styles displayed by their facility leaders, their level of motivation, job satisfaction, and team work. Using Pearson correlation, relationships among variables were identified and associations of the components of leadership styles with motivation, job satisfaction, and teamwork was found using multivariable logistic regression. Results: Health workers in Uganda preferred leaders who were transformational (62%) compared with being transactional (42%) or laissez-faire (14%). Transformational leadership was positively correlated with motivation (r=0.32), job satisfaction (r=0.38), and team work (r=0.48), while transactional leadership was positively correlated with job satisfaction (r=0.21) and teamwork (r=0.18). Motivation was positively associated with leaders who displayed idealized influence-behavior (odds ratio [OR]=3.7; 95% CI, 1.33-10.48) and intellectual stimulation (OR=2.4; 95% CI, 1.13 5.15) but negatively associated with management by exception (OR=0.4; 95% CI, 0.19-0.82). Job satisfaction was positively associated with intellectual stimulation (OR=5.7; 95% CI, 1.83-17.79). Teamwork was positively associated with idealized influence-behavior (OR=1.07-8.57), idealized influence-attributed (OR=3.9; 95% CI, 1.24-12.36), and contingent reward (OR=5.6; 95% CI, 1.87-17.01). Conclusion: Transformational styles had a positive impact on stimulating motivation, assuring job satisfaction, and consolidating teamwork among health workers compared with those who demonstrated transactional skills or laissez faire styles. Recommendation: Supporting transformational leadership skills development in health facility leaders could encourage health worker motivation, strengthen job satisfaction, and maintain cohesion among health workers for better service delivery. PMID- 29719427 TI - Barriers to participation in clinical trials: a physician survey. AB - Background: Clinical trials are vital for evidence-based cancer care. Oncologist engagement in clinical trials has an effect on patient recruitment, which in turn can affect trial success. Identifying barriers to clinical trial participation might enable interventions that could help to increase physician participation. Methods: To assess factors affecting physician engagement in oncology trials, a national survey was conducted using the online SurveyMonkey tool (SurveyMonkey, San Mateo, CA, U.S.A.; http://www.surveymonkey.com). Physicians associated with the Canadian Cancer Clinical Trials Network and the Canadian Cancer Trials Group were asked about their specialty, years of experience, barriers to participation, and motivating interventions, which included an open-ended question inviting survey takers to suggest interventions. Results: The survey collected 207 anonymous responses. Respondents were predominantly medical oncologists (46.4%), followed by radiation oncologists (24.6%). Almost 70% of the respondents had more than 10 years of experience. Significant time constraints included extra paperwork (77%), patient education (54%), and extended follow-up or clinic visits (53%). Timing of events within trials was also a barrier to participation (55%). Most respondents favoured clinical work credits (72%), academic credits (67%), a clinical trial alert system (75%), a regular meeting to review trial protocols (65%), and a screening log to aid in patient accrual (67%) as motivational strategies. Suggested interventions included increased support staff, streamlined regulatory burden, and provision of greater funding for trials and easier access to ancillary services. Conclusions: The present study confirms that Canadian oncologists are willing to participate in clinical research, but face multiple barriers to trial participation. Those barriers could be mitigated by the implementation of several interventions identified in the study. PMID- 29719428 TI - Factors associated with imaging in patients with early breast cancer after initial treatment. AB - Background: Overuse of surveillance imaging in patients after curative treatment for early breast cancer (ebc) was recently identified as one of the Choosing Wisely Canada initiatives to improve the quality of cancer care. We undertook a population-level examination of imaging practices in Ontario as they existed before the launch of that initiative. Methods: Patients diagnosed with ebc between 2006 and 2010 in Ontario were identified from the Ontario Cancer Registry. Records were linked deterministically to provincial health care databases to obtain comprehensive follow-up. We identified all advanced imaging exams [aies: computed tomography (ct), bone scan, positron-emission tomography] and basic imaging exams (bies: ultrasonography, chest radiography) occurring within the first 2 years after curative treatment. Poisson regression was used to assess associations between patient or provider characteristics and the rate of aies. Results: Of 30,006 women with ebc, 58.6% received at least 1 bie, and 30.6% received at least 1 aie in year 1 after treatment. In year 2, 52.7% received at least 1 bie, and 25.7% received at least 1 aie. The most common aies were chest cts and bone scans. The rate of aies increased with older age, higher disease stage, comorbidity, chemotherapy exposure, and prior staging investigations (p < 0.001). Imaging was ordered mainly by medical oncologists (38%), followed by primary care physicians (23%), surgeons (13%), and emergency room physicians (7%). Conclusions: Despite recommendations against its use, imaging is common in ebc survivors. Understanding the factors associated with aie use helps to identify areas for further research and is required to lower imaging rates and to improve survivorship care. PMID- 29719429 TI - Prescribing practices of endocrine therapy for ductal carcinoma in situ in British Columbia. AB - Purpose: The mainstay of treatment for ductal carcinoma in situ (dcis) involves surgery in the form of mastectomy or lumpectomy. Inconsistency in the use of endocrine therapy (et) for dcis is evident worldwide. We sought to assess the variation in et prescribing for patients with dcis across a population-based radiotherapy (rt) program and to identify variables that predict its use. Methods: Data from a breast cancer database were obtained for women diagnosed with dcis in British Columbia from 2009 to 2014. Associations between et use and patient characteristics were assessed by chi-square test and multilevel multivariate logistic regression. The Kaplan-Meier method, with propensity score matching and Cox regression analysis, was used to assess the effects of et on overall survival (os) and relapse-free survival (rfs). Results: For the 2336 dcis patients included in the study, et use was 13% in dcis patients overall, and 17% in patients with estrogen receptor-positive (er+) tumours treated with breast conserving surgery and rt. Significant variation in et use by treatment centre was observed (range: 8%-23%; p < 0.001), and prescription of et by individual oncologists varied in the range 0%-40%. After controlling for confounding factors, age less than 50 years [odds ratio (or): 1.72; p = 0.01], treatment centre, er+ status (or: 5.33; p < 0.001), and rt use (or: 1.77; p < 0.001) were significant predictors of et use. No difference in os or rfs with the use of et was observed. Conclusions: In this population-based analysis, 13% of patients with dcis in British Columbia received et, with variation by treatment centre (8% 23%) and individual oncologist (0%-40%). Age less than 50 years, er+ status, and rt use were most associated with et use. PMID- 29719430 TI - Intravenous vitamin C in the supportive care of cancer patients: a review and rational approach. AB - This article reviews intravenous vitamin C (IV C) in cancer care and offers a rational approach to enable medical oncologists and integrative practitioners to safely provide IV C combined with oral vitamin C to patients. The use of IV C is a safe supportive intervention to decrease inflammation in the patient and to improve symptoms related to antioxidant deficiency, disease processes, and side effects of standard cancer treatments. A proposed rationale, together with relevant clinical safety considerations for the application of IV C in oncologic supportive care, is provided. PMID- 29719431 TI - Connecting people with cancer to physical activity and exercise programs: a pathway to create accessibility and engagement. AB - Recent guidelines concerning exercise for people with cancer provide evidence based direction for exercise assessment and prescription for clinicians and their patients. Although the guidelines promote exercise integration into clinical care for people with cancer, they do not support strategies for bridging the guidelines with related resources or programs. Exercise program accessibility remains a challenge in implementing the guidelines, but that challenge might be mitigated with conceptual frameworks ("pathways") that connect patients with exercise-related resources. In the present paper, we describe a pathway model and related resources that were developed by an expert panel of practitioners and researchers in the field of exercise and rehabilitation in oncology and that support the transition from health care practitioner to exercise programs or services for people with cancer. The model acknowledges the nuanced distinctions between research and exercise programming, as well as physical activity promotion, that, depending on the available programming in the local community or region, might influence practitioner use. Furthermore, the pathway identifies and provides examples of processes for referral, screening, medical clearance, and programming for people after a cancer diagnosis. The pathway supports the implementation of exercise guidelines and should serve as a model of enhanced care delivery to increase the health and well-being of people with cancer. PMID- 29719432 TI - Evidence-based best practices for EGFR T790M testing in lung cancer in Canada. AB - Epidermal growth factor receptor (egfr) tyrosine kinase inhibitors (tkis) are recommended as first-line systemic therapy for patients with non-small-cell lung cancer (nsclc) having mutations in the EGFR gene. Resistance to tkis eventually occurs in all nsclc patients treated with such drugs. In patients with resistance to tkis caused by the EGFR T790M mutation, the third-generation tki osimertinib is now the standard of care. For optimal patient management, accurate EGFR T790M testing is required. A multidisciplinary working group of pathologists, laboratory medicine specialists, medical oncologists, a respirologist, and a thoracic radiologist from across Canada was convened to discuss best practices for EGFR T790M mutation testing in Canada. The group made recommendations in the areas of the testing algorithm and the pre-analytic, analytic, and post-analytic aspects of clinical testing for both tissue testing and liquid biopsy circulating tumour dna testing. The recommendations aim to improve EGFR T790M testing in Canada and to thereby improve patient care. PMID- 29719434 TI - Measuring patient-reported outcomes to improve cancer care in Canada: an analysis of provincial survey data. AB - Patient-reported outcomes measures (proms) are an important component of the shift from disease-centred to person-centred care. In oncology, proms describe the effects of cancer and its treatment from the patient perspective and ideally enable patients to communicate to their providers the physical symptoms and psychosocial concerns that are most relevant to them. The Edmonton Symptom Assessment System-revised (esas-r) is a commonly used and validated tool in Canada to assess symptoms related to cancer. Here, we describe the extent to which patient-reported outcome programs have been implemented in Canada and the severity of symptoms causing distress for patients with cancer. As of April 2017, 8 of 10 provinces had implemented the esas-r to assess patient-reported outcomes. Data capture methods, the proportion of cancer treatment sites that have implemented the esas-r, and the time and frequency of screening vary from province to province. From October 2016 to March 2017 in the 8 reporting provinces, 88.0% of cancer patients were screened for symptoms. Of patients who reported having symptoms, 44.3% reported depression, with 15.5% reporting moderate-to-high levels; 50.0% reported pain, with 18.6% reporting moderate-to high levels; 56.2% reported anxiety, with 20.4% reporting moderate-to-high levels; and 75.1% reported fatigue, with 34.4% reporting moderate-to-high levels. There are some notable areas in which the implementation of proms could be improved in Canada. Findings point to a need to increase the number of cancer treatment sites that screen all patients for symptoms; to standardize when and how frequently patients are screened across the country; to screen patients for symptoms during all phases of their cancer journey, not just during treatment; and to assess whether giving cancer care providers real-time patient-reported outcomes data has led to appropriate interventions that reduce the symptom burden and improve patient outcomes. Continued measurement and reporting at the system level will allow for a better understanding of progress in proms activity over time and of the areas in which targeted quality improvement efforts could ensure that patient symptoms and concerns are being addressed. PMID- 29719433 TI - Male Oncology Research and Education program for men at high risk for prostate cancer. AB - Three groups of men are at high risk of developing prostate cancer: men with a strong family history of prostate cancer, men of West African or Caribbean ancestry, and men with a germline pathogenic variant in a prostate cancer associated gene. Despite the fact that those men constitute a significant portion of the male population in North America, few recommendations for prostate cancer screening specific to them have been developed. For men at general population risk for prostate cancer, screening based on prostate-specific antigen (psa) has remained controversial despite the abundance of literature on the topic. As a result, recommendations made by major screening authorities are inconsistent (ranging from no psa screening to baseline psa screening at age 45), allowing physicians to pick and choose how to screen their patients. The Male Oncology Research and Education (more) program is an observational research program that serves as an academic platform for multiple research foci. For its participants, serum and dna are biobanked, medical information is collected, and contact for relevant research-related opportunities is maintained. This research program is paired with a specialized clinic called the more clinic, where men at high risk are regularly screened for prostate cancer in a standard approach that includes physical examination and serum psa measurement. In this article, we describe the goals, participant accrual to date, and projects specific to this unique program. PMID- 29719437 TI - A new predictive scoring system based on clinical data and computed tomography features for diagnosing EGFR-mutated lung adenocarcinoma. AB - Background: We aimed to develop a new EGFR mutation-predictive scoring system to use in screening for EGFR-mutated lung adenocarcinomas (lacs). Methods: The study enrolled 279 patients with lac, including 121 patients with EGFR wild-type tumours and 158 with EGFR-mutated tumours. The Student t-test, chi-square test, or Fisher exact test was applied to discriminate clinical and computed tomography (ct) features between the two groups. Using a principal component analysis (pca) model, we derived predictive coefficients for the presence of EGFR mutation in lac. Results: The EGFR mutation-predictive score includes sex, smoking history, homogeneity, ground-glass opacity (ggo) on imaging, and the presence of pericardial effusion. The pca predictive model took this form: [Formula: see text]Model scores ranged from 79 to 147. The area under the receiver operating characteristic curve was 0.752 [95% confidence interval (ci): 0.697 to 0.801] in the lac population at the optimal cut-off value of 109, and the sensitivity and specificity were 68.4% (95% ci: 60.5% to 75.5%) and 74.4% (95% ci: 65.6% to 81.9%) respectively. Conclusions: The EGFR mutation risk scoring system based on clinical data and ct features is noninvasive and user-friendly. The model appears to frame a positive predictive value and was able to determine the value of repeating a biopsy if tissue is limited. PMID- 29719435 TI - Neutrophil-lymphocyte ratio predicts response to chemotherapy in triple-negative breast cancer. AB - Background: The neutrophil-lymphocyte ratio (nlr) has been reported to correlate with patient outcome in several cancers, including breast cancer. We evaluated whether the nlr can be a predictive factor for pathologic complete response (pcr) after neoadjuvant chemotherapy (nac) in patients with triple-negative breast cancer (tnbc). Methods: We analyzed the correlation between response to nac and various factors, including the nlr, in 87 patients with tnbc who underwent nac. In addition, we analyzed the association between the nlr and recurrence-free survival (rfs) in patients with tnbc. Results: Of the 87 patients, 25 (28.7%) achieved a pcr. A high Ki-67 index and a low nlr were significantly associated with pcr. The pcr rate was higher in patients having a high Ki-67 index (>=15%) than in those having a low Ki-67 index (35.7% vs. 0%, p = 0.002) and higher in patients having a low nlr (<=1.7) than in those having a high nlr (42.1% vs. 18.4%, p = 0.018). In multiple logistic analysis, a low nlr remained the only predictive factor for pcr (odds ratio: 4.274; p = 0.008). In the survival analysis, the rfs was significantly higher in the low nlr group than in the high nlr group (5-year rfs rate: 83.7% vs. 66.9%; log-rank p = 0.016). Conclusions: Our findings that the nlr is a predictor of pcr to nac and also a prognosticator of recurrence suggest an association between response to chemotherapy and inflammation in patients with tnbc. The pretreatment nlr can be a useful predictive and prognostic marker in patients with tnbc scheduled for nac. PMID- 29719436 TI - Variation in routine follow-up care after curative treatment for head-and-neck cancer: a population-based study in Ontario. AB - Background: The actual practices of routine follow-up after curative treatment for head-and-neck cancer are unknown, and existing guidelines are not evidence based. Methods: This retrospective population-based study used administrative data to describe 5 years of routine follow-up care in 3975 head-and-neck cancer patients diagnosed between 2007 and 2012 in Ontario. Results: The mean number of visits per year declined during the follow-up period (from 7.8 to 1.9, p < 0.001). The proportion of patients receiving visits in concordance with guidelines ranged from 80% to 45% depending on the follow-up year. In at least 50% of patients, 1 head, neck, or chest imaging test was performed in the first follow-up year; that proportion subsequently declined (p < 0.001). Factors associated with follow-up practices included comorbidity, tumour site, treatment, geographic region, and physician specialty (p < 0.05). Conclusions: Given current practice variation and the absence of an evidence-based standard, the challenge in identifying a single optimal follow-up strategy might be better addressed with a harmonized approach to providing individualized follow-up care. PMID- 29719438 TI - Adherence to, and outcomes of, a galactomannan screening protocol in high-risk hematology patients. AB - Background: A twice-weekly galactomannan (gm) screening protocol was implemented in high-risk hematology inpatients. Study objectives were to determine adherence to the protocol, use of selected resources, and patient outcomes. Methods: This retrospective cohort study compared outcomes of interest before and after implementation of gm screening. Adults undergoing matched related allogeneic hematopoietic stem-cell transplantation or induction chemotherapy for acute leukemia were eligible. Patients could be enrolled more than once and were evaluated as episodes. Adherence to the gm protocol was assessed in post implementation episodes. Use of broad-spectrum antifungals (bsafs), consultations (infectious diseases, respirology), and diagnostic procedures (computed tomography imaging, bronchoalveolar lavage) were compared between phases, as were the patient outcomes of all-cause mortality and clinical success (alive and not taking a bsaf). Results: Of 182 episodes consecutively screened, 70 per phase were enrolled. Clinical characteristics and duration of assessment were similar for the phases. Full or partial adherence to the protocol was observed in 61 post implementation episodes (87%), with full adherence in 40 episodes (57%). More episodes in the pre-implementation phase than in the post-implementation phase involved receipt of bsafs, consultations, and diagnostics (27% vs. 7%, p = 0.02; 46% vs. 26%, p = 0.014; and 46% vs. 31%, p = 0.083 respectively). Although mortality was similar in the two phases, clinical success at the final assessment was observed in fewer pre-implementation than post-implementation episodes (79% vs. 98%, p < 0.001). Conclusions: Implementation of a gm screening protocol was feasible and associated with significantly fewer episodes involving receipt of bsafs and consultations, and with significantly more episodes showing clinical success. PMID- 29719439 TI - Factors affecting radiotherapy prescribing patterns in the post-mastectomy setting. AB - Background: Radiation therapy (rt) after mastectomy for breast cancer can improve survival outcomes, but has been associated with inferior cosmesis after breast reconstruction. In the literature, rt dose and fractionation schedules are inconsistently reported. We sought to determine the pattern of rt prescribing practices in a provincial rt program for patients treated with mastectomy and reconstruction. Methods: Women diagnosed with stages 0-iii breast cancer between January 2012 and December 2013 and treated with curative-intent rt were identified from a clinicopathology database. Patient demographic, tumour, and treatment information were extracted. Of the identified patients, those undergoing mastectomy were the focus of the present analysis. Results: Of 4016 patients identified, 1143 (28%) underwent mastectomy. The patients treated with mastectomy had a median age of 57 years, and 37% of them underwent reconstruction. Treatment with more than 16 fractions of rt was associated with autologous reconstruction [odds ratio (or): 37.2; 95% confidence interval (ci): 11.2 to 123.7; p < 0.001], implant reconstruction (or: 93.3; 95% ci: 45.3 to 192.2; p < 0.001), and treating centre. Hypofractionated treatment was associated with older age (or: 0.94; 95% ci: 0.92 to 0.96; p < 0.001), and living more than 400 km from a treatment centre (or: 0.37; 95% ci: 0.16 to 0.86; p = 0.02). Conclusions: Prescribing practices in breast cancer patients undergoing mastectomy are influenced by reconstruction intent, age, nodal status, and distance from the treatment centre. Those factors should be considered when making treatment decisions. PMID- 29719441 TI - Aromatase inhibitors in premenopausal women with breast cancer: the state of the art and future prospects. AB - Approximately 11% of patients with breast cancer (bca) are diagnosed before menopause, and because in most of those patients the tumour expresses a hormone receptor, treatment with endocrine interventions can be applied in any setting of disease (early or advanced). In the past, hormonal treatment consisted only of the estrogen receptor modulator tamoxifen, associated with luteinizing hormone releasing hormone (lhrh); more recently, aromatase inhibitors (ais) have come into widespread use. The ais interfere with the last enzymatic step of estrogen synthesis in which androgens are converted into estrogens. Initially, the ais were used alone in postmenopausal patients to prevent disease recurrence, but together with lhrh analogs, they can be used in premenopausal patients to produce better estrogen suppression than can be achieved with tamoxifen plus a lhrh analog. Using a systematic review of the scientific literature (prospective and retrospective studies), we set out to assess the efficacy of ais compared with other endocrine therapy in various disease settings (neoadjuvant, adjuvant, metastatic). PMID- 29719440 TI - Pharmacologic interventions for fatigue in cancer and transplantation: a meta analysis. AB - Background: Our objective was to determine whether, compared with control interventions, pharmacologic interventions reduce the severity of fatigue in patients with cancer or recipients of hematopoietic stem-cell transplantation (hsct). Methods: For a systematic review, we searched medline, embase, the Cochrane Central Register of Controlled Trials, cinahl, and Psychinfo for randomized trials of systemic pharmacologic interventions for the management of fatigue in patients with cancer or recipients of hsct. Two authors independently identified studies and abstracted data. Methodologic quality was assessed using the Cochrane Risk of Bias tool. The primary outcome was fatigue severity measured using various fatigue scales. Data were synthesized using random-effects models. Results: In the 117 included trials (19,819 patients), the pharmacologic agents used were erythropoietins (n = 31), stimulants (n = 19), l-carnitine (n = 6), corticosteroids (n = 5), antidepressants (n = 5), appetite stimulants (n = 3), and other agents (n = 48). Fatigue was significantly reduced with erythropoietin [standardized mean difference (smd): -0.52; 95% confidence interval (ci): -0.89 to -0.14] and with methylphenidate (smd: -0.36; 95% ci: -0.56 to -0.15); modafinil (or armodafinil) and corticosteroids were not effective. Conclusions: Erythropoietin and methylphenidate significantly reduced fatigue severity in patients with cancer and in recipients of hsct. Concerns about the safety of those agents might limit their usefulness. Future research should identify effective interventions for fatigue that have minimal adverse effects. PMID- 29719443 TI - Follow-up. PMID- 29719442 TI - Ataxia-telangiectasia gene (ATM) mutation heterozygosity in breast cancer: a narrative review. AB - Background: Despite the fact that heterozygosity for a pathogenic ATM variant is present in 1%-2% of the adult population, clinical guidelines to inform physicians and genetic counsellors about optimal management in that population are lacking. Methods: In this narrative review, we describe the challenges and controversies in the management of women who are heterozygous for a pathogenic ATM variant with respect to screening for breast and other malignancies, to choices for systemic therapy, and to decisions about radiation therapy. Results: Given that the lifetime risk for breast cancer in women who are heterozygous for a pathogenic ATM variant is likely greater than 25%, those women should undergo annual mammographic screening starting at least by 40 years of age. For women in this group who have a strong family history of breast cancer, earlier screening with both magnetic resonance imaging and mammography should be considered. High quality data to inform the management of established breast cancer in carriers of pathogenic ATM variants are lacking. Although deficiency in the ATM gene product might confer sensitivity to dna-damaging pharmaceuticals such as inhibitors of poly (adp-ribose) polymerase or platinum agents, prospective clinical trials have not been conducted in the relevant patient population. Furthermore, the evidence with respect to radiation therapy is mixed; some data suggest increased toxicity, and other data suggest improved clinical benefit from radiation in women who are carriers of a pathogenic ATM variant. Conclusions: As in the 2017 U.S. National Comprehensive Cancer Network guidelines, we recommend high-risk imaging for women in Ontario who are heterozygous for a pathogenic ATM variant. Currently, ATM carrier status should not influence decisions about systemic or radiation therapy in the setting of an established breast cancer diagnosis. PMID- 29719444 TI - Ductal carcinoma in situ is presumably not a metastatic disease: a reply to "Commentary: Wherein the authors attempt to minimize the confusion generated by their study 'Breast cancer mortality after a diagnosis of ductal carcinoma in situ' by several commentators who disagree with them and a few who don't: a qualitative study". PMID- 29719445 TI - Mechanisms involved in adenosine pharmacological preconditioning-induced cardioprotection. AB - Adenosine is a naturally occurring breakdown product of adenosine triphosphate and plays an important role in different physiological and pathological conditions. Adenosine also serves as an important trigger in ischemic and remote preconditioning and its release may impart cardioprotection. Exogenous administration of adenosine in the form of adenosine preconditioning may also protect heart from ischemia-reperfusion injury. Endogenous release of adenosine during ischemic/remote preconditioning or exogenous adenosine during pharmacological preconditioning activates adenosine receptors to activate plethora of mechanisms, which either independently or in association with one another may confer cardioprotection during ischemia-reperfusion injury. These mechanisms include activation of KATP channels, an increase in the levels of antioxidant enzymes, functional interaction with opioid receptors; increase in nitric oxide production; decrease in inflammation; activation of transient receptor potential vanilloid (TRPV) channels; activation of kinases such as protein kinase B (Akt), protein kinase C, tyrosine kinase, mitogen activated protein (MAP) kinases such as ERK 1/2, p38 MAP kinases and MAP kinase kinase (MEK 1) MMP. The present review discusses the role and mechanisms involved in adenosine preconditioning-induced cardioprotection. PMID- 29719446 TI - Ursolic acid in health and disease. AB - Ursolic acid (UA) is a natural triterpene compound found in various fruits and vegetables. There is a growing interest in UA because of its beneficial effects, which include anti-inflammatory, anti-oxidant, anti-apoptotic, and anti carcinogenic effects. It exerts these effects in various tissues and organs: by suppressing nuclear factor-kappa B signaling in cancer cells, improving insulin signaling in adipose tissues, reducing the expression of markers of cardiac damage in the heart, decreasing inflammation and increasing the level of anti oxidants in the brain, reducing apoptotic signaling and the level of oxidants in the liver, and reducing atrophy and increasing the expression levels of adenosine monophosphate-activated protein kinase and irisin in skeletal muscles. Moreover, UA can be used as an alternative medicine for the treatment and prevention of cancer, obesity/diabetes, cardiovascular disease, brain disease, liver disease, and muscle wasting (sarcopenia). In this review, we have summarized recent data on the beneficial effects and possible uses of UA in health and disease managements. PMID- 29719447 TI - Echinacoside, an active constituent of Herba Cistanche, suppresses epileptiform activity in hippocampal CA3 pyramidal neurons. AB - Echinacoside, an active compound in the herb Herba Cistanche, has been reported to inhibit glutamate release. In this study, we investigated the effects of echinacoside on spontaneous excitatory synaptic transmission changes induced by 4 aminopyridine (4-AP), by using the in vitro rat hippocampal slice technique and whole-cell patch clamp recordings from CA3 pyramidal neurons. Perfusion with echinacoside significantly suppressed the 4-AP-induced epileptiform activity in a concentration-dependent manner. Echinacoside reduced 4-AP-induced increase in frequency of spontaneous excitatory postsynaptic currents (sEPSCs) but it did not affect the amplitude of sEPSCs or glutamate-activated currents, implicating a presynaptic mechanism of action. Echinacoside also potently blocked sustained repetitive firing, which is a basic mechanism of antiepileptic drugs. These results suggest that echinacoside exerts an antiepileptic effect on hippocampal CA3 pyramidal neurons by simultaneously decreasing glutamate release and blocking abnormal firing synchronization. Accordingly, our study provides experimental evidence that echinacoside may represent an effective pharmacological agent for treating epilepsy. PMID- 29719448 TI - Effects of cinnamic acid on memory deficits and brain oxidative stress in streptozotocin-induced diabetic mice. AB - The present study aimed to evaluate the cinnamic acid effect on memory impairment, oxidative stress, and cholinergic dysfunction in streptozotocin (STZ) induced diabetic model in mice. In this experimental study, 48 male Naval Medical Research Institute (NMRI) mice (30-35 g) were chosen and were randomly divided into six groups: control, cinnamic acid (20 mg/kg day, i.p. ), diabetic, and cinnamic acid-treated diabetic (10, 20 and 40 mg/kg day, i.p. ). Memory was impaired by administering an intraperitoneal STZ injection of 50 mg/kg. Cinnamic acid was injected for 40 days starting from the 21st day after confirming STZ induced dementia to observe its therapeutic effect. Memory function was assessed using cross-arm maze, morris water maze and passive avoidance test. After the administration, biochemical parameters of oxidative stress and cholinergic function were estimated in the brain. Present data indicated that inducing STZ caused significant memory impairment, whereas administration of cinnamic acid caused significant and dose-dependent memory improvement. Assessment of brain homogenates indicated cholinergic dysfunction, increase in lipid peroxidation and reactive oxygen species (ROS) levels, and decrease in glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) activities in the diabetic group compared to the control animals, whereas cinnamic acid administration ameliorated these indices in the diabetic mice. The present study demonstrated that cinnamic acid improves memory by reducing the oxidative stress and cholinergic dysfunction in the brain of diabetic mice. PMID- 29719449 TI - Up-regulation of NHE8 by somatostatin ameliorates the diarrhea symptom in infectious colitis mice model. AB - Na+/H+ exchangers (NHEs) have been shown to be involved in regulating cell volume and maintaining fluid and electrolyte homeostasis. Pooled evidences have suggested that loss of Na+/H+ exchanger isoform 8 (NHE8) impairs intestinal mucosa. Whether NHE8 participates in the pathology of infectious colitis is still unknown. Our previous study demonstrated that somatostatin (SST) could stimulate the expression of intestinal NHE8 so as to facilitate Na+ absorption under normal condition. This study further explored whether NHE8 participates in the pathological processes of infectious colitis and the effects of SST on intestinal NHE8 expression in the setting of infectious colitis. Our data showed that NHE8 expression was reduced in Citrobacter rodentium (CR) infected mice. Up-regulation of NHE8 improved diarrhea symptom and mucosal damage induced by CR. In vitro, a similar observation was also seen in Enteropathogenic E. coli (EPEC) infected Caco-2 cells. Seglitide, a SST receptor (SSTR) 2 agonist, partly reversed the inhibiting action of EPEC on NHE8 expression, but SSTR5 agonist (L-817,818) had no effect on the expression of NHE8. Moreover, SST blocked the phosphorylation of p38 in EPEC-infected Caco-2 cells. Taken together, these results suggest that enhancement of intestinal NHE8 expression by SST could ameliorate the symptoms of mice with infectious colitis. PMID- 29719450 TI - Exposure to 835 MHz RF-EMF decreases the expression of calcium channels, inhibits apoptosis, but induces autophagy in the mouse hippocampus. AB - The exponential increase in the use of mobile communication has triggered public concerns about the potential adverse effects of radiofrequency electromagnetic fields (RF-EMF) emitted by mobile phones on the central nervous system (CNS). In this study, we explored the relationship between calcium channels and apoptosis or autophagy in the hippocampus of C57BL/6 mice after RF-EMF exposure with a specific absorption rate (SAR) of 4.0 W/kg for 4 weeks. Firstly, the expression level of voltage-gated calcium channels (VGCCs), a key regulator of the entry of calcium ions into the cell, was confirmed by immunoblots. We investigated and confirmed that pan-calcium channel expression in hippocampal neurons were significantly decreased after exposure to RF-EMF. With the observed accumulation of autolysosomes in hippocampal neurons via TEM, the expressions of autophagy related genes and proteins (e.g., LC3B-II) had significantly increased. However, down-regulation of the apoptotic pathway may contribute to the decrease in calcium channel expression, and thus lower levels of calcium in hippocampal neurons. These results suggested that exposure of RF-EMF could alter intracellular calcium homeostasis by decreasing calcium channel expression in the hippocampus; presumably by activating the autophagy pathway, while inhibiting apoptotic regulation as an adaptation process for 835 MHz RF-EMF exposure. PMID- 29719451 TI - Establishment and evaluation of the VX2 orthotopic lung cancer rabbit model: a ultra-minimal invasive percutaneous puncture inoculation method. AB - The purpose of the present work is to establish an ultra-minimal invasive percutaneous puncture inoculation method for a VX2 orthotopic lung cancer rabbit model with fewer technical difficulties, lower mortality of rabbits, a higher success rate and a shorter operation time, to evaluate the growth, metastasis and apoptosis of tumor by CT scans, necropsy, histological examination, flow cytometry and immunohistochemistry. The average inoculation time was 10-15 min per rabbit. The tumor-bearing rate was 100%. More than 90% of the tumor-bearing rabbits showed local solitary tumor with 2-10 mm diameters after two weeks post inoculation, and the rate of chest seeding was only 8.3% (2/24). The tumors diameters increased to 4-16 mm, and irregularly short thorns were observed 3 weeks after inoculation. Five weeks post-inoculation, the liquefaction necrosis and a cavity developed, and the size of tumor grew further. Before natural death, the CT images showed that the tumors spread to the chest. The flow cytometry and immunohistochemistry indicated that there was less apoptosis in VX2 orthotopic lung cancer rabbit model compared to chemotherapy drug treatment group. Minimal invasive percutaneous puncture inoculation is an easy, fast and accurate method to establish the VX2 orthotopic lung cancer rabbit model, an ideal in situ tumor model similar to human malignant tumor growth. PMID- 29719452 TI - Atorvastatin pretreatment attenuates kainic acid-induced hippocampal neuronal death via regulation of lipocalin-2-associated neuroinflammation. AB - Statins mediate vascular protection and reduce the prevalence of cardiovascular diseases. Recent work indicates that statins have anticonvulsive effects in the brain; however, little is known about the precise mechanism for its protective effect in kainic acid (KA)-induced seizures. Here, we investigated the protective effects of atorvastatin pretreatment on KA-induced neuroinflammation and hippocampal cell death. Mice were treated via intragastric administration of atorvastatin for 7 days, injected with KA, and then sacrificed after 24 h. We observed that atorvastatin pretreatment reduced KA-induced seizure activity, hippocampal cell death, and neuroinflammation. Atorvastatin pretreatment also inhibited KA-induced lipocalin-2 expression in the hippocampus and attenuated KA induced hippocampal cyclooxygenase-2 expression and glial activation. Moreover, AKT phosphorylation in KA-treated hippocampus was inhibited by atorvastatin pretreatment. These findings suggest that atorvastatin pretreatment may protect hippocampal neurons during seizures by controlling lipocalin-2-associated neuroinflammation. PMID- 29719453 TI - Nobiletin attenuates neurotoxic mitochondrial calcium overload through K+ influx and DeltaPsim across mitochondrial inner membrane. AB - Mitochondrial calcium overload is a crucial event in determining the fate of neuronal cell survival and death, implicated in pathogenesis of neurodegenerative diseases. One of the driving forces of calcium influx into mitochondria is mitochondria membrane potential (DeltaPsim). Therefore, pharmacological manipulation of DeltaPsim can be a promising strategy to prevent neuronal cell death against brain insults. Based on these issues, we investigated here whether nobiletin, a Citrus polymethoxylated flavone, prevents neurotoxic neuronal calcium overload and cell death via regulating basal DeltaPsim against neuronal insult in primary cortical neurons and pure brain mitochondria isolated from rat cortices. Results demonstrated that nobiletin treatment significantly increased cell viability against glutamate toxicity (100 uM, 20 min) in primary cortical neurons. Real-time imaging-based fluorometry data reveal that nobiletin evokes partial mitochondrial depolarization in these neurons. Nobiletin markedly attenuated mitochondrial calcium overload and reactive oxygen species (ROS) generation in glutamate (100 uM)-stimulated cortical neurons and isolated pure mitochondria exposed to high concentration of Ca2+ (5 uM). Nobiletin-induced partial mitochondrial depolarization in intact neurons was confirmed in isolated brain mitochondria using a fluorescence microplate reader. Nobiletin effects on basal DeltaPsim were completely abolished in K+-free medium on pure isolated mitochondria. Taken together, results demonstrate that K+ influx into mitochondria is critically involved in partial mitochondrial depolarization related neuroprotective effect of nobiletin. Nobiletin-induced mitochondrial K+ influx is probably mediated, at least in part, by activation of mitochondrial K+ channels. However, further detailed studies should be conducted to determine exact molecular targets of nobiletin in mitochondria. PMID- 29719454 TI - Physiologically-based pharmacokinetic predictions of intestinal BCRP-mediated drug interactions of rosuvastatin in Koreans. AB - It was recently reported that the Cmax and AUC of rosuvastatin increases when it is coadministered with telmisartan and cyclosporine. Rosuvastatin is known to be a substrate of OATP1B1, OATP1B3, NTCP, and BCRP transporters. The aim of this study was to explore the mechanism of the interactions between rosuvastatin and two perpetrators, telmisartan and cyclosporine. Published (cyclosporine) or newly developed (telmisartan) PBPK models were used to this end. The rosuvastatin model in Simcyp (version 15)'s drug library was modified to reflect racial differences in rosuvastatin exposure. In the telmisartan-rosuvastatin case, simulated rosuvastatin CmaxI/Cmax and AUCI/AUC (with/without telmisartan) ratios were 1.92 and 1.14, respectively, and the Tmax changed from 3.35 h to 1.40 h with coadministration of telmisartan, which were consistent with the aforementioned report (CmaxI/Cmax: 2.01, AUCI/AUC:1.18, Tmax: 5 h -> 0.75 h). In the next case of cyclosporine-rosuvastatin, the simulated rosuvastatin CmaxI/Cmax and AUCI/AUC (with/without cyclosporine) ratios were 3.29 and 1.30, respectively. The decrease in the CLint,BCRP,intestine of rosuvastatin by telmisartan and cyclosporine in the PBPK model was pivotal to reproducing this finding in Simcyp. Our PBPK model demonstrated that the major causes of increase in rosuvastatin exposure are mediated by intestinal BCRP (rosuvastatin-telmisartan interaction) or by both of BCRP and OATP1B1/3 (rosuvastatin-cyclosporine interaction). PMID- 29719455 TI - Preemptive application of QX-314 attenuates trigeminal neuropathic mechanical allodynia in rats. AB - The aim of the present study was to examine the effects of preemptive analgesia on the development of trigeminal neuropathic pain. For this purpose, mechanical allodynia was evaluated in male Sprague-Dawley rats using chronic constriction injury of the infraorbital nerve (CCI-ION) and perineural application of 2% QX 314 to the infraorbital nerve. CCI-ION produced severe mechanical allodynia, which was maintained until postoperative day (POD) 30. An immediate single application of 2% QX-314 to the infraorbital nerve following CCI-ION significantly reduced neuropathic mechanical allodynia. Immediate double application of QX-314 produced a greater attenuation of mechanical allodynia than a single application of QX-314. Immediate double application of 2% QX-314 reduced the CCI-ION-induced upregulation of GFAP and p-p38 expression in the trigeminal ganglion. The upregulated p-p38 expression was co-localized with NeuN, a neuronal cell marker. We also investigated the role of voltage-gated sodium channels (Navs) in the antinociception produced by preemptive application of QX-314 through analysis of the changes in Nav expression in the trigeminal ganglion following CCI-ION. Preemptive application of QX-314 significantly reduced the upregulation of Nav1.3, 1.7, and 1.9 produced by CCI-ION. These results suggest that long-lasting blockade of the transmission of pain signaling inhibits the development of neuropathic pain through the regulation of Nav isoform expression in the trigeminal ganglion. Importantly, these results provide a potential preemptive therapeutic strategy for the treatment of neuropathic pain after nerve injury. PMID- 29719456 TI - Increased store-operated Ca2+ entry mediated by GNB5 and STIM1. AB - Recent human genetic studies have shown that Gbeta5 is related to various clinical symptoms, such as sinus bradycardia, cognitive disability, and attention deficit hyperactivity disorder. Although the calcium signaling cascade is closely associated with a heterotrimeric G-protein, the function of Gbeta5 in calcium signaling and its relevance to clinical symptoms remain unknown. In this study, we investigated the in vitro changes of store-operated calcium entry (SOCE) with exogenous expression of Gbeta5. The cells expressing Gbeta5 had enhanced SOCE after depletion of calcium ion inside the endoplasmic reticulum. Gbeta5 also augmented Stim1- and Orai1-dependent SOCE. An ORAI1 loss-of-function mutant did not show inhibition of Gbeta5-induced SOCE, and a STIM1-ERM truncation mutant showed no enhancement of SOCE. These results suggested a novel role of GNB5 and Stim1, and provided insight into the regulatory mechanism of SOCE. PMID- 29719457 TI - Anti-apoptotic effects of autophagy via ROS regulation in microtubule-targeted and PDGF-stimulated vascular smooth muscle cells. AB - Autophagy has been studied as a therapeutic strategy for cardiovascular diseases. However, insufficient studies have been reported concerning the influence of vascular smooth muscle cells (VSMCs) through autophagy regulation. The aim of the present study was to determine the effects of VSMCs on the regulation of autophagy under in vitro conditions similar to vascular status of the equipped microtubule target agent-eluting stent and increased release of platelet-derived growth factor-BB (PDGF-BB). Cell viability and proliferation were measured using MTT and cell counting assays. Immunofluorescence using an anti-alpha-tubulin antibody was performed to determine microtubule dynamic formation. Cell apoptosis was measured by cleavage of caspase-3 using western blot analysis, and by nuclear fragmentation using a fluorescence assay. Autophagy activity was assessed by microtubule-associated protein light chain 3-II (LC-II) using western blot analysis. Levels of intracellular reactive oxygen species (ROS) were measured using H2DCFDA. The proliferation and viability of VSMCs were inhibited by microtubule regulation. Additionally, microtubule-regulated and PDGF-BB stimulated VSMCs increased the cleavage of caspase-3 more than only the microtubule-regulated condition, similar to that of LC3-II, implying autophagy. Inhibitory autophagy of microtubule-regulated and PDGF-BB-stimulated VSMCs resulted in low viability. However, enhancement of autophagy maintained survival through the reduction of ROS. These results suggest that the apoptosis of conditioned VSMCs is decreased by the blocking generation of ROS via the promotion of autophagy, and proliferation is also inhibited. Thus, promoting autophagy as a therapeutic target for vascular restenosis and atherosclerosis may be a good strategy. PMID- 29719458 TI - Molecular signaling of ginsenosides Rb1, Rg1, and Rg3 and their mode of actions. AB - Ginseng has gained its popularity as an adaptogen since ancient days because of its triterpenoid saponins, known as ginsenosides. These triterpenoid saponins are unique and classified as protopanaxatriol and protopanaxadiol saponins based on their glycosylation patterns. They play many protective roles in humans and are under intense research as various groups continue to study their efficacy at the molecular level in various disorders. Ginsenosides Rb1 and Rg1 are the most abundant ginsenosides present in ginseng roots, and they confer the pharmacological properties of the plant, whereas ginsenoside Rg3 is abundantly present in Korean Red Ginseng preparation, which is highly known for its anticancer effects. These ginsenosides have a unique mode of action in modulating various signaling cascades and networks in different tissues. Their effect depends on the bioavailability and the physiological status of the cell. Mostly they amplify the response by stimulating phosphotidylinositol-4,5-bisphosphate 3 kinase/protein kinase B pathway, caspase-3/caspase-9-mediated apoptotic pathway, adenosine monophosphate-activated protein kinase, and nuclear factor kappa-light chain-enhancer of activated B cells signaling. Furthermore, they trigger receptors such as estrogen receptor, glucocorticoid receptor, and N-methyl-d aspartate receptor. This review critically evaluates the signaling pathways attenuated by ginsenosides Rb1, Rg1, and Rg3 in various tissues with emphasis on cancer, diabetes, cardiovascular diseases, and neurodegenerative disorders. PMID- 29719459 TI - Anticancer activity and potential mechanisms of 1C, a ginseng saponin derivative, on prostate cancer cells. AB - Background: AD-2 (20(R)-dammarane-3b, 12b, 20, 25-tetrol; 25-OH-PPD) is a ginsenoside and isolated from Panax ginseng, showing anticancer activity against extensive human cancer cell lines. In this study, effects and mechanisms of 1C ((20R)-3b-O-(L-alanyl)-dammarane-12b, 20, 25-triol), a modified version of AD-2, were evaluated for its development as a novel anticancer drug. Methods: MTT assay was performed to evaluate cell cytotoxic activity. Cell cycle and levels of reactive oxygen species (ROS) were determined using flow cytometry analysis. Western blotting was employed to analyze signaling pathways. Results: 1C concentration-dependently reduces prostate cancer cell viability without affecting normal human gastric epithelial cell line-1 viability. In LNCaP prostate cancer cells, 1C triggered apoptosis via Bcl-2 family-mediated mitochondria pathway, downregulated expression of mouse double minute 2, upregulated expression of p53 and stimulated ROS production. ROS scavenger, N acetylcysteine, can attenuate 1C-induced apoptosis. 1C also inhibited the proliferation of LNCaP cells through inhibition on Wnt/beta-catenin signaling pathway. Conclusion: 1C shows obvious anticancer activity based on inducing cell apoptosis by Bcl-2 family-mediated mitochondria pathway and ROS production, inhibiting Wnt/beta-catenin signaling pathway. These findings demonstrate that 1C may provide leads as a potential agent for cancer therapy. PMID- 29719460 TI - Korean Red Ginseng exhibits no significant adverse effect on disease activity in patients with rheumatoid arthritis: a randomized, double-blind, crossover study. AB - Background: Panax ginseng is a well-known immune modulator, and there is concern that its immune-enhancing effects may negatively affect patients with rheumatoid arthritis (RA) by worsening symptoms or increasing the risk of adverse effects from other drugs. In this randomized, crossover clinical trial, we evaluated the impact of Korean Red Ginseng (KRG) on disease activity and safety in RA patients. Methods: A total of 80 female RA patients were randomly assigned to either the KRG (2 g/d, n = 40) treatment or placebo (n = 40) groups for 8 wk, followed by crossover to the other treatment group for an additional 8 wk. The primary outcome was the disease flare rate, defined as worsening disease activity according to the disease activity score 28 joints-erythrocyte sedimentation rate (DAS28-ESR). The secondary outcomes were development of adverse events (AEs) and patient reported outcomes. Outcomes were evaluated at baseline and 8 wk and 16 wk. The outcomes were compared using the Chi-square test. Results: Of the 80 patients, 70 completed the full study. Their mean age was 51.9 yr, and most exhibited low disease activity (mean DAS28-ESR 3.5 +/- 1.0) at enrollment. After intervention, the flare rate was 3.7% in each group. During KRG treatment, 10 AEs were reported, while five AEs were developed with placebo; however, this difference was not statistically significant (p = 0.16). Gastrointestinal- and nervous system-related symptoms were frequent in the KRG group. Conclusion: KRG is not significantly associated with either disease flare rate or the rate of AE development in RA patients. PMID- 29719461 TI - Qualitative and quantitative analysis of the saponins in Panax notoginseng leaves using ultra-performance liquid chromatography coupled with time-of-flight tandem mass spectrometry and high performance liquid chromatography coupled with UV detector. AB - Background: Panax notoginseng leaves (PNL) exhibit extensive activities, but few analytical methods have been established to exclusively determine the dammarane triterpene saponins in PNL. Methods: Ultra-performance liquid chromatography coupled with time-of-flight mass spectrometry (UPLC/Q-TOF MS) and HPLC-UV methods were developed for the qualitative and quantitative analysis of ginsenosides in PNL, respectively. Results: Extraction conditions, including solvents and extraction methods, were optimized, which showed that ginsenosides Rc and Rb3, the main components of PNL, are transformed to notoginsenosides Fe and Fd, respectively, in the presence of water, by removing a glucose residue from position C-3 via possible enzymatic hydrolysis. A total of 57 saponins were identified in the methanolic extract of PNL by UPLC/Q-TOF MS. Among them, 19 components were unambiguously characterized by their reference substances. Additionally, seven saponins of PNL-ginsenosides Rb1, Rc, Rb2, and Rb3, and notoginsenosides Fc, Fe, and Fd-were quantified using the HPLC-UV method after extraction with methanol. The separation of analytes, particularly the separation of notoginsenoside Fc and ginsenoside Rc, was achieved on a Zorbax ODS C8 column at a temperature of 35 degrees C. This developed HPLC-UV method provides an adequate linearity (r2 > 0.999), repeatability (relative standard deviation, RSD < 2.98%), and inter- and intraday variations (RSD < 4.40%) with recovery (98.7 106.1%) of seven saponins concerned. This validated method was also conducted to determine seven components in 10 batches of PNL. Conclusion: These findings are beneficial to the quality control of PNL and its relevant products. PMID- 29719462 TI - Genetic variability, associations, and path analysis of chemical and morphological traits in Indian ginseng [Withania somnifera (L.) Dunal] for selection of higher yielding genotypes. AB - Background: The study was carried out to assess the genetic variability present in ashwagandha and to examine the nature of associations of various traits to the root yield of the plant. Methods: Fifty-three diverse genetic stocks of ashwagandha (Withania somnifera) were evaluated for 14 quantitative characteristics. Analysis of variance, correlation, and path coefficient analysis were performed using the mean data of 2 years. Results: Analysis of variance revealed that the genotypes differed significantly for all characteristics studied. High heritability in conjunction with high genetic advance was observed for fresh root weight, 12 deoxywithastramonolide in roots, and plant height, which indicated that selection could be effective for these traits. Dry root weight has a tight linkage with plant height and fresh root weight. Further, in path coefficient analysis, fresh root weight, total alkaloid (%) in leaves, and 12 deoxywithastramonolide (%) in roots had the highest positive direct effect on dry root weight. Conclusion: Therefore, these characteristics can be exploited to improve dry root weight in ashwagandha genotypes and there is also scope for the selection of promising and specific chemotypes (based on the alkaloid content) from the present germplasm. PMID- 29719463 TI - Compound K induced apoptosis via endoplasmic reticulum Ca2+ release through ryanodine receptor in human lung cancer cells. AB - Background: Extended endoplasmic reticulum (ER) stress may initiate apoptotic pathways in cancer cells, and ER stress has been reported to possibly increase tumor death in cancer therapy. We previously reported that caspase-8 played an important role in compound K-induced apoptosis via activation of caspase-3 directly or indirectly through Bid cleavage, cytochrome c release, and caspase-9 activation in HL-60 human leukemia cells. The mechanisms leading to apoptosis in A549 and SK-MES-1 human lung cancer cells and the role of ER stress have not yet been understood. Methods: The apoptotic effects of compound K were analyzed using flow cytometry, and the changes in protein levels were determined using Western blot analysis. The intracellular calcium levels were monitored by staining with Fura-2/AM and Fluo-3/AM. Results: Compound K-induced ER stress was confirmed through increased phosphorylation of eIF2alpha and protein levels of GRP78/BiP, XBP-1S, and IRE1alpha in human lung cancer cells. Moreover, compound-K led to the accumulation of intracellular calcium and an increase in m-calpain activities that were both significantly inhibited by pretreatment either with BAPTA-AM (an intracellular Ca2+ chelator) or dantrolene (an RyR channel antagonist). These results were correlated with the outcome that compound K induced ER stress related apoptosis through caspase-12, as z-ATAD-fmk (a specific inhibitor of caspase-12) partially ameliorated this effect. Interestingly, 4-PBA (ER stress inhibitor) dramatically improved the compound K-induced apoptosis. Conclusion: Cell survival and intracellular Ca2+ homeostasis during ER stress in human lung cancer cells are important factors in the induction of the compound K-induced apoptotic pathway. PMID- 29719464 TI - Effect of azoxystrobin fungicide on the physiological and biochemical indices and ginsenoside contents of ginseng leaves. AB - Background: The impact of fungicide azoxystrobin, applied as foliar spray, on the physiological and biochemical indices and ginsenoside contents of ginseng was studied in ginseng (Panax ginseng Mey. cv. "Ermaya") under natural environmental conditions. Different concentrations of 25% azoxystrobin SC (150 g a.i./ha and 225 g a.i./ha) on ginseng plants were sprayed three times, and the changes in physiological and biochemical indices and ginsenoside contents of ginseng leaves were tested. Methods: Physiological and biochemical indices were measured using a spectrophotometer (Shimadzu UV-2450). Every index was determined three times per replication. Extracts of ginsenosides were analyzed by HPLC (Shimadzu LC20-AB) utilizing a GL-Wondasil C18 column. Results: Chlorophyll and soluble protein contents were significantly (p = 0.05) increased compared with the control by the application of azoxystrobin. Additionally, activities of superoxide dismutase, catalase, ascorbate peroxidase, peroxidase, and ginsenoside contents in azoxystrobin-treated plants were improved, and malondialdehyde content and O2- contents were reduced effectively. Azoxystrobin treatments to ginseng plants at all growth stages suggested that the azoxystrobin-induced delay of senescence was due to an enhanced antioxidant enzyme activity protecting the plants from harmful active oxygen species. When the dose of azoxystrobin was 225 g a.i./ha, the effect was more significant. Conclusion: This work suggested that azoxystrobin played a role in delaying senescence by changing physiological and biochemical indices and improving ginsenoside contents in ginseng leaves. PMID- 29719465 TI - Antinociceptive and anti-inflammatory effects of ginsenoside Rf in a rat model of incisional pain. AB - Background: Ginseng saponin has long been used as a traditional Asian medicine and is known to be effective in treating various kinds of pain. Ginsenoside Rf is one of the biologically active saponins found in ginseng. We evaluated ginsenoside Rf's antinociceptive and anti-inflammatory effects, and its mechanism of action on adrenergic and serotonergic receptors, in an incisional pain model. Methods: Mechanical hyperalgesia was induced via plantar incision in rats followed by intraperitoneal administration of increasing doses of ginsenoside Rf (vehicle, 0.5 mg/kg, 1 mg/kg, 1.5 mg/kg, and 2 mg/kg). The antinociceptive effect was also compared in a Positive Control Group that received a ketorolac (30 mg/kg) injection, and the Naive Group, which did not undergo incision. To evaluate the mechanism of action, rats were treated with prazosin (1 mg/kg), yohimbine (2 mg/kg), or ketanserin (1 mg/kg) prior to receiving ginsenoside Rf (1.5 mg/kg). The mechanical withdrawal threshold was measured using von Frey filaments at various time points before and after ginsenoside Rf administration. To evaluate the anti-inflammatory effect, serum interleukin (IL)-1beta, IL-6, and tumor necrotizing factor-alpha levels were measured. Results: Ginsenoside Rf increased the mechanical withdrawal threshold significantly, with a curvilinear dose-response curve peaking at 1.5 mg/kg. IL-1beta, IL-6, and tumor necrotizing factor-alpha levels significantly decreased after ginsenoside Rf treatment. Ginsenoside Rf's antinociceptive effect was reduced by yohimbine, but potentiated by prazosin and ketanserin. Conclusion: Intraperitoneal ginsenoside Rf has an antinociceptive effect peaking at a dose of 1.5 mg/kg. Anti-inflammatory effects were also detected. PMID- 29719467 TI - New metabolites from the biotransformation of ginsenoside Rb1 by Paecilomyces bainier sp.229 and activities in inducing osteogenic differentiation by Wnt/beta catenin signaling activation. AB - Background: Ginseng is a well-known traditional Chinese medicine that has been widely used in a range of therapeutic and healthcare applications in East Asian countries. Microbial transformation is regarded as an effective and useful technology in modification of nature products for finding new chemical derivatives with potent bioactivities. In this study, three minor derivatives of ginsenoside compound K were isolated and the inducing effects in the Wingless type MMTV integration site (Wnt) signaling pathway were also investigated. Methods: New compounds were purified from scale-up fermentation of ginsenoside Rb1 by Paecilomyces bainier sp. 229 through repeated silica gel column chromatography and high pressure liquid chromatography. Their structures were determined based on spectral data and X-ray diffraction. The inductive activities of these compounds on the Wnt signaling pathway were conducted on MC3T3-E1 cells by quantitative real-time polymerase chain reaction analysis. Results: The structures of a known 3-keto derivative and two new dehydrogenated metabolites were elucidated. The crystal structure of the 3-keto derivative was reported for the first time and its conformation was compared with that of ginsenoside compound K. The inductive effects of these compounds on osteogenic differentiation by activating the Wnt/beta-catenin signaling pathway were explained for the first time. Conclusion: This study may provide a new insight into the metabolic pathway of ginsenoside by microbial transformation. In addition, the results might provide a reasonable explanation for the activity of ginseng in treating osteoporosis and supply good monomer ginsenoside resources for nutraceutical or pharmaceutical development. PMID- 29719466 TI - Effect of high-dose ginsenoside complex (UG0712) supplementation on physical performance of healthy adults during a 12-week supervised exercise program: A randomized placebo-controlled clinical trial. AB - Background: Ginseng has been used as an ergogenic agent, although evidence for its effectiveness is weak. A randomized, double-blind, placebo-controlled clinical trial was conducted to evaluate the effect of a ginsenoside complex (UG0712) on changes in exercise performance. Methods: Sedentary individuals (n = 117) were randomly assigned into one of three groups: low-dose ginsenoside supplementation (100 mg/d, n = 39), high-dose ginsenoside supplementation (500 mg/d, n = 39), or a placebo group (500 mg/d, n = 39). All participants underwent a supervised 12-wk aerobic and resistance exercise training course. To assess the effects of supplementation on physical performance, maximal oxygen consumption (VO2max), anaerobic threshold (AT), lactic acid, and muscle strength of the dominant knee were measured at baseline, every visit, and after the training program. Results: Both ginsenoside groups showed significant increases in VO2max and muscular strength during exercise training. There were no definite changes in AT and lactic acid levels over time. After exercise training, there were definite differences in the VO2max (28.64.9 to 33.7 +/- 4.9 ml/kg/min in high-dose group vs. 30.4 +/- 6.7 to 32.8 +/- 6.6 ml/kg/min in placebo, p = 0.029) and AT (19.3 +/ 4.2 to 20.9 +/- 3.5 ml/kg/min in high-dose group vs. 20.0 +/- 5.1 to 20.0 +/- 4.9 ml/kg/min in placebo, p = 0.038) between the high-dose ginsenoside and placebo groups. However, there was no difference in VO2max between the low-dose ginsenoside and placebo groups (p = 0.254). There were no differences in muscular strength during exercise training among the three groups. Conclusion: High-dose ginsenoside supplementation (UG0712) augmented the improvement of aerobic capacity by exercise training. PMID- 29719468 TI - Study on the grading standard of Panax notoginseng seedlings. AB - Background: The quality differences in seedlings of medicinal herbs often affect the quality of medicinal parts. The establishment of the grading standard of Panax notoginseng seedlings is significant for the stable quality of medicinal parts of P. notoginseng. Methods: To establish the grading standard of P. notoginseng seedlings, a total of 36,000 P. notoginseng seedlings were collected from 30 producing areas, of which the fresh weight, root length, root diameter, bud length, bud diameter, and rootlet number were measured. The K-means clustering method was applied to grade seedlings and establish the grading standard. Results: The fresh weight and rootlet number of P. notoginseng seedlings were determined as the final indices of grading. P. notoginseng seedlings from different regions of Yunnan could be preliminarily classified into four grades: the special grade, the premium grade, the standard grade, and culled seedlings. Conclusion: The grading standard was proven to be reasonable according to the agronomic characters, emergence rate, and photosynthetic efficiency of seedlings after transplantation, and the yields and contents of active constituents of the medicinal parts from different grades of seedlings. PMID- 29719470 TI - Ginsenoside Rg5 prevents apoptosis by modulating heme-oxygenase-1/nuclear factor E2-related factor 2 signaling and alters the expression of cognitive impairment associated genes in thermal stress-exposed HT22 cells. AB - Our results suggested that thermal stress can lead to activation of hippocampal cell damage and reduction of memory-associated molecules in HT22 cells. These findings also provide a part of molecular rationale for the role of ginsenoside Rg5 as a potent cognitive impairment preventive compound in blocking the initiation of hippocampal damage. PMID- 29719471 TI - Synergistic effect of maclurin on ginsenoside compound K induced inhibition of the transcriptional expression of matrix metalloproteinase-1 in HaCaT human keratinocyte cells. PMID- 29719469 TI - The skin protective effects of compound K, a metabolite of ginsenoside Rb1 from Panax ginseng. AB - Background: Compound K (CK) is a ginsenoside, a metabolite of Panax ginseng. There is interest both in increasing skin health and antiaging using natural skin care products. In this study, we explored the possibility of using CK as a cosmetic ingredient. Methods: To assess the antiaging effect of CK, RT-PCR was performed, and expression levels of matrix metalloproteinase-1, cyclooxygenase-2, and type I collagen were measured under UVB irradiation conditions. The skin hydrating effect of CK was tested by RT-PCR, and its regulation was explored through immunoblotting. Melanin content, melanin secretion, and tyrosinase activity assays were performed. Results: CK treatment reduced the production of matrix metalloproteinase-1 and cyclooxygenase-2 in UVB irradiated NIH3T3 cells and recovered type I collagen expression level. Expression of skin hydrating factors-filaggrin, transglutaminase, and hyaluronic acid synthases-1 and -2-were augmented by CK and were modulated through the inhibitor of kappaBalpha, c-Jun N terminal kinase, or extracellular signal-regulated kinases pathway. In the melanogenic response, CK did not regulate tyrosinase activity and melanin secretion, but increased melanin content in B16F10 cells was observed. Conclusion: Our data showed that CK has antiaging and hydrating effects. We suggest that CK could be used in cosmetic products to protect the skin from UVB rays and increase skin moisture level. PMID- 29719473 TI - A new species of the land planarian Issoca sheds light on the polyphyletic status of the genus (Platyhelminthes, Tricladida, Geoplaninae). AB - A new species of the genus Issoca (Platyhelminthes, Tricladida, Geoplaninae) is described. Issoca assanga sp. n. presents the diagnostic features of the genus, with the exception of the relative position of the subneural parenchymal muscle layer with the cephalic retractor muscle, which are overlapped in the type species of the genus but are intersected in the new species. Rather than a polymorphic character, the relative position of these muscle layers might reflect the polyphyletic status of the genus. PMID- 29719472 TI - BIOGF1K, a compound K-rich fraction of ginseng, plays an antiinflammatory role by targeting an activator protein-1 signaling pathway in RAW264.7 macrophage-like cells. PMID- 29719474 TI - A revision of "blanket-hermit crabs" of the genus Paguropsis Henderson, 1888, with the description of a new genus and five new species (Crustacea, Anomura, Diogenidae). AB - For 130 years the diogenid genus Paguropsis Henderson, 1888 was considered monotypic for an unusual species, P. typica Henderson, 1888, described from the Philippines and seldom reported since. Although scantly studied, this species is known to live in striking symbiosis with a colonial sea anemone that the hermit can stretch back and forth like a blanket over its cephalic shield and part of cephalothoracic appendages, and thus the common name "blanket-crab". During a study of paguroid collections obtained during recent French-sponsored biodiversity campaigns in the Indo-West Pacific, numerous specimens assignable to Paguropsis were encountered. Analysis and comparison with types and other historical specimens deposited in various museums revealed the existence of five undescribed species. Discovery of these new species, together with the observation of anatomical characters previously undocumented or poorly described, including coloration, required a revision of the genus Paguropsis. The name Chlaenopagurus andersoni Alcock & McArdle, 1901, considered by Alcock (1905) a junior synonym of P. typica, proved to be a valid species and is resurrected as P. andersoni (Alcock, 1899). In two of the new species, the shape of the gills, length/width of exopod of maxilliped 3, width and shape of sternite XI (of pereopods 3), and armature of the dactyls and fixed fingers of the chelate pereopods 4, were found to be characters so markedly different from P. typica and other species discovered that a new genus for them, Paguropsinagen. n., is justified. As result, the genus Paguropsis is found to contain five species: P. typica, P. andersoni, P. confusasp. n., P. gigassp. n., and P. laciniasp. n. Herein, Paguropsinagen. n., is proposed and diagnosed for two new species, P. pistillatagen. et sp. n., and P. inermisgen. et sp. n.; Paguropsis is redefined, P. typica and its previously believed junior synonym, P. andersoni, are redescribed. All species are illustrated, and color photographs provided. Also included are a summary of the biogeography of the two genera and all species; remarks on the significance of the unusual morphology; and remarks on knowledge of the symbiotic anemones used by the species. To complement the morphological descriptions and assist in future population and phylogenetic investigations, molecular data for mitochondrial COI barcode region and partial sequences of 12S and 16S rRNA are reported. A preliminary phylogenetic analysis using molecular data distinctly shows support for the separation of the species into two clades, one with all five species of Paguropsis, and another with the two species Paguropsinagen. n. PMID- 29719475 TI - First description of the larva of Dinaraea Thomson, 1858, with comments on chaetotaxy, pupa, and life history based on two saproxylic species from Europe (Staphylinidae, Aleocharinae, Athetini). AB - The paper describes the morphological ultrastructure of the previously unknown early (L1) and late larval instars (L2-3) of Dinaraea, including chaetotaxy, pupal cocoon, prepupa, and pupa, based on the saproxylic species D. aequata Erichson and D. linearis Gravenhorst. Diagnostic larval characters for the genus Dinaraea are given for the first time. Morphological differences between mature larvae of these two species relate to the colouration and degree of flattening of the body, details of antennal structure, anterior margin of the labrum, mandibles, and mala. The differences are relatively small, probably because of the similar ecological preferences of both species. As in the case of other aleocharine larvae, L1 in Dinaraea differs from L2-3 in the lack of some setae on the dorsal surface of the head and thorax, and on the abdominal tergites and sternites; the presence of a subapical seta on the urogomphi; egg bursters on some thoracic and abdominal tergites; a darker antennal segment III; and the relatively longer urogomphi and their apical setae. The differences established in the features of the chaetotaxy of L1 and L2-3 between Athetini (Dinaraea), Oxypodini (Thiasophila) and Homalotini (Gyrophaena) correspond with the molecular marker-based relationships of these taxa. PMID- 29719476 TI - The genus Rhynchobanchus Kriechbaumer in China, with descriptions of a new species and first record of the genus from Oriental region (Hymenoptera, Ichneumonidae, Banchinae). AB - Six species and two subspecies of the genus Rhynchobanchus Kriechbaumer, 1894 are reported from China, of which one, Rh. flavomaculatus Sheng, sp. n., is a new species and the first record of the genus from the Oriental Region. Rhynchobanchus flavopictus orientalis Kuslitzky, 2007 is a new Chinese record. A key to the species of Rhynchobanchus occurring in China is provided. PMID- 29719477 TI - Ichthyological collection of the Museu Oceanografico D. Carlos I. AB - The collection of the Museu Oceanografico D. Carlos I is a historical specimen, instrument, and document collection that has been housed at the Aquario Vasco da Gama since 1935. The collection is largely the result of several scientific campaigns conducted by Dom Carlos de Braganca between 1896 and 1907. Specifically, the ichthyological collection consists of 675 surviving catalogue records of specimens caught, acquired or offered to D. Carlos I between 1892 to 1907, and includes the type specimen for Odontaspis nasutus Braganca, 1904 (junior synonym of Mitsukurina owstoni Jordan, 1898), along with several specimens of deep sea species. All specimens were captured in coastal Portuguese waters, and were preserved in alcohol, formalin, or mounted. PMID- 29719478 TI - New identification of the moray eel Gymnothorax minor (Temminck & Schlegel, 1846) in China (Anguilliformes, Muraenidae). AB - A new identification of Gymnothorax minor (Temminck & Schlegel, 1846) is documented based on morphological characteristics and DNA barcoding. Sixty-one individuals of G. minor were collected from the East China Sea and the South China Sea. This species was previously reported as Gymnothorax reticularis Bloch, 1795 in China because of the similarity in external shape and color. Gymnothorax minor can be easily distinguished from G. reticularis by its color pattern of 18 20 irregular dark brown vertical bars and the body having scattered small brown spots. Additionally, the teeth are uniserial on both jaws, and the vertebrae number 137-139. By combining congener sequences of the cytochrome oxidase I (COI) gene from GenBank, two groups were detected among all the COI sequences of the currently named G. minor, which further indicated that two valid species were present based on genetic distance. A divergence also occurred on the number of vertebrae between the northern and southern populations. The phylogenetic and morphological analysis strongly supports that the northern and southern populations of G. minor are two different species. Furthermore, the distribution area of the northern G. minor has expanded southward to 5 degrees 15'N in the South China Sea. More specimens of G. minor and G. reticularis are crucial in order to define their geographical distribution boundaries and provide the correct DNA barcoding. PMID- 29719479 TI - Greetings from the New President of the World Association of Radiopharmaceutical and Molecular Therapy. PMID- 29719480 TI - Nuclear Medicine in Prostate Cancer: A New Era for Radiotracers. AB - Natural history of prostate cancer (PCa) is extremely variable, as it ranges from indolent and slow growing tumors to highly aggressive histotypes. Genetic background and environmental factors co-operate to the genesis and clinical manifestation of the tumor and include among the others race, family, specific gene variants (i.e., BRCA1 and BRCA2 mutations), acute and chronic inflammation, infections, diet and drugs. In this scenario, remaining actual the clinical interest of bone scan (BS) in detecting skeletal metastases, an important role in diagnostic imaging may be also carried out by, positron emission tomography/computed tomography (PET/CT) and PET/magnetic resonance imaging (PET/MRI), which combine morphological information provided by CT and MRI with functional and metabolic data provided by PET acquisitions. With respect to PET radiotracers, being ancillary the usefulness of F-18 fluoro-deoxyglucose and not yet demonstrated the cost-effectiveness of F-18 Fluoride respect to BS, the main role is now played by choline derivatives, in particular by 11C-choline and 18F fluorocholine. More recently, a greater interest for both diagnostic and therapeutic purposes has been associated with radiotracers directed to prostate specific membrane antigen (PSMA), a transmembrane protein expressed on the cell surface, which showed high selective expression in PCa, metastatic lymph nodes and bone metastases. Several PSMA-targeted PET tracers have been developed many of which showing promising results for accurate diagnosis and staging of primary PCa and re-staging after biochemical recurrence, even in case of low prostate specific antigen values. In particular, the most widely used PSMA ligand for PET imaging is a 68Ga-labelled PSMA inhibitor, 68Ga-PSMA-HBED-CC (68Ga-PSMA-11). 99mTc-HYNIC-Glu-Urea-A for single photon emission computed tomography, and 177Lu PSMA-617 for radioligand therapy has also been applied in humans, with interesting preliminary results related to a possible theranostic approach. A potential role of PSMA radioligands in radio-guided surgery has also been proposed. PMID- 29719481 TI - To Compare and Determine the Diagnostic Accuracy of [18F]-fluorodeoxyglucose Positron Emission Tomography Scan in Predicting Pathological Response in Operated Carcinoma Esophagus Patients after Initial Neoadjuvant Chemoradiation and Neoadjuvant Chemotherapy. AB - The objective of this study was to determine whether [18F]-fluorodeoxyglucose positron emission tomography (FDG-PET) scan could predict the pathological response in esophageal carcinoma after surgery in patients receiving neoadjuvant concurrent chemoradiation (NACCRT) and neoadjuvant chemotherapy (NACT). A randomized prospective study was carried out from March 2014 to October 2016; thirty patients of histopathologically proven, locally advanced, potentially operable carcinoma esophagus comprising both squamous carcinoma and adenocarcinoma were randomized into NACCRT and NACT arms equally. Both groups had pretreatment FDG-PET-computed tomography (CT) scan and repeat scan after 5-6 weeks of neoadjuvant therapy (NAT). The change in mean %Deltamaximum standardized uptake value (%DeltaSUVmax) was compared with tumor regression grade (TRG) in the postoperative histology. Patients with TRG 1-2 were deemed responders and 3-5 were nonresponders. Pathologic response was correlated with percentage change in [18F]-FDG uptake (%DeltaSUVmax); receiver operating characteristics (ROC) analyses were done to assess sensitivity and specificity of FDG-PET to determine its diagnostic accuracy. The mean SUV in NACCRT group decreased from 15.47 +/- 2.92 to 7.31 +/- 4.07 (P < 0.001), while in NACT group, mean SUV decreased from 14.74 +/- 3.95 to 8.60 +/- 3.89 (P < 0.001). Comparison between NACCRT and NACT leads to mean SUV of 57.80 +/- 22.40 and 45.92 +/- 19.23, respectively (P = 0.13). In NACCRT and NACT, TRG had mean %DeltaSUVmax values of 2.53 +/- 1.25 and 2.93 +/- 1.28 (P = 0.393). However, we found a statistically significant correlation between SUV% reduction and TRG (P = 0.002). ROC curve analysis for FDG-PET-CT suggested an area under the curve of 0.693 and sensitivity and specificity of 80% and 46.7%, respectively. NACCRT and NACT lead to a statistically significant reduction in mean %DeltaSUVmax and with statistical significance correlation when compared with pathological response assessment. Hence, PET-CT can be used for differentiating responders and nonresponders to NAT. PMID- 29719482 TI - First Results and Experience with PRRT in South Africa. AB - Neuroendocrine tumors (NETs) are a diverse group of tumors that often present late due to nonspecific symptoms. These tumors frequently express somatostatin receptors (SSRs), which allows for positron emission tomography/computed tomography (PET/CT) imaging with Ga-68-DOTATATE. In eligible patients, this may then be followed by peptide receptor radionuclide therapy (PRRT). Here, we report our initial results and experience with PRRT in a developing country, as one of the first groups to provide this therapy in South Africa. Eligible patients with confirmed inoperable NETs were recruited prospectively and treated with Lu-177 DOTATATE. Baseline imaging was performed with either single-photon emission CT- or PET-based SSR analogs, whereas follow-up was performed with 68Ga-DOTATATE PET/CT 6 months post treatment completion. Interim treatment response evaluation was based on post therapy imaging of Lu-177-DOTATATE. A total of 48 patients with a mean age of 58 years were treated with PRRT, of whom 22 (46%) demonstrated stable disease, 20 (42%) demonstrated a partial response, and 6 (12%) demonstrated progressive disease. The median progression-free survival (PFS) was 20 months with an interquartile range (IQR)25%-75% of 4.5-30 months. The median freedom from progression duration was 32 months with an IQR25%-75% of 25-40 months, and the median overall survival was 10 months with an (IQR)25%-75% of 5 24 months. Our subgroup analysis demonstrated an inverse association between metabolic tumor volume with PFS, which requires further validation. In conclusion, PRRT with Lu-177-DOTATATE resulted in a median PFS of 20 months in patients with inoperable NETs in the absence of significant side effects. PMID- 29719483 TI - The Baseline Pattern and Age-related Developmental Metabolic Changes in the Brain of Children with Autism as Measured on Positron Emission Tomography/Computed Tomography Scan. AB - [18F] 2-fluoro-2-deoxy-D-glucose positron emission tomography-computed tomography scan was performed on 45 children with autism to study the baseline pattern and age-related developmental changes in the brain metabolism. Median standardized uptake values (SUVs) were compared with published healthy control data. Results showed that, in contrary to control data, the median SUVs in children with autism decrease linearly with increase in age. As compared to controls, autism children below 5 years showed greater metabolism and older children showed lower metabolism. In autism group, comparison of absolute SUVs within different regions of the brain revealed relatively lower metabolism in amygdala, hippocampus, parahippocampal gyrus, caudate nucleus, cerebellum, mesial temporal lobe, thalamus, superior and middle temporal pole, and higher metabolic uptake in calcarine fissure and Heschl's gyrus. These results help in understanding the baseline metabolism and developmental changes of brain among different age groups in autism. PMID- 29719484 TI - A Case of Well-differentiated Hepatocellular Carcinoma Identified on Gallium-68 Prostate-specific Membrane Antigen Positron Emission Tomography/Computed Tomography. AB - Prostate-specific membrane antigen (PSMA) is a glycosylated type-II transmembrane protein highly expressed in certain tumor cells. To the best of our knowledge, this is the first case reported of an isolated well-differentiated hepatocellular carcinoma (HCC) strongly suspected on gallium-68 (68Ga)-PSMA positron emission tomography/computed tomography (PET/CT), which was not well characterized both on magnetic resonance imaging (MRI) liver with Primovist as well as fluorine-18 (18F)-choline PET/CT. Our patient had previous prostate cancer and previously was imaged using 18F-choline PET/CT. The last scan showed an indeterminate segment VII hypodensity which was not significantly choline-avid. The lesion was initially stable on serial MRI scans but then showed growth from 1.0 to 1.5 cm. 68Ga-PSMA PET/CT was performed. The lesion was intensely tracer-avid. This was surgically excised and histology confirmed the presence of well-differentiated HCC. Well-differentiated HCC can be optimally imaged using 68Ga-PSMA PET/CT and further prospective studies are needed to look into the potential of this imaging modality. PMID- 29719485 TI - Accuracy of Quantitative Positron Emission Tomography Assessment for Differentiating Cerebral Age-related from Pathological Amyloid Deposition: A Preliminary Report from a Case-series Study. AB - Previous observational studies using old qualitative methods have not clarified the role of amyloid positron emission tomography (PET) in the assessment of dementia. Given the moderately positive predictive value, the presence of amyloid deposition does not necessarily imply the diagnosis of dementia. Conversely, the absence of amyloid PET deposition has been shown to be useful in excluding the neurodegenerative pathology, irrespective of the aging process. We describe the clinical application of new innovative software recently developed to increase the sensitivity of this technique and to discriminate pathological deposition of cerebral amyloid from the age-related changes, reporting preliminary findings from a case-series study. In three different clinical profiles, we underline the need of integrating neuropsychological assessment and findings with this new PET scan and software that provide quantitative information of the cerebral amyloid and may increase the probability of rapid and accurate assessment of Alzheimer's disease. Although this amyloid quantification is promising, these preliminary results should be confirmed in future prospective studies with adequate sample size. PMID- 29719486 TI - Role of Cholescintigraphy with Single-Photon Emission Computerized Tomography Computed Tomography in Detecting Bronchobiliary Fistula: Unusual Complication of a Common Disease. AB - Bronchobiliary fistula (BFF) is an abnormal communication between the biliary tree and airway. A patient usually presents with cough and bilioptysis, and at times, it poses diagnostic and therapeutic challenge. This case demonstrates the usefulness of cholescintigraphy with single-photon emission computerized tomography in diagnosing BFF in case of hydatid cyst of the liver. PMID- 29719487 TI - Ra223 in Bone Metastases with Osteolytic Activity. AB - Radium 223 dichloride (Ra223) is the only targeted alpha therapy able to extend survival in patients with bone metastases from prostate cancer. Mechanism of action and data currently available focused mainly on osteoblastic metastases from prostate cancer. In our institution, a patient with breast cancer affected by osteolytic metastases was treated with off-label use of Ra223. The evaluation of the deposit areas of Ra223 showed a perfect overlap with the regions of osteolysis previously detected by scintigraphy, indicating a possible therapeutic effect. This case report is the first document attesting Ra223 deposit in osteolytic metastases opening new opportunity of therapeutic development for this radiopharmaceutical. PMID- 29719488 TI - Massive Tumor Thrombus in Left Renal Vein and Inferior Vena Cava in Renal Cell Carcinoma on 18-fluorodeoxyglucose Positron Emission Tomography/computerized Tomography: "Suspension Bridge Sign". AB - Tumor thrombosis is a relatively uncommon complication of renal cell carcinoma (RCC), and its diagnosis has therapeutic and prognostic implication. Computerized tomography (CT) is the primary imaging modality for staging RCC, but it has low sensitivity to differentiate between tumor thrombus and bland or benign thrombus. 18-fluorodeoxyglucose positron emission tomography/CT (PET/CT) has a limited role in diagnosis and staging of RCC, but its diagnostic accuracy is considerably high for detection of metabolically active tumor thrombus. We are presenting a case of metastatic left-sided RCC with massive hypermetabolic tumor thrombus extending from left kidney to left renal vein and inferior vena cava giving an interesting "Suspension Bridge" appearance on PET/CT images. PMID- 29719489 TI - Renal Manifestation of Birt-Hogg-Dube Syndrome Depicted by 18F-fludeoxyglucose Positron Emission Tomography/Computed Tomography in a Patient with Hurtle Cell Thyroid Malignancy. AB - Birt-Hogg-Dube (BHD) syndrome is an autosomal dominant genetic disorder characterized by small papular skin lesions (fibrofolliculomas) causing susceptibility to kidney cancer, renal and pulmonary cysts, spontaneous pneumothoraces, and several noncutaneous tumors. We report a case of a 67-year old woman, with a previous history of right hemithyroidectomy for adenomatous lesion. She presented with a swelling in the right thyroid bed that on subsequent biopsy revealed features of metastatic carcinoma. 18F-fludeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) performed for the detection of primary malignancy showed increased high-grade metabolic activity in the right supraclavicular soft tissue mass extending into the superior mediastinum. Moreover, on low-dose CT, there have been bilateral renal interpolar cortical lesions with mild metabolic activity. Given the fact that the right neck mass was highly unlikely to represent renal metastases in the absence of widespread metastatic disease, surgical excision of the right neck mass was performed. The histology of the mass was in keeping with hurtle cell thyroid carcinoma. In regard to renal lesions, bilateral partial nephrectomy was performed, which was consistent with chromophobe renal cell carcinoma, raising the suspicion of BHD that was confirmed by the subsequent genetic evaluation. It is well established that 18F-FDG PET/CT study is not an optimal modality for evaluation of renal lesions. However, careful assessment of the CT features in conjunction with the associated metabolic activity of the 18F-FDG PET component increases the diagnostic accuracy of PET/CT. PMID- 29719490 TI - Can Gallium-68 Prostate-specific Membrane Antigen Ligand be a Potential Radiotracer for Renal Cortical Positron Emission Tomography Imaging? AB - Gallium-68 prostate-specific membrane antigen (Ga-68 PSMA) ligand (HBED-CC) is a new promising positron emission tomography (PET) tracer for prostate cancer. Intense renal parenchymal uptake is a physiologic finding on Ga-68 PSMA ligand PET images. Evaluation of kidneys in low intensity demonstrates excellent distribution of this radiotracer in renal parenchyma with excellent image quality and resolution. In this article, we present the Ga-68 PSMA ligand PET renal images of four patients with prostate cancer. In two patients, there is normal distribution of radiotracer, and in other two, there are renal cysts causing parenchymal defects. PMID- 29719491 TI - Nursing staffs self-perceived outcome from a rehabilitation 24/7 educational programme - a mixed-methods study in stroke care. AB - Background: During the past two decades, attempts have been made to describe nurses' contributions to the rehabilitation of inpatients following stroke. There is currently a lack of interventions that integrate the diversity of nurses' role and functions in stroke rehabilitation and explore their effect on patient outcomes. Using a systematic evidence- and theory-based design, we developed an educational programme, Rehabilitation 24/7, for nursing staff working in stroke rehabilitation aiming at two target behaviours; working systematically with a rehabilitative approach in all aspects of patient care and working deliberately and systematically with patients' goals. The aim of this study was to assess nursing staff members' self-perceived outcome related to their capability, opportunity and motivation to work with a rehabilitative approach after participating in the stroke Rehabilitation 24/7 educational programme. Methods: A convergent mixed-method design was applied consisting of a survey and semi structured interviews. Data collection was undertaken between February and June 2016. Data from the questionnaires (N = 33) distributed before and after the intervention were analysed using descriptive statistics and Wilcoxon sign rank test. The interviews (N = 10) were analysed using deductive content analysis. After analysing questionnaires and interviews separately, the results were merged in a side by side comparison presented in the discussion. Results: The results from both the quantitative and qualitative analyses indicate that the educational programme shaped the target behaviours that we aimed to change by addressing the nursing staff's capability, opportunity and motivation and hence could strengthen the nursing staff's contribution to inpatient stroke rehabilitation. A number of behaviours changed significantly, and the qualitative results indicated that the staff experienced increased focus on their role and functions in rehabilitation practice. Conclusion: Our study provides an understanding of the outcome of the Rehabilitation 24/7 educational programme on nursing staff's behaviours. A mixed methods approach provided extended knowledge of the changes in the nursing staff members' self-percived behaviours after the intervention. These changes suggest that educating the nursing staff on rehabilitation using the Rehabilitation 24/7 programme strengthened their knowledge and beliefs about rehabilitation, goal setting as well as their role and functions. PMID- 29719492 TI - Design and rationale of the non-interventional, edoxaban treatment in routiNe clinical prActice in patients with venous ThromboEmbolism in Europe (ETNA-VTE Europe) study. AB - Background: Venous thromboembolism (VTE, including deep vein thrombosis [DVT] and pulmonary embolism [PE]) has an annual incidence rate of 104-183 per 100,000 person-years. After a VTE episode, the two-year recurrence rate is about 17%. Consequently, effective and safe anticoagulation is paramount. Edoxaban is a direct oral anticoagulant (DOAC) approved VTE treatment. Current safety and efficacy data are derived from clinical trials, and information about treatment durations beyond 12 months are not available. Methods: ETNA-VTE-Europe is an 18 month prospective, single-arm, non-interventional, multinational post authorisation safety study. Approximately 310 sites across eight European countries (Austria, Belgium, Germany, Ireland, Italy, the Netherlands, Switzerland and the United Kingdom) will participate in the study, with the intention to represent the regional distributions of centres, healthcare settings and specialties. An estimated cohort of 2700 patients will be recruited, the only enrolment criteria being acute symptomatic VTE, no participation in an interventional study, and treating physician decision to prescribe edoxaban independently from the registry. Data from patient medical records and/or telephone interviews will be collected at baseline, 1, 3, 6, 12 and 18 months. The primary objective is to evaluate the 18-month rate of symptomatic VTE recurrence in patients with VTE treated with edoxaban outside a clinical trial. The co-primary objective is to evaluate the real-world rates of bleeding and adverse drug reactions. Secondary outcomes include rates of other patient relevant safety events, adherence to and discontinuation of edoxaban. Furthermore, 12-month ETNA-VTE-Europe data will be considered in the context of those for patients receiving different anticoagulants in the PREFER in VTE registry and Hokusai-VTE clinical trial. Conclusions: ETNA-VTE-Europe will allow the safety and effectiveness of edoxaban to be evaluated over an extended period in acute symptomatic VTE patients encountered in routine clinical practice. Findings will be informative for European practitioners prescribing edoxaban as part of real-world VTE treatment/prevention. Trial registration: ClinicalTrials.gov Identifier: NCT02943993. PMID- 29719493 TI - Effects of hydroxytyrosol dose on the redox status of exercised rats: the role of hydroxytyrosol in exercise performance. AB - Background: Hydroxytyrosol (HT) is a polyphenol found in olive oil that is known for its antioxidant effects. Here, we aimed to describe the effects of a low and high HT dose on the physical running capacity and redox state in both sedentary and exercised rats. Methods: Male Wistar rats were allocated into 6 groups: sedentary (SED; n = 10); SED consuming 20 mg/kg/d HT (SED20; n = 7); SED consuming 300 mg/kg/d HT (SED300; n = 7); exercised (EXE; n = 10); EXE consuming 20 mg/kg/d HT (EXE20; n = 10) and EXE consuming 300 mg/kg/d HT (EXE300; n = 10). All the interventions lasted 10 weeks; the maximal running velocity was assessed throughout the study, whereas daily physical work was monitored during each training session. At the end of the study, the rats were sacrificed by bleeding. Hemoglobin (HGB) and hematocrit (HCT) were measured in the terminal blood sample. Moreover, plasma hydroperoxide (HPx) concentrations were quantified as markers of lipid peroxidation. Results: In sedentary rats, HT induced an antioxidant effect in a dose-dependent manner without implications on running performance. However, if combined with exercise, the 300 mg/kg/d HT dosage exhibited a pro-oxidant effect in the EXE300 group compared with the EXE and EXE20 groups. The EXE20 rats showed a reduction in daily physical work and a lower maximal velocity than the EXE and EXE300 rats. The higher physical capacity exhibited by the EXE300 group was achieved despite the EXE300 rats expressing lower HGB levels and a lower HCT than the EXE20 rats. Conclusions: Our results suggest that a high HT dose induces a systemic pro-oxidant effect and may prevent the loss of performance that was observed with the low HT dose. PMID- 29719494 TI - Identification of serum proteins AHSG, FGA and APOA-I as diagnostic biomarkers for gastric cancer. AB - Background: The development of clinically accessible biomarkers is critical for the early diagnosis of gastric cancer (GC) in patients. High-throughput proteomics techniques could not only effectively generate a serum peptide profile but also provide a new approach to identify potentially diagnostic and prognostic biomarkers for cancer patients. Methods: In this study, we aim to identify potentially discriminating serum biomarkers for GC. In the discovery cohort, we screened potential biomarkers using magnetic-bead-based purification and matrix assisted laser desorption/ionization time-of-flight mass spectrometry in 64 samples from 32 GC patients that were taken both pre- and post-operatively and 30 healthy volunteers that served as controls. In the validation cohort, the expression patterns and diagnostic values of serum FGA, AHSG and APOA-I were further confirmed by ELISA in 42 paired GC patients (pre- and post-operative samples from 16 patients with pathologic stage I/II and 26 with stage III/IV), 30 colorectal cancer patients, 30 hepatocellular carcinoma patients, and 28 healthy volunteers. Results: ClinProTools software was used and annotated 107 peptides, 12 of which were differentially expressed among three groups (P < 0.0001, fold > 1.5). These 12 peptide peaks were further identified as FGA, AHSG, APOA-I, HBB, TXNRD1, GSPT2 and CAKP5. ELISA data suggested that the serum levels of FGA, AHSG and APOA-I in GC patients were significantly different compared with healthy controls and had favorable diagnostic values for GC patients. Moreover, we found that the serum levels of these three proteins were associated with TNM stages and could reflect tumor burden. Conclusion: Our findings suggested that FGA, AHSG and APOA-I might be potential serum biomarkers for GC diagnosis. PMID- 29719495 TI - Comparative analysis of human sperm glycocalyx from different freezability ejaculates by lectin microarray and identification of ABA as sperm freezability biomarker. AB - Background: Semen cryopreservation has been widely applied in assisted reproductive technologies and sperm bank, but it causes considerable impairments on sperm quality. It is necessary to find an evaluation indicator for determining the sperm-freezing tolerance. Methods: The glycocalyx of good freezability ejaculates was compared with poor freezability ejaculates by lectin microarray. The significant different lectins were validated by flow cytometry (FACS). To analyze the relationship between the potential biomarker and the tolerance of sperm to cryopreservation, 60 samples with different recovery rates were collected and detected the lectin-binding intensity by FACS. The receiver operating characteristic (ROC) curve was analyzed to test the capability of the lectin as a potential biomarker for detecting the sperm freezablility. Results: ABA and DSL were found to develop significant differences between them. Further validation showed that ABA was significantly negative correlated with the sperm recovery rates (r = - 0.618, P < 0.000) and could be a potential biomarker for predicting sperm freezability (AUC = 0.733 +/- 0.067, 95% CI 0.601 - 0.865, P < 0.01). Conclusion: ABA could be a potential biomarker for predicting sperm freezability. It will help to reduce sperm-freezing recovery tests and improve the efficiency of cryopreservation in human sperm bank. PMID- 29719496 TI - Effects of Oxytocin on Facial Expression and Identity Working Memory Are Found in Females but Not Males. AB - Although oxytocin (OXT) has been shown to increase the ability of face perception and processing, no study has explored whether it could improve the performance of working memory for emotional expression information in males and females. Thus, we performed a double-blind, mixed-design, placebo-controlled study to investigate the effects of OXT on temporary maintenance/manipulation of facial information through a facial expression (EMO) vs. identity (ID) working memory task, both for males (N = 45) and females (N = 46). Our results showed that in female participants, OXT increased the accuracy of the recognition of faces displaying angry and happy emotions, in the EMO tasks, and also reduced the response time to negative emotional faces, in the ID task. However, the above effects were not present in male subjects. These results indicate that OXT may increase the efficiency of working memory in face processing and this trend is reflected in females rather than in males. This study provides novel evidence for the sexually dimorphic effects of OXT on social cognition. PMID- 29719497 TI - Adar3 Is Involved in Learning and Memory in Mice. AB - The amount of regulatory RNA encoded in the genome and the extent of RNA editing by the post-transcriptional deamination of adenosine to inosine (A-I) have increased with developmental complexity and may be an important factor in the cognitive evolution of animals. The newest member of the A-I editing family of ADAR proteins, the vertebrate-specific ADAR3, is highly expressed in the brain, but its functional significance is unknown. In vitro studies have suggested that ADAR3 acts as a negative regulator of A-I RNA editing but the scope and underlying mechanisms are also unknown. Meta-analysis of published data indicates that mouse Adar3 expression is highest in the hippocampus, thalamus, amygdala, and olfactory region. Consistent with this, we show that mice lacking exon 3 of Adar3 (which encodes two double stranded RNA binding domains) have increased levels of anxiety and deficits in hippocampus-dependent short- and long-term memory formation. RNA sequencing revealed a dysregulation of genes involved in synaptic function in the hippocampi of Adar3-deficient mice. We also show that ADAR3 transiently translocates from the cytoplasm to the nucleus upon KCl mediated activation in SH-SY5Y cells. These results indicate that ADAR3 contributes to cognitive processes in mammals. PMID- 29719498 TI - Anxiety and 10-Year Risk of Incident Dementia-An Association Shaped by Depressive Symptoms: Results of the Prospective Three-City Study. AB - Background: Anxiety is common in patients with cognitive impairment and dementia. However, whether anxiety is a risk factor for dementia is still not known. We aimed to examine the association between trait anxiety at baseline and the 10 year risk of incident dementia to determine to which extent depressive symptoms influence this relationship in the general population. Methods: Data came from 5,234 community-dwelling participants from the Three-City prospective cohort study, aged 65 years at baseline and followed over 10 years. At baseline, anxiety trait was assessed using the Spielberger State-Trait Anxiety Inventory (STAI), and depressive symptoms using Center for Epidemiologic Studies-Depression Scale (CESD). Use of anxiolytic drugs was also considered. Diagnoses of dementia were made at baseline and every 2 years. To examine the relationship between anxiety exposures and risk of incident dementia, Cox proportional hazard regression models were performed. Results: Taking anxiolytic drugs or having high trait anxiety (STAI score >= 44) increased the risk of dementia assessed over 10 years of follow-up [Hazard Ratio (HR) = 1.39, 95%CI: 1.08-1.80, p = 0.01 and HR = 1.26, 95%CI: 1.01-1.57, p = 0.04, respectively], independently of a large panel of socio-demographic variables, health behaviors, cardio-metabolic disorders, and additional age-related disorders such as cardiovascular diseases, activity limitations, and cognitive deficit. However, the associations were substantially attenuated after further adjustment for depressive symptoms. Conclusion: Our findings suggest that depressive symptoms shape the association between anxiety trait and dementia. Further research is needed to replicate our findings and extrapolate our results to anxiety disorders. PMID- 29719500 TI - Valproic Acid Attenuates Traumatic Brain Injury-Induced Inflammation in Vivo: Involvement of Autophagy and the Nrf2/ARE Signaling Pathway. AB - Microglial activation and the inflammatory response in the central nervous system (CNS) play important roles in secondary damage after traumatic brain injury (TBI). Transcriptional activation of genes that limit secondary damage to the CNS are mediated by a cis-acting element called the antioxidant responsive element (ARE). ARE is known to associate with the transcription factor NF-E2-related factor 2 (Nrf2), a transcription factor that is associated with histone deacetylases (HDACs). This pathway, known as the Nrf2/ARE pathway, is a critical antioxidative factor pathway that regulates the balance of oxygen free radicals and the inflammatory response, and is also related to autophagic activities. Although valproic acid (VPA) is known to inhibit HDACs, it is unclear whether VPA plays a role in the microglia-mediated neuroinflammatory response after TBI via regulating oxidative stress and autophagy induced by the Nrf2/ARE signaling pathway. In this study, we demonstrate that microglial activation, oxidative stress, autophagy, and the Nrf2/ARE signaling pathway play essential roles in secondary injury following TBI. Treatment with VPA alleviated TBI-induced secondary brain injury, including neurological deficits, cerebral edema, and neuronal apoptosis. Moreover, VPA treatment upregulated the occurrence of autophagy and Nrf2/ARE pathway activity after TBI, and there was an increase in H3, H4 histone acetylation levels, accompanied by decreased transcriptional activity of the HDAC3 promoter in cortical lesions. These results suggest that VPA-mediated up-regulation of autophagy and antioxidative responses are likely due to increased activation of Nrf2/ARE pathway, through direct inhibition of HDAC3. This inhibition further reduces TBI-induced microglial activation and the subsequent inflammatory response, ultimately leading to neuroprotection. PMID- 29719501 TI - Acetylome in Human Fibroblasts From Parkinson's Disease Patients. AB - Parkinson's disease (PD) is a multifactorial neurodegenerative disorder. The pathogenesis of this disease is associated with gene and environmental factors. Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most frequent genetic cause of familial and sporadic PD. Moreover, posttranslational modifications, including protein acetylation, are involved in the molecular mechanism of PD. Acetylation of lysine proteins is a dynamic process that is modulated in PD. In this descriptive study, we characterized the acetylated proteins and peptides in primary fibroblasts from idiopathic PD (IPD) and genetic PD harboring G2019S or R1441G LRRK2 mutations. Identified acetylated peptides are modulated between individuals' groups. Although acetylated nuclear proteins are the most represented in cells, they are hypoacetylated in IPD. Results display that the level of hyperacetylated and hypoacetylated peptides are, respectively, enhanced in genetic PD and in IPD cells. PMID- 29719502 TI - Human Thalamic-Prefrontal Peduncle Connectivity Revealed by Diffusion Spectrum Imaging Fiber Tracking. AB - The thalamic-prefrontal peduncle (TPP) is a large bundle connecting the thalamus and prefrontal cortex. The definitive structure and function of the TPP are still controversial. To investigate the connectivity and segmentation patterns of the TPP, we employed diffusion spectrum imaging with generalized q-sampling reconstruction to perform both subject-specific and template-based analyses. Our results confirmed the trajectory and spatial relationship of the TPP in the human brain and identified the connection areas in the prefrontal cortex. The TPP connecting areas identified based on Brodmann areas (BAs) were BAs 8-11 and 45 47. Based on the automated anatomical atlas, these areas were the medial superior frontal gyrus, superior frontal gyrus, middle frontal gyrus, pars triangularis, pars orbitalis, anterior orbital gyrus, and lateral orbital gyrus. In addition, we identified the TPP connection areas in the thalamus, including the anterior and medial nuclei, and the lateral dorsal/lateral posterior nuclei. TPP fibers connected the thalamus with the ipsilateral prefrontal BAs 11, 47, 10, 46, 45, 9, and 8 seriatim from medial to lateral, layer by layer. Our results provide further details of the thalamic-prefrontal peduncle structure, and may aid future studies and a better understanding of the functional roles of the TPP in the human brain. PMID- 29719499 TI - Sphingolipid Metabolism: A New Therapeutic Opportunity for Brain Degenerative Disorders. AB - Neurodegenerative diseases represent a class of fatal brain disorders for which the number of effective therapeutic options remains limited with only symptomatic treatment accessible. Multiple studies show that defects in sphingolipid pathways are shared among different brain disorders including neurodegenerative diseases and may contribute to their complex pathogenesis. In this mini review, we discuss the hypothesis that modulation of sphingolipid metabolism and their related signaling pathways may represent a potential therapeutic approach for those devastating conditions. The plausible "druggability" of sphingolipid pathways is greatly promising and represent a relevant feature that brings real advantage to the development of new therapeutic options for these conditions. Indeed, several molecules that selectively target sphingolipds are already available and many of them currently in clinical trial for human diseases. A deeper understanding of the "sphingolipid scenario" in neurodegenerative disorders would certainly enhance therapeutic perspectives for these conditions, by taking advantage from the already available molecules and by promoting the development of new ones. PMID- 29719503 TI - Smooth Pursuit Eye Movement of Monkeys Naive to Laboratory Setups With Pictures and Artificial Stimuli. AB - When animal behavior is studied in a laboratory environment, the animals are often extensively trained to shape their behavior. A crucial question is whether the behavior observed after training is part of the natural repertoire of the animal or represents an outlier in the animal's natural capabilities. This can be investigated by assessing the extent to which the target behavior is manifested during the initial stages of training and the time course of learning. We explored this issue by examining smooth pursuit eye movements in monkeys naive to smooth pursuit tasks. We recorded the eye movements of monkeys from the 1st days of training on a step-ramp paradigm. We used bright spots, monkey pictures and scrambled versions of the pictures as moving targets. We found that during the initial stages of training, the pursuit initiation was largest for the monkey pictures and in some direction conditions close to target velocity. When the pursuit initiation was large, the monkeys mostly continued to track the target with smooth pursuit movements while correcting for displacement errors with small saccades. Two weeks of training increased the pursuit eye velocity in all stimulus conditions, whereas further extensive training enhanced pursuit slightly more. The training decreased the coefficient of variation of the eye velocity. Anisotropies that grade pursuit across directions were observed from the 1st day of training and mostly persisted across training. Thus, smooth pursuit in the step-ramp paradigm appears to be part of the natural repertoire of monkeys' behavior and training adjusts monkeys' natural predisposed behavior. PMID- 29719504 TI - Descending Inputs to Spinal Circuits Facilitating and Inhibiting Human Wrist Flexors. AB - Recently we reported in humans that electrical stimulation of the wrist extensor muscle extensor carpi radialis (ECR) could facilitate or suppress the H reflex elicited in flexor carpi radialis (FCR), for inter-stimulus intervals (ISIs) of 30 ms or 70 ms, respectively. The facilitation at 30 ms may be produced by both flexor afferents and extensor Ib afferents acting on a spinal circuit; the origin of the suppression at 70 ms is less certain. In this study, we investigated possible descending inputs to these systems. We used magnetic stimulation of the contralateral primary motor cortex, and click sound stimulation, to activate the corticospinal and the reticulospinal tracts respectively, and measured the effects on the H reflex conditioned by ECR stimulation. Corticospinal inputs reduced both the 30 ms facilitation and 70 ms suppression, indicating corticospinal inhibition of both circuits. By contrast, we failed to show any effect of clicks, either on the H reflex or on its modulation by ECR stimulation. This suggests that click-activated reticulospinal inputs to these circuits may be weak or absent. PMID- 29719506 TI - Araloside C Prevents Hypoxia/Reoxygenation-Induced Endoplasmic Reticulum Stress via Increasing Heat Shock Protein 90 in H9c2 Cardiomyocytes. AB - Araloside C (AsC) is a cardioprotective triterpenoid compound that is mainly isolated from Aralia elata. This study aims to determine the effects of AsC on hypoxia-reoxygenation (H/R)-induced apoptosis in H9c2 cardiomyocytes and its underlying mechanisms. Results demonstrated that pretreatment with AsC (12.5 MUM) for 12 h significantly suppressed the H/R injury in H9c2 cardiomyocytes, including improving cell viability, attenuating the LDH leakage and preventing cardiomyocyte apoptosis. AsC also inhibited H/R-induced ER stress by reducing the activation of ER stress pathways (PERK/eIF2alpha and ATF6), and decreasing the expression of ER stress-related apoptotic proteins (CHOP and caspase-12). Moreover, AsC greatly improved the expression level of HSP90 compared with that in the H/R group. The use of HSP90 inhibitor 17-AAG and HSP90 siRNA blocked the above suppression effect of AsC on ER stress-related apoptosis caused by H/R. Taken together, AsC could reduce H/R-induced apoptosis possibly because it attenuates ER stress-dependent apoptotic pathways by increasing HSP90 expression. PMID- 29719507 TI - Breathomics for Assessing the Effects of Treatment and Withdrawal With Inhaled Beclomethasone/Formoterol in Patients With COPD. AB - Background: Prospective pharmacological studies on breathomics profiles in COPD patients have not been previously reported. We assessed the effects of treatment and withdrawal of an extrafine inhaled corticosteroid (ICS)-long-acting beta2 agonist (LABA) fixed dose combination (FDC) using a multidimensional classification model including breathomics. Methods: A pilot, proof-of-concept, pharmacological study was undertaken in 14 COPD patients on maintenance treatment with inhaled fluticasone propionate/salmeterol (500/50 MUg b.i.d.) for at least 8 weeks (visit 1). Patients received 2-week treatment with inhaled beclomethasone dipropionate/formoterol (100/6 MUg b.i.d.) (visit 2), 4-week treatment with formoterol alone (6 MUg b.i.d.) (visit 3), and 4-week treatment with beclomethasone/formoterol (100/6 MUg b.i.d.) (visit 4). Exhaled breath analysis with two e-noses, based on different technologies, and exhaled breath condensate (EBC) NMR-based metabolomics were performed. Sputum cell counts, sputum supernatant and EBC prostaglandin E2 (PGE2) and 15-F2t-isoprostane, fraction of exhaled nitric oxide, and spirometry were measured. Results: Compared with formoterol alone, EBC acetate and sputum PGE2, reflecting airway inflammation, were reduced after 4-week beclomethasone/formoterol. Three independent breathomics techniques showed that extrafine beclomethasone/formoterol short-term treatment was associated with different breathprints compared with regular fluticasone propionate/salmeterol. Either ICS/LABA FDC vs. formoterol alone was associated with increased pre-bronchodilator FEF25-75% and FEV1/FVC (P = 0.008 0.029). The multidimensional model distinguished fluticasone propionate/salmeterol vs. beclomethasone/formoterol, fluticasone propionate/salmeterol vs. formoterol, and formoterol vs. beclomethasone/formoterol (accuracy > 70%, P < 0.01). Conclusions: Breathomics could be used for assessing ICS treatment and withdrawal in COPD patients. Large, controlled, prospective pharmacological trials are required to clarify the biological implications of breathomics changes. EUDRACT number: 2012-001749-42. PMID- 29719505 TI - Cellular and Molecular Basis of Neurodegeneration in Parkinson Disease. AB - It has been 200 years since Parkinson disease (PD) was described by Dr. Parkinson in 1817. The disease is the second most common neurodegenerative disease characterized by a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. Although the pathogenesis of PD is still unknown, the research findings from scientists are conducive to understand the pathological mechanisms. It is well accepted that both genetic and environmental factors contribute to the onset of PD. In this review, we summarize the mutations of main seven genes (alpha-synuclein, LRRK2, PINK1, Parkin, DJ-1, VPS35 and GBA1) linked to PD, discuss the potential mechanisms for the loss of dopaminergic neurons (dopamine metabolism, mitochondrial dysfunction, endoplasmic reticulum stress, impaired autophagy, and deregulation of immunity) in PD, and expect the development direction for treatment of PD. PMID- 29719509 TI - Mangiferin Enhanced Autophagy via Inhibiting mTORC1 Pathway to Prevent High Glucose-Induced Cardiomyocyte Injury. AB - Mangiferin functions as a perfect anti-oxidative compound in the diabetic heart, however, the exact mechanism remains to be elucidated. Here, we show the cardioprotective effect of mangiferin under high glucose-induced cardiotoxic condition mainly contributed to enhanced autophagy via suppressing mTORC1 downstream signal transduction. Primary neonatal rat cardiomyocytes were cultured to detect myocytes injury, autophagy, and related signal transduction under different doses of glucose and mangiferin treatment. High glucose (30 mM) reduced autophagic flux, and increased myocyte apoptosis and death compared with normal glucose (5.5 mM) as determined by variation of autophagy markers LC3-II, p62, parkin, GFP-LC3, or mRFP-LC3 fluorescence puncta, cell viability, cleaved caspase 3, cleaved PARP apoptosis indices, reactive oxygen species (ROS), MAO, and PI death indices. Conversely, mangiferin inhibited hyperglycemia associated oxidative stress by reducing ROS, MAO, cleaved caspase 3, and cleaved PARP generation, reestablishing cell viability, mitochondrial membrane potential, and enhancing autophagic flux, thereby preventing myocytes from high glucose-induced toxicity. Furthermore, cardioprotection with mangiferin was potentially related to the decreased mTOR phosphorylation and suppression of mTORC1 downstream signaling pathway. These data indicated the valuable effects of mangiferin on regulation of cardiac autophagy and pointed to the promising utilization for hyperglycemia control. PMID- 29719508 TI - The Multifaceted Effects of Alpha1-Antitrypsin on Neutrophil Functions. AB - Neutrophils are the predominant immune cells in human blood possessing heterogeneity, plasticity and functional diversity. The activation and recruitment of neutrophils into inflamed tissue in response to stimuli are tightly regulated processes. Alpha1-Antitrypsin (AAT), an acute phase protein, is one of the potent regulators of neutrophil activation via both -protease inhibitory and non-inhibitory functions. This review summarizes our current understanding of the effects of AAT on neutrophils, illustrating the interplay between AAT and the key effector functions of neutrophils. PMID- 29719510 TI - In Vivo Pharmacokinetic/Pharmacodynamic Profiles of Danofloxacin in Rabbits Infected With Salmonella typhimurium After Oral Administration. AB - Salmonella typhimurium is a highly transmissible pathogen in rabbits that causes significant losses. Danofloxacin shows excellent efficacy against S. typhimurium infections. However, there are few reports of the pharmacokinetic/pharmacodynamic (PK/PD) modeling of danofloxacin against this pathogen. The aim of this study was to evaluate the in vivo PK/PD relationship of danofloxacin in rabbits infected with S. typhimurium. We used the reduction of bacterial burden in the blood, liver, spleen, and lung as the target PD endpoints, and determined the PK/PD indexes that best correlated with the efficacy and its corresponding magnitude. Danofloxacin was administrated orally to experimentally S. typhimurium-infected rabbits once daily for three successive days. The concentrations of danofloxacin in the serum and the bacterial burden in the blood, liver, spleen, and lung were determined. The PK/PD relationships of danofloxacin against S. typhimurium were evaluated using a Sigmoid Emax model. The results showed that the area under the concentration-time curve from 0 to 24 h/minimum inhibitory concentration (AUC24 h/MIC) ratio correlated well with the in vivo antibacterial effectiveness in different organs, with an r2 of 0.8971, 0.9186, 0.9581, and 0.8708 in the blood, liver, spleen, and lung, respectively. The AUC24 h/MIC ratios for the bactericidal effect (3 * Log10 colony forming units/mL reductions) were 121.30, 354.28, 216.64, and 228.66 in the blood, liver, spleen, and lung, respectively, indicating that the in vivo effectiveness of danofloxacin against S. typhimurium using bacterial reduction in different organs as PD endpoints was not identical. This study illustrated that the selection of the target organ for bacterial reduction determination had little effect on best PK/PD parameter determination, but is critical for parameter magnitude calculation in antimicrobial PK/PD modeling, and furthermore, has an impact on the rational dosage optimization process. PMID- 29719512 TI - The Bodies in Charge of Animal Welfare: What They Do and What They Could Do? AB - The coming into force of the 2010/63/EU (Directive of the European Parliament and of the Council of 22 September 2010) Standard, regarding the protection of animals used for scientific purposes, has made it mandatory for all establishments breeding, supplying, and using said animals to have an Animal Welfare Body (AWB). The establishment of a body such as the AWB represents a strong innovation compared to previous regulations (Dir. 86/609/CEE). Building from the key concept of the 3 Rs, European Community legislators acknowledged that the effective safeguard of animal welfare depends in large part on the professional skills of personnel in charge of their care and use. The European Community legislators therefore identify a body inside the institution that houses the animals and entrust it with the task to stimulate and support the practical implementation of the 3 Rs, by informing on technical and scientific developments on the application of said principle and the subsequent training and follow-up training of personnel. The functions assigned by the Standard to the AWB therefore focus on technical-scientific support: to supply advice to personnel in charge of animals concerning their welfare, matters relating to their acquisition, housing, care, and use, and to their integration/adoption (rehoming) at the end of their use. This approach is also emphasized by vesting the AWB with the responsibility to define and review internal monitoring and communication procedures pertaining to the welfare of the animals housed in the establishment, and to follow their development and the outcome of research projects concerning the effects produced on the animals used, supplying advice on activities that could result in possible improvements. Aware of the complexity and sensitivity of the role assigned to the AWB, and of the difficulty to put into practice the directions subject matter of the Standard, The European Commission, in the years following the issue of the Directive, appointed groups of experts with the task to formulate guidelines which would be beneficial both to the establishments and to control authorities of the various Member States and guarantee the implementation of effective and to control authorities of the various Member States and guarantee the implementation of effective and harmonized solutions. (National Competent Authorities for the implementation of Directive 2010/63/EU, http://ec.europa.eu/environment/chemicals/lab_animals/pubs_guidance_en.htm). PMID- 29719511 TI - Association Between hMLH1 Promoter Methylation and Risk of Gastric Cancer: A Meta Analysis. AB - Background: Human mutL homolog 1 (hMLH1) is located on chromosome 3q21-23. As a classic tumor suppressor gene, many researchers have studied the association between hMLH1 promoter methylation and gastric cancer, but their conclusions were not always consistent. Therefore, we performed a meta-analysis to make a more integrated and precise estimate of the associations. Method: PubMed, EMBASE, and Cochrane Library were retrieved without language restrictions. Data were analyzed by Review Manager 5.2 and Stata 12.0 software. Odds ratio (OR) with 95% confidence interval (95%CI) was used to assess the statistical associations. Result: A total of 39 studies published before January 20, 2018 were included in this study. The results indicated that the frequency of hMLH1 promoter methylation in gastric cancers was substantially higher than that in non-cancer controls (OR = 7.94, 95%CI = 4.32-14.58, P < 0.001). Furthermore, hMLH1 promoter methylation had considerable associations with lymph node metastasis, microsatellite instability (MSI), and low expression of hMLH1 protein (OR = 1.53, 95%CI = 1.04-2.26, P = 0.03; OR = 15.33, 95%CI = 9.26-25.36, P < 0.001; OR = 37.86, 95%CI = 18.03-79.50, P < 0.001, respectively). No association was found between hMLH1 promoter methylation and Lauren classification or Helicobacter pylori (HP) infection status. Conclusion: The present study provides evidence that promoter methylation of hMLH1 is a major causative event in the occurrence and development of human gastric cancer. PMID- 29719513 TI - Adaptive Changes After 2 Weeks of 10-s Sprint Interval Training With Various Recovery Times. AB - Purpose: The aim of this study was to compare the effect of applying two different rest recovery times in a 10-s sprint interval training session on aerobic and anaerobic capacities as well as skeletal muscle enzyme activities. Methods: Fourteen physically active but not highly trained male subjects (mean maximal oxygen uptake 50.5 +/- 1.0 mlO2.kg-1.min-1) participated in the study. The training protocol involved a series of 10-s sprints separated by either 1-min (SIT10:1) or 4-min (SIT10:4) of recovery. The number of sprints progressed from four to six over six sessions separated by 1-2 days rest. Pre and post intervention anthropometric measurements, assessment of aerobic, anaerobic capacity and muscle biopsy were performed. In the muscle samples maximal activities of citrate synthase (CS), 3-hydroxyacylCoA dehydrogenase (HADH), carnitine palmitoyl-transferase (CPT), malate dehydrogenase (MDH), and its mitochondrial form (mMDH), as well as lactate dehydrogenase (LDH) were determined. Analysis of variance was performed to determine changes between conditions. Results: Maximal oxygen uptake improved significantly in both training groups, by 13.6% in SIT10:1 and 11.9% in SIT10:4, with no difference between groups. Wingate anaerobic test results indicated main effect of time for total work, peak power output and mean power output, which increased significantly and similarly in both groups. Significant differences between training groups were observed for end power output, which increased by 10.8% in SIT10:1, but remained unchanged in SIT10:4. Both training protocols induced similar increase in CS activity (main effect of time p < 0.05), but no other enzymes. Conclusion: Sprint interval training protocols induce metabolic adaptation over a short period of time, and the reduced recovery between bouts may attenuate fatigue during maximal exercise. PMID- 29719515 TI - Classifying Cardiac Actin Mutations Associated With Hypertrophic Cardiomyopathy. AB - Mutations in the cardiac actin gene (ACTC1) are associated with the development of hypertrophic cardiomyopathy (HCM). To date, 12 different ACTC1 mutations have been discovered in patients with HCM. Given the high degree of sequence conservation of actin proteins and the range of protein-protein interactions actin participates in, mutations in cardiac actin leading to HCM are particularly interesting. Here, we suggest the classification of ACTC1 mutations based on the location of the resulting amino acid change in actin into three main groups: (1) those affecting only the binding site of the myosin molecular motor, termed M class mutations, (2) those affecting only the binding site of the tropomyosin (Tm) regulatory protein, designated T-class mutations, and (3) those affecting both the myosin- and Tm-binding sites, called MT-class mutations. To understand the precise pathogenesis of cardiac actin mutations and develop treatments specific to the molecular cause of disease, we need to integrate rapidly growing structural information with studies of regulated actomyosin systems. PMID- 29719514 TI - Longer Work/Rest Intervals During High-Intensity Interval Training (HIIT) Lead to Elevated Levels of miR-222 and miR-29c. AB - Aim: MicroRNA-222 (miR-222) and miR-29c have been identified as important modulators of cardiac growth and may protect against pathological cardiac remodeling. miR-222 and -29c may thus serve as functional biomarkers for exercise induced cardiac adaptations. This investigation compared the effect of two workload-matched high-intensity interval training (HIIT) protocols with different recovery periods on miR-222 and -29c levels. Methods: Sixty-three moderately trained females and males (22.0 +/- 1.7 years) fulfilled the eligibility criteria and were randomized into two HIIT groups using sex and exercise capacity. During a controlled 4-week intervention (two sessions/week) a 4 * 30 HIIT group performed 4 * 30 s runs (all-out, 30 s active recovery) and a 8 * 15 HIIT group performed 8 * 15 s runs (all-out, 15 s active recovery). miR-222 and -29c as well as transforming growth factor-beta1 (TGF-beta1) mRNA levels were determined during high-intensity running as well as aerobic exercise using capillary blood from earlobes. Performance parameters were assessed using an incremental continuous running test (ICRT) protocol with blood lactate diagnostic and heart rate (HR) monitoring to determine HR recovery and power output at individual anaerobic threshold (IAT). Results: At baseline, acute exercise miR-222 and -29c levels were increased only in the 4 * 30 HIIT group (both p < 0.01, pre- vs. post exercise). After the intervention, acute exercise miR-222 levels were still increased in the 4 * 30 HIIT group (p < 0.01, pre- vs. post-exercise) while in the 8 * 15 HIIT group again no acute effect was observed. However, both HIIT interventions resulted in elevated resting miR-222 and -29c levels (all p < 0.001, pre- vs. post-intervention). Neither of the two miRNAs were elevated at any ICRT speed level at baseline nor follow-up. While HR recovery was improved by >24% in both HIIT groups (both p <= 0.0002) speed at IAT was improved by 3.6% only in the 4 * 30 HIIT group (p < 0.0132). Correlation analysis suggested an association between both miRNAs and TGF-beta1 mRNA (all p <= 0.006, r >= 0.74) as well as change in speed at IAT and change in miR-222 levels (p = 0.024, r = 0.46). Conclusions: HIIT can induce increased circulating levels of cardiac growth-associated miR-222 and -29c. miR-222 and miR-29c could be useful markers to monitor HIIT response in general and to identify optimal work/rest combinations. PMID- 29719516 TI - Odorant Binding Proteins of the Desert Locust Schistocerca gregaria (Orthoptera, Acrididae): Topographic Expression Patterns in the Antennae. AB - Odorant binding proteins (OBPs) enriched in the sensillum lymph are instrumental in facilitating the transfer of odorous molecules to the responsive receptors. In Orthopteran locust species, an in-depth understanding of this important soluble protein family is still elusive. In a previous study, we have demonstrated that the repertoire of locust OBPs can be divided into four major clades (I-IV) on the phylogenetic scale and for representatives of subfamily I-A and II-A a distinct sensilla-specific expression pattern was determined. In this study, by focusing on a representative locust species, the desert locust Schistocerca gregaria, we have explored the antennal topographic expression for representative OBPs of other subfamilies. First, subtypes of subfamily III-A and III-B were exclusively found in sensilla chaetica. Then, a similar expression pattern in this sensillum type was observed for subfamily I-B subtypes, but with a distinct OBP that was expressed in sensilla coeloconica additionally. Moreover, the atypical OBP subtype from subfamily IV-A was expressed in a subpopulation of sensilla coeloconica. Last, the plus-C type-B OBP subtype from subfamily IV-B seems to be associated with all four antennal sensillum types. These results profile diversified sensilla-specific expression patterns of the desert locust OBPs from different subfamilies and complex co-localization phenotypes of distinct OBP subtypes in defined sensilla, which provide informative clues concerning their possible functional mode as well as a potential interplay among OBP partners within a sensillum. PMID- 29719517 TI - Using Play to Improve Infant Sleep: A Mixed Methods Protocol to Evaluate the Effectiveness of the Play2Sleep Intervention. AB - Background: One in four Canadian families struggle with infant sleep disturbances. The aim of this study is to evaluate Play2Sleep in families of infants with sleep disturbances. In addition to parental education on infant sleep, Play2Sleep uses examples from a video-recorded, structured play session with mothers and fathers separately to provide feedback on parent-infant interactions and their infant's sleep-related social cues. The quantitative phase will answer the research question: Does one dose of Play2Sleep delivered during a home visit with mothers and fathers of infants aged 5 months reduce night wakings at age 7 months? The qualitative phase will answer the research question: What are parental perceptions of family experiences, processes, and contexts related to Play2Sleep and infant sleep? The overarching mixed methods research question is as follows: How do parental perceptions of family experiences, processes, and contexts related to infant sleep explain the effectiveness of Play2Sleep? Method and analysis: An explanatory sequential mixed methods design will be used. In the quantitative phase, a randomized controlled trial and RM-ANOVA will compare night wakings in infants whose parents receive Play2Sleep versus standard public health nursing information. Sixty English-speaking families (mothers and fathers) of full-term, healthy, singleton, 5-month-old infants who perceive that their infant has sleep disturbances will be recruited. The primary outcome measure will be change in the number of night wakings reported by parents. The qualitative component will use thematic analysis of family interviews to describe parental perceptions and experiences of infant sleep. Mixed methods integration will use qualitative findings to explain quantitative results. Discussion: Play2Sleep is a novel approach that combines information about infant sleep with personalized feedback on parent-infant interactions and infant cues. Including fathers and mixed methods should capture complex family experiences of infant sleep disturbances and Play2Sleep. If effective, Play2Sleep has possible application for preventing infant sleep disturbance and tailoring for other populations. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT02742155. Registered on 2016 April 23. PMID- 29719518 TI - Body Mass Index in Mild Cognitive Impairment According to Age, Sex, Cognitive Intervention, and Hypertension and Risk of Progression to Alzheimer's Disease. AB - Introduction: Mild cognitive impairment (MCI) is a prodromal stage of dementia. The association of body mass index (BMI) and progression to Alzheimer's disease (AD) in MCI subjects according to age, sex, and cognitive intervention remains unknown. We investigated the relationship between BMI and the risk of progression to AD in subjects with MCI, as well as the effect of BMI on progression to AD depending on age, sex, cognitive intervention, and chronic diseases. Methods: Three hundred and eighty-eight MCI subjects were followed for 36.3 +/- 18.4 months, prospectively. They underwent neuropsychological testing more than twice during the follow-up period. The MCI subjects were categorized into underweight, normal weight, overweight, and obese subgroups. The associations between baseline BMI and progression to AD over the follow-up period were estimated using Cox proportional hazard regression models. Data were analyzed after stratification by age, sex, cognitive intervention, and chronic diseases. Results: After adjustment for the covariates, the underweight MCI group had a higher risk of progression to AD [hazard ratio (HR): 2.38, 95% confidence interval (CI): 1.17-4.82] relative to the normal weight group. After stratifying by age, sex, cognitive intervention, and chronic diseases, this effect remained significant among females (HR: 3.15, 95% CI: 1.40-7.10), the older elderly >=75 years old (HR: 3.52, 95% CI: 1.42 8.72), the non-intervention group (HR: 3.06, 95%CI: 1.18-7.91), and the hypertensive group (HR: 4.71, 95% CI: 1.17-18.99). Conclusion: These data indicate that underweight could be a useful marker for identifying individuals at increased risk for AD in MCI subjects. This association is even stronger in females, older elderly subjects, the non-cognitive intervention group, and the hypertensive group. PMID- 29719520 TI - Eyewitness Memory in Face-to-Face and Immersive Avatar-to-Avatar Contexts. AB - Technological advances offer possibilities for innovation in the way eyewitness testimony is elicited. Typically, this occurs face-to-face. We investigated whether a virtual environment, where interviewer and eyewitness communicate as avatars, might confer advantages by attenuating the social and situational demands of a face-to-face interview, releasing more cognitive resources for invoking episodic retrieval mode. In conditions of intentional encoding, eyewitnesses were interviewed 48 h later, either face-to-face or in a virtual environment (N = 38). Participants in the virtual environment significantly outperformed those interviewed face-to-face on all episodic performance measures improved correct reporting reduced errors, and increased accuracy. Participants reported finding it easier to admit not remembering event information to the avatar, and finding the avatar easier to talk to. These novel findings, and our pattern of retrieval results indicates the potential of avatar-to-avatar communication in virtual environments, and provide impetus for further research investigating eyewitness cognition in contemporary retrieval contexts. PMID- 29719521 TI - "You Can See How Things Will End by the Way They Begin": The Contribution of Early Mutual Obligations for the Development of the Psychological Contract. AB - This study explores dynamic processes in the development of the psychological contract, focusing on the interaction of obligations related to the two parties (i.e., employees' perceptions of both their own and the organization's obligations fulfillment) on attitudinal outcomes (organizational commitment and turnover intention) during the initial stage of the employment relationship. In a twofold cross-sectional and two-wave study on newly hired correctional police officers, we examined: (a) whether perception of organizational obligations fulfillment moderates the relationship between employee obligations and their attitudes (Study 1, n.500); (b) the direct and moderated influence of perceived obligations at the entrance stage on those in the following months (Study 2, n.223). Results confirmed that, in the eyes of the newcomer, the obligations fulfillment of each of the two parties interact, having an additional effect beyond the main direct effects, in influencing both subsequent obligations perceptions and, through this, the outcome variables. Theoretical and practical implications of the findings are discussed. PMID- 29719519 TI - Psychological Intrusion - An Overlooked Aspect of Dental Fear. AB - Dental fear/anxiety is a widely recognised problem affecting a large proportion of the population. It can result in avoidance and/or difficulty accepting dental care. We believe that psychological intrusion may play a role in the aetiology and maintenance of dental fear for at least some individuals. In this narrative review we will take a developmental perspective in order to understand its impact across the lifespan. We will consider the nature of 'self,' parenting styles, the details of intrusive parenting or parental psychological control, and briefly touch upon child temperament and parental anxiety. Finally, we draw together the supporting (largely unrecognised) evidence available in the dental literature. We illustrate the paper with clinical examples and discuss possibly effective ways of addressing the problem. We conclude that psychological intrusion appears to play an important role in dental fear, for at least some individuals, and we call for detailed research into the extent and exact nature of the problem. A simple means of identifying individuals who are vulnerable to psychological intrusion would be useful for dentists. PMID- 29719522 TI - Work-Family Conflict and Mental Health Among Female Employees: A Sequential Mediation Model via Negative Affect and Perceived Stress. AB - After the implementation of the universal two-child policy in 2016, more and more working women have found themselves caught in the dilemma of whether to raise a baby or be promoted, which exacerbates work-family conflicts among Chinese women. Few studies have examined the mediating effect of negative affect. The present study combined the conservation of resources model and affective events theory to examine the sequential mediating effect of negative affect and perceived stress in the relationship between work-family conflict and mental health. A valid sample of 351 full-time Chinese female employees was recruited in this study, and participants voluntarily answered online questionnaires. Pearson correlation analysis, structural equation modeling, and multiple mediation analysis were used to examine the relationships between work-family conflict, negative affect, perceived stress, and mental health in full-time female employees. We found that women's perceptions of both work-to-family conflict and family-to-work conflict were significant negatively related to mental health. Additionally, the results showed that negative affect and perceived stress were negatively correlated with mental health. The 95% confidence intervals indicated the sequential mediating effect of negative affect and stress in the relationship between work-family conflict and mental health was significant, which supported the hypothesized sequential mediation model. The findings suggest that work-family conflicts affected the level of self-reported mental health, and this relationship functioned through the two sequential mediators of negative affect and perceived stress. PMID- 29719523 TI - The Effects of Satisfaction of Basic Psychological Needs at School on Children's Prosocial Behavior and Antisocial Behavior: The Mediating Role of School Satisfaction. AB - Grounded in Basic Psychological Need Theory, we examined the direct effects of the satisfaction of three basic psychological needs at school (i.e., satisfaction of autonomy needs at school, satisfaction of relatedness needs at school, and satisfaction of competence needs at school) on prosocial behavior and antisocial behavior as well as the mediation effects of school satisfaction on the relations between the satisfaction of three basic psychological needs at school and prosocial behavior as well as antisocial behavior. We employed a sample of 801 Chinese children (429 males; Mage = 9.47) in a three-wave longitudinal study, with each wave occurring 6 months apart. Direct and indirect effects were estimated by Structural Equation Modeling. Results indicated that: (1) Satisfaction of relatedness needs at school and competence needs at school, but not satisfaction of autonomy needs at school, displayed direct effects on prosocial behavior. Also, satisfaction of relatedness needs at school, but not satisfaction of autonomy needs at school or competence needs at school, displayed direct effects on antisocial behavior. (2) Both satisfaction of relatedness needs at school and competence needs at school displayed indirect effects on prosocial behavior and antisocial behavior via school satisfaction as a mediator. However, satisfaction of autonomy needs at school failed to have indirect effects on prosocial behavior or antisocial behavior via school satisfaction. These findings suggest differential predictors of children's prosocial and antisocial behavior, supporting the separability of the two constructs. The findings also suggest developmental differences in need satisfaction, with the satisfaction of autonomy needs playing a relatively less important role in school-age children. We also discussed limitations and practical applications of the study. PMID- 29719524 TI - The Emergence of Modern Languages: Has Human Self-Domestication Optimized Language Transmission? PMID- 29719525 TI - Personality and Party Ideology Among Politicians. A Closer Look at Political Elites From Canada and Belgium. AB - We examined the relationship between Big Five personality and the political ideology of elected politicians. To this end, we studied 303 politicians from Flanders, Wallonia, and Canada, relating their self-reported Big Five scores to a partisanship-based measure of political ideology. Our findings show that, in line with the congruency model of personality, Openness to Experience is the best and most consistent correlate of political ideology, with politicians high on Openness to Experience being more likely to be found among the more progressive left-wing political parties. PMID- 29719526 TI - Response: Commentary: A construct divided: prosocial behavior as helping, sharing, and comforting subtypes. PMID- 29719527 TI - Vestibular-Evoked Myogenic Potentials in Bilateral Vestibulopathy. AB - Bilateral vestibulopathy (BVP) is a chronic condition in which patients have a reduction or absence of vestibular function in both ears. BVP is characterized by bilateral reduction of horizontal canal responses; however, there is increasing evidence that otolith function can also be affected. Cervical and ocular vestibular-evoked myogenic potentials (cVEMPs/oVEMPs) are relatively new tests of otolith function that can be used to test the saccule and utricle of both ears independently. Studies to date show that cVEMPs and oVEMPs are often small or absent in BVP but are in the normal range in a significant proportion of patients. The variability in otolith function is partly due to the heterogeneous nature of BVP but is also due to false negative and positive responses that occur because of the large range of normal VEMP amplitudes. Due to their variability, VEMPs are not part of the diagnosis of BVP; however, they are helpful complementary tests that can provide information about the extent of disease within the labyrinth. This article is a review of the use of VEMPs in BVP, summarizing the available data on VEMP abnormalities in patients and discussing the limitations of VEMPs in diagnosing bilateral loss of otolith function. PMID- 29719528 TI - Co-Occurrence of Pheochromocytoma-Paraganglioma and Cyanotic Congenital Heart Disease: A Case Report and Literature Review. AB - Pheochromocytoma and paraganglioma (PHEO-PGL) and cyanotic congenital heart disease (CCHD) are both rare diseases. We reported a 30-year-old patient with a right adrenal gland nodule and a retroperitoneal mass and history of functional single atrium and ventricle. 123I-metaiodobenzylguanidine scintigraphy showed intense uptake in both lesions. Laboratory investigation demonstrated elevated urinary norepinephrine. Preoperative alpha-blockade was initiated. A successful open resection of right adrenal and retroperitoneal masses was performed. Pathological examination confirmed PHEO-PGL. Postoperative urinary norepinephrine returned to normal level. A systematic case review in English publications in PubMed and EMBASE suggested a hypothesis that there may exist a possible link between PHEO-PGL and hypoxia from CCHD, which was also indicated in our case. Due to higher risk for PHEO-PGL, a lower threshold of suspicion should be considered in CCHD patients. Therefore, active screening and early treatment of PHEO-PGL are recommended in CCHD patients and clinicians should keep on a long-term follow-up to monitor PHEO-PGL recurrence if hypoxia is not corrected. PMID- 29719529 TI - ANGPTL8: An Important Regulator in Metabolic Disorders. AB - Long-term controversy regarding the role of angiopoietin-like protein 8 (ANGPTL8) in beta-cell proliferation and diabetes progression made it a research spotlight. Recently, the controversy was resolved. Although ANGPTL8 could not control beta cell expansion and islet function, ANGPTL8 was still considered as a novel but atypical member in the ANGPTL family because of its unique structure and crucial effects on lipid metabolism. Besides, ANGPTL8 also participated in some other disorders such as non-alcoholic fatty liver disease and renal dysfunction. Understanding the features of ANGPTL8 may offer new diagnostic and therapeutic approaches to metabolic-related diseases. Therefore, we reviewed most recent findings about ANGPTL8 and aimed to provide an integrated picture of ANGPTL8. PMID- 29719530 TI - A Comparative Genomic Analysis Provides Novel Insights Into the Ecological Success of the Monophasic Salmonella Serovar 4,[5],12:i:. AB - Over the past decades, Salmonella 4,[5],12:i:- has rapidly emerged and it is isolated with high frequency in the swine food chain. Although many studies have documented the epidemiological success of this serovar, few investigations have tried to explain this phenomenon from a genetic perspective. Here a comparative whole-genome analysis of 50 epidemiologically unrelated S. 4,[5],12:i:-, isolated in Italy from 2010 to 2016 was performed, characterizing them in terms of genetic elements potentially conferring resistance, tolerance and persistence characteristics. Phylogenetic analyses indicated interesting distinctions among the investigated isolates. The most striking genetic trait characterizing the analyzed isolates is the widespread presence of heavy metals tolerance gene cassettes: most of the strains possess genes expected to confer resistance to copper and silver, whereas about half of the isolates also contain the mercury tolerance gene merA. A functional assay showed that these genes might be useful for preventing the toxic effects of metals, thus supporting the hypothesis that they can contribute to the success of S. 4,[5],12:i:- in farming environments. In addition, the analysis of the distribution of type II toxin-antitoxin families indicated that these elements are abundant in this serovar, suggesting that this is another factor that might favor its successful spread. PMID- 29719531 TI - Characterization of Chicken Tumor Necrosis Factor-alpha, a Long Missed Cytokine in Birds. AB - Tumor necrosis factor-alpha (TNF-alpha) is a pleiotropic cytokine playing critical roles in host defense and acute and chronic inflammation. It has been described in fish, amphibians, and mammals but was considered to be absent in the avian genomes. Here, we report on the identification and functional characterization of the avian ortholog. The chicken TNF-alpha (chTNF-alpha) is encoded by a highly GC-rich gene, whose product shares with its mammalian counterpart 45% homology in the extracellular part displaying the characteristic TNF homology domain. Orthologs of chTNF-alpha were identified in the genomes of 12 additional avian species including Palaeognathae and Neognathae, and the synteny of the closely adjacent loci with mammalian TNF-alpha orthologs was demonstrated in the crow (Corvus cornix) genome. In addition to chTNF-alpha, we obtained full sequences for homologs of TNF-alpha receptors 1 and 2 (TNFR1, TNFR2). chTNF-alpha mRNA is strongly induced by lipopolysaccharide (LPS) stimulation of monocyte derived, splenic and bone marrow macrophages, and significantly upregulated in splenic tissue in response to i.v. LPS treatment. Activation of T-lymphocytes by TCR crosslinking induces chTNF-alpha expression in CD4+ but not in CD8+ cells. To gain insights into its biological activity, we generated recombinant chTNF-alpha in eukaryotic and prokaryotic expression systems. Both, the full-length cytokine and the extracellular domain rapidly induced an NFkappaB-luciferase reporter in stably transfected CEC-32 reporter cells. Collectively, these data provide strong evidence for the existence of a fully functional TNF-alpha/TNF-alpha receptor system in birds thus filling a gap in our understanding of the evolution of cytokine systems. PMID- 29719533 TI - High Indoleamine 2,3-Dioxygenase Is Correlated With Microvessel Density and Worse Prognosis in Breast Cancer. AB - Indoleamine 2,3-dioxygenase (IDO), which catalyzes the breakdown of the essential amino acid tryptophan into kynurenine, is understood to have a key role in cancer immunotherapy. IDO has also received more attention because of its non-immune functions including regulating angiogenesis. The purpose of this study was to investigate the effects of IDO on microvessel density (MVD), and to explore its prognostic role in breast cancer. We showed IDO expression was positively correlated with MVD labeled by CD105 (MVD-CD105) rather than MVD labeled by CD31 (MVD-CD31) in breast cancer specimens. Both IDO expression and MVD-CD105 level were associated with initial TNM stage, histological grade, and tumor-draining lymph nodes (TDLNs) metastasis in breast cancer. In the prognostic analysis, TDLNs metastasis, an advanced TNM stage (III) and high histological grade (III) significantly predicted shorter survival in univariate analysis. Concentrating on IDO and MVD, the patients with IDO expression or high MVD level had poorer prognosis compared with no IDO expression [P = 0.047 for progress-free survival (PFS)] and low MVD level (P = 0.019 for OS); the patients with IDO expression and high MVD level had a tendency with shorter overall survival when compared with non IDO expression, low MVD level, or both (P = 0.062 for OS). In multivariate analysis, an advanced TNM stage (III) was significantly associated with shorter 5 year survival rate of PFS (HR: 0.126, 95% CI: 0.024-0.669, P = 0.015). In order to verify the phenomenon of IDO promoting angiogenesis, we contained the study in vitro. We detected the expression of IDO mRNA in breast cancer cell lines and measured the concentration of tryptophan and kynurenine in the supernatants of MCF-7 by high performance liquid chromatography. The ratio of Kyn and trp (kyn/trp) was calculated to estimate IDO-enzyme activity. MCF-7 cells, which produce high level of IDO and metabolize tryptophan, promoted human umbilical vein endothelial cells (HUVEC) proliferation significantly in co-culture system. Meanwhile IDO could upregulate the expression of CD105 in HUVEC, which was downregulated after adding IDO inhibitor, 1-methyl-d-trytophan. These results suggest that IDO could promote angiogenesis in breast cancer, providing a novel, potentially effective molecular or gene therapy target for angiogenesis inhibition in the future. PMID- 29719532 TI - Vasa Vasorum Angiogenesis: Key Player in the Initiation and Progression of Atherosclerosis and Potential Target for the Treatment of Cardiovascular Disease. AB - Plaque microvascularization and increased endothelial permeability are key players in the development of atherosclerosis, from the initial stages of plaque formation to the occurrence of acute cardiovascular events. First, endothelial dysfunction and increased permeability facilitate the entry of diverse inflammation-triggering molecules and particles such as low-density lipoproteins into the artery wall from the arterial lumen and vasa vasorum (VV). Recognition of entering particles by resident phagocytes in the vessel wall triggers a maladaptive inflammatory response that initiates the process of local plaque formation. The recruitment and accumulation of inflammatory cells and the subsequent release of several cytokines, especially from resident macrophages, stimulate the expansion of existing VV and the formation of new highly permeable microvessels. This, in turn, exacerbates the deposition of pro-inflammatory particles and results in the recruitment of even more inflammatory cells. The progressive accumulation of leukocytes in the intima, which trigger proliferation of smooth muscle cells in the media, results in vessel wall thickening and hypoxia, which further stimulates neoangiogenesis of VV. Ultimately, this highly inflammatory environment damages the fragile plaque microvasculature leading to intraplaque hemorrhage, plaque instability, and eventually, acute cardiovascular events. This review will focus on the pivotal roles of endothelial permeability, neoangiogenesis, and plaque microvascularization by VV during plaque initiation, progression, and rupture. Special emphasis will be given to the underlying molecular mechanisms and potential therapeutic strategies to selectively target these processes. PMID- 29719534 TI - Complement Factor H-Related Protein 4A Is the Dominant Circulating Splice Variant of CFHR4. AB - Recent research has elucidated circulating levels of almost all factor H-related (FHR) proteins. Some of these proteins are hypothesized to act as antagonists of the important complement regulator factor H (FH), fine-tuning complement regulation on human surfaces. For the CFHR4 splice variants FHR-4A and FHR-4B, the individual circulating levels are unknown, with only total levels being described. Specific reagents for FHR-4A or FHR-4B are lacking due to the fact that the unique domains in FHR-4A show high sequence similarity with FHR-4B, making it challenging to distinguish them. We developed an assay that specifically measures FHR-4A using novel, well-characterized monoclonal antibodies (mAbs) that target unique domains in FHR-4A only. Using various FHR 4A/FHR-4B-specific mAbs, no FHR-4B was identified in any of the serum samples tested. The results demonstrate that FHR-4A is the dominant splice variant of CFHR4 in the circulation, while casting doubt on the presence of FHR-4B. FHR-4A levels (avg. 2.55 +/- 1.46 ug/mL) were within the range of most of the previously reported levels for all other FHRs. FHR-4A was found to be highly variable among the population, suggesting a strong genetic regulation. These results shed light on the physiological relevance of the previously proposed role of FHR-4A and FHR 4B as antagonists of FH in the circulation. PMID- 29719535 TI - Lactose Induces Phenotypic and Functional Changes of Neutrophils and Macrophages to Alleviate Acute Pancreatitis in Mice. AB - Acute pancreatitis (AP) is one common clinical acute abdominal disease, for which specific pharmacological or nutritional therapies remain elusive. Lactose, a macronutrient and an inducer of host innate immune responses, possesses immune modulatory functions. The current study aimed to investigate potential modulatory effects of lactose and the interplay between the nutrient and pancreatic immunity during experimentally induced AP in mice. We found that either prophylactic or therapeutic treatment of lactose time-dependently reduced the severity of AP, as evidenced by reduced pancreatic edema, serum amylase levels, and pancreatic myeloperoxidase activities, as well as by histological examination of pancreatic damage. Overall, lactose promoted a regulatory cytokine milieu in the pancreas and reduced infiltration of inflammatory neutrophils and macrophages. On acinar cells, lactose was able to suppress caerulein-induced inflammatory signaling pathways and to suppress chemoattractant tumor necrosis factor (TNF)-alpha and monocyte chemotactic protein-1 production. Additionally, lactose acted on pancreas-infiltrated macrophages, increasing interleukin-10 and decreasing tumor necrosis factor alpha production. Notably, lactose treatment reversed AP associated infiltration of activated neutrophils. Last, the effect of lactose on neutrophil infiltration was mimicked by a galectin-3 antagonist, suggesting a potential endogenous target of lactose. Together, the current study demonstrates an immune regulatory effect of lactose to alleviate AP and suggests its potential as a convenient, value-added therapeutic macronutrient to control AP, and lower the risk of its systemic complications. PMID- 29719536 TI - Phosphatidyl-Inositol-3 Kinase Inhibitors Regulate Peptidoglycan-Induced Myeloid Leukocyte Recruitment, Inflammation, and Neurotoxicity in Mouse Brain. AB - Acute brain injury leads to the recruitment and activation of immune cells including resident microglia and infiltrating peripheral myeloid cells (MC), which contribute to the inflammatory response involved in neuronal damage. We previously reported that TLR2 stimulation by peptidoglycan (PGN) from Staphylococcus aureus, in vitro and in vivo, induced microglial cell activation followed by autophagy induction. In this report, we evaluated if phosphatidyl inositol-3 kinase (PI3K) pharmacological inhibitors LY294200 and 3-methyladenine (3-MA) can modulate the innate immune response to PGN in the central nervous system. We found that injection of PGN into the mouse brain parenchyma (caudate putamen) triggered an inflammatory reaction, which involved activation of microglial cells, recruitment of infiltrating MC to injection site, production of pro-inflammatory mediators, and neuronal injury. In addition, we observed the accumulation of LC3B+ CD45+ cells and colocalization of LC3B and lysosomal associated membrane protein 1 in brain cells. Besides, we found that pharmacological inhibitors of PI3K, including the classical autophagy inhibitor 3 MA, reduced the recruitment of MC, microglial cell activation, and neurotoxicity induced by brain PGN injection. Collectively, our results suggest that PI3K pathways and autophagic response may participate in the PGN-induced microglial activation and MC recruitment to the brain. Thus, inhibition of these pathways could be therapeutically targeted to control acute brain inflammatory conditions. PMID- 29719537 TI - RIOK-1 Is a Suppressor of the p38 MAPK Innate Immune Pathway in Caenorhabditis elegans. AB - Innate immunity is the primary defense mechanism against infection in metazoans. However, aberrant upregulation of innate immune-signaling pathways can also be detrimental to the host. The p38 MAPK/PMK-1 innate immune-signaling pathway has been demonstrated to play essential roles in cellular defenses against numerous infections in metazoans, including Caenorhabditis elegans. However, the negative regulators that maintain the homeostasis of this important innate immune pathway remain largely understudied. By screening a focused RNAi library against the kinome of C. elegans, we identified RIOK-1, a human RIO kinase homolog, as a novel suppressor of the p38 MAPK/PMK-1 signal pathway. We demonstrated that the suppression of riok-1 confers resistance to Aeromonas dhakensis infection in C. elegans. Using quantitative real time-PCR and riok-1 reporter worms, we found the expression levels of riok-1 to be significantly upregulated in worms infected with A. dhakensis. Our genetic epistasis analysis suggested that riok-1 acts on the upstream of the p38 MAPK/pmk-1 genetic pathway. Moreover, the suppression of riok-1 enhanced the p38 MAPK signal, suggesting that riok-1 is a negative regulator of this innate pathway in C. elegans. Our epistatic results put riok-1 downstream of skn-1, which encodes a p38 MAPK downstream transcription factor and serves as a feedback loop to the p38 MAPK pathway during an A. dhakensis infection. In conclusion, riok-1 is proposed as a novel innate immune suppressor and as a negative feedback loop model involving p38 MAPK, SKN-1, and RIOK-1 in C. elegans. PMID- 29719539 TI - Natural Killer Cell Recruitment to the Lung During Influenza A Virus Infection Is Dependent on CXCR3, CCR5, and Virus Exposure Dose. AB - Natural killer (NK) cells are vital components of the antiviral immune response, but their contributions in defense against influenza A virus (IAV) are not well understood. To better understand NK cell responses during IAV infections, we examined the magnitude, kinetics, and contribution of NK cells to immunity and protection during high- and low-dose IAV infections. Herein, we demonstrate an increased accumulation of NK cells in the lung in high-dose vs. low-dose infections. In part, this increase is due to the local proliferation of pulmonary NK cells. However, the majority of NK cell accumulation within the lungs and airways during an IAV infection is due to recruitment that is partially dependent upon CXCR3 and CCR5, respectively. Therefore, altogether, our results demonstrate that NK cells are actively recruited to the lungs and airways during IAV infection and that the magnitude of the recruitment may relate to the inflammatory environment found within the tissues during high- and low-dose IAV infections. PMID- 29719540 TI - A Novel PhoP/PhoQ Regulation Pathway Modulates the Survival of Extraintestinal Pathogenic Escherichia coli in Macrophages. AB - The extraintestinal pathogenic Escherichia coli (ExPEC) is a typical facultative intracellular bacterial pathogen. Sensing the environmental stimuli and undertaking adaptive change are crucial for ExPEC to successfully colonize in specific extraintestinal niches. The previous studies show that pathogens exploit two-component systems (TCSs) in response to the host environments during its infection. The PhoP/PhoQ is a typical TCS which is ubiquitous in Gram-negative bacteria. However, there is an incompletely understanding about critical regulatory roles of PhoP/PhoQ in ExPEC pathogenesis. Conjugative ColV-related plasmids are responsible for ExPEC virulence, which is associated with ExPEC zoonotic risk. In this study, the molecular characteristics of HlyF, Mig-14 ortholog (Mig-14p), and OmpT variant (OmpTp) encoded by ColV plasmids were identified. Mig-14p and OmpTp played important roles in conferring ExPEC resistance to cationic antimicrobial peptides (CAMPs) during the infection. Moreover, HlyF and Mig-14p acted as intracellular survival factors to promote ExPEC resistance to macrophages killing. The hlyF and Mig-14p formed an operon in ExPEC ColV plasmid, and PhoP acted as a transcriptional activator of hlyF operon by directly binding to the P hlyF promoter. The acidic pH and CAMPs could additively stimulate ExPEC PhoQ/PhoP activities to upregulate the expression of HlyF and Mig-14p. Our studies revealed that the novel PhoP/PhoQ-HlyF signaling pathway directly upregulates the production of ExPEC outer membrane vesicles. Furthermore, our study first clarified that this PhoP/PhoQ-HlyF pathway was essential for ExPEC intracellular survival in macrophages. It was required to prevent the fusion of ExPEC-containing phagosomes with lysosomes. Moreover, PhoP/PhoQ-HlyF pathway facilitated the inhibition of the phagolysosomal acidification and disruption of the phagolysosomal membranes. In addition, this pathway might promote the formation of ExPEC-containing autophagosome during ExPEC replication in macrophages. Collectively, our studies suggested that PhoP/PhoQ system and CloV plasmids could facilitate ExPEC survival and replication within macrophages. PMID- 29719541 TI - A Reappraisal on the Potential Ability of Human Neutrophils to Express and Produce IL-17 Family Members In Vitro: Failure to Reproducibly Detect It. AB - Neutrophils are known to perform a series of effector functions that are crucial for the innate and adaptive responses, including the synthesis and secretion of a variety of cytokines. In light of the controversial data in the literature, the main objective of this study was to more in-depth reevaluate the capacity of human neutrophils to express and produce cytokines of the IL-17 family in vitro. By reverse transcription quantitative real-time PCR, protein measurement via commercial ELISA, immunohistochemistry (IHC) and immunofluorescence (IF), flow cytometry, immunoblotting, chromatin immunoprecipitation (ChIP), and ChIP-seq experiments, we found that highly pure (>99.7%) populations of human neutrophils do not express/produce IL-17A, IL-17F, IL-17AF, or IL-17B mRNA/protein upon incubation with a variety of agonists. Similar findings were observed by analyzing neutrophils isolated from active psoriatic patients. In contrast with published studies, IL-17A and IL-17F mRNA expression/production was not even found when neutrophils were incubated with extremely high concentrations of IL-6 plus IL-23, regardless of their combination with inactivated hyphae or conidia from Aspergillus fumigatus. Consistently, no deposition of histone marks for active (H3K27Ac) and poised (H3K4me1) genomic regulatory elements was detected at the IL-17A and IL-17F locus of resting and IL-6 plus IL-23-stimulated neutrophils, indicating a closed chromatin conformation. Concurrent experiments revealed that some commercial anti-IL-17A and anti-IL-17B antibodies (Abs), although staining neutrophils either spotted on cytospin slides or present in inflamed tissue samples by IHC/IF, do not recognize intracellular protein having the molecular weight corresponding to IL-17A or IL-17B, respectively, in immunoblotting experiments of whole neutrophil lysates. By contrast, the same Abs were found to more specifically recognize other intracellular proteins of neutrophils, suggesting that their ability to positively stain neutrophils in cytospin preparations and, eventually, tissue samples derives from IL-17A- or IL 17B-independent detections. In sum, our data confirm and extend, also at epigenetic level, previous findings on the inability of highly purified populations of human neutrophils to express/produce IL-17A, IL-17B, and IL-17F mRNAs/proteins in vitro, at least under the experimental conditions herein tested. Data also provide a number of justifications explaining, in part, why it is possible to false positively detect IL-17A+-neutrophils. PMID- 29719542 TI - Corrigendum: Recent Advances on Nutrition in Treatment of Acute Pancreatitis. AB - [This corrects the article on p. 762 in vol. 8, PMID: 28713382.]. PMID- 29719543 TI - Low-Molecular-Weightt Polysaccharides From Pyropia yezoensis Enhance Tolerance of Wheat Seedlings (Triticum aestivum L.) to Salt Stress. AB - Soil salinity is one of the major issues worldwide that affects plant growth and reduces agricultural productivity. Seaweed polysaccharides have been shown to promote crop growth and improve the resistance of plant to abiotic stresses. Pyropia yezoensis is a commercially important edible red alga in Southeast Asia. However, there is little research on the application of polysaccharides from P. yezoensis in agriculture. The molecular weight (MW) of polysaccharides influences their properties. Therefore, in this study, four representative polysaccharides from P. yezoensis (PP) with different MWs (MW: 3.2, 10.5, 29.0, and 48.8 kDa) were prepared by microwave-assisted acid hydrolysis. The relationship between the degradation of polysaccharides from P. yezoensis (DPP) and their effects on plant salt tolerance was investigated. The results showed that exogenous PP and DPPs increased wheat seedling shoot and root lengths, and fresh and dry weights, alleviated membrane lipid peroxidation, increased the chlorophyll content and enhanced antioxidant activities. The expression level examination analysis of several Na+/K+ transporter genes suggested that DPPs could protect plants from the damage of salt stress by coordinating the efflux and compartmentation of Na+. The results demonstrated that polysaccharides could regulate antioxidant enzyme activities and modulate intracellular ion concentration, thereby to protect plants from salt stress damage. Furthermore, there was a significant correlation between the tolerance of wheat seedlings to salt stress and MW of polysaccharides. The results suggested that the lower-MW samples (DPP1, 3.2 kDa) most effectively protect wheat seedlings against salt stress. PMID- 29719538 TI - Humoral Epitope Spreading in Autoimmune Bullous Diseases. AB - Autoimmune blistering diseases are characterized by autoantibodies against structural adhesion proteins of the skin and mucous membranes. Extensive characterization of their autoantibody targets has improved understanding of pathogenesis and laid the basis for the study of antigens/epitopes diversification, a process termed epitope spreading (ES). In this review, we have reported and discussed ES phenomena in autoimmune bullous diseases and underlined their functional role in disease pathogenesis. A functional ES has been proposed: (1) in bullous pemphigoid patients and correlates with the initial phase of the disease, (2) in pemphigus vulgaris patients with mucosal involvement during the clinical transition to a mucocutaneous form, (3) in endemic pemphigus foliaceus, underlining its role in disease pathogenesis, and (4) in numerous cases of disease transition associated with an intermolecular diversification of immune response. All these findings could give useful information to better understand autoimmune disease pathogenesis and to design antigen/epitope specific therapeutic approaches. PMID- 29719544 TI - Genome Sequencing of Ancient Plant Remains: Findings, Uses and Potential Applications for the Study and Improvement of Modern Crops. AB - The advent of new sequencing technologies is revolutionizing the studies of ancient DNA (aDNA). In the last 30 years, DNA extracted from the ancient remains of several plant species has been explored in small-scale studies, contributing to understand the adaptation, and migration patterns of important crops. More recently, NGS technologies applied on aDNA have opened up new avenues of research, allowing investigation of the domestication process on the whole-genome scale. Genomic approaches based on genome-wide and targeted sequencing have been shown to provide important information on crop evolution and on the history of agriculture. Huge amounts of next-generation sequencing (NGS) data offer various solutions to overcome problems related to the origin of the material, such as degradation, fragmentation of polynucleotides, and external contamination. Recent advances made in several crop domestication studies have boosted interest in this research area. Remains of any nature are potential candidates for aDNA recovery and almost all the analyses that can be made on fresh DNA can also be performed on aDNA. The analysis performed on aDNA can shed light on many phylogenetic questions concerning evolution, domestication, and improvement of plant species. It is a powerful instrument to reconstruct patterns of crop adaptation and migration. Information gathered can also be used in many fields of modern agriculture such as classical breeding, genome editing, pest management, and product promotion. Whilst unlocking the hidden genome of ancient crops offers great potential, the onus is now on the research community to use such information to gain new insight into agriculture. PMID- 29719545 TI - Phenotypic Trait Identification Using a Multimodel Bayesian Method: A Case Study Using Photosynthesis in Brassica rapa Genotypes. AB - Agronomists have used statistical crop models to predict yield on a genotype-by genotype basis. Mechanistic models, based on fundamental physiological processes common across plant taxa, will ultimately enable yield prediction applicable to diverse genotypes and crops. Here, genotypic information is combined with multiple mechanistically based models to characterize photosynthetic trait differentiation among genotypes of Brassica rapa. Infrared leaf gas exchange and chlorophyll fluorescence observations are analyzed using Bayesian methods. Three advantages of Bayesian approaches are employed: a hierarchical model structure, the testing of parameter estimates with posterior predictive checks and a multimodel complexity analysis. In all, eight models of photosynthesis are compared for fit to data and penalized for complexity using deviance information criteria (DIC) at the genotype scale. The multimodel evaluation improves the credibility of trait estimates using posterior distributions. Traits with important implications for yield in crops, including maximum rate of carboxylation (Vcmax ) and maximum rate of electron transport (Jmax ) show genotypic differentiation. B. rapa shows phenotypic diversity in causal traits with the potential for genetic enhancement of photosynthesis. This multimodel screening represents a statistically rigorous method for characterizing genotypic differences in traits with clear biophysical consequences to growth and productivity within large crop breeding populations with application across plant processes. PMID- 29719546 TI - Metabolome Integrated Analysis of High-Temperature Response in Pinus radiata. AB - The integrative omics approach is crucial to identify the molecular mechanisms underlying high-temperature response in non-model species. Based on future scenarios of heat increase, Pinus radiata plants were exposed to a temperature of 40 degrees C for a period of 5 days, including recovered plants (30 days after last exposure to 40 degrees C) in the analysis. The analysis of the metabolome using complementary mass spectrometry techniques (GC-MS and LC-Orbitrap-MS) allowed the reliable quantification of 2,287 metabolites. The analysis of identified metabolites and highlighter metabolic pathways across heat time exposure reveal the dynamism of the metabolome in relation to high-temperature response in P. radiata, identifying the existence of a turning point (on day 3) at which P. radiata plants changed from an initial stress response program (shorter-term response) to an acclimation one (longer-term response). Furthermore, the integration of metabolome and physiological measurements, which cover from the photosynthetic state to hormonal profile, suggests a complex metabolic pathway interaction network related to heat-stress response. Cytokinins (CKs), fatty acid metabolism and flavonoid and terpenoid biosynthesis were revealed as the most important pathways involved in heat-stress response in P. radiata, with zeatin riboside (ZR) and isopentenyl adenosine (iPA) as the key hormones coordinating these multiple and complex interactions. On the other hand, the integrative approach allowed elucidation of crucial metabolic mechanisms involved in heat response in P. radiata, as well as the identification of thermotolerance metabolic biomarkers (L-phenylalanine, hexadecanoic acid, and dihydromyricetin), crucial metabolites which can reschedule the metabolic strategy to adapt to high temperature. PMID- 29719547 TI - Heterotrimeric G-Protein gamma Subunit CsGG3.2 Positively Regulates the Expression of CBF Genes and Chilling Tolerance in Cucumber. AB - Heterotrimeric guanine nucleotide-binding proteins (G proteins) composed of alpha (Galpha), beta (Gbeta), and gamma (Ggamma) subunits are central signal transducers mediating the cellular response to multiple stimuli, such as cold, in eukaryotes. Plant Ggamma subunits, divided into A, B, and C three structurally distinct types, provide proper cellular localization and functional specificity to the heterotrimer complex. Here, we demonstrate that a type C Ggamma subunit CsGG3.2 is involved in the regulation of the CBF regulon and plant tolerance to cold stresses in cucumber (Cucumis sativus L.). We showed that CsGG3.2 transcript abundance was positively induced by cold treatments. Transgenic cucumber plants (T1) constitutively over-expressing CsGG3.2 exhibits tolerance to chilling conditions and increased expression of CBF genes and their regulon. Antioxidative enzymes, i.e., superoxide dismutase, catalase, peroxidase, and glutathione reductase activities increased in cold-stressed transgenic plants. The reactive oxygen species, oxygen free radical and H2O2, production, as well as membrane lipid peroxidation (MDA) production decreased in transgenic plants, suggesting a better antioxidant system to cope the oxidative-damages caused by cold stress. These findings provide evidence for a critical role of CsGG3.2 in mediating cold signal transduction in plant cells. PMID- 29719548 TI - Novel Digital Features Discriminate Between Drought Resistant and Drought Sensitive Rice Under Controlled and Field Conditions. AB - Dynamic quantification of drought response is a key issue both for variety selection and for functional genetic study of rice drought resistance. Traditional assessment of drought resistance traits, such as stay-green and leaf rolling, has utilized manual measurements, that are often subjective, error prone, poorly quantified and time consuming. To relieve this phenotyping bottleneck, we demonstrate a feasible, robust and non-destructive method that dynamically quantifies response to drought, under both controlled and field conditions. Firstly, RGB images of individual rice plants at different growth points were analyzed to derive 4 features that were influenced by imposition of drought. These include a feature related to the ability to stay green, which we termed greenness plant area ratio (GPAR) and 3 shape descriptors [total plant area/bounding rectangle area ratio (TBR), perimeter area ratio (PAR) and total plant area/convex hull area ratio (TCR)]. Experiments showed that these 4 features were capable of discriminating reliably between drought resistant and drought sensitive accessions, and dynamically quantifying the drought response under controlled conditions across time (at either daily or half hourly time intervals). We compared the 3 shape descriptors and concluded that PAR was more robust and sensitive to leaf-rolling than the other shape descriptors. In addition, PAR and GPAR proved to be effective in quantification of drought response in the field. Moreover, the values obtained in field experiments using the collection of rice varieties were correlated with those derived from pot based experiments. The general applicability of the algorithms is demonstrated by their ability to probe archival Miscanthus data previously collected on an independent platform. In conclusion, this image-based technology is robust providing a platform-independent tool for quantifying drought response that should be of general utility for breeding and functional genomics in future. PMID- 29719550 TI - First High-Density Linkage Map and Single Nucleotide Polymorphisms Significantly Associated With Traits of Economic Importance in Yellowtail Kingfish Seriola lalandi. AB - The genetic resources available for the commercially important fish species Yellowtail kingfish (YTK) (Seriola lalandi) are relative sparse. To overcome this, we aimed (1) to develop a linkage map for this species, and (2) to identify markers/variants associated with economically important traits in kingfish (with an emphasis on body weight). Genetic and genomic analyses were conducted using 13,898 single nucleotide polymorphisms (SNPs) generated from a new high throughput genotyping by sequencing platform, Diversity Arrays Technology (DArTseqTM) in a pedigreed population comprising 752 animals. The linkage analysis enabled to map about 4,000 markers to 24 linkage groups (LGs), with an average density of 3.4 SNPs per cM. The linkage map was integrated into a genome wide association study (GWAS) and identified six variants/SNPs associated with body weight (P < 5e-8) when a multi-locus mixed model was used. Two out of the six significant markers were mapped to LGs 17 and 23, and collectively they explained 5.8% of the total genetic variance. It is concluded that the newly developed linkage map and the significantly associated markers with body weight provide fundamental information to characterize genetic architecture of growth related traits in this population of YTK S. lalandi. PMID- 29719549 TI - GLASSgo - Automated and Reliable Detection of sRNA Homologs From a Single Input Sequence. AB - Bacterial small RNAs (sRNAs) are important post-transcriptional regulators of gene expression. The functional and evolutionary characterization of sRNAs requires the identification of homologs, which is frequently challenging due to their heterogeneity, short length and partly, little sequence conservation. We developed the GLobal Automatic Small RNA Search go (GLASSgo) algorithm to identify sRNA homologs in complex genomic databases starting from a single sequence. GLASSgo combines an iterative BLAST strategy with pairwise identity filtering and a graph-based clustering method that utilizes RNA secondary structure information. We tested the specificity, sensitivity and runtime of GLASSgo, BLAST and the combination RNAlien/cmsearch in a typical use case scenario on 40 bacterial sRNA families. The sensitivity of the tested methods was similar, while the specificity of GLASSgo and RNAlien/cmsearch was significantly higher than that of BLAST. GLASSgo was on average ~87 times faster than RNAlien/cmsearch, and only ~7.5 times slower than BLAST, which shows that GLASSgo optimizes the trade-off between speed and accuracy in the task of finding sRNA homologs. GLASSgo is fully automated, whereas BLAST often recovers only parts of homologs and RNAlien/cmsearch requires extensive additional bioinformatic work to get a comprehensive set of homologs. GLASSgo is available as an easy-to-use web server to find homologous sRNAs in large databases. PMID- 29719551 TI - Importance of Reperfusion Status after Intra-Arterial Thrombectomy for Prediction of Outcome in Anterior Circulation Large Vessel Stroke. AB - Background: Reperfusion status after intra-arterial thrombectomy (IAT) is a critical predictor of functional outcome after acute ischemic stroke. However, most prognostic models have not included a detailed assessment of reperfusion status after IAT. Objective: The aim of this work was to assess the association between successful reperfusion and clinical outcome. Methods: Clinical, radiological, and procedural variables of patients treated with IAT were extracted from our prospective stroke registry. The association with functional outcome using the modified Rankin Scale (mRS) after 3 months was assessed using multivariable logistic regression. An extension of the modified TICI score, eTICI, was used to classify reperfusion status. The prognostic value of reperfusion status after IAT in addition to age, stroke severity, imaging characteristics, treatment with intravenous thrombolysis, and time from symptom onset to the end of IAT was assessed with logistic regression and summarized with receiver operating characteristic curves. Results: In total, 119 patients were included (mean age 66 years). In multivariable analysis, age >80 years (OR 6.8, 95% CI 1.2-39.8), NIHSS at presentation >15 (OR 7.3, 95% CI 2.3-23.5), and incomplete reperfusion status (eTICI score <2C; OR 10.3, 95% CI 3.5-30.6) were the strongest predictors of a poor outcome (mRS 3-6). Adding reperfusion status to the model improved the prognostic accuracy (AUC 0.88, 95% CI 0.91-0.94). Our results indicate a large difference between using an eTICI cutoff of >=2C versus >=2B: a cutoff >=2C improved the predictive value for a good clinical outcome (2C: positive predictive value, PPV, 0.78; 2B: PPV 0.32). Conclusion: Our results promote using reperfusion status for assessing prognosis in ischemic stroke patients treated with IAT. A model using eTICI >=2C had greater PPV than eTICI >=2B and could improve prognostic accuracy. PMID- 29719552 TI - Direct Aspiration Catheter Fracture and Retrieval during Neurothrombectomy. AB - Background: Application of direct aspiration catheters has revolutionized acute stroke care and has led to significant improvement in clinical outcome with a good safety profile. Catheter fracture and retention is a rare but potentially devastating complication. Case Description: Here we present two cases of acute stroke complicated by aspiration catheter fracture and retention. Successful catheter retrieval and revascularization was achieved in both cases. The stenosis or tortuosity of vascular anatomy appears to be the probable contributor to catheter breakage by anchoring the catheter with resultant fracture at the constraint point from catheter withdrawal tensile stress. Conclusion: This report describes application of snare devices in retrieving a broken catheter during thrombectomy in the anterior and posterior circulation, and therefore presents a technique that can be safely utilized to address catheter breakage complicating thrombectomy in different vascular anatomic locations. PMID- 29719553 TI - 47 Consecutive Cases of Pipeline Flex Flow Diversion Utilizing a Novel Large-Bore Intracranial Intermediate Catheter: Nuances and Institutional Experience with the Syphontrak. AB - Background: The increasing complexity of modern neurointerventions has necessitated a shift in intracranial access techniques towards more robust distal support platforms. Here we present our experience with the Syphontrak Support Catheter (Codman Neuro, Raynham, MA, USA) in the triaxial platform for the implantation of the second-generation Pipeline Flex embolization device (PED Flex; Medtronic Neurovascular, Irvine, CA, USA). Methods: We retrospectively identified patients who underwent PED Flex treatment utilizing the Syphontrak at a single institution. The procedural data collected included parent artery tortuosity, patient demographics, aneurysm characteristics, other equipment utilized, and catheter-related complications. Results: A total of 47 consecutive aneurysm flow diversions were successfully performed using the Syphontrak. The patients' age ranged from 25 to 80 years (mean 57.3 +/- 11.6) and 85% were women. The average aneurysm size was 4.8 +/- 2.7 mm (range 2-14). All cases were in the anterior circulation, with 6 (12%) aneurysms located beyond the internal carotid artery termination. Significant cervical carotid tortuosity was present in 23% (11/47) of the cases and moderate-to-severe cavernous tortuosity (cavernous grade >=2) in 51% (24/47) of the cases. The mean fluoroscopy time was 36.6 +/- 14.8 min. In 12/47 cases (26%), vasospasm prophylaxis with intra-arterial verapamil infusion was performed. The Syphontrak was tracked to the intended distal position in all cases, with a 100% technical success of PED Flex implantation. Forty-six (98%) of the 47 patients were discharged home after an average length of stay of 1.38 days. No iatrogenic catheter-related vessel injury occurred. Transient, minor neurological morbidity occurred in 3 cases (6%) and 1 patient had a minor ischemic event (NIHSS score < 4) in the periprocedural period. Conclusion: The Syphontrak is a new large-bore, multi-durometer intermediate catheter (IC) designed for use in modern neurointerventional procedures. We have shown its utility in 47 successful cases of PED Flex flow diversion of a wide range of complexity. The IC provides robust and atraumatic distal intracranial access while also providing an enhanced image quality with its large 0.060" inner diameter. PMID- 29719554 TI - Pipeline Flex Embolization of Flow-Related Aneurysms Associated with Arteriovenous Malformations: A Case Report. AB - Background: An estimated 0.1% of the population harbors brain arteriovenous malformations (AVMs). Diagnosis and workup of AVMs include thorough evaluation for characterization of AVM angioarchitecture and careful assessment for concomitant aneurysms. The presence of coexisting aneurysms is associated with an increased risk of intracranial hemorrhage, with a published risk of 7% per year compared to patients with AVMs alone with a risk of 3%. Comprehensive AVM management requires recognition of concomitant aneurysms and prioritizes treatment strategies to mitigate the aggregate risk of intracranial hemorrhage associated with AVM rupture in patients with coexisting aneurysms. Endovascular treatment of these flow-related aneurysms can offer a cure, while avoiding open surgery. Successful flow-diverting embolization techniques, efficacy, and outcomes have been previously described for a variety of aneurysm types and locations. However, use of a flow diverter has not been previously described for the treatment of high-flow aneurysms on AVM-feeding vessels. Case Presentation: We report 2 cases of large AVMs within eloquent cortex associated with flow related aneurysms in patients presenting initially with suspected intracerebral hemorrhage secondary to AVM rupture. Discussion: No consensus currently exists to guide treatment of intracranial aneurysms associated with AVMs. Surgical management addressed AVM embolization initially, as the vasculopathology with the highest rupture risk. Subsequently, Pipeline embolization of the associated aneurysms with adequate antiplatelet treatment was performed before scheduled radiosurgery to decrease the risk of AVM rupture or rebleed. This represents a novel and promising use of the Pipeline Embolization Device. Additional cases and longer follow-up will be needed to further assess the efficacy of this technique. PMID- 29719555 TI - A Review of Pre-Intervention Prognostic Scores for Early Prognostication and Patient Selection in Endovascular Management of Large Vessel Occlusion Stroke. AB - Background: Endovascular therapy (ET) has emerged as a highly effective treatment for acute large vessel occlusion stroke (LVOS). Tools that facilitate optimal patient selection of patients for ET are needed in order to maximize therapeutic benefit in a cost-effective manner. Several pre-intervention prognostic scores for prediction of outcomes in LVOS patients and patient selection for ET have been developed and validated, but their clinical use has been limited. Here, we review existing pre-intervention prognostic scores, compare their prognostic accuracies and levels of validation and identify gaps in current knowledge. Summary: We have reviewed published literature pertinent to development, validation, and implementation of pre-intervention prognostic scores for LVOS. Using receiver operating characteristic curve analysis, the prognostic accuracies of validated pre-interventional scores (Pittsburgh Response to Endovascular therapy [PRE], Totaled Health Risks in Vascular Events [THRIVE], Houston Intra Arterial Therapy-2 (HIAT-2), Stroke Prognostication using Age and NIHSS [SPAN 100]) were compared in published work. Pre-intervention scores predicted functional out comes at 3 months with moderate prognostic accuracies (area under the receiver operator characteristic curve range 0.68-0.73). Using successful reperfusion (mTICI 2B/3) as the therapeutic objective of ET and 3-month modified Rankin Score 0-2 as good clinical outcome, patients most likely to clinically benefit from endovascular reperfusion can be identified using the PRE and HIAT-2 scores. Scores that incorporate collateral imaging or perfusion-based estimation of core and penumbra have not been published. Existing scores are predominantly limited to anterior circulation LVOS, and implementation studies of pre interventional scores are lacking. Key Messages: Pre-intervention prognostic scores can serve as useful adjuncts for patient selection in ET for acute LVOS. Pre-intervention scores including HIAT-2, THRIVE, SPAN-100, and PRE have comparable moderate prognostic accuracies for good 3-month outcomes and can identify patients who derive maximal benefit from successful reperfusion. Improvements in prognostic accuracy may be achieved by incorporating variables such as collateral status and perfusion imaging data. Implementation and impact studies using pre-intervention scores are needed to guide clinical application. PMID- 29719556 TI - Association of Blood Glucose and Clinical Outcome after Mechanical Thrombectomy for Acute Ischemic Stroke. AB - Background: Elevated blood glucose levels following acute ischemic stroke have been associated with adverse clinical outcomes in thrombolytic and nonthrombolytic treated patients. The current study examined multiple blood glucose parameters and their association with modified Rankin Scale (mRS) score at 3 months following mechanical thrombectomy and hospital discharge. Methods: Acute ischemic stroke patients undergoing mechanical thrombectomy with a retrievable stent at two stroke centers were studied. Admission blood glucose level, maximum blood glucose during the hospital stay, and serial blood glucose measurements within the first 24 h of hospital admission were recorded. Variability in blood glucose level was represented by the standard deviation of the serial measurements within the first 24 h. The following demographic and clinical data was also collected: age, sex, baseline NIHSS score, onset-to reperfusion times, hemoglobin A1c, and stroke mechanism. Results: 79 patients were identified; at 3 months, 35 patients had an mRS score of 0-2 and 44 had had an mRS of 3-6. Among the blood glucose variables, standard deviation of blood glucose in the first 24 h following admission and maximum blood glucose during hospital stay were significantly higher in the mRS 3-6 group. In multivariate logistic regression analysis, only the standard deviation of blood glucose remained significant (OR = 1.07, 95% CI = 1.02-1.11, p = 0.003) in a model that adjusted for admission NIHSS score (p = 0.016) and number of stent retriever passes (p = 0.042). Conclusions: Greater blood glucose variability following acute ischemic stroke is associated with worse clinical outcome in patients undergoing mechanical thrombectomy. PMID- 29719557 TI - Stent Reconstruction of Carotid Tonsillar Loop Dissection Using Telescoping Peripheral Stents. AB - Background: Endovascular treatment options for internal carotid artery (ICA) dissection with tandem intracranial occlusion are evolving. We report 2 cases of stent reconstruction of carotid loop dissections. Methods: Two patients with symptomatic ICA dissections of true 360 degrees tonsillar loops and tandem intracranial occlusions were treated with manual aspiration thrombectomy (MAT) and telescoping Zilver self-expanding peripheral stents. Patient demographics, clinical presentations, endovascular techniques, and clinical outcomes were reviewed. Results: In both cases, MAT achieved modified Treatment in Cerebral Ischemia scale 2B reperfusion, and complete endovascular reconstruction of the dissected extracranial loop was performed. Both patients had improved pre- to postintervention National Institutes of Health Stroke Scale scores (16 to 0 and 14 to 0), and both had modified Rankin scale scores of 1 at 3-month follow-up. Conclusions: Stent reconstruction of complex cerebrovascular anatomy is increasingly feasible with advancements in stent technology and catheter support system design. This technique may be of use to neuroendovascular surgeons who encounter variant ICA anatomy. PMID- 29719559 TI - Fine needle aspiration cytology finding of a parotid mass with chondromyxoid matrix and variable epithelial cytological atypia. PMID- 29719558 TI - Pomona Large Vessel Occlusion Screening Tool for Prehospital and Emergency Room Settings. AB - Background: Early identification of patients with acute ischemic strokes due to large vessel occlusions (LVO) is critical. We propose a simple risk score model to predict LVO. Method: The proposed scale (Pomona Scale) ranges from 0 to 3 and includes 3 items: gaze deviation, expressive aphasia, and neglect. We reviewed a cohort of all acute stroke activation patients between February 2014 and January 2016. The predictive performance of the Pomona Scale was determined and compared with several National Institutes of Health Stroke Scale (NIHSS) cutoffs (>=4, >=6, >=8, and >=10), the Los Angeles Motor Scale (LAMS), the Cincinnati Prehospital Stroke Severity (CPSS) scale, the Vision Aphasia and Neglect Scale (VAN), and the Prehospital Acute Stroke Severity Scale (PASS). Results: LVO was detected in 94 of 776 acute stroke activations (12%). A Pomona Scale >=2 had comparable accuracy to predict LVO as the VAN and CPSS scales and higher accuracy than Pomona Scale >=1, LAMS, PASS, and NIHSS. A Pomona Scale >=2 had an accuracy (area under the curve) of 0.79, a sensitivity of 0.86, a specificity of 0.70, a positive predictive value of 0.71, and a negative predictive value of 0.97 for the detection of LVO. We also found that the presence of either neglect or gaze deviation alone had comparable accuracy of 0.79 as Pomona Scale >=2 to detect LVO. Conclusion: The Pomona Scale is a simple and accurate scale to predict LVO. In addition, the presence of either gaze deviation or neglect also suggests the possibility of LVO. PMID- 29719560 TI - Cytomorphological features as predictors of epidermal growth factor receptor mutation status in lung adenocarcinoma. AB - Background: Epidermal growth factor receptor mutation-positive (EGFR-p) lung adenocarcinomas are sensitive to tyrosine kinase inhibitors. Although histopathological subtype is an independent predictor of mutation status, there is a paucity of data on the cytomorphological features correlating with the EGFR mutation status. Therefore, the aim of this study was to determine whether certain cytomorphological features correlate with EGFR mutation in lung adenocarcinoma. Materials and Methods: A retrospective analysis of 48 lung adenocarcinoma cases diagnosed on fine needle aspiration cytology with known EGFR mutation status was conducted. All cytology smears with cellblock sections were reviewed. The cytomorphological features including tumor pattern, stromal features, nuclear and cytoplasmic features, and tumor grade were evaluated. Clinicoradiological features such as age, sex, smoking, tumor size, clinical stage, metastases, and presence of mass, nodule, lymphadenopathy, pleural effusion, and clinical outcome were also assessed. Results: Of 48 cases, 19 were EGFR-p and 29 were negative. EGFR-p cases showed a positive and significant correlation with flat monolayered sheets and acini, mild nuclear atypia, fine chromatin and smooth nuclear margins and these tumors were well differentiated. EGFR-negative tumors were moderate to poorly differentiated with predominance of solid clusters, moderate to marked nuclear atypia, with irregular nuclear margins and coarse chromatin. Clinically, female sex, nonsmoking status, smaller tumor size, and good clinical outcome correlated with EGFR-p status. Conclusion: Certain cytomorphological features correlate with and may suggest EGFR mutation status in advanced lung adenocarcinoma in an appropriate clinical context. PMID- 29719561 TI - Commentary on Kehl et al. "Young male mating success is associated with sperm number but not with male sex pheromone titres": Unnatural experimental conditions inflate the importance of male courtship activity on mating success in a butterfly. AB - Over the last years, several studies suggested that male courtship activity is more important than female preference for male secondary sexual traits in determining male mating success in the butterfly Bicyclus anynana. We use Kehl et al. (Front Zool 12, 2015)'s study and related publications, to highlight three methodological and conceptual aspects of laboratory experiments that distort the social environment compared to natural conditions. We argue that such experimental biases prevent the expression of female mate choice and artificially inflate the role of male activity in determining mating success. We really want to stress that any work performed in laboratory conditions using extreme cage densities or sizes impedes female mate choice and promotes male-male competition when sexual conflict occurs about mating decisions. Hence, such studies, and the derived conclusions, are only applicable to ecologically-irrelevant conditions and cannot be extrapolated to more natural laboratory or field conditions. Our concerns may be relevant to many behavioural studies quantifying sexual selection across taxa. This commentary adds to the increasing scientific awareness that: i) mating outcome is, across taxa, the result of a sexual conflict whose outcome is under female, and not male, control; ii) the social environment used to quantify mating success is of utmost importance to produce reliable estimates of the strength and the direction of sexual selection on sexually-selected traits, as they evolve in nature. PMID- 29719562 TI - A reply to Nieberding and Holveck: beyond experimental design and proximate mechanisms - mate choice in the face of sexual conflict. AB - We summarise our work on male mating behaviour in the tropical butterfly Bicyclus anynana, responding to the commentary provided by Nieberding and Holveck. We acknowledge that our laboratory studies are not free of shortcomings and potential caveats, though we attempted to address or highlight these within each paper. The concerns raised seem to stem mainly from different notions with respect to the proximate basis of old male mating advantage, and specifically the relative importance of male behaviour versus pheromone blend. In our view, our experiments provided compelling evidence for a prominent role of male behaviour, while we were unable to obtain clear evidence for a major role of male sexual pheromones. In addition to the lack of evidence we argue that a preference of females for older males based on pheromone blend is unlikely, as pheromone titres do not seem to indicate male quality and, more importantly, females actually suffer a fitness cost when mating with older males. The latter suggests that old male mating advantage arises from sexual conflict rather than cooperation. We thus highlight the importance of considering both the proximate and the ultimate level for gaining an integrative understanding of complex behavioural patterns. PMID- 29719563 TI - Knowledge of, and attitudes to giving expressed breastmilk to infants in rural coastal Kenya; focus group discussions of first time mothers and their advisers. AB - Background: The World Health Organization (WHO)/UNICEF Baby-Friendly Hospital Initiative step number five of the "Ten steps to successful breastfeeding" states "Show mothers how to breastfeed and how to maintain lactation even if they should be separated from their infants." Urban mothers in Nairobi have low rates of exclusive breastfeeding after returning to work but there are no published data on rural Kenya mothers' infant feeding practices when working or schooling away from home. Methods: We explored knowledge of, and attitudes to, the practice of giving expressed breastmilk in a mixed methods observational study of breastfeeding in rural Kenyan mothers. Fifty mothers with newborns, identified by nurses and community health workers, were asked questions about their experiences of breastfeeding and who they had sought or received advice from on breastfeeding. Focus group discussions, one with community health workers, and four each with mothers and their named advisers were held. Recordings were analyzed using a thematic framework approach. Results: The main themes were: the baby's right to feed from the breast, lack of knowledge about expressing and giving breastmilk, negative attitudes towards expressed breastmilk, and traditional customs for disposing of expressed breast milk. Most participants did not have any experience of giving expressed breastmilk to infants. They described practices of expressing and discarding milk when the mother or baby was ill, to relieve discomfort from engorgement or after the baby had died. Conclusions: Feeding expressed breastmilk to infants is a new concept in this context. Promotion of, and training in this practice would help mothers to maintain their milk supply when away from their babies and benefit the infants of working and schoolgirl mothers. PMID- 29719564 TI - Current research on child maltreatment epidemiology. PMID- 29719565 TI - The rat pancreatic body tail as a source of a novel extracellular matrix scaffold for endocrine pancreas bioengineering. AB - Background: Regenerative medicine and tissue engineering are promising approaches for organ transplantation. Extracellular matrix (ECM) based scaffolds obtained through the decellularization of natural organs have become the preferred platform for organ bioengineering. In the field of pancreas bioengineering, acellular scaffolds from different animals approximate the biochemical, spatial and vascular relationships of the native extracellular matrix and have been proven to be a good platform for recellularization and in vitro culture. However, artificial endocrine pancreases based on these whole pancreatic scaffolds have a critical flaw, specifically their difficult in vivo transplantation, and connecting their vessels to the recipient is a major limitation in the development of pancreatic tissue engineering. In this study, we focus on preparing a novel acellular extracellular matrix scaffold derived from the rat pancreatic body tail (pan-body-tail ECM scaffold). Results: Several analyses confirmed that our protocol effectively removes cellular material while preserving ECM proteins and the native vascular tree. DNA quantification demonstrated an obvious reduction of DNA compared with that of the natural organ (from 931.9 +/- 267.8 to 11.7 +/- 3.6 ng/mg, P < 0.001); the retention of the sGAG in the decellularized pancreas (0.878 +/- 0.37) showed no significant difference from the natural pancreas (0.819 +/- 0.1) (P > 0.05). After transplanted with the recellularized pancreas, fasting glucose levels declined to 9.08 +/- 2.4 mmol/l within 2 h of the operation, and 8 h later, they had decreased to 4.7 +/- 1.8 mmol/l (P < 0.05). Conclusions: The current study describes a novel pancreatic ECM scaffold prepared from the rat pancreatic body tail via perfusion through the left gastric artery. We further showed the pioneering possibility of in vivo circulation-connected transplantation of a recellularized pancreas based on this novel scaffold. By providing such a promising pancreatic ECM scaffold, the present study might represent a key improvement and have a positive impact on endocrine pancreas bioengineering. PMID- 29719566 TI - The beta-glucosidase secreted by Talaromyces amestolkiae under carbon starvation: a versatile catalyst for biofuel production from plant and algal biomass. AB - Background: In the last years, the most outstanding trend for obtaining high added-value components and second-generation (2G) biofuels consisted on exploitation of plant biomass. But recently, 3G biofuels, based in algae biomass, have emerged as a great alternative for production of energy. Results: In this work, a versatile beta-glucosidase from the ascomycete fungus Talaromyces amestolkiae has been purified, characterized, and heterologously expressed. The synthesis of this beta-glucosidase (BGL-3) was not induced by cellulose, and the presence of a specific carbon source is not required for its production, which is uncommon for beta-glucosidases. BGL-3, which was obtained from a basal medium with glucose as carbon source, was profusely secreted under carbon starvation conditions, which was corroborated by qRT-PCR assays. BGL-3 was purified from T. amestolkiae cultures in one step, and biochemically characterized. The enzyme showed high thermal stability, and very high efficiency on pNPG (Km of 0.14 mM and Vmax of 381.1 U/mg), cellobiose (Km of 0.48 mM and Vmax of 447.1 U/mg), and other cello-oligosaccharides. Surprisingly, it also showed remarkable ability to hydrolyze laminarin, a beta-1,3-glucan present in algae. The recombinant enzyme, obtained in the yeast Pichia pastoris, exhibited kinetic and physicochemical properties similar to those found for the native protein. Enzyme efficiency was examined in wheat straw saccharification processes, in which BGL-3 worked better supplementing Celluclast 1.5L than the commercial cellulase cocktail N-50010. Besides, BGL-3 hydrolyzed laminarin more efficiently than a commercial laminarinase. Conclusions: A very efficient 1,4-beta-glucosidase, which also showed activity over 1,3-beta-glucose bonds, has been produced, purified, and characterized. This is the first report of such versatility in a 1,4-beta glucosidase. The application of this enzyme for saccharification of wheat straw and laminarin and its comparison with commercial enzymes suggest that it could be an interesting tool for the production of 2G and 3G biofuels. PMID- 29719568 TI - Stepwise radical cation Diels-Alder reaction via multiple pathways. AB - Herein we disclose the radical cation Diels-Alder reaction of aryl vinyl ethers by electrocatalysis, which is triggered by an oxidative SET process. The reaction clearly proceeds in a stepwise fashion, which is a rare mechanism in this class. We also found that two distinctive pathways, including "direct" and "indirect", are possible to construct the Diels-Alder adduct. PMID- 29719567 TI - Biocatalytic synthesis of the Green Note trans-2-hexenal in a continuous-flow microreactor. AB - The biocatalytic preparation of trans-hex-2-enal from trans-hex-2-enol using a novel aryl alcohol oxidase from Pleurotus eryngii (PeAAOx) is reported. As O2 dependent enzyme PeAAOx-dependent reactions are generally plagued by the poor solubility of O2 in aqueous media and mass transfer limitations resulting in poor reaction rates. These limitations were efficiently overcome by conducting the reaction in a flow-reactor setup reaching unpreceded catalytic activities for the enzyme in terms of turnover frequency (up to 38 s-1) and turnover numbers (more than 300000) pointing towards preparative usefulness of the proposed reaction scheme. PMID- 29719569 TI - Cobalt-catalyzed directed C-H alkenylation of pivalophenone N-H imine with alkenyl phosphates. AB - A cobalt-N-heterocyclic carbene (NHC) catalyst efficiently promotes an ortho C-H alkenylation reaction of pivalophenone N-H imine with an alkenyl phosphate. The reaction tolerates various substituted pivalophenone N-H imines as well as cyclic and acyclic alkenyl phosphates. PMID- 29719571 TI - Volatiles from the xylarialean fungus Hypoxylon invadens. AB - The volatiles emitted by agar plate cultures of the xylarialean fungus Hypoxylon invadens were investigated by use of a closed loop stripping apparatus in combination with GC-MS. Several aromatic compounds were found that could only be identified by comparison to all possible constitutional isomers with different ring substitution patterns. For the set of identified compounds a plausible biosynthetic scheme was suggested that gives further support for the assigned structures. PMID- 29719570 TI - Nanoreactors for green catalysis. AB - Sustainable and environmentally benign production are key drivers for developments in the chemical industrial sector, as protecting our planet has become a significant element that should be considered for every industrial breakthrough or technological advancement. As a result, the concept of green chemistry has been recently defined to guide chemists towards minimizing any harmful outcome of chemical processes in either industry or research. Towards greener reactions, scientists have developed various approaches in order to decrease environmental risks while attaining chemical sustainability and elegancy. Utilizing catalytic nanoreactors for greener reactions, for facilitating multistep synthetic pathways in one-pot procedures, is imperative with far-reaching implications in the field. This review is focused on the applications of some of the most used nanoreactors in catalysis, namely: (polymer) vesicles, micelles, dendrimers and nanogels. The ability and efficiency of catalytic nanoreactors to carry out organic reactions in water, to perform cascade reaction and their ability to be recycled will be discussed. PMID- 29719572 TI - An uracil-linked hydroxyflavone probe for the recognition of ATP. AB - Background: Nucleotides are essential molecules in living systems due to their paramount importance in various physiological processes. In the past years, numerous attempts were made to selectively recognize and detect these analytes, especially ATP using small-molecule fluorescent chemosensors. Despite the various solutions, the selective detection of ATP is still challenging due to the structural similarity of various nucleotides. In this paper, we report the conjugation of a uracil nucleobase to the known 4'-dimethylamino-hydroxyflavone fluorophore. Results: The complexation of this scaffold with ATP is already known. The complex is held together by stacking and electrostatic interactions. To achieve multi-point recognition, we designed the uracil-appended version of this probe to include complementary base-pairing interactions. The theoretical calculations revealed the availability of multiple complex structures. The synthesis was performed using click chemistry and the nucleotide recognition properties of the probe were evaluated using fluorescence spectroscopy. Conclusions: The first, uracil-containing fluorescent ATP probe based on a hydroxyflavone fluorophore was synthesized and evaluated. A selective complexation with ATP was observed and a ratiometric response in the excitation spectrum. PMID- 29719573 TI - Synthesis and in vitro biochemical evaluation of oxime bond-linked daunorubicin GnRH-III conjugates developed for targeted drug delivery. AB - Gonadotropin releasing hormone-III (GnRH-III), a native isoform of the human GnRH isolated from sea lamprey, specifically binds to GnRH receptors on cancer cells enabling its application as targeting moieties for anticancer drugs. Recently, we reported on the identification of a novel daunorubicin-GnRH-III conjugate (GnRH III-[4Lys(Bu), 8Lys(Dau=Aoa)] with efficient in vitro and in vivo antitumor activity. To get a deeper insight into the mechanism of action of our lead compound, the cellular uptake was followed by confocal laser scanning microscopy. Hereby, the drug daunorubicin could be visualized in different subcellular compartments by following the localization of the drug in a time-dependent manner. Colocalization studies were carried out to prove the presence of the drug in lysosomes (early stage) and on its site of action (nuclei after 10 min). Additional flow cytometry studies demonstrated that the cellular uptake of the bioconjugate was inhibited in the presence of the competitive ligand triptorelin indicating a receptor-mediated pathway. For comparative purpose, six novel daunorubicin-GnRH-III bioconjugates have been synthesized and biochemically characterized in which 6Asp was replaced by D-Asp, D-Glu and D-Trp. In addition to the analysis of the in vitro cytostatic effect and cellular uptake, receptor binding studies with 125I-triptorelin as radiotracer and degradation of the GnRH III conjugates in the presence of rat liver lysosomal homogenate have been performed. All derivatives showed high binding affinities to GnRH receptors and displayed in vitro cytostatic effects on HT-29 and MCF-7 cancer cells with IC50 values in a low micromolar range. Moreover, we found that the release of the active drug metabolite and the cellular uptake of the bioconjugates were strongly affected by the amino acid exchange which in turn had an impact on the antitumor activity of the bioconjugates. PMID- 29719575 TI - Bromide-assisted chemoselective Heck reaction of 3-bromoindazoles under high speed ball-milling conditions: synthesis of axitinib. AB - A mechanically-activated chemoselective Heck coupling for the synthesis of 3 vinylindazoles has been developed with the aid of catalytic amounts of TBAB and NaBr as both dehalogenation restrainer and grinding auxiliary. After tuning of the chemical conditions and mechanical parameters, a series of non-activated 3 bromoindazoles and a broad scope of olefins worked well to give the corresponding coupling products in good to excellent yields. A further application of this protocol was performed in a two-step mechanochemical Heck/Migita cross coupling, which provided a highly efficient route for the synthesis of axitinib. PMID- 29719574 TI - Recent advances in synthetic approaches for medicinal chemistry of C-nucleosides. AB - C-nucleosides have intrigued biologists and medicinal chemists since their discovery in 1950's. In that regard, C-nucleosides and their synthetic analogues have resulted in promising leads in drug design. Concurrently, advances in chemical syntheses have contributed to structural diversity and drug discovery efforts. Convergent and modular approaches to synthesis have garnered much attention in this regard. Among them nucleophilic substitution at C1' has seen wide applications providing flexibility in synthesis, good yields, the ability to maneuver stereochemistry as well as to incorporate structural modifications. In this review, we describe recent reports on the modular synthesis of C-nucleosides with a focus on D-ribonolactone and sugar modifications that have resulted in potent lead molecules. PMID- 29719576 TI - Chlorination of phenylallene derivatives with 1-chloro-1,2-benziodoxol-3-one: synthesis of vicinal-dichlorides and chlorodienes. AB - Allyl and vinyl chlorides represent important structural motifs in organic chemistry. Herein is described the chemoselective and regioselective reaction of aryl- and alpha-substituted phenylallenes with the hypervalent iodine (HVI) reagent 1-chloro-1,2-benziodoxol-3-one. The reaction typically results in vicinal dichlorides, except with proton-containing alpha-alkyl substituents, which instead give chlorinated dienes as the major product. Experimental evidence suggests that a radical mechanism is involved. PMID- 29719578 TI - Crystal structure of the inclusion complex of cholesterol in beta-cyclodextrin and molecular dynamics studies. AB - The role of beta-cyclodextrin (beta-CD) in cholesterol removal primarily from mammalian cells and secondly from dairy products has been studied thoroughly in recent years. Although the physicochemical characterization of the inclusion compound of cholesterol in beta-CD has been achieved by various methods, no crystal structure has been determined so far. We report here the crystal structure of the inclusion compound of cholesterol in beta-CD. The inclusion complex crystallizes in the triclinic space group P1 forming head-to-head dimers which are stacked along the c-axis. One well-defined cholesterol molecule 'axially' encapsulated inside the beta-CD dimer and 22 water molecules that stabilize the complexes in the crystalline state comprise the asymmetric unit of the structure. The dimers are arranged in an intermediate (IM) channel packing mode in the crystal. Moreover, MD simulations, at 300 and 340 K, based on the crystallographically determined coordinates of the complex show that the formed cholesterol/beta-CD inclusion compound remains very stable in aqueous solution at both temperatures. PMID- 29719579 TI - One-pot synthesis of diaryliodonium salts from arenes and aryl iodides with Oxone sulfuric acid. AB - A facile synthesis of diaryliodonium salts utilizing Oxone as versatile and cheap oxidant has been developed. This method shows wide applicability and can be used for the preparation of iodonium salts containing electron-donating or electron withdrawing groups in good yields. In addition, this procedure can be applied to the preparation of symmetric iodonium salts directly from arenes via a one-pot iodination-oxidation sequence. PMID- 29719580 TI - A stereoselective and flexible synthesis to access both enantiomers of N acetylgalactosamine and peracetylated N-acetylidosamine. AB - Synthetic approaches towards N-acetylgalactosamine (GalNAc) have been attracting considerable interest since this compound is known for its pivotal role in cell cell interaction and receptor induced cell signaling. Herein, we present a synthetic route in which two of the four stereogenic centers present in the target compound are derived from enantiopure tartaric acid being selectively converted to epoxy alcohols. The key step is the Pd-catalyzed, stereo- and regioselective epoxide opening and subsequent nucleophilic substitution of an azide functionality. This approach enables the synthesis of the naturally D- and unnaturally L-configured GalNAc, as well as both enantiomers of the largely unknown N-acetylidosamine (IdoNAc). PMID- 29719577 TI - Phosphodiester models for cleavage of nucleic acids. AB - Nucleic acids that store and transfer biological information are polymeric diesters of phosphoric acid. Cleavage of the phosphodiester linkages by protein enzymes, nucleases, is one of the underlying biological processes. The remarkable catalytic efficiency of nucleases, together with the ability of ribonucleic acids to serve sometimes as nucleases, has made the cleavage of phosphodiesters a subject of intensive mechanistic studies. In addition to studies of nucleases by pH-rate dependency, X-ray crystallography, amino acid/nucleotide substitution and computational approaches, experimental and theoretical studies with small molecular model compounds still play a role. With small molecules, the importance of various elementary processes, such as proton transfer and metal ion binding, for stabilization of transition states may be elucidated and systematic variation of the basicity of the entering or departing nucleophile enables determination of the position of the transition state on the reaction coordinate. Such data is important on analyzing enzyme mechanisms based on synergistic participation of several catalytic entities. Many nucleases are metalloenzymes and small molecular models offer an excellent tool to construct models for their catalytic centers. The present review tends to be an up to date summary of what has been achieved by mechanistic studies with small molecular phosphodiesters. PMID- 29719582 TI - Platinum-based neoadjuvant chemotherapy in BRCA1-positive breast cancer: a retrospective cohort analysis and literature review. AB - Background: There is increasing evidence of high platinum sensitivity in BRCA associated breast cancer. However, evidence from randomized trials is lacking. The aim of this study was to analyze the results of platinum-based chemotherapy for BRCA1-positive breast cancer in a neoadjuvant setting. Methods: A retrospective study was performed by obtaining information from patient files. The results were compared with the available data from a literature review. Results: Twelve female patients with BRCA1 gene mutations who had stage I to III breast cancers were eligible for evaluation. They received platinum-based neoadjuvant chemotherapy between 2011 and 2016. Eleven patients received a combination of cisplatin and doxorubicin, and one patient received carboplatin and docetaxel. All patients underwent mastectomy after chemotherapy. Ten patients (83%) achieved pathological complete remission (pCR). The observed pCR rate was comparable to existing results found in similar studies. Conclusion: The results of the study confirm the high pCR rate in BRCA1-positive breast cancer after platinum-based neoadjuvant chemotherapy. Larger randomized studies and longer follow-up times are necessary to evaluate the role of platinum-based therapies in BRCA1-positive breast cancer. PMID- 29719581 TI - Adipose tissue inflammation and VDR expression and methylation in colorectal cancer. AB - Background: Lack of vitamin D (VD) has been associated with colorectal cancer (CRC). VD has anti-inflammatory effects and regulates several cellular pathways by means of its receptor, including epigenetic modifications. Adipose tissue dysfunction has been related to low-grade inflammation, which is related to diseases like cancer. The aim of this study was to explore the relationship between serum 25-hydroxyvitamin D (25(OH)D), adipose tissue gene expression of VD receptor (VDR), pro-inflammatory markers, and the epigenetic factor DNA methyltransferase 3a (DNMT3A) as well as VDR promoter methylation in CRC. Methods: Blood and visceral adipose tissue from 57 CRC and 50 healthy control subjects were collected. CRC subjects had lower serum 25(OH)D levels and higher VDR gene expression, and these were negatively correlated in the CRC group. Results: Adipose tissue NFkappaB1, IL6, and IL1B gene expression were higher in the CRC subjects than in the control subjects. 25(OH)D correlated negatively with NFkappaB1 and CRP. In turn, CRP correlated positively with NFkappaB1, IL6, IL1B, and VDR gene expression as well as NFkappaB1 that correlated positively with IL6 and IL1B. DNMT3A mRNA was negatively correlated with serum 25(OH)D and positively correlated with VDR DNA methylation. VDR DNA methylation at position 4 had lower levels in the CRC group. Global NFkappaB1 methylation at dinucleotide 3 was lower in the CRC group. Conclusion: Our results suggest that adipose tissue may be a key factor in CRC development. The low 25(OH)D levels and high adipose tissue VDR expression in CRC may, at least in part, mediate this relationship by modifying adipose tissue DNA methylation and promoting inflammation. PMID- 29719583 TI - A Novel Macroscale Acoustic Device for Blood Filtration. AB - Retransfusion of a patient's own shed blood during cardiac surgery is attractive since it reduces the need for allogeneic transfusion, minimizes cost, and decreases transfusion related morbidity. Evidence suggests that lipid micro emboli associated with the retransfusion of the shed blood are the predominant causes of the neurocognitive disorders. We have developed a novel acoustophoretic filtration system that can remove lipids from blood at clinically relevant flow rates. Unlike other acoustophoretic separation systems, this ultrasound technology works at the macroscale, and is therefore able to process larger flow rates than typical micro-electromechanical system (MEMS) scale acoustophoretic separation devices. In this work, we have first demonstrated the systematic design of the acoustic device and its optimization, followed by examining the feasibility of the device to filter lipids from the system. Then, we demonstrate the effects of the acoustic waves on the shed blood; examining hemolysis using both haptoglobin formation and lactate dehydrogenase release, as well as the potential of platelet aggregation or inflammatory cascade activation. Finally, in a porcine surgical model, we determined the potential viability of acoustic trapping as a blood filtration technology, as the animal responded to redelivered blood by increasing both systemic and mean arterial blood pressure. PMID- 29719584 TI - Drosophila PEBP1 inhibits intestinal stem cell aging via suppression of ERK pathway. AB - The intestine is a high cellular turnover tissue largely dependent on the regenerative function of stem cell throughout life, and a signaling center for the health and viability of organisms. Therefore, better understanding of the mechanisms underlying the regulation of intestinal stem cell (ISC) regenerative potential is essential for the possible intervention of aging process and age related diseases. Drosophila midgut is a well-established model system for studying the mechanisms underlying ISC regenerative potential during aging. Here, we report the requirement of Drosophila phosphatidylethanolamine binding protein 1 (PEBP1) in ISC regenerative potential. We showed that PEBP1 was strongly expressed in enterocytes (ECs) of guts and its decrease with age and oxidative stress. Furthermore, the downregulation of PEBP1 in ECs accelerates ISC aging, as evidenced by ISC hyper-proliferation, gammaH2AX accumulation, and centrosome amplification, and intestinal hyperplasia. The decrease in PEBP1 expression was associated with increased extracellular signal-regulated kinase (ERK) activity in ECs. All these phenotypes by EC-specific depletion of PEBP1 were rescued by the concomitant inhibition of ERK signaling. Our findings evidence that the age related downregulation of PEBP1 in ECs is a novel cause accelerating ISC aging and that PEBP1 is an EC-intrinsic suppressor of epidermal growth factor receptor (EGFR)/ERK signaling. Our study provides molecular insights into the tight regulation of EGFR/ERK signaling in niches for stem cell regenerative potential. PMID- 29719585 TI - Interleukin gene polymorphisms in Chinese Han population with breast cancer, a case-control study. AB - Cytokines are known as important regulators of the cancer involved in inflammatory and immunological responses. This fact and plethora of gene polymorphism data prompted us to investigate IL1 gene polymorphisms in breast cancer (BC) patients. Totally, 530 patients with BC and 628 healthy control women were studied. The genetic polymorphisms for IL1 were analyzed by Massarray Sequencing method. Three single nucleotide polymorphisms (SNPs) identified in IL1B, IL1R1 gene are thought to influence breast cancer risk. The results of the association between IL-1B, IL1R1 polymorphisms and breast cancer risk have significant. We found that the variant TT genotype of rs10490571 was associated with a significantly increased breast cancer risk (TT vs. CC: OR = 2.82, 95% CI = 1.12-7.08, P = 0.047 for the codominant model). For rs16944 (AG vs. GG: OR = 0.60, 95% CI = 0.41-0.90, P = 0.034 for the codominant model) and rs1143623 (CG vs. CC: OR = 0.65, 95% CI = 0.45-0.94, P = 0.023 for the codominant model) have significant associations were found in genetic models. In conclusion, the present analysis suggests a correlation of polymorphic markers within the IL-1 gene locus with the risk in developing breast cancer. Taken together with our finding that IL1B, IL1R1 gene three SNP are also associated with the risk for the disease, we suggest that inflammation via innate and adaptive immunity contributes to multifactorial hereditary predisposition to pathogenesis of the breast cancer. PMID- 29719586 TI - Cold atmospheric plasma as a potential tool for multiple myeloma treatment. AB - Multiple myeloma (MM) is a fatal and incurable hematological malignancy thus new therapy need to be developed. Cold atmospheric plasma, a new technology that could generate various active species, could efficiently induce various tumor cells apoptosis. More details about the interaction of plasma and tumor cells need to be addressed before the application of gas plasma in clinical cancer treatment. In this study, we demonstrate that He+O2 plasma could efficiently induce myeloma cell apoptosis through the activation of CD95 and downstream caspase cascades. Extracellular and intracellular reactive oxygen species (ROS) accumulation is essential for CD95-mediated cell apoptosis in response to plasma treatment. Furthermore, p53 is shown to be a key transcription factor in activating CD95 and caspase cascades. More importantly, we demonstrate that CD95 expression is higher in tumor cells than in normal cells in both MM cell lines and MM clinical samples, which suggests that CD95 could be a favorable target for plasma treatment as it could selectively inactivate myeloma tumor cells. Our results illustrate the molecular details of plasma induced myeloma cell apoptosis and it shows that gas plasma could be a potential tool for myeloma therapy in the future. PMID- 29719587 TI - Expression of HNF4G and its potential functions in lung cancer. AB - The hepatocyte nuclear factor 4 gamma (HNF4G), a member of orphan nuclear receptors, is up-regulated and functions as an oncoprotein in bladder cancer. In the present study, we observed that HNF4G expression was elevated in lung cancer tissues as compared to adjacent normal lung tissues. The expression of HNF4G protein was correlated with the tumor size and the prognosis of patients. Transfection with a small interference RNA (siRNA) targeting HNF4G in two lung cancer cell lines (H358 and H292 cells) significantly inhibited cell proliferation via arresting cells at G1 phase and inducing cell apoptosis. In addition, HNF4G siRNA reduced cell proliferation in a xenograft tumor-bearing model. Moreover, A549 cells, which had relative lower level of HNF4G, were ectopic expressed with HNF4G and treated with an AKT inhibitor (MK-2206). MK-2206 exposure not only attenuated the promoting effects of HNF4G overexpression on cell proliferation and cell cycle progression, but also suppressed the inhibitory effects of HNF4G overexpression on cell apoptosis. These data suggested that AKT signaling pathway was a potential upstream mediator of HNF4G. Collectively, our data indicate that HNF4G exerts as an oncogenic role in lung cancer by promoting cell proliferation and that HNF4G expression is a potential prognosis factor for lung cancer. PMID- 29719588 TI - Effects of repeated sprints training on fracture risk-associated miRNA. AB - Repeated-sprint training (RS, short-duration sprints at supramaximal intensities interspersed with brief recoveries) is a time-saving metabolically effective strategy whose effects on bone are unknown. Bone metabolism is a finely regulated process profoundly affected by exercise as assayable by studying specific systemic (e.g., hormones, cytokines) and bone-derived molecules (e.g., bone markers, miRNAs). Aim of this study was to determine the effect of a 8-week repeated-sprint on circulating levels of fracture risk-associated miRNA. Blood was collected from 9 subjects performing RS 3 times/week (EXP) and 9 age-matched inactive controls (CTRL) before the start of the protocol (T0) and after 4 (T1) and 8 weeks (T2). The relative expression of miR-21-5p, miR-23a-3p, miR-24-3p, miR93-5p, miR-100-5p, miR-122-5p, miR-124-3p, miR-125b-5p, miR-148a-3p, miR-637 was assayed by real-time PCR by the 2 -DeltaDeltaCT method (housekeeping: miR-425 5p, miR-484). Serum concentrations of bone markers (DKK1, sclerostin, osteoprotegerin, osteocalcin, osteopontin), cytokines (IL-1beta, TNFalpha), and metabolic hormones (leptin, insulin, PTH) were assayed by multiplex assay. miR 637 and miR-124-3p were undetectable. In CTRL miRNA levels remained unchanged. In EXP miR-21-5p remained unchanged. Compared to T0 miR-23a-3p and miR-24-3p were significantly decreased at T1 and T2, also compared to CTRL, miR-100 was significantly decreased at T2, miR-122-5p, miR-125-5p, and miR148a-3p were significantly decreased at T1, while miR-93-5p was significantly increased at T1. None of the metabolic hormones was affected by the intervention while, among the bone markers, DKK1, osteocalcin and sclerostin were slightly but significantly decreased. In conclusion, an 8-week repeated-sprint training downregulates the expression of circulating miRNA associated with fracture risk. PMID- 29719589 TI - Combination of interferon-expressing oncolytic adenovirus with chemotherapy and radiation is highly synergistic in hamster model of pancreatic cancer. AB - Recent clinical trials utilizing Interferon-alpha (IFN) in combination with chemoradiation have demonstrated significant improvements in the survival of patients with pancreatic cancer. However, efficacy was limited by the systemic toxicity of IFN and low intratumoral levels of the cytokine. We sought to address these drawbacks by using an Oncolytic Adenovirus expressing IFN (OAd-hamIFN) in combination with chemotherapy and/or radiation in regimens mimicking the IFN based therapies used in clinical trials. IFN expressed from OAd-hamIFN potentiated the cytotoxicity of radiation and chemotherapy (5-FU, Gemcitabine, and Cisplatin), and enhanced pancreatic cancer cell death in both in vitro and in vivo experimental settings. Notably, synergism was demonstrated in therapeutic groups that combined the interferon-expressing oncolytic virus with chemotherapy and radiation. In an in vivo immunocompetent hamster model, treatment regimens combining oncolytic virus therapy with 5-FU and radiation demonstrated significant tumor growth inhibition and enhanced survival. This is the first study to report synergism between an IFN-expressing oncolytic adenovirus and chemoradiation-based therapies. When combined with an IFN-expressing OAd, there is a significant enhancement of radiation and especially chemoradiation, which may broaden the application of this new therapeutic approach to the pancreatic cancer patients who cannot tolerate existing chemotherapy regimens. PMID- 29719590 TI - 2'-Hydroxyflavanone effectively targets RLIP76-mediated drug transport and regulates critical signaling networks in breast cancer. AB - Breast cancer (BC) is the most common cancer in women. Estrogen, epidermal growth factor receptor 2 (ERBB2, HER2), and oxidative stress represent critical mechanistic nodes associated with BC. RLIP76 is a major mercapturic acid pathway transporter whose expression is increased in BC. In the quest of a novel molecule with chemopreventive and chemotherapeutic potential, we evaluated the effects of 2'-Hydroxyflavanone (2HF) in BC. 2HF enhanced the inhibitory effects of RLIP76 depletion and also inhibited RLIP76-mediated doxorubicin transport in BC cells. RNA-sequencing revealed that 2HF induces strong reversal of the gene expression pattern in ER+MCF7, HER2+ SKBR3 and triple-negative MDA-MB-231 BC cells with minimal effects on MCF10A normal breast epithelial cells. 2HF down regulated ERalpha and enhanced inhibitory effects of imatinib mesylate/Gleevec in MCF7 cells. 2HF also down regulated ERalpha and HER2 gene networks in MCF7 and SKBR3 cells, respectively. 2HF activated TP53 and inhibited TGFbeta1 canonical pathway in MCF7 and MDA-MB-231 BC cells. 2HF also regulated the expression of a number of critical prognostic genes of MammaPrint panel and their upstream targets including TP53, CDKN2A and MYC. The collective findings from this study provide a comprehensive, direct and integrated evidence for the benefits of 2HF in targeting major and clinically relevant mechanistic regulators of BC. PMID- 29719591 TI - Acidic bile salts induces mucosal barrier dysfunction through let-7a reduction during gastric carcinogenesis after Helicobacter pylori eradication. AB - Gastric cancer (GC) after eradication for Helicobacter pylori (H.pylori) increases, but its carcinogenesis is not elucidated. It is mainly found in acid non-secretion areas (ANA), as mucosal regeneration in acid secretory areas (AA) after eradication changes the acidity and bile toxicity of gastric juice. We aimed to clarify the role of barrier dysfunction of ANA by the stimulation of pH3 bile acid cocktail (ABC) during carcinogenesis. We collected 18 patients after curative endoscopic resection for GC, identified later than 24 months after eradication, and took biopsies by Congo-red chromoendoscopy to distinguish AA and ANA (UMIN00018967). The mucosal barrier function was investigated using a mini Ussing chamber system and molecular biological methods. The reduction in mucosal impedance in ANA after stimulation was significantly larger than that in AA, 79.6% vs. 87.9%, respectively. The decrease of zonula occludens-1 (ZO-1) and let 7a and the increase of snail in ANA were significant compared to those in AA. In an in vitro study, the restoration of ZO-1 and let-7a as well as the induction of snail were observed after stimulation. High mobility group A2 (HMGA2)-snail activation, MTT proliferation, and cellular infiltration capacity were significantly increased in AGS transfected with let-7a inhibitor, and vice versa. Accordingly, using a mini-Ussing chamber system for human biopsy specimens followed by an in vitro study, we demonstrated for the first time that the exposure of acidic bile salts to ANA might cause serious barrier dysfunction through the let-7a reduction, promoting epithelial-mesenchymal transition during inflammation-associated carcinogenesis even after eradication. PMID- 29719592 TI - EGR1 interacts with TBX2 and functions as a tumor suppressor in rhabdomyosarcoma. AB - EGR1, one of the immediate-early response genes, can function as a tumor suppressor gene or as an oncogene in cancer. The function of EGR1 has not been fully characterized in rhabdomyosarcoma (RMS), a pediatric cancer derived from the muscle linage. We found that EGR1 is downregulated in the alveolar RMS (ARMS) subtype but expressed at levels comparable to normal skeletal muscle in embryonal RMS (ERMS). We found that overexpression of EGR1 in ARMS significantly decreased cell proliferation, mobility, and anchorage-independent growth while also promoting differentiation. We found that EGR1 interacts with TBX2, which we have shown functions as an oncogene in RMS. The interaction inhibits EGR1 dependent gene expression, which includes the cell cycle regulators p21 and PTEN as well as other important cell growth drivers such as NDRG1 and CST6. We also found that EGR1 induced apoptosis by triggering the intrinsic apoptosis pathway. EGR1 also activated two pro-apoptotic factors, BAX and dephosphorylated BAD, which are both located upstream of the caspase cascades in the intrinsic pathway. EGR1 also sensitized RMS cells to chemotherapeutic agents, suggesting that activating EGR1 may improve therapeutic targeting by inducing apoptosis. Our results establish the important role of EGR1 in understanding RMS pathology. PMID- 29719593 TI - Whole exome sequencing identifies mTOR and KEAP1 as potential targets for radiosensitization of HNSCC cells refractory to EGFR and beta1 integrin inhibition. AB - Intrinsic and acquired resistances are major obstacles in cancer therapy. Genetic characterization is commonly used to identify predictive or prognostic biomarker signatures and potential cancer targets in samples from therapy-naive patients. By far less common are such investigations to identify specific, predictive and/or prognostic gene signatures in patients or cancer cells refractory to a specific molecular-targeted intervention. This, however, might have a great value to foster the development of tailored, personalized cancer therapy. Based on our identification of a differential radiosensitization by single and combined beta1 integrin (AIIB2) and EGFR (Cetuximab) targeting in more physiological, three dimensional head and neck squamous cell carcinoma (HNSCC) cell cultures, we performed comparative whole exome sequencing, phosphoproteome analyses and RNAi knockdown screens in responder and non-responder cell lines. We found a higher rate of gene mutations with putative protein-changing characteristics in non responders and different mutational profiles of responders and non-responders. These profiles allow stratification of HNSCC patients and identification of potential targets to address treatment resistance. Consecutively, pharmacological inhibition of mTOR and KEAP1 effectively diminished non-responder insusceptibility to beta1 integrin and EGFR targeting for radiosensitization. Our data pinpoint the added value of genetic biomarker identification after selection for cancer subgroup responsiveness to targeted therapies. PMID- 29719594 TI - Heteronemin, a marine natural product, sensitizes acute myeloid leukemia cells towards cytarabine chemotherapy by regulating farnesylation of Ras. AB - Cytarabine is a conventionally used chemotherapeutic agent for treating acute myeloid leukemia (AML). However, chemoresistance, toxic side-effects and poor patient survival rates retard the efficacy of its performance. The current study deals with the chemosensitization of AML cells using heteronemin, a marine natural product towards cytarabine chemotherapy. Heteronemin could effectively sensitize HL-60 cells towards sub-toxic concentration of cytarabine resulting in synergistic toxicity as demonstrated by MTT assay and [3H] thymidine incorporation studies, while being safe towards healthy blood cells. Flow cytometry for Annexin-V/PI and immunoblotting for caspase cleavage proved that the combination induces enhancement in apoptosis. Heteronemin being a farnesyl transferase inhibitor (FTI) suppressed cytarabine-induced, farnesyl transferase mediated activation of Ras, as assessed by Ras pull-down assay. Upon pre-treating cells with a commercial FTI, L-744,832, the synergism was completely lost in the combination, confirming the farnesyl transferase inhibitory activity of heteronemin as assessed by thymidine incorporation assay. Heteronemin effectively down-regulated cytarabine-induced activation of MAPK, AP-1, NF-kappaB and c-myc, the down-stream targets of Ras signaling, which again validated the role of Ras in regulating the synergism. Hence we believe that the efficacy of cytarabine chemotherapy can be improved to a significant extent by combining sub-toxic concentrations of cytarabine and heteronemin. PMID- 29719595 TI - Proteomic alterations in early stage cervical cancer. AB - Laser capture microdissection (LCM) allows the capture of cell types or well defined structures in tissue. We compared in a semi-quantitative way the proteomes from an equivalent of 8,000 tumor cells from patients with squamous cell cervical cancer (SCC, n = 22) with healthy epithelial and stromal cells obtained from normal cervical tissue (n = 13). Proteins were enzymatically digested into peptides which were measured by high-resolution mass spectrometry and analyzed by "all-or-nothing" analysis, Bonferroni, and Benjamini-Hochberg correction for multiple testing. By comparing LCM cell type preparations, 31 proteins were exclusively found in early stage cervical cancer (n = 11) when compared with healthy epithelium and stroma, based on criteria that address specificity in a restrictive "all-or-nothing" way. By Bonferroni correction for multiple testing, 30 proteins were significantly up-regulated between early stage cervical cancer and healthy control, including six members of the MCM protein family. MCM proteins are involved in DNA repair and expected to be participating in the early stage of cancer. After a less stringent Benjamini-Hochberg correction for multiple testing, we found that the abundances of 319 proteins were significantly different between early stage cervical cancer and healthy controls. Four proteins were confirmed in digests of whole tissue lysates by Parallel Reaction Monitoring (PRM). Ingenuity Pathway Analysis using correction for multiple testing by permutation resulted in two networks that were differentially regulated in early stage cervical cancer compared with healthy tissue. From these networks, we learned that specific tumor mechanisms become effective during the early stage of cervical cancer. PMID- 29719596 TI - The value of whole lesion ADC histogram profiling to differentiate between morphologically indistinguishable ring enhancing lesions-comparison of glioblastomas and brain abscesses. AB - Background: Morphologically similar appearing ring enhancing lesions in the brain parenchyma can be caused by a number of distinct pathologies, however, they consistently represent life-threatening conditions. The two most frequently encountered diseases manifesting as such are glioblastoma multiforme (GBM) and brain abscess (BA), each requiring disparate therapeutical approaches. As a result of their morphological resemblance, essential treatment might be significantly delayed or even ommited, in case results of conventional imaging remain inconclusive. Therefore, our study aimed to investigate, whether ADC histogram profiling reliably can distinguish between both entities, thus enhancing the differential diagnostic process and preventing treatment failure in this highly critical context. Methods: 103 patients (51 BA, 52 GBM) with histopathologically confirmed diagnosis were enrolled. Pretreatment diffusion weighted imaging (DWI) was obtained in a 1.5T system using b values of 0, 500, and 1000 s/mm2. Whole lesion ADC volumes were analyzed using a histogram-based approach. Statistical analysis was performed using SPSS version 23. Results: All investigated parameters were statistically different in comparison of both groups. Most importantly, ADCp10 was able to differentiate reliably between BA and GBM with excellent accuracy (0.948) using a cutpoint value of 70 * 10-5 mm2 * s-1. Conclusions: ADC whole lesion histogram profiling provides a valuable tool to differentiate between morphologically indistinguishable mass lesions. Among the investigated parameters, the 10th percentile of the ADC volume distinguished best between GBM and BA. PMID- 29719597 TI - MicroRNA-193b-3p represses neuroblastoma cell growth via downregulation of Cyclin D1, MCL-1 and MYCN. AB - Neuroblastoma is the most common diagnosed tumor in infants and the second most common extracranial tumor of childhood. The survival rate of patients with high risk neuroblastoma is still very low despite intensive multimodal treatments. Therefore, new treatment strategies are needed. In recent years, miRNA-based anticancer therapy has received growing attention. Advances in this novel treatment strategy strongly depends on the identification of candidate miRNAs with broad-spectrum antitumor activity. Here, we identify miR-193b as a miRNA with tumor suppressive properties. We show that miR-193b is expressed at low levels in neuroblastoma cell lines and primary tumor samples. Introduction of miR 193b mimics into nine neuroblastoma cell lines with distinct genetic characteristics significantly reduces cell growth in vitro independent of risk factors such as p53 functionality or MYCN amplification. Functionally, miR-193b induces a G1 cell cycle arrest and cell death in neuroblastoma cell lines by reducing the expression of MYCN, Cyclin D1 and MCL-1, three important oncogenes in neuroblastoma of which inhibition has shown promising results in preclinical testing. Therefore, we suggest that miR-193b may represent a new candidate for miRNA-based anticancer therapy in neuroblastoma. PMID- 29719598 TI - Hyperandrogenism and insulin resistance contribute to hepatic steatosis and inflammation in female rat liver. AB - Women with polycystic ovary syndrome (PCOS) are at high risk for nonalcoholic fatty liver disease (NAFLD). While insulin resistance is a common trait for both PCOS and NAFLD, hyperandrogenism is also considered to be a key factor contributing to PCOS, and the molecular mechanisms behind the interactions between insulin resistance and hyperandrogenism in the female liver remain largely unexplored. Using chronic treatment with insulin and/or human chorionic gonadotropin (hCG), we showed that all female rats with different treatments induced imbalance between de novo lipogenesis and mitochondrial beta-oxidation via the Pparalpha/beta-Srebp1/2-Acc1 axis, resulting in varying degrees of hepatic steatosis. Given the fact that hepatic lipid metabolism and inflammation are tightly linked processes, we found that hCG-induced hyperandrogenic rats had strongly aggravated hepatic inflammation. Further mechanistic investigations revealed that dysregulation of the IRS-PI3K-Akt signaling axis that integrated aberrant inflammatory, apoptotic and autophagic responses in the liver was strongly associated with hyperandrogenism itself or combined with insulin resistance. Additionally, we found that hCG-treated and insulin+hCG-induced rats developed visceral adipose tissue inflammation characterized by the presence of "crown like" structure and increased inflammatory gene expression. Because a more pronounced hepatic steatosis, inflammatory responses, and hepatocyte cell damage were observed in insulin+hCG-induced PCOS-like rats, our finding suggest that NAFLD seen in PCOS patients is dependent of hyperandrogenism and insulin resistance. PMID- 29719600 TI - Chinese herbal medicine therapy and the risk of mortality for chronic hepatitis B patients with concurrent liver cirrhosis: a nationwide population-based cohort study. AB - Chronic hepatitis B (CHB) is increasingly recognized as a public health problem in Taiwan. After affected patients are diagnosed with contaminant liver cirrhosis (LC), adverse clinical outcomes, especially death, are common. This study aimed to investigate the effect of Chinese herbal medicine (CHM), an essential branch of Traditional Chinese medicine (TCM), on the mortality risk among CHB patients with contaminant LC. This longitudinal cohort study used the Taiwanese National Health Insurance Research Database to identify 1522 patients 20-70 years of age with newly diagnosed CHB with LC during 1998-2007. Among them, 508 (33.37%) had received CHM products after the onset of CHB (CHM users), and the remaining 1014 patients (66.63%) were designated as a control group (non-CHM users). All enrollees were followed until the end of 2012 to determine deaths during the study period. We applied the Cox proportional hazards regression model to compute the hazard ratio for the association of CHM use and the subsequent risk of death. During the follow-up period, 156 CHM users and 493 non-CHM users died. After controlling for potential confounders, CHM users were found to have a significantly reduced risk of death compared with non-CHM users by 56%, and the effect was predominantly observed among those treated with CHM for > 180 days. CHM therapy lowered the risk of death among CHB patients with contaminant LC, which supported CHM might provide further treatment options for those with chronic liver diseases. PMID- 29719599 TI - Fanconi anemia and homologous recombination gene variants are associated with functional DNA repair defects in vitro and poor outcome in patients with advanced head and neck squamous cell carcinoma. AB - Mutations in Fanconi Anemia or Homologous Recombination (FA/HR) genes can cause DNA repair defects and could therefore impact cancer treatment response and patient outcome. Their functional impact and clinical relevance in head and neck squamous cell carcinoma (HNSCC) is unknown. We therefore questioned whether functional FA/HR defects occurred in HNSCC and whether they are associated with FA/HR variants. We assayed a panel of 29 patient-derived HNSCC cell lines and found that a considerable fraction is hypersensitive to the crosslinker Mitomycin C and PARP inhibitors, a functional measure of FA/HR defects. DNA sequencing showed that these hypersensitivities are associated with the presence of bi allelic rare germline and somatic FA/HR gene variants. We next questioned whether such variants are associated with prognosis and treatment response in HNSCC patients. DNA sequencing of 77 advanced stage HNSCC tumors revealed a 19% incidence of such variants. Importantly, these variants were associated with a poor prognosis (p = 0.027; HR = 2.6, 1.1-6.0) but favorable response to high cumulative cisplatin dose. We show how an integrated in vitro functional repair and genomic analysis can improve the prognostic value of genetic biomarkers. We conclude that repair defects are marked and frequent in HNSCC and are associated with clinical outcome. PMID- 29719601 TI - Increased gut permeability in cancer cachexia: mechanisms and clinical relevance. AB - Intestinal disorders often occur in cancer patients, in association with body weight loss, and this alteration is commonly attributed to the chemotherapy. Here, using a mouse model of cancer cachexia induced by ectopic transplantation of C26 cancer cells, we discovered a profound alteration in the gut functions (gut permeability, epithelial turnover, gut immunity, microbial dysbiosis) independently of any chemotherapy. These alterations occurred independently of anorexia and were driven by interleukin 6. Gut dysfunction was found to be resistant to treatments with an anti-inflammatory bacterium (Faecalibacterium prausnitzii) or with gut peptides involved in intestinal cell renewal (teduglutide, a glucagon-like peptide 2 analogue). The translational value of our findings was evaluated in 152 colorectal and lung cancer patients with or without cachexia. The serum level of the lipopolysaccharide-binding protein, often presented as a reflection of the bacterial antigen load, was not only increased in cachectic mice and cancer patients, but also strongly correlated with the serum IL-6 level and predictive of death and cachexia occurrence in these patients. Altogether, our data highlight profound alterations of the intestinal homeostasis in cancer cachexia occurring independently of any chemotherapy and food intake reduction, with potential relevance in humans. In addition, we point out the lipopolysaccharide-binding protein as a new biomarker of cancer cachexia related to gut dysbiosis. PMID- 29719602 TI - Leptin-Notch axis impairs 5-fluorouracil effects on pancreatic cancer. AB - 5-FU chemotherapy is a current strategy to treat pancreatic cancer (PC), but unfortunately chemoresistance is eventually developed in most patients. Obesity is a risk factor for PC that could affect 5-FU effectiveness through the adipokine leptin, which is a known proliferation, survival factor and Notch inducer. We investigated whether leptin signaling affects 5-FU cytotoxicity on PC. To this end, tumorspheres developed from BxPC-3 and MiaPaCa-2 PC cells were treated with 5-FU, leptin, inhibitors for Notch (DAPT) and leptin signaling (IONP LPrA2) and ATP-binding cassette of proteins (Probenecid). Leptin treatment decreased 5-FU cytotoxicity, and increased cell proliferation, colony forming ability, stem cell, pluripotency, EMT markers, drug efflux proteins (ABCC5, ABCC11) and Notch. In addition, leptin reduced the 5-FU effects on apoptosis by decreasing pro-apoptotic (Bax, Caspase-3 activation and PARP degradation) and increasing anti-apoptotic factors (RIP and Bcl-XL). Leptin's effects on PC tumorspheres treated with 5-FU were reduced by IONP-LPrA2 and were mainly Notch signaling- dependent and more evident in MiaPaCa-2-derived tumorspheres. Present results suggest that leptin could impair 5-FU cytotoxicity and promote chemoresistance. Therefore, targeting the leptin-Notch axis could be a novel way to improve 5-FU therapy for PC patients, especially in obesity context. PMID- 29719603 TI - Gefitinib or lapatinib with foretinib synergistically induce a cytotoxic effect in melanoma cell lines. AB - Melanoma is an aggressive cancer type with a high mortality rate and an elevated resistance to conventional treatment. Recently, promising new tools for anti melanoma targeted therapy have emerged including inhibitors directed against frequently overexpressed receptors of growth factors implicated in the progression of this cancer. The ineffectiveness of single-targeted therapy prompted us to study the efficacy of treatment with a combination of foretinib, a MET (hepatocyte growth factor receptor) inhibitor, and gefitinib or lapatinib, EGFR (epidermal growth factor receptor) inhibitors. We observed a synergistic cytotoxic effect for the combination of foretinib and lapatinib on the viability and proliferation of the examined melanoma cell lines. This combination of inhibitors significantly decreased Akt and Erk phosphorylation, while the drugs used independently were insufficient. Additionally, after treatment with pairs of inhibitors, cells became larger, with more pronounced stress fibers and abnormally shaped nuclei. We also noticed the appearance of polyploid cells and massive enrichment in the G2/M phase. Therefore, combination treatment was much more effective against melanoma cells than a single-targeted approach. Based on our results, we conclude that both EGFR and MET receptors might be effective targets in melanoma therapy. However, variation in their levels in patients should be taken into consideration. PMID- 29719604 TI - Influence of aprepitant and localization of the patch on fentanyl exposure in patients with cancer using transdermal fentanyl. AB - Background and Objectives: The cutaneous fentanyl patch is widely used to treat continuous pain in patients with cancer. Its use is hampered by a high inter- and intrapatient pharmacokinetic variability. Factors that influence this pharmacokinetic variability are largely unclear. The aim of these studies was to test if common patient variables, i) the use of the moderate CYP3A4 inhibitor aprepitant and ii) the localization of the fentanyl patch (upper arm versus thorax) influence systemic exposure to fentanyl in patients with cancer using a transdermal fentanyl patch. Results: The AUC0-6 h of fentanyl was 7.1% (95% CI: 28% to +19%) lower if patients concurrently used aprepitant, compared to the period when patients used fentanyl only. The AUC0-4 h of fentanyl was 7.4% (95% CI: -22% to +49%) higher when the cutaneous fentanyl patch was applied to the upper arm compared to application at the thorax. Conclusions: Neither the concurrent use of aprepitant, nor the localization of the fentanyl patch showed a statistically significant influence on fentanyl pharmacokinetics. Methods: We performed two prospective cross-over pharmacokinetic intervention studies. Both studies had two eight-day study periods. At day 8 of each study period blood samples were collected for pharmacokinetic analysis. In each study 14 evaluable patients were included. PMID- 29719605 TI - In vivo safety and efficacy testing of a thermally triggered injectable hydrogel scaffold for bone regeneration and augmentation in a rat model. AB - Bone loss resulting from degenerative diseases and trauma is a significant clinical burden which is likely to grow exponentially with the aging population. In a number of conditions where pre-formed materials are clinically inappropriate an injectable bone forming hydrogel could be beneficial. The development of an injectable hydrogel to stimulate bone repair and regeneration would have broad clinical impact and economic benefit in a variety of orthopedic clinical applications. We have previously reported the development of a Laponite(r) crosslinked pNIPAM-co-DMAc (L-pNIPAM-co-DMAc) hydrogel delivery system, loaded with hydroxyapatite nanoparticles (HAPna), which was capable of inducing osteogenic differentiation of mesenchymal stem cells (MSCs) without the need for additional growth factors in vitro. However to enable progression towards clinical acceptability, biocompatibility and efficacy of the L-pNIPAM-co-DMAc hydrogel to induce bone repair in vivo must be determined. Biocompatibility was evaluated by subcutaneous implantation for 6 weeks in rats, and efficacy to augment bone repair was evaluated within a rat femur defect model for 4 weeks. No inflammatory reactions, organ toxicity or systemic toxicity were observed. In young male rats where hydrogel was injected, defect healing was less effective than sham operated controls when rat MSCs were incorporated. Enhanced bone healing was observed however, in aged exbreeder female rats where acellular hydrogel was injected, with increased deposition of collagen type I and Runx2. Integration of the hydrogel with surrounding bone was observed without the need for delivered MSCs; native cell infiltration was also seen and bone formation was observed within all hydrogel systems investigated. This hydrogel can be delivered directly into the target site, is biocompatible, promotes increased bone formation and facilitates migration of cells to promote integration with surrounding bone, for safe and efficacious bone repair. PMID- 29719606 TI - Proof of concept: prognostic value of the plasmatic concentration of circulating cell free DNA in desmoid tumors using ddPCR. AB - Since desmoid tumors (DT) exhibit an unpredictable clinical course, with stabilization and/or spontaneous regression, an initial "wait-and-see" policy is the new standard of care-thus, the actual challenge is to identify early factors of progression. We present a method of detection of CTNNB1 mutations using a targeted digital droplet PCR (ddPCR) on cell-free DNA (cfDNA) extracted from blood samples of 31 DT patients. Furthermore, we analyzed the correlation between DT evolution and plasmatic concentration of total and mutated cfDNA at the time of diagnosis. Circulating copies of CTNNB1 mutants (ctDNA) were detected in the plasma of 6 patients (33%) but their concentration was not correlated with evolution of the tumor. Concentration of total cfDNA was higher in the plasma of patients with progressive desmoids (p = 0,0009). Using a threshold <900 copies/mL of plasma to detect indolent desmoid and a threshold >1375, it was possible to predict desmoid evolution for 65% of patients by measuring the quantity of circulating DNA in their plasma as early as the time of diagnosis. Albeit showing that the detection of CTNNB1 mutants is possible in the plasma of patients harboring a desmoid tumor, the results of this preliminary study raise the hypothesis that most of the circulating DNA detected in their plasma is derived from non-neoplastic cells, most likely normal neighboring tissues being actively invaded. Our results open the perspective of using cfDNA as a biomarker to predict prognosis at the time of diagnosis and assess tumor dynamics to optimize the treatment strategy. PMID- 29719608 TI - c-Jun-dependent beta3GnT8 promotes tumorigenesis and metastasis of hepatocellular carcinoma by inducing CD147 glycosylation and altering N-glycan patterns. AB - beta3GnT8, a key polylactosamine synthase, plays a vital role in progression of various types of human cancer. The role of beta3GnT8 in hepatocellular carcinoma (HCC) and the underlying mechanisms, however, remain largely unknown. In this study, we found that beta3GnT8 and polylactosamine were highly expressed in HCC tissues compared with those in adjacent paracancer tissues. Overexpression of beta3GnT8 promoted while knockdown of beta3GnT8 inhibited HCC cell invasion and migration in vitro. Importantly, enhanced tumorigenesis was observed in nude mice inoculated with beta3GnT8-overexpressing HCC cells, suggesting that beta3GnT8 is important for HCC development in vitro and in vivo. Mechanistically, beta3GnT8 modulated the N-glycosylation patterns of CD147 and altered the polylactosamine structures in HCC cells by physically interacting with CD147. In addition, our data showed the c-Jun could directly bind to the promoter of beta3GnT8 gene and regulate beta3GnT8 expression. beta3GnT8 regulated HCC cell invasion and migration in a C-Jun-dependent manner. Collectively, our study identified beta3GnT8 as a novel regulator for HCC invasion and tumorigenesis. Targeting beta3GnT8 may be a potential therapeutic strategy against HCC. PMID- 29719607 TI - Endonuclease G promotes mitochondrial genome cleavage and replication. AB - Endonuclease G (EndoG) is a nuclear-encoded endonuclease, mostly localised in mitochondria. In the nucleus EndoG participates in site-specific cleavage during replication stress and genome-wide DNA degradation during apoptosis. However, the impact of EndoG on mitochondrial DNA (mtDNA) metabolism is poorly understood. Here, we investigated whether EndoG is involved in the regulation of mtDNA replication and removal of aberrant copies. We applied the single-cell mitochondrial Transcription and Replication Imaging Protocol (mTRIP) and PCR based strategies on human cells after knockdown/knockout and re-expression of EndoG. Our analysis revealed that EndoG stimulates both mtDNA replication initiation and mtDNA depletion, the two events being interlinked and dependent on EndoG's nuclease activity. Stimulation of mtDNA replication by EndoG was independent of 7S DNA processing at the replication origin. Importantly, both mtDNA-directed activities of EndoG were promoted by oxidative stress. Inhibition of base excision repair (BER) that repairs oxidative stress-induced DNA damage unveiled a pronounced effect of EndoG on mtDNA removal, reminiscent of recently discovered links between EndoG and BER in the nucleus. Altogether with the downstream effects on mitochondrial transcription, protein expression, redox status and morphology, this study demonstrates that removal of damaged mtDNA by EndoG and compensatory replication play a critical role in mitochondria homeostasis. PMID- 29719609 TI - Characterization of a new B-ALL cell line with constitutional defect of the Notch signaling pathway. AB - Notch signaling contribution to B-cell acute lymphoblastic leukemia (B-ALL) development is still under investigation. The serendipitous onset of B-ALL in a patient affected by the germinal Notch mutation-dependent Alagille syndrome allowed us to establish a B-ALL cell line (VR-ALL) bearing a genetic loss of function in components of Notch signaling. VR-ALL is a common-type B-ALL cell line, grows in conventional culture medium supplemented with 10% serum, and gives rise, once injected into immunodeficient NOG mice, to a mouse xenograft model of B-ALL. Exome sequencing revealed deleterious mutations in some components of Notch signaling, including Jagged1, Notch1, and Notch2. In addition, VR-ALL is sensitive both in vitro and in vivo to gamma-secretase inhibitors (GSIs) as well as conventional anti-leukemic drugs. For all these reasons, VR-ALL may help to gain more insights into the role of Notch signaling in B-ALL. PMID- 29719610 TI - A drug combination targeting hypoxia induced chemoresistance and stemness in glioma cells. AB - Hypoxia is a characteristic of solid tumors especially Glioblastoma and is critical to chemoresistance. Cancer stem cells present in hypoxic niches are known to be a major cause of the progression, metastasis and relapse. We tried to identify synergistic combinations of drugs effective in both hypoxia and normoxia in tumor cells as well as in cancer stem cells. Since COX-2 is over-expressed in subset of glioblastoma and is also induced in hypoxia, we studied combinations of a prototype Cyclooxygenase (COX-2) inhibitor, NS-398 with various drugs (BCNU, Temozolomide, 2-Deoxy-D-glucose and Cisplatin) for their ability to abrogate chemoresistance under both severe hypoxia (0.2% O2) and normoxia (20% O2) in glioma cells. The only effective combination was of NS-398 and BCNU which showed a synergistic effect in both hypoxia and normoxia. This synergism was evident at sub-lethal doses for either of the single agent. The effectiveness of the combination resulted from increased pro- apoptotic and decreased anti-apoptotic molecules and increased caspase activity. PGE2 levels, a manifestation of COX-2 activity were increased during hypoxia, but were reduced by the combination during both hypoxia and normoxia. The combination reduced the levels of epithelial-mesenchymal transition (EMT) markers. It also resulted in a greater reduction of cell migration. While single drugs could reduce the number of gliomaspheres, the combination successfully abrogated their formation. The combination also resulted in a greater reduction of the cancer stem cell marker CD133. This combination could be a prototype of possible therapy in a tumor with a high degree of hypoxia like glioma. PMID- 29719611 TI - Inhibition of IRES-dependent translation of caspase-2 by HuR confers chemotherapeutic drug resistance in colon carcinoma cells. AB - HuR plays an important role in tumor cell survival mainly through posttranscriptional upregulation of prominent anti-apoptotic genes. In addition, HuR can inhibit the translation of pro-apoptotic factors as we could previously report for caspase-2. Here, we investigated the mechanisms of caspase-2 suppression by HuR and its contribution to chemotherapeutic drug resistance of colon carcinoma cells. In accordance with the significant drug-induced increase in cytoplasmic HuR abundance, doxorubicin and paclitaxel increased the interaction of cytoplasmic HuR with the 5'untranslated region (5'UTR) of caspase 2 as shown by RNA pull down assay. Experiments with bicistronic reporter genes furthermore indicate the presence of an internal ribosome entry site (IRES) within the caspase-2-5'UTR. Luciferase activity was suppressed either by chemotherapeutic drugs or ectopic expression of HuR. IRES-driven luciferase activity was significantly increased upon siRNA-mediated knockdown of HuR implicating an inhibitory effect of HuR on caspase-2 translation which is further reinforced by chemotherapeutic drugs. Comparison of RNA-binding affinities of recombinant HuR to two fragments of the caspase-2-5'UTR by EMSA revealed a critical HuR-binding site residing between nucleotides 111 and 241 of caspase-2 5'UTR. Mapping of critical RNA binding domains within HuR revealed that a fusion of RNA recognition motif 2 (RRM2) plus the hinge region confers a full caspase-2 5'UTR-binding. Functionally, knockdown of HuR significantly increased the sensitivity of colon cancer cells to drug-induced apoptosis. Importantly, the apoptosis sensitizing effects by HuR knockdown were rescued after silencing of caspase-2. The negative caspase-2 regulation by HuR offers a novel therapeutic target for sensitizing colon carcinoma cells to drug-induced apoptosis. PMID- 29719612 TI - Comprehensive analysis of aberrantly expressed lncRNAs and construction of ceRNA network in gastric cancer. AB - Gastric cancer remains fifth most common cancer often diagnosed at an advanced stage and is the second leading cause of cancer-related death worldwide. Long non coding RNAs (lncRNAs) involved in various cellular pathways are essential for tumor occurrence and progression and they have high potential to promote or suppress the expression of many genes. In this study, we profiled 19 selected cancer-associated lncRNAs in thirty gastric adenocarcinomas and matching normal tissues by qRT-PCR. Our results showed that most of the lncRNAs were significantly upregulated (12/19). Further, we performed bioinformatic screening of miRNAs that share common miRNA response elements (MREs) with lncRNAs and their downstream mRNA targets. The prediction identified three microRNAs (miR-21, miR 145 and miR-148a) and five gastric cancer-specific target genes (EGFR, KLF4, DNMT1 and AGO4) which also showed strong correlation with lncRNAs in regression analysis. Finally, we constructed an integrated lncRNA-miRNA-mRNA interaction network of the candidate genes to understand the post-transcriptional gene regulation. The ceRNA network analysis revealed that the differentially regulated miR-21 and miR-148a were playing as central candidates coordinating sponging activity of the lncRNAs analyzed (H19, TUG1 and MALAT1) in this study and the overexpression of H19 and miR-21 could be a signature event of gastric tumorigenesis that could serve as prognostic indicators and therapeutic targets. PMID- 29719613 TI - A TRPV2 interactome-based signature for prognosis in glioblastoma patients. AB - Proteomics aids to the discovery and expansion of protein-protein interaction networks, which are key to understand molecular mechanisms in physiology and physiopathology, but also to infer protein function in a guilt-by-association fashion. In this study we use a systematic protein-protein interaction membrane yeast two-hybrid method to expand the interactome of TRPV2, a cation channel related to nervous system development. After validation of the interactome in silico, we define a TRPV2-interactome signature combining proteomics with the available physio-pathological data in Disgenet to find interactome-disease associations, highlighting nervous system disorders and neoplasms. The TRPV2 interactome signature against available experimental data is capable of discriminating overall risk in glioblastoma multiforme prognosis, progression, recurrence, and chemotherapy resistance. Beyond the impact on glioblastoma physiopathology, this study shows that combining systematic proteomics with in silico methods and available experimental data is key to open new perspectives to define novel biomarkers for diagnosis, prognosis and therapeutics in disease. PMID- 29719614 TI - The microdomain-organizing protein MPP1 is required for insulin-stimulated activation of H-Ras. AB - Signaling complexes are localized to distinct plasma-membrane domains which undergo precise spatiotemporal regulation. A crucial link between membrane dynamics and the small GTPase, H-Ras, has been suggested, connecting membrane localization, clustering and scaffolding with its activity and signal transduction. Results of this study suggest a relationship between MPP1 and/or MPP1-dependent plasma-membrane organization and H-Ras activation. Namely, we show here that in HEL cells, MPP1 knock-down lead to the disruption of signaling cascade(s) from the activated insulin receptor. The signal inhibition occurred at the level of H-Ras, as it showed impaired GDP-to-GTP exchange and further interaction with its effector molecule, Raf. Moreover, in these cells H-Ras detergent-resistant membrane localization was not sensitive to insulin treatment which may imply molecular mechanism via which MPP1 affects functions of other proteins which may be connected with functional domain formation. Understanding the link between MPP1 and activation of H-Ras, may provide an important insight into the complexity of Ras related signaling pathways which may become a potential target for associated cancer therapies. PMID- 29719615 TI - Identification of spleen tyrosine kinase as a potential therapeutic target for esophageal squamous cell carcinoma using reverse phase protein arrays. AB - The vast majority of esophageal cancers in China, India and Iran are esophageal squamous cell carcinomas (ESCC). A timely diagnosis provides surgical removal as the main therapeutic option for patients with ESCC. Currently, there are no targeted therapies available for ESCC. We carried out reverse phase protein array based protein expression profiling of seven ESCC-derivedcell lines and a non neoplastic esophageal epithelial cell line (Het-1A) to identify differentially expressed proteins in ESCC. SYK non-receptortyrosine kinase was overexpressed in six out of seven ESCC cell lines that were used in the study. We evaluated the role of SYK in ESCC using the pharmacological inhibitor entospletinib (GS-9973) and siRNA-based knock down studies. Entospletinib is a selective inhibitor of SYK, which is currently being evaluated in phase II clinical trials for hematological malignancies. Using in vivo subcutaneous tumor xenografts in mice, we demonstrate that treatment with entospletinib significantly inhibits tumor growth. Further clinical studies are needed to prove the efficacy of entospletinib as a targeted therapeutic agent for treating ESCC. PMID- 29719617 TI - Claudin3 is localized outside the tight junctions in human carcinomas. AB - Claudin3 is an integral component of the tight junction proteins in polarized epithelia. The expression of claudin3 was assessed in epithelial-derived tumors using Oncomine database. To determine the gene alteration during carcinogenesis, copy number alterations and mutations of claudin3 were evaluated using cBioPortal database. Claudin3 is overexpressed in several tumors including gynecological, bladder, breast and prostate carcinomas. 38% of the 163 evaluated studies show mutations and/or amplification of claudin3. 3D reconstruction of tissue samples following immunofluorescence analysis clearly demonstrated that, unlike in healthy tissues, claudin3 is mislocalized and unengaged in the formation of tight junction in tumor samples. These data strongly support the evaluation of unengaged claudin3 as a target for the development of novel diagnostic probes, optical approaches for real time detection of tumoral tissues during surgery, and target therapeutic drugs. PMID- 29719616 TI - Positive selection drives the evolution of endocrine regulatory bone morphogenetic protein system in mammals. AB - The rapid evolution of reproductive proteins might be driven by positive Darwinian selection. The bone morphogenetic protein family is the largest within the transforming growth factor (TGF) superfamily. A little have been known about the molecular evolution of bone morphogenetic proteins exhibiting potential role in mammalian reproduction. In this study we investigated mammalian bone morphogenetic proteins using maximum likelihood approaches of codon substitutions to identify positive Darwinian selection in various species. The proportion of positively selected sites was tested by different likelihood models for individual codon, and M8 were found to be the best model. The percentage of positively elected sites under M8 are 2.20% with omega = 1.089 for BMP2, 1.6% with omega = 1.61 for BMP 4 0.53% for BMP15 with omega = 1.56 and 0.78% for GDF9 with omega = 1.93. The percentage of estimated selection sites under M8 is strong statistical confirmation that divergence of bone morphogenetic proteins is driven by Darwinian selection. For the proteins, model M8 was found significant for all proteins with omega > 1. To further test positive selection on particular amino acids, the evolutionary conservation of amino acid were measured based on phylogenetic linkage among sequences. For exploring the impact of these somatic substitution mutations in the selection region on human cancer, we identified one pathogenic mutation in human BMP4 and one in BMP15, possibly causing prostate cancer and six neutral mutations in BMPs. The comprehensive map of selection results allows the researchers to perform systematic approaches to detect the evolutionary footprints of selection on specific gene in specific species. PMID- 29719618 TI - ONC201 kills breast cancer cells in vitro by targeting mitochondria. AB - We report a novel mechanism of action of ONC201 as a mitochondria-targeting drug in cancer cells. ONC201 was originally identified as a small molecule that induces transcription of TNF-related apoptosis-inducing ligand (TRAIL) and subsequently kills cancer cells by activating TRAIL death receptors. In this study, we examined ONC201 toxicity on multiple human breast and endometrial cancer cell lines. ONC201 attenuated cell viability in all cancer cell lines tested. Unexpectedly, ONC201 toxicity was not dependent on either TRAIL receptors nor caspases. Time-lapse live cell imaging revealed that ONC201 induces cell membrane ballooning followed by rupture, distinct from the morphology of cells undergoing apoptosis. Further investigation found that ONC201 induces phosphorylation of AMP-dependent kinase and ATP loss. Cytotoxicity and ATP depletion were significantly enhanced in the absence of glucose, suggesting that ONC201 targets mitochondrial respiration. Further analysis indicated that ONC201 indirectly inhibits mitochondrial respiration. Confocal and electron microscopic analysis demonstrated that ONC201 triggers mitochondrial structural damage and functional impairment. Moreover, ONC201 decreased mitochondrial DNA (mtDNA). RNAseq analysis revealed that ONC201 suppresses expression of multiple mtDNA encoded genes and nuclear-encoded mitochondrial genes involved in oxidative phosphorylation and other mitochondrial functions. Importantly, fumarate hydratase deficient cancer cells and multiple cancer cell lines with reduced amounts of mtDNA were resistant to ONC201. These results indicate that cells not dependent on mitochondrial respiration are ONC201-resistant. Our data demonstrate that ONC201 kills cancer cells by disrupting mitochondrial function and further suggests that cancer cells that are dependent on glycolysis will be resistant to ONC201. PMID- 29719619 TI - TP-064, a potent and selective small molecule inhibitor of PRMT4 for multiple myeloma. AB - Protein arginine methyltransferase (PRMT) 4 (also known as coactivator-associated arginine methyltransferase 1; CARM1) is involved in a variety of biological processes and is considered as a candidate oncogene owing to its overexpression in several types of cancer. Selective PRMT4 inhibitors are useful tools for clarifying the molecular events regulated by PRMT4 and for validating PRMT4 as a therapeutic target. Here, we report the discovery of TP-064, a potent, selective, and cell-active chemical probe of human PRMT4 and its co-crystal structure with PRMT4. TP-064 inhibited the methyltransferase activity of PRMT4 with high potency (half-maximal inhibitory concentration, IC50 < 10 nM) and selectivity over other PRMT family proteins, and reduced arginine dimethylation of the PRMT4 substrates BRG1-associated factor 155 (BAF155; IC50= 340 +/- 30 nM) and Mediator complex subunit 12 (MED12; IC50 = 43 +/- 10 nM). TP-064 treatment inhibited the proliferation of a subset of multiple myeloma cell lines, with affected cells arrested in G1 phase of the cell cycle. TP-064 and its negative control (TP-064N) will be valuable tools to further investigate the biology of PRMT4 and the therapeutic potential of PRMT4 inhibition. PMID- 29719620 TI - Connective tissue growth factor-specific monoclonal antibody inhibits growth of malignant mesothelioma in an orthotopic mouse model. AB - Malignant mesothelioma is an aggressive neoplasm with no particularly effective treatments. We previously reported that overexpression of connective tissue growth factor (CTGF/CCN2) promotes mesothelioma growth, thus suggesting it as a novel molecular target. A human monoclonal antibody that antagonizes CTGF (FG 3019, pamrevlumab) attenuates malignant properties of different kinds of human cancers and is currently under clinical trial for the treatment of pancreatic cancer. This study reports the effects of FG-3019 on human mesothelioma in vitro and in vivo. We analyzed the effects of FG-3019 on the proliferation, apoptosis, migration/invasion, adhesion and anchorage-independent growth in three human mesothelioma cell lines, among which ACC-MESO-4 was most efficiently blocked with FG-3019 and was chosen for in vivo experiments. We also evaluated the coexistent effects of fibroblasts on mesothelioma in vitro, which are also known to produce CTGF in various pathologic situations. Coexistent fibroblasts in transwell systems remarkably promoted the proliferation and migration/invasion of mesothelioma cells. In orthotopic nude mice model, FG-3019 significantly inhibited mesothelioma growth. Histological analyses revealed that FG-3019 not only inhibited the proliferation but also induced apoptosis in both mesothelioma cells and fibroblasts. Our data suggest that FG-3019 antibody therapy could be a novel additional choice for the treatment of mesothelioma. PMID- 29719621 TI - Histogram analysis of ADC in rectal cancer: associations with different histopathological findings including expression of EGFR, Hif1-alpha, VEGF, p53, PD1, and KI 67. A preliminary study. AB - Functional imaging modalities like Diffusion-weighted imaging are increasingly used to predict tumor behavior like cellularity and vascularity in different tumors. Histogram analysis is an emergent imaging analysis, in which every voxel is used to obtain a histogram and therefore statistically information about tumors can be provided. The purpose of this study was to elucidate possible associations between ADC histogram parameters and several immunhistochemical features in rectal cancer. Overall, 11 patients with histologically proven rectal cancer were included into the study. There were 2 (18.18%) females and 9 males with a mean age of 67.1 years. KI 67-index, expression of p53, EGFR, VEGF, and Hif1-alpha were semiautomatically estimated. The tumors were divided into PD1 positive and PD1-negative lesions. ADC histogram analysis was performed as a whole lesion measurement using an in-house matlab application. Spearman's correlation analysis revealed a strong correlation between EGFR expression and ADCmax (p=0.72, P=0.02). None of the vascular parameters (VEGF, Hif1-alpha) correlated with ADC parameters. Kurtosis and skewness correlated inversely with p53 expression (p=-0.64, P=0.03 and p=-0.81, P=0.002, respectively). ADCmedian and ADCmode correlated with Ki67 (p=-0.62, P=0.04 and p=-0.65, P=0.03, respectively). PD1-positive tumors showed statistically significant lower ADCmax values in comparison to PD1-negative tumors, 1.93 +/- 0.36 vs 2.32 +/- 0.47*10 3mm2/s, p=0.04. Several associations were identified between histogram parameter derived from ADC maps and EGFR, KI 67 and p53 expression in rectal cancer. Furthermore, ADCmax was different between PD1 positive and PD1 negative tumors indicating an important role of ADC parameters for possible future treatment prediction. PMID- 29719622 TI - Glucose transporter 1 expression as a marker of prognosis in oesophageal adenocarcinoma. AB - Background: The current TNM staging system for oesophageal adenocarcinoma (OAC) has limited ability to stratify patients and inform clinical management following neo-adjuvant chemotherapy and surgery. Results: Functional genomic analysis of the gene expression data using Gene Set Enrichment Analysis (GSEA) identified GLUT1 as putative prognostic marker in OAC.In the discovery cohort GLUT1 positivity was observed in 114 patients (80.9%) and was associated with poor overall survival (HR 2.08, 95% CI 1.1-3.94; p=0.024) following multivariate analysis. A prognostic model incorporating GLUT1, CRM and nodal status stratified patients into good, intermediate and poor prognosis groups (p< 0.001) with a median overall survival of 16.6 months in the poorest group.In the validation set 182 patients (69.5%) were GLUT1 positive and the prognostic model separated patients treated with neo-adjuvant chemotherapy and surgery (p<0.001) and surgery alone (p<0.001) into three prognostic groups. Patients and Methods: Transcriptional profiling of 60 formalin fixed paraffin-embedded (FFPE) biopsies was performed. GLUT1 immunohistochemical staining was assessed in a discovery cohort of 141 FFPE OAC samples treated with neo-adjuvant chemotherapy and surgery at the Northern Ireland Cancer Centre from 2004-2012. Validation was performed in 262 oesophageal adenocarcinomas collected at four OCCAMS consortium centres. The relationship between GLUT1 staining, T stage, N stage, lymphovascular invasion and circumferential resection margin (CRM) status was assessed and a prognostic model developed using Cox Proportional Hazards. Conclusions: GLUT1 staining combined with CRM and nodal status identifies a poor prognosis sub-group of OAC patients and is a novel prognostic marker following potentially curative surgical resection. PMID- 29719623 TI - Validation and comparison of two NGS assays for the detection of EGFR T790M resistance mutation in liquid biopsies of NSCLC patients. AB - Analysis of circulating cell-free DNA (cfDNA) derived from peripheral blood ("liquid biopsy") is an attractive alternative to identify non-small cell lung cancer (NSCLC) patients with the EGFR T790M mutation eligible for 3rd generation tyrosine kinase inhibitor therapy. We evaluated two PCR-based next generation sequencing (NGS) approaches, one including unique molecular identifiers (UMI), with focus on highly sensitive EGFR T790M mutation detection. Therefore, we extracted and sequenced cfDNA from synthetic plasma samples spiked with mutated DNA at decreasing allele frequencies and from 21 diagnostic NSCLC patients. Data evaluation was performed to determine the limit of detection (LoD), accuracy, specificity and sensitivity of both assays. Considering all tested reference dilutions and mutations the UMI assay performed best in terms of LoD (1% vs. 5%), sensitivity (95.8% vs. 81.3%), specificity (100% vs. 93.8%) and accuracy (96.9% vs. 84.4%). Comparing mutation status of diagnostic samples with both assays showed 81.3% concordance with primary mutation verifiable in 52% of cases. EGFR T790M was detected concordantly in 6/7 patients with allele frequencies from 0.1% to 27%. In one patient, the T790M mutation was exclusively detectable with the UMI assay. Our data demonstrate that both assays are applicable as multi biomarker NGS tools enabling the simultaneous detection of primary EGFR driver and resistance mutations. However, for mutations with low allelic frequencies the use of NGS panels with UMI facilitates a more sensitive and reliable detection. PMID- 29719624 TI - Distribution of erlotinib in rash and normal skin in cancer patients receiving erlotinib visualized by matrix assisted laser desorption/ionization mass spectrometry imaging. AB - Background: The development of skin rashes is the most common adverse event observed in cancer patients treated with epidermal growth factor receptor tyrosine kinase inhibitors such as erlotinib. However, the pharmacological evidence has not been fully revealed. Results: Erlotinib distribution in the rashes was more heterogeneous than that in the normal skin, and the rashes contained statistically higher concentrations of erlotinib than adjacent normal skin in the superficial skin layer (229 +/- 192 vs. 120 +/- 103 ions/mm2; P = 0.009 in paired t-test). LC-MS/MS confirmed that the concentration of erlotinib in the skin rashes was higher than that in normal skin in the superficial skin layer (1946 +/- 1258 vs. 1174 +/- 662 ng/cm3; P = 0.028 in paired t-test). The results of MALDI-MSI and LC-MS/MS were well correlated (coefficient of correlation 0.879, P < 0.0001). Conclusions: Focal distribution of erlotinib in the skin tissue was visualized using non-labeled MALDI-MSI. Erlotinib concentration in the superficial layer of the skin rashes was higher than that in the adjacent normal skin. Methods: We examined patients with advanced pancreatic cancer who developed skin rashes after treatment with erlotinib and gemcitabine. We biopsied both the rash and adjacent normal skin tissues, and visualized and compared the distribution of erlotinib within the skin using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI). The tissue concentration of erlotinib was also measured by liquid chromatography-tandem mass spectrometry (LC-MS/MS) with laser microdissection. PMID- 29719625 TI - Host chemokine signature as a biomarker for the detection of pre-cancerous cervical lesions. AB - Background: The ability to distinguish which hrHPV infections predispose to significant disease is ever more pressing as a result of the increasing move to hrHPV testing for primary cervical screening. A risk-stratifier or "triage" of infection should ideally be objective and suitable for automation given the scale of screening. Results: CCL2, CCL3, CCL4, CXCL1, CXCL8 and CXCL12 emerged as the strongest, candidate biomarkers to detect underlying disease [cervical intraepithelial neoplasia grade 2 or worse (CIN2+)]. For CIN2+, CCL2 had the highest area under the curve (AUC) of 0.722 with a specificity of 82%. A combined biomarker panel of six chemokines CCL2, CCL3, CCL4, CXCL1, CXCL8, and CXCL12 provides a sensitivity of 71% and specificity of 67%. Conclusion: The present work demonstrates that the levels of five chemokine-proteins are indicative of underlying disease. We demonstrate technical feasibility and promising clinical performance of a chemokine-based biomarker panel, equivalent to that of other triage options. Further assessment in longitudinal series is now warranted. Methods: A panel of 31 chemokines were investigated for expression in routinely taken archived and prospective cervical liquid based cytology (LBC) samples using Human Chemokine Proteomic Array kit. Nine chemokines were further validated using Procartaplex assay on the Luminex platform. PMID- 29719626 TI - Identification of specific and common diagnostic antibody markers for gastrointestinal cancers by SEREX screening using testis cDNA phage library. AB - The present study was planned to identify novel serum antibody markers for digestive organ cancers. We have used screening by phage expression cloning and identified novel fourteen antigens in this experiment. The presence of auto antibodies against these antigens in serum specimens was confirmed by western blotting. As for auto-antibodies against fourteen antigens, AlphaLISA (amplified luminescence proximity homogeneous assay) assay was performed in the sera of gastrointestinal cancers patients to confirm the results. Serum antibody levels against these fourteen recombinant proteins as antigens between healthy donors (HD) and esophageal squamous cell carcinoma (ESCC) patients, gastric cancer (GC), or colon cancer (CC) were compared. The serum levels of all fourteen auto antibodies were significantly higher in ESCC and GC than those of HD. Among those auto-antibodies, except ECSA2 and CCNL2, were also detected significantly higher levels in CC than those of HD. Receiver operating curve (ROC) revealed similar results except CCNL2 in CC. AUC values calculated by ROC were higher than 0.7 in auto-antibodies against TPI1, HOOK2, PUF60, PRDX4, HS3ST1, TUBA1B, TACSTD2, AKR1C3, BAMBI, DCAF15 in ESCC, auto-antibodies against TPI1, HOOK2, PUF60, PRDX4, TACSTD2, AKR1C3, BAMBI, DCAF15 in GC, and auto-antibodies against TPI1, HOOK2, PUF60 in CC. AUC of the combination of HOOK2 and anti-p53 antibodies in ESCC was observed to be as high as 0.8228. Higher serum antibody levels against ten antigens could be potential diagnostic tool for ESCC. Higher serum antibody levels against eight antigens could be potential diagnostic tool for GC, and serum antibody levels against three antigens could be potential diagnostic tool for CC. PMID- 29719627 TI - A comparison of arterial spin labeling and dynamic susceptibility perfusion imaging for resection control in glioblastoma surgery. AB - Resection control using magnetic resonance imaging during neurosurgical interventions increases confidence regarding the extent of tumor removal already during the procedure. In addition to morphological imaging, functional information such as perfusion might become an important marker of the presence and extent of residual tumor mass. The aim of this study was to implement arterial spin labeling (ASL) perfusion imaging as a noninvasive alternative to dynamic susceptibility contrast (DSC) perfusion imaging in patients suffering from intra-axial tumors for resection control already during surgery. The study included 15 patients suffering from glioblastoma multiforme in whom perfusion imaging using DSC and ASL was performed before, during, and after surgery. The data obtained from intraoperative scanning were analyzed by two readers blinded to any clinical information, and the presence of residual tumor mass was evaluated using a ranking scale. Similarity of results was analyzed using the intraclass correlation coefficient and Pearson's correlation coefficient. The results show that intraoperative ASL is as reliable as DSC when performing intraoperative perfusion imaging. According to the results of this study, intraoperative imaging using ASL represents an attractive alternative to contrast agent-based perfusion imaging. PMID- 29719629 TI - Improvement of non-alcoholic steatohepatitis by hepatocyte-like cells generated from iPSCs with Oct4/Sox2/Klf4/Parp1. AB - The prevalence of nonalcoholic fatty liver disease (NAFLD) is usually increased with age. Non-alcoholic steatohepatitis (NASH), a serious form of NAFLD, may lead to cirrhosis and end-stage liver diseases. Induced pluripotent stem cells (iPSCs) hold promising potential in personalized medicine. Although obviation of c-Myc reduces tumorigenic risk, it also largely reduced the generation of iPSCs. Recently, Poly(ADP-ribose) polymerase 1 (Parp1) has been reported to enhance cell reprogramming. In this study, we demonstrated that forced expression of Oct4/Sox2/Klf4/Parp1 (OSKP) effectively promoted iPSC generation from senescent somatic cells from 18-month-old mouse. The iPSCs presented regular pluripotent properties, ability to form smaller teratoma with smaller size, and the potential for tridermal differentiation including hepatocyte-like cells (OSKP-iPSC-Heps). Resembled to fetal hepatocytes but not senescent hepatocytes, these OSKP-iPSC Heps possessed antioxidant ability and were resistant to oxidative insult induced by H2O2 or exogenous fatty acid. Intrasplenic transplantation of OSKP-iPSC-Heps ameliorated the triglyceride over-accumulation and hepatitis, prevented the production of inflammatory cytokines and oxidative substances, and reduced apoptotic cells in methionine/choline-deficient diet (MCDD)-fed mice. In conclusion, we demonstrated that Parp-1 promoted iPSC generation from senescent cells, which can be used for the treatment of NASH after hepatic-specific differentiation. These findings indicated that patient-derived iPSC-Heps may offer an alternative option for treatment of NASH and NASH-associated end-stage liver diseases. PMID- 29719628 TI - Novel water-soluble lignin derivative BP-Cx-1: identification of components and screening of potential targets in silico and in vitro. AB - Identification of molecular targets and mechanism of action is always a challenge, in particular - for natural compounds due to inherent chemical complexity. BP-Cx-1 is a water-soluble modification of hydrolyzed lignin used as the platform for a portfolio of innovative pharmacological products aimed for therapy and supportive care of oncological patients. The present study describes a new approach, which combines in vitro screening of potential molecular targets for BP-Cx-1 using Diversity Profile - P9 panel by Eurofins Cerep (France) with a search of possible active components in silico in ChEMBL - manually curated chemical database of bioactive molecules with drug-like properties. The results of diversity assay demonstrate that BP-Cx-1 has multiple biological effects on neurotransmitters receptors, ligand-gated ion channels and transporters. Of particular importance is that the major part of identified molecular targets are involved in modulation of inflammation and immune response and might be related to tumorigenesis. Characterization of molecular composition of BP-Cx-1 with Fourier Transform Ion Cyclotron Resonance Mass Spectrometry and subsequent identification of possible active components by searching for molecular matches in silico in ChEMBL indicated polyphenolic components, nominally, flavonoids, sapogenins, phenanthrenes, as the major carriers of biological activity of BP-Cx 1. In vitro and in silico target screening yielded overlapping lists of proteins: adenosine receptors, dopamine receptor DRD4, glucocorticoid receptor, serotonin receptor 5-HT1, prostaglandin receptors, muscarinic cholinergic receptor, GABAA receptor. The pleiotropic molecular activities of polyphenolic components are beneficial in treatment of multifactorial disorders such as diseases associated with chronic inflammation and cancer. PMID- 29719630 TI - Genetic susceptibility to bone and soft tissue sarcomas: a field synopsis and meta-analysis. AB - Background: The genetic architecture of bone and soft tissue sarcomas susceptibility is yet to be elucidated. We aimed to comprehensively collect and meta-analyze the current knowledge on genetic susceptibility in these rare tumors. Methods: We conducted a systematic review and meta-analysis of the evidence on the association between DNA variation and risk of developing sarcomas through searching PubMed, The Cochrane Library, Scopus and Web of Science databases. To evaluate result credibility, summary evidence was graded according to the Venice criteria and false positive report probability (FPRP) was calculated to further validate result noteworthiness. Integrative analysis of genetic and eQTL (expression quantitative trait locus) data was coupled with network and pathway analysis to explore the hypothesis that specific cell functions are involved in sarcoma predisposition. Results: We retrieved 90 eligible studies comprising 47,796 subjects (cases: 14,358, 30%) and investigating 1,126 polymorphisms involving 320 distinct genes. Meta-analysis identified 55 single nucleotide polymorphisms (SNPs) significantly associated with disease risk with a high (N=9), moderate (N=38) and low (N=8) level of evidence, findings being classified as noteworthy basically only when the level of evidence was high. The estimated joint population attributable risk for three independent SNPs (rs11599754 of ZNF365/EGR2, rs231775 of CTLA4, and rs454006 of PRKCG) was 37.2%. We also identified 53 SNPs significantly associated with sarcoma risk based on single studies.Pathway analysis enabled us to propose that sarcoma predisposition might be linked especially to germline variation of genes whose products are involved in the function of the DNA repair machinery. Conclusions: We built the first knowledgebase on the evidence linking DNA variation to sarcomas susceptibility, which can be used to generate mechanistic hypotheses and inform future studies in this field of oncology. PMID- 29719631 TI - Preoperative hemoglobin-platelet ratio can significantly predict progression and mortality outcomes in patients with T1G3 bladder cancer undergoing transurethral resection of bladder tumor. AB - Objective: To investigate the prognostic role of hematological biomarkers, especially hemoglobin-platelet ratio (HPR) in the oncological outcomes in stage 1 and grade 3 (T1G3) bladder cancer. Materials and Methods: We identified 457 T1G3 bladder cancer patients who underwent transurethral resection of the bladder (TURB) between 2009 and 2014. Based on hematological parameters (hemoglobin platelet ratio (HPR), hemoglobin, and platelet counts), recurrence-free survival (RFS), progression-free survival (PFS), and overall survival (OS) and cancer specific survival (CSS) were analyzed by using Kaplan-Meier analysis. Multivariate Cox regression model was adopted to identify the predictors of oncological outcomes. Results: Kaplan-Meier survival analysis showed that low HPR (< 0.615), low hemoglobin (< 125g/l) and elevated platelet counts (> 240 * 103/MUl) were correlated with poor OS. Low HPR, but not low hemoglobin and high platelet counts, is associated with worse PFS. Low HPR and low hemoglobin, but not elevated platelet counts, are associated with worse CSS. However, no significant difference was observed in RFS according to any of these hematological markers. On multivariate analysis, low HPR (HR = 1.27, 95% CI = 0.81-1.75, P = 0.030), low hemoglobin (HR = 1.20, 95% CI = 0.79-1.84, P = 0.028) and elevated platelet counts (HR = 1.07, 95% CI = 0.72-1.32, P = 0.038) were significantly associated with OS. Low hemoglobin (HR = 1.08, 95% CI = 0.68-1.82, P = 0.041) was significantly linked with CSS. Particularly, low HPR was identified as an independent predictor of PFS (HR = 1.16, 95% CI = 0.97-1.49, P = 0.033) and CSS (HR = 1.14, 95% CI = 0.87-1.78, P = 0.029). Conclusions: Preoperative HPR can be taken into account as a factor predictive of oncological outcomes for T1G3 bladder cancer, particularly disease progression and mortality outcomes. PMID- 29719632 TI - Molecular mechanism of bystander effects and related abscopal/cohort effects in cancer therapy. AB - Cancer cells subjected to ionizing radiation may release signals which can influence nearby non-irradiated cells, termed bystander effects. The transmission of bystander effects among cancer cells involves the activation of inflammatory cytokines, death ligands, and reactive oxygen/nitrogen species. In addition to bystander effects, two other forms of non-target effects (NTEs) have been identified in radiotherapy, as one is called cohort effects and the other is called abscopal effects. Cohort effects represent the phenomenon where irradiated cells can produce signals that reduce the survival of neighboring cells within an irradiated volume. The effects suggest the importance of cellular communication under irradiation with non-uniform dose distribution. In contrast, abscopal effects describe the NTEs that typically occur in non-irradiated cells distant from an irradiated target. These effects can be mediated primarily by immune cells such as T cells. Clinical trials have shown that application of radiation along with immunotherapy may enhance abscopal effects and improve therapeutic efficacy on non-target lesions outside an irradiated field. According to NTEs, cell viability is reduced not only by direct irradiation effects, but also due to signals emitted from nearby irradiated cells. A clinical consideration of NTEs could have a revolutionary impact on current radiotherapy via the establishment of more efficient and less toxic radiobiological models for treatment planning compared to conventional models. Thus, we will review the most updated findings about these effects and outline their mechanisms and potential applications in cancer treatment with a special focus on the brain, lung, and breast cancers. PMID- 29719634 TI - Intravitreal Injections: A Historic Background. PMID- 29719635 TI - Mean Posterior Corneal Power and Astigmatism in Normal Versus Keratoconic Eyes. AB - Purpose: To compare mean posterior corneal power and astigmatism in normal versus keratoconus affected eyes and determine the optimal cut-off points to maximize sensitivity and specificity in discriminating keratoconus from normal corneas. Methods: A total of 204 normal eyes and 142 keratoconus affected eyes were enrolled in this prospective comparative study. Mean posterior corneal power and astigmatism were measured using a dual Scheimpflug camera. Correlation coefficients were calculated to assess the relationship between the magnitudes of keratometric and posterior corneal astigmatism in the study groups. Receiver operating characteristic curves were used to compare the sensitivity and specificity of the measured parameters and to identify the optimal cut-off points for discriminating keratoconus from normal corneas. Results: The mean posterior corneal power was -6.29 +/- 0.20 D in the normal group and -7.77 +/- 0.87 D in the keratoconus group (P < 0.001). The mean magnitudes of the posterior corneal astigmatisms were -0.32 +/- 0.15 D and -0.94 +/- 0.39 D in the normal and keratoconus groups, respectively (P < 0.001). Significant correlations were found between the magnitudes of keratometric and posterior corneal astigmatism in the normal (r=-0.76, P < 0.001) and keratoconus (r=-0.72, P < 0.001) groups. The mean posterior corneal power and astigmatism were highly reliable characteristics that distinguished keratoconus from normal corneas (area under the curve, 0.99 and 0.95, respectively). The optimal cut-off points of mean posterior corneal power and astigmatism were -6.70 D and -0.54 D, respectively. Conclusion: Mean posterior corneal power and astigmatism measured using a Galilei analyzer camera might have potential in diagnosing keratoconus. The cut-off points provided can be used for keratoconus screening. PMID- 29719633 TI - Molecular mechanisms of long noncoding RNAs and their role in disease pathogenesis. AB - LncRNAs are long non-coding regulatory RNAs that are longer than 200 nucleotides. One of the major functions of lncRNAs is the regulation of specific gene expression at multiple steps including, recruitment and expression of basal transcription machinery, post-transcriptional modifications and epigenetics [1]. Emerging evidence suggests that lncRNAs also play a critical role in maintaining tissue homeostasis during physiological and pathological conditions, lipid homeostasis, as well as epithelial and smooth muscle cell homeostasis, a topic that has been elegantly reviewed [2-5]. While aberrant expression of lncRNAs has been implicated in several disease conditions, there is paucity of information about their contribution to the etiology of diseases [6]. Several studies have compared the expression of lncRNAs under normal and cancerous conditions and found differential expression of several lncRNAs, suggesting thereby an involvement of lncRNAs in disease processes [7, 8]. Furthermore, the ability of lncRNAs to influence epigenetic changes also underlies their role in disease pathogenesis since epigenetic regulation is known to play a critical role in many human diseases [1]. LncRNAs thus are not only involved in homeostatic functioning but also play a vital role in the progression of many diseases, thereby underscoring their potential as novel therapeutic targets for the alleviation of a variety of human disease conditions. PMID- 29719636 TI - Effect of Cycloplegia on Corneal Biometrics and Refractive State. AB - Purpose: To determine changes in refractive state and corneal parameters after cycloplegia with cyclopentolate hydrochloride 1% using a dual Scheimpflug imaging system. Methods: In this prospective cross-sectional study patients aged 10 to 40 years who were referred for optometric evaluation enrolled and underwent autorefraction and corneal imaging with the Galilei dual Scheimpflug system before and 30 minutes after twice instillation of medication. Changes in refraction and astigmatism were investigated. Corneal biometrics including anterior and posterior corneal curvatures, total corneal power and corneal pachymetry were compared before and after cycloplegia. Results: Two hundred and twelve eyes of 106 subjects with mean age of 28 +/- 5 years including 201 myopic and 11 hyperopic eyes were evaluated. Mean spherical equivalent refractive error before cycloplegia was -3.4 +/- 2.6 D. A mean hyperopic shift of 0.4 +/- 0.5 D occurred after cycloplegia (P < 0.001). The astigmatism power did not significantly change (P = 0.8), however, 26.8% of eyes with significant astigmatism experienced a change of more than 5 degrees in the axis of astigmatism. Changes in posterior corneal curvature were scant but statistically significant (P = 0.001). Moreover, corneal thickness was slightly increased in the central and paracentral regions (P < 0.001 and P < 0.001, respectively). Conclusion: Cycloplegia causes a hyperopic shift and astigmatism axis changes, along with an increase in central and paracentral corneal thickness and change in posterior corneal curvature. The effects of cycloplegia on refraction and corneal biometrics should be considered before cataract and refractive surgeries. PMID- 29719637 TI - Histopathological Parameters in Pterygia and Significant Clinical Correlations. AB - Purpose: To evaluate the clinical and histopathological parameters of pterygium to determine significant correlations between parameters that can affect management strategies. Methods: A total of 47 pterygia were clinically examined and excised for histopathological evaluation of epithelial and stromal changes. Some samples were immunostained with P53 (a protein of 53 kilodalton used as dysplastic epithelial marker), CD20 (CD/cluster of differentiation, are group of surface receptors providing targets for cellular immunophenotyping, CD20 as a B lymphocyte marker), CD 3 (as T lymphocyte marker) or vascular endothelial growth factor (VEGF/as vascular marker). Results: Most patients were male (59.6%). Cosmetic complaints (83%), grade II redness (61.7%), grade 2 extension (63.8), and associated astigmatism of <2.5 D (83%) were observed. Histopathological features included solar elastosis (100%), squamous hyperplasia (83%), increased stromal vascularity with hemorrhage (76.6%), and lymphocytic stromal infiltration, perivascular distribution, and mild epithelial lymphocytic exocytosis in 72.3%, 74.5%, and 70.2% of cases, respectively. Other changes included goblet cell hyperplasia (31.9%), prominent epithelial pigmentation (48.9%), and, most importantly, epithelial atypia (53.2%). Clinical redness was significantly correlated with vascularity, epithelial hyperplasia, and lymphocytic stromal infiltration; lymphocytic stromal infiltration was also significantly correlated with pterygium extension and with low astigmatism. Conclusion: The inflammatory response was mild in most cases and the density was not significantly correlated with any clinical parameter. Vascularity was related to clinical redness. Treatment with anti-VEGF may be beneficial, even for grade 1 pterygia that are not dominantly fibrotic. PMID- 29719638 TI - Topical Olopatadine Hydrochloride versus Ketotifen Fumarate for Allergic Conjunctivitis. AB - Purpose: Allergic conjunctivitis (AC) is associated with itching, redness, tearing, pain, and burning sensation in the eyes. The inflammatory process is caused by the mechanism of immediate hypersensitivity due to direct contact with the allergen. This process triggers mast cells in the conjunctiva to activate and release mediators. The purpose of this study was to compare topical olopatadine and ketotifen in terms of effectiveness and safety for the management of AC. Methods: Patients clinically diagnosed with AC were randomized into two groups of 60 patients each and received either topical olopatadine HCl 0.1% or ketotifen fumarate 0.025%. They were followed up on the 4th, 15th, and 30th days to evaluate symptoms, signs, and quality of life (QOL) scoring. Results: There were a total of 120 patients (67 men and 53 women) with a mean age of 36.35 +/- 11 years. Compared to baseline, scores of itching, tearing, redness, eyelid swelling, chemosis and papillae addition of all the individual scores mentioned above and QOL scores reduced significantly (P = 0.001) by the 4th and 15th days of olopatadine and ketotifen application. Compared with ketotifen, olopatadine significantly reduced itching, tearing, hyperemia, and total AC scores by the 4th day (P = 0.001) and conjunctival papillae by the 15th day (P = 0.001). Adverse reactions were reported in 10% and 18% of patients treated with olopatadine and ketotifen, respectively. Conclusion: Compared to ketotifen, olopatadine provided quicker relief of symptoms, and improved symptoms of AC and QOL, with fewer side effects. PMID- 29719639 TI - Retinal Nerve Fiber Layer Changes Following Primary Retinal Detachment Repair with Silicone Oil Tamponade and Subsequent Oil Removal. AB - Purpose: To evaluate the correlation between the retinal nerve fiber layer (RNFL), particularly the temporal RNFL (TRNFL), and visual outcomes following surgery for rhegmatogenous retinal detachment (RRD). Methods: This retrospective study was performed at a tertiary center; 32 patients underwent single and successful vitrectomy for total RRD using silicone oil as tamponade. Data were collected after oil removal. RNFL thickness and central foveal thickness (CFT) were measured using spectral domain optical coherence tomography. RNFL thickness and CFT of normal eyes were acquired as a control to calculate percentage changes in the affected eyes. The correlation between postoperative best-corrected visual acuity (BCVA) and TRNFL changes was the primary outcome measure. Results: Postoperative BCVA correlated negatively with retinal detachment (RD) duration (Pearson coefficient 0.56, P = 0.001) and percentage loss in TRNFL thickness (Pearson Coefficient 0.41, P = 0.02). The macula lost the maximum RNFL thickness (26%). The mean percentage loss of TRNFL was significantly higher in patients with postoperative BCVA <6/60 (42.63% vs. 24.06%, P = 0.009). Patients with postoperative BCVA <6/60 had a significantly longer mean RD duration (29 days) than those with postoperative BCVA >6/60 (17.5 days) (P = 0.026). Conclusion: When eyes with RRD are successfully repaired using silicone oil tamponade, the thickness of the RNFL decreases, particularly in the macula, and less macular neuronal loss is associated with better visual outcomes. PMID- 29719640 TI - Outcomes of Light Silicone Oil Tamponade for Failed Idiopathic Macular Hole Surgery. AB - Purpose: To study the outcomes of redo macular hole surgery using light silicone oil tamponade. Methods: In this study, medical charts of consecutive patients who underwent redo pars plana vitrectomy, extended dye-assisted internal limiting membrane peel, and light silicone oil tamponade for failed previous macular hole surgery (from January 2010 to June 2014) were retrospectively reviewed. Best spectacle corrected visual acuity and anatomical closure rates were regarded as outcome measures. Results: Overall, data from 13 patients was recorded and analyzed. The mean (+/-SD) age of patients was 66 +/- 7 years, and four (30.7%) were male. Mean interval between the primary and redo surgeries was 3.7 +/- 2.0 months (range, 1 to 8 months). During redo surgeries, 11 (84.6%) subjects underwent additional internal limiting membrane peeling. Mean interval between the redo surgery and silicone oil removal was 5.9 +/- 2.1 months (range, 3 to 10 months). After silicone oil removal, patients were followed for 21.8 +/- 14.2 months (range, 3 to 51 months). Mean best spectacle corrected visual acuity improved from 20/452 before redo surgery to 20/121 in the last follow-up examination (P < 0.001). Anatomical success was achieved in 11 (84.6%) patients: nine (69.2%) macular holes were closed and two (15.4%) were flat-open. Conclusions: Redo pars plana vitrectomy with light silicone oil tamponade is an effective method for restoration of macular anatomy and function in patients with persistent macular holes. PMID- 29719641 TI - Patterns of Uveitis at a Tertiary Referral Center in Northeastern Iran. AB - Purpose: To describe the demographic and clinical patterns of patients with uveitis referred to a tertiary center in northeastern Iran. Methods: This cross sectional retrospective study included 235 patients with uveitis who had been referred to the uveitis clinic of Khatam-Al-Anbia eye hospital, affiliated to Mashhad University of Medical Sciences, from February 2013 to March 2014. Data regarding patient age, sex, anatomical location of the disease, and etiologic and clinical features were analyzed. Results: Mean patient age at the onset of uveitis was 35.75 +/- 16.3 (range: 3-82) years. The ratio of females to males was 1.5 to 1. Sixty-four percent had bilateral involvement. The predominant type of inflammation was non-granulomatous (76%). Panuveitis (46.8%, 110 cases) was the most common form of uveitis followed by anterior (37%, 87 cases), intermediate (11.9%, 28 cases), and posterior uveitis (4.25%, 10 cases). The most common diagnoses were "idiopathic" in anterior and intermediate uveitis cases, toxoplasmosis in posterior uveitis group, and Behcet and Vogt-Koyanagi-Harada diseases in panuveitis cases. Overall, noninfectious causes (80.42%) of uveitis were more frequent than infectious causes (19.57%). The proportion of noninfectious uveitis was 82.75% in anterior uveitis, 78.18% in panuveitis, 92.85% in intermediate uveitis, and 50% in posterior uveitis. The most common associated systemic disease was Behcet disease. Conclusion: In contrast to most epidemiologic studies of uveitis, the clinical and etiologic patterns of uveitis were different in a tertiary referral center in northeastern Iran. Panuveitis was the most common clinical pattern in this study, and the most common associated systemic disease was Behcet disease. PMID- 29719642 TI - OCT Based Macular Thickness in a Normal Indian Pediatric Population. AB - Purpose: Cirrus optical coherence tomography (OCT) provides high resolution cross sectional images of the retina, vitreous humor, and optic nerve head with an axial resolution of 5 MUm and a reproducibility of 1.6 MUm. An integrated normative database is available only for adult subjects >=18 years of age; the normal reference ranges of the macular thicknesses of pediatric subjects are not available. The purpose of this study was to determine the normal reference range of macular thickness of pediatric. Methods: A total of 340 eyes of 170 children 5 17 years of age were recruited for this study. Participants received a full ophthalmic examination including a vision assessment, cycloplegic refraction, fundus examination, intraocular pressure measurement, assessment of ocular motility, and alignment. Macular thickness measurements were obtained through dilated pupils using Cirrus HD-OCT. Results: The mean macular thickness was 114.88 +/- 14.74 in the right eye and 113.99 +/- 15.62 in the left eye (P = 0.589). On further evaluation, macular thickness was highest in the inner macula, followed by the outer macula and central fovea (P < 0.001). Conclusion: The normative data of macular thickness in pediatric subjects 5-17 years of age will help diagnose macular disorders. PMID- 29719643 TI - Quantitative Analysis of Macular Thickness following Open Globe Injury in Subjects with Clear Media and no Retinal Damage. AB - Purpose: To evaluate the change in macular thickness after open globe injury (OGI) in patients with clear media and without retinal damage using optical coherence tomography (OCT). Methods: In this longitudinal observational pilot study, 17 patients with clear media and without retinal damage who underwent repair of OGI for corneal, corneoscleral, or scleral laceration were studied. In addition to routine follow-up, all patients were examined at the first and third postoperative months and best corrected visual acuity (BCVA), slit-lamp examination, applanation tonometry, dilated fundus examinations, and macular OCT scans were documented. Results: In all patients, no signs of macular edema, macular thickening, cystic changes, or other signs of cystoid macular edema were present in OCT images and examinations. The Early Treatment Diabetic Retinopathy Study map indicated that there were no significant differences in macular thickness between the first and third months in all patients (P > 0.05). There was no significant relationship between macular thickness and uveal or vitreous prolapse and the size or site of laceration (P > 0.05). BCVA in the first and third months also showed no significant change (P > 0.05). There were no cases of intraocular pressure increase in any of the patients. Conclusion: Macular thickness had no significant change following OGI repair in eyes with clear media and without retinal damage; thus, it seems that OGI of this extent and its surgical repair have no effect on macular thickness. PMID- 29719644 TI - Contrast Sensitivity Abnormalities in Deaf Individuals. AB - Purpose: Hearing impaired children are heavily dependent on their sense of vision to develop efficient communication skills; any contrast sensitivity defect can negatively impact their lives because they are not able to use auditory stimuli to recognize probable dangers in the world around them. The purpose of this study was to determine the contrast sensitivity abnormalities in deaf individuals. Methods: In this cross-sectional study, contrast sensitivity of 15- to 20-year old high-school boys with hearing disability from Tehran, Iran were evaluated. Sixty-four eyes were tested for contrast sensitivity and refractive error. All subjects had an intelligence quotient (IQ) >70. We investigated their contrast sensitivity with Vector vision CVS-1000 in 4 different spatial frequencies. Results: Profound hearing loss was noted in 50% of the subjects. The frequency of contrast sensitivity abnormalities in 4 different spatial frequencies varied between 51.6% and 65.6%. The largest abnormalities were recorded at 18 cycles per degree. Only 12.5% of deaf students had corrected distance visual acuity (CDVA) greater than zero (in LogMAR). The abnormalities in contrast sensitivity showed no correlation with the type or severity of hearing loss. Conclusion: Hearing impaired boys are at a greater risk for contrast sensitivity abnormalities than boys with normal hearing. The larger frequency of contrast sensitivity abnormalities in high spatial frequencies than in other frequencies may demonstrate greater defects in the central visual system compared with the periphery in individuals with hearing loss. PMID- 29719646 TI - Intraocular Pressure Fluctuation: Is It Important? AB - Elevated intraocular pressure (IOP) is a major risk factor for the development and progression of glaucoma. Previous prospective, randomized, long-term studies have demonstrated the strength of IOP reduction in slowing the progression of disease. It is well known that IOP is not a fixed value but fluctuates considerably over time. Although there have been some studies on IOP fluctuation and the progression of glaucoma, whether IOP fluctuation is an independent risk factor for glaucomatous damage and disease progression remains controversial. In this article, we reviewed the definition of IOP fluctuation, and both the evidence and the speculation for and against the effect of IOP fluctuation on glaucoma progression. Although conclusions seem to vary from study to study, we considered that different studies examined different groups of patients, at different stages of disease, and at different IOP levels. Our conclusion is that these apparently disparate results are not conflicting, but rather can be viewed as complementary. In clinical care, we recommend the consideration of IOP "modulation" rather than just IOP "reduction" when glaucoma patients are treated. Quality-based IOP control may be more effective than quantity-based IOP reduction to prevent or retard disease progression. PMID- 29719647 TI - Common Orbital Infections ~ State of the Art ~ Part I. AB - Infections of the orbit and periorbita are relatively frequent, and can cause significant local and systemic morbidity. Loss of vision occurs in more than 10% of patients, and systemic sequelae can include meningitis, intracranial abscess, and death. Numerous organisms infect the orbit, but the most common are bacteria. There are many methods through which orbital infections occur, with infection from the neighboring ethmoid sinuses the most likely cause for all age groups. Prompt management is essential in suspected orbital cellulitis, and involves urgent intravenous antibiotics, rehydration, and treatment of any co-existent underlying systemic disease, e.g., diabetes, renal failure. This review summarizes the common infectious processes of the orbit in both pediatric and adult groups. We review pathophysiology, symptoms, signs, and treatment for infectious orbital processes. PMID- 29719649 TI - A Case of Post Encephalitic Optic Neuritis: Clinical Spectrum, Differential Diagnosis and Management. AB - Purpose: Most cases of optic neuritis are idiopathic or are associated with multiple sclerosis. We present a case in which a young female developed post infectious left optic neuritis following herpes simplex encephalitis (HSE). Case Report: A 24-year-old female presented with a severe headache, fever, and malaise of a one-week duration. Viral encephalitis was diagnosed and treated; intravenous acyclovir (750 mg every 8 h) was administered for 14 days. The patient improved clinically and was prescribed oral valacyclovir (1,000 mg, three times daily) for an additional 3 months as an outpatient. The patient presented again four weeks after the initial admission with left periocular pain and other typical manifestations of optic neuritis. We diagnosed post-infectious left optic neuritis following viral encephalitis. Corticosteroid therapy with 250 mg intravenous methylprednisolone every 6 hours was initiated and the patient showed rapid significant recovery. Conclusion: This case report highlights the patient's clinical course and includes a brief history of the systemic effects of HSE, as well as the pathophysiology, management, and differential diagnosis of post encephalitic optic neuritis. We suggest that clinicians should routinely perform an ophthalmologic examination during the follow-up visits of such patients. PMID- 29719648 TI - Rare Orbital Infections ~ State of the Art ~ Part II. AB - Infections of the orbit and periorbita are relatively frequent. Identifying unusual organisms is crucial because they can cause severe local and systemic morbidity, despite their rarity. Opportunistic infections of the orbit should be considered mainly in debilitated or immunocompromised patients. The key to successful management includes a high index of suspicion, prompt diagnosis, and addressing the underlying systemic disease. This review summarizes unusual infectious processes of the orbit, including mycobacterial, fungal, and parasitic infections, as well as their pathophysiology, symptoms, signs, and treatment. PMID- 29719645 TI - Intravitreal Injection of Anti-vascular Endothelial Growth Factor Agents for Ocular Vascular Diseases: Clinical Practice Guideline. AB - Purpose: To provide the clinical recommendations for the administration of intravitreal anti-vascular endothelial growth factor (VEGF) drugs especially bavacizumab for ocular vascular diseases including diabetic macular edema, neovascular age-related macular degeneration, myopic choroidal neovascularization, retinal vein occlusion and central serous chorioretinopathy. Methods: Twenty clinical questions were developed by the guideline technical committee. Relevant websites and databases were searched to find out the pertinent clinical practice guidelines to answer the questions. The technical committee provided possible answers (scenarios) according to the available evidences for each question. All scenarios along with their levels of evidence and the supported articles were sent to the experts for external review. If the experts did not agree on any of the scenarios for one particular clinical question, the technical committee reviewed all scenarios and their pertinent evidences and made the necessary decision. After that, the experts were asked to score them again. All confirmed scenarios were gathered as the final recommendations. Results: All the experts agreed on at least one of the scenarios. The technical committee extracted the agreed scenario for each clinical question as the final recommendation. Finally, 56 recommendations were developed for the procedure of intravitreal anti-VEGF injection and their applications in the management of ocular vascular diseases. Conclusion: The implementation of this guideline can standardize the management of the common ocular vascular diseases by intravitreal injection of anti-VEGF agents. It can lead to better policy-making and evidence-based clinical decision by ophthalmologists and optimal evidence based eye care for patients. PMID- 29719650 TI - Intraocular Lens Calcification: Clinico-pathological Report of Two Cases and Literature Review. AB - Purpose: We report the clinicopathological features and surgical outcomes of two cases of intraocular lens (IOL) calcification along with a review of the current literature. Case Report: The first patient was a 53-year-old woman with diabetes mellitus (type 2) who underwent phacoemulsification with posterior chamber IOL insertion (PCIOL), and pars plana vitrectomy. Significant clouding of the IOL was first noted after 1.5 years, and the IOL was replaced with an Artisan lens. The second patient was a 22-year-old woman with Vogt-Koyanagi-Harada syndrome; she underwent a lensectomy, PCIOL, and pars plana vitrectomy. IOL opacification was first noted 4.5 years after the initial surgery and the IOL was extracted. Conclusion: The calcification of each IOL was confirmed by a pathologist. Further studies are required to determine the primary causes and mechanisms of the calcification of biomaterials including IOLs. PMID- 29719651 TI - Combined Tenonplasty and Scleral Graft for Refractory Pseudomonas Scleritis Following Pterygium Removal with Mitomycin C Application. AB - Purpose: To report a surgical approach combining scleral patch graft and tenonplasty for successful management of refractory Pseudomonas scleritis following pterygium removal with mitomycin C application. Case Report: A 75-year old diabetic woman with a history of prior pterygium excision and mitomycin C application developed infectious necrotizing scleritis caused by Pseudomonas aeruginosa. Owing to progression of scleritis despite medical management, the patient underwent surgery. Intraoperatively, extensive scleral ischemia was noted. Therefore, debridement of the necrotic tissue, scleral graft, tenonplasty to bring blood vessels to the ischemic sclera, and amniotic membrane transplantation were performed. Postoperatively, no signs of ischemia or recurrence of infection were observed. During 6 months of follow-up, the patient achieved complete restoration of the globe integrity with a non-inflamed ocular surface. Conclusion: Through restoration of blood supply to the ischemic sclera, tenonplasty is an effective adjunctive procedure in addition to conventional scleral patch graft for the treatment of refractory Pseudomonas scleritis associated with ischemia. PMID- 29719652 TI - Simultaneous Unilateral Presentation of Three Different Ocular Manifestations of Granulomatosis with Polyangiitis. AB - Purpose: To report the simultaneous presentation of three ocular manifestations of granulomatosis with polyangiitis in one eye. Case Report: A 42-year-old man with a confirmed diagnosis of granulomatosis with polyangiitis was referred to the emergency room with sudden blurred vision. Eye examination showed hyperemic conjunctiva due to necrotizing scleritis in the superior nasal quadrant of the left eye, a mass in the left superior lid, as well as central retinal artery occlusion in the same eye. Conclusion: This case suggests that unilateral eye involvement may be a manifestation of underlying granulomatosis with polyangiitis. PMID- 29719653 TI - Scheimpflug-based Optical Densitometry for Assessment of Corneal Opacity: An Objective Method to Monitor Interstitial Keratitis. PMID- 29719654 TI - Successful Management of Proliferative Diabetic Retinopathy and Multiple Choroidal Tubercles in a Patient with Miliary Tuberculosis. PMID- 29719655 TI - VSX1 and SOD1 Mutation Screening in Patients with Keratoconus. PMID- 29719656 TI - Author's Reply. PMID- 29719657 TI - Comparative study of semen traits and histomorphometric features of testes of broiler breeder males with different phenotypic traits. AB - Fertility reduction due to sub-fertile males is a major concern in breeder flocks. Phenotypic traits of broiler breeder males and their relationships with fertility can be used as reliable indicators for identification and removal of sub-fertile males from the breeder flocks. This study was conducted to investigate semen traits (semen volume, sperm motility, sperm viability and sperm count) and testes histomorphometric features including tubule differentiation index (TDI), spermiation index (SPI), Sertoli cell index (SCI) and mitotic index (MI) of broiler breeder males with the same age but different phenotypic traits. According to phenotypic traits, 12 broiler breeder males (Ross-308 strain) were classified into three equal groups. Group 1: roosters with fertile phenotypic traits (fertile), group 2: roosters with the lowest fertile phenotypic traits (sub-fertile) and group 3: roosters with moderate fertile phenotypic traits (moderate). The results confirmed potential relationship between phenotypic traits and fertility in broiler breeder males. Semen traits and histomorphometric features of broiler breeder males' testis of the group 3 were more similar to those of the fertile roosters. Therefore, it can be concluded that exclusion of these roosters from the breeder flock may have undesirable effects on flock fertility. PMID- 29719658 TI - Occurrence and potential causative factors of immune-mediated hemolytic anemia in cattle and river buffaloes. AB - The main objectives of this study were to determine the occurrence and potential causative factors of Immune-mediated hemolytic anemia (IMHA) in native cattle and water buffaloes from southwest of Iran. Fifty-three anemic animals (37 cattle and 16 buffaloes) were studied. A full clinical history and physical examinations were undertaken for all animals. Four clinically healthy cattle and four healthy buffaloes were also used as control animals. Blood samples were subjected to a complete blood count, Coombs' test, erythrocyte osmotic fragility test and serum biochemical analysis. IMHA was diagnosed in 12 (32.43%) cattle and 6 (37.50%) buffaloes based on the Coombs' test. Underlying or concurrent diseases, including theileriosis, anaplasmosis, vaccination, and pneumonia were detected in 11 cattle and four buffaloes. Primary or idiopathic IMHA was identified in one cattle and two buffaloes that their Coombs' test was positive. Hematologic and biochemical findings in the cattle with IMHA included a nonregenerative anemia, leukopenia, thrombocytopenia, increased osmotic fragility, hyperbilirubinemia and elevated serum alkaline phosphatase, aspartate aminotransferase and lactate dehydrogenase activities. It can be concluded that IMHA occurs in a significant proportion of anemic cattle and river buffaloes in southwest of Iran. The occurrence of IMHA in both cattle and buffaloes is mostly secondary to infectious diseases especially theileriosis and anaplasmosis. Clarification of the mechanisms of primary or idiopathic and secondary IMHA in cattle and buffaloes require further studies. PMID- 29719660 TI - Evaluation of matrix metalloproteinases (MMP)-2 and MMP-9 activity in serum and biochemical and hematological parameters in spontaneous canine cutaneous tumors before and after surgical treatment. AB - Recently, matrix metalloproteinases (MMP), in particular the gelatinases MMP-2 and MMP-9, generally considered as tumor markers for clinical applications. A longitudinal 2-years follow-up survey was performed on dogs with cutaneous tumor. Serum samples were obtained from 22 dogs with different cutaneous tumors and 22 health dogs at the time of surgery and one month, three months and one year after surgery. Gelatin zymography, hematological and biochemical assessment were performed for all serum samples. The serum alkaline phosphatase activity in dogs with malignant tumors was significantly higher than that in dogs with benign tumors and control cases. Latent forms of MMP-2 and MMP-9 were detected in all of the tumor cases. Gelatin zymography showed active form of MMP-9 in 12 cases (three benign and nine malignant tumors) and active form of MMP-2 in one fibrosarcoma case. Serum activity of active-MMP-9 and total MMP-9 was significantly higher in dogs with cutaneous tumors than those in controls. Tumor cases had higher serum activity of active-MMP-9 rather than controls. MMPs and alkaline phosphatase activities in serum were decreased significantly after surgery. Only one case with perianal gland adenoma showed recurrence of tumor four months after surgery in which active form of MMP-9 had identified one month before recurrence. According to the findings, it will be useful to measure ALP, MMP-2 and MMP-9 activities in the serum of dogs with cutaneous tumor for determination of tumor behavior before surgical treatment. PMID- 29719659 TI - A methodological approach for production and purification of polyclonal antibody against dog IgG. AB - Antibodies are a class of biomolecules that has an important role in the immune system and lots of applications in biotechnological methods and in pharmaceutics. Production and purification of antibodies in laboratory animals is one of the first ways to manufacture of these prominent tools. The obtained antibodies from these process could be used in various types of bioassay techniques such as enzyme linked immunosorbent assay (ELISA), radioimmunoassay, etc. Also, antibodies employed in diagnostics applications in humans and other animals in order to detect specific antigens. In this study, we aimed to produce and purify anti-dog IgG via immunizing rabbits with dog IgG in combination with Freund's adjuvant. Polyclonal IgG were purified by ion exchange chromatography and then the purified antibody was labeled with horse radish peroxidase (HPR). Direct ELISA was used to determine the optimum titer and cross-reactivity of HRP conjugated IgG. The purity of various IgG preparations and the optimum dilution of prepared HRP conjugated IgG, respectively, was about 95.00% and 1:8000. This study showed that efficiency ion-exchange chromatography could be an appropriate method for purification of IgG antibodies. This antibody could be a useful tool for future dog immune diagnosis tests. This product characterization shown here sets the foundations for future work on dog IgGs. PMID- 29719661 TI - Protective effects of Nigella sativa on synaptic plasticity impairment induced by lipopolysaccharide. AB - In the present study the protective effect of Nigella sativa (N. sativa) on synaptic plasticity impairment induced by lipopolysaccharide (LPS) in rats was investigated. Fifty-eight rats were grouped and treated as follows: 1) control (saline), 2) LPS, 3) LPS-N. sativa, and 4) N. sativa. In a Morris water maze test, the escape latency and traveled path to find the platform as well as time spent and the traveled distance in target quadrant (Q1) were measured. Long term potentiation (LTP) from CA1 area of hippocampus followed by high frequency stimulation to Schafer collateral was studied and slope, slope 10-90% and amplitude of field excitatory field potential (fEPSP) were calculated. The escape latency and traveled path in LPS group were significantly higher than those in the control group while, in LPS-N. sativa group these parameters were significantly lower than those in LPS group. The rats in LPS group spent less time and traveled shorter distance in Q1 than the rats in the control group while, in LPS-N. sativa group the rats spent more time and traveled longer distance than the rats in LPS group. LPS significantly decreased slope, slope 10 90% and amplitude of fEPSP while, in LPS-N. sativa group these parameters increased compared to LPS group. The results indicated that the hydro-alcohol extract of N. sativa protected against synaptic plasticity and spatial learning and memory impairment induced by LPS in rats. PMID- 29719663 TI - Effect of different corn processing methods on enzyme producing bacteria, protozoa, fermentation and histomorphometry of rumen in fattening lambs. AB - The purpose of this study was to investigate the effect of different corn processing methods on rumen microbial flora, histomorphometry and fermentation in fattening male lambs. Twenty male lambs (average age and weight of 90 days and 25.00 +/- 1.10 kg, respectively) were used in a completely randomized design including four treatments and five replicates each over 80 days long period: 1) Lambs fed ground corn seeds; 2) Lambs fed steam-rolled corn; 3) Lambs fed soaked corn seeds (24 hr) and 4) Lambs fed soaked corn seeds (48 hr). At the end of the experiment, three lambs of each treatment were slaughtered and samples were collected for pH, volatile fatty acids, amylolytic, proteolytic, cellulytic and heterophilic bacteria and protozoa assessment. The number of proteolytic bacteria in soaked corn seeds was significantly increased in comparison with other treatments. The thickness of wall, papillae and muscular layers of rumen in the soaked corn seeds treatment was significantly increased. Overall, from a practical point of view, soaked corn processing could be generally used in lambs fattening system. PMID- 29719662 TI - Antioxidant effects of Spirulina platensis (Arthrospira platensis) on cyclophosphamide-induced testicular injury in rats. AB - Cyclophosphamide (CP) is known to reduce fertility. The protective effects of Spirulina plantesis (SP) against CP-induced testicular toxicity were investigated. Male Wistar rats were categorized into eight groups (n = 7). Four groups of rats were administered CP at a dose of 5 mg in 5 mL distilled water kg 1 per day orally. Two of these groups were received SP (500 and 1000 mg kg-1 per day) orally after CP administration. One of these groups was also received vitamin E (100 mg kg-1 per day) intraperitoneally. A vehicle treated control group, two SP control groups (500 and 1000 mg kg-1 per day) and a vitamin E control group were also included. Body and testes weights, sperm count, serum levels of glutathione peroxidase (GPx), malondialdehyde (MDA), histological and histomorphometric alternations in testes were investigated after four weeks. The CP-treated group exhibited significant decreases in the body and testes weights and spermatogenic activities. Several histological alterations were observed in this group. The CP treatment caused a significant reduction in sperm count, in serum level of GPx, as well increased serum concentration of MDA. The SP co administration caused an increase in GPx serum level, a decrease in MDA serum level and improvements in histological and histomorphometric alternations. Vitamin E co-treatment showed partial recovery in above-mentioned parameters. These results suggest that SP due to a reduction in oxidative stress has more effective protection against CP-induced reproductive damages in rat than vitamin E. PMID- 29719664 TI - Indigestible neutral detergent fibers: Relationship between forage fragility and neutral detergent fibers digestibility in total mixed ration and some feedstuffs in dairy cattle. AB - Indigestible neutral detergent fibers (iNDF) accurately predict forage digestibility when measured in situ. The objective of this study was to determine the effects of rumen incubation times on the estimated concentrations of iNDF for four forages (alfalfa hay, corn silage, wheat straw and orchard grass), four concentrates (barley grain, soybean meal, beet pulp and wheat bran) and two total mixed ration samples in dairy cows. The iNDF contents of the samples were evaluated in 10 feeds using three ruminally cannulated Holstein cows in a completely randomized design. Five grams of the samples were incubated up to 240 hr. The iNDF fraction was significantly affected by incubation time for all of the tested samples, but the potentially digestible NDF fraction (pdNDF) was not affected for wheat straw, barley grain and wheat bran (32.32, 10.11 and 20.60 g per 100 g of dry matter, respectively). For most of concentrates feedstuffs, the iNDF fraction could be measured after 120 hr of incubation, while for forages ruminal incubation should be lasted up to 240 hr. Statistically significant differences (p < 0.01) were observed between forage samples regarding fragility and NDF digestibility (NDFD). Also, a positive correlation was observed between fragility and NDFD. In some of the cases, it appears that NDFD can be a more helpful index in adjusting pdNDF values than direct fragility measurements. PMID- 29719665 TI - Effect of lysophosphatidic acid on the follicular development and the expression of lysophosphatidic acid receptor genes during in vitro culture of mouse ovary. AB - Lysophosphatidic acid (LPA) known as a serum-derived growth factor, is involved in several cell physiological functions in the female reproductive system including: oocyte maturation, in vitro fertilization and embryo implantation by its transmembrane G protein-coupled receptors. The aim of the present study was to examine the effect of LPA on in vitro follicular development of mouse ovarian tissue. Neonatal mouse ovarian tissues were cultured in five different concentrations of LPA (0, 5, 10, 20 and 40 uM). The developmental competence and the function of cultured ovarian tissue were assessed by morphological study using hematoxylin and eosin staining and hormonal analysis. The expression of LPA receptor (LPAR 1-4) genes were analyzed by real-time RT-PCR. The proportion of preantral follicles and the level of E2 hormone were significantly higher in the 20 uM LPA-treated group than those in the other treatment groups. There was a significant difference in the expression of LPAR 1-4 genes in 20 uM LPA treated group in comparison with 0 uM LPA (control group) treated and non-cultured groups. In addition, the expression of LPAR1 gene was higher than other receptor genes in all studied groups. In conclusion supplementation of the media with 20 uM LPA, could improve the survival and developmental potential of follicles and it had positive effects on cell function and stimulation of E2 synthesis in mouse whole ovarian tissues. PMID- 29719666 TI - Production of a monoclonal antibody against chicken immunoglobulin G: A valuable molecule with research and diagnostic applications. AB - Monoclonal antibodies (MAbs) are invaluable molecules which have several advantages over polyclonal immunoglobulins (Igs) including consistency and higher specificity and hence can be used in biological researches, diagnosis and treatment of diseases. The present study was conducted to produce monoclonal antibody against chicken IgG. The IgG molecules were purified from chicken serum and used as antigens to immunize several mice. Thereafter, a well-immunized mouse was chosen and used for fusion process. After production of hybridoma cells, several rounds of cloning were carried out and produced MAbs were examined by various immunological assays including enzyme-linked immunosorbent assay (ELISA) and western and dot blotting. Assessment of grown hybridomas indicated that only one clone (5B8) has produced desired MAb against chicken IgG. Meanwhile, using an indirect ELISA, it was shown that this MAb successfully recognizes chicken IgG molecules attached to influenza virus nucleoprotein. Evaluation of cross reactivity of MAb 5B8 with several avian serum samples revealed that this molecule specifically identifies chicken antibody molecules. However, it also recognized turkey antibodies with less affinity. In addition to research applications like isolation and purification of chicken and turkey IgG molecules, such a MAb can be applied to design and development of various immunoassays (e.g. ELISA) in these avian species. PMID- 29719667 TI - Effects of chitosan edible coating containing grape seed extract on the shelf life of refrigerated rainbow trout fillet. AB - In recent years, use of edible coatings as carriers of food additives and antimicrobial compounds has been considered in fishery products. This study was carried out to evaluate the effects of 2.00% chitosan coating singly and combined with 0.10% grape seed extract (GSE) on microbial (mesophils and psychrophils counts), chemical (thiobarbituric acid; TBA), pH and peroxide value (PV) and sensorial properties of rainbow trout fillet stored at 4 degrees C over a period of 15 days. The coating had a significant effect in reducing aerobic mesophilic and psychrophilic bacteria counts. The TBA, PV and pH of samples of chitosan coating alone and with GSE were lower than control ones indicating a significant influence of coating on fillet shelf-life. Moreover, chitosan coating represented an equal sensorial quality with controls. It can be concluded that chitosan coating containing GSE can help to maintain the sensorial quality and increase the shelf-life of rainbow trout fillets at refrigerated conditions. PMID- 29719668 TI - Molecular detection and identification of Giardia duodenalis in cattle of Urmia, northwest of Iran. AB - Giardia duodenalis is one of the most prevalent intestinal protozoa infecting humans and domestic animals. The aim of this study was to identify subspecies of G. duodenalis by polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) method from fecal samples of naturally infected cattle in the Urmia, West Azerbaijan province, Iran. Overall, 246 fecal specimens were collected from the cattle (diarrheic and healthy) and microscopically examined for G. duodenalis. The PCR-RFLP analysis of glutamate dehydrogenase (gdh) locus was used to identify the genotypes found in cattle. In this method, 432 bp expected size was amplified and then specific restriction NlaIV enzyme was used for subspecies detection. Totally, 23 (9.34%) specimens were microscopically positive for giardia cyst out of 246 examined samples. The PCR-RFLP analysis revealed that 19 samples (82.60%) have the genotype E and 4 samples (17.39%) belong to the subgroup AI. Our findings indicated that G. duodenalis infection is prevalent in cattle of Urmia and the non-zoonotic genotype E predominates in cattle in this region. PMID- 29719669 TI - Effects of blastocyst artificial collapse prior to vitrification on hatching and survival rates and the expression of klf4 gene in mouse embryos. AB - Although the rate of blastocysts implantation of embryos is higher than previous stages but their survival rate is lower than them, which could be attributed to the completely filled blastocoel cavity with liquid and increased possibility of the formation of ice crystals. This liquid could prevent the penetration of cryoprotecting materials into the embryos. In this study, we reduced the volume of blastocoel before vitrification and compared survival rate and quality of in vitro embryos through klf4 gene expression with control group. In vitro mouse blastocysts were divided into three groups. In group 1, the blastocoel volume of blastocysts were reduced before vitrification and warming. In group 2, blastocysts were just vitrified and warmed and the blastocysts of group 3 (control group) were not undergone any specific treatment and were not vitrified. The expression of klf4 gene was assessed using real-time PCR technique. Data were statistically analyzed using one-way ANOVA and Duncan's post hoc tests. Our results showed that blastocoel volume reduction before vitrification significantly increased the hatching rate of the blastocysts from the zona pellucida and klf4 gene expression compared to vitrified group. Blastocoel volume reduction before vitrification could be used as an efficient method for improving the rate of in vitro fertilization. PMID- 29719670 TI - Prevalence of avian metapneumovirus subtype B in live bird market in Gilan province, Iran. AB - Avian metapneumovirus (aMPV), also known as avian pneumovirus or turkey rhinotracheitis virus, is the causative agent of turkey rhinotracheitis and swollen head syndrome in chickens. Four aMPV subgroups (A-D) have been reported previously based on their genetic and antigenic differences. Evidence suggests that the live bird markets (LBMs) play an important role in the epidemiology of the avian viral diseases. A total number of 450 oropharyngeal samples from eight different species of birds (migratory and local) were collected from LBMs of Gilan province, Iran, from October to December 2016. The presence of aMPV was determined by reverse transcription polymerase chain reaction (RT-PCR) based on nucleoprotein gene. The aMPV was detected in 30.60% of the examined birds including chickens (37.00%), turkey (33.00%), Eurasian teal (25.00%), common blackbird (33.00%), and Eurasian woodcock (25.00%). Bioinformatics analysis and a phylogenetic tree based on partial nucleotide sequences of the N gene showed that the detected aMPVs were belonged to subtype B. This is the first report of aMPV in non-commercial birds in Iran. Knowledge of the frequency and types of infected birds with pneumoviruses allow a better understanding of the epidemiology of aMPV in Iran. PMID- 29719673 TI - Anomalous effect of non-alternant hydrocarbons on carbocation and carbanion electronic configurations. AB - Carbocations are widely viewed to be closed-shell singlet electrophiles. Here, computations show that azulenyl-substituted carbocations have triplet ground states. This triplet ground state for azulenyl carbocations stands in striking contrast to the isomeric naphthenyl carbocation, which is a normal closed-shell singlet with a large singlet-triplet gap. Furthermore, substitution of the azulenyl carbocation can substantially alter the energy gap between the different electronic configurations and can manipulate the ground state towards either the singlet or the triplet state depending on the nature and location of the substituent. A detailed investigation into the origin of this spin state reversal, including NICS calculations, structural effects, substitution patterns, orbital analysis, and detailed linear free-energy relationships allowed us to distill a set of principles that caused these azulenyl carbocations to have such low-lying diradical states. The fundamental origin of this effect mostly centers on singlet state destabilization from increasing antiaromatic character, in combination with a smaller, but important, Baird triplet state aromatic stabilization. We find that azulene is not unique, as extension of these principles allowed us to generate simple rules to predict an entire class of analogous non-alternant carbocation and carbanion structures with low-energy or ground state diradical states, including a purely hydrocarbon triplet cation with a large singlet-triplet gap of 8 kcal mol-1. Although these ions have innocuous looking Lewis structures, these triplet diradical ions are likely to have substantially different reactivity and properties than typical closed-shell singlet ions. PMID- 29719672 TI - Abnormal coherence and sleep composition in children with Angelman syndrome: a retrospective EEG study. AB - Background: Angelman syndrome (AS) is a neurodevelopmental disorder characterized by intellectual disability, speech and motor impairments, epilepsy, abnormal sleep, and phenotypic overlap with autism. Individuals with AS display characteristic EEG patterns including high-amplitude rhythmic delta waves. Here, we sought to quantitatively explore EEG architecture in AS beyond known spectral power phenotypes. We were motivated by studies of functional connectivity and sleep spindles in autism to study these EEG readouts in children with AS. Methods: We analyzed retrospective wake and sleep EEGs from children with AS (age 4-11) and age-matched neurotypical controls. We assessed long-range and short range functional connectivity by measuring coherence across multiple frequencies during wake and sleep. We quantified sleep spindles using automated and manual approaches. Results: During wakefulness, children with AS showed enhanced long range EEG coherence across a wide range of frequencies. During sleep, children with AS showed increased long-range EEG coherence specifically in the gamma band. EEGs from children with AS contained fewer sleep spindles, and these spindles were shorter in duration than their neurotypical counterparts. Conclusions: We demonstrate two quantitative readouts of dysregulated sleep composition in children with AS-gamma coherence and spindles-and describe how functional connectivity patterns may be disrupted during wakefulness. Quantitative EEG phenotypes have potential as biomarkers and readouts of target engagement for future clinical trials and provide clues into how neural circuits are dysregulated in children with AS. PMID- 29719671 TI - Delineation of the genetic and clinical spectrum of Phelan-McDermid syndrome caused by SHANK3 point mutations. AB - Background: Phelan-McDermid syndrome (PMS) is a neurodevelopmental disorder characterized by psychiatric and neurological features. Most reported cases are caused by 22q13.3 deletions, leading to SHANK3 haploinsufficiency, but also usually encompassing many other genes. While the number of point mutations identified in SHANK3 has increased in recent years due to large-scale sequencing studies, systematic studies describing the phenotype of individuals harboring such mutations are lacking. Methods: We provide detailed clinical and genetic data on 17 individuals carrying mutations in SHANK3. We also review 60 previously reported patients with pathogenic or likely pathogenic SHANK3 variants, often lacking detailed phenotypic information. Results: SHANK3 mutations in our cohort and in previously reported cases were distributed throughout the protein; the majority were truncating and all were compatible with de novo inheritance. Despite substantial allelic heterogeneity, four variants were recurrent (p.Leu1142Valfs*153, p.Ala1227Glyfs*69, p.Arg1255Leufs*25, and c.2265+1G>A), suggesting that these are hotspots for de novo mutations. All individuals studied had intellectual disability, and autism spectrum disorder was prevalent (73%). Severe speech deficits were common, but in contrast to individuals with 22q13.3 deletions, the majority developed single words, including 41% with at least phrase speech. Other common findings were consistent with reports among individuals with 22q13.3 deletions, including hypotonia, motor skill deficits, regression, seizures, brain abnormalities, mild dysmorphic features, and feeding and gastrointestinal problems. Conclusions: Haploinsufficiency of SHANK3 resulting from point mutations is sufficient to cause a broad range of features associated with PMS. Our findings expand the molecular and phenotypic spectrum of PMS caused by SHANK3 point mutations and suggest that, in general, speech impairment and motor deficits are more severe in the case of deletions. In contrast, renal abnormalities associated with 22q13.3 deletions do not appear to be related to the loss of SHANK3. PMID- 29719674 TI - Cation-pi interactions in protein-ligand binding: theory and data-mining reveal different roles for lysine and arginine. AB - We have studied the cation-pi interactions of neutral aromatic ligands with the cationic amino acid residues arginine, histidine and lysine using ab initio calculations, symmetry adapted perturbation theory (SAPT), and a systematic meta analysis of all available Protein Data Bank (PDB) X-ray structures. Quantum chemical potential energy surfaces (PES) for these interactions were obtained at the DLPNO-CCSD(T) level of theory and compared against the empirical distribution of 2012 unique protein-ligand cation-pi interactions found in X-ray crystal structures. We created a workflow to extract these structures from the PDB, filtering by interaction type and residue pKa. The gas phase cation-pi interaction of lysine is the strongest by more than 10 kcal mol-1, but the empirical distribution of 582 X-ray structures lies away from the minimum on the interaction PES. In contrast, 1381 structures involving arginine match the underlying calculated PES with good agreement. SAPT analysis revealed that underlying differences in the balance of electrostatic and dispersion contributions are responsible for this behavior in the context of the protein environment. The lysine-arene interaction, dominated by electrostatics, is greatly weakened by a surrounding dielectric medium and causes it to become essentially negligible in strength and without a well-defined equilibrium separation. The arginine-arene interaction involves a near equal mix of dispersion and electrostatic attraction, which is weakened to a much smaller degree by the surrounding medium. Our results account for the paucity of cation pi interactions involving lysine, even though this is a more common residue than arginine. Aromatic ligands are most likely to interact with cationic arginine residues as this interaction is stronger than for lysine in higher polarity surroundings. PMID- 29719675 TI - Near infrared two-photon-excited and -emissive dyes based on a strapped excited state intramolecular proton-transfer (ESIPT) scaffold. AB - Fluorophores that can undergo excited-state intramolecular proton transfer (ESIPT) represent promising scaffolds for the design of compounds that show red shifted fluorescence. Herein, we disclose new near infrared-emissive materials based on a dialkylamine-strapped 2,5-dithienylpyrrole as an ESIPT scaffold. The introduction of electron-accepting units to the terminal positions of this scaffold generates acceptor-pi-donor-pi-acceptor (A-pi-D-pi-A) type pi-conjugated compounds. Following the ESIPT, the electron-donating ability of the core scaffold increases, which results in a substantially red-shifted emission in the NIR region, while increasing the oscillator strength. The electron-accepting units play a vital role to achieve intense and red-shifted emission from the ESIPT state. The strapped dialkylamine chain that forms an intramolecular hydrogen bond is also essential to induce the ESIPT. Moreover, an extended A-pi-D pi-A skeleton enables two-photon excitation with the NIR light. One of the derivatives that satisfy these features, i.e., borylethenyl-substituted 5, exhibited an intense NIR emission in polar solvents such as acetone (lambdaem = 708 nm, PhiF = 0.55) with a strong two-photon-absorption band in the NIR region. PMID- 29719677 TI - Investigation of excited state, reductive quenching, and intramolecular electron transfer of Ru(ii)-Re(i) supramolecular photocatalysts for CO2 reduction using time-resolved IR measurements. AB - Supramolecular photocatalysts in which Ru(ii) photosensitizer and Re(i) catalyst units are connected to each other by an ethylene linker are among the best known, most effective and durable photocatalytic systems for CO2 reduction. In this paper we report, for the first time, time-resolved infrared (TRIR) spectra of three of these binuclear complexes to uncover why the catalysts function so efficiently. Selective excitation of the Ru unit with a 532 nm laser pulse induces slow intramolecular electron transfer from the 3MLCT excited state of the Ru unit to the Re unit, with rate constants of (1.0-1.1) * 104 s-1 as a major component and (3.5-4.3) * 106 s-1 as a minor component, in acetonitrile. The produced charge-separated state has a long lifetime, with charge recombination rate constants of only (6.5-8.4) * 104 s-1. Thus, although it has a large driving force (-DeltaG0CR ~ 2.6 eV), this process is in the Marcus inverted region. On the other hand, in the presence of 1-benzyl-1,4-dihydronicotinamide (BNAH), reductive quenching of the excited Ru unit proceeds much faster (kq[BNAH (0.2 M)] = (3.5-3.8) * 106 s-1) than the abovementioned intramolecular oxidative quenching, producing the one-electron-reduced species (OERS) of the Ru unit. Nanosecond TRIR data clearly show that intramolecular electron transfer from the OERS of the Ru unit to the Re unit (kET > 2 * 107 s-1) is much faster than from the excited state of the Ru unit, and that it is also faster than the reductive quenching process of the excited Ru unit by BNAH. To measure the exact value of kET, picosecond TRIR spectroscopy and a stronger reductant were used. Thus, in the case of the binuclear complex with tri(p-fluorophenyl)phosphine ligands (RuRe(FPh)), for which intramolecular electron transfer is expected to be the fastest among the three binuclear complexes, in the presence of 1,3-dimethyl-2 phenyl-2,3-dihydro-1H-benzo[d]imidazole (BIH), kET was measured as kET = (1.4 +/- 0.1) * 109 s-1. This clearly shows that intramolecular electron transfer in these RuRe binuclear supramolecular photocatalysts is not the rate-determining process in the photocatalytic reduction of CO2, which is one of the main reasons why they work so efficiently. PMID- 29719676 TI - Absolute and relative facial selectivities in organocatalytic asymmetric chlorocyclization reactions. AB - Though (DHQD)2PHAL-catalyzed chlorocyclizations of 1,1-disubstituted olefins show useful (and in some cases, reversible) asymmetric induction, stereochemically complete descriptions of these alkene additions have remained largely unknown. Herein, based on a combination of NMR, derivative, isotope labeling, and computational studies, we present detailed stereochemical analyses of chlorocyclizations of nucleophile-tethered 1,1-disubstituted styryl systems. The selectivities of the two asymmetric bond-forming processes, namely electrophilic chlorine attack and nucleophilic ring closure, are thus mapped out independently. Under the established optimal conditions, four related chlorocyclizations were subjected to this analysis. All showed a strong preference for Cl+ delivery from the same face of the alkene. However, depending on reaction conditions and substrate identity (carboxylic acid, amide or carbamate), the internal nucleophiles may close with a strong net preference for either syn or anti addition relative to the Cl atom. Studies of both uncatalyzed and (DHQD)2PHAL catalyzed processes place new boundary conditions on the role of the catalyst in these reactions. PMID- 29719679 TI - Monitoring the dynamic photocatalytic activity of single CdS nanoparticles by lighting up H2 nanobubbles with fluorescent dyes. AB - The capability of semiconductor nanomaterials to convert solar energy to chemical energy has led to many promising applications, for instance, photocatalyzed H2 generation. Studying this important photocatalytic reaction at the single nanocatalyst level provides a great opportunity to understand the microscopic reaction kinetics and mechanism by overcoming the chemical and structural heterogeneity among individuals. Here we report a fluorescence (FL) labeling strategy to visualize individual H2 nanobubbles that are generated at single CdS nanoparticles during photocatalysis. In operando imaging of nanobubble growth kinetics allows for determination of the photocatalytic activity of single nanocatalysts, which was found to randomly alternate among high activity, low activity and inactive states. In addition to H2 nanobubbles, the present labeling strategy is also suitable for other types of gas nanobubbles. Since nanomaterial catalyzed gas generation is widely involved in many important photochemical (water splitting), electrochemical (electrolysis) and chemical (nanomotors) reactions, the present work is promising for the general applicability of single nanoparticle catalysis in broad basic and industrial fields by lighting up nanobubbles under commercial and conventional FL microscopes. PMID- 29719678 TI - Direct catalytic enantioselective amination of ketones for the formation of tri- and tetrasubstituted stereocenters. AB - Herein, we report a Zn-ProPhenol catalyzed direct asymmetric amination reaction of unactivated aryl and vinyl ketones using di-tert-butyl azodicarboxylate as a cheap and practical electrophilic nitrogen source. Importantly, this methodology works with both alpha-branched and unbranched ketones for the construction of tri and tetrasubstituted N-containing stereocenters. The reaction can be run at gram scale with low catalyst loadings and features a recoverable and reusable ligand. Finally, the enantioenriched hydrazine products can be readily converted into versatile building blocks such as alpha-amino carbonyl compounds and beta-amino alcohols. PMID- 29719680 TI - Synthesis of stable polymetalated aromatic complexes through metal-macrocycle capsule-triggered cyclization. AB - Polymetalated aromatic compounds are of great interest because of their intermediate roles in many organic transformations. However, they are elusive and synthetically challenging. In this study, a dynamic coordination capsule constructed by a flexible macrocycle and silver(i) ions is applied to trigger one step or cascade cyclization reactions for various alkyne substrates, finally leading to five unprecedented polysilver heteroaromatic intermediates (including indole, quinoline, benzocarbazole and 2,2'-biindole). The acquired heteroaromatic species is doubly charged, particularly at vicinal positions, and each is surrounded by a tetrasilver aggregate. The metal-macrocycle capsule holds a great potential of flexibly adjusting its conformation to adapt different polysilver heteroaromatic species. DFT calculations further reveal that metal-perturbed aromaticity and multi-centered bonding both contribute to stabilization of the polysilver heteroaromatic complexes. PMID- 29719681 TI - Tuning protein folding in lysosomal storage diseases: the chemistry behind pharmacological chaperones. AB - Misfolding of proteins is the basis of several proteinopathies. Chemical and pharmacological chaperones are small molecules capable of inducing the correct conformation of proteins, thus being of interest for human therapeutics. The most recent developments in medicinal chemistry and in the drug development of pharmacological chaperones are discussed, with focus on lysosomal storage diseases. PMID- 29719682 TI - Quantified structural speciation in self-sorted CoII6L4 cage systems. AB - The molecular components of biological systems self-sort in different ways to function cooperatively and to avoid interfering with each other. Understanding the driving forces behind these different sorting modes enables progressively more complex self-assembling synthetic systems to be designed. Here we show that subtle ligand differences engender distinct M6L4 cage geometries - an S4 symmetric scalenohedron, or pseudo-octahedra having T point symmetry. When two different ligands were simultaneously employed during self-assembly, a mixture of homo- and heteroleptic cages was generated. Each set of product structures represents a unique sorting regime: biases toward specific geometries, preferential incorporation of one ligand over another, and the amplification of homoleptic products were all observed. The ligands' geometries, electronic properties, and flexibility were found to influence the sorting regime adopted, together with templation effects. A new method of using mass spectrometry to quantitatively analyse mixtures of self-sorted assemblies was developed to assess individual outcomes. Product distributions in complex, dynamic mixtures were thus quantified by non-chromatographic methods. PMID- 29719683 TI - Supramolecular scaffolds enabling the controlled assembly of functional molecular units. AB - To assemble functional molecular units into a desired structure while controlling positional and orientational order is a key technology for the development of high-performance organic materials that exhibit electronic, optoelectronic, biological and even dynamic functions. For this purpose, we cannot rely simply on the inherent self-assembly properties of the target functional molecular units, since it is difficult to predict, based solely on the molecular structure, what structure will be achieved upon assembly. To address this issue, it would be useful to employ molecular building blocks with self-assembly structures that can be clearly predicted and defined, to make target molecular units assemble into a desired structure. To date, various motifs of molecular assemblies, polymers, discrete and/or three-dimensional metal-organic complexes, nanoparticles and metal/metal oxide substrates have been developed to create materials with particular structures and dimensionalities. In this perspective, we define such assembly motifs as "supramolecular scaffolds". The structure of supramolecular scaffolds can be classified in terms of dimensionality, and they range in size from nano- to macroscopic scales. Functional molecular units, when attached to supramolecular scaffolds either covalently or non-covalently, can be assembled into specific structures, thus enabling the exploration of new properties, which cannot be achieved with the target molecular units alone. Through the classification and overview of reported examples, we shed new light on supramolecular scaffolds for the rational design of organic and polymeric materials. PMID- 29719684 TI - Exploring PAZ/3'-overhang interaction to improve siRNA specificity. A combined experimental and modeling study. AB - The understanding of the dynamical and mechanistic aspects that lie behind siRNA based gene regulation is a requisite to boost the performance of siRNA therapeutics. A systematic experimental and computational study on the 3' overhang structural requirements for the design of more specific and potent siRNA molecules was carried out using nucleotide analogues differing in structural parameters, such as sugar constraint, lack of nucleobase, distance between the phosphodiester backbone and nucleobase, enantioselectivity, and steric hindrance. The results established a set of rules governing the siRNA-mediated silencing, indicating that the thermodynamic stability of the 5'-end is a crucial determinant for antisense-mediated silencing but is not sufficient to avoid sense mediated silencing. Both theoretical and experimental approaches consistently evidence the existence of a direct connection between the PAZ/3'-overhang binding affinity and siRNA's potency and specificity. An overall description of the systems is thus achieved by atomistic simulations and free energy calculations that allow us to propose a robust and self-contained procedure for studying the factors implied in PAZ/3'-overhang siRNA interactions. A higher RNAi activity is associated with a moderate-to-strong PAZ/3'-overhang binding. Contrarily, lower binding energies compromise siRNA potency, increase specificity, and favor siRNA downregulation by Ago2-independent mechanisms. This work provides in-depth details for the design of powerful and safe synthetic nucleotide analogues for substitution at the 3'-overhang, enabling some of the intrinsic siRNA disadvantages to be overcome. PMID- 29719686 TI - Chiral auxiliary recycling in continuous flow: automated recovery and reuse of Oppolzer's sultam. AB - The telescoping of a three-stage, chiral auxiliary-mediated transformation in flow is described, including continuous separation of the product and auxiliary. The auxiliary can either be collected for later reuse, or directly fed back to the beginning of the process for recycling in real time, enabling each molecule of auxiliary to make multiple equivalents of chiral product and thus minimizing the step- and atom-economy issues associated with auxiliary-mediated synthesis. This concept is demonstrated for the asymmetric hydrogenation of olefins using Oppolzer's sultam, shortening the total reaction time >100 fold compared to batch, and demonstrating formal sub-stoichiometric auxiliary loading with respect to the process by automating auxiliary recycling within a closed loop. PMID- 29719685 TI - Selective imaging of cathepsin L in breast cancer by fluorescent activity-based probes. AB - Cysteine cathepsins normally function in the lysosomal degradation system where they are critical for the maintenance of cellular homeostasis and the MHC II immune response, and have been found to have major roles in several diseases and in tumor progression. Selective visualization of individual protease activity within a complex proteome is of major importance to establish their roles in both normal and tumor cells, thereby facilitating our understanding of the regulation of proteolytic networks. A generally accepted means to monitor protease activity is the use of small molecule substrates and activity-based probes. However, there are eleven human cysteine cathepsins, with a few of them displaying overlapping substrate specificity, making the development of small molecules that selectively target a single cathepsin very challenging. Here, we utilized HyCoSuL, a positional scanning substrate approach, to develop a highly-selective fluorogenic substrate and activity-based probe for monitoring cathepsin L activity in the breast cancer cell line MDA-MB-231. Use of this probe enabled us to distinguish the activity of cathepsin L from that of other cathepsins, particularly cathepsin B, which is abundant and ubiquitously expressed in normal and transformed cell types. We found that cathepsin L localization in MDA-MB-231 cells greatly overlaps with that of cathepsin B, however, several cathepsin L-rich lysosomes lacked cathepsin B activity. Overall, these studies demonstrate that HyCoSuL derived small molecule probes are valuable tools to image cathepsin L activity in living cells. This approach thus enables evaluation of cathepsin L function in tumorigenesis and is applicable to other cysteine cathepsins. PMID- 29719687 TI - Layered zinc hydroxide monolayers by hydrolysis of organozincs. AB - 2D inorganic materials and their exfoliated counterparts are both of fundamental interest and relevant for applications including catalysis, electronics and sensing. Here, a new bottom-up synthesis route is used to prepare functionalised nanoplatelets, in apolar organic solvents, via the hydrolysis of organometallic reagents; the products can be prepared in high yield, at room temperature. In particular, a series of layered zinc hydroxides, coordinated by aliphatic carboxylate ligands, were produced by the hydrolysis of diethyl zinc and zinc carboxylate mixtures, optimally at a molar ratio of [COOR]/[Zn] = 0.6. Layered zinc hydroxides coordinated by oleate ligands form high concentration solutions of isolated monolayers (3 nm thick x ~ 26 nm) in apolar organic solvents (up to 23 mg mL-1 in toluene), as confirmed by both atomic force and transmission electron microscopies of deposited species. The high solubility of the product allows the synthetic pathway to be monitored directly in situ through 1H NMR spectroscopy. The high solubility also provides a route to solution deposition of active functional materials, as illustrated by the formation of nanoporous films of optically transparent porous zinc oxide (1 MUm thickness) after annealing at 500 degrees C. This new organometallic route to 2D materials obviates common complications of top-down exfoliation syntheses, including sonochemical degradation and low yields of aggregated polydispersed layers, and may potentially be extended to a wide range of systems. PMID- 29719688 TI - Impact of ambient gases on the mechanism of [Cs8Nb6O19]-promoted nerve-agent decomposition. AB - The impact of ambient gas molecules (X), NO2, CO2 and SO2 on the structure, stability and decontamination activity of Cs8Nb6O19 polyoxometalate was studied computationally and experimentally. It was found that Cs8Nb6O19 absorbs these molecules more strongly than it adsorbs water and Sarin (GB) and that these interactions hinder nerve agent decontamination. The impacts of diamagnetic CO2 and SO2 molecules on polyoxoniobate Cs8Nb6O19 were fundamentally different from that of NO2 radical. At ambient temperatures, weak coordination of the first NO2 radical to Cs8Nb6O19 conferred partial radical character on the polyoxoniobate and promoted stronger coordination of the second NO2 adsorbent to form a stable diamagnetic Cs8Nb6O19/(NO2)2 species. Moreover, at low temperatures, NO2 radicals formed stable dinitrogen tetraoxide (N2O4) that weakly interacted with Cs8Nb6O19. It was found that both in the absence and presence of ambient gas molecules, GB decontamination by the Cs8Nb6O19 species proceeds via general base hydrolysis involving: (a) the adsorption of water and the nerve agent on Cs8Nb6O19/(X), (b) concerted hydrolysis of a water molecule on a basic oxygen atom of the polyoxoniobate and nucleophilic addition of the nascent OH group to the phosphorus center of Sarin, and (c) rapid reorganization of the formed pentacoordinated-phosphorus intermediate, followed by dissociation of either HF or isopropanol and formation of POM-bound isopropyl methyl phosphonic acid (i MPA) or methyl phosphonofluoridic acid (MPFA), respectively. The presence of the ambient gas molecules increases the energy of the intermediate stationary points relative to the asymptote of the reactants and slightly increases the hydrolysis barrier. These changes closely correlate with the Cs8Nb6O19-X complexation energy. The most energetically stable intermediates of the GB hydrolysis and decontamination reaction were found to be Cs8Nb6O19/X-MPFA-(i-POH) and Cs8Nb6O19/X-(i-MPA)-HF both in the absence and presence of ambient gas molecules. The high stability of these intermediates is due to, in part, the strong hydrogen bonding between the adsorbates and the protonated [Cs8Nb6O19/X/H]+-core. Desorption of HF or/and (i-POH) and regeneration of the catalyst required deprotonation of the [Cs8Nb6O19/X/H]+-core and protonation of the phosphonic acids i-MPA and MPFA. This catalyst regeneration is shown to be a highly endothermic process, which is the rate-limiting step of the GB hydrolysis and decontamination reaction both in the absence and presence of ambient gas molecules. PMID- 29719689 TI - Synthetic fermentation of beta-peptide macrocycles by thiadiazole-forming ring closing reactions. AB - Macrocyclic beta-peptides were efficiently prepared using a thiadiazole-forming cyclization reaction between an alpha-ketoacid and a thiohydrazide. The linear beta-peptide precursors were assembled from isoxazolidine monomers by alpha ketoacid-hydroxylamine (KAHA) ligations with a bifunctional initiator - a process we have termed 'synthetic fermentation' due to the analogy of producing natural product-like molecules from simpler building blocks. The linear synthetic fermentation products underwent Boc-deprotection/thiadiazole-forming macrocyclization under aqueous, acidic conditions to provide the cyclic products in a one-pot process. This reaction sequence proceeds from easily accessed initiator and monomer building blocks without the need for additional catalysts or reagents, enabling facile production of macrocyclic beta-peptides, a relatively underexplored structural class. PMID- 29719690 TI - Preparation of multiblock copolymers via step-wise addition of l-lactide and trimethylene carbonate. AB - Poly(l-lactide) (PLA) is a bioderived and biodegradable polymer that has limited applications due to its hard and brittle nature. Incorporation of 1,3 trimethylene carbonate into PLA, in a block copolymer fashion, improves the mechanical properties, while retaining the biodegradability of the polymer, and broadens its range of applications. However, the preparation of 1,3-trimethylene carbonate (TMC)/l-lactide (LA) copolymers beyond diblock and triblock structures has not been reported, with explanations focusing mostly on thermodynamic reasons that impede the copolymerization of TMC after lactide. We discuss the preparation of multiblock copolymers via the ring opening polymerization (ROP) of LA and TMC, in a step-wise addition, by a ferrocene-chelating heteroscorpionate zinc complex, {[fc(PPh2)(BH[(3,5-Me)2pz]2)]Zn(MU-OCH2Ph)}2 ([(fcP,B)Zn(MU-OCH2Ph)]2, fc = 1,1' ferrocenediyl, pz = pyrazole). The synthesis of up to pentablock copolymers, from various combinations of LA and TMC, was accomplished and the physical, thermal, and mechanical properties of the resulting copolymers evaluated. PMID- 29719691 TI - Injectable hyperbranched poly(beta-amino ester) hydrogels with on-demand degradation profiles to match wound healing processes. AB - Adjusting biomaterial degradation profiles to match tissue regeneration is a challenging issue. Herein, biodegradable hyperbranched poly(beta-amino ester)s (HP-PBAEs) were designed and synthesized via "A2 + B4" Michael addition polymerization, and displayed fast gelation with thiolated hyaluronic acid (HA SH) via a "click" thiol-ene reaction. HP-PBAE/HA-SH hydrogels showed tunable degradation profiles both in vitro and in vivo using diamines with different alkyl chain lengths and poly(ethylene glycol) diacrylates with varied PEG spacers. The hydrogels with optimized degradation profiles encapsulating ADSCs were used as injectable hydrogels to treat two different types of humanized excisional wounds - acute wounds with faster healing rates and diabetic wounds with slower healing and neo-tissue formation. The fast-degrading hydrogel showed accelerated wound closure in acute wounds, while the slow-degrading hydrogel showed better wound healing for diabetic wounds. The results demonstrate that the new HP-PBAE-based hydrogel in combination with ADSCs can be used as a well controlled biodegradable skin substitute, which demonstrates a promising approach in the treatment of various types of skin wounds. PMID- 29719692 TI - Photosensitizer synergistic effects: D-A-D structured organic molecule with enhanced fluorescence and singlet oxygen quantum yield for photodynamic therapy. AB - The development of photosensitizers with high fluorescence intensity and singlet oxygen (1O2) quantum yields (QYs) is of great importance for cancer diagnosis and photodynamic therapy (PDT). Diketopyrrolopyrrole (DPP) and boron dipyrromethene (BODIPY) are two kinds of building block with great potential for PDT. Herein, a novel donor-acceptor-donor (D-A-D) structured organic photosensitizer DPPBDPI with a benzene ring as a pi bridge linking DPP and BODIPY has been designed and synthesized. The results indicate that the combination of DPP with BODIPY can simultaneously increase the fluorescence QY (5.0%) and the 1O2 QY (up to 80%) significantly by the synergistic effect of the two photosensitizers. By nanoprecipitation, DPPBDPI can form uniform nanoparticles (NPs) with a diameter of less than 100 nm. The obtained NPs not only exhibit high photo-toxicity, but also present negligible dark toxicity towards HeLa cells, demonstrating their excellent photodynamic therapeutic efficacy. In vivo fluorescence imaging shows that DPPBDPI NPs can target the tumor site quickly with the enhanced permeability and retention (EPR) effect and can effectively inhibit tumor growth using photodynamic therapy even with low doses (0.5 mg kg-1). The enhanced imaging and photodynamic performance of DPPBDPI suggest that the synergistic effect of DPP and BODIPY provides a novel theranostic platform for cancer diagnosis and photodynamic therapy. PMID- 29719693 TI - Nickel-catalyzed coupling reaction of alkyl halides with aryl Grignard reagents in the presence of 1,3-butadiene: mechanistic studies of four-component coupling and competing cross-coupling reactions. AB - We describe the mechanism, substituent effects, and origins of the selectivity of the nickel-catalyzed four-component coupling reactions of alkyl fluorides, aryl Grignard reagents, and two molecules of 1,3-butadiene that affords a 1,6 octadiene carbon framework bearing alkyl and aryl groups at the 3- and 8 positions, respectively, and the competing cross-coupling reaction. Both the four component coupling reaction and the cross-coupling reaction are triggered by the formation of anionic nickel complexes, which are generated by the oxidative dimerization of two molecules of 1,3-butadiene on Ni(0) and the subsequent complexation with the aryl Grignard reagents. The C-C bond formation of the alkyl fluorides with the gamma-carbon of the anionic nickel complexes leads to the four component coupling product, whereas the cross-coupling product is yielded via nucleophilic attack of the Ni center toward the alkyl fluorides. These steps are found to be the rate-determining and selectivity-determining steps of the whole catalytic cycle, in which the C-F bond of the alkyl fluorides is activated by the Mg cation rather than a Li or Zn cation. ortho-Substituents of the aryl Grignard reagents suppressed the cross-coupling reaction leading to the selective formation of the four-component products. Such steric effects of the ortho substituents were clearly demonstrated by crystal structure characterizations of ate complexes and DFT calculations. The electronic effects of the para substituent of the aryl Grignard reagents on both the selectivity and reaction rates are thoroughly discussed. The present mechanistic study offers new insight into anionic complexes, which are proposed as the key intermediates in catalytic transformations even though detailed mechanisms are not established in many cases, and demonstrates their synthetic utility as promising intermediates for C C bond forming reactions, providing useful information for developing efficient and straightforward multicomponent reactions. PMID- 29719694 TI - Detection of antimicrobial resistance-associated proteins by titanium dioxide facilitated intact bacteria mass spectrometry. AB - Titanium dioxide-modified target plates were developed to enhance intact bacteria analysis by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. The plates were designed to photocatalytically destroy the bacterial envelope structure and improve the ionization efficiency of intracellular components, thereby promoting the measurable mass range and the achievable detection sensitivity. Accordingly, a method for rapid detection of antimicrobial resistance-associated proteins, conferring bacterial resistance against antimicrobial drugs, was established by mass spectrometric fingerprinting of intact bacteria without the need for any sample pre-treatment. With this method, the variations in resistance proteins' expression levels within bacteria were quickly measured from the relative peak intensities. This approach of resistance protein detection directly from intact bacteria by mass spectrometry is useful for fast discrimination of antimicrobial-resistant bacteria from their non-resistant counterparts whilst performing species identification. Also, it could be used as a rapid and convenient way for initial determination of the underlying resistance mechanisms. PMID- 29719695 TI - Enhanced circular dichroism at elevated temperatures through complexation-induced transformation of a three-layer cyclophane with dualistic dynamic helicity. AB - When two planes stacked one above the other are twisted, they provide a dynamic pair of helical conformations with (M)- or (P)-helicity. We designed a three layer cyclophane that consists of two such dynamic pairs: the top and middle planes, and the middle and bottom planes. Hence, several global conformations could be created for the overall molecule, e.g., double-helical forms with a pair with the same helicity [(M,M) or (P,P)], and a meso-like form with a pair with a different helicity (M,P). These conformations dynamically interconvert to each other in solution. Chiroptical properties were given by the helical-sense preference of the double-helical forms, which was brought about through complexation with a chiral hydrogen-bonding guest. In terms of the conformational energy in a complexed state, when a desirable relationship between double-helical and meso-like forms was attained, complexation-induced circular dichroism was enhanced at elevated temperatures and decreased at lowered temperatures. PMID- 29719696 TI - Efficient ammonia synthesis over a Ru/La0.5Ce0.5O1.75 catalyst pre-reduced at high temperature. AB - Ammonia is an important feedstock for producing fertiliser and is also a potential energy carrier. However, the process currently used for ammonia synthesis, the Haber-Bosch process, consumes a huge amount of energy; therefore the development of new catalysts for synthesising ammonia at a high rate under mild conditions (low temperature and low pressure) is necessary. Here, we show that Ru/La0.5Ce0.5O1.75 pre-reduced at an unusually high temperature (650 degrees C) catalysed ammonia synthesis at extremely high rates under mild conditions; specifically, at a reaction temperature of 350 degrees C, the rates were 13.4, 31.3, and 44.4 mmol g-1 h-1 at 0.1, 1.0, and 3.0 MPa, respectively. Kinetic analysis revealed that this catalyst is free of hydrogen poisoning under the conditions tested. Electron energy loss spectroscopy combined with O2 absorption capacity measurements revealed that the reduced catalyst consisted of fine Ru particles (mean diameter < 2.0 nm) that were partially covered with partially reduced La0.5Ce0.5O1.75 and were dispersed on a thermostable support. Furthermore, Fourier transform infrared spectra measured after N2 addition to the catalyst revealed that N2 adsorption on Ru atoms that interacted directly with the reduced La0.5Ce0.5O1.75 weakened the N 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 N bond and thus promoted its cleavage, which is the rate-determining step for ammonia synthesis. Our results indicate that high-temperature pre-reduction of this catalyst, which consists of Ru supported on a thermostable composite oxide with a cubic fluorite structure and containing reducible cerium, resulted in the formation of many sites that were highly active for N2 reduction by hydrogen. PMID- 29719697 TI - Fabrication of microstructured binary polymer brush "corrals" with integral pH sensing for studies of proton transport in model membrane systems. AB - Binary brush structures consisting of poly(cysteine methacrylate) (PCysMA) "corrals" enclosed within poly(oligoethylene glycol methyl ether methacrylate) (POEGMA) "walls" are fabricated simply and efficiently using a two-step photochemical process. First, the C-Cl bonds of 4-(chloromethyl)phenylsilane monolayers are selectively converted into carboxylic acid groups by patterned exposure to UV light through a mask and POEGMA is grown from unmodified chlorinated regions by surface-initiated atom-transfer radical polymerisation (ATRP). Incorporation of a ratiometric fluorescent pH indicator, Nile Blue 2 (methacryloyloxy)ethyl carbamate (NBC), into the polymer brushes facilitates assessment of local changes in pH using a confocal laser scanning microscope with spectral resolution capability. Moreover, the dye label acts as a radical spin trap, enabling removal of halogen end-groups from the brushes via in situ dye addition during the polymerisation process. Second, an initiator is attached to the carboxylic acid-functionalised regions formed by UV photolysis in the patterning step, enabling growth of PCysMA brushes by ATRP. Transfer of the system to THF, a poor solvent for PCysMA, causes collapse of the PCysMA brushes. At the interface between the collapsed brush and solvent, selective derivatisation of amine groups is achieved by reaction with excess glutaraldehyde, facilitating attachment of aminobutyl(nitrile triacetic acid) (NTA). The PCysMA brush collapse is reversed on transfer to water, leaving it fully expanded but only functionalized at the brush-water interface. Following complexation of NTA with Ni2+, attachment of histidine-tagged proteorhodopsin and lipid deposition, light-activated transport of protons into the brush structure is demonstrated by measuring the ratiometric response of NBC in the POEGMA walls. PMID- 29719698 TI - Closely related yet different: a borylene and its dimer are non-interconvertible but connected through reactivity. AB - The self-stabilizing, tetrameric cyanoborylene [(cAAC)B(CN)]4 (I, cAAC = 1-(2,6 diisopropylphenyl)-3,3,5,5-tetramethylpyrrolidin-2-ylidene) and its diborene relative, [(cAAC)(CN)B 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 B(CN)(cAAC)] (II), both react with disulfides and diselenides to yield the corresponding cAAC-supported cyanoboron bis(chalcogenides). Furthermore, reactions of I or II with elemental sulfur and selenium in various stoichiometries provided access to a variety of cAAC stabilized cyanoboron-chalcogen heterocycles, including a unique dithiaborirane, a diboraselenirane, 1,3-dichalcogena-2,4-diboretanes, 1,3,4-trichalcogena-2,5 diborolanes and a rare six-membered 1,2,4,5-tetrathia-3,6-diborinane. Stepwise addition reactions and solution stability studies provided insights into the mechanism of these reactions and the subtle differences in reactivity observed between I and II. PMID- 29719699 TI - The TensorMol-0.1 model chemistry: a neural network augmented with long-range physics. AB - Traditional force fields cannot model chemical reactivity, and suffer from low generality without re-fitting. Neural network potentials promise to address these problems, offering energies and forces with near ab initio accuracy at low cost. However a data-driven approach is naturally inefficient for long-range interatomic forces that have simple physical formulas. In this manuscript we construct a hybrid model chemistry consisting of a nearsighted neural network potential with screened long-range electrostatic and van der Waals physics. This trained potential, simply dubbed "TensorMol-0.1", is offered in an open-source Python package capable of many of the simulation types commonly used to study chemistry: geometry optimizations, harmonic spectra, open or periodic molecular dynamics, Monte Carlo, and nudged elastic band calculations. We describe the robustness and speed of the package, demonstrating its millihartree accuracy and scalability to tens-of-thousands of atoms on ordinary laptops. We demonstrate the performance of the model by reproducing vibrational spectra, and simulating the molecular dynamics of a protein. Our comparisons with electronic structure theory and experimental data demonstrate that neural network molecular dynamics is poised to become an important tool for molecular simulation, lowering the resource barrier to simulating chemistry. PMID- 29719700 TI - Direct observation of vibrational energy dispersal via methyl torsions. AB - Explicit evidence for the role of methyl rotor levels in promoting energy dispersal is reported. A set of coupled zero-order vibration/vibration-torsion (vibtor) levels in the S1 state of para-fluorotoluene (pFT) are investigated. Two dimensional laser-induced fluorescence (2D-LIF) and two-dimensional zero-kinetic energy (2D-ZEKE) spectra are reported, and the assignment of the main features in both sets of spectra reveals that the methyl torsion is instrumental in providing a route for coupling between vibrational levels of different symmetry classes. We find that there is very localized, and selective, dissipation of energy via doorway states, and that, in addition to an increase in the density of states, a critical role of the methyl group is a relaxation of symmetry constraints compared to direct vibrational coupling. PMID- 29719701 TI - Synthesis, structure and aromaticity of carborane-fused carbo- and heterocycles. AB - Conjugation between a 3-D icosahedral carborane and a fused 2-D pi-ring system is ambiguous. To address this issue, we prepared several carborane-fused carbo- and heterocycles. Detailed studies on their molecular structures, NMR data, and NICS (nucleus-independent chemical shift) and ISE (isomerization stabilization energy) values as well as molecular orbital analyses clearly suggest the presence of (1) considerable aromatic character in the exo five-membered ring of carborane-fused carbo- and heterocycles and (2) considerable conjugation between a 3-D carborane and a fused 2-D pi-ring system. These results will shed some light on the design of new carborane-based materials. PMID- 29719702 TI - Proteome-wide mapping of PQS-interacting proteins in Pseudomonas aeruginosa. AB - The opportunistic human pathogen Pseudomonas aeruginosa secretes 2-heptyl-3 hydroxy-4-quinolone (PQS), a quorum sensing (QS) signal that regulates the expression of numerous virulence genes. Here we report the development and application of chemical probes to globally map quinolone binding proteins. The revealed quinolone interactome contains both known as well as newly identified virulence factors and presents new targets for the treatment of bacterial infections. PMID- 29719703 TI - Oxidative beta-C-H sulfonylation of cyclic amines. AB - A transition metal-free strategy for the dehydrogenative beta-sulfonylation of tertiary cyclic amines is described. N-Iodosuccinimide facilitates regioselective oxidative sulfonylation at C-H bonds positioned beta to the nitrogen atom of tertiary amines, installing enaminyl sulfone functionality in cyclic systems. Mild reaction conditions, broad functional group tolerance and a wide substrate scope are demonstrated. The nucleophilic character of the enaminyl sulfone is harnessed, demonstrating potential application for scaffold diversification. PMID- 29719704 TI - Microhydration of PAH+ cations: evolution of hydration network in naphthalene+ (H2O) n clusters (n <= 5). AB - The interaction of polycyclic aromatic hydrocarbon molecules with water (H2O = W) is of fundamental importance in chemistry and biology. Herein, size-selected microhydrated naphthalene cation nanoclusters, Np+-W n (n <= 5), are characterized by infrared photodissociation (IRPD) spectroscopy in the C-H and O H stretch range to follow the stepwise evolution of the hydration network around this prototypical PAH+ cation. The IRPD spectra are highly sensitive to the hydration structure and are analyzed by dispersion-corrected density functional theory calculations (B3LYP-D3/aug-cc-pVTZ) to determine the predominant structural isomers. For n = 1, W forms a bifurcated CH...O ionic hydrogen bond (H bond) to two acidic CH protons of the bicyclic ring. For n >= 2, the formation of H-bonded solvent networks dominates over interior ion solvation, because of strong cooperativity in the former case. For n >= 3, cyclic W n solvent structures are attached to the CH protons of Np+. However, while for n = 3 the W3 ring binds in the CH...O plane to Np+, for n >= 4 the cyclic W n clusters are additionally stabilized by stacking interactions, leading to sandwich-type configurations. No intracluster proton transfer from Np+ to the W n solvent is observed in the studied size range (n <= 5), because of the high proton affinity of the naphthyl radical compared to W n . This is different from microhydrated benzene+ clusters, (Bz-W n )+, for which proton transfer is energetically favorable for n >= 4 due to the much lower proton affinity of the phenyl radical. Hence, because of the presence of polycyclic rings, the interaction of PAH+ cations with W is qualitatively different from that of monocyclic Bz+ with respect to interaction strength, structure of the hydration shell, and chemical reactivity. These differences are rationalized and quantified by quantum chemical analysis using the natural bond orbital (NBO) and noncovalent interaction (NCI) approaches. PMID- 29719706 TI - Diastereo- and enantioselective additions of alpha-nitro esters to imines for anti-alpha,beta-diamino acid synthesis with alpha-alkyl-substitution. AB - The discovery that a C2-symmetric bis(AMidine) [BAM] catalyst promotes an anti selective addition of alpha-substituted alpha-nitro esters to imines is described, providing alpha-substituted alpha,beta-diamino ester products with high diastereo- and enantioselectivity. When compared to the function of a BAM catalyst reported previously, the pair offer a rare example of diastereodivergence using a bifunctional Bronsted acid-base organocatalyst. PMID- 29719705 TI - Quantification of photoinduced bending of dynamic molecular crystals: from macroscopic strain to kinetic constants and activation energies. AB - Photomechanically reconfigurable elastic single crystals are the key elements for contactless, timely controllable and spatially resolved transduction of light into work from the nanoscale to the macroscale. The deformation in such single crystal actuators is observed and usually attributed to anisotropy in their structure induced by the external stimulus. Yet, the actual intrinsic and external factors that affect the mechanical response remain poorly understood, and the lack of rigorous models stands as the main impediment towards benchmarking of these materials against each other and with much better developed soft actuators based on polymers, liquid crystals and elastomers. Here, experimental approaches for precise measurement of macroscopic strain in a single crystal bent by means of a solid-state transformation induced by light are developed and used to extract the related temperature-dependent kinetic parameters. The experimental results are compared against an overarching mathematical model based on the combined consideration of light transport, chemical transformation and elastic deformation that does not require fitting of any empirical information. It is demonstrated that for a thermally reversible photoreactive bending crystal, the kinetic constants of the forward (photochemical) reaction and the reverse (thermal) reaction, as well as their temperature dependence, can be extracted with high accuracy. The improved kinematic model of crystal bending takes into account the feedback effect, which is often neglected but becomes increasingly important at the late stages of the photochemical reaction in a single crystal. The results provide the most rigorous and exact mathematical description of photoinduced bending of a single crystal to date. PMID- 29719707 TI - A combined experimental and computational study on the reaction of fluoroarenes with Mg-Mg, Mg-Zn, Mg-Al and Al-Zn bonds. AB - Through a combined experimental and computational (DFT) approach, the reaction mechanism of the addition of fluoroarenes to Mg-Mg bonds has been determined as a concerted SNAr-like pathway in which one Mg centre acts as a nucleophile and the other an electrophile. The experimentally determined Gibbs activation energy for the addition of C6F6 to a Mg-Mg bond of a molecular complex, DeltaG?298 K(experiment) = 21.3 kcal mol-1 is modelled by DFT with the omegaB97X functional, DeltaG?298 K(DFT) = 25.7 kcal mol-1. The transition state for C-F activation involves a polarisation of the Mg-Mg bond and significant negative charge localisation on the fluoroarene moiety. This transition state is augmented by stabilising closed-shell Mg...F ortho interactions that, in combination with the known trends in C-F and C-M bond strengths in fluoroarenes, provide an explanation for the experimentally determined preference for C-F bond activation to occur at sites flanked by ortho-fluorine atoms. The effect of modification of both the ligand coordination sphere and the nature and polarity of the M-M bond (M = Mg, Zn, Al) on C-F activation has been investigated. A series of highly novel beta-diketiminate stabilised complexes containing Zn-Mg, Zn-Zn-Zn, Zn-Al and Mg-Al bonds has been prepared, including the first crystallographic characterisation of a Mg-Al bond. Reactions of these new M-M containing complexes with perfluoroarenes were conducted and modelled by DFT. C-F bond activation is dictated by the steric accessibility, and not the polarity, of the M-M bond. The more open coordination complexes lead to enhanced Mg...F ortho interactions which in turn lower the energy of the transition states for C-F bond activation. PMID- 29719708 TI - Metal-organic framework composites with luminescent pincer platinum(ii) complexes: 3MMLCT emission and photoinduced dehydrogenation catalysis. AB - Pincer platinum(ii) complexes are well documented to exhibit weak intermolecular interactions in the solid state and 77 K glassy solutions, leading to emissive triplet metal-metal-to-ligand charge transfer (3MMLCT) excited states that often vanish in dilute solutions. In this work, metal-organic framework (MOF) materials are introduced to provide a "solid solution" environment for easy access to 3MMLCT excited states of pincer platinum(ii) complexes. Phosphorescent composites PtII@MOFs (1-4) with matrix-dependent monomers and oligomer emission properties were obtained. These PtII@MOFs are efficient catalysts for photoinduced dehydrogenation reactions. PMID- 29719709 TI - Chemical synthesis of membrane proteins: a model study on the influenza virus B proton channel. AB - In the present study we have developed and optimized a robust strategy for the synthesis of highly hydrophobic peptides, especially membrane proteins, exemplarily using the influenza B M2 proton channel (BM2(1-51)). This strategy is based on the native chemical ligation of two fragments, where the thioester fragment is formed from an oxo-ester peptide, which is synthesized using Fmoc SPPS, and features an in situ cleavable solubilizing tag (ADO, ADO2 or ADO-Lys5). The nearly quantitative production of the ligation product was followed by an optimized work up protocol, resulting in almost quantitative desulfurization and Acm-group cleavage. Circular dichroism analysis in a POPC lipid membrane revealed that the synthetic BM2(1-51) construct adopts a helical structure similar to that of the previously characterized BM2(1-33). PMID- 29719710 TI - A palette of background-free tame fluorescent probes for intracellular multi color labelling in live cells. AB - A multi-color labelling technique for visualizing multiple intracellular apparatuses in their native environment using small fluorescent probes remains challenging. This approach requires both orthogonal and biocompatible coupling reactions in heterogeneous biological systems with minimum fluorescence background noise. Here, we present a palette of BODIPY probes containing azide and cyclooctyne moieties for copper-free click chemistry in living cells. The probes, referred to as 'tame probes', are highly permeable and specific in nature, leaving no background noise in cells. Such probes, which are rationally designed through optimized lipophilicity, water solubility and charged van der Waals surface area, allow us to demonstrate rapid and efficient concurrent multi labelling of intracellular target components. We show that these probes are capable of not only labelling organelles and engineered proteins, but also showing the intracellular glycoconjugates' dynamics, through the use of metabolic oligosaccharide engineering technology in various cell types. The results demonstrated in this study thus provide flexibility for multi-spectral labelling strategies in native systems in a high spatiotemporal manner. PMID- 29719711 TI - Predictive and mechanistic multivariate linear regression models for reaction development. AB - Multivariate Linear Regression (MLR) models utilizing computationally-derived and empirically-derived physical organic molecular descriptors are described in this review. Several reports demonstrating the effectiveness of this methodological approach towards reaction optimization and mechanistic interrogation are discussed. A detailed protocol to access quantitative and predictive MLR models is provided as a guide for model development and parameter analysis. PMID- 29719712 TI - Enhancing reaction rate in a Pickering emulsion system with natural magnetotactic bacteria as nanoscale magnetic stirring bars. AB - Pickering emulsion is emerging as an advanced platform for catalysis because of the large oil/water interface area for reaction and its superior efficiency. How to enhance the mass transportation within the micro-droplets is the biggest obstacle in further improving the efficiency of the Pickering emulsion system. In this study, we propose and solve this problem for the first time using natural magnetotactic bacteria as nanoscale magnetic stirring bars, which can be encapsulated into each micro-droplet and used to stir the solution to accelerate the mass transportation under an external magnet, and thus significantly enhance the reaction rate of Pickering emulsion. Taking the epoxidation of cyclooctene in the Pickering emulsion system as a demonstration, the reaction rate was enhanced three times with nanoscale magnetic stirring bars compared to that of traditional Pickering emulsion, and was even thirty times higher than that of conventional stirrer-driven biphasic systems. We envision that this strategy will bring biphasic reactions with fundamental innovations toward more green, efficient and sustainable chemistry. PMID- 29719713 TI - Multicomponent polysaccharide-protein bioconjugation in the development of antibacterial glycoconjugate vaccine candidates. AB - A new synthetic strategy for the development of multivalent antibacterial glycoconjugate vaccines is described. The approach comprises the utilization of an isocyanide-based multicomponent process for the conjugation of functionalized capsular polysaccharides of S. pneumoniae and S. Typhi to carrier proteins such as diphtheria and tetanus toxoids. For the first time, oxo- and carboxylic acid functionalized polysaccharides could be either independently or simultaneously conjugated to immunogenic proteins by means of the Ugi-multicomponent reaction, thus leading to mono- or multivalent unimolecular glycoconjugates as vaccine candidates. Despite the high molecular weight of the two or three reacting biomolecules, the multicomponent bioconjugation proved highly efficient and reproducible. The Ugi-derived glycoconjugates showed notable antigenicity and elicited good titers of functional specific antibodies. To our knowledge, this is the only bioconjugation method that enables the incorporation of two different polysaccharidic antigens to a carrier protein in a single step. Applications in the field of self-adjuvanting, eventually anticancer, multicomponent vaccines are foreseeable. PMID- 29719714 TI - Asperphenamate biosynthesis reveals a novel two-module NRPS system to synthesize amino acid esters in fungi. AB - Amino acid esters are a group of structurally diverse natural products with distinct activities. Some are synthesized through an inter-molecular esterification step catalysed by nonribosomal peptide synthetase (NRPS). In bacteria, the formation of the intra-molecular ester bond is usually catalysed by a thioesterase domain of NRPS. However, the mechanism by which fungal NRPSs perform this process remains unclear. Herein, by targeted gene disruption in Penicillium brevicompactum and heterologous expression in Aspergillus nidulans, we show that two NRPSs, ApmA and ApmB, are sufficient for the synthesis of an amino acid ester, asperphenamate. Using the heterologous expression system, we identified that ApmA, with a reductase domain, rarely generates dipeptidyl alcohol. In contrast, ApmB was determined to not only catalyse inter-molecular ester bond formation but also accept the linear dipeptidyl precursor into the NRPS chain. The mechanism described here provides an approach for the synthesis of new small molecules with NRPS as the catalyst. Our study reveals for the first time a two-module NRPS system for the formation of amino acid esters in nature. PMID- 29719715 TI - Striking transformations of the hydroborylene ligand in a HB:->NiII complex with isocyanides and CO. AB - For the first time, the reactivity of the metal- and N-heterocyclic carbene supported monovalent hydroborylene is reported. Isocyanides react with the hydroborylene NiII complex [{cat(TMSL)Si}(Cl)Ni<-:BH(NHC)2] 1 (cat = ortho C6H4O2; TMSL = N(SiMe3)(Dipp); Dipp = 2,6-Pri2C6H3; NHC = :C[(Pri)NC(Me)]2) to form the hydride-bridged hydroborylene-NiII complexes 2. The reaction of 1 with isoelectronic CO, however, is reversible and furnishes the related unprecedented hydride- and CO-bridged hydroborylene NiII complex 2-CO, which undergoes isomerisation through silyl/NHC exchange at ambient temperature to afford the corresponding hydro(silyl)boryl NiII complex 3. Markedly, 2 readily and quantitatively react with one further molar equiv. of isocyanide to give, under borylene liberation and H/Cl ligand exchange, boraketiminium species, which represent cationic BI complexes. These latter compounds are highly reactive in solution, and can undergo quantitative transformation into previously unknown cyanoborenium cations. PMID- 29719716 TI - Expression of meis and hoxa11 in dipnoan and teleost fins provides new insights into the evolution of vertebrate appendages. AB - Background: The concerted activity of Meis and Hoxa11 transcription factors is essential for the subdivision of tetrapod limbs into proximo-distal (PD) domains; however, little is know about the evolution of this patterning mechanism. Here, we aim to study the expression of meis and hoxa11 orthologues in the median and paired rayed fins of zebrafish and in the lobed fins of the Australian lungfish. Results: First, a late phase of expression of meis1.1 and hoxa11b in zebrafish dorsal and anal fins relates with segmentation of endochondral elements in proximal and distal radials. Second, our zebrafish in situ hybridization results reveal spatial and temporal changes between pectoral and pelvic fins. Third, in situ analysis of meis1, meis3 and hoxa11 genes in Neoceratodus pectoral fins identifies decoupled domains of expression along the PD axis. Conclusions: Our data raise the possibility that the origin of stylopod and zeugopod lies much deeper in gnathostome evolution and that variation in meis and hoxa11 expression has played a substantial role in the transformation of appendage anatomy. Moreover, these observations provide evidence that the Meis/Hoxa11 profile considered a hallmark of stylopod/zeugopod patterning is present in Neoceratodus. PMID- 29719717 TI - Consideration of methods for identifying mite allergens. AB - House dust mites are small arthropods that produce proteins-found in their feces, body parts, and eggs-that are major triggers of human allergies worldwide. The goal of this review is to describe the current methods used to identify these allergens. A literature search for allergen identification methods employed between 1995 and 2016 revealed multiple techniques that can be broadly grouped into discovery and confirmation phases. The discovery phase employs screening for mite proteins that can bind IgEs in sera from animals or patients allergic to dust mites. The confirmation phase employs biochemical methods to isolate either native or recombinant mite proteins, confirms the IgE binding of the purified allergens, and uses either in vitro or in vivo assays to demonstrate that the purified antigen can stimulate an immune response. The methods used in the two phases are defined and their strengths and weaknesses are discussed. The majority of HDM-allergic patients may respond to just a small subset of proteins, but new protein discovery methods are still warranted in order to develop a complete panel of HDM allergens for component resolved diagnosis and patient-tailored therapies. PMID- 29719718 TI - A systematic review of the epidemiology of carbapenem-resistant Enterobacteriaceae in the United States. AB - Background: Carbapenem-resistant Enterobacteriaceae (CRE) pose an urgent public health threat in the United States. An important step in planning and monitoring a national response to CRE is understanding its epidemiology and associated outcomes. We conducted a systematic literature review of studies that investigated incidence and outcomes of CRE infection in the US. Methods: We performed searches in MEDLINE via Ovid, CDSR, DARE, CENTRAL, NHS EED, Scopus, and Web of Science for articles published from 1/1/2000 to 2/1/2016 about the incidence and outcomes of CRE at US sites. Results: Five studies evaluated incidence, but many used differing definitions for cases. Across the entire US population, the reported incidence of CRE was 0.3-2.93 infections per 100,000 person-years. Infection rates were highest in long-term acute-care (LTAC) hospitals. There was insufficient data to assess trends in infection rates over time. Four studies evaluated outcomes. Mortality was higher in CRE patients in some but not all studies. Conclusion: While the incidence of CRE infections in the United States remains low on a national level, the incidence is highest in LTACs. Studies assessing outcomes in CRE-infected patients are limited in number, small in size, and have reached conflicting results. Future research should measure a variety of clinical outcomes and adequately adjust for confounders to better assess the full burden of CRE. PMID- 29719719 TI - Divergent topological networks in Alzheimer's disease: a diffusion kurtosis imaging analysis. AB - Background: Brain consists of plenty of complicated cytoarchitecture. Gaussian model based diffusion tensor imaging (DTI) is far from satisfactory interpretation of the structural complexity. Diffusion kurtosis imaging (DKI) is a tool to determine brain non-Gaussian diffusion properties. We investigated the network properties of DKI parameters in the whole brain using graph theory and further detected the alterations of the DKI networks in Alzheimer's disease (AD). Methods: Magnetic resonance DKI scanning was performed on 21 AD patients and 19 controls. Brain networks were constructed by the correlation matrices of 90 regions and analyzed through graph theoretical approaches. Results: We found small world characteristics of DKI networks not only in the normal subjects but also in the AD patients; Grey matter networks of AD patients tended to be a less optimized network. Moreover, the divergent small world network features were shown in the AD white matter networks, which demonstrated increased shortest paths and decreased global efficiency with fiber tractography but decreased shortest paths and increased global efficiency with other DKI metrics. In addition, AD patients showed reduced nodal centrality predominantly in the default mode network areas. Finally, the DKI networks were more closely associated with cognitive impairment than the DTI networks. Conclusions: Our results suggest that DKI might be superior to DTI and could serve as a novel approach to understand the pathogenic mechanisms in neurodegenerative diseases. PMID- 29719720 TI - Chinese expert consensus on programming deep brain stimulation for patients with Parkinson's disease. AB - Background: Deep Brain Stimulation (DBS) therapy for the treatment of Parkinson's Disease (PD) is now a well-established option for some patients. Postoperative standardized programming processes can improve the level of postoperative management and programming, relieve symptoms and improve quality of life. Main body: In order to improve the quality of the programming, the experts on DBS and PD in neurology and neurosurgery in China reviewed the relevant literatures and combined their own experiences and developed this expert consensus on the programming of deep brain stimulation in patients with PD in China. Conclusion: This Chinese expert consensus on postoperative programming can standardize and improve postoperative management and programming of DBS for PD. PMID- 29719721 TI - Exercise stereotypes and fatigue in people living with HIV: does self-efficacy play a mediating or a moderating role? AB - Background: Recent research suggests that exercise stereotypes may influence physical activity through ego depletion and internalization mechanisms. The objective of this study was to better understand exercise stereotypes mechanisms among people living with HIV (PLHIV) by further examining the role of exercise self-efficacy and perceived physical fatigue in the relationship between exercise stereotypes and physical activity. Methods: Three hundred five people living with HIV were recruited to provide data on their stereotypes related to exercise, exercise self-efficacy, perceived physical fatigue as well as their level of physical activity (PA). Results: From the different models tested, the serial mediation model with exercise self-efficacy and perceived physical fatigue as mediators of the relationship between exercise stereotypes and PA, as well as the moderated mediation model with exercise selfefficacy as a moderator of exercise stereotypes and perceived physical fatigue a mediator, provided good fits to the data. However, the moderated mediation model (with indirect associations between negative exercise stereotypes and PA via perceived physical fatigue being moderated by exercise self-efficacy) explained the most variance in PA (R2 = .27). Conclusion: The moderated mediation model suggests that exercise stereotypes might influence PA through ego depletion mechanisms and be tempered by exercise self-efficacy. PMID- 29719722 TI - An aggravated return-to-work case of organic solvent induced chronic toxic encephalopathy. AB - Background: Organic solvent-induced chronic toxic encephalopathy (CTE) is known as a non-progressive disorder that does not progress after diagnosis. The authors present a case those symptoms worsened after continued exposure to organic solvent after returning to work. Because such a case has not been reported in South Korea to the best of our knowledge, we intend to report this case along with literature review. Case presentation: A 59-year-old man, who performed painting job at a large shipyard for 20 years, was receiving hospital treatment mainly for depression. During the inpatient treatment, severe cognitive impairment was identified, and he visited the occupational and environmental medicine outpatient clinic for assessing work relatedness. In 1984, at the age of 27, he began performing touch-up and spray painting as a shipyard painter. Before that he had not been exposure to any neurotoxic substances. In 2001, at the age of 44, after 15 years of exposure to mixed solvents including toluene, xylene and others, he was diagnosed with CTE International Solvent Workshop (ISW) type 2A. After 7 years of sick leave, he returned to work in 2006. And he repeated return to-work and sick leave in the same job due to worsening of depressive symptoms. He had worked four times (2006-2010, 2011-2011, 2011-2011, 2016-2017) for a total of 5 years as a shipyard painter after first compensation. During the return-to work period, the mean values of the mixed solvent index ranged from 0.57 to 2.15, and except for a one semiannual period, all mean values were above the standard value of 1. We excluded other diseases that can cause cognitive impairment like central nervous system diseases, brain injury, psychological diseases and metabolic diseases with physical examinations, laboratory tests, and brain image analysis. And finally, throughout neuropsychological tests, an overall deterioration in cognitive function was identified compared to 2002, and the deterioration types was similar to that often shown in the case of CTE; thus a diagnosis of CTE (ISW) type 3 was made. Conclusion: This case is showing that CTE can go on with continued exposure to mixed solvents. Appropriate "fitness to work" should be taken to prevent disease deterioration especially for the sick leave workers. PMID- 29719723 TI - Correction: Biological effect of microengineered grooved stents on strut healing: a randomised OCT-based comparative study in humans. AB - [This corrects the article DOI: 10.1136/openhrt-2016-000521.][This corrects the article DOI: 10.1136/openhrt-2016-000521.]. PMID- 29719725 TI - The incidence of injury in elite camogie, an in-season prospective study. AB - Background: Camogie is a stickhandling, high-velocity, multidirectional field sport for females which is native to Ireland, but is also played internationally. Aim: To establish the incidence, nature and severity of injuries in elite camogie players. Methods: A prospective, observational cohort study was carried out during the Provincial Championships and extending into the All-Ireland Championship until a participating team was eliminated (11 weeks). A purposive sample of 62 players from 3 of the total 11 senior intercounty teams participated to generate geographical representation. Injury data were recorded and classified by team physiotherapists using a time loss definition, consistent with consensus statements. A concurrent measure of exposure to matches and training was recorded. Results: Twenty-one incidents of injury were recorded with 14 players injured. Injury incidence rate was 26.4 (95% CI 13.44 to 47.16) per 1000 match hours and 4.2 (95% CI 2.12 to 7.46) per 1000 training hours. There were 11 contact and 10 non-contact injuries. The lower limb accounted for 71.4% (n=15), the upper limb 9.5% (n=2) and the trunk and head 19.1% (n=4) of injuries. The main tissues injured were both muscle and ligament, representing 57.2% (n=6 each). The mean duration time loss from sport per injury was 12.14 days. Conclusion: These results provide data on the incidence, nature and severity of camogie injuries using definitions that reflect international consensus statements. Further study of injury incidence over a full season or multiple seasons is recommended. PMID- 29719724 TI - A narrative review on cervical interventions in adults with chronic whiplash associated disorder. AB - Introduction: Whiplash injuries are common in society, but clinical interventions are inconclusive on the most effective treatment. Research and reviews have been completed with the goal of determining clinical interventions that are effective for whiplash injuries and disorders, but literature has not recently been summarised on best practices for cervical spine interventions for adults with chronic whiplash. Purpose: The objective of this narrative review is to update and expand on previous works, to provide recommendations for clinical interventions and future research in the area of cervical spine rehabilitation for adults with chronic whiplash-associated disorder. Method: The Arskey and O'Malley methodology was used for this narrative review. CINHAL, EMBASE, Medline, PsychInfo, Scopus, Web of Science, as well as grey literature, were searched from 2003 to April 2017. Two reviewers screened titles and abstracts for relevance to the review, and content analysis summarised the study findings. A total of 14 citations were included in the final review. Findings: Exercise-based interventions targeted at the cervical spine appear most beneficial for adults with chronic whiplash-associated disorder (WAD). Invasive interventions still require more rigorous studies to deem their effectiveness for this population. Conclusion: Further research is required to investigate and determine clinically relevant results for cervical spine intervention in patients with chronic WAD. PMID- 29719726 TI - Effect of short and long moderate-intensity exercises in modifying cardiometabolic markers in sedentary Kenyans aged 50 years and above. AB - Objectives: We compared effects of shorter moderate-intensity exercise time (<10 min bouts) on cardiometabolic parameters with the current recommendations among elderly adults. Methods: Fifty-three sedentary individuals aged >=50 years were divided into exercise groups1: male and2 female short-duration bouts (MS and FS, respectively), and3 male and4 female long-duration bouts (ML and FL, respectively). Short-duration bouts consisted three 5-10 min moderate-intensity jogging sessions daily, and long-duration bouts consisted 30-60 min sessions 3-5 days weekly. Cumulative exercise times were equivalent. Physical activity (PA) was measured by log and activity monitors. Fasting venous blood at baseline and 8 weekly intervals was used for blood chemistry. Results: After 24 weeks, MS and FS with total cholesterol (TC) of >5.2 mmol/L and >5.3 mmol/L decreased from 22.2% to 14.8% and from 30.9% to 11.5%, respectively. For ML, this decreased from 25.9% to 3.7%, while FL had 0% change. In MS and ML, TC/high-density lipoproteins (HDLs) of >5.0 mmol/L dropped from 22.2% to 7.4% and from 22.2% to 15.4%, respectively. In FS and FL, TC/HDL of >4.5 mmol/L declined from 19.2% to 7.7% and from 19.2% to 3.8%, respectively. MS and ML with fasting blood glucose of >=5.5 mmol/L declined from 40.7% to 11.1% and from 33.3% to 3.7%, respectively. Similarly, it declined from 46.2% to 0% and 42.3% to 11.5% for FS and FL, respectively. There were no differences in the changes between regimes throughout the study. Conclusion: Bouts lasting <10 min per session are as good as those lasting;>=30 min in improving cardiometabolic profiles of sedentary adults aged >=50 years. PMID- 29719727 TI - Effects of preoperative and postoperative resistance exercise interventions on recovery of physical function in patients undergoing abdominal surgery for cancer: a systematic review of randomised controlled trials. AB - Objective: To systematically review the effects of preoperative and postoperative resistance exercise training on the recovery of physical function in patients undergoing abdominal surgery for cancer. Data sources: A systematic review of English articles using Medline, Physiotherapy Evidence Database, CINAHL and the Cochrane Library electronic databases was undertaken. Eligibility criteria for selecting studies: Studies were included if they used a randomised, quasi randomised or controlled trial study design and compared the effects of a muscle strengthening exercise intervention (+/-other therapy) with a comparative non exercise group; involved adult participants (>=18 years) who had elected to undergo abdominal surgery for cancer; and used muscle strength, physical function, self-reported functional ability, range of motion and/or a performance based test as an outcome measure. Results: Following screening of titles and abstracts of the 588 publications retrieved from the initial search, 24 studies met the inclusion criteria and were accessed for review of the full-text version of the article, and 2 eligible studies met the inclusion criteria and were included in the review. One exercise programme was undertaken preoperatively and the other postoperatively, until discharge from hospital. The exercise interventions of the included studies were performed for five and eight sessions, respectively. There were no differences between groups in either study. Conclusion: The only two studies designed to determine whether preoperative or postoperative resistance muscle-strengthening exercise programmes improved or negatively affected physical function outcomes in patients undergoing abdominal surgery for cancer provide inconclusive results. PMID- 29719728 TI - Systematic development of a tennis injury prevention programme. AB - Introduction: Despite an injury incidence of up to 3.0/1000 hours of play, there are no published tennis injury prevention programmes. This article aims to describe the developmental process of TennisReady, an e-health tennis-specific injury programme for adult recreational tennis players. Five-step approach: A bottom-up, five-step approach was used with the Knowledge Transfer Scheme as a guideline. During the first step, a problem statement among targeted users was carried out. 475 (partially) completed surveys and group interviews (n=8) revealed a preference for an app-based prevention intervention of 10-15 min. As a second step, a systematic review was performed to identify prevention strategies in tennis. None were found. In step 3, during two expert group meetings (n=18), the findings of the first two steps were discussed and goals were formulated. Relevant and potential exercises for the programme were discussed. A subgroup of a total of six physical therapists, physicians and trainers developed the content of the programme in step 4. Step 5 included an evaluation of the exercises in 33 recreational tennis players. Participants evaluated the exercises during training sessions with trainers involved in the programme's development or their colleagues. Participants evaluated the programme through standardised surveys or group interviews. Based on this evaluation, the programme was adjusted by altering exercises and frequencies, and it was evaluated in a second target group (n=27). The second evaluation did not result in any major changes to the final prevention programme. Conclusion: Through a five-step approach guided by the Knowledge Transfer Scheme, we developed an e-health tennis-specific prevention programme for adult tennis players. This 10 min intervention will require testing in a randomised controlled setting. PMID- 29719729 TI - Influence of playing rugby on long-term brain health following retirement: a systematic review and narrative synthesis. AB - Objectives: The aim of this review was to systematically investigate long-term brain health in retired rugby players. Methods: Six databases were systematically searched from inception to January 2018 using Medical Subject Headings and keywords. Two reviewers independently screened studies for inclusion. Cross sectional studies of living retired male or female rugby players in which at least one cognitive test was used as an outcome measure were included. Data extraction was performed using Strengthening the Reporting of Observational Studies in Epidemiology guidelines. Methodological quality was assessed independently by two reviewers using the Downs and Black methodological quality tool. Results: This review yielded six studies with an overall methodological quality of 'moderate'. A total of 672 male retired rugby players (mean ages of 38 52 years) were included in this review. Three studies investigated neuropsychological functioning in retired rugby players in comparison with controls, with no significant evidence of decreased performance in the majority of tests when compared with controls. Five out of the six studies explored self reported measures of cognition. Three studies compared retired rugby players to controls, one of which found significantly increased subjective cognitive complaints among retired rugby players. The other two studies found that persistent postconcussion symptoms were associated with a higher number of self reported concussions. Two studies reported decreased fine motor control in retired rugby players in comparison with controls. Neurometabolites and electrophysiological changes were explored by two studies, with minimal and non significant findings. Conclusions: Overall findings are mixed. Methodological biases reduce the overall study quality and limited the conclusions that can be drawn. Findings of decreased fine motor control in retired athletes may be influenced by lack of controlling for evidence of upper limb musculoskeletal injuries. While some studies show evidence of reduced cognitive function among former athletes, the results are not significantly lower than population norms. Cognitive findings from this review are inconsistent within and across study cohorts and are biased towards positive findings when self-report methods were selected. Current evidence suggests that large gaps remain in the understanding of the cause-and-effect relationships between playing rugby and long-term brain health in retired players. PMID- 29719730 TI - Controversies in oncology: surgery for small cell lung cancer? It's time to rethink the case. PMID- 29719731 TI - Improving physical activity, sedentary behaviour and sleep in COPD: perspectives of people with COPD and experts via a Delphi approach. AB - Background: Little is known about how to achieve enduring improvements in physical activity (PA), sedentary behaviour (SB) and sleep for people with chronic obstructive pulmonary disease (COPD). This study aimed to: (1) identify what people with COPD from South Australia and the Netherlands, and experts from COPD- and non-COPD-specific backgrounds considered important to improve behaviours; and (2) identify areas of dissonance between these different participant groups. Methods: A four-round Delphi study was conducted, analysed separately for each group. Free-text responses (Round 1) were collated into items within themes and rated for importance on a 9-point Likert scale (Rounds 2-3). Items meeting a priori criteria from each group were retained for rating by all groups in Round 4. Items and themes achieving a median Likert score of >=7 and an interquartile range of <=2 across all groups at Round 4 were judged important. Analysis of variance with Tukey's post-hoc tested for statistical differences between groups for importance ratings. Results: Seventy-three participants consented to participate in this study, of which 62 (85%) completed Round 4. In Round 4, 81 items (PA n = 54; SB n = 24; sleep n = 3) and 18 themes (PA n = 9; SB n = 7; sleep n = 2) were considered important across all groups concerning: (1) symptom/disease management, (2) targeting behavioural factors, and (3) less commonly, adapting the social/physical environments. There were few areas of dissonance between groups. Conclusion: Our Delphi participants considered a multifactorial approach to be important to improve PA, SB and sleep. Recognising and addressing factors considered important to recipients and providers of health care may provide a basis for developing behaviour-specific interventions leading to long-term behaviour change in people with COPD. PMID- 29719732 TI - Applying real-time quantitative PCR to diagnosis of freemartin in Holstein cattle by quantifying SRY gene: a comparison experiment. AB - Background: Freemartinism generally occurs in female offspring of dizygotic twins in a mixed-sex pregnancy. Most bovine heterosexual twin females are freemartins. However, about 10% of bovine heterosexual twin females are fertile. Farmers mostly cull bovine fertile heterosexual twin females due to the lack of a practical diagnostic approach. Culling of such animals results in economic and genetic-material losses both for dairy and beef industry. Methods: In this study, a comparative test, including qualitative detection of SRY gene by polymerase chain reaction (PCR), quantitative detection of relative content of SRY by real time quantitative polymerase chain reaction (qPCR), and quantitative detection of H-Y antigen, was performed to establish the most accurate diagnosis for freemartin. Twelve Holstein heterosexual twin females were used in this study, while three normal Holstein bulls and three normal Holstein cows were used as a positive and negative control, respectively. Results: Polymerase chain reaction results revealed that SRY gene were absent in three heterosexual twin females and only two of them were verified as fertile in later age. The qPCR results showed that relative content of SRY was more than 14.2% in freemartins and below 0.41% in fertile heterosexual twin females. The H-Y antigen test showed no significant numerical difference between freemartin and fertile heterosexual twin female. Discussion: Our results show that relative content of SRY quantified by qPCR is a better detection method for diagnosis of freemartin in Holstein cattle as compare to qualitative detection of SRY gene by PCR or quantitative detection of H-Y antigen. To the authors' knowledge, this is the first time we applied qPCR to diagnosing freemartin by quantifying SRY gene and got relative SRY content of each freemartin and fertile heterosexual twin female. We concluded that low-level of SRY would not influence fertility of bovine heterosexual twin female. PMID- 29719733 TI - Selection of quality indicators for nutritional therapy in pediatrics: a cross sectional study conducted in Brazil. AB - Background: Quality indicators for nutritional therapy (QINT) are important in assessing care and monitoring of resources. Among the 30 indicators proposed by International Life Sciences Institute, Brazil, there is still no evaluation of the most pertinent for Pediatrics. Objective: To list the 10 main quality indicators for nutritional therapies (QINTs) for Pediatrics. Methods: This was a two-phase cross-sectional study. Firstly, a questionnaire was answered by physicians, nutritionists, nurses, and pharmacists, all with having experience in nutritional therapy (NT) with Pediatrics, in Rio de Janeiro, Brazil. Participants assessed four attributes of QINT by using the Likert scale. A Top 10 ranked QINT list for Pediatrics was established. To verify the consistency of the questionnaire, Cronbach's Alpha coefficient was calculated. Secondly, the opinions of the participants on the results that were obtained were requested and the percentages of the positive responses were calculated. Results: A total of 33 professionals participated in the first phase and 92% (n = 23 of 25) in the second phase approved the results of the selected indicators. Among the Top 10 QINTs, the three main ones were: #1: "Frequency of diarrhea in those patients on enteral nutrition" (mean = 13.194; alpha = 0.827); #2: "Frequency of dietary nutritional prescriptions upon the hospital discharge of the NT patients" (mean = 12.871; alpha = 0.822); #3: "Frequency of the NT patients who recovered their oral intake" (mean = 12.839; alpha = 0.859). Conclusion: When considering the consistency and the concordance that were obtained, it can be suggested that the list of Top 10 QINTs as proposed in this study will help in the evaluation of NT quality indicators for Pediatrics. PMID- 29719734 TI - Collagen overlays can inhibit leptin and adiponectin secretion but not lipid accumulation in adipocytes. AB - Background: White adipose tissue (WAT) is essential for energy storage as well as being an active endocrine organ. The secretion of adipokines by adipocytes can affect whole body metabolism, appetite, and contribute to overall health. WAT is comprised of lipid-laden mature adipocytes, as well as immune cells, endothelial cells, pre-adipocytes, and adipose-derived stem cells. In addition, the presence of extracellular matrix (ECM) proteins in WAT can actively influence adipocyte differentiation, growth, and function. Type I collagen is an abundant fibrous ECM protein in WAT that is secreted by developing adipocytes. However, the extent and overall effect of Type I collagen on adipokine secretion in mature adipocytes when added exogenously has not been established. Methods: We characterized the effects of Type I collagen overlays prepared using two different buffers on adipocyte physiology and function when added at different times during differentiation. In addition, we compared the effect of collagen overlays when adipocytes were cultured on two different tissue culture plastics that have different adherent capabilities. Triglyceride accumulation was analyzed to measure adipocyte physiology, and leptin and adiponectin secretion was determined to analyze effects on adipokine secretion. Results: We found that collagen overlays, particularly when added during the early differentiation stage, impaired adipokine secretion from mature adipocytes. Collagen prepared using PBS had a greater suppression of leptin than adiponectin while collagen prepared using HANKS buffer suppressed the secretion of both adipokines. The use of CellBind plates further suppressed leptin secretion. Triglyceride accumulation was not substantially impacted with any of the collagen overlays. Discussion: Adipokine secretion can be selectively altered by collagen overlays. Thus, it is feasible to selectively manipulate the secretion of adipokines by adipocytes in vitro by altering the composition or timing of collagen overlays. The use of this technique could be applied to studies of adipokine function and secretion in vitro as well as having potential therapeutic implications to specifically alter adipocyte functionality in vivo. PMID- 29719735 TI - Impact of hypoxia stress on the physiological responses of sea cucumber Apostichopus japonicus: respiration, digestion, immunity and oxidative damage. AB - Hypoxia is one of the most frequently occurring stressors confronted by industrial cultures of sea cucumber and can cause large economic losses and resource degradation. However, its responsive mechanisms are still lacking. In this paper, the physiological responses of Apostichopus japonicus to oxygen deficiency was illustrated, including induced oxidative response and immune defense and changed digestive enzymes activities. Significantly increased activities of alpha-amylase (AMS), acid phosphatase (ACP), lactate dehydrogenase, catalase, peroxidase, succinate dehydrogenase and higher content of malondialdehyde, and decreased activities of lipase and trypsin (TRY) were observed after hypoxia exposure (dissolved oxygen [DO] 2 mg/L). Expressions of key genes showed that AMS, peptidase, ACP, alkaline phosphatase, lysozyme, heat shock protein 70 and glutathione peroxidase were increased and TRY was decreased under hypoxia. With the decline of the DO level, the decreased tendency of oxygen consumption rates was different in varied weight groups. Moreover, respiratory trees were observed degraded under long-term hypoxia stress, thus leading a negative effect of respiration. These results could help to develop a better understanding of the responsive mechanism of sea cucumber under hypoxia stress and provide a theoretical basis for the prevention of hypoxia risk. PMID- 29719736 TI - Xylose fermentation to ethanol by new Galactomyces geotrichum and Candida akabanensis strains. AB - The conversion of pentoses into ethanol remains a challenge and could increase the supply of second-generation biofuels. This study sought to isolate naturally occurring yeasts from plant biomass and determine their capabilities for transforming xylose into ethanol. Three yeast strains with the ability to ferment xylose were isolated from pepper, tomato and sugarcane bagasse. The strains selected were characterized by morphological and auxanographic assays, and they were identified by homology analysis of 5.8 S and 26 S ribosomal RNA gene sequences. The identities of two lineages of microrganism were associated with Galactomyces geotrichum, and the other was associated with Candida akabanensis. Fermentative processes were conducted with liquid media containing only xylose as the carbon source. YP/S values for the production of ethanol ranging between 0.29 and 0.35 g g-1 were observed under non-optimized conditions. PMID- 29719737 TI - Parental engagement in preventive parenting programs for child mental health: a systematic review of predictors and strategies to increase engagement. AB - Background: Child mental health problems are now recognised as a key public health concern. Parenting programs have been developed as one solution to reduce children's risk of developing mental health problems. However, their potential for widespread dissemination is hindered by low parental engagement, which includes intent to enrol, enrolment, and attendance. To increase parental engagement in preventive parenting programs, we need a better understanding of the predictors of engagement, and the strategies that can be used to enhance engagement. Method: Employing a PRISMA method, we conducted a systematic review of the predictors of parent engagement and engagement enhancement strategies in preventive parenting programs. Key inclusion criteria included: (1) the intervention is directed primarily at the parent, (2) parent age >18 years, the article is (3) written in English and (4) published between 2004-2016. Stouffer's method of combining p-values was used to determine whether associations between variables were reliable. Results: Twenty-three articles reported a variety of predictors of parental engagement and engagement enhancement strategies. Only one of eleven predictors (child mental health symptoms) demonstrated a reliable association with enrolment (Stouffer's p < .01). Discussion: There was a lack of consistent evidence for predictors of parental engagement. Nonetheless, preliminary evidence suggests that engagement enhancement strategies modelled on theories, such as the Health Belief Model and Theory of Planned Behaviour, may increase parents' engagement. Systematic review registration: PROSPERO CRD42014013664. PMID- 29719738 TI - Motor experience with a sport-specific implement affects motor imagery. AB - The present study tested whether sport-specific implements facilitate motor imagery, whereas nonspecific implements disrupt motor imagery. We asked a group of basketball players (experts) and a group of healthy controls (novices) to physically perform (motor execution) and mentally simulate (motor imagery) basketball throws. Subjects produced motor imagery when they were holding a basketball, a volleyball, or nothing. Motor imagery performance was measured by temporal congruence, which is the correspondence between imagery and execution times estimated as (imagery time minus execution time) divided by (imagery time plus execution time), as well as the vividness of motor imagery. Results showed that experts produced greater temporal congruence and vividness of kinesthetic imagery while holding a basketball compared to when they were holding nothing, suggesting a facilitation effect from sport-specific implements. In contrast, experts produced lower temporal congruence and vividness of kinesthetic imagery while holding a volleyball compared to when they were holding nothing, suggesting the interference effect of nonspecific implements. Furthermore, we found a negative correlation between temporal congruence and the vividness of kinesthetic imagery in experts while holding a basketball. On the contrary, the implement manipulation did not modulate the temporal congruence of novices. Our findings suggest that motor representation in experts is built on motor experience associated with specific-implement use and thus was subjected to modulation of the implement held. We conclude that sport-specific implements facilitate motor imagery, whereas nonspecific implements could disrupt motor representation in experts. PMID- 29719739 TI - Patient-reported Outcome Measurements on the Tolerance of Magnetic Resonance Imaging-guided Radiation Therapy. AB - Purpose Magnetic resonance imaging-guided radiation therapy (MRgRT) requires patient positioning within the MR bore and prolonged MR imaging during delivery, both of which are new in radiation oncology. Patient tolerance of MRgRT was prospectively evaluated using patient-reported outcome questionnaires (PRO-Q). Methods Our MRgRT procedure involves daily high-resolution MR scanning, limited re-contouring, daily plan re-optimization, quality assurance (QA), and gated delivery. Patients with claustrophobia are excluded. Mean fraction duration was 45 and 60 minutes for stereotactic treatments during free-breathing and breath hold, respectively. Patient-controlled video-feedback was used for breath-hold delivery. PRO-Qs collected in the first 150 patients treated included questions on MR-related complaints and also evaluated aspects of active participation. Results Almost one-third of patients (29%) scored at least one PRO-Q item on MR related complaints as 'moderate' or 'very much', with noise, feeling cold, and paresthesia being the most frequently scored in this way. Considerable anxiety was reported by 5%, but no medication was required for this in any patient. Patient participation in video feedback for breath-hold delivery was appreciated by the majority of patients, all of whom completed the procedure. Only 5% of patients considered treatment duration to be unacceptably long. Conclusion Despite the lengthy MRgRT procedure, outcomes of PRO-Q indicate that it was well tolerated by patients. PMID- 29719740 TI - Abscopal Effect in a Stage IV Melanoma Patient who Progressed on Pembrolizumab. AB - In this case report, we present the clinical course of a woman with locally advanced mucosal melanoma of the oral cavity. She was initially treated with surgery with adjuvant local radiation of 50 Gy in 20 fractions. She quickly relapsed with an aggressive regional recurrence of the disease on the neck and with numerous pulmonary metastases. Immunotherapy with pembrolizumab was started, with initial good response and reduction in the size of the lesion in the neck. The regression, however, was short-lived, as the mass quickly grew at a remarkable rate and the lung lesions progressed significantly. Palliative local radiation of 24 Gy in three fractions delivered at days zero, seven, and 21 to the neck mass was eventually given with the goal to alleviate symptoms. An immediate tumor regression was observed after the first fraction of radiotherapy. Remarkably, the lung lesions had also started regressing following radiation. We believe this to be a case of abscopal effect witnessed during the delivery of radiotherapy. A review of the recent literature is also presented here. PMID- 29719741 TI - Crossed Aphasia as a Manifestation of Glioblastoma. AB - Language and speech function is commonly accepted to be a heavily lateralized function. Greater than 95% of right-handed individuals have left hemispheric dominance for language, and reports in the literature of crossed aphasia (language deficits in a right-handed individual from right-sided pathology) are scant. We report the case of a 52-year-old woman presenting with crossed aphasia from a right temporal glioblastoma. We then expand on a discussion of crossed aphasia in the setting of brain tumors. PMID- 29719742 TI - Toxic Myelitis and Arachnoiditis After Intrathecal Delivery of Bupivacaine via an Implanted Drug Delivery System: Case Report and Review of the Literature. AB - The off-label usage of amino-amide anesthetics in intrathecal drug delivery systems (IDDS) for the treatment of chronic non-malignant and malignant pain is supported in the polyanalgesic consensus guidelines as a second-line adjunctive therapy. Although strong evidence for its clinical efficacy is lacking, its clinical safety profile has been well established within established dosing parameters. Despite the rarity of neurological adverse reactions to intrathecal bupivacaine, whether given as regional anesthesia or intrathecal therapy, neurologic morbidity associated with its administration is well documented. The etiology of adverse reactions is often difficult to definitively identify, especially given the variabilities associated with compounding errors in the formulation, solvent contamination, and mechanical factors. We present a rare case of toxic myelitis and arachnoiditis resulting in paraplegia two months after the addition of bupivacaine to the intrathecal analgesic regimen and discuss possible etiological factors with a review of the literature. PMID- 29719743 TI - Ultrasound-guided Erector Spinae Plane Block in a Child Undergoing Laparoscopic Cholecystectomy. AB - Erector spinae plane block (ESP) is a recently described regional anesthesia technique that leads to the blockage of both visceral and somatic nerve fibers. While there are anecdotal reports of ESP used in children, none are for laparoscopic procedures. Herein we report a child undergoing laparoscopic cholecystectomy in which ESP was used as part of multimodal anesthesia. Ultrasound-guided ESP block is an easily performed peripheral nerve block that leads to long-lasting postoperative analgesia. It can be successfully used in pediatric laparoscopic procedures such as cholecystectomy and should be kept in mind as an option for multimodal analgesia in children. PMID- 29719744 TI - An Unusual Presentation of Primary Hepatic Diffuse Large B-cell Lymphoma of the Liver. AB - This report describes a case of primary hepatic diffuse large B-cell lymphoma (DLBCL) in a 64-year-old male who presented with constitutional symptoms, jaundice, abdominal swelling, and right upper quadrant pain. The diagnosis was confirmed on percutaneous liver biopsy. Notably, there was no evidence of extra hepatic involvement. The patient received methylprednisolone and cyclophosphamide with good response but was lost to follow-up upon being transferred. This case highlights the importance of considering primary hepatic DLBCL in patients with unexplained abnormal liver tests and atypical imaging without solitary or discrete lesions, as this rare malignancy can present furtively. PMID- 29719745 TI - Acute Acalculous Cholecystitis in the Setting of Negative Ultrasound and Computed Tomography Scan of the Abdomen. AB - Acute acalculous cholecystitis (AAC) is most commonly seen after surgery in critically ill patients. Early diagnosis and treatment is the key in the management of AAC. Ultrasound is the commonly used first modality for right upper quadrant (RUQ) pain with sensitivity equal to or greater than 80% for AAC. Computed tomography (CT) scan is reported to have a sensitivity close to 90% and if both the ultrasound and CT scan are combined, it further increases the sensitivity for the diagnosis of AAC. It is unlikely for AAC to be present in the setting of both negative ultrasound and CT scan of the abdomen. Our case report presents a similar clinical scenario where the patient was found to have both negative ultrasound and CT scan abdomen but was positive on hepatobiliary iminodiacetic acid (HIDA) scan for AAC as stated below. A 32-year-old male presented to the emergency room with complaints of RUQ pain for two days which was associated with one episode of non-bilious and non-bloody vomiting as well as subjective fever and chills. On presentation, the patient's blood pressure was 87/54 mmHg. Other vitals were unremarkable. The patient had both CT scan abdomen and ultrasound of the RUQ done which reported non-specific findings but were grossly negative for AAC. On the first night of admission, the patient's blood pressure dropped to 84/32 mmHg. The patient was transferred to the intensive care unit (ICU) given the concern for sepsis and was started on intravenous (IV) vancomycin, IV metronidazole and IV levofloxacin (patient was allergic to penicillin). Given the high clinical suspicion, a HIDA scan performed which was positive for AAC. The patient then had a cholecystostomy tube placed by the interventional radiology team. The patient improved rapidly and was eventually discharged with a 14-day course of Bactrim DS (Roche Pharmaceuticals, Nutley, NJ) and metronidazole, and four weeks of outpatient follow up with general surgery. The patient underwent outpatient cholecystectomy in the eighth week from discharge. This leads to the conclusion that even if both the ultrasound and CT scan of the abdomen are negative and clinical suspicion is still high for AAC, the patient should undergo a HIDA scan as delay in treatment is associated with greater than 50% mortality in patients with AAC. PMID- 29719746 TI - Sister Mary Joseph Nodule as a Cutaneous Manifestation of Metastatic Appendiceal Adenocarcinoma: Case Report and Literature Review. AB - Sister Mary Joseph nodule (SMJN) is an uncommon pattern of superficial periumbilical tumor metastasis, with the primary tumor most commonly associated with gynecological or gastrointestinal origins. This manifestation can represent extensive tumor development from any of the intra-abdominal or pelvic structures. Therefore, SMJN carries a poor prognosis, with a two-year survival rate of only 13.5 percent regardless of the etiology of primary cancer. In this case, a 67 year-old man with metastatic mucinous adenocarcinoma of the appendix involving the umbilicus presenting more than five years after the initial cancer diagnosis is reported. The features of patients with metastatic appendiceal carcinoma presenting as SMJN are also reviewed. With the inclusion of our patient, there are six patients who have documented SMJN due to appendiceal carcinoma: two men, two women, and two patients without demographic data. The patients ranged from the ages of 31 to 68 years, with a median age of 56.5 years at cancer diagnosis and 59 years at SMJN diagnosis. In 75 percent of the cases, SMJN was the initial clinical manifestation of a previously unsuspected appendiceal carcinoma and presented clinically one to seven months (median of five months) before the pathologic confirmation of the metastatic appendiceal carcinoma. The likelihood of SMJN presenting as the initial clinical feature of appendiceal cancer may increase in patients with extensive intraperitoneal metastasis in the form of pseudomyxoma peritonei or carcinomatosis. Therefore, the observation of a solitary umbilical nodule should prompt an investigation for an underlying primary neoplasm, as the prognosis after tumor metastasis to the umbilicus is poor. PMID- 29719747 TI - The Influence of Resident Level of Training on Fluoroscopy Time in Pediatric Supracondylar Humeral Fractures Treated with Closed Reduction and Percutaneous Pinning. AB - Objective The purpose of this study was to evaluate the effect of resident level of training on fluoroscopy duration in pediatric supracondylar humeral fractures treated with closed reduction and percutaneous pinning (CRPP). Methods After classifying the surgeons according to their seniorities, the duration of fluoroscopy time of 80 patients with extension type III supracondylar fractures during reduction and pinning was recorded. Results The time duration of reduction procedures was similar in all groups with respect to the surgical experience; however, time durations of percutaneous pinning procedures were found statistically different between groups (p=0.042). Conclusion Surgical experience is very important in the management of supracondylar humeral fractures in children, especially in percutaneous pinning rather than closed reduction. PMID- 29719748 TI - Does Early Endoscopy Improve Mortality in Patients with Acute Non-variceal Gastrointestinal Bleeding? A Retrospective review. AB - Introduction Initial management of acute upper gastrointestinal bleeding (UGIB) aims towards aggressive fluid resuscitation to maintain hemodynamic stability. Existing evidence regarding the benefit of early endoscopy is unclear with some studies suggesting mortality benefits and some suggesting otherwise. The purpose of this study is to evaluate if there is any mortality benefit of doing early endoscopy within 24 hours of presentation. Methods From July 2013 to July 2016, 179 patients admitted with a diagnosis of non-variceal UGIB were retrospectively reviewed. Clinical variables including 30-day mortality were then compared between the patients who had endoscopy within 24 hours with those who had endoscopy after greater than 24 hours. Results Out of 179 patients admitted for non-variceal UGIB, 146 underwent endoscopy within 24 hours of presentation and 33 underwent endoscopy after 24 hours. The overall mortality associated with UGIB was 6.7% (12/179). There was no statistically significant difference found in 30 day mortality between the two groups (6.8% within 24 hours vs 6.1% after 24 hours). There was also no difference in 30-day readmission or rates of rebleeding among the two groups. The length of stay was also similar in both groups (6.0 days vs 6.1 days). Conclusion This study did not find any advantage of endoscopy within 24 hours on length of stay, rate of complications, and 30-day mortality. As hemostasis is achieved in almost 90% of patients with supportive management without any endoscopic intervention, focus should be made on aggressive fluid resuscitation to achieve hemodynamic stability before endoscopy. PMID- 29719749 TI - A Case of Transudative Chylothorax: A Diagnostic Dilemma. AB - Chylothorax is a type of pleural effusion characterized by the presence of chyle in the pleural space with triglyceride levels >110 mg/dL or evidence of chylomicrons in pleural fluid. Chylous effusion is typically exudative in nature with lymphocytic predominance. Transudative chylothorax is a rare finding which has been associated with only a limited range of clinical settings. We report a case of idiopathic transudative chylothorax for which the etiological cause could not be identified despite extensive workup and it resolved spontaneously after thoracentesis. PMID- 29719750 TI - Automated image segmentation-assisted flattening of atomic force microscopy images. AB - Atomic force microscopy (AFM) images normally exhibit various artifacts. As a result, image flattening is required prior to image analysis. To obtain optimized flattening results, foreground features are generally manually excluded using rectangular masks in image flattening, which is time consuming and inaccurate. In this study, a two-step scheme was proposed to achieve optimized image flattening in an automated manner. In the first step, the convex and concave features in the foreground were automatically segmented with accurate boundary detection. The extracted foreground features were taken as exclusion masks. In the second step, data points in the background were fitted as polynomial curves/surfaces, which were then subtracted from raw images to get the flattened images. Moreover, sliding-window-based polynomial fitting was proposed to process images with complex background trends. The working principle of the two-step image flattening scheme were presented, followed by the investigation of the influence of a sliding-window size and polynomial fitting direction on the flattened images. Additionally, the role of image flattening on the morphological characterization and segmentation of AFM images were verified with the proposed method. PMID- 29719751 TI - Enzymatically promoted release of organic molecules linked to magnetic nanoparticles. AB - Magnetite-based magnetic nanoparticles have been successfully coupled to an organic system constituted of a fluorescent molecule, a tripeptide specifier and a spacer. The system is able to selectively release the fluorescent molecule upon targeted enzymatic hydrolysis promoted by a lysine/arginine specific protease. PMID- 29719752 TI - Fatigue crack growth characteristics of Fe and Ni under cyclic loading using a quasi-continuum method. AB - A quasi-continuum (QC) method based on the embedded atom method (EAM) potential was employed to investigate the fatigue crack growth and expansion characteristics of single-crystal Fe and Ni under cyclic loading modes I and II. In particular, the crack growth and expansion characteristics of Fe and Ni under cyclic loading were evaluated in terms of atomic stress fields and force-distance curves. The simulation results indicated that under cyclic loading, the initially damaged area of the crack will coalesce again after compression or shear to the initial geometry leading to a strengthening of the material. If no coalescence appears, the crack spreads rapidly and the material breaks. Moreover, under the cyclic loading of shear at any orientation, the slip dislocation observed in the materials considerably affects the release of stress. PMID- 29719753 TI - An implementation of spin-orbit coupling for band structure calculations with Gaussian basis sets: Two-dimensional topological crystals of Sb and Bi. AB - We present an implementation of spin-orbit coupling (SOC) for density functional theory band structure calculations that makes use of Gaussian basis sets. It is based on the explicit evaluation of SOC matrix elements, both the radial and angular parts. For all-electron basis sets, where the full nodal structure is present in the basis elements, the results are in good agreement with well established implementations such as VASP. For more practical pseudopotential basis sets, which lack nodal structure, an ad-hoc increase of the effective nuclear potential helps to capture all relevant band structure variations induced by SOC. In this work, the non-relativistic or scalar-relativistic Kohn-Sham Hamiltonian is obtained from the CRYSTAL code and the SOC term is added a posteriori. As an example, we apply this method to the Bi(111) monolayer, a paradigmatic 2D topological insulator, and to mono- and multilayer Sb(111) (also known as antimonene), the former being a trivial semiconductor and the latter a topological semimetal featuring topologically protected surface states. PMID- 29719754 TI - Single-crystalline FeCo nanoparticle-filled carbon nanotubes: synthesis, structural characterization and magnetic properties. AB - In the present work, we demonstrate different synthesis procedures for filling carbon nanotubes (CNTs) with equimolar binary nanoparticles of the type Fe-Co. The CNTs act as templates for the encapsulation of magnetic nanoparticles and provide a protective shield against oxidation as well as prevent nanoparticle agglomeration. By variation of the reaction parameters, we were able to tailor the sample purity, degree of filling, the composition and size of the filling particles, and therefore, the magnetic properties. The samples were analyzed by scanning electron microscopy (SEM), transmission electron microscopy (TEM), X-ray diffraction (XRD), superconducting quantum interference device (SQUID) and thermogravimetric analysis (TGA). The Fe-Co-filled CNTs show significant enhancement in the coercive field as compared to the corresponding bulk material, which make them excellent candidates for several applications such as magnetic storage devices. PMID- 29719755 TI - Non-equilibrium electron transport induced by terahertz radiation in the topological and trivial phases of Hg1-x Cd x Te. AB - Terahertz photoconductivity in heterostructures based on n-type Hg1-x Cd x Te epitaxial films both in the topological phase (x < 0.16, inverted band structure, zero band gap) and the trivial state (x > 0.16, normal band structure) has been studied. We show that both the positive photoresponse in films with x < 0.16 and the negative photoconductivity in samples with x > 0.16 have no low-energy threshold. The observed non-threshold positive photoconductivity is discussed in terms of a qualitative model that takes into account a 3D potential well and 2D topological Dirac states coexisting in a smooth topological heterojunction. PMID- 29719756 TI - Magnetic characterization of cobalt nanowires and square nanorings fabricated by focused electron beam induced deposition. AB - The magnetic properties of nanowires (NWs) and square nanorings, which were deposited by focused electron beam induced deposition (FEBID) of a Co carbonyl precursor, are studied using off-axis electron holography (EH), Lorentz transmission electron microscopy (L-TEM) and magnetic force microscopy (MFM). EH shows that NWs deposited using beam energies of 5 and 15 keV have the characteristics of magnetic dipoles, with larger magnetic moments observed for NWs deposited at lower energy. L-TEM is used to image magnetic domain walls in NWs and nanorings and their motion as a function of applied magnetic field. The NWs are found to have almost square hysteresis loops, with coercivities of ca. 10 mT. The nanorings show two different magnetization states: for low values of the applied in-plane field (0.02 T) a horseshoe state is observed using L-TEM, while for higher values of the applied in-plane field (0.3 T) an onion state is observed at remanence using L-TEM and MFM. Our results confirm the suitability of FEBID for nanofabrication of magnetic structures and demonstrate the versatility of TEM techniques for the study and manipulation of magnetic domain walls in nanostructures. PMID- 29719758 TI - Theoretical study of strain-dependent optical absorption in a doped self assembled InAs/InGaAs/GaAs/AlGaAs quantum dot. AB - A detailed theoretical study of the optical absorption in doped self-assembled quantum dots is presented. A rigorous atomistic strain model as well as a sophisticated 20-band tight-binding model are used to ensure accurate prediction of the single particle states in these devices. We also show that for doped quantum dots, many-particle configuration interaction is also critical to accurately capture the optical transitions of the system. The sophisticated models presented in this work reproduce the experimental results for both undoped and doped quantum dot systems. The effects of alloy mole fraction of the strain controlling layer and quantum dot dimensions are discussed. Increasing the mole fraction of the strain controlling layer leads to a lower energy gap and a larger absorption wavelength. Surprisingly, the absorption wavelength is highly sensitive to the changes in the diameter, but almost insensitive to the changes in dot height. This behavior is explained by a detailed sensitivity analysis of different factors affecting the optical transition energy. PMID- 29719759 TI - Room-temperature single-photon emitters in titanium dioxide optical defects. AB - Fluorescence properties of crystallographic point defects within different morphologies of titanium dioxide were investigated. For the first time, room temperature single-photon emission in titanium dioxide optical defects was discovered in thin films and commercial nanoparticles. Three-level defects were identified because the g(2) correlation data featured prominent shoulders around the antibunching dip. Stable and blinking photodynamics were observed for the single-photon emitters. These results reveal a new room-temperature single-photon source within a wide bandgap semiconductor. PMID- 29719760 TI - A simple extension of the commonly used fitting equation for oscillatory structural forces in case of silica nanoparticle suspensions. AB - Background: The ordering of molecules or particles in the vicinity of a confining surface leads to the formation of an interfacial region with layers of decreasing order normal to the confining surfaces. The overlap of two interfacial regions gives rise to the well-known phenomenon of oscillatory structural forces. These forces are commonly fitted with an exponentially decaying harmonic oscillation as introduced by Israelachvili (Israelachvili, J. N. Intermolecular & surface forces; Academic Press: San Diego, CA, USA, 1985). From the fit three important parameters are obtained, namely wavelength, amplitude and decay length, which are related to the period, the strength and the correlation length of the oscillatory structural forces, respectively. The paper addresses structural forces between a silica microsphere and a silicon wafer across silica nanoparticle suspensions measured with a colloidal probe AFM. Using the simple fitting procedure with three parameters often leads to underestimation of actually measured forces. The deviation of the fit from the experimental data is especially pronounced at small distances of the confining surfaces and at high concentrations of silica nanoparticles. As a consequence, the parameters of the common fit equation vary with the starting point of the fit. Although the wavelength is least affected and seems to be quite robust against the starting point of the fit, all three parameters show distinct oscillations, with a period similar to the wavelength of the oscillatory structural forces themselves. The oscillations of amplitude and decay length, which are of much higher magnitude, show a phase shift of 180 degrees implying not only a dependence on the starting point of the fit but also on each other. The range affected by this systematic deviation of the fit parameters is much larger than the optically perceived mismatch between fit and experimental data, giving a false impression of robustness of the fit. Results: By introducing an additional term of exponentially decaying nature the data can be fitted accurately down to very small separations and even for high silica nanoparticle concentrations (10 wt %). Furthermore wavelength, amplitude and decay length become independent of the starting point of the fit and in case of the latter two of each other. The larger forces at small separations indicate a more pronounced ordering behavior of the particles in the final two layers before the wall. This behavior is described by the proposed extension of the common fit equation. Conclusion: Thus, the extension increases the accessible data range in terms of separation and concentration and strongly increases the accuracy for all fitting parameters in the system studied here. PMID- 29719761 TI - P3HT:PCBM blend films phase diagram on the base of variable-temperature spectroscopic ellipsometry. AB - In this work we present an in-depth study of the how the composition of poly(3 hexylthiophene) (P3HT):[6,6]-phenyl-C61-butyric acid methyl ester (PCBM) blend films influences their phase transitions using variable-temperature spectroscopic ellipsometry. We demonstrate that this non-destructive method is a very sensitive optical technique to investigate the phase transitions and to determine the glass transition temperatures and melting crystallization points of the P3HT:PCBM blend films. By analyzing the influence of the temperature T on the raw ellipsometric data, we have identified a high sensitivity of the ellipsometric angle Delta at a wavelength of 280 nm to temperature changes. Characteristic temperatures determined from the slope changes of the Delta(T) plot appeared to be very good guess values for the phase transition temperatures. PMID- 29719762 TI - Imaging of viscoelastic soft matter with small indentation using higher eigenmodes in single-eigenmode amplitude-modulation atomic force microscopy. AB - In this short paper we explore the use of higher eigenmodes in single-eigenmode amplitude-modulation atomic force microscopy (AFM) for the small-indentation imaging of soft viscoelastic materials. In viscoelastic materials, whose response depends on the deformation rate, the tip-sample forces generated as a result of sample deformation increase as the tip velocity increases. Since the eigenfrequencies in a cantilever increase with eigenmode order, and since higher oscillation frequencies lead to higher tip velocities for a given amplitude (in viscoelastic materials), the sample indentation can in some cases be reduced by using higher eigenmodes of the cantilever. This effect competes with the lower sensitivity of higher eigenmodes, due to their larger force constant, which for elastic materials leads to greater indentation for similar amplitudes, compared with lower eigenmodes. We offer a short theoretical discussion of the key underlying concepts, along with numerical simulations and experiments to illustrate a simple recipe for imaging soft viscoelastic matter with reduced indentation. PMID- 29719757 TI - Review on nanoparticles and nanostructured materials: history, sources, toxicity and regulations. AB - Nanomaterials (NMs) have gained prominence in technological advancements due to their tunable physical, chemical and biological properties with enhanced performance over their bulk counterparts. NMs are categorized depending on their size, composition, shape, and origin. The ability to predict the unique properties of NMs increases the value of each classification. Due to increased growth of production of NMs and their industrial applications, issues relating to toxicity are inevitable. The aim of this review is to compare synthetic (engineered) and naturally occurring nanoparticles (NPs) and nanostructured materials (NSMs) to identify their nanoscale properties and to define the specific knowledge gaps related to the risk assessment of NPs and NSMs in the environment. The review presents an overview of the history and classifications of NMs and gives an overview of the various sources of NPs and NSMs, from natural to synthetic, and their toxic effects towards mammalian cells and tissue. Additionally, the types of toxic reactions associated with NPs and NSMs and the regulations implemented by different countries to reduce the associated risks are also discussed. PMID- 29719763 TI - Field-controlled ultrafast magnetization dynamics in two-dimensional nanoscale ferromagnetic antidot arrays. AB - Ferromagnetic antidot arrays have emerged as a system of tremendous interest due to their interesting spin configuration and dynamics as well as their potential applications in magnetic storage, memory, logic, communications and sensing devices. Here, we report experimental and numerical investigation of ultrafast magnetization dynamics in a new type of antidot lattice in the form of triangular shaped Ni80Fe20 antidots arranged in a hexagonal array. Time-resolved magneto optical Kerr effect and micromagnetic simulations have been exploited to study the magnetization precession and spin-wave modes of the antidot lattice with varying lattice constant and in-plane orientation of the bias-magnetic field. A remarkable variation in the spin-wave modes with the orientation of in-plane bias magnetic field is found to be associated with the conversion of extended spin wave modes to quantized ones and vice versa. The lattice constant also influences this variation in spin-wave spectra and spin-wave mode profiles. These observations are important for potential applications of the antidot lattices with triangular holes in future magnonic and spintronic devices. PMID- 29719764 TI - Semi-automatic spray pyrolysis deposition of thin, transparent, titania films as blocking layers for dye-sensitized and perovskite solar cells. AB - For proper function of the negative electrode of dye-sensitized and perovskite solar cells, the deposition of a nonporous blocking film is required on the surface of F-doped SnO2 (FTO) glass substrates. Such a blocking film can minimise undesirable parasitic processes, for example, the back reaction of photoinjected electrons with the oxidized form of the redox mediator or with the hole transporting medium can be avoided. In the present work, thin, transparent, blocking TiO2 films are prepared by semi-automatic spray pyrolysis of precursors consisting of titanium diisopropoxide bis(acetylacetonate) as the main component. The variation in the layer thickness of the sprayed films is achieved by varying the number of spray cycles. The parameters investigated in this work were deposition temperature (150, 300 and 450 degrees C), number of spray cycles (20 200), precursor composition (with/without deliberately added acetylacetone), concentration (0.05 and 0.2 M) and subsequent post-calcination at 500 degrees C. The photo-electrochemical properties were evaluated in aqueous electrolyte solution under UV irradiation. The blocking properties were tested by cyclic voltammetry with a model redox probe with a simple one-electron-transfer reaction. Semi-automatic spraying resulted in the formation of transparent, homogeneous, TiO2 films, and the technique allows for easy upscaling to large electrode areas. The deposition temperature of 450 degrees C was necessary for the fabrication of highly photoactive TiO2 films. The blocking properties of the as-deposited TiO2 films (at 450 degrees C) were impaired by post-calcination at 500 degrees C, but this problem could be addressed by increasing the number of spray cycles. The modification of the precursor by adding acetylacetone resulted in the fabrication of TiO2 films exhibiting perfect blocking properties that were not influenced by post-calcination. These results will surely find use in the fabrication of large-scale dye-sensitized and perovskite solar cells. PMID- 29719765 TI - Electrostatic force spectroscopy revealing the degree of reduction of individual graphene oxide sheets. AB - Electrostatic force spectroscopy (EFS) is a method for monitoring the electrostatic force microscopy (EFM) phase with high resolution as a function of the electrical direct current bias applied either to the probe or sample. Based on the dielectric constant difference of graphene oxide (GO) sheets (reduced using various methods), EFS can be used to characterize the degree of reduction of uniformly reduced one-atom-thick GO sheets at the nanoscale. In this paper, using thermally or chemically reduced individual GO sheets on mica substrates as examples, we characterize their degree of reduction at the nanoscale using EFS. For the reduced graphene oxide (rGO) sheets with a given degree of reduction (sample n), the EFS curve is very close to a parabola within a restricted area. We found that the change in parabola opening direction (or sign the parabola opening value) indicates the onset of reduction on GO sheets. Moreover, the parabola opening value, the peak bias value (tip bias leads to the peak or valley EFM phases) and the EFM phase contrast at a certain tip bias less than the peak value can all indicate the degree of reduction of rGO samples, which is positively correlated with the dielectric constant. In addition, we gave the ranking of degree for reduction on thermally or chemically reduced GO sheets and evaluated the effects of the reducing conditions. The identification of the degree of reduction of GO sheets using EFS is important for reduction strategy optimization and mass application of GO, which is highly desired owing to its mechanical, thermal, optical and electronic applications. Furthermore, as a general and quantitative technique for evaluating the small differences in the dielectric properties of nanomaterials, the EFS technique will extend and facilitate its nanoscale electronic devices applications in the future. PMID- 29719766 TI - Thermoelectric current in topological insulator nanowires with impurities. AB - In this paper we consider charge current generated by maintaining a temperature difference over a nanowire at zero voltage bias. For topological insulator nanowires in a perpendicular magnetic field the current can change sign as the temperature of one end is increased. Here we study how this thermoelectric current sign reversal depends on the magnetic field and how impurities affect the size of the thermoelectric current. We consider both scalar and magnetic impurities and show that their influence on the current are quite similar, although the magnetic impurities seem to be more effective in reducing the effect. For moderate impurity concentration the sign reversal persists. PMID- 29719767 TI - Understanding the performance and mechanism of Mg-containing oxides as support catalysts in the thermal dry reforming of methane. AB - Dry reforming of methane (DRM) is one of the more promising methods for syngas (synthetic gas) production and co-utilization of methane and carbon dioxide, which are the main greenhouse gases. Magnesium is commonly applied in a Ni-based catalyst in DRM to improve catalyst performance and inhibit carbon deposition. The aim of this review is to gain better insight into recent developments on the use of Mg as a support or promoter for DRM catalysts. Its high basicity and high thermal stability make Mg suitable for introduction into the highly endothermic reaction of DRM. The introduction of Mg as a support or promoter for Ni-based catalysts allows for good metal dispersion on the catalyst surface, which consequently facilitates high catalytic activity and low catalyst deactivation. The mechanism of DRM and carbon formation and reduction are reviewed. This work further explores how different constraints, such as the synthesis method, metal loading, pretreatment, and operating conditions, influence the dry reforming reactions and product yields. In this review, different strategies for enhancing catalytic activity and the effect of metal dispersion on Mg-containing oxide catalysts are highlighted. PMID- 29719768 TI - Bioactive characteristics and optimization of tamarind seed protein hydrolysate for antioxidant-rich food formulations. AB - Tamarind seed has been a source of valuable nutrients such as protein (contains high amount of many essential amino acids), essential fatty acids, and minerals which are recognized as additive to develop perfect balanced functional foods. The objective of present work was to optimize the process parameters for extraction and hydrolysis of protein from tamarind seeds. Papain-derived hydrolysates showed a maximum degree of hydrolysis (39.49%) and radical scavenging activity (42.92 +/- 2.83%) at optimized conditions such as enzyme-to substrate ratio (1:5), hydrolysis time (3 h), hydrolysis temperature (65 degrees C), and pH 6. From this study, papain hydrolysate can be considered as good source of natural antioxidants in developing food formulations. PMID- 29719769 TI - Purification, developmental expression, and in silico characterization of alpha amylase inhibitor from Echinochloa frumentacea. AB - Barnyard (Echinochloa frumentacea) and finger (Eleusine coracana) millet growing at northwestern Himalaya were explored for the alpha-amylase inhibitor (alpha AI). The mature seeds of barnyard millet variety PRJ1 had maximum alpha-AI activity which increases in different developmental stage. alpha-AI was purified up to 22.25-fold from barnyard millet variety PRJ1. Semi-quantitative PCR of different developmental stages of barnyard millet seeds showed increased levels of the transcript from 7 to 28 days. Sequence analysis revealed that it contained 315 bp nucleotide which encodes 104 amino acid sequence with molecular weight 10.72 kDa. The predicted 3D structure of alpha-AI was 86.73% similar to a bifunctional inhibitor of ragi. In silico analysis of 71 alpha-AI protein sequences were carried out for biochemical features, homology search, multiple sequence alignment, phylogenetic tree construction, motif, and superfamily distribution of protein sequences. Analysis of multiple sequence alignment revealed the existence of conserved regions NPLP[S/G]CRWYVV[S/Q][Q/R]TCG[V/I] throughout sequences. Superfam analysis revealed that alpha-AI protein sequences were distributed among seven different superfamilies. PMID- 29719771 TI - Bioremediation of oil-based drill cuttings by a halophilic consortium isolated from oil-contaminated saline soil. AB - Oil-based drill cuttings are hazardous wastes containing complex hydrocarbons, heavy metals, and brine. Their remediation is a crucial step before release to the environment. In this work, we enriched a halophilic consortium, from oil polluted saline soil, which is capable of degrading diesel as the main pollutant of oil-based drill cuttings. The degradation ability of the consortium was evaluated in microcosms using two different diluting agents (fine sand and biologically active soil). During the bioremediation process, the bacterial community dynamics of the microcosms was surveyed using PCR amplification of a fragment of 16S rRNA gene followed by denaturing gradient gel electrophoresis (DGGE). The diesel degradation rates were monitored by total petroleum hydrocarbon (TPH) measurement and the total count of heterotrophic and diesel degrading bacteria. After 3 months, the microcosm containing fine sand and drill cuttings with the ratio of 1:1 (initial TPH of 36,000 mg/kg) showed the highest TPH removal (40%) and its dominant bacterial isolates belonged to the genera Dietzia, Arthrobacter, and Halomonas. DGGE results also confirmed the role of these genera in drill cuttings remediation. DGGE analysis of the bacterial diversity showed that Propionibacterium, Salinimicrobium, Marinobacter, and Dietzia are dominant in active soil microcosm; whereas Bacillus, Salinibacillus, and Marinobacter are abundant in sand microcosm. Our results suggest that the bioaugmentation strategy would be more successful if the diluting agent does not contain a complex microbial community. PMID- 29719770 TI - Identification of curcumin derivatives as human LMTK3 inhibitors for breast cancer: a docking, dynamics, and MM/PBSA approach. AB - Human lemur tyrosine kinase-3 (LMTK3) is primarily involved in regulation of estrogen receptor-alpha (ERalpha) by phosphorylation activity. LMTK3 acts as key biomarker for ERalpha positive breast cancer and identified as novel drug target for breast cancer. Due to the absence of experimental reports, the computational approach has been followed to screen LMTK3 inhibitors from natural product curcumin derivatives based on rational inhibitor design. The initial virtual screening and re-docking resulted in identification of top three leads with favorable binding energy and strong interactions in critical residues of ATP binding cavity. ADME prediction confirmed the pharmacological activity of the leads with various properties. The stability and binding affinity of leads were well refined in dynamic system from 25 ns MD simulations. The behavior of protein motion towards closure of ATP-binding cavity was evaluated based on eigenvectors by PCA. In addition, MM/PBSA calculations also confirmed the relative binding free energy of LMTK3-lead complexes in favor of the effective binding. From our study, novel LMTK3 inhibitors tetrahydrocurcumin, curcumin 4,4'-diacetate, and demethoxycurcumin have been proposed with inhibition mechanism. Further experimental evaluation on reported lead candidates might prove its role in breast cancer therapeutics. PMID- 29719772 TI - Exploring expression patterns of PR-1, PR-2, PR-3, and PR-12 like genes in Arabidopsis thaliana upon Alternaria brassicae inoculation. AB - In this study, we systematically examined the expression patterns of pathogenesis related genes in model plant Arabidopsis thaliana after Alternaria brassicae inoculation using reverse transcription polymerase chain reaction(RT-PCR). Based on the results, none of the PR-1 and PR-2 like genes were induced significantly in the unwounded local or distal leaves upon A. brassicae challenge. However, only At2g14580 of the PR-1like gene showed a significant expression in wounded leave after Alternaria challenge but not in control; confirming its expression in response to A. brassicae was aided by the wounding. Among PR-3 like genes, At2g43590 showed local early expression and other PR-3 like genes showed significant distal expression after A. brassicae infection only in unwounded but not in wounded leaf samples. Although all the three PR-12 like genes were induced in local tissues, At2g26020 was the only gene showed significant induction locally as well as systemically after pathogen infection in the both with and without wounding experiments. Therefore, among the PR-1, PR-2, PR-3 and PR-12 like genes studied, At2g26020 can be the most promising candidate for the further line of research, viz, molecular characterization of its promoter to develop pathogen-inducible promoter in response to Alternaria and to develop fungus resistant transgenics in Brassica juncea. PMID- 29719773 TI - Biosynthesis of miglitol intermediate 6-(N-hydroxyethyl)-amino-6-deoxy-alpha-l sorbofuranose by an improved d-sorbitol dehydrogenase from Gluconobacter oxydans. AB - Adaptable exploitation of the catalytic potential of membrane-bound d-sorbitol dehydrogenase (mSLDH) from Gluconobacter oxydans is desperately needed in the industrial-scale production of miglitol. In the present study, a carbonyl group dependent colorimetric quantification method was developed for the assay of miglitol key intermediate 6-(N-hydroxyethyl)-amino-6-deoxy-alpha-l-sorbofuranose (6NSL), and a high-throughput screening process of positive mutants was processed. Combined with several rounds of ultraviolet irradiation mutagenesis and screening procedure, a positive mutant strain G. oxydans ZJB16009 was obtained with significant increase in mSLDH catalytic activity by 1.5-fold, which exhibited an extremely accelerated uptake rate of d-sorbitol, and the fermentation time was significantly shortened from 22 to 11 h. In a 5-L biotransformation system, 60 g/L substrate N-2-hydroxyethyl glucamine (NHEG) was catalyzed by the resting cells of the mutant strain within 36 h and accumulated 53.6 g/L 6NSL, showing a 33.6% increase in the product yield. Therefore, it was indicated that the established high-throughput screening method could provide a highly efficient platform for the breading of G. oxydans strain for the industrial biosynthesis of miglitol intermediate 6NSL. PMID- 29719774 TI - Anti-retroviral drugs: current state and development in the next decade. AB - The pace of discovery of new antiretroviral (ARV) drugs has slowed, although the efficacy and safety of once-daily fixed dose combinations have been extensively investigated. Several traditional ARV drugs remain in phase III clinical trials. This review summarizes current information on ARV drugs in phase III clinical trials and focuses on the development of ARV drugs in the next decade. PMID- 29719775 TI - An updated overview on the development of new photosensitizers for anticancer photodynamic therapy. AB - Photodynamic therapy (PDT), based on the photoactivation of photosensitizers (PSs), has become a well-studied therapy for cancer. Photofrin(r), belonging to the first generation of PS, is still widely used for the treatment of different kinds of cancers; however, it has several drawbacks that significantly limit its general clinical use. Consequently, there has been extensive research on the design of PS molecules with optimized pharmaceutical properties, with aiming of overcoming the disadvantages of traditional PS, such as poor chemical purity, long half-life, excessive accumulation into the skin, and low attenuation coefficients. The rational design of novel PS with desirable properties has attracted considerable research in the pharmaceutical field. This review presents an overview on the classical photosensitizers and the most significant recent advances in the development of PS with regard to their potential application in oncology. PMID- 29719776 TI - Designing the new generation of intelligent biocompatible carriers for protein and peptide delivery. AB - Therapeutic proteins and peptides have revolutionized treatment for a number of diseases, and the expected increase in macromolecule-based therapies brings a new set of challenges for the pharmaceutics field. Due to their poor stability, large molecular weight, and poor transport properties, therapeutic proteins and peptides are predominantly limited to parenteral administration. The short serum half-lives typically require frequent injections to maintain an effective dose, and patient compliance is a growing issue as therapeutic protein treatments become more widely available. A number of studies have underscored the relationship of subcutaneous injections with patient non-adherence, estimating that over half of insulin-dependent adults intentionally skip injections. The development of oral formulations has the potential to address some issues associated with non-adherence including the interference with daily activities, embarrassment, and injection pain. Oral delivery can also help to eliminate the adverse effects and scar tissue buildup associated with repeated injections. However, there are several major challenges associated with oral delivery of proteins and peptides, such as the instability in the gastrointestinal (GI) tract, low permeability, and a narrow absorption window in the intestine. This review provides a detailed overview of the oral delivery route and associated challenges. Recent advances in formulation and drug delivery technologies to enhance bioavailability are discussed, including the co-administration of compounds to alter conditions in the GI tract, the modification of the macromolecule physicochemical properties, and the use of improved targeted and controlled release carriers. PMID- 29719778 TI - 1,25-Dihydroxyvitamin D3 protects obese rats from metabolic syndrome via promoting regulatory T cell-mediated resolution of inflammation. AB - Vitamin D3 has been found to produce therapeutic effects on obesity-associated insulin resistance and dyslipidemia through its potent anti-inflammatory activity, but the precise immunomodulatory mechanism remains poorly understood. In the present study we found that 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], the biologically active form of vitamin D3, significantly attenuated monosodium glutamate (MSG)-induced obesity and insulin resistance as indicated by body weight reduction, oral glucose tolerance improvement, and a glucose infusion rate increase as detected with hyperinsulinemic-euglycemic clamp. Moreover, 1,25(OH)2D3 not only restored pancreatic islet functions but also improved lipid metabolism in insulin-targeted tissues. The protective effects of 1,25(OH)2D3 on glycolipid metabolism were attributed to its ability to inhibit an obesity activated inflammatory response in insulin secretory and targeted tissues, as indicated by reduced infiltration of macrophages in pancreas islets and adipose tissue while enhancing the expression of Tgf-beta1 in liver tissue, which was accompanied by increased infiltration of Treg cells in immune organs such as spleen and lymph node as well as in insulin-targeted tissues such as liver, adipose, and muscle. Together, our findings suggest that 1,25(OH)2D3 serves as a beneficial immunomodulator for the prevention and treatment of obesity or metabolic syndrome through its anti-inflammatory effects. PMID- 29719779 TI - A pilot study of the modulation of sirtuins on arylamine N-acetyltransferase 1 and 2 enzymatic activity. AB - Arylamine N-acetyltransferase (NAT; E.C. 2.3.1.5) enzymes are responsible for the biotransformation of several arylamine and hydrazine drugs by acetylation. In this process, the acetyl group transferred to the acceptor substrate produces NAT deacetylation and, in consequence, it is susceptible of degradation. Sirtuins are protein deacetylases, dependent on nicotine adenine dinucleotide, which perform post-translational modifications on cytosolic proteins. To explore possible sirtuin participation in the enzymatic activity of arylamine NATs, the expression levels of NAT1, NAT2, SIRT1 and SIRT6 in peripheral blood mononuclear cells (PBMC) from healthy subjects were examined by flow cytometry and Western blot. The in situ activity of the sirtuins on NAT enzymatic activity was analyzed by HPLC, in the presence or absence of an agonist (resveratrol) and inhibitor (nicotinamide) of sirtuins. We detected a higher percentage of positive cells for NAT2 in comparison with NAT1, and higher numbers of SIRT1+ cells compared to SIRT6 in lymphocytes. In situ NAT2 activity in the presence of NAM inhibitors was higher than in the presence of its substrate, but not in the presence of resveratrol. In contrast, the activity of NAT1 was not affected by sirtuins. These results showed that NAT2 activity might be modified by sirtuins. PMID- 29719777 TI - Mesoporous silica nanoparticles for drug and gene delivery. AB - Mesoporous silica nanoparticles (MSNs) are attracting increasing interest for potential biomedical applications. With tailored mesoporous structure, huge surface area and pore volume, selective surface functionality, as well as morphology control, MSNs exhibit high loading capacity for therapeutic agents and controlled release properties if modified with stimuli-responsive groups, polymers or proteins. In this review article, the applications of MSNs in pharmaceutics to improve drug bioavailability, reduce drug toxicity, and deliver with cellular targetability are summarized. Particularly, the exciting progress in the development of MSNs-based effective delivery systems for poorly soluble drugs, anticancer agents, and therapeutic genes are highlighted. PMID- 29719780 TI - Establishment of pseudovirus infection mouse models for in vivo pharmacodynamics evaluation of filovirus entry inhibitors. AB - Filoviruses cause severe and fatal viral hemorrhagic fever in humans. Filovirus research has been extensive since the 2014 Ebola outbreak. Due to their high pathogenicity and mortality, live filoviruses require Biosafety Level-4 (BSL-4) facilities, which have restricted the development of anti-filovirus vaccines and drugs. An HIV-based pseudovirus cell infection assay is widely used for viral entry studies in BSL-2 conditions. Here, we successfully constructed nine in vitro pseudo-filovirus models covering all filovirus genera and three in vivo pseudo-filovirus-infection mouse models using Ebola virus, Marburg virus, and Lloviu virus as representative viruses. The pseudo-filovirus-infected mice showed visualizing bioluminescence in a dose-dependent manner. A bioluminescence peak in mice was reached on day 5 post-infection for Ebola virus and Marburg virus and on day 4 post-infection for Lloviu virus. Two known filovirus entry inhibitors, clomiphene and toremiphene, were used to validate the model. Collectively, our study shows that all genera of filoviruses can be well-pseudotyped and are infectious in vitro. The pseudo-filovirus-infection mouse models can be used for in vivo activity evaluation of anti-filovirus drugs. This sequential in vitro and in vivo evaluation system of filovirus entry inhibitors provides a secure and efficient platform for screening and assessing anti-filovirus agents in BSL-2 facilities. PMID- 29719781 TI - A novel quantified bitterness evaluation model for traditional Chinese herbs based on an animal ethology principle. AB - Traditional Chinese herbs (TCH) are currently gaining attention in disease prevention and health care plans. However, their general bitter taste hinders their use. Despite the development of a variety of taste evaluation methods, it is still a major challenge to establish a quantitative detection technique that is objective, authentic and sensitive. Based on the two-bottle preference test (TBP), we proposed a novel quantitative strategy using a standardized animal test and a unified quantitative benchmark. To reduce the difference of results, the methodology of TBP was optimized. The relationship between the concentration of quinine and animal preference index (PI) was obtained. Then the PI of TCH was measured through TBP, and bitterness results were converted into a unified numerical system using the relationship of concentration and PI. To verify the authenticity and sensitivity of quantified results, human sensory testing and electronic tongue testing were applied. The quantified results showed a good discrimination ability. For example, the bitterness of Coptidis Rhizoma was equal to 0.0579 mg/mL quinine, and Nelumbinis Folium was equal to 0.0001 mg/mL. The validation results proved that the new assessment method for TCH was objective and reliable. In conclusion, this study provides an option for the quantification of bitterness and the evaluation of taste masking effects. PMID- 29719782 TI - Beneficial effects of Houttuynia cordata polysaccharides on "two-hit" acute lung injury and endotoxic fever in rats associated with anti-complementary activities. AB - Houttuynia cordata Thunb. is a traditional herb used for clearing heat and eliminating toxins, and has also been used for the treatment of severe acute respiratory syndrome (SARS). In vitro, the crude H. cordata polysaccharides (CHCP) exhibited potent anti-complementary activity through both the classical and alternative pathways by acting on components C3 and C4 of the complement system without interfering with the coagulation system. This study was to investigate the preventive effects of CHCP on acute lung injury (ALI) induced by hemorrhagic shock plus lipopolysaccharide (LPS) instillation (two-hit) and LPS induced fever in rats. CHCP significantly attenuated pulmonary injury in the "two hit" ALI model by reducing pulmonary edema and protein exudation in bronchoalveolar lavage fluid (BALF). In addition, it reduced the deposit of complement activation products in the lung and improved oxidant-antioxidant imbalance. Moreover, CHCP administration inhibited fever in rats, reduced the number of leukocytes and restored serum complement levels. The inhibition on the inappropriate activation of complement system by CHCP may play an important role in its beneficial effects on inflammatory diseases. The anti-complementary polysaccharides are likely to be among the key substances for the heat-clearing function of H. cordata. PMID- 29719783 TI - Separation and simultaneous quantitation of PGF2alpha and its epimer 8-iso PGF2alpha using modifier-assisted differential mobility spectrometry tandem mass spectrometry. AB - Because many therapeutic agents are contaminated by epimeric impurities or form epimers as a result of metabolism, analytical tools capable of determining epimers are increasingly in demand. This article is a proof-of-principle report of a novel DMS-MS/MS method to separate and simultaneously quantify epimers, taking PGF2alpha and its 8-epimer, 8-iso-PGF2alpha, as an example. Good accuracy and precision were achieved in the range of 10-500 ng/mL with a run time of only 1.5 min. Isopropanol as organic modifier facilitated a good combination of sensitivity and separation. The method is the first example of the quantitation of epimers without chromatographic separation. PMID- 29719784 TI - Rapid and sensitive liquid chromatography-tandem mass spectrometric method for the quantitative determination of potentially harmful substance 5,5' oxydimethylenebis (2-furfural) in traditional Chinese medicine injections. AB - With the rapid development and wide application of traditional Chinese medicine injection (TCMI), a number of adverse events of some TCMIs have incessantly been reported and have drawn broad attention in recent years. Establishing effective and practical analytical methods for safety evaluation and quality control of TCMI can help to improve the safety of TCMIs in clinical applications. In this study, a sensitive and rapid high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method has been developed and validated for the quantitative determination of potentially harmful substance 5,5' oxydimethylenebis (2-furfural, OMBF) in TCMI samples. Chromatographic separation was performed on a C18 reversed-phase column (150 mm * 2.1 mm, 5 um) by gradient elution, using methanol-water containing 0.1% formic acid as mobile phase at the flow rate of 0.3 mL/min. MS/MS detection was performed on a triple quadrupole mass spectrometer with positive electrospray ionization in the multiple reaction monitoring mode. The method was sensitive with a limit of quantification of 0.3 ng/mL and linear over the range of 0.3-30 ng/mL (r=0.9998). Intra- and inter-day precision for analyte was <9.52% RSD with recoveries in the range 88.0-109.67% at three concentration levels. The validated method was successfully applied to quantitatively determine the compound OMBF in TCMIs and glucose injections. Our study indicates that this method is simple, sensitive, practicable and reliable, and could be applied for safety evaluation and quality control of TCMIs and glucose injections. PMID- 29719785 TI - Correlation analysis between the chemical contents and bioactivity for the quality control of Alismatis Rhizoma. AB - In order to clarify regions of production and to discriminate processing methods, quantitative and qualitative analyses for saccharides and terpenes in 35 batches of Alismatis Rhizoma were performed. Methodologies included HPLC-PDA, HPLC-VWD and UHPLC-MS n , combined with principal component analysis (PCA) and partial least squares regression techniques (PLSR). The inhibitory effects of triterpenes and Alismatis Rhizoma extracts on lipase activity were evaluated in vitro. PLSR analysis revealed significant positive correlations (R2 = 0.5795) between the contents of triterpenes 10, 14, 15, 18 and 22 and the inhibitory effects of Alismatis Rhizoma. The present study establishes an effective method for simultaneous determination of multiple components, and identifies key bioactive triterpenes. These results can be used for systematic and novel analytical strategies for the quality control of Alismatis Rhizoma production. PMID- 29719786 TI - Comparative untargeted proteomic analysis of ADME proteins and tumor antigens for tumor cell lines. AB - In the present study, total membrane proteins from tumor cell lines including HepG2, Hep3B2, H226, Ovcar3 and N87 were extracted and digested with gammaLysC and trypsin. The resulting peptide lysate were pre-fractionated and subjected to untargeted quantitative proteomics analysis using a high resolution mass spectrometer. The mass spectra were processed by the MaxQuant and the protein abundances were estimated using total peak area (TPA) method. A total of 6037 proteins were identified, and the analysis resulted in the identification of 2647 membrane proteins. Of those, tumor antigens and absorption, metabolism, disposition and elimination (ADME) proteins including UDP glucuronosyltransferase, cytochrome P450, solute carriers and ATP-binding cassette transporters were detected and disclosed significant variations among the cell lines. The principal component analysis was performed for the cluster of cell lines. The results demonstrated that H226 is closely related with N87, while Hep3B2 aligned with HepG2. The protein cluster of Ovcar3 was apart from that of other cell lines investigated. By providing for the first time quantitative untargeted proteomics analysis, the results delineated the expression profiles of membrane proteins. These findings provided a useful resource for selecting targets of choice for anticancer therapy through advancing data obtained from preclinical tumor cell line models to clinical outcomes. PMID- 29719787 TI - Liposomes and lipid disks traverse the BBB and BBTB as intact forms as revealed by two-step Forster resonance energy transfer imaging. AB - The blood-brain barrier (BBB) and the blood-brain tumor barrier (BBTB) prevent drug and nano-drug delivery systems from entering the brain. However, ligand mediated nano-drug delivery systems have significantly enhanced the therapeutic treatment of glioma. In this study we investigated the mechanism especially the integrity of liposomes and lipid disks while traversing the BBB and BBTB both in vitro and in vivo. Fluorophores (DiO, DiI and DiD) were loaded into liposomes and lipid disks to form Forster resonance energy transfer (FRET) nano-drug delivery systems. Using brain capillary endothelial cells as a BBB model, we show that liposomes and disks are present in the cytoplasm as their intact forms and traverse the BBB with a ratio of 0.680/00 and 1.670/00, respectively. Using human umbilical vein endothelial cells as BBTB model, liposomes and disks remained intact and traversed the BBTB with a ratio of 2.310/00 and 8.320/00 at 3 h. Ex vivo imaging and immunohistochemical results revealed that liposomes and disks could traverse the BBB and BBTB in vivo as intact forms. In conclusion, these observations explain in part the mechanism by which nano-drug delivery systems increase the therapeutic treatment of glioma. PMID- 29719788 TI - Rhizospheric microbial communities are driven by Panax ginseng at different growth stages and biocontrol bacteria alleviates replanting mortality. AB - The cultivation of Panax plants is hindered by replanting problems, which may be caused by plant-driven changes in the soil microbial community. Inoculation with microbial antagonists may efficiently alleviate replanting issues. Through high throughput sequencing, this study revealed that bacterial diversity decreased, whereas fungal diversity increased, in the rhizosphere soils of adult ginseng plants at the root growth stage under different ages. Few microbial community, such as Luteolibacter, Cytophagaceae, Luteibacter, Sphingomonas, Sphingomonadaceae, and Zygomycota, were observed; the relative abundance of microorganisms, namely, Brevundimonas, Enterobacteriaceae, Pandoraea, Cantharellales, Dendryphion, Fusarium, and Chytridiomycota, increased in the soils of adult ginseng plants compared with those in the soils of 2-year-old seedlings. Bacillus subtilis 50-1, a microbial antagonist against the pathogenic Fusarium oxysporum, was isolated through a dual culture technique. These bacteria acted with a biocontrol efficacy of 67.8%. The ginseng death rate and Fusarium abundance decreased by 63.3% and 46.1%, respectively, after inoculation with B. subtilis 50-1. Data revealed that microecological degradation could result from ginseng-driven changes in rhizospheric microbial communities; these changes are associated with the different ages and developmental stages of ginseng plants. Biocontrol using microbial antagonists alleviated the replanting problem. PMID- 29719789 TI - Biosynthesis of antibiotic chuangxinmycin from Actinoplanes tsinanensis. AB - Chuangxinmycin is an antibiotic isolated from Actinoplanes tsinanensis CPCC 200056 in the 1970s with a novel indole-dihydrothiopyran heterocyclic skeleton. Chuangxinmycin showed in vitro antibacterial activity and in vivo efficacy in mouse infection models as well as preliminary clinical trials. But the biosynthetic pathway of chuangxinmycin has been obscure since its discovery. Herein, we report the identification of a stretch of DNA from the genome of A. tsinanensis CPCC 200056 that encodes genes for biosynthesis of chuangxinmycin by bioinformatics analysis. The designated cxn cluster was then confirmed to be responsible for chuangxinmycin biosynthesis by direct cloning and heterologous expressing in Streptomyces coelicolor M1146. The cytochrome P450 CxnD was verified to be involved in the dihydrothiopyran ring closure reaction by the identification of seco-chuangxinmycin in S. coelicolor M1146 harboring the cxn gene cluster with an inactivated cxnD. Based on these results, a plausible biosynthetic pathway for chuangxinmycin biosynthesis was proposed, by hijacking the primary sulfur transfer system for sulfur incorporation. The identification of the biosynthetic gene cluster of chuangxinmycin paves the way for elucidating the detail biochemical machinery for chuangxinmycin biosynthesis, and provides the basis for the generation of novel chuangxinmycin derivatives by means of combinatorial biosynthesis and synthetic biology. PMID- 29719790 TI - Genomic survey of bZIP transcription factor genes related to tanshinone biosynthesis in Salvia miltiorrhiza. AB - Tanshinones are a class of bioactive components in the traditional Chinese medicine Salvia miltiorrhiza, and their biosynthesis and regulation have been widely studied. Current studies show that basic leucine zipper (bZIP) proteins regulate plant secondary metabolism, growth and developmental processes. However, the bZIP transcription factors involved in tanshinone biosynthesis are unknown. Here, we conducted the first genome-wide survey of the bZIP gene family and analyzed the phylogeny, gene structure, additional conserved motifs and alternative splicing events in S. miltiorrhiza. A total of 70 SmbZIP transcription factors were identified and categorized into 11 subgroups based on their phylogenetic relationships with those in Arabidopsis. Moreover, seventeen SmbZIP genes underwent alternative splicing events. According to the transcriptomic data, the SmbZIP genes that were highly expressed in the Danshen root and periderm were selected. Based on the prediction of bZIP binding sites in the promoters and the co-expression analysis and co-induction patterns in response to Ag+ treatment via quantitative real-time polymerase chain reaction (qRT-PCR), we concluded that SmbZIP7 and SmbZIP20 potentially participate in the regulation of tanshinone biosynthesis. These results provide a foundation for further functional characterization of the candidate SmbZIP genes, which have the potential to increase tanshinone production. PMID- 29719791 TI - Antihyperuricemic effect of mangiferin aglycon derivative J99745 by inhibiting xanthine oxidase activity and urate transporter 1 expression in mice. AB - A mangiferin aglycon derivative J99745 has been identified as a potent xanthine oxidase (XOD) inhibitor by previous in vitro study. This study aimed to evaluate the hypouricemic effects of J99745 in experimental hyperuricemia mice, and explore the underlying mechanisms. Mice were orally administered 600 mg/kg xanthine once daily for 7 days and intraperitoneally injected 250 mg/kg oxonic acid on the 7th day to induce hyperuricemia. Meanwhile, J99745 (3, 10, and 30 mg/kg), allopurinol (20 mg/kg) or benzbromarone (20 mg/kg) were orally administered to mice for 7 days. On the 7th day, uric acid and creatinine in serum and urine, blood urea nitrogen (BUN), malondialdehyde (MDA) content and XOD activities in serum and liver were determined. Morphological changes in kidney were observed using hematoxylin and eosin (H&E) staining. Hepatic XOD, renal urate transporter 1 (URAT1), glucose transporter type 9 (GLUT9), organic anion transporter 1 (OAT1) and ATP-binding cassette transporter G2 (ABCG2) were detected by Western blot and real time polymerase chain reaction (PCR). The results showed that J99745 at doses of 10 and 30 mg/kg significantly reduced serum urate, and enhanced fractional excretion of uric acid (FEUA). H&E staining confirmed that J99745 provided greater nephroprotective effects than allopurinol and benzbromarone. Moreover, serum and hepatic XOD activities and renal URAT1 expression declined in J99745-treated hyperuricemia mice. In consistence with the ability to inhibit XOD, J99745 lowered serum MDA content in hyperuricemia mice. Our results suggest that J99745 exerts urate-lowering effect by inhibiting XOD activity and URAT1 expression, thus representing a promising candidate as an anti hyperuricemia agent. PMID- 29719792 TI - Acute exacerbation of idiopathic pulmonary fibrosis triggered by Aspergillus empyema. AB - Acute exacerbation (AE) is a severe and life-threatening complication of idiopathic pulmonary fibrosis (IPF). In 2016, the definition and diagnostic criteria for AE-IPF were updated by an international working group. The new definition includes any acute, clinically significant respiratory deterioration (both idiopathic and triggered events) characterized by evidence of new widespread alveolar abnormality in patients with IPF. There are no currently proven beneficial management strategies for idiopathic and triggered AE-IPF. This is the first report describing AE-IPF triggered by Aspergillus empyema, which was improved by a combination of corticosteroid, systemic antifungal therapy, local antifungal therapy, and additional pharmacological therapies. Future research may reveal optimal strategies for both idiopathic and triggered AE-IPF. PMID- 29719793 TI - An unusual case of lung abscess secondary to round pneumonia caused by recurrent Klebsiella pneumoniae strain and the role of occult metastases tumor. AB - Round pneumonia is an uncommon form of community-acquired pneumonia usually found in children. To this date, there has been no report on local pulmonary complications in this entity in adult patients. The present study reports a case of a 77-year-old male with lung abscess secondary to round pneumonia caused by recurrent Klebsiella pneumoniae infection accompanied by occult metastases tumor. Occult metastases may have played an important role in leading to cavity as in this present case. Further investigation regarding the relationship between recurrent infection and metastases is needed. PMID- 29719794 TI - Pleuroparenchymal sarcoidosis - A recognised but rare manifestation of disease. AB - Pleural involvement is rare in sarcoidosis. The presence of a large symptomatic effusion in a patient with sarcoidosis should therefore prompt further investigation for an alternate aetiology. Here we present a case of confirmed pleuro-parenchymal sarcoidosis. We discuss the important differential diagnoses and review the current literature. PMID- 29719795 TI - Mediastinal angiosarcoma presenting as diffuse alveolar hemorrhage. AB - Angiosarcomas are malignant vascular tumors. Angiosarcomas arising in the thorax such as angiosarcoma of the lungs, heart and mediastinum are extremely rare. There are no reports of mediastinal angiosarcomas presenting with diffuse alveolar hemorrhage, which is a clinical syndrome characterized by the presence of hemoptysis, dyspnea, hypoxia, diffuse lung infiltrates and anemia. Usually, diffuse alveolar hemorrhage is caused by pulmonary capillaritis. Local invasion is more common with these tumors than distant metastasis. These tumors are very aggressive and have a poor response to treatment modalities including surgical resection, chemotherapy, and radiation. Consequently, they carry a poor prognosis. Due to the rarity of these tumors, no standard chemotherapy or radiation protocol exists. We report a case of diffuse alveolar hemorrhage caused by a previously unreported entity: angiosarcoma of the mediastinum. PMID- 29719796 TI - Use of high-flow nasal cannula in obese patients receiving colonoscopy under intravenous propofol sedation: A case series. AB - Intravenous sedation during colonoscopy has become the standard practice in the United States given its higher patient satisfaction and procedural quality. This practice is not free of side effects as a significant proportion of patients undergoing this procedure tend to have respiratory depression and desaturation events. Obesity, as it relates to higher levels of body mass index (BMI) has a positive correlation with the incidence of hypoxemia. During colonoscopy High flow nasal cannula (HFNC) may potentially improve oxygen performance in patients receiving colonoscopy under intravenous sedation. Here we present 3 cases of patients undergoing adjunctive oxygen therapy with HFNC during colonoscopy with intravenous sedation. We found patients to have lower number of desaturation events and were satisfied with their experience. PMID- 29719797 TI - Convex-probe endobronchial ultrasound for thyroid biopsy a new hybrid method. AB - Nowadays we use novel diagnostic equipment for lung cancer. Bronchoscopy was the tip of the arrow for diagnosis, however; ultrasound systems have brought a revolution. We have the radial-endobronchial ultrasound for peripheral lesions and the convex probe endobronchial ultrasound for central lesions. Ultrasound endoscopic systems can be used for the diagnosis of any lesion that can be approached from the airways. In the current manuscript we will present two methods for the biopsy of thyroid gland. The first method is using anesthisiological tools and the second tools from the ear, nose and throat department. PMID- 29719798 TI - An unusual case of hoarseness of voice. AB - Amyloidosis is a condition wherein there is an over-expression of specific proteins culminating in the extracellular deposition of insoluble beta pleated sheets of fibres. These deposits disrupt function of the target organ. Its aetiology remains unknown. Primary Amyloidosis localized to the trachea and bronchus is a rare entity. It produces tumour like lesion in the tracheo bronchial tree. We hereby discuss a patient who presented with persistent hoarseness of voice who was referred to a tertiary care centre to rule out malignancy. PMID- 29719799 TI - Nab-paclitaxel plus carboplatin as an effective and safe chemotherapy regimen for pulmonary carcinosarcoma with interstitial lung disease: A case report. AB - Carcinosarcoma is a rare histological type of non-small cell carcinoma (NSCLC), and its prognosis has been reported to be worse compared with other NSCLCs. Nanoparticle albumin-bound paclitaxel (nab-PTX) + carboplatin (CBDCA) achieves a favorable response rate in patients with non-small cell lung cancer (NSCLC). We administered nab-PTX + CBDCA to a 68-year-old man with postoperative recurrent carcinosarcoma with interstitial lung disease (ILD). A partial response was evident after four cycles of chemotherapy. To the best of our knowledge, the present study is the first to report the safety and efficacy of nab-PTX + CBDCA for treating carcinosarcoma with ILD. PMID- 29719800 TI - Azygos lobe: A rare cause of right paratracheal opacity. AB - A 55 year old male presented with a complaint of dyspnea and non productive cough. He was found to have right paratracheal opacity on Chest X ray. Chest CT scan revealed right sided azygos lobe. An azygos lobe is a rare congenital variant of the right lung, usually diagnosed as an incidental finding. PMID- 29719802 TI - Xanthomatous pleuritis. AB - This case presentation relates to a 21 year young male, cachectic in appearance, who presented with progressive shortness of breath, and dull pain on the lower part of the chest ongoing over three months. The patient received antitubercular drugs by local physician for suspected tuberculosis with no significant improvement. He was referred to our Respiratory Department for further evaluation of his chest pain and breathlessness. His X-ray showed moderate pleural effusion on the left side which confirmed by USG chest screening which showed multiple septation with thick parietal pleura and USG abdomen was normal. Moreover, the pleural effusion aspiration was performed and pleural fluid examination revealed exudative in character and thoracoscopic view of pleura was reddish with exudatives. Pleural biopsy histological examination showed mixed cell infiltrate with predominantly foamy macrophage along with plasma cells, lymphocytes and eosinophils with capillary proliferation. This is the first care report of xanthomatous pleuritis in the literature. PMID- 29719801 TI - An unusual presentation of a case of human psittacosis. AB - Background: Chlamydia psittaci is a gram-negative, obligate intracellular organism. Birds are the main reservoir, but also non-avian domestic animals and humans can be infected. In humans it mostly causes respiratory infections due to occupational exposure with varying severity. Sensitive and specific diagnostic tests are needed to define psittacosis in humans as these tests also allow rapid tracing of the animal source. However, diagnosis in humans is often based on time consuming culture techniques and antibody detection assays as in many countries, the existing molecular diagnostic tests for psittacosis are not reimbursed by the public health insurance. Case presentation: An 82-year old female was referred to the hospital with a non-productive cough since four weeks and since one week fever up to 39 degrees C, myalgia, generalized skin rash, acral edema and generalized weakness under treatment with moxifloxacin. Blood analysis showed signs of inflammation with mild eosinophilia. Chest CT showed multiple peripheral ground glass opacities with consolidation in both lungs. Pulmonary function testing only showed a mild decrease in diffusion capacity. Viral and bacterial serology were negative. As the patient kept a pet parakeet for over ten years, a nested PCR for C. psittaci was performed on a nasopharyngeal swab of the patient and on feces of the parakeet. Both returned positive for the same genotype. Genotyping was performed by a genotype-specific real-time PCR. The patient fully recovered after a ten-day course of azithromycin. Conclusion: Due to non-specific signs during psittacosis, early detection of the infection and differentiation from hypersensitivity pneumonitis can be challenging. Culture and antibody titers for C. psittaci have a lower sensitivity than PCR-testing due to several factors. We present a case of human psittacosis (presenting as pneumonia) with diagnosis based on clinical findings confirmed by means of nested PCR. This case suggests the added value of PCR in suspect cases despite negative serology. Our current paper underlines the need for a broader implementation of PCR for early diagnosis of human psittacosis and thus early initiation of correct antibiotic treatment with reduction of morbidity and mortality. PMID- 29719803 TI - Bilateral diaphragmatic paralysis after an unusual physical effort. AB - Diaphragmatic paralysis is an uncommon cause of pulmonary dysfunction and can occur after traumatic phrenic nerve injury. Penetrating and blunt trauma to the neck is the most recognized mechanism of injury being stretching of the nerves very uncommon. We report a case of a 39-year-old man with bilateral diaphragmatic paralysis due to violent stretching of the phrenic nerves. Clinical features and diagnosis methods are also reviewed. PMID- 29719804 TI - Unilateral pulmonary artery agenesis: An unusual cause of unilateral ARDS. AB - Unilateral pulmonary artery agenesis (UPAA) is a rare malformation that can present as an isolated anomaly or may be associated with certain congenital cardiac anomalies, such as tetralogy of Fallot, atrial septal defect, coarctation of aorta, right aortic arch, truncus arteriosus and pulmonary atresia. Clinical presentation is non-specific which makes the diagnosis elusive; chronic dyspnea, hemoptysis or recurrent infections are the most common manifestations. Patients may remain asymptomatic until adulthood. There is no definitive treatment for patients with UPAA. Acute respiratory distress syndrome (ARDS) is usually a bilateral disease, unilateral ARDS has been described after lung resection or trauma. We present a case of a 39 year-old woman who developed unilateral ARDS and was later diagnosed with isolated UPAA. PMID- 29719805 TI - Malignant mesothelioma presenting as recurrent hydro-pneumothorax: An atypical case presentation and literature review. AB - Malignant Pleural Mesothelioma (MPM) is a rare pleural malignancy, with a vague presentation complicated by a decades-long latency period between environmental exposure and clinical manifestations. Spontaneous hydro-pneumothorax is a rare presentation of MPM, most often requiring invasive tissue biopsy to confirm the etiologic diagnosis. We present the case of 79-year-old male smoker with no documented history of asbestos exposure, who was found to have MPM after presenting with dyspnea and subsequently found to have recurrent hydro pneumothorax. On Literature review of the limited documented cases of MPM with hydro-pneumothorax, we found an exclusively male population with a significant smoking history, a marked right sided pathology predominance, and a generally poor prognosis. While this corresponds with the examined case, and suggests that the presence of hydro-pneumothorax implies a high-grade tumor and significant tissue invasion, and therefore poor prognosis similar to that of stage 4 disease, it differs from more generalized case reviews of MPM, most importantly in their anatomical descriptions, prognostic indicators, and epidemiologic tendencies. PMID- 29719806 TI - Daily use of guaifenesin (Mucinex) in a patient with chronic bronchitis and pathologic mucus hypersecretion: A case report. AB - We report an improvement in symptoms and quality of life with long-term use of guaifenesin for the treatment of mucus-related symptoms in a patient with chronic bronchitis, who presented with mucus hypersecretion, cough and dyspnea. PMID- 29719807 TI - Comparison of acid fast bacilli (AFB) smear for Mycobacterium tuberculosis on adult pulmonary tuberculosis (TB) patients with type 2 diabetes mellitus (DM) and without type 2 DM. AB - Background: According to the Global Tuberculosis Report 2015, Indonesia ranked as second country in the world with the highest number of pulmonary tuberculosis cases. By 2015, the number of pulmonary TB new cases in Indonesia has increased to 330.910 cases of 2014 where 324.539 cases. DM is one of the most important factors that influence the occurrence worsening TB. Now is known that DM patients have body's immune response disorder thereby facilitating M. tuberculosis infection and causing TB. Method: This research is cross sectional design. The sample in this research are adult pulmonary TB patients at General Hospital Grade C period October 1, 2013-March 31, 2016 as much as 225 patients. Result: AFB smear results in patients with type 2 DM with smear 3 + was 14 (17.28%), 2 + was 15 (18.52%), 1 + was 15 (18.52%) and negative (-) was 37 (45.68%). AFB smear results in patients without type 2 DM with smear 3 + was 3 (2.08%), 2 + was 6 (4.17%), 1 + was 19 (13.19%), negative (-) was 112 (77.78%) and have no sputum was 4 (2.78%). Number of adult pulmonary TB patients were 225 patients. Of the 225 patients, found 81 patients with type 2 DM and 144 patients without type 2 DM. Conclusion: AFB smear positive found more in adult pulmonary TB patients with type 2 DM compared to TB patient without type 2 DM. It also found statistically significant between type 2 DM with the AFB smear results on adult pulmonary TB patients. PMID- 29719808 TI - Primary endobronchial amyloidosis: A rare case of endobronchial tumor. AB - Primary localized endobronchial amyloidosis is a rare entity, as pulmonary amyloidosis most commonly occurs as a part of systemic AL amyloidosis. It can be asymptomatic or can present with nonspecific symptoms such as progressive dyspnea, cough, wheezing and rarely respiratory failure. It is frequently misdiagnosed as asthma, COPD or pneumonia. Solitary endobronchial amyloidosis having a nodular appearance can mimic endobronchial tumor. The diagnosis is usually delayed by 8-37 months. The average life expectancy for primary tracheobronchial amyloidosis is approximately 9 years, so the early diagnosis of this disease is very critical to improve the prognosis of patients. We are presenting a case of 65 year old male which was initially diagnosed and treated as asthma exacerbation with minimal improvement. Further workup was done with CT chest, bronchoscopy and biopsy because of persistent shortness of breath, which revealed primary localized solitary endobronchial amyloidosis. PMID- 29719809 TI - Autoimmune pulmonary alveolar proteinosis in an adolescent successfully treated with inhaled rhGM-CSF (molgramostim). AB - Autoimmune pulmonary alveolar proteinosis (aPAP) is a rare parenchymal lung disease characterized by accumulation of surfactant in the airways with high levels of granulocyte-macrophage colony stimulating factor (GM-CSF) antibodies in blood. Disease leads to hypoxemic respiratory failure. Whole lung lavage (WLL) is considered the first line therapy, but procedure can be quite demanding, specifically for children. Recently alternative treatment options with inhaled GM CSF have been described but no consensus about the standard treatment exists. We here describe a unique case of a 14-year-old patient who was successfully treated with WLL and subsequent inhalations with molgramostim - new recombinant human GM CSF (rhGM-CSF). PMID- 29719810 TI - Delayed Pneumothorax: A Potential Complication Of Transbronchial Lung Biopsy. AB - The purpose of this article is to report a case of secondary tension pneumothorax presenting seven weeks post Transbronchial Lung biopsy. A 62 year old male with a known history of germ cell tumor was found to have a left-sided pneumothorax which later complicated to a tension pneumothorax.To the best of our knowledge this is the second case being reported for a delayed pneumothorax post a Transbronchial Lung Biopsy .The purpose of this case report is to create awareness among physicians to consider this diagnosis even at a later stage and the importance of patient education regarding the signs and symptoms of pneumothorax. Our case adds to the medical literature, a new presentation of a rare complication of delayed pneumothorax post TBB. PMID- 29719811 TI - Unusual long survival despite severe lung disease of a child with biallelic loss of function mutations in ABCA-3. AB - Homozygous or compound heterozygous for frameshift or nonsense mutations in the ATP-binding cassette transporter A3 (ABCA3) is associated with neonatal respiratory failure and death within the first year of life without lung transplantation. We report the case of a newborn baby girl who developed severe respiratory distress soon after birth. She was diagnosed with compound heterozygous frameshift mutation of the ABCA3 gene. Despite extensive treatment (intravenous corticosteroids pulse therapy, oral corticosteroids, azithromycin, and hydroxychloroquine), she developed chronic respiratory failure. As the parents refused cardio-pulmonary transplantation and couldn't resolve to an accompaniment of end of life, a tracheostomy was performed resulting in continuous mechanical ventilation. A neurodevelopmental delay and an overall muscular dystrophy were noted. At the age of 5 years, after 2 episodes of pneumothorax, the patient died from severe respiratory failure. To our knowledge, this was the first case of a child with compound heterozygous frameshift mutation who posed such an ethical dilemma with a patient surviving till the age of five years. PMID- 29719812 TI - Peripheral T cell lymphoma not otherwise specified (PTCL-NOS) presenting as an endobronchial lesion: Case report and literature review. AB - Peripheral T cell lymphoma not otherwise specified (PTCL-NOS) is a rare entity of lymphoma. We herein report an even rarer case of a 68-year-old male with PTCL-NOS presenting as an endobronchial lesion, and review previously published cases in the literature. Initially, he was referred to our hospital for further investigation of the right upper lobe consolidation on chest radiograph. Computed tomography and 18F-fludeoxyglucose positron emission tomography revealed a right hilar mass with obstruction of the main bronchus and submandibular, right axillary and mediastinal lymphadenopathy. Pathological examination of the biopsy specimens from of the endobronchial lesion and subcutaneous nodule revealed PTCL NOS. Chemotherapy was started but he finally died due to septic shock after the second-line chemotherapy. PMID- 29719813 TI - Psoriatic arthritis due to nivolumab administration a case report and review of the literature. AB - Nowadays we have novel equipment for lung cancer diagnosis, however; due to lack of symptoms, lung cancer is still diagnosed at a late stage. Currently we have the following therapies for non-small cell lung cancer: a) non-specific cytotoxic agents, b) targeted therapies and c) immunotherapy. Each therapy has its own advantages and adverse effects. In the current case we will present a rare case of psoriacic arthritis that was presented after two cycles of nivolumab administration and we will also present a review of the literature. PMID- 29719814 TI - Transformation to small cell lung cancer after first-line afatinib treatment. AB - Acquiring resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) is inevitable. Transformation to small cell lung cancer (SCLC) is reported as a possible mechanism of this acquired resistance. We describe the case of a 35-year-old man with lung adenocarcinoma harboring EGFR exon 19 deletion. After 7 months of successful treatment with afatinib, he experienced relapse and rebiopsy revealed SCLC with EGFR exon 19 deletion. Tumor marker tests at this point showed normal levels of serum neuron-specific enolase and pro gastrin releasing peptide. Our case highlights the importance of rebiopsy for revealing SCLC transformation, a potential mechanism of acquired resistance to afatinib as with other EGFR-TKIs, and normal-range values of tumor markers for SCLC cannot exclude the possibility of SCLC transformation. PMID- 29719815 TI - Machine Learning in Radiation Oncology: Opportunities, Requirements, and Needs. AB - Machine learning (ML) has the potential to revolutionize the field of radiation oncology, but there is much work to be done. In this article, we approach the radiotherapy process from a workflow perspective, identifying specific areas where a data-centric approach using ML could improve the quality and efficiency of patient care. We highlight areas where ML has already been used, and identify areas where we should invest additional resources. We believe that this article can serve as a guide for both clinicians and researchers to start discussing issues that must be addressed in a timely manner. PMID- 29719816 TI - Local and Regional Breast Cancer Recurrences: Salvage Therapy Options in the New Era of Molecular Subtypes. AB - Isolated local or regional recurrence of breast cancer (BC) leads to an increased risk of metastases and decreased survival. Ipsilateral breast recurrence can occur at the initial tumor bed or in another quadrant of the breast. Depending on tumor patterns and molecular subtypes, the risk and time to onset of metastatic recurrence differs. HER2-positive and triple-negative (TNG) BC have a risk of locoregional relapse between six and eight times than luminal A. Thus, the management of local and locoregional relapses must take into account the prognostic factors for metastatic disease development. It is important to personalize the overall management, including or not systemic treatment according to the metastatic risk. All isolated recurrence cases should be treated with curative intent. Complete surgical resection is recommended whenever possible. Patients who did not receive postoperative irradiation during their initial management should receive full-dose radiotherapy to the chest wall and to the regional lymph nodes if appropriate. Overall, total mastectomy is the "gold standard" among patients who were previously treated by conservative surgery followed by radiation therapy. In terms of systemic therapy, the benefits of additional treatments are not conclusively proven in cases of isolated recurrence. The beneficial role of chemotherapy has been reported in at least one randomized trial, while endocrine therapy and anti-HER2 are common practice. This review will discuss salvage treatment options of local and locoregional recurrences in the new era of BC molecular subtypes. PMID- 29719818 TI - William Bradley Coley, MD, and the phenomenon of spontaneous regression. AB - The standard definition of spontaneous regression (SR) of cancer is as follows, "...when a malignant tumor partially or completely disappears without treatment or in the presence of therapy which is considered inadequate to exert a significant influence on neoplastic disease." SR is also known as Saint Peregrine tumor, the name taken from a young priest, Peregrine Laziosi (1260 [5]-1345, exact date is unknown), who had been diagnosed with a tumor of the tibia. The mass eventually grew so large that it broke through the skin and became severely infected. The available treatment for this condition was limited to amputation. Historical records report that on the day of surgery, physicians found that the tumor had disappeared and reportedly never returned. To date, the medical literature consists only of individual case studies and overviews of this phenomenon. The most cited work on the subject was done by surgeons Tilden Everson and Warren Cole who reviewed 176 published cases of SR from 1900 to 1960. While a percentage of these were found not to be cases of SR, there remained a number of unexplained cases. A frequent theme in many cases of SR is the co occurrence of infection. Given the current interest in immunotherapy in the treatment of cancer, this article discusses one of the very early pioneers of this theory, William Bradley Coley, MD, a surgeon who was clearly ahead of his time. Ostracized by colleagues for his belief that stimulation of the immune system could in fact produce a regression of cancer, Coley remained convinced that his theory was right and, while he was not familiar with cytokines such as tumor necrosis factor (TNF), interferons, and streptokinase, he knew instinctively that an innate immune response was taking place. PMID- 29719817 TI - The Role of Epstein-Barr Virus in Cervical Cancer: A Brief Update. AB - Epstein-Barr virus (EBV) belongs to the group of gamma-herpes viruses and was the first recognized human oncovirus. EBV is responsible for infectious mononucleosis and multiple lymphoid and epithelial malignancies including B-cell lymphomas (Burkitt lymphoma, Hodgkin lymphoma, and post-transplant lymphoproliferative disorder), various T-cell/NK lymphoproliferative disorders, nasopharyngeal carcinoma, and gastric carcinoma, respectively. In addition, the presence of EBV has been documented in other cancers including breast, prostate, oral, and salivary gland carcinomas. The presence and role of EBV in cervical cancer and its precursor lesions (CIN) have also been described, but the results from the literature are inconsistent, and the causal role of EBV in cervical cancer pathogenesis has not been established yet. In the present review, we briefly surveyed and critically appraised the current literature on EBV in cervical cancer and its variants (lymphoepithelioma-like carcinoma) as well as its precursor lesions (CIN). In addition, we discussed the possible interactions between EBV and human papilloma virus as well as between EBV and immune checkpoint regulators (PD-L1). Though further studies are needed, the available data suggest a possible causal relationship between EBV and cervical cancer pathogenesis. PMID- 29719819 TI - Near-Zero Thermal Expansion and Phase Transitions in HfMg1-x Zn x Mo3O12. AB - The effects of Zn2+ incorporation on the phase formation, thermal expansion, phase transition, and vibrational properties of HfMg1-x Zn x Mo3O12 are investigated by XRD, dilatometry, and Raman spectroscopy. The results show that (i) single phase formation is only possible for x <= 0.5, otherwise, additional phases of HfMo2O8 and ZnMoO4 appear; (ii) The phase transition temperature from monoclinic to orthorhombic structure of the single phase HfMg1-x Zn x Mo3O12 can be well-tailored, which increases with the content of Zn2+; (iii) The incorporation of Zn2+ leads to an pronounced reduction in the positive expansion of the b-axis and an enhanced negative thermal expansion (NTE) in the c-axes, leading to a near-zero thermal expansion (ZTE) property with lower anisotropy over a wide temperature range; (iv) Replacement of Mg2+ by Zn2+ weakens the Mo-O bonds as revealed by obvious red shifts of all the Mo-O stretching modes with increasing the content of Zn2+ and improves the sintering performance of the samples which is observed by SEM. The mechanisms of the negative and near-ZTE are discussed. PMID- 29719820 TI - Modeling Chemical Reactions by QM/MM Calculations: The Case of the Tautomerization in Fireflies Bioluminescent Systems. AB - In less than half a century, the hybrid QM/MM method has become one of the most used technique to model molecules embedded in a complex environment. A well-known application of the QM/MM method is for biological systems. Nowadays, one can understand how enzymatic reactions work or compute spectroscopic properties, like the wavelength of emission. Here, we have tackled the issue of modeling chemical reactions inside proteins. We have studied a bioluminescent system, fireflies, and deciphered if a keto-enol tautomerization is possible inside the protein. The two tautomers are candidates to be the emissive molecule of the bioluminescence but no outcome has been reached. One hypothesis is to consider a possible keto enol tautomerization to treat this issue, as it has been already observed in water. A joint approach combining extensive MD simulations as well as computation of key intermediates like TS using QM/MM calculations is presented in this publication. We also emphasize the procedure and difficulties met during this approach in order to give a guide for this kind of chemical reactions using QM/MM methods. PMID- 29719822 TI - An 81-Year-Old Woman with Recalcitrant Blisters. AB - Epidermolysis bullosa acquisita (EBA) is a rare mucocutaneous blistering disorder with typical onset in adulthood. Diagnosis and management can be difficult owing to the variability in presentation and clinical manifestation. In this case, we explore a case of EBA as well as provide a general overview of the condition and its variants. PMID- 29719823 TI - Mycetomas: The Experience of the Dermatology Unit of the University of Milan. PMID- 29719824 TI - Panniculitides in Rheumatoid Syndromes: The Role of Histopathology. PMID- 29719821 TI - The Physiopathological Role of the Exchangers Belonging to the SLC37 Family. AB - The human SLC37 gene family includes four proteins SLC37A1-4, localized in the endoplasmic reticulum (ER) membrane. They have been grouped into the SLC37 family due to their sequence homology to the bacterial organophosphate/phosphate (Pi) antiporter. SLC37A1-3 are the less characterized isoforms. SLC37A1 and SLC37A2 are Pi-linked glucose-6-phosphate (G6P) antiporters, catalyzing both homologous (Pi/Pi) and heterologous (G6P/Pi) exchanges, whereas SLC37A3 transport properties remain to be clarified. Furthermore, SLC37A1 is highly homologous to the bacterial glycerol 3-phosphate permeases, so it is supposed to transport also glycerol-3-phosphate. The physiological role of SLC37A1-3 is yet to be further investigated. SLC37A1 seems to be required for lipid biosynthesis in cancer cell lines, SLC37A2 has been proposed as a vitamin D and a phospho-progesterone receptor target gene, while mutations in the SLC37A3 gene appear to be associated with congenital hyperinsulinism of infancy. SLC37A4, also known as glucose-6 phosphate translocase (G6PT), transports G6P from the cytoplasm into the ER lumen, working in complex with either glucose-6-phosphatase-alpha (G6Pase-alpha) or G6Pase-beta to hydrolyze intraluminal G6P to Pi and glucose. G6PT and G6Pase beta are ubiquitously expressed, whereas G6Pase-alpha is specifically expressed in the liver, kidney and intestine. G6PT/G6Pase-alpha complex activity regulates fasting blood glucose levels, whereas G6PT/G6Pase-beta is required for neutrophil functions. G6PT deficiency is responsible for glycogen storage disease type Ib (GSD-Ib), an autosomal recessive disorder associated with both defective metabolic and myeloid phenotypes. Several kinds of mutations have been identified in the SLC37A4 gene, affecting G6PT function. An increased autoimmunity risk for GSD-Ib patients has also been reported, moreover, SLC37A4 seems to be involved in autophagy. PMID- 29719825 TI - Pathogenesis of Psoriasis: Focus on Autoinflammation. PMID- 29719826 TI - Obesity-Associated Lymphedematous Mucinosis: Two Further Cases and Review of the Literature. AB - Cutaneous mucinoses are a group of conditions characterized by increased amounts of acid mucin in the dermis. They can be generalized or localized and occur isolated or in the setting of systemic diseases. Obesity-associated lymphedematous mucinosis is a distinct variant of mucinosis occurring in obese patients without any thyroid dysfunction. So far, only few cases of this rare condition have been reported in the English literature. Here, we describe two new cases and discuss some histological differences with the pretibial myxedema. PMID- 29719827 TI - Sentinel Node Biopsy in Melanoma: A Short Update. AB - Several controversies are still ongoing about sentinel node biopsy in melanoma. It is basically a staging procedure for melanoma > 0.75 mm in thickness or for thinner melanoma in the presence of ulceration, high mitotic rate, and/or lymphovascular invasion. Complete lymph node dissection after a positive sentinel node can also allow a better locoregional disease control but seems not to prevent the development of distant metastases. The use of sentinel node biopsy in atypical Spitz tumors should be discouraged because of their peculiar biological properties. PMID- 29719828 TI - Spitzoid Neoplasms: Suggestions from Genomic Aberrations. PMID- 29719829 TI - Melanoma Diagnosis: The Importance of Histopathological Report. PMID- 29719830 TI - A 92-Year-Old Male with Eosinophilic Asthma Presenting with Recurrent Palpable Purpuric Plaques. AB - Churg-Strauss syndrome or eosinophilic granulomatosis with polyangiitis is a systemic vasculitis affecting the small and medium-sized vasculature. It is commonly associated with asthma and eosinophilia. Most patients are diagnosed at around the age of 40. We report a case of biopsy-confirmed Churg-Strauss syndrome in a 92-year-old male with a history of eosinophilic asthma and peripheral eosinophilia who was later diagnosed with Churg-Strauss syndrome. PMID- 29719831 TI - A 30-Year-Old Man with HIV, Fever, and a Rash. AB - Patients who present with papular rashes have a wide differential diagnosis particularly in the setting of immune compromise. A 30-year-old male diagnosed with HIV since 2009, never on antiretroviral therapy, with a nadir CD4 count of 333 cells/mm3 and a current viral load of 44,300 copies/mL, presented with a diffuse monomorphic papular eruption that began on his trunk and extremities and subsequently spread to the penis and scrotum, sparing the distal acral sites. A thorough infectious workup revealed a positive rapid plasma reagin (RPR) and varicella IgM and IgG antibodies. Interestingly, the patient had been diagnosed and treated for syphilis in the past with a recent downtrending RPR drawn prior to hospitalization. Repeat RPR was elevated and a preliminary histopathology report demonstrated folliculocentric inflammation with lymphocytes, plasma cells, and polymorphonuclear leukocyte predominance supported the diagnosis of syphilis. After receiving intramuscular penicillin G benzathine, he developed intermittent fevers and new papules. Intravenous (IV) acyclovir was initiated for presumed disseminated varicella given his positive varicella-zoster virus IgM and IgG. However, final pathology results revealed a large spirochete burden. The fevers and rash progression were attributed to the development of a Jarisch-Herxheimer reaction. IV acyclovir was discontinued and he completed a course of intramuscular penicillin G benzathine. He was also given a course of doxycycline for rectal chlamydia which was diagnosed during hospitalization. PMID- 29719832 TI - Microenvironment-Induced Non-sporadic Expression of the AXL and cKIT Receptors Are Related to Epithelial Plasticity and Drug Resistance. AB - The existence of rare cancer cells that sporadically acquire drug-tolerance through epigenetic mechanisms is proposed as one mechanism that drives cancer therapy failure. Here we provide evidence that specific microenvironments impose non-sporadic expression of proteins related to epithelial plasticity and drug resistance. Microarrays of robotically printed combinatorial microenvironments of known composition were used to make cell-based functional associations between microenvironments, which were design-inspired by normal and tumor-burdened breast tissues, and cell phenotypes. We hypothesized that specific combinations of microenvironment constituents non-sporadically impose the induction of the AXL and cKIT receptor tyrosine kinase proteins, which are known to be involved in epithelial plasticity and drug-tolerance, in an isogenic human mammary epithelial cell (HMEC) malignant progression series. Dimension reduction analysis reveals type I collagen as a dominant feature, inducing expression of both markers in pre stasis finite lifespan HMECs, and transformed non-malignant and malignant immortal cell lines. Basement membrane-associated matrix proteins, laminin-111 and type IV collagen, suppress AXL and cKIT expression in pre-stasis and non malignant cells. However, AXL and cKIT are not suppressed by laminin-111 in malignant cells. General linear models identified key factors, osteopontin, IL-8, and type VIalpha3 collagen, which significantly upregulated AXL and cKIT, as well as a plasticity-related gene expression program that is often observed in stem cells and in epithelial-to-mesenchymal-transition. These factors are co-located with AXL-expressing cells in situ in normal and breast cancer tissues, and associated with resistance to paclitaxel. A greater diversity of microenvironments induced AXL and cKIT expression consistent with plasticity and drug-tolerant phenotypes in tumorigenic cells compared to normal or immortal cells, suggesting a reduced perception of microenvironment specificity in malignant cells. Microenvironment-imposed reprogramming could explain why resistant cells are seemingly persistent and rapidly adaptable to multiple classes of drugs. These results support the notion that specific microenvironments drive drug-tolerant cellular phenotypes and suggest a novel interventional avenue for preventing acquired therapy resistance. PMID- 29719833 TI - A Survey of Enhanced Recovery After Surgery Protocols for Cesarean Delivery in Serbia. AB - Enhanced recovery after surgery (ERAS) protocols have been described for patients undergoing colon surgery. Similar protocols for cesarean delivery (CD) have been developed recently. CD is one of the most commonly performed surgical procedures, and adoption of ERAS protocols following CD might benefit patients and the health care system. We aimed to determine which Serbian hospitals reported ERAS protocols, which elements of ERAS protocols were used in CD patients, and whether ERAS and non-ERAS hospitals differed. The survey was sent to all hospitals with obstetric services and 46 of 49 responded. The questionnaire asked whether ERAS protocols had been formally adopted for surgical patients and about their use in CD patients. Specific questions on elements described in other obstetric ERAS protocols for CD included preoperative patient preparation, type of anesthesia and temperature monitoring used for CD, maternal/neonatal contact, and time to discharge. ERAS protocols are used in 24% of surveyed hospitals, 84% admit the patient the day before elective CDs, 87% use a maternal bowel preparation morning on the day of CD, and 80% administer maternal deep venous thrombosis prophylaxis. Only 33% remove IV in the first postoperative day, and 89% of women do not eat solid food until the day following their CD. Neuraxial anesthesia is used in 46% of elective CDs in ERAS hospitals compared to 9% in non-ERAS hospitals (P < 0.01), and neuraxial narcotics for post CD analgesia are given more often in ERAS hospitals. Thirty-six percentage of ERAS patients are discharged within 3 days vs. none in the non-ERAS group. Few elements of ERAS protocols reported from other centers outside Serbia are employed in Serbian hospitals performing CD. Despite significant changes that have been made recently in CD care, enhanced recovery after CD could be significantly improved in Serbian hospitals. PMID- 29719836 TI - Ability of Polyphosphate and Nucleic Acids to Trigger Blood Clotting: Some Observations and Caveats. AB - Polyphosphate plays several roles in coagulation and inflammation, while extracellular DNA and RNA are implicated in thrombosis and as disease biomarkers. We sought to compare the procoagulant activities of polyphosphate versus DNA or RNA isolated from mammalian cells. In a recent study, we found that much of the procoagulant activity of DNA isolated from mammalian cells using Qiagen kits resisted digestion with nuclease or polyphosphatase, and even resisted boiling in acid. These kits employ spin columns packed with silica, which is highly procoagulant. Indeed, much of the apparent procoagulant activity of cellular DNA isolated with such kits was attributable to silica particles shed by the spin columns. Therefore, silica-based methods for isolating nucleic acids or polyphosphate from mammalian cells are not suitable for studying their procoagulant activities. We now report that polyphosphate readily co-purified with DNA and RNA using several popular isolation methods, including phenol/chloroform extraction. Thus, cell-derived nucleic acids are also subject to contamination with traces of cellular polyphosphate, which can be eliminated by alkaline phosphatase digestion. We further report that long-chain polyphosphate was orders of magnitude more potent than cell-derived DNA (purified via phenol/chloroform extraction) or RNA at triggering clotting. Additional experiments using RNA homopolymers found that polyG and polyI have procoagulant activity similar to polyphosphate, while polyA and polyC are not procoagulant. Thus, the procoagulant activity of RNA is rather highly dependent on base composition. PMID- 29719835 TI - The Role of Imaging in Diagnosing Axial Spondyloarthritis. AB - Imaging has a central role in the diagnosis, management, and follow-up of patients with axial spondyloarthritis (axSpA). For the early diagnosis of axSpA, magnetic resonance imaging is of utmost relevance. While no novel imaging techniques were developed during the past decade, improvements to the existing modalities have been introduced. This report provides an overview of the applications and limitations of the existing imaging modalities. PMID- 29719837 TI - Epidemiological Characteristics of Traumatic Spinal Cord Injury (TSCI) in the Middle-East and North-Africa (MENA) Region: A Systematic Review and Meta Analysis. AB - Objective: To systematically search the literature and to summarize current evidence pertaining to the epidemiology of SCI in the MENA region incidence, gender, age, type of the injury and etiology of the injury. Methods: Embase, PubMed, Scopus, Web of Science and EBSCOhost were systematically searched from their dates of inception till July 2017 for English and non-English language articles. Also, regional databases were searched. Data were extracted from eligible articles and pooled under the random effect model using R. References of the included articles were also screened for potentially relevant studies. Results: We identified 29 articles from seven countries in the MENA region (Turkey, Iran, Saudi Arabia, Egypt, Jordan, Kuwait and Qatar). The mean age of the cases at time of injury was 31.32 (95% CI: 28.74-33.91). The random pooled annual incidence of TSCI per million was 23.24 (95% CI: 5.64-49.21). Pooled proportion of male gender was 77% (95% CI 73-80%) of the cases. Complete paraplegia was the most common type of injury. Thoracic level injury predominated. Also, the most commonly affected age group was 20-29 then 30-39. Motor vehicle accidents were found to be the leading cause of injury, then falls, gunshot, violence and sports. Further meta-regression analysis showed no association between age and etiology of the injury. Conclusion: This review shows lack of evidence about SCI in most countries of the MENA region. More epidemiological studies are needed. PMID- 29719834 TI - Genomic Instabilities, Cellular Senescence, and Aging: In Vitro, In Vivo and Aging-Like Human Syndromes. AB - As average life span and elderly people prevalence in the western world population is gradually increasing, the incidence of age-related diseases such as cancer, heart diseases, diabetes, and dementia is increasing, bearing social and economic consequences worldwide. Understanding the molecular basis of aging related processes can help extend the organism's health span, i.e., the life period in which the organism is free of chronic diseases or decrease in basic body functions. During the last few decades, immense progress was made in the understanding of major components of aging and healthy aging biology, including genomic instability, telomere attrition, epigenetic changes, proteostasis, nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and intracellular communications. This progress has been made by three spear-headed strategies: in vitro (cell and tissue culture from various sources), in vivo (includes diverse model and non-model organisms), both can be manipulated and translated to human biology, and the study of aging-like human syndromes and human populations. Herein, we will focus on current repository of genomic "senescence" stage of aging, which includes health decline, structural changes of the genome, faulty DNA damage response and DNA damage, telomere shortening, and epigenetic alterations. Although aging is a complex process, many of the "hallmarks" of aging are directly related to DNA structure and function. This review will illustrate the variety of these studies, done in in vitro, in vivo and human levels, and highlight the unique potential and contribution of each research level and eventually the link between them. PMID- 29719838 TI - Effectiveness of Interventions for Prevention of Road Traffic Injuries in Iran and Some Methodological Issues: A Systematic Review. AB - Objective: To review the effectiveness of Road Traffic Injuries (RTIs) interventions implemented for prevention of RTIs in Iran and to introduce some methodological issues. Methods: Required data in this systematic review study were collected through searching the following key words: "Road Traffic Injuries", "Road Traffic accidents", "Road Traffic crashes", "prevention", and Iran in PubMed, Cochrane Library electronic databases, Google Scholar, Scopus, MagIran, SID and IranMedex. Some of the relevant journals and web sites searched manually. Reference lists of the selected articles were also checked. Gray literature search and expert contact was also conducted. Results: Out of 569 retrieved articles, finally 8 articles included. Among the included studies the effectiveness of 10 interventions were assessed containing: seat belt, enforcements of laws and legislations, educational program, wearing helmet, Antilock Braking System (ABS), motorcyclists' penalty enforcement, pupil liaisons' education, provisional driver licensing, Road bumps and traffic improvement's plans. In 7 studies (9 interventions) reduction of RTIs rate were reported. Decreased rate of mortality from RTIs were reported in three studies. Only one study had mentioned financial issue (Anti-lock Brake System intervention). Inadequate data sources, inappropriate selection of statistical index and not mention about the control of Confounding Variables (CV), the most common methodological issues were. Conclusion: The results of most interventional studies conducted in Iran supported the effect of the interventions on reduction of RTIs. However due to some methodological or reporting shortcoming the results of these studies should be interpreted cautiously. PMID- 29719839 TI - A Randomized Controlled Trial on Intra-Abdominal Irrigation during Emergency Trauma Laparotomy; Time for Yet Another Paradigm Shift. AB - Objective: To determine the optimal volume of abdominal irrigation that will prevent surgical site infections (both deep and superficial), eviscerations and fistula formations; and improve 30-day mortality in trauma patients. Methods: We conducted a three-arm parallel clinical superiority randomized controlled trial comparing different volumes of effluent (5, 10 and 20 liters) used in trauma patients (both blunt and penetrating) age 14 and above undergoing an emergency laparotomy between April 2002 and July 2004 in a busy urban Level 1 trauma center. Results: After randomization, a total of 204 patients were analyzed. All patient groups were comparable with respect to age, gender distribution, admission injury severity score, and mechanism of injury, estimated blood loss and degree of contamination. The mortality rate overall was 1.96% (4/204).No differences were noted with respect to contamination, wound infection, fistula formation, and evisceration. The twenty liter group (Group III) showed a trend toward an increased incidence of deep surgical site infections when compared to the five liter (Group I) (p=0.051) and ten liter (Group II) (p=0.057) groups. This did not however reach statistical significance. Conclusion: The old surgical adage "the solution to pollution is dilution" is not applicable to trauma patients. Our results suggest that using more irrigation, even when large amounts of contamination have occurred, does not reduce post-operative complications or affect mortality; and it may predispose patients to increased incidence of abscess formation. (Trial registration number: ISRCTN66454589). PMID- 29719840 TI - Local Xenotransplantation of Bone Marrow Derived Mast Cells (BMMCs) Improves Functional Recovery of Transected Sciatic Nerve in Cat: A Novel Approach in Cell Therapy. AB - Objective: To determine the effects of bone marrow derived mast cells (BMMCs) on functional recovery of transected sciatic nerve in animal model of cat. Method: A 20-mm sciatic nerve defect was bridged using a silicone nerve guide filled with BMMCs in BMMC group. In Sham-surgery group (SHAM), the sciatic nerve was only exposed and manipulated. In control group (SILOCONE) the gap was repaired with a silicone nerve guide and both ends were sealed using sterile Vaseline to avoid leakage and the nerve guide was filled with 100 MUL of phosphate-buffered saline alone. In cell treated group ([SILOCONE/BMMC) the nerve guide was filled with 100 MUL BMMCs (2* 106 cells/100 MUL). The regenerated nerve fibers were studied, biomechanically, histologically and immunohiscochemically 6 months later. Results: Biomechanical studies confirmed faster recovery of regenerated axons in BMMCs transplanted animals compared to control group (p<0.05). Morphometric indices of the regenerated fibers showed that the number and diameter of the myelinated fibers were significantly higher in BMMCs transplanted animals than in control group (p<0.05). In immunohistochemistry, location of reactions to S-100 in BMMCs transplanted animals was clearly more positive than that in control group. Conclusion: BMMCs xenotransplantation could be considered as a readily accessible source of cells that could improve recovery of transected sciatic nerve. PMID- 29719841 TI - Pre-Treatment with Metformin in Comparison with Post-Treatment Reduces Cerebral Ischemia Reperfusion Induced Injuries in Rats. AB - Objective: To explore the effects of pre versus post ischemic treatment with metformin after global cerebral ischemia in rats. Methods: Male Wister rats underwent forebrain ischemia by bilateral common carotid artery occlusion for 17 min. Metformin (200 mg/kg) or vehicle was given orally by gavage for 7-14 days. Rats were divided into: control, metformin pre-treatment, metformin post treatment and metformin pre and post continuous treatment groups. Cerebral infarct size, histopathology, myeloperoxidase and serum malondialdehyde were measured 7 days after ischemia. Results: Histopathological analysis showed that metformin pre-treatment significantly decreased leukocyte infiltration, myeloperoxidase activity and also malondialdehyde level. Metformin pre-treatment and metformin post-treatment reduced infarct size compared with the control group, but it was not significant in the pre and post continuous treatment group. Conclusion: Our findings suggest that pre-treatment with metformin in comparison with post-treatment in experimental stroke can reduce the extent of brain damage and is more neuroprotective at least in part by inhibiting oxidative stress and inflammation. PMID- 29719842 TI - Acute Appendicitis during Pregnancy; Results of a Cohort Study in a Single Iranian Center. AB - Objective: To determine the effects of pregnancy on the presentation, management, surgical and obstetrics outcome of patients with acute appendicitis. Methods: This prospective cohort study was conducted during a 2-year period from 2014 to 2016 in Shahid Faghihi hospital of Shiraz University of Medical Sciences. We enrolled all the pregnant individuals with acute appendicitis who required surgical appendectomy. We also enrolled age-matched controls of non-pregnant women undergoing open appendectomy during the study period. The presentation, clinical and laboratory characteristics, surgical and obstetrics outcomes were determined in both study groups and were further compared between them. In order to determine the determinants of outcome, we also ran a multivariate logistic regression model. Results: Overall we included a total number of 584 patients with presumed appendicitis among whom there were 58 (9.94%) and 526 (90.06%) non pregnant individuals. The pregnant patients had significantly longer duration of symptoms (p=0.038), lower temperature (p=0.026), longer duration of hospital stay (p=0.026) and higher rate of hospital admission longer than 2 days (p=0.031). The complications of the surgical procedure were comparable between the two study groups except for the pneumonia which was significantly higher in pregnant patient (p=0.041). After adjusting for confounders such as age and ethnicity, pregnancy remained significantly associated with lower temperature (p=0.018), longer symptom duration (p=0.042) and higher rate of pneumonia (p=0.049). Conclusion: Acute appendicitis during the pregnancy was associated with longer duration of symptoms, lower body temperature and higher rate of pneumonia. The pregnancy and neonatal outcomes were comparable to the previously reported data. PMID- 29719843 TI - Diagnosis of Appendicitis in Patients with a Normal White Blood Cell Count; A Cross-Sectional Study. AB - Objective: To investigate the clinical, imaging and laboratory findings for diagnosis of acute appendicitis (AA) in patients with a normal white blood cell count (WBCC). Methods: This retrospective cross-sectional study was conducted in Ankara Numune Training and Research Hospital, Ankara, Turkey, during a 1-year period. To determine diagnostic factors in AA in patients with normal WBCC, medical records of eligible patients were reviewed for demographic and clinical variables, as well as patient outcome. Results: A total of 105 patients that had undergone appendectomy and were found to have a normal WBCC were included in the study. Of these patients, 53 (50.5%) were men and 52 (49.5%) were women. The mean age of the patients was 34.2+/-12.3 (min 14, max 78). The negative exploration rate was identified as 19%. In the multivariate analysis, only the diameter of appendix was statistically significant (p=0.002). ROC analysis revealed the cut off appendiceal diameter as 8 mm. Conclusion: In patients suspected of AA due to >=8 mm appendiceal diameter determined by imaging, we recommend surgical treatment even if WBCC and neutrophil count are normal. PMID- 29719844 TI - Risk Factors for Unfavorable Outcome in Aneurysmal Subarachnoid Hemorrhage Revisited; Odds and Ends. AB - Objectives: To evaluate the odds for unfavorable outcome of each risk factor and a combination of them in patients with aneurysmal subarachnoid hemorrhage (SAH) undergoing surgical clipping in Southern Iran. Methods: A total of 367 patients who were operated between March 2007 and March 2016 due to aneurysmal SAH were analyzed according to patients' factors, aneurysm characteristics and intra operative data. Correlation between outcomes of patients measured by modified Rankin Scale at 6-months with each factor were analyzed. Market Basket analysis was also used to identify the odds of unfavorable outcome for combinations of factors. Results: A total of 367 patients, including 199 females and 168 males with a mean age of 47.27+/- 11.53 years, who underwent operation between March 2007 and March 2016 due to aneurysmal SAH were analyzed. Unlike gender, higher age was associated with unfavorable outcome. Ischemic heart disease, Duration of operation and amount of bleeding were also found to increase the odds of unfavorable outcome (p=0.01, 0.02, 0.04 respectively). DM, Cigarette smoking and opium addiction as well as the location and multiplicity of aneurysms did not have an adverse effect on outcome. (p>=0.05). Conclusion: Among the numerous risk factors presumed to result in unfavorable outcome in aneurysmal SAH, only older age, duration of operation more than 60 minutes, previous known history of ischemic heart disease, poorer clinical grade and intra-operative bleeding more than 500 mL were found to be significant factors. PMID- 29719845 TI - The Efficacy of Glasgow Coma Scale (GCS) Score and Acute Physiology and Chronic Health Evaluation (APACHE) II for Predicting Hospital Mortality of ICU Patients with Acute Traumatic Brain Injury. AB - Objective: To compare the efficacy and functional outcome of Glasgow Coma Scale (GCS) score with that of Acute Physiology and Chronic Health Evaluation Score II (APACHE II) in patients with multiple trauma admitted to the ICU. Methods: This cross-sectional study included 125 patients with traumatic brain injury associated with systemic trauma admitted to the ICU of Shahid Kamyab Hospital, Mashhad, between September 2015 and December 2016. On the day of admission, data were collected from each patient to calculate GCS and APACHE II scores. Sensitivity, specificity, and correct outcome prediction was compared between GCS and APACHE II. Results: Positive predictive value (PPV) at the cut-off points was higher in APACHE II (80.6%) compared with GCS (69.2%). However, negative predictive value (NPV) of GCS was slightly higher in comparison with APACHE II. Moreover, the area under the receiver operating characteristic (ROC) curve for sensitivity and specificity of GCS and APACHE II showed no significant difference (0.81+/-0.04 vs. 0.83+/-0.04; p=0.278 respectively). Conclusion: Our study suggested that there was no considerable difference between GCS and APACHE II scores for predicting mortality in head injury patients. Both scales showed acceptable PPV, while APACHE II showed better results. However, the utilization of GCS in the initial assessment is recommended over APACHE II as the former provides higher time- and cost-efficiency. PMID- 29719846 TI - Epidemiology of Road Traffic Injury Fatalities among Car Users; A Study Based on Forensic Medicine Data in East Azerbaijan of Iran. AB - Objective: To study the epidemiology of car user road traffic fatalities (CURTFs) during eight years, in East Azerbaijan, Iran. Methods: A total of 3051 CURTFs registered in East Azerbaijan forensic medicine organization database, Iran, during 2006-2014, were analyzed using Stata 13 statistical software package. Descriptive statistics (p<0.05) and inferential statistical methods such as Chi squared test and multivariate logistic regression with p<0.1 were applied. Results: Of the 7818 road traffic injury (RTI) deaths, 3051 (39%) were car users of whom 71% were male (mean age of 36.7+/-18.5 years). The majority of accident mechanisms were vehicle-vehicle crashes (63.95%), followed by rollover (26.24%). Crash causing vehicle fall increased the pre-hospital death likelihood by 2.34 times. The prominent trauma causing death was head trauma (in 62.5%). In assessing the role of type of counterpart vehicle on pre-hospital mortality, considering the other cars to be the reference group for comparison, deceased victims were 1.83 times more likely to die before hospital when the counterpart vehicle was a truck and 1.66 times more for buses. Conclusion: Decreasing the car users' fatalities using appropriate strategies such as separating the roads for heavy and light vehicles and improving the injury related facilitation may be effective. Male drivers with low education could be prioritized for being trained. PMID- 29719847 TI - Characteristics of Occupational Injuries in a Pharmaceutical Company in Iran. AB - Objective: To prioritize occupational hazards in a Pharmaceutical Company in Iran using the analytical hierarchy process (AHP). Methods: This was a cross-sectional study conducted in a Pharmaceutical Company in Iran in 2017. All employees working in the administrative, production, installations and facilities, and laboratory units were studied using the consensus method (N=n=130 employees). A data collection form was designed for identifying the hazards using the Nominal Group Technique (NGT) method, as well as a pair-wise questionnaire was used for collecting required data in the quantitative phase. The collected data were analyzed using Expert Choice 10.0 and SPSS 23.0. Results: The results showed that among hazards detected in the studied units, the highest and lowest weights and priorities were, respectively, related to "inhalation of toxic gases" (W=0.253) and "being exposed to radiation" (W=0.022) in the laboratory unit, "skin injuries" (W=0.205) and "bending and straightening for a long time" (W= 0.032) in the production unit, "falling down" (W=0.271) and "standing and sitting for a long time " (W=0.037) in the installations and facilities unit, and "hand joint failure" (W=0.295) and "working in a low-light environment" (W=0.092) in the administrative unit. Conclusion: The results of the present study showed that there were hazards in all of the studied units. These results indicated a high level of hazards in the pharmaceutical company's units. Due to the increased medication diversification and increased workload for these companies, paying attention to the preventive and corrective measures in order to reduce the risk of emerging hazards is essential. PMID- 29719848 TI - A Questionnaire Study on the Attitudes and Previous Experience of Croatian Family Physicians toward their Preparedness for Disaster Management. AB - Objective: To explore family physicians' attitudes, previous experience and self assessed preparedness to respond or to assist in mass casualty incidents in Croatia. Methods: The cross-sectional survey was carried out during January 2017. Study participants were recruited through a Facebook group that brings together family physicians from Croatia. They were asked to complete the questionnaire, which was distributed via google.docs. Knowledge and attitudes toward disaster preparedness were evaluated by 18 questions. Analysis of variance, Student t test and Kruskal-Wallis test t were used for statistical analysis. Results: Risk awareness of disasters was high among respondents (M = 4.89, SD=0.450). Only 16.4 of respondents have participated in the management of disaster at the scene. The majority (73.8%) of physicians have not been participating in any educational activity dealing with disaster over the past two years. Family physicians believed they are not well prepared to participate in national (M = 3.02, SD=0.856) and local community emergency response system for disaster (M = 3.16, SD=1.119). Male physicians scored higher preparedness to participate in national emergency response system for disaster (p=0.012), to carry out accepted triage principles used in the disaster situation (p=0.003) and recognize differences in health assessments indicating potential exposure to specific agents (p=0,001) compared to their female colleagues. Conclusion: Croatian primary healthcare system attracts many young physicians, who can be an important part of disaster and emergency management. However, the lack of experience despite a high motivation indicates a need for inclusion of disaster medicine training during undergraduate studies and annual educational activities. PMID- 29719849 TI - Avulsion of Ampulla of Vater Secondary to a Blunt Abdominal Injury Treated with Pancreatoduodenectomy; A Case Report and Literature Review. AB - The incidence of complex hepatobiliary injury secondary to blunt abdominal injuries varies between 3.4 and 5%. A 25-year old male patient underwent an urgent operation due to a motorcycle accident. During intraabdominal exploration, Grade 4 laceration was detected at the liver and bleeding was controlled through primary repair. In the postoperative seventh day, he was referred due to 1500 cc bile leakage from the drainage tube. During the operation, an extensive Kocher maneuver was done and the second part of duodenum was observed to be exposed to total avulsion from the head of the pancreas. Pancreatoduodenectomy was planned due to presence of ischemic changes in the second part of duodenum. In the postoperative follow-up, the abdomen was closed with a controlled abdominal closure procedure. The clinical findings of biliary tract injuries secondary to blunt abdominal injuries often manifest themselves late and early diagnosis is possible only with suspicion. PMID- 29719850 TI - Delayed Progressive Intraparenchymal Tension Pneumocephalus after Craniotomy for Recurrent Pituitary Macroadenoma: A Case Report. AB - Pneumocephalus is defined as the presence of air in the intracranial cavity. In most cases, its evolution is asymptomatic and benign. Pneumocephalus post-surgery is a frequent complication of cranial surgery. We herein report delayed tension pneumocephalus after craniotomy for pituitary macroadenoma. A 73-year-old man with recurrent pituitary macroadenoma underwent subtotal resection via subfrontal approach. The postoperative course was uneventful and the patients regained his normal daily living activities. Two months after the surgery the patients developed decreased level of consciousness and was diagnosed to suffer from tension pneumocephalus. Another craniotomy was performed and the dural defect at the base was repair with secondary graft and bone wax. The patient improved neurologically and had no pneumocephalus. The follow-up revealed good condition and outcome. In conclusion, tension pneumocephalus can occur at any time after craniotomy and post-surgical deterioration after resection of a giant pituitary tumor should be immediately assessed. There is not enough evidence to correlated tumor size with rates of pneumocephalus in this particular report, but further cases may need to be studied to come to a conclusion. PMID- 29719851 TI - An Unforeseeable Complication; Posterior Ischemic Optic Neuropathy after Penetrating Injury to the Heart. AB - Trauma surgeons are currently encountering unusual adverse events after traumatic injuries. Ischemic optic neuropathy is a rare complication that may occur in trauma and burn patients that present in extremis and require massive resuscitation. A 29-year-old male patient sustains a penetrating injury to the heart that required primary repair. He remained hemodynamically stable and required a limited amount of resuscitative fluids and products. Postoperatively, the patient develops acute painless bilateral loss of vision. These findings were consistent with posterior ischemic optic neuropathy. Ischemic optic neuropathy are uncommon entities that arise in trauma patients who require massive resuscitation. Given the limited treatment options, early diagnosis is key in limiting the hemodynamic insult to the optic nerve. PMID- 29719852 TI - Performance survey on a new standardized formula for oral signal suppression in MRCP. AB - Background: Orally administered substances, which reduce image contamination by overlying gastrointestinal fluid signals, can be used to enhance the quality of MRCP images. Recently, a new standardized formula consisting of biological substances has become available. The objective of this study is to provide a first assessment of achievable MRCP image quality, taste and palatability of this new dedicated agent. Methods: In January 2015 to May 2015 practicing radiologists in Germany, Austria and Switzerland were asked to evaluate image quality as well as taste and palatability when using the new agent (LumiVision(r); b.e. imaging; Baden-Baden; Germany) in MRCP questionnaire. Both criteria were rated with a 6 point Likert scale ranging from "1" (best) to "6" (worst). Results: A total 185 of 475 radiologic institutions (39%) submitted feedback on image quality, 187 (39%) on the taste/palatability. Assessments of image quality regarding presence of disturbing gastrointestinal fluid signal resulted in a median of 2. The majority of patients rated the subjective taste as very good (median of 1). No side effects of relevance were recorded. Conclusion: This large survey shows that the tested product is considered effective by radiologists regarding MRCP image quality. Patients' feedback on taste and palatability was very positive. PMID- 29719853 TI - Reconstruction of white matter fibre tracts using diffusion kurtosis tensor imaging at 1.5T: Pre-surgical planning in patients with gliomas. AB - : Tractography studies for pre-surgical planning of primary brain tumors is typically done using diffusion tensor imaging (DTI), which cannot resolve crossing, kissing or highly angulated fibres. Tractography based on the estimation of the diffusion kurtosis (DK) tensor was recently demonstrated to enable tackling these limitations. However, its use in the clinical context at low 1.5T field has not yet been reported. Purpose: To evaluate if the estimation of whole-brain tractography using the DK tensor is feasible for pre-surgical investigation of patients with brain tumors at 1.5T. Methods: Eight healthy subjects and 3 patients with brain tumors were scanned at 1.5T using a 12-channel head coil. Diffusion-weighted images were acquired with repetition/echo times of 5800/107 ms, 82 * 82 resolution, 3 * 3 * 3 mm3 voxel size, b-values of 0, 1000, 2000 s/mm2 and 64 gradient sensitising directions. Whole-brain tractography was estimated using the DK tensor and corticospinal tracts (CST) were isolated using regions-of-interest placed at the cerebral peduncles and motor gyrus. Tract size, DK metrics and CST deviation index (highest curvature point) were compared between healthy subjects and patients. Results: Tract sizes did not differ between groups. The CST deviation index was significantly higher in patients compared to healthy subjects. Fractional anisotropy was significantly lower in patients, with higher mean kurtosis asymmetry index at the highest curvature point in patients. Conclusions: Corticospinal fibre bundles estimated using DK tensor in a 1.5T scanner presented similar properties in patients with brain gliomas as those reported in the literature using DTI-based tractography. PMID- 29719854 TI - Intravoxel incoherent motion (IVIM) and non-Gaussian diffusion MRI of the lactating breast. AB - Purpose: To investigate the effect of breastfeeding on IVIM and non-Gaussian diffusion MRI in the breast. Materials and methods: An IRB approved prospective study enrolled seventeen volunteers (12 in lactation and 5 with post-weaning, range 31-43 years; mean 35.4 years). IVIM (fIVIM and D*) and non-Gaussian diffusion (ADC0 and K) parameters using 16 b values, plus synthetic apparent diffusion coefficients (sADCs) from 2 key b values (b = 200 and 1500 s/mm2) were calculated using regions of interest. ADC0 maps of the whole breast were generated and their contrast patterns were evaluated by two independent readers using retroareolar and segmental semi-quantitative scores. To compare the diffusion and IVIM parameters, Wilcoxon signed rank tests were used between pre- and post-breastfeeding and Mann-Whitney tests were used between post-weaning and pre- or post-breastfeeding. Results: ADC0 and sADC values significantly decreased post-breastfeeding (1.90 vs. 1.72 * 10-3 mm2/s, P < 0.001 and 1.39 vs. 1.25 * 10 3 mm2/s, P < 0.001) while K values significantly increased (0.33 vs. 0.44, P < 0.05). fIVIM values significantly increased after breastfeeding (1.97 vs. 2.97%, P < 0.01). No significant difference was found in D* values. There was significant heterogeneity in ADC0 maps post-breastfeeding, both in retroareolar and segmental scores (P < 0.0001 and =0.0001). Conclusion: IVIM and non-Gaussian diffusion parameters significantly changed between pre- and post-breastfeeding status, and care needs to be taken in interpreting diffusion-weighted imaging (DWI) data in lactating breasts. PMID- 29719855 TI - Cerebral venous thrombosis presenting like a subdural hemorrhage at magnetic resonance imaging: An Italian case report. AB - Cerebral venous sinus thrombosis (CVST) is responsible for 1-2% of all strokes in adults. Venous occlusive disease is a less common condition than the arterial one, but probably underestimated in the past [1]. Its early detection is crucial to ensure appropriate therapy, to prevent irreversible brain injury. The neuroradiological study is crucial to formulate the diagnosis. Unenhanced computed tomography (CT) is usually the first imaging study performed on an emergency basis. We report the case of a woman who present a migrant headache, resistant to the therapy. It was at first performed an axial CT scan of the brain that was negative. Afterwards the Patient did an MRI which proves the presence of a hyperintensity rhyme, localized in the left temporal region, in the subdural space, diagnosed like a subdural hemorrhage. Considering the type and increase of headache, neurologist suggest to perform a venography PC sequence that finally demonstrate the correct diagnosis of a filling defect of left spheno-parietal sinus. PMID- 29719856 TI - Image quality with iterative reconstruction techniques in CT of the lungs-A phantom study. AB - Background: Iterative reconstruction techniques for reducing radiation dose and improving image quality in CT have proved to work differently for different patient sizes, dose levels, and anatomical areas. Purpose: This study aims to compare image quality in CT of the lungs between four high-end CT scanners using the recommended reconstruction techniques at different dose levels and patient sizes. Material and methods: A lung phantom and an image quality phantom were scanned with four high-end scanners at fixed dose levels. Images were reconstructed with and without iterative reconstruction. Contrast-to-noise ratio, modulation transfer function, and peak frequency of the noise power spectrum were measured. Results: IMR1 Sharp+ and VEO improved contrast-to-noise ratio to a larger extent than the other iterative techniques, while maintaining spatial resolution. IMR1 Sharp+ also maintained noise texture. Conclusions: IMR1 Sharp+ was the only reconstruction technique in this study which increased CNR to a large extent, while maintaining all other image quality parameters measured in this study. PMID- 29719857 TI - Foreign-body granuloma mimicking post-chemotherapy residual seminoma: A case of true-negative findings using diffusion-weighted whole-body magnetic resonance imaging with background suppression. AB - Diffusion-weighted whole-body magnetic resonance imaging with background suppression (DWIBS) is increasingly used in cancer imaging. However, little is known about its usefulness in the management of metastatic seminoma, in which evaluation of the viability of postchemotherapy residual nodules is pivotal. To date, 2-18fluoro-deoxy-d-glucose positron emission tomography (FDG-PET) has been recommended for post-chemotherapeutic assessment. We describe a case of metastatic seminoma in a 27-year-old man in which the viability of post chemotherapy residual nodules tested false-positive on FDG-PET, but true-negative on DWIBS. DWIBS may be a good alternative technique to evaluate post-chemotherapy seminoma, although further studies are required to determine its usefulness. PMID- 29719858 TI - Imaging features of neurotoxoplasmosis: A multiparametric approach, with emphasis on susceptibility-weighted imaging. AB - Background: Neurotoxoplasmosis is a common opportunistic infection in HIV/AIDS patients. Imaging identification of neurotoxoplasmosis assists in timely treatment. Purpose: To delineate the frequency of imaging abnormalities in patients with neurotoxoplasmosis on different MR sequences with a particular focus on SWI, and NCCT. Material and methods: The PACS database was retroactively searched over a 5-year period for patients with neurotoxoplasmosis who underwent MRI with SWI. Included patients had imaging features of neurotoxoplasmosis based on consensus review by two neuroradiologists, a clinical diagnosis of neurotoxoplasmosis at the time of MRI, and diagnostic confirmation based on positive serum or CSF serology or histopathology; 15 patients were included. The number of abnormal foci with restricted diffusion, increased FLAIR signal, intrinsic T1 hyperintensity, abnormal enhancement (CE-T1WI), and intrinsic hyperdensity on CT were recorded. Results: Intralesional susceptibility signal (ISS) foci on SWI were observed in 93.3% of patients with neurotoxoplasmosis (mean size 5.2 +/- 3.8 mm). The average number of ISS foci was 3.9 per patient; 3/15 (20.0%) had a single ISS. Amongst other MR sequences, hyperintense FLAIR foci were the most common abnormalities observed (12.4 lesions/patient), followed by enhancing foci (8.2 lesions/patient), foci of restricted diffusion (7.1 lesions/patient), and intrinsic T1 hyperintense foci (3.4 lesions/patient). Abnormalities were least frequently observed on NCCT: abnormalities were identified in 5/15 (33.3%) patients, at a rate of 0.4 lesions/patient. Conclusion: ISS foci are present in the vast majority of neurotoxoplasmosis patients, likely representing hemorrhage. The incidence and frequency of other abnormal foci are highest on FLAIR, and lowest on NCCT. PMID- 29719859 TI - Characterization of diffuse orbital mass using Apparent diffusion coefficient in 3-tesla MRI. AB - Purpose: To evaluate if the apparent diffusion coefficient (ADC) value in diffusion-weighted magnetic resonance imaging (DW-MRI) improves the diagnostic accuracy of diffuse orbital masses. Materials and methods: ADC DW-MRI was used to evaluate cases of diffuse orbital masses at our institution from 2000 to 2015. Lesions were grouped according to histopathologic diagnosis as, benign, pre malignant and malignant. Lymphoproliferative lesions were further subgrouped as lymphoma or other lymphoproliferative lesions. The validity of the ADC value for the diffuse orbital mass was compared between groups. The area under curve (AUC) was also calculated. Results: Thirty-nine cases of diffuse orbital masses were evaluated. The median ADC was 0.58 (25% quartile 0.48; minimum: 0.45; maximum: 1.72 * 10(-3)) for the malignant tumors and 1.19 (25% quartile 0.7; minimum: 0.5; maximum: 1.95 * 10(-3) mm(2) s(-1)) for benign lesions. This difference in ADC between lesions was statistically significant (Mann Whitney U test P < 0.001). The median ADC was 0.51 (25% quartile 0.48) for lymphomas and 0.9 (25% quartile 0.7) for other lymphoproliferative lesions. This difference in ADC was statistically significant (Mann Whitney U test P = 0.02). An ADC value of 0.8 * 10(-3) mm(2) s(-1) was noted as the ideal threshold value for differentiating malignant from benign diffuse orbital masses. The validity of ADC in predicting a malignant or benign diffuse orbital mass had a sensitivity of 87%, specificity of 67% and accuracy of 88%. Conclusion: ADC is a promising imaging metric to characterize malignant and benign diffuse orbital masses and to distinguish lymphomas from other non-lymphoproliferative lesions. PMID- 29719861 TI - Bacteria as living patchy colloids: Phenotypic heterogeneity in surface adhesion. AB - Understanding and controlling the surface adhesion of pathogenic bacteria is of urgent biomedical importance. However, many aspects of this process remain unclear (for example, microscopic details of the initial adhesion and possible variations between individual cells). Using a new high-throughput method, we identify and follow many single cells within a clonal population of Escherichia coli near a glass surface. We find strong phenotypic heterogeneities: A fraction of the cells remain in the free (planktonic) state, whereas others adhere with an adhesion strength that itself exhibits phenotypic heterogeneity. We explain our observations using a patchy colloid model; cells bind with localized, adhesive patches, and the strength of adhesion is determined by the number of patches: Nonadherers have no patches, weak adherers bind with a single patch only, and strong adherers bind via a single or multiple patches. We discuss possible implications of our results for controlling bacterial adhesion in biomedical and other applications. PMID- 29719860 TI - A physical catalyst for the electrolysis of nitrogen to ammonia. AB - Ammonia synthesis consumes 3 to 5% of the world's natural gas, making it a significant contributor to greenhouse gas emissions. Strategies for synthesizing ammonia that are not dependent on the energy-intensive and methane-based Haber Bosch process are critically important for reducing global energy consumption and minimizing climate change. Motivated by a need to investigate novel nitrogen fixation mechanisms, we herein describe a highly textured physical catalyst, composed of N-doped carbon nanospikes, that electrochemically reduces dissolved N2 gas to ammonia in an aqueous electrolyte under ambient conditions. The Faradaic efficiency (FE) achieves 11.56 +/- 0.85% at -1.19 V versus the reversible hydrogen electrode, and the maximum production rate is 97.18 +/- 7.13 MUg hour-1 cm-2. The catalyst contains no noble or rare metals but rather has a surface composed of sharp spikes, which concentrates the electric field at the tips, thereby promoting the electroreduction of dissolved N2 molecules near the electrode. The choice of electrolyte is also critically important because the reaction rate is dependent on the counterion type, suggesting a role in enhancing the electric field at the sharp spikes and increasing N2 concentration within the Stern layer. The energy efficiency of the reaction is estimated to be 5.25% at the current FE of 11.56%. PMID- 29719863 TI - Electronic zero-point fluctuation forces inside circuit components. AB - One of the most intriguing manifestations of quantum zero-point fluctuations are the van der Waals and Casimir forces, often associated with vacuum fluctuations of the electromagnetic field. We study generalized fluctuation potentials acting on internal degrees of freedom of components in electrical circuits. These electronic Casimir-like potentials are induced by the zero-point current fluctuations of any general conductive circuit. For realistic examples of an electromechanical capacitor and a superconducting qubit, our results reveal the possibility of tunable forces between the capacitor plates, or the level shifts of the qubit, respectively. Our analysis suggests an alternative route toward the exploration of Casimir-like fluctuation potentials, namely, by characterizing and measuring them as a function of parameters of the environment. These tunable potentials may be useful for future nanoelectromechanical and quantum technologies. PMID- 29719862 TI - Nonequilibrium electron and lattice dynamics of strongly correlated Bi2Sr2CaCu2O8+delta single crystals. AB - The interplay between the electronic and lattice degrees of freedom in nonequilibrium states of strongly correlated systems has been debated for decades. Although progress has been made in establishing a hierarchy of electronic interactions with the use of time-resolved techniques, the role of the phonons often remains in dispute, a situation highlighting the need for tools that directly probe the lattice. We present the first combined megaelectron volt ultrafast electron diffraction and time- and angle-resolved photoemission spectroscopy study of optimally doped Bi2Sr2CaCu2O8+delta. Quantitative analysis of the lattice and electron subsystems' dynamics provides a unified picture of nonequilibrium electron-phonon interactions in the cuprates beyond the N temperature model. The work provides new insights on the specific phonon branches involved in the nonequilibrium heat dissipation from the high-energy Cu-O bond stretching "hot" phonons to the lowest-energy acoustic phonons with correlated atomic motion along the <110> crystal directions and their characteristic time scales. It reveals a highly nonthermal phonon population during the first several picoseconds after the photoexcitation. The approach, taking advantage of the distinct nature of electrons and photons as probes, is applicable for studying energy relaxation in other strongly correlated electron systems. PMID- 29719864 TI - Readily accessible shape-memory effect in a porous interpenetrated coordination network. AB - Shape-memory effects are quite well-studied in general, but there is only one reported example in the context of porous materials. We report the second example of a porous coordination network that exhibits a sorbate-induced shape-memory effect and the first in which multiple sorbates, N2, CO2 and CO promote this effect. The material, a new threefold interpenetrated pcu network, [Zn2(4,4' biphenyldicarboxylate)2(1,4-bis(4-pyridyl)benzene)]n (X-pcu-3-Zn-3i), exhibits three distinct phases: the as-synthesized alpha phase; a denser-activated beta phase; and a shape-memory gamma phase, which is intermediate in density between the alpha and beta phases. The gamma phase is kinetically stable over multiple adsorption/desorption cycles and only reverts to the beta phase when heated at >400 K under vacuum. The alpha phase can be regenerated by soaking the gamma phase in N,N'-dimethylformamide. Single-crystal x-ray crystallography studies of all three phases provide insight into the shape-memory phenomenon by revealing the nature of interactions between interpenetrated networks. The beta and gamma phases were further investigated by in situ coincidence powder x-ray diffraction, and their sorption isotherms were replicated by density functional theory calculations. Analysis of the structural information concerning the three phases of X-pcu-3-Zn-3i enabled us to understand structure-function relationships and propose crystal engineering principles for the design of more examples of shape memory porous materials. PMID- 29719865 TI - Superadiabatic quantum friction suppression in finite-time thermodynamics. AB - Optimal performance of thermal machines is reached by suppressing friction. Friction in quantum thermodynamics results from fast driving schemes that generate nonadiabatic excitations. The far-from-equilibrium dynamics of quantum devices can be tailored by shortcuts to adiabaticity to suppress quantum friction. We experimentally demonstrate friction-free superadiabatic strokes with a trapped unitary Fermi gas as a working substance and establish the equivalence between the superadiabatic work and its adiabatic value. PMID- 29719866 TI - Superconducting pairing of topological surface states in bismuth selenide films on niobium. AB - A topological insulator film coupled to a simple isotropic s-wave superconductor substrate can foster helical pairing of the Dirac fermions associated with the topological surface states. Experimental realization of such a system is exceedingly difficult, however using a novel "flip-chip" technique, we have prepared single-crystalline Bi2Se3 films with predetermined thicknesses in terms of quintuple layers (QLs) on top of Nb substrates fresh from in situ cleavage. Our angle-resolved photoemission spectroscopy (ARPES) measurements of the film surface disclose superconducting gaps and coherence peaks of similar magnitude for both the topological surface states and bulk states. The ARPES spectral map as a function of temperature and film thickness up to 10 QLs reveals key characteristics relevant to the mechanism of coupling between the topological surface states and the superconducting Nb substrate; the effective coupling length is found to be much larger than the decay length of the topological surface states. PMID- 29719867 TI - Ultralight and fire-resistant ceramic nanofibrous aerogels with temperature invariant superelasticity. AB - Ultralight aerogels that are both highly resilient and compressible have been fabricated from various materials including polymer, carbon, and metal. However, it has remained a great challenge to realize high elasticity in aerogels solely based on ceramic components. We report a scalable strategy to create superelastic lamellar-structured ceramic nanofibrous aerogels (CNFAs) by combining SiO2 nanofibers with aluminoborosilicate matrices. This approach causes the random deposited SiO2 nanofibers to assemble into elastic ceramic aerogels with tunable densities and desired shapes on a large scale. The resulting CNFAs exhibit the integrated properties of flyweight densities of >0.15 mg cm-3, rapid recovery from 80% strain, zero Poisson's ratio, and temperature-invariant superelasticity to 1100 degrees C. The integral ceramic nature also provided the CNFAs with robust fire resistance and thermal insulation performance. The successful synthesis of these fascinating materials may provide new insights into the development of ceramics in a lightweight, resilient, and structurally adaptive form. PMID- 29719868 TI - Hydrogel microenvironments for cancer spheroid growth and drug screening. AB - Multicellular cancer spheroids (MCSs) have emerged as a promising in vitro model that replicates many features of solid tumors in vivo. Biomimetic hydrogel scaffolds for MCS growth offer a broad spectrum of biophysical and biochemical cues that help to recapitulate the behavior of natural extracellular matrix, essential for regulating cancer cell behavior. This perspective highlights recent advances in the development of hydrogel environments for MCS growth, release, and drug screening. We review the use of different types of hydrogels for MCS growth, the effect of biophysical and biochemical cues on MCS fate, the isolation of MCSs from hydrogel scaffolds, the utilization of microtechnologies, and the applications of MCSs grown in hydrogels. We conclude with the discussion of new research directions in the development of hydrogels for MCS growth. PMID- 29719869 TI - Phylogenetic Placement of Exact Amplicon Sequences Improves Associations with Clinical Information. AB - Recent algorithmic advances in amplicon-based microbiome studies enable the inference of exact amplicon sequence fragments. These new methods enable the investigation of sub-operational taxonomic units (sOTU) by removing erroneous sequences. However, short (e.g., 150-nucleotide [nt]) DNA sequence fragments do not contain sufficient phylogenetic signal to reproduce a reasonable tree, introducing a barrier in the utilization of critical phylogenetically aware metrics such as Faith's PD or UniFrac. Although fragment insertion methods do exist, those methods have not been tested for sOTUs from high-throughput amplicon studies in insertions against a broad reference phylogeny. We benchmarked the SATe-enabled phylogenetic placement (SEPP) technique explicitly against 16S V4 sequence fragments and showed that it outperforms the conceptually problematic but often-used practice of reconstructing de novo phylogenies. In addition, we provide a BSD-licensed QIIME2 plugin (https://github.com/biocore/q2-fragment insertion) for SEPP and integration into the microbial study management platform QIITA. IMPORTANCE The move from OTU-based to sOTU-based analysis, while providing additional resolution, also introduces computational challenges. We demonstrate that one popular method of dealing with sOTUs (building a de novo tree from the short sequences) can provide incorrect results in human gut metagenomic studies and show that phylogenetic placement of the new sequences with SEPP resolves this problem while also yielding other benefits over existing methods. PMID- 29719870 TI - Quantifying the Evolutionary Conservation of Genes Encoding Multidrug Efflux Pumps in the ESKAPE Pathogens To Identify Antimicrobial Drug Targets. AB - Increasing rates of antibiotic-resistant bacterial infection are one of the most pressing contemporary global health concerns. The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) have been identified as the leading global cause of multidrug-resistant bacterial infections, and overexpression of multidrug efflux (MEX) transport systems has been identified as one of the most critical mechanisms facilitating the evolution of multidrug resistance in ESKAPE pathogens. Despite efforts to develop efflux pump inhibitors to combat antibiotic resistance, the need persists to identify additional targets for future investigations. We evaluated evolutionary pressures on 110 MEX encoding genes from all annotated ESKAPE organism genomes. We identify several MEX genes under stabilizing selection-representing targets which can facilitate broad-spectrum treatments with evolutionary constraints limiting the potential emergence of escape mutants. We also examine MEX systems being evaluated as drug targets, demonstrating that divergent selection may underlie some of the problems encountered in the development of effective treatments-specifically in relation to the NorA system in S. aureus. This study provides a comprehensive evolutionary context to efflux in the ESKAPE pathogens, which will provide critical context to the evaluation of efflux systems as antibiotic targets. IMPORTANCE Increasing rates of antibiotic-resistant bacterial infection are one of the most pressing contemporary global health concerns. The ESKAPE pathogen group represents the leading cause of these infections, and upregulation of efflux pump expression is a significant mechanism of resistance in these pathogens. This has resulted in substantial interest in the development of efflux pump inhibitors to combat antibiotic-resistant infections; however, no widespread treatments have been developed to date. Our study evaluates an often-underappreciated aspect of resistance-the impact of evolutionary selection. We evaluate selection on all annotated efflux genes in all sequenced ESKAPE pathogens, providing critical context for and insight into current and future development of efflux-targeting treatments for resistant bacterial infections. PMID- 29719872 TI - SHI7 Is a Self-Learning Pipeline for Multipurpose Short-Read DNA Quality Control. AB - Next-generation sequencing technology is of great importance for many biological disciplines; however, due to technical and biological limitations, the short DNA sequences produced by modern sequencers require numerous quality control (QC) measures to reduce errors, remove technical contaminants, or merge paired-end reads together into longer or higher-quality contigs. Many tools for each step exist, but choosing the appropriate methods and usage parameters can be challenging because the parameterization of each step depends on the particularities of the sequencing technology used, the type of samples being analyzed, and the stochasticity of the instrumentation and sample preparation. Furthermore, end users may not know all of the relevant information about how their data were generated, such as the expected overlap for paired-end sequences or type of adaptors used to make informed choices. This increasing complexity and nuance demand a pipeline that combines existing steps together in a user-friendly way and, when possible, learns reasonable quality parameters from the data automatically. We propose a user-friendly quality control pipeline called SHI7 (canonically pronounced "shizen"), which aims to simplify quality control of short-read data for the end user by predicting presence and/or type of common sequencing adaptors, what quality scores to trim, whether the data set is shotgun or amplicon sequencing, whether reads are paired end or single end, and whether pairs are stitchable, including the expected amount of pair overlap. We hope that SHI7 will make it easier for all researchers, expert and novice alike, to follow reasonable practices for short-read data quality control. IMPORTANCE Quality control of high-throughput DNA sequencing data is an important but sometimes laborious task requiring background knowledge of the sequencing protocol used (such as adaptor type, sequencing technology, insert size/stitchability, paired endedness, etc.). Quality control protocols typically require applying this background knowledge to selecting and executing numerous quality control steps with the appropriate parameters, which is especially difficult when working with public data or data from collaborators who use different protocols. We have created a streamlined quality control pipeline intended to substantially simplify the process of DNA quality control from raw machine output files to actionable sequence data. In contrast to other methods, our proposed pipeline is easy to install and use and attempts to learn the necessary parameters from the data automatically with a single command. PMID- 29719871 TI - A Prospective Metagenomic and Metabolomic Analysis of the Impact of Exercise and/or Whey Protein Supplementation on the Gut Microbiome of Sedentary Adults. AB - Many components of modern living exert influence on the resident intestinal microbiota of humans with resultant impact on host health. For example, exercise associated changes in the diversity, composition, and functional profiles of microbial populations in the gut have been described in cross-sectional studies of habitual athletes. However, this relationship is also affected by changes in diet, such as changes in dietary and supplementary protein consumption, that coincide with exercise. To determine whether increasing physical activity and/or increased protein intake modulates gut microbial composition and function, we prospectively challenged healthy but sedentary adults with a short-term exercise regime, with and without concurrent daily whey protein consumption. Metagenomics- and metabolomics-based assessments demonstrated modest changes in gut microbial composition and function following increases in physical activity. Significant changes in the diversity of the gut virome were evident in participants receiving daily whey protein supplementation. Results indicate that improved body composition with exercise is not dependent on major changes in the diversity of microbial populations in the gut. The diverse microbial characteristics previously observed in long-term habitual athletes may be a later response to exercise and fitness improvement. IMPORTANCE The gut microbiota of humans is a critical component of functional development and subsequent health. It is important to understand the lifestyle and dietary factors that affect the gut microbiome and what impact these factors may have. Animal studies suggest that exercise can directly affect the gut microbiota, and elite athletes demonstrate unique beneficial and diverse gut microbiome characteristics. These characteristics are associated with levels of protein consumption and levels of physical activity. The results of this study show that increasing the fitness levels of physically inactive humans leads to modest but detectable changes in gut microbiota characteristics. For the first time, we show that regular whey protein intake leads to significant alterations to the composition of the gut virome. PMID- 29719873 TI - Ward round template: enhancing patient safety on ward rounds. AB - Introduction and aims: Concerns had been raised at clinical governance regarding the safety of our inpatient ward rounds with particular reference to: documentation of clinical observations and National Early Warning Score (NEWS), compliance with Trust guidance for venous thromboembolism (VTE) risk assessment, antibiotic stewardship, palliative care and treatment escalation plans (TEP). This quality improvement project was conceived to ensure these parameters were considered and documented during the ward round, thereby improving patient care and safety. These parameters were based on Trust patient safety guidance and CQUIN targets. Method: The quality improvement technique of plan-do-study-act (PDSA) was used in this project. We retrospectively reviewed ward round entries to record baseline measurements, based on the above described parameters, prior to making any changes. Following this, the change applied was the introduction of a ward round template to include the highlighted important baseline parameters. Monthly PDSA cycles are performed, and baseline measurements are re-examined, then relevant changes were made to the ward round template. Summary of results: Documentation of baseline measurements was poor prior to introduction of the ward round template; this improved significantly following introduction of a standardised ward round template. Following three cycles, documentation of VTE risk assessments increased from 14% to 92%. Antibiotic stewardship documentation went from 0% to 100%. Use of the TEP form went from 29% to 78%. Conclusions: Following introduction of the ward round template, compliance improved significantly in all safety parameters. Important safety measures being discussed on ward rounds will lead to enhanced patient safety and will improve compliance to Trust guidance and comissioning for quality and innovation (CQUIN) targets. Ongoing change implementation will focus on improving compliance with usage of the template on all urology ward rounds. PMID- 29719874 TI - Reducing the rate of post-surgical urinary tract infections in orthopedic patients. AB - Urinary tract infection (UTI) is the fourth leading cause of healthcare associated infections, with approximately 70%-80% being attributed to the inappropriate use of indwelling catheters. In many cases, indwelling catheters are used inappropriately without any valid indication, creating potentially avoidable and significant patient distress, discomfort, pain and activity restrictions, together with substantial care burden, cost and hospitalisation. In the Division of Orthopedic Surgery at Toronto Western Hospital (TWH), we identified UTI rate reduction as a quality improvement priority. Patients who underwent total hip and knee joint replacements and hip fracture repairs at TWH were monitored for the incidence of UTI and the usage of catheters. The data collected as part of the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) revealed UTI rate of 2.1% among 666 patients who were treated between January and June 2016. Data collected through a custom field in the ACS NSQIP workstation further revealed that indwelling catheters were overused, with 55.2% of patients receiving indwelling catheters in the same time period. These data were presented to the orthopaedic leadership group and surgeons at TWH in July 2016 to set the quality improvement target and create the working group. Nursing staff was provided education to strictly follow the institutional catheter-associated UTI prevention guidelines and change ideas based on the guidelines were implemented in July 2016. As a result, the rate of UTI decreased to 1.1% and the use of indwelling catheter decreased to 19.8% among 883 patients who were treated between July 2016 and March 2017. The study indicated that a systematic approach, engaging all front-line staff including nurse educators and nurse practitioners, helps to facilitate implementation of practice changes. We expect that ongoing reminders and education ensure that the changes are sustainable. PMID- 29719875 TI - Using an original triage and on call management tool aids identification and assessment of the acutely unwell surgical patient. AB - Until now, there have been no published surgical triage tools. We have developed the first such tool with a tiered escalation policy, aiming to improve identification and management of critically unwell patients. The existing sheet which is used to track new referrals and admissions to the surgical assessment unit was reviewed. The sheet was updated and a traffic light triage tool generated using National Early Warning Scores (NEWS), sepsis criteria and user discretion. A tiered escalation policy to guide urgency of assessment was introduced and education sessions for all staff undertaken, to ensure understanding and compliance. Through multiple 'plan-do-study-act' cycles, the new system and its efficiency have been analysed. Prior to intervention, documentation of NEWS did not occur and only 13% of admission observations were communicated to the surgical team. Following multiple cycles and interventions, 93% of patients were fully triaged, and 80% of 'red' and 'amber' patients' observations were communicated to the surgical team. The average time for a registrar to review a 'red' patient was 37 min and 79% of 'green' patients were reviewed within an hour of their presentation. Rapid identification of the unwell patient is crucial. Here we publish the first triage tool that enables early assessment of septic and otherwise potentially unwell surgical patients. PMID- 29719876 TI - Complementary feeding intervention on stunted Guatemalan children: a randomised controlled trial. AB - Objective/background: Guatemala's indigenous Maya population has one of the highest rates of childhood stunting in the world. The goal of this study was to examine the impact of an intensive, individualised approach to complementary feeding education for caregivers on feeding practices and growth over usual care. Design: An individually randomised (1:1 allocation ratio), parallel-group superiority trial, with blinding of study staff collecting outcome data. Setting: Rural Maya communities in Guatemala. Participants: 324 children aged 6-24 months with a height-for-age Z score of less than or equal to -2.5 SD were randomised, 161 to the intervention and 163 to usual care. Interventions: Community health workers conducted home visits for 6 months, providing usual care or usual care plus individualised caregiver education. Main outcomes measures: The main outcome was change in length/height-for-age Z score. Secondary outcomes were changes in complementary feeding indicators. Results: Data were analysed for 296 subjects (intervention 145, usual care 151). There was a non-significant trend to improved growth in the intervention arm (length/height-for-age Z score change difference 0.07(95% CI -0.04 to 0.18)). The intervention led to a 22% improvement in minimum dietary diversity (RR 1.22, 95% CI 1.11 to 1.35) and a 23% improvement in minimal acceptable diet (RR 1.23, 95% CI 1.08 to 1.40) over usual care. Conclusions: Complementary feeding outcomes improved in the intervention arm, and a non significant trend towards improved linear growth was observed. Community health workers in a low-resource rural environment can implement individualised caregiver complementary feeding education with significant improvements in child dietary quality over standard approaches. Clinical trial registration number: NCT02509936. Stage: Results. PMID- 29719877 TI - Identifying Geographic Disparities in Diabetes Prevalence Among Adults and Children Using Emergency Claims Data. AB - Geographic surveillance can identify hotspots of disease and reveal associations between health and the environment. Our study used emergency department surveillance to investigate geographic disparities in type 1 and type 2 diabetes prevalence among adults and children. Using all-payer emergency claims data from 2009 to 2013, we identified unique New York City residents with diabetes and geocoded their location using home addresses. Geospatial analysis was performed to estimate diabetes prevalence by New York City Census tract. We also used multivariable regression to identify neighborhood-level factors associated with higher diabetes prevalence. We estimated type 1 and type 2 diabetes prevalence at 0.23% and 10.5%, respectively, among adults and 0.20% and 0.11%, respectively, among children in New York City. Pediatric type 1 diabetes was associated with higher income (P = 0.001), whereas adult type 2 diabetes was associated with lower income (P < 0.001). Areas with a higher proportion of nearby restaurants categorized as fast food had a higher prevalence of all types of diabetes (P < 0.001) except for pediatric type 2 diabetes. Type 2 diabetes among children was only higher in neighborhoods with higher proportions of African American residents (P < 0.001). Our findings identify geographic disparities in diabetes prevalence that may require special attention to address the specific needs of adults and children living in these areas. Our results suggest that the food environment may be associated with higher type 1 diabetes prevalence. However, our analysis did not find a robust association with the food environment and pediatric type 2 diabetes, which was predominantly focused in African American neighborhoods. PMID- 29719878 TI - Increasing Body Mass Index Predicts Rapid Decline in Renal Function: A 5 Year Retrospective Study. AB - While obesity is a recognized risk factor for chronic kidney disease, it remains unclear whether change in body mass index (DeltaBMI ) is independently associated with decline in renal function (evaluated by the change in estimated glomerular filtration rate, DeltaeGFR) over time. Accordingly, to help clarify this we conducted a retrospective study to measure the association of DeltaBMI with decline in renal function in Chinese adult population. A total of 4007 adults (aged 45.3+/-13.7 years, 68.6% male) without chronic kidney disease at baseline were enrolled between 2008 and 2013. Logistic regression models were applied to explore the relationships between baseline BMI and DeltaBMI, and rapid decline in renal function (defined as the lowest quartile of DeltaeGFR ). During 5 years of follow-up, the DeltaBMI and DeltaeGFR were 0.47+/-1.6 (kg/m2) and -3.0+/-8.8 (ml/min/1.73 m2), respectively. After adjusted for potential confounders, DeltaBMI (per 1 kg/m2 increase) was independently associated with the rapid decline in renal function [with a fully adjusted OR of 1.12 (95% CI, 1.05 to 1.20). By contrast, the baseline BMI was not associated with rapid decline in renal function [OR=1.05 (95% CI, 0.98 to 1.13)]. The results were robust among 2948 hypertension-free and diabetes-free participants, the adjusted ORs of DeltaBMI and baseline BMI were 1.14 (95% CI, 1.05 to 1.23) and 1.0 (95% CI, 0.96 to 1.04) for rapid decline in renal function, respectively. The study revealed that increasing DeltaBMI predicts rapid decline in renal function. PMID- 29719879 TI - Low-Dose and Standard Overnight and Low Dose-Two Day Dexamethasone Suppression Tests in Patients with Mild and/or Episodic Hypercortisolism. AB - We previously reported on the lack of utility of the 1 mg overnight dexamethasone (DEX) test in mild and/or periodic Cushing's syndrome, as most patients with the condition suppressed to 1 mg DEX. It is possible that a lower dose of DEX as part of an overnight DEX test might be able to distinguish between mild and/or periodic Cushing's syndrome and those without the condition. The objective of the current study is to determine the sensitivity and specificity of a 0.25 mg overnight DEX suppression test, the standard 1 mg overnight DEX suppression test, and the two-day low-dose (Liddle test) DEX suppression test with and without correction for DEX levels in patients evaluated for mild and/or periodic Cushing's syndrome. Thirty patients determined to have Cushing's syndrome by biochemical testing and 14 patients determined not to have the condition had the 0.25 mg and standard 1 mg overnight DEX suppression test and the two-day low-dose DEX suppression tests. Our results show that morning serum cortisol and cortisol/DEX ratios following an overnight dexamethasone suppression test were similar in patients with Cushing's syndrome and those not having Cushing's syndrome. However, a morning cortisol value above 7.6 MUg/dl following a dose of DEX of 0.25 mg was found in 12 patients with Cushing's syndrome and none in those not having Cushing's syndrome, suggesting that a high cortisol value after this low dose of dexamethasone can indicate that further testing for Cushing's syndrome is warranted. Our data suggest that the traditional 1 mg overnight or the 2 mg/2 day DEX suppression testing should no longer be used as a screening test in patients who could have mild and/or periodic Cushing's syndrome, while the 0.25 mg dose of DEX may pick up some patients with mild Cushing's syndrome. PMID- 29719880 TI - Ethanol Extract of Crataegus Oxyacantha L. Ameliorate Dietary Non-Alcoholic Fatty Liver Disease in Rat. AB - BACKGROUND: Non-alcoholic fatty liver (NAFLD) is one the most prevalent disease worldwide which characterized by fat accumulation in liver with no established efficient therapy. We designed this study to investigate protective and therapeutic effect of Crataegus oxyacantha L. (C. oxyacantha) on NAFLD induced by high fat diet in rat models. METHODS: NAFLD was induced by High Fat Diet+fructose (HFD), 45 Wistar rats were divided to 8 groups including control, HFD, HFD+diet change, HFD+diet change+C. oxyacantha 20 mg/kg, co treatment of HFD+C. oxyacantha 10, 20 and 40 mg/kg, and normal diet+C. oxyacantha 40 mg. C. oxyacantha was administered orally. Effectiveness of the C. oxyacantha was assessed through measuring the biochemical factors, and oxidative stress marker (FRAP, GSH, and MDA). Histopathological study was performed using H & E staining. RESULTS: The diet change from high fat to low fat ameliorated liver damage. However, consumption of C. oxyacantha (10 & 20 mg/kg) caused significant reduction in the level of all examined liver biomarkers specially LDH, that showed C. oxyacantha can restore the hepatocyte damage due to HFD. The C. oxyacantha showed a protective effect which was more prominent in the animals treated with the 20 mg/kg C. oxyacantha. The administration of C. oxyacantha caused increased antioxidant status (GSH and FRAP levels) and decreased lipid peroxidation in treated animals. MAJOR CONCLUSION: Accordingly, C. oxyacantha have both therapeutic and protective effect for NAFLD and may be a potential candidate for further assessments in clinical studies. PMID- 29719881 TI - ? PMID- 29719882 TI - Differences in Neuritogenic Activity and Signaling Activation of Madecassoside, Asiaticoside, and Their Aglycones in Neuro-2a cells. AB - Madecassoside (MS) and asiaticoside (AS) along with their aglycones, madecassic acid (MA) and asiatic acid (AA), are considered the major neuroactive triterpenoid constituents of Centella asiatica. In this study, we aimed to compare MS, AS, MA, and AA for their neurite outgrowth activities and mechanisms in Neuro-2a cells. Immunofluorescent cell staining showed MS and AS significantly increased the percentage of neurite-bearing cells (%NBC) and the neurite length with higher potency than MA and AA. The triterpenoid glycosides induced sustained extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) phosphorylation, while their aglycones activated only transient signaling of ERK1/2. Suppression of ERK1/2 activation significantly abolished not only cAMP response element binding protein (CREB) phosphorylation but also the increment of %NBC and neurite length in MS- and AS-treated cells. Inhibition of ERK phosphorylation did not produce similar blockage of CREB activation and neurite outgrowth in MA- and AA treated cells. On the other hand, inactivation of protein kinase B (Akt) resulted in a suppression of neurite lengthening in all studied triterpenoids. This is the first study discerning the different signaling pathways of neurite outgrowth activity induced by C. asiatica triterpenoid glycosides and aglycones. Neurite outgrowth activity of the glycosides MS and AS was found to involve the activation of sustained ERK phosphorylation leading to CREB activation, while ERK activation was not associated with MA- and AA-induced neurite outgrowth. In addition, Akt activation was evident to be more involved in neurite elongation process. PMID- 29719883 TI - Nursing Information Flow in Long-Term Care Facilities. AB - OBJECTIVE: Long-term care (LTC), residential care requiring 24-hour nursing services, plays an important role in the health care service delivery system. The purpose of this study was to identify the needed clinical information and information flow to support LTC Registered Nurses (RNs) in care collaboration and clinical decision making. METHODS: This descriptive qualitative study combines direct observations and semistructured interviews, conducted at Alberta's LTC facilities between May 2014 and August 2015. The constant comparative method (CCM) of joint coding was used for data analysis. RESULTS: Nine RNs from six LTC facilities participated in the study. The RN practice environment includes two essential RN information management aspects: information resources and information spaces. Ten commonly used information resources by RNs included: (1) RN-personal notes; (2) facility-specific templates/forms; (3) nursing processes/tasks; (4) paper-based resident profile; (5) daily care plans; (6) RN notebooks; (7) medication administration records (MARs); (8) reporting software application (RAI-MDS); (9) people (care providers); and (10) references (i.e., books). Nurses used a combination of shared information spaces, such as the Nurses Station or RN-notebook, and personal information spaces, such as personal notebooks or "sticky" notes. Four essential RN information management functions were identified: collection, classification, storage, and distribution. Six sets of information were necessary to perform RN care tasks and communication, including: (1) admission, discharge, and transfer (ADT); (2) assessment; (3) care plan; (4) intervention (with two subsets: medication and care procedure); (5) report; and (6) reference. Based on the RN information management system requirements, a graphic information flow model was constructed. CONCLUSION: This baseline study identified key components of a current LTC nursing information management system. The information flow model may assist health information technology (HIT) developers to consolidate the design of HIT solutions for LTC, and serve as a communication tool between nurses and information technology (IT) staff to refine requirements and support further LTC HIT research. PMID- 29719885 TI - ? PMID- 29719886 TI - ? PMID- 29719887 TI - ? PMID- 29719888 TI - ? PMID- 29719884 TI - Evaluation of Multimedia Medication Reconciliation Software: A Randomized Controlled, Single-Blind Trial to Measure Diagnostic Accuracy for Discrepancy Detection. AB - BACKGROUND: The Veterans Affairs Portland Healthcare System developed a medication history collection software that displays prescription names and medication images. OBJECTIVE: This article measures the frequency of medication discrepancy reporting using the medication history collection software and compares with the frequency of reporting using a paper-based process. This article also determines the accuracy of each method by comparing both strategies to a best possible medication history. STUDY DESIGN: Randomized, controlled, single-blind trial. SETTING: Three community-based primary care clinics associated with the Veterans Affairs Portland Healthcare System: a 300-bed teaching facility and ambulatory care network serving Veteran soldiers in the Pacific Northwest United States. PARTICIPANTS: Of 212 patients with primary care appointments, 209 patients fulfilled the study requirements. INTERVENTION: Patients randomized to a software-directed medication history or a paper-based medication history. Randomization and allocation to treatment groups were performed using a computer-based random number generator. Assignments were placed in a sealed envelope and opened after participant consent. The research coordinator did not know or have access to the treatment assignment until the time of presentation. MAIN OUTCOME MEASURES: The primary analysis compared the discrepancy detection rates between groups with respect to the health record and a best possible medication history. RESULTS: Of 3,500 medications reviewed, we detected 1,435 discrepancies. Forty-six percent of those discrepancies were potentially high risk for causing an adverse drug event. There was no difference in detection rates between treatment arms. Software sensitivity was 83% and specificity was 91%; paper sensitivity was 81% and specificity was 94%. No participants were lost to follow-up. CONCLUSION: The medication history collection software is an efficient and scalable method for gathering a medication history and detecting high-risk discrepancies. Although it included medication images, the technology did not improve accuracy over a paper list when compared with a best possible medication history. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02135731. PMID- 29719892 TI - ? PMID- 29719893 TI - [The new German guideline on rhinosinusitis - an abbreviated version]. AB - At the beginning of this year, the new German guideline on rhinosinusitis was published as a joint guideline of the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery and the German College of General Practitioners and Family Physicians. The guideline was designed for the treatment of adult patients with inflammatory diseases of the paranasal sinuses and is addressed to all medical specialties involved in the management of these diseases. The current challenge is the implementation of this guideline in the clinical daily routine. For this purpose, an abbreviated version (miniature) was designed. PMID- 29719894 TI - [From the Expert's Office: Hearing Impairment due to Infrasound?] PMID- 29719895 TI - [Assessment of olfactory and gustatory function with validated tests]. AB - Approximately 5 % of the general population is affected by functional anosmia. An additional 15 % exhibit decreased olfactory function. Many of these individuals ask ENT-doctors or neurologists for help. A cornerstone of the counselling process is the assessment of olfactory function. The aim of this work is to give a differentiated overview about the administration of commonly used psychophysical tests for olfactory and gustatory function including their normative data. The use of standardized, reliable and validated tools is mandatory to provide patients with state-of the-art counseling on treatment options. PMID- 29719896 TI - ? PMID- 29719897 TI - ? PMID- 29719899 TI - ? PMID- 29719898 TI - ? PMID- 29719900 TI - ? PMID- 29719901 TI - ? PMID- 29719902 TI - ? PMID- 29719903 TI - ? PMID- 29719904 TI - ? PMID- 29719905 TI - ? PMID- 29719906 TI - Totally Laparoscopic versus Open Gastrectomy for Gastric Cancer: a Matched Pair Analysis. AB - BACKGROUND: Laparoscopic gastrectomy has been established for treatment of early gastric cancer (EGC) especially in Eastern Asian countries. Currently, it still needs evaluation for advanced gastric cancer (AGC, T >= 2). Difficulty is how far Asian study data are valid for western conditions. METHODS: Out of 502 patients who underwent gastric cancer surgery between 2003 and 2016 at Klinikum Suedstadt Rostock 90 patients were selected for a retrospective study to compare totally laparoscopic D2-gastrectomy (LG, n = 45) with open D2-gastrectomy (OG, n = 45). The groups were matched by age, gender and tumour stage (TNM). RESULTS: Average age was 62.9 years (33 - 83), 42.2% were female. There were no differences between both study groups concerning BMI, ECOG and comorbidities. Amounts of EGC and AGC were 35.5% and 64.4% in LG, 28.9% and 71.0% in OG (p = 0.931). In LG group 53.3% of the patients and in OG-group 51.1% of the patients were nodal negative (p = 0.802). 31.1% of patients in LG and in 33.3% in OG (p = 0.821) undergone perioperative chemotherapy. Total gastrectomy was performed in 73.3% in LG and 82.2% in OG, subtotal resections were done in 26.7% in LG and 17.8% in OG (p = 0.310). Resection free margins (R0) were recognized in 97.8% of the patients in both groups, and for EGC in all cases (p = 0.928). Total numbers of retrieved lymph nodes were significant higher in LG (33.1, 17 - 72) than in OG (28.2, 14 - 57). A significant longer operation time was noticed for laparoscopic gastrectomy in contrast to open surgery (+ 43.0 +/- 27.2 min, p = 0.0054). Overall morbidity in OG (44.4%) was twice as high as in LG (22.2%, p < 0.05) due to lower rate of minor complications (Clavien I - II) in LG (LG vs. OG: 13.3% vs. 37.8%, p = 0.0078). For major complications (Clavien >= III) no difference between both groups was detected (LG vs. OG: 8.8% vs. 6.6%, p = 0.69). LG showed a significant faster postoperative recovery with earlier oral fluid intake (LG vs. OG: 25.9 h vs. 46.2 h) and shorter time to first flatus (LG vs. OG: 81.6 vs. 102.6 h). Patients after LG were earlier out of bed (LG vs. OG: 69.7 h vs. 108.7 h) and also hospital stay was significantly shorter (11.9 days in LG vs. 16.3 days in OG, p = 0.037). 30- and 90-days mortality was equal for LG and OG (0 and 2.2% per group). After a median follow up of 51.9 month (1 - 117) there were similar results for 3- and 5-year overall survival (OS for LG: 75.6% and 64.6% vs. OG: 68.9% and 64.6%, p = 0.446). Also no differences for 3- and 5-year OS were detected concerning patients without lymph node metastases (LG: 91.7% and 83.4% vs. OG: 91.3% and 78.3%, p = 0.658) or lymph node positive patients (LG: 47.6% and 38.1% vs. OG: 40.9% and 31.8%, p = 0.665). CONCLUSION: Despite western conditions laparoscopic D2 gastrectomy is certainly a save and feasibly approach for surgical therapy of EGC and AGC with low morbidity and mortality, and faster postoperative recovery. The oncologic outcome seems to be equivalent to open surgery. PMID- 29719908 TI - [Treatment and Prognosis of the Oldest Old with Colorectal Cancer]. AB - INTRODUCTION: The demographic trend will lead to an increase of elderly persons in Germany in the future. The population is becoming smaller and older because of the deficiency in childbirths. This results in demographic ageing of the population in Germany. Studies addressing patients >= 85 years, the oldest old, are becoming more and more important. MATERIALS AND METHODS: The prospectively collected data of 141 patients >= 85 years with colorectal carcinoma treated between 1995 and 2014 were analysed retrospectively. Treatment, complications and prognosis were compared with a historical group of patients >= 85 years treated previously between 1978 and 1994 (n = 57) and with a less old group of patients 75 - 84 years old treated between 1995 and 2014 (n = 726). RESULTS: The cohort consisted of 64 men and 77 women. 88 patients had colon carcinoma, 53 patients rectal carcinoma. 127 patients were treated with tumour resection; 112 were classified as R0. Compared with the historical cohort (1978 - 1994), the number of patients increased, and more patients were given tumour resection (74 vs. 90%, p = 0.003) and fewer patients had synchronous distant metastases (28 vs. 14%, p = 0.015). The 5-year locoregional recurrence rate after curative resection decreased from 11.5 to 1.4% (p = 0.027). Comparison with the younger age group (75 - 84 years) revealed more women (55 vs. 42.3%, p = 0.007), more emergencies (22 vs. 9.8%, p < 0.001) and less frequent neoadjuvant treatment (11 vs. 3%, p = 0.003). Morbidity (41 vs. 31.2%, p = 0.032) and mortality (16 vs. 5%, p < 0.001) were higher in the oldest old. After curative resection and exclusion of postoperative deaths, overall survival (2-year rate 66.4%, 5-year rate 32.9%) was found to be worse than for the less old group, whereas cancer-related survival (2 year rate 93.1%, 5-year rate 86.7%) was similar. CONCLUSION: The number of oldest old patients >= 85 years with colorectal carcinoma will further increase. These patients have a higher risk of postoperative complications. After recovering from the surgery cancer-related survival is not worse than for less old patients. PMID- 29719907 TI - Perioperative and Long-term Oncological Results of Minimally Invasive Pancreatoduodenectomy as Hybrid Technique - A Matched Pair Analysis of 120 Cases. AB - BACKGROUND: Laparoscopic pancreatoduodenectomy is a highly challenging procedure. The aim of this study was to analyse post-operative morbidity and mortality as well as long term overall survival in patients undergoing hybrid LPD, as compared to open pancreaticoduodenecomy (OPD) in a single surgeon series. METHODS: Patients undergoing pancreatoduodenectomy (PD) in the period from 2000 to 2015 were identified from a prospectively maintained database. All LPD procedures were performed by one specialised pancreatic surgeon (TK). Patients were matched 1 : 1 for age, sex, BMI, ASA, histological diagnosis, pancreatic texture and portal venous resection (PVR). All LPD procedures were performed as hybrid LPD - combining laparoscopic resection and open reconstruction via mini laparotomy. RESULTS: A total of 549 patients were identified, including 489 patients in the OPD group and 60 patients in the LPD group. 60 patients were identified who underwent LPD between 2010 and 2015 versus 60 OPD patients operated in the same period. Median overall operation time was shorter in the LPD group than with OPD patients (LPD 352 vs. OPD 397 min; p = 0.002). Overall transfusion units were lower in the LPD group (LPD range 0 - 4 vs. OPD range 0 - 11; p = 0.032). Intensive care unit stay (LPD 1 vs. OPD 6 d; p = 0.008) and overall hospital stay (OHS: LPD 14 vs. OPD 18 d; p = 0.012) were shorter in the LPD groups than in the OPD group. As regards postoperative complications, LPD was associated with reduced rates of clinically relevant grade B/C postoperative pancreatic fistula (LPD 15 vs. OPD 36%; p = 0.036) and grade B/C delayed gastric emptying (LPD 8 vs. OPD 20%; p = 0.049). A total of 56 patients were diagnosed with malignant disease. The number of harvested lymph nodes and R0-resection rates were equal for LPD and OPD patients. LPD patients showed a trend to improved median overall survival (LPD mean 56 months vs. OPD mean 48 months; p = 0.056). CONCLUSION: Hybrid LPD is a safe procedure associated with a reduction in clinically relevant postoperative complications and allows faster recovery. Long term oncological outcome of hybrid LPD for malignant disease is equal to that with the standard open approach. PMID- 29719909 TI - [Prophylactic Appendectomy: Yes or No?] PMID- 29719910 TI - Erratum to: A Novel Method of Neo-osseous Flap Prefabrication: Induction of Free Calvarial Periosteum with Bioactive Glass. PMID- 29719911 TI - Proper Choice of Vessels for Supermicrosurgery Training: An Experimental Animal study. AB - BACKGROUND: Reconstruction using supermicrosurgery, a technique of microneurovascular anastomosis for smaller vessels (< 0.8 mm), has become popular. Experimental animal studies for supermicrosurgery training have been reported; however, there have been few studies performed according to vessel diameter and pedicle length. In this study, the external diameters of four vessels (femoral, superficial epigastric, axillary, and common thoracic) and pedicle length of two flaps (superficial epigastric and common thoracic-long thoracic) were measured. METHODS: The inguinal and pectoral regions of Sprague Dawley rats (n = 19) were dissected anatomically, and the external diameters of the four vessels were measured (right and left, artery and vein measured separately). After elevating the superficial epigastric and common thoracic-long thoracic flaps, the pedicle length of the flaps was also measured. RESULTS: Among the 16 vessels examined, the external diameters of 11 and 5 vessels were above and below 0.8 mm, respectively. The external diameters of the superficial epigastric vessel and common thoracic vessel (both arteries and veins) were below 0.8 mm. The external diameters of the femoral and axillary vessels (veins) were above 0.8 mm. The length of the common thoracic-long thoracic pedicle was approximately10 mm longer than that of the superficial epigastric pedicle. CONCLUSIONS: The external diameters of the superficial epigastric vessel and common thoracic vessel are small enough for supermicrosurgery training. The pedicle lengths of both the superficial epigastric and common thoracic-long thoracic flaps are sufficient to perform free flap experiments. Supermicrosurgical free flaps using these two vessels and a study of the physiology and pharmacology of the flaps will likely be possible in the future. PMID- 29719912 TI - Vascularized Bone Grafting for Reconstruction of Oncologic Defects in the Spine: A Systematic Review and Pooled Analysis of the Literature. AB - BACKGROUND: Resection of primary spinal tumors requires reconstruction for restoration of spinal column stability. Traditionally, some combination of bone grafting and instrumentation is implemented. However, delayed healing environments are associated with pseudoarthrodesis and failure. Implementation of vascularized bone grafting (VBG) to complement hardware may present a solution. We evaluated the use of VBG in oncologic spinal reconstruction via systematic review and pooled analysis of literature. METHODS: We searched PubMed/MEDLINE, Embase, Cochrane, and Scopus for studies published through September 2017 according to the PRISMA guidelines and performed a pooled analysis of studies with n > 5. Additionally, we performed retrospective review of patients at the Johns Hopkins Hospital that received spinal reconstruction with VBG. RESULTS: We identified 21 eligible studies and executed a pooled analysis of 12. Analysis indicated an 89% (95% confidence interval [CI]: 0.75-1.03) rate of successful union when VBG is employed after primary tumor resection. The overall complication rate was 42% (95% CI: 0.23-0.61) and reoperation rate was 27% (95% CI: 0.12-0.41) in the pooled cohort. Wound complication rate was 18% (95% CI: 0.11-0.26). Fifteen out of 209 patients (7.2%) had instrumentation failure and mean time-to-union was 6 months. Consensus in the literature and in the patients reviewed is that introduction of VBG into irradiated or infected tissue beds proves advantageous given decreased resorption, increased load bearing, and faster consolidation. Downsides to this technique included longer operations, donor-site morbidity, and difficulty in coordinating care. CONCLUSIONS: Our results demonstrate that complication rates using VBG are similar to those reported in studies using non-VBG for similar spinal reconstructions; however, fusion rates are better. Given rapid fusion and possible hardware independence, VBG may be useful in reconstructing defects in patients with longer life expectancies and/or with a history of chemoradiation and/or infection at the site of tumor resection. PMID- 29719913 TI - [Factors Associated with Behavioral Problems in Pre-School Age: Secondary Data Analysis of Routine Examination at School Enrolment 2010/2014 in the Hannover Region]. AB - BACKGROUND AND AIM: Mental health and the prevalence of behavioral problems in children and adolescents has been gaining increasing concern in the last years. Several studies have addressed this issue in Germany. The aim of the study presented here is to examine factors associated with behavioral problems in pre school children with focus on untreated morbidity. METHODS: Data from the routine examination at school enrolment from 2010/11 to 2014/15 (n=40,675) in the Hannover region were analyzed. Behavioral problems and socio-emotional competences were assessed by the Strengths and Difficulties Questionnaire (SDQ) for parents and by doctors' observations during examination. Children who had already been treated for behavioral problems at the time of school enrolment were excluded from the study. Using multivariable logistic regression analyses, associations between behavioral problems and sociodemographic factors, duration of kindergarten attendance, family status and gestational age were assessed. RESULTS: Education level of the parents, calculated from both parents' highest school and professional education level, is the strongest predictor for assessing behavioral problems of children at the time of school enrolment examination (OR 2.5; 95%-CI 2.3-2.7). Further factors are male sex (OR 1.5; 95%-CI 1.4-1.6), no kindergarten attendance (OR 1.3; 95%-CI 1.02-1.6) or kindergarten attendance of only one year (OR 1.4; 95%-CI 1.2-1.6), children living without their biological parents (OR 1.7; 95%-CI 1.2-2.4), preterm births (OR 1.5; 95%-CI 1.2-1.8) and age of 5 1/2 years and younger (OR 1.4; 95%-CI 1.3-1.6) at the time of examination. CONCLUSION: The results point to the importance of early development support for children from socially disadvantaged families. The results highlight public health-relevant points and enable the region Hannover to improve preventive efforts targeting such pre-school children. PMID- 29719914 TI - [Substance Abuse Poisoning Reported to the Poisons Information Centre Erfurt from 2002 to 2016]. AB - AIM OF THE STUDY: Poisoning due to substance abuse has changed significantly during the last few years. Therefore, developments of substance abuse reported to the Poisons Information Centre Erfurt were investigated and compared to other circumstances of human exposures during the last 15 years. METHODS: Retrospective analysis of all cases of human exposures (intentional abuse, accidental and unknown circumstances, and suicide attempts) for the period 2002-2016 according to substance classes, reasons of exposures, symptom severity, age groups, and gender. RESULTS: Cases of substance abuse (n=7,237, 3.5% of all exposures) continuously increased from 250 (159 with one and 91 with multiple substances) in 2002 to 830 in 2016 (398 with one and 432 with multiple substances). Cases of exposure to metamphetamine strongly increased from 10 in 2003 to 100 in 2012 and dropped to 52 in 2016. Cases of exposure to new psychoactive substances (NPS) rose from 1 in 2008 to 130 in 2015 and fell to 90 in 2016. Substance abuse significantly (p<0.001) more often caused moderate (29.1%) and severe symptoms (5.8%) than suicide attempts (11.6%; 4.9%). NPS and their subgroup synthetic cannabinoids led significantly (p<0.001 and 0.025) more frequently to moderate and severe symptoms (46.9% and 43.6%; 7.9% and 6.0%) than cannabis exposure (19.7%; 2.1%). CONCLUSIONS: Clinical significance of substance abuse is shown by the fact that it resulted more often in moderate and severe symptoms than suicide attempts. Data of substance abuse from PICs could supplement those on clinical toxicology in official annual drug reports. PMID- 29719915 TI - The Average Hazard Ratio - A Good Effect Measure for Time-to-event Endpoints when the Proportional Hazard Assumption is Violated? AB - BACKGROUND: In many clinical trial applications, the endpoint of interest corresponds to a time-to-event endpoint. In this case, group differences are usually expressed by the hazard ratio. Group differences are commonly assessed by the logrank test, which is optimal under the proportional hazard assumption. However, there are many situations in which this assumption is violated. Especially in applications were a full population and several subgroups or a composite time-to-first-event endpoint and several components are considered, the proportional hazard assumption usually does not simultaneously hold true for all test problems under investigation. As an alternative effect measure, Kalbfleisch and Prentice proposed the so-called 'average hazard ratio'. The average hazard ratio is based on a flexible weighting function to modify the influence of time and has a meaningful interpretation even in the case of non-proportional hazards. Despite this favorable property, it is hardly ever used in practice, whereas the standard hazard ratio is commonly reported in clinical trials regardless of whether the proportional hazard assumption holds true or not. OBJECTIVES: There exist two main approaches to construct corresponding estimators and tests for the average hazard ratio where the first relies on weighted Cox regression and the second on a simple plug-in estimator. The aim of this work is to give a systematic comparison of these two approaches and the standard logrank test for different time-toevent settings with proportional and nonproportional hazards and to illustrate the pros and cons in application. METHODS: We conduct a systematic comparative study based on Monte-Carlo simulations and by a real clinical trial example. RESULTS: Our results suggest that the properties of the average hazard ratio depend on the underlying weighting function. The two approaches to construct estimators and related tests show very similar performance for adequately chosen weights. In general, the average hazard ratio defines a more valid effect measure than the standard hazard ratio under non-proportional hazards and the corresponding tests provide a power advantage over the common logrank test. CONCLUSIONS: As non-proportional hazards are often met in clinical practice and the average hazard ratio tests often outperform the common logrank test, this approach should be used more routinely in applications. PMID- 29719916 TI - A Quadriparametric Model to Describe the Diversity of Waves Applied to Hormonal Data. AB - BACKGROUND: Even in normally cycling women, hormone level shapes may widely vary between cycles and between women. Over decades, finding ways to characterize and compare cycle hormone waves was difficult and most solutions, in particular polynomials or splines, do not correspond to physiologically meaningful parameters. OBJECTIVE: We present an original concept to characterize most hormone waves with only two parameters. METHODS: The modelling attempt considered pregnanediol-3-alpha-glucuronide (PDG) and luteinising hormone (LH) levels in 266 cycles (with ultrasound-identified ovulation day) in 99 normally fertile women aged 18 to 45. The study searched for a convenient wave description process and carried out an extended search for the best fitting density distribution. RESULTS: The highly flexible beta-binomial distribution offered the best fit of most hormone waves and required only two readily available and understandable wave parameters: location and scale. In bell-shaped waves (e.g., PDG curves), early peaks may be fitted with a low location parameter and a low scale parameter; plateau shapes are obtained with higher scale parameters. I-shaped, J shaped, and U-shaped waves (sometimes the shapes of LH curves) may be fitted with high scale parameter and, respectively, low, high, and medium location parameter. These location and scale parameters will be later correlated with feminine physiological events. CONCLUSION: Our results demonstrate that, with unimodal waves, complex methods (e.g., functional mixed effects models using smoothing splines, second-order growth mixture models, or functional principal-component- based methods) may be avoided. The use, application, and, especially, result interpretation of four-parameter analyses might be advantageous within the context of feminine physiological events. PMID- 29719917 TI - The Evaluation of Bivariate Mixed Models in Meta-analyses of Diagnostic Accuracy Studies with SAS, Stata and R. AB - BACKGROUND: Meta-analyses require a thoroughly planned procedure to obtain unbiased overall estimates. From a statistical point of view not only model selection but also model implementation in the software affects the results. OBJECTIVES: The present simulation study investigates the accuracy of different implementations of general and generalized bivariate mixed models in SAS (using proc mixed, proc glimmix and proc nlmixed), Stata (using gllamm, xtmelogit and midas) and R (using reitsma from package mada and glmer from package lme4). Both models incorporate the relationship between sensitivity and specificity - the two outcomes of interest in meta-analyses of diagnostic accuracy studies - utilizing random effects. METHODS: Model performance is compared in nine meta-analytic scenarios reflecting the combination of three sizes for meta-analyses (89, 30 and 10 studies) with three pairs of sensitivity/specificity values (97%/87%; 85%/75%; 90%/93%). RESULTS: The evaluation of accuracy in terms of bias, standard error and mean squared error reveals that all implementations of the generalized bivariate model calculate sensitivity and specificity estimates with deviations less than two percentage points. proc mixed which together with reitsma implements the general bivariate mixed model proposed by Reitsma rather shows convergence problems. The random effect parameters are in general underestimated. CONCLUSIONS: This study shows that flexibility and simplicity of model specification together with convergence robustness should influence implementation recommendations, as the accuracy in terms of bias was acceptable in all implementations using the generalized approach. PMID- 29719918 TI - Advanced Methods for Biosignal Interpretation, Characterization and their Applications. PMID- 29719919 TI - A Robust Method with High Time Resolution for Estimating the Cortico-Thalamo Cortical Loop Strength and the Delay when Using a Scalp Electroencephalography Applied to the Wake-Sleep Transition. AB - OBJECTIVES: This study aimed to describe a robust method with high time resolution for estimating the cortico-thalamo-cortical (CTC) loop strength and the delay when using a scalp electroencephalography (EEG) and to illustrate its applicability for analyzing the wake-sleep transition. METHODS: The basic framework for the proposed method is the parallel use of a physiological model and a parametric phenomenological model: a neural field theory (NFT) of the corticothalamic system and an autoregressive (AR) model. The AR model is a "stochastic" model that shortens the time taken to extract spectral features and is also a "linear" model that is free from the local-minimum problem. From the relationship between the transfer function of the AR model and the transfer function of the NFT in the low frequency limit, we successfully derived a direct expression of CTC loop strength and the loop delay using AR coefficients. RESULTS: Using this method to analyze sleep-EEG data, we were able to clearly track the wake-to-sleep transition, as the estimated CTC loop strength (c2) decreased to almost zero. We also found that the c2-distribution during nocturnal sleep is clearly bimodal in nature, which can be well approximated by the superposition of two Gaussian distributions that correspond to sleep and wake states, respectively. The estimated loop delay distributed ~0.08 s, which agrees well with the previously reported value estimated by other methods, confirming the validity of our method. CONCLUSIONS: A robust method with high time resolution was developed for estimating the cortico-thalamo-cortical loop strength and the delay when using a scalp electroencephalography. This method can contribute not only to detecting the wake-sleep transition, but also to further understanding of the transition, where the cortico-thalamo-cortical loop is thought to play an important role. PMID- 29719920 TI - Quantification of the Central Cardiovascular Network Applying the Normalized Short-time Partial Directed Coherence Approach in Healthy Subjects. AB - BACKGROUND: The central control of the autonomic nervous system (ANS) and the complex interplay of its components can be described by a functional integrated mode - the central autonomic network (CAN). CAN represents the integrated functioning and interaction between the central nervous system (CNS) and ANS (parasympathetic and sympathetic activity). OBJECTIVE: This study investigates the central cardiovascular network (CCVN) as a part of the CAN, during which heart rate (HR), systolic blood pressure (SYS) and frontal EEG activity in 21 healthy subjects (CON) will be analysed. The objective of this study is to determine how these couplings (central-cardiovascular) are composed by the different regulatory aspects of the CNS-ANS interaction. METHODS: To quantify the short-term instantaneous causal couplings within the CCVN, the normalized short time partial directed coherence (NSTPDC) approach was applied. It is based on an m-dimensional MAR process to determine Granger causality in the frequency domain. RESULTS: We found that CCVN were of bidirectional character, and that the causal influences of central activity towards HR were stronger than those towards systolic blood pressure. This suggests that the central-cardiac closed-loop regulation process in CON focuses mainly on adapting the heart rate via the sinoatrial node rather than focusing on SYS. The CNS-ANS coupling directions with respect to central spectral power bands were characterized as mostly bidirectional, where HR and SYS acted as drivers in nearly every frequency band (unidirectional for alpha, alpha1 and alpha2). CONCLUSION: This study provides a more indepth understanding of the interplay of neuronal and autonomic cardiovascular regulatory processes in healthy subjects, as well as a greater insight into the complex CAN. PMID- 29719921 TI - Analysis of Instantaneous Linear, Nonlinear and Complex Cardiovascular Dynamics from Videophotoplethysmography. AB - BACKGROUND: There is a fast growing interest in the use of non-contact devices for health and performance assessment in humans. In particular, the use of non contact videophotoplethysmography (vPPG) has been recently demonstrated as a feasible way to extract cardiovascular information. Nevertheless, proper validation of vPPG-derived heartbeat dynamics is still missing. OBJECTIVE: We aim to an in-depth validation of time-varying, linear and nonlinear/complex dynamics of the pulse rate variability extracted from vPPG. METHODS: We apply inhomogeneous pointprocess nonlinear models to assess instantaneous measures defined in the time, frequency, and bispectral domains as estimated through vPPG and standard ECG. Instantaneous complexity measures, such as the instantaneous Lyapunov exponents and the recently defined inhomogeneous point-process approximate and sample entropy, were estimated as well. Video recordings were processed using our recently proposed method based on zerophase principal component analysis. Experimental data were gathered from 60 young healthy subjects (age: 24+/-3 years) undergoing postural changes (rest-to-stand maneuver). RESULTS: Group averaged results show that there is an overall agreement between linear and nonlinear/complexity indices computed from ECG and vPPG during resting state conditions. However, important differences are found, particularly in the bispectral and complexity domains, in recordings where the subjects has been instructed to stand up. CONCLUSIONS: Although significant differences exist between cardiovascular estimates from vPPG and ECG, it is very promising that instantaneous sympathovagal changes, as well as time-varying complex dynamics, were correctly identified, especially during resting state. In addition to a further improvement of the video signal quality, more research is advocated towards a more precise estimation of cardiovascular dynamics by a comprehensive nonlinear/complex paradigm specifically tailored to the non-contact quantification. PMID- 29719922 TI - Scattering Transform of Heart Rate Variability for the Prediction of Ischemic Stroke in Patients with Atrial Fibrillation. AB - BACKGROUND: Atrial fibrillation (AF) is an identified risk factor for ischemic strokes (IS). AF causes a loss in atrial contractile function that favors the formation of thrombi, and thus increases the risk of stroke. Also, AF produces highly irregular and complex temporal dynamics in ventricular response RR intervals. Thus, it is hypothesized that the analysis of RR dynamics could provide predictors for IS. However, these complex and nonlinear dynamics call for the use of advanced multiscale nonlinear signal processing tools. OBJECTIVES: The global aim is to investigate the performance of a recently-proposed multiscale and nonlinear signal processing tool, the scattering transform, in predicting IS for patients suffering from AF. METHODS: The heart rate of a cohort of 173 patients from Fujita Health University Hospital in Japan was analyzed with the scattering transform. First, p-values of Wilcoxon rank sum tests were used to identify scattering coefficients achieving significant (univariate) discrimination between patients with and without IS. Second, a multivariate procedure for feature selection and classification, the Sparse Support Vector Machine (S-SVM), was applied to predict IS. RESULTS: Groups of scattering coefficients, located at several time-scales, were identified as significantly higher (p-value < 0.05) in patients who developed IS than in those who did not. Though the overall predictive power of these indices remained moderate (around 60 %), it was found to be much higher when analysis was restricted to patients not taking antithrombotic treatment (around 80 %). Further, S-SVM showed that multivariate classification improves IS prediction, and also indicated that coefficients involved in classification differ for patients with and without antithrombotic treatment. CONCLUSIONS: Scattering coefficients were found to play a significant role in predicting IS, notably for patients not receiving antithrombotic treatment. S-SVM improves IS detection performance and also provides insight on which features are important. Notably, it shows that AF patients not taking antithrombotic treatment are characterized by a slow modulation of RR dynamics in the ULF range and a faster modulation in the HF range. These modulations are significantly decreased in patients with IS, and hence have a good discriminant ability. PMID- 29719924 TI - [The panoramic x-ray in diagnostic for cervical swellings, a case report]. PMID- 29719923 TI - Application of Empirical Mode Decomposition to Mother and Infant Physical Activity. AB - BACKGROUND: The mutual dependencies between mother and infant circadian rhythms are important for examining disturbances of maternal circadian rhythms, which are considered substantial risk factors for the development of maternal depression during childrearing periods. OBJECTIVES: We characterized the mutual dependencies of maternal-infant circadian rhythms by an index of synchronization properties and then tested the hypothesis that such an index, specifically the instantaneous phase differences between their rhythms, is associated with maternal mental health. METHODS: We performed longitudinal recordings of maternal symptoms of fatigue, stress, and mood states by ecological momentary assessment, together with simultaneous measurements of mother and infant physical activity data in daily life, on 20 mother-infant pairs for a period of >1 week. The circadian components in their physical activity data were extracted by ensembled bivariate empirical mode decomposition, and the corresponding instantaneous phases were then obtained based on the Hilbert transformation. The associations between diurnal maternal symptoms and absolute phase differences between mother and infant circadian rhythms were tested by multilevel models. RESULTS: Diurnal fatigue and depressive mood scores showed positive and significant correlations (p < 0.05) with the increase in instantaneous mother-infant phase differences, indicating the significant role of synchronization of mother-infant circadian rhythms for maintaining maternal mental health. CONCLUSIONS: These findings suggest that modifications of maternal and/or infant circadian rhythms may lead to the improvement of maternal mental health during child-rearing periods. PMID- 29719925 TI - Prognostic markers in core-binding factor AML and improved survival with multiple consolidation cycles of intermediate-/high-dose cytarabine. AB - OBJECTIVES: Core-binding factor acute myeloid leukaemia (CBF AML) defined by t(8;21)(q22;q22) or inv(16)(p13q22)/t(16;16)(p13;q22) has a favourable prognosis; however, 30%-40% of patients still relapse after chemotherapy. We sought to evaluate the risk factors for relapse in a de novo CBF AML cohort. PATIENTS/MATERIALS/METHODS: A retrospective review of patients from four Australian tertiary centres from 2001 to 2012, comprising 40 t(8;21) and 30 inv(16) AMLs. RESULTS: Multivariate analysis identified age (P = .032) and white cell count (WCC)>40 (P = .025) as significant predictors for inferior OS and relapse, respectively. Relapse risk was higher in the inv(16) group vs the t(8;21) group (57% vs 18%, HR 4.31, 95% CI: 1.78-10.42, P = .001). Induction therapy had no bearing on OS or relapse-free survival (RFS); however, consolidation treatment with >3 cycles of intermediate-/high-dose cytarabine improved OS (P = .035) and RFS (P = .063). Five patients demonstrated post treatment stable q PCR positivity without relapse. CONCLUSIONS: >3 consolidation cycles of intermediate-/high-dose cytarabine improves patient outcomes Age and inv(16) CBF AML subtype are predictors of inferior OS and RFS, respectively. Stable low-level MRD by qPCR does not predict relapse Similar OS in the inv(16) cohort compared to the t(8;21) cohort, despite a higher relapse rate, confirms salvageability of relapsed disease. PMID- 29719926 TI - Reply to: Comment on "TFM classification and staging of oral submucous fibrosis: A new proposal". PMID- 29719927 TI - Comparative study of mefloquine and sulphadoxine-pyrimethamine for malaria prevention among pregnant women with HIV in southwest Nigeria. AB - OBJECTIVE: To compare the effectiveness of mefloquine and sulphadoxine pyrimethamine as intermittent preventive therapy for malaria among pregnant women with HIV. METHODS: The present randomized, controlled, prospective, open-label study enrolled women with HIV who had reached at least 16 weeks of pregnancy attending prenatal clinics at secondary and tertiary health facilities in South West Nigeria between January 1 and August 31, 2016. Block randomization was used to assign patients to treatment with mefloquine or sulphadoxine-pyrimethamine for malaria prophylaxis. The primary outcome was malaria parasitemia at delivery. Data were compared with the chi2 and t tests on a per-protocol basis. RESULTS: Of 142 women enrolled and randomized equally to each group, 131 (92.3%) completed the study (64 in the mefloquine group and 67 in the sulphadoxine-pyrimethamine group). Blood-sample malaria parasites were isolated from 6 (9%) and 5 (7%) patients in the mefloquine and sulphadoxine-pyrimethamine groups, respectively, at enrolment, and 6 (9%) and 9 (13%) patients in the mefloquine and sulphadoxine pyrimethamine groups, respectively, at delivery; the differences between the groups was not significant at enrolment (P=0.693) or delivery (P=0.466). CONCLUSION: Outcomes following prophylactic use of mefloquine for intermittent preventive therapy for malaria among pregnant women with HIV were comparable to sulphadoxine-pyrimethamine treatment; mefloquine is a feasible alternative therapy. ClinicalTrials.gov: NCT02524444. PMID- 29719928 TI - Long-term follow-up of 2 patients treated with 90 Y-rituximab radioimmunotherapy for relapse of nodular lymphocyte-predominant Hodgkin lymphoma. AB - Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a rare lymphoma (<5% of Hodgkin's lymphomas) predominantly affecting the middle-aged man, with an indolent behavior. Given the rare occurrence of this lymphoma, there are currently no clear guidelines for initial treatment or relapse. In this report, we present the follow-up of 2 patients treated by radioimmunotherapy for first relapse of their NLPHL. Both patients were initially treated with rituximab and relapsed 1 year after the end of their treatment. PMID- 29719929 TI - The effect of parity on risk of complications in pregnant women with epilepsy: a population-based cohort study. AB - INTRODUCTION: Women with epilepsy have increased risk of complications in pregnancy with consequences for the mother and child. There are no studies on the influence of parity on complications in women with epilepsy. MATERIAL AND METHODS: This was a population-based cohort study of all first and second births in the Medical Birth Registry of Norway 1999-2013. Risks were estimated and complication rates were compared in distinct women with epilepsy treatment categories. Outcomes were any hypertensive disorder, bleeding in pregnancy, induction of labor, cesarean section, postpartum hemorrhage and preterm birth. RESULTS: We examined 361 588 women, of whom 211 248 had a second birth and 1074 (0.5%) of these had a diagnosis of epilepsy in both births. Of these, 406 used antiepileptic drugs in both pregnancies with lamotrigine (n = 118), carbamazepine (n = 83), valproate (n = 44) and levetiracetam (n = 27) being the four most common monotherapies. In the second birth, only risk of elective cesarean section (adjusted odds ratio 1.7, 95% confidence interval 1.4-2.0) and induction of labor (adjusted odds ratio 1.5, 95% confidence interval 1.2-1.7) were increased in women with epilepsy compared with women without epilepsy. There was a significant reduction in any hypertensive disorder, mild preeclampsia, emergency cesarean section, postpartum hemorrhage (>500 mL) and preterm birth from first to second birth in women with epilepsy, and also a significant increase in elective cesarean section. CONCLUSIONS: Second births in women with epilepsy do not represent an increased risk of non-iatrogenic complications, independent of antiepileptic drug use. There is a significant reduction in complications from first to second births in women with epilepsy. PMID- 29719930 TI - Effect of relative humidity on inactivation of foodborne pathogens using chlorine dioxide gas and its residues on tomatoes. AB - : The effect of relative humidity (RH) on the antimicrobial efficacy of chlorine dioxide (ClO2 ) gas against foodborne pathogens on tomatoes was evaluated. Also, levels of ClO2 residues on tomatoes after exposure to ClO2 gas under different RH conditions were measured to determine the quantity of solubilized ClO2 gas on tomato surfaces. Escherichia coli O157:H7, Salmonella Typhimurium and Listeria monocytogenes were inoculated on tomatoes and exposed to ClO2 gas (5, 10, 20 and 30 ppmv) under different RH conditions (50, 70 and 90%). As ClO2 gas concentration and treatment time increased, significant differences (P < 0.05) were observed between inactivation levels under different RH conditions. Exposure to 30 ppmv of ClO2 gas (50% RH) for 20 min resulted in 1.22-1.52 log reductions of the three foodborne pathogens. Levels of the three foodborne pathogens were reduced to below the detection limit (0.48 log CFU per cm2 ) within 15 min when exposed to 30 ppmv of ClO2 gas at 70% RH and within 10 min at 90% RH. At a given ClO2 gas concentration, ClO2 residues on tomatoes significantly (P < 0.05) increased with increasing RH, and there were close correlations between log reductions of pathogens and ClO2 residues on tomatoes. SIGNIFICANCE AND IMPACT OF THE STUDY: This study reported on the correlation between the amount of ClO2 residues on produce surfaces and the level of inactivation of pathogens after ClO2 gas treatment. Variations in RH have great effect on the solubilization of ClO2 gas on tomato surfaces considering that ClO2 residues on tomatoes increased with increasing RH. Also, the amount of ClO2 residues on tomatoes is positively correlated with the level of inactivation of pathogens. The results of this study provide insights for predicting inactivation patterns of foodborne pathogens by ClO2 gas for practical application by the fresh produce industry. PMID- 29719931 TI - Effect of Ovar-DRA and Ovar-DRB1 genotype in small ruminants with haemonchosis. AB - The effect of Ovar-DRA and Ovar-DRB1 genotypes on faecal egg count (FEC) was determined in sheep and goats infected with Haemonchus contortus. One hundred and forty-three sheep from 3 different breeds (St. Croix, Katahdin and Dorper) and 150 goats from three different breeds (Spanish, Boer and Kiko) were used. Parasitological (FEC), haematological (packed cell volume) and immunological (IgA, IgG and IgM) parameters were measured. Sheep populations showed a higher FEC and humoural response than goat breeds. Genotypes were determined by high resolution melting assays and by conventional PCR. For Ovar-DRA, sheep and goats carrying the AA genotype showed significant lower FEC than AG and GG genotypes. The additive effect was found to be 115.35 less eggs per gram of faeces for the A allele for goats. For Ovar-DRB1, only in sheep, the GC genotype was associated with low FEC. The additive effect was 316.48 less eggs per gram of faeces for the G allele, and the dominance effect was 538.70 less eggs per gram of faeces. The results indicate that single nucleotide polymorphisms within Ovar-DRA and Ovar DRB1 could be potential markers to be used in selection programmes for improving resistance to Haemonchus contortus infection. PMID- 29719932 TI - The health professional experience of using antipsychotic medication for dementia in care homes: A study using grounded theory and focussing on inappropriate prescribing. AB - WHAT IS KNOWN ON THE SUBJECT: People with dementia can experience symptoms that upset them and upset the people who care for them To cope, care homes sometimes use strong medicines called antipsychotics but these can make people with dementia become more ill We do not know just why doctors and nurses caring for people with dementia still use these strong medicines more than they need to WHAT THE PAPER ADDS TO EXISTING KNOWLEDGE: Giving antipsychotics can make it easier to care for residents within busy care homes, so people tend to see and remember the benefits of antipsychotics The harm of antipsychotics is noticed less, meaning carers will use them again, in a "vicious circle" WHAT ARE THE IMPLICATIONS FOR PRACTICE: If these medicines worked before it does not make them the right choice again It might help to show carers very clearly the harms from using these medicines, to stress the dangers ABSTRACT: Introduction Treating the behavioural and psychological symptoms of dementia with antipsychotics can cause detrimental side-effects but their use in care homes remains problematic with the views of professionals not fully explored. AIM/QUESTION: To develop an in-depth explanatory model about inappropriate prescribing of antipsychotics in dementia within care homes. METHODS: Twenty-eight participants from eight different professional groups with a role in shaping treatment decisions in dementia care were recruited and interviewed. The audio-recorded interviews were transcribed and analyzed using constructivist grounded theory. RESULTS: When patients with dementia present with behavioural and psychological symptoms, the prescribing of antipsychotics allows the multitude of work in a care home to be managed; the effectiveness of antipsychotics is more perceptible than their side-effects. This perceived usefulness strengthens beliefs that these medications ought to be prescribed again in future situations, generating a self-fulfilling prophecy. DISCUSSION: Our findings may partly explain why the launch of the national dementia strategy in England has been found not to have reduced antipsychotic prescribing in care homes. IMPLICATIONS FOR PRACTICE: Positive perceptions based on past experiences with antipsychotics should be challenged through future interventions that tackle inappropriate prescribing, for example using behaviour change techniques to better highlight adverse consequences of prescribing. PMID- 29719933 TI - Prospective evaluation of the effect of deferasirox on hematologic response in transfusion-dependent patients with low-risk MDS and iron overload. AB - OBJECTIVES: To assess the reduction of transfusions rate in transfusion-dependent patients with low-risk myelodysplastic syndrome (MDS) with iron overload treated with deferasirox. METHODS: Prospective observational study. Primary endpoint was reduction in transfusion requirements (RTR) at 3 months, (assessed on 8-week period). Secondary endpoints were hematologic improvement according to International Working Group (IWG) 2006 criteria at 3, 6, and 12 months. RESULTS: Fifty-seven patients were evaluable. After 3 months of chelation, no effect was seen on transfusion requirement (5.9 packed red blood cells (PRBC) vs 5.8 before chelation). According to the Kaplan-Meier analysis, the probability of RTR at 3, 6, and 12 months was assessed as 3.5%, 9.1%, and 18.7%, respectively. Median duration of RTR was 182 days. However, during the 12-month follow-up after deferasirox initiation, 17 patients (31.5%) achieved minor erythroid response [HI E] according to IWG criteria, 10 of whom having achieved Hb improvement at month 12. CONCLUSION: After 3 months of treatment, deferasirox had no impact on transfusion requirement in regularly transfused patients with low-risk MDS. However, deferasirox could induce 31% of erythroid response during the 12-month follow-up period thus suggesting that iron chelation therapy with deferasirox may induce an effect on hematopoiesis in a subset of patients with MDS and iron overload. PMID- 29719935 TI - Prognosis and complications of immature teeth following lateral luxation: A systematic review. AB - BACKGROUND/AIMS: Lateral luxation injuries are a type of traumatic dental injury in which the tooth becomes displaced in the palatal/lingual or labial direction. This injury is common among children and can result in pulp canal obliteration or pulp necrosis. The objective of this systematic review was to gather existing data on lateral luxation injuries to immature teeth to evaluate their overall prognosis. METHODS: A systematic search was conducted using Medline, Pubmed, Scopus, Lilacs, EMBASE and Cochrane databases in October 2017. Reference lists were also hand-searched to identify additional literature. Prospective and retrospective observational studies were included. A total of 502 articles were screened and six articles were included in the study. RESULTS: Pulp canal obliteration was the most frequent complication of immature teeth with lateral luxation (31.3%). This was followed by pulp necrosis (17.5%), inflammatory resorption (5.7%), and surface resorption (3.2%). Due to the heterogeneity of the studies, a meta-analysis was not attempted. There was great variation in the reported outcomes among the studies. CONCLUSION: Accurate prognosis evaluation of traumatic dental injuries is difficult due to the nature of current studies being retrospective or prospective cohort studies. Lateral luxation is a common traumatic dental injury and has life-long concerns for a patient. It is important for future studies to report on the same outcomes to increase the quality of evidence regarding prognosis and treatment interventions, not only for lateral luxation injuries, but for all traumatic dental injuries. PMID- 29719934 TI - Pretreatment evaluation of fluorescence resonance energy transfer-based drug sensitivity test for patients with chronic myelogenous leukemia treated with dasatinib. AB - Tyrosine kinase inhibitors (TKI) are used for primary therapy in patients with newly diagnosed CML. However, a reliable method for optimal selection of a TKI from the viewpoint of drug sensitivity of CML cells has not been established. We have developed a FRET-based drug sensitivity test in which a CrkL-derived fluorescent biosensor efficiently quantifies the kinase activity of BCR-ABL of living cells and sensitively evaluates the inhibitory activity of a TKI against BCR-ABL. Here, we validated the utility of the FRET-based drug sensitivity test carried out at diagnosis for predicting the molecular efficacy. Sixty-two patients with newly diagnosed chronic phase CML were enrolled in this study and treated with dasatinib. Bone marrow cells at diagnosis were subjected to FRET analysis. The DeltaFRET value was calculated by subtraction of FRET efficiency in the presence of dasatinib from that in the absence of dasatinib. Treatment response was evaluated every 3 months by the BCR-ABL1 International Scale. Based on the DeltaFRET value and molecular response, a threshold of the DeltaFRET value in the top 10% of FRET efficiency was set to 0.31. Patients with DeltaFRET value >=0.31 had significantly superior molecular responses (MMR at 6 and 9 months and both MR4 and MR4.5 at 6, 9, and 12 months) compared with the responses in patients with DeltaFRET value <0.31. These results suggest that the FRET-based drug sensitivity test at diagnosis can predict early and deep molecular responses. This study is registered with UMIN Clinical Trials Registry (UMIN000006358). PMID- 29719936 TI - Induced PTF1a expression in pancreatic ductal adenocarcinoma cells activates acinar gene networks, reduces tumorigenic properties, and sensitizes cells to gemcitabine treatment. AB - Pancreatic acinar cells synthesize, package, and secrete digestive enzymes into the duodenum to aid in nutrient absorption and meet metabolic demands. When exposed to cellular stresses and insults, acinar cells undergo a dedifferentiation process termed acinar-ductal metaplasia (ADM). ADM lesions with oncogenic mutations eventually give rise to pancreatic ductal adenocarcinoma (PDAC). In healthy pancreata, the basic helix-loop-helix (bHLH) factors MIST1 and PTF1a coordinate an acinar-specific transcription network that maintains the highly developed differentiation status of the cells, protecting the pancreas from undergoing a transformative process. However, when MIST1 and PTF1a gene expression is silenced, cells are more prone to progress to PDAC. In this study, we tested whether induced MIST1 or PTF1a expression in PDAC cells could (i) re establish the transcriptional program of differentiated acinar cells and (ii) simultaneously reduce tumor cell properties. As predicted, PTF1a induced gene expression of digestive enzymes and acinar-specific transcription factors, while MIST1 induced gene expression of vesicle trafficking molecules as well as activation of unfolded protein response components, all of which are essential to handle the high protein production load that is characteristic of acinar cells. Importantly, induction of PTF1a in PDAC also influenced cancer-associated properties, leading to a decrease in cell proliferation, cancer stem cell numbers, and repression of key ATP-binding cassette efflux transporters resulting in heightened sensitivity to gemcitabine. Thus, activation of pancreatic bHLH transcription factors rescues the acinar gene program and decreases tumorigenic properties in pancreatic cancer cells, offering unique opportunities to develop novel therapeutic intervention strategies for this deadly disease. PMID- 29719939 TI - Psoriasis and risk of myocardial infarction before and during an era with biological therapy: a population-based follow-up study. AB - BACKGROUND: Attention towards cardiovascular disease prevention in patients with moderate to severe psoriasis increased with the introduction of biological therapy. OBJECTIVE: To determine the risk of myocardial infarction (MI) following hospital-diagnosed psoriasis compared with the general population, in eras before and following the introduction of biological therapy. METHODS: We conducted a cohort study in Denmark utilising nationwide prospectively collected data from population-based registries. For the early era cohort, we identified subjects with first time hospital-diagnosed psoriasis between 1995 and 2002, and, for the late era cohort, those diagnosed between 2006 and 2013. Comparison cohorts from the general population were matched (10:1) on sex and birth year. All individuals were followed from date of psoriasis diagnosis (index date for matched controls) until incidence of MI, death, emigration or end of study (1 January 2002 for the early era cohort; 1 January 2013 for the late era cohort). We computed the cumulative MI incidence at 5 years of follow-up, and used Cox regression to compute HRs of MI comparing psoriasis subjects with general population subjects. RESULTS: For the early era, we identified 4302 psoriatic subjects and 43 791 general population subjects; and for the late era, 4577 psoriatic subjects (4% received biologic therapy) and 46 376 general population subjects. The cumulative incidence of MI among psoriatic subjects in the early era was 2.5% and it was 2.2% in the late era. The HRs comparing MI risk in the psoriasis and general population cohorts were 1.40 (95% CI: 1.09-1.80), for the early era, and 1.39 (95% CI: 1.10-1.75) for the late era, adjusting for educational level and use of cardiovascular drugs. CONCLUSION: The increased risk of MI among patients with hospital-diagnosed psoriasis, relative to the general population, remained unchanged during the initial years of increased attention towards cardiovascular disease prevention and availability of biologic therapy. PMID- 29719938 TI - Cyclophosphamide's addition in relapsed/refractory multiple myeloma patients with biochemical progression during lenalidomide-dexamethasone treatment. AB - OBJECTIVE: The aim of this study was to evaluate the addition of cyclophosphamide in relapsed-refractory multiple myeloma patients (RRMM) who experienced biochemical relapse or progression without CRAB, during treatment with lenalidomide and dexamethasone (Rd), to slow down the progression in active relapse. METHODS: This analysis included 31 patients with RRMM treated with Rd who received cyclophosphamide (CRd) at biochemical relapse. The CRd regimen was continued until disease progression. RESULTS: The median number of CRd cycles administered was 8 (range: 1-35). A response was observed in 9 (29%) patients. After a median observation time of 11 months, the median overall survival (OS) from the beginning of CRd was 17.7 months. The median progression-free survival (PFS) from the beginning of CRd was 13.1 months. CONCLUSION: The addition of cyclophosphamide delays the progression in patients who present a biochemical relapse during Rd treatment. The response rate and the duration of PFS obtained with minimal toxicities and low costs induced us to setting up a randomized clinical trial. PMID- 29719937 TI - A novel RNA sequencing-based miRNA signature predicts with recurrence and outcome of hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the fifth most common type of cancer and the second leading cause of cancer-related deaths worldwide. Given that the rate of HCC recurrence 5 years after liver resection is as high as 70%, patient with HCC typically has a poor outcome. A biomarker or set of biomarkers that could predict disease recurrence would have a substantial clinical impact, allowing earlier detection of recurrence and more effective treatment. With the aim of identifying a new microRNA (miRNA) signature associated with HCC recurrence, we analyzed data on 306 patients with HCC for whom both miRNA expression profiles and complete clinical information were available from The Cancer Genome Atlas database. Through this analysis, we identified a six-miRNA signature that could effectively predict patients' recurrence risk; the high-risk and low-risk groups had significantly different recurrence-free survival rates. Time-dependent receiver operating characteristic analysis indicated that this signature had a good predictive performance. Multivariable Cox regression and stratified analyses demonstrated that the six-miRNA signature was independent of other clinical features. Functional enrichment analysis of the gene targets of the six prognostic miRNA indicated enrichment mainly in cancer-related pathways and important cell biological processes. Our results support use of this six-miRNA signature as an independent factor for predicting recurrence and outcome of patients with HCC. PMID- 29719940 TI - Perceptions and beliefs of lay people from northern Uganda regarding surgery for diagnosis and treatment of cervical cancer. AB - OBJECTIVE: To explore perceptions and beliefs of people in a rural community in northern Uganda regarding surgery for the diagnosis and treatment of cervical cancer. The aim of the study was to inform interventions to reduce delay and improve timely diagnosis and prompt appropriate treatments for patients with symptoms of cervical cancer. METHODS: A semi-structured study guide informed by Kleinman's explanatory model for illness was used to collect data during 24 focus group discussions involving 175 men and women aged 18 to 59 years in Gulu, northern Uganda. Using thematic analysis, themes and subthemes were identified from the data through an iterative process and consensus among the authors. RESULTS: Surgery for diagnosis and management of cervical cancer was perceived as (1) appropriate when performed at early stage of cancer and by senior doctors, but (2) a potential catalyst for the spread of cancer and early death; and (3) a challenge to childbearing and motherhood as well as a source of distress to women and families if surgery involved removal of the uterus with subsequent permanent infertility. CONCLUSIONS: There are some negative perceptions about surgery for cervical cancer that may deter prompt help-seeking for symptoms. However, targeted messages for public awareness interventions to promote help-seeking can be built on the positive perceptions and beliefs that surgery could be curative when undertaken for early-stage cancer and by skilled doctors. PMID- 29719941 TI - The reestablishment of microbial communities after surface cleaning in schools. AB - AIMS: The goal of this study was to quantify the indoor microbiome dynamics of bacterial and fungal communities on school desk surfaces during a cleaning intervention. METHODS AND RESULTS: Quantitative PCR and DNA sequenced-based approaches were employed to describe microbial community dynamics on ten desk surfaces, spread across three schools, located in the Northeast region of the United States. Six samples were taken from each desk, one precleaning, and five postcleaning at 30 min, 1, 3, 7 and 21 days. Cleaning of the desks physically removed c. 50% of bacteria, fungi, and human cells and a full recovery of the surface microbial concentrations occurred within 2-5 days. This recovery period is much shorter than the schools' once per semester cleaning schedule. The dominant source of bacteria and fungi on desks at all time points came from the human microbiome (skin, oral cavity, and gut). More than 50% fungi on desks were members of genera that contain known allergens. CONCLUSIONS: Microbial communities on these school desks are primarily generated and maintained from the deposition of human-associated bacteria and fungi. Current school surface cleaning protocols and cycles may be ineffective at reducing student exposure to fungal allergens and microbes of human origin. SIGNIFICANCE AND IMPACT OF STUDY: Multiple students often share desks in schools. Results on the removal and reestablishment of microbial communities on these surfaces are critical for setting cleaning schedules and practices that effectively interrupt exposure to surface-associated pathogens and allergens. PMID- 29719942 TI - Rhizobial biogeography and inoculation application to soybean in four regions across China. AB - AIMS: The aim of the study was to survey rhizobial biogeography and to inoculate soybean with selected rhizobia in China to enhance symbiotic nitrogen fixation (SNF). METHODS AND RESULTS: Biogeography, genetic diversity and phylogeny of soybean rhizobia were surveyed. Inocula were prepared and applied to soybean. Results showed that Bradyrhizobium elkanii and Ensifer fredii were widely distributed in acid and alkaline soils respectively. Available iron was detected as the first determinant for distribution of the two rhizobia and the soybean varieties did not greatly affect the rhizobial compatibility. Geographical latitude and precipitation in June were the main geographical and climatic factors affecting the rhizobial distribution. Inoculation with selected rhizobia increased the nodule number, fresh weight, occupation ratio, seed protein content and soybean yields. CONCLUSIONS: Selection and application of effective soybean rhizobia across China according to biogeography were clarified to promote the SNF, thereby improving soybean yield. SIGNIFICANCE AND IMPACT OF THE STUDY: Rhizobial diversity and biogeography were evaluated systematically in six sites across China. Available iron and soil pH are found to be the most important determinants for the distribution of soybean rhizobia. Inoculation to soybean enhances SNF, positively correlating to the increase in soybean yield and seed protein content. PMID- 29719943 TI - Comparison of the diagnostic yield of various systematic randomized prostate biopsy protocols using prostate phantoms made of devil's tongue jelly. AB - Purpose: The purpose of this study was to compare the diagnostic yield of five systematic randomized protocols using 12-20 biopsy cores with variably-sized phantoms. Methods: A total of 100 prostate phantom models were produced by casting liquid devil's tongue jelly using silicone molds. Sets of 20 phantoms were created with the following volumes: 20 mL, 40 mL, 60 mL, 80 mL, and 100 mL. Three focal lesions were created by injecting 0.5 mL of warm agar solution stained with red, blue, and green ink into each phantom model. The focal lesions were verified by ultrasonography. The systematic randomized biopsy protocols consisted of 12, 14, 16, 18, and 20 biopsy cores. The diagnostic yield of the multiple systematic biopsy protocols was compared. Results: The overall detection rates of each model set were 93.3% for 20 mL, 88.3% for 40 mL, 71.7% for 60 mL, 43.3% for 80 mL, and 30.0% for 100 mL. Statistically significant differences in the detection rate were found between 40 mL and 60 mL and between 60 mL and 80 mL. No statistically significant increase in the detection rate was observed within a given volume set even when the number of core biopsies increased from 12 to 20. Conclusion: The diagnostic yield of systematic randomized biopsies is inversely proportional to the phantom volume. PMID- 29719944 TI - Effects of a lighter, smaller football on acute match injuries in adolescent female football: a pilot cluster-randomized controlled trial. AB - BACKGROUND: The high injury incidence during match-play in female adolescent football is a major concern. In football, males and females play matches with the same football size. No studies have investigated the effect of football size on injury incidence in female adolescent football. Thus, the aim of the present study was to investigate the effects of introducing a lighter, smaller football on the injury pattern in female adolescent football. METHODS: We conducted a pilot cluster randomized controlled trial including 26 football teams representing 346 adolescent female football players (age 15-18 years). The teams were randomized to a new lighter, smaller football (INT, N.=12 teams) or a traditional FIFA size 5 football (CON, N.=14 teams) during a full match-season. Acute time-loss injuries and football-exposure during match-play were reported weekly by text-message questions and verified subsequently by telephone interview. RESULTS: In total, 46 acute time-loss injuries were registered (5 severe injuries), yielding an incidence rate of 15.2 injuries per 1000 hours of match-play (95% CI: 8.5-27.2) in INT and 18.6 injuries per 1000 hours of match play (95% CI: 14.0-24.8) in CON. The estimated 22% greater injury incidence rate risk (IRR: 1.22 [95% CI: 0.64-2.35]) in the CON group was not significant. With an IRR of 1.22, a future RCT main study would need to observe 793 acute time-loss injuries during match-play, in order to have a power of 80%. CONCLUSIONS: A large scaled RCT is required to definitively test for beneficial or harmful effects of a lighter, smaller football in adolescent female football. PMID- 29719945 TI - Robuvit(r): improvement of fatigue in medical convalescence. AB - BACKGROUND: The aim of this registry study was the evaluation of symptoms of fatigue following supplementation with an oak wood extract (Robuvit(r)) after disappearance of acute symptoms. Robuvit(r), with established antioxidant antifatigue activity, has been successfully used in hepatic failure and in chronic fatigue syndrome: these conditions are characterized by weakness and fatigue and are broadly comparable to convalescence that is associated to increased oxidative stress. METHODS: The registry study lasted 3 weeks. After a period (7-10 days) of flu, during the post-disease period (3 days without disease) subjects were included into the study. One group of subjects was supplemented with Robuvit(r) (300 mg/day) in addition to a standard management (SM) plan, another group of patients was treated with the standard management only. RESULTS: The SM and the supplement group were comparable in all convalescence parameters at inclusion. Weakness and heart rate were significantly reduced with Robuvit(r) in comparison with the controls (P<0.05) at 10 days and at 3 weeks; Attention and sleep patterns improved significantly at 3 weeks with Robuvit(r) (P<0.05) in comparison to controls. Recovery after efforts was normalized at 10 days in the supplement group, significantly better versus controls (P<0.05). O2 saturation increased significantly with Robuvit(r) at 10 days in comparison to controls (P<0.05). The alterations in working/concentration capacity were better improved with the supplement (P<0.05). Oxidative stress was significantly decreased (P<0.05) in comparison to controls. The improvement of health according to the Karrnofsky Scale was significantly more pronounced in the Robuvit(r) group (P<0.05). The supplement was well tolerated. CONCLUSIONS: The causative relations between Robuvit(r) supplementation, oxidative stress, vigor and fatigue in convalescence need more specific evaluations in a larger number of subjects. This preliminary study may indicate a possible supplementation in convalescence. PMID- 29719946 TI - Bilateral patellar cyst: a case report with an Ironman triathlete. PMID- 29719947 TI - Trans-tympanic Cartilage Chip Insertion for Intractable Patulous Eustachian Tube. AB - Background and Objectives: Patulous Eustachian tube (PET) causes troublesome autophony. We treated PET using tragal cartilage chip insertion to fill in the concavity within the tubal valve and evaluated the feasibility of this method. Subjects and METHODS: This study used a prospective design. Eleven patients with PET disorder were included. Tragal cartilage chip insertion via a transcanal approach into the Eustachian tube (ET) was performed in 14 ears of those patients. They were followed-up for at least 12 months after surgery and were evaluated by symptom questionnaire scores. RESULTS: The average follow-up was 16.4 months. Thirteen of fourteen ears received immediate complete relief of autophony symptoms. Autophony symptoms at the last follow-up were as follows: four ears (28.6%) had complete relief; five ears (35.7%) showed satisfactory improvement; four ears (28.6%) showed significant but unsatisfactory improvement; and one ear (7.1%) was unchanged. The PET symptom questionnaire in the affected ears showed a significant reduction in autophony (p=0.047) and improvement in breathing sound conduction (p=0.047). There were no complications such as otitis media or occlusion symptom. Conclusions: Transtympanic cartilage chip insertion into the ET provides a safe and accessible surgical option for the treatment of PET. PMID- 29719948 TI - A Case of Contrast Enhanced Cystic Mass of External Ear Canal Diagnosed as Engorged Hard Tick. AB - A 58-year-old female complained earfullness and otalgia and came to the clinic. Dark gray colored cystic mass obstructing the left ear canal was observed during the endoscopic exam. Contrast enhanced CT image showed an oval shape soft tissue lesion in the mid part of the external auditory canal with a homogenous increased contrast uptake. The mass was removed under microscopic view at outpatient clinic. While dissecting the mass in the ear canal, a pod like structure was visualized. The external organism was densely adherent to the skin and turned out to be an engorged hard tick. Considering the final diagnosis, contrast uptake observed in the CT scan implicates the patient communication of blood between host and parasite. This unique image finding differs from a benign mass lesion in the ear canal was one of the differential diagnosis points for the lesion. This article is reporting the case of tick bite in the ear canal with a rare CT scan finding. PMID- 29719949 TI - Knowledge and Perceptions of Teleaudiology Among Audiologists: A Systematic Review. AB - Background and Objectives: The knowledge and perception of teleaudiology among audiologists will determine the acceptance and success of teleaudiology practice. This systematic review was conducted to review the published literature on knowledge and perceptions of teleaudiology application among audiologists. Materials and METHODS: Five studies exploring knowledge and perceptions of teleaudiology application among audiologists published in the English language up to May 2017 were included. RESULTS: Positive attitudes was observed across the studies regarding acceptance towards application of teleaudiology. The most common sources of knowledge were on the job, graduate studies, and continuing education programs. The major barriers to the uptake of application of teleaudiology were in terms of limitations in infrastructure, reimbursement, and licensure. Conclusions: The study sheds light on the existing knowledge and perceptions of teleaudiology applications among audiologists. This will help in improving the existing teleaudiology services as well as overcome the challenges faced. PMID- 29719950 TI - Effects of Age on Speech-in-Noise Identification: Subjective Ratings of Hearing Difficulties and Encoding of Fundamental Frequency in Older Adults. AB - Background and Objectives: Numerous studies have indicated deterioration of speech perception in noisy conditions among the elderly even those with normal hearing capabilities. The aim of this study was to investigate the effects of age on the speech-in-noise identification by speech-in-noise (SIN) test, subjective ratings of hearing difficulties by speech, spatial, and qualities of hearing scale (SSQ) questionnaire and encoding of fundamental frequency (F0) by Speech auditory brainstem response (ABR) in the elderly and comparing the results with young people. Subjects and METHODS: The present study was conducted on 32 elderly people aged over 60 years old (17 male and 15 female) with the mean age of 68.9 (standard deviation=6.33) possessing normal peripheral hearing and 32 young subjects (16 male and 16 female) aged 18-25 years old. RESULTS: Findings showed that the score of SIN test is lower among the elderly people as compared with young people in signal-to-noise ratios of 0 and -10 based on Iranian version of SSQ questionnaire (p<0.001). The range of F0 amplitude in the elderly people is also lower than young people (p<0.001) in Speech ABR. Conclusions: It seems that speech processing in older people is deteriorated comparing with young people regardless of their normal peripheral auditory thresholds. This decrease will result in weaker perception and improper segregation of speech from other competing sources. PMID- 29719951 TI - Assessment of Volatile Sulfur Compounds in Adult and Pediatric Chronic Tonsillitis Patients Receiving Tonsillectomy. AB - OBJECTIVES: To study the volatile sulfur compound (VSC) concentration profile in chronic tonsillitis patients before and after tonsillectomy, and to evaluate the difference between adult and pediatric (children and adolescents) patients. METHODS: Thirty adult patients (older than 20 years old) and 30 pediatric patients (younger than 20 years old) who were assigned to get tonsillectomy due to chronic tonsillitis were enrolled in this prospective nonrandomized clinical study. The concentrations of the three main VSCs related to halitosis (hydrogen sulfide, methyl mercaptan, and dimethyl sulfide) were assessed in each patient using a portable chromatograph (Oral ChromaTM) at 1 day before operation, postoperative 1 day, 1 week, and 2 weeks. RESULTS: Average concentration of hydrogen sulfide, methyl mercaptan, and dimethyl sulfide preoperatively were 99.5 ppb, 24.6 ppb, and 9.45 ppb in adult patients, and 97.4 ppb, 26 ppb, and 10.5 ppb in pediatric patients, respectively. The concentrations of the three VSCs in both groups were highest in first day after surgery, and decreased signigicantly after 2 weeks compared to preoperative values (P<0.001). There was no significant difference of the concentration of the three VSCs between adult and pediatric patients in any time point. CONCLUSION: The concentrations of hydrogen sulfide, methyl mercaptan, and dimethyl sulfide decreased significantly after tonsillectomy in chronic tonsillitis patients. The concentrations of the three VSCs were not significantly different between pediatric and adult patients before and after tonsillectomy. PMID- 29719952 TI - PM2.5 Source Apportionment Using a Hybrid Environmental Receptor Model. AB - A hybrid environmental receptor model (HERM) that unifies the theory of effective variance chemical mass balance (EV-CMB) and positive matrix factorization (PMF) models was developed to support the weight-of-evidence approach of air pollution source apportionment. The HERM software is capable of (1) conducting EV-CMB analysis for multiple samples in a single model run; (2) calculating EV-CMB and PMF source contributions, as well as middle grounds between the two (i.e., hybrid mode), using partial source information available for the study region; (3) reporting source contribution uncertainties and sample-/species-specific fitting performance measures; and (4) interfacing with MS Excel for convenient data inputs/outputs and analysis. Initial testing with simulated and real-world PM2.5 (fine particulate air pollutants with aerodynamic diameter <2.5 MUm) data sets show that HERM reproduces EV-CMB results from existing software but with more tolerance to collinearity and better uncertainty estimates. It also shows that partial source information helps reduce rotational ambiguity in PMF, thus producing more accurate partitioning between highly correlated sources. Moreover, source profiles generated from the hybrid mode can be more representative of the study region than those acquired from other locales or calculated by PMF with no source information. Strategies to use HERM for source apportionment are recommended. PMID- 29719953 TI - Neuroinflammation in Huntington's Disease: New Insights with 11C-PBR28 PET/MRI. AB - Huntington's disease is a devastating neurodegenerative genetic disorder that causes progressive motor dysfunction, emotional disturbances, and cognitive impairment. Unfortunately, there is no treatment to cure or slow the progression of the disease. Neuroinflammation is one hallmark of Huntington's disease, and modulation of neuroinflammation has been suggested as a potential target for therapeutic intervention. The relationship between neuroinflammation markers and the disease pathology is still poorly understood. To improve our understanding of neuroinflammation in Huntington's disease, we measured translocator protein (TSPO) expression using 11C-PBR28 and simultaneous PET/MRI. Standardized-uptake value ratios, normalized by whole brain uptake, were calculated for data acquired 60-90 min after radiotracer administration. We identified distinct patterns of regional neuroinflammation (as defined by TSPO overexpression relative to a control group) in the basal ganglia of Huntington's disease patients. These patterns were observed at the individual level in all patients, with region of interest analysis confirming significant differences between patients and the control group in the putamen and the pallidum. Additionally, we observed further distinct regional and subregional signatures, which may provide insights into phenotypical variability. For example, in certain Huntington's disease patients, we observed in vivo elevation of the level of TSPO binding in subnuclei in the thalamus and brainstem that have been previously associated with visual function, motor function, and motor coordination. Our main result is an objective score, based solely on 11C-PBR28 measurements, that correlates well with measurements of brain atrophy. We conclude that PET/MR imaging using 11C-PBR28 provides a high signal-to-background ratio and has the potential to be used to assess Huntington's disease progression. Our results suggest 11C-PBR28 might prove useful in clinical trials evaluating therapies targeting neuroinflammation. PMID- 29719954 TI - Programmable Topology in New Families of Heterobimetallic Metal-Organic Frameworks. AB - Using diverse building blocks, such as different heterometallic clusters, in metal-organic framework (MOF) syntheses greatly increases MOF complexity and leads to emergent synergistic properties. However, applying reticular chemistry to syntheses involving more than two molecular building blocks is challenging and there is limited progress in this area. We are therefore motivated to develop a strategy for achieving systematic and differential control over the coordination of multiple metals in MOFs. Herein, we report the design and synthesis of a diverse series of heterobimetallic MOFs with different metal ions and clusters severally distributed throughout two or three inorganic secondary building units (SBUs). By taking advantage of the bifunctional isonicotinate linker and its derivatives, which can coordinatively distinguish between early and late transition metals, we control the assembly and topology of up to three different inorganic SBUs in one-pot solvothermal reactions. Specifically, M6(MU3-O) n(MU3 OH)8- n(CO2)12 (M = Zr4+, Hf4+, Dy3+) SBUs are formed along with metal-pyridyl complexes. By controlling the geometry of the metal-pyridyl complexes, we direct the overall topology to produce eight new MOFs with fcu, ftw, and previously unreported trinodal pfm crystallographic nets. PMID- 29719955 TI - Controllable Electrochemical Fabrication of KO2-Decorated Binder-Free Cathodes for Rechargeable Lithium-Oxygen Batteries. AB - Understanding the electrochemical property of superoxides in alkali metal oxygen batteries is critical for the design of a stable oxygen battery with high capacity and long cycle performance. In this work, a KO2-decorated binder-free cathode is fabricated by a simple and efficient electrochemical strategy. KO2 nanoparticles are uniformly coated on the carbon nanotube film (CNT-f) through a controllable discharge process in the K-O2 battery, and the KO2-decorated CNT-f is innovatively introduced into the Li-O2 battery as the O2 diffusion electrode. The Li-O2 battery based on the KO2-decorated CNT-f cathode can deliver enhanced discharge capacity, reduced charge overpotential, and more stable cycle performance compared with the battery in the absence of KO2. In situ formed KO2 particles on the surface of CNT-f cathode assist to form Li2O2 nanosheets in the Li-O2 battery, which contributes to the improvement of discharge capacity and cycle life. Interestingly, the analysis of KO2-decorated CNT-f cathodes, after discharge and cycle tests, reveals that the electrochemically synthesized KO2 seems not a conventional electrocatalyst but a partially dissolvable and decomposable promoter in Li-O2 batteries. PMID- 29719956 TI - Tailor-Made Pyrazolide-Based Metal-Organic Frameworks for Selective Catalysis. AB - The predesignable porous structures in metal-organic frameworks (MOFs) render them quite attractive as a host-guest platform to address a variety of important issues at the frontiers of science. In this work, a perfluorophenylene functionalized metalloporphyrinic MOF, namely, PCN-624, has been rationally designed, synthesized, and structurally characterized. PCN-624 is constructed by 12-connected [Ni8(OH)4(H2O)2Pz12] (Pz = pyrazolide) nodes and fluorinated 5,10,15,20-tetrakis(2,3,5,6-tetrafluoro-4-(1 H-pyrazol-4-yl)phenyl)-porphyrin (TTFPPP) linker with an ftw-a topological net. Notably, PCN-624 exhibits extinguished robustness under different conditions, including organic solvents, strong acid, and base aqueous solutions. The pore surface of PCN-624 is decorated with pendant perfluorophenylene groups. These moieties fabricate densely fluorinated nanocages resulting in the selective guest capture of the material. More importantly, PCN-624 can be employed as an efficient heterogeneous catalyst for the selective synthesis of fullerene-anthracene bisadduct. Owing to the high chemical robustness of PCN-624, it can be recycled over five times without significant loss of its catalytic activity. All of these results demonstrate that MOFs can serve as a powerful platform with great flexibility for functional design to solve various synthetic problems. PMID- 29719957 TI - Nanoscience and Nanotechnology Research at Peking University. PMID- 29719958 TI - Cyclohelminthols Y1-Y4 Metabolites Possessing Two Spirocyclopropanes in Their Structure. AB - Cyclohelminthols Y1-Y4 (1-4) were isolated from the culture broth of Helminthosporium velutinum yone96. These compounds are diastereomers to each other featuring 3-azabicyclo[3.1.0]hexane-6-spirocyclopentane linked with a cyclopentanespirocyclopropane framework. Their planar structures were established via the comparison of their spectra with the simpler analogue cyclohelminthol X as well as analysis of their HMBC spectra. Although the proton-deficient core frameworks of 1-4 prevented us from obtaining configurational information via conventional NMR analysis, their total structures involving the relative and absolute configurations were established using density functional theory (DFT) based molecular modeling calculations. The present study demonstrates the effectiveness of the comparison between the theoretical and experimental delta13C values for stereochemical analysis by focusing on the carbons that show relatively large delta13C deviations among the isomers. The G-ring of these molecules most likely originates from the cyclopropanation of the C6C7 double bond with the carbene equivalent 6 derived from cyclohelminthol IV (7), which was isolated from the same producer fungus. Preliminary biological experiments revealed the potent cytotoxicity of the (6 S)-isomers against COLO201 cells, whereas the (6 R)-isomers exhibited weak activity. The antifungal assay with Cochiobolus miyabeanus showed a slightly different profile. PMID- 29719960 TI - Cu(I)-Catalyzed Coupling of Bis(trimethylsilyl)diazomethane with Terminal Alkynes: A Synthesis of 1,1-Disilyl Allenes. AB - A Cu(I)-catalyzed cross-coupling reaction of terminal alkynes and bis(trimethylsilyl)diazomethane is reported. Mechanistically, the reaction is based on the recently developed cross-coupling reactions through metal-carbene migratory insertion. This reaction provides an efficient synthetic method for 1,1 disilyl allenes. Subsequent transformations of 1,1-disilyl allenes are investigated, which show diverse reactivities of these allenes. PMID- 29719959 TI - Gelsecorydines A-E, Five Gelsedine-Corynanthe-Type Bisindole Alkaloids from the Fruits of Gelsemium elegans. AB - Five monoterpenoid bisindole alkaloids with new carbon skeletons, gelsecorydines A-E (1-5), together with their biogenetic precursors were isolated from the fruits of Gelsemium elegans. Compounds 1-5 represent the first examples of heterodimeric frameworks composed of a gelsedine-type alkaloid and a modified corynanthe-type one. Notably, compound 2 featured an unprecedented caged skeleton with a 6/5/7/6/5/6 heterohexacyclic ring system, which possessed a pyridine ring that linked the two monomers. Their structures and absolute configurations were elucidated by spectroscopic analysis, X-ray diffraction, and electronic circular dichroism (ECD) calculation. A plausible biosynthetic pathway for compounds 1-5 is proposed. Compounds 1, 3, 4, and 5 exhibited a significant inhibitory effect against nitric oxide (NO) production in macrophages. PMID- 29719962 TI - Spotlights: Volume 9, Issue 9. PMID- 29719961 TI - An X-ray and Neutron Reflectometry Study of Iron Corrosion in Seawater. AB - The corrosive breakdown of thin iron films supported on silicon substrates under a number of conditions is presented-in particular to understand better how iron, and hence ferritic steel, behaves in a salty water environment. A combination of X-ray and neutron reflectometry was used to monitor the structures of both metal and oxide surface layers and also organic corrosion inhibitors adsorbed at the iron/aqueous interface. A range of behavior in seawater was observed, including complete dissolution and void formation under the metal surface. Importantly, two simple treatments-UV/ozone or soaking in ultrapure water-were found to significantly protect the iron surface for considerable lengths of time, although evidence of pitting corrosion began after around 10 days. The underlying causes of the efficacies of these treatments were further investigated using X-ray photoelectron spectroscopy. In addition, three potential corrosion inhibitors were investigated: (i) dodecyltrimethylammonium bromide (DTAB) demonstrated no ability to protect the surface; (ii) sodium dodecyl sulfate (SDS) appeared to accelerate corrosion; and (iii) bis(2-ethylhexyl)phosphate showed an impressive level of protection (the neutron reflectometry results indicated a thick diffuse layer of surfactant of 23% surface coverage). These findings have been interpreted in terms of preferential inhibitor adsorption at cathodic and anodic surface sites (depending on the nature of the inhibitor). PMID- 29719963 TI - Point of Care Tests VerifyNow P2Y12 and INNOVANCE PFA P2Y Compared to Light Transmittance Aggregometry After Fibrinolysis. AB - Detection of high on-treatment platelet reactivity (HPR) by point-of-care tests has not been validated after successful fibrinolysis for ST-elevation myocardial infarction. We assessed the validity of the point-of-care VerifyNow P2Y12 (VN) and INNOVANCE PFA P2Y (PFA) tests on HPR compared to light transmittance aggregometry (LTA) in these patients. The HPR was identified in 10 (34.5%) patients, 15 (51.7%) patients, and 14 (50%) patients using LTA, VN, and PFA, respectively. Discrepancies were observed between the tests despite significant correlations between platelet reactivity measures by LTA and VN ( r = 0.74; P < .0001) and LTA and PFA ( r = .75; P < .0001). Compared to LTA, VN and PFA were associated with a 92% and 53% and 92% and 64% positive predictive value (PPV) and negative predictive value (NPV), respectively, in detecting HPR. When combined, VN and PFA results yielded 90% and 100% PPV and NPV values if discrepancies between the 2 tests were considered as non-HPR. The VN or PFA identify patients without HPR correctly but overestimate the proportion of HPR patients. The association of the 2 tests, in case of HPR, improves the accuracy of the detection of HPR. PMID- 29719964 TI - Cross-Cultural Psychometric Properties of the Hamilton Depression Rating Scale. AB - OBJECTIVE: The Hamilton Depression Rating Scale (HDRS) is considered the gold standard measure of depression. The factor structure of the HDRS is generally unstable, but 4 to 8 items appear to form a general depression factor. As transcultural studies of the HDRS have received little attention, and as most of the studies have taken a data-driven approach with a tendency to yield fragmented results, it is not clear if an HDRS general depression factor can also be found in non-Western populations. This is an important issue in deciding on the appropriateness of the scale as a gold standard in transcultural psychiatry. METHOD: A systematic review was carried out to compare previously reported factor structures of the HDRS in non-Western cultures. Overlapping clusters across studies were identified and subsequently tested with confirmatory factor analysis (CFA) of responses from an independent sample. RESULTS: Fourteen relevant studies were identified, 12 of which were obtained. A general depression factor was identified, consisting of the following symptoms: depressed mood, guilt, loss of interests, retardation, suicide, and psychological anxiety. The subsequent CFA analysis supported the fit of this model. CONCLUSIONS: This study indicates that a general depression cluster is manifest in responses to the HDRS across cultures. While psychometric properties of the full-length HDRS are still debated, the general depression cluster appears pertinent to the assessment of depression across cultures. We recommend that cross-cultural clinicians and researchers focus on the use of unidimensional depression scales, which are in agreement with this cluster. PMID- 29719965 TI - Targeting systemic inflammation in atherosclerosis: Who will benefit? PMID- 29719966 TI - External validity of a cardiovascular screening including a coronary artery calcium examination in middle-aged individuals from the general population. AB - Background Coronary artery calcium is important in cardiovascular risk stratification, but this knowledge is based on studies with a significant selection bias. This study aims to evaluate the external validity of a screening programme including coronary artery calcium examination, and the association between coronary artery calcium and cardiovascular events. Design Multi-centre population based study. Methods Randomly selected middle-aged men and women ( N = 1751) free of cardiovascular disease were invited to the examination during 2009 2010. Participation rate in the examination was 70%. Participants ( n = 1227) and non-participants ( n = 524) were compared regarding: cardiovascular medical treatment, Charlson comorbidity index and socioeconomic status (evaluated by cohabitation, gross income and education). Study endpoints were cardiovascular events and mortality. Results Non-participants had a significant higher comorbidity ( p = 0.003) and a lower socioeconomic status ( p < 0.0001), while cardiovascular medical treatment was alike. Over a median follow-up time of 6.5 years the cardiovascular event and mortality rates were equal (6.7% vs. 6.4%, p = 0.80 and 0.4% vs. 0.5%, p = 0.76, respectively). Adjusted hazard ratio was 0.90 (95% confidence interval (CI) 0.63-1.37). Among participants, the extent of coronary artery calcium was significantly associated with increased risk of cardiovascular events (hazard ratio 1.92, 95% CI 1.03-3.54, hazard ratio 3.66, 95% CI 1.82-7.32, hazard ratio 6.51, 95% CI 3.17-13.36 for coronary artery calcium scores 1-99, 100-399, >=400 AU, respectively). Conclusions Non participants had a higher comorbidity index and a lower socioeconomic status, but the cardiovascular event and mortality rates were equal to those of participants. Thus, a screening programme including a coronary artery calcium examination had a high external validity regarding cardiovascular risk, but also a significant social imbalance. PMID- 29719967 TI - In the search for an ideal registry: Does the cloud have a silver lining? PMID- 29719968 TI - Association of baseline level of physical activity and its temporal changes with incident hypertension and diabetes mellitus. AB - Background The association between baseline and temporal changes in physical activity and incident hypertension or diabetes mellitus in initially non hypertensive or non-diabetic subjects is rarely known. Methods Among individuals who underwent consecutive comprehensive health screenings, their physical activity level was measured using a self-reported international physical activity questionnaire. First, subjects were classified into four categories: no regular physical activity with a sedentary lifestyle; minimal physical activity (<75 min/week); insufficient physical activity (>=75 min but <150 min/week); and sufficient physical activity (>=150 min/week). Second, subjects were sub-grouped, based on temporal changes in physical activity level between baseline and consecutive follow-up: increase, no change, and decrease. Results Finally, among 174,314 subjects (mean age 36.7 +/- 6.9 years), 5544 (3.18%) and 21,276 (12.2%) developed incident diabetes mellitus and arterial hypertension, respectively. After a multivariate adjustment, sufficient baseline physical activity was associated with significantly lower risk for incident hypertension (hazard ratio 0.89; 95% confidence interval (CI) 0.81 to 0.97), but the difference was not significant, and showed a lower trend in diabetes mellitus incidence (hazard ratio 0.87; 95% CI 0.69 to 1.04) in reference to no regular physical activity group. Regardless of the baseline physical activity level, subjects with a temporal increase in physical activity showed significantly decreased risk for incident hypertension (hazard ratio 0.93; 95% CI 0.87 to 0.99) and diabetes mellitus (hazard ratio 0.83; 95% CI 0.74 to 0.92) compared with those with a temporal decrease in their physical activity level. Conclusion Both sufficient baseline physical activity level and its temporal increase were associated with a lower risk of incident hypertension and diabetes mellitus in a large, relatively healthy, cohort. PMID- 29719969 TI - Adverse childhood experiences in substance use disorder outpatients of a Lebanese addiction center. AB - Childhood adversities (CAs) are well reviewed in mental health and addiction research internationally. However, these variables have not been studied within the framework of addiction in the Middle East region. The present study reports the prevalence of Childhood Adversities in a sample of outpatients seeking treatment for Substance Use Disorder. We used the Adverse Childhood Experiences - International Questionnaire (ACE-IQ) to map out the prevalence of childhood adversities. The studied population was composed of a clinical outpatient sample that met criteria for substance use disorder (N = 144). Results indicated that almost all the sample reported having experienced at least 1 CA, whereby three quarters of the clinical sample reported experiencing 6 or more adversities. Childhood adversities are highly prevalent in a Lebanese substance use disorder population which raises the need for better screening strategies and more understanding of Adverse Childhood Experiences in this specific population. PMID- 29719970 TI - Metal-chelating agents against viruses and parasites. PMID- 29719971 TI - Big Tobacco Finds a New Way to Make Profits: And Still Kill People. PMID- 29719972 TI - Juggling Two Balls-Smoking (Re)Normalization and Harm Reduction: E-Cigarettes Facts and Misconceptions in Taiwan. AB - The increasing popularity of e-cigarettes, especially among adolescents, has alarmed health advocates and government officials, dominating the tobacco control narrative in the past few years. According to the Global Youth Tobacco Survey, the percentage of Taiwanese teenagers reporting use of e-cigarettes in the past 30 days rose from 2.01% (95% confidence interval [CI] = 1.82% to 2.23%) in 2014 to 3.54% (95% CI = 3.30% to 3.80%) in 2017. However, during the same period, prevalence of cigarettes declined from 11.51% (95% CI = 9.84% to 13.42%) to 8.26% (95% CI = 7.80% to 8.76%) among senior high school students, and from 5.00% (95% CI = 4.36% to 5.74%) to 2.66% (95% CI = 2.38% to 2.96%) among junior high school students, with figures for both groups reaching historical lows. This trend is similar to population-level trends observed in both the United Kingdom and the United States, but only future long-term studies will be able to clarify if it is consistent or not with the fears that e-cigarette may act as a "gateway" to cigarette smoking renormalization. PMID- 29719974 TI - Global medicinal chemistry and GCPR conference. AB - Laurent Schio speaks to Benjamin Walden, Commissioning Editor. Laurent Schio is leading the group of Integrated Drug Discovery of Sanofi, France. He joined Sanofi more than 25 years ago and is an organic chemist by training. He has made most of his career in medicinal chemistry supporting and leading projects, especially in the anti-infective and then in the oncology fields. He has developed a strong expertise in kinases and lately has contributed to the discovery of several clinical candidates for cancer treatment. PMID- 29719973 TI - Efficacy of sodium dodecyl sulphate and natural extracts against E. coli biofilm. AB - The aim of this study was to determine and compare the efficacy of a standard cleaning agent, sodium dodecyl sulphate, and natural extracts from pomegranate peel grape skin and bay laurel leaf against E. coli biofilm. The biofilm was exposed for 10 minutes to three different concentrations of each tested compound. The results show that bay laurel leaf extract is the most efficient with 43% biofilm biomass reduction, followed by pomegranate peel extract (35%); sodium dodecyl sulphate and grape skin extract each have 30% efficacy. Our study demonstrated that natural extracts from selected plants have the same or even better efficacy against E. coli biofilm removal from surfaces than the tested classical cleaning agent do. All this indicates that natural plant extracts, which are acceptable from the health and environment points of view, can be potential substitutes for classical cleaning agents. PMID- 29719975 TI - Stigma phenomenon to dementia in Iranian population: A phenomenological study. AB - Introduction Dementia is considered as a serious threat for over 65years old population, because of its high prevalence rates. Dementia with a complex and multifaceted nature has negative effects on patients, family members, and their caregivers' psychological health and socioeconomic status. The current qualitative study is designed to investigate the stigma phenomenon to dementia in Iranian population. Methods This qualitative research was conducted by the descriptive phenomenological method. In order to analyze the data, the Colaizzi's descriptive phenomenological method was used. The target population consisted of all patients with dementia and their family members in neurological clinics of Tehran. We interviewed with patients and one of the main family members until data saturation. Participants included the main family members (spouse and children) of people with dementia (nine women and six men) who were selected by a nonrandom purposeful sampling method. Results Two main themes emerged from data analysis: dysfunctional beliefs and negative social attitudes. Each main theme integrates the classes and clusters which are constituted by formulated meanings. Conclusion Dimensions of stigma, such as dysfunctional beliefs and negative social attitudes, in addition to undesirable effects on patients and caregivers lives, is considered as a serious obstacle to effective caring and providing a good quality of life. It can be concluded that, higher levels of awareness, management, and coping with this powerful phenomenon are capable of preventing, rehabilitation, and improving the psychosocial health in elderly population. PMID- 29719976 TI - Common Filing Deficiencies in Abbreviated New Drug Applications Containing Clinical Endpoint Studies. AB - BACKGROUND: The objective of this report is to summarize common deficiencies identified in the filing reviews of abbreviated new drug applications (ANDAs) with clinical endpoint bioequivalence studies and skin irritation, sensitization, and adhesion (I/S/A) studies received by the US Food and Drug Administration (FDA) between 2007 and 2017, to help applicants avoid common deficiencies, minimize "refuse-to-receive" (RTR) actions, "information requests," and ANDA approval delays. METHODS: Multiple internal FDA databases were searched to evaluate and summarize common deficiencies identified in ANDA submissions containing clinical endpoint studies and skin I/S/A studies that required review by the Division of Clinical Review. A total of 275 ANDA submissions with filing reviews from January 2007 to June 2017 were analyzed in this report. RESULTS: Two hundred eighteen (79.3%) filing reviews contained one or more deficiencies. Seventy-nine (28.7%) ANDAs were issued RTR letters because of major clinical deficiencies, specifically bioequivalence and clinical deficiencies, accounting for 9% of overall identified deficiencies. Twenty-two other categories of deficiencies are summarized into 4 main categories: missing information related to the clinical studies other than data sets (38%), missing data sets (35%), formulation issues (12%), and organization/format issues (6%). CONCLUSIONS: The most common deficiency in the "missing information related to the clinical studies other than data sets" category was "missing clarification of information" (22%). We also noted that the Division of Filing Review has identified these same types of deficiencies since assuming responsibility of the filing assessment for ANDAs with clinical endpoint BE studies and skin I/S/A studies. In conclusion, to minimize "refuse-to-receive" actions, "information requests," and approval of ANDA delays for generic drug products, applicants should submit full clinical study reports, including all data sets for drug products recommending clinical studies. PMID- 29719977 TI - Regulatory/Scientific Supports for Micro-, Small-, and Medium-Sized Enterprises (SMEs) With Medicinal Products Provided by the PMDA and EMA. AB - Micro-, small-, and medium-sized enterprises (SMEs) have been considered as key players who can bring innovative medicinal products and/or technologies into the field. However, they may need much regulatory/scientific supports to provide their products, technologies, or services to the market in a timely way. Both the Pharmaceuticals and Medical Devices Agency (PMDA) and the European Medicines Agency (EMA), regulatory authorities for medicinal products in Japan and the EU, respectively, have prepared supportive measures for SMEs from the early phase of product/technology development to the postmarketing phase. With respect to supports for SMEs, both agencies have provided similar SME-specific supportive activities, including routine administrative assistance, consultations about product development strategy from an early phase, as well as specific regulatory/scientific issues and fee incentives. In addition, there is a system to register SME status in the EU, which can be a tool for regulators to know how much potential SME-driven activities have and with whom they should communicate to provide necessary supports. Furthermore, as new technologies and novel products from SMEs are not limited to the region where they are developed, close communication about these topics between the PMDA and the EMA will contribute to advancing patients' access to necessary medicinal products. PMID- 29719978 TI - Finding Real Value From Digital Diabetes Health: Is Digital Health Dead or in Need of Resuscitation? PMID- 29719979 TI - Effect sizes and cut-off points: a meta-analytical review of burnout in latin American countries. AB - Burnout is a highly prevalent globalized health issue that causes significant physical and psychological health problems. In Latin America research on this topic has increased in recent years, however there are no studies comparing results across countries, nor normative reference cut-offs. The present meta analysis examines the intensity of burnout (emotional exhaustion, cynicism and personal accomplishment) in 58 adult nonclinical samples from 8 countries (Argentina, Brazil, Chile, Colombia, Ecuador, Mexico, Peru and Venezuela). We found low intensity of burnout but there are significant differences between countries in emotional exhaustion explained by occupation and language. Social and human service professionals (police officers, social workers, public administration staff) are more exhausted than health professionals (physicians, nurses) or teachers. The samples with Portuguese language score higher in emotional exhaustion than Spanish, supporting the theory of cultural relativism. Demographics (sex, age) and study variables (sample size, instrument), were not found significant to predict burnout. The effect size and confidence intervals found are proposed as a useful baseline for research and medical diagnosis of burnout in Latin American countries. PMID- 29719980 TI - Congenital cystic adenomatoid malformation in adults, presenting as a single cyst. AB - Congenital cystic adenomatoid malformations are lung anomalies usually detected prenatally or in newborns and infants. Type 1 congenital cystic adenomatoid malformations appears as a multicystic lesion, with cysts up to 2 cm in diameter, or as a single large cyst. In the latter case, when detected in adults, the preoperative diagnosis is challenging because congenital cystic adenomatoid malformations can be confused with other more common lesions. We describe two cases of uniloculated type 1 congenital cystic adenomatoid malformation in adults. In both cases, the preoperative clinical diagnosis was missed and the patients were surgically treated with lung-sparing cyst resections. PMID- 29719982 TI - Thrombus removal prior to recanalization in vein graft occlusion intervention. AB - A saphenous vein graft chronic total occlusion intervention is uncommonly performed, partly due to the high risk of distal embolization. We described a strategy in which after successful wiring of a saphenous vein graft chronic total occlusion, balloon dilatation was performed to create a blind sac within the lesion, followed by aspiration thrombectomy to remove all the dislodged debris. Thereafter, balloon dilatation and stenting were safely performed in the distal occluded segment, to achieve complete recanalization. PMID- 29719981 TI - Surgical perspective of percutaneous device closure of atrial septal defect. AB - Background Percutaneous device closure of an ostium secundum atrial septal defect is associated with excellent outcomes and cosmetic results but at the cost of occasional serious and sometimes fatal complications as well as lifelong follow up. Surgical intervention is required in cases of device-related complications, which carries a slightly higher risk compared to primary closure of an atrial septal defect. We present a surgical perspective of device closure of atrial septal defect. Methods Our database was searched over 4 years for complications related to percutaneous device closure of atrial septal defect, which required surgical retrieval of the device and closure of the defect. We identified 14 cases that required surgical intervention. Results The median age of the 14 patients was 18 years (range 4-58 years). The size of the defect ranged from 15 to 40 mm (median 30 mm). Device embolization into any part of the cardiovascular system ( n = 8) was the most common complication, followed by malalignment of the device ( n = 5). One patient had left atrial appendage perforation causing pericardial effusion and cardiac tamponade, and underwent surgical repair. The other 13 patients underwent removal of the device and atrial septal defect closure. One patient developed severe mitral regurgitation requiring mitral valve replacement. There was no mortality. Conclusion Although the incidence of device related complications may be small, they carry a high risk of death or long-term morbidity, even with a small atrial septal defect, unlike primary surgical closure of isolated atrial septal defect. PMID- 29719983 TI - Chronic contained abdominal aortic aneurysm rupture causing vertebral erosion. AB - Erosion of vertebral bodies by an abdominal aortic aneurysm is extremely rare. Chronic contained rupture can cause difficulties in diagnosis because there are many clinical presentations: back pain, sciatic pain, or an expansive abdominal mass. Computed tomography is the gold-standard diagnostic tool. We report the case of a 49-year-old man who suffered from back pain because of a chronic ruptured aortic aneurysm. PMID- 29719985 TI - Headache and Lethargy in a 6-Year-Old. PMID- 29719984 TI - The usefulness of a trans-illuminated introducer during the Nuss procedure. AB - Background There has been an increase in the number of patients undergoing the Nuss procedure for cosmetic purposes, thus increasing the need for safer surgery. However, there are reports of massive hemorrhage and organ damage during the Nuss procedure which involves dissection of the anterior mediastinum. We have developed the trans-illuminated introducer that allows safe surgery while maintaining a small surgical incision of less than 1 cm. Methods This study was a retrospective review of 306 patients aged 3-40 years who underwent the Nuss procedure using the trans-illuminated introducer at our hospital between April 2006 and December 2014. Results There were 29 (9.5%) early postoperative complications. The most common early complication was pneumothorax (15 cases, 4.9%). Five (1.6%) patients developed hemothorax in the early postoperative period, which occurred independently of the dissection process of the anterior mediastinum. None of these patients required reoperation or blood transfusion. There were no complications caused by the introducer during dissection of the anterior mediastinum. Conclusions Using the trans-illuminated introducer, we were able to dissect the anterior mediastinum without a major complication, such as massive hemorrhage from the mediastinum, while maintaining a small surgical incision for cosmetic purposes. Therefore, we consider that the trans-illuminated introducer is useful for improving the outcome of the Nuss procedure. PMID- 29719986 TI - Linking the Medical and Educational Home to Support Children With Autism Spectrum Disorder: Practice Recommendations. AB - Children with autism spectrum disorder (ASD) present with complex medical problems that are often exacerbated by a range of other intellectual and psychiatric comorbidities. These children receive care for their physical and mental health from a range of providers within numerous child-serving systems, including their primary care clinic, school, and the home and community. Given the longitudinal nature in which care is provided for this chronic disorder, it is particularly necessary for services and providers to coordinate their care to ensure optimal efficiency and effectiveness. There are 2 primary venues that serve as a "home" for coordination of service provision for children with ASD and their families-the "medical home" and the "educational home." Unfortunately, these venues often function independently from the other. Furthermore, there are limited guidelines demonstrating methods through which pediatricians and other primary care providers (PCPs) can coordinate care with schools and school-based providers. The purpose of this article is 2-fold: (1) we highlight the provision of evidence-based care within the medical home and educational home and (2) we offer practice recommendations for PCPs in integrating these systems to optimally address the complex medical, intellectual, and psychiatric symptomology affected by autism. PMID- 29719987 TI - Strategies to Avoid Replication Failure With Evidence-Based Prevention Interventions: Case Examples From the Strengthening Families Program. AB - Research has found disturbing long-term effects of poor parenting on children's behavioral health including addiction, delinquency, depression/anxiety, and poorer health as adults. Poor parenting practices thus contribute substantially to the health crisis in America. However, skilled, nurturing parents, or caretakers can help youth avoid these developmental problems. A number of family and parenting evidence-based interventions (EBIs) that teach parenting skills are now available for dissemination. Unfortunately, replications of EBIs do not always produce the original positive results. Organizations that seek to use family EBIs to improve parenting and family skills need to avoid practices that create replication failure. We examine several possible factors that contribute to replication failure using examples from five replications of the EBI "Iowa Strengthening Families Program for ages 10-14." We then share six strategies conducive to avoid replication failures including (1) choosing the right program and implementation strategy for the population, (2) administering the right "dosage," (3) choosing and properly training implementers, (4) maintaining program integrity and adherence, (5) ensuring cultural sensitivity, and (6) ensuring accurate and complete reporting of evaluation results. These guidelines can advance prevention science to meet the demands of a growing public health agenda. PMID- 29719988 TI - A Network Analysis Perspective to Implementation: The Example of Health Links to Promote Coordinated Care. AB - Although implementation models broadly recognize the importance of social relationships, our knowledge about applying social network analysis (SNA) to formative, process, and outcome evaluations of health system interventions is limited. We explored applications of adopting an SNA lens to inform implementation planning, engagement and execution, and evaluation. We used Health Links, a province-wide program in Canada aiming to improve care coordination among multiple providers of high-needs patients, as an example of a health system intervention. At the planning phase, an SNA can depict the structure, network influencers, and composition of clusters at various levels. It can inform the engagement and execution by identifying potential targets (e.g., opinion leaders) and by revealing structural gaps and clusters. It can also be used to assess the outcomes of the intervention, such as its success in increasing network connectivity; changing the position of certain actors; and bridging across specialties, organizations, and sectors. We provided an overview of how an SNA lens can shed light on the complexity of implementation along the entire implementation pathway, by revealing the relational barriers and facilitators, the application of network-informed and network-altering interventions, and testing hypotheses on network consequences of the implementation. PMID- 29719989 TI - Challenges Facing Evidence-Based Prevention: Incorporating an Abductive Theory of Method. AB - Current systems used to determine whether prevention programs are "evidence based" rely on the logic of deductive reasoning. This reliance has fostered implementation of strategies with explicitly stated evaluation criteria used to gauge program validity and suitability for dissemination. Frequently, investigators resort to the randomized controlled trial (RCT) combined with null hypothesis significance testing (NHST) as a means to rule out competing hypotheses and determine whether an intervention works. The RCT design has achieved success across numerous disciplines but is not without limitations. We outline several issues that question allegiance to the RCT, NHST, and the hypothetico-deductive method of scientific inquiry. We also discuss three challenges to the status of program evaluation including reproducibility, generalizability, and credibility of findings. As an alternative, we posit that extending current program evaluation criteria with principles drawn from an abductive theory of method (ATOM) can strengthen our ability to address these challenges and advance studies of drug prevention. Abductive reasoning involves working from observed phenomena to the generation of alternative explanations for the phenomena and comparing the alternatives to select the best possible explanation. We conclude that an ATOM can help increase the influence and impact of evidence-based prevention for population benefit. PMID- 29719990 TI - Barriers to antiretroviral therapy adherence in developed countries: a qualitative synthesis to develop a conceptual framework for a new patient reported outcome measure. AB - Suboptimal adherence to antiretroviral therapy (ART) remains common. Patient centered tools are needed to comprehensively assess adherence barriers in HIV clinical practice. Thus, we conducted a research synthesis to produce a conceptual framework for a new patient-reported outcome measure (PRO) for use in routine HIV care in Canada and France. A PRO's conceptual framework graphically represents the concepts to be measured and the potential relationships between them. Towards ensuring the framework's relevance to the target populations' concerns, qualitative studies with HIV-positive adults on barriers to ART adherence in developed countries were synthesized with thematic analysis, attending to the cross-study prevalence and interrelationships of barrier themes. In March 2016, searches within Medline, PsychINFO, and Embase produced 5,284 records. Two reviewers determined the final sample (n = 41). Analysis generated three levels of ART adherence barrier themes. Twenty Level 2 themes and their component subthemes (Level 3) were organized into 6 higher-order themes (Level 1): Cognitive and emotional aspects (100% of studies contributing content prevalence), Lifestyle factors (95%), Social and material context (95%), Characteristics of ART (90%), Health experience and state (73%), and Healthcare services and system (66%). As to interrelationships, study authors articulated relationships between all higher-order themes (Level 3). Linkages between Level 2 barrier themes showed great variability, from 21% to 95%. Overall, this synthesis contributes an exceptionally detailed conceptual framework and report of ART adherence barriers, applicable to a wide range of PLHIV. It suggests that a key to understanding many barriers is through their interconnections. It also identifies gaps in barrier research. Concerning the new PRO's development, comprehensiveness will need to be weighed against other concerns (e.g., respondent burden) and the provision of barrier-specific guidance for clinically addressing its scores seems essential. PMID- 29719991 TI - Influence of pH value on microstructure of oil-in-water emulsions stabilized by chickpea protein flour. AB - Food industry is highly interested in the development of healthier formulations of oil-in-water emulsions, stabilized by plant proteins instead of egg or milk proteins. These emulsions would avoid allergic issues or animal fat. Among other plant proteins, legumes are a cost-competitive product. This work evaluates the influence of pH value (2.5, 5.0 and 7.5) on emulsions stabilized by chickpea based emulsions at two different protein concentration (2.0 and 4.0 wt%). Microstructure of chickpea-based emulsions is assessed by means of backscattering, droplet size distributions and small amplitude oscillatory shear measurements. Visual appearances as well as confocal laser scanning microscopy images are obtained to provide useful information on the emulsions structure. Interestingly, results indicate that the pH value and protein concentration have a strong influence on emulsion microstructure and stability. Thus, the system which contains protein surfaces positively charged shows the highest viscoelastic properties, a good droplet size distribution profile and non-apparent destabilization phenomena. Interestingly, results also reveal the importance of rheological measurements in the prediction of protein interactions and emulsion stability since this technique is able to predict destabilization mechanisms sooner than other techniques such as backscattering or droplet size distribution measurements. PMID- 29719992 TI - Undeclared Formaldehyde Levels in Patient Consumer Products: Formaldehyde Test Kit Utility. AB - Formaldehyde allergic contact dermatitis (ACD) may be due to products with free formaldehyde or formaldehyde-releasing agents, however, assessment of formaldehyde levels in such products is infrequently conducted. The present study quantifies total releasable formaldehyde from "in-use" products associated with formaldehyde ACD and tests the utility of commercially available formaldehyde spot test kits. Personal care products from 2 patients with ACD to formaldehyde were initially screened at the clinic for formaldehyde using a formaldehyde spot test kit. Formaldehyde positive products were sent to the laboratory for confirmation by gas chromatography-mass spectrometry. In addition, 4 formaldehyde spot test kits were evaluated for potential utility in a clinical setting. Nine of the 10 formaldehyde spot test kit positive products obtained from formaldehyde allergic patients had formaldehyde with total releasable formaldehyde levels ranging from 5.4 to 269.4 ug/g. Of these, only 2 shampoos tested listed a formaldehyde-releasing agent in the ingredients or product literature. Subsequently, commercially available formaldehyde spot test kits were evaluated in the laboratory for ability to identify formaldehyde in personal care products. Chemical based formaldehyde spot test were more reliable than the enzymatic based test in identifying product releasable formaldehyde content. It is concluded that product labeled ingredient lists and available information are often inadequate to confirm the potential for formaldehyde exposure and chemical based spot test kits may have utility for identification of potential formaldehyde exposure from personal care products. PMID- 29719993 TI - Architecture for Health Is Not Just for Healthcare Architects. PMID- 29719994 TI - Designing for Public Health With Healthcare Design, Part I: Research. PMID- 29719995 TI - Data quality: "Garbage in - garbage out". PMID- 29719996 TI - Antibiofilm activity of an EDTA-containing nanoemulsion on multidrug-resistant Acinetobacter baumannii. AB - Acinetobacter baumannii have evolved as an exceedingly troublesome pathogenic microorganisms and prevention and controlling this pathogen is considered to be a public health problem. Nanoemulsions (NE) are a distinctive type of decontaminator produced by integration of immiscible oil phase with aqueous phase under extreme shear forces. The effectiveness of NEs and their components was determined against four stains of A. baumannii by MBC, adherence assay, biofilm assay and SEM studies. NE dilutions ranging from 125 to 225 reduced adhesion by from 61.8 to 99.9% in NE-treated groups (p<.05) as determined by MBC. Four-day old A. baumannii biofilms were treated with NE; LIVE/DEAD staining showed dead cell intensity of 56.2-92.0% in NE-treated groups. After NE treatment and observation by SEM, cell surfaces appeared to be remarkably disintegrated. Irregular boundaries were observed and margins of cell walls were unclear. The anti-adherence, anti-biofilm and morphological disruption effects of NE suggest that this material could be useful for the development of promising antimicrobial agents. PMID- 29719997 TI - Fluorodeoxyglucose positron emission tomography for detection of tumor recurrence following radiofrequency ablation in retrospective cohort of stage I lung cancer. AB - PURPOSE: The goal of this study was to define patterns for tumor recurrence on PET following RFA, compare time to imaging recurrence by PET versus CT, evaluate whether pre-treatment tumor uptake predicts recurrence and propose an optimal post-RFA surveillance strategy. MATERIALS AND METHODS: A retrospective cohort study was performed of biopsy confirmed primary stage I lung cancers treated with RFA. FDG PET and near contemporaneous diagnostic CT imaging pre-ablation, within 30 days post-ablation, and beyond 6 months were independently and retrospectively evaluated for features supportive of recurrence. Time to imaging recurrence by PET (TTR_PET) and by CT (TTR_CT) were determined and compared. FDG avidity of untreated tumors was compared between recurrent and non-recurrent groups. RESULTS: Thirteen recurrences after 72 RFA treatments were confirmed by diagnostic CT. All recurrences were associated with focally intense and increasing FDG uptake beyond 6 months (sensitivity 100%; specificity 98.5%). Mean TTR_PET was 14 months compared to mean TTR_CT of 17 months (not statistically significant). Normalized SUVmax and total lesions glycolysis of lung cancers that recurred after RFA was 4.0 and 6.0, respectively compared to 2.8 and 5.0, respectively for cancers that did not recur (p = .068). CONCLUSION: A pattern of focally intense and increasing FDG PET uptake has high sensitivity and specificity for detecting recurrent lung cancer following RFA. Surveillance after RFA should include a contrast enhanced diagnostic CT at 1 month to diagnose procedural complications, PET at 6 months as a post-treatment metabolic baseline (with diagnostic CT if PET is abnormal) and alternating diagnostic CTs or PET every 6 months for 2 years. PMID- 29719999 TI - 38th International Congress of the European Association of Poisons Centres and Clinical Toxicologists (EAPCCT) 22-25 May 2018, Bucharest, Romania. PMID- 29719998 TI - Biologics and immunomodulators for treating Crohn's disease developing after surgery for an initial diagnosis of ulcerative colitis: a review of current literature. AB - Crohn's Disease (CD) or CD-like (CDL) conditions of the pouch are rare long-term inflammatory complications of patients who were initially diagnosed with ulcerative colitis (UC) who undergo total proctocolectomy with ileo-anal anastomosis (IPAA). There are no societal guidelines nor a consensus on their treatment, resulting in significant challenges for clinicians for their diagnosis and management. It is important to differentiate them from other more common pouch-related complications like pouchitis, cuffitis, irritable pouch syndrome, surgery associated stricture, and fistula. In this review, we focus on the less common presentation of CD and CDL conditions of the pouch and their treatment with the use of anti-TNF therapy with or without immunomodulator. PMID- 29720000 TI - A comparison of the survival and implantation rates of blastocysts that were vitrified on post-fertilization day five, six and seven. AB - The goal of this retrospective cohort study was to compare survival, implantation, clinical and ongoing pregnancy rates between blastocysts that were vitrified on post-fertilization days 5, 6 and 7. Before vitrification, blastocysts were evaluated in terms of morphology and blastocyst expansion, inner cell mass and trophectoderm quality. They were thawed and transfered in a subsequent artificial cycle. Embryo implantation rates were 39%, 25% and 25% for blastocysts that were vitrified on days 5, 6, and 7, respectively (p = 0.006). Clinical and ongoing pregnancy rates were 19%, 12%, 13% (p = 0.100) and 9%, 7%, 12% (p = 0.99) for days 5, 6 and 7 blastocysts, respectively. Day 5 blastocysts had significantly higher full-collapsing score after assisted-hatching compared to days 6 and 7 blastocysts (p = 0.014). As blastocyst quality increased, implantation and clinical pregnancy rates increased in all groups and both parameters were statistically significantly higher on day 5 blastocysts than on days 6 or 7 (p = 0.001). It was clearly found that good quality blastocysts obtained on day 5 have higher implantation and clinical pregnancy rates than 6th and 7th day cryopreserved embryos. There were no statistically significant differences between the cryopreserved embryos on days 6 and 7 regarding the implantation, clinic and ongoing pregnancy rates. PMID- 29720001 TI - Microwave ablation with chemoembolization for large hepatocellular carcinoma in patients with cirrhosis. AB - OBJECTIVE: To evaluate the safety and long-term outcomes of microwave ablation (MWA) combined with transarterial chemoembolization (TACE) in a single stage for the treatment of hepatocellular carcinoma (HCC) with a maximum diameter of 5.0 10.0 cm. METHODS: From January 2013 to December 2016, 84 consecutive HCC patients with cirrhosis from two medical centers who underwent MWA-TACE as a first-line treatment for up to three HCCs with maximum diameters of 5.0-10.0 cm were included. Feasibility, safety and effectiveness were evaluated. Recurrence-free survival (RFS) and overall survival (OS) were analyzed using the Kaplan-Meier method. Cox regression models were used to identify the prognostic factors. RESULTS: The technique was successfully performed in all the patients. Grade 3 complications consisted of two cases of hemoperitoneum requiring blood transfusions and embolization. The cumulative incidence of local tumor progression was 25.8% at 3 years, with tumor size found to be the only significant predictive factor (p = .007). The cumulative incidence of OS was 81%, 68% and 49% at 1, 2 and 3 years, respectively. According to the Cox proportional hazards model analysis, serum AFP level, Child-Pugh class and tumor number were significant prognostic factors for OS. CONCLUSION: MWA-TACE is a safe, feasible and effective therapy for the treatment of 5.0- to 10.0-cm HCC lesions in patients with cirrhosis. PMID- 29720002 TI - Early prenatal ultrasound diagnosis of congenital thoracic malformations. AB - OBJECTIVES: To evaluate and describe the spectrum and rate of congenital thoracic malformations (CTMs) diagnosed by early prenatal sonography (gestational age (GA) less than 16 weeks). METHODS: A retrospective, cross-sectional analysis of prenatal ultrasound screening tests in a community-based clinic. RESULTS: In 2001 2017, 31 261 prenatal ultrasound tests detected 31 CTMs at a gestational age of 15.2 (range, 11.6-16.0) weeks. The most common malformation was congenital pleural effusion (CPE) (15 fetuses, 0.48/1000), followed by congenital diaphragmatic hernia (CDH) (10 fetuses, 0.32/1000). Pulmonary hypoplasia (PH), congenital pulmonary airway malformation and broncho-pulmonary sequestration appeared in much smaller proportions (three, two and one fetuses, respectively). Most CTMs were associated with additional fetal lesions (15 fetuses, 48%). All early CDH (10 fetuses) and PH (three fetuses) and 6/15 with CPE had termination of pregnancy or missed abortions. CONCLUSIONS: Prenatal ultrasound before 16 GA was able to detect CTMs in 0.99/1000 of screening ultrasound (US) performed. Most CTMs tended to appear with multiple lesions and were associated with unfavorable outcomes. Earlier prenatal diagnosis may enable early termination of pregnancy in fetuses with lethal malformations. PMID- 29720003 TI - Integrating an interprofessional education initiative: Evidence from King Abdulaziz University. AB - PURPOSE: This paper examines current issues with interprofessional education (IPE) at King Abdulaziz University (KAU) and discusses initiatives for integrating IPE into the medical curricula at KAU. METHODS: We reviewed the current body of literature, studied reports from IPE conferences and workshops organized at KAU, and synthesized participants' feedback from the IPE programs, including an online survey. RESULTS: A total of 506 participants responded to the online survey. Respondents rated Interprofessional Collaborative Learning as the highest category of IPE, followed by Interprofessional Self-Improvement and Interprofessional Relationship. A hybrid conceptual framework is proposed, to tackle the issue of role clarification across all healthcare colleges at KAU. This proposition was found to be necessary due to the current state of the undergraduate curriculum which does not prepare students properly for professional collaboration. CONCLUSIONS: The hybrid model may narrow the gap in IPE by emphasizing professional identity while reducing autonomy. Recommendations toward IPE are presented. Challenges toward IPE reform are discussed in the context of implementation at KAU and at other medical schools in the region. PMID- 29720004 TI - Pulmonary Adenocarcinoma Mimicking Desquamative Interstitial Pneumonia: Report of 2 Cases With Genetic Analysis. AB - We report 2 cases of pulmonary adenocarcinoma mimicking desquamative interstitial pneumonia (DIP) with genetic analysis occurring in a 74-year-old woman and a 76 year-old woman. In both cases, the tumor was mainly composed of discohesive tumor cells, which filled and floated in the alveolar space in a DIP-like pattern. The tumor cells had abnormally large round to oval nuclei with fine chromatin and relatively abundant eosinophilic cytoplasm lacking pigmentation. Immunohistochemically, tumor cells in both cases were positive for CK7, TTF-1, napsin A, E-cadherin, beta-catenin, and PD-L1 (one case had high expression and the other had low expression), and negative for CK5/6, CK20, p40, and ALK. However, the positive pattern of E-cadherin and beta-catenin was incomplete on the circumference of the cell membrane in both cases and in one case, respectively. On genetic analysis, EGFR alteration (exon 21, L858R mutation) was observed in one case and ALK translocation was not observed in either. To the best of our knowledge, this is the first report of pulmonary adenocarcinoma mimicking DIP with genetic analysis. PMID- 29720005 TI - Pulmonary Mycobacterial Spindle Cell Pseudotumor: A Report of 3 Cases Including a Practical Approach to Histopathologic Recognition of This Unusual Entity. AB - Mycobacterial spindle cell pseudotumor (MSP) is a rare benign spindle cell lesion containing acid-fact mycobacteria. These lesions are most commonly identified in the lymph nodes, skin, spleen, or bone marrow of immunocompromised patients and only rarely involve the lungs. We report 3 cases of pulmonary MSP, which include 2 patients who are known to be HIV-positive. The histopathological diagnosis of MSP in the lung lends itself to many challenges due to its rare incidence and its spindled tumor-like appearance. The differential diagnosis is broad and includes both benign and malignant entities. We highlight the importance of the clinical context in which these lesions typically present and the morphologic spectrum of features seen, and we offer a practical approach to the workup of pulmonary mycobacterial pseudotumor. Appropriate recognition of this entity should lead to an accurate diagnosis of a treatable benign condition despite the clinical presentation often favoring malignancy. PMID- 29720006 TI - Interest and perceived barriers toward careers in academic medicine among medical students at Alfaisal University - College of Medicine: A Saudi Arabian perspective. AB - AIMS: [1] Identify the percentage of undergraduate students who are interested in academic medicine (AM) careers, [2] Explore the relationship between students' characteristics, previous experiences and interest in AM careers and [3] Determine students' perceived barriers toward AM careers at Alfaisal University - College of Medicine. METHODS: An online, anonymous, random, self-rating survey was administered during spring 2013-2014 to second-year and third-year students (n = 302). Chi-square test was used to correlate between interest in AM careers and students' characteristics. Mann-Whitney U-test was used to compare the mean 5 point Likert scale responses between male and female students. RESULTS: A total of 231 students participated in the survey (response rate: 76.5%). A total of 32 students (13.9%) expressed interest in AM careers, and this percentage significantly differed by gender, academic year, interest in teaching and research and previous research experiences (p < 0.05). The top three barriers were "lower income" (77.5%), "competing pressures to fulfill clinical-teaching research duties" (73.6%) and "lack of career advising" (69.7%). As opposed to males, females achieved higher statistically significant differences of means regarding: "competing pressures to fulfill clinical-teaching-research duties" (p < 0.001) and "lack of same-gender role models in AM careers" (p < 0.000). CONCLUSIONS: AM careers were unpopular by students. Curricular, extracurricular and institutional measures should be implemented to rectify this dilemma. PMID- 29720007 TI - Cytokine-induced expression of nitric oxide synthases in Chlamydia trachomatis infected spontaneous aborters. AB - PURPOSE: The aim of study was to evaluate expression of inducible nitric oxide synthase (iNOS), endothelial nitric oxide synthase (eNOS), interferon-gamma (IFN gamma), and tumor necrosis factor-alpha (TNF-alpha) in Chlamydia trachomatis (CT) infected spontaneous aborters (SA). MATERIALS AND METHODS: Endometrial curettage tissue was collected from 140 SA (sporadic SA- 70; recurrent SA- 70) (Group I) and 140 age-matched controls (Group II) from Department of Obstetrics and Gynecology, Safdarjung Hospital, New Delhi, India. Polymerase chain reaction was performed for diagnosis of CT. The expression of iNOS/ eNOS/ IFN-gamma/ TNF-alpha was assessed by real-time polymerase chain reaction (PCR). RESULTS: 15.7% SA were CT-positive (Group I); none in controls. Sporadic spontaneous aborters (SSA) (n = 8/70), recurrent spontaneous aborters (RSA) (n = 14/70) diagnosed as CT-positive (Group-I). Significant upregulation of iNOS/ eNOS was found in CT-positive SSA/RSA compared with CT-negative SSA/RSA and healthy controls. TNF-alpha and IFN gamma were expressed in CT-positive SSA/RSA compared with negative SSA/controls. iNOS showed a significant strong positive correlation with TNF-alpha and IFN gamma in CT-infected SA. eNOS showed a significant positive correlation with TNF alpha and no correlation with IFN-gamma in CT-infected SA. TNF-alpha was positively correlated with IFN-gamma. CONCLUSIONS: Significantly high expression of iNOS/ eNOS and proinflammatory cytokines affected pregnancy in CT-infected RSA, thereby implying that there occurs cytokine-induced expression of nitric oxide synthase (NOS). PMID- 29720008 TI - Medical school choice and quality of undergraduate education. PMID- 29720009 TI - Interprofessional learning experiences: Exploring the perception and attitudes of Saudi Arabian medical and dental students. AB - OBJECTIVE: The objective of this study is to evaluate the awareness and attitudes of medical and dental students regarding interprofessional learning (IPL). METHODS: A cross-sectional study was conducted with 278 female undergraduate Medical and Dental students from Princess Nourah bint Abdulrahman University, Riyadh. These students undertook IPL in the Foundation block, in basic science teaching, clinical skills' laboratories and in professionalism and learning skills' modules. A modified, validated RIPLS questionnaire with four subscales and 29 items was used to collect data regarding their perception and attitudes towards shared learning. A five-point Likert scale was used with a value ranging from 1 (strongly disagree) to 5 (strongly agree) for each item. Factor analysis was done using Varimox rotation. Student's t test was applied to detect difference between mean scores of medical and dental student's responses Results: The mean age of respondents was 19.8 +/- 1.7 years with the majority in the second year of each program. There was no difference in mean responses of the medical and dental students. The respondents favored shared learning in the areas of professional skills and patient care. They agreed that IPL helps to develop respect, trust and appreciation for other professions; however, both groups preferred to learn uni-professionally with regard to developing discrete professional identities and roles. CONCLUSIONS: There is an overall positive response towards IPL and the value of team work; however, more attention needs to be paid to enabling students to learn about the specific roles of each profession in the healthcare team. PMID- 29720010 TI - An explanatory mixed methods study on the validity and validation of students' assessment results in the undergraduate surgery course. AB - BACKGROUND/PURPOSE: There is inadequate evidence of reported validity of the results of assessment instruments used to assess clinical competence. This study aimed at combining multiple lines of quantitative and qualitative evidence to support interpretation and use of assessment results. METHOD: This study is a mixed methods explanatory research set in two stages of data collection and analysis (QUAN : qual). Guided by Messick's conceptual model, quantitative evidences as reliability and correlation coefficients of various validity components were calculated using students' scores, grades and success rates of the whole population of students in 2012/2013 and 2013/2014 (n= 383; 326). The underlying values that scaffold validity evidences were identified via Focus Group Discussions (FGD) with faculty and students; sampling technique was purposive; and results were analyzed by content analysis. RESULTS: (1) Themes that resulted from content analysis aligned with quantitative evidences. (2) Assessment results showed: (a) content validity (table of specifications and blueprinting in another study); (b) consequential validity (positive unintended consequences resulted from new assessment approach); (c) relationships to other variables [a statistically significant correlation among various assessment methods; with combined score (0.64-0.86) and between mid and final exam results (r = 0.672)]; (d) internal consistency (high reliability of MCQ and OSCE: 0.81, 0.80); (3) success rates and grades distribution alone could not provide evidence to advocate an argument on validity of results. CONCLUSION: The unified approach pursued in this study created a strong evidential basis for meaningful interpretation of assessment scores that could be applied in clinical assessments. PMID- 29720011 TI - Using the METRICS model for defining routes to scholarship in healthcare simulation. AB - INTRODUCTION: In this paper, we explored the utility and value of the METRICS model for modeling scholarship in healthcare simulation by: (1) describing the distribution of articles in four healthcare simulation journals across the seven areas of METRICS scholarship; and (2) appraising patterns of scholarship expressed in three programs of simulation scholarship and reflecting on how these patterns potentially influence the pursuit of future scholarly activities. METHODS: Two raters reviewed abstracts of papers published between January 2015 and August 2017 in four healthcare simulation journals and coded them using METRICS. Descriptive statistics were calculated for scholarship type and distribution across journals. Twenty-eight articles from three scholars were reviewed, with patterns of scholarship within articles mapped to METRICS. Descriptive synthesis was constructed through discussion between two reviewers. RESULTS: A total of 432 articles from four journals were reviewed. The three most commonly published areas of scholarship were: 32.2% (139/432) evaluation, 18.8% (81/432) innovation, and 15.3% (66/432) conceptual. The METRICS model was able to represent different kinds of scholarship expressed in all of the papers reviewed and across programs of research. Reflecting on patterns of scholarship within their scholarly programs was helpful for research in planning future directions. CONCLUSIONS: The METRICS model for scholarship can describe a wide range of patterns of simulation scholarship within individual articles, programs of research, or across journals. PMID- 29720012 TI - Extranodal Rosai-Dorfman Disease With Mucosal Involvement of the Stomach in a Background of Autoimmune Atrophic Gastritis. AB - Rosai-Dorfman disease (RDD), or sinus histiocytosis with massive lymphadenopathy, has been described involving both lymph nodes and extranodal sites, but extranodal RDD rarely involves the gastrointestinal tract. Although the etiology is unclear, several risk factors have been shown to be highly associated with this disease process, including viral infection and immune alterations. In this article, we present a case of a 79-year-old male with a history of autoimmune atrophic gastritis and multiple carcinoid tumors of the stomach presenting with a new stomach mass. An additional large sigmoid colon mass and adjacent enlarged lymph node was identified through imaging, prior to surgery. Through extensive pathologic analysis, we identified the first case of predominant extranodal RDD involving gastric mucosa and submucosa in a background of atrophic gastritis, with additional involvement of the sigmoid colon. Based on this case and literature review, we further discuss possible risk factors and pathogenesis of this disease process. PMID- 29720013 TI - General Practitioners' experiences of asthma management in culturally and linguistically diverse populations. AB - OBJECTIVE: The purpose of this study was to explore General Practitioners' experiences and perspectives about asthma management of culturally and linguistically diverse (CALD) people with asthma, particularly with reference to Arabic-speaking patients with low English proficiency (LEP). METHODS: Semi structured interviews guided by an interview protocol were conducted with general practitioners who deal with CALD patients with asthma. Participants were recruited from medical practices in Melbourne, Australia. Interviews were recorded and transcribed verbatim, followed by an inductive thematic analysis. RESULTS: Data saturation was achieved after 21 interviews. Interviews lasted on average 30 minutes. Thematic analyses of the interview transcripts highlighted five key emergent themes: self-autonomy, language issues, accessibility and engagement, health literacy, and cultural/beliefs issues. Many participants highlighted that CALD patients do not self-manage their asthma. Miscommunication was mentioned by some participants as stemming from language barriers. Patients' difficulty in engagement with the health system, lower accessibility to health care, social isolation, and non-acclimatization were other issues participants highlighted as problems in providing effective asthma care to CALD patients. Participants reported finding it more difficult to treat CALD patients with asthma compared to local patients. CONCLUSION: General practitioners perceived that treating culturally and linguistically diverse patients with asthma is difficult and many key barriers were observed to affect treatment. Cultural competence training for health professionals, as well as improving asthma and health system awareness in CALD patients with asthma and their carers, are key interventions that may address asthma management gaps in CALD patients. PMID- 29720014 TI - Response to: Warwick Medical School: A four-dimensional curriculum. PMID- 29720015 TI - Outcomes of vacuum-assisted vaginal deliveries of mothers with gestational diabetes mellitus. AB - OBJECTIVE: To evaluate the outcomes of vacuum-assisted vaginal deliveries (VAD) among neonates of mothers with gestational diabetes mellitus (GDM). STUDY DESIGN: Retrospective cohort study of women with singleton gestation >=37 + 0 weeks of gestation who underwent VAD at a single, tertiary, medical center (2007-2014). Women with GDM and their neonates were compared to women without diabetes and their neonates. Composite neonatal outcome was defined as >=1 of the following: shoulder dystocia, 5-min Apgar score <7, asphyxia, seizure, subgaleal, subarachnoid or subdural hemorrhage, fracture of the clavicle, humerus or skull, or Erb's palsy. RESULTS: Overall, 251 (5.2%) women with GDM were compared with 4534 (94.8%) women without GDM. Women with GDM were older, delivered earlier, with higher rates of mild preeclampsia and induction of labor. Their neonates had higher mean birth weight percentile, and higher rates of hypoglycemia, phototherapy, fracture of the humerus (3.2 versus 1.1%, aOR 2.95, 95%CI 1.38 6.30), and subarachnoid hemorrhage (1.2 versus 0.3%, aOR 4.56, 95%CI 1.28-16.26). No difference was found with regards to the composite neonatal outcome (9.2 versus 11.1%, p = .34). CONCLUSIONS: GDM is associated with a higher risk for certain birth injuries in VAD at >=37 + 0 weeks of gestation, yet the overall risk of adverse neonatal outcomes is comparable to women without GDM. PMID- 29720016 TI - Comment on: How do formative objective structured clinical examinations drive learning? Analysis of residents' perceptions. PMID- 29720017 TI - In vivo and in vitro analyses of the effects of a novel high-nitrogen low-nickel coronary stent on reducing in-stent restenosis. AB - Currently, percutaneous coronary intervention is an important treatment for coronary heart disease. However, the in-stent restenosis rate is still approximately 10-30% after stenting. Nickel ions from the stent are considered to be associated with in-stent restenosis. Therefore, in the present study, we quantitatively evaluated in-stent restenosis after implanting the novel high nitrogen low-nickel coronary stent (HNS) and studied the mechanism underlying the reduction in in-stent restenosis by using ELISA and Western blot. The in vivo results showed that the HNS could significantly reduce neointima formation and inflammation as compared to SUS316L stents (316L) at 180 days after implantation in porcine coronary arteries and that vascular endothelial growth factor-A expression in porcine coronary arteries after HNS implantation also decreased. The in vitro results showed that, in the case of the HNS, human umbilical vein endothelial cell (HUVEC) proliferation was lower and lesser IL-6 release was noted from HUVECs at one and three days after culture than in the 316L group. Furthermore, p-STAT3 expression in HUVECs on the HNS surface was downregulated after culture for seven days. Thus, we conclude that the HNS could be a promising alternative coronary stent for percutaneous coronary intervention. PMID- 29720018 TI - Microwave-assisted synthesis and evaluation of type 1 collagen-apatite composites for dental tissue regeneration. AB - The aim was to develop an economical and biocompatible collagen-based bioactive composite for tooth regeneration. Acid-soluble collagen was extracted and purified from fish scales. The design was innovated to molecularly tailor the surface charge sites of the nano-apatite providing chemical bonds with the collagen matrix via microwave irradiation technique. The obtained collagen was identified by sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis. The composites were characterized by Fourier transform infrared spectroscopy, thermogravimetric analysis/differential scanning calorimetry, and scanning electron microscopy. MC3T3-E1 cell lines were used to assess the biological effects of these materials by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-tetra zolium bromide (MTT) assay. Indirect contact test was performed by extracting representative elutes in cell culture media and sulforhodamine B analysis was performed. Chorioallantoic membrane assay was conducted to define the new vessels formation behavior. The purity of collagen extracts was determined and showed two alpha-chains, i.e. the characteristic of type I collagen. Fourier transform infrared spectroscopy showed the characteristic peaks for amide I, I, III, and phosphate for collagen and composites. Scanning electron microscopy images showed three-dimensional mesh of collagen/apatite nano-fibers. Nontoxic behavior of composites was observed and there were graded and dose-related effects on experimental compounds. The angiogenesis and vessels formation behavior were observed in bioactive collagen composite. The obtained composites have potential to be used for tooth structure regeneration. PMID- 29720019 TI - The ADL taxonomy for persons with mental disorders - adaptation and evaluation. AB - BACKGROUND: There is a lack of occupation-focused instruments to assess Activities of Daily Living (ADL) that are intended for persons with mental disorders. The ADL Taxonomy is an instrument that is widely-used within clinical practice for persons with physical impairment. The aim of this study was to adapt the ADL Taxonomy for persons with mental disorders and evaluate its validity. METHODS: An expert group of Occupational Therapists (OTs) from psychiatric care adapted the ADL Taxonomy to fit the client group, including creating three new items. OTs in psychiatric care collected client data and evaluated the instrument for usability. Rasch analysis was used to evaluate the contruct validity of 16 activities separately. RESULTS: The OTs collected 123 assessments from clients with various mental disorders. Ten activities had excellent, and four had acceptable, psychometric properties with regard to item and person fit and unidimensionality. The activity managing the day/time gave complex results and would benefit from further development. The OTs found the test version intelligible, relevant and easy to use. CONCLUSIONS: The ADL Taxonomy for persons with mental disorders has 16 activities with three to six actions each, and is now ready for clinical use. PMID- 29720020 TI - Middle meningeal artery embolization for chronic subdural hematoma: Endovascular technique and radiographic findings. AB - Background and purpose Embolization of the middle meningeal artery (MMA) has recently been proposed as an alternative to surgery for treatment of chronic subdural hematoma (SDH), and several case reports have been published supporting its efficacy. It has been suggested that the primary pathologic process in chronic SDH is repeated microhemorrhaging into the subdural collection from fragile neovasculature within the SDH membrane that arises from distal branches of the MMA. Embolization could thus provide a means of eliminating this chronic rebleeding. Materials and methods Images were selected from MMA embolization procedures performed at our institution in order to illustrate the technique and theory behind its efficacy for treatment of chronic SDH. Results Images from MMA angiograms demonstrate the variability of MMA anatomy and help illustrate the importance of avoiding potential ophthalmic collaterals and branches supplying cranial nerves. The findings of irregular wispiness of the distal MMA vasculature, contrast outlining of the SDH membrane on angiography, and homogenous increased density within the SDH on postembolization head computed tomography are described. Conclusion MMA embolization may provide a safe alternative for treatment of chronic SDH, but careful angiographic assessment of MMA anatomy should be performed to avoid potential complications. The findings illustrated here lend support to the theory that the pathologic process of chronic SDH is repeated leakage of blood products from an inflamed, abnormal arterial neovasculature within the SDH membrane that arises from the MMA, and thus selective embolization could provide an effective treatment. PMID- 29720022 TI - Cause-specific mortality in Finnish forensic psychiatric patients. AB - PURPOSE: To analyze the causes of mortality among patients committed to compulsory forensic psychiatric hospital treatment in Finland during 1980-2009 by categorizing the causes of mortality into somatic diseases, suicides and other unnatural deaths. MATERIALS AND METHODS: The causes of mortality were analyzed among 351 patients who died during the follow-up. Standardized mortality ratio (SMR) was calculated as the ratio of observed and expected number of deaths by using the subject-years methods with 95% confidence intervals, assuming a Poisson distribution. The expected number of deaths was calculated on the basis of sex-, age- and calendar-period-specific mortality rates for the Finnish population. RESULTS: The vast majority (249/351) of deaths were due to a somatic disease with SMR of 2.6 (mean age at death 61 years). Fifty nine patients committed suicide with a SMR of 7.1 (mean age at death 40 years). Four patients were homicide victims (mean age at death 40 years) and 32 deaths were accidental (mean age at death 52 years). The combined homicides and accidental deaths resulted in a SMR of 1.7. CONCLUSIONS: The results of this study point out that the high risk for suicide should receive attention when the hospital treatment and the outpatient care is being organized for forensic psychiatric patients. In addition, the risk of accidents should be evaluated and it should be assured that the patients receive proper somatic healthcare during the forensic psychiatric treatment and that it continues also in the outpatient setting. PMID- 29720021 TI - Silk flow-diverter stent for the treatment of complex intracranial aneurysms: A one-year follow-up multicenter study. AB - Background Flow-diverter stents have been successfully used in the treatment of complex aneurysms with limited therapeutic alternatives. We report our experience using the Silk flow diverter (SFD; Balt Extrusion, Montmorency, France) for the treatment of complex aneurysms in four Argentine centers. Methods We conducted a retrospective review of 246 consecutive patients who were treated with the SFD at four Argentine centers between January 2009 and January 2017. The patient and aneurysm characteristics, as well as the details of the procedure, were analyzed. The angiographic and clinical findings were recorded during and immediately after the procedure and at 12-month follow-up. Results Angiography follow-up at 12 months was possible in 235 patients (95.5%) with 282 aneurysms. A total of 265 aneurysms (93.9%) presented with complete occlusion of the aneurysmal sac (class 1) and 17 aneurysms (6.1%) presented with partial occlusion (class 2). The 12 month clinical follow-up showed 11 patients with major events (seven, scale 2; five, scale 3; and two, scale 4). The morbidity and mortality rates were 4.2% (11/289) and 2.1% (5/289), respectively. Conclusions The treatment of aneurysms with the SFD was associated with a low rate of complications and a high percentage of aneurysmal occlusion. These findings suggest that SFD is an effective and safe alternative in the endovascular treatment of complex aneurysms. PMID- 29720023 TI - Direct acting antiviral treatment of chronic hepatitis C in Denmark: factors associated with and barriers to treatment initiation. AB - OBJECTIVES: We describe factors associated with and barriers to initiation of Direct Acting Antiviral (DAA) treatment in patients with chronic hepatitis C, who fulfill national fibrosis treatment guidelines in Denmark. MATERIALS AND METHODS: In this nationwide cohort study, we included patients with chronic hepatitis C from The Danish Database for Hepatitis B and C (DANHEP) who fulfilled fibrosis treatment criteria. Factors associated with treatment initiation and treatment failure were determined by logistic regression analyses. Medical records were reviewed from patients who fulfilled fibrosis treatment criteria, but did not initiate DAA treatment to determine the cause. RESULTS: In 344 (49%) of 700 patients, who fulfilled treatment criteria, factors associated with DAA treatment initiation were transmission by other routes than injecting drug use odds ratio (OR) 2.13 (CI: 1.38-3.28), previous treatment failure OR 2.58 (CI: 1.84-3.61) and ALT above upper limit of normal OR 1.60 (CI: 1.18-2.17). The most frequent reasons for not starting treatment among 356 (51%) patients were non-adherence to medical appointments (n = 107/30%) and ongoing substance use (n = 61/17%). Treatment failure with viral relapse occurred in 19 (5.5%) patients, who were more likely to have failed previous treatment OR 4.53 (CI: 1.59-12.91). CONCLUSIONS: In this nationwide cohort study, we found non-adherence to medical appointments and active substance use to be major obstacles for DAA treatment initiation. Our findings highlight the need for interventions that can overcome these barriers and increase the number of patients who can initiate and benefit from curative DAA treatment. PMID- 29720024 TI - The Etiological Structure of Cognitive-Neurophysiological Impairments in ADHD in Adolescence and Young Adulthood. AB - OBJECTIVE: Previous studies in children with ADHD identified two partially separable familial factors underlying cognitive dysfunction, but evidence in adolescents and adults is lacking. Here, we investigate the etiological structure of cognitive-neurophysiological impairments in ADHD in adolescents and young adults. METHOD: Factor analyses and multivariate familial models were run in 356 participants from ADHD and control sibling pairs aged 11 to 27 years on data on IQ, digit span forward (DSF) and backward (DSB), and cognitive-performance and event-related potential (ERP) measures from three cognitive tasks. RESULTS: Three familial factors (cF1-3), showing substantial familial overlap with ADHD, captured the familial covariation of ADHD with nine cognitive-ERP measures. cF1 loaded on IQ, mean reaction time (MRT), and reaction-time variability (RTV); cF2 on DSF and DSB; and cF3 on number of errors and ERPs of inhibition and error processing. CONCLUSION: These results identify three partially separable etiological pathways leading to cognitive-neurophysiological impairments in adolescent and adult ADHD. PMID- 29720025 TI - Siblings and Birth Order-Are They Important for the Occurrence of ADHD? AB - OBJECTIVE: The associations of birth order, number of siblings, and ADHD was examined. METHOD: The analysis based on representative, epidemiological data from the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) study ( N = 13,488). RESULTS: An increased risk for ADHD in firstborn versus youngest born children (odds ratio [OR] = 1.31, 95% confidence interval [CI] [1.09, 1.58]) and also versus children with no sibling (OR = 1.31, 95% CI [1.03, 1.68]) was revealed, while number of siblings was not associated with ADHD. Results remained stable after controlling for confounders. CONCLUSION: Firstborn children may receive simultaneously less parental resources and more responsibilities if younger siblings are born. This happens during the vulnerable developmental period of ADHD. In addition, due to higher levels of insecurity, parents are assumed to focus more on potential physical or psychological abnormities in their firstborn children. This may result in a diagnostic bias in firstborn children. PMID- 29720026 TI - Association between interleukin-10 -592 A/C polymorphism and gastrointestinal tract cancer risk: A meta-analysis. AB - BACKGROUND: Recent evidence suggests that -592 A/C polymorphism in the interleukin-10 (IL-10) gene may influence risk of gastrointestinal tract cancer; however, individual studies have provided conflicting and inconclusive results. Therefore, this meta-analysis was conducted to assess the association between IL 10 -592 A/C polymorphism and gastrointestinal tract cancer susceptibility. METHODS: EMBASE, PubMed, Web of Science, and China National Knowledge Infrastructure databases were searched for case-control studies published before 1 May 2017. A total of 36 studies involving 8069 cases and 13,089 controls were included in the present meta-analysis according to the inclusion criteria. The random- or fixed-effect model was utilized to calculate pooled odds ratio (OR) with 95% confidence interval (CI), and to survey the association. RESULTS: By and large IL-10 -592 A/C (rs1800872) polymorphism was not associated with gastrointestinal cancer risk in five genetic models (A vs. C: OR 1.00; 95% CI 0.93, 1.08; POR = 0.960; AA vs. CC: OR 0.98; 95% CI 0.85, 1.14; POR = 0.835; CA vs. CC: OR 1.01; 95% CI 0.94, 1.08; POR = 0.776; AA+CA vs. CC: OR 1.03; 95% CI 0.94, 1.12; POR = 0.592; AA vs. CA+CC: OR 0.98; 95% CI 0.87, 1.10; POR = 0.666). Similar results were also achieved after stratification by the Hardy-Weinberg equilibrium, ethnicity, source of controls, and cancer type. CONCLUSION: The results of this meta-analysis indicated that there is no association between the IL-10 -592 A/C promoter polymorphism and gastrointestinal tract cancer susceptibility. PMID- 29720027 TI - Efficacy of Testosterone Treatment in Hemodialysis Patients as Assessed by Aging Males' Symptoms Scores: A Pilot Study. AB - Numerous reports point to the beneficial effects of testosterone replacement therapy for patients with late-onset hypogonadism (LOH) syndrome. The aim of this study was to evaluate the effect of intramuscular injection of testosterone enantholactam acid ester on Aging Males' Symptoms (AMS) scores in hemodialysis patients with LOH. A total of 24 male patients with LOH (total AMS scores >=27) were randomized into groups receiving intramuscular injections of either placebo or testosterone enantholactam acid ester at the dose of 250 mg for 6 months. In all, 13 and 11 participants from the active treatment and placebo groups, respectively, completed this study. An intramuscular injection of either placebo or testosterone enantholactam acid ester was given every 2 weeks. Self administered AMS questionnaires were completed at the start, at Week 12 and at Week 24. The total AMS score was significantly more improved in the treatment group than in the placebo group ( p = .049) during the 24-week period. The change in the mean of total AMS score was +1% in the placebo group and -13.2% in the treatment group. The mean somato-vegetative domain scores decreased significantly only in the treatment group, and not in the placebo group (-1.21 vs. -2.43, p = .028). Although a large-scale study is needed, testosterone treatment may be effective in male patients with hemodialysis who have poor health-related quality of life resulting from LOH. PMID- 29720028 TI - Physical Activity Intensity Among Adolescents and Association With Parent Adolescent Relationship and Well-Being. AB - Participation in physical activity (PA) provides young people significant health benefits, including improved well-being. However, large percentages of children and adolescents do not meet the recommendations for PA. Given that PA patterns are established during childhood and adolescence, and evolve within the context of the family, the current study explores the relationship between perceived parent-adolescent relationships and adolescents' PA levels, body mass index (BMI), and subjective well-being. The study was conducted in Israel, and the sample included 233 participants (126 girls, 107 boys) aged 13 to 18 years. Participants self-reported the following measures: demographic information, BMI, the Godin-Shephard Leisure-Time Physical Activity Questionnaire, the Personal Well-Being Index, and parent-adolescent relationship. The data were analyzed using Pearson analyses, t tests, and regressions. A clear difference emerged in strenuous PA activity by sex [ t(223) = 2.1, p < .01]; the average strenuous PA was greater for boys ( M = 3.9, SD = 2.4) than for girls ( M = 1.8, SD = .2.4). Furthermore, different predictors of strenuous PA by sex were found: for boys, parent-adolescent relationship was a significant predictor; for girls, subjective well-being was a predictor. The findings can shed light on the need for different intervention programs for adolescent boys and girls to increase their involvement in PA. PMID- 29720029 TI - Leptomeningeal enhancement of the spinal cord in sarcoidosis. PMID- 29720030 TI - Concurrent LETM and nerve root enhancement in spinal neurosarcoid: A case series. AB - Spinal neurosarcoidosis is a rare form of neurosarcoid which can be challenging to diagnose given its clinical or radiographic findings are often indistinguishable from other causes of spinal demyelinating disease. We present a series of three patients with spinal neurosarcoid, all of whom demonstrated concurrent longitudinally enhancing transverse myelitis as well as spinal nerve root enhancement. These findings may be suggestive of spinal neurosarcoid and may help clinicians make the diagnosis as well as reduce the need for invasive biopsy. PMID- 29720031 TI - Religious Preference and Hospice Choice. AB - This article will employ a database from a large hospice provider with offices in 16 states to examine the impact of religious preference on hospice choice. Little work has been done on this issue, even though religion is the only social institution that specifically addresses the end of life. Hospice work, in particular, has drawn little attention despite it effecting millions of patients and their families. Of all the medical subspecialties, hospice is one of the most effected by society's views on death and religious views of dying. It is also the only government-funded medical service that requires religious support be made available to patients. Our hypothesis is that certain religious groups have a predisposition against end-of-life interventions and will be less likely to utilize hospice. This impacts a multibillion dollar a year industry that supplies hospice service to millions of patients, and our research points to one major religious group not accessing their hospice benefit at the same rate as other denominations. PMID- 29720032 TI - The engagement of young people in their own advance care planning process: A systematic narrative synthesis. AB - BACKGROUND: An increasing number of young people are living with life-limiting conditions. Current research about advance care planning for young people indicates differing experiences for those involved. Understanding how far young people are engaged in their own advance care plan is important to shape future practice and facilitate young people's wishes. AIM: To identify and assess the current evidence to determine the barriers and facilitators to the engagement of young people in their own advance care planning process. DESIGN: A systematic narrative synthesis according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Study quality was assessed using a quality assessment framework previously used in similar research. DATA SOURCES: CINAHL Complete, MEDLINE, PubMed and PsycINFO were searched for articles published between 1 January 1990 and 31 October 2017. Grey literature was searched using Google Scholar and Open Grey. RESULTS: Most studies related to the engagement of young people were conducted in hospitals or other institutions. Research reported not only the aim to include young people in their own advance care planning but also potential barriers to engagement. Barriers include poor communication, conflict within relationships of those in the planning process and patchy education and training for healthcare professionals. Some existing studies are characterised by a lack of rigorous, high-quality research, limiting their impact. CONCLUSION: Irrespective of setting, engagement of young people would benefit their advance care planning. More detailed, high-quality research is needed to understand the extent of the barriers to young people's engagement in their own advance care plan and how to facilitate their involvement. PMID- 29720034 TI - Peptidoglycan and Lipoteichoic Acid Induces Differential mRNA Response of Immune Related Genes in PBMC of Crossbred, Tharparkar Cattle and Murrah Buffalo. AB - Subclinical mastitis, generally caused by Staphylococcus aureus, has a global economic impact all over the world. Hence, it needs to be resolved on higher priority which may be attained via. selection of mastitis resistant animals or inclusion of mastitis resistant trait into herd apart from management care. Diverse hosts with various genetic make-ups encounter pathogens in a diverse manner which in turn leads to contradicting outcome of the disease. Identification of species-wise or breed-wise differential expressed genes in response to S. aureus through relative evaluation of transcripts may be useful for judging the immuno-competency of a species or breed toward mastitis. The present study was undertaken to examine the stimulant effect of S. aureus peptidoglycan (PGN) and lipoteichoic acid (LTA) on Peripheral blood mononuclear cells (PBMC) harvested from blood samples of crossbred cattle, Tharparkar cattle, and Murrah buffaloes. After 6 h of in vitro stimulation qRT-PCR was used to measure the relative mRNA expression of TLR-2, TNF-alpha, IL-8, IFN-gamma and IL 10 genes in stimulated and un-stimulated PBMC. The selected genes revealed significant differences in the pattern of immune response among crossbred cattle, Tharparkar cattle and Murrah buffalo in spite of the same stimulant dose. PMID- 29720036 TI - Anaerobic acidification of sugar-containing wastewater for biotechnological production of organic acids and ethanol. AB - Anaerobic acidification of sugars can produce some useful end-products such as alcohol, volatile fatty acids (e.g. acetate, propionate, and butyrate) and lactic acid. The production of end-products is highly dependent on factors including pH, temperature, hydraulic retention time and the types of sugar being fermented. Results of this current study indicate that the pH and hydraulic retention time played significant roles in determining the end products from the anaerobic acidification of maltose and glucose. Under uncontrolled pH, the anaerobic acidification of maltose ceased when pH in the reactor dropped below 5 while anaerobic acidification of glucose continued and produced ethanol as the main end product. Under controlled pH, lactic acid was found to be the dominant end product produced from both maltose and glucose at pH 5. Acetate was the main end product from both maltose and glucose fermented at neutral pH (6 and 7). Short hydraulic retention time (HRT) of 2 days could induce the production of ethanol from the anaerobic acidification of glucose. However, the anaerobic acidification of maltose could stop when short HRT of 2 days was applied in the reactor. This finding is significant for industrial fermentation and waste management systems, and selective production of different types of organic acids could be achieved by managing pH and HRT in the reactor. PMID- 29720033 TI - Diagnostic accuracy of whole-brain computed tomography perfusion for detection of ischemic stroke in patients with mild neurological symptoms. AB - Mild and minor acute neurological symptoms may lead to diagnostic uncertainty, resulting in a heterogeneous group of patients with true ischemic events and stroke mimics with a potential for poor outcomes. More than half of ischemic stroke patients present as minor strokes (National Institutes of Health Stroke Scale score <6). Whole-brain computed tomography perfusion can be used as a diagnostic test for minor stroke, offering a potential method of reducing diagnostic uncertainty in these patients. We hypothesize that whole-brain computed tomography perfusion imaging features could accurately predict infarction in patients with minor neurological deficits. This retrospective chart review enrolled consecutive patients suspected of acute ischemic stroke with a National Institutes of Health Stroke Scale score <6, who underwent whole-brain computed tomography perfusion and follow-up diffusion-weighted magnetic resonance imaging at our institution. Sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios were calculated for whole-brain computed tomography perfusion, using follow-up diffusion-weighted magnetic resonance imaging as a reference standard. A total of 524 patients (mean age: 67 years; range: 17-96 years; 56% men) met the inclusion criteria. Patients were excluded for non-diagnostic ( n = 25) or missing maps ( n = 8) scans, non ischemic findings ( n = 7), and lack of follow-up magnetic resonance imaging ( n = 336). The final analysis included 148 patients who underwent diffusion-weighted magnetic resonance imaging. Whole-brain computed tomography perfusion has a sensitivity of 0.57 (95% CI: 0.45-0.69) and a specificity of 0.82 (95% CI: 0.71 0.90). The positive and negative predictive values and positive and negative likelihood ratios were 75%, 67%, 3.09, and 0.53, respectively. Our analysis suggests that although whole-brain computed tomography perfusion may offer some value as an adjunctive test for improving confidence in offering stroke treatment, it is not sufficiently sensitive or specific to accurately predict cerebral infarcts in patients with minor neurological symptoms. PMID- 29720035 TI - Clinical application of protein biomarkers in lupus erythematosus and lupus nephritis. AB - Systemic lupus erythematosus (SLE) is a type of autoimmune disease that damages multiple organs, including the heart, joints, liver and kidneys. The main characteristics of SLE are the deposition of circulating autoantibodies; autoantigen complexes in the renal system; and abnormal expression of complements, cytokines and chemokines. Lupus nephritis (LN) is the most serious manifestation of SLE and is characterized by inflammation of the kidney. This review summarizes recent clinical applications of protein biomarkers including autoantibodies, complements, cytokines and chemokines and some new protein biomarkers in SLE and LN. The clinical differential diagnosis of protein biomarkers related to prognosis and diagnosis is discussed and highlighted. Protein biomarkers play crucial roles in the study of SLE and LN. Useful biomarkers will provide insights into effective treatments for these diseases. PMID- 29720038 TI - Suspended Life Pattern: A Qualitative Study on Personal Life Among Family Caregivers of Hemodialysis Patients in Iran. AB - Purpose To determine the personal life of family caregivers of patients undergoing hemodialysis. Methodology In this qualitative study, individual semistructured interviews were carried out with 19 caregivers of hemodialysis patients. All interviews were recorded, typed, and imported into the Open Code Software. The Graneheim and Lundman's content analysis approach was used for the analysis. Findings The theme of this study was suspended life pattern that was extracted from two categories of "Imbalance between caregiving and life" and "ambiguity in life status." The category of "Imbalance between caregiving and life" included some subcategories including compulsive compliance, suspension, and deferral of roles, conflicts between leisure time and caregiving and caregivers' time limits. Moreover, the category "ambiguity in life" was extracted from two subcategories of fear and hope and life satisfaction depending on care recipients' condition. Conclusion Caring for hemodialysis patients leads to instability and ambiguity in a caregiver's personal life. Therefore, authorities, policymakers, and health-care providers should pay more attention to support these people. PMID- 29720039 TI - Palliative medicine: Advance care planning virtual issue. AB - Since the latter part of the twentith century, international research, education and practice of advance care planning has experienced a diversity of developments and defintions. Whilst this variety may seem bewildering, a continued commitment to accurate, focussed research enables better care through better understanding and better evidence. PMID- 29720040 TI - Severe arthritic syndrome due to ibrutinib use for chronic lymphocytic leukemia. AB - Although newer targeted agents improve survival in cancer patients, they have also been linked with unusual side effects. The most common side effects of Bruton tyrosine kinase inhibitors include fatigue, nausea, diarrhea, bruising, and cytopenias. We describe herein a case of an unusually severe articular syndrome with the use of ibrutinib in a patient with 17 p minus chronic lymphocytic leukemia. The severity of this side effect led to permanent discontinuation of this agent. As the causality ibrutinib-arthralgia seems legitimate, we expect further similar cases to surface in patients treated with Bruton tyrosine kinase inhibitors. PMID- 29720037 TI - Brain's compensatory response to drug-induced cognitive impairment. AB - INTRODUCTION: Topiramate (TPM), a frequently prescribed antiseizure medication, can cause severe cognitive side-effects. Though these side-effects have been studied behaviorally, the underlying neural mechanisms are unknown. In a double blind, randomized, placebo-controlled, crossover study of TPM's impact on cognition, nine healthy volunteers completed three study sessions: a no-drug baseline session and two sessions during which they received either TPM or placebo. Electroencephalogram was recorded during each session while subjects performed a working-memory task with three memory-loads. RESULTS: Comparing TPM with baseline we found the following results. (a) TPM administration led to declines in behavioral performance. (b) Fronto-central event-related potentials (ERP) elicited by probe stimuli, representing the primary task network activity, showed strong memory-load modulations at baseline, but the magnitude of these load-dependent modulations was significantly reduced during TPM session, suggesting drug-induced impairments of the primary task network. (c) ERP responses over bilateral fronto-temporal electrodes, which were not load sensitive at baseline, showed significant memory-load modulations after TPM administration, suggesting the drug-related recruitment of additional neural resources. (d) At fronto-central scalp sites, there was significant increase in response amplitude for low memory-load during TPM session compared to baseline, and the amplitude increase was dependent on TPM plasma concentration, suggesting that the primary task network became less efficient under TPM impact. (e) At bilateral fronto-temporal electrodes, there were no ERP differences when comparing low memory-load trials, but TPM administration led to an increase in ERP responses to high load, the magnitude of which was positively correlated with task performance, suggesting that the recruited neural resources were beneficial for task performance. Placebo-TPM comparison yielded similar effects albeit with generally reduced significance and effect sizes. CONCLUSION: Our findings support the hypothesis that TPM impairs the primary task network by reducing its efficiency, which triggers compensatory recruitment of additional resources to maintain task performance. PMID- 29720041 TI - Correlation between different carboplatin dosing patterns and its toxicity analysis in patients with advanced lung cancers: A retrospective study. AB - Objective To evaluate the current NCI-CTEP recommendation and the clinical use of Calvert Formula-derived carboplatin dosing pattern in the treatment of advanced lung cancer patients and assess carboplatin-related toxicity in relation to the degree of dose fluctuation. Methodology This retrospective study involved all histologically confirmed inoperable lung cancer patients receiving palliative intent carboplatin or carboplatin-combination chemotherapy from 2012 to 2016 at Kingston Health Sciences Centre. The carboplatin dosing pattern and carboplatin related toxicity were collected and analysed on SPSS IBM for Windows version 24.0 (IBM Corp., Armonk, NY, USA). Results were expressed in percentages and P values. Results Our findings ( N = 75) suggested that 24% of patients had a high-degree of fluctuation in carboplatin dose (>10% variation from initial dose) if carboplatin dose was readjusted with each new creatinine. In practice, 16% of patients had a fluctuation of greater than 10% in ordered dose in the absence of planned dose reductions. Our study found no significant association between prescribed high-risk dosing fluctuation (>10% increased from initial dose) and carboplatin-related toxicities. Discussion and conclusion In contrast to some prescribing recommendations such as NCI-CTEP, our study suggested that most medical oncologists incorporate new serum creatinine in calculating carboplatin dose for each cycle. Only 9% of patients were treated with a fixed dosing pattern (i.e. no fluctuation). Nonetheless, no significant associations were found between high-risk carboplatin dosing fluctuation and its-related toxicity. Whether such practice was due to the forcing function of the computer order entry system (CPOE), or conscious decisions by medical oncologists was unknown. Further analysis in evaluating physicians' preferences and influencing factors on dosing pattern decision would be recommended. PMID- 29720042 TI - Incidence and predictors of clinical peripheral artery disease in asymptomatic persons with a low ankle-brachial index. AB - OBJECTIVE: To determine the occurrence of clinical peripheral artery disease in a cohort of middle-aged and older persons who, though they initially had no symptoms of peripheral artery disease, had blood pressure levels in the arteries of their ankles and feet that were at least 10% lower than those in the arteries of their arms. METHODS: We analyzed data obtained in the Multi-Ethnic Study of Atherosclerosis, in which lower and upper extremity blood pressures were assessed in over 6000 Americans aged 45-84 and the ratio of these (the ankle-brachial index) was calculated. During a median follow-up of 13 years, the incidence of symptomatic peripheral artery disease (identified through annual questionnaires, review of hospital records, and notations of peripheral artery disease found in data obtained from the Center for Medicare Services) was compared between persons whose ankle-brachial index was ?9 and persons with higher ankle-brachial index values. RESULTS: The incidence of clinical peripheral artery disease was 23.0 per 1000 person-years among the 172 participants whose baseline ankle-brachial index was <0.9, compared with 2.0 per 1000 person-years in those with a higher ratio. The incidence of clinical peripheral artery disease rose steadily with decreasing ankle-brachial index below 0.9. The excess risk associated with a low ankle brachial index was present in persons with and without the other measured risk factors for peripheral artery disease (cigarette smoking, hyperten sion, diabetes, and obesity). CONCLUSIONS: Even in persons asymptomatic for peripheral artery disease, those with a low ankle-brachial index are at an appreciable risk of the development of manifestations of peripheral arterial insufficiency. PMID- 29720043 TI - Antimicrobial stewardship through telemedicine and its impact on multi-drug resistance. AB - Introduction Telemedicine technologies are increasingly being incorporated into infectious disease practice. We aimed to demonstrate the impact of antimicrobial stewardship through telemedicine on bacterial resistance rates. Methods We conducted a quasi-experimental study in a 220-bed hospital in southern Brazil. An antimicrobial stewardship program incorporating the use of telemedicine was implemented. Resistance and antimicrobial consumption rates were determined and analysed using a segmented regression model. Results After the intervention, the rate of appropriate antimicrobial prescription increased from 51.4% at baseline to 81.4%. Significant reductions in the consumption of fluoroquinolones (level change, beta = -0.80; P < 0.01; trend change, beta = -0.01; P = 0.98), first generation cephalosporins (level change, beta = -0.91; P < 0.01; trend change, beta = +0.01; P = 0.96), vancomycin (level change, beta = -0.47; P = 0.04; trend change, beta = +0.17; P = 0.66) and polymyxins (level change, beta = -0.15; P = 0.56; trend change, beta = -1.75; P < 0.01) were identified. There was an increase in the consumption of amoxicillin + clavulanate (level change, beta = +0.84; P < 0.01; trend change, beta = +0.14; P = 0.41) and cefuroxime (level change, beta = +0.21; P = 0.17; trend change, beta = +0.66; P = 0.02). A significant decrease in the rate of carbapenem-resistant Acinetobacter spp. isolation (level change, beta = +0.66; P = 0.01; trend change, beta = -1.26; P < 0.01) was observed. Conclusions Telemedicine, which provides a tool for decision support and immediate access to experienced specialists, can promote better antibiotic selection and reductions in bacterial resistance. PMID- 29720044 TI - Prediction of venous malformations with localized intravascular coagulopathy with diffusion-weighted magnetic resonance imaging. AB - Background Venous malformations may be complicated by localized intravascular coagulopathy which is a serious condition with hematological sequel. Prediction of localized intravascular coagulopathy is mandatory for prompt anticoagulation therapy. Laboratory and routine magnetic resonance imaging can predict localized intravascular coagulopathy in venous malformations; however, the results are variable. Purpose To predict venous malformations with localized intravascular coagulopathy with diffusion-weighted magnetic resonance imaging. Material and methods A retrospective analysis was performed on 55 patients (34 male, 21 female aged 14-64 years: mean 39 years) with venous malformations that underwent diffusion-weighted magnetic resonance imaging. The apparent diffusion coefficient value of venous malformations was calculated. Results The mean apparent diffusion coefficient value of venous malformations with localized intravascular coagulopathy (n = 26) (1.28 +/- 0.18 * 10-3 mm2/s) was significantly different ( P = 0.001) from venous malformations without localized intravascular coagulopathy (n = 29) (1.60 +/- 0.18 * 10-3 mm2/s). When apparent diffusion coefficient value of 1.454 * 10-3 mm2/s was used as a threshold value for the prediction of venous malformations with localized intravascular coagulopathy, the best result was obtained with an accuracy of 83.6%, sensitivity of 84.6%, specificity of 82.8%, and area under the curve of 0.895. The apparent diffusion coefficient value of venous malformations was correlated with D-dimer level ( r = -0.59, P = 0.006) and fibrinogen level ( r = 0.73, P = 0.001). Conclusion The apparent diffusion coefficient value is a non-invasive imaging parameter that can be used to predict venous malformations with localized intravascular coagulopathy. PMID- 29720045 TI - Protocol for a prospective collaborative systematic review and meta-analysis of individual patient data from randomized controlled trials of vasoactive drugs in acute stroke: The Blood pressure in Acute Stroke Collaboration, stage-3. AB - Rationale Despite several large clinical trials assessing blood pressure lowering in acute stroke, equipoise remains particularly for ischemic stroke. The "Blood pressure in Acute Stroke Collaboration" commenced in the mid-1990s focussing on systematic reviews and meta-analysis of blood pressure lowering in acute stroke. From the start, Blood pressure in Acute Stroke Collaboration planned to assess safety and efficacy of blood pressure lowering in acute stroke using individual patient data. Aims To determine the optimal management of blood pressure in patients with acute stroke, including both intracerebral hemorrhage and ischemic stroke. Secondary aims are to assess which clinical and therapeutic factors may alter the optimal management of high blood pressure in patients with acute stroke and to assess the effect of vasoactive treatments on hemodynamic variables. Methods and design Individual patient data from randomized controlled trials of blood pressure management in participants with ischemic stroke and/or intracerebral hemorrhage enrolled during the ultra-acute (pre-hospital), hyper acute (<6 h), acute (<48 h), and sub-acute (<168 h) phases of stroke. Study outcomes The primary effect variable will be functional outcome defined by the ordinal distribution of the modified Rankin Scale; analyses will also be carried out in pre-specified subgroups to assess the modifying effects of stroke-related and pre-stroke patient characteristics. Key secondary variables will include clinical, hemodynamic and neuroradiological variables; safety variables will comprise death and serious adverse events. Discussion Study questions will be addressed in stages, according to the protocol, before integrating these into a final overreaching analysis. We invite eligible trials to join the collaboration. PMID- 29720046 TI - Should Abdominal Aortic Aneurysms in Women be Repaired at a Lower Diameter Threshold? AB - Abdominal aortic aneurysm (AAA) primarily affects male patients; however, female patients with AAA have a faster rate of aneurysm growth, have higher risk of rupture even at smaller diameters, and have worse outcomes following repair of ruptured and intact aneurysms. Furthermore, early natural history studies and randomized controlled trials evaluating surveillance versus repair in small aneurysms were conducted primarily in male patients. Therefore, there are limited data regarding the ideal threshold for elective repair of AAA in women, either by aortic diameter or by alternative measures. We review the existing literature regarding AAA in women and consider the most appropriate threshold for repair. PMID- 29720048 TI - The role of simulation in medical education. PMID- 29720047 TI - Comprehensive Sexuality Education as a Primary Prevention Strategy for Sexual Violence Perpetration. AB - Sexual violence (SV) represents a serious public health problem with high rates and numerous health consequences. Current primary prevention strategies to reduce SV perpetration have been shown to be largely ineffective-not surprisingly, since as others have pointed out current prevention largely fails to draw on existing knowledge about the characteristics of effective prevention. In this article, we examine the potential of K-12 comprehensive sexuality education (CSE), guided by the National Sexuality Education Standards (NSES), to be an effective strategy. Our discussion uses socioecological and feminist theories as a guide, examines the extent to which NSES-guided CSE could both meet the qualities of effective prevention programs and mitigate the risk factors that are most implicated in perpetration behavior, and considers the potential limitations of this approach. We suggest that sequential, K-12 program has potential to prevent the emergence of risk factors associated with SV perpetration by starting prevention early on in the life course. CSE has not yet been evaluated with SV perpetration behavior as an outcome, and this article synthesizes what is known about drivers of SV perpetration and the potential impacts of CSE to argue for the importance of future research in this area. The primary recommendation is for longitudinal research to examine the impact of CSE on SV perpetration as well as on other sexual and reproductive health outcomes. PMID- 29720049 TI - An analysis of factors predicting failure after single digit replantation. AB - : The purpose of this study was to explore predictive factors for failure of digital replantation distal to the metacarpophalangeal joint-level, including D dimer. In a retrospective study on 538 cases, univariate, multivariate and linear regression analyses were applied. The survival rate of single digital replantation was 91.4% (492 of 538). Our data showed that many factors were connected with a higher risk of failure. A high level of D-dimer indicated earlier necrosis. There was a linear relation between D-dimer and age, ischaemia time and platelet count in the failure group. D-dimer can be considered an independent factor predicting replantation failure. LEVEL OF EVIDENCE: IV. PMID- 29720050 TI - The Journal of School Nursing-SAGE Writing Awards and Research About School Nursing. PMID- 29720051 TI - Analysis of Rothman Index Data to Predict Postdischarge Adverse Events in a Medical Intensive Care Unit. AB - OBJECTIVE: Currently, there are no objective metrics included in the intensive care unit (ICU) discharge decision making process. In this study, we evaluate Rothman Index(RI) data for a possible metric as part of a quality improvement project. Our objectives were to determine whether RI could predict adverse events occurring within 72 hours of ICU discharge decision, the optimal clinical cutoff value for this metric, and to determine whether there is a relation between the RI warning alert 24 hours prior to discharge and adverse events postdischarge. DESIGN: Retrospective observational study. SETTING: Single center tertiary hospital. PATIENTS: Adult medical ICU patients discharged from the ICU between January 20, 2015 and March 14, 2015. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: A total of 194 patients were studied with mean age of 62.74 (18.37) years. Data collection included RI at the time of decision-making for ICU discharge and the presence of any warning signals in the previous 24 hours. A 72 hour follow-up chart review recorded any adverse events, including readmission to a higher level of care, discontinuation of discharge due to clinical status change, emergency department visit if discharged home, rapid response activation, or cardiopulmonary arrest postdischarge. Adverse events after ICU discharge were observed in 31 (16%) patients with 9 events being ICU readmission (4.6%). Based on an age-adjusted multivariate model, a higher RI was associated with lower odds of an adverse event (odds ratio [OR] = 0.969, P = .006, confidence interval [CI]: 0.9487-0.9911). An RI value >= 50 was associated with 72% lower odds of an adverse event (OR = 0.2887, 95% CI = 0.1278-0.6517 and P = .003) compared to RI < 50. This RI cutoff value was associated with the largest decrease in odds of events. As expected, patients with a very high-risk warning alert had a higher proportion of adverse events compared to patients who did not. (31.75% vs 12.65%, P = < .02). CONCLUSIONS: Patients who have an RI < 50 or a very high-risk warning alert have a higher risk of adverse events postdischarge from the ICU. Rothman Index may be a useful metric for ICU discharge decision-making. PMID- 29720052 TI - High-Density Lipoprotein, Mean Platelet Volume, and Uric Acid as Biomarkers for Outcomes in Patients With Sepsis: An Observational Study. AB - BACKGROUND: We conducted an observational study evaluating the association between uric acid, mean platelet volume (MPV), and high-density lipoprotein (HDL) with complications and outcomes of patients with sepsis in a critical care setting. METHODS: We followed patients with a diagnosis of severe sepsis and septic shock for a maximum of 28 days. Main outcomes assessed included length of stay (LOS), the need for renal replacement therapy (RRT), assisted mechanical ventilation (AMV), and vasopressor support as well as in-unit mortality. RESULTS: The overall average age of the 37 patients enrolled was 48.1 (19.8) years; among them, 37.8% were male. Abdominal related (43.2%) and pulmonary (29.7%) were the main sites of infection. The overall Acute Physiology and Chronic Health Evaluation 2 (APACHE-2) median score was 19 (9-24). Acute kidney injury (AKI) was observed in 46.9% of the sample. In all, 54.1% required vasopressor support, 54.1% AMV, and 35.1% RRT. Patients with bacteremia were significantly more likely to require vasopressor support and those with urinary tract infections were significantly younger. We found increasing DeltaMPV levels, higher APACHE-2 scores, lower HDL values, and a reduced age to be associated with a longer LOS. Higher scores on the APACHE-2 scale and lower levels of HDL significantly associated with higher odds for developing AKI. The need for vasopressor support was significantly associated with higher values of 72-hour MPV and with higher levels of baseline uric acid and lower values of initial HCO3. Initial and 72 hour levels of MPV and higher scores in the APACHE-2 were all significantly correlated with the need for AMV. An increased probability of dying during follow up was significantly correlated with increasing age. CONCLUSION: We were able to establish significant associations between our candidate biomarkers and relevant outcomes for patients with sepsis. Our results support the use of these low-cost biomarkers in the assessment of prognosis of patients with sepsis. PMID- 29720053 TI - Prevalence, Risk Factors, and Clinical Consequences of Recurrent Activation of a Rapid Response Team: A Multicenter Observational Study. AB - INTRODUCTION: Rapid response teams (RRTs) are groups of health-care providers, implemented by hospitals to respond to distressed hospitalized patients on the hospital wards. Patients assessed by the RRT for deterioration may be admitted to the intensive care unit (ICU) or may be triaged to remain on the wards, putting them at risk of recurrent deterioration and repeat RRT activation. Previous studies evaluating outcomes of patients with recurrent deterioration and multiple RRT activations have produced conflicting results. METHODS: We used a prospectively collected multicenter registry from 2 hospitals within a single tertiary-level hospital system between 2012 and 2016. Comparisons were made between patients with a single RRT activation and those with multiple RRT activations over the course of their admission. Primary outcome was in-hospital mortality, which was analyzed using multivariable logistic regression. RESULTS: A total of 5995 patients who had any RRT activation were analyzed. Of that, 1183 (19.7%) patients had recurrent deterioration and multiple RRT activations during their admission. Risk factors for recurrent deterioration included admission from a home setting (as opposed to a long-term care facility), RRT activation during nighttime hours, and delay (>1 hour) to RRT activation. Recurrent deterioration was associated with increased odds of mortality (adjusted odds ratio [OR]: 1.44 [1.28-1.64], P = <.001). Increasing number of RRT activations were associated with increasing risk of mortality. Patients with recurrent deterioration had prolonged median hospital length of stay (21.0 days vs 12.0 days, P < .001), while patients with only a single activation were more likely to be admitted to the ICU (adjusted OR: 2.30 [1.96-2.70], P < .001). CONCLUSIONS: Recurrent deteriorations leading to RRT activations among hospitalized patients are associated with increased odds of mortality and prolonged hospital length of stay. This work identifies a group of patients who warrant closer attention to help reduce adverse outcomes. PMID- 29720054 TI - Newly Proposed Sepsis-Induced Coagulopathy Precedes International Society on Thrombosis and Haemostasis Overt-Disseminated Intravascular Coagulation and Predicts High Mortality. AB - BACKGROUND: Disseminated intravascular coagulation (DIC) has been recognized as an urgent and critical condition in patients with sepsis. Therefore, unfamiliar and time-consuming tests or a complex scoring system are not suitable for diagnosis. Sepsis-induced coagulopathy (SIC), a newly proposed category delineated by a few global coagulation tests, has been established as an early warning sign for DIC. The purpose of this study was to elucidate the characteristics of SIC, especially in relation to the score of the International Society on Thrombosis and Haemostasis (ISTH) for overt DIC. METHOD: A data set for 332 patients with sepsis who were suspected to have DIC, antithrombin activity <70%, and treated with antithrombin substitution was utilized to examine the relationship between SIC and overt DIC. The performance of SIC calculated at baseline (ie, before treatment) as well as on days 2, 4, or 7 was analyzed in terms of its ability to predict 28-day mortality and overt DIC. RESULTS: At baseline, 149 (98.7%) of 151 patients with overt DIC according to the ISTH definition were diagnosed as having SIC. Of the 49, 46 (93.9%) patients who developed overt DIC between days 2 and 4 had received a prior diagnosis of SIC. The sensitivity of baseline SIC for the prediction of death was significantly higher than that of overt DIC (86.8% vs 64.5%, P < .001). The sensitivity of SIC on days 2, 4, and 7 was significantly higher than those of overt DIC (96.1%, 92.3%, and 84.4% vs 67.1%, 57.7%, and 50.0%, P < .001, .001, and .001, respectively), although the specificity of SIC was lower at all time points. PMID- 29720055 TI - The Nobel science prizes and their constituencies. PMID- 29720057 TI - Global and local "teachable moments": The role of Nobel Prize and national pride. AB - This study examined to what extent Nobel Prize announcements and awards trigger global and local searches or "teachable moments" related to the laureates and their discoveries. We examined the longitudinal trends in Google searches for the names and discoveries of Nobel laureates from 2012 to 2017. The findings show that Nobel Prize events clearly trigger more searches for laureates, but also for their respective discoveries. We suggest that fascination with the Nobel prize creates a teachable moment not only for the underlying science, but also about the nature of science. Locality also emerged as playing a significant role in intensifying interest. PMID- 29720058 TI - Nobel laureates in fiction: From La fin du monde to The Big Bang Theory. AB - The history of the Nobel Prize, since its establishment, interlaces with the history of the public image of science. The aim of this article is to illustrate cinematic scientists, portrayed precisely in their moment of maximum glory. The films and television shows upon which the study is based compose a corpus of 189 media texts. The article identifies three main areas that concern the relation between the Nobel Prize and its audiovisual representations: biopics of real Nobel laureates, the presence of real or fictional Nobel laureates in the film or the show plot, and films and TV series that depict the Nobel ceremony. The article then focuses on four texts that deserve a detailed examination: La fin du monde, The Prize, The Simpsons and The Big Bang Theory. The conclusion compares the representation of the Nobel scientist with general changes in the image of the scientist conveyed by cinema and television. PMID- 29720056 TI - The image of the Nobel Prize. AB - This article traces the origins of the Nobel Prize as a ubiquitous symbol of excellence in science. The public image of the Nobel Prize was created and became established quickly, which can be explained by it being such a useful phenomenon for the co-production of other values and ideas such as national prestige. Through being an easily recognizable symbol for excellence, the Nobel Prize is an important factor for the public image of science. And the image of the Nobel Prize is co-produced with several other sets of values and images that range from the large and thematic to the local and specific. PMID- 29720059 TI - What's so special about the Nobel Prize? PMID- 29720060 TI - The laureate as celebrity genius: How Scientific American's John Horgan profiled Nobel Prize winners. AB - When scientists become Nobel laureates, they become famous in science and public life, but few studies have examined the nature of their scientific celebrity. This article examines how Scientific American portrayed laureates in order to identify and explain core features of Nobel fame. It examines the portrayals of seven laureates - Francis Crick, Linus Pauling, Hans Bethe, Murray Gell-Mann, Brian Josephson, Philip Anderson and Subrahmanyan Chandrasekhar - in magazine profiles written between 1992 and 1995 by science writer John Horgan. Its textual analysis finds the scientists are portrayed as combining the sociological characteristics of genius, including enormous productivity and lasting impact, with the representational characteristics of celebrities, such as the merging of public and private lives. Their form of scientific celebrity is grounded in their field-changing research, which is presented as a product of their idiosyncratic personalities. Nobel science is presented as knowledge created by an ultra-elite of exceptional individuals. PMID- 29720062 TI - From engaged citizen to lone hero: Nobel Prize laureates on British television, 1962-2004. AB - Between 1962 and 2004, Nobel Prize laureates appear in the British television science programme Horizon in various roles, denoting differing understandings of science in relation to society and culture. These representations are the outcome of an interplay of cultural and institutional factors. They vary with the broadcasting environment. Notably, the article establishes that the choice of presenting scientists as heroic characters in strongly determined storylines from the late-1990s onwards originates in a reaction to institutional imperatives as a means to preserve the existence of the Horizon series. The article shows that exigencies of the institutional context in which media professionals operate are major factors influencing the representation of science in public. PMID- 29720063 TI - The character of scientists in the Nobel Prize speeches. AB - This essay describes the ethos (i.e. the character projected to specific audiences) of the 25 Nobel Lectures in Physics, Chemistry, and Physiology or Medicine given in 2013-2015 and the 15 Presentation Speeches given at the Nobel Banquets between 2011 and 2015. A thematically focused qualitative analysis grounded in theories of epideictic discourse indicates the Nobel speakers demonstrated a range of strategies for and degrees of success in negotiating the tensions created by the implicit demands of ceremonial speeches, the scientific emphasis on didactic style and research content, and the different potential audiences (scientific experts and interested publics). Relatively few speeches explicitly displayed goodwill toward humanity instead of primarily toward the scientific community. Some speakers emphasized qualities of goodness in line with social values shared by broad audiences, but some reinforced stereotypes of scientists as anti-social. Speakers were variable in their ability to bridge the substantial gaps in resources for shared good sense. PMID- 29720064 TI - 'The winner takes it all?' Nobel laureates and the public image of science. PMID- 29720065 TI - Tuberculosis screening in an aged care residential facility in a low-incidence setting. AB - Tuberculosis (TB) remains a disease of high morbidity in Australia, with implications for both public health and the individual. Cost analyses is relevant for programmatic evaluation of TB. There is minimal published TB cost data in the Australian setting. Patients with drug sensitive active pulmonary TB (DS-PTB) and latent TB (LTBI) were enrolled in a single tertiary referral centre to evaluate healthcare provider costs. The median cost of treating drug susceptible pulmonary TB in this case series was 11,538 AUD. Approximately 50% of total costs is derived from inpatient hospitalisation bed days. In comparison, the average cost of managing latent TB was 582 AUD per completed course. We find the median provider cost of our DS-PTB treatment group comparable to costs from other regions globally with similar economic profiles. A program designed to detect and treat LTBI to prevent subsequent disease may be cost effective in appropriately selected patients and warrants further study. PMID- 29720066 TI - Prevention of perinatal hepatitis B virus transmission: are we following guidelines? AB - It is recommended that infants born to women with hepatitis B infection should have serological review following completion of a four dose vaccination schedule. A review was undertaken on 102 neonates who received hepatitis B immunoglobulin to ascertain the proportion that were fully immunised and then followed up. Of the 66 infants for whom data were available, 65 (98.5%) had appropriately received four doses of hepatitis B vaccine in infancy and a further child had received three doses. Only 19/66 (29%; 95%CI: 18-41%) infants had documented follow-up serology results, one of whom was infected and one of whom was immune through clearance of infection. All children who had no serology documented were traced and offered testing in primary care. Our results demonstrate that although adherence to the vaccination schedule in this group of infants was good, mechanisms for ensuring that infants receive serology testing need to be strengthened. PMID- 29720067 TI - National Tuberculosis Advisory Committee Guideline: Management of Tuberculosis Risk in Healthcare Workers in Australia. AB - Tuberculosis (TB) is uncommon in Australia and not commonly managed by most healthcare workers (HCWs). However, even in a low incidence setting, occasional exposure of HCWs is inevitable and transmission of TB to HCWs leading to disease does occur. In addition, HCWs may have been recruited to Australia from countries with high TB incidence. These HCWs are more likely to be infected with TB before arrival and subsequently develop active disease while working in health settings in Australia. In 2001, there were 20 TB notifications in HCWs in Australia, of which 10 were born overseas, whereas in 2013, 70 of 77 notified cases (91%) were people born overseas.1, 2 Managing the risk of TB in HCWs is multifaceted. A combination of staff education, awareness, early diagnosis, appropriate use of personal protective equipment (PPE), environmental controls and screening procedures is required to minimise the risk of transmission to HCWs and from HCWs to patients. Prevention of nosocomial transmission from HCWs is particularly important in patients that are more vulnerable, for example children and the immunocompromised. This document aims to describe the components that are considered essential for all healthcare facilities in Australia to minimise this risk. It is not intended to be operational, and reference should be made to specific state and territory TB Control Program policies for this detail. Each facility should develop its own policy for the management of TB risk in HCWs according to this jurisdictional policy and the facility specific factors that determine risk, but it should include at least the following components. PMID- 29720068 TI - National position statement for the management of latent tuberculosis infection. AB - : The primary role of any tuberculosis (TB) control program is to ensure the prompt identification and effective treatment of active disease. The host immune system often succeeds in containing the initial (or primary) infection with Mycobacterium tuberculosis (Mtb), but may fail to eliminate the pathogen. The persistence of viable organisms explains the potential for the development of active disease years or even decades after infection. This is known as latent tuberculosis infection (LTBI) although, rather than a distinct entity, this probably represents part of a dynamic spectrum. Individuals with LTBI are asymptomatic and it is therefore clinically undetectable. The World Health Organization (WHO) estimates that one-third of the global population has been infected with Mtb, with highest prevalence of LTBI in countries/regions with the highest prevalence of active disease. In 2013, 88% of 1322 notifications in Australia were in the overseas-born population (incidence 19.5 per 100,000 v. 1.0 per 100,000), with this proportion rising over the course of the last decade. Combined with epidemiological evidence of low local transmission, this strongly implies that the vast majority resulted from reactivation of latent infection acquired prior to immigration. Contrasting trends in TB incidence in other developed countries probably reflect differences in policy regarding LTBI. CONCLUSION: The diagnosis and treatment of LTBI represents an important opportunity for intervention by jurisdictional TB control programs. PMID- 29720069 TI - How much does tuberculosis cost? An Australian healthcare perspective analysis. AB - Tuberculosis (TB) remains a disease of high morbidity in Australia, with implications for both public health and the individual. Cost analyses is relevant for programmatic evaluation of TB. There is minimal published TB cost data in the Australian setting. Patients with drug sensitive active pulmonary TB (DS-PTB) and latent TB (LTBI) were enrolled in a single tertiary referral centre to evaluate healthcare provider costs. The median cost of treating drug susceptible pulmonary TB in this case series was 11,538 AUD. Approximately 50% of total costs is derived from inpatient hospitalisation bed days. In comparison, the average cost of managing latent TB was 582 AUD per completed course. We find the median provider cost of our DS-PTB treatment group comparable to costs from other regions globally with similar economic profiles. A program designed to detect and treat LTBI to prevent subsequent disease may be cost effective in appropriately selected patients and warrants further study. PMID- 29720070 TI - Sexually Transmitted Infections in Melbourne, Australia from 1918 to 2016: nearly a century of data. AB - Introduction: Our aim was to describe trends in the number of bacterial sexually transmitted infections (STIs) diagnosed at Melbourne's sexual health clinic over a century. Methods: A retrospective analysis of STI diagnoses (gonorrhoea, infectious syphilis and chancroid) among individuals attending Melbourne's sexual health service over 99 years between 1918 and 2016. Results: Substantial increases in STI rates coincided with World War II, the 'Sexual Revolution of the 1960s and 1970s', and the last 10 years. Substantial declines coincided with the advent of antibiotics and the HIV/AIDS pandemic. There were also key differences between STIs. Chancroid virtually disappeared after 1950. Syphilis fell to very low levels in women after about 1950 and has only rebounded in men. The declines in gonorrhoea were less marked. A substantial peak in gonorrhoea occurred in women in the early 1970s and rates are currently rising in women, albeit much less than in men. Conclusions: Both antibiotics and changing sexual behaviour have had a powerful effect on STI rates. These data suggest gonorrhoea is more difficult to control than syphilis or chancroid. Indeed, the past rates suggest substantial endemic gonorrhoea transmission in heterosexuals occurred in the third quarter of last century before the appearance of the HIV pandemic. Worryingly, there is a suggestion that endemic heterosexual gonorrhoea may be returning. The data also suggest that future control of gonorrhoea and syphilis in men who have sex with men is going to be challenging. PMID- 29720071 TI - The effects of culture independent diagnostic testing on the diagnosis and reporting of enteric bacterial pathogens in Queensland, 2010 to 2014. AB - Changes in diagnostic laboratory testing procedures can impact on the number of cases notified and the public health surveillance of enteric pathogens. Culture independent diagnostic testing using a multiplex polymerase chain reaction (PCR) test was introduced for the rapid detection of bacterial enteric pathogens in pathology laboratories in Queensland, Australia, from late 2013 onwards. We conducted a retrospective descriptive study using laboratory data to assess the impact of the introduction of PCR testing on four common enteric pathogens, Salmonella, Campylobacter, Shigella and Yersinia, in Queensland between 2010 and 2014. The number of stool specimens tested and the proportion positive for each of the four pathogens increased in 2014 after the introduction of culture independent diagnostic testing. Among the specimens tested by both PCR and culture, 12% of Salmonella positive stools, 36% of Campylobacter positive stools, 74% of Shigella / enteroinvasive Escherichia coli positive stools and 65% of Yersinia positive stools were PCR positive only. Including those where culture was not performed, 19% of Salmonella positive stools, 44% of Campylobacter positive stools, 83% of Shigella positive stools and 79% of Yersinia positive stools had no cultured isolate available for further characterisation. The detection and tracking of foodborne and non-foodborne gastrointestinal outbreaks will become more difficult as culture independent diagnostic testing becomes more widespread. Until new techniques for characterisation of pathogens directly from clinical specimens have been developed, we recommend laboratories continue to culture specimens concurrently or reflexively with culture independent diagnostic tests. PMID- 29720072 TI - The epidemiology of tuberculosis in the Australia Capital Territory, 2006-2015. AB - Aim: To review the epidemiology of tuberculosis (TB) in the Australian Capital Territory (ACT) over a 10 year period. Methods: A retrospective analysis of the ACT TB notification data from 1 January 2006 to 31 December 2015 was conducted. Results: Over the 10 year study period there were 171 TB notifications in the ACT, with an increasing trend in the number of notifications over time. The median age of cases was 36 years (range 14 to 91 years) and 53.8% of cases were male. Most TB cases (84.2%) were born overseas. Among Australian-born cases the most common risk factor for acquiring TB was close/household contact with a known case of TB (30.8%). The most common risk factor in the overseas-born population was past travel or residence in a high-risk country (86.9%). Of all the TB cases notified, 82.4% successfully completed treatment. Conclusion: There was an increasing trend in the number of TB notifications in the ACT over the study period. The highest rate of TB notifications remained in the overseas-born population; with other studies suggesting this is commonly due to reactivation of latent tuberculosis infection (LTBI). As Australia starts working towards TB elimination, options for the screening and management of LTBI, especially in high risk populations, need to be explored. PMID- 29720073 TI - Australian Meningococcal Surveillance Programme, 1 April to 30 June 2017. AB - The reference laboratories of the Australian Meningococcal Surveillance Programme (AMSP) report data on the number of cases of invasive meningococcal disease (IMD) confirmed by laboratory testing using culture and by non-culture based techniques. Data contained in quar-terly reports are restricted to a description of the number of cases of IMD by jurisdiction and serogroup, where known. A full analysis of laboratory confirmed cases of IMD in each calen-dar year is contained in the AMSP annual reports. PMID- 29720074 TI - Tuberculosis notifications in Australia, 2014. AB - In 2014, the National Notifiable Diseases Surveillance System received 1,339 tuberculosis (TB) notifications, representing a rate of 5.7 per 100,000 population. Australia has achieved and maintained good tuberculosis (TB) control since the mid-1980s, sustaining a low annual TB incidence rate of approximately 5 to 6 cases per 100,000 population. The number of multi-drug resistant TB (MDR-TB) cases diagnosed in Australia is low by international standards, with approximately 1-2% of notifications per year being classified as MDR-TB. Australia's overseas-born population continued to represent the majority (86%) of TB notifications and Australia's Aboriginal and Torres Strait Islander population continue to record TB rates around 6 times higher than the Australian born non Indigenous population. Whilst Australia has achieved excellent and sustained control of TB in Australia, sustained effort is still required to reduce rates further and contribute to the achievement of the World Health Organization's goal to end the global TB epidemic by 2035. PMID- 29720075 TI - Surveillance of adverse events following immunisation in Australia, 2015. AB - This report summarises Australian passive surveillance data for adverse events following immunisation (AEFI) for 2015 reported to the Therapeutic Goods Administration and compares them to long-term trends. There were 2,924 AEFI records for vaccines administered in 2015; an annual AEFI reporting rate of 12.3 per 100,000 population. There was a decline of 7% in the overall AEFI reporting rate in 2015 compared with 2014. This decline in reported adverse events in 2015 compared to the previous year was mainly attributable to fewer reports following the HPV vaccine and replacement of monovalent vaccines (Hib, MenCCV and varicella) with combination vaccines such as Hib-MenC, and MMRV. AEFI reporting rates for most individual vaccines were lower in 2015 compared with 2014. The most commonly reported reactions were injection site reaction (26%), pyrexia (17%), rash (16%), vomiting (8%) and headache (7%). The majority of AEFI reports (85%) were described as non-serious events. There were two deaths reported, but no clear causal relationship with vaccination was found. PMID- 29720076 TI - Paediatric Active Enhanced Disease Surveillance (PAEDS) annual report 2015: Prospective hospital-based surveillance for serious paediatric conditions. AB - Introduction: The Paediatric Active Enhanced Disease Surveillance (PAEDS) network is a hospital-based active surveillance system employing prospective case ascertainment for selected serious childhood conditions, particularly vaccine preventable diseases and potential adverse events following immunisation (AEFI). PAEDS data is used to better understand these conditions, inform policy and practice under the National Immunisation Program, and enable rapid public health responses for certain conditions of public health importance. PAEDS enhances data available from other Australian surveillance systems by providing prospective, detailed clinical and laboratory information on children with selected conditions. This is the second of the planned annual PAEDS reporting series, and presents surveillance data for 2015. Methods: Specialist surveillance nurses screened hospital admissions, emergency department records, laboratory and other data, on a daily basis in 5 paediatric tertiary referral hospitals in New South Wales, Victoria, South Australia, Western Australia and Queensland to identify children with the selected conditions. Standardised protocols and case definitions were used across all sites. Conditions under surveillance in 2015 included acute flaccid paralysis (a syndrome associated with poliovirus infection), acute childhood encephalitis (ACE), influenza, intussusception (IS; a potential AEFI with rotavirus vaccines), pertussis and varicella-zoster virus infection (varicella and herpes zoster). Most protocols restrict eligibility to hospitalisations, ED only presentations are also included for some conditions. Methods: : In 2015, there were 674 cases identified across all conditions under surveillance. Key outcomes of PAEDS included: contribution to national AFP surveillance to reach WHO reporting targets; identification of signals for Mycoplasma pneumoniae and parechovirus-related outbreaks (ACE surveillance); and demonstration of high influenza activity with vaccine effectiveness (VE) analysis supportive of vaccination. Surveillance for IS remains ongoing with any identified AEFIs reported to the relevant State Health Department; varicella and herpes zoster case numbers decreased slightly from previous years in older children not eligible for catch-up. Pertussis case numbers increased in early 2015 and analysis of cases in children aged <1 year demonstrated the importance of timely childhood and maternal immunisation. Conclusions: PAEDS continues to provide unique policy-relevant data on serious paediatric conditions using hospital-based sentinel surveillance. PMID- 29720077 TI - Australian Paediatric Surveillance Unit Annual Report, 2016. AB - This report summarises the cases reported to the Australian Paediatric Surveillance Unit (APSU) of rare infectious diseases or rare complications of more common infectious diseases in children. During the calendar year 2016, there were approximately 1500 paediatricians reporting to the APSU and the monthly report card return rate was 90%. APSU continued to provide unique national data on the perinatal exposure to HIV, congenital rubella, congenital cytomegalovirus, neonatal and infant herpes simplex virus, and congenital and neonatal varicella. APSU contributed 10 unique cases of Acute Flaccid Paralysis (a surrogate for polio) - these data are combined with cases ascertained through other surveillance systems including the Paediatric Active Disease Surveillance (PAEDS) to meet the World Health Organisation surveillance target. There was a decline in the number of cases of juvenile onset Recurrent Respiratory Papillomatosis which is likely to be associated with the introduction of the National HPV Vaccination Program. The number of cases of severe complications of influenza was significantly less in 2016 (N=32) than in 2015 (N=84) and for the first time in the last nine years no deaths due to severe influenza were reported to the APSU. In June 2016 surveillance for microcephaly commenced to assist with the detection of potential cases of congenital Zika virus infection and during that time there were 21 confirmed cases - none had a relevant history to suspect congenital Zika virus infection, however, these cases are being followed up to determine the cause of microcephaly. PMID- 29720078 TI - Genetic effects of fatty acid composition in muscle of Atlantic salmon. AB - BACKGROUND: The replacement of fish oil (FO) and fishmeal with plant ingredients in the diet of farmed Atlantic salmon has resulted in reduced levels of the health-promoting long-chain polyunsaturated omega-3 fatty acids (n-3 LC-PUFA) eicosapentaenoic (EPA; 20:5n-3) and docosahexaenoic acid (DHA; 22:6n-3) in their filets. Previous studies showed the potential of selective breeding to increase n 3 LC-PUFA levels in salmon tissues, but knowledge on the genetic parameters for individual muscle fatty acids (FA) and their relationships with other traits is still lacking. Thus, we estimated genetic parameters for muscle content of individual FA, and their relationships with lipid deposition traits, muscle pigmentation, sea lice and pancreas disease in slaughter-sized Atlantic salmon. Our aim was to evaluate the selection potential for increased n-3 LC-PUFA content and provide insight into FA metabolism in Atlantic salmon muscle. RESULTS: Among the n-3 PUFA, proportional contents of alpha-linolenic acid (ALA; 18:3n-3) and DHA had the highest heritability (0.26) and EPA the lowest (0.09). Genetic correlations of EPA and DHA proportions with muscle fat differed considerably, 0.60 and 0.01, respectively. The genetic correlation of DHA proportion with visceral fat was positive and high (0.61), whereas that of EPA proportion with lice density was negative. FA that are in close proximity along the bioconversion pathway showed positive correlations with each other, whereas the start (ALA) and end-point (DHA) of the pathway were negatively correlated (- 0.28), indicating active bioconversion of ALA to DHA in the muscle of fish fed high FO-diet. CONCLUSIONS: Since contents of individual FA in salmon muscle show additive genetic variation, changing FA composition by selective breeding is possible. Taken together, our results show that the heritabilities of individual n-3 LC PUFA and their genetic correlations with other traits vary, which indicates that they play different roles in muscle lipid metabolism, and that proportional muscle contents of EPA and DHA are linked to body fat deposition. Thus, different selection strategies can be applied in order to increase the content of healthy omega-3 FAin the salmon muscle. We recommend selection for the proportion of EPA + DHA in the muscle because they are both essential FA and because such selection has no clear detrimental effects on other traits. PMID- 29720079 TI - Phylogeography of Aegean green toads (Bufo viridis subgroup): continental hybrid swarm vs. insular diversification with discovery of a new island endemic. AB - BACKGROUND: Debated aspects in speciation research concern the amount of gene flow between incipient species under secondary contact and the modes by which post-zygotic isolation accumulates. Secondary contact zones of allopatric lineages, involving varying levels of divergence, provide natural settings for comparative studies, for which the Aegean (Eastern Mediterranean) geography offers unique scenarios. In Palearctic green toads (Bufo viridis subgroup or Bufotes), Plio-Pleistocene (~ 2.6 Mya) diverged species show a sharp transition without contemporary gene flow, while younger lineages, diverged in the Lower Pleistocene (~ 1.9 Mya), admix over tens of kilometers. Here, we conducted a fine scale multilocus phylogeographic analysis of continental and insular green toads from the Aegean, where a third pair of taxa, involving Mid-Pleistocene diverged (~ 1.5 Mya) mitochondrial lineages, earlier tentatively named viridis and variabilis, (co-)occurs. RESULTS: We discovered a new lineage, endemic to Naxos (Central Cyclades), while coastal islands and Crete feature weak genetic differentiation from the continent. In continental Greece, both lineages, viridis and variabilis, form a hybrid swarm, involving massive mitochondrial and nuclear admixture over hundreds of kilometers, without obvious selection against hybrids. CONCLUSIONS: The genetic signatures of insular Aegean toads appear governed by bathymetry and Quaternary sea level changes, resulting in long-term isolation (Central Cyclades: Naxos) and recent land-bridges (coastal islands). Conversely, Crete has been isolated since the end of the Messinian salinity crisis (5.3 My) and Cretan populations thus likely result from human-mediated colonization, at least since Antiquity, from Peloponnese and Anatolia. Comparisons of green toad hybrid zones support the idea that post-zygotic hybrid incompatibilities accumulate gradually over the genome. In this radiation, only one million years of divergence separate a scenario of complete reproductive isolation, from a secondary contact resulting in near panmixia. PMID- 29720080 TI - Genome-wide scan reveals population stratification and footprints of recent selection in Nelore cattle. AB - BACKGROUND: This study aimed at (1) assessing the genomic stratification of experimental lines of Nelore cattle that have experienced different selection regimes for growth traits, and (2) identifying genomic regions that have undergone recent selection. We used a sample of 763 animals genotyped with the Illumina BovineHD BeadChip, among which 674 animals originated from two lines that are maintained under directional selection for increased yearling body weight and 89 animals from a control line that is maintained under stabilizing selection. RESULTS: Multidimensional analysis of the genomic dissimilarity matrix and admixture analysis revealed a substantial level of population stratification between the directional selection lines and the stabilizing selection control line. Two of the three tests used to detect selection signatures (FST, XP-EHH and iHS) revealed six candidate regions with indications of selection, which strongly indicates truly positive signals. The set of identified candidate genes included several genes with roles that are functionally related to growth metabolism, such as COL14A1, CPT1C, CRH, TBC1D1, and XKR4. CONCLUSIONS: The current study identified genetic stratification that resulted from almost four decades of divergent selection in an experimental Nelore population, and highlighted autosomal genomic regions that present patterns of recent selection. Our findings provide a basis for a better understanding of the metabolic mechanism that underlies the growth traits, which are modified by selection for yearling body weight. PMID- 29720081 TI - SSAW: A new sequence similarity analysis method based on the stationary discrete wavelet transform. AB - BACKGROUND: Alignment-free sequence similarity analysis methods often lead to significant savings in computational time over alignment-based counterparts. RESULTS: A new alignment-free sequence similarity analysis method, called SSAW is proposed. SSAW stands for Sequence Similarity Analysis using the Stationary Discrete Wavelet Transform (SDWT). It extracts k-mers from a sequence, then maps each k-mer to a complex number field. Then, the series of complex numbers formed are transformed into feature vectors using the stationary discrete wavelet transform. After these steps, the original sequence is turned into a feature vector with numeric values, which can then be used for clustering and/or classification. CONCLUSIONS: Using two different types of applications, namely, clustering and classification, we compared SSAW against the the-state-of-the-art alignment free sequence analysis methods. SSAW demonstrates competitive or superior performance in terms of standard indicators, such as accuracy, F-score, precision, and recall. The running time was significantly better in most cases. These make SSAW a suitable method for sequence analysis, especially, given the rapidly increasing volumes of sequence data required by most modern applications. PMID- 29720082 TI - Genomic prediction of avian influenza infection outcome in layer chickens. AB - Avian influenza (AI) is a devastating poultry disease that currently can be controlled only by liquidation of affected flocks. In spite of typically very high mortality rates, a group of survivors was identified and genotyped on a 600K single nucleotide polymorphism (SNP) chip to identify genetic differences between survivors, and age- and genetics-matched controls from unaffected flocks. In a previous analysis of this dataset, a heritable component was identified and several regions that are associated with outcome of the infection were localized but none with a large effect. For complex traits that are determined by many genes, genomic prediction models using all SNPs across the genome simultaneously are expected to optimally exploit genomic information. In this study, we evaluated the diagnostic value of genomic estimated breeding values for predicting AI infection outcome within and across two highly pathogenic avian influenza viral strains and two genetic lines of layer chickens using receiver operating curves. We show that genomic prediction based on the 600K SNP chip has the potential to predict disease outcome especially within the same strain of virus (area under receiver operating curve above 0.7), but did not predict well across genetic varieties (area under receiver operating curve of 0.43). PMID- 29720083 TI - General practitioners' attitudes towards patients with poorly controlled type 2 diabetes: a qualitative study. AB - BACKGROUND: Patients with type 2 diabetes mellitus (T2DM) with poor glycaemic control can represent a challenge from the perspective of the general practitioner (GP). Apart from patient-sided factors, the understanding of GPs' attitudes may provide ideas for improved management in these patients. The aim of this study is to reveal attitudes of GPs towards T2DM patients with poor metabolic control. METHODS: Qualitative research in German general practice; 20 GPs, randomly chosen from participants of a larger study; in-depth narrative interviews, audio-recorded and transcribed; inductive coding and categorisation in a multi-professional team; abstraction of major themes in terms of attitudinal responses. RESULTS: 1) Orientation on laboratory parameters: GPs see it as their medical responsibility to achieve targets, which instil a sense of security. 2) Resignation: GPs believe their efforts are in vain and see their role as being undermined. 3) Devaluation of the patient: GPs blame the "non-compliance" of the patients and experience care as a series of conflicts. 4) Fixed role structure: The expert GP on the one hand, the ignorant patient on the other. 5) Solidarity with the patient: GPs appreciate a doctor-patient relationship in terms of partnership. CONCLUSIONS: The conflict GPs experience between their sense of duty and feelings of futility may lead to perceptions such as personal defeat and insecurity. GPs (and patients) may benefit from adjusting the patient-doctor relationship with regard to shared definitions of realistic and authentic goals. PMID- 29720084 TI - Implementation of the SMART MOVE intervention in primary care: a qualitative study using normalisation process theory. AB - BACKGROUND: Problematic translational gaps continue to exist between demonstrating the positive impact of healthcare interventions in research settings and their implementation into routine daily practice. The aim of this qualitative evaluation of the SMART MOVE trial was to conduct a theoretically informed analysis, using normalisation process theory, of the potential barriers and levers to the implementation of a mhealth intervention to promote physical activity in primary care. METHODS: The study took place in the West of Ireland with recruitment in the community from the Clare Primary Care Network. SMART MOVE trial participants and the staff from four primary care centres were invited to take part and all agreed to do so. A qualitative methodology with a combination of focus groups (general practitioners, practice nurses and non-clinical staff from four separate primary care centres, n = 14) and individual semi-structured interviews (intervention and control SMART MOVE trial participants, n = 4) with purposeful sampling utilising the principles of Framework Analysis was utilised. The Normalisation Process Theory was used to develop the topic guide for the interviews and also informed the data analysis process. RESULTS: Four themes emerged from the analysis: personal and professional exercise strategies; roles and responsibilities to support active engagement; utilisation challenges; and evaluation, adoption and adherence. It was evident that introducing a new healthcare intervention demands a comprehensive evaluation of the intervention itself and also the environment in which it is to operate. Despite certain obstacles, the opportunity exists for the successful implementation of a novel healthcare intervention that addresses a hitherto unresolved healthcare need, provided that the intervention has strong usability attributes for both disseminators and target users and coheres strongly with the core objectives and culture of the health care environment in which it is to operate. CONCLUSION: We carried out a theoretical analysis of stakeholder informed barriers and levers to the implementation of a novel exercise promotion tool in the Irish primary care setting. We believe that this process amplifies the implementation potential of such an intervention in primary care. The SMART MOVE trial is registered at Current Controlled Trials (ISRCTN99944116; Date of registration: 1st August 2012). PMID- 29720085 TI - Regional myocardial motion in patients with mild cognitive impairment: a pilot study. AB - BACKGROUND: Cardiovascular disease (CVD) is a risk factor for cognitive impairment in the elderly. Manifestations of subclinical CVDs can be found in patients with cognitive impairment. The aim of the present study was to test the hypothesis that patients with mild cognitive impairment (MCI) have different magnetic resonance imaging (MRI)-derived regional myocardial motion indices compared with healthy controls. METHODS: Eleven MCI patients (age, 65.5 years +/ 5.9; range, 55-81 years old) and 11 sex-/age-matched healthy volunteers were enrolled. All of the participants underwent a head MRI and cardiac MRI. Global cortical atrophy (GCA) was graded on the head MRI. The left ventricular ejection fraction (LVEF) and regional strain, strain rate, displacement and velocity were measured on cine images. The GCA scores, global cardiac function and regional myocardial motion indices were compared between MCI patients and healthy controls using the t-test. RESULTS: MCI patients had a higher GCA score than healthy controls (p = 0.048). However, there was no significant difference in LVEF between MCI patients and controls. Compared to healthy controls, MCI patients had a lower peak radial strain (29.1% +/- 24.1% vs. 46.4% +/- 43.4%, p < 0.001), lower peak diastolic radial strain rate (3.2 +/- 2.4 s- 1 vs. 6.0 +/- 3.0 s- 1, p < 0.001), lower peak diastolic circumferential strain rate (2.5 +/- 2.1 s- 1 vs. 3.2 +/- 2.1 s- 1, p = 0.002), lower peak systolic radial displacement (4.2 +/- 2.2 mm vs. 5.2 +/- 3.3 mm, p = 0.002), lower peak diastolic radial velocity (31 +/- 18 mm/s vs. 45 +/- 33 mm/s, p < 0.001), and lower peak diastolic circumferential velocity (178 +/- 124 degree/s vs. 217 +/- 131 degree/s, p = 0.005). CONCLUSION: MRI-derived regional myocardial strain, strain rate and velocity were found to be different between MCI patients and healthy controls. Regional myocardial motion indices have the potential to become novel quantitative imaging biomarkers for representing the risk of neurodegenerative disorders, such as Alzheimer's disease (AD). PMID- 29720086 TI - CLICK: one-step generation of conditional knockout mice. AB - BACKGROUND: CRISPR/Cas9 enables the targeting of genes in zygotes; however, efficient approaches to create loxP-flanked (floxed) alleles remain elusive. RESULTS: Here, we show that the electroporation of Cas9, two gRNAs, and long single-stranded DNA (lssDNA) into zygotes, termed CLICK (CRISPR with lssDNA inducing conditional knockout alleles), enables the quick generation of floxed alleles in mice and rats. CONCLUSIONS: The high efficiency of CLICK provides homozygous knock-ins in oocytes carrying tissue-specific Cre, which allows the one-step generation of conditional knockouts in founder (F0) mice. PMID- 29720088 TI - Three-dimensional thoracic aorta principal strain analysis from routine ECG-gated computerized tomography: feasibility in patients undergoing transcatheter aortic valve replacement. AB - BACKGROUND: Functional impairment of the aorta is a recognized complication of aortic and aortic valve disease. Aortic strain measurement provides effective quantification of mechanical aortic function, and 3-dimenional (3D) approaches may be desirable for serial evaluation. Computerized tomographic angiography (CTA) is routinely performed for various clinical indications, and offers the unique potential to study 3D aortic deformation. We sought to investigate the feasibility of performing 3D aortic strain analysis in a candidate population of patients undergoing transcatheter aortic valve replacement (TAVR). METHODS: Twenty-one patients with severe aortic valve stenosis (AS) referred for TAVR underwent ECG-gated CTA and echocardiography. CTA images were analyzed using a 3D feature-tracking based technique to construct a dynamic aortic mesh model to perform peak principal strain amplitude (PPSA) analysis. Segmental strain values were correlated against clinical, hemodynamic and echocardiographic variables. Reproducibility analysis was performed. RESULTS: The mean patient age was 81+/-6 years. Mean left ventricular ejection fraction was 52+/-14%, aortic valve area (AVA) 0.6+/-0.3 cm2 and mean AS pressure gradient (MG) 44+/-11 mmHg. CTA-based 3D PPSA analysis was feasible in all subjects. Mean PPSA values for the global thoracic aorta, ascending aorta, aortic arch and descending aorta segments were 6.5+/-3.0, 10.2+/-6.0, 6.1+/-2.9 and 3.3+/-1.7%, respectively. 3D PSSA values demonstrated significantly more impairment with measures of worsening AS severity, including AVA and MG for the global thoracic aorta and ascending segment (p<0.001 for all). 3D PSSA was independently associated with AVA by multivariable modelling. Coefficients of variation for intra- and inter-observer variability were 5.8 and 7.2%, respectively. CONCLUSIONS: Three-dimensional aortic PPSA analysis is clinically feasible from routine ECG-gated CTA. Appropriate reductions in PSSA were identified with increasing AS hemodynamic severity. Expanded study of 3D aortic PSSA for patients with various forms of aortic disease is warranted. PMID- 29720087 TI - The dehydration stress of couch grass is associated with its lipid metabolism, the induction of transporters and the re-programming of development coordinated by ABA. AB - BACKGROUND: The wild relatives of crop species represent a potentially valuable source of novel genetic variation, particularly in the context of improving the crop's level of tolerance to abiotic stress. The mechanistic basis of these tolerances remains largely unexplored. Here, the focus was to characterize the transcriptomic response of the nodes (meristematic tissue) of couch grass (a relative of barley) to dehydration stress, and to compare it to that of the barley crown formed by both a drought tolerant and a drought sensitive barley cultivar. RESULTS: Many of the genes up-regulated in the nodes by the stress were homologs of genes known to be mediated by abscisic acid during the response to drought, or were linked to either development or lipid metabolism. Transporters also featured prominently, as did genes acting on root architecture. The resilience of the couch grass node arise from both their capacity to develop an altered, more effective root architecture, but also from their formation of a lipid barrier on their outer surface and their ability to modify both their lipid metabolism and transporter activity when challenged by dehydration stress. CONCLUSIONS: Our analysis revealed the nature of dehydration stress response in couch grass. We suggested the tolerance is associated with lipid metabolism, the induction of transporters and the re-programming of development coordinated by ABA. We also proved the applicability of barley microarray for couch grass stress response analysis. PMID- 29720089 TI - Susceptibility patterns and the role of extracellular DNA in Staphylococcus epidermidis biofilm resistance to physico-chemical stress exposure. AB - BACKGROUND: Over 65% of human infections are ascribed to bacterial biofilms that are often highly resistant to antibiotics and host immunity. Staphylococcus epidermidis is the predominant cause of recurrent nosocomial and biofilm-related infections. However, the susceptibility patterns of S. epidermidis biofilms to physico-chemical stress induced by commonly recommended disinfectants [(heat, sodium chloride (NaCl), sodium hypochlorite (NaOCl) and hydrogen peroxide (H2O2)] in domestic and human healthcare settings remains largely unknown. Further, the molecular mechanisms of bacterial biofilms resistance to the physico-chemical stresses remain unclear. Growing evidence demonstrates that extracellular DNA (eDNA) protects bacterial biofilms against antibiotics. However, the role of eDNA as a potential mechanism underlying S. epidermidis biofilms resistance to physico chemical stress exposure is yet to be understood. Therefore, this study aimed to evaluate the susceptibility patterns of and eDNA release by S. epidermidis biofilm and planktonic cells to physico-chemical stress exposure. RESULTS: S. epidermidis biofilms exposed to physico-chemical stress conditions commonly recommended for disinfection [heat (60 degrees C), 1.72 M NaCl, solution containing 150 MUL of waterguard (0.178 M NaOCl) in 1 L of water or 1.77 M H2O2] for 30 and 60 min exhibited lower log reductions of CFU/mL than the corresponding planktonic cells (p < 0.0001). The eDNA released by sub-lethal heat (50 degrees C)-treated S. epidermidis biofilm and planktonic cells was not statistically different (p = 0.8501). However, 50 degrees C-treated S. epidermidis biofilm cells released significantly increased eDNA than the untreated controls (p = 0.0098). The eDNA released by 0.8 M NaCl-treated S. epidermidis biofilm and planktonic cells was not significantly different (p = 0.9697). Conversely, 5 mM NaOCl-treated S. epidermidis biofilms exhibited significantly increased eDNA release than the corresponding planktonic cells (p = 0.0015). Further, the 50 MUM H2O2-treated S. epidermidis biofilms released significantly more eDNA than the corresponding planktonic cells (p = 0.021). CONCLUSIONS: S. epidermidis biofilms were less susceptible to physico-chemical stress induced by the four commonly recommended disinfectants than the analogous planktonic cells. Further, S. epidermidis biofilms enhanced eDNA release in response to the sub-lethal heat and oxidative stress exposure than the corresponding planktonic cells suggesting a role of eDNA in biofilms resistance to the physico-chemical stresses. PMID- 29720090 TI - Sulphite oxidase (SO) - a mitochondrial autoantigen as target for humoral and cellular immune reactions in primary sclerosing cholangitis. AB - BACKGROUND: In a recent study we had evidence that sulphite oxidase (SO) may be a relevant autoantigen in primary sclerosing cholangitis (PSC). Aim of the present study was, therefore, to analyse humoral and cellular immune-reactivity towards SO in these patients in more detail. METHODS: Sera from 53 patients with PSC (30 untreated and 23 treated with ursodeoxycholic acid [UDCA] at time of analysis), from 422 patients with different hepatic and non-hepatic disorders, and from 50 healthy individuals were tested by ELISA for antibodies against full-length-SO (SO-fl) and its three major domains expressed in E.coli (SO-I, SO-II, SO-III). For epitope-mapping, 29 overlapping peptides were used. Peripheral blood mononuclear cells (PBMC) were obtained from 33 PSC-patients and analysed for SO induced proliferation, production of cytokines, and expression of the activation marker cluster of differentiation (CD) 69. RESULTS: 43% of the 30 untreated and 26% of the 23 treated PSC-patients had IgG anti-SO-antibodies predominantly reacting with SO-fl, SO-I and SO-II. Antibody-reactivity decreased after UDCA treatment. Prevalence and reactivity of anti-SO-antibodies were significantly higher in PSC than in patients with other hepatic and non-hepatic disorders. Epitope mapping revealed no distinct immuno-dominant regions within SO. Incubation of PBMC from PSC-patients (but not from controls) with SO-antigens revealed an activation of B-cells and a T-helper cell type-2 reaction pattern (production of interleukin [IL]-13, IL-10). CONCLUSIONS: PSC-patients show humoral and cellular immune response towards SO. Antibodies may be predominantly directed against conformational epitopes. SO enhances in vitro especially T helper cell type-2 immune-reactions, which may be pro-fibrotic. SO is a detoxifying enzyme present also in bacteria; further studies analysing its role in the aetiology and pathogenesis in PSC may, therefore, be important. PMID- 29720091 TI - Mobility concepts and access to health care in a rural district in Germany: a mixed methods approach. AB - BACKGROUND: Western countries are facing the challenges of an imminent shortage of physicians, especially general practitioners. As a consequence longer travel times to doctors' practices may arise. This study aimed to investigate the mobility behavior of a rural population in terms of medical consultations. METHODS: An exploratory mixed-methods design was conducted in the Waldshut district of the federal state Baden-Wurttemberg in Germany. Focus groups and a single telephone-interview with representatives, occupationally affiliated with mobility in the district (e.g. representatives of public transport, nursing services or the District Office Waldshut), were performed in 2016 and analyzed using Mayring's structuring content analysis. A questionnaire based on the collected qualitative data was subsequently distributed to a random sample of 1000 adult inhabitants living in the Waldshut district. Quantitative data were analyzed employing descriptive statistics. RESULTS: Qualitatively, four focus groups and one single telephone-interview with a total of 20 participants were performed. Therein the necessity of reaching a nearby general practitioner and the importance of individual motor traffic was emphasized. Novel mobility modes of ride sharing and telemedicine were controversially discussed as future transport and consultation options, respectively. Quantitatively, 277 questionnaires (27.7%) were valid and included in our analysis. Mean age was 51 years (SD = 18.5) and 58% (n = 160) were female. Irrespective of the mode of transport 60% (n = 166) expected to reach their general practitioner within 15 min. Using the possibility of multiple answers 47% (n = 192) stated to use a car in order to reach their general practitioner, public transport was used by 5% (n = 19). Nearly 80% (n = 220) could imagine sharing a car with well-known persons for consultations. Turning to a general practitioner via telemedicine was imaginable for 32% (n = 91). CONCLUSIONS: Individual motor car traffic seems to be an important factor in providing accessibility to rural medical care. As a supplementation, web based ride sharing has economic and structural potential for reaching a doctor's practice. However, familiarity and trustworthiness need to be guaranteed within this flexible transport mode. Furthermore, telemedicine may be a future approach in order to reduce travel time to a doctor's practice. PMID- 29720092 TI - Post percutaneous coronary interventional adverse cardiovascular outcomes and bleeding events observed with prasugrel versus clopidogrel: direct comparison through a meta-analysis. AB - BACKGROUND: Due to limitations associated with clopidogrel following percutaneous coronary intervention (PCI), other newer oral anti-platelet agents are being studied. We aimed to systematically carry out a direct comparison of outcomes observed with prasugrel versus clopidogrel following PCI. METHODS: Common online searched databases (The Cochrane library, EMBASE, MEDLINE and Google scholar) were used to retrieve relevant publications. Primary endpoints were the adverse cardiovascular outcomes. Secondary outcomes were the bleeding events. This analysis was carried out by RevMan 5.3, whereby odds ratios (OR) and 95% confidence intervals (CI) were considered as the statistical parameters. RESULTS: Eight studies with a total number of 18,122 participants were included in this direct analysis. Prasugrel was associated with significantly lower adverse cardiovascular outcomes in comparison to clopidogrel following PCI. All-cause mortality, myocardial infarction, stroke, stent thrombosis and major adverse cardiac events were all significantly lower with prasugrel (OR: 0.47, 95% CI: 0.35-0.63; P = 0.0001), (OR: 0.68, 95% CI: 0.57-0.80; P = 0.00001), (OR: 0.60, 95% CI: 0.38-0.96; P = 0.03), (OR: 0.46, 95% CI: 0.30-0.72; P = 0.0006) and (OR: 0.61, 95% CI: 0.53-0.70; P = 0.00001) respectively. When the bleeding outcomes were analyzed, Thrombolysis in Myocardial Infarction (TIMI) defined major and minor bleeding were not significantly different (OR: 0.91, 95% CI: 0.66-1.27; P = 0.59) and (OR: 1.16, 95% CI: 0.85-1.59; P = 0.35) respectively. However, the combined 'all bleeding events' was significantly higher with prasugrel (OR: 1.32, 95% CI: 1.03-1.70; P = 0.03), but when patients with STEMI and those undergoing elective PCI were separately analyzed, no significant difference in overall bleeding was observed. CONCLUSION: Adverse cardiovascular outcomes were significantly lower with the use of prasugrel in comparison to clopidogrel following PCI. In addition, TIMI defined major and minor bleeding were not significantly different showing prasugrel to be well-tolerated following PCI especially in patients with acute coronary syndrome. PMID- 29720093 TI - How general practitioners understand and handle medically unexplained symptoms: a focus group study. AB - BACKGROUND: Medically unexplained symptoms (MUS) are a common yet challenging encounter in primary care. The aim of this study was to explore how general practitioners (GPs) understand and handle MUS. METHODS: Three focus group interviews were conducted with a total of 23 GPs. Participants with varied clinical experience were purposively recruited. The data were analysed thematically, using the concept of framing as an analytical lens. RESULTS: The GPs alternated between a biomedical frame, centred on disease, and a biopsychosocial frame, centred on the sick person. Each frame shaped the GPs' understanding and handling of MUS. The biomedical frame emphasised the lack of objective evidence, problematized subjective patient testimony, and manifested feelings of uncertainty, doubt and powerlessness. This in turn complicated patient handling. In contrast, the biopsychosocial frame emphasised clinical experience, turned patient testimony into a valuable source of information, and manifested feelings of confidence and competence. This in turn made them feel empowered. The GPs with the least experience relied more on the biomedical frame, whereas their more seasoned seniors relied mostly on the biopsychosocial frame. CONCLUSION: The biopsychosocial frame helps GPs to understand and handle MUS better than the biomedical frame does. Medical students should spend more time learning biopsychosocial medicine, and to integrate the clinical knowledge of their peers with their own. PMID- 29720094 TI - Association of APEX1 and OGG1 gene polymorphisms with breast cancer risk among Han women in the Gansu Province of China. AB - BACKGROUND: Genetic variations in key DNA repair genes may influence DNA repair capacity, DNA damage and breast carcinogenesis. The current study aimed to estimate the association of APEX1 and OGG1 polymorphisms with the risk of breast cancer development. METHODS: A total of 518 patients with histopathologically confirmed breast cancer and 921 region- and age-matched cancer-free controls were genotyped for the APEX1 polymorphisms rs3136817 and rs1130409 and the OGG1 polymorphisms rs1052133 and rs2072668 using a QuantStudioTM 12 K Flex Real-Time PCR System. RESULTS: The rs3136817 heterozygous TC genotype along with the rs3136817 dominant model (TC + CC) was strongly associated with breast cancer susceptibility (odds ratio [OR] = 0.670, 95% confidence interval [95% CI]: 0.513 0.873, P = 0.003; OR = 0.682, 95% CI: 0.526 - 0.883, P = 0.004, respectively). No significant associations were observed among rs1130409, rs1052133, rs2072668 and breast cancer risk. Furthermore, an allele combination analysis revealed that APEX1 haplotypes containing C-T (alleles rs3136817 and rs1130409) conferred a significantly lower risk (corrected P < 0.001). CONCLUSION: This research is the latest report showing that an APEX1 rs3136817 heterozygous genotype may have a positive influence on DNA repair capacity in patients with breast cancer and thus may have a potential protective effect for Chinese Han women. PMID- 29720095 TI - Addressing knowledge gaps and prevention for tuberculosis-infected Indian adults: a vital part of elimination. AB - BACKGROUND: India plans to eliminate tuberculosis (TB) by 2025, and has identified screening and prevention as key activities. Household contacts (HHCs) of index TB cases are a high-risk population that would benefit from rapid implementation of these strategies. However, best practices for TB prevention and knowledge gaps among HHCs have not been studied. We evaluated TB knowledge and understanding of prevention among tuberculin skin-test (TST) positive HHCs. While extensive information is available in other high-burden settings regarding TB knowledge gaps, identifying how Indian adult contacts view their transmission risk and prevention options may inform novel screening algorithms and education efforts that will be part of the new elimination plan. METHODS: We approached adult HHC to administer a questionnaire on TB knowledge and understanding of infection. Over 1 year, 100 HHC were enrolled at a tertiary hospital in Pune, India. RESULTS: The study population was 61% (n = 61) female, with a mean age of 36.6 years (range 18-67, SD = 12). Education levels were high, with 78 (78%) having at least a high school education, and 23 (24%) had at least some college education. Four (4%) of our participants were HIV-infected. General TB knowledge among HHC was low, with a majority of participants believing that you can get TB from sharing dishes (70%) or touching something that has been coughed on (52%). Understanding of infection was also low, with 42% believing that being skin-test positive means you have disease. To assess readiness for preventive therapy, we asked participants whether they are at a higher risk of progressing to active disease because of their LTBI status. Fifty-four (55%) felt that they are at higher risk. Only 8% had heard of preventive therapy. CONCLUSION: Our TB knowledge survey among HHCs with evidence of recent exposure found that knowledge is poor and families are confused about transmission in the household. It is imperative that the Indian program develop tools and incentives that can be used to educate TB cases and their families on what infected HHCs can do to prevent disease, including preventive therapy. PMID- 29720096 TI - Celiac crisis, a rare and profound presentation of celiac disease: a case report. AB - BACKGROUND: Celiac crisis is a life-threatening manifestation of celiac disease and is rare in adults, with only a handful of cases documented worldwide and mostly in children. CASE PRESENTATION: A profoundly emaciated 43-year-old female presented with profuse diarrhoea, shortness of breath, left leg swelling with ulceration and immobility (Body Mass Index (BMI) = 14.7 kg/m2). The patient had normal anion-gap metabolic acidosis (pH = 7.16) with persisting hypokalemia, hyponatremia, hypomagnesemia and hypophosphatemia. In addition, severe vitamin deficiencies and coagulopathy were present. A computed tomography pulmonary angiogram (CT-PA) revealed bilateral massive pulmonary embolism causing infarction, arising from a left lower limb extensive deep vein thrombosis (DVT). Bone marrow suppression was seen on aspirate. The patient developed severe urosepsis in her immunocompromised state. Prolonged lower limb weakness despite supportive therapy, rehabilitation and strict adherence to a gluten-free diet prompted the magnetic resonance imaging (MRI) confirmed diagnosis of subacute combined degeneration of the spinal cord due to Vitamin-B12 deficiency. CONCLUSIONS: Celiac crisis is a rare and potentially life-threatening presentation of celiac disease, often a diagnosis of exclusion. Subacute combined degeneration of the spinal cord should be considered in patients with chronic Vitamin B12 deficiency presenting with neurological symptoms. PMID- 29720097 TI - "As du Coeur" study: a randomized controlled trial on physical activity maintenance in cardiovascular patients. AB - BACKGROUND: The benefits of supervised physical activity programs in cardiac rehabilitation have been amply demonstrated, but the quantity of physical activity often declines quickly once supervision ends. This trial assesses the effectiveness of an experimental intervention drawing on habit formation theory to maintain physical activity. METHODS: Cardiovascular patients (N = 47) were randomly assigned to one of two groups. The first group participated in two supervised physical activity (SPA) sessions per week for 20 weeks. The second group was offered a progressively autonomous physical activity (PAPA) program as follows: the same supervised program as the SPA group for 10 weeks and then a further 10 weeks with one supervised session replaced by a strategy to build and sustain the habit of autonomous physical activity. The International Physical Activity Questionnaire (IPAQ; Craig et al. Med Sci Sports Exerc 35(8):1381-1395, 2003) was used to measure the quantity of physical activity, which was the primary outcome. The number of participants was limited, and we thus took multiple IPAQ measurements (at 0, 5, 7, 9 and 12 months after the start of the intervention) and used a mixed model for analysis. Physical condition, automaticity of the physical activity behavior, motivation, and quality of life were examined for changes. RESULTS: No significant between-group differences were noted for physical activity behaviors after the program, physical condition, motivation, or behavioral automaticity. The PAPA group nevertheless completed more PA sessions during the intervention, and their quality of life was significantly higher than that of the SPA group at 12 months. CONCLUSION: Although the number of supervised sessions was lower, the progressively autonomous PA program resulted in the same or even higher positive outcomes than the fully supervised PA program. TRIAL REGISTRATION: Current Controlled Trials ISRCTN77313697 , retrospectively registered on 20 November 2015. PMID- 29720098 TI - Tigecycline-induced acute pancreatitis in a renal transplant patient: a case report and literature review. AB - BACKGROUND: The purpose of this case report is to increase the awareness of tigecycline-induced pancreatitis specifically in renal transplant patients predisposed to the condition. CASE PRESENTATION: A 48-year-old woman developed a donor-derived infection after kidney transplantation, resulting in a ruptured graft renal artery, followed by peritoneal drainage, blood and urine culture infections. Due to multiple drug resistance Acinetobacter baumannii cultured from the preservation fluid and blood, she was treated with tigecycline at the 8th post-transplant day combined with other antibiotics. After 15 days of tigecycline treatment, she was observed with recurrent fever and abdominal distension with a rise in pancreatic enzymes. CT scans showed acute pancreatitis with grade D on Balthazar score, no necrosis visible without contrast injection. These facts were sufficient to hint that pancreatitis was slowly becoming prominent. After withdrawal of tigecycline, CT scans showed that exudation around the pancreas were relieved, and blood amylase returned to the normal range in a week. CONCLUSIONS: Clinicians should pay attention to clinical signs and symptoms and the level of serum pancreatic enzymes in order to monitor the development of pancreatitis. If necessary, abdominal CT scans should be performed regularly when given tigecycline. PMID- 29720099 TI - Skill mix change between general practitioners, nurse practitioners, physician assistants and nurses in primary healthcare for older people: a qualitative study. AB - BACKGROUND: More and more older adults desire to and are enabled to grow old in their own home, regardless of their physical and mental capabilities. This change, together with the growing number of older adults, increases the demand for general practitioners (GPs). However, care for older people lacks prestige among medical students and few medical students are interested in a career in care for older people. Innovative solutions are needed to reduce the demand for GPs, to guarantee quality of healthcare and to contain costs. A solution might be found in skill mix change by introducing nurse practitioners (NPs), physician assistants (PAs) or registered nurses (RNs). The aim of this study was to describe how skill mix change is organised in daily practice, what influences it and what the effects are of introducing NPs, PAs or RNs into primary healthcare for older people. METHODS: In total, 34 care providers working in primary healthcare in the Netherlands were interviewed: GPs (n = 9), NPs (n = 10), PAs (n = 5) and RNs (n = 10). Five focus groups and 14 individual interviews were conducted. Analysis consisted of open coding, creating categories and abstraction. RESULTS: In most cases, healthcare for older people was only a small part of the tasks of NPs, PAs and RNs; they did not solely focus on older people. The tasks they performed and their responsibilities in healthcare for older people differed between, as well as within, professions. Although the interviewees debated the usefulness of proactive structural screening on frailty in the older population, when implemented, it was also unclear who should perform the geriatric assessment. Interviewees considered NPs, PAs and RNs an added value, and it was stated that the role of the GP changed with the introduction of NPs, PAs or RNs. CONCLUSIONS: The roles and responsibilities of NPs, PAs and RNs for the care of older people living at home are still not established. Nonetheless, these examples show the potential of these professionals. The establishment of a clear vision on primary healthcare for older people, including the organisation of proactive healthcare, is necessary to optimise the impact of skill mix change. PMID- 29720100 TI - Association of arterial stiffness and central hemodynamics with moderately reduced glomerular filtration rate in Chinese middle-aged and elderly community residents: a cross-sectional analysis. AB - BACKGROUND: Kidney impairment constitutes severe risk for cardiovascular disease, stroke and all-cause mortality, and early identification and prevention of kidney impairment is critical to effective management of prognostic risk in community residents. Previous studies have validated that carotid-femoral pulse wave velocity (cfPWV) is a significant factor associated with chronic kidney disease. However, whether cfPWV is associated with moderately reduced glomerular filtration rate (GFR) remains unclear. This analysis was designed to examine the association of moderately reduced GFR with cfPWV and central pulse pressure (cPP) in Chinese middle-aged and elderly community residents. METHODS: There were 875 community residents enrolled in this analysis, and then cfPWV and cPP were assessed in all participants following the standard procedure. RESULTS: Entire cohort had a median (range) age of 66 (45-88) years, and 65.4% were women. Both cfPWV and cPP differed significantly between participants with and without moderately reduced GFR (P < 0.05 for all). Logistic regression analyses indicated that cfPWV and cPP had the significant association with moderately reduced GFR (P < 0.05 for all). CONCLUSION: This analysis demonstrated the significant association of cfPWV and cPP with moderately reduced GFR in Chinese middle-aged and elderly community residents. PMID- 29720101 TI - A novel mutation in the TG gene (G2322S) causing congenital hypothyroidism in a Sudanese family: a case report. AB - BACKGROUND: Congenital hypothyroidism (CH) has an incidence of approximately 1:3000, but only 15% have mutations in the thyroid hormone synthesis pathways. Genetic analysis allows for the precise diagnosis. CASE PRESENTATION: A 3-week old girl presented with a large goiter, serum TSH > 100 mIU/L (reference range: 0.7-5.9 mIU/L); free T4 < 3.2 pmol/L (reference range: 8.7-16 pmol/L); thyroglobulin (TG) 101 MUg/L. Thyroid Tc-99 m scan showed increased radiotracer uptake. One brother had CH and both affected siblings have been clinically and biochemically euthyroid on levothyroxine replacement. Another sibling had normal thyroid function. Both Sudanese parents reported non-consanguinity. Peripheral blood DNA from the proposita was subjected to whole exome sequencing (WES). WES identified a novel homozygous missense mutation of the TG gene: c.7021G > A, p.Gly2322Ser, which was subsequently confirmed by Sanger sequencing and present in one allele of both parents. DNA samples from 354 alleles in four Sudanese ethnic groups (Nilotes, Darfurians, Nuba, and Halfawien) failed to demonstrate the presence of the mutant allele. Haplotyping showed a 1.71 centiMorgans stretch of homozygosity in the TG locus suggesting that this mutation occurred identical by descent and the possibility of common ancestry of the parents. The mutation is located in the cholinesterase-like (ChEL) domain of TG. CONCLUSIONS: A novel rare missense mutation in the TG gene was identified. The ChEL domain is critical for protein folding and patients with CH due to misfolded TG may present without low serum TG despite the TG gene mutations. PMID- 29720102 TI - Characterization of phenotypic variation and genome aberrations observed among Phytophthora ramorum isolates from diverse hosts. AB - BACKGROUND: Accumulating evidence suggests that genome plasticity allows filamentous plant pathogens to adapt to changing environments. Recently, the generalist plant pathogen Phytophthora ramorum has been documented to undergo irreversible phenotypic alterations accompanied by chromosomal aberrations when infecting trunks of mature oak trees (genus Quercus). In contrast, genomes and phenotypes of the pathogen derived from the foliage of California bay (Umbellularia californica) are usually stable. We define this phenomenon as host induced phenotypic diversification (HIPD). P. ramorum also causes a severe foliar blight in some ornamental plants such as Rhododendron spp. and Viburnum spp., and isolates from these hosts occasionally show phenotypes resembling those from oak trunks that carry chromosomal aberrations. The aim of this study was to investigate variations in phenotypes and genomes of P. ramorum isolates from non oak hosts and substrates to determine whether HIPD changes may be equivalent to those among isolates from oaks. RESULTS: We analyzed genomes of diverse non-oak isolates including those taken from foliage of Rhododendron and other ornamental plants, as well as from natural host species, soil, and water. Isolates recovered from artificially inoculated oak logs were also examined. We identified diverse chromosomal aberrations including copy neutral loss of heterozygosity (cnLOH) and aneuploidy in isolates from non-oak hosts. Most identified aberrations in non-oak hosts were also common among oak isolates; however, trisomy, a frequent type of chromosomal aberration in oak isolates was not observed in isolates from Rhododendron. CONCLUSION: This work cross-examined phenotypic variation and chromosomal aberrations in P. ramorum isolates from oak and non-oak hosts and substrates. The results suggest that HIPD comparable to that occurring in oak hosts occurs in non-oak environments such as in Rhododendron leaves. Rhododendron leaves are more easily available than mature oak stems and thus can potentially serve as a model host for the investigation of HIPD, the newly described plant pathogen interaction. PMID- 29720103 TI - Prediction of plant lncRNA by ensemble machine learning classifiers. AB - BACKGROUND: In plants, long non-protein coding RNAs are believed to have essential roles in development and stress responses. However, relative to advances on discerning biological roles for long non-protein coding RNAs in animal systems, this RNA class in plants is largely understudied. With comparatively few validated plant long non-coding RNAs, research on this potentially critical class of RNA is hindered by a lack of appropriate prediction tools and databases. Supervised learning models trained on data sets of mostly non-validated, non-coding transcripts have been previously used to identify this enigmatic RNA class with applications largely focused on animal systems. Our approach uses a training set comprised only of empirically validated long non protein coding RNAs from plant, animal, and viral sources to predict and rank candidate long non-protein coding gene products for future functional validation. RESULTS: Individual stochastic gradient boosting and random forest classifiers trained on only empirically validated long non-protein coding RNAs were constructed. In order to use the strengths of multiple classifiers, we combined multiple models into a single stacking meta-learner. This ensemble approach benefits from the diversity of several learners to effectively identify putative plant long non-coding RNAs from transcript sequence features. When the predicted genes identified by the ensemble classifier were compared to those listed in GreeNC, an established plant long non-coding RNA database, overlap for predicted genes from Arabidopsis thaliana, Oryza sativa and Eutrema salsugineum ranged from 51 to 83% with the highest agreement in Eutrema salsugineum. Most of the highest ranking predictions from Arabidopsis thaliana were annotated as potential natural antisense genes, pseudogenes, transposable elements, or simply computationally predicted hypothetical protein. Due to the nature of this tool, the model can be updated as new long non-protein coding transcripts are identified and functionally verified. CONCLUSIONS: This ensemble classifier is an accurate tool that can be used to rank long non-protein coding RNA predictions for use in conjunction with gene expression studies. Selection of plant transcripts with a high potential for regulatory roles as long non-protein coding RNAs will advance research in the elucidation of long non-protein coding RNA function. PMID- 29720104 TI - Prenatal diagnosis in a hereditary Peutz-Jeghers syndrome family with high cancer risk. AB - BACKGROUND: Peutz-Jeghers Syndrome (PJS) is a hereditary cancer predisposing syndrome caused by autosomal dominant mutations in the serine/threonine kinase 11 (STK11) gene and is associated with decreased life expectancy. Many families experience a poorer quality of life due to the psychological burden associated with the carrier status of their child. Therefore early genetic testing and confirmation of the diagnosis is important for patients' psychological status, as well as for clinical management, genetic counseling and possible prenatal family planning. METHODS: In this study, peripheral blood genomic DNA samples from a Chinese PJS family with a high cancer risk were examined for STK11 mutations using Sanger sequencing and MLPA analysis. Furthermore, prenatal PJS testing from transabdominal chorionic villi sample was performed in one female member of the family. This family was followed up for three years. RESULTS: In this family, the STK11 exon 1 deletion (c.-1114-?_290 +?del) was predicted to affect the kinase domain of the protein and co-segregated with the disease phenotype. The same mutation was detected in the fetus and genetic sequencing and MLPA of the infant's DNA and the pigmentation on his lips confirmed the result of prenatal testing. To the best of our knowledge, this is the first report on PJS prenatal diagnosis of a PJS family in China. CONCLUSIONS: An accurate and convenient PJS prenatal testing provides an opportunity for affected families to focus on polyp related symptoms and cancer prevention and may be helpful for couples in family planning decision-making. PMID- 29720105 TI - Transcriptome analysis of chrysanthemum (Dendranthema grandiflorum) in response to low temperature stress. AB - BACKGROUND: Chrysanthemum is one kind of ornamental plant well-known and widely used in the world. However, its quality and production were severely affected by low temperature conditions in winter and early spring periods. Therefore, we used the RNA-Seq platform to perform a de novo transcriptome assembly to analyze chrysanthemum (Dendranthema grandiflorum) transcription response to low temperature. RESULTS: Using Illumina sequencing technology, a total of 86,444,237 high-quality clean reads and 93,837 unigenes were generated from four libraries: T01, controls; T02, 4 degrees C cold acclimation (CA) for 24 h; T03, - 4 degrees C freezing treatments for 4 h with prior CA; and T04, - 4 degrees C freezing treatments for 4 h without prior CA. In total, 7583 differentially expressed genes (DEGs) of 36,462 annotated unigenes were identified. We performed GO and KEGG pathway enrichment analyses, and excavated a group of important cold responsive genes related to low temperature sensing and signal transduction, membrane lipid stability, reactive oxygen species (ROS) scavenging and osmoregulation. These genes encode many key proteins in plant biological processes, such as protein kinases, transcription factors, fatty acid desaturase, lipid-transfer proteins, antifreeze proteins, antioxidase and soluble sugars synthetases. We also verified expression levels of 10 DEGs using quantitative real-time polymerase chain reaction (qRT-PCR). In addition, we performed the determination of physiological indicators of chrysanthemum treated at low temperature, and the results were basically consistent with molecular sequencing results. CONCLUSION: In summary, our study presents a genome-wide transcript profile of Dendranthema grandiflorum var. jinba and provides insights into the molecular mechanisms of D. grandiflorum in response to low temperature. These data contributes to our deeper relevant researches on cold tolerance and further exploring new candidate genes for chilling-tolerance and freezing-tolerance chrysanthemum molecular breeding. PMID- 29720106 TI - GC bias lead to increased small amino acids and random coils of proteins in cold water fishes. AB - BACKGROUND: Temperature adaptation of biological molecules is fundamental in evolutionary studies but remains unsolved. Fishes living in cold water are adapted to low temperatures through adaptive modification of their biological molecules, which enables their functioning in extreme cold. To study nucleotide and amino acid preference in cold-water fishes, we investigated the substitution asymmetry of codons and amino acids in protein-coding DNA sequences between cold water fishes and tropical fishes., The former includes two Antarctic fishes, Dissostichus mawsoni (Antarctic toothfish), Gymnodraco acuticeps (Antarctic dragonfish), and two temperate fishes, Gadus morhua (Atlantic cod) and Gasterosteus aculeatus (stickleback), and the latter includes three tropical fishes, including Danio rerio (zebrafish), Oreochromis niloticus (Nile tilapia) and Xiphophorus maculatus (Platyfish). RESULTS: Cold-water fishes showed preference for Guanines and cytosines (GCs) in both synonymous and nonsynonymous codon substitution when compared with tropical fishes. Amino acids coded by GC rich codons are favored in the temperate fishes, while those coded by AT-rich codons are disfavored. Similar trends were discovered in Antarctic fishes but were statistically weaker. The preference of GC rich codons in nonsynonymous substitution tends to increase ratio of small amino acid in proteins, which was demonstrated by biased small amino acid substitutions in the cold-water species when compared with the tropical species, especially in the temperate species. Prediction and comparison of secondary structure of the proteomes showed that frequency of random coils are significantly larger in the cold-water fish proteomes than those of the tropical fishes. CONCLUSIONS: Our results suggested that natural selection in cold temperature might favor biased GC content in the coding DNA sequences, which lead to increased frequency of small amino acids and consequently increased random coils in the proteomes of cold-water fishes. PMID- 29720107 TI - The experience of women with an eating disorder in the perinatal period: a meta ethnographic study. AB - BACKGROUND: Pregnancy is a time of enormous body transformation. For those with an eating disorder during pregnancy this time of transformation can be distressing and damaging to both the mother and the child. In this meta ethnographic study, we aimed to examine the experiences of women with an Eating Disorder in the perinatal period; that is during pregnancy and two years following birth. METHOD: A meta-ethnographic framework was used in this review. After a systematic online search of the literature using the keywords such as pregnancy, eating disorders, anorexia, bulimia, binge eating disorder, perinatal, postnatal and post-partum, 11 papers, involving 94 women, were included in the review. RESULTS: A qualitative synthesis of the papers identified 2 key themes. The key theme that emerged during pregnancy was: navigating a 'new' eating disorder. The key that emerged in the perinatal period was return to the 'old' eating disorder. CONCLUSION: Following a tumultuous pregnancy experience, many described returning to their pre-pregnancy eating behaviors and thoughts. These experiences highlight the emotional difficulty experienced having an eating disorder whilst pregnant but they also point to opportunities for intervention and a continued acceptance of body image changes. More research is needed on the experiences of targeted treatment interventions specific for pregnant and postpartum women with an eating disorder and the effectiveness of putative treatment interventions during this period. PMID- 29720108 TI - The effect of implementation strength of basic emergency obstetric and newborn care (BEmONC) on facility deliveries and the met need for BEmONC at the primary health care level in Ethiopia. AB - BACKGROUND: Basic emergency obstetric and newborn care (BEmONC) is a primary health care level initiative promoted in low- and middle-income countries to reduce maternal and newborn mortality. Tailored support, including BEmONC training to providers, mentoring and monitoring through supportive supervision, provision of equipment and supplies, strengthening referral linkages, and improving infection-prevention practice, was provided in a package of interventions to 134 health centers, covering 91 rural districts of Ethiopia to ensure timely BEmONC care. In recent years, there has been a growing interest in measuring program implementation strength to evaluate public health gains. To assess the effectiveness of the BEmONC initiative, this study measures its implementation strength and examines the effect of its variability across intervention health centers on the rate of facility deliveries and the met need for BEmONC. METHODS: Before and after data from 134 intervention health centers were collected in April 2013 and July 2015. A BEmONC implementation strength index was constructed from seven input and five process indicators measured through observation, record review, and provider interview; while facility delivery rate and the met need for expected obstetric complications were measured from service statistics and patient records. We estimated the dose-response relationships between outcome and explanatory variables of interest using regression methods. RESULTS: The BEmONC implementation strength index score, which ranged between zero and 10, increased statistically significantly from 4.3 at baseline to 6.7 at follow-up (p < .05). Correspondingly, the health center delivery rate significantly increased from 24% to 56% (p < .05). There was a dose response relationship between the explanatory and outcome variables. For every unit increase in BEmONC implementation strength score there was a corresponding average of 4.5 percentage points (95% confidence interval: 2.1-6.9) increase in facility-based deliveries; while a higher score for BEmONC implementation strength of a health facility at follow-up was associated with a higher met need. CONCLUSION: The BEmONC initiative was effective in improving institutional deliveries and may have also improved the met need for BEmONC services. The BEmONC implementation strength index can be potentially used to monitor the implementation of BEmONC interventions. PMID- 29720109 TI - Altered cerebral glucose metabolism normalized in a patient with a pediatric autoimmune neuropsychiatric disorder after streptococcal infection (PANDAS)-like condition following treatment with plasmapheresis: a case report. AB - BACKGROUND: Pediatric autoimmune neuropsychiatric disorder after streptococcal infection (PANDAS) is a specific autoimmune response to group-A streptococcal infections in children and adolescents with a sudden onset of obsessive compulsive disorders or tic-like symptoms. Cerebral metabolic changes of patients have not yet been observed. CASE PRESENTATION: We present a case of an 18-year old male with a PANDAS-like condition after developing tic-like symptoms and involuntary movements three weeks after cardiac surgery. The patient had suffered from pharyngotonsillitis before the symptoms started. The anti-streptolysin O (ASO) titer was elevated (805 kU/l). Antibiotic therapy did not improve his condition. Intravenous immunoglobulins and high-dose cortisone therapy had minor beneficial effects on his involuntary movements. 18F-Fluorodeoxyglucose positron emission tomography/ computer tomography (18F-FDG PET/CT) demonstrated pronounced hypermetabolism of the basal ganglia and cortical hypometabolism. The patient was treated with five cycles of plasmapheresis. A marked clinical improvement was observed after four months. Cerebral metabolic alterations had completely normalized. CONCLUSIONS: This is the first report of cerebral metabolic changes observed on FDG-PET/CT in a patient with a PANDAS-like condition with a normalization following immunomodulatory treatment. Cerebral FDG-PET/CT might be a promising tool in the diagnosis of PANDAS. PMID- 29720110 TI - Effect of smoking on the association of HHEX (rs5015480) with diabetes among Korean women and heavy smoking men. AB - BACKGROUND: Several genome-wide association studies (GWAS) for serum fasting glucose levels have reported HHEX as possibly causal. The objective of this study was to examine the joint effect of smoking on the association of diabetes with the HHEX rs5015480 polymorphism among Korean subjects. METHODS: This replication study included a total of 4240 individuals, and multivariate linear regression and multiple logistic regression models were used. We examined the combined effect of smoking on the relationship between HHEX rs5015480 and diabetes. RESULTS: The rs5015480 SNP in the HHEX gene was related to the mean FBS level (effect per allele, 1.572 mg/dL, p = 0.0122). Females with the CC genotype had a 2.68 times higher (range, 1.05-6.82 times) risk of diabetes than those with the TT/TC genotype. Although the association was stronger in female subjects (OR, 4.46; 95% CI, 1.15-17.3, p = 0.0304) among healthy individuals (N = 2461), the association between HHEX and diabetes was much stronger in male heavy smokers (OR, 4.03; 95% CI, 1.19-13.6, p = 0.0247) than in nonsmokers (p = 0.9709) and ex smokers (p = 0.2399). The interaction of smoking was also statistically significant (P for interaction =0.0182). CONCLUSIONS: This study clearly demonstrates that a genetic variant in HHEX influences fasting glucose levels in Korean women and male heavy smokers. PMID- 29720111 TI - Cancer-derived exosomes from HER2-positive cancer cells carry trastuzumab emtansine into cancer cells leading to growth inhibition and caspase activation. AB - BACKGROUND: Trastuzumab emtansine (T-DM1) is an antibody-drug conjugate that carries a cytotoxic drug (DM1) to HER2-positive cancer. The target of T-DM1 (HER2) is present also on cancer-derived exosomes. We hypothesized that exosome bound T-DM1 may contribute to the activity of T-DM1. METHODS: Exosomes were isolated from the cell culture medium of HER2-positive SKBR-3 and EFM-192A breast cancer cells, HER2-positive SNU-216 gastric cancer cells, and HER2-negative MCF-7 breast cancer cells by serial centrifugations including two ultracentrifugations, and treated with T-DM1. T-DM1 not bound to exosomes was removed using HER2-coated magnetic beads. Exosome samples were analyzed by electron microscopy, flow cytometry and Western blotting. Binding of T-DM1-containing exosomes to cancer cells and T-DM1 internalization were investigated with confocal microscopy. Effects of T-DM1-containg exosomes on cancer cells were investigated with the AlamarBlue cell proliferation assay and the Caspase-Glo 3/7 caspase activation assay. RESULTS: T-DM1 binds to exosomes derived from HER2-positive cancer cells, but not to exosomes derived from HER2-negative MCF-7 cells. HER2-positive SKBR-3 cells accumulated T-DM1 after being treated with T-DM1-containg exosomes, and treatment of SKBR-3 and EFM-192A cells with T-DM1-containing exosomes resulted in growth inhibition and activation of caspases 3 and/or 7. CONCLUSION: T-DM1 binds to exosomes derived from HER2-positive cancer cells, and T-DM1 may be carried to other cancer cells via exosomes leading to reduced viability of the recipient cells. The results suggest a new mechanism of action for T-DM1, mediated by exosomes derived from HER2-positive cancer. PMID- 29720112 TI - Emotional predictors of bowel screening: the avoidance-promoting role of fear, embarrassment, and disgust. AB - BACKGROUND: Despite considerable efforts to address practical barriers, colorectal cancer screening numbers are often low. People do not always act rationally, and investigating emotions may offer insight into the avoidance of screening. The current work assessed whether fear, embarrassment, and disgust predicted colorectal cancer screening avoidance. METHODS: A community sample (N = 306) aged 45+ completed a questionnaire assessing colorectal cancer screening history and the extent that perceptions of cancer risk, colorectal cancer knowledge, doctor discussions, and a specifically developed scale, the Emotional Barriers to Bowel Screening (EBBS), were associated with previous screening behaviours and anticipated bowel health decision-making. RESULTS: Step-wise logistic regression models revealed that a decision to delay seeking healthcare in the hypothetical presence of bowel symptoms was less likely in people who had discussed risk with their doctor, whereas greater colorectal cancer knowledge and greater fear of a negative outcome predicted greater likelihood of delay. Having previously provided a faecal sample was predicted by discussions about risk with a doctor, older age, and greater embarrassment, whereas perceptions of lower risk predicted a lower likelihood. Likewise, greater insertion disgust predicted a lower likelihood of having had an invasive bowel screening test in the previous 5 years. CONCLUSIONS: Alongside medical and demographic factors, fear, embarrassment and disgust are worthy of consideration in colorectal cancer screening. Understanding how specific emotions impact screening decisions and behaviour is an important direction for future work and has potential to inform screening development and communications in bowel health. PMID- 29720113 TI - A randomized open-label study of guideline-driven antiemetic therapy versus single agent antiemetic therapy in patients with advanced cancer and nausea not related to anticancer treatment. AB - BACKGROUND: Nausea/vomiting (N/V) not related to anti-cancer treatment is common in patients with advanced cancer. The standard approach to management is to define a dominant cause, and treat with an antiemetic selected through pathophysiologic knowledge of emetic pathways. High rates of N/V control have been reported using both etiology-based guideline-driven antiemetic regimens and an empiric approach using single agents in uncontrolled studies. These different approaches had never been formally compared. METHODS: This randomized, prospective, open label, dose-escalating study used readily available antiemetics in accordance with etiology-based guidelines or single agent therapy with haloperidol. Participants had a baseline average nausea score of >=3/10. Response was defined as a >= 2/10 point reduction on a numerical rating scale of average nausea score with a final score < 3/10 at 72 h. RESULTS: Nausea scores and distress from nausea improved over time in the majority of the 185 patients randomized. For those who completed each treatment day, a greater response rate was seen in the guideline arm than the single agent arm at 24 h (49% vs 32%; p = 0.02), but not at 48 or 72 h. Response rates at 72 h in the intention to treat analysis were 49 and 53% respectively, with no significant difference between arms (0.04; 95% CI: -0.11, 0.19; p = 0.59). Over 80% of all participants reported an improved global impression of change. There were few adverse events worse than baseline in either arm. CONCLUSION: An etiology-based, guideline-directed approach to antiemetic therapy may offer more rapid benefit, but is no better than single agent treatment with haloperidol at 72 h. CLINICAL TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ANZCTRN12610000481077 . PMID- 29720114 TI - Adverse obstetric and neonatal outcomes complicated by psychosis among pregnant women in the United States. AB - BACKGROUND: Adverse obstetric and neonatal outcomes among women with psychosis, particularly affective psychosis, has rarely been studied at the population level. We aimed to assess the risk of adverse obstetric and neonatal outcomes among women with psychosis (schizophrenia, affective psychosis, and other psychoses). METHODS: From the 2007 - 2012 National (Nationwide) Inpatient Sample, 23,507,597 delivery hospitalizations were identified. From the same hospitalization, International Classification of Diseases diagnosis codes were used to identify maternal psychosis and outcomes. Adjusted odds ratios (aOR) and 95% confidence intervals (CI) were obtained using logistic regression. RESULTS: The prevalence of psychosis at delivery was 698.76 per 100,000 hospitalizations. After adjusting for sociodemographic characteristics, smoking, alcohol/substance abuse, and pregnancy-related hypertension, women with psychosis were at a heightened risk for cesarean delivery (aOR = 1.26; 95% CI: 1.23 - 1.29), induced labor (aOR = 1.05; 95% CI: 1.02 - 1.09), antepartum hemorrhage (aOR = 1.22; 95% CI: 1.14 - 1.31), placental abruption (aOR = 1.22; 95% CI: 1.13 - 1.32), postpartum hemorrhage (aOR = 1.18; 95% CI: 1.10 - 1.27), premature delivery (aOR = 1.40; 95% CI: 1.36 - 1.46), stillbirth (aOR = 1.37; 95% CI: 1.23 - 1.53), premature rupture of membranes (aOR = 1.22; 95% CI: 1.15 - 1.29), fetal abnormalities (aOR = 1.49; 95% CI: 1.38 - 1.61), poor fetal growth (aOR = 1.26; 95% CI: 1.19 - 1.34), and fetal distress (aOR = 1.14; 95% CI: 1.10 - 1.18). Maternal death during hospitalizations (aOR = 1.00; 95% CI: 0.30 - 3.31) and excessive fetal growth (aOR = 1.06; 95% CI: 0.98 - 1.14) were not statistically significantly associated with psychosis. CONCLUSIONS: Pregnant women with psychosis have elevated risk of several adverse obstetric and neonatal outcomes. Efforts to identify and manage pregnancies complicated by psychosis may contribute to improved outcomes. PMID- 29720115 TI - Biomarker enhanced risk prediction for development of AKI after cardiac surgery. AB - BACKGROUND: Acute kidney injury (AKI) is a common post-cardiac surgery complication and influences patient morbidity and prognosis. This study was designed to identify preoperative candidate urine biomarkers in patients undergoing cardiac surgery. METHODS: A prospective cohort study of adults undergoing cardiac surgery at increased risk for AKI at a single hospital between July 2010 and September 2012 was performed. The primary outcome was the development of AKI, defined as an absolute serum creatinine (SCr) level increase >= 0.5 mg/dL or a >= 50% relative increase within 72 h of surgery. A secondary outcome was development of AKI defined by Kidney Disease Improving Global Outcomes (KDIGO). Urine collected by voiding within 4 h prior to surgery was used for proteomic analysis and confirmatory enzyme linked immunosorbent assays (ELISAs) studies. Biomarkers were tested for AKI-prediction using Cox and Snell R2, area under the receiver operating curve (AUROC), and percent of corrected classifications. To evaluate the added effect of each candidate biomarker on AKI discrimination, receiver operator characteristic (ROC) curves, integrated discrimination improvement (IDI), and net reclassification improvement (NRI) were calculated. RESULTS: Forty-seven of 755 patients met screening criteria including 15 with AKI. Proteomic analysis identified 29 proteins with a significant >=2 fold change. Confirmatory ELISA measurements of five candidate markers showed urinary complement factor B (CFB) and histidine rich glycoprotein (HRG) concentrations were significantly increased in patients with AKI. By multivariate analysis, NRI, and IDI the addition of CFB and HRG to the standard clinical assessment significantly improved risk prediction for the primary outcome. Only HRG was a significant predictor in the 21 patients with AKI defined by KDIGO criteria. CONCLUSIONS: Pre-operative urine measurement of CFB or HRG significantly enhanced the current post-surgery AKI risk stratification for more restrictive definition of AKI. HRG, but not CFB or clinical risk stratification, predicted AKI defined by KDIGO. The ability of these biomarkers to predict risk for dialysis-requiring AKI or death could not be reliably assessed in our study due to a small number of patients with either outcome. PMID- 29720117 TI - A comparison of practices, distributions and determinants of birth attendance in two divisions with highest and lowest skilled delivery attendance in Bangladesh. AB - BACKGROUND: Delivery by skilled birth attendants (SBAs) is strongly recommended to reduce maternal and neonatal mortality. The percentage of births attended by SBAs is low in Bangladesh (42% in 2014), though this rate varies widely by divisions, with the highest 58% in Khulna and only 27% in Sylhet. Comparing and critically analyzing the practices, distributions and determinants of delivery attendance in two divisions with the highest and lowest SBA attendance could help to understand the differences and to employ the findings of the high-performing division to the low-performing division. METHODS: The 7th Bangladesh Demographic and Health Survey (BDHS 2014) data were analyzed. After reporting the types of delivery attendants, logistic regression analyses were applied to calculate the odds ratios of determinants of deliveries attended by SBAs. RESULTS: SBAs attended 225 (58.6%) and 128 (27.4%) deliveries in Khulna and Sylhet, respectively. Khulna had higher birth attendance by qualified doctors (42.5%, n = 163) than Sylhet (15.8%, n = 74). Sylhet had higher attendance by traditional attendants (60.8%, n = 285) than Khulna (33.7%, n = 129). In both regions, attendance by community skilled birth attendants (CSBAs) was very low (< 1%). Khulna had higher percentages of women with higher education level, husbands' higher education, antenatal care (ANC) visits by SBAs, and higher wealth quintiles than Sylhet. In multivariable analyses, higher education level (adjusted odds ratio (AOR): 8.4; 95% confidence interval (CI): 1.9-36.7), ANC visits (AOR: 3.6; 95% CI: 2.0-6.5), family planning workers' visit (AOR: 3.0; 95% CI: 1.6-5.4), and belonging to richer (AOR: 2.6; 95% CI: 1.4-5.1) or richest (AOR: 3.8; 95% CI: 1.9-7.6) household wealth quintiles had significant positive associations with deliveries by SBAs in Sylhet. Similarly, ANC visits (AOR: 2.5; 95% CI: 1.4-4.6) and higher wealth quintile (AOR: 4.7; 95% CI: 1.9-11.5) were positive predictors in Khulna. CONCLUSIONS: The higher proportion of educated women and their husbands, wealth status and ANC visits were associated with higher SBA utilization in Khulna compared to Sylhet. Improvement of socioeconomic status, increasing birth attendant awareness programs, providing ANC services, and family-planning workers' visits could increase the proportion of SBA-attended deliveries in Sylhet Division. CSBA program should be re-evaluated for both divisions. PMID- 29720116 TI - VISTA expression associated with CD8 confers a favorable immune microenvironment and better overall survival in hepatocellular carcinoma. AB - BACKGROUND: Hepatocellular carcinoma (HCC) often arises in the setting of chronic inflammation with multiple inhibitory immune signals. V-domain Ig suppressor of T cell activation (VISTA) is identified as a novel negative checkpoint regulator. This study sought to determine the expression and prognostic value of VISTA in HCC and classify tumor microenvironments (TMEs) based on VISTA and CD8+ tumor infiltrating lymphocytes (TILs). METHODS: The expression of VISTA and CD8 proteins was assessed in 183 HCC tissue microarrays (TMAs) by immunohistochemistry (IHC). VISTA and CD8A mRNA extracted from 372 patients with HCC in The Cancer Genome Atlas (TCGA) database was included as a validation cohort. Associations between the VISTA, clinicopathological variables, and survival were analyzed. RESULTS: VISTA expression was detected in 29.5% HCC tissues, among which 16.4% tissues were positive for tumor cells (TCs), and 16.9% tissues were positive for immune cells (ICs). VISTA expression was significantly associated with tissues with a high pathological grading (p = 0.038), without liver cirrhosis (p = 0.011), and with a high density of CD8 + TILs (p < 0.001). Kaplan-Meier curves demonstrated that patients with VISTA-positive staining in TCs (p = 0.037), but not in ICs, (p = 0.779) showed significantly prolonged overall survival (OS) than those with VISTA-negative expression. Classification of HCC TME-based VISTA and CD8 + TILs showed 4 immune subtypes: VISTA+/CD8+ (16.9%), VISTA+/CD8- (12.6%), VISTA-/CD8+ (16.4%), and VISTA-/CD8+ (54.1%). The dual positive VISTA+/CD8+ subtype showed significantly prolonged OS than other subtypes (p = 0.023). CONCLUSIONS: VISTA protein expression in HCC showed cell specific and displayed different prognosis. VISTA expression was significantly associated with CD8 + TILs, Dual positive VISTA+/CD8+ showed favorable TME and better OS. PMID- 29720118 TI - microRNA-451a regulates colorectal cancer proliferation in response to radiation. AB - BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer-related death. The biologic response of CRC to standard of care adjuvant therapies such as chemotherapy and radiation are poorly understood. MicroRNAs (miRs) have been shown to affect CRC progression and metastasis. Therefore, we hypothesized that specific miRs modulate CRC response to chemoradiation. METHODS: In this study, we used miR expression profiling and discovered a set of microRNAs upregulated rapidly in response to either a single 2 Gy dose fraction or a 10 Gy dose of gamma-radiation in mouse colorectal carcinoma models. We used gain and loss-of function studies in 2D and 3Dcell proliferation assays and colony formation assays to understand the role of the top miR candidate from our profiling. We used Student's T-tests for simple comparisons and two-factor ANOVA for evaluating significance. RESULTS: The most upregulated candidate at early time points in our signature, miR-451a inhibited tumor cell proliferation and attenuated surviving fraction in longer-term cultures. Conversely, inhibition of miR-451a increased proliferation, tumorsphere formation, and surviving fraction of tumor cells. Using a bioinformatics approach, we identified four genes, CAB39, EMSY, MEX3C, and EREG, as targets of miR-451a. Transfection of miR-451a decreased both mRNA and protein levels of these targets. Importantly, we found miR-451a expression was high and CAB39, EMSY levels were low in a small subset of rectal cancer patients who had a partial response to chemoradiation when compared to patients that had no response. Finally, analysis of a TCGA colorectal cancer dataset revealed that CAB39 and EMSY are upregulated at the protein level in a significant number of CRC patients. Higher levels of CAB39 and EMSY correlated with poorer overall survival. CONCLUSIONS: Taken together, our data indicates miR 451a is induced by radiation and may influence colorectal carcinoma proliferation via CAB39 and EMSY pathways. PMID- 29720119 TI - A comparative study to identify factors of caregiver burden between baby boomers and post baby boomers: a secondary analysis of a US online caregiver survey. AB - BACKGROUND: Baby boomers' position in the caregiving context is shifting from caregiver to care recipient as the population ages. While the unique characteristics of baby boomer caregivers are well established in caregiving literature, there is limited information about the next caregiving group after the baby boomers. In this study, the sociodemographic and caregiving-related characteristics of the two generations are compared and specific factors contributing to caregiver burden between baby boomer and post baby boomer caregivers are identified. METHODS: This cross-sectional and correlational study used secondary analysis of data from the National Alliance for Caregiving and the American Association of Retired Persons. A structured online survey was conducted in 2014 with randomly selected samples (n = 1069) in the United States focusing on sociodemographics, caregiving-related characteristics, and burden of care. Descriptive statistics, multivariate linear regression analyses, and Steiger's Z test were used to identify group differences in multivariate factors related to caregiver burden in two generational groups. RESULTS: Baby boomers and post baby boomers experienced caregiver burden to a similar degree. Caregiving-related factors are more likely to increase burden of care than sociodemographics in both groups. Caregiving without choice and spending longer hours on caregiving tasks were common factors that increased the burden in both generational groups (all p values < 0.01). However, post baby boomer caregivers reported additional challenges, such as unemployment during caregiving, the dual responsibility of both adult and child care, and a family relationship with the care recipient. CONCLUSIONS: Due to the aging population of baby boomers, post baby boomers encounter different challenges related to caregiving burden, which is often considered an additional workload in their life course. Current policy and program tailored to baby boomers should be re-designed to meet the different needs of emerging caregivers. Specific vulnerable subgroups should have priority to receive the benefits of specific policies, such as those without choice and younger, working caregivers. PMID- 29720120 TI - Telomere length differences between colorectal polyp subtypes: a colonoscopy based case-control study. AB - BACKGROUND: Short telomeres have been associated with increased risk of many cancers, particularly cancers of the gastrointestinal tract including esophagus and stomach. However, the association between telomere length (TL) and colorectal cancer and its precursors, colorectal polyps, is not clear. METHODS: We investigated the relationship between TL and risk of colorectal polyp subtypes in a colonoscopy-based study in western Washington. Participants were 35-79 year-old enrollees at an integrated health care system, who underwent a colonoscopy between 1998 and 2007 (n = 190), completed a self-administered questionnaire, provided blood samples, and were distinguished as having adenomas, serrated polyps, or as polyp-free controls through a standardized pathology review. Telomere length (T) relative to a single copy gene (S) was measured in circulating leukocytes from stored buffy coat samples using quantitative polymerase chain reaction. Multivariable polytomous logistic regression was used to compare case groups with polyp-free controls and other case groups; adjusted odds ratios (OR) and 95% confidence intervals (CI) were estimated. RESULTS: TL in the shortest tertile (T/S ratio < 0.58) was associated with increased risk of adenomas and serrated polyps [OR (95%CI) were 1.77(0.81-3.88) and 2.98(1.15 7.77), respectively). When evaluated by lesion severity within each pathway, short TL was more strongly associated with advanced adenomas and sessile serrated polyps [OR (95% CI) = 1.90(0.76-4.73) and 3.82(0.86-16.86), respectively], although the associations were not statistically significant. CONCLUSIONS: Our results suggest that short TL may be associated with an increased risk of colorectal polyps in both the adenoma-carcinoma and serrated pathways. The risk was particularly notable for sessile serrated polyps, although the association was not statistically significant and sample size was limited. PMID- 29720121 TI - C-Cbl reverses HER2-mediated tamoxifen resistance in human breast cancer cells. AB - BACKGROUND: Tamoxifen is a frontline therapy for estrogen receptor (ER)-positive breast cancer in premenopausal women. However, many patients develop resistance to tamoxifen, and the mechanism underlying tamoxifen resistance is not well understood. Here we examined whether ER-c-Src-HER2 complex formation is involved in tamoxifen resistance. METHODS: MTT and colony formation assays were used to measure cell viability and proliferation. Western blot was used to detect protein expression and protein complex formations were detected by immunoprecipitation and immunofluorescence. SiRNA was used to examine the function of HER2 in of BT474 cells. An in vivo xenograft animal model was established to examine the role of c-Cbl in tumor growth. RESULTS: MTT and colony formation assay showed that BT474 cells are resistant to tamoxifen and T47D cells are sensitive to tamoxifen. Immunoprecipitation experiments revealed ER-c-Src-HER2 complex formation in BT474 cells but not in T47D cells. However, ER-c-Src-HER2 complex formation was detected after overexpressing HER2 in T47D cells and these cells were more resistant to tamoxifen. HER2 knockdown by siRNA in BT474 cells reduced ER-c-Src-HER2 complex formation and reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was also disrupted and tamoxifen resistance was reversed in BT474 cells by the c-Src inhibitor PP2 and HER2 antibody trastuzumab. Nystatin, a lipid raft inhibitor, reduced ER-c-Src-HER2 complex formation and partially reversed tamoxifen resistance. ER-c-Src-HER2 complex formation was disrupted by overexpression of c-Cbl but not by the c-Cbl ubiquitin ligase mutant. In addition, c-Cbl could reverse tamoxifen resistance in BT474 cells, but the ubiquitin ligase mutant had no effect. The effect of c-Cbl was validated in BT474 tumor-bearing nude mice in vivo. Immunofluorescence also revealed ER-c-Src-HER2 complex formation was reduced in tumor tissues of nude mice with c-Cbl overexpression. CONCLUSIONS: Our results suggested that c-Cbl can reverse tamoxifen resistance in HER2-overexpressing breast cancer cells by inhibiting the formation of the ER-c-Src-HER2 complex. PMID- 29720122 TI - Prognostic value of Dickkopf-1 and beta-catenin expression in advanced gastric cancer. AB - BACKGROUND: Dickkopf-1 (DKK1) is a Wnt/beta-catenin pathway antagonist related to gastric cancer (GC) carcinogenesis. However, the prognostic role of combined DKK1 and beta-catenin expression in advanced GC (AGC) is not clear. METHODS: In total, 158 patients with AGC who underwent gastric resection were enrolled in this study. DKK1 and beta-catenin expression was evaluated in whole tumor sections by immunohistochemistry. RESULTS: DKK1 expression was high in 73 (46.2%) patients, while beta-catenin expression was positive in 51 (32.3%) patients. The expression of DKK1 was positively correlated with that of beta-catenin (P < 0.001). The combined expression of DKK1 and beta-catenin was significantly associated with high N stage (N2 and N3) (P = 0.042). In addition, patients with high DKK expression demonstrated poorer overall (OS) (P < 0.001) and disease-free survival (DFS) (P = 0.001). However, there were no differences between high DKK1 expression with beta-catenin positivity and high DKK1 expression with beta catenin negativity (OS, P = 0.379: DFS, P = 0.255). Multivariate analysis revealed that high DKK1 alone or high DKK1 with beta-catenin positivity were independent prognostic factors for both OS (high DKK1: hazard ratio [HR], 2.130; 95% confidence interval [CI]; 1.370-3.312, P = 0.001; high DKK1 with beta-catenin positivity: HR, 2.140; 95% CI, 1.343-3.409: P = 0.001) and DFS (high DKK1: HR, 2.092; 95% CI, 1.180-3.708; P = 0.012; high DKK1 with beta-catenin positivity: HR, 2.357; 95% CI, 1.291-4.306; P = 0.005). CONCLUSION: Our results indicate that high DKK1 expression regardless of beta-catenin positivity is a crucial prognostic factor for predicting tumor recurrence and survival in patients with resected AGC. PMID- 29720123 TI - Combined neutrophil/platelet/lymphocyte/differentiation score predicts chemosensitivity in advanced gastric cancer. AB - BACKGROUND: Gastric cancer is common in developing regions, and we hope to find out an economical but practical prognostic indicator. It was reported that pre treatment peripheral neutrophil-to-lymphocyte ratio (NLR) and platelet-to lymphocyte ratio (PLR), as well as differentiation status, were associated with cancer progression. Hence, we introduced a novel combined Neutrophil/platelet/lymphocyte/differentiation Score (cNPLDS) to improve the prediction value of palliative chemotherapeutic response in advanced gastric cancer. METHODS: According to statistical sample size estimation, 136 primary diagnosed unresectable advanced ptaients were included for a retrospective study. The follow-up end-point was progression free survival (PFS) during the first-line palliative chemotherapy. Differentiation stratified patients into well, medium and poor groups by score 1 to 3, while patients with neither elevated NLR and PLR, only one elevated, or both elevated were of the combined NLR-PLR score (cNPS) 1 to 3, respectively. The cNPLDS was calculated by multiplying the tumor differentiation score and cNPS. RESULTS: Determined by the receiver operating characteristic (ROC) curve, the optimal cut-off points for NLR and PLR were 3.04 and 223. Through univariate analysis and survival analysis, poor differentiation, high NLR, high PLR, high cNPS, and high cNPLDS respectively indicated inferior PFS during the first-line palliative chemotherapy. Patients were furhter classified into low to high risk groups by cNPLDS. Groups of elevated NLR, PLR, cNPS, and cNPLDS showed lower disease control rate. Compared to other parameters, cNPLDS significantly improved the accuracy in predicing the first-progression. CONCLUSIONS: This study indicates that the novel parameter cNPLDS is superior to NLR or PLR alone, or even cNPS, in predicting the first-line chemosensitivity in advanced gastric cancer. PMID- 29720124 TI - EHLS at School: school-age follow-up of the Early Home Learning Study cluster randomized controlled trial. AB - BACKGROUND: Targeted interventions during early childhood can assist families in providing strong foundations that promote children's health and wellbeing across the life course. There is growing recognition that longer follow-up times are necessary to assess intervention outcomes, as effects may change as children develop. The Early Home Learning Study, or 'EHLS', comprised two cluster randomized controlled superiority trials of a brief parenting intervention, smalltalk, aimed at supporting parents to strengthen the early childhood home learning environment of infants (6-12 months) or toddlers (12-36 months). Results showed sustained improvements in parent-child interactions and the home environment at the 32 week follow-up for the toddler but not the infant trial. The current study will therefore follow up the EHLS toddler cohort to primary school age, with the aim of addressing a gap in literature concerning long-term effects of early childhood interventions focused on improving school readiness and later developmental outcomes. METHODS: 'EHLS at School' is a school-aged follow-up study of the toddler cluster randomized controlled trial (n = 1226). Data will be collected by parent-, child- and teacher-report questionnaires, recorded observations of parent-child interactions, and direct child assessment when children are aged 7.5 years old. Data linkage will provide additional data on child health and academic functioning at ages 5, 8 and 10 years. Child outcomes will be compared for families allocated to standard/usual care (control) versus those allocated to the smalltalk program (group program only or group program with additional home coaching). DISCUSSION: Findings from The Early Home Learning Study provided evidence of the benefits of the smalltalk intervention delivered via facilitated playgroups for parents of toddlers. The EHLS at School Study aims to examine the long-term outcomes of this initiative to determine whether improvements in the quality of the parent-child relationship persist over time and translate into benefits for children's social, academic and behavioral skills that last into the school years. TRIAL REGISTRATION: 8 September 2011; ACTRN12611000965909 (for the original EHLS). PMID- 29720125 TI - Facilitating autonomous, confident and satisfying choices: a mixed-method study of women's choice-making in prenatal screening for common aneuploidies. AB - BACKGROUND: Population-based prenatal screening has become a common and widely available obstetrical practice in majority of developed countries. Under the patient autonomy principle, women should understand the screening options, be able to take their personal preferences and situations into account, and be encouraged to make autonomous and intentional decisions. The majority of the current research focuses on the prenatal screening uptake rate, women's choice on screening tests, and the influential factors. However, little attention has been paid to women's choice-making processes and experiences in prenatal screening and their influences on choice satisfaction. Understanding women's choice-making processes and experiences in pregnancy and childbirth is the prerequisite for designing women-centered choice aids and delivering women-centered maternity care. This paper presents a pilot study that aims to investigate women's experiences when they make choices for screening tests, quantify the choice making experience, and identify the experiential factors that affect women's satisfaction on choices they made. METHOD: We conducted a mixed-method research at Helsinki and Uusimaa Hospital District (HUS) in Finland. First, the women's choice-making experiences were explored by semi-structured interviews. We interviewed 28 women who participated in prenatal screening. The interview data was processed by thematic analysis. Then, a cross-sectional self-completion survey was designed and implemented, assessing women's experiences in choice making and identifying the experiential factors that influence choice satisfaction. Of 940 distributed questionnaires, 185 responses were received. Multivariable linear regression analysis was used to detect the effects of the variables. RESULTS: We developed a set of measurements for women's choice-making experiences in prenatal screening with seven variables: activeness, informedness, confidence, social pressure, difficulty, positive emotion and negative emotion. Regression revealed that activeness in choice-making (beta = 0.176; p = 0.023), confidence in choice-making (beta = 0.388; p < 0.001), perceived social pressure (beta = - 0.306; p < 0.001) and perceived difficulty (beta = - 0.274; p < 0.001) significantly influenced women's choice satisfaction in prenatal screening. CONCLUSIONS: This study explores the experiential dimension of women's choice making in prenatal screening. Our result will be useful for service providers to design women-centered choice environment. Women's willingness and capabilities of making active choices, their preferences, and social reliance should be well considered in order to facilitate autonomous, confident and satisfying choices. PMID- 29720126 TI - Optimal predictor for 6-mercaptopurine intolerance in Chinese children with acute lymphoblastic leukemia: NUDT15, TPMT, or ITPA genetic variants? AB - BACKGROUND: 6-mercaptopurine (6-MP) contributes substantially to remarkable improvement in the survival of childhood acute lymphoblastic leukemia (ALL) patients. However, 6-MP also has dose-limiting toxicities, particularly life threatening myelosuppression, due to genetic polymorphisms in enzymes that metabolize 6-MP. Promising biomarkers for predicting 6-MP-induced leukopenia is still unclear in Chinese population. Here, we evaluated the associations of NUDT15, TPMT and ITPA genotypes with 6-MP intolerance in our cohort of childhood ALL patients. METHODS: A total of 105 Chinese pediatric patients with a confirmed diagnosis of ALL were enrolled. We identified the NUDT15 coding variant rs116855232 (c.415C > T), a newly discovered 6-MP toxicity-related locus in Asians, and polymorphisms in TPMT rs1142345 and ITPA rs11273540. Associations between genotypes and 6-MP dose sensitivity, leukopenia, hepatotoxicity, and therapy interruption were evaluated. RESULTS: The minor allele frequencies (MAFs) of NUDT15 rs116855232, TPMT rs1142345 and ITPA rs11273540 were 15.7, 2.9, and 18.1%, respectively. NUDT15 and TPMT genetic variants were strongly associated with 6-MP dose intensity. Patients with NUDT15 homogenous genotype (TT) were highly sensitive to 6-MP (dose intensity of 60.27%) compared to these with heterozygous genotype (TC) or wild type (CC), who tolerated an average dose intensity of 83.83 and 94.24%, respectively. The NUDT15 variant was a predictor for leukopenia (OR: 3.62, 95% CI 1.377-9.501, P = 0.009) and early-onset leukopenia (OR: 9.63, 95% CI 2.764-33.514, P = 3.75 * 10- 4). No differences were found between 6-MP dose intensity and ITPA polymorphisms. CONCLUSION: NUDT15 variant is an optimal predictor for 6-MP intolerance in Chinese pediatric ALL patients and may have greatly clinical implications for individualized therapy. PMID- 29720127 TI - Primary cardiac myxofibrosarcoma: case report, literature review and pooled analysis. AB - BACKGROUND: Primary cardiac myxofibrosarcoma is a very rare cardiac malignancy. The majority of publications are limited to case reports. No pooled analyses of primary cardiac myxofibrosarcoma cases are available. Little clinical features and outcome patterns are acknowledged. The purpose of this study is to identify the clinical characteristics and prognostic factors of primary cardiac myxofibrosarcoma. CASE PRESENTATION: A case report of primary cardiac myxofibrosarcoma was presented, and a review of English language literatures of primary cardiac myxofibrosarcomas were performed electronically. Demographics, clinicopathologic data, therapy and follow-up were summarized. The median survival time and the mean survival time were calculated by Kaplan-Meier method. Survival distribution and overall survival were figured by log-rank test and cox proportional hazards models. We present a case, and retrospectively analyzed additional 30 patients derived from 24 isolated articles. The cohort consisted of 18 male and 13 female patients. The age was 41.87 +/- 17.89 years. Some common features were found in clinical presentations, pathologic features, treatments and outcome patterns of primary cardiac myxofibrosarcoma. There were special features in echocardiography, histological and immunohistochemical examinations, which should be considered in diagnosis of primary cardiac myxofibrosarcoma. The median survival time/mean survival time (MST) was 14/32.66 months. The median survival time/mean survival time (MST) was 14/32.66 months. Compared to the other groups, the following groups had shorter survival characteristics, including age >= 40 years (14/11.79 months), female (14/26.26 months), mass diameter >= 40 mm (14/14.64 months), high-grade (2/11.81 months), and no post-treatment (14/28.09 months). Statistical analyses revealed that primary cardiac myxofibrosarcomas were more likely to present with local recurrences and dismal metastases. Tumors >= 40 mm in size (P = 0.055, HR = 6.79) or with high-grade (P = 0.063, HR = 11.45) had significantly worse prognosis. CONCLUSIONS: Primary cardiac myxofibrosarcomas were more likely to present with local recurrences and dismal metastases. Echocardiography, together with histological method should be considered in ordinary diagnosis. Tumors >= 40 mm in size or with high-grade had significantly worse prognosis, which should be early diagnosed and treated with rational surgery. PMID- 29720128 TI - The efficacy of Viscocanalostomies and combined phacoemulsification with Viscocanalostomies in the treatment of patients with glaucoma: a non-randomised observational study. AB - BACKGROUND: To evaluate the outcomes of Viscocanalostomy (VC) and Phacoviscocanalostomy (PV) in controlling primary and secondary glaucoma in a large cohort of patients from a single eye unit and performed by a single surgeon. METHODS: This non-randomised, retrospective study was conducted on 620 eyes of 458 patients. All patients who had either viscocanalostomy (VC) or combined phacoemulsification and viscocanalostomy (PV) over a three-year period were included. Intraocular pressures (IOP), number of anti-glaucoma medications used, and any complications were recorded over a 3-year follow up period. Paired T-Test was used to compare preoperative and post-operative IOP at specified time points. Kaplan-Meier survival models were used to determine success rates over the study period. RESULTS: Six hundred twenty procedures were performed during the 3-year study period, of which 427 were PV and 193 VC. The mean follow-up was 31.8 months. Overall complete success (IOP <= 21 mmHg, without medication) at 3 years was achieved in 65.7% of patients, with qualified success (IOP <=21 mmHg with or without medication) achieved in 96.0%. Subgroup analysis showed complete success rate of 76.0% for PV and 63.1% for VC (p = 0.005), with qualified success 95.9% for PV and 94.0% for VC (p = 0.668). Mean pre-operative IOP (mmHg) for all procedures was 23.02 +/- 5.6, with PV and VC subgroups at 22.54 +/- 5.10 and 24.06 +/- 6.45. Post-operatively IOP at month 12 and 36 was 14.74 +/- 3.57 and 14.40 +/- 3.17 respectively for all procedures, 14.62 +/- 3.26 and 14.44 +/- 3.10 for PV, and 15.03 +/- 4.18 and 14.31 +/- 3.33 for VC. Across all procedures, pre operatively an average of 3.05 +/- 0.96 anti-glaucoma medications were used. This reduced to 0.13 +/- 0.39 in 12 months and 0.38 + 0.71 by 36 months. Sixty-five cases had complications due to trabeculo-Descemet window perforation during viscocanalostomy with 7 cases developing complications from the cataract element. In the 12.9% of patients who had complications there were no differences of IOP noted at 3 years. CONCLUSION: VC and PV have good IOP lowering capacity and are both effective at sustaining a reduction in IOP at 3 years. PV achieved a higher success rate without medication. The low complication profile with reduced post operative care means these procedures may be a preferred option for early surgical intervention. PMID- 29720129 TI - Availability, affordability and costs of pediatric medicines in Mongolia. AB - BACKGROUND: The Essential Medicines List for Children (EMLc) was developed by the World Health Organization (WHO) to assist member countries to achieve Millennium Development Goals (MDG). The Government of Mongolia has adopted a National Essential Drug List (NEDL) with the seventh update published in 2014. The objective of this study was to determine the accessibility, availability and costs of essential pediatric medicines in Mongolia. METHODS: A standardized methodology developed by the WHO and Health Action International (HAI) was employed to conduct a study on the availability, costs and affordability of pediatric medicines in Mongolia. A data collection tool collected information in regards to retail and wholesale availability and costs of essential pediatric medicines at pharmacy outlets during January and August of 2016. RESULTS: Availability of individual essential pediatric medicines varied across the country. The average availability of medicines was 72.6% in the public sector (9.1-100%). Correspondingly, average availability of all selected medicines in the private sector was 76.7% (26.7-100%). Lowest price medicines were 2.45 times higher than the international reference price (IRP) in the private sector and was 1.95 times higher in the public sector. The lowest cost medicines in the public sector were more affordable for all conditions. The least affordable treatment was estimated to be for respiratory tract infections, or otitis media using amoxicillin clavulanic acid, suspension costing up to 1.03 days wages. CONCLUSION: Procurement, supply and distribution of essential pediatric medicines needs to be regularly investigated in order to identify the availability and costs of pediatric formulations in Mongolia. PMID- 29720130 TI - Performance of a quantitative fecal immunochemical test for detecting advanced colorectal neoplasia: a prospective cohort study. AB - BACKGROUND: The fecal immunochemical test (FIT) is easier to use and more sensitive than the guaiac fecal occult blood test, but it is unclear how to optimize FIT performance. We compared the sensitivity and specificity for detecting advanced colorectal neoplasia between single-sample (1-FIT) and two sample (2-FIT) FIT protocols at a range of hemoglobin concentration cutoffs for a positive test. METHODS: We recruited 2,761 average-risk men and women ages 49-75 referred for colonoscopy within a large nonprofit, group-model health maintenance organization (HMO), and asked them to complete two separate single-sample FITs. We generated receiver-operating characteristic (ROC) curves to compare sensitivity and specificity estimates for 1-FIT and 2-FIT protocols among those who completed both FIT kits and colonoscopy. We similarly compared sensitivity and specificity between hemoglobin concentration cutoffs for a single-sample FIT. RESULTS: Differences in sensitivity and specificity between the 1-FIT and 2-FIT protocols were not statistically significant at any of the pre-specified hemoglobin concentration cutoffs (10, 15, 20, 25, and 30 MUg/g). There was a significant difference in test performance of the one-sample FIT between 50 ng/ml (10 MUg/g) and each of the higher pre-specified cutoffs. Disease prevalence was low. CONCLUSIONS: A two-sample FIT is not superior to a one-sample FIT in detection of advanced adenomas; the one-sample FIT at a hemoglobin concentration cutoff of 50 ng/ml (10 MUg/g) is significantly more sensitive for advanced adenomas than at higher cutoffs. These findings apply to a population of younger, average-risk patients in a U.S. integrated care system with high rates of prior screening. PMID- 29720132 TI - Long working hours and sickness absence-a fixed effects design. AB - BACKGROUND: While long working hours seem to lead to impaired health, several studies have also shown that long working hours are related to lower levels of sickness absence. Previous studies on the relationship between long working hours and sickness absence have compared those who work long hours to those who do not, looking only at between-individual correlations. Those results might therefore reflect relatively stable differences between employees who typically work long hours and employees who typically do not. The aim of the present study is to examine within-individual correlations between long working hours and sickness absence. METHODS: Records from the Human Resources department in a large Norwegian hospital from 2012 to 2015 provided objective data on both working hours and sickness absence. Two analyses were performed: a prospective cohort analysis to replicate the results from previous between-individual analyses and a second analysis of within-individual correlations using a fixed effect design. RESULTS: In line with existing research, both between-individual and within individual analyses showed a negative relationship between long working hours (> 48 h/week) and short-term sickness absence (1-8 days) and no significant difference in incidence of long-term sickness absence (> 8 days). CONCLUSIONS: The results indicate that the negative relationship between long working hours and sickness absence is not due only to relatively stable individual differences between those who typically work long hours and those who do not. The results from both analyses therefore still contrast with previous research showing a negative relationship between long working hours and other health indicators. PMID- 29720131 TI - Intestinal Candida parapsilosis isolates from Rett syndrome subjects bear potential virulent traits and capacity to persist within the host. AB - BACKGROUND: Rett syndrome (RTT) is a neurological disorder mainly caused by mutations in MeCP2 gene. It has been shown that MeCP2 impairments can lead to cytokine dysregulation due to MeCP2 regulatory role in T-helper and T-reg mediated responses, thus contributing to the pro-inflammatory status associated with RTT. Furthermore, RTT subjects suffer from an intestinal dysbiosis characterized by an abnormal expansion of the Candida population, a known factor responsible for the hyper-activation of pro-inflammatory immune responses. Therefore, we asked whether the intestinal fungal population of RTT subjects might contribute the sub-inflammatory status triggered by MeCP2 deficiency. METHODS: We evaluated the cultivable gut mycobiota from a cohort of 50 RTT patients and 29 healthy controls characterizing the faecal fungal isolates for their virulence-related traits, antifungal resistance and immune reactivity in order to elucidate the role of fungi in RTT's intestinal dysbiosis and gastrointestinal physiology. RESULTS: Candida parapsilosis, the most abundant yeast species in RTT subjects, showed distinct genotypic profiles if compared to healthy controls' isolates as measured by hierarchical clustering analysis from RAPD genotyping. Their phenotypical analysis revealed that RTT's isolates produced more biofilm and were significantly more resistant to azole antifungals compared to the isolates from the healthy controls. In addition, the high levels of IL-1beta and IL-10 produced by peripheral blood mononuclear cells and the mixed Th1/Th17 cells population induced by RTT C. parapsilosis isolates suggest the capacity of these intestinal fungi to persist within the host, being potentially involved in chronic, pro-inflammatory responses. CONCLUSIONS: Here we demonstrated that intestinal C. parapsilosis isolates from RTT subjects hold phenotypic traits that might favour the previously observed low-grade intestinal inflammatory status associated with RTT. Therefore, the presence of putative virulent, pro-inflammatory C. parapsilosis strains in RTT could represent an additional factor in RTT's gastrointestinal pathophysiology, whose mechanisms are not yet clearly understood. PMID- 29720133 TI - Evaluation of an electronic consultation service in psychiatry for primary care providers. AB - BACKGROUND: This study explores the effectiveness of an electronic consultation (eConsult) service between primary care providers and psychiatry, and the types and content of the clinical questions that were asked. METHODS: This is a retrospective eConsult review study. All eConsults directed to Psychiatry from July 2011 to January 2015 by Primary care providers were reviewed. Response time and the amount of time reported by the specialist to answer each eConsult was analyzed. Each eConsult was also categorized by clinical topic and question type in predetermined categories. Mandatory post-eConsult surveys for primary care providers were analyzed to determine the number of traditional consults avoided and to gain insight into the perceived value of eConsults. RESULTS: Of the 5597 eConsults, 169 psychiatry eConsults were completed during the study period. The average response time for a specialist to a primary care provider was 2.3 days. Eighty-seven percent of clinical responses were completed by the psychiatrist in less than 15 min. The primary care providers most commonly asked clinical questions were about depressive and anxiety disorders. 88.7% of PCPs rated the eConsult service a 5 (excellent value) or 4. CONCLUSIONS: This study indicates that an eConsult psychiatry service has tremendous potential to improve access to psychiatric advice and expand the capacity to treat mental illness in primary care. Future research may include follow-up with PCPs regarding the implementation of specialist advice. PMID- 29720134 TI - Rupture of a subungual glomus tumor of the finger. AB - BACKGROUND: Glomus tumor is a rare benign neoplasm, which most frequently occurs in the subungual regions of digits. Tumor rupture and infection occurred in one patient with a glomus tumor have never been reported. CASE PRESENTATION: We report a 59-year-old female presented to our hospital with a five-year history of progressively sharp pain and severe tenderness in the tip of her right middle finger. The treatment was surgical excision through a lateral incision accompanied with removal of the nail. After the surgery, the patient gained a functional recovery of her previously afflicted finger. CONCLUSIONS: To the best of our knowledge, this is the first case of finger infection caused by a ruptured subungual glomus tumor. Patients and physicians should be aware of the properties of glomus tumor so that early diagnosis and treatment of subungual glomus tumor as well as avoidance of tumor rupture and infection can be achieved. PMID- 29720135 TI - Compliance with Iron and folic acid supplementation (IFAS) and associated factors among pregnant women: results from a cross-sectional study in Kiambu County, Kenya. AB - BACKGROUND: Macro and micronutrients including iron and folic acid deficiencies are prevalent in Kenya, particularly during pregnancy resulting in anaemia. Despite efforts to control anaemia in pregnancy by adopting Iron and Folic Acid Supplementation (IFAS), this public health problem has persisted contributing to significant morbidity and mortality. The problem notwithstanding, there is poor IFAS compliance, whose reasons remain poorly understood, calling for their investigations. We sought to determine compliance status with IFAS and associated factors among pregnant women. METHODS: This was a cross-sectional study involving 364 pregnant women aged 15-49 years. Using two stage cluster sampling, one Sub County and five public health facilities in Kiambu County were selected. All pregnant women attending antenatal clinics who met inclusion criteria and consented to participate in the study were recruited. Compliance with IFAS was defined as taking supplements at least 5 out of 7 days per week. A structured interviewer-administered questionnaire consisting of sociodemographic data, IFAS maternal knowledge and compliance practices was pretested and administered. Descriptive and inferential statistics were computed using STATA. RESULTS: Of the 364 respondents interviewed, 32.7% were IFAS compliant and 40.9% scored high on its knowledge. Of those with high IFAS knowledge, 48.3% were compliant compared to those with low knowledge (21.4%, n = 46, PR = 2.25;95%CI = 1.59-3.17, p < 0.001). Women who were multigravid (30.4%) were less likely to comply compared to primigravid (37.2%, n = 45, PR = 0.68;95%CI = 0.47-0.99, p = 0.004). Multivariate analysis revealed that respondents counselled on management of IFAS side effects (100%, n = 4) were more compliant (76.2%, n = 112, aPR = 1.31;95%CI = 1.19-1.44, p < 0.001). CONCLUSION: Few pregnant women were compliant with IFAS regimen, associated with: knowledgeability on IFAS, primi-gravidity, and IFAS counselling especially on management of its side effects. These underscore the need for approaches to scale up health awareness on the benefits of IFAS, mitigation measures for the side effects, as well as targeted counselling. PMID- 29720136 TI - Prevalence and predictors of under-nutrition among school children in a rural South-eastern Nigerian community: a cross sectional study. AB - BACKGROUND: School children in developing countries like Nigeria are faced with numerous nutrition and health problems. Lack of functional school health and nutrition programmes in Enugu state, Nigeria may be associated with dearth of data on associated factors. Identifying these factors could inform the design and implementation of school-based programmes aimed at ameliorating these problems. METHODS: A cross sectional survey involving 450 primary and secondary school children aged 6-15 years was conducted in Ede-Oballa, a rural community in Enugu state, South-eastern Nigeria. Selection of the pupils was by multistage sampling technique. Data were collected through interviewer administered questionnaire, anthropometric measurements of weight and height, 3-day weighed food intake, stool microscopy and blood analyses for malaria, zinc and vitamin A. Bivariate and multivariate logistic regression analyses were used to evaluate associations of interest with significance accepted at P < 0.05. RESULTS: The school children were affected by underweight (18.2%), stunting (41.6%), thinness (20.0%), zinc (43.3%) and vitamin A (51.1%) deficiencies. After adjusting for potential confounders, weekly food expenditure was a major predictor of under-weight (AOR = 0.19, 95% CI: 0.08, 0.46), stunting (AOR = 0.36, 95% CI: 0.13, 0.95) and thinness (AOR = 0.49, 95% CI: 0.30, 0.80); household income was also a predictor of thinness (AOR = 0.47, 95% CI: 0.25, 0.88). Males had lower odds of being stunted than females (AOR = 0.31, 95% CI: 0.11, 0.83). The odd of being underweight was higher in female headed households than in households headed by males (AOR = 0.30, 95% CI: 0.12, 0.75). Tapeworm was an independent predictor of vitamin A (AOR = 3.59; 95% CI: 1.06, 12.13) and zinc (AOR = 3.64; 95% CI: 1.02, 12.98) deficiencies. Children with whipworm were more likely to be zinc (AOR = 3.80; 95% CI: 1.11, 13.04) and vitamin A (AOR = 3.79; 95% CI: 1.12, 12.89) deficient than those uninfected. CONCLUSION: Underweight, stunting, thinness, vitamin A and zinc deficiency among the school children were functions of weekly food expenditure, gender of household head and household income, tapeworm, whipworm, and sex. These findings emphasize the need for effective school- and community-based interventions. PMID- 29720139 TI - Patients' understanding of telemedicine terms required for informed consent when translated into Kiswahili. AB - BACKGROUND: In Africa, where access to specialist medical services is often limited, telemedicine, the use of information and communication technologies for the provision of healthcare at a distance, can contribute towards enhancing access to healthcare. Informed consent is considered the cornerstone of ethical practice, especially when technology and techniques are considered new and or unproven. It is advised that informed consent should be gained in the patient's mother tongue. However, many African languages have not kept pace with technology and lack the words and terms needed to describe computing and technical terms. Additionally, even when present, patients may not understand these words and terms. This affects the validity of informed consent given. METHODS: Forty relevant computer terms and words used when explaining telemedicine during the consent process were selected and translated into Kiswahili. Patients at the outpatient department of the Kilifi County Hospital in Kenya participated. The study consisted of two phases. In the first, 50 people were asked whether they understood the translated words and terms and were able to explain their meaning. In the second (n = 42) they were asked to explain the meaning of the translated word, the original English word, and those words that could not be translated. RESULTS: Of the 40 terms, 14 could not be translated (35%). A total of 92 people attending the Kilifi County Hospital participated. Their average age was 31.2 +/- 10.6 y, 70.7% were female and 55.4% were from rural areas. More than half of the respondents did not understand videoconference, store and forward, digital photograph, wireless, World Wide Web, antivirus or email in either language. No one understood the words telemedicine, firewall, encryption, decryption and tele diagnosis. CONCLUSIONS: Currently it is unlikely that valid informed consent can be obtained for a telemedicine encounter in Kiswahili. Innovative solutions are required to overcome the barrier of languages failing to keep pace with technology and their effect on consent. PMID- 29720138 TI - A formative study to understand perspectives of families eligible for a pediatric obesity program: a qualitative study. AB - BACKGROUND: Raising Well(r) (RW) was initiated in 2015 by Envolve PeopleCareTM at the request of health plans seeking a solution to work with families on Medicaid that have a child with overweight or obesity. RW uses expert clinical coaches via phone contact to deliver an educational intervention promoting lifestyle change to families with at least one overweight or obese child in an eligible Medicaid health plan. This gives RW significant potential for reach and population impact. This project aimed to understand how to maximize this impact by exploring perspectives of RW, using a conceptual framework informed by the Conceptual Model of Implementation Research, including assessment of the feasibility, acceptability, and appropriateness of RW; determining satisfaction among those experiencing coaching; identifying reasons individuals do not participate; and developing recommendations to enhance interest and participation. METHODS: Semi structured interviews were conducted with 70 RW-eligible families across four states, who were described as: active participants, respondents who dropped or stopped RW, and RW non-participants. Following the interviews, the transcripts were coded inductively and deductively using a grounded theory approach, considering themes from the conceptual framework; themes also emerged from the data. RESULTS: From this sample, 19 families reported to be active coaching participants, 24 had dropped coaching, and 27 were RW non-participants. A number of themes were identified. Feasibility themes included coaches' flexibility and willingness to work with the family's schedule. Acceptability themes suggest providing actionable strategies tailored to the family's context and needs, beyond just nutrition information and tips, early in the coaching relationship so the family perceives a benefit for continued participation. With regard to appropriateness, families were also interested in other methods of communication including email, texting, and in person visits. Access to resources for activity and healthy eating in their local community was also recommended. CONCLUSIONS: RW has the potential to improve health and promote wellness. To enhance the impact of this program, RW could incorporate these findings to promote feasibility, acceptability, and appropriateness and improve program implementation. Strategies may include modifying the information provided or the mode of delivering the information. PMID- 29720137 TI - Upregulation of bone morphogenetic protein 1 is associated with poor prognosis of late-stage gastric Cancer patients. AB - BACKGROUND: Gastric cancer is the eighth most common cancer in Taiwan, with a 40% 5-year survival rate. Approximately 40% of patients are refractory to chemotherapy. Currently, the anti-HER2 therapy is the only clinically employed targeted therapy. However, only 7% patients in Taiwan are HER2-positive. Identifying candidate target genes will facilitate the development of adjuvant targeted therapy to increase the efficacy of gastric cancer treatment. METHODS: Clinical specimens were analyzed by targeted RNA sequencing to assess the expression levels of target genes. Statistical significance of differential expression and correlation between specimens was evaluated. The correlation with patient survival was analyzed as well. In vitro cell mobility was determined using wound-healing and transwell mobility assays. RESULTS: Expression of BMP1, COL1A1, STAT3, SOX2, FOXA2, and GATA6 was progressively dysregulated through the stages of gastric oncogenesis. The expression profile of these six genes forms an ubiquitously biomarker signature that is sufficient to differentiate cancer from non-cancerous specimens. High expression status of BMP1 correlates with poor long term survival of late-stage patients. In vitro, suppression of BMP1 inhibits the mobility of the gastric cancer cell lines, indicating a role of BMP1 in metastasis. CONCLUSIONS: BMP1 is upregulated in gastric cancer and is correlated with poor patient survival. Suppression of BMP1 reduced gastric cancer mobility in vitro. Our finding suggests that anti-BMP1 therapy will likely augment the efficacy of standard chemotherapy and improve the treatment outcome. PMID- 29720140 TI - Clinical utility of blood neutrophil-lymphocyte ratio in Japanese COPD patients. AB - BACKGROUND: Neutrophil-to-lymphocyte ratio (NLR) is a biomarker of inflammation in chronic obstructive pulmonary disease (COPD) patients. But, a meaningful threshold and the longitudinal changes are unknown. We aimed to investigate the association between NLR and the clinical characteristics of COPD patients and to determine a meaningful threshold and the longitudinal changes for NLR. METHODS: Keio University and its affiliate hospitals conducted an observational COPD cohort study over 3 years. We performed a blood examination and a pulmonary function test. Blood examination was completed at baseline and annually thereafter, at a time when the disease was stable. Two hundred seventy-four patients who had at least 3 blood examinations over 3 years were included. RESULTS: Baseline NLR was correlated with baseline C-reactive protein (CRP) (r = 0.18, p = 0.003) and SAA (r = 0.34, p < 0.001). We defined an NLR score of 2.7 as the arbitrary cut-off value based on upper quartile points. COPD patients with NLR >= 2.7 were older (p = 0.037), had a lower BMI (p = 0.005) and a lower %FEV1 (p = 0.0003) compared to patients with NLR < 2.7. Receiver-operating characteristic (ROC) curves showed the optimal cutoff for the baseline NLR in the predicting moderate/severe exacerbation to be 2.7, which was same as the upper quartile points. Follow-up analysis over 3 years revealed that the differences in the trends of NLR among the three groups based on the categories of exacerbations (moderate or severe, mild, no exacerbation) were significant (p = 0.006). CONCLUSIONS: NLR is associated with COPD severity and exacerbations. For predicting exacerbations, we estimated the threshold of NLR to be 2.7 at baseline. TRIAL REGISTRATION: Clinical trial registered with the University Hospital Medication Information Network ( UMIN000003470 , April 10, 2010). PMID- 29720142 TI - Evaluation of three patient reported outcome measures following operative fixation of closed ankle fractures. AB - BACKGROUND: Several patient reported outcome measures (PROMs) are available for assessing the outcomes of ankle fracture but few have been compared for recommended measurement properties. This study compares the measurement properties of the Lower Extremity Function Scale (LEFS), Olerud Molander Ankle Score (OMAS) and Self-Reported Foot and Ankle Score (SEFAS) following ankle surgery. METHODS: The retrospective cohort study included 959 patients aged 18 years and over who underwent surgical treatment (ORIF) for unstable and closed ankle fractures in SE Norway. The PROMs were included in a postal questionnaire sent to patients' homes in 2015, three years after surgery. Missing data, structural validity, internal consistency, test-retest reliability and validity were assessed. RESULTS: Confirmatory factor analysis results showed model fit for the SEFAS and a bi-dimensional LEFS with scales of easy and difficult items. The OMAS performed less satisfactorily. Cronbach's alpha and test-retest correlations ranged from 0.82 to 0.96 and 0.91 to 0.93 respectively. The smallest detectable differences for group and individual comparisons were 14.1 to 20.6 and 0.93 to 1.55; SEFAS performed best. As hypothesised, instrument scores were highly correlated and with those for the EQ-5D and SF-36 physical functioning. Mean imputation where half or more items are completed increased usable scores by 1.4 15.7% without affecting measurement properties. CONCLUSIONS: The three instruments largely performed satisfactorily in relation to important measurement properties but the LEFS had evidence for two dimensions relating to easier and more difficult aspects of function. Mean imputation where half or more items are completed increased the number of usable responses for all three instruments. The three instruments represent different approaches to measuring outcomes and their content should be considered carefully when choosing between them. The SEFAS is designed for a range of foot disorders including ankle fractures and has the best measurement properties in this population. PMID- 29720141 TI - Solamargine, a bioactive steroidal alkaloid isolated from Solanum aculeastrum induces non-selective cytotoxicity and P-glycoprotein inhibition. AB - BACKGROUND: Solanum aculeastrum fruits are used by some cancer sufferers as a form of alternative treatment. Scientific literature is scarce concerning its anticancer activity, and thus the aim of the study was to assess the in vitro anticancer and P-glycoprotein inhibitory potential of extracts of S. aculeastrum fruits. Furthermore, assessment of the combinational effect with doxorubicin was also done. METHODS: The crude extract was prepared by ultrasonic maceration. Liquid-liquid extraction yielded one aqueous and two organic fractions. Bioactive constituents were isolated from the aqueous fraction by means of column chromatography, solid phase extraction and preparative thin-layer chromatography. Confirmation of bioactive constituent identity was done by nuclear magnetic resonance and ultra-performance liquid chromatography mass spectrometry. The crude extract and fractions were assessed for cytotoxicity and P-glycoprotein inhibition in both cancerous and non-cancerous cell lines using the sulforhodamine B and rhodamine-123 assays, respectively. RESULTS: Both the crude extract and aqueous fraction was cytotoxic to all cell lines, with the SH-SY5Y neuroblastoma cell line being most susceptible to exposure (IC50 = 10.72 MUg/mL [crude], 17.21 MUg/mL [aqueous]). Dose-dependent P-glycoprotein inhibition was observed for the crude extract (5.9 to 18.9-fold at 100 MUg/mL) and aqueous fraction (2.9 to 21.2 at 100 MUg/mL). The steroidal alkaloids solamargine and solanine were identified. While solanine was not bioactive, solamargine displayed an IC50 of 15.62 MUg/mL, and 9.1-fold P-glycoprotein inhibition at 100 MUg/mL against the SH-SY5Y cell line. Additive effects were noted for combinations of doxorubicin against the SH-SY5Y cell line. CONCLUSIONS: The crude extract and aqueous fraction displayed potent non-selective cytotoxicity and noteworthy P glycoprotein inhibition. These effects were attributed to solamargine. P glycoprotein inhibitory activity was only present at concentrations higher than those inducing cytotoxicity, and thus does not appear to be the likely mechanism for the enhancement of doxorubicin's cytotoxicity. Preliminary results suggest that non-selective cytotoxicity may hinder drug development, however, further assessment of the mode of cell death is necessary to determine the route forward. PMID- 29720143 TI - Integrating student feedback during "Dental Curriculum Hack-A-thon". AB - BACKGROUND: The future of dental education is at crossroads. This study used the parameter of the 2016 Dental Curriculum Hack-a-Thon to assess intra- and inter institutional agreement between student and faculty views regarding dental curriculums to determine if there is an impact in student perceptions towards dental education from before and after the event. METHODS: This exploratory, cross-sectional study involved two surveys, with Survey 1 being distributed among four faculty-student pairs of the four participating dental schools answering 14 questions. Survey 2 assessed the views of 20 participating dental students through 26 questions in a pre- and post- event survey design. Descriptive statistics were used to explore differences in perceptions towards dental education across both instrument surveys. RESULTS: The results revealed valuable student insights regarding intra- and inter-institutional agreement relevant for the change in dental curriculum that needs to occur. Survey 2 revealed that mandatory attendance in didactic courses, electronic based examination preferences, and the preference of preclinical courses being held in the first and second years of a four-year dental curriculum were of particular importance to student participants. CONCLUSIONS: The results of this study indicate that exposure and participation in subjects pertaining to dental education can be influential on student preferences and opinions on how dental education should be delivered in a four-year curriculum. PMID- 29720144 TI - Examining school-based hygiene facilities: a quantitative assessment in a Ghanaian municipality. AB - BACKGROUND: The crucial role of adequate water, sanitation and hygiene (WASH) facilities in influencing children's handwashing behaviour is widely reported. Report from UNICEF indicates a dearth of adequate data on WASH facilities in schools, especially in the developing world. This study sought to contribute to building the evidence-base on school hygiene facilities in Ghana. The study further explored for possible associations and differences between key variables within the context of school water, sanitation and hygiene. METHODS: Data was collected from 37 junior high schools using an observational checklist. Methods of data analysis included a Scalogram model, Fisher's exact test, and a Student's t-test. RESULTS: Results of the study showed a facility deficiency in many schools: 33% of schools had students washing their hands in a shared receptacle (bowl), 24% had students using a single cotton towel to dry hands after handwashing, and only 16% of schools had a functional water facility. Furthermore, results of a proportion test indicated that 83% of schools which had functional water facilities also had functional handwashing stations. On the other hand, only 3% of schools which had functional water facilities also had a functional handwashing stations. A test of difference in the proportions of the two sets of schools showed a statistically significant difference (p < 0.001). In addition, 40% of schools which had financial provisions for water supply also had functional handwashing stations. On the other hand, only 7% of schools which had financial provisions for water supply also had functional handwashing stations. There was a statistically significant difference in the proportions of the two sets of schools (p = 0.02). CONCLUSION: We conclude that it is essential to have a financial provision for water supply in schools as this can potentially influence the existence of a handwashing station in a school. An intervention by government, educational authorities and civil society organisations towards enabling schools in low resource areas to have a sustainable budgetary allocation for WASH facilities would be timely. PMID- 29720145 TI - Comparison of the chemical profiles and inflammatory mediator-inhibitory effects of three Siegesbeckia herbs used as Herba Siegesbeckiae (Xixiancao). AB - BACKGROUND: Herba Siegesbeckiae (HS, Xixiancao in Chinese) is a commonly used traditional Chinese medicinal herb for soothing joints. In ancient materia medica books, HS is recorded to be the aerial part of Siegesbeckia pubescens Makino (SP) which is also the only origin of HS in the 1963 edition of the Chinese Pharmacopeia (ChP). The aerial parts of Siegesbeckia orientalis L. (SO) and Siegesbeckia glabrescens Makino (SG) have been included as two additional origins for HS in each edition of ChP since 1977. However, chemical and pharmacological comparisons among these three species have not been conducted. METHODS: An HPLC with diode array detector (HPLC-DAD) method combined with similarity analysis, hierarchical cluster analysis (HCA) and principal component analysis (PCA) was developed for comparing the fingerprint chromatograms of the three species. The inhibitory effects of the three species on NO production and IL-6 secretion in LPS-stimulated RAW264.7 macrophages were compared. RESULTS: Fingerprint chromatograms of the three species showed different profiles, but had 13 common peaks. Results from HCA and PCA of the common peaks demonstrated that all 14 herbal samples of the three species tended to be grouped and separated species dependently. The extents of inhibition on NO production and IL-6 secretion of the three species were different, with SG being the most and SP the least potent. CONCLUSIONS: Both chemical profiles and inflammatory mediator-inhibitory effects of the three species were different. These findings provide a chemical and pharmacological basis for determining whether the three species can all serve as the origins of HS. PMID- 29720146 TI - SMS reminders to improve adherence and cure of tuberculosis patients in Cameroon (TB-SMS Cameroon): a randomised controlled trial. AB - BACKGROUND: In Cameroon, the National Tuberculosis Control Program that applies selective directly observed treatments faces difficulties in its implementation for a lack of resources, leading to only 65% of patients with sputum smear positive pulmonary tuberculosis being cured after 6 months of treatment. This study aimed to evaluate the effectiveness of daily Short Message Service reminders to increase adherence and the proportion of adult tuberculosis patients cured after 6 months of treatment. METHODS: A simple blinded, randomised controlled, multicentre study carried out in 12 Treatment and Diagnostic Centres of Yaounde. The patients included were randomly assigned to two groups: patients in the intervention group received daily SMS reminders in addition to the usual treatment; those in the control group received the usual treatment only. The primary outcomes were the number and proportion of treatment success at 5 months, and the number and proportion of patients cured at 6 months. Data analysis was by intention to treat. RESULTS: Two hundred and seventy-nine participants were randomized into intervention group (n = 137) and control group (n = 142). At five months, there were 111 treatment success (81%) in the intervention group and 106 (74.6%) in the control group (OR = 1.45 [0.81, 2.56]; p = 0.203). At 6 months, there were 87 patients cured (63.5%) in the intervention group and 88 (62%) in the control group (OR = 1.06 [0.65, 1.73]; p = 0.791). The number of drop-outs at 6 months was 47 (34.3%) in intervention group, and 46 (32.4%) in the control group. 48.9% (23/47) and 39.1% (18/46) of these drop-outs were sputum-negative at 5 months. At three different appointments, there were no significant differences between the two groups in any secondary outcomes. Very high and similar satisfaction was found for general management of patients in both groups: 99.5 and 99.2% (p = 0.41). CONCLUSIONS: Our study suggests that SMS reminders do not increase treatment success and cure proportions. However, the low proportion of patients cured at 6 month may be an underestimation due to a high dropout rate between the fifth and the sixth months of treatment. Future trials should focus on reducing the dropout rate. TRIAL REGISTRATION: The trial was registered on the Pan-African Clinical Trials Registry ( PACTR201307000583416 of 22 July 2013) and the protocol was published. PMID- 29720147 TI - CRBP-1 over-expression is associated with poor prognosis in tongue squamous cell carcinoma. AB - BACKGROUND: Tongue squamous cell carcinoma (TSCC) is one of the most common malignancies of oral squamous cell carcinomas. Cellular retinol binding protein-1 (CRBP-1) as a carrier protein transports retinol from the liver storage site to peripheral tissue. Up-regulated expression of CRBP-1 is associated with some tumor types such as prostate cancer, breast cancer and ovarian cancer as reported, but its role in TSCC remains uncertain. METHODS: In this study, an integrated bioinformatics analysis based on the multiple cancer microarray data sets available from Oncomine database was conducted to view the differential expression of CRBP-1 between TSCC and the adjacent non-tumorous tissues. Quantitative real-time polymerase chain reaction (qRT-PCR), western blotting (WB) and immunohistochemical (IHC) assays were performed to investigate CRBP-1 expression in 101 paraffin-embeded TSCC tissues and 48 pairs of freshly frozen tissues. Kaplan-Meier curve and univariate and multivariate Cox-regression analysis were used to estimate the association between CRBP-1 expression and patients' prognosis. Then western blotting, MTT, transwell migration and invasion assays were performed in TSCC cell lines to investigate the effects of CRBP-1 on cellular proliferation and invasion. RESULTS: Compared with the matched adjacent non-tumorous tissues, the expression of CRBP-1 was significantly up-regulated in TSCC tissues, which correlated with the differentiation state (P = 0.003), N classification (P = 0.048), the clinical stage (P = 0.048) and death (P = 0.001). The Kaplan-Meier curve showed that TSCC patients with higher CRBP-1 expression levels had lower overall survival rates than those with lower CRBP-1 expression levels. A univariate and multivariate analysis demonstrated that CRBP-1 was an independent prognostic factor (P < 0.05). Furthermore, we knocked down CRBP-1 expression and observed that TSCC cell proliferation and invasion in vitro were significantly blocked, as determined by MTT and transwell assays. CONCLUSIONS: Up regulated expression of CRBP-1 is associated with poor prognosis in TSCC, so it might potentially serve as an additional prognostic marker, and the inhibition of CRBP-1 might provide new therapeutic approaches for TSCC. PMID- 29720150 TI - Complexity of consenting for medical termination of pregnancy: prospective and longitudinal study in Paris. AB - BACKGROUND: We analyzed the patients' perception of prenatal diagnosis of fetal cardiac pathology, and the reasons for choosing to continue with pregnancy despite being eligible to receive a medical termination of pregnancy. We also identified the challenges, the motives interfering in decision-making, and the consequences of the decisions on pregnancy, child and mother. METHODS: This descriptive, prospective and longitudinal study was conducted in France, amongst pregnant women who wished to continue their pregnancy despite an unfavorable medical advice (incurable fetal cardiac pathologies). Socio-demographic data were collected through a questionnaire. Such questionnaire covered information assessing the parents/mother's perception of prenatal diagnosis, and medical termination of pregnancy, their interpretation of the established diagnosis and their motives for not considering pregnancy termination. RESULTS: 72 eligible patients were analyzed over one year: mean age 33 +/- 6.89 years, 47 patients had already given birth to >=1 healthy child. Mean gestational age at the detection of fetal cardiac pathologies was 30 +/- 4.37 weeks of amenorrhea. Patients decided to keep the child after 3 +/- 1.25 consultations. 56 (77.78%) patients made their decision with their husbands and 16 made their decision alone. Reasons for declining the medical termination were culpability and responsibility (n = 36), ideologies and convictions (n = 24), mistrust and hope (n = 12). Newborns of 67 patients died with a mean survival duration of 38 days. CONCLUSIONS: Patient informed consent should be sought before any decision in neonatology, even if conflicting with the medical team's knowledge and the pregnant mother's benefits. Decisions to accept or decline pregnancy termination depend on the patients' psychological character, ideologies, convictions, and mistrust in the diagnosis/prognosis, or hope in the fetus survival. PMID- 29720149 TI - Evaluation of concordance between CAD/CAM and clinical positions of abutment shoulder against mucosal margin: an observational study. AB - BACKGROUND: While working on CAD/CAM-customized abutments, the use of standard impression copings with a circular diameter produces inconsistency within the emergence profile. It may begin with a collapse of the supra-implant mucosa during impression taking, then lead to a computer-generated mismatch of the position and outline of the abutment shoulder, and consequently result in a compromised outcome of anticipated treatment. The aim of the study was to compare the virtual and clinical positions of the abutment shoulder in relation to the mucosal margin after the abutment delivery. METHODS: Conventional open-tray impression takings followed uncovering surgery. Master casts were scanned with a desktop scanner. Clinical examinations took place after abutment's insertion and temporization (T1) and prior to cementation of the definitive crown (T2). The distances between the abutment shoulder and marginal soft tissue were measured intraorally in four aspects and juxtaposed with those on the virtual model. RESULTS: The study evaluated 257 dental implants and CAD/CAM-customized abutments. As T1 and T2 showed, there was a positive correlation between the virtually designed abutment shoulder position and matching clinical location relative to the mucosal margin. In 42.1% of cases, the distance between the mucosal margin and the abutment shoulder did not change. It increased in 36.3% of cases while a decrease occurred in 21.6% of them. CONCLUSIONS: Computer-set position of the abutment shoulder in relation to the mucosal margin can be predictably implemented in clinical practice. PMID- 29720148 TI - Does Jacobson's relaxation technique reduce consumption of psychotropic and analgesic drugs in cancer patients? A multicenter pre-post intervention study. AB - BACKGROUND: Cancer patients often suffer from emotional distress as a result of the oncological process. The purpose of our study was to determine whether practice of Jacobson's relaxation technique reduced consumption of psychotropic and analgesic drugs in a sample of cancer patients. METHODS: This was a multicenter pre-post intervention design. Participants were 272 patients aged over 18 years attending 10 Spanish public hospitals with oncological pathologies and anxiety symptoms. The intervention consisted of a protocol of abbreviated progressive muscle relaxation training developed by Bernstein and Borkovec. This was followed up by telephone calls over a 1-month period. The intervention was performed between November 2014 and October 2015. Sociodemographic variables related to the oncological process, mental health variables, and intervention characteristics were measured. RESULTS: A reduction in the consumption of psychotropic and analgesic drugs was observed throughout the follow-up period. Improvement was observed throughout the 4-week follow-up for all the parameters assessed: anxiety, relaxation, concentration, and mastery of the relaxation technique. CONCLUSIONS: The practice of abbreviated Jacobson's relaxation technique can help to decrease the consumption of psychotropic and analgesic drugs. Patients experienced positive changes in all the evaluated parameters, at least during the 1-month follow-up. To confirm these findings, additional long term studies are needed that include control groups. TRIAL REGISTRATION: ISRCTN 81335752 , DOI 10.1186/ISRCTN81335752 17. Date of registration: 22/11/2016 (retrospectively registered). PMID- 29720151 TI - AIDS incidence trends at presentation and during follow-up among HIV-at-risk populations: a 15-year nationwide cohort study in Taiwan. AB - BACKGROUND: Although Taiwan has implemented several important interventions for various HIV-at-risk populations to combat the HIV epidemic, little is known regarding AIDS incidence at presentation and during follow-up among the various HIV-at-risk populations in Taiwan. A better understanding of AIDS incidence trends would help improve patient care and optimize public health strategies aimed at further decreasing HIV-related morbidity and mortality. METHODS: Data from Taiwan Centers for Disease Control-operated Notifiable Diseases Surveillance System and Taiwan National Health Insurance Research Database (1998-2012) was divided into five cohort periods (consecutive 3-year groups). Logistic regression was employed to identify factors associated with AIDS incidence at presentation. Time-dependent Cox regression was used to identify factors associated with AIDS incidence during the follow-up period. RESULTS: Of 22,665 patients [mean age: 32 years; male (93.03%)], 6210 (27.4%) had AIDS incidence over 2 (1.16) [median (interquartile range)] years of follow-up. AIDS developed in <=3 months of HIV diagnosis in 73.6% AIDS patients. AIDS incidence trends at presentation and during follow-up differed according to HIV transmission routes over the five periods: AIDS at presentation increased in the sexual contact groups (P < 0.001 for homosexuals/heterosexuals; 0.648 for bisexuals) but decreased to a nadir in period 3 and then increased slightly in period 5 (P < 0.001) in people who injected drugs (PWIDs). AIDS incidence during the follow-up period increased from period 1 to a peak in period 3 or 4, before declining slightly in period 5, in the sexual contact groups (P < 0.001 for homosexuals/heterosexuals; 0.549 for bisexuals). However, it increased throughout the five periods in PWIDs (P < 0.001). Older age, sexual contact group versus PWIDs, high versus low income level, cohort periods, and HIV diagnosis regions helped predict AIDS at presentation and during follow-up. CONCLUSIONS: Disparities in AIDS incidence trends in various HIV-at-risk populations reflect different sociodemographic variables of HIV exposure and the adopted HIV prevention strategies. This study suggests the urgent need for tailored strategies aimed at specific populations at presentation and during follow-up. PMID- 29720152 TI - Glycyrrhiza glabra HPLC fractions: identification of Aldehydo Isoophiopogonone and Liquirtigenin having activity against multidrug resistant bacteria. AB - BACKGROUND: Medicinal plants have been founded as traditional herbal medicine worldwide. Most of the plant's therapeutic properties are due to the presence of secondary metabolites such as alkaloids, glycosides, tannins and volatile oil. METHODS: The present investigation analyzed the High-Pressure Liquid Chromatography (HPLC) fractions of Glycyrrhiza glabra (Aqueous, Chloroform, Ethanol and Hexane) against multidrug resistant human bacterial pathogens (Escherichia coli, Acinetobacter baumannii, Staphylococcus aureus and Pseudomonas aeruginosa). All the fractions showed antibacterial activity, were subjected to LC MS/MS analysis for identification of bioactive compounds. RESULTS: Among total HPLC fractions of G. glabra (n = 20), three HPLC fractions showed potential activity against multidrug resistant (MDR) bacterial isolates. Fraction 1 (F1) of aqueous extracts, showed activity against A. baumannii (15 +/- 0.5 mm). F4 from hexane extract of G. glabra showed activity against S. aureus (10 +/- 0.2 mm). However, F2 from ethanol extract exhibited activity against S. aureus (10 +/- 0.3 mm). These active fractions were further processed by LC MS/MS analysis for the identification of compounds. Ellagic acid was identified in the F1 of aqueous extract while 6-aldehydo-isoophiopogonone was present in F4 of hexane extract. Similarly, Liquirtigenin was identified in F2 of ethanol. CONCLUSIONS: Glycyrrhiza glabra extracts HPLC fractions showed anti-MDR activity. Three bioactive compounds were identified in the study. 6-aldehydo-isoophiopogonone and Liquirtigenin were for the first time reported in G. glabra. Further characterization of the identified compounds will be helpful for possible therapeutic uses against infectious diseases caused by multidrug resistant bacteria. PMID- 29720153 TI - Identifying diabetes cases from administrative data: a population-based validation study. AB - BACKGROUND: Health care data allow for the study and surveillance of chronic diseases such as diabetes. The objective of this study was to identify and validate optimal algorithms for diabetes cases within health care administrative databases for different research purposes, populations, and data sources. METHODS: We linked health care administrative databases from Ontario, Canada to a reference standard of primary care electronic medical records (EMRs). We then identified and calculated the performance characteristics of multiple adult diabetes case definitions, using combinations of data sources and time windows. RESULTS: The best algorithm to identify diabetes cases was the presence at any time of one hospitalization or physician claim for diabetes AND either one prescription for an anti-diabetic medication or one physician claim with a diabetes-specific fee code [sensitivity 84.2%, specificity 99.2%, positive predictive value (PPV) 92.5%]. Use of physician claims alone performed almost as well: three physician claims for diabetes within one year was highly specific (sensitivity 79.9%, specificity 99.1%, PPV 91.4%) and one physician claim at any time was highly sensitive (sensitivity 93.6%, specificity 91.9%, PPV 58.5%). CONCLUSIONS: This study identifies validated algorithms to capture diabetes cases within health care administrative databases for a range of purposes, populations and data availability. These findings are useful to study trends and outcomes of diabetes using routinely-collected health care data. PMID- 29720154 TI - Comparing unplanned and potentially planned home deaths: a population-based cross sectional study. AB - BACKGROUND: There is little research on number of planned home deaths. We need information about factors associated with home deaths, but also differences between planned and unplanned home deaths to improve end-of-life-care at home and make home deaths a feasible alternative. Our aim was to investigate factors associated with home deaths, estimate number of potentially planned home deaths, and differences in individual characteristics between people with and without a potentially planned home death. METHODS: A cross-sectional study of all decedents in Norway in 2012 and 2013, using data from the Norwegian Cause of Death Registry and National registry for statistics on municipal health and care services. We defined planned home death by an indirect algorithm-based method using domiciliary care and diagnosis. We used logistic regressions models to evaluate factors associated with home death compared with nursing home and hospital; and to compare unplanned home deaths and potentially planned home deaths. RESULTS: Among 80,908 deaths, 12,156 (15.0%) were home deaths. A home death was most frequent in 'Circulatory diseases' and 'Cancer', and associated with male sex, younger age, receiving domiciliary care and living alone. Only 2.3% of home deaths were from 'Dementia'. In total, 41.9% of home deaths and 6.3% of all deaths were potentially planned home deaths. Potentially planned home deaths were associated with higher age, but declined in ages above 80 years for people who had municipal care. Living together with someone was associated with more potentially planned home deaths for people with municipal care. CONCLUSION: There are few home deaths in Norway. Our estimations indicate that even fewer people than anticipated have a potentially planned home death. PMID- 29720155 TI - The impact of HCV co-infection status on healthcare-related utilization among people living with HIV in British Columbia, Canada: a retrospective cohort study. AB - BACKGROUND: The burden of HCV among those living with HIV remains a major public health challenge. We aimed to characterize trends in healthcare-related visits (HRV) of people living with HIV (PLW-HIV) and those living with HIV and HCV (PLW HIV/HCV), in British Columbia (BC), and to identify risk factors associated with the highest HRV rates over time. METHODS: Eligible individuals, recruited from the BC Seek and Treat for Optimal Prevention of HIV/AIDS population-based retrospective cohort (N = 3955), were >= 18 years old, first started combination antiretroviral therapy (ART) between 01/01/2000-31/12/2013, and were followed for >=6 months until 31/12/2014. The main outcome was HRV rate. The main exposure was HIV/HCV co-infection status. We built a confounder non-linear mixed effects model, adjusting for several demographic and time-dependent factors. RESULTS: HRV rates have decreased since 2000 in both groups. The overall age-sex standardized HRV rate (per person-year) among PLW-HIV and PLW-HIV/HCV was 21.11 (95% CI 20.96 21.25) and 41.69 (95% CI 41.51-41.88), respectively. The excess in HRV in the co infected group was associated with late presentation for ART, history of injection drug use, sub-optimal ART adherence and a higher number of comorbidities. The adjusted HRV rate ratio for PLW-HIV/HCV in comparison to PLW HIV was 1.18 (95% CI 1.13-1.24). CONCLUSIONS: Although HRV rates have decreased over time in both groups, PLW-HIV/HCV had 18% higher HRV than those only living with HIV. Our results highlight several modifiable risk factors that could be targeted as potential means to minimize the disease burden of this population and of the healthcare system. PMID- 29720156 TI - Trends in healthcare utilization and costs associated with acute otitis media in the United States during 2008-2014. AB - BACKGROUND: Acute otitis media (AOM) is the most common cause of pediatric medical visits and antibiotic prescriptions worldwide, but its current impact on the US healthcare system is not clear. The aim of this study was to investigate changes in the incidence of AOM from 2008, just before 13-valent pneumococcal conjugate vaccine was introduced, to 2014 using US insurance records in the Truven MarketScan(r) database. The study also examined the costs associated with index AOM events during the two most recent years for which data were available (2013-2014). METHODS: AOM cases in the MarketScan database during 2008-2014 were identified using ICD9 diagnosis codes 381.xx and 382.xx. Incidence rates of healthcare utilization related to the index AOM episode were calculated using the annual number of enrolled person-years as the denominator and the number of individuals with AOM as the numerator. AOM-associated costs were calculated as the mean payment per episode during the 2 years from 2013 to 2014. RESULTS: The overall annual rate of AOM-related healthcare utilization was 60.5 per 1000 person-years and changed little from 2008 to 2014 (range, 58.4-62.6). Most of this was due to office/outpatient visits (55.7 [range, 52.0-58.8] per 1000 person years). Emergency department/urgent care visits (4.7 [range 3.7-6.3] per 1000 person-years) and hospitalization (0.0 [range, 0.0-0.1] per 1000 person-years) contributed little. The rate of AOM-related healthcare utilization per 1000 person-years was highest in the youngest children and declined with age (474.3 for < 1 year, 503.9 for 1 year, 316.3 for 2-4 years, 94.9 for 5-17 years, 33.1 for 18-49 years, 28.6 for 50-64 years, 23.7 for 65-74 years, 20.2 for 75-84 years, and 16.1 for >=85 years). The mean cost per AOM episode in 2013-2014 (95% confidence interval) was $199.0 (198.4-199.6) for office or outpatient visits, $329.6 (328.2-331.0) for emergency department/urgent care visits, and $1592.9 (1422.0-1763.8) for hospitalization. CONCLUSIONS: In the US, AOM-associated healthcare utilization and costs remain substantial. More effective preventive measures such as new vaccines are needed to reduce the burden of AOM. PMID- 29720157 TI - Increase in premature mortality due to non-communicable diseases in Sri Lanka during the first decade of the twenty-first century. AB - BACKGROUND: Globally, non-communicable diseases (NCD) are the leading cause of death and more than 40% of NCD deaths are premature occurring before the age of 70 years. In 2012, World Health Assembly declared its commitment to reduce premature NCD mortality by 25% from 2010 to 2025. The trend of premature NCD deaths in Sri Lanka has not been assessed and thus this study was done to assess it between 2001 to 2010. METHODS: Deaths due to cardiovascular diseases, cancers, chronic respiratory diseases and diabetes were studied. Premature NCD mortality was assessed using unconditional probability of dying (UPoD) due to NCDs among those aged 30 to 70 years. Number of relevant premature NCD deaths that occurred in each 5-year age interval and the respective mid-year population was used to calculate UPoD. RESULTS: During the period of 2001 to 2010, premature NCD mortality in Sri Lanka increased from 15.8% to 19.1% and males showed higher mortality compared to females throughout the period. Highest mortality was due to cardiovascular diseases followed by cancer and diabetes and all three showed an increasing trend. Chronic respiratory diseases showed an increase until 2004 and dropped thereafter. Among the four NCDs, diabetes revealed the most marked increasing trend in premature mortality during this period. CONCLUSIONS: The data revealed an increasing trend of premature NCD mortality in Sri Lanka between 2001 and 2010 although it has a relatively lower premature NCD mortality rate in the South-East Asian Region. Therefore, reducing premature NCD mortality by 25% from 2010 to 2025 is likely to be a rather challenging task in Sri Lanka and policy level changes need to be taken to achieve this target. PMID- 29720158 TI - A systematic review comparing neurodevelopmental outcome in term infants with hypoxic and vascular brain injury with and without seizures. AB - BACKGROUND: There is increasing evidence that neonatal seizures in term neonates with stroke, asphyxia or brain haemorrhage might be associated with adverse neurodevelopment and development of epilepsy. The extent of this association is not known. The objective of this study was to assess the possible impact of neonatal seizures on these outcomes and if possible calculate a relative risk. METHODS: A systematic review and meta-analysis was performed (study period January 2000-June 2015). PubMed, Medline and Embase were searched for cohort studies evaluating neurodevelopmental outcome at the age of at least 18 months or development of epilepsy in surviving term neonates with or without neonatal seizures. The methodological quality of included studies was assessed and data extractions were performed in a standardized manner by independent reviewers. Pooled Relative Risks (RR) with 95% confidence intervals for adverse outcome were calculated if possible. RESULTS: Out of 1443 eligible studies 48 were selected for full text reading leaving 9 cohort studies for the final analyses (4 studies on stroke, 4 on perinatal asphyxia and one on cerebral hemorrhage). For all cases with stroke or asphyxia combined the pooled risk ratio (RR) for adverse outcome when suffering neonatal seizures was 7.42 (3.84-14.34); for neonates with perinatal asphyxia: 8.41 (4.07-17.39) and for neonates with stroke: 4.95 (1.07 23.0). The pooled RR for development of late onset epilepsy could only be determined for infants suffering from stroke: 1.48 (0.82-2.68). Results were biased and evidence sparse. CONCLUSIONS: The presence of neonatal seizures in term newborns with vascular or hypoxic brain injury may have an impact on or be a predictor of neurodevelopmental outcome. The biased available data yield insufficient evidence about the true size of this association. PMID- 29720159 TI - Development of a baculovirus vector carrying a small hairpin RNA for suppression of sf-caspase-1 expression and improvement of recombinant protein production. AB - BACKGROUND: The Baculovirus expression vector system (BEVS) is a transient expression platform for recombinant protein production in insect cells. Baculovirus infection of insect cells will shutoff host translation and induce apoptosis and lead to the termination of protein expression. Previous reports have demonstrated the enhancement of protein yield in BEVS using stable insect cell lines expressing interference RNA to suppress the expression of caspase-1. RESULTS: In this study, short-hairpin RNA (shRNA) expression cassettes targeting Spodoptera frugiperda caspase-1 (Sf-caspase-1) were constructed and inserted into an Autographa californica multiple nucleopolyhedrovirus (AcMNPV) vector. Using the recombinant baculovirus vectors, we detected the suppression of Sf-caspase-1 expression and cell apoptosis. Green fluorescent protein (GFP), Discosoma sp. Red (DsRed) and firefly luciferase were then expressed as reporter proteins. The results showed that suppression of apoptosis enhanced the accumulation of exogenous proteins at 2 and 3 days post infection. After 4 days post infection, the activity of the reporter proteins remained higher in BEVS using the baculovirus carrying shRNA in comparison with the control without shRNA, but the accumulated protein levels showed no obvious difference between them, suggesting that apoptosis suppression resulted in improved protein folding rather than translation efficiency at the very late stage of baculovirus infection. CONCLUSIONS: The baculovirus vector developed in this study would be a useful tool for the production of active proteins suitable for structural and functional studies or pharmaceutical applications in Sf9 cells, and it also has the potential to be adapted for the improvement of protein expression in different insect cell lines that can be infected by AcMNPV. PMID- 29720160 TI - Brazilian propolis ethanol extract and its component kaempferol induce myeloid derived suppressor cells from macrophages of mice in vivo and in vitro. AB - BACKGROUND: Brazilian green propolis is produced by mixing secretions from Africanized honey bees with exudate, mainly from Baccharis dracunculifolia. Brazilian propolis is especially rich in flavonoids and cinammic acid derivatives, and it has been widely used in folk medicine owing to its anti inflammatory, anti-viral, tumoricidal, and analgesic effects. Moreover, it is applied to prevent metabolic disorders, such as type 2 diabetes and arteriosclerosis. Previously, we demonstrated that propolis ethanol extract ameliorated type 2 diabetes in a mouse model through the resolution of adipose tissue inflammation. The aims of this study were to identify the immunosuppressive cells directly elicited by propolis extract and to evaluate the flavonoids that induce such cells. METHODS: Ethanol extract of Brazilian propolis (PEE; 100 mg/kg i.p., twice a week) was injected into lean or high fat-fed obese C57BL/6 mice or C57BL/6 ob/ob mice for one month. Subsequently, immune cells in visceral adipose tissue and the peritoneal cavity were monitored using FACS analysis. Isolated macrophages and the macrophage-like cell line J774.1 were treated with PEE and its constituent components, and the expression of immune suppressive myeloid markers were evaluated. Finally, we injected one of the identified compounds, kaempferol, into C57BL/6 mice and performed FACS analysis on the adipose tissue. RESULTS: Intraperitoneal treatment of PEE induces CD11b+, Gr-1+ myeloid-derived suppressor cells (MDSCs) in visceral adipose tissue and the peritoneal cavity of lean and obese mice. PEE directly stimulates cultured M1 macrophages to transdifferentiate into MDSCs. Among twelve compounds isolated from PEE, kaempferol has an exclusive effect on MDSCs induction in vitro. Accordingly, intraperitoneal injection of kaempferol causes accumulation of MDSCs in the visceral adipose tissue of mice. CONCLUSION: Brazilian PEE and its compound kaempferol strongly induce MDSCs in visceral adipose tissue at a relatively early phase of inflammation. Given the strong anti-inflammatory action of MDSCs, the induction of MDSCs by PEE and kaempferol is expected to be useful for anti-diabetic and anti-inflammatory therapies. PMID- 29720161 TI - Evaluation of a training program of hypertension for accredited social health activists (ASHA) in rural India. AB - BACKGROUND: Hypertension is a major risk factor for cardiovascular disease, a leading cause of premature death and disability in India. Since access to health services is poor in rural India and Accredited Social Health Activists (ASHAs) are available throughout India for maternal and child health, a potential solution for improving hypertension control is by utilising this available workforce. We aimed to develop and implement a training package for ASHAs to identify and control hypertension in the community, and evaluate the effectiveness of the training program using the Kirkpatrick Evaluation Model. METHODS: The training program was part of a cluster randomised feasibility trial of a 3-month intervention to improve hypertension outcomes in South India. Training materials incorporated details on managing hypertension, goal setting, facilitating group meetings, and how to measure blood pressure and weight. The 15 ASHAs attended a five-day training workshop that was delivered using interactive instructional strategies. ASHAs then led community-based education support groups for 3 months. Training was evaluated using Kirkpatrick's evaluation model for measuring reactions, learning, behaviour and results using tests on knowledge at baseline, post-training and post-intervention, observation of performance during meetings and post-intervention interviews. RESULTS: The ASHAs' knowledge of hypertension improved from a mean score of 64% at baseline to 76% post-training and 84% after the 3-month intervention. Research officers, who observed the community meetings, reported that ASHAs delivered the self-management content effectively without additional assistance. The ASHAs reported that the training materials were easy to understand and useful in educating community members. CONCLUSION: ASHAs can be trained to lead community-based group educational discussions and support individuals for the management of high blood pressure. TRIAL REGISTRATION: The feasibility trial is registered with the Clinical Trials Registry - India (CTRI) CTRI/2016/02/006678 (25/02/2016). PMID- 29720162 TI - Uptake of health checks by residents from the Danish social housing sector - a register-based cross-sectional study of patient characteristics in the 'Your Life - Your Health' program. AB - BACKGROUND: Poor uptake among socio-economically disadvantaged and susceptible populations is a well-known challenge of general health check interventions, and is widely cited as one of the reasons for the lack of population level effects seen in many studies. We report on patient characteristics among attendees and non-attendees of health checks made available to residents in the social housing sector of the municipality of Aarhus. We focus on this general population, as well as a particular sub-group living in an exceptionally deprived social housing area, and discuss the properties of intervention uptake that we need to be aware of to qualify and compare the effects of general versus targeted health checks in socially deprived areas. METHODS: Cross-sectionally in a sample of 6650 residents of the Aarhus social housing sector who were invited for a health check in the first year of the 'Your Life - Your Health' program. The analyses consisted of 1) descriptive analysis of the characteristics of attenders/non-attenders, 2) unadjusted and adjusted Poisson regression to examine associations of patient characteristics and uptake of health checks, and 3) decision tree analyses (CHAID) to examine interaction and homogeneity in patient characteristics among attenders. RESULTS: Of the overall population 30% attended. In a nested cohort of people residing in a particularly deprived social housing settlement, 25% attended. Further, in the overall population, we found an association between the likelihood of taking up a health check and age, sex, country of origin, educational attainment, cohabitation, occupational status, and past medical treatment. In the nested cohort the association between uptake and medical treatment was non-significant, while the association between uptake and occupation was limited to people who were employed. These results resonate with past evidence on health check attendance. CONCLUSIONS: Attendance in the 'Your Life - Your Health' program is higher among people of a higher socio-economic status. This should be taken into consideration when analysing and interpreting the overall study effects. Moreover, the results suggest that a targeted approach in the social housing sector could be more effective than a mass screening approach. However, more information is required to make such assertion definitive. PMID- 29720163 TI - Caregivers' compliance with referral advice: evidence from two studies introducing mRDTs into community case management of malaria in Uganda. AB - BACKGROUND: Several malaria endemic countries have implemented community health worker (CHW) programmes to increase access to populations underserved by health care. There is considerable evidence on CHW adherence to case management guidelines, however, there is limited evidence on the compliance to referral advice and the outcomes of children under-5 referred by CHWs. This analysis examined whether caregivers complied with CHWs referral advice. METHODS: Data from two cluster (village) randomised trials, one in a moderate-to-high malaria transmission setting, another in a low-transmission setting conducted between January 2010-July 2011 were analysed. CHW were trained to recognise signs and symptoms that required referral to a health centre. CHW in the intervention arm also had training on; malaria rapid diagnostic tests (mRDT) and administering artemisinin based combination therapy (ACT); CHW in the control arm were trained to treat malaria with ACTs based on fever symptoms. Caregivers' referral forms were linked with CHW treatment forms to determine whether caregivers complied with the referral advice. Factors associated with compliance were examined with logistic regression. RESULTS: CHW saw 18,497 child visits in the moderate-to-high transmission setting and referred 15.2% (2815/18,497) of all visits; in the low transmission setting, 35.0% (1135/3223) of all visits were referred. Compliance to referral was low, in both settings < 10% of caregivers complied with referral advice. In the moderate-to-high transmission setting compliance was higher if children were tested with mRDT compared to children who were not tested with mRDT. In both settings, nearly all children treated with pre-referral rectal artesunate failed to comply with referral and compliance was independently associated with factors such as health centre distance and day of referral by a CHW. In the moderate-to-high transmission setting, time of presentation, severity of referral were also associated with compliance, whilst in the low-transmission setting, compliance was low if an ACT was prescribed. CONCLUSIONS: This analysis suggests there are several barriers to comply with CHWs referral advice by caregivers. This is concerning for children who received rectal artesunate. As CHW programmes continue scale-up, barriers to referral compliance need to be addressed to ensure a continuum of care from the community to the health centre. TRIAL REGISTRATION: The study was registered with ClinicalTrials.gov. Identifier NCT01048801 , 13th January 2010. PMID- 29720164 TI - Attitude towards working in rural areas: a cross-sectional survey of rural oriented tuition-waived medical students in Shaanxi, China. AB - BACKGROUND: Attracting and recruiting health workers to work in rural areas is still a great challenge in China. The rural-oriented tuition-waived medical education (RTME) programme has been initiated and implemented in China since 2010. This study aimed to examine the attitudes of rural-oriented tuition-waived medical students (RTMSs) in Shaanxi towards working in rural areas and the related influencing factors. METHODS: A cross-sectional survey was conducted in 2015 among 232 RTMSs in two medical universities from the first group of students enrolled in the RTME programme in Shaanxi. Descriptive and analytical statistics were used for the data analyses. RESULTS: Of the 230 valid responses, 92.6% expressed their intentions of breaking the contract for working in rural township hospitals for 6 years after their graduation under the RTME programme. After the contract expired, only 1.3% intended to remain in the rural areas, 66.5% had no intention of remaining, and 32.2% were unsure. The factors related to a positive attitude among the RTMSs towards working in rural areas (no intention of breaking the contract) included being female, having a mother educated at the level of primary school or below, having a good understanding of the policy, having a good cognition of the value of rural medical work, and being satisfied with the policy. The factors related to a positive attitude of the RTMSs towards remaining in rural areas included being female, having a rural origin, having no regular family monthly income, having a father whose occupation was farmer, having a mother educated at the level of postsecondary or above, having the RTMSs be the final arbiter of the policy choice, having a good understanding of the policy, having a good cognition of the value of rural medical work, and being satisfied with the educational scheme. CONCLUSIONS: Related policy makers and health workforce managers may benefit from the findings of this study. Appropriate strategies should be implemented to stimulate the RTMSs' intrinsic motivation and improve their willingness to work in rural areas and to better achieve the objectives of RTME policy. Meanwhile, measures to increase the retention of RTMSs should also be advanced. PMID- 29720165 TI - Perspectives of nursing professionals and older adults differ on aspects of care for older people after a nationwide improvement program. AB - BACKGROUND: The perspectives of nursing professionals might differ from those of older adults when it comes to care for older people. This cross-sectional study compares the views of older adults with the views of nursing professionals on the quality of care after a nationwide improvement program for care for older people was implemented (2008-2016) in the Netherlands. METHODS: Questionnaire data were used from 385 nursing professionals (response rate 51%) that were part of the Nursing Staff Panel, a nationwide representative group of nursing staff, and working in home care, hospitals or general practices. Additionally, questionnaire data were used from 73 older adults (response rate 81%) who were involved in regional networks to discuss project proposals and to represent the voice of older adults in the nationwide improvement program. Participants were asked to evaluate care for older people with regard to collaboration between healthcare organizations and with regard to the tailored service, accessibility, and quality of care within their organizations and in the region in which they lived. RESULTS: A majority of older adults (54%) and nursing professionals (61%) felt that collaboration with others had improved over the last few years. Approximately one third of the older adults stated that care for older people was tailored to fit individual needs and was accessible most of the time or always, as opposed to approximately two thirds of the professionals. Moreover, 17% older adults thought that the quality of care was good, compared with 54% of the nursing professionals. 77% of the nursing professionals and 94% of the older adults thought that improvements were still needed in care for older people, for example better integration of the different aspects of care and a more patient centered approach. CONCLUSION: Older adults who were involved in networks of the improvement program generally gave a less positive evaluation of aspects of care for older people and its development than nursing professionals. Considering differences in the perspectives of key stakeholders is relevant for the development and evaluation of nationwide improvement programs, for a correct interpretation of findings, and for making appropriate recommendations. PMID- 29720166 TI - Inhibitory effects of sodium pentosan polysulfate on formation and function of osteoclasts derived from canine bone marrow. AB - BACKGROUND: Sodium pentosan polysulfate (NaPPS) was testified as a chondroprotective drug in with a detailed rationale of the disease-modifying activity. This study was undertaken to determine whether anti-osteoarthritis drug, NaPPS inhibited osteoclasts (OC) differentiation and function. Canine bone marrow mononuclear cells (n = 6) were differentiated to OC by maintaining with receptor activator of nuclear factor kappa B ligand (RANKL) and macrophage colony stimulating factor (M-CSF) for up to 7 days with the treatment of NaPPS at concentration of 0, 0.2, 1 and 5 MUg/mL. Differentiation and function of OC were accessed using tartrate-resistant acid phosphate (TRAP) staining and bone resorption assay, while monitoring actin ring formation. Invasion and colocalization patterns of fluorescence-labeled NaPPS with transcribed gene in OC were monitored. Gene expression of OC for cathepsin K (CTK), matrix metallopeptidase-9 (MMP-9), nuclear factor of activated T-cells cytoplasmic 1 (NFATc1), c-Fos, activator protein-1(AP-1) and carbonic anhydrase II was examined using real-time PCR. RESULTS: Significant inhibition of OC differentiation was evident at NaPPS concentration of 1 and 5 MUg/mL (p < 0.05). In the presence of 0.2 to 5 MUg/mL NaPPS, bone resorption was attenuated (p < 0.05), while 1 and 5 MUg/mL NaPPS achieved significant reduction of actin ring formation. Intriguingly, fluorescence-labeled NaPPS invaded in to cytoplasm and nucleus while colocalizing with actively transcribed gene. Gene expression of CTK, MMP-9 and NFATc1 were significantly inhibited at 1 and 5 MUg/mL (p < 0.05) of NaPPS whereas inhibition of c-Fos and AP-1 was identified only at concentration of 5 MUg/mL (p < 0.05). CONCLUSIONS: Taken together, all the results suggest that NaPPS is a novel inhibitor of RANKL and M-CSF-induced CTK, MMP-9, NFATc1, c-Fos, AP-1 upregulation, OC differentiation and bone resorption which might be a beneficial for treatment of inflammatory joint diseases and other bone diseases associated with excessive bone resorption. PMID- 29720167 TI - Development of a neonatal curriculum for medical students in Zimbabwe - a cross sectional survey. AB - BACKGROUND: Calls have been made to reassess the curricula of medical schools throughout the world to adopt competence-based programs that address the healthcare needs of society. Zimbabwe is a country characterized by a high neonatal mortality rate of 24 per 1000 live births. The current research sought to determine the content and appropriate teaching strategies needed to guide the development of an undergraduate neonatal curriculum map for medical students at the University of Zimbabwe College of Health Sciences. METHODS: We surveyed faculty (n = 8) and non-faculty pediatricians (n = 5), senior resident medical officers (N = 26) using a self-administered questionnaire, and completed one focus group discussion with midwives (n = 11). We asked respondents their expectations regarding knowledge, psychomotor skills, competencies, and teaching strategies in a basic newborn curriculum for medical students. Relevant policy and curricula documents were reviewed to assess newborn health needs and the current training. A group of faculty educationists (n = 11) collated and finalized the findings from the document review, survey, and focus group using descriptive statistics and thematic analysis. RESULTS: The document review revealed three key neonatal health objectives according to the current national maternal and neonatal health road map. These objectives are to be met using a four tier approach comprising (i) family planning (ii) focused antenatal care (iii) clean and safe delivery and (iv) basic and comprehensive emergency obstetric & neonatal care. Existing curriculum has 15 newborn topics taught in lecture style during the pediatric rotations, and five newborn care skills to be learned through observation. The existing curriculum is silent on desired competencies. In the current study 19 cognitive areas, 17 psychomotor skills and six competency domains were identified for an ideal neonatal curriculum for undergraduate students. A combination of teaching strategies including classroom, simulation and a clinical rotation were recommended. CONCLUSION: This study revealed a significant gap between the existing neonatal curriculum and the ideal curriculum as recommended by broad stakeholders in the context of national health care needs. Next steps are to complete the development and implementation of the proposed curriculum map to better align with the ideal state. PMID- 29720168 TI - Challenges for health care providers, parents and patients who face a child hood cancer diagnosis in Zambia. AB - BACKGROUND: Zambia is experiencing high prevalence of childhood cancer. However, very few children access and complete treatment for cancer. This study aimed to document the challenges for health care providers, parents and patients who face a child hood cancer diagnosis in Zambia, and their coping strategies. METHODS: This was an exploratory health facility-based qualitative study that was conducted at a Paediatric oncology ward at referral hospital in Zambia. In-depth individual interviews conducted with fifteen (15) caregivers and seven (7) key informants were analysed using thematic analysis. RESULTS: Several challenges related to managing the childhood cancer diagnosis were recorded. Individual and family challenges were inadequate knowledge on childhood cancer, lack of finances to meet treatment and transport costs as well as long period of hospitalisation that affected women's ability to perform multiple responsibilities. Whereas challenges at community level were inadequate support to address emotional and physical distress and social stigmatisation experienced by caregivers. Health systems issues included inadequate specialised health workers, poor communication among health workers, limited space and beds as well as insufficient supplies such as blood. Cultural related factors were the belief that cancer is a product of witchcraft as well as religious beliefs regarding the role of faith healing in childhood cancer treatment. Coping strategies used by parents/ caregivers included praying to God, material support from organisations and church as well as delaying having another child. CONCLUSION: Addressing the challenges for health care providers, parents and patients who face a childhood cancer diagnosis may require adopting a systems or an ecological approach that allows developing strategies that simultaneously address challenges related to the individual, family, community, health system and cultural aspects. PMID- 29720170 TI - The use of assistive technology in shoulder exercise rehabilitation - a qualitative study of acceptability within a pilot project. AB - BACKGROUND: Painful shoulders pose a substantial socioeconomic burden accounting for 2.4% of all primary care consultations in the UK. There is a strong evidence to indicate that the majority of this shoulder pain can be managed successfully with exercise based treatments and that common surgical procedures provide no extra benefit. Patient adherence and engagement is cited as an important factor in gaining positive outcomes. The MUJO System has been designed to help target the rehabilitation of the rotator cuff muscles which are commonly recommended for the management of shoulder pain. The purpose of this qualitative study was to evaluate the acceptability of the MUJO System amongst clinicians and patients. METHODS: A qualitative study was undertaken to look at the usability of the MUJO System both from clinicians' and patients' perspectives. Patients with shoulder problems were identified by an experienced physiotherapist using the study eligibility criteria. and invited to participate. Semi-structured interviews were performed with patients and clinicians to explore factors surrounding its acceptability and feasibility of use. The study was designed using Normalisation Process Theory as a theoretical basis for the inquiry. RESULTS: Seven physiotherapists and ten patients were interviewed in the study. The Internal and External Devices were seen as having the potential to rehabilitate the rotator cuff however it posed limitations towards more functional based exercises. Patients and clinicians found the visual feedback from the Patient App enhanced the rehabilitation experience. The Internal and External Devices were acceptable to all for rehabilitation providing the devices were available for use by the patients in the community. CONCLUSION: Patients and clinicians found the MUJO System acceptable as a modality to perform shoulder exercises. For the MUJO System to be taken up as a routine part of clinical practice patients need to be able to access the devices in the community. For the MUJO System to be taken up in clinical practice it needs to be workable within the context of the treatment pathway and not interfere with standard processes. PMID- 29720169 TI - ATR-101, a selective ACAT1 inhibitor, decreases ACTH-stimulated cortisol concentrations in dogs with naturally occurring Cushing's syndrome. AB - BACKGROUND: Cushing's syndrome in humans shares many similarities with its counterpart in dogs in terms of etiology (pituitary versus adrenal causes), clinical signs, and pathophysiologic sequelae. In both species, treatment of pituitary- and adrenal-dependent disease is met with limitations. ATR-101, a selective inhibitor of ACAT1 (acyl coenzyme A:cholesterol acyltransferase 1), is a novel small molecule therapeutic currently in clinical development for the treatment of adrenocortical carcinoma, congenital adrenal hyperplasia, and Cushing's syndrome in humans. Previous studies in healthy dogs have shown that ATR-101 treatment led to rapid, dose-dependent decreases in adrenocorticotropic hormone (ACTH) stimulated cortisol levels. The purpose of this clinical study was to investigate the effects of ATR-101 in dogs with Cushing's syndrome. METHODS: ATR-101 pharmacokinetics and activity were assessed in 10 dogs with naturally occurring Cushing's syndrome, including 7 dogs with pituitary-dependent disease and 3 dogs with adrenal-dependent disease. ATR-101 was administered at 3 mg/kg PO once daily for one week, followed by 30 mg/kg PO once daily for one (n = 4) or three (n = 6) weeks. Clinical, biochemical, adrenal hormonal, and pharmacokinetic data were obtained weekly for study duration. RESULTS: ATR-101 exposure increased with increasing dose. ACTH-stimulated cortisol concentrations, the primary endpoint for the study, were significantly decreased with responders (9 of 10 dogs) experiencing a mean +/- standard deviation reduction in cortisol levels of 50 +/- 17% at study completion. Decreases in pre-ACTH-stimulated cortisol concentrations were observed in some dogs although overall changes in pre-ACTH cortisol concentrations were not significant. The compound was well-tolerated and no serious drug-related adverse effects were reported. CONCLUSIONS: This study highlights the potential utility of naturally occurring canine Cushing's syndrome as a model for human disease and provides proof of concept for ATR-101 as a novel agent for the treatment of endocrine disorders like Cushing's syndrome in humans. PMID- 29720171 TI - Improved ethanol productivity from lignocellulosic hydrolysates by Escherichia coli with regulated glucose utilization. AB - BACKGROUND: Lignocellulosic ethanol could offer a sustainable source to meet the increasing worldwide demand for fuel. However, efficient and simultaneous metabolism of all types of sugars in lignocellulosic hydrolysates by ethanol producing strains is still a challenge. RESULTS: An engineered strain Escherichia coli B0013-2021HPA with regulated glucose utilization, which could use all monosaccharides in lignocellulosic hydrolysates except glucose for cell growth and glucose for ethanol production, was constructed. In E. coli B0013-2021HPA, pta-ackA, ldhA and pflB were deleted to block the formation of acetate, lactate and formate and additional three mutations at glk, ptsG and manZ generated to block the glucose uptake and catabolism, followed by the replacement of the wild type frdA locus with the ptsG expression cassette under the control of the temperature-inducible lambda pR and pL promoters, and the final introduction of pEtac-PA carrying Zymomonas mobilis pdc and adhB for the ethanol pathway. B0013 2021HPA was able to utilize almost all xylose, galactose and arabinose but not glucose for cell propagation at 34 degrees C and converted all sugars to ethanol at 42 degrees C under oxygen-limited fermentation conditions. CONCLUSIONS: Engineered E. coli strain with regulated glucose utilization showed efficient metabolism of mixed sugars in lignocellulosic hydrolysates and thus higher productivity of ethanol production. PMID- 29720172 TI - Awareness, perceptions and intent to comply with the prospective malaria vaccine in parts of South Eastern Nigeria. AB - BACKGROUND: There are potentials of a malaria vaccine being developed sooner than expected. While focus is more on the development of a vaccine, less attention has been paid on the extent to which such vaccines could be well accepted and the readiness among caregivers to comply with its use in order to achieve the effectiveness of the vaccine in the malaria endemic areas. Compliance rates are influenced by the level of awareness, as well as the perception of the population. This cross-sectional study was aimed at assessing the awareness, perceptions and intent to comply with the prospective malaria vaccine by caregivers in Owerri West, South Eastern Nigeria. METHODS: Structured pretested questionnaires were used to collect data from 500 randomly selected consenting care givers (mostly mothers). Items used to assess the intent to comply with the vaccine include willingness to accept and use the vaccine, and allow children to be vaccinated. RESULTS: The study found that awareness of malaria as a public health problem was high (89.8%), but awareness about a prospective malaria vaccine was not high (48.2%). Up to 88.2% of respondents showed positive perception towards the vaccine, of which 65.2% had strong positive perception. The study found high level of intent to comply with the prospective malaria vaccine among the study group (95.6% positive). Significant association was established between caregivers perception and intent to comply with the prospective malaria vaccine (chi2 = 144.52; p < 0.0001). CONCLUSIONS: While malaria vaccine adoption is likely to be a welcome development in South Eastern Nigeria, proper consideration should be given to factors that are likely to influence people's perceptions about vaccines in the plans/process of malaria vaccine development and vaccination programmes. PMID- 29720174 TI - Early life diet conditions the molecular response to post-weaning protein restriction in the mouse. AB - BACKGROUND: Environmental influences fluctuate throughout the life course of an organism. It is therefore important to understand how the timing of exposure impacts molecular responses. Herein, we examine the responses of two key molecular markers of dietary stress, namely variant-specific methylation at ribosomal DNA (rDNA) and small RNA distribution, including tRNA fragments, in a mouse model of protein restriction (PR) with exposure at pre- and/or post weaning. RESULTS: We first confirm that pre-weaning PR exposure modulates the methylation state of rDNA in a genotype-dependent manner, whereas post-weaning PR exposure has no such effect. Conversely, post-weaning PR induces a shift in small RNA distribution, but there is no effect in the pre-weaning PR model. Intriguingly, mice exposed to PR throughout their lives show neither of these two dietary stress markers, similar to controls. CONCLUSIONS: The results show that the timing of the insult affects the nature of the molecular response but also, critically, that 'matching' diet exposure either side of weaning eliminates the stress response at the level of rDNA methylation and small RNA in sperm. PMID- 29720173 TI - Clinical validation and assessment of aortic hemodynamics using computational fluid dynamics simulations from computed tomography angiography. AB - BACKGROUND: Hemodynamic information including peak systolic pressure (PSP) and peak systolic velocity (PSV) carry an important role in evaluation and diagnosis of congenital heart disease (CHD). Since MDCTA cannot evaluate hemodynamic information directly, the aim of this study is to provide a noninvasive method based on a computational fluid dynamics (CFD) model, derived from multi-detector computed tomography angiography (MDCTA) raw data, to analyze the aortic hemodynamics in infants with CHD, and validate these results against echocardiography and cardiac catheter measurements. METHODS: This study included 25 patients (17 males, and 8 females; a median age of 2 years, range: 4 months-4 years) with CHD. All patients underwent both transthoracic echocardiography (TTE) and MDCTA within 2 weeks prior to cardiac catheterization. CFD models were created from MDCTA raw data. Boundary conditions were confirmed by lumped parameter model and transthoracic echocardiography (TTE). Peak systolic velocity derived from CFD models (PSVCFD) was compared to TTE measurements (PSVTTE), while the peak systolic pressure derived from CFD (PSPCFD) was compared to catheterization (PSPCC). Regions with low and high peak systolic wall shear stress (PSWSS) were also evaluated. RESULTS: PSVCFD and PSPCFD showed good agreements between PSVTTE (r = 0.968, p < 0.001; mean bias = - 7.68 cm/s) and PSPCC (r = 0.918, p < 0.001; mean bias = 1.405 mmHg). Regions with low and high PSWSS) can also be visualized. Skewing of velocity or helical blood flow was also observed at aortic arch in patients. CONCLUSIONS: Our result demonstrated that CFD scheme based on MDCTA raw data is an accurate and convenient method in obtaining the velocity and pressure from aorta and displaying the distribution of PSWSS and flow pattern of aorta. The preliminary results from our study demonstrate the capability in combining clinical imaging data and novel CFD tools in infants with CHD and provide a noninvasive approach for diagnose of CHD such as coarctation of aorta in future. PMID- 29720175 TI - Challenges for the surgical capacity building of township hospitals among the Central China: a retrospective study. AB - BACKGROUND: China's rapid transition in healthcare service system has posed considerable challenges for the primary care system. Little is known regarding the capacity of township hospitals (THs) to deliver surgical care in rural China with over 600 million lives. We aimed to ascertain its current performance, barriers, and summary lessons for its re-building in central China. METHODS: This study was conducted in four counties from two provinces in central China. The New Rural Cooperative Medical System (NRCMS) claim data from two counties in Hubei province was analyzed to describe the current situation of surgical care provision. Based on previous studies, self-administered questionnaire was established to collect key indicators from 60 THs from 2011 to 2015, and social and economic statuses of the sampling townships were collected from the local statistical yearbook. Semi-structured interviews were conducted among seven key administrators in the THs that did not provide appendectomy care in 2015. Determinants of appendectomy care provision were examined using a negative binominal regression model. RESULTS: First, with the rapid increase in inpatient services provided by the THs, their proportion of surgical service provision has been nibbled by out-of-county facilities. Second, although DY achieved a stable performance, the total amount of appendectomy provided by the 60 THs decreased to 589 in 2015 from 1389 in 2011. Moreover, their proportion reduced to 26.77% in 2015 from 41.84% in 2012. Third, an increasing number of THs did not provide appendectomy in 2015, with the shortage of anesthesiologists and equipment as the most mentioned reasons (46.43%). Estimation results from the negative binomial model indicated that the annual average per capita disposable income and tightly integrated delivery networks (IDNs) negatively affected the amount of appendectomy provided by THs. By contrast, the probability of appendectomy provision by THs was increased by performance-related payment (PRP). Out-of pocket (OOP) cost gap of appendectomy services between the two different levels of facilities, payment method, and the size of THs presented no observable improvement to the likelihood of appendectomy care in THs. CONCLUSION: The county level health system did not effectively respond to the continuously increasing surgical care need. The surgical capacity of THs declined with the surgical patterns' simplistic and quantity reduction. Deficits and critical challenges for surgical capacity building in central China were identified, including shortage of human resources and medical equipment and increasing income. Moreover, tight IDNs do not temporarily achieve capacity building. Therefore, the reimbursement rate should be further ranged, and physicians should be incentivized appropriately. The administrators, policy makers, and medical staff of THs should be aware of these findings owing to the potential benefits for the capacity building of the rural healthcare system. PMID- 29720176 TI - Six-year time-trend analysis of dyslipidemia among adults in Newfoundland and Labrador: findings from the laboratory information system between 2009 and 2014. AB - BACKGROUND: Dyslipidemia, an increased level of total cholesterol (TC), triglycerides (TG), low-density-lipoprotein cholesterol (LDL-C) and decreased level of high-density-lipoprotein cholesterol (HDL-C), is one of the most important risk factors for cardiovascular disease. We examined the six-year trend of dyslipidemia in Newfoundland and Labrador (NL), a Canadian province with a historically high prevalence of dyslipidemia. METHODS: A serial cross-sectional study on all of the laboratory lipid tests available from 2009 to 2014 was performed. Dyslipidemia for every lipid component was defined using the Canadian Guidelines for the Diagnosis and Treatment of Dyslipidemia. The annual dyslipidemia rates for each component of serum lipid was examined. A fixed and random effect model was applied to adjust for confounding variables (sex and age) and random effects (residual variation in dyslipidemia over the years and redundancies caused by individuals being tested multiple times during the study period). RESULTS: Between 2009 and 2014, a total of 875,208 records (mean age: 56.9 +/- 14.1, 47.6% males) containing a lipid profile were identified. The prevalence of HDL-C and LDL-C dyslipidemia significantly decreased during this period (HDL-C: 35.8% in 2009 [95% CI 35.5-36.1], to 29.0% in 2014 [95% CI: 28.8 29.2], P = 0.03, and LDL-C: 35.2% in 2009 [95% CI: 34.9-35.4] to 32.1% in 2014 [95% CI: 31.9-32.3], P = 0.02). A stratification by sex, revealed no significant trend for any lipid element in females; however, in men, the previously observed trends were intensified and a new decreasing trend in dyslipidemia of TC was appeared (TC: 34.1% [95% CI 33.7-34.5] to 32.3% [95%CI: 32.0-32.6], p < 0.02, HDL C: 33.8% (95%CI: 33.3-34.2) to 24.0% (95% CI: 23.7-24.3)], P < 0.01, LDL-C: 32.9% (95%CI:32.5-33.3) to 28.6 (95%CI: 28.3-28.9), P < 0.001). Adjustment for confounding factors and removing the residual noise by modeling the random effects did not change the significance. CONCLUSION: This study demonstrates a significant downward trend in the prevalence of LDL-C, HDL-C, and TC dyslipidemia, exclusively in men. These trends could be the result of males being the primary target for cardiovascular risk management. PMID- 29720177 TI - Genomic characterization of chronic lymphocytic leukemia (CLL) in radiation exposed Chornobyl cleanup workers. AB - BACKGROUND: Chronic lymphocytic leukemia (CLL) was the predominant leukemia in a recent study of Chornobyl cleanup workers from Ukraine exposed to radiation (UR CLL). Radiation risks of CLL significantly increased with increasing bone marrow radiation doses. Current analysis aimed to clarify whether the increased risks were due to radiation or to genetic mutations in the Ukrainian population. METHODS: A detailed characterization of the genomic landscape was performed in a unique sample of 16 UR-CLL patients and age- and sex-matched unexposed general population Ukrainian-CLL (UN-CLL) and Western-CLL (W-CLL) patients (n = 28 and 100, respectively). RESULTS: Mutations in telomere-maintenance pathway genes POT1 and ATM were more frequent in UR-CLL compared to UN-CLL and W-CLL (both p < 0.05). No significant enrichment in copy-number abnormalities at del13q14, del11q, del17p or trisomy12 was identified in UR-CLL compared to other groups. Type of work performed in the Chornobyl zone, age at exposure and at diagnosis, calendar time, and Rai stage were significant predictors of total genetic lesions (all p < 0.05). Tumor telomere length was significantly longer in UR-CLL than in UN-CLL (p = 0.009) and was associated with the POT1 mutation and survival. CONCLUSIONS: No significant enrichment in copy-number abnormalities at CLL associated genes was identified in UR-CLL compared to other groups. The novel associations between radiation exposure, telomere maintenance and CLL prognosis identified in this unique case series provide suggestive, though limited data and merit further investigation. PMID- 29720180 TI - Identification of key gene modules for human osteosarcoma by co-expression analysis. AB - BACKGROUND: Osteosarcoma is a type of bone cancer casting huge threat to the human health worldwide. Previously, gene expression analyses were performed to identify biomarkers for cancer; however, systemic co-expression analysis for osteosarcoma is still in need. The aim of this study was to construct a gene co expression network that predicts clusters of candidate genes associated with the pathogenesis of osteosarcoma. METHODS: Here, we extracted the large scale of datasets from the GEO database. With systematical approaches, we identified the co-expression modules by using weighted gene co-expression network analysis (WGCNA) and investigated the functional enrichments of important modules at GO and KEGG terms. RESULTS: First, seven co-expression modules, which contain different genes, were conducted for 2228 genes in the 22 human osteosarcoma samples. Then, correlation study showed that the hub genes between pairwise modules displayed great differences. Lastly, functional enrichments of the co expression modules showed that the module 5 enriched in immune response, antigen processing, and presentation, which is in consistence with GO result. Therefore, we speculated that the module 5 may play a key role in the pathogenesis of osteosarcoma. CONCLUSIONS: Here, we speculated that genes of the module 5 were the essential genes that were associated to human osteosarcoma. Together, our findings not only provided outline of co-expression gene modules for human osteosarcoma, but also promoted the understanding of these modules at functional aspects. PMID- 29720179 TI - Structural patterns of selection and diversity for Plasmodium vivax antigens DBP and AMA1. AB - BACKGROUND: Plasmodium vivax is a significant contributor to the global malaria burden, and a vaccine targeting vivax malaria is urgently needed. An understanding of the targets of functional immune responses during the course of natural infection will aid in the development of a vaccine. Antibodies play a key role in this process, with responses against particular epitopes leading to immune selection pressure on these epitopes. A number of techniques exist to estimate levels of immune selection pressure on particular epitopes, with a sliding window analysis often used to determine particular regions likely to be under immune pressure. However, such analysis neglects protein three-dimensional structural information. With this in mind, a newly developed tool, BioStructMap, was applied to two key antigens from Plasmodium vivax: PvAMA1 and PvDBP Region II. This tool incorporates structural information into tests of selection pressure. RESULTS: Sequences from a number of populations were analysed, examining spatially-derived nucleotide diversity and Tajima's D over protein structures for PvAMA1 and PvDBP. Structural patterns of nucleotide diversity were similar across all populations examined, with Domain I of PvAMA1 having the highest nucleotide diversity and displaying significant signatures of immune selection pressure (Tajima's D > 0). Nucleotide diversity for PvDBP was highest bordering the dimerization and DARC-binding interface, although there was less evidence of immune selection pressure on PvDBP compared with PvAMA1. This study supports previous work that has identified Domain I as the main target of immune mediated selection pressure for PvAMA1, and also supports studies that have identified functional epitopes within PvDBP Region II. CONCLUSIONS: The BioStructMap tool was applied to leading vaccine candidates from P. vivax, to examine structural patterns of selection and diversity across a number of geographic populations. There were striking similarities in structural patterns of diversity across multiple populations. Furthermore, whilst regions of high diversity tended to surround conserved binding interfaces, a number of protein regions with very low diversity were also identified, and these may be useful targets for further vaccine development, given previous evidence of functional antibody responses against these regions. PMID- 29720178 TI - A new approach for analysis of heart rate variability and QT variability in long term ECG recording. AB - BACKGROUND AND PURPOSE: With the emergence of long-term electrocardiogram (ECG) recordings that extend several days beyond the typical 24-48 h, the development of new tools to measure heart rate variability (HRV) and QT variability is needed to utilize the full potential of such extra-long-term ECG recordings. METHODS: In this report, we propose a new nonlinear time-frequency analysis approach, the concentration of frequency and time (ConceFT), to study the HRV QT variability from extra-long-term ECG recordings. This approach is a generalization of Short Time Fourier Transform and Continuous Wavelet Transform approaches. RESULTS: As proof of concept, we used 14-day ECG recordings to show that the ConceFT provides a sharpened and stabilized spectrogram by taking the phase information of the time series and the multitaper technique into account. CONCLUSION: The ConceFT has the potential to provide a sharpened and stabilized spectrogram for the heart rate variability and QT variability in 14-day ECG recordings. PMID- 29720181 TI - Multiplicity and molecular epidemiology of Plasmodium vivax and Plasmodium falciparum infections in East Africa. AB - BACKGROUND: Parasite genetic diversity and multiplicity of infection (MOI) affect clinical outcomes, response to drug treatment and naturally-acquired or vaccine induced immunity. Traditional methods often underestimate the frequency and diversity of multiclonal infections due to technical sensitivity and specificity. Next-generation sequencing techniques provide a novel opportunity to study complexity of parasite populations and molecular epidemiology. METHODS: Symptomatic and asymptomatic Plasmodium vivax samples were collected from health centres/hospitals and schools, respectively, from 2011 to 2015 in Ethiopia. Similarly, both symptomatic and asymptomatic Plasmodium falciparum samples were collected, respectively, from hospitals and schools in 2005 and 2015 in Kenya. Finger-pricked blood samples were collected and dried on filter paper. Long amplicon (> 400 bp) deep sequencing of merozoite surface protein 1 (msp1) gene was conducted to determine multiplicity and molecular epidemiology of P. vivax and P. falciparum infections. The results were compared with those based on short amplicon (117 bp) deep sequencing. RESULTS: A total of 139 P. vivax and 222 P. falciparum samples were pyro-sequenced for pvmsp1 and pfmsp1, yielding a total of 21 P. vivax and 99 P. falciparum predominant haplotypes. The average MOI for P. vivax and P. falciparum were 2.16 and 2.68, respectively, which were significantly higher than that of microsatellite markers and short amplicon (117 bp) deep sequencing. Multiclonal infections were detected in 62.2% of the samples for P. vivax and 74.8% of the samples for P. falciparum. Four out of the five subjects with recurrent P. vivax malaria were found to be a relapse 44-65 days after clearance of parasites. No difference was observed in MOI among P. vivax patients of different symptoms, ages and genders. Similar patterns were also observed in P. falciparum except for one study site in Kenyan lowland areas with significantly higher MOI. CONCLUSIONS: The study used a novel method to evaluate Plasmodium MOI and molecular epidemiological patterns by long amplicon ultra-deep sequencing. The complexity of infections were similar among age groups, symptoms, genders, transmission settings (spatial heterogeneity), as well as over years (pre- vs. post-scale-up interventions). This study demonstrated that long amplicon deep sequencing is a useful tool to investigate multiplicity and molecular epidemiology of Plasmodium parasite infections. PMID- 29720182 TI - Spectrum of low-density lipoprotein receptor (LDLR) mutations in a cohort of Sri Lankan patients with familial hypercholesterolemia - a preliminary report. AB - BACKGROUND: Hypercholesterolemia is a major determinant of cardiovascular disease associated morbidity and mortality. Mutations in the LDL-receptor (LDLR) gene are implicated in the majority of the cases with familial hypercholesterolemia (FH). However, the spectrum of mutations in the LDLR gene in Sri Lankan patients has not been investigated. The objective of this study was to report the frequency and spectrum of variants in LDLR in a cohort of Sri Lankan patients with FH. METHODS: A series of consecutive patients with FH, diagnosed according to Modified Simon Broome criteria or Dutch Lipid Clinic Network criteria at the University Medical Unit, Colombo, were recruited. Clinical data was recorded. DNA was extracted from peripheral blood samples. The LDLR gene was screened for genetic variants by Sanger sequencing. RESULTS: A total of 27 patients [13 (48%) males, 14 (52%) females; age range 24-73 years] were tested. Clinical features found among these 27 patients were: xanthelasma in 5 (18.5%), corneal arcus in 1 (3.7%), coronary artery disease (CAD) in 10 (37%), and a family history of hypercholesterolemia and/or CAD in 24 (88.9%) patients. In the entire cohort, mean total cholesterol was 356.8 mg/dl (+/-66.4) and mean LDL-cholesterol was 250.3 mg/dl (+/-67.7). Sanger sequencing of the 27 patients resulted in the identification of known pathogenic missense mutations in 5 (18.5%) patients. Four were heterozygotes for 1 mutation each. They were c.682G > C in 2 patients, c.1720C > A in 1 patient, and c.1855 T > A in 1 patient. One patient with severe FH phenotypes was a compound heterozygote for one known mutation, c.2289G > T, and another missense variant, c.1670C > G (p.Thr557Ser), with unknown functional impact. This latter variant has not been reported in any other population previously. CONCLUSIONS: The frequency of known mutations in the LDLR gene in this cohort of patients was markedly low compared to frequencies reported in other populations. This highlights the likelihood of a complex, polygenic inheritance of FH in Sri Lankan patients, indicating the need for a comprehensive genetic evaluation that includes the screening for mutations in other genes that cause FH, such as APOB, PCSK9, and LDLRAP1. PMID- 29720184 TI - Correction to: Polymorphisms in chloroquine resistance-associated genes in Plasmodium vivax in Ethiopia. AB - After publication of the original article [1], it came to the authors' attention that the primers mentioned in Table 1 for the amplification of the pvcrt-o gene of Plasmodium vivax are not the ones actually used for the experiments. The correct primers and PCR product size are as below. PMID- 29720183 TI - Disrupted sphingolipid metabolism following acute clozapine and olanzapine administration. AB - BACKGROUND: Second generation antipsychotics (SGAs) induce glucometabolic side effects, such as hyperglycemia and insulin resistance, which pose a therapeutic challenge for mental illness. Sphingolipids play a role in glycaemic balance and insulin resistance. Endoplasmic reticulum (ER) stress contributes to impaired insulin signalling and whole-body glucose intolerance. Diabetogenic SGA effects on ER stress and sphingolipids, such as ceramide and sphingomyelin, in peripheral metabolic tissues are unknown. This study aimed to investigate the acute effects of clozapine and olanzapine on ceramide and sphingomyelin levels, and protein expression of key enzymes involved in lipid and glucose metabolism, in the liver and skeletal muscle. METHODS: Female rats were administered olanzapine (1 mg/kg), clozapine (12 mg/kg), or vehicle (control) and euthanized 1-h later. Ceramide and sphingomyelin levels were examined using electrospray ionization (ESI) mass spectrometry. Expression of lipid enzymes (ceramide synthase 2 (CerS2), elongation of very long-chain fatty acid 1 (ELOVL1), fatty acid synthase (FAS) and acetyl CoA carboxylase 1 (ACC1)), ER stress markers (inositol-requiring enzyme 1 (IRE1) and eukaryotic initiation factor (eIF2alpha) were also examined. RESULTS: Clozapine caused robust reductions in hepatic ceramide and sphingolipid levels (p < 0.0001), upregulated CerS2 (p < 0.05) and ELOVL1 (+ 37%) and induced significant hyperglycemia (vs controls). In contrast, olanzapine increased hepatic sphingomyelin levels (p < 0.05 vs controls). SGAs did not alter sphingolipid levels in the muscle. Clozapine increased (+ 52.5%) hepatic eIF2alpha phosphorylation, demonstrating evidence of activation of the PERK/eIF2alpha ER stress axis. Hepatic IRE1, FAS and ACC1 were unaltered. CONCLUSIONS: This study provides the first evidence that diabetogenic SGAs disrupt hepatic sphingolipid homeostasis within 1-h of administration. Sphingolipids may be key candidates in the mechanisms underlying the diabetes side-effects of SGAs; however, further research is required. PMID- 29720185 TI - Exercise training and endothelial function in patients with type 2 diabetes: a meta-analysis. AB - BACKGROUND AND AIMS: Exercise training is considered a cornerstone in the management of type 2 diabetes, which is associated with impaired endothelial function. However, the association of exercise training with endothelial function in type 2 diabetes patients has not been fully understood. This meta-analysis aimed to investigate their associations with focus on exercise types. METHODS: Databases were searched up to January 2018 for studies evaluating the influences of exercise training with durations >= 8 weeks on endothelial function assessed by flow-mediated dilation (FMD) among type 2 diabetes patients or between type 2 diabetics and non-diabetics. Data were pooled using random-effects models to obtain the weighted mean differences (WMDs) and 95% confidence intervals (CIs). RESULTS: Sixteen databases were included. Exercise training resulted in an overall improvement in FMD by 1.77% (95% CI 0.94-2.59%) in type 2 diabetes patients. Specifically, both aerobic and combined aerobic and resistance exercise increased FMD by 1.21% (95% CI 0.23-2.19%) and 2.49% (95% CI 1.17-3.81%), respectively; but resistance exercise only showed a trend. High-intensity interval aerobic exercise did not significantly improve FMD over moderate intensity continuous exercise. Notably, the improvement in FMD among type 2 diabetes patients was smaller compared with non-diabetics in response to exercise training (WMD - 0.72%, 95% CI - 1.36 to - 0.08%) or specifically to aerobic exercise (WMD - 0.65%, 95% CI - 1.31 to 0.01%). CONCLUSIONS: Exercise training, in particular aerobic and combined exercise, improves endothelial function in type 2 diabetes patients, but such an improvement appears to be weakened compared with non-diabetics. Trial registration PROSPERO CRD42018087376. PMID- 29720186 TI - Correction to: Developing a tablet computer-based application ('App') to measure self-reported alcohol consumption in Indigenous Australians. AB - After publication of the original article [1] it was noted that the name of author, Peter Jack, was erroneously typeset in both the PDF and online formats of the manuscript as Peter Jack GradDipIndigH. PMID- 29720187 TI - Simulation as a preoperative planning approach in advanced heart failure patients. A retrospective clinical analysis. AB - BACKGROUND: Modelling and simulation may become clinically applicable tools for detailed evaluation of the cardiovascular system and clinical decision-making to guide therapeutic intervention. Models based on pressure-volume relationship and zero-dimensional representation of the cardiovascular system may be a suitable choice given their simplicity and versatility. This approach has great potential for application in heart failure where the impact of left ventricular assist devices has played a significant role as a bridge to transplant and more recently as a long-term solution for non eligible candidates. RESULTS: We sought to investigate the value of simulation in the context of three heart failure patients with a view to predict or guide further management. CARDIOSIM(c) was the software used for this purpose. The study was based on retrospective analysis of haemodynamic data previously discussed at a multidisciplinary meeting. The outcome of the simulations addressed the value of a more quantitative approach in the clinical decision process. CONCLUSIONS: Although previous experience, co morbidities and the risk of potentially fatal complications play a role in clinical decision-making, patient-specific modelling may become a daily approach for selection and optimisation of device-based treatment for heart failure patients. Willingness to adopt this integrated approach may be the key to further progress. PMID- 29720188 TI - Two clusters of Plasmodium knowlesi cases in a malaria elimination area, Sabang Municipality, Aceh, Indonesia. AB - In malaria elimination areas, malaria cases are sporadic and consist predominantly of imported cases. Plasmodium knowlesi cases have been reported throughout Southeast Asia where long-tailed and pig-tailed macaques and Anopheles leucosphyrus group mosquitoes are sympatric. The limitation of microscopic examination to diagnose P. knowlesi is well known. In consequence, no P. knowlesi case has previously been reported from routine health facility-based case finding activities in Indonesia. This report describes two clusters of unexpected locally acquired P. knowlesi cases found in an area where Plasmodium falciparum and Plasmodium vivax infection had been eliminated in Sabang Municipality, Aceh, Indonesia. The difficulties in diagnosis and response illustrate challenges that Southeast Asian countries will increasingly face as the formerly common malaria parasites P. falciparum and P. vivax are gradually eliminated from the region. PMID- 29720189 TI - LncRNA MT1JP functions as a ceRNA in regulating FBXW7 through competitively binding to miR-92a-3p in gastric cancer. AB - BACKGROUND: Emerging evidence has shown that dysregulation function of long non coding RNAs (lncRNAs) implicated in gastric cancer (GC). However, the role of the differentially expressed lncRNAs in GC has not fully explained. METHODS: LncRNA expression profiles were determined by lncRNA microarray in five pairs of normal and GC tissues, further validated in another 75 paired tissues by quantitative real-time PCR (qRT-PCR). Overexpression of lncRNA MT1JP was conducted to assess the effect of MT1JP in vitro and in vivo. The biological functions were demonstrated by luciferase reporter assay, western blotting and rescue experiments. RESULTS: LncRNA MT1JP was significantly lower in GC tissues than adjacent normal tissues, and higher MT1JP was remarkably related to lymph node metastasis and advance stage. Besides, GC patients with higher MT1JP expression had a well survival. Functionally, overexpression of lncRNA MT1JP inhibited cell proliferation, migration, invasion and promoted cell apoptosis in vitro, and inhibited tumor growth and metastasis in vivo. Functional analysis showed that lncRNA MT1JP regulated FBXW7 expression by competitively binding to miR-92a-3p. MiR-92a-3p and down-regulated FBXW7 reversed cell phenotypes caused by lncRNA MT1JP by rescue analysis. CONCLUSION: MT1JP, a down-regulated lncRNA in GC, was associated with malignant tumor phenotypes and survival of GC. MT1JP regulated the progression of GC by functioning as a competing endogenous RNA (ceRNA) to competitively bind to miR-92a-3p and regulate FBXW7 expression. Our study provided new insight into the post-transcriptional regulation mechanism of lncRNA MT1JP, and suggested that MT1JP may act as a potential therapeutic target and prognosis biomarker for GC. PMID- 29720190 TI - Factors associated with health-related quality of life in patients with functional dyspepsia. AB - BACKGROUND: Health-related quality of life (HRQoL) assessment is important for patients with functional dyspepsia. However, no studies have assessed factors associated with HRQoL reduction in such patients in an Asian population. This study aimed to determine the contribution of clinical, psychosocial, and demographic factors to HRQoL in affected patients in Indonesia. METHODS: In a cross-sectional study, we recruited 124 patients in a tertiary hospital with functional dyspepsia according to Rome III criteria. HRQoL was measured using the Medical Outcomes Study Short-Form 36 (SF-36) physical component summary (PCS) and mental component summary (MCS) and compared with 2009 United States population norms. The factors investigated were age, gender, symptom severity, education level, employment status, anxiety, depression, and ethnicity. Factors associated with reduced HRQoL were identified using linear regression analysis. RESULTS: All domains of HRQoL except vitality were impaired in patients with functional dyspepsia. The mean PCS was 42.3 (SD = 8.4); and the mean MCS was 47.8 (SD = 10). Increasing age (p = 0.002), female gender (p = 0.006), low-to-mid education level (p = 0.015) and greater symptom severity (p < 0.001) were significantly associated with impaired PCS (R2 = 0.36). Female gender (p = 0.047), greater symptom severity (p = 0.002), anxiety (p = 0.001), and depression (p = 0.002 were all significantly associated with an impaired MCS (R2 = 0.41). There were no significant associations between HRQoL and with ethnic group (Javanese/non Javanese) or employment status. CONCLUSIONS: There was significant HRQoL impairment in these patients with functional dyspepsia in Indonesia. Anxiety, depression, increasing age, female gender, greater symptom severity, and low-to mid education level were significant factors associated with low HRQoL. TRIAL REGISTRATION: ClinicalTrials.gov NCT03321383 . Registered 18 October 2017 retrospectively registered. PMID- 29720191 TI - Pulmonary inflammation-induced loss and subsequent recovery of skeletal muscle mass require functional poly-ubiquitin conjugation. AB - BACKGROUND: Pulmonary inflammation in response to respiratory infections can evoke muscle wasting. Increased activity of the ubiquitin (Ub)-proteasome system (UPS) and the autophagy lysosome pathway (ALP) have been implicated in inflammation-induced muscle atrophy. Since poly-Ub conjugation is required for UPS-mediated proteolysis and has been implicated in the ALP, we assessed the effect of impaired ubiquitin conjugation on muscle atrophy and recovery following pulmonary inflammation, and compared activation and suppression of these proteolytic systems to protein synthesis regulation. METHODS: Pulmonary inflammation was induced in mice by an intratracheal instillation of LPS. Proteolysis (UPS and ALP) and synthesis signaling were examined in gastrocnemius muscle homogenates. Ub-conjugation-dependency of muscle atrophy and recovery was addressed using Ub-K48R (K48R) mice with attenuated poly-ubiquitin conjugation, and compared to UBWT control mice. RESULTS: Pulmonary inflammation caused a decrease in skeletal muscle mass which was accompanied by a rapid increase in expression of UPS and ALP constituents and reduction in protein synthesis signaling acutely after LPS. Muscle atrophy was attenuated in K48R mice, while ALP and protein synthesis signaling were not affected. Muscle mass recovery starting 72 h post LPS, correlated with reduced expression of UPS and ALP constituents and restoration of protein synthesis signaling. K48R mice however displayed impaired recovery of muscle mass. CONCLUSION: Pulmonary inflammation induced muscle atrophy is in part attributable to UPS-mediated proteolysis, as activation of ALP- and suppression of protein synthesis signaling occur independently of poly-Ub conjugation during muscle atrophy. Recovery of muscle mass following pulmonary inflammation involves inverse regulation of proteolysis and protein synthesis signaling, and requires a functional poly-Ub conjugation. PMID- 29720193 TI - Assessing health-related quality of life in Japanese children with a chronic condition: validation of the DISABKIDS chronic generic module. AB - BACKGROUND: This study examined the reliability and validity of the Japanese versions of the DISABKIDS-37 generic modules, a tool for assessing the health related quality of life (HRQOL) of children and adolescents with a chronic condition. METHODS: The study was conducted using a sample of 123 children/adolescents with a chronic medical condition, aged 8-18 years, and their parents. Focus interviews were performed to ensure content validity after translation. The classical psychometric tests were used to assess reliability and scale intercorrelations. The factor structure was examined with confirmatory factor analysis (CFA). Convergent validity was assessed by the correlation between the total score and the sub-scales of DISABKIDS-37 as well as the total score of KIDSCREEN-10. RESULTS: Both the children/adolescent and parent versions of the score showed good to high internal consistency, and the test-retest reliability correlations were r = 0.91 or above. The CFA revealed that the modified models for all domains were better fit than the original 37 item scale model for both self-report and proxy-report. Moderate to high positive correlations were found for the associations within DISABKIDS-37 sub-scales and between the subscales and total score, except for the treatment sub-scale, which correlated weakly with the remaining sub-scales. The total score of the child reported version of KIDSCREEN-10 correlated significantly and positively with the total score and all the sub-scales of the child-reported version of DISABKIDS-37 except the Treatment sub-scale in adolescents. CONCLUSIONS: The modified models of Japanese version of DISABKIDS generic module were psychometrically robust enough to assess the HRQOL of children with a chronic condition. PMID- 29720192 TI - The impact of severe haemophilia and the presence of target joints on health related quality-of-life. AB - BACKGROUND: Joint damage remains a major complication associated with haemophilia and is widely accepted as one of the most debilitating symptoms for persons with severe haemophilia. The aim of this study is to describe how complications of haemophilia such as target joints influence health-related quality of life (HRQOL). METHODS: Data on hemophilia patients without inhibitors were drawn from the 'Cost of Haemophilia across Europe - a Socioeconomic Survey' (CHESS) study, a cost-of-illness assessment in severe haemophilia A and B across five European countries (France, Germany, Italy, Spain, and the UK). Physicians provided clinical and sociodemographic information for 1285 adult patients, 551 of whom completed corresponding questionnaires, including EQ-5D. A generalised linear model was developed to investigate the relationship between EQ-5D index score and target joint status (defined in the CHESS study as areas of chronic synovitis), adjusted for patient covariates including socio-demographic characteristics and comorbidities. RESULTS: Five hundred and fifteen patients (42% of the sample) provided an EQ-5D response; a total of 692 target joints were recorded across the sample. Mean EQ-5D index score for patients with no target joints was 0.875 (standard deviation [SD] 0.179); for patients with one or more target joints, mean index score was 0.731 (SD 0.285). Compared to having no target joints, having one or more target joints was associated with lower index scores (average marginal effect (AME) -0.120; SD 0.0262; p < 0.000). CONCLUSIONS: This study found that the presence of chronic synovitis has a significant negative impact on HRQOL for adults with severe haemophilia. Prevention, early diagnosis and treatment of target joints should be an important consideration for clinicians and patients when managing haemophilia. PMID- 29720194 TI - Increase in fertility following coal and oil power plant retirements in California. AB - BACKGROUND: Few studies have explored the relationship between air pollution and fertility. We used a natural experiment in California when coal and oil power plants retired to estimate associations with nearby fertility rates. METHODS: We used a difference-in-differences negative binomial model on the incident rate ratio scale to analyze the change in annual fertility rates among California mothers living within 0-5 km and 5-10 km of 8 retired power plants between 2001 and 2011. The difference-in-differences method isolates the portion of the pre- versus post-retirement contrast in the 0-5 km and 5-10 km bins, respectively, that is due to retirement rather than secular trends. We controlled for secular trends with mothers living 10-20 km away. Adjusted models included fixed effects for power plant, proportion Hispanic, Black, high school educated, and aged > 30 years mothers, and neighborhood poverty and educational attainment. RESULTS: Analyses included 58,909 live births. In adjusted models, we estimated that after power plant retirement annual fertility rates per 1000 women aged 15-44 years increased by 8 births within 5 km and 2 births within 5-10 km of power plants, corresponding to incident rate ratios of 1.2 (95% CI: 1.1-1.4) and 1.1 (95% CI: 1.0-1.2), respectively. We implemented a negative exposure control by randomly selecting power plants that did not retire and repeating our analysis with those locations using the retirement dates from original 8 power plants. There was no association, suggesting that statewide temporal trends may not account for results. CONCLUSIONS: Fertility rates among nearby populations appeared to increase after coal and oil power plant retirements. Our study design limited the possibility that our findings resulted from temporal trends or changes in population composition. These results require confirmation in other populations, given known methodological limitations of ecologic study designs. PMID- 29720196 TI - The relationship between quality of life and physical fitness in people with severe mental illness. AB - BACKGROUND: Quality of life of people with severe mental illness may be decrease by the high occurrence of metabolic and cardiovascular diseases. Physical fitness emerges as a modifying factor in this population through physical activity and this modification could influence in the quality of life of this population. The aim of the present study is to determine the contribution of physical fitness to the quality of life of people with severe mental illness. METHODS: In the current study, a physiotherapist and an occupational therapist assessed 62 people with severe mental illness. Physical fitness was measured with a range of 11 fitness tests that covered flexibility, strength, balance, and endurance. To assess quality of life the EQ-5D-3 L scale was used, which measures five dimensions (mobility, self-care, usual activities, pain-discomfort, and anxiety-depression). RESULTS: Significant correlations are presented between the quality of life and primary variables of physical fitness (balance, endurance, and upper limb strength). Endurance explained 22.9% of the variance of the quality of life in people with severe mental illness. Functional reach added another 36.2% variance to the prediction of quality of life. CONCLUSIONS: The results of the present study suggest that some variables of physical fitness are associated with quality of life in people with severe mental illness. The improvement in physical fitness of this population should be a primary objective. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02413164 "retrospective registered" Registered Febr 2017. PMID- 29720195 TI - Characterization of Plasmodium relictum, a cosmopolitan agent of avian malaria. AB - BACKGROUND: Microscopic research has shown that Plasmodium relictum is the most common agent of avian malaria. Recent molecular studies confirmed this conclusion and identified several mtDNA lineages, suggesting the existence of significant intra-species genetic variation or cryptic speciation. Most identified lineages have a broad range of hosts and geographical distribution. Here, a rare new lineage of P. relictum was reported and information about biological characters of different lineages of this pathogen was reviewed, suggesting issues for future research. METHODS: The new lineage pPHCOL01 was detected in Common chiffchaff Phylloscopus collybita, and the parasite was passaged in domestic canaries Serinus canaria. Organs of infected birds were examined using histology and chromogenic in situ hybridization methods. Culex quinquefasciatus mosquitoes, Zebra finch Taeniopygia guttata, Budgerigar Melopsittacus undulatus and European goldfinch Carduelis carduelis were exposed experimentally. Both Bayesian and Maximum Likelihood analyses identified the same phylogenetic relationships among different, closely-related lineages pSGS1, pGRW4, pGRW11, pLZFUS01, pPHCOL01 of P. relictum. Morphology of their blood stages was compared using fixed and stained blood smears, and biological properties of these parasites were reviewed. RESULTS: Common canary and European goldfinch were susceptible to the parasite pPHCOL01, and had markedly variable individual prepatent periods and light transient parasitaemia. Exo-erythrocytic and sporogonic stages were not seen. The Zebra finch and Budgerigar were resistant. Neither blood stages nor vector stages of all examined P. relictum lineages can be distinguished morphologically. CONCLUSION: Within the huge spectrum of vertebrate hosts, mosquito vectors, and ecological conditions, different lineages of P. relictum exhibit indistinguishable, markedly variable morphological forms. Parasites of same lineages often develop differently in different bird species. Even more, the variation of biological properties (parasitaemia dynamics, blood pathology, prepatent period) in different isolates of the same lineage might be greater than the variation in different lineages during development in the same species of birds, indicating negligible taxonomic value of such features. Available lineage information is excellent for parasite diagnostics, but is limited in predictions about relationships in certain host-parasite associations. A combination of experiments, field observations, microscopic and molecular diagnostics is essential for understanding the role of different P. relictum lineages in bird health. PMID- 29720197 TI - The prognostic role of hemoglobin levels in patients undergoing concurrent chemo radiation for anal cancer. AB - BACKGROUND: Concurrent chemo-radiation (CT-RT) is a standard therapy for squamous cell carcinoma of anal canal. Different clinical and biological factors may potentially affect outcome. We investigated the prognostic role of baseline hemoglobin (Hb) in a cohort of anal cancer patients submitted to CT-RT with 5 fluorouracil and mitomycin C. METHODS: Up to 161 patients with clinical stage T1 T4/N0-N3/M0 were treated. Response was assessed at 6 weeks and thereafter at 3, 6 and 12 months. Two different approaches were used:a)simultaneous integrated boost following RTOG 05-29 indications;b)first sequence of 45Gy/25 fractions to the pelvis followed by 9-14.4 Gy/5-8 fractions to the macroscopic disease. Primary endpoints were progression-free survival (PFS) and overall survival (OS). RESULTS: On multivariate analysis, pre-treatment Hb level had a significant correlation to OS (HR:0.53;95% CI:0.33-0.87; p = 0.001), but not to PFS (HR:0.78;95% CI:0.53-1.15; p = 0.12) Patients with pre-treatment Hb >= 12 g/dl had 5-year PFS and OS of 82.2%, compared to 29.3% and 32.8% for those below the threshold. The likelihood to achieve a complete remission increased by 5.6% for every single-unit (g/dl) increase in baseline Hb level over 11 g/dl. On multivariate analysis, response to treatment had a significant correlation to PFS (incomplete vs complete response - HR:5.43;95% CI:2.75-10.7; p < 0.0001) and OS (HR: 6.96;95% CI:2.96-16.5; p < 0.0001). CONCLUSIONS: We showed that baseline Hb level is a strong indicator for poor response to RT-CT in anal cancer patients. A close clinical monitoring for incomplete response to treatment should be advised in patients with low pre-treatment Hb. The hypothesis that the preservation of adequate Hb level during treatment may lead to a better outcome needs prospective evaluation. PMID- 29720198 TI - Translation and validation of the French version of the Child Perceptions Questionnaire for children aged from 8 to 10 years old (CPQ 8-10). AB - BACKGROUND: The Child Perceptions Questionnaire (CPQ) belongs to a set of questionnaires measuring Child Oral Health Quality of Life (COHQOL). The CPQ is used to collect the perceptions of children on the impact of oral diseases on their quality of life. This cross-sectional study was aimed to translate the CPQ8 10 into French language and evaluate its psychometric properties. METHODS: The translation process complied with international recommendations. The final French version was tested on children aged 8-10 years old attending consultations in a Parisian public hospital and divided into three groups: children with oral-facial clefts, children with dental anomalies linked to a rare disease other than clefts and children presumed to be healthy and without anomalies. The internal consistency relating to the reliability of CPQ8-10 was evaluated by Cronbach's alpha. The intra-class correlation was used to measure reproducibility at the test-retest level. Construct validity was evaluated by Spearman's correlation and tested using factor analysis. The discriminant validity was assessed using Kruskall Wallis test. Criterion validity was calculated using Spearman's correlation. RESULTS: One hundred seventy-six children participated in this study. During the translation process, minor changes were made. The French version showed good reliability with a Cronbach's alpha of 0.81 for the total scale. The ICC of the test-retest was excellent (=0.90) demonstrating good reproducibility. The construct validity was acceptable with a statistically significant correlation between the scores of the French-CPQ8-10 and the evaluation of oral health (r = 0. 381 and p < 0.001) and its impact on oral health quality of life (r = 0.363 and p < 0.001). The loading weights obtained in the Exploratory Factor Analysis showed that this model revealed seven factors with eigenvalue greater than 1, explaining the 63,89% of the cumulative variance. The differences observed between the scores of the study groups revealed good discriminant validity. Criterion validity was supported by significant association between CPQ scores and pain. CONCLUSION: The French-CPQ8-10 is reliable and valid for use with the children of this age group. PMID- 29720199 TI - Immunoassays for scarce tumour-antigens in exosomes: detection of the human NKG2D Ligand, MICA, in tetraspanin-containing nanovesicles from melanoma. AB - BACKGROUND: Tumour-derived exosomes can be released to serum and provide information on the features of the malignancy, however, in order to perform systematic studies in biological samples, faster diagnostic techniques are needed, especially for detection of low abundance proteins. Most human cancer cells are positive for at least one ligand for the activating immune receptor NKG2D and the presence in plasma of NKG2D-ligands can be associated with prognosis. METHODS: Using MICA as example of a tumour-derived antigen, endogenously expressed in metastatic melanoma and recruited to exosomes, we have developed two immunocapture-based assays for detection of different epitopes in nanovesicles. Although both techniques, enzyme-linked immunosorbent assay (ELISA) and Lateral flow immunoassays (LFIA) have the same theoretical basis, that is, using capture and detection antibodies for a colorimetric read-out, analysis of exosome-bound proteins poses methodological problems that do not occur when these techniques are used for detection of soluble molecules, due to the presence of multiple epitopes on the vesicle. RESULTS: Here we demonstrate that, in ELISA, the signal obtained was directly proportional to the amount of epitopes per exosome. In LFIA, the amount of detection antibody immobilized in Au nanoparticles needs to be low for efficient detection, otherwise steric hindrance results in lower signal. We describe the conditions for detection of MICA in exosomes and prove, for the first time using both techniques, the co-existence in one vesicle of exosomal markers (the tetraspanins CD9, CD63 and CD81) and an endogenously expressed tumour-derived antigen. The study also reveals that scarce proteins can be used as targets for detection antibody in LFIA with a better result than very abundant proteins and that the conditions can be optimized for detection of the protein in plasma. CONCLUSIONS: These results open the possibility of analyzing biological samples for the presence of tumour-derived exosomes using high throughput techniques. PMID- 29720200 TI - Splice-site mutation causing partial retention of intron in the FLCN gene in Birt Hogg-Dube syndrome: a case report. AB - BACKGROUND: Birt-Hogg-Dube syndrome (BHD) is an autosomal dominant disorder caused by germline mutations in the folliculin gene (FLCN). Nearly 150 pathogenic mutations have been identified in FLCN. The most frequent pattern is a frameshift mutation within a coding exon. In addition, splice-site mutations have been reported, and previous studies have confirmed exon skipping in several cases. However, it is poorly understood whether there are any splice-site mutations that cause translation of intron regions in FLCN. CASE PRESENTATION: A 59-year-old Japanese patient with multiple pulmonary cysts and pneumothorax was hospitalized due to dyspnea. BHD was suspected and genetic testing was performed. The patient exhibited the splice-site mutation of FLCN in the 5' end of intron 9 (c.1062 + 1G > A). Total mRNA was extracted from pulmonary cysts, and RT-PCR assessment and sequence analyses were done. Two distinct bands were generated; one was wild-type and the other was a larger-sized mutant. Sequence analysis of the latter transcript revealed the insertion of 130 base pairs of intron 9 from the beginning of the splice-site between exons 9 and 10. CONCLUSION: To our knowledge, this is the first report of distinct intron insertion using a BHD patient's diseased tissue-derived mRNA. The present case suggests that a splice site mutation can lead to exon skipping as well as intron reading mRNA. The splicing process may be dependent in part on whether the donor or acceptor site is affected. PMID- 29720201 TI - Creating a positive perception of childbirth experience: systematic review and meta-analysis of prenatal and intrapartum interventions. AB - BACKGROUND: A negative experience in childbirth is associated with chronic maternal morbidities. The aim of this systematic review and meta-analysis was to identify currently available successful interventions to create a positive perception of childbirth experience which can prevent psychological birth trauma. METHODS: Randomized controlled trials of interventions in pregnancy or labour which aimed to improve childbirth experience versus usual care were identified from 1994 to September 2016. Low risk pregnant or childbearing women were chosen as the study population. PEDRO scale and Cochrane risk of bias tool were used for quality assessment. Pooled effect estimates were calculated when more than two studies had similar intervention. If it was not possible to include a study in the meta-analysis, its data were summarized narratively. RESULTS: After screening of 7832 titles/abstracts, 20 trials including 22,800 participants from 12 countries were included. Successful strategies to create a positive perception of childbirth experience were supporting women during birth (Risk Ratio = 1.35, 95% Confidence Interval: 1.07 to 1.71), intrapartum care with minimal intervention (Risk Ratio = 1.29, 95% Confidence Interval:1.15 to 1.45) and birth preparedness and readiness for complications (Mean Difference = 3.27, 95% Confidence Interval: 0.66 to 5.88). Most of the relaxation and pain relief strategies were not successful to create a positive birth experience (Mean Difference = - 2.64, 95% Confidence Intervention: - 6.80 to 1.52). CONCLUSION: The most effective strategies to create a positive birth experience are supporting women during birth, intrapartum care with minimal intervention and birth preparedness. This study might be helpful in clinical approaches and designing future studies about prevention of the negative and traumatic birth experiences. PMID- 29720202 TI - Optimization of late gadolinium enhancement cardiovascular magnetic resonance imaging of post-ablation atrial scar: a cross-over study. AB - BACKGROUND: Cardiovascular magnetic resonance (CMR) imaging may be used to visualize post-ablation atrial scar (PAAS), and three-dimensional late gadolinium enhancement (3D LGE) is the most widely employed technique for imaging of chronic scar. Detection of PAAS provides a unique non-invasive insight into the effects of the ablation and may help guide further ablation procedures. However, there is evidence that PAAS is often not detected by CMR, implying a significant sensitivity problem, and imaging parameters vary between leading centres. Therefore, there is a need to establish the optimal imaging parameters to detect PAAS. METHODS: Forty subjects undergoing their first pulmonary vein isolation procedure for AF had detailed CMR assessment of atrial scar: one scan pre ablation, and two scans post-ablation at 3 months (separated by 48 h). Each scan session included ECG- and respiratory-navigated 3D LGE acquisition at 10, 20 and 30 min post injection of a gadolinium-based contrast agent (GBCA). The first post procedural scan was performed on a 1.5 T scanner with standard acquisition parameters, including double dose (0.2 mmol/kg) Gadovist and 4 mm slice thickness. Ten patients subsequently underwent identical scan as controls, and the other 30 underwent imaging with a reduced, single, dose GBCA (n = 10), half slice thickness (n = 10) or on a 3 T scanner (n = 10). Apparent signal-to-noise (aSNR), contrast-to-noise (aCNR) and imaging quality (Likert Scale, 3 independent observers) were assessed. PAAS location and area (%PAAS scar) were assessed following manual segmentation. Atrial shells with standardised %PAAS at each timepoint were then compared to ablation lesion locations to assess quality of scar delineation. RESULTS: A total of 271 3D acquisitions (out of maximum 280, 96.7%) were acquired. Likert scale of imaging quality had high interobserver and intraobserver intraclass correlation coefficients (0.89 and 0.96 respectively), and showed lower overall imaging quality on 3 T and at half-slice thickness. aCNR, and quality of scar delineation increased significantly with time. aCNR was higher with reduced, single, dose of GBCA (p = 0.005). CONCLUSION: 3D LGE CMR atrial scar imaging, as assessed qualitatively and quantitatively, improves with time from GBCA administration, with some indices continuing to improve from 20 to 30 min. Imaging should be performed at least 20 min post-GBCA injection, and a single dose of contrast should be considered. TRIAL REGISTRATION: Trial registry- United Kingdom National Research Ethics Service 08/H0802/68 - 30th September 2008. PMID- 29720203 TI - Detection rate of causal variants in severe childhood epilepsy is highest in patients with seizure onset within the first four weeks of life. AB - BACKGROUND: Epilepsy is a heterogeneous disease with a broad phenotypic spectrum and diverse genotypes. A significant proportion of epilepsies has a genetic aetiology. In our study, a custom designed gene panel with 112 genes known to be associated with epilepsies was used. In total, one hundred and fifty-one patients were tested (86 males / 65 females). RESULTS: In our cohort, the highest probability for the identification of the cause of the disease was for patients with a seizure onset within the first four weeks of life (61.9% clarification rate) - about two times more than other groups. The level of statistical significance was determined using a chi-square analysis. From 112 genes included in the panel, suspicious and rare variants were found in 53 genes (47.3%). Among the 151 probands included in the study we identified pathogenic variants in 39 patients (25.8%), likely pathogenic variants in three patients (2%), variants of uncertain significance in 40 patients (26.5%) and likely benign variants in 69 patients (45.7%). CONCLUSION: Our report shows the utility of diagnostic genetic testing of severe childhood epilepsies in a large cohort of patients with a diagnostic rate of 25.8%. A gene panel can be considered as a method of choice for the detection of pathogenic variants within patients with unknown origin of early onset severe epilepsy. PMID- 29720204 TI - Retraction Note: The microRNA-325 inhibits hepatocellular carcinoma progression by targeting high mobility group box 1. AB - The editor has retracted this article [1] because it shows significant overlap with the following articles (amongst others) [2, 3]. None of the authors responded to correspondence regarding this retraction. PMID- 29720206 TI - Antenatal tobacco use and iron deficiency anemia: integrating tobacco control into antenatal care in urban India. AB - BACKGROUND: In India, tobacco use during pregnancy is not routinely addressed during antenatal care. We measured the association between tobacco use and anemia in low-income pregnant women, and identified ways to integrate tobacco cessation into existing antenatal care at primary health centers. METHODS: We conducted an observational study using structured interviews with antenatal care clinic patients (n = 100) about tobacco use, anemia, and risk factors such as consumption of iron rich foods and food insecurity. We performed blood tests for serum cotinine, hemoglobin and ferritin. We conducted in-depth interviews with physicians (n = 5) and auxiliary nurse midwives (n = 5), and focus groups with community health workers (n = 65) to better understand tobacco and anemia control services offered during antenatal care. RESULTS: We found that 16% of patients used tobacco, 72% were anemic, 41% had iron deficiency anemia (IDA) and 29% were food insecure. Regression analysis showed that tobacco use (OR = 14.3; 95%CI = 2.6, 77.9) and consumption of green leafy vegetables (OR = 0.6; 95%CI = 0.4, 0.9) were independently associated with IDA, and tobacco use was not associated with consumption of iron-rich foods or household food insecurity. Clinics had a system for screening, treatment and follow-up care for anemic and iron-deficient antenatal patients, but not for tobacco use. Clinicians and community health workers were interested in integrating tobacco screening and cessation services with current maternal care services such as anemia control. Tobacco users wanted help to quit. CONCLUSION: It would be worthwhile to assess the feasibility of integrating antenatal tobacco screening and cessation services with antenatal care services for anemia control, such as screening and guidance during clinic visits and cessation support during home visits. PMID- 29720207 TI - The t(14;18) translocation is absent from endothelial and follicular dendritic cells of follicular lymphoma (FL) and shows heterogeneous presence in preserved FL mantle zones. AB - BACKGROUND: The translocation t(14;18)(q32;q21) is the genetic hallmark of follicular lymphoma (FL) and can be observed in 85-90% of cases. Whether the translocation is restricted to cells with germinal center B-cell phenotype or can be observed in other cell types of the microenvironment remains debated. Of interest, cases of associated histiocytic and dendritic cell sarcomas arising in the background of FL have been shown to be clonally related and carry the t(14;18), suggesting a "transdifferentiation" of the malignant FL clone into a neoplasm of a different hematopoietic lineage. METHODS: We analyzed the presence of the t(14;18)(q32;q21) as a surrogate marker of the malignant clone in cells of the FL microenvironment using combined fluorescence immunophenotyping and interphase cytogenetics targeting the BCL2 gene locus. In addition to non lymphoid cells in FL, we analysed FL with preserved IgD+ mantle zones and cases of in situ follicular neoplasia (ISFN) to investigate whether cells of non germinal center B-cell phenotype are part of the malignant clone. RESULTS: Six (40%) of 15 manifest FL cases with preserved IgD+ mantle zones did not harbour the t(14;18)(q32;q21) translocation. In all t(14;18) + FL cases, follicular dendritic cells and endothelial cells lacked the t(14;18) translocation. 2/9 FL revealed t(14;18)- IgD+ mantle zone B-cells. In the seven ISFN cases, the t(14;18) translocation was strictly confined to germinal center cells. CONCLUSIONS: The t(14;18) translocation in follicular lymphoma is limited to B cells. The origin of IgD+ mantle cells is heterogeneous, in the majority of cases belonging to the neoplastic clone, whereas a minority of cases of manifest FL show nonneoplastic mantle zones, similar to ISFN. PMID- 29720205 TI - Retrograde type a dissection in a 24th gestational week pregnant patient - the importance of interdisciplinary interaction to a successful outcome. AB - BACKGROUND: Type A Dissection in pregnancy is a devastating medical condition with 2 lives at stake and unclear strategy at early gestational stages. We describe a successful outcome, clearly dependent on the coordination of all involved disciplines. CASE PRESENTATION: This case history describes a 28 year old female with a 24th week pregnancy gravida 2 para 0 with a DeBakey Type I aortic dissection, diagnosed via ultrasound. Surgery was perfomed on the day of diagnosis. After conferral with the mother, caesarean section was performed and a 690 g fetus could be delivered and was immediately transferred to the neonatal unit. Subsequent aortic repair was performed after hysterectomy, with replacement of the ascending aorta and hemiarch treatment. Intraoperatively no entry in the ascending aorta or transverse arch could be demonstrated, so that a retrograde Type A with entry distal to the left subclavian had to be postulated. We decided to perform subsequent computer tomography, demonstrating multiple entry sites in the descending aorta distal to the left subclavian artery. Successful endovascular treatment could be performed with a Medtronic Valiant Stent via a transfemoral approach. The further hospital stay was uneventful and the patient could be discharged on the 18th postoperative day. The baby demonstrated fighter qualities and could be discharged home after a 3 month hospital stay to be reunited with his mother. CONCLUSION: Prompt diagnosis, precise coordination between all involved subspecialties and ultimately, as in this case, definitive treatment in consensus with operative and interventional departments have led to a successful outcome and encourages us in our daily struggle in this often demanding surgery. PMID- 29720208 TI - Smartphone-based ecological momentary assessment and intervention in a coping focused intervention for hearing voices (SAVVy): study protocol for a pilot randomised controlled trial. AB - BACKGROUND: Smartphone-based ecological momentary assessment and intervention (EMA/I) show promise for enhancing psychological treatments for psychosis. EMA has the potential to improve assessment and formulation of experiences which fluctuate day-to-day, and EMI may be used to prompt use of therapeutic strategies in daily life. The current study is an examination of these capabilities in the context of a brief, coping-focused intervention for distressing voice hearing experiences. METHODS/DESIGN: This is a rater-blinded, pilot randomised controlled trial comparing a four-session intervention in conjunction with use of smartphone EMA/I between sessions, versus treatment-as-usual. The recruitment target is 34 participants with persisting and distressing voice hearing experiences, recruited through a Voices Clinic based in Melbourne, Australia, and via wider advertising. Allocation will be made using minimisation procedure, balancing of the frequency of voices between groups. Assessments are completed at baseline and 8 weeks post baseline. The primary outcomes of this trial will focus on feasibility and acceptability of the intervention and trial methodology, with secondary outcomes examining preliminary clinical effects related to overall voice severity, the emotional and functional impact of the voices, and emotional distress. DISCUSSION: This study offers a highly novel examination of specific smartphone capabilities and their integration with traditional psychological treatment for distressing voices. Such technology has potential to enhance psychological interventions and promote adaptation to distressing experiences. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry, ACTRN12617000348358 . Registered on 7 March 2017. PMID- 29720209 TI - Cluster randomised controlled trial of a theory-based multiple behaviour change intervention aimed at healthcare professionals to improve their management of type 2 diabetes in primary care. AB - BACKGROUND: National diabetes audits in the UK show room for improvement in the quality of care delivered to people with type 2 diabetes in primary care. Systematic reviews of quality improvement interventions show that such approaches can be effective but there is wide variability between trials and little understanding concerning what explains this variability. A national cohort study of primary care across 99 UK practices identified modifiable predictors of healthcare professionals' prescribing, advising and foot examination. Our objective was to evaluate the effectiveness of an implementation intervention to improve six guideline-recommended health professional behaviours in managing type 2 diabetes in primary care: prescribing for blood pressure and glycaemic control, providing physical activity and nutrition advice and providing updated diabetes education and foot examination. METHODS: Two-armed cluster randomised trial involving 44 general practices. Primary outcomes (at 12 months follow-up): from electronic medical records, the proportion of patients receiving additional prescriptions for blood pressure and insulin initiation for glycaemic control and having a foot examination; and from a patient survey of a random sample of 100 patients per practice, reported receipt of updated diabetes education and physical activity and nutrition advice. RESULTS: The implementation intervention did not lead to statistically significant improvement on any of the six clinical behaviours. 1,138,105 prescriptions were assessed. Intervention (29% to 37% patients) and control arms (31% to 35%) increased insulin initiation relative to baseline but were not statistically significantly different at follow-up (IRR 1.18, 95%CI 0.95-1.48). Intervention (45% to 53%) and control practices (45% to 50%) increased blood pressure prescription from baseline to follow-up but were not statistically significantly different at follow-up (IRR 1.05, 95%CI 0.96 to 1.16). Intervention (75 to 78%) and control practices (74 to 79%) increased foot examination relative to baseline; control practices increased statistically significantly more (OR 0.84, 95%CI 0.75-0.94). Fewer patients in intervention (33%) than control practices (40%) reported receiving updated diabetes education (OR = 0.74, 95%CI 0.57-0.97). No statistically significant differences were observed in patient reports of having had a discussion about nutrition (intervention = 73%; control = 72%; OR = 0.98, 95%CI 0.59-1.64) or physical activity (intervention = 57%; control = 62%; OR = 0.79, 95%CI 0.56-1.11). Development and delivery of the intervention cost L1191 per practice. CONCLUSIONS: There was no measurable benefit to practices' participation in this intervention. Despite widespread use of outreach interventions worldwide, there is a need to better understand which techniques at which intensity are optimally suited to address the multiple clinical behaviours involved in improving care for type 2 diabetes. TRIAL REGISTRATION: ISRCTN, ISRCTN66498413 . Registered April 4, 2013. PMID- 29720210 TI - Endoscopic release of congenital muscular torticollis with radiofrequency in teenagers. AB - BACKGROUND: Congenital muscular torticollis (CMT) is due to contracture of the sternocleidomastoid muscle which may cause activity limitations of the neck, tilt of the head, craniofacial asymmetry, and deformity of the skull. The authors present their experience of arthroscopic tight fibrous band release with radiofrequency in teenagers under local anesthesia and evaluate the clinical results. METHODS: A total of 69 patients who underwent arthroscopic release of CMT with radiofrequency under local anesthesia by a single surgeon could participate in this study. Before operation, surface landmarks of sternocleidomastoid muscle, bone, and neurovascular structures were marked. Local infiltrating anesthesia of the surgical region was then performed. Through a working space created by blunt dissection, the arthroscopy and radiofrequency devices were introduced. Then, the clavicular and sternal heads of the sternocleidomastoid muscle were identified and gradually transected. The patients were followed up postoperatively with Cheng's scoring system. RESULTS: There were 31 male patients and 38 female patients. The mean age of the patients was 16.1 years. The mean length of follow-up in this series was 36.7 months (range, 28 to 67 months). During the operation, 62 patients (89.9%) had no pain, 6 patients (8.7%) felt mild pain, and only 1 patient (1.4%) regarded the procedure as very painful. At all follow-up periods, there were no repeat arthroscopies for any of these patients. At the final follow-up, the average rotation deficit improved from 22.5 degrees to 4.1 degrees postoperatively, and the average lateral bending deficit improved from 14.6 degrees to 3.3 degrees (p < 0.05). Overall, the clinical result was good or excellent in 65 patients (94.2%), fair in 4 patients, and poor in 0 patients within the follow-up period according to Cheng's scoring system. To date, no patients had any intraoperative or postoperative complications from this procedure. CONCLUSION: The arthroscopic release with radiofrequency under local anesthesia provides surgeons with an alternative to traditional open techniques for the management of congenital muscular torticollis (CMT). Our date shows that this method is minimally invasive and provides good functional recovery with a lower risk of complications. PMID- 29720211 TI - Atypical ductal hyperplasia: update on diagnosis, management, and molecular landscape. AB - BACKGROUND: Atypical ductal hyperplasia (ADH) is a common diagnosis in the mammographic era and a significant clinical problem with wide variation in diagnosis and treatment. After a diagnosis of ADH on biopsy a proportion are upgraded to carcinoma upon excision; however, the remainder of patients are overtreated. While ADH is considered a non-obligate precursor of invasive carcinoma, the molecular taxonomy remains unknown. MAIN TEXT: Although a few studies have revealed some of the key genomic characteristics of ADH, a clear understanding of the molecular changes associated with breast cancer progression has been limited by inadequately powered studies and low resolution methodology. Complicating factors such as family history, and whether the ADH present in a biopsy is an isolated lesion or part of a greater neoplastic process beyond the limited biopsy material, make accurate interpretation of genomic features and their impact on progression to malignancy a challenging task. This article will review the definitions and variable management of the patients diagnosed with ADH as well as the current knowledge of the molecular landscape of ADH and its clonal relationship with ductal carcinoma in situ and invasive carcinoma. CONCLUSIONS: Molecular data of ADH remain sparse. Large prospective cohorts of pure ADH with clinical follow-up need to be evaluated at DNA, RNA, and protein levels in order to develop biomarkers of progression to carcinoma to guide management decisions. PMID- 29720212 TI - Individualized approach to the surgical management of fibrous dysplasia of the proximal femur. AB - BACKGROUND: Fibrous dysplasia of the proximal femur presents with heterogeneous clinical manifestations dictating different surgical approaches. However, to date there are no clear recommendations to guide the choice of surgical approach and no general guidelines for the optimal orthopedic management of these lesions. The objective of this study was to evaluate treatment outcomes of angled blade plates and intramedullary nails, using as outcome indicators revision-free survival, pain, function and femoral neck-shaft-angle. Based on a review of published literature and our study findings, we propose a treatment algorithm, taking into account different factors, which may play a role in the selection of one surgical approach over another. METHODS: Data were evaluated in thirty-two patients (18 male) from a combined cohort from the Netherlands and Austria, who had a surgical intervention using an angled blade plate (n = 27) or an intramedullary nail (n = 5) between 1985 and 2015, and who had a minimal follow-up of one year. The primary outcome was success of the procedure according to the revised Henderson classification. Secondary outcomes, which were assessed at one year and at the end of follow-up included: function (as measured by walking ability), pain and change in femoral neck-shaft angle over time. RESULTS: Analysis of data showed that revision-free survival was 72% after a median follow-up of 4.1 years. Revision was necessary in two patients for structural failure due to a fracture distal to an angled blade plate and in 7 patients due to angled blade plate induced iliotibial tract pain. At the end of follow-up 91% of all patients had good walking ability and 91% were pain free. There was no significant postoperative change in femoral neck shaft angle. CONCLUSION: Our data show that fibrous dysplasia of the proximal femur can be adequately and safely treated with angled blade plates or intramedullary nails, providing these are used according to specific characteristics of the individual patient. Based on published literature and our own experience, we propose an individualized, patient-tailored approach for the surgical management of fibrous dysplasia of the proximal femur. PMID- 29720213 TI - PM2.5 exposure aggravates oligomeric amyloid beta-induced neuronal injury and promotes NLRP3 inflammasome activation in an in vitro model of Alzheimer's disease. AB - BACKGROUND: Numerous studies suggested that PM2.5 exposure was associated with increased risk of Alzheimer's disease (AD). But the precise mechanisms by which PM2.5 contributed to AD pathogenesis have not been clarified. METHODS: In the presence or absence of neurons, oligomeric amyloid beta (oAbeta)-primed microglia were stimulated with PM2.5. Firstly, we determined the effects of PM2.5 exposure on neuronal injury and inflammation in neurons-microglia co-cultures. Then, we examined whether NLRP3 inflammasome activation was involved in PM2.5-induced inflammation. After that, we investigated whether PM2.5 exposure increased ROS level in oAbeta-stimulated microglia. At last, we examined whether ROS and NLRP3 inflammasome activation was required for PM2.5-induced neuronal injury in neurons microglia co-cultures. RESULTS: In the present study, we showed that PM2.5 exposure aggravated oAbeta-induced neuronal injury and inflammation in neurons microglia co-cultures via increasing IL-1beta production. Further, PM2.5-induced IL-1beta production in oAbeta-stimulated microglia was possibly dependent on NLRP3 inflammasome activation. Meanwhile, PM2.5 exposure increased ROS level in oAbeta-stimulated microglia. ROS was required for PM2.5-induced IL-1beta production and NLRP3 inflammasome activation in oAbeta-stimulated microglia. More importantly, ROS and NLRP3 inflammasome activation was required for PM2.5-induced neuronal injury in neurons-microglia co-cultures. CONCLUSIONS: For the first time, these results suggested that the effects of PM2.5 under AD context were possibly mediated by NLRP3 inflammasome activation, which was triggered by ROS. Taken together, these findings have deepened our understanding on the role of PM2.5 in AD pathogenesis. PMID- 29720214 TI - Yoga's potential for promoting healthy eating and physical activity behaviors among young adults: a mixed-methods study. AB - BACKGROUND: A regular yoga practice may have benefits for young adult health, however, there is limited evidence available to guide yoga interventions targeting weight-related health. The present study explored the relationship between participation in yoga, healthy eating behaviors and physical activity among young adults. METHODS: The present mixed-methods study used data collected as part of wave 4 of Project EAT (Eating and Activity in Teens and Young Adults), a population-based cohort study in Minneapolis-St. Paul, Minnesota. Young adults (n = 1820) completed the Project EAT survey and a food frequency questionnaire, and a subset who reported practicing yoga additionally participated in semi structured interviews (n = 46). Analyses of survey data were used to examine cross-sectional associations between the frequency of yoga practice, dietary behaviors (servings of fruits and vegetables (FV), sugar-sweetened beverages (SSBs) and snack foods and frequency of fast food consumption), and moderate-to vigorous physical activity (MVPA). Thematic analysis of interview discussions further explored yoga's perceived influence on eating and activity behaviors among interview participants. RESULTS: Regular yoga practice was associated with more servings of FV, fewer servings of SSBs and snack foods, less frequent fast food consumption, and more hours of MVPA. Interviews revealed that yoga supported healthy eating through motivation to eat healthfully, greater mindfulness, management of emotional eating, more healthy food cravings, and the influence of the yoga community. Yoga supported physical activity through activity as part of yoga practice, motivation to do other forms of activity, increased capacity to be active, and by complementing an active lifestyle. CONCLUSIONS: Young adult yoga practitioners reported healthier eating behaviors and higher levels of physical activity than non-practitioners. Yoga should be investigated as an intervention for young adult health promotion and healthy weight management. PMID- 29720216 TI - Decreased level of irisin, a skeletal muscle cell-derived myokine, is associated with post-stroke depression in the ischemic stroke population. AB - BACKGROUND: Depression is a frequent mood disorder in stroke patient. Our aim was to determine irisin levels in serum and investigate their associations with post stroke depression (PSD) in a 6-month follow-up study in Chinese patients with first-ever acute ischemic stroke (AIS). METHODS: The subjects were first-ever AIS patients who were hospitalized at three stroke centers during the period from January 2015 to December 2016. Neurological and neuropsychological evaluations were conducted at the 6-month follow-up. Serum irisin concentrations were measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: During the study period, 1205 patients were included in the analysis. There were 370 patients (30.7%) classified as depression. The depression distribution across the irisin quartiles ranged between 49.8% (first quartile) and 9.9% (fourth quartile). In the patients with depression, serum irisin levels were lower compared with those in patients without depression (P < 0.001). In a multivariate model using the first (Q1) quartile of irisin vs. Q2-4 together with the clinical variables, the marker displayed predictive information and increased risk of PSD by 75% (odds ratio [OR] for Q1, 1.75 [95% confidence interval [CI], 1.15-2.65]). In addition, a model containing known risk factors plus irisin compared with a model containing known risk factors without irisin showed a greater discriminatory ability; the area under the curve (AUC) increased from 0.77 to 0.81 (95% CI, 0.76 0.86). CONCLUSIONS: The data suggested that reduced serum levels of irisin were powerful biological markers of risk of developing PSD even after adjustment by variables. Further studies are necessary to confirm this association, which may open the way to the proposal of new therapeutic options. TRIAL REGISTRATION: ChiCTR-OPC-17013501 . Retrospectively registered 23 September 2017. PMID- 29720217 TI - Chiluria in a lymphatic filariasis endemic area. AB - OBJECTIVE: To establish clinical and laboratory data of individuals presenting chyluria in endemic areas. RESULTS: 75 individuals were studied. The majority were females with an average age of 45 years residing in the Metropolitan Region of Recife. The mean time between the beginning of the presentation of chyluria and the first care service in the Servico de Referencia Nacional em Filarioses was approximately 5 years. The most frequent urinalysis changes were hematuria (27.6%), leukocytes (21.9%) and proteinuria (10.5%). The Addis test showed mean values of 155.43 E/min/mL of cylinders, 52,892 E/min/mL of erythrocytes and 291,660 E/min/mL of leukocytes. Among recorded cases, proteinuria had a mean value of 1372.80 mg/dL in 24 h, and the presence of lymphocytes in the urine was positive in 68.3%. Among lymphatic filariasis tests, immunochromatography was positive in 16.7%, there was circulating filarial antigen determined by detection of OG4C3 antibodies in 7.7% and microfilaremia in only 1/55. PMID- 29720215 TI - Dependence receptor UNC5A restricts luminal to basal breast cancer plasticity and metastasis. AB - BACKGROUND: The majority of estrogen receptor-positive (ERalpha+) breast cancers respond to endocrine therapies. However, resistance to endocrine therapies is common in 30% of cases, which may be due to altered ERalpha signaling and/or enhanced plasticity of cancer cells leading to breast cancer subtype conversion. The mechanisms leading to enhanced plasticity of ERalpha-positive cancer cells are unknown. METHODS: We used short hairpin (sh)RNA and/or the CRISPR/Cas9 system to knockdown the expression of the dependence receptor UNC5A in ERalpha+ MCF7 and T-47D cell lines. RNA-seq, quantitative reverse transcription polymerase chain reaction, chromatin immunoprecipitation, and Western blotting were used to measure the effect of UNC5A knockdown on basal and estradiol (E2)-regulated gene expression. Mammosphere assay, flow cytometry, and immunofluorescence were used to determine the role of UNC5A in restricting plasticity. Xenograft models were used to measure the effect of UNC5A knockdown on tumor growth and metastasis. Tissue microarray and immunohistochemistry were utilized to determine the prognostic value of UNC5A in breast cancer. Log-rank test, one-way, and two-way analysis of variance (ANOVA) were used for statistical analyses. RESULTS: Knockdown of the E2-inducible UNC5A resulted in altered basal gene expression affecting plasma membrane integrity and ERalpha signaling, as evident from ligand independent activity of ERalpha, altered turnover of phosphorylated ERalpha, unique E2-dependent expression of genes effecting histone demethylase activity, enhanced upregulation of E2-inducible genes such as BCL2, and E2-independent tumorigenesis accompanied by multiorgan metastases. UNC5A depletion led to the appearance of a luminal/basal hybrid phenotype supported by elevated expression of basal/stem cell-enriched ?Np63, CD44, CD49f, epidermal growth factor receptor (EGFR), and the lymphatic vessel permeability factor NTN4, but lower expression of luminal/alveolar differentiation-associated ELF5 while maintaining functional ERalpha. In addition, UNC5A-depleted cells acquired bipotent luminal progenitor characteristics based on KRT14+/KRT19+ and CD49f+/EpCAM+ phenotype. Consistent with in vitro results, UNC5A expression negatively correlated with EGFR expression in breast tumors, and lower expression of UNC5A, particularly in ERalpha+/PR+/HER2- tumors, was associated with poor outcome. CONCLUSION: These studies reveal an unexpected role of the axon guidance receptor UNC5A in fine tuning ERalpha and EGFR signaling and the luminal progenitor status of hormone sensitive breast cancers. Furthermore, UNC5A knockdown cells provide an ideal model system to investigate metastasis of ERalpha+ breast cancers. PMID- 29720218 TI - The anteroposterior axis of the tibia is adjusted to approximately a right angle to the anterior pelvic plane in the standing position in patients with hip dysplasia similar to normal subjects: a cross-sectional study. AB - BACKGROUND: We previously described that the anteroposterior (AP) axis of the tibia is approximately perpendicular to the transverse axis of the anterior pelvic plane (APP) in the standing position in healthy subjects. The purpose of this study was to investigate the rotational alignment between the APP and clinical epicondylar axis and the AP axis of the tibia relative to pelvic coordination in the standing position in normal subjects and in women with developmental dysplasia of the hip (DDH) to aid decision making for surgeons in the alignment of implants in total hip or knee arthroplasty. METHODS: This study included 77 Japanese women. Twenty-nine in the DDH group underwent curved periacetabular osteotomy; 48 women without lumbago and knee pain were included in the normal group. Femoral neck anteversion (FNA), condylar twist angle, and knee rotation angle were measured in femoral coordination. The angle between the femoral neck axis and clinical epicondylar axis (CEA) was measured, the transverse axis of the APP was also measured, and the angle between the AP axis of the tibia and transverse axis of the APP was calculated. RESULTS: There was a moderate negative correlation between FNA and CEA relative to the APP. This finding indicated a trend towards greater FNA leading to more internal rotation. Knee rotation angle (KRA) relative to the APP was 1.65 degrees +/- 5.58 degrees in the normal group and - 2.65 degrees +/- 7.57 degrees in the DDH group. This finding indicated that the tibia AP axis was approximately perpendicular to the APP in the standing position both in the normal and DDH groups. CONCLUSION: We found that the tibia AP axis was at approximately a right angle to the transverse axis of the APP in the standing position in both the normal and DDH groups, while the KRA was different in the normal and DDH groups. These findings may prove helpful for positional alignment investigations needed for implantation in total hip or knee arthroplasty and gait analysis. PMID- 29720220 TI - The combined effect of mammographic texture and density on breast cancer risk: a cohort study. AB - BACKGROUND: Texture patterns have been shown to improve breast cancer risk segregation in addition to area-based mammographic density. The additional value of texture pattern scores on top of volumetric mammographic density measures in a large screening cohort has never been studied. METHODS: Volumetric mammographic density and texture pattern scores were assessed automatically for the first available digital mammography (DM) screening examination of 51,400 women (50-75 years of age) participating in the Dutch biennial breast cancer screening program between 2003 and 2011. The texture assessment method was developed in a previous study and validated in the current study. Breast cancer information was obtained from the screening registration system and through linkage with the Netherlands Cancer Registry. All screen-detected breast cancers diagnosed at the first available digital screening examination were excluded. During a median follow-up period of 4.2 (interquartile range (IQR) 2.0-6.2) years, 301 women were diagnosed with breast cancer. The associations between texture pattern scores, volumetric breast density measures and breast cancer risk were determined using Cox proportional hazard analyses. Discriminatory performance was assessed using c indices. RESULTS: The median age of the women at the time of the first available digital mammography examination was 56 years (IQR 51-63). Texture pattern scores were positively associated with breast cancer risk (hazard ratio (HR) 3.16 (95% CI 2.16-4.62) (p value for trend <0.001), for quartile (Q) 4 compared to Q1). The c-index of texture was 0.61 (95% CI 0.57-0.64). Dense volume and percentage dense volume showed positive associations with breast cancer risk (HR 1.85 (95% CI 1.32 2.59) (p value for trend <0.001) and HR 2.17 (95% CI 1.51-3.12) (p value for trend <0.001), respectively, for Q4 compared to Q1). When adding texture measures to models with dense volume or percentage dense volume, c-indices increased from 0.56 (95% CI 0.53-0.59) to 0.62 (95% CI 0.58-0.65) (p < 0.001) and from 0.58 (95% CI 0.54-0.61) to 0.60 (95% CI 0.57-0.63) (p = 0.054), respectively. CONCLUSIONS: Deep-learning-based texture pattern scores, measured automatically on digital mammograms, are associated with breast cancer risk, independently of volumetric mammographic density, and augment the capacity to discriminate between future breast cancer and non-breast cancer cases. PMID- 29720221 TI - Deleterious role of hepatitis B virus infection in therapeutic response among patients with rheumatoid arthritis in a clinical practice setting: a case-control study. AB - BACKGROUND: Previous studies have revealed that hepatitis B virus (HBV) infection may be associated with rheumatoid arthritis (RA), while there are no further clinical studies regarding the role of HBV infection in RA progression during disease-modifying anti-rheumatic drug (DMARD) therapy. Here, we aimed to explore the influence of HBV infection on radiographic and clinical outcomes among patients with RA in a clinical practice setting. METHODS: Thirty-two consecutive patients with RA (Disease Activity Score 28-joint assessment based on C-reactive protein (DAS28-CRP) >=2.6) with chronic HBV infection (CHB) were retrospectively recruited as the CHB group and 128 age-matched, sex-matched, and disease activity matched contemporary patients with RA without CHB were included in the non-CHB group. Clinical data were collected at baseline and visits at month 1, 3, 6, and 12. The therapeutic target was defined as DAS28-CRP <2.6 in all patients or <3.2 in patients with long disease duration (>24 months). The primary outcome was the percentage of patients with one-year radiographic progression (a change in modified total Sharp score >=0.5). RESULTS: Compared with the non-CHB group, a significantly higher percentage of patients with one-year radiographic progression was observed in the CHB group (53% vs. 17%, p < 0.001), with smaller proportions of patients achieving therapeutic target at month 6 and month 12 (53% vs. 82% and 53% vs. 75%, both p < 0.05), remission at month 6 (DAS28-CRP <2.6, 50% vs. 72%, p = 0.039), and American College of Rheumatology (ACR)20/50 responses and good or moderate European League Against Rheumatism (EULAR) responses mainly at month 6 and 12 (all p < 0.05). Multivariate logistic regression analysis revealed that CHB status was significantly associated with one-year radiographic progression and failure to achieve therapeutic target within 6 months. HBV reactivation occurred in 34% of patients with CHB during one year follow up, with two patients suffering hepatitis flare. CONCLUSIONS: HBV infection may play a deleterious role in radiographic and clinical outcomes in patients with RA, and HBV reactivation should be paid close attention during immunosuppressive therapy. PMID- 29720219 TI - GNE myopathy: from clinics and genetics to pathology and research strategies. AB - GNE myopathy is an ultra-rare autosomal recessive disease, which starts as a distal muscle weakness and ultimately leads to a wheelchair bound state. Molecular research and animal modelling significantly moved forward understanding of GNE myopathy mechanisms and suggested therapeutic interventions to alleviate the symptoms. Multiple therapeutic attempts are being made to supplement sialic acid depleted in GNE myopathy muscle cells. Translational research field provided valuable knowledge through natural history studies, patient registries and clinical trial, which significantly contributed to bringing forward an era of GNE myopathy treatment. In this review, we are summarising current GNE myopathy, scientific trends and open questions, which would be of significant interest for a wide neuromuscular diseases community. PMID- 29720222 TI - Targeted lipidomics analysis identified altered serum lipid profiles in patients with polymyositis and dermatomyositis. AB - BACKGROUND: Polymyositis (PM) and dermatomyositis (DM) are severe chronic autoimmune diseases, characterized by muscle fatigue and low muscle endurance. Conventional treatment includes high doses of glucocorticoids and immunosuppressive drugs; however, few patients recover full muscle function. One explanation of the persistent muscle weakness could be altered lipid metabolism in PM/DM muscle tissue as we previously reported. Using a targeted lipidomic approach we aimed to characterize serum lipid profiles in patients with PM/DM compared to healthy individuals (HI) in a cross-sectional study. Also, in the longitudinal study we compared serum lipid profiles in patients newly diagnosed with PM/DM before and after immunosuppressive treatment. METHODS: Lipidomic profiles were analyzed in serum samples from 13 patients with PM/DM, 12 HI and 8 patients newly diagnosed with PM/DM before and after conventional immunosuppressive treatment using liquid chromatography tandem mass spectrometry (LC-MS/MS) and a gas-chromatography flame ionization detector (GC-FID). Functional Index (FI), as a test of muscle performance and serum levels of creatine kinase (s-CK) as a proxy for disease activity were analyzed. RESULTS: The fatty acid (FA) composition of total serum lipids was altered in patients with PM/DM compared to HI; the levels of palmitic (16:0) acid were significantly higher while the levels of arachidonic (20:4, n-6) acid were significantly lower in patients with PM/DM. The profiles of serum phosphatidylcholine and triacylglycerol species were changed in patients with PM/DM compared to HI, suggesting disproportionate levels of saturated and polyunsaturated FAs that might have negative effects on muscle performance. After immunosuppressive treatment the total serum lipid levels of eicosadienoic (20:2, n-6) and eicosapentaenoic (20:5, n-3) acids were increased and serum phospholipid profiles were altered in patients with PM/DM. The correlation between FI or s-CK and levels of several lipid species indicate the important role of lipid changes in muscle performance and inflammation. CONCLUSIONS: Serum lipids profiles are significantly altered in patients with PM/DM compared to HI. Moreover, immunosuppressive treatment in patients newly diagnosed with PM/DM significantly affected serum lipid profiles. These findings provide new evidence of the dysregulated lipid metabolism in patients with PM/DM that could possibly contribute to low muscle performance. PMID- 29720223 TI - Greater rate of cephalic screw mobilisation following proximal femoral nailing in hip fractures with a tip-apex distance (TAD) and a calcar referenced TAD greater than 25 mm. AB - BACKGROUND: To ascertain whether the tip-apex distance (TAD), calcar referenced TAD (CalTAD), and the sum of both (TADcalTAD) are predictive measurements of mobilisation of the cephalic screw in patients with trochanteric hip fractures. METHODS: Between 2014 and 2015, 68 patients (mean age 86 years, 45 females, 23 males) with a trochanteric hip fracture underwent intramedullary nailing. The TAD and CalTAD were measured, and for each parameter, we calculated sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). RESULTS: There is evidence of a statistically significant association between a TAD and CalTAD greater than 25 mm and a TADcalTAD greater than 50 mm and mobilisation of the cephalic screw. All measurements have similar sensitivity, but the TAD presents the highest specificity (p < 0.01). CONCLUSION: To avoid the risk of mobilisation of the cephalic screw and possible subsequent failure of the construct, surgeons should strive for a TAD and CalTAD less than 25 mm and a TADcalTAD less than 50 mm when using intramedullary fixation. PMID- 29720224 TI - Assessing brain volume changes in older women with breast cancer receiving adjuvant chemotherapy: a brain magnetic resonance imaging pilot study. AB - BACKGROUND: Cognitive decline is among the most feared treatment-related outcomes of older adults with cancer. The majority of older patients with breast cancer self-report cognitive problems during and after chemotherapy. Prior neuroimaging research has been performed mostly in younger patients with cancer. The purpose of this study was to evaluate longitudinal changes in brain volumes and cognition in older women with breast cancer receiving adjuvant chemotherapy. METHODS: Women aged >= 60 years with stage I-III breast cancer receiving adjuvant chemotherapy and age-matched and sex-matched healthy controls were enrolled. All participants underwent neuropsychological testing with the US National Institutes of Health (NIH) Toolbox for Cognition and brain magnetic resonance imaging (MRI) prior to chemotherapy, and again around one month after the last infusion of chemotherapy. Brain volumes were measured using NeuroreaderTM software. Longitudinal changes in brain volumes and neuropsychological scores were analyzed utilizing linear mixed models. RESULTS: A total of 16 patients with breast cancer (mean age 67.0, SD 5.39 years) and 14 age-matched and sex-matched healthy controls (mean age 67.8, SD 5.24 years) were included: 7 patients received docetaxel and cyclophosphamide (TC) and 9 received chemotherapy regimens other than TC (non-TC). There were no significant differences in segmented brain volumes between the healthy control group and the chemotherapy group pre-chemotherapy (p > 0.05). Exploratory hypothesis generating analyses focusing on the effect of the chemotherapy regimen demonstrated that the TC group had greater volume reduction in the temporal lobe (change = - 0.26) compared to the non-TC group (change = 0.04, p for interaction = 0.02) and healthy controls (change = 0.08, p for interaction = 0.004). Similarly, the TC group had a decrease in oral reading recognition scores (change = - 6.94) compared to the non-TC group (change = - 1.21, p for interaction = 0.07) and healthy controls (change = 0.09, p for interaction = 0.02). CONCLUSIONS: There were no significant differences in segmented brain volumes between the healthy control group and the chemotherapy group; however, exploratory analyses demonstrated a reduction in both temporal lobe volume and oral reading recognition scores among patients on the TC regimen. These results suggest that different chemotherapy regimens may have differential effects on brain volume and cognition. Future, larger studies focusing on older adults with cancer on different treatment regimens are needed to confirm these findings. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01992432 . Registered on 25 November 2013. Retrospectively registered. PMID- 29720225 TI - The role of exercise combined with tocilizumab in visceral and epicardial adipose tissue and gastric emptying rate in abdominally obese participants: protocol for a randomised controlled trial. AB - BACKGROUND: Exercise reduces the amount of visceral adipose tissue (VAT) and the risk of cardiometabolic diseases. The underlying mechanisms responsible for these exercise-induced adaptations are unclear, but they may involve lipolytic actions of interleukin-6 (IL-6). Contracting skeletal muscles secrete IL-6, leading to increased circulating IL-6 levels in response to exercise. The aim of this study is to investigate whether IL-6 is involved in mediating the effects of exercise on visceral and epicardial adipose tissue volume and glycaemic control. METHODS/DESIGN: Seventy-five physically inactive males and females aged > 18 years with a waist-to-height ratio > 0.5 and/or waist circumference >= 88 cm (females) or >= 102 cm (males) are being recruited to participate in a 12-week intervention study. Participants are randomly allocated to one of five groups (1:1:1:1:1). Two groups consist of supervised endurance exercise training combined with the IL-6 blocker tocilizumab (ET) or saline used as placebo (EP), two groups consist of no exercise combined with tocilizumab (NT) or placebo (NP), and one group consists of resistance exercise and placebo (RP). Although the study is an exploratory trial, the primary outcome is change in VAT volume from before to after intervention, with secondary outcomes being changes in (1) epicardial adipose tissue, (2) pericardial adipose tissue and (3) gastric emptying. Depots of adipose tissue are quantitated by magnetic resonance imaging Gastric emptying and glucose metabolism are assessed using mixed-meal tolerance tests. DISCUSSION: Understanding the role of IL-6 in mediating the effects of exercise on visceral and epicardial adipose tissue and glycaemic control may lead to novel therapeutic approaches in the prevention of cardiometabolic diseases. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02901496 . Registered on 1 August 2016 and posted retrospectively on 15 September 2016. PMID- 29720227 TI - First pediatric experience of SL-401, a CD123-targeted therapy, in patients with blastic plasmacytoid dendritic cell neoplasm: report of three cases. AB - BACKGROUND: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a highly aggressive hematological malignancy with extremely poor outcome. The median overall survival for adult patients is 9-13 months. Pediatric patients are exceedingly rare with an unclear clinical course. Currently, no standardized therapy has been established, although an acute lymphoblastic leukemia type of treatment appears to be more effective in those patients who are able to tolerate aggressive chemotherapy. SL-401 is a targeted therapy directed to CD123, a protein ubiquitously expressed at high level on the surface of BPDCN blasts. In adult phase 2 trials, it has demonstrated efficacy with 90% overall response rate. No pediatric patients with BPDCN using SL-401 have been reported. CASE PRESENTATION: Here, we report the first pediatric experience of three children with BPDCN treated with SL-401 at our institution. All patients tolerated SL-401 without significant toxicities. One patient with multiply relapsed and refractory disease had no response. The other two cases had significant and rapid clinical improvement after the two courses of treatment. However, the response was transient, and growth of soft tissue mass was observed in-between cycles in both patients with large tumor burden. CONCLUSIONS: This is the first report of SL-401 in pediatric patients with BPDCN. Sl-401 was well tolerated and can produce a promising response. Further testing this agent in children is warranted. PMID- 29720229 TI - Early achievement of deep remission predicts low incidence of renal flare in lupus nephritis class III or IV. PMID- 29720226 TI - Increased A20-E3 ubiquitin ligase interactions in bid-deficient glia attenuate TLR3- and TLR4-induced inflammation. AB - BACKGROUND: Chronic pro-inflammatory signaling propagates damage to neural tissue and affects the rate of disease progression. Increased activation of Toll-like receptors (TLRs), master regulators of the innate immune response, is implicated in the etiology of several neuropathologies including amyotrophic lateral sclerosis, Alzheimer's disease, and Parkinson's disease. Previously, we identified that the Bcl-2 family protein BH3-interacting domain death agonist (Bid) potentiates the TLR4-NF-kappaB pro-inflammatory response in glia, and specifically characterized an interaction between Bid and TNF receptor associated factor 6 (TRAF6) in microglia in response to TLR4 activation. METHODS: We assessed the activation of mitogen-activated protein kinase (MAPK) and interferon regulatory factor 3 (IRF3) inflammatory pathways in response to TLR3 and TLR4 agonists in wild-type (wt) and bid-deficient microglia and macrophages, using Western blot and qPCR, focusing on the response of the E3 ubiquitin ligases Pellino 1 (Peli1) and TRAF3 in the absence of microglial and astrocytic Bid. Additionally, by Western blot, we investigated the Bid-dependent turnover of Peli1 and TRAF3 in wt and bid-/- microglia using the proteasome inhibitor Bortezomib. Interactions between the de-ubiquitinating Smad6-A20 and the E3 ubiquitin ligases, TRAF3 and TRAF6, were determined by FLAG pull-down in TRAF6 FLAG or Smad6-FLAG overexpressing wt and bid-deficient mixed glia. RESULTS: We elucidated a positive role of Bid in both TIR-domain-containing adapter-inducing interferon-beta (TRIF)- and myeloid differentiation primary response 88 (MyD88) dependent pathways downstream of TLR4, concurrently implicating TLR3-induced inflammation. We identified that Peli1 mRNA levels were significantly reduced in PolyI:C- and lipopolysaccharide (LPS)-stimulated bid-deficient microglia, suggesting disturbed IRF3 activation. Differential regulation of TRAF3 and Peli1, both essential E3 ubiquitin ligases facilitating TRIF-dependent signaling, was observed between wt and bid -/- microglia and astrocytes. bid deficiency resulted in increased A20-E3 ubiquitin ligase protein interactions in glia, specifically A20-TRAF6 and A20-TRAF3, implicating enhanced de-ubiquitination as the mechanism of action by which E3 ligase activity is perturbed. Furthermore, Smad6 facilitated recruitment of the de-ubiquitinase A20 to E3-ligases occurred in a bid-dependent manner. CONCLUSIONS: This study demonstrates that Bid promotes E3 ubiquitin ligase-mediated signaling downstream of TLR3 and TLR4 and provides further evidence for the potential of Bid inhibition as a therapeutic for the attenuation of the robust pro-inflammatory response culminating in TLR activation. PMID- 29720228 TI - Characterization of a murine mixed neuron-glia model and cellular responses to regulatory T cell-derived factors. AB - One of the unmet clinical needs in demyelinating diseases such as Multiple Sclerosis (MS) is to provide therapies that actively enhance the process of myelin regeneration (remyelination) in the central nervous system (CNS). Oligodendrocytes, the myelinating cells of the CNS, play a central role in remyelination and originate from oligodendrocyte progenitor cells (OPCs). We recently showed that depletion of regulatory T cells (Treg) impairs remyelination in vivo, and that Treg-secreted factors directly enhance oligodendrocyte differentiation. Here we aim to further characterize the dynamics of Treg enhanced oligodendrocyte differentiation as well as elucidate the cellular components of a murine mixed neuron-glia model. Murine mixed neuron-glia cultures were generated from P2-7 C57BL/6 mice and characterized for percentage of neuronal and glial cell populations prior to treatment at 7 days in vitro (div) as well as after treatment with Treg-conditioned media at multiple timepoints up to 12 div. Mixed neuron-glia cultures consisted of approximately 30% oligodendroglial lineage cells, 20% neurons and 10% microglia. Furthermore, a full layer of astrocytes, that could not be quantified, was present. Treatment with Treg-conditioned media enhanced the proportion of MBP+ oligodendrocytes and decreased the proportion of PDGFRalpha+ OPCs, but did not affect OPC proliferation or survival. Treg-enhanced oligodendrocyte differentiation was not caused by Treg polarizing factors, was dependent on the number of activation cycles Treg underwent and was robustly achieved by using 5% conditioned media. These studies provide in-depth characterization of a murine mixed neuron-glia model as well as further insights into the dynamics of Treg-enhanced oligodendrocyte differentiation. PMID- 29720230 TI - Urate inhibits microglia activation to protect neurons in an LPS-induced model of Parkinson's disease. AB - BACKGROUND: Multiple risk factors contribute to the progression of Parkinson's disease, including oxidative stress and neuroinflammation. Epidemiological studies have revealed a link between higher urate level and a lower risk of developing PD. However, the mechanistic basis for this association remains unclear. Urate protects dopaminergic neurons from cell death induced by oxidative stress. Here, we investigated a novel role of urate in microglia activation in a lipopolysaccharide (LPS)-induced PD model. METHODS: We utilized Griess, ELISA, real-time PCR, Western blot, immunohistochemistry, and immunofluorescence to detect the neuroinflammation. For Griess, ELISA, Western blot, and immunofluorescence assay, cells were seeded in 6-well plates pre-coated with poly L-lysine (PLL) and incubated for 24 h with the indicated drugs. For real-time PCR assay, cells were seeded in 6-well plates pre-coated with PLL and incubated for 6 h with the indicated drugs. For animal experiments, rats were injected with urate or its vehicle twice daily for five consecutive days before and after stereotaxic surgery. Rats were killed and brain tissues were harvested after 4 weeks of LPS injection. RESULTS: In cultured BV2 cells and rat primary microglia, urate suppressed proinflammatory cytokine production and inducible cyclooxygenase 2 and nitric oxide synthase expression to protect dopaminergic neurons from the toxic effects of activated microglia. The neuroprotective effects of urate may also be associated with the stimulation of anti-inflammatory factors interleukin 10 and transforming growth factor beta1. Intracellular urate level was increased in a dose-dependent manner upon co-treatment with urate and LPS as compared with LPS alone, an effect that was abrogated by pretreatment with probenecid (PBN), an inhibitor of both glucose transporter 9 and urate transporter 1 (URAT1). PBN also abolished the anti-inflammatory effect of urate. Consistent with these in vitro observations, the number of tyrosine hydroxylase-positive neurons was decreased and the loss of motor coordination was reversed by urate administration in an LPS induced rat model of PD. Additionally, increased plasma urate level abolished the reduction of URAT1 expression, the increase in the expression of interleukin 1beta, and the number of ionized calcium-binding adaptor molecule 1-positive microglia along with changes in their morphology. CONCLUSIONS: Urate protects neurons against cytotoxicity induced by microglia activation via modulating urate transporter-mediated intracellular urate level. PMID- 29720231 TI - Nimodipine treatment does not benefit juvenile ferrets with kaolin-induced hydrocephalus. AB - Prior research on 3-week hydrocephalic rats showed that behavioral deficits and white matter damage could be reduced by treatment with Ca2+ channel blocker nimodipine. We hypothesized that treatment with nimodipine would be also beneficial to young ferrets with kaolin-induced hydrocephalus. Hydrocephalus was induced at 14 days of age and animals were treated either with vehicle, low dose nimodipine (3.2 mg/kg/day), or high dose nimodipine (16 mg/kg/day) for 2 weeks from 38 to 52 days age. Hydrocephalic ferrets developed progressive ventriculomegaly, behavioral changes, and in some cases cortical blindness. These changes were not ameliorated by nimodipine. Histological examination showed damage in periventricular white matter, corpus callosum thinning, axonal damage, reactive astroglial changes, and suppressed cell proliferation compared to non hydrocephalic controls. Treatment with nimodipine was not beneficial for any of the pathological changes mentioned above; only low dose nimodipine treatment was associated with normalized content of glial fibrillary acidic protein, despite larger ventricles. We conclude that young hydrocephalic ferrets experience behavioral impairments and structural brain damage that are not consistently improved by intermittent nimodipine treatment. Continuous delivery should be considered in further preclinical studies. PMID- 29720232 TI - Highly sensitive and robust peroxidase-like activity of Au-Pt core/shell nanorod antigen conjugates for measles virus diagnosis. AB - BACKGROUND: As a promising candidate for artificial enzymes, catalytically active nanomaterials show several advantages over natural enzymes, such as controlled synthesis at low cost, tunability of catalytic activities, and high stability under stringent conditions. Rod-shaped Au-Pt core/shell nanoparticles (Au@Pt NRs), prepared by Au nanorod-mediated growth, exhibit peroxidase-like activities and could serve as an inexpensive replacement for horseradish peroxidase, with potential applications in various bio-detections. The determination of measles virus is accomplished by a capture-enzyme-linked immunosorbent assay (ELISA) using Au@Pt NR-antigen conjugates. RESULTS: Based on the enhanced catalytic properties of this nanozyme probe, a linear response was observed up to 10 ng/mL measles IgM antibodies in human serum, which is 1000 times more sensitive than commercial ELISA. CONCLUSIONS: Hence, these findings provide positive proof of concept for the potential of Au@Pt NR-antigen conjugates in the development of colorimetric biosensors that are simple, robust, and cost-effective. PMID- 29720233 TI - Real-world evidence analysis of palbociclib prescribing patterns for patients with advanced/metastatic breast cancer treated in community oncology practice in the USA one year post approval. AB - BACKGROUND: Rapidly evolving understanding of cancer biology has presented novel opportunities to translate that understanding into clinically relevant therapy. Palbociclib, a novel, first-in-class cyclin-dependent kinase (CDK) 4/6 inhibitor was approved in the USA in February 2015 for the treatment of advanced/metastatic breast cancer. We examined real-world evidence in the first year post approval to understand the clinical and demographic characteristics of patients treated with palbociclib in community oncology practices and the dosing, treatment, and complete blood count (CBC) monitoring patterns. METHODS: This was a retrospective observational study of structured data from a US electronic medical record (EMR) database. Female patients receiving palbociclib after 31 January 2015 were followed through 31 March 2016. Our methodological rules were constructed to aggregate drugs received according to the order in which they are given, i.e., identify the line of therapy as first, second, or third line, etc., using treatment order and course description fields from the EMR. RESULTS: There were 763 patients initiating palbociclib who met the selection criteria. Of those, 612 (80.2%) received palbociclib concomitantly with letrozole. Mean follow up was 6.4 months and mean age at palbociclib initiation was 64 years. Of patients with a known starting dose (n = 417), 79.9% started on palbociclib 125 mg. Dose reductions were observed in 20.1% of patients. Percentages of patients according to line of therapy at initiation of palbociclib were first-line, 39.5%; second line, 15.7%; third-line, 13.1%; and fourth-line therapy or later, 31.7%. On average, two CBC tests were conducted during the first cycle of palbociclib treatment. Overall, 74.6% of patients had a neutropenic event during follow up including 47.3% and 8.0% of patients with a grade 3 or 4 occurrence, respectively. CONCLUSIONS: Real-world palbociclib use one year post US approval demonstrates a more heterogeneous patient population than that studied in the clinical trials with more than half of the patients receiving palbociclib plus letrozole in later lines of therapy. CBC testing rates suggested good provider compliance with monitoring guidelines in the USA prescribing information. The occurrence of grade 3 and 4 neutropenia (based on laboratory results) was consistent with the rates of grade 3 and 4 neutropenia in two phase-III studies (PALOMA-2, 56% and 10%; PALOMA-3, 55% and 11%, respectively). Understanding palbociclib utilization in real-world patients and how drug dosing and monitoring are performed aids in the understanding of safe and effective use of the drug. PMID- 29720234 TI - Two independent proteomic approaches provide a comprehensive analysis of the synovial fluid proteome response to Autologous Chondrocyte Implantation. AB - BACKGROUND: Autologous chondrocyte implantation (ACI) has a failure rate of approximately 20%, but it is yet to be fully understood why. Biomarkers are needed that can pre-operatively predict in which patients it is likely to fail, so that alternative or individualised therapies can be offered. We previously used label-free quantitation (LF) with a dynamic range compression proteomic approach to assess the synovial fluid (SF) of ACI responders and non-responders. However, we were able to identify only a few differentially abundant proteins at baseline. In the present study, we built upon these previous findings by assessing higher-abundance proteins within this SF, providing a more global proteomic analysis on the basis of which more of the biology underlying ACI success or failure can be understood. METHODS: Isobaric tagging for relative and absolute quantitation (iTRAQ) proteomic analysis was used to assess SF from ACI responders (mean Lysholm improvement of 33; n = 14) and non-responders (mean Lysholm decrease of 14; n = 13) at the two stages of surgery (cartilage harvest and chondrocyte implantation). Differentially abundant proteins in iTRAQ and combined iTRAQ and LF datasets were investigated using pathway and network analyses. RESULTS: iTRAQ proteomic analysis confirmed our previous finding that there is a marked proteomic shift in response to cartilage harvest (70 and 54 proteins demonstrating >= 2.0-fold change and p < 0.05 between stages I and II in responders and non-responders, respectively). Further, it highlighted 28 proteins that were differentially abundant between responders and non-responders to ACI, which were not found in the LF study, 16 of which were altered at baseline. The differential expression of two proteins (complement C1s subcomponent and matrix metalloproteinase 3) was confirmed biochemically. Combination of the iTRAQ and LF proteomic datasets generated in-depth SF proteome information that was used to generate interactome networks representing ACI success or failure. Functional pathways that are dysregulated in ACI non-responders were identified, including acute-phase response signalling. CONCLUSIONS: Several candidate biomarkers for baseline prediction of ACI outcome were identified. A holistic overview of the SF proteome in responders and non-responders to ACI has been profiled, providing a better understanding of the biological pathways underlying clinical outcome, particularly the differential response to cartilage harvest in non-responders. PMID- 29720235 TI - Effects of selexipag and its active metabolite in contrasting the profibrotic myofibroblast activity in cultured scleroderma skin fibroblasts. AB - BACKGROUND: Myofibroblasts contribute to fibrosis through the overproduction of extracellular matrix (ECM) proteins, primarily type I collagen (COL-1) and fibronectin (FN), a process which is mediated in systemic sclerosis (SSc) by the activation of fibrogenic intracellular signaling transduction molecules, including extracellular signal-regulated kinases 1 and 2 (Erk1/2) and protein kinase B (Akt). Selexipag is a prostacyclin receptor agonist synthesized for the treatment of pulmonary arterial hypertension. The study investigated the possibility for selexipag and its active metabolite (ACT-333679) to downregulate the profibrotic activity in primary cultures of SSc fibroblasts/myofibroblasts and the fibrogenic signaling molecules involved. METHODS: Fibroblasts from skin biopsies obtained with Ethics Committee (EC) approval from patients with SSc, after giving signed informed consent, were cultured until the 3rd culture passage and then either maintained in normal growth medium (untreated cells) or independently treated with different concentrations of selexipag (from 30 MUM to 0.3 MUM) or ACT-333679 (from 10 MUM to 0.1 MUM) for 48 h. Protein and gene expressions of alpha-smooth muscle actin (alpha-SMA), fibroblast specific protein 1 (S100A4), COL-1, and FN were investigated by western blotting and quantitative real-time PCR. Erk1/2 and Akt phosphorylation was investigated in untreated and ACT-333679-treated cells by western botting. RESULTS: Selexipag and ACT-333679 significantly reduced protein synthesis and gene expression of alpha-SMA, S100A4, and COL-1 in cultured SSc fibroblasts/myofibroblasts compared to untreated cells, whereas FN was significantly downregulated at the protein level. Interestingly, ACT-333679 significantly reduced the phosphorylation of Erk1/2 and Akt in cultured SSc fibroblasts/myofibroblasts. CONCLUSIONS: Selexipag and mainly its active metabolite ACT-333679 were found for the first time to potentially interfere with the profibrotic activity of cultured SSc fibroblasts/myofibroblasts at least in vitro, possibly through the downregulation of fibrogenic Erk1/2 and Akt signaling molecules. PMID- 29720236 TI - Accuracy of the HumaSensplus point-of-care uric acid meter using capillary blood obtained by fingertip puncture. AB - BACKGROUND: The uric acid (UA) level in patients with gout is a key factor in disease management and is typically measured in the laboratory using plasma samples obtained after venous puncture. This study aimed to assess the reliability of immediate UA measurement with capillary blood samples obtained by fingertip puncture with the HumaSensplus point-of-care meter. METHODS: UA levels were measured using both the HumaSensplus meter in the clinic and the routine plasma UA method in the biochemistry laboratory of 238 consenting diabetic patients. HumaSensplus capillary and routine plasma UA measurements were compared by linear regression, Bland-Altman plots, intraclass correlation coefficient (ICC), and Lin's concordance coefficient. Values outside the dynamic range of the meter, low (LO) or high (HI), were analyzed separately. The best capillary UA thresholds for detecting hyperuricemia were determined by receiver operating characteristic (ROC) curves. The impact of potential confounding factors (demographic and biological parameters/treatments) was assessed. Capillary and routine plasma UA levels were compared to reference plasma UA measurements by liquid chromatography-mass spectrometry (LC-MS) for a subgroup of 67 patients. RESULTS: In total, 205 patients had capillary and routine plasma UA measurements available. ICC was 0.90 (95% confidence interval (CI) 0.87-0.92), Lin's coefficient was 0.91 (0.88-0.93), and the Bland-Altman plot showed good agreement over all tested values. Overall, 17 patients showed values outside the dynamic range. LO values were concordant with plasma values, but HI values were considered uninterpretable. Capillary UA thresholds of 299 and 340 MUmol/l gave the best results for detecting hyperuricemia (corresponding to routine plasma UA thresholds of 300 and 360 MUmol/l, respectively). No significant confounding factor was found among those tested, except for hematocrit; however, this had a negligible influence on the assay reliability. When capillary and routine plasma results were discordant, comparison with LC-MS measurements showed that plasma measurements had better concordance: capillary UA, ICC 0.84 (95% CI 0.75-0.90), Lin's coefficient 0.84 (0.77-0.91); plasma UA, ICC 0.96 (0.94-0.98), Lin's coefficient 0.96 (0.94-0.98). CONCLUSIONS: UA measurements with the HumaSensplus meter were reasonably comparable with those of the laboratory assay. The meter is easy to use and may be useful in the clinic and in epidemiologic studies. PMID- 29720237 TI - Factors associated with physicians' prescriptions for rheumatoid arthritis drugs not filled by patients. AB - BACKGROUND: This study estimated the extent and predictors of primary nonadherence (i.e., prescriptions made by physicians but not initiated by patients) to methotrexate and to biologics or tofacitinib in rheumatoid arthritis (RA) patients who were newly prescribed these medications. METHODS: Using administrative claims linked with electronic health records (EHRs) from multiple healthcare provider organizations in the USA, RA patients who received a new prescription for methotrexate or biologics/tofacitinib were identified from EHRs. Claims data were used to ascertain filling or administration status. A logistic regression model for predicting primary nonadherence was developed and tested in training and test samples. Predictors were selected based on clinical judgment and LASSO logistic regression. RESULTS: A total of 36.8% of patients newly prescribed methotrexate failed to initiate methotrexate within 2 months; 40.6% of patients newly prescribed biologics/tofacitinib failed to initiate within 3 months. Factors associated with methotrexate primary nonadherence included age, race, region, body mass index, count of active drug ingredients, and certain previously diagnosed and treated conditions at baseline. Factors associated with biologics/tofacitinib primary nonadherence included age, insurance, and certain previously treated conditions at baseline. The area under the receiver operating characteristic curve of the logistic regression model estimated in the training sample and applied to the independent test sample was 0.86 and 0.78 for predicting primary nonadherence to methotrexate and to biologics/tofacitinib, respectively. CONCLUSIONS: This study confirmed that failure to initiate new prescriptions for methotrexate and biologics/tofacitinib was common in RA patients. It is feasible to predict patients at high risk of primary nonadherence to methotrexate and to biologics/tofacitinib and to target such patients for early interventions to promote adherence. PMID- 29720238 TI - Two versus five days of antibiotics after appendectomy for complex acute appendicitis (APPIC): study protocol for a randomized controlled trial. AB - BACKGROUND: Acute appendicitis is one of the most common indications for emergency surgery. In patients with a complex appendicitis, prolonged antibiotic prophylaxis is recommended after appendectomy. There is no consensus regarding the optimum duration of antibiotics. Guidelines propose 3 to 7 days of treatment, but shorter courses may be as effective in the prevention of infectious complications. At the same time, the global issue of increasing antimicrobial resistance urges for optimization of antibiotic strategies. The aim of this study is to determine whether a short course (48 h) of postoperative antibiotics is non inferior to current standard practice of 5 days. METHODS: Patients of 8 years and older undergoing appendectomy for acute complex appendicitis - defined as a gangrenous and/or perforated appendicitis or appendicitis in presence of an abscess - are eligible for inclusion. Immunocompromised or pregnant patients are excluded, as well as patients with a contraindication to the study antibiotics. In total, 1066 patients will be randomly allocated in a 1:1 ratio to the experimental treatment arm (48 h of postoperative intravenously administered (IV) antibiotics) or the control arm (5 days of postoperative IV antibiotics). After discharge from the hospital, patients participate in a productivity-cost questionnaire at 4 weeks and a standardized telephone follow-up at 90 days after appendectomy. The primary outcome is a composite endpoint of infectious complications, including intra-abdominal abscess (IAA) and surgical site infection (SSI), and mortality within 90 days after appendectomy. Secondary outcomes include IAA, SSI, restart of antibiotics, length of hospital stay (LOS), reoperation, percutaneous drainage, readmission rate, and cost-effectiveness. The non-inferiority margin for the difference in the primary endpoint rate is set at 7.5% (one-sided test at alpha 0.025). Both per-protocol and intention-to-treat analyses will be performed. DISCUSSION: This trial will provide evidence on whether 48 h of postoperative antibiotics is non-inferior to a standard course of 5 days of antibiotics. If non-inferiority is established, longer intravenous administration following appendectomy for complex appendicitis can be abandoned, and guidelines need to be adjusted accordingly. TRIAL REGISTRATION: Dutch Trial Register, NTR6128 . Registered on 20 December 2016. PMID- 29720239 TI - A subset of mobilized human hematopoietic stem cells express germ layer lineage genes which can be modulated by culture conditions. AB - BACKGROUND: Adult bone marrow contains stem cells that replenish the myeloid and lymphoid lineages. A subset of human and mouse CD34+ bone marrow stem cells can be propagated in culture to autonomously express embryonic stem cell genes and embryonic germ layer lineage genes. The current study was undertaken to determine whether these CD34+ stem cells could be obtained from human blood, whether gene expression could be modulated by culture conditions and whether the cells produce insulin. METHODS: Human peripheral blood buffy coat cells and mobilized CD34+ cells from human blood and from blood from C57Bl/6 J mice were cultured in hybridoma medium or neural stem cell induction medium supplemented with interleukin (IL)-3, IL-6, and stem cell factor (SCF). Changes in mRNA and protein expression were assessed by Western blot analysis and by immunohistochemistry. Mass spectrometry was used to assess insulin production. RESULTS: We were able to culture CD34+ cells expressing embryonic stem cell and embryonic germ layer lineage genes from adult human peripheral blood after standard mobilization procedures and from mouse peripheral blood. Gene expression could be modulated by culture conditions, and the cells produced insulin in culture. CONCLUSION: These results suggest a practical method for obtaining large numbers of CD34+ cells from humans to allow studies on their potential to differentiate into other cell types. PMID- 29720240 TI - Integrative analysis reveals CD38 as a therapeutic target for plasma cell-rich pre-disease and established rheumatoid arthritis and systemic lupus erythematosus. AB - BACKGROUND: Plasmablasts and plasma cells play a key role in many autoimmune diseases, such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). This study was undertaken to evaluate the potential of targeting CD38 as a plasma cell/plasmablast depletion mechanism by daratumumab in the treatment of patients with RA and SLE. METHODS: RNA-sequencing analysis of synovial biopsies from various stages of RA disease progression, flow cytometry analysis of peripheral blood mononuclear cells (PBMC) from patients with RA or SLE and healthy donors, immunohistochemistry assessment (IHC) of synovial biopsies from patients with early RA, and ex vivo immune cell depletion assays using daratumumab (an anti-CD38 monoclonal antibody) were used to assess CD38 as a therapeutic target. RESULTS: We demonstrated that the plasma cell/plasmablast related genes CD38, XBP1, IRF4, PRDM1, IGJ and TNFSF13B are significantly up regulated in synovial biopsies from patients with arthralgia, undifferentiated arthritis (UA), early RA and established RA as compared to healthy controls and control patients with osteoarthritis. In addition, the highest CD38 expression was observed on plasma cells and plasmablasts compared to natural killer (NK) cells, classical dendritic cells (DCs), plasmacytoid DCs (pDCs) and T cells, in blood from healthy controls and patients with SLE and RA. Furthermore, IHC showed CD38 staining in the same region as CD3 and CD138 staining in synovial tissue biopsies from patients with early RA. Most importantly, our data show for the first time that daratumumab effectively depletes plasma cells/plasmablasts in PBMC from patients with SLE and RA in a dose-dependent manner ex vivo. CONCLUSION: These results indicate that CD38 may be a potential target for RA disease interception and daratumumab should be evaluated clinically for the treatment of both RA and SLE. PMID- 29720241 TI - Cross-talk between microtubules and the linker of nucleoskeleton complex plays a critical role in the adipogenesis of human adipose-derived stem cells. AB - BACKGROUND: Adipose-derived stem cells (ASCs) that show multidifferentiation and anti-immune rejection capacities have been widely used in plastic and reconstructive surgery. Previous studies have indicated that mechanical and biophysical interactions between cells and their surrounding environment regulate essential processes, such as growth, survival, and differentiation, and the cytoskeleton system plays an important role in the mechanotransduction. However, the role of mechanical force in the determination of lineage fate is still unclear. METHODS: Human ASCs (hASCs) were obtained from three different donors by liposuction. Adipogenesis and osteogenesis were determined by Oil Red O and Alizarin Red staining, respectively. The mRNA levels of the cytoskeleton system, PPARgamma, and C/EBPalpha were determined by real-time polymerase chain reaction (RT-PCR). The level of cytoskeleton, PPARgamma, and C/EBPalpha protein levels were measured by Western blotting. The morphology of the cytoskeleton system during adipogenesis was observed with confocal microscopy. hASCs were transfected with a SUN2-specific shRNA to knockdown sun2, and a nontargeting shRNA was used as a control. RESULTS: We found that disrupting the physiological balance between the cytoskeleton and the linker of the nucleoskeleton and cytoskeleton (LINC) complex (especially SUN2) could impact the adipogenesis of hASCs in vitro. Microtubule (MT) depolymerization with nocodazole (which interferes with the polymerization of MTs) increased the expression of SUN2 and PPARgamma, while taxol (an inhibitor of MT disassembly) showed the opposite results. Meanwhile, hASCs with sun2 knockdown overexpressed MTs and decreased PPARgamma expression, thereby inhibiting the adipogenesis. Furthermore, knockdown of sun2 changed the structure of perinuclear MTs. CONCLUSIONS: We demonstrated the presence of cross talk between MT and SUN2, and this cross-talk plays a critical role in the rebalance of the mechanical environment and is involved in the regulation of PPARgamma transport during adipogenic differentiation of hASCs. PMID- 29720242 TI - Anorectal metastasis from breast carcinoma: a case report and review of the literature. AB - BACKGROUND: Gastrointestinal metastasis from primary breast carcinoma is uncommon, anorectal involvement is extremely rare. CASE PRESENTATION: We present the case of a 65-year old woman who underwent treatment for an infiltrative lobular carcinoma of the left breast with bone metastases and who developed metastasis of the rectum and anal canal 4 years later. CONCLUSIONS: A patient with a history of breast cancer, especially lobular carcinoma, presenting with anorectal symptoms, should raise the suspicion of metastatic disease. PMID- 29720243 TI - Fcgamma receptor-mediated influx of S100A8/A9-producing neutrophils as inducer of bone erosion during antigen-induced arthritis. AB - BACKGROUND: Osteoclast-mediated bone erosion is a central feature of rheumatoid arthritis (RA). Immune complexes, present in a large percentage of patients, bind to Fcgamma receptors (FcgammaRs), thereby modulating the activity of immune cells. In this study, we investigated the contribution of FcgammaRs, and FcgammaRIV in particular, during antigen-induced arthritis (AIA). METHODS: AIA was induced in knee joints of wild-type (WT), FcgammaRI,II,III-/-, and FcgammaRI,II,III,IV-/- mice. Bone destruction, numbers of tartrate-resistant acid phosphatase-positive (TRAP+) osteoclasts, and inflammation were evaluated using histology; expression of the macrophage marker F4/80, neutrophil marker NIMPR14, and alarmin S100A8 was evaluated using immunohistochemistry. The percentage of osteoclast precursors in the bone marrow was determined using flow cytometry. In vitro osteoclastogenesis was evaluated with TRAP staining, and gene expression was assessed using real-time PCR. RESULTS: FcgammaRI,II,III,IV-/- mice showed decreased bone erosion compared with WT mice during AIA, whereas both the humoral and cellular immune responses against methylated bovine serum albumin were not impaired in FcgammaRI,II,III,IV-/- mice. The percentage of osteoclast precursors in the bone marrow of arthritic mice and their ability to differentiate into osteoclasts in vitro were comparable between FcgammaRI,II,III,IV-/- and WT mice. In line with these observations, numbers of TRAP+ osteoclasts on the bone surface during AIA were comparable between the two groups. Inflammation, a process that strongly activates osteoclast activity, was reduced in FcgammaRI,II,III,IV-/- mice, and of note, mainly decreased numbers of neutrophils were present in the joint. In contrast to FcgammaRI,II,III,IV-/- mice, AIA induction in knee joints of FcgammaRI,II,III-/- mice resulted in increased bone erosion, inflammation, and numbers of neutrophils, suggesting a crucial role for FcgammaRIV in the joint pathology by the recruitment of neutrophils. Finally, significant correlations were found between bone erosion and the number of neutrophils present in the joint as well as between bone erosion and the number of S100A8-positive cells, with S100A8 being an alarmin strongly produced by neutrophils that stimulates osteoclast resorbing activity. CONCLUSIONS: FcgammaRs play a crucial role in the development of bone erosion during AIA by inducing inflammation. In particular, FcgammaRIV mediates bone erosion in AIA by inducing the influx of S100A8/A9 producing neutrophils into the arthritic joint. PMID- 29720244 TI - Administration of taurolidine-citrate lock solution for prevention of central venous catheter infection in adult neutropenic haematological patients: a randomised, double-blinded, placebo-controlled trial (TAURCAT). AB - BACKGROUND: Catheter-related bloodstream infection (CRBSI) is one of the most frequent complications in patients with cancer who have central venous catheters (CVCs) implanted and is associated with substantial morbidity and mortality. Taurolidine is a non-antibiotic agent with broad-spectrum antimicrobial activity, which has been used as a lock solution to prevent CRBSI in some settings. However, little is known about its usefulness in high-risk adult neutropenic patients with cancer. This prospective randomised clinical trial aims to test the hypothesis that taurolidine-citrate lock solution is more effective than placebo for preventing catheter infection in neutropenic haematological patients. METHODS: This study is a prospective, multicentre, randomised, double-blinded, parallel, superiority, placebo-controlled trial. Patients with haematological cancer who are expected to develop prolonged neutropenia (> 7 days) and who have a non-tunnelled CVC implanted will be randomised to receive prophylactic taurolidine-citrate-heparin solution using a lock technique (study group) or heparin alone (placebo group). The primary endpoint will be bacterial colonisation of the CVC hubs. The secondary endpoints will be the incidence of CRBSI, CVC removal, adverse events, and 30-day case-fatality rate. DISCUSSION: The lock technique is a preventive strategy that inhibits bacterial colonisation in the catheter hubs, which is the initial step of endoluminal catheter colonisation and the development of infection. Taurolidine is a nontoxic agent that does not develop antibiotic resistance because it acts as an antiseptic rather than an antibiotic. Taurolidine has shown controversial results in the few trials conducted in cancer patients. These studies have important limitations due to the lack of data on adult and/or high-risk neutropenic patients, the type of catheters studied (tunnelled or ports), and the lack of information regarding the intervention (e.g. dwelling of the solution, time, and periodicity of the lock technique). If our hypothesis is proven, the study could provide important solid evidence on the potential usefulness of this preventive procedure in a population at high risk of CRBSI, in whom this complication may significantly impair patient outcome. TRIAL REGISTRATION: ISRCTN, ISRCTN47102251 . Registered on 9 September 2015. PMID- 29720245 TI - Human platelet lysate in mesenchymal stromal cell expansion according to a GMP grade protocol: a cell factory experience. AB - BACKGROUND: The use of platelet lysate (PL) for the ex-vivo expansion of mesenchymal stromal/stem cells (MSCs) was initially proposed by Doucet et al. in 2005, as an alternative to animal serum. Moreover, regulatory authorities discourage the use of fetal bovine serum (FBS) or other animal derivatives, to avoid risk of zoonoses and xenogeneic immune reactions. Even if many studies investigated PL composition, there still are some open issues related to its use in ex-vivo MSC expansion, especially according to good manufacturing practice (GMP) grade protocols. METHODS: As an authorized cell factory, we report our experience using standardized PL produced by Azienda Ospedaliero Universitaria Meyer Transfusion Service for MSC expansion according to a GMP grade clinical protocol. As suggested by other authors, we performed an in-vitro test on MSCs versus MSCs cultured with FBS that still represents the best way to test PL batches. We compared 12 MSC batches cultured with DMEM 5% PL with similar batches cultured with DMEM 10% FBS, focusing on the MSC proliferation rate, MSC surface marker expression, MSC immunomodulatory and differentiation potential, and finally MSC relative telomere length. RESULTS: Results confirmed the literature data as PL increases cell proliferation without affecting the MSC immunophenotype, immunomodulatory potential, differentiation potential and relative telomere length. CONCLUSIONS: PL can be considered a safe alternative to FBS for ex-vivo expansion of MSC according to a GMP grade protocol. Our experience confirms the literature data: a large number of MSCs for clinical applications can be obtained by expansion with PL, without affecting the MSC main features. Our experience underlines the benefits of a close collaboration between the PL producers (transfusion service) and the end users (cell factory) in a synergy of skills and experiences that can lead to standardized PL production. PMID- 29720246 TI - Rapid identification of medically important mosquitoes by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. AB - BACKGROUND: Accurate and rapid identification of dipteran vectors is integral for entomological surveys and is a vital component of control programs for mosquito borne diseases. Conventionally, morphological features are used for mosquito identification, which suffer from biological and geographical variations and lack of standardization. We used matrix-assisted laser desorption/ionization time-of flight mass spectrometry (MALDI-TOF MS) for protein profiling of mosquito species from North India with the aim of creating a MALDI-TOF MS database and evaluating it. METHODS: Mosquito larvae were collected from different rural and urban areas and reared to adult stages. The adult mosquitoes of four medically important genera, Anopheles, Aedes, Culex and Armigerus, were morphologically identified to the species level and confirmed by ITS2-specific PCR sequencing. The cephalothoraces of the adult specimens were subjected to MALDI-TOF analysis and the signature peak spectra were selected for creation of database, which was then evaluated to identify 60 blinded mosquito specimens. RESULTS: Reproducible MALDI TOF MS spectra spanning over 2-14 kDa m/z range were produced for nine mosquito species: Anopheles (An. stephensi, An. culicifacies and An. annularis); Aedes (Ae. aegypti and Ae. albopictus); Culex (Cx. quinquefasciatus, Cx. vishnui and Cx. tritaenorhynchus); and Armigerus (Ar. subalbatus). Genus- and species specific peaks were identified to create the database and a score of > 1.8 was used to denote reliable identification. The average numbers of peaks obtained were 55-60 for Anopheles, 80-100 for Aedes, 30-60 for Culex and 45-50 peaks for Armigeres species. Of the 60 coded samples, 58 (96.67%) were correctly identified by MALDI-TOF MS with a score > 1.8, while there were two unreliable identifications (both Cx. quinquefasciatus with scores < 1.8). CONCLUSIONS: MALDI TOF MS appears to be a pragmatic technique for accurate and rapid identification of mosquito species. The database needs to be expanded to include species from different geographical regions and also different life-cycle stages to fully harness the technique for entomological surveillance programs. PMID- 29720247 TI - Interventions for improving pharmacist-led patient counselling in the community setting: a systematic review. AB - BACKGROUND: Pharmacist counselling is an important service that has been associated with improved outcomes. The primary aim of this review was to identify, describe, and determine the effectiveness of interventions for improving the counselling practice of community pharmacists. METHODS: We searched PubMed (from January 1990 to June 2017) and the Cochrane Library (June 2017). To supplement our database searches, we searched Google Scholar for papers that cited the identified studies. We included only studies that reported the impact of the intervention on pharmacists' behaviour during counselling. We searched for data from studies with randomised trials, non-randomised trials, controlled before-after studies, or interrupted time series study designs. Parameters including selection bias, performance bias, detection bias, and attrition bias were assessed. The data were narratively synthesised. RESULTS: We screened 2335 abstracts and 59 full-text articles and included 17 RCTs. Overall, three studies were determined to have a high risk of bias, and 14 studies were determined to have an unclear risk of bias. Fifteen studies investigated multifaceted interventions that included two or more components. The most commonly used interventions were educational meetings (n = 14), educational materials (n = 9), educational outreach visits (n = 5), feedback (n = 5), guidelines (n = 5), and local opinion leaders (n = 2). Outcomes were measured using simulated patient visits (n = 10), and the self-reported outcomes of patient or pharmacists (n = 6). Most of the included studies (n = 11) reported some degree of improvement in counselling practices. CONCLUSIONS: The included studies showed that educational meetings combined with educational materials, outreach visits, and feedback can improve pharmacist counselling in community settings. However, the unclear risk of bias and poor quality of reporting intervention components necessitate caution in interpreting the findings. Recommendations for future studies based on the evidence gap identified in this review are presented. PMID- 29720248 TI - Outcome pre-specification requires sufficient detail to guard against outcome switching in clinical trials: a case study. AB - BACKGROUND: Pre-specification of outcomes is an important tool to guard against outcome switching in clinical trials. However, if the outcome is not sufficiently clearly defined, then different definitions could be applied and analysed, with only the most favourable result reported. METHODS: In order to assess the impact that differing outcome definitions could have on treatment effect estimates, we re-analysed data from TRIGGER, a cluster randomised trial comparing two red blood cell transfusion strategies for patients with acute upper gastrointestinal bleeding. We varied several aspects of the definition of further bleeding: (1) the criteria for what constitutes a further bleeding episode; (2) how further bleeding is assessed; and (3) the time-point at which further bleeding is measured. RESULTS: There were marked discrepancies in the estimated odds ratios (OR) (range 0.23-0.94) and corresponding P values (range < 0.001-0.89) between different outcome definitions. At the extremes, differing outcome definitions led to markedly different conclusions; one definition led to very little evidence of a treatment effect (OR = 0.94, 95% confidence interval [CI] = 0.37-2.40, P = 0.89), while another led to very strong evidence of a treatment effect (OR = 0.23, 95% CI = 0.11-0.50, P < 0.001). CONCLUSIONS: Outcomes should be pre specified in sufficient detail to avoid differing definitions being analysed and only the most favourable result being reported. TRIAL REGISTRATION: Clinical Trials.gov, NCT02105532 . Registered on 7 April 2014. PMID- 29720249 TI - Image quality of arterial phase and parenchymal blood volume (PBV) maps derived from C-arm computed tomography in the evaluation of transarterial chemoembolization. AB - BACKGROUND: To evaluate the benefits of arterial phase imaging and parenchymal blood volume (PBV) maps acquired by C-arm computed tomography during TACE procedure in comparison to cross-sectional imaging (CSI) using CT or MRI. METHODS: From January 2014 to December 2016, a total of 29 patients with HCC stage A or B (mean age 65 years; range 47 to 81 years, 86% male) were included in this study. These patients were referred to our department for TACE treatment and received peri-interventional C-arm CT. Dual phase findings of each lesion in terms of overall image quality, conspicuity, tumor size and feeding arteries were compared between arterial phase imaging and PBV using 5-point semi-quantitative Likert-scale, whereby pre-interventional CSI served as reference standard. RESULTS: A significantly higher overall image quality of the PBV maps compared to arterial phase C-arm CT acquisitions (4.34 (+/-0.55) vs. 3.93 (+/-0.59), p = 0.0032) as well as a higher conspicuity of HCC lesions (4.27 +/- 0.74 vs. 3.83 +/ 1.08, p < 0.0001) was observed. Arterial phase imaging led to an overestimation of tumor size (mean size, 26.5 +/- 15.9 mm) compared to PBV (24.9 +/- 15.2 mm, p = 0.0004) as well as CSI (25.2 +/- 15.1 mm), p = 0.021). Regarding detectability of tumor feeding arterial vessels, significantly more feeding vessels were detected in arterial phase C-arm CT (n = 1.67 +/- 0.92 vessels) compared to PBV maps (n = 1.27 +/- 0.63 vessels) (p = 0.0001). One lesion was missed in pre interventional CT imaging, but detected by C-arm CT. CONCLUSION: The combination of PBV maps and arterial phase images acquired by C-arm CT during TACE procedure enables precise detection of the majority of HCC lesions and tumor feeding arteries and has therefore the potential to improve patient outcome. PMID- 29720250 TI - Efficient induction of functional ameloblasts from human keratinocyte stem cells. AB - BACKGROUND: Although adult human tissue-derived epidermal stem cells are capable of differentiating into enamel-secreting ameloblasts and forming teeth with regenerated enamel when recombined with mouse dental mesenchyme that possesses odontogenic potential, the induction rate is relatively low. In addition, whether the regenerated enamel retains a running pattern of prism identical to and acquires mechanical properties comparable with human enamel indeed warrants further study. METHODS: Cultured human keratinocyte stem cells (hKSCs) were treated with fibroblast growth factor 8 (FGF8) and Sonic hedgehog (SHH) for 18 h or 36 h prior to being recombined with E13.5 mouse dental mesenchyme with implantation of FGF8 and SHH-soaked agarose beads into reconstructed chimeric tooth germs. Recombinant tooth germs were subjected to kidney capsule culture in nude mice. Harvested samples at various time points were processed for histological, immunohistochemical, TUNEL, and western blot analysis. Scanning electronic microscopy and a nanoindentation test were further employed to analyze the prism running pattern and mechanical properties of the regenerated enamel. RESULTS: Treatment of hKSCs with both FGF8 and SHH prior to tissue recombination greatly enhanced the rate of tooth-like structure formation to about 70%. FGF8 and SHH dramatically enhanced stemness of cultured hKSCs. Scanning electron microscopic analysis revealed the running pattern of intact prisms of regenerated enamel is similar to that of human enamel. The nanoindentation test indicated that, although much softer than human child and adult mouse enamel, mechanical properties of the regenerated enamel improved as the culture time was extended. CONCLUSIONS: Application of FGF8 and SHH proteins in cultured hKSCs improves stemness but does not facilitate odontogenic fate of hKSCs, resulting in an enhanced efficiency of ameloblastic differentiation of hKSCs and tooth formation in human-mouse chimeric tooth germs. PMID- 29720251 TI - A meta-analysis of the prevalence of African animal trypanosomiasis in Nigeria from 1960 to 2017. AB - BACKGROUND: African animal trypanosomiasis is an economically significant disease that affects the livestock industry in Nigeria. It is caused by several parasites of the genus Trypanosoma. National estimates of the disease prevalence in livestock and tsetse flies are lacking, therefore a systematic review and meta analysis were performed to understand the trend of the disease prevalence over the years. METHODS: Publications were screened in Web of Science, Ovid MEDLINE, Global Health, EMBASE and PubMed databases. Using four-stage (identification, screening, eligibility and inclusion) process in the PRIMSA checklist, only studies that met the inclusion criteria for AAT and tsetse infections were analysed. Point estimates prevalence and subgroup analyses based on diagnostic techniques in livestock were evaluated at 95% confidence interval (CI). RESULTS: A total of 74 eligible studies published between 1960 and 2017 were selected for meta-analysis. This covers the six geopolitical zones, involving a total of 53,924 animals. The overall prevalence of AAT was 16.1% (95% CI: 12.3-20.3%). Based on diagnostic techniques, the prevalence of AAT in cattle was highest in PCR followed by serology and microscopy while the highest prevalence in pigs was observed with serology. Out of 12,552 tsetse flies examined from 14 eligible studies, an overall prevalence of 17.3% (95% CI: 4.5-36.0%) and subgroup prevalence of 49.7% (95% CI: 30.7-68.8%), 11.5% (95% CI: 6.1-18.5) and 4.5% (95% CI: 1.8-8.8%) in G. morsitans, G. tachinoides and G. palpalis, respectively, were observed using the random effects-model. CONCLUSIONS: The prevalence of trypanosomes in both vectors and animal hosts was high in Nigeria. Therefore, further research on risk factors, seasonal and transhumance effects, vectoral capacity and competence are warranted for an effective control of AAT in Nigeria. PMID- 29720252 TI - Estrogen induces St6gal1 expression and increases IgG sialylation in mice and patients with rheumatoid arthritis: a potential explanation for the increased risk of rheumatoid arthritis in postmenopausal women. AB - BACKGROUND: Rheumatoid arthritis (RA) preferentially affects women, with the peak incidence coinciding with estrogen decrease in menopause. Estrogen (E2) may therefore have intrinsic immune-regulatory properties that vanish with menopause. Fc sialylation is a crucial factor determining the inflammatory effector function of antibodies. We therefore analyzed whether E2 affects immunoglobulin G (IgG) sialylation. METHODS: Postmenopausal (ovariectomized) mice were immunized with ovalbumin and treated with E2 or vehicle. Total and ovalbumin-specific IgG concentrations, sialylation, and Fcgamma receptor expression were analyzed. Postmenopausal women with RA receiving hormone replacement therapy, including E2, or no treatment were analyzed for IgG sialylation. Furthermore, effects of E2 on the expression of the sialylation enzyme beta-galactoside alpha2,6 sialyltransferase 1 (St6Gal1) were studied in mouse and human antibody-producing cells. RESULTS: E2 treatment significantly increased Fc sialylation of total and ovalbumin-specific IgG in postmenopausal mice. Furthermore, E2 led to increased expression of inhibitory Fcgamma receptor IIb on bone marrow leukocytes. Treatment with E2 also increased St6Gal1 expression in mouse and human antibody producing cells, providing a mechanistic explanation for the increase in IgG-Fc sialylation. In postmenopausal women with RA, treatment with E2 significantly increased the Fc sialylation of IgG. CONCLUSIONS: E2 induces anti-inflammatory effector functions in IgG by inducing St6Gal1 expression in antibody-producing cells and by increasing Fc sialylation. These observations provide a mechanistic explanation for the increased risk of RA in conditions with low estrogen levels such as menopause. PMID- 29720253 TI - Relieving total pain in an adolescent: a case report. AB - BACKGROUND: Total pain is a concept that approaches pain holistically: physically, psychologically, socially, and spiritually. Any individual may experience pain in each domain at a different level. This is the case report of an adolescent who suffered from total pain and how his healthcare team and peers helped to relieve it. CASE PRESENTATION: A 15-years-old Thai male was diagnosed with recurrent T-cell lymphoma and readmitted to hospital. He was admitted to an adult ward and suffered from pain due to his disease and from the fear of being alienated. As a result, he had an existential crisis. His parents felt unsure whether they or the patient should make the medical decisions and advance care plan. CONCLUSIONS: This case report emphasises the importance of total pain assessment in the relief of total pain in an adolescent whose needs are different from both children and adults. It also highlights the role of medical decision making in adolescents and the importance of the social support of peers in the alleviation of pain. PMID- 29720254 TI - Concurrent interactome and metabolome analysis reveals role of AKT1 in central carbon metabolism. AB - OBJECTIVE: Signal transduction not only initiates entry into the cell cycle, but also reprograms the cell's metabolism. To control abnormalities in cell proliferation, both the aspects should be taken care of, thus pleiotropic signaling molecules are considered as crucial modulators. Considering this, we investigated the role of AKT1 in central carbon metabolism. The role of AKT1 has already been established in the process of cell cycle, but its contribution to the central carbon metabolism is sparsely studied. RESULTS: To address this, we combined the metabolomics and proteomics approaches. In accordance to our hypothesis, we found that the AKT1 kinase activity is regulating the levels of acetyl CoA through pyruvate dehydrogenase complex. Further, the decreased levels of acetyl CoA and dependency of acetyl CoA acetyl transferase protein on AKT1 kinase activity was also found to perturb the synthesis rate of palmitic acid which is a representative of fatty acid. This was analyzed in the present study using lipid labeling method through mass spectrometry. PMID- 29720255 TI - Enhanced early visual processing in response to snake and trypophobic stimuli. AB - BACKGROUND: Trypophobia refers to aversion to clusters of holes. We investigated whether trypophobic stimuli evoke augmented early posterior negativity (EPN). METHODS: Twenty-four participants filled out a trypophobia questionnaire and watched the random rapid serial presentation of 450 trypophobic pictures, 450 pictures of poisonous animals, 450 pictures of snakes, and 450 pictures of small birds (1800 pictures in total, at a rate of 3 pictures/s). The EPN was scored as the mean activity at occipital electrodes (PO3, O1, Oz, PO4, O2) in the 225-300 ms time window after picture onset. RESULTS: The EPN was significantly larger for snake pictures than for the other categories, and significantly larger for trypophobic pictures and poisonous animal pictures than for bird pictures. Remarkably, the scores on the trypophobia questionnaire were correlated with the EPN amplitudes for trypophobic pictures at the occipital cluster (r = -.46, p = .025). CONCLUSIONS: The outcome for the EPN indicates that snakes, and to a somewhat lesser extent trypophobic stimuli and poisonous animals, trigger early automatic visual attention. This supports the notion that the aversion that is induced by trypophobic stimuli reflects ancestral threat and has survival value. The possible influence of the spectral composition of snake and trypophobic stimuli on the EPN is discussed. PMID- 29720256 TI - Inflammation functions as a key mediator in the link between ACPA and erosion development: an association study in Clinically Suspect Arthralgia. AB - BACKGROUND: Anti-citrullinated protein antibodies (ACPA) are associated with more severe joint erosions in rheumatoid arthritis (RA), but the underlying mechanism is unclear. Recent in vitro and murine studies indicate that ACPAs can directly activate osteoclasts leading to bone erosions and pain. This study sought evidence for this hypothesis in humans and evaluated whether in patients with arthralgia who are at risk of RA, ACPA is associated with erosions (detected by magnetic resonance imaging (MRI)) independent of inflammation, and also independent of the presence of rheumatoid factor (RF). METHODS: Patients with Clinically Suspect Arthralgia (n = 507) underwent determination of ACPA and RF and 1.5 T contrast-enhanced MRI of the metacarpophalangeal, wrist and metatarsophalangeal joints at baseline. MRIs were scored for presence of local inflammation and erosions. Comparisons of erosion scores were performed using the Kruskal-Wallis test. To evaluate if inflammation is, in statistical terms, intermediary in the causal path of ACPA and erosions, three-step mediation analysis was performed using linear regression. RESULTS: ACPA-positive patients had higher erosion scores than ACPA-negative patients (p = 0.006). ACPA-positive patients without subclinical inflammation did not have higher erosion scores than ACPA-negative patients (p = 0.68), in contrast to ACPA-positive patients with local inflammation (p < 0.001). Mediation analyses suggested that local inflammation is in the causal path of ACPA leading to higher erosion scores. Compared to ACPA-negative/RF-negative patients, ACPA-positive/RF-negative patients did not differ (p = 0.30), but ACPA-positive/RF-positive patients had higher erosion scores (p = 0.006). CONCLUSIONS: The effect of ACPA on erosions is mediated by inflammation and is not independent of RF. PMID- 29720257 TI - Physical activity monitors to enhance the daily amount of physical activity in elderly-a protocol for a systematic review and meta-analysis. AB - BACKGROUND: To investigate the use of physical activity monitors (PAMs) for the elderly, the scientific literature should be systematically reviewed and the effect quantified, as the evidence seems inconclusive. METHODS AND DESIGN: Randomized controlled trials and randomized crossover trials, with participants with a mean age above 65 years, comparing any PAM intervention with other control interventions or no intervention, will be included. This protocol is detailed according to the recommendations of the Cochrane Handbook, and it is reported according to the Preferred Reporting Items for Systematic Reviews and Meta Analyses Protocols statement. RESULTS: We will present results from the search in a flow diagram. The results from the analyses will include regular meta-analyses, stratified analyses, and meta-regressions. The results on each outcome of interest will be presented in a summary of findings table. DISCUSSION: This paper will explore and analyze the heterogeneity of the results and try to identify variables that will enhance the effect of PAMs in elderly. The results will be useful to researchers working with elderly and/or PAMs, health care professionals working with elderly, and relatives together with the elderly themselves. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018083648 . PMID- 29720258 TI - T-type calcium channels functionally interact with spectrin (alpha/beta) and ankyrin B. AB - This study describes the functional interaction between the Cav3.1 and Cav3.2 T type calcium channels and cytoskeletal spectrin (alpha/beta) and ankyrin B proteins. The interactions were identified utilizing a proteomic approach to identify proteins that interact with a conserved negatively charged cytosolic region present in the carboxy-terminus of T-type calcium channels. Deletion of this stretch of amino acids decreased binding of Cav3.1 and Cav3.2 calcium channels to spectrin (alpha/beta) and ankyrin B and notably also reduced T-type whole cell current densities in expression systems. Furthermore, fluorescence recovery after photobleaching analysis of mutant channels lacking the proximal C terminus region revealed reduced recovery of both Cav3.1 and Cav3.2 mutant channels in hippocampal neurons. Knockdown of spectrin alpha and ankyrin B decreased the density of endogenous Cav3.2 in hippocampal neurons. These findings reveal spectrin (alpha/beta) / ankyrin B cytoskeletal and signaling proteins as key regulators of T-type calcium channels expressed in the nervous system. PMID- 29720259 TI - Human serum and platelet lysate are appropriate xeno-free alternatives for clinical-grade production of human MuStem cell batches. AB - BACKGROUND: Canine MuStem cells have demonstrated regenerative efficacy in a dog model of muscular dystrophy, and the recent characterization of human counterparts (hMuStem) has highlighted the therapeutic potential of this muscle derived stem cell population. To date, these cells have only been generated in research-grade conditions. However, evaluation of the clinical efficacy of any such therapy will require the production of hMuStem cells in compliance with good manufacturing practices (GMPs). Because the current use of fetal bovine serum (FBS) to isolate and expand hMuStem cells raises several ethical, safety, and supply concerns, we assessed the use of two alternative xeno-free blood derivatives: human serum (HS) and a human platelet lysate (hPL). METHODS: hMuStem cells were isolated and expanded in vitro in either HS-supplemented or hPL supplemented media and the proliferation rate, clonogenicity, myogenic commitment potential, and oligopotency compared with that observed in FBS-supplemented medium. Flow cytometry and high-throughput 3'-digital gene expression RNA sequencing were used to characterize the phenotype and global gene expression pattern of hMuStem cells cultured with HS or hPL. RESULTS: HS-supplemented and hPL-supplemented media both supported the isolation and long-term proliferation of hMuStem cells. Compared with FBS-based medium, both supplements enhanced clonogenicity and allowed for a reduction in growth factor supplementation. Neither supplement altered the cell lineage pattern of hMuStem cells. In vitro differentiation assays revealed a decrease in myogenic commitment and in the fusion ability of hMuStem cells when cultured with hPL. In return, this reduction of myogenic potential in hPL-supplemented cultures was rapidly reversed by substitution of hPL with HS or fibrinogen-depleted hPL. Moreover, culture of hMuStem cells in hPL hydrogel and fibrinogen-depleted hPL demonstrated that myogenic differentiation potential is maintained in heparin-free hPL derivatives. CONCLUSIONS: Our findings indicate that HS and hPL are efficient and viable alternatives to FBS for the preparation of hMuStem cell batches in compliance with GMPs. PMID- 29720260 TI - Smoking, body mass index, disease activity, and the risk of rapid radiographic progression in patients with early rheumatoid arthritis. AB - BACKGROUND: Identification of risk factors for rapid joint destruction in early rheumatoid arthritis (RA) can be helpful for optimizing treatment, and improving our understanding of destructive arthritis and its mechanisms. The objective of this study was to investigate the relationship between early RA patient characteristics and subsequent rapid radiographic progression (RRP). METHODS: An inception cohort of patients with early RA (symptom duration < 12 months), recruited during 1995-2005 from a defined area (Malmo, Sweden), was investigated. Radiographs of the hands and feet were scored in chronological order according to the modified Sharp-van der Heijde score (SHS), by a trained reader. RRP was defined as an increase of >= 5 points in SHS per year. RESULTS: Two hundred and thirty-three patients were included. Radiographs were available from 216 patients at baseline, 206 patients at 1 year, and 171 patients at 5 years. Thirty-six patients (22%) had RRP up to 5 years. In logistic regression models, rheumatoid factor (RF) and anti-cyclic citrullinated peptides (anti-CCP), and increased erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) at baseline, predicted RRP over 5 years. Patients identified as overweight or obese had a significantly reduced risk of RRP up to 5 years (odds ratio (OR) 0.26; 95% confidence interval (CI) 0.11-0.63; adjusted for RF, baseline erosions, and ESR). Similar point estimates were obtained when stratifying for antibody status, and in models adjusted for smoking. A history of ever smoking was associated with a significantly increased risk of RRP up to 5 years, independent of body mass index (BMI) (OR 3.17; 95% CI 1.22-8.28; adjusted for BMI). At the 1-year follow-up, erosive changes, Disease Activity Score of 28 joints, Health Assessment Questionnaire, swollen joint count, and patient's global assessment of disease activity and pain were also significantly associated with RRP up to 5 years. CONCLUSIONS: A history of smoking, presence of RF and/or anti-CCP and early erosions, high initial disease activity and active disease at 1 year, all increase the risk of RRP. Patients with a high BMI may have a reduced risk of severe joint damage. This pattern was not explained by differences in disease activity or antibody status. The results of this study suggest independent effects of smoking and BMI on the risk of RRP. PMID- 29720261 TI - Efficacy and safety of adding rivaroxaban to the anti-platelet regimen in patients with coronary artery disease: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Rivaroxaban, a direct factor Xa inhibitor, has seldom been used in patients with coronary artery disease. In this analysis, we aimed to systematically compare the efficacy and safety of rivaroxaban in addition to the anti-platelet regimen in patients with coronary artery disease. METHODS: Online databases (MEDLINE, EMBASE, Cochrane database, www.ClinicalTrials.gov and Google scholar were searched for randomized controlled trials which were exclusively based on patients with coronary artery disease; and which compared efficacy (cardiovascular outcomes) and safety (bleeding outcomes) outcomes with the addition of rivaroxaban to the other anti-platelet agents. Analysis was carried out by the RevMan 5.3 software whereby odds ratios (OR) and 95% confidence intervals (CI) were generated following data input. RESULTS: Four trials with a total number of 40,148 patients were included (23,231 participants were treated with rivaroxaban whereas 16,919 participants were treated with placebo) in this analysis. Patients' enrollment period varied from years 2006 to 2016. The current results showed addition of rivaroxaban to significantly lower composite endpoints (OR: 0.81, 95% CI: 0.74-0.88; P = 0.00001). In addition, all-cause death, cardiac death, myocardial infarction, and stent thrombosis were also significantly reduced (OR: 0.82, 95% CI: 0.72-0.92; P = 0.0009), (OR: 0.80, 95% CI: 0.69-0.92; P = 0.002), (OR: 0.87, 95% CI: 0.77-0.98; P = 0.03) and (OR: 0.73, 95% CI: 0.55 0.97; P = 0.03) respectively. However, stroke was not significantly different. However, TIMI defined minor and major bleeding were significantly higher with rivaroxaban (OR: 2.27, 95% CI: 1.47-3.49; P = 0.0002) and (OR: 3.44, 95% CI: 1.13 10.52; P = 0.03) respectively. In addition, intracranial hemorrhage and bleeding which was defined according to the International Society on Thrombosis and Hemostasis criteria were also significantly higher with rivaroxaban (OR: 1.63, 95% CI: 1.04-2.56; P = 0.03) and (OR: 1.80, 95% CI: 1.45-2.22; P = 0.00001) respectively. Nevertheless, fatal bleeding was not significantly different. CONCLUSIONS: Addition of rivaroxaban to the anti-platelet regimen was effective in patients with coronary artery disease, but the safety outcomes were doubtful. Further future trials will be able to completely solve this issue. PMID- 29720262 TI - Upper zone of growth plate and cartilage matrix associated protein protects cartilage during inflammatory arthritis. AB - BACKGROUND: ADAMTS aggrecanases play a major role in cartilage degeneration during degenerative and inflammatory arthritis. The cartilage-specific secreted protein Upper zone of growth plate and cartilage matrix associated protein (Ucma) has been shown to block ADAMTS-triggered aggrecanolysis in experimental osteoarthritis. Here we aimed to investigate whether and how Ucma may affect cartilage destruction and osteophyte formation in the context of inflammatory arthritis. METHODS: Ucma-ADAMTS5 protein interactions were studied using slot blot and solid phase binding assays. Chondrocyte cultures were stimulated with ADAMTS5 or IL-1beta in the presence or absence of Ucma and aggrecanolysis was assessed by neoepitope formation. Arthritis was induced by transfer of K/BxN serum into wild-type (WT), Ucma-deficient and WT mice treated with recombinant Ucma. Cartilage proteoglycan loss and cartilage damage was assessed by safranin-O stain, aggrecanase-induced neoepitope formation and histomorphometry, respectively. Osteophytes were assessed by histomorphometry, micro-computed tomography, RNA in-situ hybridisation for collagen10a1 and osteocalcin, and staining for TRAP activity. Gene expression analyses were performed using real time RT-PCR. RESULTS: Ucma physically interacted with ADAMTS5 and blocked its aggrecanase activity in chondrocyte cultures. Ucma was highly expressed in the articular cartilage and in osteophytes during arthritis. Ucma had no effect on inflammation and bone erosion. In contrast, Ucma-deficient mice developed significantly more severe cartilage proteoglycan loss and cartilage destruction. Conversely, treatment with Ucma inhibited cartilage degeneration in arthritis. Ucma effectively inhibited ADAMTS5-triggered or IL-1beta-triggered aggrecanolysis in vitro and in vivo. Furthermore, osteophyte formation was reduced in Ucma deficient mice. CONCLUSIONS: These results indicate that Ucma inhibits aggrecanolysis by physical interaction with ADAMTS5 and protects from cartilage degeneration in inflammatory arthritis. Ucma therefore represents an interesting novel and specific target for preventing cartilage degradation in the context of inflammatory arthritis. PMID- 29720263 TI - Early passaging of mesenchymal stem cells does not instigate significant modifications in their immunological behavior. AB - BACKGROUND: Bone marrow-derived allogeneic mesenchymal stem cells (MSCs) from young healthy donors are immunoprivileged and their clinical application for regenerative medicine is under evaluation. However, data from preclinical and initial clinical trials indicate that allogeneic MSCs after transplantation provoke a host immune response and are rejected. In the current study, we evaluated the effect of an increase in passage number in cell culture on immunoprivilege of the MSCs. Since only limited numbers of MSCs can be sourced at a time from a donor, it is imperative to expand them in culture to meet the necessary numbers required for cell therapy. Presently, the most commonly used passages for transplantation include passages (P)3-7. Therefore, in this study we included clinically relevant passages, i.e., P3, P5, and P7, for evaluation. METHODS: The immunoprivilege of MSCs was assessed with the mixed leukocyte reaction assay, where rat MSCs were cocultured with peripheral blood leukocytes for 72 h. Leukocyte-mediated cytotoxicity, apoptosis (Bax/Bcl-xl ratio), leukocyte proliferation, and alterations in cellular bioenergetics in MSCs were assessed after the coculture. Furthermore, the expression of various oxidized phospholipids (oxidized phosphatidylcholine (ox-PC)) was analyzed in MSCs using a lipidomic platform. To determine if the ox-PCs were acting in tandem with downstream intracellular protein alterations, we performed proteome analysis using a liquid chromatography/mass spectrometry (LC/MS) proteomic platform. RESULTS: Our data demonstrate that MSCs were immunoprivileged at all three passages since coculture with leukocytes did not affect the survival of MSCs at P3, P5, and P7. We also found that, with an increase in the passage number of MSCs, leukocytes did not cause any significant effect on cellular bioenergetics (basal respiration rate, spare respiratory capacity, maximal respiration, and coupling efficiency). Interestingly, in our omics data, we detected alterations in some of the ox-PCs and proteins in MSCs at different passages; however, these changes were not significant enough to affect their immunoprivilege. CONCLUSIONS: The outcome of this study demonstrates that an increase in passage number (from P3 to P7) in the cell culture does not have any significant effect on the immunoprivilege of MSCs. PMID- 29720264 TI - Usefulness of fluorodeoxyglucose positron emission tomography/computed tomography for detection of a neuroblastic nodule in a ganglioneuroblastoma: a case report. AB - BACKGROUND: Ganglioneuroblastoma, nodular is defined as a composite tumor of biologically distinct clones. The peripheral neuroblastic tumors in this category are characterized by the presence of grossly visible neuroblastoma nodules coexisting with ganglioneuroblastoma, intermixed, or with ganglioneuroma. Making a correct diagnosis of ganglioneuroblastoma, nodular is often difficult by biopsy or partial tumor resection, because the neuroblastic nodule could be hidden and not sampled for pathological examination. CASE PRESENTATION: We report a case of a Japanese boy aged 3 years, 8 months, with an unresectable abdominal tumor and elevated vanillylmandelic acid and homovanillic acid levels. The initial biopsy was ganglioneuroma. However, after the second biopsy from a hidden neuroblastoma nodule that was clearly highlighted by fluorodeoxyglucose positron emission tomography/computed tomography, we reached the diagnosis of ganglioneuroblastoma, nodular. Because the nodule demonstrated neuroblastoma, differentiating subtype, with a low mitosis-karyorrhexis index (favorable histology) and nonamplified MYCN, the boy was treated according to the intermediate-risk protocol and is now alive and well 4 years after the diagnosis. CONCLUSIONS: This case illustrates the critical role of fluorodeoxyglucose positron emission tomography/computed tomography for detecting a neuroblastoma nodule in a ganglioneuroblastoma. PMID- 29720265 TI - The influence of environmental conditions on safety management in hospitals: a qualitative study. AB - BACKGROUND: Hospitals are confronted with increasing safety demands from a diverse set of stakeholders, including governmental organisations, professional associations, health insurance companies, patient associations and the media. However, little is known about the effects of these institutional and competitive pressures on hospital safety management. Previous research has shown that organisations generally shape their safety management approach along the lines of control- or commitment-based management. Using a heuristic framework, based on the contextually-based human resource theory, we analysed how environmental pressures affect the safety management approach used by hospitals. METHODS: A qualitative study was conducted into hospital care in the Netherlands. Five hospitals were selected for participation, based on organisational characteristics as well as variation in their reputation for patient safety. We interviewed hospital managers and staff with a central role in safety management. A total of 43 semi-structured interviews were conducted with 48 respondents. The heuristic framework was used as an initial model for analysing the data, though new codes emerged from the data as well. RESULTS: In order to ensure safe care delivery, institutional and competitive stakeholders often impose detailed safety requirements, strong forces for compliance and growing demands for accountability. As a consequence, hospitals experience a decrease in the room to manoeuvre. Hence, organisations increasingly choose a control-based management approach to make sure that safety demands are met. In contrast, in case of more abstract safety demands and an organisational culture which favours patient safety, hospitals generally experience more leeway. This often results in a stronger focus on commitment-based management. CONCLUSIONS: Institutional and competitive conditions as well as strategic choices that hospitals make have resulted in various combinations of control- and commitment-based safety management. A balanced approach is required. A strong focus on control-based management generates extrinsic motivation in employees but may, at the same time, undermine or even diminish intrinsic motivation to work on patient safety. Emphasising commitment-based management may, in contrast, strengthen intrinsic motivation but increases the risk of priorities being set elsewhere. Currently, external pressures frequently lead to the adoption of control-based management. A balanced approach requires a shift towards more trust-based safety demands. PMID- 29720266 TI - alpha6-Integrin alternative splicing: distinct cytoplasmic variants in stem cell fate specification and niche interaction. AB - alpha6-Integrin subunit (also known as CD49f) is a stemness signature that has been found on the plasma membrane of more than 30 stem cell populations. A growing body of studies have focused on the critical role of alpha6-containing integrins (alpha6beta1 and alpha6beta4) in the regulation of stem cell properties, lineage-specific differentiation, and niche interaction. alpha6 Integrin subunit can be alternatively spliced at the post-transcriptional level, giving rise to divergent isoforms which differ in the cytoplasmic and/or extracellular domains. The cytoplasmic domain of integrins is an important functional part of integrin-mediated signals. Structural changes in the cytoplasmic domain of alpha6 provide an efficient means for the regulation of stem cell responses to biochemical stimuli and/or biophysical cues in the stem cell niche, thus impacting stem cell fate determination. In this review, we summarize the current knowledge on the structural variants of the alpha6-integrin subunit and spatiotemporal expression of alpha6 cytoplasmic variants in embryonic and adult stem/progenitor cells. We highlight the roles of alpha6 cytoplasmic variants in stem cell fate decision and niche interaction, and discuss the potential mechanisms involved. Understanding of the distinct functions of alpha6 splicing variants in stem cell biology may inform the rational design of novel stem cell-based therapies for a range of human diseases. PMID- 29720267 TI - Efficacy of postoperative pain management in head and neck cancer patients. AB - BACKGROUND: Our study quantifies the effectiveness of perioperative pain control in a cohort of patients undergoing major head and neck surgery with free flap reconstruction. Our long-term goal is to improve pain control and thereby increase mobility, decrease postoperative complications and decrease hospital stay. METHODS: A retrospective analysis was performed at a tertiary, academic head and neck surgical oncology program in Calgary, Alberta, Canada from January 1, 2015 - December 31, 2015. Pain scores were recorded prospectively. Primary outcomes were frequency of postoperative pain assessments and pain intensity using the numeric rating scale. RESULTS: The cohort included 41 patients. Analysis was limited to pain scores recorded from postoperative days 1-14. There was an average of 7.3 pain measurements per day (SD 4.6, range 1-24) with the most frequent monitoring on postoperative days 1-4. Median pain scores ranged from 0 to 4.5 with the highest median score on postoperative day 6. The daily maximum pain scores recorded ranged from 8 to 10 with scores of 10 recorded on postoperative days 1, 2, 3, 5, 7, 8, and 10. Patients most frequently had inadequate pain control on postoperative days 1, 2, 4, and 5 with the majority occurring on postoperative day 1. CONCLUSIONS: Postoperative pain control could be improved at our centre. The frequency of pain assessments is also highly variable. Ongoing measurement, audit, and feedback of analgesic protocol effectiveness is an excellent first step in improving perioperative pain management in patients undergoing major head and neck cancer surgery with free flap reconstruction. PMID- 29720268 TI - Specific markers and properties of synovial mesenchymal stem cells in the surface, stromal, and perivascular regions. AB - BACKGROUND: Synovial mesenchymal stem cells (MSCs) are an attractive cell source for cartilage and meniscus regeneration. Synovial tissue can be histologically classified into three regions; surface, stromal and perivascular region, but the localization of synovial MSCs has not been fully investigated. We identified markers specific for each region, and compared properties of MSCs derived from each region in the synovium. METHODS: The intensity of immunostaining with 19 antibodies was examined for surface, stromal, and perivascular regions of human synovium from six osteoarthritis patients. Specific markers were identified and synovial cells derived from each region were sorted. Proliferation, surface marker expression, chondrogenesis, calcification and adipogenesis potentials were compared in synovial MSCs derived from the three regions. RESULTS: We selected CD55+ CD271- for synovial cells in the surface region, CD55- CD271- in the stromal region, and CD55- CD271+ in the perivascular region. The ratio of the sorted cells to non-hematopoietic lineage cells was 5% in the surface region, 70% in the stromal region and 15% in the perivascular region. Synovial cells in the perivascular fraction had the greatest proliferation potential. After expansion, surface marker expression profiles and adipogenesis potentials were similar but chondrogenic and calcification potentials were higher in synovial MSCs derived from the perivascular region than in those derived from the surface and stromal regions. CONCLUSIONS: We identified specific markers to isolate synovial cells from the surface, stromal, and perivascular regions of the synovium. Synovial MSCs in the perivascular region had the highest proliferative and chondrogenic potentials among the three regions. PMID- 29720269 TI - Acidic preconditioning of endothelial colony-forming cells (ECFC) promote vasculogenesis under proinflammatory and high glucose conditions in vitro and in vivo. AB - BACKGROUND: We have previously demonstrated that acidic preconditioning of human endothelial colony-forming cells (ECFC) increased proliferation, migration, and tubulogenesis in vitro, and increased their regenerative potential in a murine model of hind limb ischemia without baseline disease. We now analyze whether this strategy is also effective under adverse conditions for vasculogenesis, such as the presence of ischemia-related toxic molecules or diabetes, one of the main target diseases for cell therapy due to their well-known healing impairments. METHODS: Cord blood-derived CD34+ cells were seeded in endothelial growth culture medium (EGM2) and ECFC colonies were obtained after 14-21 days. ECFC were exposed at pH 6.6 (preconditioned) or pH 7.4 (nonpreconditioned) for 6 h, and then pH was restored at 7.4. A model of type 2 diabetes induced by a high-fat and high sucrose diet was developed in nude mice and hind limb ischemia was induced in these animals by femoral artery ligation. A P value < 0.05 was considered statistically significant (by one-way analysis of variance). RESULTS: We found that acidic preconditioning increased ECFC adhesion and the release of pro angiogenic molecules, and protected ECFC from the cytotoxic effects of monosodium urate crystals, histones, and tumor necrosis factor (TNF)alpha, which induced necrosis, pyroptosis, and apoptosis, respectively. Noncytotoxic concentrations of high glucose, TNFalpha, or their combination reduced ECFC proliferation, stromal cell-derived factor (SDF)1-driven migration, and tubule formation on a basement membrane matrix, whereas almost no inhibition was observed in preconditioned ECFC. In type 2 diabetic mice, intravenous administration of preconditioned ECFC significantly induced blood flow recovery at the ischemic limb as measured by Doppler, compared with the phosphate-buffered saline (PBS) and nonpreconditioned ECFC groups. Moreover, the histologic analysis of gastrocnemius muscles showed an increased vascular density and reduced signs of inflammation in the animals receiving preconditioned ECFC. CONCLUSIONS: Acidic preconditioning improved ECFC survival and angiogenic activity in the presence of proinflammatory and damage signals present in the ischemic milieu, even under high glucose conditions, and increased their therapeutic potential for postischemia tissue regeneration in a murine model of type 2 diabetes. Collectively, our data suggest that acidic preconditioning of ECFC is a simple and inexpensive strategy to improve the effectiveness of cell transplantation in diabetes, where tissue repair is highly compromised. PMID- 29720270 TI - Quality of observational studies in prestigious journals of occupational medicine and health based on Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) Statement: a cross-sectional study. AB - OBJECTIVE: The present study applied the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement to observational studies published in prestigious occupational medicine and health journals. RESULTS: A total of 60 articles was evaluated. All sub-items were reported in 63.74% (95% confidence interval [CI], 56.24-71.24%), not reported in 29.70% (95% CI, 20.2 39.2%), and not applicable in 6.56% (95% CI, 4.86-8.26%) of the studies. Of the 45 sub-items investigated in this survey, eight were reported 100% of the time, 13 were addressed in more than 90% of the articles, 22 were included in more than 75% of the studies, and 27 sub-items were applied in more than 50% of the articles published in the journals included in this study. PMID- 29720271 TI - Mind the gut: genomic insights to population divergence and gut microbial composition of two marine keystone species. AB - BACKGROUND: Deciphering the mechanisms governing population genetic divergence and local adaptation across heterogeneous environments is a central theme in marine ecology and conservation. While population divergence and ecological adaptive potential are classically viewed at the genetic level, it has recently been argued that their microbiomes may also contribute to population genetic divergence. We explored whether this might be plausible along the well-described environmental gradient of the Baltic Sea in two species of sand lance (Ammodytes tobianus and Hyperoplus lanceolatus). Specifically, we assessed both their population genetic and gut microbial composition variation and investigated not only which environmental parameters correlate with the observed variation, but whether host genome also correlates with microbiome variation. RESULTS: We found a clear genetic structure separating the high-salinity North Sea from the low salinity Baltic Sea sand lances. The observed genetic divergence was not simply a function of isolation by distance, but correlated with environmental parameters, such as salinity, sea surface temperature, and, in the case of A. tobianus, possibly water microbiota. Furthermore, we detected two distinct genetic groups in Baltic A. tobianus that might represent sympatric spawning types. Investigation of possible drivers of gut microbiome composition variation revealed that host species identity was significantly correlated with the microbial community composition of the gut. A potential influence of host genetic factors on gut microbiome composition was further confirmed by the results of a constrained analysis of principal coordinates. The host genetic component was among the parameters that best explain observed variation in gut microbiome composition. CONCLUSIONS: Our findings have relevance for the population structure of two commercial species but also provide insights into potentially relevant genomic and microbial factors with regards to sand lance adaptation across the North Sea-Baltic Sea environmental gradient. Furthermore, our findings support the hypothesis that host genetics may play a role in regulating the gut microbiome at both the interspecific and intraspecific levels. As sequencing costs continue to drop, we anticipate that future studies that include full genome and microbiome sequencing will be able to explore the full relationship and its potential adaptive implications for these species. PMID- 29720272 TI - A chicken liver cell line efficiently supports the replication of ALV-J possibly through its high level viral receptor and efficient protein expression system. AB - In this study, we identified a chicken liver cell line (LMH) which could strongly support the replication of ALV-J (Subgroup J of avian leukosis virus) with high viral titer. Notably, ALV-J was efficiently detected by ELISA in LMH cells 1 day before DF1 cells. In comparison with DF1 cells, LMH cells not only expressed higher levels of ALV-J receptor chNHE-1, but also possessed a more efficient protein expression system for foreign genes. Thus, LMH cells could be a novel tool to shorten the ALV-J eradication approach and accelerate studies on the pathogenesis and oncogenesis of ALV-J. PMID- 29720273 TI - When insulin degludec enhances quality of life in patients with type 2 diabetes: a qualitative investigation. AB - BACKGROUND: Anecdotal reports suggest that insulin degludec (IDeg) may offer unique health-related quality of life (HRQoL) benefits. As the nature of these benefits remain unclear, this study utilized qualitative research methods to investigate and elucidate the experience of "feeling better" after initiating IDeg. METHODS: Twenty adults with type 2 diabetes (T2D) who reported "feeling better" on IDeg for > 3 months participated in 90-min interviews. One focus group and nine telephone interviews were conducted at two sites in the United States (US) and one focus group was conducted in Switzerland. Patients were >= 18 years of age, did not take mealtime insulin, and had switched to IDeg from another basal insulin. Discussions were audio-recorded, transcribed and translated (Swiss German). Utilizing grounded theory, transcripts were analyzed by sorting quotes into concepts using thematic analysis. RESULTS: Participants' mean age was 66 years and the average duration of T2D was 17.6 years. Mean duration of IDeg use was 1.45 years. Four major factors were identified as key contributors to patients' sense of "feeling better": 1) reduced sense of diabetes as burdensome and requiring excessive attention; 2) enhanced feelings of adaptability and freedom; 3) heightened sense of security, especially regarding concerns about hypoglycemia; and 4) greater sense of physical well-being (greater energy/less fatigue). Content saturation was achieved. Generally, patients from the US sites were more focused on medical results than Swiss patients, who were more likely to identify IDeg's effect on overall HRQoL. A limitation of the study was that the population was primarily white, > 60 and otherwise healthy (no comorbid physical or mental condition). CONCLUSIONS: A group of patients with T2D, who had switched to IDeg from another basal insulin, reported HRQoL benefits which were attributed to both diabetes-specific improvements (feeling less burdened by day-to-day diabetes demands) and non-specific gains (greater energy). The conclusions may have limited transferability due to the characteristics of the sample population and further research is needed. PMID- 29720274 TI - Aerobic bacteria associated with chronic suppurative otitis media in Angola. AB - BACKGROUND: Chronic suppurative otitis media (CSOM) is an important cause of hearing loss in children and constitutes a serious health problem globally with a strong association to resource-limited living conditions. Topical antibiotics combined with aural toilet is the first-hand treatment for CSOM but antimicrobial resistance and limited availability to antibiotics are obstacles in some areas. The goal of this study was to define aerobic pathogens associated with CSOM in Angola with the overall aim to provide a background for local treatment recommendations. METHODS: Samples from ear discharge and the nasopharynx were collected and cultured from 152 patients with ear discharge and perforation of the tympanic membrane. Identification of bacterial species was performed with matrix-assisted laser desorption/ionization-time of flight mass spectrometry and pneumococci were serotyped using multiplex polymerase chain reactions. Antimicrobial susceptibility testing was done according to EUCAST. RESULTS: One hundred eighty-four samples from ear discharge and 151 nasopharyngeal swabs were collected and yielded 534 and 289 individual isolates, respectively. In all patients, correspondence rate of isolates from 2 ears in patients with bilateral disease was 27.3% and 9.3% comparing isolates from the nasopharynx and ear discharge, respectively. Proteus spp. (14.7%), Pseudomonas aeruginosa (13.2%) and Enterococcus spp. (8.8%) were dominating pathogens isolated from ear discharge. A large part of the remaining species belonged to Enterobacteriaceae (23.5%). Pneumococci and Staphylococcus aureus were detected in approximately 10% of nasopharyngeal samples. Resistance rates to quinolones exceeded 10% among Enterobacteriaceae and was 30.8% in S. aureus, whereas 6.3% of P. aeruginosa were resistant. CONCLUSIONS: The infection of the middle ear in CSOM is highly polymicrobial, and isolates found in nasopharynx do not correspond well with those found in ear discharge. Pathogens associated with CSOM in Angola are dominated by gram-negatives including Enterobacteriaceae and P. aeruginosa, while gram-positive enterococci also are common. Based on the results of antimicrobial susceptibility testing topical quinolones would be the preferred antibiotic therapy of CSOM in Angola. Topical antiseptics such as aluminium acetate, acetic acid or boric acid, however, may be more feasible options due to a possibly emerging antimicrobial resistance. PMID- 29720275 TI - Different effects of granulocyte colony-stimulating factor and erythropoietin on erythropoiesis. AB - BACKGROUND: Red blood cells are the most abundant cells in the blood that deliver oxygen to the whole body. Erythropoietin (EPO), a positive regulator of erythropoiesis, is currently the major treatment for chronic anemia. Granulocyte colony-stimulating factor (G-CSF) is a multifunctional cytokine and a well-known regulator of hematopoietic stem cell proliferation, differentiation, and mobilization. The use of EPO in combination with G-CSF has been reported to synergistically improve erythroid responses in a group of patients with myelodysplastic syndromes who did not respond to EPO treatment alone; however, the mechanism remains unclear. METHODS: C57BL/6 J mice injected with G-CSF or EPO were used to compare the erythropoiesis status and the efficiency of erythroid mobilization by flow cytometry. RESULTS: In this study, we found that G-CSF induced more orthochromatophilic erythroblast production than did EPO in the bone marrow and spleen. In addition, in contrast to EPO treatments, G-CSF treatments enhanced the efficiency of the mobilization of newly synthesized reticulocytes into peripheral blood. Our results demonstrated that the effects of G-CSF on erythropoiesis and erythrocytic mobilization were independent of EPO secretion and, in contrast to EPO, G-CSF promoted progression of erythropoiesis through transition of early stage R2 (basophilic erythroblasts) to late stage R4 (orthochromatophilic erythroblasts). CONCLUSIONS: We demonstrate for the first time that G-CSF treatments induce a faster erythropoiesis-enhancing response than that of EPO. These findings suggest an alternative approach to treating acute anemia, especially when patients are experiencing a clinical emergency in remote areas without proper blood bank supplies. PMID- 29720276 TI - Ethics challenges and guidance related to research involving adolescent post abortion care: a scoping review. AB - INTRODUCTION: An increase in post abortion care (PAC) research with adolescents, particularly in low- and middle-income countries, has brought to attention several associated research ethics challenges. In order to better understand the ethics context of PAC research with adolescents, we conducted a scoping review of published literature. METHODS: Following a systematic search of PubMed, HINARI, and Google Scholar, we analysed articles meeting inclusion criteria to determine common themes across both the ethical challenges related to PAC research with adolescents and any available guidance on the identified challenges. RESULTS: The literature search identified an initial 3321 records of which 14 were included in analysis following screening. Several ethical challenges stem from abortion being a controversial, sensitive, and stigmatized topic in many settings. Ethical dilemmas experienced by researchers conducting adolescent PAC research included: difficulties in convincing local health providers to permit PAC research; challenges in recruiting and seeking consent due to sensitivity of the subject; effectively protecting confidentiality; managing negative effects of interventions; creating a non-prejudicial atmosphere for research; managing emotional issues among adolescents; and dealing with uncertainty regarding the role of researchers when observing unethical health care practices. Suggested strategies for addressing some of these challenges include: using several sources to recruit study participants, using research to facilitate dialogue on abortion, briefing health workers on any observed unethical practices after data collection, fostering a comprehensive understanding of contextual norms and values, selecting staff with experience working with study populations, and avoiding collection of personal identifiers. CONCLUSION: Addressing ethical challenges that researchers face when conducting PAC research with adolescents requires guidance at the individual, institutional, community, and international levels. Overall, despite the documentation of challenges in the published literature, guidance on handling several of these ethics challenges is sparse. We encourage further research to clarify the identified challenges and support the development of formal guidance in this area. PMID- 29720277 TI - Best PEEP trials are dependent on tidal volume. AB - : Determining the optimal positive end-expiratory pressure (PEEP) in patients with acute respiratory distress syndrome remains an area of active investigation. Most trials individualizing PEEP optimize one physiologic parameter (e.g., driving pressure) by titrating PEEP while holding other ventilator settings constant. Optimal PEEP, however, may depend on the tidal volume, and changing the tidal volume with which a best PEEP trial is performed may lead to different best PEEP settings in the same patient. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02871102. Registered on 12 August 2016. PMID- 29720278 TI - Untangling the complex relationships between incident gout risk, serum urate, and its comorbidities. AB - BACKGROUND: Many gout comorbidities (e.g., hypertension) are correlated with serum urate. In this investigation, we identified risk factors (e.g., systolic blood pressure [SBP]), that (1) are associated with incident gout, (2) have effects on gout risk that cannot be fully explained by correlated differences in serum urate, and (3) may modulate the relationship between gout and serum urate. METHODS: Using data from the Atherosclerosis Risk in Communities (ARIC) study, we estimated the unadjusted associations between gout and risk factors by calculating ORs and using chi-square tests. The adjusted associations were analyzed using logistic regression by sequentially adding (1) one risk factor at a time or (2) all risk factors, to a baseline model that includes serum urate only. Stepwise selection was used to select main effects. Two-way interactions of variables from the main effects model were also analyzed. RESULTS: Average gout incidence was 2.7 per 1000 people per year. Serum urate was highly associated with incident gout, with odd ratios of 3.16 [95% CI 2.11, 4.76] and 25.9 [95% CI 17.2, 38.4] for moderately high (6-8 mg/dl) and high serum urate (> 8 mg/dl), relative to normal serum urate (< 6 mg/dl), respectively. Ethnicity and SBP were independently and additively associated with gout after accounting for serum urate levels. No significant interactions were found between serum urate and ethnicity or SBP. CONCLUSIONS: Ethnicity and hypertension are predictive of gout risk, and the associations cannot be fully explained by serum urate. For serum urate levels near the crystallization threshold (6-8 mg/dl) African Americans and people with hypertension are at two to three times greater risk for developing gout. The gout risk for this group appears to increase before the onset of severe hyperuricemia. PMID- 29720279 TI - Analysis of rural health centres preparedness for the management of diabetic patients in Malawi. AB - OBJECTIVE: There is limited data on the quality of primary care management for diabetes mellitus across Africa. The study was aimed at assessing the availability of basic supplies for the rapid diagnosis, treatment and management of diabetes in Malawian rural health facilities. This cross-sectional study was conducted in 55 public and private health centers from 19 districts using a structured questionnaire and checklist to interview the pharmacy personnel or officer in-charge of the health centers. We focused on availability of information, diagnosis and treatment materials for diabetes. RESULTS: Of the 55 health facilities surveyed, 21, 23 and 11 were located in the central, southern and northern regions of Malawi, respectively. Overall, 38% (21/55) of the health centres had glucometers, while 24% (13/55) had urine glucose dipsticks. Only 4% (2/55) of the health centres had recommended first-line medicines for treatment of type 1 and type 2 diabetes. No health centre had diabetes patient records and information, education and communication materials. Most rural health centers in Malawi lack basic health commodities for the screening, diagnosis and treatment of diabetes and this impedes on their effective management of growing diabetes burden. Therefore, health care systems need to adequately equip primary care facilities. PMID- 29720280 TI - Exposures associated with infection with Cryptosporidium in industrialised countries: a systematic review protocol. AB - BACKGROUND: Cryptosporidium is a protozoan parasite of humans and other animals worldwide and is one of the greatest contributors to human diarrhoeal illness. Transmission can occur indirectly via contaminated food or water, or directly via contact with animals or other infected people. Risk exposures are often identified from outbreak investigations, but a subset of cases remains unexplained, and sources for sporadic disease and pathways to infection are still unclear. Given the few systematic syntheses of reported evidence in industrialised populations, the aim of this review is to consolidate the literature to describe exposures associated with human cryptosporidiosis in industrialised countries, specifically including the UK, and describe any differences between outbreak-associated and sporadic disease. METHODS/DESIGN: Where relevant, methods will follow the recommendations made in the Cochrane Handbook for Systematic Reviews of Interventions. Three steps will be used to identify the literature including electronic database searching using PubMed, Scopus, Embase and Web of Science; reference list trawling; and an exploration of the grey literature. Screening of results will be undertaken by two reviewers using pre-defined criteria. Studies conducted in industrialised countries and reporting on human subjects will be included. All observational studies will be included where they report exposures and relevant quantitative results. Data will be extracted using a standardised form. Study quality will be assessed using the ROBINS-I tool. Data will be summarised presenting the papers' main findings including population under study, outcomes, and exposures, and whether these were considered outbreak or sporadic cases. A narrative summary will also be included. Where populations are appropriate, available data will be pooled in a meta analysis combining the significant exposures across studies. DISCUSSION: This review aims to consolidate the evidence for transmission routes and exposures for Cryptosporidium in industrialised countries, with particular reference to how these may apply to the UK. In addition, the review will seek to describe differences between outbreak and sporadic cases. This will help to identify those most vulnerable, highlighting pathways where interventions and public health response may be appropriate. SYSTEMATIC REVIEW REGISTRATION: PROSPERO number CRD42017056589 . PMID- 29720281 TI - Latent class analysis of the multivariate Delirium Index in long-term care settings. AB - : ABSTRACTBackground:A few studies examine the time evolution of delirium in long term care (LTC) settings. In this work, we analyze the multivariate Delirium Index (DI) time evolution in LTC settings. METHODS: The multivariate DI was measured weekly for six months in seven LTC facilities, located in Montreal and Quebec City. Data were analyzed using a hidden Markov chain/latent class model (HMC/LC). RESULTS: The analysis sample included 276 LTC residents. Four ordered latent classes were identified: fairly healthy (low "disorientation" and "memory impairment," negligible other DI symptoms), moderately ill (low "inattention" and "disorientation," medium "memory impairment"), clearly sick (low "disorganized thinking" and "altered level of consciousness," medium "inattention," "disorientation," "memory impairment" and "hypoactivity"), and very sick (low "hypoactivity," medium "altered level of consciousness," high "inattention," "disorganized thinking," "disorientation" and "memory impairment"). Four course types were also identified: stable, improvement, worsening, and non-monotone. Class order was associated with increasing cognitive impairment, frequency of both prevalent/incident delirium and dementia, mortality rate, and decreasing performance in ADL. CONCLUSION: Four ordered latent classes and four course types were found in LTC residents. These results are similar to those reported previously in acute care (AC); however, the proportion of very sick residents at enrolment was larger in LTC residents than in AC patients. In clinical settings, these findings could help identify participants with a chronic clinical disorder. Our HMC/LC approach may help understand coexistent disorders, e.g. delirium and dementia. PMID- 29720282 TI - Cerebrospinal Fluid Biomarkers and Normal Pressure Hydrocephalus: A Perfect Duo? PMID- 29720283 TI - Submandibular gland invasion and feasibility of gland-sparing neck dissection in oral cavity carcinoma. AB - OBJECTIVE: This study investigated the incidence and routes of submandibular gland involvement in oral cavity carcinoma to determine the feasibility of submandibular gland sparing neck dissection. METHODS: The records of 155 patients diagnosed with oral cavity squamous cell carcinoma, with a total of 183 neck specimens, including those involving level I, were reviewed retrospectively. RESULTS: Submandibular gland involvement, via direct invasion from the anatomical proximity of T4a tumours, was evident in two patients. The floor of mouth location, either primarily or as an extension of the primary tumour, was the only risk factor for submandibular gland involvement in oral cavity carcinoma (p = 0.042). Tumour location, clinical and pathological tumour (T) and nodal (N) stages, and radiological suspicion of mandible invasion, were not found to be statistically relevant (p > 0.05). CONCLUSION: The results suggest the feasibility of preserving the submandibular gland in early stage oral cavity carcinoma unless the tumour is located in, or extends to, the floor of mouth. PMID- 29720284 TI - Update on: a meta-analysis of sperm donation offspring health outcomes - 2018 update. PMID- 29720286 TI - Impact of brief education on healthy seniors' attitudes and healthcare choices about Alzheimer's disease and associated symptoms. AB - : ABSTRACTObjective:The primary objective of this study was to determine whether a brief education session about Alzheimer's disease (AD) stages and associated behavioral and psychological symptoms of dementia (BPSD) changes healthy seniors' treatment choices. A secondary objective was to determine whether pharmacotherapy to reduce BPSD would be preferred over other potentially more restrictive interventions. METHODS: Participants (n = 32; 8 men; aged > 64years; no self reported dementia diagnosis) were assigned to one of ten group sessions during which they received information about AD and BPSD. Our a-priori hypotheses were: (1) education about AD stages significantly changes care preferences in moderate and severe stages, i.e. less active treatment options (no CPR/hospitalization) are chosen as the disease progresses; and (2) most participants prefer pharmacotherapy over restraints and seclusion to manage BPSD. The main outcome measure was a change in the interventions chosen including CPR and hospitalization. Participants completed three questionnaires and two decisional grids before and after the information session. Qualitative data were derived from discussions during the session. RESULTS: Participants expressed a wide range of attitudes about AD, BPSD, and their management. Those who are born in Canada, had a proxy, and a university education, each have around half of the odds of receiving treatment compared to those in the complementary group. (OR 0.47, 0.40, 0.43) Finally, not knowing someone with AD increases the odds of wanting a treatment by around six times (OR 6.4). Pharmacological measures were preferred over restraints. CONCLUSIONS: Education about dementia and advance directives should consider the person's educational background and experience with dementia. Discussing BPSD may impact a person's advance directives and preferences. PMID- 29720285 TI - Individual and contextual risk factors for chikungunya virus infection: the SEROCHIK cross-sectional population-based study. AB - The purpose of the study was to weigh the community burden of chikungunya determinants on Reunion island. Risk factors were investigated within a subset of 2101 adult persons from a population-based cross-sectional serosurvey, using Poisson regression models for dichotomous outcomes. Design-based risk ratios and population attributable fractions (PAF) were generated distinguishing individual and contextual (i.e. that affect individuals collectively) determinants. The disease burden attributable to contextual determinants was twice that of individual determinants (overall PAF value 89.5% vs. 44.1%). In a model regrouping both categories of determinants, the independent risk factors were by decreasing PAF values: an interaction term between the reporting of a chikungunya history in the neighbourhood and individual house (PAF 45.9%), a maximal temperature of the month preceding the infection higher than 28.5 degrees C (PAF 25.7%), a socio-economically disadvantaged neighbourhood (PAF 19.0%), altitude of dwelling (PAF 13.1%), cumulated rainfalls of the month preceding the infection higher than 65 mm (PAF 12.6%), occupational inactivity (PAF 11.6%), poor knowledge on chikungunya transmission (PAF 7.3%) and obesity/overweight (PAF 5.2%). Taken together, these covariates and their underlying causative factors uncovered 80.8% of chikungunya at population level. Our findings lend support to a major role of contextual risk factors in chikungunya virus outbreaks. PMID- 29720287 TI - Review: Are we using probiotics correctly in post-weaning piglets? AB - Intensive farming may involve the use of diets, environments or management practices that impose physiological and psychological stressors on the animals. In particular, early weaning is nowadays a common practice to increase the productive yield of pig farms. Still, it is considered one of the most critical periods in swine production, where piglet performance can be seriously affected and where they are predisposed to the overgrowth of opportunistic pathogens. Pig producers nowadays face the challenge to overcome this situation in a context of increasing restrictions on the use of antibiotics in animal production. Great efforts are being made to find strategies to help piglets overcome the challenges of early weaning. Among them, a nutritional strategy that has received increasing attention in the last few years is the use of probiotics. It has been extensively documented that probiotics can reduce digestive disorders and improve productive parameters. Still, research in probiotics so far has also been characterized as being inconsistent and with low reproducibility from farm to farm. Scientific literature related to probiotic effects against gastrointestinal pathogens will be critically examined in this review. Moreover, the actual practical approach when using probiotics in these animals, and potential strategies to increase consistency in probiotic effects, will be discussed. Thus, considering the boost in probiotic research observed in recent years, this paper aims to provide a much needed, in-depth review of the scientific data published to-date. Furthermore, it aims to be useful to swine nutritionists, researchers and the additive industry to critically consider their approach when developing or using probiotic strategies in weaning piglets. PMID- 29720288 TI - Prenatal malnutrition and adult cognitive impairment: a natural experiment from the 1959-1961 Chinese famine. AB - The current measures of cognitive functioning in adulthood do not indicate a long term association with prenatal exposure to the Dutch famine. However, whether such association emerges in China is poorly understood. We aimed to investigate the potential effect of prenatal exposure to the 1959-1961 Chinese famine on adult cognitive impairment. We obtained data from the Second National Sample Survey on Disability implemented in thirty-one provinces in 2006, and restricted our analysis to 387 093 individuals born in 1956-1965. Cognitive impairment was defined as intelligence quotient (IQ) score under 70 and IQ of adults was evaluated by the Wechsler Adult Intelligence Scale - China Revision. Famine severity was defined as excess death rate. The famine impact on adult cognitive impairment was estimated by difference-in-difference models, established by examining the variations of famine exposure across birth cohorts. Results show that compared with adults born in 1956-1958, those who were exposed to Chinese famine during gestation (born in 1959-1961) were at greater risk of cognitive impairment in the total sample. Stratified analyses showed that this effect was evident in males and females, but only in rural, not in urban areas. In conclusion, prenatal exposure to famine had an enduring deleterious effect on risk of cognitive impairment in rural adults. PMID- 29720289 TI - Consistency is key: interactions of current and previous farrowing system on litter size and piglet mortality. AB - Global interest in alternative indoor farrowing systems is increasing, leading to a growing number of farms utilising such systems alongside standard crates. There is evidence that interchanging sows between different farrowing systems affects maternal behaviour, whilst the subsequent effect of this on piglet mortality is unknown. The current study hypothesised that second parity piglet mortality would be higher if a sow farrowed in a different farrowing system to that of her first parity. Retrospective farm performance records were used from 753 sows during their first and second parities. Sows farrowed in either standard crates (crates), temporary crates (360s) or straw-bedded pens (pens), with mortality recorded as occurring either pre- or post-processing. Inter- and intra-parity sow consistency in performance were also investigated. Overall, total piglet mortality reduced from the first to the second parity, being significantly higher in the crates and higher in the 360s during the first or second parity, respectively. In the second parity, an interaction of the current and previous farrowing systems resulted in the lowest incidence of crushing for sows housed in the same system as their first parity for the crates and pens, but not the 360s. Post-processing mortality was significantly higher in the crates if a sow previously farrowed in the 360s and vice versa. Sows which previously farrowed in a pen had a significantly larger litter size and lower pre-processing mortality from crushing in their second parity than sows previously housed in the crates or the 360s. No inter-parity consistency of sow performance was found, whilst intra parity consistency was found in the first but not second parity. In conclusion, returning sows to the same farrowing system appears to reduce piglet mortality, whilst farrowing in a pen during the first parity significantly increased second parity litter size without increasing piglet mortality. PMID- 29720290 TI - Effectiveness of a home-based missing incident prevention program for community dwelling elderly patients with dementia. AB - : ABSTRACTBackground:Getting lost is a recognized complication in patients with dementia. Preventive measures are lacking. This study aims to investigate the effectiveness of a home-based missing incident prevention program (HMIPP) in reducing missing incidents, time of searching, and caregivers' stress. METHODS: The design was a pre- and post-intervention study. Patients were recruited from a hospital-based Geriatric Memory Clinic. Inclusion criteria were as follows: aged 60 years or above, established dementia, and Modified Functional Ambulation Categories score VI or VII. An occupational therapist performed the interventions at the patients's home. These included dementia education, prescription of assistive devices, on-site skills training, environmental modifications, community service referrals, and redesigning of daily life routine tasks. The number of missing incidents and caregivers' stress at three months and one year were compared with baseline data from one year before and the secondary outcome was time for searching of the last incident. RESULTS: A total of 54 patients were recruited. The mean age was 78.8 years and 54% were females. Majority of patients had moderate dementia. The mean number of missing incidents per year was significantly reduced at three months and one year (0.70, 0.22, and 0.14 at 0, 3, and 12 months, respectively; p < 0.001). The time for searching of last missing episode was reduced significantly (6.25, 0.13, and 0.35 hours, respectively; p < 0.001). The caregivers' stress also decreased significantly at three months and one year. CONCLUSION: The HMIPP was effective in reducing the number of missing incidents, searching time, and caregivers' stress at three months and one year. PMID- 29720291 TI - Possible case of trichinellosis associated with beaver (Castor fiber) meat. AB - Although there have been occasional reports of rare and low-level trichinellae infestation in beavers, no human cases of beaver-associated trichinellosis have been described. This report presents a possible case of human trichinellosis linked to beaver meat. Increasing consumption of beaver meat necessitates raising awareness of this potential source of trichinellosis. PMID- 29720292 TI - Induction of nuclear factor-kappaB signal-mediated apoptosis and autophagy by reactive oxygen species is associated with hydrogen peroxide-impaired growth performance of broilers. AB - The oxidative study has always been particularly topical in poultry science. However, little information about the occurrence of cellular apoptosis and autophagy through the reactive oxygen species (ROS) generation in nuclear factor kappaB (NF-kappaB) signal pathway was reported in the liver of broilers exposed to hydrogen peroxide (H2O2). So we investigated the change of growth performance of broilers exposed to H2O2 and further explored the occurrence of apoptosis and autophagy, as well as the expression of NF-kappaB in these signaling pathways in the liver. A total of 320 1-day-old Arbor Acres male broiler chickens were raised on a basal diet and randomly divided into five treatments which were arranged as non-injected treatment (Control), physiological saline (0.75%) injected treatment (Saline) and H2O2 treatments (H2O2(0.74), H2O2(1.48) and H2O2(2.96)) received an intraperitoneal injection of H2O2 with 0.74, 1.48 and 2.96 mM/kg BW. The results showed that compared to those in the control and saline treatments, 2.96 mM/kg BW H2O2-treated broilers exhibited significantly higher feed/gain ratio at 22 to 42 days and 1 to 42 days, ROS formation, the contents of oxidation products, the mRNA expressions of caspases (3, 6, 8), microtubule-associated protein 1 light chain 3 (LC3)-II/LC3-I, autophagy-related gene 6, Bcl-2 associated X and protein expressions of total caspase-3 and total LC3-II, and significantly lower BW gain at 22 to 42 days and 1 to 42 days, the activities of total superoxide dismutase and glutathione peroxidase, the expression of NF-kappaB in the liver. Meanwhile, significantly higher feed/gain ratio at 1 to 42 days, ROS formation, the contents of protein carbonyl and malondialdehyde, the mRNA expression of caspase-3 and the protein expressions of total caspase-3 and total LC3-II, as well as significantly lower BW gain at 22 to 42 days and 1 to 42 days were observed in broilers received 1.48 mM/kg BW H2O2 treatment than those in control and saline treatments. These results indicated that oxidative stress induced by H2O2 had a negative effect on histomorphology and redox status in the liver of broilers, which was associated with a decline in growth performance of broilers. This may attribute to apoptosis and autophagy processes triggered by excessive ROS that suppress the NF-kappaB signaling pathway. PMID- 29720293 TI - Using structural equation modeling to detect response shift in quality of life in patients with Alzheimer's disease. AB - : ABSTRACTBackground:Our study aims to detect different types of response shifts (RS) and true changes of quality of life (QOL) measurement in patients with Alzheimer's disease (AD) using structural equation modeling (SEM) in domain level. METHODS: Patients with AD aged over 60 years old were collected from the Department of Neurology and Geriatrics in Taiyuan Central Hospital, China. The 12 item Short Form (SF-12) Health Survey was measured in 238 patients with AD prior to hospitalization and one month following discharge. RS was detected by SEM approach. The statistical process consisted of four steps and fitted four models. We interpreted changes of parameters in models to detect RS and to assess true change. RESULTS: The results showed reprioritization of social functioning (SF) (chi2 = 4.13, p < 0.05), reconceptualization of role limitations due to emotional problems (RE) (chi2 = 17.03, p < 0.001), uniform recalibration of bodily pain (BP) (chi2 = 12.24, p < 0.001), and non-uniform recalibration of mental health (MH) (chi2 = 4.41, p < 0.05), respectively. The true changes of common factors were deteriorated in general physical health (PHYS) (-0.10, chi2 = 8.30, p < 0.005) and improved in general mental health (MENT) (+0.29, chi2 = 20.95, p < 0.001). The effect-sizes of RS were only small. CONCLUSION: This study showed that patients with AD occurred three types of RS and true changes one month following discharge. RS had effects on the QOL of patients. Better understanding of potential changes in QOL in patients with AD is crucial. PMID- 29720294 TI - Adipogenic genes expression in relation to hepatic steatosis in the liver of two duck species. AB - Some studies have shown that expression of peroxisome proliferator-activated receptor gamma (PPARG), a key regulator of adipogenesis, and of some adipocyte specific genes or adipokines are expressed in hepatic steatosis, leading to the concept of 'adipogenic hepatic steatosis' or 'hepatic adiposis.' Most of these studies were conducted in genetic obese mouse models or after manipulation of gene expression. The relevance of this concept to other species and more physiological models was here addressed in ducks which are able to develop hepatic steatosis after overfeeding. The expression of PPARG and other adipocyte specific genes was thus analyzed in the liver of ducks fed ad libitum or overfed and compared with those observed in adipose tissues. Pekin (Anas platyrhynchos) and Muscovy ducks (Cairina moschata) were analyzed, as metabolic responses to overfeeding differ according to these two species, Muscovy ducks having a greater ability to synthesize and store lipids in the liver than Pekin ducks. Our results indicate that adipocyte-specific genes are expressed in the liver of ducks, PPARG and fatty acid-binding protein 4 being upregulated and adiponectin and leptin receptor downregulated by overfeeding. However, these expression levels are much lower than those observed in adipose tissue suggesting that fatty liver cells are not transformed to adipocytes, although some hepato-specific functions are decreased in fatty liver when compared with normal liver. PMID- 29720295 TI - Methods for Investigating the Motivation of Mice to Explore and Access Food Rewards. AB - The emotional state of domestic animals is an essential component of the assessment of their welfare. In addition, sensitivity to various rewards can be a valuable indicator when investigating these states. We aimed to design an exploration test and a contrast test that did not evoke fear and anxiety in C57BL/6N mice but that instead were perceived as positive experiences and that might be used to assess sensitivity to various rewards. The exploratory arena had a larger central area and 8 smaller sections containing various objects. Motivation (measured as latency to enter the arena under conditions of increasing weight of the entrance door), anticipation (measured as latency to enter the arena under conditions of increasing delay in opening the entrance door), and the numbers of visits to the different sections were evaluated during a 5-min session in the arena. In the contrast test, after traversing a runway, half of the mice received a tasty reward (hazelnut cream), whereas the others received a neutral reward (food pellet) at the far end. Latency to reach the reward was recorded. After baseline training, rewards were swapped for half of the mice from each category for 3 d, to establish a negative and positive contrast. Mice were both motivated and showed anticipation to enter the exploration arena; after entering, they were active and visited many sections. In the contrast test, latency during the baseline period was longer for mice given the neutral reward compared with the tasty reward. Compared with baseline, latency during the postshift phase decreased for the positive-contrast group (neutral-tasty reward pattern) but did not differ for the negative-contrast group (tasty-neutral reward pattern). Overall, both tests seemed to be positive experiences for the mice and showed potential for use to investigate reward sensitivity. PMID- 29720297 TI - Setting the Stage for Better Outcomes. PMID- 29720298 TI - Addressing the Shortage of Geriatric Specialists. AB - With a population that is increasingly "gray," our nation faces a shortage of primary care providers who specialize in geriatrics. The number of geriatricians per 10,000 adults older than 65 years of age has decreased steadily since 2000. Health care providers from all disciplines (medicine, nursing, and pharmacy) tend not to choose geriatrics as a specialty area. Some are intimidated by the complexity of caring for elderly patients with geriatric syndromes and multiple morbidities. Others, who have little exposure to geriatrics in their undergraduate and graduate programs, are simply unaware of the personal and professional rewards associated with practice in geriatrics. Some choose to pursue more lucrative career paths. Regardless, geriatrics is a rewarding area of specialty, and pharmacists can pursue additional training to become specialists. Few pharmacy curricula offer intense exposure to geriatrics and elder health care. Numerous ways exist for pharmacists to help close the geriatric care gap. PMID- 29720299 TI - Effects of Denosumab After Treatment Discontinuation : A Review of the Literature. AB - OBJECTIVE: To review and summarize studies on the effects of denosumab on bone mineral density following the discontinuation of therapy. DATA SOURCES: A search of PubMed (1966-July 2017) and International Pharmaceutical Abstracts (1970-July 2017) was conducted using the Medical Subject Headings (MeSH) terms denosumab, osteoporosis, and withholding treatment in combination with free term searches including the words drug holiday, discontinue, discontin*, and drug discontinuation. STUDY SELECTION AND DATA EXTRACTION: An initial review yielded 10 articles. Four articles that addressed the effects of denosumab discontinuation on markers of overall bone health, fracture risk, or bone histology were included in the final review. DATA SYNTHESIS: Denosumab is a monoclonal antibody indicated for the treatment of osteoporosis in men and postmenopausal women. Denosumab has proven beneficial effects on bone remodeling and bone mineral density, and these effects have been noted to be reversed upon treatment discontinuation because of the agent's lack of incorporation into bone matrix. After 12 to 24 months off denosumab therapy, BMD, BTMs levels, as well as histologic and histomorphometric analyses, were reflective of baseline values. The number of studies evaluating the residual skeletal effects of denosumab is limited, and the sample sizes in the articles reviewed were relatively small. CONCLUSION: An evaluation of studies showed that the discontinuation of denosumab results in loss of bone mineral density and a decline to near baseline values within 12 months of discontinuing therapy. Larger extension studies in a more diverse population need to be conducted to extrapolate the data to other patient groups. PMID- 29720300 TI - Chronic Obstructive Pulmonary Disease and Heart Failure Self-Management Kits for Outpatient Transitions of Care. AB - OBJECTIVE: To develop heart failure (HF) and chronic obstructive pulmonary disease (COPD) self-management kits in an accountable care organization (ACO) to facilitate patients' self-care and prevent hospital readmissions. SETTING: Pharmacists practice in an outpatient-based ACO. They participate in interprofessional office visits with providers and independently manage maintenance pharmacotherapies. PRACTICE DESCRIPTION: Pharmacists collaborate with an interprofessional team within the ACO including physicians, nurses, case managers, and paramedics. Two commonly encountered diseases are chronic COPD and HF. Reducing preventable readmissions for these conditions are important quality benchmarks and cost-saving strategies. PRACTICE INNOVATION: Pharmacists were responsible for developing HF and COPD self-management kits containing patient education materials and prescriptions to facilitate self-care. Prior to kit development, pharmacists performed a literature review to determine the presence of previously published findings on these topics. MAIN OUTCOME MEASUREMENTS: The interprofessional team continually evaluates the successes and limitations of this initiative. Pharmacists developed training and instructions for ACO allied health professionals in an effort to incorporate the self-management kits in clinical practice. RESULTS: The initial literature search revealed no studies describing the intervention of interest. Innovative programs designed to help reduce preventable readmissions are lacking in primary care. Implementation of the self-management kits was accepted by interprofessional ACO leadership and is currently being integrated into allied health workflow. CONCLUSION: Patients at risk for having an exacerbation of COPD or HF should receive self-management strategies. Prompt therapy prior to exacerbations reduces hospital admissions and readmissions, speeds recovery, and slows disease progression. Pharmacist facilitated implementation of self-management kits may be developed by interprofessional health care teams. PMID- 29720301 TI - Gaps in OTC Labeling: Potentially Inappropriate Medications for Older Adults. AB - As the number of available over-the-counter (OTC) products increases, many older adults are taking health care into their own hands. It is particularly important that the labeling provided with these products is precise, leading to their effective use, especially by older adults. Suboptimally designed medication labels can increase the risk of consumption errors and adverse drug interactions among seniors. This study evaluated whether the warning labels on potentially inappropriate OTC medications are consistent with evidencebased criteria for potentially inappropriate prescribing in older adults. Future action could be taken by the Food and Drug Administration to improve labeling policies. PMID- 29720302 TI - Assessing Pneumococcal Vaccination Availability in Under-Vaccinated Rural Counties: A Pharmacy Perspective. AB - OBJECTIVE: Vaccines are a low-cost, high-impact interventions that effectively and efficiently reduce the burden of infectious diseases. Many rural populations have vaccination rates well below nationally recommended levels. Community pharmacies may offer a solution to this problem. Under a collaborative drug therapy agreement (CDTA), pharmacists can prescribe and administer immunizations. The purpose of this study was to examine pneumococcal vaccine access in rural pharmacies in Eastern Washington state. DESIGN: A qualitative descriptive design was utilized in this study. The sample included all pharmacies located in two rural Washington state counties. Interviews were conducted with pharmacy staff. Every pharmacy in the two counties was surveyed over the telephone. Data analysis included directed content analysis and descriptive statistics. FINDINGS: Each of the 10 pharmacies identified participated. Pharmacy volume varied (weekly prescription counts of 300 to 2,500). Sixty percent of pharmacies currently provide vaccines. Quoted prices of the PCV13 varied between $65 and $228. Quoted prices of the PPSV23 varied between $64 and $120. Pharmacies that vaccinated made it convenient with "walk-in" scheduling practices. Some pharmacies required a prescription from a separate provider while others could prescribe on-site through CDTA. Pharmacies that chose not to vaccinate did so for a variety of reasons. CONCLUSIONS: Access to pneumococcal vaccines will be enhanced by pharmacist administration, resulting in improved availability, accessibility, accommodation, affordability, and acceptability for patients in rural Washington. PMID- 29720303 TI - The Medicare Part D Season Begins, Again. PMID- 29720304 TI - Editorial. PMID- 29720305 TI - On-line Breath Metabolomics in Respiratory Diseases using Secondary Electrospray Ionization-Mass Spectrometry. AB - Every second we are exhaling hundreds of endogenous and exogenous compounds that originate from blood and lung tissue. Obtaining metabolic information via exhaled breath analysis has been an emerging topic since the 1970s. Secondary electrospray ionization-mass spectrometry is a relatively new technique to detect these metabolites on-line in a highly sensitive and specific fashion. Using this technique, several respiratory diseases, including chronic obstructive pulmonary disease, obstructive sleep apnea, idiopathic pulmonary fibrosis, asthma, and lung cancer have been investigated over the past years. Several new potential biomarkers for these diseases were identified and new metabolic insights into their pathophysiology could be obtained. PMID- 29720306 TI - Directed Evolution of Artificial Metalloenzymes: Genetic Optimization of the Catalytic Activity. AB - Artificial metalloenzymes (ArMs) based on the incorporation of a biotinylated metal cofactor within a streptavidin (Sav) combine attractive features of both enzymatic and homogeneous catalysis. To speed up their optimization, we present a directed evolution of an artificial transfer hydrogenase (ATHase) based on a stream-lined and optimized protocol for the design, overexpression and screening of Sav isoforms. Ten positions have been subjected to mutagenesis to yield two variants with improved catalytic activity and selectivity for the reduction of cyclic imines, along with greater stability in a biphasic medium. PMID- 29720307 TI - Understanding Non-Covalent Interactions: Correlated Energy Decomposition Analysis and Applications to Halogen Bonding. AB - Non-covalent interactions play a primordial role in chemistry. Beyond their quantification, the detailed understanding of their physical processes is necessary to rationalize chemical trends and improve designs of chemical systems. Energy decomposition analyses allow detailed insight into non-covalent interactions by extracting electrostatics, Pauli repulsion, polarization, dispersion and charge transfer components from interaction energies. Recent work has demonstrated that electronic correlation influenced significantly all of these energy components, whereas previous decompositions only partitioned correlation between dispersion and charge transfer. The MP2 energy decomposition analysis with Absolutely Localized Molecular Orbitals (MP2 ALMO-EDA) takes these results fully into account and offers a correlation correction for each extracted component. A recent detailed investigation of the CCSD dispersion energy showed that a small number of virtual orbitals is sufficient to describe dispersion interactions accurately in the long-range, which potentially offers a basis-set independent definition of dispersion. Finally, we present an application of MP2 ALMO-EDA to a series of unusual halogen bonding complexes where charge transfer dominates over the electrostatic sigma-hole interaction. PMID- 29720308 TI - Four-electron Reduction and Functionalization of N2 by a Uranium(III) Bridging Nitride. AB - N2 is a cheap and widely available but very unreactive molecule. Notably, the only industrial process for the conversion of dinitrogen is the Haber-Bosch process to form ammonia, but under very harsh conditions (high temperature and pressure). Here, we review our recent research leading to the reduction of dinitrogen by four electrons, under ambient conditions by a uranium(III) bridging nitride, K3 U-N-U, where two uranium(III) cations are linked by a nitride group and a flexible metal-ligand scaffold. We also show that the bound dinitrogen can be further functionalized under mild conditions: the addition of acid, hydrogen and protons or carbon monoxide to the uranium hydrazido complex yields to the cleavage of the N-N single bond and to the formation of new N-H and N-C bonds. PMID- 29720309 TI - Heptacoordinate Co(II) Catalyst for Light-driven Hydrogen Production in Fully Aqueous Medium. AB - Photocatalytic hydrogen production is an appealing way to store solar energy as chemical fuel. The most studied molecular catalysts for H2 production are based on earth-abundant metals such as Ni, Co and Fe. Efforts have been recently focused on the design of Co complexes with distorted octahedral geometries induced by tetra- or pentapyridyl ligands. We synthesized a new Co(II) complex based on a hexapyridyl ligand that leads to the formation of an unusual heptacoordinate structure. In this paper, we review the characterization of the new catalyst and the optimization of the conditions for hydrogen evolution. The high activity reached after two hours of irradiation under visible light (475 nm) suggests that heptacoordinate cobalt complexes, not used so far in the field of light-driven hydrogen evolution, represent a promising alternative platform for the development of highly active and stable photocatalysts. PMID- 29720310 TI - Ruthenium-based Photocatalysis in Templated Reactions. AB - Templated reactions proceed by bringing reagents in close proximity through their interaction with a template thus raising their effective concentrations. Templated reactions empower chemists to perform reactions at low concentrations in complex environments. Herein, we discuss our work on templated reactions leveraged on ruthenium photocatalysis. Over the past five years, we have used this reaction to uncage reporter molecules and sense or image nucleic acids or proteins of interest. The ruthenium photocatalysis chemistry has proven to be extremely robust and compatible with complex biological environments. PMID- 29720311 TI - Transforming Olefins into Dinucleophiles. AB - Herein we present the first example of a three-component dicarbofunctionalization of olefins under reductive conditions. Our strategy takes advantage of nickel catalysis to add aryl and alkyl groups across the double bond with remarkable selectivity. The reaction shows broad functional group compatibility and more importantly, it proves to be general in terms of the alkenes that can be functionalized compared to previous dicarbofunctionalization methods. Initial control experiments reveal different activation modes for both electrophiles and the involvement of alkyl radicals throughout the reaction. PMID- 29720312 TI - High-spin Metal Centres in Dipolar EPR Spectroscopy. AB - The substitution of Mg2+ by Mn2+ in the bacterial DnaB helicase from Helicobacter pylori, an ATP:Mg2+-fuelled protein engine, allows electron paramagnetic resonance (EPR) spectroscopy to be performed on this system. EPR experiments make it possible to monitor nucleotide binding and to estimate the fraction of bound Mn2+ through relaxation measurements. Furthermore, by measuring spin-spin distances we probe the geometry within such multimeric assemblies using ultra wideband double electron-electron resonance (DEER) and relaxation induced dipolar modulation enhancement (RIDME). The extraction of distance distributions from RIDME experiments on high-spin paramagnetic centres is influenced by the presence of dipolar frequency overtones. We show herein that we can correct for these overtones by using a modified kernel function in Tikhonov regularization analysis routines, and that the overtone coefficients for Mn2+ in the DnaB helicase are practically the same as in the previously studied Mn2+-Mn2+ model compounds. PMID- 29720313 TI - Analysis of Inorganic Nanoparticles by Single-particle Inductively Coupled Plasma Time-of-Flight Mass Spectrometry. AB - Due to the rapid development of nanotechnologies, engineered nanomaterials (ENMs) and nanoparticles (ENPs) are becoming a part of everyday life: nanotechnologies are quickly migrating from laboratory benches to store shelves and industrial processes. As the use of ENPs continues to expand, their release into the environment is unavoidable; however, understanding the mechanisms and degree of ENP release is only possible through direct detection of these nanospecies in relevant matrices and at realistic concentrations. Key analytical requirements for quantitative detection of ENPs include high sensitivity to detect small particles at low total mass concentrations and the need to separate signals of ENPs from a background of dissolved elemental species and natural nanoparticles (NNPs). To this end, an emerging method called single-particle inductively coupled plasma mass spectrometry (sp-ICPMS) has demonstrated great potential for the characterization of inorganic nanoparticles (NPs) at environmentally relevant concentrations. Here, we comment on the capabilities of modern sp-ICPMS analysis with particular focus on the measurement possibilities offered by ICP-time-of flight mass spectrometry (ICP-TOFMS). ICP-TOFMS delivers complete elemental mass spectra for individual NPs, which allows for high-throughput, untargeted quantitative analysis of dispersed NPs in natural matrices. Moreover, the multi element detection capabilities of ICP-TOFMS enable new NP-analysis strategies, including online calibration via microdroplets for accurate NP mass quantification and matrix compensation. PMID- 29720314 TI - Photoelectron Photoion Coincidence Spectroscopy to Unveil Reaction Mechanisms by Isomer-selective Detection of Elusive Molecules: From Combustion to Catalysis. AB - Elusive and reactive intermediates, such as radicals, play a central role in reaction mechanisms. Photoelectron photoion coincidence spectroscopy with tunable vacuum ultraviolet synchrotron radiation offers a multiplexed, sensitive, mass- and isomer-selective way to identify and, in some cases, determine mole fractions of reactive species. It thus helps to unveil the missing link(s) between reactants and products. After a brief overview of the technique, we review two systems in three different reactive environments. First, the unimolecular decomposition mechanism of ortho-xylyl radicals is revealed in pyrolysis experiments. Second, the insights gained are used to analyze a fuel-rich meta xylene flame, which suggests that important xylyl isomerization reactions are currently missing in combustion models. Third, photoion mass-selected threshold photoelectron spectra identify the fulvenone ketene as the crucial intermediate in the catalytic fast pyrolysis of a lignin model compound and help map heterogeneous catalysis mechanisms. PMID- 29720315 TI - Base-free Asymmetric Transfer Hydrogenation of 1,2-Di- and Monoketones Catalyzed by a Chiral Iron(II) Hydride. AB - The chiral iron(II) hydride complex [FeH(CNCEt3)(1a)](BF4) (3, 1a is a chiral macrocycle with an (NH)2P2 donor set) catalyzes the base-free transfer hydrogenation (ATH) of prochiral ketones and the hemireduction of benzils to the corresponding benzoins using iPrOH as hydrogen donor. Ketones give the same excellent enantio-selectivity (up to 99% ee) as the parent catalyst [Fe(CNCEt3)2(1a)](BF4)2 (2), which is only active upon treatment with NaOtBu. Benzoins, whose labile stereocenter is known to undergo racemization under basic conditions, are formed in up to 83% isolated yield with enantioselectivity as high as 95%. PMID- 29720316 TI - Repurposing the Selective Oestrogen Receptor Modulator Tamoxifen for the Treatment of Duchenne Muscular Dystrophy. AB - Drug discovery is a long, expensive and risky process. Evaluating drugs that have already been proved safe for use in humans and testing them for a new indication greatly reduces the time and monetary costs involved in finding treatments for life-threatening conditions. Here tamoxifen, a drug that is used for the treatment of breast cancer, is investigated in a mouse model of Duchenne muscular dystrophy. Tamoxifen was efficacious in countering the symptoms of the disease without affecting the underlying genetic cause. Based on these results, tamoxifen has been tested in other forms of muscle disease with success. Drug repurposing may not only be a cost-effective manner for treating a variety of diseases, it may also help us uncover common mechanisms between conditions that were previously thought to be unrelated. PMID- 29720317 TI - Induction of Intracellular Reductive Stress with a Photoactivatable Phosphine Probe. AB - Reductive stress is a condition present in cells that have an increased concentration of reducing species, and it has been associated with a number of pathologies, such as neurodegenerative diseases and cancer. The tools available to study reductive stress lack both in selectivity and specific targeting and some of these shortcomings can be addressed by using photoactivatable compounds. We developed a photoactivatable phosphonium probe, which upon irradiation releases a fluorescent molecule and a trialkyphosphine. The probes can permeate through the plasma membrane and the photoreleased phosphine can induce intracellular reductive stress as proven by the detection of protein aggregates. PMID- 29720318 TI - Complexation and Structure Elucidation of the Axial Conformers of Mono- and (+/-) trans-1,2-Disubstituted Cyclohexanes by Enantiopure Alleno-Acetylenic Cage Receptors. AB - Single crystal X-ray diffraction is a powerful method to unambiguously characterize the structure of molecules with atomic resolution. Herein, we review the molecular recognition of the (di)axial conformers of Mono- and (+/-)-trans 1,2-disubstituted cyclohexanes by enantiopure alleno-acetylenic cage receptors in solution and in the solid state. Single crystals of the host-guest complexes suitable for X-ray diffraction allow for the first time to study the dihedral angles of a series of Mono- and (+/-)-trans-1,2-disubstituted cyclohexanes in their (di)axial chair conformation. Theoretical studies indicate negligible influence of the host structure on the guest conformation, suggesting that the structural information obtained from the host-guest complexes give insight into the innate structures of Mono- and (+/-)-trans-1,2-disubstituted cyclohexanes. Strong deviation of the dihedral angles ?a,a(X-C(1)-C(2)-X) from the idealized 180 degrees are observed, accompanied by substantial flattening of the ring dihedral angles rho(X-C(1)-C(2)-C(3)). PMID- 29720322 TI - Swiss Youth in Science: Study Week in 'Chemistry and Materials Science'. PMID- 29720319 TI - Ag Nanoencapsulation for Antimicrobial Applications. AB - Biomaterial-related infections remain a significant challenge in medicine. Antimicrobial materials on the basis of Ag nanoparticles represent a promising solution for this issue. Therefore several Ag-containing nanocontainers and nanorattles have been synthesized and characterized that exhibit remarkable control over the release of Ag+ as antimicrobial active species. Their biological evaluation against prokaryotic as well as eukaryotic cells reveals that they fulfill the prerequisites for applications as antimicrobial implant coatings. PMID- 29720324 TI - Effects of stannous fluoride on eroded enamel permeability. AB - This study aimed to evaluate the effect in vitro of a single application of a stannous fluoride- (SnF2-) containing toothpaste on eroded enamel. Forty-eight teeth were subjected to three acid treatments: 15% hydrochloric acid for 120 s (HA group); 1% citric acid (pH=4) for 180 s (CA group); 37% phosphoric acid for 30 s (PA group). They were brushed with an electric toothbrush with pressure control and 1 g of SnF2 (1100 ppm) toothpaste for 2 min. Polyether replicas of buccal enamel surfaces were obtained at baseline, after acid exposure and after brushing, gold sputtered and inspected by SEM for fluid droplets presence. Hydrochloric and citric acid treatments increased enamel permeability while, on the contrary, phosphoric acid reduced enamel fluid release. SnF2 application of ameliorated acid induced permeability in citric and hydrochloric treated samples. Permeability in phosphoric treated enamel was unchanged after topical application of SnF2. Our data show specific acid-dependent effects on enamel permeability and demonstrate that SnF2 application can reverse acid-induced permeability. PMID- 29720325 TI - Histological evaluation of periodontal ligament in human after orthodontic treatment with piezosurgery and monolateral tooth dislocation and ligament distraction technique: a first morphologic and histologic evaluation. AB - Traditional orthodontic tooth movement is based on the concept that application of a protracted force causes alveolar bone remodelling and adaptive changes in periodontal and dental tissues. Thus, if orthodontic tooth movement is described as a biological bone reaction to orthodontic forces mediated by the periodontal ligament (PDL), this event involves a series of sophisticated signal transduction processes that allows the PDL compression with specific histologic and biomolecular modifications. However, the preservation of the integrity of the PDL is generally difficult to achieve when it is associated with a long duration of orthodontic treatment. A total of 20 Caucasian patients with different dental skeletal were treated using the Monocortical Tooth Dislocation and Ligament Distraction (MTDLD) technique with Piezosurgery associated with morphologic and histological evaluation of the PDL. The histological results obtained, confirm a good clinical outcome with an improvement of the speed on orthodontic treatment without any signs of tissue injury of PDL fiber without areas of hyalinization. The data suggests that MTDLD with Piezosurgery seems to be a valid alternative to the traditional orthodontic movement in adult patients preserving the anatomy and the integrity of PDL. PMID- 29720326 TI - Piezoelectric surgery inserts vs conventional burst: a clinical investigation. AB - Piezosurgery is a new technique that can be used to cut mineralized structures without damaging adjacent soft tissues. This device has a lot of advantages: reduced surgical time, blood loss, and inferior alveolar nerve injury in bimaxillary osteotomy. Fifty patients underwent different surgical operations (orthognathic surgery, traumatic surgery, reconstructive surgery, aesthetic procedures) with 7 different kind of piezosurgery inserts in a period of 8 months. The same two surgeons performed all the procedures. All the procedures were carried out in order to improve the precision of the osteotomy and the comfort of the surgeon. Piezoelectric devices provide an innovative ultrasonic technique for safe and effective osteotomy compared with methods that use rotating instruments. Different inserts have been developed in order to achieve the utmost advantages. PMID- 29720327 TI - Effects of clear aligners on sleep bruxism: randomized controlled trial. AB - The possible effects on sleep bruxism (SB) of clear aligners in orthodontics are unknown. This study was conducted to analyze the effects of clear aligners on SB. Sixty subjects needing orthodontic treatment and affected by SB (33 m, 27 f, 20+/ ;5 years) were enrolled in the study and randomly assigned to one of the following three groups: 20 were given clear aligners (CAT) (12 m, 8 f, 19+/-5 years), 20 occlusal splint (MOS) (9 m, 11 f, 22+/-5 years) and 20 a placebo splint (PMS) (12 m, 8 f, 24+/-3 years). All groups were followed for 6 consecutive months and monitored for SB with a portable electromyographic electrocardiographic (EMG-ECG) device (Bruxoff(r), OT Bioelettronica, Torino, Italy). MOS subjects reduced masseter contractions after 6 months of treatment (t3) (MD=-29.11, std. error 11.74, p=0.017) but increased phasic contractions related to SB after 3 months of treatment (t2) (MD=4.73, std. error 2.36, p=0.048) and tonic contractions related to SB during all the six months of treatment (t1, t2, t3) when compared to PMS. CAT subjects increased phasic contractions related to SB during the first (t1) (MD=3.94, std. error 2.27, p=0.04) and the third month (t2) of treatment (MD=4.62, std. error 2.36, p=0.046) when compared to PMS. No significant differences were found for SB index at any time for all the three groups. Although MOS and CAT affected EMG signals during sleep time differently, they did not influence the overall SB index. PMID- 29720328 TI - Evaluation of bacterial flora composition on teeth and periodontal tissues in patients in treatment with rapid palatal expander. AB - Patients in treatment with rapid palatal expander (RPE) require professional assistance and more meticulous instructions on oral hygiene, since this appliance predisposes to gingivitis and caries. The aim of this work is to analyse the variability of the oral microbial flora found in patients in treatment with RPE with occlusal acrylic splint. It was also investigated whether the association of an antimicrobial mouthwash was useful during orthodontic treatment or whether regular and specific home oral hygiene manoeuvres were sufficient to maintain a good plaque control. The last goal was to highlight which of the different mouthwashes was the most effective in reducing the bacterial load. The patients were divided into 3 test groups and each one of them had a different mouthwash (chlorhexidine and sodium fluoride, fluorine, essential oils) randomly assigned. There was also a control group. Plaque samples were analysed through cultural analysis and PCR from T0 to T4 (8 months). Chlorhexidine mouthwash reduces the bacterial count by 96.08%, the fluorine by 94.50% and the essential oils by 95.74%. The results of the three mouthwashes are superimposable and although chlorhexidine gives the highest rate of bacteria reduction, its side effects lead the authors to prefer the essential oils. PMID- 29720329 TI - Effect of dental care on the oral health of Sjogren?s syndrome patients. AB - Sjogren?s syndrome (SS) is a chronic, systemic autoimmune disease affecting the exocrine glands, particularly the salivary and lacrimal glands. Xerostomia is a major feature of this syndrome and greatly affects patient quality of life. The most typical clinical signs associated with hyposalivation are dysgeusia and dysosmia, dental caries, candidiasis, periodontal disease, gland inflammation, mucositis and oral ulcers. The aims are to investigate on Plaque Index (PI) and Gingival Index (GI) before and after dental care of SS patients. Fifty-two consecutive patients (mean age 48.9+/-2 years) were analysed. At T0, (baseline) T1 (3 months after T0) and T2 (6 months after T0), a Plaque Index and a Gingival Index were calculated. The statistical analysis was performed using one-way ANOVA test. If distribution was not normal, Friedman test was chosen instead of ANOVA. Dunn?s multiple comparison procedure was performed as post-hoc (IBM SPSS Statistics 21 software). A statistically significant decrease was observed both in PI and in GI between T0 and T1, T1 and T2, T0 and T2 (P less than 0.05). PMID- 29720330 TI - Cervical vertebrae maturation: a blinded trial study. AB - This blinded trial was conducted to analyze possible correlations between the cervical vertebrae maturation method (CVM) and the mineralization of mandibular teeth as described by Demirjian et al. (TMS). Panoramic and cephalometric radiographs of 500 orthodontic patients were analyzed by two blinded operators. TMS was utilized to analyze mineralization of second molar, second and first premolar and canine on the left side of the mandible; CVM stage was also evaluated. A blinded statistician performed statistical correlations and multiple regression analysis. Significant relations between CVM and TMS stages were identified for each tooth. Significant age differences resulted for CVM, second molar and second premolar (p<0.05). Significant correlations for second molar were observed between TMS D and CVM I-II, TMS G and CVM III, TMS H and CVM V-VI (p less than 0.01). Second molar stage G for both sexes indicates the ongoing of growth spurt. Stage G for boys and stage H for girls correlate significantly with the late part of PGS. PMID- 29720331 TI - In vitro effects of fluoride-based and desensitizing toothpastes on dentine permeability. AB - This study aims to evaluate the effectiveness in reducing dentine permeability of three different toothpastes comparing with a sodium fluoride one. Dentine permeability was measured by a fluid filtration system. Dentin discs were randomized in four experimental groups and treated with different commercial toothpastes, as it follows. Group A: Sensodyne(r) Rapid, with strontium acetate; group B: Elmex Sensitive ProfessionalTM, with arginine and 450 ppm monofluoro phosphate; group C: Colgate Total Advanced(r), with 1450 ppm NaF; group D: AZ Pro Expert(r), with 1100 ppm SnF2. After brushing specimens of each groups were assigned to two subgroups and: 1) stored in artificial saliva (2 h) and treated with 6% citric acid for 1 min; 2) stored in artificial saliva for 24 h. SEM analysis was performed to investigate dentinal tubules occlusion of acid treated and stored in artificial saliva samples. Dentin permeability proved affected by dentifrice treatments. The toothpastes specifically formulated for hypersensitivity showed significant effects concerning decrease of dentine permeability. SEM observations demonstrated the presence of dentifrice particles on dentin surface and inside dentin tubules. Stannous fluoride treated samples exhibited the greater tubules occlusion. PMID- 29720332 TI - Standard and low-dose cone beam computer tomography protocol for orthognatodontic diagnosis: a comparative evaluation. AB - Considering the diagnostic capability offered by cone-beam computed tomography (CBCT), nowadays orthodontists often use this exam for treatment planning, especially in cases of impacted teeth, maxillary ipoplasia, orthognathic surgery etc. The aim of this study was to compare the radiation doses related to a conventional CBCT setting and that of a low dose protocol, usable in orthodontic practice. The absorbed organ doses were measured using an anthropomorphic phantom loaded with thermo-luminescent dosimeters related to sensitive organs (brain, bone marrow, salivary glands, thyroid, esophagus, oral mucosa, extrathoracic airways, lymph nodes). The device used was a MyRay Hyperion X9-11x5. The standard setting of the apparatus was 90 Kv, 36 mAs, CTDI/Vol 4.09 mGy, instead the low dose one was 90 Kv, 27 mAs, CTDI/Vol 2.89 mGy. Equivalent and effective doses have been calculated; the measurement of the effective doses was based on the ICRP recommendations. For the assessment of image quality, five readers, independent and experienced orthodontists, were asked to state if the images were sufficient enough to perform an orthodontic diagnosis. The lowest organ dose (5.01 microSv) was received by the esophagus during low dose CBCT acquisition. The highest mean organ dose instead (1227.67 microSv) was received by the salivary glands during conventional setting CBCT acquisition. Image quality has been considered sufficient for orthodontic diagnostic needs for both CBCT protocols. CBCT low dose setting should be preferred over the standard one in orthodontic practice, because it provides a significant lower radiation dose to the patients ensuring a good image quality. However, further studies are necessary to evaluate the opportunity of CBCT exams in orthodontic treatment planning. PMID- 29720333 TI - Short-term in vivo evaluation of cellular DNA damage induced by fixed orthodontic appliances. AB - Metal ions accumulate inside the epithelial cells of the oral mucosa and damage the DNA. The aim of this study was to analyze whether DNA damage and/or apoptosis also occurs after a short-term exposure to the metals of fixed orthodontic appliances. 23 subjects were enrolled in the test group and 8 patients in the control group. Analyses performed on samples of oral mucosa were cell count, cellular viability, quantification of intracellular metal concentration, comet and micronuclei tests and quantification of intracellular Glutathione (GSH). The obtained results indicated that orthodontic appliances release metal ions, especially chromium, that cause inflammatory processes leading to DNA damages. These phenomenon are visible only after 30 days from application of fixed orthodontic appliances. PMID- 29720334 TI - Comparison of linear transverse measures between plaster and resin printed digital models. AB - The aim of this study was to test for dimensional variations between plaster models recorded with alginate impression and printed 3D physical replicas from an .stl file digitized with an intra-oral scanner. Eighty arches (maxillary and mandibular) from 40 different patients were analyzed. Classic alginate impressions and digital recordings with an intraoral scanner were taken on the same day, for both arches of each patient. Digital recordings were then printed into resin models. The linear intercanine (IC) and intermolar (IM) distances were measured with a manual electronic caliper and then compared. The measurements were repeated twice for each distance to verify repeatability with the intraclass correlation coefficient (ICC). The Student?s t test for paired data was used to compare the two sets of impressions. The repeatability of the measures was assessed as ICC values were higher than 0.98. The values of the IC and IM lengths showed a statistically significant difference, but not clinically significant as it was less than 0.1 mm, between the two techniques. PMID- 29720335 TI - Iatrogenic traumatic optic neuropathy: report of an injury occurring during a choanal atresia correction surgery treatment. AB - We report the case of a 36-year-old adult male patient who came to our attention for the evaluation of a possible iatrogenic injury suffered during the surgical correction of congenital choanal atresia. This case report retraces the patient's medical history and the events lapsed in the peri-operative time analyzing if any malpractice has occurred in causing the amaurosis. PMID- 29720336 TI - Hypothyroidism affects lipid and glycogen content and peroxisome proliferator activated receptor ? expression in the ovary of the rabbit. AB - Dyslipidaemia and hyperglycaemia are associated with ovarian failure and both have been related to hypothyroidism. Hypothyroidism promotes anovulation and ovarian cysts in women and reduces the size of follicles and the expression of aromatase in the ovary of rabbits. Considering that ovarian steroidogenesis and ovulation depend on lipid metabolism and signalling, the aim of the present study was to analyse the effect of hypothyroidism on the lipid content and expression of peroxisome proliferator-activated receptor (PPAR) delta in the ovary. Ovaries from female rabbits belonging to the control (n=7) and hypothyroid (n=7) groups were processed to measure total cholesterol (TC), triacylglycerol (TAG) and glycogen content, as well as to determine the presence of granules containing oxidized lipids (oxysterols and lipofuscin) and the relative expression of perilipin A (PLIN-A) and PPARdelta. Hypothyroidism increased TC and glycogen content, but reduced TAG content in the ovary. This was accompanied by a reduction in the expression of PLIN-A in total and cytosolic extracts, changes in the presence of granules containing oxidative lipids and low PPARdelta expression. The results of the present study suggest that hypothyroidism modifies the content and signalling of lipids in the ovary, possibly affecting follicle maturation. These results could improve our understanding of the association between hypothyroidism and infertility in females. PMID- 29720337 TI - Insulin promotes preantral follicle growth and antrum formation through temporal expression of genes regulating steroidogenesis and water transport in the cat. AB - The aims of the present study were to determine the effects of insulin, invitro, on: (1) the viability and growth of domestic cat ovarian follicles; (2) mRNA expression of genes regulating steroidogenesis (cytochrome P450 family 17 subfamily, A polypeptide 1 (Cyp17a1), cytochrome P450 family 19 subfamily, A polypeptide 1 (Cyp19a1) and steroidogenic acute regulatory protein (Star)) and water transport (aquaporins (AQPs) Aqp1, Aqp3, Aqp7, Aqp9); and (3) steroid production (17beta-oestradiol (E2), progesterone (P4), androstenedione (A4)). Cat secondary follicles were isolated from ovarian cortices and cultured in 0 (Control), 1 or 10ugmL-1 insulin for 14 days (Day 0=culture onset). Follicle and oocyte viability (based on neutral red staining), diameter and antrum formation were assessed every 72h and at the end of incubation (Day 14). Expression of steroidogenic and water transport genes was evaluated on Days 0, 6 and 12, and E2, P4 and A4 concentrations in the culture medium were determined on Day 12. By Day 14, 1 and 10ugmL-1 insulin had significantly promoted (P<0.05) both antrum formation in a mean (+/-s.e.m.) 26.9+/-9.0% and 78.0+/-10.0% of follicles respectively, and follicle growth (diameter 151.4+/-4.5 and 169.9+/-10.5um respectively) compared with Control (antrum formation in 3.3+/-3.3% of follicles and follicle diameter 129.1+/-6.6um). High insulin (10ugmL-1) treatment increased follicle viability compared with Control (86.0+/-9.8% vs 38.1+/-10.9% respectively; P<0.05). However, insulin had no beneficial effect (P>0.05) on oocyte diameter. Cyp17a1 expression on Days 6 and 12 was higher (P<0.05) in follicles cultured in the low (1ugmL-1) compared with high (10ugmL-1) insulin treatment, with no significant difference between low or high insulin vs Control groups. Star expression was higher (P<0.01) in the low insulin compared with Control group on Day 6, but Star was undetectable in the high insulin group by Day 12. Compared with high insulin, low insulin increased (P<0.05) Aqp1 expression on Day 6, but there were no significant differences between these two groups on Day 12. In contrast, high insulin decreased (P<0.05) Aqp9 transcript levels compared with Control. Only P4 production was affected by insulin, with P4 concentrations in the medium being higher (P<0.05) in the low compared with high insulin and Control groups. In summary, the findings indicate that insulin promotes cat ovarian follicle growth and survival invitro, including enhanced antrum formation, with the likely mechanism involving temporal expression of Cyp17a1, Star and Aqp9 genes. PMID- 29720338 TI - ? PMID- 29720339 TI - ? PMID- 29720340 TI - [The impact of complaints on clinicians]. AB - Most clinicians will sooner or later make mistakes, and occasionally it leads to litigation. One of the rationales of complaint systems like the Danish one is to contribute to the quality improvement of healthcare provision. Still, there is unsatisfactory evidence to support this while some studies point to negative aftermaths in terms of secondary victimisation, defensive medicine, etc. Further research is required on the effects of complaint measures and on reasonable ways to promote their constructive purpose. PMID- 29720341 TI - [Glucocorticoid-induced diabetes and risk factors during high-dose therapy]. AB - This review describes the cumulative incidence (CI) and risk factors of glucocorticoid (GC)-induced diabetes in patients commencing high-dose GC therapy: >= 30 mg prednisolone/day. Finally, methods of screening are discussed. In 13 studies, the CI of GC-induced diabetes ranges 12-65%, but with the current diagnostic criteria the CI is assessed to be 30-50%. Risk factors may include high age and high levels of BMI and glycated haemoglobin, respectively, before GC therapy. It is important to acknowledge, that hyperglycaemia in GC therapy is more prevalent postprandially, and screening should be planned accordingly. PMID- 29720342 TI - [The refeeding syndrome in anorexia nervosa]. AB - The refeeding syndrome (RFS) is a potentially fatal condition involving fluid and electrolyte imbalances after refeeding in patients with anorexia nervosa. Low calorie diet added thiamine and minerals is the standard approach to prevent RFS. In a recent systematic review starting with a higher calorie amount than earlier has been recommended, and in another review, it is proposed that a restriction in the amount of carbohydrates may allow for a higher calorie intake early on to enable a safe and faster weight gain. There are still many unanswered questions, but these studies may point to a future change in the guidelines. PMID- 29720343 TI - [Neurogenic autonomic dysfunction in adults]. AB - Neurogenic autonomic dysfunction (NAD) is underdiagnosed, and it is likely in patients, who have orthostatic hypotension and symptoms from multiple organ systems as well as abnormal results from a neurological examination. A clinical and neurophysiological examination of the autonomic nervous system combined with a standardised paraclinical evaluation should be performed. NAD may be present in neurodegenerative disorders, vitamin deficiency, toxicity, infection, and in paraneoplastic, metabolic, hereditary and immune-mediated conditions. PMID- 29720344 TI - [The sense of taste in a clinical setting]. AB - As a gatekeeper, taste buds forage chemicals to identify both nutrition and toxins. This can be the decisive difference between initiating the swallow reflex or spitting out the oral contents. In addition to this simple function the sense of taste takes part in more complex relations such as reflexes vs learning, perception vs expectation, and pleasure vs disgust. All relations, which can be perturbed into unbalance, create great discomfort in patients suffering from a dysfunctional sense of taste. This review discusses the most important mechanisms of taste function and dysfunction as well as the possible avenues for treatment of the disorders. PMID- 29720345 TI - [Cognitive side effects of electroconvulsive therapy]. AB - Electroconvulsive therapy (ECT) is the most effective treatment for severe depression but is associated with cognitive side effects. Side effects on executive function and memory may persist for months. Patients with a low cognitive reserve and/or poor cognition before ECT seem to be at greater risk of cognitive side effects than patients with a high cognitive reserve. However, better understanding of the nature and predictors of these side effects is needed. We recommend implementing a cognition assessment tool to monitor cognition during ECT. This may improve patient information and provide a basis for more personalised treatments. PMID- 29720346 TI - Tako-tsubo cardiomyopathy with transient global amnesia and cerebellar embolic stroke triggered by existential fear. AB - BACKGROUND: Embolic stroke is a complication of Tako-Tsubo-cardiomyopathy (TTC), transient left ventricular dysfunction mimicking myocardial infarction without coronary culprit lesion explaining the whole left ventricular dysfunction. Transient global amnesia (TGA) is characterized by sudden onset of anterograde amnesia without compromise of other neurologic functions. CASE REPORT: A 57 years old female was admitted because of sudden confusion and loss of her memory after emotional stress. TGA was diagnosed. Because of chest pain and laboratory tests indicating myocardial ischemia, she underwent coronary angiography which was normal. Within the following 24h her memory improved. She complained about severe vertigo and cerebral magnetic resonance imaging showed a recent ischemia in the left cerebellum. CONCLUSIONS: TGA is not a disease for the neurologists exclusively but also cardiac comorbidities have to be considered and cardiologists should be involved in the acute care of these patients in order not to overlook life-threatening diseases. PMID- 29720347 TI - A review of the use of direct oral anticoagulant use in orthotopic heart transplantation recipients. PMID- 29720348 TI - Impact of Adjuvant Radiotherapy in Node-positive Prostate Cancer Patients: The Importance of Patient Selection. AB - Using institutional data, we have previously developed an algorithm to identify the optimal candidates for adjuvant radiotherapy (aRT) among men with pN1 prostate cancer (PCa) at radical prostatectomy (RP). This study aimed to test the external validity of our previous findings using a nationwide database while focusing on overall mortality as an endpoint. To this end, we identified 5498 pN1 PCa patients who were treated with RP, pelvic lymph node dissection, and androgen deprivation therapy with or without aRT, within the National Cancer Database, between 2004 and 2015. Patients were divided into five groups based on our previously published algorithm. Similar to our previous report, multivariable Cox regression analysis showed that only two of these groups benefit from aRT: (1) those with one to two positive nodes, pathological Gleason score 7-10, and pT3b/4 disease or positive surgical margins (hazard ratio [HR]=0.75); and (2) those with three to four positive nodes, regardless of local tumor characteristics (HR=0.57, both p=0.01). In the remaining patients (25% of the cohort), aRT had no significant survival benefit. Results were confirmed on sensitivity analyses using 1:1 propensity score-matched cohorts, excluding men who died within 3 yr of surgery and using cut-off of 6 mo post-surgery to identify receipt of aRT. Our findings corroborate the validity of our previously published criteria and highlight the importance of patient selection in pN1 PCa patients who are considered for aRT. PMID- 29720349 TI - Exploiting polarity and chirality to probe the Hsp90 C-terminus. AB - Inhibition of the Hsp90 C-terminus is an attractive therapeutic approach for the treatment of cancer. Novobiocin, the first Hsp90 C-terminal inhibitor identified, contains a synthetically complex noviose sugar that has limited the generation of structure-activity relationships for this region of the molecule. The work described herein utilizes various ring systems as noviose surrogates to explore the size and nature of the surrounding binding pocket. PMID- 29720351 TI - A high prevalence of human papillomavirus 16 and 18 co-infections in cervical biopsies from southern Brazil. AB - HPV types 16 and 18 were studied in paraffin-fixed cervical biopsy collected in southern Brazil. HPV 16, HPV 18 and co-infection HPV 16/18 were identified in 10/57 (17.5%), 4/57 (7%) and in 43/57 (75.4%) samples, respectively. Southern Brazil has one of the highest prevalence rates of HPV 16/18 reported. PMID- 29720350 TI - Hospitalizations for asthma exacerbation in Chilean children: A multicenter observational study. AB - BACKGROUND: Asthma hospitalization rates in Chilean children have increased in the last 14 years, but little is known about the factors associated with this. OBJECTIVE: Describe clinical characteristics of children hospitalized for asthma exacerbation. METHODS: Observational prospective cohort study in 14 hospitals. Over a one-year period, children five years of age or older hospitalized with asthma exacerbation were eligible for inclusion. Parents completed an online questionnaire with questions on demographic information, about asthma, indoor environmental contaminant exposure, comorbidities and beliefs about disease and treatment. Disease control was assessed by the Asthma Control Test. Inhalation technique was observed using a checklist. RESULTS: 396 patients were enrolled. 168 children did not have an established diagnosis of asthma. Only 188 used at least one controller treatment at the time of hospitalization. 208 parents said they believed their child had asthma only when they had an exacerbation and 97 correctly identified inhaled corticosteroids as anti-inflammatory treatment. 342 patients used the wrong spacer and 73 correctly performed all steps of the checklist. CONCLUSIONS: Almost half of the patients were not diagnosed with asthma at the time of hospitalization despite having a medical history suggestive of the disease. In the remaining patients with an established diagnosis of asthma potentially modifiable factors like bad adherence to treatment and poor inhalation technique were found. Implementing a nationwide asthma program including continued medical education for the correct diagnosis and follow up of these patients and asthma education for patients and caregivers is needed to reduce asthma hospitalization rates in Chilean children. PMID- 29720352 TI - Bacteremia and meningitis caused by OXA-23-producing Acinetobacter baumannii - molecular characterization and susceptibility testing for alternative antibiotics. AB - BACKGROUND: Carbapenem-resistant Acinetobacter baumannii infection is a concern in developing countries due to high incidence, few therapeutic options, and increasing costs. OBJECTIVE: Characterize and analyze the antibiotic susceptibility patterns of carbapenem-resistant A. baumannii isolates and evaluate clinical data of meningitis and bacteremia caused by this microorganism. METHODS: Twenty-six A. baumannii isolates from 23 patients were identified by MALDI-TOF and automated methods and genotyped using pulsed field genotyping electrophoresis. Clinical data and outcomes were evaluated. Susceptibility of isolates to colistin, tigecycline, meropenem, imipenem, and doxycycline was determined. RESULTS: Mortality due to A. baumannii infections was 73.91%; all patients with meningitis and 7/8 patients with ventilator-associated pneumonia died. All isolates were susceptibility to polymyxin (100%; MIC50, MIC90: 1MUg/mL, 1MUg/mL) and colistin (100%; MIC50, MIC90: 2MUg/mL, 2MUg/mL), and 92% were susceptible to tigecycline (MIC50, MIC90: 1MUg/mL, 1MUg/mL) and doxycycline (MIC50, MIC90: 2MUg/mL, 2MUg/mL). blaOXA-23 was identified in 24 isolates. Molecular typing showed 8 different patterns: 13 isolates belonged to pattern A (50%). CONCLUSION: Carbapenem-resistant A. baumannii infections mortality is high. Alternative antimicrobial therapy (doxycycline) for selected patients with carbapenem-resistant A. baumannii infection should be considered. PMID- 29720353 TI - Autoimmune neuroretinopathy secondary to Zika virus infection. AB - CASE REPORT: A 40-year-old woman diagnosed with Zika virus infection 6 months before she arrived at this hospital. She referred to a progressive and painless vision loss, of 2 weeks onset after the infection diagnosis. She was treated with topical steroids. Previous visual acuity was recovered, but she still refers to reduced visual field and nyctalopia. Ophthalmologic examination revealed severe retinal sequels, compatible with autoimmune retinopathy. Based on the clinical features and the temporal relationship with Zika virus infection, non-para neoplastic autoimmune retinopathy was diagnosed and managed with steroids and infliximab. DISCUSSION: Zika virus can trigger a non-para-neoplastic autoimmune retinopathy. The diagnosis is based on clinical features, and requires early immunosuppressive therapy. PMID- 29720354 TI - Surface versus bulk activity of lysozyme deposited on hydrogel contact lens materials in vitro. AB - PURPOSE: To determine and compare the levels of surface versus bulk active lysozyme deposited on several commercially available hydrogel contact lens materials. METHODS: Hydrogel contact lens materials [polymacon, omafilcon A, nelfilcon A, nesofilcon A, ocufilcon and etafilcon A with polyvinylpyrrolidone (PVP)] were incubated in an artificial tear solution for 16 h. Total activity was determined using a standard turbidity assay. The surface activity of the deposited lysozyme was determined using a modified turbidity assay. The amount of active lysozyme present within the bulk of the lens material was calculated by determining the difference between the total and surface active lysozyme. RESULTS: The etafilcon A materials showed the highest amount of total lysozyme activity (519 +/- 8 MUg/lens, average of Moist and Define), followed by the ocufilcon material (200 +/- 5 MUg/lens) and these two were significantly different from each other (p < 0.05). The amount of surface active lysozyme on etafilcon and ocufilcon lens materials was significantly higher than that found on all other lenses (p < 0.05). There was no active lysozyme quantified in the bulk of the nelfilcon material, as all of the active lysozyme was found on the surface (1.7 +/- 0.3 MUg/lens). In contrast, no active lysozyme was quantified on the surface of polymacon, with all of the active lysozyme found in the bulk of the lens material (0.6 +/- 0.6 MUg/lens). CONCLUSIONS: The surface and bulk activity of lysozyme deposited on contact lenses is material dependent. Lysozyme deposited on ionic, high water content lens materials such as etafilcon A show significantly higher surface and bulk activity than many other hydrogel lens materials. PMID- 29720355 TI - Outcome of facial palsy from Lyme disease in prospectively followed patients who had received corticosteroids. AB - Although a short course of corticosteroid therapy has been shown to improve the outcome of idiopathic facial nerve palsy (Bell's palsy), it is unclear whether corticosteroids, in addition to antibiotic therapy, are beneficial, are harmful, or have no impact on the outcome of facial palsy from Lyme disease (LDFP). From 2011 through 2016, 14 patients with LDFP were enrolled into a prospective study to determine the outcome of Lyme disease over the ensuing 12 months. Eleven (78.6%) had received corticosteroids in addition to oral antibiotics and entered the study within 24 days after onset of the LDFP (median 14 days, range 2-24 days). Overall, 6 of the corticosteroid-treated patients (54.5%, 95% C.I.: 28.0% to 78.7%) had evidence of residual dysfunction of the facial nerve at the last evaluation, which occurred at a mean of 13.1 months after the baseline visit (range 9.6-19.6 months). In conclusion, although corticosteroids are frequently prescribed for LDFP, the efficacy of this therapy has not been established. Like another recent report, our study raises concern about the safety of adjunctive corticosteroid treatment for LDFP. A well-designed, prospective clinical trial is needed to determine the risk-to-benefit ratio of corticosteroid therapy for LDFP. PMID- 29720357 TI - A Mental Health Storytelling Intervention Using Transmedia to Engage Latinas: Grounded Theory Analysis of Participants' Perceptions of the Story's Main Character. AB - BACKGROUND: Transmedia storytelling was used to attract English-speaking Latina women with elevated symptoms of depression and anxiety to engage in an intervention that included videos and a webpage with links to symptom management resources. However, a main character for the storyline who was considered dynamic, compelling, and relatable by the target group was needed. OBJECTIVE: We conducted interviews with 28 English-speaking Latinas (target group) with elevated symptoms of depression or anxiety who participated in an Internet accessible transmedia storytelling intervention. The objective of this study was to examine participants' perceptions of the lead character of the story. Development of this character was informed by deidentified data from previous studies with members of the target group. Critique of the character from a panel of therapists informed editing, as did input from women of the target group. METHODS: All interviews were conducted via telephone, audio-recorded, and transcribed. Data analysis was guided by grounded theory methodology. RESULTS: Participants embraced the main character, Catalina, related to her as a person with an emotional life and a temporal reality, reported that they learned from her and wanted more episodes that featured her and her life. Grounded theory analysis led to the development of one category (She "just felt so real": relating to Catalina as a real person with a past, present, and future) with 4 properties. Properties included (1) relating emotionally to Catalina's vulnerability, (2) recognizing shared experiences, (3) needing to support others while simultaneously lacking self-support, and (4) using Catalina as a springboard for imagining alternative futures. Participants found Catalina's efforts to pursue mental health treatment to be meaningful and led them to compare themselves to her and consider how they might pursue treatment themselves. CONCLUSIONS: When creating a story-based mental health intervention to be delivered through an app, regardless of type, careful development of the main character is valuable. Theoretical guidance, previous deidentified data from the target group, critique from key stakeholders and members of the target group, and preliminary testing are likely to enhance the main character's relatability and appropriateness, which can increase sustained engagement. PMID- 29720358 TI - Translating Behavior Change Principles Into a Blended Exercise Intervention for Older Adults: Design Study. AB - BACKGROUND: Physical activity can prevent or delay age-related impairments and prolong the ability of older adults to live independently. Community-based programs typically offer classes where older adults can exercise only once a week under the guidance of an instructor. The health benefits of such programs vary. Exercise frequency and the duration of the program play a key role in realizing effectiveness. An auxiliary home-based exercise program can provide older adults the opportunity to exercise more regularly over a prolonged period of time in the convenience of their own homes. Furthermore, mobile electronic devices can be used to motivate and remotely guide older adults to exercise in a safe manner. Such a blended intervention, where technology is combined with personal guidance, needs to incorporate behavior change principles to ensure effectiveness. OBJECTIVE: The aim of this study was to identify theory-based components of a blended intervention that supports older adults to exercise at home. METHODS: The Medical Research Council framework was used to develop the blended intervention. Insights from focus group, expert panels, and literature were combined into leading design considerations. RESULTS: A client-server system had been developed that combined a tablet app with a database in the cloud and a Web-based dashboard that can be used by a personal coach to remotely monitor and guide older adults. The app contains several components that facilitate behavior change-an interactive module for goal setting, the ability to draw up a personal training schedule from a library containing over 50 exercise videos, progress monitoring, and possibilities to receive remote feedback and guidance of a personal coach. CONCLUSIONS: An evidence-based blended intervention was designed to promote physical activity among older adults. The underlying design choices were underpinned by behavior change techniques that are rooted in self-regulation. Key components of the tablet-supported intervention were a tailored program that accommodates individual needs, demonstrations of functional exercises, monitoring, and remote feedback. The blended approach combines the convenience of a home-based exercise program for older adults with the strengths of mobile health and personal guidance. PMID- 29720359 TI - Diffusion of the Digital Health Self-Tracking Movement in Canada: Results of a National Survey. AB - BACKGROUND: With the ever-increasing availability of mobile apps, consumer wearables, and smart medical devices, more and more individuals are self-tracking and managing their personal health data. OBJECTIVE: The aim of this study was to investigate the diffusion of the digital self-tracking movement in Canada. It provides a comprehensive, yet detailed account of this phenomenon. It examines the profile of digital self-trackers, traditional self-trackers, and nontrackers, further investigating the primary motivations for self-tracking and reasons for nontracking; barriers to adoption of connected care technologies; users' appreciation of their self-tracking devices, including what they perceive to be the main benefits; factors that influence people's intention to continue using connected care technologies in the future; and the reasons for usage discontinuance. METHODS: We conducted an online survey with a sample of 4109 Canadian adults, one of the largest ever. To ensure a representative sample, quota method was used (gender, age), following stratification by region. The maximum margin of error is estimated at 1.6%, 19 times out of 20. RESULTS: Our findings reveal that 66.20% (2720/4109) of our respondents regularly self-track one or more aspects of their health. About one in 4 respondents (1014/4109, 24.68%) currently owns a wearable or smart medical device, and 57.20% (580/1014) use their devices on a regular basis for self-tracking purposes. Digital self trackers are typically young or mature adults, healthy, employed, university educated, with an annual family income of over $80,000 CAD. The most popular reported device is the fitness tracker or smartwatch that can capture a range of parameters. Currently, mobile apps and digital self-tracking devices are mainly used to monitor physical activity (856/1669, 51.13%), nutrition (545/1669, 32.65%), sleep patterns (482/1669, 28.88%) and, to a much lesser extent, cardiovascular and pulmonary biomarkers (215/1669, 12.88%), medication intake (126/1669, 7.55%), and glucose level (79/1669, 4.73%). Most users of connected care technologies (481/580, 83.0%) are highly satisfied and 88.2% (511/580) intend to continue using their apps and devices in the future. A majority said smart digital devices have allowed them to maintain or improve their health condition (398/580, 68.5%) and to be better informed about their health in general (387/580, 66.6%). About 33.80% of our sample (1389/4109) is composed of people who do not monitor their health or well-being on a regular basis. CONCLUSIONS: Our study shows an opportunity to advance the health of Canadians through connected care technologies. Our findings can be used to set baseline information for future research on the rise of digital health self-tracking and its impacts. Although the use of mobile apps, consumer wearables, and smart medical devices could potentially benefit the growing population of patients with chronic conditions, the question remains as to whether it will diffuse broadly beyond early adopters and across cost inequities. PMID- 29720360 TI - Community Consultation for Planned Emergent Use Research: Experiences From an Academic Medical Center. AB - BACKGROUND: Emergent use research-research involving human subjects that have a life-threatening medical condition and who are unlikely to provide informed consent-in critical illness is fraught with challenges related to obtaining informed consent. Per federal regulations, to meet criteria to conduct such trials, the investigators have to seek community consultations. Effective ways of obtaining this consultation remains ill-defined. OBJECTIVE: We sought to describe methods, interpretations, and our experiences of conducting community consultation in a planned emergent use randomized controlled trial. METHODS: As part of a planned emergent use clinical trial in our study, community consultation consisted of four focus groups sessions with members from the community in which the clinical trial was conducted. Three focus group sessions were conducted with members who had an affiliation to Mayo Clinic, and the other focus group session was conducted with non-Mayo affiliation members. The feedback from the focus group sessions led to the creation of the public notification plan. The public was notified of the trial through community meetings as well as social media. RESULTS: As compared to community meetings, focus group sessions resulted in greater attendance with more interactive discussions. Moreover, focus group sessions resulted in greater in-depth conversations leading to institutional acceptance of the clinical trial under study. CONCLUSIONS: Exception from informed consent can be acceptable to the community. Focus groups provided better participation and valuable interactive insight as compared to community meetings in our study. This could serve as a valuable guide for investigators pursuing exception from informed consent in their research studies. PMID- 29720361 TI - Automated Modular Magnetic Resonance Imaging Clinical Decision Support System (MIROR): An Application in Pediatric Cancer Diagnosis. AB - BACKGROUND: Advances in magnetic resonance imaging and the introduction of clinical decision support systems has underlined the need for an analysis tool to extract and analyze relevant information from magnetic resonance imaging data to aid decision making, prevent errors, and enhance health care. OBJECTIVE: The aim of this study was to design and develop a modular medical image region of interest analysis tool and repository (MIROR) for automatic processing, classification, evaluation, and representation of advanced magnetic resonance imaging data. METHODS: The clinical decision support system was developed and evaluated for diffusion-weighted imaging of body tumors in children (cohort of 48 children, with 37 malignant and 11 benign tumors). Mevislab software and Python have been used for the development of MIROR. Regions of interests were drawn around benign and malignant body tumors on different diffusion parametric maps, and extracted information was used to discriminate the malignant tumors from benign tumors. RESULTS: Using MIROR, the various histogram parameters derived for each tumor case when compared with the information in the repository provided additional information for tumor characterization and facilitated the discrimination between benign and malignant tumors. Clinical decision support system cross-validation showed high sensitivity and specificity in discriminating between these tumor groups using histogram parameters. CONCLUSIONS: MIROR, as a diagnostic tool and repository, allowed the interpretation and analysis of magnetic resonance imaging images to be more accessible and comprehensive for clinicians. It aims to increase clinicians' skillset by introducing newer techniques and up-to-date findings to their repertoire and make information from previous cases available to aid decision making. The modular-based format of the tool allows integration of analyses that are not readily available clinically and streamlines the future developments. PMID- 29720362 TI - Team Resilience Training in the Workplace: E-Learning Adaptation, Measurement Model, and Two Pilot Studies. AB - BACKGROUND: The majority of resilience interventions focus on the individual. Workplace resilience is a growing field of research. Given the ever-increasing interconnectedness in businesses, teamwork is a guarantee. There is also growing recognition that resilience functions at the team level. OBJECTIVE: The objective of our work was to address three shortcomings in the study of workplace resilience interventions: lack of interventions focusing on group-level or team resilience, the need for brief interventions, and the need for more theoretical precision in intervention studies. METHODS: The authors took an established evidence-based program (Team Resilience) and modified it based on these needs. A working model for brief intervention evaluation distinguishes outcomes that are proximal (perceptions that the program improved resilience) and distal (dispositional resilience). A total of 7 hypotheses tested the model and program efficacy. RESULTS: Two samples (n=118 and n=181) of engineering firms received the Web-based training and provided immediate reactions in a posttest-only design. The second sample also included a control condition (n=201). The findings support the model and program efficacy. For example, workplace resilience was greater in the intervention group than in the control group. Other findings suggest social dissemination effects, equal outcomes for employees at different stress levels, and greater benefit for females. CONCLUSIONS: This preliminary research provides evidence for the capabilities of e-learning modules to effectively promote workplace resilience and a working model of team resilience. PMID- 29720363 TI - Users' Perspectives on mHealth Self-Management of Bipolar Disorder: Qualitative Focus Group Study. AB - BACKGROUND: Recent research indicates that current mHealth apps for bipolar disorders (BDs) show crucial shortcomings. They lack important functionality, are of inconsistent quality, and are insufficiently evidence-based. mHealth apps need to be better adapted to the needs of users. The perspectives of adult service users with BD regarding mHealth apps have not been well investigated. OBJECTIVE: The objective of this study was to examine the needs and expectations of adults with BD regarding mHealth apps. METHODS: Two focus group sessions were organized in which patients' views on self-management and design and functionality of an mHealth app for BD were assessed. During session 1, four focus groups were organized to identify users' needs regarding support for self-management. Session 2 contained three cocreation focus groups. Through this method, the desired functionality and design were explored. RESULTS: Participants indicated that they were in need of support in various ways. Not only support in psychoeducation, including daily routine, sleep pattern, maintaining social contacts, maintaining a healthy lifestyle, and avoidance of stimuli, was considered important for them but also gaining insight into their illness was found to be crucial. CONCLUSIONS: According to the participants, their illness-related information is a key factor in gaining insight into their mood pattern. Participants wanted a functional design that would increase daily use and prevent overstimulation. The results of this study should be taken into account when developing new mHealth apps. PMID- 29720364 TI - Monitoring Interest in Herpes Zoster Vaccination: Analysis of Google Search Data. AB - BACKGROUND: A new recombinant subunit vaccine for herpes zoster (HZ or shingles) was approved by the United States Food and Drug Administration on October 20, 2017 and is expected to replace the previous live attenuated vaccine. There have been low coverage rates with the live attenuated vaccine (Zostavax), ranging from 12-32% of eligible patients receiving the HZ vaccine. OBJECTIVE: This study aimed to provide insight into trends and potential reasons for interest in HZ vaccination. METHODS: Internet search data were queried from the Google Health application programming interface from 2004-2017. Seasonality of normalized search volume was analyzed using wavelets and Fisher's g test. RESULTS: The search terms "shingles vaccine," "zoster vaccine," and "zostavax" all exhibited significant periodicity in the fall months (P<.001), with sharp increases after recommendations for vaccination by public health-related organizations. Although the terms "shingles blisters," "shingles itch," "shingles rash," "skin rash," and "shingles medicine" exhibited statistically significant periodicities with a seasonal peak in the summer (P<.001), the terms "shingles contagious," "shingles pain," "shingles treatment," and "shingles symptoms" did not reveal an annual trend. CONCLUSIONS: There may be increased interest in HZ vaccination during the fall and after public health organization recommendations are broadcast. This finding points to the possibility that increased awareness of the vaccine through public health announcements could be evaluated as a potential intervention for increasing vaccine coverage. PMID- 29720365 TI - Web-Based Intervention for Women With Type 1 Diabetes in Pregnancy and Early Motherhood: Critical Analysis of Adherence to Technological Elements and Study Design. AB - BACKGROUND: Numerous Web-based interventions have been implemented to promote health and health-related behaviors in persons with chronic conditions. Using randomized controlled trials to evaluate such interventions creates a range of challenges, which in turn can influence the study outcome. Applying a critical perspective when evaluating Web-based health interventions is important. OBJECTIVE: The objective of this study was to critically analyze and discuss the challenges of conducting a Web-based health intervention as a randomized controlled trial. METHOD: The MODIAB-Web study was critically examined using an exploratory case study methodology and the framework for analysis offered through the Persuasive Systems Design model. Focus was on technology, study design, and Web-based support usage, with special focus on the forum for peer support. Descriptive statistics and qualitative content analysis were used. RESULTS: The persuasive content and technological elements in the design of the randomized controlled trial included all four categories of the Persuasive Systems Design model, but not all design principles were implemented. The study duration was extended to a period of four and a half years. Of 81 active participants in the intervention group, a maximum of 36 women were simultaneously active. User adherence varied greatly with a median of 91 individual log-ins. The forum for peer support was used by 63 participants. Although only about one-third of the participants interacted in the forum, there was a fairly rich exchange of experiences and advice between them. Thus, adherence in terms of social interactions was negatively affected by limited active participation due to prolonged recruitment process and randomization effects. Lessons learned from this critical analysis are that technology and study design matter and might mutually influence each other. In Web-based interventions, the use of design theories enables utilization of the full potential of technology and promotes adherence. The randomization element in a randomized controlled trial design can become a barrier to achieving a critical mass of user interactions in Web-based interventions, especially when social support is included. For extended study periods, the technology used may need to be adapted in line with newly available technical options to avoid the risk of becoming outdated in the user realm, which in turn might jeopardize study validity in terms of randomized controlled trial designs. CONCLUSIONS: On the basis of lessons learned in this randomized controlled trial, we give recommendations to consider when designing and evaluating Web-based health interventions. PMID- 29720367 TI - David Oliver: Learning from deaths in hospital. PMID- 29720366 TI - Studying Cannabis Use Behaviors With Facebook and Web Surveys: Methods and Insights. AB - The rapid and wide-reaching expansion of internet access and digital technologies offers epidemiologists numerous opportunities to study health behaviors. One particularly promising new data collection strategy is the use of Facebook's advertising platform in conjunction with Web-based surveys. Our research team at the Center for Technology and Behavioral Health has used this quick and cost efficient method to recruit large samples and address unique scientific questions related to cannabis use. In conducting this research, we have gleaned several insights for using this sampling method effectively and have begun to document the characteristics of the resulting data. We believe this information could be useful to other researchers attempting to study cannabis use or, potentially, other health behaviors. The first aim of this paper is to describe case examples of procedures for using Facebook as a survey sampling method for studying cannabis use. We then present several distinctive features of the data produced using this method. Finally, we discuss the utility of this sampling method for addressing specific types of epidemiological research questions. Overall, we believe that sampling with Facebook advertisements and Web surveys is best conceptualized as a targeted, nonprobability-based method for oversampling cannabis users across the United States. PMID- 29720368 TI - Margaret McCartney: Religion must defy the harms of futile medicine. PMID- 29720369 TI - Genomic Status of MET Potentiates Sensitivity to MET and MEK Inhibition in NF1 Related Malignant Peripheral Nerve Sheath Tumors. AB - Malignant peripheral nerve sheath tumors (MPNST) are highly resistant sarcomas that occur in up to 13% of individuals with neurofibromatosis type I (NF1). Genomic analysis of longitudinally collected tumor samples in a case of MPNST disease progression revealed early hemizygous microdeletions in NF1 and TP53, with progressive amplifications of MET, HGF, and EGFR To examine the role of MET in MPNST progression, we developed mice with enhanced MET expression and Nf1 ablation (Nf1fl/ko;lox-stop-loxMETtg/+;Plp-creERTtg/+ ; referred to as NF1-MET). NF1-MET mice express a robust MPNST phenotype in the absence of additional mutations. A comparison of NF1-MET MPNSTs with MPNSTs derived from Nf1ko/+;p53R172H;Plp-creERTtg/+ (NF1-P53) and Nf1ko/+;Plp-creERTtg/+ (NF1) mice revealed unique Met, Ras, and PI3K signaling patterns. NF1-MET MPNSTs were uniformly sensitive to the highly selective MET inhibitor, capmatinib, whereas a heterogeneous response to MET inhibition was observed in NF1-P53 and NF1 MPNSTs. Combination therapy of capmatinib and the MEK inhibitor trametinib resulted in reduced response variability, enhanced suppression of tumor growth, and suppressed RAS/ERK and PI3K/AKT signaling. These results highlight the influence of concurrent genomic alterations on RAS effector signaling and therapy response to tyrosine kinase inhibitors. Moreover, these findings expand our current understanding of the role of MET signaling in MPNST progression and identify a potential therapeutic niche for NF1-related MPNSTs.Significance: Longitudinal genomic analysis reveals a positive selection for MET and HGF copy number gain early in malignant peripheral nerve sheath tumor progression. Cancer Res; 78(13); 3672-87. (c)2018 AACR. PMID- 29720372 TI - Cross party approach to NHS and social care. PMID- 29720370 TI - Association of 25-Hydroxyvitamin D with Liver Cancer Incidence and Chronic Liver Disease Mortality in Finnish Male Smokers of the ATBC Study. AB - Background: Although circulating 25-hydroxyvitamin D [25(OH)D] concentrations were linked to liver cancer and chronic liver disease (CLD) in laboratory studies, few epidemiologic studies have addressed the associations.Methods: Within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study, we measured 25(OH)D in baseline serum of 202 incident liver cancer cases and 225 CLD deaths that occurred during nearly 25 years of follow-up, and 427 controls. ORs and 95% confidence intervals (CIs) were estimated using unconditional logistic regression. We examined predetermined clinically defined cut-points, and season specific and season-standardized quartiles.Results: Low serum 25(OH)D concentrations were associated with higher risk of liver cancer (<25 nmol/L vs. >=50 nmol/L: 1.98; 95% CI, 1.22-3.20; Ptrend across categories = 0.003) and CLD mortality (1.93; 95% CI, 1.23-3.03; Ptrend = 0.006) in models adjusted for age and date of blood draw. After additional adjustment for body mass index, diabetes, smoking, and other potential confounders, the association remained statistically significant for liver cancer (1.91; 95% CI, 1.16-3.15; Ptrend = 0.008), but was somewhat attenuated for CLD mortality (1.67; 95% CI, 1.02-2.75; Ptrend = 0.05). Associations were similar for analyses using season-specific and season-standardized quartiles, and after excluding participants with diabetes, or hepatitis B or C.Conclusions: Our results suggest a possible preventive role for vitamin D against liver cancer and CLD, although the importance of the liver for vitamin D metabolism and the lack of information about underlying liver disease makes reverse causality a concern.Impact: Future studies are needed to evaluate associations of vitamin D with liver cancer and liver disease in other populations, particularly those with a different constellation of risk factors. Cancer Epidemiol Biomarkers Prev; 27(9); 1075-82. (c)2018 AACR. PMID- 29720371 TI - Effect of public reporting of surgeons' outcomes on patient selection, "gaming," and mortality in colorectal cancer surgery in England: population based cohort study. AB - OBJECTIVE: To determine the effect of surgeon specific outcome reporting in colorectal cancer surgery on risk averse clinical practice, "gaming" of clinical data, and 90 day postoperative mortality. DESIGN: National cohort study. SETTING: English National Health Service hospital trusts. POPULATION: 111 431 patients diagnosed as having colorectal cancer from 1 April 2011 to 31 March 2015 included in the National Bowel Cancer Audit. INTERVENTION: Public reporting of surgeon specific 90 day mortality in elective colorectal cancer surgery in England introduced in June 2013. MAIN OUTCOME MEASURES: Proportion of patients with colorectal cancer who had an elective major resection, predicted 90 day mortality based on characteristics of patients and tumours, and observed 90 day mortality adjusted for differences in characteristics of patients and tumours, comparing patients who had surgery between April 2011 and June 2013 and between July 2013 and March 2015. RESULTS: The proportion of patients with colorectal cancer undergoing major resection did not change after the introduction of surgeon specific public outcome reporting (39 792/62 854 (63.3%) before versus 30 706/48 577 (63.2%) after; P=0.8). The proportion of these major resections categorised as elective or scheduled also did not change (33 638/39 792 (84.5%) before versus 25 905/30 706 (84.4%) after; P=0.5). The predicted 90 day mortality remained the same (2.7% v 2.7%; P=0.3), but the observed 90 day mortality fell (952/33 638 (2.8%) v 552/25 905 (2.1%)). Change point analysis showed that this reduction was over and above the existing downward trend in mortality before the introduction of public outcome reporting (P=0.03). CONCLUSIONS: This study did not find evidence that the introduction of public reporting of surgeon specific 90 day postoperative mortality in elective colorectal cancer surgery has led to risk averse clinical practice behaviour or "gaming" of data. However, its introduction coincided with a significant reduction in 90 day mortality. PMID- 29720373 TI - The 100 000 Genomes Project: bringing whole genome sequencing to the NHS. PMID- 29720376 TI - Dressings for venous leg ulcers. PMID- 29720377 TI - Analgesic effects of electroacupuncture at ST25 and CV12 in a rat model of postinflammatory irritable bowel syndrome visceral pain. AB - BACKGROUND: Treatment with electroacupuncture (EA) at ST25 and CV12 has a significant analgesic effect on postinflammatory irritable bowel syndrome (PI IBS) visceral pain. Enterochromaffin (EC) cells and serotonin (5 hydroxytryptamine (5-HT)) are important in the development of visceral hyperalgesia. OBJECTIVE: To investigate the analgesic effect and underlying mechanisms of EA at ST25 and CV12 on the treatment of trinitrobenzene sulfonic acid (TNBS)-induced PI-IBS visceral hyperalgesia in rats. METHODS: After EA at ST25 and CV12, changes in abdominal withdrawal reflex (AWR), electromyography (EMG) recordings, colonic EC cell numbers, and expression of tryptophan hydroxylase (TPH), 5-HT and 5-hydroxyindoleacetic acid (5-HIAA) of TNBS-induced PI-IBS visceral hyperalgesia in rats were examined. RESULTS: The results of AWR tests and EMG recordings indicated a significant analgesic effect of EA stimulation at ST25 and CV12on PI-IBS visceral hyperalgesia (p<0.05). In addition, the increased EC cell numbers and colonic expression of TPH and 5-HT in rats with TNBS-induced PI-IBS visceral hyperalgesia were significantly reduced by EA (p<0.05). CONCLUSIONS: EA stimulation at ST25 and CV12 can attenuate visceral hyperalgesia. This analgesic effect may be mediated via reduction of both colonic EC cell number and 5-HT concentration. PMID- 29720374 TI - Education plus exercise versus corticosteroid injection use versus a wait and see approach on global outcome and pain from gluteal tendinopathy: prospective, single blinded, randomised clinical trial. AB - OBJECTIVE: To compare the effects of a programme of load management education plus exercise, corticosteroid injection use, and no treatment on pain and global improvement in individuals with gluteal tendinopathy. DESIGN: Prospective, three arm, single blinded, randomised clinical trial. SETTING: Brisbane and Melbourne, Australia. PARTICIPANTS: Individuals aged 35-70 years, with lateral hip pain for more than three months, at least 4/10 on the pain numerical rating scale, and gluteal tendinopathy confirmed by clinical diagnosis and magnetic resonance imaging; and with no corticosteroid injection use in previous 12 months, current physiotherapy, total hip replacement, or neurological conditions. INTERVENTIONS: A physiotherapy led education and exercise programme of 14 sessions over eight weeks (EDX; n=69), one corticosteroid injection (CSI; n=66), and a wait and see approach (WS; n=69). MAIN OUTCOMES: Primary outcomes were patient reported global rating of change in hip condition (on an 11 point scale, dichotomised to success and non-success) and pain intensity in the past week (0=no pain, 10=worst pain) at eight weeks, with longer term follow-up at 52 weeks. RESULTS: Of 204 randomised participants (including 167 women; mean age 54.8 years (standard deviation 8.8)), 189 (92.6%) completed 52 week follow-up. Success on the global rating of change was reported at eight weeks by 51/66 EDX, 38/65 CSI, and 20/68 WS participants. EDX and CSI had better global improvement scores than WS (risk difference 49.1% (95% confidence interval 34.6% to 63.5%), number needed to treat 2.0 (95% confidence interval 1.6 to 2.9); 29.2% (13.2% to 45.2%), 3.4 (2.2 to 7.6); respectively). EDX had better global improvement scores than CSI (19.9% (4.7% to 35.0%); 5.0 (2.9 to 21.1)). At eight weeks, reported pain on the numerical rating scale was mean score 1.5 (standard deviation 1.5) for EDX, 2.7 (2.4) for CSI, and 3.8 (2.0) for WS. EDX and CSI participants reported less pain than WS (mean difference -2.2 (95% confidence interval -2.89 to -1.54); -1.2 ( 1.85 to -0.50); respectively), and EDX participants reported less pain than CSI ( 1.04 (-1.72 to -0.37)). Success on the global rating of change was reported at 52 weeks by 51/65 EDX, 36/63 CSI, and 31/60 WS participants; EDX was better than CSI (20.4% (4.9% to 35.9%); 4.9 (2.8 to 20.6)) and WS (26.8% (11.3% to 42.3%); 3.7 (2.4 to 8.8)). Reported pain at 52 weeks was 2.1 (2.2) for EDX, 2.3 (1.9) for CSI, and 3.2 (2.6) for WS; EDX did not differ from CSI (-0.26 (-1.06 to 0.55)), but both treatments did better than WS (1.13 (-1.93 to -0.33); 0.87 (-1.68 to 0.07); respectively). CONCLUSIONS: For gluteal tendinopathy, education plus exercise and corticosteroid injection use resulted in higher rates of patient reported global improvement and lower pain intensity than no treatment at eight weeks. Education plus exercise performed better than corticosteroid injection use. At 52 week follow-up, education plus exercise led to better global improvement than corticosteroid injection use, but no difference in pain intensity. These results support EDX as an effective management approach for gluteal tendinopathy. TRIAL REGISTRATION: Prospectively registered at the Australian New Zealand Clinical Trials Registry (ACTRN12612001126808). PMID- 29720378 TI - Immediate effects of acupuncture on the mechanosensitivity of the median nerve: an exploratory randomised trial. AB - BACKGROUND: Acupuncture appears to reduce the mechanosensitivity of peripheral nerves in animal models; yet, this possibility has not been demonstrated in humans. OBJECTIVES: The main objective of this exploratory trial was to evaluate the immediate effects of acupuncture on the mechanosensitivity of the median nerve, measured by the elbow extension range-of-motion (EE-ROM) at pain onset and maximum tolerance during the upper limb neurodynamic test 1 (ULNT1). Additional objectives were to test the effects of two different points in ULNT1 responses and critically appraise pre-/post-intervention changes for conducting future research. METHODS: Thirty-one asymptomatic individuals, randomly assigned to the PC group (n=14) or the LU group (n=17) by the coin flip procedure, underwent acupuncture (leopard spot needling) at PC5 or LU5'', respectively. Two-way mixed model analysis of variance (ANOVA) with time (pre-intervention vs post intervention) as the within-subject factor and group (PC vs LU) as the between subject factor, plus time*group interaction, were used to determine the effects of acupuncture therapy on EE-ROM at pain onset and maximum tolerance during ULNT1. RESULTS: At baseline there were no differences between groups (p>0.05). After acupuncture, mean EE-ROM increased 3.1 degrees at pain onset (p=0.029, eta2p=0.154) and 5.6 degrees at maximum tolerance (p=0.002, eta2p=0.277) with no differences between groups (p>0.05, eta2p<0.01). CONCLUSION: Immediately after acupuncture, the mechanosensitivity of the median nerve appears to be reduced as observed by an increase in EE-ROM during the ULNT1. Further studies are needed to confirm these preliminary findings. TRIAL REGISTRATION NUMBER: NCT02150915; Post results. PMID- 29720379 TI - Effectiveness of dry needling of rectus abdominis trigger points for the treatment of primary dysmenorrhoea: a randomised parallel-group trial. AB - OBJECTIVE: To compare the effectiveness of trigger point dry needling (TrP-DN) versus placebo needling, relative to an untreated control group, on pain and quality of life in primary dysmenorrhoea. METHODS: In this randomised, single blind, parallel-group trial, 56 females with primary dysmenorrhoea were randomly allocated to TrP-DN (n=19), placebo needling (n=18) or no treatment (n=19). Patients in both groups were asked to undertake a stretching exercise of the rectus abdominis daily. The needling group received a single session of TrP-DN to trigger points (TrPs) in the rectus abdominis, and the placebo group received placebo needling. The primary outcome was pain intensity (visual analogue scale). Secondary outcomes were quality of life, use of non-steroidal anti-inflammatory drugs, the number of days with pain, and self-perceived improvement, measured using a Global Rate of Change. Outcomes were assessed at baseline, and 1 and 2 months after the treatment. RESULTS: Females receiving TrP-DN exhibited greater decreases (P<0.001) in pain than those receiving placebo (1 month: Delta-19.8 mm, 25.9 to -13.7; 2 months: Delta-26.0 mm, -33.1 to -18.9) or assigned to the untreated control group (1 month: Delta-26.0mm, -32.5 to -19.5; 2 months: Delta 20.1 mm, -26.4 to -13.8). Females in the TrP-DN group also exhibited a greater decrease in the amount of medications (P<0.001). No differences in the number of days with pain or quality of life were found (all P>0.1). CONCLUSIONS: This trial suggests that a single session of TrP-DN of the rectus abdominis combined with stretching was more effective than placebo needling and stretching alone at reducing pain and the amount of medication used in primary dysmenorrhoea. TRIAL REGISTRATION NUMBER: ACTRN12616000170426 . PMID- 29720380 TI - CAR-T Cells Surface-Engineered with Drug-Encapsulated Nanoparticles Can Ameliorate Intratumoral T-cell Hypofunction. AB - One limiting factor of CAR T-cell therapy for treatment of solid cancers is the suppressive tumor microenvironment (TME), which inactivates the function of tumor infiltrating lymphocytes (TIL) through the production of immunosuppressive molecules, such as adenosine. Adenosine inhibits the function of CD4+ and CD8+ T cells by binding to and activating the A2a adenosine receptor (A2aR) expressed on their surface. This suppression pathway can be blocked using the A2aR-specific small molecule antagonist SCH-58261 (SCH), but its applications have been limited owing to difficulties delivering this drug to immune cells within the TME. To overcome this limitation, we used CAR-engineered T cells as active chaperones to deliver SCH-loaded cross-linked, multilamellar liposomal vesicles (cMLV) to tumor infiltrating T cells deep within the immune suppressive TME. Through in vitro and in vivo studies, we have demonstrated that this system can be used to effectively deliver SCH to the TME. This treatment may prevent or rescue the emergence of hypofunctional CAR-T cells within the TME. Cancer Immunol Res; 6(7); 812-24. (c)2018 AACR. PMID- 29720381 TI - Whole Exome and Transcriptome Analyses Integrated with Microenvironmental Immune Signatures of Lung Squamous Cell Carcinoma. AB - The immune microenvironment in lung squamous cell carcinoma (LUSC) is not well understood, with interactions between the host immune system and the tumor, as well as the molecular pathogenesis of LUSC, awaiting better characterization. To date, no molecularly targeted agents have been developed for LUSC treatment. Identification of predictive and prognostic biomarkers for LUSC could help optimize therapy decisions. We sequenced whole exomes and RNA from 101 tumors and matched noncancer control Korean samples. We used the information to predict subtype-specific interactions within the LUSC microenvironment and to connect genomic alterations with immune signatures. Hierarchical clustering based on gene expression and mutational profiling revealed subtypes that were either immune defective or immune competent. We analyzed infiltrating stromal and immune cells to further characterize the tumor microenvironment. Elevated expression of macrophage 2 signature genes in the immune competent subtype confirmed that tumor associated macrophages (TAM) linked inflammation and mutation-driven cancer. A negative correlation was evident between the immune score and the amount of somatic copy-number variation (SCNV) of immune genes (r = -0.58). The SCNVs showed a potential detrimental effect on immunity in the immune-deficient subtype. Knowledge of the genomic alterations in the tumor microenvironment could be used to guide design of immunotherapy options that are appropriate for patients with certain cancer subtypes. Cancer Immunol Res; 6(7); 848-59. (c)2018 AACR. PMID- 29720382 TI - Adherens junctions influence tight junction formation via changes in membrane lipid composition. AB - Tight junctions (TJs) are essential cell adhesion structures that act as a barrier to separate the internal milieu from the external environment in multicellular organisms. Although their major constituents have been identified, it is unknown how the formation of TJs is regulated. TJ formation depends on the preceding formation of adherens junctions (AJs) in epithelial cells; however, the underlying mechanism remains to be elucidated. In this study, loss of AJs in alpha-catenin-knockout (KO) EpH4 epithelial cells altered the lipid composition of the plasma membrane (PM) and led to endocytosis of claudins, a major component of TJs. Sphingomyelin with long-chain fatty acids and cholesterol were enriched in the TJ-containing PM fraction. Depletion of cholesterol abolished the formation of TJs. Conversely, addition of cholesterol restored TJ formation in alpha-catenin-KO cells. Collectively, we propose that AJs mediate the formation of TJs by increasing the level of cholesterol in the PM. PMID- 29720383 TI - Visual approach computation in feeding hoverflies. AB - On warm sunny days, female hoverflies are often observed feeding from a wide range of wild and cultivated flowers. In doing so, hoverflies serve a vital role as alternative pollinators, and are suggested to be the most important pollinators after bees and bumblebees. Unless the flower hoverflies are feeding from is large, they do not readily share the space with other insects, but instead opt to leave if another insect approaches. We used high-speed videography followed by 3D reconstruction of flight trajectories to quantify how female Eristalis hoverflies respond to approaching bees, wasps and two different hoverfly species. We found that, in 94% of the interactions, the occupant female left the flower when approached by another insect. We found that compared with spontaneous take-offs, the occupant hoverfly's escape response was performed at ~3 times higher speed (spontaneous take-off at 0.2+/-0.05 m s-1 compared with 0.55+/-0.08 m s-1 when approached by another Eristalis). The hoverflies tended to take off upward and forward, while taking the incomer's approach angle into account. Intriguingly, we found that, when approached by wasps, the occupant Eristalis took off at a higher speed and when the wasp was further away. This suggests that feeding hoverflies may be able to distinguish these predators, demanding impressive visual capabilities. Our results, including quantification of the visual information available before occupant take-off, provide important insight into how freely behaving hoverflies perform escape responses from competitors and predators (e.g. wasps) in the wild. PMID- 29720385 TI - Rates of pelvic inflammatory disease and ectopic pregnancy in Australia, 2009 2014: ecological analysis of hospital data. AB - OBJECTIVE: To analyse yearly rates of pelvic inflammatory disease (PID) and ectopic pregnancy (EP) diagnosed in hospital settings in Australia from 2009 to 2014. METHODS: We calculated yearly PID and EP diagnosis rates in three states (Victoria, New South Wales, Queensland) for women aged 15-44 years using hospital admissions and emergency department (ED) attendance data, with population and live birth denominators. We stratified PID diagnoses as chlamydial-related or gonorrhoeal-related (Chlamydia trachomatis (CT)-related or Neisseria gonorrhoeae (NG)-related), acute, unspecified and chronic, and analysed variations by year, age and residential area using Poisson regression models. RESULTS: For PID, the rate of all admissions in 2014 was 63.3 per 100 000 women (95% CI 60.8 to 65.9) and of all presentations in EDs was 97.0 per 100 000 women (95% CI 93.9 to 100.2). Comparing 2014 with 2009, the rate of all PID admissions did not change, but the rate of all presentations in EDs increased (adjusted incidence rate ratio (aIRR) 1.34, 95% CI 1.24 to 1.45), and for admissions by PID category was higher for CT-related or NG-related PID (aIRR 1.73, 95% CI 1.31 to 2.28) and unspecified PID (aIRR 1.09, 95% CI 1.00 to 1.19), and lower for chronic PID (aIRR 0.84, 95% CI 0.74 to 0.95). For EP, in 2014 the rate of all admissions was 17.4 (95% CI 16.9 to 17.9) per 1000 live births and of all ED presentations was 15.6 (95% CI 15.1 to 16.1). Comparing 2014 with 2009, the rates of all EP admissions (aIRR 1.06, 95% CI 1.04 to 1.08) and rates in EDs (aIRR 1.24, 95% CI 1.18 to 1.31) were higher. CONCLUSIONS: PID and EP remain important causes of hospital admissions for female STI-associated complications. Hospital EDs care for more PID cases than inpatient departments, particularly for young women. Updated primary care data are needed to better understand PID epidemiology and healthcare usage. PMID- 29720384 TI - Plasma Biomarkers of Inflammation and Angiogenesis Predict Cerebral Cavernous Malformation Symptomatic Hemorrhage or Lesional Growth. AB - RATIONALE: The clinical course of cerebral cavernous malformations is highly unpredictable, with few cross-sectional studies correlating proinflammatory genotypes and plasma biomarkers with prior disease severity. OBJECTIVE: We hypothesize that a panel of 24 candidate plasma biomarkers, with a reported role in the physiopathology of cerebral cavernous malformations, may predict subsequent clinically relevant disease activity. METHODS AND RESULTS: Plasma biomarkers were assessed in nonfasting peripheral venous blood collected from consecutive cerebral cavernous malformation subjects followed for 1 year after initial sample collection. A first cohort (N=49) was used to define the best model of biomarker level combinations to predict a subsequent symptomatic lesional hemorrhagic expansion within a year after the blood sample. We generated the receiver operating characteristic curves and area under the curve for each biomarker individually and each weighted linear combination of relevant biomarkers. The best model to predict lesional activity was selected as that minimizing the Akaike information criterion. In this cohort, 11 subjects experienced symptomatic lesional hemorrhagic expansion (5 bleeds and 10 lesional growths) within a year after the blood draw. Subjects had lower soluble CD14 (cluster of differentiation 14; P=0.05), IL (interleukin)-6 (P=0.04), and VEGF (vascular endothelial growth factor; P=0.0003) levels along with higher plasma levels of IL-1beta (P=0.008) and soluble ROBO4 (roundabout guidance receptor 4; P=0.03). Among the 31 weighted linear combinations of these 5 biomarkers, the best model (with the lowest Akaike information criterion value, 25.3) was the weighted linear combination including soluble CD14, IL-1beta, VEGF, and soluble ROBO4, predicting a symptomatic hemorrhagic expansion with a sensitivity of 86% and specificity of 88% (area under the curve, 0.90; P<0.0001). We then validated our best model in the second sequential independent cohort (N=28). CONCLUSIONS: This is the first study reporting a predictive association between plasma biomarkers and subsequent cerebral cavernous malformation disease clinical activity. This may be applied in clinical prognostication and stratification of cases in clinical trials. PMID- 29720386 TI - Criminalisation of HIV transmission: an overview for clinicians. PMID- 29720387 TI - MicroRNA-focused CRISPR-Cas9 library screen reveals fitness-associated miRNAs. AB - MicroRNAs (miRNAs) are post-transcriptional gene regulators that play important roles in the control of cell fitness, differentiation, and development. The CRISPR-Cas9 gene-editing system is composed of the Cas9 nuclease in complex with a single guide RNA (sgRNA) and directs DNA cleavage at a predetermined site. Several CRISPR-Cas9 libraries have been constructed for genome-scale knockout screens of protein function; however, few libraries have included miRNA genes. Here we constructed a miRNA-focused CRISPR-Cas9 library that targets 1594 (85%) annotated human miRNA stem-loops. The sgRNAs in our LX-miR library are designed to have high on-target and low off-target activity, and each miRNA is targeted by four to five sgRNAs. We used this sgRNA library to screen for miRNAs that affect cell fitness of HeLa or NCI-N87 cells by monitoring the change in frequency of each sgRNA over time. By considering the expression in the tested cells and the dysregulation of the miRNAs in cancer specimens, we identified five HeLa pro fitness and cervical cancer up-regulated miRNAs (miR-31-5p, miR-92b-3p, miR-146b 5p, miR-151a-3p, and miR-194-5p). Similarly, we identified six NCI-N87 pro fitness and gastric cancer up-regulated miRNAs (miR-95-3p, miR-181a-5p, miR-188 5p, miR-196b-5p, miR-584-5p, and miR-1304-3p), as well as three anti-fitness and down-regulated miRNAs (let-7a-3p, miR-100-5p, and miR-149-5p). Some of those miRNAs are known to be oncogenic or tumor-suppressive, but others are novel. Taken together, the LX-miR library is useful for genome-wide unbiased screening to identify miRNAs important for cellular fitness and likely to be useful for other functional screens. PMID- 29720389 TI - Access to radical resections of pancreatic cancer is region-dependent despite the public healthcare system in Finland. AB - BACKGROUND: Surgical resection is the best treatment option to improve the prognosis of pancreatic cancer (PC). Our aim was to analyse whether PC treatment strategies show regional variation in Finland, a country with a nationwide public healthcare system. METHODS: All patients diagnosed with PC in 2003 and 2008 were identified from the Finnish Cancer Registry. The data regarding tumour, treatment, demographics and timespans to treatment were recorded from the patient archives. Patients were included in the healthcare district where the diagnosis was made. The healthcare districts were classified according to experience in pancreatic surgery into three groups (high level of experience region (HLER), n=2; medium level of experience region (MLER), n=6, and low level of experience region (LLER), n=13). RESULTS: Patients included numbered 1546 (median age 72 years (range 34-97), 45% men). Demographics and the ratio of stage IV disease (53%) were similar between the regional groups. Despite this, the proportion of radical surgery was greater in HLERs than in the MLERs and LLERs (18% vs 8%-11%; p<0.01). Logistic regression analysis including age, American Society of Anesthesiologists classification, stage and level of experience showed that more radical resections were performed in the HLERs. Preoperative bile drainage showed no regional differences (p=0.137). Palliative chemotherapy only was used more frequently in MLER and LLER than in HLERs (24% vs 33%-30%; p<0.01). CONCLUSION: Access to PC curative treatment was more likely for patients in healthcare districts including a hospital with high level of experience in pancreatic surgery. This highlights the importance of centralized treatment guidance. PMID- 29720390 TI - Inequities in exposure to occupational risk factors between Maori and non-Maori workers in Aotearoa New Zealand. AB - BACKGROUND: Health inequities between indigenous and non-indigenous people are well documented. However, the contribution of differential exposure to risk factors in the occupational environment remains unclear. This study assessed differences in the prevalence of self-reported exposure to disease risk factors, including dust and chemicals, physical factors and organisational factors, between Maori and non-Maori workers in New Zealand. METHODS: Potential participants were sampled from the New Zealand electoral rolls and invited to take part in a telephone interview, which included questions about current workplace exposures. Logistic regression, accounting for differences in age, socioeconomic status and occupational distribution between Maori and non-Maori, was used to assess differences in exposures. RESULTS: In total, 2344 Maori and 2710 non-Maori participants were included in the analyses. Maori had greater exposure to occupational risk factors than non-Maori. For dust and chemical exposures, the main differences related to Maori working in occupations where these exposures are more common. However, even within the same job, Maori were more likely to be exposed to physical factors such as heavy lifting and loud noise, and organisational factors such as carrying out repetitive tasks and working to tight deadlines compared with non-Maori. CONCLUSIONS: This is one of the first studies internationally to compare occupational risk factors between indigenous and non-indigenous people. These findings suggest that the contribution of the occupational environment to health inequities between Maori and non-Maori has been underestimated and that work tasks may be unequally distributed according to ethnicity. PMID- 29720392 TI - Activation of Self-Incompatibility Signaling in Transgenic Arabidopsis thaliana Is Independent of AP2-Based Clathrin-Mediated Endocytosis. AB - Internalization of plasma membrane (PM)-localized ligand-activated receptor kinases and their trafficking to sorting endosomes have traditionally been viewed as functioning primarily in the down-regulation of receptor signaling, but are now considered to be also essential for signaling by some receptors. A major mechanism for internalization of PM proteins is clathrin-mediated endocytosis (CME). CME is mediated by the Adaptor Protein Complex 2 (AP2), which is involved in interaction of the AP2 MU-adaptin subunit with a tyrosine-based Yxxphi motif located in the cytoplasmic domain of the cargo protein. In this study, we investigated the role of AP2-mediated CME for signaling by the S-locus receptor kinase (SRK), a protein localized in the PM of stigma epidermal cells, which, together with its pollen coat-localized S-locus cysteine-rich (SCR) ligand, functions in the self-incompatibility (SI) response of the Brassicaceae. Using Arabidopsis thaliana plants that were made self-incompatible by transformation with an A. lyrata-derived SRK/SCR gene pair, we tested the effect on SI of site directed mutations in each of the two Yxxphi motifs in SRK and of a CRISPR/Cas9 induced null mutation in the AP2 MU-adaptin gene AP2M Both in vitro SRK kinase activity and the in planta SI response were abolished by substitution of tyrosine in one of the two Yxxphi motifs, but were unaffected by elimination of either the second Yxxphi motif or AP2M function. Thus, AP2-mediated CME is considered to be unnecessary for SRK signaling in the SI response. PMID- 29720388 TI - Scavenger receptor B type 1: expression, molecular regulation, and cholesterol transport function. AB - Cholesterol is required for maintenance of plasma membrane fluidity and integrity and for many cellular functions. Cellular cholesterol can be obtained from lipoproteins in a selective pathway of HDL-cholesteryl ester (CE) uptake without parallel apolipoprotein uptake. Scavenger receptor B type 1 (SR-B1) is a cell surface HDL receptor that mediates HDL-CE uptake. It is most abundantly expressed in liver, where it provides cholesterol for bile acid synthesis, and in steroidogenic tissues, where it delivers cholesterol needed for storage or steroidogenesis in rodents. SR-B1 transcription is regulated by trophic hormones in the adrenal gland, ovary, and testis; in the liver and elsewhere, SR-B1 is subject to posttranscriptional and posttranslational regulation. SR-B1 operates in several metabolic processes and contributes to pathogenesis of atherosclerosis, inflammation, hepatitis C virus infection, and other conditions. Here, we summarize characteristics of the selective uptake pathway and involvement of microvillar channels as facilitators of selective HDL-CE uptake. We also present the potential mechanisms of SR-B1-mediated selective cholesterol transport; the transcriptional, posttranscriptional, and posttranslational regulation of SR-B1; and the impact of gene variants on expression and function of human SR-B1. A better understanding of this unique pathway and SR-B1's role may yield improved therapies for a wide variety of conditions. PMID- 29720391 TI - Tissue-Specific Functions of fem-2/PP2c Phosphatase and fhod-1/formin During Caenorhabditis elegans Embryonic Morphogenesis. AB - The cytoskeleton is the basic machinery that drives many morphogenetic events. Elongation of the C. elegans embryo from a spheroid into a long, thin larva initially results from actomyosin contractility, mainly in the lateral epidermal seam cells, while the corresponding dorsal and ventral epidermal cells play a more passive role. This is followed by a later elongation phase involving muscle contraction. Early elongation is mediated by parallel genetic pathways involving LET-502/Rho kinase and MEL-11/MYPT myosin phosphatase in one pathway and FEM 2/PP2c phosphatase and PAK-1/p21 activated kinase in another. While the LET 502/MEL-11 pathway appears to act primarily in the lateral epidermis, here we show that FEM-2 can mediate early elongation when expressed in the dorsal and ventral epidermis. We also investigated the early elongation function of FHOD-1, a member of the formin family of actin nucleators and bundlers. Previous work showed that FHOD-1 acts in the LET-502/MEL-11 branch of the early elongation pathway as well as in muscle for sarcomere organization. Consistent with this, we found that lateral epidermal cell-specific expression of FHOD-1 is sufficient for elongation, and FHOD-1 effects on elongation appear to be independent of its role in muscle. Also, we found that fhod-1 encodes long and short isoforms that differ in the presence of a predicted coiled-coil domain. Based on tissue-specific expression constructions and an isoform-specific CRISPR allele, the two FHOD-1 isoforms show partially specialized epidermal or muscle function. Although fhod-1 shows only impenetrant elongation phenotypes, we were unable to detect redundancy with other C. elegans formin genes. PMID- 29720393 TI - Sex Determination in Ceratopteris richardii Is Accompanied by Transcriptome Changes That Drive Epigenetic Reprogramming of the Young Gametophyte. AB - The fern Ceratopteris richardii is an important model for studies of sex determination and gamete differentiation in homosporous plants. Here we use RNA seq to de novo assemble a transcriptome and identify genes differentially expressed in young gametophytes as their sex is determined by the presence or absence of the male-inducing pheromone called antheridiogen. Of the 1,163 consensus differentially expressed genes identified, the vast majority (1,030) are up-regulated in gametophytes treated with antheridiogen. GO term enrichment analyses of these DEGs reveals that a large number of genes involved in epigenetic reprogramming of the gametophyte genome are up-regulated by the pheromone. Additional hormone response and development genes are also up regulated by the pheromone. This C. richardii gametophyte transcriptome and gene expression dataset will prove useful for studies focusing on sex determination and differentiation in plants. PMID- 29720395 TI - Pulmonary arterial hypertension in adult congenital heart disease. AB - Pulmonary arterial hypertension (PAH) is commonly associated with congenital heart disease (CHD) and relates to type of the underlying cardiac defects and repair history. Large systemic to pulmonary shunts may develop PAH if untreated or repaired late. PAH, when present, markedly increases morbidity and mortality in patients with CHD. Significant progress has been made for patients with Eisenmenger syndrome in pathophysiology, prognostication and disease-targeting therapy (DTT), which needs to be applied to routine patient care. Patients with PAH-CHD and systemic to pulmonary shunting may benefit from late defect closure if pulmonary vascular resistance (PVR) is still normal or near normal. Patients with PAH and coincidental defects, or previous repair of CHD should be managed as those with idiopathic PAH. Patients with a Fontan circulation, despite not strictly fulfilling criteria for PAH, may have elevated PVR; recent evidence suggests that they may also benefit from DTT, but more data are required before general recommendations can be made. CHD-PAH is a lifelong, progressive disease; patients should receive tertiary care and benefit from a proactive DTT approach. Novel biomarkers and genetic advances may identify patients with CHD who should be referred for late defect closure and/or patients at high risk of developing PAH despite early closure in childhood. Ongoing vigilance for PAH and further controlled studies are clearly warranted in CHD. PMID- 29720394 TI - Tissue-Specific Transcriptome for Poeciliopsis prolifica Reveals Evidence for Genetic Adaptation Related to the Evolution of a Placental Fish. AB - The evolution of the placenta is an excellent model to examine the evolutionary processes underlying adaptive complexity due to the recent, independent derivation of placentation in divergent animal lineages. In fishes, the family Poeciliidae offers the opportunity to study placental evolution with respect to variation in degree of post-fertilization maternal provisioning among closely related sister species. In this study, we present a detailed examination of a new reference transcriptome sequence for the live-bearing, matrotrophic fish, Poeciliopsis prolifica, from multiple-tissue RNA-seq data. We describe the genetic components active in liver, brain, late-stage embryo, and the maternal placental/ovarian complex, as well as associated patterns of positive selection in a suite of orthologous genes found in fishes. Results indicate the expression of many signaling transcripts, "non-coding" sequences and repetitive elements in the maternal placental/ovarian complex. Moreover, patterns of positive selection in protein sequence evolution were found associated with live-bearing fishes, generally, and the placental P. prolifica, specifically, that appear independent of the general live-bearer lifestyle. Much of the observed patterns of gene expression and positive selection are congruent with the evolution of placentation in fish functionally converging with mammalian placental evolution and with the patterns of rapid evolution facilitated by the teleost-specific whole genome duplication event. PMID- 29720396 TI - Primary repair versus surgical and transcatheter palliation in infants with tetralogy of Fallot. AB - OBJECTIVES: Treatment of infants with tetralogy of Fallot (ToF) has evolved in the last two decades with increasing use of primary surgical repair (PrR) and transcatheter right ventricular outflow tract palliation (RVOTd), and fewer systemic-to-pulmonary shunts (SPS). We aim to report contemporary results using these treatment options in a comparative study. METHODS: This a retrospective study using data from the UK National Congenital Heart Disease Audit. All infants (n=1662, median age 181 days) with ToF and no other complex defects undergoing repair or palliation between 2000 and 2013 were considered. Matching algorithms were used to minimise confounding due to lower age and weight in those palliated. RESULTS: Patients underwent PrR (n=1244), SPS (n=311) or RVOTd (n=107). Mortality at 12 years was higher when repair or palliation was performed before the age of 60 days rather than after, most significantly for primary repair (18.7% vs 2.2%, P<0.001), less so for RVOTd (10.8% vs 0%, P=0.06) or SPS (12.4% vs 8.3%, P=0.2). In the matched groups of patients, RVOTd was associated with more right ventricular outflow tract (RVOT) reinterventions (HR=2.3, P=0.05 vs PrR, HR=7.2, P=0.001 vs SPS) and fewer pulmonary valve replacements (PVR) (HR=0.3 vs PrR, P=0.05) at 12 years, with lower mortality after complete repair (HR=0.2 versus PrR, P=0.09). CONCLUSIONS: We found that RVOTd was associated with more RVOT reinterventions, fewer PVR and fewer deaths when compared with PrR in comparable, young infants, especially so in those under 60 days at the time of the first procedure. PMID- 29720397 TI - Increased long QT and torsade de pointes reporting on tamoxifen compared with aromatase inhibitors. AB - OBJECTIVE: A prolonged QTc (LQT) is a surrogate for the risk of torsade de pointes (TdP). QTc interval duration is influenced by sex hormones: oestradiol prolongs and testosterone shortens QTc. Drugs used in the treatment of breast cancer have divergent effects on hormonal status. METHODS: We performed a disproportionality analysis using the European database of suspected adverse drug reaction (ADR) reports to evaluate the reporting OR (ROR chi2) of LQT, TdP and ventricular arrhythmias associated with selective oestrogen receptor modulators (SERMs: tamoxifen and toremifene) as opposed to aromatase inhibitors (AIs: anastrozole, exemestane and letrozole). When the proportion of an ADR is greater in patients exposed to a drug (SERMs) compared with patients exposed to control drug (AIs), this suggests an association between the specific drug and the reaction and is a potential signal for safety. Clinical and demographic characterisation of patients with SERMs-induced LQT and ventricular arrhythmias was performed. RESULTS: SERMs were associated with higher proportion of LQT reports versus AIs (26/8318 vs 11/14851, ROR: 4.2 (2.11-8.55), p<0.001). SERMs were also associated with higher proportion of TdP and ventricular arrhythmia reports versus AIs (6/8318 vs 2/14851, ROR: 5.4 (1.29-26.15), p:0.02; 16/8318 vs 12/14851, ROR: 2.38 (1.15-4.94), p:0.02, respectively). Mortality was 38% in patients presenting ventricular arrhythmias associated with SERMs. CONCLUSIONS: SERMs are associated with more reports of drug-induced LQT, TdP and ventricular arrhythmias compared with AIs. This finding is consistent with oestradiol-like properties of SERMs on the heart as opposed to effects of oestrogen deprivation and testosterone increase induced by AIs. TRIAL REGISTRATION NUMBER: NCT03259711. PMID- 29720398 TI - Crystal structures of the human 4-1BB receptor bound to its ligand 4-1BBL reveal covalent receptor dimerization as a potential signaling amplifier. AB - Human (h)4-1BB (TNFRSF9 or CD137) is an inducible tumor necrosis factor receptor (TNFR) superfamily member that interacts with its cognate ligand h4-1BBL to promote T lymphocyte activation and proliferation. h4-1BB is currently being targeted with agonists in cancer immunotherapy. Here, we determined the crystal structures of unbound h4-1BBL and both WT h4-1BB and a dimerization-deficient h4 1BB mutant (C121S) in complex with h4-1BBL at resolutions between 2.7 and 3.2 A. We observed that the structural arrangement of 4-1BBL, both unbound and in the complex, represents the canonical bell shape as seen in other similar TNF proteins and differs from the previously reported three-bladed propeller structure of 4-1BBL. We also found that the binding site for the receptor is at the crevice formed between two protomers of h4-1BBL, but that h4-1BB interacts predominantly with only one ligand protomer. Moreover, h4-1BBL lacked the conserved tyrosine residue in the DE loop that forms canonical interactions between other TNFR family molecules and their ligands, suggesting h4-1BBL engages h4-1BB through a distinct mechanism. Of note, we discovered that h4-1BB forms a disulfide-linked dimer because of the presence of an additional cysteine residue found in its cysteine-rich domain 4 (CRD4). As a result, h4-1BB dimerization, in addition to trimerization via h4-1BBL binding, could result in cross-linking of individual ligand-receptor complexes to form a 2D network that stimulates strong h4-1BB signaling. This work provides critical insights into the structural and functional properties of both h4-1BB and h4-1BBL and reveals that covalent receptor dimerization amplifies h4-1BB signaling. PMID- 29720399 TI - Crystal structure of the human 4-1BB/4-1BBL complex. AB - 4-1BBL is a member of the tumor necrosis factor (TNF) superfamily and is the ligand for the TNFR superfamily receptor, 4-1BB. 4-1BB plays an immunomodulatory role in T cells and NK cells, and agonists of this receptor have garnered strong attention as potential immunotherapy agents. Broadly speaking, the structural features of TNF superfamily members, their receptors, and ligand-receptor complexes are similar. However, a published crystal structure of human 4-1BBL suggests that it may be unique in this regard, exhibiting a three-bladed propeller-like trimer assembly that is distinctly different from that observed in other family members. This unusual structure also suggests that the human 4-1BB/4 1BBL complex may be structurally unique within the TNF/TNFR superfamily, but to date no structural data have been reported. Here we report the crystal structure of the human 4-1BB/4-1BBL complex at 2.4-A resolution. In this structure, 4-1BBL does not adopt the unusual trimer assembly previously reported, but instead forms a canonical bell-shaped trimer typical of other TNF superfamily members. The structure of 4-1BB is also largely canonical as is the 4-1BB/4-1BBL complex. Mutational data support the 4-1BBL structure reported here as being biologically relevant, suggesting that the previously reported structure is not. Together, the data presented here offer insight into structure/function relationships in the 4 1BB/4-1BBL system and improve our structural understanding of the TNF/TNFR superfamily more broadly. PMID- 29720400 TI - Interferon regulatory factor 1 and a variant of heterogeneous nuclear ribonucleoprotein L coordinately silence the gene for adhesion protein CEACAM1. AB - The adhesion protein carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) is widely expressed in epithelial cells as a short cytoplasmic isoform (S-iso) and in leukocytes as a long cytoplasmic isoform (L-iso) and is frequently silenced in cancer by unknown mechanisms. Previously, we reported that interferon response factor 1 (IRF1) biases alternative splicing (AS) to include the variable exon 7 (E7) in CEACAM1, generating long cytoplasmic isoforms. We now show that IRF1 and a variant of heterogeneous nuclear ribonucleoprotein L (Lv1) coordinately silence the CEACAM1 gene. RNAi-mediated Lv1 depletion in IRF1 treated HeLa and melanoma cells induced significant CEACAM1 protein expression, reversed by ectopic Lv1 expression. The Lv1-mediated CEACAM1 repression resided in residues Gly71-Gly89 and Ala38-Gly89 in Lv1's N-terminal extension. ChIP analysis of IRF1- and FLAG-tagged Lv1-treated HeLa cells and global treatment with the global epigenetic modifiers 5-aza-2'-deoxycytidine and trichostatin A indicated that IRF1 and Lv1 together induce chromatin remodeling, restricting IRF1 access to the CEACAM1 promoter. In interferon gamma-treated HeLa cells, the transcription factor SP1 did not associate with the CEACAM1 promoter, but binding by upstream transcription factor 1 (USF1), a known CEACAM1 regulator, was greatly enhanced. ChIP-sequencing revealed that Lv1 overexpression in IRF1-treated cells induces transcriptional silencing across many genes, including DCC (deleted in colorectal carcinoma), associated with CEACAM5 in colon cancer. Notably, IRF1, but not IRF3 and IRF7, affected CEACAM1 expression via translational repression. We conclude that IRF1 and Lv1 coordinately regulate CEACAM1 transcription, alternative splicing, and translation and may significantly contribute to CEACAM1 silencing in cancer. PMID- 29720401 TI - Methionine biosynthesis and transport are functionally redundant for the growth and virulence of Salmonella Typhimurium. AB - Methionine (Met) is an amino acid essential for many important cellular and biosynthetic functions, including the initiation of protein synthesis and S adenosylmethionine-mediated methylation of proteins, RNA, and DNA. The de novo biosynthetic pathway of Met is well conserved across prokaryotes but absent from vertebrates, making it a plausible antimicrobial target. Using a systematic approach, we examined the essentiality of de novo methionine biosynthesis in Salmonella enterica serovar Typhimurium, a bacterial pathogen causing significant gastrointestinal and systemic diseases in humans and agricultural animals. Our data demonstrate that Met biosynthesis is essential for S. Typhimurium to grow in synthetic medium and within cultured epithelial cells where Met is depleted in the environment. During systemic infection of mice, the virulence of S. Typhimurium was not affected when either de novo Met biosynthesis or high affinity Met transport was disrupted alone, but combined disruption in both led to severe in vivo growth attenuation, demonstrating a functional redundancy between de novo biosynthesis and acquisition as a mechanism of sourcing Met to support growth and virulence for S. Typhimurium during infection. In addition, our LC-MS analysis revealed global changes in the metabolome of S. Typhimurium mutants lacking Met biosynthesis and also uncovered unexpected interactions between Met and peptidoglycan biosynthesis. Together, this study highlights the complexity of the interactions between a single amino acid, Met, and other bacterial processes leading to virulence in the host and indicates that disrupting the de novo biosynthetic pathway alone is likely to be ineffective as an antimicrobial therapy against S. Typhimurium. PMID- 29720402 TI - Structural characterization of the P1+ intermediate state of the P-cluster of nitrogenase. AB - Nitrogenase is the enzyme that reduces atmospheric dinitrogen (N2) to ammonia (NH3) in biological systems. It catalyzes a series of single-electron transfers from the donor iron protein (Fe protein) to the molybdenum-iron protein (MoFe protein) that contains the iron-molybdenum cofactor (FeMo-co) sites where N2 is reduced to NH3 The P-cluster in the MoFe protein functions in nitrogenase catalysis as an intermediate electron carrier between the external electron donor, the Fe protein, and the FeMo-co sites of the MoFe protein. Previous work has revealed that the P-cluster undergoes redox-dependent structural changes and that the transition from the all-ferrous resting (PN) state to the two-electron oxidized P2+ state is accompanied by protein serine hydroxyl and backbone amide ligation to iron. In this work, the MoFe protein was poised at defined potentials with redox mediators in an electrochemical cell, and the three distinct structural states of the P-cluster (P2+, P1+, and PN) were characterized by X-ray crystallography and confirmed by computational analysis. These analyses revealed that the three oxidation states differ in coordination, implicating that the P1+ state retains the serine hydroxyl coordination but lacks the backbone amide coordination observed in the P2+ states. These results provide a complete picture of the redox-dependent ligand rearrangements of the three P-cluster redox states. PMID- 29720403 TI - Urokinase-type plasminogen activator (uPA) promotes ezrin-mediated reorganization of the synaptic cytoskeleton in the ischemic brain. AB - Synaptic repair in the ischemic brain is a complex process that requires reorganization of the actin cytoskeleton. Ezrin, radixin, and moesin (ERM) are a group of evolutionarily conserved proteins that link the plasma membrane to the actin cytoskeleton and act as scaffolds for signaling transduction. Urokinase type plasminogen activator (uPA) is a serine proteinase that upon binding to the urokinase-type plasminogen activator receptor (uPAR) catalyzes the conversion of plasminogen into plasmin on the cell surface and activates intracellular signaling pathways. Early studies indicate that uPA and uPAR expression increase during the recovery phase from an ischemic stroke and that uPA binding to uPAR promotes neurorepair in the ischemic brain. The in vitro and in vivo studies presented here show that either the release of neuronal uPA or treatment with recombinant uPA induces the local synthesis of ezrin in the synapse and the recruitment of beta3-integrin to the postsynaptic density (PSD) of cerebral cortical neurons by a plasminogen-independent mechanism. We found that beta3 integrin has a double effect on ezrin, inducing its recruitment to the PSD via the intercellular adhesion molecule-5 (ICAM-5) and its subsequent activation by phosphorylation at Thr-567. Finally, our data indicate that by triggering the reorganization of the actin cytoskeleton in the postsynaptic terminal, active ezrin induces the recovery of dendritic spines and synapses that have been damaged by an acute ischemic stroke. In summary, our data show that uPA-uPAR binding promotes synaptic repair in the ischemic brain via ezrin-mediated reorganization of the actin cytoskeleton in the postsynaptic terminal. PMID- 29720405 TI - Smad4/DPC4. AB - Smad4 or DPC4 belongs to a family of signal transduction proteins that are phosphorylated and activated by transmembrane serine-threonine receptor kinases in response to transforming growth factor beta (TGF-beta) signaling via several pathways. The gene acts as a tumour suppressor gene and inactivation of smad4/DPC4 is best recognised in pancreatic cancer. However, smad4/DPC4 is also mutated in other conditions and cancers such as juvenile polyposis syndrome with and without hereditary haemorrhagic telangiectasia, colorectal and prostate cancers.Immunohistochemistry for smad4/DPC4 protein is most useful in separating benign/reactive conditions from pancreatic cancer in needle/core biopsies. In normal and reactive states, the protein is localised to the cytoplasm and nucleus, while the protein is lost in high-grade pancreatic intraepithelial neoplasia/carcinoma in situ and pancreatic cancer. PMID- 29720404 TI - Toward a mechanistic and physiological understanding of a ferredoxin:disulfide reductase from the domains Archaea and Bacteria. AB - Disulfide reductases reduce other proteins and are critically important for cellular redox signaling and homeostasis. Methanosarcina acetivorans is a methane producing microbe from the domain Archaea that produces a ferredoxin:disulfide reductase (FDR) for which the crystal structure has been reported, yet its biochemical mechanism and physiological substrates are unknown. FDR and the extensively characterized plant-type ferredoxin:thioredoxin reductase (FTR) belong to a distinct class of disulfide reductases that contain a unique active site [4Fe-4S] cluster. The results reported here support a mechanism for FDR similar to that reported for FTR with notable exceptions. Unlike FTR, FDR contains a rubredoxin [1Fe-0S] center postulated to mediate electron transfer from ferredoxin to the active-site [4Fe-4S] cluster. UV-visible, EPR, and Mossbauer spectroscopic data indicated that two-electron reduction of the active site disulfide in FDR involves a one-electron-reduced [4Fe-4S]1+ intermediate previously hypothesized for FTR. Our results support a role for an active-site tyrosine in FDR that occupies the equivalent position of an essential histidine in the active site of FTR. Of note, one of seven Trxs encoded in the genome (Trx5) and methanoredoxin, a glutaredoxin-like enzyme from M. acetivorans, were reduced by FDR, advancing the physiological understanding of FDR's role in the redox metabolism of methanoarchaea. Finally, bioinformatics analyses show that FDR homologs are widespread in diverse microbes from the domain Bacteria. PMID- 29720406 TI - Contemporary prostate biopsy reporting: insights from a survey of clinicians' use of pathology data. AB - AIM: To determine how clinicians use data in contemporary prostate biopsy reports. METHODS: A survey was circulated to members of the British Association of Urological Surgeons and the British Uro-oncology Group. RESULTS: Responses were received from 114 respondents (88 urologists, 26 oncologists). Ninety-seven (94%) use the number of positive cores from each side and 43 (42%) use the % number of positive cores. When determining the number and percentage of positive cores, 72 (71%) would not differentiate between targeted and non-targeted samples. If multiple Gleason Scores (GS) were included in a report, 77 (78%) would use the worst GS even if present in a core with very little tumour, 12% would use the global GS and 10% the GS in the core most involved by tumour. Fifty five (55%) either never or rarely used perineural invasion for patient management. CONCLUSIONS: The number of positive cores is an important parameter for patient management but may be difficult to determine in the laboratory due to core fragmentation so the biopsy taker must indicate the number of biopsies obtained. Multiple biopsies taken from a single site are often interpreted by clinicians as separate cores when determining the number of positive cores so pathologists should also report the number of sites positive. Clinicians have a non-uniform approach to the interpretation of multiple GS in prostate biopsy reports so we recommend that pathologists also include a single 'bottom-line' GS for each case to direct the clinician's treatment decision. PMID- 29720407 TI - Diagnostic potential of stored dried blood spots for inborn errors of metabolism: a metabolic autopsy of medium-chain acyl-CoA dehydrogenase deficiency. AB - AIM: It is estimated that 1-5% of sudden infant death syndrome (SIDS) cases might be caused by undiagnosed inborn errors of metabolism (IEMs); however, the postmortem identification of IEMs remains difficult. This study aimed to evaluate the usefulness of dried blood spots (DBSs) stored after newborn screening tests as a metabolic autopsy to determine the causes of death in infants and children who died suddenly and unexpectedly. METHODS: Infants or toddlers who had suddenly died without a definite diagnosis between July 2008 and December 2012 at Kyushu University Hospital in Japan were enrolled in this study. Their Guthrie cards, which had been stored for several years at 4-8 degrees C, were used for an acylcarnitine analysis by tandem mass spectrometry to identify inborn errors of metabolism. RESULTS: Fifteen infants and children who died at less than 2 years of age and for whom the cause of death was unknown were enrolled for the study. After correcting the C0 and C8 values assuming the hydrolysation of acylcarnitine in the stored DBSs, the corrected C8 value of one case just exceeded the cut-off level for medium-chain acyl-CoA dehydrogenase (MCAD) deficiency screening. Genetic and biochemical analyses confirmed this patient to have MCAD deficiency. CONCLUSION: DBSs stored after newborn screening tests are a promising tool for metabolic autopsy. The appropriate compensation of acylcarnitine data and subsequent genetic and biochemical analyses are essential for the postmortem diagnosis of inborn errors of metabolism. PMID- 29720408 TI - Consecutive negative findings on colonoscopy during surveillance predict a low risk of advanced neoplasia in patients with inflammatory bowel disease with long standing colitis: results of a 15-year multicentre, multinational cohort study. AB - OBJECTIVES: Surveillance colonoscopy is thought to prevent colorectal cancer (CRC) in patients with long-standing colonic IBD, but data regarding the frequency of surveillance and the findings thereof are lacking. Our aim was to determine whether consecutive negative surveillance colonoscopies adequately predict low neoplastic risk. DESIGN: A multicentre, multinational database of patients with long-standing IBD colitis without high-risk features and undergoing regular CRC surveillance was constructed. A 'negative' surveillance colonoscopy was predefined as a technically adequate procedure having no postinflammatory polyps, no strictures, no endoscopic disease activity and no evidence of neoplasia; a 'positive' colonoscopy was a technically adequate procedure that included at least one of these criteria. The primary endpoint was advanced colorectal neoplasia (aCRN), defined as high-grade dysplasia or CRC. RESULTS: Of 775 patients with long-standing IBD colitis, 44% (n=340) had >1 negative colonoscopy. Patients with consecutive negative surveillance colonoscopies were compared with those who had at least one positive colonoscopy. Both groups had similar demographics, disease-related characteristics, number of surveillance colonoscopies and time intervals between colonoscopies. No aCRN occurred in those with consecutive negative surveillance, compared with an incidence rate of 0.29 to 0.76/100 patient-years (P=0.02) in those having >1 positive colonoscopy on follow-up of 6.1 (P25-P75: 4.6-8.2) years after the index procedure. CONCLUSION: Within this large surveillance cohort of patients with colonic IBD and no additional high-risk features, having two consecutive negative colonoscopies predicted a very low risk of aCRN occurrence on follow-up. Our findings suggest that longer surveillance intervals in this selected population may be safe. PMID- 29720409 TI - A simple AGED score for risk classification of primary liver cancer: development and validation with long-term prospective HBsAg-positive cohorts in Qidong, China. PMID- 29720410 TI - Mammoth grazers on the ocean's minuteness: a review of selective feeding using mucous meshes. AB - Mucous-mesh grazers (pelagic tunicates and thecosome pteropods) are common in oceanic waters and efficiently capture, consume and repackage particles many orders of magnitude smaller than themselves. They feed using an adhesive mucous mesh to capture prey particles from ambient seawater. Historically, their grazing process has been characterized as non-selective, depending only on the size of the prey particle and the pore dimensions of the mesh. The purpose of this review is to reverse this assumption by reviewing recent evidence that shows mucous-mesh feeding can be selective. We focus on large planktonic microphages as a model of selective mucus feeding because of their important roles in the ocean food web: as bacterivores, prey for higher trophic levels, and exporters of carbon via mucous aggregates, faecal pellets and jelly-falls. We identify important functional variations in the filter mechanics and hydrodynamics of different taxa. We review evidence that shows this feeding strategy depends not only on the particle size and dimensions of the mesh pores, but also on particle shape and surface properties, filter mechanics, hydrodynamics and grazer behaviour. As many of these organisms remain critically understudied, we conclude by suggesting priorities for future research. PMID- 29720411 TI - Epigenetic regulation of transcriptional plasticity associated with developmental song learning. AB - Ethologists discovered over 100 years ago that some lifelong behavioural patterns were acquired exclusively during restricted developmental phases called critical periods (CPs). Developmental song learning in zebra finches is one of the most striking examples of a CP for complex learned behaviour. After post-hatch day 65, whether or not a juvenile male can memorize the song of a 'tutor' depends on his experiences in the month prior. If he experienced a tutor, he can no longer learn, but if he has been isolated from hearing a tutor the learning period is extended. We aimed to identify how tutor experience alters the brain and controls the ability to learn. Epigenetic landscapes are modulated by experience and are able to regulate the transcription of sets of genes, thereby affecting cellular function. Thus, we hypothesized that tutor experiences determine the epigenetic landscape in the auditory forebrain, a region required for tutor song memorization. Using ChIPseq, RNAseq and molecular biology, we provide evidence that naturalistic experiences associated with the ability to learn can induce epigenetic changes, and propose transcriptional plasticity as a mediator of CP learning potential. PMID- 29720412 TI - Sexual selection predicts species richness across the animal kingdom. AB - Our improving knowledge of the animal tree of life consistently demonstrates that some taxa diversify more rapidly than others, but what contributes to this variation remains poorly understood. An influential hypothesis proposes that selection arising from competition for mating partners plays a key role in promoting speciation. However, empirical evidence showing a link between proxies of this sexual selection and species richness is equivocal. Here, we collected standardized metrics of sexual selection for a broad range of animal taxa, and found that taxonomic families characterized by stronger sexual selection on males show relatively higher species richness. Thus, our data support the hypothesis that sexual selection elevates species richness. This could occur either by promoting speciation and/or by protecting species against extinction. PMID- 29720413 TI - Urea hydrolysis by gut bacteria in a hibernating frog: evidence for urea-nitrogen recycling in Amphibia. AB - Gut bacteria that produce urease, the enzyme hydrolysing urea, contribute to nitrogen balance in diverse vertebrates, although the presence of this system of urea-nitrogen recycling in Amphibia is as yet unknown. Our studies of the wood frog (Rana sylvatica), a terrestrial species that accrues urea in winter, documented robust urease activity by enteric symbionts and hence potential to recoup nitrogen from the urea it produces. Ureolytic capacity in hibernating (non feeding) frogs, whose guts hosted an approximately 33% smaller bacterial population, exceeded that of active (feeding) frogs, possibly due to an inductive effect of high urea on urease expression and/or remodelling of the microbial community. Furthermore, experimentally augmenting the host's plasma urea increased bacterial urease activity. Bacterial inventories constructed using 16S rRNA sequencing revealed that the assemblages hosted by hibernating and active frogs were equally diverse but markedly differed in community membership and structure. Hibernating frogs hosted a greater relative abundance and richer diversity of genera that possess urease-encoding genes and/or have member taxa that reportedly hydrolyse urea. Bacterial hydrolysis of host-synthesized urea probably permits conservation and repurposing of valuable nitrogen not only in hibernating R. sylvatica but, given urea's universal role in amphibian osmoregulation, also in virtually all Amphibia. PMID- 29720414 TI - Isolation by environment in the highly mobile olive ridley turtle (Lepidochelys olivacea) in the eastern Pacific. AB - Spatial and temporal scales at which processes modulate genetic diversity over the landscape are usually overlooked, impacting the design of conservation management practices for widely distributed species. We examine processes shaping population divergence in highly mobile species by re-assessing the case of panmixia in the iconic olive ridley turtle from the eastern Pacific. We implemented a biophysical model of connectivity and a seascape genetic analysis based on nuclear DNA variation of 634 samples collected from 27 nesting areas. Two genetically distinct populations largely isolated during reproductive migrations and mating were detected, each composed of multiple nesting sites linked by high connectivity. This pattern was strongly associated with a steep environmental gradient and also influenced by ocean currents. These findings relate to meso-scale features of a dynamic oceanographic interface in the eastern tropical Pacific (ETP) region, a scenario that possibly provides different cost benefit solutions and selective pressures for sea turtles during both the mating and migration periods. We reject panmixia and propose a new paradigm for olive ridley turtles where reproductive isolation due to assortative mating is linked to its environment. Our study demonstrates the relevance of integrative approaches for assessing the role of environmental gradients and oceanographic currents as drivers of genetic differentiation in widely distributed marine species. This is relevant for the conservation management of species of highly mobile behaviour, and assists the planning and development of large-scale conservation strategies for the threatened olive ridley turtles in the ETP. PMID- 29720415 TI - The biogeographical imprint of mass extinctions. AB - Mass extinctions are defined by extinction rates significantly above background levels and have had substantial consequences for the evolution of life. Geographically selective extinctions, subsequent originations and species redistributions may have changed global biogeographical structure, but quantification of this change is lacking. In order to assess quantitatively the biogeographical impact of mass extinctions, we outline time-traceable bioregions for benthic marine species across the Phanerozoic using a compositional network. Mass extinction events are visually recognizable in the geographical depiction of bioregions. The end-Permian extinction stands out with a severe reduction of provinciality. Time series of biogeographical turnover represent a novel aspect of the analysis of mass extinctions, confirming concentration of changes in the geographical distribution of benthic marine life. PMID- 29720416 TI - Behavioural changes controlled by catecholaminergic systems explain recurrent loss of pigmentation in cavefish. AB - Multiple cave populations of the teleost Astyanax mexicanus have repeatedly reduced or lost eye and body pigmentation during adaptation to dark caves. Albinism, the complete absence of melanin pigmentation, is controlled by loss-of function mutations in the oca2 gene. The mutation is accompanied by an increase in the melanin synthesis precursor l-tyrosine, which is also a precursor for catecholamine synthesis. In this study, we show a relationship between pigmentation loss, enhanced catecholamine synthesis and responsiveness to anaesthesia, determined as a proxy for catecholamine-related behaviours. We demonstrate that anaesthesia resistance (AR) is enhanced in multiple depigmented and albino cavefish (CF), inversely proportional to the degree of pigmentation loss, controlled by the oca2 gene, and can be modulated by experimental manipulations of l-tyrosine or the catecholamine norepinephrine (NE). Moreover, NE is increased in the brains of multiple albino and depigmented CF relative to surface fish. The results provide new insights into the evolution of pigment modification because NE controls a suite of adaptive behaviours similar to AR that may represent a target of natural selection. Thus, understanding the relationship between loss of pigmentation and AR may provide insight into the role of natural selection in the evolution of albinism via a melanin catecholamine trade-off. PMID- 29720417 TI - Inconspicuous echolocation in hoary bats (Lasiurus cinereus). AB - Echolocation allows bats to occupy diverse nocturnal niches. Bats almost always use echolocation, even when other sensory stimuli are available to guide navigation. Here, using arrays of calibrated infrared cameras and ultrasonic microphones, we demonstrate that hoary bats (Lasiurus cinereus) use previously unknown echolocation behaviours that challenge our current understanding of echolocation. We describe a novel call type ('micro' calls) that has three orders of magnitude less sound energy than other bat calls used in open habitats. We also document bats flying close to microphones (less than 3 m) without producing detectable echolocation calls. Acoustic modelling indicates that bats are not producing calls that exceed 70-75 dB at 0.1 m, a level that would have little or no known use for a bat flying in the open at speeds exceeding 7 m s-1 This indicates that hoary bats sometimes fly without echolocation. We speculate that bats reduce echolocation output to avoid eavesdropping by conspecifics during the mating season. These findings might partly explain why tens of thousands of hoary bats are killed by wind turbines each year. They also challenge the long-standing assumption that bats-model organisms for sensory specialization-are reliant on sonar for nocturnal navigation. PMID- 29720418 TI - Coral resistance to ocean acidification linked to increased calcium at the site of calcification. AB - Ocean acidification threatens the persistence of biogenic calcium carbonate (CaCO3) production on coral reefs. However, some coral genera show resistance to declines in seawater pH, potentially achieved by modulating the chemistry of the fluid where calcification occurs. We use two novel geochemical techniques based on boron systematics and Raman spectroscopy, which together provide the first constraints on the sensitivity of coral calcifying fluid calcium concentrations ([Formula: see text]) to changing seawater pH. In response to simulated end-of century pH conditions, Pocillopora damicornis increased [Formula: see text] to as much as 25% above that of seawater and maintained constant calcification rates. Conversely, Acropora youngei displayed less control over [Formula: see text], and its calcification rates strongly declined at lower seawater pH. Although the role of [Formula: see text] in driving calcification has often been neglected, increasing [Formula: see text] may be a key mechanism enabling more resistant corals to cope with ocean acidification and continue to build CaCO3 skeletons in a high-CO2 world. PMID- 29720419 TI - Complex gaze stabilization in mantis shrimp. AB - Almost all animals, regardless of the anatomy of the eyes, require some level of gaze stabilization in order to see the world clearly and without blur. For the mantis shrimp, achieving gaze stabilization is unusually challenging as their eyes have an unprecedented scope for movement in all three rotational degrees of freedom: yaw, pitch and torsion. We demonstrate that the species Odontodactylus scyllarus performs stereotypical gaze stabilization in the yaw degree of rotational freedom, which is accompanied by simultaneous changes in the pitch and torsion rotation of the eye. Surprisingly, yaw gaze stabilization performance is unaffected by both the torsional pose and the rate of torsional rotation of the eye. Further to this, we show, for the first time, a lack of a torsional gaze stabilization response in the stomatopod visual system. In the light of these findings, we suggest that the neural wide-field motion detection network in the stomatopod visual system may follow a radially symmetric organization to compensate for the potentially disorientating effects of torsional eye movements, a system likely to be unique to stomatopods. PMID- 29720421 TI - Emergence of free will and consciousness in humans: implications for doctor patient interactions. AB - Human brains have about 100 billion neurons each with about 1000 dendritic connections with other neurons giving a total of 100 000 billion deterministic dendritic switches. Various voting systems that the brain may use can produce conflicting results from identical inputs without any indication as to which one or ones would be correct. Voting systems cannot deliver unequivocal results in any other than the simplest situations. It is hypothesised that these conflicting results provide an indeterminacy that underlies free will, self-awareness, awareness of others, consciousness and personal responsibility, all of which can influence doctor-patient interactions. PMID- 29720420 TI - The contribution of non-essential Schizosaccharomyces pombe genes to fitness in response to altered nutrient supply and target of rapamycin activity. AB - Nutrient fluctuations in the cellular environment promote changes in cell metabolism and growth to adapt cell proliferation accordingly. The target of rapamycin (TOR) signalling network plays a key role in the coordination of growth and cell proliferation with the nutrient environment and, importantly, nutrient limitation reduces TOR complex 1 (TORC1) signalling. We have performed global quantitative fitness profiling of the collection of Schizosaccharomyces pombe strains from which non-essential genes have been deleted. We identified genes that regulate fitness when cells are grown in a nutrient-rich environment compared with minimal environments, with varying nitrogen sources including ammonium, glutamate and proline. In addition, we have performed the first global screen for genes that regulate fitness when both TORC1 and TORC2 signalling is reduced by Torin1. Analysis of genes whose deletions altered fitness when nutrients were limited, or when TOR signalling was compromised, identified a large number of genes that regulate transmembrane transport, transcription and chromatin organization/regulation and vesicle-mediated transport. The ability to tolerate reduced TOR signalling placed demands upon a large number of biological processes including autophagy, mRNA metabolic processing and nucleocytoplasmic transport. Importantly, novel biological processes and all processes known to be regulated by TOR were identified in our screens. In addition, deletion of 62 genes conserved in humans gave rise to strong sensitivity or resistance to Torin1, and 29 of these 62 genes have novel links to TOR signalling. The identification of chromatin and transcriptional regulation, nutritional uptake and transport pathways in this powerful genetic model now paves the way for a molecular understanding of how cells adapt to the chronic and acute fluctuations in nutrient supply that all eukaryotes experience at some stage, and which is a key feature of cancer cells within solid tumours. PMID- 29720422 TI - Gremlin activates the Notch pathway linked to renal inflammation. AB - Preclinical studies suggest that Gremlin participates in renal damage and could be a potential therapeutic target for human chronic kidney diseases. Inflammation is a common characteristic of progressive renal disease, and therefore novel anti inflammatory therapeutic targets should be investigated. The Notch signaling pathway is involved in kidney development and is activated in human chronic kidney disease, but whether Gremlin regulates the Notch pathway has not been investigated. In cultured tubular cells, Gremlin up-regulated gene expression of several Notch pathway components, increased the production of the canonical ligand Jagged-1, and caused the nuclear translocation of active Notch-1 (N1ICD). In vivo administration of Gremlin into murine kidneys elicited Jagged-1 production, increased N1ICD nuclear levels, and up-regulated the gene expression of the Notch effectors hes-1 and hey-1 All these data clearly demonstrate that Gremlin activates the Notch pathway in the kidney. Notch inhibition using the gamma-secretase inhibitor DAPT impaired renal inflammatory cell infiltration and proinflammatory cytokines overexpression in Gremlin-injected mice and in experimental models of renal injury. Moreover, Notch inhibition blocked Gremlin induced activation of the canonical and noncanonical nuclear factor-kappaB (NF kappaB) pathway, identifying an important mechanism involved in the anti inflammatory actions of Notch inhibition. In conclusion, Gremlin activates the Notch pathway in the kidney and this is linked to NF-kappaB-mediated inflammation, supporting the hypothesis that Notch inhibition could be a potential anti-inflammatory strategy for renal diseases. PMID- 29720423 TI - Cutting Edge: The Histone Methyltransferase G9a Is Required for Silencing of Helper T Lineage-Associated Genes in Proliferating CD8 T Cells. AB - Helper versus cytotoxic T lineage decision in the thymus has been studied as a model for silencing of alternative lineage genes. Although the transcription factor RUNX3 is required for the initiation of Cd4 silencing in developing CD8 T cells, it is unknown how silencing of Cd4 and other helper T lineage genes is maintained. We show that the histone methyltransferase G9a is necessary for silencing helper T lineage genes in proliferating mouse CD8 T cells. Despite normal initial Cd4 downregulation, G9a-deficient CD8 T cells derepress Cd4 and other helper lineage genes during repeated division in lymphopenia or in response to tumor Ag. However, G9a was dispensable for continued silencing of those genes in CD8 T cells that respond to infection by Listeria monocytogenes These results demonstrate that G9a facilitates maintenance of cellular identity of CD8 T cells during cell division, which is further reinforced by inflammatory signals. PMID- 29720424 TI - IL-2 Enhances Gut Homing Potential of Human Naive Regulatory T Cells Early in Life. AB - Recent evidence suggests early environmental factors are important for gut immune tolerance. Although the role of regulatory T (Treg) cells for gut immune homeostasis is well established, the development and tissue homing characteristics of Treg cells in children have not been studied in detail. In this article, we studied the development and homing characteristics of human peripheral blood Treg cell subsets and potential mechanisms inducing homing molecule expression in healthy children. We found contrasting patterns of circulating Treg cell gut and skin tropism, with abundant beta7 integrin+ Treg cells at birth and increasing cutaneous lymphocyte Ag (CLA+) Treg cells later in life. beta7 integrin+ Treg cells were predominantly naive, suggesting acquisition of Treg cell gut tropism early in development. In vitro, IL-7 enhanced gut homing but reduced skin homing molecule expression in conventional T cells, whereas IL-2 induced a similar effect only in Treg cells. This effect was more pronounced in cord compared with adult blood. Our results suggest that early in life, naive Treg cells may be driven for gut tropism by their increased sensitivity to IL-2 induced beta7 integrin upregulation, implicating a potential role of IL-2 in gut immune tolerance during this critical period of development. PMID- 29720425 TI - Canonical TGF-beta Signaling Pathway Represses Human NK Cell Metabolism. AB - Cytokines stimulate rapid metabolic changes in human NK cells, including increases in both glycolysis and oxidative phosphorylation pathways. However, how these are subsequently regulated is not known. In this study, we demonstrate that TGF-beta can inhibit many of these metabolic changes, including oxidative phosphorylation, glycolytic capacity, and respiratory capacity. TGF-beta also inhibited cytokine-induced expression of the transferrin nutrient receptor CD71. In contrast to a recent report on murine NK cells, TGF-beta-mediated suppression of these metabolic responses did not involve the inhibition of the metabolic regulator mTORC1. Inhibition of the canonical TGF-beta signaling pathway was able to restore almost all metabolic and functional responses that were inhibited by TGF-beta. These data suggest that pharmacological inhibition of TGF-beta could provide a metabolic advantage to NK cells that is likely to result in improved functional responses. This has important implications for NK cell-based cancer immunotherapies. PMID- 29720426 TI - MicroRNA-155 Modulates Acute Graft-versus-Host Disease by Impacting T Cell Expansion, Migration, and Effector Function. AB - MicroRNA-155 (miR-155) is a small noncoding RNA critical for the regulation of inflammation as well as innate and adaptive immune responses. MiR-155 has been shown to be dysregulated in both donor and recipient immune cells during acute graft-versus-host disease (aGVHD). We previously reported that miR-155 is upregulated in donor T cells of mice and humans with aGVHD and that mice receiving miR-155-deficient (miR155-/-) splenocytes had markedly reduced aGVHD. However, molecular mechanisms by which miR-155 modulates T cell function in aGVHD have not been fully investigated. We identify that miR-155 expression in both donor CD8+ T cells and conventional CD4+ CD25- T cells is pivotal for aGVHD pathogenesis. Using murine aGVHD transplant experiments, we show that miR-155 strongly impacts alloreactive T cell expansion through multiple distinct mechanisms, modulating proliferation in CD8+ donor T cells and promoting exhaustion in donor CD4+ T cells in both the spleen and colon. Additionally, miR 155 drives a proinflammatory Th1 phenotype in donor T cells in these two sites, and miR-155-/- donor T cells are polarized toward an IL-4-producing Th2 phenotype. We further demonstrate that miR-155 expression in donor T cells regulates CCR5 and CXCR4 chemokine-dependent migration. Notably, we show that miR 155 expression is crucial for donor T cell infiltration into multiple target organs. These findings provide further understanding of the role of miR-155 in modulating aGVHD through T cell expansion, effector cytokine production, and migration. PMID- 29720427 TI - Up-regulation of inflammation-related LncRNA-IL7R predicts poor clinical outcome in patients with cervical cancer. AB - The long-term chronic inflammation of cervical intraepithelial neoplasia (CIN) induces the initiation and progression of cervical cancer. Long non-coding RNAs (LncRNAs) are being identified to be involved into inflammation and carcinogenesis and could function as cancer biomarkers in clinical. However, the significance of inflammation-related LncRNA (e.g. LncRNA-IL7R) in cervical cancer is limited. We, here, investigated the clinical role of inflammation-related LncRNA-IL7R (Lnc-IL7R) in healthy cervical tissue (n=15), CIN 1/2/3 (n=35), cervical cancer (n=70), and clarified its function via knockdown in vitro and in vivo The results showed that the expression of Lnc-IL7R was increased from normal tissues to neoplastic lesions and cervical cancer. Up-regulated Lnc-IL7R positively correlated to tumor size, International Federation of Gynaecology and Obstetrics (FIGO) stage, and lymph node metastasis (LNM). Patients with high expression of Lnc-IL7R had poor prognosis with short overall survival (OS) time, and Cox regression analysis revealed that Lnc-IL7R could be independent prognostic factor for cervical cancer. Moreover, knockdown of Lnc-IL7R by two different siRNAs in cervical cancer cell lines Hela and SiHa induced impaired cell vitality and caspase-3-dependent apoptosis in vitro Furthermore, inhibition of Lnc-IL7R in vivo significantly restricted the tumor growth with decreased expressions of proliferation index Ki-67 and Lnc-IL7R These data indicated that Lnc-IL7R predicts a poor clinical outcome of cervical cancer patients, and knockdown of Lnc-IL7R is amenable to the treatment of cervical cancer. PMID- 29720428 TI - False measurement of glycated hemoglobin in patients without Hemoglobin A>. AB - Background : Hemoglobin (Hb) A1c, a biochemical marker widely used in monitoring diabetes mellitus, can be quantitatively measured by various examining systems. However, significant errors still exist. In this study, we evaluated the HbA1c level in five patients with compound heterozygotes by five different examining systems and our goal is to identify the existence of erroneous HbA1c measurement. Methods: Blood samples collected from normal (no hemoglobin variants) and abnormal (compound heterozygotes) patients were analyzed by capillary electrophoresis technique and sequence analysis. The samples without HbA expression via above methods were further analyzed for HbA1c by ion exchange HPLC Variant II/ Variant IITurbo 2.0 (VII and VII-T 2.0), boronate affinity HPLC, capillary electrophoresis and Tinaquant immunoassay. Results: HbA1c expression were unexpectedly detected in the compound heterozygous samples by using additional examining systems: The HPLC VII and VII-T 2.0 detected HbA1c expression in two of five samples and failed to detect the abnormal HbA2 expression; The CE system detected HbA1c expression in one of five sample with abnormal HbA2 expression; The Ultra2 and PPI system detected the HbA1c expression of all samples without abnormal HbA2Conclusions: Five human samples without HbA expression were additionally detected with HbA1c expression with or without abnormal HbA2 expression by five analysis systems and the different examining assay potentially affected the test results. These results demonstrated that the limitations of current examining systems for monitoring patients with hemoglobin disorders, highlighting the further improvement in the method of clinical HbA examination. PMID- 29720429 TI - Clinical and Bacteriologic Analysis of Nontypeable Haemophilus influenzae Strains Isolated from Children with Invasive Diseases in Japan from 2008 to 2015. AB - Haemophilus influenzae type b (Hib) conjugate vaccines have led to dramatic reductions in Hib disease among young children worldwide. Nontypeable H. influenzae (NTHi) is now the major cause of invasive H. influenzae infections. We investigated the clinical characteristics of invasive NTHi diseases among children in Japan, to clarify the pathogenicity of isolated NTHi strains. The mortality rate was 10.7%, with deaths occurring mainly among children with underlying comorbidities. Biotypes II and III were the most common, and most strains (64.3%) had multiple amino acid substitutions at the Asp-350, Ser-357, Ser-385, and/or Met-377 sites of penicillin-binding protein 3. Two strains were beta-lactamase positive and ampicillin-clavulanate resistant. Biofilm indices varied widely, and IS1016 was detected in 10.7% of the strains tested. Moreover, there was wide variation in the characteristics of invasive NTHi strains. NTHi strains, showing great genetic diversity, are responsible for most invasive H. influenzae infections in children in the postvaccine era. Continuous monitoring of NTHi strains responsible for invasive diseases in children is important to detect changes in the epidemiology of invasive H. influenzae infections in the postvaccine era. PMID- 29720430 TI - Evaluation of a Rapid Diagnostic Test for Detection of Burkholderia pseudomallei in the Lao People's Democratic Republic. AB - Burkholderia pseudomallei causes significant global morbidity and mortality, with the highest disease burden in parts of Asia where culture-based diagnosis is often not available. We prospectively evaluated the Active Melioidosis Detect (AMD; InBios International, USA) lateral flow immunoassay (LFI) for rapid detection of B. pseudomallei in turbid blood cultures, pus, sputum, sterile fluid, urine, and sera. The performance of this test was compared to that of B. pseudomallei detection using monoclonal antibody latex agglutination (LA) and immunofluorescence assays (IFA), with culture as the gold standard. AMD was 99% (99/100; 95% confidence interval, 94.6 to 100%) sensitive and 100% (308/308; 98.8 to 100%) specific on turbid blood culture bottles, with no difference from LA or IFA. AMD specificity was 100% on pus (122/122; 97.0 to 100%), sputum (20/20; 83.2 to 100%), and sterile fluid (44/44; 92 to 100%). Sensitivity on these samples was as follows: pus, 47.1% (8/17; 23.0 to 72.2%); sputum, 33.3% (1/3; 0.84 to 90.6%); and sterile fluid, 0% (0/2; 0 to 84.2%). For urine samples, AMD had a positive predictive value of 94% (32/34; 79.7 to 98.5%) for diagnosing melioidosis in our cohort. AMD sensitivity on stored sera, collected prospectively from melioidosis cases during this study, was 13.9% (5/36; 4.7% to 29.5%) compared to blood culture samples taken on the same day. In conclusion, AMD is an excellent tool for rapid diagnosis of melioidosis from turbid blood cultures and maintains specificity across all sample types. It is a promising tool for urinary antigen detection, which could revolutionize diagnosis of melioidosis in resource-limited settings. Further work is required to improve sensitivity on nonblood culture samples. PMID- 29720432 TI - Evaluation of the illumigene Mycoplasma Direct DNA Amplification Assay. AB - Mycoplasma pneumoniae is a common cause of community-acquired pneumonia. The illumigene Mycoplasma Direct (iMD) DNA amplification assay is a qualitative in vitro test utilizing loop-mediated isothermal amplification (LAMP) technology for the direct detection of M. pneumoniae DNA in respiratory specimens. The iMD assay does not require the preextraction of nucleic acids from specimens, which is a prerequisite step for the previously approved illumigene Mycoplasma (iM) assay. The aim of this prospective multicenter study was to evaluate the performance characteristics of the newly developed iMD assay, compared with the iM assay. Subjects with symptoms of upper respiratory illnesses suggesting M. pneumoniae infection were enrolled at three sites in the United States. Respiratory specimens were obtained using dual throat swabs. One swab was tested with the iMD assay at each enrollment site. Reference testing with the iM assay was performed by the manufacturer. Among 456 specimens tested, the iM reference method detected M. pneumoniae in 25 specimens (5.5%), while the iMD assay identified 34 specimens (7.5%) as M. pneumoniae positive. There were 10 false-positive results and 1 false-negative result with the iMD assay. The overall positive and negative agreement rates were 96.0% (95% confidence interval [CI], 80.5 to 99.3%) and 97.7% (95% CI, 95.8 to 98.7%), respectively. The overall agreement rate was determined to be 97.6% (95% CI, 95.7 to 98.6%). We conclude that the iMD test results were comparable to the iM assay results. The removal of the DNA extraction step for the iMD assay simplifies testing, saves time, and reduces the costs of detecting M. pneumoniae from throat swabs, compared to the iM assay. PMID- 29720431 TI - Global Distribution of Invasive Serotype 35D Streptococcus pneumoniae Isolates following Introduction of 13-Valent Pneumococcal Conjugate Vaccine. AB - A newly recognized pneumococcal serotype, 35D, which differs from the 35B polysaccharide in structure and serology by not binding to factor serum 35a, was recently reported. The genetic basis for this distinctive serology is due to the presence of an inactivating mutation in wciG, which encodes an O acetyltransferase responsible for O-acetylation of a galactofuranose. Here, we assessed the genomic data of a worldwide pneumococcal collection to identify serotype 35D isolates and understand their geographical distribution, genetic background, and invasiveness potential. Of 21,980 pneumococcal isolates, 444 were originally typed as serotype 35B by PneumoCaT. Analysis of the wciG gene revealed 23 isolates from carriage (n = 4) and disease (n = 19) with partial or complete loss-of-function mutations, including mutations resulting in premature stop codons (n = 22) and an in-frame mutation (n = 1). These were selected for further analysis. The putative 35D isolates were geographically widespread, and 65.2% (15/23) of them was recovered after the introduction of pneumococcal conjugate vaccine 13 (PCV13). Compared with serotype 35B isolates, putative serotype 35D isolates have higher invasive disease potentials based on odds ratios (OR) (11.58; 95% confidence interval[CI], 1.42 to 94.19 versus 0.61; 95% CI, 0.40 to 0.92) and a higher prevalence of macrolide resistance mediated by mefA (26.1% versus 7.6%; P = 0.009). Using the Quellung reaction, 50% (10/20) of viable isolates were identified as serotype 35D, 25% (5/20) as serotype 35B, and 25% (5/20) as a mixture of 35B/35D. The discrepancy between phenotype and genotype requires further investigation. These findings illustrated a global distribution of an invasive serotype, 35D, among young children post-PCV13 introduction and underlined the invasive potential conferred by the loss of O-acetylation in the pneumococcal capsule. PMID- 29720433 TI - Evaluation of the Use of Rectal Swabs for Laboratory Diagnosis of Clostridium difficile Infection. AB - For the diagnosis of Clostridium difficile infection (CDI), microbiological testing is almost always accomplished through the analysis of stool specimens. We evaluated the performances of rectal swabs with liquid transport medium (FS) and nylon flocked dry swabs for the detection of C. difficile Additionally, the impact on the diagnostic yield of storing swabs at -80 degrees C for up to 3 months was evaluated. Sixty clinical stool samples positive for C. difficile by PCR were used for simulating rectal swabbing. FS and dry swabs were dipped into the stool and tested by PCR directly after swabbing at 1 and 3 months after storage at -80 degrees C. Stool and the liquid medium of FS were additionally tested by a combination of glutamate dehydrogenase antigen (GDH) testing and toxin A/B enzyme immunoassay (EIA), as well as by toxigenic culture (TC). Using dry swabs, the PCR-based detection rate of C. difficile was equal to the rate using stool samples (30/30 [100%]), whereas the detection rate in FS was significantly lower (25/30 [83.2%]; P = 0.019). The sensitivities of FS for detecting C. difficile by PCR, TC, GDH testing, and toxin A/B EIA were 83.3%, 85.7%, 88%, and 68.9%, respectively. Storage of swabs at -80 degrees C had no impact on the detection rate. FS cannot replace stool samples in the two-step laboratory diagnosis of CDI, as the sensitivities were too low, probably due to diluting effects of the fecal sample in the liquid medium. For simple PCR-based detection of C. difficile, dry swabs proved to be a suitable alternative to the use of stool samples. PMID- 29720434 TI - Evaluation of a Turbidimetric beta-d-Glucan Test for Detection of Pneumocystis jirovecii Pneumonia. AB - Currently, diagnosis of Pneumocystis jirovecii pneumonia (PJP) relies on analysis of lower respiratory specimens, either by microscopy or quantitative real-time PCR (qPCR). Thus, bronchoscopy is required, which is associated with increased risk of respiratory failure. We assessed the value of noninvasive serologic beta d-glucan (BDG) testing for laboratory diagnosis of PJP using a newly available turbidimetric assay. We identified 73 cases of PJP with positive qPCR results from lower respiratory specimens for Pneumocystis and serology samples dating from 1 week before to 4 weeks after qPCR. In addition, 25 sera from controls with suspected PJP but specimens negative for Pneumocystis by qPCR were identified. Sera were tested with a turbidimetric BDG assay (Fujifilm Wako Chemicals Europe GmbH, Neuss, Germany), using an 11-pg/ml cutoff. Sensitivity and specificity were calculated based on qPCR test results as a reference. The turbidimetric BDG assay identified 63/73 patients with positive or slightly positive qPCR tests for an overall sensitivity of 86%; after exclusion of cases with only slightly positive qPCR results, sensitivity was 91%. No correlation between serum BDG levels and respiratory specimen DNA levels was found. Serologic BDG testing was negative in 25/25 controls with negative qPCR for a specificity of 100% using the predefined cutoff. In 22/25 samples (88%), no BDG was detected. Serologic BDG testing using the turbidimetric assay showed high sensitivity and specificity compared to qPCR of lower respiratory specimens for the diagnosis of PJP. Both turnover time and test performance will allow clinicians to delay or in some cases forego bronchoscopy. PMID- 29720436 TI - Combining Spot Sign and Intracerebral Hemorrhage Score to Estimate Functional Outcome: Analysis From the PREDICT Cohort. AB - BACKGROUND AND PURPOSE: The intracerebral hemorrhage (ICH) score is the most commonly used grading scale for stratifying functional outcome in patients with acute ICH. We sought to determine whether a combination of the ICH score and the computed tomographic angiography spot sign may improve outcome prediction in the cohort of a prospective multicenter hemorrhage trial. METHODS: Prospectively collected data from 241 patients from the observational PREDICT study (Prediction of Hematoma Growth and Outcome in Patients With Intracerebral Hemorrhage Using the CT-Angiography Spot Sign) were analyzed. Functional outcome at 3 months was dichotomized using the modified Rankin Scale (0-3 versus 4-6). Performance of (1) the ICH score and (2) the spot sign ICH score-a scoring scale combining ICH score and spot sign number-was tested. RESULTS: Multivariable analysis demonstrated that ICH score (odds ratio, 3.2; 95% confidence interval, 2.2-4.8) and spot sign number (n=1: odds ratio, 2.7; 95% confidence interval, 1.1-7.4; n>1: odds ratio, 3.8; 95% confidence interval, 1.2-17.1) were independently predictive of functional outcome at 3 months with similar odds ratios. Prediction of functional outcome was not significantly different using the spot sign ICH score compared with the ICH score alone (spot sign ICH score area under curve versus ICH score area under curve: P=0.14). CONCLUSIONS: In the PREDICT cohort, a prognostic score adding the computed tomographic angiography-based spot sign to the established ICH score did not improve functional outcome prediction compared with the ICH score. PMID- 29720435 TI - Cost-Effectiveness of Patent Foramen Ovale Closure Versus Medical Therapy for Secondary Stroke Prevention. AB - BACKGROUND AND PURPOSE: Percutaneous transcatheter closure of patent foramen ovale (PFO closure) plus antiplatelet therapy has been shown to reduce the risk of recurrent stroke compared with medical therapy alone in carefully selected patients after cryptogenic stroke presumed to be from paradoxical embolism. Our objective was to determine the cost-effectiveness of PFO closure after cryptogenic stroke compared with conservative medical management from a US healthcare payer perspective. METHODS: A decision analytic Markov model estimated the 15-year cost and outcomes associated with the additional benefit of PFO closure compared with medical management alone. Model inputs were obtained from published literature, national databases, and a meta-analysis of 5 published randomized clinical trials on PFO closure. Health outcomes were measured in quality-adjusted life years (QALY). Cost-effectiveness used the incremental cost per QALY gained, whereas the net monetary benefit assumed a willingness to pay of $150 000/QALY. One-way and probabilistic sensitivity analyses estimated the uncertainty of model results. RESULTS: At 15 years, PFO closure compared with medical therapy alone improved QALY by 0.33 at a cost saving of $3568, representing an incremental net monetary benefit of $52 761 (95% interval -$8284 to $158 910). When the meta-analysis hazard ratio for stroke was increased to the 95% interval's upper bound of 0.77, one-way sensitivity analyses suggested that PFO closure's cost-effectiveness was $458 558 per additional QALY. Probabilistic sensitivity analysis suggested cost-effectiveness in 90% of simulation runs. CONCLUSIONS: PFO closure for cryptogenic strokes in the right setting is cost effective, producing benefit in QALYs gained and potential cost savings. However, patient selection remains vitally important as marginal declines in treatment effectiveness can dramatically affect cost-effectiveness. PMID- 29720438 TI - Diagnosis and Management of Active Intracranial Atherosclerotic Disease: A Case Study. PMID- 29720437 TI - Prediction of Tissue Outcome and Assessment of Treatment Effect in Acute Ischemic Stroke Using Deep Learning. AB - BACKGROUND AND PURPOSE: Treatment options for patients with acute ischemic stroke depend on the volume of salvageable tissue. This volume assessment is currently based on fixed thresholds and single imagine modalities, limiting accuracy. We wish to develop and validate a predictive model capable of automatically identifying and combining acute imaging features to accurately predict final lesion volume. METHODS: Using acute magnetic resonance imaging, we developed and trained a deep convolutional neural network (CNNdeep) to predict final imaging outcome. A total of 222 patients were included, of which 187 were treated with rtPA (recombinant tissue-type plasminogen activator). The performance of CNNdeep was compared with a shallow CNN based on the perfusion-weighted imaging biomarker Tmax (CNNTmax), a shallow CNN based on a combination of 9 different biomarkers (CNNshallow), a generalized linear model, and thresholding of the diffusion weighted imaging biomarker apparent diffusion coefficient (ADC) at 600*10-6 mm2/s (ADCthres). To assess whether CNNdeep is capable of differentiating outcomes of +/-intravenous rtPA, patients not receiving intravenous rtPA were included to train CNNdeep,-rtpa to access a treatment effect. The networks' performances were evaluated using visual inspection, area under the receiver operating characteristic curve (AUC), and contrast. RESULTS: CNNdeep yields significantly better performance in predicting final outcome (AUC=0.88+/-0.12) than generalized linear model (AUC=0.78+/-0.12; P=0.005), CNNTmax (AUC=0.72+/-0.14; P<0.003), and ADCthres (AUC=0.66+/-0.13; P<0.0001) and a substantially better performance than CNNshallow (AUC=0.85+/-0.11; P=0.063). Measured by contrast, CNNdeep improves the predictions significantly, showing superiority to all other methods (P<=0.003). CNNdeep also seems to be able to differentiate outcomes based on treatment strategy with the volume of final infarct being significantly different (P=0.048). CONCLUSIONS: The considerable prediction improvement accuracy over current state of the art increases the potential for automated decision support in providing recommendations for personalized treatment plans. PMID- 29720439 TI - Time to Decision and Treatment With tPA (Tissue-Type Plasminogen Activator) Using Telemedicine Versus an Onboard Neurologist on a Mobile Stroke Unit. AB - BACKGROUND AND PURPOSE: Mobile stroke units (MSUs) can speed treatment with intravenous tPA (tissue-type plasminogen activator). We previously showed substantial agreement between a telemedicine-based vascular neurologist (TM-VN) and an onboard vascular neurologist (OB-VN) for the evaluation of patients with stroke for tPA eligibility on an MSU. However, the time efficiency of the telemedicine-based evaluation remained uncertain. In this study, we examined the speed of decision and treatment from MSU arrival for the TM-VN compared with an OB-VN. METHODS: In 50 consecutive situations, the TM-VN served as the primary decision maker. Times from MSU arrival to tPA decision and tPA bolus were compared with the same metrics for when the OB-VN served as the primary decision maker. RESULTS: Time to tPA decision for the TM-VN was 21 minutes (interquartile range, 16.25-26) versus 18 minutes (interquartile range, 14-22) for the OB-VN (P=0.01). Initiation of tPA bolus was 24 minutes (interquartile range, 19.75-30) for the TM-VN versus 24 minutes (interquartile range, 19-27.75) for the OB-VN (P=0.5). CONCLUSIONS: Assessment by a TM-VN is comparable with an OB-VN in making decisions about tPA administration on an MSU and does not lead to treatment delays. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02190500. PMID- 29720440 TI - Association of Blood Pressure With Short- and Long-Term Functional Outcome After Stroke Thrombectomy: Post Hoc Analysis of the SIESTA Trial. AB - BACKGROUND AND PURPOSE: Outcome after mechanical thrombectomy for ischemic stroke may be influenced by blood pressure (BP). This study aims to assess the association of BP changes during general anesthesia versus conscious sedation with functional outcome after mechanical thrombectomy. METHODS: SIESTA (Sedation vs Intubation for Endovascular Stroke Treatment) was a monocentric randomized trial of general anesthesia versus conscious sedation during mechanical thrombectomy involving BP target protocols. In this post hoc analysis, BP measurements were divided into 4 phases: preintervention, prerecanalization, postrecanalization, and postintervention. We examined the association between BP and functional outcomes (defined by improvement of 24-hour National Institutes of Health Stroke Scale [NIHSS] and 3-month modified Rankin Scale). RESULTS: We found no association between the difference in systolic BP, diastolic BP, and mean arterial pressure from baseline to the different phases of intervention and NIHSS change after 24 hours. Only baseline diastolic BP was associated with a reduced improvement in NIHSS (beta=0.17, P<0.01). There was no association of BP drops with a change in modified Rankin Scale at 3 months. About sedation, only baseline mean arterial pressure preintervention revealed significant associations (beta=0.16, P<0.01) with less change in 24-hour NIHSS in conscious sedation group. Otherwise, there was no association for differences of any of the BP measurements with a change in 24-hour NIHSS and long-term functional outcome either in general anesthesia or the conscious sedation group when analyzed separately, consistent with our findings in the entire cohort. Doses of propofol (beta=0.84, P=0.04) and norepinephrine (beta=1.87, P=0.01) administered during intervention before recanalization were associated with reduced improvement of NIHSS at 24 hours. CONCLUSIONS: In a setting, where both sedation regimes general anesthesia and conscious sedation were performed according to strict protocols directed at avoiding BP extremes, our findings suggest that peri-interventional BP drops were not associated with either early neurological improvement or long term functional outcome. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02126085. PMID- 29720441 TI - Declining Rate and Severity of Hospitalized Stroke From 2004 to 2013: The National Acute Stroke Israeli Registry. AB - BACKGROUND AND PURPOSE: Stroke is a leading cause of morbidity and disability. We assessed trends in rates of hospitalized stroke and stroke severity on admission in a prospective national registry of stroke from 2004 to 2013. METHODS: All 6693 acute ischemic strokes and intracerebral hemorrhage in the National Acute Stroke Israeli participants >=20 years old were included. Data were prospectively collected in 2004 (February-March), 2007 (March-April), 2010 (April-May), and 2013 (March-April). Rates of hospitalized stroke from 2004 to 2013 were studied using generalized linear models assuming a quasi-Poisson error distribution with a log link. Stroke severity on admission was determined using the National Institutes of Health Stroke Scale score and trends were studied. Analysis was performed for stroke overall and by sex and age-group as well as by stroke type. RESULTS: Estimated average annual rates of hospitalized stroke decreased from 24.9/10 000 in 2004 to 19.5/10 000 in 2013. The age and sex-adjusted rates ratio (95% confidence interval) for hospitalized stroke overall was 0.82 (0.76-0.89) for 2007, 0.71 (0.65-0.77) for 2010, and 0.72 (0.66-0.78) for 2013 compared with 2004. Severity on admission decreased over time: rates (95% confidence interval) of severe stroke (National Institutes of Health Stroke Scale score of >=11) decreased from 27% (25%-29%) in 2004 to 19% (17%-21%) in 2013, whereas rates (95% confidence interval) of minor stroke (National Institutes of Health Stroke Scale score of <=5) increased from 46% (44%-49%) in 2004 to 60% (57%-62%) in 2013 (P<0.0001). Findings were consistent by sex, age-group, and stroke type. CONCLUSIONS: Based on our national data, rates of hospitalized stroke and severity of stroke on admission have decreased from 2004 to 2013 overall and by stroke type, in men and women. Despite the observed declines in rates and severity, stroke continues to place a considerable burden to the Israeli health system. PMID- 29720443 TI - Site-selective measurement of coupled spin pairs in an organic semiconductor. AB - From organic electronics to biological systems, understanding the role of intermolecular interactions between spin pairs is a key challenge. Here we show how such pairs can be selectively addressed with combined spin and optical sensitivity. We demonstrate this for bound pairs of spin-triplet excitations formed by singlet fission, with direct applicability across a wide range of synthetic and biological systems. We show that the site sensitivity of exchange coupling allows distinct triplet pairs to be resonantly addressed at different magnetic fields, tuning them between optically bright singlet ([Formula: see text]) and dark triplet quintet ([Formula: see text]) configurations: This induces narrow holes in a broad optical emission spectrum, uncovering exchange specific luminescence. Using fields up to 60 T, we identify three distinct triplet-pair sites, with exchange couplings varying over an order of magnitude (0.3-5 meV), each with its own luminescence spectrum, coexisting in a single material. Our results reveal how site selectivity can be achieved for organic spin pairs in a broad range of systems. PMID- 29720442 TI - Metabolic control of T cell immune response through glycans in inflammatory bowel disease. AB - Mucosal T lymphocytes from patients with ulcerative colitis (UC) were previously shown to display a deficiency in branched N-glycosylation associated with disease severity. However, whether this glycosylation pathway shapes the course of the T cell response constituting a targeted-specific mechanism in UC remains largely unknown. In this study, we demonstrated that metabolic supplementation of ex vivo mucosal T cells from patients with active UC with N-acetylglucosamine (GlcNAc) resulted in enhancement of branched N-glycosylation in the T cell receptor (TCR), leading to suppression of T cell growth, inhibition of the T helper 1 (Th1)/Th17 immune response, and controlled T cell activity. We further demonstrated that mouse models displaying a deficiency in the branched N-glycosylation pathway (MGAT5-/-, MGAT5+/-) exhibited increased susceptibility to severe forms of colitis and early-onset disease. Importantly, the treatment of these mice with GlcNAc reduced disease severity and suppressed disease progression due to a controlled T cell-mediated immune response at the intestinal mucosa. In conclusion, our human ex vivo and preclinical results demonstrate the targeted specific immunomodulatory properties of this simple glycan, proposing a therapeutic approach for patients with UC. PMID- 29720444 TI - Getting somewhere with the Red Queen: chasing a biologically modern definition of the hypothesis. AB - The Red Queen hypothesis (RQH) is both familiar and murky, with a scope and range that has broadened beyond its original focus. Although originally developed in the palaeontological arena, it now encompasses many evolutionary theories that champion biotic interactions as significant mechanisms for evolutionary change. As such it de-emphasizes the important role of abiotic drivers in evolution, even though such a role is frequently posited to be pivotal. Concomitant with this shift in focus, several studies challenged the validity of the RQH and downplayed its propriety. Herein, we examine in detail the assumptions that underpin the RQH in the hopes of furthering conceptual understanding and promoting appropriate application of the hypothesis. We identify issues and inconsistencies with the assumptions of the RQH, and propose a redefinition where the Red Queen's reign is restricted to certain types of biotic interactions and evolutionary patterns occurring at the population level. PMID- 29720446 TI - A tropical arthropod unravels local and global environmental dependence of seasonal temperature-size response. AB - In most ectotherms, adult body size decreases with warming, the so-called 'temperature-size rule' (TSR). However, the extent to which the strength of the TSR varies naturally within species is little known, and the significance of this phenomenon for tropical biota has been largely neglected. Here, we show that the adult body mass of the soil mite Rostrozetes ovulum declined as maximum temperature increased over seasons in a central Amazonian rainforest. Further, per cent decline per degrees C was fourfold higher in riparian than in upland forests, possibly reflecting differences in oxygen and/or resource supply. Adding our results to a global dataset revealed that, across terrestrial arthropods, the seasonal TSR is generally stronger in hotter environments. Our study suggests that size thermal dependence varies predictably with the environment both locally and globally. PMID- 29720445 TI - Warming under seminatural outdoor conditions in the larval stage negatively affects insect flight performance. AB - Laboratory studies indicate global warming may cause changes in locomotor performance directly relevant for fitness and dispersal. Yet, this remains to be tested under seminatural settings, and the connection with warming-induced alterations in the underlying traits has been rarely studied. In an outdoor mesocosm experiment with the damselfly Ischnura elegans, 4 degrees C warming in the larval stage decreased the flight muscle mass, which correlated with a lower flight endurance. Warming did not affect body mass, size or wing morphology. This illustrates how carry-over effects of warming under seminatural conditions during early development bridge metamorphosis and negatively impact locomotor performance through changes in a key flight-related trait. PMID- 29720447 TI - Moving like a model: mimicry of hymenopteran flight trajectories by clearwing moths of Southeast Asian rainforests. AB - Clearwing moths are known for their physical resemblance to hymenopterans, but the extent of their behavioural mimicry is unknown. We describe zigzag flights of sesiid bee mimics that are nearly indistinguishable from those of sympatric bees, whereas sesiid wasp mimics display faster, straighter flights more akin to those of wasps. In particular, the flight of the sesiids Heterosphecia pahangensis, Aschistophleps argentifasciata and Pyrophleps cruentata resembles both Tetragonilla collina and T. atripes stingless bees and, to a lesser extent, dwarf honeybees Apis andreniformis, whereas the sesiid Pyrophleps sp. resembles Tachysphex sp. wasps. These findings represent the first experimental evidence for behavioural mimicry in clearwing moths. PMID- 29720448 TI - Microbial ecology perturbation in human IgA deficiency. AB - Paradoxically, loss of immunoglobulin A (IgA), one of the most abundant antibodies, does not irrevocably lead to severe infections in humans but rather is associated with relatively mild respiratory infections, atopy, and autoimmunity. IgA might therefore also play covert roles, not uniquely associated with control of pathogens. We show that human IgA deficiency is not associated with massive quantitative perturbations of gut microbial ecology. Metagenomic analysis highlights an expected pathobiont expansion but a less expected depletion in some typically beneficial symbionts. Gut colonization by species usually present in the oropharynx is also reminiscent of spatial microbiota disorganization. IgM only partially rescues IgA deficiency because not all typical IgA targets are efficiently bound by IgM in the intestinal lumen. Together, IgA appears to play a nonredundant role at the forefront of the immune/microbial interface, away from the intestinal barrier, ranging from pathobiont control and regulation of systemic inflammation to preservation of commensal diversity and community networks. PMID- 29720450 TI - ER stress in prostate cancer: A therapeutically exploitable vulnerability? AB - Cooperative oncogenic effects resulting from the loss of PTEN and overexpression of MYC overcome the deleterious effects of endoplasmic reticulum stress not only to promote the growth of aggressive prostate cancer but also to expose a new therapy target for this disease (Nguyen et al, this issue). PMID- 29720449 TI - Development of a stress response therapy targeting aggressive prostate cancer. AB - Oncogenic lesions up-regulate bioenergetically demanding cellular processes, such as protein synthesis, to drive cancer cell growth and continued proliferation. However, the hijacking of these key processes by oncogenic pathways imposes onerous cell stress that must be mitigated by adaptive responses for cell survival. The mechanism by which these adaptive responses are established, their functional consequences for tumor development, and their implications for therapeutic interventions remain largely unknown. Using murine and humanized models of prostate cancer (PCa), we show that one of the three branches of the unfolded protein response is selectively activated in advanced PCa. This adaptive response activates the phosphorylation of the eukaryotic initiation factor 2 alpha (P-eIF2alpha) to reset global protein synthesis to a level that fosters aggressive tumor development and is a marker of poor patient survival upon the acquisition of multiple oncogenic lesions. Using patient-derived xenograft models and an inhibitor of P-eIF2alpha activity, ISRIB, our data show that targeting this adaptive brake for protein synthesis selectively triggers cytotoxicity against aggressive metastatic PCa, a disease for which presently there is no cure. PMID- 29720451 TI - TLR7 agonists induce transient viremia and reduce the viral reservoir in SIV infected rhesus macaques on antiretroviral therapy. AB - Antiretroviral therapy (ART) can halt HIV-1 replication but fails to target the long-lived latent viral reservoir. Several pharmacological compounds have been evaluated for their ability to reverse HIV-1 latency, but none has demonstrably reduced the latent HIV-1 reservoir or affected viral rebound after the interruption of ART. We evaluated orally administered selective Toll-like receptor 7 (TLR7) agonists GS-986 and GS-9620 for their ability to induce transient viremia in rhesus macaques infected with simian immunodeficiency virus (SIV) and treated with suppressive ART. In an initial dose-escalation study, and a subsequent dose-optimization study, we found that TLR7 agonists activated multiple innate and adaptive immune cell populations in addition to inducing expression of SIV RNA. We also observed TLR7 agonist-induced reductions in SIV DNA and measured inducible virus from treated animals in ex vivo cell cultures. In a second study, after stopping ART, two of nine treated animals remained aviremic for more than 2 years, even after in vivo CD8+ T cell depletion. Moreover, adoptive transfer of cells from aviremic animals could not induce de novo infection in naive recipient macaques. These findings suggest that TLR7 agonists may facilitate reduction of the viral reservoir in a subset of SIV infected rhesus macaques. PMID- 29720452 TI - Arginine vasopressin in cerebrospinal fluid is a marker of sociality in nonhuman primates. AB - Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by core social impairments. ASD remains poorly understood because of the difficulty in studying disease biology directly in patients and the reliance on mouse models that lack clinically relevant, complex social cognition abilities. We use ethological observations in rhesus macaques to identify male monkeys with naturally occurring low sociality. These monkeys showed differences in specific neuropeptide and kinase signaling pathways compared to socially competent male monkeys. Using a discovery and replication design, we identified arginine vasopressin (AVP) in cerebrospinal fluid (CSF) as a key marker of group differences in monkey sociality; we replicated these findings in an independent monkey cohort. We also confirmed in an additional monkey cohort that AVP concentration in CSF is a stable trait-like measure. Next, we showed in a small pediatric cohort that CSF AVP concentrations were lower in male children with ASD compared to age-matched male children without ASD (but with other medical conditions). We demonstrated that CSF AVP concentration was sufficient to accurately distinguish ASD cases from medical controls. These data suggest that AVP and its signaling pathway warrant consideration in future research studies investigating new targets for diagnostics and drug development in ASD. PMID- 29720453 TI - Playing 'hide-and-seek' with factor H: game-theoretical analysis of a single nucleotide polymorphism. AB - As a part of the complement system, factor H regulates phagocytosis and helps differentiate between a body's own and foreign cells. Owing to mimicry efforts, some pathogenic microorganisms such as Candida albicans are able to bind factor H on their cell surfaces and, thus, become similar to host cells. This implies that the decision between self and foreign is not clear-cut, which leads to a classification problem for the immune system. Here, two different alleles determining the binding affinity of factor H are relevant. Those alleles differ in the SNP Y402H; they are known to be associated with susceptibility to certain diseases. Interestingly, the fraction of both alleles differs in ethnic groups. The game-theoretical model proposed in this article explains the coexistence of both alleles by a battle of the sexes game and investigates the trade-off between pathogen detection and protection of host cells. Further, we discuss the ethnicity-dependent frequencies of the alleles. Moreover, the model elucidates the mimicry efforts by pathogenic microorganisms. PMID- 29720454 TI - Data-driven dynamical model indicates that the heat shock response in Chlamydomonas reinhardtii is tailored to handle natural temperature variation. AB - Global warming exposes plants to severe heat stress, with consequent crop yield reduction. Organisms exposed to high temperature stresses typically protect themselves with a heat shock response (HSR), where accumulation of unfolded proteins initiates the synthesis of heat shock proteins through the heat shock transcription factor HSF1. While the molecular mechanisms are qualitatively well characterized, our quantitative understanding of the underlying dynamics is still very limited. Here, we study the dynamics of HSR in the photosynthetic model organism Chlamydomonas reinhardtii with a data-driven mathematical model of HSR. We based our dynamical model mostly on mass action kinetics, with a few nonlinear terms. The model was parametrized and validated by several independent datasets obtained from the literature. We demonstrate that HSR quantitatively and significantly differs if an increase in temperature of the same magnitude occurs abruptly, as often applied under laboratory conditions, or gradually, which would rather be expected under natural conditions. In contrast to rapid temperature increases, under gradual changes only negligible amounts of misfolded proteins accumulate, indicating that the HSR of C. reinhardtii efficiently avoids the accumulation of misfolded proteins under conditions most likely to prevail in nature. The mathematical model we developed is a flexible tool to simulate the HSR to different conditions and complements the current experimental approaches. PMID- 29720456 TI - NHS faces huge challenge to become digitally driven by 2028, a decade later than originally promised. PMID- 29720455 TI - Flow rate of transport network controls uniform metabolite supply to tissue. AB - Life and functioning of higher organisms depends on the continuous supply of metabolites to tissues and organs. What are the requirements on the transport network pervading a tissue to provide a uniform supply of nutrients, minerals or hormones? To theoretically answer this question, we present an analytical scaling argument and numerical simulations on how flow dynamics and network architecture control active spread and uniform supply of metabolites by studying the example of xylem vessels in plants. We identify the fluid inflow rate as the key factor for uniform supply. While at low inflow rates metabolites are already exhausted close to flow inlets, too high inflow flushes metabolites through the network and deprives tissue close to inlets of supply. In between these two regimes, there exists an optimal inflow rate that yields a uniform supply of metabolites. We determine this optimal inflow analytically in quantitative agreement with numerical results. Optimizing network architecture by reducing the supply variance over all network tubes, we identify patterns of tube dilation or contraction that compensate sub-optimal supply for the case of too low or too high inflow rate. PMID- 29720458 TI - Archive of medical photographs turns back the hands of time. PMID- 29720457 TI - Five new medical schools: a decline in standards is inevitable. PMID- 29720459 TI - Impact of an antiretroviral stewardship strategy on medication error rates. AB - PURPOSE: The impact of an antiretroviral stewardship strategy on medication error rates was evaluated. METHODS: This single-center, retrospective, comparative cohort study included patients at least 18 years of age infected with human immunodeficiency virus (HIV) who were receiving antiretrovirals and admitted to the hospital. A multicomponent approach was developed and implemented and included modifications to the order-entry and verification system, pharmacist education, and a pharmacist-led antiretroviral therapy checklist. Pharmacists performed prospective audits using the checklist at the time of order verification. To assess the impact of the intervention, a retrospective review was performed before and after implementation to assess antiretroviral errors. RESULTS: Totals of 208 and 24 errors were identified before and after the intervention, respectively, resulting in a significant reduction in the overall error rate (p < 0.001). In the postintervention group, significantly lower medication error rates were found in both patient admissions containing at least 1 medication error (p < 0.001) and those with 2 or more errors (p < 0.001). Significant reductions were also identified in each error type, including incorrect/incomplete medication regimen, incorrect dosing regimen, incorrect renal dose adjustment, incorrect administration, and the presence of a major drug drug interaction. A regression tree selected ritonavir as the only specific medication that best predicted more errors preintervention (p < 0.001); however, no antiretrovirals reliably predicted errors postintervention. CONCLUSION: An antiretroviral stewardship strategy for hospitalized HIV patients including prospective audit by staff pharmacists through use of an antiretroviral medication therapy checklist at the time of order verification decreased error rates. PMID- 29720460 TI - Sixty seconds on . . . the secret tobacco papers. PMID- 29720461 TI - Doctors protest against "hostile environment" immigration policy spreading to NHS. PMID- 29720462 TI - Neurologist's 2500 patients are recalled over concerns about diagnoses. PMID- 29720463 TI - Effectiveness of a childhood obesity prevention programme delivered through schools, targeting 6 and 7 year olds: cluster randomised controlled trial (WAVES study). PMID- 29720464 TI - Existing medical schools need support to improve dropout rate. PMID- 29720465 TI - A radical proposal: to promote children's wellbeing give them the vote. PMID- 29720466 TI - Fight childhood obesity with multiple methods, not just more taxes, MPs hear. PMID- 29720468 TI - Younger, female, and BME doctors are more likely to have revalidation deferred. PMID- 29720467 TI - Home devices deliver data for dementia care. PMID- 29720470 TI - Girl awarded L19m after delayed blood transfusion at birth left her with brain injuries. PMID- 29720469 TI - Do schoolbags cause back pain in children and adolescents? A systematic review. AB - OBJECTIVE: To investigate whether characteristics of schoolbag use are risk factors for back pain in children and adolescents. DATA SOURCES: Electronic searches of MEDLINE, EMBASE and CINAHL databases up to April 2016. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Prospective cohort studies, cross-sectional and randomised controlled trials conducted with children or adolescents. The primary outcome was an episode of back pain and the secondary outcomes were an episode of care seeking and school absence due to back pain. We weighted evidence from longitudinal studies above that from cross-sectional. The risk of bias of the longitudinal studies was assessed by a modified version of the Quality in Prognosis Studies tool. RESULTS: We included 69 studies (n=72 627), of which five were prospective longitudinal and 64 cross-sectional or retrospective. We found evidence from five prospective studies that schoolbag characteristics such as weight, design and carriage method do not increase the risk of developing back pain in children and adolescents. The included studies were at moderate to high risk of bias. Evidence from cross-sectional studies aligned with that from longitudinal studies (ie, there was no consistent pattern of association between schoolbag use or type and back pain). We were unable to pool results due to different variables and inconsistent results. SUMMARY/CONCLUSION: There is no convincing evidence that aspects of schoolbag use increase the risk of back pain in children and adolescents. PMID- 29720471 TI - Bone marrow transplantation corrects haemolytic anaemia in a novel ENU mutagenesis mouse model of TPI deficiency. AB - In this study, we performed a genome-wide N-ethyl-N-nitrosourea (ENU) mutagenesis screen in mice to identify novel genes or alleles that regulate erythropoiesis. Here, we describe a recessive mouse strain, called RBC19, harbouring a point mutation within the housekeeping gene, Tpi1, which encodes the glycolysis enzyme, triosephosphate isomerase (TPI). A serine in place of a phenylalanine at amino acid 57 severely diminishes enzyme activity in red blood cells and other tissues, resulting in a macrocytic haemolytic phenotype in homozygous mice, which closely resembles human TPI deficiency. A rescue study was performed using bone marrow transplantation of wild-type donor cells, which restored all haematological parameters and increased red blood cell enzyme function to wild-type levels after 7 weeks. This is the first study performed in a mammalian model of TPI deficiency, demonstrating that the haematological phenotype can be rescued. PMID- 29720472 TI - Predicting Human Clearance of Organic Anion Transporting Polypeptide Substrates Using Cynomolgus Monkey: In Vitro-In Vivo Scaling of Hepatic Uptake Clearance. AB - This work explores the utility of the cynomolgus monkey as a preclinical model to predict hepatic uptake clearance mediated by organic anion transporting polypeptide (OATP) transporters. Nine OATP substrates (rosuvastatin, pravastatin, repaglinide, fexofenadine, cerivastatin, telmisartan, pitavastatin, bosentan, and valsartan) were investigated in plated cynomolgus monkey and human hepatocytes. Total uptake clearance and passive diffusion were measured in vitro from initial rates in the absence and presence of the OATP inhibitor rifamycin SV , respectively. Total uptake clearance values in plated hepatocytes ranged over three orders of magnitude in both species, with a similar rank order and good agreement in the relative contribution of active transport to total uptake between cynomolgus monkey and human. In vivo hepatic clearance for these nine drugs was determined in cynomolgus monkey after intravenous dosing. Hepatic clearances showed a range similar to human parameters and good predictions from respective hepatocyte parameters (with 2.7- and 3.8-fold bias on average, respectively). The use of cross-species empirical scaling factors (determined from cynomolgus monkey data either as the data set average or individual drug values) improved prediction (less bias, better concordance) of human hepatic clearance from human hepatocyte data alone. In vitro intracellular binding in hepatocytes also correlated well between species. It is concluded that the minimal species differences observed for the current data set between cynomolgus monkey and human hepatocyte uptake, both in vitro and in vivo, support future use of this preclinical model to delineate drug hepatic uptake and enable prediction of human in vivo intrinsic hepatic clearance. PMID- 29720473 TI - Review of UK malaria treatment guidelines 2016 (Public Health England Advisory Committee on Malaria Prevention). PMID- 29720474 TI - Functional and genomic characterisation of a xenograft model system for the study of metastasis in triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) represents 10-20% of all human ductal adenocarcinomas and has a poor prognosis relative to other subtypes. Hence, new molecular targets for therapeutic intervention are necessary. Analyses of panels of human or mouse cancer lines derived from the same individual that differ in their cellular phenotypes but not in genetic background have been instrumental in defining the molecular players that drive the various hallmarks of cancer. To determine the molecular regulators of metastasis in TNBC, we completed a rigorous in vitro and in vivo characterisation of four populations of the MDA-MB-231 human breast cancer line ranging in aggressiveness from non-metastatic to spontaneously metastatic to lung, liver, spleen and lymph node. Single nucleotide polymorphism (SNP) array analyses and genome-wide mRNA expression profiles of tumour cells isolated from orthotopic mammary xenografts were compared between the four lines to define both cell autonomous pathways and genes associated with metastatic proclivity. Gene set enrichment analysis (GSEA) demonstrated an unexpected association between both ribosome biogenesis and mRNA metabolism and metastatic capacity. Differentially expressed genes or families of related genes were allocated to one of four categories, associated with either metastatic initiation (e.g. CTSC, ENG, BMP2), metastatic virulence (e.g. ADAMTS1, TIE1), metastatic suppression (e.g. CST1, CST2, CST4, CST6, SCNNA1, BMP4) or metastatic avirulence (e.g. CD74). Collectively, this model system based on MDA-MB-231 cells should be useful for the assessment of gene function in the metastatic cascade and also for the testing of novel experimental therapeutics for the treatment of TNBC.This article has an associated First Person interview with the first author of the paper. PMID- 29720476 TI - Sepsis-3 and simple rules. PMID- 29720475 TI - Comparison of qSOFA with current emergency department tools for screening of patients with sepsis for critical illness. AB - OBJECTIVE: We sought to compare the quick sequential organ failure assessment (qSOFA) to systemic inflammatory response syndrome (SIRS), severe sepsis criteria and lactate levels for their ability to identify ED patients with sepsis with critical illness. METHODS: We conducted this multicenter retrospective cohort study at five US hospitals, enrolling all adult patients admitted to these hospitals from their EDs with infectious disease-related illnesses from 1 January 2016 to 30 April 2016. We abstracted clinical variables for SIRS, severe sepsis and qSOFA scores, using values in the first 6 hours of ED stay. Our primary outcome was critical illness, defined as one or more of the composite outcomes of death, vasopressor use or intensive care unit (ICU) admission within 72 hours of presentation. We determined diagnostic test characteristics for qSOFA scores, SIRS, severe sepsis criteria and lactate level thresholds. MAIN RESULTS: Of 3743 enrolled patients, 512 (13.7%) had the primary composite outcome. The qSOFA scores were >=1, >2 and 3 in 1839 (49.1%), 626 (16.7%) and 146 (3.9%) patients, respectively; 2202 (58.8%) met SIRS criteria and 1085 (29.0%) met severe sepsis criteria. qSOFA >=1 and SIRS had similarly high sensitivity [86.1% (95% CI 82.8% to 89.0%) vs 86.7% (95% CI 83.5% to 89.5%)], but qSOFA >=1 had higher specificity [56.7% (95% CI 55.0% to 58.5%) vs 45.6% (43.9% to 47.3%); mean difference 11.1% (95% CI 8.7% to 13.6%)]. qSOFA >=2 had higher specificity than severe sepsis criteria [89.1% (88.0% to 90.2%) vs 77.5% (76.0% to 78.9%); mean difference 11.6% (9.8% to 13.4%)]. qSOFA >=1 had greater sensitivity than a lactate level >=2 (mean difference 24.6% (19.2% to 29.9%)). CONCLUSION: For patients admitted from the ED with infectious disease diagnoses, qSOFA criteria performed as well or better than SIRS criteria, severe sepsis criteria and lactate levels in predicting critical illness. PMID- 29720477 TI - Picking the right tools for the job: opening up the statistical toolkit to build a compelling case in sport and exercise medicine research. PMID- 29720478 TI - Criteria for return to running after anterior cruciate ligament reconstruction: a scoping review. AB - OBJECTIVE: To describe the criteria used to guide clinical decision-making regarding when a patient is ready to return to running (RTR) after ACL reconstruction. DESIGN: Scoping review. DATA SOURCES: The MEDLINE (PubMed), EMBASE, Web of Science, PEDro, SPORTDiscus and Cochrane Library electronic databases. We also screened the reference lists of included studies and conducted forward citation tracking. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Reported at least one criterion for permitting adult patients with primary ACL reconstruction to commence running postoperatively. RESULTS: 201 studies fulfilled the inclusion criteria and reported 205 time-based criteria for RTR. The median time from when RTR was permitted was 12 postoperative weeks (IQR=3.3, range 5-39 weeks). Fewer than one in five studies used additional clinical, strength or performance-based criteria for decision-making regarding RTR. Aside from time, the most frequently reported criteria for RTR were: full knee range of motion or >95% of the non-injured knee plus no pain or pain <2 on visual analogue scale; isometric extensor limb symmetry index (LSI)>70% plus extensor and flexor LSI>70%; and hop test LSI>70%. CONCLUSIONS: Fewer than one in five studies reported clinical, strength or performance-based criteria for RTR even though best evidence recommends performance-based criteria combined with time-based criteria to commence running activities following ACL reconstruction. PMID- 29720479 TI - Scientific rationale for changing lower water temperature limits for triathlon racing to 12 degrees C with wetsuits and 16 degrees C without wetsuits. AB - OBJECTIVES: To provide a scientific rationale for lower water temperature and wetsuit rules for elite and subelite triathletes. METHODS: 11 lean, competitive triathletes completed a 20 min flume swim, technical transition including bike control and psychomotor testing and a cycle across five different wetsuit and water temperature conditions: with wetsuit: 10 degrees C, 12 degrees C and 14 degrees C; without wetsuit (skins): 14 degrees C and 16 degrees C. Deep body (rectal) temperature (Tre), psychomotor performance and the ability to complete a technical bike course after the swim were measured, as well as swimming and cycling performance. RESULTS: In skins conditions, only 4 out of 11 athletes could complete the condition in 14 degrees C water, with two becoming hypothermic (Tre<35 degrees C) after a 20 min swim. All 11 athletes completed the condition in 16 degrees C. Tre fell further following 14 degrees C (mean 1.12 degrees C) than 16 degrees C (mean 0.59 degrees C) skins swim (p=0.01). In wetsuit conditions, cold shock prevented most athletes (4 out of 7) from completing the swim in 10 degrees C. In 12 degrees C and 14 degrees C almost all athletes completed the condition (17 out of 18). There was no difference in temperature or performance variables between conditions following wetsuit swims at 12 degrees C and 14 degrees C. CONCLUSION: The minimum recommended water temperature for racing is 12 degrees C in wetsuits and 16 degrees C without wetsuits. International Triathlon Union rules for racing were changed accordingly (January 2017). PMID- 29720481 TI - Sensing space and making place: the hospital and therapeutic landscapes in two cancer narratives. AB - This article explores the role of senses in the construction and experience of place, focusing on patients' experiences of hospital care. It compares two cancer narratives for their insights into the heterogeneous ways that hospital environments are made into therapeutic landscapes, arguing that they are a product of dynamic processes rather than something that is simply built. The article draws on a relational model of space and place, alongside literary analysis, to explore the making of un/healthy environments in embodied, affective and sensory terms. It indicates that sensory experiences in hospitals are made (un)therapeutic in relation to illness and recovery, as well as a range of social and human/non-human relations. These conclusions warn against making broad claims about 'good' or 'bad' hospital sensescapes, or against treating the hospital as a homogeneous space. They also offer new opportunities for medical geography and the medical humanities, by showing how illness and recovery are part of the relational making of space and place. PMID- 29720480 TI - Targeting USP22 Suppresses Tumorigenicity and Enhances Cisplatin Sensitivity Through ALDH1A3 Downregulation in Cancer-Initiating Cells from Lung Adenocarcinoma. AB - Loss of monoubiquitination of histone H2B (H2Bub1) was found to be associated with poor-differentiation and enhanced malignancy of lung adenocarcinoma. This study investigated the association and impact of the ubiquitin-specific peptidase 22 (USP22), an H2Bub1 deubiquitinase, on stem cell-like characteristics and cisplatin resistance in cancer-initiating cells (CIC) from primary lung adenocarcinoma. CICs were isolated, enriched, and characterized from patient derived cancer tissues using both in vitro tumorsphere formation and in vivo xenograft assays. USP22 was determined to be predominantly expressed in CICs, a subpopulation of cells with high expression of the stem cell biomarkers, CD133 and CD44. The expression of USP22 in CICs is markedly reduced upon FBS/retinoic acid-induced differentiation. Moreover, knockdown of USP22 significantly suppressed tumorsphere formation and xenograft growth in NOD-SCID gamma (NSG) mice. Notably, USP22 and aldehyde dehydrogenase (ALDH) activity were elevated in tumorsphere cells that survived cisplatin treatment, whereas knockdown of USP22 significantly sensitizes tumorsphere cells to cisplatin. Interestingly, ALDH1A3, a predominant ALDH isozyme implicated in enhancing cisplatin resistance in lung adenocarcinoma, is significantly downregulated upon knockdown of USP22 in tumorsphere cells. Furthermore, knockdown of ALDH1A3 significantly sensitizes tumorsphere cells to cisplatin. Combined, these data demonstrate that USP22, predominantly expressed in CD133+ CICs, plays a critical role in tumorigenicity and cisplatin resistance in lung adenocarcinoma.Implications: Targeting USP22 represents a potential therapeutic approach to suppress CICs in lung adenocarcinoma partially through downregulation of ALDH1A3 expression. Mol Cancer Res; 16(7); 1161-71. (c)2018 AACR. PMID- 29720482 TI - Work history and radioprotection practices in relation to cancer incidence and mortality in US radiologic technologists performing nuclear medicine procedures. AB - INTRODUCTION: Technologists working in nuclear medicine (NM) are exposed to higher radiation doses than most other occupationally exposed populations. The aim of this study was to estimate the risk of cancer in NM technologists in relation to work history, procedures performed and radioprotection practices. METHODS: From the US Radiologic Technologists cohort study, 72 755 radiologic technologists who completed a 2003-2005 questionnaire were followed for cancer mortality through 31 December 2012 and for cancer incidence through completion of a questionnaire in 2012-2013. Multivariable-adjusted models were used to estimate HRs for total cancer incidence and mortality by history of ever performing NM procedures and frequency of performing specific diagnostic or therapeutic NM procedures and associated radiation protection measures by decade. RESULTS: During follow-up (mean=7.5 years), 960 incident cancers and 425 cancer deaths were reported among the 22 360 technologists who worked with NM procedures. We observed no increased risk of cancer incidence (HR 0.96, 95% CI 0.89 to 1.04) or death (HR 1.05, 95% CI 0.93 to 1.19) among workers who ever performed NM procedures. HRs for cancer incidence but not mortality were higher for technologists who began performing therapeutic procedures in 1960 and later compared with the 1950s. Frequency of performing diagnostic or therapeutic NM procedures and use of radioprotection measures were not consistently associated with cancer risk. No clear associations were observed for specific cancers, but results were based on small numbers. CONCLUSION: Cancer incidence and mortality were not associated with NM work history practices, including greater frequency of procedures performed. PMID- 29720483 TI - All in the family: proneural bHLH genes and neuronal diversity. AB - Proneural basic Helix-Loop-Helix (bHLH) proteins are required for neuronal determination and the differentiation of most neural precursor cells. These transcription factors are expressed in vastly divergent organisms, ranging from sponges to primates. Here, we review proneural bHLH gene evolution and function in the Drosophila and vertebrate nervous systems, arguing that the Drosophila gene atonal provides a useful platform for understanding proneural gene structure and regulation. We also discuss how functional equivalency experiments using distinct proneural genes can reveal how proneural gene duplication and divergence are interwoven with neuronal complexity. PMID- 29720484 TI - Ubiquitin-dependent degradation of CDK2 drives the therapeutic differentiation of AML by targeting PRDX2. AB - A distinct hallmark of acute myeloid leukemia (AML) is the arrest of leukemic myeloblasts at an immature stage of development. Therapies that overcome differentiation arrest have emerged as a powerful strategy for treating AML, but targeting leukemia differentiation remains challenging, mainly because of an incomplete mechanistic understanding of the process. Here, we unveil a new role for cyclin-dependent kinase 2 (CDK2) in blocking myeloid differentiation in AML. We show that among several interphase CDK, only CDK2 undergoes ubiquitin dependent proteasome degradation, which is accompanied by AML cell differentiation. By using the yeast 2-hybrid system and functional analyses, KLHL6 was identified as a specific E3 ubiquitin ligase regulating the degradation of CDK2. Importantly, inhibiting CDK2, but not other cyclin-dependent kinases CDK1/4/6, effectively induced granulocytic differentiation in AML cell lines and 5 major subtypes of primary patient-derived AML samples. Mechanistically, CDK2 depletion led to the reactivation of differentiation pathway translation, and the differentiation blockade function of CDK2 may be achieved directly by maintaining the activity of PRDX2. Finally, CDK2 depletion arrested tumor growth of AML cells in nude mice and extended survival in both AML cell line and PDX-AML cells derived xenograft mouse models. Thus, our work not only provides experimental evidence for validating CDK2 as a potential therapeutic target for differentiation, but also uncovers the biological function of the CDK2-PRDX2 axis in blocking AML differentiation. PMID- 29720486 TI - International cooperative study identifies treatment strategy in childhood ambiguous lineage leukemia. AB - Despite attempts to improve the definitions of ambiguous lineage leukemia (ALAL) during the last 2 decades, general therapy recommendations are missing. Herein, we report a large cohort of children with ALAL and propose a treatment strategy. A retrospective multinational study (International Berlin-Frankfurt-Munster Study of Leukemias of Ambiguous Lineage [iBFM-AMBI2012]) of 233 cases of pediatric ALAL patients is presented. Survival statistics were used to compare the prognosis of subsets and types of treatment. Five-year event-free survival (EFS) of patients with acute lymphoblastic leukemia (ALL)-type primary therapy (80% +/- 4%) was superior to that of children who received acute myeloid leukemia (AML)-type or combined-type treatment (36% +/- 7.2% and 50% +/- 12%, respectively). When ALL- or AML-specific gene fusions were excluded, 5-year EFS of CD19+ leukemia was 83% +/- 5.3% on ALL-type primary treatment compared with 0% +/- 0% and 28% +/- 14% on AML-type and combined-type primary treatment, respectively. Superiority of ALL type treatment was documented in single-population mixed phenotype ALAL (using World Health Organization and/or European Group for Immunophenotyping of Leukemia definitions) and bilineal ALAL. Treatment with ALL-type protocols is recommended for the majority of pediatric patients with ALAL, including cases with CD19+ ALAL. AML-type treatment is preferred in a minority of ALAL cases with CD19- and no other lymphoid features. No overall benefit of transplantation was documented, and it could be introduced in some patients with a poor response to treatment. As no clear indicator was found for a change in treatment type, this is to be considered only in cases with >=5% blasts after remission induction. The results provide a basis for a prospective trial. PMID- 29720488 TI - Recommendations for managing PD-1 blockade in the context of allogeneic HCT in Hodgkin lymphoma: taming a necessary evil. AB - PD-1 blockade is an effective therapy in relapsed/refractory (R/R) classical Hodgkin Lymphoma (cHL) who have relapsed after or are ineligible for autologous hematopoietic cell transplantation (HCT). Although single-agent anti-PD-1 monoclonal antibodies (mAb's) are associated with high response rates and durable remissions, available results to date suggest that a large majority of patients will eventually progress on therapy. Many of these patients are potential candidates for allogeneic HCT (allo-HCT) after receiving anti-PD-1 mAb's, and allo-HCT remains for now the only treatment with demonstrated curative potential in this setting. However, initial reports suggested that allo-HCT in this setting may be associated with increased risk of early transplant-related toxicity, likely driven by lingering effects of PD-1 blockade. Furthermore, many patients with R/R cHL who undergo allo-HCT will relapse after transplantation, most often with limited treatment options. Here again, PD-1 blockade appears to yield high response rates, but with an increased risk of attendant immune toxicity. Many questions remain regarding the use of PD-1 blockade before or after allo-HCT, especially in relation to the feasibility, outcome, optimal timing, and method of allo-HCT after PD-1 blockade. Despite the scarcity of prospective data, these questions are unavoidable and must be tackled by clinicians in the routine care of patients with advanced cHL. We provide consensus recommendations of a working group based on available data and experience, in an effort to help guide treatment decisions until more definitive data are obtained. PMID- 29720487 TI - Metabolic heterogeneity on baseline 18FDG-PET/CT scan is a predictor of outcome in primary mediastinal B-cell lymphoma. AB - An important unmet need in the management of primary mediastinal B-cell lymphoma (PMBCL) is to identify the patients for whom first-line therapy will fail to intervene before the lymphoma becomes refractory. High heterogeneity of intratumoral 18F-fluorodeoxyglucose (18FDG) uptake distribution on positron emission tomography/computed tomography (PET/CT) scans has been suggested as a possible marker of chemoresistance in solid tumors. In the present study, we investigated the prognostic value of metabolic heterogeneity (MH) in 103 patients with PMBCL prospectively enrolled in the International Extranodal Lymphoma Study Group (IELSG) 26 study, aimed at clarifying the role of PET in this lymphoma subtype. MH was estimated using the area under curve of cumulative standardized uptake value-volume histogram (AUC-CSH) method. Progression-free survival at 5 years was 94% vs 73% in low- and high-MH groups, respectively (P = .0001). In a Cox model of progression-free survival including dichotomized MH, metabolic tumor volume, total lesion glycolysis (TLG), international prognostic index, and tumor bulk (mediastinal mass > 10 cm), as well as age as a continuous variable, only TLG (P < .001) and MH (P < .001) retained statistical significance. Using these 2 features to construct a simple prognostic model resulted in early and accurate (positive predictive value, 89%; negative predictive value, >=90%) identification of patients at high risk for progression at a point that would allow the use of risk-adapted treatments. This may provide an important opportunity for the design of future trials aimed at helping the minority of patients who harbor chemorefractory PMBCL. The study is registered at ClinicalTrials.gov as NCT00944567. PMID- 29720485 TI - Consensus recommendations for the diagnosis and clinical management of Rosai Dorfman-Destombes disease. AB - Rosai-Dorfman-Destombes disease (RDD) is a rare non-Langerhans cell histiocytosis characterized by accumulation of activated histiocytes within affected tissues. RDD, which now belongs to the R group of the 2016 revised histiocytosis classification, is a widely heterogeneous entity with a range of clinical phenotypes occurring in isolation or in association with autoimmune or malignant diseases. Recent studies have found NRAS, KRAS, MAP2K1, and ARAF mutations in lesional tissues, raising the possibility of a clonal origin in some forms of RDD. More than 1000 reports have been published in the English literature; however, there is a lack of consensus regarding approach for the clinical management of RDD. Although in most cases RDD can be observed or treated with local therapies, some patients with refractory or multifocal disease experience morbidity and mortality. Here we provide the first consensus multidisciplinary recommendations for the diagnosis and management of RDD. These recommendations were discussed at the 32nd Histiocyte Society Meeting by an international group of academic clinicians and pathologists with expertise in RDD. We include guidelines for clinical, laboratory, pathologic, and radiographic evaluation of patients with RDD together with treatment recommendations based on clinical experience and review of the literature. PMID- 29720489 TI - Ensuring respect for persons in COMPASS: a cluster randomised pragmatic clinical trial. AB - : Cluster randomised clinical trials present unique challenges in meeting ethical obligations to those who are treated at a randomised site. Obtaining informed consent for research within the context of clinical care is one such challenge. In order to solve this problem it is important that an informed consent process be effective and efficient, and that it does not impede the research or the healthcare. The innovative approach to informed consent employed in the COMPASS study demonstrates the feasibility of upholding ethical standards without imposing undue burden on clinical workflows, staff members or patients who may participate in the research by virtue of their presence in a cluster randomised facility. The COMPASS study included 40 randomised sites and compared the effectiveness of a postacute stroke intervention with standard care. Each site provided either the comprehensive postacute stroke intervention or standard care according to the randomisation assignment. Working together, the study team, institutional review board and members of the community designed an ethically appropriate and operationally reasonable consent process which was carried out successfully at all randomised sites. This achievement is noteworthy because it demonstrates how to effectively conduct appropriate informed consent in cluster randomised trials, and because it provides a model that can easily be adapted for other pragmatic studies. With this innovative approach to informed consent, patients have access to the information they need about research occurring where they are seeking care, and medical researchers can conduct their studies without ethical concerns or unreasonable logistical impediments. TRIAL REGISTRATION NUMBER: NCT02588664, recruiting. This article covers the development of consent process that is currentlty being employed in the study. PMID- 29720490 TI - Implementing a Quality Management System in the Medical Microbiology Laboratory. AB - This document outlines a comprehensive practical approach to a laboratory quality management system (QMS) by describing how to operationalize the management and technical requirements described in the ISO 15189 international standard. It provides a crosswalk of the ISO requirements for quality and competence for medical laboratories to the 12 quality system essentials delineated by the Clinical and Laboratory Standards Institute. The quality principles are organized under three main categories: quality infrastructure, laboratory operations, and quality assurance and continual improvement. The roles and responsibilities to establish and sustain a QMS are outlined for microbiology laboratory staff, laboratory management personnel, and the institution's leadership. Examples and forms are included to assist in the real-world implementation of this system and to allow the adaptation of the system for each laboratory's unique environment. Errors and nonconforming events are acknowledged and embraced as an opportunity to improve the quality of the laboratory, a culture shift from blaming individuals. An effective QMS encourages "systems thinking" by providing a process to think globally of the effects of any type of change. Ultimately, a successful QMS is achieved when its principles are adopted as part of daily practice throughout the total testing process continuum. PMID- 29720492 TI - Sustained clonal hematopoiesis by HLA-lacking hematopoietic stem cells without driver mutations in aplastic anemia. AB - Clonal hematopoiesis by hematopoietic stem progenitor cells (HSPCs) that lack an HLA class I allele (HLA- HSPCs) is common in patients with acquired aplastic anemia (AA); however, it remains unknown whether the cytotoxic T lymphocyte (CTL) attack that allows for survival of HLA- HSPCs is directed at nonmutated HSPCs or HSPCs with somatic mutations or how escaped HLA- HSPC clones support sustained hematopoiesis. We investigated the presence of somatic mutations in HLA- granulocytes obtained from 15 AA patients in long-term remission (median, 13 years; range, 2-30 years). Targeted sequencing of HLA- granulocytes revealed somatic mutations (DNMT3A, n = 2; TET2, ZRSR2, and CBL, n = 1) in 3 elderly patients between 79 and 92 years of age, but not in 12 other patients aged 27 to 74 years (median, 51.5 years). The chronological and clonogenic analyses of the 3 cases revealed that ZRSR2 mutation in 1 case, which occurred in an HLA- HSPC with a DNMT3A mutation, was the only mutation associated with expansion of the HSPC clone. Whole-exome sequencing of the sorted HLA- granulocytes confirmed the absence of any driver mutations in 5 patients who had a particularly large loss of heterozygosity in chromosome 6p (6pLOH) clone size. Flow-fluorescence in situ hybridization analyses of sorted HLA+ and HLA- granulocytes showed no telomere attrition in HLA- granulocytes. The findings suggest that HLA- HSPC clones that escape CTL attack are essentially free from somatic mutations related to myeloid malignancies and are able to support long-term clonal hematopoiesis without developing driver mutations in AA patients unless HLA loss occurs in HSPCs with somatic mutations. PMID- 29720493 TI - Measuring and improving the quality of NHS care for children and young people. PMID- 29720491 TI - Rapid immune reconstitution of SCID-X1 canines after G-CSF/AMD3100 mobilization and in vivo gene therapy. AB - Hematopoietic stem-cell gene therapy is a promising treatment of X-linked severe combined immunodeficiency disease (SCID-X1), but currently, it requires recipient conditioning, extensive cell manipulation, and sophisticated facilities. With these limitations in mind, we explored a simpler therapeutic approach to SCID-X1 treatment by direct IV administration of foamy virus (FV) vectors in the canine model. FV vectors were used because they have a favorable integration site profile and are resistant to serum inactivation. Here, we show improved efficacy of our in vivo gene therapy platform by mobilization with granulocyte colony stimulating factor (G-CSF) and AMD3100 before injection of an optimized FV vector incorporating the human phosphoglycerate kinase enhancerless promoter. G CSF/AMD3100 mobilization before FV vector delivery accelerated kinetics of CD3+ lymphocyte recovery, promoted thymopoiesis, and increased immune clonal diversity. Gene-corrected T lymphocytes exhibited a normal CD4:CD8 ratio and a broad T-cell receptor repertoire and showed restored gammaC-dependent signaling function. Treated animals showed normal primary and secondary antibody responses to bacteriophage immunization and evidence for immunoglobulin class switching. These results demonstrate safety and efficacy of an accessible, portable, and translatable platform with no conditioning regimen for the treatment of SCID-X1 and other genetic diseases. PMID- 29720494 TI - Melatonin for the management of sleep problems in children with neurodevelopmental disorders: a systematic review and meta-analysis. AB - IMPORTANCE: Children with neurodevelopmental disorders have a higher prevalence of sleep disturbances. Currently there is variation in the use of melatonin; hence, an up-to-date systematic review is indicated to summarise the current available evidence. OBJECTIVE: To determine the efficacy and safety of melatonin as therapy for sleep problems in children with neurodevelopmental disorders. DATA SOURCES AND STUDY SELECTIONS: PubMed, Embase, the Cumulative Index to Nursing and Allied Health Literature and the Cochrane Central Register of Controlled Trials were searched from inception up to January 2018. Two reviewers performed data assessment and extraction. We assessed randomised controlled trials that compared melatonin with placebo or other intervention for the management of sleep disorders in children (<18 years) with neurodevelopmental disorders. DATA EXTRACTION AND SYNTHESIS: We identified 3262 citations and included 13 studies in this meta-analysis. MAIN OUTCOMES: Main outcomes included total sleep time, sleep onset latency, frequency of nocturnal awakenings and adverse events. RESULTS: Thirteen randomised controlled trials (n=682) met the inclusion criteria. A meta analysis of nine studies (n=541) showed that melatonin significantly improved total sleep time compared with placebo (mean difference (MD)=48.26 min, 95% CI 36.78 to 59.73, I2=31%). In 11 studies (n=581), sleep onset latency improved significantly with melatonin use (MD=-28.97, 95% CI -39.78 to -18.17). No difference was noted in the frequency of nocturnal awakenings (MD=-0.49, 95% CI 1.71 to 0.73). No medication-related serious adverse event was reported. CONCLUSION: Melatonin appeared safe and effective in improving sleep in the studied children. The overall quality of the evidence is limited due to heterogeneity and inconsistency. Further research is needed. PMID- 29720495 TI - Don't blame the messenger: a response to Debelle et al and the Royal College of Paediatrics and Child Health. PMID- 29720496 TI - Children in disadvantaged neighbourhoods have more out-of-hospital emergencies: a population-based study. AB - OBJECTIVE: We wanted to study whether the socioeconomic status of a neighbourhood can predict the incidence of paediatric out-of-hospital emergencies. METHODS: We conducted a population-based prospective study with all paediatric (0-15 years) out-of-hospital emergencies in Helsinki, Finland, in 2012-2013. We compared the geographical distribution of the emergencies in the paediatric population with those of mean income, unemployment level and educational level. The comparison was made both by the scene of the emergency and by the domicile of the patient. We also separately analysed the distribution of emergency medical (EM) contacts that were deemed medically unnecessary. RESULTS: The incidence of out-of-hospital emergencies was higher in areas with lower socioeconomic status and among children living inside those areas. Higher mean income was associated with lower incidence (risk ratio (RR) 0.970, 95% CI 0.957 to 0.983), and lower unemployment level to higher incidence (RR 1.046, 95% CI 1.002 to 1.092) of out-of-hospital emergencies inside a district. Higher mean income was associated with lower incidence of emergencies in the paediatric population living inside a district (RR 0.983, 95% CI 0.974 to 0.993). The distribution of medically unnecessary EM contacts was similar in all areas. CONCLUSIONS: The socioeconomic status of a neighbourhood was associated with the need for EM services (EMS) in the area, and in children living in the area. Overusing EMS for non-urgent or non-medical problems did not explain these findings. Instead, they seem to represent true differences in the incidence of paediatric emergencies. PMID- 29720497 TI - Molecular Mechanisms for Species Differences in Organic Anion Transporter 1, OAT1: Implications for Renal Drug Toxicity. AB - Species differences in renal drug transporters continue to plague drug development with animal models failing to adequately predict renal drug toxicity. For example, adefovir, a renally excreted antiviral drug, failed clinical studies for human immunodeficiency virus due to pronounced nephrotoxicity in humans. In this study, we demonstrated that there are large species differences in the kinetics of interactions of a key class of antiviral drugs, acyclic nucleoside phosphonates (ANPs), with organic anion transporter 1 [(OAT1) SLC22A6] and identified a key amino acid residue responsible for these differences. In OAT1 stably transfected human embryonic kidney 293 cells, the Km value of tenofovir for human OAT1 (hOAT1) was significantly lower than for OAT1 orthologs from common preclinical animals, including cynomolgus monkey, mouse, rat, and dog. Chimeric and site-directed mutagenesis studies along with comparative structure modeling identified serine at position 203 (S203) in hOAT1 as a determinant of its lower Km value. Furthermore, S203 is conserved in apes, and in contrast alanine at the equivalent position is conserved in preclinical animals and Old World monkeys, the most related primates to apes. Intriguingly, transport efficiencies are significantly higher for OAT1 orthologs from apes with high serum uric acid (SUA) levels than for the orthologs from species with low serum uric acid levels. In conclusion, our data provide a molecular mechanism underlying species differences in renal accumulation of nephrotoxic ANPs and a novel insight into OAT1 transport function in primate evolution. PMID- 29720498 TI - Altered Extracellular Vesicle Concentration, Cargo, and Function in Diabetes. AB - Type 2 diabetes is a chronic age-associated degenerative metabolic disease that reflects relative insulin deficiency and resistance. Extracellular vesicles (EVs) (exosomes, microvesicles, and apoptotic bodies) are small (30-400 nm) lipid-bound vesicles capable of shuttling functional proteins, nucleic acids, and lipids as part of intercellular communication systems. Recent studies in mouse models and in cell culture suggest that EVs may modulate insulin signaling. Here, we designed cross-sectional and longitudinal cohorts of euglycemic participants and participants with prediabetes or diabetes. Individuals with diabetes had significantly higher levels of EVs in their circulation than euglycemic control participants. Using a cell-specific EV assay, we identified that levels of erythrocyte-derived EVs are higher with diabetes. We found that insulin resistance increases EV secretion. Furthermore, the levels of insulin signaling proteins were altered in EVs from individuals with high levels of insulin resistance and beta-cell dysfunction. Moreover, EVs from individuals with diabetes were preferentially internalized by circulating leukocytes. Cytokine levels in the media and in EVs were higher from monocytes incubated with diabetic EVs. Microarray of these leukocytes revealed altered gene expression pathways related to cell survival, oxidative stress, and immune function. Collectively, these results suggest that insulin resistance increases the secretion of EVs, which are preferentially internalized by leukocytes, and alters leukocyte function. PMID- 29720499 TI - Gene Transfer of Engineered Calmodulin Alleviates Ventricular Arrhythmias in a Calsequestrin-Associated Mouse Model of Catecholaminergic Polymorphic Ventricular Tachycardia. AB - BACKGROUND: Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a familial arrhythmogenic syndrome characterized by sudden death. There are several genetic forms of CPVT associated with mutations in genes encoding the cardiac ryanodine receptor (RyR2) and its auxiliary proteins including calsequestrin (CASQ2) and calmodulin (CaM). It has been suggested that impairment of the ability of RyR2 to stay closed (ie, refractory) during diastole may be a common mechanism for these diseases. Here, we explore the possibility of engineering CaM variants that normalize abbreviated RyR2 refractoriness for subsequent viral mediated delivery to alleviate arrhythmias in non-CaM-related CPVT. METHODS AND RESULTS: To that end, we have designed a CaM protein (GSH-M37Q; dubbed as therapeutic CaM or T-CaM) that exhibited a slowed N-terminal Ca dissociation rate and prolonged RyR2 refractoriness in permeabilized myocytes derived from CPVT mice carrying the CASQ2 mutation R33Q. This T-CaM was introduced to the heart of R33Q mice through recombinant adeno-associated viral vector serotype 9. Eight weeks postinfection, we performed confocal microscopy to assess Ca handling and recorded surface ECGs to assess susceptibility to arrhythmias in vivo. During catecholamine stimulation with isoproterenol, T-CaM reduced isoproterenol promoted diastolic Ca waves in isolated CPVT cardiomyocytes. Importantly, T-CaM exposure abolished ventricular tachycardia in CPVT mice challenged with catecholamines. CONCLUSIONS: Our results suggest that gene transfer of T-CaM by adeno-associated viral vector serotype 9 improves myocyte Ca handling and alleviates arrhythmias in a calsequestrin-associated CPVT model, thus supporting the potential of a CaM-based antiarrhythmic approach as a therapeutic avenue for genetically distinct forms of CPVT. PMID- 29720500 TI - Xanthine Oxidase Inhibitor Allopurinol Prevents Oxidative Stress-Mediated Atrial Remodeling in Alloxan-Induced Diabetes Mellitus Rabbits. AB - BACKGROUND: There are several mechanisms, including inflammation, oxidative stress and abnormal calcium homeostasis, involved in the pathogenesis of atrial fibrillation. In diabetes mellitus (DM), increased oxidative stress may be attributable to higher xanthine oxidase activity. In this study, we examined the relationship between oxidative stress and atrial electrical and structural remodeling, and calcium handling abnormalities, and the potential beneficial effects of the xanthine oxidase inhibitor allopurinol upon these pathological changes. METHODS AND RESULTS: Ninety rabbits were randomly and equally divided into 3 groups: control, DM, and allopurinol-treated DM group. Echocardiographic and hemodynamic assessments were performed in vivo. Serum and tissue markers of oxidative stress and atrial fibrosis, including the protein expression were examined. Atrial interstitial fibrosis was evaluated by Masson trichrome staining. ICaL was measured from isolated left atrial cardiomyocytes using voltage-clamp techniques. Confocal microscopy was used to detect intracellular calcium transients. The Ca2+ handling protein expression was analyzed by Western blotting. Mitochondrial-related proteins were analyzed as markers of mitochondrial function. Compared with the control group, rabbits with DM showed left ventricular hypertrophy, increased atrial interstitial fibrosis, oxidative stress and fibrosis markers, ICaL and intracellular calcium transient, and atrial fibrillation inducibility. These abnormalities were alleviated by allopurinol treatment. CONCLUSIONS: Allopurinol, via its antioxidant effects, reduces atrial mechanical, structural, ion channel remodeling and mitochondrial synthesis abnormalities induced by DM-related increases in oxidative stress. PMID- 29720502 TI - Evaluation of the Impact of a Chronic Total Coronary Occlusion on Ventricular Arrhythmias and Long-Term Mortality in Patients With Ischemic Cardiomyopathy and an Implantable Cardioverter-Defibrillator (the eCTOpy-in-ICD Study). AB - BACKGROUND: Previous studies report conflicting results about a higher incidence of ventricular arrhythmias in patients with a chronic total coronary occlusion (CTO). We aimed to investigate this association in a large cohort of implantable cardioverter defibrillator patients with long-term follow-up. METHODS AND RESULTS: All consecutive patients from 1992 onwards who underwent implantable cardioverter defibrillator implantation for ischemic cardiomyopathy at the Leiden University Medical Center were evaluated. Coronary angiograms were reviewed for the presence of a CTO. The occurrence of ventricular arrhythmias and survival status at follow-up were compared between patients with and patients without a CTO. A total of 722 patients constitute the study cohort (age 66+/-11 years; 84% males; 74% primary prevention, median left ventricular ejection fraction 30% [first-third quartile: 25-37], 44% received a cardiac resynchronization therapy defibrillator). At baseline, 240 patients (33%) had a CTO, and the CTOs were present for at least 44 (2-127) months. The median follow-up duration was 4 (2-6) years. On long-term follow-up, CTO patients had a higher crude appropriate device therapy rate (37% versus 27%, P=0.010) and a lower crude survival rate (51% versus 67%, P<0.001) compared with patients without a CTO. Corrected for baseline characteristics including left ventricular ejection fraction, the presence of a CTO was an independent predictor for appropriate device therapy. CONCLUSIONS: The presence of a CTO in implantable cardioverter defibrillator patients was associated with more appropriate device therapy and worse prognosis at long-term follow-up. Further investigation is warranted regarding a potential beneficial effect of CTO revascularization on the incidence of ventricular arrhythmias. PMID- 29720501 TI - Bilirubin Is Inversely Associated With Cardiovascular Disease Among HIV-Positive and HIV-Negative Individuals in VACS (Veterans Aging Cohort Study). AB - BACKGROUND: Bilirubin may protect against cardiovascular disease (CVD) by reducing oxidative stress. Whether elevated bilirubin reduces the risk of CVD events among HIV+ individuals and if this differs from uninfected individuals remain unclear. We assessed whether bilirubin independently predicted the risk of CVD events among HIV+ and uninfected participants in VACS (Veterans Aging Cohort Study). METHODS AND RESULTS: We conducted a prospective cohort study using VACS participants free of baseline CVD. Total bilirubin was categorized by quartiles. CVD as well as acute myocardial infarction, heart failure, and ischemic stroke events were assessed. Cox regression was used to evaluate hazard ratios of outcomes associated with quartiles of total bilirubin in HIV+ and uninfected people after adjusting for multiple risk factors. There were 96 381 participants (30 427 HIV+); mean age was 48 years, 48% were black, and 97% were men. There were 6603 total incident CVD events over a mean of 5.7 years. In adjusted models, increasing quartiles of baseline total bilirubin were associated with decreased hazards of all outcomes (hazard ratio, 0.86; 95% confidence interval, 0.80-0.91). Among HIV+ participants, results persisted for heart failure, ischemic stroke, and total CVD, but nonsignificant associations were observed for acute myocardial infarction. CONCLUSIONS: VACS participants (regardless of HIV status) with elevated bilirubin levels had a lower risk of incident total CVD, acute myocardial infarction, heart failure, and ischemic stroke events after adjusting for known risk factors. Future studies should investigate how this apparently protective effect of elevated bilirubin could be harnessed to reduce CVD risk or improve risk estimation among HIV+ individuals. PMID- 29720503 TI - Clinical Characteristics, Sex Differences, and Outcomes in Patients With Normal or Near-Normal Coronary Arteries, Non-Obstructive or Obstructive Coronary Artery Disease. AB - BACKGROUND: Normal or near-normal coronary arteries (NNCAs) or nonobstructive coronary artery disease (CAD) are found on invasive coronary angiography in ~55% of patients. Some attribute this to frequent referral of low-risk patients. We sought to identify the referral indications, pretest risk, key clinical characteristics, sex, and outcomes in patients with NNCAs and nonobstructive CAD versus obstructive CAD on nonemergent invasive coronary angiography. METHODS AND RESULTS: Over 24 months, 925 consecutive patients were classified as having NNCAs (<=20% stenosis), nonobstructive CAD (21-49% stenosis), or obstructive CAD (>=50% stenosis). Outcomes included cardiac death, nonfatal myocardial infarction, and late revasclarization. NNCAs were found in 285 patients (31.0%), nonobstructive CAD in 125 (13.5%), and obstructive CAD in 513 (55.5%). NNCAs or nonobstructive CAD was found in 40.5% with stress ischemia, 27.9% after a non-ST-elevation myocardial infarction, and in 55.5% with stable or unstable angina. More women than men (53.5% versus 37.2%; P<0.001) had NNCAs or nonobstructive CAD across all referral indications. Pretest risk was high and ICA appropriate in 75.5% and 99.2% of patients, respectively. Annual rates of cardiac death or nonfatal myocardial infarction were 1.0%, 1.1%, and 6.7%, respectively, for patients with NNCAs, nonobstructive CAD, and obstructive CAD (P<0.001). No sex differences in outcomes were observed with either NNCAs, nonobstructive CAD, or obstructive CAD (P=0.84). CONCLUSIONS: Many (44.5%) patients undergoing nonemergent invasive coronary angiography have NNCAs or nonobstructive CAD despite high pretest risk, including ischemia and troponin elevation. Although women had more NNCAs or nonobstructive CAD, there were no differences in event rates by sex. Patients with NNCAs and nonobstructive CAD had very low event rates. PMID- 29720504 TI - Self-Reported Smoking, Urine Cotinine, and Risk of Cardiovascular Disease: Findings From the PREVEND (Prevention of Renal and Vascular End-Stage Disease) Prospective Cohort Study. AB - BACKGROUND: We aimed to compare the associations of smoking exposure as assessed by self-reports and urine cotinine with cardiovascular disease (CVD) risk and determine the potential utility of cotinine for CVD risk prediction. METHODS AND RESULTS: Smoking status by self-reports and urine cotinine were assessed at baseline in 4737 participants (mean age, 53 years) of the PREVEND (Prevention of Renal and Vascular End-Stage Disease) prospective study. Participants were classified as never, former, light current (<=10 cigarettes/day), and heavy current smokers (>10 cigarettes/day) according to self-reports and analogous cutoffs for urine cotinine. During a median follow-up of 8.5 years, 296 first CVD events were recorded. Compared with self-reported never smokers, the hazard ratios (95% confidence interval) of CVD for former, light current, and heavy current smokers were 0.86 (0.64-1.17), 1.28 (0.83-1.97), and 1.80 (1.27-2.57) in multivariate analysis. Compared with urine cotinine-assessed never smokers, the corresponding hazard ratios of CVD for urine cotinine-assessed former, light current, and heavy current smokers were 1.70 (1.03-2.81), 1.62 (1.15-2.28), and 1.95 (1.39-2.73) respectively. The C-index change on adding urine cotinine assessed smoking status to a standard CVD risk prediction model (without self reported smoking status) was 0.0098 (0.0031-0.0164; P=0.004). The corresponding C index change for self-reported smoking status was 0.0111 (0.0042-0.0179; P=0.002). CONCLUSIONS: Smoking status as assessed by self-reports and urine cotinine is associated with CVD risk; however, the nature of the association of urine cotinine with CVD is consistent with a dose-response relationship. The ability of urine cotinine to improve CVD risk assessment is similar to that of self-reported smoking status. PMID- 29720505 TI - Teaching Pediatric Peritoneal Dialysis Globally through Virtual Simulation. AB - BACKGROUND AND OBJECTIVES: Despite the increasing prevalence of childhood kidney disease worldwide, there is a shortage of clinicians trained to provide peritoneal dialysis (PD). E-learning technologies may provide a solution to improve knowledge in PD. We describe the development of a virtual PD simulator and report the first 22 months of online usage. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The PD simulator was developed and released on OPENPediatrics in January of 2016. A prospective study of international, multidisciplinary healthcare providers was conducted from January of 2016 through October of 2017. User action data were analyzed with descriptive statistics and linear regression. Paired t tests compared user pre- and post-test scores. User satisfaction was assessed by survey. RESULTS: The simulator was accessed by 1066 users in 70 countries. Users spent a median of 35 minutes (interquartile range [IQR] 14-84) in the simulator. Users who completed the structured learning curriculum (n=300) spent a median of 85 minutes (IQR 46-95), and those who completed the entire simulator (n=63) spent a median of 122 minutes (IQR 69-195). Users who completed the simulator were more likely to scroll through text and access the simulator in multiple sessions. The 300 users that completed testing showed statistically significant increases in the post- versus pretest scores, with a mean increase of 36.4 of 100 points, SD 19.9 (95% confidence interval, 34.1 to 38.6, P<0.001). Eighty-seven percent (20 of 23) of survey respondents felt the simulator was relevant to their clinical practice, and 78% (18 of 23) would recommend it to others. CONCLUSIONS: This is the first reported virtual PD simulator. Increased test scores were observed between pre- and post-tests by clinicians who completed testing, across disciplines, training levels, and resource settings. PMID- 29720506 TI - Induction of Neoantigen-Specific Cytotoxic T Cells and Construction of T-cell Receptor-Engineered T Cells for Ovarian Cancer. AB - Purpose: Current evolution of cancer immunotherapies, such as immune checkpoint blockade, has implicated neoantigens as major targets of anticancer cytotoxic T cells. Adoptive T-cell therapy with neoantigen-specific T-cell receptor (TCR) engineered T cells would be an attractive therapeutic option for advanced cancers where the host antitumor immune function is strongly inhibited. We previously developed a rapid and efficient pipeline for production of neoantigen-specific TCR-engineered T cells using peripheral blood from an HLA-matched healthy donor. Our protocol required only 2 weeks from stimulation of T cells with neoantigen loaded dendritic cells to the identification of neoantigen-specific TCRs. We conducted the pilot study to validate our protocol.Experimental Design: We used tumors from 7 ovarian cancer patients to validate our protocol.Results: We chose 14 candidate neoantigens from 7 ovarian tumors (1-3 candidates for each patient) and then successfully induced three neoantigen-specific T cells from 1 healthy donor and identified their TCR sequences. Moreover, we validated functional activity of the three identified TCRs by generating TCR-engineered T cells that recognized the corresponding neoantigens and showed cytotoxic activity in an antigen dose-dependent manner. However, one case of neoantigen-specific TCR engineered T cells showed cross-reactivity against the corresponding wild-type peptide.Conclusions: This pilot study demonstrated the feasibility of our efficient process from identification of neoantigen to production of the neoantigen-targeting cytotoxic TCR-engineered T cells for ovarian cancer and revealed the importance of careful validation of neoantigen-specific TCR engineered T cells to avoid severe immune-related adverse events. Clin Cancer Res; 24(21); 5357-67. (c)2018 AACR See related commentary by Anczurowski and Hirano, p. 5195. PMID- 29720508 TI - The role of cardiopulmonary exercise tests in pulmonary arterial hypertension. AB - Despite recent advances in the therapeutic management of patients affected by pulmonary arterial hypertension (PAH), survival remains poor. Prompt identification of the disease, especially in subjects at increased risk of developing PAH, and prognostic stratification of patients are a necessary target of clinical practice but remain challenging. Cardiopulmonary exercise test (CPET) parameters, particularly peak oxygen uptake, end-tidal carbon dioxide tension and the minute ventilation/carbon dioxide production relationship, emerged as new prognostic tools for PAH patients. Moreover, CPET provides a comprehensive pathophysiological evaluation of patients' exercise limitation and dyspnoea, which are the main and early symptoms of the disease. This review focuses on the role of CPET in the management of PAH patients, reporting guideline recommendations for CPET and discussing the pathophysiology of exercise limitation and the most recent use of CPET in the diagnosis, prognosis and therapeutic targeting of PAH. PMID- 29720509 TI - State of the art in interstitial pneumonia with autoimmune features: a systematic review on retrospective studies and suggestions for further advances. AB - The term interstitial pneumonia with autoimmune features (IPAF) has been proposed to define patients with interstitial lung disease (ILD) associated with autoimmune signs not classifiable for connective tissue diseases (CTDs). This new definition overcomes previous nomenclatures and provides a uniform structure for prospective studies through specific classification criteria.This work evaluates the characteristics of IPAF patients reported in the literature, to highlight potential limits through a comparative analysis and to suggest better performing classification criteria.Four retrospective studies on the IPAF population have been considered. The study subjects differed in age, sex, smoking habit, ILD pattern and outcomes. Another important difference lies in the diverse items considered in the classification criteria. The retrospective design of the studies and the absence from some of them of a rheumatologist clearly involved in the diagnosis may have influenced the data, but current IPAF criteria seem to include a rather heterogeneous population. To overcome these discrepancies, this review suggests a limitation in the use of single items and the exclusion of extremely specific CTD criteria. This should avoid the definition of IPAF for those diseases at different stages or at early onset. The investigation of a functional or morphological cut-off of pulmonary involvement would be useful. PMID- 29720507 TI - Comprehensive Assessment of Coronary Artery Disease in Sports-Related Sudden Cardiac Arrest. AB - Despite the cardiovascular benefits of regular sports, sudden cardiac arrest (SCA) risk is increased during or shortly after exercise. Association with coronary artery disease (CAD) has been described in small studies, mainly autopsic with potential bias given the high sports-related SCA survival, and focusing on young competitive athletes, whereas sports-related SCA occurs mostly in recreational athletes.1-5 Through the Paris Sudden Death Expertise Center prospective registry that includes all SCAs in Paris and suburbs since May 2011, we performed the first broad comprehensive CAD description in sports-related SCAs, with a comparison with matched non-sports-related SCAs. PMID- 29720510 TI - Efficacy and safety profile of xanthines in COPD: a network meta-analysis. AB - Theophylline can still have a role in the management of stable chronic obstructive pulmonary disease (COPD), but its use remains controversial, mainly due to its narrow therapeutic window. Doxofylline, another xanthine, is an effective bronchodilator and displays a better safety profile than theophylline. Therefore, we performed a quantitative synthesis to compare the efficacy and safety profile of different xanthines in COPD.The primary end-point of this meta analysis was the impact of xanthines on lung function. In addition, we assessed the risk of adverse events by normalising data on safety as a function of person weeks. Data obtained from 998 COPD patients were selected from 14 studies and meta-analysed using a network approach.The combined surface under the cumulative ranking curve (SUCRA) analysis of efficacy (change from baseline in forced expiratory volume in 1 s) and safety (risk of adverse events) showed that doxofylline was superior to aminophylline (comparable efficacy and significantly better safety), bamiphylline (significantly better efficacy and comparable safety), and theophylline (comparable efficacy and significantly better safety).Considering the overall efficacy/safety profile of the investigated agents, the results of this quantitative synthesis suggest that doxofylline seems to be the best xanthine for the treatment of COPD. PMID- 29720511 TI - Prednisolone is associated with a worse bone mineral density in primary adrenal insufficiency. AB - CONTEXT: Patients with primary adrenal insufficiency (PAI) or congenital adrenal hyperplasia (CAH) receive life-long glucocorticoid (GC) therapy. Daily GC doses are often above the physiological cortisol production rate and can cause long term morbidities such as osteoporosis. No prospective trial has investigated the long-term effect of different GC therapies on bone mineral density (BMD) in those patients. OBJECTIVES: To determine if patients on hydrocortisone (HC) or prednisolone show changes in BMD after follow-up of 5.5 years. To investigate if BMD is altered after switching from immediate- to modified-release HC. DESIGN AND PATIENTS: Prospective, observational, longitudinal study with evaluation of BMD by DXA at visit1, after 2.2 +/- 0.4 (visit2) and after 5.5 +/- 0.8 years (visit3) included 36 PAI and 8 CAH patients. Thirteen patients received prednisolone (age 52.5 +/- 14.8 years; 8 women) and 31 patients received immediate-release HC (age 48.9 +/- 15.8 years; 22 women). Twelve patients on immediate-release switched to modified-release HC at visit2. RESULTS: Prednisolone showed significantly lower Z scores compared to HC at femoral neck (-0.85 +/- 0.80 vs -0.25 +/- 1.16, P < 0.05), trochanter (-0.96 +/- 0.62 vs 0.51 +/- 1.07, P < 0.05) and total hip ( 0.78 +/- 0.55 vs 0.36 +/- 1.04, P < 0.05), but not at lumbar spine, throughout the study. Prednisolone dose decreased by 8% over study time, but no significant effect was seen on BMD. BMD did not change significantly after switching from immediate- to modified-release HC. CONCLUSIONS: The use of prednisolone as hormone replacement therapy results in significantly lower BMD compared to HC. Patients on low-dose HC replacement therapy showed unchanged Z-scores within the normal reference range during the study period. PMID- 29720512 TI - SULFATION PATHWAYS: A role for steroid sulphatase in intracrine regulation of endometrial decidualisation. AB - In women, establishment of pregnancy is dependent upon 'fine-tuning' of the endometrial microenvironment, which is mediated by terminal differentiation (decidualisation) of endometrial stromal fibroblasts (ESFs). We have demonstrated that intracrine steroid metabolism plays a key role in regulating decidualisation and is essential for time-dependent expression of key factors required for endometrial receptivity. The primary aim of the current study was to determine whether sulphated steroids can act as precursors to bioactive sex steroids during decidualisation. We used primary human ESF and a robust in vitro model of decidualisation to assess the expression of genes associated with sulphation, desulphation and transport of sulphated steroids in human ESF as well as the impact of the steroid sulphatase (STS) inhibitor STX64 (Irosustat). We found evidence for an increase in both expression and activity of STS in response to a decidualisation stimulus with abrogation of oestrone biosynthesis and decreased secretion of the decidualisation marker IGFBP1 in the presence of STX64. These results provide novel insight into the contribution of STS to the intracrine regulation of decidualisation. PMID- 29720514 TI - Secretion of Nonstructural Protein 1 of Dengue Virus from Infected Mosquito Cells: Facts and Speculations. AB - Dengue virus nonstructural protein 1 (NS1) is a multifunctional glycoprotein. For decades, the notion in the field was that NS1 is secreted exclusively from vertebrate cells and not from mosquito cells. However, recent evidence shows that mosquito cells also secrete NS1 efficiently. In this review, we discuss the evidence for secretion of NS1 of dengue virus, and of other flaviviruses, from mosquito cells, differences between NS1 secreted from mosquito and NS1 secreted from vertebrate cells, and possible roles of soluble NS1 in the insect flavivirus vector. PMID- 29720513 TI - Glucocorticoids, antenatal corticosteroid therapy and fetal heart maturation. AB - Glucocorticoids are essential in mammals to mature fetal organs and tissues in order to survive after birth. Hence, antenatal glucocorticoid treatment (termed antenatal corticosteroid therapy) can be life-saving in preterm babies and is commonly used in women at risk of preterm birth. While the effects of glucocorticoids on lung maturation have been well described, the effects on the fetal heart remain less clear. Experiments in mice have shown that endogenous glucocorticoid action is required to mature the fetal heart. However, whether the potent synthetic glucocorticoids used in antenatal corticosteroid therapy have similar maturational effects on the fetal heart is less clear. Moreover, antenatal corticosteroid therapy may increase the risk of cardiovascular disease in adulthood. Here, we present a narrative review of the evidence relating to the effects of antenatal glucocorticoid action on the fetal heart and discuss the implications for antenatal corticosteroid therapy. PMID- 29720515 TI - Small Bottleneck Size in a Highly Multipartite Virus during a Complete Infection Cycle. AB - Multipartite viruses package their genomic segments independently and thus incur the risk of being unable to transmit their entire genome during host-to-host transmission if they undergo severe bottlenecks. In this paper, we estimated the bottleneck size during one infection cycle of Faba bean necrotic stunt virus (FBNSV), an octopartite nanovirus whose segments have been previously shown to converge to particular and unequal relative frequencies within host plants and aphid vectors. Two methods were used to derive this estimate, one based on the probability of transmission of the virus and the other based on the temporal evolution of the relative frequency of markers for two genomic segments, one frequent and one rare (segment N and S, respectively), both in plants and vectors. Our results show that FBNSV undergoes severe bottlenecks during aphid transmission. Further, even though the bottlenecks are always narrow under our experimental conditions, they slightly widen with the number of transmitting aphids. In particular, when several aphids are used for transmission, the bottleneck size of the segments is also affected by within-plant processes and, importantly, significantly differs across segments. These results indicate that genetic drift not only must be an important process affecting the evolution of these viruses but also that these effects vary across genomic segments and, thus, across viral genes, a rather unique and intriguing situation. We further discuss the potential consequences of our findings for the transmission of multipartite viruses.IMPORTANCE Multipartite viruses package their genomic segments in independent capsids. The most obvious cost of such genomic structure is the risk of losing at least one segment during host-to-host transmission. A theoretical study has shown that for nanoviruses, composed of 6 to 8 segments, hundreds of copies of each segment need to be transmitted to ensure that at least one copy of each segment was present in the host. These estimations seem to be very high compared to the size of the bottlenecks measured with other viruses. Here, we estimated the bottleneck size during one infection cycle of FBNSV, an octopartite nanovirus. We show that these bottlenecks are always narrow (few viral particles) and slightly widen with the number of transmitting aphids. These results contrast with theoretical predictions and illustrate the fact that a new conceptual framework is probably needed to understand the transmission of highly multipartite viruses. PMID- 29720516 TI - Seminal Simian Immunodeficiency Virus in Chronically Infected Cynomolgus Macaques Is Dominated by Virus Originating from Multiple Genital Organs. AB - The sexual transmission of viruses is responsible for the spread of multiple infectious diseases. Although the human immunodeficiency virus (HIV)/AIDS pandemic remains fueled by sexual contacts with infected semen, the origin of virus in semen is still unknown. In a substantial number of HIV-infected men, viral strains present in semen differ from the ones in blood, suggesting that HIV is locally produced within the genital tract. Such local production may be responsible for the persistence of HIV in semen despite effective antiretroviral therapy. In this study, we used single-genome amplification, amplicon sequencing (env gene), and phylogenetic analyses to compare the genetic structures of simian immunodeficiency virus (SIV) populations across all the male genital organs and blood in intravenously inoculated cynomolgus macaques in the chronic stage of infection. Examination of the virus populations present in the male genital tissues of the macaques revealed compartmentalized SIV populations in testis, epididymis, vas deferens, seminal vesicles, and urethra. We found genetic similarities between the viral strains present in semen and those in epididymis, vas deferens, and seminal vesicles. The contribution of male genital organs to virus shedding in semen varied among individuals and could not be predicted based on their infection or proinflammatory cytokine mRNA levels. These data indicate that rather than a single source, multiple genital organs are involved in the release of free virus and infected cells into semen. These findings have important implications for our understanding of systemic virus shedding and persistence in semen and for the design of eradication strategies to access viral reservoirs.IMPORTANCE Semen is instrumental for the dissemination of viruses through sexual contacts. Worryingly, a number of systemic viruses, such as HIV, can persist in this body fluid in the absence of viremia. The local source(s) of virus in semen, however, remains unknown. To elucidate the anatomic origin(s) of the virus released in semen, we compared viral populations present in semen with those in the male genital organs and blood of the Asian macaque model, using single-genome amplification, amplicon sequencing (env gene), and phylogenetic analysis. Our results show that multiple genital tissues harbor compartmentalized strains, some of them (i.e., from epididymis, vas deferens, and seminal vesicles) displaying genetic similarities with the viral populations present in semen. This study is the first to uncover local genital sources of viral populations in semen, providing a new basis for innovative targeted strategies to prevent and eradicate HIV in the male genital tract. PMID- 29720517 TI - Antiviral Activity of HIV gp120-Targeting Bispecific T Cell Engager Antibody Constructs. AB - Today's gold standard in HIV therapy is combined antiretroviral therapy (cART). It requires strict adherence by patients and lifelong medication, which can lower the viral load below detection limits and prevent HIV-associated immunodeficiency but cannot cure patients. The bispecific T cell-engaging (BiTE) antibody technology has demonstrated long-term relapse-free outcomes in patients with relapsed and refractory acute lymphocytic leukemia. Here, we generated BiTE antibody constructs that target the HIV-1 envelope protein gp120 (HIV gp120) using either the scFv B12 or VRC01, the first two extracellular domains (1 + 2) of human CD4 alone or joined to the single chain variable fragment (scFv) of the antibody 17b fused to an anti-human CD3epsilon scFv. These engineered human BiTE antibody constructs showed engagement of T cells for redirected lysis of HIV gp120-transfected CHO cells. Furthermore, they substantially inhibited HIV-1 replication in peripheral blood mononuclear cells (PBMCs) as well as in macrophages cocultured with autologous CD8+ T cells, the most potent being the human CD4(1 + 2) BiTE [termed CD(1 + 2) h BiTE] antibody construct and the CD4(1 + 2)L17b BiTE antibody construct. The CD4(1 + 2) h BiTE antibody construct promoted HIV infection of human CD4-/CD8+ T cells. In contrast, the neutralizing B12 and the VRC01 BiTE antibody constructs, as well as the CD4(1 + 2)L17b BiTE antibody construct, did not. Thus, BiTE antibody constructs targeting HIV gp120 are very promising for constraining HIV and warrant further development as novel antiviral therapy with curative potential.IMPORTANCE HIV is a chronic infection well controlled with the current cART. However, we lack a cure for HIV, and the HIV pandemic goes on. Here, we showed in vitro and ex vivo that a BiTE antibody construct targeting HIV gp120 resulted in substantially reduced HIV replication. In addition, these BiTE antibody constructs display efficient killing of gp120 expressing cells and inhibited replication in ex vivo HIV-infected PBMCs or macrophages. We believe that BiTE antibody constructs recognizing HIV gp120 could be a very valuable strategy for a cure of HIV in combination with cART and compounds which reverse latency. PMID- 29720518 TI - Crystal Structure of Classical Swine Fever Virus NS5B Reveals a Novel N-Terminal Domain. AB - Classical swine fever virus (CSFV) is the cause of classical swine fever (CSF). Nonstructural protein 5B (NS5B) is an RNA-dependent RNA polymerase (RdRp) that is a key enzyme initiating viral RNA replication by a de novo mechanism. It is also an attractive target for the development of anti-CSFV drugs. To gain a better understanding of the mechanism of CSFV RNA synthesis, here, we solved the first crystal structure of CSFV NS5B. Our studies show that the CSFV NS5B RdRp contains the characteristic finger, palm, and thumb domains, as well as a unique N terminal domain (NTD) that has never been observed. Mutagenesis studies on NS5B validated the importance of the NTD in the catalytic activity of this novel RNA dependent RNA polymerase. Moreover, our results shed light on CSFV infection.IMPORTANCE Pigs are important domesticated animals. However, a highly contagious viral disease named classical swine fever (CSF) causes devastating economic losses. Classical swine fever virus (CSFV), the primary cause of CSF, is a positive-sense single-stranded RNA virus belonging to the genus Pestivirus, family Flaviviridae Genome replication of CSFV depends on an RNA-dependent RNA polymerase (RdRp) known as NS5B. However, the structure of CSFV NS5B has never been reported, and the mechanism of CSFV replication is poorly understood. Here, we solve the first crystal structure of CSFV NS5B and analyze the functions of the characteristic finger, palm, and thumb domains. Additionally, our structure revealed the presence of a novel N-terminal domain (NTD). Biochemical studies demonstrated that the NTD of CSFV NS5B is very important for RdRp activity. Collectively, our studies provide a structural basis for future rational design of anti-CSFV drugs, which is critically important, as no effective anti-CSFV drugs have been developed. PMID- 29720520 TI - Herpes Simplex Virus 2 Latency-Associated Transcript (LAT) Region Mutations Do Not Identify a Role for LAT-Associated MicroRNAs in Viral Reactivation in Guinea Pig Genital Models. AB - Despite the long-standing observation that herpes simplex virus (HSV) latency associated transcript (LAT) promoter deletion viruses show impaired recurrence phenotypes in relevant animal models, the mechanism by which these sequences exert this phenotypic effect is unknown. We constructed and evaluated four mutant HSV-2 isolates with targeted mutations in the LAT promoter and LAT-associated microRNAs (miRNAs) affecting (i) the LAT TATA box; (ii) the LAT ICP4-binding site; (iii) miRNA I (miR-I) and miR-II (miR-I/II), which both target ICP34.5; and (iv) miR-III, which targets ICP0. While the LAT TATA box mutant caused milder acute infections than wild-type (WT) virus, there was no difference in the recurrence phenotype between these viruses. LAT and miRNA expression during latency was not impaired by this mutation, suggesting that other promoter elements may be more important for latent HSV-2 LAT expression. Mutation of the LAT ICP4-binding site also did not cause an in vivo phenotypic difference between mutant and WT viruses. Acute infection and reactivation from latency of the miR I/II mutant were similar to those of its rescuant, although the acute infection was slightly reduced in severity relative to that caused by the wild-type virus. The miR-III mutant also exhibited WT phenotypes in acute and recurrent phases of infection. While they do not rule out an effect of these elements in human latency or reactivation, these findings do not identify a specific role for LAT or LAT-associated miRNAs in the HSV-2 LAT promoter deletion phenotype in guinea pigs. Thus, other sequences in this region may play a more important role in the long-studied LAT-associated phenotype in animals.IMPORTANCE While it has been known for several decades that specific HSV-1 and HSV-2 sequences near the LAT promoter are required for efficient viral reactivation in animal models, the mechanism is still not known. We constructed four mutant viruses with the goal of identifying critical sequence elements and of specifically testing the hypothesis that microRNAs that are expressed during latency play a role. Determination that specific LAT promoter sequences and miRNA sequences do not influence viral reactivation of HSV-2 helps to narrow down the search for the mechanism by which the virus controls its latency and recurrence phenotype. PMID- 29720519 TI - Glycan Binding Specificity and Mechanism of Human and Porcine P[6]/P[19] Rotavirus VP8*s. AB - Rotaviruses (RVs), which cause severe gastroenteritis in infants and children, recognize glycan ligands in a genotype-dependent manner via the distal VP8* head of the spike protein VP4. However, the glycan binding mechanisms remain elusive for the P[II] genogroup RVs, including the widely prevalent human RVs (P[8], P[4], and P[6]) and a rare P[19] RV. In this study, we characterized the glycan binding specificities of human and porcine P[6]/P[19] RV VP8*s and found that the P[II] genogroup RV VP8*s could commonly interact with mucin core 2, which may play an important role in RV evolution and cross-species transmission. We determined the first P[6] VP8* structure, as well as the complex structures of human P[19] VP8*, with core 2 and lacto-N-tetraose (LNT). A glycan binding site was identified in human P[19] VP8*. Structural superimposition and sequence alignment revealed the conservation of the glycan binding site in the P[II] genogroup RV VP8*s. Our data provide significant insight into the glycan binding specificity and glycan binding mechanism of the P[II] genogroup RV VP8*s, which could help in understanding RV evolution, transmission, and epidemiology and in vaccine development.IMPORTANCE Rotaviruses (RVs), belonging to the family Reoviridae, are double-stranded RNA viruses that cause acute gastroenteritis in children and animals worldwide. Depending on the phylogeny of the VP8* sequences, P[6] and P[19] RVs are grouped into genogroup II, together with P[4] and P[8], which are widely prevalent in humans. In this study, we characterized the glycan binding specificities of human and porcine P[6]/P[19] RV VP8*s, determined the crystal structure of P[6] VP8*, and uncovered the glycan binding pattern in P[19] VP8*, revealing a conserved glycan binding site in the VP8*s of P[II] genogroup RVs by structural superimposition and sequence alignment. Our data suggested that mucin core 2 may play an important role in P[II] RV evolution and cross-species transmission. These data provide insight into the cell attachment, infection, epidemiology, and evolution of P[II] genogroup RVs, which could help in developing control and prevention strategies against RVs. PMID- 29720522 TI - Complexities of Viral Mutation Rates. AB - Many viruses evolve rapidly. This is due, in part, to their high mutation rates. Mutation rate estimates for over 25 viruses are currently available. Here, we review the population genetics of virus mutation rates. We specifically cover the topics of mutation rate estimation, the forces that drive the evolution of mutation rates, and how the optimal mutation rate can be context-dependent. PMID- 29720521 TI - Short-Term Pegylated Interferon alpha2a Treatment Does Not Significantly Reduce the Viral Reservoir of Simian Immunodeficiency Virus-Infected, Antiretroviral Therapy-Treated Rhesus Macaques. AB - The major obstacle to human immunodeficiency type 1 (HIV-1) eradication is a reservoir of latently infected cells that persists despite long-term antiretroviral therapy (ART) and causes rapid viral rebound if treatment is interrupted. Type I interferons are immunomodulatory cytokines that induce antiviral factors and have been evaluated for the treatment of HIV-infected individuals, resulting in moderate reduction of viremia and inconclusive data about their effect on reservoir size. Here, we assessed the potential of pegylated IFN-alpha2a (pIFN-alpha2a) to reduce the viral reservoir in simian immunodeficiency virus (SIV)-infected, ART-treated rhesus macaques (RMs). We found that pIFN-alpha2a treatment of animals in which virus replication is effectively suppressed with ART is safe and well tolerated, as no major clinical side effects were observed. By monitoring the cellular immune response during this intervention, we established that pIFN-alpha2a administration is not associated with either CD4+ T cell depletion or increased immune activation. Importantly, we found that interferon-stimulated genes (ISGs) were significantly upregulated in IFN-treated RMs compared to control animals, confirming that pIFN alpha2a is bioactive in vivo To evaluate the effect of pIFN-alpha2a administration on the viral reservoir in CD4+ T cells, we performed cell associated proviral SIV DNA measurements in multiple tissues and assessed levels of replication-competent virus by a quantitative viral outgrowth assay (QVOA). These analyses failed to reveal any significant difference in reservoir size between IFN-treated and control animals. In summary, our data suggest that short term type I interferon treatment in combination with suppressive ART is not sufficient to induce a significant reduction of the viral reservoir in SIV infected RMs.IMPORTANCE The potential of type I interferons to reduce the viral reservoir has been recently studied in clinical trials in HIV-infected humans. However, given the lack of mechanistic data and the potential for safety concerns, a more comprehensive testing of IFN treatment in vivo in SIV-infected RMs is critical to provide rationale for further development of this intervention in humans. Utilizing the SIV/RM model in which virus replication is suppressed with ART, we addressed experimental limitations of previous human studies, in particular the lack of a control group and specimen sampling limited to blood. Here, we show by rigorous testing of blood and lymphoid tissues that virus replication and reservoir size were not significantly affected by pIFN-alpha2a treatment in SIV-infected, ART-treated RMs. This suggests that intensified and/or prolonged IFN treatment regimens, possibly in combination with other antilatency agents, are necessary to effectively purge the HIV/SIV reservoir under ART. PMID- 29720523 TI - Conservation of Mannan Synthesis in Fungi of the Zygomycota and Ascomycota Reveals a Broad Diagnostic Target. AB - Ascomycetes and zygomycetes account for the majority of (i) fungi responsible for cutaneous, subcutaneous, and invasive human fungal infections, (ii) plant fungal pathogens, (iii) fungi that threaten global biodiversity, (iv) fungal agents of agricultural spoilage, and (v) fungi in water-damaged buildings. Rapid recognition of fungal infection (or contamination) enables early treatment (or remediation). A bioinformatics search found homologues of Saccharomyces cerevisiae Mnn9p present in members of the Zygomycota and Ascomycota phyla and absent in members of the Chytridiomycota and Basidiomycota. Mnn9p is a component of the yeast mannan polymerization complex and is necessary for alpha-1,6 mannan production. A monoclonal antibody (2DA6) was produced that was reactive with purified mannans of Mucor, Rhizopus, Aspergillus, Fusarium, and Candida species. Experimentation using a 2DA6 antigen capture enzyme-linked immunosorbent assay (ELISA) and extracts of fungi from the four phyla found agreement between the presence or absence of Mnn9p homologues and production or lack of production of mannan reactive with 2DA6. Studies of cell extracts from yeast mannan mutants identified alpha-1,6 mannan as the epitope recognized by 2DA6. To translate this finding into a point-of-use diagnostic, a 2DA6 lateral flow immunoassay was constructed that detected mannan in (i) extracts of dermatophytes and fungi that produce trauma-related infection and (ii) tissue from plants infected with Grosmannia clavigera or Sclerotium cepivorum These studies (i) revealed that the conservation of alpha-1,6-linked mannan in fungi of the Zygomycota and Ascomycota can be exploited as a broad diagnostic target and (ii) have provided a means to detect that target in an immunoassay platform that is well suited for clinic or field use.IMPORTANCE A key question asked when faced with an infection, an infestation, or environmental damage is whether it is a fungus. Identification of fungi as the cause of the problem can lead to remediation or treatment. Zygomycetes and ascomycetes account for the vast majority of fungal causes of human, animal, and plant disease, large-scale biodiversity loss, agricultural spoilage, and contamination of water-damaged buildings. These studies revealed the conservation of a common cell wall structural component of zygomycetes and ascomycetes to be a diagnostic target applicable to multiple pathogenic fungi and have leveraged that insight for practical use. Monoclonal antibodies reactive with this pan-fungal structure were produced and used to construct immunoassays (including ELISA and lateral flow assay) for detection of a broad range of pathogenic fungi. PMID- 29720524 TI - High Rate of Infection by Only Oncogenic Human Papillomavirus in Amerindians. AB - Human papillomavirus (HPV), an etiological agent of cervical cancer (CC), has infected humans since ancient times. Amerindians are the furthest migrants out of Africa, and they reached the Americas more than 14,000 years ago. Some groups still remain isolated, and some migrate to towns, forming a gradient spanning urbanization. We hypothesized that, by virtue of their history, lifestyle, and isolation from the global society, remote Amerindian women have lower HPV diversity than do urban women (Amerindian or mestizo). Here we determined the diversity of the 25 most relevant cervical HPV types in 82 Amerindians spanning urbanization (low, medium, and high, consistent with the exposure to urban lifestyles of the town of Puerto Ayacucho in the Venezuelan Amazonas State), and in 29 urban mestizos from the town. Cervical, anal, oral, and introitus samples were taken, and HPVs were typed using reverse DNA hybridization. A total of 23 HPV types were detected, including 11 oncogenic or high-risk types, most associated with CC. Cervical HPV prevalence was 75%, with no differences by group, but Amerindians from low and medium urbanization level had significantly lower HPV diversity than mestizos did. In Amerindians, but not in mestizos, infections by only high-risk HPVs were higher than coinfections or by exclusively low-risk HPVs. Cervical abnormalities only were observed in Amerindians (9/82), consistent with their high HPV infection. The lower cervical HPV diversity in more isolated Amerindians is consistent with their lower exposure to the global pool, and transculturation to urban lifestyles could have implications on HPV ecology, infection, and virulence.IMPORTANCE The role of HPV type distribution on the disparity of cervical cancer (CC) incidence between human populations remains unknown. The incidence of CC in the Amazonas State of Venezuela is higher than the national average. In this study, we determined the diversity of known HPV types (the viral agent of CC) in Amerindian and mestizo women living in the Venezuelan Amazonas State. Understanding the ecological diversity of HPV in populations undergoing lifestyle transformations has important implication on public health measures for CC prevention. PMID- 29720525 TI - Antibodies to the Glycoprotein GP2 Subunit Cross-React between Old and New World Arenaviruses. AB - Arenaviruses pose a major public health threat and cause numerous infections in humans each year. Although most viruses belonging to this family do not cause disease in humans, some arenaviruses, such as Lassa virus and Machupo virus, are the etiological agents of lethal hemorrhagic fevers. The absence of a currently licensed vaccine and the highly pathogenic nature of these viruses both make the necessity of developing viable vaccines and therapeutics all the more urgent. Arenaviruses have a single glycoprotein on the surface of virions, the glycoprotein complex (GPC), and this protein can be used as a target for vaccine development. Here, we describe immunization strategies to generate monoclonal antibodies (MAbs) that cross-react between the glycoprotein complexes of both Old World and New World arenaviruses. Several monoclonal antibodies isolated from immunized mice were highly cross-reactive, binding a range of Old World arenavirus glycoproteins, including that of Lassa virus. One such monoclonal antibody, KL-AV-2A1, bound to GPCs of both New World and Old World viruses, including Lassa and Machupo viruses. These cross-reactive antibodies bound to epitopes present on the glycoprotein 2 subunit of the glycoprotein complex, which is relatively conserved among arenaviruses. Monoclonal antibodies binding to these epitopes, however, did not inhibit viral entry as they failed to neutralize a replication-competent vesicular stomatitis virus pseudotyped with the Lassa virus glycoprotein complex in vitro In addition, no protection from virus challenge was observed in in vivo mouse models. Even so, these monoclonal antibodies might still prove to be useful in the development of clinical and diagnostic assays.IMPORTANCE Several viruses in the Arenaviridae family infect humans and cause severe hemorrhagic fevers which lead to high case fatality rates. Due to their pathogenicity and geographic tropisms, these viruses remain very understudied. As a result, an effective vaccine or therapy is urgently needed. Here, we describe efforts to produce cross-reactive monoclonal antibodies that bind to both New and Old World arenaviruses. All of our MAbs seem to be nonneutralizing and nonprotective and target subunit 2 of the glycoprotein. Due to the lack of reagents such as recombinant glycoproteins and antibodies for rapid detection assays, our MAbs could be beneficial as analytic and diagnostic tools. PMID- 29720526 TI - Pseudomonas aeruginosa Protease IV Exacerbates Pneumococcal Pneumonia and Systemic Disease. AB - Pneumonia is a pulmonary disease affecting people of all ages and is consistently a leading cause of childhood mortality and adult hospitalizations. Streptococcus pneumoniae and Pseudomonas aeruginosa are major lung pathogens commonly associated with community-acquired and nosocomial pneumonia. Additionally, mixed lung infections involving these bacterial pathogens are increasing in prevalence and are frequently more severe than single infections. The cooperative interactions of these two pathogens that impact pulmonary disease severity are understudied. A major secreted virulence factor of P. aeruginosa, protease IV (PIV), cleaves interleukin 22 (IL-22), a cytokine essential for maintaining innate mucosal defenses against extracellular pathogens. Here, we investigate the ability of PIV to augment the virulence of a pneumococcal strain with limited virulence, S. pneumoniae EF3030, in a C57BL/6 murine model of pneumonia. We demonstrate that pulmonary coinfection involving P. aeruginosa 103-29 and S. pneumoniae EF3030 results in pneumococcal bacteremia that is abrogated during pneumococcal coinfection with a PIV-deficient strain. Furthermore, intratracheal administration of exogenous PIV and EF3030 resulted in abundant immune cell infiltration into the lung with large abscess formation, as well as severe bacteremia leading to 100% mortality. Heat-inactivated PIV did not worsen pneumonia or reliably induce bacteremia, suggesting that the specific activity of PIV is required. Our studies also show that PIV depletes IL-22 in vivo Moreover, PIV-mediated enhancement of pneumonia and disease severity was dependent on the expression of pneumolysin (Ply), a prominent virulence factor of S. pneumoniae Altogether, we reveal that PIV and Ply additively potentiate pneumonia in a murine model of lung infection.IMPORTANCES. pneumoniae remains the leading cause of bacterial pneumonia despite widespread use of pneumococcal vaccines, forcing the necessity for appropriate treatment to control pneumococcal infections. Coinfections involving S. pneumoniae with other bacterial pathogens threaten antibiotic treatment strategies and disease outcomes. Currently, there is not an effective treatment for alveolar-capillary barrier dysfunction that precedes bacteremia. An understanding of the dynamics of host-pathogen interactions during single and mixed pulmonary infections could elucidate proper treatment strategies needed to prevent or reduce invasive disease. Antibiotic treatment decreases bacterial burden in the lung but also increases acute pathology due to cytotoxins released via antibiotic-induced bacterial lysis. Therefore, targeted therapeutics that inhibit or counteract the effects of bacterial proteases and toxins are needed in order to limit pathology and disease progression. This study identifies the cooperative effect of PIV and Ply, products of separate lung pathogens that additively alter the lung environment and facilitate invasive disease. PMID- 29720529 TI - In Defense of an Academic Career in Microbiology. AB - The rise of Quit Lit describing the myriad reasons for leaving academia and constant complaining by mentors leave many trainees with little desire for an academic career. Although there are clearly structural and social problems in academia, I feel that they are outweighed by the benefits of working and living in an academic environment. Every academic values different things about their job, and here I outline the factors that keep me in academia. To make sure that our best scientists are not scared away from academia, we must provide balance to the negativity that regularly surrounds discussions of careers in academia. PMID- 29720530 TI - The Long and the Short of It: GA 2-oxidaseA9 Regulates Plant Height in Wheat. PMID- 29720527 TI - Improved Subtyping of Staphylococcus aureus Clonal Complex 8 Strains Based on Whole-Genome Phylogenetic Analysis. AB - Strains of Staphylococcus aureus in clonal complex 8 (CC8), including USA300, USA500, and the Iberian clone, are prevalent pathogens in the United States, both inside and outside health care settings. Methods for typing CC8 strains are becoming obsolete as the strains evolve and diversify, and whole-genome sequencing has shown that some strain types fall into multiple sublineages within CC8. In this study, we attempt to clarify the strain nomenclature of CC8, classifying the major strain types based on whole-genome sequence phylogenetics using both methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) genomes. We show that isolates of the Archaic and Iberian clones from decades ago make up the most basal clade of the main CC8 lineages and that at least one successful lineage of CC8, made up mostly of MSSA, diverged before the other well-known strain types USA500 and USA300. We also show that the USA500 type includes two clades separated by the previously described "Canadian epidemic MRSA" strain CMRSA9, that one clade containing USA500 also contains the USA300 clade, and that the USA300-0114 strain type is not a monophyletic group. Additionally, we present a rapid, simple CC8 strain-typing scheme using real-time PCR assays that target single nucleotide polymorphisms (SNPs) derived from our CC8 phylogeny and show the significant benefit of using more stable genomic markers based on evolutionary lineages over traditional S. aureus typing techniques. This more accurate and accessible S. aureus typing system may improve surveillance and better inform the epidemiology of this very important pathogen.IMPORTANCEStaphylococcus aureus is a major human pathogen worldwide in both community and health care settings. Surveillance for S. aureus strains is important to our understanding of their spread and to informing infection prevention and control. Confusion surrounding the strain nomenclature of one of the most prevalent lineages of S. aureus, clonal complex 8 (CC8), and the imprecision of current tools for typing S. aureus make surveillance and source tracing difficult and sometimes misleading. In this study, we clarify the CC8 strain designations and propose a new typing scheme for CC8 isolates that is rapid and easy to use. This typing scheme is based on relatively stable genomic markers, and we demonstrate its superiority over traditional typing techniques. This scheme has the potential to greatly improve epidemiological investigations of S. aureus. PMID- 29720528 TI - Invasive Methicillin-Resistant Staphylococcus aureus USA500 Strains from the U.S. Emerging Infections Program Constitute Three Geographically Distinct Lineages. AB - USA500 isolates are clonal complex 8 (CC8) Staphylococcus aureus strains closely related to the prominent community- and hospital-associated USA300 group. Despite being relatively understudied, USA500 strains cause a significant burden of disease and are the third most common methicillin-resistant S. aureus (MRSA) strains identified in the U.S. Emerging Infections Program (EIP) invasive S. aureus surveillance. To better understand the genetic relationships of the strains, we sequenced the genomes of 539 USA500 MRSA isolates from sterile site infections collected through the EIP between 2005 and 2013 in the United States. USA500 isolates fell into three major clades principally separated by their distribution across different U.S. regions. Clade C1 strains, found principally in the Northeast, were associated with multiple IS256 insertion elements in their genomes and higher levels of antibiotic resistance. C2 was associated with Southern states, and E1 was associated with Western states. C1 and C2 strains all shared a frameshift in the gene encoding AdsA surface-attached surface protein. We propose that the term "USA500" should be used for CC8 strains sharing a recent common ancestor with the C1, C2, and E1 strains but not in the USA300 group.IMPORTANCE In this work, we have removed some of the confusion surrounding the use of the name "USA500," placed USA500 strains in the context of the CC8 group, and developed a strategy for assignment to subclades based on genome sequence. Our new phylogeny of USA300/USA500 will be a reference point for understanding the genetic adaptations that have allowed multiple highly virulent clonal strains to emerge from within CC8 over the past 50 years. PMID- 29720531 TI - Improving on the Humble Spud. PMID- 29720532 TI - Photosynthetic Oxygen Production: New Method Brings to Light Forgotten Flux. PMID- 29720534 TI - CORRECTION: Vol. 176: 2231-2250, 2018. PMID- 29720533 TI - Turnover of Tonoplast Proteins. PMID- 29720536 TI - Benefits of Early Referral to Pediatric Palliative Care for a Child With a Rare Disease. PMID- 29720537 TI - Isosteviol ameliorates diabetic cardiomyopathy in rats by inhibiting ERK and NF kappaB signaling pathways. AB - Diabetes-induced injury of myocardium, defined as diabetic cardiomyopathy (DCM), accounts for significant mortality and morbidity in diabetic population. Alleviation of DCM by a potent drug remains considerable interests in experimental and clinical researches because hypoglycemic drugs cannot effectively control this condition. Here, we explored the beneficial effects of isosteviol sodium (STVNa) on type 1 diabetes-induced DCM and the potential mechanisms involved. Male Wistar rats were induced to diabetes by injection of streptozotocin (STZ). One week later, diabetic rats were randomly grouped to receive STVNa (STZ/STVNa) or its vehicle (STZ). After 11 weeks of treatment or 11 weeks treatment following 4 weeks of removal of the treatment, the cardiac function and structure were evaluated and related mechanisms were investigated. In diabetic rats, oxidative stress, inflammation, blood glucose and plasma advanced glycation end products (AGEs) were significantly increased, whereas superoxide dismutase 2 (SOD-2) expression and activity were decreased. STVNa treatment inhibited cardiac hypertrophy, fibrosis and inflammation, showed similar ratio of heart to body weight and antioxidant capacities almost similar to the normal controls, which can be sustained at least 4 weeks. Moreover, STVNa inhibited diabetes-inducted stimulation of both extracellular signal-regulated kinase (ERK) and nuclear factor kappaB (NF-kappaB) signal pathways. However, blood glucose, plasma AGE and insulin levels were not altered by STVNa treatment. These results indicate that STVNa may be developed into a potent therapy for DCM. The mechanism underlying this therapeutic effect involves the suppression of oxidative stress and inflammation by inhibiting ERK and NF-kappaB without changing blood glucose or AGEs. PMID- 29720535 TI - Hepatitis C Virus Screening Among Children Exposed During Pregnancy. AB - OBJECTIVES: Because of the opioid epidemic, hepatitis C virus (HCV) infection is increasing among pregnant women, resulting in an increased risk of perinatal transmission and HCV infection among children. Our primary objectives in this study were to determine the prevalence of HCV among pregnant women and the frequency of pediatric HCV screening. METHODS: A population-based, retrospective cohort of pregnant women who delivered between 2006 and 2014 was identified and classified as HCV infected or HCV uninfected by billing codes. Infant records linked to the HCV-infected pregnant women were identified and queried for HCV tests and the receipt of well-child services, which were defined as the presence of hemoglobin and/or lead testing at or after 9 months of age. RESULTS: Between 2006 and 2014, 1043 (1.2%) HCV-infected pregnant women delivered, and the HCV prevalence increased by 60%. HCV-infected women were more likely to be <30 years of age (67% vs 53%; P < .001), white (93% vs 72%; P < .001), insured by Medicaid (77% vs 29%; P < .001), and have opiate use disorder (68% vs 1%; P < .001) than HCV-uninfected women. Infants born to HCV-infected women were more likely to be preterm (<37 weeks' gestation; 22% vs 10%; P < .001) and of low birth weight (<2500 g; 23% vs 8%; P < .001). Among 1025 HCV-exposed infants with available pediatric records, 323 (31%) received well-child services, and among these, only 96 (30%) were screened for HCV. CONCLUSIONS: Despite the increased HCV prevalence among pregnant women and the risk of perinatal HCV transmission, HCV-exposed infants are not adequately screened, and many pediatric HCV infections remain undetected. PMID- 29720538 TI - Sympathetic innervation regulates macrophage activity in rats with polycystic ovary. AB - Polycystic ovarian syndrome (PCOS) is a low-grade inflammatory disease characterized by hyperandrogenism and ovarian hyperinnervation. The aim of this work is to investigate whether in vivo bilateral superior ovarian nerve (SON) section in adult rats with estradiol valerate-induced PCOS (PCO rats) affects macrophage spleen cells (MF) and modifies the steroidogenic ability of their secretions. Culture media of MF from PCO rats and PCO rats with SON section (PCO SON rats) were used to stimulate in vitro intact ovaries. Compared with macrophages PCO, macrophages from PCO-SON rats released less tumor necrosis factor-alpha and nitric oxide, expressed lower Bax and Nfkb mRNA and showed reduced TUNEL staining. Also, in PCO rats, the SON section decreased kisspeptin and nerve growth factor mRNA expressions, without changes in Trka receptor mRNA levels. Macrophage secretions from PCO-SON rats decreased androstenedione and stimulated progesterone release in PCO ovaries, compared to macrophage secretions from PCO rats. No changes were observed in ovarian estradiol response. These findings emphasize the importance of the SON in spleen MPhi, since its manipulation leads to secondary modifications of immunological and neural mediators, which might influence ovarian steroidogenesis. In PCO ovaries, the reduction of androstenedione and the improvement of progesterone release induced by PCO-SON MPhi secretion, might be beneficial considering the hormonal anomalies characteristic of PCOS. We present functional evidence that modulation of the immune-endocrine function by peripheral sympathetic nervous system might have implications for understanding the pathophysiology of PCOS. PMID- 29720539 TI - It's reticulated: the liver at the heart of atherosclerosis. AB - Platelets play a critical role in both the initiation and progression of atherosclerosis, and even more so in the ensuing atherothrombotic complications. Low-dose aspirin remains the mainstay of antiplatelet therapy in high-risk patients by reducing the risk of myocardial ischemia, stroke or death due to cardiovascular disease. However, antiplatelet therapies lose their efficacy in people with diabetes mellitus, increasing the risk of future atherothrombotic events. The molecular mechanisms that promote platelet hyperactivity remain unclear but could be due to glycation-induced conformational changes of platelet membranes resulting in impaired aspirin entry or less-efficient acetylation/compensatory increase in COX-2 expression in newborn platelets. Emerging evidence from our laboratory and elsewhere suggest that enhanced platelet turnover (thrombopoiesis), particularly the production of immature reticulated platelets from the bone marrow, could contribute to atherosclerotic complications. We have identified a major role for neutrophil-derived S100A8/A9, a damage-associated molecular pattern, in driving reticulated thrombopoiesis by directly interacting with its receptors on Kupffer cells in the liver. In this review, we discuss the role of hepatic inflammation in driving reticulated platelet production and suggest potential targets to control their production, improve efficacy of current antiplatelet therapies and reduce the risk of atherothrombotic complications. PMID- 29720540 TI - Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice. AB - WNT signaling is involved in the tumorigenesis of various cancers and regulates bone homeostasis. Palmitoleoylation of WNTs by Porcupine is required for WNT activity. Porcupine inhibitors are under development for cancer therapy. As the possible side effects of Porcupine inhibitors on bone health are unknown, we determined their effects on bone mass and strength. Twelve-week-old C57BL/6N female mice were treated by the Porcupine inhibitors LGK974 (low dose = 3 mg/kg/day; high dose = 6 mg/kg/day) or Wnt-C59 (10 mg/kg/day) or vehicle for 3 weeks. Bone parameters were assessed by serum biomarkers, dual-energy X-ray absorptiometry, uCT and histomorphometry. Bone strength was measured by the 3 point bending test. The Porcupine inhibitors were well tolerated demonstrated by normal body weight. Both doses of LGK974 and Wnt-C59 reduced total body bone mineral density compared with vehicle treatment (P < 0.001). Cortical thickness of the femur shaft (P < 0.001) and trabecular bone volume fraction in the vertebral body (P < 0.001) were reduced by treatment with LGK974 or Wnt-C59. Porcupine inhibition reduced bone strength in the tibia (P < 0.05). The cortical bone loss was the result of impaired periosteal bone formation and increased endocortical bone resorption and the trabecular bone loss was caused by reduced trabecular bone formation and increased bone resorption. Porcupine inhibitors exert deleterious effects on bone mass and strength caused by a combination of reduced bone formation and increased bone resorption. We suggest that cancer targeted therapies using Porcupine inhibitors may increase the risk of fractures. PMID- 29720542 TI - Sauna and risk of stroke: Does frequent sauna bathing prevent stroke? PMID- 29720541 TI - Risk of Type 2 Diabetes Among Lesbian, Bisexual, and Heterosexual Women: Findings From the Nurses' Health Study II. AB - OBJECTIVE: Lesbian and bisexual (LB) women are more likely than heterosexual women to exhibit risk factors for type 2 diabetes, but studies estimating the burden of type 2 diabetes among LB women are uncommon and limited to cross sectional designs. This study investigated incidence of type 2 diabetes in LB women and heterosexual women in a large, longitudinal U.S. cohort. RESEARCH DESIGN AND METHODS: Women participating in the Nurses' Health Study II (NHS II) ages 24-44 years in 1989 were prospectively followed through 2013. Self-reported clinician diagnosis of type 2 diabetes was assessed every other year to identify incidence. Of the participants, 1,267 identified as lesbian or bisexual and 92,983 identified as heterosexual. Cox proportional hazards regression was used to model incidence of type 2 diabetes. RESULTS: LB women had a 27% higher risk of developing type 2 diabetes than heterosexual women (adjusted incidence rate ratio [IRR] 1.27, 95% CI 1.05, 1.54). Differences between LB women and heterosexual women in risk of type 2 diabetes were greater during younger ages (sexual orientation-by-age interaction, P < 0.001). BMI mediated the relationship between sexual orientation and type 2 diabetes; the IRR was completely attenuated when BMI was added to the model (IRR 0.85, 95% CI 0.70, 1.03). CONCLUSIONS: Findings indicate that LB women develop type 2 diabetes at younger ages than heterosexual women. Higher BMI in LB women is an important contributor to this disparity. Public health and clinical efforts to prevent, detect, and manage obesity and type 2 diabetes among LB women are warranted. PMID- 29720543 TI - Sauna bathing reduces the risk of stroke in Finnish men and women: A prospective cohort study. AB - OBJECTIVE: To assess the association between frequency of sauna bathing and risk of future stroke. METHODS: Baseline habits of sauna bathing were assessed in 1,628 adult men and women aged 53-74 years (mean age, 62.7 years) without a known history of stroke in the Finnish Kuopio Ischemic Heart Disease prospective cohort study. Three sauna bathing frequency groups were defined: 1, 2-3, and 4-7 sessions per week. Hazard ratios (HRs) (95% confidence intervals [CIs]) were estimated for incident stroke. RESULTS: During a median follow-up of 14.9 years, 155 incident stroke events were recorded. Compared with participants who had one sauna bathing session per week, the age- and sex-adjusted HR (95% CI) for stroke was 0.39 (0.18-0.83) for participants who had 4-7 sauna sessions per week. After further adjustment for established cardiovascular risk factors and other potential confounders, the corresponding HR (95% CI) was 0.39 (0.18-0.84) and this remained persistent on additional adjustment for physical activity and socioeconomic status at 0.38 (0.18-0.81). The association between frequency of sauna bathing and risk of stroke was not modified by age, sex, or other clinical characteristics (p for interaction > 0.10 for all subgroups). The association was similar for ischemic stroke but modest for hemorrhagic stroke, which could be attributed to the low event rate (n = 34). CONCLUSIONS: This long-term follow-up study shows that middle-aged to elderly men and women who take frequent sauna baths have a substantially reduced risk of new-onset stroke. PMID- 29720544 TI - Advantages of virtual reality in the rehabilitation of balance and gait: Systematic review. AB - BACKGROUND: Virtual reality (VR) has emerged as a therapeutic tool facilitating motor learning for balance and gait rehabilitation. The evidence, however, has not yet resulted in standardized guidelines. The aim of this study was to systematically review the application of VR-based rehabilitation of balance and gait in 6 neurologic cohorts, describing methodologic quality, intervention programs, and reported efficacy. METHODS: This study follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. VR-based treatments of Parkinson disease, multiple sclerosis, acute and chronic poststroke, traumatic brain injury, and cerebral palsy were researched in PubMed and Scopus, including earliest available records. Therapeutic validity (CONTENT scale) and risk of bias in randomized controlled trials (RCT) (Cochrane Collaboration tool) and non-RCT (Newcastle-Ottawa scale) were assessed. RESULTS: Ninety-seven articles were included, 68 published in 2013 or later. VR improved balance and gait in all cohorts, especially when combined with conventional rehabilitation. Most studies presented poor methodologic quality, lacked a clear rationale for intervention programs, and did not utilize motor learning principles meticulously. RCTs with more robust methodologic designs were widely recommended. CONCLUSION: Our results suggest that VR-based rehabilitation is developing rapidly, has the potential to improve balance and gait in neurologic patients, and brings additional benefits when combined with conventional rehabilitation. This systematic review provides detailed information for developing theory-driven protocols that may assist overcoming the observed lack of argued choices for intervention programs and motor learning implementation and serves as a reference for the design and planning of personalized VR-based treatments. REGISTRATION: PROSPERO CRD42016042051. PMID- 29720546 TI - Incidence of MS has increased markedly over six decades in Denmark particularly with late onset and in women. AB - OBJECTIVE: To describe the pattern of development of incidence of multiple sclerosis (MS) over 60 years in Denmark with age-period-cohort analyses and seasonality of birth. METHODS: Data on virtually all patients with onset of MS have since 1950 been prospectively recorded and kept in the Danish Multiple Sclerosis Registry with multiple sources of notification. Annualized incidence rates per 100,000 were directly standardized to the European Standard Population. RESULTS: We have registered 19,536 cases with clinical onset of confirmed MS in Denmark from 1950 to 2009. From the 1950-1959 to the 2000-2009 onset period, incidence more than doubled in women, with an increase from 5.91 (95% confidence interval [CI]: 5.60-6.24) to 12.33 (95% CI: 11.91-12.75) per 100,000 per year compared with a modest 24% increase in men from 4.52 (95% CI: 4.24-4.81) to 6.08 (95% CI: 5.79-6.38). With age at onset of 50 years and older, incidence increased with a factor 4.30 in women and 2.72 in men. The female/male sex ratio increased over time and with year of birth. Age-period-cohort analysis revealed a significant birth cohort effect in addition to the age and period effect. We found no statistically significant seasonality of births. CONCLUSION: The incidence of MS has doubled in women, most pronounced with late onset, and has only modestly increased in men. Lifestyle changes in the female population that could include fewer childbirths, increased occurrence of obesity, and increased cigarette consumption may have a role. PMID- 29720545 TI - Multifocal demyelinating motor neuropathy and hamartoma syndrome associated with a de novo PTEN mutation. AB - OBJECTIVE: To describe a patient with a multifocal demyelinating motor neuropathy with onset in childhood and a mutation in phosphatase and tensin homolog (PTEN), a tumor suppressor gene associated with inherited tumor susceptibility conditions, macrocephaly, autism, ataxia, tremor, and epilepsy. Functional implications of this protein have been investigated in Parkinson and Alzheimer diseases. METHODS: We performed whole-exome sequencing in the patient's genomic DNA validated by Sanger sequencing. Immunoblotting, in vitro enzymatic assay, and label-free shotgun proteomic profiling were performed in the patient's fibroblasts. RESULTS: The predominant clinical presentation of the patient was a childhood onset, asymmetric progressive multifocal motor neuropathy. In addition, he presented with macrocephaly, autism spectrum disorder, and skin hamartomas, considered as clinical criteria for PTEN-related hamartoma tumor syndrome. Extensive tumor screening did not detect any malignancies. We detected a novel de novo heterozygous c.269T>C, p.(Phe90Ser) PTEN variant, which was absent in both parents. The pathogenicity of the variant is supported by altered expression of several PTEN-associated proteins involved in tumorigenesis. Moreover, fibroblasts showed a defect in catalytic activity of PTEN against the secondary substrate, phosphatidylinositol 3,4-trisphosphate. In support of our findings, focal hypermyelination leading to peripheral neuropathy has been reported in PTEN deficient mice. CONCLUSION: We describe a novel phenotype, PTEN-associated multifocal demyelinating motor neuropathy with a skin hamartoma syndrome. A similar mechanism may potentially underlie other forms of Charcot-Marie-Tooth disease with involvement of the phosphatidylinositol pathway. PMID- 29720547 TI - Free health care, great data, and new clues on multiple sclerosis. PMID- 29720548 TI - ESRD among Immigrants to Ontario, Canada: A Population-Based Study. AB - Background The epidemiology of ESRD requiring maintenance dialysis (ESRD-D) in large, diverse immigrant populations is unclear.Methods We estimated ESRD-D prevalence and incidence among immigrants in Ontario, Canada. Adults residing in Ontario in 2014 were categorized as long-term Canadian residents or immigrants according to administrative health and immigration datasets. We determined ESRD-D prevalence among these adults and calculated age-adjusted prevalence ratios (PRs) comparing immigrants to long-term residents. Among those who immigrated to Ontario between 1991 and 2012, age-adjusted ESRD-D incidence was calculated by world region and country of birth, with immigrants from Western nations as the referent group.Results Among 1,902,394 immigrants and 8,860,283 long-term residents, 1700 (0.09%) and 8909 (0.10%), respectively, presented with ESRD-D. Age-adjusted ESRD-D prevalence was higher among immigrants from sub-Saharan Africa (PR, 2.17; 95% confidence interval [95% CI], 1.84 to 2.57), Latin America and the Caribbean (PR, 2.11; 95% CI, 1.90 to 2.34), South Asia (PR, 1.45; 95% CI, 1.32 to 1.59), and East Asia and the Pacific (PR, 1.34; 95% CI, 1.22 to 1.46). Immigrants from Somalia (PR, 4.18; 95% CI, 3.11 to 5.61), Trinidad and Tobago (PR, 2.88; 95% CI, 2.23 to 3.73), Jamaica (PR, 2.88; 95% CI, 2.40 to 3.44), Sudan (PR, 2.84; 95% CI, 1.53 to 5.27), and Guyana (PR, 2.69; 95% CI, 2.19 to 3.29) had the highest age-adjusted ESRD-D PRs relative to long-term residents. Immigrants from these countries also exhibited higher age-adjusted ESKD-D incidence relative to Western Nations immigrants.Conclusions Among immigrants in Canada, those from sub-Saharan Africa and the Caribbean have the highest ESRD-D risk. Tailored kidney-protective interventions should be developed for these susceptible populations. PMID- 29720550 TI - Short-Term Plasticity Combines with Excitation-Inhibition Balance to Expand Cerebellar Purkinje Cell Dynamic Range. AB - The balance between excitation (E) and inhibition (I) in neuronal networks controls the firing rate of principal cells through simple network organization, such as feedforward inhibitory circuits. Here, we demonstrate in male mice, that at the granule cell (GrC)-molecular layer interneuron (MLI)-Purkinje cell (PC) pathway of the cerebellar cortex, E/I balance is dynamically controlled by short term dynamics during bursts of stimuli, shaping cerebellar output. Using a combination of electrophysiological recordings, optogenetic stimulation, and modeling, we describe the wide range of bidirectional changes in PC discharge triggered by GrC bursts, from robust excitation to complete inhibition. At high frequency (200 Hz), increasing the number of pulses in a burst (from 3 to 7) can switch a net inhibition of PC to a net excitation. Measurements of EPSCs and IPSCs during bursts and modeling showed that this feature can be explained by the interplay between short-term dynamics of the GrC-MLI-PC pathway and E/I balance impinging on PC. Our findings demonstrate that PC firing rate is highly sensitive to the duration of GrC bursts, which may define a temporal-to-rate code transformation in the cerebellar cortex.SIGNIFICANCE STATEMENT Sensorimotor information processing in the cerebellar cortex leads to the occurrence of a sequence of synaptic excitation and inhibition in Purkinje cells. Granule cells convey direct excitatory inputs and indirect inhibitory inputs to the Purkinje cells, through molecular layer interneurons, forming a feedforward inhibitory pathway. Using electrophysiological recordings, optogenetic stimulation, and mathematical modeling, we found that presynaptic short-term dynamics affect the balance between synaptic excitation and inhibition on Purkinje cells during high frequency bursts and can reverse the sign of granule cell influence on Purkinje cell discharge when burst duration increases. We conclude that short-term dynamics may play an important role in transforming the duration of sensory inputs arriving on cerebellar granule cells into cerebellar cortical output firing rate. PMID- 29720549 TI - The Role of Palladin in Podocytes. AB - Background Podocyte loss and effacement of interdigitating podocyte foot processes are the major cause of a leaky filtration barrier and ESRD. Because the complex three-dimensional morphology of podocytes depends on the actin cytoskeleton, we studied the role in podocytes of the actin bundling protein palladin, which is highly expressed therein.Methods We knocked down palladin in cultured podocytes by siRNA transfection or in zebrafish embryos by morpholino injection and studied the effects by immunofluorescence and live imaging. We also investigated kidneys of mice with podocyte-specific knockout of palladin (PodoPalld-/- mice) by immunofluorescence and ultrastructural analysis and kidney biopsy specimens from patients by immunostaining for palladin.Results Compared with control-treated podocytes, palladin-knockdown podocytes had reduced actin filament staining, smaller focal adhesions, and downregulation of the podocyte specific proteins synaptopodin and alpha-actinin-4. Furthermore, palladin knockdown podocytes were more susceptible to disruption of the actin cytoskeleton with cytochalasin D, latrunculin A, or jasplakinolide and showed altered migration dynamics. In zebrafish embryos, palladin knockdown compromised the morphology and dynamics of epithelial cells at an early developmental stage. Compared with PodoPalld+/+ controls, PodoPalld-/- mice developed glomeruli with a disturbed morphology, an enlarged subpodocyte space, mild effacement, and significantly reduced expression of nephrin and vinculin. Furthermore, nephrotoxic serum injection led to significantly higher levels of proteinuria in PodoPalld-/- mice than in controls. Kidney biopsy specimens from patients with diabetic nephropathy and FSGS showed downregulation of palladin in podocytes as well.Conclusions Palladin has an important role in podocyte function in vitro and in vivo. PMID- 29720551 TI - Behavioral and Neural Representations of Spatial Directions across Words, Schemas, and Images. AB - Modern spatial navigation requires fluency with multiple representational formats, including visual scenes, signs, and words. These formats convey different information. Visual scenes are rich and specific but contain extraneous details. Arrows, as an example of signs, are schematic representations in which the extraneous details are eliminated, but analog spatial properties are preserved. Words eliminate all spatial information and convey spatial directions in a purely abstract form. How does the human brain compute spatial directions within and across these formats? To investigate this question, we conducted two experiments on men and women: a behavioral study that was preregistered and a neuroimaging study using multivoxel pattern analysis of fMRI data to uncover similarities and differences among representational formats. Participants in the behavioral study viewed spatial directions presented as images, schemas, or words (e.g., "left"), and responded to each trial, indicating whether the spatial direction was the same or different as the one viewed previously. They responded more quickly to schemas and words than images, despite the visual complexity of stimuli being matched. Participants in the fMRI study performed the same task but responded only to occasional catch trials. Spatial directions in images were decodable in the intraparietal sulcus bilaterally but were not in schemas and words. Spatial directions were also decodable between all three formats. These results suggest that intraparietal sulcus plays a role in calculating spatial directions in visual scenes, but this neural circuitry may be bypassed when the spatial directions are presented as schemas or words.SIGNIFICANCE STATEMENT Human navigators encounter spatial directions in various formats: words ("turn left"), schematic signs (an arrow showing a left turn), and visual scenes (a road turning left). The brain must transform these spatial directions into a plan for action. Here, we investigate similarities and differences between neural representations of these formats. We found that bilateral intraparietal sulci represent spatial directions in visual scenes and across the three formats. We also found that participants respond quickest to schemas, then words, then images, suggesting that spatial directions in abstract formats are easier to interpret than concrete formats. These results support a model of spatial direction interpretation in which spatial directions are either computed for real world action or computed for efficient visual comparison. PMID- 29720552 TI - R-Ras1 and R-Ras2 Are Essential for Oligodendrocyte Differentiation and Survival for Correct Myelination in the Central Nervous System. AB - Rapid and effective neural transmission of information requires correct axonal myelination. Modifications in myelination alter axonal capacity to transmit electric impulses and enable pathological conditions. In the CNS, oligodendrocytes (OLs) myelinate axons, a complex process involving various cellular interactions. However, we know little about the mechanisms that orchestrate correct myelination. Here, we demonstrate that OLs express R-Ras1 and R-Ras2. Using female and male mutant mice to delete these proteins, we found that activation of the PI3K/Akt and Erk1/2-MAPK pathways was weaker in mice lacking one or both of these GTPases, suggesting that both proteins coordinate the activity of these two pathways. Loss of R-Ras1 and/or R-Ras2 diminishes the number of OLs in major myelinated CNS tracts and increases the proportion of immature OLs. In R-Ras1-/- and R-Ras2-/--null mice, OLs show aberrant morphologies and fail to differentiate correctly into myelin-forming phenotypes. The smaller OL population and abnormal OL maturation induce severe hypomyelination, with shorter nodes of Ranvier in R-Ras1-/- and/or R-Ras2-/- mice. These defects explain the slower conduction velocity of myelinated axons that we observed in the absence of R-Ras1 and R-Ras2. Together, these results suggest that R-Ras1 and R-Ras2 are upstream elements that regulate the survival and differentiation of progenitors into OLs through the PI3K/Akt and Erk1/2-MAPK pathways for proper myelination.SIGNIFICANCE STATEMENT In this study, we show that R-Ras1 and R-Ras2 play essential roles in regulating myelination in vivo and control fundamental aspects of oligodendrocyte (OL) survival and differentiation through synergistic activation of PI3K/Akt and Erk1/2-MAPK signaling. Mice lacking R-Ras1 and/or R-Ras2 show a diminished OL population with a higher proportion of immature OLs, explaining the observed hypomyelination in main CNS tracts. In vivo electrophysiology recordings demonstrate a slower conduction velocity of nerve impulses in the absence of R-Ras1 and R-Ras2. Therefore, R-Ras1 and R-Ras2 are essential for proper axonal myelination and accurate neural transmission. PMID- 29720553 TI - Distinguishing the Roles of Dorsolateral and Anterior PFC in Visual Metacognition. AB - Visual metacognition depends on regions within the prefrontal cortex (PFC). Two areas in particular have been implicated repeatedly: the dorsolateral PFC (DLPFC) and the anterior PFC (aPFC). However, it is still unclear what the function of each of these areas is and how they differ from each other. To establish the specific roles of DLPFC and aPFC in metacognition, we used online transcranial magnetic stimulation (TMS) to interfere causally with their functioning during confidence generation. Human subjects from both sexes performed a perceptual decision making and provided confidence ratings. We found a clear dissociation between the two areas: DLPFC TMS lowered confidence ratings, whereas aPFC TMS increased metacognitive ability, but only for the second half of the experimental blocks. These results support a functional architecture in which DLPFC reads out the strength of the sensory evidence and relays it to aPFC, which makes the confidence judgment by potentially incorporating additional, nonperceptual information. Indeed, simulations from a model that incorporates these putative DLPFC and aPFC functions reproduced our behavioral results. These findings establish DLPFC and aPFC as distinct nodes in a metacognitive network and suggest specific contributions from each of these regions to confidence generation.SIGNIFICANCE STATEMENT The prefrontal cortex (PFC) is known to be critical for metacognition. Two of its subregions, the dorsolateral PFC (DLPFC) and the anterior PFC (aPFC), have been specifically implicated in confidence generation. However, it is unclear whether these regions have distinct functions related to the underlying metacognitive computation. Using a causal intervention with transcranial magnetic stimulation, we demonstrate that DLPFC and aPFC have dissociable contributions: targeting DLPFC decreased average confidence ratings, whereas targeting aPFC affected metacognitive scores specifically. Based on these results, we postulated specific functions for DLPFC and aPFC in metacognitive computation and corroborated them using a computational model that reproduced our results. Our causal results reveal the existence of a specialized modular organization in PFC for confidence generation. PMID- 29720554 TI - Elucidation of the Mechanisms of Long-Distance mRNA Movement in a Nicotiana benthamiana/Tomato Heterograft System. AB - Recent heterograft analyses showed that large-scale messenger RNA (mRNA) movement takes place in the phloem, but the number of mobile transcripts reported varies widely. However, our knowledge of the mechanisms underlying large-scale mRNA movement remains limited. In this study, using a Nicotiana benthamiana/tomato (Solanum lycopersicum) heterograft system and a transgenic approach involving potato (Solanum tuberosum), we found that: (1) the overall mRNA abundance in the leaf is not a good indicator of transcript mobility to the root; (2) increasing the expression levels of nonmobile mRNAs in the companion cells does not promote their mobility; (3) mobile mRNAs undergo degradation during their movement; and (4) some mRNAs arriving in roots move back to shoots. These results indicate that mRNA movement has both regulated and unregulated components. The cellular origins of mobile mRNAs may differ between herbaceous and woody species. Taken together, these findings suggest that the long-distance movement of mRNAs is a complex process and that elucidating the physiological roles associated with this movement is challenging but remains an important task for future research. PMID- 29720555 TI - Auxin Efflux Carrier ZmPGP1 Mediates Root Growth Inhibition under Aluminum Stress. AB - Auxin has been shown to enhance root growth inhibition under aluminum (Al) stress in Arabidopsis (Arabidopsis thaliana). However, in maize (Zea mays), auxin may play a negative role in the Al-induced inhibition of root growth. In this study, we identified mutants deficient in the maize auxin efflux carrier P-glycoprotein (ZmPGP1) after ethyl methanesulfonate mutagenesis and used them to elucidate the contribution of ZmPGP1 to Al-induced root growth inhibition. Root growth in the zmpgp1 mutant, which forms shortened roots and is hyposensitive to auxin, was less inhibited by Al stress than that in the inbred line B73. In the zmpgp1 mutants, the root tips displayed higher auxin accumulation and enhanced auxin signaling under Al stress, which was also consistent with the increased expression of auxin-responsive genes. Based on the behavior of the auxin responsive marker transgene, DR5rev:RFP, we concluded that Al stress reduced the level of auxin in the root tip, which contrasts with the tendency of Al stress induced Arabidopsis plants to accumulate more auxin in their root tips. In addition, Al stress induced the expression of ZmPGP1 Therefore, in maize, Al stress is associated with reduced auxin accumulation in root tips, a process that is regulated by ZmPGP1 and thus causes inhibition of root growth. This study provides further evidence about the role of auxin and auxin polar transport in Al induced root growth regulation in maize. PMID- 29720558 TI - Two Distinct Secretory Pathways for Differential Kv2.1 Localization in Neurons. PMID- 29720556 TI - A Rice Glutamyl-tRNA Synthetase Modulates Early Anther Cell Division and Patterning. AB - Aminoacyl-tRNA synthetases (aaRSs) have housekeeping roles in protein synthesis, but little is known about how these aaRSs are involved in organ development. Here, we report that a rice (Oryza sativa) glutamyl-tRNA synthetase (OsERS1) maintains proper somatic cell organization and limits the overproliferation of male germ cells during early anther development. The expression of OsERS1 is specifically detectable in meristematic layer 2-derived cells of the early anther, and osers1 anthers exhibit overproliferation and disorganization of layer 2-derived cells, producing fused lobes and extra germ cells in early anthers. The conserved biochemical function of OsERS1 in ligating glutamate to tRNAGlu is enhanced by its cofactor aaRS OsARC. Furthermore, metabolomics profiling revealed that OsERS1 is an important node for multiple metabolic pathways, indicated by the accumulation of amino acids and tricarboxylic acid cycle components in osers1 anthers. Notably, the anther defects of the osers1 mutant are causally associated with the abnormal accumulation of hydrogen peroxide, which can reconstitute the osers1 phenotype when applied to wild-type anthers. Collectively, these findings demonstrate how aaRSs affect male organ development in plants, likely through protein synthesis, metabolic homeostasis, and redox status. PMID- 29720557 TI - ZEITLUPE in the Roots of Wild Tobacco Regulates Jasmonate-Mediated Nicotine Biosynthesis and Resistance to a Generalist Herbivore. AB - The jasmonate (JA) phytohormone signaling system is an important mediator of plant defense against herbivores. Plants deficient in JA signaling are more susceptible to herbivory as a result of deficiencies in defensive trait expression. Recent studies have implicated the circadian clock in regulating JA mediated defenses, but the molecular mechanisms linking the clock to JA signaling are unclear. Here, we report that wild tobacco (Nicotiana attenuata) plants rendered deficient in the clock component ZEITLUPE (ZTL) by RNA interference have attenuated resistance to the generalist herbivore Spodoptera littoralis This effect can be attributed in part to reduced concentrations of nicotine, an abundant JA-regulated toxin produced in N. attenuata roots and transported to shoots. RNA interference targeting ZTL dramatically affects the root circadian clock and reduces the expression of nicotine biosynthetic genes. Protein-protein interaction experiments demonstrate that ZTL regulates JA signaling by directly interacting with JASMONATE ZIM domain (JAZ) proteins in a CORONATINE-INSENSITIVE1 and jasmonoyl-isoleucine conjugate-independent manner, thereby regulating a JAZ MYC2 module that is required for nicotine biosynthesis. Our study reveals new functions for ZTL and proposes a mechanism by which a clock component directly influences JA signaling to regulate plant defense against herbivory. PMID- 29720559 TI - A Raf-Competitive K-Ras Binder Can Fail to Functionally Antagonize Signaling. AB - Mutated in approximately 30% of human cancers, Ras GTPases are the most common drivers of oncogenesis and render tumors unresponsive to many standard therapies. Despite decades of research, no drugs directly targeting Ras are currently available. We have previously characterized a small protein antagonist of K-Ras, R11.1.6, and demonstrated its direct competition with Raf for Ras binding. Here we evaluate the effects of R11.1.6 on Ras signaling and cellular proliferation in a panel of human cancer cell lines. Through lentiviral transduction, we generated cell lines that constitutively or through induction with doxycycline express R11.1.6 or a control protein YW1 and show specific binding by R11.1.6 to endogenous Ras through microscopy and co-immunoprecipitation experiments. Genetically encoded intracellular expression of this high-affinity Ras antagonist, however, fails to measurably disrupt signaling through either the MAPK or PI3K pathway. Consistently, cellular proliferation was unaffected as well. To understand this lack of signaling inhibition, we quantified the number of molecules of R11.1.6 expressed by the inducible cell lines and developed a simple mathematical model describing the competitive binding of Ras by R11.1.6 and Raf. This model supports a potential mechanism for the lack of biological effects that we observed, suggesting stoichiometric and thermodynamic barriers that should be overcome in pharmacologic efforts to directly compete with downstream effector proteins localized to membranes at very high effective concentrations. Mol Cancer Ther; 17(8); 1773-80. (c)2018 AACR. PMID- 29720560 TI - Targeting the Mevalonate Pathway Suppresses VHL-Deficient CC-RCC through an HIF Dependent Mechanism. AB - Clear cell renal cell carcinoma (CC-RCC) is a devastating disease with limited therapeutic options available for advanced stages. The objective of this study was to investigate HMG-CoA reductase inhibitors, also known as statins, as potential therapeutics for CC-RCC. Importantly, treatment with statins was found to be synthetically lethal with the loss of the von Hippel-Lindau (VHL) tumor suppressor gene, which occurs in 90% of CC-RCC driving the disease. This effect has been confirmed in three different CC-RCC cell lines with three different lipophilic statins. Inhibition of mevalonate synthesis by statins causes a profound cytostatic effect at nanomolar concentrations and becomes cytotoxic at low micromolar concentrations in VHL-deficient CC-RCC. The synthetic lethal effect can be fully rescued by both mevalonate and geranylgeranylpyrophosphate, but not by squalene, indicating that the effect is due to disruption of small GTPase isoprenylation and not the inhibition of cholesterol synthesis. Inhibition of Rho and Rho kinase (ROCK) signaling contributes to the synthetic lethality effect, and overactivation of hypoxia-inducible factor signaling resulting from VHL loss is required. Finally, statin treatment is able to inhibit both tumor initiation and progression of subcutaneous 786-OT1-based CC-RCC tumors in mice. Thus, statins represent potential therapeutics for the treatment of VHL-deficient CC-RCC. Mol Cancer Ther; 17(8); 1781-92. (c)2018 AACR. PMID- 29720561 TI - Androgen Receptor Signaling Reduces Radiosensitivity in Bladder Cancer. AB - Although radiotherapy often with chemotherapy has been shown to offer a survival benefit comparable with that of radical cystectomy in select patients with bladder cancer, the development of radiosensitization strategies may significantly enhance its application. Notably, emerging preclinical evidence has indicated the involvement of androgen receptor (AR) signaling in urothelial cancer progression. We here assessed whether AR signals could contribute to modulating radiosensitivity in bladder cancer cells. Ionizing radiation reduced the numbers of viable cells or colonies of AR-negative lines more significantly than those of AR-positive lines. Similarly, in AR-positive cells cultured in androgen-depleted conditions, dihydrotestosterone treatment lowered the effects of irradiation. Meanwhile, an antiandrogen hydroxyflutamide enhanced them in AR positive cells cultured in the presence of androgens. AR knockdown or hydroxyflutamide treatment also resulted in a delay in DNA double-strand break repair 4-24 hours after irradiation. We then established "radiation-resistant" sublines and found considerable elevation of the expression of AR as well as DNA repair genes, such as ATR, CHEK1, and PARP-1, in these sublines, compared with respective controls. Furthermore, dihydrotestosterone induced the expression of these DNA repair genes in irradiated AR-positive cells, and hydroxyflutamide antagonized the androgen effects. Finally, in a mouse xenograft model, low-dose flutamide was found to enhance the inhibitory effects of irradiation, and its tumor size was similar to that of AR knockdown line with radiation alone. These findings suggest that AR activity inversely correlates with radiosensitivity in bladder cancer. Accordingly, antiandrogenic drugs may function as sensitizers of irradiation, especially in patients with AR-positive urothelial cancer. Mol Cancer Ther; 17(7); 1566-74. (c)2018 AACR. PMID- 29720563 TI - Pharmacology of Cardio-Oncology: Chronotropic and Lusitropic Effects of B-Type Natriuretic Peptide in Cancer Patients with Early Diastolic Dysfunction Induced by Anthracycline or Nonanthracycline Chemotherapy. AB - B-type natriuretic peptide (BNP) is widely used as a diagnostic marker of systolic dysfunction. We previously conducted a clinical study in which anthracycline or nonanthracycline chemotherapy did not cause systolic dysfunction in cancer patients; however, some patients showed asymptomatic alterations in diastolic relaxation, whereas others showed persistent elevations of BNP, measured as prohormone BNP amino-terminal fragment. Here we describe post hoc pharmacologic analyses showing that: 1) impaired relaxation and persistent elevations of BNP were mutually exclusive manifestations of diastolic dysfunction; 2) in some patients, BNP elevations were induced by an early compromise of myocardial relaxation; 3) BNP elevations then halted further deterioration of relaxation in a concentration-dependent manner; and 4) high BNP increased heart rate (HR). BNP elevations therefore caused positive lusitropy and chronotropism, which might be explained by activation of natriuretic receptor associated guanylyl cyclase and production of cGMP in ventricular myocytes and sinoatrial node, respectively. BNP levels also influenced responses to a lusitropic drug, ranolazine, that was given to treat diastolic dysfunction. For patients with impaired relaxation and normal or only transiently high levels of BNP, ranolazine improved myocardial relaxation without inducing chronotropic effects. For patients in whom relaxation abnormalities were corrected by persistently high BNP levels, ranolazine substituted for BNP and decreased HR by diminishing BNP levels. These findings describe a pharmacologic scenario in which cancer drugs cause an early diastolic dysfunction that in some patients is both heralded and modulated by BNP elevations. Patients showing BNP elevations should therefore receive the adequate pharmacologic treatment of correcting diastolic dysfunction and tachycardia. PMID- 29720562 TI - Airway responsiveness to methacholine and incidence of COPD: an international prospective cohort study. AB - BACKGROUND: It has been debated, but not yet established, whether increased airway responsiveness can predict COPD. Recognising this link may help in identifying subjects at risk. OBJECTIVE: We studied prospectively whether airway responsiveness is associated with the risk of developing COPD. METHODS: We pooled data from two multicentre cohort studies that collected data from three time points using similar methods (European Community Respiratory Health Survey and Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults). We classified subjects (median age 37 years, 1st-3rd quartiles: 29-44) by their level of airway responsiveness using quintiles of methacholine dose-response slope at the first examination (1991-1994). Then, we excluded subjects with airflow obstruction at the second examination (1999-2003) and analysed incidence of COPD (postbronchodilator FEV1/FVC below the lower limit of normal) at the third examination (2010-2014) as a function of responsiveness, adjusting for sex, age, education, body mass index, history of asthma, smoking, occupational exposures and indicators of airway calibre. RESULTS: We observed 108 new cases of COPD among 4205 subjects during a median time of 9 years. Compared with the least responsive group (incidence rate 0.6 per 1000/year), adjusted incidence rate ratios for COPD ranged from 1.79 (95% CI 0.52 to 6.13) to 8.91 (95% CI 3.67 to 21.66) for increasing airway responsiveness. Similar dose-response associations were observed between smokers and non-smokers, and stronger associations were found among subjects without a history of asthma or asthma-like symptoms. CONCLUSIONS: Our study suggests that increased airway responsiveness is an independent risk factor for COPD. Further research should clarify whether early treatment in patients with high responsiveness can slow down disease progression. PMID- 29720564 TI - Evidence That Sedative Effects of Benzodiazepines Involve Unexpected GABAA Receptor Subtypes: Quantitative Observation Studies in Rhesus Monkeys. AB - In nonhuman primates we tested a new set of behavioral categories for observable sedative effects using pediatric anesthesiology classifications as a basis. Using quantitative behavioral observation techniques in rhesus monkeys, we examined the effects of alprazolam and diazepam (nonselective benzodiazepines), zolpidem (preferential binding to alpha1 subunit-containing GABAA receptors), HZ-166 (8 ethynyl-6-(2'-pyridine)-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic acid ethyl ester; functionally selective with relatively high intrinsic efficacy for alpha2 and alpha3 subunit-containing GABAA receptors), MRK-696 [7-cyclobutyl-6-(2-methyl 2H-1,2,4-triazol-2-ylmethoxy)-3-(2-flurophenyl)-1,2,4-triazolo(4,3-b)pyridazine; no selectivity but partial intrinsic activity], and TPA023B 6,2'-diflouro-5'-[3 (1-hydroxy-1-methylethyl)imidazo[1,2-b][1,2,4]triazin-7-yl]biphenyl-2 carbonitrile; partial intrinsic efficacy and selectivity for alpha2, alpha3, alpha5 subunit-containing GABAA receptors]. We further examined the role of alpha1 subunit-containing GABAA receptors in benzodiazepine-induced sedative effects by pretreating animals with the alpha1 subunit-preferring antagonist beta carboline-3-carboxylate-t-butyl ester (betaCCT). Increasing doses of alprazolam and diazepam resulted in the emergence of observable ataxia, rest/sleep posture, and moderate and deep sedation. In contrast, zolpidem engendered dose-dependent observable ataxia and deep sedation but not rest/sleep posture or moderate sedation, and HZ-166 and TPA023 induced primarily rest/sleep posture. MRK-696 induced rest/sleep posture and observable ataxia. Zolpidem, but no other compounds, significantly increased tactile/oral exploration. The sedative effects engendered by alprazolam, diazepam, and zolpidem generally were attenuated by betaCCT pretreatments, whereas rest/sleep posture and suppression of tactile/oral exploration were insensitive to betaCCT administration. These data suggest that alpha2/3-containing GABAA receptor subtypes unexpectedly may mediate a mild form of sedation (rest/sleep posture), whereas alpha1-containing GABAA receptors may play a role in moderate/deep sedation. PMID- 29720565 TI - Implementation of a cardiac PET stress program: comparison of outcomes to the preceding SPECT era. AB - BACKGROUND: Cardiac positron emission testing (PET) is more accurate than single photon emission computed tomography (SPECT) at identifying coronary artery disease (CAD); however, the 2 modalities have not been thoroughly compared in a real-world setting. We conducted a retrospective analysis of 60-day catheterization outcomes and 1-year major adverse cardiovascular events (MACE) after the transition from a SPECT- to a PET-based myocardial perfusion imaging (MPI) program. METHODS: MPI patients at Intermountain Medical Center from January 2011-December 2012 (the SPECT era, n = 6,777) and January 2014-December 2015 (the PET era, n = 7,817) were studied. Outcomes studied were 60-day coronary angiography, high-grade obstructive CAD, left main/severe 3-vessel disease, revascularization, and 1-year MACE-revascularization (MACE-revasc; death, myocardial infarction [MI], or revascularization >60 days). RESULTS: Patients were 64 +/- 13 years old; 54% were male and 90% were of European descent; and 57% represented a screening population (no prior MI, revascularization, or CAD). During the PET era, compared with the SPECT era, a higher percentage of patients underwent coronary angiography (13.2% vs. 9.7%, P < 0.0001), had high-grade obstructive CAD (10.5% vs. 6.9%, P < 0.0001), had left main or severe 3-vessel disease (3.0% vs. 2.3%, P = 0.012), and had coronary revascularization (56.7% vs. 47.1%, P = 0.0001). Similar catheterization outcomes were seen when restricted to the screening population. There was no difference in 1-year MACE-revasc (PET [5.8%] vs. SPECT [5.3%], P = 0.31). CONCLUSIONS: The PET-based MPI program resulted in improved identification of patients with high-grade obstructive CAD, as well as a larger percentage of revascularization, thus resulting in fewer patients undergoing coronary angiography without revascularization. FUNDING: This observational study was funded using internal departmental funds. PMID- 29720566 TI - Unexpected kidney-restricted role for IL-17 receptor signaling in defense against systemic Candida albicans infection. AB - Kidney injury is a frequent outcome in patients with disseminated Candida albicans fungal infections. IL-17 receptor (IL-17R) signaling is critical for renal protection against disseminated candidiasis, but the identity and function of IL-17-responsive cells in mediating renal defense remains an active area of debate. Using BM chimeras, we found that IL-17R signaling is required only in nonhematopoietic cells for immunity to systemic C. albicans infection. Since renal tubular epithelial cells (RTEC) are highly responsive to IL-17 in vitro, we hypothesized that RTEC might be the dominant target of IL-17 activity in the infected kidney. We generated mice with a conditional deletion of IL-17 receptor A (Il17ra) in RTEC (Il17raDeltaRTEC). Strikingly, Il17raDeltaRTEC mice showed enhanced kidney damage and early mortality following systemic infection, very similar to Il17ra-/- animals. Increased susceptibility to candidiasis in Il17raDeltaRTEC mice was associated with diminished activation of the renal protective Kallikrein-kinin system (KKS), resulting in reduced apoptosis of kidney-resident cells during hyphal invasion. Moreover, protection was restored by treatment with bradykinin, the major end-product of KKS activation, which was mediated dominantly via bradykinin receptor b1. These data show that IL-17R signaling in RTEC is necessary and likely sufficient for IL-17-mediated renal defense against fatal systemic C. albicans infection. PMID- 29720567 TI - Selection of phage-displayed accessible recombinant targeted antibodies (SPARTA): methodology and applications. AB - We developed a potentially novel and robust antibody discovery methodology, termed selection of phage-displayed accessible recombinant targeted antibodies (SPARTA). This combines an in vitro screening step of a naive human antibody library against known tumor targets, with in vivo selections based on tumor homing capabilities of a preenriched antibody pool. This unique approach overcomes several rate-limiting challenges to generate human antibodies amenable to rapid translation into medical applications. As a proof of concept, we evaluated SPARTA on 2 well-established tumor cell surface targets, EphA5 and GRP78. We evaluated antibodies that showed tumor-targeting selectivity as a representative panel of antibody-drug conjugates (ADCs) and were highly efficacious. Our results validate a discovery platform to identify and validate monoclonal antibodies with favorable tumor-targeting attributes. This approach may also extend to other diseases with known cell surface targets and affected tissues easily isolated for in vivo selection. PMID- 29720568 TI - pDCs in lung and skin fibrosis in a bleomycin-induced model and patients with systemic sclerosis. AB - Fibrosis is the end result of most inflammatory conditions, but its pathogenesis remains unclear. We demonstrate that, in animals and humans with systemic fibrosis, plasmacytoid DCs (pDCs) are unaffected or are reduced systemically (spleen/peripheral blood), but they increase in the affected organs (lungs/skin/bronchoalveolar lavage). A pivotal role of pDCs was shown by depleting them in vivo, which ameliorated skin and/or lung fibrosis, reduced immune cell infiltration in the affected organs but not in spleen, and reduced the expression of genes and proteins implicated in chemotaxis, inflammation, and fibrosis in the affected organs of animals with bleomycin-induced fibrosis. As with animal findings, the frequency of pDCs in the lungs of patients with systemic sclerosis correlated with the severity of lung disease and with the frequency of CD4+ and IL-4+ T cells in the lung. Finally, treatment with imatinib that has been reported to reduce and/or prevent deterioration of skin and lung fibrosis profoundly reduced pDCs in lungs but not in peripheral blood of patients with systemic sclerosis. These observations suggest a role for pDCs in the pathogenesis of systemic fibrosis and identify the increased trafficking of pDCs to the affected organs as a potential therapeutic target in fibrotic diseases. PMID- 29720570 TI - RIPK3 mediates pathogenesis of experimental ventilator-induced lung injury. AB - In patients requiring ventilator support, mechanical ventilation (MV) may induce acute lung injury (ventilator-induced lung injury [VILI]). VILI is associated with substantial morbidity and mortality in mechanically ventilated patients with and without acute respiratory distress syndrome. At the cellular level, VILI induces necrotic cell death. However, the contribution of necroptosis, a programmed form of necrotic cell death regulated by receptor-interacting protein 3 kinase (RIPK3) and mixed-lineage kinase domain-like pseudokinase (MLKL), to the development of VILI remains unexplored. Here, we show that plasma levels of RIPK3, but not MLKL, were higher in patients with MV (i.e., those prone to VILI) than in patients without MV (i.e., those less likely to have VILI) in two large intensive care unit cohorts. In mice, RIPK3 deficiency, but not MLKL deficiency, ameliorated VILI. In both humans and mice, VILI was associated with impaired fatty acid oxidation (FAO), but in mice this association was not observed under conditions of RIPK3 deficiency. These findings suggest that FAO-dependent RIPK3 mediates pathogenesis of acute lung injury. PMID- 29720571 TI - First-in-human topical microbiome transplantation with Roseomonas mucosa for atopic dermatitis. AB - The underlying pathology of atopic dermatitis (AD) includes impaired skin barrier function, susceptibility to Staphylococcus aureus skin infection, immune dysregulation, and cutaneous dysbiosis. Our recent investigation into the potential role of Gram-negative skin bacteria in AD revealed that isolates of one particular commensal, Roseomonas mucosa, collected from healthy volunteers (HVs) improved outcomes in mouse and cell culture models of AD. In contrast, isolates of R. mucosa from patients with AD worsened outcomes in these models. These preclinical results suggested that interventions targeting the microbiome could provide therapeutic benefit for patients with AD. As a first test of this hypothesis in humans, 10 adult and 5 pediatric patients were enrolled in an open label phase I/II safety and activity trial (the Beginning Assessment of Cutaneous Treatment Efficacy for Roseomonas in Atopic Dermatitis trial; BACTERiAD I/II). Treatment with R. mucosa was associated with significant decreases in measures of disease severity, topical steroid requirement, and S. aureus burden. There were no adverse events or treatment complications. We additionally evaluated differentiating bacterial metabolites and topical exposures that may contribute to the skin dysbiosis associated with AD and/or influence future microbiome-based treatments. These early results support continued evaluation of R. mucosa therapy with a placebo-controlled trial. PMID- 29720569 TI - Phosphodiesterase 2A as a therapeutic target to restore cardiac neurotransmission during sympathetic hyperactivity. AB - Elevated levels of brain natriuretic peptide (BNP) are regarded as an early compensatory response to cardiac myocyte hypertrophy, although exogenously administered BNP shows poor clinical efficacy in heart failure and hypertension. We tested whether phosphodiesterase 2A (PDE2A), which regulates the action of BNP activated cyclic guanosine monophosphate (cGMP), was directly involved in modulating Ca2+ handling from stellate ganglia (SG) neurons and cardiac norepinephrine (NE) release in rats and humans with an enhanced sympathetic phenotype. SG were also isolated from patients with sympathetic hyperactivity and healthy donor patients. PDE2A activity of the SG was greater in both spontaneously hypertensive rats (SHRs) and patients compared with their respective controls, whereas PDE2A mRNA was only high in SHR SG. BNP significantly reduced the magnitude of the calcium transients and ICaN in normal Wistar Kyoto (WKY) SG neurons, but not in the SHRs. cGMP levels stimulated by BNP were also attenuated in SHR SG neurons. Overexpression of PDE2A in WKY neurons recapitulated the calcium phenotype seen in SHR neurons. Functionally, BNP significantly reduced [3H]-NE release in the WKY rats, but not in the SHRs. Blockade of overexpressed PDE2A with Bay 60-7550 or overexpression of catalytically inactive PDE2A reestablished the modulatory action of BNP in SHR SG neurons. This suggests that PDE2A may be a key target in modulating the action of BNP to reduce sympathetic hyperactivity. PMID- 29720572 TI - Endospanin-2 enhances skeletal muscle energy metabolism and running endurance capacity. AB - Metabolic stresses such as dietary energy restriction or physical activity exert beneficial metabolic effects. In the liver, endospanin-1 and endospanin-2 cooperatively modulate calorie restriction-mediated (CR-mediated) liver adaptations by controlling growth hormone sensitivity. Since we found CR to induce endospanin protein expression in skeletal muscle, we investigated their role in this tissue. In vivo and in vitro endospanin-2 triggers ERK phosphorylation in skeletal muscle through an autophagy-dependent pathway. Furthermore, endospanin-2, but not endospanin-1, overexpression decreases muscle mitochondrial ROS production, induces fast-to-slow fiber-type switch, increases skeletal muscle glycogen content, and improves glucose homeostasis, ultimately promoting running endurance capacity. In line, endospanin-2-/- mice display higher lipid peroxidation levels, increased mitochondrial ROS production under mitochondrial stress, decreased ERK phosphorylation, and reduced endurance capacity. In conclusion, our results identify endospanin-2 as a potentially novel player in skeletal muscle metabolism, plasticity, and function. PMID- 29720573 TI - Parabiosis and single-cell RNA sequencing reveal a limited contribution of monocytes to myofibroblasts in kidney fibrosis. AB - Fibrosis is the common final pathway of virtually all chronic injury to the kidney. While it is well accepted that myofibroblasts are the scar-producing cells in the kidney, their cellular origin is still hotly debated. The relative contribution of proximal tubular epithelium and circulating cells, including mesenchymal stem cells, macrophages, and fibrocytes, to the myofibroblast pool remains highly controversial. Using inducible genetic fate tracing of proximal tubular epithelium, we confirm that the proximal tubule does not contribute to the myofibroblast pool. However, in parabiosis models in which one parabiont is genetically labeled and the other is unlabeled and undergoes kidney fibrosis, we demonstrate that a small fraction of genetically labeled renal myofibroblasts derive from the circulation. Single-cell RNA sequencing confirms this finding but indicates that these cells are circulating monocytes, express few extracellular matrix or other myofibroblast genes, and express many proinflammatory cytokines. We conclude that this small circulating myofibroblast progenitor population contributes to renal fibrosis by paracrine rather than direct mechanisms. PMID- 29720574 TI - Neutrophils are essential for induction of vaccine-like effects by antiviral monoclonal antibody immunotherapies. AB - Using a mouse retroviral model, we have shown that mAb-based immunotherapy can induce life-long endogenous protective immunity (vaccine-like effects). This observation has potentially important consequences for treating life-threatening human viral infections. Here, we investigated the role of neutrophils in this effect. Neutrophils are innate immunity effector cells with well-established microbe-killing activities that are rapidly mobilized upon infection. They are also emerging as orchestrators of innate and adaptive immunities. However, their immunomodulatory activity during antiviral mAb immunotherapies has never been studied. Our data reveal that neutrophils have an essential role in immunotherapy induced immune protection of infected mice. Unexpectedly, neutrophils have a limited effect in controlling viral propagation upon passive immunotherapy administration, which is mostly mediated by NK cells. Instead, neutrophils operate as essential inducers of a potent host humoral antiviral response. Thus, neutrophils play an unexpected key role in protective immunity induction by antiviral mAbs. Our work opens approaches to improve antiviral immunotherapies, as it suggests that preserving neutrophil functions and counts might be required for achieving mAb-induced protective immunity. PMID- 29720575 TI - Prediction of acute GVHD and relapse by metabolic biomarkers after allogeneic hematopoietic stem cell transplantation. AB - BACKGROUND: There are very few studies investigating metabolic biomarkers to predict acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Metabolic models can provide a framework for analyzing the information-rich omics data sets in this setting. METHODS: Four hundred and fifty-six samples from one hundred and fourteen consecutive patients who underwent HSCT from January 2012 to May 2014 were collected for this study. The changes in serum metabolite levels were investigated using a gas chromatography-mass spectrometry-based metabolomics approach and underwent statistical analysis. RESULTS: Significant metabolic changes were observed on day 7. The stearic acid/palmitic acid (SA/PA) ratio was effective in the diagnosis of grade II-IV aGVHD. Multivariate analysis showed that patients with high SA/PA ratios on day 7 after HSCT were less likely to develop II-IV aGVHD than patients with low SA/PA ratios (odds ratio [OR] = 0.06, 95% CI 0.02-0.18, P < 0.001). After the adjustment for clinical characteristics, the SA/PA ratio had no significant effect on overall survival (hazard ratio [HR] = 1.95, 95% CI 0.92 4.14, P = 0.08), and patients in the high SA/PA ratio group were significantly more likely to relapse than those in the low ratio group (HR = 2.26, 95% CI 1.04 4.91, P = 0.04). CONCLUSION: Our findings suggest that the SA/PA ratio on day 7 after HSCT is an excellent biomarker to predict both aGVHD and relapse. The serum SA/PA ratio measured on day 7 after transplantation may improve risk stratification for aGVHD and relapse after allogeneic stem cell transplantation. FUNDING: National Natural Science Foundation of China (81470346, 81773361), Priority Academic Program Development of Jiangsu Higher Education Institutions, Jiangsu Natural Science Foundation (BK20161204), Innovation Capability Development Project of Jiangsu Province (BM2015004), Jiangsu Medical Junior Talent Person award (QNRC2016707), and NIH (AI129582 and NS106170). PMID- 29720576 TI - Efficient exon skipping of SGCG mutations mediated by phosphorodiamidate morpholino oligomers. AB - Exon skipping uses chemically modified antisense oligonucleotides to modulate RNA splicing. Therapeutically, exon skipping can bypass mutations and restore reading frame disruption by generating internally truncated, functional proteins to rescue the loss of native gene expression. Limb-girdle muscular dystrophy type 2C is caused by autosomal recessive mutations in the SGCG gene, which encodes the dystrophin-associated protein gamma-sarcoglycan. The most common SGCG mutations disrupt the transcript reading frame abrogating gamma-sarcoglycan protein expression. In order to treat most SGCG gene mutations, it is necessary to skip 4 exons in order to restore the SGCG transcript reading frame, creating an internally truncated protein referred to as Mini-Gamma. Using direct reprogramming of human cells with MyoD, myogenic cells were tested with 2 antisense oligonucleotide chemistries, 2'-O-methyl phosphorothioate oligonucleotides and vivo-phosphorodiamidate morpholino oligomers, to induce exon skipping. Treatment with vivo-phosphorodiamidate morpholino oligomers demonstrated efficient skipping of the targeted exons and corrected the mutant reading frame, resulting in the expression of a functional Mini-Gamma protein. Antisense-induced exon skipping of SGCG occurred in normal cells and those with multiple distinct SGCG mutations, including the most common 521DeltaT mutation. These findings demonstrate a multiexon-skipping strategy applicable to the majority of limb-girdle muscular dystrophy 2C patients. PMID- 29720577 TI - Universal monitoring of minimal residual disease in acute myeloid leukemia. AB - BACKGROUND: Optimal management of acute myeloid leukemia (AML) requires monitoring of treatment response, but minimal residual disease (MRD) may escape detection. We sought to identify distinctive features of AML cells for universal MRD monitoring. METHODS: We compared genome-wide gene expression of AML cells from 157 patients with that of normal myeloblasts. Markers encoded by aberrantly expressed genes, including some previously associated with leukemia stem cells, were studied by flow cytometry in 240 patients with AML and in nonleukemic myeloblasts from 63 bone marrow samples. RESULTS: Twenty-two (CD9, CD18, CD25, CD32, CD44, CD47, CD52, CD54, CD59, CD64, CD68, CD86, CD93, CD96, CD97, CD99, CD123, CD200, CD300a/c, CD366, CD371, and CX3CR1) markers were aberrantly expressed in AML. Leukemia-associated profiles defined by these markers extended to immature CD34+CD38- AML cells; expression remained stable during treatment. The markers yielded MRD measurements matching those of standard methods in 208 samples from 52 patients undergoing chemotherapy and revealed otherwise undetectable MRD. They allowed MRD monitoring in 129 consecutive patients, yielding prognostically significant results. Using a machine-learning algorithm to reduce high-dimensional data sets to 2-dimensional data, the markers allowed a clear visualization of MRD and could detect 1 leukemic cell among more than 100,000 normal cells. CONCLUSION: The markers uncovered in this study allow universal and sensitive monitoring of MRD in AML. In combination with contemporary analytical tools, the markers improve the discrimination between leukemic and normal cells, thus facilitating data interpretation and, hence, the reliability of MRD results. FUNDING: National Cancer Institute (CA60419 and CA21765); American Lebanese Syrian Associated Charities; National Medical Research Council of Singapore (1299/2011); Viva Foundation for Children with Cancer, Children's Cancer Foundation, Tote Board & Turf Club, and Lee Foundation of Singapore. PMID- 29720579 TI - Congenital Esophageal Atresia and Microtia in a Newborn Secondary to Mycophenolate Mofetil Exposure During Pregnancy: A Case Report and Review of the Literature. AB - BACKGROUND Mycophenolate mofetil (MMF) is one of the most commonly prescribed drugs to prevent organ transplant rejection in combination with calcineurin inhibitors and steroids. It has a different toxicity profile than tacrolimus and cyclosporine. Gastrointestinal tract disturbances are the most common adverse effects. The use of MMF in pregnant women, however, holds great risk of miscarriage and fetal development defects such as external ear malformation, ocular anomalies, cleft lip and palate, and abnormality of distal limbs, heart, esophagus, and kidneys. Based on post-marketing studies, its pregnancy category was reclassified as category D by the US FDA in 2007. CASE REPORT A 20-year-old woman received a deceased-donor liver transplant for end-stage liver disease secondary to autoimmune hepatitis. She had 3 miscarriages while on MMF. In her fourth pregnancy she was exposed to MMF in the first trimester, which was stopped by week 20 of the pregnancy. Obstetric ultrasound suggested a cephalic presentation fetus with abdominal circumference. Her pregnancy resulted in an infant with tracheoesophageal fistula, esophageal atresia, and a bilateral ear canal atresia (microtia) with normal sensorineural conduction. There were no other congenital abnormalities. Thoracoscopic ligation of fistula and thoracotomy with esophageal repair were performed and a bone-anchored hearing aid for conductive hearing loss was implanted. Here, we report a case of congenital esophageal atresia and microtia secondary to mycophenolate mofetil. CONCLUSIONS MMF should be avoided during pregnancy. Transplanted female patients of reproductive age should receive appropriate counseling. PMID- 29720578 TI - Targeting inflammatory monocytes in sepsis-associated encephalopathy and long term cognitive impairment. AB - Sepsis-associated encephalopathy manifesting as delirium is a common problem in critical care medicine. In this study, patients that had delirium due to sepsis had significant cognitive impairments at 12-18 months after hospital discharge when compared with controls and Cambridge Neuropsychological Automated Test Battery-standardized scores in spatial recognition memory, pattern recognition memory, and delayed-matching-to-sample tests but not other cognitive functions. A mouse model of S. pneumoniae pneumonia-induced sepsis, which modeled numerous aspects of the human sepsis-associated multiorgan dysfunction, including encephalopathy, also revealed similar deficits in spatial memory but not new task learning. Both humans and mice had large increases in chemokines for myeloid cell recruitment. Intravital imaging of the brains of septic mice revealed increased neutrophil and CCR2+ inflammatory monocyte recruitment (the latter being far more robust), accompanied by subtle microglial activation. Prevention of CCR2+ inflammatory monocyte recruitment, but not neutrophil recruitment, reduced microglial activation and other signs of neuroinflammation and prevented all signs of cognitive impairment after infection. Therefore, therapeutically targeting CCR2+ inflammatory monocytes at the time of sepsis may provide a novel neuroprotective clinical intervention to prevent the development of persistent cognitive impairments. PMID- 29720580 TI - Targeting mTORC1/2 Complexes Inhibit Tumorigenesis and Enhance Sensitivity to 5 Flourouracil (5-FU) in Hepatocellular Carcinoma: A Preclinical Study of mTORC1/2 Targeted Therapy in Hepatocellular Carcinoma (HCC). AB - BACKGROUND Although 5-Flourouracil(5-FU) is used as the first-choice treatment for advanced hepatocellular carcinoma (HCC), it is associated with acquired and intrinsic resistance. Hyperactivation of mTOR signaling has been linked to tumorigenesis and chemoresistance in HCC. The aim of this study was to evaluate and compare the antitumor effects of mTORC1 inhibitor everolimus and mTORC1/2 inhibitor AZD8055 and to examine the interaction between 5-FU and mTORC1/2 inhibitor in HCC. MATERIAL AND METHODS Using cultured HCC cells and mouse xenograft, the antitumor effects of everolimus and AZD8055 were analyzed as mono- and combination therapy with 5-Flourouracil. RESULTS TSC2-deficient HCC cell lines were more sensitive to everolimus and AZD8055. AZD8055, but not everolimus, potently prevented cells from transitioning from G1 phase to S phase in TSC2-high expressing HCC cells. AZD8055 reduced phosphorylation of both mTORC1 and mTORC2 substrates. In contrast, everolimus reduced the phosphorylation of mTORC1 substrates, but increased the phosphorylation of AKT. Notably, AZD8055, but not everolimus, synergistically enhanced the efficacy of 5-FU via reversing 5-FU induced upregulation of P-glycoprotein (P-gp). The synergistic antitumor effect of AZD8055 and 5-FU was also observed in a HCC xenograft mouse model. CONCLUSIONS TSC2 in HCC is a promising efficacy-predicting biomarker for the treatment of mTORC1/2 inhibitor. AZD8055 showed stronger antitumor activity than everolimus in TSC2-high-expressing HCC cells. Moreover, the combination of mTORC1/2 inhibitor with 5-FU appears to be a promising option for HCC patients refractory to chemotherapy. PMID- 29720581 TI - Identification of a pyrophosphate-dependent kinase and its donor selectivity determinants. AB - Almost all kinases utilize ATP as their phosphate donor, while a few kinases utilize pyrophosphate (PPi) instead. PPi-dependent kinases are often homologous to their ATP-dependent counterparts, but determinants of their different donor specificities remain unclear. We identify a PPi-dependent member of the ribokinase family, which differs from known PPi-dependent kinases, and elucidate its PPi-binding mode based on the crystal structures. Structural comparison and sequence alignment reveal five important residues: three basic residues specifically recognizing PPi and two large hydrophobic residues occluding a part of the ATP-binding pocket. Two of the three basic residues adapt a conserved motif of the ribokinase family for the PPi binding. Using these five key residues as a signature pattern, we discover additional PPi-specific members of the ribokinase family, and thus conclude that these residues are the determinants of PPi-specific binding. Introduction of these residues may enable transformation of ATP-dependent ribokinase family members into PPi-dependent enzymes. PMID- 29720582 TI - Author Correction: A mechanistic framework for auxin dependent Arabidopsis root hair elongation to low external phosphate. AB - The original version of this Article omitted the following from the Acknowledgements: 'We also thank DBT-CREST BT/HRD/03/01/2002.' This has been corrected in both the PDF and HTML versions of the Article. PMID- 29720584 TI - Exceptional point engineered glass slide for microscopic thermal mapping. AB - Thermal sensing with fine spatial resolution is important to the study of many scientific areas. While modern microscopy systems allow optical detection at high spatial resolution, their intrinsic functions are mainly focused on imaging but limited in detecting other physical parameters, for example, mapping thermal variations. Here, with a coating of an optical exceptional point structure, we demonstrate a low-cost but efficient multifunctional microscope slide, supporting real-time monitoring and mapping of temperature distribution and heat transport in addition to conventional microscopic imaging. The square-root dependency associated with an exceptional point leads to enhanced thermal sensitivity for precise temperature measurement. With a microscale resolution, real-time thermal mapping is conducted, showing dynamic temperature variation in a spatially defined area. Our strategy of integrating low-cost and efficient optical sensing technologies on a conventional glass slide enables simultaneous detection of multiple environmental parameters, producing improved experimental control at the microscale in various scientific disciplines. PMID- 29720583 TI - CE-BLAST makes it possible to compute antigenic similarity for newly emerging pathogens. AB - Major challenges in vaccine development include rapidly selecting or designing immunogens for raising cross-protective immunity against different intra- or inter-subtypic pathogens, especially for the newly emerging varieties. Here we propose a computational method, Conformational Epitope (CE)-BLAST, for calculating the antigenic similarity among different pathogens with stable and high performance, which is independent of the prior binding-assay information, unlike the currently available models that heavily rely on the historical experimental data. Tool validation incorporates influenza-related experimental data sufficient for stability and reliability determination. Application to dengue-related data demonstrates high harmonization between the computed clusters and the experimental serological data, undetectable by classical grouping. CE BLAST identifies the potential cross-reactive epitope between the recent zika pathogen and the dengue virus, precisely corroborated by experimental data. The high performance of the pathogens without the experimental binding data suggests the potential utility of CE-BLAST to rapidly design cross-protective vaccines or promptly determine the efficacy of the currently marketed vaccine against emerging pathogens, which are the critical factors for containing emerging disease outbreaks. PMID- 29720586 TI - A silicon metal-oxide-semiconductor electron spin-orbit qubit. AB - The silicon metal-oxide-semiconductor (MOS) material system is a technologically important implementation of spin-based quantum information processing. However, the MOS interface is imperfect leading to concerns about 1/f trap noise and variability in the electron g-factor due to spin-orbit (SO) effects. Here we advantageously use interface-SO coupling for a critical control axis in a double quantum-dot singlet-triplet qubit. The magnetic field-orientation dependence of the g-factors is consistent with Rashba and Dresselhaus interface-SO contributions. The resulting all-electrical, two-axis control is also used to probe the MOS interface noise. The measured inhomogeneous dephasing time, [Formula: see text], of 1.6 MUs is consistent with 99.95% 28Si enrichment. Furthermore, when tuned to be sensitive to exchange fluctuations, a quasi-static charge noise detuning variance of 2 MUeV is observed, competitive with low-noise reports in other semiconductor qubits. This work, therefore, demonstrates that the MOS interface inherently provides properties for two-axis qubit control, while not increasing noise relative to other material choices. PMID- 29720585 TI - De novo activating mutations drive clonal evolution and enhance clonal fitness in KMT2A-rearranged leukemia. AB - Activating signaling mutations are common in acute leukemia with KMT2A (previously MLL) rearrangements (KMT2A-R). These mutations are often subclonal and their biological impact remains unclear. Using a retroviral acute myeloid mouse leukemia model, we demonstrate that FLT3 ITD , FLT3 N676K , and NRAS G12D accelerate KMT2A-MLLT3 leukemia onset. Further, also subclonal FLT3 N676K mutations accelerate disease, possibly by providing stimulatory factors. Herein, we show that one such factor, MIF, promotes survival of mouse KMT2A-MLLT3 leukemia initiating cells. We identify acquired de novo mutations in Braf, Cbl, Kras, and Ptpn11 in KMT2A-MLLT3 leukemia cells that favored clonal expansion. During clonal evolution, we observe serial genetic changes at the Kras G12D locus, consistent with a strong selective advantage of additional Kras G12D . KMT2A-MLLT3 leukemias with signaling mutations enforce Myc and Myb transcriptional modules. Our results provide new insight into the biology of KMT2A-R leukemia with subclonal signaling mutations and highlight the importance of activated signaling as a contributing driver. PMID- 29720587 TI - Ultra-confined surface phonon polaritons in molecular layers of van der Waals dielectrics. AB - Improvements in device density in photonic circuits can only be achieved with interconnects exploiting highly confined states of light. Recently this has brought interest to highly confined plasmon and phonon polaritons. While plasmonic structures have been extensively studied, the ultimate limits of phonon polariton squeezing, in particular enabling the confinement (the ratio between the excitation and polariton wavelengths) exceeding 102, is yet to be explored. Here, exploiting unique structure of 2D materials, we report for the first time that atomically thin van der Waals dielectrics (e.g., transition-metal dichalcogenides) on silicon carbide substrate demonstrate experimentally record breaking propagating phonon polaritons confinement resulting in 190-times squeezed surface waves. The strongly dispersive confinement can be potentially tuned to greater than 103 near the phonon resonance of the substrate, and it scales with number of van der Waals layers. We argue that our findings are a substantial step towards infrared ultra-compact phonon polaritonic circuits and resonators, and would stimulate further investigations on nanophotonics in non plasmonic atomically thin interface platforms. PMID- 29720588 TI - Persistent multi-scale fluctuations shift European hydroclimate to its millennial boundaries. AB - In recent years, there has been growing concern about the effect of global warming on water resources, especially at regional and continental scales. The last IPCC report on extremes states that there is medium confidence about an increase on European drought frequency during twentieth century. Here we use the Old World Drought Atlas palaeoclimatic reconstruction to show that when Europe's hydroclimate is examined under a millennial, multi-scale perspective, a significant decrease in dryness can be observed since 1920 over most of central and northern Europe. On the contrary, in the south, drying conditions have prevailed, creating an intense north-to-south dipole. In both cases, hydroclimatic conditions have shifted to, and in some regions exceeded, their millennial boundaries, remaining at these extreme levels for the longest period of the 1000-year-long record. PMID- 29720589 TI - Precisely timed inhibition facilitates action potential firing for spatial coding in the auditory brainstem. AB - The integration of excitatory and inhibitory synaptic inputs is fundamental to neuronal processing. In the mammalian auditory brainstem, neurons compare excitatory and inhibitory inputs from the ipsilateral and contralateral ear, respectively, for sound localization. However, the temporal precision and functional roles of inhibition in this integration process are unclear. Here, we demonstrate by in vivo recordings from the lateral superior olive (LSO) that inhibition controls spiking with microsecond precision throughout high frequency click trains. Depending on the relative timing of excitation and inhibition, neuronal spike probability is either suppressed or-unexpectedly-facilitated. In vitro conductance-clamp LSO recordings establish that a reduction in the voltage threshold for spike initiation due to a prior hyperpolarization results in post inhibitory facilitation of otherwise sub-threshold synaptic events. Thus, microsecond-precise differences in the arrival of inhibition relative to excitation can facilitate spiking in the LSO, thereby promoting spatial sensitivity during the processing of faint sounds. PMID- 29720591 TI - Discrepancy between pregnancy dating methods affects obstetric and neonatal outcomes: a population-based register cohort study. AB - To assess associations between discrepancy of pregnancy dating methods and adverse pregnancy, delivery, and neonatal outcomes, odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for discrepancy categories among all singleton births from the Medical Birth Register (1995-2010) with estimated date of delivery (EDD) by last menstrual period (LMP) minus EDD by ultrasound (US) -20 to +20 days. Negative/positive discrepancy was a fetus smaller/larger than expected when dated by US (EDD postponed/changed to an earlier date). Large discrepancy was <10th or >90th percentile. Reference was median discrepancy +/-2 days. Odds for diabetes and preeclampsia were higher in pregnancies with negative discrepancy, and for most delivery outcomes in case of large positive discrepancy (+9 to +20 days): shoulder dystocia [OR 1.16 (95% CI 1.01-1.33)] and sphincter injuries [OR 1.13 (95% CI 1.09-1.17)]. Odds for adverse neonatal outcomes were higher in large negative discrepancy (-4 to -20 days): low Apgar score [OR 1.18 (95% CI 1.09-1.27)], asphyxia [OR 1.18 (95% CI 1.11-1.25)], fetal death [OR 1.47 (95% CI 1.32-1.64)], and neonatal death [OR 2.19 (95% CI 1.91-2.50)]. In conclusion, especially, large negative discrepancy was associated with increased risks of adverse perinatal outcomes. PMID- 29720590 TI - Publisher Correction: Control of laser plasma accelerated electrons for light sources. AB - The original version of this Article contained an error in the last sentence of the first paragraph of the Introduction and incorrectly read 'A proper electron beam control is one of the main challenges towards the Graal of developing a compact alternative of X-ray free-electron lasers by coupling LWFA gigaelectron volts per centimetre acceleration gradient with undulators in the amplification regime in equation 11, nx(n-beta) x beta: n the two times and beta the two times should be bold since they are vectorsin Eq. 12, beta should be bold as well.' The correct version is 'A proper electron beam control is one of the main challenges towards the Graal of developing a compact alternative of X-ray free-electron lasers by coupling LWFA gigaelectron-volts per centimetre acceleration gradient with undulators in the amplification regime.'This has been corrected in both the PDF and HTML versions of the Article. PMID- 29720592 TI - Diversity of nonribosomal peptide synthetase and polyketide synthase gene clusters among taxonomically close Streptomyces strains. AB - To identify the species of butyrolactol-producing Streptomyces strain TP-A0882, whole genome-sequencing of three type strains in a close taxonomic relationship was performed. In silico DNA-DNA hybridization using the genome sequences suggested that Streptomyces sp. TP-A0882 is classified as Streptomyces diastaticus subsp. ardesiacus. Strain TP-A0882, S. diastaticus subsp. ardesiacus NBRC 15402T, Streptomyces coelicoflavus NBRC 15399T, and Streptomyces rubrogriseus NBRC 15455T harbor at least 14, 14, 10, and 12 biosynthetic gene clusters (BGCs), respectively, coding for nonribosomal peptide synthetases (NRPSs) and polyketide synthases (PKSs). All 14 gene clusters were shared by S. diastaticus subsp. ardesiacus strains TP-A0882 and NBRC 15402T, while only four gene clusters were shared by the three distinct species. Although BGCs for bacteriocin, ectoine, indole, melanine, siderophores such as deferrioxamine, terpenes such as albaflavenone, hopene, carotenoid and geosmin are shared by the three species, many BGCs for secondary metabolites such as butyrolactone, lantipeptides, oligosaccharide, some terpenes are species-specific. These results indicate the possibility that strains belonging to the same species possess the same set of secondary metabolite-biosynthetic pathways, whereas strains belonging to distinct species have species-specific pathways, in addition to some common pathways, even if the strains are taxonomically close. PMID- 29720593 TI - Nano-Photothermal ablation effect of Hydrophilic and Hydrophobic Functionalized Gold Nanorods on Staphylococcus aureus and Propionibacterium acnes. AB - The potential photothermal bactericidal activity of hydrophilic functionalized poly ethylene glycol (PEG)-gold nanorods (GNR) and hydrophobic functionalized polystyrene (PS)-GNR was evaluated towards strains of Staphylococcus aureus (S. aureus) and Propionibacterium acnes (P. acnes) by measuring the percentage reduction of bacterial viable count upon GNR excitation with a near infra-red (NIR) laser beam. Our results suggest that functionalized GNR had a minimal bactericidal activity against S. aureus and P. acnes (<=85%, i.e. <=1 log10 cycle reduction of bacterial viable count). However, the local heat generated upon exciting the functionalized GNR with NIR laser beam has a significant photothermal ablation effect (>=99.99%, i.e. >=4 log10 cycles reduction of bacterial viable count). Such photothermolysis effect could potentiate the antibacterial activity of GNR, which may call for minimum concentration and side effects of these nanotherapeutics. PMID- 29720594 TI - Quantitative comparison of different iron forms in the temporal cortex of Alzheimer patients and control subjects. AB - We present a quantitative study of different molecular iron forms found in the temporal cortex of Alzheimer (AD) patients. Applying the methodology we developed in our previous work, we quantify the concentrations of non-heme Fe(III) by Electron Paramagnetic Resonance (EPR), magnetite/maghemite and ferrihydrite by SQUID magnetometry, together with the MRI transverse relaxation rate [Formula: see text], to obtain a systematic view of molecular iron in the temporal cortex. Significantly higher values of [Formula: see text], a larger concentration of ferrihydrite, and a larger magnetic moment of magnetite/maghemite particles are found in the brain of AD patients. Moreover, we found correlations between the concentration of the iron detected by EPR, the concentration of the ferrihydrite mineral and the average iron loading of ferritin. We discuss these findings in the framework of iron dis-homeostasis, which has been proposed to occur in the brain of AD patients. PMID- 29720596 TI - Analog Approach to Constraint Satisfaction Enabled by Spin Orbit Torque Magnetic Tunnel Junctions. AB - Boolean satisfiability (k-SAT) is an NP-complete (k >= 3) problem that constitute one of the hardest classes of constraint satisfaction problems. In this work, we provide a proof of concept hardware based analog k-SAT solver, that is built using Magnetic Tunnel Junctions (MTJs). The inherent physics of MTJs, enhanced by device level modifications, is harnessed here to emulate the intricate dynamics of an analog satisfiability (SAT) solver. In the presence of thermal noise, the MTJ based system can successfully solve Boolean satisfiability problems. Most importantly, our results exhibit that, the proposed MTJ based hardware SAT solver is capable of finding a solution to a significant fraction (at least 85%) of hard 3-SAT problems, within a time that has a polynomial relationship with the number of variables(<50). PMID- 29720595 TI - Cytoglobin affects tumorigenesis and the expression of ulcerative colitis associated genes under chemically induced colitis in mice. AB - Cytoglobin (Cygb) is a member of the hemoglobin family and is thought to protect against cellular hypoxia and oxidative stress. These functions may be particularly important in inflammation-induced cancer, e.g., in patients with ulcerative colitis (UC). In this study, we investigated the development of inflammation and tumors in a murine model of inflammation-induced colorectal cancer using a combined treatment of azoxymethane and dextran sulfate sodium. A bioinformatics analysis of genome-wide expression data revealed increased colonic inflammation at the molecular level accompanied by enhanced macroscopic tumor development in Cygb-deficient mice. Moreover, the expression of the UC-associated gene neurexophilin and PC-esterase domain family member 4 (Nxpe4) depended on the presence of Cygb in the inflamed colonic mucosa. Compared to wild type mice, RT qPCR confirmed a 14-fold (p = 0.0003) decrease in Nxpe4 expression in the inflamed colonic mucosa from Cygb-deficient mice. An analysis of Cygb protein expression suggested that Cygb is expressed in fibroblast-like cells surrounding the colonic crypts. Histological examinations of early induced lesions suggested that the effect of Cygb is primarily at the level of tumor promotion. In conclusion, in this model, Cygb primarily seemed to inhibit the development of established microadenomas. PMID- 29720597 TI - 19F NMR studies provide insights into lipid membrane interactions of listeriolysin O, a pore forming toxin from Listeria monocytogenes. AB - Listeria monocytogenes is a mammalian pathogen that causes gastroenteritis, miscarriages and infections of the central nervous system in immunocompromised individuals. Its main virulence factor is listeriolysin O (LLO), a pore-forming cholesterol-dependent cytolysin (CDC), which enables bacterial escape from the phagolysosome and contributes to bacterial pathogenicity. Details of cholesterol (Chol) recognition and membrane binding mechanisms by LLO are still not known. Here we used 19F-NMR spectroscopy in order to assess LLO-Chol interactions in solution and in a Chol-rich membrane environment. LLO has six tryptophan residues located in the region of the molecule that is first in contact with lipid membranes. 19F-LLO, which contained 5-fluoro-tryptophans, was prepared by using isotopic labelling in an E. coli expression system. Signals in the 19F-NMR spectrum of 19F-LLO were unambiguously assigned by using a series of single Trp > Phe point mutations. The results employing various cholesterol preparations in solution indicate that tryptophan residues are not directly involved in Chol binding in solution. However, significant chemical shift changes were observed upon LLO binding to Chol-rich membranes, highlighting the role of tryptophan residues in membrane interactions (W512) and oligomerisation (W189 and W489). PMID- 29720599 TI - Interfacial magnetic-phase transition mediated large perpendicular magnetic anisotropy in FeRh/MgO by a heavy transition-metal capping. AB - Stacking a magnetic memory junction in spintronic devices necessarily involves making contacts with a transitional-metal capping electrode. Herein, by means of first-principles calculations, we reveal the importance of heavy transition-metal capping on magnetic-phase transition from antiferromagnetic (AFM) to ferromagnetic (FM) order and the large perpendicular magnetic anisotropy (PMA) found in Ta-capped FeRh films on MgO substrate. While magnetization of FeRh films reorients from in-plane to PMA when in contact with MgO, the presence of Ta capping further enhances the magnitude of the PMA energy by at least five times. This large PMA is associated with the AFM-FM transition at the interface, which in turn modifies the out-of-plane Fe 3d orbital states through the hybridization with the strong spin-orbit coupled Ta 5d orbitals. Furthermore, the magnetic phase transition at the interface is the result of the mutual mechanisms of the capping-induced volume/tetragonal expansion in the interfacial FeRh layers and the competition between the direct and indirect exchange interactions. These findings suggest that Ta/FeRh/MgO multilayers may represent highly favourable memory materials with net interfacial ferromagnetism and large PMA in antiferromagnet spintronics. PMID- 29720598 TI - Relationship between body mass index and renal function deterioration among the Taiwanese chronic kidney disease population. AB - This study investigated the characteristics of patients with different chronic kidney disease (CKD) stages according to various body mass index (BMI) categories and determined the influence of BMI in renal function deterioration. We conducted a multicenter, longitudinal cohort study based on the Epidemiology and Risk Factors Surveillance of CKD project (2008-2013) and National Health Insurance Research Database (2001-2013). A total of 7357 patients with CKD aged 20-85 years from 14 hospitals were included in the study. A higher male sex, diabetes mellitus (DM) and hypertension were noted among overweight and obese CKD patients, while more cancer prevalence was noted among underweight CKD patients. Charlson comorbidity index was significantly higher and correlated with BMI among late CKD patients. Patients with BMI < 18.5 kg/m2 exhibited non-significantly higher events of eGFR decline events in both early and late CKD stages than other BMI groups. BMI alone is not a determinant of CKD progression among our Taiwanese CKD patients. Obesity should be re-defined and body weight manipulation should be individualized in CKD patients. PMID- 29720601 TI - An approach to quantum-computational hydrologic inverse analysis. AB - Making predictions about flow and transport in an aquifer requires knowledge of the heterogeneous properties of the aquifer such as permeability. Computational methods for inverse analysis are commonly used to infer these properties from quantities that are more readily observable such as hydraulic head. We present a method for computational inverse analysis that utilizes a type of quantum computer called a quantum annealer. While quantum computing is in an early stage compared to classical computing, we demonstrate that it is sufficiently developed that it can be used to solve certain subsurface flow problems. We utilize a D Wave 2X quantum annealer to solve 1D and 2D hydrologic inverse problems that, while small by modern standards, are similar in size and sometimes larger than hydrologic inverse problems that were solved with early classical computers. Our results and the rapid progress being made with quantum computing hardware indicate that the era of quantum-computational hydrology may not be too far in the future. PMID- 29720600 TI - Small nuclear RNA-mediated modulation of splicing reveals a therapeutic strategy for a TREM2 mutation and its post-transcriptional regulation. AB - Loss-of-function mutations in TREM2 cause Nasu-Hakola disease (NHD), a rare genetic disease characterized by early-onset dementia with leukoencephalopathy and bone cysts. An NHD-associated mutation, c.482 + 2 T > C, disrupts the splice donor site of intron 3 and causes aberrant skipping of exon 3, resulting in the loss of full-length TREM2 protein. Here, we examined the efficacy of artificial U1 and U7 small nuclear RNAs (snRNAs) designed to enhance exon 3 inclusion. Using mutant TREM2 minigenes, we found that some modified U1, but not U7, snRNAs enhanced exon 3 inclusion and restored TREM2 protein expression. Unexpectedly, we found that exon 3 of wild-type TREM2 is an alternative exon, whose skipping leads to reduced expression of the full-length protein. Indeed, TREM2 protein levels were modulated by modified snRNAs that either promoted or repressed exon 3 inclusion. The splice donor site flanking exon 3 was predicted to be weak, which may explain both the alternative splicing of exon 3 under normal conditions and complete exon skipping when the c.482 + 2 T > C mutation was present. Collectively, our snRNA-based approaches provide a potential therapeutic strategy for NHD-associated mis-splicing and novel insights into the post-transcriptional regulation of TREM2. PMID- 29720602 TI - Satiety behavior is regulated by ASI/ASH reciprocal antagonism. AB - Appropriate decision-making is essential for ensuring survival; one such decision is whether to eat. Overall metabolic state and the safety of food are the two factors we examined using C. elegans to ask whether the metabolic state regulates neuronal activities and corresponding feeding behavior. We monitored the activity of sensory neurons that are activated by nutritious (or appetitive) stimuli (ASI) and aversive stimuli (ASH) in starved vs. well-fed worms during stimuli presentation. Starvation reduces ASH activity to aversive stimuli while increasing ASI activity to nutritious stimuli, showing the responsiveness of each neuron is modulated by overall metabolic state. When we monitored satiety quiescence behavior that reflects the overall metabolic state, ablation of ASI and ASH produce the opposite behavior, showing the two neurons interact to control the decision to eat or not. This circuit provides a simple approach to how neurons handle sensory conflict and reach a decision that is translated to behavior. PMID- 29720603 TI - Mineral dust as a driver of carbon accumulation in northern latitudes. AB - Peatlands in northern latitudes sequester one third of the world's soil organic carbon. Mineral dusts can affect the primary productivity of terrestrial systems through nutrient transport but this process has not yet been documented in these peat-rich regions. Here we analysed organic and inorganic fractions of an 8900 year-old sequence from Store Mosse (the "Great Bog") in southern Sweden. Between 5420 and 4550 cal yr BP, we observe a seven-fold increase in net peat accumulation rates corresponding to a maximum carbon-burial rate of 150 g C m-2 yr-1 - more than six times the global average. This high peat accumulation event occurs in parallel with a distinct change in the character of the dust deposited on the bog, which moves from being dominated by clay minerals to less weathered, phosphate and feldspar minerals. We hypothesize that this shift boosted nutrient input to the bog and stimulated ecosystem productivity. This study shows that diffuse sources and dust dynamics in northern temperate latitudes, often overlooked by the dust community in favour of arid and semi-arid regions, can be important drivers of peatland carbon accumulation and by extension, global climate, warranting further consideration in predictions of future climate variability. PMID- 29720604 TI - Electrochemical detection of NGF using a reduced graphene oxide- titanium nitride nanocomposite. AB - There is a correlation between the severity of neurological impairment in patients that have suffered a cerebrovascular accident and the nerve growth factor (NGF) level. This study addressed the fabrication of a titanium nitride (TiN) and reduced graphene oxide (RGO)-based composite with remarkable electrocatalytic activity towards NGF oxidation in a phosphate buffer solution (PB, 0.1 M). The proposed electrochemical sensor was linearly related to the NGF concentration in the range of 10 nM-5 MUM with a detection limit of 2.6 nM. PMID- 29720605 TI - EAAC1 gene deletion reduces adult hippocampal neurogenesis after transient cerebral ischemia. AB - Several studies have demonstrated that excitatory amino acid carrier-1 (EAAC1) gene deletion exacerbates hippocampal and cortical neuronal death after ischemia. However, presently there are no studies investigating the role of EAAC1 in hippocampal neurogenesis. In this study, we tested the hypothesis that reduced cysteine transport into neurons by EAAC1 knockout negatively affects adult hippocampal neurogenesis under physiological or pathological states. This study used young mice (aged 3-5 months) and aged mice (aged 11-15 months) of either the wild-type (WT) or EAAC1 -/- genotype. Ischemia was induced through the occlusion of bilateral common carotid arteries for 30 minutes. Histological analysis was performed at 7 or 30 days after ischemia. We found that both young and aged mice with loss of the EAAC1 displayed unaltered cell proliferation and neuronal differentiation, as compared to age-matched WT mice under ischemia-free conditions. However, neurons generated from EAAC1 -/- mice showed poor survival outcomes in both young and aged mice. In addition, deletion of EAAC1 reduced the overall level of neurogenesis, including cell proliferation, differentiation, and survival after ischemia. The present study demonstrates that EAAC1 is important for the survival of newly generated neurons in the adult brain under physiological and pathological conditions. Therefore, this study suggests that EAAC1 plays an essential role in modulating hippocampal neurogenesis. PMID- 29720606 TI - Cryptic species in a well-known habitat: applying taxonomics to the amphipod genus Epimeria (Crustacea, Peracarida). AB - Taxonomy plays a central role in biological sciences. It provides a communication system for scientists as it aims to enable correct identification of the studied organisms. As a consequence, species descriptions should seek to include as much available information as possible at species level to follow an integrative concept of 'taxonomics'. Here, we describe the cryptic species Epimeria frankei sp. nov. from the North Sea, and also redescribe its sister species, Epimeria cornigera. The morphological information obtained is substantiated by DNA barcodes and complete nuclear 18S rRNA gene sequences. In addition, we provide, for the first time, full mitochondrial genome data as part of a metazoan species description for a holotype, as well as the neotype. This study represents the first successful implementation of the recently proposed concept of taxonomics, using data from high-throughput technologies for integrative taxonomic studies, allowing the highest level of confidence for both biodiversity and ecological research. PMID- 29720607 TI - Concurrent micro- to macro-cardiac electrophysiology in myocyte cultures and human heart slices. AB - The contact cardiac electrogram is derived from the extracellular manifestation of cellular action potentials and cell-to-cell communication. It is used to guide catheter based clinical procedures. Theoretically, the contact electrogram and the cellular action potential are directly related, and should change in conjunction with each other during arrhythmogenesis, however there is currently no methodology by which to concurrently record both electrograms and action potentials in the same preparation for direct validation of their relationships and their direct mechanistic links. We report a novel dual modality apparatus for concurrent electrogram and cellular action potential recording at a single cell level within multicellular preparations. We further demonstrate the capabilities of this system to validate the direct link between these two modalities of voltage recordings. PMID- 29720608 TI - Drosophila Voltage-Gated Calcium Channel alpha1-Subunits Regulate Cardiac Function in the Aging Heart. AB - Ion channels maintain numerous physiological functions and regulate signaling pathways. They are the key targets for cellular reactive oxygen species (ROS), acting as signaling switches between ROS and ionic homeostasis. We have carried out a paraquat (PQ) screen in Drosophila to identify ion channels regulating the ROS handling and survival in Drosophila melanogaster. Our screen has revealed that alpha1-subunits (D-type, T-type, and cacophony) of voltage-gated calcium channels (VGCCs) handle PQ-mediated ROS stress differentially in a gender-based manner. Since ROS are also involved in determining the lifespan, we discovered that the absence of T-type and cacophony decreased the lifespan while the absence of D-type maintained a similar lifespan to that of the wild-type strain. VGCCs are also responsible for electrical signaling in cardiac cells. The cardiac function of each mutant was evaluated through optical coherence tomography (OCT), which revealed that alpha1-subunits of VGCCs are essential in maintaining cardiac rhythmicity and cardiac function in an age-dependent manner. Our results establish specific roles of alpha1-subunits of VGCCs in the functioning of the aging heart. PMID- 29720609 TI - Chalcogen passivation: an in-situ method to manipulate the morphology and electrical property of GaAs nanowires. AB - Recently, owing to the large surface-area-to-volume ratio of nanowires (NWs), manipulation of their surface states becomes technologically important and being investigated for various applications. Here, an in-situ surfactant-assisted chemical vapor deposition is developed with various chalcogens (e.g. S, Se and Te) as the passivators to enhance the NW growth and to manipulate the controllable p-n conductivity switching of fabricated NW devices. Due to the optimal size effect and electronegativity matching, Se is observed to provide the best NW surface passivation in diminishing the space charge depletion effect induced by the oxide shell and yielding the less p-type (i.e. inversion) or even insulating conductivity, as compared with S delivering the intense p-type conductivity for thin NWs with the diameter of ~30 nm. Te does not only provide the surface passivation, but also dopes the NW surface into n-type conductivity by donating electrons. All of the results can be extended to other kinds of NWs with similar surface effects, resulting in careful device design considerations with appropriate surface passivation for achieving the optimal NW device performances. PMID- 29720610 TI - Association between pupil dilation and implicit processing prior to object recognition via insight. AB - Insight refers to the sudden conscious shift in the perception of a situation following a period of unconscious processing. The present study aimed to investigate the implicit neural mechanisms underlying insight-based recognition, and to determine the association between these mechanisms and the extent of pupil dilation. Participants were presented with ambiguous, transforming images comprised of dots, following which they were asked to state whether they recognized the object and their level of confidence in this statement. Changes in pupil dilation were not only characterized by the recognition state into the ambiguous object but were also associated with prior awareness of object recognition, regardless of meta-cognitive confidence. Our findings indicate that pupil dilation may represent the level of implicit integration between memory and visual processing, despite the lack of object awareness, and that this association may involve noradrenergic activity within the locus coeruleus noradrenergic (LC-NA) system. PMID- 29720611 TI - Blooming Artifact Reduction in Coronary Artery Calcification by A New De-blooming Algorithm: Initial Study. AB - The aim of this study was to investigate the use of de-blooming algorithm in coronary CT angiography (CCTA) for optimal evaluation of calcified plaques. Calcified plaques were simulated on a coronary vessel phantom and a cardiac motion phantom. Two convolution kernels, standard (STND) and high-definition standard (HD STND), were used for imaging reconstruction. A dedicated de-blooming algorithm was used for imaging processing. We found a smaller bias towards measurement of stenosis using the de-blooming algorithm (STND: bias 24.6% vs 15.0%, range 10.2% to 39.0% vs 4.0% to 25.9%; HD STND: bias 17.9% vs 11.0%, range 8.9% to 30.6% vs 0.5% to 21.5%). With use of de-blooming algorithm, specificity for diagnosing significant stenosis increased from 45.8% to 75.0% (STND), from 62.5% to 83.3% (HD STND); while positive predictive value (PPV) increased from 69.8% to 83.3% (STND), from 76.9% to 88.2% (HD STND). In the patient group, reduction in calcification volume was 48.1 +/- 10.3%, reduction in coronary diameter stenosis over calcified plaque was 52.4 +/- 24.2%. Our results suggest that the novel de-blooming algorithm could effectively decrease the blooming artifacts caused by coronary calcified plaques, and consequently improve diagnostic accuracy of CCTA in assessing coronary stenosis. PMID- 29720612 TI - Author Correction: Cancer cell responses to Hsp70 inhibitor JG-98: Comparison with Hsp90 inhibitors and finding synergistic drug combinations. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29720614 TI - Quantitation of the cellular content of saliva and buccal swab samples. AB - Buccal swabs and saliva are the two most common oral sampling methods used for medical research. Often, these samples are used interchangeably, despite previous evidence that both contain buccal cells and blood leukocytes in different proportions. For some research, such as epigenetic studies, the cell types contributing to the analysis are highly relevant. We collected such samples from twelve children and twenty adults and, using Papanicolaou staining, measured the proportions of epithelial cells and leukocytes through microscopy. To our knowledge, no studies have compared cellular heterogeneity in buccal swab and saliva samples from adults and children. We confirmed that buccal swabs contained a higher proportion of epithelial cells than saliva and that children have a greater proportion of such cells in saliva compared to adults. At this level of resolution, buccal swabs and saliva contained similar epithelial cell subtypes. Gingivitis in children was associated with a higher proportion of leukocytes in saliva samples but not in buccal swabs. Compared to more detailed and costly methods such as flow cytometry or deconvolution methods used in epigenomic analysis, the procedure described here can serve as a simple and low-cost method to characterize buccal and saliva samples. Microscopy provides a low-cost tool to alert researchers to the presence of oral inflammation which may affect a subset of their samples. This knowledge might be highly relevant to their specific research questions, may assist with sample selection and thus might be crucial information despite the ability of data deconvolution methods to correct for cellular heterogeneity. PMID- 29720613 TI - Dissecting Structure-Encoded Determinants of Allosteric Cross-Talk between Post Translational Modification Sites in the Hsp90 Chaperones. AB - Post-translational modifications (PTMs) represent an important regulatory instrument that modulates structure, dynamics and function of proteins. The large number of PTM sites in the Hsp90 proteins that are scattered throughout different domains indicated that synchronization of multiple PTMs through a combinatorial code can be invoked as an important mechanism to orchestrate diverse chaperone functions and recognize multiple client proteins. In this study, we have combined structural and coevolutionary analysis with molecular simulations and perturbation response scanning analysis of the Hsp90 structures to characterize functional role of PTM sites in allosteric regulation. The results reveal a small group of conserved PTMs that act as global mediators of collective dynamics and allosteric communications in the Hsp90 structures, while the majority of flexible PTM sites serve as sensors and carriers of the allosteric structural changes. This study provides a comprehensive structural, dynamic and network analysis of PTM sites across Hsp90 proteins, identifying specific role of regulatory PTM hotspots in the allosteric mechanism of the Hsp90 cycle. We argue that plasticity of a combinatorial PTM code in the Hsp90 may be enacted through allosteric coupling between effector and sensor PTM residues, which would allow for timely response to structural requirements of multiple modified enzymes. PMID- 29720615 TI - Characterizing the role of atrial natriuretic peptide signaling in the development of embryonic ventricular conduction system. AB - Patients born with congenital heart defects frequently encounter arrhythmias due to defects in the ventricular conduction system (VCS) development. Although recent studies identified transcriptional networks essential for the heart development, there is scant information on the mechanisms regulating VCS development. Based on the association of atrial natriuretic peptide (ANP) expression with VCS forming regions, it was reasoned that ANP could play a critical role in differentiation of cardiac progenitor cells (CPCs) and cardiomyocytes (CMs) toward a VCS cell lineage. The present study showed that treatment of embryonic ventricular cells with ANP or cell permeable 8-Br-cGMP can induce gene expression of important VCS markers such as hyperpolarization activated cyclic nucleotide-gated channel-4 (HCN4) and connexin 40 (Cx40). Inhibition of protein kinase G (PKG) via Rp-8-pCPT-cGMPS further confirmed the role of ANP/NPRA/cGMP/PKG pathway in the regulation of HCN4 and Cx40 gene expression. Additional experiments indicated that ANP may regulate VCS marker gene expression by modulating levels of miRNAs that are known to control the stability of transcripts encoding HCN4 and Cx40. Genetic ablation of NPRA revealed significant decreases in VCS marker gene expression and defects in Purkinje fiber arborisation. These results provide mechanistic insights into the role of ANP/NPRA signaling in VCS formation. PMID- 29720617 TI - Modulation of the relationship between spring AO and the subsequent winter ENSO by the preceding November AO. AB - Previous studies indicated that the spring Arctic Oscillation (AO) exerts significant influences on the subsequent winter El Nino-Southern Oscillation (ENSO). This analysis suggests that the spring AO-ENSO linkage is highly modulated by its preceding November AO. When November and the subsequent spring AO indices are in phase, the spring AO has a pronounced influence on ENSO. However, when the November and spring AO indices are out of phase, the spring AO ENSO connection disappears. Modulation of the November AO on the spring AO-ENSO connection is mainly through the constructive and destructive superposition of the November and spring AO associated sea surface temperature (SST) anomalies in the tropical central-eastern Pacific in spring and summer, as well as the SST anomalies developed further in the tropical Pacific via the positive air-sea feedback. PMID- 29720616 TI - Author Correction: Endogenous Annexin-A1 Regulates Haematopoietic Stem Cell Mobilisation and Inflammatory Response Post Myocardial Infarction in Mice In Vivo. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29720618 TI - Author Correction: Genome-Guided Phylo-Transcriptomic Methods and the Nuclear Phylogenetic Tree of the Paniceae Grasses. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29720619 TI - N-Alkylation of functionalized amines with alcohols using a copper-gold mixed photocatalytic system. AB - Direct functionalization of amino groups in complex organic molecules is one of the most important key technologies in modern organic synthesis, especially in the synthesis of bio-active chemicals and pharmaceuticals. Whereas numerous chemical reactions of amines have been developed to date, a selective, practical method for functionalizing complex amines is still highly demanded. Here we report the first late-stage N-alkylation of pharmaceutically relevant amines with alcohols at ambient temperature. This reaction was achieved by devising a mixed heterogeneous photocatalyst in situ prepared from Cu/TiO2 and Au/TiO2. The mixed photocatalytic system enabled the rapid N-alkylation of pharmaceutically relevant molecules, the selective mono- and di-alkylation of primary amines, and the non symmetrical dialkylation of primary amines to hetero-substituted tertiary amines. PMID- 29720620 TI - Plasmepsin II-III copy number accounts for bimodal piperaquine resistance among Cambodian Plasmodium falciparum. AB - Multidrug resistant Plasmodium falciparum in Southeast Asia endangers regional malaria elimination and threatens to spread to other malaria endemic areas. Understanding mechanisms of piperaquine (PPQ) resistance is crucial for tracking its emergence and spread, and to develop effective strategies for overcoming it. Here we analyze a mechanism of PPQ resistance in Cambodian parasites. Isolates exhibit a bimodal dose-response curve when exposed to PPQ, with the area under the curve quantifying their survival in vitro. Increased copy number for plasmepsin II and plasmepsin III appears to explain enhanced survival when exposed to PPQ in most, but not all cases. A panel of isogenic subclones reinforces the importance of plasmepsin II-III copy number to enhanced PPQ survival. We conjecture that factors producing increased parasite survival under PPQ exposure in vitro may drive clinical PPQ failures in the field. PMID- 29720621 TI - mTOR complexes differentially orchestrates eosinophil development in allergy. AB - Eosinophil infiltration is considered a hallmark in allergic airway inflammation, and the blockade of eosinophil differentiation may be an effective approach for treating eosinophil-related disorders. Mammalian target of rapamycin (mTOR) is a vital modulator in cell growth control and related diseases, and we have recently demonstrated that rapamycin can suppress eosinophil differentiation in allergic airway inflammation. Considering its critical role in haematopoiesis, we further investigated the role of mTOR in eosinophil differentiation in the context of asthmatic pathogenesis. Intriguingly, the inhibition of mTOR, either by genetic deletion or by another pharmacological inhibitor torin-1, accelerated the eosinophil development in the presence of IL-5. However, this was not observed to have any considerable effect on eosinophil apoptosis. The effect of mTOR in eosinophil differentiation was mediated by Erk signalling. Moreover, myeloid specific knockout of mTOR or Rheb further augmented allergic airway inflammation in mice after allergen exposure. Ablation of mTOR in myeloid cells also resulted in an increased number of eosinophil lineage-committed progenitors (Eops) in allergic mice. Collectively, our data uncovered the differential effects of mTOR in the regulation of eosinophil development, likely due to the distinct functions of mTOR complex 1 or 2, which thus exerts a pivotal implication in eosinophil associated diseases. PMID- 29720622 TI - Variability and Reproducibility of 3rd-generation dual-source dynamic volume perfusion CT Parameters in Comparison to MR-perfusion Parameters in Rectal Cancer. AB - To compare in patients with untreated rectal cancer quantitative perfusion parameters calculated from 3rd-generation dual-source dynamic volume perfusion CT (dVPCT) with 3-Tesla-MR-perfusion with regard to data variability and tumour differentiation. In MR-perfusion, plasma flow (PF), plasma volume (PV) and mean transit time (MTT) were assessed in two measurements (M1 and M2) by the same reader. In dVPCT, blood flow (BF), blood volume (BV), MTT and permeability (PERM) were assessed respectively. CT dose values were calculated. 20 patients (60 +/- 13 years) were analysed. Intra-individual and intra-reader variability of duplicate MR-perfusion measurements was higher compared to duplicate dVPCT measurements. dVPCT-derived BF, BV and PERM could differentiate between tumour and normal rectal wall (significance level for M1 and M2, respectively, regarding BF: p < 0.0001*/0.0001*; BV: p < 0.0001*/0.0001*; MTT: p = 0.93/0.39; PERM: p < 0.0001*/0.0001*), with MR-perfusion this was true for PF and PV (p-values M1/M2 for PF: p = 0.04*/0.01*; PV: p = 0.002*/0.003*; MTT: p = 0.70/0.27*). Mean effective dose of CT-staging incl. dVPCT was 29 +/- 6 mSv (20 +/- 5 mSv for dVPCT alone). In conclusion, dVPCT has a lower data variability than MR-perfusion while both dVPCT and MR-perfusion could differentiate tumour tissue from normal rectal wall. With 3rd-generation dual-source CT dVPCT could be included in a standard CT staging without exceeding national dose reference values. PMID- 29720624 TI - Explicit size distributions of failure cascades redefine systemic risk on finite networks. AB - How big is the risk that a few initial failures of nodes in a network amplify to large cascades that span a substantial share of all nodes? Predicting the final cascade size is critical to ensure the functioning of a system as a whole. Yet, this task is hampered by uncertain and missing information. In infinitely large networks, the average cascade size can often be estimated by approaches building on local tree and mean field approximations. Yet, as we demonstrate, in finite networks, this average does not need to be a likely outcome. Instead, we find broad and even bimodal cascade size distributions. This phenomenon persists for system sizes up to 107 and different cascade models, i.e. it is relevant for most real systems. To show this, we derive explicit closed-form solutions for the full probability distribution of the final cascade size. We focus on two topological limit cases, the complete network representing a dense network with a very narrow degree distribution, and the star network representing a sparse network with a inhomogeneous degree distribution. Those topologies are of great interest, as they either minimize or maximize the average cascade size and are common motifs in many real world networks. PMID- 29720623 TI - Engineering of III-Nitride Semiconductors on Low Temperature Co-fired Ceramics. AB - This work presents results in the field of advanced substrate solutions in order to achieve high crystalline quality group-III nitrides based heterostructures for high frequency and power devices or for sensor applications. With that objective, Low Temperature Co-fired Ceramics has been used, as a non-crystalline substrate. Structures like these have never been developed before, and for economic reasons will represent a groundbreaking material in these fields of Electronic. In this sense, the report presents the characterization through various techniques of three series of specimens where GaN was deposited on this ceramic composite, using different buffer layers, and a singular metal-organic chemical vapor deposition related technique for low temperature deposition. Other single crystalline ceramic-based templates were also utilized as substrate materials, for comparison purposes. PMID- 29720626 TI - Author Correction: The space of genotypes is a network of networks: implications for evolutionary and extinction dynamics. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29720627 TI - Publisher Correction: First-principles design of nanostructured hybrid photovoltaics based on layered transition metal phosphates. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29720628 TI - Author Correction: Spin-orbit-torque-induced magnetic domain wall motion in Ta/CoFe nanowires with sloped perpendicular magnetic anisotropy. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29720625 TI - Systematic mapping of contact sites reveals tethers and a function for the peroxisome-mitochondria contact. AB - The understanding that organelles are not floating in the cytosol, but rather held in an organized yet dynamic interplay through membrane contact sites, is altering the way we grasp cell biological phenomena. However, we still have not identified the entire repertoire of contact sites, their tethering molecules and functions. To systematically characterize contact sites and their tethering molecules here we employ a proximity detection method based on split fluorophores and discover four potential new yeast contact sites. We then focus on a little studied yet highly disease-relevant contact, the Peroxisome-Mitochondria (PerMit) proximity, and uncover and characterize two tether proteins: Fzo1 and Pex34. We genetically expand the PerMit contact site and demonstrate a physiological function in beta-oxidation of fatty acids. Our work showcases how systematic analysis of contact site machinery and functions can deepen our understanding of these structures in health and disease. PMID- 29720629 TI - Aspirin: the miracle drug? AB - Aspirin use is associated with reduction of esophageal adenocarcinoma but it is not known if it does so by preventing the development of Barrett's esophagus or by reducing neoplastic progression in patients with Barrett's esophagus. There is sparse literature to support the former assumption especially in women. This study by Jovani et al. based on Nurses' Health Study reports 27% lower risk of Barrett's esophagus among women using aspirin. The protective effect seems to increase with higher frequency and longer duration of aspirin use. This study provides evidence for lower prevalence of Barrett's esophagus in female aspirin users. PMID- 29720630 TI - Mixed-valence insulators with neutral Fermi surfaces. AB - Samarium hexaboride is a classic three-dimensional mixed valence system with a high-temperature metallic phase that evolves into a paramagnetic charge insulator below 40 K. A number of recent experiments have suggested the possibility that the low-temperature insulating bulk hosts electrically neutral gapless fermionic excitations. Here we show that a possible ground state of strongly correlated mixed valence insulators-a composite exciton Fermi liquid-hosts a three dimensional Fermi surface of a neutral fermion, that we name the "composite exciton." We describe the mechanism responsible for the formation of such excitons, discuss the phenomenology of the composite exciton Fermi liquids and make comparison to experiments in SmB6. PMID- 29720631 TI - Structures of chaperone-substrate complexes docked onto the export gate in a type III secretion system. AB - The flagellum and the injectisome enable bacterial locomotion and pathogenesis, respectively. These nanomachines assemble and function using a type III secretion system (T3SS). Exported proteins are delivered to the export apparatus by dedicated cytoplasmic chaperones for their transport through the membrane. The structural and mechanistic basis of this process is poorly understood. Here we report the structures of two ternary complexes among flagellar chaperones (FliT and FliS), protein substrates (the filament-capping FliD and flagellin FliC), and the export gate platform protein FlhA. The substrates do not interact directly with FlhA; however, they are required to induce a binding-competent conformation to the chaperone that exposes the recognition motif featuring a highly conserved sequence recognized by FlhA. The structural data reveal the recognition signal in a class of T3SS proteins and provide new insight into the assembly of key protein complexes at the export gate. PMID- 29720632 TI - Helium in the eroding atmosphere of an exoplanet. AB - Helium is the second-most abundant element in the Universe after hydrogen and is one of the main constituents of gas-giant planets in our Solar System. Early theoretical models predicted helium to be among the most readily detectable species in the atmospheres of exoplanets, especially in extended and escaping atmospheres 1 . Searches for helium, however, have hitherto been unsuccessful 2 . Here we report observations of helium on an exoplanet, at a confidence level of 4.5 standard deviations. We measured the near-infrared transmission spectrum of the warm gas giant 3 WASP-107b and identified the narrow absorption feature of excited metastable helium at 10,833 angstroms. The amplitude of the feature, in transit depth, is 0.049 +/- 0.011 per cent in a bandpass of 98 angstroms, which is more than five times greater than what could be caused by nominal stellar chromospheric activity. This large absorption signal suggests that WASP-107b has an extended atmosphere that is eroding at a total rate of 1010 to 3 * 1011 grams per second (0.1-4 per cent of its total mass per billion years), and may have a comet-like tail of gas shaped by radiation pressure. PMID- 29720633 TI - Lightwave valleytronics in a monolayer of tungsten diselenide. AB - As conventional electronics approaches its limits 1 , nanoscience has urgently sought methods of fast control of electrons at the fundamental quantum level 2 . Lightwave electronics 3 -the foundation of attosecond science 4 -uses the oscillating carrier wave of intense light pulses to control the translational motion of the electron's charge faster than a single cycle of light5-15. Despite being particularly promising information carriers, the internal quantum attributes of spin 16 and valley pseudospin17-21 have not been switchable on the subcycle scale. Here we demonstrate lightwave-driven changes of the valley pseudospin and introduce distinct signatures in the optical readout. Photogenerated electron-hole pairs in a monolayer of tungsten diselenide are accelerated and collided by a strong lightwave. The emergence of high-odd-order sidebands and anomalous changes in their polarization direction directly attest to the ultrafast pseudospin dynamics. Quantitative computations combining density functional theory with a non-perturbative quantum many-body approach assign the polarization of the sidebands to a lightwave-induced change of the valley pseudospin and confirm that the process is coherent and adiabatic. Our work opens the door to systematic valleytronic logic at optical clock rates. PMID- 29720634 TI - Blastocyst-like structures generated solely from stem cells. AB - The blastocyst (the early mammalian embryo) forms all embryonic and extra embryonic tissues, including the placenta. It consists of a spherical thin-walled layer, known as the trophectoderm, that surrounds a fluid-filled cavity sheltering the embryonic cells 1 . From mouse blastocysts, it is possible to derive both trophoblast 2 and embryonic stem-cell lines 3 , which are in vitro analogues of the trophectoderm and embryonic compartments, respectively. Here we report that trophoblast and embryonic stem cells cooperate in vitro to form structures that morphologically and transcriptionally resemble embryonic day 3.5 blastocysts, termed blastoids. Like blastocysts, blastoids form from inductive signals that originate from the inner embryonic cells and drive the development of the outer trophectoderm. The nature and function of these signals have been largely unexplored. Genetically and physically uncoupling the embryonic and trophectoderm compartments, along with single-cell transcriptomics, reveals the extensive inventory of embryonic inductions. We specifically show that the embryonic cells maintain trophoblast proliferation and self-renewal, while fine tuning trophoblast epithelial morphogenesis in part via a BMP4/Nodal-KLF6 axis. Although blastoids do not support the development of bona fide embryos, we demonstrate that embryonic inductions are crucial to form a trophectoderm state that robustly implants and triggers decidualization in utero. Thus, at this stage, the nascent embryo fuels trophectoderm development and implantation. PMID- 29720635 TI - Hyperexpandable, self-healing macromolecular crystals with integrated polymer networks. AB - The formation of condensed matter typically involves a trade-off between structural order and flexibility. As the extent and directionality of interactions between atomic or molecular components increase, materials generally become more ordered but less compliant, and vice versa. Nevertheless, high levels of structural order and flexibility are not necessarily mutually exclusive; there are many biological (such as microtubules1,2, flagella 3 , viruses4,5) and synthetic assemblies (for example, dynamic molecular crystals6-9 and frameworks10 13) that can undergo considerable structural transformations without losing their crystalline order and that have remarkable mechanical properties8,14,15 that are useful in diverse applications, such as selective sorption 16 , separation 17 , sensing 18 and mechanoactuation 19 . However, the extent of structural changes and the elasticity of such flexible crystals are constrained by the necessity to maintain a continuous network of bonding interactions between the constituents of the lattice. Consequently, even the most dynamic porous materials tend to be brittle and isolated as microcrystalline powders 14 , whereas flexible organic or inorganic molecular crystals cannot expand without fracturing. Owing to their rigidity, crystalline materials rarely display self-healing behaviour 20 . Here we report that macromolecular ferritin crystals with integrated hydrogel polymers can isotropically expand to 180 per cent of their original dimensions and more than 500 per cent of their original volume while retaining periodic order and faceted Wulff morphologies. Even after the separation of neighbouring ferritin molecules by 50 angstroms upon lattice expansion, specific molecular contacts between them can be reformed upon lattice contraction, resulting in the recovery of atomic-level periodicity and the highest-resolution ferritin structure reported so far. Dynamic bonding interactions between the hydrogel network and the ferritin molecules endow the crystals with the ability to resist fragmentation and self-heal efficiently, whereas the chemical tailorability of the ferritin molecules enables the creation of chemically and mechanically differentiated domains within single crystals. PMID- 29720636 TI - Complete Ichthyornis skull illuminates mosaic assembly of the avian head. AB - The skull of living birds is greatly modified from the condition found in their dinosaurian antecedents. Bird skulls have an enlarged, toothless premaxillary beak and an intricate kinetic system that includes a mobile palate and jaw suspensorium. The expanded avian neurocranium protects an enlarged brain and is flanked by reduced jaw adductor muscles. However, the order of appearance of these features and the nature of their earliest manifestations remain unknown. The Late Cretaceous toothed bird Ichthyornis dispar sits in a pivotal phylogenetic position outside living groups: it is close to the extant avian radiation but retains numerous ancestral characters1-3. Although its evolutionary importance continues to be affirmed3-8, no substantial new cranial material of I. dispar has been described beyond incomplete remains recovered in the 1870s. Jurassic and Cretaceous Lagerstatten have yielded important avialan fossils, but their skulls are typically crushed and distorted 9 . Here we report four three dimensionally preserved specimens of I. dispar-including an unusually complete skull-as well as two previously overlooked elements from the Yale Peabody Museum holotype, YPM 1450. We used these specimens to generate a nearly complete three dimensional reconstruction of the I. dispar skull using high-resolution computed tomography. Our study reveals that I. dispar had a transitional beak-small, lacking a palatal shelf and restricted to the tips of the jaws-coupled with a kinetic system similar to that of living birds. The feeding apparatus of extant birds therefore evolved earlier than previously thought and its components were functionally and developmentally coordinated. The brain was relatively modern, but the temporal region was unexpectedly dinosaurian: it retained a large adductor chamber bounded dorsally by substantial bony remnants of the ancestral reptilian upper temporal fenestra. This combination of features documents that important attributes of the avian brain and palate evolved before the reduction of jaw musculature and the full transformation of the beak. PMID- 29720637 TI - Close the gender gap in Chinese science. PMID- 29720640 TI - Nature journals formalize ethical standards for human embryo and stem-cell research. PMID- 29720643 TI - North Korea's nuclear site, Mars rocks and CRISPR arguments. PMID- 29720642 TI - After the violence. PMID- 29720644 TI - In-situ visualization of solute-driven phase coexistence within individual nanorods. AB - Nanorods are promising components of energy and information storage devices that rely on solute-driven phase transformations, due to their large surface-to-volume ratio and ability to accommodate strain. Here we investigate the hydrogen-induced phase transition in individual penta-twinned palladium nanorods of varying aspect ratios with ~3 nm spatial resolution to understand the correlation between nanorod structure and thermodynamics. We find that the hydrogenated phase preferentially nucleates at the rod tips, progressing along the length of the nanorods with increasing hydrogen pressure. While nucleation pressure is nearly constant for all lengths, the number of phase boundaries is length-dependent, with stable phase coexistence always occurring for rods longer than 55 nm. Moreover, such coexistence occurs within individual crystallites of the nanorods and is accompanied by defect formation, as supported by in situ electron microscopy and elastic energy calculations. These results highlight the effect of particle shape and dimension on thermodynamics, informing nanorod design for improved device cyclability. PMID- 29720645 TI - Representation of multiple objects in macaque category-selective areas. AB - Object recognition in the natural world usually occurs in the presence of multiple surrounding objects, but responses of neurons in inferotemporal (IT) cortex, the large brain area responsible for object recognition, have mostly been studied only to isolated objects. We study rules governing responses to multiple objects by cells in two category-selective regions of macaque IT cortex, the middle lateral face patch (ML) and the middle body patch (MB). We find that responses of single ML and MB cells to pairs of objects can be explained by the widely accepted framework of normalization, with one added ingredient: homogeneous category selectivity of neighboring neurons forming the normalization pool. This rule leads to winner-take-all, contralateral-take-all, or weighted averaging behavior in single cells, depending on the category, spatial configuration, and relative contrast of the two objects. The winner-take-all behavior suggests a potential mechanism for clutter-invariant representation of face and bodies under certain conditions. PMID- 29720646 TI - Hyperosmotic tolerance of adult fish and early embryos are determined by discrete, single loci in the genus Oryzias. AB - The acquisition of environmental osmolality tolerance traits in individuals and gametes is an important event in the evolution and diversification of organisms. Although teleost fish exhibit considerable intra- and interspecific variation in salinity tolerance, the genetic mechanisms underlying this trait remain unclear. Oryzias celebensis survives in sea and fresh water during both the embryonic and adult stages, whereas its close relative Oryzias woworae cannot survive in sea water at either stage. A linkage analysis using backcross progeny identified a single locus responsible for adult hyperosmotic tolerance on a fused chromosome that corresponds to O. latipes linkage groups (LGs) 6 and 23. Conversely, O. woworae eggs fertilised with O. celebensis sperm died in sea water at the cleavage stages, whereas O. celebensis eggs fertilised with O. woworae sperm developed normally, demonstrating that maternal factor(s) from O. celebensis are responsible for hyperosmotic tolerance during early development. A further linkage analysis using backcrossed females revealed a discrete single locus relating to the maternal hyperosmotic tolerance factor in a fused chromosomal region homologous to O. latipes LGs 17 and 19. These results indicate that a maternal factor governs embryonic hyperosmotic tolerance and maps to a locus distinct from that associated with adult hyperosmotic tolerance. PMID- 29720647 TI - A midline thalamic circuit determines reactions to visual threat. AB - How our internal state is merged with our visual perception of an impending threat to drive an adaptive behavioural response is not known. Mice respond to visual threats by either freezing or seeking shelter. Here we show that nuclei of the ventral midline thalamus (vMT), the xiphoid nucleus (Xi) and nucleus reuniens (Re), represent crucial hubs in the network controlling behavioural responses to visual threats. The Xi projects to the basolateral amygdala to promote saliency reducing responses to threats, such as freezing, whereas the Re projects to the medial prefrontal cortex (Re->mPFC) to promote saliency-enhancing, even confrontational responses to threats, such as tail rattling. Activation of the Re >mPFC pathway also increases autonomic arousal in a manner that is rewarding. The vMT is therefore important for biasing how internal states are translated into opposing categories of behavioural responses to perceived threats. These findings may have implications for understanding disorders of arousal and adaptive decision-making, such as phobias, post-traumatic stress and addictions. PMID- 29720648 TI - Structural basis for dual-mode inhibition of the ABC transporter MsbA. AB - The movement of core-lipopolysaccharide across the inner membrane of Gram negative bacteria is catalysed by an essential ATP-binding cassette transporter, MsbA. Recent structures of MsbA and related transporters have provided insights into the molecular basis of active lipid transport; however, structural information about their pharmacological modulation remains limited. Here we report the 2.9 A resolution structure of MsbA in complex with G907, a selective small-molecule antagonist with bactericidal activity, revealing an unprecedented mechanism of ABC transporter inhibition. G907 traps MsbA in an inward-facing, lipopolysaccharide-bound conformation by wedging into an architecturally conserved transmembrane pocket. A second allosteric mechanism of antagonism occurs through structural and functional uncoupling of the nucleotide-binding domains. This study establishes a framework for the selective modulation of ABC transporters and provides rational avenues for the design of new antibiotics and other therapeutics targeting this protein family. PMID- 29720650 TI - Publisher Correction: Programmable base editing of A*T to G*C in genomic DNA without DNA cleavage. AB - In this Article, owing to an error during the production process, in Fig. 1a, the dark blue and light blue wedges were incorrectly labelled as 'G*C -> T*A' and 'G*C -> A*T', instead of 'C*G -> T*A' and 'C*G -> A*T', respectively. Fig. 1 has been corrected online. PMID- 29720649 TI - Subepithelial telocytes are an important source of Wnts that supports intestinal crypts. AB - Tissues that undergo rapid cellular turnover, such as the mammalian haematopoietic system or the intestinal epithelium, are dependent on stem and progenitor cells that proliferate to provide differentiated cells to maintain organismal health. Stem and progenitor cells, in turn, are thought to rely on signals and growth factors provided by local niche cells to support their function and self-renewal. Several cell types have been hypothesized to provide the signals required for the proliferation and differentiation of the intestinal stem cells in intestinal crypts1-6. Here we identify subepithelial telocytes as an important source of Wnt proteins, without which intestinal stem cells cannot proliferate and support epithelial renewal. Telocytes are large but rare mesenchymal cells that are marked by expression of FOXL1 and form a subepithelial plexus that extends from the stomach to the colon. While supporting the entire epithelium, FOXL1+ telocytes compartmentalize the production of Wnt ligands and inhibitors to enable localized pathway activation. Conditional genetic ablation of porcupine (Porcn), which is required for functional maturation of all Wnt proteins, in mouse FOXL1+ telocytes causes rapid cessation of Wnt signalling to intestinal crypts, followed by loss of proliferation of stem and transit amplifying cells and impaired epithelial renewal. Thus, FOXL1+ telocytes are an important source of niche signals to intestinal stem cells. PMID- 29720652 TI - Publisher Correction: Pervasive phosphorus limitation of tree species but not communities in tropical forests. AB - In this Letter, the y axis of the right-hand panel of Fig. 2a was mislabelled 'Phosphomonoesterase' instead of 'Phosphodiesterase'. This error has been corrected online. PMID- 29720651 TI - Publisher Correction: Adolescence and the next generation. AB - In Fig. 4a of this Analysis, owing to an error during the production process, the year in the header of the right column was '2016' rather than '2010'. In addition, in the HTML version of the Analysis, Table 1 was formatted incorrectly. These errors have been corrected online. PMID- 29720653 TI - Publisher Correction: A TRP channel trio mediates acute noxious heat sensing. AB - In this Letter, the trace is missing in Fig. 1e. This error has been corrected online. PMID- 29720654 TI - Male-killing toxin in a bacterial symbiont of Drosophila. AB - Several lineages of symbiotic bacteria in insects selfishly manipulate host reproduction to spread in a population 1 , often by distorting host sex ratios. Spiroplasma poulsonii2,3 is a helical and motile, Gram-positive symbiotic bacterium that resides in a wide range of Drosophila species 4 . A notable feature of S. poulsonii is male killing, whereby the sons of infected female hosts are selectively killed during development1,2. Although male killing caused by S. poulsonii has been studied since the 1950s, its underlying mechanism is unknown. Here we identify an S. poulsonii protein, designated Spaid, whose expression induces male killing. Overexpression of Spaid in D. melanogaster kills males but not females, and induces massive apoptosis and neural defects, recapitulating the pathology observed in S. poulsonii-infected male embryos5-11. Our data suggest that Spaid targets the dosage compensation machinery on the male X chromosome to mediate its effects. Spaid contains ankyrin repeats and a deubiquitinase domain, which are required for its subcellular localization and activity. Moreover, we found a laboratory mutant strain of S. poulsonii with reduced male-killing ability and a large deletion in the spaid locus. Our study has uncovered a bacterial protein that affects host cellular machinery in a sex specific way, which is likely to be the long-searched-for factor responsible for S. poulsonii-induced male killing. PMID- 29720655 TI - Molecular mechanism of GPCR-mediated arrestin activation. AB - Despite intense interest in discovering drugs that cause G-protein-coupled receptors (GPCRs) to selectively stimulate or block arrestin signalling, the structural mechanism of receptor-mediated arrestin activation remains unclear1,2. Here we reveal this mechanism through extensive atomic-level simulations of arrestin. We find that the receptor's transmembrane core and cytoplasmic tail which bind distinct surfaces on arrestin-can each independently stimulate arrestin activation. We confirm this unanticipated role of the receptor core, and the allosteric coupling between these distant surfaces of arrestin, using site directed fluorescence spectroscopy. The effect of the receptor core on arrestin conformation is mediated primarily by interactions of the intracellular loops of the receptor with the arrestin body, rather than the marked finger-loop rearrangement that is observed upon receptor binding. In the absence of a receptor, arrestin frequently adopts active conformations when its own C-terminal tail is disengaged, which may explain why certain arrestins remain active long after receptor dissociation. Our results, which suggest that diverse receptor binding modes can activate arrestin, provide a structural foundation for the design of functionally selective ('biased') GPCR-targeted ligands with desired effects on arrestin signalling. PMID- 29720656 TI - Overcoming the rate-distance limit of quantum key distribution without quantum repeaters. AB - Quantum key distribution (QKD)1,2 allows two distant parties to share encryption keys with security based on physical laws. Experimentally, QKD has been implemented via optical means, achieving key rates of 1.26 megabits per second over 50 kilometres of standard optical fibre 3 and of 1.16 bits per hour over 404 kilometres of ultralow-loss fibre in a measurement-device-independent configuration 4 . Increasing the bit rate and range of QKD is a formidable, but important, challenge. A related target, which is currently considered to be unfeasible without quantum repeaters5-7, is overcoming the fundamental rate distance limit of QKD 8 . This limit defines the maximum possible secret key rate that two parties can distil at a given distance using QKD and is quantified by the secret-key capacity of the quantum channel 9 that connects the parties. Here we introduce an alternative scheme for QKD whereby pairs of phase-randomized optical fields are first generated at two distant locations and then combined at a central measuring station. Fields imparted with the same random phase are 'twins' and can be used to distil a quantum key. The key rate of this twin-field QKD exhibits the same dependence on distance as does a quantum repeater, scaling with the square-root of the channel transmittance, irrespective of who (malicious or otherwise) is in control of the measuring station. However, unlike schemes that involve quantum repeaters, ours is feasible with current technology and presents manageable levels of noise even on 550 kilometres of standard optical fibre. This scheme is a promising step towards overcoming the rate-distance limit of QKD and greatly extending the range of secure quantum communications. PMID- 29720657 TI - Structural principles of distinct assemblies of the human alpha4beta2 nicotinic receptor. AB - Fast chemical communication in the nervous system is mediated by neurotransmitter gated ion channels. The prototypical member of this class of cell surface receptors is the cation-selective nicotinic acetylcholine receptor. As with most ligand-gated ion channels, nicotinic receptors assemble as oligomers of subunits, usually as hetero-oligomers and often with variable stoichiometries 1 . This intrinsic heterogeneity in protein composition provides fine tunability in channel properties, which is essential to brain function, but frustrates structural and biophysical characterization. The alpha4beta2 subtype of the nicotinic acetylcholine receptor is the most abundant isoform in the human brain and is the principal target in nicotine addiction. This pentameric ligand-gated ion channel assembles in two stoichiometries of alpha- and beta-subunits (2alpha:3beta and 3alpha:2beta). Both assemblies are functional and have distinct biophysical properties, and an imbalance in the ratio of assemblies is linked to both nicotine addiction2,3 and congenital epilepsy4,5. Here we leverage cryo electron microscopy to obtain structures of both receptor assemblies from a single sample. Antibody fragments specific to beta2 were used to 'break' symmetry during particle alignment and to obtain high-resolution reconstructions of receptors of both stoichiometries in complex with nicotine. The results reveal principles of subunit assembly and the structural basis of the distinctive biophysical and pharmacological properties of the two different stoichiometries of this receptor. PMID- 29720658 TI - Diametric neural ensemble dynamics in parkinsonian and dyskinetic states. AB - Loss of dopamine in Parkinson's disease is hypothesized to impede movement by inducing hypo- and hyperactivity in striatal spiny projection neurons (SPNs) of the direct (dSPNs) and indirect (iSPNs) pathways in the basal ganglia, respectively. The opposite imbalance might underlie hyperkinetic abnormalities, such as dyskinesia caused by treatment of Parkinson's disease with the dopamine precursor L-DOPA. Here we monitored thousands of SPNs in behaving mice, before and after dopamine depletion and during L-DOPA-induced dyskinesia. Normally, intermingled clusters of dSPNs and iSPNs coactivated before movement. Dopamine depletion unbalanced SPN activity rates and disrupted the movement-encoding iSPN clusters. Matching their clinical efficacy, L-DOPA or agonism of the D2 dopamine receptor reversed these abnormalities more effectively than agonism of the D1 dopamine receptor. The opposite pathophysiology arose in L-DOPA-induced dyskinesia, during which iSPNs showed hypoactivity and dSPNs showed unclustered hyperactivity. Therefore, both the spatiotemporal profiles and rates of SPN activity appear crucial to striatal function, and next-generation treatments for basal ganglia disorders should target both facets of striatal activity. PMID- 29720659 TI - Chromatin analysis in human early development reveals epigenetic transition during ZGA. AB - Upon fertilization, drastic chromatin reorganization occurs during preimplantation development 1 . However, the global chromatin landscape and its molecular dynamics in this period remain largely unexplored in humans. Here we investigate chromatin states in human preimplantation development using an improved assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq) 2 . We find widespread accessible chromatin regions in early human embryos that overlap extensively with putative cis-regulatory sequences and transposable elements. Integrative analyses show both conservation and divergence in regulatory circuitry between human and mouse early development, and between human pluripotency in vivo and human embryonic stem cells. In addition, we find widespread open chromatin regions before zygotic genome activation (ZGA). The accessible chromatin loci are readily found at CpG-rich promoters. Unexpectedly, many others reside in distal regions that overlap with DNA hypomethylated domains in human oocytes and are enriched for transcription factor-binding sites. A large portion of these regions then become inaccessible after ZGA in a transcription-dependent manner. Notably, such extensive chromatin reorganization during ZGA is conserved in mice and correlates with the reprogramming of the non-canonical histone mark H3K4me3, which is uniquely linked to genome silencing3-5. Taken together, these data not only reveal a conserved principle that underlies the chromatin transition during mammalian ZGA, but also help to advance our understanding of epigenetic reprogramming during human early development and in vitro fertilization. PMID- 29720660 TI - Catalytic activation of beta-arrestin by GPCRs. AB - beta-arrestins are critical regulator and transducer proteins for G-protein coupled receptors (GPCRs). beta-arrestin is widely believed to be activated by forming a stable and stoichiometric GPCR-beta-arrestin scaffold complex, which requires and is driven by the phosphorylated tail of the GPCR. Here we demonstrate a distinct and additional mechanism of beta-arrestin activation that does not require stable GPCR-beta-arrestin scaffolding or the GPCR tail. Instead, it occurs through transient engagement of the GPCR core, which destabilizes a conserved inter-domain charge network in beta-arrestin. This promotes capture of beta-arrestin at the plasma membrane and its accumulation in clathrin-coated endocytic structures (CCSs) after dissociation from the GPCR, requiring a series of interactions with membrane phosphoinositides and CCS-lattice proteins. beta arrestin clustering in CCSs in the absence of the upstream activating GPCR is associated with a beta-arrestin-dependent component of the cellular ERK (extracellular signal-regulated kinase) response. These results delineate a discrete mechanism of cellular beta-arrestin function that is activated catalytically by GPCRs. PMID- 29720663 TI - CuI p-type thin films for highly transparent thermoelectric p-n modules. AB - Developments in thermoelectric (TE) transparent p-type materials are scarce and do not follow the trend of the corresponding n-type materials - a limitation of the current transparent thermoelectric devices. P-type thermoelectric thin films of CuI have been developed by three different methods in order to maximise optical transparency (>70% in the visible range), electrical (sigma = 1.1 * 104 Sm-1) and thermoelectric properties (ZT = 0.22 at 300 K). These have been applied in the first planar fully transparent p-n type TE modules where gallium-doped zinc oxide (GZO) thin films were used as the n-type element and indium thin oxide (ITO) thin films as electrodes. A thorough study of power output in single elements and p-n modules electrically connected in series and thermally connected in parallel is inclosed. This configuration allows for a whole range of highly transparent thermoelectric applications. PMID- 29720662 TI - De novo formation of the biliary system by TGFbeta-mediated hepatocyte transdifferentiation. AB - Transdifferentiation is a complete and stable change in cell identity that serves as an alternative to stem-cell-mediated organ regeneration. In adult mammals, findings of transdifferentiation have been limited to the replenishment of cells lost from preexisting structures, in the presence of a fully developed scaffold and niche1. Here we show that transdifferentiation of hepatocytes in the mouse liver can build a structure that failed to form in development-the biliary system in a mouse model that mimics the hepatic phenotype of human Alagille syndrome (ALGS)2. In these mice, hepatocytes convert into mature cholangiocytes and form bile ducts that are effective in draining bile and persist after the cholestatic liver injury is reversed, consistent with transdifferentiation. These findings redefine hepatocyte plasticity, which appeared to be limited to metaplasia, that is, incomplete and transient biliary differentiation as an adaptation to cell injury, based on previous studies in mice with a fully developed biliary system3 6. In contrast to bile duct development7-9, we show that de novo bile duct formation by hepatocyte transdifferentiation is independent of NOTCH signalling. We identify TGFbeta signalling as the driver of this compensatory mechanism and show that it is active in some patients with ALGS. Furthermore, we show that TGFbeta signalling can be targeted to enhance the formation of the biliary system from hepatocytes, and that the transdifferentiation-inducing signals and remodelling capacity of the bile-duct-deficient liver can be harnessed with transplanted hepatocytes. Our results define the regenerative potential of mammalian transdifferentiation and reveal opportunities for the treatment of ALGS and other cholestatic liver diseases. PMID- 29720661 TI - Earliest known hominin activity in the Philippines by 709 thousand years ago. AB - Over 60 years ago, stone tools and remains of megafauna were discovered on the Southeast Asian islands of Flores, Sulawesi and Luzon, and a Middle Pleistocene colonization by Homo erectus was initially proposed to have occurred on these islands1-4. However, until the discovery of Homo floresiensis in 2003, claims of the presence of archaic hominins on Wallacean islands were hypothetical owing to the absence of in situ fossils and/or stone artefacts that were excavated from well-documented stratigraphic contexts, or because secure numerical dating methods of these sites were lacking. As a consequence, these claims were generally treated with scepticism 5 . Here we describe the results of recent excavations at Kalinga in the Cagayan Valley of northern Luzon in the Philippines that have yielded 57 stone tools associated with an almost-complete disarticulated skeleton of Rhinoceros philippinensis, which shows clear signs of butchery, together with other fossil fauna remains attributed to stegodon, Philippine brown deer, freshwater turtle and monitor lizard. All finds originate from a clay-rich bone bed that was dated to between 777 and 631 thousand years ago using electron-spin resonance methods that were applied to tooth enamel and fluvial quartz. This evidence pushes back the proven period of colonization 6 of the Philippines by hundreds of thousands of years, and furthermore suggests that early overseas dispersal in Island South East Asia by premodern hominins took place several times during the Early and Middle Pleistocene stages1-4. The Philippines therefore may have had a central role in southward movements into Wallacea, not only of Pleistocene megafauna 7 , but also of archaic hominins. PMID- 29720664 TI - Monitoring voltage fluctuations of intracellular membranes. AB - In eukaryotic cells, the endoplasmic reticulum (ER) is the largest continuous membrane-enclosed network which surrounds a single lumen. Using a new genetically encoded voltage indicator (GEVI), we applied the patch clamp technique to cultured HEK293 cells and neurons and found that there is a very fast electrical interaction between the plasma membrane and internal membrane(s). This discovery suggests a novel mechanism for interaction between the external membrane and internal membranes as well as mechanisms for interactions between the various internal membranes. The ER may transfer electrical signals between the plasma membrane and other internal organelles. The internal membrane optical signal is reversed in polarity but has a time course similar to that of the plasma membrane signal. The optical signal of the GEVI in the plasma membrane is consistent from trial to trial. However, the internal signal decreases in size with repeated trials suggesting that the electrical coupling is degrading and/or the resistance of the internal membrane is decaying. PMID- 29720665 TI - The human Vdelta2+ T-cell compartment comprises distinct innate-like Vgamma9+ and adaptive Vgamma9- subsets. AB - Vdelta2+ T cells form the predominant human gammadelta T-cell population in peripheral blood and mediate T-cell receptor (TCR)-dependent anti-microbial and anti-tumour immunity. Here we show that the Vdelta2+ compartment comprises both innate-like and adaptive subsets. Vgamma9+ Vdelta2+ T cells display semi invariant TCR repertoires, featuring public Vgamma9 TCR sequences equivalent in cord and adult blood. By contrast, we also identify a separate, Vgamma9- Vdelta2+ T-cell subset that typically has a CD27hiCCR7+CD28+IL-7Ralpha+ naive-like phenotype and a diverse TCR repertoire, however in response to viral infection, undergoes clonal expansion and differentiation to a CD27loCD45RA+CX3CR1+granzymeA/B+ effector phenotype. Consistent with a function in solid tissue immunosurveillance, we detect human intrahepatic Vgamma9- Vdelta2+ T cells featuring dominant clonal expansions and an effector phenotype. These findings redefine human gammadelta T-cell subsets by delineating the Vdelta2+ T-cell compartment into innate-like (Vgamma9+) and adaptive (Vgamma9-) subsets, which have distinct functions in microbial immunosurveillance. PMID- 29720666 TI - P53 and mTOR signalling determine fitness selection through cell competition during early mouse embryonic development. AB - Ensuring the fitness of the pluripotent cells that will contribute to future development is important both for the integrity of the germline and for proper embryogenesis. Consequently, it is becoming increasingly apparent that pluripotent cells can compare their fitness levels and signal the elimination of those cells that are less fit than their neighbours. In mammals the nature of the pathways that communicate fitness remain largely unknown. Here we identify that in the early mouse embryo and upon exit from naive pluripotency, the confrontation of cells with different fitness levels leads to an inhibition of mTOR signalling in the less fit cell type, causing its elimination. We show that during this process, p53 acts upstream of mTOR and is required to repress its activity. Finally, we demonstrate that during normal development around 35% of cells are eliminated by this pathway, highlighting the importance of this mechanism for embryonic development. PMID- 29720667 TI - The stage of seed development influences iron bioavailability in pea (Pisum sativum L.). AB - Pea seeds are widely consumed in their immature form, known as garden peas and petit pois, mostly after preservation by freezing or canning. Mature dry peas are rich in iron in the form of ferritin, but little is known about the content, form or bioavailability of iron in immature stages of seed development. Using specific antibodies and in-gel iron staining, we show that ferritin loaded with iron accumulated gradually during seed development. Immunolocalization and high resolution secondary ion mass spectrometry (NanoSIMS) revealed that iron-loaded ferritin was located at the surface of starch-containing plastids. Standard cooking procedures destabilized monomeric ferritin and the iron-loaded form. Iron uptake studies using Caco-2 cells showed that the iron in microwaved immature peas was more bioavailable than in boiled mature peas, despite similar levels of soluble iron in the digestates. By manipulating the levels of phytic acid in the digestates we demonstrate that phytic acid is the main inhibitor of iron uptake from mature peas in vitro. Taken together, our data show that immature peas and mature dry peas contain similar levels of ferritin-iron, which is destabilized during cooking. However, iron from immature peas is more bioavailable because of lower phytic acid levels compared to mature peas. PMID- 29720668 TI - Central role of the proximal tubular alphaKlotho/FGF receptor complex in FGF23 regulated phosphate and vitamin D metabolism. AB - Fibroblast growth factor 23 (FGF23) plays critical roles in phosphate handling and vitamin D metabolism in the kidney. However, the effector cells of FGF23 in the kidney remain unclear. alphaKlotho, a putative enzyme possessing beta glucuronidase activity and also a permissive co-receptor for FGF23 to bind to FGF receptors (FGFRs), is expressed most abundantly in distal convoluted tubules, whereas it is expressed modestly in proximal tubules. Key molecular players of phosphate homeostasis and vitamin D-metabolizing enzymes are known to localize in proximal tubules. To clarify the direct function of FGF23 on proximal tubules, we ablated alphaKlotho or Fgfr1-4 genes specifically from these tubules using the Cre-loxP-mediated genetic recombination. Both conditional knockout mouse lines showed similar phenotypes that resembled those of systemic alphaKlotho or Fgf23 knockout mice. Compared with control mice, they showed significantly elevated levels of plasma phosphate, FGF23 and 1,25-dihydroxyvitamin D, ectopic calcification in the kidney and aging-related phenotypes like growth retardation, osteoporosis and shortened lifespan. These findings suggest that the primary function of FGF23 on mineral metabolism is mediated through alphaKlotho/FGFR co receptors expressed in proximal tubular cells, and that the putative enzymatic function of alphaKlotho in the proximal tubule has a minor role in systemic mineral metabolism. PMID- 29720669 TI - Mixed Bacillus Species Enhance the Innate Immune Response and Stress Tolerance in Yellow Perch Subjected to Hypoxia and Air-Exposure Stress. AB - Stress enhances the disease susceptibility in fish by altering the innate immune responses, which are essential defense mechanisms. The use of probiotics is increasingly popular in the aquaculture industry. Yellow perch is a promising candidate for aquaculture. We investigated the efficiency of a mixed Bacillus species in minimizing the potential problems resulting from husbandry practices such as hypoxia and exposure to air in yellow perch. We showed that hypoxia and air exposure conditions induced a significant reduction in the early innate immune response (lysozyme activity, interferon-induced-GTP-binding protein-Mx1 [mx], interleukin-1beta [il1beta], serum amyloid-A [saa]), and a substantial increase in cortisol, heat shock protein (Hsp70), glutathione peroxidase (Gpx), superoxide dismutase (Sod1) that associated with a decline in insulin-like growth factor-1 (Igf1). Mixed Bacillus species administration improved the early innate responses, reduced cortisol, Hsp70, Gpx and Sod1, and elevated Igf1 levels. Bacillus species treated group showed faster recovery to reach the baseline levels during 24 h compared to untreated group. Therefore, mixed Bacillus species may enhance yellow perch welfare by improving the stress tolerance and early innate immune response to counterbalance the various husbandry stressors. Further studies are warranted to investigate the correlations between the aquaculture practices and disease resistance in yellow perch. PMID- 29720670 TI - First anatomical network analysis of fore- and hindlimb musculoskeletal modularity in bonobos, common chimpanzees, and humans. AB - Studies of morphological integration and modularity, and of anatomical complexity in human evolution typically focus on skeletal tissues. Here we provide the first network analysis of the musculoskeletal anatomy of both the fore- and hindlimbs of the two species of chimpanzee and humans. Contra long-accepted ideas, network analysis reveals that the hindlimb displays a pattern opposite to that of the forelimb: Pan big toe is typically seen as more independently mobile, but humans are actually the ones that have a separate module exclusively related to its movements. Different fore- vs hindlimb patterns are also seen for anatomical network complexity (i.e., complexity in the arrangement of bones and muscles). For instance, the human hindlimb is as complex as that of chimpanzees but the human forelimb is less complex than in Pan. Importantly, in contrast to the analysis of morphological integration using morphometric approaches, network analyses do not support the prediction that forelimb and hindlimb are more dissimilar in species with functionally divergent limbs such as bipedal humans. PMID- 29720671 TI - Genetic variation in 117 myelination-related genes in schizophrenia: Replication of association to lipid biosynthesis genes. AB - Schizophrenia is a serious psychotic disorder with high heritability. Several common genetic variants, rare copy number variants and ultra-rare gene-disrupting mutations have been linked to disease susceptibility, but there is still a large gap between the estimated and explained heritability. Since several studies have indicated brain myelination abnormalities in schizophrenia, we aimed to examine whether variants in myelination-related genes could be associated with risk for schizophrenia. We established a set of 117 myelination genes by database searches and manual curation. We used a combination of GWAS (SCZ_N = 35,476; CTRL_N = 46,839), exome chip (SCZ_N = 269; CTRL_N = 336) and exome sequencing data (SCZ_N = 2,527; CTRL_N = 2,536) from schizophrenia cases and healthy controls to examine common and rare variants. We found that a subset of lipid-related genes was nominally associated with schizophrenia (p = 0.037), but this signal did not survive multiple testing correction (FWER = 0.16) and was mainly driven by the SREBF1 and SREBF2 genes that have already been linked to schizophrenia. Further analysis demonstrated that the lowest nominal p-values were p = 0.0018 for a single common variant (rs8539) and p = 0.012 for burden of rare variants (LRP1 gene), but none of them survived multiple testing correction. Our findings suggest that variation in myelination-related genes is not a major risk factor for schizophrenia. PMID- 29720672 TI - FTY720 Decreases Tumorigenesis in Group 3 Medulloblastoma Patient-Derived Xenografts. AB - Group 3 tumors account for 28% of medulloblastomas and have the worst prognosis. FTY720, an immunosuppressant currently approved for treatment of multiple sclerosis, has shown antitumor effects in several human cancer cell lines. We hypothesized that treatment with FTY720 (fingolimod) would decrease tumorigenicity in medulloblastoma patient-derived xenografts (PDXs). Three Group 3 medulloblastoma PDXs (D341, D384 and D425) were utilized. Expression of PP2A and its endogenous inhibitors I2PP2A and CIP2A was detected by immunohistochemistry and immunoblotting. PP2A activation was measured via phosphatase activation kit. Cell viability, proliferation, migration and invasion assays were performed after treatment with FTY720. Cell cycle analysis was completed using flow cytometry. A flank model using D425 human medulloblastoma PDX cells was used to assess the in vivo effects of FTY720. FTY720 activated PP2A and led to decreased medulloblastoma PDX cell viability, proliferation, migration and invasion and G1 cell cycle arrest in all three PDXs. FTY720 treatment of mice bearing D425 medulloblastoma PDX tumors resulted in a significant decrease in tumor growth compared to vehicle treated animals. FTY720 decreased viability, proliferation, and motility in Group 3 medulloblastoma PDX cells and significantly decreased tumor growth in vivo. These results suggest that FTY720 should be investigated further as a potential therapeutic agent for medulloblastoma. PMID- 29720673 TI - Spectrum of antibacterial activity and mode of action of a novel tris-stilbene bacteriostatic compound. AB - The spectrum of activity and mode of action of a novel antibacterial agent, 135C, was investigated using a range of microbiological and genomic approaches. Compound 135C was active against Gram-positive bacteria with MICs for Staphylococcus aureus ranging from 0.12-0.5 MUg/ml. It was largely inactive against Gram-negative bacteria. The compound showed bacteriostatic activity in time-kill studies and did not elicit bacterial cell leakage or cell lysis. Checkerboard assays showed no synergy or antagonism when 135C was combined with a range of other antibacterials. Multi-step serial passage of four S. aureus isolates with increasing concentrations of 135C showed that resistance developed rapidly and was stable after drug-free passages. Minor differences in the fitness of 135C-resistant strains and parent wildtypes were evident by growth curves, but 135C-resistant strains did not show cross-resistance to other antibacterial agents. Genomic comparison of resistant and wildtype parent strains showed changes in genes encoding cell wall teichoic acids. 135C shows promising activity against Gram-positive bacteria but is currently limited by the rapid resistance development. Further studies are required to investigate the effects on cell wall teichoic acids and to determine whether the issue of resistance development can be overcome. PMID- 29720674 TI - Synergistic antitumour effects of rapamycin and oncolytic reovirus. AB - There are currently numerous oncolytic viruses undergoing clinical trial evaluation in cancer patients and one agent, Talimogene laherparepvec, has been approved for the treatment of malignant melanoma. This progress highlights the huge clinical potential of this treatment modality, and the focus is now combining these agents with conventional anticancer treatments or agents that enhance viral replication, and thereby oncolysis, in the tumour microenvironment. We evaluated the combination of reovirus with rapamycin in B16F10 cell, a murine model of malignant melanoma, based on potential mechanisms by which mTOR inhibitors might enhance viral oncolysis. Rapamycin was not immunomodulatory in that it had no effect on the generation of an antireovirus-neutralising antibody response in C57/black 6 mice. The cell cycle effects of reovirus (increase G0/G1 fraction) were unaffected by concomitant or sequential exposure of rapamycin. However, rapamycin attenuated viral replication if given prior or concomitantly with reovirus and similarly reduced reovirus-induced apoptotic cell death Annexin V/PI and caspase 3/7 activation studies. We found clear evidence of synergistic antitumour effects of the combination both in vitro and in vivo, which was sequence dependent only in the in vitro setting. In conclusion, we have demonstrated synergistic antitumour efficacy of reovirus and rapamycin combination. PMID- 29720675 TI - Can we accurately measure the ankle-brachial index in patients with atrial fibrillation? PMID- 29720676 TI - Making WAVES against a tsunami of childhood obesity. PMID- 29720677 TI - Circulating microRNAs disclose biology of normal cognitive function in healthy elderly people - a discovery twin study. AB - Neurobiology is regulated by miRNA. Here circulating plasma miRNAs were assayed on a 754 miRNA OpenArray platform using 90 monozygotic elderly twins (73-95 year of age) and associated with mini mental state examination (MMSE) and a five component cognitive score (CCS) in an explorative study. Both ordinary individual and twin-pair analyses were performed with level of cognitive scores. Candidate miRNAs were further associated with cognitive decline over 10 years using up to six repeated assessments. A total of 278 miRNAs were expressed in plasma from at least ten participants and 23 miRNAs were nominally associated (i.e., at an uncorrected p < 0.05) with CCS or MMSE in the paired analyses. Generally, elderly individuals with poor cognitive function had increase miRNA expression compared with equivalent individuals who performed better on the cognitive scale. Three miRNAs, miR-151a-3p, miR-212-3p and miR-1274b were associated with CCS both in the paired and the individual analysis. Four miRNAs found to be associated with CCS in cross-sectional analysis were also found to show an association in longitudinal analysis such that increase miRNA expression was associated with steeper cognitive decline. We propose a shared biological path underlies dementia and normative cognitive aging. PMID- 29720678 TI - Label-free quantitative evaluation of breast tissue using Spatial Light Interference Microscopy (SLIM). AB - Breast cancer is the most common type of cancer among women worldwide. The standard histopathology of breast tissue, the primary means of disease diagnosis, involves manual microscopic examination of stained tissue by a pathologist. Because this method relies on qualitative information, it can result in inter observer variation. Furthermore, for difficult cases the pathologist often needs additional markers of malignancy to help in making a diagnosis, a need that can potentially be met by novel microscopy methods. We present a quantitative method for label-free breast tissue evaluation using Spatial Light Interference Microscopy (SLIM). By extracting tissue markers of malignancy based on the nanostructure revealed by the optical path-length, our method provides an objective, label-free and potentially automatable method for breast histopathology. We demonstrated our method by imaging a tissue microarray consisting of 68 different subjects -34 with malignant and 34 with benign tissues. Three-fold cross validation results showed a sensitivity of 94% and specificity of 85% for detecting cancer. Our disease signatures represent intrinsic physical attributes of the sample, independent of staining quality, facilitating classification through machine learning packages since our images do not vary from scan to scan or instrument to instrument. PMID- 29720679 TI - Spillover modes in multiplex games: double-edged effects on cooperation and their coevolution. AB - In recent years, there has been growing interest in studying games on multiplex networks that account for interactions across linked social contexts. However, little is known about how potential cross-context interference, or spillover, of individual behavioural strategy impact overall cooperation. We consider three plausible spillover modes, quantifying and comparing their effects on the evolution of cooperation. In our model, social interactions take place on two network layers: repeated interactions with close neighbours in a lattice, and one shot interactions with random individuals. Spillover can occur during the learning process with accidental cross-layer strategy transfer, or during social interactions with errors in implementation. Our analytical results, using extended pair approximation, are in good agreement with extensive simulations. We find double-edged effects of spillover: increasing the intensity of spillover can promote cooperation provided cooperation is favoured in one layer, but too much spillover is detrimental. We also discover a bistability phenomenon: spillover hinders or promotes cooperation depending on initial frequencies of cooperation in each layer. Furthermore, comparing strategy combinations emerging in each spillover mode provides good indication of their co-evolutionary dynamics with cooperation. Our results make testable predictions that inspire future research, and sheds light on human cooperation across social domains. PMID- 29720680 TI - Prediction of Steam Burns Severity using Raman Spectroscopy on ex vivo Porcine Skin. AB - Skin burns due to accidental exposure to hot steam have often been reported to be more severe than the ones occurring from dry heat. While skin burns due to flames or radiant heat have been thoroughly characterized, the mechanisms leading to steam burns are not well understood and a conundrum still exists: can second degree burns occur without destruction of the epidermis, i.e. even before first degree burns are detected? Skin permeability is dependent both on temperature and on the kinetic energy of incoming water molecules. To investigate the mechanism underlying the injuries related to steam exposure, we used porcine skin as an ex vivo model. This model was exposed to either steam or dry heat before measuring the skin hydration via confocal Raman microspectroscopy. The results show that during the first minute of exposure to steam, the water content in both the epidermis and dermis increases. By analyzing different mechanisms of steam diffusion through the multiple skin layers, as well as the moisture-assisted bio heat transfer, we provide a novel model explaining why steam burns can be more severe, and why steam can penetrate deeper and much faster than an equivalent dry heat. PMID- 29720682 TI - Meteorological Controls on Local and Regional Volcanic Ash Dispersal. AB - Volcanic ash has the capacity to impact human health, livestock, crops and infrastructure, including international air traffic. For recent major eruptions, information on the volcanic ash plume has been combined with relatively coarse resolution meteorological model output to provide simulations of regional ash dispersal, with reasonable success on the scale of hundreds of kilometres. However, to predict and mitigate these impacts locally, significant improvements in modelling capability are required. Here, we present results from a dynamic meteorological-ash-dispersion model configured with sufficient resolution to represent local topographic and convectively-forced flows. We focus on an archetypal volcanic setting, Soufriere, St Vincent, and use the exceptional historical records of the 1902 and 1979 eruptions to challenge our simulations. We find that the evolution and characteristics of ash deposition on St Vincent and nearby islands can be accurately simulated when the wind shear associated with the trade wind inversion and topographically-forced flows are represented. The wind shear plays a primary role and topographic flows a secondary role on ash distribution on local to regional scales. We propose a new explanation for the downwind ash deposition maxima, commonly observed in volcanic eruptions, as resulting from the detailed forcing of mesoscale meteorology on the ash plume. PMID- 29720681 TI - The nanos1 gene was duplicated in early Vertebrates and the two paralogs show different gonadal expression profiles in a shark. AB - Nanos are RNA-binding proteins playing crucial roles in germ cell development and maintenance. Based on phylogenetic and synteny analyses, this study reveals that nanos1 gene has undergone multiple duplications and gene copies losses in Vertebrates. Chondrichthyan species display two nanos1 genes (named nanos1A/1B), which were both retrieved in some Osteichthyes at basal positions in Sarcopterygii and Actinopterygii lineages. In contrast, Teleosts have lost nanos1A but duplicated nanos1B leading to the emergence of two ohnologs (nanos1Ba/1Bb), whereas Tetrapods have lost nanos1B gene. The two successive nanos gene duplications may result from the second and third whole genome duplication events at the basis of Vertebrates and Teleosts respectively. The expression profiles of nanos1A and nanos1B paralogs were characterized in the dogfish, Scyliorhinus canicula. Nanos1A was strongly expressed in brain and also localized in all germ cell types in the polarized testis. In contrast, nanos1B was detected in testis with the highest expression in the germinative zone. In addition, Nanos1B protein was predominantly located in the nuclei of male germinal cells. In the ovary, both paralogs were detected in germinal and somatic cells. Our study opens new perspectives concerning the complex evolution of nanos1 paralogs and their potential distinct roles in Vertebrates gonads. PMID- 29720683 TI - Characterisation of Lamp2-deficient rats for potential new animal model of Danon disease. AB - Danon disease (DD) is caused by the absence or malfunction of lysosomal associated membrane protein 2 (LAMP2). Although Lamp2-deficient mice and DD patients have similar characteristics, these mice have clear limitations and are clinically inconsistent. The aim of our paper is to outline the characteristics of Lamp2-deficient rats and to contrast this model with currently available DD mouse models. The baseline levels of some serum enzymes were elevated in Lamp2y/- rats along with hypercholesterolemia and hyperglycaemia at 8 weeks. Echocardiography showed that IVSd (1.500 +/- 0.071 vs. 2.200 +/- 1.147, P < 0.01) and LVPWd (1.575 +/- 0.063 vs. 1.850 +/- 0.029, P < 0.01) were significantly increased, and GCS (-13.20 +/- 0.4814 vs. -6.954 +/- 0.665) and GRS (21.42 +/- 1.807 vs. 7.788 +/- 1.140) were sharply decreased. Meanwhile, substantial myocyte disruption, hypertrophic muscle fibres, interstitial fibrosis and microvascular hyperplasia could be observed in the heart tissue. Lamp2y/- rats also displayed abnormal behaviours in the open field and fear conditioning tests. Notably, Lamp2y/- rats manifested other system dysfunctions, such as retinopathy, chronic kidney injury and sterility. Based on these results, Lamp2-deficient rats exhibited greater similarity to DD patients in terms of onset and multisystem lesions than did mouse models, and these rats could be used as a valuable animal model for DD. PMID- 29720684 TI - Namib Desert primary productivity is driven by cryptic microbial community N fixation. AB - Carbon exchange in drylands is typically low, but during significant rainfall events (wet anomalies) drylands act as a C sink. During these anomalies the limitation on C uptake switches from water to nitrogen. In the Namib Desert of southern Africa, the N inventory in soil organic matter available for mineralisation is insufficient to support the observed increase in primary productivity. The C4 grasses that flourish after rainfall events are not capable of N fixation, and so there is no clear mechanism for adequate N fixation in dryland ecosystems to support rapid C uptake. Here we demonstrate that N fixation by photoautotrophic hypolithic communities forms the basis for the N budget for plant productivity events in the Namib Desert. Stable N isotope (delta15N) values of Namib Desert hypolithic biomass, and surface and subsurface soils were measured over 3 years across dune and gravel plain biotopes. Hypoliths showed significantly higher biomass and lower delta15N values than soil organic matter. The delta15N values of hypoliths approach the theoretical values for nitrogen fixation. Our results are strongly indicative that hypolithic communities are the foundation of productivity after rain events in the Namib Desert and are likely to play similar roles in other arid environments. PMID- 29720685 TI - Dragonfly wing decorated by gold nanoislands as flexible and stable substrates for surface-enhanced Raman scattering (SERS). AB - A flexible and stable biomimetic SERS substrate was successfully fabricated by depositing gold (Au) nanoislands on the dragonfly wings (DW) via a simple DC magnetron sputtering system. Characterizations of the Au/DW nanostructure indicated that the optimum Au/DW-45 (sputtering time was 45 min) substrate owns high sensitivity, good stability and outstanding reproducibility. The limit of detection (LOD) for Rhodamine 6 G (R6G) was as low as 10-7 M and enhancement factor (EF) was calculated to be 2.8 * 106. 70-day-duration stability tests showed that Raman intensity of R6G reduced only by 12.9% after aging for 70 days. The maximum relative standard deviations (RSD) of SERS intensities from 100 positions of Au/DW-45 substrate were less than 8.3%, revealing outstanding uniformity and reproducibility. Moreover, the flexible Au/DW-45 bioscaffold arrays were employed to solve the vital problem of pesticide residues. By directly sampling from tomato peels via a "press and peel off" approach, cypermethrin has been rapidly and reliably determined with a LOD centered at 10-3 ng/cm2 and a correlation coefficient (R2) of 0.987. The positive results demonstrated that the Au-based DW biomimetic arrays may offer an efficient SERS platform for the identification of various pesticide residues on real samples. PMID- 29720686 TI - Recurrent complex spinal tuberculosis accompanied by sinus tract formation: causes of recurrence and clinical treatments. AB - Recurrent complex spinal tuberculosis accompanied by sinus tract formation is one of the most common and complex types of recurrent tuberculosis. To date, only very few studies have reported the strategies and effectiveness of surgical treatments on postoperative recurrent spinal tuberculosis accompanied by sinus tract formation. In this study, 21 recurrent patients out of 87 patients with complex spinal tuberculosis were reviewed. The data of the patients, including age, gender, existence of drug-resistant mycobacterium tuberculosis, postoperative standard chemotherapy, completeness of lesion debridement, reconstruction of the spinal stability, nutritional status, accompaniment by tuberculosis in other regions, timing of the operations, and areas of the lesions, were collected for single- and multiple-factor analyses. The clinical outcomes were evaluated by long-term follow-ups. The results showed that 7 factors were significantly associated with postoperative recurrence of complex spinal tuberculosis accompanied by sinus tract formation. This suggested that when we treat complex spinal tuberculosis, we should pay more attention to these seven indicators to avoid postoperative recurrence, and our clinical outcomes suggested that it is difficult to treat recurrent complicated spinal tuberculosis combined with sinus tract formation. The key for successful surgical treatment includes effective chemotherapy, radical debridement and proper reconstruction of spinal stability. PMID- 29720687 TI - A new phylogeny-based tribal classification of subfamily Detarioideae, an early branching clade of florally diverse tropical arborescent legumes. AB - Detarioideae (81 genera, c. 760 species) is one of the six Leguminosae subfamilies recently reinstated by the Legume Phylogeny Working Group. This subfamily displays high morphological variability and is one of the early branching clades in the evolution of legumes. Using previously published and newly generated sequences from four loci (matK-trnK, rpL16, trnG-trnG2G and ITS), we develop a new densely sampled phylogeny to assess generic relationships and tribal delimitations within Detarioideae. The ITS phylogenetic trees are poorly resolved, but the plastid data recover several strongly supported clades, which also are supported in a concatenated plastid + ITS sequence analysis. We propose a new phylogeny-based tribal classification for Detarioideae that includes six tribes: re-circumscribed Detarieae and Amherstieae, and the four new tribes Afzelieae, Barnebydendreae, Saraceae and Schotieae. An identification key and descriptions for each of the tribes are also provided. PMID- 29720688 TI - Elevated leptin and decreased adiponectin independently predict the post thrombotic syndrome in obese and non-obese patients. AB - Post-thrombotic syndrome (PTS) is a common complication of deep vein thrombosis (DVT). Little is known about the involvement of adipokines in the pathogenesis of DVT. We evaluated whether adipokines can predict PTS. In a prospective cohort study, 320 DVT patients aged 70 years or less were enrolled. Serum adiponectin, leptin and resistin levels were measured three months since the index first-ever DVT. After 2 years' follow-up PTS was diagnosed in 83 of 309 available patients (26.9%) who had 13.9% lower adiponectin and 16% higher leptin levels compared with the remainder (both p < 0.0001). No PTS-associated differences in C-reactive protein, fibrinogen, D-dimer, plasminogen activator inhibitor-1 and resistin were observed. The multivariable logistic regression adjusted for age, sex, obesity and tissue plasminogen activator (tPa) showed that lower adiponectin (odds ratio [OR], 0.42; 95% confidence interval [CI], 0.31-0.56) and higher leptin levels (OR, 1.49; 95% CI, 1.31-1.69) are independent predictors for PTS. Obesity stratified logistic regression analysis confirmed that lower adiponectin (OR, 0.49; 95% CI, 0.38-0.64) and higher leptin (OR, 1.41; 95% Cl, 1.25-1.58) levels predicted PTS. Our findings showed that lower adiponectin and higher leptin measured 3 months after DVT, regardless of obesity, can independently predict PTS, which suggests novel links between adipokines and thrombosis. PMID- 29720689 TI - A 4-Week Model of House Dust Mite (HDM) Induced Allergic Airways Inflammation with Airway Remodeling. AB - Animal models of allergic airways inflammation are useful tools in studying the pathogenesis of asthma and potential therapeutic interventions. The different allergic airways inflammation models available to date employ varying doses, frequency, duration and types of allergen, which lead to the development of different features of asthma; showing varying degrees of airways inflammation and hyper-responsiveness (AHR) and airways remodeling. Models that also exhibit airway remodeling, a key feature of asthma, in addition to AHR and airway inflammation typically require 5-12 weeks to develop. In this report, we describe a 4-week mouse model of house dust mite (HDM)-induced allergic airways inflammation, and compare the phenotypic features of two different doses of HDM exposures (10 ug and 25 ug) for 5 days/week with a well-characterized 8-week chronic HDM model. We found that 4 weeks of intranasal HDM (25 ug in 35 ul saline; 5 days/week) resulted in AHR, airway inflammation and airway remodeling that were comparable to the 8-week model. We conclude that this new 4-week HDM model is another useful tool in studies of human asthma that offers advantages of shorter duration for development and decreased costs when compared to other models that require longer durations of exposure (5-12 weeks) to develop. PMID- 29720690 TI - Preparatory activity for purposeful arm movements in the dorsomedial parietal area V6A: Beyond the online guidance of movement. AB - Over the years, electrophysiological recordings in macaque monkeys performing visuomotor tasks brought about accumulating evidence for the expression of neuronal properties (e.g., selectivity in the visuospatial and somatosensory domains, encoding of visual affordances and motor cues) in the posterior parietal area V6A that characterize it as an ideal neural substrate for online control of prehension. Interestingly, neuroimaging studies suggested a role of putative human V6A also in action preparation; moreover, pre-movement population activity in monkey V6A has been recently shown to convey grip-related information for upcoming grasping. Here we directly test whether macaque V6A neurons encode preparatory signals that effectively differentiate between dissimilar actions before movement. We recorded the activity of single V6A neurons during execution of two visuomotor tasks requiring either reach-to-press or reach-to-grasp movements in different background conditions, and described the nature and temporal dynamics of V6A activity preceding movement execution. We found striking consistency in neural discharges measured during pre-movement and movement epochs, suggesting that the former is a preparatory activity exquisitely linked to the subsequent execution of particular motor actions. These findings strongly support a role of V6A beyond the online guidance of movement, with preparatory activity implementing suitable motor programs that subsequently support action execution. PMID- 29720691 TI - The behavioral and neural binding phenomena during visuomotor integration of angry facial expressions. AB - Different parts of our brain code the perceptual features and actions related to an object, causing a binding problem, in which the brain has to integrate information related to an event without any interference regarding the features and actions involved in other concurrently processed events. Using a paradigm similar to Hommel, who revealed perception-action bindings, we showed that emotion could bind with motor actions when relevant, and in specific conditions, irrelevant for the task. By adapting our protocol to a functional Magnetic Resonance Imaging paradigm we investigated, in the present study, the neural bases of the emotion-action binding with task-relevant angry faces. Our results showed that emotion bound with motor responses. This integration revealed increased activity in distributed brain areas involved in: (i) memory, including the hippocampi; (ii) motor actions with the precentral gyri; (iii) and emotion processing with the insula. Interestingly, increased activations in the cingulate gyri and putamen, highlighted their potential key role in the emotion-action binding, due to their involvement in emotion processing, motor actions, and memory. The present study confirmed our previous results and point out for the first time the functional brain activity related to the emotion-action association. PMID- 29720692 TI - Coupling Multi Angle Light Scattering to Ion Exchange chromatography (IEX-MALS) for protein characterization. AB - Multi-angle light scattering coupled with size exclusion chromatography (SEC MALS) is a standard and common approach for characterizing protein mass, overall shape, aggregation, oligomerization, interactions and purity. The limited resolution of analytical SEC restricts in some instances the accurate analysis that can be accomplished by MALS. These include mixtures of protein populations with identical or very similar molecular masses, oligomers with poor separation and short peptides. Here we show that combining MALS with the higher resolution separation technique ion exchange (IEX-MALS) can allow precise analyses of samples that cannot be resolved by SEC-MALS. We conclude that IEX-MALS is a valuable and complementary method for protein characterization, especially for protein systems that could not be fully analyzed by SEC-MALS. PMID- 29720693 TI - Si Nanocrystal-Embedded SiO x nanofoils: Two-Dimensional Nanotechnology-Enabled High Performance Li Storage Materials. AB - Silicon (Si) based materials are highly desirable to replace currently used graphite anode for lithium ion batteries. Nevertheless, its usage is still a big challenge due to poor battery performance and scale-up issue. In addition, two dimensional (2D) architectures, which remain unresolved so far, would give them more interesting and unexpected properties. Herein, we report a facile, cost effective, and scalable approach to synthesize Si nanocrystals embedded 2D SiO x nanofoils for next-generation lithium ion batteries through a solution evaporation-induced interfacial sol-gel reaction of hydrogen silsesquioxane (HSiO1.5, HSQ). The unique nature of the thus-prepared centimeter scale 2D nanofoil with a large surface area enables ultrafast Li+ insertion and extraction, with a reversible capacity of more than 650 mAh g-1, even at a high current density of 50 C (50 A g-1). Moreover, the 2D nanostructured Si/SiO x nanofoils show excellent cycling performance up to 200 cycles and maintain their initial dimensional stability. This superior performance stems from the peculiar nanoarchitecture of 2D Si/SiO x nanofoils, which provides short diffusion paths for lithium ions and abundant free space to effectively accommodate the huge volume changes of Si during cycling. PMID- 29720694 TI - Effects of precipitates and dislocation loops on the yield stress of irradiated iron. AB - Plastic deformation of crystalline materials is governed by the features of stress-driven motion of dislocations. In the case of irradiated steels subject to applied stresses, small dislocation loops as well as precipitates are known to interfere with the dislocation motion, leading to an increased yield stress as compared to pure crystals. We study the combined effect of precipitates and interstitial glissile [Formula: see text] dislocation loops on the yield stress of iron, using large-scale three-dimensional discrete dislocation dynamics simulations. Precipitates are included in the simulations using our recent multi scale implementation [A. Lehtinen et al., Phys. Rev. E 93 (2016) 013309], where the strengths and pinning mechanisms of the precipitates are determined from molecular dynamics simulations. In the simulations we observe dislocations overcoming precipitates with an atypical Orowan mechanism which results from pencil-glide of screw segments in iron. Even if the interaction mechanisms with dislocations are quite different, our results suggest that in relative terms, precipitates and loops of similar sizes contribute equally to the yield stress in multi-slip conditions. PMID- 29720695 TI - DNA Methylation of T1R1 Gene in the Vegetarian Adaptation of Grass Carp Ctenopharyngodon idella. AB - Although previous studies have indicated importance of taste receptors in food habits formation in mammals, little is known about those in fish. Grass carp is an excellent model for studying vegetarian adaptation, as it shows food habit transition from carnivore to herbivore. In the present study, pseudogenization or frameshift mutations of the umami receptors that hypothesized related to dietary switch in vertebrates, were not found in grass carp, suggesting other mechanisms for vegetarian adaptation in grass carp. T1R1 and T1R3 strongly responded to L Arg and L-Lys, differing from those of zebrafish and medaka, contributing to high species specificity in amino acid preferences and diet selection of grass carp. After food habit transition of grass carp, DNA methylation levels were higher in CPG1 and CPG3 islands of upstream control region of T1R1 gene. Luciferase activity assay of upstream regulatory region of T1R1 (-2500-0 bp) without CPG1 or CPG3 indicated that CPG1 and CPG3 might be involved in transcriptional regulation of T1R1 gene. Subsequently, high DNA methylation decreased expression of T1R1 in intestinal tract. It could be a new mechanism to explain, at least partially, the vegetarian adaptation of grass carp by regulation of expression of umami receptor via epigenetic modification. PMID- 29720696 TI - Spectroscopic features of ultrahigh-pressure impact glasses of the Kara astrobleme. AB - The state of substances under ultrahigh pressures and temperatures (UHPHT) now raises a special interest as a matter existing under extreme conditions and as potential new material. Under laboratory conditions only small amounts of micrometer-sized matter are produced at a pressure up to 100 GPa and at room temperature. Simultaneous combination of ultrahigh pressures and temperatures in a lab still requires serious technological effort. Here we describe the composition and structure of the UHPHT vein-like impact glass discovered by us in 2015 on the territory of the Kara astrobleme (Russia) and compare its properties with impact glass from the Ries crater (Germany). A complex of structural and spectroscopic methods presents unusual high pressure marks of structural elements in 8-fold co-ordination that had been described earlier neither in synthetic nor natural glasses. The Kara natural UHPHT glasses being about 70 Ma old have well preserved initial structure, presenting some heterogeneity as a result of partial liquation and crystallization differentiation where an amorphous component is proposed to originate from low level polymerization. Homogeneous parts of the UHPHT glasses can be used to deepened fundamental investigation of a substance under extreme PT conditions and to technological studies for novel material creations. PMID- 29720699 TI - The Role of Intelligence in Social Learning. AB - Studies in cultural evolution have uncovered many types of social learning strategies that are adaptive in certain environments. The efficiency of these strategies also depends on the individual characteristics of both the observer and the demonstrator. We investigate the relationship between intelligence and the ways social and individual information is utilised to make decisions in an uncertain environment. We measure fluid intelligence and study experimentally how individuals learn from observing the choices of a demonstrator in a 2-armed bandit problem with changing probabilities of a reward. Participants observe a demonstrator with high or low fluid intelligence. In some treatments they are aware of the intelligence score of the demonstrator and in others they are not. Low fluid intelligence individuals imitate the demonstrator more when her fluid intelligence is known than when it is not. Conversely, individuals with high fluid intelligence adjust their use of social information, as the observed behaviour changes, independently of the knowledge of the intelligence of the demonstrator. We provide evidence that intelligence determines how social and individual information is integrated in order to make choices in a changing uncertain environment. PMID- 29720698 TI - Exploring Leptospiral proteomes to identify potential candidates for vaccine design against Leptospirosis using an immunoinformatics approach. AB - Leptospirosis is the most widespread zoonotic disease, estimated to cause severe infection in more than one million people each year, particularly in developing countries of tropical areas. Several factors such as variable and nonspecific clinical manifestation, existence of large number of serovars and asymptomatic hosts spreading infection, poor sanitation and lack of an effective vaccine make prophylaxis difficult. Consequently, there is an urgent need to develop an effective vaccine to halt its spread all over the world. In this study, an immunoinformatics approach was employed to identify the most vital and effective immunogenic protein from the proteome of Leptospira interrogans serovar Copenhageni strain L1-130 that may be suitable to stimulate a significant immune response aiding in the development of peptide vaccine against leptospirosis. Both B-cell and T-cell (Helper T-lymphocyte (HTL) and cytotoxic T lymphocyte (CTL)) epitopes were predicted for the conserved and most immunogenic outer membrane lipoprotein. Further, the binding interaction of CTL epitopes with Major Histocompatibility Complex class I (MHC-I) was evaluated using docking techniques. A Molecular Dynamics Simulation study was also performed to evaluate the stability of the resulting epitope-MHC-I complexes. Overall, this study provides novel vaccine candidates and may prompt further development of vaccines against leptospirosis. PMID- 29720697 TI - Transcription Elongation Factor GreA Plays a Key Role in Cellular Invasion and Virulence of Francisella tularensis subsp. novicida. AB - Francisella tularensis is a facultative intracellular Gram-negative bacterium that causes the zoonotic disease tularemia. We identified the transcription elongation factor GreA as a virulence factor in our previous study, but its role was not defined. Here, we investigate the effects of the inactivation of the greA gene, generating a greA mutant of F. tularensis subsp. novicida. Inactivation of greA impaired the bacterial invasion into and growth within host cells, and subsequently virulence in mouse infection model. A transcriptomic analysis (RNA Seq) showed that the loss of GreA caused the differential expression of 196 bacterial genes, 77 of which were identified as virulence factors in previous studies. To confirm that GreA regulates the expression of virulence factors involved in cell invasion by Francisella, FTN_1186 (pepO) and FTN_1551 (ampD) gene mutants were generated. The ampD deletion mutant showed reduced invasiveness into host cells. These results strongly suggest that GreA plays an important role in the pathogenesis of Francisella by affecting the expression of virulence genes and provide new insights into the complex regulation of Francisella infection. PMID- 29720702 TI - Seasonal food habits and prey selection of Amur tigers and Amur leopards in Northeast China. AB - We analyzed the scats of Amur tigers and Amur leopards, and examined their annual and seasonal food habits in Northeast China to comprehend their coexistence. Wild boar had the highest annual and seasonal consumption frequencies by the tigers, while both roe deer and sika deer were mostly preyed by the leopards annually. The three species appeared to be the key preys in terms of high proportion of consumed biomass by the two felids. Our data also revealed numerous mid-sized carnivores and small mammals included in the two felids' food list. We used the relative abundance and biomass density estimation in prey density estimation to calculate the prey preferences of tigers and leopards, and both methods confirmed that Amur tigers strongly preferred wild boar. However, preference estimations of Amur leopards were not consistant, or even opposite to one another from the two methods. The results of the study suggested that prey preference of predators is largely determined by body size of the prey species. Variation in diet composition of the two felids suggests that resource partitioning may contribute to their coexistence. PMID- 29720701 TI - Bidirectional regulation of bone formation by exogenous and osteosarcoma-derived Sema3A. AB - Semaphorin 3A (Sema3A), a secreted member of the Semaphorin family, increases osteoblast differentiation, stimulates bone formation and enhances fracture healing. Here, we report a previously unknown role of Sema3A in the regulation of ectopic bone formation and osteolysis related to osteosarcoma. Human recombinant (exogenous) Sema3A promoted the expression of osteoblastic phenotype in a panel of human osteosarcoma cell lines and inhibited the ability of these cells to migrate and enhance osteoclastogenesis in vitro. In vivo, administration of exogenous Sema3A in mice after paratibial inoculation of KHOS cells increased bone volume in non-inoculated and tumour-bearing legs. In contrast, Sema3A overexpression reduced the ability of KHOS cells to cause ectopic bone formation in mice and to increase bone nodule formation by engaging DKK1/beta-catenin signalling. Thus, Sema3A is of potential therapeutic efficacy in osteosarcoma. However, inhibition of bone formation associated with continuous exposure to Sema3A may limit its long-term usefulness as therapeutic agent. PMID- 29720700 TI - In silico assessment of the conduction mechanism of the Ryanodine Receptor 1 reveals previously unknown exit pathways. AB - The ryanodine receptor 1 is a large calcium ion channel found in mammalian skeletal muscle. The ion channel gained a lot of attention recently, after multiple independent authors published near-atomic cryo electron microscopy data. Taking advantage of the unprecedented quality of structural data, we performed molecular dynamics simulations on the entire ion channel as well as on a reduced model. We calculated potentials of mean force for Ba2+, Ca2+, Mg2+, K+, Na+ and Cl- ions using umbrella sampling to identify the key residues involved in ion permeation. We found two main binding sites for the cations, whereas the channel is strongly repulsive for chloride ions. Furthermore, the data is consistent with the model that the receptor achieves its ion selectivity by over-affinity for divalent cations in a calcium-block-like fashion. We reproduced the experimental conductance for potassium ions in permeation simulations with applied voltage. The analysis of the permeation paths shows that ions exit the pore via multiple pathways, which we suggest to be related to the experimental observation of different subconducting states. PMID- 29720704 TI - Diagnostic value of highly-sensitive chimerism analysis after allogeneic stem cell transplantation. AB - Conventional analysis of host chimerism (HC) frequently fails to detect relapse before its clinical manifestation in patients with hematological malignancies after allogeneic stem cell transplantation (allo-SCT). Quantitative PCR (qPCR) based highly-sensitive chimerism analysis extends the detection limit of conventional (short tandem repeats-based) chimerism analysis from 1 to 0.01% host cells in whole blood. To date, the diagnostic value of highly-sensitive chimerism analysis is hardly defined. Here, we applied qPCR-based chimerism analysis to 901 blood samples of 71 out-patients with hematological malignancies after allo-SCT. Receiver operating characteristics (ROC) curves were calculated for absolute HC values and for the increments of HC before relapse. Using the best cut-offs, relapse was detected with sensitivities of 74 or 85% and specificities of 69 or 75%, respectively. Positive predictive values (PPVs) were only 12 or 18%, but the respective negative predictive values were 98 or 99%. Relapse was detected median 38 or 45 days prior to clinical diagnosis, respectively. Considering also durations of steadily increasing HC of more than 28 days improved PPVs to more than 28 or 59%, respectively. Overall, highly-sensitive chimerism analysis excludes relapses with high certainty and predicts relapses with high sensitivity and specificity more than a month prior to clinical diagnosis. PMID- 29720703 TI - Modulation of Haemophilus influenzae interaction with hydrophobic molecules by the VacJ/MlaA lipoprotein impacts strongly on its interplay with the airways. AB - Airway infection by nontypeable Haemophilus influenzae (NTHi) associates to chronic obstructive pulmonary disease (COPD) exacerbation and asthma neutrophilic airway inflammation. Lipids are key inflammatory mediators in these disease conditions and consequently, NTHi may encounter free fatty acids during airway persistence. However, molecular information on the interplay NTHi-free fatty acids is limited, and we lack evidence on the importance of such interaction to infection. Maintenance of the outer membrane lipid asymmetry may play an essential role in NTHi barrier function and interaction with hydrophobic molecules. VacJ/MlaA-MlaBCDEF prevents phospholipid accumulation at the bacterial surface, being the only system involved in maintaining membrane asymmetry identified in NTHi. We assessed the relationship among the NTHi VacJ/MlaA outer membrane lipoprotein, bacterial and exogenous fatty acids, and respiratory infection. The vacJ/mlaA gene inactivation increased NTHi fatty acid and phospholipid global content and fatty acyl specific species, which in turn increased bacterial susceptibility to hydrophobic antimicrobials, decreased NTHi epithelial infection, and increased clearance during pulmonary infection in mice with both normal lung function and emphysema, maybe related to their shared lung fatty acid profiles. Altogether, we provide evidence for VacJ/MlaA as a key bacterial factor modulating NTHi survival at the human airway upon exposure to hydrophobic molecules. PMID- 29720705 TI - Recommendations from the European Society for Blood and Marrow Transplantation (EBMT) for a curriculum in hematopoietic cell transplantation. AB - Hematopoietic cell transplantation (HCT) is increasingly used worldwide. This treatment approach is complex and requires specific knowledge and training. The European Society for Blood and Marrow Transplantation (EBMT) identified the need for a set of international recommendations for the clinical training of physicians to qualify them as being competent in performing HCT procedures as well as novel cellular immune therapies and taking care of such patients. The goal is to implement an EBMT HCT-focused global curriculum (EBMT-GC) that can serve as a tool for the development of the HCT sub-specialty worldwide. Despite the diversity and heterogeneity of health and educational systems around the globe, this set of recommendations can be fairly adopted by any national educational and health authorities and can be adjusted to specific conditions and resources of a given country, if needed. The ultimate goal of the EBMT-GC is to define standards for personal knowledge in allogeneic stem cell transplantation for physicians worldwide in order to ensure that all patients will receive treatment by well-trained physicians. PMID- 29720706 TI - Can Wolbachia save the day? PMID- 29720707 TI - Implant infections: adhesion, biofilm formation and immune evasion. AB - Medical device-associated infections account for a large proportion of hospital acquired infections. A variety of opportunistic pathogens can cause implant infections, depending on the type of the implant and on the anatomical site of implantation. The success of these versatile pathogens depends on rapid adhesion to virtually all biomaterial surfaces and survival in the hostile host environment. Biofilm formation on implant surfaces shelters the bacteria and encourages persistence of infection. Furthermore, implant-infecting bacteria can elude innate and adaptive host defences as well as biocides and antibiotic chemotherapies. In this Review, we explore the fundamental pathogenic mechanisms underlying implant infections, highlighting orthopaedic implants and Staphylococcus aureus as a prime example, and discuss innovative targets for preventive and therapeutic strategies. PMID- 29720709 TI - Tuft cells revealed as norovirus target. PMID- 29720708 TI - Subwavelength hyperspectral THz studies of articular cartilage. AB - Terahertz-spectroscopy probes dynamics and spectral response of collective vibrational modes in condensed phase, which can yield insight into composition and topology. However, due to the long wavelengths employed (lambda = 300 MUm at 1THz), diffraction limited imaging is typically restricted to spatial resolutions around a millimeter. Here, we demonstrate a new form of subwavelength hyperspectral, polarization-resolved THz imaging which employs an optical pattern projected onto a 6 MUm-thin silicon wafer to achieve near-field modulation of a co-incident THz pulse. By placing near-field scatterers, one can measure the interaction of object with the evanescent THz fields. Further, by measuring the temporal evolution of the THz field a sample's permittivity can be extracted with 65 MUm spatial resolution due to the presence of evanescent fields. Here, we present the first application of this new approach to articular cartilage. We show that the THz permittivity in this material varies progressively from the superficial zone to the deep layer, and that this correlates with a change in orientation of the collagen fibrils that compose the extracellular matrix (ECM) of the tissue. Our approach enables direct interrogation of the sample's biophysical properties, in this case concerning the structure and permittivity of collagen fibrils and their anisotropic organisation in connective tissue. PMID- 29720710 TI - A novel role for ATR/Rad3 in G1 phase. AB - Checkpoint kinases are important in cellular surveillance pathways that help cells to cope with DNA damage and protect their genomes. In cycling cells, DNA replication is one of the most sensitive processes and therefore all organisms carefully regulate replication initiation and progression. The checkpoint kinase ATR plays important roles both in response to DNA damage and replication stress, and ATR inhibitors are currently in clinical trials for cancer treatment. Therefore, it is important to understand the roles of ATR in detail. Here we show that the fission yeast homologue Rad3 and the human ATR regulate events also in G1 phase in an unperturbed cell cycle. Rad3Delta mutants or human cells exposed to ATR inhibitor in G1 enter S phase prematurely, which results in increased DNA damage. Furthermore, ATR inhibition in a single G1 reduces clonogenic survival, demonstrating that long-term effects of ATR inhibition during G1 are deleterious for the cell. Interestingly, ATR inhibition through G1 and S phase reduces survival in an additive manner, strongly arguing that different functions of ATR are targeted in the different cell-cycle phases. We propose that potential effects of ATR inhibitors in G1 should be considered when designing future treatment protocols with such inhibitors. PMID- 29720712 TI - The effect of N-ethyl-N-hydroxyethyl perfluorooctanoamide on wettability alteration of shale reservoir. AB - The wettability of the formation is critical for the flow back of the fracturing fluid and can further affect the gas production. So it is very necessary to study the wettability of shale reservoir. Here, a novel fluorocarbon surfactant, N ethyl-N-hydroxyethyl perfluorooctanoamide, was synthesized and characterized by different methods. the contact angles of water and n-decane on the shale increased from 36 degrees and 0 degrees to 121 degrees and 105 degrees , respectively, after treated by N-ethyl-N-hydroxyethyl perfluorooctanoamide (0.5 wt.%). The surface free energy reduced from 72 mN/m to 7.4 mN/m. The results agreed with that of imbibition and capillary tube rise test. Additionally, the analysis of scanning electron microscope (SEM) and energy dispersive spectroscopy (EDS) showed that the roughness of shale surface remarkably increased. These results fully proved that the shale wettability is changed to super gas-wetting. Besides, the thermal analysis revealed that the novel fluorocarbon surfactant has good thermal stability. This indicates that it can be better applied to reservoir modifications at higher temperatures. PMID- 29720711 TI - In Vitro and In Vivo Characterization of PCC0104005, a Novel Modulator of Serotonin-Dopamine Activity, as an Atypical Antipsychotic Drug. AB - PCC0104005 is a novel drug candidate for treating schizophrenia that displays high affinity for serotonin, dopamine, and noradrenaline receptors, including partial agonism at dopamine D2, D3, D4, serotonin 5-HT1A, and 5-HT2A receptors and antagonism at 5-HT2B, 5-HT6, and 5-HT7 receptors. PCC0104005 blocks MK-801 induced hyperactivity in rats, consistent with the reduction in dopamine D2 receptor stimulation and increased dopamine release in the medial prefrontal cortex. PCC0104005 inhibits 5-HTP-induced head twitches in rats, due to its moderate affinity for human 5-HT2A receptors (Ki = 5.1 nM). PCC0104005 significantly reduced the escape latency of rats and improved the MK-801-induced memory impairment. In the object recognition experiment, PCC0104005 significantly improved the recognition disorder induced by MK-801. PCC0104005 did not significantly increase the plasma prolactin level, which is thought to be related to the preferential affinity of PCC0104005 for dopamine D2 receptors compared with 5-HT1A receptors, as well as the relative antagonistic activity toward the D2 receptor. Due to its 5-HT1A agonism, PCC0104005 does not produce catalepsy in mice, a behaviour predictive of the occurrence of extra-pyramidal syndrome (EPS) in humans. PCC0104005 has unique affinities for dopamine receptors and serotonin receptors, which may lead to clinical advantages, as well as fewer adverse reactions. PMID- 29720713 TI - Treatment resistance in urothelial carcinoma: an evolutionary perspective. AB - The emergence of treatment-resistant clones is a critical barrier to cure in patients with urothelial carcinoma. Setting the stage for the evolution of resistance, urothelial carcinoma is characterized by extensive mutational heterogeneity, which is detectable even in patients with early stage disease. Chemotherapy and immunotherapy both act as selective pressures that shape the evolutionary trajectory of urothelial carcinoma throughout the course of the disease. A detailed understanding of the dynamics of evolutionary drivers is required for the rational development of curative therapies. Herein, we describe the molecular basis of the clonal evolution of urothelial carcinomas and the use of genomic approaches to predict treatment responses. We discuss various mechanisms of resistance to chemotherapy with a focus on the mutagenic effects of the DNA dC->dU-editing enzymes APOBEC3 family of proteins. We also review the evolutionary mechanisms underlying resistance to immunotherapy, such as the loss of clonal tumour neoantigens. By dissecting treatment resistance through an evolutionary lens, the field will advance towards true precision medicine for urothelial carcinoma. PMID- 29720715 TI - Comment on when to stop surveillance colonoscopy. PMID- 29720716 TI - Ultrafast magnetization modulation induced by the electric field component of a terahertz pulse in a ferromagnetic-semiconductor thin film. AB - High-speed magnetization control of ferromagnetic films using light pulses is attracting considerable attention and is increasingly important for the development of spintronic devices. Irradiation with a nearly monocyclic terahertz pulse, which can induce strong electromagnetic fields in ferromagnetic films within an extremely short time of less than ~1 ps, is promising for damping-free high-speed coherent control of the magnetization. Here, we successfully observe a terahertz response in a ferromagnetic-semiconductor thin film. In addition, we find that a similar terahertz response is observed even in a non-magnetic semiconductor and reveal that the electric-field component of the terahertz pulse plays a crucial role in the magnetization response through the spin-carrier interactions in a ferromagnetic-semiconductor thin film. Our findings will provide new guidelines for designing materials suitable for ultrafast magnetization reversal. PMID- 29720714 TI - Wolbachia significantly impacts the vector competence of Aedes aegypti for Mayaro virus. AB - Wolbachia, an intracellular endosymbiont present in up to 70% of all insect species, has been suggested as a sustainable strategy for the control of arboviruses such as Dengue, Zika and Chikungunya. As Mayaro virus outbreaks have also been reported in Latin American countries, the objective of this study was to evaluate the vector competence of Brazilian field-collected Ae. aegypti and the impact of Wolbachia (wMel strain) upon this virus. Our in vitro studies with Aag2 cells showed that Mayaro virus can rapidly multiply, whereas in wMel infected Aag2 cells, viral growth was significantly impaired. In addition, C6/36 cells seem to have alterations when infected by Mayaro virus. In vivo experiments showed that field-collected Ae. aegypti mosquitoes are highly permissive to Mayaro virus infection, and high viral prevalence was observed in the saliva. On the other hand, Wolbachia-harboring mosquitoes showed significantly impaired capability to transmit Mayaro virus. Our results suggest that the use of Wolbachia-harboring mosquitoes may represent an effective mechanism for the reduction of Mayaro virus transmission throughout Latin America. PMID- 29720717 TI - Inherent flexibility of CLIC6 revealed by crystallographic and solution studies. AB - Chloride intracellular channels (CLICs) are a family of unique proteins, that were suggested to adopt both soluble and membrane-associated forms. Moreover, following this unusual metamorphic change, CLICs were shown to incorporate into membranes and mediate ion conduction in vitro, suggesting multimerization upon membrane insertion. Here, we present a 1.8 A resolution crystal structure of the CLIC domain of mouse CLIC6 (mCLIC6). The structure reveals a monomeric arrangement and shows a high degree of structural conservation with other CLICs. Small-angle X-ray scattering (SAXS) analysis of mCLIC6 demonstrated that the overall solution structure is similar to the crystallographic conformation. Strikingly, further analysis of the SAXS data using ensemble optimization method unveiled additional elongated conformations, elucidating high structural plasticity as an inherent property of the protein. Moreover, structure-guided perturbation of the inter-domain interface by mutagenesis resulted in a population shift towards elongated conformations of mCLIC6. Additionally, we demonstrate that oxidative conditions induce an increase in mCLIC6 hydrophobicity along with mild oligomerization, which was enhanced by the presence of membrane mimetics. Together, these results provide mechanistic insights into the metamorphic nature of mCLIC6. PMID- 29720718 TI - Incorporating non-equilibrium dynamics into demographic history inferences of a migratory marine species. AB - Understanding how dispersal and gene flow link geographically separated the populations over evolutionary history is challenging, particularly in migratory marine species. In southern right whales (SRWs, Eubalaena australis), patterns of genetic diversity are likely influenced by the glacial climate cycle and recent history of whaling. Here we use a dataset of mitochondrial DNA (mtDNA) sequences (n = 1327) and nuclear markers (17 microsatellite loci, n = 222) from major wintering grounds to investigate circumpolar population structure, historical demography and effective population size. Analyses of nuclear genetic variation identify two population clusters that correspond to the South Atlantic and Indo Pacific ocean basins that have similar effective breeder estimates. In contrast, all wintering grounds show significant differentiation for mtDNA, but no sex biased dispersal was detected using the microsatellite genotypes. An approximate Bayesian computation (ABC) approach with microsatellite markers compared the scenarios with gene flow through time, or isolation and secondary contact between ocean basins, while modelling declines in abundance linked to whaling. Secondary contact scenarios yield the highest posterior probabilities, implying that populations in different ocean basins were largely isolated and came into secondary contact within the last 25,000 years, but the role of whaling in changes in genetic diversity and gene flow over recent generations could not be resolved. We hypothesise that these findings are driven by factors that promote isolation, such as female philopatry, and factors that could promote dispersal, such as oceanographic changes. These findings highlight the application of ABC approaches to infer the connectivity in mobile species with complex population histories and, currently, low levels of differentiation. PMID- 29720721 TI - Pharmacogenomic survey of Qatari populations using whole-genome and exome sequences. AB - The Arabs represent one of the most genetically heterogeneous populations characterized by a high prevalence of Mendelian disorders due to consanguinity. Population-scale genomic datasets provide a unique opportunity to understand the epidemiology of variants associated with differential therapeutic response. We analyzed publicly available genomic data for 1005 Qatari individuals encompassing five subpopulations. The frequencies of known and novel pharmacogenetic variants were compared with global populations. Impact of genetic substructure on the pharmacogenetic landscape of the population was studied. We report an average of three clinically actionable pharmacogenetic variants with FDA-recommended genetic testing per Qatari individual regardless of their genetic ancestry. We observed extensive differences in the frequencies of clinically actionable pharmacogenetic variants among the Qatari subpopulations. Our analysis revealed 3579 deleterious pharmacogenetic variants potentially altering the function of 1163 genes associated with 1565 drugs. This study has thus compiled the first comprehensive landscape of pharmacogenetic variants for any Arab population. PMID- 29720719 TI - Surgical navigation improves reductions accuracy of unilateral complicated zygomaticomaxillary complex fractures: a randomized controlled trial. AB - Accurate reduction is the key to successful treatment of bone fractures. Complicated zygomaticomaxillary complex fracture, known as one of the most challenging facial bone fractures, is often hard to achieve an accurate reduction, thus leading to facial deformity. In this study, twenty patients with unilateral complicated zygomaticomaxillary complex fractures were included and randomly divided into experimental and control groups, which is with and without the aid of surgical navigation, respectively. The pre- and postoperative imaging data were collected and then analysed using Geomagic Studio 11 software and Brainlab iPlan CMF 3.0. A more precise reduction was showed in the experimental group according to the measurement results of both software programmes than in the control group. In conclusion, surgical navigation showed great value in performing accurate reductions of complicated zygomaticomaxillary complex fractures and restoring facial contour. PMID- 29720720 TI - Gamma-aminobutyric acid (GABA) receptors genes polymorphisms and risk for restless legs syndrome. AB - The possible role of gammaaminobutyric acid (GABA) in the pathophysiology of restless legs syndrome (RLS) is suggested by the symptomatic improvement achieved with GABAergic drugs. Thalamic GABA levels have shown positive correlation with periodic limb movements indices and with RLS severity. We tried to investigate the possible association between the most common single nucleotide polymorphisms (SNPs) in the GABA receptors (GABR) genes rho1, 2, and 3 (GABRR1, GABRR2, GABRR3), alpha4 (GABRA4), epsilon (GABRE), and theta (GABRQ) with the risk of developing RLS. We studied the genotype and allelic variant frequencies of the most common SNPs in the GABRR1(rs12200969, rs1186902), GABRR2(rs282129), GABRR3(rs832032), GABRA4(rs2229940), GABRE(rs1139916), and GABRQ(rs3810651) genes in 205 RLS patients and 230 age- and gender-matched healthy controls using specific TaqMan assays. The frequencies of the GABRR3 rs832032TT genotype and the allelic variant GABRR3 rs832032T were significantly higher in RLS patients than in controls (odds ratio [95% confidence intervals] 7.08[1.48-46.44] and 1.66[1.16 2.37], respectively), although only the higher frequency of the rs832032T allele remained as significant after multiple comparison analysis, both in the whole series and in the female gender. The frequencies of the other genotypes of allelic variants did not differ significantly between RLS patients and controls. RLS patients carrying the GABRA4 rs2229940TT genotype showed a significantly younger age at onset of RLS symptoms than those with the other two genotypes. These results suggest association between GABRR3rs832032 polymorphism and the risk for RLS, and a modifier effect of GABRA4 rs2229940 on the age of onset of RLS. PMID- 29720722 TI - Development of comorbidities in men with prostate cancer treated with androgen deprivation therapy: an Australian population-based cohort study. AB - BACKGROUND: The increasing use of androgen deprivation therapy has prompted further evaluation of its potential adverse effects as the treatment may exacerbate or increase the risk of developing new comorbid diseases. This study aims to assess the patterns of comorbidities among Australian men with prostate cancer treated with androgen deprivation therapy. METHODS: Pharmaceutical Benefits Scheme (PBS) 10% data between 1 January 2003 and 31 December 2014 was utilised in this retrospective cohort study. Men who had received their first androgen deprivation therapy between 2004 and 2010 were selected as the prostate cancer cohort. Comorbidities were identified using the dispensing claims data and classified with the Rx-Risk-V model. Comparisons were made between the prostate cancer cohort and specific control groups (age-matched and sex-matched without any dispensing of anti-neoplastic agents during the study period and without the individual comorbidity of interest evaluated at baseline at 1:10 ratio) for the development of nine individual comorbidities over time using Cox regression models. RESULTS: The prostate cancer cohort had a significant higher risk of developing cardiovascular conditions (hazard ratio 1.37, 95% CI: 1.26-1.48), depression (1.86, 95% CI: 1.73-2.01), diabetes (1.30, 95% CI: 1.15-1.47), gastric acid disorders (1.48, 95% CI: 1.39-1.57), hyperlipidaemia (1.18, 95% CI: 1.09 1.29), osteoporosis (1.65, 95% CI: 1.48-1.85) and pain/pain-inflammation (1.47, 95% CI: 1.39-1.55) compared to the control groups. The hazard ratios for cardiovascular conditions and depression were highest in the first year and declined over time. There were no significant differences between the two groups for reactive airway diseases and Alzheimer's disease. CONCLUSION: Men with prostate cancer treated with androgen deprivation therapy had a higher likelihood of developing new comorbidities than men who did not receive androgen deprivation therapy. Our results support the need for developing coordinated care models that effectively address multiple chronic diseases experienced by prostate cancer survivors. PMID- 29720724 TI - Fibroblast-derived CXCL12 promotes breast cancer metastasis by facilitating tumor cell intravasation. AB - The chemokine CXCL12 has been shown to regulate breast tumor growth, however, its mechanism in initiating distant metastasis is not well understood. Here, we generated a novel conditional allele of Cxcl12 in mice and used a fibroblast specific Cre transgene along with various mammary tumor models to evaluate CXCL12 function in the breast cancer metastasis. Ablation of CXCL12 in stromal fibroblasts of mice significantly delayed the time to tumor onset and inhibited distant metastasis in different mouse models. Elucidation of mechanisms using in vitro and in vivo model systems revealed that CXCL12 enhances tumor cell intravasation by increasing vascular permeability and expansion of a leaky tumor vasculature. Furthermore, our studies revealed CXCL12 enhances permeability by recruiting endothelial precursor cells and decreasing endothelial tight junction and adherence junction proteins. High expression of stromal CXCL12 in large cohort of breast cancer patients was directly correlated to blood vessel density and inversely correlated to recurrence and overall patient survival. In addition, our analysis revealed that stromal CXCL12 levels in combination with number of CD31+ blood vessels confers poorer patient survival compared to individual protein level. However, no correlation was observed between epithelial CXCL12 and patient survival or blood vessel density. Our findings describe the novel interactions between fibroblasts-derived CXCL12 and endothelial cells in facilitating tumor cell intrvasation, leading to distant metastasis. Overall, our studies indicate that cross-talk between fibroblast-derived CXCL12 and endothelial cells could be used as novel biomarker and strategy for developing tumor microenvironment based therapies against aggressive and metastatic breast cancer. PMID- 29720723 TI - Pro-tumorigenic roles of fibroblast activation protein in cancer: back to the basics. AB - Fibroblast activation protein (FAP) is a cell-surface serine protease that acts on various hormones and extracellular matrix components. FAP is highly upregulated in a wide variety of cancers, and is often used as a marker for pro tumorigenic stroma. It has also been proposed as a molecular target of cancer therapies, and, especially in recent years, a great deal of research has gone into design and testing of diverse FAP-targeted treatments. Yet despite this growing field of research, our knowledge of FAP's basic biology and functional roles in various cancers has lagged behind its use as a tumor-stromal marker. In this review, we summarize and analyze recent advances in understanding the functions of FAP in cancer, most notably its prognostic value in various tumor types, cellular effects on various cell types, and potential as a therapeutic target. We highlight outstanding questions in the field, the answers to which could shape preclinical and clinical studies of FAP. PMID- 29720725 TI - Inhibition of GPR158 by microRNA-449a suppresses neural lineage of glioma stem/progenitor cells and correlates with higher glioma grades. AB - To identify biomarkers for glioma growth, invasion and progression, we used a candidate gene approach in mouse models with two complementary brain tumour phenotypes, developing either slow-growing, diffusely infiltrating gliomas or highly proliferative, non-invasive primitive neural tumours. In a microRNA screen we first identified microRNA-449a as most significantly differentially expressed between these two tumour types. miR-449a has a target dependent effect, inhibiting cell growth and migration by downregulation of CCND1 and suppressing neural phenotypes by inhibition of G protein coupled-receptor (GPR) 158. GPR158 promotes glioma stem cell differentiation and induces apoptosis and is highest expressed in the cerebral cortex and in oligodendrogliomas, lower in IDH mutant astrocytomas and lowest in the most malignant form of glioma, IDH wild-type glioblastoma. The correlation of GPR158 expression with molecular subtypes, patient survival and therapy response suggests a possible role of GPR158 as prognostic biomarker in human gliomas. PMID- 29720726 TI - HRI-mediated translational repression reduces proteotoxicity and sensitivity to bortezomib in human pancreatic cancer cells. AB - Human cancer cells display extensive heterogeneity in their sensitivities to the proteasome inhibitor bortezomib (Velcade). The molecular mechanisms underlying this heterogeneity remain unclear, and strategies to overcome resistance are limited. Here, we discover that inherent differences in eIF2alpha phosphorylation among a panel of ten human pancreatic cancer cell lines significantly impacts bortezomib sensitivity, and implicate the HRI (heme-regulated inhibitor) eIF2alpha kinase as a novel therapeutic target. Within our panel, we identified a subset of cell lines with defective induction of eIF2alpha phosphorylation, conferring a high degree of sensitivity to bortezomib. These bortezomib-sensitive cells exhibited impaired translation attenuation followed by toxic accumulation of protein aggregates and reactive oxygen species (ROS), whereas the bortezomib resistant cell lines displayed increased phosphorylation of eIF2alpha, decreased translation, few protein aggregates, and minimal ROS production. Importantly, we identified HRI as the primary bortezomib-activated eIF2alpha kinase, and demonstrated that HRI knockdown promoted cell death in the bortezomib-resistant cells. Overall, our data implicate inducible HRI-mediated phosphorylation of eIF2alpha as a central cytoprotective mechanism following exposure to bortezomib and provide proof-of-concept for the development of HRI inhibitors to overcome proteasome inhibitor resistance. PMID- 29720727 TI - Recapitulation of pharmacogenomic data reveals that invalidation of SULF2 enhance sorafenib susceptibility in liver cancer. AB - Gene mutations play critical roles during cancer development and progression, and therefore represent targets for precision medicine. Here we recapitulated the pharmacogenomic data to delineate novel candidates for actionable mutations and therapeutic target drugs. As a proof-of-concept, we demonstrated that the loss-of function of SULF2 by mutation (N491K) or inhibition enhanced sorafenib sensitivity in liver cancer cells and in vivo mouse models. This effect was mediated by deregulation of EGFR signaling and downstream expression of LCN2. We also report that the liver cancer patients non-responding to sorafenib treatment exhibit higher expression of SULF2 and LCN2. In conclusion, we suggest that SULF2 plays a key role in sorafenib susceptibility and resistance in liver cancer via deregulation of LCN2. Diagnostic or therapeutic targeting of SULF2 (e.g., OKN 007) and/or LCN2 can be a novel precision strategy for sorafenib treatment in cancer patients. PMID- 29720728 TI - Myoferlin controls mitochondrial structure and activity in pancreatic ductal adenocarcinoma, and affects tumor aggressiveness. AB - Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer related death. Therapeutic options remain very limited and are based on classical chemotherapies. Energy metabolism reprogramming appears as an emerging hallmark of cancer and is considered a therapeutic target with considerable potential. Myoferlin, a ferlin family member protein overexpressed in PDAC, is involved in plasma membrane biology and has a tumor-promoting function. In the continuity of our previous studies, we investigated the role of myoferlin in the context of energy metabolism in PDAC. We used selected PDAC tumor samples and PDAC cell lines together with small interfering RNA technology to study the role of myoferlin in energetic metabolism. In PDAC patients, we showed that myoferlin expression is negatively correlated with overall survival and with glycolytic activity evaluated by 18F-deoxyglucose positron emission tomography. We found out that myoferlin is more abundant in lipogenic pancreatic cancer cell lines and is required to maintain a branched mitochondrial structure and a high oxidative phosphorylation activity. The observed mitochondrial fission induced by myoferlin depletion led to a decrease of cell proliferation, ATP production, and autophagy induction, thus indicating an essential role of myoferlin for PDAC cell fitness. The metabolic phenotype switch generated by myoferlin silencing could open up a new perspective in the development of therapeutic strategies, especially in the context of energy metabolism. PMID- 29720729 TI - Electrophysiological dynamics of Chinese phonology during visual word recognition in Chinese-English bilinguals. AB - Silent word reading leads to the activation of orthographic (spelling), semantic (meaning), as well as phonological (sound) information. For bilinguals, native language information can also be activated automatically when they read words in their second language. For example, when Chinese-English bilinguals read words in their second language (English), the phonology of the Chinese translations is automatically activated. Chinese phonology, however, consists of consonants and vowels (segmental) and tonal information. To what extent these two aspects of Chinese phonology are activated is yet unclear. Here, we used behavioural measures, event-related potentials and oscillatory EEG to investigate Chinese segmental and tonal activation during word recognition. Evidence of Chinese segmental activation was found when bilinguals read English words (faster responses, reduced N400, gamma-band power reduction) and when they read Chinese words (increased LPC, gamma-band power reduction). In contrast, evidence for Chinese tonal activation was only found when bilinguals read Chinese words (gamma band power increase). Together, our converging behavioural and electrophysiological evidence indicates that Chinese segmental information is activated during English word reading, whereas both segmental and tonal information are activated during Chinese word reading. Importantly, gamma-band oscillations are modulated differently by tonal and segmental activation, suggesting independent processing of Chinese tones and segments. PMID- 29720730 TI - A proteomic analysis of an in vitro knock-out of miR-200c. AB - Loss of miR-200c is correlated to advanced cancer-subtypes due to increased EMT and decreased treatment efficacy by chemotherapeutics. As miRNAs regulate a multitude of targets, the analysis of differentially expressed proteins upon a genomic knock-out (KO) is of interest. In this study, we generated a TALENs KO of miR-200c in MCF7 breast cancer cells, excluded its compensation by family-members and evaluated the impact on the proteome by analyzing three individual KO-clones. We identified 26 key proteins and a variety of enrichments in metabolic and cytoskeletal pathways. In six of these targets (AGR2, FLNA/B, ALDH7A1, SCIN, GSTM3) the differential expression was additionally detected at mRNA level. Together, these alterations in protein abundance accounted for the observed biological phenotypes, i.e. increased migration and chemoresistance and altered metabolism, found in the miR-200c-KO clones. These findings provide novel insights into miR-200c and pave the way for further studies. PMID- 29720731 TI - Front-line therapies for elderly patients with transplant-ineligible multiple myeloma and high-risk cytogenetics in the era of novel agents. AB - In multiple myeloma, certain cytogenetic abnormalities, such as t(4;14), t(14;16), and del(17p), are considered high risk and are associated with worse prognosis. Patients with these high-risk cytogenetic abnormalities, as well as those who are elderly and transplant ineligible, have not experienced the same degree of improved survival outcomes that other patients have seen with recent advances in the treatment of multiple myeloma. To date, no treatment regimen has demonstrated sustained and consistent survival benefits in elderly, transplant ineligible patients with high-risk cytogenetic abnormalities and newly diagnosed multiple myeloma. Thus, there is an unmet need to identify effective treatment options for these patients and achieve outcomes parity with standard-risk patients. In this review, we assessed clinical trials of both doublet and triplet regimens for newly diagnosed multiple myeloma that included elderly, transplant ineligible patients with high-risk cytogenetic abnormalities and that provided outcomes data stratified by cytogenetic risk status. We concluded that regimens containing an IMiD agent as the foundation of therapy, combined with agents that have synergistic mechanisms of action-including novel therapies-may in future investigations help overcome the poor prognosis of high-risk cytogenetic abnormalities in this vulnerable patient population. PMID- 29720732 TI - FGFR1 fusion kinase regulation of MYC expression drives development of stem cell leukemia/lymphoma syndrome. AB - Oncogenic transformation of hematopoietic stem cells by chimeric fusion kinases causing constitutive activation of FGFR1 leads to a stem cell leukemia/lymphoma (SCLL) syndrome, accompanied by widespread dysregulation of gene activity. We now show that FGFR1 activation is associated with upregulation of MYC and pharmacological suppression of FGFR1 activation leads to downregulation of MYC and suppression of MYC target genes. Luciferase reporter assays demonstrate that FGFR1 can directly regulate MYC expression and this effect is enhanced in the presence of chimeric FGFR1 kinases. In SCLL cells, a truncated form of FGFR1 is generated by granzyme B cleavage of the chimeric kinases, producing a nucleus restricted derivative that can bind MYC regulatory regions. Mutation of the granzyme B cleavage site prevents relocation to the nucleus but does not suppress MYC activation, suggesting additional mechanisms of MYC activation in the presence of cytoplasm-restricted chimeric kinases. We show that one of these mechanisms involves activating cytoplasmic STAT5, which upregulates MYC independent of the truncated FGFR1 kinase. Targeting MYC function using shRNA knockdown and 10054-F8 in SCLL cells leads to inhibition of cell proliferation and synergizes with the BGJ398 FGFR1 inhibitor, suggesting a combination therapy that could be used in the treatment of SCLL. PMID- 29720734 TI - Phase 1/2 trial of GCLAM with dose-escalated mitoxantrone for newly diagnosed AML or other high-grade myeloid neoplasms. AB - Outcomes with "7 + 3" are often unsatisfactory in acute myeloid leukemia (AML). Trials demonstrating improved outcomes with high-dose cytarabine, addition of cladribine, or escalated anthracycline doses prompted a phase 1/2 study (NCT02044796) of G-CSF, cladribine, high-dose cytarabine, and dose-escalated mitoxantrone (GCLAM) in adults with newly-diagnosed AML or other high-grade myeloid neoplasms. One hundred and twenty-one patients, median age 60 (range 21 81) years, were enrolled. In phase 1, cohorts of 6-12 patients were assigned to 12-18 mg/m2/day of mitoxantrone as part of GCLAM. Because all dose levels were well-tolerated, mitoxantrone at 18 mg/m2 was declared the recommended phase 2 dose (RP2D). 74/94 (79%) patients treated at the RP2D achieved a complete remission (CR; 67/74 without measureable residual disease [MRD]) for an overall MRDneg CR rate of 71% (primary phase 2 endpoint). Seven patients achieved a CR with incomplete blood count recovery (CRi; 7%, 5 MRDneg) for a CR/CRi rate of 81/94 (86%). Four-week mortality was 2%. After adjustment, the MRDneg CR and CR/CRi rates compared favorably to 100 matched controls treated with 7 + 3 at our center and 245 matched patients treated with 7 + 3 on a cooperative group trial. Our data indicate GCLAM with mitoxantrone at 18 mg/m2/day is safe and induces high-quality remissions in adults with newly-diagnosed AML. PMID- 29720733 TI - Adding dasatinib to intensive treatment in core-binding factor acute myeloid leukemia-results of the AMLSG 11-08 trial. AB - In this phase Ib/IIa study (ClinicalTrials.gov Identifier: NCT00850382) of the German-Austrian AML Study Group (AMLSG) the multikinase inhibitor dasatinib was added to intensive induction and consolidation chemotherapy and administered as single agent for 1-year maintenance in first-line treatment of adult patients with core-binding factor (CBF) acute myeloid leukemia (AML). The primary combined end point in this study was safety and feasibility, and included the rates of early (ED) and hypoplastic (HD) deaths, pleural/pericardial effusion 3 degrees /4 degrees and liver toxicity 3 degrees /4 degrees , and the rate of refractory disease. Secondary end points were cumulative incidence of relapse (CIR) and death in complete remission (CID), and overall survival (OS). Eighty-nine pts [median age 49.5 years, range: 19-73 years; t(8;21), n = 37; inv (16), n = 52] were included. No unexpected excess in toxicity was observed. The rates of ED/HD and CR/CRi were 4.5% (4/89) and 94% (84/89), respectively. The 4-year estimated CIR, CID, and OS were 33.1% [95%-CI (confidence interval), 22.7-43.4%], 6.0% (95% CI, 0.9-11.2%), and 74.7% (95% CI, 66.1-84.5%), respectively. On the basis of the acceptable toxicity profile and favorable outcome in the AMLSG 11-08 trial, a confirmatory randomized phase III trial with dasatinib in adults with CBF-AML is ongoing (ClinicalTrials.gov Identifier: NCT02013648). PMID- 29720736 TI - Seasonal dynamics of typhoid and paratyphoid fever. AB - Typhoid and paratyphoid fever may follow a seasonal pattern, but this pattern is not well characterized. Moreover, the environmental drivers that influence seasonal dynamics are not fully understood, although increasing evidence suggests that rainfall and temperature may play an important role. We compiled a database of typhoid, paratyphoid, or enteric fever and their potential environmental drivers. We assessed the seasonal dynamics by region and latitude, quantifying the mean timing of peak prevalence and seasonal variability. Moreover, we investigated the potential drivers of the seasonal dynamics and compared the seasonal dynamics for typhoid and paratyphoid fever. We observed a distinct seasonal pattern for enteric and typhoid fever by latitude, with seasonal variability more pronounced further from the equator. We also found evidence of a positive association between preceding rainfall and enteric fever among settings 35 degrees -11 degrees N and a more consistent positive association between temperature and enteric fever incidence across most regions of the world. In conclusion, we identified varying seasonal dynamics for enteric or typhoid fever in association with environmental factors. The underlying mechanisms that drive the seasonality of enteric fever are likely dependent on the local context and should be taken into account in future control efforts. PMID- 29720735 TI - Prevention and management of adverse events of novel agents in multiple myeloma: a consensus of the European Myeloma Network. AB - During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved the treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drug classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events. PMID- 29720737 TI - Parameter Estimation for Gravitational-wave Bursts with the BayesWave Pipeline. AB - We provide a comprehensive multi-aspect study of the performance of a pipeline used by the LIGO-Virgo Collaboration for estimating parameters of gravitational wave bursts. We add simulated signals with four different morphologies (sine Gaussians (SGs), Gaussians, white-noise bursts, and binary black hole signals) to simulated noise samples representing noise of the two Advanced LIGO detectors during their first observing run. We recover them with the BayesWave (BW) pipeline to study its accuracy in sky localization, waveform reconstruction, and estimation of model-independent waveform parameters. BW localizes sources with a level of accuracy comparable for all four morphologies, with the median separation of actual and estimated sky locations ranging from 25 degrees .1 to 30 degrees .3. This is a reasonable accuracy in the two-detector case, and is comparable to accuracies of other localization methods studied previously. As BW reconstructs generic transient signals with SG wavelets, it is unsurprising that BW performs best in reconstructing SG and Gaussian waveforms. The BW accuracy in waveform reconstruction increases steeply with the network signal-to-noise ratio (S/Nnet), reaching a 85% and 95% match between the reconstructed and actual waveform below S/Nnet ~ 20 and S/Nnet ~ 50, respectively, for all morphologies. The BW accuracy in estimating central moments of waveforms is only limited by statistical errors in the frequency domain, and is also affected by systematic errors in the time domain as BW cannot reconstruct low-amplitude parts of signals that are overwhelmed by noise. The figures of merit we introduce can be used in future characterizations of parameter estimation pipelines. PMID- 29720738 TI - Business model configuration and dynamics for technology commercialization in mature markets. AB - Purpose: The food industry is a well-established and complex industry. New entrants attempting to penetrate it via the commercialization of a new technological innovation could face high uncertainty and constraints. The capability to innovate through collaboration and to identify suitable strategies and innovative business models (BMs) can be particularly important for bringing a technological innovation to this market. However, although the potential for these capabilities has been advocated, we still lack a complete understanding of how new ventures could support the technology commercialization process via the development of BMs. The paper aims to discuss these issues. Design/methodology/approach: To address this gap, this paper builds a conceptual framework that knits together the different bodies of extant literature (i.e. entrepreneurship, strategy and innovation) to analyze the BM innovation processes associated with the exploitation of emerging technologies; determines the suitability of the framework using data from the exploratory case study of IT IS 3D - a firm which has started to exploit 3D printing in the food industry; and improves the initial conceptual framework with the findings that emerged in the case study. Findings: From this analysis it emerged that: companies could use more than one BM at a time; hence, BM innovation processes could co-exist and be run in parallel; the facing of high uncertainty might lead firms to choose a closed and/or a familiar BM, while explorative strategies could be pursued with open BMs; significant changes in strategies during the technology commercialization process are not necessarily reflected in a radical change in the BM; and firms could deliberately adopt interim strategies and BMs as means to identify the more suitable ones to reach the market. Originality/value: This case study illustrates how firms could innovate the processes of their BM development to face the uncertainties linked with the entry into a mature and highly conservative industry (food). PMID- 29720739 TI - The impact of food preservation on food waste. AB - Purpose: The purpose of this paper is to demonstrate the relationship between food preservation and reducing consumer waste is of value in developing sustainable meal options. The research reports insights into Austrian marketplace for frozen and fresh foods that have been obtained from a consumer survey. Design/methodology/approach: The consumer survey methodologies indicate how preservation can change meal planning and lower food waste across frozen and fresh and ambient food purchases using freezing preservation methods. Findings: The results show food waste can be reduced by six-fold when frozen foods are compared with fresh foods. Research limitations/implications: This study highlights the requirement for a greater understanding of the probability that specific foods will be wasted with respect to the frequency of purchase. This is a limitation of the current study that has been investigated by other researchers. Practical implications: This research has enabled the identification of different food waste amounts for different food product categories. The data presented could be used to guide food product development so that less consumer waste is produced. Social implications: The research suggests a decision matrix approach can be used to can guide new product development and a model of this matrix is presented so that it may provide fit-for-purpose food preservation options for consumers. Originality/value: This paper will continue to highlight the overlooked value of food preservation during processing and manufacturing of foods and their preparation in households. PMID- 29720740 TI - Measuring and explaining multi-directional inefficiency in the Malaysian dairy industry. AB - Purpose: The purpose of this paper is to measure the technical inefficiency of dairy farms and subsequently investigate the factors affecting technical inefficiency in the Malaysian dairy industry. Design/methodology/approach: This study uses multi-directional efficiency analysis to measure the technical inefficiency scores on a sample of 200 farm observations and single-bootstrap truncated regression model to define factors affecting technical inefficiency. Findings: Managerial and program inefficiency scores are presented for intensive and semi-intensive production systems. The results reveal marked differences in the inefficiency scores across inputs and between production systems. Practical implications: Intensive systems generally have lowest managerial and program inefficiency scores in the Malaysian dairy farming sector. Policy makers could use this information to advise dairy farmers to convert their farming system to the intensive system. Social implications: The results suggest that the Malaysian Government should redefine its policy for providing farm finance and should target young farmers when designing training and extension programs in order to improve the performance of the dairy sector. Originality/value: The existing literature on Southeast Asian dairy farming has neither focused on investigating input-specific efficiency nor on comparing managerial and program efficiency. This paper aims to fill this gap. PMID- 29720741 TI - Shopping list development and use of advertisements' pre-store food-buying practices within different socio-economic status areas in South Africa. AB - Purpose: The purpose of this paper is to determine whether there is a difference in the development of shopping lists and use of advertisements as pre-store food buying practices in terms of planned shopping by South African consumers who dwell in different socio-economic status (SES) areas. The paper also considers the influence of shopper and socio-demographic characteristics on pre-store food buying practices in a developing country. Design/methodology/approach: A self administered questionnaire was used to survey 1 200 consumers in retail stores in low, middle and high SES areas in South Africa. A generalised linear model was employed for the statistical analysis of pre-store food-buying practices within the SES area groups in a developing country. Findings: South African consumers that reside in high SES area displayed the largest of shopping list development, while consumers who dwell in low SES areas showed the highest incidence of advertisement usage. Several shopper and socio-demographic characteristics were also found to have an influence on pre-store food-buying practices in different SES areas in South Africa. Research limitations/implications: A qualitative approach would offer a deeper understanding of consumers' pre-store food shopping predispositions as opposed to the quantitative approach, which was adopted for this study. A longitudinal design would also provide a more extensive representation of pre-store food shopping practices over a longer time frame than cross-sectional research. The survey was conducted on Saturdays, whereas consumers who shop during the week may have different shopping and socio demographic characteristics. Practical implications: Astute food brands, marketers and grocery stores could use the findings of this study to assist with their marketing efforts that they direct at consumers in different SES areas in South Africa and other developing countries. Social implications: The findings of this study may assist consumers in developing countries, especially those who reside in low SES areas, with food-buying strategies to reduce food costs, make wiser purchase decisions and reduce shopping. Originality/value: No study (to the best of the researchers' knowledge) has considered shopping list development and use of advertisements' pre-store food-buying practices in different SES areas in a developing country. Furthermore, there is a dearth of research analysing shopper and socio-demographic characteristics in relation to pre-store food buying practices among different SES areas in developing and developed countries. PMID- 29720742 TI - Self-crafting vegetable snacks: testing the IKEA-effect in children. AB - Purpose: The purpose of this paper is to test whether the IKEA-effect (Norton et al., 2012) - better liking for self-crafted products than for identical products crafted by others - can be exploited to increase liking and consumption of vegetable snacks in children. Design/methodology/approach: A between-subjects experiment was conducted at an after school care facility. In total, 86 children aged four to six either crafted a peacock with vegetables or with non-food objects following an example. After the task, children ate snack vegetables ad libitum, and rated their liking for the vegetables and pride in crafting the peacock. Findings: No significant main effect of the vegetable snack creation on consumption and liking was observed. Also, perceived pride did not mediate the effect of self-crafting vegetable snacks on consumption of and liking for vegetables. Research limitations/implications: Vegetable consumption did not differ between children who were either simply exposed to vegetable snacks while crafting or those who were crafting the vegetable snacks themselves. The equal consumption might suggest that this is caused by simple exposure, but more research is needed comparing self-crafting and exposure to a condition where there is no initial exposure to vegetables. Originality/value: Although the IKEA effect has been demonstrated in adults, this is one of the first studies evaluating the IKEA-effect in children and as a means to increase liking for a generally disliked product in this target group, i.e. vegetables. The IKEA-effect could not be replicated under these more stringent conditions, where the experimental set-up enabled disentangling exposure and crafting effects. PMID- 29720745 TI - The Influence of Maternal Obesity on Pregnancy Complications and Neonatal Outcomes in Diabetic and Nondiabetic Women. AB - Introduction: This study aimed to investigate the influence of obesity on pregnancy complications and neonatal outcomes in diabetic and nondiabetic women. Materials and Methods: This retrospective case control study was conducted on 1193 pregnant women and their neonates at a tertiary level maternity hospital between March 2007 and 2011. The pregnant women were classified into 2 groups according to the presence of diabetes mellitus. Six hundred and seven patients with gestational diabetes or pregestational diabetes formed the diabetic group (study group) and 586 patients were in the nondiabetic group (control group). Demographic characteristics, body mass index, gestational weight gain, obstetric history, smoking status, type of delivery, gestational ages, pregnancy complications, neonatal outcomes were recorded for each patient. Multivariable logistic regression analysis was performed to evaluate the effect of obesity and diabetes on the pregnancy complications and neonatal outcomes. Results: The mean age and pre-pregnancy body mass indices of women with diabetes mellitus were significantly higher than the control group's (p < 0.001). Gestational weight gain and number of smokers were similar among the groups. Multiparity and obesity were more prevalent in the diabetic group compared to controls (both p < 0.001). Although gestational age at birth was earlier in the diabetic group, birth weights were higher in this group than in the control group (both p < 0.001). Cesarean delivery rates, the incidence of macrosomia, and neonatal intensive care unit admission rates were significantly higher in the diabetes group both with normal and increased body mass index (all p < 0.001). However, adverse pregnancy outcomes were comparable between the groups (p = 0.279). Multivariable logistic regression analysis showed that obesity is a significant risk factor for pregnancy complications (OR = 1.772 [95% CI, 1.283 - 2.449], p = 0.001) but not for adverse neonatal outcomes (OR = 1.068 [95% CI, 0.683 - 1.669], p = 0.773). Conclusion: While obesity increases risk of developing a pregnancy complication, diabetes worsens neonatal outcomes. PMID- 29720744 TI - Peripartum Haemorrhage, Diagnosis and Therapy. Guideline of the DGGG, OEGGG and SGGG (S2k Level, AWMF Registry No. 015/063, March 2016). AB - Purpose: This is an official interdisciplinary guideline, published and coordinated by the German Society of Gynaecology and Obstetrics (DGGG), the Austrian Society of Gynaecology and Obstetrics (OEGGG) and the Swiss Society of Gynaecology and Obstetrics (SGGG). The guideline was developed for use in German speaking countries and is backed by the German Society of Anaesthesiology and Intensive Medicine (DGAI), the Society of Thrombosis and Haemostasis Research (GTH) and the German Association of Midwives. The aim is to provide a consensus based overview of the diagnosis and management of peripartum bleeding obtained from an evaluation of the relevant literature. Methods: This S2k guideline was developed from the structured consensus of representative members of the various professional associations and professions commissioned by the Guideline Commission of the DGGG. Recommendations: The guideline encompasses recommendations on definitions, risk stratification, prevention and management. PMID- 29720743 TI - Recurrent Miscarriage: Diagnostic and Therapeutic Procedures. Guideline of the DGGG, OEGGG and SGGG (S2k-Level, AWMF Registry Number 015/050). AB - Purpose: Official guideline of the German Society of Gynecology and Obstetrics (DGGG), the Austrian Society of Gynecology and Obstetrics (OGGG) and the Swiss Society of Gynecology and Obstetrics (SGGG). The aim of this guideline was to standardize the diagnosis and treatment of couples with recurrent miscarriage (RM). Recommendations were based on the current literature and the views of the involved committee members. Methods: Based on the current literature, the committee members developed the statements and recommendations of this guideline in a formalized process which included DELPHI rounds and a formal consensus meeting. Recommendations: Recommendations for the diagnosis and treatment of patients with RM were compiled based on the international literature. Specific established risk factors such as chromosomal, anatomical, endocrine, hemostatic, psychological, infectious and immunological disorders were taken into consideration. PMID- 29720746 TI - Comparison of Nerve Fiber Density between Patients with Uterine Leiomyoma with and without Pain: a Prospective Clinical Study. AB - Introduction: We aimed to compare the presence and the amount of nerve fibers in endometrial, myometrial and leiomyoma tissues using protein gene product 9.5 (PGP 9.5) and neurofilament (NF) immunohistochemical staining in uterine leiomyoma patients with and without pain complaint. Methods: Patients undergoing hysterectomy for uterine leiomyoma were prospectively enrolled in the study. Twenty-five uterine leiomyoma patients without pelvic pain complaint (visual analog scale (VAS) < 5) were assigned to Group 1; 23 uterine leiomyoma patients with pelvic pain complaint (VAS >= 5) were assigned to Group 2. Endometrial, myometrial and leiomyoma tissues obtained from hysterectomy specimens were stained immunohistochemically using PGP 9.5 and NF dyes. The presence and density of nerve fibers were compared between the two groups. Results: None of the endometrial samples in either groups stained with PGP 9.5 and NF dyes. There was no statistically significant difference in the number of nerve fibers in myometrial and leiomyoma tissues between the two groups with either of the stains (PGP 9.5: p = 0.39 and p = 0.29; NF: p = 0.83 and p = 0.65, respectively). There was agreement between PGP 9.5 and NF immunohistochemical staining for nerve fiber detection in myometrial and leiomyoma tissues (p < 0.05/kappa = 0.622 and p < 0.05/kappa = 0.388, respectively). Conclusion: This study demonstrates that the quantity and density of nerve fibers in myometrial and leiomyoma tissue in patients with pain were similar to that in patients without pain. PMID- 29720748 TI - Target controlled infusion total intravenous anaesthesia and Indian patients: Do we need our own data? PMID- 29720747 TI - Wnt Signaling Pathway in Uterus of Normal and Seminal Vesicle Excised Mated Mice during Pre-implantation Window. AB - Introduction: The importance of seminal vesicle secretion and uterine Wnt signaling for uterus preparation and embryo implantation has been described. Materials and Methods: In this study, we evaluated the gene expression of Wnt ligands (Wnt4 and Wnt5a) and their corresponding receptors (Fzd2 and Fzd6) using qRT-PCR and active beta-catenin protein levels using western blotting in the uterine tissue of female mice mated with intact and seminal vesicle-excised (SVX) males during the pre-implantation window. We evaluated the association between these factors and implantation rates and embryo spacing. Results: mRNA expression of Wnt4 and Wnt5a and active beta-catenin protein levels decreased from Day 1 to Day 4, but reached a peak on the fifth day of pregnancy. Fzd2 also reached its highest level on Day 5. Fzd6 expression showed a decreasing trend towards the day of implantation. Lack of seminal vesicle secretion decreased Wnt4 and Wnt5a expression on Days 1 and 5 and beta-catenin levels on Day 5. There were almost no significant differences in expression levels of the Fzd2 and Fzd6 receptors between groups. There were positive and negative correlations, respectively, between implantation rates and embryo spacing and Wnt4, Wnt5a and active beta catenin in the control group, but such correlations were not observed in the SVX mated mice. Conclusions: Significant changes occurred in the expression of several Wnt signaling members and there was a significant association between Wnt signaling and embryo implantation. Seminal vesicle secretion affects Wnt signaling in mice and consequently also affects murine embryo implantation. PMID- 29720749 TI - Use of supraglottic airway devices in paediatric patients in the Indian context - some we know, some we need to know and march ahead. PMID- 29720751 TI - Effect site concentration of propofol at induction and recovery of anaesthesia - A correlative dose-response study. AB - Background and Aims: Sound knowledge about effect site concentration (Ce) of propofol aids in smooth induction, maintenance and early recovery. We studied the correlation between Ce of propofol at loss of response to verbal command and recovery concentration using target-controlled infusion (TCI) in Indian patients who underwent spine surgeries. Methods: Ninety patients undergoing spine surgeries were included. Total intravenous anaesthesia (TIVA) technique with TCI for propofol using modified Marsh model was used. Entropy and neuromuscular transmission were used. Ce at induction and recovery and the corresponding state entropy (SE) values were noted. Results: The mean propofol Ce and SE at induction were 2.34 +/- 0.24 MUg/ml and 52 +/- 8, respectively. The mean propofol Ce and SE at recovery were 1.02 +/- 0.22 MUg/ml and 86.80 +/- 2.86, respectively. The Ce at recovery was approximately 50% of the induction value. The correlation coefficient 'r' between Ce at induction and recovery was 0.56. The mean infusion dose of propofol during the maintenance period was 81 +/- 14.33 MUg/kg/min. The average induction dose of propofol was 1.17 +/- 0.2 mg/kg. Conclusion: There is a positive correlation between Ce at induction and recovery. Ce for recovery may have to be set at a lower level during TCI-TIVA and appropriately infusion should be stopped for early recovery. The induction and maintenance doses of propofol are lower than the recommended doses. Data emphasise the need for pharmacokinetic model based on our population characteristics. PMID- 29720750 TI - Newer regional analgesia interventions (fascial plane blocks) for breast surgeries: Review of literature. AB - Surgical resection of the primary tumour with axillary dissection is one of the main modalities of breast cancer treatment. Regional blocks have been considered as one of the modalities for effective perioperative pain control. With the advent of ultrasound, newer interventions such as fascial plane blocks have been reported for perioperative analgesia in breast surgeries. Our aim is to review the literature for fascial plane blocks for analgesia in breast surgeries. The research question for initiating the review was 'What are the reported newer regional anaesthesia techniques (fascial plane blocks) for female patients undergoing breast surgery and their analgesic efficacy?.' The participants, intervention, comparisons, outcomes and study design were followed. Due to the paucity of similar studies and heterogeneity, the assessment of bias, systematic review or pooled analysis/meta-analysis was not feasible. Of the 989 manuscripts, the present review included 28 manuscripts inclusive of all types of published manuscripts. 15 manuscripts directly related to the administration of fascial plane blocks for breast surgery across all type of study designs and cases were reviewed for the utility of fascial plane blocks in breast surgeries. Interfascial blocks score over regional anaesthetic techniques such as paravertebral block as they have no risk of sympathetic blockade, intrathecal or epidural spread which may lead to haemodynamic instability and prolonged hospital stay. This review observed that no block effectively covers the whole of breast and axilla, thus a combination of blocks should be used depending on the site of incision and extent of surgical resection. PMID- 29720752 TI - Current practice patterns of supraglottic airway device usage in paediatric patients amongst anaesthesiologists: A nationwide survey. AB - Background and Aims: Supraglottic airway devices (SGADs) are increasingly being used for airway management in paediatric patients undergoing general anaesthesia. This survey was designed to assess the nationwide practice patterns of SGAD usage in paediatric patients. Methods: A questionnaire of 28 questions was circulated amongst 16,532 members of the Indian Society of Anaesthesiologists through online survey engine Google Forms(r) and served manually to 500 delegates attending the Asian Society of Paediatric Anaesthesiologists conference 2017. Percentage, mean and standard deviation were calculated using Microsoft Excel 2016 (Redmond, WA, USA). Results: Four hundred and five (2.3%) valid responses were obtained. The most commonly used device was i-gel(c) (60.74%). Three hundred and four (75.06%) respondents had access to second-generation SGADs. Second-generation devices (60.74%) were more commonly used than first-generation devices (39.26%). Anaesthesiologists utilised SGADs in various challenging scenarios such as in the difficult airway (53.33%), remote locations (55.47%), ophthalmologic (38.77%) and long-duration surgeries (17.53%). Sixty per cent respondents did not use SGADs in laparoscopic surgery. Disposable SGADs were reused by 77.28% respondents. Oropharyngeal seal and intracuff pressures were not measured by 86.91% and 56.92% respondents, respectively. Difficulty in size selection (84.19%), securing position (82.22%) and maintaining unobstructed ventilation (78.76%) were common problems encountered while using SGADs. Conclusion: Although there is a widespread use of second-generation SGADs in Indian paediatric anaesthesia, safe practices such as using capnography, measurement of oropharyngeal seal pressure, cuff pressure and appropriate disinfection are lacking. PMID- 29720753 TI - Comparison of landmark versus pre-procedural ultrasonography-assisted midline approach for identification of subarachnoid space in elective caesarean section: A randomised controlled trial. AB - Background and Aims: Identification of subarachnoid space in pregnant patients can pose a great challenge to anaesthesiologists. This study was designed to compare conventional landmark technique with pre-procedural ultrasonography assisted midline approach for identification of the subarachnoid space in elective caesarean section. Methods: After institute ethics committee approval and written informed consent, 100 parturients scheduled for elective caesarean section under spinal anaesthesia were included in this prospective randomised control trial and divided into Group L (n = 50) (landmark technique) and Group U (n = 50) (ultrasound-guided technique). Parameters such as time taken for the identification of the interspace, distance between skin and dura mater, number of insertion attempts (the primary outcome), number of passes and time taken were recorded in both the groups. Statistical analysis was done using SPSS software 16. Results: Demographic profiles of both groups were comparable. The number of attempts for needle insertion (1.04 +/- 0.19 vs. 1.97 +/- 0.77), number of passes in the same interspinous space (1.26 +/- 0.44 vs. 1.90 +/- 0.51) and the total time for successful lumbar puncture (31.90 +/- 6.30 vs. 51.80 +/- 12.28 s) were significantly less in Group U as compared to Group L, but the time of identification of interspinous space was significantly more in Group U (56.70 +/- 13.08 s) as compared to Group L (47.10 +/- 10.45 s). Conclusion: Pre-procedural ultrasound is a useful tool for successful lumbar puncture in parturients as it reduces the number of attempts with fewer side effects as compared to conventional landmark technique. PMID- 29720754 TI - Effects of adding dexamethasone or ketamine to bupivacaine for ultrasound-guided thoracic paravertebral block in patients undergoing modified radical mastectomy: A prospective randomized controlled study. AB - Background and Aims: Pain after modified radical mastectomy (MRM) has been successfully managed with thoracic paravertebral block (TPVB). The purpose of this study was to evaluate the effect of adding dexamethasone or ketamine as adjuncts to bupivacaine in TPVB on the quality of postoperative analgesia in participants undergoing MRM. Methods: This prospective randomised controlled study enrolled ninety adult females scheduled for MRM. Patients were randomised into three groups (30 each) to receive ultrasound-guided TPVB before induction of general anaesthesia. Group B received bupivacaine 0.5% + 1 ml normal saline, Group D received bupivacaine 0.5% + 1 ml dexamethasone (4 mg) and Group K received bupivacaine 0.5% + 1 ml ketamine (50 mg). Patients were observed for 24 h postoperatively to record time to first analgesic demand as a primary outcome, pain scores, total rescue morphine consumption and incidence of complications. Results: Group K had significantly longer time to first analgesic demand than group D and control group (18.0 +/- 6.0, 10.3 +/- 4.5 and 5.3 +/- 3.1 hours respectively; P = 0.0001). VAS scores were significantly lower in group D and group K compared to control group at 6h and 12 h postoperative (p 0.0001 and 0.0001 respectively) while group K had lower VAS at 18 hours compared to other two groups (P = 0.0001). Control group showed the highest mean 24 h opioid consumption (8.9 +/- 7.9 mg) compared to group D and group K (3.60 +/- 6.92 and 2.63 +/- 5.24 mg, P = 0.008,0.001 respectively). No serious adverse events were observed. Conclusion: Ketamine 50 mg or dexamethasone 4 mg added to bupivacaine 0.5% in TPVB for MRM prolonged the time to first analgesic request with no serious side effects. PMID- 29720755 TI - A comparative study to evaluate ultrasound-guided transversus abdominis plane block versus ilioinguinal iliohypogastric nerve block for post-operative analgesia in adult patients undergoing inguinal hernia repair. AB - Background and Aims: Both transversus abdominis plane (TAP) block and combined ilioinguinal-iliohypogastric (IIN/IHN) blocks are used routinely under ultrasound (USG) guidance for postoperative pain relief in patients undergoing inguinal hernia surgery. This study compares USG guided TAP Vs IIN/IHN block for post operative analgesic efficacy in adults undergoing inguinal hernia surgery. Methods: Sixty adults aged 18 to 60 with American Society of Anesthesiologsts' grade I or II were included. After general anaesthesia, patients in Group I received USG guided unilateral TAP block using 0.75% ropivacaine 3 mg/kg (maximum 25 mL) and those in Group II received IIN/IHN block using 10 mL 0.75% ropivacaine. Postoperative rescue analgesia was with tramadol (intravenous) IV +/ diclofenac IV in the first 4 h followed by oral diclofenac subsequently. Total analgesic consumption in the first 24 h was the primary objective, intraoperative haemodynamics, number of attempts and time required for performing the block as well as the postoperative pain scores were also evaluated. Results: Time to first analgesic request was 319.8 +/- 115.2 min in Group I and 408 +/- 116.4 min in Group II (P = 0.005). Seven patients (23.33%) in Group I and two (6.67%) in Group II required tramadol in first four hours. No patient in either groups received diclofenac IV. The average dose of tablet diclofenac was 200 +/- 35.96 mg in Group I and 172.5 +/- 34.96 mg in Group II (P = 0. 004). Conclusion: USG guided IIN/IHN block reduces the postoperative analgesic requirement compared to USG guided TAP block. PMID- 29720756 TI - Anaesthesia for laparoscopic nephrectomy: Does end-tidal carbon dioxide measurement correlate with arterial carbon dioxide measurement? AB - Background and Aims: Not many studies have explored the correlation between arterial carbon dioxide tension (PaCO2) and end-tidal carbon dioxide tension (ETCO2) in surgeries requiring pneumoperitoneum of more than 1 hour duration with the patient in non-supine position. The aim of our study was to evaluate the correlation of ETCO2 with PaCO2 in patients undergoing laparoscopic nephrectomy under general anaesthesia. Methods: A descriptive study was performed in thirty patients undergoing laparoscopic nephrectomy from September 2014 to August 2015. The haemodynamic parameters, minute ventilation, PaCO2 and ETCO2 measured at three predetermined points during the procedure were analysed. Correlation was checked using Pearson's Correlation Coefficient Test. P <0.05 was considered statistically significant. Results: Statistical analysis of the values showed a positive correlation between ETCO2 and PaCO2 (P < 0.05). Following carbon dioxide insufflation, both ETCO2 and PaCO2 increased by 5.4 and 6.63 mmHg, respectively, at the end of the 1st hour. The PaCO2-ETCO2 gradient was found to increase during the 1st hour following insufflation (4.07 +/- 2.05 mmHg); it returned to the pre insufflation values in another hour (2.93 +/- 1.43 mmHg). Conclusion: Continuous ETCO2 monitoring is a reliable indicator of the trend in arterial CO2 fluctuations in the American Society of Anesthesiologists Grades 1 and 2 patients undergoing laparoscopic nephrectomy under general anaesthesia. PMID- 29720757 TI - Sono-anatomical analysis of right internal jugular vein and carotid artery at different levels of positive end-expiratory pressure in anaesthetised paralysed patients. AB - Background and Aims: Increasing the cross-sectional area (CSA) of the internal jugular vein (IJV) improves the success rate of cannulation and decreases complications. Application of positive end-expiratory pressure (PEEP) may increase the CSA of IJV beyond that achieved in Trendelenburg position. However, the optimum PEEP to achieve maximal increase in CSA of IJV and the effect of PEEP on IJV and CA relationship is not known. Methods: In this prospective, blinded, randomised controlled study, 120 anesthetised paralysed patients of the American Society of Anesthesiologists physical Status I-II were placed in 20 degrees Trendelenburg position. Patients were randomised into four groups as follows: PEEP of 0, 5, 10 and 15 cmH2O. CSA, anteroposterior (AP) diameter and transverse diameter (Td) of IJV and overlapping of IJV with CA were assessed using two dimensional ultrasound. Statistical analysis was performed in SPSS version 21.0 software using Chi-square/Fisher's exact test (categorical data) and analysis of variance (continuous data) tests and P < 0.05 was considered statistically significant. Results: There was significant increase in AP diameter, CSA and Td with the application of PEEP 10-15 cmH2O. Increase in CSA up to 25% with PEEP 10 and 44% with PEEP 15 was noted. There was a significant decrease in the overlapping of the internal CA with an increase in PEEP. It ranged from 21% at P0 to 17% P15. Conclusion: Application of PEEP 10-15 cmH2O in Trendelenburg position significantly increased CSA and AP diameter of IJV and decreased CA overlap of IJV in anesthetised paralysed patients. PMID- 29720759 TI - Bilateral transmuscular quadratus lumborum block performed in single lateral decubitus position without changing position to the contralateral side. PMID- 29720758 TI - Ultra-modified rapid sequence induction with transnasal humidified rapid insufflation ventilatory exchange: Challenging convention. AB - During positive pressure ventilation, gastric inflation and subsequent pulmonary aspiration can occur. Rapid sequence induction (RSI) technique is an age-old formula to prevent this. We adopted a novel approach of RSI for patients with high risk of aspiration and evaluated it further in patients undergoing laparoscopic surgeries. We believe that, in patients with risk of gastric insufflation and pulmonary aspiration, transnasal humidified rapid-insufflation ventilatory exchange can be useful in facilitating pre- and apnoeic oxygenation till tracheal isolation is achieved. PMID- 29720760 TI - Post-operative seizures after spine surgery: A dilemma. PMID- 29720761 TI - Unusual adverse effect of dexmedetomidine and its management. PMID- 29720762 TI - Tracheostomy over Ambu(r) Aura40TM in cannot intubate situation due to effects of chemoradiation. PMID- 29720763 TI - Should single medial canthus injection be the default option for peribulbar blocks? PMID- 29720764 TI - Safer methods of ophthalmic block. PMID- 29720765 TI - The link between pulmonary hypertension and adverse renal transplant outcome may be renal venous hypertension. PMID- 29720766 TI - Reply to 'The link between pulmonary hypertension and adverse renal transplant outcome may be renal venous hypertension'. PMID- 29720768 TI - The evaluation of alternative method of ferrous ions assessment in pharmaceutical preparations. AB - Abstract: The atomic absorption spectrometry (AAS) method is one of the most accessible procedures for ferrous ions testing in various compositions including pharmaceutical preparations. The aim of the study was to develop and partially validate analytical method which could be an excellent alternative to the routine procedure performed within dissolution studies. Electric conductivity is simple, fast, and hassle-free method. The samples during dissolution process were measured using conductivity probe in entire dissolution assessment protocol. The conductivity results were compared to data obtained from AAS. The dissolution studies were performed according to modified pharmacopoeial standards, in 900 cm3 of purified water as an acceptor medium, at 37 degrees C, until the achievement of an equilibrium state for every tested composition. Validity study of the developed method confirmed acceptable linearity of obtained calibration plots (r2 > 0.9553). Linearity at 100% level was found to be 100.59, 97.49, and 94.82, respectively, for drug compositions A, B, and C. Precision results were 100.45, 95.97, and 95.73, respectively, for A, B, and C, with RSD below 2% between all samples in all above mentioned formulations. The drug composition D hindered the proper validation of the method due to the high variability between samples. The method has acceptable performance features for evaluation of three of four solid drug composition containing ferrous ions. Graphical abstract: PMID- 29720767 TI - Current Perspective on MDMA-Assisted Psychotherapy for Posttraumatic Stress Disorder. AB - The present paper discusses the current literature with regard to substance assisted psychotherapy with Methylenedioxymethamphetamine (MDMA) for posttraumatic stress disorder (PTSD). The aim of the paper is to give a comprehensive overview of the development from MDMA's early application in psychotherapy to its present and future role in the treatment of PTSD. It is further attempted to increase the attention for MDMA's therapeutic potential by providing a thorough depiction of the scientific evidence regarding its theorized mechanism of action and potential harms of its application in the clinical setting (e.g., misattribution of therapeutic gains to medication instead of psychological changes). Empirical support for the use of MDMA-assisted psychotherapy, including the randomized, double-blind, placebo-controlled trails that have been conducted since 2008, is discussed. Thus far, an overall remission rate of 66.2% and low rates of adverse effects have been found in the six phase two trials conducted in clinical settings with 105 blinded subjects with chronic PTSD. The results seem to support MDMA's safe and effective use as an adjunct to psychotherapy. Even though preliminary studies may look promising, more studies of its application in a psychotherapeutic context are needed in order to establish MDMA as a potential adjunct to therapy. PMID- 29720769 TI - The influence of physical division of tablets on the variability of release kinetics of gliclazide. AB - Abstract: Tablets are often used in splitting process when the appropriated, registered dose is not available on the market or patients exhibit swallowing difficulties caused by the size of the tablet. The aim of the work was to assess the impact of physical division of tablets on the kinetics of in vitro gliclazide release from the intact and divided tablets. Gliclazide was released from prolonged release tablets containing 30 or 60 mg of the drug into a phosphate buffer, pH 7.4 and the amount of the drug in acceptor fluid was determined by UV Vis spectrophotometry. The dissolution profiles were fit to zero- and first-order kinetics as well as to the Korsmeyer-Peppas equation. The largest discrepancy in the values of rate constants was obtained in the case of the release of gliclazide from intact and from splitting tablets using zero- and first-order kinetics. The values of the rate constants k0 obtained from the release of the drug from the intact tablets and from fragments with a dose of the drug of 30 mg were (4.2 +/- 0.1) * 10-5 g min-1 and (5.8 +/- 0.1) * 10-5 g min-1, respectively, and k1 were (2.3 +/- 0.1) * 10-3 min-1 and (4.7 +/- 0.6) * 10-3 min-1, respectively. These discrepancies were confirmed by the value of f2 coefficient that was 45.9. The results suggest that physical division of tablets accelerate the release of gliclazide from its prolonged form. Graphical abstract: PMID- 29720770 TI - Application of X-ray powder diffraction and differential scanning calorimetry for identification of counterfeit drugs. AB - Abstract: X-ray analysis confirmed that in all investigated samples, the active API (acetylsalicylic acid and ascorbic acid) was present. The values of the interplanar distance dhkl for the studied samples are in good accordance with those presented in the ICDD database. The intensities of the diffraction lines depend on the content of the component in the tested preparation. Therefore, different intensities of lines for the APIs were observed in the obtained diffraction patterns. Thermal analysis of the studied substances showed that during the thermal analysis, the following phenomena might occur: dehydration and (or) melting, crystalline transformation. Moreover, it was found that the chemical structure of the studied compounds affects the process of their thermal decomposition. The data obtained during these investigations can be useful in quick tests of physicochemical discrepancies and abnormalities between potential components of pharmaceutical preparations. The evidence for the interaction can be obtained by comparing DSC and TG curves of the drug and the excipient, as well as those of their physical mixtures. For this reason, the study of characteristics of thermal decomposition of drugs and excipients is necessary. Based on the above investigations, it may be stated that a combination of two methods: XRPD and DSC can be used to distinguish the original drugs from counterfeit products, e.g., by checking for the presence of the correct API or by a comparison of the drugs fingerprint. Graphical Abstract: PMID- 29720771 TI - Forced Migration and Changing Livelihoods in the Brazilian Amazon. AB - Forced migration due to development projects or environmental change impacts livelihoods, as affected households are faced with new-and often less favorable environmental, social, and economic conditions. This article examines changing livelihood strategies among a population of rural agricultural households displaced by the Belo Monte Dam in the Brazilian Amazon. Using longitudinal data, I find that many households used compensation payments to concentrate income generation efforts on the most lucrative strategies-cacao and cattle production and business or rental income. Poorer households and those that received the least compensation were more likely to continue relying on agricultural wage labor-a less desirable income source associated with not owning land or with persons needing to supplement income with additional work as a day laborer. Results also indicate that the amount of compensation received by most households was sufficient to enable them to make productive investments beyond attaining replacement land and housing. Many households invested in assets such as agricultural infrastructure, cattle, rental houses, or tractors-all of which directly contribute to future income. Displacement compensation, similar to remittances or conditional cash transfers, can therefore act as an important infusion of capital to promote socioeconomic development and poverty reduction. PMID- 29720772 TI - Dimensional Analysis on Forest Fuel Bed Fire Spread. AB - A dimensional analysis was performed to correlate the fuel bed fire rate of spread data previously reported in the literature. Under wind condition, six pertinent dimensionless groups were identified, namely dimensionless fire spread rate, dimensionless fuel particle size, fuel moisture content, dimensionless fuel bed depth or dimensionless fuel loading density, dimensionless wind speed, and angle of inclination of fuel bed. Under no-wind condition, five similar dimensionless groups resulted. Given the uncertainties associated with some of the parameters used to estimate the dimensionless groups, the dimensionless correlations using the resulting dimensionless groups correlate the fire rates of spread reasonably well under wind and no-wind conditions. PMID- 29720773 TI - A physics based multiscale modeling of cavitating flows. AB - Numerical modeling of cavitating bubbly flows is challenging due to the wide range of characteristic lengths of the physics at play: from micrometers (e.g., bubble nuclei radius) to meters (e.g., propeller diameter or sheet cavity length). To address this, we present here a multiscale approach which integrates a Discrete Singularities Model (DSM) for dispersed microbubbles and a two-phase Navier Stokes solver for the bubbly medium, which includes a level set approach to describe large cavities or gaseous pockets. Inter-scale schemes are used to smoothly bridge the two transitioning subgrid DSM bubbles into larger discretized cavities. This approach is demonstrated on several problems including cavitation inception and vapor core formation in a vortex flow, sheet-to-cloud cavitation over a hydrofoil, cavitation behind a blunt body, and cavitation on a propeller. These examples highlight the capabilities of the developed multiscale model in simulating various form of cavitation. PMID- 29720774 TI - A Cold-Pole Enhancement in Mercury's Sodium Exosphere. AB - The Ultraviolet and Visible Spectrometer (UVVS) component of the Mercury Atmospheric and Surface Composition Spectrometer (MASCS) on the MESSENGER spacecraft characterized the local-time distribution of the sodium exosphere over the course of its orbital mission. The observations show that the sodium exosphere is enhanced above Mercury's cold-pole longitudes. Based on previously published sodium exosphere models we infer that these regions act as nightside surface reservoirs, temporary sinks to the exosphere that collect sodium atoms transported anti-sunward. The reservoirs are revealed as exospheric enhancements when they are exposed to sunlight. As in the models the reservoir is depleted as the cold poles rotate from dawn to dusk, but unlike the models the depletion is only partial. The persistence of the reservoir means that it could, over the course of geologically long periods of time, contribute to an increase in the bulk concentration of sodium near the cold-pole longitudes. PMID- 29720775 TI - The implicit power motive predicts decisions in line with perceived instrumentality. AB - Past research suggests that the implicit power motive (i.e., an unconsciously held motivational disposition to derive pleasure from having impact on others) predicts a preference to interact with individuals having submissive-looking faces. The present research extends this finding by testing whether the relation between the implicit power motive and approaching submissiveness depends on instrumentality. In two experiments, participants were assigned to a group that would ostensibly compete with another group. Within this intergroup context, they were asked to select persons as leaders or members for the in-group or the out group. Potential leaders and members were displayed as submissive-looking or dominant-looking. Results showed that the implicit power motive predicted decisions favoring dominant-looking persons as in-group leaders, and submissive looking persons as out-group leaders (Study 1) or in-group members (Study 2). These findings indicate that the tendency for people high in the implicit power motive to approach submissive-looking persons depends on the perceived instrumentality for gaining influence over others. PMID- 29720776 TI - Motivation to comply with task rules and multitasking performance: The role of need for cognitive closure and goal importance. AB - In three studies, we examined the role task rules play in multitasking performance. We postulated that rules should be especially important for individuals highly motivated to have structure and clear answers, i.e., those high on need for cognitive closure (NFC). High NFC should thus be related to greater compliance with task rules. Specifically, given high goal importance, NFC should be more strongly related to a multitasking strategy when multitasking is imposed by the rules, and to a mono-tasking strategy when monotasking is imposed by the rules. This should translate into better multitasking or mono-tasking performance, depending on condition. Overall, the results were supportive as NFC was related to a more mono-tasking strategy in the mono-tasking condition (Studies 1 and 2 only) and more dual-tasking strategy in the dual-tasking condition (Studies 1-3). This translated into respective differences in performance. The effects were significant only when goal importance was high (Study 1) and held when cognitive ability was controlled for (Study 2). PMID- 29720777 TI - Hierarchical Nearest-Neighbor Gaussian Process Models for Large Geostatistical Datasets. AB - Spatial process models for analyzing geostatistical data entail computations that become prohibitive as the number of spatial locations become large. This article develops a class of highly scalable nearest-neighbor Gaussian process (NNGP) models to provide fully model-based inference for large geostatistical datasets. We establish that the NNGP is a well-defined spatial process providing legitimate finite-dimensional Gaussian densities with sparse precision matrices. We embed the NNGP as a sparsity-inducing prior within a rich hierarchical modeling framework and outline how computationally efficient Markov chain Monte Carlo (MCMC) algorithms can be executed without storing or decomposing large matrices. The floating point operations (flops) per iteration of this algorithm is linear in the number of spatial locations, thereby rendering substantial scalability. We illustrate the computational and inferential benefits of the NNGP over competing methods using simulation studies and also analyze forest biomass from a massive U.S. Forest Inventory dataset at a scale that precludes alternative dimension reducing methods. Supplementary materials for this article are available online. PMID- 29720778 TI - Life Problems and Perceptions of Giving Support: Implications for Aging Mothers and Middle-Aged Children. AB - Giving support may be a stressful or rewarding experience, little is known about how family members perceive giving support amidst problems or crises. Using a sample of 226 mother-child dyads (mother mean age = 75.04; child mean age = 49.57), we examine how mothers and their middle-aged children perceive giving support in the context of life problems. Actor-partner interdependence models tested whether associations between problems and perceptions of support are moderated by frequency of support given and if associations were stronger for daughters or sons. Children perceived giving support to their mother as more stressful when they had more of their own problems and gave high levels of support. Daughters, but not sons, considered helping their mother more stressful when their mother had more problems and they gave high levels of support. Distinctions between mother-son and mother-daughter dyads demonstrate the merit of a dyadic approach to understanding mother-child relationships. PMID- 29720779 TI - HOW OLD IS IT? - 241PU/241AM NUCLEAR FORENSIC CHRONOLOGY REFERENCE MATERIALS. AB - One material attribute for nuclear forensics is material age. 241Pu is almost always present in uranium- and plutonium-based nuclear weapons, which pose the greatest threat to our security. The in-growth of 241Am due to the decay of 241Pu provides an excellent chronometer of the material. A well-characterized 241Pu/241Am standard is needed to validate measurement capability, as a basis for between-laboratory comparability, and as material for verifying laboratory performance. This effort verifies the certification of a 38 year old 241Pu Standard Reference Material (SRM4340) through alpha-gamma anticoincidence counting, and also establishes the separation date to two weeks of the documented date. PMID- 29720780 TI - Corpus-Based Transitivity Biases in Individuals with Aphasia. AB - Background: This study investigated whether individuals with aphasia (IWA) retain verb biases in expressive language. Verb biases refer to the likelihood that a given verb will occur in different sentence structures. We focused on the likelihood of verbs occurring in transitive and intransitive structures. Aims: The main goal of this study was to determine whether IWA and controls show similar verb biases or whether IWA show a preference for transitive or intransitive structures that supersedes individual verb biases. We also investigated whether IWA show a preference for intransitively or transitively biased verbs, whether verb biases differ as a function of aphasia type, and how verb bias affects errors in IWA's speech production. Methods: The current study analyzed 236 transcribed interviews of IWA from AphasiaBank. All uses of 54 verbs were coded based on the sentence structure and the presence of errors. We report data from 11 transitively biased and 11 intransitively biased verbs. Outcomes and Results: IWA's transitivity biases were indistinguishable from controls' biases. In addition, IWA produced more intransitively biased verbs than transitively biased verbs overall. In ungrammatical productions, IWA's error rates were higher in sentence structures that conflicted with verb bias and highest when an intransitively biased verb was attempted in a transitive structure. Main Conclusions: These findings indicate that IWA are sensitive to verb bias and verb complexity within expressive language. The effects are consistent with previous literature concerning IWA's sensitivity to verb bias in receptive language tasks and to verb complexity in verb retrieval tasks. PMID- 29720781 TI - Ultrastructural evidence for nutritional relationships between a marine colonial invertebrate (Bryozoa) and its bacterial symbionts. AB - Autozooids of the cheilostome bryozoan Aquiloniella scabra contain rod-like bacteria in the funicular bodies - the complex swellings of the funicular strands. Each funicular body contains symbionts in the central cavity surrounded by a large, synthetically active internal "sheath-cell" (bacteriocyte) and a group of the flat external cells. The tightly interdigitating lobes of these cells form a capsule well-isolated from the body cavity. Slit-like spaces between bacteria are filled with electron-dense matrix and cytoplasmic processes of various sizes and shapes (often branching) produced by the "sheath-cell". The cell ultrastructure and complex construction of the funicular bodies as well as multiplication of the bacteria in them suggest metabolic exchange between host and symbiont, involving the nourishment of bacteria. We suggest that the bacteria, in turn, influence the bryozoan mesothelial tissue to form the funicular bodies as capsules for bacterial incubation. We present ultrastructural data, discuss possible variants in the development of the funicular bodies in Bryozoa, and propose the possible role of bacteria in the life of their bryozoan host. PMID- 29720782 TI - Condom-Insistence Conflict in Women's Alcohol-Involved Sexual Encounters with a New Male Partner. AB - First-time sexual intercourse with a new male partner, relative to other sexual encounters, is associated with heightened risk to women for contracting sexually transmitted infections. Little is known, however, about women's condom-related decision-making processes during these first-time sexual encounters. In the present study, we surveyed a community sample of 179 women aged 18-30 about their alcohol consumption, desire to use a condom, perception of their partner's desire to use a condom, condom-insistence conflict, and condom-decision abdication and use during their most recent alcohol-involved first-time sexual encounter with a new partner. With structural equation modeling we tested a cognitive mediation model with various configurations of alcohol effects on abdication and condom use (direct, indirect, moderator). A moderated mediation model fit the data best. Women experienced elevated condom-insistence conflict when they wanted to use a condom and perceived their partner did not; conflict, in turn, was associated with higher likelihood of abdication and lower likelihood of condom use. Higher alcohol intoxication attenuated the associations of desire to use a condom, and perceived partner's desire to use a condom, with conflict. Results support an alcohol myopia-conflict inhibition-reduction model and emphasize the importance of sex education programs that teach young women not only about condom-related assertiveness and the effects of alcohol, but also prepare them to respond to experiences of conflict that arise during sexual encounters. PMID- 29720783 TI - GaN Nanowire MOSFET with Near-Ideal Subthreshold Slope. AB - Wrap-around gate GaN nanowire MOSFETs using Al2O3 as gate oxide have been experimentally demonstrated. The fabricated devices exhibit a minimum subthreshold slope of 60 mV/dec, an average subthreshold slope of 68 mV/dec over three decades of drain current, drain-induced barrier lowering of 27 mV/V, an on current of 42 MUA/MUm (normalized by nanowire circumference), on/off ratio over 108, an intrinsic transconductance of 27.8 MUS/MUm, for a switching efficiency figure of merit, Q=gm/SS of 0.41 MUS/MUm-dec/mV. These performance metrics make GaN nanowire MOSFETs a promising candidate for emerging low-power applications such as sensors and RF for the internet of things. PMID- 29720784 TI - Child Conduct Problems across Home and School Contexts: A Person-Centered Approach. AB - To examine patterns of conduct problems across the home and school context, we used latent class analysis to analyze primary caregivers' and teachers' ratings on the conduct problems subscale of the Strengths and Difficulties Questionnaire (R. Goodman, 1997) in the Family Life Project (N = 1,292), a prospective study of child development in rural and small town contexts. We found a similar four-class solution at five and seven years of age. In decreasing prevalence, the following classes were identified: (1) low symptoms reported by both informants (low cross context); (2) high parent-reported symptoms, low teacher-reported symptoms (home context); (3) low parent-reported symptoms, moderate teacher-reported symptoms (school context); and (4) high symptoms reported by both informants (high cross context). Classes exhibited stability from age five to age seven: children were more likely to remain in the same class than to transition to a different class, and longitudinal stability was especially high for children in the low cross context class at age 5. A number of child and family characteristics measured in early childhood (executive function, verbal ability, poverty-related risk, sensitive parenting, and parental depressive symptoms) were associated with class membership at age five and age seven, but were generally not associated with longitudinal transitions between classes. PMID- 29720785 TI - Household Chaos and Children's Cognitive and Socio-Emotional Development in Early Childhood: Does Childcare Play a Buffering Role? AB - Evidence suggests that household chaos is associated with less optimal child outcomes. Yet, there is an increasing indication that children's experiences in childcare may buffer them against the detrimental effects of such environments. Our study aims were to test: (1) whether children's experiences in childcare mitigated relations between household chaos and children's cognitive and social development, and (2) whether these (conditional) chaos effects were mediated by links between chaos and executive functioning. Using data from The Family Life Project (n = 1,235)-a population-based sample of families from low-income, rural contexts-our findings indicated that household disorganization in early childhood was predictive of worse cognitive and social outcomes at approximately age five. However, these relations were substantially attenuated for children attending greater childcare hours. Subsequent models indicated that the conditional associations between household disorganization and less optimal outcomes at age five were mediated by conditional links between disorganization and less optimal executive functioning. PMID- 29720786 TI - Uranium removal from seawater by means of polymeric fabrics grafted with diallyl oxalate through a single-step, solvent-free process. AB - In order to test the effectiveness of oxalate-based polymeric adsorbents in the recovery of uranium from seawater, diallyl oxalate (DAOx) was grafted onto nylon 6 fabrics by exposing the fabric, immersed in pure liquid DAOx or in a surfactant stabilized dispersion of DAOx in water, to electron beam or gamma radiation. Following drying and weighing to determine the degree of grafting (DoG), the presence of oxalate in the fabrics was verified using XPS. Zeta potential measurements showed the fabric surfaces to be negatively charged. The fabrics were tested by rotating them for 7 days in a rotary agitator with actual seawater spiked with 0.2 or 1.0 mg?L-1 uranium. The fraction of uranium in the solution which was removed due to uptake on the fabrics was found to rise with increasing DoG at both uranium concentrations. EDS measurements were used to map the distribution of adsorbed uranium on the polymeric fibers. PMID- 29720787 TI - Measuring Maternal Behaviors in the Neonatal Intensive Care Unit. AB - One of the most important considerations in designing clinical infant research studies is the selection of reliable and valid measurement procedures. Few measures of caregiver-child interactions have been studied with newborns, particularly premature infants. The main objective of this study was to examine psychometric properties of the NICHD Mother-Child Interaction Qualitative Ratings in a sample of premature infants and their mothers to evaluate its use in the Neonatal Intensive Care Unit (NICU). Mother-baby dyads (N=24) were videotaped in a 10-minute interaction in the NICU. Nine raters independently assessed dyadic interactions using the NICHD Mother-Child Interaction Qualitative Ratings in a fully-crossed research design. Rater reliability was strong for mother and infant ratings, (.76 to .94). Scores yielded normal distributions for maternal sensitivity, positive regard, and flatness of affect and skewed distributions for maternal intrusiveness, detachment, negative regard, and all child ratings. Positive maternal behaviors correlated positively with one another and negatively with negative maternal behaviors. Thus, preliminary analyses suggest that scores obtained using the NICHD Mother-Child Interaction Qualitative Ratings with premature babies and their mothers in the NICU demonstrate adequate inter-rater reliability, and distributional properties provide preliminary evidence of face validity. PMID- 29720788 TI - Spin Dynamics of (Sc[Formula: see text]Lu[Formula: see text])[Formula: see text]In Studied by Electron Spin Resonance. AB - The electron spin resonance (ESR) of conduction electrons is reported for the weak itinerant ferromagnet Sc[Formula: see text]In which, upon chemical substitution with Lu, shows a suppression of ferromagnetic correlations. A well defined ESR lineshape of Dysonian type characterizes the spectra. The ESR linewidth, determined by the spin dynamics, displays a broad minimum only for the Sc[Formula: see text]In compound. We discuss the results using the mechanism of exchange enhancement of spin-lifetimes. PMID- 29720789 TI - As I Sign in.... PMID- 29720790 TI - Brain at Risk. PMID- 29720791 TI - Recent Advances in Antisense Oligonucleotide Therapy in Genetic Neuromuscular Diseases. AB - Genetic neuromuscular diseases are caused by defective expression of nuclear or mitochondrial genes. Mutant genes may reduce expression of wild-type proteins, and strategies to activate expression of the wild-type proteins might provide therapeutic benefits. Also, a toxic mutant protein may cause cell death, and strategies that reduce mutant gene expression may provide therapeutic benefit. Synthetic antisense oligonucleotide (ASO) can recognize cellular RNA and control gene expression. In recent years, advances in ASO chemistry, creation of designer ASO molecules to enhance their safety and target delivery, and scientific controlled clinical trials to ascertain their therapeutic safety and efficacy have led to an era of plausible application of ASO technology to treat currently incurable neuromuscular diseases. Over the past 1 year, for the first time, the United States Food and Drug Administration has approved two ASO therapies in genetic neuromuscular diseases. This overview summarizes the recent advances in ASO technology, evolution and use of synthetic ASOs as a therapeutic platform, and the mechanism of ASO action by exon-skipping in Duchenne muscular dystrophy and exon-inclusion in spinal muscular atrophy, with comments on their advantages and limitations. PMID- 29720793 TI - Edgar Adrian and Patrick Merton: Names Blurred with the Passage of Time. AB - Edgar Douglas Adrian and Patrick Anthony Merton are two supreme neurophysiologists from England in the last century whose names are almost forgotten these days. Adrian's work on all-or-none phenomenon in nerve and muscle excitability ushered in a new era and Merton's servo theory of muscular movement and muscle fatigue added a new dimension to the understanding of stretch reflex and deep tendon reflexes. Both of them trained and worked at Trinity College, Cambridge and both were elected as Fellow of the Royal Society and Adrian in addition, was awarded the Nobel Prize in 1932 along with Charles Scott Sherrington. PMID- 29720792 TI - Preventing "Neurophobia": Remodeling Neurology Education for 21st-Century Medical Students through Effective Pedagogical Strategies for "Neurophilia". AB - Neurology has a reputation, particularly as a complex "head-to-toe" discipline for undergraduate medical students. Neurophobia syndrome, a global phenomenon, fundamentally stems from pedagogical deficiencies during the undergraduate curriculum, the lack of vertical integration between basic neurosciences and clinical bedside neurology, the lack of clinical reasoning exercises, cognitive heuristics, and clinical problem-solving, errors in diagnostic competence, and hyposkilia. This ultimately results in poor clinical competence and proficiency in clinical neurology and causes attrition in nurturing a passion for learning the neurology discipline. This article explores plausible factors that contribute to the genesis of neurophobia and multifaceted strategies to nurture interest in neurosciences and provide possible solutions to demystify neurology education, especially the need for evidence-based educational interventions. Remodeling neurology education through effective pedagogical strategies and remedial measures, and using the Miller's pyramid, would provide a framework for assessing clinical competence in clinical bedside neurology. Technology-enhanced education and digital classrooms would undoubtedly stamp out neurophobia in medical students of the 21st century. It will not frighten off another generation of nonneurologist physicians to empower them to hone expertise in order to tackle the increasing burden of neurological disorders in India. Furthermore, promoting neurophilia would facilitate the next generation of medical students in pursuing career options in neurology which would be quintessential not only in closing India's looming neurologist workforce gap but also in fostering interest in research imperatives in the next generation of medical students. PMID- 29720794 TI - Evaluation of Various Movement Disorders in Patients of Genetically Proven Spinocerebellar Ataxia: A Study from a Tertiary Care Center in Northern India. AB - Background: Movement disorders are one of the prominent nonataxic symptoms in patients of spinocerebellar ataxia (SCA). The type of movement disorder may provide clinical clue to the type of SCA. Objective: The objective of this study is to evaluate various movement disorders in patients of genetically proven SCAs and to establish a probable clinico-genetic correlation. Methods: Ninety-Five patients of genetically proven SCAs were assessed for the presence of various movement disorders. Results: Patients with SCA (75.8% males) with at least one movement disorder contributed 43.16%. Age for onset of movement disorder was 43.39 +/- 13.43 years. SCA-12 (38.95%) was the most common subtype. Among the patients with at least one movement disorder, action tremor of hands contributed majority (90.2%). Dystonia and parkinsonism were present in 17.07% and 12.2% of patients (with movement disorder), respectively. Action tremor of hands was present in 34 patients with SCA-12 (91.89%), and 20 patients (54.05%) had onset of hand tremor preceding the onset of ataxia. Majority of patients with SCA-12 (81%) were of the same ethnic origin belonging to Agrawal community. Patients with movement disorder had a later onset (45 +/- 13.88 years) of ataxic symptoms compared to those without a movement disorder (32.8 +/- 11.92) (P = <0.0005). There was no significant association between severity of ataxia and presence of movement disorder. Conclusion: Movement disorders are present in about 43% of patients with SCA and can precede or succeed the onset of ataxia. Tremor onset SCA predicted SCA-12, especially in Agrawal community. PMID- 29720795 TI - Determinants of Remission in Medically Treated Carpal Tunnel Syndrome: Study from Central India. AB - Background: The factors associated with the spontaneous remission (SR) of symptoms in carpal tunnel syndrome (CTS) are not well known. Objectives: To look for determinants of SR in medically treated, electrophysiologically proven patients of CTS. Methods: We revisited the medical records and nerve conduction study data of 130 hands with CTS and divided them into two groups as per the absence or persistence of the symptoms when contacted after a median time lapse of 3 years following the diagnosis. Results: SR occurred in 46.1% of the hands. Higher odds of SR were linked with female gender, symptoms restriction to lateral fingers, symptom duration <10 months, mildly delayed median motor and sensory distal latencies, and median sensory amplitude >20 MUV. We developed a seven point scale, on which a score of >=4 had a strong association (odds ratio 4.31) with SR. Discussion and Conclusion: No single risk factor, standalone, can predict SR in patients with CTS, which could lead to an invasive treatment (Surgery or local injection) to them. We propose that patients scoring >=4 on our 7 point scale should be treated medically for the initial 10 months after the symptom onset. PMID- 29720796 TI - Value of Motor Nerve Conduction Studies in the Diagnosis of Idiopathic Tarsal Tunnel Syndrome: A Single-center Prospective Observational Study from India. AB - Background: Nerve conduction studies are considered to be the gold standard for diagnosing secondary tarsal tunnel syndrome (s TTS), but their utility in the diagnosis of idiopathic tarsal tunnel syndrome (i TTS) is largely unknown. Objective: We sought to investigate the value of motor nerve conductions studies (MNCS) in the diagnosis of clinically suspected iTTS. Materials and Methods: Twenty-six (52 limbs) adult patients of clinically suspected iTTS were subjected to motor nerve conductions of posterior tibial nerve, and its branches and motor conduction parameters were compared with those of 45 healthy controls. Results: Symptoms were bilateral in 70% (P = 0.02), with heel pain in 95% of symptomatic limbs. MNCS was abnormal in 32 (80%) of symptomatic limbs and 8 (66.6%) of asymptomatic limbs (P = 0.004). Out of electrophysiologically abnormal nerves (n = 67), the pathological process could be identified in all the nerves with abnormal MNCS (P = 0.02). Probable demyelination was seen in 58.2% of the electrophysiologically abnormal nerves. Discussion: The present study shows that iTTS are gender and Body Mass Index neutral with bilateral symptoms being common. Tinel's sign was inconsistent. Heel pain did not correlate with abnormal inferior calcaneal nerve conductions. Motor nerve conduction study was abnormal in a significant number of symptomatic limbs. "Probable demyelination" was more frequent in symptomatic limbs. Conclusion: MNCS is significantly abnormal in symptomatic limbs of subjects with iTTS. Demyelination is slightly more common than axonopathy in iTTS. With a sensitivity of 80% and specificity of 33.3%, MNCS seems to be useful as a screening tool in clinically suspected iTTS. This study is Level II: Lesser quality randomized controlled trial or prospective comparative study. PMID- 29720798 TI - Mercury Toxicity Following Unauthorized Siddha Medicine Intake - A Mimicker of Acquired Neuromyotonia - Report of 32 Cases. AB - Context: Mercury is used extensively in the preparation of Siddha medicines, after purification. In this study, we present 32 patients of mercury toxicity following unauthorized Siddha medicine intake who mimicked neuromyotonia clinically. We analyzed the clinical features of these patients, the role of autoimmunity in etiopathology, and compared it with acquired neuromyotonia. Subjects and Methods: This is a retrospective study to analyze inpatients in a tertiary care center, admitted with mercury toxicity following Siddha medicine intake from August 2012 to October 2016. We analyzed the clinical features, laboratory data including mercury, arsenic and lead levels in blood, and serum voltage-gated potassium channels (VGKC)-CASPR2 Ab in selected patients. Results: Thirty-two patients who had high blood mercury levels following Siddha medicine intake were included in the study. All patients (100%) had severe intractable neuropathic pain predominantly involving lower limbs. Twenty-six (81.25%) patients had fasciculations and myokymia. Fifteen patients (46.86%) had autonomic dysfunction (postural hypotension and resting tachycardia). Nine (28.12%) patients had encephalopathic features such as dullness, apathy, drowsiness, or delirium. Anti-VGKC Ab was positive in 12 patients with myokymia. All the patients in the study consumed Siddha medicines obtained from unauthorized dealers. Conclusions: Mercury toxicity following Siddha medicine intake closely mimics acquired neuromyotonia; severe intolerable neuropathic pain is the hallmark feature; Positive VGKC-CASPR2 antibody in some patients must be due to triggered autoimmunity secondary to mercury toxicity due to Siddha medicine intake. The government should establish licensing system to prevent distribution of unauthorized Siddha medicines. PMID- 29720797 TI - The Spectrum of Autonomic Dysfunction in Myasthenic Crisis. AB - Background: Autoimmune autonomic dysfunction is described in Myasthenia Gravis. In myasthenic crisis, the spectrum of autonomic dysfunction is hitherto uncharacterized. Objective: The objective of this study is to describe the spectrum of autonomic dysfunction in myasthenic crises using the composite autonomic symptom scale 31 (COMPASS 31) autonomic symptom questionnaire and power spectral analysis of heart rate variability (HRV), which is a simple way of estimating general autonomic dysfunction. Methods: Adult patients with myasthenic crisis from January 1, 2014 to March 15, 2015, were prospectively included in this study. The COMPASS 31 questionnaire for symptoms of autonomic dysfunction and power spectral analysis of HRV were assessed. These were compared with the patient's demographic and clinical parameters and with previous literature. IRB approval was obtained. Results: Sixteen patients were included (M:F 3:1). 15/16 patents (93%) had autonomic dysfunction on COMPASS 31 questionnaire. The domains of involvement were gastrointestinal (80%), orthostatic (67.7%), pupillomotor (67.7%); sudomotor (33.3%), and vasomotor (13.3%). Parasympathetic dysfunction predominance was suggested by the symptom profile. HRV analysis showed a low frequency (LF) spectral shift suggesting slowed parasympathetic responsiveness (LF normalized unit (nu): high frequency [HF] nu mean 8.35, standard deviation +/ 5.4, 95% confidence interval 2.2-12.5), which significantly exceeded the mean LF nu: HF nu ratios of the majority of previously reported noncrises myasthenic populations. Conclusions: Myasthenic crisis has autonomic dysfunction involving multiple organ systems. Increased latency of parasympathetic reflexes is suggested. A comprehensive management protocol addressing different autonomic domains is required for holistic patient care. PMID- 29720799 TI - Phrenic Nerve Conduction Study in the Early Stage of Guillain-Barre Syndrome as a Predictor of Respiratory Failure. AB - Background: Guillain-Barre syndrome (GBS) has unpredictable clinical course with severe complication of respiratory failure. Objective: To identify clinical profiles and electrophysiological study particularly non-invasive Phrenic nerve conduction study in patients of early GBS to predict respiratory failure. Methods: 64 adult (age>=18yrs) patients of early GBS (onset <= 14 days) during the study period from January 2014 to October 2015 were evaluated by clinical profiles of age, gender, antecedent infection, time to peak disability, single breath counts, cranial nerve involvement, autonomic dysfunction and non-invasive Phrenic nerve conduction study. Patients with predisposition factors of polyneuropathy like diabetes mellitus, hypothyroidism, vitamin deficiency, renal failure were excluded. Results: Among 64 patients abnormal phrenic nerve conduction study was seen in 65.62% cases (42/64) and 45.23% (19/42) of them developed respiratory failure. Phrenic nerve sum latency, amplitude, duration and area were abnormal in those who developed respiratory failure and they had sum of phrenic nerve latency >28 msec, sum of CMAP amplitude <300 MUV, sum of CMAP duration >50 msec and sum of area < 4 mVmS. None with normal phrenic nerve study developed respiratory failure. It was found that age, gender, preceding infection, autonomic involvement and types of GB syndrome had no influence on development of respiratory failure (p>0.05). Rapid disease progression to peak disability, more severe disease, shorter single breath counts and cranial nerve involvement were seen more often in patients with respiratory failure. Conclusion: Abnormal Phrenic nerve conduction study in the early Guillain-Barre syndrome might be of great value independently in predicting impending respiratory failure. PMID- 29720800 TI - Necrotizing Autoimmune Myopathy: Clinicopathologic Study from a Single Tertiary Care Centre. AB - Background: Idiopathic inflammatory myopathies (IIMs) are a group of chronic, autoimmune disorders which include a new entity, necrotizing autoimmune myopathy (NAM). NAM lacks inflammation and presents with markedly elevated creatinine phosphokinase (CPK) levels. It is associated with connective tissue diseases (CTDs), statin use, malignancies, and most cases are idiopathic. Objectives: The objectives of this study are to describe the clinicopathologic features in muscle biopsy-proven cases of NAM. To emphasize the role of laboratory parameters such as CPK levels and myositis profile in the diagnosis of NAM. Materials and Methods: This is a retrospective study including 15 patients of NAM diagnosed on muscle biopsy over a period of 2 years. The slides of the biopsies were reviewed, and clinical data, electromyography findings, and CPK levels were obtained. Myositis profile was done. Results: Necrotizing myopathy accounted for 13.63% (15 cases) of total inflammatory myopathies (110 cases) in the study. These were grouped into CTD-associated NAM, statin-associated NAM, paraneoplastic NAM and idiopathic NAM which was the common type. All cases presented with progressive proximal muscle weakness and had markedly elevated CPK levels. Anti-3-hydroxy-3 methyl-glutaryl-coenzyme A reductase and antisignal recognition particle antibodies were seen to be positive in six patients. Muscle biopsies showed predominant fiber necrosis with significant fiber degeneration and regeneration in the absence of inflammation. All patients received immunotherapy with significant improvement was seen in six patients with two mortalities. Conclusion: Necrotizing myopathy is a new addition to the spectrum of IIM. Clinicopathologic correlation is important for appropriate diagnosis. It is found to be refractory to corticosteroids monotherapy. The course of illness is not uniform, and in some patients, there can be rapid worsening with mortality. PMID- 29720801 TI - Spinocerebellar Ataxia-21 in a Turkish Child. AB - Hereditary cerebellar ataxias are genetically heterogeneous disorders. Autosomal recessive spinocerebellar ataxia-21 (SCAR21) is a neurologic disorder characterized by the onset of cerebellar ataxia, recurrent episodes of liver failure, peripheral neuropathy, and learning disabilities. Herein, we reported a case presented with gait and balance problems, swallowing difficulties, mild delayed motor development, and mild learning disability with SCAR21 that confirmed by mutation analysis in a Turkish child. To the best of our knowledge, this is the first case of SCAR21 from Turkey. PMID- 29720802 TI - A Viral Polymyositis Masquerade: Life-Threatening Case of Juvenile Dermatomyositis Complicated by Systemic Capillary Leak Syndrome. AB - This is a case report of an 8-year-old boy who developed an atypical, rare subphenotype of autoimmune inflammatory acute juvenile dermatomyositis (JDM), initially masquerading as viral polymyositis (PM)-like presentation, that was complicated by a hitherto unreported fulminant, life-threatening pediatric systemic capillary leak syndrome (SCLS). We highlight the close differential between viral PM and JDM, the baffling clinical syndromic constellation of hypotension with hemoconcentration - a "shock"-like syndrome, hypoalbuminemia without albuminuria, and generalized edema with the atypical JDM presentation, and stress crucial need to implement early aggressive, multipronged immunomodulatory treatment along with intensive fluid resuscitation which saved the life, this patient from a stormy, and turbulent 4-week clinical illness. This is the first published case description in the current literature of the association of an aggressive subphenotype of JDM and life-threatening pediatric SCLS. This report opens the Pandora's Box to explore the genetic and pathomechanisms of both disorders. PMID- 29720803 TI - Unilateral Limb Thinning -Thinking Out of the Box. AB - We report an unusual presentation in a 9-year-old girl with unilateral circumferential thinning of the entire right upper limb without any other neurological deficit, with normal nerve conduction and electromyography initially thought of as a neurodegenerative disorder based on clinical presentation. Magnetic resonance imaging of the upper limb showed partial lipoatrophy with normal glucose metabolism and lipid profile and negativity for HIV and autoimmune disease (panniculitis) with no family history of similar disorder. Remember to think out of box before labeling neurodegenerative disease. PMID- 29720804 TI - Cervical Myelopathy after High-voltage Electrical Burn of the Head: Report of an Unusual Case. AB - High-voltage electrical injuries are uncommonly reported and may predispose to both immediate and delayed neurologic complications. We present a case of 27-year old male who experienced a high-voltage electrical burn of the head resulting in quadriparesis. High-voltage electrocution injuries are a serious problem with potential for immediate, delayed, and long-term neurologic sequelae. The existing literature regarding effective treatment of neurologic complications is limited. Multidisciplinary management and long-term follow up are required. PMID- 29720805 TI - Uncommon Anatomical Variant - Types Artery of Percheron Infarcts: Clinical radiological Correlations. PMID- 29720806 TI - Cysts in White Matter: A Novel Neuroimaging Finding in Infantile GM1 Gangliosidosis. PMID- 29720807 TI - Pseudo-subarachnoid Hemorrhage Sign. PMID- 29720808 TI - Chronic Lymphocytic Leukemia Involvement of Central Nervous System: Clinical Diversity, Diagnostic Algorithm and Therapeutic Challenges. PMID- 29720809 TI - Spinal Intramedullary Cysticercosis: A Summary of Three Cases in Thailand. PMID- 29720810 TI - Recovery of Visual Scotomas by Vortioxetine in a Patient with Symptomatic Occipital Lobe Epilepsy. PMID- 29720811 TI - Worst Headaches of the Humankind. PMID- 29720812 TI - Cluster Headache: Epidemiology, Pathophysiology, Clinical Features, and Diagnosis. AB - Cluster headache is a primary headache disorder affecting up to 0.1% of the population. Patients suffer from cluster headache attacks lasting from 15 to 180 min up to 8 times a day. The attacks are characterized by the severe unilateral pain mainly in the first division of the trigeminal nerve, with associated prominent unilateral cranial autonomic symptoms and a sense of agitation and restlessness during the attacks. The male-to-female ratio is approximately 2.5:1. Experimental, clinical, and neuroimaging studies have advanced our understanding of the pathogenesis of cluster headache. The pathophysiology involves activation of the trigeminovascular complex and the trigeminal-autonomic reflex and accounts for the unilateral severe headache, the prominent ipsilateral cranial autonomic symptoms. In addition, the circadian and circannual rhythmicity unique to this condition is postulated to involve the hypothalamus and suprachiasmatic nucleus. Although the clinical features are distinct, it may be misdiagnosed, with patients often presenting to the otolaryngologist or dentist with symptoms. The prognosis of cluster headache remains difficult to predict. Patients with episodic cluster headache can shift to chronic cluster headache and vice versa. Longitudinally, cluster headache tends to remit with age with less frequent bouts and more prolonged periods of remission in between bouts. PMID- 29720813 TI - Treatment of Cluster Headache. AB - Cluster headache (CH) is a debilitating primary headache disorder. Although uncommon, affecting only 0.1% of population, it is one of the most painful conditions known to humankind. Three strategies are employed for effective treatment of CH, namely, abortive therapy, transitional therapy, and preventive therapy. Being an uncommon condition, there is a paucity of large-scale controlled trials and evidence of various therapies are based on smaller studies. This review primarily focuses on therapies with highest quality of evidence and also on the emerging therapies for CH. PMID- 29720814 TI - Paroxysmal Hemicrania. AB - Paroxysmal hemicrania (PH) is a primary headache disorder belonging to the group of trigeminal autonomic cephalalgias(TACs). Patients typically experience intense lateralzsed headaches with pain primarily in the ophthalmic trigeminal distribution (V1) associated with superimposed ipsilateral cranial autonomic features. PH is distinguished from other TACs by an exquisite responsiveness to therapeutic doses of indomethacin. Patients may need to be maintained on indomethacin for several months before trials of reduction can be attempted. The disorder does have a tendency toward chronicity. PH is uncommon, but early recognition will prompt initiation of effective treatment to avoid unsuccessful trials of drugs effective in other primary headaches. As with other TACs, hypothalamic and trigeminovascular mechanisms are implicated in the pathophysiologic mechanism of PH. Neuroimaging findings in PH demonstrate a posterior hypothalamic activation similar to that observed in the other TACs. This review will address the epidemiology, clinical presentation, pathophysiology, evaluation, and treatment of PH. PMID- 29720815 TI - Hemicrania Continua. AB - Hemicrania continua (HC) is an indomethacin responsive primary chronic headache disorder which is currently classified as a subtype of trigeminal autonomic cephalalgias (TACs). It is not very uncommon. There are >1000 cases of HC in the literature, and it constitutes 1.7% of total headache in the clinic settings. Misdiagnosis for HC is very common at all clinical settings. A diagnosis of HC is missed even by neurologists and headache specialists. It is characterized by a continuous strictly unilateral headache with superimposed exacerbations. Just like other TACs, exacerbations are associated with cranial autonomic symptoms and restlessness. A large number of patients may have migrainous features (nausea, vomiting, photophobia, and phonophobia) during exacerbations phase. The "key" feature of HC is persistent featureless background headaches. However, patients and physicians may focus only on the exacerbation part. As durations, frequency and associated symptoms of exacerbations are highly variables; it may mimic a large number of primary and secondary headache disorders. Migraine and cluster headache are two most common misdiagnosed conditions. Another specific feature of HC is remarkable repose to indomethacin. A "complete" response to indomethacin is as "sine qua non" for HC. However, a few other medications may also be effective in a subset of HC patients. Various surgical procedures have been tried with mixed results in patients who were intolerant to indomethacin or other drugs. PMID- 29720816 TI - Short-Lasting Unilateral Neuralgiform Headache Attacks. AB - Short-lasting unilateral neuralgiform headache attacks (SUNHA) is characterized by strictly unilateral trigeminal distribution pain that occurs in association with ipsilateral cranial autonomic features. There are two subtypes: short lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA). These disorders are rare but highly disabling. The management of SUNHA can be challenging. The abortive therapies are not generally useful as the attacks are relatively short-lasting. A myriad of pharmacological preventive treatments has been tried in single case reports or small series in an open-label fashion. Lamotrigine, as an oral preventive treatment, and lidocaine, as an intravenous transitional treatment, seems to be the most effective therapies. For medically intractable SUNHA, several surgical approaches have been tried. These include ablative procedures involving the trigeminal nerve or the Gasserian ganglion, microvascular decompression (MVD) of the trigeminal nerve, and neurostimulation techniques. MVD, occipital nerve stimulation, and ventral tegmental area deep brain stimulation have all been found to be effective in open-label series with relatively high-response rates. There is a considerable clinical, therapeutic, and radiological overlap between SUNCT, SUNA, and trigeminal neuralgia (TN). Despite being considered distinct conditions, the emerging evidence suggests a broader nosological concept of SUNCT, SUNA, and TN; these conditions may constitute a continuum of the same disorder, rather than separate clinical entities. Consideration needs to be given to classifying SUNHA with TN as a cranial neuralgia rather than as a trigeminal autonomic cephalalgia. PMID- 29720818 TI - Classification of Trigeminal Autonomic Cephalalgia: What has Changed in International Classification of Headache Disorders-3 Beta? AB - The term "Trigeminal Autonomic Cephalalgia (TAC)" was first coined by Goadsby and Lipton[1] to include a group of relatively rare primary headache disorders characterized by moderate to severe, short-lived head pain in the trigeminal distribution with unilateral cranial parasympathetic autonomic features, such as lacrimation, rhinorrhea, conjunctival injection, eyelid edema, and ptosis. In the current International Classification of Headache Disorders (ICHD-3 beta),[2] the TAC group includes cluster headache (CH), paroxysmal hemicrania (PH), short lasting unilateral neuralgiform headache attacks (SUNHAs) and their 2 subforms - SUNHAs with conjunctival injection and tearing (SUNCT), SUNHAs with cranial autonomic symptoms (SUNA). Hemicrania Continua (HC) is also now included in the TAC group. Although the entities included under TACs seem broadly similar, they differ in attack duration, frequency and their response to different treatments. At one end of the spectrum lies CH, the prototypic TAC where the duration of attacks is the longest and at the other end is the SUNCT syndrome where the duration is shortest. There is some overlap across the entities; they are not difficult to recognize and subclassify. The umbrella term "TAC" for the short lasting headaches with autonomic features was for the first time introduced in The ICHD, 2nd edition (ICHD-2) published in 2004.[3] The beta version of the 3rd edition of The ICHD[2] was published in 2013. Headache classification being an evolving process, there have been some changes within the TAC group between ICHD 2 and ICHD-3 beta.[45] Diagnostic criteria have been revised to reflect pathophysiological and clinical observations. Neuroimaging has provided insights into the pathophysiology of TACs. Functional neuroimaging has helped to elucidate key structures activated during attacks of TACs. Correct diagnosis remains the key to correct management of the TACs because treatment options vary. The aim of this article will be to highlight the changes in ICHD-3 beta to this group and to emphasize the clinical implications of these changes. Description of individual entities included under TACs are included elsewhere and will therefore not be detailed here. PMID- 29720817 TI - Overview of Trigeminal Autonomic Cephalalgias: Nosologic Evolution, Diagnosis, and Management. AB - The term trigeminal autonomic cephalalgias (TACs) encompasses four primary headache disorders - cluster headache, paroxysmal hemicrania (PH), hemicrania continua (HC), short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT)/short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA). All of these except HC are characterized by short-lasting headaches. HC is characterized by a continuous unilateral headache that waxes and wanes in its intensity without complete resolution. It is included in the TACs group given the overlap in the activation of the posterior hypothalamic grey, and the shared clinical feature of unilateral head pain with ipsilateral cranial autonomic symptoms. The present review gives an overview of the nosologic evolution, diagnosis, and management of TACs. PMID- 29720819 TI - Functional Neuroimaging in Trigeminal Autonomic Cephalalgias. AB - Functional neuroimaging was able to identify key structures for the pathophysiology of trigeminal autonomic cephalalgias (TACs) including cluster headache, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing or cranial autonomic features and hemicrania continua. The posterior hypothalamus was the structure most consistently depicted with functional imaging in different states of disease with and without pain. Network-oriented imaging techniques such as resting-state functional resonance imaging were able to show a broader involvement of human trigeminal pain processing in the underlying pathophysiological mechanisms of the different TACs, highlighting similarities between this distinct group of primary headache disorders, while also demonstrating the differences in brain activation across these disorders. The most important clinical assignment for neuroimaging research from the treating physician remains the objective and reliable distinction of each individual TAC syndrome from one another, to make the correct clinical diagnosis as the foundation for proper treatment. More research will be necessary to fulfill this unmet need. PMID- 29720820 TI - Secondary (Symptomatic) Trigeminal Autonomic Cephalalgia. AB - Primary trigeminal autonomic cephalalgias (TACs) are uncommon group of headache disorders. These are defined and diagnosed by the criteria given by the International Classification of Headache Disorders 3beta version. Over the past few decades, a number of secondary (symptomatic) cases have been described in the literature with headache features indistinguishable from primary TACs. Many structural and other pathologies have been found in these patients that can be causally related to the headaches. This review attempts to critically analyze the existing literature including the new cases published during 2015-2017. PMID- 29720821 TI - Chemical Composition and Cytotoxic Activity of Methanol Extract and its Fractions of Streblus asper Leaves on Human Cancer Cell Lines. AB - Background: Streblus asper, family Moraceae is well-known important medicinal plant used in the Indian system of medicine. In Ayurveda, stem bark of S. asper is recommended against elephantiasis for which there is still no any other effective medicine in the modern system of medicine. Objectives: In the present work, methanol extract (SAM) and its fractions of S. asper leave tested for in vitro anticancer activity against cancer cell lines (MCF-7, A-549, Hep-G2, and K 562) which claims its folklore importance in cancer and gas chromatography-mass spectrometry identification of extracts was also performed. Materials and Methods: Shade dried plant material was extracted with methanol and fractionated sequentially with hexane, chloroform, and butanol. Results: All tested extracts found highly effective against human lung cancer cell line (A-549) with IC50 <10 MUg/mL. On Hep-G2 cancer cell line, only chloroform fraction are highly active with IC50 <10 MUg/mL. Methanol and hexane fraction showed potent anticancer activity on K-562 cancer cell line with IC50 <10 MUg/mL. Conclusion: Qualitative phytochemical analysis confirmed the presence of fatty acids, phytosterol, triterpenoids, polyol, sugar acid, aldehyde, diterpene, terpene, carboxylic compounds, acid and sugar in S. asper leaves extract. Topmost abundant compounds in SAM are alpha-D-glucopyranoside (10.60%), glycerol (7.96%), myo-inositol (4.90%), and butanedioic acid (3.30%). Hexane consists of the higher amount of hexadecanoic acid (18.07%), octadecanoic acid (7.39%), beta-sitosterol (4.50%), and alpha-D-glucopyranoside (4.03%). Higher component in chloroform extract is lupenyl acetate (11.25%). SUMMARY: All extracts of Streblus asper found potential anticancer activity against lung cancer cell line (A-549)Chloroform fraction is highly active on hepatoma cancer cell line (Hep-G2) whereas methanolic, and hexane fractions have highly cytotoxic potency against leukemia cancer cell line (K-562)Methanolic extract of S. asper is rich source of glycosides, fatty acids, and phytosterolIn Gas chromatography-mass spectrometry evaluation of S. asper beta-stigmasterol, beta-sitosterol, lycopene, and lupeol identified as an anticancer agent from previously reported literature. Abbreviations used: SRB: Sulforhodamine B assay; SAM: Methanol extract; SAH: Hexane extract; SAC: Chloroform extract. PMID- 29720822 TI - Herbal Medicines Showing Synergistic Effects with Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL) against A549 TRAIL-resistant Lung Cancer Cells: A Screening Study. AB - Background: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine that activates apoptosis through death receptors on the cell surface and is regarded as a potential anticancer agent. However, many cancer cells are resistant to TRAIL-induced apoptosis. Objective: The aim is to identify the herbal medicines that could help overcome resistance in TRAIL-resistant lung cancer cells. Materials and Methods: TRAIL-resistant A549 cells and 13 herbal medicines with known apoptosis-related anticancer effects were used in this study: Clematidis Radix, Corydalis Tuber Rhizoma, Paeoniae Radix Rubra, Corni Fructus, Curcumae longae Rhizoma (CLR), Moutan Cortex, Salviae miltiorrhizae Radix, Phellodendri Cortex, Farfarae Flos, Paeoniae Radix Alba, Angelicae gigantis Radix, Coptidis Rhizoma (CR), and Taraxaci Herba. Cytotoxic effects were investigated after a 48-h incubation, using an 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide assay, to identify the herbal medicines with the most potent synergistic effects with TRAIL. Results: The majority of the 13 medicines exhibited concentration-dependent cytotoxicity against A549 cells. Among them, CR and CLR showed the most potent cytotoxic effects, based on the IC50. We then investigated the use of these two medicines in combination with TRAIL and identified synergistic cytotoxic effects against TRAIL-resistant A549 cells. Conclusion: Synergistic cytotoxic effects of the combination of TRAIL and herbal medicines, in particular, CR and CLR, were confirmed in A549 cells. Therefore, CR and CLR showed potential to be used as candidates to overcome TRAIL resistance. Future studies to identify their underlying mechanism of action are required. SUMMARY: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an attractive anticancer agent which can induce apoptosis in tumor cells without causing cytotoxicity to normal cellsHowever, resistance to TRAIL is often observed in some tumor cells, including nonsmall cell lung cancers, which may limit its cytotoxic efficacy in cancer treatmentThe combination treatment of TRAIL and herbal medicines, particularly Coptidis Rhizoma (CR) and Curcumae longae Rhizoma (CLR), can induce the synergistic cytotoxic effects against TRAIL resistant A549 cells, indicating that TRAIL resistance was reduced by combination therapy. Abbreviations used: TRAIL: Tumor necrosis factor-related apoptosis inducing ligand; CLR: Curcumae longae Rhizoma; CR: Coptidis Rhizoma; NSCLC: non small cell lung cancer. PMID- 29720823 TI - In vitro Induction and Generation of Tetraploid Plants of Sophora tonkinensis Gapnep. AB - Background: Sophora tonkinensis Gapnep. is an important medical plant in China. Early researches of S. tonkinensis were focused on rapid propagation and quality analysis of in vitro tissue culture plantlet, and still no research focuses on the plant breeding of and there were no excellent varieties for artificial cultivation of S. tonkinensis. Objective: To set up a method to generate and select the best varieties of S. tonkinensis by polyploid breeding after induction by colchicine treatment. Materials and Methods: The adventitious buds were submerged in different concentrations of aqueous colchicine solution for different lengths of time to induce polyploidy in the plants, and the induced buds were identified by root-tip chromosome determination and leaf characteristics comparison. The contents of matrine and oxymatrine of radix ex rhizoma in 13 selected tetraploid lines were collected after 90 days in vitro rooting culture and were evaluated to provide evidence of good qualities of tetraploid S. tonkinensis. Results: The results showed that the highest percentage of tetraploid induction was 23.33% and occurred in the 0.2% (w/v) colchicine treatment for 30 h. Fifty lines of tetraploid plants were obtained and 12 of the 13 selected tetraploid lines exhibited higher productivity of total contents of matrine and oxymatrine when compared to controls. Conclusion: The data demonstrate that polyploidy induction can be beneficial for improving the medicinal value of S. tonkinensis. SUMMARY: Colchicine has a good in vitro induction effect on the tetraploid plants of Sophora tonkinensisThe leaf indices and stomatal apparatus of tetraploid plants were slightly larger than diploid plantsThe total content of matrine and oxymatrine of some tetraploid lines for 90 day-old in vitro rooting culture was higher than the diploid. Abbreviations used: MS medium: Murashige and Skoog medium; BAP: 6-benzylaminopurine; NAA: A naphthaleneacetic acid; IAA: Indole-3-acetic acid; KT: Kinetin; IBA: Indole-3 butyric acid; ABT: Rooting power. PMID- 29720824 TI - Optimization of Extraction Conditions for Phenolic Acids from the Leaves of Melissa officinalis L. Using Response Surface Methodology. AB - Background: Melissa officinalis L. is a well-known medicinal plant from the family Lamiaceae, which is distributed throughout Eastern Mediterranean region and Western Asia. Objective: In this study, response surface methodology (RSM) was utilized to optimize the extraction conditions for bioactive compounds from the leaves of M. officinalis L. Materials and Methods: A Box-Behnken design (BBD) was utilized to evaluate the effects of three independent variables, namely extraction temperature ( degrees C), methanol concentration (%), and solvent-to material ratio (mL/g) on the responses of the contents of caffeic acid and rosmarinic acid. Results: Regression analysis showed a good fit of the experimental data. The optimal condition was obtained at extraction temperature 80.53 degrees C, methanol concentration 29.89%, and solvent-to-material ratio 30 mL/g. Conclusion: These results indicate the suitability of the model employed and the successful application of RSM in optimizing the extraction conditions. This study may be useful for standardizing production quality, including improving the efficiency of large-scale extraction systems. SUMMARY: The optimum conditions for the extraction of major phenolic acids from the leaves of Melissa officinalis L. were determined using response surface methodologyBox-Behnken design was utilized to evaluate the effects of three independent variablesQuadratic polynomial model provided a satisfactory description of the experimental dataThe optimized condition for simultaneous maximum contents of caffeic acid and rosmarinic acid was determined. Abbreviations used: RSM: Response surface methodology, BBD: Box-Behnken design, CA: Caffeic acid, RA: Rosmarinic acid, HPLC: High-performance liquid chromatography. PMID- 29720825 TI - Determination of Five Chemical Markers in DF Formula, the Herbal Composition of Ephedra intermedia, Rheum palmatum, and Lithospermum erythrorhizon, Using High performance Liquid Chromatography-ultraviolet Detection. AB - Background: DF formula is a herbal preparation comprised three medicinal herbs, namely, Ephedra intermedia, Rheum palmatum, and Lithospermum erythrorhizon, which is being used for the treatment of obesity and liver fibrosis in Korean local clinics. Objective: Since the abovementioned three herbs exist with different proportions in DF formula and their chemical markers have different physiochemical properties; it is quite challenging to develop an analytical methodology for the determination of these chemical markers. Materials and Methods: For the analysis of the three herbs, five chemicals, (+)-pseudoephedrine (1) and (-)-ephedrine (2) for E. intermedia, aloe-emodin (3), and chrysophanol (4) for R. palmatum, and shikonin (5) for L. erythrorhizon, were selected for method validation of DF formula, and the analytical conditions were optimized and validated using high-performance liquid chromatography coupled with an ultraviolet detector (HPLC-UV). Results: The specificities for the five compounds 1-5 were determined by their UV absorption spectra (1-4: 215 nm and 5: 520 nm). Their calibration curves showed good linear regressions with high correlation coefficient values (R2 > 0.9997). The limits of detection of these five markers were in the range 0.4-2.1 ng/mL, with the exception of 5 (12.7 ng/mL). The intraday variability for all the chemical markers was less than a Relative standard deviation (RSD) of 3%, except for 5 (RSD = 12.6%). In the case of interday analysis, 1 (1.0%), 2 (3.1%), and 4 (3.7%) showed much lower variabilities (RSD < 5%) than 3 (7.6%) and 5 (8.2%). Moreover, the five chemical markers showed good recoveries with good accuracies in the range of 90%-110%. Conclusions: The developed HPLC-UV method for the determination of the five chemical markers of the components of DF formula was validated. SUMMARY: DF formula, the herbal composition of Ephedra intermedia, Rheum palmatum and Lithospermum erythrorhizonFive chemical markers in DF formula were (+) pseudoephedrine (1) and (-)-ephedrine (2) for E. intermedia, aloe-emodin (3) and chrysopanol (4) for R. palmatum, and shikonin (5) for L. erythrorhizon, with quite different physico-chemical propertiesFive chemical markers in DF formula were determined by HPLC-UV Abbreviations used: EP: (-)-ephedrine; PSEP: (+) pseudoephedrine; HPLC: High-performance liquid chromatography; UV: Ultraviolet; LOD: Limit of detection; LOQ: Limit of quantification; RSD: Relative standard deviation. PMID- 29720826 TI - The Effects of Hesperidin and Quercetin on Serum Tumor Necrosis Factor-Alpha and Interleukin-6 Levels in Streptozotocin-induced Diabetes Model. AB - Background: Diabetes mellitus (DM) is a metabolic disorder that occurs as a result of absolute or relative insufficiency of insulin release and/or insulin effect due to impairment of carbohydrate, fat and protein metabolism, and it is characterized by hyperglycemia and leads to various complications. Objective: In this study, it was aimed to investigate the effects of hesperidin (HP) and quercetin, which are natural flavonoids, on serum malondialdehyde (MDA), glutathione (GSH), tumor necrosis factor alpha (TNF-alpha), and interleukin-6 (IL 6) levels in rats with streptozotocin (STZ)-induced diabetes. Materials and Methods: The experimental animals were divided into four groups, each group comprising ten rats designated as follows: Group 1 served as control rats (C); Group 2 served as diabetic rats (DM); Group 3 served as diabetic rats administered HP (DM + HP) (100 mg/kg b. w.); and Group 4 served as diabetic rats administered quercetin (DM + Q) (100 mg/kg b. w.). Results: Serum MDA and GSH levels were significantly higher in STZ-induced DM group than control group (P < 0.05). In DM + HP and DM + Q groups, MDA levels were significantly decreased compared to DM groups (P < 0.05), but there was no significant difference GSH levels between DM, DM + HP, and DM + Q groups (P > 0.05). TNF-alpha levels in STZ induced DM group were significantly decreased compared to control group (P < 0.05), and groups of DM + HP and DM + Q had higher serum TNF-alpha levels than STZ-induced DM group (P < 0.05). In STZ-induced DM group, serum IL-6 levels were decreased compared to control group (P < 0.05). Conclusion: As a result, in this study, we determined that HP and quercetin may play an effective role in regulating insulin metabolism metabolism in diabetes. However, considering the incompatibility of various results in the literature as well as our own results, we think that the actual role of cytokines in the pathogenesis of diabetes is one of the issues that need to be clarified in further studies. SUMMARY: Hesperidin (HP) and quercetin reduced the insulin, total cholesterol, triglyceride, low density lipoprotein cholesterol, and malondialdehyde (MDA) serum levels and raised the glutathione (GSH) levels compared to diabetes mellitus (DM) groupSZT induced DM increased the MDA serum levels and decreased the GSH levels compared to control groupHP and quercetin-treated rats showed higher interleukin-6 and tumor necrosis factor alpha cytokine levels than DM groupHP and quercetin may play an effective role in regulating insulin metabolism in diabetes. Abbreviations used: DM: Diabetes mellitus, MDA: Malondialdehyde, GSH: Glutathione; IL-6: Interleukin-6, TNF-alpha: Tumor necrosis factor alpha, HP: Hesperidin, Q; Quercetin, STZ: Streptozotocin, TC: Total cholesterol, TG: Triglyceride, HDL-C: High density lipoprotein cholesterol, LDL-C: Low density lipoprotein cholesterol, VLDL-C: Very-low-density lipoprotein cholesterol. PMID- 29720828 TI - Hepatoprotective Evaluation of Trapa natans against Drug-induced Hepatotoxicity of Antitubercular Agents in Rats. AB - Background: Medicinal herbs are significantly effective against a variety of liver disorders and Trapa natans was traditionally used for the treatment of anti inflammatory, pain disorder, and various types of hepatic ailment. Objective: The purpose of this study was to evaluate the hepatoprotective activity of T. natans fruit peel extract against antitubercular drugs (isoniazid + rifampicin [INH + RIF])-induced hepatotoxicity in rats. Materials and Methods: Liver toxicity was induced by INH + RIF at a dose level of 50 mg/kg each, intraperitoneally. for 15 days. Fifty percent ethanolic extract of T. natans (TNE) at a dose of 200 and 400 mg/kg was administered orally once daily for 15 days. The hepatoprotective activity was assessed using various biochemical parameters such as aspartate transaminase, alanine transaminase, alkaline phosphate, lactate dehydrogenase, albumin, cholesterol, and bilirubin. Furthermore, in vivo antioxidant activities and histopathological investigation were performed to assess hepatoprotective activity. Results: Obtained results demonstrated that the level of liver marker enzymes and antioxidant parameters were significantly altered by INH + RIF treatment. Treatment with T. natans peel extract causes significant (P < 0.01 to P < 0.001) reduction in liver injury & normalized all altered liver marker enzymes. In addition, TNE significantly normalized the activity of antioxidant enzymes, namely, lipid peroxidation (P < 0.01 to P < 0.001), reduced glutathione (P < 0.05 to P < 0.001), superoxide dismutase (P < 0.05 to P < 0.001), and catalase (P < 0.01 to P < 0.001) in the liver tissue of INH + RIF-treated groups. Histological observations of the liver tissues correlated with the biochemical observations. Conclusion: These findings powerfully support that the protective effect of T. natans fruit peel extract against liver injury which may be attributed to its hepatoprotective activity due to normalizes the altered liver marker enzymes and antioxidant defense status and thereby contributed to its antihepatotoxic potential. SUMMARY: Hepatotoxicity was induced in rats by intraperitoneal injection of antitubercular drugs (Isoniazid + Rifampicin at dose level of 50 mg/kg each) for 15 daysThe liver was screened for various marker enzymes and antioxidant parameters, which showed significant increase in the level of marker enzymes confirming induced hepatotoxicityHepatotoxic rats on treatment with T. natans peel extract (200 and 400 mg/kg) resulted in significant (P < 0.01 to P< 0.001) reduction in liver marker enzymes and antioxidant parametersThus, it can be concluded that Trapa natans fruit peel extract showed hepatoprotective potential against antitubercular drugs induced hepatotoxicity. Abbreviations used: INH: Isoniazid; RIF: Rifampicin; DIH: Drug-induced hepatotoxicity; CMC: Carboxy methyl cellulose; ALT: Alanine transaminase; ALP: Alkaline phosphate; CHL: Total cholesterol; ALB: Albumin; LDH: Lactate dehydrogenase; LPO: Lipid peroxidation; CAT: Catalase; GSH: Reduced glutathione; SOD: Superoxide dismutase; TNE: Trapa natans extract. PMID- 29720827 TI - Anti-inflammatory Effects of Brassica oleracea Var. capitata L. (Cabbage) Methanol Extract in Mice with Contact Dermatitis. AB - Background: Cabbage, Brassica oleracea var. capitata L., is one of the most common vegetables in the world. Because of its high levels of flavonoids and anthocyanins, cabbage has long been used as a herbal medicine. The antioxidant and anti-inflammatory properties of cabbage were also recently been reported. Objective: This study was designed to investigate the anti-inflammatory effects of cabbage in mice with contact dermatitis (CD). Materials and Methods: We investigated the effects of methanol extract of B. oleracea var. capitata L. (MEBO) on ear swelling, erythema, and histopathological changes in CD mice. Moreover, the effects on cytokine production and the spleen/body weight ratio were investigated. Results: Topical treatment with MEBO inhibited ear swelling and erythema significantly. MEBO also significantly inhibited epidermal hyperplasia and infiltration of immune cells. Furthermore, the levels of tumor necrosis factor-alpha, interferon-gamma, interleukin-6, and monocyte chemotactic protein-1 in inflamed tissues were effectively lowered by MEBO. Finally, MEBO did not affect body weight gain or spleen body weight ratio. Conclusions: These results indicate that cabbage can be used for the treatment of skin inflammation and that its anti-inflammatory activity is closely related to the inhibition of Th1 skewing reactions. SUMMARY: MEBO inhibited ear thickness, weight, and erythema in inflamed skinMEBO also prevented epidermal hyperplasia and infiltration of immune cellsThe levels of tumor necrosis factor-alpha, interferon gamma, interleukin-6, and monocyte chemotactic protein-1 in inflamed tissues were lowered by MEBO. Abbreviations used: AOO: Acetone and olive oil (4:1), CBA: Cytometric bead array, CD: Contact dermatitis, DEX: Dexamethasone, DNFB: 1-fluoro 2,4-dinitrofluorobenzene, GM-CSF: Granulocyte-macrophage colony-stimulating factor, ICAM-1: Intercellular Adhesion Molecule-1, LPS: Lipopolysaccharide, MEBO: Methanol extract of Brassica oleracea, MCP-1: Monocyte chemotactic protein-1, NO: Nitric oxide. PMID- 29720829 TI - Biochemical Evidence for the Antitumor Potential of Garcinia mangostana Linn. On Diethylnitrosamine-Induced Hepatic Carcinoma. AB - Background: Garcinia mangostana is extensively used in most of the Indian herbal pharmaceuticals and nutraceuticals. Objective: The objective of this study was to elucidate the underlying biochemical protective mechanism of G. Mangostana Linn. fruit extract (GME) in deterioration of diethylnitrosamine (DEN)-induced hepatic carcinoma (HCC) in rats. Materials and Methods: The cancer was induced using DEN to the experimental rats and treated with GME (200, 400, and 600 mg/kg) to find its anticancer property. The cancer biomarkers such as alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA), hepatic hydroxyl proline, total tissue protein, and tumor necrosis factor-alpha levels were measured using ELISA. The vascular endothelial growth factor expressions were also seen in liver tissues using immunohistochemistry. Results: In addition, there was a significant increase in serum AFP, CEA, hepatic hydroxylproline, and total tissue protein levels in HCC group versus the negative control group. In contrast, the groups with HCC subjected to either high or low dose of GME elicited significant reduction of AFP, CEA, hepatic hydroxylproline, and increase in total protein in serum compared to the untreated HCC rats. Interestingly, treatment with GME elicited marked improvement in the liver histological feature and downregulation of tumor necrosis factor-alpha levels in HCC groups. GME extract may have chemopreventive benefits by reducing the tumor promoting growth factor levels in HCC-induced group. Conclusion: To sum up, all findings on curative groups had proved clearly that the GME has anticarcinogenic effect on the development of liver cancer induced by DEN in rats. SUMMARY: Garcinia mangostana Linn. (GME) may have chemopreventive property by reducing the tumor promoting growth factor and tumor necrosis factor-alpha levels in diethylnitrosamine (DEN)-induced hepatic cancerThe suppression in the levels of cancer biomarkers by GME due to the presence of anticancer phytoconstituentsThe histological studies proved the effective dose of GME against DEN-induced experimental hepatic cancer. Abbreviations used: TNF-alpha: Tumor necrosis factor-alpha, PBS: Phosphate buffered saline, ROS: Reactive oxygen species, DNA: Deoxyribonucleic acid, GSH: Glutathione, VEGF: Vascular endothelial growth factor. PMID- 29720830 TI - Total Phenolics, Total Flavonoids, Antioxidant Capacities, and Volatile Compounds Gas Chromatography-Mass Spectrometry Profiling of Moringa oleifera Ripe Seed Polar Fractions. AB - Background: Academic reports have confirmed Moringa oleifera leaves to possess significant antioxidant capacities; however, such studies are unavailable for its ripe seeds even though they are more desirous for consumption due to their sweet taste. Objective: In this study, we investigated antioxidant capacities of four polar extracts (crude water, ethanol, butanol, and aqueous residue) from the plant's ripe seeds. Materials and Methods: Phytochemicals were extracted from the ripe seeds of M. oleifera using ethanol and water solvents at initial stage. Butanol and aqueous residue were then subsequently fractioned out from the ethanol extract. Phenolic and flavonoid contents of the polar extracts were determined. Then, their antioxidant capacities were quantified by 2,2'-azino bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) and 2,2-diphenyl-1 picrylhydrazyl (DPPH) radical scavenging assays. Finally, gas chromatography-mass spectrometry (GC-MS) analyses of the extracts were performed. Results: DPPH and ABTS tests showed that the polar extracts possess significant antioxidant capacities that ranged from 29 to 35.408 MUM Trolox equivalence antioxidant capacity (TEAC)/mg sample and 7 to 29 MUM TEAC/mg sample, respectively. The antioxidant capacities of the extracts corresponded to their phenolic and flavonoid contents that varied from 13.61 to 20.42 mg gallic acid equivalence/g sample and 0.58 to 9.81 mg quercetin equivalence/g sample, respectively. Finally, GC-MS analyses revealed antimicrobial phenolic compounds, 4-hydroxybenzaldehyde in crude water extract and 4-hydroxybenzene acetonitrile in the ethanol and butanol extracts, and aqueous residue. Conclusion: Our results established that M. oleifera ripe seeds have significant antioxidant activity which may be due to its phenolic and nonphenolic compounds content. SUMMARY: In this study, polar phytochemicals from ripe seeds of Moringa oleifera were extracted by water and ethanol solvents, and butanol extract and aqueous residue were subsequently fractioned out of the ethanol extract. The four polar extracts were shown to have significant antioxidant capacities which correspond to their phenolic contents. Further, antimicrobial compounds 4-hydroxybenzaldehyde and 4-hydroxybenzene acetonitrile were identified in the extracts by gas chromatography-mass spectrometry analyses. Abbreviations used: ABTS: 2,2'-azino-bis(3 ethylbenzothiazoline-6-sulfonic acid); DPPH: 2,2-diphenyl-1-picrylhydrazyl; TEAC: Trolox equivalence antioxidant capacity; QE: Quercetin equivalence; GAE: Gallic acid equivalence; GC-MS: Gas chromatography-mass spectrometry. PMID- 29720831 TI - Phytochemical Composition and Antioxidant Activities of Dianthus Thunbergii Hooper and Hypoxis Argentea Harv Ex Baker: Plants Used for the Management of Diabetes Mellitus in Eastern Cape, South Africa. AB - Background: Inhabitants of the Eastern Cape Province of South Africa use the roots of Dianthus thunbergii and corms of Hypoxis argentea to treat diabetes mellitus and other ailments. Objective: The objective of this study was to analyze the phytochemical composition and antioxidant activities of the aqueous and ethanol extracts of the roots and corms of two plants. Materials and Methods: Total phenolics, flavonoids, flavonols, proanthocyanidins, tannins, and alkaloids were determined by standard methods. The scavenging activities of the extracts against 1,1 diphenyl-2-picrylhydrazyl (DPPH), 2'-azino-bis (3-ethylbenthiazoline 6-sulfonic acid (ABTS), nitric oxide (NO), hydrogen peroxide (H2O2), and their ferric-reducing antioxidant potentials (FRAPs) were measured. Results: The ethanol extract of H. argentea had the highest content of phenolics (66.71 +/- 2.71 mg gallic acid equivalent/g) and tannins (1.18 +/- 0.07 mg TAE/g), while the ethanol extract of D. thunbergii gave higher contents of flavonoids and proanthocyanidins (62.21 +/- 1.75 mg Qe/g and 432.62 +/- 2.43 mg Ca/g, respectively). Flavonols were the most predominant in the aqueous extract of H. argentea (25.51 +/- 1.92 mg Qe/g). We observed a concentration-dependent response in the ABTS- and H2O2-scavenging activities and FRAP values of the extracts and standards (Vitamin C, butylated hydroxytoluene, and rutin). The ethanol extracts of both plants generally demonstrated better antioxidant activities against H2O2, NO, and ABTS while also possessing better reducing power than the aqueous extracts. The aqueous extract of D. thunbergii, however, showed the best DPPH scavenging activity. Conclusion: The higher content of phytochemicals and antioxidant capacity obtained for the ethanol extracts of D. thunbergii and H. argentea may prove to be valuable information in selecting suitable extraction solvents for the medicinal applications of both plants. SUMMARY: Ethanol extracts of Hypoxis argentea had the highest levels of phenolics and tanninsEthanol extracts of Dianthus thunbergii had the highest levels of flavonoids and proanthocyanidinsEthanol extracts of both plants possess better antioxidant activityagainst hydrogen peroxide, nitric oxide, and ABTS as well as higher reducingpower than the aqueous extractsAqueous extract of Dianthus thunbergii had the highest free radical scavenging activity as measured with DPPH. Abbreviations used: ABTS: 2'-azino-bis (3-ethylbenthiazoline-6-sulfonic acid); BHT: Butylated hydroxytoluene; DPPH: 1,1 diphenyl-2-picrylhydrazyl; DTA: Dianthus thunbergii aqueous extract (16.6%); DTE: Dianthus thunbergii ethanol extract (2.4%); Fe3+ TPTZ: Ferric tripyridyltriazine; FRAP: Ferric-reducing antioxidant potentials; GAE: Gallic acid equivalent; HAA: Hypoxis argentea aqueous extract (3.2%); HAE: Hypoxis argentea ethanol extract (1.8%); Qe: Quercetin equivalence; ROS: Reactive oxygen species; TBA: Thiobarbituric acid;TCA: Trichloroacetic acid. PMID- 29720832 TI - Study on Extraction and Purification of Apigenin and the Physical and Chemical Properties of Its Complex with Lecithin. AB - Background: The apigenin has important medicinal value. However, the low solubility of apigenin in water significantly reduced its application. Objective: In this study, the apigenin was extracted, and the complex of apigenin and lecithin was obtained by the solvent method and its physical and chemical properties were investigated. Materials and Methods: The apigenin was extracted from the leaves of Adinandra nitida. Afterward, its apigenin was obtained by hydrolysis and recrystallization. The solvent method was used to synthesis the complex of apigenin and lecithin. Tetrahydrofuran was used as the solvent. The physicochemical properties of the complex were investigated by the various methods such as ultraviolet (UV)-visible spectrometry, infrared spectrometry (IR), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and X-ray diffractometry. Results: No distinct difference was examined between the complex and physical mixture according to the UV analysis. While the result of Fourier transform-IR analysis indicated the characteristic absorption peaks of apigenin was subdued by the absorption peaks of lecithin. SEM showed the irregular form of the complex. In the DSC thermogram of the complex, the characteristic endothermic peak belonging to apigenin disappears, and the apparent amorphous properties are shown in the X-ray X-diffractograms of the complex. Conclusion: The synthetic process does not break the conjugated structure of apigenin. The complex is held together by Hydrogen bonding and van der Waals force and processes new physical and chemical characteristics. The industrial application of apigenin might be enhanced by the increase of the bioavailability. SUMMARY: The apigenin was extracted from the leaves of Adinandra nitidaThe complex of apigenin and lecithin was obtained by solvent methodThe physical and chemical properties of the complex were investigatedThe complex is held together by Hydrogen bonding and van der Waals force and processes new physical and chemical characteristics. Abbreviation used: SLA: The synthesis of the complex of soy lecithin and apigenin, PMSLA: The manufacture of a physical mixture of soybean lecithin and apigenin, UV: Ultraviolet, IR; Infrared Radiation, FT-IR: Fourier transform infrared, NMR: Nuclear magnetic resonance, SEM: Scanning electron microscopy, DSC: Differential scanning calorimetry, XRD: X ray diffractometry. PMID- 29720833 TI - Evidence for the Involvement of COX-2/VEGF and PTEN/Pl3K/AKT Pathway the Mechanism of Oroxin B Treated Liver Cancer. AB - Background: Oroxin B (OB) is one of flavonoids isolated from traditional Chinese herbal medicine Oroxylum indicum (L.) Vent. Recent studies suggest that flavonoids have obvious anti-liver tumors effect, but the precise molecular mechanism is still unclear. Objective: The current study was performed to investigate the antitumor effects of OB on human hepatoma cell line SMMC-772 and explore the part of molecular mechanisms in this process. Materials and Methods: MTT method, terminal deoxynucleotidyl transferase dUTP nick end labeling assay and flow cytometry were utilized to detect the inhibition of proliferation and the apoptosis after treating OB in of SMMC-7721 cells. The mRNA and proteins expressions of COX-2, vascular endothelial growth factor (VEGF), phosphatidylinositol-3-kinase (PI3K), p-AKT, and PTEN were measured by a real time polymerase chain reaction and Western Blot method. Results: The results showed that OB inhibited proliferation of SMMC-7721 cell in a dose-dependent manner, and induced its apoptosis. Moreover, OB unregulated PTEN and downregulated COX-2, VEGF, p-AKT, and PI3K. Conclusion: Our results demonstrated that OB significantly inhibits proliferation and induce apoptosis, which may be strongly associated with the inhibiting COX-2/VEGF and PTEN/PI3K/AKT pathway signaling pathway in SMMC-7721 cells, OB potentially be used as a novel therapeutic agent for liver cancer. SUMMARY: OB (Oroxin B) is one of the effective flavonoid components of traditional Chinese medicine O. indicum (L.)OB can inhibite the proliferation and promoted apoptosis of the human hepatoma cell line SMMC 7721OB plays a role of antitumor effect may to regulate COX 2/VEGF and PTEN/PI3K/AKT pathways directly or indirectly. Abbreviations used: OB: Oroxin B; MTT: 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide; COX-2: cyclooxygenase-2; PI3K: phosphatidylinositol 3 kinase; PTEN: Phosphatase and tensin homolog deleted on chromosome ten; VEGF: Vascular endothelial growth factor; RT-PCR: Reverse transcription polymerase chain reaction; DAPI: Diamidino 2 phenylindole; PBS: Phosphate buffer saline; FITC: Fluorescein isothiocyanate; PI: Propidium Iodide; RIPA: Radio immunoprecipitation assay lysis buffer; PMSF: Phenylmethanesulfonyl fluoride; PAGE: Polyacrylamide gel electrophoresis. PMID- 29720834 TI - Comparison of Bran-Processed and Crude Atractylodes Lancea Effects on Spleen Deficiency Syndrome in Rats. AB - Background: The rhizome of Atractylodes lancea (AL) is usually used for the treatment of various diseases such as spleen deficiency syndrome (SDS). Both bran processed and crude AL is included in Chinese Pharmacopoeia. The different efficacies of bran-processed and crude AL on SDS are largely unknown, and the mechanisms of AL effects have not been fully elucidated. Objective: The objective of the study was to compare the effects of bran-processed and crude AL and then assess the mechanisms of treating SDS. Materials and Methods: The model of SDS in rats was established using excessive exertion, combined with an irregular diet and intragastric administration of the extract of Sennae Folium, and different doses of bran-processed and crude AL were gavaged. The serum was analyzed by an enzyme-linked immunosorbent assay (ELISA), and small intestinal tissues were analyzed by reverse transcription-polymerase chain reaction (RT-PCR). Results: The injury of SDS was alleviated by the treatment of bran-processed and crude AL. Compared to model group, the indexes of trypsin (TRY), amylase (AMS), vasoactive intestinal peptide (VIP), somatostatin (SS), gastrin (GAS), substance P (SP), Na+ K+-ATPase, and succinic dehydrogenase in serum of each administration group were increased by ELISA, and the mRNA expressions of VIP, SS, GAS, and SP in small intestinal tissues were increased by RT-PCR. Furthermore, in a dose-dependent manner, the bran-processed and crude AL increased the levels of TRY, AMS, VIP, and GAS and the mRNA expression levels of VIP. Compared with the crude AL, the bran-processed AL was more effective in treating SDS. Conclusion: Through the mechanisms of treating SDS by AL, both bran-processed and crude AL has alleviated the symptoms of SDS. SUMMARY: Both bran-processed and crude Atractylodes lancea (AL) alleviated symptoms of spleen deficiency syndrome (SDS)Comparing with crude AL, bran. processed AL was more effective in treating SDSThe efficacy of AL could be partly attributed to digestive enzyme activity, gastrointestinal hormone levels, membrane protein activity, and changes in mitochondrial activity. Abbreviations used: AL: Atractylodes lancea; TRY: Trypsin; AMS: Amylase; VIP: Vasoactive intestinal peptide; SS: Somatostatin; GAS: Gastrin; SP: Substance P; ELISA: The enzyme-linked immunosorbent assay; mRNA: Messenger ribonucleic acid; SDH: Succinic dehydrogenase; RT-PCR: Reverse transcription-polymerase chain reaction; TCM: Traditional Chinese medicine; SDS: Spleen deficiency syndrome. PMID- 29720835 TI - Combination of Garcinia cambogia Extract and Pear Pomace Extract Additively Suppresses Adipogenesis and Enhances Lipolysis in 3T3-L1 Cells. AB - Background: Inhibition of adipogenesis has been a therapeutic target for reducing obesity and obesity-related disorders such as diabetes, hypertension, atherosclerosis, and cancer. For decades, anti-adipogenic potential of many herbal extracts has been investigated. One example is Garcinia cambogia extract (GE) containing (-)-hydroxycitric acid as an active ingredient. GE is currently marketed as a weight loss supplement, used alone or with other ingredients. Pear pomace extract (PE), another natural product, has been also shown to have anti adipogenic activity in a recent report. Objective: It was tested if the mixture of PE and GE (MIX) would produce more effective anti-adipogenic activity than PE or GE alone. Materials and Methods: Differentiation of 3T3-L1 preadipocyte was induced by adding insulin, dexamethasone, and isobutylmethylxanthine and lipid accumulation was measured by Oil Red O staining. Cellular markers for adipogenesis and lipolysis such as CCAAT/enhancer binding protein (C/EBP-alpha), peroxisome proliferator-activated receptor gamma (PPAR-gamma), fatty acid synthase (FAS), and hormone-sensitive lipase (HSL) was measured using immunocytochemistry. Results: MIX, compared to PE or GE alone, showed greater inhibition of lipid accumulation. Furthermore, MIX reduced the expression of adipogenesis-related factors C/EBP-alpha, PPAR-gamma, and FAS more than PE or GE alone did. In contrast, the expression of HSL the enzyme required for lipolysis was further enhanced in MIX-treated adipocytes compared to the PE or GE alone treated groups. Conclusions: Anti-adipogenic effect of PE and GE appears synergistic, and the MIX may be a useful therapeutic combination for the treatment of obesity and obesity-related diseases. SUMMARY: PE and GE efficiently inhibited adipocyte differentiation by suppressing the expression of adipogenic transcription factor CEBP-alpha and PPAR-gamma.PE and GE significantly decreased the expression of adipogenic enzyme FAS.PE and GE increased the expression of lipid degrading enzyme HSL.Mixture of PE and GE exhibited additive or moderately synergistic effect on adipocyte differentiation and lipid accumulation. Abbreviations used: CEBP-a: CCAT/enhancer binding protein alpha, CI: Combination Index, FAS: Fatty acid synthase, GE: Garcinia cambogia extract, HSL: Hormone sensitive lipase, PE: Pear pomace extract, PPAR-gamma: Peroxisome proliferator activated receptor gamma. PMID- 29720836 TI - Identification of Potential Anticancer Protein Targets in Cytotoxicity Mediated by Tropical Medicinal Fern Extracts. AB - Background: Medicinal fern species represent a potentially important source for both food and medicinal applications. Previously, two underutilized tropical fern species (Blechnum orientale and Phymatopteris triloba) were reported with cytotoxic activities against selected cancer cell lines. However, the exact mechanism remains elusive. Objective: In this paper, we reported the identification of six differentially expressed proteins isolated from cancer cells, following exposure to the cytotoxic fern extracts. Materials and Methods: The identities of these cancer proteins were determined by matrix-assisted laser desorption ionization time-of-flight protein sequencing. Results: The cancer proteins were identified as follows: elongation factor 1-gamma, glyceraldehydes-3 phosphate dehydrogenase, heat shock protein 90-beta, heterogeneous nuclear ribonucleoprotein-A2/B1, truncated nucleolar phosphoprotein B23, and tubulin-beta chain. To the best of our knowledge, this paper represents the first time these cancer proteins are being reported, following exposure to the aforementioned cytotoxic fern extracts. Conclusion: It is hoped that further efforts in this direction could lead to the identification and development of target-specific chemotherapeutic agents. SUMMARY: Cytotoxic fern extracts were tested in anti cancer proteomic works.Six differentially-expressed cancer proteins were identified.Potential anti-cancer protein targets were reported. Abbreviations used: EF: Elongation factor; HRP: Horseradish peroxidase; HSP: Heat shock protein; MALDI: Matrix-assisted laser desorption/ionization. PMID- 29720837 TI - Ingenine F: A New Cytotoxic Tetrahydro Carboline Alkaloid from the Indonesian Marine Sponge Acanthostrongylophora ingens. AB - Background: Marine organisms are established to be a wealthy source of bioactive compounds with diverse chemical structures and bioactivities. Acanthostrongylophora ingens is known to be rich with pyrimidine b-carboline and manzamine-type alkaloids. The goal of the present work is to isolate and identify new alkaloids from A. ingens as well as to assess the cytotoxic potential of these metabolites towards various cancer cell lines. Methods: The crude MeOH extract of the sponge was separated by vacuum liquid chromatography (VLC), using n-hexane, EtOAc, and MeOH. The EtOAc fraction was chromatographed on VLC, SiO2, sephadex LH-20, and RP18 columns, affording four metabolites. Their structures were identified using infrared, ultraviolet, high-resolution mass spectrometry, and nuclear magnetic resonance spectroscopic techniques, as well as comparison with the published data. Results: A new 1,2,3,4-tetrahydro-beta-carboline (THbetaCs) alkaloid, ingenine F (4) and three known compounds: Annomontine (1), acanthomine A (2), and 1-oxo-1,2,3,4-THbetaCs (3) were isolated and identified. Ingenine F (4) exhibited cytotoxic activity toward hormone-dependent breast carcinoma (MCF7), colon carcinoma (HCT116), and lung carcinoma (A549) cell lines with IC50 values of 2.82, 1.00, and 2.37 MUM, respectively, compared to doxorubicin (IC50 0.012, 0.036, and 0.102 MUM, respectively). Conclusion: It is the first report for the isolation of THbetaCs alkaloids from A. ingens. The THbetaCs alkaloid with N-methylbutyramide unit as found in ingenine F is very rarely encountered in nature. Ingenine F may provide new promising candidates for potential cytotoxic agent. SUMMARY: Ingenine F, a new 1,2,3,4-THbetaCs derivative (4) and three known alkaloids (1-3) were isolated from A. ingens. Their structures were verified by various spectroscopic analyses. Compound 4 had potent cytotoxic effect toward MCF7, HCT116, and A549 cancer cell lines. Abbreviations used: 1D: One-dimensional; 2D: Two-dimensional; CC: Column chromatography; COSY: Correlations spectroscopy; DMSO: Dimethyl sulfoxide; HMBC: Heteronuclear multiple bond correlation experiment; HRESIMS: High resolution electrospray ionization mass spectrometry; HSQC: Heteronuclear single quantum correlation; IR: Infrared; LCQ: Liquid chromatography quadrupole; LTQ: Linear trap quadropole; NMR: Nuclear magnetic resonance; RP: Reversed phase; SiO2: Silica gel; TLC: Thin-layer chromatography; UV: Ultraviolet; VLC: Vacuum liquid chromatography. PMID- 29720838 TI - Optimal Processing Conditions of Boswellia carteri Birdw. Using Response Surface Methodology. AB - Background: Boswellia carteri Bridw. is being widely used for its anti inflammatory properties, as well as for wound healing, antimicrobial, and immunomodulatory properties, and boswellic acids (BAs) are considered to be the main active constituents. Objectives: To investigate optimal conditions of stir baking process for the resin of B. carteri with vinegar of using response surface methodology (RSM). Materials and Methods: The concentration of acetic acid, heating temperature, and heating time were set as influential factors, and the yields of chemical compounds were the response values which were optimally designed by a Box-Behnken design. The amounts of 11-keto-beta-boswellic acid (KBA) and alpha-boswellic acid (alphaBA) in B. carteri resin were quantified using high-performance liquid chromatography analysis. Results: Maximum amounts of KBA and alphaBA in B. carteri resin were obtained using 6% acetic acid for 10 min at 90 degrees C in preliminary test. Two factor interactions, such as acetic acid concentration-heating temperature and heating temperature-heating time, were significantly observed by multiple regression analysis. Optimal processing conditions from RSM were 5.83% for acetic acid concentration, 9.56 min for heating time, and 89.87 degrees C for heating temperature. Under the modified conditions, the experimental value of the response was 11.25 mg/g, which was similar to the predicted value. Conclusions: The results suggest that the optimal conditions for the stir-baking process of B. carteri resin were determined by RSM, which was reliable and applicable to practical processing of herbal medicine. SUMMARY: The resin of Boswellia carteri was macerated in aqueous acetic acid and heated using an oven for stir baking processThe interaction between heating temperature and heating time was the most significantOptimal conditions for processing B. carteri resin were determined as 5.83% acetic acid, 9.56 min for heating time, and 89.87 degrees C for heating temperature. Abbreviations used: BAs: Boswellic acids; KBA: 11 keto beta boswellic acid; alphaBA: alpha boswellic acid; BBD: Box-Behnken design; RSM: Response surface method; HPLC: High performance liquid chromatography; LOD: Limits of determination; LOQ: Limits of quantification; RSD: Relative standard deviation; ANOVA: Analysis of variance. PMID- 29720839 TI - Protective Effect of Water Extracted Spirulina maxima on Glutamate-induced Neuronal Cell Death in Mouse Hippocampal HT22 Cell. AB - Introduction: Spirulina maxima was used as important nutritional source in the Aztec civilization because it is rich in proteins and vitamins. It contains various antioxidants such as phycocyanin and flavonoids. Based on abundant antioxidants, S. maxima is known to possess anti-inflammatory effect, especially on neuronal cells. Materials and Methods: S. maxima was extracted in water and contain of phycocyanin was identified by high-performance liquid chromatography. Cell viability test was performed with treatment of S. maxima extract. After, oxidative stress-related mechanisms were evaluated by detecting the accumulation of reactive oxygen species (ROS) and Ca2+ influx, and decrease of mitochondrial membrane potential (MMP) level. Then, the glutathione (GSH) related assays were conducted. Results: The water extracted S. maxima exerted the neuroprotective activity by attenuating the ROS and Ca2+ formation, maintaining the MMP level, and protecting the activity of the antioxidant enzymes by increasing reduced GSH against oxidative stress compared to control. Conclusion: The results suggested that water extracted S. maxima showed powerful neuroprotective effect through the mechanism related to antioxidant activity, able to preventing the radical mediated cell death. SUMMARY: Water extracted Spirulina maxima contains C phycocyaninWater extracted Spirulina maxima exerts neuroprotective effect on HT22 cellTo investigate the protective mechanisms, reactive oxygen species, Ca2+, mitochondrial membrane potential, Glutathione-related assays were performed. Abbreviations used: ROS: Reactive oxygen species; MMP: Mitochondrial membrane potential; GSH: Glutathione; GSSG: Glutathione disulfide, oxidized glutathione; GPx: Glutathione peroxidase; GR: Glutathione reductase; DMEM: Dulbecco's modified Eagle's medium; FBS: Fetal bovine serum; DCF-DA: 2',7'-dichlorofluorescein diacetate; PBS: Phosphate buffered serum; Rho 123: Rhodamine 123; NADPH: Nicotinamide adenine dinucleotide phosphate; DTNB: 5,5'-dithiobis-2-nitrobenzoic acid, Ellman's reagent; GSSG-R: Glutathione disulfide reductase; MTT: 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide; DMSO: Dimethyl sulfoxide; HPLC: High-performance liquid chromatography. PMID- 29720840 TI - Rapid Screening and Characterization of Acetylcholinesterase Inhibitors from Yinhuang Oral Liquid Using Ultrafiltration-liquid Chromatography-electrospray Ionization Tandem Mass Spectrometry. AB - Background: At present, approximately 17-25 million people in the world suffer from Alzheimer's disease (AD). The most efficacious and acceptable therapeutic drug clinically are the acetylcholinesterase inhibitors (AChEIs). Yinhuang oral liquid is a Chinese medicine preparation which contains AChEIs according to the literatures. However, no strategy has been presented for rapid screening and identification of AChEIs from Yinhuang oral liquid. Objective: To develop a method for rapid screening and identification of AChEIs from Yinhuang oral liquid using ultrafiltration-liquid chromatography-electrospray ionization tandem mass spectrometry (UF-LC-ESI-MS/MS). Materials and Methods: In this study, UF incubation conditions such as enzyme concentration, incubation time, and incubation temperature were optimized so as to get better screening results. The AChEIs from Yinhuang oral liquid were identified by high-performance liquid chromatography-ESI-MS and the improved Ellman method was used for the AChE inhibitory activity test in vitro. Results: The results showed that Yinhuang oral liquid can inhibit the activity of AChE. We screened and identified seven compounds with potential AChE inhibitory activity from Yinhuang oral liquid, which provided experimental basis for the treatment and prevention of AD. Conclusion: The current technique was used to directly screen the active ingredients with acetylcholinesterase inhibition from complex traditional Chinese medicine, which was simple, rapid, accurate, and suitable for high-throughput screening of AChEI from complex systems. SUMMARY: A UF-LC-ESI-MS/MS method for rapid screening and identification of AChEIs from Yinhuang oral liquid was developedSeven compounds were screened and identified with potential AChE inhibitory activity from Yinhuang oral liquidIt provided experimental basis of Yinhuang oral liquid for the treating and preventing AD. Abbreviations used: (AD): Alzheimer's disease; (UF-LC-ESI-MS/MS): ultrafiltration-liquid chromatography-electrospray ionization tandem mass spectrometry; (AChEIs): acetylcholinesterase inhibitors. PMID- 29720841 TI - A Novel Method to Mask the Bitter Taste of Berberine Hydrochloride: Powder Surface Modification. AB - Background: Berberine hydrochloride (BH) is widely used as a nonprescription drug to treat diarrhea without drug resistance and side effects worldwide. However, its drastic bitterness affects patient compliance severely. Hence, it is essential to mask the bitter taste of BH. Objective: Powder surface modification technology is attempted to mask the bitterness of BH through changing the surface properties in vibromill. The purpose of this study was to apply this technology to mask the bitterness of BH and improve the patient compliance. Materials and Methods: Initially, to prepare the modifier-BH composites, some parameters were optimized, including type of modifiers, ratio between BH and modifiers, and composite time. Then, the contact angles, scanning electron microscopy, and infrared (IR) spectroscopy were utilized to evaluate the microstructure of composites. Moreover, electronic tongue measurement, animal performance test, and bitterness evaluation methods were applied to evaluate the masking effect. Results: Based on the results of bitter taste evaluations, mannitol was chosen as the best modifier, and the optimal ratio of BH and mannitol was 6:4 with grinding together for 2 min in vibromill. For the composites prepared by this process, the IR spectroscopy and surface properties were similar with that of mannitol, and the microstructure was also demonstrated that small particles of mannitol successfully coated on the surface of BH. Special structure of the composites decreased the contact area between BH and external media and finally inhibited the bitterness. This effect was confirmed by three different kinds of methods. Conclusion: Our study provides a novel method to mask the bitter taste of drugs. It will be of great interest to pharmaceutical experts and pharmacists. SUMMARY: Powder surface modification, a novel and different from previous technology, is used to prepare modifier-berberine hydrochloride composites to mask the bitter taste of BHElectronic tongue measurement, animal performance test, human sensory test, and chemical evaluation method were simultaneously applied to evaluate the masking effectA novel method to mask the bitter taste of drugs was provided. Abbreviations used: BH:Berberine hydrochloride; CDI: Clostridium difficile infection; ODT: Orally disintegrating tablets; HPLC: High-performance liquid chromatography; CAs: Contact angles; SEM: Scanning electron microscopy; IR: Infrared spectrogram. PMID- 29720842 TI - In vitro Antioxidant Potentials of Cyperus rotundus L. Rhizome Extracts and Their Phytochemical Analysis. AB - Background: Cyperus rotundus L. (family Cyperaceae), native to India, is a multivalent medicinal plant widely used in conventional medicine. The research reports on bioactive components from C. rotundus L. are scanty. Objective: The objective of the study was to optimize the best solvent system and bioprospect the possible phytochemicals in C. rotundus L. rhizome (CRR). Materials and Methods: The phytochemicals were extracted from the rhizomes of C. rotundus L. by successive Soxhlet technique with solvents of increasing polarity. The resultant extracts were analyzed for their total flavonoid content (TFC), total phenolic content (TPC), total proanthocyanidin content (TPAC), in vitro antioxidant potential, and inhibition of lipid peroxidation. The 70% acetone extract of CRR was analyzed using gas chromatography-mass spectrometry (GC-MS) for probable phytochemicals. Results and Discussion: The TPC, TFC, and TPAC estimates ranged from 0.036 +/- 0.002 to 118.924 +/- 5.946 MUg/mg extract, 7.196 +/- 0.359 to 200.654 +/- 10.032 MUg/mg extract, and 13.115 +/- 0.656 to 45.901 +/- 2.295 MUg/mg extract, respectively. The quantities of TPC, TFC, and TPAC were found to be the highest in 70% acetone extract. The 70% acetone and 70% methanol extracts revealed best radical scavenging effect. GC-MS analysis of CRR extract revealed the presence of a novel compound 1 (2)-acetyl-3 (5)-styryl-5 (3) methylthiopyrazole. Conclusion: The study indicated that 70% acetone and 70% methanol extracts of CRRs can be a potential source of antioxidants. SUMMARY: The studies suggest 70% methanol and acetone as the suitable solvents for the extraction of phytochemicalsNovel compound 1(2)-Acetyl-3(5)-styryl-5(3) methylthiopyrazole was detected in 70% acetone extract. Abbreviations used: ACRE: Acetone C. rotundus L. rhizome extract; AlCl3: Aluminum chloride; AQRE: Aqueous C. rotundus L. rhizome extract; CE: Catechin Equivalent; CHRE: Chloroform C. rotundus L. rhizome extract; CRR: C. rotundus L. rhizome; DPPH: 2,2 diphenyl-1 picrylhydrazyl; ETRE: Ethanolic C. rotundus L. rhizome extract; EARE: Ethyl acetate C. rotundus L. rhizome extract; FRP: Ferric reducing power; GAE: Gallic acid equivalent; GC-MS: Gas chromatography-mass spectrometry; HERE: Hexane C. rotundus L. rhizome extract; MERE: Methanolic C. rotundus L. rhizome extract; PERE: Petroleum ether C. rotundus L. rhizome extract; QE: Quercetin equivalent; RNS: Reactive nitrogen species; ROS: Reactive oxygen species; TFC: Total flavonoid content; TPC: Total phenolic content; TPAC: Total proanthocyanidin content. PMID- 29720844 TI - A law of iterated logarithm for the subfractional Brownian motion and an application. AB - Let [Formula: see text] be a sub-fractional Brownian motion with Hurst index [Formula: see text]. In this paper, we give a local law of the iterated logarithm of the form [Formula: see text] almost surely, for all [Formula: see text], where [Formula: see text] for [Formula: see text]. As an application, we introduce the [Formula: see text]-variation of [Formula: see text] driven by [Formula: see text] [Formula: see text] with [Formula: see text]. PMID- 29720843 TI - Modulatory Effect of Carotenoid Supplement Constituting Lutein and Zeaxanthin (10:1) on Anti-oxidant Enzymes and Macular Pigments Level in Rats. AB - Background: Human eye is constantly exposed to different wavelengths and intensities of light. Oxidative stress results in distinct changes to retinal organs and tissues. Macular pigments (lutein and zeaxanthin), present in the central macular region, provide protection from photodamages by absorption of high energy blue light and also by virtue of their anti-oxidant activity. Ocular phototoxicity is thus prevented by our efficient anti-oxidant system, in both young and old. One of the best commercial sources of pure lutein and zeaxanthin is Marigold flowers. Objective: In the present study, oil-soluble dietary carotenoid supplement constituting lutein and zeaxanthin in the ratio of 10:1 was evaluated for its modulatory effect on anti-oxidant enzymes and macular pigments in the serum and macula of the Swiss albino rats. Materials and Methods: Male Swiss albino rats were treated with carotenoid supplement constituting lutein and trans-Zeaxanthin (10:1) at two different doses daily, under standard experimental conditions for 42 days. End of the treatment, serum and macula were collected and used for measurement of lutein and zeaxanthin levels along with anti-oxidant parameters. Statistical Analysis Used: Statistical differences were assessed by analysis of variance (ANOVA) followed by Dunnet's test. P < 0.05 was considered statistically significant. All the results were expressed as mean +/- standard deviation. Results: The supplement exhibited significant elevation of anti oxidant enzyme levels in treated animals in dose-dependent manner. Concomitantly, the total anti-oxidant capacity has also been found to show similar increment at the end of the study period. This study revealed significant expression of the two macular pigments investigated. Conclusions: Our study, therefore, provides a strong claim for the anti-oxidant effect of the oil-soluble dietary carotenoid supplement, and thus substantiates its use in the prevention of phototoxic damage to the eye on long-term supplementation. SUMMARY: Apart from its ornamental value, Marigold (Tagetes erecta L.) flowers are well known as an herbal remedy due to its antimicrobial, anti-inflammatory, and anti-oxidant activities. Epidemiological studies have implicated prolonged exposure to ultraviolet radiations & blue light and in turn oxidative stress in the pathogenesis of the majority of the eye diseases, since childhood. Studies have shown that with age a number of changes occur predisposing the retinal various organs and tissues to oxidative stress. These changes manifest in decreased levels in plasma of Vitamin C, Vitamin E, glutathione, Retinal Pigment Epithelium (RPE), Catalase (CAT), Super Oxide Dismutase (SOD), Thiobarbituric Acid Reactive Substance (TBARS), and total anti-oxidant capacity (TAC). Age- and diet-related loss of Lutein and Zeaxanthin enhance phototoxic damage to the eye, and thus supplementation of these carotenoids becomes vital for maintaining optimal eye healthIn the present study, XanMax(r) 2002 oil, a supplement constituting lutein and trans-Zeaxanthin, extracted from the flowers of T. erecta, was evaluated for its modulatory effect on anti-oxidant enzymes and macular pigments in the serum and macula of the Swiss albino rats. XanMax(r) 2002 oil exhibited significant elevation of anti-oxidant enzyme levels in treated animals in dose-dependent manner. Concomitantly, the TAC has also been found to show similar increment at the end of the study period. This study revealed significant expression of the two macular pigments investigated. Abbreviations used: AMD: Age related Macular Diseases; RPE: Retinal Pigment Epithelium; CAT: Catalase; SOD: Super Oxide Dismutase; TAC: Total Antioxidant Capacity; ROS: Reactive Oxygen Species; LC-MS: Liquid chromatography mass spectrometry; p.o.: Per Orally; CMC Carboxymethyl cellulose. PMID- 29720845 TI - A Cauchy type inequality for Mobius operations. AB - In this article, we show two fundamental features of the restriction of Mobius operations to the real numbers, that is, a Cauchy type inequality and a criterion for convergence of series. PMID- 29720846 TI - Sherman's and related inequalities with applications in information theory. AB - In this paper we give extensions of Sherman's inequality considering the class of convex functions of higher order. As particular cases, we get an extended weighted majorization inequality as well as Jensen's inequality which have direct connection to information theory. We use the obtained results to derive new estimates for Shannon's and Renyi's entropy, information energy, and some well known measures between probability distributions. Using the Zipf-Mandelbrot law, we introduce new functionals to derive some related results. PMID- 29720847 TI - On Kedlaya-type inequalities for weighted means. AB - In 2016 we proved that for every symmetric, repetition invariant and Jensen concave mean [Formula: see text] the Kedlaya-type inequality [Formula: see text] holds for an arbitrary [Formula: see text] ([Formula: see text] stands for the arithmetic mean). We are going to prove the weighted counterpart of this inequality. More precisely, if [Formula: see text] is a vector with corresponding (non-normalized) weights [Formula: see text] and [Formula: see text] denotes the weighted mean then, under analogous conditions on [Formula: see text], the inequality [Formula: see text] holds for every [Formula: see text] and [Formula: see text] such that the sequence [Formula: see text] is decreasing. PMID- 29720848 TI - Existence of weak solutions of stochastic delay differential systems with Schrodinger-Brownian motions. AB - By using new Schrodinger type inequalities appearing in Jiang and Uso (J. Inequal. Appl. 2016:233, 2016), we study the existence of weak solutions of stochastic delay differential systems with Schrodinger-Brownian motions. PMID- 29720849 TI - Split-dose bowel preparation versus water exchange and adenoma detection rate: have we arrived there yet? PMID- 29720850 TI - Diagnosis and treatment of superficial esophageal cancer. AB - Endoscopy allows for the screening, early diagnosis, treatment and follow up of superficial esophageal cancer. Endoscopic submucosal dissection has become the gold standard for the resection of superficial squamous cell neoplasia. Combinations of endoscopic mucosal resection and radiofrequency ablation are the mainstay of the management of Barrett's associated neoplasia. However, protruded, non-lifting or large lesions may be better managed by endoscopic submucosal dissection. Novel ablation tools, such as argon plasma coagulation with submucosal lifting and cryoablation balloons, are being developed for the treatment of residual Barrett's esophagus, since iatrogenic strictures still hamper the development of extensive circumferential resections in the esophagus. Optimal surveillance modalities after endoscopic resection are still to be determined. The assessment of the risk of lymph-node metastases, as well as of the need for additional treatments based on qualitative and quantitative histological criteria, balanced to the patient's condition, requires a dedicated multidisciplinary team decision process. The need for trained endoscopists, expert pathologists and surgeons, and specialized multidisciplinary meetings underlines the role of expert centers in the management of superficial esophageal cancer. PMID- 29720851 TI - Role of bile acids in inflammatory bowel disease. AB - Bile acids (BAs) are the end product of cholesterol catabolism. Their synthesis is regulated by the nuclear receptor farnesoid X receptor, also involved in the control of their enterohepatic circulation. Inflammatory bowel diseases (IBD), which include Crohn's disease (CD) and ulcerative colitis (UC), are multifactorial diseases characterized by diarrhea. The pathogenesis of diarrhea in IBD is still debated. The most important factor is the inflammatory process of the intestinal wall, causing alterations of solute and water absorption/secretion, deterioration of epithelial cell integrity, disruption of the intestinal microflora homeostasis, and impairment of specific transport mechanisms within the gut (including that of BAs). In this review, we summarize the current state of the art in this area and we critically evaluate the alterations of BA metabolism in patients with CD and UC. PMID- 29720852 TI - Gastrointestinal dysmotility in critically ill patients. AB - Gastrointestinal (GI) motility disorders are commonly present in critical illness. Up to 60% of critically ill patients have been reported to experience GI dysmotility of some form necessitating therapeutic intervention. It has been attributed to various factors, related to both the underlying disease and the therapeutic interventions undertaken. The assessment of motility disturbances can be challenging in critically ill patients, as the available tests used to detect abnormal motility have major limitations in the setting of an Intensive Care Unit. Critically ill patients with GI dysmotility require a multifaceted treatment approach that addresses multiple causes and utilizes multiple pharmacological pathways. In this review, we discuss the pathophysiology, assessment and management of GI dysmotility in critically ill patients. PMID- 29720853 TI - Secondary metastatic lesions to colon and rectum. AB - Metastatic lesions of the colon are a rare clinical entity that may present difficulties in management. The incidence of these metastases appears to be increasing, as a result of physicians' greater awareness during follow-up investigations of a primary neoplasm. Furthermore, the presence of a greater proportion of these abnormalities at autopsy should be a triggering factor for further investigation for doctors dealing with colorectal oncology. Their clinical presentation may vary from asymptomatic to signs similar to those of colorectal cancer. However, immunohistological analysis is considered the cornerstone for differentiating metastases to the colon, originating from other primaries, from primary colorectal neoplasms. Survival reports and treatment options vary. This article concisely presents the main characteristics of the secondary lesions to the colon from neoplasms that metastasize to the large intestine (namely, lung, ovary, breast, prostate, kidney, and melanoma) focusing on their incidence, their clinical presentation and the workup investigation. Physicians aware of this uncommon entity are much better prepared to apply an efficient diagnosis and workup, as well as an appropriate treatment strategy. PMID- 29720854 TI - Non-alcoholic fatty liver disease: controlling an emerging epidemic, challenges, and future directions. AB - Non-alcoholic fatty liver disease (NAFLD) affects over 30% of the United States population and is projected to become a leading cause of chronic liver disease by 2020. As a result, the economic and societal burden of NAFLD is far-reaching. The cost of managing NAFLD complications has an estimated 10 year economic burden of $908 billion. This review provides an overview of current knowledge on NAFLD, with emphasis on identifying gaps in its diagnosis and management, and proposes future directions to address these limitations. Despite the increasing prevalence of NAFLD, there is limited knowledge and practice regarding its natural history, staging, diagnosis, and management. Though a challenging task, opportunities for bridging these gaps should focus on the development of noninvasive biomarkers, the elucidation of biological pathways, the creation of up-to-date screening guidelines, and the organization of clinical trials of longer duration to determine clinical endpoints and assess the safety of new treatment options. PMID- 29720855 TI - Analogy between non-alcoholic steatohepatitis (NASH) and hypertension: a stepwise patient-tailored approach for NASH treatment. AB - Non-alcoholic steatohepatitis (NASH) is a common liver disorder worldwide. Although there has been improvement in our understanding of the natural history and pathogenesis of the disease, there is still no approved therapy for NASH. NASH shares many similarities with primary hypertension, in that both are extremely common disorders that can easily lead to serious complications if left untreated. Both conditions are viewed as "silent killers", because the disease can progress over a period of time prior to the occurrence of potentially deadly outcomes. While attempts to find the "miracle pill" for NASH are unrealistic, we can make an analogy with the "stepwise combination" approach developed over the last few decades for the treatment of hypertension. In the present review, we summarize some of the similarities in the concepts that underlie NASH and hypertension. The development of a stepwise patient-tailored method for the treatment of NASH is presented. PMID- 29720858 TI - Preoperative elective transjugular intrahepatic portosystemic shunt for cirrhotic patients undergoing abdominal surgery. AB - Despite improvements in the surgical techniques, anesthesia and intensive care, abdominal surgery in patients with cirrhosis remains a challenge. Transjugular intrahepatic portosystemic shunt (TIPS) has been used to manage complications of portal hypertension. Preoperative TIPS (prophylactic) can theoretically improve outcomes in this population. Seven original studies were identified with 24 patients who underwent prophylactic TIPS before abdominal surgery. No perioperative mortality or major abdominal bleeding attributable to portal hypertension was reported for this cohort. One patient had poor wound healing post surgery (4.2%), one had right heart failure (4.2%), and five developed hepatic encephalopathy (20.8%) post surgery. More evidence is needed to optimize the timing of surgery post TIPS and the selection of an appropriate stent size to further decrease the associated morbidity. Overall, the decision for prophylactic TIPS placement for cirrhotic patients undergoing abdominal surgery needs individualization to allow its safe use with concomitant improvement in perioperative morbidity. PMID- 29720856 TI - Nuon-invasive screening for esophageal varices in patients with liver cirrhosis. AB - Esophageal varices are one of the main complications of liver cirrhosis. Upper gastrointestinal endoscopy is the gold standard for the detection of esophageal varices. Many less invasive methods for screening of varices have been investigated and the most recent Baveno VI guidelines suggest that endoscopy is not necessary in patients with liver stiffness <20 kPa and platelets >150,000/MUL. A critical review of the literature was performed concerning non invasive or minimally invasive methods of screening for esophageal varices. Liver and spleen elastography, imaging methods including computed tomography, magnetic resonance imaging and ultrasound, laboratory tests and capsule endoscopy are discussed. The accuracy of each method, and its advantages and limitations compared to endoscopy are analyzed. There are data to support the Baveno VI guidelines, but there is still a lack of large prospective studies and low specificity has been reported for the liver stiffness and platelet count combination. Spleen elastography has shown promising results, as there are data to support its superiority to liver elastography, but it needs further assessment. Computed tomography has shown high diagnostic accuracy and can be part of the diagnostic work up of cirrhotic patients in the future, including screening for varices. PMID- 29720859 TI - Endoscopic submucosal dissection versus endoscopic mucosal resection for type 0 II superficial gastric lesions larger than 20 mm. AB - Background: Endoscopic mucosal resection (EMR) and endoscopic submucosal dissection (ESD) are increasingly used for the treatment of superficial gastrointestinal neoplasia. However, the limits and the indications for each technique are still debated. Our retrospective study aimed to compare these techniques in patients with gastric flat lesions larger than 20 mm without the non-lifting sign. Methods: Between January 2013 and July 2016, a total of 36 patients with early gastric flat lesions larger than 20 mm and without the non lifting sign were resected by ESD and were followed up by endoscopy. As a control group, 40 EMR cases from our database were matched. En bloc and curative resection were compared between the two groups according to histological assessment, tumor size, recurrence, complication rate, and procedure time. A Kaplan-Meier comparison was performed for both groups with a log-rank test to compare the survival curves; the chi-square test was employed for other parameters. Results: En bloc resection rate and curative resection rate were significantly higher in the ESD group than in the EMR group. Procedure time was significantly longer in the ESD group. No significant differences were found in the recurrence and complication rates, although the former were higher in the EMR group and the latter in the ESD group. Survival curves were similar for both groups. Conclusions: Our retrospective analysis seems to confirm a clear advantage for ESD over EMR in removing early superficial gastric neoplasm. Although ESD has expanded the endoscopic resectability of endoscopic gastric lesions, EMR may still be considered one of the therapeutic options for flat gastric lesions without the non-lifting sign. PMID- 29720860 TI - Continued versus interrupted aspirin use and bleeding risk after endoscopic submucosal dissection of gastric neoplasms: a meta-analysis. AB - Background: Balancing the risk of bleeding and thromboembolic events for patients who use aspirin and need to undergo endoscopic submucosal dissection (ESD) for gastric neoplasms is a delicate process. The current guidelines from different associations provide inconsistent recommendations. Methods: MEDLINE and EMBASE databases were searched through August 2017 for studies that compared the risk of post-ESD bleeding in patients who continued aspirin vs. those who discontinued aspirin preoperatively. Pooled odds ratios (OR) and 95% confidence intervals (CI) were calculated using a random-effect model, generic inverse variance method. The between-study heterogeneity was quantified using the Q statistic and I2 . Results: A total of five studies that included 700 patients were identified. Our meta-analysis could not demonstrate a significantly increased risk of post-ESD bleeding among the aspirin-continued group compared to the aspirin-interrupted group, the pooled OR being 1.81 (95%CI 0.85-3.83). The statistical heterogeneity was insignificant, with an I2 of 25%. Nine thrombotic events occurred in the aspirin-interrupted group whereas none occurred in the aspirin-continued group. Conclusions: This meta-analysis could not demonstrate that continuation of aspirin significantly increases the risk of post-ESD bleeding. However, the analysis was restricted by the small sample size and the observational nature of the primary studies. Randomized controlled trials are still needed to clarify this risk. PMID- 29720857 TI - Portal vein thrombosis in cirrhosis: diagnosis, natural history, and therapeutic challenges. AB - Portal vein thrombosis (PVT) is a frequent complication in cirrhosis and its prevalence increases with disease severity. Several factors are involved in the development and progression of PVT. The challenge for the management of PVT is the precise evaluation of the bleeding risk as opposed to life-threatening extension of thrombosis. Nevertheless, the impact on the progression and outcome of liver disease is unclear. A critical evaluation of the available data discloses that treating PVT in cirrhotics is safe and effective. However, there are open issues, such as which anticoagulant could represent a safer therapeutic option, and when and for how long this treatment should be administered to cirrhotic patients with PVT. PMID- 29720861 TI - Quality of life of ulcerative colitis patients treated surgically with proctocolectomy and J-pouch formation: a comparative study before surgery and after closure of the defunctioning ileostomy. AB - Background: Ulcerative colitis (UC) is a lifelong disease with a relapse remission pattern that affects patients' social and psychological wellbeing. Restorative proctocolectomy and J-pouch formation is the gold-standard surgical procedure in cases where symptoms are refractory to currently available medical treatment. The aim of this study was to assess patients' quality of life (QoL) in order to evaluate the efficiency of surgery and patients' symptomatology. Methods: We performed a prospective comparative study of the QoL of 47 patients with UC, treated surgically. As research tools, we used the Inflammatory Bowel Disease Questionnaire (IBDQ) and the Cleveland Global Quality of Life (CGQL) questionnaire. Parametric and non-parametric tests were used in order to correlate areas of QoL and other selected factors, such as marital status, sex, age, and education. Results: The mean scores before and after closure of the ileostomy were 153.29 and 178 for the IBDQ (P=0.0025), and 17.4 and 23.42 for the CGQL (P<0.001), suggesting an overall improvement in QoL. The research showed that there was no specific QoL factor, such as intestinal, systemic, emotional or social life symptoms, that improved significantly more than the others (P=0.99). The IBDQ showed that patients aged less than 20 years (P<0.001), female patients (P=0.03) and patients with secondary education (P<0.001) reported the greatest improvement. Conclusions: The QoL in UC patients treated surgically improved following closure of the de-functioning ileostomy. QoL studies are encouraged to optimize and maintain high standards of surgical care, and they could potentially be used for assessment of therapeutic efficacy. PMID- 29720862 TI - Split- versus single-dose preparation tolerability in a multiethnic population: decreased side effects but greater social barriers. AB - Background: This study was performed to compare patient-reported tolerability and its barriers in single- vs. split-dose 4-L polyethylene glycol (PEG) bowel preparation for colonoscopy in a large multiethnic, safety-net patient population. Methods: A cross-sectional, dual-center study using a multi-language survey was used to collect patient-reported demographic, medical, socioeconomic, and tolerability data from patients undergoing outpatient colonoscopy. Univariate and multivariate analyses were used to identify demographic and clinical factors significantly associated with patient-reported bowel preparation tolerability. Results: A total of 1023 complete surveys were included, of which 342 (33.4%) completed single-dose and 681 (66.6%) split-dose bowel preparation. Thirty-nine percent of the patients were Hispanic, 50% had Medicaid or no insurance, and 34% had limited English proficiency. Patients who underwent split-dose preparation were significantly more likely to report a tolerable preparation, with less severe symptoms, than were patients who underwent single-dose preparation. Multiple logistic regression revealed that male sex and instructions in the preferred language were associated with tolerability of the single-dose preparation, while male sex and concerns about medications were associated with tolerability of the split-dose preparation. Conclusions: In a large multiethnic safety-net population, split-dose bowel preparation was significantly more tolerable and associated with less severe gastrointestinal symptoms than single dose preparation. The tolerability of split-dose bowel preparation was associated with social barriers, including concerns about interfering with other medications. PMID- 29720863 TI - Hepatitis B and C coinfection in a real-life setting: viral interactions and treatment issues. AB - Background: Only limited data concerning hepatitis B (HBV) and C viruses (HCV) coinfection are available. Direct-acting antivirals (DAAs) may be more effective for HCV clearance than interferon (IFN)-based regimens with a risk of HBV reactivation. Methods: We retrospectively enrolled 40 HBV/HCV-coinfected patients to evaluate their clinical profile and treatment outcomes. Results: Chronic dual infection was present in 25/40 (62.5%) patients, acute HCV superinfection in 5/40 (12.5%) patients and acute HBV superinfection in 10/40 (25%). Twenty-five patients (62.5%) were treated: 16/25 (64%) with IFN, 4/25 (16%) with nucleot(s)ide analogs (NUCs) and 5/25 (20%) with DAAs. Of the 16 patients treated with IFN-based therapy, 6 (37.5%) achieved both sustained virological response (SVR) and HBsAg clearance. Of the 4 patients treated with NUCs, one (25%) achieved both SVR and HBsAg clearance. All five patients treated with DAAs (100%) achieved SVR, while one case of HBV reactivation was recorded. Fifteen of the 40 patients (37.5%) did not receive any treatment. Eight of them (53.5%) presented with acute HBV superinfection: spontaneous HCV clearance was recorded in 5/8 (62.5%), while HBsAg clearance occurred in 6/8 (75%). Three of them (20%) presented with acute HCV superinfection; spontaneous HCV clearance was recorded in one of the three (33.5%). The other four patients (26.5%) presented with dual HBV/HCV infection. Conclusions: A significant proportion of patients presented with active HBV replication. Treatment with DAAs seems to be efficacious for HCV eradication. However, clinicians should be aware of HBV reactivation. HBV superinfection may lead to both HBsAg and HCV clearance. PMID- 29720864 TI - Role of thrombophilia in splanchnic venous thrombosis in acute pancreatitis. AB - Background: Splanchnic venous thrombosis (SVT) is a common vascular complication of acute pancreatitis (AP). We conducted this study to prospectively investigate the frequency, risk factors, and extent of SVT in patients with AP and to evaluate the role of thrombophilia in its causation. Methods: Patients with AP presenting between January 2015 and June 2016 were prospectively evaluated with contrast-enhanced computed tomography (CT) for the presence of SVT. These patients underwent a detailed analysis of coagulation parameters. Results: We evaluated 96 patients with AP (73 male, mean age 31.85+/-13.34 years), of whom 26 (27.1%) had SVT. Splenic vein, portal vein, and superior mesenteric vein involvement were seen in 22 (84.6%), 11 (42.3%), and 4 (15.3%) patients, respectively. Necrotizing pancreatitis, CT severity index (CTSI) >6 and modified CTSI >6 were significantly more frequent in patients with SVT than in those without (96.2% vs. 78.6%, 76.9% vs. 47.1%, and 92.3% vs. 67.1%, respectively). Proteins C and S, and antithrombin III deficiency were found in 23.8%, 33.3% and 31.0% of patients, respectively. Anti-beta2-glycoprotein I and lupus anticoagulant were positive in 4.8% and 11.9% of patients, respectively. Factor V Leiden mutation analysis was positive in 6.1% of patients. Coagulation abnormality did not differ significantly between the patients with and without SVT. Conclusions: SVT is more common in patients with necrotizing pancreatitis, suggesting that local inflammation plays a major role in its causation. Thrombophilia is seen in one third of patients with AP but does not seem to increase the risk of SVT. PMID- 29720865 TI - Use of vedolizumab in a patient with chronic and refractory pouchitis. PMID- 29720866 TI - Submucosal pocket creation using a traction device in colorectal endoscopic submucosal dissection. PMID- 29720867 TI - Synchronous gastric and duodenal metastases from head and neck squamous cell carcinoma: a unique presentation of upper gastrointestinal bleeding. AB - Metastatic disease to the stomach or duodenum is an infrequent diagnosis, and head and neck squamous cell carcinoma (HNSCC) is one of the least common primary malignancies that lead to gastric or duodenal metastases. We report the case of a 65-year-old man with human immunodeficiency virus infection and previously diagnosed HNSCC who presented with melena. The patient had a percutaneous endoscopic gastrostomy tube placed 3 months prior to his presentation. Laboratory testing was significant for normocytic anemia and a digital rectal examination was positive for melena. Esophagogastroduodenoscopy revealed numerous cratered nodules with contact bleeding in the stomach as well as the duodenum that appeared malignant. Biopsies of the gastric and duodenal nodules were positive for p40 and CK 5/6, consistent with metastatic squamous cell carcinoma. PMID- 29720868 TI - Immigration and knowledge, education, and practices regarding chronic hepatitis B in pregnancy. PMID- 29720869 TI - Authors' reply. PMID- 29720870 TI - Exploring Proteins Containing Amyloidogenic Regions in the Proteomes of Bacteria of the Order Rhizobiales. AB - Amyloids are protein fibrils with a highly ordered spatial structure called cross beta. To date, amyloids were shown to be implicated in a wide range of biological processes, both pathogenic and functional. In bacteria, functional amyloids are involved in forming biofilms, storing toxins, overcoming the surface tension, and other functions. Rhizobiales represent an economically important group of Alphaproteobacteria, various species of which are not only capable of fixing nitrogen in the symbiosis with leguminous plants but also act as the causative agents of infectious diseases in animals and plants. Here, we implemented bioinformatic screening for potentially amyloidogenic proteins in the proteomes of more than 80 species belonging to the order Rhizobiales. Using SARP (Sequence Analysis based on the Ranking of Probabilities) and Waltz bioinformatic algorithms, we identified the biological processes, where potentially amyloidogenic proteins are overrepresented. We detected protein domains and regions associated with amyloidogenic sequences in the proteomes of various Rhizobiales species. We demonstrated that amyloidogenic regions tend to occur in the membrane or extracellular proteins, many of which are involved in pathogenesis-related processes, including adhesion, assembly of flagellum, and transport of siderophores and lipopolysaccharides, and contain domains typical of the virulence factors (hemolysin, RTX, YadA, LptD); some of them (rhizobiocins, LptD) are also related to symbiosis. PMID- 29720872 TI - Adherence to subcutaneous interferon beta-1a treatment using an electronic injection device: a prospective open-label Scandinavian noninterventional study (the ScanSmart study). AB - Background: Disease modifying drugs help control the course of relapsing remitting multiple sclerosis (RRMS); however, good adherence is needed for long term outcomes. Objective: To evaluate patient adherence to treatment with subcutaneous interferon beta-1a using RebiSmart(r) and assess injection-site reactions and treatment satisfaction. Methods: This prospective, single-arm, open label, noninterventional multicenter Phase IV trial included disease modifying drug-experienced mobile patients with RRMS. Adherence was measured over 12 weeks. Items 13-23, 35, 37, and 38 of the Multiple Sclerosis Treatment Concerns Questionnaire (injection-site reactions and treatment satisfaction) were recorded at 12 weeks. Results: Sixty patients were recruited (mean age 43.7 [+/-SD 7.9] years; 83% female; mean years since multiple sclerosis diagnosis 6.7 [SD 4.5]). Adherence data were obtained in 54 patients only due to technical problems with six devices. Over 12 weeks, 89% (n=48) of patients had >=90% adherence to treatment. Most patients experienced mild influenza-like symptoms and injection site reactions, and global side effects were minimal. Most patients (78%) rated the convenience as the most important aspect of the device, and most experienced no or mild pain. Conclusion: RRMS patients treated with subcutaneous interferon beta-1a, administered with RebiSmart, demonstrated generally good adherence, and the treatment was generally well tolerated. PMID- 29720873 TI - The impact on quality of life of dialysis patients with renal insufficiency. AB - Aim: The aim of the study was the subjective assessment of the quality of life (QoL) of 140 patients treated with dialysis (peritoneal dialysis and hemodialysis). Background: Chronic kidney disease and the methods of its treatment play an important part in shaping the QoL of patients receiving dialysis. As a result, kidney failure causes many limitations in patients' physical, mental, and social activities. Methods: The instrument to measure the QoL was the authors' own questionnaire made on the basis of Kidney Disease and Quality of Life Short Form version 1.2 (KDQOL - SF 1.2) and their selection of areas influencing the perceived QoL of chronically ill patients. Results: The research showed that patients receiving peritoneal dialysis assessed their QoL in its different dimensions as much higher than patients receiving hemodialysis. The parameter having the biggest negative impact on the QoL of patients receiving hemodialysis was an impeded possibility to continue work or studies and a change of life plans. The will to live was more highly assessed by patients receiving peritoneal dialysis as compared to patients receiving hemodialysis. Conclusion: In order to improve the functioning of hemodialysis patients in a manner most similar to healthy persons, the renal replacement therapy should consider patients' individual needs and expectations, ie, guarantee flexible hours of work or study and of receiving dialysis. In addition, patients treated with hemodialysis should receive psychological care, in particular those demonstrating emotional problems, in order to achieve better results in therapy and improve their QoL. PMID- 29720871 TI - Islet protection and amelioration of type 2 diabetes mellitus by treatment with quercetin from the flowers of Edgeworthia gardneri. AB - Background and purpose: The traditional Chinese medicine - the flower of Edgeworthia gardneri - is reported as an effective therapeutic for type 2 diabetes mellitus (T2DM). Nevertheless, most constituents of the flowers of E. gardneri have not yet been studied. This study was conducted to investigate the effect of quercetin extracted from the flowers of E. gardneri on islet protection and amelioration in T2DM and explore its mechanism. Method: Quercetin was extracted from the flowers of E. gardneri and verified by high-performance liquid chromatography. Quercetin or crude extract's effect on insulin secretion was investigated. ERK1/2 and phospho-ERK1/2 were detected by Western blot analysis, and fluo-3 AM was used to detect intracellular Ca2+. The anti-apoptosis effect of quercetin or crude extract on MIN-6 cells was investigated by thiazolyl blue tetrazolium bromide (MTT) assay and flow cytometry analysis. Activation of caspases and expression of Bcl-2 and BAX were tested by Western blot analysis. In addition, the mitochondrial membrane potential was determined by JC-1 probe. Moreover, in vivo activity was also tested in db/db mice. Results: A quercetin level of >10 MUmol/L could induce insulin secretion. Intracellular Ca2+ and ERK1/2 were involved in the signaling pathway of quercetin-induced insulin secretion. We also observed that quercetin could inhibit palmitic acid-induced cell apoptosis via suppressing the activation of caspase-3, -9, -12; increasing the ratio of Bcl-2/BAX and reversing the impaired mitochondrial membrane potential. Crude extract's effect on insulin secretion was similar to that of pure extracted quercetin, while it possessed higher anti-apoptosis activity. Additionally, intraperitoneal glucose tolerance, plasma insulin level, hepatic triglyceride, hepatic glycogen and the pathological histology of both pancreatic islet and liver in db/db mice were significantly improved by the administration of the extracted quercetin. Conclusion: Our study indicated that quercetin extracted from the flowers of E. gardneri exerted excellent properties in islet protection and amelioration. PMID- 29720874 TI - Living with cystic fibrosis - a qualitative study of a life coaching intervention. AB - Background: Cystic fibrosis (CF) is a chronic, life-shortening disease with a significant treatment burden. To support young adults with CF in their everyday life, we previously conducted a life coaching feasibility trial (published elsewhere). The aim of the current study was to explore how life coaching was experienced by study participants within the context of their lives with CF. Methods: A qualitative study using individual interviews. Respondents (n=14) were recruited from the intervention group after participation in life coaching. Data were analyzed from a phenomenologic-hermeneutical perspective, inspired by Ricoeur's theory. Findings: Periodic exacerbations of CF led to worry about disease progression, and interrupted the respondents' ability to fulfill daily life roles satisfactory. The treatment burden demanded self-discipline and this was sometimes at the expense of social life or career. The young adults rarely spoke to others about their situation; therefore, they valued opening up to a professional coach about life and concerns. We identified three themes: 1) living an unpredictable life; 2) the conflict between freedom and the constraints of illness; and 3) the value of telling one's story. In relation to all three themes, coaching promoted reflection over life situations, reframed thoughts, and facilitated finding new ways to manage everyday life. Conclusion: Life coaching is an intervention that is valued for those who feel challenged by their CF disease. Coaching programs should be designed to include the participants, when they feel a need for coaching and are open for change. Screening parameters to identify persons who will most likely benefit from life coaching are needed. PMID- 29720875 TI - Patient engagement in type 2 diabetes mellitus research: what patients want. AB - Background: As patients are the ultimate stakeholder in their health, their perspectives should be included along with researchers, providers, and funders of research design, execution, and interpretation. Despite the high prevalence of type 2 diabetes mellitus (T2DM), patients are rarely directly included in these decisions. Purpose: We sought to determine areas of research most important to patients with T2DM, identify ways through which patients with T2DM want to engage in research, and evaluate online patient research networks as a source for obtaining patient perspectives on research engagement. Patients and methods: This study used an online patient community forum (PatientsLikeMe) to host two asynchronous moderated discussions, each with three to four prompted discussion posts. A qualitative summary of themes was derived from the posts. Results: Eighty-eight participants with T2DM took part. Participants were mostly white (86%), averaged 58.6 years of age, half were female (50%), and over half (62%) resided in the US. Research priorities included managing T2DM with comorbidities, controlling blood sugar levels, finding a cure, and understanding causes of T2DM. Participants wanted to see direct applications of research to their lives. Clinical research was perceived to have overly restrictive eligibility criteria and to measure outcome sets that do not adequately address patient health concerns. Participants indicated broad interest in partnering in research and a willingness to apply their skills and educational background to specific stages in the research process. Conclusion: Patients with T2DM would like researchers to address outcomes that have meaning in patients' daily lives. Initiatives to involve patients in research should leverage and enable patients to contribute as participants, advisors, or co-investigators, going beyond research topic prioritization to full participation throughout the research process based on their abilities and interest. This study provides support for the use of online patient research network discussions to generate rich qualitative data to engage patients in research. PMID- 29720876 TI - Can a single session of motor imagery promote motor learning of locomotion in older adults? A randomized controlled trial. AB - Purpose: To investigate the influence of a single session of locomotor-based motor imagery training on motor learning and physical performance. Patients and methods: Thirty independent adults aged >65 years took part in the randomized controlled trial. The study was conducted within an exercise science laboratory. Participants were randomly divided into three groups following baseline locomotor testing: motor imagery training, physical training, and control groups. The motor imagery training group completed 20 imagined repetitions of a locomotor task, the physical training group completed 20 physical repetitions of a locomotor task, and the control group spent 25 minutes playing mentally stimulating games on an iPad. Imagined and physical performance times were measured for each training repetition. Gait speed (preferred and fast), timed-up-and-go, gait variability and the time to complete an obstacle course were completed before and after the single training session. Results: Motor learning occurred in both the motor imagery training and physical training groups. Motor imagery training led to refinements in motor planning resulting in imagined movements better matching the physically performed movement at the end of training. Motor imagery and physical training also promoted improvements in some locomotion outcomes as demonstrated by medium to large effect size improvements after training for fast gait speed and timed-up-and-go. There were no training effects on gait variability. Conclusion: A single session of motor imagery training promoted motor learning of locomotion in independent older adults. Motor imagery training of a specific locomotor task also had a positive transfer effect on related physical locomotor performance outcomes. PMID- 29720877 TI - Acute necrotizing encephalopathy in an adult with influenza A infection. AB - Acute necrotizing encephalopathy following influenza infection is a rapidly progressing disease with high morbidity. Although the neurological disorder is sometimes reported in children, it is very rare in adults. We herein describe an adult with acute necrotizing encephalopathy captured on a series of brain magnetic resonance images. A 55-year-old man had fever and impaired consciousness. He was diagnosed with influenza A (H1N1). Brain magnetic resonance imaging revealed symmetrical lesions in the cerebellum and basal nucleus, showing typical acute necrotizing encephalopathy. Physicians should know that influenza associated acute necrotizing encephalopathy can occur even in middle-aged adults. PMID- 29720878 TI - EGFR, KRAS, BRAF, PTEN, and PIK3CA mutation in plasma of small cell lung cancer patients. AB - Background: Small cell lung cancer (SCLC) is an aggressive and deadly neuroendocrine tumor derived from bronchial epithelial cells. Although it results in a 95% mortality rate, the development of targeted therapies for SCLCs has lagged behind. The aim of this study is to better research mutation characteristics of SCLC and identify potential biomarkers for target therapy. Methods: We utilized high-resolution melting analysis to identify the mutations in epidermal growth factor receptor (EGFR), Kirsten rat sarcoma viral oncogene (KRAS), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), phosphatase and tensin homolog (PTEN), and phosphatidylinositol-3-kinase catalytic (PIK3CA) from the blood. A cohort of 99 SCLC patients including 44 limited-stage disease patients and 55 extensive-stage disease patients were prospectively collected. Results: EGFR 18 (G719X) mutation was found in 5 patients, EGFR 19 (del) mutation in 2, EGFR 20 (T790M) in 3, EGFR 21 (L858R) in 2, KRAS 2 (G13D) in 5, BRAF 15 (V600E) in 1, PIK3CA 9 (E542K) in 1, and no mutations in PTEN 5 (R130G), PTEN 6 (R173C), PTEN 8 (T319fs*1), and PIK3CA 20 (H1047R) were identified. Among these patients, two harbored EGFR double mutation, one patient with EGFR double mutation and KRAS 2 (G13D) mutation. Conclusion: The mutation form of EGFR may differ from lung adenocarcinoma, and mutations of KRAS, BRAF, and PIK3CA were rare in SCLC. These results aided us in comprehensively analyzing genetic features and laid the foundation for exploring the possibility of target therapy. PMID- 29720879 TI - Fetal chondrodysplasia punctata associated with maternal autoimmune diseases: a review. AB - Chondrodysplasia punctata (CDP) is a skeletal abnormality characterized by premature calcification that is usually noticeable in the prenatal period and infancy. Etiologically, the condition is heterogeneous, and the causes include fetal conditions such as chromosome abnormalities, peroxisomal disorders, lysosomal storage disorders, cholesterol synthesis defects and abnormal vitamin K metabolism, as well as maternal diseases such as severe malabsorption and exposure to teratogens. An association between CDP and maternal autoimmune disease was first observed and reported by Curry et al and Costa et al in 1993 and expanded by Chitayat et al in 2010. This review lists the clinical characteristics and radiologic findings of all cases reported to date in English and discuss the possible etiology of this interesting fetal finding. PMID- 29720880 TI - Blood pressure control status and associated factors among adult hypertensive patients on outpatient follow-up at University of Gondar Referral Hospital, northwest Ethiopia: a retrospective follow-up study. AB - Background: Large segments of the hypertensive population in the world are either untreated or inadequately treated. The incidence of heart failure and mortality from cardiovascular complications of hypertension is high among patients with uncontrolled blood pressure (BP). But BP control status of hypertensive patients has not been investigated in the study area. The study aimed to assess BP control status and determinant factors among adult hypertensive patients on antihypertensive medication attending outpatient follow-up at University of Gondar Referral Hospital, northwest Ethiopia. Methods: An institution-based retrospective follow-up study was conducted from September 2015 to April 2016. Data were collected using a structured and pretested questionnaire adopted from the World Health Organization STEPwise approach. BP records of 6 months were used, and patients were classified as having controlled BP if their BP readings were <140/90 mmHg for all adults >=18 years of age and <150/90 mmHg for adults aged >=60 years. A generalized estimating equation was fitted, and the odds ratio with a 95% confidence level was used to determine the effect of covariates on BP control status. Results: Among 395 participants, 50.4% (95% CI: 45-55) of them controlled their BP in the last 6 months of the survey. Physical activity (adjusted odds ratio [AOR]=1.95, 95% CI: 1.41-2.68), duration on antihypertensive drugs of 2-4 years (AOR=1.70, 95% CI: 1.13-2.56) and 5 years or more (AOR=1.96, 95% CI: 1.32-2.92), and high adherence (AOR=2.18, 95% CI: 1.14-4.15) to antihypertensive drugs were positively associated with BP control, while salt intake (AOR=0.67, 95% CI: 0.49-0.93), overweight (AOR=0.50, 95% CI: 0.36-0.68), and obesity (AOR=0.56, 95% CI: 0.36-0.87) were inversely associated with BP control. Conclusion: In this study, only half of the hypertensive patients controlled their BP. Thus, health care providers need to be made aware about the importance of counseling hypertensive patients on drug adherence, moderate physical activity, and salt restriction to improve BP control. PMID- 29720881 TI - A novel nomogram for the prediction of intrahepatic cholangiocarcinoma in patients with intrahepatic lithiasis complicated by imagiologically diagnosed mass. AB - Background: Accurate preoperative diagnosis of intrahepatic cholangiocarcinoma (ICC) among patients with imagiologically intrahepatic lithiasis (IHL) complicated by mass is crucial for timely and effective surgical intervention. The aim of the present study was to develop a nomogram to identify ICC associated with IHL (IHL-ICC). Patients and methods: Data were obtained from a total of 252 consecutive patients with IHL complicated by mass. Multivariate logistic regression analysis was conducted to identify the clinicopathologic and imagiological characteristics that were potentially associated with ICC. A nomogram was developed based on the results of the multivariate analysis, and the value for prediction of ICC was assessed. Results: The study revealed six potential predictors for IHL-ICC, including comprehensive imagiological diagnosis, biliary tract operation history, fever, ascites, cancer antigen (CA) 19-9, and carcinoembryonic antigen (CEA). The optimal cutoff value was 3.75 MUg/L for serum CEA and 143.15 U/mL for serum CA 19-9. The accuracy of the nomogram in predicting ICC was 78.5%. The Youden index provided a value of 0.348, corresponding to a cutoff of 95 points, with an area under the curve of 0.863. Conclusion: The nomogram holds promise as a novel and accurate tool in identifying IHL-ICC for hepatectomy, and in the differentiation of benign occupying lesions in IHL patients, resulting in the avoidance of unnecessary surgical resection. PMID- 29720882 TI - Drospirenone-containing oral contraceptives and venous thromboembolism: an analysis of the FAERS database. AB - Introduction: Substantial evidence suggests that drospirenone-containing oral contraceptives may cause a higher risk of venous thrombotic events than earlier generation oral contraceptives. Methods: To gain insight into recent real-world implications, we conducted an analysis using the US Food and Drug Administration's Adverse Event Reporting System. Results: Venous thrombotic events continue to be reported at a much higher rate with drospirenone-containing oral contraceptives than the general background. The disproportionality has been rising since 2010. The same behavior is not seen with levonorgestrel-containing oral contraceptives. Conclusion: Our results are consistent with decreased physician and patient awareness of risks associated with drospirenone-containing oral contraceptives. PMID- 29720883 TI - A novel approach for effective integration of new faculty leadership. AB - Purpose: We report on an accelerated and effective way of assimilating a new leader into a team at a large academic dental school department. Methods: At University of California, San Francisco (UCSF), a new Chair was recruited through a national search to lead its largest department in the School of Dentistry. Two months after arrival, the new Chair embarked on a process of leadership assimilation among her executive team, facilitated by a professional consultant. Within four weeks, team members participated in one-on-one interviews with the professional facilitator consultant and then completed the leadership assimilation questionnaire and returned it electronically to the facilitator. The facilitator then summarized all answers into themes and met with the team members without the Chair to debrief. Thereafter, the facilitator met with the Chair to discuss the major themes. Next, the Chair met with the team members in a facilitated session to discuss the results and negotiate a path forward. Results: Approximately half of the feedback described the "how" of leadership: comments on communication, building relationships, building trust, and understanding UCSF history. The remaining half described the "what": comments on vision, strategy, and operations. Team members indicated that the first debriefing session was helpful to alleviate initial anxiety and to start building team spirit. The session with the Chair was perceived as open and fruitful in which team members were able to express their concerns and hopes for the Department, while the Chair showed commitment to the team and the communication process. Conclusion: Leader assimilation allows teams to share their expectations and anxieties with the new leader early in the relationship in an open way, before new habits and beliefs are formed. Conversely, for the leader, it effectively and efficiently allows a window into the team members' thinking at a critical time period when otherwise first impressions occur. With a safe space created for open communication, the process allowed siloed individual division leaders to move toward a cohesive group while at the same time solidifying a commitment to the success of the new leader. PMID- 29720884 TI - The perceived impact of the group practice model on enhancing interpersonal skills of predoctoral dental students. AB - Purpose: The purpose of this study was to assess if a clinical group practice model has an impact on enhancing the interpersonal skills of predoctoral dental students, what factors may influence the development of these skills, and what, if any, are innovative and technological solutions that can potentially influence interpersonal skills in predoctoral dental students. Methods: This study surveyed the faculty responsible for teaching the dental students in a recently developed group practice model. Out of 18 eligible group practice leaders at one US dental school, 17 respondents (94.4%) completed the survey. In addition, this study asked the faculty to provide qualitative response and recommendations to improve interpersonal skills. Based on the feedback, a focus group was conducted to explore opportunities to further enhance the skills. Results: The results of the study suggest that the group practice model has a positive and distinct impact on the development of overall interpersonal skills for students. Further research suggests that the greatest impacted areas of personal development are critical thinking skills and teamwork. However, as a way to make the model more effectual, most faculty suggested the need for additional time, for both students and faculty. To some extent, using technology and innovative teaching pedagogies could potentially address the challenge of limited time. Conclusion: Based on the results of the survey, one may conclude that with adequate design and conditions, the group practice model can have a positive effect on the interpersonal skills of its students. PMID- 29720885 TI - Successful Second-Line Metronomic Temozolomide in Metastatic Paraganglioma: Case Reports and Review of the Literature. AB - Metastatic pheochromocytoma and paraganglioma (mPHEO/PGL) are frequently associated with succinate dehydrogenase B (SDHB) mutations. Cyclophosphamide dacarbazine-vincristine (CVD) regimen is recommended as standard chemotherapy for advanced mPHEO/PGL. There is limited evidence to support the role of metronomic schemes (MS) of chemotherapy in mPHEO/PGL treatment. We report 2 patients with SDHB-related mPGL who received a regimen consisting of MS temozolomide (TMZ) and high-dose lanreotide after progression on both CVD chemotherapy and high-dose lanreotide. Molecular profiling of the tumor tissue from both patients revealed hypermethylation of the O6-methylguanine-DNA-methyltransferase (MGMT) promoter. In one patient, progression-free survival was 13 months and the second patient remained under treatment after 27 months of stabilization of metabolic response of his disease. Treatment was well tolerated, and adverse effects were virtually absent. A modification in the scheme of TMZ from standard schemes to MS is safe and feasible and can be considered in patients with progressive mPHEO/PGL refractory to dacarbazine in standard doses. PMID- 29720886 TI - Therapist tips for the brief behavioural activation therapy for depression - revised (BATD-R) treatment manual practical wisdom and clinical nuance. AB - Objective: This article aims to provide supportive guidance for clinicians using the brief behavioral activation treatment for depression - revised (BATD-R) manual. Expanding upon key points less explicitly addressed in the treatment manual, the goal is to convey practical wisdom and clinical nuance beyond that available in the manual, thereby enhancing therapist comfort with the approach and improving treatment delivery. Methods: In preparation for a randomised control trial of behavioural activation treatment for depression among substance users (the Activate Study), Professor Carl Lejuez, an author on the manual, provided training to our research team. This occurred over four days in May 2013 at the National Drug and Alcohol Research Centre in Sydney, Australia and involved in-depth discussion about treatment delivery, often addressing important issues implied but not addressed in-depth in the manual. Reflections were discussed throughout training and subsequently collated into key themes. Results: Intricacies associated with treatment delivery were identified. Seven key themes emerged, covering: provision of the treatment rationale; therapeutic alliance and self-disclosure; behaviour monitoring; values; angles and steps; contracts; and drawing from other therapeutic approaches. A detailed discussion of how to approach these themes in treatment forms the basis of this article. Conclusions: The current article seeks to guide therapists and provide a supplement to the BATD-R manual that will enhance the flexibility and accessibility for therapists utilising this treatment. The suggestions made are useful for straightforward cases of depression and more complicated comorbid presentations, serving as a useful complement for therapists using the manual. PMID- 29720887 TI - Rapid progress towards elimination of lymphatic filariasis in endemic regions of Myanmar as a result of 16 years of anti-filarial activities (2001-2016). AB - Background: As Myanmar progresses towards lymphatic filariasis (LF) elimination, it is important to know how well the anti-filarial activities have performed. The present study was conducted to study the implementation of the key anti-filarial activities and their impact on key indicators of LF transmission. Methods: A secondary analysis of aggregate program data on the anti-filarial activities was conducted in four endemic state/regions of Myanmar receiving at least six mass drug administration (MDA) rounds during 2001-2016. Results: MDA coverage has been expanded to cover all the endemic implementation units (IUs), i.e., 45 by 2015 and 6 IUs out of them have already stopped MDA. The reported coverage of MDA ranges from 87 to 100% whereas surveyed coverage ranges from 78 to 100% among the eligible population. The prevalence of microfilaria has significantly declined especially in Magway from 4.7 to 0.2% and Sagaing region from 7.9 to 1.3% during 2001-2016. Around 2.5% of estimated cases of hydrocele were reported to the program during 2009-2014. Conclusion: Myanmar has achieved significant success in interrupting LF transmission through several MDA rounds with high coverage. However, morbidity reporting and management, being in its initial phase requires an active surveillance system for identifying and managing people with LF associated morbidities under the program. PMID- 29720888 TI - Measuring higher order ambiguity preferences. AB - We report the results from an experiment designed to measure attitudes towards ambiguity beyond ambiguity aversion. In particular, we implement recently proposed model-free preference conditions of ambiguity prudence and ambiguity temperance. Ambiguity prudence has been shown to play an important role in precautionary behavior and the mere presence of ambiguity averse agents in markets. We observe that the majority of individuals' decisions are consistent with ambiguity aversion, ambiguity prudence and ambiguity temperance. This finding confirms the prediction of many popular (specifications of) ambiguity models and has important implications for models of prevention behavior. PMID- 29720890 TI - Higher-order risk preferences in social settings. AB - We study prudence and temperance (next to risk aversion) in social settings. Previous experimental studies have shown that these higher-order risk preferences affect the choices of individuals deciding privately on lotteries that only affect their own payoff. Yet, many risky and financially relevant decisions are made in the social settings of households or organizations. We elicit higher order risk preferences of individuals and systematically vary how an individual's decision is made (alone or while communicating with a partner) and who is affected by the decision (only the individual or the partner as well). In doing so, we can isolate the effects of other-regarding concerns and communication on choices. Our results reveal that the majority of choices are risk averse, prudent, and temperate across social settings. We also observe that individuals are influenced significantly by the preferences of a partner when they are able to communicate and choices are payoff-relevant for both of them. PMID- 29720889 TI - The BCD of response time analysis in experimental economics. AB - For decisions in the wild, time is of the essence. Available decision time is often cut short through natural or artificial constraints, or is impinged upon by the opportunity cost of time. Experimental economists have only recently begun to conduct experiments with time constraints and to analyze response time (RT) data, in contrast to experimental psychologists. RT analysis has proven valuable for the identification of individual and strategic decision processes including identification of social preferences in the latter case, model comparison/selection, and the investigation of heuristics that combine speed and performance by exploiting environmental regularities. Here we focus on the benefits, challenges, and desiderata of RT analysis in strategic decision making. We argue that unlocking the potential of RT analysis requires the adoption of process-based models instead of outcome-based models, and discuss how RT in the wild can be captured by time-constrained experiments in the lab. We conclude that RT analysis holds considerable potential for experimental economics, deserves greater attention as a methodological tool, and promises important insights on strategic decision making in naturally occurring environments. PMID- 29720891 TI - Ultra-small dye-doped silica nanoparticles via modified sol-gel technique. AB - In modern biosensing and imaging, fluorescence-based methods constitute the most diffused approach to achieve optimal detection of analytes, both in solution and on the single-particle level. Despite the huge progresses made in recent decades in the development of plasmonic biosensors and label-free sensing techniques, fluorescent molecules remain the most commonly used contrast agents to date for commercial imaging and detection methods. However, they exhibit low stability, can be difficult to functionalise, and often result in a low signal-to-noise ratio. Thus, embedding fluorescent probes into robust and bio-compatible materials, such as silica nanoparticles, can substantially enhance the detection limit and dramatically increase the sensitivity. In this work, ultra-small fluorescent silica nanoparticles (NPs) for optical biosensing applications were doped with a fluorescent dye, using simple water-based sol-gel approaches based on the classical Stober procedure. By systematically modulating reaction parameters, controllable size tuning of particle diameters as low as 10 nm was achieved. Particles morphology and optical response were evaluated showing a possible single-molecule behaviour, without employing microemulsion methods to achieve similar results. Graphical abstractWe report a simple, cheap, reliable protocol for the synthesis and systematic tuning of ultra-small (< 10 nm) dye doped luminescent silica nanoparticles. PMID- 29720892 TI - More on the holographic Ricci dark energy model: smoothing Rips through interaction effects? AB - The background cosmological dynamics of the late Universe is analysed on the framework of a dark energy model described by an holographic Ricci dark energy component. Several kind of interactions between the dark energy and the dark matter components are considered herein. We solve the background cosmological dynamics for the different choices of interactions with the aim to analyse not only the current evolution of the universe but also its asymptotic behaviour and, in particular, possible future singularities removal. We show that in most of the cases, the Big Rip singularity, a finger print of this model in absence of an interaction between the dark sectors, is substituted by a de Sitter or a Minkowski state. Most importantly, we found two new future bouncing solutions leading to two possible asymptotic behaviours, we named Little Bang and Little Sibling of the Big Bang. At a Little Bang, as the size of the universe shrinks to zero in an infinite cosmic time, the Hubble rate and its cosmic time derivative blow up. In addition, at a Little sibling of the Big Bang, as the size of the universe shrinks to zero in an infinite cosmic time, the Hubble rate blows up but its cosmic time derivative is finite. These two abrupt events can happen as well in the past. PMID- 29720893 TI - The impact of kin availability, parental religiosity, and nativity on fertility differentials in the late 19th-century United States. AB - METHODS: Most quantitative research on fertility decline in the United States ignores the potential impact of cultural and familial factors. We rely on new complete-count data from the 1880 U.S. census to construct couple-level measures of nativity/ethnicity, religiosity, and kin availability. We include these measures with a comprehensive set of demographic, economic, and contextual variables in Poisson regression models of net marital fertility to assess their relative importance. We construct models with and without area fixed effects to control for unobserved heterogeneity. CONTRIBUTION: All else being equal, we find a strong impact of nativity on recent net marital fertility. Fertility differentials among second generation couples relative to the native-born white population of native parentage were in most cases less than half of the differential observed among first generation immigrants, suggesting greater assimilation to native-born American childbearing norms. Our measures of parental religiosity and familial propinquity indicated a more modest impact on marital fertility. Couples who chose biblical names for their children had approximately 3% more children than couples relying on secular names while the presence of a potential mother-in-law in a nearby households was associated with 2% more children. Overall, our results demonstrate the need for more inclusive models of fertility behavior that include cultural and familial covariates. PMID- 29720896 TI - Towards accessible integrated palliative care: Perspectives of leaders from seven European countries on facilitators, barriers and recommendations for improvement. AB - Purpose: Literature suggests that integrated palliative care (IPC) increases the quality of care for palliative patients at lower costs. However, knowledge on models encompassing all integration levels for successfully implementing IPC is scarce. The purpose of this paper is to describe the experiences of IPC leaders in seven European countries regarding core elements, facilitators and barriers of IPC implementation and provides recommendations for future policy and practice. Design/methodology/approach: A qualitative interview study was conducted between December 2013 and May 2014. In total, 34 IPC leaders in primary and secondary palliative care or public health in Belgium, Germany, Hungary, Ireland, the Netherlands, Spain and the UK were interviewed. Transcripts were analysed using thematic data analysis. Findings: IPC implementation efforts involved a multidisciplinary team approach and cross-sectional coordination. Informal professional relationships, basic medical education and general awareness were regarded as facilitators of IPC. Identified barriers included lack of knowledge about when to start palliative care, lack of collaboration and financial structures. Recommendations for improvement included access, patient centeredness, coordination and cooperation, financing and ICT systems. Originality/value: Although IPC is becoming more common, action has been uneven at different levels. IPC implementation largely remains provisional and informal due to the lack of standardised treatment pathways, legal frameworks and financial incentives to support multilevel integration. In order to make IPC more accessible, palliative care education as well as legal and financial support within national healthcare systems needs to be enhanced. PMID- 29720895 TI - Monocyte Chemoattractant Protein-1 in Antineutrophil Cytoplasmic Autoantibody Associated Vasculitis: Biomarker Potential and Association with Polymorphisms in the MCP-1 and the CC Chemokine Receptor-2 Gene. AB - Antineutrophil cytoplasmic autoantibody- (ANCA-) associated vasculitis (AAV) are relapsing-remitting disorders with unpredictable prognosis. There is a need of biomarkers for distinguishing which patients will have a more severe outcome and also for predicting relapses in disease activity. This study confirms the previous results of urinary MCP-1 (uMCP-1) as a prognostic marker and explores its potential as a marker of disease activity. Method. 114 patients with AAV were followed regularly between 2002 and 2011 at Skane University Hospital. Urine samples, blood samples, and clinical status were registered. The urine samples were analyzed in an in-house-developed ELISA. PCR-RLFP was used to analyze the MCP-1 and CCR2 genes. Results. Patients with severe prognosis had significantly higher levels of uMCP-1 compared to patients with nonsevere prognosis and healthy controls. Patients with renal damage had higher levels compared to patients who did not have renal damage. There was also a tendency of higher uMCP-1 levels in active disease as compared to remission. AA in the -2518 position in the MCP-1 gene was associated with a more severe outcome compared to the A/G or the G/G genotype. The A/A genotype were also associated with higher levels of uMCP-1. No significant associations were seen for the CCR2-V64I. Conclusion. This study confirmed the connection between high uMCP-1 levels and poor prognosis and also disease activity. It also suggests an association of the A/A genotype at position -2518 in the MCP-1 gene and poor prognosis in AAV. uMCP-1 is clearly a candidate biomarker of potential clinical value. The A/A genotype association needs further evaluation. PMID- 29720897 TI - The emotional labour of boundary spanning. AB - Purpose: Within public services there is a widely recognised role for workers who operate across organisational and professional boundaries. Much of this literature focusses on the organisational implications rather than on how boundary spanners engage with citizens. An increased number of public service roles require boundary spanning to support citizens with cross-cutting issues. The purpose of this paper is to explicate the emotional labour within the interactions that boundary spanners have with citizens, requiring adherence to display rules and building trust. Design/methodology/approach: This is a conceptual paper which draws on illustrative examples to draw out the emotional labour within two types of boundary spanning: explicit and emergent. Findings: Emotional labour theory offers a way to classify these interactions as requiring high, medium or low degrees of emotional labour. Boundary spanning theory contributes an understanding of how emotional labour is likely to be differently experienced depending on whether the boundary spanning is an explicit part of the job, or an emergent property. Originality/value: Drawing on examples from public service work in a range of advanced democracies, the authors make a theoretical argument, suggesting that a more complete view of boundary spanning must account for individual-level affect and demands upon workers. Such a focus captures the "how" of the boundary spanning public encounter, and not just the institutional, political and organisational dimensions examined in most boundary spanning literatures. PMID- 29720894 TI - Pleiotropic Associations of RARRES2 Gene Variants and Circulating Chemerin Levels: Potential Roles of Chemerin Involved in the Metabolic and Inflammation Related Diseases. AB - Chemerin, an adipokine and inflammatory mediator, is associated with metabolic, inflammation- and immune-mediated diseases. The genetic, clinical, and biomarker correlates of circulating chemerin levels have not been completely elucidated. We analyzed the determinants and correlates of retinoic acid receptor responder 2 (RARRES2; encoding chemerin) gene variants and chemerin levels in the Taiwanese population. In total, 612 individuals were recruited. Clinical and metabolic phenotypes, 13 inflammatory markers, 5 adipokines, and 6 single-nucleotide polymorphisms (SNPs) covering the RARRES2 region were analyzed. High chemerin levels and chemerin level tertiles were positively associated with multiple metabolic phenotypes and circulating inflammatory marker and adipokine levels and negatively associated with high-density lipoprotein cholesterol and adiponectin levels and estimated glomerular filtration rates (eGFRs). Genotype and haplotype analyses showed that RARRES2 SNPs were significantly associated with chemerin, fibrinogen, interleukin 6, and lipocalin 2 levels. Stepwise logistic regression analysis showed that C-reactive protein level, leptin level, triglyceride level, eGFR, rs3735167 genotypes, sex, and soluble P-selectin level were independently associated with chemerin levels. In conclusion, pleiotropic associations were noted between RARRES2 variants, circulating chemerin levels and multiple metabolic phenotypes and inflammatory marker levels. This study provides further evidence for the potential roles of chemerin in metabolic and inflammation related diseases. PMID- 29720898 TI - Karin M. Hardiman, MD, PhD. PMID- 29720899 TI - Translational Research in Colorectal Cancer. PMID- 29720900 TI - Update on Sporadic Colorectal Cancer Genetics. AB - Our understanding of the genetics of colorectal cancer has changed dramatically over recent years. Colorectal cancer can be classified in multiple different ways. Along with the advent of whole-exome sequencing, we have gained an understanding of the scale of the genetic changes found in sporadic colorectal cancer. We now know that there are multiple pathways that are commonly involved in the evolution of colorectal cancer including Wnt/beta-catenin, RAS, EGFR, and PIK3 kinase. Another recent leap in our understanding of colorectal cancer genetics is the recognition that many, if not all tumors, are actually genetically heterogeneous within individual tumors and also between tumors. Recent research has revealed the prognostic and possibly therapeutic implications of various specific mutations, including specific mutations in BRAF and KRAS . There is increasing interest in the use of mutation testing for screening and surveillance through stool and circulating DNA testing. Recent advances in translational research in colorectal cancer genetics are dramatically changing our understanding of colorectal cancer and will likely change therapy and surveillance in the near future. PMID- 29720901 TI - Updates on Translational Research on Prevention of Polyps and Colorectal Cancer. AB - Morbidity and mortality from colorectal cancer (CRC) can be effectively reduced through early detection and prevention. To date, strategies for managing CRC risk have focused primarily on secondary prevention, through screening asymptomatic individuals for colorectal neoplasia. In the United States, implementation of screening among individuals age >=50 has led to not only decreased CRC-related mortality but also reduced CRC incidence through colonoscopic removal of precancerous polyps. In contrast to screening's endpoint of early detection, the goal of primary prevention of CRC is to arrest and/or reverse colorectal carcinogenesis. Observational studies and randomized clinical trials continue to examine effects of specific pharmacologic agents (chemoprevention) and dietary interventions on development of advanced colorectal neoplasia. This review will present an overview of strategies for primary and secondary prevention of CRC, including endoscopic, pharmacologic, and dietary interventions. PMID- 29720902 TI - Translational Research in Familial Colorectal Cancer Syndromes. AB - Growing knowledge of inherited colorectal cancer syndromes has led to better surveillance and better care of this subset of patients. The most well-known entities, including Lynch syndrome and familial adenomatous polyposis, are continually being studied and with the advent of more sophisticated genetic testing, additional genetic discoveries have been made in the field of inherited cancer. This article will summarize many of the updates to both the familiar and perhaps less familiar syndromes that can lead to inherited or early-onset colorectal cancer. PMID- 29720903 TI - Colorectal Cancer in Inflammatory Bowel Disease. AB - Patients with inflammatory bowel disease (IBD) are at significantly increased risk of colorectal cancer (CRC), principally resulting from the pro-neoplastic effects of chronic intestinal inflammation. Epidemiologic studies continue to highlight the increased risk of CRC in IBD. However, the incidence has declined over the past 30 years, attributed to both successful CRC-surveillance programs and improved control of mucosal inflammation. Risk factors that further increase the risk of IBD-related CRC include disease duration, extent and severity, the presence of inflammatory pseudopolyps, coexistent primary sclerosing cholangitis, and a family history of CRC. All major professional societies agree that IBD-CRC surveillance should occur more frequently than in the general population. Yet, guidelines and consensus statements differ on the surveillance schedule and preferred method of surveillance. Improved sensitivity to previously "invisible" flat dysplastic lesions using high definition and chromoendoscopy methods has resulted in many guidelines abandoning requirements for random untargeted biopsies of the colon. While colonic dysplasia remains a worrisome finding, and several clinical scenarios remain best addressed by total proctocolectomy due to concerns of synchronous undetected lesions and the unpredictable tempo of progression to malignancy, better detection techniques have also increased opportunities for endoscopic resection of dysplastic lesions that can be clearly delineated. Finally, the expanding armamentarium of medical options in IBD, including anti-tumor necrosis factor and anti-adhesion biologic therapies, have substantially improved our ability to control severe inflammation and likely reduce the risk of CRC over time. PMID- 29720904 TI - Emerging Systemic Therapies for Colorectal Cancer. AB - Despite advances over the past 20 years in colorectal cancer (CRC) screening, diagnosis, and treatment, survival outcomes remain suboptimal. Five-year survival for patients with locally advanced CRC is 69%; 5-year survival drops to 12% for patients with metastatic disease. Novel, effective systemic therapies are needed to improve long-term outcomes. In this review, we describe currently available systemic therapies for the treatment of locally advanced and metastatic CRC and discuss emerging therapies, including encouraging advances in identifying novel targeted agents and exciting responses to immunotherapeutic agents. PMID- 29720905 TI - The Role of the Gut Microbiome in Colorectal Cancer. AB - There is increasing evidence that the gut microbiome, which consists of trillions of microbes representing over 1,000 species of bacteria with over 3 million genes, significantly impacts intestinal health and disease. The gut microbiota not only is capable of promoting intestinal homeostasis and antitumor responses but can also contribute to chronic dysregulated inflammation as well as have genotoxic effects that lead to carcinogenesis. Whether the gut microbiota maintains health or promotes colon cancer may ultimately depend on the composition of the gut microbiome and the balance within the microbial community of protective and detrimental bacterial populations. Disturbances in the normal balanced state of a healthful microbiome, known as dysbiosis, have been observed in patients with colorectal cancer (CRC); however, whether these alterations precede and cause CRC remains to be determined. Nonetheless, studies in mice strongly suggest that the gut microbiota can modulate susceptibility to CRC, and therefore may serve as both biomarkers and therapeutic targets. PMID- 29720906 TI - Development of Preclinical Models to Understand and Treat Colorectal Cancer. AB - The establishment and validation of preclinical models that faithfully recapitulate the pathogenesis and treatment response of human colorectal cancer (CRC) is critical to expedient therapeutic advances in the clinical management of this disease. Integral to the application of precision medicine for patients diagnosed with metastatic CRC is the need to understand the molecular determinants of response for a given therapy. Preclinical models of CRC have proven invaluable in answering many of our basic questions relating to the molecular aberrations that drive colorectal tumor progression. This review will address the comparative merits and limitations of the broad spectrum of in vitro and in vivo models available for study of colorectal tumors and their response to experimental therapies. PMID- 29720907 TI - Sedation and Analgesia Using Medications Delivered via the Extravascular Route in Children Undergoing Laceration Repair. AB - OBJECTIVES: To describe the method of delivery, dosage regimens, and outcomes of sedatives and analgesics administered via the extravascular route for laceration repair in children. METHODS: Medline, Embase, and International Pharmaceutical Abstracts were searched using the keywords "child," "midazolam," "ketamine," dexmedetomidine," "fentanyl," "nitrous oxide" (N2O), and "laceration repair." Articles evaluating the use of extravascular sedation in children for laceration repair published in the English language between 1946 and June 2017 were included. Two authors independently screened each article for inclusion. Reports were excluded if they did not contain sufficient details on dosage regimen and outcomes. RESULTS: A total of 16 reports representing 953 children receiving sedatives and analgesics via the extravascular route were included for analyses. A statistical analysis was not performed because of heterogeneity in dosing and types of analyses conducted. Midazolam and N2O were the most common agents, with oral (PO) midazolam being the most common agent. Other agents that have supporting data were intranasal (IN) dexmedetomidine, IN ketamine, IN midazolam, PO diazepam, PO ketamine, transmucosal (TM) midazolam, and TM fentanyl. CONCLUSIONS: Most of the agents administered through the extravascular route were efficacious. Selection of the agents should be based on perceived need for analgesia versus sedation, patient accessibility, and adverse drug events. Future research is needed to determine the optimal agent and route for laceration repair. PMID- 29720908 TI - Implementation and Impact of an Antimicrobial Stewardship Program at a Non freestanding Children's Hospital. AB - OBJECTIVES: Pediatric Antimicrobial Stewardship Programs (ASP) have been associated with improvements in antibiotic utilization and patient outcomes; however, ASP studies originating from non-freestanding children's hospitals are lacking. In this study, we present the implementation and impact of a multidisciplinary ASP that employs a collaborative physician and pharmacist driven thrice-weekly prospective audit-with-feedback approach at a non freestanding children's hospital. METHODS: Implementation was assessed via descriptive design. Pediatric inpatients maintained on predefined targeted antibiotics of interest for 48 to 72 hours preceding ASP review were eligible for inclusion. Outcomes evaluated included ASP recommendation and provider acceptance rates (overall and by antibiotic and provider specialty). Impact was examined using an interrupted time series design (with a preimplementation period of August 1, 2013, to July 31, 2014 and postimplementation period of December 1, 2014 to May 31, 2016). Eligibility included all targeted antibiotic usage among pediatric inpatients, with a control group comprising those who received antibiotics requiring preauthorization. Outcomes analyzed included days of antibiotic therapy per 1000 patient days (DOT/1000 PD) and 30-day hospital readmission rates over time. RESULTS: Postimplementation, 882 antibiotic reviews were performed on 637 patients, with 327 recommendations generated. Reviews of patients maintained on vancomycin and clindamycin, and of those under care of intensivist and hospitalist physicians, were most likely to prompt recommendations. A mean targeted antibiotic usage decrease of 24.8 DOT/1000 PD (95% confidence interval, -62 to 14) was observed postimplementation, with no change in 30-day readmissions (0.64% during both periods). CONCLUSIONS: ASP implementation at a non-freestanding children's hospital was feasible and allowed for identification of areas for targeted quality improvement, while demonstrating modest antibiotic use reduction without adversely impacting patient care. PMID- 29720910 TI - A Retrospective Review of Infants Receiving Sildenafil. AB - OBJECTIVE: The purpose of the study was to assess mortality in an infant population receiving sildenafil. METHODS: A retrospective review of hospitalized infants at Children's Hospital Los Angeles who received sildenafil between 2008 and 2012 was conducted. Patient characteristics, comorbidities, and treatment characteristics were analyzed. Primary outcome was mortality at discharge. Sildenafil dosage ranges were based on the Sildenafil in Treatment-Naive Children, Aged 1-17 Years, With Pulmonary Arterial Hypertension trial and were categorized as small (<1.5 mg/kg/day), medium (1.5-3.75 mg/kg/day), large (3.76 7.5 mg/kg/day), and very large (>7.5 mg/kg/day). RESULTS: A total of 147 infants were studied. A total of 82% of patients had severe pulmonary hypertension. Our data revealed 29% mortality at discharge. Mortality increased with increasing sildenafil dosage: 14% (small), 19% (medium), 49% (large), and 90% (very large). On multivariate analysis of sildenafil dosage, other pulmonary hypertension therapies, presence of persistent cardiac shunts, and duration of sildenafil, odds of dying were significantly higher with combined high and very high sildenafil dosage groups compared with combined low and medium dosage groups (OR, 13.2; CI, 4.4-39.5; p < 0.0001). CONCLUSION: Sildenafil was given to critically ill infants with multiple risk factors for mortality. Although higher doses cannot be causally related to mortality, there appears to be no added benefit by escalating the sildenafil dose. PMID- 29720909 TI - Use of Individual Pharmacokinetics to Improve Time to Therapeutic Vancomycin Trough in Pediatric Oncology Patients. AB - OBJECTIVE: Optimization of vancomycin dosing is difficult in children, given rapid drug clearance and patient heterogeneity. We sought to evaluate the impact of dosing using individual pharmacokinetic parameters on time to goal trough concentration in pediatric oncology patients. METHODS: A retrospective review was conducted to assess vancomycin dosing in the pediatric oncology unit at Loma Linda University Children's Hospital between January 2013 and August 2013 (standard dosing group [SDG]). These patients were compared to those in a prospective arm that used pharmacokinetic dosing (pharmacokinetic dosing group [PKG]) between March 2014 and May 2015. Outcomes included percent of patients reaching a target trough by the specified time points, number of dose adjustments, number of serum concentrations drawn, and number of patients with supratherapeutic troughs. RESULTS: Of 35 patients meeting inclusion criteria for the SDG, 2 (5.7%) reached goal trough concentration by 48 hours, compared with 14 of 16 patients (87%) in the PKG (p = 0.0001). Significantly more patients reached their goal trough at each time point in the PKG. There was no difference in number of dose adjustments, but significantly more concentrations were drawn on average in the PKG (mean, 4.6 versus 3.1, p = 0.02). In the SDG and PKG, respectively, 1 patient and 3 patients had supratherapeutic trough concentrations (p = 0.09). CONCLUSIONS: Dosing using individual pharmacokinetic parameters led to a significant reduction in time to attain the desired vancomycin trough concentration in our pediatric oncology patients. Given the wide variation in dose requirements in this and other studies, application of patient-specific pharmacokinetics is essential to optimize vancomycin dosing in pediatric patients. PMID- 29720911 TI - Association Between Thiopurine S-Methyltransferase (TPMT) Genetic Variants and Infection in Pediatric Heart Transplant Recipients Treated With Azathioprine: A Multi-Institutional Analysis. AB - OBJECTIVES: Bone marrow suppression is a common adverse effect of the immunosuppressive drug azathioprine. Polymorphisms in the gene encoding thiopurine S-methyltransferase (TPMT) can alter the metabolism of azathioprine, resulting in marrow toxicity and life-threatening infection. In a multicenter cohort of pediatric heart transplant (HT) recipients, we determined the frequency of TPMT genetic variation and assessed whether azathioprine-treated recipients with TPMT variants were at increased risk of infection. METHODS: We genotyped TPMT in 264 pediatric HT recipients for the presence of the TPMT*2, TPMT*3A, and TPMT*3C variant alleles. Data on infection episodes and azathioprine use were collected as part of each patient's participation in the Pediatric Heart Transplant Study. We performed unadjusted Kaplan-Meier analyses comparing infection outcomes between groups. RESULTS: TPMT variants were identified in 26 pediatric HT recipients (10%): *3A (n = 17), *3C (n = 8), and *2 (n = 1). Among those with a variant allele, *3C was most prevalent in black patients (4 of 5) and *3A most prevalent among white and Hispanic patients (16 of 20). Among 175 recipients (66%) who received azathioprine as part of the initial immunosuppressive regimen, we found no difference in the number of infections at 1 year after HT (0.7 +/- 1.3; range, 0-6 versus 0.5 +/- 0.9; range, 0-3; p = 0.60) or in freedom from infection and bacterial infection between non-variant and variant carriers. There was 1 infection-related death in each group. CONCLUSIONS: In this multicenter cohort of pediatric HT recipients, the prevalence of TPMT variants was similar across racial/ethnic groups to what has been previously reported in non-pediatric HT populations. We found no association between variant alleles and infection in the first year after HT. Because clinically detected cytopenia could have prompted dose adjustment or cessation, we recommend future studies assess the relationship of genotype to leukopenia/neutropenia in the pediatric transplantation population. PMID- 29720912 TI - Use of Arginine Hydrochloride in the Treatment of Metabolic Alkalosis or Hypochloremia in Pediatric Patients. AB - OBJECTIVES: Dosing of arginine for treatment of hypochloremia or metabolic alkalosis is laborious and has inherent variability in dose selection. The primary objective of this study was to determine the efficacy of arginine in the treatment of metabolic alkalosis and hypochloremia. Secondary objectives were to determine an optimal dose, route, and frequency for arginine administration in the treatment of these conditions. METHODS: This single center, retrospective, descriptive study was conducted in children who received arginine for treatment of hypochloremia or metabolic alkalosis. Treatment success was assessed by measuring serum chloride and bicarbonate concentrations after arginine administration. RESULTS: Of the 464 orders analyzed, 177 met inclusion criteria in 82 unique patients. Fifty percent (n = 81) of arginine administrations used to manage hypochloremia saw normalization of abnormal chloride levels, and 83% (n = 62) of arginine administrations used to treat metabolic alkalosis saw normalization of abnormal bicarbonate levels. Patients who received arginine to resolve hypochloremia were statistically significantly more likely to have their hypochloremia resolve if they used alternative dosing methods compared to established dosing methods (76 vs. 5, p = 0.001). However, this relationship was not seen for patients with metabolic alkalosis (11 vs. 51, p = 1.000). The median percentage of calculated daily dose of arginine needed for resolution of hypochloremia was 59% and was 35% for metabolic alkalosis. CONCLUSIONS: Arginine is effective to improve metabolic alkalosis and hypochloremia. Established dosing methods are not more effective than other methods in resolving metabolic alkalosis or hypochloremia. Further prospective studies are warranted to validate these results. PMID- 29720913 TI - Effects of Methadone on Corrected Q-T Interval Prolongation in Critically Ill Children. AB - OBJECTIVES: This study aimed to determine the association between methadone use and corrected Q-T interval (QTc) prolongation in critically ill children. METHODS: A retrospective cohort study of critically ill children receiving methadone at a tertiary care pediatric hospital was conducted. Patients younger than 19 years who had been admitted to the intensive care unit between January 1, 2009, and June 21, 2013, who had received methadone while inpatients, and who had had electrocardiograms (ECGs) performed within 30 days before and after methadone initiation were included. The primary outcome was the net change in QTc interval between baseline and postmethadone ECGs. Secondary outcomes included percent change in QTc interval and the proportion of patients whose QTc intervals changed from normal to prolonged following methadone initiation. We also evaluated potential predictors of QTc interval prolongation, including age, sex, admission diagnosis category, exposure to other QTc-prolonging medications, presence of congenital heart disease or known arrhythmias, and methadone daily dose and route of administration. RESULTS: Sixty-four patients met the inclusion criteria. The median (25th, 75th percentiles) change in QTc interval following methadone initiation was -8 msec (-34, 13.5 msec; p = 0.19). Five patients (8%) had a baseline normal QTc interval that became prolonged after methadone initiation. We identified no statistically significant predictors of QTc prolongation after methadone initiation. CONCLUSIONS: In this dedicated pediatric safety study, methadone initiation did not result in prolongation of the QTc interval. Although these findings suggest methadone initiation may not have a substantial effect of QTc prolongation in critically ill children, a controlled, prospective evaluation in this population remains warranted. PMID- 29720914 TI - Vancomycin Versus Vancomycin Plus Rifampin for the Treatment of Acute Pulmonary Exacerbations of Cystic Fibrosis. AB - OBJECTIVES: This study aimed to compare the change in pulmonary function in children and adolescents with cystic fibrosis (CF) who were infected with methicillin-resistant Staphylococcus aureus (MRSA) treated with either vancomycin (VAN) alone or vancomycin plus rifampin (VAN-RIF). METHODS: Included patients were ages 6 to 20 years; hospitalized for an acute pulmonary exacerbation (APE) of CF from May 1, 2012, to April 30, 2014; had a respiratory tract culture positive for MRSA within 1 month of index hospital admission; received at least 48 consecutive hours of VAN or VAN-RIF; and had admission and discharge pulmonary function tests. The primary end point was change in percent predicted forced expiratory volume in 1 second (FEV1). RESULTS: A total of 39 encounters met inclusion criteria: 24 in the VAN group (mean age 15.1 years) and 15 in the VAN RIF group (mean age 13.7 years). There were no between-group differences in mean percent change in FEV1 (32.6% +/- 28.8% vs. 21.1% +/- 12.1%; p = 0.091), mean percent change in forced vital capacity (22.6% +/- 25.8% vs. 14% +/- 9.4%; p = 0.127), or return to baseline FEV1 (20 [83.3%] vs. 14 [93.3%] patients; p = 0.631). Median (IQR) length of stay (13 days [11-14 days] vs. 13 days [9-14 days]; p = 0.6) and median (IQR) time to readmission (82 days [43-129 days] vs. 147 days [78-219 days]; p = 0.2) were similar between the VAN and VAN-RIF groups, respectively. CONCLUSIONS: Vancomycin monotherapy appears to be adequate when treating APEs of CF in children and adolescents with moderate lung disease and high MRSA VAN minimum inhibitory concentrations. Therefore, the addition of RIF may be unnecessary; however, larger studies are needed to confirm these findings. PMID- 29720915 TI - Resource Use Evaluation of Tobramycin Formulations in a State Medicaid Program. AB - OBJECTIVE: Patients with cystic fibrosis (CF) often suffer from chronic infection with Pseudomonas aeruginosa. For patients with CF, 6 years of age and older, with P aeruginosa persistently present in cultures of the airways, the Cystic Fibrosis Foundation recommends the chronic use of inhaled tobramycin to reduce exacerbations. To ease treatment burden, a new dry powder formulation was developed. The objective of this research was to compare resource utilization between tobramycin inhaled solution (TIS) and a new tobramycin dry powder (TIP) formulation in a state Medicaid program. METHODS: Members that switched from TIS to TIP were matched to TIS-only beneficiaries via propensity score based on age, sex, race, and residence location. The outcomes (tobramycin reimbursement, inpatient hospital reimbursement, additional antibiotic therapy reimbursement, length of inpatient stays, odds of adherence, odds of inpatient hospital stay, and additional mean days of antibiotic therapy) were assessed by using multivariable regression and included baseline clinical surrogates. RESULTS: No difference was found between 54 matched members for tobramycin reimbursement, length of inpatient stays, odds of adherence, or odds of hospital stay. Cost of additional antibiotic therapy was higher for TIP (+$518, p < 0.001) and inpatient reimbursement was higher for TIS (+$503, p = 0.031). Additional mean days of antibiotic therapy were lower for TIP (8.6 vs. 10.1, p = 0.374), but was not statistically significant. CONCLUSIONS: In patients that switched from TIS to TIP, an increase in cost of additional antibiotic therapy was observed, while inpatient costs were lower. Research should be considered in larger populations to fully determine the impact of the new dry powder formulation on overall resource use and outcomes. PMID- 29720916 TI - Evaluation of Timing and Dosing of Caffeine Citrate in Preterm Neonates for the Prevention of Bronchopulmonary Dysplasia. AB - OBJECTIVE: The aim of this study was to evaluate the timing and dosing of caffeine therapy in relation to the development of bronchopulmonary dysplasia (BPD). METHODS: This was a single-center, retrospective cohort study comparing early (days of life 0-2) to late (day of life 3 or greater) caffeine initiation in extremely low birth weight neonates, with a secondary analysis of large (10 mg/kg/day) to small dose (5 mg/kg/day) caffeine. RESULTS: There were 138 patients in the primary timing analysis. The early caffeine group had a lower incidence and reduced odds of the composite outcome of BPD or all-cause mortality, compared with the late caffeine group (64% vs. 88%, respectively; adjusted p < 0.05; adjusted OR 0.36 [95% CI 0.13-0.98]). No statistically significant difference was found between dosing groups (p = 0.29) in the primary outcome; however, there was a lower rate of patent ductus arteriosus requiring treatment (p = 0.05) and decreased likelihood of discharging home on oxygen (p = 0.02) in the large-dose group compared with the small-dose group. CONCLUSIONS: Early caffeine initiation significantly decreased the incidence of BPD or all-cause mortality in extremely low birth weight neonates. Patients receiving large-dose caffeine had improved secondary outcomes, although no difference in BPD was noted. Further studies are needed to determine the optimal dosing of caffeine. PMID- 29720917 TI - Comparison of the Pharmacoeconomics of Calfactant and Poractant Alfa in Surfactant Replacement erapy. AB - OBJECTIVE: To compare the pharmacy costs of calfactant (Infasurf, ONY, Inc.) and poractant alfa (Curosurf, Chiesi USA, Inc., Cary, NC). METHODS: The University of South Alabama Children's and Women's Hospital switched from calfactant to poractant alfa in 2013 and back to calfactant in 2015. Retrospectively, we used deidentified data from pharmacy records that provided type of surfactant administered, gestational age, birth weight, and number of doses on each patient. We examined differences in the number of doses by gestational ages and the differences in costs by birth weight cohorts because cost per dose is based on weight. RESULTS: There were 762 patients who received calfactant and 432 patients who received poractant alfa. The average number of doses required per patient was 1.6 administrations for calfactant-treated patients and 1.7 administrations for poractant alfa-treated patients, p = 0.03. A higher percentage of calfactant patients needed only 1 dose (53%) than poractant alfa patients (47%). The distribution of the number of doses for calfactant-treated patients was significantly lower than for the poractant alfa-patients, p < 0.001. Gestational age had no consistent effect on the number of doses required for either calfactant or poractant alfa. Per patient cost was higher for poractant alfa than for calfactant in all birth weight cohorts. Average per patient cost was $1160.62 for poractant alfa, 38% higher than the average per patient cost for calfactant ($838.34). Using poractant alfa for 22 months is estimated to have cost $202,732.75 more than it would have cost if the hospital had continued using calfactant. CONCLUSION: Our experience showed a strong pharmacoeconomic advantage for the use of calfactant compared to the use of poractant alfa because of similar average dosing and lower per patient drug costs. PMID- 29720918 TI - Safety of Extended Interval Tobramycin in Cystic Fibrosis Patients Less an 6 Years Old. AB - OBJECTIVES: The primary objective of this study was to assess the nephrotoxicity and ototoxicity risks of extended interval tobramycin in cystic fibrosis (CF) patients who are <6 years old. A secondary objective included analyzing pharmacokinetic parameters in this age group. METHODS: A retrospective chart review was conducted of patients with CF who were <6 years old, admitted for an acute pulmonary exacerbation from January 1, 2003, to January 1, 2014, and treated with intravenous tobramycin. RESULTS: The median baseline serum creatinine (SCr) was 0.26 mg/dL among the 31 patients included in the study. Of the 20 patients who experienced increases in SCr, the absolute median increase was 0.065 mg/dL (0.033-0.1 mg/dL). Abnormal audiograms seen in 4 patients are attributable to middle ear effusion present on exam. The median dose of tobramycin was 11.7 mg/kg (11.3-12 mg/kg), the elimination constant was 0.4 hr 1(0.32-0.47 hr-1), half-life was 1.7 hr (1.5-2.1 hr), volume of distribution was 0.37 L/kg (0.31-0.47 L/kg), and median peaks and troughs fell within ranges of 20 to 30 mg/L (20.9-32.7 mg/L) and <0.01 mg/L, respectively. CONCLUSIONS: Extended interval dosing tobramycin is safe in CF patients who are <6 years old. There was no drug-related ototoxicity, and some nephrotoxicity was observed. When dosed at 12 mg/kg, similar pharmacokinetics were seen among all age groups, and concentrations were within the desired range. PMID- 29720919 TI - Extended Interval Tobramycin Pharmacokinetics in a Pediatric Patient With Primary Ciliary Dyskinesia Presenting With an Acute Respiratory Exacerbation. AB - The pharmacokinetics of tobramycin in patients with ciliary dyskinesia have not been previously reported. A 10-year-old female patient with primary ciliary dyskinesia was admitted to the general pediatrics floor with an acute respiratory exacerbation after several months of worsening lung function that was unresponsive to oral antibiotics. Extrapolating from cystic fibrosis dosing regimens, she was given intravenous tobramycin 320 mg (10.3 mg/kg/day) on admission as a result of concern for a Pseudomonas aeruginosa infection. Two point pharmacokinetic monitoring revealed a maximum serum concentration (Cmax) of 18.9 mg/L and a 24-hour area under the curve (AUC0-24hr) of 58.8 (mg * hr)/L, as well as a volume of distribution (Vd) of 0.5 L/kg and an elimination rate (Ke) of 0.34 hr-1. After a dosage increase to tobramycin 400 mg (12.8 mg/kg/day), pharmacokinetic parameters on 2 assessments were as follows: Vd 0.37 to 0.39 L/kg, Ke 0.33 to 0.39 hr-1, Cmax 27.8 to 28.7 mg/L, and AUC0-24h 78.4 to 89.4 (mg * hr)/L. This was the first case report of aminoglycoside pharmacokinetics in a patient with ciliary dyskinesia. The administration of larger doses (up to 12.8 mg/kg/day) of extended-interval tobramycin, similar to the treatment recommendation of at least 10 mg/kg/day for cystic fibrosis patients, was necessary in this patient to achieve serum concentrations that were appropriate for treatment. PMID- 29720920 TI - A Unique Preparation and Delivery Method for Acitretin for Neonatal Harlequin Ichthyosis. AB - Harlequin ichthyosis is a rare form of congenital ichthyosis with a distinct phenotypic appearance. We describe a case of a newborn baby with harlequin ichthyosis who was treated with an oral formulation of acitretin. The treatment resulted in a satisfactory improvement in the skin condition of the patient. The tolerance to the drug was good with no side effects in the patient. The aim of this case report is to highlight an extemporaneous preparation of acitretin from the commonly available capsule form, which is effective for use in neonates with harlequin ichthyosis. It also highlights the risk of exposure to health care providers to acitretin. PMID- 29720921 TI - Disulfiram-like Reaction Involving Ceftriaxone in a Pediatric Patient. AB - Several medications have been shown to cause disulfiram-like reactions in patients concomitantly exposed to ethanol, including specific cephalosporin antibiotics that possess a methylthiotetrazole substituent. Within the cephalosporin class, there are few reports of disulfiram-like reactions with ceftriaxone. This case report is the first to involve a pediatric patient, and it describes a mild but likely disulfiram-like reaction manifesting as facial flushing in an 8-year-old male upon receiving a ceftriaxone infusion preceded by a dose of prednisolone elixir (5% ethanol by volume) for presumed community acquired pneumonia thought to be complicated by an asthma exacerbation. The patient's flushing resolved with intravenous diphenhydramine, did not reappear, and was diagnosed as an allergy to ceftriaxone. Upon further evaluation, a hypersensitivity reaction was considered unlikely, and the allergy history was revised. The patient's antibiotic treatment was switched to azithromycin without steroids, and he had no further issues. This case suggests there is benefit in increased monitoring of pediatric patients receiving certain cephalosporins along with alcohol-containing medications, and it demonstrates how disulfiram reactions can easily be misinterpreted as hypersensitivity reactions. Aside from just alcohol-cephalosporin interactions, this case underscores the need for general vigilance when using alcohol-containing drug preparations in pediatric patients in an effort to prevent adverse effects and potential drug interactions. PMID- 29720922 TI - PEDIATRIC NEWS. PMID- 29720923 TI - Tumor-Shed Antigen Affects Antibody Tumor Targeting: Comparison of Two 89Zr Labeled Antibodies Directed against Shed or Nonshed Antigens. AB - We investigated the effect of shed antigen mesothelin on the tumor uptake of amatuximab, a therapeutic anti-mesothelin mAb clinically tested in mesothelioma patients. The B3 mAb targeting a nonshed antigen was also analyzed for comparison. The mouse model implanted with A431/H9 tumor, which expresses both shed mesothelin and nonshed Lewis-Y antigen, provided an ideal system to compare the biodistribution and PET imaging profiles of the two mAbs. Our study demonstrated that the tumor and organ uptakes of 89Zr-B3 were dose-independent when 3 doses, 2, 15, and 60 MUg B3, were compared at 24 h after injection. In contrast, tumor and organ uptakes of 89Zr-amatuximab were dose-dependent, whereby a high dose (60 MUg) was needed to achieve tumor targeting comparable to the low dose (2 MUg) of 89Zr-B3, suggesting that shed mesothelin may affect amatuximab tumor targeting as well as serum half-life. The autoradiography analysis showed that the distribution of 89Zr-B3 was nonuniform with the radioactivity primarily localized at the tumor periphery independent of the B3 dose. However, the autoradiography analysis for 89Zr-amatuximab showed dose-dependent distribution profiles of the radiolabel; at 10 MUg dose, the radiolabel penetrated toward the tumor core with its activity comparable to that at the tumor periphery, whereas at 60 MUg dose, the distribution profile became similar to those of 89Zr-B3. These results suggest that shed antigen in blood may act as a decoy requiring higher doses of mAb to improve serum half-life as well as tumor targeting. Systemic mAb concentration should be at a severalfold molar excess to the shed Ag in blood to overcome the hepatic processing of mAb-Ag complexes. On the other hand, mAb concentration should remain lower than the shed Ag concentration in the tumor ECS to maximize tumor penetration by passing binding site barriers. PMID- 29720924 TI - Citropin 1.1 Trifluoroacetate to Chloride Counter-Ion Exchange in HCl-Saturated Organic Solutions: An Alternative Approach. AB - In view of the increasing interest in peptides in various market sectors, a stronger emphasis on topics related to their production has been seen. Fmoc-based solid phase peptide synthesis, although being fast and efficient, provides final products with significant amounts of trifluoroacetate ions in the form of either a counter-ion or an unbound impurity. Because of the proven toxicity towards cells and peptide activity inhibition, ion exchange to more biocompatible one is purposeful. Additionally, as most of the currently used counter-ion exchange techniques are time-consuming and burdened by peptide yield reduction risk, development of a new approach is still a sensible solution. In this study, we examined the potential of peptide counter-ion exchange using non-aqueous organic solvents saturated with HCl. Counter-ion exchange of a model peptide, citropin 1.1 (GLFDVIKKVASVIGGL-NH2), for each solvent was conducted through incubation with subsequent evaporation under reduced pressure, dissolution in water and lyophilization. Each exchange was performed four times and compared to a reference method-lyophilization of the peptide from an 0.1 M HCl solution. The results showed superior counter-ion exchange efficiency for most of the organic solutions in relation to the reference method. Moreover, HCl-saturated acetonitrile and tert-butanol provided a satisfying exchange level after just one repetition. Thus, those two organic solvents can be potentially introduced into routine peptide counter-ion exchange. PMID- 29720925 TI - Gaussian Accelerated Molecular Dynamics: Theory, Implementation, and Applications. AB - A novel Gaussian Accelerated Molecular Dynamics (GaMD) method has been developed for simultaneous unconstrained enhanced sampling and free energy calculation of biomolecules. Without the need to set predefined reaction coordinates, GaMD enables unconstrained enhanced sampling of the biomolecules. Furthermore, by constructing a boost potential that follows a Gaussian distribution, accurate reweighting of GaMD simulations is achieved via cumulant expansion to the second order. The free energy profiles obtained from GaMD simulations allow us to identify distinct low energy states of the biomolecules and characterize biomolecular structural dynamics quantitatively. In this chapter, we present the theory of GaMD, its implementation in the widely used molecular dynamics software packages (AMBER and NAMD), and applications to the alanine dipeptide biomolecular model system, protein folding, biomolecular large-scale conformational transitions and biomolecular recognition. PMID- 29720927 TI - Association of dietary patterns and hyperuricemia: a cross-sectional study of the Yi ethnic group in China. AB - Background: Diet plays an important role in the development of hyperuricemia (HUA), but evidence for association between overall dietary patterns and HUA is scarce and inconsistent. The present study aims to explore association of dietary patterns and HUA among the Yi ethnic group of China. Methods: This is a cross sectional study involving people aged more than 18 years. Principal component factor analysis (PCFA) on food groups from a semi-quantitative 52-item food frequency questionnaire was applied to identify dietary patterns. HUA status was regressed on tertiles of factor scores to estimate prevalence ratio (PR) by using log-binomial model. Results: Of the 1,893 participants (18-96 years), 398 (21.0%) were diagnosed with HUA. Three dietary patterns were identified: 'plant-based', 'animal products', and 'mixed food'. The 'animal products' was characterized by high intake of fish, animal giblets, fresh meat, and wheat products. After adjustment for potential confounders, the highest tertile of 'animal products' pattern score was associated with higher prevalence of HUA when compared with the lowest tertile (PR: 1.34, 95% CI: 1.06-1.70). The other two patterns were not related to HUA. Conclusions: 'Animal products' dietary pattern was correlated with HUA among the Yi ethnic group of China. PMID- 29720926 TI - The study of atmospheric ice-nucleating particles via microfluidically generated droplets. AB - Ice-nucleating particles (INPs) play a significant role in the climate and hydrological cycle by triggering ice formation in supercooled clouds, thereby causing precipitation and affecting cloud lifetimes and their radiative properties. However, despite their importance, INP often comprise only 1 in 103 106 ambient particles, making it difficult to ascertain and predict their type, source, and concentration. The typical techniques for quantifying INP concentrations tend to be highly labour-intensive, suffer from poor time resolution, or are limited in sensitivity to low concentrations. Here, we present the application of microfluidic devices to the study of atmospheric INPs via the simple and rapid production of monodisperse droplets and their subsequent freezing on a cold stage. This device offers the potential for the testing of INP concentrations in aqueous samples with high sensitivity and high counting statistics. Various INPs were tested for validation of the platform, including mineral dust and biological species, with results compared to literature values. We also describe a methodology for sampling atmospheric aerosol in a manner that minimises sampling biases and which is compatible with the microfluidic device. We present results for INP concentrations in air sampled during two field campaigns: (1) from a rural location in the UK and (2) during the UK's annual Bonfire Night festival. These initial results will provide a route for deployment of the microfluidic platform for the study and quantification of INPs in upcoming field campaigns around the globe, while providing a benchmark for future lab-on-a chip-based INP studies. PMID- 29720928 TI - Evaluation of a short Food Frequency Questionnaire to assess cardiovascular disease-related diet and lifestyle factors. AB - Background: The Vascular lifestyle-Intervention and Screening in phArmacies (VISA) study investigates diet and lifestyle factors associated with risk of cardiovascular disease (CVD). As part of the study methodology, a short Food Frequency Questionnaire (FFQ), the VISA-FFQ, was adapted from the Norwegian NORDIET-FFQ. Objective: The aim of this study was to evaluate the VISA-FFQ and its ability to estimate intakes of foods and lifestyle factors in screening for elevated risk of CVD. The evaluation included assessment of relative validity of intake of milk fat and assessment of reproducibility of several foods and lifestyle factors. Design: Relative validity of milk fat estimated from the VISA FFQ was assessed in 307 participants by comparing estimated dietary intake of the fatty acids pentadecanoic acid (15:0) and heptadecanoic acid (17:0), from milk fat with whole blood biomarkers 15:0 and 17:0. Reproducibility was evaluated in 122 participants by comparing consistency in intakes of different foods and lifestyle factors reported by the VISA-FFQ and administered twice with a 4-week interval. Results: Dietary 15:0 milk fat estimated from the VISA-FFQ correlated positively with whole blood 15:0 (r = 0.32, P < 0.05). Men presented higher correlations than women did. Acceptable and consistent reproducibility (r = 0.44 0.94 and no large difference between test and retest) was observed for most beverages, milk products, spreads on bread and meat (all of which included food items categorised into at least two fat categories) and also for eggs, fruits and vegetables, nuts, pasta and rice, dessert/sweets, smoking and physical activity. Reproducibility did not consistently meet a satisfactory standard (r <= 0.41 or large difference between test and retest) for unsweetened cereals, fatty fish, cakes, oils, white-, bread, crispbread and rice. Conclusion: The validity of the VISA-FFQ was acceptable for intake of milk fat, and there was an overall satisfactory, though variable, reproducibility for intake of several foods and lifestyle factors in the VISA-FFQ. PMID- 29720929 TI - Antioxidant effects of compound walnut oil capsule in mice aging model induced by D-galactose. AB - Background: Many plant original foods have been shown beneficial effects in humans. In the previous work, we have developed a compound capsule which contains major constituents of walnut oil and grape seed extract. Objective: To investigate the antioxidant effects of the Compound Walnut Oil Capsule (WOC) in aging model induced by D-gal. Design: 70 C57BL/6J mice were randomly divided into seven groups. Mice in normal group received daily subcutaneous injection of saline while the control group, WOC groups, Vitamin C (VC) group and pure walnut oil group received daily subcutaneous injection of D-galactose (D-gal) for 8 weeks. Total antioxidant capacity (T-AOC), super dismutase (SOD), glutathione peroxidase (GSH-Px) and malondialdehyde (MDA) in serum, liver and brain were determined. The expression of Heme Oxygenase (HO-1), iNOS and Klotho in liver and brain were obtained. Results: WOC could improve the pathologic lesions caused by oxidative stress and significantly enhance the T-AOC, increase the activities of SOD, GSH-Px and decrease the contents of MDA in serum, liver and brain. Also, the WOC could obviously up-regulate the expression of HO-1 and Klotho and down regulate the expression of iNOS. Conclusion: WOC can be used as an anti-aging food for its effectively eliminating free radicals, enhancing the antioxidant capacity and alleviating the damages of oxidative stress. PMID- 29720930 TI - National nutrition surveys in Europe: a review on the current status in the 53 countries of the WHO European region. AB - Objectives: The objectives of this study were (1) to determine the coverage of national nutrition surveys in the 53 countries monitored by the World Health Organization (WHO) Regional Office for Europe and identify gaps in provision, (2) to describe relevant survey attributes and (3) to check whether energy and nutrients are reported with a view to providing information for evidence-based nutrition policy planning. Design: Dietary survey information was gathered using three methods: (1) direct email to survey authors and other relevant contacts, (2) systematic review of literature databases and (3) general web-based searches. Survey characteristics relating to time frame, sampling and dietary methodology and nutrients reported were tabled from all relevant surveys found since 1990. Setting: Fifty-three countries of the WHO Regional Office for Europe, which have need for an overview of dietary surveys across the life course. Subjects: European individuals (adults and children) in national diet surveys. Results: A total of 109 nationally representative dietary surveys undertaken post-1990 were found across 34 countries. Of these, 78 surveys from 33 countries were found post 2000, and of these, 48 surveys from 27 countries included children and 60 surveys from 30 countries included adults. No nationally representative surveys were found for 19 of 53 countries, mainly from Central and Eastern Europe. Multiple 24hr recall and food diaries were the most common dietary assessment methods. Only 22 countries reported energy and nutrient intakes from post-2000 surveys; macronutrients were more widely reported than micronutrients. Conclusions: Less than two-thirds of WHO Europe countries have nationally representative diet surveys, mainly collected post-2000. The main availability gaps lie in Central and Eastern European countries, where nutrition policies may therefore lack an appropriate evidence base. Dietary methodological differences may limit the scope for inter-country comparisons. PMID- 29720931 TI - Assessment of nutritional status in the elderly: a proposed function-driven model. AB - Background: There is no accepted or standardized definition of 'malnutrition'. Hence, there is also no definition of what constitutes an adequate nutritional status. In elderly people, assessment of nutritional status is complex and is complicated by multi-morbidity and disabilities combined with nutrition-related problems, such as dysphagia, decreased appetite, fatigue, and muscle weakness. Objective: We propose a nutritional status model that presents nutritional status from a comprehensive functional perspective. This model visualizes the complexity of the nutritional status in elderly people. Design and results: The presented model could be interpreted as the nutritional status is conditional to a person's optimal function or situation. Another way of looking at it might be that a person's nutritional status affects his or her optimal situation. The proposed model includes four domains: (1) physical function and capacity; (2) health and somatic disorders; (3) food and nutrition; and (4) cognitive, affective, and sensory function. Each domain has a major impact on nutritional status, which in turn has a major impact on the outcome of each domain. Conclusions: Nutritional status is a multifaceted concept and there exist several knowledge gaps in the diagnosis, prevention, and optimization of treatment of inadequate nutritional status in elderly people. The nutritional status model may be useful in nutritional assessment research, as well as in the clinical setting. PMID- 29720933 TI - The Scalp Time-Varying Networks of N170: Reference, Latency, and Information Flow. AB - Using the scalp time-varying network method, the present study is the first to investigate the temporal influence of the reference on N170, a negative event related potential component (ERP) appeared about 170 ms that is elicited by facial recognition, in the network levels. Two kinds of scalp electroencephalogram (EEG) references, namely, AR (average of all recording channels) and reference electrode standardization technique (REST), were comparatively investigated via the time-varying processing of N170. Results showed that the latency and amplitude of N170 were significantly different between REST and AR, with the former being earlier and smaller. In particular, the information flow from right temporal-parietal P8 to left P7 in the time varying network was earlier in REST than that in AR, and this phenomenon was reproduced by simulation, in which the performance of REST was closer to the true case at source level. These findings indicate that reference plays a crucial role in ERP data interpretation, and importantly, the newly developed approximate zero reference REST would be a superior choice for precise evaluation of the scalp spatio-temporal changes relating to various cognitive events. PMID- 29720932 TI - Influence of Musical Enculturation on Brain Responses to Metric Deviants. AB - The ability to recognize metric accents is fundamental in both music and language perception. It has been suggested that music listeners prefer rhythms that follow simple binary meters, which are common in Western music. This means that listeners expect odd-numbered beats to be strong and even-numbered beats to be weak. In support of this, studies have shown that listeners exposed to Western music show stronger novelty and incongruity related P3 and irregularity detection related mismatch negativity (MMN) brain responses to attenuated odd- than attenuated even-numbered metric positions. Furthermore, behavioral evidence suggests that music listeners' preferences can be changed by long-term exposure to non-Western rhythms and meters, e.g., by listening to African or Balkan music. In our study, we investigated whether it might be possible to measure effects of music enculturation on neural responses to attenuated tones on specific metric positions. We compared the magnetic mismatch negativity (MMNm) to attenuated beats in a "Western group" of listeners (n = 12) mainly exposed to Western music and a "Bicultural group" of listeners (n = 13) exposed for at least 1 year to both Sub-Saharan African music in addition to Western music. We found that in the "Western group" the MMNm was higher in amplitude to deviant tones on odd compared to even metric positions, but not in the "Bicultural group." In support of this finding, there was also a trend of the "Western group" to rate omitted beats as more surprising on odd than even metric positions, whereas the "Bicultural group" seemed to discriminate less between metric positions in terms of surprise ratings. Also, we observed that the overall latency of the MMNm was significantly shorter in the Bicultural group compared to the Western group. These effects were not biased by possible differences in rhythm perception ability or music training, measured with the Musical Ear Test (MET). Furthermore, source localization analyses suggest that auditory, inferior temporal, sensory-motor, superior frontal, and parahippocampal regions might be involved in eliciting the MMNm to the metric deviants. These findings suggest that effects of music enculturation can be measured on MMNm responses to attenuated tones on specific metric positions. PMID- 29720934 TI - Reticulospinal Systems for Tuning Motor Commands. AB - The pontomedullary reticular formation (RF) is a key site responsible for integrating descending instructions to execute particular movements. The indiscrete nature of this region has led not only to some inconsistencies in nomenclature, but also to difficulties in understanding its role in the control of movement. In this review article, we first discuss nomenclature of the RF, and then examine the reticulospinal motor command system through evolution. These command neurons have direct monosynaptic connections with spinal interneurons and motoneurons. We next review their roles in postural adjustments, walking and sleep atonia, discussing their roles in movement activation or inhibition. We propose that knowledge of the internal organization of the RF is necessary to understand how the nervous system tunes motor commands, and that this knowledge will underlie strategies for motor functional recovery following neurological injuries or diseases. PMID- 29720936 TI - The Effects of Tai Chi Intervention on Healthy Elderly by Means of Neuroimaging and EEG: A Systematic Review. AB - Aging is a process associated with a decline in cognitive and motor functions, which can be attributed to neurological changes in the brain. Tai Chi, a multimodal mind-body exercise, can be practiced by people across all ages. Previous research identified effects of Tai Chi practice on delaying cognitive and motor degeneration. Benefits in behavioral performance included improved fine and gross motor skills, postural control, muscle strength, and so forth. Neural plasticity remained in the aging brain implies that Tai Chi-associated benefits may not be limited to the behavioral level. Instead, neurological changes in the human brain play a significant role in corresponding to the behavioral improvement. However, previous studies mainly focused on the effects of behavioral performance, leaving neurological changes largely unknown. This systematic review summarized extant studies that used brain imaging techniques and EEG to examine the effects of Tai Chi on older adults. Eleven articles were eligible for the final review. Three neuroimaging techniques including fMRI (N = 6), EEG (N = 4), and MRI (N = 1), were employed for different study interests. Significant changes were reported on subjects' cortical thickness, functional connectivity and homogeneity of the brain, and executive network neural function after Tai Chi intervention. The findings suggested that Tai Chi intervention give rise to beneficial neurological changes in the human brain. Future research should develop valid and convincing study design by applying neuroimaging techniques to detect effects of Tai Chi intervention on the central nervous system of older adults. By integrating neuroimaging techniques into randomized controlled trials involved with Tai Chi intervention, researchers can extend the current research focus from behavioral domain to neurological level. PMID- 29720937 TI - The NLRP3-Caspase 1 Inflammasome Negatively Regulates Autophagy via TLR4-TRIF in Prion Peptide-Infected Microglia. AB - Prion diseases are neurodegenerative disorders characterized by the accumulation of misfolded prion protein, spongiform changes in the brain, and brain inflammation as a result of the wide-spread activation of microglia. Autophagy is a highly conserved catabolic process for the clearance of cytoplasmic components, including protein aggregates and damaged organelles; this process also eliminates pathological PrPSc as it accumulates during prion infection. The NALP3 inflammasome is a multiprotein complex that is a component of the innate immune system and is responsible for the release of pro-inflammatory cytokines. Our previous study showed that the neurotoxic prion peptide PrP106-126 induces NALP3 inflammasome activation and subsequent IL-1beta release in microglia. Autophagy is involved in the regulation of the immune responses and inflammation in many diseases including neurodegenerative diseases. However, the relationship between autophagy and NALP3 inflammasome in prion diseases has not been investigated. In this study, we demonstrated that the processing and release of mature IL-1beta is significantly enhanced by the inhibition of autophagy. Conversely, gene-silencing of the NALP3 inflammasome promotes autophagy. Suppression of TRIF or TLR4 by siRNA attenuated PrP106-126-induced autophagy, which is indicating that the TLR4 TRIF signaling pathway is involved in PrP106-26-induced autophagy. Caspase 1 directly cleaved TRIF to diminish TLR-4-TRIF mediated autophagy. Our findings suggest that the inhibition of autophagy by NALP3 inflammasome is probably mediated by activated Caspase-1-induced TRIF cleavage. This is the first study reporting that the NALP3 inflammasome complex negatively regulates autophagy in response to PrP106-126 stimulation in microglia, and partly explains the mechanism of autophagy inhibition by Caspase-1 in PrP106-126-induced BV2 cell activation. Our findings suggest that autophagy up-regulation and inhibition of Caspase-1 may protect against prion-induced neuroinflammation and accelerate misfolded protein degradation and are potential therapeutic approaches for prion diseases. PMID- 29720935 TI - Brain Oscillatory and Hemodynamic Activity in a Bimanual Coordination Task Following Transcranial Alternating Current Stimulation (tACS): A Combined EEG fNIRS Study. AB - Motor control is associated with synchronized oscillatory activity at alpha (8-12 Hz) and beta (12-30 Hz) frequencies in a cerebello-thalamo-cortical network. Previous studies demonstrated that transcranial alternating current stimulation (tACS) is capable of entraining ongoing oscillatory activity while also modulating motor control. However, the modulatory effects of tACS on both motor control and its underlying electro- and neurophysiological mechanisms remain ambiguous. Thus, the purpose of this study was to contribute to gathering neurophysiological knowledge regarding tACS effects by investigating the after effects of 10 Hz tACS and 20 Hz tACS at parietal brain areas on bimanual coordination and its concurrent oscillatory and hemodynamic activity. Twenty-four right-handed healthy volunteers (12 females) aged between 18 and 30 (M = 22.35 +/ 3.62) participated in the study and performed a coordination task requiring bimanual movements. Concurrent to bimanual motor training, participants received either 10 Hz tACS, 20 Hz tACS or a sham stimulation over the parietal cortex (at P3/P4 electrode positions) for 20 min via small gel electrodes (3,14 cm2 Ag/AgCl, amperage = 1 mA). Before and three time-points after tACS (immediately, 30 min and 1 day), bimanual coordination performance was assessed. Oscillatory activities were measured by electroencephalography (EEG) and hemodynamic changes were examined using functional near-infrared spectroscopy (fNIRS). Improvements of bimanual coordination performance were not differently between groups, thus, no tACS-specific effect on bimanual coordination performance emerged. However, physiological measures during the task revealed significant increases in parietal alpha activity immediately following 10 Hz tACS and 20 Hz tACS which were accompanied by significant decreases of Hboxy concentration in the right hemispheric motor cortex compared to the sham group. Based on the physiological responses, we conclude that tACS applied at parietal brain areas provoked electrophysiological and hemodynamic changes at brain regions of the motor network which are relevant for bimanual motor behavior. The existence of neurophysiological alterations immediately following tACS, especially in the absence of behavioral effects, are elementary for a profound understanding of the mechanisms underlying tACS. The lack of behavioral modifications strengthens the need for further research on tACS effects on neurophysiology and behavior using combined electrophysiological and neuroimaging methods. PMID- 29720939 TI - Promiscuous, Multi-Target Lupane-Type Triterpenoids Inhibits Wild Type and Drug Resistant HIV-1 Replication Through the Interference With Several Targets. AB - Current research on antiretroviral therapy is mainly focused in the development of new formulations or combinations of drugs belonging to already known targets. However, HIV-1 infection is not cured by current therapy and thus, new approaches are needed. Bevirimat was developed by chemical modification of betulinic acid, a lupane-type pentacyclic triterpenoid (LPT), as a first-in-class HIV-1 maturation inhibitor. However, in clinical trials, bevirimat showed less activity than expected because of the presence of a natural mutation in Gag protein that conferred resistance to a high proportion of HIV-1 strains. In this work, three HIV-1 inhibitors selected from a set of previously screened LPTs were investigated for their targets in the HIV-1 replication cycle, including their maturation inhibitor effect. LPTs were found to inhibit HIV-1 infection acting as promiscuous compounds with several targets in the HIV-1 replication cycle. LPT12 inhibited HIV-1 infection mainly through reverse transcription, integration, viral transcription, viral proteins (Gag) production and maturation inhibition. LPT38 did it through integration, viral transcription or Gag production inhibition and finally, LPT42 inhibited reverse transcription, viral transcription or Gag production. The three LPTs inhibited HIV-1 infection of human primary lymphocytes and infections with protease inhibitors and bevirimat resistant HIV-1 variants with similar values of IC50. Therefore, we show that the LPTs tested inhibited HIV-1 infection through acting on different targets depending on their chemical structure and the activities of the different LPTs vary with slight structural alterations. For example, of the three LPTs under study, we found that only LPT12 inhibited infectivity of newly-formed viral particles, suggesting a direct action on the maturation process. Thus, the multi target behavior gives a potential advantage to these compounds since HIV-1 resistance can be overcome by modulating more than one target. PMID- 29720938 TI - Isolation and Characterization of Two New Secondary Metabolites From Quercus incana and Their Antidepressant- and Anxiolytic-Like Potential. AB - The ethyl acetate fraction of Quercus incana yielded two new compounds [1 and 2]. The characterization and structure elucidation of these compounds were carried out through various spectroscopic techniques such as mass spectrometry along with one- and two-dimensional NMR techniques. The structural formula was deduced to be 2-(4-hydroxybutan-2-yl)-5-methoxyphenol [1] and 4-hydroxy-3-(hydroxymethyl) pentanoic acid [2]. The elevated plus maze (EPM) and light-dark box (LDB) tests (classical mouse models) were performed in order to reveal the anxiolytic potential of both compounds [1 and 2]. Both compounds displayed dose-dependent increases in open-arm entries and time spent in open arms in EPM (*P < 0.05, **P < 0.01), and increased the time spent in the lit compartment and increased transitions between the two compartments in LDB test (*P < 0.05, **P < 0.01). Co administration of selective benzodiazepine (BZP) receptor antagonist, flumazenil (2.5 mg/kg) with compounds [1 and 2] decreased the anxiolytic-like activity of both compounds in the EPM indicating BZP-binding site of GABA-A receptors are involved in the anxiolytic-like effect. Similarly, both compounds at the dose level of 10 and 30 mg/kg, i.p. exerted pronounced antidepressant-like effect in both forced swimming as well as tail suspension tests (*P < 0.05, **P < 0.01; ANOVA followed by Dunnett's post hoc test). The effect at 30 mg/kg was comparable to the reference drug imipramine (60 mg/kg). PMID- 29720940 TI - Osteoinductivity and Antibacterial Properties of Strontium Ranelate-Loaded Poly(Lactic-co-Glycolic Acid) Microspheres With Assembled Silver and Hydroxyapatite Nanoparticles. AB - Bone-related infection rates are 4-64% in long open bone fractures and nearly 1% in joint-related surgeries. Treating bone infections and infection-related bone loss is very important. The present study prepared strontium ranelate (SR)-loaded poly(lactic-co-glycolic acid) (PLGA) microspheres (PM) with assembled silver nanoparticles (AgNPs) and hydroxyapatite nanoparticles (HANPs) (SR-PM-Ag-HA) through a novel solid-in-oil nanosuspension (S/O/N) method to achieve osteoinductivity and antibacterial properties. We evaluated the microstructure, drug release, biocompatibility, osteoinductivity, and antibacterial activity in vitro. The microspheres showed a stable shape and size. The cumulative drug release reached a maximum of ~90% after 22 days. All groups loaded with SR enhanced MC3T3-E1 cell proliferation to a greater degree than pure PM. The osteoinductivity behavior was investigated by ALP staining and real-time PCR of osteogenic differentiation marker genes. The antibacterial activity was evaluated using antibacterial ability and biofilm formation assays. SR-PM-Ag-HA greatly enhanced osteogenic differentiation and showed excellent antibacterial properties. These results indicated that SR-PM-Ag-HA could be biocompatible and suitable for drug delivery, osteoinduction, and antibiosis, and therefore, have potential applications in the treatment of bone-related infections and promotion of bone formation at infected sites. PMID- 29720941 TI - Neonatal Seizure Models to Study Epileptogenesis. AB - Current therapeutic strategies for epilepsy include anti-epileptic drugs and surgical treatments that are mainly focused on the suppression of existing seizures rather than the occurrence of the first spontaneous seizure. These symptomatic treatments help a certain proportion of patients, but these strategies are not intended to clarify the cellular and molecular mechanisms underlying the primary process of epilepsy development, i.e., epileptogenesis. Epileptogenic changes include reorganization of neural and glial circuits, resulting in the formation of an epileptogenic focus. To achieve the goal of developing "anti-epileptogenic" drugs, we need to clarify the step-by-step mechanisms underlying epileptogenesis for patients whose seizures are not controllable with existing "anti-epileptic" drugs. Epileptogenesis has been studied using animal models of neonatal seizures because such models are useful for studying the latent period before the occurrence of spontaneous seizures and the lowering of the seizure threshold. Further, neonatal seizure models are generally easy to handle and can be applied for in vitro studies because cells in the neonatal brain are suitable for culture. Here, we review two animal models of neonatal seizures for studying epileptogenesis and discuss their features, specifically focusing on hypoxia-ischemia (HI)-induced seizures and febrile seizures (FSs). Studying these models will contribute to identifying the potential therapeutic targets and biomarkers of epileptogenesis. PMID- 29720942 TI - Glutathione S-Transferase P1 Protects Against Amodiaquine Quinoneimines-Induced Cytotoxicity but Does Not Prevent Activation of Endoplasmic Reticulum Stress in HepG2 Cells. AB - Formation of the reactive amodiaquine quinoneimine (AQ-QI) and N desethylamodiaquine quinoneimine (DEAQ-QI) plays an important role in the toxicity of the anti-malaria drug amodiaquine (AQ). Glutathione conjugation protects against AQ-induced toxicity and GSTP1 is able to conjugate its quinoneimine metabolites AQ-QI and DEA-QI with glutathione. In this study, HepG2 cells transiently transfected with the human GSTP1 construct were utilized to investigate the protective effect of GSTP1 in a cellular context. HepG2 cells were exposed to synthesized QIs, which bypasses the need for intracellular bioactivation of AQ or DEAQ. Exposure was accompanied by decreased cell viability, increased caspase 3 activity, and decreased intracellular GSH levels. Using high-content imaging-based BAC-GFP reporters, it was shown that AQ-QI and DEAQ-QI specifically activated the endoplasmic reticulum (ER) stress response. In contrast, oxidative stress, DNA damage, or inflammatory stress responses were not activated. Overexpression of GSTP1 resulted in a two-fold increase in GSH conjugation of the QIs, attenuated QI-induced cytotoxicity especially under GSH depletion condition, abolished QIs-induced apoptosis but did not significantly inhibit the activation of the ER stress response. In conclusion, these results indicate a protective role of GSTP1 by increasing enzymatic detoxification of AQ QI and DEAQ-QI and suggest a second protective mechanism by interfering with ER stress induced apoptosis. PMID- 29720943 TI - MicroRNA-200a/200b Modulate High Glucose-Induced Endothelial Inflammation by Targeting O-linked N-Acetylglucosamine Transferase Expression. AB - Background and Aims: Increased O-linked N-acetylglucosamine (O-GlcNAc) modification of proteins by O-GlcNAc transferase (OGT) is associated with diabetic complications. Furthermore, oxidative stress promotes endothelial inflammation during diabetes. A previous study reported that microRNA-200 (miR 200) family members are sensitive to oxidative stress. In this study, we examined whether miR-200a and miR-200b regulate high-glucose (HG)-induced OGT expression in human aortic endothelial cells (HAECs) and whether miRNA-200a/200b downregulate OGT expression to control HG-induced endothelial inflammation. Methods: HAECs were stimulated with high glucose (25 mM) for 12 and 24 h. Real time polymerase chain reaction (PCR), western blotting, THP-1 adhesion assay, bioinformatics predication, transfection of miR-200a/200b mimic or inhibitor, luciferase reporter assay, and transfection of siRNA OGT were performed. The aortic endothelium of db/db diabetic mice was evaluated by immunohistochemistry staining. Results: HG upregulated OGT mRNA and protein expression and protein O GlcNAcylation levels (RL2 antibody) in HAECs, and showed increased intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), and E selectin gene expression; ICAM-1 expression; and THP-1 adhesion. Bioinformatics analysis revealed homologous sequences between members of the miR-200 family and the 3'-untranslated region (3'-UTR) of OGT mRNA, and real-time PCR analysis confirmed that members of miR-200 family were significantly decreased in HG stimulated HAECs. This suggests the presence of an impaired feedback restraint on HG-induced endothelial protein O-GlcNAcylation levels because of OGT upregulation. A luciferase reporter assay demonstrated that miR-200a/200b mimics bind to the 3'-UTR of OGT mRNA. Transfection with miR-200a/200b mimics significantly inhibited HG-induced OGT mRNA expression, OGT protein expression; protein O-GlcNAcylation levels; ICAM-1, VCAM-1, and E-selectin gene expression; ICAM-1 expression; and THP-1 adhesion. Additionally, siRNA-mediated OGT depletion reduced HG-induced protein O-GlcNAcylation; ICAM-1, VCAM-1, and E-selectin gene expression; ICAM-1 expression; and THP-1 adhesion, confirming that HG-induced endothelial inflammation is partially mediated via OGT-induced protein O GlcNAcylation. These results were validated in vivo: tail-vein injection of miR 200a/200b mimics downregulated endothelial OGT and ICAM-1 expression in db/db mice. Conclusion: miR-200a/200b are involved in modulating HG-induced endothelial inflammation by regulating OGT-mediated protein O-GlcNAcylation, suggesting the therapeutic role of miR-200a/200b on vascular complications in diabetes. PMID- 29720944 TI - Identification of Biomarkers Associated With Pathological Stage and Prognosis of Clear Cell Renal Cell Carcinoma by Co-expression Network Analysis. AB - Clear cell renal cell carcinoma (ccRCC) is the most common subtype among renal cancer whose prognostic is affected by the tumor progression associated with complex gene interactions. However, there is currently no available molecular markers associated with ccRCC progression and used or clinical application. In our study, microarray data of 101 ccRCC samples and 95 normal kidney samples were analyzed and 2,425 differentially expressed genes (DEGs) were screened. Weighted gene co-expression network analysis (WGCNA) was then conducted and 11 co expressed gene modules were identified. Module preservation analysis revealed that two modules (red and black) were found to be most stable. In addition, Pearson's correlation analysis identified the module most relevant to pathological stage(patho-module) (r = 0.44, p = 3e-07). Functional enrichment analysis showed that biological processes of the patho-module focused on cell cycle and cell division related biological process and pathway. In addition, 29 network hub genes highly related to ccRCC progression were identified from the stage module. These 29 hub genes were subsequently validated using 2 other independent datasets including GSE53757 (n = 72) and TCGA (n = 530), and the results indicated that all hub genes were significantly positive correlated with the 4 stages of ccRCC progression. Kaplan-Meier survival curve showed that patients with higher expression of each hub gene had significantly lower overall survival rate and disease-free survival rate, indicating that all hub genes could act as prognosis and recurrence/progression biomarkers of ccRCC. In summary, we identified 29 molecular markers correlated with different pathological stages of ccRCC. They may have important clinical implications for improving risk stratification, therapeutic decision and prognosis prediction in ccRCC patients. PMID- 29720945 TI - Decrease of Perivascular Adipose Tissue Browning Is Associated With Vascular Dysfunction in Spontaneous Hypertensive Rats During Aging. AB - Functional perivascular adipose tissue (PVAT) is necessary to maintain vascular physiology through both mechanical support and endocrine or paracrine ways. PVAT shows a brown adipose tissue (BAT)-like feature and the browning level of PVAT is dependent on the anatomic location and species. However, it is not clear whether PVAT browning is involved in the vascular tone regulation in spontaneously hypertensive rats (SHRs). In the present study, we aimed to illustrate the effect of aging on PVAT browning and subsequent vasomotor reaction in SHRs. Herein we utilized histological staining and western blot to detect the characteristics of thoracic PVAT (tPVAT) in 8-week-old and 16-week-old SHR and Wistar-Kyoto (WKY) rats. We also detected vascular reactivity analysis to determine the effect of tPVAT on vasomotor reaction during aging. The results showed that tPVAT had a similar phenotype to BAT, including smaller adipocyte size and positive uncoupling protein-1 (UCP1) staining. Interestingly, the tPVAT of 8-week-old SHR showed increased BAT phenotypic marker expression compared to WKY, whereas the browning level of tPVAT had a more dramatic decrease from 8 to 16 weeks of age in SHR than age-matched WKY rats. The vasodilation effect of tPVAT on aortas had no significant difference in 8-week-old WKY and SHR, whereas this effect is obviously decreased in 16-week-old SHR compared to WKY. In contrast, tPVAT showed a similar vasoconstriction effect in 8- or 16-week-old WKY and SHR rats. Moreover, we identified an important vasodilator adenosine, which regulates adipocyte browning and may be a potential PVAT-derived relaxing factor. Adenosine is dramatically decreased from 8 to 16 weeks of age in the tPVAT of SHR. In summary, aging is associated with a decrease of tPVAT browning and adenosine production in SHR rats. These may result in attenuated vasodilation effect of the tPVAT in SHR during aging. PMID- 29720946 TI - Are the Hypertrophic Adaptations to High and Low-Load Resistance Training Muscle Fiber Type Specific? PMID- 29720948 TI - The Oxygen Consumption and Metabolic Cost of Walking and Running in Adults With Achondroplasia. AB - The disproportionate body mass and leg length of Achondroplasic individuals may affect their net oxygen consumption ([Formula: see text]O2) and metabolic cost (C) when walking at running compared to those of average stature (controls). The aim of this study was to measure submaximal [Formula: see text]O2 and C during a range of set walking speeds (SWS; 0.56 - 1.94 m?s-1, increment 0.28 m?s-1), set running speeds (SRS; 1.67 - 3.33 m?s-1, increment 0.28 m?s-1) and a self-selected walking speed (SSW). [Formula: see text]O2 and C was scaled to total body mass (TBM) and fat free mass (FFM) while gait speed was scaled to leg length using Froude's number (Fr). Achondroplasic [Formula: see text]O2TBM and [Formula: see text]O2FFM were on average 29 and 35% greater during SWS (P < 0.05) and 12 and 18% higher during SRS (P < 0.05) than controls, respectively. Achondroplasic CTBM and CFFM were 29 and 33% greater during SWS (P < 0.05) and 12 and 18% greater during SRS (P < 0.05) than controls, respectively. There was no difference in SSW [Formula: see text]O2TBM or [Formula: see text]O2FFM between groups (P > 0.05), but CTBM and CFFM at SSW were 23 and 29% higher (P < 0.05) in the Achondroplasic group compared to controls, respectively. [Formula: see text]O2TBM and [Formula: see text]O2FFM correlated with Fr for both groups (r = 0.984 - 0.999, P < 0.05). Leg length accounted for the majority of the higher [Formula: see text]O2TBM and [Formula: see text]O2FFM in the Achondroplasic group, but further work is required to explain the higher Achondroplasic CTBM and CFFM at all speeds compared to controls. New and Noteworthy: There is a leftward shift of oxygen consumption scaled to total body mass and fat free mass in Achondroplasic adults when walking and running. This is nullified when talking into account leg length. However, despite these scalars, Achondroplasic individuals have a higher walking and metabolic cost compared to age matched non-Achondroplasic individuals, suggesting biomechanical differences between the groups. PMID- 29720947 TI - A Fly's Eye View of Natural and Drug Reward. AB - Animals encounter multiple stimuli each day. Some of these stimuli are innately appetitive or aversive, while others are assigned valence based on experience. Drugs like ethanol can elicit aversion in the short term and attraction in the long term. The reward system encodes the predictive value for different stimuli, mediating anticipation for attractive or punishing stimuli and driving animal behavior to approach or avoid conditioned stimuli. The neurochemistry and neurocircuitry of the reward system is partly evolutionarily conserved. In both vertebrates and invertebrates, including Drosophila melanogaster, dopamine is at the center of a network of neurotransmitters and neuromodulators acting in concert to encode rewards. Behavioral assays in D. melanogaster have become increasingly sophisticated, allowing more direct comparison with mammalian research. Moreover, recent evidence has established the functional modularity of the reward neural circuits in Drosophila. This functional modularity resembles the organization of reward circuits in mammals. The powerful genetic and molecular tools for D. melanogaster allow characterization and manipulation at the single-cell level. These tools are being used to construct a detailed map of the neural circuits mediating specific rewarding stimuli and have allowed for the identification of multiple genes and molecular pathways that mediate the effects of reinforcing stimuli, including their rewarding effects. This report provides an overview of the research on natural and drug reward in D. melanogaster, including natural rewards such as sugar and other food nutrients, and drug rewards including ethanol, cocaine, amphetamine, methamphetamine, and nicotine. We focused mainly on the known genetic and neural mechanisms underlying appetitive reward for sugar and reward for ethanol. We also include genes, molecular pathways, and neural circuits that have been identified using assays that test the palatability of the rewarding stimulus, the preference for the rewarding stimulus, or other effects of the stimulus that indicate how it can modify behavior. Commonalities between mechanisms of natural and drug reward are highlighted and future directions are presented, putting forward questions best suited for research using D. melanogaster as a model organism. PMID- 29720949 TI - Active Recovery After High-Intensity Interval-Training Does Not Attenuate Training Adaptation. AB - Objective: High-intensity interval training (HIIT) can be extremely demanding and can consequently produce high blood lactate levels. Previous studies have shown that lactate is a potent metabolic stimulus, which is important for adaptation. Active recovery (ACT) after intensive exercise, however, enhances blood lactate removal in comparison with passive recovery (PAS) and, consequently, may attenuate endurance performance improvements. Therefore, the aim of this study was to examine the influence of regular ACT on training adaptations during a HIIT mesocycle. Methods: Twenty-six well-trained male intermittent sport athletes (age: 23.5 +/- 2.5 years; O2max: 55.36 +/- 3.69 ml min kg-1) participated in a randomized controlled trial consisting of 4 weeks of a running-based HIIT mesocycle with a total of 12 HIIT sessions. After each training session, participants completed 15 min of either moderate jogging (ACT) or PAS. Subjects were matched to the ACT or PAS groups according to age and performance. Before the HIIT program and 1 week after the last training session, the athletes performed a progressive incremental exercise test on a motor-driven treadmill to determine O2max, maximum running velocity (vmax), the running velocity at which O2max occurs (vO2max), and anaerobic lactate threshold (AT). Furthermore, repeated sprint ability (RSA) were determined. Results: In the whole group the HIIT mesocycle induced significant or small to moderate changes in vmax (p < 0.001, effect size [ES] = 0.65,), vO2max (p < 0.001, ES = 0.62), and AT (p < 0.001, ES = 0.56) compared with the values before the intervention. O2max and RSA remained unchanged throughout the study. In addition, no significant differences in the changes were noted in any of the parameters between ACT and PAS except for AT (p < 0.05, ES = 0.57). Conclusion: Regular use of individualized ACT did not attenuate training adaptations during a HIIT mesocycle compared to PAS. Interestingly, we found that the ACT group obtained a significantly higher AT following the training program compared to the PAS group. This could be because ACT allows a continuation of the training at a low intensity and may activate specific adaptive mechanisms that are not triggered during PAS. PMID- 29720950 TI - Sensorimotor Gating in Depressed and Euthymic Patients with Bipolar Disorder: Analysis on Prepulse Inhibition of Acoustic Startle Response Stratified by Gender and State. AB - Background: Prepulse inhibition (PPI) of the acoustic startle reflex is an operational measure of sensorimotor gating. The findings on PPI deficits in bipolar disorder (BD) are inconsistent among studies due to various confounding factors such as gender. This study aimed to assess sensorimotor gating deficits in patients with BD stratified by gender and state (depressed/euthymic), and to explore related clinical variables. Methods: Subjects were 106 non-manic BD patients (26 BD I and 80 BD II; 63 with depression and 43 euthymic) and 232 age-, gender-, and ethnicity-matched (Japanese) healthy controls. Depression severity was assessed using the Hamilton Depression Rating Scale-21. The electromyographic activity of the orbicularis oculi muscle was measured by a computerized startle reflex test unit. Startle magnitude, habituation, and PPI were compared among the three clinical groups: depressed BD, euthymic BD, and healthy controls. In a second analysis, patients were divided into four groups using the quartile PPI levels of controls of each gender, and a ratio of the low-PPI group (<1st quartile of controls) was compared. Effects of psychosis and medication status were examined by the Mann-Whitney U test. Clinical correlates such as medication dosage and depression severity with startle measurements were examined by Spearman's correlation. Results: Male patients with depression, but not euthymic male patients, showed significantly lower PPI at a prepulse of 86 dB and 120 ms lead interval than did male controls. More than half of the male patients with depression showed low-PPI. In contrast, PPI in female patients did not differ from that in female controls in either the depressed or euthymic state. Female patients with active psychosis showed significantly lower PPI than those without psychosis. Female patients on typical antipsychotics had significantly lower PPI, than those without such medication. PPI showed a significant positive correlation with lamotrigine dosage in male patients and lithium dosage in female patients. Conclusion: These findings suggest that sensorimotor gating is impaired in male BD patients with depression. However, we obtained no evidence for such abnormalities in female BD patients except for those with current psychosis. The observed associations between medication and startle measurements warrant further investigation. PMID- 29720951 TI - A Retrospective Administrative Database Analysis of Suicide Attempts and Completed Suicide in Patients With Chronic Pancreatitis. AB - Background: The actual incidence rate of suicide attempt and the suicide-related fatality rate (completed suicide) in patients with chronic pancreatitis (CP) have not been mentioned in the literature. Methods: We conducted a nationwide population-based cohort study by analyzing data from Taiwan's National Health Insurance Research Database (NHIRD) to compare the rate of suicide attempt between a CP cohort and a non-CP cohort. For the study cohort, we identified 17,733 patients (age >= 20 years) diagnosed as having CP between 2000 and 2010 from the NHIRD in Taiwan. Beneficiaries with no history of CP were matched with the study cohort at a 2:1 ratio according to age, sex, and index date. To determine the incidence of suicide, all patients were followed until the end of 2011 or until their withdrawal from the Taiwan National Health Insurance program. Results: Patients with CP had an increased risk of suicide attempt, compared with those without CP (adjusted hazard ratio [aHR] = 2.72, 95% confidence interval [CI] = 1.69-4.37). The suicide-related fatality in the CP cohort was higher than that in the non-CP cohort, but the difference was not statistically significant (aHR = 1.21, 95% CI = 0.39-3.78). Conclusion: Our population-based cohort study reveals a close association between CP and subsequent suicide attempt. Compared with the non-CP cohort, the suicide-related fatality was higher in the CP cohort, although the result was not statistically significant. These findings necessitate surveying patients with CP and providing psychological support to prevent suicide. PMID- 29720953 TI - Psychometric Properties and Measurement Invariance of the Brief Symptom Inventory 18 Among Chinese Insurance Employees. AB - This study aimed to examine the psychometric properties and factorial invariance of the Brief Symptom Inventory-18 (BSI-18). Confirmatory factor analyses (CFAs) were performed to verify the BSI-18's factor structure in a large sample of Chinese insurance professionals (N = 2363, 62.7% women; age range = 19-70). Multigroup CFA were performed to test the measurement invariance of the model with the best fit across genders. In addition, structural equation modeling was conducted to test the correlations between the BSI-18 and two covariates - social support perception and grit trait. Results indicated that the bi-factor model best fit the data and was also equivalent across genders. The BSI-18's general factor, and somatization and depression dimensions were significantly related to social support perception and grit trait, whereas the anxiety dimension was not. Overall, our findings suggested that the BSI-18's can be a promising tool in assessing general psychological distress in Chinese employees. PMID- 29720952 TI - Spanish Adaptation and Validation of the Transplant Effects Questionnaire (TxEQ Spanish) in Liver Transplant Recipients and Its Relationship to Posttraumatic Growth and Quality of Life. AB - The valid assessment of the impact of transplantation on psychological well-being is highly relevant to optimize treatment. However, to date there is no standardized instrument available in Spain. The Transplant Effects Questionnaire (TxEQ) evaluates the specific problems associated with organ transplantation, such as worry about transplant, guilt regarding the donor, disclosure of having undergone transplantation, adherence to medical treatment and responsibility toward the donor, family, friends, or medical staff. Against this backdrop the English original version of the TxEQ was translated into Spanish and validated in a sample of 240 liver transplant recipients. Participants also filled in the Posttraumatic Growth Inventory (PTGI), and the 12-Item Short Form Health Survey (SF-12v.2). Confirmatory factor analysis of the TxEQ-Spanish revealed a five factor structure equivalent to the English original version, and satisfactory internal consistency (Cronbach's alpha: worry alpha = 0.82, guilt alpha = 0.77, disclosure alpha = 0.91, adherence alpha = 0.82, responsibility alpha = 0.83). Results showed that better mental quality of life was associated with higher adherence and disclosure, as well as less worry and guilt. Higher posttraumatic growth was significantly associated with worry, guilt, and responsibility. Interestingly, the most powerful predictor of posttraumatic growth was worry. Analysis of variance showed an interaction effect of PTG and mental quality of life on adherence, with medium PTG being associated with significantly stronger adherence in participants with better mental quality of life. In conclusion our study could successfully adapt and validate the Spanish version of the TxEQ in a large sample of liver transplant recipients. Our findings show a complex relationship between emotional reactions to transplantation, mental quality of life, and posttraumatic growth, which give further insight into inner processes supporting psychological well-being and adherence after liver transplantation. PMID- 29720954 TI - The Internet Is Not a Tool: Reappraising the Model for Internet-Addiction Disorder Based on the Constraints and Opportunities of the Digital Environment. PMID- 29720956 TI - Leaders' Expressed Humility and Followers' Feedback Seeking: The Mediating Effects of Perceived Image Cost and Moderating Effects of Power Distance Orientation. AB - We developed and tested a model to identify the role of leaders' expressed humility on employees' feedback-seeking processes. The data used in our study was from a sample of 248 employees and 57 of their immediate supervisors. The results revealed that: (1) leader's expressed humility positively related to employees' feedback seeking mediated by employees' perceived image cost; and (2) power distance orientation moderated the relationship between leader's expressed humility and employees' perceived image costs, such that the relationship was stronger when the power distance orientation was lower rather than higher. The results offer new insight into potential managerial practices that aim at stimulating feedback seeking. We conclude with a discussion for future research. PMID- 29720955 TI - Environmental Strategies of Affect Regulation and Their Associations With Subjective Well-Being. AB - Environmental strategies of affect regulation refer to the use of natural and urban socio-physical settings in the service of regulation. We investigated the perceived use and efficacy of environmental strategies for regulation of general affect and sadness, considering them in relation to other affect regulation strategies and to subjective well-being. Participants from Australia, Finland, Germany, Great Britain, Italy, India, the Netherlands, Portugal, and Sweden (N = 507) evaluated the frequency of use and perceived efficacy of affect regulation strategies using a modified version of the Measure of Affect Regulation Styles (MARS). The internet survey also included the Satisfaction with Life Scale (SWLS), emotional well-being items from the RAND 36-Item Health Survey, and a single-item measure of perceived general health. Environmental regulation formed a separate factor of affect regulation in the exploratory structural equation models (ESEM). Although no relations of environmental strategies with emotional well-being were found, both the perceived frequency of use and efficacy of environmental strategies were positively related to perceived health. Moreover, the perceived efficacy of environmental strategies was positively related to life satisfaction in regulating sadness. The results encourage more explicit treatment of environmental strategies in research on affect regulation. PMID- 29720957 TI - CCNG2 Overexpression Mediated by AKT Inhibits Tumor Cell Proliferation in Human Astrocytoma Cells. AB - The cyclin family protein CCNG2 has an important inhibitory role in cancer initiation and progression, but the exact mechanism is still unknown. In this study, we examined the relationship between CCNG2 and the malignancy of astrocytomas and whether the AKT pathway, which is upregulated in astrocytomas, may inhibit CCNG2 expression. CCNG2 expression was found to be negatively associated with the pathological grade and proliferative activity of astrocytomas, as the highest expression was found in control brain tissue (N = 31), whereas the lowest expression was in high-grade glioma tissue (N = 31). Additionally, CCNG2 overexpression in glioma cell lines, T98G and U251 inhibited proliferation and arrested cells in the G0/G1 phase. Moreover, CCNG2 overexpression could increase glioma cells apoptosis. In contrast, AKT activity increased in glioma cells that had low CCNG2 expression. Expression of CCNG2 was higher in cells treated with the AKT kinase inhibitor MK-2206 indicating that the presence of phosphorylated AKT may inhibit the expression of CCNG2. Inhibition of AKT also led to decreased colony formation in T98G and U251 cells and knocked down of CCNG2 reversed the result. Finally, overexpression of CCNG2 in glioma cells reduced tumor volume in a murine model. To conclude, low expression of CCNG2 correlated with the severity astrocytoma and CCNG2 overexpression could induce apoptosis and inhibit proliferation. Inhibition of AKT activity increased the expression of CCNG2. The present study highlights the regulatory consequences of CCNG2 expression and AKT activity in astrocytoma tumorigenesis and the potential use of CCNG2 in anticancer treatment. PMID- 29720958 TI - Crossed Leg Sign Is Associated With Severity of Unilateral Spatial Neglect After Stroke. AB - Background: The crossed leg sign in patients with right hemisphere stroke is thought to be associated with perceptual disorders, such as unilateral spatial neglect (USN). The aim of this study was to compare the crossed leg sign with the severity of USN during the acute phase of stroke. Experimental procedures: This was an observational and prospective clinical study of individuals with a diagnosis of right parietal stroke, as confirmed by neuroimaging. The occurrence of the crossed leg sign, the time at which this occurred after the stroke, and a clinical diagnosis of USN were measured and recorded. The patients' age, sex, and lesion severity, as determined by the National Institutes of Health Stroke Scale and Glasgow coma scale, were included in the analyses as confounding variables. The outcome of interest was the degree of USN, as measured by the cancellation and bisection tests. Binary logistic regression was used to analyze the effect of crossed leg syndrome on the severity of USN. In the adjusted multiple regression model, a p-value of <0.05 was considered statistically significant. Results: Overall, 60 patients were included in this study. There were no associations between patient demographics and the presence of the crossed leg sign. There was, however, an association between the crossed leg sign and the absolute value of the deviation in the line bisection test (B = -0.234; p = 0.039). The crossed leg sign was not associated with other measures of USN. Conclusion: Based on the results of our study, we can conclude that a crossed leg sign in the acute phase of stroke is associated with USN severity, specifically the misinterpretation of the midline. PMID- 29720959 TI - Role of Neuroimaging as a Biomarker for Neurodegenerative Diseases. AB - It has recently been recognized that neurodegenerative diseases are caused by common cellular and molecular mechanisms including protein aggregation and inclusion body formation. Each type of neurodegenerative disease is characterized by the specific protein that aggregates. In these days, the pathway involved in protein aggregation has been elucidated. These are leading to approaches toward disease-modifying therapies. Neurodegenerative diseases are fundamentally diagnosed pathologically. Therefore, autopsy is essential for a definitive diagnosis of a neurodegenerative disease. However, recently, the development of various molecular brain imaging techniques have enabled pathological changes in the brain to be inferred even without autopsy. Some molecular imaging techniques are described as biomarker in diagnostic criteria of neurodegenerative disease. Magnetic resonance imaging (MRI), single photon emission computed tomography (SPECT), positron emission tomography (PET), and amyloid imaging are described in the diagnostic guidelines for Alzheimer's disease in the National Institute on Aging-Alzheimer's Association. MRI, dopamine transporter (DAT) imaging, and 123I metaiodobenzyl-guanidine (MIBG) myocardial scintigraphy listed in the guidelines for consensus clinical diagnostic criteria for dementia with Lewy bodies are described as potential biomarkers. The Movement Disorder Society Progressive Supranuclear Palsy Study Group defined MRI, SPECT/PET, DAT imaging, and tau imaging as biomarkers. Other diagnostic criteria for neurodegenerative disease described neuroimaging findings as only characteristic finding, not as biomarker. In this review, we describe the role of neuroimaging as a potential biomarker for neurodegenerative diseases. PMID- 29720960 TI - Increased Requirement of Replacement Doses of Levothyroxine Caused by Liver Cirrhosis. AB - Background: Since hypothyroidism is a fairly common dysfunction, levothyroxine (L T4) is one of the most prescribed medications. Approximately 70% of the administered L-T4 dose is absorbed. The absorption process takes place in the small intestine. Some disorders of the digestive system and some medicines, supplements, and drinks cause L-T4 malabsorption, resulting in failure of serum TSH to be normal. Only rarely liver cirrhosis is mentioned as causing L-T4 malabsorption. Case report: In this study, we report increased requirement of daily doses of l-thyroxine in two patients with the atrophic variant of Hashimoto's thyroiditis and liver cirrhosis. In one patient, this increased requirement could have been contributed by the increased serum levels of the estrogen-dependent thyroxine-binding globulin (TBG), which is the major plasma carrier of thyroid hormones. In the other patient, we switched from tablet L-T4 to liquid L-T4 at the same daily dose. Normalization of TSH levels was achieved, but TSH increased again when she returned to tablet L-T4. Conclusion: Liver cirrhosis can cause increased L-T4 requirements. In addition to impaired bile secretion, the mechanism could be increased serum TBG. A similar increased requirement of L-T4 is observed in other situations characterized by elevation of serum TBG. Because of better intestinal absorption, L-T4 oral liquid formulation is able to circumvent the increased need of L-T4 in these patients. PMID- 29720961 TI - Osteoporosis Therapy With Denosumab in Organ Transplant Recipients. AB - Objective: Osteoporosis and fragility fractures represent serious complications for the solid organ transplant population. The recommended osteoporosis therapy for organ recipients involves supplementation with calcium and vitamin D and bisphosphonate administration. However, these options can prove limited for patients with impaired renal function. An alternative therapy option is offered by denosumab, a monoclonal antibody that targets receptor activator of nuclear factor kappa-B ligand. Patients and methods: We evaluated 63 patients with osteoporosis (23 males and 40 females, age 56.4 +/- 13.1 years) following solid organ transplantation (15 diabetic patients after simultaneous transplantation of the kidney and pancreas, 34 patients after kidney transplantation, and 14 patients with liver grafts). Osteoporosis was diagnosed according to standard DEXA examination using the Lunar Prodigy apparatus. Transplanted patients with impaired renal function were treated for osteoporosis of the lumbar spine (L spine) and/or proximal femur with calcium and vitamin D supplementation and 60 mg of denosumab every 6 months between the years 2012 and 2017. The mean duration of the therapy was 1.65 +/- 0.7 years. Results: After denosumab therapy, L-spine T scores improved across the whole group, ranging from -2.7 +/- 0.09 to -1.8 +/- 1.0 (p < 0.001). T-score values for the proximal femur increased from -2.5 +/- 0.8 to -2.0 +/- 0.7 after the therapy (p < 0.01). We observed only a mild, statistically insignificant improvement in distal forearm T-scores. The mean increase in L-spine bone mineral density (BMD) was 11.5 +/- 6.2% in subjects with osteoporosis at this site and 10.4 +/- 6.1% in the case of all patients. BMD of the proximal femur increased by 10.4 +/- 8.3% in patients with osteoporosis and by 7.5 +/- 7.3% in all patients. Denosumab therapy decreased the prevalence of osteoporosis in the L-spine from 75 to 27% (p < 0.001) and proximal femur osteoporosis from 54 to 36% (p < 0.05). Denosumab therapy reduced elevated levels of osteocalcin and beta-crosslaps (betaCTX) in comparison with baseline levels (p < 0.001) across the whole group of graft recipients. Conclusion: Denosumab therapy was well-tolerated and improved bone density in our group of solid organ transplant recipients. The indications are that denosumab could be a viable therapeutic option for transplanted patients with osteoporosis, especially in those with renal function impairment or bisphosphonate intolerance. PMID- 29720962 TI - Sex Differences in Medium Spiny Neuron Excitability and Glutamatergic Synaptic Input: Heterogeneity Across Striatal Regions and Evidence for Estradiol-Dependent Sexual Differentiation. AB - Steroid sex hormones and biological sex influence how the brain regulates motivated behavior, reward, and sensorimotor function in both normal and pathological contexts. Investigations into the underlying neural mechanisms have targeted the striatal brain regions, including the caudate-putamen, nucleus accumbens core (AcbC), and shell. These brain regions are of particular interest to neuroendocrinologists given that they express membrane-associated but not nuclear estrogen receptors, and also the well-established role of the sex steroid hormone 17beta-estradiol (estradiol) in modulating striatal dopamine systems. Indeed, output neurons of the striatum, the medium spiny neurons (MSNs), exhibit estradiol sensitivity and sex differences in electrophysiological properties. Here, we review sex differences in rat MSN glutamatergic synaptic input and intrinsic excitability across striatal regions, including evidence for estradiol mediated sexual differentiation in the nucleus AcbC. In prepubertal animals, female MSNs in the caudate-putamen exhibit a greater intrinsic excitability relative to male MSNs, but no sex differences are detected in excitatory synaptic input. Alternatively, female MSNs in the nucleus AcbC exhibit increased excitatory synaptic input relative to male MSNs, but no sex differences in intrinsic excitability were detected. Increased excitatory synaptic input onto female MSNs in the nucleus AcbC is abolished after masculinizing estradiol or testosterone exposure during the neonatal critical period. No sex differences are detected in MSNs in prepubertal nucleus accumbens shell. Thus, despite possessing the same neuron type, striatal regions exhibit heterogeneity in sex differences in MSN electrophysiological properties, which likely contribute to the sex differences observed in striatal function. PMID- 29720964 TI - Preoperative Molecular Markers in Thyroid Nodules. AB - The need for distinguishing benign from malignant thyroid nodules has led to the pursuit of differentiating molecular markers. The most common molecular tests in clinical use are Afirma(r) Gene Expression Classifier (GEC) and Thyroseq(r) V2. Despite the rapidly developing field of molecular markers, several limitations exist. These challenges include the recent introduction of the histopathological diagnosis "Non-Invasive Follicular Thyroid neoplasm with Papillary-like nuclear features", the correlation of genetic mutations within both benign and malignant pathologic diagnoses, the lack of follow-up of molecular marker negative nodules, and the cost-effectiveness of molecular markers. In this manuscript, we review the current published literature surrounding the diagnostic value of Afirma(r) GEC and Thyroseq(r) V2. Among Afirma(r) GEC studies, sensitivity (Se), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV) ranged from 75 to 100%, 5 to 53%, 13 to 100%, and 20 to 100%, respectively. Among Thyroseq(r) V2 studies, Se, Sp, PPV, and NPV ranged from 40 to 100%, 56 to 93%, 13 to 90%, and 48 to 97%, respectively. We also discuss current challenges to Afirma(r) GEC and Thyroseq(r) V2 utility and clinical application, and preview the future directions of these rapidly developing technologies. PMID- 29720963 TI - Deoxyribonucleotide Triphosphate Metabolism in Cancer and Metabolic Disease. AB - The maintenance of a healthy deoxyribonucleotide triphosphate (dNTP) pool is critical for the proper replication and repair of both nuclear and mitochondrial DNA. Temporal, spatial, and ratio imbalances of the four dNTPs have been shown to have a mutagenic and cytotoxic effect. It is, therefore, essential for cell homeostasis to maintain the balance between the processes of dNTP biosynthesis and degradation. Multiple oncogenic signaling pathways, such as c-Myc, p53, and mTORC1 feed into dNTP metabolism, and there is a clear role for dNTP imbalances in cancer initiation and progression. Additionally, multiple chemotherapeutics target these pathways to inhibit nucleotide synthesis. Less is understood about the role for dNTP levels in metabolic disorders and syndromes and whether alterations in dNTP levels change cancer incidence in these patients. For instance, while deficiencies in some metabolic pathways known to play a role in nucleotide synthesis are pro-tumorigenic (e.g., p53 mutations), others confer an advantage against the onset of cancer (G6PD). More recent evidence indicates that there are changes in nucleotide metabolism in diabetes, obesity, and insulin resistance; however, whether these changes play a mechanistic role is unclear. In this review, we will address the complex network of metabolic pathways, whereby cells can fuel dNTP biosynthesis and catabolism in cancer, and we will discuss the potential role for this pathway in metabolic disease. PMID- 29720966 TI - Synergistic Effect of Diallyl Sulfide With Zinc Oxide Nanorods: A Novel and Effective Approach for Treatment of Acute Dermatitis in Model Animals. AB - Besides inciting persistent and recurrent nosocomial afflictions, Staphylococcus aureus (S. aureus), a biofilm forming pathogen, poses an increased risk of several skin as well as respiratory tract infections as well. Emerging antimicrobial resistance trend asks to search for an alternate non-antibiotic based option to combat S. aureus pathogen. In the present study, we evaluated synergistic antimicrobial potential of Zinc oxide nanorods (ZnO-NRs) and diallyl sulphide (DAS) emulsion against methicillin resistant Staphylococcus aureus (MRSA). The antimicrobial assessment study suggests that the ZnO-NR and DAS emulsion effectively suppressed both sensitive S. aureus as well as MRSA isolates. The combination treatment showed enhanced activity even at a lower concentration as compared to the single treatment based on ZnO-NRs and DAS emulsion alone. The ZnO-NRs-DAS combination showed significant inhibition of MRSA biofilm as well. The data suggest that a combination therapy, comprising of ZnO NRs and DAS emulsion, successfully treated experimental dermatitis infection caused by MRSA in mice model. PMID- 29720965 TI - Mechanisms of Aerobic Exercise Impairment in Diabetes: A Narrative Review. AB - The prevalence of diabetes in the United States and globally has been rapidly increasing over the last several decades. There are now estimated to be 30.3 million people in the United States and 422 million people worldwide with diabetes. Diabetes is associated with a greatly increased risk of cardiovascular mortality, which is the leading cause of death in adults with diabetes. While exercise training is a cornerstone of diabetes treatment, people with diabetes have well-described aerobic exercise impairments that may create an additional diabetes-specific barrier to adding regular exercise to their lifestyle. Physiologic mechanisms linked to exercise impairment in diabetes include insulin resistance, cardiac abnormalities, mitochondrial function, and the ability of the body to supply oxygen. In this paper, we highlight the abnormalities of exercise in type 2 diabetes as well as potential therapeutic approaches. PMID- 29720967 TI - How Does Salinity Shape Bacterial and Fungal Microbiomes of Alnus glutinosa Roots? AB - Black alder (Alnus glutinosa Gaertn.) belongs to dual mycorrhizal trees, forming ectomycorrhizal (EM) and arbuscular (AM) root structures, as well as represents actinorrhizal plants that associate with nitrogen-fixing actinomycete Frankia sp. We hypothesized that the unique ternary structure of symbionts can influence community structure of other plant-associated microorganisms (bacterial and fungal endophytes), particularly under seasonally changing salinity in A. glutinosa roots. In our study we analyzed black alder root bacterial and fungal microbiome present at two forest test sites (saline and non-saline) in two different seasons (spring and fall). The dominant type of root microsymbionts of alder were ectomycorrhizal fungi, whose distribution depended on site (salinity): Tomentella, Lactarius, and Phialocephala were more abundant at the saline site. Mortierella and Naucoria (representatives of saprotrophs or endophytes) displayed the opposite tendency. Arbuscular mycorrhizal fungi belonged to Glomeromycota (orders Paraglomales and Glomales), however, they represented less than 1% of all identified fungi. Bacterial community structure depended on test site but not on season. Sequences affiliated with Rhodanobacter, Granulicella, and Sphingomonas dominated at the saline site, while Bradyrhizobium and Rhizobium were more abundant at the non-saline site. Moreover, genus Frankia was observed only at the saline site. In conclusion, bacterial and fungal community structure of alder root microsymbionts and endophytes depends on five soil chemical parameters: salinity, phosphorus, pH, saturation percentage (SP) as well as total organic carbon (TOC), and seasonality does not appear to be an important factor shaping microbial communities. Ectomycorrhizal fungi are the most abundant symbionts of mature alders growing in saline soils. However, specific distribution of nitrogen fixing Frankia (forming root nodules) and association of arbuscular fungi at early stages of plant development should be taken into account in further studies. PMID- 29720970 TI - Editorial: Application of Nanotechnology in Food Science and Food Microbiology. PMID- 29720968 TI - Biosynthetic Potential of Bioactive Streptomycetes Isolated From Arid Region of the Thar Desert, Rajasthan (India). AB - Acquisition of Actinobacteria, especially Streptomyces from previously underexplored habitats and the exploration of their biosynthetic potential have gained much attention in the rejuvenated antibiotics search programs. Herein, we isolated some Streptomyces strains, from an arid region of the Great Indian Thar Desert, which possess an ability to produce novel bioactive compounds. Twenty-one morphologically distinctive strains differing in their aerial and substrate mycelium were isolated by employing a stamping method. Among them, 12 strains were identified by a two-level antimicrobial screening method, exerting antimicrobial effects against a panel of indicator strains including methicillin resistant Staphylococcus aureus and vancomycin-resistant Enterococcus species. Based on their potent antimicrobial activity, four isolates were further explored by 16S rRNA gene-based identification, genetic screening, and metabolomic analysis; and it was found that these strains belong to the genus Streptomyces. The selected strains were found to have polyketide synthase and non-ribosomal peptide synthetase systems. In addition, extracellular metabolomic screening revealed that the isolates produced analogs of doxorubicinol, pyrromycin, erythromycin, and 6-13 other putative novel metabolites. These results demonstrate the significance of Streptomyces inhabiting the arid region of Thar Desert, suggesting that similar arid environments can be considered as the reservoirs of novel Streptomyces strains that could have biotechnological significance. PMID- 29720969 TI - Variations of Bacterial Community Diversity Within the Rhizosphere of Three Phylogenetically Related Perennial Shrub Plant Species Across Environmental Gradients. AB - Rhizosphere microbial communities are of great importance to mediate global biogeochemical cycles, plant growth, and fitness. Yet, the processes that drive their assembly remain unclear. The perennial shrubs Caragana spp., which is well known for their role in soil and water conservation, provides an ideal system to study the biogeography of rhizosphere microorganism communities within natural ecosystems. In order to detect how bacterial rhizosphere communities vary in terms of community diversity and composition, the rhizosphere bacterial community of three Caragana species, Caragana microphylla Lam., C. liouana Zhao, and C. korshinskii Kom., which distributed in arid and semi-arid region of northern China were investigated. Across species, Proteobacteria (61.1%), Actinobacteria (16.0%), Firmicutes (8.6%), Bacteroidetes (3.0%), Acidobacteria (3.5%), Gemmatimonadetes (1.4%), and Cyanobacteria (1.0%) were the most dominant phyla in the rhizosphere of the three Caragana species. The relative abundance of Cyanobacteria was significantly higher in rhizosphere of C. korshinskii Kom. compared with C. microphylla Lam. and C. liouana Zhao, while the opposite was found for Gemmatimonadetes in rhizosphere of C. microphylla Lam. relative to C. liouana Zhao. Stepwise multiple linear regression analysis showed that both diversity and richness of the bacterial rhizosphere communities significantly and positively correlated with soil pH (p < 0.01). Distance-based redundancy analysis indicated that soil properties and non-soil parameters detected there accounted for 47.5% of bacterial phylogenetic structure variation (p < 0.01) all together. Meanwhile, soil total phosphorus accounted for the greatest proportion of community structure variance (9.7%, p < 0.01), followed by electrical conduction (6.5%), altitude (5.8%), soil pH (5.4%), mean annual precipitation (3.6%) and total nitrogen (3.6%, p < 0.05 in all cases). Furthermore, partial Mantel test suggested that bacterial rhizosphere community structure significantly correlated with geographical distance, indicating that the less geographical distant sample sites tend to harbor more similar bacterial rhizosphere community. Our results shed new light on the mechanisms of coevolution and interaction between long lived plants and their rhizosphere bacterial communities across environmental gradients. PMID- 29720972 TI - SpoT-Mediated Regulation and Amino Acid Prototrophy Are Essential for Pyocyanin Production During Parasitic Growth of Pseudomonas aeruginosa in a Co-culture Model System With Aeromonas hydrophila. AB - The opportunistic pathogen Pseudomonas aeruginosa employs its complex quorum sensing (QS) network to regulate the expression of virulence factors such as pyocyanin. Besides cell density, QS in this bacterium is co-regulated by environmental cues. In this study, we employed a previously established co culture model system to identify metabolic influences that are involved in the regulation of pyocyanin production in P. aeruginosa. In this co-culture consisting of P. aeruginosa and the chitinolytic bacterium Aeromonas hydrophila, parasitic growth of P. aeruginosa is strictly dependent on the production of pyocyanin. We could show that in this co-culture, pyocyanin production is likely induced by the stringent response mediated by SpoT in response to nutrient limitation. Pyocyanin production by stringent response mutants in the co-culture could not be complemented by overexpression of PqsE. Via transposon mutagenesis, several amino acid auxotrophic mutants were identified that were also unable to produce pyocyanin when PqsE was overexpressed or when complementing amino acids were present. The inability to produce pyocyanin even though PqsE was overexpressed was likely a general effect of amino acid auxotrophy. These results show the value of the co-culture approach to identify both extra- and intracellular metabolic influences on QS that might be important in infection processes as well. PMID- 29720971 TI - Oligomannose-Rich Membranes of Dying Intestinal Epithelial Cells Promote Host Colonization by Adherent-Invasive E. coli. AB - A novel mechanism is revealed by which clinical isolates of adherent-invasive Escherichia coli (AIEC) penetrate into the epithelial cell layer, replicate, and establish biofilms in Crohn's disease. AIEC uses the FimH fimbrial adhesin to bind to oligomannose glycans on the surface of host cells. Oligomannose glycans exposed on early apoptotic cells are the preferred binding targets of AIEC, so apoptotic cells serve as potential entry points for bacteria into the epithelial cell layer. Thereafter, the bacteria propagate laterally in the epithelial intercellular spaces. We demonstrate oligomannosylation at two distinct sites of a glycoprotein receptor for AIEC, carcinoembryonic antigen related cell adhesion molecule 6 (CEACAM6 or CD66c), on human intestinal epithelia. After bacterial binding, FimH interacts with CEACAM6, which then clusters. The presence of the highest-affinity epitope for FimH, oligomannose-5, on CEACAM6 is demonstrated using LC-MS/MS. As mannose-dependent infections are abundant, this mechanism might also be used by other adherent-invasive pathogens. PMID- 29720973 TI - A Deubiquitinating Enzyme Ubp14 Is Required for Development, Stress Response, Nutrient Utilization, and Pathogenesis of Magnaporthe oryzae. AB - Ubiquitination is an essential protein modification in eukaryotic cells, which is reversible. Deubiquitinating enzymes (DUBs) catalyze deubiquitination process to reverse ubiquitination, maintain ubiquitin homeostasis or promote protein degradation by recycling ubiquitins. In order to investigate effects of deubiquitination process in plant pathogenic fungus Magnaporthe oryzae, we generated deletion mutants of MoUBP14. Ortholog of MoUbp14 was reported to play general roles in ubiquitin-mediated protein degradation in Saccharomyces cerevisiae. The DeltaMoubp14 mutant lost its pathogenicity and was severely reduced in mycelial growth, sporulation, carbon source utilization, and increased in sensitivity to distinct stresses. The mutant was blocked in penetration, which could due to defect in turgor generation. It is also blocked in invasive growth, which could due to reduction in stress tolerance and nutrient utilization. Deletion of UBP14 also led to accumulation of free polyubiquitin chains. Pulldown assay identified some proteins related to carbohydrate metabolism and stress response may putatively interact with MoUbp14, including two key rate-limiting enzymes of gluconeogenesis, MoFbp1 and MoPck1. These two proteins were degraded when the glucose was supplied to M. oryzae grown in low glucose media for a short period of time (~12 h), and this process required MoUbp14. In summary, pleiotropic phenotypes of the deletion mutants indicated that MoUbp14 is required for different developments and pathogenicity of M. oryzae. PMID- 29720974 TI - Erratum: Addendum: Comparative Genomic Analysis of the Class Epsilonproteobacteria and Proposed Reclassification to Epsilonbacteraeota (phyl. nov.). AB - [This corrects the article on p. 682 in vol. 8, PMID: 28484436.]. PMID- 29720975 TI - Matrix Remodeling Associated 7 Deficiency Alleviates Carbon Tetrachloride-Induced Acute Liver Injury in Mice. AB - Matrix remodeling associated 7 (MXRA7) was first noted to co-express with a group of matrix remodeling related genes, and its biological functions had remained unclear. In this study, we investigated the presumed function of MXRA7 in a carbon tetrachloride (CCl4)-induced acute liver injury model in mice. Wild-type, MXRA7-/- mice, and mice that were pulsed with hydrodynamic injection of vehicle or MXRA7-harboring plasmids were challenged with a single dose of CCl4 for injury induction. The sera, spleens, and livers were harvested from mice for assay of cytokines/chemokines expression, cellular responses, or histological features. We found that MXRA7 deficiency alleviated, and MXRA7 overexpression aggravated liver damage in CCl4-challenged mice. FACS analysis showed that MXRA7 deficiency reduced the recruitment of neutrophils through downregulation the expression of CXCL1 and CXCL2 in liver, decreased the number of CD8+ T cells in liver and spleen, suppressed the release of IFNgamma and TNFalpha from T cells, and decreased IFNgamma in serum and liver. Western blot assay demonstrated that MXRA7 deficiency suppressed the activation of MAPK pathway and AKT/NF-kappaB pathway, respectively. Lastly, MXRA7 deficiency or overexpression regulated the expression of two matrix remodeling-related genes (fibronectin and TIMP1) in the liver. We concluded that MXRA7 was an active player in CCl4-induced liver injury, hypothetically by mediating the inflammation or immune compartments and matrix remodeling processes. Further exploration of MXRA7 as a possible new therapeutic target for management of inflammation-mediated liver injury was discussed. PMID- 29720976 TI - Carbonate Apatite Nanoparticles Act as Potent Vaccine Adjuvant Delivery Vehicles by Enhancing Cytokine Production Induced by Encapsulated Cytosine-Phosphate Guanine Oligodeoxynucleotides. AB - Vaccine adjuvants that can induce not only antigen-specific antibody responses but also Th1-type immune responses and CD8+ cytotoxic T lymphocyte responses are needed for the development of vaccines against infectious diseases and cancer. Of many available adjuvants, oligodeoxynucleotides (ODNs) with unmethylated cytosine phosphate-guanine (CpG) motifs are the most promising for inducing the necessary immune responses, and these adjuvants are currently under clinical trials in humans. However, the development of novel delivery vehicles that enhance the adjuvant effects of CpG ODNs, subsequently increasing the production of cytokines such as type-I interferons (IFNs), is highly desirable. In this study, we demonstrate the potential of pH-responsive biodegradable carbonate apatite (CA) nanoparticles as CpG ODN delivery vehicles that can enhance the production of type-I IFNs (such as IFN-alpha) relative to that induced by CpG ODNs and can augment the adjuvant effects of CpG ODNs in vivo. In contrast to CpG ODNs, CA nanoparticles containing CpG ODNs (designated CA-CpG) induced significant IFN alpha production by mouse dendritic cells and human peripheral blood mononuclear cells in vitro; and production of interleukin-12, and IFN-gamma was higher in CA CpG-treated groups than in CpG ODNs groups. In addition, treatment with CA-CpG resulted in higher cytokine production in draining lymph nodes than did treatment with CpG ODNs in vivo. Furthermore, vaccination with CA-CpG plus an antigen, such as ovalbumin or influenza virus hemagglutinin, resulted in higher antigen specific antibody responses and CD8+ cytotoxic T lymphocyte responses in vivo, in an interleukin-12- and type-I IFN-dependent manner, than did vaccination with the antigen plus CpG ODNs; in addition, the efficacy of the vaccine against influenza virus was higher with CA-CpG as the adjuvant than with CpG ODNs as the adjuvant. These data show the potential of CA nanoparticles to serve as CpG ODN delivery vehicles that increase the production of cytokines, especially IFN-alpha, induced by CpG ODNs and thus augment the efficacy of CpG ODNs as adjuvants. We expect that the strategy reported herein will facilitate the design and development of novel adjuvant delivery vehicles for vaccines. PMID- 29720979 TI - Ultra-Low Dosage Regimen of Rituximab in Autoimmune Blistering Skin Conditions. PMID- 29720977 TI - Enterococcus faecalis AHG0090 is a Genetically Tractable Bacterium and Produces a Secreted Peptidic Bioactive that Suppresses Nuclear Factor Kappa B Activation in Human Gut Epithelial Cells. AB - Enterococcus faecalis is an early coloniser of the human infant gut and contributes to the development of intestinal immunity. To better understand the functional capacity of E. faecalis, we constructed a broad host range RP4 mobilizable vector, pEHR513112, that confers chloramphenicol resistance and used a metaparental mating approach to isolate E. faecalis AHG0090 from a fecal sample collected from a healthy human infant. We demonstrated that E. faecalis AHG0090 is genetically tractable and could be manipulated using traditional molecular microbiology approaches. E. faecalis AHG0090 was comparable to the gold-standard anti-inflammatory bacterium Faecalibacterium prausnitzii A2-165 in its ability to suppress cytokine-mediated nuclear factor kappa B (NF-kappaB) activation in human gut-derived LS174T goblet cell like and Caco-2 enterocyte-like cell lines. E. faecalis AHG0090 and F. prausnitzii A2-165 produced secreted low molecular weight NF-kappaB suppressive peptidic bioactives. Both bioactives were sensitive to heat and proteinase K treatments although the E. faecalis AHG0090 bioactive was more resilient to both forms of treatment. As expected, E. faecalis AHG0090 suppressed IL-1beta-induced NF-kappaB-p65 subunit nuclear translocation and expression of the NF-kappaB regulated genes IL-6, IL-8 and CXCL-10. Finally, we determined that E. faecalis AHG0090 is distantly related to other commensal strains and likely encodes niche factors that support effective colonization of the infant gut. PMID- 29720978 TI - Pathogen-Specific Binding Soluble Down Syndrome Cell Adhesion Molecule (Dscam) Regulates Phagocytosis via Membrane-Bound Dscam in Crab. AB - The Down syndrome cell adhesion molecule (Dscam) gene is an extraordinary example of diversity that can produce thousands of isoforms and has so far been found only in insects and crustaceans. Cumulative evidence indicates that Dscam may contribute to the mechanistic foundations of specific immune responses in insects. However, the mechanism and functions of Dscam in relation to pathogens and immunity remain largely unknown. In this study, we identified the genome organization and alternative Dscam exons from Chinese mitten crab, Eriocheir sinensis. These variants, designated EsDscam, potentially produce 30,600 isoforms due to three alternatively spliced immunoglobulin (Ig) domains and a transmembrane domain. EsDscam was significantly upregulated after bacterial challenge at both mRNA and protein levels. Moreover, bacterial specific EsDscam isoforms were found to bind specifically with the original bacteria to facilitate efficient clearance. Furthermore, bacteria-specific binding of soluble EsDscam via the complete Ig1-Ig4 domain significantly enhanced elimination of the original bacteria via phagocytosis by hemocytes; this function was abolished by partial Ig1-Ig4 domain truncation. Further studies showed that knockdown of membrane-bound EsDscam inhibited the ability of EsDscam with the same extracellular region to promote bacterial phagocytosis. Immunocytochemistry indicated colocalization of the soluble and membrane-bound forms of EsDscam at the hemocyte surface. Far-Western and coimmunoprecipitation assays demonstrated homotypic interactions between EsDscam isoforms. This study provides insights into a mechanism by which soluble Dscam regulates hemocyte phagocytosis via bacteria-specific binding and specific interactions with membrane-bound Dscam as a phagocytic receptor. PMID- 29720980 TI - Controlling the Immune Suppressor: Transcription Factors and MicroRNAs Regulating CD73/NT5E. AB - The NT5E (CD73) molecule represents an ecto-5'-nucleotidase expressed on the cell surface of various cell types. Hydrolyzing extracellular adenosine monophosphate into adenosine and inorganic phosphate, NT5E performs numerous homeostatic functions in healthy organs and tissues. Importantly, NT5E can act as inhibitory immune checkpoint molecule, since free adenosine generated by NT5E inhibits cellular immune responses, thereby promoting immune escape of tumor cells. MicroRNAs (miRNAs) are small non-coding RNA molecules regulating gene expression on posttranscriptional level through binding to mRNAs, resulting in translational repression or degradation of the targeted mRNA molecule. In tumor cells, miRNA expression patterns are often altered which in turn might affect NT5E surface expression and eventually influence the efficacy of antitumor immune responses. This review describes the diverse roles of NT5E, summarizes current knowledge about transcription factors controlling NT5E expression, and highlights the significance of miRNAs involved in the posttranscriptional regulation of NT5E expression. PMID- 29720983 TI - Editorial: Epitope Discovery and Synthetic Vaccine Design. PMID- 29720981 TI - The Neutral Sphingomyelinase 2 Is Required to Polarize and Sustain T Cell Receptor Signaling. AB - By promoting ceramide release at the cytosolic membrane leaflet, the neutral sphingomyelinase 2 (NSM) is capable of organizing receptor and signalosome segregation. Its role in T cell receptor (TCR) signaling remained so far unknown. We now show that TCR-driven NSM activation is dispensable for TCR clustering and initial phosphorylation, but of crucial importance for further signal amplification. In particular, at low doses of TCR stimulatory antibodies, NSM is required for Ca2+ mobilization and T cell proliferation. NSM-deficient T cells lack sustained CD3zeta and ZAP-70 phosphorylation and are unable to polarize and stabilize their microtubular system. We identified PKCzeta as the key NSM downstream effector in this second wave of TCR signaling supporting dynamics of microtubule-organizing center (MTOC). Ceramide supplementation rescued PKCzeta membrane recruitment and MTOC translocation in NSM-deficient cells. These findings identify the NSM as essential in TCR signaling when dynamic cytoskeletal reorganization promotes continued lateral and vertical supply of TCR signaling components: CD3zeta, Zap70, and PKCzeta, and functional immune synapses are organized and stabilized via MTOC polarization. PMID- 29720984 TI - Activation of Invariant Natural Killer T Cells Redirects the Inflammatory Response in Neonatal Sepsis. AB - Sepsis is the third leading cause of death in the neonatal population, due to susceptibility to infection conferred by immaturity of both the innate and adaptive components of the immune system. Invariant natural killer T (iNKT) cells are specialized adaptive immune cells that possess important innate-like characteristics and have not yet been well-studied in septic neonates. We hypothesized that iNKT cells would play an important role in mediating the neonatal immune response to sepsis. To study this, we subjected 5- to 7-day-old neonatal C57BL/6 mice to sepsis by intraperitoneal (i.p.) cecal slurry (CS) injection. Thirty hours prior to or immediately following sepsis induction, pups received i.p. injection of the iNKT stimulator KRN7000 (KRN, 0.2 ug/g) or vehicle. Ten hours after CS injection, blood and tissues were collected for various analyses. Thirty-hour pretreatment with KRN resulted in better outcomes in inflammation, lung injury, and survival, while immediate treatment with KRN resulted in worse outcomes compared to vehicle treatment. We further analyzed the activation status of neonatal iNKT cells for 30 h after KRN administration, and showed a peak in frequency of CD69 expression on iNKT cells and serum IFN-gamma levels at 5 and 10 h, respectively. We then used CD1d knockout neonatal mice to demonstrate that KRN acts through the major histocompatibility complex-like molecule CD1d to improve outcomes in neonatal sepsis. Finally, we identified that KRN pretreatment exerts its protective effect by increasing systemic levels of TGF-beta1. These findings support the importance of iNKT cells for prophylactic immunomodulation in neonates susceptible to sepsis. PMID- 29720985 TI - Molecular Reconstruction of an Old Pedigree of Diploid and Triploid Hydrangea macrophylla Genotypes. AB - The ornamental crop species Hydrangea macrophylla exhibits diploid and triploid levels of ploidy and develops lacecap (wild type) or mophead inflorescences. In order to characterize a H. macrophylla germplasm collection, we determined the inflorescence type and the 2C DNA content of 120 plants representing 43 cultivars. We identified 78 putative diploid and 39 putative triploid plants by flow cytometry. In our collection 69 out of 98 flowering plants produced lacecap inflorescences, whereas 29 plants developed mophead inflorescences. Surprisingly, 12 cultivars included diploid as well as triploid plants, while 5 cultivars contained plants with different inflorescence types. We genotyped this germplasm collection using 12 SSR markers that detected 2-7 alleles per marker, and identified 51 different alleles in this collection. We detected 62 distinct fingerprints, revealing a higher genetic variation than the number of cultivars suggested. Only one genotype per cultivar is expected due to the vegetative propagation of Hydrangea cultivars; however we identified 25 cultivars containing 2-4 different genotypes. These different genotypes explained the variation in DNA content and inflorescence type. Diploid and triploid plants with the same cultivar name were exclusively mix-ups. We therefor assume, that 36% of the tested plants were mislabeled. Based on the "Wadenswil" pedigree, which includes 31 of the tested cultivars, we predicted cultivar-specific fingerprints and identified at least 21 out of 31 cultivars by SSR marker-based reconstruction of the "Wadenswil" pedigree. Furthermore, we detected 4 putative interploid crosses between diploid and triploid plants in this pedigree. These interploid crosses resulted in diploid or/and triploid offspring, suggesting that crosses with triploids were successfully applied in breeding of H. macrophylla. PMID- 29720982 TI - The Potential Biomarkers and Immunological Effects of Tumor-Derived Exosomes in Lung Cancer. AB - Lung cancer remains the leading cause of cancer-related deaths worldwide. Despite considerable achievements in lung cancer diagnosis and treatment, the global control of the disease remains problematic. In this respect, greater understanding of the disease pathology is crucially needed for earlier diagnosis and more successful treatment to be achieved. Exosomes are nano-sized particles secreted from most cells, which allow cross talk between cells and their surrounding environment via transferring their cargo. Tumor cells, just like normal cells, also secrete exosomes that are termed Tumor-Derived Exosome or tumor-derived exosome (TEX). TEXs have gained attention for their immuno modulatory activities, which strongly affect the tumor microenvironment and antitumor immune responses. The immunological activity of TEX influences both the innate and adaptive immune systems including natural killer cell activity and regulatory T-cell maturation as well as numerous anti-inflammatory responses. In the context of lung cancer, TEXs have been studied in order to better understand the mechanisms underlying tumor metastasis and progression. As such, TEX has the potential to act both as a biomarker for lung cancer diagnosis as well as the response to therapy. PMID- 29720986 TI - A Nitrogen Molecular Sensing System, Comprised of the ALLANTOINASE and UREIDE PERMEASE 1 Genes, Can Be Used to Monitor N Status in Rice. AB - Nitrogen (N) is an essential nutrient for plant growth and development, but its concentration in the soil is often insufficient for optimal crop production. Consequently, improving N utilization in crops is considered as a major target in agricultural biotechnology. However, much remains to be learnt about crop N metabolism for application. In this study, we have developed a molecular sensor system to monitor the N status in rice (Oryza sativa). We first examined the role of the ureide, allantoin, which is catabolized into allantoin-derived metabolites and used as an N source under low N conditions. The expression levels of two genes involved in ureide metabolism, ALLANTOINASE (OsALN) and UREIDE PERMEASE 1 (OsUPS1), were highly responsive to the N status. OsALN was rapidly up-regulated under low N conditions, whereas OsUPS1 was up-regulated under high N conditions. Taking advantage of the responses of these two genes to N status, we generated transgenic rice plants harboring the molecular N sensors, proALN::ALN-LUC2 and proUPS1::UPS1-LUC2, comprising the gene promoters driving expression of the luciferase reporter. We observed that expression of the transgenes mimicked transcriptional regulation of the endogenous OsALN and OsUPS1 genes in response to exogenous N status. Importantly, the molecular N sensors showed similar levels of specificity to nitrate and ammonium, from which we infer their sensing abilities. Transgenic rice plants expressing the proUPS1::UPS1-LUC2 sensor showed strong luminescence under high exogenous N conditions (>1 mM), whereas transgenic plants expressing the proALN::ALN-LUC2 sensor showed strong luminescence under low exogenous N conditions (<0.1 mM). High exogenous N (>1 mM) substantially increased internal ammonium and nitrate levels, whereas low exogenous N (<0.1 mM) had no effect on internal ammonium and nitrate levels, indicating the luminescence signals of molecular sensors reflect internal N status in rice. Thus, proALN::ALN-LUC2 and proUPS1::UPS1-LUC2 represent N molecular sensors that operate over a physiological and developmental range in rice. PMID- 29720987 TI - Surface Properties and Permeability to Calcium Chloride of Fagus sylvatica and Quercus petraea Leaves of Different Canopy Heights. AB - Plant surfaces have a considerable degree of chemical and physical variability also in relation to different environmental conditions, organs and state of development. The potential changes on plant surface properties in association with environmental variations have been little explored so far. Using two model tree species (i.e., Quercus petraea, sessile oak and Fagus sylvatica, beech) growing in 'Montejo de la Sierra Forest,' we examined various traits of the abaxial and adaxial surface of leaves of both species collected at a height of approximately 15 m (top canopy), versus 3.5-5.5 m for beech and sessile oak, lower canopy leaves. Leaf surface ultra-structure was analyzed by scanning and transmission electron microscopy, and the surface free energy and related parameter were estimated after measuring drops of 3 liquids with different degrees of polarity and apolarity. The permeability of the adaxial and abaxial surface of top and bottom canopy leaves to CaCl2 was estimated by depositing 2 drops of 3-4 MUl per cm2 and comparing the concentration of Ca in leaf tissues 24 h after treatment, and also Ca and Cl concentrations in the washing liquid. Higher Ca concentrations were recorded after the application of CaCl2 drops onto the veins and adaxial blade of top canopy beech leaves, while no significant evidence for foliar Ca absorption was gained with sessile oak leaves. Surprisingly, high amounts of Cl were recovered after washing untreated, top canopy beach and sessile oak leaves with deionised water, a phenomenon which was not traced to occur on lower canopy leaves of both species. It is concluded that the surface of the two species analyzed is heterogeneous in nature and may have areas favoring the absorption of water and solutes as observed for the veins of beech leaves. PMID- 29720988 TI - Wheat miRNA TaemiR408 Acts as an Essential Mediator in Plant Tolerance to Pi Deprivation and Salt Stress via Modulating Stress-Associated Physiological Processes. AB - MicroRNAs (miRNA) families act as critical regulators for plant growth, development, and responses to abiotic stresses. In this study, we characterized TaemiR408, a miRNA family member of wheat (Triticum aestivum), for the role in mediating plant responses to Pi starvation and salt stress. TaemiR408 targets six genes that encode proteins involving biochemical metabolism, microtubule organization, and signaling transduction. 5'- and 3'-RACE analyses confirmed the mRNA cleavage of target genes mediated by this wheat miRNA. TaemiR408 showed induced expression patterns upon Pi starvation and salt stress and whose upregulated expression was gradually repressed by the normal recovery treatments. The target genes of TaemiR408 exhibited reverse expression patterns to this miRNA, whose transcripts were downregulated under Pi starvation and salt stress and the reduced expression was recovered by the followed normal condition. These results suggest the regulation of the target genes under TaemiR408 through a cleavage mechanism. Tobacco lines with TaemiR408 overexpression exhibited enhanced stress tolerance, showing improved phenotype, biomass, and photosynthesis behavior compared with wild type under both Pi starvation and salt treatments, which closely associate increased P accumulation upon Pi deprivation and elevated osmolytes under salt stress, respectively. Phosphate transporter (PT) gene NtPT2 displays upregulated transcripts in the Pi-deprived TaemiR408 overexpressors; knockdown of this PT gene reduces Pi acquisition under low-Pi stress, confirming its role in improving plant Pi taken up. Likewise, NtPYL2 and NtSAPK3, genes encoding abscisic acid (ABA) receptor and SnRK2 protein, respectively, exhibited upregulated transcripts in salt-challenged TaemiR408 overexpressors; knockdown of them caused deteriorated growth and lowered osmolytes amounts of plants upon salt treatment. Thus, TaemiR408 is crucial for plant adaptations to Pi starvation and salt stress through regulating Pi acquisition under low-Pi stress and remodel ABA signaling pathway and osmoprotects biosynthesis under salt stress. PMID- 29720989 TI - Molecular Mechanisms of Acclimatization to Phosphorus Starvation and Recovery Underlying Full-Length Transcriptome Profiling in Barley (Hordeum vulgare L.). AB - A lack of phosphorus (P) in plants can severely constrain growth and development. Barley, one of the earliest domesticated crops, is extensively planted in poor soil around the world. To date, the molecular mechanisms of enduring low phosphorus, at the transcriptional level, in barley are still unclear. In the present study, two different barley genotypes (GN121 and GN42)-with contrasting phosphorus efficiency-were used to reveal adaptations to low phosphorus stress, at three time points, at the morphological, physiological, biochemical, and transcriptome level. GN121 growth was less affected by phosphorus starvation and recovery than that of GN42. The biomass and inorganic phosphorus concentration of GN121 and GN42 declined under the low phosphorus-induced stress and increased after recovery with normal phosphorus. However, the range of these parameters was higher in GN42 than in GN121. Subsequently, a more complete genome annotation was obtained by correcting with the data sequenced on Illumina HiSeq X 10 and PacBio RSII SMRT platform. A total of 6,182 and 5,270 differentially expressed genes (DEGs) were identified in GN121 and GN42, respectively. The majority of these DEGs were involved in phosphorus metabolism such as phospholipid degradation, hydrolysis of phosphoric enzymes, sucrose synthesis, phosphorylation/dephosphorylation and post-transcriptional regulation; expression of these genes was significantly different between GN121 and GN42. Specifically, six and seven DEGs were annotated as phosphorus transporters in roots and leaves, respectively. Furthermore, a putative model was constructed relying on key metabolic pathways related to phosphorus to illustrate the higher phosphorus efficiency of GN121 compared to GN42 under low phosphorus conditions. Results from this study provide a multi-transcriptome database and candidate genes for further study on phosphorus use efficiency (PUE). PMID- 29720990 TI - The Zinc-Finger Thylakoid-Membrane Protein FIP Is Involved With Abiotic Stress Response in Arabidopsis thaliana. AB - Many plant genes have their expression modulated by stress conditions. Here, we used Arabidopsis FtsH5 protease, which expression is regulated by light stress, as bait in a yeast two-hybrid screen to search for new proteins involved in the stress response. As a result, we found FIP (FtsH5 Interacting Protein), which possesses an amino proximal cleavable transit peptide, a hydrophobic membrane anchoring region, and a carboxyl proximal C4-type zinc-finger domain. In vivo experiments using FIP fused to green fluorescent protein (GFP) showed a plastid localization. This finding was corroborated by chloroplast import assays that showed FIP inserted in the thylakoid membrane. FIP expression was down-regulated in plants exposed to high light intensity, oxidative, salt, and osmotic stresses, whereas mutant plants expressing low levels of FIP were more tolerant to these abiotic stresses. Our data shows a new thylakoid-membrane protein involved with abiotic stress response in Arabidopsis thaliana. PMID- 29720991 TI - A Survey of MIKC Type MADS-Box Genes in Non-seed Plants: Algae, Bryophytes, Lycophytes and Ferns. AB - MADS box transcription factors have been studied extensively in flowering plants but remain less studied in non-seed plants. MADS box is one such example of a gene which is prevalent across many classes of plants ranging from chlorophyta to embryophyta as well as fungi and animals. MADS box transcription factors are of two types, Type I and Type II. Type II transcription factors (TF) that consist of a MADS domain, I region, K domain, and C terminal domain are discussed in this review. The Type II/ MIKC class is widespread across charophytes and all major lineages of land plants but unknown in green and red algae. These transcription factors have been implicated in floral development in seed plants and thus the question arises, "What is their role in non-seed plants?" From the studies reviewed here it can be gathered that unlike seed plants, MIKCC genes in non-seed plants have roles in both gametophytic and sporophytic generations and contribute to the development of both vegetative and reproductive structures. On the other hand as previously observed in seed plants, MIKC* genes of non-seed plants have a conserved role during gametophyte development. With respect to evolution of MIKC genes in non-seed plants, the number of common ancestors is probably very few at each branch. The expansion of this gene family in seed plants and increased plant complexity seem to be correlated. As gradually the genomes of non-seed plants are becoming available it is worthwhile to gather the existing information about MADS box genes in non-seed plants. This review highlights various MIKC MADS box genes discovered so far in non-seed plants, their possible roles and an insight into their evolution. PMID- 29720993 TI - The Soybean GmNARK Affects ABA and Salt Responses in Transgenic Arabidopsis thaliana. AB - GmNARK (Glycine max nodule autoregulation receptor kinase) is the homolog of Arabidopsis thaliana CLAVATA1 (CLV1) and one of the most important regulators in the process of AON (Autoregulation of Nodulation), a process that restricts excessive nodule numbers in soybean. However, except for the function in AON, little is known about this gene. Here, we report that GmNARK plays important roles in process of plant response to abiotic stresses. Bioinformatic analysis and subcellular localization experiment results showed that GmNARK was a putative receptor like kinase and located at membrane. The promoter of GmNARK contains manifold cis regulatory elements that are responsive to hormone and stresses. Gene transcript expression pattern analysis in soybean revealed GmNARK was induced by ABA and NaCl treatment in both shoot and root. Overexpression of GmNARK in Arabidopsis resulted in higher sensitivity to ABA and salt treatment during seed germination and greening stages. We also checked the expression levels of some ABA response genes in the transgenic lines; the results showed that the transcript level of all the ABA response genes were much higher than that of wild type under ABA treatment. Our results revealed a novel role of GmNARK in response to abiotic stresses during plant growth and development. PMID- 29720994 TI - Domestication of Pea (Pisum sativum L.): The Case of the Abyssinian Pea. AB - Phylogenetic relationships of the Abyssinian pea (Pisum sativum ssp. abyssinicum) to other subspecies and species in the genus were investigated to test between different hypotheses regarding its origin and domestication. An extensive sample of the Pisum sativum ssp. sativum germplasm was investigated, including groups a 1, a-2, b, c, and d as identified by Kwon et al. (2012). A broad sample of P. fulvum but relatively few P. s. ssp. elatius accessions were analyzed. Partial sequences of 18 genes were compared and these results combined with comparisons of additional genes done by others and available in the literature. In total, 54 genes or gene fragment sequences were involved in the study. The observed affinities between alleles in P. ssp. sativum, P. s. ssp. abyssinicum, P. s. ssp. elatius, and P. fulvum clearly demonstrated a close relationship among the three P. sativum subspecies and rejected the hypothesis that the Abyssinian pea was formed by hybridization between one of the P. sativum subspecies and P. fulvum. If hybridization were involved in the generation of the Abyssinian pea, it must have been between P. s. ssp. sativum and P. s. ssp. elatius, although the Abyssinian pea possesses a considerable number of highly unique alleles, implying that the actual P. s. ssp. elatius germplasm involved in such a hybridization has yet to be tested or that the hybridization occurred much longer ago than the postulated 4000 years bp. Analysis of the P. s. ssp. abyssinicum alleles in genomic regions thought to contain genes critical for domestication indicated that the indehiscent pod trait was independently developed in the Abyssinian pea, whereas the loss of seed dormancy was either derived from P. s. ssp. sativum or at least partially developed before the P. s. ssp. abyssinicum lineage diverged from that leading to P. s. ssp. sativum. PMID- 29720992 TI - Tools for Genetic Studies in Experimental Populations of Polyploids. AB - Polyploid organisms carry more than two copies of each chromosome, a condition rarely tolerated in animals but which occurs relatively frequently in the plant kingdom. One of the principal challenges faced by polyploid organisms is to evolve stable meiotic mechanisms to faithfully transmit genetic information to the next generation upon which the study of inheritance is based. In this review we look at the tools available to the research community to better understand polyploid inheritance, many of which have only recently been developed. Most of these tools are intended for experimental populations (rather than natural populations), facilitating genomics-assisted crop improvement and plant breeding. This is hardly surprising given that a large proportion of domesticated plant species are polyploid. We focus on three main areas: (1) polyploid genotyping; (2) genetic and physical mapping; and (3) quantitative trait analysis and genomic selection. We also briefly review some miscellaneous topics such as the mode of inheritance and the availability of polyploid simulation software. The current polyploid analytic toolbox includes software for assigning marker genotypes (and in particular, estimating the dosage of marker alleles in the heterozygous condition), establishing chromosome-scale linkage phase among marker alleles, constructing (short-range) haplotypes, generating linkage maps, performing genome wide association studies (GWAS) and quantitative trait locus (QTL) analyses, and simulating polyploid populations. These tools can also help elucidate the mode of inheritance (disomic, polysomic or a mixture of both as in segmental allopolyploids) or reveal whether double reduction and multivalent chromosomal pairing occur. An increasing number of polyploids (or associated diploids) are being sequenced, leading to publicly available reference genome assemblies. Much work remains in order to keep pace with developments in genomic technologies. However, such technologies also offer the promise of understanding polyploid genomes at a level which hitherto has remained elusive. PMID- 29720995 TI - Transcriptome-Wide Annotation of m5C RNA Modifications Using Machine Learning. AB - The emergence of epitranscriptome opened a new chapter in gene regulation. 5 methylcytosine (m5C), as an important post-transcriptional modification, has been identified to be involved in a variety of biological processes such as subcellular localization and translational fidelity. Though high-throughput experimental technologies have been developed and applied to profile m5C modifications under certain conditions, transcriptome-wide studies of m5C modifications are still hindered by the dynamic and reversible nature of m5C and the lack of computational prediction methods. In this study, we introduced PEA m5C, a machine learning-based m5C predictor trained with features extracted from the flanking sequence of m5C modifications. PEA-m5C yielded an average AUC (area under the receiver operating characteristic) of 0.939 in 10-fold cross-validation experiments based on known Arabidopsis m5C modifications. A rigorous independent testing showed that PEA-m5C (Accuracy [Acc] = 0.835, Matthews correlation coefficient [MCC] = 0.688) is remarkably superior to the recently developed m5C predictor iRNAm5C-PseDNC (Acc = 0.665, MCC = 0.332). PEA-m5C has been applied to predict candidate m5C modifications in annotated Arabidopsis transcripts. Further analysis of these m5C candidates showed that 4nt downstream of the translational start site is the most frequently methylated position. PEA-m5C is freely available to academic users at: https://github.com/cma2015/PEA-m5C. PMID- 29720996 TI - Rare Compound Heterozygous Frameshift Mutations in ALMS1 Gene Identified Through Exome Sequencing in a Taiwanese Patient With Alstrom Syndrome. AB - Alstrom syndrome (AS) is a rare autosomal recessive disorder that shares clinical features with other ciliopathy-related diseases. Genetic mutation analysis is often required in making differential diagnosis but usually costly in time and effort using conventional Sanger sequencing. Herein we describe a Taiwanese patient presenting cone-rod dystrophy and early-onset obesity that progressed to diabetes mellitus with marked insulin resistance during adolescence. Whole exome sequencing of the patient's genomic DNA identified a novel frameshift mutation in exons 15 (c.10290_10291delTA, p.Lys3431Serfs*10) and a rare mutation in 16 (c.10823_10824delAG, p.Arg3609Alafs*6) of ALMS1 gene. The compound heterozygous mutations were predicted to render truncated proteins. This report highlighted the clinical utility of exome sequencing and extended the knowledge of mutation spectrum in AS patients. PMID- 29720998 TI - Coding and Non-coding RNAs, the Frontier Has Never Been So Blurred. PMID- 29720997 TI - Transposable Element Genomic Fissuring in Pyrenophora teres Is Associated With Genome Expansion and Dynamics of Host-Pathogen Genetic Interactions. AB - Pyrenophora teres, P. teres f. teres (PTT) and P. teres f. maculata (PTM) cause significant diseases in barley, but little is known about the large-scale genomic differences that may distinguish the two forms. Comprehensive genome assemblies were constructed from long DNA reads, optical and genetic maps. As repeat masking in fungal genomes influences the final gene annotations, an accurate and reproducible pipeline was developed to ensure comparability between isolates. The genomes of the two forms are highly collinear, each composed of 12 chromosomes. Genome evolution in P. teres is characterized by genome fissuring through the insertion and expansion of transposable elements (TEs), a process that isolates blocks of genic sequence. The phenomenon is particularly pronounced in PTT, which has a larger, more repetitive genome than PTM and more recent transposon activity measured by the frequency and size of genome fissures. PTT has a longer cultivated host association and, notably, a greater range of host-pathogen genetic interactions compared to other Pyrenophora spp., a property which associates better with genome size than pathogen lifestyle. The two forms possess similar complements of TE families with Tc1/Mariner and LINE-like Tad-1 elements more abundant in PTT. Tad-1 was only detectable as vestigial fragments in PTM and, within the forms, differences in genome sizes and the presence and absence of several TE families indicated recent lineage invasions. Gene differences between P. teres forms are mainly associated with gene-sparse regions near or within TE-rich regions, with many genes possessing characteristics of fungal effectors. Instances of gene interruption by transposons resulting in pseudogenization were detected in PTT. In addition, both forms have a large complement of secondary metabolite gene clusters indicating significant capacity to produce an array of different molecules. This study provides genomic resources for functional genetics to help dissect factors underlying the host-pathogen interactions. PMID- 29720999 TI - The contribution of gender and age on early and late mortality following ST segment elevation myocardial infarction: results from the Korean Acute Myocardial Infarction National Registry with Registries. AB - Background: Although previous studies using Korean data have already reported higher rates of mortality in women, it is less clear whether these gender differences in prognosis post ST-segment elevation myocardial infarction (STEMI), are age dependent. The aim of this study is to examine the gender-age interaction with early and late mortality in patients with STEMI enrolled in the Korean nationwide registry. Methods: This prospective study stratified outcomes according to gender and age from 17,021 STEMI patients. We compared in-hospital, early (30 days) and late (12 months) mortality between gender to examine the gender-age interaction in multivariable models. Results: In younger women (< 60 years), in-hospital [5.8% vs. 2.5%, P < 0.001; unadjusted odds ratios (OR): 2.41, 95% confidence intervals (CI): 1.59-3.66], early (6.2% vs. 2.6%, P < 0.001; unadjusted OR: 2.4, 95% CI: 2.12-2.72) and late mortality (7.0% vs. 3.1%, P > 0.001; unadjusted OR: 2.33, 95% CI: 2.08-2.61) were significantly higher compared with men. However, after adjustment for patient characteristics, Killip class >= 3, symptom to balloon time and major bleeding, and in-hospital bleeding, overall early and late mortality were no longer related to gender in any age groups. Conclusions: Among a Korean population with STEMI, higher early and late mortality in younger women may be explained by poor patient characteristics, higher Killip class >= 3, longer symptom to balloon time and more frequent major bleeding. Therefore, based on gender-age differences, more precise and aggressive preventive strategies focused on risk factor reduction, education and more intensive management for younger women should be performed. PMID- 29721000 TI - Association between preoperative high sensitive troponin I levels and cardiovascular events after hip fracture surgery in the elderly. AB - Objective: Cardiovascular complications contribute to postoperative morbidity and mortality in elderly hip fracture patients. Limited data are available regarding which preoperative risk factors predict cardiovascular course following hip fracture surgery (HFS). We used high sensitive troponin I (hs-TnI) assays and clinical parameters to identify preoperative risk factors associated with major adverse cardiac events (MACE) in elderly hip fracture patients. Method: From August 2014 to November 2016, 575 patients with hip fracture were enrolled in a retrospective, single-center registry. A total of 262 of these patients underwent HFS and hs-TnI assays. MACE was defined as postoperative all-cause deaths, heart failure (HF), new-onset atrial fibrillation (AF), myocardial infarction (MI) and cardiovascular re-hospitalization that occurred within 90 days postoperative. Results: Of 262 HFS patients, MACE developed following HFS in 65 (24.8%). Patients with MACE were older and had higher rates of renal insufficiency, coronary artery disease, prior HF, low left ventricular ejection fraction and use of beta blockers; higher levels of hs-TnI and N-terminal pro-brain natriuretic peptide (NT-proBNP) and higher revised cardiac risk index. A preoperative hs-TnI >= 6.5 ng/L was associated with high risk of postoperative HF, new-onset AF and MACE. In multivariable analysis, preoperative independent predictors for MACE were age > 80 years [adjusted hazard ratio (HR): 1.79, 95% confident interval (CI): 1.03-3.13, P = 0.04], left ventricular ejection fraction (LVEF) < 50% (adjusted HR: 3.17, 95% CI: 1.47-6.82, P < 0.01) and hs-TnI > 6.5 ng/L (adjusted HR: 3.75, 95% CI: 2.09-6.17, P < 0.01). Conclusion: In elderly patients with hip fracture who undergo HFS, a preoperative assessment of hs-TnI may help the risk refinement of cardiovascular complications. PMID- 29721001 TI - The subcutaneous implantable cardioverter defibrillator--review of the recent data. AB - The subcutaneous implantable cardioverter defibrillators (SICD) is an alternative to the transvenous ICD for the prevention of sudden cardiac death (SCD). Multiple studies have shown that the SICD is safe and effective in treating ventricular arrhythmias. While earlier studies mainly enrolled younger patients with channelopathies, more recent reports included patients with "typical" indications for ICD therapy for the prevention of SCD. In this review we summarize the data available to date on the SICD while highlighting its pros and cons. PMID- 29721003 TI - Successful conservative management of Class III iatrogenic aortic dissection. PMID- 29721002 TI - Should atrial fibrillation patients with hypertension as an additional risk factor of the CHA2DS2-VASc score receive oral anticoagulation? AB - Hypertension has been found to be increased a risk of stroke in atrial fibrillation (AF). Both the European and U.S. guidelines advocate the use of the CHA2DS2-VASc (congestive heart failure, hypertension, age > 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65-74 years, sex category) scheme for risk stratification. Although vitamin K antagonists is more effective than acetylsalicylic acid at preventing ischaemic stroke, its benefit is offs by an increased haemorrhage risk. The risk of ischemic stroke in patients with AF and a CHA2DS2-VASc score of 1 are considered to be low risk and may be not expected to benefit from anticoagulation therapy. Hypertension carries an increased risk of ischemic stroke, however, it is also a clear risk factor for hemorrhage in AF. Therefore, the optimal antithrombotic management is highlighted in patients with AF with only one risk factor especially hypertension. PMID- 29721005 TI - Simultaneous multiple coronary arteries thrombosis in patients with STEMI. PMID- 29721004 TI - Anterior myocardial pseudoinfarction in a patient with diabetic ketoacidosis. PMID- 29721006 TI - Mitral pseudostenosis due to a large left atrial myxoma. PMID- 29721007 TI - Takotsubo cardiomyopathy after pacemaker implantation. PMID- 29721008 TI - Entire solutions for a reaction-diffusion equation with doubly degenerate nonlinearity. AB - This paper is concerned with the existence of entire solutions for a reaction diffusion equation with doubly degenerate nonlinearity. Here the entire solutions are the classical solutions that exist for all [Formula: see text]. With the aid of the comparison theorem and the sup-sub solutions method, we construct some entire solutions that behave as two opposite traveling front solutions with critical speeds moving towards each other from both sides of x-axis and then annihilating. In addition, we apply the existence theorem to a specially doubly degenerate case. PMID- 29721010 TI - Targeted Neuromodulation of Abnormal Interhemispheric Connectivity to Promote Neural Plasticity and Recovery of Arm Function after Stroke: A Randomized Crossover Clinical Trial Study Protocol. AB - Background: Despite intensive rehabilitation efforts, most stroke survivors have persistent functional disability of the paretic arm and hand. These motor impairments may be due in part to maladaptive changes in structural and functional connections between brain regions. The following early stage clinical trial study protocol describes a noninvasive brain stimulation approach to target transcallosally mediated interhemispheric connections between the ipsi- and contralesional motor cortices (iM1 and cM1) using corticocortical paired associative stimulation (ihPAS). This clinical trial aims to characterize ihPAS induced modulation of interhemispheric connectivity and the effect on motor skill performance and learning in chronic stroke survivors. Methods/Design: A repeated measures, cross-over design study will recruit 20 individuals post-stroke with chronic mild-moderate paretic arm impairment. Each participant will complete an active ihPAS and control ihPAS session. Assessments of cortical excitability and motor skill performance will be conducted prior to and at four time points following the ihPAS intervention. The primary outcome measures will be: TMS evoked interhemispheric motor connectivity, corticomotor excitability, and response time on a modified serial reaction time task. Discussion/Conclusion: The findings from this single-site early stage clinical trial will provide foundational results to inform the design of larger-scale, multisite clinical trials to evaluate the therapeutic potential of ihPAS-based neuromodulation for upper limb recovery after stroke. This trial is registered with NCT02465034. PMID- 29721009 TI - Biomarkers of Rehabilitation Therapy Vary according to Stroke Severity. AB - Biomarkers that capture treatment effects could improve the precision of clinical decision making for restorative therapies. We examined the performance of candidate structural, functional, and angiogenesis-related MRI biomarkers before and after a 3-week course of standardized robotic therapy in 18 patients with chronic stroke and hypothesized that results vary significantly according to stroke severity. Patients were 4.1 +/- 1 months poststroke, with baseline arm Fugl-Meyer scores of 20-60. When all patients were examined together, no imaging measure changed over time in a manner that correlated with treatment-induced motor gains. However, when also considering the interaction with baseline motor status, treatment-induced motor gains were significantly related to change in three functional connectivity measures: ipsilesional motor cortex connectivity with (1) contralesional motor cortex (p = 0.003), (2) contralesional dorsal premotor cortex (p = 0.005), and (3) ipsilesional dorsal premotor cortex (p = 0.004). In more impaired patients, larger treatment gains were associated with greater increases in functional connectivity, whereas in less impaired patients larger treatment gains were associated with greater decreases in functional connectivity. Functional connectivity measures performed best as biomarkers of treatment effects after stroke. The relationship between changes in functional connectivity and treatment gains varied according to baseline stroke severity. Biomarkers of restorative therapy effects are not one-size-fits-all after stroke. PMID- 29721011 TI - A New Scoring System to Predict Poor Clinical Outcomes in Acute Nonvariceal Upper Gastrointestinal Bleeding Patients with High-Risk Stigmata. AB - Aims: To explore the risk factors for rebleeding in acute nonvariceal upper gastrointestinal bleeding patients with high-risk stigmata after endoscopic hemostasis and to develop a new scoring system for them. Methods: A retrospective single-center study was conducted from January 2012 to June 2017. The logistic regression model was used to explore risk factors of poor clinical outcomes. Accuracy of new scoring systems was compared with Rockall score (RS) and Glasgow Blatchford score (GBS) using receiver operating characteristics curve. Results: Two hundred nine patients were included. In multivariate regression analysis, systolic blood pressure, endoscopic hemostasis method, hemoglobin, blood urea nitrogen, and serum creatinine were identified as indicators for rebleeding. New scoring systems with 4 variables and 5 variables based on these 5 risk factors were chosen. The 4-variable scoring system outperformed GBS in predicting rebleeding while 5-variable scoring system outperformed RS and GBS in predicting rebleeding significantly. Score 2 was identified as the best cut-off of these 2 scoring systems. Conclusions: Systolic blood pressure, endoscopic hemostasis method, hemoglobin, blood urea nitrogen, and serum creatinine were all associated with poor clinical outcomes. The new scoring systems had greater accuracy than RS and GBS in predicting rebleeding. Further external validation should be performed to verify the results. PMID- 29721013 TI - Changes in Hepatic Blood Flow and Liver Function during Closed Abdominal Hyperthermic Intraperitoneal Chemotherapy following Cytoreduction Surgery. AB - Background: The increase in intra-abdominal pressure (IAP) during closed abdominal hyperthermic intraperitoneal chemotherapy (HIPEC) leads to major haemodynamic changes and potential organ dysfunction. We investigated these effects on hepatic blood flow (HBF) and liver function in patients undergoing HIPEC following cytoreductive surgery and fluid management guided by dynamic preload indices. Methods: In this prospective observational clinical study including 15 consecutive patients, we evaluated HBF by transesophageal echocardiography and liver function by determination of the indocyanine green plasma disappearance rate (ICG-PDR). Friedman's two-way analysis of variance by ranks and Wilcoxon signed-rank test were performed for statistical analysis. Results: During HIPEC, HBF was markedly reduced, resulting in the loss of any pulsatile Doppler flow signal in all but one patient. The ICG-PDR, expressed as median (interquartile 25-75), decreased from 23 (20-30) %/min to 18 (12.5-19) %/min (p < 0.001). Despite a generous crystalloid infusion rate (27 (22-35) ml/kg/h), cardiac index decreased during the increased IAP period, inferior vena cava diameter decreased, stroke volume variation and pulse pressure variation increased, lung compliance dropped, and there was an augmentation in plateau pressure. All changes were significant (p < 0.001) and reversed to baseline values post HIPEC. Conclusion: Despite optimizing intravenous fluids during closed abdominal HIPEC, we observed a marked decrease in HBF and liver function. Both effects were transient and limited to the period of HIPEC but could influence the choice between closed or open abdominal cavity procedure for HIPEC and should be considered in similar clinical situations of increased IAP. PMID- 29721012 TI - Prevalence of Sleep Bruxism in IBD Patients and Its Correlation to Other Dental Disorders and Quality of Life. AB - Background: Patients with inflammatory bowel diseases could experience mouth and teeth disorders and alterations in psychological mood. Vice versa, the psychological status may influence the presence of oral diseases. Aim: To evaluate in inflammatory bowel disease patients the prevalence of sleep bruxism and its correlation with the presence of oral diseases, quality of sleep, and psychological disturbances. Methods: Patients were consecutively recruited in our clinic and examined for temporomandibular disorders, dental enamel disorders, sleep bruxism, and recurrent aphthous stomatitis by two dentists. Patients also underwent Pittsburgh Sleep Quality Index and Beck Depression Inventory Scale questionnaires. Results: 47 patients and 46 controls were included. Sleep bruxism and enamel wear disorders were more frequent in Crohn's disease patients when compared with ulcerative colitis patients and controls (p = 0.03 and p = 0.02, resp.). Among groups, no differences were noted for enamel hypoplasia, temporomandibular disorders, recurrent aphthous stomatitis, depression, and quality of sleep. We found a positive correlation between bruxism and temporomandibular disorders (Spearman 0.6, p < 0.001) and between bruxism and pathological sleep (Pittsburgh Sleep Quality Index > 5) (Spearman 0.3, p < 0.005). Conclusion: Bruxism and enamel wear disorders should be routinely searched in Crohn's disease patients. Moreover, the attention of healthcare givers to sleep disturbances should be addressed to all inflammatory bowel disease patients. PMID- 29721014 TI - Direct Photocoagulation Guided by Merged Retinal Images for the Treatment of Focal Diabetic Macular Edema. AB - Purpose: To introduce a novel laser photocoagulation (PC) protocol named merged image-guided PC (MIG-PC), which included merging the images of the fundus, optical coherence tomography (OCT) map, and fluorescein angiography (FA). We compared the anatomical and functional results between MIG-PC and FA-guided PC (FG-PC) for the treatment of focal diabetic macular edema (DME). Method: We examined the treatment outcomes in 27 consecutive eyes treated with MIG-PC compared with 28 matched eyes treated with FG-PC. We identified the microaneurysms (MAs) located in the focal edema areas and ablated them using focal PC. Best-corrected visual acuity (BCVA) and retinal thickness (RT) measured using OCT were compared between the groups at baseline and 2, 4, 8, 12, and 24 weeks after treatment. Results: The foveal and perifoveal RT were reduced after treatment in both the groups, and the perifoveal RT in the MIG-PC group was significantly lower than that in the FG-PC group at 4 weeks and thereafter. BCVA in the MIG-PC group was significantly higher than that in the FG-PC group at 12 and 24 weeks. The numbers of laser spots (p = 0.0001), additional laser treatments (p = 0.0121), and intravitreal injection of ranibizumab (p = 0.0012) in the MIG-PC group were significantly lower than those in the FG-PC group (Mann Whitney test). Conclusion: MIG-PC contributed to the improvement in BCVA and reduction in RT, number of laser shots required, and retreatment rates. Based on our data, MIG-PC can be recommended for the treatment of focal DME. This trial is registered with ID UMIN000030390. PMID- 29721015 TI - A Comparative Assessment of Cardiovascular Autonomic Reflex Testing and Cardiac 123I-Metaiodobenzylguanidine Imaging in Patients with Type 1 Diabetes Mellitus without Complications or Cardiovascular Risk Factors. AB - Aim: To compare the cardiovascular autonomic reflex tests (CARTs) with cardiac sympathetic innervation imaging with 123I-metaiodobenzylguanidine (MIBG) in patients with type 1 diabetes mellitus (T1DM). Patients and Methods: Forty-nine patients (29 males, mean age 36 +/- 10 years, mean T1DM duration 19 +/- 6 years) without cardiovascular risk factors were prospectively enrolled. Participants were evaluated for autonomic dysfunction by assessing the mean circular resultant (MCR), Valsalva maneuver (Vals), postural index (PI), and orthostatic hypotension (OH). Within one month from the performance of these tests, patients underwent cardiac MIBG imaging and the ratio of the heart to upper mediastinum count density (H/M) at 4 hours postinjection was calculated (abnormal values, H/M < 1.80). Results: Twenty-nine patients (59%) had abnormal CARTs, and 37 (76%) patients had an H/M_4 < 1.80 (p = 0.456). MCR, PI, Vals, and OH were abnormal in 29 (59%), 8 (16%), 5 (10%), and 11 (22%) patients, respectively. When using H/M_4 < 1.80 as the reference standard, a cutoff point of >=2 abnormal CARTs had a sensitivity of 100% but a specificity of only 33% for determining CAN. Conclusions: CARTs are not closely associated with 123I-MIBG measurements, which can detect autonomic dysfunction more efficiently than the former. In comparison to semiquantitative cardiac MIBG assessment, the recommended threshold of >=2 abnormal CARTs to define cardiovascular autonomic dysfunction is highly sensitive but of limited specificity and is independently determined by the duration of T1DM. PMID- 29721016 TI - The Association of Thyroid Nodules with Metabolic Status: A Cross-Sectional SPECT China Study. AB - Purpose: The aim of this study was to investigate the association of thyroid nodules (TNs) and their ultrasound (US) characteristics related to malignancy with metabolic status. Methods: The data were obtained from a cross-sectional study (SPECT-China, 2014-2015). The study included 9898 participants older than 18 years. Participants underwent several checkups, which included the measurement of anthropometric parameters, blood pressure, TSH levels, glucose, and lipid profiles. TN and nonalcoholic fatty liver disease (NAFLD) were diagnosed by US. TN US characteristics, including microcalcification and a taller-than-wide shape, were recorded. Results: Participants with TN [TN(+)] had a higher prevalence of metabolic syndrome (Met-S), obesity, central obesity, hyperlipidaemia, diabetes, hypertension, and NAFLD, especially women (all P <= 0.001). After full adjustment, logistic regression analysis indicated that metabolic syndrome, obesity, central obesity, and hyperlipidaemia were all independent risk factors for the increased prevalence of TN in both genders (P < 0.05). In terms of TN US imaging characteristics associated with malignancy, being female with obesity, central obesity, and NAFLD had 1.91-fold, 2.09-fold, and 1.75-fold increased risks of developing a taller-than-wide nodule (P = 0.014, 0.004, and 0.027, resp.). Conclusions: The status of metabolic disorders might be associated with higher risks of TN in both genders. In women, obesity, central obesity, and NAFLD might contribute to the development of a taller-than-wide nodule. The potential role of metabolic status in the pathogenesis of the thyroid nodule and thyroid cancer remains to be elucidated. PMID- 29721018 TI - Efficacy and Safety of Insulin Degludec versus Insulin Glargine: A Systematic Review and Meta-Analysis of Fifteen Clinical Trials. AB - Aims: Insulin degludec (IDeg) and insulin glargine (IGlar) are both proved to be effective in diabetes. This study aimed to assess the effects and safety of IDeg versus IGlar. Methods: A systematic literature search was conducted using the PubMed, EMBASE, and Cochrane Library electronic databases to identify all randomized controlled trials (RCTs). Results: Fifteen RCTs were identified. The combined data showed that the decrease in the glycosylated hemoglobin (HbA1c) level was slightly different, and the proportion of patients who achieved HbA1c < 7% was similar between the IDeg and IGlar groups. Further, a statistically significant decrease in the fasting plasma glucose level was observed in the IDeg group as compared to the IGlar group. In patients with T2DM, IDeg was associated with lower rates of overall hypoglycemia. Nocturnal hypoglycemia was significantly lower in the case of IDeg than in the case of IGlar in both T1DM and T2DM patients. No statistically significant differences were observed between the groups. Conclusions: Compared with IGlar, IDeg is associated with equivalent glycemic control and a statistically significantly lower rate of nocturnal hypoglycemia in patients with T1DM and T2DM. In T2DM patients, IDeg also provides better results in terms of overall hypoglycemia. PMID- 29721017 TI - Elevated and Correlated Expressions of miR-24, miR-30d, miR-146a, and SFRP-4 in Human Abdominal Adipose Tissue Play a Role in Adiposity and Insulin Resistance. AB - Objective: We explored the relationships among microRNAs (miRNAs) and SFRP4, as they relate to adipose tissue functions including lipolysis, glucose and glycerol turnover, and insulin sensitivity. Methods: Abdominal adipose tissue (AbdAT) levels of thirteen microRNAs (miRNAs), SFRP4, and VEGF in lean nondiabetic subjects (n = 7), subjects with obesity (n = 5), and subjects with obesity and type 2 diabetes (T2DM) (n = 5) were measured by qPCR. Insulin sensitivity was measured by the euglycemic-hyperinsulinemic clamp. Osmium fixation and Coulter counting were used for adipocyte sizing. Data were analyzed using generalized linear models that adjusted for age, gender, and ethnicity. Results: AbdAT miR 24, miR-30d, and miR-146a were elevated in subjects with obesity (P < 0.05) and T2DM (P < 0.1) and positively correlated with measures of percent body fat by DXA (rmiR.24 = 0.894, rmiR.146a = 0.883, P < 0.05), and AbdAT SFRP4 (rmiR.30 = 0.93, rmiR.146a = 0.88, P < 0.05). These three miRNAs additionally correlated among themselves (rmiR.24~miR.146a = 0.90, rmiR.30~miR.146a = 0.85, P < 0.01). Conclusions: This study suggests a novel association between the elevated levels of miRNAs miR-24, miR-30d, and miR-146a (apparently coregulated) and the level of SFRP4 transcript in AbdAT of subjects with obesity and T2DM. These molecules might be part of a regulatory loop involved in AbdAT remodeling/adiposity and systemic insulin resistance. This trial is registered with NCT00704197. PMID- 29721019 TI - Establishing Differences in Thermographic Patterns between the Various Complications in Diabetic Foot Disease. AB - Aim: To evaluate the potential of thermography as an assessment tool for the detection of foot complications by understanding the variations in temperature that occur in type 2 diabetes mellitus (DM). Methods: Participants were categorized according to a medical examination, ankle brachial index, doppler waveform analysis, and 10-gram monofilament testing into five groups: healthy adult, DM with no complications, DM with peripheral neuropathy, DM with neuroischaemia, and DM with peripheral arterial disease (PAD) groups. Thermographic imaging of the toes and forefeet was performed. Results: 43 neuroischaemic feet, 41 neuropathic feet, 58 PAD feet, 21 DM feet without complications, and 126 healthy feet were analyzed. The temperatures of the feet and toes were significantly higher in the complications group when compared to the healthy adult and DM healthy groups. The higher the temperatures of the foot in DM, the higher the probability that it is affected by neuropathy, neuroischaemia, or PAD. Conclusions: Significant differences in mean temperatures exist between participants who were healthy and those with DM with no known complications when compared to participants with neuroischaemia, neuropathy, or PAD. As foot temperature rises, so does the probability of the presence of complications of neuropathy, neuroischaemia, or peripheral arterial disease. PMID- 29721021 TI - Molecular Typing and Antimicrobial Susceptibility of Methicillin-Resistant Staphylococcus aureus Isolated from Bovine Milk in Tanzania. AB - Methicillin-resistant Staphylococcus aureus (MRSA) in raw milk can be transmitted from animals to humans, and in Tanzania raw milk is sold in local markets and consumed as purchased. This study was performed to determine the molecular characteristics and antimicrobial susceptibility pattern of MRSA strains isolated from raw bovine milk sold at local markets in Tanzania. A total of 117 raw milk samples were cultured on Baird-Parker medium to isolate S. aureus and PCR was used for amplification of gltB gene for S. aureus identification and the presence of mecA gene for methicillin-resistant strains. Coagulase-negative (CN) S. aureus were reconfirmed using tube coagulase, DNase, and API Staph tests. MRSA isolates were spa typed whereas antimicrobial susceptibility testing was performed by the disc diffusion method. Forty-six coagulase positives (CP) and two CN S. aureus were identified. Most strains were resistant to penicillin (72%), and 3 isolates: 2 CN S. aureus and 1 coagulase-negative Staphylococci (CNS), were phenotypically resistant to vancomycin, oxacillin, and cefoxitin and were confirmed to carry mecA. Resistance to clindamycin, trimethoprim-sulfamethoxazole, and tetracycline was 23.9%, 30.4%, and 41.3%, respectively. Twelve isolates exhibited multidrug resistance; however, only one mecA positive strain among the three was typeable and belonged to spa type t2603. This study reports for the first time the presence of CN variant of MRSA, which was assigned the spa type t2603, and the presence of multidrug resistant S. aureus isolates from bovine milk in Morogoro, Tanzania. PMID- 29721020 TI - Detection of HIV-1 and Human Proteins in Urinary Extracellular Vesicles from HIV+ Patients. AB - Background: Extracellular vesicles (EVs) are membrane bound, secreted by cells, and detected in bodily fluids, including urine, and contain proteins, RNA, and DNA. Our goal was to identify HIV and human proteins (HPs) in urinary EVs from HIV+ patients and compare them to HIV- samples. Methods: Urine samples were collected from HIV+ (n = 35) and HIV- (n = 12) individuals. EVs were isolated by ultrafiltration and characterized using transmission electron microscopy, tandem mass spectrometry (LC/MS/MS), and nanoparticle tracking analysis (NTA). Western blots confirmed the presence of HIV proteins. Gene ontology (GO) analysis was performed using FunRich and HIV Human Interaction database (HHID). Results: EVs from urine were 30-400 nm in size. More EVs were in HIV+ patients, P < 0.05, by NTA. HIV+ samples had 14,475 HPs using LC/MS/MS, while only 111 were in HIV-. HPs in the EVs were of exosomal origin. LC/MS/MS showed all HIV+ samples contained at least one HIV protein. GO analysis showed differences in proteins between HIV+ and HIV- samples and more than 50% of the published HPs in the HHID interacted with EV HIV proteins. Conclusion: Differences in the proteomic profile of EVs from HIV+ versus HIV- samples were found. HIV and HPs in EVs could be used to detect infection and/or diagnose HIV disease syndromes. PMID- 29721022 TI - Reprogramming of Mouse Calvarial Osteoblasts into Induced Pluripotent Stem Cells. AB - Previous studies have demonstrated the ability of reprogramming endochondral bone into induced pluripotent stem (iPS) cells, but whether similar phenomenon occurs in intramembranous bone remains to be determined. Here we adopted fluorescence activated cell sorting-based strategy to isolate homogenous population of intramembranous calvarial osteoblasts from newborn transgenic mice carrying both Osx1-GFP::Cre and Oct4-EGFP transgenes. Following retroviral transduction of Yamanaka factors (Oct4, Sox2, Klf4, and c-Myc), enriched population of osteoblasts underwent silencing of Osx1-GFP::Cre expression at early stage of reprogramming followed by late activation of Oct4-EGFP expression in the resulting iPS cells. These osteoblast-derived iPS cells exhibited gene expression profiles akin to embryonic stem cells and were pluripotent as demonstrated by their ability to form teratomas comprising tissues from all germ layers and also contribute to tail tissue in chimera embryos. These data demonstrate that iPS cells can be generated from intramembranous osteoblasts. PMID- 29721024 TI - Docking, Synthesis and Anticonvulsant Activity of N-substituted Isoindoline-1,3 dione. AB - A series of compounds related to ameltolide were studied for anticonvulsant potential in the subcutaneous pentylenetetrazol (sc Ptz) test in mice. These compounds were synthesized and characterized by TLC followed by IR and H1NMR. In vivo screening data acquired indicate that most of analogs have the ability to protect against PTZ-induced seizure. Phenytoin (PHT) was employed as the reference prototype antiepileptic drug. All compounds exerted their maximal effects 30 min after administration. Out of the 6 compounds, compound 2 at 40 mg/Kg dose is more potent than phenytoin (reference drug) on clonic seizure. Using a model of the open pore of the Na channel, docking study was performed by AutoDock 4.2 program. Docking study has revealed that these compounds are stabilized through at least one hydrogen bond rises from ketone of phthalimide and residue Thr-87 of domain G of sodium channel. PMID- 29721023 TI - MiRNA-17 encoded by the miR-17-92 cluster increases the potential for steatosis in hepatoma cells by targeting CYP7A1. AB - Background: The miRNA cluster miR-17-92 is known to act as an oncogene in various cancers. Members of this cluster were also found to be involved in some other pathological process, such as steatosis, which is a pivotal event in the initiation and progression of nonalcoholic fatty liver disease (NAFLD). This study aimed to explore whether miR-17, one of the most functional miRNAs in the miR-17-92 family, participates in the process of steatosis in hepatoma cells. Methods: We developed both a miR-17-expressing transgenic mouse model and a miR 17-expressing HepG2 cell model, the latter was established via stable transfection. Real-time PCR and western blot were applied to measure the expression levels of miR-17 and the potential target gene CYP7A1. The luciferase assay was used to confirm direct binding of miR-17 and CYP7A1. The oleic acid induction assay and Oil-Red-O staining were performed to support the determination of steatotic changes in HepG2 cell. Results: Extensive steatotic changes were observed in the livers of transgenic mice. Fewer were seen in the wild-type animals. CYP7A1 was confirmed as a target gene of miR-17, and the expression of CYP7A1 was found to be negatively regulated in both the transgenic mice liver cells and the miR-17-expressing HepG2 cells. CYP7A1 was found to participate in miR-17-induced steatosis, as its repressed expression in miR-17 HepG2 cells exacerbated steatotic change. Re-introduction of CYP7A1 into miR-17 HepG2 cell partially alleviated steatosis. Conclusions: miR-17 is a novel regulator of CYP7A1 signaling in hepatic lipid metabolism, suggesting a potential therapeutic approach for fatty liver. PMID- 29721025 TI - Enhanced Dissolution Rate of Tadalafil Nanoparticles Prepared by Sonoprecipitation Technique: Optimization and Physicochemical Investigation. AB - Nanocrystals of tadalafil, a poorly water-soluble drug, were successfully prepared by sonoprecipitation technique for improving the solubility and dissolution rate. Tween 80 was selected as an efficient surfactant to inhibit aggregation in stabilization of drug nanocrystals. Response surface methodology based on central composite design (CCD) was utilized to evaluate the formulation factors affecting the size of nanosuspensions. Under optimum conditions, relatively spherical nanocrystals with a mean particle size of 358.47 +/- 11.95nm were obtained. FTIR analysis indicated that the precipitated nanoparticles had the same chemical structure as the raw tadalafil. By DSC analysis, no substantial crystalline change was found in the nanocrystals compared with the unprocessed drug. In addition, the dissolution rate of the processed tadalafil nanocrystals in 120 min was significantly increased (3.61-fold) as compared to that of the raw material. Therefore, it was concluded that the sonoprecipitation technique could be a simple and useful technique to prepare poorly water-soluble drug particles with reduction in particle size, a narrow particle size distribution and enhanced dissolution properties. PMID- 29721027 TI - Acupuncture for Acne Vulgaris: A Systematic Review and Meta-Analysis. AB - Purpose: To conduct a systematic review and meta-analysis to determine the current best available evidence of the efficacy and safety of acupuncture and related therapies for acne vulgaris. Methods: Eleven English and Chinese databases were searched to identify randomized controlled trials (RCTs) of acne vulgaris compared to pharmacotherapies, no treatment, and sham or placebo acupuncture. Methodological quality was assessed using Cochrane Collaboration's risk of bias tool. Meta-analysis was conducted using RevMan software. Results: Twelve RCTs were included in the qualitative review and 10 RCTs were included in meta-analysis. Methodological quality of trials was generally low. The chance of achieving >=30% change in lesion count in the acupuncture group was no different to the pharmacotherapy group (RR: 1.07 [95% CI 0.98, 1.17]; I2 = 8%) and >=50% change in lesion count in the acupuncture group was not statistically different to the pharmacotherapy group (RR: 1.07 [95% CI 0.98, 1.17]; I2 = 50%). Conclusions: While caution should be exercised due to quality of the included studies, acupuncture and auricular acupressure were not statistically different to guideline recommended treatments but were with fewer side effects and may be a treatment option. Future trials should address the methodological weaknesses and meet standard reporting requirements stipulated in STRICTA. PMID- 29721026 TI - Association of Ozone with 5-Fluorouracil and Cisplatin in Regulation of Human Colon Cancer Cell Viability: In Vitro Anti-Inflammatory Properties of Ozone in Colon Cancer Cells Exposed to Lipopolysaccharides. AB - Introduction: Ozone therapy is an effective medical treatment for different diseases like mucositis, psoriasis, acute pain, neurovascular diseases, and cancer. The aim of this study is based on the association of different ozone concentration with 5-fluorouracil and cisplatin in human colon cancer cell (HT29 cell line) in order to investigate possible anticancer synergistic effects. Methods: HT29 cells were incubated with ozone at different concentration ranging from 10 up to 50 MUg/ml at different incubation time alone or in combination with cisplatin and 5-fluorouracil. Cell viability was performed by using a modified MTT method. Anti-inflammatory studies were conducted incubating HT29 with or without 20, 30, or 50 MUg/ml of ozone before exposure to lipopolysaccharides. Results: Ozone alone has a time and concentration dependent cytotoxicity against HT29 cells (IC50 at 24 h: 30 MUg/ml). Association of ozone with drugs increases cytotoxicity by 15-20%. Preincubation of ozone at 50 MUg/ml decreases IL-8, IL-6, and IL-1beta production by 50, 56, and 70%, respectively, compared to untreated cells. Conclusion: These results indicated that ozone could be useful in colon cancer management in combination with 5-fluorouracil and cisplatin with significant inhibition of cytokines having a central role in colon cancer cell survival and chemoresistance. PMID- 29721028 TI - Tauroursodeoxycholic Acid Protects Nucleus Pulposus Cells from Compression Induced Apoptosis and Necroptosis via Inhibiting Endoplasmic Reticulum Stress. AB - Tauroursodeoxycholic acid (TUDCA) is a kind of hydrophilic bile acid, which could protect cells from death via inhibiting endoplasmic reticulum (ER) stress. However, the role of TUDCA in compression-induced intervertebral disc degeneration (IVDD) has not been elucidated. Here, we used a previously described device to mimic in vivo compression conditions. NP cells treated with DMSO or TUDCA were exposed to compression. Then, cell viability, morphology, and apoptosis were detected. Furthermore, apoptosis-related proteins and necroptosis markers were detected too. To investigate the specific cytoprotective mechanisms of TUDCA in IVDD, we detected the ER morphology by electron microscopy. In addition, the ER stress of nucleus pulposus (NP) cells was quantitatively evaluated by analyzing the level of ER-stress-associated proteins. Our results revealed that TUDCA could protect NP cells from excessive compression-induced death by reducing the apoptosis and necroptosis. In addition, ER stress is involved in pathogenesis of IVDD induced by excessive compression and plays a detrimental role. TUDCA exerts its protective functions by inhibiting ER stress. In conclusion, TUDCA could protect NP cells from compression-induced death, which suggested that treatment by TUDCA may be a potential method to retard IVDD. PMID- 29721029 TI - Effects of Modified Sanzi Yangqin Decoction on Tyrosine Phosphorylation of IRS-1 in Skeletal Muscle of Type 2 Diabetic Rats. AB - This study aimed to investigate the effect of Modified Sanzi Yangqin Decoction on tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) in skeletal muscle of type 2 diabetic rats. The rat model of type 2 diabetes was induced by high-fat diet and multiple low-dose streptozotocin injections. Diabetic model rats were randomly divided into 5 groups: the model control group, the metformin group, and Modified Sanzi Yangqin Decoction groups of low, medium, and high doses. OGTT was conducted every two weeks during treatment period. At the end of the treatment, the fasting blood glucose (FBG) level and the fasting C-peptide level were measured to calculate insulin resistance index. The levels of IRS-1, p IRS-1(Tyr895), and protein tyrosine phosphates 1B (PTP1B) in skeletal muscle were also measured. Modified Sanzi Yangqin Decoction significantly reduced the FBG level, increased the fasting C-peptide level, and lowered the insulin resistance index in type 2 diabetic rats. It also significantly increased the protein level of p-IRS-1(Tyr895) and reduced the PTP1B protein level in skeletal muscle of type 2 diabetic rats. Modified Sanzi Yangqin Decoction increases tyrosine phosphorylation of IRS-1 in skeletal muscle of type 2 diabetic rats, which results from the increase of p-IRS-1(Tyr895) protein and is related to the suppression of PTP1B protein. PMID- 29721031 TI - House sparrows' (Passer domesticus) behaviour in a novel environment is modulated by social context and familiarity in a sex-specific manner. AB - Background: Exploratory behaviour is one of the best-investigated behavioural traits. However, little is known about how differences in familiarity, i.e. in the knowledge and previous experience with a companion can influence the exploration of a novel environment. However, to our knowledge, such a critical feature of the social environment has never been the target of a study relating it to exploratory behaviour in birds. Here we examined if familiarity with a conspecific could affect behavioural responses of individuals confronted with a novel environment. We recorded the latency to land on the ground, latency to feed, time spent feeding and number of sectors visited of 48 female and 48 male house sparrows (Passer domesticus) in an indoor aviary in three contexts: alone (individual context), with an unfamiliar and with a familiar same-sex companion. Results: House sparrows landed sooner on the ground when in the familiar context than when in the individual context. Birds in unfamiliar pairs followed each other less than familiar birds, but this difference diminished with time spent exploring. Moreover, males and females differed in their behavioural responses in the unfamiliar context. Females with a familiar companion landed sooner than when they were paired with an unfamiliar conspecific, whereas only the presence of a companion but not familiarity reduced males latency to land on the ground. Finally, when considering the unfamiliar context males had shorter latencies to forage and thus spent more time eating than females. Conclusions: The presence or absence of a companion and its familiarity with the focal individual influenced differently the behavioural responses of male and female house sparrows in a novel environment. As house sparrows are strongly sociable, the influence of the social environment is likely to be of paramount importance to understand the selective pressures acting on them, particularly in recently colonized areas with ephemeral food sources. Our results shed light on the complex influence that the social environment has on the behavioural responses of a cosmopolitan bird. PMID- 29721032 TI - Iron physiological requirements in Chinese adults assessed by the stable isotope labeling technique. AB - Background: Iron is a kind of essential trace mineral in the human body, while the studies on its physiological requirement are very limited recently, especially in China. And most studies were performed with the radioisotope tracer technique, which was harmful to health. This study aimed to first get the value of iron physiological requirements in Chinese adults assessed by the stable isotope labeling technique. Methods: Forty-four eligible young Chinese healthy adults were randomly recruited from the Bethune Military Medical College (Shijiazhuang, Hebei, China) between January 2010 and March 2011, and 19 subjects were included in the final data analysis. After adaptive diets and observation, subjects received 58Fe intravenously. The baseline venous blood sample and general information were collected on day 0. Venous blood samples were also collected on day 14, 30, 60, 100, 120, 150, 240, 330, 425, 515, 605, 767, 1155, respectively. The blood samples were acid digested by a Microwave Digestion System and then analyzed by the MC-ICP-MS and Atomic Absorption Spectroscopy to get the abundance of Fe isotopes and the total iron concentration respectively. The circulation rate (the proportion of blood iron to whole body iron) could be calculated by the intake amount, background content and the peak isotope content. When the abundance changed stably, the iron physiological requirement could be calculated by the iron loss in a period of time. Results: The abundance of 58Fe reached its peak on day 14, and changed stably from day 425. The average circulation rate was 84%, with no significance difference between the 2 genders. The mean iron requirement in females was 1101.68 MUg/d, and the mean requirement adjusted by body weight was 20.69 MUg/kg.d. For males, the mean iron requirement was 959.9 MUg/d, and the requirement adjusted by body weight was 14.04 MUg/kg.d. Conclusion: Our study has obtained the data about the iron physiological requirements of Chinese adults using stable isotope labeling technique, which could provide the basis for adjusting iron DRIs of Chinese people in the future. Trial registration: The trial was registered at the Chinese Clinical Trial Registry (No: ChiCTR-TRC-09000581). PMID- 29721030 TI - Meta-populational demes constitute a reservoir for large MHC allele diversity in wild house mice (Mus musculus). AB - Background: The MHC class I and II loci mediate the adaptive immune response and belong to the most polymorphic loci in vertebrate genomes. In fact, the number of different alleles in a given species is often so large that it remains a challenge to provide an evolutionary model that can fully account for this. Results: We provide here a general survey of MHC allele numbers in house mouse populations and two sub-species (M. m. domesticus and M. m. musculus) for H2 class I D and K, as well as class II A and E loci. Between 50 and 90% of the detected different sequences constitute new alleles, confirming that the discovery of new alleles is indeed far from complete. House mice live in separate demes with small effective population sizes, factors that were proposed to reduce, rather than enhance the possibility for the maintenance of many different alleles. To specifically investigate the occurrence of alleles within demes, we focused on the class II H2-Aa and H2-Eb exon 2 alleles in nine demes of M. m. domesticus from two different geographic regions. We find on the one hand a group of alleles that occur in different sampling regions and three quarters of these are also found in both sub-species. On the other hand, the larger group of different alleles (56%) occurs only in one of the regions and most of these (89%) only in single demes. We show that most of these region-specific alleles have apparently arisen through recombination and/or partial gene conversion from already existing alleles. Conclusions: Demes can act as sources of alleles that outnumber the set of alleles that are shared across the species range. These findings support the reservoir model proposed for human MHC diversity, which states that large pools of rare MHC allele variants are continuously generated by neutral mutational mechanisms. Given that these can become important in the defense against newly emerging pathogens, the reservoir model complements the selection based models for MHC diversity and explains why the exceptional diversity exists. PMID- 29721033 TI - Child and adolescent mental health services: longitudinal data sheds light on current policy for psychological interventions in the community. AB - Purpose: The purpose of this paper is to expand upon policy implications of a recent study assessing adolescent mental health service contact and subsequent depression. Design/methodology/approach: Review of related evidence from academic and grey literature. Findings: Studies assessing the role of mental health services in reducing mental disorder during adolescence are sparse, and even prevalence figures for adolescent mental disorders are out-of-date. Adolescent mental health service contact rates are shown to fall concurrent with budgetary decreases. School-based counselling is highlighted as an important source of help that may be at risk of being cut. Increased training of General Practitioners and school counsellors is needed to improve efficiency in specialist Child and Adolescent Mental Health Services (CAMHS). Practical implications: Longitudinal studies of young people's mental health should include mental health service usage and its relationship with subsequent mental health outcomes. Social implications: Funding cuts to CAMHS must be avoided, school-based counselling must be protected, and service referrers should be better trained. Originality/value: This paper highlights the need for increased CAMHS data, sustained funding, and improved training for this vital service. PMID- 29721034 TI - Mental Wellbeing Impact Assessment (MWIA) in the workplace. AB - Purpose: The Mental Wellbeing Impact Assessment (MWIA) is an evidence-based tool that guides decision makers, such as policy makers and service managers, about the potential impacts of a new programme or policy change. It was initially used in urban regeneration but has subsequently been used in housing, children's centres and education. The purpose of this paper is to report, for the first time, on the strengths and weaknesses of using the MWIA in the workplace. Design/methodology/approach: Feedback was collected from staff who participated in stakeholder workshops as part of the MWIA process at two different public sector organisations. Findings: The MWIA can be used as an effective workplace assessment tool and is valuable as both a diagnostic tool and as an intervention in its own right. The MWIA generates tailored action plans focussed on addressing the organisation or team-specific issues. The weaknesses of the MWIA in the workplace are mainly focussed around management cooperation and commitment to the process which should be screened for prior to engaging in the full stakeholder workshop. Originality/value: This is the first report of MWIA's use in the workplace but suggests that it is a useful tool which can be used to support workplace wellbeing, especially in relation to a policy or organisational change. Further studies should be carried out to fully understand the impact of the MWIA in the workplace. PMID- 29721036 TI - How migrants keep Italian families Italian: badanti and the private care of older people. AB - Purpose: The purpose of this paper is to describe how migration affects the care of older people in Italy. Design/methodology/approach: The paper is based on anthropological fieldwork by one of the authors. This consisted of in-depth interviews with 20 "badanti" (migrant caregivers), with relatives of older people and with social workers in the city of Verona, Italy. It further included extensive study of secondary materials on the topic of migrant care of older people. Findings: Badanti, Italian families and older people find themselves locked in an uneasy contract: badanti because they are exploited and often unable to find better, formal employment; Italian families because they are aware that they fail to render their moral duty to their aged parents and grandparents; and older people because they feel neglected and maltreated by their children. Yet the three parties also rely on each other to make the best of a precarious situation. The relationship between badanti and Italian elderly highlights the contradictions within Italian politics on care and migration. This case study shows how migrants help Italian families to hold on to the tradition of family care for ageing parents. Research limitations/implications: The small sample of badanti and families provides a detailed and profound insight of the complexity of elder care in Italy but does not allow generalisation for developments in the country as a whole. Practical implications: Policy makers should take notice of the indispensability of informal migrant care in present day Italy. Originality/value: The originality of the paper lies in the in-depth conversations with badanti and in the way in which elderly care is contextualised in the Italian tradition of care and present day politics. PMID- 29721035 TI - "What is the score?" A review of football-based public mental health interventions. AB - Purpose: Football exercise as an intervention for people with severe mental health problems has seen an increasing interest in the past years. To date, there is, however, no comprehensive review of the empirical evidence regarding the effectiveness of these interventions. In this review, the authors have comprised the research findings from the peer-review literature as well as the theoretical approaches to football exercise as an adjunct treatment. This overview will be informative to everybody who is planning to develop a football intervention for this population as well as to the people who are preparing evaluation studies that measure the effectiveness of such interventions. The paper aims to discuss these issues. Design/methodology/approach: The authors identified research papers in the peer-review literature that feature empirical findings on "football interventions" that aim at improving mental and/or physical well-being in participants with mental health problems. The authors are using the term "football intervention" here in the sense that the participants actively took part in football exercise, so the authors excluded studies in which the participants only watched football or used football as a metaphor to discuss mental health problems. In a table, the authors indicate the definition of the target group, targeted outcomes, measured outcomes, form and frequency of the intervention as well as the research method(s). Findings: The authors identified 16 studies on 15 projects. The majority of studies were qualitative and had positive findings in which the participants reported increased well-being and connectedness, elevation of symptoms and improved physical well-being. The outcomes of the quantitative studies, however, were mixed with some results suggesting that not all intended goals were achieved. There seems to be a need for more quantitative studies to triangulate the qualitative findings. Interestingly, most interventions take place in the UK. Many studies fail to give detailed methodological information and often the aims of the interventions are vague or not stated at all. Research limitations/implications: Due to the heterogeneity of the studies and relative scarcity of evaluation projects on football interventions for people with mental health problems, the authors could not conduct an in-depth systematic review. Furthermore, the information on methods was often unsatisfying and despite efforts to get more detailed input from the authors of cited papers, those gaps could not always be filled. Instead of coming up with a crystal-clear summary of whether and how football interventions work for everybody, topics were identified that need to be addressed in the planning of interventions, in evaluation studies, in implementation efforts and in the theoretical discourse. Practical implications: This paper constitutes a helpful overview for everybody who is interested in the theoretical background of football interventions for people with mental health problems, for people who are planning to develop respective interventions, for researchers who engage in evaluation projects that look into the effectiveness of football interventions (or similar exercise interventions) as well as for the people who are interested in how football interventions can be implemented. This paper is likely to make a contribution to the advancement of alternative exercise interventions that aim at improving mental, physical and social health in people with mental health problems. Social implications: This paper will help putting the topic of football interventions (and similar, alternative exercise interventions) further up on the public health agenda by providing an overview of the empirical evidence at hand and by specifying advantages of the approach as well as pointing out actions that need to be taken to make football a recognised, evidence based and viable option for adjunct mental health treatment that is attractive to potential participants as well as funders as well as to the potential participants. Originality/value: There is no comprehensive summary to date that provides a (reasonably) systematic overview of empirical findings for football interventions for people with MH problems. Furthermore, the literature on the theoretical background of these interventions has been somewhat patchy and heterogonous. This paper aims at filling both these gaps and identifies the issues that need to be covered in the planning of respective interventions and evaluations. This paper will be useful to everybody who is developing football interventions (or similar alternative adjunct exercise interventions), who is conducting evaluation research in this area and who is interested in the implementation of football interventions. PMID- 29721037 TI - Automated Segmentation Methods of Drusen to Diagnose Age-Related Macular Degeneration Screening in Retinal Images. AB - Existing drusen measurement is difficult to use in clinic because it requires a lot of time and effort for visual inspection. In order to resolve this problem, we propose an automatic drusen detection method to help clinical diagnosis of age related macular degeneration. First, we changed the fundus image to a green channel and extracted the ROI of the macular area based on the optic disk. Next, we detected the candidate group using the difference image of the median filter within the ROI. We also segmented vessels and removed them from the image. Finally, we detected the drusen through Renyi's entropy threshold algorithm. We performed comparisons and statistical analysis between the manual detection results and automatic detection results for 30 cases in order to verify validity. As a result, the average sensitivity was 93.37% (80.95%~100%) and the average DSC was 0.73 (0.3~0.98). In addition, the value of the ICC was 0.984 (CI: 0.967~0.993, p < 0.01), showing the high reliability of the proposed automatic method. We expect that the automatic drusen detection helps clinicians to improve the diagnostic performance in the detection of drusen on fundus image. PMID- 29721038 TI - Consequences of cyberbullying behaviour in working life: The mediating roles of social support and social organisational climate. AB - Purpose: The purpose of this paper is to explore health- and work-related outcomes of cyberbullying behaviour and the potential mediating role of social organisational climate, social support from colleagues and social support from superiors. Design/methodology/approach: Altogether 3,371 respondents participated in a questionnaire study. Findings: The results of this study indicate that social organisational climate can have a mediating role in the relationship between cyberbullying behaviour and health, well-being, work engagement and intention to quit. Contrary to earlier face-to-face bullying research, the current study showed that cyberbullying behaviour had stronger indirect than direct relationships to health, well-being, work engagement and intention to quit. Practical implications: Communication through digital devices in work life is becoming more prevalent, which in turn increases the risk for cyberbullying behaviour. Organisations need therefore to develop occupational health and safety policies concerning the use of digital communication and social media in order to prevent cyberbullying behaviour and its negative consequences. Originality/value: Cyberbullying behaviour among working adults is a relatively unexplored phenomenon and therefore this study makes valuable contribution to the research field. PMID- 29721039 TI - Workplace policies and practices promoting physical activity across England: What is commonly used and what works? AB - Purpose: Many adults fail to achieve sufficient moderate-to-vigorous physical activity (MVPA). The purpose of this paper is to understand how workplaces most effectively promote physical activity for the benefit of public health. Design/methodology/approach: Data were collected via two online surveys. First, 3,360 adults employed at 308 workplaces across England self-reported their MVPA, activity status at work and frequency of journeys made through active commuting. From this sample, 588 participants reported on the policies and practices used in their workplace to promote physical activity. Factor and cluster analysis identified common practice. Regression models examined the association between the workplace factors and engagement in physical activity behaviours. Findings: Five factors emerged: targeting active travel, availability of information about physical activity outside the workplace, facilities and onsite opportunities, sedentary behaviour, and information about physical activity within the workplace. Further, five clusters were identified to illustrate how the factors are typically being utilised by workplaces across England. Commonly used practices related to promoting active travel, reducing sedentary behaviour and the provision of information but these practices were not associated with meeting MVPA guidelines. The provision of facilities and onsite exercise classes was associated with the most positive physical activity behaviour outcomes; however, these structures were rarely evident in workplaces. Originality/value: Previous research has identified a number of efficacious actions for promoting physical activity in the workplace, however, research investigating which of these are likely to be acceptable to worksites is limited. The present study is the first to combine these two important aspects. Five common profiles of promoting physical activity in worksites across England were identified and related to physical activity outcomes. Guidance is given to workplace managers to enable them to maximise the resources they have for the greatest gains in employee health. Where feasible, facilities, and classes should be provided to achieve the most positive outcomes. PMID- 29721040 TI - Methane-yielding microbial communities processing lactate-rich substrates: a piece of the anaerobic digestion puzzle. AB - Background: Anaerobic digestion, whose final products are methane and carbon dioxide, ensures energy flow and circulation of matter in ecosystems. This naturally occurring process is used for the production of renewable energy from biomass. Lactate, a common product of acidic fermentation, is a key intermediate in anaerobic digestion of biomass in the environment and biogas plants. Effective utilization of lactate has been observed in many experimental approaches used to study anaerobic digestion. Interestingly, anaerobic lactate oxidation and lactate oxidizers as a physiological group in methane-yielding microbial communities have not received enough attention in the context of the acetogenic step of anaerobic digestion. This study focuses on metabolic transformation of lactate during the acetogenic and methanogenic steps of anaerobic digestion in methane-yielding bioreactors. Results: Methane-yielding microbial communities instead of pure cultures of acetate producers were used to process artificial lactate-rich media to methane and carbon dioxide in up-flow anaerobic sludge blanket reactors. The media imitated the mixture of acidic products found in anaerobic environments/digesters where lactate fermentation dominates in acidogenesis. Effective utilization of lactate and biogas production was observed. 16S rRNA profiling was used to examine the selected methane-yielding communities. Among Archaea present in the bioreactors, the order Methanosarcinales predominated. The acetoclastic pathway of methane formation was further confirmed by analysis of the stable carbon isotope composition of methane and carbon dioxide. The domain Bacteria was represented by Bacteroidetes, Firmicutes, Proteobacteria, Synergistetes, Actinobacteria, Spirochaetes, Tenericutes, Caldithrix, Verrucomicrobia, Thermotogae, Chloroflexi, Nitrospirae, and Cyanobacteria. Available genome sequences of species and/or genera identified in the microbial communities were searched for genes encoding the lactate-oxidizing metabolic machinery homologous to those of Acetobacterium woodii and Desulfovibrio vulgaris. Furthermore, genes for enzymes of the reductive acetyl-CoA pathway were present in the microbial communities. Conclusions: The results indicate that lactate is oxidized mainly to acetate during the acetogenic step of AD and this comprises the acetotrophic pathway of methanogenesis. The genes for lactate utilization under anaerobic conditions are widespread in the domain Bacteria. Lactate oxidation to the substrates for methanogens is the most energetically attractive process in comparison to butyrate, propionate, or ethanol oxidation. PMID- 29721041 TI - Verteporfin inhibits papillary thyroid cancer cells proliferation and cell cycle through ERK1/2 signaling pathway. AB - Verteporfin, a FDA approved second-generation photosensitizer, has been demonstrated to have anticancer activity in various tumors, but not including papillary thyroid cancer (PTC). In current pre-clinical pilot study, we investigate the effect of verteporfin on proliferation, apoptosis, cell cycle and tumor growth of PTC. Our results indicate verteporfin attenuates cell proliferation, arrests cell cycle in G2/S phase and induces apoptosis of PTC cells. Moreover, treatment of verteporfin dramatically suppresses tumor growth from PTC cells in xenograft mouse model. We further illustrate that exposure to MEK inhibitor U0126 inactivates phosphorylation of ERK1/2 and MEK in verteporfin treated PTC cells. These data suggest verteporfin exhibits inhibitory effect on PTC cells proliferation and cell cycle partially via ERK1/2 signalling pathway, which strongly encourages the further application of verteporfin in the treatment against PTC. PMID- 29721042 TI - A Real-World Data Study to Evaluate Treatment Patterns, Clinical Characteristics and Survival Outcomes for First- and Second-Line Treatment in Locally Advanced and Metastatic Urothelial Cancer Patients in Germany. AB - Background: Worldwide, urothelial carcinoma (UC) is a common cause of morbidity and mortality. In particular, the incidence of bladder cancer varies widely across Europe; Germany has the ninth highest international age-standardized incidence. For advanced UC or metastatic UC (mUC), platinum-based combination chemotherapy is the standard first-line (1L) treatment; however, there is wide heterogeneity of second-line (2L) treatments, ranging from vinflunine in parts of Europe to taxanes and other agents elsewhere in Europe, in the United States and globally. Limited data exist on treatment patterns and outcomes in patients with advanced UC or mUC in the routine clinical setting in Germany. The objective of this study was to describe clinical characteristics, treatment patterns and subsequent outcomes in this setting. Methods: This retrospective observational cohort analysis evaluated 1L and 2L treatment patterns and overall survival (OS) in patients aged >=18 years with advanced UC or mUC (T4b, N2-3 and/or M1) at office-based urology and academic as well as nonacademic urology clinics throughout Germany between 1 November 2009 and 2 June 2016. Data were obtained through the GermanOncology database and additional treatment centers using similar electronic case report forms. Results: Among the 435 patients included in the analysis, 435 received 1L treatment and 125 received 2L treatment. Median age at start of 1L treatment was 69 years, 75% of patients were male, 75% were current or ex-smokers, 15% had hemoglobin <10 g/dL and 44% had creatinine clearance<60 mL/min/1.73; proportions were similar with 2L treatment. Cardiovascular disease was the most frequently reported comorbidity (65%), followed by diabetes (19%). Most patients (77%) received 1L platinum-based combination treatment (most commonly gemcitabine + cisplatin, 83%). Of those treated with 2L treatment, 66% received a single agent (most commonly vinflunine, 71%). Median OS (95% CI) with 1L treatment was 16.1 months (13.7-19.2) overall and 17.7 months (14.4-24.2) with 1L cisplatin + gemcitabine. In the 1L setting, 12-month OS was 61%, 24-month OS was 39% and 36-month OS was 26%. Median (95% CI) OS with 2L treatment was 9.2 months (5.5-11.6) overall and 5.9 months (4.1-12.6) with 2L vinflunine. In the 2L setting, OS rates for the same time periods were 40%, 22% and 8%, respectively. Median (95% CI) progression-free survival was 7 months (6.4-8.1) and 4 months (3.0-4.8), respectively, in the 1L and 2L settings. Objective response rates were 34% in the 1L setting and 14% in the 2L setting. No difference in OS by sex or smoking status was noted. Patients with or without renal impairment had a 12-month OS of 54% or 69%, respectively. OS at 12 months was 63% among patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 to 1 vs 53% among patients with an ECOG PS of >=2. Cox regression analysis found no difference in OS between vinflunine and other 2L treatments (P = 0.69). Conclusions: This study provides a contemporary multicenter assessment of real-world treatment patterns and outcomes among palliatively treated patients with UC in Germany. The findings were generally consistent with the poor treatment outcomes observed globally, underscoring the need for effective 1L and 2L treatment for advanced UC or mUC. PMID- 29721043 TI - TRIM32 promotes proliferation and confers chemoresistance to breast cancer cells through activation of the NF-kappaB pathway. AB - Dysregulation of TRIM32 has been implicated in several human cancers, however, its clinical significance and biological function in breast cancer have not been investigated. Using immunohistochemistry, we found that TRIM32 expression is upregulated in breast cancer tissues and that it correlates with advanced stage and poor prognosis. TRIM32 is also overexpressed in 4/7 breast cancer cell lines. CCK8 and colony formation assays showed that TRIM32 depletion inhibited proliferation and colony formation in the T47D cell line, while TRIM32 overexpression promoted MCF-7 cell growth and colony formation. Cell viability and Annexin V/PI staining demonstrated that TRIM32 maintained breast cancer cell survival and reduced apoptosis rate when cells were treated with cisplatin. Western blot analysis demonstrated that TRIM32 overexpression resulted in an upregulation of p-IkappaB, p-p65, cIAP1, and cIAP2 and a downregulation of p21 and p27 in MCF-7 cells. TRIM32 depletion in T47D cells demonstrated the opposite results, suggesting that TRIM32 may activate the NF-kappaB pathway. The NF-kappaB inhibitor BAY 11-7082 blocked the effects of TRIM32 on cisplatin resistance and cIAP1/2 protein regulation. Taken together, the present study demonstrates that TRIM32 downregulates p21/p27 and upregulates IAP family proteins to facilitate breast cancer cell growth and inhibit drug-induced apoptosis, possibly through the NF-kappaB signaling pathway. PMID- 29721044 TI - Anti-Cervical Cancer Role of Matrine, Oxymatrine and Sophora Flavescens Alkaloid Gels and its Mechanism. AB - Background: Cervical cancer is one of the leading severe malignancies throughout the world. Sophra flavescens alkaloid (SFA) gels, a compound Traditional Chinese Medicine, has been clinically used in China for many years. Its individual active ingredients are matrine and oxymatrine, which has been showed that they can restrain primary tumorigenesis, while the underlying molecular mechanisms of SFA gels in cervical cancer cells remain unclear. Methods: To detect the effect of SFA gels and its active ingredients, CCK-8 assay and colony assay were used on cervical cancer cells proliferation. Transwell assay was used to detect cancer cell migration. Apoptosis and cell cycle arrest were used to detect whether SFA gels effect the cervical cancer cells proliferation. Western blot was used to detect whether SFA gels regulate the cervical cancer cells via the suppression of AKT/mTOR signaling pathway. Results: SFA gels can restrain cervical cancer cell proliferation, inhibit metastasis, induce cell cycle arrest in G2/M phase, induce cellular apoptosis through stimulation of Bax and E-cadherin, and suppression of Bcl-2, cyclin A, MMP2. Further study shows that SFA gels may regulate the cervical cancer cells via the suppression of AKT/mTOR signaling pathway. Conclusions: SFA gels, like its active ingredients, can restrain cervical cancer cells proliferation, suppress cervical cancer cell migration, induce the apoptosis and cell cycle arrest in cervical cancer cells. SFA gels may be a potential anti-tumor therapeutic agent for treating cervical cancer. PMID- 29721045 TI - Long-Term Outcome of Oxaliplatin and Capecitabine (XELOX) Concomitant with Neoadjuvant Radiotherapy and Extended to the Resting Period in High Risk Locally Advanced Rectal Cancer. AB - Purpose: This study aimed at investigating the long-term outcomes of oxaliplatin and capecitabine (XELOX) administered concurrently with preoperative radiation and extended to the resting period in patients with high-risk locally advanced rectal cancer (LARC). Methods: From January 2010 to December 2013, 45 patients were recruited. Study treatment consisted two cycles of XELOX regimen concomitant with preoperative radiation and then followed by an additional cycle of XELOX regimen between completion of neoadjuvant radiotherapy and surgery. Disease-free survival (DFS) time and overall survival (OS) time were analyzed. Results: The median follow-up was 51 months. Twelve (26.7%) patients developed local recurrence or distant metastasis, including 10 (22.2%) patients developing distant metastasis only, 1 (2.2%) patient local recurrence only, and 1 (2.2%) patient both local recurrence and distant metastasis. The estimated 3-year DFS and OS was 75.5% (95% CI, 63.0%-88.0%) and 88.6% (95% CI, 98.0%-79.2%), respectively. Receiving adjuvant chemotherapy was a significant predictor for DFS, with hazard ratio 0.24 (95% CI: 0.08-0.74). Conclusion: This intensified strategy with oxaliplatin and capecitabine (XELOX) administered concomitantly with neoadjuvant radiotherapy and then extended to the resting period in high risk LARC patients is efficient. The long-term outcome is promising. Further study of this strategy is warranted. PMID- 29721046 TI - Association between the SNPs of the TOB1 gene and gastric cancer risk in the Chinese Han population of northeast China. AB - The TOB1 (ErbB-2,1) gene is an anti-proliferative factor that has the potential to regulate cell growth and encodes a member of the transducer of erbB-2/B-cell translocation gene protein. The association between the polymorphisms of the TOB1 gene and gastric cancer (GC) risk is still unclear. In this study, 506 GC cases and 548 healthy controls (HCs) were collected to evaluate the association between the eleven SNPs (rs35220381, rs12950561, rs7221352, rs61482741, rs9303568, rs34700818, rs12949115, rs9903822, rs12601477, rs11656976 and rs4626) of the TOB1 gene and GC risk in the population of northeast China. The results showed that there were significant associations of haplotype GCCTTGC, haplotype ATCTTGG, and haplotype GCCACGC with GC risk (P < 0.05, P < 0.001, and P <0.001, respectively). The association between rs12601477 GA+AA genotypes and GC risk was significant among individuals older than 58 (adjusted OR=1.53, 95% CI=1.05-2.22, P< 0.05). The association between rs4626 AG+GG genotypes and GC risk was significant among individuals older than 58 (adjusted OR=1.54, 95% CI = 1.03-2.28, P<0.05). The rs34700818 CT+TT genotypes were associated with a significantly increased risk of T3-T4 (CT+TT vs CC, adjusted OR=1.71, 95% CI= 1.01-2.88, P<0.05) and TNM stage II (CT+TT vs CC, adjusted OR=2.40, 95% CI =1.27-4.52, P<0.01). The rs61482741 CG+GG genotypes were also associated with a significantly increased risk of T3-T4 (CG+GG vs CC, adjusted OR=1.71, 95% CI = 1.01-2.88, P<0.05) and TNM stage II (CG+GG vs CC, adjusted OR=2.40, 95% CI=1.27-4.52, P<0.01). The results suggest that four SNPs (rs12601477, rs4626, rs34700818 and rs61482741) of the TOB1 gene play an important role in the occurrence and development of GC in the Chinese Han population of northeast China. PMID- 29721047 TI - Oxytocin inhibits ovarian cancer metastasis by repressing the expression of MMP-2 and VEGF. AB - Breastfeeding is associated with a decreased risk of ovarian cancer. However, the mechanism underlying this apparent clinical benefit is unknown. Oxytocin (OXT), a hypothalamic nonapetide, plays a crucial role in many reproductive and behavioural functions. In recent year, OXT acts as a growth regulator in many kind of tumor tissues, through the activation of a specific G-coupled transmembrane receptor, the oxytocin receptor (OXTR). OXT has been proved to inhibit the proliferation, migration and invasion of ovarian cancer SKOV3 cells in vitro. But, the underlying mechanisms remain unknown. Here, we found OXT inhibited proliferation, and critically migration and invasion of human ovarian cancer cells SKOV3 and A2780. Strikingly, OXT inhibited ovarian cancer metastasis by repressing the expressions of MMP-2 and VEGF. Moreover, OXT inhibited vascular endothelial cell tube formation by reducing the VEGF production from ovarian cancer cells. Our findings may provide a possible explanation for breastfeeding associated protective effects and suggest new therapeutic opportunities for ovarian cancer. PMID- 29721048 TI - Multiple Antigen Stimulating Cellular Therapy (MASCT) For Hepatocellular Carcinoma After Curative Treatment: A Retrospective Study. AB - Background & Aims: The prognosis of hepatocellular carcinoma (HCC) remains poor and available treatment options are limited. This retrospective study evaluated the efficacy of Multiple Antigen Stimulating Cell Therapy (MASCT) as an adjuvant therapy for the treatment of HCC after curative treatment. Methods: Patients who underwent HCC curative treatments were classified into two groups: the MASCT group, in which patients received MASCT treatment after curative treatment (n = 47), and the control group, in which patients did not receive any treatment after curative treatment (n = 99). Patients who received >= 5 courses of MASCT treatment before recurrence or death (n = 26) were further stratified into a subgroup (multiple-course MASCT group) for analysis. The primary endpoint was overall survival (OS). The secondary endpoints were disease-free survival (DFS) and safety. Results: Kaplan-Meier analysis showed no statistically significant difference in OS between the MASCT group and the control group (P = 0.132), nor in DFS (P = 0.310) (median: 36.17 vs. 24.27 months). However, when comparing the multiple-course MASCT treated group to the control group, Kaplan-Meier analysis showed a significant difference in OS (P = 0.011), but not in DFS (P = 0.104) (median: 47.10 vs. 24.27 months). The overall incidences of treatment-related adverse events in the MASCT group and control group were 14.89% (7/47) and 19.19% (19/99), respectively. No MASCT treatment-related serious adverse events were reported. Conclusions: Although the MASCT group was not associated with significantly longer OS or DFS, the multiple-course MASCT group showed significantly improved overall survival after curative treatment, and the treatment procedures were well-tolerated. Multiple-course MASCT may therefore provide another choice for patients with HCC after curative treatment. PMID- 29721049 TI - Protein arginine methyltransferase 8 gene enhances the colon cancer stem cell (CSC) function by upregulating the pluripotency transcription factor. AB - Objective: Cancer stem cells play a crucial role in tumor multidrug resistance and metastasis, which can produce heterogeneous tumor cells and have self-renewal ability. The related literature reported that PRMT8 was overexpressed in tumor stem cells and pluripotent stem cells. However, it's unclear how PRMT8 acts on the stemness of colon tumor cells. This study is designed to detect functions by transfecting with PRMT8 plasmid to colon cancer cells. Methods: In this study we investigated colon cancer cell sphere and its differential expression of PRMT8 compared with colon cancer cells grown by static adherence. RKO Sphere formation assay was used to identify CSCs and verified PRMT8 and pluripotent transcription factors SOX2, OCT4, Nanog expression level in colon cell sphere. Colon cancer cell HCT-8 and RKO up-regulated PRMT8 expression by being transfected with PRMT8 plasmid to evaluate its effect on the stemness of colon tumor cell. Results: In RKO cell sphere, stem cell surface marker CD133 and CD44 were highly expressed. And PRMT8, SOX2, OCT4 and Nanog were also highly expressed in RKO cell sphere. After PRMT8 was up-regulated in HCT-8 and RKO cells, flow cytometry proved that PRMT8 group cells have a significant increase of the side population (SP) cells with cancer stem cell surface markers CD133 and CD44. And overexpression of PRMT8 in HCT-8 and RKO cells facilitated their aggressive traits, which contained proliferation, invasion and migration, as well as leading to their drug resistance. PRMT8 may play a role in colon cancer stem cells (CSC) through its regulation of pluripotent transcription factors, such as Nanog Homeobox (Nanog), octamer-binding transcription factor-4 (Oct4) and SRY-related high-mobility group(HMG)-box protein-2 (Sox2). Conclusion: PRMT8 may promote the formation of colon cancer stem cells and, thus, be considered a potential therapeutic target for the treatment of malignant colon tumor. PMID- 29721050 TI - Secretory Clusterin Mediates Oxaliplatin Resistance via the Gadd45a/PI3K/Akt Signaling Pathway in Hepatocellular Carcinoma. AB - Purpose: Systemic therapy has often been used for patients with advanced hepatocellular carcinoma (HCC). However, due to drug resistance, the use of cytotoxic chemotherapy in the treatment of patients with advanced HCC has typically demonstrated low response rates. Secretory clusterin (sCLU) is expressed in aggressive late-stage tumors and associated with resistance to chemotherapy, including that in HCC cases. The present research aimed to investigate the biological role of sCLU in HCC. Methods: sCLU expression in HCC and normal tissues was examined using immunohistochemical staining, followed by analysis of the correlation between sCLU expression and clinical indicators. In addition, the role and internal mechanism of sCLU in cell proliferation and apoptosis were investigated in HCC cells. Results: sCLU expression was significantly upregulated in HCC tissues; and was associated with histological grade and poor overall survival. The levels of sCLU were significantly increased in Bel7402, SMMC7721 and resistant HCC cells (Bel7404-OR). Inhibiting the activity of sCLU enhanced the chemosensitivity of Bel7402 and SMMC7721 cells. Downregulation of sCLU could increase the expression of Gadd45a in HCC cells. Overexpression of sCLU contributed to drug resistance in Bel7402, SMMC7721 and Bel7404-OR cells; whereas, overexpression of Gadd45a alone overcame drug resistance in the cells above. No significant expression changes of sCLU and Gadd45a were observed in HCC cells after the interference of a selective inhibitor of the PI3K/Akt signaling pathway. However, regulation of the expression of Gadd45a could influence the phosphorylation level of Akt; and further regulate the expression of Bcl-2 and Bax proteins involved in the mitochondrial apoptosis pathways. Conclusions: The results demonstrate that sCLU/Gadd45a/PI3K/Akt signaling represents a novel pathway that could regulate drug resistance in a one-way manner in HCC cells. PMID- 29721051 TI - LncRNA PCAT1 and its genetic variant rs1902432 are associated with prostate cancer risk. AB - Emerging evidence has showed that lncRNAs and trait-associated loci in lncRNAs play a crucial role in the progression of cancer including prostate cancer (PCa).This study aimed to investigate the molecular mechanisms of lncRNA PCAT1 involved in PCa development and its genetic variant associated with PCa risk. We applied cell proliferation and apoptosis assays to assess the effect of PCAT1 on PCa cell phenotypes. In addition, the genome-wide profiling of gene expression was assessed from three pairs of DU145 cells transfected with PCAT1 overexpression vector or negative control (NC) vector. Furthermore, a case control study was conducted to explore the associations of four tagging single nucleotide polymorphisms (tagSNPs) and PCa risk in 850 PCa cases and 860 cancer free controls. Our results showed that lncRNA PCAT1 promoted cell proliferation and inhibited cell apoptosis. Ingenuity pathway analysis (IPA) indicated that dysregulated mRNAs induced by overexpression of PCAT1 were primarily enriched in androgen-independent prostate tumor term and implicated in the disease and functions networks, such as cell death and survival, cell proliferation and gene expression. Besides, rs1902432 in PCAT1 was significantly associated with increased risk of PCa (Additive model: OR = 1.19, P = 0.014; Co-dominant model: CC vs. TT, OR = 1.45, P =0.012; Recessive model: CC vs. TT/CT, OR= 1.34, P = 0.027). This study suggests that PCAT1 may act as an oncogene through promoting cell proliferation and suppressing cell apoptosis in PCa development, and genetic variant in PCAT1 contributes to the susceptibility to PCa. PMID- 29721052 TI - Survival Outcomes for Patients with Surgical and Non-Surgical Treatments in Stages I-III Small-Cell Lung Cancer. AB - Objectives: Chemotherapy and radiation therapy are the standard treatments for patients with small-cell lung cancer (SCLC). However, recent studies suggest that patients with limited stage (I-III) SCLC may benefit from surgical treatment. This study was performed to evaluate the survival outcomes of surgery for stage I III SCLC. Methods: This analysis used data from the Surveillance, Epidemiology, and End Results (SEER) database. All stage I-III (excluding N3 and Nx) SCLC patients received a diagnosis between 2004 and 2014. Overall survival (OS) and lung cancer-specific survival (LCSS) were determined by Kaplan-Meier analysis and compared using the log-rank test. A Cox proportional hazard model identified relevant survival variables. Results: A total of 4,780 histologically confirmed patients were identified from the SEER database, comprising 1,018 patients (21.3%) with stage I disease; 295 (6.2%) with stage II; and 3,467 (72.5%) with stage III disease. Among all of the patients, 520 had been treated with surgery, the majority (n = 344; 66.2%) of whom had stage I disease. The hazard ratio (HR) for OS and LCSS, in patients who underwent surgery, according to stage were as follows: OS, 0.369 and LCSS, 0.335 in stage I; OS, 0.549 and LCSS, 0.506 in stage II; and OS, 0.477 and LCSS, 0.456 in stage III (all p < 0.001). Patients who underwent surgery had significantly better OS, and lobectomy was associated with the best outcome. Conclusions: Surgical resection was associated with significantly improved OS outcomes and should be considered in the management of stage I-III SCLC. PMID- 29721053 TI - Survivorship and Advocacy in Inflammatory Breast Cancer. AB - In February 2017, the Morgan Welch Inflammatory Breast Cancer (IBC) Research Program and Clinic hosted a scientific conference in Houston to commemorate the tenth anniversary of the opening of the first IBC-dedicated clinic in the world. Attendees included basic science researchers, clinicians who treat IBC, as well as patients and their caregivers. Several US-based and international IBC-focused nonprofit organizations were also represented. In this third paper from the conference, we report on the breakout session regarding survivorship and advocacy issues related to IBC, sharing an overview of the educational content presented and discussions regarding the future of IBC advocacy. Panelists focused on lymphedema research and clinical solutions, integrative medicine, and social work, with time provided for questions in small groups. IBC nonprofits that are leading advocacy efforts were introduced, and ways to become involved in these initiatives were discussed. Priorities for future advocacy and clinical care needs were also highlighted. In addition to summarizing these topics, we provide a suggested integrated IBC-specific plan of care that could be provided to the patient at the beginning of care and referred to throughout treatment and follow up. PMID- 29721054 TI - International Consensus on the Clinical Management of Inflammatory Breast Cancer from the Morgan Welch Inflammatory Breast Cancer Research Program 10th Anniversary Conference. AB - National and international experts in inflammatory breast cancer (IBC) from high volume centers treating IBC recently convened at the 10th Anniversary Conference of the Morgan Welch Inflammatory Breast Cancer Research Program at The University of Texas MD Anderson Cancer Center in Houston Texas. A consensus on the clinical management of patients with IBC was discussed, summarized, and subsequently reviewed. All participants at the conference (patients, advocates, researchers, trainees, and clinicians) were queried using the MDRing electronic survey on key management issues. A summary of the expert consensus and participant voting is presented. Bilateral breast and nodal evaluation, breast magnetic resonance imaging, positron emission tomography/computed tomography, and medical photographs were endorsed as optimal. Neoadjuvant systemic therapy, modified radical mastectomy and level I and II ipsilateral axillary node dissection, post mastectomy radiotherapy, adjuvant targeted therapy and hormonal therapy as indicated, and delayed reconstruction were agreed-upon fundamental premises of standard non-protocol-based treatment for IBC. Consideration for local-regional therapy in de novo stage IV IBC was endorsed to provide local control whenever feasible. Variation across centers and special circumstances were discussed. PMID- 29721056 TI - The Efficacy and Toxicity of Gefitinib in Treating Non-small Cell Lung Cancer: A Meta-analysis of 19 Randomized Clinical Trials. AB - Background: This meta-analysis evaluated the efficacy and toxicity of gefitinib with other commonly used drugs in different treatment settings and epidermal growth factor receptor (EGFR) mutation status. Methods: Nineteen randomize clinical trials (RCTs) of 6,554 patients with NSCLC were pooled in this meta analysis by random-effects or fixed-effects model, whichever is proper. Results: In first-line therapy, gefitinib showed higher odds than chemotherapy (OR = 2.19, 95% CI: 1.20-4.01), but less than other targeted therapies (OR = 0.58, 95% CI: 0.38-0.88). As non-first-line therapy, the overall survival (OS) and progression free survival (PFS) were similar between gefitinib and controls (HR = 1.00, 95% CI: 0.93-1.08; HR = 0.91, 95% CI: 0.72-1.15), respectively. With the regard to toxicity, the incidences of dry skin, rash and pruritus were higher in gefitinib compared with controls, while gefitinib significantly reduced the incidence of hematologic toxicity. Conclusion: Gefitinib might be more efficient than chemotherapy, but less efficient than other targeted therapies in ORR, especially in EGFR mutation-positive patients. Gefitinib can decrease the odds of hematologic toxicity compared to controls. Future studies, especially those with EGFR mutation-positive patients, will be needed to confirm our findings. PMID- 29721055 TI - Genetic Variants Within MTORC1 Genes Predict Gastric Cancer Prognosis in Chinese Populations. AB - Objective: Mammalian target of rapamycin complex 1 (mTORC1) plays an important role in maintaining proper cellular functions in gastric cancer (GC). Previous studies demonstrated genetic variants within mTORC1 genes were associated with GC risk. However, no studies reported the associations between genetic variants within mTORC1 genes and GC prognosis. Herein, we firstly assessed the associations of genetic variants of mTORC1 genes with overall survival (OS) of GC in Chinese populations. Methods: We genotyped eight single nucleotide polymorphisms (SNPs) in mTORC1 genes (i.e., rs2536 T>C and rs1883965 G>A for mTOR, rs3160 T>C and rs26865 A>G for MLST8, rs3751934 C>A, rs1062935 T>C, rs3751932 T>C and rs12602885 G>A for RPTOR) by the TaqMan method in 197 Chinese GC patients who had surgical resection in Xinhua Hospital. We conducted Kaplan Meier survival plots and Cox hazards regression analysis to explore the associations of these SNPs with OS. Results: The single-locus analysis indicated that RPTOR rs1062935 T>C was associated with an increased risk of poor GC prognosis (CC vs. TT/TC: adjusted Hazard ratio (HR) = 1.71, 95% confidence interval (CI) = 1.04-2.82). The combined analysis of all eight SNPs showed that patients with more than three risk genotypes significantly increased risk of death (adjusted HR = 2.44, 95% CI = 1.30-4.58), when compared to those with three or less risk genotypes. Conclusions: Our findings indicated that genetic variants within mTORC1 genes may predict GC prognosis in Chinese populations. The results need to be validated in future studies with larger sample sizes. PMID- 29721057 TI - Survival Contradiction Between Stage IIA and Stage IIIA Rectal Cancer: A Retrospective Study. AB - Background: When compared with patients harboring stage IIB and stage IIC disease, those with stage IIIA colorectal cancer have a better prognosis. We aimed to compare the cause-specific survival (CSS) of the patients with stage IIA rectal cancer with that of the patients with stage IIIA rectal cancer. Methods: Data analyzed about patients with stage IIA and stage IIIA rectal cancer was from the US Surveillance, Epidemiology, and End Results (SEER) database. We then validated the results using data derived from Fudan University Shanghai Cancer Center (FUSCC). Results: A total of 16,788 patients (13,551 staged IIA and 3,237 staged IIIA) were identified in SEER database. A multivariate analysis manifested that patients with stage IIIA disease were more likely to have a better CSS (HR 0.894, 95% CI 0.816-0.979, p=0.016) compared with patients with stage IIA rectal cancer. In the subgroup of patients whose number of lymph nodes harvested (LNH) <12, multivariate analysis signified that patients with stage IIIA disease were more prone to have favorable CSS (HR 0.805, 95% CI 0.719-0.901, p<0.001) compared with patients with stage IIA rectal cancer. In LNH>=12 subgroup, the Kaplan-Meier analysis revealed no significant difference between patients experiencing stage IIA and IIIA rectal cancer (p=0.618). Validation of data from FUSCC proved that patients with stage IIIA rectal cancer were more inclined to have better CSS (HR 0.407, 95% CI 0.187-0.885, p=0.019) in comparison to those with stage IIA rectal cancer. Specifically, in LNH<12 subgroup, the survival outcomes of stage IIIA patients were significantly better than that of the stage IIA patients (p=0.019), while there was no statistical significance between these two stages in the subgroup of patients with LNH>=12 (p=0.180). Conclusions: Patients with stage IIA rectal cancer have poorer CSS than patients with stage IIIA rectal cancer, particularly when inadequate lymph nodes are harvested. PMID- 29721058 TI - EGFR Target Therapy Combined with Gemox for Advanced Biliary Tract Cancers: a Meta-analysis based on RCTs. AB - Background: Controversy exists regarding whether EGFR-targeted therapy combined with GEMOX (gemcitabine and oxaliplatin) provides additional benefits over GEMOX alone for biliary tract cancer patients. Therefore, this meta-analysis of randomized controlled trials (RCTs) was performed to assess the efficacy and safety of the GEMOX + EGFR-targeted regimen, and subgroup analysis was conducted to identify groups that might benefit from targeted therapy. Methods: The PubMed, Cochrane Library, and ClinicalTrials.gov registries were searched for published studies. Hazard ratios (HRs) for progression-free survival (PFS) and overall survival (OS) were pooled using a fix-effect model. Risk-ratios (RRs) were used to analyse the objective response rate (ORR) and adverse events. Results: Four RCTs were assessed. GEMOX + EGFR-targeted therapy significantly improved PFS (HR = 0.80, 95% CI 0.66-0.94, P = 0.03) and was associated with a better ORR (RR = 1.52, 95% CI 1.13-2.04, P = <0.01), whereas the TKI group achieved a better ORR in subgroup analysis. Patients with cholangiocarcinoma responded well to the GEMOX + EGFR-targeted regimen, leading to a better ORR (RR = 1.78, 95% CI 1.21 2.61, P = <0.01). Unfortunately, PFS benefits were not translated into OS benefits (HR = 0.92, 95% CI 0.75-1.08, P = 0.39). Conclusion: GEMOX + EGFR targeted therapy is a considerable and tolerable treatment option for patients with advanced BTCs, improving both PFS and ORR but not prolonging patient survival. Patients with cholangiocarcinoma would benefit the most from EGFR targeted therapy. PMID- 29721059 TI - Cancer Stem Cells are Regulated by STAT3 Signalling in Wilms Tumour. AB - The survival rates associated with Wilms tumour (WT) remain dismal despite advancements in detection and treatment strategies. Cancer stem cells (CSCs) are correlated with the initiation, recurrence and metastasis of tumours, but its impact on Wilms cancer stem cell (WCSC) maintenance remains unclear. In this study, CD133+ cells were successfully isolated from a single-cell suspension of the G401 Wilms tumour cell line using magnetic activated cell sorting (MACS). Signal transducers and activators of transcription 3 (STAT3) has been implicated in tumorigenesis, but its contribution to the metastatic progression of WCSCs has not been investigated. Here, we show that STAT3 is overexpressed in WCSCs. Activation of STAT3 in WCSCs initiated a forward feedback loop that was responsible for mediating the aggressive malignant character of Wilms tumour cells in vitro and in vivo. Treatment of CD133+ cells with stattic, a STAT3 inhibitor, also inhibited tumour formation and progression in xenograft animal models in vivo. Collectively, these studies revealed a critical role of STAT3 signalling in WCSC proliferation and motility and a role for CD133 in cancer stem like cell function, providing evidence for CD133 as a potential therapeutic target in Wilms tumour. PMID- 29721060 TI - Shared liver-like transcriptional characteristics in liver metastases and corresponding primary colorectal tumors. AB - Background & Aims: Primary tumors of colorectal carcinoma (CRC) with liver metastasis might gain some liver-specific characteristics to adapt the liver micro-environment. This study aims to reveal potential liver-like transcriptional characteristics associated with the liver metastasis in primary colorectal carcinoma. Methods: Among the genes up-regulated in normal liver tissues versus normal colorectal tissues, we identified "liver-specific" genes whose expression levels ranked among the bottom 10% ("unexpressed") of all measured genes in both normal colorectal tissues and primary colorectal tumors without metastasis. These liver-specific genes were investigated for their expressions in both the primary tumors and the corresponding liver metastases of seven primary CRC patients with liver metastasis using microdissected samples. Results: Among the 3958 genes detected to be up-regulated in normal liver tissues versus normal colorectal tissues, we identified 12 liver-specific genes and found two of them, ANGPTL3 and CFHR5, were unexpressed in microdissected primary colorectal tumors without metastasis but expressed in both microdissected liver metastases and corresponding primary colorectal tumors (Fisher's exact test, P < 0.05). Genes co expressed with ANGPTL3 and CFHR5 were significantly enriched in metabolism pathways characterizing liver tissues, including "starch and sucrose metabolism" and "drug metabolism-cytochrome P450". Conclusions: For primary CRC with liver metastasis, both the liver metastases and corresponding primary colorectal tumors may express some liver-specific genes which may help the tumor cells adapt the liver micro-environment. PMID- 29721061 TI - The Interaction of Smoking with Gene Polymorphisms on Four Digestive Cancers: A Systematic Review and Meta-Analysis. AB - The main purpose of this study was to perform a meta-analysis to assess the interaction between smoking and nine genes (GSTM1, GSTT1, GSTP1, CYP1A1, NAT2, SULT1A1, hOGG1, XRCC1 and p53) on colorectal cancer, gastric cancer, liver cancer and oesophageal cancer. Published articles from the PubMed, ISI and EMBASE databases were retrieved. A total of 67 case-control studies or nested case control studies were identified for the analysis. The pooled jodds ratio (OR) with 95% confidence interval (CI) was calculated using the random effect model. The overall study showed that the GSTM1 polymorphism was associated with the risk of the four digestive cancers among Asian population (OR 1.284, 95% CI: 1.122 1.470, p: 0). Subgroup analyses by cancer site showed that GSTM1 null genotype increased the gastric cancer risk in total population (OR 1.335, 95% CI: 1.145 1.556, p: 0). However, the association of GSTM1 null genotype with the oesophageal cancer risk was found in smokers (OR 1.382, 95% CI: 1.009-1.894, p:0.044), but not in non-smokers (OR 1.250, 95% CI: 0.826-1.891, p:0.290). Moreover, smokers with the CYP1A1 IIe462Val polymorphism were at an increased cancer risk in Asian population (OR=1.585, 95% CI 1.029-2.442, p: 0.037). None of the other gene-smoking interactions was observed in the above cancers. This meta analysis reveals two potential gene-smoking interactions, one is between smoking and GSTM1 on oesophageal cancer, and the other is between smoking and CYP1A1 IIe462Val on the four cancers in Asian population. Future studies need to be conducted to verify the conclusions. PMID- 29721062 TI - Expression of Minichromosome Maintenance Proteins (MCM) and Cancer Prognosis: A meta-analysis. AB - Minichromosome maintenance proteins (MCM) played a critical role in replication and cell cycle progression. However, their prognostic roles in cancer remain controversial. Therefore, we performed a meta-analysis to investigate the prognostic value of MCMs in cancers. Totally 31 eligible articles with 7653 cancer patients were included in this meta-analysis. We evaluated the relationship between MCMs expression and overall survival (OS) in various cancer patients by using pooled hazard ratios (HRs) and risk ratios (RRs) with 95% confidence intervals (CIs). The meta-analysis showed that carriers with high expression of MCM5 and MCM7 were significantly associated with short OS for pooled HR (HR=1.04, 95% CI=1.01-1.08, P=0.020, HR=1.78, 95% CI=1.04-3.02, P=0.035, respectively). For pooled RR, individuals with increased MCM2 and MCM7 expression were significantly correlated with poor OS (RR=2.30, 95% CI=1.14-4.63, P=0.019; RR=3.52, 95% CI=2.01-6.18, P<0.001, respectively). The findings suggest that high expression of MCM2, MCM5 and MCM7 might serve as predictive biomarkers for poor prognosis in cancers. PMID- 29721063 TI - Photoacoustic Imaging as an Early Biomarker of Radio Therapeutic Efficacy in Head and Neck Cancer. AB - The negative impact of tumor hypoxia on radiotherapeutic efficacy is well recognized. However, an easy to use, reliable imaging method for assessment of tumor oxygenation in routine clinical practice remains elusive. Photoacoustic imaging (PAI) is a relatively new imaging technique that utilizes a combination of light and ultrasound (US) to enable functional imaging of tumor hemodynamic characteristics in vivo. Several clinical trials are currently evaluating the utility of PAI in cancer detection for breast, thyroid, and prostate cancer. Here, we evaluated the potential of PAI for rapid, label-free, non-invasive quantification of tumor oxygenation as a biomarker of radiation response in head and neck cancer. Methods: Studies were performed human papilloma virus- positive (HPV+) and -negative (HPV-) patient-derived xenograft (PDX) models of head and neck squamous cell carcinoma (HNSCC). PAI was utilized for longitudinal assessment of tumor hemodynamics (oxygenation saturation and hemoglobin concentration) before, during and after fractionated radiation therapy (fRT). Imaging datasets were correlated with histologic measures of vascularity (CD31), DNA damage (phosphorylated gammaH2AX) and statistical modeling of tumor growth. Results: A differential response to fRT was observed between HPV+ and HPV- xenografts. Temporal changes in tumor hemodynamics (oxygen saturation and hemoglobin concentration) measured by PAI showed significant association with treatment outcomes. PAI-based changes in oxygen saturation were detected within days after initiation of fRT prior to detectable change in tumor volume, highlighting the potential of PAI to serve as an early biomarker of therapeutic efficacy. Consistent with PAI results, immunohistochemical staining of vascularity (CD31) and DNA damage (phosphorylated gammaH2AX) revealed distinct patterns of response in HPV+ and HPV- xenografts. Conclusion: Collectively, our observations demonstrate the utility of PAI for temporal mapping of tumor hemodynamics and the value of PAI read-outs as surrogate measures of radiation response in HNSCC. PMID- 29721064 TI - Coronary Serum Exosomes Derived from Patients with Myocardial Ischemia Regulate Angiogenesis through the miR-939-mediated Nitric Oxide Signaling Pathway. AB - Rationale: Angiogenesis is a crucial step towards tissue repair and regeneration after ischemia. The role of circulating exosomes in angiogenic signal transduction has not been well elucidated. Thus, this study aims to investigate the effects of coronary serum exosomes from patients with myocardial ischemia on angiogenesis and to elucidate the underlying mechanisms. Methods and Results: The patients were enrolled according to the inclusion and exclusion criteria. Coronary blood was obtained from the angiography catheter. Serum exosomes were purified and characterized by their specific morphology and surface markers. In vitro analysis showed that compared to exosomes from healthy controls (con-Exo), exosomes from patients with myocardial ischemia (isc-Exo) enhanced endothelial cell proliferation, migration and tube formation. In a mouse hind-limb ischemia model, blood perfusion and histological staining demonstrated that isc-Exo significantly promoted blood flow recovery and enhanced neovascularization compared to con-Exo. Further, we revealed that cardiomyocytes, but not cardiac fibroblasts or endothelial cells, were initiated to release exosomes under ischemic stress; cardiomyocytes might be the source of bioactive exosomes in coronary serum. In addition, microarray analysis indicated that miR-939-5p was significantly down-regulated in isc-Exo. By knockdown and overexpression analyses, we found that miR-939-5p regulated angiogenesis by targeting iNOS. miR 939-5p inhibited both iNOS's expression and its activity, attenuated endothelial NO production, and eventually impaired angiogenesis. Conclusions: Exosomes derived from patients with myocardial ischemia promote angiogenesis via the miR 939-iNOS-NO pathway. Our study highlights that coronary serum exosomes serve as an important angiogenic messenger in patients suffering from myocardial ischemia. PMID- 29721065 TI - Development of a novel albumin-based and maleimidopropionic acid-conjugated peptide with prolonged half-life and increased in vivo anti-tumor efficacy. AB - Angiogenesis plays a critical role in tumor aggressiveness, and a lot of anti angiogenic agents have been used in clinical therapy. The therapeutic efficacy of peptides are generally restricted by the short in vivo life-time, thus, we were interested in developing a novel albumin-based and maleimidopropionic acid conjugated peptide to prolong the half-life and improve the anti-tumor effect. Methods: We developed a peptide F56 with a maleimidopropionic acid (MPA) at the C terminal (denoted as F56-CM), which allows immediate and irreversible conjugation with serum albumin. Biological property and anti-tumor activity of F56-CM were evaluated in vitro and in vivo. Results: We showed that F56-CM reduced migration and tube formation of endothelial cells in vitro and inhibited the generation of subintestinal vessels (SIV) in zebrafish embryos in vivo. F56-CM inhibited vascular endothelial growth factor (VEGF) induced phosphorylation of VEGFR1 and activation of the PI3K-AKT axis. Furthermore, F56-CM rapidly conjugated with albumin upon intravenous injection and extended the biological half-life of F56 from 0.4249 h to 6.967 h in rats. Compared with F56, F56-CM exhibited stronger anti-tumor activity on both BGC-823 gastric cancer and HT-29 colon cancer xenografts in nude mice, and the statistical difference was remarkable. More significantly, the efficacy of F56-CM inhibiting lung metastasis of BGC-823 cells was also better than that of F56. The inhibition rates were 62.1% and 78.9% for F56 and F56-CM respectively when administrated every day, and 43.8% and 63.1% when administrated every four days at equal dose. Conclusions: Taken together, our results demonstrated that F56-CM has considerable potential for cancer therapy. PMID- 29721066 TI - Amino Acid Uptake Measured by [18F]AFETP Increases in Response to Arginine Starvation in ASS1-Deficient Sarcomas. AB - Rational: In a subset of cancers, arginine auxotrophy occurs due to the loss of expression of argininosuccinate synthetase 1 (ASS1). This loss of ASS1 expression makes cancers sensitive to arginine starvation that is induced by PEGylated arginine deiminase (ADI-PEG20). Although ADI-PEG20 treatment is effective, it does have important limitations. Arginine starvation is only beneficial in patients with cancers that are ASS1-deficient. Also, these tumors may metabolically reprogram to express ASS1, transforming them from an auxotrophic phenotype to a prototrophic phenotype and thus rendering ADI-PEG20 ineffective. Due to these limitations of ADI-PEG20 treatment and the potential for developing resistance, non-invasive tools to monitor sensitivity to arginine starvation are needed. Methods: Within this study, we assess the utility of a novel positron emission tomography (PET) tracer to determine sarcomas reliant on extracellular arginine for survival by measuring changes in amino acid transport in arginine auxotrophic sarcoma cells treated with ADI-PEG20. The uptake of the 18F-labeled histidine analogue, (S)-2-amino-3-[1-(2-[18F]fluoroethyl)-1H-[1,2,3]triazol-4 yl]propanoic acid (AFETP), was assessed in vitro and in vivo using human-derived sarcoma cell lines. In addition, we examined the expression and localization of cationic amino acid transporters in response to arginine starvation with ADI PEG20. Results: In vitro studies revealed that in response to ADI-PEG20 treatment, arginine auxotrophs increase the uptake of L-[3H]arginine and [18F]AFETP due to an increase in the expression and localization to the plasma membrane of the cationic amino acid transporter CAT-1. Furthermore, in vivo PET imaging studies in mice with arginine-dependent osteosarcoma xenografts showed increased [18F]AFETP uptake in tumors 4 days after ADI-PEG20 treatment compared to baseline. Conclusion: CAT-1 transporters localizes to the plasma membrane as a result of arginine starvation with ADI-PEG20 in ASS1-deficient tumor cells and provides a mechanism for using cationic amino acid transport substrates such as [18F]AFETP for identifying tumors susceptible to ADI-PEG20 treatment though non invasive PET imaging techniques. These findings indicate that [18F]AFETP-PET may be suitable for the early detection of tumor response to arginine depletion due to ADI-PEG20 treatment. PMID- 29721067 TI - 3D Imaging and Quantitative Analysis of Vascular Networks: A Comparison of Ultramicroscopy and Micro-Computed Tomography. AB - RATIONALE: Classic histology is the gold standard for vascular network imaging and analysis. The method however is laborious and prone to artefacts. Here, the suitability of ultramicroscopy (UM) and micro-computed tomography (CT) was studied to establish potential alternatives to histology. METHODS: The vasculature of murine organs (kidney, heart and atherosclerotic carotid arteries) was visualized using conventional 2D microscopy, 3D light sheet ultramicroscopy (UM) and micro-CT. Moreover, spheroid-based human endothelial cell vessel formation in mice was quantified. Fluorescently labeled Isolectin GS-IB4 A647 was used for in vivo labeling of vasculature for UM analysis, and analyses were performed ex vivo after sample preparation. For CT imaging, animals were perfused postmortem with radiopaque contrast agent. RESULTS: Using UM imaging, 3D vascular network information could be obtained in samples of animals receiving in vivo injection of the fluorescently labeled Isolectin GS-IB4. Resolution was sufficient to measure single endothelial cell integration into capillaries in the spheroid-based matrigel plug assay. Because of the selective staining of the endothelium, imaging of larger vessels yielded less favorable results. Using micro-CT or even nano-CT, imaging of capillaries was impossible due to insufficient X-ray absorption and thus insufficient signal-to-noise ratio. Identification of lumen in murine arteries using micro-CT was in contrast superior to UM. CONCLUSION: UM and micro-CT are two complementary techniques. Whereas UM is ideal for imaging and especially quantifying capillary networks and arterioles, larger vascular structures are easier and faster to quantify and visualize using micro-CT. 3D information of both techniques is superior to 2D histology. UM and micro-CT together may open a new field of clinical pathology diagnosis. PMID- 29721068 TI - Enhancement of Cancer-Specific Protoporphyrin IX Fluorescence by Targeting Oncogenic Ras/MEK Pathway. AB - Protoporphyrin IX (PpIX) is an endogenous fluorescent molecule that selectively accumulates in cancer cells treated with the heme precursor 5-aminolevulinic acid (5-ALA). This cancer-specific accumulation of PpIX is used to distinguish tumor from normal tissues in fluorescence-guided surgery (FGS) and to destroy cancer cells by photodynamic therapy (PDT). In this study, we demonstrate that oncogenic Ras/mitogen-activated protein kinase kinase (MEK) pathway can modulate PpIX accumulation in cancer cells. Methods: To identify Ras downstream elements involved in PpIX accumulation, chemical inhibitors were used. To demonstrate the increase of PpIX accumulation by MEK inhibition, different human normal and cancer cell lines, BALB/c mice bearing mammary 4T1 tumors and athymic nude mice bearing human tumors were used. To identify the mechanisms of PpIX regulation by MEK, biochemical and molecular biological experiments were conducted. Results: Inhibition of one of the Ras downstream elements, MEK, promoted PpIX accumulation in cancer cells treated with 5-ALA, while inhibitors against other Ras downstream elements did not. Increased PpIX accumulation with MEK inhibition was observed in different types of human cancer cell lines, but not in normal cell lines. We identified two independent cellular mechanisms that underlie this effect in cancer cells. MEK inhibition reduced PpIX efflux from cancer cells by decreasing the expression level of ATP binding cassette subfamily B member 1 (ABCB1) transporter. In addition, the activity of ferrochelatase (FECH), the enzyme responsible for converting PpIX to heme, was reduced by MEK inhibition. Finally, we found that in vivo treatment with MEK inhibitors increased PpIX accumulation (2.2- to 2.4-fold) within mammary 4T1 tumors in BALB/c mice injected with 5-ALA without any change in normal organs. Similar results were also observed in a human tumor xenograft model. Conclusion: Our study demonstrates that inhibition of oncogenic Ras/MEK significantly enhances PpIX accumulation in vitro and in vivo in a cancer-specific manner. Thus, suppressing the Ras/MEK pathway may be a viable strategy to selectively intensify PpIX fluorescence in cancer cells and improve its clinical applications in FGS. PMID- 29721071 TI - Adipocyte-Derived Exosomal MiR-27a Induces Insulin Resistance in Skeletal Muscle Through Repression of PPARgamma. AB - The mechanism by which adipocyte-derived endocrine factors promote insulin resistance in skeletal muscle are not fully understood. MiR-27a is highly expressed in sera of obese individuals with prediabetes and T2DM, and mainly derived by adipose tissues. Thus, miR-27a secreted into circulation by adipose tissue may regulate insulin resistance in skeletal muscle. Methods: The association between miR-27a and insulin resistance in skeletal muscle was determined in obese children, high-fat diet-induced miR-27a knockdown obese mice, db/db mice and C2C12 cells overexpressing miR-27a. The crosstalk mediated by exosomal miR-27a between adipose tissue and skeletal muscle was determined in C2C12 cells incubated with conditioned medium prepared from palmitate-treated 3T3 L1 adipocytes. Results: We showed that serum miR-27a level correlated positively with obesity and insulin resistance in obese children, and that elevated serum miR-27a levels correlated with insulin resistance in leptin receptor-deficient db/db mice, and with obesity and insulin resistance in high-fat diet-fed C57BL/6J mice. MiR-27a released from adipocytes of high-fat diet-fed C57BL/6J mice was associated with triglyceride accumulation. MiR-27a derived from these adipocytes induced insulin resistance in C2C12 skeletal muscle cells through miR-27a mediated repression of PPARgamma and its downstream genes involved in the development of obesity. Conclusions: These results identify a novel crosstalk signaling pathway between adipose tissue and skeletal muscle in the development of insulin resistance, and indicate that adipose tissue-derived miR-27a may play a key role in the development of obesity-triggered insulin resistance in skeletal muscle. PMID- 29721069 TI - Release of MicroRNAs into Body Fluids from Ten Organs of Mice Exposed to Cigarette Smoke. AB - Purpose: MicroRNAs are small non-coding RNAs that regulate gene expression, thereby playing a role in a variety of physiological and pathophysiological states. Exposure to cigarette smoke extensively downregulates microRNA expression in pulmonary cells of mice, rats, and humans. Cellular microRNAs are released into body fluids, but a poor parallelism was previously observed between lung microRNAs and circulating microRNAs. The purpose of the present study was to validate the application of this epigenetic biomarker by using less invasive collection procedures. Experimental design: Using microarray analyses, we measured 1135 microRNAs in 10 organs and 3 body fluids of mice that were either unexposed or exposed to mainstream cigarette smoke for up to 8 weeks. The results obtained with selected miRNAs were validated by qPCR. Results: The lung was the main target affected by smoke (190 dysregulated miRNAs), followed by skeletal muscle (180), liver (138), blood serum (109), kidney (96), spleen (89), stomach (36), heart (33), bronchoalveolar lavage fluid (32), urine (27), urinary bladder (12), colon (5), and brain (0). Skeletal muscle, kidney, and lung were the most important sources of smoke-altered microRNAs in blood serum, urine, and bronchoalveolar lavage fluid, respectively. Conclusions: microRNA expression analysis was able to identify target organs after just 8 weeks of exposure to smoke, well before the occurrence of any detectable histopathological alteration. The present translational study validates the use of body fluid microRNAs as biomarkers applicable to human biomonitoring for mechanistic studies, diagnostic purposes, preventive medicine, and therapeutic strategies. PMID- 29721070 TI - Tumor-targeted Dual-modality Imaging to Improve Intraoperative Visualization of Clear Cell Renal Cell Carcinoma: A First in Man Study. AB - Intraoperative imaging with antibodies labeled with both a radionuclide for initial guidance and a near-infrared dye for adequate tumor delineation may overcome the main limitation of fluorescence imaging: the limited penetration depth of light in biological tissue. In this study, we demonstrate the feasibility and safety of intraoperative dual-modality imaging with the carbonic anhydrase IX (CAIX)-targeting antibody 111In-DOTA-girentuximab-IRDye800CW in clear cell renal cell carcinoma (ccRCC) patients. Methods: A phase I protein dose escalation study was performed in patients with a primary renal mass who were scheduled for surgery. 111In-DOTA-girentuximab-IRDye800CW (5, 10, 30, or 50 mg, n=3 ccRCC patients per dose level) was administered intravenously and after 4 days SPECT/CT imaging was performed. Seven days after antibody injection, surgery was performed with the use of a gamma probe and near-infrared fluorescence camera. Results: In total, fifteen patients were included (12 ccRCC, 3 CAIX negative tumors). No study-related serious adverse events were observed. All ccRCC were visualized by SPECT/CT and localized by intraoperative gamma probe detection (mean tumor-to-normal kidney (T:N) ratio 2.5 +/- 0.8), while the T:N ratio was 1.0 +/- 0.1 in CAIX-negative tumors. ccRCC were hyperfluorescent at all protein doses and fluorescence imaging could be used for intraoperative tumor delineation, assessment of the surgical cavity and detection of (positive) surgical margins. The radiosignal was crucial for tumor localization in case of overlying fat tissue. Conclusion: This first in man study shows that tumor targeted dual-modality imaging using 111In-DOTA-girentuximab-IRDye800CW is safe and can be used for intraoperative guidance of ccRCC resection. PMID- 29721073 TI - OVOL2 links stemness and metastasis via fine-tuning epithelial-mesenchymal transition in nasopharyngeal carcinoma. AB - Rationale: Metastasis is the leading cause of disease-related death among patients with nasopharyngeal carcinoma (NPC). Mounting evidence suggest that epithelial-mesenchymal transition (EMT) is crucial for cancer cells to acquire metastatic ability. In this study, we aim to clarify the extent to which EMT is involved in various cancer properties and identify novel markers for predicting the prognosis of NPC patients. Methods: Two cellular models derived from the same NPC cell line with distinct metastasis ability were used for microarray analysis to identify key transcriptional factors that drive metastasis. Cell migration and invasion were analyzed by wound healing and Transwell analysis. Lung metatasis was determined by tail vein injection assay. Cancer stemness was analyzed using colony formation and xenograft assay. The EMT extent was evaluated using immunoblotting, RT-qPCR and immunofluorescence of EMT markers. The value of OVOL2 in prognosis was determined by immunohistochemistry in NPC biopsies. Results: OVOL2 was the most significantly down-regulated EMT transcription factor (EMT-TF) in cellular models of NPC metatasis. Low levels of OVOL2 were associated with poor overall survival of NPC patients and the reduced expression is partly due to promoter methylation and epithelial dedifferentiation. Knockout of OVOL2 in epithelial-like NPC cells partially activates EMT program and significantly promotes cancer stemness and metastatic phenotypes. Conversely, ectopically expression of OVOL2 in mesenchymal-like cells leads to a partial transition to an epithelial phenotype and reduced malignancy. Reversing EMT by depleting ZEB1, a major target of OVOL2, does not eliminate the stemness advantage of OVOL2 deficient cells but does reduce their invasion capacity. A comparison of subpopulations at different stages of EMT revealed that the extent of EMT is positively correlated with metastasis and drug resistance; however, only the intermediate EMT state is associated with cancer stemness. Conclusion: Distinct from other canonical EMT-TFs, OVOL2 only exhibits modest effect on EMT but has a strong impact on both metastasis and tumorigenesis. Therefore, OVOL2 could serve as a prognostic indicator for cancer patients. PMID- 29721072 TI - Glucocorticoids Inhibit Oncogenic RUNX1-ETO in Acute Myeloid Leukemia with Chromosome Translocation t(8;21). AB - Acute myeloid leukemia (AML) is a major blood cancer with poor prognosis. New therapies are needed to target oncogene-driven leukemia stem cells, which account for relapse and resistance. Chromosome translocation t(8;21), which produces RUNX1-ETO (R-E) fusion oncoprotein, is found in ~13% AML. R-E dominance negatively inhibits global gene expression regulated by RUNX1, a master transcription factor for hematopoiesis, causing increased self-renewal and blocked cell differentiation of hematopoietic progenitor cells, and eventually leukemia initiation. Methods: Connectivity-Map followed by biological activity testing were used to identify candidate compounds that can inhibit R-E-mediated gene transcription. Molecular mechanistic studies were also performed. Results: Glucocorticoid drugs, such as betamethasone and dexamethasone, were found to exhibit potent and selective in vitro and in vivo activities against R-E leukemia, as well as strong synergy when combined with chemotherapeutics. Microarray analysis showed that treatment with glucocorticoids significantly inhibited R-E's activity and reactivated that of RUNX1. Such gene expression changes caused differentiation and apoptosis of R-E leukemia cells. Our studies also show a possible molecular mechanism for the targeted therapy. Upon treatment with a glucocorticoid drug, more glucocorticoid receptor (GR) was translocated into the nucleus and bound to DNA, including promoters of RUNX1 target genes. GR was found to associate with RUNX1, but not R-E. This interaction increased binding of RUNX1 to DNA and reduced that of R-E, shifting to a RUNX1 dominance. Conclusion: Glucocorticoid drugs represent a targeted therapy for AML with chromosome translocation t(8:21). Given their high activity, favorable human pharmacokinetics as well as synergy with chemotherapeutics, glucocorticoids could be clinically useful to treat R-E AML. PMID- 29721075 TI - Combining photothermal therapy and immunotherapy against melanoma by polydopamine coated Al2O3 nanoparticles. AB - Photothermal therapy (PTT) can be an effective antitumor therapy, but it may not completely eliminate tumor cells, leading to the risk of recurrence or metastasis. Here we describe nanocarriers that allow combination therapy involving PTT and immunotherapy. Nanocarriers are prepared by coating Al2O3 nanoparticles with non-toxic, biodegradable polydopamine, which shows high photothermal efficiency. A near-infrared laser irradiation can kill the majority of tumor tissues, resulting in the release of tumor-associated antigens. The Al2O3 within the nanoparticles, together with CpG, acts as an adjuvant to trigger robust cell-mediated immune responses that can help eliminate the residual tumor cells and reduce the risk of tumor recurrence. Methods: The characteristics and photothermal performance of polydopamine-coated Al2O3 nanoparticles were examined after one-step preparation. Then we studied their internalization, photothermal toxicity and immunostimulatory activity in vitro. For in vivo experiments, these nanocarriers were injected directly into B16F10 melanoma allografts in mice to ensure specific localization. After photothermal irradiation on day 0, mice were subcutaneously injected with CpG adjuvant on day 1, 3 and 5. Tumor volumes and number of living mice were recorded every two days. Moreover, various immune responses induced by our combined therapy were tested for mechanism research. Results: 50% of mice after our combined treatment successfully achieved the goal of tumor eradication, and survived for 120 days, which was the end point of the experiment. Mechanism studies demonstrated the combined therapy efficiently led to dendritic cell maturation, resulting in the secretion of antibodies and cytokines as well as the proliferation of splenocytes and lymphocytes for anti tumor immunotherapy. Conclusion: Taken together, these results demonstrated the promise of our combined photothermal therapy and immunotherapy for tumor shrinkage, which merited further research. PMID- 29721076 TI - OVOL2 in metastasis prevention in NPC. AB - Metastasis remains a critical - and largely elusive - target in the race to prevent cancer-related deaths. Such is true in nasopharyngeal carcinoma (NPC), where the presentation or development of metastatic disease is usually fatal. In this edition of Theranostics, Qi et al. demonstrate a critical role of the zinc finger transcription factor, OVOL2, in suppressing metastasis and maintaining an epithelial phenotype. These data add to the depth of understanding of the metastatic program in NPC, and may eventually lead to a druggable target in late stage NPC. PMID- 29721074 TI - Polyamine-Targeting Gefitinib Prodrug and its Near-Infrared Fluorescent Theranostic Derivative for Monitoring Drug Delivery and Lung Cancer Therapy. AB - The therapy of non-small-cell lung cancer (NSCLC) is challenging because of poor prognosis. There are urgent demands for targeting anti-tumor drugs with reliable efficacy and clear pharmacokinetics. Methods: We designed and synthesized an active tumor-targeting prodrug for the precision therapy of NSCLC. The prodrug polyamine analog Gefitinib (PPG) was derived from the conjugation between a tumor targeting ligand polyamine analog (PA) and an epidermal growth factor receptor tyrosine kinase inhibitor Gefitinib via a cleavable disulfide linker. Furthermore, the integration of the near-infrared azo-BODIPY fluorophore into the structure of the prodrug PPG yielded an activatable fluorescent theranostics (TPG), which could be used to monitor the in real-time delivery of prodrug PPG and initiate precise medicine in vivo. Results: PPG efficiently delivered the anti-tumor drug to cancer cells and reduced the serious side effects of the drug to normal cells, thereby increasing the potent of the anti-tumor drug. PPG was not only efficacious for killing Gefitinib-sensitive PC9 cells, but also for inhibiting the growth of Gefitinib-resistant H1650 cells. We provided a new evidence that the tumor-targeting PA ligand could inhibit the Akt pathway in H1650 cells, and had a synergistic effect with Gefitinib for anticancer efficacy. The in vivo results on nude mice bearing tumors of NSCLC cell lines demonstrated that PPG could target tumor lesions and had the expected therapeutic effects. Finally, we used TPG for fluorescent labeling of transbronchial lung biopsy (TBLB) specimens. The results indicated that TPG could provide rapid diagnosis for lung cancer within 4 h. Conclusion: Our work had identified that PPG could be effectively used for the treatment of Gefitinib-resistance NSCLC in cells and in mice models. The theranostic TPG emerged as a promising fluorescent imaging tool for the application in the therapy and diagnosis of NSCLC. PMID- 29721077 TI - Cyclin D1-mediated microRNA expression signature predicts breast cancer outcome. AB - Background: Genetic classification of breast cancer based on the coding mRNA suggests the evolution of distinct subtypes. Whether the non-coding genome is altered concordantly with the coding genome and the mechanism by which the cell cycle directly controls the non-coding genome is poorly understood. Methods: Herein, the miRNA signature maintained by endogenous cyclin D1 in human breast cancer cells was defined. In order to determine the clinical significance of the cyclin D1-mediated miRNA signature, we defined a miRNA expression superset from 459 breast cancer samples. We compared the coding and non-coding genome of breast cancer subtypes. Results: Hierarchical clustering of human breast cancers defined four distinct miRNA clusters (G1-G4) associated with distinguishable relapse-free survival by Kaplan-Meier analysis. The cyclin D1-regulated miRNA signature included several oncomirs, was conserved in multiple breast cancer cell lines, was associated with the G2 tumor miRNA cluster, ERalpha+ status, better outcome and activation of the Wnt pathway. The coding and non-coding genome were discordant within breast cancer subtypes. Seed elements for cyclin D1-regulated miRNA were identified in 63 genes of the Wnt signaling pathway including DKK. Cyclin D1 restrained DKK1 via the 3'UTR. In vivo studies using inducible transgenics confirmed cyclin D1 induces Wnt-dependent gene expression. Conclusion: The non-coding genome defines breast cancer subtypes that are discordant with their coding genome subtype suggesting distinct evolutionary drivers within the tumors. Cyclin D1 orchestrates expression of a miRNA signature that induces Wnt/beta-catenin signaling, therefore cyclin D1 serves both upstream and downstream of Wnt/beta-catenin signaling. PMID- 29721078 TI - Localized delivery of curcumin into brain with polysorbate 80-modified cerasomes by ultrasound-targeted microbubble destruction for improved Parkinson's disease therapy. AB - Rationale: Treatment for Parkinson's disease (PD) is challenged by the presence of the blood-brain barrier (BBB) that significantly limits the effective drug concentration in a patient's brain for therapeutic response throughout various stages of PD. Curcumin holds the potential for alpha-synuclein clearance to treat PD; however, its applications are still limited due to its low bioavailability and poor permeability through the BBB in a free form. Methods: Herein, this paper fabricated curcumin-loaded polysorbate 80-modified cerasome (CPC) nanoparticles (NPs) with a mean diameter of ~110 nm for enhancing the localized curcumin delivery into the targeted brain nuclei via effective BBB opening in combination with ultrasound-targeted microbubble destruction (UTMD). Results: The liposomal nanohybrid cerasome exhibited superior stability towards PS 80 surfactant solubilization and longer circulation lifetime (t1/2 = 6.22 h), much longer than free curcumin (t1/2 = 0.76 h). The permeation was found to be 1.7-fold higher than that of CPC treatment only at 6 h after the systemic administration of CPC NPs. Notably, motor behaviors, dopamine (DA) level and tyrosine hydroxylase (TH) expression all returned to normal, thanks to alpha-synuclein (AS) removal mediated by efficient curcumin delivery to the striatum. Most importantly, the animal experiment demonstrated that the 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced PD mice had notably improved behavior disorder and dopamine depletion during two-week post-observation after treatment with CPC NPs (15 mg curcumin/kg) coupled with UTMD. Conclusion: This novel CPC-UTMD formulation approach could be an effective, safe and amenable choice with higher therapeutic relevance and fewer unwanted complications than conventional chemotherapeutics delivery systems for PD treatment in the near future. PMID- 29721079 TI - DNA Methylation Signatures Predicting Bevacizumab Efficacy in Metastatic Breast Cancer. AB - Background: Biomarkers predicting response to bevacizumab in breast cancer are still missing. Since epigenetic modifications can contribute to an aberrant regulation of angiogenesis and treatment resistance, we investigated the influence of DNA methylation patterns on bevacizumab efficacy. Methods: Genome wide methylation profiling using the Illumina Infinium HumanMethylation450 BeadChip was performed in archival FFPE specimens of 36 patients with HER2 negative metastatic breast cancer treated with chemotherapy in combination with bevacizumab as first-line therapy (learning set). Based on objective response and progression-free survival (PFS) and considering ER expression, patients were divided in responders (R) and non-responders (NR). Significantly differentially methylated gene loci (CpGs) with a strong change in methylation levels (Deltabeta>0.15 or Deltabeta<-0.15) between R and NR were identified and further investigated in 80 bevacizumab-treated breast cancer patients (optimization set) and in 15 patients treated with chemotherapy alone (control set) using targeted deep amplicon bisulfite sequencing. Methylated gene loci were considered predictive if there was a significant association with outcome (PFS) in the optimization set but not in the control set using Spearman rank correlation, Cox regression, and logrank test. Results: Differentially methylated loci in 48 genes were identified, allowing a good separation between R and NR (odds ratio (OR) 101, p<0.0001). Methylation of at least one cytosine in 26 gene-regions was significantly associated with progression-free survival (PFS) in the optimization set, but not in the control set. Using information from the optimization set, the panel was reduced to a 9-gene signature, which could divide patients from the learning set into 2 clusters, thereby predicting response with an OR of 40 (p<0.001) and an AUC of 0.91 (LOOCV). A further restricted 3-gene methylation model showed a significant association of predicted responders with longer PFS in the learning and optimization set even in multivariate analysis with an excellent and good separation of R and NR with AUC=0.94 and AUC=0.86, respectively. Conclusion: Both a 9-gene and 3-gene methylation signature can discriminate between R and NR to a bevacizumab-based therapy in MBC and could help identify patients deriving greater benefit from bevacizumab. PMID- 29721080 TI - Paper-based electrochemiluminescence sensor for highly sensitive detection of amyloid-beta oligomerization: Toward potential diagnosis of Alzheimer's disease. AB - Development of a rapid and sensitive method for Abeta(1-42) aggregation detection is of great importance to overcome the limitations of conventional techniques. In this study, we developed a label-free paper-based electrochemiluminescence sensor for amyloid-beta aggregation detection toward potential diagnosis of Alzheimer's disease (AD). The paper-based chip used in the system serves as a low-cost and disposable detection method. In this detection platform, the bonding of [Ru(phen)2dppz]2+ to Abeta(1-42) aggregates results in enhanced electrochemiluminescence due to the change in the polarity of the microenvironment when [Ru(phen)2dppz]2+ intercalated into the beta-sheets during oligomerization. The oligomerization process of Abeta(1-42) can be monitored in real time by the novel method, and as low as 100 pM equivalent monomer concentration of Abeta(1-42) could be detected simultaneously. In addition, the cerebrospinal fluid of transgenic AD model mice was tested by this method, which is highly consistent with genetic identification. In addition, we demonstrated that this detection platform could be a potential new method for the screening of Abeta(1-42) aggregation inhibitors, highlighting the practical application capacity of this platform. The platform is label free, low cost and sensitive. Therefore, the proposed platform holds great promise for the diagnosis of AD. PMID- 29721081 TI - Companion Diagnostic 64Cu-Liposome Positron Emission Tomography Enables Characterization of Drug Delivery to Tumors and Predicts Response to Cancer Nanomedicines. AB - Deposition of liposomal drugs into solid tumors is a potentially rate-limiting step for drug delivery and has substantial variability that may influence probability of response. Tumor deposition is a shared mechanism for liposomal therapeutics such that a single companion diagnostic agent may have utility in predicting response to multiple nanomedicines. Methods: We describe the development, characterization and preclinical proof-of-concept of the positron emission tomography (PET) agent, MM-DX-929, a drug-free untargeted 100 nm PEGylated liposome stably entrapping a chelated complex of 4-DEAP-ATSC and 64Cu (copper-64). MM-DX-929 is designed to mimic the biodistribution of similarly sized therapeutic agents and enable quantification of deposition in solid tumors. Results: MM-DX-929 demonstrated sufficient in vitro and in vivo stability with PET images accurately reflecting the disposition of liposome nanoparticles over the time scale of imaging. MM-DX-929 is also representative of the tumor deposition and intratumoral distribution of three different liposomal drugs, including targeted liposomes and those with different degrees of PEGylation. Furthermore, stratification using a single pre-treatment MM-DX-929 PET assessment of tumor deposition demonstrated that tumors with high MM-DX-929 deposition predicted significantly greater anti-tumor activity after multi-cycle treatments with different liposomal drugs. In contrast, MM-DX-929 tumor deposition was not prognostic in untreated tumor-bearing xenografts, nor predictive in animals treated with small molecule chemotherapeutics. Conclusions: These data illustrate the potential of MM-DX-929 PET as a companion diagnostic strategy to prospectively select patients likely to respond to liposomal drugs or nanomedicines of similar molecular size. PMID- 29721082 TI - A Novel Theranostic Combination of Near-infrared Fluorescence Imaging and Laser Irradiation Targeting c-KIT for Gastrointestinal Stromal Tumors. AB - It is difficult to distinguish gastrointestinal stromal tumors (GISTs) from other types of submucosal tumors under conventional gastrointestinal endoscopy. We aimed to detect GISTs by molecular fluorescence imaging using a near-infrared (NIR) photosensitizer (IR700)-conjugated anti-c-KIT antibody and to treat GISTs by photoimmunotherapy with NIR irradiation as a non-invasive theranostic procedure. We also investigated the therapeutic mechanisms. Methods: Human GIST cell lines GIST-T1 and GIST-882M were incubated with IR700-conjugated anti-c-KIT antibody, IR700-12A8, and observed by confocal laser microscopy. Mice with GIST T1 xenografts or rats with orthotopic xenografts were injected with IR700-12A8 or AF488-conjugated antibody, and observed under IVIS or autofluorescence imaging (AFI) endoscopy. GIST cells were treated with IR700-12A8 and NIR light in vitro and vivo, and cell viability, histology and apoptosis were evaluated. Results: Strong red fluorescence of IR700-12A8 was observed on the cell membrane of GIST cells and was gradually internalized into the cytoplasm. Tumor-specific accumulation of IR700-12A8 was observed in GIST-T1 xenografts in mice. Under AFI endoscopy, a strong fluorescence signal was observed in orthotopic GIST xenografts in rats through the normal mucosa covering the tumor. The percentage of dead cells significantly increased in a light-dose-dependent manner and both acute necrotic and late apoptotic cell death was observed with annexin/PI staining. Cleaved PARP expression was significantly increased after IR700-12A8 mediated NIR irradiation, which was almost completely reversed by NaN3. All xenograft tumors (7/7) immediately regressed and 4/7 tumors completely disappeared after IR700-12A8-mediated NIR irradiation. Histologic assessment and TUNEL staining revealed apoptosis in the tumors. Conclusion: NIR fluorescence imaging using IR700-12A8 and subsequent NIR irradiation could be a very effective theranostic technology for GIST, the underlying mechanism of which appears to involve acute necrosis and supposedly late apoptosis induced by singlet oxygen. PMID- 29721084 TI - A novel USP9X substrate TTK contributes to tumorigenesis in non-small-cell lung cancer. AB - The X-linked deubiquitinase, USP9X, is implicated in multiple cancers by targeting various substrates. Increased expression of USP9X is observed in non small-cell lung cancer (NSCLC) and is correlated with poor prognosis. However, the molecular mechanism for USP9X regulation of tumor cell survival and tumorigenesis in NSCLC is less defined. Methods: In this study, chemical labeling, quantitative proteomic screening was applied to analyze A549 cells with or without USP9X RNA interference. Functional in vitro and in vivo experiments were performed to confirm the oncogenic effects of USP9X in NSCLC and to investigate the underlying mechanisms. Results: The resulting data suggested that dual specificity protein kinase TTK is a potential substrate of USP9X. Further experimental evidences confirmed that USP9X stabilized TTK via direct interaction and efficient deubiquitination of TTK on K48 ubiquitin chain. Moreover, knockdown of USP9X or TTK inhibited cell proliferation, migration and tumorigenesis, and the immunohistochemical analysis of clinical NSCLC samples showed that the protein expression levels of USP9X and TTK were significantly elevated and positively correlated in tumor tissues. Conclusions: In summary, our data demonstrated that the USP9X-TTK axis may play a critical role in NSCLC, and could be considered as a potential therapeutic target. PMID- 29721083 TI - Targeting CPT1A-mediated fatty acid oxidation sensitizes nasopharyngeal carcinoma to radiation therapy. AB - Nasopharyngeal carcinoma (NPC) has a particularly high prevalence in southern China, southeastern Asia and northern Africa. Radiation resistance remains a serious obstacle to successful treatment in NPC. This study aimed to explore the metabolic feature of radiation-resistant NPC cells and identify new molecular targeted agents to improve the therapeutic effects of radiotherapy in NPC. Methods: Radiation-responsive and radiation-resistant NPC cells were used as the model system in vitro and in vivo. Metabolomics approach was used to illustrate the global metabolic changes. 13C isotopomer tracing experiment and Seahorse XF analysis were undertaken to determine the activity of fatty acid oxidation (FAO). qRT-PCR was performed to evaluate the expression of essential FAO genes including CPT1A. NPC tumor tissue microarray was used to investigate the prognostic role of CPT1A. Either RNA interference or pharmacological blockade by Etomoxir were used to inhibit CPT1A. Radiation resistance was evaluated by colony formation assay. Mitochondrial membrane potential, apoptosis and neutral lipid content were measured by flow cytometry analysis using JC-1, Annexin V and LipidTOX Red probe respectively. Molecular markers of mitochondrial apoptosis were detected by western blot. Xenografts were treated with Etomoxir, radiation, or a combination of Etomoxir and radiation. Mitochondrial apoptosis and lipid droplets content of tumor tissues were detected by cleaved caspase 9 and Oil Red O staining respectively. Liquid chromatography coupled with tandem mass spectrometry approach was used to identify CPT1A-binding proteins. The interaction of CPT1A and Rab14 were detected by immunoprecipitation, immunofluorescence and in situ proximity ligation analysis. Fragment docking and direct coupling combined computational protein-protein interaction prediction method were used to predict the binding interface. Fatty acid trafficking was measured by pulse-chase assay using BODIPY C16 and MitoTracker Red probe. Results: FAO was active in radiation resistant NPC cells, and the rate-limiting enzyme of FAO, carnitine palmitoyl transferase 1 A (CPT1A), was consistently up-regulated in these cells. The protein level of CPT1A was significantly associated with poor overall survival of NPC patients following radiotherapy. Inhibition of CPT1A re-sensitized NPC cells to radiation therapy by activating mitochondrial apoptosis both in vitro and in vivo. In addition, we identified Rab14 as a novel CPT1A binding protein. The CPT1A-Rab14 interaction facilitated fatty acid trafficking from lipid droplets to mitochondria, which decreased radiation-induced lipid accumulation and maximized ATP production. Knockdown of Rab14 attenuated CPT1A-mediated fatty acid trafficking and radiation resistance. Conclusion: An active FAO is a vital signature of NPC radiation resistance. Targeting CPT1A could be a beneficial regimen to improve the therapeutic effects of radiotherapy in NPC patients. Importantly, the CPT1A-Rab14 interaction plays roles in CPT1A-mediated radiation resistance by facilitating fatty acid trafficking. This interaction could be an attractive interface for the discovery of novel CPT1A inhibitors. PMID- 29721085 TI - Efficient delivery of nucleic acid molecules into skin by combined use of microneedle roller and flexible interdigitated electroporation array. AB - Rationale: Delivery of nucleic acid molecules into skin remains a main obstacle for various types of gene therapy or vaccine applications. Here we propose a novel electroporation approach via combined use of a microneedle roller and a flexible interdigitated electroporation array (FIEA) for efficient delivery of DNA and siRNA into mouse skin. Methods: Using micromachining technology, closely spaced gold electrodes were made on a pliable parylene substrate to form a patch like electroporation array, which enabled close surface contact between the skin and electrodes. Pre-penetration of the skin with a microneedle roller resulted in the formation of microchannels in the skin, which played a role as liquid electrodes in the skin and provided a uniform and deep electric field in the tissue when pulse stimulation was applied by FIEA. Results: Using this proposed method, gene (RFP) expression and siRNA transfection were successfully achieved in normal mice skin. Anti-SCD1 siRNA electroporated via this method mediated significant gene silencing in the skin. Moreover, electroporation assisted by the microneedle roller showed significant advantages over treatment with FIEA alone. This allowed nucleic acid transportation at low voltage, with ideal safety outcomes. Principal conclusions: Hence, the proposed electroporation approach in this study constitutes a novel way for delivering siRNA and DNA, and even other nucleic acid molecules, to mouse skin in vivo, potentially supporting clinical application in the treatment of skin diseases or intradermal/subcutaneous vaccination. PMID- 29721086 TI - A Supramolecular Approach for Liver Radioembolization. AB - Hepatic radioembolization therapies can suffer from discrepancies between diagnostic planning (scout-scan) and the therapeutic delivery itself, resulting in unwanted side-effects such as pulmonary shunting. We reasoned that a nanotechnology-based pre-targeting strategy could help overcome this shortcoming by directly linking pre-interventional diagnostics to the local delivery of therapy. Methods: The host-guest interaction between adamantane and cyclodextrin was employed in an in vivo pre-targeting set-up. Adamantane (guest) functionalized macro albumin aggregates (MAA-Ad; d = 18 MUm) and (radiolabeled) Cy5 and beta-cyclodextrin (host)-containing PIBMA polymers (99mTc Cy50.5CD10PIBMA39; MW ~ 18.8 kDa) functioned as the reactive pair. Following liver or lung embolization with (99mTc)-MAA-Ad or (99mTc)-MAA (control), the utility of the pre-targeting concept was evaluated after intravenous administration of 99mTc-Cy50.5CD10PIBMA39. Results: Interactions between MAA-Ad and Cy50.5CD10PIBMA39 could be monitored in solution using confocal microscopy and were quantified by radioisotope-based binding experiments. In vivo the accumulation of the MAA-Ad particles in the liver or lungs yielded an approximate ten-fold increase in accumulation of 99mTc-Cy50.5CD10PIBMA39 in these organs (16.2 %ID/g and 10.5 %ID/g, respectively) compared to the control. Pre-targeting with MAA alone was shown to be only half as efficient. Uniquely, for the first time, this data demonstrates that the formation of supramolecular interactions between cyclodextrin and adamantane can be used to drive complex formation in the chemically challenging in vivo environment. Conclusion: The in vivo distribution pattern of the cyclodextrin host could be guided by the pre-administration of the adamantane guest, thereby creating a direct link between the scout-scan (MAA-Ad) and delivery of therapy. PMID- 29721088 TI - Imaging, myeloid precursor immortalization, and genome editing for defining mechanisms of leukocyte recruitment in vivo. AB - Recruitment of leukocytes from the blood to sites of inflammation poses a promising target for new diagnostic and therapeutic approaches. We aimed to develop a novel method to non-invasively analyze molecular mechanisms of leukocyte migration in pre-clinical models of inflammation in vivo. Methods: We used the ER-HoxB8 system to transiently immortalize murine myeloid precursors from wildtype and CD18- as well as MRP14-deficient mice. A VLA4alpha-/- cell line was generated by CRISPR/Cas9-mediated gene editing. We analyzed the migration of wildtype and knockout leukocytes in vivo by optical and nuclear imaging in mice with irritant contact dermatitis, cutaneous granuloma, experimental arthritis and myocardial infarction. Results: Transient immortalization, gene editing and in vivo imaging can be combined to analyze migratory mechanisms of murine leukocytes, even for gene deletions resulting in lethal phenotypes in mice. We reliably confirmed known migratory defects of leukocytes deficient for the adhesion molecules CD18 or VLA4alpha. Also, using our new method we identified a new role of the most abundant calcium-binding proteins in phagocytes and major alarmins in many inflammatory diseases, MRP8 and MRP14, for transmigration in vivo. Conclusion: We provide a combinatorial approach to rapidly characterize molecular mechanisms of leukocyte recruitment in vivo, with the potential to aid in identification of diagnostic and therapeutic targets in inflammatory pathologies. PMID- 29721089 TI - High-Discrimination Factor Nanosensor Based on Tetrahedral DNA Nanostructures and Gold Nanoparticles for Detection of MiRNA-21 in Live Cells. AB - While detection of microRNA with or without signal amplification is highly informative, nanosensors with high specificity for cell-specific RNA detection are rare. Methods: In this study, a tetrahedral DNA nanostructure (TDN) with a specific function was combined with gold nanoparticles (Au-NP) possessing fluorescence quenching effects and a large surface area to fabricate a fluorescence resonance energy transfer based nanosensor (Au-TDNN). The presence of miR-21 (target) can separate the fluorescent dye-labeled detection probe on Au TDNNs from Au-NPs, which separates the donor and acceptor, thus inducing an intensive fluorescence signal. High specificity for discerning point mutation targets was achieved by rationally designing the nucleic acid strand displacement reaction to occur spontaneously with DeltaG0 ~ 0 based on thermodynamic parameters; under this condition, slight thermodynamic changes caused by base mismatch exert significant effects on hybridization yield. Results: Chemically synthesized DNA of three single-base-changed analogues of target, let-7d, and miR 200b were tested. A discrimination factor (DF) of 15.4 was produced by the expected detection probe on Au-NPs for proximal single-base mismatch. As the control group, the DF produced by an ordinary detection probe on Au-NPs only reached 2.4. The feasibility of the proposed strategy was also confirmed using hepatocyte cancer cells (HepG2). Conclusion: This improved nanosensor opens a new avenue for the specific and easy detection of microRNA in live cells. PMID- 29721087 TI - Resveratrol counteracts bone loss via mitofilin-mediated osteogenic improvement of mesenchymal stem cells in senescence-accelerated mice. AB - Rational: Senescence of mesenchymal stem cells (MSCs) and the related functional decline of osteogenesis have emerged as the critical pathogenesis of osteoporosis in aging. Resveratrol (RESV), a small molecular compound that safely mimics the effects of dietary restriction, has been well documented to extend lifespan in lower organisms and improve health in aging rodents. However, whether RESV promotes function of senescent stem cells in alleviating age-related phenotypes remains largely unknown. Here, we intend to investigate whether RESV counteracts senescence-associated bone loss via osteogenic improvement of MSCs and the underlying mechanism. Methods: MSCs derived from bone marrow (BMMSCs) and the bone-specific, senescence-accelerated, osteoblastogenesis/osteogenesis-defective mice (the SAMP6 strain) were used as experimental models. In vivo application of RESV was performed at 100 mg/kg intraperitoneally once every other day for 2 months, and in vitro application of RESV was performed at 10 MUM. Bone mass, bone formation rates and osteogenic differentiation of BMMSCs were primarily evaluated. Metabolic statuses of BMMSCs and the mitochondrial activity, transcription and morphology were also examined. Mitofilin expression was assessed at both mRNA and protein levels, and short hairpin RNA (shRNA)-based gene knockdown was applied for mechanistic experiments. Results: Chronic intermittent application of RESV enhances bone formation and counteracts accelerated bone loss, with RESV improving osteogenic differentiation of senescent BMMSCs. Furthermore, in rescuing osteogenic decline under BMMSC senescence, RESV restores cellular metabolism through mitochondrial functional recovery via facilitating mitochondrial autonomous gene transcription. Molecularly, in alleviating senescence-associated mitochondrial disorders of BMMSCs, particularly the mitochondrial morphological alterations, RESV upregulates Mitofilin, also known as inner membrane protein of mitochondria (Immt) or Mic60, which is the core component of the mitochondrial contact site and cristae organizing system (MICOS). Moreover, Mitofilin is revealed to be indispensable for mitochondrial homeostasis and osteogenesis of BMMSCs, and that insufficiency of Mitofilin leads to BMMSC senescence and bone loss. More importantly, Mitofilin mediates resveratrol-induced mitochondrial and osteogenic improvements of BMMSCs in senescence. Conclusion: Our findings uncover osteogenic functional improvements of senescent MSCs as critical impacts in anti osteoporotic practice of RESV, and unravel Mitofilin as a novel mechanism mediating RESV promotion on mitochondrial function in stem cell senescence. PMID- 29721090 TI - Harmine enhances type H vessel formation and prevents bone loss in ovariectomized mice. AB - : Recently, researchers identified a distinct vessel subtype called type H vessels that couple angiogenesis and osteogenesis. We previously found that type H vessels are reduced in ovariectomy (OVX)-induced osteoporotic mice, and preosteoclasts are able to secrete platelet-derived growth factor-BB (PDGF-BB) to stimulate type H vessel formation and thereby to promote osteogenesis. This study aimed to explore whether harmine, a beta-carboline alkaloid, is capable of preventing bone loss in OVX mice by promoting preosteoclast PDGF-BB-induced type H vessel formation. METHODS: The impact of harmine on osteoclastogenesis of RANKL stimulated RAW264.7 cells was verified by gene expression analysis and tartrate resistant acid phosphatase (TRAP) staining. Enzyme-linked immunosorbent assay (ELISA) was conducted to test PDGF-BB production by preosteoclasts. A series of angiogenesis-related assays in vitro were performed to assess the pro-angiogenic effects of the conditioned media from RANKL-stimulated RAW264.7 cells treated with or without harmine. Meanwhile, the role of PDGF-BB in this process was determined. In vivo, OVX mice were intragastrically administrated with harmine emulsion or an equal volume of vehicle. 2 months later, bone samples were collected for uCT, histological, immunohistochemical and immunofluorescent analyses to evaluate bone mass, osteogenic and osteoclastic activities, as well as the numbers of type H vessels. Bone marrow PDGF-BB concentrations were assessed by ELISA. RESULTS: Exposure of RANKL-stimulated RAW264.7 cells to harmine enhanced the formation of preosteoclasts and the production of PDGF-BB. Harmine augmented the ability of RANKL-stimulated RAW264.7 cells to promote angiogenesis of endothelial cells, whereas the effect was blocked by PDGF-BB inhibition. In vivo, the oral administration of harmine emulsion to OVX mice resulted in enhanced trabecular bone mass and osteogenic responses, increased numbers of preosteoclasts, as well as reduced numbers of osteoclasts and fat cells. Moreover, OVX mice treated with harmine exhibited higher levels of bone marrow PDGF-BB and much more type H vessels in bone. CONCLUSION: Harmine may exert bone-sparing effects by suppression of osteoclast formation and promotion of preosteoclast PDGF-BB-induced angiogenesis. PMID- 29721091 TI - Soluble CD146 is a predictive marker of pejorative evolution and of sunitinib efficacy in clear cell renal cell carcinoma. AB - The objective of the study was to use CD146 mRNA to predict the evolution of patients with non-metastatic clear cell renal cell carcinoma (M0 ccRCC) towards metastatic disease, and to use soluble CD146 (sCD146) to anticipate relapses on reference treatments by sunitinib or bevacizumab in patients with metastatic ccRCC (M1). Methods: A retrospective cohort of M0 patients was used to determine the prognostic role of intra-tumor CD146 mRNA. Prospective multi-center trials were used to define plasmatic sCD146 as a predictive marker of sunitinib or bevacizumab efficacy for M1 patients. Results: High tumor levels of CD146 mRNA were linked to shorter disease-free survival (DFS) and overall survival (OS). ccRCC patients from prospective cohorts with plasmatic sCD146 variation <120% following the first cycle of sunitinib treatment had a longer progression-free survival (PFS) and OS. The plasmatic sCD146 variation did not correlate with PFS or OS for the bevacizumab-based treatment. In vitro, resistant cells to sunitinib expressed high levels of CD146 mRNA and protein in comparison to sensitive cells. Moreover, recombinant CD146 protected cells from the sunitinib-dependent decrease of cell viability. Conclusion: CD146/sCD146 produced by tumor cells is a relevant biological marker of ccRCC aggressiveness and relapse on sunitinib treatment. PMID- 29721092 TI - Endogenous IgG-based affinity-controlled release of TRAIL exerts superior antitumor effects. AB - The inefficiency of recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-based clinical regimens has been dominantly attributed to the short half-life of TRAIL. Affinity-controlled release using endogenous long acting proteins, such as IgG and albumin, as carriers is extremely attractive for improving the pharmacokinetics of TRAIL. Up to now, it is unclear whether IgG binding is efficient for affinity-controlled release of TRAIL. Methods: An IgG binding affibody, IgBD, was genetically fused to the N-terminus of TRAIL to produce IgBD-TRAIL.The IgG-binding ability, cytotoxicity, serum half-life, and in vivo antitumor effect of IgBD-TRAIL were compared with that of TRAIL. In addition, an albumin-binding affibody, ABD, was fused to TRAIL to produce ABD TRAIL. The cytototoxicity, serum half-life, and antitumor effect of IgBD-TRAIL and ABD-TRAIL were compared. Results: IgBD fusion endowed TRAIL with high affinity (nM) for IgG without interference with its cytotoxicity. The serum half life of IgBD-TRAIL is 50-60 times longer than that of TRAIL and the tumor uptake of IgBD-TRAIL at 8-24 h post-injection was 4-7-fold that of TRAIL. In vivo antitumor effect of IgBD-TRAIL was at least 10 times greater than that of TRAIL. Owing to the high affinity (nM) for albumin, the serum half-life of ABD-TRAIL was 80-90 times greater than that of TRAIL. However, after binding to albumin, the cytotoxicity of ABD-TRAIL was reduced more than 10 times. In contrast, binding to IgG had little impact on the cytotoxicity of IgBD-TRAIL. Consequently, intravenously injected IgBD-TRAIL showed antitumor effects superior to those of ABD-TRAIL. Conclusions: Endogenous long-acting proteins, particularly IgG-based affinity-controlled release, prolonged the serum half-life as well as significantly enhanced the antitumor effect of TRAIL. IgBD-mediated endogenous IgG binding might be a novel approach for the affinity-controlled release of other protein drugs. PMID- 29721093 TI - Graphene oxide sensitizes cancer cells to chemotherapeutics by inducing early autophagy events, promoting nuclear trafficking and necrosis. AB - Rationale: Cisplatin (CDDP) is a broad-spectrum anticancer drug but chemoresistance to CDDP impedes its wide use for cancer therapy. Autophagy is an event occurring in the cytoplasm and cytoplasmic LC3 puncta formation is a hallmark of autophagy. Graphene oxide (GO) is a nanomaterial that provokes autophagy in CT26 colon cancer cells and confers antitumor effects. Here we aimed to evaluate whether combined use of GO with CDDP (GO/CDDP) overcomes chemoresistance in different cancer cells and uncover the underlying mechanism. Methods: We treated different cancer cells with GO/CDDP and evaluated the cytotoxicity, death mechanism, autophagy induction and nuclear entry of CDDP. We further knocked down genes essential for autophagic flux and deciphered which step is critical to nuclear import and cell death. Finally, we performed immunoprecipitation, mass spectrometry and immunofluorescence labeling to evaluate the association of LC3 and CDDP. Results: We uncovered that combination of GO and CDDP (GO/CDDP) promoted the killing of not only CT26 cells, but also ovarian, cervical and prostate cancer cells. In the highly chemosensitized Skov-3 cells, GO/CDDP significantly enhanced concurrent nuclear import of CDDP and autophagy marker LC3 and elevated cell necrosis, which required autophagy initiation and progression but did not necessitate late autophagy events (e.g., autophagosome completion and autolysosome formation). The GO/CDDP-elicited nuclear trafficking and cell death also required importin alpha/beta, and LC3 also co-migrated with CDDP and histone H1/H4 into the nucleus. In particular, GO/CDDP triggered histone H4 acetylation in the nucleus, which could decondense the chromosome and enable CDDP to more effectively access chromosomal DNA to trigger cell death. Conclusion: These findings shed light on the mechanisms of GO/CDDP-induced chemosensitization and implicate the potential applications of GO/CDDP to treat multiple cancers. PMID- 29721094 TI - Safety of panitumumab-IRDye800CW and cetuximab-IRDye800CW for fluorescence-guided surgical navigation in head and neck cancers. AB - Purpose: To demonstrate the safety and feasibility of leveraging therapeutic antibodies for surgical imaging. Procedures: We conducted two phase I trials for anti-epidermal growth factor receptor antibodies cetuximab-IRDye800CW (n=12) and panitumumab-IRDye800CW (n=15). Adults with biopsy-confirmed head and neck squamous cell carcinoma scheduled for standard-of-care surgery were eligible. For cetuximab-IRDye800CW, cohort 1 was intravenously infused with 2.5 mg/m2, cohort 2 received 25 mg/m2, and cohort 3 received 62.5 mg/m2. For panitumumab-IRDye800CW, cohorts received 0.06 mg/kg, 0.5 mg/kg, and 1 mg/kg, respectively. Electrocardiograms and blood samples were obtained, and patients were followed for 30 days post-study drug infusion. Results: Both fluorescently labeled antibodies had similar pharmacodynamic properties and minimal toxicities. Two infusion reactions occurred with cetuximab and none with panitumumab. There were no grade 2 or higher toxicities attributable to cetuximab-IRDye800CW or panitumumab-IRDye800CW; fifteen grade 1 adverse events occurred with cetuximab IRDye800CW, and one grade 1 occurred with panitumumab-IRDye800CW. There were no significant differences in QTc prolongation between the two trials (p=0.8). Conclusions: Panitumumab-IRDye800CW and cetuximab-IRDye800CW have toxicity and pharmacodynamic profiles that match the parent compound, suggesting that other therapeutic antibodies may be repurposed as imaging agents with limited preclinical toxicology data. PMID- 29721096 TI - First-in-human study of PET and optical dual-modality image-guided surgery in glioblastoma using 68Ga-IRDye800CW-BBN. AB - Purpose: Despite the use of fluorescence-guided surgery (FGS), maximum safe resection of glioblastoma multiforme (GBM) remains a major challenge. It has restricted surgeons between preoperative diagnosis and intraoperative treatment. Currently, an integrated approach combining preoperative assessment with intraoperative guidance would be a significant step in this direction. Experimental design: We developed a novel 68Ga-IRDye800CW-BBN PET/near-infrared fluorescence (NIRF) dual-modality imaging probe targeting gastrin-releasing peptide receptor (GRPR) in GBM. The preclinical in vivo tumor imaging and FGS were first evaluated using an orthotopic U87MG glioma xenograft model. Subsequently, the first-in-human prospective cohort study (NCT 02910804) of GBM patients were conducted with preoperative PET assessment and intraoperative FGS. Results: The orthotopic tumors in mice could be precisely resected using the near infrared intraoperative system. Translational cohort research in 14 GBM patients demonstrated an excellent correlation between preoperative positive PET uptake and intraoperative NIRF signal. The tumor fluorescence signals were significantly higher than those from adjacent brain tissue in vivo and ex vivo (p < 0.0001). Compared with pathology, the sensitivity and specificity of fluorescence using 42 loci of fluorescence-guided sampling were 93.9% (95% CI 79.8%-99.3%) and 100% (95% CI 66.4%-100%), respectively. The tracer was safe and the extent of resection was satisfactory without newly developed neurologic deficits. Progression-free survival (PFS) at 6 months was 80% and two newly diagnosed patients achieved long PFS. Conclusions: This initial study has demonstrated that the novel dual-modality imaging technique is feasible for integrated pre- and intraoperative targeted imaging via the same molecular receptor and improved intraoperative GBM visualization and maximum safe resection. PMID- 29721095 TI - Encoding activities of non-coding RNAs. AB - The universal expression of various non-coding RNAs (ncRNAs) is now considered the main feature of organisms' genomes. Many regions in the genome are transcribed but not annotated to encode proteins, yet contain small open reading frames (smORFs). A widely accepted opinion is that a vast majority of ncRNAs are not further translated. However, increasing evidence underlines a series of intriguing translational events from the ncRNAs, which were previously considered to lack coding potential. Recent studies also suggest that products derived from such novel translational events display important regulatory functions in many fundamental biological and pathological processes. Here we give a critical review on the potential coding capacity of ncRNAs, in particular, about what is known and unknown in this emerging area. We also discuss the possible underlying coding mechanisms of these extraordinary ncRNAs and possible roles of peptides or proteins derived from the ncRNAs in disease development and theranostics. Our review offers an extensive resource for studying the biology of ncRNAs and sheds light into the use of ncRNAs and their corresponding peptides or proteins for disease diagnosis and therapy. PMID- 29721099 TI - MicroRNA-378 suppresses myocardial fibrosis through a paracrine mechanism at the early stage of cardiac hypertrophy following mechanical stress. AB - Rationale: Excessive myocardial fibrosis is the main pathological process in the development of cardiac remodeling and heart failure; therefore, it is important to prevent excessive myocardial fibrosis. We determined that microRNA-378 (miR 378) is cardiac-enriched and highly repressed during cardiac remodeling. We therefore proposed that miR-378 has a critical role in regulation of cardiac fibrosis, and examined the effects of miR-378 on cardiac fibrosis after mechanical stress. Methods: Mechanical stress was respectively imposed on mice through a transverse aortic constriction (TAC) procedure and on cardiac fibroblasts by stretching silicon dishes. A chemically modified miR-378 mimic (Agomir) or an inhibitor (Antagomir) was administrated to mice by intravenous injection and to cells by direct addition to the culture medium. MiR-378 knockout mouse was constructed. Cardiac fibroblasts were cultured in the conditioned media from the cardiomyocytes with either miR-378 depletion or treatment with sphingomyelinase inhibitor GW4869. Quantitative real-time polymerase chain reaction analysis of gene and miRNA expression, Western blot analysis, immunochemistry and electron microscopy were performed to elucidate the mechanisms. Results: Mechanical stress induced significant increases in fibrotic responses, including myocardial fibrosis, fibroblast hyperplasia, and protein and gene expression of collagen and matrix metalloproteinases (MMPs) both in vivo and in vitro. All these fibrotic responses were attenuated by treatment with a chemically modified miR-378 mimic (Agomir) but were exaggerated by treatment with an inhibitor (Antagomir). MiR-378 knockout mouse models exhibited aggravated cardiac fibrosis after TAC. Media from the cardiomyocytes with either miR-378 depletion or treatment with sphingomyelinase inhibitor GW4869 enhanced the fibrotic responses of stimulated cardiac fibroblasts, confirming that miR-378 inhibits fibrosis in an extracellular vesicles-dependent secretory manner. Mechanistically, the miR-378-induced anti-fibrotic effects manifested partially through the suppression of p38 MAP kinase phosphorylation by targeting MKK6 in cardiac fibroblasts. Conclusions: miR-378 is secreted from cardiomyocytes following mechanical stress and acts as an inhibitor of excessive cardiac fibrosis through a paracrine mechanism. PMID- 29721098 TI - CAPG enhances breast cancer metastasis by competing with PRMT5 to modulate STC-1 transcription. AB - Macrophage-capping protein (CAPG) has been shown to promote cancer cell metastasis, although the mechanism remains poorly understood. Methods: Breast cancer (BC) tissue microarray was used to test the role of CAPG in the prognosis of BC patients. Xenograft mice model was used to validate the metastasis promotion role of CAPG in vivo. Gene expression array, chromatin immunoprecipitation and luciferase report assay were performed to search for the target genes of CAPG. Protein immunoprecipitation, MS/MS analysis, tissue microarray and histone methyltransferase assay were used to explore the mechanism of CAPG regulating stanniocalcin 1 (STC-1) transcription. Results: We demonstrate a novel mechanism by which CAPG enhances BC metastasis via promoting the transcription of the pro-metastatic gene STC-1, contributing to increased metastasis in BC. Mechanistically, CAPG competes with the transcriptional repressor arginine methyltransferase 5 (PRMT5) for binding to the STC-1 promoter, leading to reduced histone H4R3 methylation and enhanced STC-1 transcription. Our study also indicates that both CAPG and PRMT5 are independent prognostic factors for BC patient survival. High CAPG level is associated with poor survival, while high PRMT5 expression favors a better prognosis in BC patients. Conclusion: Our findings identify a novel role of CAPG in the promotion of BC metastasis by epigenetically enhancing STC-1 transcription. PMID- 29721097 TI - Surface impact on nanoparticle-based magnetic resonance imaging contrast agents. AB - Magnetic resonance imaging (MRI) is one of the most widely used diagnostic tools in the clinic. To improve imaging quality, MRI contrast agents, which can modulate local T1 and T2 relaxation times, are often injected prior to or during MRI scans. However, clinically used contrast agents, including Gd3+-based chelates and iron oxide nanoparticles (IONPs), afford mediocre contrast abilities. To address this issue, there has been extensive research on developing alternative MRI contrast agents with superior r1 and r2 relaxivities. These efforts are facilitated by the fast progress in nanotechnology, which allows for preparation of magnetic nanoparticles (NPs) with varied size, shape, crystallinity, and composition. Studies suggest that surface coatings can also largely affect T1 and T2 relaxations and can be tailored in favor of a high r1 or r2. However, the surface impact of NPs has been less emphasized. Herein, we review recent progress on developing NP-based T1 and T2 contrast agents, with a focus on the surface impact. PMID- 29721101 TI - The effect of aging on pacing strategies of cross-country skiers and the role of performance level. AB - Background: The participation of master cross-country (XC) skiers in training and competition has increased during the last decades; however, little is known yet about whether these athletes differ from their younger counterparts in aspects of performance such as pacing. Therefore, the aim of the present study was to examine the combined effect of age and performance (race time) on pacing in cross country (XC) skiing. We analyzed all finishers (n = 79,722) in 'Vasaloppet' from 2012 to 2017, the largest cross-country skiing race in the world, classified according to their race time into 10 groups: 3-4 h, 4-5 h, ..., 12-13 h. Results: A trivial main effect of sex on total pace range was observed (p < 0.001, eta2 = 0.002), where women (44.1 +/- 10.2%) had larger total pace range than men (40.9 +/- 11.8%). A large main effect of performance group on total pace range was shown (p < 0.001, eta2 = 0.160), where the smallest total pace range was 21.8 +/- 1.9% (3-4 h group) and the largest 50.1 +/- 9.9% (10-11 h group). A trivial sex*performance group interaction on total pace range was found (p < 0.001, eta2 = 0.001) with the largest sex difference in pacing shown in 9-10 h group. A trivial and small main effect of age was found in women (p < 0.001, eta2 = 0.005) and men (p < 0.001, eta2 = 0.011), respectively, where the masters had smaller total pace range than their younger counterparts. A trivial age group*performance group interaction on total pace range was observed in both women (p < 0.001, eta2 = 0.008) and men (p < 0.001, eta2 = 0.006) with smaller differences among age groups in the faster performance groups. Conclusions: In summary, master XC skiers adopted a relatively even pacing independently from their race time and the differences in pacing from the younger XC skiers were more pronounced in the slower masters. These findings suggest that exercise attenuates the decline of performance in master XC skiers as shown by the similar pacing strategies between fast master XC skiers and their younger counterparts. PMID- 29721100 TI - Establishing sheep as an experimental species to validate ultrasound-mediated blood-brain barrier opening for potential therapeutic interventions. AB - Rationale: Treating diseases of the brain such as Alzheimer's disease (AD) is challenging as the blood-brain barrier (BBB) effectively restricts access of a large number of potentially useful drugs. A potential solution to this problem is presented by therapeutic ultrasound, a novel treatment modality that can achieve transient BBB opening in species including rodents, facilitated by biologically inert microbubbles that are routinely used in a clinical setting for contrast enhancement. However, in translating rodent studies to the human brain, the presence of a thick cancellous skull that both absorbs and distorts ultrasound presents a challenge. A larger animal model that is more similar to humans is therefore required in order to establish a suitable protocol and to test devices. Here we investigated whether sheep provide such a model. Methods: In a stepwise manner, we used a total of 12 sheep to establish a sonication protocol using a spherically focused transducer. This was assisted by ex vivo simulations based on CT scans to establish suitable sonication parameters. BBB opening was assessed by Evans blue staining and a range of histological tests. Results: Here we demonstrate noninvasive microbubble-mediated BBB opening through the intact sheep skull. Our non-recovery protocol allowed for BBB opening at the base of the brain, and in areas relevant for AD, including the cortex and hippocampus. Linear time-shift invariant analysis and finite element analysis simulations were used to optimize the position of the transducer and to predict the acoustic pressure and location of the focus. Conclusion: Our study establishes sheep as a novel animal model for ultrasound-mediated BBB opening and highlights opportunities and challenges in using this model. Moreover, as sheep develop an AD-like pathology with aging, they represent a large animal model that could potentially complement the use of non-human primates. PMID- 29721102 TI - Self- vs proxy-reported mobility using the mobility assessment tool-short form in elderly preoperative patients. AB - Background: Mobility is fundamental to maintenance of an independent lifestyle and can predict clinical outcomes after health events among older individuals. However, certain clinical situations do not accommodate physical or self assessments. This investigation examines whether proxy-reported assessments of function using the Mobility Assessment Tool-short (MAT-sf) form is a reliable alternative. Methods: Sixty-six older persons (>= age 70) and their proxies were enrolled. Proxies rated patients' mobility using the MAT-sf as did the patients. Results: The mean age of patients was 78.4 yr. (+/-6.2); 44% were female and 86% were white. Spouses made up 55% of the proxies, while 39% were children/in-laws. The correlation coefficient between patient and proxy MAT-sf scores was 0.81 (p < 0.01); a comparison of the slope of the regression line relating patient- and proxy-reported MAT-sf to a line of identity showed disagreement (p < 0.01), with proxy reports underreporting patient responses by 8.3% in lower mobility patients. The intra-class correlation characterizing agreement between repeated proxy reports 0.81. Conclusion: Proxy reports of mobility in older patients have good reliability. However, in patients with poor mobility, the proxies tend to report a lower mobility than the patients. PMID- 29721104 TI - Apelin and Atrial Fibrillation: The Role in the Arrhythmia Recurrence Prognosis. AB - Apelin is a novel peptide of wide expression and multiple biological functions including the crucial role in cardiovascular homeostasis. The apelin role in the pathophysiology of heart rhythm disorders is considered, although the reports are scarce so far. The purpose of this study is to investigate the potential utility of apelin as a marker of arrhythmia recurrence after direct-current cardioversion (DC). The prospective, observational study included 60 patients (aged 41-86; 30% female) with nonvalvular, persistent atrial fibrillation from the group of 204 consecutive patients scheduled for DC during the 12-month period (from May 2010 to May 2011) in the Cardiology Clinic Medical University of Lodz, Poland. The study group was divided into SCD (successful DC), 45 (75%) patients, and NDC (nonsuccessful DC), 15 (25%) patients. Within the SCD group, the subgroups were distinguished depending on the time sinus rhythm maintenance after DC: up to 7 days (SDC-7), 11 patients; 7 to 30 days (SDC-30), 12 patients; over 90 days (SDC 90), 22 patients. Patients were evaluated during the hospitalization and within the 3-month follow-up period. The apelin level was determined within the plasma samples collected at the admission, using the commercially available enzyme linked immunosorbent assay (ELISA) Kit for apelin-36. It was found that the median value of initial apelin in the subset of patients from groups NDC + SDC-7 + SDC-30 is significantly higher than from group SDC-90 (p = 0.0463); there was no relationship between NDC and SCD overall. Neither of the compared subgroup pairs revealed statistically significant correlation between the proBNP concentration and the DC effectiveness in our population. In conclusion, in our study, proBNP was not a marker of arrhythmia recurrence whereas higher apelin concentration at the admission indicated patients in whom DC was not effective or they had an arrhythmia recurrence within a month-period observation. PMID- 29721103 TI - MEST mediates the impact of prenatal bisphenol A exposure on long-term body weight development. AB - Background: Exposure to endocrine-disrupting chemicals can alter normal physiology and increase susceptibility to non-communicable diseases like obesity. Especially the prenatal and early postnatal period is highly vulnerable to adverse effects by environmental exposure, promoting developmental reprogramming by epigenetic alterations. To obtain a deeper insight into the role of prenatal bisphenol A (BPA) exposure in children's overweight development, we combine epidemiological data with experimental models and BPA-dependent DNA methylation changes. Methods: BPA concentrations were measured in maternal urine samples of the LINA mother-child-study obtained during pregnancy (n = 552), and BPA associated changes in cord blood DNA methylation were analyzed by Illumina Infinium HumanMethylation450 BeadChip arrays (n = 472). Methylation changes were verified by targeted MassARRAY analyses, assessed for their functional translation by qPCR and correlated with children's body mass index (BMI) z scores at the age of 1 and 6 years. Further, female BALB/c mice were exposed to BPA from 1 week before mating until delivery, and weight development of their pups was monitored (n >= 8/group). Additionally, human adipose-derived mesenchymal stem cells were treated with BPA during the adipocyte differentiation period and assessed for exposure-related epigenetic, transcriptional and morphological changes (n = 4). Results: In prenatally BPA-exposed children two CpG sites with deviating cord blood DNA-methylation profiles were identified, among them a hypo methylated CpG in the promoter of the obesity-associated mesoderm-specific transcript (MEST). A mediator analysis suggested that prenatal BPA exposure was connected to cord blood MEST promoter methylation and MEST expression as well as BMI z scores in early infancy. This effect could be confirmed in mice in which prenatal BPA exposure altered Mest promoter methylation and transcription with a concomitant increase in the body weight of the juvenile offspring. An experimental model of in vitro differentiated human mesenchymal stem cells also revealed an epigenetically induced MEST expression and enhanced adipogenesis following BPA exposure. Conclusions: Our study provides evidence that MEST mediates the impact of prenatal BPA exposure on long-term body weight development in offspring by triggering adipocyte differentiation. PMID- 29721105 TI - Plasma Neuregulin 4 Levels Are Associated with Metabolic Syndrome in Patients Newly Diagnosed with Type 2 Diabetes Mellitus. AB - Neuregulin 4 (Nrg4) has been proposed to play a role in the pathogeneses of obesity, insulin resistance, and dyslipidemia. However, information about the link between Nrg4 and metabolic syndrome (MetS) is scarce, especially in patients with newly diagnosed type 2 diabetes mellitus (nT2DM). This study aimed at investigating whether Nrg4 is associated with MetS in nT2DM patients. A total of 311 patients with nT2DM were recruited. Plasma Nrg4 concentration was determined by ELISA. Plasma Nrg4 concentration was lower in nT2DM patients with MetS than in nT2DM patients without MetS (P = 0.001). Nrg4 concentration showed negative correlations with most of the analyzed indicators of MetS. MetS was less prevalent among subjects in the highest quartile of plasma Nrg4 concentration than among those in the lowest quartile (P < 0.01). Age- and sex-adjusted plasma Nrg4 concentrations were positively correlated with concentrations of high density lipoprotein cholesterol (HDL-C) and apolipoprotein A (both P < 0.05) and negatively correlated with triglyceride, high-sensitivity C-reactive protein (hs CRP), and gamma-glutamyltransferase concentrations, neutrophil count, and white blood cell (WBC) count (all P < 0.05). In multivariate analysis, Nrg4 was independently associated with hs-CRP level, WBC count, and HDL-C level (P = 0.001 or P < 0.05). Multiple logistic regression analysis of MetS prediction by Nrg4 revealed an odds ratio of 0.560 (95% CI: 0.374-0.837; P < 0.01). Decreased plasma Nrg4 levels, which may be associated with augmented oxidative stress, inflammation, and dyslipidemia, might be involved in the development of MetS in nT2DM patients. PMID- 29721107 TI - Atrial fibrillation and cryptogenic stroke. What is the current evidence? Role of electrocardiographic monitoring. AB - The diagnosis of cryptogenic stroke is made by exclusion. However, current evidence supports the role of atrial fibrillation episodes as a cause of this condition. Prospective data have demonstrated the benefits of long-term electrocardiographic monitoring to identify atrial fibrillation in association with cryptogenic stroke. This aim of this article was to analyze the contemporary evidence for the possible relationship between atrial fibrillation and cryptogenic stroke and the role of continuous electrocardiographic monitoring to clarify this hypothesis. PMID- 29721108 TI - Implantable cardioverter defibrillator in nonischemic cardiomyopathy: A systematic review and meta-analysis. AB - The evidence to support implantable cardioverter defibrillator (ICD) in subjects with nonischemic cardiomyopathy (NICM) for primary prevention of sudden cardiac death (SCD) is not robust. This meta-analysis intends to assess the impact of routine ICD implantation for primary prevention of mortality due to SCD in NICM based on all the published randomized clinical trials (RCTs). Six RCTs were selected using PubMed/Medline, EMBASE, and CENTRAL from inception to December 2016. Outcomes were calculated as random-effects relative risk (RR) and risk difference (RD) with 95% confidence interval (CI). Patients were randomized to ICD arm and control arm (usual care, medical treatment, and anti-arrhythmic drugs). ICD significantly reduced all-cause mortality in NICM patients (RR, 0.74, 95% CI, 0.56-0.97, P = .03, I2 = 40). Mortality benefit was achieved due to a significant reduction in sudden cardiac death (SCD) (RR, 0.47, 95% CI, 0.30-0.73, P < .001, I2 = 0). There were no statistical differences between two groups with regard to risk of noncardiac mortality, non-SCD, cardiac arrest, cardiac transplant, sustained ventricular tachycardia (VT), and VT requiring medical treatment. Our results support efficacy of ICDs at reducing all-cause mortality due to a reduction in SCD. PMID- 29721110 TI - Use of microelectrode near-field signals to determine catheter contact. AB - Background: The utility of standard distal bipolar electrograms (sEGMs) for assessing catheter-tissue contact may be obscured by the presence of far-field signals. Microelectrode electrograms (mEGMs) may overcome this limitation. Methods: We compared 5 mEGM characteristics (amplitude, frequency content, temporal signal variability, presence of injury current, and amplitude differential between bipoles) with the sEGM for determining tissue contact in 20 patients undergoing ablation of typical atrial flutter. Visualization of catheter tissue contact by intracardiac echocardiography (ICE) served as the gold standard for assessing contact. Correlation between electrograms and ICE-verified contact level was reported as percent concordance. Results: Three of 5 mEGM characteristics demonstrated significantly better concordance with ICE-verified contact level than the sEGM (52% concordance with ICE): mEGM frequency content (59% concordance with ICE, P < .001 for comparison with sEGM); mEGM amplitude (concordance 59%, P < .001); and mEGM presence of injury current (56% concordance, P = .001). Concordance of amplitude differential between mEGM bipoles with ICE (49%) was not significantly different than the sEGM (P = .638) whereas mEGM temporal variability (39%) was significantly worse than the sEGM. Using a median of all 5 mEGM characteristics provided additive information (concordance with ICE 64%) and was significantly better than all of the individual mEGM characteristics except frequency content (P = .976). Conclusion: Microelectrode EGMs (in particular frequency content, amplitude, and presence of injury current) can improve real-time assessment of catheter contact compared to the use of standard bipolar EGMs. Broader use of mEGMs may enhance ablation efficacy. PMID- 29721109 TI - Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) in clinical practice. AB - Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is an inherited myocardial disease characterized by fibro-fatty replacement of the right ventricular myocardium, and associated with paroxysmal ventricular arrhythmias and sudden cardiac death (SCD). It is currently the second most common cause of SCD after hypertrophic cardiomyopathy in young people <35 years of age, causing up to 20% of deaths in this patient population. This condition has a male preponderance and is more commonly found in individuals of Italian and Greek descent. To date, there is no single diagnostic test for ARVC/D and the diagnosis is made based on clinical, electrocardiographic, and radiological findings according to the Revised 2010 Task Force Criteria. In this review, we will discuss the mainstay treatment which includes pharmacotherapy, implantable cardioverter-defibrillator insertion for abortion of sudden cardiac death, and in the advanced stages of the disease cardiac transplantation. PMID- 29721111 TI - Risk factors and prevention of dabigatran-related gastrointestinal bleeding in patients with atrial fibrillation. AB - Introduction: Dabigatran, as compared with warfarin, was associated with lower rates of stroke and systemic embolism with similar rates of major hemorrhage. But it has a significantly higher risk of gastrointestinal bleeding (GIB). There are limited data on how to prevent GIB from dabigatran and what are the risk factors. Methods: We performed a retrospective cohort study of patients with atrial fibrillation who have ever taken dabigatran for thromboprophylaxis from October 2010 to February 2013. Results: A total of 247 patients were identified. There were 10 (4%) patients who developed GIB (6 (6.5%) in PPI/H2RA users vs 4 (2.6%) in non-PPI/H2RA users; P = .184). History of GIB within 1 year prior to dabigatran initiation and HAS-BLED score >=3 are independent risk factors for GIB, with odds ratio of 25.14 (95% CI, 2.85-221.47; P < .01) and 5.85 (95% CI, 1.31-26.15; P = .021), respectively. Conclusion: In this real-world cohort, PPI/H2RA use was not associated with reduced GIB events. HAS-BLED score >=3 and prior history of GIB within 1 year are independent risk factors for GIB among dabigatran users. PMID- 29721112 TI - What factors lead to the acceleration of ventricular tachycardia during antitachycardia pacing?-Results from over 1000 episodes. AB - Introduction: Ventricular tachycardia (VT) acceleration due to antitachycardia pacing (ATP) therapy could be often observed in patients with implantable cardioverter defibrillator (ICD), which usually results in additional shock. However, few studies focused on the risk factors for VT acceleration caused by ATP therapy. The purpose of this study was to investigate risk factors for VT acceleration due to ATP delivery. Methods: We retrospectively reviewed 1056 ATP episodes in 33 patients with structural heart diseases, of whom clinical characteristics and episodes details were evaluated. Results: At individual patient level, number of VT morphologies recorded in electrograms during follow up was a risk factor with cutoff point of 1 (AUC 0.79, sensitivity 72.7%, specificity 77.3%, P < .001) to predict ATP acceleration (OR 3.50, P = .008). From episode-based analysis, VT cycle length (VTCL) and mean variation in VTCL were risk factors to predict ATP acceleration (OR 0.98, P < 0.001 vs OR 1.06, P < .001, respectively), with cutoff points of 347 ms (AUC 0.67, sensitivity 82.5%, specificity 47.6%, P < .001) and 7.3 ms (AUC 0.66, sensitivity 77.5%, specificity 56.7%, P < .001), respectively. In addition, VTs with cycle length less than 347 ms were more likely to be accelerated by burst stimulation with more pulse numbers (OR 3.31, P < .001). Conclusions: Number of VT morphologies, VTCL, and mean variation in VTCL are risk factors predicting ATP acceleration. Burst stimulation with less pulse numbers should be performed in VTs with cycle length less than 347 ms. PMID- 29721113 TI - Long-term outcomes of heart failure patients who received primary prevention implantable cardioverter-defibrillator: An observational study. AB - Background: Implantable cardioverter-defibrillator (ICD) therapy is indicated for selected heart failure patients for the primary prevention of sudden cardiac death. Little is known about the outcomes in patients selected for primary prevention device therapy in the northern region of New Zealand. Method: Heart failure patients with systolic dysfunction who underwent primary prevention ICD/cardiac resynchronization therapy-defibrillator (CRT-D) implantation between January 1, 2007, and June 1, 2015, were included. Complications, mortality, and hospitalization events were reviewed. Results: Three hundred and eighty-five primary prevention devices were implanted (269 ICD, 116 CRT-D). Mean age at implant was 59.1 +/- 11.4 years. Mean duration of follow-up was 3.64 +/- 2.17 years. The commonest cause of death was heart failure (41.8%). Only 2 patients died from sudden arrhythmic death. The 5-year heart failure mortality rate was 6%, whereas the 5-year sudden arrhythmic death rate was 0.3%. Heart failure hospitalizations were commoner in those who received ICD than CRT-D (67.7% vs 25.8%, P < .001). Maori patients have low implant rates (14%) with relatively high rates of admissions with heart failure and ventricular arrhythmia admissions. Conclusions: Even in appropriately selected heart failure patients who received primary prevention devices, only a small percentage died as a result of sudden arrhythmic death. CRT-D should be the device of choice where appropriate in heart failure patients. Significant challenges remain to improve access to device therapy and maximize benefit to those who do get implanted. PMID- 29721114 TI - Comparison of triple-site ventricular pacing versus conventional cardiac resynchronization therapy in patients with systolic heart failure: A meta analysis of randomized and observational studies. AB - Background: Conventional cardiac resynchronization therapy (CRT, Bi-V) is associated with no response in about 40% patients due to an insufficient resynchronization. Some studies showed triple-site ventricular (Tri-V) pacing had greater benefits compared with Bi-V pacing, but the results of these studies were conflicting. We hypothesized that Tri-V pacing had greater benefits on long-term outcomes compared with Bi-V pacing in patients with heart failure. Methods: PubMed, EMBASE, and the Cochrane Library were searched for clinical studies with related outcomes. Weighted mean differences (WMD) and 95% confidence intervals (CIs) were calculated to compare the change in left ventricular ejection fraction (LVEF), left ventricular geometry, functional capacity, and quality of life between Tri-V pacing group and control group. Results: Five trials with 251 patients were included in the analysis. Patients in the Tri-V pacing group had a greater improvement in LVEF (WMD 4.04; 95% CI 2.15-5.92, P < .001) and NYHA classes (WMD -0.27; 95% CI -0.42 to -0.11, P = .001) compared with control group. However, there were no significant differences in left ventricular geometry, six min walk distance, or Minnesota Living With Heart Failure Questionnaire score between the two groups. The subgroup analyses showed there might be a greater improvement in LVEF in the Tri-V pacing group in patients with QRS duration >= 155 ms (WMD 5.60; 95% CI 3.09-8.10, P < .001). Conclusions: The present analysis suggests that Tri-V pacing has greater benefits in terms of an improvement in LVEF and functional capacity in patients with systolic heart failure, especially in patients with the duration of QRS >= 155 ms. PMID- 29721106 TI - Biomarkers in Urachal Cancer and Adenocarcinomas in the Bladder: A Comprehensive Review Supplemented by Own Data. AB - Urachal cancer (UrC) is a rare but aggressive cancer. Due to overlapping histomorphology, discrimination of urachal from primary bladder adenocarcinomas (PBAC) and adenocarcinomas secondarily involving the bladder (particularly colorectal adenocarcinomas, CRC) can be challenging. Therefore, we aimed to give an overview of helpful (immunohistochemical) biomarkers and clinicopathological factors in addition to survival analyses and included institutional data from 12 urachal adenocarcinomas. A PubMed search yielded 319 suitable studies since 1930 in the English literature with 1984 cases of UrC including 1834 adenocarcinomas (92%) and 150 nonadenocarcinomas (8%). UrC was more common in men (63%), showed a median age at diagnosis of 50.8 years and a median tumor size of 6.0 cm. No associations were noted for overall survival and progression-free survival (PFS) and clinicopathological factors beside a favorable PFS in male patients (p = 0.047). The immunohistochemical markers found to be potentially helpful in the differential diagnostic situation are AMACR and CK34betaE12 (UrC versus CRC and PBAC), CK7, beta-Catenin and CD15 (UrC and PBAC versus CRC), and CEA and GATA3 (UrC and CRC versus PBAC). Serum markers like CEA, CA19-9 and CA125 might additionally be useful in the follow-up and monitoring of UrC. PMID- 29721115 TI - Electrocardiographic changes and exposure to solvents. AB - Background: Occupational exposures can cause cardiovascular disorders. Some exposures may be harmful, and exposures to chemicals such as metal welding fumes, gases, and pesticides, and stress related to physical and occupational hazard, which results in cardiovascular disorders such as arrhythmia, could be prevented. The objective of this study was to determine the electrocardiographic changes in occupational exposure to organic solvents. Methods: It was a historical cohort study and was carried out on workers of industries. The study was carried out with flexible interview, physical examination, checklist for obtaining clinical history, and electrophysiology test. Group 1 included the workers in the production line of solvent and paint, group 2 included administrative personnel, and group 3 included workers from other industries who did not have solvent exposure. A number of participants in group 1, group 2, and group 3 were 500, 498, and 501, respectively. Electrocardiographic changes were recorded in health issues. Results: The frequency of arrhythmia, P wave, and QRS complex changes were highest in group 1. The risk of arrhythmia was 1.15 (1.08-1.49), P wave change was 1.02 (1.01-2.28) which was significant and considered as highest risk,, and QRS complex change was highest in group 1, whose relative risk was 1.53 (1.46-1.61). ST segment and T wave changes (depression or elevation) were highest in group 1 and had no significant differences (P < .05). Conclusion: Working in solvent industry is a risk of developing arrhythmia. Exposure to chemical especially solvent agents mostly affects the cardiovascular system and is effective on electrocardiography, which must be prevented. PMID- 29721116 TI - Ventricular tachycardia storm originating from interventricular septum successfully treated with surgical cryoablation with electroanatomic and electrophysiological mapping before dual valve replacement. AB - A 58-year-old man with dilated cardiomyopathy was admitted with heart failure. He had a history of two catheter ablation procedures for ventricular tachycardia (VT) originating from the intraventricular septum (IVS). Before dual valve replacement (DVR), he suffered a VT storm. An electrophysiological study revealed an extended low-voltage area at the IVS with the exit of the induced VT at the anterior side. Radiofrequency application was performed at the VT exit as a landmark for surgical cryoablation (SA). During the DVR, SA was performed at the IVS using this landmark. After SA, the patient had no ventricular tachyarrhythmia. PMID- 29721117 TI - Delayed right ventricular perforation complicated by intracardiac thrombosis after implantable cardioverter-defibrillator implantation. AB - Cardiac perforation and intracardiac thrombosis are infrequent complications after implantable cardioverter-defibrillator (ICD) implantation, and a case of lead perforation complicated by thrombosis is extremely rare. We report the case of a 66-year-old man with delayed ICD lead perforation concomitant with intracardiac lead thrombosis successfully treated by anticoagulant therapy followed by transvenous lead management. PMID- 29721118 TI - Temporary external implantable cardioverter-defibrillator as a bridge to reimplantation after infected device extraction. AB - Patients with cardiac implantable electronic devices (CIED) and endovascular infection represent a difficult management group. The explantation of an implantable cardioverter-defibrillator (ICD) system deprives the patient of the protection against life-threatening ventricular tachyarrhythmias. In this study, we describe feasibility and clinical outcomes of bridging with temporary dual coil ICD lead and external ICD following the extraction of a CIED due to endovascular infection and compare the performance of this approach to other available options. PMID- 29721119 TI - Subcutaneous ICD implantation in a patient with hypertrophic cardiomyopathy after transvenous ICD failure: A case report. AB - We describe the case of a patient with hypertrophic cardiomyopathy who experienced the failure of a transvenous implantable cardioverter defibrillator (T-ICD) lead and the following inability of a second T-ICD to convert a ventricular fibrillation. A subcutaneous ICD (S-ICD) was finally implanted and was effective at defibrillation test. PMID- 29721120 TI - Experience managing pain associated with supraclavicular nerves compressed by a cardiac implantable electrical device, diagnosed by the local nerve block. AB - A 72-year-old man with ischemic cardiomyopathy was referred to undergo an implantation of a cardiac implantable electrical device (CIED). A pocket was created subcutaneously on the left anterior chest. After the operation, he complained of severe pain irradiating to his left posterior shoulder. The local anesthetic nerve block by a local infusion of mepivacaine revealed the pain was associated with the supraclavicular nerve. We re-created the pocket and shifted the generator toward the inner side, and the irradiating pain vanished. A local anesthetic supraclavicular nerve block is an important option for the diagnosis of pain after a CIED implantation. PMID- 29721121 TI - Acute electrical and hemodynamic effects of endocardial biventricular pacing using the WiSE CRT system and conventional epicardial biventricular pacing. AB - Wireless left ventricular endocardial pacing with the WiSE CRT system has recently become available as alternative to conventional epicardial CRT pacing. We report the first comparison of the acute electrical and hemodynamic response produced by the two CRT pacing modalities in a patient undergoing WiSE CRT implant after a failed conventional CRT procedure. WiSE CRT pacing showed an additive acute benefit compared with conventional CRT. These findings could potentially translate into long-term clinical benefit and introduce the potential for tri-ventricular pacing using both systems simultaneously. PMID- 29721122 TI - Atrial fibrillation deteriorates tricuspid regurgitation following implantable cardioverter defibrillator lead placement in patient with hypertrophic obstructive cardiomyopathy. AB - Although atrial fibrillation (AF) often exists in patients with hypertrophic obstructive cardiomyopathy (HOCM), combination of tricuspid regurgitation (TR) and AF after implantation of pacemaker/implantable cardioverter defibrillator (ICD) lead and its optimal management have not been well discussed in this population. Herein, we present a patient with HOCM who subsequently died due to severe heart failure and deterioration of TR following ICD lead placement with AF. Autopsy findings demonstrated that ICD leads were entrapped by anomaly structure in the right atrium and ventricle, which might affect deterioration of TR. PMID- 29721123 TI - Effective and safe lead extraction using the bidirectional rotational Evolution(r) sheath in a child with congenital heart disease. AB - We reported a challenging transvenous lead extraction procedure for lead failure in a child with congenital heart disease. Our report demonstrates that the new hand-powered bidirectional rotational Evolution RL (Cook Medical, USA) mechanical extraction sheath is an effective and safe tool for the extraction of chronically implanted leads in children. PMID- 29721124 TI - Transcutaneous electrical nerve stimulation electromagnetic interference in an implantable loop recorder. PMID- 29721125 TI - Contrast-enhanced ultrasound identifies early extrahepatic collateral contributing to residual hepatocellular tumor viability after transarterial chemoembolization. AB - The mainstay of treatment for unresectable hepatocellular carcinoma is locoregional therapy including percutaneous ablation and transarterial chemo- and radioembolization. While monitoring for tumor response after transarterial chemoembolization is crucial, current imaging strategies are suboptimal. The standard of care is contrast-enhanced magnetic resonance imaging or computed tomography imaging performed at least 4 to 6 weeks after therapy. We present a case in which contrast-enhanced ultrasound identified a specific extra-hepatic collateral from the gastroduodenal artery supplying residual viable tumor and assisting with directed transarterial management. PMID- 29721126 TI - Simultaneous occurrence of spinal epidural abscess and disk herniation causing irreversible neurologic deficits: A case report and review of the literature. PMID- 29721127 TI - LATENT SPACE MODELS FOR MULTIVIEW NETWORK DATA. AB - Social relationships consist of interactions along multiple dimensions. In social networks, this means that individuals form multiple types of relationships with the same person (e.g., an individual will not trust all of his/her acquaintances). Statistical models for these data require understanding two related types of dependence structure: (i) structure within each relationship type, or network view, and (ii) the association between views. In this paper, we propose a statistical framework that parsimoniously represents dependence between relationship types while also maintaining enough flexibility to allow individuals to serve different roles in different relationship types. Our approach builds on work on latent space models for networks [see, e.g., J. Amer. Statist. Assoc.97 (2002) 1090-1098]. These models represent the propensity for two individuals to form edges as conditionally independent given the distance between the individuals in an unobserved social space. Our work departs from previous work in this area by representing dependence structure between network views through a multivariate Bernoulli likelihood, providing a representation of between-view association. This approach infers correlations between views not explained by the latent space model. Using our method, we explore 6 multiview network structures across 75 villages in rural southern Karnataka, India [Banerjee et al. (2013)]. PMID- 29721128 TI - Structural and Kinetic Hydrogen Sorption Properties of Zr0.8Ti0.2Co Alloy Prepared by Ball Milling. AB - The effects of ball milling on the hydrogen sorption kinetics and microstructure of Zr0.8Ti0.2Co have been systematically studied. Kinetic measurements show that the hydrogenation rate and amount of Zr0.8Ti0.2Co decrease with increasing the ball milling time. However, the dehydrogenation rate accelerates as the ball milling time increases. Meanwhile, the disproportionation of Zr0.8Ti0.2Co speeds up after ball milling and the disproportionation kinetics is clearly inclined to be linear with time at 500 degrees C. It is found from X-ray powder diffraction (XRD) results that the lattice parameter of Zr0.8Ti0.2Co gradually decreases from 3.164 A to 3.153 A when the ball milling time extends from 0 h to 8 h, which is mainly responsible for the hydrogen absorption/desorption behaviors. In addition, scanning electron microscope (SEM) images demonstrate that the morphology of Zr0.8Ti0.2Co has obviously changed after ball milling, which is closely related to the hydrogen absorption kinetics. Besides, high-resolution transmission electron microscopy (HRTEM) images show that a large number of disordered microstructures including amorphous regions and defects exist after ball milling, which also play an important role in hydrogen sorption performances. This work will provide some insights into the principles of how to further improve the hydrogen sorption kinetics and disproportionation property of Zr0.8Ti0.2Co. PMID- 29721130 TI - Incidence and determinants of stillbirth among women who gave birth in Jimma University specialized hospital, Ethiopia. AB - Introduction: Worldwide approximately 2.7 million are stillborn, more than 98% of these occur in developing countries. To address the problem, incidence and determinants of stillbirth must be understood. Therefore the aim of this study was to assess incidence and determinants of stillbirth among women who gave birth in Jimma University specialized hospital. Methods: A cross-sectional study design among 413 mothers who gave birth in Jimma specialized hospital was employed. Study subjects were selected by systematic sampling technique from the list of women who gave birth in hospital in one month study period. Data were collected by using pretested and structured questionnaire. Data were edited, cleaned, coded, entered and analyzed using SPSS-20 statistical software. Univarate and bivariate (logistic regressions) analysis was employed. Results: The incidence rate of stillbirth in the Hospital during a month period was 8% or 80 per 1000 total births. The predictors that showed an independent close association with stillbirth were absence of complication (OR = 0.1, 95% CI (0.04-0.2)), referral from other health facility (OR = 0.3, 95% CI (0.1-0.7)), having antenatal care (OR = 0.3, 95% CI (0.1-0.7)) and normal vaginal delivery (OR = 0.2, 95% CI ( 0.1 0.8)). Conclusion: The incidence rate of stillbirths in our setting is high and the identified determinants were related to both ante-partum and intra-partum period. Therefore, effort should be made to improve antenatal, obstetric services and delivery services in terms awareness, access, timing and referral system to emergency care and specialized service to reduce the number of stillbirths. PMID- 29721129 TI - Rheumatic heart disease in pregnancy: a report of 2 cases. AB - Pregnant women with severe mitral stenosis tend to experience clinical decompensation with approximately 50% mortality and they may experience adverse effects of the medication they are taking, notably congenital malformations from warfarin exposure. Corrective heart surgery may increase the risk of pregnancy loss. We present 2 cases of RHD in pregnancy. The first case was a 27-year-old patient in her first pregnancy with severe mitral stenosis. Caesarean section was done for foetal distress and she delivered a small for gestational age baby. She was closely monitored postpartum and was stable on discharge. She presented with supraventricular tachycardia and died in the coronary care unit 4 weeks postpartum. The second case was a 28-year-old who was on warfarin for a mechanical mitral valve. A foetal anomaly scan done at 20 weeks showed severe congenital malformations which were not compatible with extra-uterine life. The pregnancy was terminated and she recovered well. The first case illustrates the significant mortality risk with uncorrected severe rheumatic heart disease. The second case highlights the risks of warfarin on the foetus and the need to avoid mechanical heart valves if possible in young women. RHD patients require preconception counselling so they can make informed reproductive choices. PMID- 29721131 TI - "Missing head sign". PMID- 29721132 TI - [Prognosis of referred patients with an obstetric emergency at the Yaounde Gynaecology, Obstetrics and Pediatrics Hospital]. AB - Introduction: The impact of referred patients with an obstetric emergency due to complications is not yet known. This study aimed to identify the complications associated with obstetric emergency in referred patients in Yaounde. Methods: We conducted a cross-sectional descriptive and analytical study at the Yaounde Gynaecology, Obstetrics and Pediatrics Hospital from 1 February to 31 July 2015. We compared the women referred to the Emergency Department with the non-referred women and their newborns respectively. Consecutive and comprehensive sampling technique was used for early analysis of the sociodemographic, obstetric and neonatal features. Chi-squared tests and Fisher exact probability test helped to compare the qualitative variables. Logistic regression analysis helped to eliminate the confounding factors. The significant level was set at p < 0.05. Results: After multivariate analysis, statistically significant obstetric complications in referred patients were: premature rupture of membranes (adjusted OR = 9.37, CI 95%: 2,52-66,98, p = 0.002); preterm birth (adjusted OR = 4.14 (1,88-9,16; p < 0.001) and death after severe neonatal asphyxia (adjusted OR = 6.48 (1,17-35,80); p = 0.032). Conclusion: Premature rupture of the membranes, preterm birth and death after severe neonatal asphyxia are the complications associated with obstetric emergency in referred patients in Yaounde. PMID- 29721133 TI - [The tree that hides the forest: aspergillosis associated with bronchial carcinoma (about two cases)]. AB - Endobronchial aspergilloma and intracavitary pulmonary aspergilloma may clinically and radiologically mimic a bronchial neoplasia, hence the importance of systematically searching for an association. A confirmed association completely changes the prognosis as well as the therapeutic approach. We here report two cases with two different forms of pulmonary aspergilloma associated with bronchial carcinoma. PMID- 29721134 TI - [Cutaneous ulceration: metastases should be suspected]. AB - We report the case of a 68-year old patient, with a history of chronic smoking, presenting with cutaneous swelling at the level of the anterior chest wall evolving over a period of 5 months and gradually increasing in size. It was associated with gradually worsening exertional dyspnoea evolving in a context of an alteration of general state and 15kg weight loss. Mucocutaneous examination objectified rounded, well-defined cutaneous swelling measuring 5cm x 5cm, with erythematous border and with ulcerated surface (A). Lymph nodes examination showed two painless, mobile, bilateral axillary adenopathies with a firm consistency, each measuring 2cm. Histological and immuno-histochemical examination of skin biopsy specimen showed adenocarcinoma compatible with a lung origin (B and C). Chest CT scan confirmed the presence of left lingular pulmonary process (D). The therapeutic approach was based on pemetrexed + platinum salt chemotherapy. The patient died 4 months after the diagnosis of the disease. PMID- 29721135 TI - Penetrating head trauma: 03 rare cases and literature review. AB - Penetrating head trauma (PHT) include all open head injuries with foreign object in the brain. Although less common than closed head trauma, penetrating head trauma carry a worse prognosis. We received three unusual cases of penetrating head injuries whose prognosis was different according to clinical presentation and initial management of the patient. Treatment of penetrating head trauma aims at controlling bleeding, controlling intracranial pressure and preventing infections. Despite the efforts made by national authorities as well as the adequate management in hospitals, penetrating head injuries are still frequent with significant mortality and morbidity. PMID- 29721137 TI - Elderly woman with soft tissue ossification. PMID- 29721136 TI - ? AB - Heterotopic pregnancy is defined as the coexistence of intrauterine pregnancy (IP) and ectopic pregnancy (EP), regardless of its location. It is a type of bi ovular dizygotic twin pregnancy, its occurrence in a spontaneous cycle is rare. This is a rare and serious pathology which may compromise maternal prognosis. We report two cases of heterotopic pregnancy treated in the Department of Gynecology and Obstetrics I at the University Hospital Hassan II of Fez, over a one-year period. Clinical, ecographic and therapeutic data of this pathology were reported. Pelvic pain was the main reason for consultation. The diagnosis of heterotopic pregnancy was suspected on ultrasound in both cases. The first patient underwent conservative treatment by laparoscopy while the second patient underwent salpingectomy by mini-transverse laparotomy. IP outcome was favorable both cases. PMID- 29721138 TI - Evaluation of the adverse events following immunizations surveillance system in Harare City, Zimbabwe, 2016: a descriptive cross sectional study. AB - Introduction: Vaccines safety are monitored by looking for Adverse Events Following Immunizations (AEFIs). A review of the 2014 Harare City consolidated monthly return form (T5) revealed that 28 AEFIs were seen in 2014. However, only 21 were reported through the system. We therefore evaluated the Harare City AEFI surveillance system to assess its usefulness. Methods: A descriptive cross sectional study was conducted. Twenty one of 41 clinics were randomly selected and 51 health workers were randomly recruited. Interviewer administered questionnaires were used to collect data. Epi info 7 was used to generate frequencies, means and proportions. Results: Out of 51 respondents, 50 (98%) knew the purpose of AEFI system, 48 (94%) knew at least two presenting symptoms of AEFIs and 39 (77%) knew the correct date of form submission to the next level. Receiving no feedback 24 (47.1%), fear of victimisation 16 (31.4%) and work overload 11 (21.6%) were the major reasons for under reporting. Eighty six percent perceived the system to be simple and 43 (84%) were willing to continue participating. Fifty three percent (27) reported taking public health actions (such as awareness campaigns & making follow ups) basing on AEFI data collected. All 46 reviewed forms were completely filled and submitted in time. All 21 clinics had written AEFI guidelines and case definitions. Only 14 of 21 clinics had adequately stocked emergency drugs. The total cost for a single notification was estimated at US$22.30. Conclusion: The system was useful, simple, acceptable, timely, stable, representative but costly. The good performance of the system reported in this evaluation could be attributed to high health worker knowledge. Following this evaluation, replenishment of out of stock drugs and follow up of missing 2014 AEFI feedback from MCAZ were done. In addition, making the system electronic is recommended. PMID- 29721139 TI - What do you think of an unusual axillary mass? AB - Skin apocrine carcinoma is a rare malgnancy of epidermal adnexa, most frequent in axillary seat, where apocrine sweat gland are abundant, the neoplasm can arise in groin, anogenital, lips, eyelid, characterized by a plate or surface area of nodules hummocky. Etiology and incidence are not known. The prognosis is influenced by the risk of locoregional recurrence and metastatic evolution. We describe the case of 61-year-old man who presented a left axillary slow-growing mass since 2 years ago. The cutaneous biopsy objectified an apocrine adenocarcinoma. The paraclinic exams performed to detect primary breast were tumor negative, first step before confirming the diagnosis. Standard treatment is surgical excision with margins of 2 to 3cm for local tumor, for apocrine adenocarcinoma regional lymph node dissection if nodes were clinically positive is wide surgical excision. This kind of tumour is chemoresistant. In this case, adjuvant chemotherapy was indicated, before surgery to reduce tumoral volume. This case illustrates the importance clinicopathological correlation of skin cancer, particularly apocrine one. Clinical particularity and careful analyses histology helps diagnosis approach. PMID- 29721140 TI - Acceptance of sugar reduction in yoghurt among Moroccan population. AB - Introduction: Morocco has recently developed a plan of reducing sugar consumption to reinforce prevention of non-communicable diseases and to contribute to the achievement of global voluntary targets for non-communicable diseases set by ICN2 by 2025. The objective of the present study was to assess acceptance of yogurts with different percentage reduction of sugar by the Moroccan population. Methods: A total of 201 participants (age > 15 y.) were recruited to determine the level of sugar reduction in yogurt. Sucrose was added to a plain yoghurt in the following different concentrations 166.5; 149.8; 133.2; 116.5; 99; 83.2 mM/l, corresponding to the reduction of sugar of 0%, -10%, -20%, -30%, -40% and -50%, respectively, compared available yogurt in local market. Overall, the acceptability scores of the different yoghurts were based on liking, "Just About Right" (JAR) and purchase intent scales was used to score the different yoghurts. Results: Yogurts containing -20% and -30% added sugar were highly accepted by 81% and 74% of respondents. Based on JAR score, yoghurt with 20% (133.2mM/l) and 30% (116.5 mM/l) reduction were considered as "Just about right" by 42.7% and 44.3% respectively. Best average score of purchase intent was obtained for sucrose concentration of 149.8 mM/l. 35.8% and 40.3% for yoghurt with sucrose concentration of 133.2 mM/l and 116.5 mM/l respectively. Conclusion: The finding from this study indicated that yogurts containing -20% and -30% added sugar were most accepted by respondents. Advocacy before dairy industry to have them commit towards sugar reduction in yogurt is needed, in order to help achieving the national sugar reduction strategy in Morocco. PMID- 29721142 TI - Bilateral plantar deep cleft. PMID- 29721143 TI - [A rare case of ocular scarrings in a patient with Vogt-Koyanagi-Harada disease]. AB - We here report the case of a 27-year old patient, followed-up in our Department for treatment of chronic Vogt-Koyanagi-Harada disease ( VKH disease). Fundus examination showed depigmentation of the retinal pigment epithelium and of the choroid, appearing as a pseudotumoral peripapillary lesion. Vogt-Koyanagi-Harada disease is a multisystem disorder, characterized by bilateral granulomatous panuveitis with serous exudative multifocal retinal detachment. Pathophysiology of this disease is unknown, but an immunological cellular reaction against melanocytes of the skin, the meninges, the retina, the uvea, the cochlea and the labyrinth is suspected. This disease mainly occurs in young subjects from the Far East as well as in pigmented subjects. Ocular involvement is often associated with neurological (meningeal stiffness, headache, sometimes associated with focal deficit and erebrospinal fluid (CSF) pleocytosis), auditory ( perceptive deafness) and cutaneous (vitiligo, poliosis, alopecia and canities) manifestations. It usually evolves in three phases: a prodromal phase mainly characterized by neurological signs, an acute uveitic phase, a chronic phase of convalescence characterized by choroidal and tegument depigmentation or a phase of recurrence during which subretinal neovessels and subretinal fibrosis may appear. Scarrings manifest during the chronic phase of VKH disease, which is dominated by diffuse depigmentation of the fundus of the eye, scars due to nummular chorioretinal atrophy, wheals due to diffuse depigmentation, macular scar remodeling. Pseudotumoral appearance is rare and atypical during the chronic phase of VKH disease. Treatment is based on intravenous corticosteroids followed by a cycle of oral therapy. Patient should be early treated with massive and prolonged therapy to improve prognosis. PMID- 29721141 TI - Cultural influences behind cholera transmission in the Far North Region, Republic of Cameroon: a field experience and implications for operational level planning of interventions. AB - Introduction: In recent years, the Far North Region of Cameroon has experienced serious and recurrent cholera outbreaks. Yet, understanding of cultural influences on outbreaks and spread remain poorly understood. This qualitative study explored cultural influences on cholera exposure in this region. Methods: Interviews and group discussions were conducted in two phases. Phase I involved key informants and phase II included focus group and household discussions. Thematic techniques including word repetition, key-indigenous-terms, and key words-in-context were used for qualitative data analysis. Results: Key informants attributed cholera etiology to dirt and spread through water (caneri) and food (group eating or faire-un-rond) while group discussions attributed it to a reprimand from god and transmission through the air. Participants suggested that funerals, weddings, open defecation, and mountaintop burial might influence cholera exposure and facilitate its spread. Hospital avoidance and non-adherence with cholera treatment regimens were linked to favorable beliefs about traditional medicine (rural-urban mentality confrontation). Furthermore, a multiplicity of ethnic languages, mistrust of message sources, culture of dependency and sentimental animal husbandry were barriers to the reception of public health messages. Conclusion: Many participants had limited scientific knowledge about cholera etiology and transmission. The cultural practice of mountain burial seemed to explain the high cholera attack rate in the mountainous terrain compared to the floodplains. Cultural factors are likely to play important roles in the exposure to and spread of cholera. Understanding cultural context, individual and community perceptions of risk and disease may help public health agencies in response to outbreak prevention and control. PMID- 29721144 TI - Breast cancer: descriptive profile of 80 women attending breast cancer care in the Department of General and Digestive Surgery of CHU-YO. AB - Introduction: Breast cancer is a common cause of death among women in Burkina Faso. The aim of this study was to determine a descriptive profile of 80 women and establish a description of risk factors associated with breast cancer in these women. Methods: This cross-sectional study recruited women with breast cancer in Ouagadougou. Teaching Hospital Yalgado Ouedraogo in Burkina Faso from January 2015 to February 2016. We have collected data on socio-demographic characteristics, reproductive status, clinical information, treatment and molecular characteristics. Results: The average age of the study population was 48.2+/-12.4 years. Family history of breast cancer was reported in 18.75% of the studied participants against 16.25% family history for other types of cancer. Patients from urban areas represented 87.5% of our studied population with 58.75% of household, multiparous (55.0%), no aborts status (56.2%), post-menopausal women (53.75%), no oral contraception (63.75%), regular menstrual cycle (71.25%) and the prevalence of obesity was 12.5%. The clinical and molecular characteristics showed that left-sided breast cancer accounted for 51.25 %, high grade (II and III) represented 93.75 % of cases and the majority of tumors were infiltrating ductal carcinomas (93.75%) with stages III and IV accounted for 50.0%. Conclusion: This study described the distribution of risks factors in a population of breast cancer women. Although more research are needed to support these findings, a clear understanding of risk factors associated with breast cancer would contribute to significantly reduce breast cancer incidence and mortality in Burkina Faso. PMID- 29721146 TI - Retention of children under 18 months testing HIV positive in care in Swaziland: a retrospective study. AB - Introduction: Significant progress has been made with respect to the initiation of children on antiretroviral therapy (ART) in Southern Africa including Swaziland, however retention of these children in care poses a major challenge. The aim of the study was to assess retention to care in children testing HIV positive taking into account the number of return child welfare care (CWC) visits the child made. Methods: A retrospective cross sectional study and was conducted at 4 facilities in Swaziland. All children who were HIV infected from 0 to 18 months were identified using the child welfare register (CWC). Infant characteristics were obtained from the child welfare register and early infant diagnosis logbooks. Proportion of patients retained in care were calculated at three, six, nine and twelve months. Results: Of the 32 HIV positive children identified tested between December 2014 up to July 2016, sixty eight percent (n = 22) of the children that tested HIV positive were retained at three months, 40.6% at six months, 18.8% at nine months and 12.5% at twelve months. Children that resided in urban areas, more male than female children, children from mothers who were on antiretroviral treatment, children initiated on antiretroviral treatment, mothers on antiretroviral treatment for more than one year and children who received Infant Nevirapine were more likely to be retained. Conclusion: Facilities are performing well in terms of identifying HIV positive children within the first two months of life and linking them into care. However, as time progresses the retention of children in care declines. Innovative strategies need to be developed to enhance patient retention. PMID- 29721145 TI - [Can medical students' motivation for a course of basic physiology education integrating into lectures some active learning methods be improved?] AB - Students' motivation is a critical component of learning and students' perception of activity value is one of the three major components of their motivation. How can we make students perceive the usefulness and the interest of their university courses while increasing their motivation? The aim of our study was to determine students' perception of basic physiology education value and to assess the impact of lecture integration into some active learning methods on the motivation of the students of the first cycle of Medicine in a junior faculty. We conducted a prospective study, involving the students in their second year of medical studies. At first, we assessed students' motivation for university courses through a first questionnaire, after we integrated two educational activities: the case study and the realization of a conceptual map for the lectures of the physiology module and then we evaluated, through a second questionnaire, the impact of these two activities on students' motivation. Out of 249 students in their second year of medical studies 131 and 109 students have completed and returned the 1st and 2nd questionnaire respectively. Overall students' motivation for their university courses was very favorable, even if the motivation for physiology course (70.8%) was slightly lower than for all the courses (80%). Our students enjoyed the two proposed activities and only 13% (for the case study) and 16.8% (for the map) were not satisfied. 40.9% of students completed a conceptual map whose quality judged on the identification of concepts and of the links between concepts was globally satisfactory for a first experience. Students' motivation is influenced by multiple internal and external factors and is a big problem in the university environment. In this context, a rigorous planning of diversified and active educational activities is one of the main gateways for teacher to encourage motivation. PMID- 29721147 TI - ? AB - Diastematomyelia is a rare spinal dysraphism in which the spinal cord and its content are split. Two types of diastematomyelia have been described. We report the case of a 12 year old male patient presenting with reduced lower limb muscle strength without associated sphincteric disorders. The patient underwent axial, sagittal and coronal T1 and T2-weighted MRI sequence of the spine. MRI showed a bifid appearance of the bone marrow of thoracolumbar vertebrae in two hemi-cords without bone spur separating the two hemi-marrows, compatible with type 1 diastematomyelia. It was associated with low tethered spinal cord with syringomyelic cavity involving the left hemi-marrow and with biloculated fibrotic lesion at the level of the right hemi-marrow compatible with a neuroenteric cyst. MRI also showed incomplete closure of the posterior arch of D12 vertebra which communicated with a subcutaneous pocket in relation to a dermal sinus. Diastematomyelia is a rare abnormality of the spine which can be associated with other malformations. Therapeutic strategy essentially depends on the progression of the clinical signs (neurological) and of associated malformations. PMID- 29721148 TI - Yellow and black-stained fingers in a patient with headache. PMID- 29721149 TI - Low-Frequency Intermittent Hypoxia Promotes Subcutaneous Adipogenic Differentiation. AB - Obstructive sleep apnea (OSA), characterized by intermittent hypoxia (IH), is associated with obesity and metabolic disorders. The mass and function of adipose tissue are largely dependent on adipogenesis. The impact of low-frequency IH on adipogenesis is unknown. Sprague-Dawley rats were subjected to IH (4 min for 10% O2 and 2 min for 21% O2) or intermittent normoxia (IN) for 6 weeks. The degree of adipogenic differentiation was evaluated by adipogenic transcriptional factors, adipocyte-specific proteins, and oily droplet production in both subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). Upregulation of proadipogenic markers (CEBPalpha, PPARgamma, and FABP4) and downregulation of antiadipogenic markers CHOP in line with smaller size of adipocytes were found in IH-exposed SAT. In vitro experiments using human preadipocytes (HPAs) of subcutaneous lineage during differentiation phase, subjected to IH (1% O2 for 10 min and 21% O2 for 5 min; 5% CO2) or IN treatment, were done to investigate the insulin-like growth factor 1 receptor (IGF-1R)/Akt pathway in adipogenesis. IH promoted the accumulation of oily droplets and adipogenesis-associated markers. IGF-1R kinase inhibitor NVP-AEW541 attenuated the proadipogenic role in IH exposed HPAs. In summary, relatively low frequency of IH may enhance adipogenesis preferentially in SAT. PMID- 29721150 TI - p66Shc Inactivation Modifies RNS Production, Regulates Sirt3 Activity, and Improves Mitochondrial Homeostasis, Delaying the Aging Process in Mouse Brain. AB - Programmed and damage aging theories have traditionally been conceived as stand alone schools of thought. However, the p66Shc adaptor protein has demonstrated that aging-regulating genes and reactive oxygen species (ROS) are closely interconnected, since its absence modifies metabolic homeostasis by providing oxidative stress resistance and promoting longevity. p66Shc(-/-) mice are a unique opportunity to further comprehend the bidirectional relationship between redox homeostasis and the imbalance of mitochondrial biogenesis and dynamics during aging. This study shows that brain mitochondria of p66Shc(-/-) aged mice exhibit a reduced alteration of redox balance with a decrease in both ROS generation and its detoxification activity. We also demonstrate a strong link between reactive nitrogen species (RNS) and mitochondrial function, morphology, and biogenesis, where low levels of ONOO- formation present in aged p66Shc(-/-) mouse brain prevent protein nitration, delaying the loss of biological functions characteristic of the aging process. Sirt3 modulates age-associated mitochondrial biology and function via lysine deacetylation of target proteins, and we show that its regulation depends on its nitration status and is benefited by the improved NAD+/NADH ratio in aged p66Shc(-/-) brain mitochondria. Low levels of protein nitration and acetylation could cause the metabolic homeostasis maintenance observed during aging in this group, thus increasing its lifespan. PMID- 29721151 TI - Strategies for high-altitude adaptation revealed from high-quality draft genome of non-violacein producing Janthinobacterium lividum ERGS5:01. AB - A light pink coloured bacterial strain ERGS5:01 isolated from glacial stream water of Sikkim Himalaya was affiliated to Janthinobacterium lividum based on 16S rRNA gene sequence identity and phylogenetic clustering. Whole genome sequencing was performed for the strain to confirm its taxonomy as it lacked the typical violet pigmentation of the genus and also to decipher its survival strategy at the aquatic ecosystem of high elevation. The PacBio RSII sequencing generated genome of 5,168,928 bp with 4575 protein-coding genes and 118 RNA genes. Whole genome-based multilocus sequence analysis clustering, in silico DDH similarity value of 95.1% and, the ANI value of 99.25% established the identity of the strain ERGS5:01 (MCC 2953) as a non-violacein producing J. lividum. The genome comparisons across genus Janthinobacterium revealed an open pan-genome with the scope of the addition of new orthologous cluster to complete the genomic inventory. The genomic insight provided the genetic basis of freezing and frequent freeze-thaw cycle tolerance and, for industrially important enzymes. Extended insight into the genome provided clues of crucial genes associated with adaptation in the harsh aquatic ecosystem of high altitude. PMID- 29721152 TI - Tumor cell death after electrotransfer of plasmid DNA is associated with cytosolic DNA sensor upregulation. AB - Cytosolic DNA sensors are a subgroup of pattern recognition receptors (PRRs) and are activated by the abnormal presence of the DNA in the cytosol. Their activation leads to the upregulation of pro-inflammatory cytokines and chemokines and can also induce cell death. The presence of cytosolic DNA sensors and inflammatory cytokines in TS/A murine mammary adenocarcinoma and WEHI 164 fibrosarcoma cells was demonstrated using real time reverse transcription polymerase chain reaction (RT-PCR), western blotting and enzyme-linked immunosorbent assay (ELISA). After electrotransfer of plasmid DNA (pDNA) using two pulse protocols, the upregulation of DNA-depended activator of interferon regulatory factor or Z-DNA binding protein 1 (DAI/ZBP1), DEAD (Asp-Glu-Ala-Asp) box polypeptide 60 (DDX60) and interferon-inducible protein 204 (p204) mRNAs was observed in both tumor cell lines, but their expression was pulse protocol dependent. A decrease in cell survival was also observed; it was cell type, DNA concentration and pulse protocol dependent. Furthermore, the different protocols of electrotransfer led to different cell death outcomes, necrosis and apoptosis, as indicated by an annexin V and 7AAD assays. The obtained data provide new insights on the presence of cytosolic DNA sensors in tumor cells and the activation of different types of cells death after electrotransfer of pDNA. These observations have important implications on the planning of gene therapy or DNA vaccination protocols. PMID- 29721154 TI - Consensus molecular subtypes classification of colorectal cancer as a predictive factor for chemotherapeutic efficacy against metastatic colorectal cancer. AB - The consensus molecular subtypes (CMS) classification is one of the most robust colorectal cancer (CRC) classifications based on comprehensive gene expression profiles. This study aimed to clarify whether the CMS is a predictive factor for therapeutic effects of standard chemotherapies for metastatic CRC (mCRC). We retrospectively enrolled 193 patients with mCRCs, and using comprehensive gene expression data, classified them into 4 subtypes: CMS1-CMS4. The associations between the subtypes and treatment outcomes were analyzed. Regarding first-line chemotherapy, irinotecan (IRI)-based chemotherapy was significantly superior to oxaliplatin (OX)-based chemotherapy for progression-free survival (PFS; hazard ratio [HR] = 0.31, 95% confidence interval [CI] 0.13-0.64) and overall survival (OS; HR = 0.45, 95% CI 0.19-0.99) in CMS4. Regarding the anti-epidermal growth factor receptor (anti-EGFR) therapy, CMS1 showed particularly worse PFS (HR = 2.50, 95% CI 1.31-4.39) and OS (HR = 4.23, 95% CI 1.83-9.04), and CMS2 showed particularly good PFS (HR = 0.67, 95% CI 0.44-1.01) and OS (HR = 0.49, 95% CI 0.27-0.87) compared with the other subtypes. The biological characteristics of CMS may influence the efficacy of chemotherapy. CMS might be a new predictive factor for the efficacy of chemotherapy against mCRCs. PMID- 29721153 TI - Application of polymersomes engineered to target p32 protein for detection of small breast tumors in mice. AB - Triple negative breast cancer (TNBC) is the deadliest form of breast cancer and its successful treatment critically depends on early diagnosis and therapy. The multi-compartment protein p32 is overexpressed and present at cell surfaces in a variety of tumors, including TNBC, specifically in the malignant cells and endothelial cells, and in macrophages localized in hypoxic areas of the tumor. Herein we used polyethylene glycol-polycaprolactone polymersomes that were affinity targeted with the p32-binding tumor penetrating peptide LinTT1 (AKRGARSTA) for imaging of TNBC lesions. A tyrosine residue was added to the peptide to allow for 124I labeling and PET imaging. In a TNBC model in mice, systemic LinTT1-targeted polymersomes accumulated in early tumor lesions more than twice as efficiently as untargeted polymersomes with up to 20% ID/cc at 24 h after administration. The PET-imaging was very sensitive, allowing detection of tumors as small as ~20 mm3. Confocal imaging of tumor tissue sections revealed a high degree of vascular exit and stromal penetration of LinTT1-targeted polymersomes and co-localization with tumor-associated macrophages. Our studies show that systemic LinTT1-targeted polymersomes can be potentially used for precision-guided tumor imaging and treatment of TNBC. PMID- 29721155 TI - Comprehensive analysis of telomerase inhibition by gallotannin. AB - Gallotannin (or tannic acid) is a naturally occurring compound that inhibits cell growth and activity of different DNA-polymerases, including telomerase. The purpose of the present study was to gain insight into the mechanism of telomerase inhibition by gallotannin. We determined that gallotannin inhibits telomerase in vitro with an half maximal inhibitory concentrations value of 130 nM, but it does not affect telomerase complex assembly and component levels in vivo. The inhibitory activity of gallotannin against telomerase provides an additional explanation for the anti-cancer activities of this compound. PMID- 29721156 TI - Pro-tumoral immune cell alterations in wild type and Shb-deficient mice in response to 4T1 breast carcinomas. AB - To assess mechanisms responsible for breast carcinoma metastasis, 4T1 breast carcinomas were grown orthotopically in wild type or Shb knockout mice. Tumor growth, metastasis, vascular characteristics and immune cell properties were analyzed. Absence of Shb did not affect tumor growth although it increased lung metastasis. Shb knockout mouse tumors showed decreased redness and less developed vascular plexa located at the periphery of the tumors. No difference in overall tumor vascular density, leakage or pericyte coverage was noted between the genotypes although the average vessel size was smaller in the knockout. Tumors induced an increase of CD11b+ cells in spleen, lymph node, thymus, bone marrow and blood. Numbers of Shb knockout CD11b/CD8+ cells were decreased in lymph nodes and bone marrow of tumor bearing mice. Mice with tumors had reduced numbers of CD4+ lymphocytes in blood/lymphoid organs, whereas in most of these locations the proportion of CD4+ cells co-expressing FoxP3 was increased, suggesting a relative increase in Treg cells. This finding was reinforced by increased blood interleukin-35 (IL-35) in wild type tumor bearing mice. Shb knockout blood showed in addition an increased proportion of IL-35 expressing Treg cells, supporting the notion that absence of Shb further promotes tumor evasion from immune cell recognition. This could explain the increased number of lung metastases observed under these conditions. In conclusion, 4T1 tumors alter immune cell responses that promote tumor expansion, metastasis and escape from T cell recognition in an Shb dependent manner. PMID- 29721158 TI - Acquired resistance to temsirolimus is associated with integrin alpha7 driven chemotactic activity of renal cell carcinoma in vitro. AB - The mechanistic target of the rapamycin (mTOR) inhibitor, temsirolimus, has significantly improved the outcome of patients with renal cell carcinoma (RCC). However, development of temsirolimus-resistance limits its effect and metastatic progression subsequently recurs. Since integrin alpha7 (ITGA7) is speculated to promote metastasis, this investigation was designed to investigate whether temsirolimus-resistance is associated with altered ITGA7 expression in RCC cell lines and modified tumor cell adhesion and invasion. Caki-1, KTCTL-26, and A498 RCC cell lines were driven to temsirolimus-resistance by exposing them to temsirolimus over a period of 12 months. Subsequently, adhesion to human umbilical vein endothelial cells, to immobilized fibronectin, or collagen was investigated. Chemotaxis was evaluated with a modified Boyden chamber assay and ITGA7 expression by flow cytometry and western blotting. Chemotaxis significantly decreased in temsirolimus-sensitive cell lines upon exposure to low-dosed temsirolimus, but increased in temsirolimus-resistant tumor cells upon reexposure to the same temsirolimus dose. The increase in chemotaxis was accompanied by elevated ITGA7 at the cell surface membrane with simultaneous reduction of intracellular ITGA7. ITGA7 knock-down significantly diminished motility of temsirolimous-sensitive cells but elevated chemotactic activity of temsirolimus resistant Caki-1 and KTCTL-26 cells. Therefore, ITGA7 appears closely linked to adhesion and migration regulation in RCC cells. It is postulated that temsirolimus-resistance is associated with translocation of ITGA7 from inside the cell to the outer surface. This switch forces RCC migration forward. Whether ITGA7 can serve as an important target in combatting RCC requires further investigation. PMID- 29721157 TI - BET inhibition is an effective approach against KRAS-driven PDAC and NSCLC. AB - Effectively treating KRAS-driven tumors remains an unsolved challenge. The inhibition of downstream signaling effectors is a way of overcoming the issue of direct targeting of mutant KRAS, which has shown limited efficacy so far. Bromodomain and Extra-Terminal (BET) protein inhibition has displayed anti-tumor activity in a wide range of cancers, including KRAS-driven malignancies. Here, we preclinically evaluate the effect of BET inhibition making use of a new BET inhibitor, BAY 1238097, against Pancreatic Ductal Adenocarcinoma (PDAC) and Non Small Cell Lung Cancer (NSCLC) models harboring RAS mutations both in vivo and in vitro. Our results demonstrate that BET inhibition displays significant therapeutic impact in genetic mouse models of KRAS-driven PDAC and NSCLC, reducing both tumor area and tumor grade. The same approach also causes a significant reduction in cell number of a panel of RAS-mutated human cancer cell lines (8 PDAC and 6 NSCLC). In this context, we demonstrate that while BET inhibition by BAY 1238097 decreases MYC expression in some cell lines, at least in PDAC cells its anti-tumorigenic effect is independent of MYC regulation. Together, these studies reinforce the use of BET inhibition and prompt the optimization of more efficient and less toxic BET inhibitors for the treatment of KRAS-driven malignancies, which are in urgent therapeutic need. PMID- 29721159 TI - Synapsin I and Synapsin II regulate neurogenesis in the dentate gyrus of adult mice. AB - Adult neurogenesis is emerging as an important player in brain functions and homeostasis, while impaired or altered adult neurogenesis has been associated with a number of neuropsychiatric diseases, such as depression and epilepsy. Here we investigated the possibility that synapsins (Syns) I and II, beyond their known functions in developing and mature neurons, also play a role in adult neurogenesis. We performed a systematic evaluation of the distinct stages of neurogenesis in the hippocampal dentate gyrus of Syn I and Syn II knockout (KO) mice, before (2-months-old) and after (6-months-old) the appearance of the epileptic phenotype. We found that Syns I and II play an important role in the regulation of adult neurogenesis. In juvenile mice, Syn II deletion was associated with a specific decrease in the proliferation of neuronal progenitors, whereas Syn I deletion impaired the survival of newborn neurons. These defects were reverted after the appearance of the epileptic phenotype, with Syn I KO and Syn II KO mice exhibiting significant increases in survival and proliferation, respectively. Interestingly, long-term potentiation dependent on newborn neurons was present in both juvenile Syn mutants while, at later ages, it was only preserved in Syn II KO mice that also displayed an increased expression of brain derived neurotrophic factor. This study suggests that Syns I and II play a role in adult neurogenesis and the defects in neurogenesis associated with Syn deletion may contribute to the alterations of cognitive functions observed in Syn deficient mice. PMID- 29721160 TI - Integrated multigene expression panel to prognosticate patients with gastric cancer. AB - Most of the proposed individual markers had limited clinical utility due to the inherent biological and genetic heterogeneity of gastric cancer. We aimed to build a new molecular-based model to predict prognosis in patients with gastric cancer. A total of 200 patients who underwent gastric resection for gastric cancer were divided into learning and validation cohorts using a table of random numbers in a 1:1 ratio. In the learning cohort, mRNA expression levels of 15 molecular markers in gastric tissues were analyzed and concordance index (C index) values of all single and combinations of the 15 candidate markers for overall survival were calculated. The multigene expression panel was designed according to C-index values and the subpopulation index. Expression scores were determined with weighting according to the coefficient of each constituent. The reproducibility of the panel was evaluated in the validation cohort. C-index values of the 15 single candidate markers ranged from 0.506-0.653. Among 32,767 combinations, the optimal and balanced expression panel comprised four constituents (MAGED2, SYT8, BTG1, and FAM46) and the C-index value was 0.793. Using this panel, patients were provisionally categorized with scores of 1-3, and clearly stratified into favorable, intermediate, and poor overall survival groups. In the validation cohort, both overall and disease-free survival rates decreased incrementally with increasing expression scores. Multivariate analysis revealed that the expression score was an independent prognostic factor for overall survival after curative gastrectomy. We developed an integrated multigene expression panel that simply and accurately stratified risk of patients with gastric cancer. PMID- 29721161 TI - Findings of multiple HPV genotypes in cervical carcinoma are associated with poor cancer-specific survival in a Swedish cohort of cervical cancer primarily treated with radiotherapy. AB - Cervical cancer (CC) is one of the most common cancers in women and virtually all cases of CC are a result of a persistent infection of human papillomavirus (HPV). For disease detected in early stages there is curing treatment but when diagnosed late with recurring disease and metastasis there are limited possibilities. Here we evaluate HPV impact on treatment resistance and metastatic disease progression. Prevalence and distribution of HPV genotypes and HPV16 variants in a Swedish CC patient cohort (n=209) was evaluated, as well as HPV influence on patient prognosis. Tumor samples suitable for analysis (n=204) were genotyped using two different real-time PCR methods. HPV16 variant analysis was made using pyrosequencing. Results showed that HPV prevalence in the total series was 93%. Of the HPV-positive samples, 13% contained multiple infections, typically with two high-risk HPV together. Primary cure rate for the complete series was 95%. Recurrence rate of the complete series was 28% and distant recurrences were most frequent (20%). Patients with tumors containing multiple HPV-strains and particularly HPV genotypes belonging to the alpha 7 and 9 species together had a significantly higher rate of distant tumor recurrences and worse cancer-specific survival rate. PMID- 29721162 TI - Does perioperative chemotherapy improve survival in upper tract urothelial carcinoma? A population based analysis. AB - Objectives: To evaluate the utilization and outcomes of perioperative chemotherapy in non-metastatic UTUC patients over the past decade using a large national database. Methods: All patients aged 18 and older diagnosed with non metastatic UTUC between 2004 and 2013 were identified within the Surveillance, Epidemiology and End Results (SEER) database. Relevant clinical data was collected and predictors of cancer specific mortality (CSM) and other cause mortality (OCM) were analyzed. Results: The total cohort included 8,762 patients. Of these, 1,402 (16%) patients received chemotherapy, including only 35% of high risk patients (>pT2 or N1). Treated patients had higher CSM (21.3% vs. 13.1%, p<0.001). Predictors of chemotherapy utilization included residence in Midwest states, tumor located in the ureter, higher stage and grade. Predictors of CSM included older age, residence in southern states, receipt of chemotherapy (HR = 1.151, 95% CI: 1.003-1.32, p=0.044), higher stage and grade. OCM was predicted by male gender, older age, ureteral tumor, and higher stage. A subset analysis of patients younger than 65 showed similar predictors, while an analysis of high risk patients demonstrated that chemotherapy receipt did not predict CSM or OCM. Conclusions: In this large contemporary non-metastatic UTUC cohort, chemotherapy utilization was found to be quite infrequent, but increasing steadily. Perioperative chemotherapy had no effect on CSM in high-risk patients, while correlated to higher CSM in the younger patients. PMID- 29721163 TI - A phase II trial of 1st-line modified-FOLFOXIRI plus bevacizumab treatment for metastatic colorectal cancer harboring RAS mutation: JACCRO CC-11. AB - FOLFOXIRI plus bevacizumab is considered a standard initial therapy for metastatic colorectal cancer (mCRC). However, few prospective trials have evaluated triplet therapy plus bevacizumab in patients with RAS mutant mCRC. Patients with an age of 20 to 75 years, and unresectable, measurable tumors harboring RAS mutation were given first-line treatment with bevacizumab (5 mg/kg on day 1) plus modified-FOLFOXIRI (irinotecan 150 mg/m2, oxaliplatin 85 mg/m2, levofolinate 200 mg/m2, and fluorouracil 2400 mg/m2 as a 46-h continuous infusion on day 1, repeated every 2 weeks). The primary endpoint was the objective response rate (ORR) as evaluated by an external review board. Progression-free survival (PFS), overall survival, early tumor shrinkage (ETS), depth of response (DpR), and safety were secondary endpoints. Among 64 patients who were enrolled between October 2014 and August 2016, 62 were evaluable for efficacy (right-sided tumors in 27%). ORR and disease control rate were 75.8% (95% confidence interval [CI] 65.1-86.5) and 96.8%, respectively. ETS was 73.8%, and median DpR was 49.2%. Median PFS was 11.5 (95% CI 9.5-14.0) months as of the cut-off date of September 2017. Adverse events of grade 3 or 4 were neutropenia (54%), hypertension (32%), diarrhea (13%), anorexia (11%), peripheral neuropathy (2%), and febrile neutropenia (5%). In conclusion, this prospective trial demonstrated for the first time that FOLFOXIRI plus bevacizumab is an active first-line treatment for patients with RAS mutant mCRC. Modified-FOLFOXIRI plus bevacizumab might become an alternative regimen of triplet chemotherapy for mCRC in Japan. PMID- 29721164 TI - Novel therapeutic features of disulfiram against hepatocellular carcinoma cells with inhibitory effects on a disintegrin and metalloproteinase 10. AB - Our previous genome-wide association study identified the anti-tumor ligand MHC class I polypeptide-related sequence A (MICA) as a susceptibility gene for hepatitis C virus-induced hepatocellular carcinoma (HCC). We subsequently proved that pharmacological restoration of membrane-bound MICA in HCC cells boosted natural killer cell-mediated anti-cancer effects, confirming that a MICA sheddase, a disintegrin and metalloproteinase 10 (ADAM10), is a therapeutic target. We here searched for approved drugs with inhibitory effects on ADAM10 in vitro, and the anti-alcoholism agent, disulfiram, was identified. Disulfiram elevated membrane-bound MICA levels and reduced production of soluble MICA, an immunological decoy, while simultaneously not having unfavorable off-target effects on natural killer cells and normal human hepatocytes. Functional analyses indicated a mode of non-zinc-binding inhibition of ADAM10 by disulfiram, which also suppressed HCC cell migration. These effects of disulfiram against HCC are expected to further the development of novel therapeutic regimens. PMID- 29721165 TI - Precision cancer therapy: profiting from tumor specific defects in the DNA damage tolerance system. AB - DNA damage tolerance (DDT) enables replication to continue in the presence of a damaged template and constitutes a key step in DNA interstrand crosslink repair. In this way DDT minimizes replication stress inflicted by a wide range of endogenous and exogenous agents, and provides a critical first line defense against alkylating and platinating chemotherapeutics. Effective DDT strongly depends on damage-induced, site-specific PCNA-ubiquitination at Lysine (K) 164 by the E2/E3 complex (RAD6/18). A survey of The Cancer Genome Atlas (TCGA) revealed a high frequency of tumors presents RAD6/RAD18 bi-allelic inactivating deletions. For instance, 11% of renal cell carcinoma and 5% of pancreatic tumors have inactivating RAD18-deletions and 7% of malignant peripheral nerve sheath tumors lack RAD6B. To determine the potential benefit for tumor-specific DDT defects, we followed a genetic approach by establishing unique sets of DDT-proficient PcnaK164 and -defective PcnaK164R lymphoma and breast cancer cell lines. In the absence of exogenous DNA damage, PcnaK164R tumors grew comparably to their PcnaK164 controls in vitro and in vivo. However, DDT-defective lymphomas and breast cancers were compared to their DDT-proficient controls hypersensitive to the chemotherapeutic drug cisplatin (CsPt), both in vitro and in vivo. CsPt strongly inhibited tumor growth and the overall survival of tumor bearing mice greatly improved in the DDT-defective condition. These insights open new therapeutic possibilities for precision cancer medicine with DNA damaging chemotherapeutics and optimize Next-Generation-Sequencing (NGS)-based cancer diagnostics, -therapeutics, and -prognosis. PMID- 29721167 TI - Glycine: a non-invasive imaging biomarker to aid magnetic resonance spectroscopy in the prediction of survival in paediatric brain tumours. AB - Paediatric brain tumours have a high mortality rate and are the most common solid tumour of childhood. Identification of high risk patients may allow for better treatment stratification. Magnetic Resonance Spectroscopy (MRS) provides a non invasive measure of brain tumour metabolism and quantifies metabolite survival markers to aid in the clinical management of patients. Glycine can be identified using MRS and has been recently found to be important for cancer cell proliferation in tumours making it a valuable prognostic marker. The aims of this study were to investigate glycine and its added value to MRS as a prognostic marker for paediatric brain tumours in a clinical setting. 116 children with newly diagnosed brain tumours were examined with short echo-time MRS at the Birmingham Children's Hospital and followed up for five years. Survival analysis was performed using Cox regression on the entire metabolite basis set with focus on glycine and three other established survival markers for comparison: n acetylaspartate, scyllo-inositol and lipids at 1.3 ppm. Multivariate Cox regression was used in conjunction with risk values to establish if glycine added prognostic power when combined to the established survival markers. Glycine was found to be a marker of poor prognosis in the cohort (p < 0.05) and correlated with tumour grade (p < 0.01). The addition of glycine improved the prognostic power of MRS compared to using the combination of established survival markers alone. Tumour glycine was found to improve the MRS prediction of reduced survival in paediatric brain tumours aiding the non-invasive assessment of these children. PMID- 29721168 TI - Recruitment of mitofusin 2 into "lipid rafts" drives mitochondria fusion induced by Mdivi-1. AB - The regulation of the mitochondrial dynamics and the balance between fusion and fission processes are crucial for the health and fate of the cell. Mitochondrial fusion and fission machinery is controlled by key proteins such as mitofusins, OPA-1 and several further molecules. In the present work we investigated the implication of lipid rafts in mitochondrial fusion induced by Mdivi-1. Our results underscore the possible implication of lipid "rafts" in mitochondrial morphogenetic changes and their homeostasis. PMID- 29721166 TI - Isolated metastasis of an EGFR-L858R-mutated NSCLC of the meninges: the potential impact of CXCL12/CXCR4 axis in EGFRmut NSCLC in diagnosis, follow-up and treatment. AB - Brain and leptomeningeal metastasis (LMM) of non-small cell lung cancer is still associated with poor prognosis. Moreover, the current diagnostic standard for LMM often yields false negative results and the scientific progress in this field is still unsatisfying. We present a case of a 71-year old patient with an isolated LMM. While standard diagnostics could only diagnose a cancer of unknown primary, the use of [68Ga]-Pentixafor-PET/CT (CXCR4-PET/CT, a radiotracer targeting CXCR4) and a liquid biopsy of the cerebrospinal fluid revealed the primary NSCLC. The detection of L858R-EGFR, a common driver mutation in NSCLC, enabled us to treat the patient with Afatinib and monitor treatment using [68Ga]-Pentixafor PET/CT. To estimate the impact of CXCR4 signaling and its ligands in NSCLC brain metastasis we looked at their expression and correlation with EGFR mutations in a primary and brain metastasis data set and investigated the previously described binding of extracellular ubiquitin to CXCR4. In conclusion, we describe a novel approach to improve diagnostics towards LMM and underline the impact of the CXCL12/CXCR4 axis in brain metastasis in a subset of NSCLC patients. We cannot confirm a correlation of CXCR4 expression with EGFR mutations or the binding of extracellular ubiquitin as previously reported. PMID- 29721169 TI - Differentiation-inducing therapeutic effect of Notch inhibition in reversing malignant transformation of liver normal stem cells via MET. AB - Background: Liver cancer stem cells (LCSCs) are the key factors for cancer metastasis, recurrent, and drug resistance. LCSCs are originated from either hepatocytes dedifferentiation or differentiation arresting of liver normal stem cells (LNSCs). Differentiation-inducing therapy is a novel strategy in solid tumors. Furthermore, Notch signaling pathway has been proved to play important role in the process of hepatocytes differentiation. In previous study, a malignant transformation cellular model of LNSCs has been built up, and in this study we are trying to illustrate whether inhibition of Notch can reverse this malignant tendency and drive these malignant cells back to differentiate into mature hepatocytes. Results: Inhibition of Notch signaling pathway can down regulate the stemness-related cancer markers, lower the proliferative status, alleviate the invasive characteristic, or attenuate the metastasis tendency. What is more, it can help the malignantly transformed cells to regain the mature hepatic function of glucagon synthesis, urea metabolism, albumin production, and indocyanine-green (ICG) clearance. Materials and Methods: HOX transcript antisense RNA (HOTAIR) expression was enhanced in LNSCs via lentivirus transduction to set up the malignant transformation cellular model. Then, a Notch inhibitor was applied to induce malignantly transformed cells differentiate into mature hepatocytes, and malignant abilities of proliferation, invasiveness, tumorigenesis as well as mature hepatocyte function were observed and compared. Conclusions: The data demonstrate that the anti-tumor effects of Notch inhibition may lie not only on killing the cancer cells or LCSCs directly, it can also induce the LCSCs differentiation into mature hepatocytes via mesenchymal epithelial transition (MET) progress or downgrade the malignancy. PMID- 29721170 TI - DNMT1 ablation suppresses tumorigenesis by inhibiting the self-renewal of esophageal cancer stem cells. AB - Cancer stem cells (CSCs) have been isolated from many tumors and considered as the main reason of cancer recurrence and metastasis. DNA methyltransferase 1 (DNMT1) mediates DNA methylation and plays an important role in CSCs maintenance. However, the function of DNMT1 in CSCs of esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we examined the role of DNMT1 in regulating self-renewal in CSCs of ESCC. We found a high expression of DNMT1 in both side population (SP) cells and sphere formation cells that represented as substitutes for CSCs in KYSE150 and EC109 ESCC cell lines. We performed the knockdown of DNMT1 using lentivirus-mediated RNA interference (RNAi) methods. We revealed that ablation of DNMT1 resulted in the numbers and self-renewal abilities of CSCs refrained significantly in ESCC cells. As a result of the CSCs inhibition, the malignant phenotypes such as cell proliferation, colony formation, migration and drug resistance abilities were dramatically inhibited in ESCC cells. Treatment of 5-aza-2'-deoxycytidine (5-aza-dC), a DNMT inhibitor, also resulted in the inhibition of CSCs and malignant profiles in ESCC cells. Our findings also provided the first evidence that 5-aza-dC inhibited the colony and sphere formation of CSCs. Thus, our results indicated that DNMT1 was important for the self-renewal maintenance of CSCs in ESCC, and 5-aza-dC could be a potential therapy for the CSCs of ESCC. PMID- 29721171 TI - Assessment of the Palliative Prognostic Index in hospitalized oncologic patients treated by a palliative care team: impact of acute concomitant diseases. AB - The differential prognostic accuracy of the Palliative Prognostic Index (PPI) in hospitalized oncologic patients treated by a palliative care team according to the presence or absence of acute concomitant diseases was analyzed. All patients (n = 322) hospitalized in a palliative unit of a university hospital were included in a 2-year prospective study. PPI was determined at the time of hospital admission and discharge. Patients were grouped into two categories according to the causes of hospitalization (presence and absence of acute concomitant diseases). Metastases, PPI punctuation, refractory symptoms, and the presence of acute concomitant diseases were analyzed as survival-related factors. The absence of acute concomitant diseases and a PPI calculated at admission >4 or >6 were related with survival at 3 and 6 weeks, respectively. After hospital discharge, the accuracy of PPI was lower, decreasing the positive predictive value from 84% (PPI calculated at the time of hospital admission) to 67% (PPI calculated at the time of discharge) for survival <6 weeks. In conclusion, the impact of acute concomitant diseases on survival should be considered in prediction models for patients receiving palliative care. PMID- 29721172 TI - Loss of nuclear NOTCH1, but not its negative regulator NUMB, is an independent predictor of cervical malignancy. AB - The participation of NOTCH signaling in invasive cervical cancer (ICC) remains controversial since both tumor suppressive and oncogenic properties have been described. Additionally, the role of NUMB, a negative regulator of NOTCH, remains unclear in ICC. We aimed to investigate the role of NOTCH1 and NUMB expression and their localization in cervical intraepithelial neoplasia (CIN) and ICC samples. A total of 144 biopsies were obtained from the Instituto Nacional de Cancerologia, Mexico from 2004 to 2017, and were subjected to immunohistochemistry for NOTCH1 and NUMB. We found that nuclear NOTCH1 expression was more frequently found in CIN samples compared with ICC (77.55% vs. 15.79%, p = 0.001). NUMB was almost exclusively found in the nucleus of CIN samples (32.65% vs. 6.32%, p = 0.001). Cytoplasmic expression of NOTCH1 (44.21%) and NUMB (35.79%) was the most frequent localization in ICC. Multivariable-adjusted analysis showed that the loss of nuclear NOTCH1 expression was an independent predictor of malignancy (beta = -3.428, 95% confidence interval [95% CI] = 5.127, -1.728, p = 0.001). In contrast, the association between cytoplasmic NUMB expression and cervical cancer was lost after adjusting for nuclear NOTCH1 expression (beta = 2.074, 95% [CI] = -0.358, 4.506, P = 0.094). Additionally, patients with cytoplasmic NOTCH1 expression showed a borderline association with longer overall survival (OS) than those with nuclear NOTCH1 expression (P = 0.08). Our data suggest that the loss of nuclear NOTCH1 but not NUMB might be an independent predictor of malignancy in cervical cancer. PMID- 29721173 TI - Salivary microRNAs as new molecular markers in cleft lip and palate: a new frontier in molecular medicine. AB - MicroRNAs (miRNAs) are endogenous non-coding RNAs of about twenty-two nucleotides that regulate gene expression through post-transcriptional control. The purpose of the present study was to identify and describe the salivary miRNAs in cleft lip and palate (CLP) patients comparing them with a control healthy group. Twelve patients (mean age 11.9 +/- 2.42 years; 6M/6F) formed the study group. The control group was created selecting twelve healthy subjects matched for age and sex with study group. We recorded differences in miRNA expression profile between the saliva of CLP patients and the control group. Specifically, miR-141, miR-223, and miR-324-3p were mostly deregulated between the study and control groups. Interestingly, these three miRNAs are the regulators of the following genes correlated to cleft palate and lip development: MTHFR, SATB2, PVRL1. The present study showed that collecting saliva samples is a non-invasive procedure and is well accepted by CLP patients. MiRNAs can be easily isolated and identified. The differences in regulation of miR-141, miR-223 and miR-324-3p between the two groups of salivary samples suggest that these molecules are valid prognostic biomarkers and therapy dynamic response indicators, also for the accuracy and non invasive sampling and dosing system. PMID- 29721174 TI - Epigenetic hypomethylation and upregulation of NLRC4 and NLRP12 in Kawasaki disease. AB - INTRODUCTION: Kawasaki disease (KD) is a type of childhood febrile systemic vasculitis. Inflammasomes control inflammatory signaling and are related with the development of KD. In this study, we performed a survey of transcripts and global DNA methylation levels of inflammasome sensors of NOD-like receptors (NLRs) and the downstream interleukin 1beta (IL-1beta). MATERIALS AND METHODS: In this study, for the chip studies, we recruited a total of 18 KD patients, who we analyzed before receiving intravenous immunoglobulin (IVIG) and at least 3 weeks after IVIG treatment, as well as 36 non-fever controls by Illumina HumanMethylation 450 BeadChip and Affymetrix GeneChip(r) Human Transcriptome Array 2.0. A separate group of 78 subjects was performed for real-time quantitative PCR validations. RESULTS: The expressions of mRNA levels of NLRC4, NLRP12, and IL-1beta were significantly upregulated in KD patients compared to the controls (p<0.05). Once KD patients underwent IVIG treatment, these genes considerably decreased. In particular, the methylation status of the CpG sites of these genes indicated a significant opposite tendency between the KD patients and the controls. Furthermore, mRNA levels of IL-1beta represented a positive correlation with NLRC4 (p=0.002). We also observed that the mRNA levels of NLRP12 were lower in KD patients who developed coronary arterial lesions (p<0.005). CONCLUSION: This study is among the first to report epigenetic hypomethylation, increased transcripts, and the upregulation of NLRC4, NLRP12 and IL-1beta in KD patients. Moreover, a decreased upregulation of NLRP12 was related to coronary arterial lesion formation in KD patients. PMID- 29721175 TI - The decrease of glycolytic enzyme hexokinase 1 accelerates tumor malignancy via deregulating energy metabolism but sensitizes cancer cells to 2-deoxyglucose inhibition. AB - Malignant tumors often display an aberrant energy metabolism that relies primarily on glycolysis to produce adenosine triphosphate (ATP) the so-called Warburg effect or aerobic glycolysis. Thus, the elucidation of this energetic alteration in malignant tumors is important in the search for more effective therapeutics against malignant cancers, the most deadly human disease. To investigate whether attenuated glycolytic activity modulates tumor progression, the effects of silencing the first and rate-limiting glycolytic enzyme hexokinase (HK) isozymes HK1 and HK2 were examined. There was an inverse correlation between the expression of HK1 and HK2 in human cancer cells. In cervical carcinoma cells, the HK1 but not HK2 knockdown induced a phenotypic change characteristic of epithelial-mesenchymal transition, which accelerated tumor growth and metastasis both in vitro and in vivo analyses. Notably, the silencing of HK1 disrupted aerobic respiration and increased glycolysis, but it had no effect on ATP generation. These metabolic changes were associated with higher HK2 and lactate dehydrogenase 1 expression but a lower citrate synthase level. Particularly, the HK1 knockdown induced aberrant energy metabolism that was almost recapitulated by HK2 overexpression. Moreover, the HK1-silenced cells showed strong glucose dependent growth and 2-deoxyglucose (2-DG) induced cell proliferation inhibition. These results clearly indicate that the silencing of HK1, but not HK2, alters energy metabolism and induces an EMT phenotype, which enhances tumor malignancy, but increases the susceptibility of cancer cells to 2-DG inhibition. In addition, this work also suggests that the glycolytic inhibitors should be used only to treat cancers with elevated glycolytic activity. PMID- 29721176 TI - Pretreatment monocyte counts and neutrophil counts predict the risk for febrile neutropenia in patients undergoing TPF chemotherapy for head and neck squamous cell carcinoma. AB - Background: Febrile neutropenia (FN) is the most serious hematologic toxicity of systemic chemotherapy. However, accurate prediction of FN development has been difficult because the risk varies largely depending on the chemotherapy regimen and various individual factors. Methods: We retrospectively analyzed diverse clinical factors including pretreatment hematological parameters to clarify the reliable predictors of FN development during chemotherapy with a docetaxel, cisplatin, and fluorouracil (TPF) regimen in patients with head and neck squamous cell carcinoma. Results: Among the 50 patients, grade >=3 neutropenia, grade 4 neutropenia, and FN developed in 36 (72%), 21 (42%), and 12 (24%) patients, respectively. Multivariate logistic regression revealed that a pretreatment absolute monocyte count (AMC) <370/mm3 is an independent predictor of TPF chemotherapy-induced FN (odds ratio=6.000, p=0.017). The predictive performance of the model combining AMC and absolute neutrophil count (ANC), in which the high risk group was defined as having an AMC <370/mm3 and/or ANC <3500/mm3, was superior (area under the curve [AUC]=0.745) to that of the model with a cutoff for AMC alone (AUC=0.679). Conclusions: On the basis of our results, we recommend primary prophylactic use of granulocyte colony-stimulating factor and/or antibiotics selectively for patients predicted to be at high risk for TPF chemotherapy-induced FN. PMID- 29721177 TI - A pilot study of durvalumab and tremelimumab and immunogenomic dynamics in metastatic breast cancer. AB - Immune checkpoint inhibitors produce modest responses in metastatic breast cancer, however, combination approaches may improve responses. A single arm pilot study was designed to determine the overall response rate (ORR) of durvalumab and tremelimumab, and evaluate immunogenomic dynamics in metastatic endocrine receptor (ER) positive or triple negative breast cancer (TNBC). Simon two-stage design indicated at least four responses from the first 18 patients were needed to proceed with the second stage. T-cell receptor (TCR) sequencing and immune gene expression profiling were conducted at baseline and two months, whole exome sequencing was conducted at baseline. Eighteen evaluable patients were accrued (11 ER-positive; seven TNBC). Only three patients had a response (ORR = 17%), thus the study did not proceed to the second stage. Responses were only observed in patients with TNBC (ORR = 43%). Responders versus non-responders had upregulation of CD8, granzyme A, and perforin 1 gene expression, and higher mutational and neoantigen burden. Patients with TNBC had an oligoclonal shift of the most abundant TCR-beta clonotypes compared to those with ER-positive disease, p = 0.004. We conclude responses are low in unselected metastatic breast cancer, however, higher rates of clinical benefit were observed in TNBC. Immunogenomic dynamics may help identify phenotypes most likely to respond to immunotherapy. PMID- 29721179 TI - Glypican-1 is enriched in circulating-exosomes in pancreatic cancer and correlates with tumor burden. AB - Background: Glypican-1 (GPC1) is expressed in pancreatic ductal adenocarcinoma (PDAC) cells and adjacent stromal fibroblasts. Recently, GPC1 circulating exosomes (crExos) have been shown to be able to detect early stages of PDAC. In this study, we investigated the usefulness of crExos GPC1 as a biomarker for PDAC. Methods: Plasma was obtained from patients with benign pancreatic disease (n = 16) and PDAC (n = 27) prior to pancreatectomy, and crExos were isolated by ultra-centrifugation. Protein was extracted from surgical specimens (adjacent normal pancreas, n = 13; and PDAC, n = 17). GPC1 levels were measured using enzyme-linked immunosorbent assay (ELISA). Results: There was no significant difference in GPC1 levels between normal pancreas and PDAC tissues. This was also true when comparing matched pairs. However, GPC1 levels were enriched in PDAC crExos (n = 11), compared to the source tumors (n = 11; 97 +/- 54 vs. 20.9 +/- 12.3 pg/mL; P < 0.001). In addition, PDACs with high GPC1 expression tended to have crExos with higher GPC1 levels. Despite these findings, we were unable to distinguish PDAC from benign pancreatic disease using crExos GPC1 levels. Interestingly, we found that in matched pre and post-operative plasma samples there was a significant drop in crExos GPC1 levels after surgical resection for PDAC (n = 11 vs. 11; 97 +/- 54 vs. 77.8 +/- 32.4 pg/mL; P = 0.0428). Furthermore, we found that patients with high crExos GPC1 levels have significantly larger PDACs (>4 cm; P = 0.012). Conclusions: High GPC1 crExos may be able to determine PDAC tumor size and disease burden. However, further efforts are needed to elucidate its role as a diagnostic and/or prognostic biomarker using larger cohorts of PDAC patients. PMID- 29721178 TI - Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a novel marker for patients with BRAF-mutated metastatic melanoma. AB - Metastatic melanoma carrying BRAF mutations represent a still unmet medical need as success of BRAF inhibitors is limited by development of resistance. Nicotinamide phosphoribosyltransferase (NAMPT) is a key enzyme in NAD biosynthesis. An extracellular form (eNAMPT) possesses cytokine-like functions and is up-regulated in inflammatory disorders, including cancer. Here we show that eNAMPT is actively released in culture supernatants of melanoma cell lines. Furthermore, cells that become resistant to BRAF inhibitors (BiR) show a significant increase of eNAMPT levels. Plasma from mice xenografted with BiR cell lines contain higher eNAMPT levels compared to tumor-free animals. Consistently, eNAMPT levels are elevated in 113 patients with BRAF-mutated metastatic melanoma compared to 50 with localized disease or to 38 healthy donors, showing a direct correlation with markers of tumor burden, such as LDH, or aggressive disease (such as PD-L1). eNAMPT concentrations decrease in response to therapy with BRAF/MEK inhibitors, but increase again at progression, as inferred from the serial analysis of 50 patients. Lastly, high eNAMPT levels correlate with a significantly shorter overall survival. Our findings suggest that eNAMPT is a novel marker of tumor burden and response to therapy in patients with metastatic melanoma carrying BRAF mutations. PMID- 29721180 TI - miRNA expression profile of bone marrow resident cells from children with neuroblastoma is not significantly different from that of healthy children. AB - The miRNA expression profiles of bone marrow resident cells from children with neuroblastoma were compared to that of healthy children. No significant difference was found between localized and metastatic neuroblastoma, or between children with neuroblastoma and healthy children. By considering the fold change we identified six miRNAs over-expressed by more than 150 fold in neuroblastoma. Validation confirmed miR-221 over-expression in BM resident cells from children with neuroblastoma, regardless of localized or metastatic disease. MiR-221 over expression was unlikely derived from neuroblastoma primary tumors or from bone marrow-infiltrating metastatic cells, since neuroblastoma cells expressed lower or similar amount of miR-221 than BM cells, respectively. To get insight on the genes potentially regulated by miR-221 we merged the list of miR-221 potential targets with the genes under-expressed by BM resident cells from children with neuroblastoma, as compared with healthy children. In silico analysis demonstrated that none of the miR-221 target genes belonged to heme biosynthetic processes found altered in children with neuroblastoma, whereas two genes associated with mitochondria. However, the encoded proteins were not under-expressed in children with neuroblastoma, making unlikely that altered erythrocyte maturation in children with neuroblastoma was mediated by miR-221. In conclusion, miRNA expression profiles of BM resident cells from children with localized and metastatic neuroblastoma were similar to that of BM resident cells from healthy children. Moreover, miRNAs expressed by neuroblastoma primary tumors or by BM infiltrating NB cells do not appear to be involved in mediating the functional defect of erythrocyte maturation recently observed in children with neuroblastoma. PMID- 29721181 TI - Near infrared photoimmunotherapy targeting bladder cancer with a canine anti epidermal growth factor receptor (EGFR) antibody. AB - Anti-epidermal growth factor receptor (EGFR) antibody therapy is used in EGFR expressing cancers including lung, colon, head and neck, and bladder cancers, however results have been modest. Near infrared photoimmunotherapy (NIR-PIT) is a highly selective tumor treatment that employs an antibody-photo-absorber conjugate which is activated by NIR light. NIR-PIT is in clinical trials in patients with recurrent head and neck cancers using cetuximab-IR700 as the conjugate. However, its use has otherwise been restricted to mouse models. This is an effort to explore larger animal models with NIR-PIT. We describe the use of a recombinant canine anti-EGFR monoclonal antibody (mAb), can225IgG, conjugated to the photo-absorber, IR700DX, in three EGFR expressing canine transitional cell carcinoma (TCC) cell lines as a prelude to possible canine clinical studies. Can225-IR700 conjugate showed specific binding and cell-specific killing after NIR-PIT on EGFR expressing cells in vitro. In the in vivo study, can225-IR700 conjugate demonstrated accumulation of the fluorescent conjugate with high tumor to-background ratio. Tumor-bearing mice were separated into 4 groups: (1) no treatment; (2) 100 ug of can225-IR700 i.v. only; (3) NIR light exposure only; (4) 100 ug of can225-IR700 i.v., NIR light exposure. Tumor growth was significantly inhibited by NIR-PIT treatment compared with the other groups (p < 0.001), and significantly prolonged survival was achieved (p < 0.001 vs. other groups) in the treatment groups. In conclusion, NIR-PIT with can225-IR700 is a promising treatment for canine EGFR-expressing cancers, including invasive transitional cell carcinoma in pet dogs, that could provide a pathway to translation to humans. PMID- 29721182 TI - Crosstalk between Akt signaling and cold shock proteins in mediating invasive cell phenotypes. AB - Cold shock proteins are up-regulated by cellular stress and orchestrate inflammatory responses, cell proliferation, and differentiation. Enhanced cold shock protein expression promotes malignant cell transformation; up-regulation is detected in most cancers and associated with poor prognosis. Akt1, a serine/threonine kinase, is a potent oncogene, which activates pro-proliferative and anti-apoptotic signaling pathways, and phosphorylates the cold shock domain. Unexpectedly, chicken-YB-1 abrogates PI3K-Akt-dependent oncogenic cell transformation in embryonic fibroblasts. Here, we addressed the question whether chicken and human Y-box binding protein-1 (YB-1) act differently on cell transformation, and how a related protein, DNA-binding protein-A (DbpA) behaves in comparison. NIH3T3 cells were transduced with lentiviral vectors encoding for myristoylated (constitutive active) Akt1, YB-1, DbpA, or shRNA targeting YB-1 expression. Colony formation assays showed that human YB-1 acts similar to chicken on Akt-dependent cell transformation. This activity was not titratable. Given the correlation of nuclear YB-1 and upregulated DbpA expression in a series of clear cell renal cell carcinomas (n = 40) the colony formation assay was extended to include ectopic DbpA expression. DbpA alone prominently induced cell transformation, which was enhanced when constitutive active Akt1 or concomitant YB-1 expression was present. Notably, co-expression of DbpA together with YB-1 abrogated the repressive effect on Akt1 signaling observed with YB-1 alone. Macroscopically, some colonies yielded a remarkable "invasive" phenotype. Thus, cold shock proteins may convey profound anti- and pro-oncogenic effects on Akt dependent cell transformation. DbpA is able to overcome the anti-oncogenic effects seen with combined YB-1 and Akt signaling in an in vitro model of colonial growth. PMID- 29721184 TI - Correlation between lower balance of Th2 helper T-cells and expression of PD L1/PD-1 axis genes enables prognostic prediction in patients with glioblastoma. AB - Common cancer treatments include radiation therapy, chemotherapy including molecular targeted drugs and anticancer drugs, and surgical treatment. Recent studies have focused on investigating the mechanisms by which immune cells attack cancer cells and produce immune tolerance-suppressing cytokines, as well as on their potential application in cancer immunotherapy. We conducted expression profiling of CD274 (PD-L1), GATA3, IFNG, IL12R, IL12RB2, IL4, PDCD1 (PD-1), PDCD1LG2 (PD-L2), and TBX21 (T-bet) using data of 158 glioblastoma multiforme (GBM) patients with clinical information available at The Cancer Genome Atlas. Principal component analysis of the expression profiling data was used to derive an equation for evaluating the status of Th1 and Th2 cells. GBM specimens were divided based on the median of the Th scores. The results revealed that Th1HighTh2Low and Th1LowTh2Low statuses indicated better prognosis than Th1HighTh2High, and were evaluated based on the downregulation of PD-L1, PD-L2, and PD-1. Furthermore, Th2Low divided based on the threshold, as well as CD274Low and PDCD1Low, were associated with good prognosis. In the Th2Low subgroup, 14 genes were identified as potential prognostic markers. Of these, SLC11A1Low, TNFRSF1BLow, and LTBRLow also indicated good prognosis. These results suggest that low Th2 balance and low activity of the PD-L1/PD-1 axis predict good prognosis in GBM. The set of genes identified in the present study could reliably predict survival in GBM patients and serve as useful molecular markers. Furthermore, this set of genes could prove to be novel targets for cancer immunotherapy. PMID- 29721183 TI - Delineating the HMGB1 and HMGB2 interactome in prostate and ovary epithelial cells and its relationship with cancer. AB - High Mobility Group B (HMGB) proteins are involved in cancer progression and in cellular responses to platinum compounds used in the chemotherapy of prostate and ovary cancer. Here we use affinity purification coupled to mass spectrometry (MS) and yeast two-hybrid (Y2H) screening to carry out an exhaustive study of HMGB1 and HMGB2 protein interactions in the context of prostate and ovary epithelia. We present a proteomic study of HMGB1 partners based on immunoprecipitation of HMGB1 from a non-cancerous prostate epithelial cell line. In addition, HMGB1 and HMGB2 were used as baits in yeast two-hybrid screening of libraries from prostate and ovary epithelial cell lines as well as from healthy ovary tissue. HMGB1 interacts with many nuclear proteins that control gene expression, but also with proteins that form part of the cytoskeleton, cell-adhesion structures and others involved in intracellular protein translocation, cellular migration, secretion, apoptosis and cell survival. HMGB2 interacts with proteins involved in apoptosis, cell motility and cellular proliferation. High confidence interactors, based on repeated identification in different cell types or in both MS and Y2H approaches, are discussed in relation to cancer. This study represents a useful resource for detailed investigation of the role of HMGB1 in cancer of epithelial origins, as well as potential alternative avenues of therapeutic intervention. PMID- 29721186 TI - Myofibroblast androgen receptor expression determines cell survival in co cultures of myofibroblasts and prostate cancer cells in vitro. AB - Fibroblasts express androgen receptor (AR) in the normal prostate and during prostate cancer development. We have reported that loss of AR expression in prostate cancer-associated fibroblasts is a poor prognostic indicator. Here we report outcomes of direct and indirect co-cultures of immortalised AR-positive (PShTert-AR) or AR-negative (PShTert) myofibroblasts with prostate cancer cells. In the initial co-cultures the AR-negative PC3 cell line was used so AR expression and signalling were restricted to the myofibroblasts. In both direct and indirect co-culture with PShTert-AR myofibroblasts, paracrine signalling to the PC3 cells slowed proliferation and induced apoptosis. In contrast, PC3 cells proliferated with PShTert myofibroblasts irrespective of the co-culture method. In direct co-culture PC3 cells induced apoptosis in and destroyed PShTerts by direct signalling. Similar results were seen in direct co-cultures with AR negative DU145 and AR-positive LNCaP and C4-2B prostate cancer cell lines. The AR ligand 5alpha-dihydrotestosterone (DHT) inhibited the proliferation of the PShTert-AR myofibroblasts, thereby reducing the extent of their inhibitory effect on cancer cell growth. These results suggest loss of stromal AR would favour prostate cancer cell growth in vivo, providing an explanation for the clinical observation that reduced stromal AR is associated with a poorer outcome. PMID- 29721185 TI - An epigenetic regulator-related score (EpiScore) predicts survival in patients with diffuse large B cell lymphoma and identifies patients who may benefit from epigenetic therapy. AB - Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma and shows considerable clinical and biological heterogeneity. Much research is currently focused on the identification of prognostic markers for more specific patients' risk stratification and on the development of therapeutic approaches to improve the long-term outcome. Epigenetic alterations are involved in various cancers, including lymphoma. Interestingly, epigenetic alterations are reversible and drugs to target some of them have been developed. In this study, we demonstrated that the gene expression profile of epigenetic regulators has a prognostic value in DLBCL and identified pathways that could be involved in DLBCL poor outcome. We then designed a new risk score (EpiScore) based on the gene expression level of the epigenetic regulators DNMT3A, DOT1L, SETD8. EpiScore was predictive of overall survival in DLBCL and allowed splitting patients with DLBCL from two independent cohorts (n = 414 and n = 69) in three groups (high, intermediate and low risk). EpiScore was an independent predictor of survival when compared with previously described prognostic factors, such as the International Prognostic Index (IPI), germinal center B cell and activated B cell molecular subgroups, gene expression-based risk score (GERS) and DNA repair score. Immunohistochemistry analysis of DNMT3A in 31 DLBCL samples showed that DNMT3A overexpression (>42% of positive tumor cells) correlated with reduced overall and event-free survival. Finally, an HDAC gene signature was significantly enriched in the DLBCL samples included in the EpiScore high-risk group. We conclude that EpiScore identifies high-risk patients with DLBCL who could benefit from epigenetic therapy. PMID- 29721187 TI - Total lesion glycolysis on FDG-PET/CT before salvage surgery predicts survival in laryngeal or pharyngeal cancer. AB - We investigated whether 18F-fluorodeoxyglucose uptake parameters using positron emission tomography combined with computed tomography predicts several survival outcomes, including lung metastasis-free survival, in patients with laryngeal or pharyngeal cancer who underwent salvage surgery. The maximum standardized uptake value, metabolic tumor volume, and total lesion glycolysis were calculated as 18F fluorodeoxyglucose uptake parameters in 51 patients with laryngeal or pharyngeal cancer before salvage surgery. In univariate analysis, the maximum standardized uptake value >= 22.8, metabolic tumor volume >= 2.4, and total lesion glycolysis >= 5.4 were significantly correlated with shorter overall survival. In multivariate analysis with adjustment for clinical stage, patients with total lesion glycolysis >= 5.4 exhibited significantly shorter overall survival. Furthermore, total lesion glycolysis >= 5.4 was significantly correlated with shorter disease-specific survival, distant metastasis-free survival, and lung metastasis-free survival in univariate analysis. In conclusion, total lesion glycolysis predicts the survival outcomes including lung metastasis in patients with laryngeal or pharyngeal cancer who underwent salvage surgery. PMID- 29721188 TI - Hypoxia-inducible factor-2 alpha up-regulates CD70 under hypoxia and enhances anchorage-independent growth and aggressiveness in cancer cells. AB - Hypoxia-inducible factors (HIFs) facilitate cellular adaptation to environmental stress such as low oxygen conditions (hypoxia) and consequently promote tumor growth. While HIF-1alpha functions in cancer progression have been increasingly recognized, the contribution of HIF-2alpha remains widely unclear despite accumulating reports showing its overexpression in cancer cells. Here, we report that HIF-2alpha up-regulates the expression of CD70, a cancer-related surface antigen that improves anchorage-independent growth in cancer cells and is associated with poor clinical prognosis, which can be induced via epigenetic modifications mediated by DNMT1. The ablation of CD70 by RNAi led to decreased colony forming efficiency in soft agar. Most strikingly, we identified the emergence of CD70-expressing cells derived from CD70-negative cell lines upon prolonged hypoxia exposure or DNMT1 inhibition, both of which significantly reduced CpG-nucleotide methylations within CD70 promoter region. Interestingly, DNMT1 expression was decreased under hypoxia, which was rescued by HIF-2alpha knockdown. In addition, the expression of CD70 and colony forming efficiency in soft agar were decreased by knockdown of HIF-2alpha. These findings indicate that CD70 expression and an aggressive phenotype of cancer cells is driven under hypoxic conditions and mediated by HIF-2alpha functions and epigenetic modifications. This provides additional insights into the role of HIF-2alpha in coordinated regulation of stem-like functions and epigenetics that are important for cancer progression and may present additional targets for the development of novel combinatorial therapeutics. PMID- 29721189 TI - Assessment of micro RNAs expression in leukemic cells as prognostic markers in chronic lymphocytic leukemia: micro RNAs can predict survival in a course of the disease. AB - Numerous genetic alterations predicting prognosis and clinical outcome are revealed recently in chronic lymphocytic leukemia (CLL). Among them the deregulated expression of micro RNAs that can induce tumor growth, or act as tumor suppressors seem to be of great importance. This study aimed to analyze the possible role of chosen micro RNAs as markers of prognosis in patients with CLL. We assessed the expression of miR-21, miR-34a, miR-181a, miR-199a/b and miR-221 in previously separated leukemic cells with the use of qRQ-PCR technique at the moment of diagnosis. The results were then analyzed in regards to presence of prognostic factors, clinical data and the end points like progression free survival (PFS), time to progression (TP) and overall survival time (OS). We detected significant correlations between expression of the analyzed micro RNAs and CLL prognostic markers particularly as far as miR-221 and miR-181a were concerned. The subsequent analysis revealed that high expression of miR-34a and miR-181a as well as low miR-21 expression indicated longer TTP, while miR-221 was predictor of OS. The obtained results prove the role of micro RNAs as CLL prognostic markers, particularly as factors predicting survival in a course of the disease. PMID- 29721190 TI - CD200fc enhances anti-tumoral immune response and inhibits visceral metastasis of breast carcinoma. AB - CD200 is a widely expressed cell surface glycoprotein that inhibits excessive inflammation in autoimmunity, transplantation, and viral infections. We previously observed that visceral metastasis of highly aggressive and inflammatory 4THM breast carcinoma cells was markedly decreased in CD200 transgenic mice. The goal of this study was to determine whether exogenous exposure to CD200fc mimics the effects of endogenously over expressed CD200. Female BALB/c mice were injected with CD200fc two times a week for five times. Injection was started two days after orthotopic injection of 4THM cells. Tumor infiltrating Gr1+Cd11b+ cells were decreased while CD8+ cells were increased in CD200fc-treated animals. CD200fc injection significantly decreased lung and liver metastasis and the growth of primary tumors. CD200fc injection enhanced the tumor induced IFN-g response while suppressing the IL-10 response. We observed excessive basal IL-6 secretion in MLC which was significantly decreased in CD200fc treated mice 12 days after injection of 4TM cells. These results are in accord with previous data from CD200 transgenic mice, and demonstrate for the first time that CD200 analogues might have therapeutic potential in the treatment of aggressive breast carcinoma which induces excessive systemic inflammation. PMID- 29721191 TI - MicroRNA-652 induces NED in LNCaP and EMT in PC3 prostate cancer cells. AB - MicroRNAs (miRNAs) are small noncoding RNA molecules that post-transcriptionally regulate gene expression. Dysregulation of miRNAs is frequently associated with disease and, in particular, is involved in prostate cancer progression. Next generation miRNA sequencing identified a panel of five miRNAs associated with prostate cancer recurrence and metastasis. High expression of one of these five miRNAs, miR-652, correlated significantly with an increased rate of prostate cancer biochemical recurrence. Overexpression of miR-652 in prostate cancer cells, PC3 and LNCaP, resulted in increased growth, migration and invasion. Prostate cancer cell xenografts overexpressing miR-652 showed increased tumorigenicity and metastases. We found that miR-652 directly targets the B" regulatory subunit, PPP2R3A, of the tumor suppressor PP2A, inducing epithelial mesenchymal transition (EMT) in PC3 cells and neuroendocrine-like differentiation (NED) in LNCaP cells. The mesenchymal marker N-cadherin increased and epithelial marker E-cadherin decreased in PC3 cells overexpressing miR-652. In LNCaP cells and xenografted tumors, overexpression of miR-652 increased markers of NED, including chromogranin A, neuron specific enolase, and synaptophysin. MiR-652 may contribute to prostate tumor progression by promoting NED through decreased PP2A function. MiR-652 expression could serve as a biomarker for aggressive prostate cancer, as well as provide an opportunity for novel therapy in prostate cancer. PMID- 29721194 TI - Identification of an EPC2-PHF1 fusion transcript in low-grade endometrial stromal sarcoma. AB - Recurrent chromosomal translocations leading to gene fusion formation have been described in uterine sarcomas, including low-grade endometrial stromal sarcoma (LG-ESS). Involvement of the PHF1 gene in chromosomal rearrangements targeting band 6p21 has been found in LG-ESS with different partners from JAZF1 mapping in 7p15, to EPC1 from 10p11, MEAF6 from 1p34, and BRD8 from 5q31. In the present study, RNA sequencing of a LG-ESS showed a novel recombination of PHF1 with the Enhancer of Polycomb homolog 2 (EPC2). RT-PCR followed by Sanger sequencing and FISH analysis confirmed the EPC2-PHF1 fusion transcript. PMID- 29721193 TI - Impact of pigment epithelium-derived factor on colorectal cancer in vitro and in vivo. AB - Pigment epithelial derived factor (PEDF) is a secreted glycoprotein that is a non inhibitory member of the serine protease inhibitor (serpin) family. PEDF exhibits multiple biological properties including neuroprotective, anti-angiogenic, and immune-modulating. Interestingly, PEDF exerts the inhibitory effects in cancers derived from certain tissues, including prostatic, ovarian, and pancreatic carcinomas. The current study aimed to elucidate its role in colorectal cancer development. PEDF expression in human colorectal cancer tissue was assessed using quantitative polymerase chain reaction (qPCR) and immunohistochemical staining (IHC). The effect of treatment with recombinant PEDF on cellular function was examined using in vitro functional assays. PEDF expression was downregulated in colorectal cancer cell tissue. Treatment with recombinant PEDF resulted in significant decreases in the rate of colorectal cancer cell migration and invasion and an increase in cellular adhesion in colorectal cancer cell lines examined. These results indicate that upregulation of PEDF expression may serve as a new strategy for further investigation of therapeutic relevance to the prevention of the metastatic spread of colorectal cancer. PMID- 29721192 TI - PD-L1 expression in medulloblastoma: an evaluation by subgroup. AB - Background: This study evaluated the expression of PD-L1 and markers of immune mediated resistance in human medulloblastoma (MB), the most common malignant pediatric brain tumor. Results: Overall levels of PD-L1 in human MB were low; however, some cases demonstrated robust focal expression associated with increased immune infiltrates. The case with highest PD-L1 expression was a sonic hedgehog (SHH) MB. In cell lines, SHH MB, which are low-MYC expressing, demonstrated both constitutive and inducible expression of PD-L1 while those in Group 3/4 that expressed high levels of MYC had only inducible expression. In vitro, IFN-gamma robustly stimulated the expression of PD-L1 in all cell lines while radiation induced variable expression. Forced high MYC expression did not significantly alter PD-L1. Methods: Human MB tumor samples were evaluated for expression of PD-L1 and immune cell markers in relation to molecular subgroup assignment. PD-L1 expression was functionally analyzed under conditions of interferon gamma (IFN-gamma), radiation, and MYC overexpression. Conclusions: MB expresses low levels of PD-L1 facilitating immune escape. Importantly, TH1 cytokine stimulation appears to be the most potent inducer of PD-L1 expression in vitro suggesting that an inflamed tumor microenvironment is necessary for PD-1 pathway activation in this tumor. PMID- 29721195 TI - Myoferlin regulates epithelial cancer cell plasticity and migration through autocrine TGF-beta1 signaling. AB - Epithelial cancer cells can undergo an epithelial-mesenchymal transition (EMT), a complex genetic program that enables cells to break free from the primary tumor, breach the basement membrane, invade through the stroma and metastasize to distant organs. Myoferlin (MYOF), a protein involved in plasma membrane function and repair, is overexpressed in several invasive cancer cell lines. Depletion of myoferlin in the human breast cancer cell line MDA-MB-231 (MDA-231MYOFKD) reduced migration and invasion and caused the cells to revert to an epithelial phenotype. To test if this mesenchymal-epithelial transition was durable, MDA-231MYOFKD cells were treated with TGF-beta1, a potent stimulus of EMT. After 48 hr with TGF beta1, MDA-231MYOFKD cells underwent an EMT. TGF-beta1 treatment also decreased directional cell motility toward more random migration, similar to the highly invasive control cells. To probe the potential mechanism of MYOF function, we examined TGF-beta1 receptor signaling. MDA-MB-231 growth and survival has been previously shown to be regulated by autocrine TGF-beta1. We hypothesized that MYOF depletion may result in the dysregulation of TGF-beta1 signaling, thwarting EMT. To investigate this hypothesis, we examined production of endogenous TGF beta1 and observed a decrease in TGF-beta1 protein secretion and mRNA transcription. To determine if TGF-beta1 was required to maintain the mesenchymal phenotype, TGF-beta receptor signaling was inhibited with a small molecule inhibitor, resulting in decreased expression of several mesenchymal markers. These results identify a novel pathway in the regulation of autocrine TGF-beta signaling and a mechanism by which MYOF regulates cellular phenotype and invasive capacity of human breast cancer cells. PMID- 29721196 TI - Comprehensive genomic transcriptomic tumor-normal gene panel analysis for enhanced precision in patients with lung cancer. AB - A CMS approved test for lung cancer is based on tumor-only analysis of a targeted 35 gene panel, specifically excluding the use of the patient's normal germline tissue. However, this tumor-only approach increases the risk of mistakenly identifying germline single nucleotide polymorphisms (SNPs) as somatically derived cancer driver mutations (false positives). 621 patients with 30 different cancer types, including lung cancer, were studied to compare the precision of tumor somatic variant calling in 35 genes using tumor-only DNA sequencing versus tumor-normal DNA plus RNA sequencing. When sequencing of lung cancer was performed using tumor genomes alone without normal germline controls, 94% of variants identified were SNPs and thus false positives. Filtering for common SNPs still resulted in as high as 48% false positive variant calling. With tumor-only sequencing, 29% of lung cancer patients had a false positive variant call in at least one of twelve genes with directly targetable drugs. RNA analysis showed 18% of true somatic variants were not expressed. Thus, sequencing and analysis of both normal germline and tumor genomes is necessary for accurate identification of molecular targets. Treatment decisions based on tumor-only analysis may result in the administration of ineffective therapies while also increasing the risk of negative drug-related side effects. PMID- 29721197 TI - Backtracked analysis of preleukemic fusion genes and DNA repair foci in umbilical cord blood of children with acute leukemia. AB - The first event in origination of many childhood leukemias is a specific preleukemic fusion gene (PFG) that arises, often in utero, in hematopoietic stem/progenitor cells (HSPC) from misrepaired DNA double strand break (DSB). An immanently elevated level of DSB and impaired apoptosis may contribute to origination and persistence of PFG and donor cell-derived leukemia in recipients of allogeneic transplantation of umbilical cord blood (UCB). We investigated DSB, apoptosis and PFG in the backtracked UCB cells of leukemic patients. RNA from UCB of three patients with acute lymphoblastic leukemia, patient with acute megakaryoblastic leukemia and Down syndrome, and four healthy children was screened for common PFG by RT-qPCR. Presence of PFG was validated by sequencing. Endogenous gammaH2AX and 53BP1 DNA repair foci, cell populations, and apoptosis were analyzed in UCB CD34+/- cells with imaging and standard flow cytometry. We found MLL2-AF4 and BCR-ABL (p190) fusion genes in UCB of two out from four pediatric patients, apparently not detected at diagnosis, while UCB cells of TEL AML1+ ALL patient were tested negative for this PFG and no PFG were detected in UCB cells of healthy children. No significant difference in DNA damage and apoptosis between UCB CD34+/- cells from healthy children and leukemic patients was observed, while Down syndrome trisomy increased DNA damage and resulted in distribution of cell populations resembling transient abnormal myelopoiesis. Our findings indicate increased genetic instability in UCB HSPC of leukemic patients and may be potentially used for diagnostics and exclusion of possibly affected UCB from transplantation. PMID- 29721198 TI - Global burden of neuroendocrine tumors and changing incidence in Kentucky. AB - Background: Neuroendocrine tumors (NETs) have a low incidence but relatively high prevalence. Over the last three decades, the incidence of NETs has risen 6-fold in the United States. We conducted an observational study to compare the incidence of NETs reported to the Kentucky Cancer Registry (KCR) versus that reported to Surveillance, Epidemiology, and End Results Program (SEER). We also provide a systematic review of the state of neuroendocrine tumors worldwide, and compare the available global and local published data. Methods: KCR and SEER databases were queried for NET cases between 1995 and 2015. A detailed literature review of epidemiological data for various nations worldwide summarize epidemiological data from various countries. Results: KCR recorded 6179 individuals with newly diagnosed NETs between 1995 and 2015. Between 1995-2012, the incidence of NETs in KCR increased from 3.1 to 7.1 per 100,000 cases, while it increased from 3.96 to 6.61 in the SEER database. The incidence rates in both KCR and SEER databases were linear. 90.57% were Caucasians with 54.74% females. 27.67% of the Kentucky population was from the Appalachian region. Patients aged 50-64 years had the highest prevalence (38%). Lung NET (30.60%) formed the bulk of cases, followed by small intestine (16.82%), rectum/anus (11.35%) and colon (9.71%). Conclusions: NETs incidence between 1995 and 2015 show a linear increase in both KCR and SEER databases. Because of this increased incidence it is imperative for community oncologists to familiarize themselves with this entity, which until recently was under-studied and with few viable treatment options. PMID- 29721199 TI - Rapid methods to create a positive control and identify the PAX8/PPARgamma rearrangement in FNA thyroid samples by molecular biology. AB - Thyroid cancer is the most common malignancy of the endocrine system and includes well-differentiated forms, namely papillary and follicular carcinomas, and the poorly differentiated and undifferentiated forms that result from the transformation of thyroid follicular cells (anaplastic carcinomas). Notably, 5 10% of all thyroid cancers are medullary thyroid cancers that arise from parafollicular cells also known as C cells. The most common genetic mutations in papillary and follicular thyroid cancers are point mutations of the BRAF or RAS genes, while the most common chromosomal alterations are RET/PTC and PAX8/PPARgamma rearrangements. The most frequent initial manifestation of thyroid cancer is the appearance of a nodule most of which are benign; indeed, less than 5% are malignant. However, some cases are misdiagnosed, and many patients undergo unnecessary surgery. Therefore, an accurate pre-surgery evaluation is crucial. The most reliable diagnostic test for thyroid nodules is fine needle aspiration (FNA) cytology, which accurately distinguishes between a benign and malignant lesion in most cases. However, cytological discrimination between malignant and benign follicular cancer is often difficult because of poor quality samples. Here we describe rapid methods to create a positive control and identify the PAX8/PPARgamma rearrangement in FNA thyroid samples by molecular biology. PMID- 29721201 TI - Antitumor efficacy of Kisspeptin in human malignant mesothelioma cells. AB - Purpose: Kisspeptin signaling, via its receptors GPR54, could be an essential players in the inhibition of mesothelioma progression, invasion and metastasis formation. The loss of KiSS1 by tumor cells has been associated with a metastatic phenotype but the mechanistic insights of this process are still unknown. Experimental design: The blockade of the metastatic process at early stage is a hot topic in cancer research. We studied the role of KiSS1 on proliferation, invasiveness, migration abilities of mesothelioma cell lines focusing on the effect on epithelial-to-mesenchymal transition (EMT). Results: Treatment with the KiSS1 peptide or with a synthesis peptide with longer half-life, the FTM080, significantly inhibited cell proliferation, migration and invasion of mesothelioma cell lines; the same treatment reduced the activity of MMP-2 and MMP 9 determining consequently a marked reduction in the invasiveness of primary tumors and metastases. Thespecificexpression of EMT markers, as E-caderin, Vimentin, Slug and Snail, suggested the inhibition of EMT after treatment with KiSS1 as well as the preservation of epithelial components. Conclusion: Our results support anti-proliferative effect of KiSS1 in cancer cells and suggest that targeting the KiSS1/GPR54 system may represent a novel therapeutic approach for mesothelioma. PMID- 29721200 TI - Recombinant methioninase combined with doxorubicin (DOX) regresses a DOX resistant synovial sarcoma in a patient-derived orthotopic xenograft (PDOX) mouse model. AB - Synovial sarcoma (SS) is a recalcitrant subgroup of soft tissue sarcoma (STS). A tumor from a patient with high grade SS from a lower extremity was grown orthotopically in the right biceps femoris muscle of nude mice to establish a patient-derived orthotopic xenograft (PDOX) mouse model. The PDOX mice were randomized into the following groups when tumor volume reached approximately 100 mm3: G1, control without treatment; G2, doxorubicin (DOX) (3 mg/kg, intraperitoneal [i.p.] injection, weekly, for 2 weeks; G3, rMETase (100 unit/mouse, i.p., daily, for 2 weeks); G4 DOX (3mg/kg), i.p. weekly, for 2 weeks) combined with rMETase (100 unit/mouse, i.p., daily, for 2 weeks). On day 14 after treatment initiation, all therapies significantly inhibited tumor growth compared to untreated control, except DOX: (DOX: p = 0.48; rMETase: p < 0.005; DOX combined with rMETase < 0.0001). DOX combined with rMETase was significantly more effective than both DOX alone (p < 0.001) and rMETase alone (p < 0.05). The relative body weight on day 14 compared with day 0 did not significantly differ between any treatment group or untreated control. The results indicate that r METase can overcome DOX-resistance in this recalcitrant disease. PMID- 29721202 TI - Circulating tumor cells, tumor-derived extracellular vesicles and plasma cytokeratins in castration-resistant prostate cancer patients. AB - Purpose: The presence of Circulating Tumor Cells (CTCs) in Castration-Resistant Prostate Cancer (CRPC) patients is associated with poor prognosis. In this study, we evaluated the association of clinical outcome in 129 CRPC patients with CTCs, tumor-derived Extracellular Vesicles (tdEVs) and plasma levels of total (CK18) and caspase-cleaved cytokeratin 18 (ccCK18). Experimental Design: CTCs and tdEVs were isolated with the CellSearch system and automatically enumerated. Cut-off values dichotomizing patients into favorable and unfavorable groups of overall survival were set on a retrospective data set of 84 patients and validated on a prospective data set of 45 patients. Plasma levels of CK18 and ccCK18 were assessed by ELISAs. Results: CTCs, tdEVs and both cytokeratin plasma levels were significantly increased in CRPC patients compared to healthy donors (HDs). All biomarkers except for ccCK18 were prognostic showing a decreased median overall survival for the unfavorable groups of 9.2 vs 21.1, 8.1 vs 23.0 and 10.0 vs 21.5 months respectively. In multivariable Cox regression analysis, tdEVs remained significant. Conclusions: Automated CTC and tdEV enumeration allows fast and reliable scoring eliminating inter- and intra- operator variability. tdEVs provide similar prognostic information to CTC counts. PMID- 29721204 TI - Comparison and evaluation of two RGD peptides labelled with 68Ga or 18F for PET imaging of angiogenesis in animal models of human glioblastoma or lung carcinoma. AB - The aim of this study was to evaluate two RGD radiotracers radiolabelled with fluorine-18 or gallium-68, in detecting angiogenesis in grafted human tumours and monitoring their treatment with the anti-angiogenic agent bevacizumab. Sixteen mice bearing an U87MG tumour in one flank and a contralateral A549 tumour were treated with intravenous injections of bevacizumab twice a week for 3 weeks. PET images with 18F-RGD-K5 and 68Ga-RGD were acquired before treatment (baseline), after three bevacizumab injections (t1) and after seven bevacizumab injections (t2). In A549 tumours, the treatment stopped the tumour growth, with a tumour volume measured by calliper remaining between 0.28 and 0.40 cm3. The decrease in tumour uptake of both RGD tracers was non-significant. Therefore it was not possible to predict this efficacy on tumour growth based on RGD PET results, whereas ex vivo measurements showed a significantly lower tumour uptake of both tracers in mice sacrificed at t2 vs. at baseline. In U87MG tumours, the uptake measured on PET decreased during treatment, reflecting the partial therapeutic effect observed on tumour volume, consisting in a decrease in the slope of tumour growth. Using 18F-RGD-K5, this decrease in tumour SUVmax became significant at t1, whereas it was also observed with the 68Ga-RGD tracer, but only at t2. 18F RGD-K5 appeared more efficient than 68Ga-RGD in the visualisation and follow-up of U87MG tumours. The comparison of those results with those of immunohistochemistry at baseline and at t2 favoured the hypothesis that tumour RGD uptake reflects other cancer properties than just its angiogenic capacity. PMID- 29721203 TI - Patient derived xenografts (PDX) predict an effective heparanase-based therapy for lung cancer. AB - Heparanase, the sole heparan sulfate (HS) degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, metastasis, angiogenesis, and inflammation. Heparanase accomplishes this by degrading HS and thereby facilitating cell invasion and regulating the bioavailability of heparin binding proteins. HS mimicking compounds that inhibit heparanase enzymatic activity were examined in numerous preclinical cancer models. While these studies utilized established tumor cell lines, the current study utilized, for the first time, patient-derived xenografts (PDX) which better resemble the behavior and drug responsiveness of a given cancer patient. We have previously shown that heparanase levels are substantially elevated in lung cancer, correlating with reduced patients survival. Applying patient-derived lung cancer xenografts and a potent inhibitor of heparanase enzymatic activity (PG545) we investigated the significance of heparanase in the pathogenesis of lung cancer. PG545 was highly effective in lung cancer PDX, inhibiting tumor growth in >85% of the cases. Importantly, we show that PG545 was highly effective in PDX that did not respond to conventional chemotherapy (cisplatin) and vice versa. Moreover, we show that spontaneous metastasis to lymph nodes is markedly inhibited by PG545 but not by cisplatin. These results reflect the variability among patients and strongly imply that PG545 can be applied for lung cancer therapy in a personalized manner where conventional chemotherapy fails, thus highlighting the potential benefits of developing anti-heparanase treatment modalities for oncology. PMID- 29721205 TI - Treosulfan induces distinctive gonadal toxicity compared with busulfan. AB - Treosulfan (L-treitol-1,4-bis-methanesulfonate) has been increasingly incorporated as a main conditioning protocol for hematopoietic stem cell transplantation in pediatric malignant and non-malignant diseases. Treosulfan presents lower toxicity profile than other conventional alkylating agents containing myeloablative and immunosuppressive traits such as busulfan. Yet, whereas busulfan is considered highly gonadotoxic, the gonadal toxicity profile of treosulfan remains to be elucidated. To study the gonadotoxicity of treosulfan, pubertal and prepubertal male and female mice were injected with treosulfan or busulfan and sacrificed one week, one month or six months later. Testicular function was assessed by measurements of sperm properties, testes and epididymides weights as well as markers for testicular reserve, proliferation and apoptosis. Ovarian function was assessed by measurements of ovary weight and markers for ovarian reserve, proliferation and apoptosis. Treosulfan testicular toxicity was milder than that of busulfan toxicity; possibly by sparing the stem spermatogonia in the testicular sanctuary. By contrast, ovarian toxicity of both treosulfan and busulfan was severe and permanent and displayed irreversible reduction of reserve primordial follicles in the ovaries. Our data indicate that treosulfan exerts a different gonadal toxicity profile from busulfan, manifested by mild testicular toxicity and severe ovarian toxicity. PMID- 29721206 TI - Stress and stem cells: adult Muse cells tolerate extensive genotoxic stimuli better than mesenchymal stromal cells. AB - Mesenchymal stromal cells (MSCs) are not a homogenous population but comprehend several cell types, such as stem cells, progenitor cells, fibroblasts, and other types of cells. Among these is a population of pluripotent stem cells, which represent around 1-3% of MSCs. These cells, named multilineage-differentiating stress enduring (Muse) cells, are stress-tolerant cells. Stem cells may undergo several rounds of intrinsic and extrinsic stresses due to their long life and must have a robust and effective DNA damage checkpoint and DNA repair mechanism, which, following a genotoxic episode, promote the complete recovery of cells rather than triggering senescence and/or apoptosis. We evaluated how Muse cells can cope with DNA damaging stress in comparison with MSCs. We found that Muse cells were resistant to chemical and physical genotoxic stresses better than non Muse cells. Indeed, the level of senescence and apoptosis was lower in Muse cells. Our results proved that the DNA damage repair system (DDR) was properly activated following injury in Muse cells. While in non-Muse cells some anomalies may have occurred because, in some cases, the activation of the DDR persisted by 48 hr post damage, in others no activation took place. In Muse cells, the non homologous end joining (NHEJ) enzymatic activity increases compared to other cells, while single-strand repair activity (NER, BER) does not. In conclusion, the high ability of Muse cells to cope with genotoxic stress is related to their quick and efficient sensing of DNA damage and activation of DNA repair systems. PMID- 29721207 TI - Impact of mutational studies on the diagnosis and the outcome of high-risk myelodysplastic syndromes and secondary acute myeloid leukemia patients treated with 5-azacytidine. AB - Myelodysplastic syndromes (MDS) are stem cell disorders caused by various gene abnormalities. We performed targeted deep sequencing in 39 patients with high risk MDS and secondary acute myeloid leukemia (sAML) at diagnosis and follow-up (response and/or relapse), with the aim to define their mutational status, to establish if specific mutations are biomarkers of response to 5-azacytidine (AZA) and/or may have impact on survival. Overall, 95% of patients harbored at least one mutation. TP53, DNMT3A and SRSF2 were the most frequently altered genes. Mutations in TP53 correlated with higher risk features and shorter overall survival (OS) and progression free survival (PFS) in univariate analysis. Patients with SRSF2 mutations were associated with better OS and PFS. Response rate was 55%; but we could not correlate the presence of TET2 and TP53 mutations with AZA response. Patients with sAML presented more variations than patients with high-risk MDS, and usually at relapse the number of mutations increased, supporting the idea that in advanced stages of the disease there is a greater genomic complexity. These results confirm that mutation analysis can add prognostic value to high-risk MDS and sAML patients, not only at diagnosis but also at follow-up. PMID- 29721208 TI - Circulating and tumor-associated caspase-4: a novel diagnostic and prognostic biomarker for non-small cell lung cancer. AB - Late diagnosis limits therapeutic options and survival rate of non-small cell lung cancer (NSCLC) patients. Therefore the identification of biomarkers represents an emerging medical need. A highly sensitive and specific test was developed to identify/quantify a novel/selective diagnostic biomarker for NSCLC patients, caspase-4. This test was validated by using i) plasma from 125 NSCLC patients and 79 healthy (non-pathological) subjects, ii) plasma from 139 smokers and iii) from 70 chronic-obstructive pulmonary disease (COPD) patients. Caspase-4 quantification was also assessed in the lung tumor mass of 98 paired NSCLC patients compared to 10 non-tumor lung tissues (i.e. tuberculosis). Circulating caspase-4 was detected in both healthy and NSCLC patients; however at different range values: 2.603-3.372 ng/ml for NSCLC patients (95% CI) compared to 0.3994 0.6219 ng/ml for healthy subjects (95% CI). The sensitivity of the test ranged from 97.07% to 100%; the specificity was 88.1% with a positive predictive value of 92.54%, accuracy of 95.19% and AUC of 0.971. Smokers (95% CI, 0.3947-0.6197 ng/ml) and COPD patients (95% CI, 1.703-2.995 ng/ml) showed intermediate values of circulating caspase-4. Tissue levels of caspase-4 in the tumor mass showed that 72 (72.7%) out of 99 patients were positive. More importantly, higher levels (cut-off value = 0.307 ng/ml) of caspase-4 in the tumor mass were associated to reduced overall survival (median 0.92 years) compared to NSCLC patients with lower levels (median 3.02 years). We report for the first time caspase-4 as a novel diagnostic and prognostic biomarker, opening new therapeutic perspectives for NSCLC patients. PMID- 29721209 TI - Radiotherapy increases plasma levels of tumoral cell-free DNA in non-small cell lung cancer patients. AB - We investigated the plasma levels of tumor-specific cell-free DNA (cfDNA) in 17 stage I-II (early) and IV (advanced) non-small cell lung cancer (NSCLC) patients who underwent radiotherapy. Digital polymerase chain reaction (PCR) and targeted sequencing showed that total and tumor-specific cfDNA levels increased in response to radiotherapy in both early- and advanced-stage NSCLC patients. We detected high copy numbers of epidermal growth factor receptor mutations (L858R and T790M) in the cfDNA samples from stage IV NSCLC patients who underwent stereotactic body radiation therapy to treat brain metastasis related to tyrosine kinase inhibitor (TKI) treatment failure. In conclusion, our study demonstrates that radiotherapy increases tumoral cfDNA levels in the plasma and shows potential to serve as an indicator for diagnosing drug-resistant tumor-related gene mutations in early-stage NSCLC patients or those undergoing molecular targeted therapy. PMID- 29721210 TI - Treatment with epigenetic agents profoundly inhibits tumor growth in leiomyosarcoma. AB - Leiomyosarcomas are rare mesenchymal neoplasms characterized by a smooth muscle differentiation pattern. Due to the extremely poor prognosis in patients, the development of novel chemotherapeutic regimens remains critically important. In this study, multiple leiomyosarcoma cell lines, SK-UT1, SK-LMS1, and MES-SA were treated with varying doses of the DNA Methyltransferase Inhibitors (DNMTi) 5 azacitidine (Aza), 5-aza-2-deoxycytidine (DAC), and guadecitabine (SGI-110). The effect of these epigenetic modulators was measured using both in-vitro and in vivo models. Of the three epigenetic modulators, Guadecitabine was the most effective at decreasing cell survival in LMS cell lines. SK-UT1 was found to be the more sensitive to all three epigenetic modulators, while SK-LMS1 and MES-SA were more resistant. The contrast in sensitivity seen was also represented by the increase in apoptosis in Aza and guadecitabine. In parallel with Aza, guadecitabine was observed to also arrest the cell cycle. Treatment with guadecitabine led to a decrease in growth across the spectrum of sensitivity in LMS cell lines, both in a delayed in vitro and in vivo model; in parallel experiments, apoptotic pathways were activated in sensitive and less sensitive lines. Additional studies are required to explore potential therapeutic applications and mechanisms for leiomyosarcoma treatment. PMID- 29721212 TI - Efficacy and safety of sorafenib for advanced renal cell carcinoma: real-world data of patients with renal impairment. AB - Background: We retrospectively analysed the efficacy and safety of sorafenib in patients with advanced renal cell carcinoma with renal impairment. Methods: Patients were divided into two groups by an estimated glomerular filtration rate (eGFR) cut-off of 45 mL/min/1.73 m2. Background factors considered to affect prognosis were well balanced by propensity score matching between the groups. Demographics, dose modification, adverse events, tumour response, progression free survival, and renal function (eGFR) were evaluated. Results: Among 935 and 2008 patients with an eGFR of <45 and >=45, respectively, 613 pairs were matched. The mean starting dose was significantly lower in patients with an eGFR of <45; however, the mean daily dose, median treatment duration, progression-free survival, and tumour response were similar between the groups. In terms of safety, no significant differences were found in serious adverse events, although cytopaenia (16.6% vs 10.6%) and renal dysfunction (4.4% vs 0.7%) were higher in patients with an eGFR of <45 than >=45 in all adverse events. There were also no differences in dose modification, including dose reduction, dose interruption, and treatment discontinuation. Conclusion: Throughout the 12-month observation period, sorafenib in patients with an eGFR of <45 and >=45 showed similar safety and efficacy, and treatment was continued without affecting renal function. PMID- 29721211 TI - Advanced pancreatic cancer: a meta-analysis of clinical trials over thirty years. AB - Background: In contrast to other cancers, survival rates for pancreatic ductal adenocarcinoma (PDAC) patients have improved but minimally over the past thirty years. The aim of this study was to perform a meta-analysis of clinical trials published since 1986 to determine trends in median overall survival in primarily metastatic PDAC. Materials and methods: All Phase 2-4 clinical trials published during or after 1986 investigating first-line systemic chemotherapy in metastatic PDAC were included in the meta-analysis. Publications obtained through PubMed and www.ClinicalTrials.gov were cross-referenced to identify additional trials. Trials enrolling fewer than 50% of study participants with metastatic disease were excluded. Results: Of 19,488 patients enrolled in 151 clinical trials, 84% had metastatic disease and 16% had locally advanced pancreatic cancer. In clinical trials published from 1986 to 2016, the weighted median overall survival (wMOS) increased by 3.0 months. The median wMOS was higher in combination therapy (7.31 months, IQR 5.4 to 8.5) compared to non-gemcitabine, single-agent therapy (4.76 months, IQR 3.5 to 6.0), gemcitabine monotherapy (6.48 months, IQR 5.9 to 7.2), and gemcitabine plus single-agent therapy (7.09 months, IQR 6.3 to 8.2). Of all regimens used in more than one study arm, FOLFIRINOX had the highest wMOS (10.9 months). Conclusions: Regardless of treatment regimen, survival rates in PDAC have minimally improved over time. Of drugs used in two or more study arms, only FOLFIRINOX has a wMOS greater than ten months. Emphasis should, therefore, be placed on identification of novel targets that promote early diagnosis and intervention. Funding: The authors on this manuscript are in parts, supported by grants from the National Institutes of Health (EDRN U01 CA200466, SPORE P50 CA127297, R01 CA183459, R21 AA026428 and R01 CA 195586). PMID- 29721213 TI - Anabolic androgenic steroids and carcinogenicity focusing on Leydig cell: a literature review. AB - Anabolic androgenic steroids (AAS) are some of the most common drugs used among athletes, frequently in combination with resistance training, to improve physical performance or for aesthetic purpose. A great number of scientific reports showed the detrimental effects of anabolic androgenic steroids on different organs and tissues. In this literature review, we analyzed the AAS-mediated carcinogenicity, focusing on Leydig cell tumor. AAS-induced carcinogenicity can affect DNA transcription through two pathways. It can act directly via the androgen receptor, by means of dihydrotestosterone (DHT) produced by the action of 5-a reductase. It can also work through the estrogen receptor, by means of estradiol produced by CYP19 aromatase. In addition, nandrolone and stanazolol can activate the PI3K/AKT and PLC/PKC pathways via IGF-1. This would result in cell proliferation in Leydig cell cancer, or magnify cyclin D1 concentration inducing breast cell proliferation. AAS abuse is becoming a serious public health concern in view of the severe health consequences secondary to AAS abuse. The negative role of AAS in supraphysiological dosage impairs the expression of enzymes involved in testosterone biosynthesis. Abnormal synthesis of testosterone plays has a negative effect on the hormonal changes/regulation, and might be involved in certain carcinogenic mechanisms. At the light of this review, it could become very interesting to perform an information campaign more strengthened in gyms and schools in order to prevent male fertility impairment and other tissues damage. PMID- 29721214 TI - Distinct molecular subtypes of gastric cancer: from Lauren to molecular pathology. AB - In Western countries the majority of gastric cancers (GC) are usually diagnosed in advanced stages reporting a 5-year survival rate of only 26%. The Lauren classification of GC was most widely used in clinical practice since it reflects GC morphology, epidemiology, tumor biology, clinical management and outcome. Despite the initial promise of individualizing antitumor treatment, the management of GC still remains relatively broad and general. Apart from clinical staging, molecular profiling enables targeting of the identified underlying alterations, rather than histology. In contrast to breast carcinoma, molecular classification of GC does not yet imply treatment modality. Molecular classifications of GC and their therapeutic implications are therefore extensively studied. The current proposed molecular divisions of GC come from three different parts of the world where different standard treatment modalities for advanced GC are recommended. Wider use of GC molecular subtyping may solve problems, such as susceptibility to novel systemic therapy regimens or selection of patients for aggressive surgery and targeted adjuvant/conversion therapy. In any case, the rapid entry of novel molecular targeted therapies into routine oncology practice clearly underscores the urgent need for clinicians to be aware of these new possibilities. PMID- 29721216 TI - Correction: Niclosamide and its analogs are potent inhibitors of Wnt/beta catenin, mTOR and STAT3 signaling in ovarian cancer. AB - [This corrects the article DOI: 10.18632/oncotarget.13466.]. PMID- 29721215 TI - Epigenetic regulation of long non-coding RNAs in gastric cancer. AB - Gastric cancer is one of the most common cancers and is the second leading cause of cancer mortality worldwide. Therefore, it is urgent to explore new molecular biomarkers for early diagnosis, early treatment and prognosis for gastric cancer patients. Recently, increasing evidence has shown that epigenetic changes, such as aberrant DNA methylation, histone modifications, and noncoding RNAs (ncRNAs) expression, play substantial roles in the development and progression of malignancies. Among these changes, long non-coding RNAs (lncRNAs), a novel class of ncRNAs, are emerging as highly versatile actors in a variety of cellular processes by regulating gene expression at the epigenetic level as well as at the transcriptional and post-transcriptional levels. Hundreds of lncRNAs become dysregulated in the various pathological processes of gastric cancer, and multiple lncRNAs have been reported to function as tumor-suppressors or oncogenes, although the underlying mechanisms are still under investigation. Here, we provide an overview of the epigenetic regulation of chromatin and the molecular functions of lncRNAs; we focus on lncRNA-mediated epigenetic regulation of cancer-related gene expression in gastric cancer, as well as discuss the clinical implications of lncRNAs on epigenetic-related cancer treatments, which may contribute helpful approaches for the development of new potential strategies for future diagnosis and therapeutic intervention in human cancers. PMID- 29721217 TI - Knowledge, Attitudes and Perceptions of Secondary School Teenagers towards HIV Transmission and Prevention in Rural and Urban Areas of Central Uganda. AB - HIV/AIDS has remained a challenge in Uganda among adolescent despite the ABC strategy used globally to prevent HIV infection. The study assessed the knowledge, attitudes and perceptions of secondary school teenagers towards HIV transmission and prevention in rural and urban schools of central Uganda. A cross sectional study using self-administered questionnaires and structured interviews was used to collect data from adolescents in secondary schools in Kampala and Buikwe districts. Eight schools were randomly selected with 4 schools in each district. A total of 245 students from schools were recruited in the study with 120 and 125 students from urban Kampala and rural Buikwe district schools respectively. Data were analyzed using SPSS version 11. The results were expressed as percentages in a 2 * 2 tables. The mean age of the participants was 15.9 +/- 2.5 years. Results showed that 95.1% participants had knowledge on HIV/AIDS in both urban and rural schools and 27.4% knew all the modes of HIV transmission. About 83.7% knew the ABC strategy for HIV prevention and 37.6% would talk about HIV/AIDS mainly with friends. For HIV cure, 62.0% of study participants reported non-cure and 24.9% were not sure. The remaining 13.1% of the study participants in both urban and rural schools reported that HIV can be cured. And the modes of curing HIV that were mentioned by participants included spiritual healing, transmitting it to others through sexual intercourse and that antiretroviral (ARVs) drugs can cure it as well as that it can be cured abroad. About 65.7% of participants reported recognition of one with HIV/ AIDS and by having red lips, being sickly; weight loss, skin rash and being very rich were mentioned. About 39.2% of the study participants mentioned that they cannot get infected with HIV and can't contract HIV at all and 18.4% believed that chances of getting HIV infection were high. On perception and attitude on condoms and their use, participants reported that it is a sign of mistrust, reduces sexual pleasures and they are embarrassing to buy. Majority of the participants in both urban and rural schools had some knowledge on HIV/AIDS and the ABC strategy for HIV prevention. However, there was a knowledge gap on the various modes of HIV transmission and prevention. There was misconception of the participants on HIV/AIDS cure, condom use and on the chances of contracting HIV. About the source of HIV/AIDS information, majority of the participants were getting information on HIV/AIDS from friends of which some information was misleading. This false information could be the reason for the increased HIV prevalence reported among the adolescents in the schools. Generally, participants had some knowledge on HIV/AIDS though they had knowledge gap on HIV transmission and prevention. PMID- 29721218 TI - Combined effects of electric toothbrushing and dentifrice on artificial stain removal: An in vitro study. AB - Background: This in vitro study aimed to clarify the combined effect of electric toothbrushing and dentifrice on the removal of artificial stain. Material and Methods: Twenty-five bovine incisors were cut at the cervix and the crown was embedded in auto-cured acrylic resin. Specimens were abraded using #240 SiC paper to obtain a flat enamel surface, and 20 specimens were treated with 10% citric acid / 3% ferric chloride solution followed by 1% tannic acid solution to produce surface staining. They were divided into four groups: 1) brushing with an electric toothbrush and whitening dentifrice (group S+B); 2) brushing with an electric toothbrush and fluoride dentifrice (group S+C); 3) brushing with an electric toothbrush and no dentifrice (group S); and 4) no brushing (control group). The remaining five specimens were used as a baseline. Color values (L*, a*, and b* were measured before brushing (0 min), and at 1 min, 5 min, 10 min, and 20 min using a microscopic area spectrophotometer. The color change (DeltaE) was calculated by subtracting the baseline values from the final color values obtained at each time point. The data were statistically analyzed using two-way repeated-measures analysis of variance and Tukey's honest significant difference test as a post hoc test (p<0.05). Results: The L* values of groups S+B and S+C increased over time (p<0.05), but no significant differences were observed in group S and the control group at any of the time points (p>0.05). Groups S+B and S+C demonstrated greater DeltaE values than group S. Conclusions: The combination of electric toothbrushing and dentifrice removed the artificial stain more effectively than brushing without dentifrice. However, the stain removal was limited. The two dentifrices evaluated in this study exhibited similar stain removal effects. Key words:Color change, stain removal, dentifrice, electric toothbrush, whitening effect. PMID- 29721219 TI - In vitro quantitative comparison of erosive potential of infant mouthwashes on glass ionomer cement. AB - Background: The widespread use of mouthwashes, specially in children, is a concern, since the long-term use may modify the topography of dental materials. However, this process still unclear regarding the wear related to infant mouthwashes on glass ionomer cement. Thus, the purpose of this investigation was evaluate the erosive potential of infant mouthwashes on glass ionomer cement specimens. Material and Methods: Forty round-shaped specimens were divided into 4 groups (N=10) and submitted to erosive cycling for 15 days, being exposed 2X/day in the following children's active agents mouthwash solutions: G1- cetylpyridinium chloride, G2- xylitol and triclosan and G3 - Malva sylvestris and xylitol. Prior to cycling, the specimens were submitted to the surface roughness measurement. After erosive cycling, the specimens were reanalyzed, and calculated the increase of roughness (?Ra). Additionally, it was adopted distilled water as a negative control (G4). As an extra analysis, the mouthwashes had their pH values measured. The results were submitted to T-test and ANOVA followed by Tukey test at 5%. Results: In relation to pH values, G2 presented the most acidic pH value (pH = 6.83) in comparison to other substances. Regarding the comparison of the final roughness values (R) among the groups, it was verified that the mouthwashes showed significant roughness increase in comparison to control group, especially to G3 group (Rf = 1.67 +/- 0.14) as well the DeltaRa values with statistical difference in comparison to distilled water. Still, with exception of control group outcome, an increase of roughness of each mouthwash was verified after the studied period. Conclusions: Active agents present in infant mouthwashes were capable of roughness increased of glass ionomer cement surface, demonstrating an erosive potential of this material largely used in pediatric dentistry. Key words:Dental erosion, dental cements, mouthwash. PMID- 29721220 TI - Approaches used to care for carious primary molars among pediatric dentists and general dental practitioners in Saudi Arabia. AB - Background: The aim of this cross sectional study was (1) to identify and compare the approaches which are used to care for carious primary molars between pediatric dentists (PDs) and general dental practitioners (GDPs) in Saudi Arabia and (2) to evaluate the knowledge level of the most appropriate treatment decisions for both groups with regard to caries in primary molars and its relation with demographic variables. Material and Methods: A random sample of 600 GDPs and all registered PDs (n = 100) in the Saudi dental society in 2016 were emailed a two part questionnaire; the first part included questions about demographic data and the second part investigated knowledge of the participants of the most appropriate treatment decision in four hypothetical case scenarios in which the severity of caries in a single primary first molar differed. Data were analyzed using chi square and ordinal logistic regression statistical tests. The significance was set at 0.05. Results: The average knowledge score was 1.28 for GDPs and 1.80 for PDs. There were significant differences between both groups on their choice of the most appropriate treatment option in three out of four scenarios. Two factors significantly improved the participants' knowledge; age and qualification (P<0.050.05). PDs were more interventionists, ready to perform pulpotomy and extraction in the absence of equally appropriate treatment options. Conclusions: GDPs and PDs in Saudi Arabia had different treatment approaches of different carious conditions affecting primary molars. PDs had moderate but significantly better knowledge of the most appropriate treatment option than GDPs. Key words:Dental caries, general dental practitioners, pediatric dentists, primary molars, treatment approaches. PMID- 29721221 TI - Caries and quality of life in portuguese adolescents: Impact of diet and behavioural risk factors. AB - Background: The aim of this study was to assess the impact of diet and behavioural risk factors on caries appearance, and on oral health-related quality of life (OHRQoL) among Portuguese adolescents. Material and Methods: An epidemiological study conducted on 782 adolescents between 11-17 years, from randomly selected public schools of the 3rd cycle of basic education. All participants were asked for self-perceived general status health, about tooth brushing habits and about the using of toothpaste with fluoride and a Food Frequency Questionnaire. The DMFT index (decayed, missing and filled teeth) was evaluated according to WHO criteria. To evaluate the OHRQoL, the 49-items Oral Health Impact Profile questionnaire (OHIP-49) was applied. Results: Consumption more than once a week of tea with sugar, milk with sugar and biscuits were significantly associated with DMFT index. Lower levels in OHRQoL was reported by students who consumed frequently (more than once a week) fast food, chocolate flakes and those who brushed their teeth once a day or less frequently instead of 2-3 times a day. Conclusions: Frequency of consumption of sweetened/fast food was a significant factor associated with caries and quality of life. Key words:Oral health-related quality of life, adolescent, diet, DMFT, epidemiology. PMID- 29721222 TI - The retention characteristics of Hawley and vacuum-formed retainers with different retention protocols. AB - Background: This study aimed to compare the effectiveness of two different protocols of wearing vacuum-formed retainers (VFRs) with the standard protocol of wearing Hawley retainer in maintaining the results of orthodontic treatment. Material and Methods: This single-blind randomized clinical trial consisted of 90 patients who finished orthodontic treatment at the Department of Orthodontics of Mashhad Dental School, and required removable retainers. The participants were randomly divided into 3 groups and received the following treatments. Group 1: Hawley retainers (4 months full-time and then night-only); group 2: VFR_4M (4 months full-time and then night-only); group 3: VFR_1W (1 week full-time and then night-only). The study models were prepared after debond and at 4 and 8 months later, and intercanine width, intermolar width, arch length and the Little's irregularity index were compared between groups. Results: No significant differences were found in intercanine and intermolar widths between groups (P<05). Upper arch length was significantly lower in Hawley group than the two VFR groups (p<0.05), but lower arch length values were comparable. Upper irregularity index was significantly lower in two VFR groups compared to Hawley group (p<0.05), whereas in the lower jaw, only VFR_4M group showed significantly lower crowding than Hawley group (p<0.05). Conclusions: Both retention regimens of VFRs were more effective than Hawley retainer in maintaining arch length and tooth alignment in the upper arch. For better incisor alignment in the lower jaw, the patients should be advocated to wear VFR 4 months full-time and then at night instead of wearing Hawley retainer. Key words:Essix, Hawley retainer, orthodontic treatment, retention, vacuum-formed retainer. PMID- 29721223 TI - Periopathogenic bacteria in dental plaque of Congolese patients with periodontitis: A pilot study. AB - Background: Periopathogenic bacteria play an important role in the etiology of periodontal disease. At present, no study screening for periopathogens in the DR Congo was carried out. The aim of this pilot study was to investigate the prevalence of five periopathogens in Congolese patients with periodontitis and to determine the association between these bacteria. Material and Methods: Twelve patients (eight women and four men) with a mean age of 45 +/- 19 years from those consulted in dental services of two medical centers of Kinshasa from April 2017 to October 2017 were included. Full mouth examination was registered, the probing pocket depth and clinical attachment level were assessed at six sites per tooth. Dental subgingival plaque samples were taken in the deepest pocket per arch in the maxilla and mandible. DNA analysis was performed using DNA-strip technology. The Fisher Exact test and Pearson correlation were used for statistical analysis. Results: Porphyromonas gingivalis and Tannerella forsythia were detected at high level of 92%, Prevotella intermedia at a rate of 75% whereas Treponema denticola was detected in all patients. Aggregatibacter actinomycetemcomitans was not detected. Strong associations were found between three bacteria of the red complex and between T. denticola and P. intermedia (r=1). Conclusions: This first study investigating periopathogens in subgingival plaque of Congolese with periodontitis demonstrated a high prevalence of the red complex (P. gingivalis, T. forsythia and T. denticola). Associations between different bacteria of this complex were strong. Key words:Association, bacteria, periopathogen, periodontitis, prevalence. PMID- 29721224 TI - Porosity analysis of MTA and Biodentine cements for use in endodontics by using micro-computed tomography. AB - Background: The purpose of this study is to compare the porosity of two repair cements, White ProRoot(r) MTA and Biodentine(r). These samples were analyzed by using micro-computed microtomography. Material and Methods: Sixteen samples were used in the study that were divided according to the composition of the materials used. White ProRoot(r) MTA (n = 8) and Biodentine(r) (n = 8) were the samples prepared according to the manufacturer's instructions. They were placed in silicone molds of 5 +/- 0.1mm in height and an internal diameter of 5 +/- 0.1mm, 24 hours after its preparation, the samples were scanned through a micro-CT, the porosity results were analyzed statistically by independent "t" tests. Results: It is evident that Biodentine(r) has better porosity properties than ProRoot(r) MTA. The results of the study quantify a smaller number of pores per surface, a smaller volume in each pore per mm3 and a lower total porosity present in samples of Biodentine(r) unlike ProRoot(r) MTA samples which is larger in both. Conclusions: The results obtained in computerized microtomography endodontic biomaterial samples concluded that Biodentine(r) has a lower porosity than ProRoot(r) MTA. Key words:Porosity, microleakage, micro-CT, endodontic cements. PMID- 29721226 TI - Enamel evaluation by scanning electron microscopy after debonding brackets and removal of adhesive remnants. AB - Background: The bonding of accessories in the dental crown during the orthodontic treatment creates microporosities, thus promoting micromechanical retention of the adhesive to the enamel structure. After debonding brackets, at the end of the active orthodontic treatment, a certain amount of adhesive remnants must be mechanically removed from the enamel. The objective of this study was to compare, by means of scanning electron microscopy, three different methods to remove the adhesive remnants after orthodontic bracket removal. Material and Methods: An experimental analytical study was conducted on human premolar specimens, extracted within a year or less. The preparation of the enamel was carried out with the application of 35% phosphoric acid and Transbond XT Light Cure Adhesive Primer(r) adhesive. Edgwise Standart prescription brackets, slot .022 "(Morelli Orthodontia) were glued to the enamel using Transbond XT(r) bonding resin. The brackets were placed on the center of the vestibular face of the clinical crown, and a 300-gram pressure was exerted against the surface of the enamel, measured with an orthodontic dynamometer. The brackets were debonded with adhesive removing pliers, and the samples were divided into groups, according to the protocol used for adhesive remnant removal: high-speed multi-laminated drill bit, low-speed multi-laminated drill bit, and low-speed glass fiber. After removal of the adhesive remnants, the samples went through scanning electron microscopy, obtaining electro micrographs with a magnification range of 150 X, 500 X, and 2,000 X. Results: The tested method showed that the best effectiveness for the removal of the adhesive remnants after bracket debonding was the use of a tungsten carbide multi-laminated high speed, followed by the use of a tungsten carbide multi-laminated, low-rotation drill. The use of fiberglass drill alone has proved to be inefficient for clinical use, given the large amounts of adhesive remnants it leaves on the enamel. Conclusions: All methods evaluated in this study proved to be inefficient for total removal of adhesive remnants from the enamel. Key words:Dental enamel, microscopy, orthodontics. PMID- 29721225 TI - Expansion of permanent first molars with rapid maxillary expansion appliance anchored on primary second molars. AB - Background: To evaluate how the amount of expansion of the primary second molars, the patient's age, and the skeletal maturation stage influence the amount of expansion at the level of the permanent first molars. Material and Methods: Fifty five patients aged between 6 and 11 years with a cervical vertebral maturation stage of CS1 or CS2 were retrospectively selected. The intermolar width was measured before and after expansion to evaluate the amount of expansion achieved at the level of the primary second molars and the permanent first molars. Stepwise multiple linear regression was used to evaluate how the amount of primary molars expansion, the patient's age, and the cervical vertebral maturation stage predict the amount of permanent molar expansion. Results: A significant regression equation was found, and for every 1 mm of primary molar expansion, 0.91 mm of permanent molar expansion can be expected. An age between 6 and 11 years and the CS1 or CS2 skeletal maturation stage were not significant predictors of permanent molar expansion. Conclusions: A rapid maxillary expansion appliance anchored on primary second molars is effective in expanding the permanent molars to correct a transverse maxillary deficiency in prepubertal patients, transferring the risks associated with the large forces used to the primary teeth. Key words:Maxillary expansion, transversal deficiency, primary molars. PMID- 29721228 TI - Antibiotic prescription for the prevention and treatment of postoperative complications after routine dental implant placement. A cross-sectional study performed in Spain. AB - Background: As there are no established guidelines for antibiotic prescription after dental implant placement a study was made to determine the current prescribing habits of several groups of practitioners regarding antibiotics to prevent and/or treat postoperative complications - early failures and infections in relation to routine dental implant placement. Material and Methods: An electronic survey was sent to postgraduate students and professionals with experience in routine dental implant placement who practice in Spain. The questions asked were related to whether antibiotics were routinely prescribed either pre- or postoperatively to prevent and/or treat postoperative complications during routine dental implant placement, and, if so, what antibiotics, dosage, frequency, and duration were used. Descriptive and bivariate analyses of the data were performed. Results: Two hundred and forty-seven responses were obtained. Preventively, 17 respondents (6.9%) prescribed antibiotics only preoperatively (95% confidence interval (CI): 3.7 to 10.0%), 100 (40.5%) preferred to give them exclusively during the postoperative period (95%CI 34.4 to 46.6%) and 94 practitioners (38.1%) prescribed antibiotics both pre- and post-operatively (95%CI 32.0 to 44.1%). The most common preoperative regime was amoxicillin 2 g given orally 1 hour before the procedure (21.6%, n = 24) following amoxicillin 750 mg given orally 1 day prior to surgery (21.6%, n = 24). The most common routine postoperative regime was amoxicillin 750 mg given orally for 7 days (34.0%, n = 66). To treat postoperative infections during the osseointegration period, 233 respondents (93.2%) prescribed antibiotics (95%CI 91.4 to 97.2%). The most common regime used was amoxicillin and potassium clavulanate 875/125 mg, given orally for 7 days (51.9%, n = 121). Conclusions: There is no consensus among dental clinicians regarding antibiotic use during routine dental implant placement to prevent postoperative complications and/or early failures. Moreover, the most commonly-prescribed regimes differ from that recommend in the latest published studies. Key words:Antibiotics, dental implants, oral implantology, complications, postoperative wound infection, early failure. PMID- 29721227 TI - Accuracy of fit of implant-supported bars fabricated on definitive casts made by different dental stones. AB - Background: The purpose of this study was to evaluate the accuracy of fitting of an implant supported screw-retained bar made on definitive casts produced by 4 different dental stone products. Material and Methods: The dental stones tested were QuickRock (Protechno), FujiRock (GC), Jade Stone (Whip Mix) and Moldasynt (Heraeus). Three external hexagon implants were placed in a polyoxymethylene block. Definitive impressions were made using monophase high viscosity polyvinylsiloxane in combination with custom trays. Then, definitive models from the different types of dental stones were fabricated. Three castable cylinders with a machined non-enganging base were cast and connected with a very small quantity of PMMA to a cast bar, which was used to verify the marginal discrepancies between the abutments and the prosthetic platforms of the implants. For that purpose special software and a camera mounted on an optical microscope were used. The gap was measured by taking 10 measurements on each abutment, after the Sheffield test was applied. Twelve definitive casts were fabricated for each gypsum product and 40 measurements were performed for each cast. Mean, minimum, and maximum values were calculated. The Shapiro-Wilk test of normality was performed. Mann-Whitney test (P<.06) was used for the statistical analysis of the measurements. Results: The non-parametric Kruskal-Wallis test revealed a statistically significant effect of the stone factor on the marginal discrepancy for all Sheffield test combinations: 1. Abutment 2 when screw was fastened on abutment 1 (chi2=3, df=35.33, P<0.01), 2. Abutment 3 when the screw was fastened on abutment 1 (chi2=3, df=37.74, P<0.01), 3. Abutment 1 when the screw was fastened on abutment 3 (chi2=3, df=39.79, P<0.01), 4. Abutment 2 when the screw was fastened on abutment 3 (chi2=3, df=37.26, P<0.01). Conclusions: A significant correlation exists between marginal discrepancy and different dental gypsum products used for the fabrication of definitive casts for implant supported bars. The smallest marginal discrepancy was noted on implant supported bars fabricated on definitive casts made by Type III mounting stone. The biggest marginal discrepancy was noted on implant supported bars fabricated on definitive casts made by Type V dental stone. The marginal discrepancies presented on implant supported bars fabricated on definitive casts made by two types of Type IV dental stone were not significantly different. Key words:Dental implant, passive fit, dental stones, marginal discrepancy. PMID- 29721229 TI - Evidence of variable bacterial colonization on coloured elastomeric ligatures during orthodontic treatment: An intermodular comparative study. AB - Background: Besides, other factors, the choice of materials used as orthodontic ligatures could be one of the many tools to counter the effects of microbial adhesion, that culminates into dental ailments. Therefore, we assessed bacterial adhesion on elastomeric ligatures with special reference to coloured elastomeric rings during orthodontic treatment. Material and Methods: A split mouth study, involving 240 samples of different elastomeric ligatures from forty orthodontic patients possessing good oral hygiene was carried out. The archwire was ligated to the brackets on both arches with elastomeric rings (superslick, clear transparent , blue and pink) at predetermined quadrants. After six weeks, ligatures from second premolars were removed and processed for bacterial enumeration using standard techniques. Bacterial counts were also determined for stimulated saliva samples taken at 0 and 6 weeks. Results: A statistically significant difference in bacterial counts was obtained amongst different elastomeric modules used. Maximum bacterial counts were found on conventional pigmented elastomeric modules, followed by Superslick module and clear module. More number of bacteria associated with the conventional pink as compared to the conventional blue pigmented modules, however it was not statistically significant. The three bacterial genera Streptococcus Staphylococcus and Aerobic Lactobacilli adhered to elastomeric modules in following predominant pattern i.e. Conventional pink>Conventional Blue>Superslick>Clear. Conclusions: The studies evidenced colour and material dependent bacterial colonization on orthodontic modules and could be an indicator of bacterial biofilm forming potential based on surface chemistries and a clinically efficacious tool to redesign conventional and modified elastomeric rings as orthodontic ligation accessories. Key words:Bacterial colonization, biofilm, coloured elastomers, orthodontic ligatures. PMID- 29721230 TI - Role of coefficient of thermal expansion on bond strength of ceramic veneered yttrium-stabilized zirconia. AB - Background: Incompatible coefficient of thermal expansion (CTE) is supposed to be a reason for chipping of ceramic veneered zirconia. This study evaluates the effect of veneering ceramic at varied CTE on bond strength to zirconia. Material and Methods: Zirconia disks (Z, O 10 mm, 1.0 mm thickness) were prepared from Y TZP (Cercon(r)) and sintered at 1350 degrees C for 6 hours. All zirconia disks were veneered with ceramics ((O 7.0 mm, 1.5 mm thickness) with varied CTE including VITADur(r) alpha (VDalpha), VITAVM(r)7 (VM7), VITAVM(r)9 (VM9), Cercon(r) ceramkiss (CCK), IPSe.max(r) ceram (IeC), and IPS dSIGN(r) (IdS) (n=15). The specimens were thermo-cycled (5-55 degrees C, 500 cycles) prior to determine the shear bond strength on a universal testing machine. The veneering ceramic and zirconia rods (O 4 mm, 30 mm length) were prepared for CTE evaluation. ANOVA and Tukey's multiple comparisons were used to determine the statistically significant difference (alpha=0.05). Weibull analysis was applied for survival probability, Weibull modulus (m), and characteristics strength (sigmao) of the shear bond. The interfaces were microscopically examined. The phase transformation of zirconia was determined using X ray diffraction. Results: The mean+/-sd (MPa), m, and sigmao of bond strength were 20.45+/-2.32, 9.25, and 21.53 for Z-VDalpha, 19.47+/-4.53, 4.66, and 20.31 for Z-VM7, 21.05+/-3.96, 5.61, and 21.88 for Z-IeC, 25.85+/-2.74, 9.93, and 27.15 for Z-VM9, 25.82+/-4.39, 6.27, and 27.06 for Z-CCK, and 2.96+/-0.73, 4.11, and 3.28 for Z-IdS. The CTE (*10-6/ degrees C) were 10.80, 7.83, 7.87, 9.86, 9.93, 10.03, and 12.95 for Z, VDalpha, VM7, IeC, VM9, CCK, and IdS. The bond strength was significantly affected by the CTE difference (p<0.05). The t->m phase transformation related with the CTE difference. Conclusions: The CTE's differences induced stress that affected the bond strength. CTE's compatibility of veneering ceramic to zirconia is crucial for enhancing the bond strength. The CTE difference approximately 0.77-0.87*10-6/ degrees C was recommended. Key words:Bond strength, coefficient of thermal expansion, zirconia. PMID- 29721231 TI - Cystic mass of the floor of the mouth. AB - Background: Epidermoid and dermoid cysts in the oral cavity are relatively uncommon lesions of developmental origin. They often remain asymptomatic for years until they grow enough to interfere with speech, deglutition and less often with breathing which can pose a critical risk to the airway and require immediate surgery. Case description: A case of an epidermoid cyst of the floor of the mouth affecting a 37-year-old man is presented; this lesion was surgically enucleated with an intraoral approach. Patient did well postoperatively and there was no evidence of recurrence up to 2 years of follow up. Clinical implications: Floor of the mouth is a challenging site for the diagnosis of a broad variety of lesions which the surgeon should be aware. Depending on the anatomical relation to the muscles of the floor of the mouth dermoid cysts are classified as supramylohyoid or inframylohyoid, and they will both have different clinical and radiological features. This article also includes literature review about the etiopathological, clinical, radiological and histological features, the differential diagnosis and its treatment. Key words:Epidermoid cyst, dermoid cyst, floor of mouth. PMID- 29721232 TI - Management of symptomatic florid cemento-osseous dysplasia: Literature review and a case report. AB - Introduction: Cemento-osseous dysplasia is a jaw disorder characterized by a reactive process in which normal bone is replaced by connective tissue matrix. There are different Cemento-osseous dysplasia entities. The treatment of these lesions, once diagnosed by radiology, is not required because generally they are asymptomatic. The localization is in the tooth-bearing areas of the jaws and its distribution is symmetric. Case Reports: In this case report, a 57-year-old Caucasian female patient was referred to our attention complaining of painful inflammatory events localized in the right angle of the jaw. The radiographic appearance, the distribution of several lesions and the positive vitality test of the involved teeth, supported the diagnosis of Florid Cemento-osseous dysplasia. Because of the symptomatology, the patient was submitted to surgery and the lesion and the second inferior right molar were removed. The histological examination of the specimens confirmed the diagnosis. Discussion: Many lesions that may exhibit a similar sclerotic appearance on conventional radiographs have to be differentiated and dental imaging can be used to discriminate between Florid COD and other lesions. Diagnosis of Florid Cemento-osseous dysplasia can be made with accurate clinical and radiographic assessment. In asymptomatic cases no treatment is required and the patient should have regular follow-up, but in this symptomatic case it was necessary to proceed with surgical intervention. The surgery treatment in the symptomatic case had a favourable prognosis and the two years follow-up has shown a complete healing. Given the abow, it is concluded that the choice of treatment must be selective according to the disease sites. Key words:Cemento-ossifying dysplasia, fibro-osseous lesions, florid cemento osseous dysplasia, cementoma. PMID- 29721233 TI - Dentigerous cyst with parietal and intracystic calcifications: A case report and literature review. AB - Background: Dentigerous cyst appears surrounding the crown of an included tooth. On the radiographic exam, a radiolucent rounded well-defined lesion can be observed. Material and Methods: This study reports a clinical case of a 34-years old man with a pericoronal radiolucent lesion associated to an impacted lower third molar with the presence of radiopaque material inside. The radiological differential diagnosis was calcifying odontogenic tumor, adenomatoid odontogenic tumor and dentigerous cyst. The impacted third molar was removed and the lesion was sent for the histopathological exam. Results: The histopathological diagnosis was dentigerous cyst with capsular calcifications. Specifically, parietal calcifications on its connective wall and a piece of cemento-osseous tissue inside. Conclusions: Non-neoplastic lesions such as dentigerous cysts could develop radiopacities inside the radiolucent pericoronal area. Key words:Dentigerous cyst, calcifications, third molar, differential diagnosis. PMID- 29721234 TI - Mucormycosis of maxilla following tooth extraction in immunocompetent patients: Reports and review. AB - Mucormycosis is a rare, fulminant, rapidly spreading fungal infection, which usually affects patient with underlying immune deficiency. If not managed promptly, the disease is characterized by progressive necrosis and is often fatal. A review of English literature shows that only fourteen cases of mucormycosis have been reported after tooth extraction. This paper highlights two cases of mucormycosis subsequent to tooth extraction in healthy adult patients. This first patient presented with an oroantral fistula and extensive maxillary necrosis. Whereas the second case was localized and presented as non-healing extraction socket with alveolar necrosis. This adds two more cases of this rare and serious complication of tooth extraction, to the present literature. Key words:Fungal, infection, zygomycosis, exodontia, complication, jaw, necrosis. PMID- 29721235 TI - Does Alpha-lipoic Acid Supplementation Modulate Cardiovascular Risk Factors in Patients with Stroke? A Randomized, Double-blind Clinical Trial. AB - Background: Stroke as a devastating condition is one of the major causes of death worldwide. It is accountable for long time disability with high personal and social cost in adults. There are several risk factors for stroke such as diabetes and hypertension. Alpha-lipoic acid (ALA) as an antioxidant can be a risk modifier in these patients. We designed this trial to scrutinize the possible effects of ALA consumption on some cardiovascular risk factors in patients experienced stroke. Methods: In this randomized, double-blind, placebo-controlled clinical trial, 67 patients experienced stroke were randomly allocated into two groups (taking a 600 mg ALA supplement or placebo daily for 12 weeks). Fasting blood sugar (FBS), fasting insulin and systolic (SBP), and diastolic blood pressure (DBP) were measured before and after intervention in this study. Statistical analyses were performed using SPSS version 16 (SPSS Inc., Chicago, IL, USA) software. Results: Primary features were similar in the intervention and placebo groups (P > 0.05). After the intervention period, SBP (P < 0.001), DBP (P < 0.001) and FBS (P < 0.001) reduced in ALA group compared with placebo group, significantly. No significant change was seen in insulin level (P = 0.82). Conclusions: Results of this trial indicated that 12 weeks supplementation with 600 mg ALA has beneficial effects on SBP, DBP, and FBS but has no effect on insulin level. PMID- 29721236 TI - Determinants of Problematic Internet use and its Association with Disordered Eating Attitudes among Minia University Students. AB - Background: To determine the association between problematic Internet use (PIU) and disordered eating attitudes (DEAs) and to detect the potential risk factors for PIU among University students in Minia, Egypt. Methods: A cross-sectional study was carried out among a random sample (n = 2365) of Minia University students. PIU was assessed using The Problematic Internet Use Scale (PIUS), and the DEAs were assessed using eating attitudes test-26 questionnaire. Results: Of the 2365 students, 424 (17.9%) had DEAs, and it was more in females than males (22.3% and 14.5%, respectively). The mean of the PIUS score also was significantly higher in males than females (120.3 +/- 30.5, and 117.5 +/- 30.6, respectively). A positive moderate correlation (r = 0.48, P < 0.05) was detected between PIU and DEAs. Conclusions: The results of this study indicate that PIU is significantly correlated with DEAs among University students in Minia, Egypt, and further studies are needed to identify the association between DEAs and PIU. PMID- 29721237 TI - Association of Omega-3 Fatty Acid and Epileptic Seizure in Epileptic Patients: A Systematic Review. AB - The evidence on the association between omega-3 consumption and epileptic seizure is inconsistent. Therefore, we have conducted this systematic review to clarify the possible relationship. Original articles were searched in electronic databases (PubMed, Scopus, Google Scholar, Cochrane, and Ovid) and by reviewing the reference lists of retrieved articles. The main evaluated outcome was the epileptic seizures. We included the English language studies that reported the original data on the effect of omega-3 on epileptic human patients. We included the nine articles with 230 patients in the present systematic review. The mean +/ standard deviation age of them was about 31.01 +/- 14.99 years. The average of study duration was 22 +/- 15.27 weeks. Omega-3 fatty acid supplements were defined as the sum of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) (1100 mg/d); as the sum of EPA, DHA, and alpha-linolenic acid (5 g/d); and as the sum of EPA alone (565 mg/d) in different studies. Among the nine studies, four studies reported a significant positive association between omega-3 fatty acids and epileptic seizures. However, power and quality of these studies are low, and we cannot consider the beneficial effect of omega-3 on seizures. In addition, five studies did not reveal any significant effect. Majority of the included studies did not show a significant association between omega-3 and epileptic seizure in epileptic patients, but further studies are necessary. It is controversial whether omega-3 fatty acids can produce positive effects on epileptic patients or not. PMID- 29721238 TI - Unresolved issues in hepatitis C: The role of liver non-parenchymal cells and semaphorins. PMID- 29721239 TI - Meningitis, spondylodiscitis, pneumonia and septic shock with Streptococcus pneumoniae in a previously healthy woman with isolated IgG2-, IgG3-, IgA deficiency and monoclonal gammopathy of undetermined significance. AB - A 66 years old Caucasian woman with pneumococcal meningitis was treated and discharged after an uncomplicated course. Five months later she was readmitted with fever and right side abdominal pain and diagnosed with pneumococcal spondylodiscitis. One year later she was treated for a severe chest X-ray confirmed left lobar pneumonia. Two years later she was diagnosed with a pneumococcal pneumonia in her left lung with septic shock. An immune deficiency screen revealed slightly reduced IgA levels, low IgG2 levels, low IgG3 levels and high IgG1 levels. No other immune defects were identified. She did not respond serologically on vaccination with 13-valent conjugate and 23-valent polysaccharide pneumococcal vaccines. Further evaluations revealed a positive M component in her blood and a bone marrow biopsy diagnosed her to have monoclonal gammopathy of undetermined significance. To protect her against future life threatening pneumococcal infections she was started on treatment with intravenous immunoglobulin. The case report illustrates the importance of thorough evaluation of patients with unusual infectious disease entities or unusual frequency of infections in individual patients. To optimize prophylactic measures and active treatment options in the individual patient, it is important to identify underlying causes of diseases and immune deficiencies that potentially can lead to life threatening infections. This is illustrated in our case by an undiagnosed monoclonal gammopathy of undetermined significance in an apparently healthy woman with at least three life threatening documented pneumococcal infections in a two year period and poor pneumococcal vaccine response. PMID- 29721240 TI - Mexican patients with HIV have a high prevalence of vertebral fractures. AB - Low bone mineral density (BMD) and fragility fractures are common in individuals infected with HIV, who are undergoing antiretroviral therapy (ART). In high income countries, dual energy X-ray absorptiometrry is typically used to evaluate osteopenia or osteoporosis in HIV infected individuals. However, this technology is unavailable in low andmiddle income countries, so a different approach is needed. The aim of this study was to use X-ray scans of the spine to determine the prevalence of and associated risk factors for vertebral fractures in HIVinfected patients in a tertiary-care hospital in Mexico. We conducted a cross sectional study of outpatients who were >40 years old and receiving ART at the Hospital de Infectologia, La Raza National Medical Center in Mexico City, Mexico. We used semi-quantitative morphometric analysis of centrally digitized X-ray images to assess vertebral deformities in the spine. Anterior, middle and posterior vertebral heights were measured, and height ratios were calculated. For each vertebral body, fractures were graded on the basis of height ratio reductions, and a spine deformity index' (SDI) value was calculated by summing the grades of the vertebral deformities: An SDI>1 was indicative of a vertebral fracture. We included 104 patients, 87% of whom were men. The median age was 49 years [interquartile range (IQR) 42-52]. The most common stage of HIV infection, as defined by the Centers for Disease Control, was B2 in 40 (39%) of patients. Forty seven (45%) patients were on ART regimens that included protease inhibitors (PIs) and 100 (96%) being treated with tenofovir. The median time of ART was 6.5 years (IQR 1.6-9.0). Of the 104 patients in our study, 83 (80%) had undetectable viral load, as assessed by HIV-1 RNA levels, 32 (31%) showed evidence of a previous fracture, 4 (4%) were co-infected with hepatitis C virus, and 57 (55%) had a history of corticosteroid treatment. The prevalence of vertebral fractures was 25%, 95% confidence interval 17-34%. We assessed whether gender, HCV co infection, previous corticosteroid use, AIDS, total HIV viral load, and current and previous use of PIs were associated with fractures in our study group, but we did not observe a significant association between any of these factors and vertebral fractures. The prevalence of vertebral fractures was high among HIV infected patients. We propose that screening for bone disease should be performed in HIV individuals who are at risk of fragility fractures. Furthermore, we suggest that X-ray based assessment of the spine should be considered in patients who are at increased risk of fragility fractures, irrespective of BMD levels, particularly in elderly patients in low and middle income countries. PMID- 29721241 TI - Syphilis infection in an HIV patient presenting with leukemoid reaction: Case report and review of the literature. AB - Leukemoid reaction (LR) is an uncommon though dreadful sign for the treating physician, as it is related to increased mortality. In the few series that have addressed its incidence and clinical significance, infectious causes count for about half of the cases of LR, the rest accounting for cancer, drugs or rarer causes. In the HIV setting, it represents an even rarer event, owing probably to the impaired granulocytic response of AIDS patients to bacterial agents. However no report exists as to the incidence of LR to the immune-restored HIV patients adequately treated with antiretroviral therapy (ART). Syphilis is a well known cause of mild lymphocytosis, though only one report of LR exists in the congenital setting. We hereby report a case of an HIV patient adequately treated with ART, who presented with LR with a lymphomonocytic preponderance after infection with treponema pallidum. PMID- 29721242 TI - Abdominal rectus muscle pyomyositis: Report of a case and review of the literature. AB - Pyomyositis is an uncommon primary bacterial infection of skeletal muscles, usually caused by Staphylococcus aureus. Predisposing factors for pyomyositis include immunodeficiency, trauma, injection drug use, concurrent infection and malnutrition. The diagnosis, staging of the disease and differential diagnosis are established by ultrasound, CT and MRI. Treatment involves surgical drainage and antibiotic therapy. We report a case of abdominal rectus muscle pyomyositis, which constitutes, as far as we know, the second reported in bibliography, while Prevotella disiens is firstly reported as causative agent. PMID- 29721243 TI - Opportunistic infections in end stage liver disease. AB - Liver cirrhosis is the 10th most common cause of death in Western world and infection is associated with a high morbidity and mortality, and represents the leading cause of acute liver decompensation. Patients with end-stage liver disease exhibit an important impairment of immune system. This condition, called cirrhosis-associated immune dysfunction, summarizes both local and systemic immune system alterations in liver cirrhosis that play a pivotal role in determining both the high incidence of infections and the ominous infections related mortality in this population. Another concerning feature of infections in cirrhotic patients is the growing prevalence of multidrug- resistant or extensively drug-resistant pathogens, which are associated with higher mortality, increased length of in-hospital stay and higher healthcare related costs if compared with infection caused by susceptible strains. Finally, patient with liver cirrhosis have several unique pathophysiological characteristics including hypoalbuminemia and reduction binding to proteins; altered distribution; altered clearance of the antimicrobials that can affect the pharmacokinetic/ pharmacodynamic of antimicrobials. PMID- 29721245 TI - An infantile alantoaxial dislocation with patent foramen ovale managed with titanium cabling and allogenic bone grafts. AB - Atlantoaxial dislocation is a disorder that is characterized with loss of stability of the atlas and axis (C1-C2) with consequential loss of usual articulation. Although this condition is very common, no one has reported a case as young as our patients. We present a 7-month infant with bilateral paralysis of the lower limbs for four (4) months with no history of trauma. Computer tomographic (CT-scan) imaging revealed alantoaxial dislocation with severe cervical spinal cord compression. The odontoid process is displaced outwardly with no bone destruction. Doppler echocardiogram done revealed patent foramen ovale. Thorough physical examination as well as radiological evaluation revealed no feather malformations. Electrophysio - logical studies reveal normal compound muscle action potentials (CMAP) and sensory nerve action potentials (SNAPs) in all the limbs. Electromyography (EMG) also revealed normal nerves in the limbs and the trunk. We attained a stable fusion and anatomical reduction using a posterior titanium wire and an iliac bone graft harvested from his mother. This is the youngest patient reported in literature. Infantile alantoaxial dislocation should be managed at early stage to prevent long-term neurologic disorders. PMID- 29721246 TI - Acute encephalopathy with biphasic seizures and late reduced diffusion associated with Streptococcus sanguinis sepsis. AB - Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) develops in association with systemic as well as central nervous system (CNS) viral or bacterial infections. AESD is most often noted with influenza or human herpesvirus 6 infection in previously healthy infants. However, AESD has also been reported in an infant with developmental retardation and in a mentally and motor-disabled adolescent. Here, we report the case of a 4- year-old female with significant development delay due to spinal muscular atrophy, who developed AESD during Streptococcus sanguinis sepsis with no apparent CNS infection. Although the patient had extremely high serum procalcitonin (45.84 ng/mL, reference; <0.4) on admission indicating a poor prognosis, she was successfully managed for sepsis and AESD. PMID- 29721247 TI - Anesthesia in Mowat-Wilson syndrome: information on 11 Italian patients. AB - Mowat-Wilson syndrome is a genetic disease caused by heterozygous mutations or deletions of the ZEB2 gene and characterized by typical clinical features. The congenital malformations typical of this syndrome call for early diagnostic and surgical procedures requiring general anesthesia, but few information about the anesthesiology management of such patients is available. We enrolled 11 families of patients with Mowat-Wilson syndrome who had undergone surgical or diagnostic procedures requiring general anesthesia, and sent them a retrospective questionnaire including 16 open questions about the procedures. They were further contacted by phone for a semistructured interview. A total of 37 procedures requiring general anesthesia was reported in 11 patients. Only two patients reported anesthesia-related complications during the procedure. No true additional anesthesiarelated risk was present for the patients with MW syndrome, besides difficult intubation, weaning and lower respiratory tract infection. Perception of risk, however, is derived by non-medical observation on the part of the parents. PMID- 29721244 TI - Epidemiology of vertebral fractures in pediatric and adolescent patients. AB - Spinal injuries in children and adolescents are rare injuries, but consequences for the growing skeleton can be devastating. Knowledge of accident causes, clinical symptoms and diagnostics should be part of every trauma department treating these patients. We retrospectively analyzed patients with radiographically proven vertebral fractures of the spine. After clinical examination and tentative diagnosis the fractures and injuries were proven with conventional X-ray, computed tomography (CT) scans or magnetic resonance imaging (MRI). The study included 890 fractures in 546 patients with an average age of 12.8+/-6.2 (6.6-19.4) years. Females had an average age of 13.7+/-6.3 (7.4-20.0) years, whereas males were on average 12.0 (6.0-18.0) years old. Fall from height (58%) was the main cause of accident and the most common region of fracture was the thoracolumbar spine with a shift towards the thoracic spine the more fractures occurred. Merely 3.7% of all patients required operative treatment. If a vertebral fracture is found in children and adolescents, it is highly recommended to exclude synchronous additional spine fractures in other levels; prevention should concentrate on fall and traffic accidents. PMID- 29721248 TI - Isolated tubal torsion: A rare cause of acute abdomen in childhood. AB - Isolated fallopian tube torsion is a rare cause of acute abdomen mostly seen in women of reproductive age. It is often diagnosed during surgery. In this study we aimed to present a case of isolated fallopian tube torsion in a child. An 11-year old girl presented with abdominal pain. With the help of radiological evaluation we diagnosed. It should be kept in mind that even if ovarian blood flow is normal in girls with abdominal pain, it may be an isolated tubular torsion and requires immediate intervention. PMID- 29721250 TI - Congenital methemoglobinemia misdiagnosed as polycythemia vera: Case report and review of literature. AB - Methemoglobinemia is a rare overlooked differential diagnosis in patients presented with cyanosis and dyspnea unrelated to cardiopulmonary causes. Our patient is 29 year old Indian non-smoker male, his story started 6 months prior to presentation to our center when he had generalized fatigue and discoloration of hands. He presented with persistent polycythemia with elevated hemoglobin level. The patient was misdiagnosed in another center as polycythemia and treated with Imatinib. The diagnosis of PV was revisited and ruled out in view of negative JAK2, normal erythropoietin level and absence of features of panmyelosis. Clinical cyanosis and lowoxygen saturation in the presence of normal arterial oxygen tension was highly suggestive of methemoglobinemia. Arterial blood gas revealed a methemoglobin level of 38% (normal: 0-1.5%). Cytochrome B5 reductase (Methemoglobin reductase B) was deficient at level of <2.6 U/g Hb) (normal: 6.6-13.3), consistent with methemoglobin reductase (cytochrome b5) deficiency and hence the diagnosis of congenital methemoglobinemia was established. The role of Imatinib in provoking methemoglobinemia is questionable and association between Imatinib and methemoglobinemia never described before. In our case, there were no other offending drugs in aggravating the patients' symptoms and cyanosis. The patient started on Vitamin C 500 mg once daily for which he responded well with less cyanosis and significant reduction of methemoglobin level. Congenital methemoglobinemia is a rare underreported hemoglobin disease and often clinically missed. Upon extensive review of English literature for cases of congenital methemoglobinemia due to deficiency of cytochrome b5 reductase, we found 23 cases diagnosed as type I (including the case reported here). 17 cases (~74%) of type I and 6 cases (27%) of type II. There is male predominance 73% versus 26% in females. Almost half of reported cases 12 cases (52%) are Indian, 2 Japanese, 3 English, 2 Arabic, one case Spanish and one case Italian. For type I, the median calculated age is 31 years with cyanosis and shortness of breath being the most common sign and symptoms. For type II: Six cases were reported in English literature, all in pediatric age group with median calculated age at presentation is 6 years with neurologic manifestations and mental retardation are the most common type II associated symptoms. Due to lack of systematic epidemiological studies, congenital methemoglobinemia is under diagnosed as it is under investigated and usually overlooked especially when presenting in adulthood and in absence of obvious acquired agents. PMID- 29721249 TI - Extranodal diffuse large B-cell lymphomas: A retrospective case series and review of the literature. AB - Non-Hodgkin lymphomas commonly show extranodal involvement (25-30%) but primary diffuse large B-cell lymphomas (DLBCL) with extranodal localization represent clinically and molecularly distinct entities. The present study involved retrospective analysis of case records of 4 patients who were diagnosed with extranodal DLBCL between 2010 and 2016 at the Medical Oncology and Hematology Departments of the Ioannina University Hospital, Greece. Median age of presentation was 69 years (range 60-77 years). There were 2 males and 2 females. The sites of DLBCL involvement included adrenal gland, mandible, cervix uteri, and ileum. Two patients had B symptoms while none had bone marrow involvement. After staging workup, all the patients fell into IE stage. The treatment approach included chemotherapy combined with rituximab (R), whereas one patient received additionally irradiation therapy. Post-treatment positron emission tomography computed tomography scan was performed in 3 patients. In terms of the outcome, 3 patients are alive in complete response, whereas one was lost in follow-up. Further prospective data analyses are required so as to better elucidate the biology and course of extranodal DLBCL. PMID- 29721251 TI - Bone-targeted agents in multiple myeloma. AB - Osteolytic bone disease, characterized by bone pain, increased risk of pathologic fractures, tumor-induced hypercalcemia known as skeletal-related events (SREs), is a frequent complication of patients with multiple myeloma (MM) and persists even in the absence of active disease, resulting in a major cause of morbidity and mortality. The interaction between myeloma cells and their surrounding cells in the bone marrow (BM) microenvironment promotes both myeloma cell growth and bone destruction and forms the vicious cycle of MM bone disease. Therefore, therapeutic strategies targeting the interaction between myeloma cells and cellular components including osteoclasts (OCs), stromal cells and osteoblasts (OBs) in the BM is crucial not only to attain tumor regression but also to prevent or delay the incidence of SREs, which leads to improve survival and quality of life in affected patients. Recently, several novel targets which act on components of the cycle for treating MM-associated bone disease have been identified in addition to current treatments including nitrogen-containing bisphosphonates. This review focuses on the overview of pathophysiology in MM associated bone disease and summarizes its current clinical management. Several novel bone-targeted agents in preclinical setting will be also discussed. PMID- 29721252 TI - Acute monocytic leukemia diagnosed by flow cytometry includes acute myeloid leukemias with weakly or faintly positive non-specific esterase staining. AB - A diagnosis of acute monocytic leukemia (AML-M5) based on alpha-naphthyl butyrate esterase (alpha-NB) staining has some problems, because AML-M5 leukemic cells often show weak or faint positivity on alpha-NB staining. In these situations, some cases of AML-M5 tend to be misdiagnosed as AML-M0. Therefore, we evaluated the significance of weak or faint alpha-NB staining in AML-M5 diagnosed by flow cytometry (FCM). Nineteen AML cases in which leukemic cells were negative for naphthol AS-D chloroacetate esterase staining were studied. For FCM, we defined leukemic cells as having a monocytic nature when more than 10% of the leukemic cells were positive for at least one of the following antigens: CD4, CD11c, CD14, and CD64. The monocytic nature determined by FCM was consistent with positive or weak positivity on alpha-NB staining. Five of 6 cases in which leukemic cells exhibited faint positivity for alpha-NB staining could be diagnosed as AML-M5 by FCM, while negative alpha-NB staining was consistent with a diagnosis of AML-M0. These results suggest that AML-M5 should be taken into consideration even when leukemic cells are faintly positive for alpha-NB staining. PMID- 29721253 TI - Neurofibromatosis type I and multiple myeloma coexistence: A possible link? AB - The association between Neurofibromatosis type I (NF1) and multiple myeloma (MM), a plasma cell, dyscrasia is very rare. Here we put to the attention of the scientific community two new cases. The first one is a patient with active MM whereas the second with smoldering MM. Both patients present typical features of NF1 but skeletal alterations were present only in the second case including dysplasia, marked scoliosis and osteoporosis. MM osteolytic lesions were absent in both patients. In addition to the clinical diagnosis of NF1, a molecular testing for NF1 gene mutations has been performed finding that patient one was heterozygous for the c.6855C>A (Tyr2285Ter) mutation, while patient two was heterozygous for the c.7838dupC (Lys2614GlufsTer20) mutation. The two mutations were diagnosed both in genomic DNA from peripheral blood and from MM cells. The potential link between NF1 mutation and the increased risk of MM is discussed in the report. PMID- 29721254 TI - Chromosome positioning in interphase nuclei of hematopoietic stem cell and myeloid precursor. AB - Human myelopoiesis is an intriguing biological process during which multipotent stem cells limit their differentiation potential generating precursors that evolve into terminally differentiated cells. The differentiation process is correlated with differential gene expression and changes in nuclear architecture. In interphase, chromosomes are distinct entities known as chromosome territories and they show a radial localization that could result in a constrain of inter homologous distance. This element plays a role in genome stability and gene expression. Here, we provide the first experimental evidence of 3D chromosomal arrangement considering two steps of human normal myelopoiesis. Specifically, multicolor 3D-FISH and 3D image analysis revealed that, in both normal human hematopoietic stem cells and myelod precursors CD14-, chromosomal position is correlated with gene density. However, we observed that inter-homologue distances are totally different during differentiation. This could be associated with differential gene expression that we found comparing the two cell types. Our results disclose an unprecedented framework relevant for deciphering the genomic mechanisms at the base of normal human myelopoiesis. PMID- 29721255 TI - Paroxysmal nocturnal hemoglobinuria: When delay in diagnosis and long therapy occurs. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal disorder characterized by hemolytic anemia, bone marrow failure and thrombosis, caused by a somatic mutation in PIG-A gene that results in the absence of CD55 and CD59, two important complement regulatory proteins. In this paper, a case of PNH is retrospectively examined looking for clinical and laboratory features, and the entire course of the disease from the onset of the symptoms is described, together with an adequate follow- up over a 7-years treatment period. In this case, the not specificity and the limited clinical relevance of the symptoms led to a delay in diagnosis. After thrombosis, Eculizumab therapy has been shown to be effective, and during seven years of followup no events have occurred that put the patient's life at risk. A multidisciplinary approach is crucial in cases like this, in order to allow early diagnosis and minimize the risks for the patients. PMID- 29721257 TI - Assessment of Raw Cow Milk Quality in Smallholder Dairy Farms in Pemba Island Zanzibar, Tanzania. AB - Milk quality depends on the physicochemical characteristics, hygienic standards, and nutritional quality; however, animal husbandry practices, unhygienic harvesting and processing, may affect its quality. A cross-sectional study was conducted between August 2010 and July 2011 to assess the hygiene of cow milk production environment, raw cow milk physicochemical characteristics, and microbial quality and estimate the prevalence of antimicrobial residues using standard methods in Pemba Island. A total of 98 raw cow milk samples from selected smallholder dairy farms were analyzed, and the judgement on the quality used the East African Standards. Generally, the milk production chain was done under the unhygienic condition, and dirty plastic containers were used for collection and storage of milk under room temperature. Some milk samples had abnormal colour (2.1%), abnormal smell (7.1%), and pH below normal (35.7%), clotted on alcohol test (9.2%), and had the specific gravity below normal (13.3%). All the milk samples had mineral contents within the recommended range. Milk samples with butterfat below normal were 29.6%, while 14.3% had total solids below recommended values. The mean total viable count (TVC) of milk container surfaces was 9.7 +/- 10.5 log CFU/100 cm2, while total coliform count (TCC) was 7.8 +/- 8.5 log CFU/100 cm2. Up to 55.1% of milk had TVC beyond the recommended levels. The milk mean TVC was 11.02 +/- 11.6 log CFU/ml and TCC was 6.7 +/- 7.3 log CFU/ml. Up to 26.5% of milk samples had the TCC beyond levels. Results on physicochemical characteristics and nutritional analysis show that the raw cow milk in Pemba Island is of inferior quality. Microbiological results of this study imply heavy contaminations of milk. Antimicrobial residues were detected in 83% of the samples and most of them were from Wete District. Unhygienic milk production chain accelerates microbial contaminations, and antimicrobial residues in milk are a big problem that needs urgent attention from the responsible authority. PMID- 29721256 TI - The role of retinoic acid signaling in starfish metamorphosis. AB - Background: Although retinoic acid (RA) signaling plays a crucial role in the body patterning of chordates, its function in non-chordate invertebrates, other than its mediation of environmental cues triggering metamorphosis in cnidarians, is largely unknown. We investigated the role of RA signaling in the metamorphosis of starfish (Echinodermata). Results: We found that exogenous RA treatment induced metamorphosis in starfish larvae. In contrast, inhibitors of RA synthesis and RA receptors suppressed metamorphosis triggered by attachment to a substrate. Gene expressions of the RA signaling component were detected in competent larvae. Conclusions: This study provides insight into the ancestral function of RA signaling, which is conserved in the metamorphosis of cnidarians and starfish. PMID- 29721260 TI - The temperature-size rule in Daphnia magna across different genetic lines and ontogenetic stages: Multiple patterns and mechanisms. AB - Ectotherms tend to grow faster, but reach a smaller size when reared under warmer conditions. This temperature-size rule (TSR) is a widespread phenomenon. Despite the generality of this pattern, no general explanation has been found. We therefore tested the relative importance of two proposed mechanisms for the TSR: (1) a stronger increase in development rate relative to growth rate at higher temperatures, which would cause a smaller size at maturity, and (2) resource limitation placing stronger constraints on growth in large individuals at higher temperatures, which would cause problems with attaining a large size in warm conditions. We raised Daphnia magna at eight temperatures to assess their size at maturity, asymptotic size, and size of their offspring. We used three clonal lines that differed in asymptotic size and growth rate. A resource allocation model was developed and fitted to our empirical data to explore the effect of both mechanisms for the TSR. The genetic lines of D. magna showed different temperature dependence of growth and development rates resulting in different responses for size at maturity. Also, at warm temperatures, growth was constrained in large, but not in small individuals. The resource allocation model could fit these empirical data well. Based on our empirical results and model explorations, the TSR of D. magna at maturity is best explained by a stronger increase in development rate relative to growth rate at high temperature, and the TSR at asymptotic size is best explained by a size-dependent and temperature dependent constraint on growth, although resource limitation could also affect size at maturity. In conclusion, the TSR can take different forms for offspring size, size at maturity, and asymptotic size and each form can arise from its own mechanism, which could be an essential step toward finding a solution to this century-old puzzle. PMID- 29721259 TI - Comparing the consequences of natural selection, adaptive phenotypic plasticity, and matching habitat choice for phenotype-environment matching, population genetic structure, and reproductive isolation in meta-populations. AB - Organisms commonly experience significant spatiotemporal variation in their environments. In response to such heterogeneity, different mechanisms may act that enhance ecological performance locally. However, depending on the nature of the mechanism involved, the consequences for populations may differ greatly. Building on a previous model that investigated the conditions under which different adaptive mechanisms (co)evolve, this study compares the ecological and evolutionary population consequences of three very different responses to environmental heterogeneity: matching habitat choice (directed gene flow), adaptive plasticity (associated with random gene flow), and divergent natural selection. Using individual-based simulations, we show that matching habitat choice can have a greater adaptive potential than plasticity or natural selection: it allows for local adaptation while protecting genetic polymorphism despite global mating or strong environmental changes. Our simulations further reveal that increasing environmental fluctuations and unpredictability generally favor the emergence of specialist genotypes but that matching habitat choice is better at preventing local maladaptation by individuals. This confirms that matching habitat choice can speed up the genetic divergence among populations, cause indirect assortative mating via spatial clustering, and hence even facilitate sympatric speciation. This study highlights the potential importance of directed dispersal in local adaptation and speciation, stresses the difficulty of deriving its operation from nonexperimental observational data alone, and helps define a set of ecological conditions which should favor its emergence and subsequent detection in nature. PMID- 29721258 TI - Host species, and not environment, predicts variation in blood parasite prevalence, distribution, and diversity along a humidity gradient in northern South America. AB - Environmental factors strongly influence the ecology and evolution of vector borne infectious diseases. However, our understanding of the influence of climatic variation on host-parasite interactions in tropical systems is rudimentary. We studied five species of birds and their haemosporidian parasites (Plasmodium and Haemoproteus) at 16 sampling sites to understand how environmental heterogeneity influences patterns of parasite prevalence, distribution, and diversity across a marked gradient in water availability in northern South America. We used molecular methods to screen for parasite infections and to identify parasite lineages. To characterize spatial heterogeneity in water availability, we used weather-station and remotely sensed climate data. We estimated parasite prevalence while accounting for spatial autocorrelation, and used a model selection approach to determine the effect of variables related to water availability and host species on prevalence. The prevalence, distribution, and lineage diversity of haemosporidian parasites varied among localities and host species, but we found no support for the hypothesis that the prevalence and diversity of parasites increase with increasing water availability. Host species and host * climate interactions had stronger effects on infection prevalence, and parasite lineages were strongly associated with particular host species. Because climatic variables had little effect on the overall prevalence and lineage diversity of haemosporidian parasites across study sites, our results suggest that independent host-parasite dynamics may influence patterns in parasitism in environmentally heterogeneous landscapes. PMID- 29721261 TI - Livelihood changes matter for the sustainability of ecological restoration: A case analysis of the Grain for Green Program in China's largest Giant Panda Reserve. AB - Payments for ecosystem services (PES) are expected to promote ecological restoration while simultaneously improving human livelihoods. As an adaptive management tool, PES programs should be dynamic and adjusted according to changing natural and socio-economic contexts. Taking the implementation of China's famous ecological restoration policy known as the Grain for Green Program (GGP) in the Wolong National Nature Reserve as an example, we analyzed changes in the livelihood capitals and strategies of local households that had participated in the GGP over a 10-year period and discussed the implications of these changes for the next stage of the program's implementation. Data were collected from a locally implemented questionnaire in both 2004 and 2015. We found that local livelihood capitals and strategies had experienced dramatic change over the 10 year period. Natural capital decreased and was unequally distributed among local respondents. In terms of financial capital, despite that agricultural and nonagricultural income increased, compensation from the GGP decreased and did not keep pace with increasing cost of cropland, household income and more broadly national economic development and inflation. Regarding human capital, the local labor force is facing huge transformational pressures. In particular, there is a increase in the supply of local labor force aged between 21 and 40 and the implications of this for the future of the GGP should be given more attention. The findings have demonstrated that: Some changes in participants' livelihood were expected by the GGP but were not evenly distributed among the participants; and PES programs are embedded in changing and multi-dimensional socio-economic contexts, and so their design and implementation must be coordinated with other related policies if they are to achieve long-term success. PMID- 29721262 TI - Thinning-induced canopy opening exerted a specific effect on soil nematode community. AB - Changes in microclimate, soil physicochemical properties, understory vegetation cover, diversity, and composition as well as soil microbial community resulting from silvicultural practices are expected to alter soil food webs. Here, we investigated whether and how contrasting-sized canopy openings affect soil nematode community within a 30 year-aged spruce plantation. The results indicated that the responses of soil nematodes to canopy opening size were dependant on their feeding habit. The abundance of total nematodes and that of free-living nematodes was negatively correlated with soil bulk density, whereas the abundance of omnivore-predators was negatively correlated with soil bulk density and shrubs cover, respectively. The ratio of the sum abundance of predators and omnivores to the plant parasites' abundance, Simpson's dominance index, Pielou's evenness index, and sigma maturity index, maturity index (MI), MI 2-5, basal index, enrichment index, and structure index was sensitive to alteration in canopy opening size. Multivariate analysis indicated that thinning-induced gap size resulted in contrasting nematode assemblages. In conclusion, soil nematodes should be integrated as an indicator to monitor soil multifunctionality change due to thinning. PMID- 29721263 TI - Long-term ecological data for conservation: Range change in the black-billed capercaillie (Tetrao urogalloides) in northeast China (1970s-2070s). AB - Long-term ecological data can be an effective tool to help ecologists integrate future projections with historical contexts and provide unique insights into the long-term dynamics of endangered species. However, hampered by data limitations, including incomplete and spatially biased data, relatively few studies have used multidecadal datasets or have examined changes in biogeography from a historical perspective. The black-billed capercaillie (Tetrao urogalloides) is a large capercaillie (classified as Least Concern [LC] on the IUCN red list) that has undergone a dramatic decline in population during the late 20th century and is considered endangered. Its conservation status is pessimistic, and the species requires immediate protection. Therefore, we supplemented a historical dataset to identify changes in this bird's range and population in northeast China over the long term. The study area spanned Heilongjiang Province, Jilin Province, and the northeast corner of Inner Mongolia in northeast China. We integrated an ecological niche model (BIOMOD2) with long-term ecological data on this species to estimate the magnitude of change in distribution over time. Our results revealed a 35.25% reduction in the current distribution of this species compared to their potential distribution in the 1970s. This decline is expected to continue under climate change. For example, the future range loss was estimated to be 38.79 +/- 0.22% (8.64-90.19%), and the actual state could be worse, because the baseline range of the model was greater than the real range in the 2000s, showing a 12.39% overestimation. To overcome this poor outlook, a conservation strategy should be established in sensitive areas, including the southwestern Greater Khingan Mountains and northern Lesser Khingan Mountains. Actions that should be considered include field investigations, establishing a monitor network, designing ecological corridors, and cooperating with local inhabitants, governments, and conservation biologists to improve the conservation of the black billed capercaillie. PMID- 29721265 TI - Heard but not seen: Comparing bat assemblages and study methods in a mosaic landscape in the Western Ghats of India. AB - We used capture (mist-netting) and acoustic methods to compare the species richness, abundance, and composition of a bat assemblage in different habitats in the Western Ghats of India. In the tropics, catching bats has been more commonly used as a survey method than acoustic recordings. In our study, acoustic methods based on recording echolocation calls detected greater bat activity and more species than mist-netting. However, some species were detected more frequently or exclusively by capture. Ideally, the two methods should be used together to compensate for the biases in each. Using combined capture and acoustic data, we found that protected forests, forest fragments, and shade coffee plantations hosted similar and diverse species assemblages, although some species were recorded more frequently in protected forests. Tea plantations contained very few species from the overall bat assemblage. In riparian habitats, a strip of forested habitat on the river bank improved the habitat for bats compared to rivers with tea planted up to each bank. Our results show that shade coffee plantations are better bat habitat than tea plantations in biodiversity hotspots. However, if tea is to be the dominant land use, forest fragments and riparian corridors can improve the landscape considerably for bats. We encourage coffee growers to retain traditional plantations with mature native trees, rather than reverting to sun grown coffee or coffee shaded by a few species of timber trees. PMID- 29721264 TI - Environmental determinism, and not interspecific competition, drives morphological variability in Australasian warblers (Acanthizidae). AB - Interspecific competition is thought to play a key role in determining the coexistence of closely related species within adaptive radiations. Competition for ecological resources can lead to different outcomes from character displacement to, ultimately, competitive exclusion. Accordingly, divergent natural selection should disfavor those species that are the most similar to their competitor in resource use, thereby increasing morphological disparity. Here, we examined ecomorphological variability within an Australo-Papuan bird radiation, the Acanthizidae, which include both allopatric and sympatric complexes. In addition, we investigated whether morphological similarities between species are related to environmental factors at fine scale (foraging niche) and/or large scale (climate). Contrary to that predicted by the competition hypothesis, we did not find a significant correlation between the morphological similarities found between species and their degree of range overlap. Comparative modeling based on both a priori and data-driven identification of selective regimes suggested that foraging niche is a poor predictor of morphological variability in acanthizids. By contrast, our results indicate that climatic conditions were an important factor in the formation of morphological variation. We found a significant negative correlation between species scores for PC1 (positively associated to tarsus length and tail length) and both temperature and precipitation, whereas PC2 (positively associated to bill length and wing length) correlated positively with precipitation. In addition, we found that species inhabiting the same region are closer to each other in morphospace than to species outside that region regardless of genus to which they belong or its foraging strategy. Our results indicate that the conservative body form of acanthizids is one that can work under a wide variety of environments (an all-purpose morphology), and the observed interspecific similarity is probably driven by the common response to environment. PMID- 29721266 TI - Characterizing the contribution of plasticity and genetic differentiation to community-level trait responses to environmental change. AB - The match between functional trait variation in communities and environmental gradients is maintained by three processes: phenotypic plasticity and genetic differentiation (intraspecific processes), and species turnover (interspecific). Recently, evidence has emerged suggesting that intraspecific variation might have a potentially large role in driving functional community composition and response to environmental change. However, empirical evidence quantifying the respective importance of phenotypic plasticity and genetic differentiation relative to species turnover is still lacking. We performed a reciprocal transplant experiment using a common herbaceous plant species (Oxalis montana) among low-, mid-, and high-elevation sites to first quantify the contributions of plasticity and genetic differentiation in driving intraspecific variation in three traits: height, specific leaf area, and leaf area. We next compared the contributions of these intraspecific drivers of community trait-environment matching to that of species turnover, which had been previously assessed along the same elevational gradient. Plasticity was the dominant driver of intraspecific trait variation across elevation in all traits, with only a small contribution of genetic differentiation among populations. Local adaptation was not detected to a major extent along the gradient. Fitness components were greatest in O. montana plants with trait values closest to the local community-weighted means, thus supporting the common assumption that community-weighted mean trait values represent selective optima. Our results suggest that community-level trait responses to ongoing climate change should be mostly mediated by species turnover, even at the small spatial scale of our study, with an especially small contribution of evolutionary adaptation within species. PMID- 29721267 TI - Broad infectivity of Leidynema appendiculatum (Nematoda: Oxyurida: Thelastomatidae) parasite of the smokybrown cockroach Periplaneta fuliginosa (Blattodea: Blattidae). AB - Host specificity of parasites is important for the understanding of evolutionary strategies of parasitism that would be a basis of predictions of the disease expansion when parasitized hosts invade new environments. The nematode order Oxyurida is an interesting parasite group for studying the evolution of parasitism as it includes parasites of both invertebrates and vertebrates. In our survey, we found that the smokybrown cockroach Periplaneta fuliginosa was primarily infected with only one nematode species Leidynema appendiculatum. In two cases, L. appendiculatum was isolated from two additional cockroach species Pycnoscelus surinamensis, sold in Japan as a reptile food, and Blatta lateralis, captured in the field and cultured in the laboratory. Inoculation of L. appendiculatum into three additional cockroach species P. japonica, Blattella nipponica, and P. surinamensis also resulted in parasitism. Infection prevalence was high, and timing of postembryonic development from hatched nematode larva to mature adult in these hosts was identical with that in P. fuliginosa. While ecological interactions strongly determine the host range, such broad infectivity is still possible in this parasitic nematode. PMID- 29721268 TI - Effects of nitrogen addition and mowing on rodent damage in an Inner Mongolian steppe. AB - Rodent damage is a serious threat to sustainable management of grassland. The effects of nitrogen (N) deposition and grassland management on rodent damage have been scarcely studied. Here, we reported the effects of 2 years of N addition and mowing on burrow density and damage area of Citellus dauricus in a semiarid steppe in Inner Mongolia. N addition significantly aggravated, while mowing alleviated rodent damage in the grassland under study. Burrow density and damage area increased 2.8-fold and 4.7-fold, in N addition plots compared to the ambient N addition treatment, respectively. Conversely, mowing decreased burrow density and damage area by 75.9% and 14.5%, respectively, compared to no mowing plots. Observed changes in rodent damage were mainly due to variations in plant community cover, height, and aboveground net primary productivity. Our findings demonstrate that N addition and mowing can affect the rodent density and activity in grassland, suggesting that the effects of a changing atmospheric composition and land use on rodent damage must be considered in order to achieve better grassland management. PMID- 29721269 TI - Size-assortative choice and mate availability influences hybridization between red wolves (Canis rufus) and coyotes (Canis latrans). AB - Anthropogenic hybridization of historically isolated taxa has become a primary conservation challenge for many imperiled species. Indeed, hybridization between red wolves (Canis rufus) and coyotes (Canis latrans) poses a significant challenge to red wolf recovery. We considered seven hypotheses to assess factors influencing hybridization between red wolves and coyotes via pair-bonding between the two species. Because long-term monogamy and defense of all-purpose territories are core characteristics of both species, mate choice has long-term consequences. Therefore, red wolves may choose similar-sized mates to acquire partners that behave similarly to themselves in the use of space and diet. We observed multiple factors influencing breeding pair formation by red wolves and found that most wolves paired with similar-sized conspecifics and wolves that formed congeneric pairs with nonwolves (coyotes and hybrids) were mostly female wolves, the smaller of the two sexes. Additionally, we observed that lower red wolf abundance relative to nonwolves and the absence of helpers increased the probability that wolves consorted with nonwolves. However, successful pairings between red wolves and nonwolves were associated with wolves that maintained small home ranges. Behaviors associated with territoriality are energetically demanding and behaviors (e.g., aggressive interactions, foraging, and space use) involved in maintaining territories are influenced by body size. Consequently, we propose the hypothesis that size disparities between consorting red wolves and coyotes influence positive assortative mating and may represent a reproductive barrier between the two species. We offer that it may be possible to maintain wild populations of red wolves in the presence of coyotes if management strategies increase red wolf abundance on the landscape by mitigating key threats, such as human-caused mortality and hybridization with coyotes. Increasing red wolf abundance would likely restore selection pressures that increase mean body and home-range sizes of red wolves and decrease hybridization rates via reduced occurrence of congeneric pairs. PMID- 29721270 TI - Increased DNA typing success for feces and feathers of capercaillie (Tetrao urogallus) and black grouse (Tetrao tetrix). AB - Noninvasive sampling, for example, of droppings or feathers, is a promising approach for molecular genetic studies on endangered and elusive animal species. Yet, such specimens are known for containing only minute amounts of DNA, resulting in lower typing success rates relative to analyses on fresh tissues such as muscle or blood. Furthermore, artefactual signals as well as contamination are more likely to occur when DNA is limited. To increase the reliability of DNA typing from noninvasive samples, optimized DNA extraction and polymerase chain reaction protocols were developed, taking advantage of developments in the forensic field aiming at successful molecular genetic analysis of DNA templates being low in quality and quantity. In the framework of an extensive monitoring project on population dynamics of capercaillie and black grouse in the Tyrolean Alps, feces samples and molted feathers from both species were collected. On a subset comprising about 200 specimens of either species, eight polymorphic short tandem repeat (STR) markers were analyzed to test these improved protocols. Besides optimizing DNA yields, both lowered sample consumption and reduced hands-on time were achieved, and the rates of informative profiles amounted to 90.7% for capercaillie and 92.4% for black grouse. Similarly, high success rates had not been achieved in earlier studies and demonstrate the benefit of the improved methodology, which should be easily adaptable for use on animal species other than those studied here. The STR genotypes were not only powerful enough to discriminate among unrelated birds but also appeared fit for telling apart closely related animals, as indicated by Pi and Pisib values. The software package allelematch aided analysis of genotypes featuring possible dropout and drop-in effects. Finally, a comparison between molecular genetic and morphology-based species-of-origin determination revealed a high degree of concordance. PMID- 29721271 TI - Reduction and recovery of keystone predation pressure after disease-related mass mortality. AB - Disturbances such as disease can reshape communities through interruption of ecological interactions. Changes to population demographics alter how effectively a species performs its ecological role. While a population may recover in density, this may not translate to recovery of ecological function. In 2013, a sea star wasting syndrome outbreak caused mass mortality of the keystone predator Pisaster ochraceus on the North American Pacific coast. We analyzed sea star counts, biomass, size distributions, and recruitment from long-term intertidal monitoring sites from San Diego to Alaska to assess regional trends in sea star recovery following the outbreak. Recruitment, an indicator of population recovery, has been spatially patchy and varied within and among regions of the coast. Despite sea star counts approaching predisease numbers, sea star biomass, a measure of predation potential on the mussel Mytilus californianus, has remained low. This indicates that post-outbreak populations have not regained their full predation pressure. The regional variability in percent of recovering sites suggested differences in factors promoting sea star recovery between regions but did not show consistent patterns in postoutbreak recruitment on a coast-wide scale. These results shape predictions of where changes in community composition are likely to occur in years following the disease outbreak and provide insight into how populations of keystone species resume their ecological roles following mortality-inducing disturbances. PMID- 29721272 TI - Contrasting patterns of Andean diversification among three diverse clades of Neotropical clearwing butterflies. AB - The Neotropical region is the most biodiverse on Earth, in a large part due to the highly diverse tropical Andean biota. The Andes are a potentially important driver of diversification within the mountains and for neighboring regions. We compared the role of the Andes in diversification among three subtribes of Ithomiini butterflies endemic to the Neotropics, Dircennina, Oleriina, and Godyridina. The diversification patterns of Godyridina have been studied previously. Here, we generate the first time-calibrated phylogeny for the largest ithomiine subtribe, Dircennina, and we reanalyze a published phylogeny of Oleriina to test different biogeographic scenarios involving the Andes within an identical framework. We found common diversification patterns across the three subtribes, as well as major differences. In Dircennina and Oleriina, our results reveal a congruent pattern of diversification related to the Andes with an Andean origin, which contrasts with the Amazonian origin and multiple Andean colonizations of Godyridina. In each of the three subtribes, a clade diversified in the Northern Andes at a faster rate. Diversification within Amazonia occurred in Oleriina and Godyridina, while virtually no speciation occurred in Dircennina in this region. Dircennina was therefore characterized by higher diversification rates within the Andes compared to non-Andean regions, while in Oleriina and Godyridina, we found no difference between these regions. Our results and discussion highlight the importance of comparative approaches in biogeographic studies. PMID- 29721273 TI - Within trophic level shifts in collagen-carbonate stable carbon isotope spacing are propagated by diet and digestive physiology in large mammal herbivores. AB - Stable carbon isotope analyses of vertebrate hard tissues such as bones, teeth, and tusks provide information about animal diets in ecological, archeological, and paleontological contexts. There is debate about how carbon isotope compositions of collagen and apatite carbonate differ in terms of their relationship to diet, and to each other. We evaluated relationships between delta13Ccollagen and delta13Ccarbonate among free-ranging southern African mammals to test predictions about the influences of dietary and physiological differences between species. Whereas the slopes of delta13Ccollagen delta13Ccarbonate relationships among carnivores are <=1, herbivore delta13Ccollagen increases with increasing dietary delta13C at a slower rate than does delta13Ccarbonate, resulting in regression slopes >1. This outcome is consistent with predictions that herbivore delta13Ccollagen is biased against low protein diet components (13C-enriched C4 grasses in these environments), and delta13Ccarbonate is 13C-enriched due to release of 13C-depleted methane as a by product of microbial fermentation in the digestive tract. As methane emission is constrained by plant secondary metabolites in browse, the latter effect becomes more pronounced with higher levels of C4 grass in the diet. Increases in delta13Ccarbonate are also larger in ruminants than nonruminants. Accordingly, we show that Delta13Ccollagen-carbonate spacing is not constant within herbivores, but increases by up to 5 0/00 across species with different diets and physiologies. Such large variation, often assumed to be negligible within trophic levels, clearly cannot be ignored in carbon isotope-based diet reconstructions. PMID- 29721274 TI - New biomolecular tools for aerobiological monitoring: Identification of major allergenic Poaceae species through fast real-time PCR. AB - Grasses (Poaceae) are very common plants, which are widespread in all environments and urban areas. Despite their economical importance, they can represent a problem to humans due to their abundant production of allergenic pollen. Detailed information about the pollen season for these species is needed in order to plan adequate therapies and to warn allergic people about the risks they take in certain areas at certain moments. Moreover, precise identification of the causative species and their allergens is necessary when the patient is treated with allergen-specific immunotherapy. The intrafamily morphological similarity of grass pollen grains makes it impossible to distinguish which particular species is present in the atmosphere at a given moment. This study aimed at developing new biomolecular tools to analyze aerobiological samples and identifying major allergenic Poaceae taxa at subfamily or species level, exploiting fast real-time PCR. Protocols were tested for DNA extraction from pollen sampled with volumetric and gravimetric methods. A fragment of the matK plastidial gene was amplified and sequenced in Poaceae species known to have high allergological impact. Species- and subfamily-specific primer-probe systems were designed and tested in fast real-time PCRs to evaluate the presence of these taxa in aerobiological pollen samples. Species-specific systems were obtained for four of five studied species. A primer-probe set was also proposed for the detection of Pooideae (a grass subfamily that includes also major cereal grains) in aerobiological samples, as this subfamily includes species carrying both grass allergens from groups 1 and 5. These, among the 11 groups in which grass pollen allergens are classified, are considered responsible for the most frequent and severe symptoms. PMID- 29721275 TI - A new strategy to infer circularity applied to four new complete frog mitogenomes. AB - We applied a novel strategy to infer sequence circularity and complete assembly of four mitochondrial genomes (mitogenomes) of the frog families Bufonidae (Melanophryniscus moreirae), Dendrobatidae (Hyloxalus subpunctatus and Phyllobates terribilis), and Scaphiopodidae (Scaphiopus holbrookii). These are the first complete mitogenomes of these four genera and Scaphiopodidae. We assembled mitogenomes from short genomic sequence reads using a baiting and iterative mapping strategy followed by a new ad hoc mapping strategy developed to test for assembly circularization. To assess the quality of the inferred circularization, we used Bowtie2 alignment scores and a new per-position sequence coverage value (which we named "connectivity"). Permutation tests with 400 iterations per specimen and 1% or 5% chance of mutation at the ends of the putative circular sequences showed that the proposed method is highly sensitive, with a single nucleotide insertion or deletion being sufficient for circularity to be rejected. False positives comprised only 2% of all observations and possessed significantly lower alignment scores. The size, gene content, and gene arrangement of each mitogenome differed among the species but matched the expectations for their clades. We argue that basic studies on circular sequences can benefit from the results and bioinformatics procedures introduced here, especially when closely related references are lacking. PMID- 29721277 TI - The environmental zero-point problem in evolutionary reaction norm modeling. AB - There is a potential problem in present quantitative genetics evolutionary modeling based on reaction norms. Such models are state-space models, where the multivariate breeder's equation in some form is used as the state equation that propagates the population state forward in time. These models use the implicit assumption of a constant reference environment, in many cases set to zero. This zero-point is often the environment a population is adapted to, that is, where the expected geometric mean fitness is maximized. Such environmental reference values follow from the state of the population system, and they are thus population properties. The environment the population is adapted to, is, in other words, an internal population property, independent of the external environment. It is only when the external environment coincides with the internal reference environment, or vice versa, that the population is adapted to the current environment. This is formally a result of state-space modeling theory, which is an important theoretical basis for evolutionary modeling. The potential zero point problem is present in all types of reaction norm models, parametrized as well as function-valued, and the problem does not disappear when the reference environment is set to zero. As the environmental reference values are population characteristics, they ought to be modeled as such. Whether such characteristics are evolvable is an open question, but considering the complexity of evolutionary processes, such evolvability cannot be excluded without good arguments. As a straightforward solution, I propose to model the reference values as evolvable mean traits in their own right, in addition to other reaction norm traits. However, solutions based on an evolvable G matrix are also possible. PMID- 29721276 TI - Habitat quality is more important than matrix quality for bird communities in protected areas. AB - Protected areas are meant to preserve native local communities within their boundaries, but they are not independent from their surroundings. Impoverished habitat quality in the matrix might influence the species composition within the protected areas through biotic homogenization. The aim of this study was to determine the impacts of matrix quality on species richness and trait composition of bird communities from the Finnish reserve area network and whether the communities are being subject of biotic homogenization due to the lowered quality of the landscape matrix. We used joint species distribution modeling to study how characteristics of the Finnish forest reserves and the quality of their surrounding matrix alter species and trait compositions of forest birds. The proportion of old forest within the reserves was the main factor in explaining the bird community composition, and the bird communities within the reserves did not strongly depend on the quality of the matrix. Yet, in line with the homogenization theory, the beta-diversity within reserves embedded in low-quality matrix was lower than that in high-quality matrix, and the average abundance of regionally abundant species was higher. Influence of habitat quality on bird community composition was largely explained by the species' functional traits. Most importantly, the community specialization index was low, and average body size was high in areas with low proportion of old forest. We conclude that for conserving local bird communities in northern Finnish protected forests, it is currently more important to improve or maintain habitat quality within the reserves than in the surrounding matrix. Nevertheless, we found signals of bird community homogenization, and thus, activities that decrease the quality of the matrix are a threat for bird communities. PMID- 29721278 TI - Co-occurrence dynamics of endangered Lower Keys marsh rabbits and free-ranging domestic cats: Prey responses to an exotic predator removal program. AB - The Lower Keys marsh rabbit (Sylvilagus palustris hefneri) is one of many endangered endemic species of the Florida Keys. The main threats are habitat loss and fragmentation from sea-level rise, development, and habitat succession. Exotic predators such as free-ranging domestic cats (Felis catus) pose an additional threat to these endangered small mammals. Management strategies have focused on habitat restoration and exotic predator control. However, the effectiveness of predator removal and the effects of anthropogenic habitat modifications and restoration have not been evaluated. Between 2013 and 2015, we used camera traps to survey marsh rabbits and free-ranging cats at 84 sites in the National Key Deer Refuge, Big Pine Key, Florida, USA. We used dynamic occupancy models to determine factors associated with marsh rabbit occurrence, colonization, extinction, and the co-occurrence of marsh rabbits and cats during a period of predator removal. Rabbit occurrence was positively related to freshwater habitat and patch size, but was negatively related to the number of individual cats detected at each site. Furthermore, marsh rabbit colonization was negatively associated with relative increases in the number of individual cats at each site between survey years. Cat occurrence was negatively associated with increasing distance from human developments. The probability of cat site extinction was positively related to a 2-year trapping effort, indicating that predator removal reduced the cat population. Dynamic co-occurrence models suggested that cats and marsh rabbits co-occur less frequently than expected under random conditions, whereas co-detections were site and survey-specific. Rabbit site extinction and colonization were not strongly conditional on cat presence, but corresponded with a negative association. Our results suggest that while rabbits can colonize and persist at sites where cats occur, it is the number of individual cats at a site that more strongly influences rabbit occupancy and colonization. These findings indicate that continued predator management would likely benefit endangered small mammals as they recolonize restored habitats. PMID- 29721279 TI - Long-term persistence of horse fecal DNA in the environment makes equids particularly good candidates for noninvasive sampling. AB - Fecal DNA collected noninvasively can provide valuable information about genetic and ecological characteristics. This approach has rarely been used for equids, despite the need for conservation of endangered species and management of abundant feral populations. We examined factors affecting the efficacy of using equid fecal samples for conservation genetics. First, we evaluated two fecal collection methods (paper bag vs. ethanol). Then, we investigated how time since deposition and month of collection impacted microsatellite amplification success and genotyping errors. Between May and November 2014, we collected feral horse fecal samples of known age each month in a feral horse Herd Management Area in western Colorado and documented deterioration in the field with photographs. Samples collected and dried in paper bags had significantly higher amplification rates than those collected and stored in ethanol. There was little difference in the number of loci that amplified per sample between fresh fecal piles and those that had been exposed to the environment for up to 2 months (in samples collected in paper bags). After 2 months of exposure, amplification success declined. When comparing fresh (0-2 months) and old (3-6 months) fecal piles, samples from fresh piles had more matching genotypes across samples, better amplification success and less allelic dropout. Samples defecated during the summer and collected within 2 months of deposition had highest number of genotypes matching among samples, and lowest rates of amplification failure and allelic dropout. Due to the digestive system and amount of fecal material produced by equids, as well as their occurrence in arid ecosystems, we suggest that they are particularly good candidates for noninvasive sampling using fecal DNA. PMID- 29721280 TI - The potential influence of Atlantic salmon Salmo salar and brown trout Salmo trutta on density and breeding of the white-throated dipper Cinclus cinclus. AB - Interactions between birds and fish are often overlooked in aquatic ecosystems. We studied the influence of Atlantic salmon and brown trout on the breeding population size and reproductive output of the white-throated dipper in a Norwegian river. Acidic precipitation led to the extinction of salmon, but salmon recolonized after liming was initiated in 1991. We compared the dipper population size and reproductive output before (1978-1992) and after (1993-2014) salmon recolonization. Despite a rapid and substantial increase in juvenile salmon, the breeding dipper population size and reproductive output were not influenced by juvenile salmon, trout, or total salmonid density. This might be due to different feeding strategies in salmonids and dippers, where salmonids are mainly feeding on drift, while the dipper is a benthic feeder. The correlation between the size of the dipper population upstream and downstream of a salmonid migratory barrier was similar before and after recolonization, indicating that the downstream territories were not less attractive after the recolonization of salmon. Upstream dipper breeding success rates declined before the recolonization event and increased after, indicating improved water quality due to liming, and increasing invertebrate prey abundances and biodiversity. Surprisingly, upstream the migratory barrier, juvenile trout had a weak positive effect on the dipper population size, indicating that dippers may prey upon small trout. It is possible that wider downstream reaches might have higher abundances of alternative food, rending juvenile trout unimportant as prey. Abiotic factors such as winter temperatures and acidic precipitation with subsequent liming, potentially mediated by prey abundance, seem to play the most important role in the life history of the dipper. PMID- 29721281 TI - Effects of a zoonotic pathogen, Borrelia burgdorferi, on the behavior of a key reservoir host. AB - Most emerging infectious diseases of humans are transmitted to humans from other animals. The transmission of these "zoonotic" pathogens is affected by the abundance and behavior of their wildlife hosts. However, the effects of infection with zoonotic pathogens on behavior of wildlife hosts, particularly those that might propagate through ecological communities, are not well understood. Borrelia burgdorferi is a bacterium that causes Lyme disease, the most common vector-borne disease in the USA and Europe. In its North American range, the pathogen is most frequently transmitted among hosts through the bite of infected blacklegged ticks (Ixodes scapularis). Using sham and true vaccines, we experimentally manipulated infection load with this zoonotic pathogen in its most competent wildlife reservoir host, the white-footed mouse, Peromyscus leucopus, and quantified the effects of infection on mouse foraging behavior, as well as levels of mouse infestation with ticks. Mice treated with the true vaccine had 20% fewer larval blacklegged ticks infesting them compared to mice treated with the sham vaccine, a significant difference. We observed a nonsignificant trend for mice treated with the true vaccine to be more likely to visit experimental foraging trays (20% 30% effect size) and to prey on gypsy moth pupae (5%-20% effect size) compared to mice treated with the sham vaccine. We observed no difference between mice on true- versus sham-vaccinated grids in risk-averse foraging. Infection with this zoonotic pathogen appears to elicit behavioral changes that might reduce self grooming, but other behaviors were affected subtly or not at all. High titers of B. burgdorferi in mice could elicit a self-reinforcing feedback loop in which reduced grooming increases tick burdens and hence exposure to tick-borne pathogens. PMID- 29721283 TI - Trait and phylogenetic diversity provide insights into community assembly of reef associated shrimps (Palaemonidae) at different spatial scales across the Chagos Archipelago. AB - Coral reefs are the most biodiverse marine ecosystem and one of the most threatened by global climate change impacts. The vast majority of diversity on reefs is comprised of small invertebrates that live within the reef structure, termed the cryptofauna. This component of biodiversity is hugely understudied, and many species remain undescribed. This study represents a rare analysis of assembly processes structuring a distinct group of cryptofauna, the Palaemonidae, in the Chagos Archipelago, a reef ecosystem under minimal direct human impacts in the central Indian Ocean. The Palaemonidae are a diverse group of Caridae (infraorder of shrimps) that inhabit many different niches on coral reefs and are of particular interest because of their varied habitat associations. Phylogenetic and trait diversity and phylogenetic signal were used to infer likely drivers of community structure. The mechanisms driving palaemonid community assembly and maintenance in the Chagos Archipelago showed distinct spatial patterns. At local scales, among coral colonies and among reefs fringing individual atolls, significant trait, and phylogenetic clustering patterns suggest environmental filtering may be a dominant ecological process driving Palaemonidae community structure, although local competition through equalizing mechanisms may also play a role in shaping the local community structure. Importantly, we also tested the robustness of phylogenetic diversity to changes in evolutionary information as multi-gene phylogenies are resource intensive and for large families, such as the Palaemonidae, are often incomplete. These tests demonstrated a very modest impact on phylogenetic community structure, with only one of the four genes (PEPCK gene) in the phylogeny affecting phylogenetic diversity patterns, which provides useful information for future studies on large families with incomplete phylogenies. These findings contribute to our limited knowledge of this component of biodiversity in a marine locality as close to undisturbed by humans as can be found. It also provides a rare evaluation of phylogenetic diversity methods. PMID- 29721284 TI - The role of the reef flat in coral reef trophodynamics: Past, present, and future. AB - The reef flat is one of the largest and most distinctive habitats on coral reefs, yet its role in reef trophodynamics is poorly understood. Evolutionary evidence suggests that reef flat colonization by grazing fishes was a major innovation that permitted the exploitation of new space and trophic resources. However, the reef flat is hydrodynamically challenging, subject to high predation risks and covered with sediments that inhibit feeding by grazers. To explore these opposing influences, we examine the Great Barrier Reef (GBR) as a model system. We focus on grazing herbivores that directly access algal primary productivity in the epilithic algal matrix (EAM). By assessing abundance, biomass, and potential fish productivity, we explore the potential of the reef flat to support key ecosystem processes and its ability to maintain fisheries yields. On the GBR, the reef flat is, by far, the most important habitat for turf-grazing fishes, supporting an estimated 79% of individuals and 58% of the total biomass of grazing surgeonfishes, parrotfishes, and rabbitfishes. Approximately 59% of all (reef wide) turf algal productivity is removed by reef flat grazers. The flat also supports approximately 75% of all grazer biomass growth. Our results highlight the evolutionary and ecological benefits of occupying shallow-water habitats (permitting a ninefold population increase). The acquisition of key locomotor and feeding traits has enabled fishes to access the trophic benefits of the reef flat, outweighing the costs imposed by water movement, predation, and sediments. Benthic assemblages on reefs in the future may increasingly resemble those seen on reef flats today, with low coral cover, limited topographic complexity, and extensive EAM. Reef flat grazing fishes may therefore play an increasingly important role in key ecosystem processes and in sustaining future fisheries yields. PMID- 29721282 TI - Variation in sleep and metabolic function is associated with latitude and average temperature in Drosophila melanogaster. AB - Regulation of sleep and metabolic homeostasis is critical to an animal's survival and under stringent evolutionary pressure. Animals display remarkable diversity in sleep and metabolic phenotypes; however, an understanding of the ecological forces that select for, and maintain, these phenotypic differences remains poorly understood. The fruit fly, Drosophila melanogaster, is a powerful model for investigating the genetic regulation of sleep and metabolic function, and screening in inbred fly lines has led to the identification of novel genetic regulators of sleep. Nevertheless, little is known about the contributions of naturally occurring genetic differences to sleep, metabolic phenotypes, and their relationship with geographic or environmental gradients. Here, we quantified sleep and metabolic phenotypes in 24 D. melanogaster populations collected from diverse geographic localities. These studies reveal remarkable variation in sleep, starvation resistance, and energy stores. We found that increased sleep duration is associated with proximity to the equator and elevated average annual temperature, suggesting that environmental gradients strongly influence natural variation in sleep. Further, we found variation in metabolic regulation of sleep to be associated with free glucose levels, while starvation resistance associates with glycogen and triglyceride stores. Taken together, these findings reveal robust naturally occurring variation in sleep and metabolic traits in D. melanogaster, providing a model to investigate how evolutionary and ecological history modulate these complex traits. PMID- 29721285 TI - Structural and functional responses of plant communities to climate change mediated alterations in the hydrology of riparian areas in temperate Europe. AB - The hydrology of riparian areas changes rapidly these years because of climate change-mediated alterations in precipitation patterns. In this study, we used a large-scale in situ experimental approach to explore effects of drought and flooding on plant taxonomic diversity and functional trait composition in riparian areas in temperate Europe. We found significant effects of flooding and drought in all study areas, the effects being most pronounced under flooded conditions. In near-stream areas, taxonomic diversity initially declined in response to both drought and flooding (although not significantly so in all years) and remained stable under drought conditions, whereas the decline continued under flooded conditions. For most traits, we found clear indications that the functional diversity also declined under flooded conditions, particularly in near-stream areas, indicating that fewer strategies succeeded under flooded conditions. Consistent changes in community mean trait values were also identified, but fewer than expected. This can have several, not mutually exclusive, explanations. First, different adaptive strategies may coexist in a community. Second, intraspecific variability was not considered for any of the traits. For example, many species can elongate shoots and petioles that enable them to survive shallow, prolonged flooding but such abilities will not be captured when applying mean trait values. Third, we only followed the communities for 3 years. Flooding excludes species intolerant of the altered hydrology, whereas the establishment of new species relies on time-dependent processes, for instance the dispersal and establishment of species within the areas. We expect that altered precipitation patterns will have profound consequences for riparian vegetation in temperate Europe. Riparian areas will experience loss of taxonomic and functional diversity and, over time, possibly also alterations in community trait responses that may have cascading effects on ecosystem functioning. PMID- 29721286 TI - Competition matters: Determining the drivers of land snail community assembly among limestone karst areas in northern Vietnam. AB - The insular limestone karsts of northern Vietnam harbor a very rich biodiversity. Many taxa are strongly associated with these environments, and individual species communities can differ considerably among karst areas. The exact processes that have shaped the biotic composition of these habitats, however, remain largely unknown. In this study, the role of two major processes for the assembly of snail communities on limestone karsts was investigated, interspecific competition and filtering of taxa due to geographical factors. Communities of operculate land snails of the genus Cyclophorus were studied using the dry and fluid-preserved specimen collections of the Natural History Museum, London. Phylogenetic distances (based on a Bayesian analysis using DNA sequence data) and shell characters (based on 200 semilandmarks) were used as proxies for ecological similarity and were analyzed to reveal patterns of overdispersion (indicating competition) or clustering (indicating filtering) in observed communities compared to random communities. Among the seven studied karst areas, a total of 15 Cyclophorus lineages were found. Unique communities were present in each area. The analyses revealed phylogenetic overdispersion in six and morphological overdispersion in four of seven karst areas. The pattern of frequent phylogenetic overdispersion indicated that competition among lineages is the major process shaping the Cyclophorus communities studied. The Coastal Area, which was phylogenetically overdispersed, showed a clear morphological clustering, which could have been caused by similar ecological adaptations among taxa in this environment. Only the community in the Cuc Phuong Area showed a pattern of phylogenetic clustering, which was partly caused by an absence of a certain, phylogenetically very distinct group in this region. Filtering due to geographical factors could have been involved here. This study shows how museum collections can be used to examine community assembly and contributes to the understanding of the processes that have shaped karst communities in Vietnam. PMID- 29721287 TI - The effect of gut microbiota elimination in Drosophila melanogaster: A how-to guide for host-microbiota studies. AB - In recent years, there has been a surge in interest in the effects of the microbiota on the host. Increasingly, we are coming to understand the importance of the gut microbiota in modulating host physiology, ecology, behavior, and evolution. One method utilized to evaluate the effect of the microbiota is to suppress or eliminate it, and compare the effect on the host with that of untreated individuals. In this study, we evaluate some of these commonly used methods in the model organism, Drosophila melanogaster. We test the efficacy of a low-dose streptomycin diet, egg dechorionation, and an axenic or sterile diet, in the removal of gut bacteria within this species in a fully factorial design. We further determine potential side effects of these methods on host physiology by performing a series of standard physiological assays. Our results showed that individuals from all treatments took significantly longer to develop, and weighed less, compared to normal flies. Males and females that had undergone egg dechorionation weighed significantly less than streptomycin reared individuals. Similarly, axenic female flies, but not males, were much less active when analyzed in a locomotion assay. All methods decreased the egg to adult survival, with egg dechorionation inducing significantly higher mortality. We conclude that low-dose streptomycin added to the dietary media is more effective at removing the gut bacteria than egg dechorionation and has somewhat less detrimental effects to host physiology. More importantly, this method is the most practical and reliable for use in behavioral research. Our study raises the important issue that the efficacy of and impacts on the host of these methods require investigation in a case-by-case manner, rather than assuming homogeneity across species and laboratories. PMID- 29721288 TI - The effects of food and parasitism on reproductive performance of a wild rodent. AB - Food and parasitism can have complex effects on small mammal reproduction. In this study, we tested the effects of sex, food, and parasitism on reproductive performance of the Taiwan field mouse (Apodemus semotus). In a field experiment, we increased food availability for a portion of the mice in the population by providing sorghum seeds to a set of food stations. We reduced parasite intensity of randomly chosen mice through ivermectin treatment. We determined the number and quality of offspring for the mice using paternity analysis. We quantified seed consumption with stable carbon isotope values of mouse plasma and parasite intensity with fecal egg counts of intestinal nematodes and cestodes (FEC). In a laboratory experiment, we reduced parasite intensity of randomly chosen mice through ivermectin treatment. We quantified their immune functions by total white blood cell count, percent granulocyte count, and percent lymphocyte count through hematological analyses. We measured the FEC and energy intake of the mice. From the field experiment, the number of offspring in A. semotus increased with increasing seed consumption. Due to the trade-off between number and quality of offspring, the offspring quality decreased with increasing seed consumption for the females. The ivermectin treatment did not affect offspring number or quality. However, the FEC was positively correlated with number of offspring. In the laboratory experiment, the percent lymphocyte/granulocyte count changed with parasite intensity at low energy intake, which was relaxed at high energy intake. This study demonstrated positive effects of food availability and neutral effects of parasitism on A. semotus reproduction. However, the benefits of food availability for the females need to take into account the offspring number quality trade-off, and at high infection intensity, parasitism might negatively affect offspring quality for the males. We suggest that food availability could mediate the relationships between parasite intensity and immune responses. PMID- 29721289 TI - Fish assemblage changes over half a century in the Yellow River, China. AB - Riverine environments have been threatened by anthropogenic perturbations worldwide, whereby their fish assemblages have been modified by habitat changes and nonendemic species invasions. We assessed changes in fish assemblages by comparing the species presence in historical and contemporary fish data in the Yellow River from 1965 to 2015. The temporal change in species assemblages was found with increased nonendemic species and fewer natives. Fish species richness of the river declined 35.4% over the past fifty years. Moreover, the decreased mean Bray-Curtis dissimilarity among reaches suggested that the fish assemblages of different reaches in the Yellow River were becoming more similar over time. However, temporal patterns of fish assemblages varied among reaches. In the upper Yellow River, higher species richness and more invasive species were found than those in the historical record, while the lower reaches experienced significant species loss. Dam constructions, exotic fish invasions, and flow reductions played the vital role in structuring the temporal fish assemblages in the Yellow River. It is suggested that river basins which experienced different types and levels of stressors by anthropogenic perturbations can produce varied effects on their temporal trends of species assemblages. PMID- 29721290 TI - An in vitro evaluation of browser and grazer fermentation efficiency and microbiota using European moose spring and summer foods. AB - Evolutionary morphological and physiological differences between browsers and grazers contribute to species-specific digestion efficiency of food resources. Rumen microbial community structure of browsers is supposedly adapted to characteristic nutrient composition of the diet source. If this assumption is correct, domesticated ruminants, or grazers, are poor model animals for assessing the nutritional value of food consumed by browsing game species. In this study, typical spring and summer foods of the European moose (Alces alces) were combined with rumen fluid collected from both dairy cows (Bos taurus) and from moose, with the aim of comparing fermentation efficiency and microbial community composition. The nutritional value of the food resources was characterized by chemical analysis and advanced in vitro measurements. The study also addressed whether or not feed evaluation based on in vitro techniques with cattle rumen fluid as inoculum could be a practical alternative when evaluating the nutritional value of plants consumed by wild browsers. Our results suggest that the fermentation characteristics of moose spring and summer food are partly host-specific and related to the contribution of the bacterial phyla Firmicutes and Bacteriodetes to the rumen microbial community. Host-specific adaptations of the ruminal microbial community structure could be explained from the evolutionary adaptations related to feeding habitats and morphophysiological differences between browsers and grazers. However, the observed overall differences in microbial community structure could not be related to ruminal digestion parameters measured in vitro. The in vitro evaluation of digestion efficiency reveals that equal amounts of methane were produced across all feed samples regardless of whether the ruminal fluid was from moose or dairy cow. The results of this study suggested that the nutritional value of browsers' spring and summer food can be predicted using rumen fluid from domesticated grazers as inoculum in in vitro assessments of extent of digestion when excluding samples of the white water lily root, but not of fermentation characteristics as indicated by the proportions of individual fermentation fatty acids to the total of volatile fatty acids. PMID- 29721291 TI - Our use, misuse, and abandonment of a concept: Whither habitat? AB - The foundational concept of habitat lies at the very root of the entire science of ecology, but inaccurate use of the term compromises scientific rigor and communication among scientists and nonscientists. In 1997, Hall, Krausman & Morrison showed that 'habitat' was used correctly in only 55% of articles. We ask whether use of the term has been more accurate since their plea for standardization and whether use varies across the broader range of journals and taxa in the contemporary literature (1998-2012). We searched contemporary literature for 'habitat' and habitat-related terms, ranking usage as either correct or incorrect, following a simplified version of Hall et al.'s definitions. We used generalized linear models to compare use of the term in contemporary literature with the papers reviewed by Hall et al. and to test the effects of taxa, journal impact in the contemporary articles and effects due to authors that cited Hall et al. Use of the term 'habitat' has not improved; it was still only used correctly about 55% of the time in the contemporary data. Proportionately more correct uses occurred in articles that focused on animals compared to ones that included plants, and papers that cited Hall et al. did use the term correctly more often. However, journal impact had no effect. Some habitat terms are more likely to be misused than others, notably 'habitat type', usually used to refer to vegetation type, and 'suitable habitat' or 'unsuitable habitat', which are either redundant or nonsensical by definition. Inaccurate and inconsistent use of the term can lead to (1) misinterpretation of scientific findings; (2) inefficient use of conservation resources; (3) ineffective identification and prioritization of protected areas; (4) limited comparability among studies; and (5) miscommunication of science-based findings. Correct usage would improve communication with scientists and nonscientists, thereby benefiting conservation efforts, and ecology as a science. PMID- 29721292 TI - Habitat properties and plant traits interact as drivers of non-native plant species' seed production at the local scale. AB - To answer the long-standing question if we can predict plant invader success based on characteristics of the environment (invasibility) or the invasive species (invasiveness), or the combination of both, there is a need for detailed observational studies in which habitat properties, non-native plant traits, and the resulting invader success are locally measured. In this study, we assess the interaction of gradients in the environmental and trait space on non-native species fitness, expressed as seed production, for a set of 10 invasive and noninvasive non-native species along a wide range of invaded sites in Flanders. In our multidimensional approach, most of the single environmental gradients (temperature, light availability, native plant species diversity, and soil fertility) and sets of non-native plant traits (plant size, photosynthesis, and foliar chemical attributes) related positively with invader seed production. Yet correlation with seed production was much stronger when several environmental gradients were assessed in interaction, and even more so when we combined plant traits and habitat properties. The latter increased explanatory power of the models on average by 25% for invasive and by 7% for noninvasive species. Additionally, we report a 70-fold higher seed production in invasive than in noninvasive species and fundamentally different correlations of seed production with plant traits and habitat properties in noninvasive versus invasive species. We conclude that locally measured traits and properties deserve much more attention than they currently get in invasion literature and thus encourage further studies combining this level of detail with the generality of a multiregion and multispecies approach across different stages of invasion. PMID- 29721293 TI - Tree seed rain and seed removal, but not the seed bank, impede forest recovery in bracken (Pteridium aquilinum (L.) Kuhn)-dominated clearings in the African highlands. AB - Considerable areas dominated by bracken Pteridium aquilinum (L.) Kuhn occur worldwide and are associated with arrested forest recovery. How forest recovery is impeded in these areas remains poorly understood, especially in the African highlands. The component processes that can lead to recruitment limitation including low seed arrival, availability and persistence-are important determinants of plant communities and offer a potential explanation for bracken persistence. We investigated key processes that can contribute to recruitment limitation in bracken-dominated clearings in the Bwindi Impenetrable National Park, Uganda. We examined if differences in seed rain (dispersal limitation), soil seed bank, or seed removal (seed viability and persistence) can, individually or in combination, explain the differences in tree regeneration found between bracken-dominated areas and the neighboring forest. These processes were assessed along ten 50-m transects crossing the forest-bracken boundary. When compared to the neighboring forest, bracken clearings had fewer seedlings (bracken 11,557 +/- 5482 vs. forest 34,515 +/- 6066 seedlings/ha), lower seed rain (949 +/- 582 vs. 1605 +/- 335 tree seeds m-2 year-1), comparable but sparse soil seed bank (304 +/- 236 vs. 264 +/- 99 viable tree seeds/m2), higher seed removal (70.1% +/- 2.4% vs. 40.6% +/- 2.4% over a 3-day interval), and markedly higher rodent densities (25.7 +/- 5.4 vs. 5.0 +/- 1.6 rodents per 100 trapping sessions). Camera traps revealed that rodents were the dominant animals visiting the seeds in our seed removal study. Synthesis: Recruitment limitation contributes to both the slow recovery of forest in bracken-dominated areas, and to the composition of the tree species that occur. Low seed arrival and low persistence of unburied seeds can both explain the reduced density of seedlings found in bracken versus neighboring forest. Seed removal, likely due to rodents, in particular appears sufficient to constrain forest recovery and impacts some species more severely than others. PMID- 29721294 TI - Edge disturbance drives liana abundance increase and alteration of liana-host tree interactions in tropical forest fragments. AB - Closed-canopy forests are being rapidly fragmented across much of the tropical world. Determining the impacts of fragmentation on ecological processes enables better forest management and improves species-conservation outcomes. Lianas are an integral part of tropical forests but can have detrimental and potentially complex interactions with their host trees. These effects can include reduced tree growth and fecundity, elevated tree mortality, alterations in tree-species composition, degradation of forest succession, and a substantial decline in forest carbon storage. We examined the individual impacts of fragmentation and edge effects (0-100-m transect from edge to forest interior) on the liana community and liana-host tree interactions in rainforests of the Atherton Tableland in north Queensland, Australia. We compared the liana and tree community, the traits of liana-infested trees, and determinants of the rates of tree infestation within five forest fragments (23-58 ha in area) and five nearby intact-forest sites. Fragmented forests experienced considerable disturbance induced degradation at their edges, resulting in a significant increase in liana abundance. This effect penetrated to significantly greater depths in forest fragments than in intact forests. The composition of the liana community in terms of climbing guilds was significantly different between fragmented and intact forests, likely because forest edges had more small-sized trees favoring particular liana guilds which preferentially use these for climbing trellises. Sites that had higher liana abundances also exhibited higher infestation rates of trees, as did sites with the largest lianas. However, large lianas were associated with low-disturbance forest sites. Our study shows that edge disturbance of forest fragments significantly altered the abundance and community composition of lianas and their ecological relationships with trees, with liana impacts on trees being elevated in fragments relative to intact forests. Consequently, effective control of lianas in forest fragments requires management practices which directly focus on minimizing forest edge disturbance. PMID- 29721295 TI - An evaluation of government-recommended stocking systems for sustaining pastoral businesses and ecosystems of the Alpine Meadows of the Qinghai-Tibetan Plateau. AB - China introduced the "Retire Livestock and Restore Grassland" policy in 2003. It was strengthened in 2011 by additional funding for on-farm structures. On the Qinghai-Tibetan Plateau (QTP), fences were erected, livestock excluded from degraded areas, rotational stocking introduced, nighttime shelters were built, forages grown, and seed sown. However, the effectiveness of these actions and their value to Tibetan herders has been questioned. We conducted a sheep stocking experiment for 5 years in an Alpine Meadow region of the QTP to evaluate stocking options recommended by Government. Cold and warm season stocking each at three rates (0, 8, and 16 sheep/ha) and continuous stocking at 0 and 4 sheep/ha were compared. We measured live weights of sheep, plant species richness and evenness, root biomass and carbon (C), nitrogen (N) and phosphorus (P) contents of the 0-10 cm of soil. We found that resting grassland from stocking during the warm season for later cold season stocking significantly reduced plant species richness and evenness and root biomass but not soil C, N, and P. During cold season stocking, live weights of sheep declined whether at a stocking rate of 8 or 16 per ha. In contrast, sheep continuously stocked on grassland at 4 per ha gained weight throughout both the warm and cold seasons and plant species richness and evenness were maintained. Warm season stocking at 8 and 16 sheep/ha increased plant species richness and root biomass but reduced plant species evenness. Resting these alpine grasslands from stocking in the warm season has adverse consequences for plant conservation. Fencing from stocking in the warm season is not justified by this study; all grassland should be judiciously stocked during the warm season to maintain plant species richness. Neither resting nor stocking during the cold season appears to have any adverse consequences but sheltering and in-door feeding of sheep during the cold season may be more profitable than cold season stocking with use of open nighttime yards. PMID- 29721296 TI - Strong population structure but no equilibrium yet: Genetic connectivity and phylogeography in the kelp Saccharina latissima (Laminariales, Phaeophyta). AB - Kelp aquaculture is globally developing steadily as human food source, along with other applications. One of the newer crop species is Saccharina latissima, a northern hemisphere kelp inhabiting temperate to arctic rocky shores. To protect and document its natural genetic variation at the onset of this novel aquaculture, as well as increase knowledge on its taxonomy and phylogeography, we collected new genetic data, both nuclear and mitochondrial, and combined it with previous knowledge to estimate genetic connectivity and infer colonization history. Isolation-with-migration coalescent analyses demonstrate that gene flow among the sampled locations is virtually nonexistent. An updated scenario for the origin and colonization history of S. latissima is developed as follows: We propose that the species (or species complex) originated in the northwest Pacific, crossed to the northeast Pacific in the Miocene, and then crossed the Bering Strait after its opening ~5.5 Ma into the Arctic and northeast Atlantic. It subsequently crossed the Atlantic from east to west. During the Pleistocene, it was compressed in the south with evidence for northern refugia in Europe. Postglacial recolonization led to secondary contact in the Canadian Arctic. Saccharina cichorioides is shown to probably belong to the S. latissima species complex and to derive from ancestral populations in the Asian North Pacific. Our novel approach of comparing inferred gene flow based on coalescent analysis versus Wright's island model suggests that equilibrium levels of differentiation have not yet been reached in Europe and, hence, that genetic differentiation is expected to increase further if populations are left undisturbed. PMID- 29721297 TI - Identifying important conservation areas for the clouded leopard Neofelis nebulosa in a mountainous landscape: Inference from spatial modeling techniques. AB - The survival of large carnivores is increasingly precarious due to extensive human development that causes the habitat loss and fragmentation. Habitat selection is influenced by anthropogenic as well as environmental factors, and understanding these relationships is important for conservation management. We assessed the environmental and anthropogenic variables that influence site use of clouded leopard Neofelis nebulosa in Bhutan, estimated their population density, and used the results to predict the species' site use across Bhutan. We used a large camera-trap dataset from the national tiger survey to estimate for clouded leopards, for the first time in Bhutan, (1) population density using spatially explicit capture-recapture models and (2) site-use probability using occupancy models accounting for spatial autocorrelation. Population density was estimated at D^Bayesian=0.40 (0.10 SD) and D^maximum-likelihood=0.30 (0.12 SE) per 100 km2. Clouded leopard site use was positively associated with forest cover and distance to river while negatively associated with elevation. Mean site-use probability (from the Bayesian spatial model) was psi^spatial=0.448 (0.076 SD). When spatial autocorrelation was ignored, the probability of site use was overestimated, psi^nonspatial=0.826 (0.066 SD). Predictive mapping allowed us to identify important conservation areas and priority habitats to sustain the future of these elusive, ambassador felids and associated guilds. Multiple sites in the south, many of them outside of protected areas, were identified as habitats suitable for this species, adding evidence to conservation planning for clouded leopards in continental South Asia. PMID- 29721298 TI - Predictable ecological response to rising CO2 of a community of marine phytoplankton. AB - Rising atmospheric CO 2 and ocean acidification are fundamentally altering conditions for life of all marine organisms, including phytoplankton. Differences in CO 2 related physiology between major phytoplankton taxa lead to differences in their ability to take up and utilize CO 2. These differences may cause predictable shifts in the composition of marine phytoplankton communities in response to rising atmospheric CO 2. We report an experiment in which seven species of marine phytoplankton, belonging to four major taxonomic groups (cyanobacteria, chlorophytes, diatoms, and coccolithophores), were grown at both ambient (500 MUatm) and future (1,000 MUatm) CO 2 levels. These phytoplankton were grown as individual species, as cultures of pairs of species and as a community assemblage of all seven species in two culture regimes (high-nitrogen batch cultures and lower-nitrogen semicontinuous cultures, although not under nitrogen limitation). All phytoplankton species tested in this study increased their growth rates under elevated CO 2 independent of the culture regime. We also find that, despite species-specific variation in growth response to high CO 2, the identity of major taxonomic groups provides a good prediction of changes in population growth and competitive ability under high CO 2. The CO 2-induced growth response is a good predictor of CO 2-induced changes in competition (R2 > .93) and community composition (R2 > .73). This study suggests that it may be possible to infer how marine phytoplankton communities respond to rising CO 2 levels from the knowledge of the physiology of major taxonomic groups, but that these predictions may require further characterization of these traits across a diversity of growth conditions. These findings must be validated in the context of limitation by other nutrients. Also, in natural communities of phytoplankton, numerous other factors that may all respond to changes in CO2, including nitrogen fixation, grazing, and variation in the limiting resource will likely complicate this prediction. PMID- 29721299 TI - Temperature effects on ballistic prey capture by a dragonfly larva. AB - Understanding the effects of temperature on prey-predator interactions is a key issue to predict the response of natural communities to climate change. Higher temperatures are expected to induce an increase in predation rates. However, little is known on how temperature influences close-range encounter of prey predator interactions, such as predator's attack velocities. Based on the speed accuracy trade-off concept, we hypothesized that the increase in predator attack velocity by increasing temperature reduces the accuracy of the attack, leading to a lower probability of capture. We tested this hypothesis on the dragonfly larvae Anax imperator and the zooplankton prey Daphnia magna. The prey-predator encounters were video-recorded at high speed, and at three different temperatures. Overall, we found that (1) temperature had a strong effect on predator's attack velocities, (2) prey did not have the opportunity to move and/or escape due to the high velocity of the predator during the attack, and (3) neither velocity nor temperature had significant effects on the capture success. By contrast, the capture success mainly depended on the accuracy of the predator in capturing the prey. We found that (4) some 40% of mistakes were undershooting and some 60% aimed below or above the target. No lateral mistake was observed. These results did not support the speed-accuracy trade-off hypothesis. Further studies on dragonfly larvae with different morphological labial masks and speeds of attacks, as well as on prey with different escape strategies, would provide new insights into the response to environmental changes in prey-predator interactions. PMID- 29721300 TI - Brain gene expression analyses in virgin and mated queens of fire ants reveal mating-independent and socially regulated changes. AB - Transcriptomes of dissected brains from virgin alate and dealate mated queens from polygyne fire ants (Solenopsis invicta) were analyzed and compared. Thirteen genes were upregulated in mated queen brain, and nine were downregulated. While many of the regulated genes were either uncharacterized or noncoding RNAs, those annotated genes included two hexamerin proteins, astakine neuropeptide, serine proteases, and serine protease inhibitors. We found that for select differentially expressed genes in the brain, changes in gene expression were most likely driven by the changes in physiological state (i.e., age, nutritional status, or dominance rank) or in social environment (released from influence of primer pheromone). This was concluded because virgins that dealated after being separated from mated queens showed similar patterns of gene expression in the brain as those of mated queens for hexamerin 1, astakine, and XR_850909. Abaecin (XR_850725), however, appears upregulated only after mating. Therefore, our findings contribute to distinguish how specific gene networks, especially those influenced by queen primer pheromone, are regulated in queen ants. Additionally, to identify brain signaling pathways, we mined the fire ant genome and compiled a list of G-protein-coupled receptors (GPCRs). The expression level of GPCRs and other genes in the "genetic toolkit" in the brains of virgin alates and mated dealate queens is reported. PMID- 29721301 TI - Phenotypic responses to microbial volatiles render a mold fungus more susceptible to insect damage. AB - In decomposer systems, fungi show diverse phenotypic responses to volatile organic compounds of microbial origin (volatiles). The mechanisms underlying such responses and their consequences for the performance and ecological success of fungi in a multitrophic community context have rarely been tested explicitly. We used a laboratory-based approach in which we investigated a tripartite yeast-mold insect model decomposer system to understand the possible influence of yeast borne volatiles on the ability of a chemically defended mold fungus to resist insect damage. The volatile-exposed mold phenotype (1) did not exhibit protein kinase A-dependent morphological differentiation, (2) was more susceptible to insect foraging activity, and (3) had reduced insecticidal properties. Additionally, the volatile-exposed phenotype was strongly impaired in secondary metabolite formation and unable to activate "chemical defense" genes upon insect damage. These results suggest that volatiles can be ecologically important factors that affect the chemical-based combative abilities of fungi against insect antagonists and, consequently, the structure and dynamics of decomposer communities. PMID- 29721302 TI - The energetic consequences of behavioral variation in a marine carnivore. AB - Intraspecific variability in foraging behavior has been documented across a range of taxonomic groups, yet the energetic consequences of this variation are not well understood for many species. Understanding the effect of behavioral variation on energy expenditure and acquisition is particularly crucial for mammalian carnivores because they have high energy requirements that place considerable pressure on prey populations. To determine the influence of behavior on energy expenditure and balance, we combined simultaneous measurements of at sea field metabolic rate (FMR) and foraging behavior in a marine carnivore that exhibits intraspecific behavioral variation, the California sea lion (Zalophus californianus). Sea lions exhibited variability in at-sea FMR, with some individuals expending energy at a maximum of twice the rate of others. This variation was in part attributable to differences in diving behavior that may have been reflective of diet; however, this was only true for sea lions using a foraging strategy consisting of epipelagic (<200 m within the water column) and benthic dives. In contrast, sea lions that used a deep-diving foraging strategy all had similar values of at-sea FMR that were unrelated to diving behavior. Energy intake did not differ between foraging strategies and was unrelated to energy expenditure. Our findings suggest that energy expenditure in California sea lions may be influenced by interactions between diet and oxygen conservation strategies. There were no apparent energetic trade-offs between foraging strategies, although there was preliminary evidence that foraging strategies may differ in their variability in energy balance. The energetic consequences of behavioral variation may influence the reproductive success of female sea lions and result in differential impacts of individuals on prey populations. These findings highlight the importance of quantifying the relationships between energy expenditure and foraging behavior in other carnivores for studies addressing fundamental and applied physiological and ecological questions. PMID- 29721303 TI - Seasonal variations in body melanism and size of the wolf spider Pardosa astrigera (Araneae: Lycosidae). AB - Variations in species morphology and life-history traits strongly correlate with geographic and climatic characteristics. Most studies on morphological variations in animals focus on ectotherms distributed on a large geographic scale across latitudinal and/or altitudinal gradient. However, the morphological variations of spiders living in the same habitats across different seasons have not been reported. In this study, we used the wolf spider, Pardosa astrigera, as a model to determine seasonal differences in adult body size, melanism, fecundity, and egg diameter both in the overwintering and the first generation for 2010 and 2016. The results showed that in 2010, both females and males of the overwintering generation were significantly darker than the first generation. Moreover, the overwintering females were markedly larger and produced more and bigger eggs than the first generation in both 2010 and 2016. Considering the overwintering P. astrigera experiencing low temperature and/or desiccation stress, these results suggest that substantially darker and larger body of the overwintering generation is adaptive to adverse conditions. PMID- 29721304 TI - Diversity and evolution of rice progenitors in Australia. AB - In the thousands of years of rice domestication in Asia, many useful genes have been lost from the gene pool. Wild rice is a key source of diversity for domesticated rice. Genome sequencing has suggested that the wild rice populations in northern Australia may include novel taxa, within the AA genome group of close (interfertile) wild relatives of domesticated rice that have evolved independently due to geographic separation and been isolated from the loss of diversity associated with gene flow from the large populations of domesticated rice in Asia. Australian wild rice was collected from 27 sites from Townsville to the northern tip of Cape York. Whole chloroplast genome sequences and 4,555 nuclear gene sequences (more than 8 Mbp) were used to explore genetic relationships between these populations and other wild and domesticated rices. Analysis of the chloroplast and nuclear data showed very clear evidence of distinctness from other AA genome Oryza species with significant divergence between Australian populations. Phylogenetic analysis suggested the Australian populations represent the earliest-branching AA genome lineages and may be critical resources for global rice food security. Nuclear genome analysis demonstrated that the diverse O. meridionalis populations were sister to all other AA genome taxa while the Australian O. rufipogon-like populations were associated with the clade that included domesticated rice. Populations of apparent hybrids between the taxa were also identified suggesting ongoing dynamic evolution of wild rice in Australia. These introgressions model events similar to those likely to have been involved in the domestication of rice. PMID- 29721305 TI - MSL: Facilitating automatic and physical analysis of published scientific literature in PDF format. AB - Published scientific literature contains millions of figures, including information about the results obtained from different scientific experiments e.g. PCR-ELISA data, microarray analysis, gel electrophoresis, mass spectrometry data, DNA/RNA sequencing, diagnostic imaging (CT/MRI and ultrasound scans), and medicinal imaging like electroencephalography (EEG), magnetoencephalography (MEG), echocardiography (ECG), positron-emission tomography (PET) images. The importance of biomedical figures has been widely recognized in scientific and medicine communities, as they play a vital role in providing major original data, experimental and computational results in concise form. One major challenge for implementing a system for scientific literature analysis is extracting and analyzing text and figures from published PDF files by physical and logical document analysis. Here we present a product line architecture based bioinformatics tool 'Mining Scientific Literature (MSL)', which supports the extraction of text and images by interpreting all kinds of published PDF files using advanced data mining and image processing techniques. It provides modules for the marginalization of extracted text based on different coordinates and keywords, visualization of extracted figures and extraction of embedded text from all kinds of biological and biomedical figures using applied Optimal Character Recognition (OCR). Moreover, for further analysis and usage, it generates the system's output in different formats including text, PDF, XML and images files. Hence, MSL is an easy to install and use analysis tool to interpret published scientific literature in PDF format. PMID- 29721306 TI - Case Report: Cerebral leukodystrophy and the gonadal endocrinopathy: a rare but real association. AB - A 30 year old married Pakistani woman presented in January 2018 with an eight month history of progressive left sided weakness, ataxia, spasticity, underdeveloped secondary sexual characteristics and primary infertility. She was the elder sister of a 19 year old bed bound woman who was diagnosed with vanishing white matter (VWM) disease 12 months previously. The MRI scan of the brain demonstrated diffuse leukodystrophy and her hormonal assays were significant for premature ovarian failure. Results from her genetic tests demonstrated a point mutation in eukaryotic initiation factor 2B (EIF2B). Thus, she was the second confirmed case of VWM from her family of 12 siblings with normal parents. PMID- 29721307 TI - Intraocular pressure elevation precedes a phagocytosis decline in a model of pigmentary glaucoma. AB - Background: Outflow regulation and phagocytosis are key functions of the trabecular meshwork (TM), but it is not clear how the two are related in secondary open angle glaucomas characterized by an increased particle load. We hypothesized that diminished TM phagocytosis is not the primary cause of early ocular hypertension and recreated pigment dispersion in a porcine ex vivo model. Methods: Sixteen porcine anterior chamber cultures received a continuous infusion of pigment granules (Pg), while 16 additional anterior chambers served as controls (C). Pressure transducers recorded the intraocular pressure (IOP). The phagocytic capacity of the trabecular meshwork was determined by fluorescent microspheres. Results: The baseline IOPs in Pg and C were similar ( P=0.82). A significant IOP elevation occurred in Pg at 48, 120, and 180 hours (all P<0.01, compared to baseline). The pigment did not cause a reduction in TM phagocytosis at 48 hours, when the earliest IOP elevation occurred, but at 120 hours onward ( P=0.001 compared to C). This reduction did not result in an additional IOP increase at 120 or 180 hours compared to the first IOP elevation at 48 hours ( P>0.05). Conclusions: In this porcine model of pigmentary glaucoma, an IOP elevation occurs much earlier than when phagocytosis fails, suggesting that two separate mechanisms might be at work. PMID- 29721308 TI - Extended pharmacological miosis is superfluous after glaucoma angle surgery: A retrospective study. AB - Background: Pilocarpine is commonly used after angle surgery for glaucoma despite a host of side effects and risks. We hypothesized that a pharmacological miosis during the first two months does not improve short- and long-term results of trabectome-mediated ab interno trabeculectomy. Methods: In this retrospective comparative 1-year case series, we compared 187 trabectome surgery eyes with (P+) or without (P-) 1% pilocarpine for two months. Primary outcome measures were the surgical success defined as intraocular pressure (IOP) <= 21 mmHg and decreased >= 20%, and no secondary glaucoma surgery. Secondary outcome measures were the number of glaucoma medications, complications, and IOP. Results: We categorized 86 (46%) eyes as P- and 101 (54%) eyes as P+. The mean age was 69.8+/-10.1 in P- and 70.5+/-9.4 in P+ (P=0.617) with equal gender distribution (P=0.38). The cumulative probability of qualified success at 12 months was 78.1% in the P- and 81% in the P+ (P=0.35). The IOP was decreased significantly from 20.2+/-6.8 mmHg at baseline to 15.0+/-4.8 mmHg at 12 months follow-up in P- (P=0.001) and 18.8+/ 5.3 and 14.7+/-4.0, respectively (P=0.001). The medications decreased significantly from 1.4+/-1.2 in P- and 1.4+/-1.2 in P+ at baseline to 1.0+/-1.2 and 0.7+/-1.0, respectively (P=0.183). P- and P+ did not differ in IOP or medications (all P>0.05). In Multivariate Cox Regression models, the baseline IOP and central corneal thickness were associated with failure. Conclusions: Use of postoperative pilocarpine does not improve the efficacy of trabectome surgery. PMID- 29721310 TI - Identification of microsatellite loci in sea anemones Aulactinia stella and Cribrinopsis albopunctata (family Actiniidae). AB - From the DNA libraries enriched by the repeat motifs (AAAC) 6, (AATC) 6, (ACAG) 6, (ACCT) 6, (ACTC) 6, ACTG) 6, (AAAT) 8, (AACT) 8, (AAGT) 8, (AGAT) 8, for two viviparous sea anemones Aulactinia stella and Cribrinopsis albopunctata, 41 primer pairs were developed. These primer pairs resulted in the identification of 41 candidate microsatellite loci in either A. stella or C. albopunctata. Polymorphic loci were identified in both sea anemone species for 13 of the primer pairs and can be applicable for population genetics researches. PMID- 29721309 TI - Unraveling endometriosis-associated ovarian carcinomas using integrative proteomics. AB - Background: To elucidate potential markers of endometriosis and endometriosis associated endometrioid and clear cell ovarian carcinomas using mass spectrometry based proteomics. Methods: A total of 21 fresh, frozen tissues from patients diagnosed with clear cell carcinoma, endometrioid carcinoma, endometriosis and benign endometrium were subjected to an in-depth liquid chromatography-tandem mass spectrometry analysis on the Q-Exactive Plus. Protein identification and quantification were performed using MaxQuant, while downstream analyses were performed using Perseus and various bioinformatics databases. Results: Approximately 9000 proteins were identified in total, representing the first in depth proteomic investigation of endometriosis and its associated cancers. This proteomic data was shown to be biologically sound, with minimal variation within patient cohorts and recapitulation of known markers. While moderate concordance with genomic data was observed, it was shown that such data are limited in their abilities to represent tumours on the protein level and to distinguish tumours from their benign precursors. Conclusions: The proteomic data suggests that distinct markers may differentiate endometrioid and clear cell carcinoma from endometriosis. These markers may be indicators of pathobiology but will need to be further investigated. Ultimately, this dataset may serve as a basis to unravel the underlying biology of the endometrioid and clear cell cancers with respect to their endometriotic origins. PMID- 29721311 TI - Gene Unprediction with Spurio: A tool to identify spurious protein sequences. AB - We now have access to the sequences of tens of millions of proteins. These protein sequences are essential for modern molecular biology and computational biology. The vast majority of protein sequences are derived from gene prediction tools and have no experimental supporting evidence for their translation. Despite the increasing accuracy of gene prediction tools there likely exists a large number of spurious protein predictions in the sequence databases. We have developed the Spurio tool to help identify spurious protein predictions in prokaryotes. Spurio searches the query protein sequence against a prokaryotic nucleotide database using tblastn and identifies homologous sequences. The tblastn matches are used to score the query sequence's likelihood of being a spurious protein prediction using a Gaussian process model. The most informative feature is the appearance of stop codons within the presumed translation of homologous DNA sequences. Benchmarking shows that the Spurio tool is able to distinguish spurious from true proteins. However, transposon proteins are prone to be predicted as spurious because of the frequency of degraded homologs found in the DNA sequence databases. Our initial experiments suggest that less than 1% of the proteins in the UniProtKB sequence database are likely to be spurious and that Spurio is able to identify over 60 times more spurious proteins than the AntiFam resource. The Spurio software and source code is available under an MIT license at the following URL: https://bitbucket.org/bateman-group/spurio. PMID- 29721312 TI - The acid tolerance response and pH adaptation of Enterococcus faecalis in extract of lime Citrus aurantiifolia from Aceh Indonesia. AB - Background: The objective of the present study was to evaluate the acid tolerance response and pH adaptation when Enterococcusfaecalis interacted with extract of lime ( Citrus aurantiifolia). Methods: We used E. faecalis ATCC 29212 and lime extract from Aceh, Indonesia. Both materials were analyzed for their pH adaptation, acid tolerance response, adhesion assay, and mass profiles using a light microscope with a magnification of x1000. Further, statistical tests were performed to analyze both correlation and significance of the acid tolerance and pH adaptation also the interaction activity. Results:E. faecalis was able to adapt to a very acidic environment (pH 2.9), which was characterized by an increase in its pH (reaching 4.2) at all concentrations of the lime extract (p < 0.05). E. faecalis was also able to provide acid tolerance response to lime extract based on spectrophotometric data (595 nm) (p < 0.05). Also, the interaction activity of E. faecalis and the lime extract was relatively stable within 6 up to 12 hours (p < 0.05), but it became unstable within 24-72 hours (p > 0.05) based on the mass profiles of its interaction activity. Conclusions:E. faecalis can adapt to acidic environments (pH 2.9-4.2); it is also able to tolerate acid generated by Citrus aurantiifolia extract, revealing a stable interaction in the first 6-12 hours. PMID- 29721313 TI - Evaluating disparities in the U.S. technology transfer ecosystem to improve bench to business translation. AB - Background: A large number of highly impactful technologies originated from academic research, and the transfer of inventions from academic institutions to private industry is a major driver of economic growth, and a catalyst for further discovery. However, there are significant inefficiencies in academic technology transfer. In this work, we conducted a data-driven assessment of translational activity across United States (U.S.) institutions to better understand how effective universities are in facilitating the transfer of new technologies into the marketplace. From this analysis, we provide recommendations to guide technology transfer policy making at both the university and national level. Methods: Using data from the Association of University Technology Managers U.S. Licensing Activity Survey, we defined a commercialization pipeline that reflects the typical path intellectual property takes; from initial research funding to startup formation and gross income. We use this pipeline to quantify the performance of academic institutions at each step of the process, as well as overall, and identify the top performing institutions via mean reciprocal rank. The corresponding distributions were visualized and disparities quantified using the Gini coefficient. Results: We found significant discrepancies in commercialization activity between institutions; a small number of institutions contribute to the vast majority of total commercialization activity. By examining select top performing institutions, we suggest improvements universities and technology transfer offices could implement to emulate the environment at these high-performing institutions. Conclusion: Significant disparities in technology transfer performance exist in which a select set of institutions produce a majority share of the total technology transfer activity. This disparity points to missed commercialization opportunities, and thus, further investigation into the distribution of technology transfer effectiveness across institutions and studies of policy changes that would improve the effectiveness of the commercialization pipeline is warranted. PMID- 29721314 TI - Preliminary investigation of deoxyoligonucleotide binding to ribonuclease A using mass spectrometry: An attempt to develop a lab experience for undergraduates. AB - Deoxyoligonucleotide binding to bovine pancreatic ribonuclease A (RNase A) was investigated using electrospray ionization ion-trap mass spectrometry (ESI-IT MS). Deoxyoligonucleotides included CCCCC (dC 5) and CCACC (dC 2AC 2). This work was an attempt to develop a biochemistry lab experience that would introduce undergraduates to the use of mass spectrometry for the analysis of protein-ligand interactions. Titration experiments were performed using a fixed RNase A concentration and variable deoxyoligonucleotide concentrations. Samples at equilibrium were infused directly into the mass spectrometer under native conditions. For each deoxyoligonucleotide, mass spectra showed one-to-one binding stoichiometry, with marked increases in the total ion abundance of ligand bound RNase A complexes as a function of concentration, but the accurate determination of dC 5 and dC 2AC 2 dissociation constants was problematic. PMID- 29721315 TI - Effects of body fat mass and therapeutic weight loss on vitamin D status in privately owned adult dogs. AB - More than one-third of humans and companion dogs in Western societies are overweight or obese. In people, vitamin D deficiency is widespread and associated with obesity, a now recognised inflammatory state. Low vitamin D status occurs in dogs with inflammatory conditions, but its relationship with obesity has not been investigated. In otherwise healthy privately owned adult dogs of ideal body condition (control, n 7) and dogs with overweight to obese body condition (treatment, n 8), serum 25-hydroxyvitamin D (25(OH)D) concentration and body composition as inferred from 2H-labelled water dilution space were evaluated. Subsequently, the dogs were transitioned to a commercial canine therapeutic weight-loss diet; control dogs were fed to maintain body weight and treatment dogs were energy-restricted to achieve a safe weight-loss rate. Thereafter, serum 25(OH)D concentration was re-evaluated 8 weeks after diet transition, and at the study end, which was 6 months or when ideal body condition was achieved. At study end, body composition analysis was repeated. Initial body condition scores and percentage body fat were positively correlated (rho = 0.891; P < 0.001). However, percentage body fat and serum 25(OH)D concentration were not significantly correlated. Final serum 25(OH)D concentrations were greater (P < 0.05) than initial concentrations for control and treatment groups, indicating a diet but not weight-loss effect on vitamin D status. These findings suggest that vitamin D status of dogs is not affected by obesity or loss of body fat with therapeutic weight reduction. PMID- 29721316 TI - Effects of dietary supplementation with milk fat globule membrane on the physical performance of community-dwelling Japanese adults: a randomised, double-blind, placebo-controlled trial. AB - We conducted a randomised, double-blind, placebo-controlled trial to elucidate the effects of dietary milk fat globule membrane (MFGM) on the physical performance of community-dwelling Japanese adults. For this 24-week study, 115 middle-aged subjects (range 50-70 years old) were invited, of whom 113 (seventy two women, forty-one men) completed the trial. Participants were then divided into either the placebo control or MFGM group. Measurements of physical performance (without undertaking any mandatory exercise) examining muscle strength, agility and balance were tested every 6 weeks until 24 weeks. Analyses were performed using the intention-to-treat method for all participants. Although the effects of MFGM on muscle strength and agility were not significant, we noted that the parameter for balance (such as the ability to stand on one leg with eyes closed for longer durations) increased in the MFGM group (mean 10.1 (95 % CI 8.25, 12.4) s) compared with the placebo (mean 7.53 (95 % CI 6.11, 9.30) s) (P = 0.046). Similarly, application of the mixed-effect model for repeated measures under unstructured covariance also revealed that the effect of MFGM was significant when compared with the placebo (10.2 (95 % CI 8.33, 12.4) v. 7.61 (95 % CI 6.17, 9.30) s) (P = 0.045). In conclusion, we demonstrated that MFGM had an effect on the physical performance of community-dwelling Japanese adults despite mandatory exercise. However, studies using larger cohorts of individuals from different demographic backgrounds are required to further elucidate the mechanisms underlying these effects and to extend the application of MFGM. PMID- 29721318 TI - Central airway obstruction caused by adenoid cystic carcinoma in pregnancy: a case report and review of the literature. AB - Malignancy complicates one in a thousand pregnancies. The most frequently diagnosed of these are breast, cervical, melanoma, ovarian, and haematological neoplasms. Tumours of respiratory origin are very uncommon during pregnancy. We present a case of tracheal adenoid cystic carcinoma (ACC), a rare type of primary airway tumour, diagnosed in a pregnant woman. To our knowledge, this is the third reported case of tracheal ACC complicating pregnancy. We discuss potential barriers to timely diagnosis of malignancies during pregnancy and consider optimal management strategies, taking into account the potential harm to the mother and foetus in a field with a limited evidence base. PMID- 29721319 TI - Successful ventilator weaning following vascular bypass in patient with vascular tracheobronchial compression. AB - A 74-year-old man, who had undergone thoracoplasty for tuberculous sequelae 54 years earlier, was referred to our hospital with a chief complaint of dyspnea. He had recently received mechanical ventilation due to pneumonia. However, although the pneumonia had improved, extubation was prevented by the presence of hypercapnic respiratory failure with tracheal stenosis due to compression of the right aortic arch and the left common carotid artery. Bypass surgery was performed, during which the left subclavian artery was placed over the left common carotid artery. Surgery resulted in expansion of the cross-sectional tracheal stenosis area from 11.60 mm2 to 62.62 mm2, and the patient was successfully weaned off ventilatory support. PMID- 29721320 TI - Accuracy of the first interpretation of early brain CT images for predicting the prognosis of post-cardiac arrest syndrome patients at the emergency department. AB - Background: Early brain CT is one of the most useful tools for estimating the prognosis in patients with post-cardiac arrest syndrome (PCAS) at the emergency department (ED). The aim of this study was to evaluate the prognosis-prediction accuracy of the emergency physicians' interpretation of the findings on early brain CT in PCAS patients treated by targeted temperature management (TTM). Methods: This was a double-center, retrospective, observational study. Eligible subjects were cardiac arrest patients admitted to the intensive care unit (ICU) for TTM between April 2011 and March 2017. We performed the McNemar test to compare the predictive accuracies of the interpretation by emergency physicians and radiologists and calculated the kappa statistic for determining the concordance rate between the interpretations by these two groups. Results: Of the 122 eligible patients, 106 met the inclusion criteria for this study. The predictive accuracies (sensitivity, specificity) of the interpretations by the emergency physicians and radiologists were (0.34, 1.00) and (0.41, 0.93), respectively, with no significant difference in either the sensitivity or specificity as assessed by the McNemar test. The kappa statistic calculated to determine the concordance between the two interpretations was 0.66 (0.48-0.83), which showed a good conformity. Conclusions: The emergency physicians' interpretation of the early brain CT findings in PCAS patients treated by TTM was as reliable as that of radiologists, in terms of prediction of the prognosis. PMID- 29721321 TI - Machine learning of big data in gaining insight into successful treatment of hypertension. AB - Despite effective medications, rates of uncontrolled hypertension remain high. Treatment protocols are largely based on randomized trials and meta-analyses of these studies. The objective of this study was to test the utility of machine learning of big data in gaining insight into the treatment of hypertension. We applied machine learning techniques such as decision trees and neural networks, to identify determinants that contribute to the success of hypertension drug treatment on a large set of patients. We also identified concomitant drugs not considered to have antihypertensive activity, which may contribute to lowering blood pressure (BP) control. Higher initial BP predicts lower success rates. Among the medication options and their combinations, treatment with beta blockers appears to be more commonly effective, which is not reflected in contemporary guidelines. Among numerous concomitant drugs taken by hypertensive patients, proton pump inhibitors (PPIs), and HMG CO-A reductase inhibitors (statins) significantly improved the success rate of hypertension. In conclusions, machine learning of big data is a novel method to identify effective antihypertensive therapy and for repurposing medications already on the market for new indications. Our results related to beta blockers, stemming from machine learning of a large and diverse set of big data, in contrast to the much narrower criteria for randomized clinic trials (RCTs), should be corroborated and affirmed by other methods, as they hold potential promise for an old class of drugs which may be presently underutilized. These previously unrecognized effects of PPIs and statins have been very recently identified as effective in lowering BP in preliminary clinical observations, lending credibility to our big data results. PMID- 29721322 TI - Direct and cytokine-mediated effects of albumin-fused growth hormone, TV-1106, on CYP enzyme expression in human hepatocytes in vitro. AB - Some biologics can modulate cytokines that may lead to changes in expression of drug-metabolizing enzymes and cause drug-drug interactions (DDI). DDI potential of TV-1106-an albumin-fused growth hormone (GH)-was investigated. In this study, human blood was exposed to recombinant human growth hormone (rhGH) or TV-1106, followed by isolation of the plasma and its application to human hepatocytes. While the treatment of blood with rhGH increased multiple cytokines, treatment of blood with TV-1106 had no effect on any of the nine cytokines tested. The interleukin (IL)-6 concentration was higher in the rhGH then in the TV-1106 treated plasma (P < .05). While rhGH had little or no effect on CYP1A2 or CYP2C19 mRNA but increased CYP3A4 mRNA twofold, TV-1106 had little or no effect on cytochrome P450 (CYP) mRNAs in hepatocytes. Although the plasma from rhGH-treated blood lowered CYP1A2 activity, the TV-1106 plasma had no effect on CYP activities. The CYP1A2 activity was lower in the rhGH- then in the TV-1106-plasma treated hepatocytes (P < .05). The results indicated that fusing GH with albumin made TV-1106 an unlikely participant of CYP1A2, CYP2C19 or CYP3A4-facilitated, direct or cytokine-driven DDI. PMID- 29721317 TI - Does intra-ruminal nitrogen recycling waste valuable resources? A review of major players and their manipulation. AB - Nitrogenous emissions from ruminant livestock production are of increasing public concern and, together with methane, contribute to environmental pollution. The main cause of nitrogen-(N)-containing emissions is the inadequate provision of N to ruminants, leading to an excess of ammonia in the rumen, which is subsequently excreted. Depending on the size and molecular structure, various bacterial, protozoal and fungal species are involved in the ruminal breakdown of nitrogenous compounds (NC). Decelerating ruminal NC degradation by controlling the abundance and activity of proteolytic and deaminating microorganisms, but without reducing cellulolytic processes, is a promising strategy to decrease N emissions along with increasing N utilization by ruminants. Different dietary options, including among others the treatment of feedstuffs with heat or the application of diverse feed additives, as well as vaccination against rumen microorganisms or their enzymes have been evaluated. Thereby, reduced productions of microbial metabolites, e.g. ammonia, and increased microbial N flows give evidence for an improved N retention. However, linkage between these findings and alterations in the rumen microbiota composition, particularly NC-degrading microbes, remains sparse and contradictory findings confound the exact evaluation of these manipulating strategies, thus emphasizing the need for comprehensive research. The demand for increased sustainability in ruminant livestock production requests to apply attention to microbial N utilization efficiency and this will require a better understanding of underlying metabolic processes as well as composition and interactions of ruminal NC-degrading microorganisms. PMID- 29721323 TI - Inconsistencies in dosage practice in children with overweight or obesity: A retrospective cohort study. AB - Obesity can affect the pharmacokinetics of most drugs, which may result in under- or overdosing if traditional pediatric dosing strategies are used. To investigate currently applied dosage strategies in children with overweight or obesity (overweight/obesity), in a clinical treatment facility. In particular, whether dosing guidelines were available and metrics of body size applied. A retrospective cohort study of 200 patients admitted to the Danish Children's Obesity Clinic. Data were collected from 2007 to 2015. Overweight/obese children 3-18 years were included if they had at least one drug prescription. Overall there were 658 prescriptions, primarily analgesics, psychotropics, asthma medications, and antibiotics. Except for one prescription, guidelines for dosage of overweight/obese children were not available in the clinic. In one prescription of gentamicin, the dose was adjusted by a metric body size. Otherwise dose was predominately prescribed either by total body weight or as fixed dose by age, in accordance with the recommendations of normal weight children. In drugs with a narrow therapeutic interval, we found large interindividual variations in dosing regimens, that is, for gentamicin, paracetamol, and prednisolone. Reduction of dose to the maximum recommended adult dose was common practice, when the dose calculated by total body weight (ie, mg/kg) exceeded this maximum. This study highlights the shortage of dosing guidelines in overweight/obese children. We found a large interindividual variability in dosage regimens, even in drugs with narrow therapeutic intervals. The clinicians rely on "best practice", as evidence-based dosage regimens are missing for many drugs prescribed during childhood. PMID- 29721325 TI - Regeneration mechanisms in Syllidae (Annelida). AB - Syllidae is one of the most species-rich groups within Annelida, with a wide variety of reproductive modes and different regenerative processes. Syllids have striking ability to regenerate their body anteriorly and posteriorly, which in many species is redeployed during sexual (schizogamy) and asexual (fission) reproduction. This review summarizes the available data on regeneration in syllids, covering descriptions of regenerative mechanisms in different species as well as regeneration in relation to reproductive modes. Our survey shows that posterior regeneration is widely distributed in syllids, whereas anterior regeneration is limited in most of the species, excepting those reproducing by fission. The latter reproductive mode is well known for a few species belonging to Autolytinae, Eusyllinae, and Syllinae. Patterns of fission areas have been studied in these animals. Deviations of the regular regeneration pattern or aberrant forms such as bifurcated animals or individuals with multiple heads have been reported for several species. Some of these aberrations show a deviation of the bilateral symmetry and antero-posterior axis, which, interestingly, can also be observed in the regular branching body pattern of some species of syllids. PMID- 29721327 TI - Investigation into the cellular origins of posterior regeneration in the annelid Capitella teleta. AB - Many animals can regenerate, although there is great diversity in regenerative capabilities. A major question in regenerative biology is determining the cellular source of newly formed tissue. The polychaete annelid, Capitella teleta, can regenerate posterior segments following transverse amputation. However, the source, behavior and molecular characteristics of the cells that form new tissue during regeneration are largely unknown. Using an indirect cell tracking method involving 5'-ethynyl-2'-deoxyuridine (EdU) incorporation, we show that cell migration occurs during C. teleta posterior regeneration. Expression of the multipotency/germ line marker CapI-vasa led us to hypothesize that stem cells originate from a multipotent progenitor cell (MPC) cluster, migrate through the coelomic cavity, and contribute to regeneration of tissue. We show that the capacity for posterior regeneration and segment formation is greater with than without the MPC cluster. Finally, we propose a working model of posterior regeneration in C. teleta. This work is the first in C. teleta that addresses the potential source of cells contributing to posterior regeneration, and may provide clues as to why some animals are highly successful regenerators. PMID- 29721328 TI - High throughput measurement of metabolism in planarians reveals activation of glycolysis during regeneration. AB - Planarians are outstanding models for studying mechanisms of regeneration; however, there are few methods to measure changes in their metabolism. Examining metabolism in planarians is important because the regenerative process is dependent on numerous integrated metabolic pathways, which provide the energy required for tissue repair as well as the ability to synthesize the cellular building blocks needed to form new tissue. Therefore, we standardized an extracellular flux analysis method to measure mitochondrial and glycolytic activity in live planarians during normal growth as well as during regeneration. Small, uninjured planarians showed higher rates of oxygen consumption compared with large planarians, with no difference in glycolytic activity; however, glycolysis increased during planarian regeneration. Exposure of planarians to koningic acid, a specific inhibitor of glyceraldehyde-3-phosphate dehydrogenase, completely abolished extracellular acidification with little effect on oxygen consumption, which suggests that the majority of glucose catabolized in planarians is fated for aerobic glycolysis. These studies describe a useful method for measuring respiration and glycolysis in planarians and provide data implicating changes in glucose metabolism in the regenerative response. PMID- 29721329 TI - Schistosoma haematobium, Plasmodium falciparum infection and anaemia in children in Accra, Ghana. AB - Background: Urinary Schistosomiasis and malaria are endemic in Sub-Saharan Africa. There are public health concerns and implications of these parasites. This study sought to assess the prevalence of malaria, urinary schistosomiasis, and anaemia in children of school going age in two municipalities in Ghana. Methods: A cross-sectional study design was used to investigate the prevalence of S. haematobium, P. falciparum infection and the haemoglobin concentration of respondents. A total of 404 (231 males and 173 females) school children between ages 9 - 14 years (mean age 11.8 +/- 1.4 years) were recruited for the survey. Urine and blood samples were collected using standard operating procedures for urinary schistosomiasis and malaria diagnosis. Haemoglobin concentration was measured using a Hemocue(r) Hb 201 m. Results: The prevalence of mono-infection was 4.7 and 12.9% for S. haematobium and P. falciparum respectively with a small proportion (0.9%) of the respondents infected with both parasites. The prevalence of anaemia in the study population was 59.9%. The risk of developing anaemia was not associated with being infected with any of the parasites. All co-infected children had anaemia. Conclusion: High prevalence of anaemia was observed within the study population. Prevalence of malaria was higher compared to schistosomiasis. Interventions to address the high levels of anaemia is required within the community. PMID- 29721326 TI - Axonal regeneration in zebrafish spinal cord. AB - In the present review we discuss two interrelated events-axonal damage and repair known to occur after spinal cord injury (SCI) in the zebrafish. Adult zebrafish are capable of regenerating axonal tracts and can restore full functionality after SCI. Unlike fish, axon regeneration in the adult mammalian central nervous system is extremely limited. As a consequence of an injury there is very little repair of disengaged axons and therefore functional deficit persists after SCI in adult mammals. In contrast, peripheral nervous system axons readily regenerate following injury and hence allow functional recovery both in mammals and fish. A better mechanistic understanding of these three scenarios could provide a more comprehensive insight into the success or failure of axonal regeneration after SCI. This review summarizes the present understanding of the cellular and molecular basis of axonal regeneration, in both the peripheral nervous system and the central nervous system, and large scale gene expression analysis is used to focus on different events during regeneration. The discovery and identification of genes involved in zebrafish spinal cord regeneration and subsequent functional experimentation will provide more insight into the endogenous mechanism of myelination and remyelination. Furthermore, precise knowledge of the mechanism underlying the extraordinary axonal regeneration process in zebrafish will also allow us to unravel the potential therapeutic strategies to be implemented for enhancing regrowth and remyelination of axons in mammals. PMID- 29721330 TI - Attitudes of people working in mental health non-governmental organisations in Australia: A comparison with other mental health professionals. AB - Research suggests that stigma impacts help-seeking behaviour and health outcomes for people affected by mental illness. This study compared the attitudes of Australian non-governmental organisation support workers towards people with mental illness with those of other health professionals. Three hundred and seventy four support workers were randomly allocated to answer questions about one of the six vignettes. Results indicated that non-governmental organisation support workers held more positive attitudes towards people with mental illness than those of general practitioners, psychiatrists and psychologists measured in prior research. These results suggest that non-governmental organisations may be a more positive and comfortable entry and referral point for mental health clients. PMID- 29721324 TI - The diversity of myeloid immune cells shaping wound repair and fibrosis in the lung. AB - In healthy circumstances the immune system coordinates tissue repair responses in a tight balance that entails efficient inflammation for removal of potential threats, proper wound closure, and regeneration to regain tissue function. Pathological conditions, continuous exposure to noxious agents, and even ageing can dysregulate immune responses after injury. This dysregulation can lead to a chronic repair mechanism known as fibrosis. Alterations in wound healing can occur in many organs, but our focus lies with the lung as it requires highly regulated immune and repair responses with its continuous exposure to airborne threats. Dysregulated repair responses can lead to pulmonary fibrosis but the exact reason for its development is often not known. Here, we review the diversity of innate immune cells of myeloid origin that are involved in tissue repair and we illustrate how these cell types can contribute to the development of pulmonary fibrosis. Moreover, we briefly discuss the effect of age on innate immune responses and therefore on wound healing and we conclude with the implications of current knowledge on the avenues for future research. PMID- 29721331 TI - The development of an occupational therapy intervention for adults with a diagnosed psychotic disorder following discharge from hospital. AB - Background: A deterioration in mental health and admission to an acute mental health unit can result in skill loss and decreased participation in daily life. Furthermore, discharge from hospital is associated with high risks of social isolation and suicide. This intervention development study aims to describe the rationale, methods and processes of developing an intervention for adults with a diagnosed psychotic disorder following discharge from hospital. The intervention aims to increase participation in self-care and leisure, wellbeing and quality of life and reduce crisis service use. Methods: The UK Medical Research Council framework for the development of complex interventions was used to guide the process of developing the intervention to ensure the developed intervention is empirically justifiable and evidence based. The development involved a systematic and literature reviews and focus groups with people with psychosis and clinical staff to understand the problems the intervention should address and approaches to resolving these. Results: A manualised 4-month intervention named Graduating Living skills Outside the Ward (GLOW) was developed for use by occupational therapists for people with a diagnosed psychotic disorder following discharge from hospital. The one-to-one stepped intensity intervention is of 4 months in duration and takes place in the person's home and in community locations. The intervention aims to increase occupational performance of domestic and personal self-care, leisure and some productive roles. Conclusions: The intervention developed in this study has potential to improve the efficiency of community mental health services following discharge from hospital as it is evidence-based, time-limited and manualised and aims to reduce hospital admissions and crisis service use. The intervention will be tested to assess its clinical and cost effectiveness in a randomised controlled trial. PMID- 29721332 TI - A pilot randomised double blind controlled trial of the efficacy of purified fatty acids for the treatment of women with endometriosis-associated pain (PurFECT): study protocol. AB - Background: Endometriosis affects 6-10% of women and is associated with debilitating pelvic pain. It costs the UK > L2.8 billion per year in loss of productivity. Endometriosis can be managed by surgical excision or medically by ovarian suppression. However, ~ 75% symptoms recur after surgery and available medical treatments have undesirable side effects and are contraceptive. Omega-3 purified fatty acids (PUFA) have been shown in animal models to reduce factors that are thought to lead to endometriosis-associated pain, have minimal side effects, and no effects on fertility. This paper presents a protocol for a two arm, pilot parallel randomised controlled trial (RCT) which aims to inform the planning of a future multicentre trial to evaluate the efficacy of Omega-3 PUFA in the management of endometriosis-associated pain in women. Methods: The study will recruit women with endometriosis over a 12-month period in the National Health Service (NHS) Lothian, UK, and randomise them to 8 weeks of treatment with Omega-3 PUFA or comparator (olive oil). The primary objective is to assess recruitment and retention rates. The secondary objectives are to determine the effectiveness/acceptability to participants of the proposed methods of recruitment/randomisation/treatments/questionnaires, to inform the sample size calculation and to refine the research methodology for a future large randomised controlled trial. Response to treatment will be monitored by pain scores and questionnaires assessing physical and emotional function compared at baseline and 8 weeks. Discussion: We recognise that there may be potential difficulties in mounting a large randomised controlled trial for endometriosis to assess Omega-3 PUFA because they are a dietary supplement readily available over the counter and already used by women with endometriosis. We have therefore designed this pilot study to assess practical feasibility and following the 'Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials' recommendations for the design of chronic pain trials. Trial registration: ISRCTN44202346. PMID- 29721334 TI - Ectopic Fgf signaling induces the intercalary response in developing chicken limb buds. AB - Background: Intercalary pattern formation is an important regulatory step in amphibian limb regeneration. Amphibian limb regeneration is composed of multiple steps, including wounding, blastema formation, and intercalary pattern formation. Attempts have been made to transfer insights from regeneration-competent animals to regeneration-incompetent animalsat each step in the regeneration process. In the present study, we focused on the intercalary mechanism in chick limb buds. In amphibian limb regeneration, a proximodistal axis is organized as soon as a regenerating blastema is induced. Intermediate structures are subsequently induced (intercalated) between the established proximal and distal identities. Intercalary tissues are derived from proximal tissues. Fgf signaling mediates the intercalary response in amphibian limb regeneration. Results: We attempted to transfer insights into intercalary regeneration from amphibian models to the chick limb bud. The zeugopodial part was dissected out, and the distal and proximal parts were conjunct at st. 24. Delivering ectopic Fgf2 + Fgf8 between the distal and proximal parts resulted in induction of zeugopodial elements. Examination of HoxA11 expression, apoptosis, and cell proliferation provides insights to compare with those in the intercalary mechanism of amphibian limb regeneration. Furthermore, the cellular contribution was investigated in both the chicken intercalary response and that of axolotl limb regeneration. Conclusions: We developed new insights into cellular contribution in amphibian intercalary regeneration, and found consistency between axolotl and chicken intercalary responses. Our findings demonstrate that the same principal of limb regeneration functions between regeneration-competent and -incompetent animals. In this context, we propose the feasibility of the induction of the regeneration response in amniotes. PMID- 29721333 TI - Diabetes mellitus and bone health: epidemiology, etiology and implications for fracture risk stratification. AB - Skeletal fractures can result when there are co-morbid conditions that negatively impact bone strength. Fractures represent an important source of morbidity and mortality, especially in older populations. Diabetes mellitus is a metabolic disorder that has reached worldwide epidemic proportions and is increasingly being recognized as a risk factor for fracture. Type 1 and Type 2 diabetes have different effects on bone mineral density but share common pathways, which lead to bone fragility. In this review, we discuss the available data on diabetes and fractures, bone density and the clinical implications for fracture risk stratification in current practice. PMID- 29721335 TI - Doctors' Knowledge of Hypertension Guidelines Recommendations Reflected in Their Practice. AB - Aim: To evaluate doctors' knowledge, attitude, and practices and predictors of adherence to Malaysian hypertension guidelines (CPG 2008). Methods: Twenty-six doctors involved in hypertension management at Penang General Hospital were enrolled in a cross-sectional study. Doctors' knowledge and attitudes towards guidelines were evaluated through a self-administered questionnaire. Their practices were evaluated by noting their prescriptions written to 520 established hypertensive outpatients (20 prescriptions/doctor). SPSS 17 was used for data analysis. Results: Nineteen doctors (73.07%) had adequate knowledge of guidelines. Specialists and consultants had significantly better knowledge about guidelines' recommendations. Doctors were positive towards guidelines with mean attitude score of 23.15 +/- 1.34 points on a 30-point scale. The median number of guidelines compliant prescriptions was 13 (range 5-20). Statistically significant correlation (rs = 0.635, P < 0.001) was observed between doctors' knowledge and practice scores. A total of 349 (67.1%) prescriptions written were guidelines compliant. In multivariate analysis hypertension clinic (OR = 0.398, P = 0.008), left ventricular hypertrophy (OR = 0.091, P = 0.001) and heart failure (OR = 1.923, P = 0.039) were significantly associated with guidelines adherence. Conclusion: Doctors' knowledge of guidelines is reflected in their practice. The gap between guidelines recommendations and practice was seen in the pharmacotherapy of uncomplicated hypertension and hypertension with left ventricular hypertrophy, renal disease, and diabetes mellitus. PMID- 29721336 TI - Impact of Admission Blood Glucose on Coronary Collateral Flow in Patients with ST Elevation Myocardial Infarction. AB - In patients with acute myocardial infarction, glucose metabolism is altered and acute hyperglycemia on admission is common regardless of diabetes status. The development of coronary collateral is heterogeneous among individuals with coronary artery disease. In this study, we aimed to investigate whether glucose value on admission is associated with collateral flow in ST-elevation myocardial infarction (STEMI) patients. We retrospectively evaluated 190 consecutive patients with a diagnosis of first STEMI within 12 hours of onset of chest pain. Coronary collateral development was graded according to Rentrop classification. Rentrop 0-1 was graded as poor collateral development, and Rentrop 2-3 was graded as good collateral development. Admission glucose was measured and compared between two groups. Mean admission glucose level was 173.0 +/- 80.1 mg/dl in study population. Forty-five (23.7%) patients had good collateral development, and 145 (76.3%) patients had poor collateral development. There were no statistically significant differences in demographic characteristics between two groups. Three-vessel disease was more common in patients with good collateral development (p=0.026). Mean admission glucose level was higher in patients with poor collateral than good collateral (180.6 +/- 84.9 mg/dl versus 148.7 +/- 56.6 mg/dl, resp., p=0.008). In univariate analysis, higher admission glucose was associated with poor collateral development, but multivariate logistic regression analysis revealed a borderline result (odds ratio 0.994, 95% CI 0.989-1.000, p=0.049). Our results suggest that elevated glucose on admission may have a role in the attenuation of coronary collateral blood flow in acute myocardial infarction. Further studies are needed to validate our results. PMID- 29721337 TI - Influence of Seasonality and Circulating Cytokines on Serial QuantiFERON Discordances. AB - Objectives. An 18-month prospective study serially tested healthcare workers (HCWs) for tuberculosis infection (TBI) and reported discordant QuantiFERON Gold In-Tube(r) (QFT) results in some participants. The purpose of the current study was to investigate whether the interferon-gamma (IFN-gamma) measured by QFT in discordant individuals could be influenced by other circulating cytokines that vary seasonally at the time of phlebotomy. Methods. The CDC funded TBESC Task Order 18 (TO18) project to assess the use of Interferon Gamma Release Assays (IGRAs), T-SPOT.TB(r) and QFT, compared to the tuberculin skin test (TST) for the serial testing of TBI in HCW at 4 US sites. Unstimulated plasma from 9 discordant TO18 participants at 4 different time points from the Houston site was multiplexed to determine the association between circulating cytokines and antigen stimulated IFN-gamma levels. Results. IL-12, IL-1beta, IL-3, GCSF, and IL 7 were associated with the amount of IFN-gamma measured in response to antigen stimulation. In addition to these cytokines, a significant relationship was found between a positive QFT result and the spring season. Conclusions. Allergens during the spring season can result in the upregulation of IL-1beta and IL-3, and this upregulation was observed with the amount of IFN-gamma measured in discordant results. PMID- 29721338 TI - Decision-Making in Multiple Sclerosis Patients: A Systematic Review. AB - Background: Multiple sclerosis (MS) is frequently associated with cognitive and behavioural deficits. A growing number of studies suggest an impact of MS on decision-making abilities. The aim of this systematic review was to assess if (1) performance of MS patients in decision-making tasks was consistently different from controls and (2) whether this modification was associated with cognitive dysfunction and emotional alterations. Methods: The search was conducted on Pubmed/Medline database. 12 studies evaluating the difference between MS patients and healthy controls using validated decision-making tasks were included. Outcomes considered were quantitative (net scores) and qualitative measurements (deliberation time and learning from feedback). Results: Quantitative and qualitative decision-making impairment in MS was present in 64.7% of measurements. Patients were equally impaired in tasks for decision-making under risk and ambiguity. A correlation to other cognitive functions was present in 50% of cases, with the highest associations in the domains of processing speed and attentional capacity. Conclusions: In MS patients, qualitative and quantitative modifications may be present in any kind of decision-making task and can appear independently of other cognitive measures. Since decision-making abilities have a significant impact on everyday life, this cognitive aspect has an influential importance in various MS-related treatment settings. PMID- 29721339 TI - The Effect of Therapeutic Exercise on Long-Standing Adductor-Related Groin Pain in Athletes: Modified Holmich Protocol. AB - Objective: The Holmich protocol in therapeutic exercise is the most appropriate method for the treatment of long-standing adductor-related groin pain (LSAGP). Herein, we evaluated a modified Holmich protocol to resolve the possible limitations intrinsic to the Holmich protocol in terms of the rate of return to sport and the recovery period for athletes with LSAGP. Design: The study followed a single-blind, before/after study design, where 15 athletes with LSAGP (mean age = 26.13 years; SD = 4.48) performed a 10-week modified Holmich therapeutic exercise protocol. Results: Outcome scores related to pain, hip adductor and abductor muscle strengths, and the ratio of maximum isometric and eccentric hip adduction to abduction strength increased significantly. Likewise, hip abduction and internal rotation ROM improved significantly compared to that at baseline. Furthermore, functional records (t-test, Edgren Side Step Test, and Triple Hop Test) showed significant improvement after treatment. Finally, 13 athletes (86.6% of the participants) successfully returned to sports activity in a mean time of 12.06 weeks (SD = 3.41). Conclusion: The findings of this study objectively show that the modified Holmich protocol may be safer and more effective than the Holmich protocol in athletes with LSAGP in promoting their return to sports activity. This trial is registered with IRCT2016080829269N1. PMID- 29721340 TI - Miniplate-Aided Mandibular Dentition Distalization as a Camouflage Treatment of a Class III Malocclusion in an Adult. AB - This case report describes orthodontic camouflage treatment for a 32-year-old African American male patient with Class III malocclusion. The treatment included nonextraction, nonsurgical orthodontic camouflage by en masse distalization of the mandibular teeth using skeletal anchorage devices. The total treatment time was 23 months. Normal overjet and overbite with Class I occlusion were obtained despite the compensated dentition to the skeletal malocclusion. His smile esthetics was significantly improved at the completion of his treatment. PMID- 29721341 TI - Bilateral Carotid and Vertebral Artery Dissection from Blunt Trauma. AB - Carotid and vertebral artery injuries are rare following blunt trauma. They can, however, lead to severe consequences with a significant associated rate of stroke and intracranial hemorrhage, particularly if the diagnosis and treatment are delayed. We report a case of a 23-year-old female who presented to the Emergency Department with bilateral carotid and vertebral artery dissection following a motor vehicle collision (MVC). PMID- 29721342 TI - Hepatotoxicity Associated with Use of the Weight Loss Supplement Garcinia cambogia: A Case Report and Review of the Literature. AB - The use of herbal and dietary supplements for weight loss is becoming increasingly common as obesity is becoming major health problem in the United States. Despite the popularity of these natural supplements, there are no guidelines for their therapeutic doses and their safety is always a concern. Garcinia cambogia extract with its active ingredient "hydroxycitric acid" is a component of many weight loss regimens. It suppresses fatty acid biosynthesis and decreases appetite. However, its prolonged use in weight maintenance is unknown. Here we describe a case of acute hepatitis after the use of Garcinia cambogia for weight loss. PMID- 29721343 TI - Secondary Chondrosarcoma Presenting with Symptoms Similar to Thoracic Outlet Syndrome. AB - Thoracic outlet syndrome (TOS) is caused by heterogeneous factors that compress the brachial plexus and subclavian artery; tumor is rarely a cause of TOS. Here, we present the case of a 26-year-old man with secondary chondrosarcoma arising from osteochondroma of the left clavicle causing TOS, with a direct compression of the brachial plexus and subclavian artery. Immediately after surgery, the symptoms of TOS reduced. To our knowledge, this is the first case of a secondary chondrosarcoma of the clavicle causing TOS, which is possibly the key symptom for diagnosing malignant transformation of osteochondroma of the clavicle. PMID- 29721344 TI - Urethral Duplication with a Cystic Phallic Urethra Associated with a Uterus Didelphys, Partial Agenesis of the Tibia, and an Equinovarus Foot. AB - Urethral duplication is a rare congenital malformation, especially in females. It may be associated with complex urogenital malformations, but the association with a cystic phallic urethra and a uterus didelphys is exceptional. We report a case of a newborn with urethral duplication, with the accessory urethra exteriorized by a large cyst, associated with a uterus didelphys and bone malformations. We discuss the clinical, radiographic, and therapeutic aspects as well as a literature review. PMID- 29721345 TI - A Midgut Duplication Cyst Lined by Respiratory Epithelium. AB - Duplication cysts are an uncommon finding. Majority of these cases are found in the region of the midgut, and many have been reported in literature. However, there has been only one previous case of a midgut duplication cyst lined by respiratory epithelium. This is a rare pathology, of which very little is known about. The pathophysiology of these cases is also difficult to explain. We aim to present a case of a midgut duplication cyst in a paediatric patient, who had other abnormalities as well. We also aim to offer a hypothesis for this case. PMID- 29721346 TI - HSCT-GAVE as a Manifestation of Chronic Graft versus Host Disease: A Case Report and Review of the Existing Literature. AB - Gastric antral vascular ectasia or "watermelon stomach" is a significant cause of nonvariceal upper GI bleeding and is characterized by red, tortuous ectatic vessels along longitudinal folds in the gastric antrum. The existing literature links GAVE to patients with cirrhosis, scleroderma, bone marrow transplantation, and chronic renal failure among other associations, but its pathophysiology remains ill-defined. Over 30 cases of hematopoietic stem cell transplant-related GAVE (HSCT-GAVE) have been reported in the literature to date and there are likely many more that go undiagnosed or are attributed to another cause of upper gastrointestinal bleeding. Interestingly, a busulfan-containing conditioning regimen has been the primary factor implicated in the etiology of HSCT-GAVE because this was common to all cases in the literature to date. Here, we present the first case of HSCT-GAVE in a patient that was treated with a non-busulfan containing conditioning regimen. We propose a link between chronic GVHD and the development of HSCT-GAVE that is supported by a similar development of GAVE in patients with systemic sclerosis. PMID- 29721347 TI - Endoscopic surgery via a combined frontal and suboccipital approach for cerebellar hemorrhage. AB - Background: Spontaneous cerebellar hemorrhages (CHs), which frequently require surgical intervention, are life-threatening and can be complicated by intraventricular hemorrhages (IVHs) and obstructive hydrocephalus. Commonly, endoscopic surgery is performed to remove CHs via a suboccipital approach (SA) alone. At our institution, when patients exhibited supratentorial IVH-associated hydrocephalus, we used a combined frontal and suboccipital approach (CA) to evacuate both CHs and supratentorial IVHs. The present study retrospectively evaluated the effectiveness and safety of this CA, as no prior studies examining this approach currently exist. Methods: Twenty-six patients with spontaneous CH were surgically treated at our hospital from April 2009 to March 2016. Twenty-two patients who could independently perform activities of daily living before the onset underwent endoscopic surgery to evacuate the CHs; among these, 13 patients underwent the SA alone, while nine underwent the CA. We assessed and compared the patients' baseline characteristics, surgical results, and prognosis at 1 month after the intervention between the SA and CA groups. Results: Patients who underwent the CA had significantly poorer consciousness before the surgery owing to IVH extension and obstructive hydrocephalus. However, the surgical results and prognosis at 1 month were not significantly different between the two approaches. The CH-associated IVHs were successfully removed with the CA and resulted in shorter external ventricular drainage (EVD) placement durations. Conclusion: Endoscopic surgery performed via the CA appeared to neutralize the deteriorating effects of CH-associated IVHs. Surgical strategies employing the CA may have the potential to improve the prognosis of patients with CH. PMID- 29721348 TI - Atypical epidural hemangiopericytoma presenting with visual disturbance. AB - Background: Hemangiopericytomas are a rare entity commonly presenting as subdural tumors. Case Description: A 57-year-old man presented with a progressive visual disturbance over a period of 3 weeks. Cranial computed tomography scans revealed an isodense mass at the tip of the left middle fossa, extending into the orbital apex, and accompanying bony erosions in the sphenoid ridge. On magnetic resonance imaging, the lesion appeared isointense both on T1- and T2-weighted sequences, and intensely enhanced on contrast examinations. A frontotemporal craniotomy revealed a dura-based, capsulized tumor located entirely in the epidural space. A gross total resection was achieved for the tumor and histologically verified as hemangiopericytoma. Conclusion: Hemangiopericytoma should be assumed in a differential diagnosis when encountering epidural tumors, and total resection should be attempted when possible. PMID- 29721349 TI - Abscess due to textiloma (gossypiboma: Retained surgical cottonoid). AB - Background: Surgical site infections following spinal surgery, including spinal abscesses, are rare but serious as they are major causes of morbidity, and even mortality. They are, however, rarely attributed to infected, retained surgical cottonoids or sponges (textiloma or gossypiboma) inadvertently left in an operative field. Case Description: A 53-year-old female with a history of two prior spinal operations at the L4-S1 levels (11 and 2 years previously) presented over a few weeks with the acute onset of a cauda equina syndrome (e.g., paraparesis and acute urinary incontinence). The patient demonstrated a mildly elevated white blood cell count (12,600/mm3) and abnormally increased C-reactive protein level that correlated with the magnetic resonance imaging that showed a dorsal epidural abscess extending from the L4 to S1 levels. At surgery, an encapsulated posterior epidural abscess was drained. Surgical findings included a granulomatous lesion consistent with a retained surgical cottonoid and was removed from the antero-inferior portion of the abscess wall at S1. Culture of the thick fibrotic abscess wall grew Klebsiella oxytoca. After 2 months of ciprofloxacin, the patient's infection cleared but the motor deficit only partially resolved. Conclusion: Most spinal textilomas (gossypibomas) are aseptic and are found in paraspinal areas without neurological symptoms or sequelae. These lesions may remain silent for years and may only rarely cause neurologic or infectious symptoms/signs. Notably, textilomas following spinal surgery may be largely avoided if proper cottonoid and sponge counts are done prior to closing spinal wounds. PMID- 29721351 TI - Resolution of symptomatic secondary empty sella syndrome following lumbar peritoneal shunt. AB - Background: Post-surgical empty sella is related to the removal of pituitary tumors either from the transcranial or transphenoidal route, rendering diaphragma sellae incompetent at the end of the procedure. This subsequently leads to herniation of the third ventricle and optic apparatus into the empty sella. Studies have shown that in 50% of the cases, individuals with primary and secondary empty sella syndrome have developed defects in the visual fields. Benign increased intracranial pressure, cerebrospinal rhinorrhea, papilledema, and abnormalities affecting visual acuity may also occur as a result of empty sella. Case Description: This case report discusses a rare treatment option for the symptomatic secondary empty sella syndrome. Patient underwent lumbar drain placement and that resulted in astonishingly significant improvement in vision. Keeping in view the beneficial effect of lumbar drain, lumbar-peritoneal (LP) shunt was inserted which showed drastic improvement in vision. Conclusion: The surgical outcome of symptomatic cases of ESS is favorable. Various common surgical options were reported in literature; however, we have discussed an unconventional surgical option with an impressive outcome. PMID- 29721350 TI - The impact of neurosurgical procedure on cognitive resources: Results of bypass training. AB - Background: Neurosurgeons are exposed to unavoidable distractions in their natural operating environment. Distractions can affect both the surgeon's concentration and the safety and duration of the surgery. Such distraction can be studied by applying a simultaneous cognitive task during a surgical procedure. Methods: We used a previously described cognitive task: a forward (DF) and backward digit (DB) repetition task to interfere with the surgeon's attention during a training bypass. A pilot study was performed to find suitable digit repetition lengths. For the main experiment, we used four-digit strings. The test task was alternated across two consecutive sutures (n = 153, 8 bypasses), followed by two consecutive control sutures without digit repetition. The duration and the number of correct answers for the digit repetition task were compared to a baseline digit repetition without simultaneous surgery. Results: During the bypass surgery, digit repetitions (especially DB) became slower (P < 0.0001). More errors were made during DB compared to DF only during simultaneous bypass (P < 0.0001). However, we found no effect of digit repetition tasks on individual suture times (P = 0.823). Conclusions: The ability to engage in simultaneous tasks while performing surgery is diminished. A surgeon with extensive training can withstand external distraction without an effect on performance; however, this is achieved by partially ignoring the simultaneous task. Our data support that during surgery other cognitive tasks should be avoided to ensure safety. PMID- 29721352 TI - Dorsal hemangioblastoma manifesting as holocord syringomyelia. AB - Background: Intramedullary spinal hemangioblastomas are known to be accompanied by syringomyelia. Case Description: Here, we report a patient who presented with symptoms of a Chiari malformation but was found to have a D4 intramedullary hemangioblastoma with a holocord syrinx. Conclusions: Although rare, neurosurgeons should keep in mind the possibility of an intramedullary hemangioblastoma in patients presenting with symptoms of a Chiari malformation. PMID- 29721354 TI - Unilateral S2 alar-iliac screws for spinopelvic fixation. AB - Background: This study compared the clinical complications, radiographic measurements of deformity, and quality of life outcomes for patients with de novo scoliosis undergoing thoracolumbar fusions for spinopelvic fixation (SPF) utilizing unilateral S2 alar-iliac (S2AI) screw or unilateral iliac bolt fixation. Methods: This retrospective review was performed in 29 patients who underwent SPF at one institution; 10 patients received unilateral S2AI screws, and 19 patients received unilateral iliac bolts. The following variables were studied: reoperation rates, pseudarthrosis, sacral insufficiency fracture, hardware prominence, infection, proximal junctional kyphosis (PJK), deformity correction (radiographs), windshield wipering, hardware fracture, and hardware removal. Outcomes were analyzed utilizing both the visual analog scale (VAS) and Oswestry Disability Index (ODI). The mean follow-up period was 27 months. Results: The reoperation rate for unilateral S2AI screws was 30% vs. 53% for unilateral iliac bolts (P = 0.43); reoperations were performed with a 1:5 ratio for infection, a 1:4 ratio for pseudarthrosis, and 1:1 a ratio for PJK comparing S2AI screws to iliac bolts, respectively. Conclusion: There were no significant differences in postoperative complications and reoperation rates between unilateral S2AI screws and unilateral iliac bolts utilized for SPF. For the S2AI screw group, there were no instances of hardware prominence or need for removal. The use of unilateral S2AI screws resulted in adequate fixation and comparably low complication rates. PMID- 29721355 TI - Pituitary fossa chondrosarcoma: An unusual cause of a sellar suprasellar mass masquerading as pituitary adenoma. AB - Background: Chondrosarcoma is a mesenchymal malignant tumor composed of tumor cells producing cartilage. It is more commonly found in older age group and usually affects the axial skeleton. Intracranial chondrosarcoma is extremely rare, and chondrosarcoma arising from the sellar region are even rarer with only a few cases described in the literature. We report a case of chondrosarcoma mimicking a sellar suprasellar mass with parasellar extension. Case Description: A 22-year old male presented with generalized intermittent headache along with diplopia and diminished visual acuity without any history of sexual dysfunction or galactorrhea. His endocrine tests were within normal limits. Magnetic resonance imaging of the brain revealed a large mass which was apparently arising from the sella with a significant suprasellar and left parasellar component with mild compression over the left optic chiasm and deviation of infundibulum to the right. The patient underwent pterional craniotomy and decompression of the mass. The pathologic diagnosis was chondrosarcoma. The patient received postoperative radiotherapy. Conclusion: This case demonstrates that chondrosarcoma of the sellar region may mimic clinical, endocrinological, and radiological features of more commonly encountered lesions in this region such as nonfunctioning pituitary tumor, craniopharyngioma, meningioma, or chordoma. We discuss the origin, areas of involvement, management, and long-term prognosis of these rare tumors. PMID- 29721356 TI - Accuracy of percutaneous pedicle screw insertion in spinal fixation of traumatic thoracic and lumbar spine fractures. AB - Background: Percutaneous insertion of pedicle screws was developed as a minimally invasive alternative to the different open spinal procedures. Here, we determined the accuracy of percutaneous pedicle screw insertion. Methods: For 60 consecutive patients with thoracic/lumbar spine fractures, computed tomography (CT) studies were utilized to assess the accuracy of percutaneous pedicle screw positioning. A screw was identified as cortical encroachment if the pedicle cortex could not be visualized, while Frank penetration was defined if screw trajectory being located obviously outside the pedicle boundaries [e.g., subdivided as minor (<3 mm), moderate (3-6 mm), and severe (>6 mm)]. Results: Sixty patients received 410 pedicle screws placed percutaneously. Of these, 294 screws (71.7%) were ideally placed inside the pedicle. Alternatively, 56 screws (13.6%: 18 cases) showed pedicle encroachment and 60 screws (14.6%: 23 cases) showed pedicle penetration, e.g., 38 (9.2%) minor penetration and 22 (5.3%) were malpositioned (4.8% moderate and 0.5% severe). New postoperative neurological symptoms were identified in two cases (3.3%), where severe screw penetration was identified. Conclusion: Percutaneous pedicle screw insertion in 60 patients receiving 410 percutaneously placed pedicle screws yielded 294 ideally placed, 56 showing pedicle encroachment, 60 (14.3%, 23 cases) exhibiting varying degrees of pedicle penetration, with 2 showing new postoperative neurological deficits (severe screw misplacement). Of interest, this technique proved to be more challenging in the thoracic spine. Larger series are needed to better establish the average rate of neurological injuries associated with percutaneous thoracic/lumbar screw misplacement. PMID- 29721357 TI - Spinal angiolipoma mimicking a schwannoma: A case report. AB - Background: Angiolipomas rarely involve the spinal canal/foramina, and may prove difficult to differentiate from schwannomas. Case Description: Here we report a patient who presented with a spinal angiolipoma contributing to spinal cord and neural foraminal compression that was difficult to differentiate from a schwannoma. Conclusion: Spinal angiolipomas rarely involve the spinal canal/foramina. Utilizing neurodiagnostic studies with pathological confirmation, these lesions may be differentiated from schwannomas. PMID- 29721358 TI - Mirror image of bilateral DACA aneurysm with its successful surgical management. AB - Background: Among various locations of intracranial aneurysms reported in the literature, two different aneurysms situated symmetrically opposite on bilateral distal anterior cerebral arteries (DACA) are very rare. Case Description: Here, we report a rare case of mirror image distal anterior cerebral aneurysm in a middle-aged male patient. The patient presented with severe headache and loss of consciousness. Angiography was done which suggested mirror imaging of two aneurysms located over both DACA. It was treated through microsurgical approach with a successful outcome. Conclusion: Careful analysis of intracranial vasculature should be done using angiography, particularly in different views and stages to rule out multiple aneurysms at different locations in the same artery or at different arteries. Mirror images of bilateral DACA aneurysms are very rare. Fundamental surgical strategy of securing the parent artery and clipping the neck after meticulous dissection should be followed. PMID- 29721359 TI - Acute cauda equina syndrome following orthopedic procedures as a result of epidural anesthesia. AB - Background: Cauda equina syndrome (CES) is a rare complication of spinal or epidural anesthesia. It is attributed to direct mechanical injury to the spinal roots of the cauda equina that may result in saddle anesthesia and paraplegia with bowel and bladder dysfunction. Case Description: The first patient underwent a hip replacement and received 5 mL of 1% lidocaine epidural anesthesia. Postoperatively, when the patient developed an acute CES, the lumbar magnetic resonance imaging (MRI) scan demonstrated clumping/posterior displacement of nerve roots of the cauda equina consistent with adhesive arachnoiditis attributed to the patient's previous L4-L5 lumbar decompression/fusion. The second patient underwent spinal anesthesia (injection of 10 mg of isobaric bupivacaine for an epidural block) for a total knee replacement. When the patient developed an acute CES following surgery, the lumbar MRI scan showed an abnormal T2 signal in the conus and lower thoracic spinal cord over 4.3 cm. Conclusions: Acute CES should be considered in patients undergoing spinal or epidural anesthesia for joint replacement surgery. Prompt evaluation with MRI studies may lead to appropriate medical/surgical measures to reverse the deficit. PMID- 29721353 TI - Immunoexcitotoxicity as the central mechanism of etiopathology and treatment of autism spectrum disorders: A possible role of fluoride and aluminum. AB - Our review suggests that most autism spectrum disorder (ASD) risk factors are connected, either directly or indirectly, to immunoexcitotoxicity. Chronic brain inflammation is known to enhance the sensitivity of glutamate receptors and interfere with glutamate removal from the extraneuronal space, where it can trigger excitotoxicity over a prolonged period. Neuroscience studies have clearly shown that sequential systemic immune stimulation can activate the brain's immune system, microglia, and astrocytes, and that with initial immune stimulation, there occurs CNS microglial priming. Children are exposed to such sequential immune stimulation via a growing number of environmental excitotoxins, vaccines, and persistent viral infections. We demonstrate that fluoride and aluminum (Al3+) can exacerbate the pathological problems by worsening excitotoxicity and inflammation. While Al3+ appears among the key suspicious factors of ASD, fluoride is rarely recognized as a causative culprit. A long-term burden of these ubiquitous toxins has several health effects with a striking resemblance to the symptoms of ASD. In addition, their synergistic action in molecules of aluminofluoride complexes can affect cell signaling, neurodevelopment, and CNS functions at several times lower concentrations than either Al3+ or fluoride acting alone. Our review opens the door to a number of new treatment modes that naturally reduce excitotoxicity and microglial priming. PMID- 29721360 TI - Psychological Aspects of Utilizing Telecytology for Rapid On-Site Adequacy Assessments. AB - Rapid On-Site Evaluation (ROSE) has been well documented in its ability to improve the diagnostic yield and accuracy of fine needle aspirations across many sites, resulting in better quality of patient management and a simultaneous reduction in treatment costs. Telecytology makes it possible for cytology laboratories to offer ROSE in a cost effective manner, whilst employing only a small number of trained cytopathologists to cover many sites from a single connected location. However, the adoption of telecytology for ROSE has been lackluster. We believe that this reluctance is not only due to barriers such as technology limitations and financial obstacles, but also due to overlooked psychological factors. This article discusses the unaddressed psychological considerations of telecytology for ROSE. PMID- 29721361 TI - Constant Quest for Quality: Digital Cytopathology. AB - Background: Special consideration should be given when creating and selecting cytopathology specimens for digitization to maximize quality. Advances in scanning and viewing technology can also improve whole-slide imaging (WSI) output quality. Methods: Accumulated laboratory experience with digitization of glass cytopathology slides was collected. Results: This paper describes characteristics of a cytopathology glass slide that can reduce quality on resulting WSI. Important points in the glass cytopathology slide selection process, preparation, scanning, and WSI-editing process that will maximize the quality of the resulting acquired digital image are covered. The paper outlines scanning solutions which have potential to predict issues with a glass cytopathology slide before image acquisition, allowing for adjustment of the scanning approach. WSI viewing solutions that better simulate the traditional microscope experience are also discussed. Conclusion: In addition to taking advantage of technical advances, practical steps can taken to maximize quality of cytopathology WSI. PMID- 29721362 TI - Career Paths of Pathology Informatics Fellowship Alumni. AB - Background: The alumni of today's Pathology Informatics and Clinical Informatics fellowships fill diverse roles in academia, large health systems, and industry. The evolving training tracks and curriculum of Pathology Informatics fellowships have been well documented. However, less attention has been given to the posttraining experiences of graduates from informatics training programs. Here, we examine the career paths of subspecialty fellowship-trained pathology informaticians. Methods: Alumni from four Pathology Informatics fellowship training programs were contacted for their voluntary participation in the study. We analyzed various components of training, and the subsequent career paths of Pathology Informatics fellowship alumni using data extracted from alumni provided curriculum vitae. Results: Twenty-three out of twenty-seven alumni contacted contributed to the study. A majority had completed undergraduate study in science, technology, engineering, and math fields and combined track training in anatomic and clinical pathology. Approximately 30% (7/23) completed residency in a program with an in-house Pathology Informatics fellowship. Most completed additional fellowships (15/23) and many also completed advanced degrees (10/23). Common primary posttraining appointments included chief medical informatics officer (3/23), director of Pathology Informatics (10/23), informatics program director (2/23), and various roles in industry (3/23). Many alumni also provide clinical care in addition to their informatics roles (14/23). Pathology Informatics alumni serve on a variety of institutional committees, participate in national informatics organizations, contribute widely to scientific literature, and more than half (13/23) have obtained subspecialty certification in Clinical Informatics to date. Conclusions: Our analysis highlights several interesting phenomena related to the training and career trajectory of Pathology Informatics fellowship alumni. We note the long training track alumni complete in preparation for their careers. We believe flexible training pathways combining informatics and clinical training may help to alleviate the burden. We highlight the importance of in-house Pathology Informatics fellowships in promoting interest in informatics among residents. We also observe the many important leadership roles in academia, large community health systems, and industry available to early career alumni and believe this reflects a strong market for formally trained informaticians. We hope this analysis will be useful as we continue to develop the informatics fellowships to meet the future needs of our trainees and discipline. PMID- 29721363 TI - Prolonged survival of transplanted stem cells after ischaemic injury via the slow release of pro-survival peptides from a collagen matrix. AB - Stem-cell-based therapies hold considerable promise for regenerative medicine. However, acute donor-cell death within several weeks after cell delivery remains a critical hurdle for clinical translation. Co-transplantation of stem cells with pro-survival factors can improve cell engraftment, but this strategy has been hampered by the typically short half-lives of the factors and by the use of Matrigel and other scaffolds that are not chemically defined. Here, we report a collagen-dendrimer biomaterial crosslinked with pro-survival peptide analogues that adheres to the extracellular matrix and slowly releases the peptides, significantly prolonging stem cell survival in mouse models of ischaemic injury. The biomaterial can serve as a generic delivery system to improve functional outcomes in cell-replacement therapy. PMID- 29721364 TI - Audio Recording for Independent Confirmation of Clinical Assessments in Generalized Anxiety Disorder. AB - Objective: The assessment of patients with generalized anxiety disorder (GAD) to deteremine whether a medication intervention is necessary is not always clear and might benefit from a second opinion. However, second opinions are time consuming, expensive, and not practical in most settings. We obtained independent, second opinion reviews of the primary clinician's assessment via audio-digital recording. Design: An audio-digital recording of key site-based assessments was used to generate site-independent "dual" reviews of the clinical presentation, symptom severity, and medication requirements of patients with GAD as part of the screening procedures for a clinical trial (ClinicalTrials.gov: NCT02310568). Results: Site-independent reviewers affirmed the diagnosis, symptom severity metrics, and treatment requirements of 90 moderately ill patients with GAD. The patients endorsed excessive worry that was hard to control and essentially all six of the associated DSM-IV-TR anxiety symptoms. The Hamilton Rating Scale for Anxiety scores revealed moderately severe anxiety with a high Pearson's correlation (r=0.852) between site-based and independent raters and minimal scoring discordance on each scale item. Based upon their independent reviews, these "second" opinions confirmed that these GAD patients warranted a new medication intervention. Thirty patients (33.3%) reported a previous history of a major depressive episode (MDE) and had significantly more depressive symptoms than patients without a history of MDE. Conclusion: The audio-digital recording method provides a useful second opinion that can affirm the need for a different treatment intervention in these anxious patients. A second live assessment would have required additional clinic time and added patient burden. The audio-digital recording method is less burdensome than live second opinion assessments and might have utility in both research and clinical practice settings. PMID- 29721365 TI - Interleukin 10 (IL10) proximal promoter polymorphisms beyond clinical response in classical Hodgkin lymphoma: Exploring the basis for the genetic control of the tumor microenvironment. AB - Interleukin-10 (IL10) is an immune regulatory cytokine. Single nucleotide polymorphisms (SNPs) in IL10 promoter have been associated with prognosis in adult classical Hodgkin lymphoma (cHL). We analyzed IL10 SNPs -1082 and -592 in respect of therapy response, gene expression and tumor microenvironment (TME) composition in 98 pediatric patients with cHL. As confirmatory results, we found that -1082AA/AG; -592CC genotypes and ATA haplotype were associated with unfavourable prognosis: Progression-free survival (PFS) was shorter in -1082AA+AG (72.2%) than in GG patients (100%) (P = 0.024), and in -592AA (50%) and AC (74.2%) vs. CC patients (87.0%) (P = 0.009). In multivariate analysis, the -592CC genotype and the ATA haplotype retained prognostic impact (HR: 0.41, 95% CI 0.2 0.86; P = 0.018, and HR: 3.06 95% CI 1.03-9.12; P = 0.044, respectively). Our analysis further led to some new observations, namely: (1) Low IL10 mRNA expression was associated with -1082GG genotype (P = 0.014); (2) IL10 promoter polymorphisms influence TME composition;-1082GG/-592CC carriers showed low numbers of infiltrating cells expressing MAF transcription factor (20 vs. 78 and 49 vs. 108 cells/mm2, respectively; P< 0.05); while ATA haplotype (high expression) associated with high numbers of MAF+ cells (P = 0.005). Specifically, -1082GG patients exhibited low percentages of CD68+MAF+ (M2-like) intratumoral macrophages (15.04% vs. 47.26%, P = 0.017). Considering ours as an independent validation cohort, our results give support to the clinical importance of IL10 polymorphisms in the full spectrum of cHL, and advance the concept of genetic control of microenvironment composition as a basis for susceptibility and therapeutic response. PMID- 29721366 TI - TNFa and IL-2 armed adenoviruses enable complete responses by anti-PD-1 checkpoint blockade. AB - Releasing the patient's immune system against their own malignancy by the use of checkpoint inhibitors is delivering promising results. However, only a subset of patients currently benefit from them. One major limitation of these therapies relates to the inability of T cells to detect or penetrate into the tumor resulting in unresponsiveness to checkpoint inhibition. Virotherapy is an attractive tool for enabling checkpoint inhibitors as viruses are naturally recognized by innate defense elements which draws the attention of the immune system. Besides their intrinsic immune stimulating properties, the adenoviruses used here are armed to express tumor necrosis factor alpha (TNFa) and interleukin 2 (IL-2). These cytokines result in immunological danger signaling and multiple appealing T-cell effects, including trafficking, activation and propagation. When these viruses were injected into B16.OVA melanoma tumors in animals concomitantly receiving programmed cell-death protein 1 (PD-1) blocking antibodies both tumor growth control (p < 0.0001) and overall survival (p < 0.01) were improved. In this set-up, the addition of adoptive cell therapy with OT-I lymphocytes did not increase efficacy further. When virus injections were initiated before antibody treatment in a prime-boost approach, 100% of tumors regressed completely and all mice survived. Viral expression of IL2 and TNFa altered the cytokine balance in the tumor microenvironment towards Th1 and increased the intratumoral proportion of CD8+ and conventional CD4+ T cells. These preclinical studies provide the rationale and schedule for a clinical trial where oncolytic adenovirus coding for TNFa and IL-2 (TILT-123) is used in melanoma patients receiving an anti-PD-1 antibody. PMID- 29721367 TI - Tumor-derived thymic stromal lymphopoietin enhances lung metastasis through an alveolar macrophage-dependent mechanism. AB - It is well-recognized that macrophages, which arise from circulating precursors, enhance tumor progression in patients and animal models. However, less is known regarding the role of tissue-resident macrophages in metastasis. Moreover, the identification of tumor factors which influence macrophage function in the metastatic niche remains incomplete. Here, we investigated one such cytokine known as thymic stromal lymphopoietin (TSLP). Our rationale to focus on TSLP was based on two non-overlapping findings; first, TSLP exacerbates asthma in part by altering the lung macrophage response and, secondly, TSLP is produced by certain mouse and human tumor systems, although its role in neoplasia remains understudied. Thus, we tested the hypothesis that tumor-derived TSLP augments lung metastasis by rendering alveolar macrophages pro-tumorigenic. To test this hypothesis, we principally employed the 4T1 tumor model, which produces high levels of TSLP and metastasizes to the lung. TSLP loss-of-function significantly reduced spontaneous lung metastasis, as well as lung colonization. Moreover, similar outcomes were observed in both wild-type and immune-deficient hosts, suggesting that TSLP acted on innate immune cells such as macrophages. To test this notion, pharmacologic depletion of alveolar macrophages significantly reduced lung tumor growth of the TSLP-expressing, but not TSLP-deficient tumor population. In contrast, depleting macrophages originating from the circulation did not impact lung tumor growth. Lastly, TSLP increased the invasive and angiogenic gene expression profile of the alveolar macrophage population. Altogether, our study identified a novel TSLP-alveolar macrophage axis in lung metastasis, which offers new insights into mechanisms of metastasis and potential therapeutic targets. PMID- 29721368 TI - Cell-surface vimentin-positive macrophage-like circulating tumor cells as a novel biomarker of metastatic gastrointestinal stromal tumors. AB - The clinical utility of circulating tumor cells (CTCs) has been investigated in numerous publications, but CTCs that express very typical immune cell markers have not been reported. Here we report a novel class of CTCs-CSV-positive macrophage-like CTCs (ML-CTCs). This nomenclature was based on the fact that this class of CTCs can be captured from blood samples of gastrointestinal stromal tumors (GISTs) patients using either the macrophage marker CD68 or our proprietary tumor-specific cell-surface vimentin (CSV) antibody 84-1; likewise, the captured ML-CTCs can be co-stained with both typical macrophage markers (CD14, CD68) and tumor cell markers (DOG-1, C-kit) but not CD45. Patients with metastatic GIST had significantly greater numbers of ML-CTCs than patients with localized GIST or cancer-free blood donors (P<0.0001). Unexpectedly, the classic CSV positive CTCs was abundant in metastatic disease but failed to predict GIST metastasis. Only CSV-positive ML-CTCs was able to serve as a solid and novel biomarker for prediction of metastatic risk in GIST patients. PMID- 29721369 TI - Specific ADAM10 inhibitors localize in exosome-like vesicles released by Hodgkin lymphoma and stromal cells and prevent sheddase activity carried to bystander cells. AB - Shedding of ADAM10 substrates, like TNFalpha, MICA or CD30, is reported to affect both anti-tumor immune response and antibody-drug-conjugate (ADC)-based immunotherapy. Soluble forms of these molecules and ADAM10 can be carried and spread in the microenvironment by exosomes released by tumor cells. We reported new ADAM10 inhibitors able to prevent MICA shedding in Hodgkin lymphoma (HL), leading to recognition of HL cells by cytotoxic lymphocytes. In this paper, we show that the mature bioactive form of ADAM10 is released in exosome-like vesicles (ExoV) by HL cells and lymph node mesenchymal stromal cells (MSC). We demonstrate that ADAM10 inhibitors are released in ExoV by MSC or HL cells, endocytosed by bystander cells and localized in the endolysosomal compartment in HL MSC. ExoV released by HL cells can enhance MICA shedding by MSC, while ExoV from MSC induce TNFalpha or CD30 shedding by HL cells. Of note, ADAM10 sheddase activity carried by ExoV is prevented with the ADAM10 inhibitors LT4 and CAM29, pretreating either the ExoV-producing or the ExoV-receiving cells. In particular, both inhibitors reduce CD30 shedding maintaining the anti-tumor effects of the ADC Brentuximab-Vedotin or the anti-CD30 Iratumumab on HL cells. Thus, spreading of ADAM10 activity due to ExoV can result in the release of cytokines, like TNFalpha, a lymphoma growth factor, or soluble molecules, like sMICA or sCD30, that potentially interfere with host immune surveillance or immunotherapy. ADAM10 blockers can interfere with this process, allowing the development of anti lymphoma immune response and/or efficient ADC-based or human antibody-based immunotherapy. PMID- 29721370 TI - A PI3K p110alpha-selective inhibitor enhances the efficacy of anti-HER2/neu antibody therapy against breast cancer in mice. AB - Combination therapies with phosphoinositide 3-kinase (PI3K) inhibitors and trastuzumab (anti-human epidermal growth factor receptor [HER]2/neu antibody) are effective against HER2+ breast cancer. Isoform-selective PI3K inhibitors elicit anti-tumor immune responses that are distinct from those induced by inhibitors of class I PI3K isoforms (pan-PI3K inhibitors). The present study investigated the therapeutic effect and potential for stimulating anti-tumor immunity of combined therapy with an anti-HER2/neu antibody and pan-PI3K inhibitor (GDC-0941) or a PI3K p110alpha isoform-selective inhibitor (A66) in mouse models of breast cancer. The anti-neu antibody inhibited tumor growth and enhanced anti-tumor immunity in HER2/neu+ breast cancer TUBO models, whereas GDC-0941 or A66 alone did not. Anti-neu antibody and PI3K inhibitor synergistically promoted anti-tumor immunity by increasing functional T cell production. In the presence of the anti neu antibody, A66 was more effective than GDC-0941 at increasing the fraction of CD4+, CD8+, and IFN-gamma+CD8+ T cells in the tumor-infiltrating lymphocyte population. Detection of IFN-gamma levels by enzyme-linked immunospot assay showed that the numbers of tumor-specific T cells against neu and non-neu tumor antigens were increased by combined PI3K inhibitor plus anti-neu antibody treatment, with A66 exhibiting more potent effects than GDC-0941. In a TUBO (neu+) and TUBO-P2J (neu-) mixed tumor model representing immunohistochemistry 2+ tumors, A66 suppressed tumor growth and prolonged survival to a greater extent than GDC-0941 when combined with anti-neu antibody. These results demonstrate that a PI3K p110alpha-isoform-selective inhibitor is an effective adjunct to trastuzumab in the treatment of HER2-positive breast cancer. PMID- 29721372 TI - Protective effects against tumors and infection by interleukin-27 through promotion of expansion and differentiation of hematopoietic stem cells into myeloid progenitors. AB - Interleukin (IL)-27 is a multifunctional cytokine that belongs to the IL-6/IL-12 family and has potent antitumor activity through various mechanisms. Our novel findings indicate that IL-27 directly acts on hematopoietic stem cells and promotes their expansion and differentiation into myeloid progenitors to control infection and to eradicate tumors. PMID- 29721371 TI - Complimentary mechanisms of dual checkpoint blockade expand unique T-cell repertoires and activate adaptive anti-tumor immunity in triple-negative breast tumors. AB - Triple-negative breast cancer (TNBC) is an aggressive and molecularly diverse breast cancer subtype typified by the presence of p53 mutations (~80%), elevated immune gene signatures and neoantigen expression, as well as the presence of tumor infiltrating lymphocytes (TILs). As these factors are hypothesized to be strong immunologic prerequisites for the use of immune checkpoint blockade (ICB) antibodies, multiple clinical trials testing single ICBs have advanced to Phase III, with early indications of heterogeneous response rates of <20% to anti-PD1 and anti-PDL1 ICB. While promising, these modest response rates highlight the need for mechanistic studies to understand how different ICBs function, how their combination impacts functionality and efficacy, as well as what immunologic parameters predict efficacy to different ICBs regimens in TNBC. To address these issues, we tested anti-PD1 and anti-CTLA4 in multiple models of TNBC and found that their combination profoundly enhanced the efficacy of either treatment alone. We demonstrate that this efficacy is due to anti-CTLA4-driven expansion of an individually unique T-cell receptor (TCR) repertoire whose functionality is enhanced by both intratumoral Treg suppression and anti-PD1 blockade of tumor expressed PDL1. Notably, the individuality of the TCR repertoire was observed regardless of whether the tumor cells expressed a nonself antigen (ovalbumin) or if tumor-specific transgenic T-cells were transferred prior to sequencing. However, responsiveness was strongly correlated with systemic measures of tumor specific T-cell and B-cell responses, which along with systemic assessment of TCR expansion, may serve as the most useful predictors for clinical responsiveness in future clinical trials of TNBC utilizing anti-PD1/anti-CTLA4 ICB. PMID- 29721373 TI - CD44v6 as innovative sarcoma target for CAR-redirected CIK cells. AB - Purpose of our study was to explore a new immunotherapy for high grade soft tissue sarcomas (STS) based on cytokine-induced killer cells (CIK) redirected with a chimeric antigen receptor (CAR) against the tumor-promoting antigen CD44v6. We aimed at generating bipotential killers, combining the CAR specificity with the intrinsic tumor-killing ability of CIK cells (CAR+.CIK). We set a patient-derived experimental platform. CAR+.CIK were generated by transduction of CIK precursors with a lentiviral vector encoding for anti-CD44v6-CAR. CAR+.CIK were characterized and assessed in vitro against multiple histotypes of patient derived STS. The anti-sarcoma activity of CAR+.CIK was confirmed in a STS xenograft model. CD44v6 was expressed by 40% (11/27) of patient-derived STS. CAR+.CIK were efficiently expanded from patients (n = 12) and killed multiple histotypes of STS (including autologous targets, n = 4). The killing activity was significantly higher compared with unmodified CIK, especially at low effector/target (E/T) ratios: 98% vs 82% (E/T = 10:1) and 68% vs 26% (1:4), (p<0.0001). Specificity of tumor killing was confirmed by blocking with anti CD44v6 antibody. CAR+.CIK produced higher amounts of IL6 and IFN-gamma compared to control CIK. CAR+.CIK were highly active in mice bearing subcutaneous STS xenografts, with significant delay of tumor growth (p<0.0001) without toxicities. We report first evidence of CAR+.CIK's activity against high grade STS and propose CD44v6 as an innovative target in this setting. CIK are a valuable platform for the translation of CAR-based strategies to challenging field of solid tumors. Our findings support the exploration of CAR+.CIK in clinical trials against high grade STS. PMID- 29721374 TI - PPARgamma-activation increases intestinal M1 macrophages and mitigates formation of serrated adenomas in mutant KRAS mice. AB - To identify novel hubs for cancer immunotherapy, we generated C57BL/6J mice with concomitant deletion of the drugable transcription factor PPARgamma and transgenic overexpression of the mutant KRASG12V oncogene in enterocytes. Animals developed epithelial hyperplasia, transmural inflammation and serrated adenomas in the small intestine with infiltration of CD3+ FOXP3+ T-cells and macrophages into the lamina propria of the non-malignant mucosa. Within serrated polyps, CD3+ CD8+ T-cells and phosphorylated ERK1/2 were reduced and the senescence marker P21 and macrophage counts up-regulated, indicative of an immunosuppressive tissue microenvironment. Treatment of mutant KRASG12V mice with the PPARgamma-agonist rosiglitazone augmented M1 macrophage numbers, reduced IL4 expression and diminished polyp load in mice. Rosiglitazone also promoted M1 polarisation of human THP1-derived macrophages and decreased Il4 mRNA in isolated murine lymphocytes. Thus, inhibition of the oncogenic driver mutant RAS by PPARgamma in epithelial and immune cell compartments may be a future target for the prevention or treatment of human malignancies associated with intestinal inflammation. PMID- 29721375 TI - High beta-1,4-Galactosyltransferase-I expression in peripheral T-lymphocytes is associated with a low risk of relapse in germ-cell cancer patients receiving high dose chemotherapy with autologous stem cell reinfusion. AB - Survival of patients with germ-cell cancer (GCC) and primary progression or relapse after cisplatin-based first-line chemotherapy is highly heterogeneous, ranging from close to zero to more than 70%. We investigated beta-1,4 Galactosyltransferase-I (B4GALT1) expression levels in peripheral lymphocytes in a cohort of 46 testicular cancer patients. B4GALT1 enhances immune cell crosstalk via glycosylation of surface molecules. A high expression level of B4GALT1 in T lymphocytes, but not in monocytes, was associated with a lower risk of relapse with a hazard ratio (HR) of 0.66 (95% confidence interval (CI) of HR: 0.45-0.97; p = 0.02) upon multivariate Cox regression analysis. Correspondingly, interleukin 10 (IL10), a cytokine released by cytotoxic T-cells, was likewise significantly elevated in T-lymphocytes of non-relapse GCC patients (HR: 0.3; 95% CI of HR: 0.14-0.65; p = 0.002). Our data indicate that glycosylation and activation of T lymphocytes may play a pivotal role in disease control in GCC patients with primary progressive or relapsed disease. PMID- 29721376 TI - PD-L1 expression is regulated by both DNA methylation and NF-kB during EMT signaling in non-small cell lung carcinoma. AB - Tumor cells, which undergo Epithelial-mesenchymal transition (EMT) acquire increased capacities of proliferation, invasion and have the ability to generate metastases by escaping the immune system during their systemic migration. To escape the immune system, cancer cells may induce tolerance or resist elimination by immune effectors via multiple mechanisms and we hypothesized that EMT may control the expression of immune checkpoint inhibitors, then promoting immune evasion. PD-L1 (programmed cell death ligand 1) but not PD-L2 nor Galectin 9 or Death receptor (DR4, DR5 and Fas) and ligands (FasL and TRAIL) expression was up regulated during cytokine-driven EMT in a reversible manner. Moreover PD-L1 is overexpressed in VIMENTIN positive NSCLC tissues. We also demonstrated that the expression of PD-L1 required both TNFalpha and TGFbeta1. Indeed, TGFbeta1 decreased DNMT1 content and that resulted in PD-L1 promoter demethylation whereas TNFalpha induced the NF-kappaB pathway that promoted expression of demethylated PD-L1 promoter. PMID- 29721377 TI - Oncolytic influenza virus infection restores immunocompetence of lung tumor associated alveolar macrophages. AB - Non-small-cell lung cancer (NSCLC) is the most frequent type of lung cancer and demonstrates high resistance to radiation and chemotherapy. These tumors evade immune system detection by promoting an immunosuppressive tumor microenvironment. Genetic analysis has revealed oncogenic activation of the Ras/Raf/MEK/ERK signaling pathway to be a hallmark of NSCLCs, which promotes influenza A virus (IAV) infection and replication in these cells. Thus, we aimed to unravel the oncolytic properties of IAV infection against NSCLCs in an immunocompetent model in vivo. Using Raf-BxB transgenic mice that spontaneously develop NSCLCs, we demonstrated that infection with low-pathogenic IAV leads to rapid and efficient oncolysis, eliminating 70% of the initial tumor mass. Interestingly, IAV infection of Raf-BxB mice caused a functional reversion of immunosuppressed tumor associated lung macrophages into a M1-like pro-inflammatory active phenotype that additionally supported virus-induced oncolysis of cancer cells. Altogether, our data demonstrate for the first time in an immunocompetent in vivo model that oncolytic IAV infection is capable of restoring and redirecting immune cell functions within the tumor microenvironment of NSCLCs. PMID- 29721378 TI - A phase II study of combined therapy with a BRAF inhibitor (vemurafenib) and interleukin-2 (aldesleukin) in patients with metastatic melanoma. AB - Background: Approximately 50% of melanomas harbor BRAF mutations. Treatment with BRAF +/- MEK inhibition is associated with favorable changes in the tumor microenvironment thus providing the rationale for combining targeted agents with immunotherapy. Methods: Patients with unresectable Stage III or IV BRAFV600E mutant melanoma were enrolled in a single-center prospective study (n = 6). Patients were eligible to receive two courses of HD-IL-2 and vemurafenib twice daily. The primary endpoint was progression-free survival (PFS) with secondary objectives including overall survival (OS), response rates (RR), and safety of combination therapy as compared to historical controls. Immune profiling was performed in longitudinal tissue samples, when available. Results: Overall RR was 83.3% (95% CI: 36%-99%) and 66.6% at 12 weeks. All patients eventually progressed, with three progressing on treatment and three progressing after the vemurafenib continuation phase ended. Median PFS was 35.8 weeks (95% CI: 16-57 weeks). Median OS was not reached; however, the time at which 75% of patients were still alive was 104.4 weeks. Change in circulating BRAFV600E levels correlated with response. Though combination therapy was associated with enhanced CD8 T cell infiltrate, an increase in regulatory T cell frequency was seen with HD-IL-2 administration, suggesting a potential limitation in this strategy. Conclusion: Combination vemurafenib and HD-IL-2 is well tolerated and associated with treatment responses. However, the HD-IL-2 induced increase in Tregs may abrogate potential synergy. Given the efficacy of regimens targeting the PD-1 pathway, strategies combining these regimens with BRAF-targeted therapy are currently underway, and the role of combination vemurafenib and HD-IL-2 is uncertain. Trial Registration: Clinical trial information: NCT01754376; https://clinicaltrials.gov/show/NCT01754376. PMID- 29721379 TI - Increased immune infiltration and chemokine receptor expression in head and neck epithelial tumors after neoadjuvant immunotherapy with the IRX-2 regimen. AB - IRX-2 is an injectable cancer immunotherapy composed of cytokines purified from stimulated normal-donor peripheral blood mononuclear cells. In a phase 2a trial (n = 27), neoadjuvant IRX-2 significantly increased lymphocyte infiltration (LI) into resected head and neck tumors and was associated with changes in fibrosis and necrosis. Event-free survival was 65% at 2 years, and overall survival 65% at 5 years. Overall survival was longer for patients with LI greater versus lower than the median. This substudy of the mechanisms responsible for the increase in LI with neoadjuvant IRX-2 employed multiplex immunohistochemistry (IHC) and transcriptome analysis to interrogate matched pre- and post-treatment tumor specimens from 7 available phase 2a trial patients. Multiplex IHC showed substantial increases in CD68-expressing cells (5 patients), T-cell density (4 patients), and PDL1 mean fluorescent intensity (4 patients). Consistent with IRX 2 activation of multiple immune cells, transcriptome analysis showed mean increases in expression of genes associated with NK cells, B cells, CD4+ T cells, CD8+ T cells, and dendritic cells, but not of genes associated with neutrophils. There were increases in mean expression of genes for most immune subsets, most markedly (2- to 3-fold) for B cells and dendritic cells. Mean increases in gene expression for chemokines suggest that tumor LI may be driven in part by IRX-2 induced production of chemo-attractants. Upregulation of checkpoint genes including PDL1 and CTLA4 along with increased T-cell infiltration suggests a functional antitumor immune response such that the efficacy of IRX-2 may be enhanced by combination with immune checkpoint inhibitors. PMID- 29721380 TI - Targeted overexpression of prostacyclin synthase inhibits lung tumor progression by recruiting CD4+ T lymphocytes in tumors that express MHC class II. AB - Lung-specific overexpression of prostacyclin synthase (PGIS) decreases tumor initiation in murine lung cancer models. Prostacyclin analogs prevent lung tumor formation in mice and reverse bronchial dysplasia in former smokers. However, the effect of prostacyclin on lung cancer progression has not been well studied. We investigated the effects of pulmonary PGIS overexpression in an orthotopic immunocompetent mouse model of lung cancer using two murine lung cancer cell lines. Pulmonary PGIS overexpression significantly inhibited CMT167 lung tumor growth, increased CXCL9 expression, and increased CD4+ tumor-infiltrating lymphocytes. Immunodepletion of CD4+ T cells abolished the inhibitory effect of pulmonary PGIS overexpression on CMT167 lung tumor growth. In contrast, pulmonary PGIS overexpression failed to inhibit growth of a second murine lung cancer cell line, Lewis Lung Carcinoma (LLC) cells, and failed to increase CXCL9 expression or CD4+ T lymphocytes in LLC lung tumors. Transcriptome profiling of CMT167 cells and LLC cells recovered from tumor-bearing mice demonstrated that in vivo, CMT167 cells but not LLC cells express MHC class II genes and cofactors necessary for MHC class II processing and presentation. These data demonstrate that prostacyclin can inhibit lung cancer progression and suggest that prostacyclin analogs may serve as novel immunomodulatory agents in a subset of lung cancer patients. Moreover, expression of MHC Class II by lung cancer cells may represent a biomarker for response to prostacyclin. PMID- 29721381 TI - FOXO1 promotes resistance of non-Hodgkin lymphomas to anti-CD20-based therapy. AB - Diminished overall survival rate of non-Hodgkin lymphoma (NHL) patients treated with a combination regimen of rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone (R-CHOP) has been recently linked to recurrent somatic mutations activating FOXO1. Despite of the clinical relevance of this finding, the molecular mechanism driving resistance to R-CHOP therapy remains largely unknown. Herein, we investigated the potential role of FOXO1 in the therapeutic efficacy of rituximab, the only targeted therapy included in the R-CHOP regimen. We found CD20 transcription is negatively regulated by FOXO1 in NHL cell lines and in human lymphoma specimens carrying activating mutations of FOXO1. Furthermore, both the expression of exogenous mutants of FOXO1 and the inhibition of AKT led to FOXO1 activation in lymphoma cells, increased binding to MS4A1 promoter and diminished CD20 expression levels. In contrast, a disruption of FOXO1 with CRISPR/Cas9 genome-editing (sgFOXO1) resulted in CD20 upregulation, improved the cytotoxicity induced by rituximab and the survival of mice with sgFOXO1 tumors. Accordingly, pharmacological inhibition of FOXO1 activity in primary samples upregulated surface CD20 levels. Importantly, FOXO1 was required for the downregulation of CD20 levels by the clinically tested inhibitors of BTK, SYK, PI3K and AKT. Taken together, these results indicate for the first time that the AKT-unresponsive mutants of FOXO1 are important determinant of cell response to rituximab-induced cytotoxicity, and suggest that the genetic status of FOXO1 together with its transcriptional activity need further attention while designing anti-CD20 antibodies based regimens for the therapy of pre-selected lymphomas. PMID- 29721383 TI - Myeloid-derived macrophages and secreted HSP90alpha induce pancreatic ductal adenocarcinoma development. AB - We detected a significant elevation of serum HSP90alpha levels in pancreatitis patients and even more in pancreatic ductal adenocarcinoma (PDAC) patients. However, there was no significant difference in the serum HSP90alpha levels between patients with early-stage and late-stage PDAC. To study whether elevation of serum HSP90alpha levels occurred early during PDAC development, we used LSL KrasG12D/Pdx1-Cre transgenic mice as a studying model. Elevated serum HSP90alpha levels were detected before PDAC formation and an extracellular HSP90alpha (eHSP90alpha) inhibitor effectively prevented PDAC development. Both serum HSP90alpha level and pancreatic lesion were suppressed when the mice were administered a CD11b-antagonizing antibody, suggesting that CD11b+-myeloid cells were associated with eHSP90alpha levels and pancreatic carcinogenesis. Consistently, in CD11b-DTR-EGFP transgenic mouse model with CD11b+-myeloid cells depletion, serum HSP90alpha levels were suppressed and Panc-02 cell grafts failed to develop tumors. Macrophages and granulocytes are two common tissue infiltrating CD11b+-myeloid cells. Duplex in situ hybridization assays suggested that macrophages were predominant HSP90alpha-expressing CD11b+-myeloid cells during PDAC development. Immunohistochemical and immunohistofluorescent staining results revealed that HSP90alpha-expressing cells included not only macrophages but also pancreatic ductal epithelial (PDE) cells. Cell culture studies also indicated that eHSP90alpha could be produced by macrophages and macrophage stimulated PDE cells. Macrophages not only secreted significant amount of HSP90alpha, but also secreted interleukin-6 and interleukin-8 to induce a JAK2 STAT3 signaling axis in PDE cells, stimulating them to express and secrete HSP90alpha. eHSP90alpha further promoted cellular epithelial-mesenchymal transition, migration, and invasion in PDE cells. Besides myeloid cells, eHSP90alpha can be potentially taken as a target to suppress PDAC pathogenesis. PMID- 29721384 TI - Low dose gemcitabine increases the cytotoxicity of human Vgamma9Vdelta2 T cells in bladder cancer cells in vitro and in an orthotopic xenograft model. AB - Human gammadeltaT cell immunotherapy is well tolerated and has shown promising results in clinical trials; however, its antitumor efficacy is limited, including results in solid tumors. Ex-vivo expanded gammadeltaT cell stimulated by zoledronic acid (ZOL) activates the gammadeltaT cell subpopulation of so called Vgamma9Vdelta2 T cells. To improve the clinical outcomes of Vgamma9Vdelta2 T cell (abbreviated as gammadeltaT cell here) immunotherapy, we aimed to increase the cytotoxicity of gammadeltaT cells by focusing on two issues: recognition of tumor cells by gammadeltaT cells and the effector (gammadeltaT cell)-to-target (tumor cell) (E/T) ratio. Ex vivo-expanded gammadeltaT cells showed potent cytotoxicity against urinary bladder cancer (UBC) cells in in vitro assays. Combination treatment with standard anticancer agents showed that low dose gemcitabine pretreatment significantly enhanced the cytotoxicity of gammadeltaT cells by upregulating the expression of MICA and MICB (MICA/B), which are tumor-associated antigens recognized by gammadeltaT cells. These effects were abrogated by small interfering RNA-mediated knockdown of MICA/B in UBC cells, suggesting that pre exposing cancer cells to anticancer agents could be a promising strategy. A bladder instillation approach was used to increase the E/T ratio. The efficacy of ex vivo-expanded gammadeltaT cell immunotherapy was examined in an orthotopic xenograft model. In Vivo Imaging System analysis revealed the potent cytotoxicity of weekly intravesical administration of gammadeltaT cells, and weekly gemcitabine pretreatment enhanced the cytotoxicity of gammadeltaT cells in vivo. In conclusion, intravesical gammadeltaT cell immunotherapy and combination therapy with low dose gemcitabine may be a promising strategy in UBC. PMID- 29721382 TI - Expression of LLT1 and its receptor CD161 in lung cancer is associated with better clinical outcome. AB - Co-stimulatory and inhibitory receptors expressed by immune cells in the tumor microenvironment modulate the immune response and cancer progression. Their expression and regulation are still not fully characterized and a better understanding of these mechanisms is needed to improve current immunotherapies. Our previous work has identified a novel ligand/receptor pair, LLT1/CD161, that modulates immune responses. Here, we extensively characterize its expression in non-small cell lung cancer (NSCLC). We show that LLT1 expression is restricted to germinal center (GC) B cells within tertiary lymphoid structures (TLS), representing a new hallmark of the presence of active TLS in the tumor microenvironment. CD161-expressing immune cells are found at the vicinity of these structures, with a global enrichment of NSCLC tumors in CD161+ CD4+ and CD8+ T cells as compared to normal distant lung and peripheral blood. CD161+ CD4+ T cells are more activated and produce Th1-cytokines at a higher frequency than their matched CD161-negative counterparts. Interestingly, CD161+ CD4+ T cells highly express OX40 co-stimulatory receptor, less frequently 4-1BB, and display an activated but not completely exhausted PD-1-positive Tim-3-negative phenotype. Finally, a meta-analysis revealed a positive association of CLEC2D (coding for LLT1) and KLRB1 (coding for CD161) gene expression with favorable outcome in NSCLC, independently of the size of T and B cell infiltrates. These data are consistent with a positive impact of LLT1/CD161 on NSCLC patient survival, and make CD161-expressing CD4+ T cells ideal candidates for efficient anti-tumor recall responses. PMID- 29721385 TI - Prognosis of ovarian cancer is associated with effector memory CD8+ T cell accumulation in ascites, CXCL9 levels and activation-triggered signal transduction in T cells. AB - The accumulation of intratumoral CD8+ T cells is associated with the survival of high grade serous ovarian carcinoma patients, but it is unclear which CD8+ T cell subsets contribute to this effect and how they are affected by the peritoneal tumor microenvironment. Here, we provide evidence for a functional link between long relapse-free survival, accumulation of CD8+ effector memory T (TEM) cells in peritoneal effusion (ascites), and the level of the CD8+ TEM attracting chemokine CXCL9, produced by macrophages as a major source. We also propose a novel mechanism by which the tumor microenvironment could contribute to T cell dysfunction and shorter survival, i.e., diminished expression levels of essential signaling proteins, including STAT5B, PLCgamma1 and NFATc2. CD8+ TEM cells in ascites, CXCL9 levels and the expression of crucial signal transduction proteins may therefore be important biomarkers to gauge the efficiency of immune therapies and potentially represent therapeutic targets. PMID- 29721387 TI - Development of anti-drug antibodies is associated with shortened survival in patients with metastatic melanoma treated with ipilimumab. AB - Introduction: Checkpoint inhibitors, including the CTLA-4 blocking antibody ipilimumab, have become the new standard therapy for many metastatic cancers. Development of anti-drug antibodies (ADAs) after treatment with other biopharmaceuticals has been thoroughly described, but the induction of ADAs after treatment with checkpoint inhibitors has been inadequately investigated. In this retrospective study, we relate ipilimumab serum levels and anti-ipilimumab antibody levels to clinical outcomes in patients with metastatic melanoma (MM). Method: Serum samples from 31 patients with MM were analyzed for serum levels of ipilimumab and ADAs to ipilimumab at baseline, and before the 2nd and 4th infusion using an in-house bead-based assay. The results were correlated with progression-free survival (PFS) and overall survival (OS). Results: Low serum levels of ipilimumab before the 2nd infusion correlated significantly with a shorter OS (p = 0.01) and PFS (p = 0.02). Eight patients (26%) were ADA-positive at either timepoint. ADA positivity correlated significantly with a shorter OS (p = 0.03) with a hazard ratio (HR) of 3.0 (95% CI: 1.2-7.8). Four of 8 ADA-positive patients (50%) discontinued therapy before the 4th infusion due to disease progression, compared to three of 23 (13%) ADA-negative patients. Conclusion: We confirm that low serum levels of ipilimumab are associated with a shortened OS, and we show for the first time that ADAs to ipilimumab are associated with shorter OS in patients with MM. PMID- 29721386 TI - In situ delivery of allogeneic natural killer cell (NK) combined with Cetuximab in liver metastases of gastrointestinal carcinoma: A phase I clinical trial. AB - Despite successful introduction of NK-based cellular therapy in the treatment of myeloid leukemia, the potential use of NK alloreactivity in solid malignancies is still elusive. We performed a phase I clinical trial to assess the safety and efficacy of in situ delivery of allogeneic NK cells combined with cetuximab in liver metastasis of gastrointestinal origin. The conditioning chemotherapy was administrated before the allogeneic NK cells injection via hepatic artery. Three escalating doses were tested (3.106, 8.106 and 12.106 NK cells/kg) following by a high-dose interleukin-2 (IL-2). Cetuximab was administered intravenously every week for 7 weeks. Nine patients with liver metastases of colorectal or pancreatic cancers were included, three per dose level. Hepatic artery injection was successfully performed in all patients with no report of dose-limiting toxicity. Two patients had febrile aplasia requiring a short-term antibiotherapy. Grade 3/4 anemia and thrombopenia were also observed related to the chemotherapy. Objective clinical responses were documented in 3 patients and among them 2 occurred in patients injected with cell products harboring two KIR ligand mismatches and one in a patient with one KIR ligand mismatch. Immune monitoring revealed that most patients presented an increase but transient of IL-15 and IL-7 cytokines levels one week after chemotherapy. Furthermore, a high expansion of FoxP3+regulatory T cells and PD-1+ T cells was observed in all patients, related to IL-2 administration. Our results demonstrated that combining allogeneic NK cells transfer via intra-hepatic artery, cetuximab and a high-dose IL-2 is feasible, well tolerated and may result in clinical responses. PMID- 29721388 TI - Circulating tumor DNA evaluated by Next-Generation Sequencing is predictive of tumor response and prolonged clinical benefit with nivolumab in advanced non small cell lung cancer. AB - Nivolumab is an anti-PD1 antibody, given in second-line or later treatment in advanced non-small cell lung cancer (NSCLC). The objective of this study was to describe the predictive value of circulating tumor DNA (ctDNA) on the efficacy of nivolumab in advanced NSCLC. We prospectively included all consecutive patients with advanced NSCLC treated with nivolumab in our Department between June 2015 and October 2016. Plasma samples were obtained before the first injection of nivolumab and at the first tumor evaluation with nivolumab. ctDNA was analyzed by Next-Generation Sequencing (NGS), and the predominant somatic mutation was followed for each patient and correlated with tumor response, clinical benefit (administration of nivolumab for more than 6 months), and progression-free survival (PFS). Of 23 patients, 15 had evaluable NGS results at both times of analysis. ctDNA concentration at the first tumor evaluation and ctDNA change correlated with tumor response, clinical benefit and PFS. ROC curve analyses showed good diagnostic performances for tumor response and clinical benefit, both for ctDNA concentration at the first tumor evaluation (tumor response: positive predictive value (PPV) at 100.0% and negative predictive value (NPV) at 71.0%; clinical benefit: PPV at 83.3% and NPV 77.8%) and the ctDNA change (tumor response: PPV 100.0% and NPV 62.5%; clinical benefit: PPV 100.0% and NPV 80.0%). Patients without ctDNA concentration increase >9% at 2 months had a long-term benefit of nivolumab. In conclusion, NGS analysis of ctDNA allows the early detection of tumor response and long-term clinical benefit with nivolumab in NSCLC. PMID- 29721390 TI - CD96 targeted antibodies need not block CD96-CD155 interactions to promote NK cell anti-metastatic activity. AB - CD96 is a transmembrane glycoprotein Ig superfamily receptor, expressed on various T cell subsets and NK cells, that interacts with nectin and nectin-like proteins, including CD155/polio virus receptor (PVR). Here, we have compared three rat anti-mouse CD96 mAbs, including two that block CD96-CD155 (3.3 and 6A6) and one that does not block CD96-CD155 (8B10). Using flow cytometry, we demonstrated that both mAbs 3.3 and 6A6 bind to the first Ig domain of mouse CD96 and compete with CD155 binding, while mAb 8B10 binds to the second Ig domain and does not block CD155. While Fc isotype was irrelevant concerning the anti metastatic activity of 3.3 mAb, in four different experimental metastases models and one spontaneous metastasis model, the relative order of anti-metastatic potency was 6A6 > 3.3 > 8B10. The metastatic burden control of all of the anti CD96 clones was highly dependent on NK cells and IFN-gamma. Consistent with its inability to block CD96-CD155 interactions, 8B10 retained anti-metastatic activity in CD155-deficient mice, whereas 3.3 and 6A6 lost potency in CD155 deficient mice. Furthermore, 8B10 retained most of its anti-metastatic activity in IL-12p35-deficient mice whereas the activity of 3.3 and 6A6 were partially lost. All three mAbs were inactive in CD226-deficient mice. Altogether, these data demonstrate anti-CD96 need not block CD96-CD155 interactions (ie. immune checkpoint blockade) to promote NK cell anti-metastatic activity. PMID- 29721389 TI - Bacterial ghosts as adjuvant to oxaliplatin chemotherapy in colorectal carcinomatosis. AB - Colorectal cancer (CRC) is one of the most commonly diagnosed cancers and a major cause of cancer mortality worldwide. At late stage of the disease CRC often shows (multiple) metastatic lesions in the peritoneal cavity which cannot be efficiently targeted by systemic chemotherapy. This is one major factor contributing to poor prognosis. Oxaliplatin is one of the most commonly used systemic treatment options for advanced CRC. However, drug resistance - often due to insufficient drug delivery - is still hampering successful treatment. The anticancer activity of oxaliplatin includes besides DNA damage also a strong immunogenic component. Consequently, the aim of this study was to investigate the effect of bacterial ghosts (BGs) as adjuvant immunostimulant on oxaliplatin efficacy. BGs are empty envelopes of gram-negative bacteria with a distinct immune-stimulatory potential. Indeed, we were able to show that the combination of BGs with oxaliplatin treatment had strong synergistic anticancer activity against the CT26 allograft, resulting in prolonged survival and even a complete remission in this murine model of CRC carcinomatosis. This synergistic effect was based on an enhanced induction of immunogenic cell death and activation of an efficient T-cell response leading to long-term anti-tumor memory effects. Taken together, co-application of BGs strengthens the immunogenic component of the oxaliplatin anticancer response and thus represents a promising natural immune adjuvant to chemotherapy in advanced CRC. PMID- 29721391 TI - A genetic IFN/STAT1/FAS axis determines CD4 T stem cell memory levels and apoptosis in healthy controls and Adult T-cell Leukemia patients. AB - Adult T-cell leukemia (ATL) is an aggressive, chemotherapy-resistant CD4+CD25+ leukemia caused by HTLV-1 infection, which usually develops in a minority of patients several decades after infection. IFN + AZT combination therapy has shown clinical benefit in ATL, although its mechanism of action remains unclear. We have previously shown that an IFN-responsive FAS promoter polymorphism in a STAT1 binding site (rs1800682) is associated to ATL susceptibility and survival. Recently, CD4 T stem cell memory (TSCM) Fashi cells have been identified as the hierarchical cellular apex of ATL, but a possible link between FAS, apoptosis, proliferation and IFN response in ATL has not been studied. In this study, we found significant ex vivo antiproliferative, antiviral and immunomodulatory effects of IFN-alpha treatment in short-term culture of primary mononuclear cells from ATL patients (n = 25). Bayesian Network analysis allowed us to integrate ex vivo IFN-alpha response with clinical, genetic and immunological data from ATL patients, thereby revealing a central role for FAS -670 polymorphism and apoptosis in the coordinated mechanism of action of IFN-alpha. FAS genotype dependence of IFN-induced apoptosis was experimentally validated in an independent cohort of healthy controls (n = 20). The same FAS -670 polymorphism also determined CD4 TSCM levels in a genome-wide twin study (p = 7 * 10-11, n = 460), confirming a genetic link between apoptosis and TSCM levels. Transcriptomic analysis and cell type deconvolution confirmed the FAS genotype/TSCM link and IFN alpha-induced downregulation of CD4 TSCM-specific genes in ATL patient cells. In conclusion, ex vivo IFN-alpha treatment exerts a pleiotropic effect on primary ATL cells, with a genetic IFN/STAT1/Fas axis determining apoptosis vs. proliferation and underscoring the CD4 TSCM model of ATL leukemogenesis. PMID- 29721392 TI - Bufalin Suppresses Migration and Invasion of Hepatocellular Carcinoma Cells Elicited by Poly (I:C) Therapy. AB - The Toll-like receptor 3 (TLR3) agonists as polyriboinosinic-polyribocytidylic acid (poly (I:C)) have been implicated as potential immunotherapy adjuvant for cancer whereas the exact roles of TLR3 agonists in hepatocellular carcinoma (HCC) treatment have not been clearly evaluated. In consistent with previous reports, we found that poly (I:C) triggering of TLR3 inhibited cell proliferation and induced apoptosis in HCC cells. However, poly (I:C), when used at lower concentration that cannot remarkably inhibit proliferation and induce apoptosis in HCC cells, enhanced the migration and invasion in vitro and the metastasis in vivo. More importantly, we found that bufalin, a prominent component of toad venom, could suppress poly (I:C)-inspired migration, invasion and metastasis of HCC cells despite that bufalin could not potentiate poly (I:C)-induced inhibition of proliferation and induction of apoptosis. In MHCC97 H cells, bufalin impaired poly (I:C)-induced activation of Tank-binding kinase 1 (TBK1) and interferon regulatory factor 3 (IRF3) pathway and NF-kappaB pathway. Inhibitor for TBK1 but not NF-kappaB suppressed poly (I:C)-inspired migration and invasion, which was further supported by using TBK1 deficient (Tbk1-/- ) cells. In another model using poly (I:C) transfection, bufalin could also suppress the migration and invasion of HCC cells, which was not observed in Tbk1-/- MHCC97 H cells. Our data suggest that bufalin can suppress the metastasis of HCC cells in poly (I:C) therapy by impairing TBK1 activation, indicating that bufalin may be used in combination with poly (I:C) therapy in HCC treatment for the sake of reversing poly (I:C)-triggered metastasis of HCC cells. PMID- 29721393 TI - Immune heterogeneity and clinicopathologic characterization of IGFBP2 in 2447 glioma samples. AB - Glioblastoma is an immunosuppressive, deadly brain tumor. IGFBP2, a circulating biomarker for cancer diagnosis and a potential immunotherapeutic target, is attracting more and more attention from oncologists and clinicians. Thus, it is urgent to thoroughly investigate the immune biological process of IGFBP2 to understand tumor immune complexity and provide potential evidence for anti-IGFBP2 therapy. Through authoritative public databases, we enrolled a total of 2447 glioma samples with gene expression profiles. Then, the clinical characteristics and immunosuppressive status of IGFBP2 in the glioma samples were analyzed. Immunohistochemical staining detected the expression of immunosuppressive biomarkers. We found that IGFBP2 expression was upregulated in high-grade glioma and GBM and downregulated in IDH mutant glioma. Increased IGFBP2 accompanied PTEN loss and EGFR amplification. Bioinformatic analysis revealed that IGFBP2 is related to immunological processes. We further selected specific immunologic related gene sets and found IGFBP2 predominated immunosuppressive activities in GBM. Furthermore, we explored the relationship between IGFBP2 and genes that were well-characterized glioma-mediated immunosuppressive molecules to investigate the potential effect of IGFBP2. We discovered that IGFBP2 was correlated with CHI3L1, TNFRSF1A, LGALS1, TIMP1, VEGFA, ANXA1 and LGALS3, which were classic immunosuppressive biomarkers. Higher IGFBP2 expression predicted unfavorable survival for patients with GBM. Our findings implied that IGFBP2 is involved in immunosuppressive activities and is an independent unfavorable prognostic biomarker for patients with GBM. IGFBP2 is a potential immunotherapeutic target for GBM in future clinical trials. PMID- 29721394 TI - Merkel cell carcinoma expresses the immunoregulatory ligand CD200 and induces immunosuppressive macrophages and regulatory T cells. AB - Merkel cell carcinoma (MCC) is a rare and aggressive skin cancer that responds to PD-1/PD-L1 immune checkpoint inhibitors. CD200 is another checkpoint modulator whose receptor is found on tumor-promoting myeloid cells, including M2 macrophages. We found high CD200 mRNA expression in MCC tumors, and CD200 immunostaining was demonstrated on 95.5% of MCC tumors. CD200R-expressing myeloid cells were present in the MCC tumor microenvironment. MCC-associated macrophages had a higher average CD163:CD68 staining ratio (2.67) than controls (1.13), indicating an immunosuppressive M2 phenotype. Accordingly, MCC tumors contained increased densities of FOXP3+ regulatory T-cells. Intravenous administration of blocking anti-CD200 antibody to MCC xenograft mice revealed specific targeting of drug to tumor. In conclusion, MCC are highly CD200 positive and associated with immunosuppressive M2 macrophages and regulatory T-cells. As anti-CD200 antibody effectively targets CD200 on MCC tumor cells in vivo, this treatment may provide a novel immunotherapy for MCC independent of PD-1/PD-L1 blockade. PMID- 29721395 TI - Super-charged NK cells inhibit growth and progression of stem-like/poorly differentiated oral tumors in vivo in humanized BLT mice; effect on tumor differentiation and response to chemotherapeutic drugs. AB - Therapeutic role of NK cells in solid tumors was challenged previously even though their role in hematological malignancies has clearly been established. Furthermore, functions and numbers of NK cells are greatly suppressed in oral cancer patients necessitating effective future NK immunotherapeutic strategies to aid in the control of disease. The humanized-BLT (hu-BLT) mice were used to implant stem-like/undifferentiated oral tumors to study the role of super-charged NK cells with and without feeding with AJ2 probiotic bacteria. Implanted CSC/undifferentiated tumors resected from NK-injected mice exhibited differentiated phenotype, grew slowly, and did not cause weight loss, whereas those from tumor-bearing mice without NK-injection remained relatively more stem like/poorly-differentiated, grew faster, and caused significant weight loss. Moreover, in vitro NK-differentiated tumors were sensitive to chemotherapeutic drugs, and when implanted in the oral-cavity grew no or very small tumors in mice. When NK-mediated differentiation of tumors was blocked by IFN-gamma and TNF alpha antibodies before implantation, tumors grew rapidly, remained stem like/poorly-differentiated and became resistant to chemotherapeutic drugs. Loss of NK cytotoxicity and decreased IFN-gamma secretion in tumor-bearing mice in PBMCs, splenocytes, bone marrow derived immune cells and enriched NK cells was restored by the injection of super-charged NK cells with or without feeding with AJ2. Much greater infiltration of CD45+ and T cells were observed in tumors resected from the mice, along with the restored secretion of IFN-gamma from purified T cells from splenocytes in NK-injected tumor-bearing mice fed with AJ2 probiotic bacteria. Thus, super-charged NK cells prevent tumor growth by restoring effector function resulting in differentiation of CSCs/undifferentiated tumors in hu-BLT mice. PMID- 29721396 TI - M7824, a novel bifunctional anti-PD-L1/TGFbeta Trap fusion protein, promotes anti tumor efficacy as monotherapy and in combination with vaccine. AB - Tumors evade host immune surveillance through multiple mechanisms, including the generation of a tumor microenvironment that suppresses immune effector function. Secretion of TGFbeta and upregulation of immune checkpoint programmed cell death ligand-1 (PD-L1) are two main contributors to immune evasion and tumor progression. Here, we examined the efficacy of a first-in-class bifunctional checkpoint inhibitor, the fusion protein M7824, comprising the extracellular domain of human TGFbetaRII (TGFbeta Trap) linked to the C-terminus of human anti PD-L1 heavy chain (alphaPD-L1). We demonstrate that M7824 reduces plasma TGFbeta1, binds to PD-L1 in the tumor, and decreases TGFbeta-induced signaling in the tumor microenvironment in mice. In murine breast and colon carcinoma models, M7824 decreased tumor burden and increased overall survival as compared to targeting TGFbeta alone. M7824 treatment promoted CD8+ T cell and NK cell activation, and both of these immune populations were required for optimal M7824 mediated tumor control. M7824 was superior to TGFbeta- or alphaPD-L1-targeted therapies when in combination with a therapeutic cancer vaccine. These findings demonstrate the value of using M7824 to simultaneously target TGFbeta and PD L1/PD-1 immunosuppressive pathways to promote anti-tumor responses and efficacy. The studies also support the potential clinical use of M7824 as a monotherapy or in combination with other immunotherapies, such as therapeutic cancer vaccines, including for patients who have progressed on alphaPD-L1/alphaPD-1 checkpoint blockade therapies. PMID- 29721397 TI - Diagnostic Efficiency of Multidetector Computed Tomography in the Evaluation of Clinically Equivocal Cases of Acute Appendicitis with Surgical Correlation. AB - Acute appendicitis is one of the most frequent causes of lower abdominal pain and requires immediate surgical intervention. The diagnosis often poses a lot of challenge even to experienced surgeon. Those patients with equivocal symptoms may require different imaging modalities like radiography, contrast examination and ultrasound with limited utility. Multidetector computed tomography (MDCT) used in suspected acute appendicitis has, however, resulted in improved diagnostic accuracy and also reduction of negative surgeries. Objective We intend to determine the diagnostic efficiency of MDCT in clinically equivocal cases of acute appendicitis correlating it with surgical/histopathological findings. Materials and methods A group of 116 patients was included in this study. Spiral MDCT was performed in all these cases after administration of oral and intravenous contrast. All these patients underwent surgery and the CT findings were correlated with histopathology. Out of these 116 patients, 60 patients were male and 56 female. The age range was from three to seventy years and mean age was 28+1 years. Results The results proved that MDCT had a sensitivity of 97.5%, specificity of 97.0%, and accuracy of 97.4% for the diagnosis of appendicitis with one false positive and two false negative cases. The study showed 100% accuracy in diagnosing acute appendicitis in children. In 33 patients, an alternate cause was identified with CT. The alternate diagnosis made on CT findings was consistent with the final diagnosis in 27 (81.8%) of 33 patients in whom there was no evidence of acute appendicitis. The clinical diagnosis disagreed with the CT diagnosis in six patients (18.18%). Conclusion Our study verifies that MDCT plays an important role in evaluation and consequent management of equivocal cases of acute appendicitis. MDCT is also able to diagnose appendicitis or detect alternative diagnosis in pediatric population. PMID- 29721398 TI - Myoclonus from Antibiotic Therapy (Ceftazidime-induced Neurotoxicity): A Case Report and Review. AB - A 78-year-old Chinese man with a history of end-stage renal disease (ESRD) presented with fever of one-day duration. He was treated for catheter-related sepsis with intravenous piperacillin and tazobactam, which was later switched to vancomycin and ceftazidime secondary to persistent fever with negative cultures. On the fifth day of treatment with vancomycin and ceftazidime, he developed new onset upper limb myoclonus which progressed to bilateral upper limb ataxia. A provisional diagnosis of myoclonus and ataxia secondary to neurotoxicity related to ceftazidime was made and the ceftazidime was ceased. His symptoms resolved over three days and he returned to his baseline neurological status by day 5 following cessation. PMID- 29721399 TI - Emergency Management of Spontaneous Bacterial Peritonitis - A Clinical Review. AB - Spontaneous bacterial peritonitis (SBP) has a high mortality rate; early antimicrobial therapy is essential for improving patient outcomes. Given that cirrhotic patients are often coagulopathic, the perceived risk of bleeding may prevent providers from performing a paracentesis and ruling out this potentially deadly disease. We examine the pathophysiology and risk factors for SBP, and current guidelines for its diagnosis and treatment. We then review the time sensitive nature of performing a paracentesis, and the current controversies and contraindications for performing this procedure in patients at risk for SBP. Cirrhotic patients with ascites and clinical suspicion for SBP-abdominal pain or tenderness, fever or altered mental status-should have a diagnostic paracentesis. Although most patients with cirrhosis and liver dysfunction will have prolonged prothrombin time, paracentesis is not contraindicated. Limited data support platelet administration prior to paracentesis if <40,000-50,000/MUL. Timely antimicrobial therapy includes a third-generation cephalosporin for community acquired infection; nosocomial infections should be treated empirically with a carbapenem or with piperacillin-tazobactam, or based on local susceptibility testing. Patients with gastrointestinal (GI) hemorrhage should receive ceftriaxone prophylactically for GI hemorrhage. SBP has a high mortality rate. Early diagnosis and antimicrobial therapy are essential for improving patient outcomes. Cirrhotic patients with ascites with clinical suspicion for SBP, abdominal pain or tenderness, altered mental status or fever should have a diagnostic paracentesis performed prior to admission unless platelets <40,000 50,000/MUL. PMID- 29721400 TI - A Direct Aspiration First Pass Technique for Mechanical Thrombectomy in the Setting of a Suspected Cerebral Aneurysm. AB - There is little guidance in the literature on which thrombectomy technique is preferred in patients with acute ischemic stroke and concomitant aneurysms. Here, we present the case of a 58-year-old female with an acute ischemic stroke requiring emergent thrombectomy that was complicated by the presence of multiple, nonruptured intracranial aneurysms. Imaging confirmed an occlusion of the right middle cerebral artery and multiple nonruptured intracranial aneurysms. The patient was administered intravenous recombinant tissue plasminogen activator and the thrombus was aspirated via a direct aspiration first pass technique (ADAPT). Her symptoms improved significantly postoperatively with a consequent National Institutes of Health Stroke Scale (NIHSS) score of 0. The purpose of this case report is to give an overview and compare various techniques that can help guide the physician for safe, early revascularization while reducing recanalization time in patients having an ischemic stroke who also harbor intracranial aneurysms. PMID- 29721401 TI - Marine litter plastics and microplastics and their toxic chemicals components: the need for urgent preventive measures. AB - Persistent plastics, with an estimated lifetime for degradation of hundreds of years in marine conditions, can break up into micro- and nanoplastics over shorter timescales, thus facilitating their uptake by marine biota throughout the food chain. These polymers may contain chemical additives and contaminants, including some known endocrine disruptors that may be harmful at extremely low concentrations for marine biota, thus posing potential risks to marine ecosystems, biodiversity and food availability. Although there is still need to carry out focused scientific research to fill the knowledge gaps about the impacts of plastic litter in the marine environment (Wagner et al. in Environ Sci Eur 26:9, 2014), the food chain and human health, existing scientific evidence and concerns are already sufficient to support actions by the scientific, industry, policy and civil society communities to curb the ongoing flow of plastics and the toxic chemicals they contain into the marine environment. Without immediate strong preventive measures, the environmental impacts and the economic costs are set only to become worse, even in the short term. Continued increases in plastic production and consumption, combined with wasteful uses, inefficient waste collection infrastructures and insufficient waste management facilities, especially in developing countries, mean that even achieving already established objectives for reductions in marine litter remains a huge challenge, and one unlikely to be met without a fundamental rethink of the ways in which we consume plastics. This document was prepared by a working group of Regional Centres of the Stockholm and Basel Conventions and related colleagues intended to be a background document for discussion in the 2017 Conference of the Parties (COP) of the Basel Convention on hazardous wastes and the Stockholm Convention on persistent organic pollutants (POPs). The COP finally approved that the issue of plastic waste could be dealt by its Regional Centres and consistently report their activities on the matter to next COP's meetings. PMID- 29721402 TI - Scaffold Diversity Synthesis Delivers Complex, Structurally, and Functionally Distinct Tetracyclic Benzopyrones. AB - Complexity-generating chemical transformations that afford novel molecular scaffolds enriched in sp3 character are highly desired. Here, we present a highly stereoselective scaffold diversity synthesis approach that utilizes cascade double-annulation reactions of diverse pairs of zwitterionic and non-zwitterionic partners with 3-formylchromones to generate highly complex tetracyclic benzopyrones. Each pair of annulation partners adds to the common chroman-4-one scaffold to build two new rings, supporting up to four contiguous chiral centers that include an all-carbon quaternary center. Differently ring-fused benzopyrones display different biological activities, thus demonstrating their immense potential in medicinal chemistry and chemical biology research. PMID- 29721403 TI - Nanostructured surfaces for analysis of anticancer drug and cell diagnosis based on electrochemical and SERS tools. AB - Discovering new anticancer drugs and screening their efficacy requires a huge amount of resources and time-consuming processes. The development of fast, sensitive, and nondestructive methods for the in vitro and in vivo detection of anticancer drugs' effects and action mechanisms have been done to reduce the time and resources required to discover new anticancer drugs. For the in vitro and in vivo detection of the efficiency, distribution, and action mechanism of anticancer drugs, the applications of electrochemical techniques such as electrochemical cell chips and optical techniques such as surface-enhanced Raman spectroscopy (SERS) have been developed based on the nanostructured surface. Research focused on electrochemical cell chips and the SERS technique have been reviewed here; electrochemical cell chips based on nanostructured surfaces have been developed for the in vitro detection of cell viability and the evaluation of the effects of anticancer drugs, which showed the high capability to evaluate the cytotoxic effects of several chemicals at low concentrations. SERS technique based on the nanostructured surface have been used as label-free, simple, and nondestructive techniques for the in vitro and in vivo monitoring of the distribution, mechanism, and metabolism of different anticancer drugs at the cellular level. The use of electrochemical cell chips and the SERS technique based on the nanostructured surface should be good tools to detect the effects and action mechanisms of anticancer drugs. PMID- 29721404 TI - Consequences of Inadequate Intakes of Vitamin A, Vitamin B12, Vitamin D, Calcium, Iron, and Folate in Older Persons. AB - Purpose of Review: This review broadly discusses the consequences of inadequate consumption, by deficit or excess, of selected micronutrients on the quality of life and morbidity during aging, specifically considering increases in life expectancy and the costs of care in the older persons. Recent Findings: A literature review of the periods 2012 to 2018, focusing on vitamins A, B12, and D, calcium, iron and folate, was completed as these micronutrients are found to significantly affect the aging process. Causation and application of these micronutrients to disorders related to aging are controversial and mixed. This review highlights research needs and controversial points on the role of these micronutrients. Summary: Micronutrient deficiencies are a common and avoidable contributor to decreased quality of life and healthcare costs in the older persons. Further research is needed to determine adequate intakes and innovative uses, including appropriate thresholds for improved health outcomes for this population. PMID- 29721405 TI - Highly Efficient Infrared Photodetection in a Gate-Controllable Van der Waals Heterojunction with Staggered Bandgap Alignment. AB - In recent years, various van der Waals (vdW) materials have been used in implementing high-performance photodetectors with high photoresponsivity over a wide detection range. However, in most studies reported so far, photodetection in the infrared (IR) region has not been achieved successfully. Although several vdW materials with narrow bandgaps have been proposed for IR detection, the devices based on these materials exhibit notably low photoresponsivity under IR light illumination. Here, highly efficient near-infrared (NIR) photodetection based on the interlayer optical transition phenomenon in a vdW heterojunction structure consisting of ReS2 and ReSe2 is demonstrated. In addition, by applying the gate control function to the two-terminal vdW heterojunction photodetector, the photoresponsivity is enhanced to 3.64 * 105 A W-1 at lambda = 980 nm and 1.58 * 105 A W-1 at lambda = 1310 nm. Compared to the values reported for previous vdW photodetectors, these results are the highest levels of photoresponsivity in the NIR range. The study offers a novel device platform for achieving high performance IR photodetectors. PMID- 29721406 TI - Focused Ultrasound-Augmented Delivery of Biodegradable Multifunctional Nanoplatforms for Imaging-Guided Brain Tumor Treatment. AB - The blood brain barrier is the main obstacle to delivering diagnostic and therapeutic agents to the diseased sites of brain. It is still of great challenge for the combined use of focused ultrasound (FUS) and theranostic nanotechnology to achieve noninvasive and localized delivery of chemotherapeutic drugs into orthotopic brain tumor. In this work, a unique theranostic nanoplatform for highly efficient photoacoustic imaging-guided chemotherapy of brain tumor both in vitro and in vivo, which is based on the utilization of hollow mesoporous organosilica nanoparticles (HMONs) to integrate ultrasmall Cu2-x Se particles on the surface and doxorubicin inside the hollow interior, is synthesized. The developed multifunctional theranostic nanosystems exhibit tumor-triggered programmed destruction due to the reducing microenvironment-responsive cleavage of disulfide bonds that are incorporated into the framework of HMONs and linked between HMONs and Cu2-x Se, resulting in tumor-specific biodegradation and on demand drug-releasing behavior. Such tumor microenvironment-responsive biodegradable and biocompatible theranostic nanosystems in combination with FUS provide a promising delivery nanoplatform with high performance for orthotopic brain tumor imaging and therapy. PMID- 29721407 TI - 3D Fabrication with Integration Molding of a Graphene Oxide/Polycaprolactone Nanoscaffold for Neurite Regeneration and Angiogenesis. AB - Treating peripheral nerve injury faces major challenges and may benefit from bioactive scaffolds due to the limited autograft resources. Graphene oxide (GO) has emerged as a promising nanomaterial with excellent physical and chemical properties. GO has functional groups that confer biocompatibility that is better than that of graphene. Here, GO/polycaprolactone (PCL) nanoscaffolds are fabricated using an integration molding method. The nanoscaffolds exhibit many merits, including even GO nanoparticle distribution, macroporous structure, and strong mechanical support. Additionally, the process enables excellent quality control. In vitro studies confirm the advantages of the GO/PCL nanoscaffolds in terms of Schwann cell proliferation, viability, and attachment, as well as neural characteristics maintenance. This is the first study to evaluate the in vivo performance of GO-based nanoscaffolds in this context. GO release and PCL biodegradation is analyzed after long-term in vivo study. It is also found that the GO/PCL nerve guidance conduit could successfully repair a 15 mm sciatic nerve defect. The pro-angiogenic characteristic of GO is evaluated in vivo using immunohistochemistry. In addition, the AKT-endothelial nitric oxide synthase (eNOS)-vascular endothelial growth factor (VEGF) signaling pathway might play a major role in the angiogenic process. These findings demonstrate that the GO/PCL nanoscaffold efficiently promotes functional and morphological recovery in peripheral nerve regeneration, indicating its promise for tissue engineering applications. PMID- 29721409 TI - In Situ Monitoring of MicroRNA Replacement Efficacy and Accurate Imaging-Guided Cancer Therapy through Light-Up Inter-Polyelectrolyte Nanocomplexes. AB - Replacement of downregulated tumor-suppressive microRNA (Ts-miRNA) is recognized as an alternative approach for tumor gene therapy. However, in situ monitoring of miRNA replacement efficacy in a real-time manner via noninvasive imaging is continually challenging. Here, glutathione (GSH)-activated light-up peptide polysaccharide-inter-polyelectrolyte nanocomplexes are established through self assembly of carboxymethyl dextran with disulfide-bridged ("S-S") oligoarginine peptide (S-Arg4), in which microRNA-34a (miR-34a) and indocyanine green (ICG) are simultaneously embedded and the nanocomplexes are subsequently stabilized by intermolecular cross-linking. Upon confinement within the robust nanocomplexes, the near-infrared fluorescence (NIRF) of ICG is considerably quenched ("off") due to the aggregation-caused quenching effect. However, after intracellular delivery, the disulfide bond in S-Arg4 can be cleaved by intracellular GSH, which leads to the dissociation of nanocomplexes and triggers the simultaneous release of miR-34a and ICG. The NIRF of ICG is concomitantly activated through dequenching of the aggregated ICG. Very interestingly, a good correlation between time-dependent increase in NIRF intensity and miR-34a replacement efficacy is found in nanocomplexes-treated tumor cells and tumor tissues through either intratumoral or intravenous injections. Systemic nanocomplexes-mediated miR-34a replacement significantly suppresses the growth of HepG-2- and MDA-MB-231-derived tumor xenografts, and provides a pronounced survival benefit in these animal models. PMID- 29721410 TI - Metal-Organic Framework-Derived ZnO/ZnS Heteronanostructures for Efficient Visible-Light-Driven Photocatalytic Hydrogen Production. AB - Developing highly active, recyclable, and inexpensive photocatalysts for hydrogen evolution reaction (HER) under visible light is significant for the direct conversion of solar energy into chemical fuels for various green energy applications. For such applications, it is very challenging but vitally important for a photocatalyst to simultaneously enhance the visible-light absorption and suppress photogenerated electron-hole recombination, while also to maintain high stability and recyclability. Herein, a metal-organic framework (MOF)-templated strategy has been developed to prepare heterostructured nanocatalysts with superior photocatalytic HER activity. Very uniquely, the synthesized photocatalytic materials can be recycled easily after use to restore the initial photocatalytic activity. It is shown that by controlling the calcination temperature and time with MOF-5 as a host and guest thioacetamide as a sulfur source, the chemical compositions of the formed heterojunctions of ZnO/ZnS can be tuned to further enhance the visible-light absorption and photocatalytic activity. The nanoscale heterojunction ZnO/ZnS structural feature serves to reduce the average free path of charge carriers and improve the charge separation efficiency, thus leading to significantly enhanced HER activity under visible light irradiation (lambda > 420 nm) with high stability and recyclability without any cocatalyst. PMID- 29721411 TI - Tin Selenide (SnSe): Growth, Properties, and Applications. AB - The indirect bandgap semiconductor tin selenide (SnSe) has been a research hotspot in the thermoelectric fields since a ZT (figure of merit) value of 2.6 at 923 K in SnSe single crystals along the b-axis is reported. SnSe has also been extensively studied in the photovoltaic (PV) application for its extraordinary advantages including excellent optoelectronic properties, absence of toxicity, cheap raw materials, and relative abundance. Moreover, the thermoelectric and optoelectronic properties of SnSe can be regulated by the structural transformation and appropriate doping. Here, the studies in SnSe research, from its evolution to till now, are reviewed. The growth, characterization, and recent developments in SnSe research are discussed. The most popular growth techniques that have been used to prepare SnSe materials are discussed in detail with their recent progress. Important phenomena in the growth of SnSe as well as the problems remaining for future study are discussed. The applications of SnSe in the PV fields, Li-ion batteries, and other emerging fields are also discussed. PMID- 29721408 TI - Polysaccharide-Based Controlled Release Systems for Therapeutics Delivery and Tissue Engineering: From Bench to Bedside. AB - Polysaccharides or polymeric carbohydrate molecules are long chains of monosaccharides that are linked by glycosidic bonds. The naturally based structural materials are widely applied in biomedical applications. This article covers four different types of polysaccharides (i.e., alginate, chitosan, hyaluronic acid, and dextran) and emphasizes their chemical modification, preparation approaches, preclinical studies, and clinical translations. Different cargo fabrication techniques are also presented in the third section. Recent progresses in preclinical applications are then discussed, including tissue engineering and treatment of diseases in both therapeutic and monitoring aspects. Finally, clinical translational studies with ongoing clinical trials are summarized and reviewed. The promise of new development in nanotechnology and polysaccharide chemistry helps clinical translation of polysaccharide-based drug delivery systems. PMID- 29721413 TI - Superhydrophobic WS2-Nanosheet-Wrapped Sponges for Underwater Detection of Tiny Vibration. AB - Underwater vibration detection is of great importance in personal safety, environmental protection, and military defense. Sealing layers are required in many underwater sensor architectures, leading to limited working-life and reduced sensitivity. Here, a flexible, superhydrophobic, and conductive tungsten disulfide (WS2) nanosheets-wrapped sponge (SCWS) is reported for the high sensitivity detection of tiny vibration from the water surfaces and from the grounds. When the SCWS is immersed in water, a continuous layer of bubbles forms on its surfaces, providing the sensor with two special abilities. One is sealing free feature due to the intrinsic water-repellent property of SCWS. The other is functioning as a vibration-sensitive medium to convert mechanical energy into electric signals through susceptible physical deformation of bubbles. Therefore, the SCWS can be used to precisely detect tiny vibration of water waves, and even sense those caused by human footsteps, demonstrating wide applications of this amphibious (water/ground) vibration sensor. Results of this study can initiate the exploration of superhydrophobic materials with elastic and conductive properties for underwater flexible electronic applications. PMID- 29721412 TI - Exosome-Liposome Hybrid Nanoparticles Deliver CRISPR/Cas9 System in MSCs. AB - Targeted delivery of clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system to the receptor cells is essential for in vivo gene editing. Exosomes are intensively studied as a promising targeted drug delivery carrier recently, while limited by their low efficiency in encapsulating of large nucleic acids. Here, a kind of hybrid exosomes with liposomes is developed via simple incubation. Different from the original exosomes, the resultant hybrid nanoparticles efficiently encapsulate large plasmids, including the CRISPR-Cas9 expression vectors, similarly as the liposomes. Moreover, the resultant hybrid nanoparticles can be endocytosed by and express the encapsulated genes in the mesenchymal stem cells (MSCs), which cannot be transfected by the liposome alone. Taken together, the exosome-liposome hybrid nanoparticles can deliver CRISPR-Cas9 system in MSCs and thus be promising in in vivo gene manipulation. PMID- 29721414 TI - Oxygen-Vacancy Abundant Ultrafine Co3O4/Graphene Composites for High-Rate Supercapacitor Electrodes. AB - The metal oxides/graphene composites are one of the most promising supercapacitors (SCs) electrode materials. However, rational synthesis of such electrode materials with controllable conductivity and electrochemical activity is the topical challenge for high-performance SCs. Here, the Co3O4/graphene composite is taken as a typical example and develops a novel/universal one-step laser irradiation method that overcomes all these challenges and obtains the oxygen-vacancy abundant ultrafine Co3O4 nanoparticles/graphene (UCNG) composites with high SCs performance. First-principles calculations show that the surface oxygen vacancies can facilitate the electrochemical charge transfer by creating midgap electronic states. The specific capacitance of the UCNG electrode reaches 978.1 F g-1 (135.8 mA h g-1) at the current densities of 1 A g-1 and retains a high capacitance retention of 916.5 F g-1 (127.3 mA h g-1) even at current density up to 10 A g-1, showing remarkable rate capability (more than 93.7% capacitance retention). Additionally, 99.3% of the initial capacitance is maintained after consecutive 20 000 cycles, demonstrating enhanced cycling stability. Moreover, this proposed laser-assisted growth strategy is demonstrated to be universal for other metal oxide/graphene composites with tuned electrical conductivity and electrochemical activity. PMID- 29721415 TI - A Ultrasensitive Near-Infrared Fluorescent Probe Reveals Pyroglutamate Aminopeptidase 1 Can Be a New Inflammatory Cytokine. AB - Previous study showed that pyroglutamate aminopeptidase 1 (PGP-1) has a relationship with the immune response in cells. However, whether PGP-1 is involved in inflammatory response in vivo and can serve as a new inflammatory cytokine are still unclear. To address these issues, a new near-infrared fluorescent probe, which exhibits high selectivity and super sensitivity, is developed. With this probe, the up-regulation of PGP-1 (evidenced by western blot) in BALB/c mice legs and livers under the stimulation of two main immunopotentiators is revealed for the first time. The occurrence of inflammatory process (including tissue necrosis) in mice is determined by up-regulation of tumor necrosis factor-alpha and hematoxylin-eosin staining. Interestingly, it is revealed for the first time that knocking down PGP-1 leads to the weakness of inflammatory process in RAW264.7 cells. These new findings suggest that PGP-1 is indeed involved in inflammatory response in vivo and can be a new inflammatory cytokine. PMID- 29721416 TI - A Platform for High-Throughput Assessments of Environmental Multistressors. AB - A platform compatible with microtiter plates to parallelize environmental treatments to test the complex impacts of multiple stressors, including parameters relevant to climate change and point source pollutants is developed. This platform leverages (1) the high rate of purely diffusive gas transport in aerogels to produce well-defined centimeter-scale gas concentration gradients, (2) spatial light control, and (3) established automated liquid handling. The parallel gaseous, aqueous, and light control provided by the platform is compatible with multiparameter experiments across the life sciences. The platform is applied to measure biological effects in over 700 treatments in a five parameter full factorial study with the microalgae Chlamydomonas reinhardtii. Further, the CO2 response of multicellular organisms, Lemna gibba and Artemia salina under surfactant and nanomaterial stress are tested with the platform. PMID- 29721417 TI - Recent Advances in Sensitized Photocathodes: From Molecular Dyes to Semiconducting Quantum Dots. AB - The increasing demand for sustainable and environmentally benign energy has stimulated intense research to establish highly efficient photo-electrochemical (PEC) cells for direct solar-to-fuel conversion via water splitting. Light absorption, as the initial step of the catalytic process, is regarded as the foundation of establishing highly efficient PEC systems. To make full use of visible light, sensitization on photoelectrodes using either molecular dyes or semiconducting quantum dots provides a promising method. In this field, however, there remain many fundamental issues to be solved, which need in-depth study. Here, fundamental knowledge of PEC systems is introduced to enable readers a better understanding of this field. Then, the development history and current state in both molecular dye- and quantum dot-sensitized photocathodes for PEC water splitting are discussed. A systematical comparison between the two systems has been made. Special emphasis is placed on the research of quantum dot sensitized photocathodes, which have shown superiority in both efficiency and durability towards PEC water splitting at the present stage. Finally, the opportunities and challenges in the future for sensitized PEC water-splitting systems are proposed. PMID- 29721419 TI - Aluminum Chloride-Graphite Batteries with Flexible Current Collectors Prepared from Earth-Abundant Elements. AB - In the search for low-cost and large-scale stationary storage of electricity, nonaqueous aluminum chloride-graphite batteries (AlCl3-GBs) have received much attention due to the high natural abundances of their primary constituents, facile manufacturing, and high energy densities. Much research has focused on the judicious selection of graphite cathode materials, leading to the most notable recent advances in the performance of AlCl3-GBs. However, the major obstacle to commercializing this technology is the lack of oxidatively stable, inexpensive current collectors that can operate in chloroaluminate ionic liquids and are composed of earth-abundant elements. This study presents the use of titanium nitride (TiN) as a compelling material for this purpose. Flexible current collectors can be fabricated by coating TiN on stainless steel or flexible polyimide substrates by low-cost, rapid, scalable methods such as magnetron sputtering. When these current collectors are used in AlCl3-GB coin or pouch cells, stable cathodic operation is observed at voltages of up to 2.5 V versus Al3+/Al. Furthermore, these batteries have a high coulombic efficiency of 99.5%, power density of 4500 W kg-1, and cyclability of at least 500 cycles. PMID- 29721420 TI - A Micropatterned Multielectrode Shell for 3D Spatiotemporal Recording from Live Cells. AB - Microelectrode arrays (MEAs) have proved to be useful tools for characterizing electrically active cells such as cardiomyocytes and neurons. While there exist a number of integrated electronic chips for recording from small populations or even single cells, they rely primarily on the interface between the cells and 2D flat electrodes. Here, an approach that utilizes residual stress-based self folding to create individually addressable multielectrode interfaces that wrap around the cell in 3D and function as an electrical shell-like recording device is described. These devices are optically transparent, allowing for simultaneous fluorescence imaging. Cell viability is maintained during and after electrode wrapping around the cel and chemicals can diffuse into and out of the self folding devices. It is further shown that 3D spatiotemporal recordings are possible and that the action potentials recorded from cultured neonatal rat ventricular cardiomyocytes display significantly higher signal-to-noise ratios in comparison with signals recorded with planar extracellular electrodes. It is anticipated that this device can provide the foundation for the development of new-generation MEAs where dynamic electrode-cell interfacing and recording substitutes the traditional method using static electrodes. PMID- 29721421 TI - Cation Substitution in Earth-Abundant Kesterite Photovoltaic Materials. AB - As a promising candidate for low-cost and environmentally friendly thin-film photovoltaics, the emerging kesterite-based Cu2ZnSn(S,Se)4 (CZTSSe) solar cells have experienced rapid advances over the past decade. However, the record efficiency of CZTSSe solar cells (12.6%) is still significantly lower than those of its predecessors Cu(In,Ga)Se2 (CIGS) and CdTe thin-film solar cells. This record has remained for several years. The main obstacle for this stagnation is unanimously attributed to the large open-circuit voltage (VOC) deficit. In addition to cation disordering and the associated band tailing, unpassivated interface defects and undesirable energy band alignment are two other culprits that account for the large VOC deficit in kesterite solar cells. To capture the great potential of kesterite solar cells as prospective earth-abundant photovoltaic technology, current research focuses on cation substitution for CZTSSe-based materials. The aim here is to examine recent efforts to overcome the VOC limit of kesterite solar cells by cation substitution and to further illuminate several emerging prospective strategies, including: i) suppressing the cation disordering by distant isoelectronic cation substitution, ii) optimizing the junction band alignment and constructing a graded bandgap in absorber, and iii) engineering the interface defects and enhancing the junction band bending. PMID- 29721423 TI - Moving to Aqueous Binder: A Valid Approach to Achieving High-Rate Capability and Long-Term Durability for Sodium-Ion Battery. AB - Polyanionic Na3V2(PO4)2F3 with a NASICON-type structure is heralded as a promising cathode material for sodium-ion batteries due to its fast ionic conduction, high working voltage, and favorable structural stability. However, a number of challenging issues remain regarding its rate capability and cycle life, which must be addressed to enable greater application compatibility. Here, a facile and effective approach that can be used to overcome these disadvantages by introducing an aqueous carboxymethyl cellulose (CMC) binder is reported. The resulting conductive network serves to accelerate the diffusion of Na+ ions across the interface as well as in the bulk. The strong binding force of the CMC and stable solid permeable interface protect the electrode from degradation, leading to an excellent capacity of 75 mA h g-1 at an ultrahigh rate of 70 C (1 C = 128 mA g-1) and a long lifespan of 3500 cycles at 30 C while sustaining 79% of the initial capacity value. A full cell based on this electrode material delivers an impressive energy density as high as 216 W h kg-1, indicating the potential for application of this straightforward and cost-effective route for the future development of advanced battery technologies. PMID- 29721418 TI - Advanced Architectures and Relatives of Air Electrodes in Zn-Air Batteries. AB - Zn-air batteries are becoming the promising power sources for portable and wearable electronic devices and hybrid/electric vehicles because of their high specific energy density and the low cost for next-generation green and sustainable energy technologies. An air electrode integrated with an oxygen electrocatalyst is the most important component and inevitably determines the performance and cost of a Zn-air battery. This article presents exciting advances and challenges related to air electrodes and their relatives. After a brief introduction of the Zn-air battery, the architectures and oxygen electrocatalysts of air electrodes and relevant electrolytes are highlighted in primary and rechargeable types with different configurations, respectively. Moreover, the individual components and major issues of flexible Zn-air batteries are also highlighted, along with the strategies to enhance the battery performance. Finally, a perspective for design, preparation, and assembly of air electrodes is proposed for the future innovations of Zn-air batteries with high performance. PMID- 29721424 TI - NIR-Triggered Crystal Phase Transformation of NiTi-Layered Double Hydroxides Films for Localized Chemothermal Tumor Therapy. AB - Construction of localized drug-eluting systems with synergistic chemothermal tumor-killing abilities is promising for biomedical implants directly contacting with tumor tissues. In this study, an intelligent and biocompatible drug-loading platform, based on a gold nanorods-modified butyrate-inserted NiTi-layered double hydroxides film (Au@LDH/B), is prepared on the surface of nitinol alloy. The prepared films function as drug-loading "sponges," which pump butyrate out under near-infrared (NIR) irradiation and resorb drugs in water when the NIR laser is shut off. The stimuli-responsive release of butyrate is verified to be related with the NIR-triggered crystal phase transformation of Au@LDH/B. In vitro and in vivo studies reveal that the prepared films possess excellent biosafety and high efficiency in synergistic thermochemo tumor therapy, showing a promising application in the construction of localized stimuli-responsive drug-delivery systems. PMID- 29721422 TI - Runx2/Osterix and Zinc Uptake Synergize to Orchestrate Osteogenic Differentiation and Citrate Containing Bone Apatite Formation. AB - Citrate is essential to biomineralization of the bone especially as an integral part of apatite nanocomposite. Citrate precipitate of apatite is hypothesized to be derived from mesenchymal stem/stromal cells (MSCs) upon differentiation into mature osteoblasts. Based on 13C-labeled signals identified by solid-state multinuclear magnetic resonance analysis, boosted mitochondrial activity and carbon-source replenishment of tricarboxylic acid cycle intermediates coordinate to feed forward mitochondrial anabolism and deposition of citrate. Moreover, zinc (Zn2+) is identified playing dual functions: (i) Zn2+ influx is influenced by ZIP1 which is regulated by Runx2 and Osterix to form a zinc-Runx2/Osterix-ZIP1 regulation axis promoting osteogenic differentiation; (ii) Zn2+ enhances citrate accumulation and deposition in bone apatite. Furthermore, age-related bone loss is associated with Zn2+ and citrate homeostasis; whereas, restoration of Zn2+ uptake alleviates age-associated declining osteogenic capacity and amount of citrate deposition. Together, these results indicate that citrate is not only a key metabolic intermediate meeting the emerging energy demand of differentiating MSCs but also participates in extracellular matrix mineralization, providing mechanistic insight into Zn2+ homeostasis and bone formation. PMID- 29721425 TI - Bioinspired Superdurable Pestle-Loop Mechanical Interlocker with Tunable Peeling Force, Strong Shear Adhesion, and Low Noise. AB - Velcro, the most typical hook-loop interlocker, often suffers from undesirable deformation, breaking, and noise because of the structure of the hook. Inspired by the arrester system of dragonfly, a new mechanical interlocker with a nylon pestle instead of the traditional hook is developed. The pestle-loop mechanical interlocker shows a tunable peeling force from 0.4 +/- 0.14 to 6.5 +/- 0.72 N and the shear adhesion force of pestle-loop mechanical interlocker is about twice as much as that of velcro. The pestle tape can be separated and fastened with the loop tape up to 30 000 cycles while keeping the original adhesive force and the pestle structure. In comparison, only after 4000 cycles most hooks of the commercial velcro are deformed and even broken, completely losing their adhesive function and their hook structure. These experimental results are further supported by finite element simulitions-the base of pestle mainly bears the separation-caused strain while the middle of hook does. Notably, the sound volume during the separation of pestle-loop mechanical interlocker is merely 49 +/- 7.4 dB, much lower than 70 +/- 3.5 dB produced by the velcro. PMID- 29721426 TI - Hybrid Perovskites: Prospects for Concentrator Solar Cells. AB - Perovskite solar cells have shown a meteoric rise of power conversion efficiency and a steady pace of improvements in their stability of operation. Such rapid progress has triggered research into approaches that can boost efficiencies beyond the Shockley-Queisser limit stipulated for a single-junction cell under normal solar illumination conditions. The tandem solar cell architecture is one concept here that has recently been successfully implemented. However, the approach of solar concentration has not been sufficiently explored so far for perovskite photovoltaics, despite its frequent use in the area of inorganic semiconductor solar cells. Here, the prospects of hybrid perovskites are assessed for use in concentrator solar cells. Solar cell performance parameters are theoretically predicted as a function of solar concentration levels, based on representative assumptions of charge-carrier recombination and extraction rates in the device. It is demonstrated that perovskite solar cells can fundamentally exhibit appreciably higher energy-conversion efficiencies under solar concentration, where they are able to exceed the Shockley-Queisser limit and exhibit strongly elevated open-circuit voltages. It is therefore concluded that sufficient material and device stability under increased illumination levels will be the only significant challenge to perovskite concentrator solar cell applications. PMID- 29721427 TI - Nonspiro, Fluorene-Based, Amorphous Hole Transporting Materials for Efficient and Stable Perovskite Solar Cells. AB - Novel nonspiro, fluorene-based, small-molecule hole transporting materials (HTMs) V1050 and V1061 are designed and synthesized using a facile three-step synthetic route. The synthesized compounds exhibit amorphous nature with a high glass transition temperature, a good solubility, and decent thermal stability. The planar perovskite solar cells (PSCs) employing V1050 generated an excellent power conversion efficiency of 18.3%, which is comparable to 18.9% obtained with the state-of-the-art Spiro-OMeTAD. Importantly, the devices based on V1050 and V1061 show better stability compared to devices based on Spiro-OMeTAD when aged without any encapsulation under uncontrolled humidity conditions (relative humidity around 60%) in the dark and under continuous full sun illumination. PMID- 29721428 TI - High Performance Amplifier Element Realization via MoS2/GaTe Heterostructures. AB - 2D layered materials (2DLMs), together with their heterostructures, have been attracting tremendous research interest in recent years because of their unique physical and electrical properties. A variety of circuit elements have been made using mechanically exfoliated 2DLMs recently, including hard drives, detectors, sensors, and complementary metal oxide semiconductor field-effect transistors. However, 2DLM-based amplifier circuit elements are rarely studied. Here, the integration of 2DLMs with 3D bulk materials to fabricate vertical junction transistors with current amplification based on a MoS2/GaTe heterostructure is reported. Vertical junction transistors exhibit the typical current amplification characteristics of conventional bulk bipolar junction transistors while having good current transmission coefficients (alpha ~ 0.95) and current gain coefficient (beta ~ 7) at room temperature. The devices provide new attractive prospects in the investigation of 2DLM-based integrated circuits based on amplifier circuits. PMID- 29721429 TI - Spin Solid versus Magnetic Charge Ordered State in Artificial Honeycomb Lattice of Connected Elements. AB - The nature of magnetic correlation at low temperature in two-dimensional artificial magnetic honeycomb lattice is a strongly debated issue. While theoretical researches suggest that the system will develop a novel zero entropy spin solid state as T -> 0 K, a confirmation to this effect in artificial honeycomb lattice of connected elements is lacking. This study reports on the investigation of magnetic correlation in newly designed artificial permalloy honeycomb lattice of ultrasmall elements, with a typical length of ~12 nm, using neutron scattering measurements and temperature-dependent micromagnetic simulations. Numerical modeling of the polarized neutron reflectometry data elucidates the temperature-dependent evolution of spin correlation in this system. As temperature reduces to ~7 K, the system tends to develop novel spin solid state, manifested by the alternating distribution of magnetic vortex loops of opposite chiralities. Experimental results are complemented by temperature dependent micromagnetic simulations that confirm the dominance of spin solid state over local magnetic charge ordered state in the artificial honeycomb lattice with connected elements. These results enable a direct investigation of novel spin solid correlation in the connected honeycomb geometry of 2D artificial structure. PMID- 29721431 TI - Ultrathin Organic Solar Cells with a Power Conversion Efficiency of Over ~13.0%, Based on the Spatial Corrugation of the Metal Electrode-Cathode Fabry-Perot Cavity. AB - The application of nanophotonic structures for organic solar cells (OSCs) is quite popular and successful, and has led to increased optical absorption, better spectral overlap with solar irradiances, and improved charge collection. Significant improvements in the power conversion efficiency (PCE) have also been reported, exceeding 11%. Nonetheless, with the given material properties of OSCs with low optical absorption, narrow spectrum, short transport length of carriers, and nonuniform photocarrier generations resulting from the nanophotonic structure, the PCE of single-junction OSCs has been stagnant over the past few years, at a barrier of 12%. Here, an ultrathin inverted OSC structure with the highest efficiency of ~13.0%, while being made from widely used organic materials, is demonstrated. By introducing a smooth spatial corrugation to the vertical plasmonic cavity enclosing the active layer, in-plane propagation modes and hybridized Fabry-Perot cavity modes inside the corrugated cavity are derived to achieve an ultralow Q, uniform coverage of optical absorption, in addition to uniform photocarrier generation and transport. As the first demonstration of ultra-broadband absorption with the introduction of spatial corrugation to the ultrathin metal film electrode-cathode Fabry-Perot cavity, future applications of the same concept in other light-harvesting devices utilizing different materials and structures are expected. PMID- 29721430 TI - Triboelectric-Based Transparent Secret Code. AB - Private and security information for personal identification requires an encrypted tool to extend communication channels between human and machine through a convenient and secure method. Here, a triboelectric-based transparent secret code (TSC) that enables self-powered sensing and information identification simultaneously in a rapid process method is reported. The transparent and hydrophobic TSC can be conformed to any cambered surface due to its high flexibility, which extends the application scenarios greatly. Independent of the power source, the TSC can induce obvious electric signals only by surface contact. This TSC is velocity-dependent and capable of achieving a peak voltage of ~4 V at a resistance load of 10 MOmega and a sliding speed of 0.1 m s-1, according to a 2 mm * 20 mm rectangular stripe. The fabricated TSC can maintain its performance after reciprocating rolling for about 5000 times. The applications of TSC as a self-powered code device are demonstrated, and the ordered signals can be recognized through the height of the electric peaks, which can be further transferred into specific information by the processing program. The designed TSC has great potential in personal identification, commodity circulation, valuables management, and security defense applications. PMID- 29721432 TI - High-Efficiency Fullerene Solar Cells Enabled by a Spontaneously Formed Mesostructured CuSCN-Nanowire Heterointerface. AB - Fullerenes and their derivatives are widely used as electron acceptors in bulk heterojunction organic solar cells as they combine high electron mobility with good solubility and miscibility with relevant semiconducting polymers. However, studies on the use of fullerenes as the sole photogeneration and charge-carrier material are scarce. Here, a new type of solution-processed small-molecule solar cell based on the two most commonly used methanofullerenes, namely [6,6]-phenyl C61-butyric acid methyl ester (PC60BM) and [6,6]-phenyl-C71-butyric acid methyl ester (PC70BM), as the light absorbing materials, is reported. First, it is shown that both fullerene derivatives exhibit excellent ambipolar charge transport with balanced hole and electron mobilities. When the two derivatives are spin-coated over the wide bandgap p-type semiconductor copper (I) thiocyanate (CuSCN), cells with power conversion efficiency (PCE) of ~1%, are obtained. Blending the CuSCN with PC70BM is shown to increase the performance further yielding cells with an open-circuit voltage of ~0.93 V and a PCE of 5.4%. Microstructural analysis reveals that the key to this success is the spontaneous formation of a unique mesostructured p-n-like heterointerface between CuSCN and PC70BM. The findings pave the way to an exciting new class of single photoactive material based solar cells. PMID- 29721433 TI - Lectin binding patterns and immunohistochemical antigen detection in placenta and lungs of Brucella abortus-bovine infected fetuses. AB - Lectin binding relies on the affinity of these substances for specific terminal sugars. The method facilitates the identification of complex structures to which the terminal sugar attaches and may reveal physiological or pathological changes in cells, intracellular interactions or extracellular transport pathways. This study was carried out to investigate the effect of infection with Brucella abortus on the pattern of lectin binding in bovine fetal lungs (n=6) and bovine placentas (n=5). Fetal lungs and placenta from heifers experimentally inoculated with B. abortus, strain 2308 were examined by histological, lectin-histochemical, immunohistochemical and cultural techniques. B. abortus antigens were immunohistochemically detected in fetal lungs and placenta. An increase in the labeling with UEA-1, DBA, PNA, RCA-1 and SBA was found in the lungs and an increase in the labeling with UEA-1, ConA, PNA, DBA was found in the placentas. The present lectin histochemical study revealed a distinctive pattern of oligosaccharide distribution in the lungs and placenta of B. abortus-infected fetuses. PMID- 29721434 TI - Physiological parameter values in greyhounds before and after high-intensity exercise. AB - Dog sports competitions have greatly expanded. The availability of reference values for each type of activity could help assess fitness accurately. Heart rate (HR), blood lactate (BL) and rectal temperature (RT) are relevant physiological parameters to determine the dogs response to effort. Previous studies in greyhounds have reported the effect of high-intensity exercise on many physiological parameters immediately after completing different racing distances and recovery times. However, there are no studies concerning physiological changes over shorter racing distances. We therefore assessed the effect of sprint exercise on HR, BL and RT in nine greyhounds performing sprint exercise over a 100-m distance chasing a lure. After the exercise, dogs underwent a passive 10 min recovery phase. Before the exercise, immediately after it and at 5 and 10 min during recovery, HR and RT were assessed and blood samples were collected for BL determination. HR, BL and RT values increased significantly after the exercise (P<0.01). Whereas HR returned to pre-exercise values at 10 min during the recovery phase (P>0.1), BL concentration and RT remained increased (P<0.01). The abrupt increase in HR, BL and RT values observed immediately after the exercise indicates the high intensity of the effort performed. Similarly, BL concentration after the exercise exceeded the 4 mmol/L lactate threshold, suggesting a predominant anaerobic metabolism during effort. Although HR returned to pre exercise values 10 min after the exercise, a more extensive recovery phase would be necessary for a total return to resting values, particularly for BL and RT. In greyhounds subjected to high-intensity exercise, HR, BL and RT were reliable physiological parameters to accurately assess the physiological response to effort. The use of sprint exercises over short racing distances could be useful for appropriately monitoring fitness in sporting dogs. PMID- 29721435 TI - The influence of the tonometer position on canine intraocular pressure measurements using the Tonovet(r) rebound tonometer. AB - The objective of this study was to assess the variability of readings made using the Tonovet(r) rebound tonometer for measurement of intraocular pressure (IOP) in the peripheral cornea and in angulated positions on the canine corneal surface. Forty-six client-owned dogs admitted for ophthalmic evaluation at the Queen's Veterinary School Hospital, University of Cambridge were included in the study. IOP readings were taken at a variety of locations and using the tonometer at a number of different angles to the cornea: 1) Perpendicularly at center of the cornea (CC); 2) At the center of the cornea but with the tonometer positioned at four angles, and 3) At four different points on the peripheral cornea. All values were compared with the values recorded at the recommended CC position. IOP values were significantly underestimated in seven positions, with median and interquartile range from 12.1 +/- 4 mmHg (nasal on periphery) to 15 +/- 5 mmHg (laterally angled at center), varying between 0 mmHg to 2.9 mmHg from the CC value. While dorsally angled in the central cornea were not significantly different from those at CC (p = 0.09). Median values were lower for measurements in peripheral positions when compared to angled central positions. These results demonstrate that angling the tonometer or measuring in peripheral regions can result in small but statistically significant underestimation of IOP values. PMID- 29721436 TI - Overexpression of 11beta-hydroxysteroid dehydrogenase 1 in visceral adipose tissue and underexpression of endothelial nitric oxide synthase in the adrenal cortex of dogs with hyperadrenocorticism. AB - 11beta-Hydroxysteroid dehydrogenase 1 (11beta-HSD1) is an enzyme that activates cortisone into cortisol in tissues. Alterations in this enzyme are related to the development of metabolic syndrome, obesity and hyperadrenocorticism (HAC). Endothelial nitric oxide synthase (eNOS) produces nitric oxide and is related to the regulation of adrenal steroidogenesis. The aim of the study was to evaluate 11beta-HSD1 and eNOS expression in dogs with HAC. Visceral adipose tissue samples were taken to evaluate 11beta-HSD1 expression by immunohistochemistry and western blotting. In parallel, adrenal gland samples were collected to evaluate eNOS expression by immunohistochemistry. 11beta-HSD1 expression was significantly higher in the adipocytes of dogs with HAC than in those of the control dogs. eNOS expression in the adrenal cortex (zona fasciculata) was significantly lower in the dogs with HAC than in the control dogs. 11beta-HSD1 overexpression and eNOS underexpression could play a role in the maintenance of hypercortisolism in dogs with HAC. PMID- 29721437 TI - Decrease of nitric oxide and increase in diastolic blood pressure are two events that affect renal function in dogs with pituitary dependent hyperadrenocorticism. AB - Hyperadrenocorticism is a frequent disease in dogs. The excess of circulating cortisol affects different organs and metabolic pathways, producing severe adverse effects that endanger the animal's life. Among these effects, hypertension and renal damage can be mentioned. A group of 20 dogs with pituitary dependent hyperadrenocorticism (PDH) and 12 control dogs were used to study the following parameters: cortisol and nitric oxide (NO nit/nit) concentrations, diastolic and systolic blood pressure, renal artery resistance index by Doppler ultrasound, the rate of glomerular filtration by radio-renogram excretion and the presence of proteins in urine. Dogs with PDH showed a significantly lower NO nit/nit (P<0.0001) than the controls and this correlated with high values of diastolic and systolic pressure (r = -0.87; P<0.0001 and r = -0.81; P<0.0001 respectively). Most dogs (80%) are hypertensive mainly due to an increase in diastolic pressure, which correlated positively with the UPC (r = 0.8; P<0.001) and negatively with the glomerular rate of filtration (r = -0.58; P=0.007). Systolic pressure only increased in 60% of the cases and did not correlate with the mentioned variables. In PDH the decrease of NO affects blood pressure. The diastolic pressure would seem to have the greatest impact on the kidneys, therefore its evaluation and control are important to avoid and/or control renal damage. PMID- 29721438 TI - Correlations between the equine metacarpophalangeal joint angulation and toe conformation in statics. AB - The angulation of the equine fetlock determines the load of associated tendons and probably their predisposition for injuries. However, it is questionable how the individual toe conformation and tendon properties interact with the dorsal metacarpophalangeal joint angle (DMPJ). Data are needed for a tangible evaluation of the equine limb conformation for more specific orthopaedic treatment. The aim was to evaluate the correlation between the DMPJ, toe conformation and cross sectional area (CSA) of both flexor tendons; the superficial digital flexor tendon (SDFT) and deep digital flexor tendon (DDFT). Thirty Warmblood horses were available for the study. Lateromedial radiographs of the toe and fetlock and transverse ultrasound images of both flexor tendons were obtained from three zones. The DMPJ, length and angle of the phalanges and CSA SDFT/DDFT were measured. In addition, hoof angle, wither height, age, and sex were documented. Correlations were calculated using Pearson's test. A paired t-test was used to evaluate left-right differences. Length and angle of the proximal and middle phalanx were significantly associated with the DMPJ (r = -0.28 - -0.45, p<0.001 0.04). Neither the angle of the hoof and distal phalanx nor the CSA SDFT/DDFT, showed a noticeable correlation with the DMPJ. Significant left-right differences occurred for the DMPJ (p<0.002) and the angle of the proximal and middle phalanx (p<0.01 - 0.002). A moderate negative correlation was shown between the DMPJ and wither height (r = - 0.31, p=0.04). Results represent only a specific population. The study provides only a static evaluation of a dynamic situation. In a clinical context, it might be useful to focus on the angulation and length of the pastern to evaluate the individual load affecting the DMPJ and its associated structures. These findings might be relevant for orthopaedic treatments and shoeing recommendations. PMID- 29721439 TI - Recent approaches in food bio-preservation - a review. AB - Bio-preservation is a technique of extending the shelf life of food by using natural or controlled microbiota or antimicrobials. The fermentation products as well as beneficial bacteria are generally selected in this process to control spoilage and render pathogen inactive. The special interest organism or central organism used for this purpose is lactic acid bacteria (LAB) and their metabolites. They are capable to exhibit antimicrobial properties and helpful in imparting unique flavour and texture to the food products. The major compounds produced by LAB are bacteriocin, organic acids and hydrogen peroxide. Bacteriocin is peptides or proteins with antimicrobial activity. On the basis of size, structure and post-translational modification, bacteriocin is divided into four different classes. Due to non-toxic, non-immunogenic, thermo-resistance characteristics and broad bactericidal activity, LAB bacteriocins are considered good bio-preservative agents. The most common LAB bactriocin is nisin which has wider applications in food industry and has been Food and Drug Administration (FDA) approved. Nisin and other bacteriocin are being used in vegetables products, dairy and meat industries. Apart from LAB metabolites, bacteriophages and endolysins has promising role in food processing, preservation and safety. Bacteriocins and endolysins are more suitable for DNA shuffling and protein engineering to generate highly potent variants with expanded activity spectrum. Genetically modified bacteriophages may also be helpful in bio-preservation, however; their safety issues must be addressed properly before selection as bio preservative agent. PMID- 29721440 TI - Detection of virulence-associated genes in Brucella melitensis biovar 3, the prevalent field strain in different animal species in Egypt. AB - The current study involved detection of three virulence genes (bvfA, virB, ure) by PCR in 52 isolates of Brucella melitensis biovar 3, recovered from different animal species (28 sheep, 10 goats, 9 cattle and 5 buffaloes). Of the 52 B. melitensis strains; 48 (92.3%) isolates carried bvfA genes, 51 (98.1%) isolates had virB genes and 50 (96.2%) isolates were positive for ure genes. The distribution of the virulence genes is not affected by crossing the original host barriers of the animal species, as the three virulence factors (bvfA, virB and ure) detected in 28 B. melitensis isolates obtained from ovine species in a ratio of 26/28 (92.9%), 27/28 (96.4%) and 28/28 (100%), respectively. While 10 isolates originating from goats revealed a ratio of 10/10 (100%), 10/10 (100%) and 9/10 (90%) to the same order of virulence genes. Nearly, similar results of virulence genes detection were obtained in B. melitensis obtained from bovine (8/9, 9/9 and 8/9) and Buffalos (4/5, 5/5 and 5/5), respectively. The high prevalence of virulence-associated genes among the B. melitensis isolates detected from different animal species in Egypt indicates a potential virulence of this bacterium. PMID- 29721441 TI - Indolent, T-cell, large granular lymphocytic leukaemia in a dog presenting with severe neutropenia and an absence of lymphocytosis. AB - In humans, large granular lymphocytic leukaemia (LGLL) is a low-grade, indolent lymphoproliferative disorder of large granular lymphocytes (LGL) associated with autoimmune disorders; including rheumatoid arthritis and single or multiple cytopenias; particularly neutropenia. Therapy largely centres around immunosuppression which aims to resolve the immune-mediated secondary pathology, often without eradicating the neoplastic clone. The most effective agents appear to be cyclophosphamide, cyclosporine and methotrexate. This case report describes the presentation, diagnostics, therapeutic approach and outcome of a 6 year-old Golden Retriever presenting with severe neutropenia. Chlorambucil, prednisolone and cyclosporine failed to improve the neutropenia but subsequent cyclophosphamide resulted in a sustained albeit temporary improvement in neutrophil count and the ability to withdraw prophylactic antibacterials. This case closely mirrors the diagnostics and therapeutic response in human LGLL. PMID- 29721442 TI - Phacoemulsification of bilateral cataracts in two pet rabbits. AB - Two 3 year-old, healthy, client-owned Lop rabbits presented with bilateral cataracts. After performing a physical examination, bloodwork, ocular ultrasonography and electroretinography, both animals were deemed good surgical candidates for phacoemulsification. Bilateral cataract surgery was performed and both rabbits regained vision in both eyes. Both animals developed post-operative ocular hypertension and one animal developed corneal ulcers immediately after surgery. Both surgical complications resolved with medical management. This case series describes phacoemulsification of bilateral cataracts in 2 companion rabbits and the use of an intraocular lens in 1 rabbit. Surgical treatment of cataracts can be considered as a treatment option whenever a healthy rabbit is visually impaired due to cataracts. PMID- 29721443 TI - First isolation and molecular characterization of Suid herpesvirus type 1 from a domestic dog in Argentina. AB - Since Aujeszky's disease (pseudorabies), which is caused by Suid herpesvirus type 1 (SuHV-1), was first notified in Argentina in 1978, many SuHV-1 strains have been isolated from swine. However, this disease can affect other vertebrates, such as dogs (secondary hosts), and lead to fatal neurological disease. The objective of the current work is to report the first isolation and molecular characterization of SuHV-1 from a dead domestic dog from Santa Fe Province (Argentina), which had had nervous signs compatible with pseudorabies. Samples of brain and trigeminal ganglia from this dog were obtained and fixed in formol for histopathology, and virology studies were conducted after cell disruption. Supernatants of both samples were inoculated onto RK13 cells and, after 72 h, DNA was extracted with phenol-chloroform. Purified DNA was cut with a restriction enzyme and subjected to agarose gel and an aliquot was used to amplify the gD and gC genes by PCR. The gC sequence was compared with other public sequences. The strain isolated from the dog was similar to other Argentinean swine strains. PMID- 29721444 TI - Limited clinical utility of HLA-Cw6 genotyping for outcome prediction in psoriasis patients under ustekinumab therapy: a monocentric, retrospective analysis. AB - Purpose: Several studies have suggested that an HLA-Cw6+ allele can predict an improved outcome of treatment in psoriasis patients. The aim of the study was to assess whether the published association between HLA-Cw6 allele carriers and response to ustekinumab has the potential to impact treatment decisions. Patients and methods: Differences in Psoriasis Activity and Severity Index 50, 75, and 90; Nail Psoriasis Severity Index; and Dermatology Life Quality Index at 16 weeks were evaluated between HLA-Cw6 allele carriers vs. non-carriers. Thirty patients with moderate-to-severe psoriasis under treatment with ustekinumab were included in our study. Results: There was no difference between the two groups with respect to Psoriasis Activity and Severity Index 50, 75, and 90 or in terms of change in Nail Psoriasis Severity Index or Dermatology Life Quality Index. Conclusion: In our retrospectively analyzed cohort, we could not detect the previously reported better response in HLA-Cw6+ vs. HLA-Cw6- patients. PMID- 29721445 TI - Pharmacy travel health services: current perspectives and future prospects. AB - Rates of international travel are increasing annually, with particular growth observed in travel to Southeast Asia and to emerging economies. While all patients traveling across geographic regions are recommended to receive a pre travel consultation to consider their individual risks, many do not, or receive care and recommendations that are not consistent with current evidence-based guidelines. As experts in drug therapy, and given the largely preventive nature of most travel health recommendations, pharmacists are well suited to help address this need. Pharmacists generally possess a high degree of knowledge and confidence with more commonly observed travel health topics in community practice such as travelers' diarrhea; however, training in more specialized travel health topics such as travel vaccinations and traveling at altitude has generally been lacking from pharmacy curricula. Pharmacists with an interest in providing pre travel consultations are encouraged to pursue additional training in this specialty and to consider Certificate in Travel Health designation from the International Society of Travel Medicine. Future roles for pharmacists to include the prescribing of medications and vaccines for travel and the in-pharmacy administration of travel vaccinations may improve patient access to pre-travel consultations and recommended preventive measures, improving the health of travelers and potentially reducing the burden of communicable disease worldwide. Pharmacists providing travel care to patients are also reminded to consider noninfectious risks of illness and injury abroad and to counsel patients on strategies to minimize these risks in addition to providing drug and vaccine recommendations. PMID- 29721446 TI - A Contemporary Review of Evidence for Transoral Robotic Surgery in Laryngeal Cancer. AB - Numerous studies have shown that transoral robotic surgery (TORS) for oropharyngeal cancers is safe and that it yields satisfactory functional and oncological outcomes. For many teams worldwide, it is therefore a standard surgical approach with eligible patients. In the same time, TORS is increasingly being used and described in the context of laryngeal cancer surgery. It is proposed as an alternative to open approaches, which may yield inconsistent functional results and significant rates of postoperative complications. It may also be an alternative to definitive radiotherapy, which entails significant early and late toxicities. Moreover, it has been explored as an alternative to endoscopic laser surgery in patients with difficult exposure, even though there is still a lack of evidence about which procedure provides better vizualization of the vocal cords. This article provides a review of the indications for TORS in laryngeal cancer, the peri-operative morbidity, functional outcomes, and oncological results. PMID- 29721448 TI - Arthroscopy and sport. PMID- 29721447 TI - Continuous publication: changing the publishing model. PMID- 29721449 TI - Biomechanics: a fundamental tool with a long history (and even longer future!). PMID- 29721450 TI - Multibody modelling of ligamentous and bony stabilizers in the human elbow. AB - : The elbow ligamentous and bony structures play essential roles in the joint stability. Nevertheless, the contribution of different structures to joint stability is not yet clear and a comprehensive experimental investigation into the ligament and osseous constraints changes in relation to joint motions would be uphill and somehow unattainable, due to the impossibility of obtaining all the possible configurations on the same specimen. Therefore, a predictive tool of the joint behavior after the loss of retentive structures would be helpful in designing reconstructive surgeries and in pre-operative planning. In this work, a multibody model consisting of bones and non-linear ligamentous structures is presented and validated through comparison with experimental data. An accurate geometrical model was equipped with non-linear ligaments bundles between optimized origin and insertion points. The joint function was simulated according to maneuvers accomplished in published experimental studies which explored the posteromedial rotatory instability (PMRI) in coronoid and posterior medial collateral ligament (PB) deficient elbows. Moreover, a complete design of experiments (DOE) was explored, investigating the influence of the elbow flexion degree, of the coronoid process and of the medial collateral ligaments (MCL) structures (anterior and posterior bundles) in the elbow joint opening. The implemented computational model accurately predicted the joint behavior with intact and deficient stabilizing structures at each flexion degree, and highlighted the statistically significant influence of the MCL structures (P<0.05) on the elbow stability. The predictive ability of this multibody elbow joint model let foresee that future investigations under different loading scenarios and injured or surgically reconstructed states could be effectively simulated, helping the ligaments reconstruction optimization in terms of bone tunnel localizations and grafts pre-loading. Level of evidence: V. PMID- 29721451 TI - Biomechanical response of the plantar tissues of the foot in healthy and degenerative conditions. AB - Introduction: This work reports a set of results on the mechanical response of foot plantar tissues in healthy and degenerative conditions during the gait cycle, by means of a computational approach. Methods: A three dimensional finite element model of the foot was developed starting from the analysis of biomedical images. Different constitutive models were defined to interpret the mechanical response of the biological tissues. In particular, a specific visco-hyperelastic constitutive formulation was provided for foot plantar soft tissue considering the general features of tissue mechanics. Degenerative phenomena induce histomorphological alterations and modification of the mechanical properties, as stiffening and lower damping capabilities. Different constitutive parameters for healthy and degenerative conditions were identified by the inverse analysis of experimental data from mechanical tests. Results: The three dimensional numerical model interprets the capability of the plantar soft tissue to act under mechanical actions in different conditions during the phases of the gait cycle. Conclusion: Numerical results highlight aspects of the different stress and strain distributions at the heel strike and the midstance of the healthy and degenerative conditions. Level of evidence: V. PMID- 29721452 TI - Finite element comparison between the human and the ovine lumbar intervertebral disc. AB - Introduction: Nowadays it is still not clear which loading conditions are responsible for lumbar intervertebral disc failure. Many studies have been conducted to investigate the effect of different loading conditions on the herniation processes, and many of them were based on the ovine model. However, the biomechanical similarities between the human and the ovine lumbar disc have been demonstrated in the main planes only, whereas it is not known if they are comparable under complex loading conditions too. The aim of this study was to compare the mechanical response of the ovine and the human lumbar intervetebral disc under complex loading conditions, in order to investigate differences and similarities between the species.The loading scenarios described in a finite element study on a human lumbar segment were applied to a model of the ovine disc, and the results were then compared.It has been shown that combined loads generated highest strains in both the models, and the maximum strains had the same location in the posterior or in the postero-lateral region of the annulus, according to the loading scenario. Conclusion: The ovine disc can be used in spinal research to investigate herniation process under any loading conditions. Level of evidence: V. PMID- 29721453 TI - Tibiofemoral wear in standard and non-standard squat: implication for total knee arthroplasty. AB - Introduction: Due to the more resilient biomaterials, problems related to wear in total knee replacements (TKRs) have decreased but not disappeared. In the design related factors, wear is still the second most important mechanical factor that limits the lifetime of TKRs and it is also highly influenced by the local kinematics of the knee. During wear experiments, constant load and slide-roll ratio is frequently applied in tribo-tests beside other important parameters. Nevertheless, numerous studies demonstrated that constant slide-roll ratio is not accurate approach if TKR wear is modelled, while instead of a constant load, a flexion-angle dependent tibiofemoral force should be involved into the wear model to obtain realistic results. Methods: A new analytical wear model, based upon Archard's law, is introduced, which can determine the effect of the tibiofemoral force and the varying slide-roll on wear between the tibiofemoral connection under standard and non-standard squat movement. Results: The calculated total wear with constant slide-roll during standard squat was 5.5 times higher compared to the reference value, while if total wear includes varying slide-roll during standard squat, the calculated wear was approximately 6.25 times higher. With regard to non-standard squat, total wear with constant slide-roll during standard squat was 4.16 times higher than the reference value. If total wear included varying slide-roll, the calculated wear was approximately 4.75 times higher. Conclusions: It was demonstrated that the augmented force parameter solely caused 65% higher wear volume while the slide-roll ratio itself increased wear volume by 15% higher compared to the reference value. These results state that the force component has the major effect on wear propagation while non-standard squat should be proposed for TKR patients as rehabilitation exercise. PMID- 29721454 TI - Automatic characterization of soft tissues material properties during mechanical tests. AB - Introduction: The estimation of the non-linear viscoelastic characteristics of human soft tissues, such as ligaments and tendon, is often affected by the implemented procedure. This study aims at developing and validating a protocol, associated with a contactless and automatic procedure, enabling the determination of the material behavior and properties of any soft tissues. Methods: Several markers were drawn onto the soft tissue specimen analyzed under uniaxial tensile test. An automatic contactless procedure, that uses a camera for recording the position of the markers during the test, was developed to compute the displacement, and the force applied, enabling the calculation of the true stress/strain curve of the material. Young's modulus and Poisson's ratio can be calculated, on demand, for selected regions of interest of the soft tissues. The repeatability and reproducibility of the procedure were analyzed. The procedure was initially tested and verified on an artificial silicone material and later applied for investigating the mechanical behavior of a pig Achilles tendon and of a human patellar tendon. Results: The procedure show a high repeatability, independent by the operator, reliability and accuracy for the tested synthetic material (with a maximum error of 3.7% for Young's modulus). Additionally, the developed protocol was also suitable for the analysis of animal and human soft tissues. Conclusion: A protocol to automatically and accurately determine material properties in soft tissues was developed, tested and validated. Such approach could successfully be implemented for the mechanical characterization of any biological soft-tissue. Level of evidence: V. PMID- 29721455 TI - Full-field in vitro investigation of hard and soft tissue strain in the spine by means of Digital Image Correlation. AB - Introduction: The spine deserves careful biomechanical investigation, because of the different types of degeneration deriving from daily stress, trauma, and hard and soft tissue pathologies. Many biomechanical studies evaluated the range of motion, structural stiffness of spine segments under different loading conditions, without addressing the strain distribution. Strain gauges have been used to measure strain in the vertebral body, in a pointwise way.What is currently missing is a method to measure the distribution of strain in the soft tissues (intervertebral discs and ligaments), and an integration between measurements in the hard and soft tissues. Digital Image Correlation (DIC) is a recently developed optical technique, which allows measuring the distribution of displacements and deformation in a contact-less way. It can provide a full-field view of the examined surface under load. DIC can therefore give a more complete knowledge of the biomechanics of the spine. Methods: This study was performed multisegmental porcine spine specimens with two loading configurations (flexion and lateral bending), while DIC was used to measure the strain distribution. The tests showed the different deformation in the vertebral body, intervertebral discs and ligaments in compression and tension. At the same time it was possible to visualize the growth plates, which are Conclusion: Significantly softer than the vertebral bone.This work showed the feasibility of investigating the spine in a full-field way, and to quantify the strain inhomogeneity in the vertebrae and soft tissues. Therefore DIC can help improve implantable devices and the surgical technique. PMID- 29721457 TI - Mechanoreceptors of the Achilles tendon: a histomorphological study in pigs with clinical significance for humans. AB - Introduction: Tendons contain neurosensory elements called mechanoreceptors which contribute to the neuromuscular system as sources of reflex signals. The literature is lacking in histological assessment of mechanoreceptors of the Achilles tendon in piglets and our aim was to indicate their types, location and quantity. Methods: The study was performed using histological tissue samples from the Achilles tendon of ten healthy pigs, five left, five right, six males, four females. The samples were taken up to 12 hours after death. Immediately after removal, the tendons were placed in the laboratory where sections were taken and examined microscopically. The tendons were stained with the gold chloride method. Results: The results showed that Golgi tendon organs, free nerve endings and Pacinian-like corpuscles were found in the Achilles tendon of pigs. Most structures were near the osteotendinous and myotendinous junctions, away from the middle portion of the tendon. Conclusion: As shown in other studies and similarly in ours, mechanoreceptors tend to be close to the distant thirds and not in the middle third of the tendon. This study could have clinical application on human Achilles tendon and its repair after damage. Level of evidence: IV. PMID- 29721456 TI - Sensitivity analysis of the material properties of different soft-tissues: implications for a subject-specific knee arthroplasty. AB - Introduction: While developing a subject-specific knee model, different kinds of data-inputs are required. If information about geometries can be definitely obtained from images, more effort is necessary for the in vivo properties. Consequently, such information are recruited from the literature as common habit. However, the effects of the combined sources still need to be evaluated. Methods: This work aims at developing an intact native subject-specific knee model for performing a sensitivity analysis on soft-tissues. The impacts on the biomechanical outputs were analysed during a daily activity for which articular knee kinetics and kinematics were compared among the different configurations. Prior to the sensitivity analysis, experimental and literature data were checked for the model reliability. Results: Average values of mixed sources allowed the agreement with experimental data for personalized outputs. From the sensitivity analysis, knee kinematics did not significantly change in the selected ranges of properties for the soft-tissues (in rotation less than 0.5 degrees ), while contact stresses were greatly affected, especially for the articular cartilage (with differences in the results more than 100%). Conclusion: In conclusion, during the development of a personalized knee model, the selection of the correct material properties is fundamental because wrong values could highly affect the numerical results. Level of evidence: III a. PMID- 29721458 TI - Tripled semitendinosus with single harvesting is as effective but less invasive compared to standard gracilis-semitendinosus harvesting. AB - Introduction: The anterior cruciate ligament (ACL) reconstruction with pes anserinus tendons has been increasingly used throughout the last years. Although less invasive compared to other autologous grafts, a reduction of internal rotation and flexion strength after gracilis and semitendinosus harvesting has been reported. Harvesting one tendon instead of two from the pes anserinus can reduce the deficit of the knee flexor strength and improve the functional recover without weakening the reconstructed ligament. Methods: Forty-five (45) patients who had ACL reconstruction with triple semitendinosus graft (ST3) have been compared with other 45 similar patients who had ACL reconstruction with double gracilis-semitendinosus tendons (GST). Patients have been evaluated at a minimum of 12 months after surgery: IKDC scale, KT-1000, One Leg Hop Test for the objective stability; Isokinetic test for the strength; Tegner scale, Lysholm and IKDC subjective evaluation form for the function. Results: No differences have been detected between the groups for the objective item assessed. Male patients' subjective IKDC score was statistically better for the ST3 group. Recreational soccer players showed a higher Lysholm and subjective IKDC score in ST3 group compared to GST group. There was no difference regarding the return to sport. Conclusion: ST3 guarantees the same objective knee stability compared to a GST. It is a viable option for ACL reconstruction that allows a better preservation of patient's anatomy and a less invasive harvesting surgery. Level of evidence: III b, case control study. PMID- 29721459 TI - Differences between the sexes in athletes' body composition and lower limb bioimpedance values. AB - Introduction: The differences between the sexes in body composition are well established, although sports activity at an elite level seems to reduce them. The aim of this study is a comparison of the sexes in terms of athletes' body composition with a three-compartment model and a localized bioimpedance analysis in elite soccer players. Methods: 18 female and 18 male elite soccer players of the same age were matched (female=26.2+/-2.4, male 26.9+/-2.5; p=0.87). An assessment of body composition was performed through the integration of anthropometrics parameters, skinfold thickness and bioimpedance data. The evaluations were carried out in the morning on a group of athletes who were in a rested condition, having not exercised in the previous 12 hours and having fasted for breakfast. Results: A body composition assessment shows higher values in females for hip circumference/ height (female: 0.55+/-0.03, male: 0.52+/-0.02; p<0.01) and fat mass index (female: 3.7+/-0.7 kg/m2, male: 2.4+/-0.4 kg/m2; p<0.001), while there is no difference between the genders in the extra cellular mass index (female: 7.1+/-1.2 kg/m2, male: 7.6+/-0.4 kg/m2; p=0.11). A localized bioimpedance analysis describes well-defined differences in the thighs, while in the calves these differences are reversed for the reactance values. Conclusion: Sports activity seems to slightly reduce differences in the whole body. The different adaption at the same physical effort appears to be mainly related to cellular mass. This study shows for the first time localized bioimpedance values in female athletes. Level of evidence: II b. PMID- 29721460 TI - Flexibility responses to different stretching methods in young elite basketball players. AB - Introduction: The aims of study were: 1) to verify the effectiveness of different stretching methods and training; 2) to compare the effects with only training on the flexibility of joints in basketball players. Methods: 30 males basketball players (age: 17+/-1yrs; BMI: 23.4+/-3.1), divided into 2 groups (15 experimental group - EG - and 15 control group, CG), participated to study. EG performed 5 different stretching method: passive stretching, active stretching, postural protocol, PNF and dynamic stretching. To assess differences (p<0.05) between groups, an ANOVA was applied to anthropometrics characteristic (age; height; weight and BMI) and flexibility performances (leg raise in a supine position; forward trunk bending). ANOVA for repeated measurements was conducted to asses differences in each group with time (i.e., pre-post). Results: Results showed a variation linked to time (F=21.9; p<0.0001) and an effect of the treatment of the leg raise in a supine position test (F=25.1; p<0.0001). Also in flexion test of trunk, the average values could be linked to time of measurement (F=9.96; p<0.0001) and group (F=8.65; p<0.0001). Conclusion: The results suggest that a specific different stretching protocol should be used in different part of body to offer performance benefit and decreasing of the incidents of injuries. Level of evidence: IV. PMID- 29721461 TI - The effect of deep shoulder infections on patient outcomes after arthroscopic rotator cuff repair: a retrospective comparative study. AB - Introduction: The purpose of this study was to evaluate the effects of deep shoulder infections after RCR on patient outcomes. Methods: A retrospective chart review was conducted involving all patients with deep shoulder infections after arthroscopic RCR (study group). Another group of patients who were matched with the study group by age, gender and rotator cuff tear size, and did not develop deep shoulder infections after arthroscopic RCR were randomly identified (control group). The two groups were compared in terms of time to start physiotherapy, shoulder function, and delay in return to work. Results: There were 10 patients in each group. The mean time to start physiotherapy after surgery was 145.3 (SD=158.8) days for the study group and 40.0 (SD=13.7) days for the control group (p=.051). The average forward elevation of the operated shoulder was 133 (SD=33.4) degrees for the study group, and 172 (SD=12.0) degrees for the control group (p=0.003). The average time to return to work at preoperative level was 5.6 months for the study group and 3 months for the control group. Conclusion: Deep shoulder infections after RCR significantly impedes time to start physiotherapy, shoulder function, and patients' ability to return to work. Level of evidence: III b [retrospective comparative (case-control) study]. PMID- 29721462 TI - Lower limb strength, but not sensorial integration, explains the age-associated postural control impairment. AB - Introduction: The aging process leads to functional decline of sensorial organs, muscle mass and strength, as well as the sensorimotor integration, culminating in age-associated postural control impairments. The purpose of this study was to compare the balance, the sensorial integration process and the lower limb strength among three old aged groups. Methods: Eighty-one community-dwelling healthy old people (58% women), assigned into three age groups [60-69 years (n=30), 70-79 years (n=40), and >=80 years (n=11)], participated in this study. All participants were submitted to anthropometric and stabilometric evaluation, and carried out a Chair stand test. Stabilometric parameters obtained from time [amplitude displacement of center of pressure (CoP)] and frequency (oscillations of CoP at sub 0.3 Hz and 1-3 Hz bands) domain analysis were used as the indicators of balance performance and sensorial integration, respectively. Results: Our results revealed that the CoP amplitude displacement was significantly greater in the older aged group, without differences in spectral bands, while the performance in the Chair stand test was smaller in the older aged group. Conclusion: These data indicate that the age-associated postural control impairment is explained by the lower limb strength declines, but not by the age-associated changes in sensorial integration. Level of evidence: III. PMID- 29721463 TI - Trapeziometacarpal joint osteoarthritis: a prospective trial on two widespread conservative therapies. AB - Introduction: The trapeziometacarpal (TMC) joint osteoarthritis (OA) is at the origin of important secondary functional disability to pinch as well as a painful grip. Several conservative therapies are often considered in the early stages of TMC OA to decrease pain, recover function and slow the evolution of OA. They include massage therapy, heat applications, stretching of the first web span and assisted mobilization of the TMC joint. However, as with other arthritic joints, many physicians often suggest administering intra-articular corticosteroids. The aim of this study was to assess the effect of 10 sessions of physiotherapy versus a single corticoid intra-articular injection. Both treatments were associated with TMC splinting. Methods: Two groups of twenty-five patients received either physiotherapy or a corticoid injection. They were followed over a one-year period. All of them were assessed for pain, function, strength at 2, 6 and 12 months and overall satisfaction at the end of the study. Results: With the infiltrative therapy, the parameters improve more quickly, whereas patients treated with physiotherapy show longer persistence regarding remission of pain. The final functional evaluation scores at one year are similar to pretreatment scores. Conclusion: In early stages of TMC OA, corticosteroids articular injections and physiotherapy treatments can improve the painful symptoms but treatment with corticosteroids is faster. Although hand functions return to average scores similar to those of pre-treatment, physiotherapy program is associated with a longer remission of pain. PMID- 29721464 TI - Unicompartmental knee replacement in patients aged 70 years and older. AB - Introduction: The management of isolated unicompartmental osteoarthritis in the patient aged 70 years and older is an issue of debate. The purpose of the present study was to retrospectively evaluate the outcomes of patients aged over 70 years who underwent unicompartmental knee replacement (UKR) for the treatment of isolated unicompartmental osteoarthritis. The hypothesis was that this represents a safe and viable procedure leading to improved functional outcome in elderly patients affected by isolated unicompartmental osteoarthritis. Methods: 22 consecutive medial compartment UKRs performed between 1998 and 2008 were retrospectively evaluated. Mean age was 74 years (range 70-93 years). Patients were evaluated preoperatively and after an average follow-up of 6.2 years (range 2 to 8). Assessment included KOOS score, WOMAC score, Knee Society Score. Standard X-rays were performed prior to surgery and at follow-up. Results: Twenty patients showed a statistically significant improvement in all parameters. One patient who was 93 years old at the time of surgery died for unrelated causes. One patient required conversion to a total knee arthroplasty. Discussion: UKR is a safe and clinically effective procedure, which has been proven valuable for the treatment of elderly patients with isolated unicompartmental osteoarthritis and with initial degenerative signs in the other compartments. Conclusion: Age more than 70 does not appear to be a contraindication to the procedure. Level of evidence: IV (case series). PMID- 29721465 TI - Editorial. PMID- 29721466 TI - Role of magnetic resonance imaging in breast cancer management. AB - Magnetic resonance imaging (MRI) of the breast is primarily used as a supplemental tool to breast screening with mammography or ultrasound. A breast MRI is mainly used for women who have been diagnosed with breast cancer, to help measure the size of the cancer, look for other tumors in the breast, and to check for tumors in the opposite breast. For certain women at high risk for breast cancer, a screening MRI is recommended along with a yearly mammogram. MRI is known to give some false positive results which mean more test and/or biopsies for the patient. Thus, although breast MRI is useful for women at high risk, it is rarely recommended as a screening test for women at average risk of breast cancer. Also, breast MRI does not show calcium deposits, known as micro calcifications which can be a sign of breast cancer. PMID- 29721468 TI - Practical consensus recommendations regarding role of mastectomy in metastatic breast cancer. AB - Whether to recommend mastectomy in metastatic disease or not has been a matter of debate. Is local therapy, such as mastectomy, of any benefit in advanced breast cancer is the main question. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at these practical consensus recommendations for the benefit of community oncologists. PMID- 29721467 TI - Practical consensus recommendations for tumor margins and breast conservative surgery. AB - My suggestion: There is no difference in survival of breast cancer patients treated with either mastectomy or with breast conservation therapy combined with external beam radiotherapy. A positive margin (s) is an important factor contributing to the increased risk of local recurrence. However, in published literature, there is a lack of consensus on the definition of acceptable margin (s). As a result decision process about need for re-excision after positive margins remains uncrear. PMID- 29721469 TI - Practical consensus recommendatons for Paget's disease in breast cancer. AB - Paget's disease of the breast is a rare type of cancer of the nipple-areola complex and that is often associated with an underlying in situ or invasive carcinoma. Diagnosis and treatment of Paget's disease is controversial. Expert oncologists discuss on the update on the approaches of Paget's disease diagnosis and its treatment options. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at this practical consensus recommendations for the benefit of community oncologists. PMID- 29721470 TI - Practical consensus recommendations regarding role of postmastectomy radiation therapy. AB - The use of radiation therapy after mastectomy (PMRT) has been limited to those patients who are at significant risk of cancer recurring in the chest wall or in the nodal basins. The use of PMRT has been widely accepted for patients with four or more positive lymph nodes,[1],[2] but there is still controversy regarding the value of PMRT for those with one to three positive nodes. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at these practical consensus recommendations for the benefit of community oncologists. PMID- 29721471 TI - Practical consensus recommendaton for adjuvant bone-modifying agents in breast cancer. AB - Bone-modifying therapy is a primary research interest in breast cancer. Several features contribute to the importance of the bone environment in the management of breast cancer. Firstly, bone metastases represent the most common site of breast cancer metastases and secondly, the emergence of cancer treatment-induced bone loss (CTIBL) among breast cancer survivors and patients is of increasing concern. In the adjuvant setting, bisphosphonates can be given to prevent and treat tumor therapy-induced bone loss in premenopausal and postmenopausal women and, owing to their beneficial effect on bone turnover, have also been evaluated for prevention of bone metastases occurrence. Expert oncologists discusses on the update on the approaches of Bone-modifying Agents and its treatment options. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at this practical consensus recommendations for the benefit of community oncologists. PMID- 29721472 TI - Practical consensus recommendations on management of HR + ve early breast cancer with specific reference to genomic profiling. AB - Breast cancer is a heterogeneous disease and patients are managed clinically based on ER, PR, HER2 expression, and key risk factors. The use of gene expression assays for early stage disease is already common practice. These tests have found a place in risk stratifying the heterogeneous group of stage I-II breast cancers for recurrence, for predicting chemotherapy response, and for predicting breast cancer-related mortality. Most guidelines for hormone receptor (HR)-positive early breast cancer recommend addition of adjuvant chemotherapy for most women, leading to overtreatment, which causes considerable morbidity and cost. Expert oncologist discussed about strategies of gene expression assays and aid in chemotherapy recommendations for treatment of HR + ve EBC and the expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at this practical consensus recommendations for the benefit of community oncologists. PMID- 29721473 TI - Practical consensus recommendations regarding the management of HER2 neu positive early breast cancer. AB - Over-expression of HER2 is generally considered to be a negative prognostic feature because it accompanies an increase in breast cancer mortality. However, the development of agents that specifically target HER2 has improved the management of patients with these tumours. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at these practical consensus recommendations with regards to the use of these agents and the management of HER2 neu early breast cancer for the benefit of community oncologists. PMID- 29721474 TI - Practical consensus recommendation on when to do BRCA testing. AB - BRCA-mutation associated breast cancer and to future cancer risks and sensitivity to systemic therapies. Now that rapid genetic testing for BRCA1 and BRCA2 mutations is available, BRCA mutation status can be considered when making treatment and prevention decisions for BRCA testing, BRCA mutation carriers with breast cancer. Expert group used data from published literature, practical experience, and opinion of a large group of academic oncologists, to arrive at practical consensus recommendations for use by the community oncologists. PMID- 29721475 TI - Practical consensus recommendations on fertility preservation in patients with breast cancer. AB - Young women diagnosed with cancer today have a greater chance of long-term survival than ever before. Successful survivorship for this group of patients includes maintaining a high quality of life after a cancer diagnosis and treatment; however, lifesaving treatments such as chemotherapy, radiation, and surgery can impact survivors by impairing reproductive and endocrine health. Expert oncologists along with reproductive medicine specialists discuss fertility preservation options in this chapter since fertility preservation is becoming a priority for young women with breast cancer. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at these practical consensus recommendations for the benefit of community oncologists. PMID- 29721476 TI - Practical consensus recommendations for gestational breast cancer. AB - This manuscript provides a practical and easy to use consensus recommendation to community oncologists on how to manage gestational breast cancer. PMID- 29721478 TI - Practical consensus recommendations regarding the management of hormone receptor positive early breast cancer in elderly women. AB - Breast cancer is a leading cause of death among women, and its incidence increases with age. Currently the treatment of breast cancer in older patients is almost identical to their younger counterparts. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at these practical consensus recommendations for the benefit of community oncologists regarding the management of early breast cancer specifically in elderly women. PMID- 29721477 TI - Practical consensus recommendations on Her2 +ve breast cancer with solitary brain mets. AB - Breast cancer is a common cause of brain metastases, with metastases occurring in at least 10-16% of patients. Longer survival of patients with metastatic breast cancer and the use of better imaging techniques are associated with an increased incidence of brain metastases. Current therapies include surgery, whole-brain radiation therapy, stereotactic radiosurgery, chemotherapy and targeted therapies. However, the timing and appropriate use of these therapies is controversial and careful patient selection by using available prognostic tools is extremely important. Expert oncologist discussed on the mode of treatment to extend the OS and improve the quality of life ofHER2-positivebreast cancer patients with Solitary brain metastases. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at this practical consensus recommendations for the benefit of community oncologists. PMID- 29721479 TI - Practical consensus recommendations on management of triple-negative metastatic breast cancer. AB - Patients with breast cancer along with metastatic estrogen and progesterone receptor (ER/PR)- and human epidermal growth factor receptor 2 (HER2)-negative tumors are referred to as having metastatic triple-negative breast cancer (mTNBC) disease. Resistance to current standard therapies such as anthracyclines or taxanes limits the available options for previously treated patients with metastatic TNBC to a small number of non-cross-resistant regimens, and there is currently no preferred standard chemotherapy. Clinical experience suggests that many women with triple-negative metastatic breast cancer (MBC) relapse quickly. Expert oncologist discussed about new chemotherapeutic strategies and agents used in treatment of mTNBC and the expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at this practical consensus recommendations for the benefit of community oncologists. PMID- 29721480 TI - Practical consensus recommendations regarding the management of sentinel lymph node issues in early breast cancer. AB - Axillary lymph node involvement is a very important poor prognostic factor in the clinical staging and management of breast cancer patients. Traditionally, axillary lymph node dissection (ALND) has been used for determining the status of the axillary lymph nodes. More recently the sentinel lymph node biopsy (SLNB) procedure has gained wider acceptance as the standard of care, having the advantage of being less invasivewhile providing good accuracy. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at these practical consensus recommendations in regards with the use of the two different procedures and other issues in patients with early breast cancer for the benefit of community oncologists. PMID- 29721481 TI - Practical consensus recommendations regarding the use of hormonal therapy in metastatic breast cancer. AB - Metastatic breast cancer (MBC) is cancer that has spread from the breast to another part of the body or has come back in another distant location. Treatment options for MBC depend on several factors. One of these factors is the levels of hormone receptors (HRs) in the tumor. Cancers with high levels of HRs, called HR positive, use the hormones estrogen and progesterone to grow and spread. Hormonal therapy is a type of treatment specifically for HR-positive breast cancer. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at these practical consensus recommendations in regards with the use of hormonal therapy and the management of HR-positive MBC for the benefit of community oncologists. PMID- 29721482 TI - Practical consensus recommendations on duration of adjuvant hormonal therapy in breast cancer. AB - Optimization of adjuvant systemic therapy in women with early-stage hormone receptor-positive breast cancer includes the consideration of chemotherapy and duration of hormone therapy. Adjuvant hormonal therapy significantly improves long-term survival of breast cancer patients with hormone receptor-positive disease. Despite the proven clinical efficacy of tamoxifen and aromatase inhibitors, many breast cancer survivors either fail to take the correct dosage at the prescribed frequency (adherence) or discontinue therapy (persistence). Expert oncologist discussed on the duration of adjuvant hormonal therapy for improvement of OS and quality of life of breast cancer patients by providing reduction in recurrence and mortality. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at this practical consensus recommendations for the benefit of community oncologists. PMID- 29721483 TI - Practical consensus recommendations regarding the management of HER2 neu positive metastatic breast cancer. AB - Metastatic breast cancer (MBC) is cancer that has spread from the breast to another part of the body or has come back in another distant location. Treatment options for MBC depend on several factors, including where the cancer has spread, the patient's overall health, and the levels of hormone receptors and HER2 in the tumour. Over-expression of HER2 is generally considered to be a negative prognostic feature because it accompanies an increase in breast cancer mortality. However, the development of agents that specifically target HER2 has improved the management of patients with these tumours.[7],[8],[9],[10] This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at these practical consensus recommendations in regards with the use of these agents and the management of HER2 positive MBC for the benefit of community oncologists. PMID- 29721485 TI - Practical consensus recommendations for neo-adjuvant chemotherapy in triple negative breast cancer. AB - This manuscript provides a practical and easy to use consensus recommendation to community oncologists on how to use neoadjuvant chemotherapy in triple negative breast cancer patients. PMID- 29721484 TI - Practical consensus recommendations on ovarian suppression in early breast cancer (adjuvant). AB - Substantial survival benefits exist for patients with early-stage breast cancer who undergo treatment with single-modality ovarian suppression, but its value is uncertain. Expert oncologist discussed to determine whether additional benefits exist with ovarian suppression plus multiple adjuvant therapy which provides a new treatment option that reduces the risk of recurrence in early breast cancer. This expert group used data from published literature, practical experience and opinion of a large group of academic oncologists to arrive at this practical consensus recommendations for the benefit of community oncologists. PMID- 29721486 TI - Speculation of the Time-Dependent Change of FIB4 Index in Patients with Nonalcoholic Fatty Liver Disease: A Retrospective Study. AB - Aim: To speculate on the time-dependent change of FIB4 index in patients with nonalcoholic fatty liver disease (NAFLD) and its increase-decrease rate per year, simply and accurately. Methods: In all 23 patients with NAFLD with the value of FIB4 index over 1.30 at the peak, the period from the first to each examination date was calculated and this period (years) was regarded as x. Next, the mean value of FIB4 index during the past year to each examination date was regarded as y. In every y, the minimum and the maximum y value were found out. Between x corresponding to this minimum y and x corresponding to this maximum y, the correlation between x and y was analyzed as the main subject. Then, the slope of each correlation was investigated, because it should indicate increase-decrease rate per year. Results: In all 23 patients, the correlations as the main subject were recognized and the mean absolute value of correlation coefficient (r) was 0.91 +/- 0.08. As for the slope, the mean absolute value was 0.1371 +/- 0.1147 (/year). Conclusion: Simply and accurately, the time-dependent change of FIB4 index and its increase-decrease rate per year could be approximately speculated. PMID- 29721488 TI - Don't Judge a Book by Its Cover: Factitious Disorder Imposed on Children-Report on 2 Cases. AB - Factitious Disorder Imposed on Another (FDIA), also known as Munchausen Syndrome by Proxy (MSbP) is a very serious form of child abuse. The perpetrator, usually the mother, invents symptoms or causes real ones in order to make her child appear sick. Usually this is due to a maladaptive disorder or to an excessive of attention-seeking on her part. We report here two new cases of FDIA. The first one is a 9-year-old boy with a history of convulsive episodes, reduced verbal production, mild psychomotor disorder and urological problems who underwent several invasive procedures and hospitalizations before a diagnosis of FDIA was made. The second is a 12 year-old girl with headache, abdominal pain, lipothymic episodes, seizures and a gait impairment, who was hospitalized in several hospitals before an FDIA was diagnosed. PMID- 29721489 TI - The Brotherhood Medical Center: Collaborative Foundation of Maternity and Children's Healthcare Facility for Displaced Syrians. AB - The United Nations has declared the Syrian conflict, with more than 50% of Syria's population currently displaced, as the worst humanitarian crisis of the twenty-first century. The Syrian conflict has led to a collapse of infrastructure, including access to critical and lifesaving healthcare services. Women and children account for approximately 75% of internally displaced Syrians and refugees. This population is also particularly vulnerable to poor health outcomes, a condition worsened by lack of access to maternal and child health services. In response to this crisis, a partnership of Saudi and Syrian physicians established a non-profit healthcare facility named the Brotherhood Medical Center (BMC) to serve women and children within a safe area near the Syrian-Turkish border. The project began in September 2014 and was implemented in three phases of establishment, phased construction and formal launch and operation. Currently, the BMC is working at about 70% of its capacity and is run in partnership with the Syrian Expatriate Medical Association. Although there was strong initial support from donors, the BMC continues to face many financial and operational challenges, including difficulties in transferring money to Syria, shortage of medical supplies, and lack of qualified medical personnel. Despite these challenges, the BMC represents a critical model and an important case study of the challenges of delivering healthcare services to underserved populations during an ongoing conflict. However, more robust support from the international community is needed to ensure it continues its important health and humanitarian mission. PMID- 29721487 TI - Executive Function Deficits in Seriously Ill Children-Emerging Challenges and Possibilities for Clinical Care. AB - The past years have seen an incredible increase in the quality and success rates of treatments in pediatric medicine. One of the resulting major challenges refers to the management of primary or secondary residual executive function deficits in affected children. These deficits lead to problems in the ability to acquire, understand, and apply abstract and complex knowledge and to plan, direct, and control actions. Executive functions deficits are important to consider because they are highly predictive of functioning in social and academic aspects of daily life. We argue that current clinical practice does not sufficiently account for the complex cognitive processes in this population. This is because widely applied pharmacological interventions only rarely account for the complexity of the underlying neuronal mechanisms and do not fit well into possibly powerful "individualized medicine" approaches. Novel treatment approaches targeting deficits in executive functions in seriously ill children could focus on neuronal oscillations, as these have some specific relations to different aspects of executive function. Importantly, such treatment approaches can be individually tailored to the individuals' deficits and can be transferred into home-treatment or e-health solutions. These approaches are easy-to-use, can be easily integrated into daily life, and are becoming increasingly cost-effective. PMID- 29721490 TI - Impact of a "Diagonal" Intervention on Uptake of Sexual and Reproductive Health Services by Female Sex Workers in Mozambique: A Mixed-Methods Implementation Study. AB - Background: Female sex workers (FSWs) have high risks for adverse sexual and reproductive health (SRH) outcomes, yet low access to services. Within an implementation research project enhancing uptake of SRH services by FSWs, we piloted a "diagonal" intervention, which combined strengthening of FSW-targeted services (vertical) with making public health facilities more FSW-friendly (horizontal), and tested its effect. Methods: The study applied a convergent parallel mixed-methods design to assess changes in access to SRH services. Results of structured interviews with FSWs pre-intervention (N = 311) and thereafter (N = 404) were compared with the findings of eight post-intervention focus group discussions (FGDs) with FSWs and two with FSW-peer educators (PEs). Results: Marked and statistically significant rises occurred in consistent condom use with all partners (55.3-67.7%), ever use of female condoms (37.9-54.5%), being tested for HIV in the past 6 months (56.0-76.6%), using contraception (84.5 95.4%), ever screened for cervical cancer (0.0-16.9%) and having >=10 contacts with a PE in the past year (0.5-24.45%). Increases mostly resulted from FSW targeted outreach, with no rise detected in utilization of public health facilities. FGD participants reported that some facilities had become more FSW friendly, but barriers such as stock-outs, being asked for bribes and disrespectful treatment persisted. Conclusion: The combination of expanding FSW targeted SRH services with improving access to the public health services resulted in an overall increased uptake of services, but almost exclusively because of the strengthened targeted (vertical) outreach services. Utilization of public SRH services had not yet increased and many barriers to access remained. Our diagonal approach was thus only successful in its vertical component. Improving access to the general health services remains nevertheless important and further research is needed how to reduce barriers. Ideally, the combination approach should be maintained and more successful approaches to increase utilization of public services should be explored. PMID- 29721492 TI - Carbon Cloth Supported Nano-Mg(OH)2 for the Enrichment and Recovery of Rare Earth Element Eu(III) From Aqueous Solution. AB - Nano-Mg(OH)2 is attracting great attention as adsorbent for pre-concentration and recovery of rare earth elements (REEs) from low-concentration solution, due to its superior removal efficiency for REEs and environmental friendliness. However, the nanoparticles also cause some severe problems during application, including aggregation, blockage in fixed-bed column, as well as the difficulties in separation and reuse. Herein, in order to avoid the mentioned problems, a carbon cloth (CC) supported nano-Mg(OH)2 (nano-Mg(OH)2@CC) was synthesized by electrodeposition. The X-ray diffraction and scanning electron microscopy analysis demonstrated that the interlaced nano-sheet of Mg(OH)2 grew firmly and uniformly on the surface of carbon cloth fibers. Batch adsorption experiments of Eu(III) indicated that the nano-Mg(OH)2@CC composite maintained the excellent adsorption performance of nano-Mg(OH)2 toward Eu(III). After adsorption, the Eu containing composite was calcined under nitrogen atmosphere. The content of Eu2O3 in the calcined material was as high as 99.66%. Fixed-bed column experiments indicated that no blockage for Mg(OH)2@CC composite was observed during the treatment, while the complete blockage of occurred to nano-Mg(OH)2 at an effluent volume of 240 mL. Moreover, the removal efficiency of Mg(OH)2@CC was still higher than 90% until 4,200 mL of effluent volume. This work provides a promising method for feasible application of nanoadsorbents in fixed-bed process to recycle low concentration REEs from wastewater. PMID- 29721493 TI - Insights Into Highly Improved Solar-Driven Photocatalytic Oxygen Evolution Over Integrated Ag3PO4/MoS2 Heterostructures. AB - Oxygen evolution has been considered as the rate-determining step in photocatalytic water splitting due to its sluggish four-electron half-reaction rate, the development of oxygen-evolving photocatalysts with well-defined morphologies and superior interfacial contact is highly important for achieving high-performance solar water splitting. Herein, we report the fabrication of Ag3PO4/MoS2 nanocomposites and, for the first time, their use in photocatalytic water splitting into oxygen under LED light illumination. Ag3PO4 nanoparticles were found to be anchored evenly on the surface of MoS2 nanosheets, confirming an efficient hybridization of two semiconductor materials. A maximum oxygen generating rate of 201.6 MUmol . L-1 . g-1 . h-1 was determined when 200 mg MoS2 nanosheets were incorporated into Ag3PO4 nanoparticles, which is around 5 times higher than that of bulk Ag3PO4. Obvious enhancements in light-harvesting property, as well as electron-hole separation and charge transportation are revealed by the combination of different characterizations. ESR analysis verified that more active oxygen-containing radicals generate over illuminated Ag3PO4/MoS2 composite photocatalysts rather than irradiated Ag3PO4. The improvement in oxygen evolution performance of Ag3PO4/MoS2 composite photocatalysts is ascribed to wide spectra response in the visible-light region, more efficient charge separation, and enhanced oxidation capacity in the valence band (VB). This study provides new insights into the design and development of novel composite photocatalytic materials for solar-to-fuel conversion. PMID- 29721491 TI - Computational Modeling of Cobalt-Based Water Oxidation: Current Status and Future Challenges. AB - A lot of effort is nowadays put into the development of novel water oxidation catalysts. In this context, mechanistic studies are crucial in order to elucidate the reaction mechanisms governing this complex process, new design paradigms and strategies how to improve the stability and efficiency of those catalysts. This review is focused on recent theoretical mechanistic studies in the field of homogeneous cobalt-based water oxidation catalysts. In the first part, computational methodologies and protocols are summarized and evaluated on the basis of their applicability toward real catalytic or smaller model systems, whereby special emphasis is laid on the choice of an appropriate model system. In the second part, an overview of mechanistic studies is presented, from which conceptual guidelines are drawn on how to approach novel studies of catalysts and how to further develop the field of computational modeling of water oxidation reactions. PMID- 29721494 TI - Cerasomes and Bicelles: Hybrid Bilayered Nanostructures With Silica-Like Surface in Cancer Theranostics. AB - Over years, theranostic nanoplatforms have provided a new avenue for the diagnosis and treatment of various cancer types. To this end, a myriad of nanocarriers such as polymeric micelles, liposomes, and inorganic nanoparticles (NPs) with distinct physiochemical and biological properties are routinely investigated for preclinical and clinical studies. So far, liposomes have received great attention for various biomedical applications, however, it still suffers from insufficient morphological stability. On the other hand, inorganic NPs depicting excellent therapeutic ability have failed to address biocompatibility issues. This has raised a serious concern about the clinical approval of multifunctional organic or inorganic-based theranostic agents. Recently, partially silica coated nanohybrids such as cerasomes and bicelles demonstrating both diagnostic and therapeutic ability in a single system, have drawn profound attention as a fascinating novel drug delivery system. Compared with traditional liposomal or inorganic-based nanoformulations, this new and highly stable nanocarriers integrates the functional attributes of biomimetic liposomes and silica NPs, therefore, synergize strengths and functions, or even surpass weaknesses of individual components. This review at its best enlightens the emerging concept of such partially silica coated nanohybrids, fabrication strategies, and theranostic opportunities to combat cancer and related diseases. PMID- 29721497 TI - Immune Cells and Microbiota Response to Iron Starvation. AB - Metal ions are essential for life on Earth, mostly as crucial components of all living organisms; indeed, they are necessary for bioenergetics functions as crucial redox catalysts. Due to the essential role of iron in biological processes, body iron content is finely regulated and is the battlefield of a tug of-war between the host and the microbiota. PMID- 29721495 TI - Current Strategies for the Manufacture of Small Size Tissue Engineering Vascular Grafts. AB - Occlusive arterial disease, including coronary heart disease (CHD) and peripheral arterial disease (PAD), is the main cause of death, with an annual mortality incidence predicted to rise to 23.3 million worldwide by 2030. Current revascularization techniques consist of angioplasty, placement of a stent, or surgical bypass grafting. Autologous vessels, such as the saphenous vein and internal thoracic artery, represent the gold standard grafts for small-diameter vessels. However, they require invasive harvesting and are often unavailable. Synthetic vascular grafts represent an alternative to autologous vessels. These grafts have shown satisfactory long-term results for replacement of large- and medium-diameter arteries, such as the carotid or common femoral artery, but have poor patency rates when applied to small-diameter vessels, such as coronary arteries and arteries below the knee. Considering the limitations of current vascular bypass conduits, a tissue-engineered vascular graft (TEVG) with the ability to grow, remodel, and repair in vivo presents a potential solution for the future of vascular surgery. Here, we review the different methods that research groups have been investigating to create TEVGs in the last decades. We focus on the techniques employed in the manufacturing process of the grafts and categorize the approaches as scaffold-based (synthetic, natural, or hybrid) or self-assembled (cell-sheet, microtissue aggregation and bioprinting). Moreover, we highlight the attempts made so far to translate this new strategy from the bench to the bedside. PMID- 29721496 TI - The Role of Plasma Transfusion in Massive Bleeding: Protecting the Endothelial Glycocalyx? AB - Massive hemorrhage is a leading cause of death worldwide. During the last decade several retrospective and some prospective clinical studies have suggested a beneficial effect of early plasma-based resuscitation on survival in trauma patients. The underlying mechanisms are unknown but appear to involve the ability of plasma to preserve the endothelial glycocalyx. In this mini-review, we summarize current knowledge on glycocalyx structure and function, and present data describing the impact of hemorrhagic shock and resuscitation fluids on glycocalyx. Animal studies show that hemorrhagic shock leads to glycocalyx shedding, endothelial inflammatory changes, and vascular hyper-permeability. In these animal models, plasma administration preserves glycocalyx integrity and functions better than resuscitation with crystalloids or colloids. In addition, we briefly present data on the possible plasma components responsible for these effects. The endothelial glycocalyx is increasingly recognized as a critical component for the physiological vasculo-endothelial function, which is destroyed in hemorrhagic shock. Interventions for preserving an intact glycocalyx shall improve survival of trauma patients. PMID- 29721499 TI - Predictors of Broad Dimensions of Psychopathology among Patients with Panic Disorder after Cognitive-Behavioral Therapy. AB - Background: Many patients with panic disorder meet criteria for at least one other diagnosis, most commonly other anxiety or mood disorders. Cognitive behavioral therapy is the best empirically supported psychotherapy for panic disorder. There is now evidence indicating that cognitive-behavioral therapy for panic disorder yields positive benefits upon comorbid disorders. Objectives: The present study aimed to examine the predictors of broad dimensions of psychopathology in panic disorder after cognitive-behavioral therapy. Methods: Two hundred patients affected by panic disorder were treated with manualized group cognitive-behavioral therapy. We examined if the baseline personality dimensions of NEO Five Factor Index predicted the subscales of Symptom Checklist 90 Revised at endpoint using multiple regression analysis based on the intention to-treat principle. Results: Conscientiousness score of NEO Five Factor Index at baseline was a predictor of four Symptom Checklist-90 Revised subscales including obsessive-compulsive (beta = -0.15, P < 0.01), depression (beta = -0.13, P < 0.05), phobic anxiety (beta = -0.15, P < 0.05), and Global Severity Index (beta = -0.13, P < 0.05). Conclusion: Conscientiousness at baseline may predict several dimensions of psychopathology in patients with panic disorder after cognitive behavioral therapy. For the purpose of improving a wide range of psychiatric symptoms with patients affected by panic disorder, it may be useful to pay more attention to this personal trait at baseline. PMID- 29721498 TI - Aquaporins as Targets of Dietary Bioactive Phytocompounds. AB - Plant-derived bioactive compounds have protective role for plants but may also modulate several physiological processes of plant consumers. In the last years, a wide spectrum of phytochemicals have been found to be beneficial to health interacting with molecular signaling pathways underlying critical functions such as cell growth and differentiation, apoptosis, autophagy, inflammation, redox balance, cell volume regulation, metabolic homeostasis, and energy balance. Hence, a large number of biologically active phytocompounds of foods have been isolated, characterized, and eventually modified representing a natural source of novel molecules to prevent, delay or cure several human diseases. Aquaporins (AQPs), a family of membrane channel proteins involved in many body functions, are emerging among the targets of bioactive phytochemicals in imparting their beneficial actions. Here, we provide a comprehensive review of this fast growing topic focusing especially on what it is known on the modulatory effects played by several edible plant and herbal compounds on AQPs, both in health and disease. Phytochemical modulation of AQP expression may provide new medical treatment options to improve the prognosis of several diseases. PMID- 29721500 TI - Antioxidant Enzyme Activities and Secondary Metabolite Profiling of Oil Palm Seedlings Treated with Combination of NPK Fertilizers Infected with Ganoderma boninense. AB - Oil palm (Elaeis guineensis Jacq) is one of the major sources of edible oil. Reducing the effect of Ganoderma, main cause of basal stem rot (BSR) on oil palm, is the main propose of this study. Understanding the oil palm defense mechanism against Ganoderma infection through monitoring changes in the secondary metabolite compounds levels before/after infection by Ganoderma under different fertilizing treatment is required. Oil palm requires macro- and microelements for growth and yield. Manipulating the nutrient for oil palm is a method to control the disease. The 3-4-month-old oil palm seedlings were given different macronutrient treatments to evaluate induction of defense related enzymes and production of secondary metabolite compounds in response to G. boninense inoculation. The observed trend of changes in the infected and uninfected seedlings was a slightly higher activity for beta-1,3-glucanases, chitinase, peroxidase, and phenylalanine ammonia-lyase during the process of pathogenesis. It was found that PR proteins gave positive response to the interaction between oil palm seedlings and Ganoderma infection. Although the responses were activated systematically, they were short-lasting as the changes in enzymes activities appeared before the occurrence of visible symptoms. Effect of different nutrients doses was obviously observed among the results of the secondary metabolite compounds. Many identified/unidentified metabolite compounds were presented, of which some were involved in plant cell defense mechanism against pathogens, mostly belonging to alkaloids with bitter-tasting nitrogenous-compounds, and some had the potential to be used as new markers to detect basal stem rot at the initial step of disease. PMID- 29721501 TI - Resveratrol Prevents Diabetic Cardiomyopathy by Increasing Nrf2 Expression and Transcriptional Activity. AB - Objective: This study investigated if resveratrol ameliorates diabetic cardiomyopathy by targeting associated oxidative stress mechanisms. Method: Type 1 diabetes mellitus (DM) in FVB mice was induced by several intraperitoneal injections of a low dose of streptozotocin. Hyperglycemic and age-matched control mice were given resveratrol (10 mg/kg per day) for 1 month and subsequently monitored for an additional 6 months. Mice were assigned to four groups: control, resveratrol, DM, and DM/resveratrol. Cardiac function and blood pressure were assessed at 1, 3, and 6 months after DM induction. Oxidative damage and cardiac fibrosis were analyzed by histopathology, real-time PCR, and Western blot. Result: Mice in the DM group exhibited increased blood glucose levels, cardiac dysfunction, and high blood pressure at 1, 3, and 6 months after DM induction. Resveratrol did not significantly affect blood glucose levels and blood pressure; however, resveratrol attenuated cardiac dysfunction and hypertrophy in DM mice. Resveratrol also reduced DM-induced fibrosis. In addition, DM mice hearts exhibited increased oxidative damage, as evidenced by elevated accumulation of 3 nitrotyrosine and 4-hydroxynonenal, which were both attenuated by resveratrol. Mechanistically, resveratrol increased NFE2-related factor 2 (Nrf2) expression and transcriptional activity, as well as Nrf2's downstream antioxidative targets. Conclusion: We demonstrated that resveratrol prevents DM-induced cardiomyopathy, in part, by increasing Nrf2 expression and transcriptional activity. PMID- 29721502 TI - Diagnosis and Management of Ovarian Tumor in Mayer-Rokitansky-Kuster-Hauser (MRKH) Syndrome. AB - In the most recent publications on Mayer-Rokitansky-Kuster-Hauser (MRKH) syndrome, the uterine remnants and ovaries in patients may develop uterine remnant leiomyoma, adenomyosis, or ovarian tumor, and this can lead to problems in differential diagnosis. Here we summarize the diagnosis methods and available interventions for ovarian tumor in MRKH syndrome, with emphasis on the relevant clinical findings and illustrative relevant case. According to the clinical findings and illustrative relevant case, with the help of imaging techniques, ovarian tumors can be detected in the pelvis in patients with MRKH syndrome and evaluated in terms of size. Laparoscopy could further differentiate ovarian tumors into different pathological types. In addition, laparoscopic surgery not only is helpful for the diagnosis of MRKH combined ovarian tumor, but also has a good treatment role for excising ovarian tumor at the same time. Moreover, laparoscopic removals of ovarian tumor can be considered as a safe and reliable treatment for conservative management. PMID- 29721503 TI - Radiofrequency versus Cryoballoon Ablation of Atrial Fibrillation: An Evaluation Using ECG, Holter Monitoring, and Implantable Loop Recorders to Monitor Absolute and Clinical Effectiveness. AB - Introduction: While several studies have compared the radiofrequency current (RFC) and cryoablation for the treatment of patients with atrial fibrillation (AF), no study has monitored the long-term outcomes with the usage of implantable loop recorders (ILRs). Methods: We enrolled 89 consecutive patients with nonvalvular paroxysmal AF (N = 44 for RFC and N = 45 for cryoballoon). The primary efficacy end point was the assessment of effectiveness for each group (RFC versus cryoballoon) when examining freedom from arrhythmia by monitoring with ECG, Holter, and implantable loop recoder (ILR). The primary safety end point compared rates of adverse events between both groups. The secondary efficacy end point examined the duration of the postablation blanking period from ILR retrieved data. Results: The mean age of the study population was 56.6 +/- 10.2 years, and the follow-up duration was 12 months. There were no differences in baseline patient characteristics between groups. At 12 months, the absolute effectiveness (measured by ILR) was 65.9% in the RFC group and 51.1% in the cryoballoon group (OR = 1.85; 95% CI: 0.79-4.35; p = 0.157), and the clinical effectiveness (measured by ECG and Holter) was 81.8% in the RFC group and 55.6% in the cryoballoon group (OR = 3.6; 95% CI: 1.37-9.46; p = 0.008). There was no difference in safety between both groups. Asymptomatic episodes were significantly more present in the RFC group as measured by ILRs (p < 0.010). In cryoballoon group, arrhythmia episodes were recorded equally irrespective of the follow-up method (i.e., ECG and Holter versus ILR (p > 0.010)). The blanking period does not seem to be as important in cryoballoon as compared to RFC. Conclusion: RFC and cryoballoon ablation had similar absolute effectiveness at 12 months. ECG and Holter were effective when assessing the efficacy of the cryoballoon ablation; however, in the RFC group, ILR was necessary to accurately assess long-term efficacy. PMID- 29721504 TI - Multicomponent Exercise Improves Physical Functioning but Not Cognition and Hemodynamic Parameters in Elderly Osteoarthritis Patients Regardless of Hypertension. AB - The present study aimed to investigate the impact of a 6-month multicomponent exercise program (MCEP) on physical function, cognition, and hemodynamic parameters of elderly normotensive (NTS) and hypertensive (HTS) osteoarthritis patients. A total of 99 elderly osteoarthritis patients (44 NTS and 55 HTS) were recruited and submitted to functional, cognitive, and hemodynamic evaluations before and after six months of a MCEP. The program of exercise was performed twice a week at moderate intensity. The physical exercises aggregated functional and walking exercises. Results indicate that 6 months of MCEP were able to improve one-leg stand and mobility (walking speeds) of osteoarthritis patients regardless of hypertension. On the other hand, cognitive and hemodynamic parameters were not altered after the MCEP. The findings of the present study demonstrate that 6 months of MCEP were able to improve the physical functioning (i.e., usual and maximal walking speed and balance) of osteoarthritis patients regardless of hypertensive condition. PMID- 29721505 TI - Salivary Biomarkers in Systemic Sclerosis Disease. AB - Scleroderma or systemic sclerosis (SSc) is frequently detected at an advanced stage due to diagnosis difficulties. Salivary biomarkers, if existing, could be used for predictive diagnosis of this disease. Human saliva contains a large number of proteins that can be used for diagnosis and are of great potential in clinical research. The use of proteomic analysis to characterize whole saliva (WS) in SSc has gained an increasing attention in the last years and the identification of salivary proteins specific for SSc could lead to early diagnosis or new therapeutic targets. This review will present an overview about the use of WS in SSc studies. The proteomic technologies currently used for global identification of salivary proteins in SSc, as well as the advantages and limitations for the use of WS as a diagnostic tool, will be presented. PMID- 29721506 TI - Vildagliptin Can Alleviate Endoplasmic Reticulum Stress in the Liver Induced by a High Fat Diet. AB - Purpose. We investigated whether a DDP-4 inhibitor, vildagliptin, alleviated ER stress induced by a high fat diet and improved hepatic lipid deposition. Methods. C57BL/6 mice received standard chow diet (CD), high fat diet (HFD), and HFD administered with vildagliptin (50 mg/Kg) (V-HFD). After administration for 12 weeks, serum alanine aminotransferase, glucose, cholesterol, triglyceride, and insulin levels were analyzed. Samples of liver underwent histological examination and transmission electron microscopy, real-time PCR for gene expression levels, and western blots for protein expression levels. ER stress was induced in HepG2 cells with palmitic acid and the effects of vildagliptin were investigated. Results. HFD mice showed increased liver weight/body weight (20.27%) and liver triglycerides (314.75%) compared to CD mice, but these decreased by 9.27% and 21.83%, respectively, in V-HFD mice. In the liver, HFD induced the expression of ER stress indicators significantly, which were obviously decreased by vildagliptin. In vitro, the expressions of molecular indicators of ER stress were reduced in HepG2 when vildagliptin was administered. Conclusions. Vildagliptin alleviates hepatic ER stress in a mouse high fat diet model. In HepG2 cells, vildagliptin directly reduced ER stress. Therefore, vildagliptin may be a potential agent for nonalcoholic fatty liver disease. PMID- 29721507 TI - Cytogenomic Integrative Network Analysis of the Critical Region Associated with Wolf-Hirschhorn Syndrome. AB - Deletions in the 4p16.3 region are associated with Wolf-Hirschhorn syndrome (WHS), a contiguous gene deletion syndrome involving variable size deletions. In this study, we perform a cytogenomic integrative analysis combining classical cytogenetic methods, fluorescence in situ hybridization (FISH), chromosomal microarray analysis (CMA), and systems biology strategies, to establish the cytogenomic profile involving the 4p16.3 critical region and suggest WHS-related intracellular cell signaling cascades. The cytogenetic and clinical patient profiles were evaluated. We characterized 12 terminal deletions, one interstitial deletion, two ring chromosomes, and one classical translocation 4;8. CMA allowed delineation of the deletions, which ranged from 3.7 to 25.6 Mb with breakpoints from 4p16.3 to 4p15.33. Furthermore, the smallest region of overlapping (SRO) encompassed seven genes in a terminal region of 330 kb in the 4p16.3 region, suggesting a region of susceptibility to convulsions and microcephaly. Therefore, molecular interaction networks and topological analysis were performed to understand these WHS-related symptoms. Our results suggest that specific cell signaling pathways including dopamine receptor, NAD+ nucleosidase activity, and fibroblast growth factor-activated receptor activity are associated with the diverse pathological WHS phenotypes and their symptoms. Additionally, we identified 29 hub-bottlenecks (H-B) nodes with a major role in WHS. PMID- 29721508 TI - Risk Factors for Failure of Direct Current Cardioversion in Patients with Type 2 Diabetes Mellitus and Atrial Fibrillation. AB - Introduction: Type 2 diabetes mellitus (T2DM) is a well-recognised risk factor for cardiovascular disease and the prevalence of atrial fibrillation (AF) is higher among patients with T2DM. Direct current cardioversion (DCCV) is an important management option in persistent AF. We sought to determine independent risk factors for immediate and short-term outcomes of DCCV for treatment of AF in patients with T2DM. Methods: Retrospective outcome analysis of DCCV for persistent AF in 102 T2DM patients compared with 102 controls. Results: DCCV was successful in 68 (66.6%) people with T2DM compared to 86 (84.3%) in the control group (P = 0.003). After initial successful cardioversion, only 38 (37.2%) T2DM patients remained in sinus rhythm compared to 63 (61.8%) in the control group (P = 0.007) at a median follow-up of 74.5 days (IQR 69.4-77.4). Multiple logistic regression analysis showed that the presence of T2DM (P = 0.014), digoxin use (P = 0.01), statin use (P = 0.005), left-atrial size (P = 0.01), and LV ejection fraction (P = 0.008) were independent risk factors for immediate DCCV failure. T2DM (P = 0.034) was an independent risk factor for AF relapse. Among patients with T2DM, previous DCCV (P = 0.033), digoxin use (P = 0.035), left-atrial size (P = 0.01), LV ejection fraction (P = 0.036), and HbA1c (P = 0.011) predicted immediate failure of DCCV whilst digoxin use (P = 0.026) was an independent risk factor for relapse of AF. Conclusion: T2DM, higher HbA1c, digoxin treatment, and structural and functional cardiac abnormalities are independent risk factors for immediate DCCV failure and AF relapse. PMID- 29721509 TI - Anthocyanins Function as Anti-Inflammatory Agents in a Drosophila Model for Adipose Tissue Macrophage Infiltration. AB - Epidemiological and preclinical studies have demonstrated that bioactive foods like flavonoids, polyphenolic compounds derived from fruits and vegetables, exert a protective action against obesity, cardiovascular disorders, and Adipocyte Tissue Macrophage infiltration (ATM). All these pathologies are characterized by increase in reactive oxygen species (ROS) and in proinflammatory cytokines that have been shown to favor the migration of immune cells, particularly of macrophages, in metabolically active organs like the liver and adipose tissue, that in Drosophila are constituted by a unique organ: the fat body. This study, using a unique Drosophila model that mimics human ATM, reveals the beneficial effects of flavonoids to reduce tissue inflammation. Our data show that anthocyanin-rich food reduces the number of hemocytes, Drosophila macrophages, infiltrating the fat cells, a process that is associated with reduced production of ROS and reduced activation of the JNK/SAPK p46 stress kinase, suggesting a fundamental function for anthocyanins as antioxidants in chronic inflammation and in metabolic diseases. PMID- 29721512 TI - Etanercept-Induced Hypoglycemia in a Patient With Psoriatic Arthritis and Diabetes. AB - Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis and inflammation involving the axial skeleton and/or peripheral joints. It is more likely to be associated with metabolic syndrome and diabetes when compared with other inflammatory arthritides. Tumor necrosis factor-alpha (TNF-alpha) is one of several cytokines often elevated in rheumatologic disorders including PsA and has also been found to be elevated in patients with obesity, metabolic syndrome, diabetes, and/or atherosclerotic disease. We describe the case of a patient with PsA as well as poorly controlled type 2 diabetes mellitus who experienced not only improvement in his psoriasis and arthritis with the anti-TNF alpha agent etanercept but also recurrent hypoglycemia and significant improvement in hemoglobin A1c despite discontinuation of all conventional therapy for diabetes. PMID- 29721514 TI - Epstein-Barr Virus-Positive Mucocutaneous Ulcer in an Immunosuppressed Patient. AB - Immunosuppressive medications, frequently used to treat inflammatory bowel disease, have been linked to the development of Epstein-Barr virus (EBV) associated lymphoproliferative disorders (LPD). We describe a case of an EBV positive mucocutaneous ulcer involving the palate in an elderly woman with inactive Crohn's disease. This patient had been on high-dose azathioprine for a decade. Following diagnosis of her LPD and discontinuation of azathioprine, her oral ulcers resolved completely. PMID- 29721510 TI - Evaluation of Skeletal Muscle Function and Effects of Early Rehabilitation during Acute Heart Failure: Rationale and Study Design. AB - Background: Acute heart failure (AHF) is associated with disturbances of the peripheral perfusion leading to the dysfunction of many organs. Consequently, an episode of AHF constitutes a "multiple organ failure" which may also affect the skeletal muscles. However, the abnormalities within skeletal muscles during AHF have not been investigated so far. The aim of this project is to comprehensively evaluate skeletal muscles (at a functional and tissue level) during AHF. Methods: The study will include >=63 consecutive AHF patients who will be randomized into 2 groups: >=42 with cardiac rehabilitation group versus >=21 with standard pharmacotherapy alone. The following tests will be conducted on the first and last day of hospitalization, at rest and after exercise, and 30 days following the discharge: clinical evaluation, medical interview, routine physical examination, echocardiography, and laboratory tests (including the assessment of NT-proBNP, inflammatory markers, and parameters reflecting the status of the kidneys and the liver); hemodynamic evaluation, noninvasive determination of cardiac output and systemic vascular resistance using the impedance cardiography; evaluation of biomarkers reflecting myocyte damage, immunochemical measurements of tissue-specific enzymatic isoforms; evaluation of skeletal muscle function, using surface electromyography (sEMG) (maximum tonus of the muscles will be determined along with the level of muscular fatigability); evaluation of muscle tissue perfusion, assessed on the basis of the oxygenation level, with noninvasive direct continuous recording of perfusion in peripheral tissues by local tissue oximetry, measured by near-infrared spectroscopy (NIRS). Results and Conclusions: Our findings will demonstrate that the muscle tissue is another area of the body which should be taken into consideration in the course of treatment of AHF, requiring a development of targeted therapeutic strategies, such as a properly conducted rehabilitation. PMID- 29721511 TI - Vitamin D status and its influence on outcomes following major burn injury and critical illness. AB - Vitamin D deficiency is common among the general population. It is also observed in up to 76% of critically ill patients. Despite the high prevalence of hypovitaminosis D in critical illness, vitamin D is often overlooked by medical staff as the clinical implications and consequences of vitamin D deficiency in acute contexts remain to be fully understood. Vitamin D has a broad range of pleotropic effects on various processes and systems including the immune inflammatory response. 1alpha,25-dihydroxyvitamin D (1,25(OH)2D), has been shown to promote a tolerogenic immune response limiting deleterious inflammatory effects, modulation of the innate immune system, and enhancement of anti microbial peptides. Vitamin D deficiency is frequently observed in critically ill patients and has been related to extrinsic causes (i.e., limited sunlight exposure), magnitude of injury/illness, or the treatment started by medical doctors including fluid resuscitation. Low levels of vitamin D in critically ill patients have been associated with sepsis, organ failure, and mortality. Despite this, there are subpopulations of critical illness, such as burn patients, where the literature regarding vitamin D status and its influence on outcomes remain insufficient. Thermal injury results in damage to both burned and non-burned tissues, as well as induces an exaggerated and persistent immune-inflammatory and hypermetabolic response. In this review, we propose potential mechanisms in which burn injury affects the vitamin D status and summarizes current literature investigating the influence of vitamin D status on outcomes. In addition, we reviewed the literature and trials investigating vitamin D supplementation in critically ill patients and discuss the therapeutic potential of vitamin D supplementation in burn and critically ill patients. We also highlight current limitations of studies that have investigated vitamin D status and supplementation in critical illness. Thermal injury influences vitamin D status. More studies investigating vitamin D depletion in burn patients and its influence on prognosis, via standardized methodology, are required to reach definitive conclusions and influence clinical practice. PMID- 29721513 TI - An Unusual Presentation of Glycogenic Hepatopathy with Bridging Fibrosis. AB - Glycogenic hepatopathy is a rare and under-recognized complication of poorly controlled diabetes mellitus. We report a patient who presented with predominant elevation in alkaline phosphatase and liver biopsy showing bridging fibrosis, which is an unusual presentation of glycogenic hepatopathy. This case emphasizes the fact that glycogenic hepatopathy can also present with a cholestatic pattern of liver abnormality and with liver fibrosis, which warrants further study because severe fibrosis can progress to cirrhosis. PMID- 29721515 TI - Combination of computer extracted shape and texture features enables discrimination of granulomas from adenocarcinoma on chest computed tomography. AB - Differentiation between benign and malignant nodules is a problem encountered by radiologists when visualizing computed tomography (CT) scans. Adenocarcinomas and granulomas have a characteristic spiculated appearance and may be fluorodeoxyglucose avid, making them difficult to distinguish for human readers. In this retrospective study, we aimed to evaluate whether a combination of radiomic texture and shape features from noncontrast CT scans can enable discrimination between granulomas and adenocarcinomas. Our study is composed of CT scans of 195 patients from two institutions, one cohort for training ([Formula: see text]) and the other ([Formula: see text]) for independent validation. A set of 645 three-dimensional texture and 24 shape features were extracted from CT scans in the training cohort. Feature selection was employed to identify the most informative features using this set. The top ranked features were also assessed in terms of their stability and reproducibility across the training and testing cohorts and between scans of different slice thickness. Three different classifiers were constructed using the top ranked features identified from the training set. These classifiers were then validated on the test set and the best classifier (support vector machine) yielded an area under the receiver operating characteristic curve of 77.8%. PMID- 29721516 TI - Model-based beamforming with plane wave synthesis in medical ultrasound. AB - We are interested in examining how our model-based beamforming algorithm, referred to as aperture-domain model image reconstruction (ADMIRE), performs on plane wave sequences in conjunction with synthetic aperture beamforming. We also aim to identify the impact of ADMIRE applied before and after synthetic focusing. We employed simulated phantoms using Field II and tissue-mimicking phantoms to evaluate ADMIRE as applied to synthetic sequencing. We generated plane wave images with and without synthetic aperture focusing (SAF) and measured contrast and contrast-to-noise ratio (CNR). For simulated cyst images formed from single plane waves, the contrast for delay-and-sum (DAS) and ADMIRE are 15.64 and 28.34 dB, respectively, whereas the CNR are 1.76 and 3.90 dB, respectively. We also applied ADMIRE to simulated resolution phantoms having a point target at 3 cm depth on-axis. We simulated the point spread functions from data obtained from 1 plane wave and 75 steered plane waves, along with linear scans with 3 and 4 cm- focal depths. We then compared the outcome of applying ADMIRE before and after SAF using 3 and 11 steered plane waves. Finally, we applied this to an in vivo carotid artery. Based on the findings in this study, ADMIRE can be adapted to full field insonification sequences to improve image quality in plane wave imaging. Additionally, we investigated how robustly ADMIRE performs in the presence of random noise. We then address identified limitations using a conventional envelope detection method with decluttered signals. PMID- 29721517 TI - Automated erythrocyte detection and classification from whole slide images. AB - Blood smear is a crucial diagnostic aid. Quantification of both solitary and overlapping erythrocytes within these smears, directly from their whole slide images (WSIs), remains a challenge. Existing software designed to accomplish the computationally extensive task of hematological WSI analysis is too expensive and is widely unavailable. We have thereby developed a fully automated software targeted for erythrocyte detection and quantification from WSIs. We define an optimal region within the smear, which contains cells that are neither too scarce/damaged nor too crowded. We detect the optimal regions within the smear and subsequently extract all the cells from these regions, both solitary and overlapped, the latter of which undergoes a clump splitting before extraction. The performance was systematically tested on 28 WSIs of blood smears obtained from 13 different species from three classes of the subphylum vertebrata including birds, mammals, and reptiles. These data pose as an immensely variant erythrocyte database with diversity in size, shape, intensity, and textural features. Our method detected [Formula: see text] more cells than that detected from the traditional monolayer and resulted in a testing accuracy of 99.14% for the classification into their respective class (bird, mammal, or reptile) and a testing accuracy of 84.73% for the classification into their respective species. The results suggest the potential employment of this software for the diagnosis of hematological disorders, such as sickle cell anemia. PMID- 29721519 TI - Role of Tetra Amino Acid Motif Properties on the Function of Protease-Activatable Viral Vectors. AB - Protease-activatable viruses (PAV) based on adeno-associated virus have previously been generated for gene delivery to pathological sites characterized by elevated extracellular proteases. "Peptide locks", composed of a tetra aspartic acid motif flanked by protease cleavage sequences, were inserted into the virus capsid to inhibit virus-host cell receptor binding and transduction. In the presence of proteases, the peptide locks are cleaved off the capsid, restoring the virus' ability to bind cells and deliver cargo. Although promising, questions remained regarding how the peptide locks prevented cell binding. In particular, it was unclear if the tetra-amino acid (4AA) motif blocks receptor binding via electrostatic repulsion or steric obstruction. To explore this question, we generated a panel of PAVs with lock designs incorporating altered 4AA motifs, each wielding various chemical properties (negative, positive, uncharged polar, and hydrophobic) and characterized the resultant PAV candidates. Notably, all mutants display reduced receptor binding and decreased transduction effciency in the absence of proteases, suggesting simple electrostatics between heparin and the D4 motif do not play an exclusive role in obstructing virus receptor binding. Even small hydrophobic (A4) and uncharged polar (SGGS) motifs confer a reduction in heparin binding compared to the wild type. Furthermore, both uncharged polar N4 and Q4 mutants (comparable in size to the D4 and E4 motifs respectively, but lacking the negative charge) demonstrate partial ablation of heparin binding. Collectively, these results support a possible dual mechanism of PAV lock operation, where steric hindrance and electrostatics make nonredundant contributions to the disruption of virus-receptor interactions. Finally, because of high virus titer production and superior capsid stability, only the negatively charged 4AA motifs remain viable design choices for PAV construction. Future studies probing the structure-function relationship of PAVs will further expand its promise as a gene delivery vector able to target diseased tissues exhibiting elevated extracellular proteases. PMID- 29721520 TI - A Conversation With Paola D'Angelo. PMID- 29721521 TI - Looking for Finland's Future in Its Forests. PMID- 29721518 TI - New approaches to the analysis of eye movement behaviour across expertise while viewing brain MRIs. AB - Brain tumour detection and diagnosis requires clinicians to inspect and analyse brain magnetic resonance images. Eye-tracking is commonly used to examine observers' gaze behaviour during such medical image interpretation tasks, but analysis of eye movement sequences is limited. We therefore used ScanMatch, a novel technique that compares saccadic eye movement sequences, to examine the effect of expertise and diagnosis on the similarity of scanning patterns. Diagnostic accuracy was also recorded. Thirty-five participants were classified as Novices, Medics and Experts based on their level of expertise. Participants completed two brain tumour detection tasks. The first was a whole-brain task, which consisted of 60 consecutively presented slices from one patient; the second was an independent-slice detection task, which consisted of 32 independent slices from five different patients. Experts displayed the highest accuracy and sensitivity followed by Medics and then Novices in the independent-slice task. Experts showed the highest level of scanning pattern similarity, with medics engaging in the least similar scanning patterns, for both the whole-brain and independent-slice task. In the independent-slice task, scanning patterns were the least similar for false negatives across all expertise levels and most similar for experts when they responded correctly. These results demonstrate the value of using ScanMatch in the medical image perception literature. Future research adopting this tool could, for example, identify cases that yield low scanning similarity and so provide insight into why diagnostic errors occur and ultimately help in training radiologists. PMID- 29721522 TI - Detecting the Sweet Biomarker on Cancer Cells. PMID- 29721523 TI - Nanoscopic Resolution of the Glass Transition within Spatially Inhomogeneous Polymer Mixtures. PMID- 29721524 TI - Elegant Approach to the Controllability of the Mechanical Properties of a Microgel via the Self-Assembly of Internal Molecules. PMID- 29721525 TI - Small Biomolecules for Big Applications. PMID- 29721526 TI - Stable Metal-Organic Frameworks with Group 4 Metals: Current Status and Trends. AB - Group 4 metal-based metal-organic frameworks (MIV-MOFs), including Ti-, Zr-, and Hf-based MOFs, are one of the most attractive classes of MOF materials owing to their superior chemical stability and structural tunability. Despite being a relatively new field, MIV-MOFs have attracted significant research attention in the past few years, leading to exciting advances in syntheses and applications. In this outlook, we start with a brief overview of the history and current status of MIV-MOFs, emphasizing the challenges encountered in their syntheses. The unique properties of MIV-MOFs are discussed, including their high chemical stability and strong tolerance toward defects. Particular emphasis is placed on defect engineering in Zr-MOFs which offers additional routes to tailor their functions. Photocatalysis of MIV-MOF is introduced as a representative example of their emerging applications. Finally, we conclude with the perspective of new opportunities in synthesis and defect engineering. PMID- 29721527 TI - A One-Step Chemoenzymatic Labeling Strategy for Probing Sialylated Thomsen Friedenreich Antigen. AB - Abnormal expression of sialylated Thomsen-Friedenreich antigen (Neu5Acalpha2 3Galbeta1-3GalNAcalpha-O-Ser/Thr, sialyl-T) has a strong relationship with various types of human cancers and many other diseases. However, the size and structural complexity, and relatively lower abundance of sialyl-T have posed a significant challenge to its detection. Therefore, details about the role of sialyl-T in a variety of physiological and pathological processes are still poorly understood. Here, a one-step chemoenzymatic labeling strategy to probe sialyl-T is described. This approach enables the sensitive, selective, and rapid detection of sialyl-T, and global profiling and identification of unknown sialyl T-attached glycoproteins, which are potential therapeutic targets or biomarkers. The use of one-step labeling strategy not only has a higher sensitivity than a typical two-step reporter strategy but also avoids undergoing an additional chemical reaction step to introduce a reporter group after the labeling reaction, making it particularly useful for detecting low-abundance glycan epitopes on living cells. PMID- 29721528 TI - Development and Application of Yeast and Phage Display of Diverse Lanthipeptides. AB - Peptide display has enabled identification and optimization of ligands to many targets. These ligands are usually linear or disulfide-containing peptides that are vulnerable to proteolysis or reduction. We report yeast surface and phage display of lanthipeptides, macrocyclic ribosomally synthesized and post translationally modified peptides (RiPPs). Lanthipeptides contain multiple thioether cross-links that bestow their biological activities. We developed C terminal yeast display of the class II lanthipeptides lacticin 481 and haloduracin beta, and randomization of the C-ring of the former was used to select tight binders to alphavbeta3 integrin. This represents the first examples of bacterial RiPP production in Saccharomyces cerevisiae for identification of variants with new biological activities. We also report N-terminal phage display of the class I lanthipeptide nisin and randomization of its A- and B-rings to enrich binders to a small molecule, lipid II. The successful display and randomization of both class I and II lanthipeptides demonstrates the versatility and potential of RiPP display. PMID- 29721529 TI - Mosquito-Derived Anophelin Sulfoproteins Are Potent Antithrombotics. AB - The anophelins are small protein thrombin inhibitors that are produced in the salivary glands of the Anopheles mosquito to fulfill a vital role in blood feeding. A bioinformatic analysis of anophelin sequences revealed the presence of conserved tyrosine residues in an acidic environment that were predicted to be post-translationally sulfated in vivo. To test this prediction, insect cell expression of two anophelin proteins, from Anopheles albimanus and Anopheles gambiae, was performed, followed by analysis by mass spectrometry, which showed heterogeneous sulfation at the predicted sites. Homogeneously sulfated variants of the two proteins were subsequently generated by chemical synthesis via a one pot ligation-desulfurization strategy. Tyrosine sulfation of the anophelins was shown to significantly enhance the thrombin inhibitory activity, with a doubly sulfated variant of the anophelin from A. albimanus exhibiting a 100-fold increase in potency compared with the unmodified homologue. Sulfated anophelins were also shown to exhibit potent in vivo anticoagulant and antithrombotic activity. PMID- 29721530 TI - Increasing Elasticity through Changes in the Secondary Structure of Gelatin by Gelation in a Microsized Lipid Space. AB - Even though microgels are used in a wide variety of applications, determining their mechanical properties has been elusive because of the difficulties in analysis. In this study, we investigated the surface elasticity of a spherical microgel of gelatin prepared inside a lipid droplet by using micropipet aspiration. We found that gelation inside a microdroplet covered with lipid membranes increased Young's modulus E toward a plateau value E* along with a decrease in gel size. In the case of 5.0 wt % gelatin gelled inside a microsized lipid space, the E* for small microgels with R <= 50 MUm was 10-fold higher (35 39 kPa) than that for the bulk gel (~3 kPa). Structural analysis using circular dichroism spectroscopy and a fluorescence indicator for ordered beta sheets demonstrated that the smaller microgels contained more beta sheets in the structure than the bulk gel. Our finding indicates that the confinement size of gelling polymers becomes a factor in the variation of elasticity of protein-based microgels via secondary structure changes. PMID- 29721531 TI - Extra-Large Pore Mesoporous Silica Nanoparticles Enabling Co-Delivery of High Amounts of Protein Antigen and Toll-like Receptor 9 Agonist for Enhanced Cancer Vaccine Efficacy. AB - Cancer vaccine aims to invoke antitumor adaptive immune responses to detect and eliminate tumors. However, the current dendritic cells (DCs)-based cancer vaccines have several limitations that are mostly derived from the ex vivo culture of patient DCs. To circumvent the limitations, direct activation and maturation of host DCs using antigen-carrying materials, without the need for isolation of DCs from patients, are required. In this study, we demonstrate the synthesis of extra-large pore mesoporous silica nanoparticles (XL-MSNs) and their use as a prophylactic cancer vaccine through the delivery of cancer antigen and danger signal to host DCs in the draining lymph nodes. Extra-large pores of approximately 25 nm and additional surface modification of XL-MSNs resulted in significantly higher loading of antigen protein and toll-like receptor 9 (TLR9) agonist compared with conventional small-pore MSNs. In vitro study showed the enhanced activation and antigen presentation of DCs and increased secretion of proinflammatory cytokines. In vivo study demonstrated efficient targeting of XL MSNs co-delivering antigen and TLR9 agonist to draining lymph nodes, induction of antigen-specific cytotoxic T lymphocytes (CTLs), and suppression of tumor growth after vaccination. Furthermore, significant prevention of tumor growth after tumor rechallenge of the vaccinated tumor-free mice resulted, which was supported by a high level of memory T cells. These findings suggest that mesoporous silica nanoparticles with extra-large pores can be used as an attractive platform for cancer vaccines. PMID- 29721532 TI - Mapping Catalytically Relevant Edge Electronic States of MoS2. AB - Molybdenum disulfide (MoS2) is a semiconducting transition metal dichalcogenide that is known to be a catalyst for both the hydrogen evolution reaction (HER) as well as for hydro-desulfurization (HDS) of sulfur-rich hydrocarbon fuels. Specifically, the edges of MoS2 nanostructures are known to be far more catalytically active as compared to unmodified basal planes. However, in the absence of the precise details of the geometric and electronic structure of the active catalytic sites, a rational means of modulating edge reactivity remain to be developed. Here we demonstrate using first-principles calculations, X-ray absorption spectroscopy, as well as scanning transmission X-ray microscopy (STXM) imaging that edge corrugations yield distinctive spectroscopic signatures corresponding to increased localization of hybrid Mo 4d states. Independent spectroscopic signatures of such edge states are identified at both the S L2,3 and S K-edges with distinctive spatial localization of such states observed in S L2,3-edge STXM imaging. The presence of such low-energy hybrid states at the edge of the conduction band is seen to correlate with substantially enhanced electrocatalytic activity in terms of a lower Tafel slope and higher exchange current density. These results elucidate the nature of the edge electronic structure and provide a clear framework for its rational manipulation to enhance catalytic activity. PMID- 29721533 TI - Direct Measurement of the Local Glass Transition in Self-Assembled Copolymers with Nanometer Resolution. AB - Nanoscale compositional heterogeneity in block copolymers can impart synergistic property combinations, such as stiffness and toughness. However, until now, there has been no experimental method to locally probe the dynamics at a specific location within these structured materials. Here, this was achieved by incorporating pyrene-bearing monomers at specific locations along the polymer chain, allowing the labeled monomers' local environment to be interrogated via fluorescence. In lamellar-forming poly(butyl methacrylate-b-methyl methacrylate) diblock copolymers, a strong gradient in glass transition temperature, Tg, of the higher-Tg block, 42 K over 4 nm, was mapped with nanometer resolution. These measurements also revealed a strongly asymmetric influence of the domain interface on Tg, with a much smaller dynamic gradient being observed for the lower-Tg block. PMID- 29721535 TI - Erratum for the Research Article: "Dynamic conservation for migratory species" by M. Reynolds, B. L. Sullivan, E. Hallstein, S. Matsumoto, S. Kelling, M. Merrifield, D. Fink, A. Johnston, W. M. Hochachka, N. E. Bruns, M. E. Reiter, S. Veloz, C. Hickey, N. Elliot, L. Martin, J. W. Fitzpatrick, P. Spraycar, G. H. Golet, C. McColl and S. A. Morrison. AB - [This corrects the article DOI: 10.1126/sciadv.1700707.]. PMID- 29721534 TI - Machine Learning To Predict Cell-Penetrating Peptides for Antisense Delivery. AB - Cell-penetrating peptides (CPPs) can facilitate the intracellular delivery of large therapeutically relevant molecules, including proteins and oligonucleotides. Although hundreds of CPP sequences are described in the literature, predicting efficacious sequences remains difficult. Here, we focus specifically on predicting CPPs for the delivery of phosphorodiamidate morpholino oligonucleotides (PMOs), a compelling type of antisense therapeutic that has recently been FDA approved for the treatment of Duchenne muscular dystrophy. Using literature CPP sequences, 64 covalent PMO-CPP conjugates were synthesized and evaluated in a fluorescence-based reporter assay for PMO activity. Significant discrepancies were observed between the sequences that performed well in this assay and the sequences that performed well when conjugated to only a small-molecule fluorophore. As a result, we envisioned that our PMO-CPP library would be a useful training set for a computational model to predict CPPs for PMO delivery. We used the PMO activity data to fit a random decision forest classifier to predict whether or not covalent attachment of a given peptide would enhance PMO activity at least 3-fold. To validate the model experimentally, seven novel sequences were generated, synthesized, and tested in the fluorescence reporter assay. All computationally predicted positive sequences were positive in the assay, and one sequence performed better than 80% of the tested literature CPPs. These results demonstrate the power of machine learning algorithms to identify peptide sequences with particular functions and illustrate the importance of tailoring a CPP sequence to the cargo of interest. PMID- 29721536 TI - Age-related hearing loss: Unraveling the pieces. AB - : Age-related hearing loss (ARHL) is the most common cause of hearing loss in the world. The development of ARHL in each individual is multifactorial, involving both intrinsic and extrinsic factors. This review highlights several of the key findings in the ARHL literature and discusses future directions. Level of Evidence: NA. PMID- 29721537 TI - Oral and intratympanic steroid therapy for idiopathic sudden sensorineural hearing loss. AB - Objective: To investigate the role of intratympanic (IT) therapy in the treatment of idiopathic sudden sensorineural hearing loss (ISSNHL). Methods: This study was a retrospective review. Patients were treated for ISSNHL from January 1, 2011 to April 12, 2015 with the following: pre/posttreatment audios, treatment initiated <=90 days and idiopathic etiology. Fifty-three ISSNHL patients were analyzed in the following subgroups: oral steroids (n = 8), combination oral+IT (n = 39), and IT (n = 6). Main outcomes measured were pre/posttreatment pure tone average (PTA) scores. Results: The PTA changes for all treatment groups improved by 8.0 +/- 19.5 dB (P = .004); for 31 patients treated <=2 weeks after onset, PTA improved by 13.8 +/- 16.6 dB (P < .001). Multivariable generalized linear model for repeated measures was conducted to investigate the association between PTA changes for treatment groups adjusted for age, gender, time-to-treatment, and vertigo. Earlier time-to-treatment and older age were statistically correlated towards improved outcomes. As time-to-treatment increased by each day, change in PTA decreased by 0.324 (95% CI [0.12, 0.52], P = .002). As age increased by each year, PTA changes increased by 0.802 (95% CI [0.36, 1.24], P < .001). For the oral+IT group, PTA changes for concurrent oral+IT (n = 20, 7.10 dB) and delayed/salvage oral+IT (n = 19, 5.43 dB) were not statistically different (P = .79); earlier time-to-treatment (P = .001), and older age (P = .006) remained statistically correlated towards improved outcomes. Conclusion: Results suggest outcomes can be improved with early identification and oral steroid therapy by primary care providers. Poorer prognosis for younger patients potentially suggests a need for more aggressive diagnostic and therapeutic management for this subgroup. Level of Evidence: 3b. PMID- 29721538 TI - Upper airway obstruction in neonates: Does sleep exacerbate symptoms? AB - Objective: Describe the factors that exacerbate upper airway obstructions (UAOs) in neonates. Study Design: Retrospective chart review. Setting: Pediatric tertiary care hospital. Subjects and Methods: All neonates hospitalized between 1/1/2010 and 12/31/2014 diagnosed with either: 1) laryngomalacia, 2) Pierre Robin sequence, or 3) vocal cord paralysis were included in this study. Patient charts were reviewed to determine factors that exacerbated symptoms of airway obstruction. The independent variable was patient diagnosis, and the outcome measure was exacerbating factors. Results: In patients with laryngomalacia (n = 31), 41.9% worsened with agitation, 38.7% worsened with feeding, 16.1% worsened with positioning, 0.0% worsened during sleep, and 25.8% had no aggravating factors. In Pierre-Robin patients (n = 31), 48.4% worsened with agitation, 16.1% worsened with feeding, 61.3% worsened with positional changes, 0.0% worsened during sleep, and 12.9% had no aggravating factors. In vocal cord paralysis patients (n = 25), 72.0% worsened with agitation, 8.0% worsened with feeding, 20.0% worsened with positional changes, 4.0% worsened during sleep, and 24.0% had no aggravating factors. Conclusion: Airway obstruction was not reliably exacerbated during sleep for any of the diagnoses studied in this review. Our findings show that agitation exacerbates airway obstruction in most patients with vocal cord paralysis, and positioning exacerbates airway obstruction in the majority of patients with PRS. Aggravating factors in laryngomalacia are variable. These findings question the utility of polysomnography as a diagnostic tool for hospitalized neonates with these conditions. Level of Evidence: 4. PMID- 29721539 TI - Simulation of the upper airways in patients with obstructive sleep apnea and nasal obstruction: A novel finite element method. AB - Objective: To evaluate the biomechanical properties of the soft palate and velopharynx in patients with obstructive sleep apnea (OSA) and nasal obstruction. Study design: Prospective experimental study. Materials and methods: Two finite element (FE) models of the soft palate were created in six patients undergoing nasal surgery, one homogeneous model based on CT images, and one layered model based on soft tissue composition. The influence of anatomy on displacement caused by a gravitational load and closing pressure were evaluated in both models. The strains in the transverse and longitudinal direction were obtained for each patient. Results: The individual anatomy influences both its structural stiffness and its gravitational displacement. The soft palate width was the sole anatomical parameter correlated to the critical closing pressure, but the maximal displacement due to gravity may have a relationship to closing pressure of possibly an exponential order. The airway occlusion occurred mainly at the lateral attachments of the soft palate. The total transverse strain showed a strong correlation with maximal closing pressure. There was no relationship between the critical closing pressure and the preoperative AHI levels, or the change in AHI after surgery. Conclusion: Hyperelastic FE models both in the homogeneous and layered model represent a novel method of evaluating soft tissue biomechanics of the upper airway. The obstruction occurs mainly at the level of the lateral attachments to the pharyngeal wall, and the width of the soft palate is an indicator of the degree of critical closing pressure. A less negative closing pressure corresponds to small total transverse strain. The effect of nasal surgery on OSA is most likely not explained by change in soft palate biomechanics. Level of Evidence: NA. PMID- 29721540 TI - Association of alterations in smell and taste with depression in older adults. AB - Objective: Examine the relationship between depression and changes in smell or taste. Study Design: Cross-sectional analysis of 2011-2012 and 2013-2014 National Health and Nutrition Examination Survey (NHANES). Methods: We examined 5,275 adults >=40 years old who completed smell and taste questionnaires as well as a validated depression assessment instrument, the Patient Health Questionnaire (PHQ 9). Analyses incorporated sampling weights to account for the complex sampling design and associations were analyzed using multivariate logistic regression adjusted for related demographics and socioeconomic data. Results: The prevalence of altered smell and taste was 23.0% (95% CI: 20.7-25.3%) and 11.9% (95% CI: 10.7 13.1%), respectively. Among those who met criteria for major depressive disorder, the prevalence of altered smell and taste was higher at 39.8% (95% CI: 33.4 46.1%) and 23.7% (95% CI: 18.7-28.7%), respectively. In a multivariate model adjusting for age, gender, education, major comorbidities, smoking history, heavy alcohol use, sinus disease, cold symptoms, and trauma history, adults >=40 and <65 years old who reported alterations in smell (OR: 1.64, p = 0.004) and adults >=40 years old who reported alterations in taste (OR: 1.77, p = 0.001) were more likely to meet criteria for major depressive disorder. Conclusion: There is a strong association between major depression and alterations in smell and taste among certain age groups in the general U.S. population. Primary care providers should screen for depression when patients report changes in smell or taste. Level of Evidence: 4. PMID- 29721541 TI - Cutting-edge endonasal surgical approaches to thyroid ophthalmopathy. AB - Objective: Thyroid orbitopathy is a poorly understood extrathyroidal manifestation of Graves' disease that can cause disfiguring proptosis and vision loss. Orbital decompression surgery for Graves' orbitopathy (GO) can address both cosmetic and visual sequelae of this autoimmune condition. Endonasal endoscopic orbital decompression provides unmatched visualization and access to inferomedial orbital wall and orbital apex. This review examines the state of the art approaches employed in endonasal endoscopic orbital decompression for GO. Methods: Review of literature evaluating novel surgical maneuvers for GO. Results: Studies examining the efficacy of endonasal endoscopic orbital decompression are heterogenous and retrospective in design; however, they reveal this approach to be a safe and effective technique in the management of GO. Conclusion: Subtle variations in endoscopic techniques significantly affect postsurgical outcomes and can be tailored to the specific clinical indication in GO making endonasal endoscopic decompression the most versatile approach available. Level of Evidence: NA. PMID- 29721542 TI - The endoscopic modified lothrop procedure: Review of single institution experience and long-term outcomes. AB - Background: Endoscopic Modified Lothrop Procedure (EMLP) has become a fundamental practice in rhinology. Improvements in symptom burden, ostial patency, morbidity, and costs have surpassed that of an open approach to the frontal sinus. Long-term efficacy has not been well established. Objective: This study details the long term outcomes of EMLP and risk factors for subsequent surgical revision at a single institution. Methods: This study utilized a retrospective review of patients who underwent EMLP from September 2006 to February 2017 by a single surgeon at an academic tertiary referral center. Patient demographics, indications, symptom burden, and endoscopic assessment of frontal ostium patency were analyzed for their effect on surgical outcome. Risk factors for failures were identified. Results: Seventy-six consecutive patients with an average age of 58.1 years met the inclusion and exclusion criteria and underwent EMLP for chronic rhinosinusitis (CRS, 59%), neoplasm (26%), and mucoceles (15%). The average number of standard endoscopic sinus surgeries prior to EMLP was 2.9. The mean follow-up of the cohort was 34.8 months, at the end of which, EMLP was successful in 78% of all patients, requiring no further surgery. Ninety percent of patients reported significant clinical improvement at the most recent follow up. Subgroup analysis of CRS patients revealed an equally high success rate but a higher likelihood of ostial closure. Recurrent disease necessitated revision endoscopic surgery in 17 patients, the majority of whom suffered CRS. Only tissue eosinophilia was identified to significantly increase the risk of revision surgery. Conclusions: The majority of the patients who undergo EMLP achieve sustained patency of the frontal sinus outflow tract and adequate symptom improvement. Prominent tissue eosinophilia identifies patients at risk of requiring additional frontal sinus surgery. Level of Evidence: 4. PMID- 29721543 TI - Odontogenic sinusitis: A review of the current literature. AB - Objectives: To present current literature on the topic of odontogenic sinusitis. Data Source: PubMed literature search for odontogenic sinusitis. Results: Odontogenic sinusitis is an inflammatory condition of the paranasal sinuses that is the result of dental pathology, most often resulting from prior dentoalveolar procedures, infections of maxillary dentition, or maxillary dental trauma. Infections are often polymicrobial with an anaerobe-predominant microbiome requiring special considerations for antimicrobial therapy. Medical management and treatment of the underlying dental pathology remains a critical initial step in the treatment of odontogenic sinusitis, however recent literature suggests that a significant portion of patients may require endoscopic sinus surgery for successful disease resolution. Conclusions: This review describes the essential epidemiological and etiological factors, relevant clinical findings and diagnostic modalities, microbiologic and antimicrobial considerations, as well as the medical and surgical treatment approaches commonly utilized for the management of odontogenic sinusitis. Level of Evidence: NA. PMID- 29721545 TI - Revisiting vascular contraindications for transoral robotic surgery for oropharyngeal cancer. AB - Objective: We analyzed the outcomes for patients with a retropharyngeal internal carotid artery (ICA) who underwent a transoral robotic surgery (TORS) procedure involving a cervical-transoral robotic oropharyngectomy course with free flap reconstruction. Methods: Patients were included in the prospective multicentric trial NCT02517125. These patients were scheduled to undergo surgery for an oropharyngeal localization. By pre-operative CT scan and MRI it was determined that they had a retropharyngeal internal carotid artery. Results: Three patients had a retropharyngeal ICA: a patient with a 35 mm synovial sarcoma of the tonsillar fossa, a patient with a T2N2b squamous-cell carcinoma (SCC) of the glossotonsillar sulcus, and a patient with a T3N0 SCC of the tonsillar fossa in a previously irradiated field. These patients encountered neither preoperative nor postoperative complications. Conclusions: In our experience, TORS for oropharyngeal cancers appears to be feasible in patients with a retropharyngeal ICA, provided that the procedure has been adapted for complex situations. Level of evidence: 4. PMID- 29721544 TI - Defining the low-risk salvage laryngectomy-A single-center retrospective analysis of pharyngocutaneous fistula. AB - Objectives: Salvage total laryngectomies (STL) are not a homogeneous group. Most will fall into two groups: i) Patients with previous AJCC stage I/II larynx cancer who have had radiotherapy to the larynx only (STL-LOR), or ii) Patients who have had previous AJCC stage III/IV larynx cancer and subsequent radiotherapy to the larynx and draining nodal basins with concurrent cisplatin chemotherapy (STL-CRT). We aimed to compare PCF rates following STL in these two groups. Methods: A retrospective review of the department's cohort between January 2010 and August 2015 was conducted. Results: Seventy-seven patients underwent total laryngectomy for larynx cancer between January 2010 and August 2015. There were 10 post-laryngectomy fistulas (13.0%). Three of these occurred in the 38 patients undergoing primary total laryngectomy (PTL), and seven in the 39 patients undergoing STL, rates of 7.9% and 17.9%, respectively. Twenty-two patients had received radiation to the larynx alone without chemotherapy (STL-LOR) for initial Stage I/II disease. Eleven patients had received laryngeal and neck irradiation plus cisplatin chemotherapy (STL-CRT) for initial stage III/IV disease. Of the 22 STL-LOR patients, two developed PCF (9.1%). Of the 11 STL-CRT patients, five developed PCF. There was no difference in the rate of PCF between PTL and STL LOR. There was a statistically significant increase in PCF in STL-CRT versus PTL (p = .009) and in PCF in STL-CRT versus STL-LOR (p = .027). Conclusion: Salvage laryngectomies are often treated as a homogenous group. We demonstrate that PCF rates vary significantly depending on preoperative radiation fields and the use of chemotherapy. Level of Evidence: 2b. PMID- 29721546 TI - Surgical approach to the intrathoracic goiter. AB - Objective: In a retrospective study, the authors analyzed the surgical approach to the intrathoracic goiter to avoid sternotomy or thoracotomy. Methods: We selected 70 intrathoracic cases of multinodular goiter out of 988 cases of thyroidectomy and compared them with cervical goiter cases. Surgical technique, results, and postsurgical complications were assessed. Results: The analyzed cases presented the retrosternal goiter (n = 53; 75.7%), the retrotracheal goiter (n = 9; 12.8%), and the retroesophageal goiter (n = 8; 11.4%). Complaining of chest pressure or discomfort was specific for intrathoracic cases (50%; 35 of 70). All goiters except one were removed via cervical incision. The surgeons used head reclination and isthmus dissection when removing sizable goiters. Mean weight of goiters was 180 g. The recurrent laryngeal nerve was more often temporarily damaged in intrathoracic cases in comparison with cervical cases (4.3% vs. 2.8%, P = .04), but the difference in permanent injury was less significant (P = .09). The incidence of temporary hypoparathyroidism was significantly higher in intrathoracic cases (P = .01). Conclusion: In cases of multinodular goiter the goiters of various extensions can be successfully removed via the cervical incision in most of the cases even if they occupy the retrosternal, retrotracheal, or retroesophageal position. The transthoracic approaches and sternotomy might be justified in malignant cases. Level of Evidence: 4. PMID- 29721547 TI - Evaluation of the pharyngeal airway using computational fluid dynamics in patients with acromegaly. AB - Objectives: Perioperative airway management may be particularly challenging in patients with acromegaly undergoing trans-sphenoidal pituitary surgery (TSS). Management for airway obstruction is required prior to pituitary surgery to minimize perioperative hypoxia. The purpose of this retrospective study was to evaluate airway obstruction by simulation of computational fluid dynamics (CFD) using computed tomography (CT) images in patients who had undergone TSS. Methods: CT images of the nasopharyngeal airways of patients with acromegaly (n = 5) or nonfunctional pituitary adenoma (n = 6) undergoing TSS from April 2012 to January 2017 were used to construct these airways in three dimensions. Estimated airflow pressure and velocity in the retropalatal airway (RA), oropharyngeal airway (OA), and hypopharyngeal airway (HA) were simulated using CFD. Results: Estimated pharyngeal airflow pressure in the HA, OA, and RA was significantly greater in patients with acromegaly than in those with nonfunctional pituitary adenomas whereas the estimated pharyngeal airflow velocity was significantly impaired only in the RA of patients with acromegaly. Minimum postoperative SpO2 both within 3 hours and from 3 to 12 hours after the end of anesthesia was significantly lower in the patients with acromegaly. Additionally, estimated volume of tongue and pharyngeal airflow pressure in the HA, OA, and RA correlated with minimum postoperative SpO2. Conclusion: Pharyngeal airflow pressure estimated from CT images is high in patients with acromegaly, and these values correlate with postoperative minimum values for SpO2. Preoperative evaluation of CT images by CFD can predict difficulty in airway management and perioperative hypoxia. Level of Evidence: 4. PMID- 29721548 TI - Nrf2 Deficiency Promotes Melanoma Growth and Lung Metastasis. AB - The role of Nrf2, a key regulator of antioxidant and cytoprotective genes, in tumorigenesis remains controversial. Here we showed that Nrf2 deficiency led to increased local tumor growth in mice following subcutaneous injection of B16-F10 melanoma cells, as indicated by increased proportion of animals with locally palpable tumor mass and time-dependent increases in tumor volume at the injection site. In vivo bioluminescence imaging also revealed increased growth of melanoma in Nrf2-null mice as compared with wild-type mice. By using a highly sensitive bioluminometric assay, we further found that Nrf2 deficiency resulted in a remarkable increase in lung metastasis of B16-F10 melanoma cells as compared with wild-type mice. Taken together, the results of this short communication for the first time demonstrated that Nrf2 deficiency promoted melanoma growth and lung metastasis following subcutaneous inoculation of B16-F10 cells in mice. PMID- 29721549 TI - MitoSOX-Based Flow Cytometry for Detecting Mitochondrial ROS. AB - MitoSOX-based assays are widely used to detect mitochondrial reactive oxygen species (ROS), especially superoxide. To this end, 5 MUM MitoSOX is commonly used. In this ROS Protocols article, we described the flow cytometric protocol involving the use of various concentrations of MitoSOX (1, 2.5, 5 MUM) for detecting mitochondrial ROS in control and mitochondrial DNA-deficient (MD) melanoma B16-F10 cells. We also compared the MitoSOX-based flow cytometry with lucigenin-derived chemiluminometry for their ability to reliably detect the relative differences in mitochondrial ROS formation in the control and MD cells. Our results suggested that 1 MUM, rather than the commonly used 5 MUM, appeared to be the optimal concentration of MitoSOX for detecting mitochondrial ROS via flow cytometry. PMID- 29721550 TI - Evaluation of functional and structural leg length discrepancy in patients with adolescent idiopathic scoliosis using the EOS imaging system: a prospective comparative study. AB - Background: To our knowledge, no studies have reported the exact structural leg length discrepancies (LLDs) in patients with adolescent idiopathic scoliosis (AIS). Therefore, this study aimed to evaluate the differences between functional and structural LLDs and to examine the correlations between LLDs and spinopelvic parameters in patients with AIS using an EOS imaging system, which permits the three-dimensional reconstruction of spinal and lower-limb bony structures. Methods: Eighty-two consecutive patients with AIS underwent whole-body EOS radiography in a standing position between August 2014 and March 2016. Functional LLD, lumbar Cobb angle, thoracic curve Cobb angle, coronal balance, and pelvic obliquity were measured using two-dimensional EOS radiography. Structural LLDs were measured using three-dimensional EOS-reconstructed images. The comparison between LLDs was assessed using paired t test. Pearson's correlation coefficient (r) was used to determine potential correlations between the LLDs and spinopelvic alignment parameters. Results: Functional LLDs were significantly larger than structural LLDs (5.6 +/- 5.0 vs. 0.2 +/- 3.6 mm, respectively; p < 0.001). Both functional and structural LLDs were significantly correlated with pelvic obliquity (r = 0.69 and r = 0.51, respectively; p < 0.001 for both). Functional LLD, but not structural LLD, was correlated with lumbar Cobb angle (r = 0.44, p < 0.001; r = 0.17, p = 0.12, respectively). In addition, functional and structural LLDs were not correlated with thoracic Cobb angle (r = 0.09 and r = - 0.05, respectively; p >= 0.68 for both). Conclusions: Although patients with AIS often have functional LLDs, structural LLDs tend to be smaller. The correlation between functional LLDs and the lumbar Cobb angle indicates that functional LLDs compensate for the lumbar curve. Thus, the difference between functional and structural LLDs indicates a compensatory mechanism involving extension and flexion of the lower limbs. PMID- 29721551 TI - Investigating the role of Rts1 in DNA replication initiation. AB - Background: Understanding DNA replication initiation is essential to understand the mis-regulation of replication seen in cancer and other human disorders. DNA replication initiates from DNA replication origins. In eukaryotes, replication is dependent on cell cycle kinases which function during S phase. Dbf4-dependent kinase (DDK) and cyclin-dependent kinase (CDK) act to phosphorylate the DNA helicase (composed of mini chromosome maintenance proteins: Mcm2-7) and firing factors to activate replication origins. It has recently been found that Rif1 can oppose DDK phosphorylation. Rif1 can recruit protein phosphatase 1 (PP1) to dephosphorylate MCM and restricts origin firing. In this study, we investigate a potential role for another phosphatase, protein phosphatase 2A (PP2A), in regulating DNA replication initiation. The PP2A regulatory subunit Rts1 was previously identified in a large-scale genomic screen to have a genetic interaction with ORC2 (a DNA replication licensing factor). Deletion of RTS1 synthetically rescued the temperature-sensitive (ts-) phenotype of ORC2 mutants. Methods: We deleted RTS1 in multiple ts-replication factor Saccharomyces cerevisiae strains, including ORC2. Dilution series assays were carried out to compare qualitatively the growth of double mutant ?rts1 ts-replication factor strains relative to the respective single mutant strains. Results: No synthetic rescue of temperature-sensitivity was observed. Instead we found an additive phenotype, indicating gene products function in separate biological processes. These findings are in agreement with a recent genomic screen which found that RTS1 deletion in several ts-replication factor strains led to increased temperature-sensitivity. Conclusions: We find no evidence that Rts1 is involved in the dephosphorylation of DNA replication initiation factors. PMID- 29721552 TI - Expression of miR-145-5p During Chondrogenesis of Mesenchymal Stem Cells. AB - Assessing the quality of tissue engineered (TE) cartilage has historically been performed by endpoint measurements including marker gene expression. Until the adoption of promoter-driven reporter constructs capable of quantitative and real time non-destructive expression analysis, temporal gene expression assessments along a timeline could not be performed on TE constructs. We further exploit this technique to utilize microRNA (miRNA or miR) through the use of firefly luciferase reporter (Luc) containing a 3' UTR perfect complementary target sequence to the mature miR-145-5p. We report the development and testing of a firefly luciferase (Luc) reporter responsive to miR-145-5p for longitudinal tracking of miR-145-5p expression throughout MSC chondrogenic differentiation. Plasmid reporter vectors containing a miR-145-5p responsive reporter (Luc reporter with a perfect complementary target sequence to the mature miR-145-5p sequence in the 3'UTR), a Luc reporter driven by a truncated Sox9 (one of the targets of miR-145-5p) promoter, or the Luc backbone (control) vector without a specific miRNA target were transfected into MSCs by electroporation. Transfected MSCs were mixed with untransfected MSC to generate chondrogenic pellets. Pellets were imaged by bioluminescent imaging (BLI) and harvested along a preset time line. The imaging signals from miR-145-5p responsive reporter and Sox9 promoter driven reporter showed correlated time-courses (measured by BLI and normalized to Luc-control reporter; Spearman r=0.93, p=0.0002) during MSC chondrogenic differentiation. Expression analysis by qRT-PCR suggests an inverse relationship between miR-145-5p and Sox9 gene expression during MSC chondrogenic differentiation. Non-destructive cell-pellet imaging is capable of supplementing histological analyses to characterize TE cartilage. The miR-145-5p responsive reporter is relatively simple to construct and generates a consistent imaging signal responsive to miR-145-5p during MSC chondrogenesis in parallel to certain molecular and cellular events. PMID- 29721553 TI - Innovative Assessments Help Elucidate Sustained Improvements in Fitness and Metabolic Health in Obese Children. AB - Objective: Treatment of childhood obesity is a medical challenge and limited data are available describing successful long term interventions. This study presents a multi-disciplinary intervention that resulted in sustained physiological improvement over a one-year period. Methods: The criterion outcome variables include cardiovascular fitness (CVF) measured by a population-specific treadmill test to predict maximal oxygen uptake (predicted VO2 max) and the body composition (BC) variables of fat mass, non-bone lean mass and percent body fat from whole body dual energy x-ray absorptiometry (DXA) scans. Subjects were overweight and obese children (N=79) evaluated at baseline, 6 and 12 months at a University Hospital-based pediatric fitness clinic. Results: Statistically significant improvements in non-bone lean body mass (+4.24 kg +/- 5.0, p<0.0001) and predicted VO2 max (+0.14L/min +/- 0.10, p<0.0001) were seen at 6 months. These significant improvements were sustained over 12 months: body fat percentage (-2.28 +/- 3.49, p<0.0001), lean mass (+6.0 kg +/- 4.0, p<0.0001) and predicted VO2 max (+0.22 L/min +/- 0.19, p<0.0001). These results were observed despite increases in weight and body mass index (BMI) at 6-months (weight: +6.6 kg +/- 6.93, p<0.0001; BMI: +0.37 +/- 1.21, p=0.47) and 12-months (weight: +6.3 kg +/- 5.8, p<0.0001; BMI: +0.91 +/- 2.06, p=0.0002). Conclusion: These results reflect the sustained effect of a multidisciplinary approach, and the value of using valid and reliable assessment methods to measure sustained physiological changes in a sample of 79 overweight and obese children. PMID- 29721555 TI - Metal ions induced secondary structure rearrangements: mechanically interlocked lasso vs. unthreaded branched-cyclic topoisomers. AB - Metal ions can play a significant role in a variety of important functions in protein systems including cofactor for catalysis, protein folding, assembly, structural stability and conformational change. In the present work, we examined the influence of alkali (Na, K and Cs), alkaline earth (Mg and Ca) and transition (Co, Ni and Zn) metal ions on the conformational space and analytical separation of mechanically interlocked lasso peptides. Syanodin I, sphingonodin I, caulonodin III and microcin J25, selected as models of lasso peptides, and their respective branched-cyclic topoisomers were submitted to native nESI trapped ion mobility spectrometry-mass spectrometry (TIMS-MS). The high mobility resolving power of TIMS permitted to group conformational families regardless of the metal ion. The lower diversity of conformational families for syanodin I as compared to the other lasso peptides supports that syanodin I probably forms tighter binding interactions with metal ions limiting their conformational space in the gas phase. Conversely, the higher diversity of conformational families for the branched-cyclic topologies further supports that the metal ions probably interact with a higher number of electronegative groups arising from the fully unconstraint C-terminal part. A correlation between the lengths of the loop and the C-terminal tail with the conformational space of lasso peptides becomes apparent upon addition of metal ions. It was shown that the threaded C-terminal region in lasso peptides allows only for distinct interactions of the metal ion with either residues in the loop or tail region. This limits the size of the interacting region and apparently leads to a bias of metal ion binding in either the loop or tail region, depending whichever section is larger in the respective lasso peptide. For branched-cyclic peptides, the non-restricted C-terminal tail allows metal coordination by residues throughout this region, which can result in gas-phase structures that are sometimes even more compact than the lasso peptides. The high TIMS resolution also resulted in the separation of almost all lasso and branched-cyclic topoisomer metal ions (r ~ 2.1 on average). It is also shown that the metal incorporation (e.g., doubly cesiated species) can lead to the formation of a simplified IMS pattern (or preferential conformers), which results in baseline analytical separation and discrimination between lasso and branched-cyclic topologies using TIMS-MS. PMID- 29721556 TI - Test strips based on iron(iii)-impregnated alginate/polyacrylonitrile nanofibers for naked eye screening of tetracycline. AB - Tetracycline (TC) is an inexpensive broad-spectrum antibiotic used to treat infectious diseases and to promote growth in animals. However, driven by economic interest, abuse of TC poses a serious threat to human beings, and it remains a significant challenge to create easy-to-use TC colorimetric test strips for public use. Herein, we present a strategy to prepare free-standing, nanofibrous structured test strips with tortuous porous structure and large surface area by combining polyacrylonitrile nanofibrous membranes (PAN NMs), alginate, and Fe3+. In this approach, alginate was first functionalized on the PAN NMs and then, Fe3+ was assembled into the alginate to construct a TC-sensing surface. The resultant test strips exhibited the following integrated properties: fast sensing process (10 min), low naked eye detection limit (5 MUg kg-1), excellent anti-interference ability, and satisfactory reusability. Furthermore, the TC concentration dependent color change (yellow to maroon) was quantitatively visualized by an iPhone read-out hue parameter. All the findings indicate that this intriguing approach may pave the way for versatile designing of NMs to serve as a preventive treatment for the public. PMID- 29721554 TI - Supporting Collaborative Health Tracking in the Hospital: Patients' Perspectives. AB - The hospital setting creates a high-stakes environment where patients' lives depend on accurate tracking of health data. Despite recent work emphasizing the importance of patients' engagement in their own health care, less is known about how patients track their health and care in the hospital. Through interviews and design probes, we investigated hospitalized patients' tracking activity and analyzed our results using the stage-based personal informatics model. We used this model to understand how to support the tracking needs of hospitalized patients at each stage. In this paper, we discuss hospitalized patients' needs for collaboratively tracking their health with their care team. We suggest future extensions of the stage-based model to accommodate collaborative tracking situations, such as hospitals, where data is collected, analyzed, and acted on by multiple people. Our findings uncover new directions for HCI research and highlight ways to support patients in tracking their care and improving patient safety. PMID- 29721557 TI - Rare earth indates (RE: La-Yb): influence of the synthesis route and heat treatment on the crystal structure. AB - Rare earth indates are an interesting class of compounds with rich crystallography. The present study explores the crystallographic phases observed in REInO3 (RE: La-Yb) systems and their dependence on synthesis routes and annealing temperature. All REInO3 compositions were synthesized by a solid state route as well as gel-combustion synthesis (GC) followed by annealing at different temperatures. The systems were well characterized by powder XRD studies and were analysed by Rietveld refinement for the structural parameters. The cell parameters were observed to decrease in accordance with the trend in ionic radii on proceeding from lighter to heavier rare earth ions. Interestingly, the synthesis route and the annealing temperature had a profound bearing on the phase relationships observed in the REInO3 series. The solid state synthesized samples depicted an orthorhombic phase (Pbnm) field for LaInO3 to SmInO3, followed by a hexagonal-type phase (P63cm) for GdInO3 to DyInO3. However, the phase field distribution was greatly influenced upon employing gel-combustion (GC) wherein both single-phasic hexagonal and orthorhombic phase fields were found to shrink. Annealing the GC-synthesized compositions to still higher temperatures (1250 degrees C) further evolved the phase boundaries. An important outcome of the study is observance of polymorphism in SmInO3 which crystallized in the hexagonal phase when synthesized by GC and orthorhombic phase by solid state synthesis. This reveals the all-important role played by synthesis conditions. The existence and energetics of the two polymorphs have been elucidated and discussed with the aid of theoretical studies. PMID- 29721559 TI - Eliminating common biases in modelling the electrical conductivity of carbon nanotube-polymer nanocomposites. AB - Modelling carbon nanotube-polymer nanocomposites to predict their electrical conductivity demands high computational power. Past research has led to the assumption that conductive networks follow a periodic pattern; however, the impact of the underlying biases had never been investigated. This work provides insights into evaluating such biases and eliminating them to improve simulation accuracy. PMID- 29721558 TI - Tuning the Kondo resonance in two-dimensional lattices of cerium molecular complexes. AB - Cerium intermetallics have raised a lot of interest for the past forty years thanks to their very unusual and interesting electronic and magnetic properties. This can be explained by the peculiar electronic configuration of Ce (4f1) that allows different oxidation states leading to singular behavior such as quantum phase transitions, heavy-fermion behavior and the Kondo effect. In this work, we used a mixed-valence molecular analogue to study the Kondo effect down to the atomic scale by means of scanning tunneling microscopy/spectroscopy (STM/STS) for which new many-body effects are expected to emerge due to reduced dimensionality and specific chemical environment of the 4f-ion. For that purpose, double-decker molecular complexes hosting a Ce ion were synthesized and adsorbed onto Ag and Cu (111) surfaces forming two-dimensional lattices. As a result, we observed a zero bias conductance resonance on Ag only indicative of a Kondo effect arising from the coupling between a molecular spin and the conducting electrons of the metallic surface. The emergence of the Kondo effect is discussed in terms of intermolecular and molecule/substrate interactions. This work expands the little knowledge to date on the structural and related electronic properties of Ce-based molecular systems on surfaces. In particular, it shows that Ce-based double deckers are good platforms to obtain insight into 4f-induced many-body effects down to the nanometer scale and in two-dimensional lattices. Moreover, this outcome has a strong impact for future applications of molecular devices in which both metals are commonly used as electrical contacts. PMID- 29721560 TI - Self-assembly of a mixed-valence FeII-FeIII tetranuclear star. AB - A unique self-assembled mixed-valence FeII-FeIII tetranuclear star has been comprehensively characterised showing a large magnetic anisotropy at the peripheral FeII centres, ferromagnetic coupling between the iron centres and field-induced SMM behaviour. PMID- 29721561 TI - Cyclometalated iridium(iii) complexes induce mitochondria-derived paraptotic cell death and inhibit tumor growth in vivo. AB - The development of iridium complexes as potent anticancer agents has received increasing attention in recent years. In this study, four cyclometalated Ir(iii) complexes with good photophysical properties and potent anticancer activity have been synthesized and characterized. They are taken up by human lung adenocarcinoma A549 cells very quickly and specifically target mitochondria. Mechanism studies reveal that one of them, namely IrM2, induces paraptosis accompanied by excessive mitochondria-derived cytoplasmic vacuoles. Meanwhile, IrM2 affects the ubiquitin-proteasome system (UPS) and mitogen-activated protein kinase (MAPK) signaling pathways. Furthermore, IrM2 rapidly induces a series of mitochondria-related dysfunctional events, including the loss of mitochondrial membrane potential, cellular ATP depletion, mitochondrial respiration inhibition and reactive oxygen species (ROS) elevation. The rapid loss of mitochondrial functions, elevation of ROS and impairment of the UPS induced by IrM2 lead to the collapse of mitochondria and the subsequent cytoplasmic vacuolation before the cells are ready to start the mechanisms of apoptosis and/or autophagy. Among the ROS, superoxide anion radicals play a critical role in IrM2-mediated cell death. In vivo studies reveal that IrM2 can significantly inhibit tumor growth in a mouse model. This work gives useful insights into the design and anticancer mechanisms of new metal-based anticancer agents. PMID- 29721562 TI - Tetrathiomolybdate inhibits the reaction of cisplatin with human copper chaperone Atox1. AB - Cisplatin is a widely used anticancer drug in clinic, and ammonium tetrathiomolybdate ([(NH4)2MoS4], TM) is a copper chelator used in clinic for the treatment of Wilson's disease. Recently, TM has been found to enhance the therapeutic effect of cisplatin; however, the origin of this effect is not clear. Here we found that TM can inhibit the reaction of cisplatin with Cu-Atox1 and prevent the protein unfolding and aggregation induced by cisplatin. Although Ag(i) binds to Atox1 in a way similar to Cu(i)-Atox1, TM does not prevent the reaction of Ag-Atox1 with cisplatin. This result indicates that the formation of a Mo-centered trimeric protein cluster in the TM-Cu-Atox1 system plays a role in the inhibitory effect. This work provides new insights into the mechanism by which TM enhances the cytotoxic efficacy of cisplatin and helps to circumvent cisplatin resistance of tumor cells. PMID- 29721563 TI - Multiheme proteins: effect of heme-heme interactions. AB - The family of multiheme proteins constitutes one of the fascinating molecular machineries designed by Nature to execute a large variety of functions. A high level of conservation among the structural arrangement of heme units is evident among various multiheme cytochromes. The relative arrangement of the heme centers and the intermacrocyclic interactions therein have been found to exhibit a major role in functional properties of such a widely distributed family. The existence of more than one heme center provides an effective and efficient tool to modulate various structures and properties that are needed for its function. This Frontier overviews a brief account of our on-going efforts to examine some of the design principles in which the inter-heme distance and their relative orientations are appropriately chosen to elucidate, at the molecular level, the effects of heme heme interactions and electronic communication in the synthetic dihemes. PMID- 29721564 TI - Chitosan nanoparticles' functionality as redox active drugs through cytotoxicity, radical scavenging and cellular behaviour. AB - Targeting the oxidative stress response has recently emerged as a promising strategy for the development of therapeutic drugs for a broad spectrum of diseases. Supporting this strategy, we have reported that chitosan nanoparticles synthesized with a controlled size had selective cytotoxicity in leukemia cells through the mechanism related to reactive oxygen species (ROS) generation. Herein, we found that the cellular uptake of chitosan nanoparticles was enhanced in a time dependent manner and inhibited the cellular proliferation of leukemia cells in a dose dependent manner with elevation of the reactive oxygen species (ROS) showing a stronger effect on apoptosis, associated with the upregulation of caspase activity and the depletion of reduced glutathione. Propidium iodide and calcein staining demonstrated the central role of the chitosan nanoparticles in triggering elevated ROS, inducing cell death and intracellular oxidative activity. The enhanced free radical scavenging activity of the chitosan nanoparticles further iterates its antioxidant activity. In vitro quantitative phase imaging studies at the single cell level further demonstrated the inhibition of cellular proliferation with significant changes in cellular behavior and this supported our hypothesis. Hemocompatibility tests demonstrated that chitosan nanoparticles could be used safely for in vivo applications. Our findings suggest that chitosan nanoparticles may be a promising redox active candidate for therapeutic applications. PMID- 29721565 TI - Capturing the effect of [PF3(C2F5)3]-vs. [PF6]-, flexible anion vs. rigid, and scaled charge vs. unit on the transport properties of [bmim]+-based ionic liquids: a comparative MD study. AB - Comprehensive molecular dynamics simulations are performed to study the average single-particle dynamics and the transport properties of 1-butyl-3 methylimidazolium hexafluorophosphate, [bmim][PF6], and 1-butyl-3 methylimidazolium tris(pentafluoroethyl)trifluorophosphate, [bmim][FAP], ionic liquids (ILs) at 400 K. We applied one of the most widely used nonpolarizable all atom force fields for ILs, both with the original unit (+/-1) charges on each ion and with the partial charges uniformly scaled to 80-85%, taking into account the average polarizability and tracing the experimentally compatible transport properties. In all simulations, [bmim]+ was considered to be flexible, while the effect of a flexible vs. rigid structure of the anions and the effect of two applied charge sets on the calculated properties were separately investigated in detail. The simulation results showed that replacing [PF6]- with [FAP]-, considering anion flexibility, and applying the charge-scaled model significantly enhanced the ionic self-diffusion, ionic conductivity, inverse viscosity, and hyper anion preference (HAP). Both of the calculated self-diffusion coefficients from the long-time linear slope of the mean-square displacement (MSD) and from the integration of the velocity autocorrelation function (VACF) for the centers of mass of the ions were used for evaluation of the ionic transference number, HAP, ideal Nernst-Einstein ionic conductivity (sigmaNE), and the Stokes-Einstein viscosity. In addition, for quantification of the degree of complicated ionic association (known as the Nernst-Einstein deviation parameter, Delta) and ionicity phenomena in the two studied ILs, the ionic conductivity was determined more rigorously by the Green-Kubo integral of the electric-current autocorrelation function (ECACF), and then the sigmaGK/sigmaNE ratio was evaluated. It was found that the correlated motion of the (cationanion) neighbors in [bmim][FAP] is smaller than in [bmim][PF6]. The relaxation times of the normalized reorientational autocorrelation functions were computed to gain a deep, molecular-level insight into the rotational motion of the ions. The geometric shape of the ion is a key factor in determining its reorientational dynamics. [bmim]+ shows faster translational and slower rotational dynamics in contrast to [PF6]-. PMID- 29721566 TI - The effect of ligand symmetry on the ratiometric luminescence characteristics of lanthanides. AB - This work demonstrated that the ligand symmetry of europium(iii) complexes controls the ratiometric luminescence characteristics of lanthanides. Nona coordinated europium(iii) complexes having unsymmetrical beta-diketonate ligands (Cs) exhibit distinctive ratiometric spectral variations in the extremely narrow f-f transition bands over the temperature range from 253 to 323 K. In contrast, no such ratiometric change can be observed in a series of nona-coordinated europium(iii) complexes containing symmetrical beta-diketonate ligands (C2v). The remarkable difference depending on the ligand symmetry (Csvs. C2v) suggests that the coordination rearrangement of beta-diketonate in the complex causes ratiometric spectral variations in extremely narrow f-f transition bands, where two europium(iii) complex isomers exist in the solution equilibrium. A self calibration method using dual iso-emissive points is reported, where self calibration using the two emission intensities at the iso-emissive points reduces the coefficient of variation in luminescence thermometry. PMID- 29721567 TI - The kinetics of dimethylhydroxypyridinone interactions with iron(iii) and the catalysis of iron(iii) ligand exchange reactions: implications for bacterial iron transport and combination chelation therapies. AB - Many microbes acquire environmental Fe by secreting organic chelators, siderophores, which possess the characteristics of a high and specific binding affinity for iron(iii) that results in the formation of thermodynamically stable, and kinetically inert iron(iii) complexes. Mechanisms to overcome the kinetic inertness include the labilization of iron(iii) by means of ternary complex formation with small chelators. This study describes a kinetic investigation of the labilization of iron(iii) between two stable binding sites, the prototypical siderophore ferrioxamine B and EDTA, by the bidentate siderophore mimic, 1,2 dimethyl-3-hydroxy-4-pyridinone (L1, H(DMHP)). The proposed mechanism is substantiated by investigating the iron(iii) exchange reaction between ferrioxamine B and H(DMHP) to form Fe(DMHP)3, as well as the iron(iii) exchange from Fe(DMHP)3 to EDTA. It is also shown that H(DMHP) is a more effective catalyst for the iron(iii) exchange reaction than bidentate hydroxamate chelators reported previously, supporting the hypothesis that chelator structure and iron(iii) affinity influence low denticity ligand facilitated catalysis of iron(iii) exchange reactions. The results are also discussed in the context of the design and use of combination chelator therapies in the treatment of Fe overload in humans. PMID- 29721569 TI - MoS2/ZnO van der Waals heterostructure as a high-efficiency water splitting photocatalyst: a first-principles study. AB - Previous investigations [H. L. Zhuang and R. G. Hennig, J. Phys. Chem. C, 2013, 117, 20440-20445; J. Kang, S. Tongay, J. Zhou, J. Li and J. Wu, Appl. Phys. Lett., 2013, 102, 012111] demonstrated that molybdenum disulfide (MoS2) is a potential photocatalyst for water splitting. However, the photogenerated electron hole pairs in MoS2 remain in the same spatial regions, resulting in a high rate of recombination. Using first-principles calculations, we designed a MoS2-based heterostructure by stacking MoS2 on two-dimensional zinc oxide (ZnO) and investigated its structural, electronic, and optical properties. The interaction at the MoS2/ZnO interface was found to be dominated by van der Waals (vdW) forces. The energy levels of both water oxidation and reduction lie within the bandgap of the MoS2/ZnO vdW heterostructure, which guarantee their occurrence for water splitting. Moreover, a type-II band alignment and a large built-in electric field are formed at the MoS2/ZnO interface, which ensure the enhanced separation of the photogenerated electron-hole pairs. In addition, strong optical absorption in the visible region was also found in the MoS2/ZnO vdW heterostructure, indicating that it has potential for application in photovoltaic and photocatalytic devices. PMID- 29721568 TI - Hepatoprotection of auraptene from peels of citrus fruits against thioacetamide induced hepatic fibrosis in mice by activating farnesoid X receptor. AB - Hepatic fibrosis is a pathological process that eventually leads to the development of cirrhosis and liver cancer by various types of chronic liver disease. To date, there is no standard treatment for the progression of liver fibrosis. This study aims to investigate the hepatoprotection of auraptene (AUR), a simple coumarin contained in the peels of citrus fruits such as grapefruit, against thioacetamide (TAA)-induced hepatic fibrosis in mice. The involvement of farnesoid X receptor (FXR) in the anti-fibrotic effect of AUR was further elucidated using in vivo and in vitro experiments. AUR was found to remarkably protect against liver injury induced by TAA in mice and maintain the homeostasis of bile acids via the regulation of FXR-target genes including Bsep, Mrp2, Ntcp, Cyp7a1 and Cyp8b1. Masson and Sirius red staining indicated a reduction of the collagen content in the liver of AUR treated mice. Furthermore, AUR inhibited the activation of hepatic stellate cells (HSCs) by down-regulating the expression of TGF-beta1 and alpha-SMA and expressed anti-inflammatory effects by reducing the expression of NF-kappaB, TNF-alpha and IL-1beta. However, the changes in these genes and protein as well as ameliorative liver histology induced by AUR were abrogated by FXR antagonist guggulsterone in vivo and FXR siRNA in vitro. Overall, AUR protects against TAA-induced hepatic fibrosis due to the reduction of toxic bile acids and inhibition of hepatic stellate cell (HSC) activation and inflammation, which were all in association with FXR activation. AUR might be efficacious for the prevention and treatment of hepatic fibrosis in mice. PMID- 29721570 TI - Unveiling the atomistic mechanisms for oxygen intercalation in a strongly interacting graphene-metal interface. AB - The atomistic mechanisms involved in the oxygen (O) intercalation in the strongly interacting graphene (G) on Rh(111) system are characterized in a comprehensive experimental and theoretical study, combining scanning tunneling microscopy and density functional theory (DFT) calculations. Experimental evidence points out that the G areas located just above the metallic steps of the substrate are the active sites for initializing the intercalation process when some micro-etching points appear after molecular oxygen gas exposure. These regions are responsible for both the dissociation of the oxygen molecules and the subsequent penetration to the G-metal interface. Unlike in other species, the DFT calculations exclude single-point defects as additional entry paths to the interface. After penetration, the intercalation proceeds inwards due to the high mobility of atomic oxygen at the interface following mid-height paths connecting the higher areas of the rippled graphene structure. At larger coverages, the accumulation of O atoms under the high areas increases the G-metal distance in the neighboring low areas, paving the way for the O incorporation and the G detachment that leads to the final O-(2 * 1) structure. Furthermore, our results show that these mechanisms are possible only at temperatures slightly lower than those in which graphene etching takes place. PMID- 29721571 TI - A coumarin-based fluorescent probe for monitoring labile ferrous iron in living systems. AB - Labile Fe2+ has been considered to be a metabolically active and regulatory form of cellular iron. Monitoring the dynamic level of labile Fe2+ in biological systems is vital for evaluating the iron related biological processes and diseases as well as dissecting the exact physiological and pathophysiological functions of the labile Fe2+. Herein, we rationally constructed a coumarin-based fluorescent probe for sensing labile Fe2+ in living systems based on a novel Fe2+ meditated cyclization reaction strategy. The probe showed a highly selective and sensitive response to Fe2+, and the detection limit was determined to be 45 nM. Significantly, the probe displayed fast response to Fe2+, with the sensing reaction completed in 2 min, which is beneficial for real time sensing. The application of the probe for sensing different concentrations of labile Fe2+ in living cells has been conducted. In addition, the basal and endogenous levels of labile Fe2+ in living systems were also successfully monitored. PMID- 29721572 TI - Regulation of antibiotic production in Actinobacteria: new perspectives from the post-genomic era. AB - Covering: 2000 to 2018 The antimicrobial activity of many of their natural products has brought prominence to the Streptomycetaceae, a family of Gram positive bacteria that inhabit both soil and aquatic sediments. In the natural environment, antimicrobial compounds are likely to limit the growth of competitors, thereby offering a selective advantage to the producer, in particular when nutrients become limited and the developmental programme leading to spores commences. The study of the control of this secondary metabolism continues to offer insights into its integration with a complex lifecycle that takes multiple cues from the environment and primary metabolism. Such information can then be harnessed to devise laboratory screening conditions to discover compounds with new or improved clinical value. Here we provide an update of the review we published in NPR in 2011. Besides providing the essential background, we focus on recent developments in our understanding of the underlying regulatory networks, ecological triggers of natural product biosynthesis, contributions from comparative genomics and approaches to awaken the biosynthesis of otherwise silent or cryptic natural products. In addition, we highlight recent discoveries on the control of antibiotic production in other Actinobacteria, which have gained considerable attention since the start of the genomics revolution. New technologies that have the potential to produce a step change in our understanding of the regulation of secondary metabolism are also described. PMID- 29721573 TI - The utility of polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS) in surface and in situ studies: new data processing and presentation approach. AB - Infrared spectroscopy is a powerful non-destructive technique for the identification and quantification of organic molecules widely used in scientific studies. For many years, efforts have been made to adopt this technique for the in situ monitoring of reactions. From these efforts, polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS) was developed three decades ago. Unfortunately, because of the complexity of data processing and interpretation, PM-IRRAS had been avoided in lieu of the single potential alteration infrared spectroscopy (SPAIRS) and subtractively normalized interfacial Fourier transform infrared (SNIFTIR). In this work, we present a new approach for PM-IRRAS data processing and presentation, which provides more insight into in situ and surface studies besides dramatically improving the S/N. In this new approach, we recommend three complementary methods of data treatment (eqn (7), (9) and (10)) as the new protocols for presenting PM-IRRAS data. These equations are robust in visualising the surface processes at the solid-liquid and solid-gas interphases. Eqn (7) contrasts the surface adsorbed species with respect to the isotropic background with or without the influence of the applied potential. Eqn (9) highlights the surface potential-driven changes between the sample and the reference spectra. Eqn (10) focuses on the bulk-phase (solution/gas and surface species) potential-driven changes between the sample and the reference spectra, and hence it can be used to track the production of species, which desorb from the surface upon their formation. Examples of ethanol electro-oxidation reaction are provided as a test system for in situ studies and PVP deposited on glassy carbon for thin-film studies to illustrate the utility of the new PM-IRRAS data handling protocol, which is poised to improve the understanding of the chemistry and physics of surface processes. PMID- 29721574 TI - Lack of phototoxicity potential with delafloxacin in healthy male and female subjects: comparison to lomefloxacin. AB - AIMS: Delafloxacin is a fluoroquinolone antibiotic recently approved by the FDA for treatment of acute bacterial skin and skin structure infections (ABSSSI). Delafloxacin was assessed for phototoxicity potential compared with a known phototoxic fluoroquinolone. METHODS: A Phase 1, investigator-blind, placebo/active-controlled, randomized, parallel-group study was conducted in 52 healthy male and female volunteers who received 200 or 400 mg of oral delafloxacin, 400 mg oral lomefloxacin or placebo once daily for 6 days. This study evaluated the photosensitizing potential and possible wavelength dependency of delafloxacin by comparing the response of the skin to ultraviolet A (UVA), ultraviolet B (UVB) and visible radiation prior to and during administration of delafloxacin, lomefloxacin as a positive control, or placebo. Adverse events were monitored throughout the study. RESULTS: Forty-seven subjects completed six days of dosing, and no evidence of phototoxicity was seen with delafloxacin. Delafloxacin at 200 and 400 mg day-1 and placebo did not demonstrate differences in percent change from baseline in minimal erythema dose at all tested wavelengths (295-430 nm) by monochromator and solar simulator. Lomefloxacin, the positive control, had statistically significant differences (p < 0.05) at UVA wavelengths of 335 and 365 +/- 30 nm 24 hours after radiation exposure (maximum response). The phototoxic index results were significantly higher for lomefloxacin at 335 nm and 365 nm compared to placebo and delafloxacin. CONCLUSIONS: 200 and 400 mg of delafloxacin administered for 6 days were well tolerated in healthy adult volunteers. Delafloxacin and placebo failed to demonstrate a phototoxic effect but lomefloxacin, the positive control, demonstrated moderate phototoxicity. PMID- 29721575 TI - Iron excess upregulates SPNS2 mRNA levels but reduces sphingosine-1-phosphate export in human osteoblastic MG-63 cells. AB - : We aimed to study the mechanisms involved in bone-related iron impairment by using the osteoblast-like MG-63 cell line. Our results indicate that iron impact the S1P/S1PR signalizing axis and suggest that iron can affect the S1P process and favor the occurrence of osteoporosis during chronic iron overload. INTRODUCTION: Systemic iron excess favors the development of osteoporosis, especially during genetic hemochromatosis. The cellular mechanisms involved are still unclear despite numerous data supporting a direct effect of iron on bone biology. Therefore, the aim of this study was to characterize mechanisms involved in the iron-related osteoblast impairment. METHODS: We studied, by using the MG 63 cell lines, the effect of iron excess on SPNS2 gene expression which was previously identified by us as potentially iron-regulated. Cell-type specificity was investigated with hepatoma HepG2 and enterocyte-like Caco-2 cell lines as well as in iron-overloaded mouse liver. The SPNS2-associated function was also investigated in MG-63 cells by fluxomic strategy which led us to determinate the S1P efflux in iron excess condition. RESULTS: We showed in MG-63 cells that iron exposure strongly increased the mRNA level of the SPNS2 gene. This was not observed in HepG2, in Caco-2 cells, and in mouse livers. Fluxomic study performed concomitantly on MG-63 cells revealed an unexpected decrease in the cellular capacity to export S1P. Iron excess did not modulate SPHK1, SPHK2, SGPL1, or SGPP1 gene expression, but decreased COL1A1 and S1PR1 mRNA levels, suggesting a functional implication of low extracellular S1P concentration on the S1P/S1PR signalizing axis. CONCLUSIONS: Our results indicate that iron impacts the S1P/S1PR signalizing axis in the MG-63 cell line and suggest that iron can affect the bone-associated S1P pathway and favor the occurrence of osteoporosis during chronic iron overload. PMID- 29721576 TI - Inter-laboratory study for the certification of trace elements in seawater certified reference materials NASS-7 and CASS-6. AB - Certification of trace metals in seawater certified reference materials (CRMs) NASS-7 and CASS-6 is described. At the National Research Council Canada (NRC), column separation was performed to remove the seawater matrix prior to the determination of Cd, Cr, Cu, Fe, Pb, Mn, Mo, Ni, U, V, and Zn, whereas As was directly measured in 10-fold diluted seawater samples, and B was directly measured in 200-fold diluted seawater samples. High-resolution inductively coupled plasma mass spectrometry (HR-ICPMS) was used for elemental analyses, with double isotope dilution for the accurate determination of B, Cd, Cr, Cu, Fe, Pb, Mo, Ni, U, and Zn in seawater NASS-7 and CASS-6, and standard addition calibration for As, Co, Mn, and V. In addition, all analytes were measured using standard addition calibration with triple quadrupole (QQQ)-ICPMS to provide a second set of data at NRC. Expert laboratories worldwide were invited to contribute data to the certification of trace metals in NASS-7 and CASS-6. Various analytical methods were employed by participants including column separation, co-precipitation, and simple dilution coupled to ICPMS detection or flow injection analysis coupled to chemiluminescence detection, with use of double isotope dilution calibration, matrix matching external calibration, and standard addition calibration. Results presented in this study show that majority of laboratories have demonstrated their measurement capabilities for the accurate determination of trace metals in seawater. As a result of this comparison, certified/reference values and associated uncertainties were assigned for 14 elements in seawater CRMs NASS-7 and CASS-6, suitable for the validation of methods used for seawater analysis. PMID- 29721578 TI - Circumventricular organs of human brain visualized on post-contrast 3D fluid attenuated inversion recovery imaging. AB - PURPOSE: Although contrast-enhanced three-dimensional T2 fluid-attenuated inversion recovery (3D T2-FLAIR) images are useful for assessing various neuronal diseases, physiological enhancement of the circumventricular organs on the images have not been investigated. We aimed to assess the physiological appearance of the circumventricular organs on contrast-enhanced 3D T2-FLAIR images. METHODS: We studied 3-T MR images of the brain of 30 individuals with no apparent brain abnormalities. In ten areas of the brain, the degree of contrast enhancement on 3D T2-FLAIR and magnetization-prepared rapid gradient-echo (MPRAGE) images was evaluated using a 4-point grading system. The pre- and post-contrast mean contrast ratios (CRs) of the anterior pituitary gland, median eminence, and pineal gland were compared. RESULTS: On post-contrast 3D T2-FLAIR images, marked enhancement was most frequently scored in the median eminence, followed by the choroid plexus, posterior pituitary gland, and pineal gland. In 10 of the 30 cases, the vascular organ of the lamina terminalis and the area postrema were enhanced but the subcommissural organ was not. The difference in the mean pre- and post-contrast CRs of the median eminence and pineal gland was statistically significant, while that of the anterior pituitary gland was not. CONCLUSION: On contrast-enhanced 3D T2-FLAIR images, the circumventricular organs show variable enhancement. Our findings help to recognize physiological and abnormal enhancement of brain structures on contrast-enhanced 3D T2-FLAIR images. PMID- 29721577 TI - Curcumin protects heart tissue against irinotecan-induced damage in terms of cytokine level alterations, oxidative stress, and histological damage in rats. AB - Irinotecan (CPT-11), commonly used in the treatment of many cancer types, may have several side effects that limit the use of CPT-11 in specific tissues such as the heart. In the current study, positive effects of curcumin (CRC) was determined in terms of antioxidant and anti-inflammatory properties against heart damage, caused by CPT-11, in rats. Rats were divided randomly into four equal groups (Control, CPT-11, CRC, and CPT-11 + CRC). CPT-11 10 mg/kg/day was administered intraperitoneally and CRC 100 mg/kg-1 was given orally. Blood and tissue samples were collected from all groups at day 30 for the detection of oxidative stress, histological changes, and cytokine levels. Results showed that CPT-11 caused dramatic changes in heart tissue for oxidative stress parameters (TBARS, SOD, CAT, GSH, and GPx levels), histological tissue damage, and cytokine levels (TNF and IL-4). CRC therapy reversed the elevated oxidative stress, histological tissue damages, and immunological changes and protected cardiac tissue against CPT-11 toxicity when given together with CPT-11.In conclusion, CPT 11 caused adverse effects on cytokine levels, histological alterations, and oxidative stress in rats. However, CRC treatment eliminated these toxic effects with its antioxidant and anti-inflammatory properties. Thus, these results suggest that CRC may play a protective role against CPT-11 toxicity in heart tissue of rats. PMID- 29721580 TI - Domain-Specific Proteogenomic Analysis of Collagens to Evaluate De Novo Sequencing Results and Database Information. AB - Collagen is an important structural protein and the most abundant protein in mammals. In several research fields, structural analysis of collagens is performed. Fibrillar collagens almost entirely consist of continuous repeats of GXY, where G is glycine, X is often proline or alanine and Y is often hydroxyproline or alanine. In the present study, the collagen structure was investigated in detail at the nucleotide, codon group, amino acid and target peptide level using sequence analyses. One of the most important findings was that a selection of codon groups is predominantly involved in amino acid changes between closely related collagens and that other change routes come up when collagens are less related. The findings of the sequence analyses were used to evaluate reported sequences of non-avian dinosaur species and database entries of duck and chicken collagen. The duck assessment was supported by an experimental data set, obtained by collagen extraction from duck skin and subsequent digestion and LC-MS analysis. It was found that database entries of chicken and duck collagen 3alpha1 contained unreliable features, such as missing parts, no continuous GXY pattern and too many interspecies differences. As an example, the erroneous nature of one of these unreliable features was confirmed experimentally using LC-MS. Finally, dino and bird collagen 1alpha1 were compared. The presented results will show that performing a domain-specific proteogenomic analysis provides very useful information to assess de novo sequencing results and database information of collagens. Furthermore, it offers deeper insight in the functional restrictions and routes of evolutionary divergence. PMID- 29721581 TI - Glycyrrhizin Suppresses RANKL-Induced Osteoclastogenesis and Oxidative Stress Through Inhibiting NF-kappaB and MAPK and Activating AMPK/Nrf2. AB - The treatment for osteoporosis involves inhibiting bone resorption and osteoclastogenesis. Glycyrrhizin (GLY) is a triterpenoid saponin glycoside known to be as the most medically efficacious component of the licorice plant. It has strong anti-inflammatory, antioxidant, and antitumor properties. We investigated the effect of GLY on osteoclastogenesis, bone resorption, and intracellular oxidative stress and its molecular mechanisms. In vitro osteoclastogenesis assays were performed using bone marrow monocytes with and without glycyrrhizin. We also evaluated the effects of glycyrrhizin on the secretion of TNF-alpha, IL-1beta, and IL-6 in LPS-stimulated RAW 264.7 cells using ELISA. The effects of glycyrrhizin on the expression of osteoclast-related genes, such as Nfatc1, c fos, Trap, and cathepsin K (CK), were investigated by RT-PCR. Intracellular reactive oxygen species (ROS) were detected in receptor activator of nuclear factor kappa-Beta ligand (RANKL)-stimulated osteoclasts in the presence and absence of glycyrrhizin. During the inhibition of osteoclastogenesis by glycyrrhizin, phosphorylation of AMPK, Nrf2, NF-kappaB, and MAPK was analyzed using western blotting. Our results showed that glycyrrhizin significantly inhibited RANKL-induced osteoclastogenesis, downregulated the expression of NFATc1, c-fos, TRAP, CK, DC-STAMP, and OSCAR, and inhibited p65, p38, and JNK. Glycyrrhizin was found to significantly decrease the secretion of inflammatory cytokines (TNF-alpha, IL-1beta, and IL-6). Additionally, glycyrrhizin reduced the formation of ROS in osteoclasts by inducing AMPK phosphorylation and nuclear transfer of NRF2, resulting in an upregulation of antioxidant enzymes, such as HO 1, NQO-1, and GCLC. In summary, we found that glycyrrhizin inhibited RANKL induced osteoclastogenesis. It was also indicated that glycyrrhizin could reduce oxidative stress by inhibiting the MAPK and NF-kappaB pathways and activating the AMPK/NRF2 signaling. Therefore, glycyrrhizin may be used as an effective therapeutic agent against osteoporosis and bone resorption. PMID- 29721583 TI - A Different Perspective: How Much Innovation Is Really Needed for Monoclonal Antibody Production Using Mammalian Cell Technology? AB - As biopharmaceutical companies have optimized cell line and production culture process development, titers of recombinant antibodies have risen steadily to 3-8 g/L for fed-batch mammalian cultures at production scales of 10 kL or larger. Most new antibody products are produced from Chinese Hamster Ovary (CHO) cell lines, and there are relatively few alternative production hosts under active evaluation. Many companies have adopted a strategy of using the same production cell line for early clinical phases as well as commercial production, which reduces the risk of product comparability issues during the development lifecycle. Product quality and consistency expectations rest on the platform knowledge of the CHO host cell line and processes used for the production of many licensed antibodies. The lack of impact of low-level product variants common to this platform on product safety and efficacy also builds on the established commercial history of recombinant antibodies, which dates back to 1997.Efforts to increase titers further will likely yield diminishing returns. Very few products would benefit significantly from a titer greater than 8 g/L; in many cases, a downstream processing bottleneck would preclude full recovery from production scale bioreactors for high titer processes. The benefits of a process platform based on standard fed-batch production culture include predictable scale-up, process transfer, and production within a company's manufacturing network or at a contract manufacturing organization. Furthermore, the confidence in an established platform provides key support towards regulatory flexibility (e.g., design space) for license applications following a quality-by-design strategy.These factors suggest that novel technologies for antibody production may not provide a substantial return on investment. What, then, should be the focus of future process development efforts for companies that choose to launch antibody products using their current platform? This review proposes key focus areas in an effort to continually improve process consistency, assure acceptable product quality, and establish appropriate process parameter limits to enable flexible manufacturing options. PMID- 29721582 TI - Darunavir concentration in PBMCs may be a better indicator of drug exposure in HIV patients. AB - PURPOSE: The clinical efficacies of some antiretroviral drugs are known to not depend on its concentration in blood. To establish a method of dosage adjustment for darunavir (DRV) based on pharmacokinetic theory, we analyzed the correlation between DRV levels in peripheral blood mononuclear cells (PBMCs) and plasma. METHODS: The concentrations of DRV and ritonavir (RTV) in plasma and PBMCs of 31 samples obtained from 19 patients were analyzed. An in vitro kinetic study using MOLT-4 cells was performed to assess the contribution of RTV to the intracellular accumulation of DRV. RESULTS: DRV levels in PBMCs varied between 7.91 and 29.36 ng/106 cells (CV 37.5%), while those in plasma were greater. No significant correlation was found between the trough level of DRV in plasma and that in PBMCs (p = 0.575). The inter-day difference in DRV levels in PBMCs seemed smaller than that in plasma (- 41.6-23.0% vs - 83.3-109.1%). In the in vitro study, the elimination half-life of cellular efflux of DRV was 15.7 h in the absence of RTV and extended to 47.6 h in the presence of RTV. CONCLUSIONS: We found a poor correlation between intracellular DRV and plasma DRV levels in patients receiving highly active antiretroviral therapy. The efflux rate of DRV from cells was slow; therefore, the concentration of DRV in PBMCs may reflect average exposure to the drug and clinical efficacy. PMID- 29721584 TI - [Therapy-resistant and therapy-refractory arterial hypertension]. AB - Therapy-resistant and therapy-refractory arterial hypertension differ in prevalence, pathogenesis, prognosis and therapy. In both cases, a structured approach is required, with the exclusion of pseudoresistance and, subsequently, secondary hypertension. Resistant hypertension has been reported to be more responsive to intensified diuretic therapy, whereas refractory hypertension is presumed to require sympathoinhibitory therapy. Once the general measures and the drug-based step-up therapy have been exhausted, interventional procedures are available. PMID- 29721579 TI - GABAA receptor polymorphisms in alcohol use disorder in the GWAS era. AB - Alcohol use disorder (AUD) is a chronic, relapsing, neuro-psychiatric illness of high prevalence and with a serious public health impact worldwide. It is complex and polygenic, with a heritability of about 50%, and influenced by environmental causal heterogeneity. Risk factors associated with its etiology have a genetic component. GABA (gamma-aminobutyric acid) is a major inhibitory neurotransmitter in mammalian brain. GABAA receptors are believed to mediate some of the physiological and behavioral actions of alcohol. In this critical review, relevant genetic terms and type and methodology of the genetic studies are briefly explained. Postulated candidate genes that encode subunits of GABAA receptors, with all the reported SNPs, are presented. Genetic studies and meta analyses examining polymorphisms of the GABAA receptor and their association with AUD predisposition are presented. The data are critically examined with reference to recent GWAS studies that failed to show relations between GABAA receptors and AUD. Restrictions and perspectives of the different findings are discussed. PMID- 29721585 TI - Lon in maintaining mitochondrial and endoplasmic reticulum homeostasis. AB - As a vital member of AAA+ (ATPase associated with diverse cellular activities) protein superfamily, Lon, a homo-hexameric ring-shaped protein complex with a serine-lysine catalytic dyad, is highly conserved throughout almost all prokaryotic and eukaryotic organisms. Lon protease (LONP) plays an important role in maintaining mitoproteostasis through selectively recognizing and degrading oxidatively modified mitoproteins within mitochondrial matrix, such as oxidized aconitase, phosphorylated mitochondrial transcription factor A, etc. Furthermore, the up-regulated LONP increased mitochondrial ROS generation to promote cell survival, cell proliferation, epithelial-mesenchymal transition, and cell migration, which was attributed to the up-regulation of NADH:ubiquinone oxidoreductase core subunit S8 via interaction with chaperone Lon under hypoxic or oxidative stress in tumorigenesis. In addition, Lon also participated in protein kinase RNA (PKR)-like endoplasmic reticulum kinase signaling pathway under endoplasmic reticulum (ER) stress. In short, Lon, as a pivotal stress responsive protein that involved in the crosstalks among mitochondria, ER and nucleus, participated in multifarious important cellular processes crucial for cell survival, such as the mitochondrial protein quality control system, the mitochondrial unfolded protein response, the mtDNA maintenance, and the ER unfolded protein response. PMID- 29721586 TI - Corticosteroid-binding globulin, induced in testicular Leydig cells by perfluorooctanoic acid, promotes steroid hormone synthesis. AB - Perfluorooctanoic acid (PFOA) is an abundant perfluoroalkyl substance widely applied in industrial and consumer products. It is a ubiquitous environmental pollutant and suspected endocrine disruptor. Corticosteroid-binding globulin (CBG) is a monomeric glycoprotein that can bind specifically to anti-inflammatory steroids, such as glucocorticoids and progesterone, in circulation. Our previous proteomic profile analysis revealed that CBG levels increased in testes after PFOA treatment. In the present study, we verified its increase in mouse testes following oral exposure to PFOA (0, 1.25 and 5 mg/kg/day for 28 days) by immunohistochemical analysis and Western blotting. In addition, RNA fluorescence in situ hybridization (FISH) confirmed that testicular CBG was specifically expressed in Leydig cells. Serum CBG levels in all three PFOA groups also increased, accompanied by increased corticosterone in the 5 and 20 mg/kg/day groups and decreased adrenocorticotropic hormone in the 20 mg/kg/day group. Thus, the influence of PFOA on blood CBG may change free steroid hormone concentrations, thereby serving as an endocrine disruptor. A stimulation effect of PFOA on CBG was also observed in vitro using the Leydig tumor mLTC-1 cell line. Overexpression of CBG in mLTC-1 cells increased progesterone release in culture media. In addition, CBG-induced proteins involved in steroidogenesis in mLTC-1 cells, including steroidogenic acute regulatory protein (StAR), cytochrome P450 cholesterol side-chain cleavage enzyme (CYP11A1), 17alpha-hydroxylase/17,20 lyase (CYP17A1), and 3beta-hydroxysteroid dehydrogenase (3beta-HSD), which may be the mechanism behind increased progesterone. Furthermore, the production and release of CBG in mLTC-1 cells were also induced by luteinizing hormone, though this mechanism requires further exploration. PMID- 29721587 TI - Prenatal arsenic exposure and dietary folate and methylcobalamin supplementation alter the metabolic phenotype of C57BL/6J mice in a sex-specific manner. AB - Inorganic arsenic (iAs) is an established environmental diabetogen. The link between iAs exposure and diabetes is supported by evidence from adult human cohorts and adult laboratory animals. The contribution of prenatal iAs exposure to the development of diabetes and underlying mechanisms are understudied. The role of factors that modulate iAs metabolism and toxicity in adults and their potential to influence diabetogenic effects of prenatal iAs exposure are also unclear. The goal of this study was to determine if prenatal exposure to iAs impairs glucose metabolism in mice and if maternal supplementation with folate and methylcobalamin (B12) can modify this outcome. C57BL/6J dams were exposed to iAs in drinking water (0, 100, and 1000 ug As/L) and fed a folate/B12 adequate or supplemented diet from before mating to birth of offspring. After birth, dams and offspring drank deionized water and were fed the folate/B12 adequate diet. The metabolic phenotype of offspring was assessed over the course of 14 weeks. Male offspring from iAs-exposed dams fed the folate/B12-adequate diet developed fasting hyperglycemia and insulin resistance. Maternal folate/B12 supplementation rescued this phenotype but had only marginal effects on iAs metabolism in dams. The diabetogenic effects of prenatal iAs exposure in male offspring were not associated with changes in global DNA methylation in the liver. Only minimal effects of prenatal iAs exposure or maternal supplementation were observed in female offspring. These results suggest that prenatal iAs exposure impairs glucose metabolism in a sex-specific manner and that maternal folate/B12 supplementation may improve the metabolic phenotype in offspring. Further studies are needed to identify the mechanisms underlying these effects. PMID- 29721588 TI - The pharmacokinetics and metabolism of diclofenac in chimeric humanized and murinized FRG mice. AB - The pharmacokinetics of diclofenac were investigated following single oral doses of 10 mg/kg to chimeric liver humanized and murinized FRG and C57BL/6 mice. In addition, the metabolism and excretion were investigated in chimeric liver humanized and murinized FRG mice. Diclofenac reached maximum blood concentrations of 2.43 +/- 0.9 ug/mL (n = 3) at 0.25 h post-dose with an AUCinf of 3.67 ug h/mL and an effective half-life of 0.86 h (n = 2). In the murinized animals, maximum blood concentrations were determined as 3.86 +/- 2.31 ug/mL at 0.25 h post-dose with an AUCinf of 4.94 +/- 2.93 ug h/mL and a half-life of 0.52 +/- 0.03 h (n = 3). In C57BL/6J mice, mean peak blood concentrations of 2.31 +/- 0.53 ug/mL were seen 0.25 h post-dose with a mean AUCinf of 2.10 +/- 0.49 ug h/mL and a half-life of 0.51 +/- 0.49 h (n = 3). Analysis of blood indicated only trace quantities of drug-related material in chimeric humanized and murinized FRG mice. Metabolic profiling of urine, bile and faecal extracts revealed a complex pattern of metabolites for both humanized and murinized animals with, in addition to unchanged parent drug, a variety of hydroxylated and conjugated metabolites detected. The profiles in humanized mice were different to those of both murinized and wild-type animals, e.g., a higher proportion of the dose was detected in the form of acyl glucuronide metabolites and much reduced amounts as taurine conjugates. Comparison of the metabolic profiles obtained from the present study with previously published data from C57BL/6J mice and humans revealed a greater, though not complete, match between chimeric humanized mice and humans, such that the liver humanized FRG model may represent a model for assessing the biotransformation of such compounds in humans. PMID- 29721589 TI - Cardiovascular outcome in type 2 diabetes and atrial fibrillation. AB - Diabetes is an independent risk factor for atrial fibrillation (AF). Frequently, it is part of the metabolic syndrome cluster, which includes obesity and hypertension that are independently associated with AF. The risk appears to be higher with longer duration of diabetes and inadequate glycemic control. Patients with diabetes and AF have a substantially increased risk of death and serious cardiovascular complications compared with those in sinus rhythm. Conversely, good metabolic control appears to be associated with maintenance of rhythm after successful therapeutic conversion to sinus rhythm by catheter ablation or electrical cardioconversion of AF. AF puts patients with type 2 diabetes at a high risk of cardiovascular complications and death, which could be successfully addressed by new classes of antidiabetic agents such as incretin analogues or sglt-2 inhibitors. Thus, a diagnostic strategy that addresses the increased risk for AF is urgently recommended, in addition to diabetes monitoring in routine outpatient practice. In order to prevent thromboembolic complications, which frequently determine the prognosis for this patient population, appropriate anticoagulation remains the mainstay of therapy, whereas the prognostic value of reinstalling sinus rhythm awaits further evidence. PMID- 29721590 TI - Psychiatric morbidity and subsequent divorce: a couple-level register-based study in Finland. AB - PURPOSE: Studies that assess the role of mental health for the risk of divorce are scarce and mostly rely on individual-level data, although divorce is a couple level phenomenon. Using data on couples, we examine the effects of both spouses' psychiatric morbidity on the risk of divorce, and whether socio-demographic factors affect these associations. METHODS: We followed 96,222 Finnish married couples for 6 years using register-based data on both spouses and their household. New incidence of psychiatric morbidity and subsequent divorce was identified from dates of prescription medication purchases and hospital admissions, and dates of registered divorce. Socio-demographic factors were measured annually for both spouses and their household. The effect of incident psychiatric morbidity on divorce risk was analyzed using Cox regression. RESULTS: Psychiatric morbidity in men increased the age-adjusted risk of divorce more than twofold and in women nearly twofold. The risk of divorce was particularly pronounced immediately after new incidence of psychiatric morbidity, before settling to a persistently high level. Psychiatric morbidity in both spouses increased the risk of divorce almost threefold. Adjustment for socio-economic factors had little effect on these associations. CONCLUSIONS: Psychiatric morbidity is a persistent risk factor of divorce. The risk is larger when both spouses experience psychiatric morbidity compared to only one spouse. The findings are consistent with the idea that poor relationship quality and dissatisfaction in couples suffering from mental health problems have long-term consequences for marital stability. Treatment of psychiatric morbidity should not focus only on the individual but on couple-level dynamics. PMID- 29721591 TI - Inhalant use in adolescents in northern Russia. AB - PURPOSE: To determine the prevalence of inhalant use in Russian adolescents and to investigate associated psychosocial problems from a gender perspective. METHODS: Data on inhalant use and comorbid psychopathology were collected by means of self-reports from 2892 (42.4% boys) sixth to tenth grade students in public schools in Arkhangelsk, Russia. Multivariate analysis of covariance was used to assess differences in the levels of internalizing and externalizing problems in boys and girls, who were non-users and users of inhalants. RESULTS: The prevalence of inhalant use was 6.1% among boys and 3.4% among girls. Compared with non-users, inhalant users scored significantly higher on internalizing and externalizing problems, functional impairment and lower on academic motivation, with psychopathology increasing with age. While there were no gender differences for internalizing problems, increased levels of externalizing problems in inhalant users were gender-specific (significantly higher in boys). CONCLUSIONS: Inhalant use is related to significantly higher levels of comorbid psychopathology in Russian adolescents. Comprehensive, evidence-based prevention and intervention policies are needed to address inhalant use and its harmful effects. PMID- 29721592 TI - Social inequalities in mental disorders and substance misuse in young adults : A birth cohort study in Southern Brazil. AB - PURPOSE: To investigate the association between mental disorders and substance misuse at 30 years of age with gender, socioeconomic position at birth, and family income trajectories. METHODS: The 1982 Pelotas Birth Cohort was used; all 5914 children born alive at hospital were originally enrolled (99.2% of all city births). In 2012, 3701 subjects were located and interviewed (68% retention rate). Mental disorders and substance misuse were assessed, and their prevalence analysed according to gender, socioeconomic status at birth, and four different income trajectories: always poor, never poor, poor at birth/non-poor at age 30, and non-poor at birth/poor at age 30. RESULTS: While women presented higher prevalence of mental disorders, substance misuse was much more frequent among men. Individuals in the lowest income quintile at birth presented 2-5 times more mental disorders and substance misuse than those in the highest quintile. Young adults who were always poor or were not poor at birth but were poor at 30 years of age had a higher prevalence of mental disorders than the other groups. CONCLUSIONS: The high rates of mental disorders and lifetime suicide attempts in young adults, especially those who were always poor or became poor after childhood, suggest that recent socioeconomic-related stressful situations may have a higher impact on the current mental health than events earlier in life. However, we could not identify at what specific ages socioeconomic changes were more important. PMID- 29721593 TI - Mortality and hospitalization at the end of life in newly admitted nursing home residents with and without dementia. AB - PURPOSE: The proportion of deaths occurring in nursing homes is increasing and end of life hospitalizations in residents are common. This study aimed to obtain the time from nursing home admission to death and the frequency of hospitalizations prior to death among residents with and without dementia. METHODS: This retrospective cohort study analyzed claims data of 127,227 nursing home residents aged 65 years and older newly admitted to a nursing home between 2010 and 2014. We analyzed hospitalizations during the last year of life and assessed mortality rates per 100 person-years. Factors potentially associated with time to death were analyzed in Cox proportional hazard models. RESULTS: The median time from nursing home admission to death was 777 and 635 days in residents with and without dementia, respectively. Being male, older age and a higher level of care decreased the survival time. Sex and age had a higher influence on survival time in residents with dementia, whereas level of care was found to have a higher influence in residents without dementia. Half of the residents of both groups were hospitalized during the last month and about 37% during the last week before death. Leading causes of hospitalizations were infections (with dementia: 20.6% vs. without dementia: 17.2%) and cardiovascular diseases (with dementia: 16.6% vs. without dementia: 19.0%). CONCLUSIONS: A high proportion of residents with and without dementia are hospitalized shortly before death. There should be an open debate about the appropriateness of hospitalizing nursing home residents especially those with dementia near death. PMID- 29721594 TI - Increasing rates of self-harm among children, adolescents and young adults: a 10 year national registry study 2007-2016. AB - PURPOSE: Rates of hospital-treated self-harm are highest among young people. The current study examined trends in rates of self-harm among young people in Ireland over a 10-year period, as well as trends in self-harm methods. METHODS: Data from the National Self-Harm Registry Ireland on presentations to hospital emergency departments (EDs) following self-harm by those aged 10-24 years during the period 2007-2016 were included. We calculated annual self-harm rates per 100,000 by age, gender and method of self-harm. Poisson regression models were used to examine trends in rates of self-harm. RESULTS: The average person-based rate of self-harm among 10-24-year-olds was 318 per 100,000. Peak rates were observed among 15-19 year-old females (564 per 100,000) and 20-24-year-old males (448 per 100,000). Between 2007 and 2016, rates of self-harm increased by 22%, with increases most pronounced for females and those aged 10-14 years. There were marked increases in specific methods of self-harm, including those associated with high lethality. CONCLUSIONS: The findings indicate that the age of onset of self-harm is decreasing. Increasing rates of self-harm, along with increases in highly lethal methods, indicate that targeted interventions in key transition stages for young people are warranted. PMID- 29721595 TI - PAH Baselines for Amazonic Surficial Sediments: A Case of Study in Guajara Bay and Guama River (Northern Brazil). AB - The 16 priority PAH were determined in sediment samples from the insular zone of Guajara Bay and Guama River (Southern Amazon River mouth). Low hydrocarbon levels were observed and naphthalene was the most representative PAH. The low molecular weight PAH represented 51% of the total PAH. Statistical analysis showed that the sampling sites are not significantly different. Source analysis by PAH ratios and principal component analysis revealed that PAH are primary from a few rate of fossil fuel combustion, mainly related to the local small community activity. All samples presented no biological stress or damage potencial according to the sediment quality guidelines. This study discuss baselines for PAH in surface sediments from Amazonic aquatic systems based on source determination by PAH ratios and principal component analysis, sediment quality guidelines and through comparison with previous studies data. PMID- 29721596 TI - Contaminants of Emerging Concern in Wastewaters in Barbados, West Indies. AB - There have been few reports in the peer-reviewed literature on the levels of contaminants of emerging concern (CECs) in municipal wastewater from the Caribbean region. In this study of wastewater collected from two wastewater treatment plants in Barbados, caffeine and ibuprofen were detected at ug/L concentrations, whereas two steroid hormones (i.e. androstenedione, estrone) and several prescription pharmaceuticals were detected at ng/L concentrations. Among drugs of abuse, benzoylecgonine (i.e. metabolite of cocaine), MDMA (i.e. Ecstasy) and MDA (i.e. 3,4-methylenedioxyamphetamine) were present at the highest concentrations in untreated wastewater. Overall, these data show that there is potential impact in the marine environment in Barbados from CECs discharged into the coastal zone. PMID- 29721597 TI - Brominated Flame Retardants in Sediments of Four Coastal Lagoons of Yucatan, Mexico. AB - We examined the sediments of four coastal lagoons (Ria Lagartos, Bocas de Dzilam, Laguna de Chelem and Ria Celestun) from the state of Yucatan, Mexico, for three widely used commercial polybrominated diphenyl ethers formulations (penta-, octa- and deca-BDE). The most commonly found congeners in all four lagoons were BDEs 47, 99 and 100 (all in the penta-BDE formulation) and BDE209 (deca-BDE formulation). The greatest variety and highest concentrations of brominated flame retardants were found in Ria Lagartos, which also showed the highest BDE 100 concentration (24.129 ng/g). Hexabromocyclododecane was found in all lagoons, but at lower concentrations than those of the various polybrominated diphenyl ethers. Dispersal routes of these compounds are discussed, such as a ring of sinkholes (cenotes) adjacent to the lagoons. Moreover, electronic waste is a serious problem because municipal landfills have been the primary disposal method for these wastes and therefore represent a reservoir of brominated fire retardants. PMID- 29721598 TI - Current utilization and procedural practices in pediatric whole-body MRI. AB - BACKGROUND: Whole-body magnetic resonance imaging (MRI) is an evolving and increasingly powerful imaging tool with a variety of applications in the pediatric patient population. Variability exists among radiology practices in how this MRI tool is used and how it is performed. OBJECTIVE: Our objective was to gain an improved understanding of technical and utilization practices in pediatric whole-body MRI across North America by exploring indications for exam performance, determining referral patterns, and assessing technical protocols and procedures. MATERIALS AND METHODS: A 19-question survey was generated in Survey Monkey and distributed in 2016 to the Society for Pediatric Radiology membership. The survey asked questions that included practice type, imaging modality preferences for diseases commonly evaluated with whole-body MRI, MRI field strength and sequence selection, and billing practices. RESULTS: Data were obtained from 62 unique responses to the survey, representing 471 physicians. The majority (93%) practice in an academic institution or private practice with academic affiliation and most practices have utilized whole-body MRI for less than 6 years. Whole-body MRI is performed in pediatric patients 0 to 18 years of age, and was the preferred imaging modality for diagnosis/staging/follow-up in neurofibromatosis, type 1 (75%), chronic recurrent multifocal osteomyelitis (CRMO) (74%), cancer predisposition syndromes (75%), vasculopathies (50%) and disseminated/multifocal infection (49%). The most commonly utilized sequences are coronal short tau inversion recovery (STIR) (90%), coronal T1 with or without fat saturation (65%), and axial diffusion-weighted imaging (DWI) (48%). No preference was shown for either 1.5-T or 3-T systems. Wide variability was seen in preference for billing code utilization, though the majority use chest/abdomen/pelvis (57%) or unlisted MRI (37%) codes. CONCLUSION: Radiology practitioners - represented by the Society for Pediatric Radiology pediatric radiologists - are using whole-body MRI in the imaging care of pediatric patients for a variety of indications. Survey results reveal some variability in exam utilization and technical performance practices among those pediatric radiologists who perform whole-body MRI. PMID- 29721600 TI - [Nuclear Magnetic Resonance: Pioneers of discovery]. PMID- 29721599 TI - Optimization of magnetization-prepared rapid gradient echo (MP-RAGE) sequence for neonatal brain MRI. AB - BACKGROUND: Sequence optimization in neonates might improve detection sensitivity of abnormalities for a variety of conditions. However this has been historically challenging because tissue properties such as the longitudinal relaxation time and proton density differ significantly between neonates and adults. OBJECTIVE: To optimize the magnetization-prepared rapid gradient echo (MP-RAGE) sequence to enhance both signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) efficiencies. MATERIALS AND METHODS: We optimized neonatal MP-RAGE sequence through (1) reducing receive bandwidth to decrease noise, (2) shortening acquisition train length (acquisition number per repetition time or total number of read-out radiofrequency rephrasing pulses) using slice partial Fourier acquisition and (3) simulating the solution of Bloch's equation under optimal receive bandwidth and acquisition train length. Using the optimized sequence parameters, we scanned 12 healthy full-term infants within 2 weeks of birth and four preterm infants at 40 weeks' corrected age. RESULTS: Compared with a previously published neonatal protocol, we were able to reduce the total scan time by reduce the total scan time by 60% and increase the average SNR efficiency by 160% (P<0.001) and the average CNR efficiency by 26% (P=0.029). CONCLUSION: Our in vivo neonatal brain imaging experiments confirmed that both SNR and CNR efficiencies significantly increased with our proposed protocol. Our proposed optimization methodology could be readily extended to other populations (e.g., older children, adults), as well as different organ systems, field strengths and MR sequences. PMID- 29721601 TI - [Boys' health survey-between gender gap and information backlog]. AB - BACKGROUND: Early detection examinations take place from birth to the age of 6 years. The youth screening is a continuation of the screening of the "U-series" and should be carried out between the age of 12-15 and 16-17, respectively. Afterwards adolescent girls have good contact with a gynecologist, but adolescent boys usually do not have a medical contact person who they can trust in. MATERIALS AND METHODS: To evaluate the state of knowledge on boys' health, a 15 item comprehensive knowledge survey was conducted among ninth grade students at 7 secondary schools (Gymnasien) in North Rhine-Westphalia. The knowledge survey took place at three specified times (before, immediately after and approximately 3 months after adolescent sexual education classes). Only completed questionnaires were analyzed and evaluated in a gender-specific manner. RESULTS: Overall, 459 students participated from March-September 2017. Before sexual education instruction, about half of all questions were answered correctly by the students. Immediately after class, the proportion increased by a factor of 1.5 to a total of 79.24%. Then 2-3 months after the class, the percentage was 69.67%. Considering gender separately, this resulted in an increase of 15.32% for the female students and 16.99% for the male students. CONCLUSION: The knowledge survey reveals a need to catch up on facts on the subject of boys' health. Despite evidence of an increase in knowledge of both sexes after sexual education instruction, there is a gender gap. Hence, a preventive check-up especially for boys should be established and offered. Issues such as the prevention of sexually transmitted diseases, options for vaccination against human papillomavirus, etc. should be actively addressed. PMID- 29721602 TI - [Robotic-assisted vs. laparoscopic rectum resection-effect on conversion rate]. PMID- 29721603 TI - Pneumatosis Intestinalis Associated with the Tyrosine Kinase Inhibitor Nintedanib. PMID- 29721604 TI - Trans-algorithmic nature of learning in biological systems. AB - Learning ability is a vitally important, distinctive property of biological systems, which provides dynamic stability in non-stationary environments. Although several different types of learning have been successfully modeled using a universal computer, in general, learning cannot be described by an algorithm. In other words, algorithmic approach to describing the functioning of biological systems is not sufficient for adequate grasping of what is life. Since biosystems are parts of the physical world, one might hope that adding some physical mechanisms and principles to the concept of algorithm could provide extra possibilities for describing learning in its full generality. However, a straightforward approach to that through the so-called physical hypercomputation so far has not been successful. Here an alternative approach is proposed. Biosystems are described as achieving enumeration of possible physical compositions though random incremental modifications inflicted on them by active operating resources (AORs) in the environment. Biosystems learn through algorithmic regulation of the intensity of the above modifications according to a specific optimality criterion. From the perspective of external observers, biosystems move in the space of different algorithms driven by random modifications imposed by the environmental AORs. A particular algorithm is only a snapshot of that motion, while the motion itself is essentially trans algorithmic. In this conceptual framework, death of unfit members of a population, for example, is viewed as a trans-algorithmic modification made in the population as a biosystem by environmental AORs. Numerous examples of AOR utilization in biosystems of different complexity, from viruses to multicellular organisms, are provided. PMID- 29721605 TI - Estimation of critical end-test torque using neuromuscular electrical stimulation of the quadriceps in humans. AB - Characterization of critical power/torque (CP/CT) during voluntary exercise requires maximal effort, making difficult for those with neuromuscular impairments. To address this issue we sought to determine if electrically stimulated intermittent isometric exercise resulted in a critical end-test torque (ETT) that behaved similar to voluntary CT. In the first experiment participants (n = 9) completed four bouts of stimulated exercise at a 3:2 duty cycle, at frequencies of 100, 50, 25 Hz, and a low frequency below ETT (Sub-ETT; <= 15 Hz). The second experiment (n = 20) consisted of four bouts at a 2:2 duty cycle-two bouts at 100 Hz, one at an intermediate frequency (15-30 Hz), and one at Sub-ETT. The third experiment (n = 12) consisted of two bouts at 50 Hz at a 3:2 duty* cycle with proximal blood flow occlusion during one of the bouts. ETT torque was similar (p >= 0.43) within and among stimulation frequencies in experiment 1. No fatigue was observed during the Sub-ETT bouts (p > 0.05). For experiment 2, ETT was similar at 100 Hz and at the intermediate frequency (p >= 0.29). Again, Sub ETT stimulation did not result in fatigue (p > 0.05). Altering oxygen delivery by altering the duty cycle (3:2 vs. 2:2; p = 0.02) and by occlusion (p < 0.001) resulted in lower ETT values. Stimulated exercise resulted in an ETT that was consistent from day-to-day and similar regardless of initial torque, as long as that torque exceeded ETT, and was sensitive to oxygen delivery. As such we propose it represents a parameter similar to voluntary CT. PMID- 29721606 TI - The effects of different durations of static stretching within a comprehensive warm-up on voluntary and evoked contractile properties. AB - Evidence for performance decrements following prolonged static stretching (SS) has led to a paradigm shift in stretching routines within a warm-up. Rather than SS, dynamic stretching (DS) and dynamic activity (DA) have replaced SS within warm-up routines. The objective of the present study was to compare the effect of differing lower limb SS durations (30 [SS30s], 60 [SS60s] or 120 s [SS120s] of SS per muscle group or no-stretch control) within a comprehensive warm-up protocol consisting of aerobic activity, DS and DA. Sixteen male participants completed the four stretching conditions in a randomized order, after a 5-min low-intensity (cycle) warm-up and before a DS/DA component on separate days. Tests included passive hip and knee ranges of motion (ROM), maximum voluntary knee extensor/flexor force, force produced at 100 ms (F100), vertical jump height and evoked knee extensor contractile properties. For hip flexion (hamstrings) ROM, SS120s provided the largest increase (5.6-11.7%) followed by SS60s (4.3-11.4%), control (4.4-10.6%) and SS30s (3.6-11.1%). For knee flexion (quadriceps) ROM, SS30s provided the largest increase (9.3-18.2%) followed by SS120s (6.5-16.3%), SS60s (7.2-15.2%) and control (6.3-15.2%). There were decreases in quadriceps F100 following SS in SS120s (29.6%) only. There were increases in vertical jump performance in the control (6.2%), SS60s (4.6%) and SS30s (3.3%). While 120 s SS per muscle increased ROM, even within a comprehensive warm-up routine, it also elicited notable performance decrements. However, moderate durations of SS were observed to improve ROM whilst either having negligible or beneficial (but not detrimental) effects on specific aspects of athletic performance. PMID- 29721607 TI - Hydrogen sulphide facilitates exocytosis by regulating the handling of intracellular calcium by chromaffin cells. AB - Gasotransmitter hydrogen sulphide (H2S) has emerged as a regulator of multiple physiological and pathophysiological processes throughout. Here, we have investigated the effects of NaHS (fast donor of H2S) and GYY4137 (GYY, slow donor of H2S) on the exocytotic release of catecholamines from fast-perifused bovine adrenal chromaffin cells (BCCs) challenged with sequential intermittent pulses of a K+-depolarizing solution. Both donors caused a concentration-dependent facilitation of secretion. This was not due to an augmentation of Ca2+ entry through voltage-activated Ca2+ channels (VACCs) because, in fact, NaHS and GYY caused a mild inhibition of whole-cell Ca2+ currents. Rather, the facilitation of exocytosis seemed to be associated to an augmented basal [Ca2+]c and the K+ elicited [Ca2+]c transients; such effects of H2S donors are aborted by cyclopiazonic acid (CPA), that causes endoplasmic reticulum (ER) Ca2+ depletion through sarcoendoplasmic reticulum Ca2+ ATPase inhibition and by protonophore carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP), that impedes the ability of mitochondria to sequester cytosolic Ca2+ during cell depolarization. Inasmuch as CPA and FCCP reversed the facilitation of secretion triggered by K+ in the presence of NaHS and GYY, is seems that such facilitation is tightly coupled to Ca2+ handling by the ER and mitochondria. On the basis of these results, we propose that H2S regulates catecholamine secretory responses triggered by K+ in BCCs by (i) mobilisation of ER Ca2+ and (ii) interference with mitochondrial Ca2+ circulation. In so doing, the clearance of the [Ca2+]c transient will be delayed and the Ca2+-dependent trafficking of secretory vesicles will be enhanced to overfill the secretory machinery with new vesicles to enhance exocytosis. PMID- 29721608 TI - c-MYC amplification and c-myc protein expression in pancreatic acinar cell carcinomas. New insights into the molecular signature of these rare cancers. AB - The molecular alterations of pancreatic acinar cell carcinomas (ACCs) and mixed acinar-neuroendocrine carcinomas (MANECs) are not completely understood, and the possible role of c-MYC amplification in tumor development, progression, and prognosis is not known. We have investigated c-MYC gene amplification in a series of 35 ACCs and 4 MANECs to evaluate its frequency and a possible prognostic role. Gene amplification was investigated using interphasic fluorescence in situ hybridization analysis simultaneously hybridizing c-MYC and the centromere of chromosome 8 probes. Protein expression was immunohistochemically investigated using a specific monoclonal anti-c-myc antibody. Twenty cases had clones with different polysomies of chromosome 8 in absence of c-MYC amplification, and 5 cases had one amplified clone and other clones with chromosome 8 polysomy, while the remaining 14 cases were diploid for chromosome 8 and lacked c-MYC amplification. All MANECs showed c-MYC amplification and/or polysomy which were observed in 54% pure ACCs. Six cases (15.3%) showed nuclear immunoreactivity for c-myc, but only 4/39 cases showed simultaneous c-MYC amplification/polysomy and nuclear protein expression. c-myc immunoreactivity as well as c-MYC amplification and/or chromosome 8 polysomy was not statistically associated with prognosis. Our study demonstrates that a subset of ACCs shows c-MYC alterations including gene amplification and chromosome 8 polysomy. Although they are not associated with a different prognostic signature, the fact that these alterations are present in all MANECs suggests a role in the acinar-neuroendocrine differentiation possibly involved in the pathogenesis of MANECs. PMID- 29721609 TI - MMP-7 expression may influence the rate of distant recurrences and disease specific survival in HPV-positive oropharyngeal squamous cell carcinoma. AB - The objective of this study was to determine if matrix metalloproteinase-7 (MMP 7) expression is related to human papilloma virus (HPV) status, clinical parameters, and outcome in oropharyngeal squamous cell carcinoma (OPSCC). Tumor tissue specimens from 201 OPSCC patients treated with curative intent were available for immunohistochemistry, and the samples were stained with monoclonal MMP-7 antibody. All the patients were followed up at least 3 years or until death. MMP-7 expression did not differ between HPV-positive and HPV-negative patients. MMP-7 was not prognostic among patients with HPV-negative OPSCC. In the HPV-positive subgroup, patients with moderate, high, or very high MMP-7 expression had significantly worse 5-year disease-specific survival (DSS) (56.6%) than patients with absent, or low MMP-7 expression (77.2%), and MMP-7 expression appeared as a prognostic factor in the multivariate analysis. In addition, among HPV-positive OPSCC with moderate, high, or very high MMP-7 expression, the 5-year distant recurrence-free survival was significantly lower (69.6%) than in those who had low or absent MMP-7 expression (97.5%). Our results suggest that among HPV-positive OPSCC patients, high MMP-7 expression is related to worse 5-year DSS and increased rate of distant recurrences. PMID- 29721612 TI - Correction to: Lower limb pain among workers: a cross-sectional analysis of the fifth European Working Conditions Survey. AB - The article Lower limb pain among workers: a cross-sectional analysis of the fifth European Working Conditions Survey. PMID- 29721611 TI - Recurrence, progression and cancer-specific mortality according to stage at re TUR in T1G3 bladder cancer patients treated with BCG: not as bad as previously thought. AB - PURPOSE: The goals of transurethral resection of a bladder tumor (TUR) are to completely resect the lesions and to make a correct diagnosis to adequately stage and treat the patient. Persistent disease after TUR is not uncommon and is why re TUR is recommended in T1G3 patients. When there is T1 tumor in the re-TUR specimen, very high risks of progression (82%) have been reported. We analyze the risks of recurrence, progression to muscle-invasive disease and cancer-specific mortality (CSM) according to tumor stage at re-TUR in T1G3 patients treated with BCG. METHODS: In our retrospective cohort of 2451 T1G3 patients, 934 patients (38.1%) underwent re-TUR. 667 patients had residual disease (71.4%): Ta in 378 (40.5%), T1 in 289 (30.9%) patients. Times to recurrence, progression and CSM in the three groups were estimated using cumulative incidence functions and compared using the Cox regression model. RESULTS: During a median follow-up of 5.2 years, 512 patients recurred. The recurrence rate was significantly higher in patients with a T1 at re-TUR (P < 0.001). Progression rates differed according to the pathology at re-TUR, 25.3% in T1, 14.6% in Ta and 14.2% in case of no residual tumor (P < 0.001). Similar trends were seen in both patients with and without muscle in the original TUR specimen. CONCLUSIONS: Patients with T1G3 tumors and no residual disease or Ta at re-TUR have better recurrence, progression and CSM rates than previously reported, with a CSM rate of 13.1 and a 25.3% progression rate in re-TUR T1 disease. PMID- 29721610 TI - Mitogen-activated protein kinases concentrate in the vicinity of chromosomes and may regulate directly cellular patterning in Vicia faba embryos. AB - MAIN CONCLUSION: Mitogen-activated protein kinases seem to mark genes which are set up to be activated in daughter cells and thus they may play a direct role in cellular patterning during embryogenesis. Embryonic patterning starts very early and after the first division of zygote different genes are expressed in apical and basal cells. However, there is an ongoing debate about the way these different transcription patterns are established during embryogenesis. The presented data indicate that mitogen-activated protein kinases (MAPKs) concentrate in the vicinity of chromosomes and form visible foci there. Cells in the apical and basal regions differ in number of foci observed during the metaphase which suggests that cellular patterning may be determined by activation of diverse MAPK-dependent genes. Different number of foci in each group of separating chromatids and the specified direction of these mitoses in apical basal axis indicate that the unilateral auxin accumulation in a single cell may regulate the number of foci in each group of chromatids. Thus, we put forward a hypothesis that MAPKs localized in the vicinity of chromosomes during mitosis mark those genes which are set up to be activated in daughter cells after division. It implies that the chromosomal localization of MAPKs may be one of the mechanisms involved in establishment of cellular patterns in some plant species. PMID- 29721613 TI - Identification of dizzy patients who will develop an acute cerebrovascular syndrome: a descriptive study among emergency department patients. AB - PURPOSE: To calculate the incidence of subsequent acute cerebrovascular syndrome in emergency department patients with vertigo or dizziness symptoms and to determine predictors of subsequent acute cerebrovascular syndrome in these patients. METHODS: Descriptive and retrospective hospital based-population study among emergency department patients with vertigo or dizziness symptoms in 1 year. One year follow-up since the medical visit was performed. Chi-square and Fisher tests were used for qualitative variables; Mann-Whitney U test for quantitative variables. A multivariate model was created. RESULTS: 1243 dizzy patients who visited emergency department during 2015 were identified, finally 928 were included. 12 acute cerebrovascular syndromes were identified; 8 strokes and 4 transient ischemic attacks. Percentages over the sample size: 1.29% for acute cerebrovascular syndromes, 0.43% for transient ischemic attack and 0.86% for stroke. Odds ratio values to develop an event over the general population were 7.24 for acute cerebrovascular syndrome, 95% CI (3.98-13.12); 14.9 for transient ischemic attack, 95% CI (4.8-40.9) and 5.86 for stroke, 95% CI (2.72-12.0). Atrial fibrillation and diabetes mellitus were identified as significant risk factors to develop an acute cerebrovascular syndrome. CONCLUSION: Emergency department patients with symptoms of vertigo or dizziness had sevenfold higher risk of acute cerebrovascular syndromes than the general population. Atrial fibrillation and diabetes mellitus are risk factors associated with high risk of acute cerebrovascular syndromes in these patients. PMID- 29721615 TI - Image-Guided Thermal Ablation for Non-resectable Recurrence of Renal Cell Cancer Following Nephrectomy: Clinical Experience with Eleven Patients. AB - PURPOSE: To assess the feasibility, safety and clinical outcomes of image-guided percutaneous thermal ablation as salvage therapy for local recurrence of renal cell carcinoma (RCC) in patients initially treated surgically with curative intent. MATERIALS AND METHODS: A retrospective review of 11 consecutive patients (M/F = 8:3, mean age = 76 years) who underwent computed tomography (CT)-guided thermal ablation for locally recurrent RCC after partial (72%, 8/11) or radical nephrectomy (28%, 3/11) with a mean time to recurrence of 48 months (range 2 156). Assessment of technical success, complication (peri- and post-procedural), oncological outcome and survival analysis were performed. Patient baseline and follow-up renal function surrogates including creatinine level (Cr) and estimated glomerular filtration rate (eGFR) were statistically compared. RESULTS: Eleven biopsy-proven recurrent RCC measuring 1.4-3.9 cm (mean = 2.8 cm) were treated with CT-guided thermal ablation. Technical success was achieved in 100% (11/11) of the cases. There were no major complications except for one (9%) asymptomatic hemorrhage (Clavien-Dindo grade I complication). Complete response, local progression-free and overall survival rate were 91, 91 and 82% during the mean follow-up time of 2.5 years (range 0.1-7.1). Renal function was overall stable without significant change at 1 month and last follow-up (p = 0.21; GFR, p = 0.10; creatinine). CONCLUSIONS: Image-guided percutaneous thermal ablation is a feasible, safe and effective for local recurrence after nephrectomy, representing a non-surgical alternative for unresectable disease. PMID- 29721614 TI - A score for the differential diagnosis of bradykinin- and histamine-induced head and neck swellings. AB - PURPOSE: Acute edema of the head and neck region may lead to life-threatening dyspnea and require quick and targeted treatment. They can be subdivided in bradykinin- and histamine-mediated swellings, which require treatment with different classes of pharmaceuticals. Clinical pathways for differential diagnoses do not exist so far, although it is known that early treatment is decisive for faster symptom relief and reduced expression of the swellings. Aim of the study was the creation of a clinical algorithm for identification of bradykinin-mediated angioedema. METHODS: 188 patients that presented to our outpatient department between 2010 and 2016 with an acute, non-inflammatory swelling of the head and neck region were included in our retrospective study. All available anamnestic and clinical parameters were obtained from patient files. Parameters showing significant differences between the two groups were included in our score. Utilization of the Youden's index allowed determination of an optimal cut-off value. RESULTS: 76 patients could be assigned to the histamine and 112 patients to bradykinin group. The following parameters were included in our score: age, dyspnea, itching or erythema, glucocorticoid response and intake of ACEi/AT-II blockers. The cut-off value is set at three points. The proposed score yielded a sensitivity for identification of bradykinin-mediated angioedema of 96%, a specificity of 84%, a positive predictive value of 91% and a negative predictive value of 93%. CONCLUSIONS: Utilization of the proposed score allows quick and reliable assignment of patients to the correct subgroup and thereby reduces time for treatment. PMID- 29721616 TI - Development of a Robust Algorithm for Detection of Nuclei and Classification of White Blood Cells in Peripheral Blood Smear Images. AB - Peripheral Blood Smear analysis plays a vital role in diagnosis of many diseases such as leukemia, anemia, malaria, lymphoma and infections. Unusual variations in color, shape and size of blood cells indicate abnormal condition. We used a total of 117 images from Leishman stained peripheral blood smears acquired at a magnification of 100X. In this paper we present a robust image processing algorithm for detection of nuclei and classification of white blood cells based on features of the nuclei. We used novel image enhancement method to manage illumination variations and TissueQuant method to manage color variations for the detection of nuclei. Dice similarity coefficient of 0.95 was obtained for nucleus detection. We also compared the proposed method with a state-of-the-art method and the proposed method was found to be better. Shape and texture features of the detected nuclei were used for classifying white blood cells. We considered classification of WBCs using two approaches such as 5-class and cell-by-cell approaches using neural network and hybrid-classifier respectively. We compared the results of both the approaches for classification of white blood cells. Cell by-cell approach offered 1.4% higher sensitivity in comparison with the 5-class approach. We obtained an accuracy of 100% for lymphocyte and basophil detection. Hence, we conclude that lymphocytes and basophils can be accurately detected even when the analysis is limited to the features of nuclei whereas, accurate detection of other types of WBCs will require analysis of the cytoplasm too. PMID- 29721617 TI - The effect of cyclic heat treatment on the physicochemical properties of bio hydroxyapatite from bovine bone. AB - This paper focus on physicochemical changes in bio-hydroxyapatite (BIO-HAp) from bovine femur obtained by calcination at high temperatures: 520-620 (each 20 degrees C) at 7.4 degrees C/min and from 700 to 1100 degrees C (each 100 degrees C) at three heating rates: 7.4, 9.9, and 11.1 degrees C/min. BIO-HAp samples were obtained using a multi-step process: cleaning, milling, hydrothermal process, calcination in an air atmosphere, and cooling in furnace air. Inductively Couple Plasma (ICP) showed that the presence of Mg, K, S, Ba, Zn, and Na, is not affected by the annealing temperature and heating rate. While Scanning Electron Microscopy (SEM) images showed the continuous growth of the HAp crystals during the calcination process due to the coalescence phenomenon, and the Full Width at the Half Maximum for the X-ray patterns for temperatures up to 700 is affected by the annealing temperature and the heating rate. Through X-ray diffraction, thermal, and calorimetric analysis (TGA-DSC), a partial dehydroxylation of hydroxyapatite was found in samples calcined up to 900 degrees C for the three heating rates. Also, Ca/P molar ratio decreased for samples calcined up to 900 degrees C as a result of the dehydroxylation process. NaCaPO4, CaCO3, Ca3(PO4)2, MgO, and Ca(H2PO4)2 are some phases identified by X ray diffraction; some of them are part of the bone and others were formed during the calcination process as a function of annealing temperature and heating rate, as it is the case for MgO. PMID- 29721619 TI - A study of the aromaticity of heteroannelated cyclooctatetraene derivatives. AB - The aromaticity of the rings of thiophene, pyrrole, furan, and benzene annelated cyclooctatetraene (COT) derivatives and of their double charged ions was studied using the graph-theoretical theory of aromaticity. On the basis of topological resonance energy, it was found that the global aromaticity is dependent upon on the arrangement of heteroatoms in the given molecule. Relative stability of these molecules when in different charged states can been explained in terms of the topological charge stabilization rule. We expect that fusing the COT ring with an increasing number of aromatic rings will lead to an increase in the aromaticity of the molecule. According to the bond resonance energy (BRE) and circuit resonance energy (CRE) indices, local antiaromaticity of the COT ring is weakened as the number of fused rings increases, and these changes play a significant role in the global aromaticity of the molecule. For some compounds, our BRE and CRE indices do not predict the same order of magnitude of the local aromatic character of certain rings that the nucleus independent chemical shift (NICS(0) and (NICS(1)) methods predict. Finally, for the available compounds, correlations between the diatropic and paratropic chemical shifts of the protons and our ring current results were analyzed and good agreement was found. PMID- 29721620 TI - Multiple vertebral fractures sustained 5 months after Roux-en-Y gastric bypass: a case report. AB - INTRODUCTION: We report a case of a patient sustaining multiple simultaneous vertebral fractures 5 months after Roux-en-Y gastric bypass (RYGB) surgery. Obesity is associated with increased rates of morbidity and mortality and obesity rates globally continue to rise. Bariatric surgical procedures are successful in inducing sustained weight loss with many improved health outcomes. Potential complications include nutritional deficiencies and adverse effects on bone mineral metabolism with increased rates of fracture. CASE STUDY: We have recently cared for a 40-year-old female who sustained multiple vertebral fractures after bending forwards, occurring only 5 months after she underwent RYGB surgery, with post-operative weight loss of 55 kg. Blood tests performed several months after the fractures occurred revealed she had biochemical secondary hyperparathyroidism with low serum vitamin D levels. DISCUSSION: It has been previously demonstrated that RYGB surgery is associated with an increased incidence of fractures, and with reduction in bone mineral density. Patients undergoing bariatric surgery are frequently vitamin D deficient pre-operatively and show variable responses to vitamin D supplementation in the post-operative period. With particular reference to the RYGB procedure, there is evidence from several studies that bone mineral density is reduced at 12 and 24 post-operative months. To the best of our knowledge, this case may be the first time that multiple vertebral fractures have been documented so soon after weight loss surgery. It therefore highlights the growing conclusion that early consideration must be given to the maintenance of bone health in patients undergoing weight loss surgery. PMID- 29721618 TI - Square prism micropillars improve osteogenicity of poly(methyl methacrylate) surfaces. AB - Osteogenicity and osteointegration of materials is one of the key elements of the success of bone implants. Poly(methyl methacrylate) (PMMA) is the basic compound of bone cement and has been widely investigated for other orthopedic applications, but its poor osteointegration and the subsequent loosening of implant material limits its widespread use as bone implants. Micropillar features on substrate surfaces were recently reported to modulate cell behavior through alteration of cell morphology and promotion of osteogenesis. Utilization of this pillar-decorated topography may be an effective approach to enhance osteogenicity of polymeric surfaces. The aim of this study was to investigate the effect of cell morphology on the micropillar features on attachment, proliferation, and osteogenic activity of human osteoblast-like cells. A series of solvent cast PMMA films decorated with 8 um high square prism micropillars with pillar width and interpillar distances of 4, 8 and 16 um were prepared from photolithographic templates, and primary human osteoblast-like cells (hOB) isolated from bone fragments were cultured on them. Micropillars increased cell attachment and early proliferation rate compared to unpatterned surfaces, and triggered distinct morphological changes in cell body and nucleus. Surfaces with pillar dimensions and gap width of 4 um presented the best osteogenic activity. Expression of osteogenic marker genes was upregulated by micropillars, and cells formed bone nodule-like aggregates rich in bone matrix proteins and calcium phosphate. These results indicated that micropillar features enhance osteogenic activity on PMMA films, possibly by triggering morphological changes that promote the osteogenic phenotype of the cells. PMID- 29721623 TI - Promoting bone health management in women diagnosed with breast cancer: a pilot randomized controlled trial. AB - : This study investigates, in women diagnosed with breast cancer, the feasibility of evaluating the effects of educational material and its delivery method, on bone health management. The study results suggest educational material may improve rates of bone mineral density testing. INTRODUCTION: Educational materials improve bone mineral density (BMD) testing rates in high-risk patients, but the effect is unknown in women diagnosed with breast cancer. Methods of delivering educational materials may also affect testing rates. The purposes of this study were to determine the feasibility of the protocol and to pilot-test the effects of educational material and its delivery methods on BMD testing rates. METHOD: Pilot randomized controlled trial with block randomization. Fifty four women (aged 65-75 and diagnosed with breast cancer >= 3 years ago (2010 2012) and not taking osteoporosis medication) were recruited from February to May 2016 and randomized to three groups: control without educational material, educational material delivered by postal mail, and educational material delivered by patient choice of postal mail, email, or text messaging. Outcome measures were primarily evaluated using self-report questionnaires. RESULTS: The participation rate, defined as the proportion of eligible participants who consented to participate, was 39.1%. Primary outcome measure was obtained for 98% of the recruited women. During the 6-month follow-up period, BMD testing rates were significantly higher in the groups receiving educational materials by mail (26%, 95%CI = 10 to 49) and by patient choice (18%, 95%CI = 5 to 41), when compared with the control group (6%, 95%CI = 0.3 to 25). Educational material was associated with a 17% higher BMD testing rate. CONCLUSIONS: The study protocol is feasible for a large-scale study. The educational material intervention is broadly accepted by the study participants with a promising positive effect on BMD testing rates. PMID- 29721622 TI - Monitoring concentration and isotopic composition of methane in groundwater in the Utica Shale hydraulic fracturing region of Ohio. AB - Degradation of groundwater quality is a primary public concern in rural hydraulic fracturing areas. Previous studies have shown that natural gas methane (CH4) is present in groundwater near shale gas wells in the Marcellus Shale of Pennsylvania, but did not have pre-drilling baseline measurements. Here, we present the results of a free public water testing program in the Utica Shale of Ohio, where we measured CH4 concentration, CH4 stable isotopic composition, and pH and conductivity along temporal and spatial gradients of hydraulic fracturing activity. Dissolved CH4 ranged from 0.2 MUg/L to 25 mg/L, and stable isotopic measurements indicated a predominantly biogenic carbonate reduction CH4 source. Radiocarbon dating of CH4 in combination with stable isotopic analysis of CH4 in three samples indicated that fossil C substrates are the source of CH4 in groundwater, with one 14C date indicative of modern biogenic carbonate reduction. We found no relationship between CH4 concentration or source in groundwater and proximity to active gas well sites. No significant changes in CH4 concentration, CH4 isotopic composition, pH, or conductivity in water wells were observed during the study period. These data indicate that high levels of biogenic CH4 can be present in groundwater wells independent of hydraulic fracturing activity and affirm the need for isotopic or other fingerprinting techniques for CH4 source identification. Continued monitoring of private drinking water wells is critical to ensure that groundwater quality is not altered as hydraulic fracturing activity continues in the region. Graphical abstract A shale gas well in rural Appalachian Ohio. Photo credit: Claire Botner. PMID- 29721624 TI - Human and economic resources for empowerment and pregnancy-related mental health in the Arab Middle East: a systematic review. AB - This systematic review synthesizes research on the influence of human and economic resources for women's empowerment on their pre- and postnatal mental health, understudied in the Arab world. We include articles using quantitative methods from PubMed and Web of Science. Two researchers reviewed databases and selected articles, double reviewing 5% of articles designated for inclusion. Twenty-four articles met inclusion criteria. All 24 articles measured depression as an outcome, and three included additional mental health outcomes. Nine of 17 studies found an inverse association between education and depression; two of 12 studies found contradictory associations between employment and depression, and four of six studies found a positive association between financial stress and depression. These results suggest that there is a negative association between education and depression and a positive association between financial stress and depression among women in the Arab world. Firm conclusions warrant caution due to limited studies meeting inclusion criteria and large heterogeneity in mental health scales used, assessment measures, and definitions of human and economic resources for women's empowerment. It is likely that education reduces depression among postpartum women and that financial stress increases their depression. These findings can be used to aid in the design of interventions to improve mother and child outcomes. However, more research in the Arab world is needed on the relationship between human and economic resources for women's empowerment and perinatal mental health, and more consistency is needed in how resources and mental health are measured. PMID- 29721625 TI - [Acute life-threatening drug reactions of the skin]. AB - Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are acutely occurring, unpredictable, often life-threatening reactions that are a huge challenge in clinical practice. They are characterized by extensive blistering of skin and mucosa and are considered as one disease entity of different severity. Thus, they are summarized as SJS/TEN or EN (for epidermal or epithelial necrolysis). The diagnosis can be confirmed through synopsis of clinical pattern and histopathological findings. To identify the inducing factors, it is crucial to obtain a detailed and thorough medication and infection history. Based on the results of large epidemiological studies, potentially inducing drugs can be narrowed down even in cases of multimedication and underlying diseases. Agents with a high risk for SJS/TEN are allopurinol, antibacterial sulfonamides, non steroidal anti-inflammatory drugs of the oxicam-type, various antiepileptics and nevirapine. They alone explain more than half of the cases of SJS/TEN. Typically, the reaction occurs during the first continuous use of the medication, while the beginning of use most often is one to four weeks prior to reaction onset. However, a drug is not always the cause of the reaction, but in approximately 70 75% of the cases very likely. In other cases infections may be potential causes. If certain medications are thought to be the inducing factors, they should be withdrawn without delay. In addition, symptomatic treatment should be initiated. In case of progression, an additional immunomodulating therapy should be considered. In this respect, systematic reviews have shown best results for cyclosporine A and systemic steroids. PMID- 29721621 TI - Advances in the design of nanomaterial-based electrochemical affinity and enzymatic biosensors for metabolic biomarkers: A review. AB - This review (with 340 refs) focuses on methods for specific and sensitive detection of metabolites for diagnostic purposes, with particular emphasis on electrochemical nanomaterial-based sensors. It also covers novel candidate metabolites as potential biomarkers for diseases such as neurodegenerative diseases, autism spectrum disorder and hepatitis. Following an introduction into the field of metabolic biomarkers, a first major section classifies electrochemical biosensors according to the bioreceptor type (enzymatic, immuno, apta and peptide based sensors). A next section covers applications of nanomaterials in electrochemical biosensing (with subsections on the classification of nanomaterials, electrochemical approaches for signal generation and amplification using nanomaterials, and on nanomaterials as tags). A next large sections treats candidate metabolic biomarkers for diagnosis of diseases (in the context with metabolomics), with subsections on biomarkers for neurodegenerative diseases, autism spectrum disorder and hepatitis. The Conclusion addresses current challenges and future perspectives. Graphical abstract This review focuses on the recent developments in electrochemical biosensors based on the use of nanomaterials for the detection of metabolic biomarkers. It covers the critical metabolites for some diseases such as neurodegenerative diseases, autism spectrum disorder and hepatitis. PMID- 29721626 TI - [Individual prevention of occupational contact dermatitis: protective gloves and skin protection recommendations as part of the patient management scheme by the public statutory employers' liability insurance]. AB - The dermatologist's procedure is a pivotal tool for early recognition of occupational contact dermatitis (OCD), for reporting OCD cases to the statutory accident insurance and for treating the diseases. The employer is in charge of implementing skin protection measures at the workplace. However, in terms of an individual prevention approach it may be necessary to propose targeted skin protection recommendations in specific patient cases. The patient's own skin protection behavior significantly contributes to regenerating and maintaining healthy skin. This behavior includes the use of occupational skin products, and in particular the correct use of appropriately selected protective gloves. Protective gloves are the most important personal protective measure in the prevention of OCD. Prevention services, occupational health and safety specialists, occupational physicians and centers specialized in occupational dermatology can support the identification of suitable protective measures. Nowadays, suitable protective gloves exist for (almost) every occupational activity and exposure. However, improper use in practice can become a risk factor by itself for the skin (e. g., incorrectly used gloves). Therefore, it is of utmost importance to identify application errors, to educate patients in terms of skin protection and to motivate them to perform an appropriate skin protection behavior. With particular focus on protective gloves, this article gives an overview of various types, materials and potentially glove-related allergens, presents strategies for reducing occlusion effects and discusses some typical application errors and solutions. PMID- 29721628 TI - Impact of tumor localization on the outcomes of surgery for an intrahepatic cholangiocarcinoma. AB - BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) shows differing clinical outcomes depending on its localization. METHODS: We reviewed the surgical outcomes of 104 ICC patients who underwent liver resection at our institution. We divided ICC into hilar type (HICC) and peripheral type (PICC) depending on positive contact with the hepatic hilum on preoperative computed tomography (CT). RESULTS: The survival outcomes were significantly poorer in HICC patients. HICCs showed a larger tumor size and more frequent bile duct invasion, lymph node metastasis, and non-curative resection than PICC. Resections for HICC had greater blood loss and required a longer operation time, larger hepatectomy, and more frequent extrahepatic bile duct resection. HICCs, even if small in size, also showed a greater tendency to metastasize to the lymph nodes of the hepatoduodenal ligament. Univariate analysis of the ICCs in our current cohort revealed that tumor size, multiple tumors, bile duct invasion, lymph node metastasis, non curative resection, and HICC are associated with a poorer overall survival outcome. Multivariate analysis indicated that multiple tumors and non-curative resection were independent prognostic factors for survival. Among the curative resection cases, however, survival did not differ significantly between HICC and PICC. The accuracy rate of our CT-based classification for the pathological classification was 81.7%. CONCLUSIONS: HICC shows more frequent bile duct invasion and lymph node metastasis, requires more extensive surgery, and has a higher rate of non-curative resection than PICC. However, if curative resection is achieved, the survival outcomes are expected to be equivalent between HICC and PICC. PMID- 29721627 TI - [Type IV contact allergies in the food processing industry: an update]. AB - BACKGROUND: The food sector is one of the high-risk areas for occupational irritative and allergic contact eczema. OBJECTIVES: The present work provides an overview of the main allergens as well as sensitization frequencies and risk in various food industry occupations. METHODS: The literature on type IV sensitization in the food sector is summarized. RESULTS: The relative risk of developing a work-related eczema in food processing is increased by more than 3 times. The comparison group was calculated on the basis of the proportion of documented cases in the IVDK (Informationsverbund Dermatologischer Kliniken) network per 100,000 working persons in relation to the average of the years 2005 and 2010. For this purpose, the average risk of all patients was set as reference to 1. Bakers, pastry chefs, cooks and meat and fish processors are mainly affected. In addition to irritant contact eczema, allergic contact eczema and protein contact dermatitis often occur. Leading haptens (main allergens) are rubber ingredients, but also disinfectants and compositae. CONCLUSION: Only a few contact allergens are responsible for the majority of job-relevant sensitizations in the food industry. PMID- 29721630 TI - Characteristic features and proposed classification in 69 cases of intracranial microcystic meningiomas. AB - Microcystic meningioma (MM) is a rare subtype of intracranial meningiomas, with clinical and radiologic features not well characterized in the literature. Based on our experience, we propose a classification system of intracranial MMs. We reviewed the medical records, radiographic studies, and operative notes of a group of consecutive patients with intracranial MM. The mean age of the 69 patients was 46.8 +/- 10.6 years (range, 21-75 years). Three types of intracranial MMs could be identified. Type 1 MMs presented as a solid lesion, hypointense or isointense on T1WI, hyperintense on T2WI, and homogeneous or heterogeneous enhancement, and were found in 43 patients (67.2%). Type 2 MMs represented signals similar to CSF both on T1WI and T2WI, and faint reticular enhancement with marginal enhancement, and these were found in 7 patients (10.9%). Type 3 MMs consisted of cystic-solid or cystic lesion and were found in 14 patients (21.9%). Significant differences were observed among the different types of MMs for the following variables: sex, presence of severe peritumoral brain edema (PTBE), and extent of tumor resection. Females were found in all of patients with type 2 MMs, but were only 35.7% of those with type 3 MMs (P = 0.018). Severe PTBEs were more common among patients with type 1 MMs (55.8%) than among those with type 2 (14.3%) and type 3 MMs (14.3%) (P = 0.007). Type 1 MMs (97.7%) were associated with a significantly higher rate of gross total resection compared with the other two types (71.4 and 78.6%) (P = 0.019). Total length of hospital stay after craniotomy ranged from 4 to 30 days (median, 8 days). There were no significant differences in progression-free survival among the three types of MMs (P = 0.788). The current classification identifies three distinct types of intracranial MM based on their radiological findings and growth patterns. The type 1 MMs are more commonly associated with severe PTBE. Type 2 and Type 3 MMs have a higher predilection towards parasaggital location with venous involvement and therefore have a lower rate of gross total resection. PMID- 29721629 TI - Direct visualization transversus abdominis plane blocks offer superior pain control compared to ultrasound guided blocks following open posterior component separation hernia repairs. AB - PURPOSE: Transversus abdominis plane (TAP) blockade with long-acting anesthetic can be used during open ventral hernia repair (VHR) with posterior component separation (PCS). TAP block can be performed under ultrasound guidance (US-TAP) or under direct visualization (DV-TAP). We hypothesized that US-TAP and DV-TAP provide equivalent postoperative analgesia following open VHR. METHODS: A retrospective review of patients undergoing open VHR with PCS who received TAP blocks with 266 mg of liposomal bupivacaine was performed. Data included demographics, comorbidities, length of stay (LOS), average postoperative day (POD) pain scores, and narcotic requirements (normalized to mg oral morphine). Statistical analysis utilized Student's t test and Fisher's exact test. RESULTS: Thirty-nine patients were identified (22 DV-TAP). There were no differences between the groups with respect to demographics, comorbidities, pre-operative pain medication usage (narcotic and non-narcotic) or herniorrhaphy-related data. The average POD0 pain score was lower for the DV-TAP group (2.35 vs 4.18; p = 0.019). Narcotic requirements on POD0 (48.0 vs 103.76 mg; p = 0.02), POD1 (128.45 vs 273.82 mg; p = 0.03), POD4 (54.29 vs 160.75 mg; p = 0.042), and during the complete hospitalization (408.52 vs 860.92 mg; p = 0.013) were lower in the DV TAP group. There were no differences between initiation of diet or LOS. During the study, no changes were made to the VHR enhanced recovery pathway. CONCLUSIONS: DV-TAP blocks appear to provide superior analgesia in the immediate postoperative period. To achieve similar post-operative pain scores, patients in the US-TAP group required significantly more narcotic administration during their hospitalization. The study highlights DV-TAP as a valuable addition to VHR recovery pathways. PMID- 29721631 TI - Multiple chemo-genetic interactions between a toxic metabolite and the ubiquitin pathway in yeast. AB - AICAR is the precursor of ZMP, a metabolite with antiproliferative properties in yeast and human. We aim at understanding how AICAR (and its active form ZMP) affects essential cellular processes. In this work, we found that ZMP accumulation is synthetic lethal with a hypomorphic allele of the ubiquitin activating enzyme Uba1. A search for gene-dosage suppressors revealed that ubiquitin overexpression was sufficient to restore growth of the uba1 mutant upon AICAR treatment, suggesting that the ubiquitin pool is critical for cells to cope with AICAR. Accordingly, two mutants with constitutive low ubiquitin, ubp6 and doa1, were highly sensitive to AICAR, a phenotype that could be suppressed by ubiquitin overexpression. We established, by genetic means, that these new AICAR sensitive mutants act in a different pathway from the rad6/bre1 mutants which were previously reported as sensitive to AICAR (Albrecht et al., Genetics 204:1447-1460, 2016). Two ubiquitin-conjugating enzymes (Ubc4 and Cdc34) and a ubiquitin ligase (Cdc4) were found to contribute to the ability of cells to cope with ZMP. This study illustrates the complexity of chemo-genetic interactions and shows how genetic analyses allow deciphering the implicated pathways, the individual gene effects, and their combined phenotypic contribution. Based on additivity and suppression patterns, we conclude that AICAR treatment shows synthetic interactions with distinct branches of the yeast ubiquitin pathway. PMID- 29721632 TI - Acute lower limb ischemia and intestinal necrosis due to arterial tumor embolism from advanced lung cancer: a case report and literature review. AB - BACKGROUND: Arterial tumor embolism (ATE) is a rare but life-threating complication. PRESENTATION OF CASE: A 55-year-old man with acute lower-limb ischemia was referred to our hospital after endovascular intervention failed and underwent above-the-knee amputation for severe limb necrosis. On postoperative day 8, he developed small bowel necrosis and underwent resection. Histopathological examination of the resected bowel revealed that the submucosal arterial emboli were positive for the markers of squamous cells. He had unresectable lung squamous cell carcinoma with left atrium invasion. The subsequent embolisms were thought to be caused by the advanced lung cancer. CONCLUSION: ATE is rare but should be considered as a differential diagnosis for unidentified arterial occlusion. PMID- 29721633 TI - Decreased VMAT2 in the pancreas of humans with type 2 diabetes mellitus measured in vivo by PET imaging. AB - AIMS/HYPOTHESIS: The progressive loss of beta cell function is part of the natural history of type 2 diabetes. Autopsy studies suggest that this is, in part, due to loss of beta cell mass (BCM), but this has not been confirmed in vivo. Non-invasive methods to quantify BCM may contribute to a better understanding of type 2 diabetes pathophysiology and the development of therapeutic strategies. In humans, the localisation of vesicular monoamine transporter type 2 (VMAT2) in beta cells and pancreatic polypeptide cells, with minimal expression in other exocrine or endocrine pancreatic cells, has led to its development as a measure of BCM. We used the VMAT2 tracer [18F]fluoropropyl (+)-dihydrotetrabenazine to quantify BCM in humans with impaired glucose tolerance (prediabetes) or type 2 diabetes, and in healthy obese volunteers (HOV). METHODS: Dynamic positron emission tomography (PET) data were obtained for 4 h with metabolite-corrected arterial blood measurement in 16 HOV, five prediabetic and 17 type 2 diabetic participants. Eleven participants (six HOV and five with type 2 diabetes) underwent two abdominal PET/computed tomography (CT) scans for the assessment of test-retest variability. Standardised uptake value ratio (SUVR) was calculated in pancreatic subregions (head, body and tail), with the spleen as a reference region to determine non-specific tracer uptake at 3-4 h. The outcome measure SUVR minus 1 (SUVR-1) accounts for non-specific tracer uptake. Functional beta cell capacity was assessed by C-peptide release following standard (arginine stimulus test [AST]) and acute insulin response to the glucose enhanced AST (AIRargMAX). Pearson correlation analysis was performed between the binding variables and the C-peptide AUC post-AST and post-AIRargMAX. RESULTS: Absolute test-retest variability (aTRV) was <=15% for all regions. Variability and overlap of SUVR-1 was measured in all groups; HOV and participants with prediabetes and with type 2 diabetes. SUVR-1 showed significant positive correlations with AIRargMAX (all groups) in all pancreas subregions (whole pancreas p = 0.009 and pancreas head p = 0.009; body p = 0.019 and tail p = 0.023). SUVR-1 inversely correlated with HbA1c (all groups) in the whole pancreas (p = 0.033) and pancreas head (p = 0.008). SUVR-1 also inversely correlated with years since diagnosis of type 2 diabetes in the pancreas head (p = 0.049) and pancreas tail (p = 0.035). CONCLUSIONS/INTERPRETATION: The observed correlations of VMAT2 density in the pancreas and pancreas regions with years since diagnosis of type 2 diabetes, glycaemic control and beta cell function suggest that loss of BCM contributes to deficient insulin secretion in humans with type 2 diabetes. PMID- 29721635 TI - Advances in dialysis encephalopathy research: a review. AB - Dialysis encephalopathy (DE) is a progressive, fatal disease with a high mortality rate. Understanding the causes of this disease and the efforts to prevent and treat it would help improve the prognosis and quality of life of affected patients. This paper reviews the etiology, clinical features, methods of examining accessory features, diagnosis, treatment, and prevention of DE. We found that DE is likely to be related to aluminum poisoning. The clinical manifestations of DE include language disorders, mental and behavioral disorders, cognitive decline, and movement disorders. Electroencephalogram (EEG) findings mainly consist of an abundance of low waves, intermittent bilateral synchronous high-amplitude spikes, and ridge waves. Assessing the clinical features and obtaining an EEG are of great value in diagnosis, and DE is treated by both reducing aluminum intake and increasing aluminum excretion. Deferoxamine (DFO) is an effective treatment for DE. PMID- 29721636 TI - Adipose-derived stem cells (MYSTEM(r) EVO Technology) as a treatment for complex transsphincteric anal fistula. PMID- 29721637 TI - Application of an enhanced recovery pathway for ileostomy closure: a case-control trial with surprising results. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) protocols have been widely validated in colorectal surgery; however, few data exist on loop ileostomy closure. The aim of this study was to compare clinical outcomes before and after introduction of ERAS for loop ileostomy closure. METHODS: Data on outcomes after loop ileostomy closure were retrospectively collected before ERAS was applied at our department (control group). These results were compared to results of patients undergoing loop ileostomy closure within the original colorectal ERAS pathway (ERAS 1 group); after analysis of these results, adaptations were made to the ERAS pathway regarding the postoperative diet, and this second category of patients was analyzed (ERAS 2 group). RESULTS: Forty-eight patients in the control group were compared to 46 ERAS 1 and 69 ERAS 2 patients. First stool was significantly faster in ERAS 2 group versus control and ERAS 1 group [median 1 (range 1-2) days vs 2 (2-3) days p value 0.01]. The incidence of vomiting increased from 26% in the control group to 45% in ERAS 1 group, and then decreased to 29% in the ERAS 2 group (p value 0.41). Length of stay was significantly shorter during the ERAS 2 protocol: median 4 (range 3-6) days versus 5 (4-8) days in the control group (p value < 0.01). CONCLUSIONS: After application of the 'colorectal' ERAS pathway to loop ileostomy closure, results were initially not improved. Minor corrections were sufficient to avoid increased incidence of vomiting and to allow for reduced hospital stay. Uncritical extrapolation of an ERAS colorectal protocol to other types of surgery should be monitored and needs audit for corrections. PMID- 29721639 TI - Letter to the Editor: A Prospective Comparative Study on Improvement of Hyperthyroid Cardiovascular Dysfunction in Patients Undergoing Total Thyroidectomy Versus Medical Management. PMID- 29721638 TI - Prepared for Mission? A Survey of Medical Personnel Training Needs Within the International Committee of the Red Cross. AB - BACKGROUND: Humanitarian organizations such as the International Committee of the Red Cross (ICRC) provide worldwide protection and medical assistance for victims of disaster and conflict. It is important to gain insight into the training needs of the medical professionals who are deployed to these resource scarce areas to optimally prepare them. This is the first study of its kind to assess the self perceived preparedness, deployment experiences, and learning needs concerning medical readiness for deployment of ICRC medical personnel. METHODS: All enlisted ICRC medical employees were invited to participate in a digital questionnaire conducted during March 2017. The survey contained questions about respondents' personal background, pre-deployment training, deployment experiences, self perceived preparedness, and the personal impact of deployment. RESULTS: The response rate (consisting of nurses, surgeons, and anesthesiologists) was 54% (153/284). Respondents rated their self-perceived preparedness for adult trauma with a median score of 4.0 on a scale of 1 (very unprepared) to 5 (more than sufficient); and for pediatric trauma with a median score of 3.0. Higher rates of self-perceived preparedness were found in respondents who had previously been deployed with other organizations, or who had attended at least one master class, e.g., the ICRC War Surgery Seminar (p < 0.05). Additional training was requested most frequently for pediatrics (65/150), fracture surgery (46/150), and burns treatment (45/150). CONCLUSION: ICRC medical personnel felt sufficiently prepared for deployment. Key points for future ICRC pre-deployment training are to focus on pediatrics, fracture surgery, and burns treatment, and to ensure greater participation in master classes. PMID- 29721634 TI - Discordant association of the CREBRF rs373863828 A allele with increased BMI and protection from type 2 diabetes in Maori and Pacific (Polynesian) people living in Aotearoa/New Zealand. AB - AIMS/HYPOTHESIS: The A (minor) allele of CREBRF rs373863828 has been associated with increased BMI and reduced risk of type 2 diabetes in the Samoan populations of Samoa and American Samoa. Our aim was to test rs373863828 for associations with BMI and the odds of type 2 diabetes, gout and chronic kidney disease (CKD) in Maori and Pacific (Polynesian) people living in Aotearoa/New Zealand. METHODS: Linear and logistic regression models were used to analyse the association of the A allele of CREBRF rs373863828 with BMI, log-transformed BMI, waist circumference, type 2 diabetes, gout and CKD in 2286 adults. The primary analyses were adjusted for age, sex, the first four genome-wide principal components and (where appropriate) BMI, waist circumference and type 2 diabetes. The primary analysis was conducted in ancestrally defined groups and association effects were combined using meta-analysis. RESULTS: For the A allele of rs373863828, the effect size was 0.038 (95% CI 0.022, 0.055, p = 4.8 * 10-6) for log-transformed BMI, with OR 0.59 (95% CI 0.47, 0.73, p = 1.9 * 10-6) for type 2 diabetes. There was no evidence for an association of genotype with variance in BMI (p = 0.13), and nor was there evidence for associations with serum urate (beta = 0.012 mmol/l, pcorrected = 0.10), gout (OR 1.00, p = 0.98) or CKD (OR 0.91, p = 0.59). CONCLUSIONS/INTERPRETATION: Our results in New Zealand Polynesian adults replicate, with very similar effect sizes, the association of the A allele of rs373863828 with higher BMI but lower odds of type 2 diabetes among Samoan adults living in Samoa and American Samoa. PMID- 29721640 TI - Assessment of the renal collecting system using a pocket-sized ultrasound device. AB - PURPOSE: To assess the performance of a pocket-sized ultrasound device (PUD) for evaluating dilatation of the renal collecting system with high-end ultrasound devices (HUDs) as a reference standard. METHODS: One sonographer examined both kidneys using a PUD to evaluate dilatation of the collecting system. The grading of the dilatation ranged from 0 to 4. Immediately after the examination, another sonographer blinded to the previous results performed a formal examination with a HUD. RESULTS: Two hundred kidneys in 100 patients were included in the analysis. The agreement of grades between the PUD and HUDs was excellent (weighted kappa = 0.83; P < 0.001). When hydronephrosis was defined as grade 1 or higher, the test characteristics of the PUD were as follows: sensitivity 91% (95% confidence interval (CI) 79-97%), positive predictive value 73% (95% CI 60-83%), and negative predictive value 96% (95% CI 92-99%). When hydronephrosis was defined as grade 2 or higher, the test characteristics were as follows: sensitivity 88% (95% CI 73-97%), positive predictive value 75% (95% CI 59-87%), and negative predictive value 98% (95% CI 94-99%). CONCLUSION: Ultrasound using a PUD is useful for evaluating dilatation of the collecting system, especially for ruling out its presence. PMID- 29721641 TI - Synthesis and Properties of Water-Soluble Blue-Emitting Mn-Alloyed CdTe Quantum Dots. AB - In this work, we prepared CdTe quantum dots, and series of Cd1-xMnxTe-alloyed quantum dots with narrow size distribution by an ion-exchange reaction in water solution. We found that the photoluminescence peaks are shifted to higher energies with the increasing Mn2+ content. So far, this is the first report of blue-emitting CdTe-based quantum dots. By means of cyclic voltammetry, we detected features of electrochemical activity of manganese energy levels formed inside the Cd1-xMnxTe-alloyed quantum dot band gap. This allowed us to estimate their energy position. We also demonstrate paramagnetic behavior for Cd1-xMnxTe alloyed quantum dots which confirmed the successful ion-exchange reaction. PMID- 29721642 TI - Computational simulation and modeling of the blood-brain barrier pathology. AB - In silico methods and models in the pathology of the blood-brain barrier (BBB) or also called BBB "computational pathology", are based on using mathematical approaches together with complex, high-dimensional experimental data to evaluate and predict disease-related impacts on the CNS. These computational methods and tools have been designed to deal with BBB-linked neuropathology at the molecular, cellular, tissue, and organ levels. The molecular and cellular levels mainly include molecular docking and molecular dynamics simulations (atomistic and coarse-grain) of mutated or misfolded tight junction proteins, receptors, and various BBB transporters. The tissue and organ levels encompass the mechanistic and pharmacokinetic models as well as finite-element method and pathway analyses enriched with multiple sources of raw data (e.g., in vitro and in vivo, histopathological records, "-omics", and imaging data). Overall, this review discusses comprehensive computational techniques and strategies at different levels of complexity, providing new insights and future directions for diagnosis, treatment improvement, and a deeper understanding of BBB-related neuropathological events. PMID- 29721643 TI - The distribution patterns of COMP and matrilin-3 in septal, alar and triangular cartilages of the human nose. AB - The biomechanical characteristics of septal cartilage depend strongly on the distinct extracellular matrix of cartilage tissue; therefore, it is essential that the components of this matrix are identified and understood. Cartilage oligomeric matrix protein (COMP) and matrilin-3 are localised in articular cartilage. This study was the first to examine all subtypes of mature human nasal cartilages (alar, triangular and septal) with specific attention to the distribution of COMP and matrilin-3. Three whole fresh-frozen noses from human donors were dissected, and exemplary biopsies were examined using histochemical staining (haematoxylin and eosin and Alcian blue) and immunohistochemistry (collagen II, COMP and matrilin-3). The following three zones within the nasal cartilage were identified: superficial, intermediate and central. COMP was detected as highest in the intermediate zones in all three subtypes of nasal cartilage, whereas matrilin-3 was detected with pericellular deposition mainly within septal cartilage predominantly in the superficial zones. The distinct staining patterns of COMP and matrilin-3 underscore the different functional roles of both proteins in nasal cartilage. According to the literature, COMP might be involved with collagen II in the formation of networks, whereas matrilin 3 is reported to prevent ossification or regulate mechanosensitivity. The predominant staining observed in septal cartilage suggests matrilin-3's modulatory role because of its presence in the osteochondral junctional zone and given that the biomechanical load in septal cartilage is different from that in alar or triangular cartilage. In conclusion, COMP and matrilin-3 were detected in mature human nasal cartilage but displayed different staining patterns that might be explained by the functional roles of the respective matrix protein; however, further research is necessary to identify and define the functional aspects of this morphological difference. PMID- 29721645 TI - Midazolam increases preload dependency during endotoxic shock in rabbits by affecting venous vascular tone. AB - BACKGROUND: Septic patients often require sedation in intensive care unit, and midazolam is one of the most frequently used sedatives among them. But the interaction between midazolam and septic shock is not known. The aim of this study is to investigate the effects of midazolam on preload dependency in an endotoxic shock model by evaluating systemic vascular tone and cardiac function. METHODS: Eighteen rabbits were randomly divided into three groups: Control group, MID1 group and MID2 group. Rabbits underwent ketamine anaesthesia and mechanical ventilation, and haemodynamic assessments were recorded in three groups (T0). Endotoxic shock was induced by lipopolysaccharide intravenously, and fluid resuscitation and norepinephrine were administered to obtain the baseline mean arterial pressure (MAP) (T1). Rabbits received equivalent normal saline (Control) and two consecutive dosages of midazolam: 0.3 mg kg-1 h-1 (MID1) and 3 mg kg-1 h 1 (MID2) (T2). Rabbits received another round of fluid challenge and norepinephrine infusion to return the MAP to normal (T3). RESULTS: No significant differences in haemodynamic parameters were observed in three groups at T0, T1 or T3. Midazolam infusion significantly increased pulse pressure variation (PPV) and stroke volume variation (SVV) compared to the values in Control group, and MAP, central venous pressure (CVP), mean systemic filling pressure (Pmsf) and cardiac output (CO) decreased at T2. Same effects were observed with increasing doses of midazolam, and resistance for venous return (Rvr) decreased (MID1 vs. MID2) at T2. PPV and SVV increased significantly at T2 compared to the values at T1. MAP, CVP, Pmsf and CO decreased in MID1 and MID2 groups. Rvr also decreased in MID2 group (T2 vs. T1). Midazolam did not affect cardiac function index, systemic vascular resistance or artery resistance (T2 vs. T1). CONCLUSIONS: Midazolam administration promoted preload dependency in septic shock models via decreased venous vascular tone without affecting cardiac function. PMID- 29721644 TI - Morphology-oriented epigenetic research. AB - Cytosine methylation plays a major role in the regulation of sequential and tissue-specific expression of genes. De novo aberrant DNA methylation and demethylation are also crucial processes in tumorigenesis and tumor progression. The mechanisms of how and when such aberrant methylation and demethylation occur in tumor cells are still obscure, however. To evaluate subtle epigenetic alteration among minor subclonal populations, morphology-oriented epigenetic analysis is requisite, especially where heterogeneity and flexibility are as notable as in the process of cancer progression and cellular differentiation at critical stages. Therefore, establishment of reliable morphology-oriented epigenetic studies has become increasingly important in not only the experimental but also the diagnostic field. By selecting a subset of cells based on characteristic morphological features disclosed by microdissection or in situ hybridization, we discovered how methylation at certain CpG sites outside of CpG islands would play a crucial epigenetic role in the versatility and flexibility of gene expression during cancer progression. In this review, we first introduce technical aspects of two morphology-oriented epigenetic studies: (1) histoendonuclease-linked detection of methylated sites of DNA (HELMET), and (2) padlock probe and rolling circle amplification (RCA) for in situ identification of methylated cytosine in a sequence-dependent manner. We then present our observation of a novel MeCP2-mediated gene-silencing mechanism through the addition of methylation to a single-CpG-locus upstream of the TATA-box of the receptor activator of NF-kappaB ligand (RANKL) and of secreted frizzled-related protein 4 (SFRP4) gene promoters. PMID- 29721646 TI - Meta-Analysis of the Effects of Computerized Cognitive Training on Executive Functions: a Cross-Disciplinary Taxonomy for Classifying Outcome Cognitive Factors. AB - The growing prevalence of neurodegenerative disorders associated with aging and cognitive decline has generated increasing cross-disciplinary interest in non pharmacological interventions, such as computerized cognitive training (CCT), which may prevent or slow cognitive decline. However, inconsistent findings across meta-analytic reviews in the field suggest a lack of cross-disciplinary consensus and on-going debate regarding the benefits of CCT. We posit that a contributing factor is the lack of a theoretically-based taxonomy of constructs and representative tasks typically used. An integration of the Cattell-Horn Carroll (CHC) taxonomy of broad and narrow cognitive factors and the Miyake unity diversity theory of executive functions (EF) is proposed (CHC-M) as an attempt to clarify this issue through representing and integrating the disciplines contributing to CCT research. The present study assessed the utility of this taxonomy by reanalyzing the Lampit et al. (2014) meta-analysis of CCT in healthy older adults using the CHC-M framework. Results suggest that: 1) substantively different statistical effects are observed when CHC-M is applied to the Lampit et al. meta-analytic review, leading to importantly different interpretations of the data; 2) typically-used classification practices conflate Executive Function (EF) tasks with fluid reasoning (Gf) and retrieval fluency (Gr), and Attention with sensory perception; and 3) there is theoretical and practical advantage in differentiating attention and working-memory tasks into the narrow shifting, inhibition, and updating EF domains. Implications for clinical practice, particularly for our understanding of EF are discussed. PMID- 29721648 TI - Comparison of adductor canal block and IPACK block (interspace between the popliteal artery and the capsule of the posterior knee) with adductor canal block alone after total knee arthroplasty: a prospective control trial on pain and knee function in immediate postoperative period. AB - BACKGROUND: Adductor canal block (ACB) is a peripheral nerve blockade technique that provides good pain control in patients undergoing total knee arthroplasty which however does not relieve posterior knee pain. The recent technique of an ultrasound-guided local anesthetic infiltration of the interspace between popliteal artery and the capsule of posterior knee (IPACK) has shown promising results in providing significant posterior knee analgesia without affecting the motor nerves. MATERIALS AND METHODS: A prospective study was conducted from September 2016 to March 2017 in a total of 120 patients undergoing unilateral total knee arthroplasty. The initial 60 consecutive patients received ACB + IPACK (Group 1, n = 60), and the subsequent 60 patients received ACB alone (Group 2, n = 60). All patients were evaluated with VAS score for pain recorded at 8 h, postoperative day (POD) 1 and POD 2 after the surgery. The secondary outcome measures assessed were the range of movement (ROM) and ambulation distance. RESULTS: VAS score showed significantly (p < 0.005) better values in ACB + IPACK group compared to the ACB group. The mean ROM of knee and ambulation distance also showed significantly better values in ACB + IPACK group compared to the ACB group. CONCLUSION: ACB + IPACK is a promising technique that offers improved pain management in the immediate postoperative period without affecting the motor function around the knee joint resulting in better ROM and ambulation compared to ACB alone. PMID- 29721647 TI - Cardiac autonomic modulation impairments in advanced breast cancer patients. AB - AIM: To compare cardiac autonomic modulation in early- versus advanced-stage breast cancer patients before any type of cancer treatment and investigate associated factors. METHODS AND RESULTS: This cross-sectional study included women (30-69 years old) with primary diagnosis of breast cancer and women with benign breast tumors. We evaluated cardiac modulation by heart rate variability and assessed factors of anxiety, depression, physical activity, and other relevant medical variables. Patients were divided into three groups based on TNM staging of cancer severity: early-stage cancer (n = 42), advanced-stage cancer (n = 37), or benign breast tumors to serve as a control (n = 37). We analyzed heart rate variability in time and frequency domains. The advanced-stage cancer group had lower vagal modulation than early-stage and benign groups; also, the advance stage group had lower overall heart rate variability when compared to benign conditions. Heart rate variability was influenced by age, menopausal status, and BMI. CONCLUSIONS: Heart rate variability seems to be a promising, non-invasive tool for early diagnosis of autonomic dysfunction in breast cancer and detection of cardiovascular impairments at cancer diagnosis. Cardiac autonomic modulation is inversely associated with breast cancer staging. PMID- 29721649 TI - Malunited lateral condyle fracture of humerus with elbow dislocation: a diagnostic dilemma. AB - Fracture of lateral condyle with dislocation of the elbow joint is rare in pediatric age. Diagnosis and management of these injuries could be a challenge. Delayed presentation of such injuries could be mistaken for a malunited supracondylar fracture of the humerus and treatment of these injuries remains controversial. We present 2 such cases, where the diagnosis of dislocation of elbow was missed at initial presentation and caused diagnostic confusion at late presentation. The problems faced in the diagnosis of these injuries and the management of late presenting cases are discussed. PMID- 29721651 TI - [Indications for loop recorder implantation for syncope]. AB - Implantable loop recorder with discontinuous ECG recording enables monitoring of heart rhythm over several years. Consequently, in patients with recurrent syncope it is possible to record an ECG during the next syncopal event to obtain symptom ECG correlations. In patients with recurrent syncope of unknown origin, the implantation of a loop recorder leads to an earlier diagnosis and an asystole is more often detected as the cause of the recurrent syncope. In addition, the loop recorder identifies patients who will benefit from pacemaker implantation. An established indication for early implantation of a loop recorder is given in patients with recurrent syncope and no high-risk marker, e. g., reduced left ventricular function, valve disease, history of myocardial infarction or ECG findings such as bifascicular block, pre-excitation, long QT syndrome or an epsilon wave. These patients should receive a complete cardiological work-up with the aim of detecting the underlying heart disease. Patients with no conclusive findings should also receive a loop recorder. A relative indication is given for patients with recurrent syncope and injuries in order to predict the effect of pacemaker implantation. Possible indication is given for patients with transient loss of consciousness to rule out an arrhythmogenic origin. PMID- 29721650 TI - Automated assessment of FDG-PET for differential diagnosis in patients with neurodegenerative disorders. AB - PURPOSE: To review literature until November 2015 and reach a consensus on whether automatic semi-quantification of brain FDG-PET is useful in the clinical setting for neurodegenerative disorders. METHODS: A literature search was conducted in Medline, Embase, and Google Scholar. Papers were selected with a lower limit of 30 patients (no limits with autopsy confirmation). Consensus recommendations were developed through a Delphi procedure, based on the expertise of panelists, who were also informed about the availability and quality of evidence, assessed by an independent methodology team. RESULTS: Critical outcomes were available in nine among the 17 papers initially selected. Only three papers performed a direct comparison between visual and automated assessment and quantified the incremental value provided by the latter. Sensitivity between visual and automatic analysis is similar but automatic assessment generally improves specificity and marginally accuracy. Also, automated assessment increases diagnostic confidence. As expected, performance of visual analysis is reported to depend on the expertise of readers. CONCLUSIONS: Tools for semi quantitative evaluation are recommended to assist the nuclear medicine physician in reporting brain FDG-PET pattern in neurodegenerative conditions. However, heterogeneity, complexity, and drawbacks of these tools should be known by users to avoid misinterpretation. Head-to-head comparisons and an effort to harmonize procedures are encouraged. PMID- 29721653 TI - [Instability after operative and conservative treatment of isolated Mason type II fractures]. AB - BACKGROUND: Radial head fractures are the most frequent fractures of the elbow joint in adults. For Mason type II fractures without concomitant injuries favorable results have been shown with operative and conservative management. There is insufficient evidence concerning elbow joint stability after conservative treatment compared to open reduction and internal fixation (ORIF). MATERIALS AND METHODS: All patients with isolated Mason type II (two part fracture displaced >2 mm and <5 mm) radial head fractures between 1 January 2003 and 1 April 2013 were retrospectively reviewed. Exclusion criteria were age <18 years, associated fractures of the ipsilateral extremity or elbow luxation. A total of 50 patients (mean age 44.2 years, range 19-71 years) who received either ORIF (n = 31) or conservative treatment (n = 19) were included. The mean follow up was 43.2 months (range 9-61 months). Patients were evaluated using the Disability of the Arm, Shoulder and Hand (DASH) score, Mayo Elbow Performance score (MEPS), and Oxford Elbow score (OES). Joint stability (varus and valgus stress) was assessed under fluoroscopy and a distinction was made between slight instability (angulation <10 degrees ), moderate instability (angulation >=10 degrees ) and gross instability (elbow dislocation). RESULTS: Residual fracture displacement (conservative: 2.7 mm, ORIF: 1.4 mm, p < 0.042) and varus/valgus joint stability (3% ORIF vs. 26% conservative, p = 0.031) showed significant differences. The stability as tested by a radiological dynamic procedure showed an instability after ORIF in 3% of the joints compared to 26% after conservative treatment; however, this did not influence the short to mid-term clinical outcome: No significant differences were found in the DASH score (conservative 33 points, ORIF 36 points), MEPS (conservative 76 points, ORIF 78 points) and OES (conservative 41 points, ORIF 43 points). DISCUSSION: Both conservative management and operative treatment had a good functional outcome. Operative treatment showed a positive tendency concerning radiological and functional outcome without statistical significance. PMID- 29721652 TI - A Preliminary Evaluation of a School-Based Media Education and Reduction Intervention. AB - While media education and reduction programs have been proposed to prevent adverse health and academic outcomes related to heavy electronic media use among school-aged children, few have been formally piloted and evaluated. We used a quasi-experimental design to evaluate the effectiveness of Take the Challenge (TtC), a school-based media education/reduction program for the primary prevention of sleep deprivation, dysfunctional social-emotional behaviors, and poor academic performance. Sixth- to eighth-grade students at a rural Midwestern U.S. middle school received the TtC program, while a similar school in the same district served as the comparison group. Health-related and academic measures were collected from students and teachers at both schools before and after the intervention. The primary outcome measure was student-reported electronic media use (television, video games, Internet). Secondary measures included student health behaviors (student-reported sleep, exercise, and outdoor play) and academic activities (teacher-reported homework and classroom performance). Compared to the comparison group, students receiving TtC slept more and reduced television viewing, background television time, after-school video gaming, and weekend Internet use. Teachers reported increases in the extent to which TtC students completed homework assignments and stayed on task in the classroom. Well designed school-based programs such as TtC can reduce electronic media use among middle-school children and improve related health and academic outcomes. PMID- 29721654 TI - [Physician assistants in surgery : A young profession through graduates' eyes]. AB - BACKGROUND: In Germany, physician assistant (PA) is a comparatively young profession. The concept paper by the German Medical Association (BAK) and the Federation of Statutory Health Insurance Physicians (KBV) from 2017 defines the new occupational profile in detail. In contrast, there is hardly any information on the day to day working life of a PA in Germany OBJECTIVE: The aim of this study was to map the employment reality of the PA graduates of the study program of the Baden-Wuerttemberg Cooperative State University Karlsruhe. MATERIAL AND METHODS: Graduates of the PA study program were interviewed using the web-based evaluation system EvaSys V7.1 (Electric Paper Evaluationssysteme GmbH, Luneburg, Deutschland) in the spring of 2018. The information was evaluated descriptively. RESULTS: The response rate was 70% (48 out of 69 graduates), 44 graduates were employed as a PA and 27 worked in a surgical department. The core tasks of the surgically active PA, which were often performed to varying frequency included assisting surgery and the performance of simple wound closures. In addition, activities in the areas of documentation, communication and information sharing were emphasized. The average salary of a surgical PA was 3718 ?. This amount was rated by 44.4% as appropriate or very appropriate. The current occupational situation for 81.5% of the study participants was much better or better than expected before the start of their PA studies. Overall satisfaction was very high: 85.1% of the graduates were satisfied to very satisfied. CONCLUSION: The graduates' level of job satisfaction is remarkable. Many of the activities mentioned in the concept paper of the BAK and KBV were carried out frequently or very frequently by the PA. Nonetheless, the PA profession has significant development potential, especially in the realm of surgical PAs. PMID- 29721655 TI - Varestrongylus (Nematoda: Protostrongylidae), lungworms of ungulates: a phylogenetic framework based on comparative morphology. AB - Varestrongylus Bhalerao, 1932 comprises ten valid lungworm species infecting wild and domestic ungulates from Eurasia and North America. Here, we present a phylogenetic hypothesis for the genus based on morphological characters in a broader context for the family Protostrongylidae and discuss species relationships and aspects of character evolution. Phylogenetic analysis of 25 structural attributes, including binary and multistate characters, among the 10 species of Varestrongylus resulted in one fully resolved most parsimonious tree (61 steps; consistency index = 0.672, retention index = 0.722, and consistency index excluding uninformative characters = 0.667). Varestrongylus forms a monophyletic clade and is the sister of Pneumostrongylus, supporting recognition of the subfamily Varestrongylinae. Monophyly for Varestrongylus is diagnosed by six unequivocal synapomorphies, all associated with structural characters of the copulatory system of males. Varestrongylus pneumonicus is basal, and sister to all other species within the genus, which form two subclades. The subclade I contains V. sagittatus + V. tuvae and V. qinghaiensis + V. longispiculatus. Subclade II contains V. alpenae, V. capricola, V. capreoli, and V. eleguneniensis + V. alces. Both subclades are diagnosed by two unambiguous synapomorphies. Highlighted is the continuing importance of phylogenetic assessments based on comparative morphology as a foundation to explore the structure of the biosphere across space and time. PMID- 29721656 TI - Effects of miconazole/clotrimazole and praziquantel combinations against the liver fluke Opisthorchis felineus in vivo and in vitro. AB - The liver fluke Opisthorchis felineus (Rivolta, 1884) is the causative agent of opisthorchiasis felinea in Eurasia. Opisthorchiasis is a serious human and fish eating animal's disease affecting bile ducts and the gall bladder. Currently, the main drug for specific therapy of opisthorchiasis is praziquantel. We have previously shown that azole inhibitors of O. felineus cytochrome P450 significantly reduced survival of the worms in vitro. Here, we studied in vitro anthelmintic effects of drug combinations involving azole substances approved by the US Food and Drug Administration together with praziquantel against adult or juvenile O. felineus liver flukes. A synergistic interaction was shown for praziquantel-clotrimazole (CI = 0.68) combination and for praziquantel-miconazole (CI = 0.68) combination against adult helminths in vitro. Praziquantel-miconazole (CI = 0.30) had a strongly synergistic effect against newly excysted metacercariae. We also tested anthelmintic effects of azole substances and their combinations with praziquantel in vivo in an animal model of chemotherapy. The treatment of juvenile worms (1 day postinfection) with 100 mg/kg miconazole resulted in a worm burden reduction (WBR) of 37.5% (P = 0.049), with 100 mg/kg clotrimazole causing a WBR of 31.25% (P = 0.025). The treatment of adult worms (5 6 weeks postinfection) with 100 mg/kg or 200 mg/kg miconazole yielded a WBR of 23.8% (P = 0.01) and 21.4% (P = 0.006), respectively. When praziquantel was administered together with clotrimazole or with miconazole, a WBR slightly greater than the effect of ED50 praziquantel was observed (WBR of 59.5 and 54.7%, respectively).In conclusion, the synergistic effect of the praziquantel clotrimazole and praziquantel-miconazole combinations observed in vitro was not confirmed in vivo. Thus, this combination chemotherapy revealed no benefits over praziquantel monotherapy in the treatment of opisthorchiasis felinea. PMID- 29721657 TI - Long-term occurrence of Trichuris species in wild ruminants in the Czech Republic. AB - The aim of this study was to identify Trichuris species in wild ruminants from 32 localities in the Czech Republic using morphological and molecular methods (ITS1 5.8S RNA-ITS2 region polymorphisms). Trichurids were obtained from 176 wild ruminants (roe deer, sika deer, red deer, fallow deer and mouflons) that were culled between 2009 and 2017. Trichuris discolor is the predominant trichurid of all of the above-mentioned wild ruminants, whereas Trichuris ovis was identified less frequently in roe deer, fallow deer, sika deer and mouflons. Red deer were parasitised exclusively by T. discolor. Young hosts under 1 year of age were more intensively infected by trichurids than were adults (chi2 = 32.02, p = 0.00). Trichurid prevalence results obtained through coprological methods and those based on parasitological dissections differed significantly (chi2 = 16.26, p = 0.00). The regression analysis indicated that the eggs per gram (EPG) threshold (20 EPG) was exceeded only if the host was parasitised by more than 7 trichurid females. Full concordance between the positive results obtained by the coprological methods and those obtained via direct dissections was achieved when the number of trichurid females per host exceeded 51. PMID- 29721658 TI - Occurrence and molecular characterization of Clinostomum complanatum (Trematoda: Clinostomidae) in freshwater fishes caught from Turkey. AB - The metacercariae of Clinostomum species which known as yellow grubs have zoonotic potential by infecting humans. In the present study, a total of 403 freshwater fish specimens belonging to different genera from Central Anatolia Region of Turkey were examined for yellow grub metacercariae infections. Only three specimens belonging to Squalius cephalus were found to be infected with metacercariae with a prevalence on this host species of 2.4% and an overall prevalence of 0.7%. All the metacercariae were morphologically identified as Clinostomum complanatum. Partial fragments of mitochondrial cytochrome oxidase I (mt-COI) gene and internal transcribed spacer 2 (ITS-2) were amplified for sequence and phylogenetic analyses. The sequence analyses of ITS-2 and mt-COI revealed three and nine polymorphic sites leading to detection of four and five haplotypes within the related gene regions, respectively. Moreover, the intraspecific genetic distances for C. complanatum isolates ranged from 0.0 to 0.7% for ITS-2 and 0.0 to 1.4% for mt-COI data sets. Consequently, the present study has provided first combined morphologic and molecular data on C. complanatum infecting Turkish freshwater fishes. PMID- 29721659 TI - WHO disability assessment schedule 2.0 is related to upper and lower extremity disease-specific quality of life. AB - PURPOSE: We evaluated whether two disease-specific quality of life instruments (Disabilities of the Arm, Shoulder and Hand, DASH and Western Ontario & McMaster Universities Osteoarthritis Index, WOMAC) reflect a patient's perception of general disability using the WHO Disability Assessment Schedule 2.0 (WHODAS 2.0) and determined whether disability components are explained by upper and lower extremity HRQOL. METHODS: We recruited 421 participants, 50 years or older without stroke, cancer, or history of surgery for musculoskeletal disease, who participated in the NAMGARAM Cohort. Upper extremity HRQOL was determined with the DASH score and lower extremity HRQOL with the WOMAC; as a measure of disability, we obtained WHODAS 2.0 component. Multiple regression modeling was used to assess the relative contributions made by upper and lower extremity HRQOL to disability. RESULTS: When adjusted for covariates, the DASH total score was correlated with getting around (beta = 0.217, p < 0.001) and social participation (beta = 0.226, p < 0.001), and the WOMAC total score was correlated with getting around (beta = 0.363, p < 0.001), life activation (beta = 0.363, p < 0.001), and social participation (beta = 0.301, p < 0.001). QOL significantly correlated with upper extremity disorders (beta = 0.081, p = 0.018) or lower extremity disorders (beta = 0.095 p = 0.004). CONCLUSION: We found that in a community-based population, perceived activity limitation and social participation were associated with upper and lower extremity HRQOL. Since the WHODAS 2.0 does not target a specific disease (as opposed to DASH and WOMAC), it can be used to compare disabilities caused by different diseases. PMID- 29721661 TI - Description of a new species of Amblyomma Koch, 1844 (Acari: Ixodidae), parasite of deer (Artiodactyla: Cervidae) and wild pigs (Artiodactyla: Suidae) in the Philippines. AB - Amblyomma anicornuta n. sp. (Acari: Ixodidae) is described based on adults and nymphs ex deer (Artiodactyla: Cervidae) and wild pigs (Artiodactyla: Suidae) from Luzon, Philippines. Adults of A. anicornuta n. sp. are similar to those of several Asian and Australasian species of Amblyomma Koch, 1844 with a 4/4 dental formula on the hypostome but can be distinguished by the colouration and pattern of punctations on the conscutum in the male and scutum in the female, the absence of a marginal groove on the conscutum in the male, the possession of long, thick, prominent setae on the alloscutum in the female, projections on anal valves and sclerotised ring around them in the male, a large median sclerite ventrally in the male, as well by the shape of the genital aperture in the female and the size and shape of spurs on coxae I-IV in both sexes. The nymph of A. anicornuta n. sp. is somewhat similar to that of A. babirussae Schulze, 1933 and A. geoemydae (Cantor, 1847) but can be distinguished by the colouration pattern on the scutum, the presence of dorsal cornua and the size of the spurs on coxae I-IV. PMID- 29721660 TI - Isospora lopesi n. sp. (Apicomplexa: Eimeriidae) from the eastern white-throated spadebill Platyrinchus mystaceus Vieillot (Passeriformes: Tyranni: Tyrannidae) in South America. AB - A species of Isospora Schneider, 1881 (Protozoa: Apicomplexa: Eimeriidae) considered as new to science is described and characterised molecularly from the eastern white-throated spadebill Platyrinchus mystaceus Vieillot in the Parque Nacional do Itatiaia, southeastern Brazil. Isospora lopesi n. sp. has oocysts that are subspheroidal to ovoidal, 18-24 * 18-22 (20.6 * 19.7) um, with smooth, bilayered wall, c.1.5 MUm thick. Micropyle and oocyst residuum are absent, but one polar granule is present. Sporocysts are ellipsoidal, 12-16 * 8-11 (14.4 * 8.6) um. The Stieda body is flattened to half-moon-shaped and sub-Stieda body is rounded. Sporocyst residuum is present, consisting of numerous spherules of different sizes. Sporozoites are vermiform with anterior and posterior refractile bodies and nucleus. Molecular analysis was conducted at the mitochondrial cytochrome c oxidase subunit 1 (cox1) gene. This new isolate exhibited similarity greater than 98% with Isospora spp. isolates from spectacled warblers Sylvia conspicillata Temminck, 1820. This is the fourth isosporoid coccidian described from New World tyrannid birds, but is the first to have a complementary molecular characterisation. PMID- 29721662 TI - Outflow enhancement by three different ab interno trabeculectomy procedures in a porcine anterior segment model. AB - PURPOSE: To evaluate three different microincisional ab interno trabeculectomy procedures in a porcine eye perfusion model. METHODS: In perfused porcine anterior segments, 90 degrees of trabecular meshwork (TM) was ablated using the Trabectome (T; n = 8), Goniotome (G; n = 8), or Kahook device (K; n = 8). After 24 h, additional 90 degrees of TM was removed. Intraocular pressure (IOP) and outflow facility were measured at 5 and 10 MUl/min perfusion to simulate an elevated IOP. Structure and function were assessed with canalograms and histology. RESULTS: At 5 MUl/min infusion rate, T resulted in a greater IOP reduction than G or K from baseline (76.12% decrease versus 48.19% and 47.96%, P = 0.013). IOP reduction between G and K was similar (P = 0.420). Removing another 90 degrees of TM caused an additional IOP reduction only in T and G but not in K. Similarly, T resulted in the largest increase in outflow facility at 5 MUl/min compared with G and K (first ablation, 3.41 times increase versus 1.95 and 1.87; second ablation, 4.60 versus 2.50 and 1.74) with similar results at 10 MUl/min (first ablation, 3.28 versus 2.29 and 1.90 (P = 0.001); second ablation, 4.10 versus 3.01 and 2.01 (P = 0.001)). Canalograms indicated circumferential flow beyond the ablation endpoints. CONCLUSIONS: T, G, and K significantly increased the outflow facility. In this model, T had a larger effect than G and K. PMID- 29721663 TI - Combined VEGF/PDGF inhibition using axitinib induces alphaSMA expression and a pro-fibrotic phenotype in human pericytes. AB - PURPOSE: Large trials on anti-VEGF/PDGF (vascular endothelial/platelet-derived growth factor) combination therapy have been established to improve management of neovascular activity in age-related macular degeneration. Targeting pericytes, PDGF is thought to induce vessel regression and reduce fibrovascular scarring. The fate of pericytes exposed to anti-VEGF/PDGF combination therapy is not clear. Therefore, this study was designed to study the influence of anti-VEGF/PDGF on pericyte phenotype and cellular behavior. METHODS: Human pericytes from placenta (hPC-PL) were treated with axitinib, a tyrosine kinase inhibitor targeting VEGFR1 3 and PDGFR. Toxic effects were excluded using live/dead staining. Phenotypic changes were evaluated using phalloidin staining for actin cytoskeleton and the expression of stress fibers. MRNA and protein expression levels of alpha-smooth muscle actin (alphaSMA) as a marker of proto-myofibroblastic transition were evaluated with real-time PCR and Western blotting. Influences of fibrotic cellular mechanisms were evaluated with a scratch wound migration and a collagen gel contraction assay. RESULTS: Treatment with 0.5, 1, and 2.5 MUg/ml axitinib strongly induced a proto-myofibroblast-like actin cytoskeleton with a marked increase in stress fibers. Quantitative real-time PCR and Western blotting revealed these changes to be linked to dose-dependent increases in alphaSMA mRNA and protein expression. However, fibrotic cellular mechanisms were significantly reduced in the presence of axitinib (scratch wound closure: up to - 78.4%, collagen gel contraction: up to - 37.4%). CONCLUSIONS: Combined anti-VEGF/PDGF inhibition seems to induce a proto-myofibroblast-like phenotype in human pericytes in vitro, but reduce profibrotic cellular mechanisms due to prolonged anti-PDGF inhibition. PMID- 29721664 TI - Echocardiographic measurements of epicardial adipose tissue and comparative ability to predict adverse cardiovascular outcomes in patients with coronary artery disease. AB - The present study aimed to compare echocardiography measurements of epicardial adipose tissue (EAT) thickness and other risk factors regarding their ability to predict adverse cardiovascular outcomes in patients with coronary artery disease (CAD). Outcomes of 107 patients (86 males, 21 females, mean age 63.6 years old) submitted to diagnostic echocardiography and coronary angiography were prospectively analyzed. EAT (measures over the right ventricle, interventricular groove and complete bulk of EAT) and left ventricle ejection fraction (LVEF) were performed by echocardiography. Coronary complexity was evaluated by Syntax score. Primary endpoints were major adverse cardiovascular events (MACE's), composite of cardiovascular death, myocardial infarction, unstable angina, intra-stent re stenosis and episodes of decompensate heart failure requiring hospital attention during a mean follow up of 15.94 +/- 3.6 months. Mean EAT thickness was 4.6 +/- 1.9 mm; and correlated with Syntax score and body mass index; negatively correlated with LVEF. Twenty-three cases of MACE's were recorded during follow up, who showed higher EAT. Diagnostic ability of EAT to discriminate MACE's was comparable to LVEF (AUROC > 0.5); but higher than Syntax score. Quartile comparison of EAT revealed that measurement of the complete bulk of EAT provided a better discrimination range for MACE's, and higher, more significant adjusted risk (cutoff 4.6 mm, RR = 3.91; 95% CI 1.01-15.08; p = 0.04) than the other risk factors. We concluded that echocardiographic measurement of EAT showed higher predicting ability for MACE's than the other markers tested, in patients with CAD. Whether location for echocardiographic measurement of EAT impacts the diagnostic performance of this method deserves further study. PMID- 29721666 TI - Author Correction: Mitochondrial DNA variants in colorectal carcinogenesis: Drivers or passengers? AB - The affiliation detail for the corresponding author, Edoardo Errichiello, was published incorrectly. The correct detail read as follows. PMID- 29721665 TI - Status and future directions in the management of pancreatic cancer: potential impact of nanotechnology. AB - Pancreatic ductal adenocarcinoma (PDAC) is typically diagnosed at a late stage, has limited treatments, and patients have poor survival rates. It currently ranks as the seventh leading cause of cancer deaths globally and has increasing rates of diagnosis. Improved PDAC treatment requires the development of innovative, effective, and economical therapeutic drugs. The late stage diagnosis limits options for surgical resection, and traditional PDAC chemotherapeutics correlate with increased organ and hematologic toxicity. In addition, PDAC tumor tissue is dense and highly resistant to many traditional chemotherapeutic applications, making the disease difficult to treat and impeding options for palliative care. New developments in nanotechnology may offer innovative options for targeted PDAC therapeutic drug delivery. Nanotechnology can be implemented using multimodality methods that offer increased opportunities for earlier diagnosis, precision enhanced imaging, targeted long-term tumor surveillance, and controlled drug delivery, as well as improved palliative care and patient comfort. Nanoscale delivery methods have demonstrated the capacity to infiltrate the dense, fibrous tumor tissue associated with PDAC, increasing delivery and effectiveness of chemotherapeutic agents and reducing toxicity through the loading of multiple drug therapies on a single nano delivery vehicle. This review presents an overview of nanoscale drug delivery systems and multimodality carriers at the forefront of new PDAC treatments. PMID- 29721668 TI - Physician interpretation of variants of uncertain significance. AB - A growing number of physicians will interact with genetic test results as testing becomes more commonplace. While variants of uncertain significance can complicate results, it is equally important that physicians understand how to incorporate these results into clinical care. An online survey was created to assess physician self-reported comfort level with genetics and variants of uncertain significance. Physicians were asked to respond to three case examples involving genetic test results. The survey was sent to 488 physicians at Mayo Clinic FL on 8/16/2017. Physicians from all specialties were invited to participate. A total of 92 physicians responded to the survey. Only 13/84 (14.6%) responded to all three case examples with the answer deemed "most correct" by review of literature. Physicians that specialized in cancer were more likely to answer questions appropriately (P = .02). Around half (39/84) of the physicians incorrectly defined a variant of uncertain significance (VUS). Over 75% made a recommendation for genetic testing that was not warranted. Many physicians have never received formal genetics training; however, they will be expected to provide an accurate explanation of the genetic test results and subsequent evidence-based medical management recommendations. These results demonstrate that a substantial proportion of physicians lack a true understanding of the implications a VUS. Utilization of supplemental genetics training programs coupled with increase awareness of genetic services may help to improve patient care. PMID- 29721667 TI - The influence of mutational status and biological characteristics of acute myeloid leukemia on xenotransplantation outcomes in NOD SCID gamma mice. AB - PURPOSE: This study aimed at analyzing the association of gene mutations and other acute myeloid leukemia (AML) characteristics with engraftment outcomes in immunodeficient mice and to select the engraftment outcomes that best reflect patient survival. METHODS: Mutations in 19 genes as well as leukemia- and patient related characteristics were analyzed for a group of 47 de novo AML samples with respect to three engraftment outcomes: engraftment ability, engraftment intensity (percentage of hCD45+ cells) and engraftment latency. Leukemia-related characteristics were additionally analyzed in an extended group of 68 samples that included the 47 de novo samples, and additional 21 samples from refractory and relapsed cases. Engraftment outcomes were compared with overall and event free survival of the patients. RESULTS: For the 47 de novo samples, no single mutation influenced engraftment, whereas the NPM1 mut /DNMT3A mut co-mutation was associated with higher engraftment ability. NPM1 mut /FLT3-ITD neg had lower engraftment intensity. Among leukemia-related characteristics, a complex karyotype was associated with higher engraftment intensity. Among patient-related characteristics, higher cytogenetic risk was associated with higher engraftment intensity, and failure to achieve clinical remission was associated with shorter engraftment latency. In the extended group of 68 samples, white blood count was associated with higher engraftment ability, and the presence of a complex karyotype was associated with higher engraftment intensity. Association with patient overall survival was seen only for engraftment intensity. CONCLUSIONS: The engraftment of AML was influenced by mutation-interactions and other AML characteristics, rather than by single mutated genes, and engraftment intensity best reflected clinical penetrance of AML. PMID- 29721669 TI - Analysis of spatial-temporal variation in NPP based on hydrothermal conditions in the Lancang-Mekong River Basin from 2000 to 2014. AB - Against the background of global climate change, spatial-temporal variation in net primary productivity (NPP) has attracted much attention. To analyze NPP spatial-temporal variation within the context of changes in hydrothermal conditions, the Vegetation Photosynthesis Model (VPM) is used to elucidate the mathematical relationship between NPP and hydrothermal conditions. Based on this spatial-temporal pattern of NPP and hydrothermal conditions in the Lancang-Mekong River Basin, regression statistics, an empirical model of land evaporation, and the water and thermal product index (K) are used to evaluate correlations between NPP and hydrothermal conditions in terms of their distribution pattern and interaction. The results show the following. (1) From 2000 to 2014, NPP in the Lancang-Mekong River Basin was highest in the central region and gradually decreased toward the southwest and northwest, whereas the annual change rate in NPP showed no significant increasing trend. (2) In the Lancang Basin, the correlation between hydrothermal conditions and NPP was high with respect to their distribution patterns, though this correlation was low in the Mekong Basin. (3) Correlation between K and NPP is high in the region where the effects of water and thermal factors on vegetation growth are similar. (4) K is an effective complement to the correlation between a single hydrothermal factor (temperature or precipitation) and NPP, and the influence of hydrothermal conditions on NPP was positive in the Lancang River and negative in the Mekong River Basin. Our study quantitatively analyzes the spatial-temporal correlation between NPP and hydrothermal conditions. The findings can reflect the vegetation change tendency and provide scientific data for ecological environment development and protection in the study area. PMID- 29721670 TI - Non-verbal Communication in a Neonatal Intensive Care Unit: A Video Audit Using Non-verbal Immediacy Scale (NIS-O). AB - Effective communication with parents is a very important skill for pediatricians especially in a neonatal setup. The authors analyzed non-verbal communication of medical caregivers during counseling sessions. Recorded videos of counseling sessions from the months of March-April 2016 were audited. Counseling episodes were scored using Non-verbal Immediacy Scale Observer Report (NIS-O). A total of 150 videos of counseling sessions were audited. The mean (SD) total score on (NIS O) was 78.96(7.07). Female counseled sessions had significantly higher proportion of low scores (p < 0.001). No video revealed high score. Overall 67(44.67%) sessions revealed low total score. This reflects an urgent need to develop strategies to improve communication skills in a neonatal unit. This study lays down a template on which other Neonatal intensive care units (NICUs) can carry out gap defining audits. PMID- 29721671 TI - Markers of Maternal and Neonatal Cobalamin Status and Risk Assessment of Neurodevelopmental Disorders in Infants. PMID- 29721672 TI - Outcomes of patients requiring extracorporeal membrane oxygenation in transcatheter aortic valve implantation: a clinical case series. AB - Transcatheter aortic valve implantation (TAVI) has been established as a low invasive therapy for aortic stenosis, but circulatory collapse necessitating mechanical circulatory support could occur during TAVI due to procedure itself or procedural complications. The purpose of this study is to describe the outcomes of patients requiring extracorporeal membrane oxygenation (ECMO) in TAVI. Among 384 consecutive patients undergoing TAVI from April 2010 to July 2017 in Sakakibara Heart Institute, we evaluated seven patients (1.8%) who required ECMO during procedure. The definitions of outcome were derived from Valve Academic Research Consortium-2 criteria. The indication of ECMO included bridge to emergent surgery due to mechanical complication (n = 3) [aortic root rupture (n = 2), and left-ventricle rupture (n = 1); emergent use], bridge to recovery from cardiac stunning (n = 3; emergent use), and circulatory support for cardiogenic shock (n = 1; prophylactic use). All patients were cannulated from femoral artery and vein, and there was no ECMO-related complication. Six out of seven patients were weaned from ECMO during the TAVI procedure, whereas the other patient with annulus rupture died the following day after TAVI. Five patients survived to discharge [postoperative hospital stay: 27.6 +/- 24.3 (23) days]. During mean follow-up of 253 days, a total of three patients died due to annulus rupture, refractory heart failure, and pneumonia, respectively. ECMO is effective and a safe mechanical support device during TAVI. The mid-term outcomes of patients who needed ECMO were unfavorable. Further evolution of transcatheter heart valve is essential, and prophylactic ECMO may contribute to better prognosis in selected patients. PMID- 29721673 TI - Linagliptin prevents atrial electrical and structural remodeling in a canine model of atrial fibrillation. AB - Dipeptidyl peptidase 4 (DPP-4) inhibitors have recently been reported to exhibit additional cardioprotective effects; however, their effect in atrial remodeling, such as in atrial fibrillation (AF), remains unclear. In this study, the effect of linagliptin on atrial electrical and structural remodeling was evaluated in a canine AF model. Sixteen beagle dogs with 3-week atrial rapid stimulation were divided into the linagliptin group (9 mg/kg/day, n = 8) and pacing control group (n = 8). Three additional dogs without rapid pacing were assigned into non-pacing group, which was used as sham in this study. In the dogs with rapid pacing, the atrial effective refractory period (AERP), conduction velocity (CV), and AF inducibility were evaluated and blood was sampled every week. After the entire protocol, atrial tissue was sampled for histological examinations using HE, Azan, and dihydroethidium (DHE) staining to evaluate any tissue damage or oxidative stress. The pacing control group exhibited a gradual AERP shortening and CV decrease along the time course as previously reported. In the linagliptin group, the AERP shortening was not affected, but the CV decrease was suppressed in comparison to the control group (p < 0.05). The AF inducibility was increased in the control group and suppressed in the linagliptin group (p < 0.05). The control group exhibited tissue fibrosis, the degree of which was suppressed in the linagliptin group. DHE staining exhibited suppression of the reactive oxygen species expression in the linagliptin group in comparison to the pacing control group. Linagliptin, a DPP-4-inhibitor, suppressed the AF inducibility, CV decrease, and overexpression of oxidative stress in the canine AF model. Such suppressive effects of linagliptin on AF in the canine model may possibly be related to the anti-oxidative effect. PMID- 29721674 TI - Use of the wearable cardioverter-defibrillator (WCD) and WCD-based remote rhythm monitoring in a real-life patient cohort. AB - The wearable cardioverter-defibrillator (WCD) was introduced to provide protection from sudden cardiac death (SCD) in patients with transiently elevated risk or during ongoing risk stratification. Benefits and clinical characteristics of routine WCD use remain to be assessed in larger patient populations. This study aims to identify determinants of WCD compliance, therapies, and inappropriate alarms in a real-life cohort. A total of 106 cases (68.9% male) were included between 11/2010 and 04/2016. WCD therapies, automatically recorded arrhythmia episodes, inappropriate WCD alarms, patient compliance, and outcome after WCD prescription were analyzed. Median duration of WCD use was 58.5 days. Average daily wearing time was 22.7 h. Compliance was reduced in patients <= 50 years. Three patients received WCD therapies (2.8%). In one case ventricular fibrillation (VF) was appropriately terminated with the first shock. Two patients received inappropriate WCD therapies due to WCD algorithm activation during ventricular pacemaker stimulation. One patient died of asystole while carrying a WCD (0.9%). Additional arrhythmias detected comprised self-terminating sustained ventricular tachycardia (VT; 2.8%), non-sustained VT (2.8%), and supraventricular arrhythmias (5.7%). Inappropriate WCD alarms due to over-/undersensing occurred in 77/106 patients (72.6%), of which 41 (38.7%) experienced >= 10 inappropriate WCD alarms during the prescription period. Thirteen patients (12.3%) displayed a mean of > 1 inappropriate alarms/day. WCD use was associated with high compliance and provided protection from VT/VF-related SCD. The majority of patients experienced inappropriate WCD alarms. Alterations in QRS morphology during pacemaker stimulation require consideration in WCD programming to prevent inappropriate alarms. PMID- 29721675 TI - Coronary artery-left ventricular shunt: an important cause of chest pain in patients with hypertrophic cardiomyopathy. AB - The influence of shunts between the coronary artery (CA) and the left ventricle (LV), on chest pain (CP) in patients with hypertrophic cardiomyopathy (HCM) is unknown. We examined the incidence of CA-LV shunts and their influence on CP in HCM patients. Twenty normal control subjects (NCS), 3 with CP due to CA-LV shunts (CP patients), and 60 with HCM participated. Interventricular septal wall thickness (IVST), LV posterior wall thickness (LVPWT), cardiac and stroke indexes (CI and SI), LV end-diastolic pressure (LVEDP), and proximal diameters of the CA were measured. Twenty-five HCM patients had a CA-LV shunt (41.7%). Both IVST and LVPWT were greater in the HCM patients than in NCS and CP patients. These values showed no significant differences between the HCM with shunt and HCM without shunt groups. CI and SI were lower in the HCM patients than in NCS and CP patients. LVEDP was higher in the HCM and CP patients than in NCS. CA diameters were larger in the HCM and CP patients than in NCS. CP was found in 32 HCM patients (53%). The incidence of CP was greater in the HCM with shunt group than in HCM without shunt group (80 vs. 34%, p < 0.0005). There was no significant difference in CA diameters between the HCM patients with CP and those without CP. CA-LV shunts are often found in HCM patients and are closely related to CP. Thus, CA-LV shunts are an important factor behind CP in HCM patients. PMID- 29721676 TI - Enhanced hypocrellin production via coexpression of alpha-amylase and hemoglobin genes in Shiraia bambusicola. AB - Shiraia bambusicola is an important and valuable macrofungus and hypocrellins are its main secondary metabolites which have been widely applied in many medical fields. However, during SSF process of this filamentous fungus, use ratio of corn substrate and dissolved oxygen supply are two main limiting factors, which influence production cost, yield and product quality. To solve these problems, overexpressions of amy365-1 and vgb in S. bambusicola were investigated and three overexpression transformants were constructed. Results demonstrated that expressions and coexpression of AMY365-1 and VHb not only increased the productions of biomass, amylase, hypocrellin, but also up-regulated relative expression levels of four central carbon metabolism genes (pdc, ald, acs, acc) and seven hypocrellin biosynthesis genes (fad, mono, zftf, omef, msf, pks, mco). Furthermore, expression of VHb decreased SSF period. When amy365-1 and vgb were coexpressed, relative expression levels of zftf and pks reached their highest levels at 72 h under liquid fermentation, hypocrellin production reached the highest level 75.85 mg/gds which was 2.99-fold compared with wild type strain within 11 days under SSF, and residual starch of solid substrates was decreased from 35.47 to 14.57%. PMID- 29721678 TI - What is the relationship between physical fitness level and macro- and micronutrient intake in Spanish older adults? AB - PURPOSE: The aim of this study was to assess the association between physical fitness (PF) and energy and nutrient intake in Spanish older adults. METHODS: Three hundred and twenty-four participants (59.9% females, aged over 55 years) performed a battery of four validated PF tests and participants were divided into three: low, medium, and high PF. Dietary intake was assessed by two non consecutive 24 h dietary recalls. Energy and nutrient intake was calculated using the ALIMENTA software. Energy expenditure (EE) was calculated using a validated questionnaire. RESULTS: Median energy intake (EI) was 2135, 1999, and 2111 kcal/day in the low, medium, and high PF in males, respectively. In females, the median EI was 1576, 1564, and 1625 kcal/day in the low, medium, and high PF groups. There were significant and positive associations between participants in the high PF group and intake of phosphorous, selenium, vitamin B6, C, D, E, niacin, and folates (all p < 0.05). However, subjects in the high PF group presented negative associations with thiamine and riboflavin intake (all p < 0.05). A total of 8.3% of participants presented inadequate intake of 11 micronutrients. PF seems to affect total nutrient intake. CONCLUSIONS: Higher protein and fat intake was observed in the high PF group compared to the other PF groups in males, although participants in the high PF group had also higher EE. However, females presented different patterns. In both sexes participants in the high PF group showed a better micronutrient intake profile than the other PF groups. There is a need to develop combined nutritional and fitness programs. PMID- 29721679 TI - The association of household food insecurity with the risk of type 2 diabetes mellitus in adults: a systematic review and meta-analysis. AB - BACKGROUND: The link between household food insecurity and risk of type 2 diabetes mellitus still remains controversial. Therefore, we performed a systematic review and meta-analysis to clarify the association between household food insecurity and type 2 diabetes mellitus. METHODS: EMBASE, PubMed, ISI Web of Science and Scopus databases were searched up to March 2017. The selection of studies, data extraction and assessing the risk of bias in the included studies were carried out by two reviewers independently. Study-specific odds ratios (ORs) were pooled using a random effects model. RESULTS: A total of 18 articles including a total of 55,353,915 adult participants were included in the meta analysis. The pooled ORs of the cross-sectional studies revealed that household food insecurity was significantly associated with the odds of T2DM (OR 1.27, 95% CI 1.11-1.42) with no evidence of publication bias (p = 0.63) but heterogeneity between studies (I2 = 61.1%). Similarly, subgroup analyses showed that the country where the study conducted and household food insecurity assessment tool used to influence the effect of household food insecurity on the odds of T2DM. However, the pooled ORs for two case-control and one cohort studies were not significantly associated between household food insecurity and T2DM in adults. CONCLUSION: This study strengthens the hypothesis of the household food insecurity effect on the odds of T2DM among adults. Further longitudinal studies based on larger, and more representative samples are needed to identify the underlying relationships between food insecurity and type 2 diabetes mellitus. PMID- 29721677 TI - Value of abdominal ultrasound in management of necrotizing enterocolitis: a systematic review and meta-analysis. AB - PURPOSE: Necrotizing enterocolitis (NEC) remains a life-threatening disease among infants in the NICU. Early diagnosis and careful monitoring are essential to improve outcomes. Abdominal ultrasound (AUS) seems a promising addition to current diagnostic modalities, but its clinical utility is uncertain. The aim of this study was to identify AUS features associated with definite NEC (i.e. Bell stage >= II), failed medical treatment, surgery, and death. METHODS: Embase, MEDLINE, Web of Science and CINAHL databases were searched for studies that addressed any NEC-related AUS feature in relation to any of the four outcomes. After critical appraisal of relevant study methods, meta-analyses were conducted using a random-effect model. RESULTS: 15 out of 1215 studies were included. All AUS features had sensitivities below 70% and specificities largely above 80% for diagnosing definite NEC; several AUS features were significantly associated with failed medical treatment and surgery. Substantial heterogeneity, poor reporting quality and uncertain risk of bias were found. CONCLUSIONS: While clear associations of AUS features with failed medical treatment exist and AUS may detect definite NEC, substantial heterogeneity, poor reporting quality and an uncertain risk of bias impair the use of AUS for clinical decision making. A prospective, well-designed validation study is needed. PMID- 29721680 TI - The Decision Decoding ToolBOX (DDTBOX) - A Multivariate Pattern Analysis Toolbox for Event-Related Potentials. AB - In recent years, neuroimaging research in cognitive neuroscience has increasingly used multivariate pattern analysis (MVPA) to investigate higher cognitive functions. Here we present DDTBOX, an open-source MVPA toolbox for electroencephalography (EEG) data. DDTBOX runs under MATLAB and is well integrated with the EEGLAB/ERPLAB and Fieldtrip toolboxes (Delorme and Makeig 2004; Lopez-Calderon and Luck 2014; Oostenveld et al. 2011). It trains support vector machines (SVMs) on patterns of event-related potential (ERP) amplitude data, following or preceding an event of interest, for classification or regression of experimental variables. These amplitude patterns can be extracted across space/electrodes (spatial decoding), time (temporal decoding), or both (spatiotemporal decoding). DDTBOX can also extract SVM feature weights, generate empirical chance distributions based on shuffled-labels decoding for group-level statistical testing, provide estimates of the prevalence of decodable information in the population, and perform a variety of corrections for multiple comparisons. It also includes plotting functions for single subject and group results. DDTBOX complements conventional analyses of ERP components, as subtle multivariate patterns can be detected that would be overlooked in standard analyses. It further allows for a more explorative search for information when no ERP component is known to be specifically linked to a cognitive process of interest. In summary, DDTBOX is an easy-to-use and open-source toolbox that allows for characterising the time-course of information related to various perceptual and cognitive processes. It can be applied to data from a large number of experimental paradigms and could therefore be a valuable tool for the neuroimaging community. PMID- 29721681 TI - Combined electrochemiluminescent and electrochemical immunoassay for interleukin 6 based on the use of TiO2 mesocrystal nanoarchitectures. AB - A dual-responsive sandwich-type immunosensor is described for the detection of interleukin 6 (IL-6) by combining electrochemiluminescent (ECL) and electrochemical (EC) detection based on the use of two kinds of TiO2 mesocrystal nanoarchitectures. A composite was prepared from TiO2 (anatase) mesocages (AMCs) and a carboxy-terminated ionic liquid (CTIL) and then placed on a glassy carbon electrode (GCE). In the next step, the ECL probe Ru(bpy)3(II) and antibody against IL-6 (Ab1) were immobilized on the GCE. Octahedral anatase TiO2 mesocrystals (OAMs) served as the matrix for immobilizing acid phosphatase (ACP) and secondary antibody (Ab2) labeled with horseradish peroxidase (HRP) to form a bioconjugate of type Ab2-HRP/ACP/OAMs. It was self-assembled on the GCE by immunobinding. 1-Naphthol, which is produced in-situ on the surface of the GCE due to the hydrolysis of added 1-naphthyl phosphate by ACP, is oxidized by HRP in the presence of added H2O2. This results in an electrochemical signal (typically measured at 0.4 V vs. Ag/AgCl) that increases linearly in the 10 fg.mL-1 to 90 ng.mL-1 IL-6 concentration range with a detection limit of 0.32 fg.mL-1. Secondly, the oxidation product of 1-naphthol quenches the ECL emission of Ru(bpy)32+. This leads to a decrease in ECL intensity which is linear in the 10 ag.mL-1 to 90 ng.mL-1 concentration range, with a detection limit of 3.5 ag.mL-1. The method exhibits satisfying selectivity and good reproducibility which demonstrates its potential in clinical testing and diagnosis. Graphical abstract A dual-responsive sandwich-type immunosensor was fabricated for the detection of interleukin 6 by combining electrochemiluminescence and electrochemical detection based on the use of two kinds of TiO2 mesocrystal nanoarchitectures. PMID- 29721682 TI - [Infarct-related cardiogenic shock : Prognosis and treatment]. AB - Patients with ST segment elevation myocardial infarction (STEMI) and non-ST segment elevation myocardial infarction (NSTEMI) experience cardiogenic shock in about 6-10% of cases during the hospital treatment. In recent years, the incidence seems to be decreasing due to invasive diagnostics and therapy after myocardial infarction. Early diagnosis is important to initiate immediate revascularization using percutaneous coronary intervention (PCI) with stent implantation as part of cardiogenic shock treatment. Thus, a significant improvement in survival can be achieved. Pharmacological and mechanical support is needed to maintain perfusion of the myocardium and organs. Drug therapy for infarct cardiogenic shock relies on dobutamine for inotropic agent and norepinephrine as a vasopressor. For further inotropic support, data on additional levosimendan treatment are available. The pharmacological therapy is supplemented by mechanical support systems such as Impella (ABIOMED, Danvers, MA, USA) or extracorporeal membrane oxygenation (ECMO). The intra-aortic balloon pump (IABP) is hardly used anymore. The majority of cardiogenic shock survivors have little functional cardiac impairment in the long term. This shows the transient damage component (stunning, inflammation), which underlines the need for a fast and effective cardiovascular supportive therapy. PMID- 29721683 TI - Pediatric Neuromyelitis Optica Spectrum Disorders. AB - PURPOSE OF REVIEW: Neuromyelitis optica spectrum disorders (NMOSDs) are a group of inflammatory and demyelinating disorders of the central nervous system that can occur in children and adults. The classic presentation of NMOSD is characterized by optic neuritis and transverse myelitis, but other presentations are also recognized, expanding the disease as NMO spectrum disorders. The purpose of this review is to discuss the clinical features, along with management and treatment options, including potential future therapeutic options, in pediatric NMOSD. RECENT FINDINGS: The aquaporin-4 antibody (AQP4 ab) is specific for NMOSD; however, recently another antibody, the myelin oligodendrocyte glycoprotein (MOG ab) has been found in a subset of AQP4 ab-negative patients including in children. Most treatment studies are reported in adults, but retrospective studies on efficacy and safety of mycophenolate mofetil, azathioprine, and rituximab in pediatric NMOSD are available. While some pediatric NMOSD-specific treatment studies are available, more research is needed in the mechanisms of early onset and specific treatment options in children, including whether different treatment considerations are needed for AQP4 ab as opposed to MOG ab positive disease. PMID- 29721684 TI - Association of subchondral bone texture on magnetic resonance imaging with radiographic knee osteoarthritis progression: data from the Osteoarthritis Initiative Bone Ancillary Study. AB - OBJECTIVES: To assess whether initial or 12-18-month change in magnetic resonance imaging (MRI) subchondral bone texture is predictive of radiographic knee osteoarthritis (OA) progression over 36 months. METHODS: This was a nested case control study including 122 knees/122 participants in the Osteoarthritis Initiative (OAI) Bone Ancillary Study, who underwent MRI optimised for subchondral bone assessment at either the 30- or 36-month and 48-month OAI visits. Case knees (n = 61) had radiographic OA progression between the 36- and 72-month OAI visits, defined as >= 0.7 mm minimum medial tibiofemoral radiographic joint space (minJSW) loss. Control knees (n = 61) without radiographic OA progression were matched (1:1) to cases for age, sex, body mass index and initial medial minJSW. Texture analysis was performed on the medial femoral and tibial subchondral bone. We assessed the association of texture features with radiographic progression by creating a composite texture score using penalised logistic regression and calculating odds ratios. We evaluated the predictive performance of texture features for predicting radiographic progression using c-statistics. RESULTS: Initial (odds ratio [95% confidence interval] = 2.13 [1.41-3.40]) and 12- 18-month change (3.76 [2.04-7.82]) texture scores were significantly associated with radiographic OA progression. Combinations of texture features were significant predictors of radiographic progression using initial (c-statistic [95% confidence interval] = 0.65 [0.64 0.65], p = 0.003) and 12-18-month change (0.68 [0.68-0.68], p < 0.001) data. CONCLUSIONS: Initial and 12-18-month changes in MRI subchondral bone texture score were significantly associated with radiographic progression at 36 months, with better predictive performance for 12-18-month change in texture. These results suggest that texture analysis may be a useful biomarker of subchondral bone in OA. KEY POINTS: * Subchondral bone MRI texture analysis is a promising knee osteoarthritis imaging biomarker. * In this study, subchondral bone texture was associated with knee osteoarthritis progression. * This demonstrates predictive and concurrent validity of MRI subchondral bone texture analysis. * This method may be useful in clinical trials with interventions targeting bone. PMID- 29721685 TI - How many versus how much: comprehensive haemodynamic evaluation of partial anomalous pulmonary venous connection by cardiac MRI. AB - OBJECTIVES: The objective of this study was to investigate the effect of location and number of anomalously connected pulmonary veins and any associated atrial septal defect (ASD) on the magnitude of left-to-right shunting in patients with partial anomalous pulmonary venous connection (PAPVC), and how that influences right ventricular volume loading. METHODS AND RESULTS: The cardiac magnetic resonance (CMR) and echocardiography examinations of 26 paediatric patients (mean age, 11.2 +/- 5.1 years) with unrepaired PAPVC were analysed. Fourteen patients had right-sided, 11 left-sided and 1 patient bilateral PAPVC. An ASD was present in 11 patients, of which none had a Qp/Qs < 1.5 and 8 had a Qp/Qs>= 2.0. No patient with isolated left upper PAPVC experienced a Qp/Qs >= 2.0 compared to 9/12 patients with right upper PAPVC. Qp/Qs correlated with indexed right ventricle (RV) end-diastolic volume (RVEDVi, r = 0.59, p = 0.002) by CMR and with echocardiographic right ventricular end-diastolic dimension (RVED) z-score (r = 0.68, p = 0.003). A RVEDVi >124 ml/m2 by CMR and a RVED z-score >2.2 by echocardiography identified patients with a Qp/Qs >=1.5 with good sensitivity and specificity. CONCLUSIONS: An asymptomatic patient with a single anomalously connected left upper pulmonary vein and without an ASD is unlikely to have a significant left-to-right shunt. On the other hand, right-sided PAPVC is frequently associated with a significant left-to-right shunt, especially when an ASD is present. KEY POINTS: * Patients with PAPVC and ASD routinely have a significant left-to-right shunt. * Patients with right PAPVC are likely to have a significant left-to-right shunt. * Patients with left PAPVC are unlikely to have a significant left-to-right shunt. * CMR is helpful in decision-making for patients with PAPVC. PMID- 29721687 TI - Stylus/tablet user input device for MRI heart wall segmentation: efficiency and ease of use. AB - OBJECTIVES: To determine whether use of a stylus user input device (UID) would be superior to a mouse for CMR segmentation. METHODS: Twenty-five consecutive clinical cardiac magnetic resonance (CMR) examinations were selected. Image analysis was independently performed by four observers. Manual tracing of left (LV) and right (RV) ventricular endocardial contours was performed twice in 10 randomly assigned sessions, each session using only one UID. Segmentation time and the ventricular function variables were recorded. The mean segmentation time and time reduction were calculated for each method. Intraclass correlation coefficients (ICC) and Bland-Altman plots of function variables were used to assess intra- and interobserver variability and agreement between methods. Observers completed a Likert-type questionnaire. RESULTS: The mean segmentation time (in seconds) was significantly less with the stylus compared to the mouse, averaging 206+/-108 versus 308+/-125 (p<0.001) and 225+/-140 versus 353+/-162 (p<0.001) for LV and RV segmentation, respectively. The intra- and interobserver agreement rates were excellent (ICC>=0.75) regardless of the UID. There was an excellent agreement between measurements derived from manual segmentation using different UIDs (ICC>=0.75), with few exceptions. Observers preferred the stylus. CONCLUSION: The study shows a significant reduction in segmentation time using the stylus, a subjective preference, and excellent agreement between the methods. KEY POINTS: * Using a stylus for MRI ventricular segmentation is faster compared to mouse * A stylus is easier to use and results in less fatigue * There is excellent agreement between stylus and mouse UIDs. PMID- 29721686 TI - Quantitative correlation between uptake of Gd-BOPTA on hepatobiliary phase and tumor molecular features in patients with benign hepatocellular lesions. AB - PURPOSE: The purpose of our study was to correlate the quantitative analysis of benign hepatocellular tumor uptake on delayed hepatobiliary phase (HBP) imaging with the quantitative level of OATP expression. METHODS: This single-center retrospective study, which took place between September 2009 and March 2015, included 20 consecutive patients with a proven pathologic and immunohistochemical (IHC) diagnosis of FNH or HCA, including quantification of the OATP expression. The patients underwent Gd-BOPTA-enhancement MRI, including an HBP. The analysis of HBP uptake was performed using the liver-to-lesion contrast enhancement ratio (LLCER). Mean LLCER and OATP expressions were compared between FNH and HCA, and the expression of OATP was correlated with the LLCER value. RESULTS: Of the 23 benign hepatocellular tumors, 9 (39%) were FNH and 14 (61%) were HCA, including 6 inflammatory, 2 HNF1a inactivated, 3 beta-catenin-mutated and 3 unclassified HCAs. On HBP, 100% of the FNH appeared hyper- or isointense, and 79% of the adenomas appeared hypointense. The mean OATP expression of FNH (46.67 +/- 26.58%) was significantly higher than that of HCA (22.14 +/- 30.74%) (p = 0.0273), and the mean LLCER of FNH (10.66 +/- 7.403%) was significantly higher than that of HCA (-13.5 +/- 12.25%) (p < 0.0001). The mean LLCER of beta-catenin-mutated HCA was significantly higher than that of other HCAs (p = 0.011). Significant correlation was found between the OATP expression and LLCER values (r = 0.661; p = 0.001). CONCLUSION: In benign hepatocellular tumors, the quantitative analysis of hepatobiliary contrast agent uptake on HBP is correlated with the level of OATP expression and could be used as an imaging biomarker of the molecular background of HCA and FNH. KEY POINTS: * Gd-BOPTA uptake on HBP correlates with the OATP level in benign hepatocellular tumors * FNH and beta-catenin-mutated HCA showed an increased lesion-to-liver contrast enhancement ratio (LLCER) * Increased LLCER may be explained by activation of the Wnt beta-catenin pathway. PMID- 29721689 TI - Education as "Dilemmatic Field". AB - Psychology of education must discuss a number of relevant ethical, political and societal issues that cannot be simply overlooked as non pertinent to the discipline. For too long educational and developmental psychology have take divergent routes and have not enough dialogued with other fields such as pedagogy. I argue that it is first of all necessary to conceptualize the work of schooling, that is educational processes of teaching and learning in specific social contexts, as complex and dilemmatic fields. I discuss contributions from the past and current debate to support my claim that education is inherently ambivalent and dilemmatic, while educational psychology is too often normative and prescriptive. As many authors have discussed educational processes as battlefields between political and economic tendencies, we cannot avoid to discuss the relationship of such tendencies and the developmental processes of the person. The work of schooling is an action projected towards an imagined future, and educational psychology cannot avoid questioning the predictions emerging from the current socio-economic and political trends. PMID- 29721688 TI - Radiogenomics correlation between MR imaging features and major genetic profiles in glioblastoma. AB - OBJECTIVES: To assess the association between MR imaging features and major genomic profiles in glioblastoma. METHODS: Qualitative and quantitative imaging features such as volumetrics and histogram analysis from normalised CBV (nCBV) and ADC (nADC) were evaluated based on both T2WI and CET1WI. The imaging parameters of different genetic profile groups were compared and regression analyses were used for identifying imaging-molecular associations. Progression free survival (PFS) was analysed by a Kaplan-Meier test and Cox proportional hazards model. RESULTS: An IDH mutation was observed in 18/176 patients, and ATRX loss was positive in 17/158 of the IDH-wt cases. The IDH-mut group showed a larger volume on T2WI and a higher volume ratio between T2WI and CET1WI than the IDH-wt group (p < 0.05). In the IDH-mut group, higher mean nADC values were observed compared with the IDH-wt tumours (p < 0.05). Among the IDH-wt tumours, IDH-wt, ATRX-loss tumours revealed higher 5th percentile nADC values than the IDH wt, ATRX-noloss tumours (p = 0.03). PFS was the longest in the IDH-mut group, followed by the IDH-wt, ATRX-loss groups and the IDH-wt, ATRX-noloss groups, consecutively (p < 0.05). We found significant associations of PFS with the genetic profiles and imaging parameters. CONCLUSION: Major genetic profiles of glioblastoma showed a significant association with MR imaging features, along with some genetic profiles, which are independent prognostic parameters for GBM. KEY POINTS: * Significant correlation exists between radiological parameters such as volumetric and ADC values and major genomic profiles such as IDH mutation and ATRX loss status * Radiological parameters such as the ADC value were feasible predictors of glioblastoma patients' prognosis * Imaging features can predict major genomic profiles of the tumours and the prognosis of glioblastoma patients. PMID- 29721691 TI - Nonoperative Treatment of PCL Injuries: Goals of Rehabilitation and the Natural History of Conservative Care. AB - PURPOSE OF REVIEW: To review the current practices of nonoperative management of posterior cruciate ligament (PCL) injuries, the natural history of conservative care, and the latest PCL rehabilitation strategies. RECENT FINDINGS: PCL injuries often occur as part of a multiligamentous knee injury and occasionally occur in isolation. Although patients may be able to tolerate or compensate for a PCL deficient knee, long-term outcomes after conservative care demonstrate a high rate of arthrosis in the medial and patellofemoral compartments resulting from altered knee kinematics and loads. Good subjective outcomes and a high rate of return to sport have been reported after nonoperative treatment of isolated PCL injuries. However, PCL laxity grade on objective exam does not typically correlate with subjective outcomes, nor does it correlate with the risk of developing osteoarthritis. Although more research is needed on the optimal PCL rehabilitation strategies, general principles include avoiding posterior tibial translation in the initial period to optimize ligament healing, followed by progressive range of motion and strengthening of the quadriceps and core musculature. At 12 weeks, patients may begin an interval running program, followed by agility work and progressive sports-specific training to allow for return to sports. Nonoperative treatment of isolated PCL injuries results in good subjective outcomes and high rate of return to sport. PMID- 29721690 TI - Advances in Patellofemoral Arthroplasty. AB - PURPOSE OF REVIEW: To describe current indications, implants, economic benefits, comparison to TKA, and functional and patient-reported outcomes of patellofemoral arthroplasty. RECENT FINDINGS: Modern onlay implants and improved patient selection have allowed for recent improvements in short- and long-term outcomes after patellofemoral joint replacement surgery. Patellofemoral arthroplasty has become an increasingly utilized technique for the successful treatment of isolated patellofemoral arthritis. Advances in patient selection, implant design, and surgical technique have resulted in improved performance and longevity of these implants. Although short- and mid-term data for modern patellofemoral arthroplasties appear promising, further long-term clinical studies are needed to evaluate how new designs and technologies will affect patient outcomes and long term implant performance. PMID- 29721692 TI - Tibial Tubercle Osteotomies: a Review of a Treatment for Recurrent Patellar Instability. AB - PURPOSE OF REVIEW: The goal of this review is to provide an overview of current surgical treatment options for tibial tubercle osteotomies as a treatment for recurrent patellofemoral instability. As such we sought to provide the reader with the most current answers to why treatment practices have changed and how this has affected the outcome of surgical treatment for patellar instability. RECENT FINDINGS: As our understanding of patellofemoral biomechanics have grown, appropriate surgical and non-surgical treatment options have followed suit to address these findings. A clear understanding of the pathomechanics causing the patient's patellar instability is germane to choosing the most appropriate surgical intervention to address this instability. Likewise, understanding the goal of the intervention chosen-e.g., unloading, realignment-is paramount. These surgical techniques may be technically challenging and surgical specialists with experience in these techniques are recommended for optimal outcomes. PMID- 29721693 TI - Nutritional intervention in patients with juvenile systemic lupus erythematosus: protective effect against the increase in fat mass. AB - Patients with juvenile systemic lupus erythematosus (JSLE) usually have an increase in fat mass and decrease in lean body mass. The purpose of this study was to assess the effect of a nutritional intervention on changes in body composition and food consumption of adolescents with JSLE compared with a control group and its variation over time and to assess the association of total fat mass with clinical parameters. This randomized controlled study evaluated 31 girls. Body composition and food intake were evaluated at baseline. The patients were randomly allocated into a nutritional intervention group and a control group. The intervention group received monthly nutritional guidelines for 9 months. After this period, evaluations were repeated. The carbohydrates intake decreased in the intervention group compared with the control group (p = 0.031) at the end of the study period. Additionally, a significant decrease was observed in the intake of energy (p = 0.023), carbohydrates (p = 0.031), protein (p = 0.024), total fat (p = 0.027), saturated fat (p = 0.012), and trans fat (p = 0.029) in the intervention group between baseline and the end of the study. There was an average increase of 3.7 kg (95% CI 0.8-6.5) in the total fat mass (p = 0.013) and 0.36 kg/m2 (95% CI 0.10-0.62) in the appendicular fat mass (p = 0.007) in the control group during the study period; this finding was not observed in the intervention group. A 9-month nutritional intervention in JSLE patients improved their eating habits and protected against the excessive gain of weight and body fat. PMID- 29721694 TI - Current status of ultrasound and dual-energy computed tomography in the evaluation of gout. AB - Gout is the most common inflammatory arthritis and is increasing in relevance due to its rising prevalence and incidence. Dual-energy CT (DECT) and ultrasound (US) are the most frequently used imaging modalities for the diagnosis of gout and for the follow-up of patients receiving therapy. Although DECT has the highest diagnostic accuracy for gout and shows consistently excellent reader agreement in the assessment of urate deposition change after therapy, US also performs well and remains just as important an imaging tool in these realms due to its practical advantages in cost, availability, and safety. This article reports the current status of these two modalities in regard to diagnosis and therapy follow up. PMID- 29721695 TI - Inverse Gottron papules in juvenile dermatomyositis: an under recognized clinical entity. AB - The objective of this study was to report four children having juvenile dermatomyositis (JDM) with inverse Gottron sign along with a brief review of literature of similarly published cases. This is a retrospective review of case records of all children diagnosed with JDM at a single tertiary care centre in North India. Children who were found to have Gottron papules over palmar surface were identified. A total of 127 children were diagnosed with JDM in the last 24 years (1994-2017). Out of these 127 patients, 4 were found to have Gottron papules over palmar surface. The median age at presentation of these four patients was 9 years (range 8-10). The distribution for inverse Gottron papules was over the palmar aspect of proximal and distal interphalangeal joints, palmar creases and lateral aspects of proximal and distal interphalangeal joints. One child also had features of systemic scleroderma overlap and one patient had patchy lipoatrophy. ANA were positive in two patients. High-resolution computed tomography (HRCT) chest was carried out in all four patients and three of them were found to have changes consistent with interstitial lung disease. Prednisolone was used for all patients, methotrexate in three, azathioprine in two and cyclophosphamide in one patient. Inverse Gottron papule is a hitherto uncommonly recognized cutaneous manifestation of JDM. The clinical implications of this sign are yet not clear in children with JDM. Children with JDM with palmar Gottron papules may be screened for ILD as this may change their management and prognosis. PMID- 29721696 TI - Pyoderma gangrenosum-like ulcerations in granulomatosis with polyangiitis: two cases and literature review. AB - Granulomatosis with polyangiitis (GPA) is a systemic necrotizing small vessel vasculitis associated with circulating anti-neutrophil cytoplasmic antibodies (ANCAs). Skin manifestations, mostly represented by palpable purpura, papulonodular lesions and livedo reticularis, are present in up to 50% of the cases. Ulcerations with undermined, raised erythematous-violaceous border resembling pyoderma gangrenosum (PG) have rarely been reported as skin involvement in GPA. The presence of circulating ANCAs with a cytoplasmic labelling pattern, the involvement of internal organs, particularly of the lung, and the absence on histology of a mainly neutrophilic infiltrate in early phases of the cutaneous lesions may be regarded as clues to rule out true PG and confirm the diagnosis of GPA skin ulcerations simulating PG. Herein, we describe two paradigmatic cases of such a unique presentation of GPA and a literature review focusing on clinicopathological features of GPA presenting with PG-like ulcerations in the skin has been provided. Moreover, referring to the scenario observed in these two cases, an easy-to-use working approach for the differential diagnosis between the two conditions has also been proposed. PMID- 29721697 TI - Spectrum of systemic lupus erythematosus in Oman: from childhood to adulthood. AB - SLE is a disease that mainly affects women of childbearing age, however, a total of 15-20% of cases present in children. Although adult onset SLE (aSLE) and childhood onset SLE (cSLE) share the same diagnostic criteria, differences have been identified. The aim of this study is to compare the similarities and differences in between cSLE and aSLE in an Arab population from Oman. We evaluated 225 SLE patients, 139 adults and 86 children, who fulfilled the criteria for diagnosis. At disease onset, 99% of SLE cohort fulfilled the SLICC criteria; however the ACR 1997 criteria were fulfilled in 66% aSLE and 80% cSLE. The clinical features of SLE in cSLE showed higher frequency of renal (50 vs 19%; p < 0.001), musculoskeletal (67 vs 53%; p = 0.036) and pulmonary involvement (13 vs 2.9%, p = 0.005); while aSLE showed higher frequency of hematological (64 vs 49%; p = 0.25) and mucocutaneous (24 vs 10%; p = 0.13) involvement. The mean disease activity score at disease onset and during disease course was also higher in cSLE (13 vs 8.5; p < 0.0005) (16 vs 11.8; p < 0.0005), respectively. Differences in autoantibody profile were also noted in cSLE with higher positivity of anti-dsDNA and antiphospholipid antibody (94 vs 84%; p = 0.027) (53 vs 37%; p = 0.25), respectively. cSLE patients were more likely than aSLE to be treated with immunosuppressant such as cyclophosphamide (51 vs 22%; p < 0.001) and MMF (70 vs 54%; p = 0.019). Similarities and differences between aSLE and cSLE in a cohort from Oman of Arab ethnicity were identified. It appears that individual races and ethnicities may exhibit differences in disease susceptibility and manifestations. PMID- 29721698 TI - Intuitive optics: what great apes infer from mirrors and shadows. AB - There is ongoing debate about the extent to which nonhuman animals, like humans, can go beyond first-order perceptual information to abstract structural information from their environment. To provide more empirical evidence regarding this question, we examined what type of information great apes (chimpanzees, bonobos, and orangutans) gain from optical effects such as shadows and mirror images. In an initial experiment, we investigated whether apes would use mirror images and shadows to locate hidden food. We found that all examined ape species used these cues to find the food. Follow-up experiments showed that apes neither confused these optical effects with the food rewards nor did they merely associate cues with food. First, naive chimpanzees used the shadow of the hidden food to locate it but they did not learn within the same number of trials to use a perceptually similar rubber patch as indicator of the hidden food reward. Second, apes made use of the mirror images to estimate the distance of the hidden food from their own body. Depending on the distance, apes either pointed into the direction of the food or tried to access the hidden food directly. Third, apes showed some sensitivity to the geometrical relation between mirror orientation and mirrored objects when searching hidden food. Fourth, apes tended to interpret mirror images and pictures of these mirror images differently depending on their prior knowledge. Together, these findings suggest that apes are sensitive to the optical relation between mirror images and shadows and their physical referents. PMID- 29721699 TI - Spatio-temporal organization during group formation in rats. AB - In the present study, the dynamic process of group formation in eight unfamiliar rats was followed in order to reveal how the group becomes oriented together in time and space, in light of the complexity that accompanies grouping. The focus was on who, where, and when joined together. We found that rats preferred to be in companionship over remaining alone, with all the rats gradually shifting to share the same location as a resting place. Group formation can be viewed as a tri-phasic process, with some rats gradually becoming more social than others, and thus playing a key role in group formation. Starting with seemingly independent traveling, the rats gradually converged to share the same location as a terminal (home base) for roundtrips in the arena. Because such a terminal is considered as the organizer of an individual's spatial behavior, the shared home base location may be viewed as the organizer of spatial behavior of the entire group. Despite huddling together, the rats continued to travel alone or in duos throughout the 3 h of testing. We suggest that resting together and traveling alone or in duos enabled the maintenance of communal relationship while reducing the complexity involved in traveling in relatively large groups. Taken together, the present results demonstrate the dynamic process during which unfamiliar rats shift from independent to group spatial behavior. PMID- 29721701 TI - Potable Water Reuse: What Are the Microbiological Risks? AB - PURPOSE OF REVIEW: With the increasing interest in recycling water for potable reuse purposes, it is important to understand the microbial risks associated with potable reuse. This review focuses on potable reuse systems that use high-level treatment and de facto reuse scenarios that include a quantifiable wastewater effluent component. RECENT FINDINGS: In this article, we summarize the published human health studies related to potable reuse, including both epidemiology studies and quantitative microbial risk assessments (QMRA). Overall, there have been relatively few health-based studies evaluating the microbial risks associated with potable reuse. Several microbial risk assessments focused on risks associated with unplanned (or de facto) reuse, while others evaluated planned potable reuse, such as indirect potable reuse (IPR) or direct potable reuse (DPR). The reported QMRA-based risks for planned potable reuse varied substantially, indicating there is a need for risk assessors to use consistent input parameters and transparent assumptions, so that risk results are easily translated across studies. However, the current results overall indicate that predicted risks associated with planned potable reuse scenarios may be lower than those for de facto reuse scenarios. Overall, there is a clear need to carefully consider water treatment train choices when wastewater is a component of the drinking water supply (whether de facto, IPR, or DPR). More data from full-scale water treatment facilities would be helpful to quantify levels of viruses in raw sewage and reductions across unit treatment processes for both culturable and molecular detection methods. PMID- 29721703 TI - Functional Calixphyrins: Synthetic Strategies and Applications. AB - Calixphyrins are hybrid macrocycles that contain both sp2- and sp3-hybridized carbon atoms and hence bear analogy to both porphyrins and calixpyrroles. Due to the presence of sp3-hybridized carbon atoms, pi-conjugation is disrupted in calixphyrins, which leads to conformational flexibility. Hence, these molecules find a use in anion binding, host-guest chemistry and metal-coordination chemistry. During the last decade, studies on calixphyrins have been a topic of wide interest to researchers. Various functionalities have been introduced to the structure of calixphyrins, leading to the development of expanded calixphyrins, core-modified calixphyrins and N-confused calixphyrins with diverse applications. This review outlines the detailed historical origin of the synthesis of calixphyrins with emphasis on current research and development in this area. The modular syntheses of normal calixphyrins, expanded calixphyrins, core-modified calixphyrins and N-confused calixphyrins are also discussed, along with their applicative aspects. PMID- 29721702 TI - First 100 consecutive robotic inguinal hernia repairs at a Veterans Affairs hospital. AB - The utilization of robotics in general surgery has increased significantly including usage in the Veterans Affairs (VA) system. We implemented a robotic inguinal hernia repair (RIHR) program in our VA hospital and report on initial experience with safety and outcomes. The first 100 consecutive RIHR at a VA hospital were reviewed and compared against the results of contemporaneous open inguinal hernia repair (OIHR). Data were collected for operative characteristics, surgical complications and pain related outcomes. Overall, operative times for OIHR were less than RIHR (83.7 vs. 109.7 min, p < 0.0001); however, there was no difference in operative time for bilateral repairs (121.5 vs. 121.9 min, p = ns). Complication rates were similar between the groups. RIHR patients had less pain at POD 1 than OIHR patients (p = 0.05). RIHR were less likely to have multiple post-op visits for pain than OIHR patients (p = 0.003). RIHR can be implemented in the VA system with acceptable surgical outcomes. RIHR may be associated with less post-operative pain in the early post-operative period. PMID- 29721700 TI - Climate Change Impacts on Waterborne Diseases: Moving Toward Designing Interventions. AB - PURPOSE: Climate change threatens progress achieved in global reductions of infectious disease rates over recent decades. This review summarizes literature on potential impacts of climate change on waterborne diseases, organized around a framework of questions that can be addressed depending on available data. RECENT FINDINGS: A growing body of evidence suggests that climate change may alter the incidence of waterborne diseases, and diarrheal diseases in particular. Much of the existing work examines historical relationships between weather and diarrhea incidence, with a limited number of studies projecting future disease rates. Some studies take social and ecological factors into account in considerations of historical relationships, but few have done so in projecting future conditions. The field is at a point of transition, toward incorporating social and ecological factors into understanding the relationships between climatic factors and diarrheal diseases and using this information for future projections. The integration of these components helps identify vulnerable populations and prioritize adaptation strategies. PMID- 29721704 TI - Workup and Management of Patients With Paradoxical Low-Flow, Low-Gradient Aortic Stenosis. AB - About 60% of patients with paradoxical low-flow, low-gradient (PLF-LG) aortic stenosis (AS) have a severe disease that justifies aortic valve replacement (AVR). The first step in patients with symptomatic PLF AS should be to rule out measurement errors and treat hypertension. The second step is to distinguish pseudo-severe from true severe AS (TSAS). The third step is to select the optimal treatment modality at the right time. Regarding the second step, projected aortic valve area calculated using stress echocardiography is superior to traditional severity criteria (AVA < 1.0 cm2 and mean gradient >= 40 mmHg) to unmask TSAS and predict outcomes. Aortic valve calcification score quantitated by computed tomography is helpful to identify TSAS by applying thresholds of 2000 and 1200 AU, respectively, for men and women. This modality should be considered, particularly if stress echocardiography is either not feasible or inconclusive. Once AS severity is confirmed, a risk stratification based on symptomatic status and the importance of left ventricular (LV) systolic impairment will guide therapeutic decision. Symptomatic assessment should not solely rely on patient reported symptom status, but rather include an objective exercise test. The presence of symptomatic PLF-LG TSAS is a class IIa indication for AVR in the guidelines. In asymptomatic patients, a markedly reduced stroke volume, the presence of myocardial fibrosis by cardiac magnetic resonance imaging, a poor longitudinal LV function as assessed by speckle tracking echocardiography, and/or a moderate to severe LV diastolic dysfunction are predictors of poor outcome in PLF-LG patients and may indicate the need of early AVR. The type of AVR should be discussed within a multidisciplinary team, bearing in mind that transcatheter AVR (TAVR) is superior to medical treatment in inoperable patients. Furthermore, TAVR may be a useful alternative to surgical AVR (SAVR) in high-risk patients. Nevertheless, the potential benefits of TAVR, including the lower risk of severe patient-prosthesis mismatch, should be weighed against the risk of paravalvular regurgitation, which is likely poorly tolerated by patients with PLF-LG who often harbor a small and non-compliant LV cavity. PMID- 29721705 TI - Knowledge of Adverse Drug Reaction Reporting and the Pharmacovigilance of Biological Medicines: A Survey of Healthcare Professionals in Ireland. AB - BACKGROUND: In Europe, changes to pharmacovigilance legislation, which include additional monitoring of medicines, aim to optimise adverse drug reaction (ADR) reporting systems. The legislation also makes provisions related to the traceability of biological medicines. OBJECTIVE: The objective of this study was to assess (i) knowledge and general experience of ADR reporting, (ii) knowledge, behaviours, and attitudes related to the pharmacovigilance of biologicals, and (iii) awareness of additional monitoring among healthcare professionals (HCPs) in Ireland. METHODS: Hospital doctors (n = 88), general practitioners (GPs) (n = 197), nurses (n = 104) and pharmacists (n = 309) completed an online questionnaire. RESULTS: There were differences in mean knowledge scores relating to ADR reporting and the pharmacovigilance of biologicals among the HCP groups. The majority of HCPs who use biological medicines in their practice generally record biologicals by brand name but practice behaviours relating to batch number recording differed between some professions. HCPs consider batch number recording to be valuable but also regard it as being more difficult than brand name recording. Most respondents were aware of the concept of additional monitoring but awareness rates differed between some groups. Among those who knew about additional monitoring, there was higher awareness of the inverted black triangle symbol among pharmacists (> 86.4%) compared with hospital doctors (35.1%), GPs (35.6%), and nurses (14.9%). Hospital pharmacists had more experience and knowledge of ADR reporting than other practising HCPs. CONCLUSION: This study highlights the important role hospital pharmacists play in post-marketing surveillance. There is a need to increase pharmacovigilance awareness of biological medicines and improve systems to support their batch traceability. PMID- 29721706 TI - Efficacy of toothpastes in the prevention of erosive tooth wear in permanent and deciduous teeth. AB - AIM: To evaluate the erosive preventive effect of toothpastes in permanent (PT) and deciduous teeth (dt). DESIGN: Enamel samples were divided into five groups (n = 20): G1: placebo toothpaste; G2: NaF toothpaste; G3: AmF-NaF-SnCl2 anti-erosion toothpaste; G4: SnF2-toothpaste; and G5: NaF anti-erosion toothpaste for children. The samples were exposed to five erosion-abrasion cycles (artificial saliva incubation; 3 min in 1% citric acid; 2 min in slurry, toothbrush abrasion, 50 strokes, 200 g). Surface microhardness (SMH), surface specular reflection intensity (SRI), and cumulative surface loss (CSL) were measured. Comparisons among toothpastes were evaluated using Kruskal-Wallis tests and comparisons between PT and dt were evaluated using Wilcoxon's rank sum test. RESULTS: G1 exhibited significantly lower SMH values in PT than the other toothpastes (p < 0.05), with no significant differences among the others groups. In dt, G1 and G4 exhibited significantly different values than the other groups (p < 0.05). G4 exhibited lower values of SRI in both types of teeth. Deciduous teeth presented significantly higher SRI than PT (p < 0.05), except for G3. Deciduous teeth generally presented higher CSL than PT, except for G3. CONCLUSIONS: Deciduous teeth were more prone to mineral loss than permanent teeth. G5 exhibited better efficacy for both teeth, while G3 exhibited a better preventive effect only for deciduous teeth. CLINICAL RELEVANCE: Erosive tooth wear prevalence in children is growing and deciduous teeth are more susceptible than permanent teeth. Considering this, it is important to know the preventive effect of different toothpastes in an initial erosion-abrasion model. PMID- 29721708 TI - Electromagnetic field exposure (50 Hz) impairs response to noxious heat in American cockroach. AB - Exposure to electromagnetic field (EMF) induces physiological changes in organism that are observed at different levels-from biochemical processes to behavior. In this study, we evaluated the effect of EMF exposure (50 Hz, 7 mT) on cockroach's response to noxious heat, measured as the latency to escape from high ambient temperature. We also measured the levels of lipid peroxidation and glutathione content as markers of oxidative balance in cockroaches exposed to EMF. Our results showed that exposure to EMF for 24, 72 h and 7 days significantly increases the latency to escape from noxious heat. Malondialdehyde (MDA) levels increased significantly after 24-h EMF exposure and remained elevated up to 7 days of exposure. Glutathione levels significantly declined in cockroaches exposed to EMF for 7 days. These results demonstrate that EMF exposure is a considerable stress factor that affects oxidative state and heat perception in American cockroach. PMID- 29721710 TI - Subcellular localisation of lipoproteins of Vibrio vulnificus by the identification of outer membrane vesicles components. AB - Vibrio vulnificus, a Gram-negative halophilic bacterium, is an opportunistic human pathogen that is responsible for the majority of seafood-associated deaths worldwide. Lipoproteins are important components of the bacterial cell envelope and have been shown to be involved in a wide variety of cellular processes. Little is known about the localisation or transport mechanism of lipoproteins in V. vulnificus. To assess the localisation of lipoproteins in V. vulnificus, we tested two established techniques for the rapid separation of membrane-associated proteins: detergent extraction with Sarkosyl and outer membrane vesicles (OMVs) preparation. The results showed that Sarkosyl extraction was not useful for the separation of lipoproteins from the different membranes of V. vulnificus. On the other hand, we confirmed that OMVs produced by V. vulnificus contained lipoproteins from the outer but not the inner membrane. Analysis of the OMVs components confirmed the localisation of several well-known lipoproteins to membranes that were different from expected, based on their predicted functions. Using this technique, we found that Asp at position +2 of mature lipoproteins can function as an inner membrane retention signal in V. vulnificus. Interestingly, the Escherichia coli "+2 rule" does not apply to the V. vulnificus lipoprotein IlpA (G2D) mutant, as a Ser to Asp mutation at position +2 of IlpA did not affect its outer membrane localisation. Furthermore, an IlpA tether-mRFP chimeric lipoprotein and its G2D mutant also behaved like IlpA. Together, these results suggest that the sorting rule of lipoproteins in V. vulnificus might be different from that in E. coli. PMID- 29721707 TI - Resected primary mucinous cholangiocarcinoma of the liver. AB - BACKGROUND: Mucinous cholangiocarcinoma (MC) is a very rare variant of intrahepatic cholangiocarcinoma. MC is characterized by rapid growth, widespread metastasis, and poor prognosis. We report a case of resected MC of the liver. CASE PRESENTATION: We found a 13.6-cm hypovascular tumor in the left hepatic lobe of a 68-year-old man, which we initially diagnosed as a mass-forming intrahepatic cholangiocarcinoma. Left lobe and caudate resection was performed without major intraoperative or postoperative complications. He was discharged home on postoperative day 9 and had no recurrence for 6 months. Pathological examination showed a mucous lobulated tumor with abundant mucus in the cytoplasm and extracellular regions. After differential diagnosis that considered invasive intraductal papillary neoplasm of the bile duct and metastatic liver tumors from the digestive tract, this tumor was diagnosed as a cholangiocarcinoma rare variant: primary mucinous carcinoma of the liver. CONCLUSION: Analysis of previous reports suggests that primary MC of the liver could be classified into two subtypes: pure MC and combined hepatocellular carcinoma and MC. Notably, the latter has been reported only in patients with chronic liver disease, whereas the former has only been reported in patients with no underlying disease. PMID- 29721709 TI - Isolation and characterization of a group of new Proteus bacteriophages. AB - Four lytic Proteus bacteriophages, PM75, PM85, PM93, and PM116, which are active against multi-drug-resistant strains of P. mirabilis, were isolated from cattle and poultry samples. According to electron microscopy data, all of the investigated phages belonged to the family Podoviridae. They all demonstrated lytic activity against sensitive strains of P. mirabilis, and three of the phages, PM85, PM93, and PM116, are potential candidates for use in antibacterial treatment. The genomes and putative proteins of bacteriophages PM85, PM93, and PM116 were similar to those of Proteus phage vB_PmiP_Pm5460 [KP890822], and the investigated phages formed a distinct clade within the genus Sp6virus, subfamily Autographivirinae. The genome sequence of phage PM75 was similar to that of a previously described Proteus phage, PM16 [KF319020], and both of them demonstrated low nucleotide sequence identity to the genomes of the other most similar phages, namely, Vibrio phage VP93, Pantoea phage LIMElight, and KP34-like bacteriophages. According to cluster analysis of the complete genome sequences and phylogenetic analysis of the proteins essential for their life cycle, phages PM75 and PM16 are distinct from other similar phages from the phiKMV supergroup and should be recognized as constituting a new genus, "Pm16virus", within the subfamily Autographivirinae. PMID- 29721712 TI - A retrospective analysis of medication prescription records for determining the levels of compliance and persistence to urate-lowering therapy for the treatment of gout and hyperuricemia in The Netherlands. AB - Urate-lowering therapy (ULT) is a recommended life-long treatment for gout patients. However, despite these recommendations, recurrent gout attacks are commonly observed in clinical practice. The purpose of this study was to assess the levels of compliance and persistence to ULT in The Netherlands, in order to reflect on the current gout care delivered by health professionals. Anonymous prescription records were obtained from IQVIA's Dutch retrospective longitudinal prescription database, containing ULT dispensing data for allopurinol, febuxostat, and benzbromarone from November 2013 to July 2017. Compliance to ULT was determined by calculating the proportion of days covered (PDC) over 12 months. Persistence over 12 months was evaluated by determining the time to discontinuation, without surpassing a refill gap of > 30 days. Association of PDC and persistence with age, gender, and first prescriber were examined using beta regression- and cox-regression models, respectively. There were 45,654 patients who met the inclusion criteria. Overall, 51.7% of the patients had a ULT coverage of >= 80% of the days in 1 year (PDC >= 0.80), and 42.7% of the patients were still persistent after 1 year. Men, older patients, and patients whose first prescriber was a rheumatologist were more persistent and had a higher PDC. Our results show that medication adherence to ULT after 1 year is suboptimal, considering that current guidelines recommend ULT as a life-long treatment. Future studies addressing the reasons for treatment cessation and improving treatment adherence seem warranted. PMID- 29721711 TI - Rare taxa and dark microbial matter: novel bioactive actinobacteria abound in Atacama Desert soils. AB - An "in house" taxonomic approach to drug discovery led to the isolation of diverse actinobacteria from hyper-arid, extreme hyper-arid and very high altitude Atacama Desert soils. A high proportion of the isolates were assigned to novel taxa, with many showing activity in standard antimicrobial plug assays. The application of more advanced taxonomic and screening strategies showed that strains classified as novel species of Lentzea and Streptomyces synthesised new specialised metabolites thereby underpinning the premise that the extreme abiotic conditions in the Atacama Desert favour the development of a unique actinobacterial diversity which is the basis of novel chemistry. Complementary metagenomic analyses showed that the soils encompassed an astonishing degree of actinobacterial 'dark matter', while rank-abundance analyses showed them to be highly diverse habitats mainly composed of rare taxa that have not been recovered using culture-dependent methods. The implications of these pioneering studies on future bioprospecting campaigns are discussed. PMID- 29721713 TI - Medicaid or Medicare insurance payer status and household income are associated with outcomes after primary total hip arthroplasty. AB - Our objective was to examine if Medicaid/Medicare health insurance and household income were associated with poorer outcomes after primary total hip arthroplasty (THA). We used multivariable-adjusted Cox regression analyses to assess whether insurance payer type and household income were independently associated with health care utilization outcomes or complications post-THA in a cohort of hospital discharges from the 1998-2014 US National Inpatient Sample, adjusting for demographics, underlying diagnosis for THA, medical comorbidity, and hospital characteristics. In a national cohort of 4,116,485 primary THAs, the mean age was 65.5 years, 57% were female, 87% White, and 83% had osteoarthritis. Compared to private insurance, patients with Medicaid had significantly higher hazard ratio (HR) (95% confidence interval (CI)) for hospital charges above the median, 1.18 (1.15, 1.21); discharge to a rehabilitation/inpatient facility, 1.67 (1.62, 1.72); length of hospital stay > 3 days, 1.62 (1.58, 1.67); and in-hospital post operative complications including infection, 1.70 (1.47, 1.97); transfusion, 1.13 (1.09, 1.16); revision, 1.55 (1.32, 1.82); and mortality, 1.89 (1.35, 2.63). Results were similar for those with Medicare payer status. Compared to the highest quartile, the lowest income quartile was associated with significantly higher HR (95% CI) of hospital charges above median, 1.43 (1.41, 1.45), and a lower HR of discharge to a rehabilitation/inpatient facility, 0.78 (0.77, 0.79); hospital stay > 3 days, 0.82 (0.80, 0.83); infection, 0.57 (0.50, 0.65); and transfusion, 0.80 (0.79, 0.82). The association of Medicaid/Medicare insurance and income with post-THA health care utilization and complications implies that a better understanding of underlying reasons is needed to improve post-THA outcomes. PMID- 29721715 TI - A prognostic scoring model for survival after locoregional therapy in de novo stage IV breast cancer. AB - BACKGROUND: The role of locoregional treatment (LRT) remains controversial in de novo stage IV breast cancer (BC). We sought to analyze the role of LRT and prognostic factors of overall survival (OS) in de novo stage IV BC patients treated with LRT utilizing the National Cancer Data Base (NCDB). The objective of the current study is to create and internally validate a prognostic scoring model to predict the long-term OS for de novo stage IV BC patients treated with LRT. METHODS: We included de novo stage IV BC patients reported to NCDB between 2004 and 2015. Patients were divided into LRT and no-LRT subsets. We randomized LRT subset to training and validation cohorts. In the training cohort, a seventeen point prognostic scoring system was developed based on the hazard ratios calculated using Cox-proportional method. We stratified both training and validation cohorts into two "groups" [group 1 (0-7 points) and group 2 (7-17 points)]. Kaplan-Meier method and log-rank test were used to compare OS between the two groups. Our prognostic score was validated internally by comparing the OS between the respective groups in both the training and validation cohorts. RESULTS: Among 67,978 patients, LRT subset (21,200) had better median OS as compared to that of no-LRT (45 vs. 24 months; p < 0.0001). The group 1 and group 2 in the training cohort showed a significant difference in the 3-year OS (p < 0.0001) (68 vs. 26%). On internal validation, comparable OS was seen between the respective groups in each cohort (p = 0.77). CONCLUSIONS: Our prognostic scoring system will help oncologists to predict the prognosis in de novo stage IV BC patients treated with LRT. Although firm treatment-related conclusions cannot be made due to the retrospective nature of the study, LRT appears to be associated with a better OS in specific subgroups. PMID- 29721714 TI - Effect of early oral feeding on length of hospital stay following gastrectomy for gastric cancer: a Japanese multicenter, randomized controlled trial. AB - PURPOSE: This multicenter, randomized controlled study evaluates the safety of early oral feeding following gastrectomy, and its effect on the length of postoperative hospital stay. METHODS: The subjects of this study were patients who underwent distal gastrectomy (DG) or total gastrectomy (TG) for gastric cancer between January 2014 and December 2015. Patients were randomly assigned to the early oral feeding group (intervention group) or the conventional postoperative management group (control group) for each procedure. We evaluated the length of postoperative hospital stay and the incidence of postoperative complications in each group. RESULTS: No significant differences in length of postoperative stay were found between the intervention and control groups of the patients who underwent DG. The incidence of postoperative complications was significantly greater in the DG intervention group. In contrast, the length of postoperative stay was significantly shorter in the TG intervention group, although the TG group did not attain the established target sample size. CONCLUSION: Early oral feeding did not shorten the postoperative hospital stay after DG. The higher incidence of postoperative complications precluded the unselected adoption of early oral feeding for DG patients. Further confirmative studies are required to definitively establish the potential benefits of early oral feeding for TG patients. PMID- 29721717 TI - AIDS-Affected Orphans in Sub-Saharan Africa: A Scoping Review on Outcome Differences in Rural and Urban Environments. AB - Currently, there are more than 11 million AIDS-affected orphans that suffer from various adverse effects, most of whom reside in sub-Saharan Africa. The difference between whether a child resides in a rural or urban environment can have a significant role in a child's education, health status and access to healthcare, and social or family relationships. A scoping review was conducted in order to understand any possible environment-based differences on orphans directly affected by HIV/AIDS in sub-Saharan Africa. There were 233 sources used for this review; however, 164 manuscripts focused more so on a general review of orphans within a rural or urban environment. Thus, after eliminating for various factors, 69 manuscripts were removed, which focused primarily on the social aspect of orphans due to HIV/AIDS. Rural environments provided more family support, while urban environments generally had more resources available to orphans (e.g. school fees). Unfortunately, both rural and urban environments were found to be fairly non-supportive of orphans and their development. This scoping review found, in general, that orphans in both urban and rural environments continue to suffer from the consequential effects of low parental support due to AIDS mortality. These conclusions suggest that specific support to orphans through school and social relationships encourage better development outcomes in sub-Saharan Africa. PMID- 29721716 TI - Effect of Gambogenic Acid on Cytochrome P450 1A2, 2B1 and 2E1, and Constitutive Androstane Receptor in Rats. AB - BACKGROUND AND OBJECTIVES: Gambogenic acid (GNA), which possesses diverse antitumor activities both in vitro and in vivo, is regarded as a potential anticancer compound. Cytochrome P450 (CYP) enzymes play an important role in the metabolism of most xenobiotics; constitutive androstane receptor (CAR), a nuclear receptor that might be activated by xenobiotics and associated with the expression of some CYPs. In this study, we determined the effect of GNA on multiple rat liver CYP isoforms (CYP1A2, 2B1, and 2E1) and CAR as well as the potential of GNA to interact with co-administered drugs. METHODS: Male SD rats were randomly divided into the control, and the low (5 mg/kg)-, medium (25 mg/kg) , and high- (100 mg/kg) dose GNA groups. After the intragastric administration of GNA for 14 consecutive days, a cocktail method was adopted to evaluate the activities of CYP1A2, 2B1, and 2E1. The liver expression of CYP1A2, 2B1, and 2E1 and CAR was analyzed by Western blotting (WB) and quantitative real-time reverse transcription polymerase chain reaction (RT-qPCR). RESULTS: The 14-day administration of GNA significantly increased both the mRNA and protein expressions and the activity of CYP2E1. Additionally, the mRNA and protein expressions of CYP1A2 were clearly induced, while only the high GNA dose increased the activity of liver CYP1A2. Moreover, the mRNA expression levels of CYP2B1 and CAR were increased, but their protein levels and the activity parameters of CYP2B1 did not show significant changes. CONCLUSIONS: The obtained results suggest that the CYP1A2 and CYP2E1 enzymes could be induced in rats after treatment with GNA. Therefore, when GNA is administrated with other drugs, potential drug-drug interactions (DDI) mediated by CYP1A2 and CYP2E1 induction should be taken into consideration. PMID- 29721718 TI - An Up to Date Review of Pseudotumor Cerebri Syndrome. AB - PURPOSE OF REVIEW: Idiopathic intracranial hypertension (IIH), pseudotumor cerebri syndrome (PTCS), and benign intracranial hypertension are all terms that have been used for a neurologic syndrome consisting of elevated intracranial pressure (ICP), headache and vision loss without mass lesion or underlying infection or malignancy. In this review article, categorization, diagnostic criteria, symptom management strategies, and disease treatment options for pseudotumor cerebri syndrome will be discussed. RECENT FINDINGS: The Idiopathic Intracranial Hypertension Treatment Trial has now proven that acetazolamide should be the first line therapy in primary PTCS, but other treatment options exist in patients who cannot tolerate acetazolamide or in selected cases, which requires surgical intervention for PTCS which acutely threatens vision. Headache has also been shown to require focused treatment beyond therapies that lower ICP, specifically targeting coexistent primary headache disorders and medication overuse. Advances in treatment and diagnostic modalities have improved understanding of PTCS types and their treatment. The pathophysiology of primary PTCS, however, remains incompletely understood, but continued evaluation of cerebrospinal fluid flow dynamics, aquaporins, hormones, natriuretic peptides, and the link with female gender and obesity may lead to future answers. PMID- 29721719 TI - A Systematic Review of Land-Based Self-Exclusion Programs: Demographics, Gambling Behavior, Gambling Problems, Mental Symptoms, and Mental Health. AB - Systematic and quantitative reviews on the effects of land-based self-exclusion are scarce. Therefore, the current review aimed to provide a comprehensive summary of (1) the demographic characteristics of land-based self-excluders and changes after exclusion, including (2) gambling behavior, (3) gambling problems, (4) mental symptoms, and (5) mental health. A systematic database and literature search was performed following PRISMA guidelines. Nineteen naturalistic studies met the eligibility criteria. The quality of all included records was rated via adaption of the Newcastle-Ottawa Scale. Results from higher-quality records were more heavily weighted. Self-excluders were predominantly men in their early or middle forties. Changes after exclusion revealed wide ranges in the rates of abstinence (13-81%), rates of gambling reduction (29-92%), and rates of exclusion breaches (8-59%). The records consistently demonstrated significant changes in pathological gambling from before exclusion (61-95%) to after exclusion (13-26%). Up to 73% of self-excluders exhibited symptoms of anxiety, depression, and substance use disorders at program enrollment. Several aspects of mental health improved after exclusion, e.g., quality of life. Problem and pathological gambling are most prevalent in young men, but self-exclusion was most prominent in middle-aged men. The magnitude of effects widely differed between studies despite overall benefits of self-exclusion, and many individuals continued gambling after exclusion. This shortcoming could be minimized using improved access controls and the extension of exclusion to other gambling segments. High rates of pathological gambling and other mental disorders in self-excluders highlight the need for improved early detection and treatment accessibility. PMID- 29721720 TI - Comparison of paired human nasal and bronchial airway epithelial cell responses to rhinovirus infection and IL-13 treatment. AB - BACKGROUND: Because of its advantage as a minimally invasive procedure, nasal brushings have been increasingly used and proposed as a valuable approach to study lower airway diseases in lieu of bronchial epithelial cells. However, there is limited or conflicting evidence pertaining to whether nasal samples can be surrogates to bronchial samples. The goal of the present study is to test whether nasal epithelial cells have similar antiviral and inflammatory responses to IL-13 treatment and rhinovirus infection, a condition mimicking virally induced asthma exacerbation. Nasal and bronchial airway epithelial cells taken from the same patient were cultured under submerged and air-liquid interface (ALI) culture in the absence or presence of rhinovirus and IL-13 treatment. Inflammatory cytokines IP-10 and eotaxin-3, antiviral gene Mx1 and viral levels were measured. RESULTS: In the absence of IL-13 treatment, nasal and bronchial cells showed a similar IP 10 response in both ALI and submerged cultures. Under the ALI culture, short term (e.g., 3 days) IL-13 treatment had a minimal effect on viral and Mx1 levels in both cell types. However, prolonged (e.g., 14 days) IL-13 treatments in both cell types decreased viral load and Mx1 expression. Under the submerged culture, IL-13 treatment in both cell types has minimal effects on viral load, IP-10 and Mx1. IL 13-induced eotaxin-3 production was similar in both types of cells under either submerged or ALI culture, which was not affected by viral infection. CONCLUSIONS: Our data suggest that nasal epithelial cells could serve as a surrogate to bronchial epithelial cells in future studies aimed at defining the role of type 2 cytokine IL-13 in regulating pro-inflammatory and antiviral responses. PMID- 29721722 TI - Proceedings of Reanimation 2018, the French Intensive Care Society International Congress: physiotherapists' communications. PMID- 29721723 TI - Olfactory Function Relates to Sexual Experience in Adults. AB - The olfactory system contributes significantly to human social behavior and especially to mate choice and empathic functioning. In this context, previous research examining individuals with impaired olfactory function indicated an influence of the sense of smell on different aspects of sexuality. However, the applied samples, methods, and results are diverse and an involvement of confounding factors, such as breathing problems, depression or social insecurity cannot be ruled out. The present study examined the potential correlation between odor threshold in healthy participants and their sexual desire, sexual experience, and sexual performance. In 70 adults (28 male, 42 female; mean age 24.8 +/- 4.1 years), odor threshold was assessed using the "Sniffin' Sticks." The participants also responded to a battery of questions on sexual desire (Sexual Desire Inventory), sexual experience (orgasm frequency, perceived pleasantness of sexual activities on a visual analogue scale) as well as sexual performance (frequency of having sex, average duration of sexual intercourse). Odor sensitivity correlated positively with sexual experience: Participants with high olfactory sensitivity reported higher pleasantness of sexual activities. Further, women with high olfactory sensitivity reported a higher frequency of orgasms during sexual intercourse. These findings were exclusively present for sexual experience; no significant correlations were detected for sexual desire or sexual performance. The experience of sexual interactions appears to be enriched by olfactory input. We discuss that the perception of certain body odors may contribute to the concept of sexual pleasure by enhanced recruitment of reward areas. PMID- 29721721 TI - Sorghum CCoAOMT and CCoAOMT-like gene evolution, structure, expression and the role of conserved amino acids in protein activity. AB - Sorghum is a crop plant that is grown for seeds, sucrose, forage and biofuel production. In all these applications, lignin is a superfluous component that decreases the efficiency of technological processes. Caffeoyl-coenzyme A O methyltransferase (CCoAOMT) is an enzyme involved in monolignol synthesis that affects the efficiency of lignification and lignin composition. The sorghum genome harbors one CCoAOMT gene and six closely related CCoAOMT-like genes. The structures of four sorghum CCoAOMT-like enzymes suggest that these proteins might methylate caffeoyl coenzyme A and contribute to monolignol synthesis. In this study, two sorghum genes, CCoAOMT and one CCoAOMT-like, were found to be highly expressed in leaves, stems and immature seeds. The promoters of these genes possess clusters of transcription factor-binding sites specific for lignification, and this suggests that they are important for lignification. Phylogenetic analysis revealed that one sorghum CCoAOMT-like enzyme is closely related to ancestral cyanobacterial CCoAOMT-like proteins. The remaining CCoAOMT like enzymes, including the one highly expressed in the leaves and stem, are closely related to CCoAOMT. Genes from these two groups possess different, evolutionarily conserved gene structures. The structure of the sorghum CCoAOMT like protein from the ancestral clade was modeled and differences between enzymes from the two clades were analyzed. These results facilitate a better understanding of the evolution of genes involved in lignification, and provide valuable data for sorghum improvement through traditional breeding or molecular genetic techniques. The findings suggest that CCoAOMT-like genes might be recruited in lignification and raise questions of the frequency of such functional shifts. PMID- 29721724 TI - Malignant Peritoneal Mesothelioma: National Practice Patterns, Outcomes, and Predictors of Survival. AB - PURPOSE: This study of a large, contemporary national database evaluated management patterns, outcomes, and prognostic factors of malignant peritoneal mesothelioma (MPM) in the USA. METHODS: The National Cancer Data Base was queried for newly diagnosed nonmetastatic MPM. Patients were divided into five cohorts: observation, chemotherapy alone, cytoreductive surgery (CRS) alone, CRS/chemo [referring to any non-hyperthermic intraperitoneal chemotherapy (HIPEC) chemotherapy], and CRS/HIPEC. Statistics included multivariable logistic regression, Kaplan-Meier analysis, and Cox proportional hazards modeling. RESULTS: Of 1514 patients, 379 (25%) underwent observation, 370 (24%) received chemotherapy only, 197 (13%) CRS alone, 352 (23%) CRS/chemo, and 216 (14%) CRS/HIPEC. No major temporal trends in management were noted. Factors predictive of CRS administration included younger age, female gender, insurance status, residence in educated areas, living farther from treating institutions, and treatment at academic centers (p < 0.05 for all). Compared with epithelioid histology, those with sarcomatoid and biphasic histology were less and more likely to undergo CRS, respectively (p < 0.05 for both). In all CRS patients, 30- and 90-day mortality rates were 0.8 and 1.2%, respectively. At median follow-up of 50 months, median OS in the respective groups was 6, 17, 21, 52, and 61 months (p < 0.001). Poor prognostic factors included advanced age, male gender, uninsured/Medicaid insurance, and sarcomatoid/biphasic histology (p < 0.05 for all). CONCLUSIONS: In the USA, MPM is treated using a wide variety of strategies. Many factors impact the type of treatment delivered, including age, sociodemographics, geography, histology, and facility type. Although these data do not imply causation, combined-modality management seems associated with the longest OS. PMID- 29721725 TI - The Impact of Metronomic Adjuvant Chemotherapy in Patients with Advanced Oral Cancer. AB - BACKGROUND: This study evaluated the efficacy of tegafur-uracil for advanced oral cancer. METHODS: From January 2008 to December 2013, clinical data from 356 patients with stage III or IV oral squamous cell carcinoma who received curative surgical resection and postoperative concurrent chemoradiotherapy, treated with or without tegafur-uracil, were analyzed from a prospectively designed database. Tegafur-uracil was orally administered to 114 of the 356 patients. Disease specific survival (DSS), disease-free survival (DFS), and overall survival (OS) rates were studied. RESULTS: In our study, the 5-year OS (p = 0.0008), DFS (p = 0.0034), and DSS (p = 0.0029) rates were significantly better in the tegafur uracil group than in the control group. Distant metastasis occurred in 16.28% of patients in the tegafur-uracil group and 45.28% in the control group (odds ratio 4.3). The distant metastasis rate in the tegafur-uracil group was significantly lower than the control group, indicating that administration of tegafur-uracil after curative surgical treatment and concurrent chemoradiotherapy prevented distant metastasis and improved the OS, DFS, and DSS rate. CONCLUSIONS: The result of tegafur-uracil treatment in patients with advanced oral cancer showed significant improvement in the 5-year OS, DFS, and DSS rate, while also showing a decreased distant metastasis rate. Tegafur-uracil treatment is a useful, effective, and well-tolerated anticancer treatment for advanced oral cancer. PMID- 29721726 TI - Association between serum lipid levels, osteoprotegerin and depressive symptomatology in psychotic disorders. AB - Although the relationship between positive and negative symptoms of psychosis and dyslipidemia has been thoroughly investigated in recent studies, the potential link between depression and lipid status is still under-investigated. We here examined the association between lipid levels and depressive symptomatology in patients with psychotic disorders, in addition to their possible inflammatory associations. Participants (n = 652) with the following distribution: schizophrenia, schizophreniform and schizoaffective disorder (schizophrenia group, n = 344); bipolar I, II, NOS, and psychosis NOS (non-schizophrenia group, n = 308) were recruited consecutively from the Norwegian Thematically Organized Psychosis (TOP) Study. Clinical data were obtained by Positive and Negative Syndrome Scale (PANSS), and Calgary Depression Scale for Schizophrenia (CDSS). Blood samples were analyzed for total cholesterol (TC), low-density lipoprotein (LDL), triglyceride (TG), C-reactive protein (CRP), soluble tumor necrosis factor receptor 1(sTNF-R1), osteoprotegerin (OPG), and interleukin 1 receptor antagonist (IL-1Ra). After adjusting for age, gender, BMI, smoking, and dyslipidemia inducing antipsychotics, TC and LDL scores showed significant associations with depression [beta = 0.13, p = 0.007; beta = 0.14, p = 0.007], and with two inflammatory markers: CRP [beta = 0.14, p = 0.007; beta = 0.16, p = 0.007] and OPG [beta = 0.14, p = 0.007; beta = 0.11, p = 0.007]. Total model variance was 17% for both analyses [F(12, 433) = 8.42, p < 0.001; F(12, 433) = 8.64, p < 0.001]. Current findings highlight a potential independent role of depression and inflammatory markers, CRP and OPG in specific, in the pathophysiology of dyslipidemia in psychotic disorders. PMID- 29721727 TI - Schizotypy and smooth pursuit eye movements as potential endophenotypes of obsessive-compulsive disorder. AB - Patients with obsessive-compulsive disorder (OCD) show dysfunctions of the fronto striatal circuitry, which imply corresponding oculomotor deficits including smooth pursuit eye movements (SPEM). However, evidence for a deficit in SPEM is inconclusive, with some studies reporting reduced velocity gain while others did not find any SPEM dysfunctions in OCD patients. Interestingly, psychosis-like traits have repeatedly been linked to both OCD and impaired SPEM. Here, we examined a large sample of n = 168 patients with OCD, n = 93 unaffected first degree relatives and n = 171 healthy control subjects to investigate whether elevated levels of schizotypy and SPEM deficits represent potential endophenotypes of OCD. We applied a SPEM task with high demands on predictive pursuit that is more sensitive to assess executive dysfunctions than a standard task with continuous visual feedback, as episodes of target blanking put increased demands on basal ganglia and prefrontal involvement. Additionally, we examined the relation between schizotypy and SPEM performance in OCD patients and their relatives. Results indicate that OCD patients and unaffected relatives do not show deficient performance in either standard or predictive SPEM. Yet, both patients and relatives exhibited elevated levels of schizotypy, and schizotypy was significantly correlated with velocity gain during standard trials in unmedicated and depression-free OCD patients. These findings highlight the role of schizotypy as a candidate endophenotype of OCD and add to the growing evidence for predisposing personality traits in OCD. Furthermore, intact gain may represent a key characteristic that distinguishes the OCD and schizophrenia patient populations. PMID- 29721728 TI - Use of multiple water surface flow constructed wetlands for non-point source water pollution control. AB - Multiple free water surface flow constructed wetlands (multi-FWS CWs) are a variety of conventional water treatment plants for the interception of pollutants. This review encapsulated the characteristics and applications in the field of ecological non-point source water pollution control technology. The roles of in-series design and operation parameters (hydraulic residence time, hydraulic load rate, water depth and aspect ratio, composition of influent, and plant species) for performance intensification were also analyzed, which were crucial to achieve sustainable and effective contaminants removal, especially the retention of nutrient. The mechanism study of design and operation parameters for the removal of nitrogen and phosphorus was also highlighted. Conducive perspectives for further research on optimizing its design/operation parameters and advanced technologies of ecological restoration were illustrated to possibly interpret the functions of multi-FWS CWs. PMID- 29721729 TI - The Untreated Addiction: Going Tobacco-Free in a VA Substance Abuse Residential Rehabilitation Treatment Program (SARRTP). AB - Despite negative effects of tobacco on the human body and the high prevalence of smoking among those who enter treatment for substance use, few residential programs endorse a tobacco-free policy. Conventional wisdom suggests that it is overwhelming to quit more than one substance at a time, and as a result, many clinicians believe that a shift to a tobacco-free treatment environment is unfeasible. However, the most recent scientific literature suggests the opposite: targeting tobacco use during substance use treatment can increase abstinence rates from both smoking and substances of choice. Therefore, the purpose of the current project is to outline the process by which a residential substance use treatment program within a Veterans Affairs (VA) medical center implemented a tobacco-free policy. In addition, preliminary program evaluation data dispels the myth that eliminating tobacco use in a residential treatment program leads to a decline in patient interest and program utilization. PMID- 29721730 TI - "Madonna of the Pinks" and "Madonna Dell'Impannata": Raphael Sanzio (1483-1520). PMID- 29721731 TI - Assessment of the direct effects of DDAH I on tumour angiogenesis in vivo. AB - Nitric oxide (NO) has been strongly implicated in glioma progression and angiogenesis. The endogenous inhibitors of NO synthesis, asymmetric dimethylarginine (ADMA) and N-monomethyl-L-arginine (L-NMMA), are metabolized by dimethylarginine dimethylaminohydrolase (DDAH), and hence, DDAH is an intracellular factor that regulates NO. However, DDAH may also have an NO independent action. We aimed to investigate whether DDAH I has any direct role in tumour vascular development and growth independent of its NO-mediated effects, in order to establish the future potential of DDAH inhibition as an anti-angiogenic treatment strategy. A clone of rat C6 glioma cells deficient in NO production expressing a pTet Off regulatable element was identified and engineered to overexpress DDAH I in the absence of doxycycline. Xenografts derived from these cells were propagated in the presence or absence of doxycycline and susceptibility magnetic resonance imaging used to assess functional vasculature in vivo. Pathological correlates of tumour vascular density, maturation and function were also sought. In the absence of doxycycline, tumours exhibited high DDAH I expression and activity, which was suppressed in its presence. However, overexpression of DDAH I had no measurable effect on tumour growth, vessel density, function or maturation. These data suggest that in C6 gliomas DDAH has no NO-independent effects on tumour growth and angiogenesis, and that the therapeutic potential of targeting DDAH in gliomas should only be considered in the context of NO regulation. PMID- 29721732 TI - A prospective randomized double-blind study of pain control by topical calcium channel blockers versus placebo after Milligan-Morgan hemorrhoidectomy. AB - INTRODUCTION: Post-hemorrhoidectomy pain is significantly associated with a hypertonicity of the internal anal sphincter. We evaluated the effects of topical diltiazem, a calcium channel blocker, in reducing pain after hemorrhoidectomy. Purpose of our study was to determine difference in extent of pain control by application of topical calcium channel blocker (diltiazem 2%) versus placebo ointment. METHODS: This was a prospective randomized double-blind clinical study conducted at Sawai Man Singh Hospital, Jaipur, from May 2016 to May 2017. Sixty patients, who had undergone hemorrhoid, were randomly assigned to receive 2% diltiazem ointment (n = 30) or a placebo ointment (n = 30) postoperatively. Ointments were applied to the perianal region three times daily for 7 days. Pain scores were recorded using visual analog scale at 6, 24, and 48 h and seventh day postoperatively and number of analgesic doses consumed by patients in the first 3 days. RESULTS: Patients using the diltiazem ointment had significantly less pain and greater benefit than those in the placebo group throughout the first postoperative week (p < 0.001) except for reading at 6 h. Also, there was significantly less number of analgesic doses consumed in the diltiazem group compared to the placebo group. CONCLUSION: Perianal application of 2% diltiazem ointment after hemorrhoidectomy significantly reduces postoperative pain and is perceived as beneficial. PMID- 29721733 TI - Time between suspected and confirmed diagnoses of Crohn's disease and ulcerative colitis in patients followed in gastroenterological practices in Germany. AB - AIMS: The goal of the present study was to analyze the time between suspected and confirmed diagnoses of Crohn's disease (CD) and ulcerative colitis (UC) in patients followed in gastroenterological practices in Germany. METHODS: The study included individuals who received a suspected diagnosis of CD or UC (index date) and were followed in 47 gastroenterological practices in Germany between January 2007 and December 2016. The main outcome measure of the study was the time between suspected and confirmed diagnoses of CD and UC. Covariables included age, sex, and type of health insurance (private or statutory). A multivariate linear regression model was used to analyze the impact of the different variables on the time between suspected and confirmed diagnoses of CD and UC. RESULTS: The study included 2657 patients with a suspected diagnosis of CD and UC between 2007 and 2016. The mean age was 39.7 (SD 15.9) and 41.3 (16.8) in the CD and UC groups, respectively. Median time between suspected and confirmed diagnoses was 46 days in the CD group and 43 days in the UC group. Median time ranged from 8 to 112 days in the different gastroenterology practices and was significantly shorter in individuals with private health insurance coverage than in those with statutory health insurance. CONCLUSIONS: Median time between suspected and confirmed diagnoses of CD or UC was around 45 days in patients followed in gastroenterological practices in Germany. Health insurance was the only factor to have a significant impact on this time. PMID- 29721735 TI - Evaluation of anthocyanins in Aronia melanocarpa/BSA binding by spectroscopic studies. AB - The interaction between Anthocyanins in Aronia melanocarpa (AMA) and bovine serum albumin (BSA) were studied in this paper by multispectral technology, such as fluorescence quenching titration, circular dichroism (CD) spectroscopy and Fourier transform infrared spectroscopy (FTIR). The results of the fluorescence titration revealed that AMA could strongly quench the intrinsic fluorescence of BSA by static quenching. The apparent binding constants KSV and number of binding sites n of AMA with BSA were obtained by fluorescence quenching method. The thermodynamic parameters, enthalpy change (DeltaH) and entropy change (DeltaS), were calculated to be 18.45 kJ mol-1 > 0 and 149.72 J mol-1 K-1 > 0, respectively, which indicated that the interaction of AMA with BSA was driven mainly by hydrophobic forces. The binding process was a spontaneous process of Gibbs free energy change. Based on Forster's non-radiative energy transfer theory, the distance r between the donor (BSA) and the receptor (AMA) was calculated to be 3.88 nm. Their conformations were analyzed using infrared spectroscopy and CD. The results of multispectral technology showed that the binding of AMA to BSA induced the conformational change of BSA. PMID- 29721734 TI - Short-term outcomes and benefits of ERAS program in elderly patients undergoing colorectal surgery: a case-matched study compared to conventional care. AB - PURPOSE: The aim of the study was to evaluate the benefits of implementing Enhanced Recovery After Surgery (ERAS) protocols in elderly patients undergoing elective colorectal surgery. METHODS: A retrospective non-randomized cohort study was conducted from September 2012 to December 2016. We included patients >= 70 years undergoing elective colorectal surgery. Outcome measures, compliance with interventions, and postoperative complications of patients treated under ERAS were case-matched (based on gender, age, type of surgery, and the presence/absence of a temporal stoma) to a retrospective group of patients >= 70 years treated under conventional care. RESULTS: A total of 312 patients (156 ERAS vs. 156 non-ERAS) were included in the study. The ERAS group had a significant reduction of grade III/IV Dindo-Clavien's postoperative complications when compared with conventional care. ERAS had a positive effect in reducing anastomotic leakage (14.7% non-ERAS vs. 9%) and postoperative mortality (11.5% non-ERAS vs. 1.9% ERAS; p = 0.001). A reduction of 2 days in length of hospital stay was achieved after implementing ERAS (8 (6.75) vs. 6 (5.25); p < 0.0001), while readmission rates remained unaffected. The average of global compliance (GC) with all ERAS interventions was 42%. GC was significantly lower in patients with permanent/temporary stomas and in patients in whom an open approach was performed. CONCLUSION: In our experience, ERAS should be implemented without reservations in elderly patients expecting the same goals and benefits as with other age groups. Barriers in achieving a high compliance rate are common and will require a great effort in patient's education, an intensive perioperative care, and sometimes a change in the surgeons' practice. PMID- 29721736 TI - Patient and medication factors associated with preventable medication waste and possibilities for redispensing. AB - Background Knowledge on factors related to preventable medication waste and waste reducing interventions, including redispensing unused medications, is needed to maximise effectiveness. Objective To assess patient and medication factors associated with preventable medication waste and possibilities for redispensing unused medications. Setting Dutch community pharmacies. Methods In this cross sectional study, pharmacy-staff registered patient and medication characteristics of prescription medications returned to 41 Dutch community pharmacies during 1 week in 2014. Medications were classified as preventable waste if the remaining amount could have been prevented and as theoretically eligible for redispensing if the package was unopened, undamaged and >= 6 months until the expiry date. Associations were analysed using multivariate logistic regression. Main outcome measures Proportion of medications classified as preventable waste and as eligible for redispensing, including factors associated with these medications. Results Overall, 279 persons returned 759 (low-cost) medications, and 39.3% was classified as preventable waste. These medications were more frequently used by men than women (OR; 1.7[1.2-2.3]) and by older (> 65 years) than younger patients (OR; 1.4[1.0-2.0]). Medications dispensed for longer periods were more often unnecessary wasted (1-3 months OR; 1.8[1.1-3.0], > 3 months 3.2[1.5-6.9]). Of all returned medications, 19.1% was eligible for redispensing. These medications were more frequently used by men than women (OR; 1.9[1.3-2.9]). Medications chronically used were more frequently eligible for redispensing than acute use (OR; 2.1[1.0-4.3]), and used for longer periods (1-3 months OR; 4.6[2.3-8.9], > 3 months 7.8[3.3-18.5]). Conclusions Over one-third of waste due to medications returned to community pharmacies can be prevented. One-fifth of returned medications can be redispensed, but this seems less interesting from an economic viewpoint. PMID- 29721737 TI - Evaluation of community pharmacists' knowledge and awareness of food-drug interactions in Palestine. AB - Background Food-drug interactions can produce undesirable outcomes during the therapy process. The pharmacist is responsible for providing patients counseling about common food-drug interactions. Knowledge of such interactions is important to avoid their occurrence. Objective This study aimed to assess the knowledge and awareness of community pharmacists about common food-drug interactions. Setting Pharmacists working in community pharmacies across Northern Palestine. Method This is a cross-sectional study, which involved a convenience sample of 259 pharmacists working in community pharmacies in Palestine. A self-administered questionnaire consisted of 29 questions (mainly yes/no questions) was used to assess pharmacists' knowledge towards the most common and clinically significant interactions between food and medicines. Main outcome measure Pharmacists' issues related to the knowledge of food drug interactions were evaluated. Results A total of 320 questionnaires were distributed of which 259 were completed providing a response rate 80.9%. One pharmacist from each community pharmacy was asked to complete the questionnaire. The overall knowledge score of food-drug interactions for the pharmacists was 17.9 (61.7%) out of a possible maximum of 29. The pharmacists surveyed in this study have demonstrated good knowledge of some interactions; but poor knowledge of others. Conclusion Pharmacists' knowledge about common food-drug interactions is inadequate. These findings support the need for training and educational courses for pharmacists regarding food-drug interactions. PMID- 29721738 TI - Patient-pharmacist communication during a post-discharge pharmacist home visit. AB - Background With the shifting role of community pharmacists towards patient education and counselling, they are well-positioned to conduct a post-discharge home visit which could prevent or solve drug-related problems. Gaining insight into the communication during these home visits could be valuable for optimizing and consequently improving patient safety at readmission to primary care. Objective To assess patient-pharmacist communication during a post-discharge home visit. Setting The homes of patients recently discharged from a single general hospital in the Netherlands. Methods Pharmacists used a semi-structured protocol to guide the consultations and audiorecorded them. Sixty audio-recordings were included for a qualitative analysis in this study with the help of NVivo version 11 software. Main outcome measure (1) Initiator and topics under discussion. (2) Frequency of discussion of topics as per coded in themes and subthemes. Results Issues regarding the administration and use of medication, e.g. regimen and actual drug-taking issues, knowledge gaps regarding their medication and patients' health were discussed most frequently, followed by medication logistics and medication effectiveness. Patients' beliefs about their medication and adherence were less frequently discussed. The pharmacist initiated the majority of these topics. Additional non-protocolled topics were scarce and consisted mainly of patient-initiated dissatisfaction regarding the community pharmacy or health insurers. Conclusion Community pharmacists most frequently initiated practical issues, but explored patients' medication beliefs less adequately. Discussing these beliefs might be easier by increasing patient engagement in the consultation and providing training programs for pharmacists. PMID- 29721739 TI - Evaluation of a pharmacy-driven methicillin-resistant Staphylococcus aureus surveillance protocol in pneumonia. AB - Background Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of pneumonia and clinicians must determine when empiric antimicrobial therapy directed toward MRSA is needed. Objective To evaluate the effect of a pharmacy-driven protocol utilizing the nasal swab MRSA polymerase chain reaction (PCR) test to discontinue vancomycin on duration of vancomycin therapy and clinical outcomes in patients with suspected community-acquired pneumonia (CAP) or healthcare-associated pneumonia (HCAP). Setting A teaching hospital in Huntington, WV, USA. Methods This retrospective study included adult patients who received at least one dose of vancomycin for suspected CAP or HCAP. The pre intervention group consisted of patients prior to the addition of the nasal swab MRSA PCR test to the CAP/HCAP order set. The post-intervention group consisted of patients after the addition of the nasal swab MRSA PCR test to the CAP/HCAP order set. Main outcome measure The primary outcome was vancomycin hours of therapy. Results Of the 196 patients included in the study, 121 patients were in the pre intervention group and 75 patients were in the post-intervention group. The median duration of vancomycin therapy was significantly shorter in the post intervention group than the pre-intervention group (49 vs. 18 h, p < 0.001). There were no statistically significant differences in the secondary outcomes including hospital length of stay, 30-day readmission rate, and in-hospital all cause mortality. Conclusion The addition of a pharmacy-driven protocol utilizing the nasal swab MRSA PCR test was associated with shorter duration of empiric vancomycin therapy by approximately 31 h per patient without increasing adverse clinical outcomes. PMID- 29721740 TI - Off-label and unlicensed prescribing in Europe: implications for patients' informed consent and liability. AB - This article reviews the implications of off-label (OL) and unlicensed (UL) medicine use with respect to the legal duty to inform patients and the liability for failure to provide the patient with adequate information on benefits and risks. Informed consent is a legal prerequisite to any medical treatment and requires the physician to inform the patient about benefits and risks important for the patient's decision. Since OL/UL medicine use is common in all fields of medical practice, physicians must be aware of the stricter requirements for information of the patient. The UK High Supreme Court ruled in the case Montgomery v. Lanarkshire Health Board that physicians' information duty is not limited to the level of information that the physician finds important, but to what the patient deems important. In general, violations of the rule of informed consent does not constitute a physical injury, and patients can only claim compensation for damages, if adequate disclosure had been given, and its likely, that patients would have either rejected or opted for an alternative treatment. PMID- 29721743 TI - Aging Well on the Autism Spectrum: An Examination of the Dominant Model of Successful Aging. AB - There is a gap in our knowledge of aging with autism. The present study examined the applicability of the popular gerontology concept of "aging well" to autistic adults. Using survey data, a model of "aging well" was operationalised and applied to 92 autistic adults and 60 controls. A very small proportion (3.3%) of autistic adults were found to be aging well. Significantly less autistic adults were "maintaining physical and cognitive functioning" and "actively engaging with life" in comparison to controls. Whilst important differences in health and functioning status were found, the current dominant model of "aging well" is limited for examining autistic individuals. Suggested adjustments include development of a broader, more flexible and strengths -based model. PMID- 29721741 TI - Off-label and unlicensed drug use in hospitalized newborns in a Saudi tertiary care hospital: a cohort study. AB - Objective To determine the extent of off-label and unlicensed prescribing in hospitalized newborns and to identify patient-related risk factors associated with off-label prescribing. Methods A prospective cohort study was conducted between January and March 2016 at a neonatology department of a tertiary-care hospital in the Eastern province. All consecutive admissions to all neonatal care levels meeting the inclusion and exclusion criteria were eligible for enrollment. All prescriptions were classified as off-label or unlicensed according to drug product monograph. Clinical and prescription data were extracted using a pilot tested structured data collection sheet. Results During the study period 583 prescriptions were made for 138 newborns, of which 29.7% (173/583) and 12.9% (75/583) were classified as off-label and unlicensed drugs respectively for use in neonates. Thirty-four percent (47/138) of patients received at least one off label/unlicensed medicine. Mechanical ventilation, admission to the neonatal intensive care unit and length of hospital stay were identified as independent risk factors associated with prescribing of at least one off-label medication. Conclusion Use of off-label and unlicensed drugs in hospitalized newborns seems to be a common practice in this Saudi hospital. Future research should evaluate safety and efficacy of off-label and/or unlicensed use of drugs in neonates. PMID- 29721744 TI - Students with Autism Spectrum Disorder and Their Parents in the Transition into Higher Education: Impact on Dynamics in the Parent-Child Relationship. AB - This study examined how 34 senior students and first-year college students with autism spectrum disorder, their mothers (n = 34) and fathers (n = 26) navigate the higher education transition, and how this context impacts on dynamics in the parent-child relationships. Semi-structured interviews were analyzed based on grounded theory and dyadic analysis principles. Both parties were confronted with an abundance of challenges and experienced strong feelings of ambivalence, stress and anxiety. Differences in perspectives occurred regarding the construction of adulthood, the acquisition of autonomy, disclosure and subscribing to support services. These differences caused tensions in the parent-child relationship, hindering the transformation of the relationship into an adult-like mutual relationship. Clinical implications are extrapolated on the basis of these findings. PMID- 29721742 TI - Herbal medicine use among Type 2 diabetes mellitus patients in Nigeria: understanding the magnitude and predictors of use. AB - Background Patients with chronic diseases exploit complementary and alternative treatment options to manage their conditions better and improve well-being. Objective To determine the prevalence and predictors of herbal medicine use among Type 2 Diabetes patients in Lagos, Nigeria. Setting Secondary healthcare facilities in Lagos state, Nigeria. Method The study design was a cross sectional survey. A two-stage sampling approach was used to select the health facilities and patients were recruited consecutively to attain the sample size. Data was collected using a structured and standardized interviewer-administered questionnaire. Characteristics, prevalence and predictors of herbal medicine use were assessed using descriptive statistics and multivariate regression analyses. Main outcome measure Herbal medicine use among Type 2 diabetes mellitus patients. Results 453 patients were surveyed, 305 (67.3%) reported herbal medicine use, among whom 108 (35.4%) used herbal and conventional medicines concurrently; 206 (67.5%) did not disclose use to their physician. Herbal medicine use was significantly associated with age (p = 0.045), educational level (p = 0.044), occupation (p = 0.013), duration of diabetes disease (p = 0.007), mode of diabetes management (p = 0.02), a positive history of diabetes (p = 0.011) and presence of diabetes complication (p = 0.033). Formulations or whole herbs of Vernonia amygdalina, Moringa oleifera, Ocimum gratissimum, Picralima nitida, and herbal mixtures were the commonest herbal medicine. Beliefs and perceptions about herbal medicine varied between the users and non-users. Conclusion The use of herbal medicine among Type 2 diabetes mellitus patients in Lagos, Nigeria is high. There is dire need for health care practitioners to frequently probe patients for herbal medicine use and be aware of their health behaviour and choices, with a view to manage the disease better. PMID- 29721746 TI - Signal Propagation in Sensing and Reciprocating Cellular Systems with Spatial and Structural Heterogeneity. AB - Sensing and reciprocating cellular systems (SARs) are important for the operation of many biological systems. Production in interferon (IFN) SARs is achieved through activation of the Jak-Stat pathway, and downstream upregulation of IFN regulatory factor (IRF)-7 and IFN transcription, but the role that high- and low affinity IFNs play in this process remains unclear. We present a comparative between a minimal spatio-temporal partial differential equation model and a novel spatio-structural-temporal (SST) model for the consideration of receptor, binding, and metabolic aspects of SAR behaviour. Using the SST framework, we simulate single- and multi-cluster paradigms of IFN communication. Simulations reveal a cyclic process between the binding of IFN to the receptor, and the consequent increase in metabolism, decreasing the propensity for binding due to the internal feedback mechanism. One observes the effect of heterogeneity between cellular clusters, allowing them to individualise and increase local production, and within clusters, where we observe 'subpopular quiescence'; a process whereby intra-cluster subpopulations reduce their binding and metabolism such that other such subpopulations may augment their production. Finally, we observe the ability for low-affinity IFN to communicate a long range signal, where high affinity cannot, and the breakdown of this relationship through the introduction of cell motility. Biological systems may utilise cell motility where environments are unrestrictive and may use fixed system, with low-affinity communication, where a localised response is desirable. PMID- 29721745 TI - Hemoglobin level and XRCC1 polymorphisms to select patients with locally advanced rectal cancer candidate for neoadjuvant chemoradiotherapy with concurrent capecitabine and a platinum salt. AB - A platinum salt (oxaliplatin or cisplatin) is widely used to enhance chemoradation (CRT) response. The potential of cisplatin in neoadjuvant CRT for locally advanced rectal cancer (LARC) has not been fully investigated. Consecutive patients with histologically confirmed LARC were treated with standard pelvic radiotherapy and concurrent cisplatin plus capecitabine (CisCape CRT). Surgery and eight cycles of adjuvant FOLFOX4 were offered to all patients after CRT. Common biochemical variables and key germline genetic polymorphisms were analyzed as predictors of pathological complete response (pCR). Fifty-one patients were enrolled. pCR (regression AJCC grade 0) was documented in 7 patients (14%), nearly complete response (AJCC grade 1) in 10 pts. There was a strong association between disease-free survival and AJCC grade (p 0.0047). Grade 3-4 toxicities (mainly diarrhea) was observed in 41% of patients. Among all analyzed variables, baseline hemoglobin (Hb) was significantly associated with AJCC grade 0-1 response (p 0.027). As for the pharmacogenetic analysis, XRCC1 rs25487 polymorphism was significantly associated with AJCC grade 0-1, Odds Ratio 25.8, p 0.049. AJCC grade 0-1 response rate for patients with high Hb and/or XRCC1 rs25487 G/G genotype was as high as 57%. Baseline Hb and XRCC1 polymorphisms are valuable selection criteria for the CisCape CRT regimen, given its otherwise meaningful toxicity. PMID- 29721747 TI - Causal null hypotheses of sustained treatment strategies: What can be tested with an instrumental variable? AB - Sometimes instrumental variable methods are used to test whether a causal effect is null rather than to estimate the magnitude of a causal effect. However, when instrumental variable methods are applied to time-varying exposures, as in many Mendelian randomization studies, it is unclear what causal null hypothesis is tested. Here, we consider different versions of causal null hypotheses for time varying exposures, show that the instrumental variable conditions alone are insufficient to test some of them, and describe additional assumptions that can be made to test a wider range of causal null hypotheses, including both sharp and average causal null hypotheses. Implications for interpretation and reporting of instrumental variable results are discussed. PMID- 29721748 TI - Oncological outcomes of robotic-assisted laparoscopic versus open lateral lymph node dissection for locally advanced low rectal cancer. AB - BACKGROUND: The long-term outcomes of robotic-assisted laparoscopic lateral lymph node dissection (RALLD) have not been fully investigated. This study aimed to assess the oncological and long-term outcomes of RALLD for rectal cancer through comparison with those of open lateral lymph node dissection (OLLD) in a retrospective study. METHODS: Between September 2002 and October 2014, the medical data of 426 patients who underwent total mesorectal excision with lateral lymph node dissection for primary rectal cancer were collected. Of these, 115 patients were excluded after data collection (stage IV, n = 61; total pelvic exenteration, n = 31; multiple cancer, n = 20; conventional laparoscopic surgery, n = 3). Before matching, 311 patients with clinical stage II/III were analyzed. Using exact matching, patients were stratified into RALLD (n = 78) and OLLD (n = 78) groups. Pathological findings and long-term outcomes were compared between the groups. RESULTS: The pathological stage and number of harvested lymph nodes showed no significant differences between the groups. The rate of positive resection margin in the RALLD group tended to be lower compared with that of the OLLD group (p = 0.059). The median follow-up duration was 54.0 months in 156 patients. The 5-year overall survival rate was 95.4 and 87.8% in the RALLD and OLLD groups, respectively (p = 0.106). The 5-year relapse-free survival rate was 79.1 and 69.9% in the RALLD and OLLD groups, respectively (p = 0.157). The 5-year local relapse-free survival rate was 98.6 and 90.9% in the RALLD and OLLD groups, respectively (p = 0.029). CONCLUSIONS: The short- and long-term outcomes indicated that RALLD may be a useful modality for locally advanced low rectal cancer. PMID- 29721750 TI - Mechanism for the depolymerization of cellulose under alkaline conditions. AB - The mechanism for the hydroxyl-radical-induced depolymerization of cellulose under alkaline conditions in air was investigated using density functional theory at the B3LYP/6-31+G(d,p) level as well as electron transfer theory. The pathway for the depolymerization of cellulose was obtained theoretically and H abstraction from the C(3) atom of the pyran ring during the cleavage of the glucosidic bond was found to be the rate-limiting step due to its high energy barrier (16.81 kcal/mol) and low reaction rate constant (4.623 * 104 mol L-1 s 1). Calculations of the electron transfer between O2 and the saccharide radical performed with the HARLEM software package revealed that following the H abstraction, the oxygen molecule approaches C(2) on the saccharide radical and obtains an electron from the radical, even though no bond forms between the oxygen molecule and the radical. The rate constant for electron transfer could be as high as 1.572 * 1011 s-1. Furthermore, an enol intermediate is obtained during the final stage of the depolymerization. PMID- 29721752 TI - Prediction of survival in patients affected by glioblastoma: histogram analysis of perfusion MRI. AB - PURPOSE: The identification of prognostic biomarkers plays a pivotal role in the management of glioblastoma. The aim of this study was to assess the role of magnetic resonance dynamic susceptibility contrast imaging (DSC-MRI) with histogram analysis in the prognostic evaluation of patients suffering from glioblastoma. MATERIALS AND METHODS: Sixty-eight patients with newly diagnosed pathologically verified GBM were retrospectively evaluated. All patients underwent MRI investigations, including DSC-MRI, surgical procedure and received postoperative focal radiotherapy plus daily temozolomide (TMZ), followed by adjuvant TMZ therapy. Relative cerebral blood volume (rCBV) histograms were generated from a volume of interest covering the solid portions of the tumor and statistically evaluated for kurtosis, skewness, mean, median and maximum value of rCBV. To verify if histogram parameters could predict survival at 1 and 2 years, receiver operating characteristic (ROC) curves were obtained. Kaplan-Meier method was used to calculate patient's overall survival. RESULTS: rCBV kurtosis and rCBV skewness showed significant differences between subjects surviving > 1 and > 2 years, According to ROC analysis, the rCBV kurtosis showed the best statistic performance compared to the other parameters; respectively, values of 1 and 2.45 represented an optimised cut-off point to distinguish subjects surviving over 1 or 2 years. Kaplan-Meier curves showed a significant difference between subjects with rCBV kurtosis values higher or lower than 1 (respectively 1021 and 576 days; Log-rank test: p = 0.007), and between subjects with rCBV kurtosis values higher or lower than 2.45 (respectively 802 and 408 days; Log-rank test: p = 0.001). CONCLUSION: The histogram analysis of perfusion MRI proved to be a valid method to predict survival in patients affected by glioblastoma. PMID- 29721753 TI - Leisure-time physical activity among adolescents and subsequent use of antidepressant and hypnotic drugs: a prospective register linkage study. AB - In this prospective study, the association between physical activity and subsequent use of antidepressant and hypnotic drug use in adolescents aged 15-16 years was examined. This study is based on information retrieved from the Norwegian Youth Health Surveys (2000-2003) and linked to prescription data from the Norwegian Prescription Database (2004-2013). In total, the study included 10711 participants with a participation rate of 87%. Adolescents were asked how many hours per week they spent on physical activity that made them sweat and/or be out of breath outside of school. Incident psychotropic drug use (outcome measure) was defined as >= 1 prescription of one of the following psychotropic drugs: hypnotics and antidepressants registered in the Norwegian Prescription Database. In the crude model for the time period 2004-2007, the odds of incident hypnotic use were lower for those who were physically active 1-2 h per week (OR 0.48-0.64), compared to those who were physically inactive (< 1 h per week). However, the association become non-significant 4-year post-baseline (2008-2010 and 2011-2013). In the crude model for the time periods 2004-2007, 2008-2010 and 2011-2013, the odds of incident antidepressant use were lower for physically active adolescents (2004-2007: OR 0.46-0.71, 2008-2010: OR 0.40-0.67 and 2011 2013: OR 0.37-0.58, compared to those who were physically inactive < 1 h. However, after adjustment for confounders, the association became non-significant in all time periods except in physical activity 5-7 and 8-10 h in the period 2008 2010. Physical activity does not indicate any association with later use of antidepressants, and the significant association with incident hypnotic drug use was for short-term follow-up only and disappeared on longer term follow-up periods. Given the scarcity of longitudinal studies examining the association between physical activity and mental health as well as psychotropic drug use among young people, the current study adds to previous research. PMID- 29721749 TI - A scoping review of assessment tools for laparoscopic suturing. AB - BACKGROUND: A needs assessment identified a gap in teaching and assessment of laparoscopic suturing (LS) skills. The purpose of this review is to identify assessment tools that were used to assess LS skills, to evaluate validity evidence available, and to provide guidance for selecting the right assessment tool for specific assessment conditions. METHODS: Bibliographic databases were searched till April 2017. Full-text articles were included if they reported on assessment tools used in the operating room/simulation to (1) assess procedures that require LS or (2) specifically assess LS skills. RESULTS: Forty-two tools were identified, of which 26 were used for assessing LS skills specifically and 26 for procedures that require LS. Tools had the most evidence in internal structure and relationship to other variables, and least in consequences. CONCLUSION: Through identification and evaluation of assessment tools, the results of this review could be used as a guideline when implementing assessment tools into training programs. PMID- 29721751 TI - The influence of preoperative dependency on mortality, functional recovery and complications after microsurgical resection of intracranial tumors. AB - INTRODUCTION: The decision whether to operate on patients with intracranial tumors is complex and influenced by patient-specific factors, including the preoperative functional status. This work assesses the risks for mortality and complications, and post-operative recovery in functionally dependent patients undergoing microsurgical resection of intracranial tumors. METHODS: Observational two-center study, analyzing institutional registry data. Dependency was defined as admission Karnofsky Performance Scale (KPS) of <= 50. The primary endpoint was in-hospital mortality. Secondary endpoints were rate and type [Clavien-Dindo grade (CDG)] of complications, as well as postoperative change in KPS until the 3 month follow-up (M3). RESULTS: Of n = 1951 patients, n = 98 (5.0%) were dependent. Mortality rates were 2.0% for dependent and 0.4% for independent patients (p = 0.018). In univariable analysis, dependent patients were more likely than independent patients to die in hospital (OR 5.49, 95% CI 1.12-26.8, p = 0.035). In a multivariable model, the effect was slightly attenuated (OR 4.75, 95% CI 0.91-24.7, p = 0.064). Dependent patients tended to experience more postoperative complications. They were more likely to suffer from a severe complication (CDG 4 and 5; OR 3.55, 95% CI 1.49-8.46, p = 0.004). In 40.8 and 52.4% of cases, dependent patients regained functional independence at discharge and M3, respectively. CONCLUSIONS: In operated patients with intracranial tumors presenting functionally dependent at admission, the risk for in-hospital mortality and complications is elevated. However, if conducted successfully, surgery may lead to regain of independence in every second patient within 3 months. PMID- 29721755 TI - Human acute myeloid leukemia cells express Neurokinin-1 receptor, which is involved in the antileukemic effect of Neurokinin-1 receptor antagonists. AB - The substance P/neurokinin-1 receptor system has been implicated in tumor cell proliferation. Neurokinin-1 receptor has been identified in different solid tumors but not frequently in hematopoietic malignant cells. We investigated the presence of the Neurokinin-1 receptor in acute myeloid leukemia cell lines (KG-1 and HL-60), demonstrating that acute myeloid leukemia cell lines overexpress the truncated Neurokinin-1 receptor isoform compared with lymphocytes from healthy donors. Using the MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2 (4-sulfophenyl)-2H-tetrazolium) method, we demonstrated that substance P induced cell proliferation in both acute myeloid leukemia cell lines. We also observed that four different Neurokinin-1 receptor antagonists (L-733,060, L-732,138, CP 96-345 and aprepitant) elicited inhibition of acute myeloid leukemia cell growth lines in a concentration-dependent manner, while growth inhibition was only marginal in lymphocytes; the specific antitumor action of Neurokinin-1 receptor antagonists occurs via the Neurokinin-1 receptor, and leukemia cell death is due to apoptosis. Finally, administration of high doses of daily intraperitoneal fosaprepitant to NOD scid gamma mice previously xenografted with the HL60 cell line increased the median survival from 4 days (control group) to 7 days (treated group) (p = 0.059). Taken together, these findings suggest that Neurokinin-1 receptor antagonists suppress leukemic cell growth and may be considered to be potential antitumor drugs for the treatment of human acute myeloid leukemia. PMID- 29721754 TI - Effects of three-dimensional spheroid culture on equine mesenchymal stem cell plasticity. AB - Mesenchymal stem cells (MSCs) are useful candidates for tissue engineering and cell therapy fields. We optimize culture conditions of equine adipose tissue derived MSCs (eAD-MSCs) for treatment of horse fractures. To investigate enhancing properties of three-dimensional (3D) culture system in eAD-MSCs, we performed various sized spheroid formation and determined changes in gene expression levels to obtain different sized spheroid for cell therapy. eAD-MSCs were successfully isolated from horse tailhead. Using hanging drop method, spheroid formation was generated for three days. Quantitative real-time PCR was performed to analyze gene expression. As results, expression levels of pluripotent markers were increased depending on spheroid size and the production of PGE2 was increased in spheroid formation compared to that in monolayer. Ki-67 showed a remarkable increase in the spheroid formed with 2.0 * 105 cells/drop as compared to that in the monolayer. Expression levels of angiogenesis-inducing factors such as VEGF, IL-6, IL-8, and IL-18 were significantly increased in spheroid formation compared to those in the monolayer. Expression levels of bone morphogenesis-inducing factors such as Cox-2 and TGF-beta1 were also significantly increased in spheroid formation compared to those in the monolayer. Expression levels of osteocyte-specific markers such as RUNX2, osteocalcin, and differentiation potential were also significantly increased in spheroid formation compared to those in the monolayer. Therefore, spheroid formation of eAD-MSCs through the hanging drop method can increases the expression of angiogenesis inducing and bone morphogenesis-inducing factors under optimal culture conditions. PMID- 29721756 TI - Successful oral desensitization with osimertinib following osimertinib-induced fever and hepatotoxicity: a case report. AB - Osimertinib is a standard second-line therapy for patients who develop EGFR Thr790Met resistance mutation after treatment with first-line epidermal growth factor receptor tyrosine kinase inhibitors. Although no other effective targeted treatment option exists for these patients, osimertinib might be permanently discontinued owing to the onset of severe drug-induced toxicities like hepatotoxicity. Herein, we report a case of successful oral desensitization with osimertinib after the patient developed osimertinib-induced fever and hepatotoxicity. In the present case report, a 62-year-old Japanese woman received osimertinib as the sixth-line therapy for non-small cell lung carcinoma harboring EGFR Thr790Met-mutation. After 15 days of treatment, she developed general malaise. Although we reduced the drug at a lower dose, she again presented with high fever and elevated serum AST/ALT levels three days after re-initiating treatment. We then attempted oral desensitization with osimertinib over a two week period. Thereafter, the patient continued osimertinib treatment for 6 months without the recurrence of side effects. In conclusion, oral desensitization may be a useful method in treating hepatotoxicity and drug fever caused by osimertinib. PMID- 29721758 TI - A checklist of the ticks (Acari: Argasidae, Ixodidae) of Japan. AB - Ticks significantly affect the health of humans and animals in Japan. However, no complete checklist has been produced for the Japanese tick fauna in English, and even recent checklists in Japanese do not include all presently known tick species found on the Japanese islands. Here, a complete species list of all tick taxa known to occur within Japan is presented. The status of several controversial Japanese tick species is also discussed. PMID- 29721757 TI - NMR 1H,13C, 15N backbone and 13C side chain resonance assignment of the G12C mutant of human K-Ras bound to GDP. AB - K-Ras is a key driver of oncogenesis, accounting for approximately 80% of Ras driven human cancers. The small GTPase cycles between an inactive, GDP-bound and an active, GTP-bound state, regulated by guanine nucleotide exchange factors and GTPase activating proteins, respectively. Activated K-Ras regulates cell proliferation, differentiation and survival by signaling through several effector pathways, including Raf-MAPK. Oncogenic mutations that impair the GTPase activity of K-Ras result in a hyperactivated state, leading to uncontrolled cellular proliferation and tumorogenesis. A cysteine mutation at glycine 12 is commonly found in K-Ras associated cancers, and has become a recent focus for therapeutic intervention. We report here 1HN, 15N, and 13C resonance assignments for the 19.3 kDa (aa 1-169) human K-Ras protein harboring an oncogenic G12C mutation in the GDP-bound form (K-RASG12C-GDP), using heteronuclear, multidimensional NMR spectroscopy. Backbone 1H-15N correlations have been assigned for all non-proline residues, except for the first methionine residue. PMID- 29721759 TI - The fossil record and the origin of ticks revisited. AB - The fossil record of ticks has been classically used to discern the probable vicariance events of these arthropods, and to date the split moments of the different lineages. Although new techniques based on molecular clock methods are already available, tick fossil record still stands as a valuable source of information if correctly interpreted. Here we report about a male specimen of Ornithodoros (Alectorobius) sp. found in Dominican amber of about 25 millions years, illustrating its main morphological features. We also discuss the findings in a recent paper, which may contain unreliable interpretations on some fossil ticks. We support previous data on the presence of Argasidae in Miocene Dominican amber, and provide comments on the presence of ticks in Burmese amber. We further elaborate on the spread of ticks in the light of the record and description of a new family found in Cretaceous amber. PMID- 29721760 TI - Diagnosis and Management of Presacral (Retrorectal) Tumors. PMID- 29721761 TI - A Cross-Sectional Study Assessing the Contributions of Body Fat Mass and Fat-Free Mass to Body Mass Index Scores in Male Youth Rugby Players. AB - BACKGROUND: In some sports such as rugby, a large body size is an advantage, and the desire to gain weight can bring young players to become overweight or obese. The aim of this study was to evaluate the prevalence of overweight and obesity and the contribution of body fat mass index (BFMI) and fat-free mass index (FFMI) to body mass index (BMI) changes among young male rugby players (15-a-side rugby). METHODS: The criteria of the International Obesity Task Force were used to define overweight and obesity from BMI. The method of skinfold thickness was used to assess percentage of body fat (%BF), BFMI, and FFMI. Excess body fat was defined by using BFMI and %BF above the 75th percentile. Data were grouped according to the age categories of the French Rugby Federation (U11, under 11 years; U13, under 13 years; U15, under 15 years) and to BMI status (NW normal weight versus OW/OB overweight/obese). RESULTS: Overall, 32.8% of the young players were overweight, and 13.8% were obese. However, 53% of young players classified as obese and overweight by BMI had an excess body fat by using BFMI above the 75th percentile. FFMI increased significantly between U11 and U13 in both groups, without significant change in BMI and BFMI. Both groups had similar significant gains in BMI and FFMI between U13 and U15, while BFMI only increased significantly in OW/OB (+ 18.5%). The strong correlations between BMI and %BF were systematically lower than those between BMI and BFMI. FFMI was strongly or moderately associated with BFMI. CONCLUSIONS: Chart analysis of BFMI and FFMI could be used to distinguish changes in body composition across age categories in young male rugby players classified as normal-weight, overweight, and obese by BMI. PMID- 29721762 TI - Effects of Diet on Bile Acid Metabolism and Insulin Resistance in Type 2 Diabetic Rats after Roux-en-Y Gastric Bypass. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) is effective for the treatment of type 2 diabetes mellitus; however, the mechanism remains unclear. METHODS: The effects of RYGB on postprandial responses to three different diets (low carbohydrate (CH)-rich diet, high CH-rich diet, and fat-rich diet) of different nutritional composition in a Goto-Kakizaki (GK) diabetic rat model were assessed by measuring glucose tolerance, insulin resistance, incretin responses, and bile acid (BA) metabolism. RESULTS: GK-RYGB group rats lost weight and preferred low CH-rich diet, but there were no significant differences in BW among the different diets. Glucose tolerance and insulin resistance were improved in rats who underwent RYGB, together with higher levels of circulating BAs, plasma GLP-1, and PYY levels. GK-RYGB rats fed high CH-rich or fat-rich diet showed increased glucose level and insulin resistance, together with high plasma BA, GIP, and PYY levels compared to those fed a low CH-rich diet. CONCLUSION: RYGB improves glucose tolerance and insulin resistance which may be related to BA metabolism and hormone levels, and the nutrient composition of the diet affects the treatment effect of RYGB on T2DM. PMID- 29721763 TI - Optimization of a closed rat tibial fracture model. AB - BACKGROUND: The use of a closed fracture model has become the preferred model to study the fracture healing process, given that the periosteum and the soft tissue surrounding the fracture site play an important role in the fracture healing process. Some techniques like osteotomy, drilling the long bones and the use of the guillotine-like apparatus to induce fracture are characterized by some undesirable effects and complications. The aim of this study is to optimize and evaluate an in vivo fracture model using three-point bending pliers that can be used to study secondary bone fracture healing in rats. METHODS: Modified three point bending pliers were used as a device to create the closed rat tibial bone fracture that was prefixed with an intramedullary pin (23 G * 11/2") in rats. The exact location of the induced closed fracture was along the long bone. The presence of bone comminution, and the fracture bone alignment were immediately examined after the induction of the fracture until the 6th week. RESULTS: All fractures induced were transverse, located in the middle to proximal one third of the tibia, and they all healed without complications. Bone union as shown radiographically occurred within 2-3 weeks postoperative. The average angle of the fracture line with the axis of the tibia was 89.41 +/- 2.11 degrees . The lateral and anterio-posterior pin angulation views were 167.33 +/- 3.67 degrees and 161.60 +/- 4.87 degrees respectively. The average length of proximal end of the fractured bone in comparison with the whole length of intact bone was 41.02 +/- 3.27%. There was a significant difference in percentage of the gross callus area and gross callus index, while there was no significant difference in X-ray callus index. There was no significant difference of the gross callus area between slight comminution (n = 4) and non comminution (n = 21). CONCLUSION: The optimized rat tibial fracture model resulted in mainly transverse tibial mid shaft fractures with minimal bone comminution and absence of surrounding soft tissue damage. The size area of consequent soft callus formation and the extent to which the closed fracture model was reproducible are very good outcomes making it feasible for in vivo laboratory research use. PMID- 29721764 TI - 18-FDG-PET in a patient cohort suspected for cardiac sarcoidosis: Right ventricular uptake is associated with pathological uptake in mediastinal lymph nodes. AB - INTRODUCTION: In up to 65% of cardiac sarcoidosis patients, the disease is confined to the heart. Diagnosing isolated cardiac sarcoidosis is challenging due to the low sensitivity of endomyocardial biopsy. If cardiac sarcoidosis is part of biopsy-confirmed systemic sarcoidosis, the diagnosis can be based on cardiac imaging studies. We compared the imaging features of patients with isolated cardiac FDG uptake on positron emission tomography with those who had findings indicative of systemic sarcoidosis. MATERIALS AND METHODS: 137 consecutive cardiac FDG-PET/CT studies performed on subjects suspected of having cardiac sarcoidosis were retrospectively analyzed. RESULTS: 33 patients had pathological left ventricular FDG uptake, and 12 of these also had pathological right ventricular uptake. 16/33 patients with pathological cardiac uptake had pathological extracardiac uptake. 10/12 patients with both LV- and RV-uptake patterns had extracardiac uptake compared to 6/21 of those with pathological LV uptake without RV uptake. SUVmax values in the myocardium were higher among patients with abnormal extracardiac uptake. The presence of extracardiac uptake was the only imaging-related factor that could predict a biopsy indicative of sarcoidosis. CONCLUSION: Right ventricular involvement seems to be more common in patients who also have findings suggestive of suspected systemic sarcoidosis, compared with patients with PET findings indicative of isolated cardiac disease. PMID- 29721765 TI - A survey of perceptions, attitudes, knowledge and practices of medical oncologists about cancer pain management in Spain. AB - PURPOSE: To monitor oncologists' perspective on cancer pain management. METHODS: An anonymized survey was conducted in two waves. First, over a convenience sample of oncologists known to be particularly concerned with the management of pain. Second, using a random sample of oncologists. RESULTS: In total, 73 and 82 oncologists participated in the first and second wave, respectively. Many oncologists reported to have good knowledge of analgesic drugs (95.9%), the mechanism of action of opioids (79.5%), and good skills to manage opioid-related bowel dysfunction (76.7%). Appropriate adjustment of background medication to manage breakthrough pain was reported by 95.5% of oncologists. Additionally, 87.7% (68.3% in the second wave, p = 0.035) of oncologists reported suitable opioid titration practices, and 90.4% reported to use co-adjuvant medications for neuropathic pain confidently. On the other hand, just 9.6% of oncologists participated in multidisciplinary pain management teams, and merely 30.3 and 27.1% reported to routinely collaborate with the Pain Clinics or involve other staff, respectively. Only 26.4% of the oncologists of the second wave gave priority to pain pathophysiology to decide therapies, and up to 75.6% reported difficulties in treating neuropathic pain. Significantly less oncologists of the second wave (82.9 vs. 94.5%, p = 0.001) used opioid rotation routinely. CONCLUSIONS: Unlike in previous surveys, medical oncologists reported in general good knowledge and few perceived limitations and barriers for pain management. However, multi-disciplinary management and collaboration with other specialists are still uncommon. Oncologists' commitment to optimize pain management seems important to improve and maintain good practices. PMID- 29721766 TI - Radiotherapy volume delineation using 18F-FDG-PET/CT modifies gross node volume in patients with oesophageal cancer. AB - PURPOSE: Evidence supporting the use of 18F-FDG-PET/CT in the segmentation process of oesophageal cancer for radiotherapy planning is limited. Our aim was to compare the volumes and tumour lengths defined by fused PET/CT vs. CT simulation. MATERIALS AND METHODS: Twenty-nine patients were analyzed. All patients underwent a single PET/CT simulation scan. Two separate GTVs were defined: one based on CT data alone and another based on fused PET/CT data. Volume sizes for both data sets were compared and the spatial overlap was assessed by the Dice similarity coefficient (DSC). RESULTS: The gross tumour volume (GTVtumour) and maximum tumour diameter were greater by PET/CT, and length of primary tumour was greater by CT, but differences were not statistically significant. However, the gross node volume (GTVnode) was significantly greater by PET/CT. The DSC analysis showed excellent agreement for GTVtumour, 0.72, but was very low for GTVnode, 0.25. CONCLUSIONS: Our study shows that the volume definition by PET/CT and CT data differs. CT simulation, without taking into account PET/CT information, might leave cancer-involved nodes out of the radiotherapy-delineated volumes. PMID- 29721767 TI - Effect of Sodium Thiosulfate Postconditioning on Ischemia-Reperfusion Injury Induced Mitochondrial Dysfunction in Rat Heart. AB - The recent research on the therapeutic applications of sodium thiosulfate (STS) has gained importance in the treatment of cardiovascular diseases. Progressively through the present work, we have demonstrated that postconditioning of isolated rat heart subjected to ischemia-reperfusion injury using STS had preserved the mitochondrial structure, function, and number. Heart comprising of two mitochondrial subpopulations interfibrillar (IFM-involved in contractile function) and subsarcolemmal (SSM-involved in metabolic function), STS postconditioning imparted a state of hypometabolism to SSM, thereby reducing the metabolic demand of the reperfused heart. The IFM, on the other hand, provided the energy required to maintain contraction. Moreover, the hypometabolic state induced in SSM can lower the free radical release in addition to STS innate ability to act as an antioxidant and radical scavenger, all of which collectively provided cardioprotection. Therefore, drugs targeting IFM specifically or those reducing the energy demand for SSM can be suitable targets for myocardial ischemia-reperfusion injury. PMID- 29721768 TI - Altered resting state functional connectivity of the cognitive control network in fibromyalgia and the modulation effect of mind-body intervention. AB - This study examines altered resting state functional connectivity (rsFC) of the cognitive control network (CCN) in fibromyalgia patients as compared to healthy controls, as well as how an effective mind-body intervention, Tai Chi, can modulate the altered rsFC of the CCN. Patients with fibromyalgia and matched healthy subjects were recruited in this study. Fibromyalgia patients were scanned 12 weeks before and after intervention. The bilateral dorsolateral prefrontal cortex (DLPFC) was used as a seed to explore the rsFC of the CCN. Data analysis was conducted with 21 patients and 20 healthy subjects. Compared to healthy subjects, fibromyalgia patients exhibited increased rsFC between the DLPFC and the bilateral rostral anterior cingulate cortex (rACC) and medial prefrontal cortex (MPFC) at baseline. The rsFC between the CCN and rACC/MPFC further increased after Tai Chi intervention, and this increase was accompanied by clinical improvements. This rsFC change was also significantly associated with corresponding changes in the Overall Impact domain of the Revised Fibromyalgia Impact Questionnaire (FIQR). Further analysis showed that the rACC/MPFC rsFC with both the PAG and hippocampus significantly decreased following Tai Chi intervention. Our study suggests that fibromyalgia is associated with altered CCN rsFC and that effective mind-body treatment may elicit clinical improvements by further increasing this altered rsFC. Elucidating this mechanism of enhancing the allostasis process will deepen our understanding of the mechanisms underlying mind-body interventions in fibromyalgia patients and facilitate the development of new pain management methods. PMID- 29721769 TI - Characterization of the complex between native and reduced bovine serum albumin with aquacobalamin and evidence of dual tetrapyrrole binding. AB - Serum albumin binds to a variety of endogenous ligands and drugs. Human serum albumin (HSA) binds to heme via hydrophobic interactions and axial coordination of the iron center by protein residue Tyr161. Human serum albumin binds to another tetrapyrrole, cobalamin (Cbl), but the structural and functional properties of this complex are poorly understood. Herein, we investigate the reaction between aquacobalamin (H2OCbl) and bovine serum albumin (BSA, the bovine counterpart of HSA) using Ultraviolet-Visible and fluorescent spectroscopy, and electron paramagnetic resonance. The reaction between H2OCbl and BSA led to the formation of a BSA-Cbl(III) complex consistent with N-axial ligation (amino). Prior to the formation of this complex, the reactants participate in an additional binding event that has been examined by fluorescence spectroscopy. Binding of BSA to Cbl(III) reduced complex formation between the bound cobalamin and free cyanide to form cyanocobalamin (CNCbl), suggesting that the beta-axial position of the cobalamin may be occupied by an amino acid residue from the protein. Reaction of BSA containing reduced disulfide bonds with H2OCbl produces cob(II)alamin and disulfide with intermediate formation of thiolate Cbl(III)-BSA complex and its decomposition. Finally, in vitro studies showed that cobalamin binds to BSA only in the presence of an excess of protein, which is in contrast to heme binding to BSA that involves a 1:1 stoichiometry. In vitro formation of BSA-Cbl(III) complex does not preclude subsequent heme binding, which occurs without displacement of H2OCbl bound to BSA. These data suggest that the two tetrapyrroles interact with BSA in different binding pockets. PMID- 29721770 TI - Selenoprotein S inhibits inflammation-induced vascular smooth muscle cell calcification. AB - Vascular calcification is a prominent feature of many diseases including atherosclerotic cardiovascular disease (CVD), leading to high morbidity and mortality rates. A significant association of selenoprotein S (SelS) gene polymorphism with atherosclerotic CVD has been reported in epidemiologic studies, but the underlying mechanism is far from clear. To investigate the role of SelS in inflammation-induced vascular calcification, osteoblastic differentiation and calcification of vascular smooth muscle cells (VSMCs) induced by lipopolysaccharide (LPS) or tumor necrosis factor (TNF)-alpha were compared between the cells with and without SelS knockdown. LPS or TNF-alpha induced osteoblastic differentiation and calcification of VSMCs, as showed by the increases of runt-related transcription factor 2 (Runx2) protein levels, Runx2 and type I collagen mRNA levels, alkaline phosphatase activity, and calcium deposition content. These changes were aggravated when SelS was knocked down by small interfering RNA. Moreover, LPS activated both classical and alternative pathways of nuclear factor-kappaB (NF-kappaB) signaling in calcifying VSMCs, which were further enhanced under SelS knockdown condition. SelS knockdown also exacerbated LPS-induced increases of proinflammatory cytokines TNF-alpha and interleukin-6 expression, as well as increases of endoplasmic reticulum (ER) stress markers glucose-regulated protein 78 and inositol-requiring enzyme 1alpha expression in calcifying VSMCs. In conclusion, the present study suggested that SelS might inhibit inflammation-induced VSMC calcification probably by suppressing activation of NF-kappaB signaling pathways and ER stress. Our findings provide new understanding of the role of SelS in vascular calcification, which will be potentially beneficial to the prevention of atherosclerotic CVD. PMID- 29721771 TI - Oxidative stress stimulates invasive potential in rat C6 and human U-87 MG glioblastoma cells via activation and cross-talk between PKM2, ENPP2 and APE1 enzymes. AB - Maintaining genomic integrity is essential for cell survival and viability. Reactive oxygen species (ROS) overproduction results in oxidative stress leading to the genomic instability via generation of small base lesions in DNA and these unrepaired DNA damages lead to various cellular consequences including cancer. Recent data support the concept "oxidative stress is an indispensable participant in fostering proliferation, survival, and migration" in various cancer cell types including glioblastoma cells. In this study we demonstrate that treatment of non cytotoxic doses of oxidants such as amyloid beta [Abeta(25-35)] peptide, glucose oxidase (GO), and hydrogen peroxide (H2O2) for 24 h and 48 h time points found to increase the expression level and activity of a multifunctional enzyme Apurinic/apyrimidinic endonuclease (APE1), a key enzyme of base excision repair (BER) pathway which takes care of base damages; and also resulted in modulation in the expression levels of downstream BER-pathway enzymes viz. PARP-1, XRCC1, DNA polbeta, and ligase IIIalpha was observed upon oxidative stress in C6 and U 87 MG cells. Oxidants treatment to the C6 and U-87 MG cells also resulted in an elevation in the intracellular expression of glycolytic pathway enzyme Pyruvate kinase M2 (PKM2) and the metastasis inducer protein Ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2) as analyzed using Western blotting and Immunofluorescence microscopic studies. Our study also reports that oxidative stress induced for 24 h and 48 h in C6 and U-87 MG cells resulted in extracellular secretion of APE1 and ENPP2 as analyzed using Western blotting in conditioned media. However, the biological significance of extracellular secreted APE1 remains elusive. Oxidative stress also elevated the ENPP2's LysoPLD activity in conditioned media of C6 and U-87 MG cells. Our results also demonstrate that oxidative stress affects the expression level and localization of APE1, PKM2, and ENPP2 in C6 and U-87 MG cells. As evidenced by the colocalization pattern at 24 h and 48 h time points, it can be attributed that oxidative stress mediates crosstalk between APE1, PKM2, and ENPP2. In addition, when C6 and U-87 MG cells were treated with lysophosphatidic acid (LPA), a bioactive lipid that negatively regulates ENPP2's LysoPLD activity at 10 MUM concentration, demonstrated strong migratory potential in C6 and U-87 MG cells, and also induced migration upon oxidative stress. Altogether, the findings demonstrate the potential of C6 and U 87 MG cells to utilize three proteins viz. APE1, PKM2, and ENPP2 towards migration and survival of gliomas. Thus the knowledge on oxidative stress induced APE1's interaction with PKM2 and ENPP2 opens a new channel for the therapeutic target(s) for gliomas. PMID- 29721773 TI - Prolonged Cecal Insertion Time Is Not Associated with Decreased Adenoma Detection When a Longer Withdrawal Time Is Achieved. AB - BACKGROUND: The association between withdrawal time and adenoma detection has been established; however, the effect of cecal insertion time on adenoma detection remains unclear. AIM: To determine the association between cecal insertion time and adenoma detection. METHODS: This study completed a retrospective analysis of data collected in 4 prospective randomized-controlled trials related to screening and surveillance colonoscopy at a single tertiary care from 2010 to 2016. The primary outcome was cecal insertion time and its association with mean number of adenomas per patient and adenoma detection rate (ADR). RESULTS: 1303 patients met inclusion criteria (average age 59.7 +/- 8.7 years; 759 females (58.3%), and 763 Caucasians (58.6%). Mean cecal insertion time was significantly longer in patients who were female (p < 0.001), received moderate sedation (p = 0.001), had fellow involvement (p < 0.001), older (p = 0.002), and lower Boston bowel preparation scale (p < 0.001). Withdrawal time was found to increase as mean cecal insertion time increased (p < 0.001). The mean cecal insertion time was not different in patients with or without adenomas (p = 0.94). Cecal insertion time did not correlate with the mean number of adenomas or advanced adenomas per patient (p > 0.05), which was also true on Poisson regression analysis. Adenomas and advanced adenomas per patient were found to decrease when cecal insertion to withdrawal time ratios were greater than 1 (p < 0.001). CONCLUSIONS: Prolonged cecal insertion time was not associated with a decrease in ADR, mean number of adenomas or advanced adenomas per patient. When withdrawal times were longer than cecal insertion times, the number of adenomas and advanced adenomas detected per patient was significantly improved. PMID- 29721774 TI - Concise Commentary: Calling in Your Marker-Rectal CD30-Positive Cells Differentiate Ulcerative Colitis from Crohn's Disease. PMID- 29721772 TI - Telmisartan attenuates hydrogen peroxide-induced apoptosis in differentiated PC12 cells. AB - The present study investigated the protective actions of telmisartan, an angiotensin II type 1 receptor blocker (ARBs), against the cell apoptosis induced by exposure to hydrogen peroxide (H2O2) in differentiated PC12 cells. Preincubation of PC12 cells with telmisartan prevented H2O2-induced cytotoxicity as indicated by increased MTT (3,(4,5-dimethylthiazole-2-yl)2,5-diphenyl tetrazolium bromide) reduction, decreased lactate dehydrogenase (LDH) release, and improved morphological changes. Hoechst 33,258 staining showed that telmisartan markedly reduced shrunken nuclei of the cells, and Western blot analysis indicated that telmisartan significantly attenuated caspase-3 activity, as indicated by decreased ratio of cleaved Caspase-3 to its precursor and increased ratio of Bcl-2/Bax. The present findings showed that telmisartan protected against cellular oxidative damages by inhibiting apoptotic response. PMID- 29721776 TI - Formation of lamellar bodies in rat liver mitochondria in hyperthyroidism. AB - In the present work, ultrastructural changes of rat liver mitochondria in hyperthyroidism were studied. Hyperthyroidism was induced in male Wistar rats by daily administration of 100 MUg thyroxin per 100 g body weight for 5 days. The level of triiodothyronine and thyroxine increased 3- and 4-fold, respectively, in comparison with the same parameters in the control group, indicating the development of hyperthyroidism in experimental animals. It was found that under this experimental pathology 58% of the mitochondria are swollen, with their matrix enlightened, as compared to the control. In 40% of the profiles, the swollen mitochondria in the liver under hyperthyroidism exhibited rounded mono- or multilayer membrane structures, called lamellar bodies (LBs), presumably at different stages of their development: from the formation to the release from the organelles. Most LBs were located in the mitochondria near the nuclear zone (27%), while their number was reduced in the part of the cell adjacent to the plasma membrane. In a number of swollen mitochondria the cristae were shown to change their orientation, being directed radially toward the center of the mitochondria. We suggested that it is the first stage of formation of LBs. The second stage can be attributed to the formation of monomembrane structures in the center of the organelles. The third stage is characterized by the fact that the membrane of the lamellar bodies consists of several layers, and in this case the bodies were located closer to the outer mitochondrial membrane. The evagination of the outer mitochondrial membrane and its connection with lamellar structure can be recognized as the fourth stage of formation of LBs. At the fifth stage the developed lamellar formations exited the mitochondria. At the same time, following the exit of LBs from the mitochondria, no damage to the mitochondrial membrane was registered, and the structure of the remaining part of the mitochondria was similar to the control. The nucleus of the hepatocyte also underwent structural changes in hyperthyroidism, exhibiting changes in the membrane configuration, and chromatin condensation. The nature and structure of the LBs, as well as their functional role in the liver mitochondria in hyperthyroidism, require further investigation. PMID- 29721775 TI - Spleen Regulates Hematopoietic Stem/Progenitor Cell Functions Through Regulation of EGF in Cirrhotic Hypersplenism. AB - BACKGROUND: Hematopoietic abnormality is a common cause of cirrhotic hypersplenism (CH) complications and death; it causes serious adverse effects and is associated with bleeding, anemia, infection in CH patients. However, the underlying mechanism is unclear. AIMS: We aimed to investigate the effects of the spleen on hematopoiesis and hematopoietic stem/progenitor cells (HSPCs) in CH patients. METHODS: Eleven CH patients were enrolled to assess the effects of the spleen on HSPC functions. Hematopoietic changes were examined by flow cytometry analysis. HSPC functions were detected with colony-forming assays and in vitro cell cultures. Enzyme-linked immunosorbent assay (ELISA) was used to test the concentration of epithelial growth factor (EGF). RESULTS: The number of HSPCs was decreased in CH patients and was rescued after splenectomy. Serum from CH patients dysregulated HSPCs function, and serum from splenectomy patients restored the dysregulated HSPC function in vitro. The concentration of EGF was decreased in CH patients and was restored to normal level after splenectomy. EGF rescued the dysregulated HSPCs function in vitro. CONCLUSIONS: The spleen can regulate the functions of HSPCs in CH patients by regulating EGF signaling. EGF may be a therapeutic target for CH treatment. PMID- 29721777 TI - Ideal cardiovascular health and incidence of atherosclerotic cardiovascular disease among Chinese adults: the China-PAR project. AB - Existing evidence on the relationship between cardiovascular health (CVH) metrics and cardiovascular disease (CVD) was primarily derived from western populations. We aimed to evaluate the benefits of ideal CVH metrics on preventing incident atherosclerotic CVD (ASCVD) in Chinese population. This study was conducted among 93,987 adults from the China-PAR project (Prediction for ASCVD Risk in China) who were followed up until 2015. Cox proportional hazard regression models were used to estimate the hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) of CVH metrics for the risk of ASCVD, including coronary heart disease (CHD), stroke and ASCVD death. We further estimated the population attributable risk percentage (PAR%) of these metrics in relation to each outcome. We observed gradient inverse associations between the number of ideal CVH metrics and ASCVD incidence. Compared with participants having <=2 ideal CVH metrics, the multivariable-adjusted HRs (95% CIs) of ASCVD for those with 3, 4, 5, 6 and 7 ideal CVH metrics were 0.83 (0.74-0.93), 0.66 (0.59-0.74), 0.55 (0.48-0.61), 0.44 (0.38-0.50) and 0.24 (0.18-0.31), respectively (P for trend <0.0001). Approximately 62.1% of total ASCVD, 38.7% of CHD, 66.4% of stroke, and 60.5% of ASCVD death were attributable to not achieving all the seven ideal CVH metrics. After adjusting effects of ideal health factors, having four ideal health behaviors could independently bring adults health benefits in preventing 17.4% of ASCVD, 18.0% of CHD, 16.7% of stroke, and 10.1% of ASCVD death. Among all the seven CVH metrics, to keep with ideal blood pressure (BP) implied the largest public health gains against various ASCVD events (PAR% between 33.0% and 47.2%), while ideal diet was the metric most difficult to be achieved in the long term. Our study indicates that the more ideal CVH metrics adults have, the less ASCVD burden there is in China. Special efforts of health education and behavior modification should be made on keeping ideal BP and dietary habits in general Chinese population to prevent the epidemic of ASCVD. PMID- 29721778 TI - Microbes and host dance in harmony or disarray? PMID- 29721780 TI - The Influence of Patient Identification and Narrative Transportation on Intentions to Participate in Cancer Research. AB - Cancer decision-making interventions commonly utilize narratives as a persuasive strategy to increase identification with the message source, promote involvement with the topic, and elicit greater willingness to adopt recommended behaviors. However, there is little empirical research examining the mechanisms underlying the effectiveness of this strategy in the context of cancer research participation. Data for the current manuscript were collected as part of a larger study conducted with cancer patients (N = 413) from the USA, UK, and the Republic of Ireland. Participants viewed and evaluated video-recorded vignettes, illustrating different strategies for discussing clinical trials participation with family members. Results showed nationality was a significant predictor of identification with the main character (i.e., patient) in the vignette. Unexpectedly, these cross-national differences in identification disappeared when patients currently undergoing treatment had higher perceived susceptibility of their cancer. Identification with the main character in the vignettes was a significant predictor of intentions to participate in cancer research, but only when the mediating role of narrative transportation was considered. The findings demonstrate the importance of considering how individual and social identities influence identification with characters in cancer narratives and yield practical guidance for developing arts-based interventions to increase cancer research participation. PMID- 29721779 TI - Novel treatment strategy with radiofrequency ablation and surgery for pregnant patients with hepatocellular carcinoma: a case report. AB - BACKGROUND: Hepatocellular carcinoma (HCC) during pregnancy is rare, with a poor prognosis. Recently, however, increasing resection rates have improved survival rate. Currently, various surgeries are safely performed after the second trimester and termination of pregnancy is not always necessary. However, surgery is sometimes limited by gestational age or the patient's will. When patients with HCC refuse surgery during pregnancy, we face specific problems with respect to curability and fetal life. Meanwhile, previous studies have revealed radiofrequency ablation (RFA) as a possible alternative to surgery for the treatment of early HCC and shown its favorable local control rate for advanced HCC. However, no case of HCC treated with RFA during pregnancy has yet been reported. CASE PRESENTATION: Here, we present the case of a 33-year-old woman, who was a hepatitis B virus carrier. The patient had been followed up because HBV carrier could develop hepatitis or HCC. And she was diagnosed with a 40-mm HCC tumor at 17 weeks of gestation. She refused surgery because she was pregnant and wanted to continue her pregnancy; therefore, we performed RFA for the local control of her HCC at 17 weeks of gestation and radical surgery at postpartum. She delivered a healthy baby and has survived without recurrence for 6 years after the surgery. CONCLUSIONS: Surgery is potentially a curative treatment for HCC whether the patient is pregnant or not. However, various problems unique to pregnancy make it difficult to perform a straightforward surgery. Our case revealed that RFA can be safely performed in pregnant patients during the second trimester, and the combination of RFA and surgery can radically increase the resection rate of HCC during pregnancy. PMID- 29721781 TI - Implicit video feedback produces positive changes in landing mechanics. AB - BACKGROUND: Implicit (IF) and explicit (EF) feedback are two motor learning strategies demonstrated to alter movement patterns. There is conflicting evidence on which strategy produces better outcomes. The purpose of this study was to examine the effects of reduced IF and EF video feedback on lower extremity landing mechanics. METHODS: Thirty participants (24 +/- 2 years, 1.7 +/- 0.1 m, 70 +/- 11 kg) were randomly assigned to three groups: IF (n = 10), EF (n = 10), and control (CG) (n = 10). They performed twelve box-drop jumps three times a week on the training sessions for six weeks. Only IF and EF groups received video feedback on the training sessions. IF was cued to focus their attention on the overall jump, while EF was cued to focus on position of their knees. 3D lower extremity biomechanics were tested on testing sessions with no feedback. All sessions were at least 24 h apart from another. Testing sessions included baseline testing (pretest), testing after 3 training sessions with 100% feedback (pst1), testing after 6 training sessions with 33.3% feedback (pst2), testing after 6 training sessions with 16.6% feedback (Pst3), and testing 1 month after with no feedback (retention - ret). ANOVA compared differences between groups and time at initial contact and peak for hip flexion (HF, degrees ) and abduction angle (HA, degrees ), hip abduction moment (HAM, Nm/kgm), knee flexion (KF, degrees ) and abduction angle (KA, degrees ), knee abduction moment (KAM, Nm/kgm) and VGRF (N) (p < 0.05). RESULTS: A significant main effect for group was found between IF and EF groups for HA (IF = - 6.7 +/- 4; EF = - 9.4 +/- 4.1) and KAM (IF = 0.05 +/- 0.2; EF = - 0.07 +/- 0.2) at initial contact, and peaks HA (IF = - 3.5 +/- 4.5; EF = - 7.9 +/- 4.7) and HAM (IF = 1.1 +/- 0.6; EF = 0.9 +/- 0.4). A significant main effect for time at initial contact for HF (pre = 32.4 +/ 3.2; pst2 = 36.9 +/- 3.2; pst3 = 37.9 +/- 3.7; ret. = 34.1 +/- 3.7), HAM (pre = 0.1 +/- 0.1; pst1 = 0.04 +/- 0.1; pst3 = 0.1 +/- 0.01), KA (pre = 0.7 +/- 1.1; pst1 = 0.2 +/- 1.2; pst3 = 1.7 +/- 1), and KAM (pre = 0.003 +/- 0.1; pst3 = 0.01 +/- 0.1) was found. DISCUSSION/CONCLUSION: We found that implicit feedback produced positive changes in landing mechanics while explicit feedback degraded motor learning. Our results indicate that implicit feedback should be used in programs to lower the ACL injury risk. We suggest that implicit feedback should be frequent in the beginning and not be reduced as much following the acquisition phase. PMID- 29721782 TI - Herpes zoster in frail elderly patients: prevalence, impact, management, and preventive strategies. AB - Population aging is a worldwide phenomenon with significant and manifold impacts on society. Advanced age correlates with the onset of frailty. In this vulnerable state, the immune response is weakened and a higher susceptibility to infectious diseases is observed. The present narrative review aims to cover the topic of herpes zoster (HZ) and its complications in frail populations. The lifetime risk of developing HZ is estimated at about 20-30%, and the risk increases with age. In older people, HZ can lead to the inability to recover the lifestyle, the interests, and the level of activity that existed before its development. Severity of the disease at presentation and depression are the major correlates of pain burden in patients with acute HZ and postherpetic neuralgia (PHN). The frail elderly need careful assessment prior to treatment initiation and could be affected to a greater extent by treatment-related adverse events. In light of the significant burden caused by HZ and its complications in the frail elderly, the adoption of a preventive strategy appears to be promising, particularly using vaccination in appropriate age- and risk-groups. Although very few vaccine studies consider explicitly the frail elderly as their study population, there is evidence that the live, attenuated vaccine induces significant immunological responses. An adjuvanted recombinant subunit vaccine has recently been approved in Canada, in the United States, in the European Union, and in Japan, and will likely provide additional opportunities for prevention. PMID- 29721783 TI - Study of diagnostic accuracy of Fagan's two-step nomogram in increasing the value of predictive tools for prostate cancer: application of specific spatial distribution of positive/negative bioptic cores to predict extracapsular extension. AB - BACKGROUND: Prostate cancer (PC) represents the second most frequent cancer in the male population worldwide. It is mandatory to have a very accurate staging to choice the best possible treatment. AIMS: To test the possibility of improving the performance of Partin's tables in predicting the pathological staging of PC by introducing bioptic parameters through an innovative statistic tool (Fagan's two-step nomogram). METHODS: We prospectivelly collected data of all 1048 consecutive patients undergoing saturation 24-core transrectal prostate biopsy. Then, in eligible 94 patients, we compared the prediction of presence/absence of extracapsular extension of neoplasm (EPE+/-), with pathological assessment of invasion through (pseudo)capsule in the prostatectomy specimens. Starting from the probability of EPE- (pre-test probability, calculated with formula "100%-risk of EPE+"), we used Fagan's nomogram to examine the diagnostic sensitivity (DSe) and specificity (DSp) of negative "lateral" bioptic cores. RESULTS: We specifically analyzed the status of "lateral" cores in each side (94 patients * 2 sides = 188 sides). "Lateral" cores were negative in 42.5% of sides (80/188) with a DSe and DSp of 91.7 and 45.4%, respectively. In these sides, the mean probability of EPE+ according to Partin's tables was 21.6%. With Fagan's nomogram, the post-test probability of EPE+ when all "lateral" cores were negative was 14.1%, with a substantial gain of 7.5%. DISCUSSION: The spatial distribution of bioptic positive cores allowed us to demonstrate the role Fagan's nomogram in increasing the accuracy of already existing, predictive tools for PC. CONCLUSIONS: This pioneering study may justify the use of the above nomogram in testing "local" predictive parameters in combination with pre-existing nomograms. PMID- 29721784 TI - Subtractive Genomics, Molecular Docking and Molecular Dynamics Simulation Revealed LpxC as a Potential Drug Target Against Multi-Drug Resistant Klebsiella pneumoniae. AB - The emergence and dissemination of pan drug resistant clones of Klebsiella pneumoniae are great threat to public health. In this regard new therapeutic targets must be highlighted to pave the path for novel drug discovery and development. Subtractive proteomic pipeline brought forth UDP-3-O-[3 hydroxymyristoyl] N-acetylglucosamine deacetylase (LpxC), a Zn+2 dependent cytoplasmic metalloprotein and catalyze the rate limiting deacetylation step of lipid A biosynthesis pathway. Primary sequence analysis followed by 3-dimensional (3-D) structure elucidation of the protein led to the detection of K. pneumoniae LpxC (KpLpxC) topology distinct from its orthologous counterparts in other bacterial species. Molecular docking study of the protein recognized receptor antagonist compound 106, a uridine-based LpxC inhibitory compound, as a ligand best able to fit the binding pocket with a Gold Score of 67.53. Molecular dynamics simulation of docked KpLpxC revealed an alternate binding pattern of ligand in the active site. The ligand tail exhibited preferred binding to the domain I residues as opposed to the substrate binding hydrophobic channel of subdomain II, usually targeted by inhibitory compounds. Comparison with the undocked KpLpxC system demonstrated ligand induced high conformational changes in the hydrophobic channel of subdomain II in KpLpxC. Hence, ligand exerted its inhibitory potential by rendering the channel unstable for substrate binding. PMID- 29721786 TI - Data-driving methods: More than merely trendy buzzwords? PMID- 29721785 TI - Prodigiosin stimulates endoplasmic reticulum stress and induces autophagic cell death in glioblastoma cells. AB - Prodigiosin, a secondary metabolite isolated from marine Vibrio sp., has antimicrobial and anticancer properties. This study investigated the cell death mechanism of prodigiosin in glioblastoma. Glioblastoma multiforme (GBM) is an aggressive primary cancer of the central nervous system. Despite treatment, or standard therapy, the median survival of glioblastoma patients is about 14.6 month. The results of the present study clearly showed that prodigiosin significantly reduced the cell viability and neurosphere formation ability of U87MG and GBM8401 human glioblastoma cell lines. Moreover, prodigiosin with fluorescence signals was detected in the endoplasmic reticulum and found to induce excessive levels of autophagy. These findings were confirmed by observation of LC3 puncta formation and acridine orange staining. Furthermore, prodigiosin caused cell death by activating the JNK pathway and decreasing the AKT/mTOR pathway in glioblastoma cells. Moreover, we found that the autophagy inhibitor 3-methyladenine reversed prodigiosin induced autophagic cell death. These findings of this study suggest that prodigiosin induces autophagic cell death and apoptosis in glioblastoma cells. PMID- 29721787 TI - An optimal stopping approach for onset of fish migration. AB - Comprehending life history of migratory fish, onset of migration in particular, is a key biological and ecological research topic that still has not been clarified. In this paper, we propose a simple mathematical model for the onset of fish migration in the context of a stochastic optimal stopping theory, which is a new attempt to our knowledge. Finding the criteria of the onset of migration reduces to solving a variational inequality of a degenerate elliptic type. As a first step of the new mathematical modeling, mathematical and numerical analyses with particular emphasis on whether the model is consistent with the past observation results of fish migration are examined, demonstrating reasonable agreement between the theory and observation results. The present mathematical model thus potentially serves as a simple basis for analyzing onset of fish migration. PMID- 29721788 TI - Diagnostic Accuracy of Chinese Medicine Diagnosis Scale of Phlegm and Blood Stasis Syndrome in Coronary Heart Disease: A Study Protocol. AB - BACKGROUND: Phlegm and blood stasis syndrome (PBSS) is one of the main syndromes in coronary heart disease (CHD). Syndromes of Chinese medicine (CM) are lack of quantitative and easyimplementation diagnosis standards. To quantify and standardize the diagnosis of PBSS, scales are usually applied. OBJECTIVE: To evaluate the diagnostic accuracy of CM diagnosis scale of PBSS in CHD. METHODS: Six hundred patients with stable angina pectoris of CHD, 300 in case group and 300 in control group, will be recruited from 5 hospitals across China. Diagnosis from 2 experts will be considered as the "gold standard". The study design consists of 2 phases: pilot test is used to evaluate the reliability and validity, and diagnostic test is used to assess the diagnostic accuracy of the scale, including sensitivity, specififi city, likelihood ratio and area under the receiver operator characteristic (ROC) curve. DISCUSSION: This study will evaluate the diagnostic accuracy of CM diagnosis scale of PBSS in CHD. The consensus of 2 experts may not be ideal as a "gold standard", and itself still requires further study. (No. ChiCTR-OOC-15006599). PMID- 29721789 TI - Groundwater vulnerability assessment in karstic aquifers using COP method. AB - Access to safe and reliable drinking water is amongst the important indicators of development in each society, and water scarcity is one of the challenges and limitations affecting development at national and regional levels and social life and economic activity areas. Generally, there are two types of drinking water sources: the first type is surface waters, including lakes, rivers, and streams and the second type is groundwaters existing in aquifers. Amongst aquifers, karst aquifers play an important role in supplying water sources of the world. Therefore, protecting these aquifers from pollution sources is of paramount importance. COP method is amongst the methods to investigate the intrinsic vulnerability of this type of aquifers, so that areas susceptible to contamination can be determined before being contaminated and these sources can be protected. In the present study, COP method was employed in order to spot the regions that are prone to contamination in the region. This method uses the properties of overlying geological layers above the water table (O factor), the concentration of flow (C factor), and precipitation (P factor) over the aquifer, as the parameters to assess the intrinsic vulnerability of groundwater resources. In this regard, geographical information system (GIS) and remote sensing (RS) were utilized to prepare the mentioned factors and the intrinsic vulnerability map was obtained. The results of COP method indicated that the northwest and the west of the region are highly and very vulnerable. This study indicated that regions with low vulnerability were observed in eastern areas, which accounted for 15.6% of the area. Moderate vulnerability was 40% and related to the northeast and southeast of the area. High vulnerability was 38.2% and related to western and southwestern regions. Very high vulnerability was 6.2% and related to the northwest of the area. By means of the analysis of sensitivity of the model, it was determined that the focus factor of the flow has the greatest impact on the creation of vulnerability in the region. Also, these results were validated through electrical conductivity and discharge time series of the regional springs that are located in the vulnerable zones. PMID- 29721790 TI - Efficient removal of benzene in air at atmospheric pressure using a side-on type 172 nm Xe2 excimer lamp. AB - The photochemical removal of benzene was studied in air at atmospheric pressure using a side-on type 172 nm Xe2 excimer lamp with a wide irradiation area. After 1.5 min photoirradiation, C6H6 (1000 ppm) in air was completely converted to HCOOH, CO, and CO2 at a total flow rate of 1000 mL/min. The initial decomposition rate of C6H6 was determined to be 1.18 min-1. By using a flow system, C6H6 (200 ppm) was completely removed at a total flow rate of 250 mL/min. The conversion of C6H6 and the energy efficiency in the removal of C6H6 changed in the 31-100% and 0.48-1.2 g/kWh range, respectively, depending on the flow rate, the O2 concentration, and the chamber volume. On the basis of kinetic model simulation, dominant reaction pathways were discussed. Results show that the O(3P) + C6H6 reaction plays a significant role in the initial stage of the C6H6 decomposition. Important experimental parameters required for further improvement of the C6H6 removal apparatus using a 172 excimer lamp were discussed based on model calculations. PMID- 29721791 TI - Combined effects of phosphate-solubilizing bacterium XMT-5 (Rhizobium sp.) and submerged macrophyte Ceratophyllum demersum on phosphorus release in eutrophic lake sediments. AB - Simulation experiments were conducted using sediments collected from the Taihu Lake to determine the combined effects of submerged macrophytes Ceratophyllum demersum and phosphate-solubilizing bacteria (PSB) strain XMT-5 (Rhizobium sp.) on phosphorus (P) concentrations in overlying waters and sediments. After 30 days of experimental incubation, the total phosphorus (TP) and dissolved total phosphorus (DTP) concentrations of the overlying water subjected to AMB and AHMB treatments (both with the combined effects of PSB cells and submerged macrophytes) were generally lower than those of the AM (with individual effects of inoculated C. demersum) and AB (with individual effects of a smaller amount of inoculated PSB cells) control treatments but higher than that of the A (with no effects of inoculated PSB cells or C. demersum) and AHB (with individual effects of a larger amount of inoculated PSB) control treatments. The TP contents of the sediment in the AMB and AHMB treatments were significantly lower than those of the other control treatments. The TP contents of the C. demersum cocultured with the PSB strain XMT-5 cells in the AMB and AHMB treatments were all significantly higher than that of the AM treatment, indicating the enhancement of P uptake by submerged plants inoculated with PSB. The bacterial diversity structures of the rhizosphere sediment subjected to different treatments were also analyzed by the high-throughput sequencing method. According to the ACE and Chao 1 indices, the bacterial diversity in the AMB and AHMB treatments were the highest. Although many sources contributed to the decrease in the nutrient loads of the lake sediment, harvesting macrophytes inoculated with PSB cells prior to their senescence might constitute a significant in-lake measure for reducing internal P load. PMID- 29721792 TI - Efficient removal of cadmium from soil-washing effluents by garlic peel biosorbent. AB - Paddy field soil contaminated by cadmium may produce cadmium-contained corns causing Itai-itai disease, and in situ washing of soil with the organic acid is a good technical choice due to its convenience and cost-effectiveness. While the bottleneck of this technique is how to recycle the huge volume of washing effluent in an efficient and economical way. Biosorption of cadmium on the garlic peel was attempted in present study and it was found quite satisfactorily effective to remove all cadmium from the real soil leaching effluent after three time sequential adsorption. The systematical investigation on the effect of various parameters on the adsorption of cadmium on garlic peel in the existence of tartaric ligand was performed and it was found that tartrate could change Cd2+ into Cd(tar)0 species whose electrical charge state would restrain its approach to the adsorbent particles. The porous microstructure in the transversal surface of garlic peel and the abundant groups of -COOH are the main factors affecting the adsorption capability. A demonstrative flowsheet of soil remediation by chemical washing coupled with biosorption was proposed correspondingly, in which the cadmium could be recovered from the soil washing effluent, and the recovered effluent was reused for next soil washing, and recovered garlic peel was reused for cadmium adsorption from the effluents again, showing a great prospect in the remediation of paddy field soil contaminated by cadmium. Garlic peel was used to remove the cadmium from the soil washing effluent. PMID- 29721793 TI - Reactive oxygen species, antioxidant enzyme activity, and gene expression patterns in a pair of nearly isogenic lines of nicosulfuron-exposed waxy maize (Zea mays L.). AB - Nicosulfuron is a post-emergence herbicide used for weed control in maize fields (Zea mays L.). Here, the pair of nearly isogenic inbred lines SN509-R (nicosulfuron resistant) and SN509-S (nicosulfuron sensitive) was used to study the effect of nicosulfuron on growth, oxidative stress, and the activity and gene expression of antioxidant enzymes in waxy maize seedlings. Nicosulfuron treatment was applied at the five-leaf stage and water treatment was used as control. After nicosulfuron treatment, the death of SN509-S might be associated with increased oxidative stress. Compared with SN509-R, higher O2.- and H2O2 accumulations were observed in SN509-S, which can severely damage lipids and proteins, thus reducing membrane stability. The effects were exacerbated with extended exposure time. Both O2.- and H2O2 detoxification is regulated by enzymes. After nicosulfuron treatment, superoxide dismutase (SOD), catalase, ascorbate peroxidase (APX), monodehydroascorbate reductase (MDHAR), dehydroascorbate reductase (DHAR), glutathione reductase (GR), and glutathione-S-transferase (GST) of SN509-S were significantly lower than those of SN509-R. Compared to SN509-R, ascorbate content (AA), glutathione (GSH) content, GSH to glutathione disulfide ratios, and AA to dehydroascorbate ratios significantly declined with increasing exposure time in SN509-S. Compared to SN509-S, nicosulfuron treatment increased the transcript levels of most of the APX genes except for APX1, and in contrast to Gst1, upregulated the transcription of sod9, MDHAR, DHAR, and GR genes in SN509-R. These results suggest that on a transcription level and in accordance with their responses, detoxifying enzymes play a vital role in the O2.- and H2O2 detoxification of maize seedlings under nicosulfuron exposure. PMID- 29721795 TI - TOPSIS-based parametric optimization of compression ignition engine performance and emission behavior with bael oil blends for different EGR and charge inlet temperature. AB - The demand for higher fuel energy and lesser exhaust emissions of diesel engines can be achieved by fuel being used and engine operating parameters. In the present work, effects of engine speed (RPM), injection timing (IT), injection pressure (IP), and compression ratio (CR) on performance and emission characteristics of a compression ignition (CI) engine were investigated. The ternary test fuel of 65% diesel + 25% bael oil + 10% diethyl ether (DEE) was used in this work and test was conducted at different charge inlet temperature (CIT) and exhaust gas recirculation (EGR). All the experiments are conducted at the tradeoff engine load that is 75% engine load. When operating the diesel engine with 320 K CIT, brake thermal efficiency (BTE) is improved to 28.6%, and carbon monoxide (CO) and hydrocarbon (HC) emissions have been reduced to 0.025% and 12.5 ppm at 18 CR. The oxide of nitrogen (NOx) has been reduced to 240 ppm at 1500 rpm for 30% EGR mode. Technique for Order of Preference by Similarity to Ideal Solution (TOPSIS) method is frequently used in multi-factor selection and gray correlation analysis method is used to study uncertain of the systems. PMID- 29721794 TI - Analysis of short-term and sub-chronic effects of ambient air pollution on preterm birth in central China. AB - Recently, an increasing number of studies have reported the possible linkage between maternal exposure to ambient air pollution and adverse birth outcomes. This retrospective cohort study aimed to evaluate the effect of short-term and sub-chronic exposure to air pollutants on preterm birth occurred in Shiyan and Jingzhou, Hubei province, China from 2014 to 2016. General additive models (GAM) were performed to examine the impact of the daily and cumulative weekly air pollutants exposure. The non-linear patterns between adverse birth outcomes and weather condition were assessed by including penalized smoothing splines in the model. The demographic characteristics of pregnant women were also included in the model as covariates. A total of 16,035 cases were analyzed. Significant short term effects of air pollution exposure at lag 1 day on preterm birth were observed. In adjusted single-pollutant city-specific model, the association between acute air pollutant exposure and preterm birth was significant in Shiyan (PM2.5: OR = 1.066, 95% CI 1.027, 1.106; PM10: OR = 1.048, 95% CI 1.022, 1.076; O3: OR = 1.029, 95% CI 1.004, 1.056) and Jingzhou (PM2.5: OR = 1.037, 95% CI 1.008, 1.068; PM10: OR = 1.025, 95% CI 1.007, 1.043; SO2: OR = 1.082, 95% CI 1.023, 1.144; NO2: OR = 1.211, 95% CI 1.098, 1.335) per 10 MUg/m3 increment. Also, weekly average cumulative air pollution exposure was significantly associated with preterm birth in both areas. PMID- 29721796 TI - Removal of nickel from aqueous solution using supported zeolite-Y hollow fiber membranes. AB - This work describes the development of supported zeolite-Y membranes, prepared using the hydrothermal method, for the removal of nickel from an aqueous solution. Alumina hollow fibers prepared using the phase inversion and sintering technique were used as an inert support. The supported zeolite-Y membranes were characterized using the field emission scanning electron microscope (FESEM), X ray diffraction (XRD), and the water permeation and rejection test. The performance of the supported zeolite-Y membranes for heavy metal removal using batch adsorption and filtration test was studied using the atomic absorption spectroscopy (AAS). The adsorption study shows that the removal of nickel was pH dependent but affected by the presence of alpha-alumina. The seeded zeolite-Y membrane gave the highest adsorption capacity which was 126.2 mg g-1. This enabled the membrane to remove 63% of nickel ions from the aqueous solution within 180 min of contact time. The adsorption mechanism of nickel onto the zeolite-Y membrane was best fitted to the Freundlich isotherm. The kinetic study concluded that the adsorption was best fitted to pseudo-second-order model with higher correlation coefficient (R2 = 0.9996). The filtration study proved that the zeolite-Y membrane enabled to reduce the concentration of heavy metal at parts per billion level. PMID- 29721797 TI - A review on the engine performance and exhaust emission characteristics of diesel engines fueled with biodiesel blends. AB - Biodiesels have gained much popularity because they are cleaner alternative fuels and they can be used directly in diesel engines without modifications. In this paper, a brief review of the key studies pertaining to the engine performance and exhaust emission characteristics of diesel engines fueled with biodiesel blends, exhaust aftertreatment systems, and low-temperature combustion technology is presented. In general, most biodiesel blends result in a significant decrease in carbon monoxide and total unburned hydrocarbon emissions. There is also a decrease in carbon monoxide, nitrogen oxide, and total unburned hydrocarbon emissions while the engine performance increases for diesel engines fueled with biodiesels blended with nano-additives. The development of automotive technologies, such as exhaust gas recirculation systems and low-temperature combustion technology, also improves the thermal efficiency of diesel engines and reduces nitrogen oxide and particulate matter emissions. PMID- 29721798 TI - Effects of the chloro-s-triazine herbicide terbuthylazine on DNA integrity in human and mouse cells. AB - Terbuthylazine belongs to the chloro-s-triazine group of herbicides and acts primarily as a photosynthesis inhibitor. The mechanisms of action related to its exposure, relevant both in animals and humans, are still insufficiently investigated. This comprehensive study focused on the outcomes of terbuthylazine exposure at cell level in vitro, and a mice model in vivo. Experiments in vitro were conducted on whole human peripheral blood, isolated lymphocytes, and HepG2 cells exposed for 4 h to terbuthylazine at 8.00, 0.80, and 0.58 ng/mL, which is comparable with current reference values set by the European Commission in 2011. Terbuthylazine cytotoxicity was evaluated using dual fluorescent staining with ethidium bromide and acridine orange on lymphocytes, and CCK-8 colorimetric assay on HepG2 cells. The levels of DNA damage were measured using alkaline and hOGG1 modified comet assays. The potency of terbuthlyazine regarding induction of oxidative stress in vitro was studied using a battery of standard oxidative stress biomarkers. The in vivo experiment was conducted on Swiss albino mice exposed to terbuthlyazine in the form of an active substance and its formulated commercial product Radazin TZ-50 at a daily dose of 0.0035 mg/kg bw for 14 days. Following exposure, the DNA damage levels in leukocytes, bone marrow, liver, and kidney cells of the treated mice were measured using an alkaline comet assay. In vitro results suggested low terbuthylazine cytotoxicity in non-target cells. The highest tested concentration (8.00 ng/mL) reduced lymphocyte viability by 15%, mostly due to apoptosis, while cytotoxic effects in HepG2 cells at the same concentration were negligible. Acute in vitro exposure of human lymphocytes and HepG2 cells to terbuthylazine resulted in low-level DNA instability, as detected by the alkaline comet assay. Further characterization of the mechanisms behind the DNA damage obtained using the hOGG1-modified comet assay indicated that oxidative DNA damage did not prevail in the overall damage. This was further confirmed by the measured levels of oxidative stress markers, which were mostly comparable to control. Results obtained in mice indicate that both the active substance and formulated commercial product of terbuthylazine produced DNA instability in all of the studied cell types. We found that DNA in liver and kidney cells was more prone to direct toxic effects of the parent compound and its metabolites than DNA in leukocytes and bone marrow cells. The overall findings suggest the formation of reactive terbuthylazine metabolites capable of inducing DNA cross-links, which hinder DNA migration. These effects were most pronounced in liver cells in vivo and HepG2 cells in vitro. To provide a more accurate explanation of the observed effects, additional research is needed. Nevertheless, the present study provides evidence that terbuthylazine at concentrations comparable with current reference values possesses toxicological risk because it caused low-level DNA instability, both at cellular and animal organism level, which should be further established in forthcoming studies. PMID- 29721799 TI - Vertical shift in ciliate body-size spectrum and its environmental drivers in western Arctic pelagic ecosystems. AB - As an inherent functional trait, body-size spectrum is widely used as an informative indicator to summarize community structures in taxon-free space. The vertical shift in the body-size spectrum of pelagic ciliates and its environmental drivers were explored at eight depth layers from the water surface to a depth of 100 m in western Arctic pelagic ecosystems. A total of 85 samples were collected at 23 sampling stations during the summer sea-ice reduction period from August 5 to August 24, 2016. Based on equivalent spherical diameter (ESD), six body-size ranks were identified, of which ranks S2 (15-25 MUm), S3 (26-38 MUm), S4 (39-60 MUm), and S6 (79-91 MUm) were the top four levels in frequency of occurrence and ranks S2 and S3 were the dominant levels in abundance. The body size spectrum of the ciliates showed a clear vertical shift, with a significant succession among the dominant body-size units from the water surface to deeper layers in the water column. Multivariate analysis demonstrated a significant vertical variation in the body-size spectrum of the ciliates among the eight depths, which was significantly correlated with nutrients (phosphate and nitrite + nitrate) and chlorophyll a (Chl a), alone or in combination with dissolved oxygen. Four body-size diversity/distinctness indices were significantly correlated with the levels of phosphate, nitrite + nitrate, ammonium, and Chl a. Our results demonstrated that the body-size spectrum of pelagic ciliates can be shifted by environmental drivers (mainly nutrients and Chl a); thus, we suggest that it may be used to indicate water quality status on a vertical scale in the water column in deep seas. PMID- 29721800 TI - The timing of parathyroid hormone measurement defines the cut-off values to accurately predict postoperative hypocalcemia: a prospective study. AB - PURPOSE: Serum intact parathyroid hormone (iPTH) level is an early marker of post thyroidectomy hypocalcemia. However, lack of methodological standardization to define timing and cut-off points of iPTH measurement limit its clinical applicability. Here, we evaluated the relationship between two distinct postoperative time sampling and iPTH accuracy on predicting hypocalcemia. METHODS: iPTH was measured within 4 h after surgery (iPTH 4 h) and on the morning of the first postoperative day (iPTH 1st PO). Hypocalcemia was defined by levels of total calcium corrected by serum albumin <= 8.0 mg/dL and/or by the presence of symptoms. The most accurate iPTH cut-off point for hypocalcemia prediction was established from a ROC curve comparing both time-points. RESULTS: The study included 101 patients. The mean age was 52.4 +/- 12.9 years, 93 were women (92.1%) and 69 patients underwent total thyroidectomy (68.3%). Hypocalcemia occurred in 25 patients (24.8%), of whom 12 were symptomatic. Total thyroidectomy, longer duration of surgery, surgical complications related to parathyroid glands and lower levels of iPTH 4 h and iPTH 1st PO were associated with postoperative hypocalcaemia (all P < 0.05). Using the ROC curve, the optimal cut-off points were 19.55 pg/mL and 14.35 pg/mL for iPTH 4 h and iPTH 1st PO, respectively. The comparison of the AUC showed no significant difference between these two points of evaluation (0.935 vs. 0.940; P = 0.415). CONCLUSIONS: Serum iPTH levels measured within 4 h or on the first morning after surgery are predictors of postoperative hypocalcemia. Notably, both time-points have the same accuracy to predict postoperative hypocalcemia (with different cutoff points). PMID- 29721803 TI - Appraisal of interpretation criteria for the single intra-dermal comparative cervical tuberculin test for the diagnosis of tuberculosis in dromedary camels in Ethiopia. AB - Dromedary camels are the main sources of milk, meat and income for the Ethiopian pastoralists as they withstand the harsh environments of the regions of the country. Tuberculosis (TB) affects dromedary camels causing morbidity and mortality in these animals. Hence, early diagnosis and identification of infected camels play a significant role in reducing the transmission of TB in camels. This study was conducted on 168 camels between October 2014 and July 2015 to evaluate the performance of single intra-dermal comparative cervical tuberculin (SICCT) to diagnose TB in camels. Gross pathology was used as a gold standard to define disease status of each camel. The result showed that at the cutoff value of >= 3 mm SICCT had optimum performance with sensitivity and specificity of 60.7 and 85%, respectively. Moreover, at a cutoff >= 3 mm, the receiver operating characteristics (ROC) revealed area under the ROC curve was 0.729 (0.615-0.842) which is statistically significant (p = 0.000). Thus, the result of the present study could suggest the use of >= 3 mm cutoff value for the diagnosis of TB in dromedary camels in Ethiopia. PMID- 29721804 TI - Effects of supplementing Barodon, Bacillus subtilis, and Ampbio on growth performance, biochemical metabolites, and hormone levels in Korean native heifers. AB - An experiment was conducted to evaluate the effects of supplementing feed additives of Barodon(r), effective microorganism(r) (Bacillus (B.) subtilis), and Ampbio(r) on the growth performance, blood metabolites, stress, and reproductive hormone levels of Korean native heifers. A total of 48 Korean native heifers were assigned to four groups with 6 heifers in each group. The groups were control, Barodon (0.2%), beneficial microorganism (1%), and Ampbio (1%). Animals in all groups were fed a basal diet composed of selected feed additives and water ad libitum for 99 days. Results showed that there are significant changes in body weight and daily gain in the Ampbio-supplemented group as compared with the control and other feed additives groups (p < 0.05). The increased level of feed intake (7.30 +/- 0.03 kg) and feed requirements (10.81 +/- 0.52 kg) was observed in the Ampbio-fed group followed by the effective microorganism (EM), Barodon, and control groups. There were no significant changes in albumin, glucose, glutamic oxaloacetic transaminase (SGOT), serum pyruvic transaminase (SGPT), and total protein level, but the decreased levels of total cholesterol and triglycerides and the increased level of blood urea nitrogen were noted in the Ampbio-fed group as compared with the control and other feed additive groups. The reduced level of cortisol (p < 0.05) and elevated levels of progesterone and estradiol (p > 0.05) were noted in the Ampbio-fed group as compared to the other feed additive groups. It is therefore concluded that incorporation of Barodon, EM (B. subtilis), and Ampbio in the recommended diet improved the growth and health performance of Korean native heifers. PMID- 29721801 TI - The emerging role of aldosterone/mineralocorticoid receptors in the pathogenesis of erectile dysfunction. AB - PURPOSE: Aldosterone is an old hormone that has been discovered for more than fifty years. The clinical application of its receptors' inhibitors, especially spirolactone, has benifited patients for decades worldwide. In this review, we briefly summarized the molecular mechanism of aldosterone/mineralocorticoid receptors (Ald-MRs) signaling in cardiovascular diseases and its emerging role in erectile dysfunction. METHODS: We searched PubMed, Web of Science, and Scopus for manuscripts published prior to December 2017 using key words " aldosterone " AND " erectile dysfunction " OR " cardiovascular disease " OR " mineralocorticoid receptors ". Related literature and clinical perspectives were collated, summarized and discussed in this review. RESULTS: The increase of reactive oxygen species production, inhibition of endothelial nitric oxide synthase system, and induction of inflammation are ubiquitous in vascular endothelial cells or vascular smooth muscle cells after the activation of Ald-MRs pathway. In addition, in cardiovascular diseases with over-active Ald-MRs signaling, MRs blockade could reverse the injury and improve the prognosis. Notably, multiple studies have correlated aldosterone and MRs to the pathogenesis of erectile function, while the mechanism is largely unperfectly identified. CONCLUSION: In conclusion, we summarize the current evidence to highlight the potential role of aldosterone in erectile dysfunction and provide critical insights into the treatment of the disease. PMID- 29721805 TI - Leptospirosis is strongly associated to estrus repetition on cattle. AB - Although prevalent, the exact impact of infectious diseases on reproductive failures remains to be determined. Among them, leptospirosis has commonly been reported as cause of abortions on outbreaks. Nevertheless, the majority of the animals present a chronic, silent form of the disease, which is characterized by low reproductive efficiency and is frequently neglected. In that context, we conducted a study that aims to estimate the impact of chronic leptospirosis on reproductive disorders on cattle. A total of 25 different dairy herds with history of reproductive losses from Rio de Janeiro, Brazil, were selected. From each herd, a questionnaire was applied and sera from 20 cows were randomly tested for leptospirosis (totaling 500 cows). Chi-square was performed to estimate the association of seroreactivity with reproductive disorders. A total of 32% of the herds were positive, all of them against serogroup Sejroe. Estrus repetition was the most important reported reproductive problem and it was strongly associated to seroreactivity against leptospirosis. Besides, specific vaccination against leptospirosis was an important protection factor against that disorder. In conclusion, control programs including, but not limited to, vaccines must be implemented on those herds in order to reduce reproductive losses, particularly estrus repetition. PMID- 29721806 TI - Optimal administration frequency and dose of teriparatide for acceleration of biomechanical healing of long-bone fracture in a mouse model. AB - Despite preclinical studies demonstrating the effectiveness of teriparatide for skeletal repair in small animals, inconclusive data from clinical trials have raised questions regarding the optimal teriparatide dosing regimen for bone repair. To address this, we assessed the effect of teriparatide frequency and dose on long-bone healing using a mouse femur osteotomy/fracture model. Eight week-old male ICR mice were subjected to open femur osteotomies, then randomized into following five groups (n = 8 per group): vehicle; low dose/high frequency: 3 MUg/kg/dose, 3 times/day; low dose/low frequency: 9 MUg/kg/dose, 1 time/day; high dose/high frequency: 9 MUg/kg/dose, 3 times/day; high dose/low frequency: 27 MUg/kg/dose, 1 time/day. Skeletal repair was assessed by microcomputed tomography, mechanical testing, and histology 4 weeks after surgery. High-dose and/or high-frequency teriparatide treatment increased callus bone volume but failed to have a significant impact on the biomechanical recovery of fractured femurs, possibly because of impaired cortical shell formation in fracture calluses. Meanwhile, low-dose/low-frequency teriparatide therapy enhanced callus bone formation without interfering with cortical shell formation despite a lesser increase in callus bone volume, leading to significant two and fourfold increases in ultimate load and stiffness, respectively. Our findings demonstrate that administering teriparatide at higher doses and/or higher frequencies raises fracture callus volume but does not always accelerate the biomechanical recovery of fractured bone, which points to the importance of finding the optimal teriparatide dosing regimen for accelerating skeletal repair. PMID- 29721802 TI - Microbiota and metabolic diseases. AB - The microbiota is a complex ecosystem of microorganisms consisting of bacteria, viruses, protozoa, and fungi, living in different districts of the human body, such as the gastro-enteric tube, skin, mouth, respiratory system, and the vagina. Over 70% of the microbiota lives in the gastrointestinal tract in a mutually beneficial relationship with its host. The microbiota plays a major role in many metabolic functions, including modulation of glucose and lipid homeostasis, regulation of satiety, production of energy and vitamins. It exerts a role in the regulation of several biochemical and physiological mechanisms through the production of metabolites and substances. In addition, the microbiota has important anti-carcinogenetic and anti-inflammatory actions. There is growing evidence that any modification in the microbiota composition can lead to several diseases, including metabolic diseases, such as obesity and diabetes, and cardiovascular diseases. This is because alterations in the microbiota composition can cause insulin resistance, inflammation, vascular, and metabolic disorders. The causes of the microbiota alterations and the mechanisms by which microbiota modifications can act on the development of metabolic and cardiovascular diseases have been reported. Current and future preventive and therapeutic strategies to prevent these diseases by an adequate modulation of the microbiota have been also discussed. PMID- 29721808 TI - The characteristics of clinical changes in primary hyperparathyroidism in Chinese patients. AB - In Western countries, the presentation of primary hyperparathyroidism (PHPT) changed from a symptomatic to an asymptomatic disease after the 1970s, whereas in China, only one study has evaluated the changing clinical characteristics and biochemical profiles of PHPT patients. The aim of this study was to explore changes in the clinical characteristics of PHPT in Chinese patients. Overall, 140 consecutive patients with PHPT were studied between January 1, 2010 and June 30, 2016. The patients were divided into two groups: 32 consecutive patients from January 1, 2010 to March 31, 2013 were included in group 1, and 108 consecutive patients from April 1, 2013 to June 30, 2016 were included in group 2. The most frequent complaints were ostealgia (46.02%), urolithiasis (41.59%), constipation (25.66%), fatigue (18.58%), polydipsia and polyuria (15.93%) and fracture history (15.04%). The number of cases in group 2 was 3.38-fold greater than that of group 1. The parathyroid hormone (PTH) and fasting blood glucose (FPG) levels were higher in group 1 than those in group 2 (p = 0.039, p < 0.001). In 62.14% of patients with PHPT, the proportion of the first diagnosis due to hypercalcemia found using a multichannel autoanalyzer in group 1 was lower than that found in group 2 (p = 0.039), and the proportion of the first diagnosis due to parathyroid lesions captured using routine neck ultrasonography in group 1 was higher than in group 2 (p = 0.003). The proportion of parathyroid carcinoma cases was higher in group 1 than group 2 (p = 0.036). Cases of PHPT increased with time, but the proportion of parathyroid carcinoma cases was lower in group 1 than that in group 2. Over time, the first diagnosis switched from parathyroid lesions captured by routine neck ultrasound to hypercalcemia found by a multichannel autoanalyser. At our centre, PHPT in Chinese patients still demonstrates classic characteristics. PMID- 29721807 TI - Potential association with early changes in serum calcium level after starting or switching to denosumab combined with eldecalcitol. AB - The aims of this study are to investigate changes in serum calcium (Ca) level after switching from either non-therapy, bisphosphonate, selective estrogen receptor modulators (SERM) or teriparatide treatments to a combination therapy of denosumab (DMAb), and eldecalcitol, and the association between early changes in serum calcium and changes in bone metabolic markers and bone mineral density (BMD). 129 patients with postmenopausal osteoporosis (32 non-pretreatment, 50 bisphosphonates, 18 SERM, and 29 teriparatide) were recruited and switched to DMAb plus eldecalcitol. Serum calcium levels, bone metabolism markers, and BMD measurements of the lumbar spine and femoral neck were evaluated. All groups showed an increase in BMD 6 months and 1 year after DMAb administration compared to baseline via suppression of bone metabolism markers. The TPD group showed a significant decrease in serum calcium level 1 week after the first injection of DMAb and eldecalcitol compared to baseline and the bisphosphonate group. Changes in serum calcium level from baseline to 1 week after the first injection of DMAb trended to correlate with changes in bone metabolism markers and lumbar BMD. The risks of DMAb-induced hypocalcemia are different between starting and switching from bone resorption inhibitors and bone formation promoters. Therefore, appropriate assessment before administration of DMAb, including pretreatment therapy as well as serum Ca and bone metabolic markers will help identify the risk of hypocalcemia following DMAb in combination with eldecalcitol. Our findings also showed that early change in serum Ca level after DMAb initiation could potentially predict the efficacy for therapy reaction. PMID- 29721809 TI - Gushukang exerts osteopreserve effects by regulating vitamin D and calcium metabolism in ovariectomized mice. AB - Calcium homeostasis plays vital roles in the management of bone health. Traditional herbal formula Gushukang (GSK) was clinically applied to treat primary osteoporosis. This study aimed to explore the osteoprotective effects of GSK and its roles in maintaining calcium homeostasis in ovariectomized (OVX) mice. The OVX mice were orally treated with low (0.38 g/kg), middle (0.76 g/kg) and high (1.52 g/kg) dose of GSK for 8 weeks. GSK treatment dramatically increased serum calcium level and decreased urinary calcium excretion as well as enhanced calcium content in bone of OVX mice. Serum level of 25-hydroxyvitamin D was significantly increased in OVX mice with exposure to GSK. Treatment with GSK improved bone mass and micro-structure of trabecular bone at distal metaphysis of femur and proximal metaphysis of tibia in OVX mice shown by safranin O staining and micro-CT measurement. GSK treatment at all doses up-regulated mRNA expression of calcium-binding protein-28k and vitamin D receptor in kidney of OVX mice, and dose-dependently decreased mRNA expression of claudin-14 and elevated mRNA expression of claudin-16 in duodenum of OVX mice. Taken together, GSK exerted beneficial effects on trabecular bone of OVX mice by improving calcium homeostasis via regulating paracellular calcium absorption in duodenum and transcellular calcium reabsorption in kidney. PMID- 29721811 TI - Life quality of patients who underwent breast reconstruction after prophylactic mastectomy: systematic review. AB - BACKGROUND: Prophylactic mastectomy is used to reduce the incidence of breast cancer in women with genetic predisposition and family history of breast cancer, and the rate of application is increased nowadays. Chronic pain, body image, and sexuality may negatively affect quality of life, while patients generally have increased quality of life and satisfaction after prophylactic mastectomy. The aim of this study is the evaluation of the results of the studies about quality of life of patients who underwent breast reconstruction after prophylactic mastectomy. METHODS: For the 1996-2016 literature, we searched the databases of Scopus, Science Direct, PubMed, EBSCO, Cochrane, Medline Complete, Ovid, Springer Link, Google Academic, Taylor & Francis, PsychINFO databases. For the gray literature, National Thesis Center and ULAKBIM databases were searched. Seven studies complying with the criteria were included in the review. RESULTS: Seven studies included in this study aimed to investigate the effect of prophylactic mastectomy on breast pain, numbness, sexuality and quality of life. When the studies were reviewed, we were found that the majority of the patients were satisfied with the results of the procedure, although the body image perception and pain/ movement/ perception and sexual problems were experienced after the breast surgery. CONCLUSIONS: While overall satisfaction with cosmetic results was high, most women were not satisfied with the softness of the reconstructed breasts, and had problems with breast hardness, numbness and sex. Therefore, it is very important to inform the patients about the complications that may develop after the operation, while there is not enough data about the importance of informing the patients before the operation. PMID- 29721810 TI - Aspartic acid racemization of root dentin used for dental age estimation in a Polish population sample. AB - Precise age determination of unidentified bodies and human remains is one of the essential tasks of forensic science. The aim of this study was to assess the applicability of using the enantiomeric composition of aspartic acid racemization in root and crown dentin for dental age estimation using a Polish population sample. Coronal and root dentin from four teeth groups from the mandible were studied using gas chromatography with mass spectrometry. The results demonstrated a very high correlation between the chronological age and enantiomeric composition in both of the dentin samples. Individual linear equations of root dentin with correlation coefficients between 0.96 and 0.98 and a standard estimation error of +/-2.95-4.84 years validated the application of aspartic acid racemization as a significant practical contribution to everyday forensic medical practice. Discrepancies in methodological aspects and modifications that simplify the protocol are presented. PMID- 29721812 TI - Development and evaluation of a mother-centered toolkit for postpartum behavioral and psychosocial health. AB - The well-being of mothers and infants is influenced by mothers' behavioral and psychosocial health (B&PH), yet it is often neglected during healthcare visits. To address this gap, this study aimed to develop and evaluate acceptability of a postpartum toolkit (screening questionnaire, feedback template, and decision aid) to promote B&PH. Using a decision-making model and participatory design (N = 24), a B&PH screening questionnaire was refined, and prototypes of feedback templates and decision aids for selecting health goals were developed. Most mothers in this multi-ethnic sample rated the resulting toolkit as easy to understand/use and useful, and reported they were likely to act on their health goals. Toolkit ease of use and usefulness ratings were largely unrelated to education, ethnicity, and acculturation. In conclusion, findings support the toolkit's acceptability and applicability to women of diverse backgrounds. The toolkit is a promising strategy to engage mothers in setting goals to promote B&PH. PMID- 29721813 TI - Pioneer baby: suggestions for pre- and postnatal health promotion programs from rural English and Spanish-speaking pregnant and postpartum women. AB - In the United States, more than 9 million rural women (15-44 years old) experience limited access and delivery of reproductive healthcare services. Rurality coupled with lower socio-economic status are associated with increased maternal and neonatal morbidity and mortality. The purpose of this qualitative study was to gain in-depth information from underserved English- and Spanish speaking pregnant and postpartum rural women on what they would value in a health promotion program. Three focus group sessions were conducted exploring four domains: (1) physical activity, (2) dietary habits, (3) fetal movement/kick counts, and (4) breastfeeding and other support resources. Five overarching themes were observed across domains, with the following health promotion needs: (1) information on safe exercises, (2) advice on healthy food and drink, (3) breastfeeding support, (4) guidance on counting fetal movement, and (5) self- and peer-education. Study findings will inform intervention programming that aims to improve pregnancy and birth outcomes. PMID- 29721814 TI - Pre-Incarceration Rates of Nonmedical Use of Prescription Drugs among Black Men from Urban Counties. AB - There are inconsistent findings regarding the rates of nonmedical prescription drug use (NMPDU) among Black Americans. The majority of previous studies used pharmaceutical names of drugs and relied on national data that excludes incarcerated populations, in which Black men are overrepresented. Therefore, the current study aimed to describe pre-incarceration rates of NMPDU among Black men in prison using culturally relevant alternative drug names. We recruited 208 incarcerated (adult age 18 or older) Black men nearing community reentry to urban counties from four state prisons in Kentucky. Results indicated the majority of participants engaged in lifetime NMPDU. The most commonly endorsed class of prescription drug was, "Other Sedatives, Hypnotics, and Tranquilizers" and the most commonly endorsed specific prescription drugs were "Syrup," Lortab/Hydrocodone, and Xanax. There were significant age differences in the number of days that drugs were used in the year prior to incarceration. The current study contributes to the dearth of literature on NMPDU among Black Americans. These findings have implications for disease transmission, overdose risk, and culturally relevant data collection methods and interventions aimed at reducing NMPDU among Black men. PMID- 29721815 TI - Tyrosinase inhibitory components from the seeds of Cassia tora. AB - Ten compounds (1-10) isolated from the seeds of Cassia tora were evaluated for tyrosinase inhibition. Compounds 3, 4, and 7 inhibited tyrosinase enzymatic activity in a dose-dependent manner, with IC50 values of 3.0 +/- 0.8, 7.0 +/- 0.4, and 9.2 +/- 3.4 MUM, respectively. Kinetic analyses revealed a mechanism consistent with competitive inhibition. In silico molecular docking showed that compounds 3 and 4 docked in the active site of tyrosinase, whereas 7 interacted with Ala246 and Val248 at outside of the active site, and His244 and Glu256 at inside. Additionally, compounds 3, 4, and 7 suppressed melanogenesis in alpha-MSH treated B16F10 melanoma cells at a concentration of 10 MUM. PMID- 29721816 TI - Underlying Systemic Diseases in Pyoderma Gangrenosum: A Systematic Review and Meta-Analysis. AB - BACKGROUND: There is little consensus regarding the prevalence and distribution of underlying systemic diseases among patients with pyoderma gangrenosum. OBJECTIVE: The objective of this study was to synthesize existing data on the prevalence of associated systemic diseases in patients with pyoderma gangrenosum. METHODS: We performed a systematic review and meta-analysis of observational studies in MEDLINE, EMBASE, and Scopus (1823-2017). The quality of evidence was assessed using a modified Newcastle-Ottawa Scale. A meta-analysis was performed using random-effects models to estimate pooled prevalence rates with 95% confidence intervals. RESULTS: Twenty-one eligible studies comprising 2611 patients with pyoderma gangrenosum were included in the quantitative synthesis. The overall random-effects pooled prevalence of associated systemic diseases was 56.8% (95% confidence interval 45.5-67.4). The leading underlying disease was inflammatory bowel disease (17.6%; 95% confidence interval 13.0-22.7), followed by arthritis (12.8%; 95% confidence interval 9.2-16.9), hematological malignancies (8.9%; 95% confidence interval 6.5-11.6), and solid malignancies (7.4%; 95% confidence interval 5.8-9.1). In 16.3% (95% confidence interval 7.7 27.1) of cases, the onset of pyoderma gangrenosum was attributed to the pathergy phenomenon. CONCLUSIONS: More than half of patients with pyoderma gangrenosum present with a relevant underlying disease. Inflammatory bowel disease and arthritis are the most frequently associated diseases. Relative to the reported literature, the pooled prevalence of arthritis and hematological malignancies is lower, while the pooled prevalence of solid malignancies is higher. Owing to the high level of heterogeneity among most of the comparisons, results should be interpreted with caution. PMID- 29721817 TI - The impact of hyperoxia on outcomes after cardiac surgery: a systematic review and narrative synthesis. AB - PURPOSE: Historically, cardiac surgery patients have often been managed with supraphysiologic intraoperative oxygen levels to protect against the risks of cellular hypoxia inherent in the un-physiologic nature of surgery and cardiopulmonary bypass. This may result in excessive reactive oxygen species generation and exacerbation of ischemia-reperfusion injury. In this review, we synthesize all available data from randomized controlled trials (RCTs) to investigate the impact that hyperoxia has on postoperative organ dysfunction, length of stay, and mortality during adult cardiac surgery. SOURCE: We searched Medline, Embase, Scopus, and Cochrane Central Register of Controlled Trials databases using a high-sensitivity strategy for RCTs that compared oxygenation strategies for adult cardiac surgery. Our primary outcome was postoperative organ dysfunction defined by postoperative increases in myocardial enzymes, acute kidney injury, and neurologic dysfunction. Secondary outcomes were mortality, ventilator days, and length of stay in the hospital and intensive care unit. PRINCIPAL FINDINGS: We identified 12 RCTs that met our inclusion criteria. Risk of bias was unclear to high in all but one trial. Significant heterogeneity in timing of the treatment period and the oxygenation levels targeted was evident and precluded meta-analysis. The large majority of trials found no difference between hyperoxia and normoxia for any outcome. Two trials reported reduced postoperative myocardial enzymes and one trial reported reduced mechanical ventilation time in the normoxia group. CONCLUSIONS: Hyperoxia had minimal impact on organ dysfunction, length of stay, and mortality in adult cardiac surgery. The current evidence base is small, heterogeneous, and at risk of bias. TRIAL REGISTRATION: International Prospective Register of Systematic Reviews (PROSPERO) (CRD42017074712). Registered 17 August 2017. PMID- 29721819 TI - Correction to: Structural and functional aspects of the interaction partners of the small heat-shock protein in Synechocystis. AB - Table 1 in the original publication has been corrected. PMID- 29721818 TI - Correction to: The obesity paradox and osteoporosis. AB - Unfortunately, the author's first name and the family name were swapped and published in the original publication. PMID- 29721821 TI - Active Safety Surveillance in Africa: Pragmatism and Agility. PMID- 29721820 TI - Hypothermic total liquid ventilation after experimental aspiration-associated acute respiratory distress syndrome. AB - BACKGROUND: Ultrafast cooling by total liquid ventilation (TLV) provides potent cardio- and neuroprotection after experimental cardiac arrest. However, this was evaluated in animals with no initial lung injury, whereas out-of-hospital cardiac arrest is frequently associated with early-onset pneumonia, which may lead to acute respiratory distress syndrome (ARDS). Here, our objective was to determine whether hypothermic TLV could be safe or even beneficial in an aspiration associated ARDS animal model. METHODS: ARDS was induced in anesthetized rabbits through a two-hits model including the intra-tracheal administration of a pH = 1 solution mimicking gastric content and subsequent gaseous non-protective ventilation during 90 min (tidal volume [Vt] = 10 ml/kg with positive end expiration pressure [PEEP] = 0 cmH2O). After this initial period, animals either received lung protective gas ventilation (LPV; Vt = 8 ml/kg and PEEP = 5 cmH2O) under normothermic conditions, or hypothermic TLV (TLV; Vt = 8 ml/kg and end expiratory volume = 15 ml/kg). Both strategies were applied for 120 min with a continuous monitoring of respiratory and cardiovascular parameters. Animals were then euthanized for pulmonary histological analyses. RESULTS: Eight rabbits were included in each group. Before randomization, all animals elicited ARDS with arterial oxygen partial pressure over inhaled oxygen fraction ratios (PaO2/FiO2) below 100 mmHg, as well as decreased lung compliance. After randomization, body temperature rapidly decreased in TLV versus LPV group (32.6 +/- 0.6 vs. 38.2 +/- 0.4 degrees C after 15 min). Static lung compliance and gas exchanges were not significantly different in the TLV versus LPV group (PaO2/FiO2 = 62 +/- 4 vs. 52 +/- 8 mmHg at the end of the procedure, respectively). Mean arterial pressure and arterial bicarbonates levels were significantly higher in TLV versus LPV. Histological analysis also showed significantly lower inflammation in TLV versus LPV group (median histological score = 3 vs. 4.5/5, respectively; p = 0.03). CONCLUSION: Hypothermic TLV can be safely induced in rabbits during aspiration associated ARDS. It modified neither gas exchanges nor respiratory mechanics but reduced lung inflammation and hemodynamic failure in comparison with LPV. Since hypothermic TLV was previously shown to provide neuro- and cardio protective effects after cardiac arrest, these findings suggest a possible use of TLV in the settings of cardiac arrest-associated ARDS. PMID- 29721822 TI - Challenges and Opportunities for the Traceability of (Biological) Medicinal Products. AB - This article provides an overview of the current situation regarding the traceability of medicinal products, with a focus on drug safety and biologics. Limited traceability of biologics, in particular with regard to the batch number, is associated with incomplete recording of exposure information in clinical practice. The current pharmaceutical barcode standards in the EU do not support the automatic recording of dynamic product information, such as batch numbers and expiry dates, by means of electronic barcode scanning in clinical practice. New barcode requirements, such as the 2D DataMatrix with encoded batch numbers and expiry dates, provided on both the primary and the secondary package, can facilitate routine barcode scanning at all points in the supply chain in different healthcare settings. To build a full track-and-trace system for medicines with electronic capture of relevant exposure information, alignment with other topics, such as the Falsified Medicines Directive and initiatives to reduce medication errors, is needed to increase the buy-in from all stakeholders and to solve multiple issues with a joint effort. PMID- 29721823 TI - Isolation and Evaluation of New Antagonist Bacillus Strains for the Control of Pathogenic and Mycotoxigenic Fungi of Fig Orchards. AB - Bacillus is an antagonistic bacteria that shows high effectiveness against different phytopathogenic fungi and produces various lytic enzymes, such as chitosanase, chitinase, protease, and gluconase. The aim of this study is to determine Bacillus spp. for lytic enzyme production and to evaluate the antifungal effects of the selected strains for biocontrol of mycotoxigenic and phytopathogenic fungi. A total of 92 endospore-forming bacterial isolates from the 24 fig orchard soil samples were screened for chitosanase production, and six best chitosanolytic isolates were selected to determine chitinase, protease, and N-acetyl-beta-hexosaminidase activity and molecularly identified. The antagonistic activities of six Bacillus strains against Aspergillus niger EGE-K 213, Aspergillus foetidus EGE-K-211, Aspergillus ochraceus EGE-K-217, and Fusarium solani KCTC 6328 were evaluated. Fungal spore germination inhibition and biomass inhibition activities were also measured against A. niger EGE-K-213. The results demonstrated that Bacillus mojavensis EGE-B-5.2i and Bacillus thuringiensis EGE-B-14.1i were more efficient antifungal agents against A. niger EGE-K-213. B. mojavensis EGE-B-5.2i has shown maximum inhibition of the biomass (30.4%), and B. thuringiensis EGE-B-14.1i has shown maximum inhibition of spore germination (33.1%) at 12 h. This is the first study reporting the potential of antagonist Bacillus strains as biocontrol agents against mycotoxigenic fungi of fig orchads. PMID- 29721824 TI - Exosomes: Definition, Role in Tumor Development and Clinical Implications. AB - Exosomes are microvesicles released by cells in both physiological and pathological situations. They are surrounded by a lipid bilayer with proteins derived from the origin cell, and contain a variety of molecules, such as nucleic acids. They represent an emerging mechanism of intercellular communication, and they play an important role in the pathogenesis of cancer, stimulating proliferation and aggressiveness of cancer cells, inducing a microenvironment favorable to tumor development and controlling immune responses. Because of the growing understanding of the potential implications of extracellular vesicles in the development of malignancies, research on exosomes, and its role as a diagnostic and therapeutic tool, constitutes nowadays a very exciting and promising field. PMID- 29721825 TI - Cure of tuberculosis using nanotechnology: An overview. AB - Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), a major health issue of the present era. The bacterium inhabits the host macrophage and other immune cells where it modulates the lysosome trafficking protein, hinders the formation of phagolysosome, and blocks the TNF receptor-dependent apoptosis of host macrophage/monocytes. Other limitations such as resistance to and low bioavailability and bio-distribution of conventional drugs aid to their high virulence and human mortality. This review highlights the use of nanotechnology based approaches for drug formulation and delivery which could open new avenues to limit the pathogenicity of tuberculosis. Moreover phytochemicals, such as alkaloids, phenols, saponins, steroids, tannins, and terpenoids, extracted from terrestrial plants and mangroves seem promising against M. tuberculosis through different molecular mechanisms. Further understanding of the genomics and proteomics of this pathogenic microbe could also help overcome various research gaps in the path of developing a suitable therapy against tuberculosis. PMID- 29721827 TI - Burkholderia alba sp. nov., isolated from a soil sample on Halla mountain in Jeju island. AB - A rod-shaped, round and white colony-forming strain AD18T was isolated from the soil on Halla mountain in Jeju Island, Republic of Korea. Comparative analysis of 16S rRNA gene sequence revealed that this strain was closely related to Burkholderia oklahomensis C6786T (98.8%), Burkholderia thailandensis KCTC 23190T (98.5%). DNA-DNA relatedness (14.6%) indicated that the strain AD18T represents a distinct species that is separate from B. oklahomensis C6786T. The isolate grew at pH 5.0-9.0 (optimum, pH 7.0), 0-3% (w/v) NaCl (optimum, 0%), and temperature 10-40 degrees C (optimum 35 degrees C). The sole quinone of the strain was Q-8, and the predominant fatty acids were C16:0, C17:0 cyclo, and C19:0 cyclo omega8c. The genomic DNA G + C content of AD18T was 65.6 mol%. Based on these findings, strain AD18T is proposed to be a novel species in the genus Burkholderia, for which the name Burkholderia alba sp. nov. is proposed (= KCCM 43268T = JCM 32403T). The type strain is AD18T. PMID- 29721826 TI - Importance of differential identification of Mycobacterium tuberculosis strains for understanding differences in their prevalence, treatment efficacy, and vaccine development. AB - Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a serious global health problem in the 21st century because of its high mortality. Mtb is an extremely successful human-adapted pathogen that displays a multifactorial ability to control the host immune response and to evade killing by drugs, resulting in the breakdown of BCG vaccine-conferred anti-TB immunity and development of multidrug-resistant (MDR) and extensively drug-resistant (XDR) Mtb. Although genetic components of the genomes of the Mtb complex strains are highly conserved, showing over 99% similarity to other bacterial genera, recently accumulated evidence suggests that the genetic diversity of the Mtb complex strains has implications for treatment outcomes, development of MDR/XDR Mtb, BCG vaccine efficacy, transmissibility, and epidemiological outbreaks. Thus, new insights into the pathophysiological features of the Mtb complex strains are required for development of novel vaccines and for control of MDR/XDR Mtb infection, eventually leading to refinement of treatment regimens and the health care system. Many studies have focused on the differential identification of Mtb complex strains belonging to different lineages because of differences in their virulence and geographical dominance. In this review, we discuss the impact of differing genetic characteristics among Mtb complex strains on vaccine efficacy, treatment outcome, development of MDR/XDR Mtb strains, and epidemiological outbreaks by focusing on the best-adapted human Mtb lineages. We further explore the rationale for differential identification of Mtb strains for more effective control of TB in clinical and laboratory settings by scrutinizing current diagnostic methods. PMID- 29721828 TI - Characterization of Flavobacterium aquimarinum sp. nov., a halotolerant bacterium isolated from seawater. AB - A novel, aerobic, Gram-stain-negative, non-motile, non-spore forming, rod-shaped bacterium, designated strain Dol 15-39T, was isolated from a seawater sample near Geoje Island in the South Sea, Republic of Korea. The strain was found to be oxidase-negative and catalase-positive. The isolate was observed to grow at temperatures from 4 to 37 degrees C, at salinities of up to 7%, and at pH levels from 6 to 9; moreover, it was not able to degrade starch, DNA, esculin, or tyrosine. Phylogenetic analysis based on 16S rRNA gene sequences showed that Dol 15-39T was most closely related to Flavobacterium jumunjinense HME7102T with a sequence similarity of 97.3%. However, the levels of DNA-DNA relatedness between Dol 15-39T and the most closely related species were much lower than 70%, confirming that they represented distinct genomic species. The genomic DNA G + C content of Dol 15-39T was calculated to be 32.6 mol%. MK-6 was the predominant respiratory quinine, while iso-C15:0 (25.0%), iso-C15:1 G (17.0%), and iso-C17:0 3-OH (10.4%) were the major cellular fatty acids. Phosphatidylethanolamine was identified as a major polar lipid, while various unidentified aminolipids and polar lipids were also detected. Based on polyphasic taxonomic data, Dol 15-39T represents a novel species of the genus Flavobacterium, for which the name F. aquimarinum sp. nov. is proposed. The type strain is accessible under the culture collection numbers (KEMB 9005-617T = JCM 31930T). PMID- 29721829 TI - Tardibacter chloracetimidivorans gen. nov., sp. nov., a novel member of the family Sphingomonadaceae isolated from an agricultural soil from Jeju Island in Republic of Korea. AB - A pale yellow bacterial strain, designated JJ-A5T, was isolated form an agricultural soil from Jeju Island in Republic of Korea. Cells of the strain were Gram-stain-negative, motile, flagellated and rod-shaped. The strain grew at 15-30 degrees C, pH 6.0-9.0, and in the presence of 0-1.5% (w/v) NaCl. Growth occurred on R2A, but not on Luria-Bertani agar, nutrient agar, trypticase soy agar and MacConkey agar. The strain utilized alachlor as a sole carbon source for growth. The strain JJ-A5T showed 16S rRNA gene sequence similarities lower than 95.4% with members of the family Sphingomonadaceae. Phylogenetic analysis showed that the strain belongs to the family Sphingomonadaceae and strain JJ-A5T was distinctly separated from established genera of this family. The strain contained Q-10 as dominant ubiquinone and spermidine as major polyamine. The predominant cellular fatty acids were summed feature 8 (C18:1omega7c and/or C18:1omega6c), summed feature 3 (C16:1omega7c and/or C16:1omega6c), 11-methyl C18:1omega7c, C16:0 and C14:0 2-OH. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol, sphingoglycolipid, and phosphatidylcholine. The DNA G + C content of the strain was 62.7 mol%. On the basis of the phenotypic, genomic and chemotaxonomic characteristics, strain JJ-A5T is considered to represent a novel genus and species within the family Sphingomonadaceae, for which the name Tardibacter chloracetimidivorans gen. nov., sp. nov. is proposed. The type strain of Tardibacter chloracetimidivorans is JJ-A5T (= KACC 19450T = NBRC 113160T). PMID- 29721831 TI - Highly diverse endophytes in roots of Cycas bifida (Cycadaceae), an ancient but endangered gymnosperm. AB - As an ancient seed plant, cycads are one of the few gymnosperms that develop a root symbiosis with cyanobacteria, which has allowed cycads to cope with harsh geologic and climatic conditions during the evolutionary process. However, the endophytic microbes in cycad roots remain poorly identified. In this study, using next-generation sequencing techniques, we investigated the microbial diversity and composition of both the coralloid and regular roots of Cycas bifida (Dyer) K.D. Hill. Highly diverse endophytic communities were observed in both the coralloid and regular roots. Of the associated bacteria, the top five families were the Nostocaceae, Sinobacteraceae, Bradyrhizobiaceae, Bacillaceae, and Hyphomicrobiaceae. The Nectriaceae, Trichocomaceae, and Incertae sedis were the predominant fungal families in all root samples. A significant difference in the endophytic bacterial community was detected between coralloid roots and regular roots, but no difference was observed between the fungal communities in the two root types. Cyanobacteria were more dominant in coralloid roots than in regular roots. The divergence of cycad root structures and the modified physiological processes may have contributed to the abundance of cyanobionts in coralloid roots. Consequently, the colonization of cyanobacteria inhibits the assemblage of other endophytes. Our results contribute to an understanding of the species diversity and composition of the cycad-endophyte microbiome and provide an abbreviated list of potential ecological roles of the core microbes present. PMID- 29721830 TI - Terrabacter ginsengisoli sp. nov., isolated from ginseng cultivating soil. AB - A Gram-positive, strictly aerobic, nonmotile, yellowish, coccus-rod-shaped bacterium (designated Gsoil 653T) isolated from ginseng cultivating soil was characterized using a polyphasic approach to clarify its taxonomic position. The strain Gsoil 653T exhibited optimal growth at pH 7.0 on R2A agar medium at 30 degrees C. Phylogenetic analysis based on 16S rRNA gene sequence similarities, indicated that Gsoil 653T belongs to the genus Terrabacter of the family Humibacillus, and was closely related to Terrabacter tumescens DSM 20308T (98.9%), Terrabacter carboxydivorans PY2T (98.9%), Terrabacter terrigena ON10T (98.8%), Terrabacter terrae PPLBT (98.6%), and Terrabacter lapilli LR-26T (98.6%). The DNA G + C content was 70.5 mol%. The major quinone was MK-8(H4). The primary polar lipids were phosphatidylglycerol, diphosphatidylglycerol, phosphatidyl-ethanolamine. The predominant fatty acids were iso-C15:0, iso-C16:0, iso-C14:0, and anteiso-C15:0, as in the case of genus Terrabacter, thereby supporting the categorization of strain Gsoil 653T. However, the DNA-DNA relatedness between Gsoil 653T and closely related strains of Terrabacter species was low at less than 31%. Moreover, strain Gsoil 653T could be both genotypically and phenotypically distinguished from the recognized species of the genus Terrabacter. This isolate, therefore, represents a novel species, for which the name Terrabacter ginsengisoli sp. nov. is proposed with the type strain Gsoil 653T (= KACC 19444T = LMG 30325T). PMID- 29721832 TI - Core gut microbiota in Jinhua pigs and its correlation with strain, farm and weaning age. AB - Gut microbial diversity and the core microbiota of the Jinhua pig, which is a traditional, slow-growing Chinese breed with a high body-fat content, were examined from a total of 105 fecal samples collected from 6 groups of pigs at 3 weaning ages that originated from 2 strains and were raised on 3 different pig farms. The bacterial community was analyzed following high-throughput pyrosequencing of 16S rRNA genes, and the fecal concentrations of short-chain fatty acids (SCFAs) were measured by gas chromatograph. Our results showed that Firmicutes and Bacteroidetes were the dominant phyla, and Lactobacillus, Streptococcus, Clostridium, SMB53, and Bifidobacterium were the most abundant genera. Fifteen predominant genera present in every Jinhua pig sample constituted a phylogenetic core microbiota and included the probiotics Lactobacillus and Bifidobacterium, and the SCFA-producing bacteria Clostridium, Prevotella, Bacteroides, Coprococcus, Roseburia, Ruminococcus, Blautia, and Butyricicoccus. Comparisons of the microbiota compositions and SCFA concentrations across the 6 groups of pigs demonstrated that genetic background and weaning age affected the structure of the gut microbiota more significantly than the farm. The relative abundance of the core genera in the pigs, including Lactobacillus, Clostridium, Prevotella, Bacteroides, Roseburia, Ruminococcus, Blautia, and Butyricicoccus varied dramatically in pigs among the 2 origins and 3 weaning ages, while Oscillospira, Megasphaera, Parabacteroides, and Corynebacterium differed among pigs from different farms. Interestingly, there was a more significant influence of strain and weaning age than of rearing farm on the SCFA concentrations. Therefore, strain and weaning age appear to be the more important factors shaping the intestinal microbiome of pigs. PMID- 29721835 TI - Erratum to: A murine colitis model developed using a combination of dextran sulfate sodium and Citrobacter rodentium. AB - In the article by Park et al. published in Journal of Microbiology 2018; 56, 272 279, the supplementary data Figs S1 and S2 should be corrected as below. The original article can be found online at https://doi.org/10.1007/s12275-018-7504-x . PMID- 29721834 TI - Comparative genomic analysis of Geosporobacter ferrireducens and its versatility of anaerobic energy metabolism. AB - Members of the family Clostridiaceae within phylum Firmicutes are ubiquitous in various iron-reducing environments. However, genomic data on iron-reducing bacteria of the family Clostridiaceae, particularly regarding their environmental distribution, are limited. Here, we report the analysis and comparison of the genomic properties of Geosporobacter ferrireducens IRF9, a strict anaerobe that ferments sugars and degrades toluene under iron-reducing conditions, with those of the closely related species, Geosporobacter subterraneus DSM 17957. Putative alkyl succinate synthase-encoding genes were observed in the genome of strain IRF9 instead of the typical benzyl succinate synthase-encoding genes. Canonical genes associated with iron reduction were not observed in either genome. The genomes of strains IRF9 and DMS 17957 harbored genes for acetogenesis, that encode two types of Rnf complexes mediating the translocation of H+ and Na+ ions, respectively. Strain IRF9 harbored two different types of ATPases (Na+-dependent F-type ATPase and H+-dependent V-type ATPase), which enable full exploitation of ion gradients. The versatile energy conservation potential of strain IRF9 promotes its survival in various environmental conditions. PMID- 29721833 TI - An efficient Agrobacterium-mediated transformation method for aflatoxin generation fungus Aspergillus flavus. AB - Aspergillus flavus often invade many important corps and produce harmful aflatoxins both in preharvest and during storage stages. The regulation mechanism of aflatoxin biosynthesis in this fungus has not been well explored mainly due to the lack of an efficient transformation method for constructing a genome-wide gene mutant library. This challenge was resolved in this study, where a reliable and efficient Agrobacterium tumefaciens-mediated transformation (ATMT) protocol for A. flavus NRRL 3357 was established. The results showed that removal of multinucleate conidia, to collect a homogenous sample of uninucleate conidia for use as the transformation material, is the key step in this procedure. A. tumefaciens strain AGL-1 harboring the ble gene for zeocin resistance under the control of the gpdA promoter from A. nidulans is suitable for genetic transformation of this fungus. We successfully generated A. flavus transformants with an efficiency of ~ 60 positive transformants per 106 conidia using our protocol. A small-scale insertional mutant library (~ 1,000 mutants) was constructed using this method and the resulting several mutants lacked both production of conidia and aflatoxin biosynthesis capacity. Southern blotting analysis demonstrated that the majority of the transformants contained a single T DNA insert on the genome. To the best of our knowledge, this is the first report of genetic transformation of A. flavus via ATMT and our protocol provides an effective tool for construction of genome-wide gene mutant libraries for functional analysis of important genes in A. flavus. PMID- 29721836 TI - Roultella ornithinolytica infection in infancy: a case of febrile urinary tract infection. AB - Raoultella ornithinolytica is a Gram-negative, non-motile, encapsulated, aerobic bacillus belonging to the Enterobacteriaceae family. R. ornithinolytica is a not very common, but emergent causal agent of human infection, and its expression of beta-lactamase provides resistance to commonly used antibiotics. The pathogenetic potential of R. ornithinolytica isolates in human disease has become increasingly important. Several cases of hospital-acquired infection, mostly associated with invasive procedures, or in patients with co-morbidity caused by R. ornithinolytica, have been previously reported in the adult population. In pediatric population, two cases in immunocompromised children, one case in an infant with visceral heterotaxy and one case of catheter-related bacteraemia are described. Here, we present the first case of febrile urinary tract infection due to R. ornithinolytica in an 8-month-old infant, recovered from a previous febrile UTI caused by E. coli and without co-morbidity. The empiric therapy with ceftriaxone, followed by cefpodoxime proxetil, resolved symptoms: the clinical condition of the infant improved rapidly and the treatment eradicated urine from the R. ornithinolytica infection. Since other pathogens rather than R. ornithinolytica are usually identified in children with urinary tract infections, including Escherichia coli, Proteus, Klebsiella and Pseudomonas, the identification of this microorganism in our patient's urine was also unexpected. PMID- 29721837 TI - Change-of-Direction Biomechanics: Is What's Best for Anterior Cruciate Ligament Injury Prevention Also Best for Performance? AB - Change-of-direction maneuvers (e.g., side-step cutting) are an important aspect of performance in multi-directional sports, but these maneuvers are also associated with anterior cruciate ligament (ACL) injury. Despite this, the impact of biomechanics on ACL injury risk and performance is often examined in isolation. The purpose of this review was to examine the alignment between biomechanical recommendations for ACL injury prevention and performance with regard to change-of-direction maneuvers. Several studies linking change-of direction biomechanics to both ACL injury risk and performance were examined. A degree of overlap was identified between biomechanical strategies that could both reduce ACL injury risk and enhance performance during change-of-direction maneuvers. A fore-foot footfall pattern along with trunk rotation and lateral flexion in the intended cutting direction were identified as biomechanical strategies that could both reduce potentially hazardous knee joint moments and enhance change-of-direction speed. Minimizing knee valgus during change-of direction maneuvers may also reduce ACL injury risk, with this biomechanical strategy found to have no impact on performance. Certain biomechanical strategies proposed to reduce ACL injury risk were linked to reduced change-of-direction performance. A narrow foot placement and "soft" landings with greater knee flexion were identified as ACL injury prevention strategies that could have a negative impact on performance. The findings of this review emphasize the need to consider both ACL injury risk and performance when examining the biomechanics of change-of-direction maneuvers. PMID- 29721838 TI - Relationships Between Neighbourhood Physical Environmental Attributes and Older Adults' Leisure-Time Physical Activity: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Activity-friendly neighbourhood physical environments with access to recreational facilities are hypothesised to facilitate leisure-time physical activity (LTPA) among older adults (>= 65 years old). The aim of the current study was to systematically review and quantitatively summarise study findings on the relationships between physical environmental attributes and LTPA among older adults. METHODS: An extensive search of literature, including grey literature, yielded 72 articles eligible for inclusion. The reported associations between seven categories of environmental attributes and six LTPA outcomes were extracted, weighted by sample size and study quality, and quantitatively summarised. Reported moderating effects of individual and environmental characteristics and neighbourhood definition were also examined. RESULTS: We observed positive associations for walkability (p = 0.01), land-use mix-access (p = 0.02) and aesthetically pleasing scenery (p < 0.001) with leisure-time walking. For leisure-time walking within the neighbourhood, evidence was found for positive associations with land-use mix-access (p = 0.03) and access to public transit (p = 0.05), and a negative association with barriers to walking/cycling (p = 0.03). Evidence for positive relationships between overall LTPA and access to recreational facilities (p = 0.01) and parks/open space (p = 0.04) was found. Several environmental attribute-LTPA outcome combinations were insufficiently studied to draw conclusions. No consistent moderating effects were observed for individual and environmental characteristics and neighbourhood definition. CONCLUSIONS: The observed significant relationships can be used to inform policy makers and planners on how to (re-)design neighbourhoods that promote LTPA among older adults. Many environmental attribute-LTPA outcome relationships have been studied insufficiently and several methodological issues remain to be addressed. SYSTEMATIC REVIEW REGISTRATION NUMBER: PROSPERO 2016:CRD42016051180. PMID- 29721840 TI - Letter to Editor: Fleming D, Stone J, Tansley P. Spontaneous Regression and Resolution of Breast Implant-Associated Anaplastic Large Cell Lymphoma: Implications for Research, Diagnosis and Clinical Management, APS 2018. PMID- 29721841 TI - Histomorphometric analysis of the choroid of donkeys, buffalos, camels and dogs. AB - AIM: The present study was carried out to investigate the morphological and histomorphometric characters of choroid in donkeys, buffalos, camels and dogs. RESULTS: The findings of the study revealed that, macroscopically, the choroid was consisted of two areas in all studied animals, except in camel which consists of one area. Histologically, the choroid consists of five layers. Interestingly, the anterior borders of all investigated animals were free of pigments except in camel. Morphometric analysis revealed significant species differences in the mean total thickness of the choroid and its different layers. In addition, significant differences were also found between the ratios of the means of different layers to the total thickness of the choroid. CONCLUSION: In conclusion, these variations might be related to the different lifestyles and visual behavior of the investigated animals. PMID- 29721839 TI - Association of Lower Limb Compression Garments During High-Intensity Exercise with Performance and Physiological Responses: A Systematic Review and Meta analysis. AB - BACKGROUND: Although compression garments are used to improve sports performance, methodological approaches and the direction of evidence regarding garments for use in high-intensity exercise settings are diverse. OBJECTIVES: Our primary aim was to summarize the association between lower-limb compression garments (LLCGs) and changes in sports performance during high-intensity exercise. We also aimed to summarize evidence about the following physiological parameters related to sports performance: vertical jump height (VJ), maximal oxygen uptake (VO2max), submaximal oxygen uptake (VO2submax), blood lactate concentrations ([La]), and ratings of perceived exertion (RPE, 6-20 Borg scale). METHODS: We searched electronic databases (PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov) and reference lists for previous reviews. Eligible studies included randomized controlled trials with athletes or physically active subjects (>= 18 years) using any type of LLCG during high-intensity exercise. The results were described as weighted mean difference (WMD) with a 95% confidence interval (95% CI). RESULTS: The 23 included studies showed low statistical heterogeneity for the pooled outcomes. We found that LLCGs yielded similar running performance to controls (50 400 m: WMD 0.06 s [95% CI - 1.99 to 2.11]; 800-3000 m: WMD 6.10 s [95% CI - 7.23 to 19.43]; > 5000 m: WMD 1.01 s [95% CI - 84.80 to 86.82]). Likewise, we found no evidence that LLCGs were superior in secondary outcomes (VJ: WMD 2.25 cm [95% CI 2.51 to 7.02]; VO2max: WMD 0.24 mL.kg-1.min-1 [95% CI - 1.48 to 1.95]; VO2submax: WMD - 0.26 mL.kg-1.min-1 [95% CI - 2.66 to 2.14]; [La]: WMD 0.19 mmol/L [95% CI - 0.22 to 0.60]; RPE: WMD - 0.20 points [95% CI - 0.48 to 0.08]). CONCLUSIONS: LLCGs were not associated with improved performance in VJ, VO2max, VO2submax, [La], or RPE during high-intensity exercise. Such evidence should be taken into account when considering using LLCGs to enhance running performance. PMID- 29721842 TI - Pigment dispersion syndrome and pigmentary glaucoma: a review and update. AB - INTRODUCTION: Potential factors influencing stereopsis were investigated in patients with both refractive accommodative esotropia (RAE) and amblyopia. Pigment dispersion syndrome (PDS) is a condition where anomalous iridozonular contact leads to pigment dispersion throughout the anterior segment and the released pigment is abnormally deposited on various ocular structures. CLINICAL PRESENTATION: The clinical presentation of PDS is defined by the presence of pigmented cells on the corneal endothelium, an increase of pigmentation of the trabecular meshwork, and mid-periphery transillumination defects of the iris. This syndrome, more common in myopes, is usually bilateral and can be associated with ocular hypertension or glaucoma. Secondary open-angle pigmentary glaucoma (PG) can develop due to reduction of the outflow of aqueous humour and consequent increase in intraocular pressure leading to glaucomatous optic neuropathy. Diagnosis of PG is commonly between 40 and 50 years of age, occurring more frequently in men. The advent of ultrasound biomicroscopy and anterior segment optical coherence tomography has contributed to enhancing our knowledge on the condition. Typical alterations of the anterior segment are the posterior insertion of the iris and iris concavity. Treatment of PG should be initiated early to hinder disease progression, glaucomatous damage, and vision loss. Management is based on medical therapy, laser iridotomy, selective laser trabeculoplasty, and filtration procedures. CONCLUSIONS: The differential diagnosis of PDS with other disorders can be challenging and awareness of the condition together with meticulous ophthalmologic examination allows early diagnosis followed by appropriate management strategies. The present review is a comprehensive report on the clinical characteristics, pathogenesis, current management, and status quo of PDS and PG. PMID- 29721843 TI - Hyperthyroxinemia at birth: a cause of idiopathic neonatal hyperbilirubinemia? AB - BACKGROUND: Some neonates develop idiopathic hyperbilirubinemia (INHB) requiring phototherapy, yet with no identifiable causes. We searched for an association between abnormal thyroid levels after birth and INHB. METHODS: Of 5188 neonates, 1681 (32.4%) were excluded due to one or more risk factors for hyperbilirubinemia. Total thyroxine (TT4) and thyroid stimulating hormone values were sampled routinely at 40-48 hours of age and measured in the National Newborn Screening Program. RESULTS: Of the 3507 neonates without known causes for hyperbilirubinemia, 61 (1.7%) developed INHB and received phototherapy. Univariate analyses found no significant association between mode of delivery and INHB (vacuum-delivered neonates were a priori excluded). Nonetheless, in cesarean delivered (CD) neonates, two variables had significant association with INHB: TT4 >= 13 ug/dL and birth at 38-38.6 weeks. In vaginally delivered (VD) born neonates, INHB was associated with weight loss > 7.5% up to 48 hours of age. Multivariate logistic regression analysis showed a strong effect of mode of delivery on possible significant association with INHB. In CD neonates, such variables included: TT4 >= 13 ug/dL [P = 0.025, odds ratio (OR) 5.49, 95% confidence interval (CI) 1.23-24.4] and birth at 38-38.6 weeks (P = 0.023, OR 3.44, 95% CI 1.19-9.97). In VD neonates, weight loss > 7.5% (P = 0.019, OR 2.1, 95% CI 1.13-3.83) and 1-min Apgar score < 9 (P < 0.001, OR 3.8, 95% CI 1.83-7.9), but not TT4, showed such an association. CONCLUSIONS: INHB was significantly associated with birth on 38-38.6 week and TT4 (>= 13 ug/dL) in CD neonates, and with a weight loss > 7.5% in VD neonates. We herein highlight some acknowledged risk factors for neonatal hyperbilirubinemia, and thus minimize the rate of INHB. PMID- 29721845 TI - Integrity in Biomedical Research: A Systematic Review of Studies in China. AB - Recent empirical evidence has demonstrated that research misconduct occurs to a substantial degree in biomedical research. It has been suggested that scientific integrity is also of concern in China, but this seems to be based largely on anecdotal evidence. We, therefore, sought to explore the Chinese situation, by making a systematic review of published empirical studies on biomedical research integrity in China. One of our purposes was also to summarize the existing body of research published in Chinese. We searched the China National Knowledge Infrastructure, Wanfang Data, PubMed and Web of Science for potentially relevant studies, and included studies meeting our inclusion criteria, i.e. mainly those presenting empirically obtained data about the practice of research in China. All the data was extracted and synthesized using an inductive approach. Twenty-one studies were included for review. Two studies used qualitative methods (interviews) and nineteen studies used quantitative methods (questionnaires). Studies involved mainly medical postgraduates and nurses and they investigated awareness, attitudes, perceptions and experiences of research integrity and misconduct. Most of the participants in these 21 studies reported that research integrity is of great importance and that they obey academic norms during their research. Nevertheless, the occurrence of research misbehaviors, such as fabrication, falsification, plagiarism, improper authorship and duplicate submission was also reported. Strengthening research integrity training, developing the governance system and improving the scientific evaluation system were areas of particular attention in several studies. Our review demonstrates that a substantial number of articles have been devoted to research integrity in China, but only a few studies provide empirical evidence. With more safeguard measures of research integrity being taken in China, it would be crucial to conduct more research to explore researchers' in-depth perceptions and evaluate the changes. PMID- 29721844 TI - Medicines Information and the Regulation of the Promotion of Pharmaceuticals. AB - Many factors contribute to the inappropriate use of medicines, including not only a lack of information but also inaccurate and misleading promotional information. This review examines how the promotion of pharmaceuticals directly affects the prescribing and use of medicines. We define promotion broadly as all actions taken directly by pharmaceutical companies with the aim of enhancing product sales. We look in greater detail at promotion techniques aimed at prescribers, such as sales representatives, pharmaceutical advertisements in medical journals and use of key opinion leaders, along with the quality of information provided and the effects thereof. We also discuss promotion to the public, through direct to-consumer advertising, and its effects. Finally, we consider initiatives to regulate promotion that come from industry, government and nongovernmental organizations. PMID- 29721846 TI - Demographic Variables of Corruption in the Chinese Construction Industry: Association Rule Analysis of Conviction Records. AB - Corruption in the construction industry is a serious problem in China. As such, fighting this corruption has become a priority target of the Chinese government, with the main effort being to discover and prosecute its perpetrators. This study profiles the demographic characteristics of major incidences of corruption in construction. It draws on the database of the 83 complete recorded cases of construction related corruption held by the Chinese National Bureau of Corruption Prevention. Categorical variables were drawn from the database, and 'association rule mining analysis' was used to identify associations between variables as a means of profiling perpetrators. Such profiling may be used as predictors of future incidences of corruption, and consequently to inform policy makers in their fight against corruption. The results signal corruption within the Chinese construction industry to be correlated with age, with incidences rising as managers' approach retirement age. Moreover, a majority of perpetrators operate within government agencies, are department deputies in direct contact with projects, and extort the greatest amounts per case from second tier cities. The relatively lengthy average 6.4-year period before cases come to public attention corroborates the view that current efforts at fighting corruption remain inadequate. PMID- 29721847 TI - [Diagnosis F45 is scientifically reliable]. PMID- 29721848 TI - Pyogenic granuloma originating in the pulmonary artery. AB - We herein report an unreported case of pyogenic granuloma that originated in the pulmonary artery. A 38-year-old man was urgently hospitalized with dyspnea and back pain. He had been on hemodialysis for 2 years due to chronic renal failure. We performed contrast-enhanced computed tomography and detected a mass occluding the left main pulmonary artery. The maximum standardized uptake value (SUVmax) of 18F-fluorodeoxy glucose (FDG) in the mass was 4.1. We made a tentative diagnosis of pulmonary artery tumor, and planned an operation. We performed median sternotomy and left anterolateral thoracotomy. As the tumor had not reached the bottom of the left pulmonary artery, we first performed left upper lobectomy. We then performed resection of the pulmonary artery tumor under cardiopulmonary bypass and reconstructed the pulmonary artery with self-pericardium. The pathological diagnosis was pyogenic granuloma. To our knowledge, pyogenic granuloma originating in the pulmonary artery has never been reported before. PMID- 29721849 TI - Sunitinib does not acutely alter left ventricular systolic function, but induces diastolic dysfunction. AB - PURPOSE: Cancer chemotherapies have improved the prognosis of cancer patients in recent years; however, their side effects on the cardiovascular systems have emerged as a major concern in the field of both cardiology and oncology. In particular, multi-targeted tyrosine kinase inhibitors are known to induce various types of cardiovascular adverse events including hypertension, QT-interval prolongation and heart failure, but their underlying mechanisms remain elusive. To explore how to better predict such drug-induced cardiovascular adverse events, we assessed the electropharmacological effects of sunitinib using the halothane anesthetized dogs (n = 5), while plasma concentrations of cardiac enzymes including aspartate aminotransferase, lactate dehydrogenase, creatinine kinase and cardiac troponin I were measured. METHODS: Sunitinib was intravenously administered at 0.01 and 0.1 mg/kg for 10 min with 20 min interval. RESULTS: Sunitinib decreased the amplitude of maximum downstroke velocity of the left ventricular pressure, prolonged the isovolumic relaxation time and increased the left ventricular end-diastolic pressure in a dose-related manner without affecting the other cardiohemodynamic and electrophysiological variables. More importantly, sunitinib significantly elevated cardiac troponin I level for 30-60 min after the high dose without altering the other biomarkers. CONCLUSIONS: Monitoring of the cardiac diastolic function together with cardiac troponin I after the start of sunitinib administration may become a reliable measure to predict the onset of sunitinib-induced cardiovascular adverse events. PMID- 29721850 TI - Exposure-response relationship for ramucirumab from the randomized, double-blind, phase 3 REVEL trial (docetaxel versus docetaxel plus ramucirumab) in second-line treatment of metastatic non-small cell lung cancer. AB - PURPOSE: Ramucirumab plus docetaxel improved survival in REVEL, a randomized phase 3 trial for patients with Stage IV non-small cell lung cancer after standard platinum-based chemotherapy. This exploratory analysis evaluated the exposure-response relationship of ramucirumab from REVEL. METHODS: Patients received ramucirumab (10 mg/kg) or placebo plus docetaxel (75 mg/m2) every 3 weeks. Pharmacokinetic samples were collected. A population pharmacokinetic analysis predicted ramucirumab minimum concentration after first-dose administration (Cmin,1) and average concentration at steady state (Cave,ss). Predicted Cmin,1 and Cave,ss were used to evaluate the relationship between ramucirumab exposure and efficacy and safety, respectively. Exposure-efficacy was assessed by Kaplan-Meier and Cox regression analyses; exposure-safety was assessed by ordered categorical analyses. RESULTS: Analyses included 376 patients treated with ramucirumab plus docetaxel and 366 patients treated with placebo plus docetaxel (364 for safety population). After adjusting for corresponding prognostic factors, the association between overall survival (OS) and Cmin,1 was statistically significant (p = 0.0110), although progression-free survival (PFS) showed a marginal association (p = 0.0515). At high ramucirumab exposures (Cmin,1), greater improvements (smaller hazard ratios) were seen for OS and PFS when stratified by Cmin,1 exposure quartiles. A statistically significant correlation was observed between ramucirumab Cave,ss and grade >= 3 febrile neutropenia and hypertension. CONCLUSIONS: An association was observed between ramucirumab exposure and efficacy. Higher ramucirumab exposure was associated with improved clinical outcomes and increased toxicity in this analysis. Two exposure-response prospective randomized trials are being conducted to address causation (NCT02443883 and NCT02514551), with encouraging preliminary results (Ajani et al. in Ann Oncol 28:abstr 698P, 2017). PMID- 29721851 TI - Deconstructing Schizophrenia: Advances in Preclinical Models for Biomarker Identification. AB - Schizophrenia is considered to develop as a consequence of genetic and environmental factors impacting on brain neural systems and circuits during vulnerable neurodevelopmental periods, thereby resulting in symptoms in early adulthood. Understanding of the impact of schizophrenia risk factors on brain biology and behaviour can help in identifying biologically relevant pathways that are attractive for informing clinical studies and biomarker development. In this chapter, we emphasize the importance of adopting a reciprocal forward and reverse translation approach that is iteratively updated when additional new information is gained, either preclinically or clinically, for offering the greatest opportunity for discovering panels of biomarkers for the diagnosis, prognosis and treatment of schizophrenia. Importantly, biomarkers for identifying those at risk may inform early intervention strategies prior to the development of schizophrenia. Given the emerging nature of this approach in the field, this review will highlight recent research of preclinical biomarkers in schizophrenia that show the most promise for informing clinical needs with an emphasis on relevant imaging, electrophysiological, cognitive behavioural and biochemical modalities. The implementation of this reciprocal translational approach is exemplified firstly by the production and characterization of preclinical models based on the glutamate hypofunction hypothesis, genetic and environmental risk factors for schizophrenia (reverse translation), and then the recent clinical recognition of the thalamic reticular thalamus (TRN) as an important locus of brain dysfunction in schizophrenia as informed by preclinical findings (forward translation). PMID- 29721852 TI - Smaller caliber of the internal carotid artery in patients with ipsilateral aplasia of the A1 segment of the anterior cerebral artery: a study with CTA. AB - To measure the diameter and the transsectional area of the internal carotid arteries (ICA) on CT Angiography (CTA) in patients with aplasia of the A1-segment of the ACA (A1) and in patients with symmetrical A1, the mean diameter and area of the ICA on both sides were measured at a level of 2 cm below the skull base with a commercially available CT software in 41 consecutive patients with aplasia of A1 observed during a 12-month period on CTA and in 41 control patients with symmetrical A1. The mean diameter of the ipsilateral ICA was 3.83 +/- 0.60 mm versus 4.86 +/- 0.60 mm as mean diameter of the contralateral ICA and versus 4.40 +/- 0.60 mm as mean diameter of both ICAs in the control group of patients. The mean area of the ipsilateral ICA was 11.58 +/- 3.80 mm2 versus 18. 82 +/- 7.39 mm2 as mean area of the contralateral ICA and versus 15.29 +/- 4.42 mm2 as mean area of both ICA in the control group of patients. These differences are statistically highly significant. In patients with symmetrical A1, there was no statistical difference between the diameter or area of both internal carotid arteries. In conclusion, in patients with aplasia of A1, the ipsilateral diameter and area of the cervical ICA is smaller than the diameter and area of the contralateral ICA and smaller than the diameter and area of both internal carotid arteries in patients with symmetrical A1. PMID- 29721853 TI - Uncommon and/or bizarre features of dementia: Part III. AB - Clinical neurologists have long recognized that dementia can present as atypical or variant syndromes/symptoms. This study aimed at describing uncommon or bizarre symptoms/syndromes observed in patients suffering from dementia. Medline and Google scholar searches were conducted for relevant articles, chapters, and books published before 2018. Search terms used included compulsion, dementia, extracampine hallucination, disordered gambling, humour, and obsession. Publications found through this indexed search were reviewed for further relevant references. The uncommon/bizarre feature of dementia was described as case reports and there were no systematic investigations. PMID- 29721854 TI - Abscisic Acid Supplementation Rescues High Fat Diet-Induced Alterations in Hippocampal Inflammation and IRSs Expression. AB - Accumulated evidence indicates that neuroinflammation induces insulin resistance in the brain. Moreover, both processes are intimately linked to neurodegenerative disorders, including Alzheimer's disease. Potential mechanisms underlying insulin resistance include serine phosphorylation of the insulin receptor substrate (IRS) or insulin receptor (IR) misallocation. However, only a few studies have focused on IRS expression in the brain and its modulation in neuroinflammatory processes. This study used the high-fat diet (HFD) model of neuroinflammation to study the alterations of IR, an insulin-like growth factor receptor (IGF1R) and IRS expressions in the hippocampus. We observed that HFD effectively reduced mRNA and protein IRS2 expression. In contrast, a HFD induced the upregulation of the IRS1 mRNA levels, but did not alter an IR and IGF1R expression. As expected, we observed that a HFD increased hippocampal tumor necrosis factor alpha (TNFalpha) and amyloid precursor protein (APP) levels while reducing brain-derived neurotrophic factor (BDNF) expression and neurogenesis. Interestingly, we found that TNFalpha correlated positively with IRS1 and negatively with IRS2, whereas APP levels correlated positively only with IRS1 but not IRS2. These results indicate that IRS1 and IRS2 hippocampal expression can be affected differently by HFD-induced neuroinflammation. In addition, we aimed to establish whether abscisic acid (ABA) can rescue hippocampal IRS1 and IRS2 expression, as we had previously shown that ABA supplementation prevents memory impairments and improves neuroinflammation induced by a HFD. In this study, ABA restored HFD induced hippocampal alterations, including IRS1 and IRS2 expression, TNFalpha, APP, and BDNF levels and neurogenesis. In conclusion, this study highlights different regulations of hippocampal IRS1 and IRS2 expression using a HFD, indicating the important differences of these scaffolding proteins, and strongly supports ABA therapeutic effects. PMID- 29721855 TI - Id1 and Sonic Hedgehog Mediate Cell Cycle Reentry and Apoptosis Induced by Amyloid Beta-Peptide in Post-mitotic Cortical Neurons. AB - Amyloid beta-peptide (Abeta), the neurotoxic component of senile plaques in Alzheimer's disease (AD) brains, is known to trigger cell cycle reentry in post mitotic neurons followed by apoptosis. However, the underlying mechanisms remain unclear. Recently, we have reported that Abetas stimulate the expression of inhibitor of differentiation-1 (Id1) to induce sonic hedgehog (SHH) (Hung et al., Mol Neurobiol 53(2):793-809, 2016), and both are mitogens capable of triggering cell cycle progression. In this work, we tested the hypothesis that Abeta-induced Id1 and SHH contribute to cell cycle reentry leading to apoptosis in neurons. We found that Abeta triggered cell cycle progression in the post-mitotic neurons, as indicated by the increased expression of two G1-phase markers including cyclin D1 and phosphorylated retinoblastoma protein (pRb), two G2-phase markers such as proliferating cell nuclear antigen (PCNA) and incorporation of 5-bromo-2' deoxyuridine (BrdU) into newly synthesized DNA, as well as the mitotic marker histone H3 phosphorylated at Ser-10. As expected, Abeta also enhanced caspase-3 cleavage in the cortical neurons. Id1 siRNA, the neutralization antibody against SHH (SHH-Ab), and the cyclin-dependent kinase (CDK)-4/6 inhibitor PD0332991 all attenuated, in part or in full, the Abeta-induced expression of these cell cycle markers. Indeed, exogenous recombinant Id1 protein and the biologically active N terminal fragment of SHH (SHH-N) were both sufficient to enhance the expression of cell cycle markers independent of Abeta. Taken together, our results revealed the critical roles of Id1 and SHH mediating Abeta-dependent cell cycle reentry and subsequently caspase-dependent apoptosis in the fully differentiated post mitotic neurons, at least in vitro. PMID- 29721856 TI - Lignin-Based Composite Materials for Photocatalysis and Photovoltaics. AB - Depleting conventional fuel reserves has prompted the demand for the exploration of renewable resources. Biomass is a widely available renewable resource that can be valorized to produce fuels, chemicals, and materials. Among all the fractions of biomass, lignin has been underutilized. Due to its complex structure, recalcitrant nature, and heterogeneity, its valorization is relatively challenging. This review focuses on the utilization of lignin for the preparation of composite materials and their application in the field of photocatalysis and photovoltaics. Lignin can be used as a photocatalyst support for its potential application in photodegradation of contaminants. The interaction between the components in hybrid photocatalysts plays a significant role in determining the photocatalytic performance. The application of lignin as a photocatalyst support tends to control the size of the particles and allows uniform distribution of the particles that influence the characteristics of the photocatalyst. Lignin as a semiconductive polymer dopant for photoanodes in photovoltaic cells can improve the photoconversion efficiency of the cell. Recent success in the development of lignosulfonates dopant for hole transport materials in photovoltaics will pave the way for further research in lignin-based high-performance organic electronic devices. PMID- 29721857 TI - Correction to: Identification of novel mutations in FFPE lung adenocarcinomas using DEPArray sorting technology and next-generation sequencing. AB - In the original article, part of Table 1 headings and entries were missing. The correct Table is as shown below. The original article has been corrected. PMID- 29721858 TI - Correction to: Impact of Prenatal and Postnatal Treatment of Sodium Fluoride and Aluminum Chloride on Some Hormonal and Sensorimotor Aspects in Rats. AB - The original version of this article contained a mistake: The author name Ahood A. Al-Eidan was incorrectly written as Ahoud A. Al-Eidan. PMID- 29721859 TI - Health Risk Assessment and Urinary Excretion of Children Exposed to Arsenic through Drinking Water and Soils in Sonora, Mexico. AB - Environmental arsenic exposure is associated with increased risk of non-cancerous chronic diseases and a variety of cancers in humans. The aims of this study were to carry out for the first time a health risk assessment for two common arsenic exposure routes (drinking water and soil ingestion) in children living in the most important agricultural areas in the Yaqui and Mayo valleys in Sonora, Mexico. Drinking water sampling was conducted in the wells of 57 towns. A cross sectional study was done in 306 children from 13 villages in the valleys. First morning void urine samples were analyzed for inorganic arsenic (InAs) and monomethyl and dimethyl arsenic (MMA and DMA) by HPLC/ICP-MS. The results showed a wide range of arsenic levels in drinking water between 2.7 and 98.7 MUg As/L. Arsenic levels in agricultural and backyard soils were in the range of < 10-27 mg As/kg. The hazard index (HI) = ?hazard quotient (HQ) for drinking water, agricultural soil, and backyard soil showed values > 1 in 100% of the study towns, and the carcinogenic risk (CR) was greater than 1E-04 in 85%. The average of arsenic excreted in urine was 31.7 MUg As/L, and DMA had the highest proportion in urine, with averages of 77.8%, followed by InAs and MMA with 11.4 and 10.9%, respectively, percentages similar to those reported in the literature. Additionally, positive correlations between urinary arsenic levels and HI values were found (r = 0.59, P = 0.000). These results indicated that this population is at high risk of developing chronic diseases including cancer. PMID- 29721860 TI - Correction to: Cervical pedicle screw instrumentation is more reliable with O-arm based 3D navigation: analysis of cervical pedicle screw placement accuracy with O arm-based 3D navigation. AB - Unfortunately, the second author name of the above-mentioned article was incorrectly published in original publication. The complete correct name is given below: Hamid Rahmatullah Bin Abd Razak. The original article has been corrected. PMID- 29721861 TI - Lumbar epidural lipomatosis is associated with visceral fat and metabolic disorders. AB - PURPOSE: Lumbar spinal epidural lipomatosis (LEL) is a condition characterized by excessive deposition of epidural fat in the spinal canal. Metabolic abnormalities may be associated with LEL, but few validated reports exist. Thus, we investigated the association between LEL and metabolic disorders in this study. METHODS: A total of 218 patients who had neurological symptoms due to neural compression in the lumbar spinal canal were examined by magnetic resonance imaging (MRI), abdominal computed tomography (CT) scans and blood tests. We evaluated the epidural fat, dural sac and spinal canal areas using MRI, and the visceral fat and subcutaneous fat areas using abdominal CT. We compared the patients' demographics and the radiological parameters between the LEL and non LEL patients. RESULTS: There were 58 LEL patients and 160 non-LEL patients. The LEL group included more men than women. In the MRI measurement, the dural sac area was similar between the LEL and non-LEL patients; however, the epidural fat/spinal canal ratio was much greater in the LEL group. In the LEL patients, factors associated with metabolic disorders, such as visceral fat area, uric acid (UA) and insulin levels, were significantly greater, compared to the non-LEL patients. In the logistic regression analysis, UA and visceral fat area were the independent explanatory factors in the pathogenesis of LEL. CONCLUSIONS: LEL patients had significantly more visceral fat and increased levels of insulin, UA and ferritin, which are closely related with metabolic disorders. This study indicates that the increased epidural fat in the spinal canal seen in the LEL patients is associated with metabolic syndrome. These slides can be retrieved under Electronic Supplementary material. PMID- 29721862 TI - ? PMID- 29721863 TI - ? PMID- 29721864 TI - ? PMID- 29721866 TI - ? PMID- 29721865 TI - ? PMID- 29721867 TI - ? PMID- 29721868 TI - ? PMID- 29721870 TI - [Extended applications for cochlear implantation]. PMID- 29721869 TI - [Indications for conversion of laparoscopic to open cholecystectomy]. PMID- 29721871 TI - [Smoking cessation - physician's advice needs to be improved]. PMID- 29721872 TI - [Setting realistic goals for pain therapy in chronic non-tumor pain]. PMID- 29721873 TI - [Hands off the ultrasound!] PMID- 29721874 TI - ? PMID- 29721876 TI - ? PMID- 29721875 TI - ? PMID- 29721877 TI - ? PMID- 29721878 TI - ? PMID- 29721879 TI - ? PMID- 29721880 TI - ? PMID- 29721881 TI - ? PMID- 29721883 TI - ? PMID- 29721882 TI - ? PMID- 29721884 TI - ? PMID- 29721886 TI - ? PMID- 29721885 TI - ? PMID- 29721887 TI - ? PMID- 29721888 TI - ? PMID- 29721889 TI - ? PMID- 29721890 TI - ? PMID- 29721891 TI - ? PMID- 29721893 TI - ? PMID- 29721892 TI - ? PMID- 29721894 TI - ? PMID- 29721896 TI - [Bacteriophage therapy: Fighting bacteria with viruses]. PMID- 29721895 TI - ? PMID- 29721897 TI - ? PMID- 29721898 TI - ? PMID- 29721899 TI - ? PMID- 29721901 TI - ? PMID- 29721900 TI - ? PMID- 29721902 TI - ? PMID- 29721903 TI - ? PMID- 29721905 TI - ? PMID- 29721907 TI - ? PMID- 29721904 TI - ? PMID- 29721909 TI - ? PMID- 29721908 TI - ? PMID- 29721910 TI - ? PMID- 29721911 TI - [Overview of treatment of localized and metastatic renal cell carcinoma (RCC)]. PMID- 29721912 TI - A Middle Eastern Founder Mutation Expands the Genotypic and Phenotypic Spectrum of Mitochondrial MICU1 Deficiency: A Report of 13 Patients. AB - MICU1 encodes a Ca2+ sensing, regulatory subunit of the mitochondrial uniporter, a selective calcium channel within the organelle's inner membrane. Ca2+ entry into mitochondria helps to buffer cytosolic Ca2+ transients and also activates ATP production within the organelle. Mutations in MICU1 have previously been reported in 17 children from nine families with muscle weakness, fatigue, normal lactate, and persistently elevated creatine kinase, as well as variable features that include progressive extrapyramidal signs, learning disabilities, nystagmus, and cataracts. In this study, we report the clinical features of an additional 13 patients from consanguineous Middle Eastern families with recessive mutations in MICU1. Of these patients, 12/13 are homozygous for a novel founder mutation c.553C>T (p.Q185*) that is predicted to lead to a complete loss of function of MICU1, while one patient is compound heterozygous for this mutation and an intragenic duplication of exons 9 and 10. The founder mutation occurs with a minor allele frequency of 1:60,000 in the ExAC database, but in ~1:500 individual in the Middle East. All 13 of these patients presented with developmental delay, learning disability, muscle weakness and easy fatigability, and failure to thrive, as well as additional variable features we tabulate. Consistent with previous cases, all of these patients had persistently elevated serum creatine kinase with normal lactate levels, but they also exhibited elevated transaminase enzymes. Our work helps to better define the clinical sequelae of MICU1 deficiency. Furthermore, our work suggests that targeted analysis of the MICU1 founder mutation in Middle Eastern patients may be warranted. PMID- 29721913 TI - A Theoretical Simulation of the Radiation Responses of Si, Ge, and Si/Ge Superlattice to Low-Energy Irradiation. AB - In this study, the low-energy radiation responses of Si, Ge, and Si/Ge superlattice are investigated by an ab initio molecular dynamics method and the origins of their different radiation behaviors are explored. It is found that the radiation resistance of the Ge atoms that are around the interface of Si/Ge superlattice is comparable to bulk Ge, whereas the Si atoms around the interface are more difficult to be displaced than the bulk Si, showing enhanced radiation tolerance as compared with the bulk Si. The mechanisms for defect generation in the bulk and superlattice structures show somewhat different character, and the associated defects in the superlattice are more complex. Defect formation and migration calculations show that in the superlattice structure, the point defects are more difficult to form and the vacancies are less mobile. The enhanced radiation tolerance of the Si/Ge superlattice will benefit for its applications as electronic and optoelectronic devices under radiation environment. PMID- 29721915 TI - Clinical, biochemical, and molecular overview of transaldolase deficiency and evaluation of the endocrine function: update of 34 patients. AB - BACKGROUND: Transaldolase deficiency (TALDO-D) is a rare autosomal recessive inborn error of the pentose phosphate pathway. Since its first description in 2001, several case reports have been published, but there has been no comprehensive overview of phenotype, genotype, and phenotype-genotype correlation. METHODS: We performed a retrospective questionnaire and literature study of clinical, biochemical, and molecular data of 34 patients from 25 families with proven TALDO-D. In some patients, endocrine abnormalities have been found. To further evaluate these abnormalities, we performed biochemical investigations on blood of 14 patients. RESULTS AND CONCLUSIONS: Most patients (n = 22) had an early-onset presentation (prenatally or before 1 month of age); 12 patients had a late-onset presentation (3 months to 9 years). Main presenting symptoms were intrauterine growth restriction, dysmorphic facial features, congenital heart disease, anemia, thrombocytopenia, and hepato(spleno)megaly. An older sib of two affected patients was asymptomatic until the age of 9 years, and only after molecular diagnosis was hepatomegaly noted. In some patients, there was gonadal dysfunction with low levels of testosterone and secondary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) abnormalities later in life. This overview provides information that can be helpful for managing patients and counseling families regarding prognosis. Diagnostic guidelines, possible genotype phenotype correlations, treatment options, and pathophysiological disease mechanisms are proposed. PMID- 29721914 TI - Echocardiography in Arterial Hypertension. AB - Hypertension is a condition characterized by pressure and/or volume overloads and echocardiography is helpful and feasible to understand hemodynamic mechanisms. Echocardiographic information is sometimes critical and susceptible of modifying decision making. In this review, we provide detailed descriptions of the parameters that can be derived from a standard transthoracic echocardiogram, including some more recent techniques. We will also explain how each parameter might have impact in the evaluation of the hypertensive patient and give indications on when to refer patients to echo-labs, which parameters are critical and which ones might be redundant, and how to use the information obtained in the report. Cardiac geometry, LV systolic and diastolic function, LV pump performance, output impedance and left atrial function are parameters that might be altered in arterial hypertension, but not necessarily doctors need the whole information for decision making. The critical measures are provided. PMID- 29721916 TI - Integration of genomics and metabolomics for prioritization of rare disease variants: a 2018 literature review. AB - Many inborn errors of metabolism (IEMs) are amenable to treatment; therefore, early diagnosis and treatment is imperative. Despite recent advances, the genetic basis of many metabolic phenotypes remains unknown. For discovery purposes, whole exome sequencing (WES) variant prioritization coupled with clinical and bioinformatics expertise is the primary method used to identify novel disease causing variants; however, causation is often difficult to establish due to the number of plausible variants. Integrated analysis of untargeted metabolomics (UM) and WES or whole genome sequencing (WGS) data is a promising systematic approach for identifying disease-causing variants. In this review, we provide a literature based overview of UM methods utilizing liquid chromatography mass spectrometry (LC-MS), and assess approaches to integrating WES/WGS and LC-MS UM data for the discovery and prioritization of variants causing IEMs. To embed this integrated omics approach in the clinic, expansion of gene-metabolite annotations and metabolomic feature-to-metabolite mapping methods are needed. PMID- 29721918 TI - Patterns, evolution, and severity of striatal injury in insidious- versus acute onset glutaric aciduria type 1. AB - BACKGROUND: Striatal injury in patients with glutaric aciduria type 1 (GA1) results in a complex, predominantly dystonic, movement disorder. Onset may be acute following acute encephalopathic crisis (AEC) or insidious without apparent acute event. METHODS: We analyzed clinical and striatal magnetic resonance imaging (MRI) findings in 21 symptomatic GA1 patients to investigate if insidious and acute-onset patients differed in timing, pattern of striatal injury, and outcome. RESULTS: Eleven patients had acute and ten had insidious onset, two with later AEC (acute-on-insidious). The median onset of dystonia was 10 months in both groups, and severity was greater in patients after AEC (n = 8 severe, n = 5 moderate) than in insidious onset (n = 4 mild, n = 3 moderate, n = 1 severe). Deviations from guideline-recommended basic metabolic treatment were identified in six insidious-onset patients. Striatal lesions were extensive in all acute onset patients and restricted to the dorsolateral putamen in eight of ten insidious-onset patients. After AEC, the two acute-on-insidious patients had extensive striatal changes superimposed on pre-existing dorsolateral putaminal lesions. Two insidious-onset patients with progressive dystonia without overt AEC also had extensive striatal changes, one with sequential striatal injury revealed by diffusion-weighted imaging. Insidious-onset patients had a latency phase of 3.5 months to 6.5 years between detection and clinical manifestation of dorsolateral putaminal lesions. CONCLUSIONS: Insidious-onset type GA1 is characterized by dorsolateral putaminal lesions, less severe dystonia, and an asymptomatic latency phase, despite already existing lesions. Initially normal MRI during the first months and deviations from guideline-recommended treatment in a large proportion of insidious-onset patients substantiate the protective effect of neonatally initiated treatment. PMID- 29721917 TI - Presentation, progression, and predictors of ovarian insufficiency in classic galactosemia. AB - Classic galactosemia (CG) is an inherited metabolic disorder that affects about 1 in 50,000 live births in the United States and many other countries. With the benefit of early detection by newborn screening and rapid dietary restriction of galactose, generally achieved by removing dairy from the diet, most affected infants are spared the acute and potentially lethal symptoms of disease. Despite early detection and life-long dietary intervention, however, most patients grow to experience a constellation of long-term complications that include premature ovarian insufficiency in the vast majority of girls and young women. Our goal in the study reported here was to define the presentation, progression, and predictors of ovarian insufficiency in a cohort of 102 post-pubertal girls and women with CG. To our knowledge, this is the largest cohort studied to date. We found that 68% of the girls and women in our study achieved spontaneous menarche, while 32% achieved menarche only after starting hormone replacement therapy (HRT). Of those who achieved spontaneous menarche, fewer than 50% were still cycling regularly after 3 years, and fewer than 15% were still cycling regularly after 10 years. Of factors tested for possible association with spontaneous menarche, only detectable (>= 0.04 ng/mL) plasma anti-Mullerian hormone (AMH) level was significant. These results extend substantially from prior studies and confirm that detectable plasma AMH is a useful predictor of ovarian function in girls and women with CG. PMID- 29721919 TI - Severe ichthyosis in MPDU1-CDG. AB - Congenital disorders of glycosylation (CDG) have a broad spectrum of clinical manifestations. They can affect multiple organ systems, including skin and subcutaneous tissue. We report on an infant with severe ichthyosis caused by MPDU1 mutations. The case illustrates that skin manifestations are an important feature of CDG syndromes. Therefore, metabolic investigations should be included in the workup of infantile ichthyosis disorders. PMID- 29721921 TI - Oxidative Stress Regulation and DJ-1 Function in the Retinal Pigment Epithelium: Implications for AMD. AB - In the retina, oxidative stress can initiate a cascade of events that ultimately leads to a focal loss of RPE cells and photoreceptors, a major contributing factor in geographic atrophy. Despite these implications, the molecular regulation of RPE oxidative metabolism under physiological and pathological conditions remains largely unknown. DJ-1 functions as an antioxidant, redox sensitive molecular chaperone, and transcription regulator, which protected cells from oxidative stress. Here we discuss our progress toward characterization of the DJ-1 function in the protection of RPE to oxidative stress. PMID- 29721922 TI - Mitochondria: Potential Targets for Protection in Age-Related Macular Degeneration. AB - Age-related macular degeneration (AMD) is the leading cause of blindness in older adults in developed countries. The molecular mechanisms of disease pathogenesis remain poorly understood; however, evidence suggests that mitochondrial dysfunction may contribute to the progression of the disease. Studies have shown that mitochondrial DNA lesions are increased in the retinal pigment epithelium (RPE) of human patients with the disease and that the number of these lesions increases with disease severity. Additionally, microscopy of human RPE from patients with dry AMD shows severe disruptions in mitochondrial inner and outer membrane structure, mitochondrial size, and mitochondrial cellular organization. Thus, improving our understanding of mitochondrial dysfunction in dry AMD pathogenesis may lead to the development of targeted therapies. We propose that mitochondrial dysfunction in the RPE can lead to the chronic oxidative stress associated with the disease. Therefore, one protective strategy may involve the use of small molecule therapies that target the regulation of mitochondrial biogenesis and mitochondrial fission and mitophagy. PMID- 29721920 TI - Acquired peripheral pulmonary artery aneurysms: morphological spectrum of disease and multidetector computed tomography angiography findings-cases series and literature review. AB - BACKGROUND: Acquired peripheral or intraparenchymal pulmonary artery aneurysms (PPAA) are rare entities but are important to recognize because of the associated morbidity. Hemoptysis is their principal complication and is a potentially fatal condition. PURPOSE: To illustrate the causes, multidetector CT angiography (MDCTA) findings and differential diagnosis of acquired PPAA. MATERIALS AND METHODS: The institutional review boards approved this study. We conducted a retrospective review of the demographic data and the results of clinical and laboratory examinations, and imaging studies of patients managed between January 2012 and January 2017 in two institutions. RESULTS: A total of 19 patients had acquired PPAA that were detected at MDCTA, 9 patients with normal pulmonary artery pressures and 10 with pulmonary hypertension. Nine patients developed PPAA related acute symptoms. MDCTA features of PPAA include: a lobulated vascular mass, an indistinct irregular arterial wall, aneurysmal thrombosis or wall calcification, findings of impending rupture including perianeurysmal edema, gas or a soft tissue mass. CONCLUSION: PPAA are rare. In our series, endocarditis and pulmonary hypertension are the PPAA leading causes. The treatment modality preferred is embolization, especially as surgery poses a very high risk for patients with severe pulmonary hypertension. Further clarification of the natural history of these rare arterial aneurysms is needed. PMID- 29721923 TI - Toll-Like Receptors and Age-Related Macular Degeneration. AB - Age-related macular degeneration (AMD) is the leading cause of central vision loss in the over 50s worldwide. Activation of the immune system has been implicated in disease progression, but while polymorphisms in genes associated with the immune system have been identified as risk factors for disease, the underlying pathways and mechanisms involved in disease progression remain incompletely characterised. Typically inflammatory responses are mediated by microbial infection; however, in chronic conditions, a form of 'sterile' inflammation exists whereby immune responses occur in areas of the body, in the absence of microbes; 'sterile' inflammation is likely to be central to AMD. In this case the innate immune response is triggered when alarm signals released by stressed cells or damaged tissue are identified by pattern recognition receptors (PRRs). Toll-like receptors (TLRs) are a family of membrane-spanning PRRs for which host-derived ligands have been identified; these include heat shock proteins, extracellular matrix breakdown products, mRNA from necrotic cells and modified lipids. Here we review the evidence for TLR involvement in the pathogenesis of AMD. PMID- 29721924 TI - Alterations in Extracellular Matrix/Bruch's Membrane Can Cause the Activation of the Alternative Complement Pathway via Tick-Over. AB - Given the complex etiology of age-related macular degeneration (AMD), treatments are developed to target intermediate/late stages of the disease. Unfortunately, the design of therapies for early stages of the disease is limited by our understanding of the mechanisms involved in the formation of basal deposits and drusen, the first clinical signs of AMD. During the last decade, the identification of common and rare alleles in complement genes as risk AMD variants in addition to the presence of active complement components in basal deposits and drusen has provided compelling evidence that the complement system plays a key role in the pathobiology of AMD. However, the mechanisms for complement activation in AMD are unknown. Here we propose that the activation of the complement system is a consequence of alterations in the aged extracellular matrix (ECM) of the retinal pigment epithelium (RPE)/Bruch's membrane (BrM), which favors the anchoring of complement C3b generated by convertase-independent cleavage of C3 via tick-over and produces a chronic activation of the alternative complement pathway. PMID- 29721925 TI - MicroRNA as Therapeutics for Age-Related Macular Degeneration. AB - MicroRNA (miRNA) are a class of endogenously expressed small non-coding RNA molecules that function by repressing or silencing post-transcriptional gene expression. While miRNAs were only identified in humans as recently as the turn of this century, some miRNA-based agents are already in Phase 2 clinical trials (Christopher et al. 2016). This rapid progress from initial discovery to drug development reflects the effectiveness of miRNAs as therapeutic targets. Further, their use as therapeutic agents in the treatment of diseases such as Alzheimer's disease (Wang et al. 2014) supports their use in other neurodegenerative diseases, such as Age-Related Macular Degeneration (AMD). However, despite ~300 miRNAs reportedly expressed in the human retina (Xu 2009), relatively little research has been conducted into the therapeutic potential of miRNAs for the treatment of AMD. This review will investigate the use of miRNAs as therapeutic and diagnostic molecules for AMD. PMID- 29721926 TI - Anaphylatoxin Signaling in Retinal Pigment and Choroidal Endothelial Cells: Characteristics and Relevance to Age-Related Macular Degeneration. AB - Age-related macular degeneration (AMD) is the leading cause of blindness in the USA. Polymorphisms in various complement components are associated with an increased risk for AMD, and it has been hypothesized that an overactive complement system is partially responsible for the pathology of AMD. AMD is classified as early, intermediate, or late AMD, depending on the degree of the associated pathologies. Late AMD can be characterized as either lesions associated with neovascular AMD or geographic atrophy. Both sets of lesions are associated with pathology at the RPE/choroid interface, which include a thickening of Bruch's membrane, presence of drusen, and pigmentary alterations, and deterioration of the blood-retina barrier has been reported. These changes can lead to the slow degeneration and atrophy of the photoreceptors in the macula in dry AMD, or progress to choroidal neovascularization (CNV) and leakage of these new vessels in wet AMD. It has been shown previously that complement anaphylatoxins C3a and C5a, signaling via their respective G-protein-coupled receptors, can alter RPE cell function and promote choroidal neovascularization. However, it is important to note these components also play a role in tissue repair. Here we discuss anaphylatoxin signaling in AMD-related target cells and the potential implications for the design of anti-complement therapeutics. PMID- 29721927 TI - Estimations of Retinal Blue-Light Irradiance Values and Melatonin Suppression Indices Through Clear and Yellow-Tinted Intraocular Lenses. AB - Spectral transmittance values in the wavelength range of 300 to 800 nanometers were measured using a spectrophotometer for 18 intraocular lenses (IOLs) including clear (ZCB00) and yellow-tinted (ZCB00V, both from AMO Japan) IOLs with three different lens powers. Also measured were the blue-light irradiance (BLI) values, which might reflect retinal damage caused by sunlight, and the melatonin suppression indices (MSIs), which might reflect the nonvisual photoreception function, through these IOLs. The BLIs (in mWcm-2) calculated were 7.62, 7.50, and 7.46 for the +10-diopter (D), +20-D, and +30-D ZCB00 IOLs, respectively; 4.10, 3.92, and 4.00 for the +10-D, +20-D, and +30-D ZCB00V IOLs, respectively; 5.76 for phakic eyes; and 15.00 for aphakic eyes. The MSIs (in mWcm-2sr-1) calculated were 1.18, 1.19, and 1.18 for the +10-D, +20-D, and +30-D ZCB00 IOLs, respectively; 0.98, 0.94, and 0.95 for the +10-D, +20-D, and +30-D ZCB00V IOLs, respectively; 1.03 for phakic eyes; and 1.21 for aphakic eyes. The data from the six clear IOLs (SA60AT, Alcon Japan; VA-60BBR, Hoya; AU6 K, Kowa, N4-18B, Nidek; X-60, Santen; KS-3Ai, Staar Japan) and seven yellow-tinted IOLs (SN60AT; YA 60BBR, Hoya; AU6N, Kowa; N4-18YG, Nidek; NX-60, Santen; KS-AiN, Staar Japan; XY 1, Hoya) reported previously also were discussed. Compared to aphakic eyes, ZCB00 and ZCB00V IOLs reduce the BLI values by 49-50% and 73-74%, respectively; and currently available ultraviolet-blocking clear and yellow-tinted IOLs reduce the BLI values by 43-82%, respectively. Yellow-tinted IOLs absorb more circadian rhythm-associated light than clear IOLs. Although the data presented in this study cannot be applied directly to IOL implanted in patients, the balance between photoprotection and photoreception must be considered when using IOLs in a clinical setting. PMID- 29721928 TI - Co-Expression of Wild-Type and Mutant S163R C1QTNF5 in Retinal Pigment Epithelium. AB - The pathogenic mutation S163R in C1QTNF5 causes a disorder known as autosomal dominant late-onset retinal degeneration (L-ORD), characterized by the presence of thick extracellular sub-RPE deposits, similar histopathologically to those found in AMD patients. We have previously shown that the S163R C1QTNF5 mutant forms globular aggregates within the RPE in vivo following its AAV-mediated expression in the RPE and exhibits a reversely polarized distribution, being routed toward the basal rather than apical RPE. We show here that when both wild type and mutant S163R C1QTNF5 are simultaneously delivered subretinally to mouse RPE cells, the mutant impairs the wild-type protein secretion from the RPE, and both proteins are dispersed toward the basal and lateral RPE membrane. This result has mechanistic and therapeutic implications for L-ORD disorder. PMID- 29721929 TI - Mini-Review: Cell Type-Specific Optogenetic Vision Restoration Approaches. AB - The expression of light-sensitive microbial opsins is a promising mutation independent approach to restore vision in retinal degenerative diseases. Using viral vectors, optogenetic tools can be genetically expressed in various subpopulations of retinal neurons. The choice of cell type depends on the availability of surviving retinal cells. If cones are still alive but they lack outer segments, they can be targeted with optogenetic inhibitors, such as halorhodopsin. Alternatively, it is possible to bypass the photoreceptors and to target bipolar cells. In late-stage degeneration, when bipolar cells degenerate, "artificial photoreceptors" can be made from retinal ganglion cells, but with this approach, upstream retinal processing cannot be utilized. However, when ganglion cells are stimulated directly, higher brain regions might be able to compensate for some loss of retinal processing, which is indicated by clinical studies with epiretinal implants, where patients can perform simple visual tasks. Finally, optogenetics in combination with neuroprotective approaches could serve as a valuable strategy to restore the function of remaining cells, as well as to rescue retinal neurons from progressive degeneration. PMID- 29721930 TI - Mutation-Independent Gene Therapies for Rod-Cone Dystrophies. AB - The clinical success of gene replacement therapies in recent years has served as a proof of concept for the treatment of inherited retinal degenerations using adeno-associated virus (AAV) as viral vector. However, inherited retinal degenerative diseases showcase a broad genetic and mechanistic heterogeneity, challenging the development of mutation-specific therapies for each specific mutation. Mutation-independent approaches must be developed to slow down retinal degeneration regardless of the underlying genetic mutation and onset of the disease. New understanding of cell death mechanisms in rod-cone dystrophies have led to promising rescue of photoreceptor cell death by virally mediating expression of anti-apoptotic factors and secretion of retinal neurotrophic factors. Optogenetic therapies are also able to restore light sensitivities in blind retinas. PMID- 29721931 TI - Antisense Oligonucleotide-Based Splice Correction of a Deep-Intronic Mutation in CHM Underlying Choroideremia. AB - Choroideremia is a progressive genetic eye disorder caused by mutations in the CHM gene that encodes the Rab escort protein-1 (REP-1). One of the many CHM mutations described so far is a deep-intronic variant, c.315-4587T>A, that creates a novel splice acceptor site resulting in the insertion of a 98-bp pseudoexon in the CHM transcript. Antisense oligonucleotides (AONs) are a potential therapeutic tool for correcting splice defects, as they have the properties to bind to the pre-mRNA and redirect the splicing process. Previously, we used AONs to correct aberrant splicing events caused by a recurrent intronic mutation in CEP290 underlying Leber congenital amaurosis. Here, we expand the use of these therapeutic molecules for the c.315-4587T>A deep-intronic mutation in CHM by demonstrating splice correction in patient-derived lymphoblast cells. PMID- 29721932 TI - Gene Therapy Approaches to Treat the Neurodegeneration and Visual Failure in Neuronal Ceroid Lipofuscinoses. AB - Neuronal ceroid lipofuscinoses (NCLs) are a group of fatal, inherited lysosomal storage disorders mostly affecting the central nervous system of children. Symptoms include vision loss, seizures, motor deterioration and cognitive decline ultimately resulting in premature death. Studies in animal models showed that the diseases are amenable to gene supplementation therapies, and over the last decade, major advances have been made in the (pre)clinical development of these therapies. This mini-review summarises and discusses current gene therapy approaches for NCL targeting the brain and the eye. PMID- 29721933 TI - Success of Gene Therapy in Late-Stage Treatment. AB - Retinal gene therapy has yet to achieve sustained rescue after disease onset - perhaps because transduction efficiency is insufficient ("too little") and/or the disease is too advanced ("too late") in humans. To test the latter hypothesis, we used a mouse model for retinitis pigmentosa (RP) that allowed us to restore the mutant gene in all diseased rod photoreceptor cells, thereby generating optimally treated retinas. We then treated mice at an advanced disease stage and analyzed the rescue. We showed stable, sustained rescue of photoreceptor structure and function for at least 1 year, demonstrating gene therapy efficacy after onset of degeneration. The results suggest that RP patients are treatable, even when the therapy is administered at late disease stages. PMID- 29721934 TI - Optimizing Non-viral Gene Therapy Vectors for Delivery to Photoreceptors and Retinal Pigment Epithelial Cells. AB - Considerable progress has been made in the design and delivery of non-viral gene therapy vectors, but, like their viral counterparts, therapeutic levels of transgenes have not met the requirements for successful clinical applications so far. The biggest advantage of polymer-based nanoparticle vectors is the ease with which they can be modified to increase their ability to penetrate the cell membrane and target specific cells by simply changing the formulation of the nanoparticle compaction. We took advantage of this characteristic to improve transfection rates of our particles to meet the transgene levels which will be needed for future treatment of patients. For this study, we successfully investigated the possibility of our established pegylated polylysine particles to be administered via intravitreal rather than subretinal route to ease the damage during injection. We also demonstrated that our particles are flexible enough to sustain changes in the formulation to accommodate additional targeting sequences without losing their efficiency in transfecting neuronal cells in the retina. Together, these results give us the opportunity to even further improve our particles. PMID- 29721935 TI - Nanoparticles as Delivery Vehicles for the Treatment of Retinal Degenerative Diseases. AB - Over the last few years, huge progress has been made in the understanding of molecular mechanisms underlying the pathogenesis of retinal degenerative diseases. Such knowledge has led to the development of gene therapy approaches to treat these devastating disorders. Non-viral gene delivery has been recognized as a prospective treatment for retinal degenerative diseases. In this review, we will summarize the constituent characteristics and recent applications of three representative nanoparticles (NPs) in ocular therapy. PMID- 29721936 TI - Overexpression of Type 3 Iodothyronine Deiodinase Reduces Cone Death in the Leber Congenital Amaurosis Model Mice. AB - Leber congenital amaurosis (LCA) is a devastating pediatric retinal degenerative disease, accounting for 20% of blindness in children attending schools for the blind. Mutations in the RPE65 gene, which encodes the retinal pigment epithelium specific isomerohydrolase RPE65, account for 16% of all LCA cases. Recent findings have linked cone photoreceptor viability to thyroid hormone (TH) signaling. TH signaling regulates cell proliferation, differentiation, and metabolism. At the cellular level, TH action is regulated by the two iodothyronine deiodinases, DIO2 and DIO3. DIO2 converts the prohormone thyroxine (T4) to the bioactive hormone triiodothyronine (T3), and DIO3 inactivates T3 and T4. The present work investigates the effects of overexpression of DIO3 to suppress TH signaling and thereby modulate cone death/survival. Subretinal delivery of AAV5-IRBP/GNAT2-hDIO3 induced robust expression of DIO3 in the mouse retina and significantly reduced the number of TUNEL-positive cells in the cone dominant LCA model Rpe65 -/- /Nrl -/- mice. Our work shows that suppressing TH signaling by overexpression of DIO3 preserves cones, supporting that suppressing TH signaling locally in the retina may represent a treatment strategy for LCA management. PMID- 29721937 TI - In Vivo Functional Imaging of Retinal Neurons Using Red and Green Fluorescent Calcium Indicators. AB - Adaptive optics retinal imaging of fluorescent calcium indicators is a minimally invasive method used to study retinal physiology over extended periods of time. It has potential for discovering novel retinal circuits, tracking retinal function in animal models of retinal disease, and assessing vision restoration therapy. We previously demonstrated functional adaptive optics imaging of retinal neurons in the living eye using green fluorescent calcium indicators; however, the use of green fluorescent indicators presents challenges that stem from the fact that they are excited by short-wavelength light. Using red fluorescent calcium indicators such as jRGECO1a, which is excited with longer-wavelength light (~560 nm), makes imaging approximately five times safer than using short wavelength light (~500 nm) used to excite green fluorescent calcium indicators such as GCaMP6s. Red fluorescent indicators also provide alternative wavelength imaging regimes to overcome cross talk with the sensitivities of intrinsic photoreceptors and blue light-activated channelrhodopsins. Here we evaluate jRGECO1a for in vivo functional adaptive optics imaging of retinal neurons using single-photon excitation in mice. We find that jRGECO1a provides similar fidelity as the established green indicator GCaMP6s. PMID- 29721938 TI - Optimizing ERG Measures of Scotopic and Photopic Critical Flicker Frequency. AB - A visual response to flickering light requires complex retinal computation, and thus ERG measures are an excellent test of retinal circuit fidelity. Critical flicker frequency (CFF) is the frequency at which the retinal response is no longer modulated. Traditionally, CFF is obtained with a series of steady flicker stimuli with increasing frequencies. However, this method is slow and susceptible to experimental drift and/or adaptational effects. The current study compares the steady flicker method to CFF measurements obtained using a frequency sweep protocol. We introduce a light source programmed to produce a linear sweep of frequencies in a single trial. Using the traditional steady flicker method and a criterion response of 3 MUV, we obtained a scotopic CFF of 18.4 +/- 0.66 Hz and a photopic CFF of 44.4 +/- 1.67 Hz. Our sweep flicker method, used on the same animals, produces a waveform best analyzed by Fourier transform; wherein a 6.18 log MUV2 threshold was found to yield CFF values equal to those of the steady flicker method. Thus, the two flicker ERG techniques give comparable results, under both dark- and light-adapted conditions, and the flicker sweep method is faster to administer and analyze and may be less susceptible to blinking, breathing, and eye movement artifacts. PMID- 29721939 TI - Repeatability and Reproducibility of In Vivo Cone Density Measurements in the Adult Zebrafish Retina. AB - Zebrafish (Danio rerio) are widely used as an experimental model for a wide range of retinal diseases. Previously, optical coherence tomography (OCT) was introduced for quantitative analysis of the zebrafish cone photoreceptor cell mosaic; however no data exists on the intersession reproducibility or intrasession repeatability of such measurements. We imaged 14 wild-type (WT) fish three times each, with 48 h between each time point. En face images of the UV cone mosaic were generated from the OCT volume scans at each time point. These images were then aligned and the overlapping area cropped for analysis. Using a semiautomated cone-counting algorithm, a single observer identified each cone to calculate the cone density for every image, counting each image twice (84 total counts). The OCT cone density measurements were found to have an intersession reproducibility of 0.9988 (95% CI = 0.9978-0.9999) and an intrasession repeatability of 136.0 +/- 10.5 cones/mm2 (about 0.7%). Factors affecting image quality include gill movement during acquisition of the OCT volume and variable inclusion of non-UV cone mosaics in the contours used to generate the en face images. PMID- 29721940 TI - Normative Retinal Thicknesses in Common Animal Models of Eye Disease Using Spectral Domain Optical Coherence Tomography. AB - Purpose This study demonstrates a standardized approach to measuring retinal thickness (RT) using spectral domain optical coherence tomography (SD-OCT) in commonly used animal models of disease and reports a normative data set for future use. Materials and Methods Twenty normal eyes of 4 adult animal models (5 rats, 5 rabbits, 5 canines, and 5 mini-pigs) were used. Manual measurements were made on the commercially available Heidelberg SpectralisTM SD-OCT to determine the total, inner, and outer retinal thickness (RT) at fixed distances from the optic nerve head (ONH) (1, 2, 3, 4, 5, and 6 mm away) in order to control for normal variation in retinal thickness. Analysis of variance (ANOVA) with P value <0.05 indicated statistical significance. Results Total RT significantly decreased with increasing distance from the ONH for the canine, mini-pig, and rabbit vascular models. Inner RT significantly decreased for the canine, mini pig, rabbit vascular, and rabbit avascular models; and outer RT significantly decreased for only the canine model. Among the animal models, RT at similar distances from the ONH were significantly different for total, inner, and outer RT. Conclusion There are significant differences in the total, inner, and outer RT of normal canine, mini-pig, rabbit, and rat retinas with SD-OCT using a standardized approach. These measurements provide a normative reference for future studies and illustrate a standardized method of assessing RT. PMID- 29721941 TI - A Novel Approach for Integrating AF-SLO and SDOCT Imaging Data Demonstrates the Ability to Identify Early Retinal Abnormalities in Mutant Mice and Evaluate the Effects of Genetic and Pharmacological Manipulation. AB - Noninvasive ocular imaging platforms are undeniably useful in identifying retinal abnormalities. The purpose of this study was to investigate a novel method for integrating information acquired from two independent imaging platforms, AF-SLO and SDOCT, in order to demonstrate retinal perturbations as a result of genetic or pharmacological manipulation. Two cohorts of mice were investigated, Nyx nob and C57BL/6 J. In Nyx nob mice, SLO revealed an atypical but variable amount of autofluorescent foci (AFF); SDOCT showed altered photoreceptor outer segment architecture. Naive Nyx nob had significantly more AFF than C57BL/6 J, suggesting that Nyx nob have some predisposition for developing AFF. Interestingly, both findings were significantly ameliorated in diabetic Nyx nob mice as compared to the controls. These data were incorporated into a novel analysis plot comparing AF-SLO and SDOCT results. The integration of the qualitative changes and accompanying quantitative analysis approach described herein provide a sensitive means for detecting whether a mouse model is susceptible to degeneration before other hallmark indicators are observed. PMID- 29721942 TI - The Role of Hypoxia, Hypoxia-Inducible Factor (HIF), and VEGF in Retinal Angiomatous Proliferation. AB - In industrialized countries, age-related macular degeneration (AMD) is the leading cause of blindness in elderly people. Hallmarks of the non-neovascular (dry) form of AMD are the formation of drusen and geographic atrophy, whereas the exudative (wet) form of the disease is characterized by invading blood vessels. In retinal angiomatous proliferation (RAP), a special form of wet AMD, intraretinal vessels grow from the deep plexus into the subretinal space. Little is known about the mechanisms leading to intraretinal neovascularization, but age related changes such as reduction of choroidal blood flow, accumulation of drusen, and thickening of the Bruch's membrane may lead to reduced oxygen availability in photoreceptors. Such a chronic hypoxic situation may induce several cellular response pathways including the stabilization of hypoxia inducible factors (HIFs) and the production of angiogenic factors, such as vascular endothelial growth factor (VEGF). Here, we discuss the potential contribution of hypoxia and HIFs in RAP disease pathology and in some mouse models for subretinal neovascularization. PMID- 29721943 TI - Neuroinflammation in Retinitis Pigmentosa, Diabetic Retinopathy, and Age-Related Macular Degeneration: A Minireview. AB - The eye is an immuno-privileged organ. However, certain diseases such as uveitis are intrinsically linked to inflammation. In several retinal degenerative diseases, there is a unique damage at the onset of the disease, but evidence suggests that chronic and low-grade inflammatory processes play an important role in their progression. Studies have identified similar signaling pathways and changes in resident immune cells within the retina among these diseases. Herein, we will discuss some of these studies and propose how understanding this inflammatory response could aid in the development of therapies. PMID- 29721944 TI - Autoimmune Retinopathy: An Immunologic Cellular-Driven Disorder. AB - Autoimmune retinopathy (AIR) was often mistaken for retinitis pigmentosa (RP), due to an overlap of clinical findings, but increasingly has been recognized as a unique entity in the last decade. AIR has distinctive features: sudden onset of photopsias and scotomata in patients with no family history of RP, followed by visual field and central vision loss. Initially, retina exams are normal with no sign of pigment deposits or retinal degeneration. A family history of autoimmune diseases (all types) occurs in 60% of patients. One hallmark of AIR has been the presence of anti-retinal autoimmune antibodies (ARAs) in patients' sera, but patients can continue to have ARAs even when the disease has been quiescent for years. The accumulation of ARAs represents a breakdown of retinal immune tolerance with many different immunoreactive bands found at different reference weights in AIR patients. We began investigating cellular immunity using flow cytometry and found abnormal distributions (>2 StDev) of increased memory lymphocytes and NK cells and decreased regulatory B cell subsets in many AIR patients compared to normal controls. Culture of patient lymphocytes with small amounts (25 MUg) of recoverin protein for 6 days led to significant elevations of interferon gamma (IFNgamma) and in some cases tumor necrosis factor alpha (TNFalpha) production. We found the IFNgamma/IL-10 ratio in response to recoverin was elevated in patients with more active disease (defined by visual field contraction between visits), but in some patients, there also appeared to be independent factors influencing severity, suggesting other autoimmune mechanisms were at play. These cellular immune parameters may provide improved markers for active AIR. PMID- 29721945 TI - Inflammation-Induced Photoreceptor Cell Death. AB - Neuroinflammation is an important aspect of many diseases of the eye, and experimental animal models have been widely used to determine its impact on retinal homeostasis and neuron survival. Physical separation of the neurosensory retina from the underlying retinal pigment epithelium (RPE) results in activation and infiltration of macrophages. Numerous studies have shown the critical role of macrophages in retinal disease processes. In retinal detachment, accumulation of macrophages in the subretinal space is associated with changes in cytokine and chemokine profile which lead to photoreceptor cell death. Targeted disruption of macrophage chemotaxis significantly reduces retinal detachment-induced photoreceptor degeneration. Apoptosis is the predominant mechanism of cell death; however regulated necrosis is also a contributor of photoreceptor loss. Therefore, effective neuroprotective approaches could integrate combined inhibition of both apoptotic and regulated necrosis pathways. PMID- 29721946 TI - Sall1 Regulates Microglial Morphology Cell Autonomously in the Developing Retina. AB - Retinal degeneration often accompanies microglial activation and infiltration of monocyte-derived macrophages into the retina, resulting in the coexistence of microglia and monocyte-derived macrophages in the retina. We previously showed that the Sall1 zinc-finger transcriptional factor is expressed specifically in microglia within the retinal phagocyte pool, and analyses of Sall1 knockout mice revealed that microglial morphology changed from a ramified to a more amoeboid appearance in the developing retina. To investigate further whether Sall1 functions autonomously in microglia, we generated Sall1 conditional knockout mice, in which Sall1 was depleted specifically in the Cx3cr1+ microglial compartment of the developing retina. Sall1-deficient microglia exhibited morphological abnormalities on embryonic day 18 that strikingly resembled the phenotype observed in Sall1 knockout mice, demonstrating that Sall1 regulates microglial morphology cell autonomously. Analysis of the postnatal retina revealed that Sall1-deficient microglia extended their processes and their morphology became comparable to that of wild-type microglia on postnatal day 21, indicating that Sall1 is essential for microglial ramification in the developing retina, but not in the postnatal retina. PMID- 29721947 TI - Whole-Exome Sequencing Identifies Novel Variants that Co-segregates with Autosomal Recessive Retinal Degeneration in a Pakistani Pedigree. AB - PURPOSE: To identify the molecular basis of inherited retinal degeneration (IRD) in a familial case of Pakistani origin using whole-exome sequencing. METHODS: A thorough ophthalmic examination was completed, and genomic DNA was extracted using standard protocols. Whole exome(s) were captured with Agilent V5 + UTRs probes and sequenced on Illumina HiSeq genome analyzer. The exomeSuite software was used to filter variants, and the candidate causal variants were prioritized, examining their allele frequency and PolyPhen2, SIFT, and MutationTaster predictions. Sanger dideoxy sequencing was performed to confirm the segregation with disease phenotype and absence in ethnicity-matched control chromosomes. RESULTS: Ophthalmic examination confirmed retinal degeneration in all affected individuals that segregated as an autosomal recessive trait in the family. Whole exome sequencing identified two homozygous missense variants: c.1304G > A; p.Arg435Gln in ZNF408 (NM_024741) and c.902G > A; p.Gly301Asp in C1QTNF4 (NM_031909). Both variants segregated with the retinal phenotype in the PKRD320 and were absent in ethnically matched control chromosomes. CONCLUSION: Whole exome sequencing coupled with bioinformatics analysis identified potential novel variants that might be responsible for IRD. PMID- 29721948 TI - Identification of Novel Deletions as the Underlying Cause of Retinal Degeneration in Two Pedigrees. AB - Retinal dystrophies are a phenotypically and genetically complex group of conditions. Because of this complexity, it can be challenging in many families to determine the inheritance based on pedigree analysis alone. Clinical examinations were performed and blood samples were collected from a North American (M1186) and a consanguineous Pakistani (PKRD168) pedigree affected with two different retinal dystrophies (RD). Based on the structure of the pedigrees, inheritance patterns in the families were difficult to determine. In one family, linkage analysis was performed with markers on X-chromosome. In the second family, whole-exome sequencing (WES) was performed. Subsequent Sanger sequencing of genes of interest was performed. Linkage and haplotype analysis localized the disease interval to a 70 Mb region on the X chromosome that encompassed RP2 and RPGR in M1186 . The disease haplotype segregated with RD in all individuals except for an unaffected man (IV:3) and his affected son (V:1) in this pedigree. Subsequent analysis identified a novel RPGR mutation (p. Lys857Glu fs221X) in all affected members of M1186 except V:1. This information suggests that there is an unidentified second cause of retinitis pigmentosa (RP) within the family. A novel two-base-pair deletion (p. Tyr565Ter fsX) in CHM (choroideremia) was found to segregate with RD in PKRD168. This paper highlights the challenges of interpreting family history in families with RD and reports on the identification of novel mutations in two RD families. PMID- 29721949 TI - Molecular Findings in Families with an Initial Diagnose of Autosomal Dominant Retinitis Pigmentosa (adRP). AB - Genetic testing of probands in families with an initial diagnosis of autosomal dominant retinitis pigmentosa (adRP) usually confirms the diagnosis, but there are exceptions. We report results of genetic testing in a large cohort of adRP families with an emphasis on exceptional cases including X-linked RP with affected females; homozygous affected individuals in families with heterozygous, dominant disease; and independently segregating mutations in the same family. Genetic testing was conducted in more than 700 families with a provisional or probable diagnosis of adRP. Exceptions to the proposed mode of inheritance were extracted from our comprehensive patient and family database. In a subset of 300 well-characterized families with a probable diagnosis of adRP, 195 (70%) have dominant mutations in known adRP genes but 25 (8%) have X-linked mutations, 3 (1%) have multiple segregating mutations, and 3 (1%) have dominant-acting mutations in genes previously associated with recessive disease. It is currently possible to determine the underlying disease-causing gene and mutation in approximately 80% of families with an initial diagnosis of adRP, but 10% of "adRP" families have a variant mode of inheritance. Informed genetic diagnosis requires close collaboration between clinicians, genetic counselors, and laboratory scientists. PMID- 29721950 TI - Pleiotropic Effects of Risk Factors in Age-Related Macular Degeneration and Seemingly Unrelated Complex Diseases. AB - Age-related macular degeneration (AMD) is a complex disease with both environmental and genetic factors influencing disease risk. Genome-wide case control association studies, candidate gene analyses, and epidemiological studies reinforced the notion that AMD is predominantly a disease of an impaired complement system and an altered high-density lipoprotein (HDL) metabolism. Recent reports demonstrated the pleiotropic role of the complement system and HDL in complex diseases such as cardiovascular disease, autoimmune disorders, cancer, and Alzheimer's disease. In light of these findings, we explore current evidence for a shared genetic and environmental risk of AMD and unrelated complex diseases based on epidemiological studies. Shared risk factors may indicate common pathways in disease pathology and thus may have implications for novel treatment options of AMD pathology. PMID- 29721951 TI - Mapping of Canine Models of Inherited Retinal Diseases. AB - The gene/mutation discovery approaches for inherited retinal diseases (RDs) in the dog model have seen considerable development over the past 25 years. Initial attempts were focused on candidate genes, followed by genome-wide approaches including linkage analysis and DNA-chip-based genome-wide association study. Combined, there are as many as 32 mutations in 27 genes that have been associated with canine retinal diseases to date. More recently, next-generation sequencing has become one of the key methods of choice. With increasing knowledge of the molecular basis of RDs and follow-up surveys in different subpopulations, the conventional understanding of RDs as simple Mendelian traits is being challenged. Modifiers and involvement of multiple genes that alter the disease expression are complicating the prediction of the disease course. In this chapter, advances in the gene/mutation discovery approaches for canine RDs are reviewed, and a multigenic form of canine RD is discussed using a form of canine cone-rod dystrophy as an example. PMID- 29721952 TI - A Mini-Review: Leber Congenital Amaurosis: Identification of Disease-Causing Variants and Personalised Therapies. AB - Leber congenital amaurosis (LCA) encompasses a group of severe inherited retinal dystrophies (IRDs) responsible for early childhood blindness. There are currently 25 genes implicated in the pathogenesis of these diseases, and identification of disease-causing variants will be required for personalised therapies. Whole exome and whole genome sequencing is informative for detecting novel disease-causing genes, whilst next-generation sequencing has excelled at detecting novel variants in known disease-causing genes.A global effort will be required to identify patient populations for early intervention. At the Australian Inherited Retinal Disease Registry and DNA Bank, we seek to identify genetic variants in individuals with IRDs in the Australian population to identify potential candidates for clinical trials, to inform clinical management of patients including reproductive options and to expand existing knowledge of IRDs.Due to the diversity of genes implicated, personalised strategies are likely to be the benchmark for treating these diseases, and a combined approach of different therapies may be optimal in treating some of these diseases. PMID- 29721953 TI - Role of Fibulins 2 and 5 in Retinal Development and Maintenance. AB - Fibulins 2 and 5 are part of a seven-member family of proteins integral to the retinal extracellular matrix. Our study aimed to further explore the roles of both fibulins in retinal function. We obtained knockout mouse models of both fibulins and performed immunohistochemistry, electroretinography, and histology to investigate the outcome of eliminating these proteins. Immunohistochemical analysis showed that both fibulins are localized to the RPE, choroid, and Bruch's membrane. Functional testing showed a significantly reduced scotopic A response at 1 month of age, when compared to their wild-type counterpart. This functional reduction remained constant throughout the age of the animal and only declined as a result of normal aging. The functional decline was associated with reduced number of photoreceptor cells. The results presented clearly demonstrate that fibulins 2 and 5, as extracellular proteins, are necessary for normal retinal development. PMID- 29721954 TI - Identifying Key Networks Linked to Light-Independent Photoreceptor Degeneration in Visual Arrestin 1 Knockout Mice. AB - When visual arrestin 1 (ARR1, S-antigen, 48 KDa protein) was genetically knocked out in mice (original Arr1 -/- , designated Arr1 -/-A ), rod photoreceptors degenerated in a light-dependent manner. Subsequently, a light-independent cone dystrophy was identified with minimal rod death in ARR1 knockout mice (Arr1 -/-A Arr4 +/+, designated Arr1 -/-B ), which were F2 littermates from breeding the original Arr1 -/-A and cone arrestin knockout 4 (Arr4 -/- ) mice. To resolve the genetic and phenotypic differences between the two ARR1 knockouts, we performed AffymetrixTM exon array analysis to focus on the potential differential gene expression profile and to explore the molecular and cellular pathways leading to this observed susceptibility to cone dystrophy in Arr1 -/-B compared to Arr1 -/-A or control Arr1 +/+ Arr4 +/+ (wild type [WT]). Only in the Arr1 -/-B retina did we observe an up-regulation of retinal transcripts involved in the immune response, inflammatory response and JAK-STAT signaling molecules, OSMRbeta and phosphorylation of STAT3. Of these responses, the complement system was significantly higher, and a variety of inflammatory responses by complement regulation and anti-inflammatory cytokine or factors were identified in Arr1 -/-B retinal transcripts. This discovery supports that Arr1 -/-B has a distinct genetic background from Arr1 -/-A that results in alterations in its retinal phenotype leading to susceptibility to cone degeneration induced by inappropriate inflammatory and immune responses. PMID- 29721955 TI - How Excessive cGMP Impacts Metabolic Proteins in Retinas at the Onset of Degeneration. AB - Aryl-hydrocarbon receptor interacting protein-like 1 (AIPL1) is essential to stabilize cGMP phosphodiesterase 6 (PDE6) in rod photoreceptors. Mutation of AIPL1 leads to loss of PDE6, accumulation of intracellular cGMP, and rapid degeneration of rods. To understand the metabolic basis for the photoreceptor degeneration caused by excessive cGMP, we performed proteomics and phosphoproteomics analyses on retinas from AIPL1-/- mice at the onset of rod cell death. AIPL1-/- retinas have about 18 times less than normal PDE6a and no detectable PDE6b. We identified twelve other proteins and thirty-nine phosphorylated proteins related to cell metabolism that are significantly altered preceding the massive degeneration of rods. They include transporters, kinases, phosphatases, transferases, and proteins involved in mitochondrial bioenergetics and metabolism of glucose, lipids, amino acids, nucleotides, and RNA. In AIPLI-/- retinas mTOR and proteins involved in mitochondrial energy production and lipid synthesis are more dephosphorylated, but glycolysis proteins and proteins involved in leucine catabolism are more phosphorylated than in normal retinas. Our findings indicate that elevating cGMP rewires cellular metabolism prior to photoreceptor degeneration and that targeting metabolism may be a productive strategy to prevent or slow retinal degeneration. PMID- 29721956 TI - Protein Carbonylation-Dependent Photoreceptor Cell Death Induced by N-Methyl-N nitrosourea in Mice. AB - Retinal degenerative diseases, such as retinitis pigmentosa, are characterized by night blindness and peripheral vision loss caused by the slowly progressive loss of photoreceptor cells. A comprehensive molecular mechanism of the photoreceptor cell death remains unclear. We previously reported that heat shock protein 70 (HSP70), which has a protective effect on neuronal cells, was cleaved by a calcium-dependent protease, calpain, in N-methyl-N-nitrosourea (MNU)-treated mice retina. Carbonylated HSP70 is much more vulnerable than noncarbonylated HSP70 to calpain cleavage. However, it was not known whether protein carbonylation occurs in MNU-treated mice retina. In this study, we clearly show protein carbonylation dependent photoreceptor cell death induced by MNU in mice. Therefore, protein carbonylation and subsequent calpain-dependent cleavage of HSP70 are key events in MNU-mediated photoreceptor cell death. Our data provide a comprehensive molecular mechanism of the photoreceptor cell death. PMID- 29721957 TI - Muller Glia Reactivity and Development of Gliosis in Response to Pathological Conditions. AB - Within the mammalian retina, both Muller glia and astrocytes display reactivity in response to many forms of retinal injury and disease in a process termed gliosis. Reactive gliosis is a complex process that is considered to represent a cellular response to protect the retina from further damage and to promote its repair following pathological insult. It includes morphological, biochemical and physiological changes, which may vary depending on the type and degree of the initial injury. Not only does gliosis have numerous triggers, but also there is a great degree of heterogeneity in the glial response, creating multiple levels of complexity. For these reasons, understanding the process of glial scar formation and how this process differs in different pathological conditions and finding strategies to circumvent these barriers represent major challenges to the advancement of many ocular therapies. PMID- 29721959 TI - Binary Function of ARL3-GTP Revealed by Gene Knockouts. AB - UNC119 and PDEdelta are lipid-binding proteins and are thought to form diffusible complexes with transducin-alpha and prenylated OS proteins, respectively, to mediate their trafficking to photoreceptor outer segments. Here, we investigate mechanisms of trafficking which are controlled by Arf-like protein 3 (Arl3), a small GTPase. The activity of ARL3 is regulated by a GEF (ARL13b) and a GAP (RP2). In a mouse germline knockout of RP2, ARL3-GTP is abundant as its intrinsic GTPase activity is extremely low. High levels of ARL3-GTP impair binding and trafficking of cargo to the outer segment. Germline knockout of ARL3 is embryonically lethal generating a syndromic ciliopathy-like phenotype. Retina- and rod-specific knockout of ARL3 allow to determine the precise mechanisms leading to photoreceptor degeneration. The knockouts reveal binary functions of ARL3-GTP as a key molecule in late-stage photoreceptor ciliogenesis and cargo displacement factor. PMID- 29721960 TI - Do cGMP Levels Drive the Speed of Photoreceptor Degeneration? AB - Humans with mutations in the phototransduction pathway develop forms of retinal degeneration, such as retinitis pigmentosa, cone dystrophy, or Leber congenital amaurosis. Similarly, numerous phototransduction mutant animal models resemble retinal degeneration. In our lab, using a zebrafish model, we study cone-specific phototransduction mutants. cGMP is the second messenger in the phototransduction pathway, and abnormal cGMP levels are associated with photoreceptor death. Rd1, a rod-specific phosphodiesterase 6 (Pde6) subunit mutant in mice, is one of the most widely used animal models for retinal degeneration. Rd1 mutant mice accumulate cGMP, causing rapid photoreceptor degeneration. However, much less is known about photoreceptor mutants producing abnormally low levels of cGMP. Here, focusing on Pde6 mutants in zebrafish and mice, we propose a correlation between cGMP levels and speed of photoreceptor degeneration. PMID- 29721958 TI - Underdeveloped RPE Apical Domain Underlies Lesion Formation in Canine Bestrophinopathies. AB - Canine bestrophinopathy (cBest) is an important translational model for BEST1 associated maculopathies in man that recapitulates the broad spectrum of clinical and molecular disease aspects observed in patients. Both human and canine bestrophinopathies are characterized by focal to multifocal separations of the retina from the RPE. The lesions can be macular or extramacular, and the specific pathomechanism leading to formation of these lesions remains unclear. We used the naturally occurring canine BEST1 model to examine factors that underlie formation of vitelliform lesions and addressed the susceptibility of the macula to its primary detachment in BEST1-linked maculopathies. PMID- 29721961 TI - Early Endosome Morphology in Health and Disease. AB - Early endosomes are organelles that receive macromolecules and solutes from the extracellular environment. The major function of early endosomes is to sort these cargos into recycling and degradative compartments of the cell. Degradation of the cargo involves maturation of early endosomes into late endosomes, which, after acquisition of hydrolytic enzymes, form lysosomes. Endosome maturation involves recruitment of specific proteins and lipids to the early endosomal membrane, which drives changes in endosome morphology. Defects in early endosome maturation are generally accompanied by alterations in morphology, such as increase in volume and/or number. Enlarged early endosomes have been observed in Alzheimer's disease and Niemann Pick Disease type C, which also exhibit defects in endocytic sorting. This article discusses the mechanisms that regulate early endosome morphology and highlights the potential importance of endosome maturation in the retinal pigment epithelium. PMID- 29721963 TI - The Role of c-Jun N-Terminal Kinase (JNK) in Retinal Degeneration and Vision Loss. AB - c-Jun N-terminal kinase (JNK), a member of stress-induced mitogen-activated protein (MAP) kinase family, has been shown to modulate a variety of biological processes associated with neurodegenerative pathology of the retina. In particular, various retinal cell culture and animal models related to glaucoma, age-related macular degeneration (AMD), and retinitis pigmentosa indicate that JNK signaling may contribute to disease pathogenesis. This mini-review discusses the impact of JNK signaling in retinal disease, with a focus on retinal ganglion cells (RGCs), photoreceptor cells, retinal pigment epithelial (RPE) cells, and animal studies, with particular attention to modulation of JNK signaling as a potential therapeutic target for the treatment of retinal disease. PMID- 29721962 TI - The Retinal Circadian Clock and Photoreceptor Viability. AB - Circadian rhythms are present in most living organisms, and these rhythms are not just a consequence of the day/night fluctuation, but rather they are generated by endogenous biological clocks with a periodicity of about 24 h. In mammals, the master pacemaker of circadian rhythms is localized in the suprachiasmatic nuclei (SCN) of the hypothalamus. The SCN controls circadian rhythms in peripheral organs. The retina also contains circadian clocks which regulate many aspects of retinal physiology, independently of the SCN. Emerging experimental evidence indicates that the retinal circadian clocks also affect ocular health, and a few studies have now demonstrated that disruption of retinal clocks may contribute to the development of retinal diseases. Our study indicates that in mice lacking the clock gene Bmal1, photoreceptor viability during aging is significantly reduced. Bmal1 knockout mice at 8-9 months of age have 20-30% less nuclei in the outer nuclear layer. No differences were observed in the other retinal layers. Our study suggests that the retinal circadian clock is an important modulator of photoreceptor health. PMID- 29721964 TI - The Evaluation of BMI1 Posttranslational Modifications During Retinal Degeneration to Understand BMI1 Action on Photoreceptor Death Execution. AB - Retinitis Pigmentosa (RP) is a class of hereditary retinal dystrophy associated with gradual visual failure and a subsequent loss of light-sensitive cells in the retina, leading to blindness. Many mutated genes were found to be causative of this disease. Despite a number of compiling efforts, the process of cell death in photoreceptors remains to be clearly elucidated. We recently reported an abnormal cell cycle reentry in photoreceptors undergoing degeneration in Rd1 mice, a model of RP, and identified the polycomb repressive complex 1 (PRC1) core component BMI1 as a critical molecular factor orchestrating the cell death mechanism. As the cell death rescue in Rd1;Bmi-1 KO mice was independent on the conventional Ink4a/Arf pathways, we now explored the structural properties of BMI1 in order to examine the differential expression of its posttranslational modifications in Rd1 retina. Our results suggest that BMI1 cell death induction in Rd1 is not related to its phosphorylation status. We therefore propose the epigenetic activity of BMI1 as an alternative route for BMI1-mediated toxicity in Rd1. PMID- 29721965 TI - Primary Rod and Cone Degeneration Is Prevented by HDAC Inhibition. AB - Photoreceptor cell death in inherited retinal degeneration is accompanied by over activation of histone deacetylases (HDAC). Excessive HDAC activity is found both in primary rod degeneration (such as in the rd10 mouse) and in primary cone death, including the cone photoreceptor function loss 1 (cpfl1) mouse. We evaluated the potential of pharmacological HDAC inhibition to prevent photoreceptor degeneration in primary rod and cone degeneration. We show that a single in vivo treatment of cpfl1 mice with the HDAC inhibitor trichostatin A (TSA) resulted in a significant protection of cpfl1 mutant cones. Similarly, HDAC inhibition with the clinically approved HDAC inhibitor vorinostat (SAHA) resulted in a significant improvement of rod survival in rd10 retinal explant cultures. Altogether, these results highlight the feasibility of targeted neuroprotection in vivo and create hope to maintain vision in patients suffering from both rod and cone dystrophies. PMID- 29721967 TI - The Leber Congenital Amaurosis-Linked Protein AIPL1 and Its Critical Role in Photoreceptors. AB - Mutations in the photoreceptor/pineal-expressed gene, aryl hydrocarbon receptor interacting protein-like 1 (AIPL1), are mainly associated with autosomal recessive Leber congenital amaurosis (LCA), the most severe form of inherited retinopathy that occurs in early childhood. AIPL1 functions as a photoreceptor specific molecular co-chaperone that interacts specifically with the molecular chaperones HSP90 and HSP70 to facilitate the correct folding and assembly of the retinal cGMP phosphodiesterase (PDE6) holoenzyme. The absence of AIPL1 leads to a dramatic degeneration of rod and cone cells and a complete loss of any light dependent electrical response. Here we review the important role of AIPL1 in photoreceptor functionality. PMID- 29721966 TI - Impact of MCT1 Haploinsufficiency on the Mouse Retina. AB - The monocarboxylate transporter 1 (MCT1) is highly expressed in the outer retina, suggesting that it plays a critical role in photoreceptors. We examined MCT1 +/- heterozygotes, which express half of the normal complement of MCT1. The MCT1 +/- retina developed normally and retained normal function, indicating that MCT1 is expressed at sufficient levels to support outer retinal metabolism. PMID- 29721968 TI - Alternative Splicing for Activation of Coagulation Factor XIII-A in the Fish Retina After Optic Nerve Injury. AB - Factor XIII-A (FXIII-A), which has become known as cellular transglutaminase, plays important roles in mediating cross-linking reactions in various tissues. FXIII-A acts as one of the regeneration molecules in the fish retina and optic nerve after optic nerve injury and becomes activated at the site of injury within a few hours. Previous research has shown that activated FXIII-A induces neurite outgrowth from injured retinal ganglion cells and supports elongation of the regenerating optic nerve. However, the activation mechanism of FXIII-A remains unknown. Furthermore, the injured tissues do not express thrombin, a known activator of plasma FXIII. Here, we investigated the mRNA expression of FXIII-A based on two different regions, one encoding the activation peptide and the other encoding the enzymatic active site. We found that expression of the region encoding the activation peptide was markedly suppressed compared with the region encoding the active site. An overexpression study with a short-type FXIII-A cDNA lacking the activation peptide revealed induction of long neurite outgrowth in fish retinal explant cultures compared with full-length FXIII-A cDNA. The present findings suggest that alternative splicing may occur in the FXIII-A gene, resulting in deletion of the region encoding the activation peptide and thus allowing direct production of activated FXIII-A protein in the fish retina and optic nerve after optic nerve injury. PMID- 29721969 TI - Bisretinoid Photodegradation Is Likely Not a Good Thing. AB - Retinaldehyde adducts (bisretinoids) accumulate in retinal pigment epithelial (RPE) cells as lipofuscin. Bisretinoids are implicated in some inherited and age related forms of macular degeneration that lead to the death of RPE cells and diminished vision. By comparing albino and black-eyed mice and by rearing mice in darkness and in cyclic light, evidence indicates that bisretinoid fluorophores undergo photodegradation in the eye (Ueda et al. Proc Natl Acad Sci 113:6904 6909, 2016). Given that the photodegradation products modify and impair cellular and extracellular molecules, these processes likely impart cumulative damage to retina. PMID- 29721970 TI - Further Characterization of the Predominant Inner Retinal Degeneration of Aging Cln3 Deltaex7/8 Knock-In Mice. AB - Neuronal ceroid lipofuscinosis (NCL) is the most common group of neurogenetic storage diseases typically beginning in childhood. The juvenile form (JNCL), also known as Batten disease, is the most common form. Vision-related problems are often an early sign, appearing prior to motor and mental deficits. We have previously investigated disease progression with age in the Cln3 Deltaex7/8 KI mouse model for JNCL and showed a decline of visual acuity and a predominant decline of the inner retinal function in mice, similar to human disease. The aim of this study was to further characterize this degeneration by means of flicker ERGs. For the scotopic flicker ERG, we found a significantly lower magnitude for Cln3 Deltaex7/8 KI mice already at 6 months of age for low stimulus frequencies, while the difference declines with increasing frequency. Under photopic conditions there was no magnitude difference at 6 months, but a cumulative magnitude reduction with further aging. For both conditions the phases were similar for both groups. There was a similar magnitude reduction for the responses of both the slow and fast rod pathway in the 15 Hz experiments, and there were no differences in response phase. Low-frequency flicker responses seem to be sensitive to very early disease manifestations, and while the degeneration is associated with a reduction of predominating inner retinal responses in the scotopic flash ERG, this predominance seems not to be related to a selective involvement of the slow and fast rod pathways. PMID- 29721971 TI - Differential Exon Expression in a Large Family of Retinal Genes Is Regulated by a Single Trans Locus. AB - Transcription and RNA processing can generate many variant mRNAs (isoforms) from a given genomic locus. The more we learn about RNA processing the more we realize how complex it can be. Examining the expression profiles of individual exons, we observed that specific exons were differentially expressed across a large number of genes in mice. We found that each isoform or exon is independently expressed compared to other exons from the same gene and regulated separately in trans. Each trans locus was identified by mapping using linkage analysis in a large mouse recombinant inbred strain set. We present evidence for a limited number of these master regulatory loci in the retina. One major locus controls about half the expression of the individual exons and resides on Chromosome 4, between 133 and 136 Mb. PMID- 29721973 TI - The Role of Microbiota in Retinal Disease. AB - The ten years since the first publications on the human microbiome project have brought enormous attention and insight into the role of the human microbiome in health and disease. Connections between populations of microbiota and ocular disease are now being established, and increased accessibility to microbiome research and insights into other diseases is expected to yield enormous information in the coming years. With the characterization of the ocular microbiome, important insights have already been made regarding corneal and conjunctival tissues. Roles for non-ocular microbiomes in complex retinal diseases are now being evaluated. For example, the gut microbiome has been implicated in the pathogenesis of uveitis. This short review will summarize the few studies linking gut or oral microbiota to diabetic retinopathy (DR), glaucoma, and age-related macular degeneration (AMD). We will also conjecture where the most significant findings still remain to be elucidated. Finally, we will propose the gut-retina axis, related but distinct from the gut-brain axis. PMID- 29721972 TI - Molecular Chaperone ERp29: A Potential Target for Cellular Protection in Retinal and Neurodegenerative Diseases. AB - The molecular chaperone endoplasmic reticulum protein 29 (ERp29) plays a critical role in protein folding, trafficking, and secretion. Though ubiquitously expressed, ERp29 is upregulated in response to ER stress and is found at higher levels in certain cell types such as secretory epithelial cells and neurons. As an ER resident protein, ERp29 shares many structural and functional similarities with protein disulfide isomerases, but is not regarded as part of this family due to several key differences. The broad expression and myriad roles of ERp29 coupled with its upregulation via the unfolded protein response (UPR) upon ER stress have implicated ERp29 in a range of cellular processes and diseases. We summarize the diverse activities of ERp29 in protein trafficking, cell survival and apoptosis, and ER homeostasis and highlight a potential role of ERp29 in neuroprotection in retinal and neurodegenerative diseases. PMID- 29721974 TI - Current Pharmacological Concepts in the Treatment of the Retinitis Pigmentosa. AB - Retinitis pigmentosa (RP) encompasses a heterogeneous group of inherited retinal disorders characterized by progressive photoreceptor and/or retinal pigment epithelial (RPE) degenerations with a prevalence approximately 1 in 4000 in the general population. Over 70 causative genes have been defined in RP families, and a number of animal models have been identified so far. However there have been no widely recognized treatments able to recover or reverse the degenerating retina, to prevent the disease deterioration, ultimately to restore the remaining vision. Therapeutics advancements have been achieved including gene therapy, pharmacotherapy, cell replacement, neurotrophic factors, and retinal prosthesis. In this review, we focus on the pharmaceutical drugs for RP with emphases on the context of drug discovery, development, and clinical translation. PMID- 29721975 TI - Valproic Acid Inhibits Human Retinal Pigment Epithelial (hRPE) Cell Proliferation Via a P38 MAPK Signaling Mechanism. AB - Valproic acid (VPA) has been reported to inhibit cancer cell growth and has therapeutic use in retinal diseases. However, the mechanism of this action remains unclear. In order to explore this mechanism, primary human retinal pigment epithelial (hRPE) cell cultures were established. Cell viability was assessed by the trypan blue exclusion method (T), and the cell proliferation was measured by 3H-thymidine incorporation (3H-thy). P38 synthesis was quantitated by using 14C-methionine-labeled P38 (14C-P38) by using P38-specific antibody. SB203580 (SB), a selective inhibitor of p38 MAPK, was also used to test the specificity of P38 stimulation. Antinuclear staining (NS) studies were performed by DAPI. Statistical significance was established by student's t-test. We observed that VPA (1 mM) inhibited 10% fetal bovine serum (FBS)-stimulated cell proliferation (1.75 +/- 0.37 vs. 3.25 +/- 0.68 cells per 1 MUl +/- SEM, p < 0.05, n = 4). VPA also stimulated 14C-P38 synthesis in a dose-dependent manner. SB (30 MUM) inhibited VPA (4 mM)-stimulated 14C-P38 synthesis (197.74 +/- 41.17 vs. 425.89 +/- 59.17, CPM +/- SEM, p < 0.05, n = 4) and increased hRPE cell proliferation (1.79 +/- 0.45 vs. 4.93 +/- 1.12 cells per 1 MUl +/- SEM, p < 0.05, n = 4); NS demonstrated VPA-induced cell damage. We conclude that VPA inhibits hRPE cell growth via P38 MAP mechanism and may be of therapeutic value in treating or preventing proliferative eye diseases. PMID- 29721976 TI - Pigment Epithelium-derived Factor Protects Retinal Pigment Epithelial Cells Against Cytotoxicity "In Vitro". AB - Oxidative stress has been implicated in neurodegenerative diseases, such as age related macular degeneration. Hydrogen peroxide and sodium iodate can mediate oxidative injury. Sodium iodate induces a selective retinal degeneration targeting the RPE. We describe a method of chronic sodium iodate-mediated injury on RPE cells that may serve to evaluate protective factors against oxidative stress. Cytotoxicity and cell viability curves of ARPE-19 cells with sodium iodate were generated. The antioxidant pigment epithelium-derived factor decreased sodium iodate-mediated cytotoxicity without affecting ARPE-19 cell viability. A cell culture system to evaluate protection against oxidative stress injury with PEDF is discussed. PMID- 29721977 TI - Brain-Derived Neurotrophic Factor as a Treatment Option for Retinal Degeneration. AB - This review discusses the therapeutic potential of brain-derived neurotrophic factor (BDNF) for retinal degeneration. BDNF, nerve growth factor (NGF), neurotrophin 3 (NT-3) and NT-4/NT-5 belong to the neurotrophin family. These neuronal modulators activate a common receptor and a specific tropomyosin-related kinase (Trk) receptor. BDNF was identified as a photoreceptor protectant in models of retinal degeneration as early as 1992. However, development of effective therapeutics that exploit this pathway has been difficult due to challenges in sustaining therapeutic levels in the retina. PMID- 29721978 TI - VEGF as a Trophic Factor for Muller Glia in Hypoxic Retinal Diseases. AB - Age-related macular degeneration (AMD) and diabetic retinopathy (DR), leading causes of blindness, share a common retinal environment: hypoxia which is a major stimulator for the upregulation of vascular endothelial growth factor (VEGF), a cardinal pathogenic factor for the breakdown of blood-retina barrier (BRB). As a result of intensive studies on VEGF pathobiology, anti-VEGF strategy has become a major therapeutics for wet AMD and DR. To investigate the potential impact of anti-VEGF strategy on major retinal supporting cells, Muller glia (MG), we disrupted VEGF receptor-2 (VEGFR2) in MG with conditional knockout (CKO) and examined the effect of VEGFR2-null on MG viability and neuronal integrity in mice. VEGFR2 CKO mice demonstrated a significant loss of MG density in diabetes/hypoxia, which in turn resulted in accelerated retinal degeneration. These defects appear similar to the clinical characteristics in a significant portion of wet-AMD patients with long-term anti-VEGF therapies. In this article, we will discuss the potential relevance of these clinical characteristics to the critical role of VEGF signaling in MG viability and neuronal integrity in hypoxia. PMID- 29721979 TI - Muller Cell Biological Processes Associated with Leukemia Inhibitory Factor Expression. AB - Muller cells provide support to photoreceptors under many conditions of stress and degeneration. Leukemia inhibitory factor is known to be expressed in Muller cells, which is necessary to promote photoreceptor survival in stress. We hypothesize that Muller cells that express LIF are undergoing other biological processes or functions which may benefit photoreceptors in disease. In this study, we analyze an existing single Muller cell microarray dataset to determine which processes are upregulated in Muller cells that express LIF, by correlating LIF expression to the expression of other genes using a robust correlation method. Some enriched processes include divalent inorganic cation homeostasis, negative regulation of stem cell proliferation, and gamma-glutamyl transferase activity. PMID- 29721980 TI - Retbindin Is Capable of Protecting Photoreceptors from Flavin-Sensitized Light Mediated Cell Death In Vitro. AB - Retbindin (Rtbdn) is a novel protein of unknown function found exclusively in the retina. Recently, our group has suggested, from in silico analysis of the peptide sequence and in vitro binding data, that Rtbdn could function to bind riboflavin (RF) and its derivatives flavin adenine dinucleotide (FAD) and flavin mononucleotide (FMN), collectively known as flavins. Here we confirm that Rtbdn is capable of flavin binding and that this characteristic can protect photoreceptors from flavin-sensitized light damage. PMID- 29721981 TI - Constitutive Activation Mutant mTOR Promote Cone Survival in Retinitis Pigmentosa Mice. AB - Studies form our laboratory and others show that the oncogenic tyrosine kinase and serine threonine kinase signaling pathways are essential for cone photoreceptor survival. These pathways are downregulated in mouse models of retinal degenerative diseases. In the present study, we found that activation mutants of mTOR delayed the death of cones in a mouse model of retinal degeneration. These studies suggest that oncogenic protein kinases may be useful as therapeutic agents to treat retinal degenerations that affect cones. PMID- 29721982 TI - Maintaining Cone Function in Rod-Cone Dystrophies. AB - Retinal degenerative diseases are a major cause of untreatable blindness due to a loss of photoreceptors. Recent advances in genetics and gene therapy for inherited retinal dystrophies (IRDs) showed that therapeutic gene transfer holds a great promise for vision restoration in people with currently incurable blinding diseases. Due to the huge genetic heterogeneity of IRDs that represents a major obstacle for gene therapy development, alternative therapeutic approaches are needed. This review focuses on the rescue of cone function as a therapeutic option for maintaining central vision in rod-cone dystrophies. It highlights recent developments in better understanding the mechanisms of action of the trophic factor RdCVF and its potential as a sight-saving therapeutic strategy. PMID- 29721983 TI - PKG-Dependent Cell Death in 661W Cone Photoreceptor-like Cell Cultures (Experimental Study). AB - In humans cone photoreceptors are responsible for high-resolution colour vision. A variety of retinal diseases can compromise cone viability, and, at present, no satisfactory treatment options are available. Here, we present data towards establishing a reliable, high-throughput assay system that will facilitate the search for cone neuroprotective compounds using the murine-photoreceptor cell line 661 W. To further characterize 661 W cells, a retinal marker study was performed, followed by the induction of cell death using paradigms over activating cGMP-dependent protein kinase G (PKG). We found that 661 W cells may be used to mimic specific aspects of cone degeneration and may thus be valuable for future compound screening studies. PMID- 29721984 TI - More Than Meets the Eye: Current Understanding of RPGR Function. AB - This article summarizes the recent advances in our understanding of a major retinal disease gene RPGR (retinitis pigmentosa GTPase regulator), mutations in which are associated with majority of X-linked forms of retinal degenerations. A great deal of work has been done to uncover the ciliary localization of RPGR and its interacting proteins in the retina. However, the molecular mechanisms of action of RPGR in the photoreceptors are still unclear. Recent studies have begun to shed light on the intracellular pathways in which RPGR is likely involved. The deregulation of such pathways may underlie the pathogenesis of severe retinal degeneration associated with RPGR. With the recent advances in the gene augmentation therapy for RPGR-associated disease, there is a lot of excitement in the field. Patients with RPGR mutations, however, present with clinically heterogeneous manifestations. It is therefore imperative to examine the function of RPGR in detail, so that we can design patient-oriented therapeutic strategies for this disease. PMID- 29721985 TI - Polarized Exosome Release from the Retinal Pigmented Epithelium. AB - The retinal pigmented epithelium (RPE) forms the outer blood-retinal barrier and provides nutrients and recycling of visual pigment to the photoreceptors, among many other functions. The RPE is also a key site of pathophysiological changes in age-related macular degeneration, making it an important focus of study in both visual health and disease. Exosomes are nanometer-sized vesicles that are released by cells in a controlled fashion and mediate a range of extra- and intercellular activities. Some key exosome actions include cell-cell communication, immune modulation, extracellular matrix turnover, stem cell division/differentiation, neovascularization, and cellular waste removal. While much is known about their role in cancer and cardiovascular disease, exosome function in the many specialized tissues of the eye is just beginning to undergo rigorous study. Here we review current knowledge of the functions and roles of exosomes and other small extracellular vesicles released from the RPE. In particular, we discuss the potential role and importance of polarized exosome release from the RPE. PMID- 29721986 TI - The Impact of Adherens and Tight Junctions on Physiological Function and Pathological Changes in the Retina. AB - The formation of solid tissues is not a simple aggregation of individual cells but rather an ordered assembly of cells connected by junctions. These junctions provide a diffusion barrier as well as mechanical support and a conduit for signalling changes in the environment to the cells. Cell junctions are functionally categorized as occluding (e.g. tight junctions, TJs), anchoring (e.g. adherens junctions, AJs) and communicating junctions (e.g. gap junctions). Each type of the cell junction is formed by protein complexes with extracellular domains and/or intracellular domains, which bind partners that provide scaffolding and signalling components. Cell junctions are ubiquitously expressed in multiple tissues and organs, including the retina. In the retina, their biological impact is not limited to regulating tissue growth and development. Disruption of the complexes mediates both congenital and postnatal pathogenesis. In this review, we will focus on cell junctions, specifically AJs and TJs in the external limiting membrane, in order to articulate their influence on pathophysiology of the retina. PMID- 29721987 TI - TRPV4 Does Not Regulate the Distal Retinal Light Response. AB - The transient receptor potential vanilloid isoform 4 (TRPV4) functions as polymodal transducer of swelling, heat, stretch, and lipid metabolites, is widely expressed across sensory tissues, and has been implicated in pressure sensing in vertebrate retinas. Although TRPV4 knockout mice exhibit a variety of mechanosensory, nociceptive, and thermo- and osmoregulatory phenotypes, it is not known whether the transmission of light-induced signals in the eye is affected by the loss of TRPV4. We utilized field potentials, a measure of rod and cone signaling, to determine whether TRPV4 impacts on the generation and/or transmission of the photoreceptor light response and neurotransmission. Luminance intensity-response relationships were acquired in anesthetized wild-type and TRPV4-/- mice and evaluated for peak amplitude and implicit time under scotopic and photopic conditions. We found that the morphology of the outer retina is unaffected by the ablation of the Trpv4 gene. Calcium imaging of dissociated Muller glia showed that selective TRPV4 stimulation induces oscillatory calcium signals in adjacent rods. However, no differences in scotopic or photopic light evoked signaling in the distal retina were observed in TRPV4-/- eyes, suggesting that TRPV4 signaling in healthy Muller cells does not modulate the transmission of light-evoked signals at rod and cone synapses. PMID- 29721988 TI - Role of Sirtuins in Retinal Function Under Basal Conditions. AB - Sirtuins are NAD+-dependent enzymes that govern cellular homeostasis by regulating the acylation status of their diverse target proteins. We recently demonstrated that both rod and cone photoreceptors rely on NAMPT-mediated NAD+ biosynthesis to meet their energetic requirements. Moreover, we found that this NAD+-dependent retinal homeostasis relies, in part, on maintenance of optimal activity of the mitochondrial sirtuins and of SIRT3 in particular. Nonetheless, it is unknown whether other sirtuin family members also play important roles in retinal homeostasis. Our results suggest that SIRT1, SIRT2, SIRT4, and SIRT6 are dispensable for retinal survival at baseline, as individual deletion of each of these sirtuins does not cause retinal degeneration by fundus biomicroscopy or retinal dysfunction by ERG. These findings have significant implications and inform future studies investigating the mechanisms underlying the central role of NAD+ biosynthesis in retinal survival and function. PMID- 29721989 TI - The Retinol-Binding Protein Receptor 2 (Rbpr2) Is Required for Photoreceptor Survival and Visual Function in the Zebrafish. AB - Vitamin A/retinol (ROL) and its metabolites (retinoids) play critical roles in eye development and photoreception. Short-term dietary vitamin A deficiency (VAD) manifests clinically as night blindness, while prolonged VAD is known to cause retinal pigment epithelium (RPE) and photoreceptor degeneration. Therefore, sustained uptake of dietary vitamin A, for ocular retinoid production, is essential for photoreceptor health and visual function. The mechanisms influencing the uptake, storage, and supply of dietary vitamin A, for ocular retinoid production, however, are not fully understood. We investigated, in zebrafish, the physiological role of the retinol-binding protein receptor 2 (Rbpr2), for the uptake of dietary ROL, which is necessary for vision. NIH3T3 cells expressing zebrafish Rbpr2 showed plasma membrane localization patterns and were capable of ROL uptake from its bound form. Using whole-mount in situ hybridization, Rbpr2 was found to be expressed exclusively in the liver, intestine, and pancreas, of staged zebrafish larvae. At 5.5 days post fertilization, TALEN-generated rbpr2 mutants (rbpr2 -/- ) had smaller eyes and shorter OS lengths and showed loss of PNA (cones) and rhodopsin (rods) by immunofluorescence staining. Finally, tests for visual function using optokinetic response (OKR) showed no consistent OKR in rbpr2 -/- larval zebrafish. Our analysis, therefore, suggests that Rbpr2 is capable of ROL uptake and loss of this membrane receptor in zebrafish results in photoreceptor defects that adversely affect visual function. PMID- 29721990 TI - Opposite Roles of MerTK Ligands Gas6 and Protein S During Retinal Phagocytosis. AB - MerTK is required for photoreceptor outer segment (POS) phagocytosis by retinal pigment epithelial (RPE) cells, a diurnal function essential for vision maintenance. In vivo, MerTK is stimulated at the time of the phagocytic peak through an intracellular signaling pathway. However, MerTK ligands Gas6 and Protein S are expressed in both RPE cells and photoreceptors, and at least one of them required for phagocytosis to occur. Still, their exact role in the retina was not clear until recently. This review combines results from different studies to shed the light on a tissue-specific regulation of MerTK function by its ligands. Indeed, with opposite effects on RPE phagocytosis and changes in their expression levels around the time of POS uptake, Gas6 and Protein S may contribute to the tight control of the acute phagocytic peak in the retina. PMID- 29721991 TI - Redundant and Nonredundant Functions of Akt Isoforms in the Retina. AB - Serine/threonine kinase Akt is a downstream effector of the phosphoinositide 3 kinase pathway that is involved in many processes, including providing neuroprotection to stressed photoreceptor cells. Akt exists in three isoforms designated as Akt1, Akt2, and Akt3. All of these isoforms are expressed in the retina. We previously reported that Akt2 knockout mice were susceptible to light stress-induced photoreceptor degeneration, whereas Akt1 deletion had no effect on the retina. We hypothesized that the phenotype of Akt2 knockout mice may be due to the inactivation of specific substrate(s) in the retina. Yeast two-hybrid screening of a bovine retinal cDNA library with Akt2 identified a multidomain protein, POSH (plenty of SH3s), that acts as a scaffold for the JNK pathway of neuronal death. Our results suggest a stable interaction between Akt2 and POSH. Previous studies show that overexpression of POSH leads to cell death. The cell death that we observed in Akt2 knockout mice could be due to the absence of inactivation of POSH-mediated JNK signaling in the retina. PMID- 29721993 TI - Preservation of Photoreceptor Nanostructure for Electron Tomography Using Transcardiac Perfusion Followed by High-Pressure Freezing and Freeze Substitution. AB - The phototransductive membrane disks of a vertebrate photoreceptor outer segment (OS) are highly susceptible to perturbations during preservation for electron microscopy. To optimize their preservation for nanostructural studies, such as with electron tomography (ET), we developed a protocol, using a combination of chemical and physical fixation approaches, including transcardiac perfusion, high pressure freezing, and freeze-substitution. PMID- 29721992 TI - Photoreceptor Outer Segment Isolation from a Single Canine Retina for RPE Phagocytosis Assay. AB - Protocols for photoreceptor outer segment (POS) isolation that can be used in phagocytosis assays of retinal pigment epithelium (RPE) cells have routinely used a large number of cow or pig eyes. However, when working with large animal models (e.g., dog, cats, transgenic pigs) of inherited retinal degenerative diseases, access to retinal tissues may be limited. An optimized protocol is presented in this paper to isolate sufficient POS from a single canine retina for use in RPE phagocytosis assays. PMID- 29721994 TI - Microtubule-Associated Protein 1 Light Chain 3 (LC3) Isoforms in RPE and Retina. AB - Microtubule-associated protein 1 light chain 3 (MAP1LC3), a human homologue of yeast Atg8, is an essential component of autophagy. LC3 plays a critical role in hybrid degradation pathways in which some but not all components of autophagy are coupled with phagocytosis in a process known as LC3-associated phagocytosis (LAP). LC3 exists as three highly homologous isoforms in human (LC3A, LC3B, and LC3C) with two of these (LC3A and LC3B) in mouse. LC3B predominated in both fetal and adult human retinal pigment epithelium (RPE) relative to LC3A and LC3C, while in mouse RPE and neural retina, LC3A and LC3B were expressed at approximately equivalent levels. In situ hybridization studies localized LC3A and LC3B transcripts in the retina and RPE. LC3B protein was detected in C57Bl6/J RPE and retinal lysates and was absent in the LC3BKO mouse. PMID- 29721995 TI - The iPSc-Derived Retinal Tissue as a Tool to Study Growth Factor Production in the Eye. AB - Traumatic, inherited, and age-related degenerative diseases of the retina, such as retinal detachment, glaucoma, retinitis pigmentosa, and age-related macular degeneration, are characterized by the irreversible loss of retinal neurons. Several growth factors, including glial cell-derived neurotrophic factor and pigment epithelium-derived factor, have been shown to rescue retinal neurons in animal models of retinal disease. Here we describe a scalable and robust system to study the growth factor induction in the retina: retinal organoids derived from the induced pluripotent stem cells. We have demonstrated that they secrete GDNF and PEDF at the levels tenfold above detection limit for ELISA. We also have shown that growth factor production in this system may be upregulated by specific trigger, demonstrating the feasibility of this approach for drug discovery. PMID- 29721996 TI - Stem Cell-Based RPE Therapy for Retinal Diseases: Engineering 3D Tissues Amenable for Regenerative Medicine. AB - Recent clinical trials based on human pluripotent stem cell-derived retinal pigment epithelium cells (hPSC-RPE cells) were clearly a success regarding safety outcomes. However the delivery strategy of a cell suspension, while being a smart implementation of a cell therapy, might not be sufficient to achieve the best results. More complex reconstructed tissue formulations are required, both to improve functionality and to target pathological conditions with altered Bruch's membrane like age-related macular degeneration (AMD). Herein, we describe the various options regarding the stem cell source choices and the different strategies elaborated in the recent years to develop engineered RPE sheets amenable for regenerative therapies. PMID- 29721997 TI - Validation of iPS Cell-Derived RPE Tissue in Animal Models. AB - Previous work suggests that replacing diseased Retinal Pigment Epithelium (RPE) with a healthy autologous RPE sheet can provide vision rescue for AMD patients. We differentiated iPSCs into RPE using a directed differentiation protocol. RPE cells at the immature RPE stage were purified and seeded onto either electrospun poly(lactic-co-glycolic acid) (PLGA) scaffolds or non-biodegradable polyester cell culture inserts and compared the two tissues. In vitro, PLGA and polyester substrates produced functionally similar results. Following in vitro evaluation, we tested RPE tissue in animal models for safety and function. Safety studies were conducted in RNU rats using an injection composed of intact cells and homogenized scaffolds. To assess function and develop surgical procedures, the tissues were implanted into an acute RPE injury model pig eye and evaluated using optical coherence tomography (OCT), multifocal ERG (mfERG), and histology. Subretinal injection studies in rats demonstrated safety of the implant. Biodegradability and biocompatibility data from a pig model demonstrated that PLGA scaffold is safe, with the added benefit of being resorbed by the body over time, leaving no foreign material in the eye. We confirmed that biodegradable substrates provide suitable support for RPE maturation and transplantation. PMID- 29721998 TI - Cell Transplantation for Retinal Degeneration: Transition from Rodent to Nonhuman Primate Models. AB - Transplantation of potentially therapeutic cells into the subretinal space is a promising prospective therapy for the treatment of retinal degenerative diseases including age-related macular degeneration (AMD). In rodent models with photoreceptor degeneration, subretinal transplantation of cell suspensions has repeatedly been demonstrated to rescue behaviorally measured vision, maintain electrophysiological responses from the retina and the brain, and slow the degeneration of rod and cone photoreceptors for extended periods. These studies have led to the initiation of a number of FDA-approved clinical trials for application of cell-based therapy for AMD and other retinal degenerative diseases. However, translation from rodent models directly into human clinical trials skips an important intermediary preclinical step that is needed to address critical issues for intraocular cell transplantation. These include determination of the most appropriate and least problematic surgical approach, the application of treatment in an eye with similar size and structure including the presence of a macula, and a thorough understanding of the immunological considerations regarding graft survival and the consequences of grafted cell rejection. This chapter will review these and related issues and will document current efforts to address these concerns. PMID- 29721999 TI - Talaumidin Promotes Neurite Outgrowth of Staurosporine-Differentiated RGC-5 Cells Through PI3K/Akt-Dependent Pathways. AB - Talaumidin, a tetrahydrofuran neolignan isolated from the root of Aristolochia arcuata, was an interesting small molecule with neurotrophic activity in the cultured neuron. Talaumidin can promote neurite outgrowth from neurons. However, the mechanism by which talaumidin exerts its neurotrophic actions on retinal neurons has not been elucidated to date. In this study, we describe that talaumidin has neurotrophic properties such as neurite outgrowth in neuroretinal cell line, RGC-5. Talaumidin promotes staurosporine-induced neurite outgrowth in RGC-5 cells. The neurite outgrowth effect of talaumidin was inhibited by phosphatidylinositol 3-kinase (PI3K) inhibitor, LY294002, but not by Erk inhibitor, PD98059. These data suggest that talaumidin promotes neurite outgrowth through PI3K/Akt pathway and that the potential of talaumidin serves as a promising lead compound for the treatment of retinal degenerative disorders. PMID- 29722000 TI - Review of diagnostic, prognostic, and predictive biomarkers in melanoma. AB - Melanoma is an aggressive cutaneous malignancy with rapidly rising incidence. Diagnosis of controversial melanocytic lesions, correct prognostication of patients, selection of appropriate adjuvant and systemic therapies, and prediction of response to a given therapy remain very real challenges. Despite these challenges, multiple high throughput, nucleic-acid based biomarkers have been developed that can be assayed from histologic tissue specimens. FISH, CGH, Decision-Dx, and other multi-marker assays have been combined to improve overall predictability. This review discusses some of the most promising nucleic acid based assays that can be obtained from tissue specimens to assist with diagnosis, prognostication, and prediction of treatment response. PMID- 29722001 TI - Cystatin C takes part in melanoma-microglia cross-talk: possible implications for brain metastasis. AB - The development of melanoma brain metastasis is largely dependent on mutual interactions between the melanoma cells and cells in the brain microenvironment. Here, we report that the extracellular cysteine protease inhibitor cystatin C (CysC) is involved in these interactions. Microglia-derived factors upregulated CysC secretion by melanoma. Similarly, melanoma-derived factors upregulated CysC secretion by microglia. Whereas CysC enhanced melanoma cell migration through a layer of brain endothelial cells, it inhibited the migration of microglia cells toward melanoma cells. CysC was also found to promote the formation of melanoma three-dimensional structures in matrigel. IHC analysis revealed increased expression levels of CysC in the brain of immune-deficient mice bearing xenografted human melanoma brain metastasis compared to the brain of control mice. Based on these in vitro and in vivo experiments we hypothesize that CysC promotes melanoma brain metastasis. Increased expression levels of CysC were detected in the regenerating brain of mice after stroke. Post-stroke brain with melanoma brain metastasis showed an even stronger expression of CysC. The in vitro induction of stroke-like conditions in brain microenvironmental cells increased the levels of CysC in the secretome of microglia cells, but not in the secretome of brain endothelial cells. The similarities between melanoma brain metastasis and stroke with respect to CysC expression by and secretion from microglia cells suggest that CysC may be involved in shared pathways between brain metastasis and post-stroke regeneration. This manifests the tendency of tumor cells to highjack physiological molecular pathways in their progression. PMID- 29722004 TI - Meroterpenoids from Ganoderma Species: A Review of Last Five Years. AB - Meroterpenoids are hybrid natural products that partially originate from the terpenoid pathway. Ganoderma meroterpenoids (GMs) are a type of meroterpenoids containing a 1,2,4-trisubstituted phenyl and a polyunsaturated terpenoid part. Over last 5 years, great efforts have been made to conduct phytochemistry research on the genus Ganoderma, which have led to the isolation and identification of a number of GMs. These newly reported GMs showed diverse structures and a wide range of biological activities. This review gives an overview of new GMs from genus Ganoderma and their biological activities and biosynthetic pathway, focusing on the period from 2013 until 2018. PMID- 29722003 TI - Optimal long-term antithrombotic management of atrial fibrillation: life cycle management. AB - Optimal antithrombotic management of atrial fibrillation equals balancing between prevention of arterial thromboembolism, predominantly ischaemic stroke, and haemorrhagic complications. Over time different antithrombotic agents and strategies have been developed. At present, non-vitamin K antagonist oral anticoagulants (NOACs) are the first-line therapy for stroke prevention in patients with non-valvular atrial fibrillation (i.e. without a mechanical valve prosthesis or rheumatic heart disease). Considering the impact of the suboptimal adoption of recommended oral anticoagulant therapy, as experienced with the previous first-line vitamin K antagonists, this review focuses on adequate use of NOACs. As such, we address the most important and clinically challenging issues in the antithrombotic life cycle management for long-term stroke prevention in atrial fibrillation. PMID- 29722005 TI - Physician-Assisted Suicide: Why Neutrality by Organized Medicine Is Neither Neutral Nor Appropriate. AB - It has been proposed that medical organizations adopt neutrality with respect to physician-assisted suicide (PAS), given that the practice is legal in some jurisdictions and that membership is divided. We review developments in end-of life care and the role of medical organizations with respect to the legalization of PAS since the 1990s. We argue that moving from opposition to neutrality is not ethically neutral, but a substantive shift from prohibited to optional. We argue that medical organizations already oppose many practices that are legal in many jurisdictions, and that unanimity among membership has not been required for any other clinical or ethical policy positions. Moreover, on an issue so central to the meaning of medical professionalism, it seems important for organized medicine to take a stand. We subsequently review the arguments in favor of PAS (arguments from autonomy and mercy, and against the distinction between killing and allowing to die (K/ATD)) and the arguments against legalization (the limits of autonomy, effects on the patient-physician relationship, the meaning of healing, the validity of the K/ATD distinction, the social nature of suicide, the availability of alternatives, the propensity for incremental extension, and the meaning of control). We conclude that organized medicine should continue its opposition to PAS. PMID- 29722007 TI - White matter properties and reading in children born preterm: a step forward. PMID- 29722002 TI - Genetics of metastasis: melanoma and other cancers. AB - Melanoma is a malignant neoplasm of melanocytes that accounts for the majority of skin cancer deaths despite comprising less than 5% of all cutaneous malignancies. Its incidence has increased faster than that of any other cancer over the past half-century and the annual costs of treatment in the United States alone have risen rapidly. Although the majority of primary melanomas are cured with local excision, metastatic melanoma historically carries a grim prognosis, with a median survival of 9 months and a long-term survival rate of 10%. Given the urgent need to develop treatment strategies for metastatic melanoma and the explosion of genetic technologies over the past 20 years, there has been extensive research into the genetic alterations that cause melanocytes to become malignant. More recently, efforts have focused on the genetic changes that drive melanoma metastasis. This review aims to summarize the current knowledge of the genetics of primary cutaneous and ocular melanoma, the genetic changes associated with metastasis in melanoma and other cancer types, and non-genetic factors that may contribute to metastasis. PMID- 29722006 TI - A One-Year Survey of Norovirus in UK Oysters Collected at the Point of Sale. AB - Contamination of bivalve shellfish, particularly oysters, with norovirus is recognised as a food safety risk and a potential contributor to the overall burden of gastroenteritis in the community. The United Kingdom (UK) has comprehensive national baseline data on the prevalence, levels, and seasonality of norovirus in oysters in production areas resulting from a previous two-year study (2009-2011). However, previously, data on final product as sold to the consumer have been lacking. As part of a wider project to establish the overall burden of foodborne norovirus in the UK, this study aimed to address this data gap. A one-year survey of oysters collected from the point-of-sale to the consumer was carried out from March 2015 to March 2016. A total of 630 samples, originating in five different European Union Member States, were collected from 21 regions across the UK using a randomised sampling plan, and tested for norovirus using a method compliant with ISO 15216-1, in addition to Escherichia coli as the statutory indicator of hygiene status. As in the previous production area study, norovirus RNA was detected in a high proportion of samples (68.7%), with a strong winter seasonality noted. Some statistically significant differences in prevalences and levels in oysters from different countries were noted, with samples originating in the Netherlands showing lower prevalences and levels than those from either the UK or Ireland. Overall, levels detected in positive samples were considerably lower than seen previously. Investigation of potential contributing factors to this pattern of results was carried out. Application of normalisation factors to the data from the two studies based on both the numbers of norovirus illness reports received by national surveillance systems, and the national average environmental temperatures during the two study periods resulted in a much closer agreement between the two data sets, with the notably different numbers of illness reports making the major contribution to the differences observed in norovirus levels in oysters. The large majority of samples (76.5%) contained no detectable E. coli; however, in a small number of samples (2.4%) levels above the statutory end product standard (230 MPN/100 g) were detected. This study both revealed the high prevalence of norovirus RNA in oysters directly available to the UK consumer, despite the high level of compliance with the existing E. coli-based health standards, while also highlighting the difficulty in comparing the results of surveys carried out in different time periods, due to variability in risk factors. PMID- 29722008 TI - Veterinary education: how we got to where we are. PMID- 29722010 TI - The Rewards and Challenges of Writing for a Mass Media Audience. PMID- 29722012 TI - Hydroxychloroquine retinal toxicity in two patients with dermatological conditions. AB - Two patients with dermatological conditions developed retinal toxicity after treatment with hydroxychloroquine that exceeded dosing recommendations. There is no treatment for hydroxychloroquine retinal toxicity and associated visual loss, so appropriate monitoring is imperative. All members of a patient's multidisciplinary team should be aware of the ocular risks of hydroxychloroquine, the importance of dosing within recommended guidelines and appropriate monitoring in reducing the risk of visual loss. PMID- 29722009 TI - White matter properties associated with pre-reading skills in 6-year-old children born preterm and at term. AB - AIM: To assess associations between white matter properties and pre-reading skills (phonological awareness and receptive and expressive language) in children born preterm and at term at the onset of reading acquisition. METHOD: Six-year old children born preterm (n=36; gestational age 22-32wks) and at term (n=43) underwent diffusion magnetic resonance imaging and behavioural assessments. Tracts were selected a priori based on findings from a study of 6-year-old children born at term: the left-hemisphere arcuate fasciculus and superior longitudinal fasciculus, and right-hemisphere uncinate fasciculus. Using linear regression, we assessed associations between fractional anisotropy of tracts and phonological awareness and receptive and expressive language scores. We investigated whether associations were moderated by prematurity. RESULTS: Fractional anisotropy of the left-hemisphere arcuate fasciculus contributed unique variance to phonological awareness across birth groups. The association between fractional anisotropy of the right-hemisphere uncinate fasciculus and receptive and expressive language was significantly moderated by prematurity. INTERPRETATION: A left-hemisphere tract was associated with phonological awareness in both birth groups. A right-hemisphere tract was associated with language only in the term group, suggesting that expressive and receptive language is mediated by different white matter pathways in 6-year-old children born preterm. These findings provide novel insights into similarities and differences of the neurobiology of pre-reading skills between children born preterm and at term at reading onset. WHAT THIS PAPER ADDS: White matter properties and pre-reading abilities were associated in children born preterm at the onset of reading. The neurobiology of phonological awareness was similar in children born preterm versus children born at term at 6 years. The neurobiology of language was different in children born preterm versus children born at term at 6 years. PMID- 29722013 TI - Effect of shading intensity on morphological and color traits and on chemical components of new tea (Camellia sinensis L.) shoots under direct covering cultivation. AB - BACKGROUND: Use of covering cultivation to shade tea (Camellia sinensis L.) trees to produce high-quality, high-priced green tea has recently increased in Japan. Knowledge of shading effects on morphological and color traits and on chemical components of new tea shoots is important for product quality and productivity. We assessed these traits of tea shoots and their relationships under covering cultivation of various radiation intensities. RESULTS: Leaf thickness, leaf mass per area, and leaf density of new tea leaves were smaller under covering culture than under open-field culture. SPAD values and chlorophyll contents were larger under covering culture than under open culture. The derived exponential equation for estimating chlorophyll contents from SPAD values was improved by considering leaf thickness. Covering culture decreased epicatechin and epigallocatechin contents, and increased theanine and caffeine contents. Principal component analysis on shoot and leaf traits indicated that leaf mass per area, chlorophyll, epicatechin, and epigallocatechin contents were strongly associated with shading effects. CONCLUSION: The morphological traits, color traits, and chemical components of new tea shoots and leaves varied depending on radiation intensity, shoot growth, and cropping season. These findings are useful for covering cultivation with high quality and high productivity in tea gardens. (c) 2018 Society of Chemical Industry. PMID- 29722011 TI - End-stage renal disease, dialysis, kidney transplantation and their impact on CD4+ T-cell differentiation. AB - Premature aging of both CD4+ regulatory T (Treg) and CD4+ responder-T (Tresp) cells in patients with end-stage renal disease (ESRD) is expected to affect the success of later kidney transplantation. Both T-cell populations are released from the thymus as inducible T-cell co-stimulator-positive (ICOS+ ) and ICOS- recent thymic emigrant (RTE) Treg/Tresp cells, which differ primarily in their proliferative capacities. In this study, we analysed the effect of ESRD and subsequent renal replacement therapies on the differentiation of ICOS+ and ICOS- RTE Treg/Tresp cells into ICOS+ CD31- or ICOS- CD31- memory Treg/Tresp cells and examined whether diverging pathways affected the suppressive activity of ICOS+ and ICOS- Treg cells in co-culture with autologous Tresp cells. Compared with healthy controls, we found an increased differentiation of ICOS+ RTE Treg/Tresp cells and ICOS- RTE Treg cells through CD31+ memory Treg/Tresp cells into CD31- memory Treg/Tresp cells in ESRD and dialysis patients. In contrast, ICOS- RTE Tresp cells showed an increased differentiation via ICOS- mature naive (MN) Tresp cells into CD31- memory Tresp cells. Thereby, the ratio of ICOS+ Treg/ICOS+ Tresp cells was not changed, whereas that of ICOS- Treg/ICOS- Tresp cells was significantly increased. This differentiation preserved the suppressive activity of both Treg populations in ESRD and partly in dialysis patients. After transplantation, the increased differentiation of ICOS+ and ICOS- RTE Tresp cells proceeded, whereas that of ICOS+ RTE Treg cells ceased and that of ICOS- RTE Treg cells switched to an increased differentiation via ICOS- MN Treg cells. Consequently, the ratios of ICOS+ Treg/ICOS+ Tresp cells and of ICOS- Treg/ICOS- Tresp cells decreased significantly, reducing the suppressive activity of Treg cells markedly. Our data reveal that an increased tolerance-inducing differentiation of ICOS+ and ICOS- Treg cells preserves the functional activity of Treg cells in ESRD patients, but this cannot be maintained during long-term renal replacement therapy. PMID- 29722014 TI - Interleukin-23 promotes intestinal T helper type17 immunity and ameliorates obesity-associated metabolic syndrome in a murine high-fat diet model. AB - We addressed the role of interleukin-23 (IL-23) in driving the intestinal T helper type 17 (Th17) response during obesity and metabolic syndrome progression induced by a high-fat diet (HFD). Diet-induced obese and lean mice received HFD or control diet (CTD), respectively, for 20 weeks. The nutritional, metabolic and immune parameters were examined at weeks 9 and 20. Gene and protein IL-23p19 and IL-23 receptor expression was increased in the ileum of obese wild-type mice (WT) fed the HFD for 9 weeks. Mice lacking IL-23 and fed the HFD exhibited greater weight gain, higher fat accumulation, adipocyte hypertrophy and hepatic steatosis. Notably, these mice had more glucose intolerance, insulin resistance and associated metabolic alterations, such as hyperinsulinaemia and hyperlipidaemia. IL-23 deficiency also significantly reduced protein levels of IL 17, CCL20 and neutrophil elastase in the ileum and reduced Th17 cell expansion in the mesenteric lymph nodes of the HFD mice. Of importance, IL-23-deficient mice exhibited increased gut permeability and blood bacterial translocation compared with WT mice fed HFD. Finally, metagenomics analysis of gut microbiota revealed a dramatic outgrowth of Bacteroidetes over Firmicutes phylum with the prevalence of Bacteroides genera in the faeces of IL-23-deficient mice after HFD. In summary, IL-23 appears to maintain the Th17 response and neutrophil migration into the intestinal mucosa, minimizing the gut dysbiosis and protecting against obesity and metabolic disease development in mice. PMID- 29722015 TI - EAST/SeSAME syndrome: Review of the literature and introduction of four new Latvian patients. AB - EAST (Epilepsy, Ataxia, Sensorineural deafness, Tubulopathy) or SeSAME (Seizures, Sensorineural deafness, Ataxia, Mental retardation, and Electrolyte imbalance) syndrome is a rare autosomal recessive syndrome first described in 2009 independently by Bockenhauer and Scholl. It is caused by mutations in KCNJ10, which encodes Kir4.1, an inwardly rectifying K+ channel found in the brain, inner ear, kidney and eye. To date, 16 mutations and at least 28 patients have been reported. In this paper, we review mutations causing EAST/SeSAME syndrome, clinical manifestations in detail, and efficacy of treatment in previously reported patients. We also report a new Latvian kindred with 4 patients. In contrast to the majority of previous reports, we found a progressive course of the disorder in terms of hearing impairment and neurologic deficit. The treatment is based on antiepileptic drugs, electrolyte replacement, hearing aids and mobility devices. Future research should concentrate on recognizing the lesions in the central nervous system to evaluate new potential diagnostic criteria and on formally evaluating intellectual disability. PMID- 29722016 TI - Triarabinosylation is required for nodulation-suppressive CLE peptides to systemically inhibit nodulation in Pisum sativum. AB - Legumes form root nodules to house beneficial nitrogen-fixing rhizobia bacteria. However, nodulation is resource demanding; hence, legumes evolved a systemic signalling mechanism called autoregulation of nodulation (AON) to control nodule numbers. AON begins with the production of CLE peptides in the root, which are predicted to be glycosylated, transported to the shoot, and perceived. We synthesized variants of nodulation-suppressing CLE peptides to test their activity using petiole feeding to introduce CLE peptides into the shoot. Hydroxylated, monoarabinosylated, and triarabinosylated variants of soybean GmRIC1a and GmRIC2a were chemically synthesized and fed into recipient Pisum sativum (pea) plants, which were used due to the availability of key AON pathway mutants unavailable in soybean. Triarabinosylated GmRIC1a and GmRIC2a suppressed nodulation of wild-type pea, whereas no other peptide variant tested had this ability. Suppression also occurred in the supernodulating hydroxyproline O arabinosyltransferase mutant, Psnod3, but not in the supernodulating receptor mutants, Pssym29, and to some extent, Pssym28. During our study, bioinformatic resources for pea became available and our analyses identified 40 CLE peptide encoding genes, including orthologues of nodulation-suppressive CLE peptides. Collectively, we demonstrated that soybean nodulation-suppressive CLE peptides can function interspecifically in the AON pathway of pea and require arabinosylation for their activity. PMID- 29722017 TI - Evidence of Strict Stereospecificity in the Structure of sn-1,2-Diacyl-3-Acetyl Glycerols from Euonymus maximowiczianus Seeds Using Nuclear Magnetic Resonance Spectroscopy. AB - Asymmetric, optically active sn-1,2-diacyl-3-acetyl-glycerols (AcDAG) have been known to scientists for several decades. However, to date, the problem of their structure has not been definitely resolved, which has led to a vast diversity of terms used for their designation in the literature. Using two-dimensional nuclear magnetic resonance, we have investigated AcDAG from the mature seeds of Euonymus maximowiczianus, from which we have been able to both identify a correlation of the methyl group in acetic acid residue with protons at the carbon atom at sn-3 position in the glycerol residue of the AcDAG molecule and, for the first time, demonstrate that this correlation is observed exclusively with one carbon atom at the alpha-position, but not with two as would have been expected in case of a racemic mixture. Moreover, results of our analysis of AcDAG isolated from the seeds of E. maximowiczianus directly confirm that diacylglycerol-3-acetyl transferase is responsible for their biosynthesis, which reveals a strict specificity not only to acetyl-CoA as one of the substrates but also to the sn-3 position of the glycerol residue in sn-1,2-diacylglycerol during their biosynthesis. PMID- 29722019 TI - Suitability of fluorescence indices for the estimation of fruit maturity compounds in tomato fruits. AB - BACKGROUND: We examined the suitability of chlorophyll fluorescence-based indices to monitor and predict concentrations of fruit maturity compounds during tomato ripening under different growing conditions in the greenhouse. The aim of this study was to evaluate the effects of chlorophyll concentration changes on fluorescence-based indices and to exploit the relation between fluorescence and reflectance indices with the corresponding maturity compounds determined analytically. RESULTS: Fruits grown under water deficit matured faster than control fruits as recorded with fluorescence-based indices. The SFR_R index correlated well with the analytical determination of chlorophyll content, whereas the single-signal FRF_G correlated with lycopene content even if the sensor was unable to differentiate precisely between maturity stages 2 to 4. Neither the FLAV index nor the FLAV_UV index was suitable for flavonoid prediction in tomato fruits. Compared with fluorescence indices, the relation between the reflection index and pigment concentrations was lower for chlorophyll and higher for lycopene. CONCLUSION: Chlorophyll and lycopene content in tomato fruits can be estimated by means of fluorescence indices during the pre-harvest phase. Since the chlorophyll decrease during tomato ripening is the driving force affecting all fluorescence signals, the methods are not reliable for estimation of other maturity compounds in tomato fruits. (c) 2018 Society of Chemical Industry. PMID- 29722018 TI - Hippocampal PPARalpha is a novel therapeutic target for depression and mediates the antidepressant actions of fluoxetine in mice. AB - BACKGROUND AND PURPOSE: Developing novel pharmacological targets beyond the monoaminergic system is now a popular strategy for treating depression. PPARalpha is a nuclear receptor protein that functions as a transcription factor, regulating gene expression. We have previously reported that both WY14643 and fenofibrate, two pharmacological agonists of PPARalpha, have antidepressant-like effects in mice, implying that PPARalpha is a potential antidepressant target. EXPERIMENTAL APPROACH: We first used various biotechnological methods to evaluate the effects of chronic stress and fluoxetine on hippocampal PPARalpha. The viral mediated genetic approach was then employed to explore whether hippocampal PPARalpha was an antidepressant target. PPARalpha inhibitors, PPARalpha-knockout (KO) mice and PPARalpha-knockdown (KD) mice were further used to determine the role of PPARalpha in the antidepressant effects of fluoxetine. KEY RESULTS: Chronic stress significantly decreased mRNA and protein levels of PPARalpha in the hippocampus, but not other regions, and also fully reduced the recruitment of hippocampal PPARalpha to the cAMP response element-binding (CREB) promoter. Genetic overexpression of hippocampal PPARalpha induced significant antidepressant-like actions in mice by promoting CREB-mediated biosynthesis of brain-derived neurotrophic factor. Moreover, fluoxetine notably restored the stress-induced negative effects on hippocampal PPARalpha. Using PPARalpha antagonists fully blocked the antidepressant effects of fluoxetine in mice, and similarly, both PPARalpha-KO and PPARalpha-KD abolished the effects of fluoxetine. Besides, PPARalpha-KO and PPARalpha-KD aggravated depression in mice. CONCLUSIONS AND IMPLICATIONS: Hippocampal PPARalpha is a potential novel antidepressant target that mediates the antidepressant actions of fluoxetine in mice. PMID- 29722020 TI - Atrioventricular canal defect and genetic syndromes: The unifying role of sonic hedgehog. AB - The atrioventricular canal defect (AVCD) is a congenital heart defect (CHD) frequently associated with extracardiac anomalies (75%). Previous observations from a personal series of patients with AVCD and "polydactyly syndromes" showed that the distinct morphology and combination of AVCD features in some of these syndromes is reminiscent of the cardiac phenotype found in heterotaxy, a malformation complex previously associated with functional cilia abnormalities and aberrant Hedgehog (Hh) signaling. Hh signaling coordinates multiple aspects of left-right lateralization and cardiovascular growth. Being active at the venous pole the secondary heart field (SHF) is essential for normal development of dorsal mesenchymal protrusion and AVCD formation and septation. Experimental data show that perturbations of different components of the Hh pathway can lead to developmental errors presenting with partially overlapping manifestations and AVCD as a common denominator. We review the potential role of Hh signaling in the pathogenesis of AVCD in different genetic disorders. AVCD can be viewed as part of a "developmental field," according to the concept that malformations can be due to defects in signal transduction cascades or pathways, as morphogenetic units which may be altered by Mendelian mutations, aneuploidies, and environmental causes. PMID- 29722022 TI - An ST2-dependent role of bone marrow-derived group 2 innate lymphoid cells in pulmonary fibrosis. AB - Recent evidence supports that bone marrow (BM)-derived hematopoietic progenitor cells play an important role in lung injury and fibrosis. While these cells give rise to multiple cell types, the ST2 (Il1rl1)-expressing group 2 innate lymphoid cells (ILC2s) derived from BM progenitors have been implicated in tissue repair and remodeling, including in lung fibrosis. To further investigate the precise role of BM-derived ILC2s in the pathogenesis of fibrotic lung disease, their importance in the bleomycin-induced lung fibrosis model was evaluated by analyzing the effects of selective ST2 deficiency in the BM compartment. The results showed that while ST2-sufficient control mice exhibited activation of lung IL-33/ST2 signaling, ILC2 recruitment, IL-13 induction, and fibrosis, these responses were significantly diminished in ST2-deficient-BM chimera mice, with selective loss of ST2 expression only in the BM. This diminished response to bleomycin was similar to that seen in ST2 global knockout mice, suggesting the predominant importance of ST2 from the BM compartment. In wild-type mice, ILC2 recruitment to the lung was accompanied by a concomitant decrease in ST2+ BM cells. ST2-deficient BM cells were unresponsive to IL-33-induced ILC2 maturation. Finally, lineage-negative wild-type, but not ST2-deficient BM cells from bleomycin-treated mice stimulated lung fibroblast type I collagen expression, which was associated with elevated TGFbeta expression in the BM cells. Taken together, these findings suggested that the BM-derived ILC2s were recruited to fibrotic lung through the IL-33/ST2 pathway, and contributed to fibroblast activation to promote lung fibrosis. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29722024 TI - The effect of treatment with anti-interleukin-17 in patients with allergic contact dermatitis. PMID- 29722021 TI - Differential T-cell receptor signals for T helper cell programming. AB - Upon encounter with their cognate antigen, naive CD4 T cells become activated and are induced to differentiate into several possible T helper (Th) cell subsets. This differentiation depends on a number of factors including antigen-presenting cells, cytokines and co-stimulatory molecules. The strength of the T-cell receptor (TCR) signal, related to the affinity of TCR for antigen and antigen dose, has emerged as a dominant factor in determining Th cell fate. Recent studies have revealed that TCR signals of high or low strength do not simply induce quantitatively different signals in the T cells, but rather qualitatively distinct pathways can be induced based on TCR signal strength. This review examines the recent literature in this area and highlights important new developments in our understanding of Th cell differentiation and TCR signal strength. PMID- 29722025 TI - Tacrolimus-induced symmetric drug-related intertriginous and flexural exanthema (SDRIFE). PMID- 29722023 TI - Discovery of 4 exonic and 1 intergenic novel susceptibility loci for leprosy. AB - Seven new risk coding variants have been identified through an exome-wide association study (EWAS), which studied the contributions of protein-coding variants to leprosy susceptibility. But some potential susceptibility loci were not studied in the previous EWAS study because of the project consideration. Seventeen unstudied potential susceptibility loci of the previous EWAS were validated in 3169 cases and 9814 controls in this study. Four disease-associated exonic loci were identified: rs671 in ALDH2 (P = 2.0 * 10-20 , odds ratio [OR] = 1.35), rs13259978 in SLC7A2 (P = 1.74 * 10-8 , OR = 1.28), rs925368 in GIT2 (P = 9.18 * 10-17 , OR = 1.44), and rs75680863 in TCN2 (P = 8.37 * 10-21 , OR = 0.74). Potentially implicating ZFP36L1 as a new susceptibility gene, 1 intergenic single nucleotide polymorphism (SNP), rs1465788 (P = 7.81 * 10-6 , OR = 0.88), was also suggested to be associated with leprosy. A luciferase reporter assay showed that the rs1465788 risk allele notably decreased the transcription activity of the flanking sequence. These findings suggest the possible involvement of lipid metabolism, NF-kappaB homeostasis and macrophage antimicrobial pathways in leprosy pathogenesis. PMID- 29722026 TI - Standard practices and awareness concerning p-phenylenediamine among salons that provide eyelash dyeing services. PMID- 29722027 TI - Fenofibrate photoallergy - relevance of patch and photopatch testing. PMID- 29722029 TI - A regulatory loop connecting WNT signaling and telomere capping: possible therapeutic implications for dyskeratosis congenita. AB - The consequences of telomere dysfunction are most apparent in rare inherited syndromes caused by genetic deficiencies in factors that normally maintain telomeres. The principal disease is known as dyskeratosis congenita (DC), but other syndromes with similar underlying genetic defects share some clinical aspects with this disease. Currently, there are no curative therapies for these diseases of telomere dysfunction. Here, we review recent findings demonstrating that dysfunctional (i.e., uncapped) telomeres can downregulate the WNT pathway, and that restoration of WNT signaling helps to recap telomeres by increasing expression of shelterins, proteins that naturally bind and protect telomeres. We discuss how these findings are different from previous observations connecting WNT and telomere biology, and discuss potential links between WNT and clinical manifestations of the DC spectrum of diseases. Finally, we argue for exploring the use of WNT agonists, specifically lithium, as a possible therapeutic approach for patients with DC. PMID- 29722030 TI - Metabolic adaptation of short-living growth hormone transgenic mice to methionine restriction and supplementation. AB - Extension of mammalian health and life span has been achieved using various dietary interventions. We previously reported that restricting dietary methionine (MET) content extends life span only when growth hormone signaling is intact (no life span increase in GH deficiency or GH resistance). To understand the metabolic responses of altered dietary MET in the context of accelerated aging (high GH), the current study evaluated MET and related pathways in short-living GH transgenic (GH Tg) and wild-type mice following 8 weeks of restricted (0.16%), low (0.43%), or enriched (1.3%) MET consumption. Liver MET metabolic enzymes were suppressed in GH Tg compared to diet-matched wild-type mice. MET metabolite levels were differentially affected by GH status and diet. SAM:SAH ratios were markedly higher in GH Tg mice. Glutathione levels were lower in both genotypes consuming 0.16% MET but reduced in GH Tg mice when compared to wild type. Tissue thioredoxin and glutaredoxin were impacted by diet and GH status. The responsiveness to the different MET diets is reflected across many metabolic pathways indicating the importance of GH signaling in the ability to discriminate dietary amino acid levels and alter metabolism and life span. PMID- 29722028 TI - Emerging disease-modifying strategies targeting alpha-synuclein for the treatment of Parkinson's disease. AB - Parkinson's disease is the most common neurodegenerative movement disorder. It arises as a result of neuronal cell death in specific brain regions, notably the substantia nigra pars compacta, and is characterized by the accumulation of alpha synuclein in these brain regions. Current pharmacological therapies alleviate the motor symptoms of the disease and are particularly effective in the early stages of the disease. Ongoing drug development efforts focus on disease-modifying strategies that aim to halt or slow disease progression. In this review, we explore a number of emerging disease-modifying strategies with a focus on direct and indirect targeting of alpha-synuclein dysfunction. We summarize newer classes of small molecules and biological agents intended to attenuate protein aggregation or to target enzymes that may increase the degradation of the pathogenic forms of alpha-synuclein. Finally, we discuss emerging strategies that are demonstrating the potential for disease modification at the preclinical stage. PMID- 29722031 TI - Indirect-acting strategy of opioid action instead of direct receptor activation: dual-acting enkephalinase inhibitors (DENKIs). AB - WHAT IS KNOWN AND OBJECTIVE: Although pain is one of the most common afflictions, it is often inadequately managed because the available analgesic options are relatively limited due to insufficient efficacy, unacceptable adverse effects or the potential for misuse or abuse. However, recent publications suggest that an alternative approach-indirect enhancement of endogenous pain-relieving pathways might be desirable. We review this approach, in particular the dual enkephalinase inhibitors (DENKIs). METHODS: Published literature and Internet sources were searched for information related to the basic science and clinical data on inhibition of metabolic pathways of endogenous analgesic agents. The identified sources were reviewed, assessed and synthesized. Emphasis was placed on the benefits of the approach, as well as on the individual agents. RESULTS: Inhibition of the enzymes that degrade the endogenous opioid ligands Met- and Leu enkephalin results in an increased synaptic concentration of the enkephalins and an analgesic effect in a variety of animal models of pain and in preliminary trials in humans. The design of compounds that inhibit both of the two major enkephalin-degrading enzymes (neprilysin and aminopeptidase N) has been found to be better than those that inhibit only one of the enzymes. These dual-acting enkephalinase inhibitors yield analgesia with less adverse effects than current opioid drugs. WHAT IS NEW AND CONCLUSION: Unlike currently available analgesics, inhibitors of the metabolic degradation of endogenous analgesic substances attempt to elicit a more "natural" and targeted analgesic effect. This indirect approach offers an opportunity for novel additions to the otherwise relatively limited choice of analgesic classes. PMID- 29722032 TI - High frequency/ultrasonic communication in a critically endangered nocturnal primate, Claire's mouse lemur (Microcebus mamiratra). AB - The critically endangered Claire's mouse lemur, only found in the evergreen rain forest of the National Park Lokobe (LNP) and a few lowland evergreen rain forest fragments of northern Madagascar, was described recently. The present study provides the first quantified information on vocal acoustics of calls, sound associated behavioral context, acoustic niche, and vocal activity of this species. We recorded vocal and social behavior of six male-female and six male male dyads in a standardized social-encounter paradigm in June and July 2016 at the LNP, Nosy Be island. Over six successive nights per dyad, we audio recorded and observed behaviors for 3 hr at the beginning of the activity period. Based on the visual inspection of spectrograms and standardized multiparametric sound analysis, we identified seven different call types. Call types can be discriminated based on a combination of harmonicity, fundamental frequency variation, call duration, and degree of tonality. Acoustic features of tonal call types showed that for communication, mouse lemurs use the cryptic, high frequency/ultrasonic frequency niche. Two call types, the Tsak and the Grunt call, were emitted most frequently. Significant differences in vocal activity of the Tsak call were found between male-female and male-male dyads, linked primarily to agonistic conflicts. Dominant mouse lemurs vocalized more than subdominant ones, suggesting that signaling may present an honest indicator of fitness. A comparison of our findings of the Claire's mouse lemur with published findings of five bioacoustically studied mouse lemur species points to the notion that a complex interplay between ecology, predation pressure, and phylogenetic relatedness may shape the evolution of acoustic divergence between species in this smallest-bodied primate radiation. Thus, comparative bioacoustic studies, using standardized procedures, are promising to unravel the role of vocalization for primate species diversity and evolution and for identifying candidates for vocalization-based non-invasive monitoring for conservation purposes. PMID- 29722033 TI - Introduction to photodynamic therapy issue. PMID- 29722034 TI - Surviving in the urban-rural interface: Feeding and ranging behavior of brown howlers (Alouatta guariba clamitans) in an urban fragment in southern Brazil. AB - Wild primates that live in urban areas face extreme threats that are less frequent in nonurban fragments, such as the presence of dangerous matrix elements (e.g., roads, power lines, buildings, and a high density of domestic dogs near food patches), that could influence their movements, feeding behavior, and survival. However, the scarcity of studies addressing this issue hinders our understanding of the behavioral adjustments that favor the survival of primates in urban areas. For 12 months, we studied a six-individual group of brown howlers (Alouatta guariba clamitans) in an urban fragment to determine (i) their diet richness and its relationships with food availability, (ii) their daily path length (DPL) and the matrix elements used during movement, and (iii) the main ecological drivers of the DPL. Sampling effort totaled 72 days, 787 hr, and 3,224 instantaneous scans. We found that the diet of brown howlers contained 35 plant species (including seven cultivated crops) belonging to 33 genera and 21 families. The consumption of fruits and young leaves was directly related to their temporal availability. The average DPL (446 m) was smaller than that reported for groups of howlers inhabiting large nonurban fragments. To move between food patches, animals used three main matrix elements: trees, power lines, and roofs. The number of plant species used during the day was the main driver of DPL. Our findings highlighted that the generalist-opportunistic diet of brown howlers and their ability to move across the anthropogenic matrix using artificial elements such as power lines, roofs, and wildlife crossings represent a remarkable part of their behavioral repertory in Lami. However, there are potential costs associated with these strategies, namely, electrocution and predation by domestic dogs. Thus, it is urgent to further investigate how these behaviors could affect the long-term survival of these animals. PMID- 29722035 TI - Time and temperature dependence of radiofrequency ablation in the human placenta. AB - OBJECTIVE: The objective of the study is to compare radiofrequency (RF) effects on fresh placentae with varying levels of sustained time (Ts) and degrees of target temperature ( degrees t). METHOD: A total of 108 pieces of fresh placentae were coagulated with a 2-cm RF needle at 60 W in an organ bath. The vertical and horizontal diameters (Vd, Hd) of tissue coagulation visualized by ultrasound were measured. The impacts of 12 different Ts- degrees t combinations on the ablation size ascertained on pathological examination (Vdp , Hdp ) were compared using 2 way ANOVA. The agreement between sonographic and pathological findings was assessed using Bland-Altman analysis. RESULTS: Considerable changes in the Vdp and Hdp were associated with increasing the Ts and degrees t. The impact of RF on tissue coagulation was greatest when the degrees t was set at 100 degrees C, with further destruction as the Ts progressed to 7 minutes of exposure. The ablation size estimated by ultrasound exhibited an overestimation by an average of 5.65% and 21.02% for Vd and Hd, respectively. CONCLUSION: A prolonged Ts at a higher degrees t contributes to progressive placental tissue destruction by RF, with maximum destruction at 100 degrees C for 7 minutes in an ex vivo nonperfused placenta. Tissue injury that is apparent on ultrasound may extend beyond pathological damage. PMID- 29722036 TI - Curcumin in turmeric: Basic and clinical evidence for a potential role in analgesia. AB - WHAT IS KNOWN AND OBJECTIVE: Current analgesic pharmacotherapy-opioids, non steroidal anti-inflammatory drugs (NSAIDs), acetaminophen (paracetamol) and related drugs-is effective for acute pain, but their use is limited by adverse effects on the renal, hepatic, cardiovascular or gastrointestinal systems, or they have potential for abuse. Therefore, alternative options are desired. Compounds used in traditional medicine might offer such alternatives, but the evidence must be based on pharmacologic properties and on clinical trial data. This review summarizes the evidence for one of these: the analgesic properties of turmeric and other curcumins. METHODS: The PubMed database and other sources were searched using keywords related to turmeric, curcumin, antinociception and analgesia. Primary sources and reviews of preclinical and clinical studies were identified, assessed and summarized. Bibliographies within these sources provided additional information. RESULTS: Turmeric has consistently been demonstrated to produce analgesic and anti-inflammatory effects in animal models and in clinical trials, and appears to have less serious adverse effects than many current analgesics. WHAT IS NEW AND CONCLUSIONS: Turmeric (curcumin) appears to be a possible candidate for consideration for use as a stand-alone analgesic, or in analgesic combinations as part of opioid-, NSAID- or paracetamol (acetaminophen) sparing strategies. PMID- 29722037 TI - Electroencephalography in the monitoring of lithium toxicity: A case report. AB - WHAT IS KNOWN AND OBJECTIVE: If lithium toxicity occurs during treatment by lithium, treatment is performed while monitoring serum lithium levels. CASE SUMMARY: We report a case of lithium toxicity in a patient with bipolar affective disorder who developed neurotoxic symptoms associated with elevated serum lithium level and abnormal electroencephalography (EEG) changes. The elevated serum lithium level decreased before EEG normalization, which was associated with disappearance of all neurotoxic symptoms. WHAT IS NEW AND CONCLUSION: Monitoring EEG changes is useful for the diagnosis and treatment of lithium toxicity accompanied by abnormal EEG changes. PMID- 29722038 TI - Long-term abiraterone withdrawal syndrome. AB - WHAT IS KNOWN AND OBJECTIVE: Abiraterone acetate (AA) is an androgen receptor axis inhibitor, indicated together with prednisone, for metastatic castration resistant prostate cancer. Withdrawal syndrome for classical antiandrogen treatments is well known, but not so known for AA. Abiraterone withdrawal syndrome (AWS) could be related to simultaneous prednisone discontinuation or to an androgenic effect of AA metabolites. CASE DESCRIPTION: A case is described of a patient with long-term AWS without prednisone discontinuation. The clinical and prostate-specific antigen (PSA) response allowed an 8-month delay in docetaxel treatment. WHAT IS NEW AND CONCLUSION: Prednisone did not play a role in AWS in this case. The long-term response allowed a delay in future treatment. PMID- 29722039 TI - Mortality from adverse drug reaction-related hospitalizations in south-west Ethiopia: A cross-sectional study. AB - WHAT IS KNOWN AND OBJECTIVE: Adverse drug reactions (ADRs) are an important cause of mortality during medical care. To our knowledge, no Ethiopian studies have reported on mortality due to ADRs in patients presenting to hospital from the community setting. The aim of this study was to determine the mortality rate attributable to ADRs in patients presenting to hospital, identify drugs implicated in the ADR-related deaths and identify factors contributing to ADR related mortality at Jimma University Specialised Hospital (JUSH), south-west Ethiopia METHODS: This cross-sectional study included 1001 patients aged >=18 years consecutively admitted to medical wards from May 2015 to August 2016. ADR related mortality was determined through detailed review of medical records, laboratory tests and patient interviews followed by causality assessment by the Naranjo algorithm and expert consensus. RESULTS: Of 1001 patients, 15, 1.5% (95% confidence interval [CI]: 0.80%-2.30%) died with an ADR. The primary suspected causes of death were drug-induced hepatotoxicity (7, 43.8%) followed by acute kidney injury (4, 25.0%). Isoniazid (6, 33.3%), pyrazinamide (3, 16.7%), efavirenz (2, 11.1%) and tenofovir (2, 11.1%) were commonly implicated drugs. The majority of ADRs (14, 93.8%) were preventable. Unadjusted bivariate comparisons suggested patients who died with ADRs were more likely to have pre-existing liver disease (40.0% vs 7.0%; 95% confidence interval [CI]: 8.1%-57.8%), a history of ADRs (40% vs 1.4%; 95% CI: 13.8%-63.4%), a lower mean (+/-SD) body mass index (BMI, 17.6 +/- 2.1 vs 20.0 +/- 2.9 kg/m2 ; 95% CI = 0.9-3.9), exposure to antitubercular (46.7% vs 18.9%; 95% CI: 2.3%-53.1%) and antiretroviral (40.0% vs 7.7%; 95% CI: 7.5%-57.2%) therapies, and a higher mean number of medications (7.1 +/- 3.3 vs 3.8 +/- 2.1; 95% CI: 2.2-4.4) and Charlson Comorbidity Index (3.9 +/- 2.9 vs 1.6 +/- 1.8; 95% CI: 1.4-3.2) than surviving patients without ADRs. WHAT IS NEW AND CONCLUSION: Fatal ADRs were common in patients presenting to hospital. The drugs implicated were mostly antitubercular and antiretroviral therapies, reflecting the high burden of HIV and tuberculosis in the study population. ADR related deaths were significantly associated with poor nutritional status. The majority of ADR-related deaths were preventable, highlighting the need to develop a multidisciplinary approach to closely monitor patients who are prescribed antitubercular and antiretroviral therapies, particularly in patients with hepatic disease, a history of ADRs, who are malnourished and who are exposed to multiple medications. PMID- 29722040 TI - Prevalence of chew and spit and its relation to other features of disordered eating in a community sample. AB - BACKGROUND: Until recently, research into Chew and Spit (CHSP) behavior has predominantly focused on clinical samples, and little is known of its prevalence in the community. The current study aimed to bridge this gap by exploring CHSP features in a representative sample of the general population. We hypothesized that the point-prevalence of CHSP would be less than 1%; concurrent with other eating disorder symptomology, and associated with poorer health related quality of life (HRQoL). METHODOLOGY: Using the 2016, respondent-based, South Australian Health Omnibus Survey (HOS), data were collected on 3047 participants aged >=15 years old. HRQoL was assessed with the Short-Form health-questionnaire-v1 (SF 12). RESULTS: CHSP point prevalence was 0.4% (95% CI .23 to .69%; n = 13), and was more prevalent in people with compensatory disordered eating behaviors. The median age of those with CHSP was 39, and both mental and physical HRQoL were reduced compared with the general population (Mdn: MHQoL = 49; HRQoL = 50), with MHQoL being significantly lower in those with symptoms of a clinically diagnosable ED and concurrently engaged in CHSP (z = -2.33, p = .020). CONCLUSIONS: Due to the low prevalence of CHSP, the reliability of inferential statistics may increase the chance of Type II errors, therefore, future studies should use larger samples. Although CHSP is not "common" in a wider community sample, its prevalence appears to be similar to other ED associated symptoms. PMID- 29722041 TI - Independence screening for high dimensional nonlinear additive ODE models with applications to dynamic gene regulatory networks. AB - Mechanism-driven low-dimensional ordinary differential equation (ODE) models are often used to model viral dynamics at cellular levels and epidemics of infectious diseases. However, low-dimensional mechanism-based ODE models are limited for modeling infectious diseases at molecular levels such as transcriptomic or proteomic levels, which is critical to understand pathogenesis of diseases. Although linear ODE models have been proposed for gene regulatory networks (GRNs), nonlinear regulations are common in GRNs. The reconstruction of large scale nonlinear networks from time-course gene expression data remains an unresolved issue. Here, we use high-dimensional nonlinear additive ODEs to model GRNs and propose a 4-step procedure to efficiently perform variable selection for nonlinear ODEs. To tackle the challenge of high dimensionality, we couple the 2 stage smoothing-based estimation method for ODEs and a nonlinear independence screening method to perform variable selection for the nonlinear ODE models. We have shown that our method possesses the sure screening property and it can handle problems with non-polynomial dimensionality. Numerical performance of the proposed method is illustrated with simulated data and a real data example for identifying the dynamic GRN of Saccharomyces cerevisiae. PMID- 29722042 TI - Bicarbonate refractory QRS prolongation and left bundle-branch block following escitalopram and lamotrigine overdose: A case report and literature review of toxic left bundle-branch block. AB - WHAT IS KNOWN AND OBJECTIVE: Toxic prolongation of the QRS interval most often results from blockade of cardiac voltage-gated sodium channels and manifests on electrocardiogram with a right bundle-branch block-like morphology. Rarely, a left bundle-branch block (LBBB) morphology has been reported. CASE REPORT: We report a case of transient LBBB resultant from ingestion of lamotrigine and citalopram which was refractory to sodium bicarbonate therapy and eventually resolved spontaneously. WHAT IS NEW AND CONCLUSION: Cases of toxic LBBB are less likely to respond to bicarbonate therapy, suggesting that this finding is due to a mechanism other than sodium channel blockade. PMID- 29722043 TI - A taxonomy and cultural analysis of intra-hospital patient transfers. AB - Existing research on intra-hospital patient transitions focuses chiefly on handoffs, or exchanges of information, between clinicians. Less is known about patient transfers within hospitals, which include but extend beyond the exchange of information. Using participant observations and interviews at a 1,541-bed, academic, tertiary medical center, we explored the ways in which staff define and understand patient transfers between units. We conducted observations of staff (n = 16) working in four hospital departments and interviewed staff (n = 29) involved in transfers to general medicine floors from either the Emergency Department or the Medical Intensive Care Unit between February and September 2015. The collected data allowed us to understand transfers in the context of several hospital cultural microsystems. Decisions were made through the lens of the specific unit identity to which staff felt they belonged; staff actively strategized to manage workload; and empty beds were treated as a scarce commodity. Staff concepts informed the development of a taxonomy of intra hospital transfers that includes five categories of activity: disposition, or determining the right floor and bed for the patient; notification to sending and receiving staff of patient assignment, departure and arrival; preparation to send and receive the patient; communication between sending and receiving units; and coordination to ensure that transfer components occur in a timely and seamless manner. This taxonomy widens the study of intra-hospital patient transfers from a communication activity to a complex cultural phenomenon with several categories of activity and views them as part of multidimensional hospital culture, as constructed and understood by staff. PMID- 29722044 TI - A flexible quantile regression model for medical costs with application to Medical Expenditure Panel Survey Study. AB - Medical costs are often skewed to the right and heteroscedastic, having a sophisticated relation with covariates. Mean function regression models with low dimensional covariates have been extensively considered in the literature. However, it is important to develop a robust alternative to find the underlying relationship between medical costs and high-dimensional covariates. In this paper, we propose a new quantile regression model to analyze medical costs. We also consider variable selection, using an adaptive lasso penalized variable selection method to identify significant factors of the covariates. Simulation studies are conducted to illustrate the performance of the estimation method. We apply our method to the analysis of the Medical Expenditure Panel Survey dataset. PMID- 29722045 TI - Targeting body dissatisfaction among women with overweight or obesity: A proof-of concept pilot study. AB - OBJECTIVE: This proof-of-concept study was designed to replicate the effects of the empirically-supported Body Project intervention on body dissatisfaction when combined with behavioral recommendations for weight loss among women with overweight or obesity. METHOD: Women with overweight or obesity who reported body dissatisfaction and a desire to lose weight were randomized to one of two 4-week treatment conditions. Individuals assigned to the standard group (n = 15) were directed to track diet and activity level daily. Body project (n = 17) participants tracked daily diet and activity, in addition to attending four weekly, group-based body project intervention sessions. Body mass index, body dissatisfaction, body appreciation, and internalization of thin ideal and weight stigma were evaluated before and after the treatment period. RESULTS: Feasibility data suggest the Body Project can be implemented with this novel sample. Preliminary estimates suggest greater effects on body appreciation in the Body Project group than in the standard group (ES = 0.43), but no group effects for other body image variables. CONCLUSIONS: With minor modifications, the Body Project was successfully implemented among women with overweight or obesity. The effect on body appreciation is encouraging and worthy of further investigation. Modification to the intervention may be necessary to enhance treatment effects on other body image variables. PMID- 29722046 TI - Pharmacogenomic biomarkers: Interpretation of information included in United States and Japanese drug labels. AB - WHAT IS KNOWN AND OBJECTIVES: Many drug labels contain information on pharmacogenomic biomarkers (PGBMs), but the information is not necessarily actionable. Pharmacogenomics Knowledgebase (PharmGKB) aims to clarify the level of action for PGBMs (PGx levels) implied in each label as issued by the US Food and Drug Administration. We wished to evaluate the association between the PGx level for US and Japanese drug labels and the insurance coverage for PGBM testing or approval for in vitro diagnostics (IVDs) in each country. METHODS: We investigated the information on PGBMs in US and Japanese drug labels with PGx levels, insurance coverage of PGBM tests and IVD approval in the US and Japan. We analysed the relationship of PGx levels with insurance coverage. RESULTS: A total of 243 labels were listed by PharmGKB, and 215 (88%) had PGx levels for US labels and 52 (21%) for Japanese labels. Of the 215 US labels, 54 were designated as "Testing Required" in PGx levels. PGx levels in US labels were strongly associated with coverage of PGBM testing. Tests in 52 (96%) of the 54 labels with Testing Required had insurance coverage, 2 (50%) of 4 in "Testing Recommended," 38 (38%) of 100 in "Actionable PGx," 11 (19%) of 57 in "Informative PGx" and 3 (11%) of 28 in "No Level." In Japanese labels, only 14 of 52 were listed as Testing Required, and all were covered by the National Health Insurance in Japan. WHAT IS NEW AND CONCLUSION: The PGx level given in drug labels provides information on availability of PGBM testing. Higher PGx levels, based on better evidence of usefulness of PGBM testing, provide a route to broader test coverage. PMID- 29722047 TI - The acceptability, feasibility, and possible benefits of a neurobiologically informed 5-day multifamily treatment for adults with anorexia nervosa. AB - OBJECTIVE: Novel treatments for adults with anorexia nervosa (AN) are lacking. Recent scientific advances have identified neurobiologically-driven temperament contributors to AN symptoms that may guide development of more effective treatments. This preliminary study evaluates the acceptability, feasibility and possible benefits of a multicenter open trial of an intensive 5-day neurobiologically-informed multifamily treatment for adults with AN and their supports (SU). The temperament-focused treatment combines psychoeducation of AN neurobiology and SU involvement to develop skills to manage traits contributing to disease chronicity. METHOD: Fifty-four adults with AN and at least one SU (n = 73) received the 5-day treatment. Acceptability, feasibility, and attrition were measured post-treatment. Clinical outcome (BMI, eating disorder psychopathology, family function) was assessed post-treatment and at >3-month follow-up. RESULTS: The treatment had low attrition, with only one drop-out. Patients and SU rated the intervention as highly acceptable, and clinicians reported good feasibility. At post-treatment, patients demonstrated significantly increased BMI, reduced eating disorder psychopathology, and improved family function. Benefits were maintained in the 39 patients who completed follow-up assessment, with 62% reporting full or partial remission. DISCUSSION: Preliminary results are promising and suggest this novel treatment is feasible and acceptable. To establish treatment efficacy, fully-powered randomized controlled trials are necessary. PMID- 29722048 TI - Intermittent pair-housing, pair relationship qualities, and HPA activity in adult female rhesus macaques. AB - Laboratory rhesus macaques are often housed in pairs and may be temporarily or permanently separated for research, health, or management reasons. While both long-term social separations and introductions can stimulate a stress response that impacts inflammation and immune function, the effects of short-term overnight separations and whether qualities of the pair relationship mediate these effects are unknown. In this study, we investigated the effects of overnight separations on the urinary cortisol concentration of 20 differentially paired adult female rhesus macaques (Macaca mulatta) at the California National Primate Research Center. These females were initially kept in either continuous (no overnight separation) or intermittent (with overnight separation) pair housing and then switched to the alternate pair-housing condition part way through the study. Each study subject was observed for 5 weeks, during which we collected measures of affiliative, aggressive, anxious, abnormal, and activity state behaviors in both pair-housing conditions. Additionally, up to three urine samples were collected from each subject per week and assayed for urinary free cortisol and creatinine. Lastly, the behavioral observer scored each pair on four relationship quality attributes ("Anxious," "Tense," "Well-meshed," and "Friendly") using a seven-point scale. Data were analyzed using a generalized linear model with gamma distribution and an information theoretic approach to determine the best model set. An interaction between the intermittent pairing condition and tense pair adjective rating was in the top three models of the best model set. Dominance and rates of affiliation were also important for explaining urinary cortisol variation. Our results suggest that to prevent significant changes in HPA-axis activation in rhesus macaque females, which could have unintended effects on research outcomes, pairs with "Tense" relationships and overnight separations preventing tactile contact should be avoided. PMID- 29722049 TI - Refractory diffuse large B-cell lymphoma after first-line immuno-CT: Treatment options and outcomes. AB - In the rituximab era, one-third of diffuse large B-cell lymphoma patients experience relapse/refractory disease after first-line anthracycline-based immunochemotherapy. Optimal management remains an unmet medical need. The aim of this study was to report the outcomes of a cohort of refractory patients according to their patterns of refractoriness and the type of salvage option. We performed a retrospective analysis, which included 104 diffuse large B-cell lymphoma patients treated at Lyon Sud University Hospital (2002-2017) who presented with refractory disease. Refractoriness was defined as progressive/stable disease during first-line treatment (primary refractory, N = 47), a partial response after the end of first-line treatment that required subsequent treatment (residual disease, N = 19), or relapse within 1 year of diagnosis after an initial complete response (CR) (early relapse, N = 38). The 2 year overall survival (OS) rates for primary refractory, early relapse, and residual disease patients were 27%, 25%, and 52%, respectively, while the event free survival rates for those groups were 13%, 13%, and 42%, respectively. In a univariate analysis, lactate dehydrogenase level, Ann Arbor stage, poor performance status, high age-adjusted International Prognostic Index score, and age > 65 years were associated with shorter OS. The use of rituximab and platinum based chemo during the first salvage treatment was associated with prolonged OS. In a multivariate analysis, age (HR:2.06) and rituximab use (HR:0.54) were associated with OS. Among patients <65 years who achieved a CR, autologous stem cell transplant was associated with higher 2-year OS (90% vs 74%, P = 0.10). Patients who were treated with a targeted therapy in the context of a clinical trial after second-line treatment had a higher 2-year OS (34% vs 19%, P = 0.06). In conclusion, patients with primary refractory disease or early relapse have very poor outcomes but may benefit from rituximab retreatment during the first salvage treatment. PMID- 29722050 TI - Simultaneous determination of multicomponent of acetylkitasamycin and kitasamycin by LC-MS/MS in swine plasma and its application in a pharmacokinetic study. AB - A simple and reliable LC-MS/MS method was established for simultaneous determination of 12 components from acetylkitasamycin and kitasamycin in swine plasma. The analytes were separated on a Shim-pack VP-ODS column with a 25 min gradient elution using 5 mmol/L ammonium acetate and acetonitrile as the mobile phase at a flow rate of 0.2 mL/min. Identification and quantification were accomplished by electrospray ionization) in positive mode using multiple reaction monitoring. The limits of quantitation of acetylkitasamycin A1 A3 , A13 and kitasamycin A3 , A13 were 3 MUg/L, and that of the other eight components was 5 MUg/L. The mean recoveries of kitasamycin and acetylkitasamycin ranged from 85.3 to 103.5%. The developed method was successfully applied to a pharmacokinetic study in swine after intravenous (i.v.) and oral (p.o.) administration of acetylkitasamycin. The result showed that the plasma concentrations of acetylkitsamycin components were much higher than that of kitasamycin in swine after i.v. and p.o., in which acetylkitsamycin A4 A5 was the highest component at each time point. PMID- 29722051 TI - Liquid chromatographic-tandem mass spectrometry assay for the quantification of MDT-637 in human nasal wash. AB - MDT-637 is a new chemical entity that shows potent and selective antiviral activity against respiratory syncytial virus. As part of the new drug development program, a method for quantitating MDT-637 in nasal wash collected from human subjects was required. This article describes the method development and validation and application of a bioanalytical assay for MDT-637 in human nasal wash using liquid chromatography-tandem mass spectrometry. Sample pretreatment utilized supported liquid extraction and final extracts were injected onto an Agilent Poroshell 120 EC-C18 column and eluted under isocratic conditions of 65:35 (v/v) 10 mm ammonium formate in water and acetonitrile Detection was performed on an API 5000 tandem mass spectrometer operating in negative electrospray ionization mode applying multiple reaction monitoring. The assay was validated in accordance with the US Food and Drug Administration guidance on bioanalytical method validation and was applied in support of a Phase IIa human safety and tolerability study. PMID- 29722052 TI - The methodological quality of guidelines for hospital-acquired pneumonia and ventilator-associated pneumonia: A systematic review. AB - WHAT IS KNOWN AND OBJECTIVES: Clinical practice guidelines serve as a framework for physicians to make decisions and to support best practice for optimizing patient care. However, if the guidelines do not address all the important components of optimal care sufficiently, the quality and validity of the guidelines can be reduced. The objectives of this study were to systematically review current guidelines for hospital-acquired pneumonia (HAP) and ventilator associated pneumonia (VAP), evaluate their methodological quality and highlight the similarities and differences in their recommendations for empirical antibiotic and antibiotic de-escalation strategies. METHODS: This review is reported in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement. Electronic databases including MEDLINE, CINAHL, PubMed and EMBASE were searched up to September 2017 for relevant guidelines. Other databases such as NICE, Scottish Intercollegiate Guidelines Network (SIGN) and the websites of professional societies were also searched for relevant guidelines. The quality and reporting of included guidelines were assessed using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. RESULTS AND DISCUSSION: Six guidelines were eligible for inclusion in our review. Among 6 domains of AGREE-II, "clarity of presentation" scored the highest (80.6%), whereas "applicability" scored the lowest (11.8%). All the guidelines supported the antibiotic de-escalation strategy, whereas the majority of the guidelines (5 of 6) recommended that empirical antibiotic therapy should be implemented in accordance with local microbiological data. All the guidelines suggested that for early-onset HAP/VAP, therapy should start with a narrow spectrum empirical antibiotic such as penicillin or cephalosporins, whereas for late-onset HAP/VAP, the guidelines recommended the use of a broader spectrum empirical antibiotic such as the penicillin extended spectrum carbapenems and glycopeptides. WHAT IS NEW AND CONCLUSIONS: Expert guidelines promote the judicious use of antibiotics and prevent antibiotic overuse. The quality and validity of available HAP/VAP guidelines would be enhanced by improving their adherence to accepted best practice for the management of HAP and VAP. PMID- 29722054 TI - Pathoarchitectonics of the cerebral cortex in chorea-acanthocytosis and Huntington's disease. AB - AIMS: Quantitative estimation of cortical neurone loss in cases with chorea acanthocytosis (ChAc) and its impact on laminar composition. METHODS: We used unbiased stereological tools to estimate the degree of cortical pathology in serial gallocyanin-stained brain sections through the complete hemispheres of three subjects with genetically verified ChAc and a range of disease durations. We compared these results with our previous data of five Huntington's disease (HD) and five control cases. Pathoarchitectonic changes were exemplarily documented in TE1 of a 61-year-old female HD-, a 60-year-old female control case, and ChAc3. RESULTS: Macroscopically, the cortical volume of our ChAc cases (ChAc1 3) remained close to normal. However, the average number of neurones was reduced by 46% in ChAc and by 33% in HD (P = 0.03 for ChAc & HD vs. controls; P = 0.64 for ChAc vs. HD). Terminal HD cases featured selective laminar neurone loss with pallor of layers III, V and VIa, a high density of small, pale, closely packed radial fibres in deep cortical layers VI and V, shrinkage, and chromophilia of subcortical white matter. In ChAc, pronounced diffuse astrogliosis blurred the laminar borders, thus masking the complete and partial loss of pyramidal cells in layer IIIc and of neurones in layers III, V and VI. CONCLUSION: ChAc is a neurodegenerative disease with distinct cortical neurodegeneration. The hypertrophy of the peripheral neuropil space of minicolumns with coarse vertical striation was characteristic of ChAc. The role of astroglia in the pathogenesis of this disorder remains to be elucidated. PMID- 29722055 TI - Perceived Discrimination and Suicide Ideation: Moderating Roles of Anxiety Symptoms and Ethnic Identity among Asian American, African American, and Hispanic Emerging Adults. AB - Suicide is a leading cause of death for vulnerable ethnic minority emerging adults in the United States (Web-based injury statistics query and reporting system [WISQARS], 2015). Perceived discrimination (Journal of Youth and Adolescence, 40, 2011, 1465) and anxiety symptoms (Asian American Journal of Psychology, 1, 2010, 18) are two predictors that are theoretically and conceptually related, but have yet to be examined in a simultaneous model for suicide ideation. Existing theory and research suggest that these variables activate similar pathways (American Behavioral Scientist, 51, 2007, 551). This study sought to address this gap in the literature by examining the simultaneous relationship between perceived discrimination and anxiety symptoms as predictors of suicide ideation. The moderating effect of anxiety symptoms on the relationship between perceived discrimination and suicide ideation was examined in a multiethnic sample of emerging adults. Results indicated that anxiety symptoms moderated the perceived discrimination-suicide ideation relationship for Hispanic emerging adults, but not for their Asian American and African American counterparts. Furthermore, ethnic identity has been shown to mitigate suicide risk in the face of other stressors (Cultural Diversity and Ethnic Minority Psychology, 14, 2008, 75). Ethnic identity emerged as a protective factor for Hispanic emerging adults by further interacting with perceived discrimination and anxiety symptoms to negatively predict suicide ideation. The implications of these findings are discussed. PMID- 29722053 TI - The role of maternal anorexia nervosa and bulimia nervosa before and during pregnancy in early childhood wheezing: Findings from the NINFEA birth cohort study. AB - OBJECTIVE: This study evaluates associations of maternal eating disorders (bulimia nervosa, anorexia nervosa, and purging behaviors) with infant wheezing and examines the effects of eating disorders on several wheezing determinants. METHOD: We studied 5,150 singletons from the NINFEA birth cohort. Maternal bulimia nervosa and anorexia nervosa diagnoses were ascertained from the questionnaires completed in pregnancy and 6 months after delivery, and were analyzed as: ever diagnosis, only before pregnancy, and during pregnancy. Purging behaviors were assessed for 12 months before or during pregnancy. The associations with wheezing between 6 and 18 months of age were assessed in models adjusted for a priori selected confounders. RESULTS: Children born to mothers with lifetime eating disorders were at an increased risk of developing wheezing (adjusted OR 1.68; [95% CI: 1.08, 2.60]), and this risk further increased when the disorders were active during pregnancy (2.52 [1.23, 5.19]). Increased risk of offspring wheezing was observed also for purging behaviors without history of eating disorder diagnosis (1.50 [1.10, 2.04]). The observed associations were not explained by comorbid depression and/or anxiety. Bulimia nervosa and/or anorexia nervosa during pregnancy were also associated with several risk factors for wheezing, including maternal smoking, adverse pregnancy outcomes, shorter breastfeeding duration, and day-care attendance. DISCUSSION: The associations of maternal eating disorders with offspring wheezing suggest long-term adverse respiratory outcomes in children of mothers with eating disorders. A better understanding of mechanisms implicated is necessary to help reduce the respiratory disease burden in these children. PMID- 29722056 TI - Systematic Review and Quality Appraisal of Practice Guidelines for Self-Harm in Children and Adolescents. AB - This study aimed to systematically identify and appraise clinical practice guidelines (CPGs) relating to the assessment and management of suicide risk and self-harm in children and adolescents. Our research question is as follows: For young people (under 18 years old) presenting to clinical care with suicide ideation or a history of self-harm, what is the quality of up-to-date CPGs? Using the PRISMA format, we systematically identified CPGs meeting our inclusion and exclusion criteria. Subsequently, two independent raters conducted appraisals of the eligible CPGs using the Appraisal of Guidelines for Research and Evaluation II instrument. CPGs were then classified as "poor quality," "minimum quality," and "high quality" using operationally defined criteria developed a priori. We identified 10 eligible CPGs published or renewed between 2005 and May 2017. Only the long-term management of self-harm CPGs produced by the National Institute for Health and Care Excellence met "high-quality" criteria. Despite multiple options of CPGs published to choose from, only one was identified as "high quality," where bias is adequately minimized. Clinicians are advised to direct resources to implementing the "high-quality" CPG. PMID- 29722057 TI - A systematic review of effort-reward imbalance among health workers. AB - The purpose of this article is to systematically collate effort-reward imbalance (ERI) rates among health workers internationally and to assess gender differences. The effort-reward (ER) ratio ranges quite widely from 0.47 up to 1.32 and the ERI rate from 3.5% to 80.7%. Many studies suggested that health workers contribute more than they are rewarded, especially in Japan, Vietnam, Greece, and Germany-with ERI rates of 57.1%, 32.3%, 80.7%, and 22.8% to 27.6%, respectively. Institutions can utilize systems such as the new appraisal and reward system, which is based on performance rather than the traditional system, seniority, which creates a more competitive working climate and generates insecurity. Additionally, an increased workload and short stay patients are realities for workers in a health care environment, while the structure of human resources for health care remains inadequate. Gender differences within the ER ratio can be explained by the continued impact of traditional gender roles on attitudes and motivations that place more pressure to succeed for men rather than for women. This systematic review provides some valued evidence for public health strategies to improve the ER balance among health workers in general as well as between genders in particular. An innovative approach for managing human resources for health care is necessary to motivate and value contributions made by health workers. PMID- 29722058 TI - Breast cancer intratumour heterogeneity: current status and clinical implications. AB - Breast cancer (BC) is a heterogeneous disease that varies in presentation, morphological features, behaviour, and response to therapy. High-throughput molecular profiling studies have revolutionised our understanding of BC heterogeneity, and have demonstrated that molecular profiles of tumours are variable not only between tumours, but also within individual tumours. Current evidence indicates that spatial and temporal intratumour heterogeneity of BC exists at levels beyond what are commonly expected. Intratumour heterogeneity poses critical challenges in the diagnosis, prediction of behaviour and management of BC. For instance, heterogeneous expression of oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 can be seen not only in primary tumours between different regions, but also between primary tumours and their corresponding metastatic/recurrent lesions. The demonstration of molecularly distinct subclones within individual tumours may explain, at least in part, the mechanisms controlling the variable behaviour of BC, and may change our approach to BC sampling and treatment. In this review, BC intratumour heterogeneity is highlighted, with a special emphasis on the current knowledge pertaining to the relationship between intratumour heterogeneity and BC pathogenesis, evolution, and progression, with consideration of its impact on disease diagnosis, management, and the emergence of novel therapeutic targets. The key role of high-throughput molecular and imaging techniques is also addressed. PMID- 29722059 TI - Insanity findings and evaluation practices: A state-wide review of court-ordered reports. AB - Evaluations of legal sanity are some of the most complex and consequential mental health evaluations that forensic clinicians perform for the courts. Thus, there is strong reason to monitor the wide-scale process and conclusions of sanity evaluations. In this study, we review 1,111 court-ordered sanity evaluation reports submitted by 74 evaluators in Virginia from the first year after the state initiated an oversight system that allowed for such comprehensive review. Overall, the base rate of insanity findings was 16.9%, although base rates of insanity findings among individual evaluators varied from 0% to 50%. Similarly, most evaluators cited the cognitive (rather than volitional) criteria of the insanity defense as the basis for their insanity findings, although evaluators varied in their patterns of citing these underlying insanity criteria. Our review revealed other trends in practice, such as the rarity of psychological testing (2% of cases) and the frequency of conveying conclusions in "ultimate issue" format (76%). Overall, findings reveal that a majority of reports seem reasonably consistent with practice guidelines, but also reveal some idiosyncratic practices or patterns that suggest there is opportunity for improvement. PMID- 29722060 TI - Structure and properties of AB21, a novel Agaricus bisporus protein with structural relation to bacterial pore-forming toxins. AB - We report the characterization of the dimeric protein AB21 from Agaricus bisporus, one of the most commonly and widely consumed mushrooms in the world. The protein shares no significant sequence similarity with any protein of known function, and it is the first characterized member of its protein family. The coding sequence of the ab21 gene was determined and the protein was expressed in E. coli in a recombinant form. We demonstrated a high thermal and pH stability of AB21 and proved the weak affinity of the protein to divalent ions of some transition metals (nickel, zinc, cadmium, and cobalt). The reported crystallographic structure exhibits an interesting rod-like helical bundle fold with structural similarity to bacterial toxins of the ClyA superfamily. By immunostaining, we demonstrated an abundance of AB21 in the fruiting bodies of A. bisporus. PMID- 29722061 TI - Cellular energy metabolism maintains young status in old queen honey bees (Apis mellifera). AB - Trophocytes and oenocytes of queen honey bees are used in studies of cellular longevity, but their cellular energy metabolism with age is poorly understood. In this study, the molecules involved in cellular energy metabolism were evaluated in the trophocytes and oenocytes of young and old queen bees. The findings indicated that there were no significant differences between young and old queen bees in beta-oxidation, glycolysis, and protein synthesis. These results indicate that the cellular energy metabolism of trophocytes and oenocytes in old queen bees is similar to young queen bees and suggests that maintaining cellular energy metabolism in a young status may be associated with the longevity of queen bees. Fat and glycogen accumulation increased with age indicating that old queen bees are older than young queen bees. PMID- 29722062 TI - Patient-to-patient peer mentor support in dialysis: Improving the patient experience. AB - Greater focus on patient-reported outcome measures for dialysis patients and an increased patient engagement focus has highlighted a lack of formal patient generated strategies. Patient-to-patient peer mentoring is one approach that may improve the outcomes for people receiving dialysis. This review aims to synthesize quantitative and qualitative studies investigating dialysis-associated patient-to-patient peer mentor support among adults with chronic kidney disease and end stage kidney disease. Research studies describe the benefits of peer mentor programs in dialysis to include: improved goal setting, decision-making and increased self-management. While a variety of program formats exist, a combination of face-to-face and telephone peer support models are recommended and formal training of mentors is required. In addition, the formal support of dialysis clinicians, nephrologists and administrators is vital for the success of a dialysis patient-to-patient peer mentor program. PMID- 29722063 TI - A discrete polar Stockwell transform for enhanced characterization of tissue structure using MRI. AB - PURPOSE: The purpose of this study was to present an effective algorithm for computing the discrete polar Stockwell transform (PST), investigate its unique multiscale and multi-orientation features, and explore potentially new applications including denoising and tissue segmentation. THEORY AND METHODS: We investigated PST responses using both synthetic and MR images. Moreover, we compared the features of PST with both Gabor and Morlet wavelet transforms, and compared the PST with two wavelet approaches for denoising using MRI. Using a synthetic image, we also tested the edge effect of PST through signal-padding. Then, we constructed a partially supervised classifier using radial, marginal PST spectra of T2-weighted MRI, acquired from postmortem brains with multiple sclerosis. The classification involved three histology-verified tissue types: normal appearing white matter (NAWM), lesion, or other, along with 5-fold cross validation. RESULTS: The PST generated a series of images with varying orientations or rotation-invariant scales. Radial frequencies highlighted image structures of different size, and angular frequencies enhanced structures by orientation. Signal-padding helped suppress boundary artifacts but required attention to incidental artifacts. In comparison, the Gabor transform produced more redundant images and the wavelet spectra appeared less spatially smooth than the PST. In addition, the PST demonstrated lower root-mean-square errors than other transforms in denoising and achieved a 93% accuracy for NAWM pixels (296/317), and 88% accuracy for lesion pixels (165/188) in MRI segmentation. CONCLUSIONS: The PST is a unique local spectral density-assessing tool which is sensitive to both structure orientations and scales. This may facilitate multiple new applications including advanced characterization of tissue structure in standard MRI. PMID- 29722064 TI - High wrist ratio is a risk factor for carpal tunnel syndrome. AB - Carpal tunnel syndrome (CTS) is the most common upper extremity entrapment neuropathy and various risk factors have been implicated in the etiology. In this study, we aimed to determine whether anthropometric measurements are independent risk factors for CTS. Patients with symptoms of CTS (n = 27) and asymptomatic controls (n = 27) were enrolled following electrophysiological confirmation. Body mass index (BMI) was recorded and anthropometric measurements of the hand were made by a digital caliper. BMI, wrist width, wrist depth, palm length, hand width, wrist ratio, wrist/palm ratio, and wrist/hand ratio were significantly higher in the CTS group. BMI, wrist ratio, wrist/palm ratio, and wrist/hand ratio were independent variables in the logistic regression analysis; wrist ratio was the only significant predictor of CTS. Patients with a wrist ratio higher than 0.69 were 8.2 times more likely to have CTS. This study suggests that wrist ratio may be considered as an independent risk factor for CTS. Clin. Anat. 31:698-701, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29722065 TI - The structure of the N-terminal module of the cell wall hydrolase RipA and its role in regulating catalytic activity. AB - RipA plays a vital role during cell division of Mycobacterium tuberculosis by degrading the cell wall peptidoglycan at the septum, allowing daughter cell separation. The peptidoglycan degrading activity relies on the NlpC/P60 domain, and as it is potentially harmful when deregulated, spatial and temporal control is necessary in this process. The N-terminal domain of RipA has been proposed to play an inhibitory role blocking the C-terminal NlpC/P60 domain. Accessibility of the active site cysteine residue is however not limited by the presence of the N terminal domain, but by the lid-module of the inter-domain linker, which is situated in the peptide binding groove of the crystal structures of the catalytic domain. The 2.2 A resolution structure of the N-terminal domain, determined by Se SAD phasing, reveals an all-alpha-fold with 2 long alpha-helices, and shows similarity to bacterial periplasmic protein domains with scaffold-building role. Size exclusion chromatography and SAXS experiments are consistent with dimer formation of this domain in solution. The SAXS data from the periplasmic two domain RipA construct suggest a rigid baton-like structure of the N-terminal module, with the catalytic domain connected by a 24 residue long flexible linker. This flexible linker allows for a catalytic zone, which is part of the spatiotemporal control of peptidoglycan degradation. PMID- 29722066 TI - Placentophagy among women planning community births in the United States: Frequency, rationale, and associated neonatal outcomes. AB - BACKGROUND: Limited systematic research on maternal placentophagy is available to maternity care providers whose clients/patients may be considering this increasingly popular practice. Our purpose was to characterize the practice of placentophagy and its attendant neonatal outcomes among a large sample of women in the United States. METHODS: We used a medical records-based data set (n = 23 242) containing pregnancy, birth, and postpartum information for women who planned community births. We used logistic regression to determine demographic and clinical predictors of placentophagy. Finally, we compared neonatal outcomes (hospitalization, neonatal intensive unit admission, or neonatal death in the first 6 weeks) between placenta consumers and nonconsumers, and participants who consumed placenta raw vs cooked. RESULTS: Nearly one-third (30.8%) of women consumed their placenta. Consumers were more likely to have reported pregravid anxiety or depression compared with nonconsumers. Most (85.3%) placentophagic mothers consumed their placentas in encapsulated form, and nearly half (48.4%) consumed capsules containing dehydrated, uncooked placenta. Placentophagy was not associated with any adverse neonatal outcomes. Women with home births were more likely to engage in placentophagy than women with birth center births. The most common reason given (73.1%) for engaging in placentophagy was to prevent postpartum depression. [Corrections added on 16 May 2018, after first online publication: The percentage values in the Results sections were updated.] CONCLUSIONS: The majority of women consumed their placentas in uncooked/encapsulated form and hoping to avoid postpartum depression, although no evidence currently exists to support this strategy. Preparation technique (cooked vs uncooked) did not influence adverse neonatal outcomes. Maternity care providers should discuss the range of options available to prevent/treat postpartum depression, in addition to current evidence with respect to the safety of placentophagy. PMID- 29722067 TI - Is distribution of health expenditure in Iran pro-poor? AB - BACKGROUND: The size and distribution of households' health care expenditure indicate the financial burden on different income groups. Since the distribution of health expenditure evaluates the performance of health systems, this study aims to examine the health expenditure distribution among urban and rural households in Iran. METHODS: This research was conducted on the distribution of health expenditure among urban and rural households in 2014. The effects of households' health expenditure on distribution of personal incomes were measured by using Kakwani and Reynolds-Smolensky indices. In addition, Theil T index was used to classify provinces based on inequality in health expenditure distribution. The calculations were made by using EXCEL. RESULTS: The Kakwani indices for urban and rural households were calculated around -0.572 and -0.485, respectively. Reynolds-Smolensky indices for urban and rural households were measured as much as -0.038 and -0.031, respectively. Regardless of income distribution, Theil T index shows that urban households face with the most unequal distribution in health expenditure. CONCLUSION: Based on calculations, the distribution of health expenditure is against the poor households. In addition, this distribution is more regressive in urban than rural households. As well, Reynolds-Smolensky indices indicate more uneven income distribution after paying for health care, and inequality is larger among urban than rural households. To this research, the health policymaking priorities should be given to the provinces with the highest inequality, and the expenditure burden of low income households should be reduced through expanding insurance coverage. PMID- 29722068 TI - Differential ability of formononetin to stimulate proliferation of endothelial cells and breast cancer cells via a feedback loop involving MicroRNA-375, RASD1, and ERalpha. AB - For postmenopausal cardiovascular disease, long-term estrogen therapy may increase the risk of breast cancer. To reduce this risk, estrogen may be replaced with the phytoestrogen formononetin, but how formononetin acts on vascular endothelial cells (ECs) and breast cancer cells is unclear. Here, we show that low concentrations of formononetin induced proliferation and inhibited apoptosis more strongly in cultured human umbilical vein endothelial cells (HUVECs) than in breast cancer cells expressing estrogen receptor alpha (ERalpha) (MCF-7, BT474) or not (MDA-MB-231), and that this differential stimulation was associated with miR-375 up-regulation in HUVECs. For the first time, we demonstrate the presence of a feedback loop involving miR-375, ras dexamethasone-induced 1 (RASD1), and ERalpha in normal HUVECs, and we show that formononetin stimulated this feedback loop in HUVECs but not in MCF-7 or BT474 cells. In all three cell lines, formononetin increased Akt phosphorylation and Bcl-2 expression. Inhibiting miR 375 blocked these changes and increased proliferation in HUVECs, but not in MCF-7 or BT474 cells. In ovariectomized rats, formononetin increased uterine weight and caused similar changes in levels of miR-375, RASD1, ERalpha, and Bcl-2 in aortic ECs as in cultured HUVECs. In mice bearing MCF-7 xenografts, tumor growth was stimulated by 17beta-estradiol but not by formononetin. These results suggest selective action of formononetin in ECs (proliferation stimulation and apoptosis inhibition) relative to breast cancer cells, possibly via a feedback loop involving miR-375, RASD1, and ERalpha. This differential effect may explain why formononetin may not increase the risk of postmenopausal breast cancer. PMID- 29722069 TI - Investigating cumulative effects across ecological scales. AB - Species, habitats, and ecosystems are increasingly exposed to multiple anthropogenic stressors, fueling a rapidly expanding research program to understand the cumulative impacts of these environmental modifications. Since the 1970s, a growing set of methods has been developed through two parallel, sometimes connected, streams of research within the applied and academic realms to assess cumulative effects. Past reviews of cumulative effects assessment (CEA) methods focused on approaches used by practitioners. Academic research has developed several distinct and novel approaches to conducting CEA. Understanding the suite of methods that exist will help practitioners and academics better address various ecological foci (physiological responses, population impacts, ecosystem impacts) and ecological complexities (synergistic effects, impacts across space and time). We reviewed 6 categories of methods (experimental, meta analysis, single-species modeling, mapping, qualitative modeling, and multispecies modeling) and examined the ability of those methods to address different levels of complexity. We focused on research gaps and emerging priorities. We found that no single method assessed impacts across the 4 ecological foci and 6 ecological complexities considered. We propose that methods can be used in combination to improve understanding such that multimodel inference can provide a suite of comparable outputs, mapping methods can help prioritize localized models or experimental gaps, and future experiments can be paired from the outset with models they will inform. PMID- 29722071 TI - Texting atopic dermatitis patients to optimize learning and eczema area and severity index scores: A pilot randomized control trial. AB - BACKGROUND/OBJECTIVES: Atopic dermatitis is a common, chronic, debilitating disease. Poor adherence to treatment is the most important preventable contributor to adverse outcomes. Thus, improving adherence can improve patient outcomes. Text message reminders with embedded condition-specific information have been shown to improve pediatric immunization adherence but have not been assessed in atopic dermatitis. The objective was to assess the effect of daily text messages on Eczema Area Severity Index scores and caregiver knowledge of atopic dermatitis. METHODS: In this pilot randomized controlled trial, caregivers of children with atopic dermatitis enrolled during their initial appointment with a pediatric dermatologist and randomized 1:1 to standard care or daily text messages with patient education material and treatment reminders. Participants completed a multiple-choice atopic dermatitis knowledge quiz at initial and follow-up visits, and Eczema Area Severity Index scores were assessed. RESULTS: Forty-two patients enrolled, and 30 completed the study: 16 standard care group, 14 text message group. There was no significant difference in Eczema Area Severity Index score between the standard care and text message groups at follow up, with mean decreases in Eczema Area Severity Index score of 53% and 58%, respectively. Mean score on follow-up atopic dermatitis knowledge quiz was significantly higher in the text message group (84% correct) than in the standard care group (75% correct) (P = .04). CONCLUSION: This pilot study did not demonstrate a difference in Eczema Area Severity Index scores with text message reminders. The significantly higher follow-up atopic dermatitis quiz score in the text message group indicates that participants read and retained information from text messages. Limitations include small sample size and short duration of follow up. PMID- 29722070 TI - Simplified and robust one-step radiosynthesis of [18 F]DCFPyL via direct radiofluorination and cartridge-based purification. AB - [18 F]DCFPyL is a clinical-stage PET radiotracer used to image prostate cancer. This report details the efficient production of [18 F]DCFPyL using single-step direct radiofluorination, without the use of carboxylic acid-protecting groups. Radiolabeling reaction optimization studies revealed an inverse correlation between the amount of precursor used and the radiochemical yield. This simplified approach enabled automated preparation of [18 F]DCFPyL within 28 minutes using HPLC purification (26% +/- 6%, at EOS, n = 4), which was then scaled up for large batch production to generate 1.46 +/- 0.23 Ci of [18 F]DCFPyL at EOS (n = 7) in high molar activity (37 933 +/- 4158 mCi/MUmol, 1403 +/- 153 GBq/MUmol, at EOS, n = 7). Further, this work enabled the development of [18 F]DCFPyL production in 21 minutes using an easy cartridge-based purification (25% +/- 9% radiochemical yield, at EOS, n = 3). PMID- 29722072 TI - hTERT promotes tumor progression by enhancing TSPAN13 expression in osteosarcoma cells. AB - Telomerase complex maintains the length of the telome, cbre, and protects erosion of the physical ends of the eukaryotic chromosome in all actively dividing cells including cancer cells. Telomerase activation extends the lifespan of cells in culture by maintaining the length of the telomere. Compared to terminally differentiated somatic cells, telomerase activity remains high in over 90% of cancer cells. It has now become clear that the role of telomerase is much more complex than just telomere lengthening. The remaining 10% of cancers deploy ALT (alternative lengthening of telomeres) pathway to maintain telomere length. Telomerase inhibitors offer a good therapeutic option. Also, telomerase associated molecules can be targeted provided their roles are clearly established. In any case, it is necessary to understand the major role of telomerase in cancer cells. Many studies have already been done to explore gene profiling of a telomerase positive cell by knocking down expression of hTERT (telomerase reverse transcriptase). To complement these studies, we performed global gene profiling of a telomerase negative cell by ectopically expressing hTERT and studied changes in the global gene expression patterns. Analysis of microarray data for telomerase negative cells ectopically expressing telomerase showed 76 differentially regulated genes, out of which 39 genes were upregulated, and 37 were downregulated. Three upregulated genes such as TSPAN13, HMGCS2, DLX5, and three downregulated genes like DHRS2, CRYAB, and PDLIM1 were validated by real-time PCR. Knocking down of TSAPN13 in hTERT overexpressing U2OS cells enhanced the apoptosis of the cells. TSPAN13 knockdown in these cells suppressed mesenchymal properties and enhanced epithelial character. PMID- 29722074 TI - Analysis of caudate lobe biliary anatomy and its implications in living donor liver transplantation - a single centre prospective study. AB - Biliary complications are a significant cause of morbidity after living donor liver transplant (LDLT). Bile leak may occur from bile duct (anastomotic site in recipient and repaired bile duct stump in donor), cystic duct stump, cut surface pedicles or from divided caudate ducts. The first three sites are amenable to post-operative endoscopic stenting as they are in continuation with biliary ductal system. However, leaks from divided isolated caudate ducts can be stubborn. To minimize caudate duct bile leaks, it is important to understand the anatomy of hilum with attention to the caudate lobe biliary drainage. This single centre prospective study of 500 consecutive LDLTs between December 2011 and December 2016 aims to define the biliary anatomy of the caudate lobe in liver donors based on intraoperative cholangiograms (IOCs) with special attention to crossover caudate ducts and to study their implications in LDLT. Caudate ducts were identified in 468 of the 500 IOCs. Incidence of left-to-right crossover drainage was 61.37% and right to left was 21.45%. Incidence of bile leak in donors was 0.8% and in recipients was 2.2%. Proper intraoperative identification and closure of divided isolated caudate ducts can prevent bile leak in donors as well as recipients. PMID- 29722073 TI - Complications related to chronic supratherapeutic use of codeine containing compound analgesics in a cohort of patients presenting for codeine withdrawal. AB - INTRODUCTION AND AIMS: This study aimed to compare complications arising due to the supratherapeutic use of paracetamol/codeine or ibuprofen/codeine containing compound analgesics in primary codeine-dependent patients presenting to a drug and alcohol withdrawal service. Data was compared to determine if there was any difference in the number of complications observed between the two groups. DESIGN AND METHODS: A retrospective case review of patients presenting for primary codeine dependence from 2009 to 2014. Sixty patients (42F, 36 +/- 10 years) using ibuprofen/codeine and 46 (26F, 39 +/- 10 years) using paracetamol/codeine containing compound analgesics were compared. A P value of <0.05 was considered significant. RESULTS: Patients consumed similar daily doses of codeine (699 +/- 45 vs. 636 +/- 50 mg) with those consuming ibuprofen/codeine containing compound analgesics ingesting twice as many tablets daily (median 60 vs. 30 tablets; P < 0.0001). Complications related to supratherapeutic use of codeine containing compound analgesics occurred more commonly in patients taking ibuprofen/codeine (52/60; 87%) versus paracetamol/codeine compound analgesics (30/46; 65%) (P < 0.01). Patients taking ibuprofen/codeine containing compound analgesics were more likely to have gastrointestinal bleeding (P < 0.05), anaemia (P < 0.0001) and renal tubular acidosis (P < 0.05). There were two deaths in the group abusing ibuprofen/codeine compound analgesics. DISCUSSION AND CONCLUSIONS: In patients with primary codeine dependence, there were more complications related to the supratherapeutic use of ibuprofen/codeine versus paracetamol/codeine containing compound analgesics. The patients in both groups ingested similar total daily codeine amounts. Increased daily tablet intake in the ibuprofen/codeine group could possibly have been linked to lower codeine content per tablet. PMID- 29722075 TI - Natural actives for wound healing: A review. AB - Nature has been a source of medicinal treatments for thousands of years, with the use of plants as prototypes for drug development and for the extraction of active compounds. Skin injuries occur regularly in everyday life, and the human skin has the ability to promote repair spontaneously under healthy conditions. However, some intrinsic and external factors may interfere with skins' natural ability, leading to nonhealing lesions and chronic wounds, which directly affect health and quality of life. Thus, attention should be given to this health problem, using an appropriated management when necessary. In this scenario, phytotherapy may be an option for cutaneous wound treatment, although further high-quality studies are needed to firmly establish the clinical efficacy of plants. This article reviews traditionally used natural actives for wound healing, highlighting their characteristics and mode of action. PMID- 29722077 TI - ANRIL as a genetic marker for cardiovascular events in renal transplant patients an observational follow-up cohort study. AB - Cardiovascular disease is the leading cause of morbidity and mortality in kidney transplant recipients. Several single-nucleotide polymorphisms (SNPs) in the ANRIL gene pathway have been associated with cardiovascular events (CE). The main objective was to ascertain whether ANRIL (rs10757278) and CARD8 (rs2043211) SNPs could mediate susceptibility to CE. This was an observational follow-up cohort study of renal transplant recipients at Bellvitge University Hospital (Barcelona) from 2000 to 2014. A total of 505 recipients were followed up until achievement of a CE. Patients who did not achieve the endpoint were followed up until graft loss, lost to follow-up or death. Survival analysis was used to ascertain association between genetic markers, clinical data, and outcome. Fifty-three patients suffered a CE after renal transplantation. Results showed a significant association between ANRIL SNP and CE. Homozygous GG for the risk allele showed higher risk for CE than A carriers for the protective allele [HR = 2.93(1.69 5.11), P < 0.0001]. This effect was maintained when it was analyzed in combination with CARD8, suggesting that CARD8 SNP could play a role in the ANRIL mechanism. However, our study does not clarify the molecular mechanism for the CARD8 SNP regulation by ANRIL. ANRIL SNP may predispose to the development of CE after successful kidney transplantation. PMID- 29722078 TI - Aptamer-Functionalized Magnetic Conjugated Organic Framework for Selective Extraction of Traces of Hydroxylated Polychlorinated Biphenyls in Human Serum. AB - A solid-phase extraction adsorbent based on an aptamer-functionalized magnetic conjugated organic framework (COF) was developed for selective extraction of traces of hydroxylated polychlorinated biphenyls. This material has advantages such as superparamagnetism of the magnetic core, high surface area and porous structure of the COF, and high specific affinity of the aptamer. In combination with HPLC-MS, the aptamer-functionalized magnetic COF was used for the capture of hydroxy-2',3',4',5,5'-pentachlorobiphenyl in human serum. The method provided a linear range of 0.01-40 ng mL-1 with a good correlation coefficient (R2 =0.9973). The limit of detection was as low as 2.1 pg mL-1 . Furthermore, the material showed good reusability and could be applied in at least ten extraction cycles with recoveries greater than 90 %. PMID- 29722076 TI - Functional and evolutionary analysis of viral proteins containing a Rossmann-like fold. AB - Viruses are the most abundant life form and infect practically all organisms. Consequently, these obligate parasites are a major cause of human suffering and economic loss. Rossmann-like fold is the most populated fold among alpha/beta folds in the Protein Data Bank and proteins containing Rossmann-like fold constitute 22% of all known proteins 3D structures. Thus, analysis of viral proteins containing Rossmann-like domains could provide an understanding of viral biology and evolution as well as could propose possible targets for antiviral therapy. We provide functional and evolutionary analysis of viral proteins containing a Rossmann-like fold found in the evolutionary classification of protein domains (ECOD) database developed in our lab. We identified 81 protein families of bacterial, archeal, and eukaryotic viruses in light of their evolution-based ECOD classification and Pfam taxonomy. We defined their functional significance using enzymatic EC number assignments as well as domain level family annotations. PMID- 29722079 TI - Electrodermal activity patterns in sleep stages and their utility for sleep versus wake classification. AB - As the prevalence of sleep disorders is increasing, new methods for ambulatory sleep measurement are required. This paper presents electrodermal activity in different sleep stages and a sleep detection algorithm based on electrodermal activity. We analysed electrodermal activity and polysomnographic data of 43 healthy subjects and 48 patients with sleep disorders. Electrodermal activity was measured using an ambulatory device worn at the wrist. Two parameters to describe electrodermal activity were defined based on previous literature: EDASEF (electrodermal activity-smoothed feature) as parameter for skin conductance level; and EDAcounts (number of electrodermal activity-peaks) as skin conductance responses. Analysis of variance indicated significant EDASEF differences between the sleep stages wake versus N1, wake versus N2, wake versus slow-wave sleep, and wake versus rapid eye movement. The analysis of EDAcounts also showed significant differences, especially in the stages slow-wave sleep versus rapid eye movement. Between healthy subjects and patients, a significant disparity of EDAcounts was revealed in stage N1. Furthermore, the variances of EDASEF and EDAcounts in N1, N2 slow-wave sleep and rapid eye movement were higher in the patient group (p [F test] < .05). Next, an electrodermal activity-based sleep/wake discriminating algorithm was constructed. The optimized algorithm achieved an average sensitivity and specificity for sleep detection of 97% and 75%. The epoch agreement rate (average accuracy) was 86%. These outcomes are comparative to sleep detection algorithms based on actigraphy or heart rate variability. The results of this study indicate that electrodermal activity is not only a robust parameter for describing sleep, but also a potential suitable method for ambulatory sleep monitoring. PMID- 29722080 TI - Selenium-Based Nanozyme as Biomimetic Antioxidant Machinery. AB - A self-assembly nanocomposite was designed to mimic intracellular enzymatic and non-enzymatic antioxidants-constituted antioxidant defense machinery. In this work, selenium nanocomponent served as one model to mimic antioxidant enzyme, whereas polydopamine was able to mimic non-enzymatic antioxidant biomolecule in living systems. With the excellent glutathione peroxidase-mimic capacity of selenium and the reducibility of polydopamine, this Se@pDA nanozyme could achieve synergetic antioxidative efficiency to protect cellular components against oxidative damage. The pneumonia model of mice further proved the potential of our nanocomposites for anti-inflammation therapy. PMID- 29722081 TI - Liver alone or simultaneous liver-kidney transplant? Pretransplant chronic kidney disease and post-transplant outcome - a retrospective study. AB - The new Organ Procurement and Transplant Network/United Organ Sharing Network (OPTN/UNOS) simultaneous liver-kidney transplant (SLK) policy has been implemented. The aim of this study was to review liver transplant outcomes utilizing the new SLK policy. Liver transplant alone (LTA) and SLK patients between 2009 and 2015 were reviewed. Graft survival and post-transplant kidney function were investigated among LTA patients meeting the chronic kidney disease (CKD) criteria of the new policy (LTA-CKD group). To validate our findings, we reviewed and applied our analysis to the OPTN/UNOS registry. A total of 535 patients were eligible from our series. The LTA-CKD group (n = 27) showed worse 1 year graft survival, compared with the SLK group (n = 44), but not significant (81% vs. 93%, P = 0.15). The LTA-CKD group significantly increased a risk of post transplant dialysis (odds ratio = 5.59 [95% CI = 1.27-24.7], P = 0.02 [Ref. normal kidney function]). Post-transplant dialysis was an independent risk factor for graft loss (hazard ratio = 7.25, 95% CI = 3.3-15.91, P < 0.001 [Ref. SLK]). In the validation analysis based on the OPTN/UNOS registry, the hazard of 1-year graft loss in the LTA-CKD group (n = 751) was 34.8% higher than the SLK group (n = 2856) (hazard ratio = 1.348, 95% CI = 1.157-1.572, P < 0.001). Indicating SLK for patients who meet the CKD criteria may significantly improve transplant outcomes. PMID- 29722082 TI - The reliability of the Epworth Sleepiness Score in a sleep clinic population. AB - Despite the Epworth Sleepiness Score being widely used, there are limited studies of its reliability in clinical practice. The aim of this study was to assess the reliability of the Epworth Sleepiness Score in a clinical population. The study included patients referred to Middlemore Hospital sleep service between October and November 2014, aged over 17 years, with at least two Epworth Sleepiness Score measurements at up to three different points on the diagnostic pathway: on General Practitioner referral (GP Epworth Sleepiness Score); at overnight oximetry assessment (Oximetry Epworth Sleepiness Score); and at a specialist clinic (Specialist Epworth Sleepiness Score). No treatment was administered between scores. One-hundred and thirty-three patients were included in the study. There was a median of 91 days from GP Epworth Sleepiness Score to Oximetry Epworth Sleepiness Score, and 11 days from Oximetry Epworth Sleepiness Score to Specialist Epworth Sleepiness Score. There was poor test-retest reliability between GP Epworth Sleepiness Score and Specialist Epworth Sleepiness Score; 72.4% and 17.8% of patients had an absolute difference of more than 2 and 8 Epworth Sleepiness Score points, respectively. A Bland-Altman plot of mean Epworth Sleepiness Score versus the difference between GP Epworth Sleepiness Score and Specialist Epworth Sleepiness Score demonstrated a wide scatter of data and 95% confidence interval for the difference in Epworth Sleepiness Score for an individual patient of -14 to +10. There was similar variability between GP Epworth Sleepiness Score and Oximetry Epworth Sleepiness Score. The reliability of the Epworth Sleepiness Score is unproven in clinical settings. This study shows poor test-retest reliability of Epworth Sleepiness Score, particularly between primary and secondary care, arguing against the use of Epworth Sleepiness Score for clinical decision-making or prioritisation of services without first assessing the reliability of the Epworth Sleepiness Score in the relevant clinical population. PMID- 29722083 TI - Segmental Mobility Studies of Poly(N-isopropyl acrylamide) Interactions with Gold Nanoparticles and Its Use as a Thermally Driven Trapping System. AB - Thermal desolvation of poly(N-isopropylacrylamide) (PNIPAM) in the presence of a low concentration of gold nanoparticles incorporates the nanoparticles resulting in suspended aggregates. By covalently incorporating <1% acenaphthylene into the polymerization feed this copolymer is enabled to be used as a model to study the segmental mobility of the PNIPAM backbone in response to gold nanoparticles both below and above the desolvation temperature, showing that there is a physical conformational rearrangement of the soluble polymer at ultralow nanoparticle loadings, indicating low affinity interactions with the nanoparticles. Thermal desolvation is capable of extracting >99.9% of the nanoparticles from their solutions and hence demonstrates that poly(N-isopropylacrylamide) can act as an excellent scrubbing system to remove metallic nanomaterial pollutants from solution. PMID- 29722084 TI - The effects of maternal risk factors during pregnancy on the onset of sleep difficulties in infants at 3 months old. AB - Sleep problems in young children are among the most common concerns reported to paediatricians. Sleep is thought to have important regulatory functions, and sleep difficulties in early childhood are linked to several psychosocial and physiological problems. Moreover, several prenatal factors have been found to influence infants' sleep. Among them, most of the studies have been focused on maternal prenatal depression and/or anxiety as potential risk factors for sleep problems in childhood, whereas other relevant psychological factors during pregnancy have not received as much attention. Therefore, we aimed to examine the effect of several psychiatric maternal risk factors during pregnancy (i.e. symptoms of anxiety, depression, insomnia, alcohol use, seasonality, attention deficit and hyperactivity disorder and/or stressful life events) on the onset of some sleep problems related to sleep quality and sleep practices in 3-month-old infants. We examined 1,221 cases from a population-based birth cohort, with subjective measures during pregnancy in mothers, and at 3 months after birth in the infants. The findings showed that all the maternal risk factors during pregnancy, except for symptoms of alcoholism and sleepiness, were related to sleep difficulties in infants. Interestingly, attention deficit and hyperactivity disorder symptomatology in mothers during pregnancy was the only variable that predicted more than two sleeping difficulties (i.e. long sleep-onset latency, co sleeping with parents and irregular sleeping routines) at 3 months old. Our results highlight the relevance of maternal risk factors during pregnancy, and not only prenatal depression and/or anxiety, as variables to be considered when examining sleep difficulties in infants. PMID- 29722085 TI - Polyhistidine-Based Metal Coordination Hydrogels with Physiologically Relevant pH Responsiveness and Enhanced Stability through a Novel Synthesis. AB - Utilizing the abnormal physiological conditions of disease tissues can result in a site-specific functionality with high control and efficiency of stimuli responsive hydrogels. Here, a physiologically relevant pH-responsive and self healing hydrogel is reported based on coordination between Ni2+ and four-arm poly(ethylene glycol)-b-polyhistidine (4PEG-PHis) that is synthesized by a novel and facile PHis preparation method using amino-terminalized four-arm PEG as the macroinitiator. Reversible PHis?Ni coordination bonds endow the hydrogel with multistimuli-triggered sol-gel transition (physiologically relevant pH, EDTA) and self-healing properties. It is also demonstrated that 4PEG-PHis could be used as an injectable hydrogel in phosphate buffer (pH 7.4), and excellent stability in neutral buffer via multivalent coordination is shown, thus indicating its potential applications in controlled drug release systems. PMID- 29722086 TI - Apoptotic effect of lambertianic acid through AMPK/FOXM1 signaling in MDA-MB231 breast cancer cells. AB - Though lambertianic acid (LA) was known to exert antitumor effect in liver and prostate cancers, its underlying anticancer mechanism is never reported in breast cancers so far. Thus, in this study, apoptotic mechanism of LA was elucidated in MDA-MB-231 breast cancer cells. Here, LA increased cytotoxicity in MCF-7 and MDA MB-231 cells; enhanced sub-G1 population, G2/M arrest, and cleaved poly(ADP ribose) polymerase; activated phosphorylation of AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase pathway; and also suppressed phosphorylation of AKT and the expression of forkhead box M1 (FOXM1), X-linked inhibitor of apoptosis protein, B-cell lymphoma 2, and CyclinB1 in MDA-MB-231 cells. Furthermore, AMPK inhibitor compound C reversed the effect of LA on FOXM1, Cyclin B1, and cleaved poly(ADP-ribose) polymerase in MDA-MB-231 cells. Notably, immunoprecipitation revealed that LA disturbed the direct binding of AKT and FOXM1 in MDA-MB-231 cells. Overall, these findings suggest that LA-induced apoptosis is mediated via activation of AMPK and inhibition of AKT/FOXM1 signaling pathway. PMID- 29722087 TI - Photoinduced Reversible Morphological Transformation of Azobenzene-Containing Pseudo-2D Polymers. AB - 2D polymer sheets containing azobenzene are successfully prepared by a facile strategy of "2D self-assembly polymerization (2DSP)" via free radical polymerization in solution. A bola amphiphile containing azobenzene as a novel monomer is designed and synthesized. The results indicate that single-layer covalent pseudo-2D polymers on a micrometer scale are obtained after polymerization with vinyl monomers. Moreover, the 2D polymer sheets are highly sensitive to UV light due to incorporation of azobenzene groups into the polymer. Upon alternative irradiation with UV and visible light, the morphological transformation between sheets and rolled-up nanotubes can be achieved based on the reversible trans-to-cis photoisomerization of azobenzene units in the 2D polymer sheets. PMID- 29722088 TI - Declarative virtual water maze learning and emotional fear conditioning in primary insomnia. AB - Healthy sleep restores the brain's ability to adapt to novel input through memory formation based on activity-dependent refinements of the strength of neural transmission across synapses (synaptic plasticity). In line with this framework, patients with primary insomnia often report subjective memory impairment. However, investigations of memory performance did not produce conclusive results. The aim of this study was to further investigate memory performance in patients with primary insomnia in comparison to healthy controls, using two well characterized learning tasks, a declarative virtual water maze task and emotional fear conditioning. Twenty patients with primary insomnia according to DSM-IV criteria (17 females, three males, 43.5 +/- 13.0 years) and 20 good sleeper controls (17 females, three males, 41.7 +/- 12.8 years) were investigated in a parallel-group study. All participants completed a hippocampus-dependent virtual Morris water maze task and amygdala-dependent classical fear conditioning. Patients with insomnia showed significantly delayed memory acquisition in the virtual water maze task, but no significant difference in fear acquisition compared with controls. These findings are consistent with the notion that memory processes that emerge from synaptic refinements in a hippocampal-neocortical network are particularly sensitive to chronic disruptions of sleep, while those in a basic emotional amygdala-dependent network may be more resilient. PMID- 29722089 TI - Centrosymmetric Thiophenemethyleneoxindole-Based Donor-Acceptor Copolymers for Organic Field-Effect Transistors. AB - Two novel, donor-acceptor-type pi-conjugated polymers (P1 and P2) with 3' (thieno[3,2-b]thiophene-2,5-diylbis(methan-1-yl-1-ylidene))bis-(indolin-2-one) (ITTI) as the acceptor and thiophene/bithiophene as the donor are designed and synthesized by palladium-catalyzed Stille coupling. The optical and electrochemical properties of these polymers are characterized and further implemented into organic field-effect transistors (OFET). Both polymers exhibit excellent thermal stability, broad UV-vis absorption, and high highest occupied molecular orbital energy levels. Thermal annealing induces a well-ordered structure, a highly planar pi-system (oxygen-sulfur interaction), and a bathochromic shift in the polymers; furthermore, significant enhancement of the long wavelength intensity is also observed. Both polymers exhibit p-type charge transport behavior, with hole mobilities up to 0.51 cm2 V-1 s-1 for P1 and 0.65 cm2 V-1 s-1 for P2. This work demonstrates that ITTI can be a promising building block for the construction of donor-acceptor polymers with high-performance OFETs. PMID- 29722090 TI - Controlled Delivery of Insulin Using Rapidly Separating Microneedles Fabricated from Genipin-Crosslinked Gelatin. AB - Rapidly separating genepin-crosslinked gelatin (RS-GC) microneedles (MNs) mounted on the polyvinyl alcohol (PVA)-coated polylactic acid (PLA) MNs (RS-PGC-MNs) are fabricated, in which GC-MNs deliver insulin within the skin and the PLA supporting array is easily separated by the dissolution of the PVA layer. The release of insulin is controlled by utilizing the virtue of genipin as a crosslinking agent for producing biocompatible GC-MNs. The degree of crosslinking enhances the mechanical strength as well as humidity resistance. The in vitro and in vivo insulin release tests show significant changes in the release rates in the RS-PGC-MNs with different crosslinking degree. The hypoglycemic effect in diabetic mice demonstrate that the higher crosslinking GC-MNs result in characteristic controlled insulin release compared with other treatments and prolonged effectiveness of the RS-PGC-MNs. The proposed RS-PGC-MNs is a promising device for effective use as a noninvasive and painless controlled insulin delivery system. PMID- 29722091 TI - Printable Skin-Driven Mechanoluminescence Devices via Nanodoped Matrix Modification. AB - Mechanically driven light generation is an exciting and under-exploited phenomenon with a variety of possible practical applications. However, the current driving mode of mechanoluminescence (ML) devices needs strong stimuli. Here, a flexible sensitive ML device via nanodopant elasticity modulus modification is introduced. Rigid ZnS:M2+ (Mn/Cu)@Al2 O3 microparticles are dispersed into soft poly(dimethylsiloxane) (PDMS) film and printed out to form flexible devices. For various flexible and sensitive scenes, SiO2 nanoparticles are adopted to adjust the elasticity modulus of the PDMS matrix. The doped nanoparticles can concentrate stress to ZnS:M2+ (Mn/Cu)@Al2 O3 microparticles and achieve intense ML under weak stimuli of the moving skin. The printed nano /microparticle-doped matrix film can achieve skin-driven ML, which can be adopted to present fetching augmented animations expressions. The printable ML film, amenable to large areas, low-cost manufacturing, and mechanical softness will be versatile on stress visualization, luminescent sensors, and open definitely new functional skin with novel augmented animations expressions, the photonic skin. PMID- 29722092 TI - Administration of Cripto in GRP78 overexpressed human MSCs enhances stem cell viability and angiogenesis during human MSC transplantation therapy. AB - OBJECTIVES: The purpose of this study was to explore the effectiveness of concurrent GRP78 overexpression combined with Cripto on hMSC proliferation and migration both in vitro and in vivo. Specifically, we explored whether the treatment enhances effectiveness of hMSC transplantation in ischaemic tissue. MATERIALS AND METHODS: Human MSCs obtained from human adipose tissue were cultured in alpha-minimum essential medium (Hyclone, Logan, UT, USA) supplemented with 10% (v/v) foetal bovine serum (Hyclone), 100 U mL-1 penicillin and 100 MUg mL-1 streptomycin. Murine hindlimb ischaemic model was generated with 8-week-old male nude BALB/c mice (Biogenomics, Seoul, Korea) maintained under a 12-h light/dark cycle following the established protocol with minor modification. Cellular injection was performed no later than 3 hour after surgery. Lipofectamine transfection, single-cell cultivation assay, transwell assay, scratch wound-healing migration assay, immunohistochemistry and western blotting assays were performed. RESULTS: Overexpression of GRP78 along with Cripto enhanced hMSC proliferation, migration and invasion. It increased interaction of surface GRP78 receptor with Cripto via JAK2/STAT3 pathway. We confirmed our proposed mechanism by showing that treatment with GRP78 antibody blocks the enhancement in vitro. In vivo, we observed that Cripto induced by the hypoxic environment in hindlimb ischaemic model interacts with the overexpressed GRP78 and increases hMSC proliferation, migration and invasion potentials as well as angiogenesis around transplanted ischaemic site via cytokine secretions. CONCLUSIONS: These results demonstrate supporting evidences that GRP78-Cripto combination technique offers novel strategy to enhance MSC proliferation, migration and invasion potentials as well as angiogenesis around ischaemic site, ultimately facilitating MSC-based transplantation therapy in ischaemic conditions. PMID- 29722093 TI - Geophagic earths consumed by women in western Kenya contain dangerous levels of lead, arsenic, and iron. AB - OBJECTIVES: Geophagy is commonly reported by pregnant women and children, yet its causes and consequences remain poorly understood. Therefore, we sought to determine if geophagy could contribute micronutrients and/or be a source of heavy metal exposure by examining the elemental composition of earths consumed in Kakamega, Kenya. METHODS: Ten samples of earths commonly consumed during pregnancy were collected by study enumerators and analyzed using inductively coupled plasma-atomic emission spectroscopy. Samples were either collected at markets or from walls of participants' homes, based on where participants reported most commonly sourcing their consumed earths. RESULTS: Based on estimated intakes (40 g/day), all samples had lead levels that exceeded the provisional maximum tolerable daily intake, and one sample exceeded the threshold for arsenic. Further, estimated intakes of iron for all samples were at least 8.9 times higher than the established threshold. Elemental concentrations were also compared by the site of sample collection (market vs. household wall); market samples had significantly higher iron concentrations and lower calcium concentrations than wall samples. CONCLUSIONS: Geophagic earths in Kakamega may be harmful because of dangerously high levels of lead, arsenic, and iron. The prevalence of geophagy among vulnerable populations underscores the importance of understanding its causes and consequences for accurate public health messaging. PMID- 29722094 TI - Reconfigurable Polymer Shells on Shape-Anisotropic Gold Nanoparticle Cores. AB - Reconfigurable hybrid nanoparticles made by decorating flexible polymer shells on rigid inorganic nanoparticle cores can provide a unique means to build stimuli responsive functional materials. The polymer shell reconfiguration has been expected to depend on the local core shape details, but limited systematic investigations have been undertaken. Here, two literature methods are adapted to coat either thiol-terminated polystyrene (PS) or polystyrene-poly(acrylic acid) (PS-b-PAA) shells onto a series of anisotropic gold nanoparticles of shapes not studied previously, including octahedron, concave cube, and bipyramid. These core shapes are complex, rendering shell contours with nanoscale details (e.g., local surface curvature, shell thickness) that are imaged and analyzed quantitatively using the authors' customized analysis codes. It is found that the hybrid nanoparticles based on the chosen core shapes, when coated with the above two polymer shells, exhibit distinct shell segregations upon a variation in solvent polarity or temperature. It is demonstrated for the PS-b-PAA-coated hybrid nanoparticles, the shell segregation is maintained even after a further decoration of the shell periphery with gold seeds; these seeds can potentially facilitate subsequent deposition of other nanostructures to enrich structural and functional diversity. These synthesis, imaging, and analysis methods for the hybrid nanoparticles of anisotropically shaped cores can potentially aid in their predictive design for materials reconfigurable from the bottom up. PMID- 29722095 TI - Image velocimetry and spectral analysis enable quantitative characterization of larval zebrafish gut motility. AB - BACKGROUND: Normal gut function requires rhythmic and coordinated movements that are affected by developmental processes, physical and chemical stimuli, and many debilitating diseases. The imaging and characterization of gut motility, especially regarding periodic, propagative contractions driving material transport, are therefore critical goals. Previous image analysis approaches have successfully extracted properties related to the temporal frequency of motility modes, but robust measures of contraction magnitude, especially from in vivo image data, remain challenging to obtain. METHODS: We developed a new image analysis method based on image velocimetry and spectral analysis that reveals temporal characteristics such as frequency and wave propagation speed, while also providing quantitative measures of the amplitude of gut motion. KEY RESULTS: We validate this approach using several challenges to larval zebrafish, imaged with differential interference contrast microscopy. Both acetylcholine exposure and feeding increase frequency and amplitude of motility. Larvae lacking enteric nervous system gut innervation show the same average motility frequency, but reduced and less variable amplitude compared to wild types. CONCLUSIONS & INFERENCES: Our image analysis approach enables insights into gut dynamics in a wide variety of developmental and physiological contexts and can also be extended to analyze other types of cell movements. PMID- 29722096 TI - The 14th International Workshops on Opportunistic Protists (IWOP 14). AB - The 14th International Workshops on Opportunistic Protists (IWOP-14) was held August 10-12, 2017 in Cincinnati, OH, USA. The IWOP meetings focus on opportunistic protists (OIs); for example, free-living amoebae, Pneumocystis spp., Cryptosporidium spp., Toxoplasma, the Microsporidia, and kinetoplastid flagellates. The highlights of Pneumocystis spp. research included the reports of primary homothallism for mating; a potential requirement for sexual replication in its life cycle; a new antigen on the surface of small asci; roles for CLRs, Dectin-1, and Mincle in host responses; and identification of MSG families and mechanisms used for surface variation. Studies of Cryptosporidia spp. included comparative genomics, a new cryopreservation method; the role of mucin in attachment and invasion, and epidemiological surveys illustrating species diversity in animals. One of the five identified proteins in the polar tube of Microsporidia, PTP4, was shown to play a role in host infection. Zebrafish were used as a low cost vertebrate animal model for an evaluation of potential anti toxoplasma drugs. Folk medicine compounds with anti-toxoplasma activity were presented, and reports on the chronic toxoplasma infection provided evidence for increased tractability for the study of this difficult life cycle stage. Escape from the parasitophorus vacuole and cell cycle regulation were the topics of the study in the acute phase. PMID- 29722097 TI - Productive and economic parameters of pigs supplemented from weaning to finishing with prebiotic and probiotic feed additives. AB - Practical evidence suggests possible beneficial effects with the combined use of prebiotics and probiotics which can improve production parameters. The objective of the study was to investigate the addition of Saccharomyces cerevisiae (SC) as prebiotic and the combination of Lactobacillus spp. (L), Bacillus spp. (B) as probiotics on productive parameters and economic feasibility. Four hundred male pigs, hybrids of commercial genetic lines (Pietrain), were used: T1 = control group, T2 = 4 kg/tonne SC, T3 = 0.8 kg/tonne feed L and B, T4 = 4 kg/tonne SC + 0.8 kg/tonne L and B. Productive parameters were recorded in the treatment groups for four periods. Then, the viscera of five pigs per treatment were collected after slaughter to evaluate the histological changes and cytokine concentrations in the ileum. The weight gains of groups at 70-100, 100-125 and 125-150 days in the T4 group showed statistically increases (p < .05). Feed intake had a significant difference (p < .05) in T3 versus T1. The feed-conversion ratio improved for all periods in the T4 group (p < .05). The eosinophil, mononuclear infiltration and cytokines (tumor necrosis factor-alpha and interleukin-6) in the mucosa were lower for treatments with probiotics. In conclusion, there was an economic benefit when using both prebiotics and probiotics in the diet of pigs from weaning to finishing. PMID- 29722098 TI - Does LINE addiction exist? Potential concerns about Japan's most popular form of social media on smartphones. PMID- 29722099 TI - Deficient supplementary motor area at rest: Neural basis of limb kinetic deficits in Parkinson's disease. AB - Parkinson's disease (PD) patients frequently suffer from limb kinetic apraxia (LKA) affecting quality of life. LKA denotes an impairment of precise and independent finger movements beyond bradykinesia, which is reliably assessed by coin rotation (CR) task. BOLD fMRI detected activation of a left inferior parietal-premotor praxis network in PD during CR. Here, we explored which network site is most critical for LKA using arterial spin labeling (ASL). Based on a hierarchical model, we hypothesized that LKA would predominantly affect the functional integrity of premotor areas including supplementary motor areas (SMA). Furthermore, we suspected that for praxis function with higher demand on temporal spatial processing such as gesturing, inferior parietal lobule (IPL) upstream to premotor areas would be essential. A total of 21 PD patients and 20 healthy controls underwent ASL acquisition during rest. Behavioral assessment outside the scanner involved the CR, finger tapping task, and the test of upper limb apraxia (TULIA). Whole-brain analysis of activity at rest showed a significant reduction of CR-related perfusion in the left SMA of PD. Furthermore, the positive correlation between SMA perfusion and CR, seen in controls, was lost in patients. By contrast, TULIA was significantly associated with the perfusion of left IPL in both patients and controls. In conclusion, the findings suggest that LKA in PD are linked to an intrinsic disruption of the left SMA function, which may only be overcome by compensatory network activation. In addition, gestural performance relies on IPL which remains available for functional recruitment in early PD. PMID- 29722100 TI - Estimating pediatric general anesthesia exposure: Quantifying duration and risk. AB - INTRODUCTION: Understanding the duration of pediatric general anesthesia exposure in contemporary practice is important for identifying groups at risk for long general anesthesia exposures and designing trials examining associations between general anesthesia exposure and neurodevelopmental outcomes. METHODS: We performed a retrospective cohort analysis to estimate pediatric general anesthesia exposure duration during 2010-2015 using the National Anesthesia Clinical Outcomes Registry. RESULTS: A total of 1 548 021 pediatric general anesthetics were included. Median general anesthesia duration was 57 minutes (IQR: 28-86) with 90th percentile 145 minutes. Children aged <1 year had the longest median exposure duration (79 minutes, IQR: 39-119) with 90th percentile 210 minutes, and 13.7% of this very young cohort was exposed for >3 hours. High ASA physical status and care at a university hospital were associated with longer exposure times. CONCLUSION: While the vast majority (94%) of children undergoing general anesthesia are exposed for <3 hours, certain groups may be at increased risk for longer exposures. These findings may help guide the design of future trials aimed at understanding neurodevelopmental impact of prolonged exposure in these high-risk groups. PMID- 29722101 TI - Recent developments in the genetics of attention-deficit hyperactivity disorder. AB - Attention-deficit hyperactivity disorder (ADHD) is a developmental psychiatric disorder that affects children and adults. ADHD is one of the psychiatric disorders with the strongest genetic basis according to familial, twin, and single nucleotide polymorphisms (SNP)-based epidemiological studies. In this review, we provide an update of recent insights into the genetic basis of ADHD. We discuss recent progress from genome-wide association studies (GWAS) looking at common variants as well as rare copy number variations. New analysis of gene groups, so-called functional ontologies, provide some insight into the gene networks afflicted, pointing to the role of neurodevelopmentally expressed gene networks. Bioinformatic methods, such as functional enrichment analysis and protein-protein network analysis, are used to highlight biological processes of likely relevance to the etiology of ADHD. Additionally, copy number variations seem to map on important pathways implicated in synaptic signaling and neurodevelopment. While some candidate gene associations of, for example, neurotransmitter receptors and signaling, have been replicated, they do not seem to explain significant variance in recent GWAS. We discuss insights from recent case-control SNP-GWAS that have presented the first whole-genome significant SNP in ADHD. PMID- 29722102 TI - Ultrathin Titanate Nanosheets/Graphene Films Derived from Confined Transformation for Excellent Na/K Ion Storage. AB - Confined transformation of assembled two-dimensional MXene (titanium carbide) and reduced graphene oxide (rGO) nanosheets was employed to prepare the free-standing films of the integrated ultrathin sodium titanate (NTO)/potassium titanate (KTO) nanosheets sandwiched between graphene layers. The ultrathin Ti-based nanosheets reduce the diffusion distance while rGO layers enhance conductivity. Incorporation of graphene into the titanate films produced efficient binder-free anodes for ion storage. The resulting flexible NTO/rGO and KTO/rGO electrodes exhibited excellent rate performances and long cycling stability characterized by reversible capacities of 72 mA h g-1 at 5 A g-1 after 10000 cycles and 75 mA h g 1 after 700 cycles at 2 A g-1 for sodium and potassium ion batteries, respectively. These results demonstrate the superiority of the unique sandwich type electrodes. PMID- 29722103 TI - Synthesis of Sub-100 nm Glycosylated Nanoparticles via a One Step, Free Radical, and Surfactant Free Emulsion Polymerization. AB - The facile synthesis of sub-100 nm glyco nanoparticles is presented via a one step, free radical, and surfactant free emulsion polymerization. It is shown that by using sterically large, hydrophilic glycomonomers such as a lactose acrylamide with the charged azo initiator 4,4'-azobis(4-cyanovaleric acid), growing particles are stabilized enough to reproducibly produce well defined (PDi <= 0.1) glycoparticles with diameters below 100 nm. PMID- 29722105 TI - A therapist version of the Alliance Negotiation Scale. AB - The aim of the current study was to design and evaluate a therapist version of the Alliance Negotiation Scale (ANS). The ANS was created in order to operationalize the construct of dyadic negotiation in psychotherapy and to augment existing conceptualizations of the working alliance. The ANS has existed only as a client self-report form since its inception and has demonstrated promise as a psychotherapy process measure. This research intended to develop a complementary therapist self-report version of the measure. The scale creation process is discussed in detail, and the results of a preliminary psychometric investigation are reported. The ANS-Therapist version (ANS-T) was developed using a sample of therapists (n = 114) through a principal components analysis procedure. The ANS-T contains 9 unidimensional items and was moderately correlated with therapist-reported working alliance (r = .468). The results of the study support the composition of the ANS-T and provide initial support for the reliability and validity of the measure. PMID- 29722104 TI - Long noncoding RNA NORAD regulates transforming growth factor-beta signaling and epithelial-to-mesenchymal transition-like phenotype. AB - Long noncoding RNAs are involved in a variety of cellular functions. In particular, an increasing number of studies have revealed the functions of long noncoding RNA in various cancers; however, their precise roles and mechanisms of action remain to be elucidated. NORAD, a cytoplasmic long noncoding RNA, is upregulated by irradiation and functions as a potential oncogenic factor by binding and inhibiting Pumilio proteins (PUM1/PUM2). Here, we show that NORAD upregulates transforming growth factor-beta (TGF-beta) signaling and regulates TGF-beta-induced epithelial-to-mesenchymal transition (EMT)-like phenotype, which is a critical step in the progression of lung adenocarcinoma, A549 cells. However, PUM1 does not appear to be involved in this process. We thus focused on importin beta1 as a binding partner of NORAD and found that knockdown of NORAD partially inhibits the physical interaction of importin beta1 with Smad3, inhibiting the nuclear accumulation of Smad complexes in response to TGF-beta. Our findings may provide a new mechanism underlying the function of NORAD in cancer cells. PMID- 29722106 TI - Renewable Polyethers via GaBr3 -Catalyzed Reduction of Polyesters. AB - Herein, a novel approach is reported for the synthesis of medium- and long-chain aliphatic polyethers 2 based on the GaBr3 -catalysed reduction of polyesters 1 with TMDS as the reducing agent. Thus, various linear and branched aliphatic polyesters 1 were prepared and systematically investigated for this reduction strategy, demonstrating the applicability and versatility of this new polyether synthesis protocol. Medium- and long-chain chain polyethers were obtained from the respective polyesters without or with minor chain degradation, whereas short chain polyesters, such as poly-l-lactide 1 i and poly[(R)-3-hydroxybutanoate] 1 j, showed major chain degradation. In this way, previously unavailable and uncommon polyethers were obtained and studied. PMID- 29722107 TI - Key roles of hepatologists in successful liver transplantation. AB - Liver transplantation (LT) has been carried out for acute liver failure, end stage liver disease, and congenital metabolic disease in more than 7000 cases in Japan. Liver transplantation has been established as a treatment option, and survival rates have improved. In 2016, a new registration/allocation policy and a new scoring system for deceased donor LT were established. The management of perioperative patients and preoperative therapy for liver failure, nutrition, and preventing infection were upgraded. Moreover, methods for preventing disease recurrence, and treating hepatitis C and B have been developed and are particularly crucial for good outcomes in LT. Treatment of the complications of obesity, lifestyle-related diseases, and malignancy is also required post-LT. Managing patients after LT contributes to better survival and quality of life. The role of hepatologists is becoming broader and more important. PMID- 29722108 TI - Asymmetric Covalent Triazine Framework for Enhanced Visible-Light Photoredox Catalysis via Energy Transfer Cascade. AB - Complex multiple-component semiconductor photocatalysts can be constructed that display enhanced catalytic efficiency via multiple charge and energy transfer, mimicking photosystems in nature. In contrast, the efficiency of single-component semiconductor photocatalysts is usually limited due to the fast recombination of the photogenerated excitons. Here, we report the design of an asymmetric covalent triazine framework as an efficient organic single-component semiconductor photocatalyst. Four different molecular donor-acceptor domains are obtained within the network, leading to enhanced photogenerated charge separation via an intramolecular energy transfer cascade. The photocatalytic efficiency of the asymmetric covalent triazine framework is superior to that of its symmetric counterparts; this was demonstrated by the visible-light-driven formation of benzophosphole oxides from diphenylphosphine oxide and diphenylacetylene. PMID- 29722109 TI - Toxoplasma gondii Histone 4 Affects Some Functions of Murine Ana-1 Macrophages In Vitro. AB - Toxoplasma gondii (T. gondii) is an obligate intracellular protozoan that can infect almost all nucleated cells. Histone proteins and DNA form the nucleosomes, which are the fundamental building blocks of eukaryotic chromatin. Histone 4 is an essential component of a histone octamer. In the present study, T. gondii histone 4 (TgH4) was cloned and the regulatory effect of TgH4 on murine macrophages was characterized. Bioinformatics analysis revealed that TgH4 was highly conserved in structure. Recombinant TgH4 (rTgH4) protein was identified by sera from rats experimentally infected with T. gondii and native TgH4 in the total soluble protein of T. gondii tachyzoites was recognized by polyclonal antibodies against rTgH4, as indicated by immunoblotting analysis. Immunofluorescence assay showed that TgH4 binds to macrophages. Following incubation with rTgH4, the toll-like receptor 4 (TLR4) level of the macrophages was downregulated. Meanwhile, chemotaxis and the proliferation of macrophages were inhibited. However, rTgH4 can promote phagocytosis, apoptosis, and the secretion of nitric oxide, interleukin-6, and tumor necrosis factor-alpha from macrophages. Just 80 MUg/ml rTgH4 can significantly elevate the secretion of interleukin-10 and interleukin-1beta (p < 0.05 and p < 0.01). Viewed together, these outcomes indicated that rTgH4 can affect the functions of murine macrophages in vitro. PMID- 29722110 TI - Biochemical Comparison of 8-hour Haemodialysis and 4-hour Haemodiafiltration, and Two Dialysis Membranes, in a Randomised Cross-over Trial. AB - AIM: Extended-hours haemodialysis has long been regarded as the optimal form of dialysis for solute clearance. With emerging benefits of haemodiafiltration, we wanted to compare these two head-to-head. METHODS: In this randomised cross-over trial, we recruited existing nocturnal haemodialysis patients, who had not been hospitalised in the prior three months. After a baseline 8-hour haemodialysis session, subjects were randomised to either 2 weeks of 8-hour haemodialysis or 4 hour haemodiafiltration with cross-over to the alternative treatment after a 2 week washout period. Subjects were additionally randomised to the Fresenius FX80 or Nipro Elisio in a parallel design. Blood and dialysate samples were collected at baseline and at the end of both study periods. RESULTS: 12 patients completed the study. Mean (SD) age and body mass index were 55.1 +/-11.5 years and 36.4 +/ 10.8 respectively. Urea and creatinine reduction ratios were higher with extended hours haemodialysis compared to haemodiafiltration (difference 14.0%, 95% CI 10.6,17.3, p<0.001 & 9.1% 95% CI 11.0,7.2, p<0.001). Fibroblast growth factor 23 (FGF23) clearance was superior with haemodiafiltration (difference 20.1%, 95% CI 8.7,31.6, p=0.001). No difference was seen in reduction ratios for phosphate, retinol binding protein, alpha-1-microglobulin, beta-2-microglobulin and fetuin with both modalities. Compared to Nipro Elisio, Fresenius FX80 dialyser achieved higher beta-2-microglobulin clearance (Period 1:difference 7.8%, 95% CI 1.3, 14.4, P=0.02, Period 2:7.5%, 95% CI 1.0, 14.1, p=0.02). CONCLUSIONS: Small solute clearance was superior with extended-hours haemodialysis while haemodiafiltration enhanced FGF23 clearance. Beta-2-microglobulin clearance was improved with Fresenius FX80 dialyser, but this difference is unlikely to be clinically significant. PMID- 29722111 TI - An Abnormal 3.7 Volt O3-Type Sodium-Ion Battery Cathode. AB - Layered O3-type sodium oxides (NaMO2 , M=transition metal) commonly exhibit an O3 P3 phase transition, which occurs at a low redox voltage of about 3 V (vs. Na+ /Na) during sodium extraction and insertion, with the result that almost 50 % of their total capacity lies at this low voltage region, and they possess insufficient energy density as cathode materials for sodium-ion batteries (NIBs). Therefore, development of high-voltage O3-type cathodes remains challenging because it is difficult to raise the phase-transition voltage by reasonable structure modulation. A new example of O3-type sodium insertion materials is presented for use in NIBs. The designed O3-type Na0.7 Ni0.35 Sn0.65 O2 material displays a highest redox potential of 3.7 V (vs. Na+ /Na) among the reported O3 type materials based on the Ni2+ /Ni3+ couple, by virtue of its increased Ni-O bond ionicity through reduced orbital overlap between transition metals and oxygen within the MO2 slabs. This study provides an orbital-level understanding of the operating potentials of the nominal redox couples for O3-NaMO2 cathodes. The strategy described could be used to tailor electrodes for improved performance. PMID- 29722112 TI - The development of central venous thrombosis in hemodialyzed patients is associated with catheter tip depth and localization. AB - INTRODUCTION: The aim of our work was to analyze the incidence of tunneled hemodialysis catheters-related thrombosis in hemodialyzed patients depending on catheter tip depth and position and to evaluate the impact of other established risk factors responsible for development of central venous thrombosis. METHODS: The presence of central vein thrombosis, location, and the depth of the catheter tip was reviewed by two experienced radiologists. All patients with suspected central venous thrombosis had factor V Leiden, lupus anticoagulant, and cardiolipin antibodies checked (acIgM and acIgG) and were evaluated with cat-scan venography. FINDINGS: A total of 68 tunneled hemodialysis catheters were analyzed with CT venography for central venous thrombosis. There were no signs of central venous thrombosis when catheter tips were placed in the right atrium. There was significantly higher number of catheter tips located on the vein wall than located centrally in patients with central venous thrombosis. Higher percentage of central venous thrombosis, smaller number of tips placed in the right atrium, higher values of IgM cardiolipin antibodies, and higher number of patients with positive factor V Leiden mutation were found in group of patients with catheter tips located on vein wall. DISCUSSION: Higher incidence of central venous thrombosis in patients with the catheter tip placed on the vein wall is a consequence of a catheter tip depth proximal of the right atrium. Increased factor V Leiden mutation and acIgM values in these patients should be observed as a result of the vein stasis caused by inappropriate catheter tip depth and localization. PMID- 29722115 TI - Editorial: Year 2017 report. PMID- 29722113 TI - Primary aldosteronism in patients with adrenal incidentaloma: Is screening appropriate for everyone? AB - Primary aldosteronism (PA) is a common form of secondary hypertension. Several guidelines recommend that patients with adrenal incidentaloma have a high probability of suffering from PA. We conducted a prospective study of 269 consecutive adults with adrenal incidentaloma to investigate the prevalence and clinical characteristics of PA. In total, 9 participants were detected with PA, suggesting a prevalence of 3.35% among the study population. PA participants had a higher blood pressure level by 14/20.8 mm Hg and a lower serum potassium level by 0.8 mmol/L (P < .05). Importantly, all patients with PA presented with concurrent indications (hypertension with or without hypokalemia) for screening of the disease, but they have not undergone relative screening by the referring physician, thus casting doubts about the appropriate implementation of current guidelines in real-life practice. Intense efforts are needed to familiarize physicians with recommendations for PA to minimize undiagnosed cases and the detrimental sequelae of this endocrine form of hypertension. PMID- 29722116 TI - Blood glucose reduction by diabetic drugs with minimal hypoglycaemia risk for cardiovascular outcomes: Evidence from meta-regression analysis of randomized controlled trials. AB - AIMS: To investigate the effects of blood glucose control with antihyperglycaemic agents with minimal hypoglycaemia risk on cardiovascular outcomes in patients with type 2 diabetes (T2D). MATERIALS AND METHODS: Randomized controlled trials (RCTs) comparing the relative efficacy and safety of antidiabetic drugs with less hypoglycaemia risk were comprehensively researched in MEDLINE, Embase and the Cochrane Library up to January 27, 2018. Mixed-effects meta-regression analysis was conducted to explore the relationship between haemoglobin A1c (HbA1c) reduction and the risk of major adverse cardiovascular events (MACE), myocardial infarction, stroke, cardiovascular death, all-cause death, and hospitalization for heart failure. RESULTS: Ten RCTs comprising 92 400 participants with T2D were included and provided information on 9773 MACE during a median follow-up of 2.6 years. The mean HbA1c concentration was 0.42% lower (range, 0.27%-0.86%) for participants given antihyperglycaemic agents than those given placebo. The meta regression analysis demonstrated that HbA1c reduction was significantly associated with a decreased risk of MACE (beta value, -0.39 to -0.55; P < 0.02) even after adjusting for possible confounding factors including age, sex, baseline HbA1c, duration of follow-up, difference in achieved systolic blood pressure, difference in achieved body weight, and risk difference in hypoglycaemia. Lowering HbA1c by 1% conferred a significant risk reduction of 30% (95% confidence interval, 17%-40%) for MACE. By contrast, the meta-regression analysis for trials using conventional agents failed to demonstrate a significant relationship between achieved HbA1c difference and MACE risk (P > 0.74). CONCLUSIONS: Compared with placebo, newer T2D agents with less hypoglycaemic hazard significantly reduced the risk of MACE. The MACE reduction appears to be associated with HbA1c reduction in a linear relationship. PMID- 29722117 TI - Upregulation of CD80 on glomerular podocytes plays an important role in development of proteinuria following pig-to-baboon xeno-renal transplantation - an experimental study. AB - We have previously reported that co-transplantation of the kidney with vascularized donor thymus from alpha-1,3-galactosyltransferase gene knockout pigs with an anti-CD154 with rituximab-based regimen led to improved xenograft survival in baboons with donor-specific unresponsiveness. However, nephrotic syndrome emerged as a complication in which the glomeruli showed mild mesangial expansion with similarities to minimal change disease (MCD) in humans. Since MCD is associated with CD80 expression in glomeruli and elevated urinary excretion, we evaluated a potential role for CD80 in xenograft nephropathy. Study 1 confirmed high urinary CD80 excretion in nephrotic animals with renal xenografts showing CD80 expression in glomeruli. In Study 2, baboons receiving xenografts received CTLA4-Ig once a week from the second postoperative week or no CTLA4-Ig. The non-CTLA4-Ig group developed severe proteinuria with modest mesangial expansion with high urinary excretion of CD80 and documented CD80 expression in glomerular podocytes. All of the recipients in non-CTLA4-Ig groups had to be euthanized before POD 60. In contrast, CTLA4-Ig group showed a marked reduction in proteinuria and survived significantly longer, up to 193 days. These results demonstrate that anti-CD80 targeted therapy represents a promising strategy for reduction of proteinuria following renal xeno-transplantation with improved survival. PMID- 29722118 TI - Multiple target site resistance to glyphosate in junglerice (Echinochloa colona) lines from California orchards. AB - BACKGROUND: In California specialty cropping systems such as vineyards and orchards, Echinochloa colona is present as a summer annual weed. It is able to germinate throughout the growing season whenever favorable conditions are present, and management relies heavily on glyphosate applications. Glyphosate resistant (GR) E. colona biotypes are present in the state, but the levels of resistance observed suggest that there may be differences in mechanisms of resistance among populations. RESULTS: Echinochloa colona lines collected from different regions of California's Central Valley presented resistance levels ranging from 1.4 to 4.3-fold compared to susceptible lines. No differences in the absorption and translocation of [14 C]-glyphosate were observed among lines. Resistant lines accumulated eight-fold less shikimic acid after treatment with 435 and 870 g a.e. ha-1 glyphosate compared to the most susceptible line. Sequencing of a region of the EPSPS gene revealed three single nucleotide changes leading to amino acid substitutions at Proline 106, including Pro106Leu, Pro106Thr and Pro106Ser. CONCLUSION: These results indicate that an altered target site in EPSPS is contributing to resistance in these lines and resistance has evolved independently, multiple times in the Central Valley of California. Additional research is needed to further understand the genomic contributions of resistance loci in this polyploid weed species. (c) 2018 Society of Chemical Industry. PMID- 29722119 TI - Development of mesoporous bioactive glass nanoparticles and its use in bone tissue engineering. AB - The incidence of bone disorders, from trauma, tissue degeneration due to ageing, pathological conditions to cancer, has been increasing. The pursuit for bone graft substitutes to assist in regenerating large bone defects is ever growing as a result of the shortage in conventional autografts and allografts, in addition to the associated risks of disease transmission. However, the use of alloplastic biomaterials is limited in clinical settings, as further investigations are required to address the properties of synthetic grafts to mimic the native bone tissue and deliver desirable biomolecules to facilitate bone regeneration. This review discusses the fundamental structure and properties of bone with the emphasis on organic and inorganic components that are important for the biomaterial design. The main focus will be on the advancement and usage of bioactive glass (BG) for bone tissue engineering due to its similarity to the natural inorganic constituent of bone. The various BG synthetic processes, modifications of composition, as well as the biomolecule delivery will be discussed in great detail. As the properties of BG are tuneable according to clinical needs, it creates a new paradigm in addition to displaying its superior potential for bone tissue engineering and translational medicine in the field of orthopedic surgery. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 106B: 2878-2887, 2018. PMID- 29722120 TI - Comparative efficacy of anti-CD40 antibody-mediated costimulation blockade on long-term survival of full-thickness porcine corneal grafts in nonhuman primates. AB - Porcine corneas may be good substitutes for human corneas in donor shortage. Therefore, we evaluated the efficacy and safety of an anti-CD40 antibody-based regimen compared with an anti-CD20 antibody-based regimen on the survival of full thickness corneas in pig-to-rhesus xenotransplant. Thirteen Chinese rhesuses underwent full-thickness corneal xenotransplant. Six were administered anti-CD40 antibody, and the others were administered anti-CD20 antibody, basiliximab, and tacrolimus. Graft survival and changes in lymphocyte, donor-specific and anti Galalpha1,3Galbeta1,4GlcNAc-R (alphaGal) antibody, and aqueous complement levels were evaluated. Treatment with the anti-CD40 antibody (>511, >422, >273, >203, >196, 41 days) and anti-CD20 antibody (>470, 297, >260, >210, >184, 134, >97 days) resulted in long-term survival of grafts. In the anti-CD20 group, the number of activated B cells was significantly lower than that in the anti-CD40 group, and the level of aqueous complements at 6 months was significantly higher than the preoperative level. There were no differences in the levels of T cells or donor-specific and anti-alphaGal antibodies between the 2 groups. In the anti CD20 group, 3 primates had adverse reactions. In conclusion, both the anti-CD40 antibody- and the anti-CD20 antibody-based protocols were effective for the long term survival of full-thickness corneal xenografts, but the anti-CD40 antibody based treatment had fewer adverse effects. PMID- 29722121 TI - In vivo confocal microscopy characteristics of equine epithelial and subepithelial nonulcerative keratomycosis. AB - OBJECTIVE: To describe the in vivo confocal microscopy features of horses with epithelial and subepithelial nonulcerative keratomycosis. ANIMALS STUDIED: Four horses with a clinical diagnosis of epithelial or subepithelial keratomycosis. PROCEDURES: Horses were examined on one or more occasions by in vivo laser scanning confocal microscopy of the cornea. Confocal microscopic examination characteristics were correlated with clinical, cytological, and histopathological findings for the horses. RESULTS: All horses had an irregular corneal epithelial surface during slit-lamp biomicroscopy examination. Epithelial or subepithelial corneal opacities were present in multifocal or diffuse patterns. Positive rose bengal corneal staining was present focally or diffusely in all cases. Fungal hyphae were detected in cytological or histopathological corneal samples from all horses. Aspergillus, Fusarium, and Penicillium spp. were cultured from corneal samples. Confocal microscopy detected hyphae diffusely distributed over the axial cornea in horses with epithelial clinical disease. Fungal hyphae were present in all layers of the corneal epithelium and associated with disorganized and sloughing epithelial cells with minimal leukocytes. Subepithelial keratomycosis was correlated with focal, dense accumulations of hyphae in the immediate subepithelial anterior stroma that were surrounded by moderate numbers of leukocytes. Two horses were examined by confocal microscopy on multiple occasions during the course of medical therapy, and fungal hyphae were observed to migrate from the epithelium into the subepithelial stroma as the clinical corneal disease progressed. CONCLUSIONS: With in vivo confocal microscopy, both epithelial and subepithelial keratomycosis appear as unique clinical entities. Equine epithelial keratomycosis is a potential precursor to subepithelial keratomycosis. PMID- 29722122 TI - A comparison of the bone regeneration and soft-tissue-formation capabilities of various injectable-grafting materials in a rabbit calvarial defect model. AB - Restoring adequate blood supply is essential to the success of bone repair and augmentation procedures in craniofacial surgery. Nevertheless, the manner by which the incorporation of collagen gels (which can potentially induce angiogenesis), particulated deproteinized bovine bone grafts, or a combination of both can accelerate or delay bone regeneration in a clinical setting remains controversial. The objective of this study was to evaluate radiographically and histologically the capacity and functionality of particulated bone grafts and collagen gels on bone ossification and soft tissue formation in a rabbit calvarial defect. Bilateral calvarial defects in adult white New Zealand rabbits were filled or left either unfilled with bone grafts (DBBM), collagen gels (Gel), or a combination of both (DBBM + Gel). The defects were allowed to heal for 1, 2, and 6 months postoperatively before termination. Healing and regeneration patterns were assessed by 3D uCT and histological methods, and the biomechanical properties of regenerated tissue constructs were investigated and compared with autogenous calvarial bone. Results show that implanted DBBM and DBBM + Gel significantly enhanced immature bone formation compared with the empty and Gel groups; the latter treatment improved soft tissue formation and impeded immature bone formation but yielded no significant effect on mature bone formation. Implantation of DBBM not only effectively reconstructed 188.83 +/- 25.25% of the tissue volume of the original defect, but it also regenerated bone tissue with similar tissue composition and biomechanical properties as the original autogenous bone. We also show that implanting different biomaterials can control the composition of soft and hard tissue in reconstructed tissue constructs in calvarial bone defects. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. PMID- 29722123 TI - A tricalcium phosphate/polyether ether ketone anchor bionic fixation device for anterior cruciate ligament reconstruction: Safety and efficacy in a beagle model. AB - The goal of this study was to develop a bionic fixation device based on the use of a tricalcium phosphate/polyether ether ketone anchor and harvesting of the ulnar carpal flexor muscle tendon for application as a ligament graft in a beagle anterior cruciate ligament (ACL) reconstruction model, with the goal of accelerating the ligament graft-to-bone tunnel healing and providing a robust stability through exploration of this new kind of autologous ligament graft. The safety and efficacy of this fixation device were explored 3 and 6 months after surgery in a beagle ACL reconstruction model using biomechanical tests and comprehensive histological observation. The data were compared using a two-tailed Student's t test and a paired t test. A p value <0.05 was defined as statistically significant. All the models were successfully established. This fixation device possessed the excellent mechanical properties for ACL reconstruction. A comprehensive histological observation revealed that a cartilage layer was visible in the transition zone between the tendon and bone interface at both 3 and 6 months postoperation. The trabecular of the new bone was observed six months after surgery and was found to be similar to a direct connection. This fixation technique provided not only a robust primary mechanical fixation but also a bionic fixation for long-term knee joint stability by accelerating the healing of the tendon to the bone tunnel, showing a high potential for use in clinical practice. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. PMID- 29722125 TI - Sample size determination and treatment screening in two-stage phase II clinical trials via ROC curve. AB - In pharmaceutical-related research, we usually use clinical trials methods to identify valuable treatments and compare their efficacy with that of a standard control therapy. Although clinical trials are essential for ensuring the efficacy and postmarketing safety of a drug, conducting clinical trials is usually costly and time-consuming. Moreover, to allocate patients to the little therapeutic effect treatments is inappropriate due to the ethical and cost imperative. Hence, there are several 2-stage designs in the literature where, for reducing cost and shortening duration of trials, they use the conditional power obtained from interim analysis results to appraise whether we should continue the lower efficacious treatments in the next stage. However, there is a lack of discussion about the influential impacts on the conditional power of a trial at the design stage in the literature. In this article, we calculate the optimal conditional power via the receiver operating characteristic curve method to assess the impacts on the quality of a 2-stage design with multiple treatments and propose an optimal design using the minimum expected sample size for choosing the best or promising treatment(s) among several treatments under an optimal conditional power constraint. In this paper, we provide tables of the 2-stage design subject to optimal conditional power for various combinations of design parameters and use an example to illustrate our methods. PMID- 29722124 TI - New Flavonoid Glucuronate Esters with Anti-inflammatory Activities from Scutellaria regeliana. AB - Two new flavonoid glucuronate esters, named scuregeliosides A and B (1 and 2), as well as three known ones, chrysin-7-O-beta-d-glucuronic acid methyl ester (3), 5,7,4'-trihydroxyflavone-8-O-beta-d-glucuronic acid methyl ester (4) and apigenin 7-O-beta-d-glucuronic acid ethyl ester (5), were isolated from the ethanolic extract of the whole plant of Scutellaria regeliana. Their chemical structures were elucidated on the basis of comprehensive spectroscopic analyses. Five compounds were screened for anti-inflammatory activity in vitro. As the results, the inhibition rates of release of beta-glucuronidase from rat polymorphonuclear leukocytes were in the range of 42.2 - 47.1% at a concentration of 10 MUm. PMID- 29722126 TI - Reproducibility of gastric emptying assessed with scintigraphy in patients with upper GI symptoms. AB - BACKGROUND: The reproducibility of gastric emptying (GE) measured with scintigraphy in patients is poorly understood. Our aims were to assess the intra and inter-individual reproducibility of these parameters in patients with upper gastrointestinal symptoms. METHODS: Sixty patients (21 diabetics, 39 non diabetics) with upper gastrointestinal symptoms underwent scintigraphic assessment of GE of a solid meal (296 kcal, 30% fat) over 4 hours on two occasions at an average interval of 15 days. The concordance correlation coefficient (CCC), intra and inter-individual coefficients of variation (COV) of GE endpoints were analyzed. RESULTS: The GE t1/2 was 134 +/- 8 minutes (mean +/- SEM) for the first and 128 +/- 6 minutes for the second study. The mean (95% CI) CCC between the two studies was 0.79 (0.67, 0.87) for GE at 1 hour, 0.83 (0.75, 0.9) for GE at 2 hours, 0.54 (0.34, 0.7) for GE at 4 hours, and 0.79 (0.68, 0.86) for GE t1/2 . However, in 18 of 60 patients (30%), the characterization of GE as normal, delayed, or rapid differed between the first and second studies. For gastric empting t1/2 , the inter-individual coefficients of variation was 40%; the intra-individual COV was 20%, comparable in diabetics and non-diabetics, and greater in patients with rapid (28%) than delayed (18%) or normal GE (12%). CONCLUSIONS & INFERENCES: Among patients with upper gastrointestinal symptoms, GE measured with scintigraphy is relatively reproducible. In 30% of cases, the interpretation was different between the two assessments. Hence, a diagnosis of gastroparesis based on a single study may occasionally be inaccurate. PMID- 29722127 TI - The SHH/Gli axis regulates CD90-mediated liver cancer stem cell function by activating the IL6/JAK2 pathway. AB - The cell surface antigen CD90 has recently been established as a promising marker for liver cancer stem cells. This study aimed to investigate potential implications of SHH/Gli signalling in CD90+ liver cancer stem cells. Correlation of the expression of SHH signalling components and CD90 in liver cancer cells and clinical tissues, as well as in enriched CD90+ liver cancer stem cells and the TCGA database, were analysed by quantitative RT-PCR, Western blotting and flow cytometry. Functional analysis was conducted by siRNA-mediated CD90, Gli1 and Gli3 gene knockdown, SHH treatment and application of the JAK2 inhibitor AZD1480 and IL6 neutralizing antibody in CD90+ liver cancer stem cells, followed by cell proliferation, migration, sphere formation and tumorigenicity assays. CD90 expression exhibited a high positive correlation with Gli1 and Gli3 in multiple liver cancer cell lines and human cancerous liver tissues, both of which showed a significant increase in liver cancer. Analysis of TCGA data revealed an association of CD90, Gli1 and Gli3 with a short overall survival and positive correlation between CD90 expression and Gli3 expression level. The stem cell potentials of CD90+ 97L liver cancer cells were greatly impaired by Gli1/3 knockdown with siRNA but enhanced by SHH treatment. Application of the JAK2 inhibitor AZD1480 and IL6 neutralizing antibody showed the CD90 and SHH/Gli regulated liver cancer stem cell functions were mediated by the IL6/JAK2/STAT3 pathway. The stem cell properties of CD90+ liver cancer cells are regulated by the downstream SHH/Gli and IL6/JAK2/STAT3 signalling pathways. PMID- 29722129 TI - Ecological and evolutionary drivers of the elevational gradient of diversity. AB - Ecological, evolutionary, spatial and neutral theories make distinct predictions and provide distinct explanations for the mechanisms that control the relationship between diversity and the environment. Here, we test predictions of the elevational diversity gradient focusing on Iberian bumblebees, grasshoppers and birds. Processes mediated by local abundance and regional diversity concur in explaining local diversity patterns along elevation. Effects expressed through variation in abundance were similar among taxa and point to the overriding role of a physical factor, temperature. This determines how energy is distributed among individuals and ultimately how the resulting pattern of abundance affects species incidence. Effects expressed through variation in regional species pools depended instead on taxon-specific evolutionary history, and lead to diverging responses under similar environmental pressures. Local filters and regional variation also explain functional diversity gradients, in line with results from species richness that indicate an (local) ecological and (regional) historical unfolding of diversity-elevation relationships. PMID- 29722128 TI - Five-year outcomes in kidney transplant patients randomized to everolimus with cyclosporine withdrawal or low-exposure cyclosporine versus standard therapy. AB - HERAKLES was a 1-year randomized, multicenter trial. Patients were randomized at 3 months after kidney transplantation to remain on cyclosporine-based therapy, switch to everolimus without a calcineurin inhibitor (CNI), or switch to everolimus with low-exposure cyclosporine. Overall, 417 of 497 (83.9%) patients from the core study entered a 4-year extension study. The randomized regimen was continued to year 5 in 75.9%, 41.9% and 24.6% of patients in the standard-CNI, CNI-free and low-CNI groups, respectively. Adjusted estimated GFR at year 5 was significantly higher in the CNI-free group versus standard CNI (difference 7.2 mL/min/1.73 m2 , P < .001) or low CNI (difference 7.6 mL/min/1.73 m2 , P < .001). For patients who continued randomized therapy for 5 years, differences were 14.4 mL/min/1.73 m2 and 10.1 mL/min/1.73 m2 , respectively. Biopsy-proven acute rejection occurred during the 4-year extension study in 7.6%, 8.6%, and 9.0% of patients in the standard-CNI, CNI-free and low-CNI groups, respectively (P = .927). In conclusion, conversion to a CNI-free everolimus regimen 3 months after kidney transplantation improved long-term graft function, particularly in patients who continued the CNI-free regimen. Low CNI with everolimus did not improve renal function. Efficacy was comparable between groups but frequent immunosuppression changes should be taken into account. PMID- 29722130 TI - Esophageal squamous cell carcinomas in a Malaysian cohort show a lack of association with human papillomavirus. AB - OBJECTIVE: With an age-standardized incidence rate of 2 per 100 000, esophageal cancer is not common among Malaysians, but they are nevertheless important due to its poor prognosis. The study is to clarify whether the human papillomavirus (HPV) is associated with esophageal cancer in Malaysians as there has been no report to date on this in Malaysians and other South East Asians. METHODS: Altogether 67 esophageal squamous cell carcinomas histologically diagnosed between 1 January 2004 and 31 December 2014 at the Department of Pathology, University of Malaya Medical Center, Malaysia were considered for HPV analysis using two commercially available methods, polymerase chain reaction with flow through hybridization (21 HPV GenoArray Diagnostic Kit) and multiplex real-time polymerase chain reaction (Anyplex II HPV28 Detection). The DNA amplifiability of the formalin-fixed, paraffin-embedded tumor was checked by amplification of a 268 bp segment of the human beta-globin gene (GH20/PC04) prior to HPV detection. RESULTS: HPV detection was finally carried out in 51 patients. HPV16 was detected in the moderately differentiated, stage IV lower esophageal tumor of a 32-year old Malaysian-born Chinese woman by both methods. Except for a predilection for Indians, the clinical characteristics of esophageal squamous cell carcinomas in this Malaysian cohort were generally similar to those of other populations. CONCLUSION: It appears that HPV is rare and an unlikely oncovirus in esophageal squamous cell carcinomas of Malaysians. PMID- 29722131 TI - The Science of Salt: A focused review on salt-related knowledge, attitudes and behaviors, and gender differences. AB - The aim of the current review was to examine the scope of studies published in the Science of Salt Weekly that contained a measure of self-reported knowledge, attitudes, and behavior (KAB) concerning salt. Specific objectives were to examine how KAB measures are used to evaluate salt reduction intervention studies, the questionnaires used, and whether any gender differences exist in self-reported KAB. Studies were reviewed from the commencement of Science of Salt Weekly, June 2013 to the end of August 2017. Seventy-five studies had relevant measures of KAB and were included in this review, 13 of these were salt-reduction intervention-evaluation studies, with the remainder (62) being descriptive KAB studies. The KAB questionnaires used were specific to the populations studied, without evidence of a best practice measure. 40% of studies used KAB alone as the primary outcome measure; the remaining studies used more quantitative measures of salt intake such as 24-hour urine. Only half of the descriptive studies showed KAB outcomes disaggregated by gender, and of those, 73% showed women had more favorable KAB related to salt. None of the salt intervention-evaluation studies showed disaggregated KAB data. Therefore, it is likely important that evaluation studies disaggregate, and are appropriately powered to disaggregate all outcomes by gender to address potential disparities. PMID- 29722133 TI - Pediatric en bloc kidney transplantation from very small (<=10 kg) donation after circulatory death (versus brain death) donors: Single-center matched-pair analysis of 130 transplants. AB - En bloc kidney transplants (EBK) from very small pediatric donation after circulatory death (DCD) donors are infrequent because of the perception that DCD adversely impacts outcomes. We retrospectively studied 130 EBKs from donors <=10 kg (65 consecutive DCD vs 65 donation after brain death [DBD] transplants; pair matched for donor weight and terminal creatinine, and for preservation time). For DCD vs DBD, median donor weight was 5.0 vs 5.0 kg; median recipient age was 57 vs 48 years (P = .006). Graft losses from thrombosis (DCD, 5%; DBD, 7%) or primary nonfunction (DCD, 3%; DBD, 0%) were similar in both groups (P = .7). Delayed graft function rate was higher for DCD (25%) vs DBD (14%) (P = .2). Graft survival (death-censored) for DCD vs DBD at 5 years was 87% vs 91% (P = .3). Median estimated GFR (mL/min per 1.73 m2 ) was significantly lower for DCD recipients at 1 and 3 months; at 6 years it remained stable at 100 (DCD) and 99 (DBD). DCD impacted early posttransplant graft function, but did not appear to impart added risk for graft loss and long-term function. Very small (<=10 kg) DCD EBK donors should be considered as an option to augment the deceased kidney donor pool; larger studies with longer follow-up must confirm these findings. PMID- 29722132 TI - A comparison of food habits and prey preferences of Amur tiger (Panthera tigris altaica) at the southwest Primorskii Krai in Russia and Hunchun in China. AB - A small, isolated Amur tiger population ranges across the southwest Primorskii Krai region in Russia and Hunchun region in China. Many individuals, with "dual nationality," cross the border frequently. Formulating effective conservation strategies requires a clear understanding of tiger food requirements in both countries. While the diets of tigers ranging in Russia is clearly understood, little is known of the tigers' feeding habits in China.. We used scat analysis combined with data on the abundance of 4 prey species to examine Amur tiger diet and prey preferences in Hunchun. We examined 53 tiger scat samples from 2011 to 2016 and found that tigers preyed on 12 species (11 species in winter), 4 of which were domestic animals with 33.58% biomass contribution; this was the first record of Amur tigers eating lynx in this area. Tigers showed a strong preference for wild boar (Jacobs index: +0.849), which were also the most frequently consumed prey, and a strong avoidance of roe deer (Jacobs index: -0.693). On the Russian side, domestic animals (just dog) were rarely found in tiger scat, and tigers did not show strong avoidance of roe deer, but of sika deer. We also found red deer footprints during winter surveys and that tigers ate red deer on the Chinese side, while there was no record of red deer feeding on the Russian side. Reducing or eliminating human disturbance, such as grazing, is essential to recovering tiger prey and habitat in this area and the Sino-Russian joint ungulate annual survey is indispensable for prey estimates of this small, isolated Amur tiger population. PMID- 29722135 TI - Stopping the Train of Thought: A Pilot Study Using an Ecological Momentary Intervention with Twice-Daily Exposure to Natural versus Urban Scenes to Lower Stress and Rumination. AB - BACKGROUND: Stress, and specifically perseverative cognition, is considered to have considerable detrimental effects on mental and physical health. Interventions that can offer temporary stress relief could, therefore, bring considerable health benefits. Previous research has pointed to stress-reducing effects of exposure to nature after acute stressors, but has not yet investigated effects in the realm of everyday life. The present pilot study explores whether an ecological momentary intervention using exposure to natural images could be effective in lowering stress and improve mood. METHODS: Fifteen participants (12 females) scoring above threshold on stress, depression, or anxiety completed two study periods of 6 days. They watched an urban (control) or natural slideshow twice daily. Using Ecological Momentary Assessment, effects on mood, and stress related complaints were measured in everyday life. RESULTS: Compliance to the study protocol was high, especially in the first week, with slightly more videos watched in the morning than in the evening. We found indications of improvements in mood, self-reported worrying (but not stress levels), and heart rate. CONCLUSIONS: The results suggest that twice-daily exposure to restorative visual content could be a viable Ecological Momentary Intervention, with the potential to reduce self-reported worry, lower autonomic activity, and increase positive affect. PMID- 29722134 TI - A novel PDE9 inhibitor WYQ-C36D ameliorates corticosterone-induced neurotoxicity and depression-like behaviors by cGMP-CREB-related signaling. AB - BACKGROUND: Major depressive disorder (MDD) is a mental disease characterized by depressed mood, lifetime anxiety, and deficits of learning and memory. Inhibition of phosphodiesterase 9 (PDE9) has been reported to improve rodent cognitive and memory function. However, the role of PDE9 in MDD, in particular its manifestations of depression and anxiety, has not been investigated. METHODS: We examined the protective effects of WYQ-C36D (C36D), a novel PDE9 inhibitor, against corticosterone-induced cytotoxicity, pCREB/CREB and BDNF expression by cell viability, and immunoblot assays in HT-22 cells. The potential effects of C36D at doses of 0.1, 0.5, and 1 mg/kg on stress-induced depression- and anxiety like behaviors and memory deficits were also examined in mice. RESULTS: C36D significantly protected HT-22 cells against corticosterone-induced cytotoxicity and rescued corticosterone-induced decreases in cGMP, CREB phosphorylation, and BDNF expression. All these effects were otherwise blocked by the PKG inhibitor Rp 8-Br-PET-cGMPS (Rp8). In addition, when tested in vivo in stressed mice, C36D produced antidepressant-like effects on behavior, as shown by decreased immobility time both in the forced swimming and tail suspension tests. C36D also showed anxiolytic-like and memory-enhancing effects in the elevated plus-maze and novel object recognition tests. CONCLUSION: Our results show that inhibition of PDE9 by C36D produces antidepressant- and anxiolytic-like behavioral effects and memory enhancement by activating cGMP/PKG signaling pathway. PDE9 inhibitors may have the potential as a novel class of drug to treat MDD. PMID- 29722136 TI - Phospho-regulation of intrinsically disordered proteins for actin assembly and endocytosis. AB - Actin filament assembly contributes to the endocytic pathway pleiotropically, with active roles in clathrin-dependent and clathrin-independent endocytosis as well as subsequent endosomal trafficking. Endocytosis comprises a series of dynamic events, including the initiation of membrane curvature, bud invagination, vesicle abscission and subsequent vesicular transport. The ultimate success of endocytosis requires the coordinated activities of proteins that trigger actin polymerization, recruit actin-binding proteins (ABPs) and organize endocytic proteins (EPs) that promote membrane curvature through molecular crowding or scaffolding mechanisms. A particularly interesting phenomenon is that multiple EPs and ABPs contain a substantial percentage of intrinsically disordered regions (IDRs), which can contribute to protein coacervation and phase separation. In addition, intrinsically disordered proteins (IDPs) frequently contain sites for post-translational modifications (PTMs) such as phosphorylation, and these modifications exhibit a high preference for IDR residues [Groban ES et al. (2006) PLoS Comput Biol 2, e32]. PTMs are implicated in regulating protein function by modulating the protein conformation, protein-protein interactions and the transition between order and disorder states of IDPs. The molecular mechanisms by which IDRs of ABPs and EPs fine-tune actin assembly and endocytosis remain mostly unexplored and elusive. In this review, we analyze protein sequences of budding yeast EPs and ABPs, and discuss the potential underlying mechanisms for regulating endocytosis and actin assembly through the emerging concept of IDR mediated protein multivalency, coacervation, and phase transition, with an emphasis on the phospho-regulation of IDRs. Finally, we summarize the current understanding of how these mechanisms coordinate actin cytoskeleton assembly and membrane curvature formation during endocytosis in budding yeast. PMID- 29722137 TI - Effects of the Y-chromosome and the dominant hemimelia mutation on the morphology of the mouse mandible. AB - The aims of this study were to test whether the Y-chromosome and the autosomal dominant hemimelia (Dh) mutation can affect mandible morphology in mice. I analyzed mandible size and shape using landmark-based geometric morphometrics in 16 DH-Chr Y@ -+/+ (@ represents one of the inbred strain names) strains and observed significant differences in mandible size. The largest mandible was identified in strain DH-Chr YC3H and the smallest in strain DH-Chr YKK . Canonical variate and discriminant function analyses suggested that the mandible shapes of strains DH-Chr YC3H and DH-Chr YKK differed from those of the other strains. Because seven of the DH-Chr Y@ -+/+ strains were maintained with dominant hemimelia, I also analyzed the potential influence of dominant hemimelia on mandible morphology because dominant hemimelia is known to cause various skeletal malformations. There were no significant differences in mandible size in seven sets of DH-Chr Y@ -+/+ and DH-Chr Y@ -Dh/+ strains. However, canonical variate analysis mapped strains DH-Chr YCAS -Dh/+ and DH-Chr YCBA -Dh/+ mapped distantly from the rest. Additionally, I observed similar patterns of shape change between DH-Chr YCAS -+/+ and DH-Chr YCAS -Dh/+, and between DH-Chr YCBA +/+ and DH-Chr YCBA -Dh/+. These data indicate that the Y-chromosome affects the size and shape of the mouse mandible. Dominant hemimelia affects mandible shape but not size, and its effects emerge depending on the kinds of Y-chromosomes. PMID- 29722138 TI - Behavioural thermoregulation is highly repeatable and unaffected by digestive status in Agama atra. AB - The precision and the extent of behavioral thermoregulation are likely to provide fitness benefits to ectotherms. Yet the factors driving variation in selected or preferred body temperature (Tset ) and its usefulness as a proxy for optimal physiological temperature (Topt ) are still debated. Although Tset is often conserved among closely related species, substantial variation at the individual, population, and species level has also been reported but repeatability (sensu the intra-class correlation coefficient, ICC) of Tset is generally low. One factor that influences Tset is feeding status, with fed reptiles typically showing higher Tset , a process thought to aid meal digestion. Here using experiments simulating realistic ranges of feeding and fasting regimes in Agama atra, a heliothermic lizard from southern Africa, we test if Tset and its repeatability under these two states significantly differ. Daily Tset ranged from 33.7 to 38.4 degrees C, with a mean (+/- SE) of 36.7 +/- 0.1 degrees C for fed and 36.6 +/- 0.1 degrees C for unfed individuals. Comparisons of repeatability showed that females tend to be more consistent in the selection of body temperature than males, but not significantly so regardless of feeding status. We report some of the highest repeatability estimates of Tset to date (full range: 0.229 - 0.642), and that the weak positive effects of feeding status on Tset detected here do not hinder obtaining relatively high repeatability estimates. In conclusion, one of the major prerequisites for natural selection, consistent among-individual variation, is present, making the adaptive significance of Tset considerably more plausible. This article is protected by copyright. All rights reserved. PMID- 29722139 TI - Molecular recognition and quantitative analysis of leucine and isoleucine using photodissociation of cold gas-phase noncovalent complexes. PMID- 29722141 TI - Useful maneuvers for precise laparoscopic liver resection. AB - Laparoscopic liver resection has evolved over the past decade and nearly replaced open exploration. This procedure not only provides comparable oncological outcomes, but it also has improved recovery after surgery. Many of the challenges presented by limitations of instruments and techniques have been overcome through adaptations and new developments, and it is possible that the remaining obstacles will be overcome within a few years. Moreover, as surgeons continue to gain experience, their technical knowledge has supported further improvement in minimally invasive approaches. This review examines every important procedures in performing a precise laparoscopic liver resection. PMID- 29722140 TI - The WHO global influenza surveillance and response system (GISRS)-A future perspective. AB - In the centenary year of the devastating 1918-19 pandemic, it seems opportune to reflect on the success of the WHO Global Influenza Surveillance and Response System (GISRS) initiated 70 years ago to provide early warning of changes in influenza viruses circulating in the global population to help mitigate the consequences of such a pandemic and maintain the efficacy of seasonal influenza vaccines. Three pandemics later and in the face of pandemic threats from highly pathogenic zoonotic infections by different influenza A subtypes, it continues to represent a model platform for global collaboration and timely sharing of viruses, reagents and information to forestall and respond to public health emergencies. PMID- 29722142 TI - Age-related differences in GABA levels are driven by bulk tissue changes. AB - Levels of GABA, the main inhibitory neurotransmitter in the brain, can be regionally quantified using magnetic resonance spectroscopy (MRS). Although GABA is crucial for efficient neuronal functioning, little is known about age-related differences in GABA levels and their relationship with age-related changes in brain structure. Here, we investigated the effect of age on GABA levels within the left sensorimotor cortex and the occipital cortex in a sample of 85 young and 85 older adults using the MEGA-PRESS sequence. Because the distribution of GABA varies across different brain tissues, various correction methods are available to account for this variation. Considering that these correction methods are highly dependent on the tissue composition of the voxel of interest, we examined differences in voxel composition between age groups and the impact of these various correction methods on the identification of age-related differences in GABA levels. Results indicated that, within both voxels of interest, older (as compared to young adults) exhibited smaller gray matter fraction accompanied by larger fraction of cerebrospinal fluid. Whereas uncorrected GABA levels were significantly lower in older as compared to young adults, this age effect was absent when GABA levels were corrected for voxel composition. These results suggest that age-related differences in GABA levels are at least partly driven by the age-related gray matter loss. However, as alterations in GABA levels might be region-specific, further research should clarify to what extent gray matter changes may account for age-related differences in GABA levels within other brain regions. PMID- 29722143 TI - Palladium-Catalyzed ortho C-H Arylation of Benzaldehydes Using ortho-Sulfinyl Aniline as Transient Auxiliary. AB - A PdII -catalyzed ortho-(Csp2 )-H arylation reaction of benzaldehydes using a catalytic amount of 2-(methylsulfinyl)aniline as transient auxiliary was developed. This reaction is compatible with a broad range of benzaldehyde and aryl iodide substrates. Compared with other related reaction systems, an excellent regioselectivity for ortho-C(sp2 )-H bonds over benzylic C(sp3 )-H bonds was obtained for ortho-alkyl-benzaldehyde substrates. PMID- 29722144 TI - Are the number and size of scales in Liolaemus lizards driven by climate? AB - Ectothermic vertebrates are sensitive to thermal fluctuations in the environments where they occur. To buffer these fluctuations, ectotherms use different strategies, including the integument, which is a barrier that minimizes temperature exchange between the inner body and the surrounding air. In lizards, this barrier is constituted by keratinized scales of variable size, shape and texture, and its main function is protection, water loss avoidance and thermoregulation. The size of scales in lizards has been proposed to vary in relation to climatic gradients; however, it has also been observed that in some groups of Iguanian lizards it could be related to phylogeny. Thus, here, we studied the area and number of scales (dorsal and ventral) of 60 species of Liolaemus lizards distributed in a broad latitudinal and altitudinal gradient to determine the nature of the variation of the scales with climate, and found that the number and size of scales are related to climatic variables, such as temperature and geographical variables as altitude. The evolutionary process that best explained how these morphological variables evolved was the Ornstein Uhlenbeck model. The number of scales seemed to be related to common ancestry, whereas dorsal and ventral scale areas seemed to vary as a consequence of ecological traits. In fact, the ventral area is less exposed to climate conditions such as ultraviolet radiation or wind and is, thus, under less pressure to change in response to alterations in external conditions. It is possible that scale ornamentation, such as keels and granulosity, may bring some more information in this regard. PMID- 29722145 TI - High levels of CCL2 or CCL4 in the tumor microenvironment predict unfavorable survival in lung adenocarcinoma. AB - BACKGROUND: Tumor-associated immune factors are heterogeneous and play an important role in determining outcome in cancer patients. In this study, the expression levels of immune factors in tumor tissue-conditioned media from lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) were analyzed. METHODS: LUAD and LUSC tissue specimens were collected immediately after surgery for antibody array analysis and real-time quantitative PCR. RESULTS: Higher levels of chemokines MCP1/CCL2 (21.11-fold increase) and MIP-1beta/CCL4 (19.33 fold increase) were identified in LUAD than in LUSC. Western blot and quantitative real-time PCR analyses showed higher co-expression of CCL2 and CCL4 in LUAD tissues compared to LUSC (P < 0.0001). Immunofluorescent co-staining showed a high percentage of CCL2+ /CD68+ and CCL4+ /CD68+ tumor-associated macrophages in LUAD compared to LUSC tissues, which might be responsible for the higher expression of CCL2 and CCL4 in LUAD samples. Kaplan-Meier curves showed that CCL2 overexpression in patients with LUSC was associated with beneficial overall survival (OS; P = 0.048) and progression-free survival (PFS; P = 0.012); however, LUAD patients with higher CCL2 expression had unfavorable OS (P = 6.7e 08) and PFS (P = 0.00098). Similarly, CCL4 overexpression predicted favorable PFS (P = 0.021) in patients with LUSC, but patients with high CCL4 levels in LUAD had shorter OS (P = 0.013). CONCLUSION: Our study revealed that CCL2 and CCL4 expression levels could serve as potential prognostic biomarkers and therapeutic targets for NSCLC patients. PMID- 29722146 TI - Prevention of post-sphincterotomy bleeding by proton pump inhibitor: A randomized controlled trial. AB - OBJECTIVE: Post-endoscopic sphincterotomy (EST) bleeding is one of the most frequent complications of endoscopic retrograde cholangiopancreatography (ERCP). Although the use of proton pump inhibitors (PPIs) reduces the risk of peptic ulcer bleeding, their role in preventing EST bleeding has not been evaluated. This study aimed to assess the use of pre-emptive PPIs in patients undergoing EST. METHODS: This was an investigator-initiated, open-label, randomized study. Consecutive patients scheduled to undergo ERCP and EST were enrolled after excluding those who had previous EST or used acid-suppression agents. Eligible patients were randomized to receive either PPI or standard care. The PPI group received intravenous esomeprazole 4 h before the EST and then every 12 h for 1 day, followed by high-dose oral esomeprazole for 10 days. All patients were followed up for 30 days. The primary outcome was the proportion of patients with combined immediate and delayed overt post-EST bleeding. RESULTS: Altogether 125 patients (60 in the PPI arm and 65 in the standard care arm) who had undergone EST were analyzed. Immediate bleeding was noted in nine (15.0%) patients in the PPI group and four (6.2%) in the standard care group (P = 0.14). Overt delayed post-EST bleeding was seen in two (3.3%) and five (7.7%) patients in PPI and standard care arms, respectively (P = 0.44). There were no significant differences in other outcomes, including a decrease in hemoglobin of >20 g/L, the need for blood transfusion, length of hospital stay and 30-day mortality. CONCLUSION: Pre-emptive PPI did not reduce the risk of post-EST bleeding. PMID- 29722147 TI - A bioinspired polydopamine approach toward the preparation of gold-modified magnetic nanoparticles for the magnetic solid-phase extraction of steroids in multiple samples. AB - In this work, a simple, facile, and sensitive magnetic solid-phase extraction method was developed for the extraction and enrichment of three representative steroid hormones before high-performance liquid chromatography analysis. Gold modified Fe3 O4 nanoparticles, as novel magnetic adsorbents, were prepared by a rapid and environmentally friendly procedure in which polydopamine served as the reductant as well as the stabilizer for the gold nanoparticles, thus successfully avoiding the use of some toxic reagents. To obtain maximum extraction efficiency, several significant factors affecting the preconcentration steps, including the amount of adsorbent, extraction time, pH of the sample solution, and the desorption conditions, were optimized, and the enrichment factors for three steroids were all higher than 90. The validity of the established method was evaluated and good analytical characteristics were obtained. A wide linearity range (0.8-500 MUg/L for all the analytes) was attained with good correlation (R2 >= 0.991). The low limits of detection were 0.20-0.25 MUg/L, and the relative standard deviations ranged from 0.83 to 4.63%, demonstrating a good precision. The proposed method was also successfully applied to the extraction and analysis of steroids in urine, milk, and water samples with satisfactory results, which showed its reliability and feasibility in real sample analysis. PMID- 29722149 TI - Fragment-Based Phenotypic Lead Discovery: Cell-Based Assay to Target Leishmaniasis. AB - A rapid and practical approach for the discovery of new chemical matter for targeting pathogens and diseases is described. Fragment-based phenotypic lead discovery (FPLD) combines aspects of traditional fragment-based lead discovery (FBLD), which involves the screening of small-molecule fragment libraries to target specific proteins, with phenotypic lead discovery (PLD), which typically involves the screening of drug-like compounds in cell-based assays. To enable FPLD, a diverse library of fragments was first designed, assembled, and curated. This library of soluble, low-molecular-weight compounds was then pooled to expedite screening. Axenic cultures of Leishmania promastigotes were screened, and single hits were then tested for leishmanicidal activity against intracellular amastigote forms in infected murine bone-marrow-derived macrophages without evidence of toxicity toward mammalian cells. These studies demonstrate that FPLD can be a rapid and effective means to discover hits that can serve as leads for further medicinal chemistry purposes or as tool compounds for identifying known or novel targets. PMID- 29722148 TI - EGFR mutations in early-stage and advanced-stage lung adenocarcinoma: Analysis based on large-scale data from China. AB - BACKGROUND: EGFR-tyrosine kinase inhibitors play an important role in the treatment of advanced non-small cell lung cancer (NSCLC). EGFR mutations in advanced NSCLC occur in approximately 35% of Asian patients and 60% of patients with adenocarcinoma. However, the frequency and type of EGFR mutations in early stage lung adenocarcinoma remain unclear. METHODS: We retrospectively collected data on patients diagnosed with lung adenocarcinoma tested for EGFR mutation. Early stage was defined as pathological stage IA-IIIA after radical lung cancer surgery, and advanced stage was defined as clinical stage IIIB without the opportunity for curative treatment or stage IV according to the American Joint Committee on Cancer Staging Manual, 7th edition. RESULTS: A total of 1699 patients were enrolled in this study from May 2014 to May 2016; 750 were assigned to the early-stage and 949 to the advanced-stage group. Baseline characteristics of the two groups were balanced, except that there were more smokers in the advanced-stage group (P < 0.001). The total EGFR mutation rate in the early-stage group was similar to that in the advanced-stage group (53.6% vs. 51.4%, respectively; P = 0.379). There was no significant difference in EGFR mutation type between the two groups. In subgroup analysis of smoking history, there was no difference in EGFR mutation frequency or type between the early-stage and advanced-stage groups. CONCLUSION: Early-stage and advanced-stage groups exhibited the same EGFR mutation frequencies and types. PMID- 29722150 TI - Nomenclature for factors of the HLA system, update February 2018. PMID- 29722152 TI - Modulation of forebrain function by nucleus incertus and relaxin-3/RXFP3 signaling. AB - The nucleus incertus (NI) in the pontine tegmentum sends ascending projections to the midbrain, hypothalamus, amygdala, basal forebrain, hippocampus, and prefrontal cortex, and has a postulated role in modulating several forebrain functions. A substantial population of GABAergic NI neurons expresses the neuropeptide, relaxin-3, which acts via the Gi/o -protein-coupled receptor, RXFP3, present throughout the forebrain target regions. Broad and specific manipulations of these systems by activation or inhibition of the NI or modulating RXFP3 signaling have revealed key insights into the likely influence of the NI/relaxin-3/RXFP3 system on modalities including arousal, feeding, stress responses, anxiety and addiction, and attention and memory. This range of actions corresponds to a likely impact of NI/(relaxin-3) projections on multiple integrated circuits, but makes it difficult to draw conclusions about a generalized function for this network. This review will focus on the key physiological process of oscillatory theta rhythm and the neural circuits that promote it during behavioral activation, highlighting the ability of NI and relaxin-3/RXFP3 signaling systems to modulate these circuits. A better understanding of these mechanisms may provide a way to therapeutically adjust malfunction of forebrain activity present in several pathological conditions. PMID- 29722153 TI - Biological buffers and the impacts of climate change. AB - This article is protected by copyright. All rights reserved. PMID- 29722155 TI - Cold adaptation does not alter ATP homeostasis during cold exposure in Drosophila melanogaster. AB - In insects and other ectotherms, cold temperatures cause a coma resulting from loss of neuromuscular function, during which ionic and metabolic homeostasis are progressively lost. Cold adaptation improves homeostasis during cold exposure, but the ultimate targets of selection are still an open question. Cold acclimation and adaptation remodels mitochondrial metabolism in insects, suggesting that aerobic energy production during cold exposure could be a target of selection. Here, we test the hypothesis that cold adaptation improves the ability to maintain rates of aerobic energy production during cold exposure by using 31 P NMR on live flies. Using lines of Drosophila melanogaster artificially selected for fast and slow recovery from a cold coma, we show that cold exposure does not lower ATP levels and that cold adaptation does not alter aerobic ATP production during cold exposure. Cold-hardy and cold-susceptible lines both experienced a brief transition to anaerobic metabolism during cooling, but this was rapidly reversed during cold exposure, suggesting that oxidative phosphorylation was sufficient to meet energy demands below the critical thermal minimum, even in cold-susceptible flies. We thus reject the hypothesis that performance under mild low temperatures is set by aerobic ATP supply limitations in D. melanogaster, excluding oxygen and capacity limitation as a weak link in energy supply. This work suggests that the modulations to mitochondrial metabolism resulting from cold acclimation or adaptation may arise from selection on a biosynthetic product(s) of those pathways rather than selection on ATP supply during cold exposure. This article is protected by copyright. All rights reserved. PMID- 29722154 TI - Will housing tenure drive unequal outcomes for Consumer-Directed Care recipients? AB - Initiatives to promote consumer choice are increasingly a feature of Australian welfare policies and programs. Consumer Directed Care (CDC) for older people and the National Disability Insurance Scheme for people younger than 65 years with a disability are two examples of this move towards consumer choice in policy and program development. The ability for service users to benefit from these programs is premised on the fact that their housing is stable and suitable. Yet, there is evidence that this is not the case, and many older people and people with disabilities experience significant housing challenges and stress. This article focuses on CDC and its implications for one particular group under housing stress - low-income older renters. Might they be at risk of limited access to home care services, and what are the broader local neighbourhood implications of this policy? PMID- 29722156 TI - Hydrostatic pressure suppresses fibrotic changes via Akt/GSK-3 signaling in human cardiac fibroblasts. AB - Mechanical stresses play important roles in the process of constructing and modifying heart structure. It has been well established that stretch force acting on cardiac fibroblasts induces fibrosis. However, the effects of compressive force, that is, hydrostatic pressure (HP), have not been well elucidated. We thus evaluated the effects of HP using a pressure-loading apparatus in human cardiac fibroblasts (HCFs) in vitro. In this study, high HP (200 mmHg) resulted in significant phosphorylation of Akt in HCFs. HP then greatly inhibited glycogen synthase kinase 3 (GSK-3)alpha, which acts downstream of the PI3K/Akt pathway. Similarly, HP suppressed mRNA transcription of inflammatory cytokine-6, collagen I and III, and matrix metalloproteinase 1, compared with an atmospheric pressure condition. Furthermore, HP inhibited collagen matrix production in a three dimensional HCF culture. Taken together, high HP suppressed the differentiation of fibroblasts into the myofibroblast phenotype. HP under certain conditions suppressed cardiac fibrosis via Akt/GSK-3 signaling in HCFs. These results might help to elucidate the pathology of some types of heart disease. PMID- 29722157 TI - Nickel-Catalyzed Regioselective C(2)-H Difluoroalkylation of Indoles with Difluoroalkyl Bromides. AB - Regioselective C(2)-H difluoroalkylation of C-3 unsubstituted indoles with commonly available fluoroalkyl bromides is successfully achieved employing a simple nickel catalyst system, (DME)NiCl2 /Xantphos. This methodology shows excellent regioselectivity and exhibits a broad substrate scope. Various functional groups, such as -OMe, -F, and -Br, are tolerated on the indole backbone to give the difluoroalkylated products in moderate to good yields. Preliminary mechanistic findings demonstrate that the reaction is homogeneous in nature and involves a radical manifold. Synthetic utility of this nickel catalyzed method is demonstrated by synthesizing melatonin receptor antagonist Luzindole derivative. PMID- 29722151 TI - Specifying neural crest cells: From chromatin to morphogens and factors in between. AB - Neural crest (NC) cells are a stem-like multipotent population of progenitor cells that are present in vertebrate embryos, traveling to various regions in the developing organism. Known as the "fourth germ layer", these cells originate in the ectoderm between the neural plate (NP), which will become the brain and spinal cord, and nonneural tissues that will become the skin and the sensory organs. NC cells can differentiate into more than 30 different derivatives in response to the appropriate signals including, but not limited to, craniofacial bone and cartilage, sensory nerves and ganglia, pigment cells, and connective tissue. The molecular and cellular mechanisms that control the induction and specification of NC cells include epigenetic control, multiple interactive and redundant transcriptional pathways, secreted signaling molecules, and adhesion molecules. NC cells are important not only because they transform into a wide variety of tissue types, but also because their ability to detach from their epithelial neighbors and migrate throughout developing embryos utilizes mechanisms similar to those used by metastatic cancer cells. In this review, we discuss the mechanisms required for the induction and specification of NC cells in various vertebrate species, focusing on the roles of early morphogenesis, cell adhesion, signaling from adjacent tissues, and the massive transcriptional network that controls the formation of these amazing cells. This article is categorized under: Nervous System Development > Vertebrates: General Principles Gene Expression and Transcriptional Hierarchies > Regulatory Mechanisms Gene Expression and Transcriptional Hierarchies > Gene Networks and Genomics Signaling Pathways > Cell Fate Signaling. PMID- 29722160 TI - Cardioselective ultra-short-acting beta-blockers for patients with Takotsubo syndrome? PMID- 29722159 TI - Visible-Light-Driven Hydrogen Production and Polymerization using Triarylboron Functionalized Iridium(III) Complexes. AB - The development of novel iridium(III) complexes has continued as an important area of research owing to their highly tunable photophysical properties and versatile applications. In this report, three heteroleptic dimesitylboron containing iridium(III) complexes, [Ir(p-B-ppy)2 (N^N)]+ {p-B-ppy=2-(4 dimesitylborylphenyl)pyridine; N^N=dipyrido[3,2-a:2',3'-c]phenazine (dppz) (1), dipyrido[3,2-d:2',3'-f]quinoxaline (dpq) (2), and 1,10-phenanthroline (phen) (3)}, were prepared and fully characterized electrochemically, photophysically, and computationally. Altering the conjugated length of the N^N ligands allowed us to tailor the photophysical properties of these complexes, especially their luminescence wavelength, which could be adjusted from lambda=583 to 631 nm in CH2 Cl2 . All three complexes were evaluated as visible-light-absorbing sensitizers for the photogeneration of hydrogen from water and as photocatalysts for the photopolymerization of methyl methacrylate. The results showed that all of them were active in both photochemical reactions. High activity for the photosensitizer (over 1158 turnover numbers with 1) was observed, and the system generated hydrogen even after 20 h. Additionally, poly(methyl methacrylate) with a relatively narrow molecular-weight distribution was obtained if an initiator (i.e., ethyl alpha-bromophenylacetate) was used. The living character of the photoinduced polymerization was confirmed on the basis of successful chain extension experiments. PMID- 29722161 TI - We need more useful surrogate markers for the efficacy of beta-blockers for the treatment of Takotsubo cardiomyopathy. PMID- 29722162 TI - Acute water intoxication in an older woman despite a relatively small amount of water loading. PMID- 29722158 TI - LARP1 on TOP of ribosome production. AB - The ribosome is an essential unit of all living organisms that commands protein synthesis, ultimately fuelling cell growth (accumulation of cell mass) and cell proliferation (increase in cell number). The eukaryotic ribosome consists of 4 ribosomal RNAs (rRNAs) and 80 ribosomal proteins (RPs). Despite its fundamental role in every living organism, our present understanding of how higher eukaryotes produce the various ribosome components is incomplete. Uncovering the mechanisms utilized by human cells to generate functional ribosomes will likely have far reaching implications in human disease. Recent biochemical and structural studies revealed La-related protein 1 (LARP1) as a key new player in RP production. LARP1 is an RNA-binding protein that belongs to the LARP superfamily; it controls the translation and stability of the mRNAs that encode RPs and translation factors, which are characterized by a 5' terminal oligopyrimidine (5'TOP) motif and are thus known as TOP mRNAs. The activity of LARP1 is regulated by the mammalian target of rapamycin complex 1 (mTORC1): a eukaryotic protein kinase complex that integrates nutrient sensing with mRNA translation, particularly that of TOP mRNAs. In this review, we provide an overview of the role of LARP1 in the control of ribosome production in multicellular eukaryotes. This article is categorized under: Translation > Translation Regulation RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications RNA Processing > Capping and 5' End Modifications. PMID- 29722163 TI - Clinical features of Mycoplasma pneumoniae pneumonia in older adults. PMID- 29722164 TI - How a phase image of a cell with nucleus refractive index smaller than that of the cytoplasm should look like?: A Comment on two papers by Steelman et al. and Schurmann et al. Read the Responses to this Comment: e201800091 and e201800095. AB - In recent papers Steelman et al. ("Is the nuclear refractive index lower than cytoplasm? Validation of phase measurements and implications for light scattering technologies") and Schurmann et al. ("Cell nuclei have lower refractive index and mass density than cytoplasm") obtained quantitative phase images of whole cells of various types and corresponding isolated nuclei and concluded that the refractive index (RI) of the nucleus is significantly smaller than that of the cytoplasm. The comment shows that this conclusion and assumptions used in retrieving the RI necessarily imply a characteristic dip in the center of the whole-cell phase images. This dip is not present in any of the phase images in the discussed papers, which is a strong argument against the conclusion of smaller nucleus RI. It is also discussed whether a different processing of the phase images can help to clarify this issue. PMID- 29722165 TI - Response to Comment on "Cell nuclei have lower refractive index and mass density than cytoplasm": A Comment on "How a phase image of a cell with nucleus refractive index smaller than that of the cytoplasm should look like?", e201800033. AB - In a recent study entitled "Cell nuclei have lower refractive index and mass density than cytoplasm," we provided strong evidence indicating that the nuclear refractive index (RI) is lower than the RI of the cytoplasm for several cell lines. In a complementary study in 2017, entitled "Is the nuclear refractive index lower than cytoplasm? Validation of phase measurements and implications for light scattering technologies," Steelman et al. observed a lower nuclear RI also for other cell lines and ruled out methodological error sources such as phase wrapping and scattering effects. Recently, Yurkin composed a comment on these 2 publications, entitled "How a phase image of a cell with nucleus refractive index smaller than that of the cytoplasm should look like?," putting into question the methods used for measuring the cellular and nuclear RI in the aforementioned publications by suggesting that a lower nuclear RI would produce a characteristic dip in the measured phase profile in situ. We point out the difficulty of identifying this dip in the presence of other cell organelles, noise, or blurring due to the imaging point spread function. Furthermore, we mitigate Yurkin's concerns regarding the ability of the simple-transmission approximation to compare cellular and nuclear RI by analyzing a set of phase images with a novel, scattering-based approach. We conclude that the absence of a characteristic dip in the measured phase profiles does not contradict the usage of the simple transmission approximation for the determination of the average cellular or nuclear RI. Our response can be regarded as an addition to the response by Steelman, Eldridge and Wax. We kindly ask the reader to attend to their thorough ascertainment prior to reading our response. PMID- 29722166 TI - One percent alendronate and aloe vera gel local host modulating agents in chronic periodontitis patients with class II furcation defects: A randomized, controlled clinical trial. AB - AIM: Alendronate (ALN) has antiresorptive and osteostimulative properties. The major component of aloe vera (AV) gel is acemannan, which has been found to have osteogenic properties. The aim of the present study is to explore the effectiveness of 1% ALN and AV gel as an adjunct to scaling and root planing (SRP) in chronic periodontitis patients with class II furcation defects. METHODS: Ninety volunteers were randomly assigned to three treatment groups: (a) SRP plus placebo gel; (b) SRP plus 1% ALN gel; and (c) SRP plus AV gel. Clinical and radiographic parameters were recorded at baseline and at 6 and 12 months. RESULTS: The mean probing depth reduction and relative horizontal clinical attachment level (CAL) and relative vertical CAL gains were greater in the ALN group than in the AV and placebo groups at 6 and 12 months. Furthermore, a significantly greater mean percentage of defect depth reduction (DDR) was found in the ALN group (38.09 +/- 9.53, 44.86 +/- 6.29) than the AV groups (11.94 +/- 15.10, 14.59 +/- 25.49) at 6 and 12 months, respectively. CONCLUSION: ALN showed significant improvement in all clinical parameters, along with greater DDR, compared to AV in the treatment of class II furcation defects as an adjunct to SRP. PMID- 29722167 TI - Artificial light pollution: Shifting spectral wavelengths to mitigate physiological and health consequences in a nocturnal marsupial mammal. AB - The focus of sustainable lighting tends to be on reduced CO2 emissions and cost savings, but not on the wider environmental effects. Ironically, the introduction of energy-efficient lighting, such as light emitting diodes (LEDs), may be having a great impact on the health of wildlife. These white LEDs are generated with a high content of short-wavelength 'blue' light. While light of any kind can suppress melatonin and the physiological processes it regulates, these short wavelengths are potent suppressors of melatonin. Here, we manipulated the spectral composition of LED lights and tested their capacity to mitigate the physiological and health consequences associated with their use. We experimentally investigated the impact of white LEDs (peak wavelength 448 nm; mean irradiance 2.87 W/m2 ), long-wavelength shifted amber LEDs (peak wavelength 605 nm; mean irradiance 2.00 W/m2 ), and no lighting (irradiance from sky glow < 0.37 * 10-3 W/m2 ), on melatonin production, lipid peroxidation, and circulating antioxidant capacity in the tammar wallaby (Macropus eugenii). Night-time melatonin and oxidative status were determined at baseline and again following 10 weeks exposure to light treatments. White LED exposed wallabies had significantly suppressed nocturnal melatonin compared to no light and amber LED exposed wallabies, while there was no difference in lipid peroxidation. Antioxidant capacity declined from baseline to week 10 under all treatments. These results provide further evidence that short-wavelength light at night is a potent suppressor of nocturnal melatonin. Importantly, we also illustrate that shifting the spectral output to longer wavelengths could mitigate these negative physiological impacts. PMID- 29722169 TI - Response to Comment on "Is the nuclear refractive index lower than cytoplasm? Validation of phase measurements and implications for light scattering technologies": A Comment on "How a phase image of a cell with nucleus refractive index smaller than that of the cytoplasm should look like?", e201800033. AB - Recently, Maxim A. Yurkin commented on our paper "Is the nuclear refractive index lower than cytoplasm? Validation of phase measurements and implications for light scattering technologies" as well as on a complementary study "Cell nuclei have lower refractive index and mass density than cytoplasm" from Schurmann et al. In his comment, Yurkin concluded that quantitative phase images of cells with nuclei that are less optically dense than the cytoplasm must exhibit a characteristic concavity, the absence of which is evidence against our conclusion of a less dense nucleus. In this response, we suggest that Yurkin's conclusion is reached through an oversimplification of the spatial refractive index distribution within cells, which does not account for high index inclusions such as the nucleolus. We further cite recent studies in 3-dimensional refractive index imaging, in which the preponderance of studies supports our conclusion. Finally, we comment on the current state of knowledge regarding subcellular refractive index distributions in living cells. PMID- 29722168 TI - A novel plasma circular RNA circFARSA is a potential biomarker for non-small cell lung cancer. AB - Emerging evidence indicates that circular RNAs (circRNAs) are implicated in cancer development. This study aimed to evaluate whether circulating circRNAs may serve as novel biomarkers for non-small cell lung cancer (NSCLC). We used RNA sequencing (RNA-seq) and quantitative real-time PCR to explore cancer-related circRNAs. Bioinformatics and functional analyses were performed to reveal biological effects of circRNAs on lung cancer cells. A total of 5471 distinct circRNAs were identified by total RNA-seq, in which 185 were differentially expressed between cancerous and adjacent normal tissues. A circRNA derived from exon 5-7 of the FARSA gene, termed circFARSA, was observed to increase in cancerous tissues (P = 0.016), and was more abundant in patients' plasma than controls (P < 0.001). Overexpression of circFARSA in A549 cell line significantly promoted cell migration and invasion. In silico analysis suggested that circFARSA might sponge miR-330-5p and miR-326, thereby relieving their inhibitory effects on oncogene fatty acid synthase. Summarily, this study revealed circRNA profile of NSCLC for the first time and provided the evidence of plasma circFARSA as a potential noninvasive biomarker for this malignancy. PMID- 29722170 TI - Clinicopathological characteristics and survival outcomes in Paget disease: a SEER population-based study. AB - The objective of this study was to investigate the clinicopathological characteristics and survival outcomes of Paget disease (PD), Paget disease concomitant infiltrating duct carcinoma (PD-IDC), and Paget disease concomitant intraductal carcinoma (PD-DCIS). We identified 501,631 female patients from 2000 to 2013 in the Surveillance, Epidemiology, and End Results (SEER) database. These identified patients included patients with PD (n = 469), patients with PD-IDC (n = 1832), and patients with PD-DCIS (n = 1130) and infiltrating ductal carcinoma (IDC) (n = 498,076). Then, we compared the clinical characteristics of these patients with those who were diagnosed with IDC during the same period. The outcomes of these subtypes of breast carcinoma were different. Based on the overall survival, the patients with PD-IDC had the worst prognosis (5-year survival rate = 84.1%). The PD-DCIS had the best prognosis (5-year survival rate = 97.5%). Besides, among patients with Paget disease, the one who was married had a better prognosis than who were not. And, according to our research, the marital status was associated with the hormone receptor status in patients with PD-IDC. Among three subtypes of Paget disease, patients with PD-IDC had the worst prognosis. Besides, patients who were unmarried had worse outcomes. And the marital status of patients with PD-IDC is associated with hormone status. The observation underscores the importance of individualized treatment. PMID- 29722171 TI - Parabens generate reactive oxygen species in human spermatozoa. AB - Parabens are used as antimicrobial preservative agent in many commercial products including cosmetics and pharmaceuticals. Weak oestrogenic and antiandrogenic activities have been attributed to parabens in in vitro and in vivo studies. In this study, human spermatozoa were exposed to different concentrations of an equimolar paraben mixture containing methyl, ethyl, propyl and butylparaben as well as to methylparaben alone at a concentration that is typical of commercially available vaginal lubricants. The induction of oxidative stress and DNA damage was then assessed at different time points. Our results demonstrate that the paraben mixture was capable of stimulating the generation of mitochondrial and cytosolic reactive oxygen species (ROS), inhibiting sperm motility and viability in a dose-dependent manner. The ability of individual parabens to activate ROS generation and induce oxidative DNA damage was related to alkyl chain length. At the concentration used clinically, methylparaben inhibited sperm motility after both 2 and 5 h exposure (p < 0.05) and affected cell viability (p < 0.01) while augmenting ROS production and oxidative DNA damage. However, DNA fragmentation was not evident following methylparaben exposure. Based on these results, we conclude that, at the concentrations used in commercially available formulations, parabens may impair sperm motility, enhance the generation of mitochondrial ROS and stimulate the formation of oxidative DNA adducts. Taken together, these data underline the potential cytotoxic and genotoxic impact of such compounds in a clinical setting. PMID- 29722172 TI - Papanicolaou induced fluorescence, Ziehl-Neelsen and Auramine O stains on lymph node fine needle aspiration biopsy specimens from children: A comparative study. AB - BACKGROUND: The rapid diagnosis of extrapulmonary tuberculosis in children remains challenging. The presence of enlarged lymph nodes provides an opportunity to obtain diagnostic material through fine needle aspiration biopsy (FNAB). Mycobacterial culture, traditionally the reference standard, has a slow turnaround time and PCR-based methods are not widely available in developing countries. Direct visualization of mycobacteria on microscopy can be a rapid method to confirm the diagnosis. This study compared three staining methods to visualize mycobacteria. METHODS: Hundred FNAB specimens from persistently enlarged lymph nodes in children, clinically suspicious for tuberculosis, were evaluated for the presence of mycobacteria by three staining methods: Papanicolaou induced fluorescence (PIF) and Auramine O staining using fluorescence microscopy and Ziehl-Neelsen (ZN) staining using conventional light microscopy. These methods were evaluated against mycobacterial culture. RESULTS: PIF positivity was 30%, with 38% and 48% for Auramine O and ZN respectively. The combined ZN/PIF positivity was 56%. The highest diagnostic accuracy (73%) was demonstrated by ZN alone and in combination with PIF, with PIF alone showing the lowest (49%) accuracy. Although the combined test showed the highest sensitivity, it had the lowest specificity, while ZN was significantly more sensitive than both other staining modalities. No statistical difference in specificity was seen among the tests. CONCLUSION: This study suggests that Auramine O staining on previously ZN stained slides does not significantly improve diagnostic accuracy. While currently widely available methods of direct visualization of mycobacteria suffer from low sensitivity, the ZN stain remains a useful diagnostic test, particularly in resource-constrained countries. PMID- 29722173 TI - Fluorescence in situ hybridization analysis on cytologic smears: An accurate and efficient method in the diagnosis of melanotic Xp11 translocation renal cancer. AB - Melanotic Xp11 translocation renal cancer is a rare category of MiTF/TFE3 neoplasms morphologically resembling Xp11 translocation renal cell carcinoma, Xp11 translocation perivascular epithelioid cell tumor, and melanoma. The diagnosis requires demonstration of TFE3 gene rearrangement, by either fluorescence in situ hybridization (FISH) at the Xp11.2 locus or by TFE3 immunohistochemistry. As cytology smears can be useful adjuncts in cytogenetic and molecular testing, we demonstrate TFE3 rearrangement by FISH analysis on cytologic smears in melanotic Xp11 translocation renal cancer. An 18-year-old girl presented with a large right renal mass. Intraoperative scrape smears were performed on suspicious aortocaval lymph nodes. A subset of smears was stained (Papanicolaou and DiffQuik). Morphologically, the neoplastic cells exhibited abundant clear vacuolated cytoplasm and moderate to marked nuclear pleomorphism. Unstained and destained smears were examined for TFE3 rearrangement by FISH. Positive TFE3 FISH results on formalin-fixed paraffin-embedded tissue correlated with the positive FISH findings of TFE3 gene rearrangement on cytologic smears. Therefore, the diagnosis of melanotic Xp11 translocation renal cancer was rendered. In Xp11 translocation associated neoplasms, FISH analysis on cytologic smears can be an efficient, accurate, and cost-effective method for evaluating TFE3 rearrangement. PMID- 29722174 TI - First isolation of West Nile virus in Zambia from mosquitoes. AB - Mosquito surveillance studies to identify mosquito-borne flaviviruses have identified West Nile Virus (WNV) for the first time in Zambia. The Zambian WNV isolate from Culex quinquefasciatus mosquitoes collected in the Western Province was closely related genetically to WNV lineage 2 South African strains which have been previously shown to be highly neuroinvasive. These data provide the first evidence of the circulation of WNV in Zambia and suggest there should be an increased awareness of possible associated human and animal diseases in that country. PMID- 29722175 TI - Lack of transformation zone in cervical Pap tests, should it be a concern? A quality assurance initiative. AB - BACKGROUND: Bethesda guidelines do not require presence of transformation zone (TZ) for a cervical Pap test to be deemed adequate. However, clinicians are concerned with specimens that are reported to lack TZ. METHODS: We analyzed 566 ThinPrep cases reported as negative for intraepithelial lesion or malignancy (NILM) with no cervical abnormality detected in previous 4 years (2007-2011). These cases were divided into two cohorts; those with TZ (ETZ) and those without TZ (NTZ). Patients' age, HPV status, time of sample collection (>14 days after last menstrual period), subsequent management, interval of subsequent Pap test (<1, 1-3, and >3 years), and result of subsequent examination were compared over a 5-year period. RESULTS: The rate of abnormal Pap test on 5 year follow-up was not statistically significant (P < .9520) between cohorts. Our data demonstrates lack of statistical significance between the variables studied. Five year follow up of all abnormal Pap smears were analyzed (93% ETZ and 7% NTZ). Of the ETZ group, 25% ASCUS remained as ASCUS and 75% were reported as NILM in subsequent Pap smears. Additionally, 75% of the LSIL were subsequently reported as NILM and 25% reported as ASCUS. One patient reported as HSIL underwent hysterectomy. Two Pap smears performed two years after surgery were negative. Within the NTZ group, one case of ASCUS was NILM upon follow-up. CONCLUSION: Pap smears with NTZ were not at a higher risk for subsequent detection of cervical abnormalities, making earlier repeat testing unnecessary. Rescreening cases without TZ is neither cost effective nor necessary. PMID- 29722176 TI - Accreditation of histocompatibility and immunogenetics laboratories: Achievements and future prospects from the European Federation for Immunogenetics Accreditation Programme. AB - The importance of demonstrating adherence to good practice in the provision of clinical services is well recognised, and there are many legislative and regulatory requirements that aim to ensure that services are appropriately reviewed and certified. Therefore, for regulatory purposes, laboratories must provide assurance of the quality of the services they provide. Additionally in the field of transplantation, where donor organs and stem cells are exchanged across national boundaries, adoption of a common set of standards by laboratories across many different countries is an important factor. The European Federation for Immunogenetics (EFI) Accreditation Programme was established to provide assurance that Histocompatibility & Immunogenetics laboratories providing services for transplantation, transfusion, and disease association testing meet the requirements of the specialty specific EFI standards. The first H&I laboratories achieved EFI accreditation in 1995, and currently there are over 260 EFI accredited laboratories in 36 countries. The programme depends on the voluntary participation of the inspectors, who are all experts in the field of H&I, and who, over the last 22 years, have performed over 1400 onsite inspections of laboratories. Inspection findings show the areas that are most frequently found to be deficient in meeting the requirements of the standards, and this can be used to inform educational and other activities with the aim of improving laboratory compliance with the standards. The EFI standards have been regularly updated to reflect the changes in the field with 19 versions over the last 22 years, and the data from the accreditation programme show how laboratories have changed their practices to incorporate new techniques that support patient care. PMID- 29722177 TI - The Iowa Personality Disorder Screen: A validation study in a psychiatric population that receives long-term group psychotherapy for personality related problems. AB - Personality disorder (PD) is common among psychiatric patients, and diagnosing such disorders is of great importance for the choice of treatment. Diagnosing PD is a demanding and time-consuming process. The utilities of several PD screening instruments have been studied in different populations, but not in a population who receives long-term group psychotherapy. In the current study, we investigate the predictive properties of the Iowa Personality Disorder Screen (IPDS) in a sample of 694 psychiatric outpatients with and without PD who were admitted for psychodynamic long-term group therapy from 2012 to 2014. The definitive, reference diagnoses were defined according to the SCID-II, by which 484 patients (68%) warranted a PD diagnosis. The IPDS correctly classified 67.4 percent of all participants. Sensitivity (0.75) and specificity (0.51) were lower than in previous validation studies of IPDS. We discuss possible explanations related to the general concept of PD and, more specifically, to our study sample. Because of the weaker predictive properties of IPDS, we advise caution in use of the IPDS in similar clinical settings. Copyright (c) 2018 John Wiley & Sons, Ltd. PMID- 29722178 TI - External validation of the Rapid Assessment Prioritisation and Referral Tool for multidisciplinary teams in medical assessment and planning units. AB - OBJECTIVE: The Rapid Assessment Prioritisation and Referral Tool (RAPaRT) was developed for identifying appropriate referrals to allied members of the multidisciplinary team in hospital medical assessment and planning units (MAPUs). This study examined the performance of the RAPaRT for identifying appropriate referrals as well as predicting requirement for admission to hospital and length of stay. METHODS: A prospective cohort study was conducted. The RAPaRT, inclusive of seven mandatory items, was completed by nurses for 195 patients presenting to a hospital ED and assessed in a MAPU external to the instrument development site. Members of the multidisciplinary team (dietetics, occupational therapy, physiotherapy, social work and speech pathology) assessed participants to determine whether a referral to their profession was warranted and this was compared to RAPaRT responses. RESULTS: All health professionals reviewed n = 175/195 (90%) participants, with n = 117/195 (60%) considered appropriate for referral to an allied health professional. At least one positive response to the RAPaRT items was recorded for n = 123 (63%) participants. Patterns of sensitivity and specificity for each item, and the instrument as a whole were consistent with the development study. The RAPaRT also predicted which patients required admission to an acute hospital ward (odds ratio = 1.22; 95% CI 1.01, 1.47) and their length of stay in hospital (coefficient = 0.18; 95% CI 0.14, 0.22). CONCLUSION: Findings supported the external validation of the RAPaRT. In addition, this investigation made a novel contribution in demonstrating that positive RAPaRT responses were associated with requirement for admission to an acute hospital ward and length of stay. PMID- 29722179 TI - Co-administration of kla-TAT peptide and iRGD to enhance the permeability on A549 3D multiple sphere cells and accumulation on xenograft mice. AB - To enhance the anticancer activity, tumor penetration ability of the hybrid anticancer peptide, in this study, a TAT (RKKRRQRRR) peptide modified kla peptide (KLAKLAKKLAKLAK, with all D-amino acids), named kla-TAT, was co-administrated with the homing/penetrating peptide iRGD which could enhance the permeability of chemical drug in solid tumor and tumor vessel by co-administration. In this study, the nonsmall cell lung cancer A549 cell line with the iRGD targeting receptor neuropilin-1 high expression was selected to establish the 2D monolayer cell, 3D multiple cell spheroids, and xenograft mice model. The co-administration of iRGD strengthened the permeability of kla-TAT peptide against A549 2D and 3D sphere model with the penetration improvement property of iRGD; more importantly, co-administration with iRGD dramatically enhanced the accumulation of kla-TAT peptide in tumor tissue on the xenograft mice model with the homing property of iRGD. The co-administration of iRGD strategy confers targeting ability to the hybrid peptide kla-TAT. We believe the chemical conjugation plus co administration approach may provide a promising way for cancer treatment in clinical practices. PMID- 29722180 TI - Facilitation- vs. competition-driven succession: the key role of resource-ratio. AB - Symbiotic nitrogen (N)-fixing plants are abundant during primary succession, as typical bedrocks lack available N. In turn, fixed N accumulates in soils through biomass turnover and recycling, favouring more nitrophilous organisms. Yet, it is unclear how this facilitation mechanism interacts with competition for other limiting nutrients such as phosphorus (P) and how this affects succession. Here, we introduce a resource-explicit, community assembly model of N-fixing species and analyze successional trajectories along resource availability gradients using contemporary niche theory. We show that facilitation-driven succession occurs under low N and high enough P availabilities, and is characterised by autogenic ecosystem development and relatively ordered trajectories. We show that late facilitation-driven succession is sensitive to catastrophic shifts, highlighting the need to invoke other mechanisms to explain ecosystem stability near the climax. Put together with competition-driven succession, these results lead to an enriched version of Tilman's resource-ratio theory of succession. PMID- 29722181 TI - Behavioral type, in interaction with body size, affects the recapture rate of brown trout Salmo trutta juveniles in their nursery stream. AB - Movement activity levels of wild animals often differ consistently among individuals, reflecting different behavioral types. Previous studies have shown that laboratory-scored activity can predict several ecologically relevant characteristics. In an experiment on wild brown trout Salmo trutta, spanning from June to October, we investigated how spring swimming activity, measured in a standardized laboratory test, related to relative recapture probability in autumn. Based on laboratory activity scores, individuals clustered into 2 groups, which showed contrasting patterns in the size-dependency of their recapture probability. Size had a slightly positive effect on recapture probability for passive fish but a clear negative effect on active fish. Our results show that the population structure in a cohort, in terms of relative proportions of behavioral types in different size classes, can vary over time. The results of this study could depend on either selective mortality or migration. However, selective disappearance of individuals with specific phenotypes, regardless of the mechanism, will have implications for trout population management, such as stocking efficiency of hatchery fish with high growth rates or maintenance of fishways past migration barriers. PMID- 29722182 TI - Building an international health economics teaching network. PMID- 29722183 TI - Near infrared low-level laser therapy and cell proliferation: The emerging role of redox sensitive signal transduction pathways. AB - Lasers devices are widely used in various medical fields (eg, surgery, dermatology, dentistry, rehabilitative medicine, etc.) for different applications, ranging from surgical ablation of tissues to biostimulation and pain relief. Laser is an electromagnetic radiation, which effects on biological tissues strongly depends on a number of physical parameters. Laser wavelength, energy output, irradiation time and modality, temperature and tissue penetration properties have to be set up according to the clinical target tissue and the desired effect. A less than optimal operational settings, in fact, could result in a null or even lethal effect. According to the first law of photobiology, light absorption requires the presence of a specific photoacceptor that after excitation could induce the activation of downstream signaling pathways. Low level lasers operating in the red/near infrared portion of the light spectra are generally used for biostimulation purposes, a particular therapeutic application based on the radiant energy ability to induce nonthermal responses in living cells. Biostimulation process generally promotes cell survival and proliferation. Emerging evidences support a low-level laser stimulation mediated increase in "good" reactive oxygen species, able to activate redox sensitive signal transduction pathways such as Nrf-2, NF-kB, ERK which act as key redox checkpoints. PMID- 29722184 TI - Synthesis and antibacterial activities of novel pleuromutilin derivatives bearing an aminothiophenol moiety. AB - We synthesized a series of novel thioether pleuromutilin derivatives incorporating 2-aminothiophenol moieties into the C14 side chain via acylation reactions under mild conditions. We evaluated the in-vitro antibacterial activities of the derivatives against methicillin-resistant Staphylococcus aureus (MRSA, ATCC 43300), Staphylococcus aureus (ATCC 29213) and Escherichia coli (ATCC 25922). The majority of the synthesized derivatives possessed moderate antibacterial activities. Compound 8 was found to be the most active antibacterial derivative against MRSA. We conducted docking experiments to understand the possible mode of interactions between compounds 8, 9b, 11a and 50S ribosomal subunit. The docking results proved that there is a reasonable correlation between the binding free energy and the antibacterial activity. Compound 8 was evaluated for its in-vivo antibacterial activity and showed higher efficacy than tiamulin against MRSA in mouse infection model. PMID- 29722185 TI - Recurrent ventricular arrhythmia in a patient with aortitis and myocardial inflammation due to possible immunoglobulin G4-related disease. PMID- 29722186 TI - Nuclear medicine in the era of personalised medicine. PMID- 29722187 TI - Amantadine in Chinese 'Cold and Flu' tablets: the cause of psychosis in a healthy man. PMID- 29722188 TI - Haemochromatosis: a clinical update for the practising physician. AB - Haemochromatosis is most commonly due to the autosomal recessive inheritance of a C282Y substitution in the HFE protein, whereby both alleles of the corresponding gene are affected. The disease is characterised by an inappropriate increase in intestinal iron absorption due to reduced expression of the iron regulatory protein, hepcidin. Progressive iron deposition in parenchymal tissues may ultimately lead to liver and other organ toxicity. The characteristic biochemical abnormalities are raised serum ferritin and transferrin saturation, which can be used in conjunction with genetic tests and emerging magnetic resonance imaging based techniques to diagnose patients with the disorder. Progressive iron overload can manifest clinically as advanced fibrosis, cirrhosis and hepatocellular carcinoma. Enigmatically, the penetrance of both raised iron indices and clinically significant disease is incomplete in patients with hereditary haemochromatosis. Regardless, advanced clinical presentations of the disease have become less common due to increased awareness and earlier diagnosis. On the other hand, obesity and alcohol have been identified as major risk factors that can compound the risk of liver injury in people with hereditary (HFE) haemochromatosis. The prospect of modifying genes that may contribute to the clinical expression of the disease is the subject of ongoing research. Treatment with phlebotomy remains the first-line therapy, and if instigated early leads to a normal life expectancy. A healthy, well-balanced diet is recommended to be incorporated as part of the ongoing management of the disease. PMID- 29722189 TI - Utility of photoplethysmography for heart rate estimation among inpatients. AB - The accuracy of photoplethysmography (PPG) for heart rate (HR) estimation in cardiac arrhythmia is unknown. PPG-HR was evaluated in 112 hospitalised inpatients (cardiac arrhythmias (n = 60), sinus rhythm (n = 52)) using a continuous electrocardiogram monitoring as a reference standard. Strong agreement was observed in sinus rhythm HR < 100 and atrial flutter (bias 1 beat), modest agreement in sinus tachycardia (bias 24 beats) and complete heart block (bias -6 beats) and weak agreement with significant HR underestimation was seen in atrial fibrillation (bias 23 beats). Routine utilisation of PPG for HR estimation may delay early recognition of clinical deterioration in certain arrhythmias and sinus tachycardia. PMID- 29722190 TI - Buruli (Bairnsdale) ulcer in the setting of long-term adalimumab treatment for Crohn disease. PMID- 29722191 TI - Author reply. PMID- 29722192 TI - Clinical presentations of contrast-induced encephalopathy in end-stage renal disease. PMID- 29722193 TI - Hypothalamic demyelination causing panhypopituitarism. AB - Hypothalamic involvement in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) is rare and endocrinopathies involving the hypothalamic pituitary axis in patients with demyelinating conditions have rarely been reported. We present two cases of MS/NMOSD with associated hypothalamic-pituitary involvement and subsequent hypopituitarism, including the first report of a patient with hypothalamic demyelination causing panhypopituitarism. Differential diagnoses, including alemtuzumab-related and primary pituitary pathology are discussed. PMID- 29722194 TI - Author reply. PMID- 29722195 TI - Breaking the routine of peripheral venous catheter replacement. PMID- 29722196 TI - Seafood-borne parasitic diseases in Australia: are they rare or underdiagnosed? AB - Australia is a multicultural country surrounded by water where seafood is regularly consumed. Literature suggests that some popular edible fish sold in fish markets may be infected with parasites transmissible to humans (notably, anisakids and other helminths); however the number of reported human cases due to these parasites is low. In this article we critically review topical publications to understand whether the low number of human infection is due to lack of expertise in Australia to identify and diagnose accurately seafood-borne parasitic infections. The risk these parasites pose to humans may be underestimated due to: (i) errors or inability of diagnosing these infections, primarily due to less sensitive and specific serological tests and misidentifying parasites without a taxonomist in the diagnostic team; and (ii) medical practitioners not being aware of these parasites or not considering them in the differential diagnosis even in patients with history of regular raw or undercooked seafood consumption. PMID- 29722197 TI - Isolated lower limb vasculitis. PMID- 29722199 TI - Bloodwork statistical prediction model for giant cell arteritis. PMID- 29722198 TI - Author reply. PMID- 29722200 TI - Emergency department presentations in early stage breast cancer patients receiving adjuvant and neoadjuvant chemotherapy. AB - (Neo)adjuvant chemotherapy for early stage breast cancer is associated with side effects, resulting in increased emergency department (ED) presentations. Treatment-related toxicity can affect quality of life, compromise chemotherapy delivery and treatment outcomes, and increase healthcare use. We performed a retrospective study of ED presentations in patients receiving curative chemotherapy for early breast cancer to identify factors contributing to ED presentations. Of 102 patients, 39 (38%) presented to ED within 30 days of chemotherapy, resulting in 63 ED presentations in total. Most common reasons were non-neutropenic fever (17 presentations/27%), neutropenic fever (15/24%), pain (9/14%), drug reaction (6/10%) and infection (4/6%). Factors significantly associated with ED presentation were adjuvant chemotherapy timing compared to neoadjuvant timing (P = 0.031), prophylactic antibiotics (P = 0.045) and docetaxel-containing regimen (P = 0.018). PMID- 29722201 TI - Treating cachexia using soluble ACVR2B improves survival, alters mTOR localization, and attenuates liver and spleen responses. AB - BACKGROUND: Cancer cachexia increases morbidity and mortality, and blocking of activin receptor ligands has improved survival in experimental cancer. However, the underlying mechanisms have not yet been fully uncovered. METHODS: The effects of blocking activin receptor type 2 (ACVR2) ligands on both muscle and non-muscle tissues were investigated in a preclinical model of cancer cachexia using a recombinant soluble ACVR2B (sACVR2B-Fc). Treatment with sACVR2B-Fc was applied either only before the tumour formation or with continued treatment both before and after tumour formation. The potential roles of muscle and non-muscle tissues in cancer cachexia were investigated in order to understand the possible mechanisms of improved survival mediated by ACVR2 ligand blocking. RESULTS: Blocking of ACVR2 ligands improved survival in tumour-bearing mice only when the mice were treated both before and after the tumour formation. This occurred without effects on tumour growth, production of pro-inflammatory cytokines or the level of physical activity. ACVR2 ligand blocking was associated with increased muscle (limb and diaphragm) mass and attenuation of both hepatic protein synthesis and splenomegaly. Especially, the effects on the liver and the spleen were observed independent of the treatment protocol. The prevention of splenomegaly by sACVR2B-Fc was not explained by decreased markers of myeloid derived suppressor cells. Decreased tibialis anterior, diaphragm, and heart protein synthesis were observed in cachectic mice. This was associated with decreased mechanistic target of rapamycin (mTOR) colocalization with late endosomes/lysosomes, which correlated with cachexia and reduced muscle protein synthesis. CONCLUSIONS: The prolonged survival with continued ACVR2 ligand blocking could potentially be attributed in part to the maintenance of limb and respiratory muscle mass, but many observed non-muscle effects suggest that the effect may be more complex than previously thought. Our novel finding showing decreased mTOR localization in skeletal muscle with lysosomes/late-endosomes in cancer opens up new research questions and possible treatment options for cachexia. PMID- 29722204 TI - Towards Hydrogen Storage through an Efficient Ruthenium-Catalyzed Dehydrogenation of Formic Acid. AB - Hydrogen is of fundamental importance for the construction of modern clean-energy supply systems. In this context, the catalytic dehydrogenation of formic acid (FA) is a convenient method to generate H2 gas from an easily available liquid. One of the issues associated with current catalytic dehydrogenation systems is insufficient stability. Here, we present a robust and recyclable system for FA dehydrogenation by combining a ruthenium 1,1,1 tris(diphenylphosphinomethyl)ethane complex and aluminum trifluoromethanesulfonate (Al(OTf)3 ). This robust system allows steady H2 production under pressure and recycling for an additional 14 runs without any apparent loss of activity (turnover frequencies up to 1920 h-1 , turnover numbers up to 20 000). Notably, the catalyst can also be used for the dehydrogenation of formates and the reverse hydrogenation of bicarbonates and CO2 . PMID- 29722203 TI - One-pot synthesis and antiproliferative activity of novel double-modified derivatives of the polyether ionophore monensin A. AB - Monensin A (MON) is a polyether ionophore antibiotic, which shows a wide spectrum of biological activity. New MON derivatives such as double-modified ester carbonates and double-modified amide-carbonates were obtained by a new and efficient one-pot synthesis with triphosgene as the activating reagent and the respective alcohol or amine. All new derivatives were tested for their antiproliferative activity against two drug-sensitive (MES-SA, LoVo) and two drug resistant (MES-SA/DX5, LoVo/DX) cancer cell lines, and were also studied for their antimicrobial activity against different Staphylococcus aureus and Staphylococcus epidermidis bacterial strains. For the first time, the activity of MON and its derivatives against MES-SA and MES-SA/DX5 were evaluated. PMID- 29722205 TI - EVIDENCE-BASED RENAL CARE: DOES IT MATTER? PMID- 29722207 TI - Caenorhabditis nomenclature. AB - Genetic nomenclature for Caenorhabditis species and other nematodes is supervised by WormBase in collaboration with the Caenorhabditis Genetics Center (CGC) and with essential input from the community of scientists working on C. elegans and other nematodes. PMID- 29722202 TI - Nomenclature for factors of the HLA system, update January 2018. PMID- 29722208 TI - [Effects of simulated warming and functional group removal on survival and growth of Abies faxoniana seedlings]. AB - Warming and herbaceous functional group removal experiment was conducted in subalpine meadow to examine the effects of herbaceous species on Abies faxoniana seedlings by analyzing its physiological responses. The survival rate and non structural carbohydrate content were significantly increased, but the growth and root/shoot of A. faxoniana were decreased. Seedling survival was significantly positively correlated with non-structural carbohydrate content, especially with soluble sugar. Under the treatment without warming, herbaceous species inhibited the survival of A. faxoniana, increased height growth and aboveground biomass. Grasses and forbs decreased the root length and belowground biomass of A. faxoniana. In the warming treatment, forbs increased the survival of A. faxoniana, sedges decreased root length and belowground biomass of A. faxoniana, and grasses and forbs decreased height growth and aboveground biomass of A. faxoniana. Simulated warming increased the survival of A. faxoniana seedlings, but also made it face stronger competition from herbaceous and thus inhibited its growth. PMID- 29722209 TI - [Response of seed reproduction of two dominant lakeside species to experimental warming in a typical plateau wetland in Northwestern Yunnan Plateau, China]. AB - Based on the forecasted warming scenarios by IPCC, we studied the impacts of warming (increased by 2.0 and 3.5 C) on seed reproduction of two lakeside dominant species (Schoeno-plectus tabernaemontani and Sparganium stoloniferum) in a typical plateau wetland (Napahai) in Northwestern Yunnan, by using "open-top chamber" technique. The results showed that warming had significant effects on the seed setting rate of both species, though with interspecific variation. The seed setting rate of S. tabernaemontani was significantly increased under two warming treatments, while that of S. stoloniferum was significantly decreased under the 2.0 C warming treatment and had no variation under the 3.5 C warming treatment. Warming promoted the spike growth of both species. For S. tabernaemontani, under the warming of 2.0 and 3.5 C treatments, the spike length was increased by 82.9% and 89.0%, the spikelet number was increased by 133.3% and 150.0%, the biomass of each individual was increased by 10.1% and 89.6%, and the rate between biomass of per plant panicle and total biomass was increased by 79.5% and 409.3%, respectively. For S. stoloniferum, under the warming of 2.0 and 3.5 C treatments, the spike length was increased by 66.1% and 95.2%, and the rate between biomass of per plant panicle and total biomass was increased by 878.8% and 1052.6%, respectively. Warming significantly increased seed yield of both species. Under the warming of 2.0 and 3.5 C treatments, the seed yield per panicle of S. tabernaemontani was increased by 33.7% and 58.3%, respectively. For S. stoloniferum, the seed yield was increased by 3.4% and 69.5%, respectively. Under the warming of 2.0 and 3.5 C treatments, the seed length of S. tabernaemontani was increased by 5.4% and 6.9%, and the seed length/width was increased by 9.1% and 5.3%, respectively. Warming had no significant effects on the seed shape of S. stoloniferum. The maximum and minimum temperatures were dominant factors affecting seed reproductions of both species. The advance of growing season, the prolonging of nutrition growing period, and accumulation of organic matter induced by warming would provide sufficient nutrient and energy accumulation for the reproduction and development of plants, which would promote seed reproduction capability of both species under the warming conditions. PMID- 29722210 TI - [Effects of soil warming on specific respiration rate and non-structural carbohydrate concentration in fine roots of Chinese fir seedlings]. AB - A field mesocosm experiment with Chinese fir (Cunninghamia lanceolata) seedlings was conducted in Chenda State-Owned Forest Farm, Sanming, Fujian Province. The effects of soil warming (ambient +5 C) on specific respiration rates and nonstructural carbohydrate (NSC) concentrations in fine roots were measured by the ingrowth core method, to reveal the belowground responses and the adaptability of Chinese fir to global warming. The results showed that soil warming caused significant changes of fine root NSC in the second year. The NSC and starch concentrations in 0-1 mm fine roots, and the NSC and sugar concentrations in 1-2 mm fine roots decreased signifi-cantly in January. The NSC, sugar and starch concentrations in 0-1 mm roots and the starch concentration in 1 2 mm roots increased in July. Soil warming had no significant effect on fine root NSC in the third year. The specific root respiration rate of the 0-1 mm roots significantly increased in July of the second year but significantly decreased in July of the third year in the warmed plots. Compared with the 0-1 mm roots, soil warming had no significant effect on the specific root respiration rate of the 1 2 mm roots. In conclusion, the responses of fine root respiration to soil warming depended on the duration of warming. Fine root respiration partly acclimated to soil warming with increasing duration of soil warming, which kept fine root NSC being relatively stable. PMID- 29722211 TI - [Simulating the effects of climate change and fire disturbance on aboveground biomass of boreal forests in the Great Xing'an Mountains, Northeast China]. AB - Predicting the effects of climate warming and fire disturbance on forest aboveground biomass is a central task of studies in terrestrial ecosystem carbon cycle. The alteration of temperature, precipitation, and disturbance regimes induced by climate warming will affect the carbon dynamics of forest ecosystem. Boreal forest is an important forest type in China, the responses of which to climate warming and fire disturbance are increasingly obvious. In this study, we used a forest landscape model LANDIS PRO to simulate the effects of climate change on aboveground biomass of boreal forests in the Great Xing'an Mountains, and compared direct effects of climate warming and the effects of climate warming induced fires on forest aboveground biomass. The results showed that the aboveground biomass in this area increased under climate warming scenarios and fire disturbance scenarios with increased intensity. Under the current climate and fire regime scenario, the aboveground biomass in this area was (97.14+/-5.78) t.hm-2, and the value would increase up to (97.93+/-5.83) t.hm-2 under the B1F2 scenario. Under the A2F3 scenario, aboveground biomass at landscape scale was relatively higher at the simulated periods of year 100-150 and year 150-200, and the value were (100.02+/-3.76) t.hm-2 and (110.56+/-4.08) t.hm-2, respectively. Compared to the current fire regime scenario, the predicted biomass at landscape scale was increased by (0.56+/-1.45) t.hm-2 under the CF2 scenario (fire intensity increased by 30%) at some simulated periods, and the aboveground biomass was reduced by (7.39+/-1.79) t.hm-2 in CF3 scenario (fire intensity increased by 230%) at the entire simulation period. There were significantly different responses between coniferous and broadleaved species under future climate warming scenarios, in that the simulated biomass for both Larix gmelinii and Betula platyphylla showed decreasing trend with climate change, whereas the simulated biomass for Pinus sylvestris var. mongolica, Picea koraiensis and Populus davidiana showed increasing trend at different degrees during the entire simulation period. There was a time lag for the direct effect of climate warming on biomass for coniferous and broadleaved species. The response time of coniferous species to climate warming was 25-30 years, which was longer than that for broadleaf species. The forest landscape in the Great Xing'an Mountains was sensitive to the interactive effect of climate warming (high CO2 emissions) and high intensity fire disturbance. Future climate warming and high intensity forest fire disturbance would significantly change the composition and structure of forest ecosystem. PMID- 29722212 TI - [Sap flow characteristics of Quercus liaotungensis in response to sapwood area and soil moisture in the loess hilly region, China]. AB - To examine the characteristics of sap flow in Quercus liaotungensis and their response to environmental factors under different soil moisture conditions, Granier-type thermal dissipation probes were used to measure xylem sap flow of trees with different sapwood area in a natural Q. liaotungensis forest in the loess hilly region. Solar radiation, air temperature, relative air humidity, precipitation, and soil moisture were monitored during the study period. The results showed that sap flux of Q. liaotungensis reached daily peaks earlier than solar radiation and vapor pressure deficit. The diurnal dynamics of sap flux showed a similar pattern to those of the environmental factors. Trees had larger sap flux during the period with higher soil moisture. Under the same soil moisture conditions, trees with larger diameter and sapwood areas had significantly higher sap flux than those with smaller diameter and sapwood areas. Sap flux could be fitted with vapor pressure deficit, solar radiation, and the integrated index of the two factors using exponential saturation function. Differences in the fitted curves and parameters suggested that sap flux tended to reach saturation faster under higher soil moisture. Furthermore, trees in the smaller diameter class were more sensitive to the changes of soil moisture. The ratio of daily sap flux per unit vapor pressure deficit under lower soil moisture condition to that under higher soil moisture condition was linearly correlated to sapwood area. The regressive slope in smaller diameter class was larger than that in bigger diameter class, which further indicated the higher sensitivity of trees with smaller diameter class to soil moisture. These results indicated that wider sapwood of larger diameter class provided a buffer against drought stress. PMID- 29722213 TI - [Effects of stand density on understory species diversity and soil physicochemical properties of Pinus massoniana plantation]. AB - We analyzed understory species diversity, soil physicochemical traits and their relationships in the 25-year-old non-commercial Pinus massoniana plantations with five different stand densities, i.e., 1057, 1136, 1231, 1383 and 1515 trees.hm-2, in Wenfeng Mountain, Xinjin District, Sichuan Province, China. The results showed that a total of 110 species were found, belonging to 57 families and 98 genera. With the increase of tree density, the understory species showed a succession pattern from positive to moderate to shady. Different densities had significant effects on the contents of total potassium and organic matter in the soils. With the increase ofdensity, the contents of organic matter and total potassium in understory vegetation first increased and then decreased. The trends of the relationship between both diversity and soil physiochemical characteristics and tree density were similar. Both of them increased with the increase of density, with the maximum value presented at the density of 1136 trees.hm-2. The concentrations of total phosphorus, available potassium, total potassium and total nitrogen was closely related to plant diversity index. The results suggested that the density at 1136 trees.hm-2 would be more beneficial to improve the stability of species diversity and soil fertility of P. massoniana non commercial plantations in Wenfeng Mountain. PMID- 29722214 TI - [Optimizing vegetation pattern for the riparian buffer zone along the lower Yellow River based on slope hydrological connectivity]. AB - Riparian buffer zone is important ecological transitional region between river and upland. Restoring the degraded vegetation system is important for preventing soil erosion, improving ecological environment and helping to achieve the sustainable development of ecosystems. Based on the scenario simulation of vegetation pattern and flow length index, we analyzed the responses of hydrological connectivity to vegetation pattern under different vegetation coverages and slope gradients, and explored the optimal vegetation pattern of soil and water conservation in riparian buffer zone in the lower reaches of the Yellow River. The results showed that the midslope-coarsness-clustered distribution of vegetation configuration, which exhibited the shortest flow length and the weakest hydrological connectivity, being the optimal vegetation pattern for controlling slope runoff generation and flow concentration. For the optimal vegetation pattern, its flow length increased with increasing slope length, namely, the longer slope length the more significant difference of hydrological connectivity between different slope gradients. Meanwhile, flow length of the optimal vegetation pattern decreased with increasing vegetation coverage. The differences between different slope gradients were obvious under low vegetation coverage, while it was unobvious on slope with vegetation coverage of 45%. Compared with the irregular variation trend of flow length on the actual vegetation slope, there was a consistent trend of first increase and then decrease on the simulated slope with the optimal vegetation pattern. Within the pre-set slope gradient range (5 degrees -20 degrees ), the optimal vegetation pattern changed the variation of flow length between different slope gradients in the process of coverage change, which highlighted the influence of riparian buffer zone vegetation pattern on hydrological connectivity. PMID- 29722215 TI - [Characteristics of soil organic carbon mineralization in low altitude and high altitude forests in Wuyi Mountains, southeastern China]. AB - Examining the variations of soil organic carbon mineralization at different altitudes is crucial for better understanding of soil organic carbon (SOC) dynamics. We selected the low altitude and high altitude broad-leaved forest soils in Wuyi Mountains as the research object, and incubated them under particular annual average temperature (17 and 9 C, respectively) in laboratory to investigate the difference of SOC mineralization characteristics. The results showed that the cumulative SOC mineralization had no significant difference between forest soils at low and high altitude in a 126-day incubation period under ambient temperature. Soil organic carbon content of high altitude soil was significantly higher than that from low altitude. The dynamics of SOC mineralization could fitted by the first-order kinetics. Both mineralization potential (CP) and mineralization rate constant (K) values of two soils had no significant difference, but CP/SOC value and mineralization ratio were significantly higher at low altitude, indicating that the carbon sequestration capacity of low altitude soil was relatively lower than that of high altitude under ambient temperature. Soil microbial biomass carbon and microbial quotients were significantly higher than that of low altitude with the increase of incubation time, indicating that the ability of microbial carbon assimilation was greater at high altitude. On the other hand, the activities of beta-1,4 glucosidase and cellobiohydrolase in high altitude soil were higher, suggesting that more labile carbon would be decomposed by soil microbes. The carbon sequestration capacity and microbial carbon utilization efficiency in high altitude soil would be reduced and thus result in a decline of soil organic carbon storage under the scenarios of climate warming. PMID- 29722216 TI - [Effects of naphthalene on soil respiration, dissolved organic matter and microbial biomass in the subalpine forest of western Sichuan, China]. AB - The effects of naphthalene on soil respiration, dissolved organic matter and microbial biomass, and its inhibition efficiency for soil fauna of subalpine forest in western Sichuan were studied by in situ control experiment. The results showed that naphthalene application significantly inhibited the individual density and group number of soil macro- and meso-/micro- arthropods, with the individual density being decreased by 76.3%-78.5% and 83.3%-84.8% respectively, and the number of groups being decreased by 48.3%-56.1% and 45.8%-58.3%, respectively. The seasonal dynamics of soil respiration rate showed single peak curves in both naphthalene treatment and control. The lowest and the highest soil respiration rates were observed in February and August, respectively. The naphthalene treatment had little effect on soil respiration. Compared with the control, naphthalene treatment significantly reduced the contents of soil dissolved carbon and dissolved nitrogen in August and October as well as microbial biomass carbon (MBC) in April and August, but increased MBC/MBN in April. The naphthalene treatment and sampling time significantly interacted to affect the MBC and MBN, but had no significant effect on individual density, the number of groups of soil fauna and DC content. In all, naphthalene as biocide could effectively inhibit the soil arthropods and had no significant effect on soil respiration, but it had varying degrees of effects on soil carbon and nitrogen components in subalpine forest of western Sichuan. PMID- 29722217 TI - [Characteristics of soil moisture variation in different land use types in the hilly region of the Loess Plateau, China]. AB - Soil water availability is a key factor restricting the ecological construction and sustainable land use in the loess hilly region. It is of great theoretical and practical significance to understand the soil moisture status of different land use types for the vegetation restoration and the effective utilization of land resources in this area. In this study, EC-5 soil moisture sensors were used to continuously monitor the soil moisture content in the 0-160 cm soil profile in the slope cropland, terraced fields, jujube orchard, and grassland during the growing season (from May to October) in the Yuanzegou catchment on the Loess Plateau, to investigate soil moisture dynamics in these four typical land use types. The results showed that there were differences in seasonal variation, water storage characteristics, and vertical distribution of soil moisture under different land use types in both the normal precipitation (2014) and dry (2015) years. The terraced fields showed good water retention capacity in the dry year, with the average soil moisture content of 0-60 cm soil layer in the growing season being 2.6%, 4.2%, and 1.8% higher than that of the slope cropland, jujube orchard, and grassland (all P<0.05). The water storage of 0-160 cm soil profile was 43.90, 32.08, and 18.69 mm higher than that of slope cropland, jujube orchard, and grassland, respectively. In the normal precipitation year, the average soil moisture content of 0-60 cm soil layer in jujube orchard in the growing season was 2.9%, 3.8%, and 4.5% lower than that of slope cropland, terraced fields, and grassland, respectively (all P<0.05). In the dry year, the effective soil water storage of 0-160 cm soil profile in the jujube orchard accounted for 35.0% of the total soil water storage. The grey relational grade between the soil moisture in the surface layer (0-20 cm) and soil moisture in the middle layer (20-100 cm) under different land use types was large, and the trend for the similarity degree of soil moisture variation followed terraced fields > grassland > slope cropland > jujube orchard. The slope cropland in this area could be transformed into terraced fields to improve the utilization of precipitation and promote the construction of ecological agriculture. Aiming at resolving the severe water shortage in the rain-fed jujube orchard for the sustainable development of jujube orchard in the loess hilly region, appropriate water management measures should be taken to reduce the water consumption of jujube trees and other inefficient water consumption. PMID- 29722218 TI - [Non-structural carbohydrates characteristics of different forest layers in monsoon broad-leaved evergreen forest in Pu'er, Yunnan Province, China]. AB - Based on cluster analysis of species vertical stratification, the variations in concentration, allocation and seasonal dynamics of non-structural carbohydrates were investigated in a monsoon broad-leaved evergreen forest in Pu'er, Yunnan Province. The results showed that the concentrations of soluble sugar (3.9%) and nonstructural carbohydrates (NSC, 13.3%) were the highest in the sub-canopy. In contrast, the sugar/starch (0.76) of understory was the lowest. There was no significant difference in starch content among three forest layers. For all forest stories, the soluble sugar was mainly allocated to leaves and the roots had more starch and NSC. The soluble sugar contents in leaves and trunks of sub canopy species were higher than canopy and understory species. There were no significant differences in soluble sugar content of twigs and roots among three different forest layers. The starch content of leaves increased with decreasing height of forest layers. In contrast, the lowest starch content (10.7%) of roots was in understory. There was no significant difference in starch content of twigs and trunks among three different forest layers. The NSC content of leaves was lower in canopy (10.7%) than that in sub-canopy (12.3%) and understory (12.0%). The lowest NSC content of roots was in understory (14.2%). The lowest sugar/starch of leaves, twigs, and trunks presented in understory, while the lowest sugar/starch of roots presented in canopy (0.79). There were dramatic seasonal variations in concentrations and components of NSC. The concentration of soluble sugar and the sugar/starch were higher in the rainy season than that in the dry season. However, the concentration of starch and NSC were higher in the dry season than in the rainy season. The variations in concentration of NSC and its components among forest layers indicated that species with different heights varied in their utilization strategies of carbon, which partly explained species coexistence. PMID- 29722219 TI - [Biomass and morphological characteristics of fine roots and their affecting factors in diffe-rent vegetation restoration stages in depressions between karst hills]. AB - This study focused on four vegetation restoration stages of grasslands, shrublands, secondary forests and primary forests in the typical karst peak cluster depression. The soil core method was used to collect fine roots with 2 mm or less in diameter in three layers (0-10, 10-20, 20-30 cm). The biomass, morphological characteristics of fine roots and their relationship with soil properties were analyzed. The results showed that fine root biomass ranged between 194.63 and 255.19 g.cm-2 in different vegetation restoration stages. Most of fine roots distributed in the surface soil of 0-10 cm, which accounted for more than 60% of the total biomass in the soil layer of 0-30 cm. No significant difference was found among different stages in fine root biomass. There was significant difference among different stages in the specific root length and specific surface area of fine roots. Both parameters were gradually decreased with vegetation forward restoration from grassland to primary forest. More than 66% root length and 64% root area were distributed in the surface soil of 0-10 cm. The length and area of most of the fine root were in the diameter class of 0 0.5 mm and 0.5-1mm, respectively. These two levels of the root length and root area accounted for more than 87% and 72% of the total amount, respectively. Results from the redundancy analysis showed that there were different correlations between karst peak-cluster depression vegetation community characteristics and soil properties, with soil organic carbon, available potassium, and total nitrogen having a great influence on the characteristics of fine roots. It is an effective strategy for plants to better adapt to the habitats. PMID- 29722220 TI - [The impact of phylogenetic uncertainty on the metrics of community phylogenetic structure]. AB - Phylogeny has been widely used to quantify community phylogenetic structure and to infer the underlying mechanism. Many studies, however, neglected phylogeny uncertainty and its potential impact on community phylogenetic structure. In this study, we explored the potential impact of phylogenetic uncertainty among 150 species in a 20 hm2 plot in Tiantong, Zhejiang. One consensus tree and 999 phylogenetic trees representing the phylogenetic uncertainty were estimated based on two cpDNA fragments (rbcL and matK). Combined with the species distribution data, community phylogenetic structure was quantified by two common indices (NRI and NTI) and their significances were tested by the independent swap null model. Our results showed that tree topology and node age showed a large uncertainty. The uncertainty was larger for young species and significantly increased with mean phylogenetic distance. Phylogenetic uncertainty increased the variation of both standardized NRI and NTI in each quadrat. These impacts were independent between both indices in either spatial pattern or the degree of impact. NRI was more sensitive than NTI to the uncertainty. At community scale, phylogenetic uncertainty also affected the variation of the mean standardized NRI and NTI of all quadrats, with mean standard deviation of 0.37 and 0.077, respectively. Such a result suggests that mean standardized NRI at community level was more vulnerable to the phylogenetic uncertainty, which is consistent with the result at the sample level. Our findings showed that phylogenetic uncertainty could add different variation into the NRI and NTI series indices and might increase biases in the quantification of community phylogenetic structure and its underlying ecological processes. Our results implied that non-random community phylogenetic structure was probably overestimated in the previous studies which ignored phylogenetic uncertainty. PMID- 29722221 TI - [Effects of exogenous glucose on growth and root nitrogen metabolism in Malus baccata]. AB - To examine the effects of external glucose on growth, root architecture and nitrogen metabolism of Malus baccata seedlings in low carbon soil condition, Malus baccata seedlings were grown in sandy soil with the concentration of soil organic matter being 0.65%. The experiment consisted of three treatments: Control, with 2 g.kg-1 glucose that equal to the ambient microbial biomass carbon (MBC), and with 10 g.kg-1 glucose that was five times higher than the ambient MBC. The plant height, biomass, total root length and superficial area of the five times MBC group were 12.3%, 26.4%, 23.2% and 14.6% higher than that of the control, respectively. Root diameter, root volume and average diameter exhibited no significant difference under glucose treatments. The root activity was significantly increased under equal and five times MBC-glucose treatments, and reached its peak at 3 d and 15 d, about 119.1% and 75.7% higher than the control, respectively. Exogenous glucose addition significantly enhanced the concentrations of NO3-, NO2- and NH4+ in roots. The activities of nitrate reductase, glutamine synthetase, glutamate dehydrogenase, glutamate synthase, glutamic-oxalacetic transaminase and glutamic-pyruvic transaminase were substantially increased in the roots, especially under five times MBC treatment. Five times higher than the ambient MBC of external carbon source promoted biomass accumulation, root growth, morphogenesis and N absorption of plants in low carbon sandy soil. PMID- 29722222 TI - [Module growth and biomass allocation of Chloris virgate clone at different growth stages in Songnen Plain, China]. AB - The growth characteristic and strategies of Chloris virgate at different growth stages were examined in Songnen Plain by analyzing the quantitative characters and biomass allocation of aboveground and belowground parts at shooting and ripening stages in C. virgate population, with a large amount of sampling. The results showed that height, total root length, total root surface area, root volume, aboveground biomass, belowground biomass, and total biomass were significantly different between the two growth stages. There was power allometric relationship between total biomass and biomass allocation of aboveground and belowground, respectively. At shooting stage, there was a significant linear isometric growth between the total biomass and the number of ramets, total root length, total root surface area and root volume, but there was a power allometric growth at ripening stage. C. virgate clone showed different growth strategies under different growth stages, with a priority expansion strategy of clonal outer space at shooting stage and a complementary and expansive strategy in the inner and outer space of the clones at ripening stage. PMID- 29722223 TI - [Physiological integration of growth and photosynthesis of Zoysia japonica clonal ramets under nutrient heterogeneity]. AB - This study was carried out to analyze the changes of growth and photosynthesis of clonal ramets under nutrient heterogeneity, where the connected and disconnected ramets were treated with different nutrient levels. The results showed that under the nutrient heterogeneity the parent ramets in middle or high nutrient levels improved leaf length, leaf width, root mass, leaf mass, net photosynthetic rate, stomatal conductance, transpiration rate and water use efficiency of the connected daughter ramets, with an increase of 16.0%, 8.3%, 24.4%, 58.1%, 30.3%, 54.0%, 9.2% and 21.9% in high nutrient level, respectively, but reduced the root/shoot and intercellular CO2 concentration of the connected daughter ramets, with a decreases of 21.6% and 31.5% in high nutrient level, respectively. In contrast, the daughter ramets in the middle or high nutrient level had no significant impacts on the growth and photosynthesis of the connected parent ramets. There was a physiological integration from the parent ramets to the daughter ramets. The larger the nutrient differences of ramets was, the stronger the intensity of physiological integration was. The daughter ramets were the unidirectional beneficiary from the physiological integration, as the daughter ramets benefited from the parent ramets but had no positive effects on the daughter ramets. PMID- 29722224 TI - [Effects of cultivation patterns on wheat yield and grain nutrient concentration in dryland]. AB - A field experiment was conducted to examine the effects of plastic film mulching (PM), straw retention (SR) and planting green manure (GM) on grain yield and nutrient concentrations of winter wheat. Compared to the traditional pattern (TP), plastic film mulching showed no significant effect on the average yield over the three years but increased the average phosphorus (P) uptake and concentration in grain by 8.4% and 13.0%, respectively. The average uptake of nitrogen (N), sulfur (S) and iron (Fe) was decreased by 12.6%, 15.0% and 11.1%, and the corresponding concentration was decreased by 12.1%, 12.9% and 10.1%, respectively. There was no significant effect on grain zinc (Zn) concentration. Straw retention decreased grain yield by 12.1%, reduced the average uptake of N, S and Fe decreased by 22.5%, 21.0% and 19.8%, and their corresponding concentration by 10.1%, 9.4% and 3.8%, respectively. The average uptake of P in grain was decreased by 9.8% with straw retention, while the P concentration was increased by 5.0%. There was no significant effect of straw retention on Zn concentration in grain. Planting green manure decreased the grain yield by 12.1%. It had no significant effect on the average uptake of N and Zn, but increased the grain N and Zn concentration by 12.1% and 12.6%, respectively. It showed no impact on P, S and Fe concentration in grain. The discordance between variation of grain yield and its nutrient uptake under different cultivations was the key reason for the changes of their nutrient concentration. Considering the potential adverse effects of plastic film mulching and straw retention on the quantity and quality of grain yield, suitable N fertilization should be applied to ensure the nutrient requirement for grain yield and regulate the uptake and utilization of N, S and Fe for improving the grain quality. Planting green manure could improve soil fertility and increase grain N and Zn concentration, but the yield reduction deserves more attention. PMID- 29722225 TI - [Characteristics of CO2 flux and its influence factors over winter wheat agroecosystem in the North China Plain]. AB - Using CO2 flux data of winter wheat recorded by eddy covariance system, combined with the meteorological data, we examined the diurnal variations of CO2 fluxes in four growth stages (tillering stage, overwintering stage, jointing stage and filling stage) of winter wheat in an agroecosystem of the North China Plain from 2013 to 2014. The seasonal variation of net ecosystem exchange and its relationship with meteorological factors were investigated. The results showed that the net ecosystem exchange in the whole growing season was -360.15 g C.m-2. The gross primary productivity in the whole growing season was 1920.01 g C.m-2. The winter wheat agroecosystem had strong capacity in carbon sequestration. The CO2 fluxes showed an obvious diurnal and seasonal variation characteristics in winter wheat agroecosystem. This ecosystem was a carbon source in tillering stage, while it was a carbon sink in overwintering stage, jointing stage and filling stage. The mean value of apparent initial light energy utilization was 0.03 mg CO2.MUmol-1. The mean value of ecosystem production was 1.53 mg CO2.m-2.s 1 when light was saturated. The monthly average value of ecosystem respiration was 193.92 g C.m-2.month-1. The net ecosystem exchange and photosynthetically active radiation had a significant correlation in four growth stages of winter wheat. The correlations between net ecosystem exchange and vapor pressure deficit were significant in all the growth stages. There was a positive correlation between daily total net ecosystem exchange and soil temperature in tillering stage, overwintering stage and filling stage, but a negative correlation between them in jointing stage. PMID- 29722226 TI - [Soil quality assessment under different cropping system and straw management in farmland of arid oasis region]. AB - To reveal the regulatory mechanism of agricultural management practices on soil quality, an experiment was carried out to study the different cropping system and straw management on soil organic carbon and fractions and soil enzyme activity in farmland of arid oasis region, which would provide a scientific basic for enhancing agricultural resources utilization and sustainable development. In crop planting planning area, we took the mainly crop (cotton, wheat, maize) as research objects and designed long-term continues cropping and crop rotation experiments. The results showed that the soil organic carbon (SOC), soil microbial biomass C, labile C, water-soluble organic C, and hot-water-soluble organic C content were increased by 3.6%-9.9%, 41.8%-98.9%, 3.3%-17.0%, 11.1% 32.4%, 4.6%-27.5% by crop rotation compared to continues cropping, and 12%-35.9%, 22.4%-49.7%, 30.7%-51.0%, 10.6%-31.9%, 41.0%-96.4% by straw incorporated compared to straw removed, respectively. The soil catalase, dehydrogenase, beta glucosidase, invertase glucose, cellulase glucose activity were increased by 6.4% 10.9%, 6.6%-18.8%, 5.9%-15.3%, 10.0%-27.4%, 28.1%-37.5% by crop rotation compared to continues cropping, and 31.4%-47.5%, 19.9%-46.6%, 13.8%-20.7%, 19.8%-55.6%, 54.1%-70.9% by straw incorporated compared to straw removed, respectively. There were significant positive linear correlations among SOC, labile SOC fractions and soil enzyme. Therefore, we concluded that labile SOC fractions and soil enzyme were effective index for evaluating the change of SOC and soil quality. Based on factor analysis, in arid region, developing agricultural production using cropland management measures, such as straw-incorporated and combined short-term continues cotton and crop rotation, could enhance SOC and labile SOC fractions contents and soil enzyme activity, which could improve soil quality and be conducive to agricultural sustainable development. PMID- 29722227 TI - [Carbon footprint of wheat-summer direct-seeding peanut planting system in Shandong Pro-vince, China]. AB - Clarifying the carbon emissions in wheat-summer direct-seeding peanut planting (W P) system could help realize the synergistic effects of high yield and low carbon emissions. Based on whole life cycle method, we constructed a carbon footprint model to calculate the carbon emissions of W-P system. We found that the net income of W-P system was 71.2%-88.3% higher than that of wheat-maize rotation (W M) system. The carbon emissions per unit area under W-P system was 6977.9-8018.5 kg.hm-2, being 6.2% higher than that of W-M system. The carbon emission of per net income under W-P system was 0.23-0.28 kg CO2-eq.yuan-1, which was 37.4%-44.1% lower than that of W-M system. Combining the net income and carbon emissions of per net income, W-P system could achieve synergistic effects of high yield and low carbon emissions, which would fulfill the targets of agricultural supply-side structural reform with optimizing supply, enhancing quality and efficiency, and increasing income of peasants. PMID- 29722228 TI - [Responses of organic carbon mineralization and priming effect to phosphorus addition in paddy soils]. AB - To understand the coupled controlling of carbon (C) and phosphorus (P) on the minera-lization of soil organic carbon and amended substrates in paddy soil, we investigated the effects of P addition on the decomposition of organic carbon and its induced priming effect by using 13C isotope probing technique in microcosm. The results showed that P addition accelerated the release of CO2 but inhibited the release of CH4, leading to 53.1% reduction of total accumulated CH4 and 70.5% reduction of the 13CH4 derived from exotic glucose-13C. P addition altered the carbon distribution during the microbial turnover progress, with 3.6% of glucose 13C being transferred into the labile carbon pool, therein significantly increased potential of the mineralization rate of exogenous C. A transient negative priming effect was observed in the early stage of incubation. With time prolonging, the priming effect on CO2 emission (PECO2) generally increased and then decreased after a peak. The priming effect on CH4 emission (PECH4) kept increasing and finally fluctuated at a relative stable value until the end of the experiment (100 days). P addition increased PECO2 by 32.3% but reduced PECH4 by 93.4%. Results from the RDA and Pearson analysis showed that electric conductivity, oxidation-reduction potential and dissolved organic carbon significantly affected soil C mineralization. There were significantly negative correlations between available phosphorus (Olsen-P) and 13CH4, and between Olsen P and PECH4. In conclusion, with the addition of exogenous organic matter, P application could reduce CH4 emissions and inhibit its priming effect, acce lerate the mineralization of SOC, probably improve the nutrient supply, and thus enhance the avai-lability of organic C and promote C cycling in paddy soil. PMID- 29722229 TI - [Responses of main characters of root system to salt stress among cotton varieties with diffe-rent salt tolerance]. AB - A pot experiment was carried out to test the effects of salt levels on root morphology as well as the relationship between root morphology and salt tolerance with four cotton cultivars (salt-sensitive cultivar CCRI45, weak salt-resistance cultivar XLZ17, moderate salt-resistance cultivar XLZ13 and salt-resistance cultivar CCRI35). Results showed that dry mass and K+/Na+ ratio of cotton root and leaf were significantly reduced by salt stress. Dry mass of root and leaf and K+/Na+ ratio of root of cultivars XLZ13 and CCRI35 were 69.3%-104.4%, 24.8%-45.3% and 25.0%-45.8% higher than those of cultivar CCRI45, respectively. Root development was significantly restrained by salt stress. Total root length, total root surface area and total root volume of cultivars XLZ13 and CCRI35 were 15.2% 85.8%, 12.0%-68.5% and 31.7%-217.8% higher than those of cultivar CCRI45, respectively. Furthermore, the length of fine and middle roots, root surface area and root volume of cultivars XLZ13 and CCRI35 in 0-10 cm soil layer were 27.2% 73.9%, 39.6%-74.3% and 99.0%-309.7% higher than those of cultivar CCRI45, respectively. Results from principal component analysis showed that the variations of specific root length, root length ratio at 0-10 cm soil layer and fine root length ratio at 0-10 cm soil layer among cultivars was significant. Specific root length, root length ratio at 0-10 cm soil layer and fine root length ratio at 0-10 cm soil layer were the main root characters to distinguish different salt tolerant cotton cultivars. Results from the stepwise regression analysis showed that specific root length, coarse root length, coarse root area, and coarse root volume at 0-10 cm and 10-20 cm soil layers, as well as fine root area and middle root ratio at 0-10 cm soil layer were sensitive to salt. Salt tolerant cultivar adapted to salt stress through increasing root length ratio, fine length ratio, and specific root length. PMID- 29722230 TI - [Effects of spraying paclobutrazol at different stages on physiological characteristics, yield and quality of peanut]. AB - To explore the optimum stage of spraying with paclobutrazol (PBZ) for different peanut cultivars under high yield condition, we investigated the effects of spraying PBZ at different stages on chlorophyll content, root activity, protective enzymes, nitrogen and carbon metabolism enzymes of leaves, pod yield and kernel quality of peanut, with Huayu 20 and Huayu 25 as materials. The results showed that spraying PBZ at different stages increased root activity, chlorophyll content, SOD, POD, CAT, SS, SPS, PEPC activities and decreased the MDA content, NR, GS, GDH and GOGAT activities for pod setting stage of two cultivars. These results suggested that the effects would be more obvious at earlier spray time. For HY25, the most significant effects of spraying PBZ on those parameters of pod filling stage could be obtained when the main stem height was 25 cm. For HY20, spraying PBZ when the main stem height was 25 cm decreased the activities of protective enzymes. Earlier spraying time to HY20 would lead to early senescence, lower chlorophyll content, root activity and carbon metabolism enzyme activity. For HY20, the most significant effects of spraying PBZ on those parameters of pod filling stage could be obtained when the main stem height was 30 cm. Our results indicated that PBZ treatments at the optimum stage could improve pod yield and economic coefficient of both cultivars and enhance the fat content and the relative content of oleic acid and the O/L. Under high yield condition, the optimum stage of spraying PBZ was 25 cm height of the main stem for HY25 and 30 cm for HY20. PMID- 29722231 TI - [Effects of light intensities after anthesis on the photosynthetic characteristics and chloroplast ultrastructure in mesophyll cell of summer maize (Zea mays L. )]. AB - We examined the changes of photosynthetic characteristics and chloroplast ultrastructure in mesophyll cell of summer maize in response to different light intensities in the field, with the summer maize hybrid Denghai 605 as experimental material. Two treatments of both shading (S) and increasing light (L) from flowering to physiological maturity stage were designed, with the ambient sunlight treatment as control (CK). Under shading treatment, poorly developed thylakoid structure, blurry lamellar structure, loose granum, large gap between slices and warping granum were the major characteristics in chloroplast. Meanwhile, photosynthetic rate (Pn), transpiration rate, stomatal conductance, chlorophyll content, and actual photo-chemical efficiency (PhiPSII) decreased, whereas the maximal photochemical efficiency and non-photochemical quenching increased, which resulted in decreases in grain yield under shading treatment. However, a better development was observed in chloroplasts for L treatment, with the number of grana and lamellae increased and lamellae arranged compactly. In addition, Pn and PhiPSII increased under L treatment, which increased grain yield. The chloroplast arrangement dispersed in mesophyll cells and chloroplast ultrastructure was destroyed after shading, and then chlorophyll synthesis per unit leaf area and photosynthetic capacity decreased. In contrast, the number of grana and lamellae increased and lamellae arranged compactly after increasing light, which are beneficial for corn yield. PMID- 29722232 TI - [Effects of exogenous spermidine and arbuscular mycorrhizal fungi on plant growth of cucumber]. AB - Effects of spermidine (Spd) and arbuscular mycorrhizal fungi (AMF) on the growth and photosynthesis of cucumber (Cucumis sativus L., cv. Jinchun 2) seedlings, fruit yield and quality, microorganism and enzymatic activity in rhizosphere were investigated. The results showed that combined Spd and AMF addition significantly promoted the growth of cucumber seedlings, increased the root activity, fruit production and quality, enhanced nutrients absorption of seedlings. Net photosynthetic rate, actual photochemical efficiency, light quantum efficiency, carboxylation efficiency and light respiration rate of cucumber seedlings were increased by combined addition of Spd and AMF. The abundance of bacteria and actinomycetes in the rhizosphere of cucumber seedlings were increased, but that of fungi was decreased. The activities of enzymes, including sucrase, neutral phosphatase, catalase, and urease, were enhanced. These results suggested that the light utilization efficiency of cucumber seedlings was improved by combined addition of Spd and AMF. The growth substrate has been changed from a low fertility type caused by fungi to a high-fertility one caused by bacteria. The decomposition and transformation of organic phosphorus and nitrogen in substrate were increased by combined addition of Spd and AMF, and thus could provide more N and P for the growth and development of cucumber, which further led to enhanced seedling growth, higher yield and quality of fruits. Moreover, Spd could increase the infection rate of AMF in cucumber roots, and together they had a synergistic effect on the growth of cucumber. Our results suggest that it is an effective method to enhance the infection rate of AMF by using Spd. PMID- 29722233 TI - [Effects of exogenous 2,4-epibrassinolide on the growth and redox balance of cucumber seedlings under NaHCO3 stress]. AB - The effects of 0.2 MUmol.L-1 exogenous 2,4-epibrassinolide (EBR) on the growth and reactive oxygen species metabolism of cucumber seedlings ('Jinyan 4' cucumber) under salt-alkaline stress (30 mmol.L-1 NaHCO3) were examined by hydroponics method. The results showed that NaHCO3 stress significantly induced production of O2-. and accumulation of H2O2 in leaves and roots, resulting in the increases of MDA content and electrolyte leakage. Under NaHCO3 stress, activities of superoxide dismutase, peroxidase, catalase, ascorbate peroxidase, dehydroascorbatereductase, monodehydrodroascorbate reductase, and glutathione reductase as well as contents of ascorbic acid and glutathione were firstly increased and then decreased with progress of stress time. Exogenous EBR application significantly increased the activities of antioxidant enzymes and contents of antioxidants as well as the ratio of AsA/DHA (dehydroascorbic acid) and GSH/GSSG (L-glutathione oxidized) in leaves and roots of cucumber under NaHCO3 stress. Such changes improved the redox hemostasis in plants, reduced the level of reactive oxygen species, and alleviated the membrane lipid peroxidation. Together, they increased the alkaline tolerance of cucumber seedlings. PMID- 29722234 TI - [Effects of intercropping Chinese milk vetch on functional characteristics of soil microbial community in rape rhizosphere]. AB - The application of green manure is facing serious problems in purple soil region of southwest China. With the aim to explore the potential application of green manure, we examined the functional characteristics of soil microbial community in a system of Chinese milk vetch intercropped with rape. The innovations are the application of Chinese milk vetch in dry land of the southwest China and the establishment of new planting pattern of rape by providing empirical data. Results showed that the intercropping with Chinese milk vetch decreased the carbon resource use efficiency of microbial community in rape rhizosphere, especially for the utilization of carbohydrates. At the same time, Shannon index, Simpson index, and richness were reduced, but evenness index was increased by intercropping. Those results from cluster analysis and principal component analysis suggest that the soil microbial community composition was significantly different between monocropping and intercropping. The carbohydrates, amino acids and carboxylic acids were the sensitive carbon sources for differentiating the changes of the microbial community induced by monocropping and intercropping. Intercropping Chinese milk vetch could decrease functional activity, change community composition, and reduce diversity of soil microbial community in rape rhizosphere. PMID- 29722235 TI - [Effects of habitat conditions on the genetic diversity of Apis cerana cerana]. AB - To assess the effects of different habitat conditions on the genetic diversity of Apis cerana cerana, 2400 individual workers from 120 colonies in four localities of South Anhui mountainous area were analyzed using microsatellite DNA loci. Results showed that in the tea tree monoculture, the number of alleles, average expected heterozygosity and polymorphism information content showed no significant difference with those in the natural forest. The number of alleles and polymorphic information content in domesticated population were significantly different from those in the wild population. The average expected heterozygosity was not significantly different between those two populations. The number of alleles, the average expected heterozygous and polymorphic information content were significantly different from those in the wild for samples collected in 2006. There was significant genetic differentiation among populations, with an average differential coefficient of 0.32. Our results indicated that the cultivation of tea plantation in South Anhui would not affect the genetic structure and conservation of bees. PMID- 29722237 TI - [Fate of fertilizer nitrogen and soil nitrogen pool budget of Fuji apple from germination stage to new shoot growing stage]. AB - 15N trace technique were used to explore the fertilizer nitrogen (N) absorption and utilization, soil residue and soil nitrogen pool budget under different nitrogen fertilization levels (0, 50, 100, 150, 200, 250 kg.hm-2) for five-year old 'Yanfu 3'/SH6/M. hupehensis Rehd. from germination stage to new shoot growing stage. The results showed that 15N were preferentially distributed to the roots and then transported to aboveground for the construction of new organs after N application in early spring. After the end of new shoot growing (two months later after N application), 5.9%-9.9% of fertilizer N was absorbed by apple tree, 29.8% 33.4% of fertilizer N was resided in 0-60 cm soil, and 56.7%-64.4% of fertilizer N was lost. With the increases of N application rate, the amount of fertilizer N absorbed by trees and the amount of soil residual N gradually increased, the utilization ratio of fertilizer N and soil residual ratio decreased, and the loss and the loss ratio of N were increased. With the increases of N application rates, the total balance of soil N changed from deficit to surplus, and the surplus increasing significantly with the increases of N application rates. The results indicated that low N application rate could cause a decrease of soil N fertility and the excessive application of nitrogen could increase the accumulation of N and increase the risk of N pollution. Fertilizer N levels showed a significant linear correlation with soil total N balance, with the regression equation being y=0.3511x-20.808 (R2=0.9927). In the stages from germination to new shoot growing, soil N pool reached balance when the N application rate was 59.27 kg.hm-2. PMID- 29722238 TI - [Analysis of influence on spatial distribution of fishing ground for Antarctic krill fishery in the northern South Shetland Islands based on GWR model]. AB - Based on Antarctic krill fishery and marine environmental data collected by scientific observers, using geographically weighted regression (GWR) model, we analyzed the effects of the factors with spatial attributes, i.e., depth of krill swarm (DKS) and distance from fishing position to shore (DTS), and sea surface temperature (SST), on the spatial distribution of fishing ground in the northern South Shetland Islands. The results showed that there was no significant aggregation in spatial distribution of catch per unit fishing effort (CPUE). Spatial autocorrelations (positive) among three factors were observed in 2010 and 2013, but were not in 2012 and 2016. Results from GWR model showed that the extent for the impacts on spatial distribution of CPUEs varied among those three factors, following the order DKS>SST>DTS. Compared to the DKS and DTS, the impact of SST on the spatial distribution of CPUEs presented adverse trend in the eastern and western parts of the South Shetland Islands. Negative correlations occurred for the spatial effects of DKS and DTS on distribution of CPUEs, though with inter-annual and regional variation. Our results provide metho-dological reference for researches on the underlying mechanism for fishing ground formation for Antarctic krill fishery. PMID- 29722236 TI - [Effects of nutrient solution supply amount on yield, quality and volatile matter of tomato]. AB - We examined the effects of different amounts of nutrient solution supply on the yield, quality and volatile substances of tomato fruit by substrate cultivation. Using tomato cultivar 'HL2109' as experimental material, four treatments were set, including Control: irrigating with 117 L pure water for each plant; T1: irrigating each plant with 39.0 L of nutrient solution; T2: irrigating each plant with 58.5 L of nutrient solution; T3: irrigating each plant with 117 L of nutrient solution. The quality and volatile substances of tomato fruits were determined by using chemical method and SPME-GC-MS technique. The results showed that the yield per plant and the gross production increased and then decreased with the increases of nutrient solution supply. The yield of T2 was the highest among all treatments. The yields of T1, T2 and T3 were 29.3%, 72.6% and 47.0% higher than that in Control, respectively. The irrigation water use efficiency of T1 was the highest and T2 took second place, though the difference being not significant. The soluble solids content and sugar acid ratio of tomato fruits in T2 were the highest, and the flavor and quality were significantly improved. The content of ascorbic acid and soluble protein gradually increased with the increases of nutrient solution supply. The contents of total soluble sugar and reducing sugar were first increased and then decreased, both being highest in T2. Using GC-MS analysis, a total of 69 volatile compounds were detected. The total content of volatile compounds from T1, T2 and T3 were higher than that in Control, which presented as T2>T1>T3>CK. Among them, the content of volatile compounds from T2 was 6971 MUg.kg-1, which was 1.97 times higher than that in the Control. The content from T3 was 4070 MUg.kg-1, being 0.73 times of that in the Control. The contents of 1-Pentene-3-one, 6-Methyl-5-hepten-2-one, hexanal, hexanoic acid, Phenylacetaldehyde and cis-3-hexenal were highest in T2 among all treatments. Moreover, the content of characteristic volatile compounds, the quantity and total content of volatile compounds were highest in T2. Taken together, the T2 treatment (irrigating each plant with 58.5 L of nutrient solution) had the best effects, with the quality and content of volatile compounds in tomato fruit being improved. PMID- 29722239 TI - [Subhabitat selection and differences of diet composition for Acanthogobius ommaturus in the Dongtan wetland of the Yangtze estuary, China]. AB - We examined the temporal and spatial variation in the abundance and diet composition of Acanthogobius ommaturus at three subhabitats (mudflat, salt marsh, and creek) of the Dongtan wetland of Yangtze Estuary with monthly field samplings from July 2015 to June 2016. The results showed that the samples of A. ommaturus were mainly composed of young individuals in the period of June-November, whereas no fish was collected during the other months. Most of the samples were collected in July (71) and only three individuals was collected in November. Most of the samples were collected (93) in creek, which was 5.2 and 4.9 times of those in mudflat and salt marsh, respectively. The diet of the A. ommaturus included 10 taxa and 30 prey species, dominated by shrimps. In the taxonomic level, the dominant preys were the Exopalaemon annandalei or other Exopalaemon sp. of shrimps, the Sesarma sp. of crabs and Micromecta quadriseta of insects. Compared with other taxonomic groups, the fish prey had relatively higher mass percentage but lower abundance percentage. The prey composition of A. ommaturus differed among subhabitats. The feeding level of A. ommaturus increased gradually from July to November and reached 3.0 in late autumn. The differences in the abundances of A. ommaturus among subhabitats would be induced by prey composition. PMID- 29722241 TI - [Draft of soil environmental function regionalization of China]. AB - Soil environmental function regionalization is of significance for soil environmental classification management in China. In this paper, we discussed the broad and narrow concept of soil environmental function and its corresponding attributes. Based on the constraint analysis on the soil environmental quality to function, relationship between soil environmental function and quality was illustrated. Compared with different methods and indices of soil environmental function regionalization, we established the index system of soil environmental function regionalization according to the soil environmental suitability and function. The proposed draft of soil environmental function regionalization included four first-class function types, 10 second-class function types, and 75 soil environmental functional areas. According to the differences among those functional areas, we proposed corresponding management countermeasures. The results provided scientific basis for the control and prevention of soil pollution and the control of regional risk in China. PMID- 29722240 TI - [Sagittal otolith morphology and the relationship between its mass and the age of Liza haematocheila in the Yangtze Estuary, China]. AB - To examine the relationship of morphological characters of sagittal otolith and the age of Liza haematocheila in the Yangtze Estuary, we analyzed the morphological parameters of 324 pairs of otoliths extracted from 358 L. haematocheila specimens from the Yangtze Estuary in February to June of 2017. The results showed that sagittal otolith had rostrum, antirostrum and obvious central notch. The size and shape of sagittal otolith significantly changed with their growth, from regular melon seeds shape outline to long narrow leaf shape and increasing irregular wavy outline. The average density of sagittal otolith was 1.52 mg.mm-2. The average rectangularity was 0.68. The length of sagittal otolith was 0.021%-0.047% of entire body length (BL), the width was 0.009%-0.021% of entire BL, and the mass was 0.0450/00-0.7310/00 of the entire body mass (BM). Otolith length (OL), otolith width (OW) and otolith mass (OM) were all significantly related to the BL, with the determination coefficient for OW and OM model being the highest (R2=0.928). The relationship between OM and BL was described best by exponential regression: OM=0.0009BL1.8737(R2=0.967). The relationships between OM and age (A), BL and A were well fitted by multinomial regressions, respectively: OM=2.9262A2+4.8437A+2.1894 (R2=0.847), BL= 3.2248A2+102.54A+38.373 (R2=0.858). In addition, OM was linearly correlated with A. The estimated otolith's ages from the model did not significantly variate from the real ages counting from annulus counts. Therefore, OM could be an effective parameter for the age estimation of L. haematocheila. PMID- 29722242 TI - [Variations in growth response and cadmium accumulation of different gender Morus alba seedlings to combined treatments of Cd and acid rain]. AB - To investigate sex-specific adaptive responses and cadmium accumulation of Morus alba seedlings, we analyzed growth parameters, photosynthetic capacity and chlorophyll fluorescence parameters, and Cd accumulation and allocation of Qiangsang 1 (female) and Nongsang 14 (male) under different treatments [cadmium (Cd, 100 mg.kg-1), acid rain (AR, pH 3.0) and their combinations (Cd+AR)]. When exposed to Cd stress alone, females showed higher cadmium content in root, stem and leaf than males. The root, stem and total biomass, and maximum net photosynthetic rate (Amax) of males were significantly decreased, while those of females (except Amax) showed no significant changes. Cd had no effect on maximal photochemical efficiency (Fv/Fm), photochemical quenching coefficient (qP), non photochemical quenching coefficient (qN) in both sexes. When exposed to Cd+AR stress, the total biomass and Amax of males and females decreased. Compared to Cd stress alone, the cadmium content in root and leaf of females significantly increased while those of males did not under Cd+AR. In addition, Cd+AR stress had no effect on Fv/Fm and qP, but significantly increased qN in both sexes. Our results suggested that females had greater tolerance than males when exposed to Cd stress alone in short term. Acid rain would decrease the tolerance of females to Cd stress, which might attribute to the enhanced absorption and accumulation of cadmium. PMID- 29722243 TI - [Terrain gradient effect of ecosystem service value in middle reach of Yangtze River, China]. AB - Using land use data in the year 1995, 2005 and 2014, this study estimated the ecosystem service value (ESV) in each county located in the middle reach of Yangtze River and analyzed its spatiotemporal variation features and terrain gradient effects based on "the equivalent value per unit area of ecosystem services in China". The results showed that ESV in the middle reach of Yangtze River was generally higher in mountainous area but lower in plain region, with an obvious terrain gradient effect. Specifically, the relationship of the relief degree of land surface (RDLS) and the ESV showed significant logarithm function at county scale with a high curve fitting degree of 0.53. The ESV increased from 400.35*104 yuan.km-2 to 554.57*104 yuan.km-2 with the increasing RDLS (grade 1-5) in 2014. During 1995-2004, the ecosystem service value variation changed from decreasing to stable with the increases of the RDLS. With a perspective of ecosystem service values, the value of food production and waste treatment service value decreased with the increase of the RDLS, while the others increased in general, such as the production of raw materials and gas regulation service value, because of the influences of dynamic land use structure in varied topography and distinct dominant ecosystem services from different land types. PMID- 29722245 TI - [A diachronic study on resettlers' perceptions toward ecological relocation in world heritage site: A case study of Wulingyuan Scenic Area, China]. AB - Perceptions of residents in ecological resettlement area are important for evaluating the implementation effect of ecological relocation and sustainable development of world heritage site. With the residents from three different resettlement communities in Wulingyuan Scenic Area as the research object, we carried out a diachronic study on changes of the resettlers' perceptions of ecological relocation at different times and the main driving factors based on systematic survey data in 2010 and 2016. The results showed that in the year 2010 and 2016, resettlers reacted negatively to the indicators such as "enhancement of employment opportunity", "improvement of education and training opportunity", "enhanced environment in scenic area", "recognizing the identity change 'from rural to non-rural' after relocation". They favored the indicators such as "undermining traditional value", "lack of supervision during the implementation of policies". In 2016, resettlers of different gender, age and average monthly income had substantial different opinions on the economic and psychological impacts of ecological relocation. Education and income level had great impacts on their opinions of ecological relocation policies. Resettlers relocated by the way of investment for developing perceived were more sensitive to the economic impacts. Economic and policy impacts became the dominant driving factors for their general perception of ecological relocation. They pay more attention to employment, children's education opportunity as well as social security system for relocation. PMID- 29722244 TI - [Quantitative assessment of urban ecosystem services flow based on entropy theory: A case study of Beijing, China]. AB - Quantitative evaluation of ecosystem service is a primary premise for rational resources exploitation and sustainable development. Examining ecosystem services flow provides a scientific method to quantity ecosystem services. We built an assessment indicator system based on land cover/land use under the framework of four types of ecosystem services. The types of ecosystem services flow were reclassified. Using entropy theory, disorder degree and developing trend of indicators and urban ecosystem were quantitatively assessed. Beijing was chosen as the study area, and twenty-four indicators were selected for evaluation. The results showed that the entropy value of Beijing urban ecosystem during 2004 to 2015 was 0.794 and the entropy flow was -0.024, suggesting a large disordered degree and near verge of non-health. The system got maximum values for three times, while the mean annual variation of the system entropy value increased gradually in three periods, indicating that human activities had negative effects on urban ecosystem. Entropy flow reached minimum value in 2007, implying the environmental quality was the best in 2007. The determination coefficient for the fitting function of total permanent population in Beijing and urban ecosystem entropy flow was 0.921, indicating that urban ecosystem health was highly correlated with total permanent population. PMID- 29722246 TI - [Research progress on DNA barcoding analysis methods]. AB - DNA barcode is a fragment of short DNA sequence from a standard part of the genome. DNA barcoding is an effective taxonomic method for species identification through analyzing the DNA barcodes. With the dramatic increasing of DNA barcode sequences, the analysis methods have developed rapidly, which promoted their applications in molecular identification for organisms. Since 2003, DNA barcoding has been widely used in species identification for animals, plants, fungi, etc. It has also robustly promoted the development of scientific disciplines, such as taxonomy, biodiversity science, and ecology. Based on review of DNA barcoding techniques, we summarized five main analysis methods on DNA barcodes, i.e. the genetic distance-, genetic similarity-, phylogenetic tree-, sequence characters-, and statistical classification-based methods. Moreover, we proposed a prospect for research and applications of DNA barcoding in the future. PMID- 29722247 TI - [Progress on the regulation of quorum sensing in wastewater treatment]. AB - Quorum sensing is a phenomenon that microorganisms secrete some signal molecules, when such molecules accumulate to a threshold level, which would realize the information communication by regulating specific gene expression. Quorum sensing, which is widely found in information communication of various microorganisms, regulates a variety of social behaviors, such as biofilm formation, public goods production, and gene horizontal transfer of bacteria. The phenomenon of quorum sensing is widespread in biological aggregates, such as activated sludge, biofilm and granular sludge. Learning and understanding the regulation behavior between quorum sensing and microorganisms plays an important role in wastewater treatment. Here, we reviewed the classification of the sensing signal molecule, regulation mechanism of quorum sensing, as well as the regulation behavior of quorum sensing in activated sludge, biofilm, aerobic granular sludge, and anaerobic granular sludge. The future researches of quorum sensing in wastewater treatment were discussed. This review could deepen the understanding of the regulation of quorum sensing in wastewater treatment. PMID- 29722248 TI - Standardized, musculoskeletal ultrasonographic reference values for healthy Korean adults. AB - Background/Aims: To define standard reference values for musculoskeletal ultrasonography (MSUS) in Korea. Methods: A total of 251 healthy adults were recruited for this study. Ultrasonography was performed by experienced rheumatologists who had undergone four appropriate training programs in Korea. A General Electric LOGIQ electronic ultrasound device fitted with a 12 MHz linear transducer was employed. Mean values +/- standard deviations (SDs) were defined as standard reference values. Intraclass correlation coefficients was employed to evaluate the extent of inter- and intraobserver agreement when MSUS measurements were made. Results: The 251 study participants included 122 males. Mean subject age was 28.6 years. The average bone-to-capsule distance of the right-side second and third metacarpophalangeal (MCP) joints were 0.68 and 0.72 mm respectively, and those of the left-side joints 0.62 and 0.68 mm. The cartilage thicknesses of the rightside second and third MCP joints were 0.55 and 0.55 mm, and those of the leftside joints were 0.55 and 0.56 mm, respectively. The bone-to-capsule distances of the right and left wrists were 0.80 and 0.82 mm. In 12.4% of participants (31/251), the erosion score of the humeral head was 1.71. In the right-side knee joint, mean cartilage thicknesses of the medial and lateral condyles were 1.86 and 2.03 mm in longitudinal scans. High overall interobserver agreement was evident after appropriate training that included instruction on standard MSUS methodology. Conclusions: We defined standard reference values for MSUS in healthy Korean adults. The reliabilities of interobserver agreements were high after appropriate training program. PMID- 29722250 TI - The effects of 8 weeks of two different training methods on on-sight lead climbing performance. AB - BACKGROUND: Despite climbing being an increasingly popular sporting pursuit, there have been very few scientific evaluations of appropriate training methods for competitive climbers. The aim of this study was to investigate the effects of an 8-week climbing-specific muscular hypertrophy (MH) or muscular endurance (ME) resistance training program on the on-sight lead climbing performance in a similar setting to a world cup. METHODS: Twenty-three elite male and female climbers (age: 25.5+/-6.7 years; height: 1.72+/-0.08 m; body mass: 63.4+/-7.7 kg; measured on-sight level: 20.8+/-2.0 IRCRA (International Rock Climbing Research Association)) participated in 8 weeks' worth of MH (N=11) or ME (N=12) training. Before the training (FT1), after 8 weeks of training (FT2), and after a 2-week tapering period (FT3), the participants climbed an on-sight lead route in a similar setting to a world cup. RESULTS: Climbers were able to perform significantly more moves (p=0.019; p<0.001) and climb significantly harder (p=0.014; p<0.001) with FT2 and FT3 versus FT1. Climbing moves per unit time increased significantly when comparing FT2 to FT1 (p=0.007) and showed a tendency to increase when comparing FT3 to FT1 (p=0.061). However, there was no interaction effect between the groups. CONCLUSIONS: Our findings demonstrated that climbing-specific ME, as well as MH resistance training, improved on-sight lead climbing performance in a similar setting to a world cup. For competing climbers and climbing coaches, we recommend inclusion of the same proportions of climbing-specific ME and MH resistance training in their training programs to enhance on-sight lead climbing performance. PMID- 29722249 TI - The neutrophil-to-lymphocyte ratio prechemotherapy and postchemotherapy as a prognostic marker in metastatic gastric cancer. AB - BACKGROUND/AIMS: Markers of inflammation have been associated with outcomes in various cancers. The purpose of this study was to evaluate whether systemic inf lammatory markers and their f luctuations can predict survival and chemotherapy response in patients with metastatic gastric cancer (mGC). METHODS: We retrospectively reviewed the records of 502 patients who received first-line palliative chemotherapy for mGC between 2007 and 2013. The neutrophil-to lymphocyte ratio (NLR) and modified Glasgow prognostic score (mGPS) were assessed before and after chemotherapy to evaluate their association with survival. The NLR values were categorized into two groups based on a cut-off value of 3; mGPS values were classified as high versus low. RESULTS: High prechemotherapy NLR was significantly associated with poor overall survival on univariate analysis (p = 0.002). On multivariate analysis, high prechemotherapy NLR (hazard ratio, 1.43; p < 0.001) was an independent prognostic factor for poor overall survival. However, the prechemotherapy mGPS was not significantly associated with survival. Continuously high NLR or a shift to high NLR postchemotherapy was associated with poor chemotherapy response as well as survival, while NLR reduction was associated with a good response (linear by linear association, p < 0.001) and a favorable prognosis. CONCLUSION: Prechemotherapy NLR can be used as a prognostic factor in mGC, while the postchemotherapy NLR value may predict the chemotherapeutic response and prognosis. In contrast, mGPS has limited prognostic utility in mGC. PMID- 29722251 TI - Effects of local versus remote ischemic preconditioning on repeated sprint running performance. AB - BACKGROUND: The aim of this study was to compare the effect of local and remote ischemic preconditioning (IPC) on repeated sprint exercise. METHODS: Twelve males (age 22 +/- 2 years; stature 1.79+/-0.07 m; body mass 77.8+/-8.4 kg; mean +/- SD) completed four trials consisting of remote (arm) and local (leg) IPC and SHAM interventions prior to repeated sprint exercise (3 x (6 x 15 + 15-m) shuttle sprints), in a double-blind, randomised, crossover designed study. These tests were immediately preceded by IPC (4 x 5 minute intervals at 220 mmHg bilateral occlusion) or SHAM treatment (4 x 5 minute intervals at 20 mmHg bilateral occlusion). Sprint performance and percentage decrement score alongside measurement of tissue saturation index, blood lactate and RPE were measured throughout the intervention. During the IPC / SHAM intervention there was a large decrease in TSI for IPC-arm in comparison to IPC-leg (p < 0.05), however IPC-legs resulted in greater soreness compared with the other three conditions (p < 0.05). RESULTS: There was no main effects or interaction effects for sprint performance. There was a significant effect of condition (p = 0.047, r = 0.56) on percentage decrement score across all 18 sprints with IPC demonstrating less fatigue than SHAM. There were no other effects of IPC during the sprint trials for any other physiological measure. CONCLUSIONS: In conclusion local IPC resulted in more pain / soreness during the IPC / SHAM intervention but both remote and local IPC reduced the fatigue associated with repeated sprint exercise. PMID- 29722252 TI - Creatine monohydrate supplementation during eight weeks of progressive resistance training increases strength in as little as two weeks without reducing markers of muscle damage. AB - BACKGROUND: Creatine supplementation (Cr) increases strength during resistance training, but the time course of this strength increase is unclear. The aim was to determine the precise time course by which Cr could increase strength and whether Cr prevents muscle damage during eight weeks of resistance training. METHODS: Young males were randomized (double blind) to Cr (n=9, 0.07g/kg/d) and placebo (n=9) during 8-weeks of resistance training (3d/week). Strength was assessed across six exercises every two weeks. Venous blood samples obtained at baseline, and 24 and 48 hours after the final resistance training session were assessed for creatine kinase [CK] and lactate dehydrogenase [LDH] as measures of muscle damage. RESULTS: Strength was significantly higher in the Cr versus placebo group (p<0.05) after two weeks of training for three of the six exercises (bench press, leg press, shoulder press). By the end of the eight weeks of training, strength was significantly higher in the Cr versus placebo group (p<0.05) for four of the six exercises (bench press, leg press, shoulder press, and triceps extension, but not biceps curl or lat-pulldown). Creatine supplementation did not prevent muscle damage. Indeed, muscle damage markers increased in the Cr compared to placebo group (p<0.05). CONCLUSIONS: Cr increased muscular strength in as little as two weeks during a resistance training program; however, this was not accompanied by decreased muscle damage. Greater muscle damage with Cr may be due to a greater training intensity enabled by Cr supplementation. This might lead to greater protein turnover and enhanced muscle adaptation. PMID- 29722253 TI - Running economy and energy cost of running with backpacks. AB - BACKGROUND: Running is a popular recreational activity and additional weight is often carried in backpacks on longer runs. Our aim was to examine running economy and other physiological parameters while running with a 1kg and 3 kg backpack at different submaximal running velocities. METHODS: 10 male recreational runners (age 25 +/- 4.2 years, VO2peak 60.5 +/- 3.1 ml.kg-1.min-1) performed runs on a motorized treadmill of 5 minutes durations at three different submaximal speeds of 70, 80 and 90% of anaerobic lactate threshold (LT) without additional weight, and carrying a 1kg and 3 kg backpack. Oxygen consumption, heart rate, lactate and RPE were measured and analysed. RESULTS: Oxygen consumption, energy cost of running and heart rate increased significantly while running with a backpack weighing 3kg compared to running without additional weight at 80% of speed at lactate threshold (sLT) (p=0.026, p=0.009 and p=0.003) and at 90% sLT (p<0.001, p=0.001 and p=0.001). Running with a 1kg backpack showed a significant increase in heart rate at 80% sLT (p=0.008) and a significant increase in oxygen consumption and heart rate at 90% sLT (p=0.045 and p=0.007) compared to running without additional weight. While running at 70% sLT running economy and cardiovascular effort increased with weighted backpack running compared to running without additional weight, however these increases did not reach statistical significance. CONCLUSIONS: Running economy deteriorates and cardiovascular effort increases while running with additional backpack weight especially at higher submaximal running speeds. Backpack weight should therefore be kept to a minimum. PMID- 29722254 TI - Assessing the use of psychological skills by sports category and the relation with sports performance satisfaction. AB - BACKGROUND: The evaluation of psychological skills by athletes and their relationship with sports performance and satisfaction has been of great interest in recent decades. Likewise, there has been an emergent tendency to focus on developing specific psychological skills for each sport. The principal aim of this study was to determine the frequency with which athletes deploy psychological skills whilst competing and whether their frequency varies in accordance with the technical, tactical and physical characteristics of the sport in question. A further objective was to establish the connection between the frequency of use of psychological skills and athletes' degree of satisfaction with their performance. METHODS: The study comprised 1003 athletes practising 43 different sports, grouped into 7 categories based on the similarities between them. Frequency of use of the psychological skills was measured with the Test of Performance Strategies 3. RESULTS: The data analyses allowed the following conclusions to be drawn: the degree to which psychological skills are used is dependent on the technical, tactical and physical characteristics of each sport; and the higher the frequency of the use of psychological skills, the greater the athletes' degree of satisfaction with their performance. CONCLUSIONS: These results allow athletes and coaches to increase levels of sports performance by working on the use of psychological skills, adapted to the technical, tactical or physical requirements of the category in which their sport is included. In addition, working on different psychological skills will improve their satisfaction with sports performance. PMID- 29722255 TI - Physiological demands of standing and wheelchair fencing in able-bodied fencers. AB - BACKGROUND: The purpose of this study was to determine the cardiorespiratory demands of standing and wheelchair (seated) fencing in a group of able-bodied fencers during simulated competitive bouts. METHODS: Participants were ten male able-bodied fencers of regional level with previous training experience in wheelchair fencing. After a standardised warm-up participants performed two series of simulated competitive epee bouts (5 and 15 touches) in a random order, either while standing or while sitting in a wheelchair. Expired gas was analyzed for oxygen consumption (V O2) and respiratory exchange ratio (RER) and heart rate were continually monitored. Energy expenditure (EE) was subsequently calculated. RESULTS: V O2, HR and EE peak responses were greater during standing than seated fencing (p< .05). Mean V O2 during all ST bouts (5 and 15 touch) was 43% greater than in WC fencing (44.2 +/- 7.8 vs. 25.1 +/- 5.4 ml.kg-1.min-1). Mean HR during the standing 5 and 15 touch bouts was 91% +/- 20% and 84% +/- 7% of that recorded during the seated bouts. HR,VO2 and EE data also indicated that the 15-touch bouts were more physiologically demanding than the 5-touch bouts (P < .01). The HR-V O2 relationship was similar between both fencing modes. The duration of the 5 and 15 touch bouts were shorter for the seated than the standing bouts (P < .01). CONCLUSIONS: The physiological demands of wheelchair fencing are lower than those for standing fencing. Furthermore, the physiology of 5 vs. 15 touch bouts, similar to those undertaken in fencing competition, also differs. PMID- 29722256 TI - Photo-Electrosensitive Memristor Using Oxygen Doping in HgTe Nanocrystal Films. AB - Nanocrystal-based electronic devices with multiple functionalities offer one avenue toward novel passive and active electronic components. Here, we exhibit a planar and fully air-processed thin film device that demonstrates a photoinduced memristive behavior and can be used as a transistor, photodetector, or memory device. Following long-term (60 h) air exposure, unpackaged nanocrystal films develop reliable memristive characteristics in tandem with temperature, gate, and photoresponse. The on/off values of more than 50 are achieved, and the devices show long-term stability, producing repeatable metrics over days of measurement. The on/off behavior is shown to be dependent on the previous charge flow and carrier density, implying a memristive rather than switching behavior. These observations are described within a long-term trap-filling model. This work represents an advance in the integration of nanocrystal films into electronic devices, which may lead to the development of multifunctional electronic components. PMID- 29722257 TI - Graphene Oxide-Facilitated Comprehensive Analysis of Cellular Nucleic Acid Binding Proteins for Lung Cancer. AB - Nucleic acid binding proteins (NABPs) mediate a broad range of essential cellular functions. However, it is very challenging to comprehensively extract whole cellular NABPs due to the lack of approaches with high efficiency. To this end, carbon nanomaterials, including graphene oxide (GO), carboxylated graphene (cG), and carboxylated carbon nanotube (cCNT), were utilized to extract cellular NABPs in this study through a new strategy. Our data demonstrated that GO, cG, and cCNT could extract nearly 100% cellular DNA in vitro. Conversely, their RNA extraction efficiencies were 60, 50, and 29%, respectively, partially explaining why GO has the highest NABPs yield compared to cG and cCNT. We further found that ionic bond mediated by cations between RNA and functional groups of nanomaterials facilitated RNA absorption on nanomaterials. About 2400 proteins were successfully identified from GO-enriched NABPs sample, and 88% of annotated NABPs were enriched at least 2 times compared to cell lysate, indicating the high selectivity of our strategy. The developed method was further applied to compare the NABPs in two lung cancer cell lines with different tumor progression abilities. According to label-free quantification results, 118 differentially expressed NABPs were discovered and 6 candidate NABPs, including ACAA2, GTF2I, VIM, SAMHD1, LYAR, and IGF2BP1, were successfully validated by immunoassay. The level of SAMHD1 in the serum of lung cancer patients was measured, which significantly increased upon cancer progression. Our results collectively demonstrated that GO is an ideal nanomaterial for NABPs selective extraction, which could be broadly used in varied physiological and pathophysiological settings. PMID- 29722258 TI - Diet Impacts Pre-implantation Histotroph Proteomes in Beef Cattle. AB - In ruminants, the period from fertilization to implantation is relatively prolonged, and the survival of embryos depends on uterine secretions known as histotroph. Our objective was to determine if the pre-breeding diet affected histotroph proteomes in beef cattle. Cows were assigned to one of four diets: a control diet (CON), a high-protein diet (PROT), a high-fat diet (OIL), or a high protein and high-fat diet (PROT + OIL). After 185 days on these diets, an intravaginal progesterone implant (CIDR) was inserted for 7 days. At 9 days after CIDR removal, animals with a corpus luteum were selected ( n = 16; 4 per treatment). Proteins were isolated from the histotroph collected by uterine lavage and analyzed with liquid chromatography-tandem mass spectrometry. Over 2000 proteins were expressed ( n >= 3 cows per treatment), with 1239 proteins being common among all of the groups. There were 20, 37, 85, and 123 proteins unique to CON, PROT + OIL, PROT, and OIL, respectively. Relative to CON, 23, 14, and 51 proteins were differentially expressed in PROT + OIL, PROT, and OIL, respectively. Functional analysis found that 53% of histotroph proteins were categorized as extracellular exosome, 3.28% as cell-cell adhesion, and 17.4% in KEGG metabolic pathways. Differences in proteomes among treatments support the idea that pre-breeding diet affects histotroph. Understanding the impact of diet on histotroph proteins may help improve conception rates. PMID- 29722259 TI - Multifunctional Optical Sensors for Nanomanometry and Nanothermometry: High Pressure and High-Temperature Upconversion Luminescence of Lanthanide-Doped Phosphates-LaPO4/YPO4:Yb3+-Tm3. AB - Upconversion luminescence of nano-sized Yb3+ and Tm3+ codoped rare earth phosphates, that is, LaPO4 and YPO4, has been investigated under high-pressure (HP, up to ~25 GPa) and high-temperature (293-773 K) conditions. The pressure dependent luminescence properties of the nanocrystals, that is, energy red shift of the band centroids, changes of the band ratios, shortening of upconversion lifetimes, and so forth, make the studied nanomaterials suitable for optical pressure sensing in nanomanometry. Furthermore, thanks to the large energy difference (~1800 cm-1), the thermalized states of Tm3+ ions are spectrally well separated, providing high-temperature resolution, required in optical nanothermometry. The temperature of the system containing such active nanomaterials can be determined on the basis of the thermally induced changes of the Tm3+ band ratio (3F2,3 -> 3H6/3H4 -> 3H6), observed in the emission spectra. The advantage of such upconverting optical sensors is the use of near-infrared light, which is highly penetrable for many materials. The investigated nanomanometers/nanothermometers have been successfully applied, as a proof-of concept of a novel bimodal optical gauge, for the determination of the temperature of the heated system (473 K), which was simultaneously compressed under HP (1.5 and 5 GPa). PMID- 29722260 TI - Conformation-Directed Micelle-to-Vesicle Transition of Cholesterol-Decorated Polypeptide Triggered by Oxidation. AB - Hierarchical self-assembly of synthetic polypeptides has attracted increasing interests due to its protein-mimetic structure and great potential in nanotechnology and biomedical applications. However, controlling the morphology and function of polymeric nanostructures via secondary structures remains largely unexplored. Here, we report an unusual micelle-to-vesicle transformation of cholesterol-decorated poly(l-cysteine) copolymer assemblies in response to reactive oxygen species (ROS). We found that the interesting morphological transition correlates with the alteration in conformations from beta-sheet to alpha-helix, which grants an attractive "on-off" switch for triggered release and cellular interaction. We further demonstrated the usefulness of the conformation regulated assembly strategy both in vitro and in vivo, taking cancer treatment as a model. The work offers a new insight on the folding and hierarchical assembly of polypeptides and a novel approach for the development of smart platforms in biosensing, disease treatment, and diagnostic applications. PMID- 29722261 TI - Multifunctional Micelles Dually Responsive to Hypoxia and Singlet Oxygen: Enhanced Photodynamic Therapy via Interactively Triggered Photosensitizer Delivery. AB - Nanoparticulate antitumor photodynamic therapy (PDT) has been suffering from the limited dose accumulation in tumor. Herein, we report dually hypoxia- and singlet oxygen-responsive polymeric micelles to efficiently utilize the photosensitizer deposited in the disease site and hence facilely improve PDT's antitumor efficacy. Tailored methoxy poly(ethylene glycol)-azobenzene-poly(aspartic acid) copolymer conjugate with imidazole as the side chains was synthesized. The conjugate micelles (189 +/- 19 nm) obtained by self-assembly could efficiently load a model photosensitizer, chlorin e6 (Ce6) with a loading of 4.1 +/- 0.5% (w/w). The facilitated cellular uptake of micelles was achieved by the triggered azobenzene collapse that provoked poly(ethylene glycol) shedding; rapid Ce6 release was enabled by imidazole oxidation that induced micelle disassembly. In addition, the singlet oxygen-mediated cargo release not only addressed the limited diffusion range and short half-life of singlet oxygen but also decreased the oxygen level, which could in turn enhance internalization and increase the intracellular Ce6 concentration. The hypoxia-induced dePEGylation and singlet oxygen-triggered Ce6 release was demonstrated both in aqueous buffer and in Lewis lung carcinoma (LLC) cells. The cellular uptake study demonstrated that the dually responsive micelles could deliver significantly more Ce6 to the cells, which resulted in a substantially improved cytotoxicity. This concurred well with the superior in vivo antitumor ability of micelles in a LLC tumor-bearing mouse model. This study presented an intriguing nanoplatform to realize interactively triggered photosensitizer delivery and improved antitumor PDT efficacy. PMID- 29722263 TI - Shape-Dependent Motion of Structured Photoactive Microswimmers. AB - We investigate the dynamics of structured photoactive microswimmers and show that morphology sensitively determines the swimming behavior. Particular to this study, a major portion of the light-activated particles' underlying structure is built from a photocatalytic material, made possible by dynamic physical vapor deposition (DPVD). We find that swimmers of this type exhibit unique shape dependent autonomous swimming that is distinct from what is seen in systems with similar structural morphology but not fabricated directly from the catalyst. Notably, the direction of motion is a function of these parameters. Because the swimming behavior is strongly correlated with particle shape and material composition, DPVD allows for engineering small-scale propulsion by adjusting the fabrication parameters to match the desired performance. PMID- 29722262 TI - Efficient Solution-Processed Nanoplatelet-Based Light-Emitting Diodes with High Operational Stability in Air. AB - Colloidal nanoplatelets (NPLs), owing to their efficient and narrow-band luminescence, are considered as promising candidates for solution-processable light-emitting diodes (LEDs) with ultrahigh color purity. To date, however, the record efficiencies of NPL-LEDs are significantly lower than those of more investigated devices based on spherical nanocrystals. This is particularly true for red-emitting NPL-LEDs, the best-reported external quantum efficiency (EQE) of which is limited to 0.63% (EQE = 5% for green NPL-LEDs). Here, we address this issue by introducing a charge-regulating layer of a polar and polyelectrolytic polymer specifically engineered with complementary trimethylammonium and phosphonate functionalities that provide high solubility in orthogonal polar media with respect to the NPL active layer, compatibility with the metal cathode, and the ability to control electron injection through the formation of a polarized interface under bias. Through this synergic approach, we achieve EQE = 5.73% at 658 nm (color saturation 98%) in completely solution processed LEDs. Remarkably, exposure to air increases the EQE to 8.39%, exceeding the best reports of red NPL-LEDs by over 1 order of magnitude and setting a new global record for quantum-dot LEDs of any color embedding solution-deposited organic interlayers. Considering the emission quantum yield of the NPLs (40 +/- 5%), this value corresponds to a near-unity internal quantum efficiency. Notably, our devices show exceptional operational stability for over 5 h of continuous drive in air with no encapsulation, thus confirming the potential of NPLs for efficient, high-stability, saturated LEDs. PMID- 29722264 TI - Anti-EGFR Peptide-Conjugated Triangular Gold Nanoplates for Computed Tomography/Photoacoustic Imaging-Guided Photothermal Therapy of Non-Small Cell Lung Cancer. AB - Non-small cell lung cancer (NSCLC) is difficult to cure because of the high recurrence rate and the side effects of current treatments. It is urgent to develop a new treatment that is safer and more effective than current treatments against NSCLC. Herein, we constructed anti-epidermal growth factor receptor (EGFR) peptide-conjugated PEGylated triangular gold nanoplates (TGN-PEG-P75) as a targeting photothermal therapy (PTT) agent to treat NSCLC under the guidance of computed tomography (CT) and photoacoustic (PA) imaging. The surface of TGNs is successfully conjugated with a novel peptide P75 that has the specific affinity to epidermal growth factor receptor (EGFR). It is found that the EGFR is overexpressed in NSCLC cells. The TGN-PEG-P75 has uniform edge length (77.9 +/- 7.0 nm) and neutrally charged surface. The cell uptake experiments demonstrate remarkable affinity of the TGN-PEG-P75 to high EGFR expression cells than low EGFR expression cells (5.1-fold). Thanks to the strong near-infrared absorbance, high photothermal conversion efficiency, and the increased accumulation in tumor cells via the interaction of P75 and EGFR, TGN-PEG-P75 exhibits 3.8-fold superior therapeutic efficacy on HCC827 cells than TGN-PEG. The in vivo CT/PA dual-modal imaging of the TGN-PEG-P75 is helpful in selecting the optimal treatment time and providing real-time visual guidance of PTT. Furthermore, treatments on HCC827 tumor-bearing mouse model demonstrate that the growth of NSCLC cells can be effectively inhibited by the TGN-PEG-P75 through PTT, indicating the great promise of the nanoplatform for treating NSCLC in vivo. PMID- 29722265 TI - Near-Infrared Fluorescent Ag2S Nanodot-Based Signal Amplification for Efficient Detection of Circulating Tumor Cells. AB - The level of circulating tumor cells (CTCs) plays a critical role in tumor metastasis and personalized therapy, but it is challenging for highly efficient capture and detection of CTCs because of the extremely low concentration in peripheral blood. Herein, we report near-infrared fluorescent Ag2S nanodot-based signal amplification combing with immune-magnetic spheres (IMNs) for highly efficient magnetic capture and ultrasensitive fluorescence labeling of CTCs. The near-infrared fluorescent Ag2S nanoprobe has been successfully constructed through hybridization chain reactions using aptamer-modified Ag2S nanodots, which can extremely improve the imaging sensitivity and reduce background signal of blood samples. Moreover, the antiepithelial-cell-adhesion-molecule (EpCAM) antibody-labeled magnetic nanospheres have been used for highly capture rare tumor cells in whole blood. The near-infrared nanoprobe with signal amplification and IMNs platform exhibits excellent performance in efficient capture and detection of CTCs, which shows great potential in cancer diagnostics and therapeutics. PMID- 29722266 TI - Chemical-Mediated Digestion: An Alternative Realm for Middle-down Proteomics? AB - Protein digestion in mass spectrometry (MS)-based bottom-up proteomics targets mainly lysine and arginine residues, yielding primarily 0.6-3 kDa peptides for the proteomes of organisms of all major kingdoms. Recent advances in MS technology enable analysis of complex mixtures of increasingly longer (>3 kDa) peptides in a high-throughput manner supporting the development of a middle-down proteomics (MDP) approach. Generating longer peptides is a paramount step in launching an MDP pipeline, but the quest for the selection of a cleaving agent that would provide the desired 3-15 kDa peptides remains open. Recent bioinformatics studies have shown that cleavage at the rarely occurring amino acid residues such as methionine (Met), tryptophan (Trp), or cysteine (Cys) would be suitable for MDP approach. Interestingly, chemical-mediated proteolytic cleavages uniquely allow targeting these rare amino acids, for which no specific proteolytic enzymes are known. Herein, as potential candidates for MDP-grade proteolysis, we have investigated the performance of chemical agents previously reported to target primarily Met, Trp, and Cys residues: CNBr, BNPS-Skatole (3 bromo-3-methyl-2-(2-nitrophenyl)sulfanylindole), and NTCB (2-nitro-5-thiobenzoic acid), respectively. Figures of merit such as digestion reproducibility, peptide size distribution, and occurrence of side reactions are discussed. The NTCB-based MDP workflow has demonstrated particularly attractive performance, and NTCB is put forward here as a potential cleaving agent for further MDP development. PMID- 29722267 TI - Recommendations to report and interpret HLA genetic findings in coeliac disease. AB - Coeliac disease (CD) is a chronic autoimmune enteropathy triggered by gluten and related prolamines in genetically predisposed individuals. Although CD is a polygenic disease, there is a strong association with genes of the human leukocyte antigen (HLA) region. Most patients present the HLA-DQ2 heterodimer, specifically the DQ2.5 isoform, which is present in around 90-96% of patients of European ancestry. PMID- 29722269 TI - Intramural esophageal dissection. A rare occurrence in pediatric eosinophilic esophagitis. AB - Eosinophilic esophagitis (EoE) is a chronic immune-mediated esophageal disease, with a rising incidence in childhood. The diagnosis is confirmed by esophageal mucosa eosinophil-predominant inflammation. Rare complications, such as intramural esophageal dissection (IED) due to progressive transmural inflammatory and fibrotic process, may occur in young adults. While severe cases can require immediate surgical intervention, conservative management may be also effective, as recently reported by Ibanez-Sanz et al., decreasing the risk of surgery related complications. PMID- 29722268 TI - Focal Pneumatosis cystoides intestinalis: optic colonoscopy and virtual colonoscopy features. AB - Pneumatosis intestinalis refers to lineal or cystic gas collections in the intestinal wall. Pneumatosis cystoides intestinalis (PCI) is a benign primary cause. This is a rare disease characterized by multiple gas cysts in the submucosa or subserosa, principally within the colon. PMID- 29722271 TI - Endoscopic ultrasound (EUS) guided fine needle biopsy (FNB) with the ProcoreTM needle provides inadequate material for the histological diagnosis of early chronic pancreatitis. AB - BACKGROUND: diagnosis of early chronic pancreatitis (CP) is hampered due to the low accuracy of current imaging techniques and the absence of methods for histological confirmation. We aimed to evaluate the efficacy of endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) for the histological diagnosis of early CP. METHODS: a prospective, cross-sectional, single-center study was designed. Consecutive patients referred for EUS with a clinical suspicion of CP were evaluated for inclusion into the study. Inclusion criteria were age > 18 years and indeterminate EUS findings for the diagnosis of CP according to the Rosemont classification. EUS-FNB of the body of the pancreas was performed with ProcoreTM needles. Tissue samples were immersed into a methanol-based buffered preservative solution for cytohistological evaluation. The quality of the samples obtained and the histological findings were evaluated. Procedure-related complications were recorded. RESULTS: the study was stopped after eleven patients were included due to safety concerns and poor diagnostic yield. The mean age of the patients was 50.3 years (range 33-70 years) and six were male. Samples were of poor quality in five cases, but were sufficient for cell-block evaluation. An inflammatory infiltration with mild fibrosis was identified in two cases and neither inflammatory infiltration nor fibrosis was identified in three cases. With regard to the other six cases, isolated inflammatory cells were observed in one case, although the cellularity was poor and unsuitable for cytological evaluation in five cases. There was one major complication (9.1%) of acute pancreatitis that required hospitalization for 48 hours. CONCLUSION: EUS-FNB is technically feasible in patients with EUS findings categorized as indeterminate for a CP diagnosis. However, the diagnostic yield is poor and there is a non negligible risk of complications. PMID- 29722270 TI - Proctitis and perirectal abscesses: is there anything else to think about? AB - Lymphogranuloma venereum (LGV) is a condition caused by invasive serovars of Chlamydia trachomatis. The classical inguinal presentation that is characterized by the development of transient genital ulcer(s) and inguinal or femoral lymphadenopathy has decreased in our environment. At present, infection by this bacterium has emerged as an important cause of proctitis and proctocolitis in men who have sex with other men. We report the case of a homosexual man with acute proctitis that was complicated by a perirectal abscess secondary to a Chlamydia trachomatis infection. PMID- 29722272 TI - Gallbladder cancer: a journey of a thousand steps. AB - This article traces the journey of one of the teams from India that has been actively managing and researching gallbladder cancer for more than a decade, providing insights into the work carried out and highlighting areas that warrant future research in this cancer traditionally known for its dismal outcomes. PMID- 29722273 TI - Physiology and transcriptome analyses reveal a protective effect of the radical scavenger melatonin in aging maize seeds. AB - To determine the role of melatonin in aging maize seeds ( Zea mays L.), we investigated the physiological characteristics and performance analysis of the transcriptome after applying melatonin to maize seeds as a response to aging. In this study, we demonstrated that applying exogenous melatonin alleviated aging induced oxidative damage, improved the activity of aging seeds, promoted growth of the germ and radical, enhanced antioxidant enzyme activity and reduced membrane lipid peroxidation. In addition, transcriptome sequencing revealed that various metabolic processes were induced by exogenous melatonin application in aging maize seeds, including hormone signal transduction, cellular processes, carbohydrate metabolism, secondary metabolites, and amino acid metabolism. In summary, the findings provide a more comprehensive understanding for analyzing the protective effect of melatonin in aging maize seeds. PMID- 29722274 TI - Statins use and cancer: an update. AB - After initial concerns regarding the association of statins with increased incidences of cancer and elevated cancer-related mortality, there are now plenty of data on the antitumor, cytostatic and cytotoxic effectiveness of this class of drugs. Here, we present a short review of possible mechanisms of antineoplastic activity obtained from preclinical research and the influence of statins on cancer treatment. In the second part of the article, we focus on the most recent data from observational clinical trials, as well as meta-analyses regarding cancer incidence and mortality in patients treated with statins. PMID- 29722275 TI - Eliminating HIV/HCV co-infection in gay and bisexual men: is it achievable through scaling up treatment? AB - INTRODUCTION: Broad availability of direct-acting antiviral therapy for hepatitis C virus (HCV) raises the possibility that HCV prevalence and incidence can be reduced through scaling-up treatment, leading to the elimination of HCV. High rates of linkage to HIV care among HIV-infected gay and bisexual men may facilitate high uptake of HCV treatment, possibly making HCV elimination more achievable in this group. Areas covered: This review covers HCV elimination in HIV-infected gay and bisexual men, including epidemiology, spontaneous clearance and long term sequelae in the absence of direct-acting antiviral therapy; direct acting antiviral therapy uptake and effectiveness in this group; HCV reinfection following successful treatment; and areas for further research. Expert commentary: Early data from the direct-acting antiviral era suggest that treatment uptake is increasing among HIV infected GBM, and SVR rates are very promising. However, in order to sustain current treatment rates, additional interventions at the behavioral, physician, and structural levels may be required to increase HCV diagnosis, including prompt detection of HCV reinfection. Timely consideration of these issues is required to maximize the population-level impact of HCV direct-acting antiviral therapy. Potential HCV transmissions from HIV uninfected GBM, across international borders, and from those who are not GBM also warrant consideration. PMID- 29722276 TI - Sustained reductions in migraine days, moderate-to-severe headache days and days with acute medication use for HFEM and CM patients taking fremanezumab: Post-hoc analyses from phase 2 trials. AB - Background In phase 2 and 3 studies, fremanezumab, a monoclonal CGRP antibody, was an effective preventive treatment for high-frequency episodic migraine (HFEM) and chronic migraine (CM). Objective Post-hoc analyses evaluated population-wise 50%, 75% and 100% responder rates, and the extent to which individual responders sustained a 50%, 75% and 100% reduction in migraine days, moderate-to-severe (M/S) headache days and days of acute medication use during all three treatment months of the fremanezumab phase 2 studies. Design/methods HFEM patients received either placebo or three once-monthly injections of 225 mg or 675 mg. CM patients received either placebo or three once-monthly injections of 900 mg, or an initial loading dose of 675 mg and subsequent injections of 225 mg. Patients reported headache-related data daily using an electronic diary. Results In the HFEM study, the percent of patients on fremanezumab doses 225 mg and 675 mg were greater compared to the percent of placebo patients with sustained 50% reduction in migraine days (39% and 35% vs. 10% for placebo, both p < 0.0001), M/S headache days (36% and 38% vs. 16% placebo, p = 0.0017 and p = 0.0007 respectively), and acute medication use days (36% and 27% vs. 8% placebo, p < 0.0001 and p = 0.0003). Likewise, although there were fewer patients with sustained 75% reduction, there were increases in the percent of patients on fremanezumab 225 mg and 675 mg in the HFEM study relative to placebo patients in migraine days (19% and 11% vs. 3% placebo, p = 0.0002 and p = 0.0176), M/S headache days (19% and 15% vs. 2% placebo, p = 0.0001 and p = 0.0011) and days of acute medication use (16% and 8% vs. 2% placebo, p = 0.0005 and p = 0.0377). In the CM study, there were increases in the percent of patients on fremanezumab 675/225 mg and 900 mg with 50% sustained reduction in M/S headache days (32% and 40% vs. 15% placebo, p = 0.0058 and p = 0.0002) and days of acute medication use (26% and 22% vs. 11% placebo, p = 0.0098 and p = 0.0492). There were also increases in the percent of patients on fremanezumab 675/225 mg and 900 mg compared to patients on placebo with 75% sustained reduction in M/S headache days (10% and 13% vs. 3%, p = 0.0665 and p = 0.0203). Few patients had 100% sustained reductions in these parameters in either study. Conclusions Post-hoc results must be interpreted with caution; nonetheless, a statistically significant percentage of patients who initially responded to fremanezumab within 1 month sustained this response over the subsequent 2 months. Sustained reduction in individual patients may provide a novel patient-centric, clinically meaningful endpoint for future trials assessing the effectiveness of preventive migraine treatments. Trials are registered as http://clinical trials.gov as NCT02025556 and NCT02021773. PMID- 29722277 TI - Elder Mistreatment Among Older Chinese Americans: The Role of Family Cohesion. AB - Cultural values are believed to influence perceptions of and solutions to elder mistreatment (EM) perpetrated by family members. This study aimed to understand the influence of family cohesion on EM reported by community-dwelling older Chinese Americans. A mixed-method approach consisting of a quantitative survey built on focus group interviews was utilized. Focus group interviews were conducted to ensure subsequent survey questions about EM were culturally and linguistically appropriate. The revised survey questionnaires were then administered to 266 Chinese American older adults to assess estimated EM prevalence and the effects of family cohesion. Survey findings indicate that 1 in 10 reported at least one occurrence of EM in the past year. Depressed Chinese older adults (OR= 1.14) and those reporting low levels of family cohesion (OR = .82) were more likely to experience EM. Multigenerational family interventions can be designed to reduce older adults' depression levels and promote family cohesion. PMID- 29722279 TI - Unmet needs and quality of life in multiple myeloma patients. AB - This cross-sectional study analysed the contributors and moderators of quality of life. The sample comprised 124 Portuguese multiple myeloma patients assessed on social support, spirituality, unmet needs, psychological morbidity and quality-of life measures. Results showed that being older and a woman, as well as psychological morbidity and unmet emotional needs were significant predictors of worse quality of life as measured by the QLQ-C30. Unmet financial needs moderated the relationship between psychological morbidity and quality of life. Results emphasize the importance of intervening in patients' unmet emotional needs and psychological morbidity in order to promote quality of life, in this population. PMID- 29722280 TI - Development and testing of a self-regulation model for recurrent depression. AB - Self-regulation is a strategy for self-management of depression. Study aims were to (1) describe development of an intervention based on metacognition and self regulation, (2) test intervention feasibility and utility, and (3) determine its effectiveness in reducing depressive symptoms. The Self-Regulated Illness Management of Depression intervention was developed and taught to 22 participants with recurrent depression. There was no attrition 6 months post intervention. At 6 months, there was a significant decrease in depressive symptoms ( M = 10.21, standard deviation = 8.0), t(18) = 5.60, p < .001, and 73 percent of participants used Self-Regulated Illness Management of Depression frequently. Results indicated that Self-Regulated Illness Management of Depression was feasible and useful. PMID- 29722281 TI - Effects of a physical activity program on post-bariatric patients: A qualitative study from a self-determination theory perspective. AB - This study provides an in-depth analysis of the psychosocial benefits that 10 post-bariatric patients (nine female, 31-59 years) perceived from their participation in an exercise program grounded in self-determination theory. Qualitative data were collected through observations and interviews. Participants reported many factors which facilitated basic psychological need satisfaction such as the instructors caring about their opinion, affection, fitness improvement, pain reduction, and knowledge acquisition. These factors were associated with autonomous motivation, enjoyment, intention to be physically active, happiness, and self-confidence. The results suggest that self determination theory-based exercise programs could be designed to achieve positive outcomes in this population. PMID- 29722278 TI - Cold atmospheric-pressure plasma induces DNA-protein crosslinks through protein oxidation. AB - Reactive oxygen and nitrogen species (ROS and RNS) generated by cold atmospheric pressure plasma could damage genomic DNA, although the precise types of these DNA damage induced by plasma are poorly characterized. Understanding plasma-induced DNA damage will help to elucidate the biological effect of plasma and guide the application of plasma in ROS-based therapy. In this study, it was shown that ROS and RNS generated by physical plasma could efficiently induce DNA-protein crosslinks (DPCs) in bacteria, yeast, and human cells. An in vitro assay showed that plasma treatment resulted in the formation of covalent DPCs by activating proteins to crosslink with DNA. Mass spectrometry and hydroperoxide analysis detected oxidation products induced by plasma. DPC formation were alleviated by singlet oxygen scavenger, demonstrating the importance of singlet oxygen in this process. These results suggested the roles of DPC formation in DNA damage induced by plasma, which could improve the understanding of the biological effect of plasma and help to develop a new strategy in plasma-based therapy including infection and cancer therapy. PMID- 29722283 TI - Communication between doctors and lawyers. PMID- 29722284 TI - Latest developments in the field of stem cell research and regenerative medicine compiled from publicly available information and press releases from nonacademic institutions 1 November - 31 December 2017. PMID- 29722285 TI - Optimal neuromuscular blocking effects of remifentanil during tracheal intubation under general anesthesia. AB - Objective This study was performed to determine the effect of the remifentanil dose on the onset time of rocuronium with electromyography. Methods This retrospective comparative study included 75 patients undergoing general anesthesia for elective surgery. Patients received lidocaine (40 mg) and propofol (2 mg/kg) followed by rocuronium (0.6 mg/kg) with either saline infusion (Group S), remifentanil at 0.5 ug/kg/minute (Group R 0.5), or remifentanil at 1.0 ug/kg/minute (Group R 1.0). Neuromuscular block was monitored by train-of-four (TOF) electromyography, and the times taken to reach TOF 0 and TOF ratio (TOFR) 25% were recorded. Results The times taken to reach TOF 0 and TOFR 25% were significantly higher in Groups R 0.5 and R 1.0 than in Group S. The time taken to reach TOF 0 was 130.0 +/- 6.4 s in Group S, 142.6 +/- 6.0 s in Group R 0.5, and 183.0 +/- 11.6 s in Group R 1.0. The time taken to reach TOFR 25% was also higher in Groups R 0.5 and R 1.0 than in Group S. Conclusions As the remifentanil dose increases, the intubation time required to reach TOF 0 also increases. Remifentanil has an effect on the onset of rocuronium. PMID- 29722287 TI - Effects of enteral different-dose levothyroxinesodium pretreatment on serum thyroid hormone levels and myocardial ischemia-reperfusion injury. AB - INTRODUCTION: The available evidence shows that perioperative oral thyroid hormone can significantly attenuate the postoperative decline in the serum hormone level and improve postoperative hemodynamic and prognostic parameters. However, there has been no study assessing the effects of preoperative oral different-dose thyroid hormone on serum hormone levels and myocardial ischemia reperfusion injury (IRI) after cardiac surgery. METHODS: Forty-eight healthy Wistar rats, aged 35 days, were randomly allocated into six groups: Group BC, Group C and four pretreatment groups in which the rats were given levothyroxine sodium of 10 MUg, 20 MUg, 40 MUg and 80 MUg/100 g. On the eighth day, the serum thyroid hormone levels were determined and then an isolated heart ischemia reperfusion model was established with a Langendorff apparatus. RESULTS: Compared with Groups BC and C, serum thyroid hormone levels on the eighth day did not significantly change in Group 10 MUg, but were significantly increased in Groups 20 MUg, 40 MUg and 80 MUg. The cardiac enzyme myocardial-bound creatine kinase levels in the coronary effluent during reperfusion were significantly lower in Groups 10 MUg and 20 MUg and 40 MUg than in Group C. The recovery rates of + dp/dtmax and - dp/dtmax at 30 min during reperfusion were significantly lower in Groups 40 MUg and 80 MUg than in Groups 10 MUg and 20 MUg. Compared with Group C, myocardial expressions of heat shock protein 70 and myosin heavy chain alpha were increased in the four experiment groups and myocardial expression of thyroid hormone receptor alpha1 was significantly increased in Groups 20 MUg, 40 MUg and 80 MUg. CONCLUSIONS: The pretreatment with enterally smaller doses levothyroxine sodium does not significantly affect serum thyroid hormone levels and produces protection against myocardial IRI, whereas pretreatment with enterally larger doses of levothyroxine-sodium can only provide an attenuated or insignificant cardioprotection because of hyperthyroxinemia. Cardioprotection by levothyroxine sodium pretreatment is probably attributable to increased myocardial expression of heat shock protein 70 and myosin heavy chain alpha. PMID- 29722286 TI - New insertion support device assisted the accurate placement of tunneled cuffed catheter: First experience of 10 cases. AB - INTRODUCTION: The tunneled cuffed catheter is used in hemodialysis patients for whom an arteriovenous fistula or arteriovenous graft is not suitable or for bridging usage of them. Accurate placement of a tunneled cuffed catheter is necessary for safe hemodialysis, but placement is sometimes difficult because of individual body differences. We developed a new device to support accurate placement of the tunneled cuffed catheter. In this study, we report our first clinical experience of the device. METHODS: We made the device by expanded polytetrafluoroethylene with some special processes. The processes enable it to maintain plasticity and temporary shape in the autoclaved condition. The device is laid on the surface of the patient's body to mark the root of the catheter with a felt-tipped marker before catheterization. That enables us to know the accurate catheter root and tunneled cuffed catheter exit site on the body surface. Ten patients underwent tunneled cuffed catheter insertion according to the marking. CASE DESCRIPTION: The mean age was 71.3 +/- 12.8 years. The tunneled cuffed catheter was safely placed according to the marking in all patients, and all catheter tips were placed in the right atrium. The mean verification tip location difference before and after catheterization was 0.70 +/- 0.48 cm. This result indicated that the device could assist in inserting a catheter accurately within an error of 1.18 cm. The tunneled cuffed catheters were patent in all the cases, without replacement and complications until the end of bridging use or during the observation period. CONCLUSION: Our newly developed insertion support device enhances safety and prevents catheter waste during replacement. PMID- 29722288 TI - Ultrasound-guided central venous tip confirmation via right external jugular vein using a right supraclavicular fossa view. AB - INTRODUCTION: Ultrasound-guided central venous catheter tip confirmation has a potential to precisely locate the central venous catheter, preventing its misplacement, using real-time guidance. This observational study sought to determine the accuracy of central venous catheter tip positioning via the external jugular vein via a supraclavicular fossa view under ultrasound guidance. METHODS: In total, 77 patients scheduled for central venous catheter insertion via the right external jugular vein were enrolled. The depth of central venous catheter insertion was determined by advancing the tip of the guidewire to the junction of the superior vena cava and right pulmonary artery, using a right supraclavicular fossa view ultrasound method. We determined the reference insertion depth to the carina using a postoperative chest x-ray photograph method. We then compared insertion depths obtained by the ultrasound and x-ray photograph methods and body-height formula. RESULTS: In total, 62 patients were able to advance the guidewire and underwent ultrasound-guided central venous catheter insertion. In four patients, we corrected for misplaced guidewires. According to Bland-Altman plots, the insertion depth was 0.88 cm shorter for the ultrasound method (95% limits of agreement, -1.66 to 3.41 cm) and 0.90 cm shorter for the formulaic method (95% limits of agreement, -2.77 to 4.56 cm), compared with the x-ray photograph method. The x-ray photograph method had significantly positive correlations with the ultrasound (r = 0.73) and formulaic methods (r = 0.27). CONCLUSION: A right supraclavicular fossa view improves the accuracy of central venous catheter tip positioning and prevents central venous catheter misplacement via the right external jugular vein. PMID- 29722289 TI - Corrigendum: Transcription factor VdCmr1 is required for pigment production, protection from UV irradiation, and regulates expression of melanin biosynthetic genes in Verticillium dahliae. PMID- 29722290 TI - Feasibility of polymer gel-based measurements of radiation isocenter accuracy in magnetic fields. AB - For conventional irradiation devices, the radiation isocenter accuracy is determined by star shot measurements on films. In magnetic resonance (MR)-guided radiotherapy devices, the results of this test may be altered by the magnetic field and the need to align the radiation and imaging isocenter may require a modification of measurement procedures. Polymer dosimetry gels (PG) may offer a way to perform both, the radiation and imaging isocenter test, however, first it has to be shown that PG reveal results comparable to the conventionally applied films. Therefore, star shot measurements were performed at a linear accelerator using PG as well as radiochromic films. PG were evaluated using MR imaging and the isocircle radius and the distance between the isocircle center and the room isocenter were determined. Two different types of experiments were performed: i) a standard star-shot isocenter test and (ii) a star shot, where the detectors were placed between the pole shoes of an experimental electro magnet operated either at 0 T or 1 T. For the standard star shot, PG evaluation was independent of the time delay after irradiation (1 h, 24 h, 48 h and 216 h) and the results were comparable to those of film measurements. Within the electro magnet, the isocircle radius increased from 0.39 +/- 0.01 mm to 1.37 +/- 0.01 mm for the film and from 0.44 +/- 0.02 mm to 0.97 +/- 0.02 mm for the PG-measurements, respectively. The isocenter distance was essentially dependent on the alignment of the magnet to the isocenter and was between 0.12 +/- 0.02 mm and 0.82 +/- 0.02 mm. The study demonstrates that evaluation of the PG directly after irradiation is feasible, if only geometrical parameters are of interest. This allows using PG for star shot measurements to evaluate the radiation isocenter accuracy with comparable accuracy as with radiochromic films. PMID- 29722291 TI - Effect of nickel diffusion and oxygen behavior on heterojunction Schottky diodes of Au/NiO/ZnO with a NiO interlayer prepared by radio-frequency magnetron sputtering. AB - The rectifying characteristic of Au/ZnO Schottky diodes (SDs) was remarkably improved by introducing a NiO layer in-between the Au and ZnO layers. Compared with the Au/ZnO SDs, the introduction of the NiO layer significantly enhanced the rectification ratio from 1.38 to 1300, and reduced the ideality factor from 5.78 to 2.14. The NiO and ZnO layers were deposited on an indium-tin-oxide/glass substrate by radio-frequency magnetron sputtering. Secondary ion mass spectroscopy showed that Ni atoms diffused from NiO to ZnO, leading to a graded distribution of Ni in ZnO. X-ray diffraction demonstrated that the diffusion of Ni atoms increased the grain size and electron concentration of ZnO. X-ray photoelectron spectroscopy showed that the interstitial oxygen (Oi) atoms in NiO and ZnO compensated the oxygen vacancies (OV) at the NiO/ZnO interface; the amount of OV was significantly reduced, while Oi vanished at the interface. The band diagram revealed a potential drop in the bulk ZnO, owing to the graded distribution of Ni in ZnO, which accelerated the carriers, collected by the outer circuit. The carriers at the NiO/ZnO interface easily crossed over the barrier height, instead of being recombined by OV, owing to the lower amount of OV at the interface. PMID- 29722292 TI - Angiogenic potential of spheroids from umbilical cord and adipose-derived multipotent mesenchymal stromal cells within fibrin gel. AB - One of the essential goals in regenerative medicine is microvascularization which enables an effective blood supply within de novo constructed tissues and organs. In our study, we used two common multipotent mesenchymal stromal cell (MMSC) sources (subcutaneous adipose tissue and Wharton's jelly of the umbilical cord) where is a subpopulation of endothelial precursors. In the medium supplemented with VEGF, the 3D cultures of UC MMSCs and ADSCs promoted the endothelial cell differentiation. To evaluate their ability to form a capillary-like network, we encapsulated spheroids within non-modified and PEGylated fibrin hydrogels. The PEGylated hydrogel supported better the formation of multibranched cords than the pure fibrin gel. Analysis of tubule growth rate, length, and branching showed that the differentiated ADSCs had higher angiogenic potential than the differentiated hUC MMSCs. Our study can be a basis for the development of new strategies in tissue engineering and treatment of vascular diseases. PMID- 29722293 TI - Magnetic domain structure imaging near sample surface with alternating magnetic force microscopy by using AC magnetic field modulated superparamagnetic tip. AB - For magnetic domain imaging, with a very high spatial resolution magnetic force microscope, the tip-sample distance should be as small as possible. However, magnetic imaging near the sample surface is very difficult with conventional magnetic force microscopy (MFM) because the interactive forces between the tip and sample include van der Waals and electrostatic forces along with a magnetic force. In this study, we proposed alternating MFM which only extracts a magnetic force near the sample surface without any topographic and electrical crosstalk. In the present method, the magnetization of an FeCo-GdO x superparamagnetic tip is modulated by an external AC magnetic field in order to measure the magnetic domain structure without any perturbation from the other forces near the sample surface. Moreover, it is demonstrated that the proposed method can also measure the strength and identify the polarities of the second derivative of the perpendicular stray field from a thin film permanent magnet with a DC demagnetized state and remanent state. PMID- 29722294 TI - Gold nanochestnut arrays as ultra-sensitive SERS substrate for detecting trace pesticide residue. AB - In comparison to conventional spectroscopic techniques based on chromatography, surface-enhanced Raman spectroscopy (SERS) enables the rapid identification and detection of trace pesticide residues present in trace amounts in the environment and foods. Herein, a facile approach to fabricate unique gold nanochestnuts (GNCs) as an ultra-sensitive SERS substrate for detecting trace pesticide residues has been developed based on anodic aluminum oxide (AAO) templates. The GNCs are synthesized through the galvanic replacement of Ag on the top of Ni nanorod arrays. The as-prepared GNCs have well-controlled structural parameters, and importantly have unique anisotropic morphologies that benefit the enhancement in SERS performance. As a result, rhodamine 6 G (R6G) can be efficiently detected with GNCs as the SERS substrate even with a concentration of only 10-12 M, and the Raman enhancement factor reaches up to 5.4 * 109 at this concentration. Further SERS measurement of thiram indicates a remarkable SERS-active sensitivity of the as-prepared GNCs with a detection limit of thiram up to 10-14 M. The GNCs also exhibit a high signal-to-noise ratio. PMID- 29722295 TI - Luminescence imaging of water during uniform-field irradiation by spot scanning proton beams. AB - Luminescence was found during pencil-beam proton irradiation to water phantom and range could be estimated from the luminescence images. However, it is not yet clear whether the luminescence imaging is applied to the uniform fields made of spot-scanning proton-beam irradiations. For this purpose, imaging was conducted for the uniform fields having spread out Bragg peak (SOBP) made by spot scanning proton beams. We designed six types of the uniform fields with different ranges, SOBP widths and irradiation fields. One of the designed fields was irradiated to water phantom and a cooled charge coupled device camera was used to measure the luminescence image during irradiations. We estimated the ranges, field widths, and luminescence intensities from the luminescence images and compared those with the dose distribution calculated by a treatment planning system. For all types of uniform fields, we could obtain clear images of the luminescence showing the SOBPs. The ranges and field widths evaluated from the luminescence were consistent with those of the dose distribution calculated by a treatment planning system within the differences of -4 mm and -11 mm, respectively. Luminescence intensities were almost proportional to the SOBP widths perpendicular to the beam direction. The luminescence imaging could be applied to uniform fields made of spot scanning proton beam irradiations. Ranges and widths of the uniform fields with SOBP could be estimated from the images. The luminescence imaging is promising for the range and field width estimations in proton therapy. PMID- 29722296 TI - Reconstruction-of-difference (RoD) imaging for cone-beam CT neuro-angiography. AB - Timely evaluation of neurovasculature via CT angiography (CTA) is critical to the detection of pathology such as ischemic stroke. Cone-beam CTA (CBCT-A) systems provide potential advantages in the timely use at the point-of-care, although challenges of a relatively slow gantry rotation speed introduce tradeoffs among image quality, data consistency and data sparsity. This work describes and evaluates a new reconstruction-of-difference (RoD) approach that is robust to such challenges. A fast digital simulation framework was developed to test the performance of the RoD over standard reference reconstruction methods such as filtered back-projection (FBP) and penalized likelihood (PL) over a broad range of imaging conditions, grouped into three scenarios to test the trade-off between data consistency, data sparsity and peak contrast. Two experiments were also conducted using a CBCT prototype and an anthropomorphic neurovascular phantom to test the simulation findings in real data. Performance was evaluated primarily in terms of normalized root mean square error (NRMSE) in comparison to truth, with reconstruction parameters chosen to optimize performance in each case to ensure fair comparison. The RoD approach reduced NRMSE in reconstructed images by up to 50%-53% compared to FBP and up to 29%-31% compared to PL for each scenario. Scan protocols well suited to the RoD approach were identified that balance tradeoffs among data consistency, sparsity and peak contrast-for example, a CBCT-A scan with 128 projections acquired in 8.5 s over a 180 degrees + fan angle half scan for a time attenuation curve with ~8.5 s time-to-peak and 600 HU peak contrast. With imaging conditions such as the simulation scenarios of fixed data sparsity (i.e. varying levels of data consistency and peak contrast), the experiments confirmed the reduction of NRMSE by 34% and 17% compared to FBP and PL, respectively. The RoD approach demonstrated superior performance in 3D angiography compared to FBP and PL in all simulation and physical experiments, suggesting the possibility of CBCT-A on low-cost, mobile imaging platforms suitable to the point-of-care. The algorithm demonstrated accurate reconstruction with a high degree of robustness against data sparsity and inconsistency. PMID- 29722297 TI - 4D cone-beam computed tomography (CBCT) using a moving blocker for simultaneous radiation dose reduction and scatter correction. AB - Four-dimensional (4D) x-ray cone-beam computed tomography (CBCT) is important for a precise radiation therapy for lung cancer. Due to the repeated use and 4D acquisition over a course of radiotherapy, the radiation dose becomes a concern. Meanwhile, the scatter contamination in CBCT deteriorates image quality for treatment tasks. In this work, we propose the use of a moving blocker (MB) during the 4D CBCT acquisition ('4D MB') and to combine motion-compensated reconstruction to address these two issues simultaneously. In 4D MB CBCT, the moving blocker reduces the x-ray flux passing through the patient and collects the scatter information in the blocked region at the same time. The scatter signal is estimated from the blocked region for correction. Even though the number of projection views and projection data in each view are not complete for conventional reconstruction, 4D reconstruction with a total-variation (TV) constraint and a motion-compensated temporal constraint can utilize both spatial gradient sparsity and temporal correlations among different phases to overcome the missing data problem. The feasibility simulation studies using the 4D NCAT phantom showed that 4D MB with motion-compensated reconstruction with 1/3 imaging dose reduction could produce satisfactory images and achieve 37% improvement on structural similarity (SSIM) index and 55% improvement on root mean square error (RMSE), compared to 4D reconstruction at the regular imaging dose without scatter correction. For the same 4D MB data, 4D reconstruction outperformed 3D TV reconstruction by 28% on SSIM and 34% on RMSE. A study of synthetic patient data also demonstrated the potential of 4D MB to reduce the radiation dose by 1/3 without compromising the image quality. This work paves the way for more comprehensive studies to investigate the dose reduction limit offered by this novel 4D MB method using physical phantom experiments and real patient data based on clinical relevant metrics. PMID- 29722300 TI - Bridging the gap: axonal fusion drives rapid functional recovery of the nervous system. AB - Injuries to the central or peripheral nervous system frequently cause long-term disabilities because damaged neurons are unable to efficiently self-repair. This inherent deficiency necessitates the need for new treatment options aimed at restoring lost function to patients. Compared to humans, a number of species possess far greater regenerative capabilities, and can therefore provide important insights into how our own nervous systems can be repaired. In particular, several invertebrate species have been shown to rapidly initiate regeneration post-injury, allowing separated axon segments to re-join. This process, known as axonal fusion, represents a highly efficient repair mechanism as a regrowing axon needs to only bridge the site of damage and fuse with its separated counterpart in order to re-establish its original structure. Our recent findings in the nematode Caenorhabditis elegans have expanded the promise of axonal fusion by demonstrating that it can restore complete function to damaged neurons. Moreover, we revealed the importance of injury-induced changes in the composition of the axonal membrane for mediating axonal fusion, and discovered that the level of axonal fusion can be enhanced by promoting a neuron's intrinsic growth potential. A complete understanding of the molecular mechanisms controlling axonal fusion may permit similar approaches to be applied in a clinical setting. PMID- 29722298 TI - Acupuncture and neuroregeneration in ischemic stroke. AB - Acupuncture is potentially beneficial for post-stroke rehabilitation and is considered a promising preventive strategy for stroke. Electroacupuncture pretreatment or treatment after ischemic stroke by using appropriate electroacupuncture parameters generates neuroprotective and neuroregenerative effects that increase cerebral blood flow, regulate oxidative stress, attenuate glutamate excitotoxicity, maintain blood-brain barrier integrity, inhibit apoptosis, increase growth factor production, and induce cerebral ischemic tolerance. PMID- 29722299 TI - The adjustment of gamma-aminobutyric acidA tonic subunits in Huntington's disease: from transcription to translation to synaptic levels into the neostriatum. AB - gamma-Aminobutyric acid (GABA), plays a key role in all stages of life, also is considered the main inhibitory neurotransmitter. GABA activates two kind of membrane receptors known as GABAA and GABAB, the first one is responsible to render tonic inhibition by pentameric receptors containing alpha4-6, beta3, delta, or rho1-3 subunits, they are located at perisynaptic and/or in extrasynaptic regions. The biophysical properties of GABAA tonic inhibition have been related with cellular protection against excitotoxic injury and cell death in presence of excessive excitation. On this basis, GABAA tonic inhibition has been proposed as a potential target for therapeutic intervention of Huntington's disease. Huntington's disease is a neurodegenerative disorder caused by a genetic mutation of the huntingtin protein. For experimental studies of Huntington's disease mouse models have been developed, such as R6/1, R6/2, HdhQ92, HdhQ150, as well as YAC128. In all of them, some key experimental reports are focused on neostriatum. The neostriatum is considered as the most important connection between cerebral cortex and basal ganglia structures, its cytology display two pathways called direct and indirect constituted by medium sized spiny neurons expressing dopamine D1 and D2 receptors respectively, they display strong expression of many types of GABAA receptors, including tonic subunits. The studies about of GABAA tonic subunits and Huntington's disease into the neostriatum are rising in recent years, suggesting interesting changes in their expression and localization which can be used as a strategy to delay the cellular damage caused by the imbalance between excitation and inhibition, a hallmark of Huntington's disease. PMID- 29722301 TI - Collagen for brain repair: therapeutic perspectives. AB - Biomaterials have increasingly become a focus of research on neuroprotection and neuroregeneration. Collagen, in terms of brain repair, presents many advantages such as being remarkably biocompatible, biodegradable, versatile and non-toxic. Collagen can be used to form injectable scaffolds and micro/nano spheres in order to: (i) locally release therapeutic factors with the aim of protecting degenerating neurons in neurodegenerative conditions such as Alzheimer's or Parkinson's diseases, (ii) encapsulate stem cells for safe delivery, (iii) encapsulate genetically modified cells to provide a long term source of trophic factors, (iv) fill in the voids from injury to serve as a structural support and provide a permissive microenvironment to promote axonal growth. This mini-review summarizes different applications of collagen biomaterial for central nervous system protection and repair, as well as the future perspectives. Overall, collagen is a promising natural biomaterial with various applications which has the potential to progress the development of therapeutic strategies in central nervous system injuries and degeneration. PMID- 29722305 TI - Young blood products: emerging treatment for Alzheimer's disease? AB - Alzheimer's disease is the most common neurodegenerative disorder and no disease modifying treatment is currently available. Research has shown that while brain neurogenesis continues in adult life, it declines with age. Using parabiosis, plasma transfusions and direct administration of neural growth factors, animal studies have demonstrated the positive impact of exposure to young blood products on neurogenesis and synaptic plasticity in an aging brain. The hippocampus and the sub-ventricular zones were identified as the main regions affected. Promising findings have prompted researchers to experiment their effects in subjects with an established neurocognitive disorder, such as Alzheimer's disease. They argued that modification of brain vasculature, reactivation of adult neural stem cells, and remodeling of their synaptic activity/plasticity may lead to cognitive enhancement and increased neurogenesis. One pilot human study found that young donor plasma infusion protocols for adults with Alzheimer's disease were safe and feasible; however, no statistically significant improvements in cognition were detected. There is a need to conduct additional placebo-controlled human studies in larger samples. Future studies should focus on identifying an "optimal age" at which an intervention in humans may yield significant cognitive enhancement, as well as determining the types of transfusions with the best efficacy and tolerability profiles. PMID- 29722303 TI - Harnessing migraines for neural regeneration. AB - The success of naturalistic or therapeutic neuroregeneration likely depends on an internal milieu that facilitates the survival, proliferation, migration, and differentiation of stem cells and their assimilation into neural networks. Migraine attacks are an integrated sequence of physiological processes that may protect the brain from oxidative stress by releasing growth factors, suppressing apoptosis, stimulating neurogenesis, encouraging mitochondrial biogenesis, reducing the production of oxidants, and upregulating antioxidant defenses. Thus, the migraine attack may constitute a physiologic environment conducive to stem cells. In this paper, key components of migraine are reviewed - neurogenic inflammation with release of calcitonin gene-related peptide (CGRP) and substance P, plasma protein extravasation, platelet activation, release of serotonin by platelets and likely by the dorsal raphe nucleus, activation of endothelial nitric oxide synthase (eNOS), production of brain-derived neurotrophic factor (BDNF) and, in migraine aura, cortical spreading depression - along with their potential neurorestorative aspects. The possibility is considered of using these components to facilitate successful stem cell transplantation. Potential methods for doing so are discussed, including chemical stimulation of the TRPA1 ion channel, conjoint activation of a subset of migraine components, invasive and noninvasive deep brain stimulation of the dorsal raphe nucleus, transcranial focused ultrasound, and stimulation of the Zusanli (ST36) acupuncture point. PMID- 29722306 TI - Dissecting the multifactorial nature of demyelinating disease. AB - Chondroitin sulfate proteoglycan-4 (CSPG4) is a surface component of two key cell types (oligodendrocyte progenitor cells (OPCs) and myeloid cells) present in lysolecithin-induced lesions in mouse spinal cord. Two types of CSPG4 manipulations have been used to study the roles of these cells in myelin damage and repair: (1) OPC and myeloid-specific ablation of CSPG4, and (2) transplantation of enhanced green fluorescent protein (EGFP)-labeled progenitors to distinguish between bone marrow-derived macrophages and resident microglia. Ablation of CSPG4 in OPCs does not affect myelin damage, but decreases myelin repair, due to reduced proliferation of CSPG4-null OPCs that diminishes generation of mature oligodendrocytes for remyelination. Ablation of CSPG4 in myeloid cells greatly decreases recruitment of macrophages to spinal cord lesions, resulting in smaller initial lesions, but also in significantly diminished myelin repair. In the absence of macrophage recruitment, OPC proliferation is greatly impaired, again leading to decreased generation of myelinating oligodendrocytes. Macrophages may promote OPC proliferation via phagocytosis of myelin debris and/or secretion of factors that stimulate OPC mitosis. Microglia are not able to substitute for macrophages in promoting OPC proliferation. An additional feature of lesions in myeloid-specific CSPG4 null mice is the persistence of poorly-differentiated platelet-derived growth factor receptor alpha (PDGFRalpha) + macrophages that may prolong damage. PMID- 29722307 TI - Do large brains of long-living mammals prefer non-newly generated, immature neurons? PMID- 29722302 TI - Stimulating effect of thyroid hormones in peripheral nerve regeneration: research history and future direction toward clinical therapy. AB - Injury to peripheral nerves is often observed in the clinic and severe injuries may cause loss of motor and sensory functions. Despite extensive investigation, testing various surgical repair techniques and neurotrophic molecules, at present, a satisfactory method to ensuring successful recovery does not exist. For successful molecular therapy in nerve regeneration, it is essential to improve the intrinsic ability of neurons to survive and to increase the speed of axonal outgrowth. Also to induce Schwann cell phenotypical changes to prepare the local environment favorable for axonal regeneration and myelination. Therefore, any molecule that regulates gene expression of both neurons and Schwann cells could play a crucial role in peripheral nerve regeneration. Clinical and experimental studies have reported that thyroid hormones are essential for the normal development and function of the nervous system, so they could be candidates for nervous system regeneration. This review provides an overview of studies devoted to testing the effect of thyroid hormones on peripheral nerve regeneration. Also it emphasizes the importance of combining biodegradable tubes with local administration of triiodothyronine for future clinical therapy of human severe injured nerves. We highlight that the local and single administration of triiodothyronine within biodegradable nerve guide improves significantly the regeneration of severed peripheral nerves, and accelerates functional recovering. This technique provides a serious step towards future clinical application of triiodothyronine in human severe injured nerves. The possible regulatory mechanism by which triiodothyronine stimulates peripheral nerve regeneration is a rapid action on both axotomized neurons and Schwann cells. PMID- 29722308 TI - Epigenetic interventions for brain rejuvenation: anchoring age-related transposons. PMID- 29722304 TI - Synaptic dysfunction in Alzheimer's disease: the effects of amyloid beta on synaptic vesicle dynamics as a novel target for therapeutic intervention. AB - The most prevalent form of dementia in the elderly is Alzheimer's disease. A significant contributing factor to the progression of the disease appears to be the progressive accumulation of amyloid-beta42 (Abeta42), a small hydrophobic peptide. Unfortunately, attempts to develop therapies targeting the accumulation of Abeta42 have not been successful to treat or even slow down the disease. It is possible that this failure is an indication that targeting downstream effects rather than the accumulation of the peptide itself might be a more effective approach. The accumulation of Abeta42 seems to affect various aspects of physiological cell functions. In this review, we provide an overview of the evidence that implicates Abeta42 in synaptic dysfunction, with a focus on how it contributes to defects in synaptic vesicle dynamics and neurotransmitter release. We discuss data that provide new insights on the Abeta42 induced pathology of Alzheimer's disease and a more detailed understanding of its contribution to the synaptic deficiencies that are associated with the early stages of the disease. Although the precise mechanisms that trigger synaptic dysfunction are still under investigation, the available data so far has enabled us to put forward a model that could be used as a guide to generate new therapeutic targets for pharmaceutical intervention. PMID- 29722309 TI - Fluorescence detection of Europium-doped very small superparamagnetic iron oxide nanoparticles in murine hippocampal slice cultures. PMID- 29722310 TI - Axotomy induces damage to glial cells remote from the transection site in the peripheral nervous system. PMID- 29722311 TI - Targeted tissue engineering: hydrogels with linear capillary channels for axonal regeneration after spinal cord injury. PMID- 29722312 TI - Neuromodulator interactions and spinal cord injury in lamprey. PMID- 29722313 TI - Ketamine enhances structural plasticity in human dopaminergic neurons: possible relevance for treatment-resistant depression. PMID- 29722315 TI - Dopaminergic mediation in the brain aging and neurodegenerative diseases: a role of senescent cells. PMID- 29722314 TI - Impacts of increased alpha-synuclein on clathrin-mediated endocytosis at synapses: implications for neurodegenerative diseases. PMID- 29722316 TI - Astrocytic Kir4.1 potassium channels as a novel therapeutic target for epilepsy and mood disorders. PMID- 29722317 TI - Exendin-4 inhibits high-altitude cerebral edema by protecting against neurobiological dysfunction. AB - The anti-inflammatory and antioxidant effects of exendin-4 (Ex-4) have been reported previously. However, whether (Ex-4) has anti-inflammatory and antioxidant effects on high-altitude cerebral edema (HACE) remains poorly understood. In this study, two rat models of HACE were established by placing rats in a hypoxic environment with a simulated altitude of either 6000- or 7000-m above sea level (MASL) for 72 hours. An altitude of 7000 MASL with 72-hours of hypoxia was found to be the optimized experimental paradigm for establishing HACE models. Then, in rats where a model of HACE was established by introducing them to a 7000 MASL environment with 72-hours of hypoxia treatment, 2, 10 and, 100 MUg of Ex-4 was intraperitoneally administrated. The open field test and tail suspension test were used to test animal behavior. Routine methods were used to detect change in inflammatory cells. Hematoxylin-eosin staining was performed to determine pathological changes to brain tissue. Wet/dry weight ratios were used to measure brain water content. Evans blue leakage was used to determine blood brain barrier integrity. Enzyme-linked immunosorbent assay (ELISA) was performed to measure markers of inflammation and oxidative stress including superoxide dismutase, glutathione, and malonaldehyde values, as well as interleukin-6, tumor necrosis factor-alpha, cyclic adenosine monophosphate levels in the brain tissue. Western blot analysis was performed to determine the levels of occludin, ZO-1, SOCS-3, vascular endothelial growth factor, EPAC1, nuclear factor-kappa B, and aquaporin-4. Our results demonstrate that Ex-4 preconditioning decreased brain water content, inhibited inflammation and oxidative stress, alleviated brain tissue injury, maintain blood-brain barrier integrity, and effectively improved motor function in rat models of HACE. These findings suggest that Ex-4 exhibits therapeutic potential in the treatment of HACE. PMID- 29722318 TI - Panax ginseng extract attenuates neuronal injury and cognitive deficits in rats with vascular dementia induced by chronic cerebral hypoperfusion. AB - Panax ginseng is a slow-growing perennial plant. Panax ginseng extract has numerous biological activities, including antitumor, anti-inflammatory and antistress activities. Panax ginseng extract also has a cognition-enhancing effect in rats with alcohol-induced memory impairment. In this study, we partially occluded the bilateral carotid arteries in the rat to induce chronic cerebral hypoperfusion, a well-known model of vascular dementia. The rats were then intragastrically administered 50 or 100 mg/kg Panax ginseng extract. Morris water maze and balance beam tests were used to evaluate memory deficits and motor function, respectively. Protein quantity was used to evaluate cholinergic neurons. Immunofluorescence staining was used to assess the number of glial fibrillary acidic protein-positive cells. Western blot assay was used to evaluate protein levels of vascular endothelial growth factor, basic fibroblast growth factor, Bcl-2 and Bax. Treatment with Panax ginseng extract for 8 weeks significantly improved behavioral function and increased neuronal density and VEGF and bFGF protein expression in the hippocampal CA3 area. Furthermore, Panax ginseng extract reduced the number of glial fibrillary acidic protein immunoreactive cells, and it decreased apoptosis by upregulating Bcl-2 and downregulating Bax protein expression. The effect of Panax ginseng extract was dose-dependent and similar to that of nimodipine, a commonly used drug for the treatment of vascular dementia. These findings suggest that Panax ginseng extract is neuroprotective against vascular dementia induced by chronic cerebral hypoperfusion, and therefore might have therapeutic potential for preventing and treating the disease. PMID- 29722319 TI - Dry needling at myofascial trigger points mitigates chronic post-stroke shoulder spasticity. AB - Post-stroke spasticity is associated with restriction in the range of motion of the shoulder. Reducing muscular dystrophy may help relieve muscular dysfunction in patients with post-stroke shoulder spasticity. Dry needle therapy is a method of needling the trigger points using a syringe needle without the use of a drug. Dry needle therapy is commonly used for pain at the shoulder, neck, waist, and back. In this case study, a 62-year-old male patient affected with cerebral hemorrhage of the right frontal lobe had received rehabilitative treatment for 12 years. However, he still experienced shoulder spasticity. The patient received daily dry needling at the trigger points of infraspinatus, teres minor, posterior deltoid, and pectoralis major on 9 days. After the first and ninth treatment, the Modified Ashworth Scale and the passive range of motion of the shoulder was used to assess the effect of the treatment. The spasticity and range of motion of the shoulder showed obvious improvement. These results indicate that dry needling at the myofascial trigger points can effectively treat chronic post-stroke shoulder spasticity. PMID- 29722320 TI - The Rho-associated kinase inhibitors Y27632 and fasudil promote microglial migration in the spinal cord via the ERK signaling pathway. AB - Rho-associated kinase (ROCK) is a key regulatory protein involved in inflammatory secretion in microglia in the central nervous system. Our previous studies showed that ROCK inhibition enhances phagocytic activity in microglia through the extracellular signal-regulated kinase (ERK) signaling pathway, but its effect on microglial migration was unknown. Therefore, in this study, we investigated the effects of the ROCK inhibitors Y27632 and fasudil on the migratory activity of primary cultured microglia isolated from the spinal cord, and we examined the underlying mechanisms. The microglia were treated with Y27632, fasudil and/or the ERK inhibitor U0126. Cellular morphology was observed by immunofluorescence. Transwell chambers were used to assess cell migration. ERK levels were measured by in-cell western blot assay. Y27632 and fasudil increased microglial migration, and the microglia were irregularly shaped and had many small processes. These inhibitors also upregulated the levels of phosphorylated ERK protein. The ERK inhibitor U0126 suppressed these effects of Y27632 and fasudil. These findings suggest that the ROCK inhibitors Y27632 and fasudil promote microglial migration in the spinal cord through the ERK signaling pathway. PMID- 29722321 TI - Macrophage depletion and Schwann cell transplantation reduce cyst size after rat contusive spinal cord injury. AB - Schwann cell transplantation is a promising therapy for the treatment of spinal cord injury (SCI) and is currently in clinical trials. In our continuing efforts to improve Schwann cell transplantation strategies, we sought to determine the combined effects of Schwann cell transplantation with macrophage depletion. Since macrophages are major inflammatory contributors to the acute spinal cord injury, and are the major phagocytic cells, we hypothesized that transplanting Schwann cells after macrophage depletion will improve cell survival and integration with host tissue after SCI. To test this hypothesis, rat models of contusive SCI at thoracic level 8 were randomly subjected to macrophage depletion or not. In rat subjected to macrophage depletion, liposomes filled with clodronate were intraperitoneally injected at 1, 3, 6, 11, and 18 days post injury. Rats not subjected to macrophage depletion were intraperitoneally injected with liposomes filled with phosphate buffered saline. Schwann cells were transplanted 1 week post injury in all rats. Biotinylated dextran amine (BDA) was injected at thoracic level 5 to evalute axon regeneration. The Basso, Beattie, and Bresnahan locomotor test, Gridwalk test, and sensory test using von Frey filaments were performed to assess functional recovery. Immunohistochemistry was used to detect glial fibrillary acidic protein, neurofilament, and green fluorescent protein (GFP), and also to visulize BDA-labelled axons. The GFP labeled Schwann cell and cyst and lesion volumes were quantified using stained slides. The numbers of BDA positive axons were also quantified. At 8 weeks after Schwann cell transplantation, there was a significant reduction in cyst and lesion volumes in the combined treatment group compared to Schwann cell transplantation alone. These changes were not associated, however, with improved Schwann cell survival, axon growth, or locomotor recovery. Although combining Schwann cell transplantation with macrophage depletion does improve histopathology of the injury site, the effect on axon growth and behavioral recovery appears no better than what can be achieved with Schwann cell transplants alone. PMID- 29722322 TI - Treatment with acetyl-L-carnitine exerts a neuroprotective effect in the sciatic nerve following loose ligation: a functional and microanatomical study. AB - Peripheral neuropathies are chronic painful syndromes characterized by allodynia, hyperalgesia and altered nerve functionality. Nerve tissue degeneration represents the microanatomical correlate of peripheral neuropathies. Aimed to improve the therapeutic possibilities, this study investigated the hypersensitivity and the neuromorphological alterations related to the loose ligation of the sciatic nerve in rats. Effects elicited by treatment with acetyl L-carnitine (ALCAR) in comparison to gabapentin were assessed. Axonal injury, reduction of myelin deposition and accumulation of inflammatory cells were detected in damaged nerve. A decrease of phosphorylated 200-kDa neurofilament (NFP) immunoreactivity and a redistribution in small clusters of myelin basic like-protein (MBP) were observed in ipsilateral nerves. Treatment with ALCAR (100 mg/kg intraperitoneally - i.p.) and gabapentin (70 mg/kg i.p.) administered bis in die for 14 days induced a significant pain relieving effect. ALCAR, but not gabapentin, significantly countered neuromorphological changes and increased axonal NFP immunoreactivity. These findings indicate that both ALCAR and gabapentin significantly decreased the hypersensitivity related to neuropathic lesions. The observation of the positive ALCAR effect on axonal and myelin sheath alterations in damaged nerve supports its use as neurorestorative agent against neuropathies through mechanism(s) consistent to those focused in this study. PMID- 29722323 TI - End-to-end and end-to-side neurorrhaphy between thick donor nerves and thin recipient nerves: an axon regeneration study in a rat model. AB - During nerve reconstruction, nerves of different thicknesses are often sutured together using end-to-side neurorrhaphy and end-to-end neurorrhaphy techniques. In this study, the effect of the type of neurorrhaphy on the number and diameter of regenerated axon fibers was studied in a rat facial nerve repair model. An inflow-type end-to-side and end-to-end neurorrhaphy model with nerve stumps of different thicknesses (2:1 diameter ratio) was created in the facial nerve of 14 adult male Sprague-Dawley rats. After 6 and 12 weeks, nerve regeneration was evaluated in the rats using the following outcomes: total number of myelinated axons, average minor axis diameter of the myelinated axons in the central and peripheral sections, and axon regeneration rate. End-to-end neurorrhaphy resulted in a significantly greater number of regenerated myelinated axons and rate of regeneration after 6 weeks than end-to-side neurorrhaphy; however, no such differences were observed at 12 weeks. While the regenerated axons were thicker at 12 weeks than at 6 weeks, no significant differences in axon fiber thickness were detected between end-to-end and end-to-side neurorrhaphy. Thus, end-to-end neurorrhaphy resulted in greater numbers of regenerated axons and increased axon regeneration rate during the early postoperative period. As rapid reinnervation is one of the most important factors influencing the restoration of target muscle function, we conclude that end-to-end neurorrhaphy is desirable when suturing thick nerves to thin nerves. PMID- 29722324 TI - Brain remodeling after chronic median nerve compression in a rat model. AB - Carpal tunnel syndrome is the most common compressive neuropathy, presenting with sensorimotor dysfunction. In carpal tunnel syndrome patients, irregular afferent signals on functional magnetic resonance imaging are associated with changes in neural plasticity during peripheral nerve injury. However, it is difficult to obtain multi-point neuroimaging data of the brain in the clinic. In the present study, a rat model of median nerve compression was established by median nerve ligation, i.e., carpal tunnel syndrome model. Sensory cortex remodeling was determined by functional magnetic resonance imaging between normal rats and carpal tunnel syndrome models at 2 weeks and 2 months after operation. Stimulation of bilateral paws by electricity for 30 seconds, alternating with 30 seconds of rest period (repeatedly 3 times), resulted in activation of the contralateral sensorimotor cortex in normal rats. When carpal tunnel syndrome rats received this stimulation, the contralateral cerebral hemisphere was markedly activated at 2 weeks after operation, including the primary motor cortex, cerebellum, and thalamus. Moreover, this activation was not visible at 2 months after operation. These findings suggest that significant remodeling of the cerebral cortex appears at 2 weeks and 2 months after median nerve compression. PMID- 29722326 TI - Intracerebroventricularly-administered 1-methyl-4-phenylpyridinium ion and brain derived neurotrophic factor affect catecholaminergic nerve terminals and neurogenesis in the hippocampus, striatum and substantia nigra. AB - Parkinson's disease is a progressive neurological disease characterized by the degeneration of dopaminergic neurons in the substantia nigra. A highly similar pattern of neurodegeneration can be induced by 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium ion (MPP+), which cause the death of dopaminergic neurons. Administration of MPTP or MPP+ results in Parkinson's disease-like symptoms in rodents. However, it remains unclear whether intracerebroventricular MPP+ administration affects neurogenesis in the substantia nigra and subgranular zone or whether brain-derived neurotrophic factor alters the effects of MPP+. In this study, MPP+ (100 nmol) was intracerebroventricularly injected into mice to model Parkinson's disease. At 7 days after administration, the number of bromodeoxyuridine (BrdU)-positive cells in the subgranular zone of the hippocampal dentate gyrus increased, indicating enhanced neurogenesis. In contrast, a reduction in BrdU-positive cells was detected in the substantia nigra. Administration of brain-derived neurotrophic factor (100 ng) 1 day after MPP+ administration attenuated the effect of MPP+ in the subgranular zone and the substantia nigra. These findings reveal the complex interaction between neurotrophic factors and neurotoxins in the Parkinsonian model that result in distinct effects on the catecholaminergic system and on neurogenesis in different brain regions. PMID- 29722325 TI - Induced dural lymphangiogenesis facilities soluble amyloid-beta clearance from brain in a transgenic mouse model of Alzheimer's disease. AB - Impaired amyloid-beta clearance from the brain is a core pathological event in Alzheimer's disease. The therapeutic effect of current pharmacotherapies is unsatisfactory, and some treatments cause severe side effects. The meningeal lymphatic vessels might be a new route for amyloid-beta clearance. This study investigated whether promoting dural lymphangiogenesis facilitated the clearance of amyloid-beta from the brain. First, human lymphatic endothelial cells were treated with 100 ng/mL recombinant human vascular endothelial growth factor-C (rhVEGF-C) protein. Light microscopy verified that rhVEGF-C, a specific ligand for vascular endothelial growth factor receptor-3 (VEGFR-3), significantly promoted tube formation of human lymphatic endothelial cells in vitro. In an in vivo study, 200 MUg/mL rhVEGF-C was injected into the cisterna magna of APP/PS1 transgenic mice, once every 2 days, four times in total. Immunofluorescence staining demonstrated high levels of dural lymphangiogenesis in Alzheimer's disease mice. One week after rhVEGF-C administration, enzyme-linked immunosorbent assay results showed that levels of soluble amyloid-beta were decreased in cerebrospinal fluid and brain. The Morris water maze test demonstrated that spatial cognition was restored. These results indicate that the upregulation of dural lymphangiogenesis facilities amyloid-beta clearance from the brain of APP/PS1 mice, suggesting the potential of the VEGF-C/VEGFR-3 signaling pathway as a therapeutic target for Alzheimer's disease. PMID- 29722327 TI - Structural neural connectivity of the vestibular nuclei in the human brain: a diffusion tensor imagingS study. AB - Many animal studies have reported on the neural connectivity of the vestibular nuclei (VN). However, little is reported on the structural neural connectivity of the VN in the human brain. In this study, we attempted to investigate the structural neural connectivity of the VN in 37 healthy subjects using diffusion tensor tractography. A seed region of interest was placed on the isolated VN using probabilistic diffusion tensor tractography. Connectivity was defined as the incidence of connection between the VN and each brain region. The VN showed 100% connectivity with the cerebellum, thalamus, oculomotor nucleus, trochlear nucleus, abducens nucleus, and reticular formation, irrespective of thresholds. At the threshold of 5 streamlines, the VN showed connectivity with the primary motor cortex (95.9%), primary somatosensory cortex (90.5%), premotor cortex (87.8%), hypothalamus (86.5%), posterior parietal cortex (75.7%), lateral prefrontal cortex (70.3%), ventromedial prefrontal cortex (51.4%), and orbitofrontal cortex (40.5%), respectively. These results suggest that the VN showed high connectivity with the cerebellum, thalamus, oculomotor nucleus, trochlear nucleus, abducens nucleus, and reticular formation, which are the brain regions related to the functions of the VN, including equilibrium, control of eye movements, conscious perception of movement, and spatial orientation. PMID- 29722328 TI - Compound of icariin, astragalus, and puerarin mitigates iron overload in the cerebral cortex of Alzheimer's disease mice. AB - Increasing evidence indicates that disruption of normal iron homeostasis may contribute to pathological development of Alzheimer's disease. Icariin, astragalus, and puerarin have been shown to suppress iron overload in the cerebral cortex and improve spatial learning and memory disorders in Alzheimer's disease mice, although the underlying mechanism remains unclear. In the present study, APPswe/PS1DeltaE9 transgenic mice were administered icariin, astragalus, and puerarin (120, 80, and 80 mg/kg, respectively, once a day, for 3 months). Iron levels were detected by flame atomic absorption spectroscopy. Interleukin 1beta, interleukin-6, and tumor necrosis factor-alpha levels were measured in the cerebral cortex by enzyme linked immunosorbent assay. Glutathione peroxidase and superoxide dismutase activity and malondialdehyde content were determined by colorimetry. Our results demonstrate that after treatment, iron levels and malondialdehyde content are decreased, while glutathione peroxidase and superoxide dismutase activities are increased. Further, interleukin-1beta, interleukin-6, and tumor necrosis factor-alpha levels were reduced. These results confirm that compounds of icariin, astragalus, and puerarin may alleviate iron overload by reducing oxidative stress and the inflammatory response. PMID- 29722329 TI - Alpha-7 nicotinic acetylcholine receptor agonist treatment in a rat model of Huntington's disease and involvement of heme oxygenase-1. AB - Neuroinflammation is a common element involved in the pathophysiology of neurodegenerative diseases. We recently reported that repeated alpha-7 nicotinic acetylcholine receptor (alpha7nAChR) activations by a potent agonist such as PHA 543613 in quinolinic acid-injured rats exhibited protective effects on neurons. To further investigate the underlying mechanism, we established rat models of early-stage Huntington's disease by injection of quinolinic acid into the right striatum and then intraperitoneally injected 12 mg/kg PHA 543613 or sterile water, twice a day during 4 days. Western blot assay results showed that the expression of heme oxygenase-1 (HO-1), the key component of the cholinergic anti inflammatory pathway, in the right striatum of rat models of Huntington's disease subjected to intraperitoneal injection of PHA 543613 for 4 days was significantly increased compared to the control rats receiving intraperitoneal injection of sterile water, and that the increase in HO-1 expression was independent of change in alpha7nAChR expression. These findings suggest that HO-1 expression is unrelated to alpha7nAChR density and the increase in HO-1 expression likely contributes to alpha7nAChR activation-related neuroprotective effect in early stage Huntington's disease. PMID- 29722331 TI - Contrast-Enhanced Ultrasonography: A Promising Method for Blood Flow and Perfusion Evaluation in Critically Ill Patients. PMID- 29722332 TI - Pharmacotherapy for Adult Patients with Acute Respiratory Distress Syndrome. PMID- 29722330 TI - Use of curcumin in diagnosis, prevention, and treatment of Alzheimer's disease. AB - This review summarizes and describes the use of curcumin in diagnosis, prevention, and treatment of Alzheimer's disease. For diagnosis of Alzheimer's disease, amyloid-beta and highly phosphorylated tau protein are the major biomarkers. Curcumin was developed as an early diagnostic probe based on its natural fluorescence and high binding affinity to amyloid-beta. Because of its multi-target effects, curcumin has protective and preventive effects on many chronic diseases such as cerebrovascular disease, hypertension, and hyperlipidemia. For prevention and treatment of Alzheimer's disease, curcumin has been shown to effectively maintain the normal structure and function of cerebral vessels, mitochondria, and synapses, reduce risk factors for a variety of chronic diseases, and decrease the risk of Alzheimer's disease. The effect of curcumin on Alzheimer's disease involves multiple signaling pathways: anti-amyloid and metal iron chelating properties, antioxidation and anti-inflammatory activities. Indeed, there is a scientific basis for the rational application of curcumin in prevention and treatment of Alzheimer's disease. PMID- 29722333 TI - Effect of Rhubarb on Gastrointestinal Dysfunction in Critically Ill Patients: A Retrospective Study Based on Propensity Score Matching. AB - Background: Gastrointestinal dysfunction plays a critical role in the prognosis of critically ill patients. Previous studies showed rhubarb, a traditional Chinese herb, can protect the intestinal barrier function, prevent intestinal bacterial translocation, and promote gastrointestinal peristalsis, but the clinical studies are less. The aim of this study was to evaluate the effects of rhubarb on gastrointestinal dysfunction in critically ill patients. Methods: From June 2015 to May 2017, a total of 368 critically ill patients with Grade I-III acute gastrointestinal injury (AGI) were enrolled in this study. Patients were divided into two groups according to the exposure factors (whether the patients received rhubarb treatment): the rhubarb group and the usual treatment group. Clinical data were collected within the first 24 h of the Intensive Care Unit (ICU) admission and 7 days after treatment. Survival data on day 28 after ICU admission and the durations of ICU and total hospitalization were also collected. Propensity score matching (PSM) was conducted to reduce confounding bias between the groups. The logistic regression was conducted to screen the influence factors. Results: The eligible patients were divided into rhubarb group (n = 219, 59.5%) and usual treatment group (n = 149, 40.5%). Before PSM, the remission rate of feeding intolerance in rhubarb group and usual treatment group were 59.8% and 39.6%, respectively. After PSM, the remission rate of feeding intolerance in rhubarb group and usual treatment group was 77.9% and 30.9%, respectively. The remission rates of feeding intolerance in rhubarb group were significantly higher than those in the usual treatment group (all P < 0.05). Compared with the usual treatment group, the rhubarb group had a higher rate of AGI improvement, lower level of C-reactive protein, shorter stay in ICU before and after PSM (P < 0.05). There was no significant difference in 28-day mortality between rhubarb and usual treatment groups before and after PSM (48 vs. 33, P = 0.959; and 16 vs. 21, P = 0.335). The logistic regression analysis showed that the single factor, whether receiving rhubarb therapy, affected the proportion of patients whose enteral nutrition needs >=83.7 kJ.kg-1.d-1 after 7 days of treatment (odds ratio: 7.908, 95% confidence interval: 3.661-17.083, P < 0.001). No serious adverse effects were found in two groups. Conclusions: The rhubarb might significantly improve feeding tolerance and relieve gastrointestinal dysfunction in critically ill patients, without serious adverse reactions. It provided proof for the treatment of gastrointestinal dysfunction with rhubarb during clinical practice. PMID- 29722334 TI - Antibiotics De-Escalation in the Treatment of Ventilator-Associated Pneumonia in Trauma Patients: A Retrospective Study on Propensity Score Matching Method. AB - Background: Antimicrobial de-escalation refers to starting the antimicrobial treatment with broad-spectrum antibiotics, followed by narrowing the drug spectrum according to culture results. The present study evaluated the effect of de-escalation on ventilator-associated pneumonia (VAP) in trauma patients. Methods: This retrospective study was conducted on trauma patients with VAP, who received de-escalation therapy (de-escalation group) or non-de-escalation therapy (non-de-escalation group). Propensity score matching method was used to balance the baseline characteristics between both groups. The 28-day mortality, length of hospitalization and Intensive Care Unit stay, and expense of antibiotics and hospitalization between both groups were compared. Multivariable analysis explored the factors that influenced the 28-day mortality and implementation of de-escalation. Results: Among the 156 patients, 62 patients received de escalation therapy and 94 patients received non-de-escalation therapy. No significant difference was observed in 28-day mortality between both groups (28.6% vs. 23.8%, P = 0.620). The duration of antibiotics treatment in the de escalation group was shorter than that in the non-de-escalation group (11 [8-13] vs. 14 [8-19] days, P = 0.045). The expenses of antibiotics and hospitalization in de-escalation group were significantly lower than that in the non-de escalation group (6430 +/- 2730 vs. 7618 +/- 2568 RMB Yuan, P = 0.043 and 19,173 +/- 16,861 vs. 24,184 +/- 12,039 RMB Yuan, P = 0.024, respectively). Multivariate analysis showed that high Acute Physiology and Chronic Health Evaluation II (APACHE II) score, high injury severity score, multi-drug resistant (MDR) infection, and inappropriate initial antibiotics were associated with patients' 28-day mortality, while high APACHE II score, MDR infection and inappropriate initial antibiotics were independent factors that prevented the implementation of de-escalation. Conclusions: De-escalation strategy in the treatment of trauma patients with VAP could reduce the duration of antibiotics treatments and expense of hospitalization, without increasing the 28-day mortality and MDR infection. PMID- 29722335 TI - Role of Combining Peripheral with Sublingual Perfusion on Evaluating Microcirculation and Predicting Prognosis in Patients with Septic Shock. AB - Background: Measurement of general microcirculation remains difficult in septic shock patients. The peripheral perfusion index (PI) and sublingual microcirculation monitoring are thought to be possible methods. This study was performed to determine whether assessing microcirculation by PI and a new parameter, proportion of perfusion vessel change rate (?PPV) from sublingual microcirculation monitoring, can be associated with patients' outcome. Methods: A prospective observational study was carried out, including 74 patients with septic shock in a mixed intensive care unit. Systemic hemodynamic variables were obtained at T0 and 6 h after (T6). PI and sublingual microcirculation indicators were obtained using a bedside monitor and a sidestream dark-field device, respectively. The t-test, analysis of variance, Mann-Whitney U-test, Kruskal Wallis test, receiver operating characteristic curve analysis with the Hanley McNeil test, survival curves using the Kaplan-Meier method, and the log-rank (Mantel-Cox) test were used to statistical analysis. Results: Systemic hemodynamics and microcirculation data were obtained and analyzed. Patients were divided into two groups based on whether the first 6 h lactate clearance (LC) was >=20%; PI and ?PPV were lower at T6 in the LC <20% group compared with LC >=20% (PI: 1.52 [0.89, 1.98] vs. 0.79 [0.44, 1,81], Z = -2.514, P = 0.012; ?PPV: 5.9 +/ 15.2 vs. 17.9 +/- 20.0, t = -2.914, P = 0.005). The cutoff values of PI and ?PPV were 1.41% and 12.1%, respectively. The cutoff value of the combined indicators was 1.379 according to logistic regression. Area under the curve demonstrated 0.709 (P < 0.05), and the sensitivity and specificity of using combined indicators were 0.622 and 0.757, respectively. Based on the PI and ?PPV cutoff, all the participants were divided into the following groups: (1) high PI and high ?PPV group, (2) high PI and low ?PPV group, (3) low PI and high ?PPV group, and (4) low PI and low ?PPV group. The highest Sequential Organ Failure Assessment score (14.5 +/- 2.9) was in the low PI and low ?PPV group (F = 13.7, P < 0.001). Post hoc tests showed significant differences in 28-day survival rates among these four groups (log rank [Mantel-Cox], 20.931; P < 0.05). Conclusion: PI and ?PPV in septic shock patients are related to 6 h LC, and combining these two parameters to assess microcirculation can predict organ dysfunction and 28-day mortality in patients with septic shock. PMID- 29722336 TI - Mitochondrial Autophagy and NLRP3 Inflammasome in Pulmonary Tissues from Severe Combined Immunodeficient Mice after Cardiac Arrest and Cardiopulmonary Resuscitation. AB - Background: The incidence of cancer, diabetes, and autoimmune diseases has been increasing. Furthermore, there are more and more patients with solid organ transplants. The survival rate of these immunocompromised individuals is extremely low when they are severely hit-on. In this study, we established cardiac arrest cardiopulmonary resuscitation (CPR) model in severe combined immunodeficient (SCID) mice, analyzed the expression and activation of mitochondrial autophagy and NLRP3 inflammasome/caspase-1, and explored mitochondrial repair and inflammatory injury in immunodeficiency individual during systemic ischemia-reperfusion injury. Methods: A potassium chloride induced cardiac arrest model was established in C57BL/6 and nonobese diabetic/SCID (NOD/SCID) mice. One hundred male C57BL/6 mice and 100 male NOD/SCID mice were randomly divided into five groups (control, 2 h post-CPR, 12 h post-CPR, 24 h post-CPR, and 48 h post-CPR). A temporal dynamic view of alveolar epithelial cells, macrophages, and neutrophils from bronchoalveolar lavage fluid (BALF) was obtained using Giemsa staining. Spatial characterization of phenotypic analysis of macrophages in the lung interstitial tissue was analyzed by flow cytometry. The morphological changes of mitochondria 48 h after CPR were studied by transmission electron microscopy and quantified according to the Flameng grading system. Western blotting analysis was used to detect the expression and activation of the markers of mitochondrial autophagy, NLRP3 inflammasome, and caspase-1. Results: (1) In NOD/SCID mice, macrophages were disintegrated in BALF, and many alveolar epithelial cells were shed at 48 h after resuscitation. Compared with C57BL/6 mice, the ratio of macrophages/total cells peaked at 12 h and was significantly higher in NOD/SCID mice (31.17 +/- 4.13 vs. 49.69 +/- 2.43, t = 14.46, P = 0.001). After 24 h, the results showed a downward trend. Furthermore, a large number of macrophages were disintegrated in the BALF. (2) Mitochondrial autophagy was present in both C57BL/6 and NOD/SCID mice after CPR, but it began late in the NOD/SCID mice. Compared with C57BL/6 mice, phos-ULK1 (Ser327) expression was significantly lower at 2 h and 12 h after CPR (2 h after CPR: 1.88 +/- 0.36 vs. 1.12 +/- 0.11, t = -1.36, P < 0.01 and 12 h after CPR: 1.52 +/- 0.16 vs. 1.05 +/- 0.12, t = -0.33, P < 0.01), whereas phos-ULK1 (Ser757) expression was significantly higher at 2 h and 12 h after CPR in NOD/SCID mice (2 h after CPR: 1.28 +/- 0.12 vs. 1.69 +/- 0.14, t = 1.7, P < 0.01 and 12 h after CPR: 1.33 +/- 0.10 vs. 1.94 +/- 0.13, t = 2.75, P < 0.01). (3) Furthermore, NLRP3 inflammasome/caspase-1 activation in the pulmonary tissues occurred early and for only a short time in C57BL/6 mice, but this phenomenon was sustained in NOD/SCID mice. The expression of the NLRP3 inflammasome increased modestly in the C57 mice, but the increase was higher in the NOD/SCID mice than in the C57BL/6 mice, especially at 12, 24, 48 h after CPR (48 h after CPR: 1.46 +/- 0.13 vs. 2.97 +/- 0.19, t = 5.34, P = 0.001). The expression of caspase-1-20 generally followed the same pattern as the NLRP3 inflammasome. Conclusions: There is a regulatory relationship between the NLRP3 inflammasome and mitochondrial autophagy after CPR in the healthy mice. This regulatory relationship was disturbed in the NOD/SCID mice because the signals for mitochondrial autophagy occurred late, and NLRP3 inflammasome- and caspase-1-dependent cell injury was sustained. PMID- 29722337 TI - Accelerated Autophagy of Cecal Ligation and Puncture-Induced Myocardial Dysfunction and Its Correlation with Mammalian Target of Rapamycin Pathway in Rats. AB - Background: Recent studies have indicated that autophagy is involved in sepsis induced myocardial dysfunction. This study aimed to investigate the change of autophagy in cecal ligation and puncture (CLP)-induced myocardium dysfunction and its relationship with mammalian target of rapamycin (mTOR) pathway. Methods: Totally, 12 rats were randomly divided into CLP group or sham-operated (SHAM) group. Cardiac tissues were harvested 18 h after CLP or sham operation. Pathology was detected by hematoxylin and eosin staining, cardiac functions by echocardiography, distribution of microtubule-associated protein light chain 3 type II (LC3II) by immunohistochemical staining, and autophagic vacuoles by transmission electron microscopy. Moreover, phosphorylation of mTOR (p-mTOR), phosphorylation of S6 kinase-1 (PS6K1), and LC3II and p62 expression were measured by western blotting. Pearson's correlation coefficient was used to analyze the correlation of two parameters. Results: The results by pathology and echocardiography revealed that there was obvious myocardial injury in CLP rats (left ventricle ejection fraction: SHAM 0.76 +/- 0.06 vs. CLP 0.59 +/- 0.11, P < 0.01; fractional shortening: SHAM 0.51 +/- 0.09 vs. CLP 0.37 +/- 0.06, P < 0.05). We also found that the autophagy process was elevated by CLP, the ratio of LC3II/LC3I was increased (P < 0.05) while the expression of p62 was decreased (P < 0.05) in the CLP rats, and there were also more autophagosomes and autolysosomes in the CLP rats. Furthermore, the mTOR pathway in CLP myocardium was inhibited when compared with the sham-operated rats; p-mTOR (P < 0.01) and PS6K1 (P < 0.05) were both significantly suppressed following CLP challenge. Interestingly, we found that the mTOR pathway was closely correlated with the autophagy processes. In our study, while p-mTOR in the myocardium was significantly correlated with p62 (r = 0.66, P = 0.02), PS6K1 was significantly positively correlated with p62 (r = 0.70, P = 0.01) and negatively correlated with LC3II (r = -0.71, P = 0.01). Conclusions: The autophagy process in the myocardium was accelerated in CLP rats, which was closely correlated with the inhibition of the mTOR pathway. PMID- 29722338 TI - Inhibition of the Hedgehog Signaling Pathway Depresses the Cigarette Smoke Induced Malignant Transformation of 16HBE Cells on a Microfluidic Chip. AB - Background: The hedgehog signaling system (HHS) plays an important role in the regulation of cell proliferation and differentiation during the embryonic phases. However, little is known about the involvement of HHS in the malignant transformation of cells. This study aimed to detect the role of HHS in the malignant transformation of human bronchial epithelial (16HBE) cells. Methods: In this study, two microfluidic chips were designed to investigate cigarette smoke extract (CSE)-induced malignant transformation of cells. Chip A contained a concentration gradient generator, while chip B had four cell chambers with a central channel. The 16HBE cells cultured in chip A were used to determine the optimal concentration of CSE for inducing malignant transformation. The 16HBE cells in chip B were cultured with 12.25% CSE (Group A), 12.25% CSE + 5 MUmol/L cyclopamine (Group B), or normal complete medium as control for 8 months (Group C), to establish the in vitro lung inflammatory-cancer transformation model. The transformed cells were inoculated into 20 nude mice as cells alone (Group 1) or cells with cyclopamine (Group 2) for tumorigenesis testing. Expression of HHS proteins was detected by Western blot. Data were expressed as mean +/- standard deviation. The t-test was used for paired samples, and the difference among groups was analyzed using a one-way analysis of variance. Results: The optimal concentration of CSE was 12.25%. Expression of HHS proteins increased during the process of malignant transformation (Group B vs. Group A, F = 7.65, P < 0.05). After CSE exposure for 8 months, there were significant changes in cellular morphology, which allowed the transformed cells to grow into tumors in 40 days after being inoculated into nude mice. Cyclopamine could effectively depress the expression of HHS proteins (Group C vs. Group B, F = 6.47, P < 0.05) and prevent tumor growth in nude mice (Group 2 vs. Group 1, t = 31.59, P < 0.01). Conclusions: The activity of HHS is upregulated during the CSE-induced malignant transformation of 16HBE cells. Cyclopamine can effectively depress expression of HHS proteins in vitro and prevent tumor growth of the transformed cells in vivo. PMID- 29722339 TI - Effect of Long-Term Systolic Blood Pressure Trajectory on Kidney Damage in the Diabetic Population: A Prospective Study in a Community-Based Chinese Cohort. AB - Background: Previous studies have shown that hypertension is an important factor contributing to the occurrence and progression of diabetic kidney damage. However, the relationship between the patterns of blood pressure (BP) trajectory and kidney damage in the diabetic population remains unclear. This prospective study investigated the effect of long-term systolic BP (SBP) trajectory on kidney damage in the diabetic population based on an 8-year follow-up community-based cohort. Methods: This study included 4556 diabetic participants among 101,510 participants. BP, estimated glomerular filtration rate (eGFR), and urinary protein were measured every 2 years from 2006 to 2014. SBP trajectory was identified by the censored normal modeling. Five discrete SBP trajectories were identified according to SBP range and the changing pattern over time. Kidney damage was evaluated through eGFR and urinary protein value. A multivariate logistic regression model was used to analyze the influence of different SBP trajectory groups on kidney damage. Results: We identified five discrete SBP trajectories: low-stable group (n = 864), moderate-stable group (n = 1980), moderate increasing group (n = 609), elevated decreasing group, (n = 679), and elevated stable group (n = 424). The detection rate of kidney damage in the low stable group (SBP: 118-124 mmHg) was the lowest among the five groups. The detection rate of each kidney damage index was higher in the elevated stable group (SBP: 159-172 mmHg) compared with the low-stable group. For details, the gap was 4.14 (11.6% vs. 2.8%) in eGFR <60 ml.min-1.1.73 m-2 and 3.66 (17.2% vs. 4.7%), 3.38 (25.0% vs. 7.4%), and 1.8 (10.6% vs. 5.9%) times in positive urinary protein, eGFR <60 ml.min-1.1.73 m-2 and/or positive urinary protein, and eGFR decline >=30%, respectively (P < 0.01). Conclusion: An elevated stable SBP trajectory is an independent risk factor for kidney damage in the diabetic population. PMID- 29722343 TI - Personalized Critical Hemodynamic Therapy Concept for Shock Resuscitation. PMID- 29722341 TI - Halogen Inhalation-Induced Lung Injury and Acute Respiratory Distress Syndrome. AB - Objective: Exposure to halogens, such as chlorine or bromine, results in environmental and occupational hazard to the lung and other organs. Chlorine is highly toxic by inhalation, leading to dyspnea, hypoxemia, airway obstruction, pneumonitis, pulmonary edema, and acute respiratory distress syndrome (ARDS). Although bromine is less reactive and oxidative than chlorine, inhalation also results in bronchospasm, airway hyperresponsiveness, ARDS, and even death. Both halogens have been shown to damage the systemic circulation and result in cardiac injury as well. There is no specific antidote for these injuries since the mechanisms are largely unknown. Data Sources: This review was based on articles published in PubMed databases up to January, 2018, with the following keywords: "chlorine," "bromine," "lung injury," and "ARDS." Study Selection: The original articles and reviews including the topics were the primary references. Results: Based on animal studies, it is found that inhaled chlorine will form chlorine derived oxidative products that mediate postexposure toxicity; thus, potential treatments will target the oxidative stress and inflammation induced by chlorine. Antioxidants, cAMP-elevating agents, anti-inflammatory agents, nitric oxide modulating agents, and high-molecular-weight hyaluronan have shown promising effects in treating acute chlorine injury. Elevated free heme level is involved in acute lung injury caused by bromine inhalation. Hemopexin, a heme-scavenging protein, when administered postexposure, decreases lung injury and improves survival. Conclusions: At present, there is an urgent need for additional research to develop specific therapies that target the basic mechanisms by which halogens damage the lungs and systemic organs. PMID- 29722340 TI - Role of Recursive Partitioning Analysis and Graded Prognostic Assessment on Identifying Non-Small Cell Lung Cancer Patients with Brain Metastases Who May Benefit from Postradiation Systemic Therapy. AB - Background: The role of postradiation systemic therapy in non-small cell lung cancer (NSCLC) patients with brain metastasis (BM) was controversial. Thus, we explored the role of Radiation Therapy Oncology Group recursive partitioning analysis (RTOG-RPA) and graded prognostic assessment (GPA) in identifying population who may benefit from postradiation systemic therapy. Methods: The clinical data of NSCLC patients with documented BM from August 2007 to April 2015 of two hospitals were studied retrospectively. Cox regression was used for multivariate analysis. Survival of patients with or without postradiation systemic therapy was compared in subgroups stratified according to RTOG-RPA or GPA. Results: Of 216 included patients, 67.1% received stereotactic radiosurgery (SRS), 24.1% received whole-brain radiation therapy (WBRT), and 8.8% received both. After radiotherapy, systemic therapy was administered in 58.3% of patients. Multivariate analysis found that postradiation systemic therapy (yes vs. no) (hazard ratio [HR] = 0.361, 95% confidence interval [CI] = 0.202-0.648, P = 0.001), radiation technique (SRS vs. WBRT) (HR = 0.462, 95% CI = 0.238-0.849, P = 0.022), extracranial metastasis (yes vs. no) (HR = 3.970, 95% CI = 1.757-8.970, P = 0.001), and Karnofsky performance status (<70 vs. >=70) (HR = 5.338, 95% CI = 2.829-10.072, P < 0.001) were independent factors for survival. Further analysis found that subsequent tyrosine kinase inhibitor (TKI) therapy could significantly reduce the risk of mortality of patients in RTOG-RPA Class II (HR = 0.411, 95% CI = 0.183-0.923, P = 0.031) or with a GPA score of 1.5-2.5 (HR = 0.420, 95% CI = 0.182-0.968, P = 0.042). However, none of the subgroups stratified according to RTOG-RPA or GPA benefited from the additional conventional chemotherapy. Conclusion: RTOG-RPA and GPA may be useful to identify beneficial populations in NSCLC patients with BM if TKIs were chosen as postradiation systemic therapy. PMID- 29722344 TI - Three-Center Experience on Patients with Influenza-Associated Acute Respiratory Distress Syndrome in Chongqing, China. PMID- 29722342 TI - Gastric Cancer Screening by Combined Determination of Serum Helicobacter pylori Antibody and Pepsinogen Concentrations: ABC Method for Gastric Cancer Screening. AB - Objective: Gastroscopy combined with gastric mucosa biopsies is currently regarded as a gold standard for diagnosis of gastric cancer. However, its application is restricted in clinical practice due to its invasive property. A new noninvasive population screening process combining the assay of anti Helicobacter pylori antibody and serum pepsinogen (PG) (ABC method) is adopted to recognize the high-risk patients for further endoscopy examination, avoiding the unnecessary gastroscopy for most population and saving the cost consumption for mass screening annually. Nevertheless, controversies exist for the grouping of ABC method and the intervals of gastroscopy surveillance for each group. In this review, we summarized these popular concerned topics for providing useful references to the healthcare practitioner in clinical practice. Data Sources: The PubMed databases were systematically searched from the inception dates to November 22, 2017, using the keywords "Helicobacter pylori," "Pepsinogens," and "Stomach Neoplasms." Study Selection: Original articles and reviews on the topics were selected. Results: Anti-H. pylori antibody and serum PG concentration showed significant changes under the different status of H. pylori infection and the progression of atrophic gastritis, which can be used for risk stratification of gastric cancer in clinic. In addition, anti-H. pylori antibody titer can be used for further risk stratification of gastric cancer contributing to determine better endoscopy surveillance interval. Conclusions: The early detection and diagnosis of gastric cancer benefit from the risk stratification, but the cutoff values for H. pylori antibody and serum PG concentration require further modification. PMID- 29722345 TI - Characterizing the Molecular Abnormalities in Rare De Novo Ph+ Acute Myeloid Leukemia. PMID- 29722346 TI - IgA Type Multiple Myeloma, Clinical Features, and Prognosis. PMID- 29722348 TI - Candida Balanitis with Hyperplastic Plaque Mimicking Vascular Neoplasm. PMID- 29722347 TI - Acute Myocardial Infarction Induced by Anaphylaxis. PMID- 29722349 TI - Altered Matrix Metalloproteinases Expression in Placenta from Patients with Gestational Diabetes Mellitus. PMID- 29722350 TI - Assessing Influences of Perioperative Transfusion on Early- and Late-Term Outcomes after Living Donor Liver Transplantation: Methodological Issues. PMID- 29722352 TI - Epilepsy. AB - Epilepsy affects all age groups and is one of the most common and most disabling neurological disorders. The accurate diagnosis of seizures is essential as some patients will be misdiagnosed with epilepsy, whereas others will receive an incorrect diagnosis. Indeed, errors in diagnosis are common, and many patients fail to receive the correct treatment, which often has severe consequences. Although many patients have seizure control using a single medication, others require multiple medications, resective surgery, neuromodulation devices or dietary therapies. In addition, one-third of patients will continue to have uncontrolled seizures. Epilepsy can substantially impair quality of life owing to seizures, comorbid mood and psychiatric disorders, cognitive deficits and adverse effects of medications. In addition, seizures can be fatal owing to direct effects on autonomic and arousal functions or owing to indirect effects such as drowning and other accidents. Deciphering the pathophysiology of epilepsy has advanced the understanding of the cellular and molecular events initiated by pathogenetic insults that transform normal circuits into epileptic circuits (epileptogenesis) and the mechanisms that generate seizures (ictogenesis). The discovery of >500 genes associated with epilepsy has led to new animal models, more precise diagnoses and, in some cases, targeted therapies. PMID- 29722351 TI - Predictive Factors of Skip Metastasis in Papillary Thyroid Cancer. AB - BACKGROUND Skip metastasis is defined as metastasis incident to the lateral compartment without involvement of the central compartment, and is generally unpredictable in papillary thyroid cancer (PTC). The present study aimed to investigate the frequency and predictor value of skip metastasis in PTC patients. MATERIAL AND METHODS A total of 355 patients diagnosed with thyroid cancer who had received a prior complete thyroidectomy with bilateral central neck and ipsilateral lateral neck lymph node dissection were enrolled in this study. The clinicopathological and ultrasound features were analyzed. A univariate and multivariate analysis were performed to identify the risk factors of skip metastasis. RESULTS The frequency of skip metastasis was 12.4% (44/355). The PTC patients with skip metastasis exhibited fewer lymph node metastasis, which was more commonly detected in tumor size <=1 cm (OR 9.354; p=0.001; 95% confidence interval (CI) 1.865-26.735), tumors located in upper pole (OR 3.822; p<0.001; 95% CI 1.935-7.549), without a well-defined margin (OR 2.528; p=0.016; CI 1.191 5.367), and extrathyroidal extension (OR 2.406; p=0.013; CI 1.691-4.367). CONCLUSIONS Skip metastasis was common in PTC. The PTC patients with a tumor size <=1.0 cm, located in the upper pole, without a well-defined margin and extrathyroidal extension should be carefully evaluated for skip metastasis. PMID- 29722353 TI - Epilepsy. PMID- 29722354 TI - Critical Role of Pathologists in the Accurate Subclassification of Non-Small Cell Lung Carcinoma (NSCLC) for Targeted Therapies: Evidence- Based Practice and the Role of IHC Markers. PMID- 29722355 TI - Corrigendum to: Effects of salmon DNA fraction in vitro and in a monosodium iodoacetate-induced osteoarthritis rat model. AB - [This corrects the article on p. 163 in vol. 22, PMID: 29520169.]. PMID- 29722356 TI - Evaluation of the new respiratory gating system. AB - Objective: The newly released Respiratory Gating for Scanners (RGSC; Varian Medical Systems, Palo Alto, CA, USA) system has limited existing quality assurance (QA) protocols and pertinent publications. Herein, we report our experiences of the RGSC system acceptance and QA. Methods: The RGSC system integration was tested with peripheral equipment, spatial reproducibility, and dynamic localization accuracy for regular and irregular breathing patterns, respectively. A QUASAR Respiratory Motion Phantom and a mathematical fitting method were used for data acquisition and analysis. Results: The results showed that the RGSC system could accurately measure regular motion periods of 3-10 s. For irregular breathing patterns, differences from the existing Real-time Position Management (RPM; Varian Medical Systems, Palo Alto, CA) system were observed. For dynamic localization measurements, the RGSC system showed 76% agreement with the programmed test data within +/-5% tolerance in terms of fitting period. As s comparison, the RPM system showed 66% agreement within +/-5% tolerance, and 65% for the RGSC versus RPM measurements. Conclusions: New functions and positioning accuracy improve the RGSC system's ability to achieve higher dynamic treatment precision. A 4D phantom is helpful for the QA tests. Further investigation is required for the whole RGSC system performance QA. PMID- 29722357 TI - Corrigendum: Chloroplast Glutamine Synthetase, the Key Regulator of Nitrogen Metabolism in Wheat, Performs Its Role by Fine Regulation of Enzyme Activity via Negative Cooperativity of Its Subunits. AB - [This corrects the article on p. 191 in vol. 9, PMID: 29520285.]. PMID- 29722358 TI - Reading Margery Kempe's inner voices. AB - This article draws on research from the major collaborative research project Hearing the Voice, based at Durham University, to reconsider and foreground Margery Kempe's inner voices, and hence, to return to an emphasis on inner, spiritual experience as shaping her Book. The richness of Margery's multi-sensory experience, and the care with which it is depicted, is illuminated by and illuminates the experience of contemporary voice-hearers, offering a powerful alternative perspective to often reductive bio-medical understandings. Contemporary cognitive frameworks, particularly scientific accounts of inner speech, are in turn employed to open out Margery's inner voices and to offer insights into the psychology of spiritual meditation. PMID- 29722359 TI - Correction: Role of novel histone modifications in cancer. AB - [This corrects the article DOI: 10.18632/oncotarget.23356.]. PMID- 29722361 TI - Erratum: Engraftment, neuroglial transdifferentiation and behavioral recovery after complete spinal cord transection in rats. AB - [This corrects the article on p. 19 in vol. 9, PMID: 29497572.]. PMID- 29722360 TI - Gravity Spy: integrating advanced LIGO detector characterization, machine learning, and citizen science. AB - With the first direct detection of gravitational waves, the advanced laser interferometer gravitational-wave observatory (LIGO) has initiated a new field of astronomy by providing an alternative means of sensing the universe. The extreme sensitivity required to make such detections is achieved through exquisite isolation of all sensitive components of LIGO from non-gravitational-wave disturbances. Nonetheless, LIGO is still susceptible to a variety of instrumental and environmental sources of noise that contaminate the data. Of particular concern are noise features known as glitches, which are transient and non Gaussian in their nature, and occur at a high enough rate so that accidental coincidence between the two LIGO detectors is non-negligible. Glitches come in a wide range of time-frequency-amplitude morphologies, with new morphologies appearing as the detector evolves. Since they can obscure or mimic true gravitational-wave signals, a robust characterization of glitches is paramount in the effort to achieve the gravitational-wave detection rates that are predicted by the design sensitivity of LIGO. This proves a daunting task for members of the LIGO Scientific Collaboration alone due to the sheer amount of data. In this paper we describe an innovative project that combines crowdsourcing with machine learning to aid in the challenging task of categorizing all of the glitches recorded by the LIGO detectors. Through the Zooniverse platform, we engage and recruit volunteers from the public to categorize images of time-frequency representations of glitches into pre-identified morphological classes and to discover new classes that appear as the detectors evolve. In addition, machine learning algorithms are used to categorize images after being trained on human classified examples of the morphological classes. Leveraging the strengths of both classification methods, we create a combined method with the aim of improving the efficiency and accuracy of each individual classifier. The resulting classification and characterization should help LIGO scientists to identify causes of glitches and subsequently eliminate them from the data or the detector entirely, thereby improving the rate and accuracy of gravitational-wave observations. We demonstrate these methods using a small subset of data from LIGO's first observing run. PMID- 29722362 TI - Focused ultrasound with microbubbles induces sterile inflammatory response proportional to the blood brain barrier opening: Attention to experimental conditions. AB - This editorial highlights the findings of McMahon [1] and demonstrates the need for careful attention to experimental conditions that influence microbubble concentration and pharmacokinetics contributed to focused ultrasound-induced blood brain barrier opening and sterile inflammation. PMID- 29722364 TI - Erratum: Review of Static Approaches to Surgical Correction of Presbyopia. AB - [This corrects the article on p. 413 in vol. 12, PMID: 29090052.]. PMID- 29722365 TI - Commentary: Measuring Depression in a Non-Western War-Affected Displaced Population: Measurement Equivalence of the Beck Depression Inventory. PMID- 29722363 TI - Pediatric Kaposi sarcoma in context of the HIV epidemic in sub-Saharan Africa: current perspectives. AB - The global experience with pediatric Kaposi sarcoma (KS) has evolved immensely since the onset of HIV (human immunodeficiency virus). In this review, current perspectives on childhood KS are discussed in the context of the HIV epidemic in sub-Saharan Africa. Endemic (HIV-unrelated) KS was first described over 50 years ago in central and eastern Africa, regions where human herpesvirus-8, the causative agent of KS, is endemic. With the alarming rise in HIV prevalence over the past few decades, KS has become not only the most common HIV-related malignancy in Africa, but also one of the most common overall childhood cancers throughout the central, eastern, and southern regions of the continent. The unique clinical features of pediatric KS that were described in those early endemic KS reports have been re-affirmed by the contemporary experience with HIV related KS. These characteristics include a predilection for primary lymph node involvement, significant proportions of patients lacking prototypical cutaneous lesions, and the potential for fulminant disease progression. Other clinical features that distinguish childhood KS from adult disease include disease presentation with severe cytopenias, and the common occurrence of childhood KS without severe CD4 count suppression. Distinct clinical heterogeneity in disease presentation and treatment response have been demonstrated. Long-term complete remission and event-free survival can be achieved-especially in children with lymphadenopathic KS-utilizing treatment with antiretroviral therapy plus mild moderate chemotherapy regimens that are well tolerated, even in low-income settings. A pediatric-specific staging classification and risk-stratification platform have been retrospectively validated, and may help guide therapeutic strategies. With expansion of the HIV treatment infrastructure throughout Africa, coupled with recent developments in establishing comprehensive pediatric oncology programs, there is great potential for improving outcomes for children with KS. Increased awareness of the unique clinical nuances and collaborative evaluations of pediatric-specific treatment paradigms are required to optimize survival for children with KS. PMID- 29722366 TI - Erratum: Prospective interepisodal mood monitoring in patients with affective disorders: a feasibility study [Corrigendum]. AB - [This corrects the article on p. 517 in vol. 14, PMID: 29491711.]. PMID- 29722367 TI - Erratum: Distribution of Different Sized Ocular Surface Vessels in Diabetics and Normal Individuals. AB - [This corrects the article on p. 361 in vol. 12, PMID: 29090043.]. PMID- 29722368 TI - Commentary: RNA editing with CRISPR-Cas13. PMID- 29722369 TI - Correction: New localization and function of calpain-2 in nucleoli of colorectal cancer cells in ribosomal biogenesis: effect of KRAS status. AB - [This corrects the article DOI: 10.18632/oncotarget.23888.]. PMID- 29722370 TI - From confident medical students to confident doctors through exposure to simulated and clinical resuscitation. PMID- 29722371 TI - Pediatric chronic fatigue syndrome: current perspectives. AB - Pediatric chronic fatigue syndrome is an important illness as it is relatively common and also very disabling with a wide range of impacts on the child, the family, and health care systems. It is a complicated illness but the majority of children get better with specialist treatment. This literature review provides an update on the epidemiology of chronic fatigue syndrome / myalgic encephalomyelitis, including factors associated with it, and discusses the current evidence for treatment. PMID- 29722372 TI - Reply to Kovacs et al.: Concerning acute inflammatory response following focused ultrasound and microbubbles in the brain. PMID- 29722373 TI - Chemical formation of soft metal electrodes for flexible and wearable electronics. AB - Flexible and wearable electronics is one major technology after smartphones. It shows remarkable application potential in displays and informatics, robotics, sports, energy harvesting and storage, and medicine. As an indispensable part and the cornerstone of these devices, soft metal electrodes (SMEs) are of great significance. Compared with conventional physical processes such as vacuum thermal deposition and sputtering, chemical approaches for preparing SMEs show significant advantages in terms of scalability, low-cost, and compatibility with the soft materials and substrates used for the devices. This review article provides a detailed overview on how to chemically fabricate SMEs, including the material preparation, fabrication technologies, methods to characterize their key properties, and representative studies on different wearable applications. PMID- 29722374 TI - Anisotropic convergence of dendritic macromolecules facilitated by a heteroleptic metal-organic polyhedron scaffold. AB - Anisotropic dendrimers with bipolar shapes were systematically obtained using a heteroleptic metal-organic polyhedron (MOP) as a robust core scaffold. The structure of one of these polyhedral shapes was unambiguously determined by single-crystal X-ray analysis, which revealed that the bulky dendrons converge to both axial positions of the heteroleptic MOP core. PMID- 29722375 TI - Observing ground state vibrational coherence and excited state relaxation dynamics of a cyanine dye in pure solvents. AB - Using a degenerate pump probe technique at 800 nm, Ground State Vibrational Coherence (GSVC) of a cyanine dye (IR780) is explored in various solvents. Five representative solvents were studied, of which GSVC is present in three: methanol (MeOH), ethanol (EtOH) and dichloromethane (DCM). The maximum number of damped oscillations was observed in DCM solvent and the oscillations persisted for 1.2 ps. However, GSVC is absent in two solvents: acetonitrile (ACN) and dimethyl sulfoxide (DMSO). For nondegenerate pump probe studies with a 400 nm pump and a supercontinuum probe, GSVC was absent for IR780 in all of the five solvents studied. Instead these studies showed excited state absorption corresponding to S1 -> Sn absorption bands in the 450 to 650 nm range. Decay profiles for these correspond to the higher electronic states (Sn, n >= 2) in contrast to the degenerate case involving S1. Complete dynamics of IR780 with 30 fs pulses are reported by invoking three time-constants to fit the kinetic traces that can, in turn, be assigned as: vibrational cooling, intermediate state time, and ground state recovery (GSR). All these dynamics exhibit noticeable solvent dependence. A plateau region is also observed in the early part of the GSR dynamics, strongly suggesting the existence of an intermediate state between the ground (S0) and excited singlet (S1) states. PMID- 29722376 TI - Anomalous toluene transport in model segmented polyurethane-urea/clay nanocomposites. AB - The kinetics of liquid solvent sorption in polymeric systems and their nanocomposites often deviate from normal Fickian behaviour. This needs to be understood and interpreted, in terms of their underlying mechanistic origins. In the present study, the results of time dependent toluene sorption measurements in model segmented polyurethane-urea/clay nanocomposites have been analysed at room temperature. The studies revealed pronounced S-shaped sorption curves and unusually higher swelling of the nanocomposites compared to the neat polyurethane urea matrix. Dynamic mechanical analysis (DMA) and small angle X-ray scattering (SAXS) measurements on the nanocomposites in the dry and liquid toluene saturated state have been carried out. The DMA studies revealed a significant decrease in the alpha relaxation temperature and storage modulus of the nanocomposites in the swollen state compared to the dry samples. The SAXS results showed that the nanoclay dispersion morphology transformed from intercalation in the dry state to exfoliation in the swollen state and the interdomain distance between hard segments increased upon swelling. Thermodynamic analysis of the Flory-Huggins interaction parameter (chi) of nanocomposite/toluene systems revealed increasingly negative chi values with increased clay loading. These results imply a significant plasticization effect of toluene on the nanocomposites. An interpretation of these data, which relates the abovementioned results, is presented in the framework of differential swelling stress (DSS) induced deviation from Fickian transport characteristics. We expect that these findings and methods may provide new insight into the analysis of the solvent diffusion process in heterogeneous polymers and their nanocomposites. PMID- 29722377 TI - A planarized B-phenyldibenzoborepin: impact of structural constraint on its electronic properties and Lewis acidity. AB - A B-phenyldibenzo[b,f]borepin planarized with two methylene bridges was synthesized. The structural constraint on the B-phenyl group resulted in a bathochromic shift of the absorption and fluorescence properties as well as enhanced Lewis acidity. A donor-pi-acceptor type derivative based on this scaffold exhibited intense fluorescence irrespective of the solvent polarity. PMID- 29722380 TI - Synthesis and luminescence of Mn-doped Cs2AgInCl6 double perovskites. AB - Metal halide double perovskites (DPs) are being explored as stable and non-toxic alternatives of Pb-halide perovskites. Typically DPs exhibit a wide (>2.5 eV) and/or indirect bandgap, limiting their applications in the visible region. Here we impart the visible-light emission property in direct bandgap Cs2AgInCl6 DPs by doping Mn2+ ions. Synthesis, characterization and luminescence of metal halide double perovskites are reported. PMID- 29722382 TI - A review of Winkler's foundation and its profound influence on adhesion and soft matter applications. AB - Few advanced mechanics of materials solutions have found broader and more enduring applications than Emil Winkler's beam on elastic foundation analysis, first published in 1867. Now, 150 years after its introduction, this concept continues to enjoy widespread use in its original application field of civil engineering, and has also had a profound effect on the field of adhesion mechanics, including for soft matter adhesion phenomena. A review of the model is presented with a focus on applications to adhesion science, highlighting classical works that utilize the model as well as recent usages that extend its scope. The special case of the behavior of plates on incompressible (e.g., elastomeric and viscous liquid) foundations is reviewed because of the significant relevance to the behavior of soft matter interlayers between one or more flexible adherends. PMID- 29722388 TI - Aromaticity of acenes: the model of migrating pi-circuits. AB - In this work we extend the concept of migrating Clar's sextets to explain local aromaticity trends in linear acenes predicted by theoretical calculations and experimental data. To assess the link between resonance and reactivity and to rationalize the constant-height AFM image of pentacene we used the electron density of delocalized bonds and other functions of the one-electron density from conceptual density functional theory. The presented results provide evidence for migration of Clar's pi-sextets and larger circuits in these systems, and clearly show that the link between the theoretical concept of aromaticity and the real electronic structure entails the separation of intra- and inter-ring resonance effects, which in the case of [n]acenes (n = 3, 4, 5) comes down to solving a system of simple linear equations. PMID- 29722390 TI - Phenyl radical + propene: a prototypical reaction surface for aromatic-catalyzed 1,2-hydrogen-migration and subsequent resonance-stabilized radical formation. AB - The C9H11 potential energy surface (PES) was experimentally and theoretically explored because it is a relatively simple, prototypical alkylaromatic radical system. Although the C9H11 PES has already been extensively studied both experimentally (under single-collision and thermal conditions) and theoretically, new insights were made in this work by taking a new experimental approach: flash photolysis combined with time-resolved molecular beam mass spectrometry (MBMS) and visible laser absorbance. The C9H11 PES was experimentally accessed by photolytic generation of the phenyl radical and subsequent reaction with excess propene (C6H5 + C3H6). The overall kinetics of C6H5 + C3H6 was measured using laser absorbance with high time-resolution from 300 to 700 K and was found to be in agreement with earlier measurements over a lower temperature range. Five major product channels of C6H5 + C3H6 were observed with MBMS at 600 and 700 K, four of which were expected: hydrogen (H)-abstraction (measured by the stable benzene, C6H6, product), methyl radical (CH3)-loss (styrene detected), H-loss (phenylpropene isomers detected) and radical adduct stabilization. The fifth, unexpected product observed was the benzyl radical, which was rationalized by the inclusion of a previously unreported pathway on the C9H11 PES: aromatic-catalysed 1,2-H-migration and subsequent resonance stabilized radical (RSR, benzyl radical in this case) formation. The current theoretical understanding of the C9H11 PES was supported (including the aromatic-catalyzed pathway) by quantitative comparisons between modelled and experimental MBMS results. At 700 K, the branching to styrene + CH3 was 2-4 times greater than that of any other product channel, while benzyl radical + C2H4 from the aromatic-catalyzed pathway accounted for ~10% of the branching. Single-collision conditions were also simulated on the updated PES to explain why previous crossed molecular beam experiments did not see evidence of the aromatic-catalyzed pathway. This experimentally validated knowledge of the C9H11 PES was added to the database of the open-source Reaction Mechanism Generator (RMG), which was then used to generalize the findings on the C9H11 PES to a slightly more complicated alkylaromatic system. PMID- 29722396 TI - Ammonolysis of ketene as a potential source of acetamide in the troposphere: a quantum chemical investigation. AB - Quantum chemical calculations at the CCSD(T)/CBS//MP2/aug-cc-pVTZ levels of theory have been carried out to investigate a potential new source of acetamide in Earth's atmosphere through the ammonolysis of the simplest ketene. It was found that the reaction can occur via the addition of ammonia at either the C[double bond, length as m-dash]C or C[double bond, length as m-dash]O bond of ketene. The potential energy surface as well as calculated rate coefficients indicate that under tropospheric conditions, ammonolysis would occur almost exclusively via ammonia addition at the C[double bond, length as m-dash]O bond with negligible contribution from addition at the C[double bond, length as m dash]C bond. The reaction of ketene with water has also been investigated in order to compare between hydrolysis and ammonolysis, as the former is known to be responsible for the formation of acetic acid. The rate coefficient for the formation of acetamide was found to be ~106 to 109 times higher than that for the formation of acetic acid from the same ketene source in the troposphere. By means of the relative rate of ammonolysis with respect to hydrolysis, it was shown that acetamide formation would dominate over acetic acid formation at various altitudes in the troposphere. PMID- 29722397 TI - Atomistic modeling of La3+ doping segregation effect on nanocrystalline yttria stabilized zirconia. AB - The effect of La3+ doping on the structure and ionic conductivity change in nanocrystalline yttria-stabilized zirconia (YSZ) was studied using a combination of Monte Carlo and molecular dynamics simulations. The simulation revealed the segregation of La3+ at eight tilt grain boundary (GB) structures and predicted an average grain boundary (GB) energy decrease of 0.25 J m-2, which is close to the experimental values reported in the literature. Cation stabilization was found to be the main reason for the GB energy decrease, and energy fluctuations near the grain boundary are smoothed out with La3+ segregation. Both dynamic and energetic analysis on the Sigma13(510)/[001] GB structure revealed La3+ doping hinders O2- diffusion in the GB region, where the diffusion coefficient monotonically decreases with increasing La3+ doping concentration. The effect was attributed to the increase in the site-dependent migration barriers for O2- hopping caused by segregated La3+, which also leads to anisotropic diffusion at the GB. PMID- 29722398 TI - Conformationally controlled ultrafast intersystem crossing in bithiophene systems. AB - Bithiophenes serve as model systems for larger polythiophenes used in solar cell applications and molecular electronics. We report a study of ultrafast dynamics of two bithiophene systems measured with femtosecond time-resolved photoelectron spectroscopy, and show that their intersystem crossing takes place within the first few picoseconds after excitation, in line with previous studies. We show that the intersystem crossing rate can be explained in terms of arguments based on symmetry of the S1 minimum energy geometry, which depends on the specific conformation of bithiophene. Furthermore, this work shows that the minor cis conformer contributes to an even higher intersystem crossing rate than the major trans conformer. The work presented here can provide guiding principles towards the design of solar cell components with even faster formation of long-lived excited states for solar energy harvesting. PMID- 29722399 TI - Intramolecular and interfacial dynamics of triarylamine-based hole transport materials. AB - We present steady-state and time-resolved spectroscopic investigations combined with detailed kinetic modelling for the triarylamine derivatives X60 and PTAA which serve as hole transport materials (HTMs) in perovskite solar cells and represent model compounds for organic electronic materials. Photoexcitation of the spiro-fluorene-xanthene X60 populates its S1 state which decays via intersystem crossing (ISC) as well as fluorescence and internal conversion on a nanosecond time scale. Photoexcitation of the PTAA polymer leads to the formation of singlet excitons which relax and migrate in the time regime from a few to about a hundred picoseconds and decay to the ground state with a lifetime of ca. 900 ps. Both X60 and PTAA exhibit efficient photoinduced electron injection into mesoporous TiO2 thin films forming radical cations with characteristic spectral bands, as confirmed by spectroelectrochemistry in solution. Photoluminescence (PL) experiments performed for the HTMs on methylammonium lead iodide perovskite deposited on mesoporous TiO2 show that small molecular HTMs, such as X60, quench the PL much better than the PTAA polymer. Ultrafast transient absorption experiments on the other hand suggest that the hole transfer at the interface between the perovskite and these HTMs is very fast, regardless of the type of HTM. It is therefore concluded that small molecular HTMs infiltrate much better into mesoporous structures and therefore more efficiently accept holes from the perovskite on such thin film architectures due to the better interfacial contact compared with their polymer-based counterparts. PMID- 29722402 TI - Photochemical investigation of cyanoazobenzene derivatives as components of artificial supramolecular pumps. AB - Among the plethora of photochromes reported so far, azobenzene has been proven to be the most suitable photoswitch for molecular systems and materials, due to its highly efficient and clean E-Z photoisomerization. Here we report two ammonium based molecular axles bearing one or two p-cyanoazobenzene units at the extremities, able to form pseudorotaxanes with a crown ether macrocycle. The photochemistry of these compounds was studied in the isolated forms and in the pseudorotaxanes, showing that the functionalization speeds up the threading process without affecting the photochemical properties of the system. These results suggest that the investigated pseudorotaxanes can form the basis of new prototypes of artificial molecular-level pumps. PMID- 29722404 TI - Identification of the binding site between bovine serum albumin and ultrasmall SiC fluorescent biomarkers. AB - Ultrasmall silicon carbide nanoparticles (SiC USNPs) are very promising biomarkers for developing new applications in diagnostics, cell monitoring or drug delivery, even though their interaction with biological molecules such as different proteins has not yet been investigated in detail. In this study, the biological behaviour of SiC USNPs in a medium modeling a living organism was investigated in detail through the dependence of the fluorescence on interactions between bovine serum albumin (BSA) and SiC USNPs. The interaction shows transient nanoparticle-protein associations due to the restricted diffusion behaviour of the nanoparticles in the vicinity of a protein. The transient association manifests in a complex fluorescence quenching mechanism where the dynamic component was dominated by Forster resonance energy transfer. By studying SiC nanoparticles of different sizes, it can be concluded that the transient effect is an ultrasmall nanoparticle behaviour. PMID- 29722406 TI - Study of the thixotropic behaviors of ferrofluids. AB - The thixotropic behaviors of ferrofluid samples of different particle concentration were studied using different measurement methods, including the three interval thixotropic test and the hysteresis loop test. The experimental results demonstrated that ferrofluids exhibit significant thixotropic behaviors and the microstructural evolution in ferrofluids behind the macroscopic rheological mechanics is discussed. The influence of magnetic field strength, particle concentration and temperature on the thixotropy of ferrofluids was also analyzed. Microscopic ferrofluid theory was adopted to study the thixotropic behaviors of ferrofluids under different shearing conditions, indicating that different thixotropic behaviors of ferrofluids can be induced by the presence and evolution of different kinds of microstructures, such as linear chain-like and dense drop-like structures. Furthermore, a phenomenal thixotropic model was employed to analyze the experimental results, indicating that a more specific model for ferrofluids is needed. These findings contribute to a better understanding of the microscopic mechanism of the complex rheological behaviors of ferrofluids. PMID- 29722407 TI - A gold-nanoparticle stoppered [2]rotaxane. AB - The construction of molecular machines has captured the imagination of scientists for decades. Despite significant progress in the synthesis and studies of the properties of small-molecule components (smaller than 2-5 kilo Dalton), challenges regarding the incorporation of molecular components into real devices are still eminent. Nano-sized molecular machines operate the complex biological machinery of life, and the idea of mimicking the amazing functions using artificial nano-structures is intriguing. Both in small-molecule molecular machine components and in many naturally occurring molecular machines, mechanically interlocked molecules and structures are key functional components. In this work, we describe our initial efforts to interface mechanically interlocked molecules and gold-nanoparticles (AuNPs); the molecular wire connecting the AuNPs is covered in an insulating rotaxane-layer, thus mimicking the macroscopic design of a copper wire. Taking advantage of recent progress in the preparation of supramolecular complexes of the cucurbit[7]uril (CB[7]) macrocycle, we have prepared a bis-thiol functionalised pseudo-rotaxane that enables us to prepare a AuNP-stoppered [2]rotaxane in water. The pseudo-rotaxane is held together extremely tightly (Ka > 1013 M-1), Ka being the association constant. We have studied the solution and gas phase guest-host chemistry using NMR spectroscopy, mass spectroscopy, and electrochemistry. The bis-thiol functionalised pseudo-rotaxane holds further a ferrocene unit in the centre of the rotaxane; this ferrocene unit enables us to address the system in detail with and without CB[7] and AuNPs using electrochemical methods. PMID- 29722411 TI - Visible light-promoted alkylation of imines using potassium organotrifluoroborates. AB - A mild, redox-neutral, alkylation of imines with potassium alkyltrifluoroborates is described. The reaction proceeds under photoredox conditions at ~30 degrees C with primary, secondary, and tertiary alkyltrifluoroborates, leading to alkylation products in moderate to good yield in most cases. Aryl-, vinyl-, and cyclopropyltrifluoroborates failed to react under the reported conditions. PMID- 29722412 TI - Polyester elastomers for soft tissue engineering. AB - Polyester elastomers are soft, biodegradable and biocompatible and are commonly used in various biomedical applications, especially in tissue engineering. These synthetic polyesters can be easily fabricated using various techniques such as solvent casting, particle leaching, molding, electrospinning, 3-dimensional printing, photolithography, microablation etc. A large proportion of tissue engineering research efforts have focused on the use of allografts, decellularized animal scaffolds or other biological materials as scaffolds, but they face the major concern of triggering immunological responses from the host, on top of other issues. This review paper will introduce the recent developments in elastomeric polyesters, their synthesis and fabrication techniques, as well as their application in the biomedical field, focusing primarily on tissue engineering in ophthalmology, cardiac and vascular systems. Some of the commercial and near-commercial polyesters used in these tissue engineering fields will also be described. PMID- 29722415 TI - Atomic origins of high electrochemical CO2 reduction efficiency on nanoporous gold. AB - First principles calculations show that gold atoms with low generalized coordination numbers possess high activity for electroreduction of CO2 to CO. Atom-resolved three-dimensional reconstruction reveals that dealloyed nanoporous gold possesses such a favourable structure characteristic, which results in a faradaic efficiency as high as 94% for CO production. PMID- 29722417 TI - Floxuridine-containing nucleic acid nanogels for anticancer drug delivery. AB - Herein, we report the self-assemblies of floxuridine-containing DNA and RNA nanogels with a precise drug loading ratio as effective drug delivery systems. Based on the structural similarity between the nucleoside analogue floxuridine (F) and the natural nucleoside thymidine (T), F can be incorporated into nucleic acid strands via either solid-phase synthesis or enzyme-mediated transcription. With the retained property of molecular recognition, the synthesized F-integrated DNA or RNA strands can be used as building units and further assembled into nucleic acid based spherical nanogels, which can be efficiently taken up by cancer cells and then release the therapeutic agents. As such, the drug containing nucleic acid nanogels exhibit excellent inhibitory activity against cancer cells. PMID- 29722420 TI - Correction: A computational exploration of the crystal energy and charge-carrier mobility landscapes of the chiral [6]helicene molecule. AB - Correction for 'A computational exploration of the crystal energy and charge carrier mobility landscapes of the chiral [6]helicene molecule' by Beth Rice et al., Nanoscale, 2018, 10, 1865-1876. PMID- 29722421 TI - Carbon nanotubes (CNTs) based advanced dermal therapeutics: current trends and future potential. AB - The search for effective and non-invasive delivery modules to transport therapeutic molecules across skin has led to the discovery of a number of nanocarriers (viz.: liposomes, ethosomes, dendrimers, etc.) in the last few decades. However, available literature suggests that these delivery modules face several issues including poor stability, low encapsulation efficiency, and scale up hurdles. Recently, carbon nanotubes (CNTs) emerged as a versatile tool to deliver therapeutics across skin. Superior stability, high loading capacity, well developed synthesis protocol as well as ease of scale-up are some of the reason for growing interest in CNTs. CNTs have a unique physical architecture and a large surface area with unique surface chemistry that can be tailored for vivid biomedical applications. CNTs have been thus largely engaged in the development of transdermal systems such as tuneable hydrogels, programmable nonporous membranes, electroresponsive skin modalities, protein channel mimetic platforms, reverse iontophoresis, microneedles, and dermal buckypapers. In addition, CNTs were also employed in the development of RNA interference (RNAi) based therapeutics for correcting defective dermal genes. This review expounds the state-of-art synthesis methodologies, skin penetration mechanism, drug liberation profile, loading potential, characterization techniques, and transdermal applications along with a summary on patent/regulatory status and future scope of CNT based skin therapeutics. PMID- 29722422 TI - Expression of plakophilin 3 in diffuse malignant pleural mesothelioma. AB - Diffuse malignant pleural mesothelioma (DMPM) is the most common primary malignant pleural neoplasm still posing major diagnostic, prognostic and therapeutic challenges. Plakophilins are structural proteins considered to be important for cell stability and adhesion in both tumor and normal tissues. Plakophilin 3 is a protein present in desmosomes of stratified and simple epithelia of normal tissues with presence in malignant cells of various tumors where it participates in the process of tumorigenesis. The aim of this study was to investigate the expression of plakophilin 3 protein in DMPM, but also to study its prognostic significance and relation to histologically accessible parameters of aggressive growth. Archival samples of tissue with established diagnosis of DMPM and samples of normal pleural tissue were used. Tumor samples were classified into three histological types of DMPM (epithelioid, sarcomatoid and biphasic). Additional subclassification of epithelioid mesotheliomas into nine patterns based on the prevalent histological component of the tumor was then performed. After immunohistochemical staining, cytoplasmic and membrane immunopositivity of tumor cells was assesed by scoring the intensity of the staining from 0 (no staining) to 4 (very strong staining). Prognostic value and expression of plakophilin 3 with consideration to histologically estimated aggression in tumor growth were then statistically analyzed using non- parametric tests. The results demonstrated higher level of plakophilin 3 expression in tumor samples with histologically more aggressive tumor growth, but no significant prognostic value. According to our study, plakophilin 3 appears to be involved in tumor invasion in malignant mesothelioma. PMID- 29722423 TI - Mutations in mevalonate pathway genes in patients with familial or sporadic porokeratosis. AB - Porokeratosis comprises heterogeneous keratinization disorders that are characterized by one or more atrophic patches surrounded by a ridge-like cornoid lamella. In this study, we evaluated seven families affected by porokeratosis and five sporadic patients of the disease in a Chinese population. We performed Sanger sequencing of exons and flanking intron-exon boundaries of mevalonate pathway genes (MVD, MVK, PMVK and FDPS) and of SLC17A9. In five familial and three sporadic patients, we detected six variations, including four novel mutations (MVD c.1A>G; p.Met1?, c.916G>A; p.Ala306Thr, c.1013+1G>A, and PMVK c.65A>G; p.Lys22Arg) and two recurrent mutations (MVD c.746T>C; p.Phe249Ser, and MVK c.1028T>C; p.Leu343Pro). We then applied I-TASSER and iGEMDOCK to assess these variants for probable functional impacts. The findings of this study extend the mutation spectrum of porokeratosis and provide further evidence for the genetic basis of this disease. PMID- 29722424 TI - Hearing impairment: A secondary symptom in a congenital ichthyosiform erythroderma patient with ABCA12 mutations. PMID- 29722426 TI - ADDRESSING SUBSTANCE-USE PROBLEMS IN TRIBAL HOME VISITING. AB - Given the high rates for substance use among women and men of childbearing age, perinatal and early childhood home-visiting programs serving tribal communities must consider how they will address substance-use problems among the families they support. In this study, we explored the approaches to identifying and addressing family-based substance-use problems that were implemented by nine home visiting programs serving American Indian/Alaska Native (AI/AN) communities that are funded through the federal Tribal Maternal, Infant, and Early Childhood Home Visiting Program (Tribal MIECHV). These programs demonstrated a high awareness of substance-use problems and took concrete action to address them above and beyond that included in the home-visiting model they used. All nine programs reported that they provided substance-use preventive services and screened for substance use problems. While all programs referred to substance-use treatment programs when needed, in six programs the home visitor provided substance-use services. Through Tribal MIECHV, the intense need for substance-use education, assessment, service delivery, and referral in many AI/AN communities is pushing the home visiting field forward to address this increasingly critical issue for low-income families across the United States and the world. PMID- 29722425 TI - Comparative study of the bactericidal effects of indocyanine green- and methyl aminolevulinate-based photodynamic therapy on Propionibacterium acnes as a new treatment for acne. AB - Acne vulgaris is one of the most common dermatological problems, and its therapeutic options include topical and systemic retinoids and antibiotics. However, increase in problems associated with acne treatment, such as side effects from conventional agents and bacterial resistance to antibiotics, has led to greater use of photodynamic therapy. The purpose of this study was to compare the bactericidal effects of indocyanine green- and methyl aminolevulinate-based photodynamic therapy on Propionibacterium acnes. P. acnes were cultured under anaerobic conditions; then they were divided into three groups (control, treated with indocyanine green and treated with methyl aminolevulinate) and illuminated with different lights (630-nm light-emitting diode, 805-nm diode laser and 830-nm light-emitting diode). The bactericidal effects were evaluated by comparing each group's colony-forming units. The cultured P. acnes were killed with an 805-nm diode laser and 830-nm light-emitting diode in the indocyanine green group. No bactericidal effects of methyl aminolevulinate-based photodynamic therapy were identified. The clinical efficacy of indocyanine green-based photodynamic therapy in 21 patients was retrospectively analyzed. The Korean Acne Grading System was used to evaluate treatment efficacy, which was significantly decreased after treatment. The difference in the efficacy of the 805-nm diode laser and 830-nm light-emitting diode was not statistically significant. Although the methyl aminolevulinate-based photodynamic therapy showed no bactericidal effect, the indocyanine green-based photodynamic therapy has bactericidal effect and clinical efficacy. PMID- 29722427 TI - Scapular breadth does not discriminate suspension from clambering in hominoids: A response to Spear and Williams. PMID- 29722429 TI - Bart's syndrome in a family affected three consecutive generations with mutation c.6007G>A in COL7A1. AB - Bart's syndrome (BS), characterized by aplasia cutis congenita (ACC, also called congenital localized absence of skin) and epidermolysis bullosa (EB), is diagnosed clinically based on the disorder's unique signs and symptoms. We report the case of a family, three members of which presented with ACC at birth and one had blisters on the mucous membranes. The patient was treated conservatively with topical antibacterial ointment and wet gauze dressing. Periodic follow up showed complete healing with minimal scarring. Whole-exome sequencing confirmed a heterozygous mutation (rs121912832, c.6007G>A, p.G2003R) within exon 73 of COL7A1, which was confirmed by the only two genetic studies available, is suggested to be the molecular basis for the family's disorder. As a consequence, we suggest that c.6007G>A within exon 73 of COL7A1 could be a specific mutation for BS in antenatal screening. It is of great value to extend the genetic test among affected families and uncover the mechanism behind this unique syndrome. PMID- 29722428 TI - Futility of current urine salbutamol doping control. AB - AIMS: Salbutamol is used in the management of obstructive bronchospasm, including that of some elite athletes. It is claimed that high salbutamol (oral) doses may also have an anabolic effect. Therefore, inhalation of salbutamol is restricted by the World Anti-Doping Agency (WADA) to a maximal daily dose. Urine is tested for violations, but recent cases have resulted in a debate regarding the validity of this approach. It was our aim to determine whether current approaches are sufficiently able to differentiate approved usage from violations. METHODS: We extracted pharmacokinetic parameters from literature for salbutamol and its sulphated metabolite. From these parameters, a semi-physiological pharmacokinetic model of inhaled and orally administered salbutamol was synthesized, validated against literature data, and used to perform clinical trial simulations (n = 1000) of possible urine concentrations over time resulting from WADA-allowed and oral unacceptable dosages. RESULTS: The synthesized model was able to predict the literature data well. Simulations showed a very large range of salbutamol concentrations, with a significant portion of virtual subjects (15.4%) exceeding the WADA threshold limit of 1000 ng ml-1 at 1 h post-dose. CONCLUSIONS: The observed large variability in urine concentrations indicates that determining the administered dose from a single untimed urine sample is not feasible. The current threshold inadvertently leads to incorrect assumptions of violation, whereas many violations will go unnoticed, especially when samples are taken long after drug administration. These issues, combined with the dubious assertion of its anabolic effect, leads us to conclude that the large effort involved in testing should be reconsidered. PMID- 29722430 TI - Review article: short chain fatty acids as potential therapeutic agents in human gastrointestinal and inflammatory disorders. AB - BACKGROUND: Butyrate, propionate and acetate are short chain fatty acids (SCFA), important for maintaining a healthy colon and are considered as protective in colorectal carcinogenesis. However, they may also regulate immune responses and the composition of the intestinal microbiota. Consequently, their importance in a variety of chronic inflammatory diseases is emerging. AIMS: To review the physiology and metabolism of SCFA in humans, cellular and molecular mechanisms by which SCFA may act in health and disease, and approaches for therapeutic delivery of SCFA. METHODS: A PubMed literature search was conducted for clinical and pre clinical studies using search terms: 'dietary fibre', short-chain fatty acids', 'acetate', 'propionate', 'butyrate', 'inflammation', 'immune', 'gastrointestinal', 'metabolism'. RESULTS: A wide range of pre-clinical evidence supports roles for SCFA as modulators of not only colonic function, but also multiple inflammatory and metabolic processes. SCFA are implicated in many autoimmune, allergic and metabolic diseases. However, translating effects of SCFA from animal studies to human disease is limited by physiological and dietary differences and by the challenge of delivering sufficient amounts of SCFA to the target sites that include the colon and the systemic circulation. Development of novel targeted approaches for colonic delivery, combined with postbiotic supplementation, may represent desirable strategies to achieve adequate targeted SCFA delivery. CONCLUSIONS: There is a large array of potential disease modulating effects of SCFA. Adequate targeted delivery to the sites of action is the main limitation of such application. The ongoing development and evaluation of novel delivery techniques offer potential for translating promise to therapeutic benefit. PMID- 29722431 TI - Capillary malformation in the midline of the face: Salmon patch or port-wine stain? PMID- 29722434 TI - Changes in hardness and resilience of i-gelTM cuffs with temperature: a benchtop study. AB - The i-gelTM is a supraglottic airway with a gel-like thermoplastic cuff. It has been suggested that the seal around the larynx improves following insertion. Perhaps the most intuitive hypothesis proposed for this is that cuff softening occurs during warming from ambient to body temperature. We investigated this using a food industry texture analyser over a wide temperature range. Size 2 and 3 i-gels were secured to a platform within a temperature-controlled water bath, which was in turn mounted on a texture analyser test stand. Both water and i-gel cuff temperatures were recorded. A spherical probe was advanced 4 mm into the surface of each i-gel at a rate of 1 mm.s-1 , then retracted at the same rate while the upward pressure on the probe was recorded. Three runs made at each of the 11 temperatures (10 degrees C to 60 degrees C, 5 degrees C increments) gave 105,864 data points, from which values for hardness (the peak force on the probe at maximum indentation), and resilience (the rate at which the material recovers its original shape) were calculated. Over 10 to 60 degrees C, the smallest hardness value expressed as a proportion of the largest was 88.2% and 89.8% for size 2 and 3 i-gels, respectively, and for resilience these were 92.8% and 86.2%, respectively. Over room temperature to body temperature range (21-37.4 degrees C), hardness decreased by 3.15% and increased by 0.47% for i-gel sizes 2 and 3, respectively, whereas resilience values decreased by 1.85% and 2.68%, respectively. Cuff hardness and resilience did generally reduce with warming, but the effect was minimal over temperature ranges that may be encountered during clinical use. PMID- 29722432 TI - Transcriptome analysis of different sizes of 3-mercaptopropionic acid-modified cadmium telluride quantum dot-induced toxic effects reveals immune response in rat hippocampus. AB - Recently, the increasing number of bio-safety assessments on cadmium-containing quantum dots (QDs) suggested that they could lead to detrimental effects on the central nervous system (CNS) of living organisms, but the underlying action mechanisms are still rarely reported. In this study, whole-transcriptome sequencing was performed to analyze the changes in genome-wide gene expression pattern of rat hippocampus after treatments of cadmium telluride (CdTe) QDs with two sizes to understand better the mechanisms of CdTe QDs causing toxic effects in the CNS. We identified 2095 differentially expressed genes (DEGs). Fifty-five DEGs were between the control and 2.2 nm CdTe QDs, 1180 were between the control and 3.5 nm CdTe QDs and 860 were between the two kinds of CdTe QDs. It seemed that the 3.5 nm CdTe QD exposure might elicit severe effects in the rat hippocampus than 2.2 nm CdTe QDs at the transcriptome level. After bioinformatics analysis, we found that most DEG-enriched Gene Ontology subcategories and Kyoto Encyclopedia of Genes and Genomes pathways were related with the immune system process. For example, the Gene Ontology subcategories included immune response, inflammatory response and T-cell proliferation; Kyoto Encyclopedia of Genes and Genomes pathways included NOD/Toll-like receptor signaling pathway, nuclear factor-kappaB signaling pathway, tumor necrosis factor signaling pathway, natural killer cell-mediated cytotoxicity and T/B-cell receptor signaling pathway. The traditional toxicological examinations confirmed the systemic immune response and CNS inflammation in rats exposed to CdTe QDs. This transcriptome analysis not only revealed the probably molecular mechanisms of CdTe QDs causing neurotoxicity, but also provided references for the further related studies. PMID- 29722435 TI - Stature estimation equations for South Asian skeletons based on DXA scans of contemporary adults. AB - OBJECTIVES: Stature estimation from the skeleton is a classic anthropological problem, and recent years have seen the proliferation of population-specific regression equations. Many rely on the anatomical reconstruction of stature from archaeological skeletons to derive regression equations based on long bone lengths, but this requires a collection with very good preservation. In some regions, for example, South Asia, typical environmental conditions preclude the sufficient preservation of skeletal remains. Large-scale epidemiological studies that include medical imaging of the skeleton by techniques such as dual-energy X ray absorptiometry (DXA) offer new potential datasets for developing such equations. MATERIALS AND METHODS: We derived estimation equations based on known height and bone lengths measured from DXA scans from the Andhra Pradesh Children and Parents Study (Hyderabad, India). Given debates on the most appropriate regression model to use, multiple methods were compared, and the performance of the equations was tested on a published skeletal dataset of individuals with known stature. RESULTS: The equations have standard errors of estimates and prediction errors similar to those derived using anatomical reconstruction or from cadaveric datasets. As measured by the number of significant differences between true and estimated stature, and the prediction errors, the new equations perform as well as, and generally better than, published equations commonly used on South Asian skeletons or based on Indian cadaveric datasets. CONCLUSIONS: This study demonstrates the utility of DXA scans as a data source for developing stature estimation equations and offer a new set of equations for use with South Asian datasets. PMID- 29722433 TI - How can mortality increase population size? A test of two mechanistic hypotheses. AB - Overcompensation occurs when added mortality increases survival to the next life cycle stage. Overcompensation can contribute to the Hydra effect, wherein added mortality increases equilibrium population size. One hypothesis for overcompensation is that added mortality eases density dependence, increasing survival to adulthood ("temporal separation of mortality and density dependence"). Mortality early in the life cycle is therefore predicted to cause overcompensation, whereas mortality later in the life cycle is not. Another hypothesis for overcompensation is that threat of mortality (e.g., from predation) causes behavioral changes that reduce overexploitation of resources, allowing resource recovery, and increasing production of adults ("prudent resource exploitation"). Behaviorally active predation cues alone are therefore predicted to cause overcompensation. We tested these predictions in two experiments with larvae of two species of Aedes. As predicted, early mortality yielded greater production of adults, and of adult females, and greater estimated rate of population increase than did later mortality. Addition of water-borne predation cues usually reduced browsing on surfaces in late-stage larvae, but contrary to prediction, resulted in neither significantly greater production of adult mosquitoes nor significantly greater estimated rate of increase. Thus we have strong evidence that timing of mortality contributes to overcompensation and the Hydra effect in mosquitoes. Evidence that predation cues alone can result in overcompensation via prudent resource exploitation is lacking. We expect the overcompensation in response to early mortality will be common in organisms with complex life cycles, density dependence among juveniles, and developmental control of populations. PMID- 29722438 TI - Influence of CNTs decomposition during reactive friction-stir processing of an Al Mg alloy on the correlation between microstructural characteristics and microtextural components. AB - Multipass friction-stir processing was employed to uniformly disperse multiwalled carbon nanotubes (MW-CNTs) within an Al-Mg alloy metal matrix. Decomposition of MW-CNTs occurs in situ as a result of solid-state chemical reactions, forming fullerene (C60) and aluminium carbide (Al4 C3 ) phases during reactive high temperature severe plastic processing. The effects of this decomposition on the microstructural features, dynamic restoration mechanisms and crystallographic microtextural developments are studied for the first time by using electron backscatter diffraction (EBSD) and transmission electron microscopy (TEM) analysis. The formation of an equiaxed grain structure with an average size of ~1.5 MUm occurs within the stirred zone (SZ) under the influence of inclusions which hinder grain boundary migration via Zener-Smith pinning mechanisms during the discontinuous dynamic recrystallisation (DDRX). Formation of two strong Cubic and Brass microtextural components in the heat affected zone (HAZ) and thermomechanical affected zone (TMAZ) was noted as compared to the completely random and Cube components found in the base and SZ regions, respectively. The microstructural modification led to hardening and tensile strength improvement for the processed nanocomposite by ~55% and 110%, respectively with respect to the annealed Al-Mg base alloy. PMID- 29722436 TI - Cigarette smoke up-regulates PDE3 and PDE4 to decrease cAMP in airway cells. AB - BACKGROUND AND PURPOSE: cAMP is a central second messenger that broadly regulates cell function and can underpin pathophysiology. In chronic obstructive pulmonary disease, a lung disease primarily provoked by cigarette smoke (CS), the activation of cAMP-dependent pathways, via inhibition of hydrolyzing PDEs, is a major therapeutic strategy. Mechanisms that disrupt cAMP signalling in airway cells, in particular regulation of endogenous PDEs, are poorly understood. EXPERIMENTAL APPROACH: We used a novel Forster resonance energy transfer (FRET) based cAMP biosensor in mice in vivo, ex vivo precision cut lung slices (PCLS) and in human cell models, in vitro, to track the effects of CS exposure. KEY RESULTS: Under fenoterol stimulation, FRET responses to cilostamide were significantly increased in in vivo, ex vivo PCLS exposed to CS and in human airway smooth muscle cells exposed to CS extract. FRET signals to rolipram were only increased in the in vivo CS model. Under basal conditions, FRET responses to cilostamide and rolipram were significantly increased in in vivo, ex vivo PCLS exposed to CS. Elevated FRET signals to rolipram correlated with a protein up regulation of PDE4 subtypes. In ex vivo PCLS exposed to CS extract, rolipram reversed down-regulation of ciliary beating frequency, whereas only cilostamide significantly increased airway relaxation of methacholine pre-contracted airways. CONCLUSION AND IMPLICATIONS: Exposure to CS, in vitro or in vivo, up-regulated expression and activity of both PDE3 and PDE4, which affected real-time cAMP dynamics. These mechanisms determine the availability of cAMP and can contribute to CS-induced pulmonary pathophysiology. PMID- 29722437 TI - The opioid oxycodone use-dependently inhibits the cardiac sodium channel NaV 1.5. AB - BACKGROUND AND PURPOSE: Oxycodone is a potent semi-synthetic opioid that is commonly used for the treatment of severe acute and chronic pain. However, treatment with oxycodone can lead to cardiac electrical changes, such as long QT syndrome, potentially inducing sudden cardiac arrest. Here, we investigate whether the cardiac side effects of oxycodone can be explained by modulation of the cardiac Nav 1.5 sodium channel. EXPERIMENTAL APPROACH: Heterologously expressed human Nav 1.5, Nav 1.7 (HEK293 cells) or Nav 1.8 channels (mouse N1E 115 cells) were used for whole-cell patch-clamp electrophysiology. A variety of voltage-clamp protocols were used to test the effect of oxycodone on different channel gating modalities. Human stem cell-derived cardiomyocytes were used to measure the effect of oxycodone on cardiomyocyte beating. KEY RESULTS: Oxycodone inhibited Nav 1.5 channels, concentration and use-dependently, with an IC50 of 483 MUM. In addition, oxycodone slows recovery of Nav 1.5 channels from fast inactivation and increases slow inactivation. At high concentrations, these effects lead to a reduced beat rate in cardiomyocytes and to arrhythmia. In contrast, no such effects could be observed on Nav 1.7 or Nav 1.8 channels. CONCLUSIONS AND IMPLICATIONS: Oxycodone leads to an accumulation of Nav 1.5 channels in inactivated states, with a slow time course. Although the concentrations needed to elicit cardiac arrhythmias in vitro are relatively high, some patients under long-term treatment with oxycodone as well as drug abusers and addicts might suffer from severe cardiac side effects induced by the slowly developing effects of oxycodone on Nav 1.5 channels. PMID- 29722440 TI - Comparison of positive ratio for red meat-specific immunoglobulin E between endemic and non-endemic area for Japanese spotted fever in Mie Prefecture, Japan. PMID- 29722439 TI - High efficacy of direct-acting anti-viral agents in hepatitis C virus-infected cirrhotic patients with successfully treated hepatocellular carcinoma. AB - BACKGROUND: The efficacy of direct-acting anti-viral (DAA) therapy in patients with a history of hepatocellular carcinoma (HCC) is unknown. AIM: We prospectively evaluated whether previously treated HCC affects DAA efficacy in a large real-life cohort of cirrhotic patients. METHODS: From January to December 2015 all consecutive HCV mono-infected patients with cirrhosis and/or history of HCC attending 10 Italian tertiary liver centres were enrolled. Baseline characteristics and response to therapy were recorded. 1927 patients were enrolled (mean age: 62.1 +/- 10.9 years; 1.205 males). Genotype 1 was the most frequent (67.9%) followed by genotypes 3 (12.4%), 2 (11.2%) and 4 (8.6%). 88.4% and 10.9% of cases were classified Child A and B, respectively, and 14 (<1%) cases were classified Child C. Ascites and hepatic encephalopathy occurred in 10.7% and 3.2% of patients, respectively. Varices were detected in 39.3% of patients. Suboptimal and optimal treatment was prescribed: 15.9% of patients received sofosbuvir/simeprevir, 33.4% sofosbuvir/ledipasvir, 20.2% a Viekirax + Exviera regimen, 15.7% sofosbuvir/ribavirin, 9.9% sofosbuvir/daclatasvir and 3.4% Viekirax; 1.3% of patients received an interferon-based regimen. RESULTS: The sustained virologic response (SVR) rate at intention-to-treat analysis was 95.1%. It differed significantly across Child classes, that is, 96.3%, 86.1% and 71.4% Child A, B and C, respectively (P < 0.0001) and across genotypes (P = 0.002). The SVR rate did not differ between patients with (95.0%) and those without previous HCC (95.1%). At multivariable analysis, SVR was significantly associated with HCV genotype, Child class. CONCLUSION: This large real-life study proves that the efficacy of DAA in cirrhotic patients is not impaired by successfully treated HCC. PMID- 29722441 TI - Systematic review: safety of mesalazine in ulcerative colitis. AB - BACKGROUND: Mesalazine is the most commonly prescribed medication for mild to moderate ulcerative colitis. It is generally well tolerated with some reported side effects. AIM: To summarise adverse drug events to mesalazine and recommend techniques for management. Furthermore, to determine if there is a dose-dependent relationship between high (>2.4 g/day) vs low dosing (<=2.4 g/day) and occurrence of adverse drug events. METHODS: A literature search for relevant studies from inception to 1 December 2017 of the MEDLINE database was conducted. Two reviewers screened all titles identified. Data obtained from randomised controlled trials was used to estimate incidence rates of each adverse event. Two reviewers independently assessed methodological risk of bias and performed data extraction. RESULTS: 3581 articles were initially considered. Of these, 3573 were screened, 622 reviewed and 91 included. Adverse events attributed to mesalazine included inflammatory reactions, pancreatitis, cardiotoxicity, hepatotoxicity, musculoskeletal complaints, respiratory symptoms, nephropathies and sexual dysfunction. There does not appear to be a dose-dependent relationship of mesalazine and occurrence of adverse events. CONCLUSION: Patients on mesalazine should be monitored for worsening of ulcerative colitis and development of new onset organ dysfunction. High-dose mesalazine appears to have similar safety profile as low dose, and is not associated with greater risk of adverse events. Prior to placing a patient on mesalazine, baseline liver and renal function should be evaluated. Renal function should be periodically assessed, whereas other testing should be performed depending on development of symptoms. PMID- 29722442 TI - Electronic and structural properties of Lin @Be2 B8 (n = 1-14) and Lin @Be2 B36 (n = 1-21) nanoflakes shed light on possible anode materials for Li-based batteries. AB - Systematic addition of Li atoms to the Be2 B8 and Be2 B36 backbones has been studied by density functional theory-based calculations with the aim to investigate properties of interest on possible anode materials for Li-based batteries. For the Be2 B8 Lin (n = 1-8) and the Be2 B36 Lin (n = 1-20) systems, lithium salts are dominant whereas a clear electride feature shows up for Be2 B8 Lin (n = 9-14) and Be2 B36 Li21 . Addition of hydrogen radicals to these systems shows that the Be2 B8 Li14 electride becomes a Be2 B8 Li14 H2 hydride electride whereas Be2 B36 Li21 leads to a Be2 B36 Li21 H salt. Moreover, for the addition of Li atoms to Be2 B8 and the Be2 B36 backbones, large values of the interaction and of the adsorption energy per Li atom, high specific capacity of Be2 B8 Li14 and of Be2 B36 Li21 (1860 and 1017 mAh g-1 , respectively) and low and flat voltage associated with lithiation have been found. Likewise, the considerable thermodynamic driving force (DeltaG degrees = -29.66 kcal/mol) and the small energy barrier ( DeltaG# = 0.26 kcal/mol) associated with electron transfer in Be2 B36 Li21 and Be2 B36 species confirm that boron rich species have potential abilities to be used in the Li-based battery. (c) 2018 Wiley Periodicals, Inc. PMID- 29722443 TI - Biomonitoring of bisphenol A, triclosan and perfluorooctanoic acid in hair samples of children and adults. AB - Bisphenol A (BPA), triclosan (TCS) and perfluorooctanoic acid (PFOA) are endocrine disruptors linked with negative health effects such as developmental, reproductive and cardiovascular toxicity. The aim of this study was to determine simultaneously the concentration of BPA, TCS and PFOA in hair from children and adults and examine possible associations between biomonitoring data and age, gender, dietary habits and body mass index. Methanolic extraction was applied and the compounds were determined by liquid chromatography-mass spectrometry. Low levels of exposure to PFOA were detected for children and adults at concentrations below limit of quantification. The mean concentration of BPA in children and adults was 20.6 and 16.6 pg mg-1 , while for TCS 275.2 and 687.0 pg mg-1 , respectively. Children were highly exposed to BPA relative to adults (P = .011) although adults had greater exposure to TCS (P = .003). Hair from girls had a greater burden of BPA (P = .06) compared to boys. Moreover, higher TCS levels were depicted for females in both examined groups (children P = .200 and adults P = .213) compared to males, but no statistical differences were observed. Significant differences were also observed between age groups (P = .0007) for TCS. No correlations were found between BPA or TCS levels and body mass index or dietary habits for both children and adults. Children have a greater exposure to BPA compared to adults, whereas exposure of adults to TCS seems to be higher than that in children and elderly people. Exposure to BPA occurs mainly via ingestion whereas exposure to TCS mainly via dermal absorption. PMID- 29722444 TI - Systematic evaluation and refinement of existing all-atom force fields for the simulation of liquid acetonitrile. AB - The reliability of a molecular dynamics (MD) simulation study mainly depends on the accuracy of the applied force field. Unlike the ability of some potential models for reasonably predicting the thermodynamic properties of acetonitrile (ACN), simulated dynamical properties such as self-diffusion are generally underestimated compared to experimental values. The present work focuses on the evaluation and refinement of several available all-atom force fields for ACN and proposes a refined flexible six-site potential model. The main modification is related to the reduction of intermolecular LJ parameters (sigma and E) for hydrogen atoms, especially E, significantly affecting the dynamical behavior. Besides, the adjustment of sigma and E for nitrile carbon and nitrogen atoms helps reach optimum results. Our refined model shows an excellent agreement with the experiment for self-diffusion coefficient and thermodynamic quantities as well as providing a qualitative description of the microscopic structure of liquid ACN. (c) 2018 Wiley Periodicals, Inc. PMID- 29722445 TI - Review article: the prevention of hepatitis B-related hepatocellular carcinoma. AB - BACKGROUND: Ample evidence indicates an aetiological association of persistent hepatitis B virus (HBV) infection with hepatocellular carcinoma (HCC). Several viral, host and external risk factors for the development of HBV-related HCC have been documented. AIMS: To summarise and discuss the risk stratification and the preventive strategies of HBV-related HCC. METHODS: Recent published studies identified from PubMed were comprehensively reviewed. The key words included chronic hepatitis B, HBV, hepatocellular carcinoma, prevention and antiviral therapy. RESULTS: The incidence of HCC is extremely high in HBV hyperendemic areas. For HBV patients left untreated, significant risk factors for HCC include male gender, aging, advanced hepatic fibrosis, persistent serum transaminase elevation, specific HBV entry receptor (NTCP) genotype, PM2.5 exposure, HBeAg positivity, HBV genotype C/D/F, high proportion of core promoter mutation, pre-S deletion, high serum levels of HBV DNA and HBsAg as well as co-infection with HCV, HDV and HIV. Primary prevention of HBV-related HCC can be achieved through universal HBV vaccination and anti-viral prophylaxis for high viraemic mothers. The goal of secondary prevention has been reached by effective anti-viral therapy to reduce the risk of HCC development in chronic hepatitis B patients. However, whether HCC is prevented or delayed deserves further examination. Finally, several studies confirmed the tertiary preventive effect of anti-viral therapy in reducing risk of HCC recurrence after curative therapies. CONCLUSIONS: Through the strategies of three-level prevention, the global burden of HBV-related HCC should decline over time and even be eliminated in conjunction with HBV cure. PMID- 29722446 TI - Transferability and within- and between-laboratory reproducibilities of EpiSensA for predicting skin sensitization potential in vitro: A ring study in three laboratories. AB - The epidermal sensitization assay (EpiSensA) is an in vitro skin sensitization test method based on gene expression of four markers related to the induction of skin sensitization; the assay uses commercially available reconstructed human epidermis. EpiSensA has exhibited an accuracy of 90% for 72 chemicals, including lipophilic chemicals and pre-/pro-haptens, when compared with the results of the murine local lymph node assay. In this work, a ring study was performed by one lead and two naive laboratories to evaluate the transferability, as well as within- and between-laboratory reproducibilities, of EpiSensA. Three non-coded chemicals (two lipophilic sensitizers and one non-sensitizer) were tested for the assessment of transferability and 10 coded chemicals (seven sensitizers and three non-sensitizers, including four lipophilic chemicals) were tested for the assessment of reproducibility. In the transferability phase, the non-coded chemicals (two sensitizers and one non-sensitizer) were correctly classified at the two naive laboratories, indicating that the EpiSensA protocol was transferred successfully. For the within-laboratory reproducibility, the data generated with three coded chemicals tested in three independent experiments in each laboratory gave consistent predictions within laboratories. For the between-laboratory reproducibility, 9 of the 10 coded chemicals tested once in each laboratory provided consistent predictions among the three laboratories. These results suggested that EpiSensA has good transferability, as well as within- and between laboratory reproducibility. PMID- 29722447 TI - Trichloroethylene exposure results in the phosphorylation of histone H2AX in a human hepatic cell line through cytochrome P450 2E1-mediated oxidative stress. AB - Trichloroethylene (TCE), a chlorinated hydrocarbon, was recently reclassified as a human carcinogen by the International Agency for Research on Cancer. Genotoxic events are known to be crucial steps in the initiation of cancer. The genotoxic properties of TCE have been examined in many studies using a standard battery of genotoxicity tests both in vitro and in vivo. However, consistent results have not been obtained, and studies investigating the mechanism behind the genotoxicity of this compound are lacking. In the present study, we examined the genotoxicity of TCE by assessing phosphorylated histone H2AX (gamma-H2AX), a new sensitive and reliable marker of DNA damage, in WRL-68 cells, cultured human hepatocytes and mouse livers. Our results showed that TCE exposure results in the generation of gamma-H2AX, both in vitro and in vivo. By investigating the in vitro mechanism, we found that TCE increases the levels of intracellular reactive oxygen species (ROS) and that this increase in ROS levels is attenuated in the presence of disulfiram, a specific cytochrome P450 2E1 (CYP2E1) inhibitor. Furthermore, gamma-H2AX induced by TCE was also attenuated by CYP2E1 inhibitors and the antioxidant N-acetylcysteine. These results suggested that ROS, produced via cytochrome P450 2E1-mediated metabolic processing, is a major causal factor for gamma-H2AX generation upon exposure to TCE. PMID- 29722448 TI - Titanium dioxide nanoparticles translocate through differentiated Caco-2 cell monolayers, without disrupting the barrier functionality or inducing genotoxic damage. AB - The widespread use of titanium dioxide nanoparticles (TiO2 NPs) in commercial food products makes intestinal cells a suitable target. Accordingly, we have used the human colon adenocarcinoma Caco-2 cells to detect their potential harmful effects. Caco-2 cells can differentiate in to enterocytic-like cells, forming consistent cell monolayers and are used as a model of the intestinal barrier. Using both undifferentiated and differentiated Caco-2 cells, we have explored a set of biomarkers, aiming to evaluate undesirable effects associated to TiO2 NP exposure. Results indicate non-toxic effects in exposures ranging 1-200 MUg ml-1 . Significant differences were observed in cell uptake, with a higher amount of incorporated TiO2 NPs in undifferentiated cells, as visualized using confocal microscopy. In well-established monolayers, translocation was detected using both confocal microscopy and transmission electron microscopy with energy-dispersive X ray spectroscopy. In spite of the observed uptake and translocation, TiO2 NP exposures did not modify the integrity of the monolayer, as measured using the transepithelial electrical resistance and Lucifer yellow methods. The potential genotoxic effects in differentiated cells were evaluated in the comet assay, with and without formamidopyrimidine DNA glycosylase enzyme to detect oxidatively the damaged DNA bases. Although some changes were detected at the lower dose (10 MUg ml-1 ), no effects were observed at higher doses. PMID- 29722449 TI - Overactivity, impulsivity and repetitive behaviour in males with fragile X syndrome: contrasting developmental trajectories in those with and without elevated autism symptoms. AB - BACKGROUND: Hyperactivity and repetitive behaviour are characteristic features of fragile X syndrome (FXS). However, little is known about the influence of autism symptomatology on how these characteristics develop over time. We investigate the profiles and developmental trajectories of overactivity, impulsivity and repetitive behaviour, in males with FXS over three time points spanning 8 years. METHOD: Participants formed two subgroups, those who displayed elevated symptoms of autism at Time 1 (n = 37; Mage = 16.32; age range = 6.61-43.51) and those who did not (n = 32; Mage = 8.43; age range = 8.94-47.49). RESULTS: Participants without elevated symptoms of autism showed a reduction in impulsivity and repetitive questioning over time, whereas those with elevated symptoms of autism did not. Differences between the two subgroups in several topographies of repetitive behaviour emerged at Time 3 only. CONCLUSIONS: These results further understanding of the relationship between autistic phenomenology and behavioural characteristics in FXS. PMID- 29722452 TI - Assembly of ZIF-67 Metal-Organic Framework over Tin Oxide Nanoparticles for Synergistic Chemiresistive CO2 Gas Sensing. AB - Metal-organic frameworks (MOFs) are widely known for their record storage capacities of small gas molecules (H2 , CO2 , and CH4 ). Assembly of such porous materials onto well-known chemiresistive gas sensing elements such as SnO2 could be an attractive prospect to achieve novel sensing properties as this affects the surface chemistry of SnO2 . Cobalt-imidazole based ZIF-67 MOF was grown onto preformed SnO2 nanoparticles to realize core-shell like architecture and explored for greenhouse gas CO2 sensing. CO2 sensing over SnO2 is a challenge because its interaction with SnO2 surface is minimal. The ZIF-67 coating over SnO2 improved the response of SnO2 up to 12-fold (for 50 % CO2 ). The SnO2 @ZIF-67 also showed a response of 16.5+/-2.1 % for 5000 ppm CO2 (threshold limit value (TLV)) at 205 degrees C, one of the best values reported for a SnO2 -based sensor. The observed novel CO2 sensing characteristics are assigned to electronic structure changes at the interface of ZIF-67 and SnO2 . PMID- 29722451 TI - Pentafluoroethylated Compounds of Silicon, Germanium and Tin. AB - In this contribution we present an account on pentafluoroethylated compounds of silicon, germanium and tin. The pronounced electron-withdrawing effect of the pentafluoroethyl group leads to a markedly increased Lewis acidity at the central atom which results in the stabilization of hypervalent complexes, anionic element(II) species as well as remarkable reactivities of element-element and element-hydrogen bonds. By addition to unsaturated C-C bonds or by reaction with organic halides as well as transition-metal complexes the molecules bearing a pentafluoroethyl-element group are readily accessible. Moreover, the utilization of pentafluoroethyl groups facilitates the formation of donor-stabilized germylenes and stannylenes. A series of such compounds serves as suitable pentafluoroethylation reagents. Conversely to the well-studied trifluoromethyl derivatives these compounds frequently exhibit a higher thermostability, which allows a more convenient handling. PMID- 29722454 TI - Elephants, Parkinson's Disease, and Proof-of-Concept Clinical Trials. PMID- 29722450 TI - Crius: A novel fragment-based algorithm of de novo substrate prediction for enzymes. AB - The study of enzyme substrate specificity is vital for developing potential applications of enzymes. However, the routine experimental procedures require lot of resources in the discovery of novel substrates. This article reports an in silico structure-based algorithm called Crius, which predicts substrates for enzyme. The results of this fragment-based algorithm show good agreements between the simulated and experimental substrate specificities, using a lipase from Candida antarctica (CALB), a nitrilase from Cyanobacterium syechocystis sp. PCC6803 (Nit6803), and an aldo-keto reductase from Gluconobacter oxydans (Gox0644). This opens new prospects of developing computer algorithms that can effectively predict substrates for an enzyme. PMID- 29722455 TI - The importance of an independent validation cohort for metabolomics biomarker studies. PMID- 29722453 TI - High-resolution crystal structures reveal a mixture of conformers of the Gly61 Asp62 peptide bond in an oxidized flavodoxin from Bacillus cereus. AB - Flavodoxins (Flds) are small proteins that shuttle electrons in a range of reactions in microorganisms. Flds contain a redox-active cofactor, a flavin mononucleotide (FMN), and it is well established that when Flds are reduced by one electron, a peptide bond close to the FMN isoalloxazine ring flips to form a new hydrogen bond with the FMN N5H, stabilizing the one-electron reduced state. Here, we present high-resolution crystal structures of Flavodoxin 1 from Bacillus cereus in both the oxidized (ox) and one-electron reduced (semiquinone, sq) state. We observe a mixture of conformers in the oxidized state; a 50:50 distribution between the established oxidized conformation where the peptide bond is pointing away from the flavin, and a conformation where the peptide bond is pointing toward the flavin, approximating the conformation in the semiquinone state. We use single-crystal spectroscopy to demonstrate that the mixture of conformers is not caused by radiation damage to the crystal. This is the first time that such a mixture of conformers is reported in a wild-type Fld. We therefore carried out a survey of published Fld structures, which show that several proteins have a pronounced conformational flexibility of this peptide bond. The degree of flexibility seems to be modulated by the presence, or absence, of stabilizing interactions between the peptide bond carbonyl and its surrounding amino acids. We hypothesize that the degree of conformational flexibility will affect the Fld ox/sq redox potential. PMID- 29722456 TI - Comment on 'Distinct Metabolomic Signature in Cerebrospinal Fluid in Early Parkinson's Disease' by Hiller et al. PMID- 29722458 TI - Levodopa-Induced Dyskinesia: "TRAP"ping the Culprit. PMID- 29722457 TI - Enantiomeric composition of nicotine in tobacco leaf, cigarette, smokeless tobacco, and e-liquid by normal phase high-performance liquid chromatography. AB - Evaluating the source of nicotine in e-liquid is a problem. Tobacco-derived nicotine contains predominantly (S)-(-)-nicotine, whereas tobacco-free nicotine products may not. Thus, we developed a new normal phase high-performance liquid chromatography method to determinate the enantiomeric composition of nicotine in 10 kinds of flue-cured tobacco, 3 kinds of burley, 1 kind of cigar tobacco, 2 kinds of oriental tobacco, 5 kinds of Virginia cigarette, 5 kinds of blend cigarette, 10 kinds of e-liquid, and 4 kinds of smokeless tobacco. The amount of (R)-(+)-nicotine ranged from ~0.02% to ~0.76% of total nicotine. An e-liquid sample had the highest level of (R)-(+)-nicotine. The extraction and purification processes used to obtain commercial (S)-(-)-nicotine from the tobacco do not decrease the amount of (R)-(+)-nicotine in tobacco. So the amount of (R)-(+) nicotine in samples in our work were the same as tobacco samples. PMID- 29722460 TI - Irreversible electroporation-A hot topic. PMID- 29722459 TI - Selective On/Off-Nitroxides as Radical Probes to Investigate Non-radical Enzymatic Activity by Electron Paramagnetic Resonance. AB - A nitroxide carrying a peptide specific to the binding pocket of the serine proteases chymotrypsin and cathepsin G is prepared. This peptide is attached as an enol ester to the nitroxide. Upon enzymatic hydrolysis of the peptide, the enol ester moiety is transformed into a ketone moiety. This transformation affords a difference of 5 G in phosphorus hyperfine coupling constant between the electronic paramagnetic resonance (EPR) signals of each nitroxide. This property is used to monitor the enzymatic activity of chymotrypsin and cathepsin G by EPR. Michaelis constants were determined and match those reported for conventional optical probes. PMID- 29722461 TI - Transition-Metal-Catalyzed Carboxylation Reactions with Carbon Dioxide. AB - Driven by the inherent synthetic potential of CO2 as an abundant, inexpensive and renewable C1 chemical feedstock, the recent years have witnessed renewed interest in devising catalytic CO2 fixations into organic matter. Although the formation of C-C bonds via catalytic CO2 fixation remained rather limited for a long period of time, a close look into the recent literature data indicates that catalytic carboxylation reactions have entered a new era of exponential growth, evolving into a mature discipline that allows for streamlining the synthesis of carboxylic acids, building blocks of utmost relevance in industrial endeavors. These strategies have generally proven broadly applicability and convenient to perform. However, substantial challenges still need to be addressed reinforcing the need to cover metal-catalyzed carboxylation area in a conceptual and concise manner, delineating the underlying new principles that are slowly emerging in this vibrant area of expertise. PMID- 29722462 TI - The Alkylquinolone Repertoire of Pseudomonas aeruginosa is Linked to Structural Flexibility of the FabH-like 2-Heptyl-3-hydroxy-4(1H)-quinolone (PQS) Biosynthesis Enzyme PqsBC. AB - Pseudomonas aeruginosa is a bacterial pathogen that causes life-threatening infections in immunocompromised patients. It produces a large armory of saturated and mono-unsaturated 2-alkyl-4(1H)-quinolones (AQs) and AQ N-oxides (AQNOs) that serve as signaling molecules to control the production of virulence factors and that are involved in membrane vesicle formation and iron chelation; furthermore, they also have, for example, antibiotic properties. It has been shown that the beta-ketoacyl-acyl-carrier protein synthase III (FabH)-like heterodimeric enzyme PqsBC catalyzes the last step in the biosynthesis of the most abundant AQ congener, 2-heptyl-4(1H)-quinolone (HHQ), by condensing octanoyl-coenzyme A (CoA) with 2-aminobenzoylacetate (2-ABA), but the basis for the large number of other AQs/AQNOs produced by P. aeruginosa is not known. Here, we demonstrate that PqsBC uses different medium-chain acyl-CoAs to produce various saturated AQs/AQNOs and that it also biosynthesizes mono-unsaturated congeners. Further, we determined the structures of PqsBC in four different crystal forms at 1.5 to 2.7 A resolution. Together with a previous report, the data reveal that PqsBC adopts open, intermediate, and closed conformations that alter the shape of the acyl binding cavity and explain the promiscuity of PqsBC. The different conformations also allow us to propose a model for structural transitions that accompany the catalytic cycle of PqsBC that might have broader implications for other FabH enzymes, for which such structural transitions have been postulated but have never been observed. PMID- 29722463 TI - Highly Luminescent Inks: Aggregation-Induced Emission of Copper-Iodine Hybrid Clusters. AB - Aggregation-induced emission (AIE) is an attractive phenomenon in which materials display strong luminescence in the aggregated solid states rather than in the conventional dissolved molecular states. However, highly luminescent inks based on AIE are hard to be obtained because of the difficulty in finely controlling the crystallinity of AIE materials at nanoscale. Herein, we report the preparation of highly luminescent inks via oil-in-water microemulsion induced aggregation of Cu-I hybrid clusters based on the highly soluble copper iodide tris(3-methylphenyl)phosphine (Cu4 I4 (P-(m-Tol)3 )4 ) hybrid. Furthermore, we can synthesize a series of AIE inks with different light-emission colors to cover the whole visible spectrum range via a facile ligand exchange processes. The assemblies of Cu-I hybrid clusters with AIE characteristics will pave the way to fabricate low-cost highly luminescent inks. PMID- 29722464 TI - Structural Insight into the Allosteric Coupling of Cu1 Site and Trinuclear Cu Cluster in CotA Laccase. AB - In laccase, type 1 copper (Cu1) was connected to the trinuclear copper center (TNC) by the conserved Cys-His bridge. An allosteric coupling between the two redox sites has been reported; however, the molecular mechanism underlining the allosteric coupling is unknown. In this study, ligands of the two type 3 copper sites, including His491 and His493, in CotA were mutated to Cys or Ala. The crystal structures revealed that mutations at His491 and His493 caused rearrangement of the hydrogen-bond network and geometric distortion of the TNC, which severely impaired the activities of mutants H493A, H493C, and H491C. In addition, the change in TNC affected hydrogen bonds around Cys492 in the mutants and led to Cu1 being partially reduced. These results not only decipher the mechanism of allosteric coupling between Cu1 and TNC in laccase, but also pave the way for laccase protein engineering. PMID- 29722465 TI - Three brain states in the hippocampus and cortex. AB - Contemporary brain research seeks to understand how cognition is reducible to neural activity. Crucially, much of this effort is guided by a scientific paradigm that views neural activity as essentially driven by external stimuli. In contrast, recent perspectives argue that this paradigm is by itself inadequate, and that understanding patterns of activity intrinsic to the brain is needed to explain cognition. Yet despite this critique, the stimulus-driven paradigm still dominates - possibly because a convincing alternative has not been clear. Here we review a series of experimental findings in the hippocampus suggesting such an alternative. These findings indicate that hippocampal neural activity occurs in one of three brain states that have radically different anatomical, physiological, representational, and behavioral correlates, together implying different roles in cognition. This three-state framework also indicates that hippocampal neural representations follow a surprising pattern of organization at the timescale of ~1 s or longer. Lastly, beyond the hippocampus, recent breakthroughs indicate three parallel states in cortex, suggesting shared principles and brain-wide organization of intrinsic neural activity. This article is protected by copyright. All rights reserved. PMID- 29722467 TI - Wide complex tachycardia in a patient with Ebstein's anomaly. PMID- 29722466 TI - Postprocedural LGE-CMR comparison of laser and radiofrequency ablation lesions after pulmonary vein isolation. AB - INTRODUCTION: The purpose of this study was to compare the anatomical characteristics of scar formation achieved by visual-guided laser balloon (Laser) and radiofrequency (RF) pulmonary vein isolation (PVI), using late-gadolinium enhanced cardiac magnetic resonance imaging (LGE-CMR). METHODS AND RESULTS: We included 17 patients with paroxysmal or early persistent drug resistant AF who underwent Laser ablation; 2 were excluded due to procedure-related complications. The sample was matched with a historical group of 15 patients who underwent PVI using RF. LGE-CMR sequences were acquired before and 3 months post-PVI. Ablation gaps were defined as pulmonary vein (PV) perimeter sections showing no gadolinium enhancement. The number of ablation gaps was lower in Laser versus RF ablations (median 7 vs. 14, P = 0.015). Complete anatomical PVI (circumferential scar around PV, without gaps) was more frequently achieved with Laser than with RF (39% vs. 19% of PVs, P = 0.025). Fewer gaps were present at the superior and anterior left PV and posterior right PV antral regions in the Laser group, compared to RF. Scar extension into the PVs was similar in both groups, although RF produced more extensive ablation scar toward the LA body. AF recurrences at 1 year were similar in both groups (Laser 36% vs. RF 27%, P = 1.00). CONCLUSIONS: Compared to RF, Laser ablation achieved more complete anatomical PVI, with less LA scar extension. However, AF recurrence appears to be similar after Laser compared to RF ablation. Further studies are needed to assess whether the anatomical advantages of Laser ablation translate into clinical benefit in patients with AF. PMID- 29722468 TI - Comparison of treatment outcomes between convergent procedure and catheter ablation for paroxysmal atrial fibrillation evaluated with implantable loop recorder monitoring. AB - INTRODUCTION: While catheter ablation (CA) is an established treatment for symptomatic paroxysmal atrial fibrillation (AF), convergent epicardial and endocardial ablation procedure (CVP) has been primarily used to treat persistent AF. The aim of this single-center, prospective, randomized study was to compare treatment efficacy of CA and CVP in paroxysmal AF patients by monitoring AF, atrial tachycardia (AT), and atrial flutter (AFL) recurrence with Implantable Loop Recorder (ILR). METHODS AND RESULTS: Fifty patients (74% male) with history of paroxysmal AF were randomized between CA and CVP. Outcomes were determined by ILRs; every episode of AF/AT/AFL lasting 6 minutes or more was defined as a recurrence. AF burden (AFB) and required AF reinterventions (cardioversions and repeat ablations) were quantified after a 3-month blanking period. Total procedural (266 +/- 44 vs. 242 +/- 39 minutes) and ablation duration (52 +/- 10 vs. 48 +/- 12 minutes) was similar in both groups. Recurrence of AF/AT/AFL was more likely in the CA group compared to the CVP group (OR 3.78 (95% CI (1.17, 12.19), P = 0.048)). During the follow-up period (mean 30.5 +/- 6.9 months), higher AF burden and more reinterventions for recurrent AF were recorded in the CA group. There were more periprocedural complications in the CVP group (12.5%) compared to the CA group (0%). CONCLUSION: Treatment of paroxysmal AF with CVP showed less arrhythmia recurrence compared to CA. In addition, patients after CVP had fewer reinterventions and lower AF burden, but more periprocedural complications. PMID- 29722470 TI - Metabolic abnormalities in heart failure patients treated with ultrafiltration versus diuretics. PMID- 29722469 TI - Incidence of pericardial effusion after left atrial appendage closure: The impact of underlying heart rhythm-Data from the EWOLUTION study. AB - INTRODUCTION: Pericardial effusion/tamponade (PE/PT) is a rare but serious complication following left atrial appendage closure (LAAC). It may be speculated that LAA contraction during sinus rhythm (SR) exerts mechanical force on the device that eventually leads to PE. We sought to determine the incidence and predictors of PE following LAAC using Watchman with special emphasis on the underlying heart rhythm during implant. METHODS AND RESULTS: From 47 centers in 13 European countries 1,020 patients underwent LAAC and data on baseline rhythm were available from 1,010 patients (mean age 73 +/- 9 years, 60% male, median CHA2DS2-VASc = 4). Data were collected via electronic case report forms. A Cox proportional hazard model was calculated adjusting for multiple variables: age, gender, number of recaptures, and device oversizing. During implant, 41% and 59% of patients were in SR and atrial fibrillation (AF), respectively. PE/PT rate was significantly lower in patients implanted during AF at day 30 postimplant (n = 1; 0.2% vs. n = 6; 1.5%; P = 0.02). No PE requiring intervention occurred in the AF group compared to 5 events (1.2%) in the SR group (P = 0.01). While univariate analysis identified SR and gender as predictors for PE/tamponade, multivariate analysis only showed a statistical trend for both variables. CONCLUSION: The overall incidence of PE/PT was very low after LAAC using Watchman. Although SR was not identified as an independent predictor of PE/PT, all events requiring intervention occurred in patients with SR. It may be advisable to perform an extended echocardiographic follow-up in that patient population. PMID- 29722471 TI - Repetitive levosimendan for a LION's heart? PMID- 29722472 TI - Fulminant group A streptococcal infection without gangrene in the extremities: Analysis of five autopsy cases. AB - Five autopsy cases of fulminant group A streptococcal infection without gangrene in the extremities are presented. Clinical course of the fulminant illness was short (2-4 days). One pathological autopsy case was aged (86-years-old), and hemorrhagic cystitis was observed. The other four forensic autopsy cases were young (24-38 years-old) with the mean age of 32, and the primary infective lesions were located in the postpartum endometrium, tonsil and bronchus (2 cases). Systemic coccal dissemination with poor neutrophilic reaction was seen in two of five cases. Bilateral renal cortical necrosis was noted in three cases (including two with bacterial embolism). Hemophagocytosis, probably resulting from hypercytokinemia, was characteristic in three cases without bacterial embolism. Gram-positive cocci colonizing the hemorrhagic and necrotizing lesions were consistently immunoreactive for streptococcal antigens and Strep A (a carbohydrate antigen on group A streptococci). Neutrophilic reaction was mild in the primary infected foci. Clinicians should note that fulminant streptococcal infection (streptococcal toxic shock syndrome) in young and immunocompetent patients may not be associated with gangrene in the extremities. Autopsy prosecutors (diagnostic and forensic pathologists) must recognize the difficulty in making an appropriate autopsy diagnosis, particularly when bacterial embolism is not associated. PMID- 29722473 TI - Weight Stigma Affects Men Too. PMID- 29722474 TI - Identification of the critical isthmus of a reentrant ventricular tachycardia at a glance. PMID- 29722475 TI - Spontaneously Self-Assembled Naphthalimide Nanosheets: Aggregation-Induced Emission and Unveiling a-PET for Sensitive Detection of Organic Volatile Contaminants in Water. AB - A simple design strategy of long alkyl chain substitution was formulated to block the detrimental pi-pi interaction that potentially transforms the aggregation caused quenching (ACQ) chromophores into aggregation-induced emission (AIE) active smart nanomaterials. The long octadecyl pendant chain substituted naphthalimide (NI) derivatives self-assembled into fluorescent nanosheets (NS) like structures that spontaneously have surfaces coated with NI cores in water. The fluorescent NS were subsequently used to recognize the organic volatile contaminants (OVCs) at ppb levels via an acceptor-excited photoinduced electron transfer (a-PET) mechanism, unveiled as the first representative example. A new design strategy is thereby provided to detect toxic xylene derivatives in water using smart nanomaterials. PMID- 29722476 TI - Identification of Children's BMI Trajectories and Prediction from Weight Gain in Infancy. AB - OBJECTIVE: The goal of this study was to identify patterns of BMI changes across childhood (ages 24 months to 13 years) and to assess whether demographic characteristics, birth weight, and percent infant weight gain from birth to 15 months predicted BMI patterns. METHODS: Eleven waves of data from the Study of Early Child Care and Youth Development were used. Trained technicians assessed children's weight at birth and 10 times from 15 months to eighth grade (N = 1364). Latent growth modeling was used to estimate BMI change trajectories, and logistic regression was used to predict membership in trajectory classes. RESULTS: Children in the high-rising and low-to-high BMI patterns had the highest BMI of all trajectory groups during middle childhood. Birth weight and infant weight gain were stronger predictors of trajectory membership than gender or race/ethnicity. Infant weight gain predicted high-rising membership over and above the effect of birth weight. African American children had lower birth weight, faster infant weight increase, and higher odds of being in one of the rising trajectories. Risk algorithms are provided. CONCLUSIONS: Clinicians should monitor weight gain during infancy independent of birth weight. Researchers should continue investigating the lasting physiological effects of early rapid weight gain in infancy. PMID- 29722477 TI - Small center, big heart. PMID- 29722478 TI - Successful reduced-intensity conditioning hematopoietic stem cell transplantation for paroxysmal nocturnal hemoglobinuria with aplastic anemia in two children. AB - Paroxysmal nocturnal hemoglobinuria (PNH) is an extremely rare cause of bone marrow failure in children. We report two children who presented with pancytopenia, and were diagnosed with PNH with severe aplastic anemia. Both children underwent upfront, successful hematopoietic stem cell transplantation with reduced-intensity conditioning. One patient had a syngeneic donor, and one patient had a 10/10 matched unrelated donor. Neither patient developed graft versus host disease, infections, or recurrent PNH. Reduced-intensity conditioning hematopoietic stem cell transplantation is a reasonable therapy for PNH with marrow failure in children. PMID- 29722479 TI - Molecular Simulation Results on Charged Carbon Nanotube Forest-Based Supercapacitors. AB - Electrochemical double-layer capacitances of charged carbon nanotube (CNT) forests with tetraethyl ammonium tetrafluoro borate electrolyte in propylene carbonate are studied on the basis of molecular dynamics simulation. Direct molecular simulation of the filling of pore spaces of the forest is feasible even with realistic, small CNT spacings. The numerical solution of the Poisson equation based on the extracted average charge densities then yields a regular experimental dependence on the width of the pore spaces, in contrast to the anomalous pattern observed in experiments on other carbon materials and also in simulations on planar slot-like pores. The capacitances obtained have realistic magnitudes but are insensitive to electric potential differences between the electrodes in this model. This agrees with previous calculations on CNT forest supercapacitors, but not with experiments which have suggested electrochemical doping for these systems. Those phenomena remain for further theory/modeling work. PMID- 29722480 TI - 3,3'-Diindolylmethane Enhances Glucose Uptake Through Activation of Insulin Signaling in 3T3-L1 Adipocytes. AB - OBJECTIVE: Indole-3-carbinol (I3C), a naturally occurring compound found in cruciferous vegetables, and its metabolite 3,3'-diindolylmethane (DIM) reduce body mass and serum glucose levels in high-fat-diet-induced obese mice. This study aimed to determine whether I3C or DIM could increase glucose uptake via enhanced insulin sensitivity in 3T3-L1 adipocytes, as well as the mechanism involved. METHODS: 3T3-L1 preadipocytes were differentiated by using a mixture of adipogenic inducers, including a suboptimal concentration of insulin. RESULTS: DIM, but not I3C, increased adipocyte differentiation through upregulation of peroxisome proliferator-activated receptor gamma and CCAAT/enhancer-binding protein alpha. DIM also enhanced glucose uptake by increasing expression of glucose transporter 4 in adipocytes. This was associated with DIM-enhanced phosphorylation of the signaling intermediates Akt, insulin receptor substrate-1, and insulin receptor early in differentiation. CONCLUSIONS: Our findings suggest that DIM may improve insulin sensitivity through the activation of the insulin signaling pathway, leading to enhanced glucose uptake. PMID- 29722481 TI - Randomized web-based physical activity intervention in adolescent survivors of childhood cancer. AB - BACKGROUND: Healthy lifestyle choices, including participation in regular physical activity, may improve health outcomes in survivors of childhood cancer. We aimed to evaluate the efficacy of a web-delivered physical activity intervention among adolescent survivors to increase moderate to vigorous physical activity (MVPA) and improve fitness and neurocognitive and health-related quality of life (HRQoL) over 24 weeks. PROCEDURE: This randomized controlled trial was conducted among survivors (aged >=11 to <15 years) treated at a single institution. Participants were randomized to either a physical activity intervention delivered over the internet or a control group. The intervention group received educational materials, an activity monitor, and access to an interactive website designed to motivate increased physical activity via rewards; the control group received an activity monitor and educational materials. Physical activity, fitness, and neurocognitive and HRQoL outcomes were assessed at baseline and at 24 weeks. Mean changes were compared between groups using paired t-tests. RESULTS: Of the 97 survivors enrolled, 78 completed the study; the mean age was 12.7 (standard deviation 1.1), 80% were White, and 55.1% were female. Fifty-three survivors were assigned to the intervention and 25 to the control group. While survivors in the intervention group increased, and those in the control group decreased (4.7 +/- 119.9 vs. -24.3 +/- 89.7 min) weekly MVPA, this difference was not significant (P = 0.30). However, hand grip strength, number of sit-ups and pushups, neurocognitive function, and HRQoL outcomes improved in the intervention, but not in the control group. CONCLUSIONS: An interactive, rewards-based intervention designed to increase MVPA is feasible in adolescent survivors of childhood cancer. PMID- 29722483 TI - Presentation: A Pragmatic Approach to Understanding Sociologists' Differing Views on Value-Neutrality. PMID- 29722482 TI - Five year neurodevelopment outcomes of perinatally HIV-infected children on early limited or deferred continuous antiretroviral therapy. AB - INTRODUCTION: Early antiretroviral therapy (ART) has improved neurodevelopmental outcomes of HIV-infected (HIV-positive) children; however, little is known about the longer term outcomes in infants commencing early ART or whether temporary ART interruption might have long-term consequences. In the children with HIV early antiretroviral treatment (CHER) trial, HIV-infected infants <=12 weeks of age with CD4 >=25% were randomized to deferred ART (ART-Def); immediate time-limited ART for 40 weeks (ART-40W) or 96 weeks (ART-96W). ART was restarted in the time limited arms for immunologic/clinical progression. Our objective was to compare the neurodevelopmental profiles in all three arms of Cape Town CHER participants. METHODS: A prospective, longitudinal observational study was used. The Griffiths mental development scales (GMDS), which includes six subscales and a global score, were performed at 11, 20, 30, 42 and 60 months, and the Beery-Buktenica developmental tests for visual motor integration at 60 months. HIV-exposed uninfected (HEU) and HIV-unexposed (HU) children were enrolled for comparison. Mixed model repeated measures were used to compare groups over time, using quotients derived from standardized British norms. RESULTS: In this study, 28 ART Def, 35 ART-40W, 33 ART-96W CHER children, and 34 HEU and 39 HU controls were enrolled. GMDS scores over five years were similar between the five groups in all subscales except locomotor and general Griffiths (interaction p < 0.001 and p = 0.02 respectively), driven by early lower scores in the ART-Def arm. At 60 months, scores for all groups were similar in each GMDS scale. However, Beery visual perception scores were significantly lower in HIV-infected children (mean standard scores: 75.8 ART-Def, 79.8 ART-40W, 75.9 ART-96W) versus 84.4 in HEU and 90.5 in HU (p < 0.01)). CONCLUSIONS: Early locomotor delay in the ART-Def arm resolved by five years. Neurodevelopmental outcomes at five years in HIV-infected children on early time-limited ART were similar to uninfected controls, apart from visual perception where HIV-infected children scored lower. Poorer visual perception performance warrants further investigation. PMID- 29722485 TI - Foreword. PMID- 29722484 TI - Introduction: Canadian Visual Methodologies and Visual Sociology. PMID- 29722486 TI - ? PMID- 29722487 TI - ? PMID- 29722488 TI - [The use of the permanent sample (eps) to study the returnto- work after cancer. Challenges and opportunities for research]. AB - INTRODUCTION: The introduction of early cancer detection and the improvement in treatment efficacy have led to a significant increase in the survival and the prevalence of (ex) cancer patients. Approximately 40 % of new cancer cases are diagnosed every year in the working age population (20-64 years). Maintaining their quality of life results, among others, in their retain on the labour market. Even though it is necessary to realize the scale of the phenomenon and to plan interventions, no measure allows assessing the rate of return to work among of (ex) cancer patients in Belgium nowadays. METHODS: We observe during a five year period the socio-professional status (inability, disability, unemployment or death) of 645 workers identified in the permanent sample (EPS), having had an oncological multidisciplinary consultation (MOC) in 2011. RESULTS: By the end of follow-up, 24 % of the workers were deceased. Among those who survived 26 % are unable to work, 12 % are unemployed and 63 % do not receive any social benefit. Women and young workers (20-44 years) seemed to have encountered difficulties the most. CONCLUSIONS: The results of this study allow giving a prudent first estimation of the return to work of socially insured Belgian citizens of almost 40 %, five years after the first MOC. Nevertheless, the structure of the EPS presents many limitations to the interpretation and reliability of results. We suggest some modifications of the EPS that might offer scientists better opportunities to improve the performance and reliability of such cohort studies. PMID- 29722489 TI - [Study of diagnostic value of natremia in a cohort of patients with hypercalcemia]. AB - INTRODUCTION: Hypercalcemia is a common pathological condition in clinical practice. The two most common causes are primary hyperparathyroidism and cancer. SIADH is often encountered in cancer cases and is the most common cause of hyponatremia. The aim of this study is to evaluate serum sodium levels in a cohort of patients with hypercalcemia and consider its predictive value in determining the origin of this hypercalcemia. MATERIALS AND METHODS: We performed a retrospective study on a series of 15.284 blood tests among adult patients with hypercalcemia. After selection, the study population had 151 patients. We studied mainly serum sodium and etiology of hypercalcemia in our population. RESULTS: We observed a statistically significant association between the presence of hyponatremia and the neoplastic etiology of hypercalcemia. This association persisted after exclusion of patients under treatment with loop diuretics. Conversely, there was no association between hypernatremia and cancer-related hypercalcemia. Among 151 patients with hypercalcemia, 16 presented hyponatremia and 7 with hypernatremia. SIADH was the main cause of hyponatremia. We performed univariate and multivariate logistic regression showing the association between the presence of cancer and the presence of hyponatremia. CONCLUSION: Our study shows that there is an association between the presence of hyponatremia and neoplastic origin of hypercalcemia. Besides, the association described between hyponatremia and cancer is not faulted by the presence of hypercalcemia, a potential cause of acquired nephrogenic diabetes insipidus. PMID- 29722490 TI - [CT Scan in early detection of lung cancer in patients with chronic obstructive pulmonary disease : a retrospective monocentric study]. AB - OBJECTIVE: To explore the possible benefit of detecting lung cancer in COPD patients and to assess the pulmonologist's compliance with the Fleischner Society guidelines for management of pulmonary nodules. METHODS: This monocentric retrospective study was approved by the institutional ethical Committee. Patients with COPD undergoing a CT scan between January 2010 and March 2017 were included. Depending on CT indication (respectively screening or other indications), patients were divided into Group 1 and 2. Follow-up intervals were compared to those recommended in the Fleischner Society guidelines. Data were compared between groups using Chisquared test, Student test, or Wilcoxon test when appropriate. RESULTS: 254 patients were included (134 in Group 1 and 120 in Group 2). 235 opacities were found in 119 patients (47 %). 13 among 254 patients had a lung cancer; 9 in Group 1 (6.7 %) and 4 in Group 2 (3.3 %). The median follow-up by CT after nodule detection was six months regardless of their diameter or attenuation. No statistical significance was found between the observed follow-up and recommendations (P = 0.058). CONCLUSION: COPD in patients with a history of smoking is associated with a higher CT detection rate of lung cancer. This finding may be useful when evaluating selection criteria in lung screening programs. In contrast with the recommendations, CT detected nodules are followed up regardless of their diameter and attenuation. PMID- 29722491 TI - [Routine preoperative testing in adults undergoing elective non-cardiothoracic surgery]. AB - INTRODUCTION: The Belgian Health Care Knowledge Center (KCE) developed a guideline about routine preoperative testing in adults undergoing elective non cardiothoracic surgery. The guideline is intended for all care providers involved in the preoperative and perioperative management (incl. anesthesiologists, surgeons, cardiologists, lung specialists, radiologists, clinical biologists, general practitioners, etc). METHOD: A recent English guideline published by NICE (National Institute for Health and Care Excellence) was used as a starting point and adapted to the Belgian context. Clinical questions not included in the NICE guideline were developed de novo. RESULTS: The following tests are recommended under specific conditions: resting electrocardiogram, full blood count test, kidney function tests, haemostasis tests, urinalysis and urine culture, non invasive cardiac stress imaging. The following tests are not routinely recommended: resting echocardiography, cardiopulmonary exercise testing, chest X ray, polysomnography, lung function tests (including arterial blood gas analysis), glycated haemoglobin test, liver function tests, coronary CT angiography. CONCLUSIONS: This guideline supports clinicians in the choice of ad hoc preoperative testing based on the most recent evidence and specific history of their patients to ensure optimal quality and safety. Tools are provided with this guideline to improve daily usage. PMID- 29722492 TI - [Koro syndrome : when culture interacts with psychopathology]. AB - Koro syndrome is a psychiatric disorder specific to certain Asian cultures. It is characterized by acute and intense anxiety with fear of a retraction of the penis into the body and resultant death. We report the case of a 43-year-old Moroccan male presenting with persistent anxiety associated with avoidance behaviors and a chronic belief that his genitalia may shrink or disappear and lead to his death. This impacted his professional and family functioning. The diagnosis of culture bound syndrome was considered although the presenting syndrome was chronic and sporadic. The Moroccan culture, which attributes a great importance to the male sex, would explain this syndrome. PMID- 29722493 TI - [Oligometastatic breast cancer : therapeutic implications of a new paradigm]. AB - INTRODUCTION: Oligometastatic breast cancer incidence is recently increasing thanks to screening and imaging improvements. Unlike patients with metastatic disease, a small number of oligometastatic patients may expect a definitive remission, in case of aggressive management performed with intent to cure. We report the atypical evolution of an oligometastatic breast cancer patient, who lately relapsed with a different Her2 status. RESULTS: A 46 year old women was treated for an infiltrating duct breast carcinoma, initially diagnosed with oligometastases and an Her2- negative status. Treatments were performed in intent to cure but the patient relapsed 5 years later with a solitary Her2-positive liver metastasis. The aggressive local and systemic (using an anti- Her2 targeted therapy) management induced a still complete remission at last follow-up. CONCLUSION: Prognosis of breast oligometastatic cancer is unpredictable, but an aggressive with intent-to-cure management may bring benefits to patients. However very rare, the switch of Her2 status between initial diagnosis and relapse highlights tumor heterogeneity, and the fact that a cell population featuring targetable characteristics may appear due to anticancer drug induced-cell selection. PMID- 29722494 TI - ? PMID- 29722496 TI - ? PMID- 29722495 TI - ? AB - The present chapter deals with the contribution of Professor Paul A. Bastenie, as Chief of the Department of Medicine of the Saint-Pierre Hospital and Director of the Laboratory of Experimental Medicine at Brussels Free University, in the field of diabetes with emphasis on the role of insulin in glucose homeostasis. The knowledge and experimental work under consideration is covering the period from 1955 to 1974. They entail not only three treatises contributed by Bastenie but also fundamental and clinical investigations, such as those presented in eight doctoral dissertations submitted for aggregation examination at Brussels Free University. These theses are dealing with the measurement of glucose assimilation (V. Conard), the measurement of insulin activity in men (J.R.M. Franckson), the mechanisms of action of hypoglycemic drugs (R. Bellens), the study of energy metabolism in children (H. Loeb), the study of insulin secretion in vitro (W. Malaisse), the distribution of insulin in body fluids as influenced by the permeability and structure of blood capillaries (E. Rasio), the regulation of the extra-hepatic metabolism of ketone bodies in anesthetized dogs (E.O. Balasse) and the use of radioiodinated insulin as tracers in biology (H.A. Ooms). PMID- 29722498 TI - [The immunosuppressed traveler : vaccination guidelines]. AB - The number of immunosuppressed travelers has exponentially increased in the past few years. This is a positive development as these patients, owing to much improved management, are now in a condition allowing them to plan activities abroad comparable to healthy persons. However, pre-travel consultation and vaccinations are particularly important to reduce the risks and/or the complications of travel-related diseases. Although we already published a review on this topic in 2013, the recent increase of immunosuppressive agents available in Switzerland justifies this update. PMID- 29722497 TI - [Travelers' exposure to HIV and HIV-infected travelers]. AB - In Switzerland, 20 % of the population travel to the tropics every year and many have unprotected sexual practices during their stay. A third of newly diagnosed HIV infections among Swiss citizens are acquired abroad. Travel clinics are probably important partners in the fight against sexually transmitted infections and HIV. People living with HIV often travel to the tropics but rarely attend a travel clinic before leaving. Travels are a risk factor of HIV viral rebound and antiretroviral treatment failure, particularly in sub-Saharan African patients. Pre-travel counselling should be part of a usual follow-up medical consultation with a focus on treatment adherence. PMID- 29722499 TI - [Immunization and autoimmune neurological diseases]. AB - Autoimmune neurological diseases involve a broad spectrum of diseases that may affect the central or peripheral nervous system, the neuromuscular junction and the muscle. The risk of vaccinating a patient with an autoimmune neurological disease frequently arises in view of fears, often scientifically unfounded, to reactivate the immune system and cause or aggravate the disease. The questions should also include the risks of not vaccinating a patient, and particularly the risk of the disease getting worse in case of infection that could have been potentially prevented by vaccination. Finally, the danger of not vaccinating an immunosuppressed patient must also be taken into account (increased infectious risk). PMID- 29722500 TI - [Travel Apps: applications and websites of travel medicine]. AB - Advancements in technology have led to the development of medical applications (Apps) and websites. Their use is especially relevant in the field of travel medicine, be it for travelers before their trip to get specific information on how to best prevent diseases and medical emergencies, or during their trip on what to do in case of health problem while abroad. These resources are also relevant for health professionals to prepare their clients before departure and know how to deal with medical problems they are not familiar with. We searched for apps and websites for the general public and health professionals in the field of travel medicine, based on the findings of an already published systematic review, updated and adapted to make it appropriate for local use in Switzerland. PMID- 29722501 TI - [Imported malaria in Geneva between 2005 and 2016]. AB - As part of the epidemiological surveillance of malaria, cases reported in Geneva during the period 2005-2016 were analyzed and compared to a similar retrospective study covering the period 1998-2004. A total of 600 cases were reported, averaging 50 cases per year. African patients traveling to visit friends and relatives remain at particular risk. The disease was acquired in Africa in 89,6% of cases and Plasmodium falciparum was the predominant species (84,2 %). 41% of patients did not benefit from a pre-travel consultation. The recent rise in imported malaria observed in Geneva since 2014 is a reminder of the need to apply effective prevention measures (chemoprophylaxis) in highly endemic countries, and to train all physicians to screen for malaria all febrile travelers returning from the tropics. PMID- 29722502 TI - [Diagnosis of urinary schistosomiasis by identification of miracidia of Schistosoma haematobium]. AB - Although rarely diagnosed in Switzerland, urinary tract schistosomiasis is common in the migrants' regions of origin, such as sub-Saharan Africa and the Middle East. Early recognition of this condition, even if asymptomatic, is crucial, because it increases the risk for HIV transmission and, if left untreated, can result in infertility and is associated with the development of bladder cancer. The diagnosis of urinary schistosomiasis should be especially suspected in case of terminal haematuria and eosinophilia in patients with a history of skin exposure to fresh water in endemic areas. The diagnosis is based on the identification by microscope of schistosome eggs or miracidia (a less common form of the Schistosoma sp lifecycle) in urine. The established treatment consists of praziquantel 40 mg/kg as single dose to be repeated at one month. PMID- 29722503 TI - [Improving understanding of the physiological mechanisms of exercise to better treat depression]. AB - According to the Swiss Health Survey one in five people will suffer from a major depressive episode at least once during their lifetime. Antidepressants and psychotherapy play a prominent role in patient management. In recent years, many studies have shown that physical activity also reduces depressive symptoms. Among mechanisms involved in the antidepressant effects of exercise, a recent study based on animal models of depression suggests that lactate may contribute to reducing depressive symptoms in response to physical activity. Elucidation of the mechanisms underlying the antidepressant effects of lactate may contribute to identify novel therapeutic targets for the treatment of depression. PMID- 29722504 TI - ? PMID- 29722505 TI - ? PMID- 29722506 TI - ? PMID- 29722507 TI - ? PMID- 29722508 TI - ? PMID- 29722509 TI - ? PMID- 29722510 TI - Evidence-based position paper on Physical and Rehabilitation Medicine (PRM) professional practice for people with respiratory conditions. The European PRM position (UEMS PRM Section). AB - Chronic respiratory conditions are among the top causes of death and disability. The aim of the paper was to improve Physical and Rehabilitation Medicine (PRM) physicians' professional practice for people with chronic respiratory conditions in order to promote their functioning and to reduce activity limitations and/or participation restrictions. A systematic review of the literature and a Consensus procedure by means of a Delphi process have been performed involving the delegates of all European countries represented in the UEMS PRM Section. The systematic literature review is reported together with twenty-three recommendations resulting from the Delphi procedure. The professional role of PRM physicians having expertise in the rehabilitation of chronic respiratory conditions is to lead pulmonary rehabilitation programs in multiprofessional teams, working in collaboration with other disciplines in a variety of settings to improve functioning of people with chronic respiratory conditions. This evidence-based position paper represents the official position of the European Union through the UEMS PRM Section and designates the professional role of PRM physicians for people with respiratory conditions. PMID- 29722511 TI - Evidence-based position paper on Physical and Rehabilitation Medicine (PRM) professional practice for people with cardiovascular conditions. The European PRM position (UEMS PRM Section). AB - Cardiovascular conditions are significant causes of mortality and morbidity leading to substantial disability. The aim of the paper is to improve Physical and Rehabilitation Medicine (PRM) physicians' professional practice for people with cardiovascular conditions in order to promote their functioning and to reduce activity limitations and/or participation restrictions. A systematic review of the literature and a Consensus procedure by means of a Delphi process have been performed involving the delegates of all European countries represented in the UEMS PRM Section. The systematic literature review is reported together with thirty recommendations resulting from the Delphi procedure. The professional role of PRM physicians having expertise in the rehabilitation of cardiovascular conditions is to lead cardiac rehabilitation programs in multiprofessional teams, working in collaboration with other disciplines in a variety of settings to improve functioning of people with cardiovascular conditions. This evidence-based position paper represents the official position of the European Union through the UEMS PRM Section and designates the professional role of PRM physicians in persons with cardiovascular conditions. PMID- 29722512 TI - Angiography with Sodium Bicarbonate and Acetylcysteine. PMID- 29722513 TI - Angiography with Sodium Bicarbonate and Acetylcysteine. PMID- 29722514 TI - History of Childhood Kidney Disease and Risk of Adult End-Stage Renal Disease. PMID- 29722515 TI - History of Childhood Kidney Disease and Risk of Adult End-Stage Renal Disease. PMID- 29722516 TI - History of Childhood Kidney Disease and Risk of Adult End-Stage Renal Disease. PMID- 29722517 TI - Pharmacomechanical Therapy for Deep-Vein Thrombosis. PMID- 29722519 TI - Pleural Disease. PMID- 29722518 TI - Pleural Disease. PMID- 29722520 TI - Microbubble-Triggered Spontaneous Separation of Transparent Thin Films from Substrates Using Evaporable Core-Shell Nanocapsules. AB - The spontaneous separation of a polymer thin film from a substrate is an innovative technology that will enable material recycling and reduce manufacturing cost in the film industry, and this can be applied in a wide range of applications, from optical films to wearable devices. Here, we present an unprecedented spontaneous strategy for separating transparent polymer films from substrates on the basis of microbubble generation using nanocapsules containing an evaporable material. The core-shell nanocapsules are prepared from poly(methyl methacrylate)-polyethyleneimine nanoparticles via the encapsulation of methylcyclohexane (MCH). A spherical nanostructure with a vaporizable core is obtained, with the heat-triggered gas release ability leading to the formation of microbubbles. Our separation method applied to transparent polymer films doped with a small amount of the nanocapsules encapsulating evaporable MCH enables spontaneous detachment of thin films from substrates via vacuum-assisted rapid vaporization of MCH over a short separation time, and clear detachment of the film is achieved with no deterioration of the inherent optical transparency and adhesive property compared to a pristine film. PMID- 29722521 TI - Protein-Induced Fluorescence Enhancement Based Detection of Plasmodium falciparum Glutamate Dehydrogenase Using Carbon Dot Coupled Specific Aptamer. AB - A novel 90-mer long ssDNA aptamer (NG3) covering a 40-mer random region targeting Plasmodium falciparum glutamate dehydrogenase ( PfGDH) developed through systematic evolution of ligands by exponential enrichment (SELEX) technique. The binding affinity of the aptamer to PfGDH discerned by circular dichroism (CD) was 0.5 +/- 0.04 MUM. The specificity of the aptamer toward the target was confirmed by gel electrophoresis and CD studies. The presence of two quadruplex forming regions, two big and four small stem loop structures with a deltaG of -7.99 kcal mol-1 for NG3 were deduced by computational studies. The spherical carbon dots (Cdots) of size 2-4 nm, synthesized by pyrolysis method using l-glutamate as a substrate were covalently linked to the amine modified aptamer. The Cdot with a band gap of 2.8 eV and a quantum yield of 34% produced fluorescence at ~ lambda410 nm when excited at lambda320nm. The quantum yield of Cdot-aptamer assembly was increased up to 40% in the presence of the PfGDH in solution. A linear relationship with a dynamic range of 0.5 nM to 25 nM (R2 = 0.98) and a limit of detection (LOD) of 0.48 nM was observed between the fluorescence intensity of the Cdots-aptamer conjugate and the concentration of PfGDH. The method could detect PfGDH with an LOD of 2.85 nM in diluted serum sample. This novel simple, sensitive and specific protein induced fluorescence enhancement based detection of PfGDH has a great potential to develop as a method for malaria detection. PMID- 29722522 TI - Reed Leaf-Inspired Graphene Films with Anisotropic Superhydrophobicity. AB - Controlling the wettability of graphene and its derivatives is critical for broader applications. However, the dynamic dewetting performance of graphene is usually overlooked. Currently, superhydrophobic graphene with an anisotropic wettability is rare. Inspired by natural reed leaves, we report an ingenious fabrication process combining photolithography and laser holography technologies to create biomimetic graphene surfaces that demonstrate anisotropic wettability along two directions of grooved hierarchical structures, which are similar to reed leaf veins. Microgrooved structures with a period of 200 MUm were fabricated via photolithography to endow the substrate with an obvious anisotropic wettability. Two-beam laser interference treatments of the graphene oxide (GO) film on the grooved substrate removed most of the hydrophilic oxygen-containing groups on the GO sheets and increased the surface roughness by introducing additional hierarchical micro-nanostructures. The combined effects endowed the resultant graphene films with a unique anisotropic superhydrophobicity similar to that of reed leaves. Superhydrophobic graphene surfaces with anisotropic antiwetting behavior might allow further innovations based on graphene in the fields of bionics and electronics. PMID- 29722523 TI - Framework-Nucleic-Acid-Enabled Biosensor Development. AB - Nucleic acids have been actively exploited to develop various exquisite nanostructures due to their unparalleled programmability. Especially, framework nucleic acids (FNAs) with tailorable functionality and precise addressability hold great promise for biomedical applications. In this review, we summarize recent progress of FNA-enabled biosensing in homogeneous solutions, on heterogeneous surfaces, and inside cells. We describe the strategies to translate the structural order and rigidity of FNAs to interfacial engineering with high controllability, and approaches to realize multiplexing for highly parallel in vitro detection. We also envision the marriage of the currently available FNA tool sets with other emerging technologies to develop a new generation of biosensors for precision diagnosis and bioimaging. PMID- 29722525 TI - One-Pot Isolation of a Desired Human Genome Fragment by Using a Biotinylated pcPNA/S1 Nuclease Combination. AB - Scission of the human genome at predetermined sites and isolation of a particular fragment are of great interest for the analysis of lesion/modification sites, in proteomics, and for gene therapy. However, methods for human genome scission and specific fragment isolation are limited. Here, we report a novel one-pot method for the site-specific scission of DNA by using a biotinylated pcPNA/S1 nuclease combination and isolation of a desired fragment by streptavidin-coated magnetic beads. The proof of concept was initially demonstrated for the clipping of plasmid DNA and isolation of the required fragment. Our method was then successfully applied for the isolation of a fragment from the cell-derived human genome. PMID- 29722524 TI - A Targeted Proteomic Approach for Heat Shock Proteins Reveals DNAJB4 as a Suppressor for Melanoma Metastasis. AB - Heat shock proteins are molecular chaperones that are involved in protein folding. In this study, we developed a targeted proteomic method, relying on LC MS/MS in the parallel-reaction monitoring (PRM) mode, for assessing quantitatively the human heat shock proteome. The method facilitated the coverage of approximately 70% of the human heat shock proteome and displayed much better throughput and sensitivity than the shotgun proteomic approach. We also applied the PRM method for assessing the differential expression of heat shock proteins in three matched primary/metastatic pairs of melanoma cell lines. We were able to quantify ~45 heat shock proteins in each pair of cell lines, and the quantification results revealed that DNAJB4 is down-regulated in the three lines of metastatic melanoma cells relative to the corresponding primary melanoma cells. Interrogation of The Cancer Genome Atlas data showed that lower levels of DNAJB4 expression conferred poorer prognosis in melanoma patients. Moreover, we found that DNAJB4 suppresses the invasion of cultured melanoma cells through diminished expression and activities of matrix metalloproteinases 2 and 9 (MMP-2 and MMP-9). Together, we established, for the first time, a high-throughput targeted proteomics method for profiling quantitatively the human heat shock proteome and discovered DNAJB4 as a suppressor for melanoma metastasis. PMID- 29722526 TI - Hydrogen Peroxide-Releasing Hydrogels for Enhanced Endothelial Cell Activities and Neovascularization. AB - Reactive oxygen species (ROS) have been implicated as a critical modulator for various therapeutic applications such as treatment of vascular disorders, wound healing, and cancer treatment. Specifically, growing evidence has recently demonstrated that transient or low levels of hydrogen peroxide (H2O2) facilitates tissue regeneration and wound repair through acute oxidative stress that can evaluate intracellular ROS levels in cells or tissues. Herein, we report a gelatin-based H2O2-releasing hydrogel formed by dual enzyme-mediated reaction using horseradish peroxidase and glucose oxidase (GO x). The release behavior of H2O2 from the hydrogel matrices can be precisely controlled by varying the GO x concentrations. We demonstrate that H2O2-releasing hydrogels with the optimal condition increase transient upregulation of intracellular ROS levels in the endothelial cells (ECs), enhance proliferative activities of ECs in vitro, and facilitate neovascularization in ovo. We suggest that our H2O2-releasing hydrogels hold great potential as an injectable and dynamic matrix for the treatment of vascular disorders as well as in tissue regenerative medicine. PMID- 29722527 TI - First-Row Transition-Metal-Catalyzed Carbonylative Transformations of Carbon Electrophiles. AB - The main contributions in the field of first-row transition-metal-catalyzed (base metal-catalyzed) carbonylative transformations have been summarized and discussed. The contents have been divided according to the electrophiles applied, followed by the different types of nucleophiles. Their reaction mechanisms and applications have been emphatically discussed. PMID- 29722528 TI - Insights into Laser Ablation Processes of Heterogeneous Samples: Toward Analysis of Through-Silicon-Vias. AB - State-of-the-art three-dimensional very large-scale integration (3D-VLSI) relies, among other factors, on the purity of high-aspect-ratio Cu interconnects such as through-silicon-vias (TSVs). Accurate spatial chemical analysis of electroplated TSV structures has been proven to be challenging due to their large aspect ratios and their multimaterial composition (Cu and Si) with distinct physical properties. Here, we demonstrate that these structures can be accurately analyzed by femtosecond (fs) laser beam ablation techniques in combination with ionization mass spectrometry (LIMS). We specifically report on novel preparation approaches for the postablation analysis of craters formed upon TSV depth profiling. The novel TSV sample preparation is based on deep and material-selective reactive-ion etching of the Si matrix surrounding the Cu interconnects thus facilitating systematic focused-ion-beam (FIB) investigations of the high-aspect-ratio TSV structures upon ablation. The particular structure of the TSV analyte combined with the ?beam > ?Cu-TSV condition allowed for an in-depth investigation of fundamental laser ablation processes, particularly focusing on the redeposition of ablated material at the inner side-walls of the LIMS craters. This phenomenon is of imminent importance for the ultimate quantification in any laser ablation based depth profiling. In addition, we have developed a new method which allows the unambiguous determination of the crossing-point of the Si/Cu||bare Si interface upon Cu-TSV depth profiling which is based on pronounced, depth dependent changes in the mass-spectrometric detection of those Si xy+ species formed upon the LIMS depth erosion. PMID- 29722529 TI - Targeting Transient Receptor Potential Vanilloid 1 (TRPV1) Channel Softly: The Discovery of Passerini Adducts as a Topical Treatment for Inflammatory Skin Disorders. AB - Despite being an old molecule, capsaicin is still a hot topic in the scientific community, and the development of new capsaicinoids is a promising pharmacological approach in the management of skin disorders related to inflammation and pruritus. Here we report the synthesis and the evaluation of capsaicin soft drugs that undergo deactivation by the hydrolyzing activity of skin esterases. The implanting of an ester group in the lipophilic moiety of capsaicinoids by the Passerini multicomponent reaction affords both agonists and antagonists that retain transient receptor potential vanilloid 1 channel (TRPV1) modulating activity and, at the same time, are susceptible to hydrolysis. The most promising antagonist identified shows in vivo anti-nociceptive activity on pruritus and hyperalgesia without producing hyperthermia, thus validating it as novel treatment for dermatological conditions that implicate TRPV1 channel dysfunction. PMID- 29722531 TI - Merging Cation Exchange and Photocatalytic Charge Separation Efficiency in an Anatase/K2Ti4O9 Nanobelt Heterostructure for Metal Ions Fixation. AB - Efficient collection and safe disposal of toxic metals ions from aqueous solutions is critical for applications in environmental remediation. Although extensive efforts have been devoted to the synthesis of functional TiO2 materials, photocatalytic reduction (photoreduction) of aqueous metal ions into solid metals remains a challenge. We designed a TiO2 nanoparticle-decorated layered titanate (K2Ti4O9) material that retained the cation exchange ability of K2Ti4O9 but also possessed the enhanced charge separation efficiency of K2Ti4O9. Combining cation exchange with enhanced charge separation efficiency results in a heterostructured material with remarkably high activity for the photoreduction of metal ions. Initially we demonstrated how the photocatalyst can efficiently reduce aqueous Ni2+ cations, whereas the benchmark TiO2-based P25 catalyst showed little to no activity. The resulting Ni-deposited heterostructure can then be used as a catalyst for visible light-induced photocatalytic H2 evolution in water. PMID- 29722532 TI - Particle Rotation in Colloidal Processing under a Strong Rotating Magnetic Field. AB - Functional ceramics with oriented crystals prepared by colloidal processing in a strong magnetic field are expected to show improved functionality. In this study, the orientation rate of particles with low magnetic susceptibility in a concentrated slurry under a strong rotating magnetic field was experimentally demonstrated using a fast photopolymerization reaction. A slurry of (Sr,Ca)2NaNb5O15 particles dispersed in an ultraviolet curable resin with a catalyst was consolidated using UV irradiation under a strong rotating magnetic field. The degree of particle orientation increased with increasing processing time and became saturated after 20 s. The orientation time was observed experimentally; the period required to achieve particle orientation was proportional to the measured viscosity of the slurry and the inverse of the square of the magnetic flux density. PMID- 29722530 TI - High-Pressure Synthesis, Structures, and Properties of Trivalent A-Site-Ordered Quadruple Perovskites RMn7O12 (R = Sm, Eu, Gd, and Tb). AB - A-site-ordered quadruple perovskites RMn7O12 with R = Sm, Eu, Gd, and Tb were synthesized at high pressure and high temperature (6 GPa and ~1570 K), and their structural, magnetic, and dielectric properties are reported. They crystallize in space group I2/ m at room temperature. All four compounds exhibit a high temperature phase transition to the cubic Im3 structure at ~664 K (Sm), 663 K (Eu), 657 K (Gd), and 630 K (Tb). They all show one magnetic transition at TN1 ~ 82-87 K at zero magnetic field, but additional magnetic transitions below TN2 ~ 12 K were observed in SmMn7O12 and EuMn7O12 at high magnetic fields. Very weak kinklike dielectric anomalies were observed at TN1 in all compounds. We also observed pyroelectric current peaks near 14 K and frequency-dependent sharp steps in dielectric constant (near 18-35 K)-these anomalies are probably caused by dielectric relaxation, and they are not related to any ferroelectric transitions. TbMn7O12 shows signs of nonstoichiometry expressed as (Tb1- xMn x)Mn7O12, and these samples exhibit negative magnetization or magnetization reversal effects of an extrinsic origin on zero-field-cooled curves in intermediate temperature ranges. The crystal structures of SmMn7O12 and EuMn7O12 were refined from neutron powder diffraction data at 100 K, and the crystal structures of GdMn7O12 and (Tb0.88Mn0.12)Mn7O12 were studied by synchrotron X-ray powder diffraction at 295 K. PMID- 29722533 TI - Advancing Predictive Hepatotoxicity at the Intersection of Experimental, in Silico, and Artificial Intelligence Technologies. AB - Adverse drug reactions, particularly those that result in drug-induced liver injury (DILI), are a major cause of drug failure in clinical trials and drug withdrawals. Hepatotoxicity-mediated drug attrition occurs despite substantial investments of time and money in developing cellular assays, animal models, and computational models to predict its occurrence in humans. Underperformance in predicting hepatotoxicity associated with drugs and drug candidates has been attributed to existing gaps in our understanding of the mechanisms involved in driving hepatic injury after these compounds perfuse and are metabolized by the liver. Herein we assess in vitro, in vivo (animal), and in silico strategies used to develop predictive DILI models. We address the effectiveness of several two- and three-dimensional in vitro cellular methods that are frequently employed in hepatotoxicity screens and how they can be used to predict DILI in humans. We also explore how humanized animal models can recapitulate human drug metabolic profiles and associated liver injury. Finally, we highlight the maturation of computational methods for predicting hepatotoxicity, the untapped potential of artificial intelligence for improving in silico DILI screens, and how knowledge acquired from these predictions can shape the refinement of experimental methods. PMID- 29722535 TI - In Situ Preparation of Stabilized Iron Sulfide Nanoparticle-Impregnated Alginate Composite for Selenite Remediation. AB - Iron sulfide (FeS) nanoparticles have been applied for selenite (Se(IV)) remediation in recent decades. However, the easy aggregation and oxidization of FeS hamper their reactivity. In this study, in situ immobilization technology was applied to prepare FeS nanoparticle-impregnated alginate composite (FeS-SA) for Se(IV) remediation. FeS-SA removed 100% of the Se(IV) (0.13 mM), whereas pure nonstabilized FeS and sodium alginate (SA) beads eliminated only 27 and 20% of the Se(IV), respectively. The removal efficiency increased to 73% when pure stabilized FeS was used. Therefore, FeS-SA showed superior removal efficiency that was comparable with the joint effect of pure stabilized FeS and SA beads due to the homogeneous distribution of FeS in SA matrix. Furthermore, minor differences were established in the oxidation retardation effect of FeS exerted by SA beads under anoxic and oxic conditions. The biogenic regenerated FeS-SA still showed 40% removal efficiency for Se(IV) after five cycles due to the Fe leaching. XPS technique combined with the reference compounds and electron balance revealed that FeSe and metal selenium were the main selenium species after treatment. This in situ preparation of stabilized FeS-SA exhibited an excellent application prospect in the remediation of Se(IV). PMID- 29722536 TI - Chemical Cross-Linking of Anatase Nanoparticle Thin Films for Enhanced Mechanical Properties. AB - Titania nanoparticle-based thin films are highly attractive for a vast range of commercial applications. Although their application on polymer-based substrates is particularly appealing, the requirement of low process temperatures results in low mechanical stability. Highly crystalline anatase nanoparticles were used as the building blocks for coatings through a two-stage process. The main benefits of this method, over the more common sol-gel ones, are the relatively low temperature required for the production of metal oxide coatings, allowing the use of polymer-based substrates, and the defined crystallinity of the resulting thin films. Although in several cases moderate temperatures can be utilized for drying the films, the mechanical stability of the respective coatings remains a critical issue. In this contribution, we present a strategy to achieve network formation between TiO2 nanoparticles in a preformed thin film on the basis of the cross linking of the functionalized nanoparticles. In the first stage, the nanoparticles were functionalized by dicarboxylic acids, concurrently leading to a stable colloidal dispersion that could be utilized for dip-coating to obtain TiO2 thin films with high homogeneity and optical transparence. During the second stage, the films were immersed in a solution of a diamine as the linker molecule, to achieve cross-linking between the nanoparticles within the film. It is demonstrated that indeed covalent bonding was realized and functional coatings with significantly enhanced mechanical properties were obtained by our strategy. PMID- 29722534 TI - Role of Seroalbumin in the Cytotoxicity of cis-Dichloro Pt(II) Complexes with (N^N)-Donor Ligands Bearing Functionalized Tails. AB - Given the potent anticancer properties of cis-diamminedichloroplatinum(II) and knowing its mode of action, we synthesized four new cis-[PtCl2(N^N)] organoplatinum complexes, two with N-substituted pbi ligands (pbiR = 1-R-2-(2 pyridyl)benzimidazole) (namely, 1 and 2) and two more with 4,4'-disubstituted bpy ligands (bpy = 2,2'-bipyridine) (namely, 3 and 4). We explored their cytotoxicity and ability to bind to deoxyguanosine monophosphate (dGMP), DNA, and albumin models. By 1H NMR and UV-vis spectroscopies, circular dichroism, agarose gel electrophoresis, differential scanning calorimetry measurements, and density functional theory calculations, we verified that only 3 can form aquacomplex species after dimethyl sulfoxide solvation; surprisingly, 1, 2, and 3 can bind covalently to DNA, whereas 4 can form a noncovalent complex. Interestingly, only complexes 1 and 4 exhibit good cytotoxicity against human ovarian carcinoma (HeLa) cell line, whereas 2 and 3 are inactive. Although lung carcinoma (A549) cells are more resistant to the four platinum complexes than HeLa cells, when the protein concentration in the extracellular media is lower, the cytotoxicity becomes substantially enhanced. By native electrophoresis of bovine seroalbumin (BSA) and inductively coupled plasma mass spectrometry uptake studies we bear out, on one hand, that 2 and 3 can interact strongly with BSA and its cellular uptake is negligible and, on the other hand, that 1 and 4 can interact with BSA only weakly, its cellular uptake being higher by several orders. These results point up the important role of the protein binding features on their biological activity and cellular uptake of cis-"PtCl2" derivatives. Our results are valuable in the future rational design of new platinum complexes with improved biological properties, as they expose the importance not only of their DNA binding abilities but also of additional factors such as protein binding. PMID- 29722537 TI - Improving Photocatalytic Water Treatment through Nanocrystal Engineering: Mesoporous Nanosheet-Assembled 3D BiOCl Hierarchical Nanostructures That Induce Unprecedented Large Vacancies. AB - Vacancy control can significantly enhance the performance of photocatalytic semiconductors for water purification. However, little is known about the mechanisms and approaches that could generate stable large vacancies. Here, we report a new mechanism to induce vacancy formation on nanocrystals for enhanced photocatalytic activity: the introduction of mesopores. We synthesized two nanosheet-assembled hierarchical 3D BiOCl mesoporous nanostructures with similar morphology and exposed facets but different nanosheet thickness. Positron annihilation analysis detected unprecedentedly large VBi''' VO** VBi''' VO** VBi''' vacancy associates (as well as VBi''' VO** VBi''') on BiOCl assembled from 3-6 nm nanosheets but only VBi''' VO** VBi''' vacancy associates on BiOCl assembled from thicker (10-20 nm) nanosheets. Comparison of vacancy properties with 2D ultrathin 2.7 nm nanosheets (with VBi''' VO** VBi''' and VBi''') indicates that nanosheet thinness alone cannot explain the formation of such large atom vacancies. On the basis of density functional theory computations of formation energy of isolated Bi vacancy, we show that mesopores facilitate the formation of large vacancies to counterbalance thermodynamic instability caused by incompletely coordinated Bi and O atoms along the mesopore perimeters. We corroborate that the extraordinarily large VBi''' VO** VBi''' VO** VBi''' vacancy associates facilitate photoexcitation of electrons and prevent the recombination of electron-hole pairs, which significantly enhances photocatalytic activity. This is demonstrated by the rapid mineralization of bisphenol A (10-5 M) with low photocatalyst loading (1 g L-1), as well as enhanced bacterial disinfection. Improved electron-hole separation is also corroborated by enhanced photocatalytic reduction of nitrate. PMID- 29722538 TI - Phosphorus Stress-Induced Changes in Plant Root Exudation Could Potentially Facilitate Uranium Mobilization from Stable Mineral Forms. AB - Apparent deficiency of soil mineral nutrients often triggers specific physio morphological changes in plants, and some of these changes could also inadvertently increase the ability of plants to mobilize radionuclides from stable mineral forms. This work, through a series of sand-culture, hydroponics, and batch-equilibration experiments, investigated the differential ability of root exudates of Andropogon virginicus grown under conditions with variable phosphorus (P) availability (KH2PO4, FePO4, Ca3(PO4)2, and no P) to solubilize uranium (U) from the uranyl phosphate mineral Chernikovite. The mineral form of P, and hence the bioavailability of P, affected the overall composition of the root exudates. The lower bioavailable forms of P (FePO4 and Ca3(PO4)2), but not the complete absence of P, resulted in a higher abundance of root metabolites with chelating capacity at 72 hrs after treatment application. In treatments with lower P-bioavailability, the physiological amino acid concentration inside of the roots increased, whereas the concentration of organic acids in the roots decreased due to the active exudation. In batch dissolution experiments, the organic acids, but not amino acids, increase the dissolution U from Chernikovite. The root exudate matrix of plants exposed to low available forms of P induced a >60% increase in U dissolution from Chernikovite due to 5-16 times greater abundance of organic acids in these treatments. However, this was ca. 70% of the theoretical dissolution achievable by this exudate matrix. These results highlight the potential of using active management of soil P as an effective tool to alter the plant-mediated mobilization of U in contaminated soil. PMID- 29722540 TI - Impact of Physicochemical Properties on Dose and Hepatotoxicity of Oral Drugs. AB - A database containing maximum daily doses of 1841 marketed oral drugs was used to examine the influence of physicochemical properties on dose and hepatotoxicity (drug induced liver injury, DILI). Drugs in the highest ~20% dose range had significantly reduced mean lipophilicity and molecular weight, increased fractional surface area, increased % of acids, and decreased % of bases versus drugs in the lower ~60% dose range. Drugs in the ~20-40% dose range had intermediate mean properties, similar to the mean values for the full drug set. Drugs that are both large and highly lipophilic almost invariably do not have doses in the upper ~20% range. The results show that oral druglike physicochemical properties are different according to these dose ranges, and this is consistent with maintenance of acceptable safety profiles as efficacious exposure increases. Verified DILI annotations from a compilation of >1000 approved drugs (Chen, M.; et al. Drug Discov. Today, 2016, 21, 648 ) were used. The drugs classified as "No DILI" ( n = 163) had significantly lower dose and lipophilicity, and higher Fsp3 (fraction of carbon atoms that are sp3 hybridized) versus the "Most DILI" ( n = 163) drugs. The percentages of acids were reduced and bases increased in the "No DILI" versus the "Most DILI" groups. Drugs classified as "Less DILI" or "Ambiguous DILI" had intermediate mean values of dose, lipophilicity, Fsp3, and % acids and bases. The impact of lipophilicity and Fsp3 on DILI increases in the upper 20% versus the lower 80% dose range, and a simple decision tree model predicted "No DILI" versus "Most DILI" outcomes with 82% accuracy. The model correctly classified 19 of 22 drugs (86%) that failed in development due to human hepatotoxicity. Because many oral drugs lacking DILI annotations are predicted to be "Most DILI", the model is best used preclinically in conjunction with experimental DILI mitigation. PMID- 29722539 TI - Enhanced S-Adenosylmethionine Production by Increasing ATP Levels in Baker's Yeast ( Saccharomyces cerevisiae). AB - In the biosynthesis of S-adenosylmethionine (SAM) in baker's yeast ( Saccharomyces cerevisiae), ATP functions as both a precursor and a driving force. However, few published reports have dealt with the control of ATP concentration using genetic design. In this study we have adopted a new ATP regulation strategy in yeast for enhancing SAM biosynthesis, including altering NADH availability and regulating the oxygen supply. Different ATP regulation systems were designed based on the introduction of water-forming NADH oxidase, Vitreoscilla hemoglobin, and phosphite dehydrogenase in combination with overexpression of the gene SAM2. Via application of this strategy, after 28 h cultivation, the SAM titer in the yeast strain ABYSM-2 reached a maximum level close to 55 mg/L, an increase of 67% compared to the control strain. The results show that the ATP regulation strategy is a valuable tool for SAM production and might further enhance the synthesis of other ATP-driven metabolites in yeast. PMID- 29722542 TI - Repolarization of Tumor-Associated Macrophages in a Genetically Engineered Nonsmall Cell Lung Cancer Model by Intraperitoneal Administration of Hyaluronic Acid-Based Nanoparticles Encapsulating MicroRNA-125b. AB - Tumor-associated macrophages (TAMs) acquire a pro-tumor (M2) phenotype, which promotes tumor growth, angiogenesis, and metastasis. Certain microRNAs (miRs), such as miR-125b, can reprogram TAMs into an antitumor/pro-inflammatory (M1) phenotype. Using CD44 targeting hyaluronic acid-poly(ethylenimine) (HA-PEI)-based nanoparticles encapsulating miR-125b, we have herein shown macrophage-specific delivery and transfection upon intraperitoneal (i.p.) administration. We have exploited the inherent ability of peritoneal macrophages to migrate toward the inflammation/injury and demonstrated that following intraperitoneal administration of HA-PEI nanoparticles, there is an accumulation of HA-PEI nanoparticles in the macrophage-ablated lung tissues of both naive and KRAS/p53 double mutant genetically engineered (KP-GEM) nonsmall cell lung cancer (NSCLC) mouse model. Additionally, upon transfection with miR-125b, we observed a >6-fold increase in the M1 to M2 macrophage ratio and 300-fold increase in the iNOS (M1 marker)/Arg-1 (M2 marker) ratio in TAMs as compared to the untreated control group. The results of these studies show that i.p. administered macrophage specific HA-PEI nanoparticles can successfully transfect TAMs in lung tissues of both naive mice and a KP-GEM NSCLC mouse model. Successful TAM repolarization toward the M1 phenotype has significant implication in anticancer immunotherapy. PMID- 29722541 TI - Overexpression of Malonyl-CoA: ACP Transacylase in Schizochytrium sp. to Improve Polyunsaturated Fatty Acid Production. AB - Polyunsaturated fatty acids (PUFAs) have been widely applied in the food and medical industry. In this study, malonyl-CoA: ACP transacylase (MAT) was overexpressed through homologous recombination to improve PUFA production in Schizochytrium. The results showed that the lipid and PUFA concentration were increased by 10.1 and 24.5% with MAT overexpression, respectively. Metabolomics analysis revealed that the intracellular tricarboxylic acid cycle was weakened and glucose absorption was accelerated in the engineered strain. In the mevalonate pathway, intracellular carotene content was decreased, and the carbon flux was then redirected toward PUFA synthesis. Furthermore, a glucose fed-batch fermentation was finally performed with the engineered Schizochytrium. The total lipid yield was further increased to 110.5 g/L, 39.6% higher than the wild strain. Docosahexaenoic acid and eicosapentaenoic acid yield were enhanced to 47.39 g/L and 1.65 g/L with an increase of 81.5 and 172.5%, respectively. This study provided an effective metabolic engineering strategy for industrial PUFA production. PMID- 29722543 TI - Effective dose reduction using collimation function in digital panoramic radiography and possible clinical implications in dentistry. AB - OBJECTIVES:: The primary aim was to evaluate the effective dose for a full size panoramic image and nine different panoramic protocols using collimation. The secondary aim was to estimate possible reduction of effective dose in clinical situations. METHODS: Effective dose, according to International Commission on Radiological Protection 2007 was determined for a full size panoramic image and nine different panoramic protocols applying collimation on an anthropomorphic Rando phantom, using metal-oxide semiconductor field-effect transistor dosemeters. The collimation protocols were chosen based on common diagnostic questions. 10 exposures were made for each protocol using a Planmeca ProMax(r) 2D (Helsinki, Finland). The mean effective doses were calculated according to clinical default exposure settings and compared for all protocols. A retrospective analysis of 252 referrals to a specialist clinic in dentomaxillofacial radiology assessed usability and dose reduction applying nine different collimation protocols, based on possible collimation of panoramic images. Dose reduction was calculated applying collimation feature in comparison to constant use of full size panoramic imaging. Referrals were categorized according to indication for radiographic examination. RESULTS:: Effective dose of a full size panoramic radiograph was 17.6 uSv at 8 mA and 66 kV. The dose reduction for the collimated images compared to a full size panoramic radiograph ranged from 4.5 to 86.9%. Potential total dose reduction in the studied sample was 35% if collimation feature had been applied. In four out of five of the referrals, collimation was possible and in 61% of the referrals the indication for radiographic examination was restricted to the dental alveolar region, reducing the dose by 40.3% compared with a full size panoramic image. CONCLUSIONS:: Since the effective dose may be reduced without losing diagnostic information in the area of interest, collimation feature of panoramic imaging should be routinely applied when the diagnostic task allows. PMID- 29722545 TI - Translational Research and Innovation in Human and Health Science. PMID- 29722544 TI - Histone acetylation maps in aged mice developmentally exposed to lead: epigenetic drift and Alzheimer-related genes. AB - AIM: Early life exposure to lead (Pb) has been shown to increase late life biomarkers involved in Alzheimer's disease (AD) pathology. Here, we tested the hypothesis that latent over expression of AD-related genes may be regulated through histone activation pathways. METHODS: Chromatin immunoprecipitation sequencing was used to map the histone activation mark (H3K9Ac) to the mouse genome in developmentally Pb exposed mice on postnatal days 20, 270 and 700. RESULTS: Exposure to Pb resulted in a global downregulation of H3K9Ac across the lifespan; except in genes associated with the Alzheimer pathway. DISCUSSION: Early life exposure to Pb results in an epigenetic drift in H3K9Ac consistent with latent global gene repression. Alzheimer-related genes do not follow this trend. PMID- 29722547 TI - Adherence and economic impact of paliperidone palmitate versus oral atypical antipsychotics in a Medicare population. AB - AIM: To compare adherence, healthcare utilization and costs among real world, Medicare-eligible patients with schizophrenia using long-acting injectable paliperidone palmitate (PP) versus oral atypical antipsychotics. Patients & methods: Historical cohort study used Medicare Advantage claims data. Inverse probability of treatment weighting was applied to adjust for baseline differences. 12-month adherence, healthcare utilization and costs were compared. RESULTS: Patients using PP were more adherent (proportion of days covered >=0.8; 48.1 vs 32.6%; p < 0.001), had lower odds of hospitalization (odds ratio [OR]: 0.81; 95% CI: 0.68-0.96) and lower medical costs ($11,095; 95% CI: $10,374-11,867 vs $15,551; 95% CI: $14,584-16,583), but higher pharmacy costs ($14,787; 95% CI: $14,117-15,488 vs $5781; 95% CI: $5530-6043). CONCLUSION: Compared with patients using oral atypical antipsychotics, PP had lower hospitalizations and medical costs with greater medication adherence accompanied by higher pharmacy costs. PMID- 29722546 TI - EUPS-argues that lung cancer screening should be implemented in 18 months. AB - The European Position Statement (EUPS) expert group comprised of individuals who have been actively involved in the planning and execution of all the low dose CT (LDCT) randomised controlled European screening trials. They have argued that as lung cancer screening with LDCT saves lives, planning for implementation needs to be started by the national health organisations throughout Europe. The EUPS examined the current evidence which supports the planning for the implementation of lung cancer screening, as well as areas which require further work. One of the major areas the EUPS focused on was the management of prevalent lung nodules in CT-screening programmes, lung nodules at incident screening (newly detected) and CT-detected lung nodules in clinical practice should be managed with different protocols, due to different pre-test lung cancer probability. The EUPS provides nine recommendations and a "Call to Action" for implementation, which is naturally dependent on the outcome of the NELSON trial. Clearly, the issue is how Europe can take this forward as part of the political agenda of individual countries, as well as that of the EU Commission. An EU policy document has been developed, which focuses on the key steps in the implementation of cost effective lung cancer screening in Europe. PMID- 29722548 TI - In vitro P-glycoprotein activity does not completely explain in vivo efficacy of novel centrally effective oxime acetylcholinesterase reactivators. AB - Novel-substituted phenoxyalkyl pyridinium oxime acetylcholinesterase (AChE) reactivators (US patent 9,227,937) that showed convincing evidence of penetration into the brains of intact rats were developed by our laboratories. The oximes separated into three groups based on their levels of brain AChE reactivation following exposure of rats to the sarin surrogate nitrophenyl isopropyl methylphosphonate (NIMP). P-glycoprotein (P-gp) is a major blood-brain barrier (BBB) transporter and requires ATP for efflux. To determine if P-gp affinity screening could be used to reduce animal use, we measured in vitro oxime stimulated ATPase activity to see if the in vivo reactivation efficacies related to the oximes' functions as P-gp substrates. High efficacy oximes were expected to be poor P-gp substrates, thus remaining in the brain longer. The high efficacy oximes (24-35% brain AChE reactivation) were worse P-gp substrates than the low efficacy oximes (0-7% brain AChE reactivation). However, the oxime group with medium in vivo reactivation of 10-17% were even worse P-gp substrates than the high efficacy group so their reactivation ability was not reflected by P-gp export. The results suggest that in vitro P-gp ATPase activity can remove the low efficacy oximes from in vivo testing, but is not sufficient to differentiate between the top two tiers. PMID- 29722550 TI - Antioxidant responses and DNA damage in primary hepatocytes of Van fish (Alburnus tarichi, Guldenstadt 1814) exposed to nonylphenol or octylphenol. AB - Alkylphenols, a nonionic surface-active agent group, such as nonylphenol (NP) and octylphenol (OP) are important endocrine-disrupting chemicals (EDC). In this study, the dose- and time-dependent effects of NP and OP were investigated in the primary hepatocyte culture of Van Fish. In this study, samples were taken at different times and biochemical parameters were studied separately. The effects of the chemicals used on SOD, CAT, GSH-Px, MDA, and 8-OHdG were investigated in hepatocyte culture. The antioxidants SOD and CAT were observed to increase in all groups in the primary hepatocyte cultures at the 24th hour after NP and OP administration, whereas the GSH-Px level was observed to increase with OP at the 24th hour and with NP at the 48th hour. The MDA level was observed to reach its highest value for both chemicals in the 24th hour, and the 8-OHdG level was observed to increase toward the end of the follow-up time, compared to the control group (p < 0.05). In conclusion, different doses of NP and OP were found to induce an increase in the levels of antioxidants and the MDA level in Van Fish primary hepatocyte culture. DNA damage, on the other hand, may be considered to appear after longer-term exposure to NP and OP. PMID- 29722551 TI - Placentation-related processes in a human first-trimester extravillous trophoblast cell line (HTR-8/SVneo cells) are affected by several xenobiotics. AB - Our aim was to investigate the effect of some xenobiotics on placentation-related processes in an extravillous trophoblastic cell line (HTR-8/SVneo cells). Amphetamine, MDMA, theophylline, and fluoxetine, but not nicotine, cocaine, and caffeine, had a negative effect on cell proliferation rates, culture growth, viability, or migratory capacity. These compounds have a detrimental effect in placentation-related processes of HTR-8/SVneo cells. PMID- 29722549 TI - Effects of Equol Supplement on Bone and Cardiovascular Parameters in Middle-Aged Japanese Women: A Prospective Observational Study. AB - OBJECTIVE: To examine changes in the bone and cardiovascular parameters and tolerability in middle-aged Japanese women taking equol supplement for a year. DESIGN: This was a prospective observational study. SUBJECTS AND SETTING: Participants were 74 women receiving outpatient care at Hamasite Medical Clinic, Minato-ku, Tokyo, from 2013 to 2015. INTERVENTIONS: Participants received per oral equol-containing supplement, 10 mg/day. OUTCOME MEASURES: The primary outcome measures were percent changes in bone and cardiovascular parameters after 1 year supplementation with equol. The secondary measures included factors affecting the parameter changes and adverse effects associated with equol use for a year. RESULTS: Reduction in arterial stiffness was observed after 12 months of equol supplement (1402.3 cm/s vs.1367.3 cm/s, p < 0.001). Significant reductions in respective parameters were observed in women with moderate and high risk for arteriosclerosis (median [95% confidence interval]: -3.2% [-5.79 to -0.74]; 12.65% [-18.52 to -4.28]; respectively); hypertriglyceridemia -45.53% [-70.24 to 5.58]; bone resorption risk (-15.15% [-23.71 to 1.56]; and bone fracture risk 26.68% [-76.43 to -5.99]. All 15 women with high baseline parathyroid hormone levels had achieved a median of 50% [-54.11 to -31.69] reduction from their baseline values. These associations were further confirmed in the results of multiple linear regression analysis. There were no reported adverse events or abnormal findings in the blood chemistry, Pap smear, mammography, and transvaginal ultrasound during periodic follow-ups. CONCLUSION: One year equol supplement was tolerable and induced improvement of certain bone and cardiovascular parameters, especially in higher risk groups. Further controlled studies are needed to explore long-term equol use for wellbeing of middle-aged women. PMID- 29722553 TI - Protective role of zinc against the neurotoxicity induced by exposure to cadmium during gestation and lactation periods on hippocampal volume of pups tested in early adulthood. AB - The present study was conducted to assess the possible effect of cadmium (Cd) throughout gestation and lactation on the volume of the subregion of the hippocampus as well as the potential protective role of zinc (Zn) against Cd neurotoxicity. For this purpose, female rats received either tap water, Cd, Zn or Cd + Zn in their drinking water during gestation and lactation. At postnatal day 35 (PND35), the male pups were sacrificed, and their brains were taken for histologic, chemical, and biochemical analysis. Hippocampal volume was measured in histologic brain slices using Cavalieri's principle. Zn depletion was observed in the brains of pups issued from mothers exposed to Cd. Biochemical analysis further revealed that Cd exposure significantly increases the superoxide dismutase (SOD) activity, as well as the metallothionein (MT) level. During histologic investigation, our results showed that gestational and lactational exposure to Cd significantly altered and decreased the volume of CA1, CA3 pyramidal cell layer and the dentate gyrus. However, there were no marked differences shown in CA2 subfield. Compared to Cd group, co-treatment with Cd and Zn provided correction of the changes induced by the Cd exposure. These results highlight the protective role of Zn against Cd-induced alteration in the hippocampus which is a crucial structure implicated in learning and memory processes. PMID- 29722554 TI - Effective suicide prevention: Where is the discussion on alcohol? PMID- 29722555 TI - Exploring health services accessibility by indigenous women in Asia and identifying actions to improve it: a scoping review. AB - OBJECTIVES: The aim of this scoping review was to uncover and summarize what is known in the literature about the experiences of Indigenous women in Asia regarding access to health services. DESIGN: The study was informed by the scoping review methodology proposed by Arksey and O'Malley [2005. "Scoping Studies: Towards a Methodological Framework." International Journal of Social Research Methodology 8 (1): 19-32. doi: 10.1080/1364557032000119616 ]. A comprehensive search of the databases for peer-reviewed studies and grey literature was conducted between January 2000 and December 2016. The data of selected papers and abstracts were analysed by three independent researchers through a protocol of data charting, descriptive numerical summary, and thematic analysis. RESULTS: Sixteen articles and two abstracts met the inclusion criteria for this scoping review. These 18 peer-reviewed documents consisted of eight qualitative studies, seven quantitative studies, and three mixed-method studies, which included the peer-reviewed poster and oral presentation abstracts from international conferences. The findings were sorted and grouped under the following themes: health care access for Indigenous women in Asia, facilitators to accessing healthcare services, barriers to accessing healthcare services, and cultural contexts impacting health and access. CONCLUSION: There is limited information about the experiences, facilitators, barriers, and cultural contexts faced by Indigenous women in Asia related to health services accessibility, and even less information related to improving health services accessibility and health outcomes. This scoping review in particular highlights the dearth of literature relating to Indigenous women's postpartum health and access to postnatal supports and services. Generally, it indicates that Indigenous women in Asia are more vulnerable to poor health in comparison to non-Indigenous women, and continue to face challenges and barriers in accessing quality and equitable health services. The barriers identified in this review are useful in explaining why inequities in health and access to health care for Indigenous women living in Asia continue to exist. Recommendations for future research directions are described. PMID- 29722556 TI - Long term effect of sulfur mustard exposure on hematologic and respiratory status, a case control study. AB - The long term effect of sulfur mustard (SM) exposure including, total and differential white blood cells (WBC), hematological parameters, pulmonary function tests (PFT), and respiratory symptoms (RS) in chemical war victims (CWV) exposed to SM 27-30 years ago were examined. Forty-six CWV and 42 control subjects with similar age from the general population were studied. Hematologic parameters, RS including; chest wheezing, night cough, night wheezing and cough, wheezing due to exercise (by Persian questionnaire), and PFT were assessed in all subjects. Total WBC count (p < 0.001), hematocrit, and mean corpuscular volume (MCV) were significantly higher (p < 0.05 and 0.001, respectively) but mean corpuscular hemoglobin concentration (MCHC) and the percent of monocyte were lower in veterans than control group (p < 0.001 and 0.01, respectively). All PFT values were also lower in CWV compared to control subjects (p < 0.001 for all cases). Maximal mid expiratory flow (MMEF) and maximal expiratory flow at 75% of forced vital capacity (MEF75) were the most affected PFT values in CWV and were 50% or lower of predicted values. All CWV reported respiratory symptoms, including; chest wheezing, night cough, night wheezing and cough, and wheezing due to exercise were higher in the veterans compared to control group (p < 0.001 for all cases). Increased total WBC count and RS but reduction in monocyte, MCHC, and PFT values were shown in CWV 27-30 years after exposure to SM. These results indicated profound hematologic (mainly WBC) and pulmonary effect of SM long time after exposure. PMID- 29722557 TI - Augmentation of diethylnitrosamine-induced early stages of rat hepatocarcinogenesis by 1,2-dimethylhydrazine. AB - Diethylnitrosamine (DEN) and 1,2-dimethylhydrazine (DMH) are classical carcinogens used in experimental rodent carcinogenesis. However, the interaction effects of these carcinogens on biochemical and molecular changes during carcinogenesis have not been investigated. Therefore, the effect of DEN and DMH co-administration on preneoplastic lesion formation and its molecular mechanism in rats were determined. Triple intraperitoneal administrations of DEN were made before, during or after double subcutaneous injections of DMH. At week 8 of the experiment, the preneoplastic hepatic glutathione-S-transferase placental form (GST-P) positive foci and colonic aberrant crypt foci (ACF) were analyzed. The combined treatment of these carcinogens increased toxicity to rats. Administration of DMH alone did not induce hepatic GST-P positive foci, while co treatment with DMH enhanced hepatic GST-P positive foci formation. However, DEN did not influence the size or number of colonic ACF. The treatment with DMH alone induced CYP2E1 and P450 reductase, demonstrating that DMH enhanced DEN metabolism in DEN- and DMH-treated rats. These findings were related to increases in hepatic O6-methylguanine DNA adducts and hepatotoxicity, which are associated with the induction of cell proliferation and liver cancer development. DEN-induced early stages of rat hepatocarcinogenesis were synergistically promoted by DMH via metabolic enzyme induction leading to enhanced DNA mutation and hepatocarcinogenicity. PMID- 29722558 TI - Is the fibroblast growth factor signaling pathway a victim of receptor tyrosine kinase inhibition in pulmonary parenchymal and vascular remodeling? AB - Idiopathic pulmonary arterial hypertension (IPAH), pulmonary hypertension (PH) due to lung disease and/or hypoxia and idiopathic pulmonary fibrosis (IPF) are increasingly recognized as important contributors to mortality and morbidity worldwide. Among others, the current treatment paradigm considers broad inhibition of receptor tyrosine kinases, a strategy that likely leads to collateral inhibition of signaling pathways that are critical for lung repair and regeneration. Fibroblast growth factor 7 (FGF7) and FGF10 signaling in the lung through FGF receptor 2 (FGFR2) are involved in epithelial cell protection and renewal, and mutations in their corresponding genes in humans are linked to increased susceptibility to lung pathologies, such as chronic obstructive pulmonary disease and bronchopulmonary dysplasia. In this report, we present data demonstrating significant upregulation of FGF7, FGF10, and FGFR2 in IPF and IPAH lungs compared with donor lungs. These ligands and their cognate receptor converged on the remodeled parenchyma and vasculature of IPF and IPAH lungs. Interestingly, the expression levels of FGFR1, which has been previously shown to play a pathological role in PH development, were not significantly changed in either disease state. Intriguingly, the expression levels of FGF7, FGF10, and FGFR2 were lower in IPF lung regions undergoing active remodeling, and inversely correlated with IPAH severity, indicating that increased expression might reflect lung repair rather than lung pathology, and warranting further research on the precise role of FGF signaling in pulmonary parenchymal and vascular remodeling. PMID- 29722559 TI - miR-142-3p is associated with aberrant WNT signaling during airway remodeling in asthma. AB - Asthma is characterized by a chronic inflammation and remodeling of the airways. Although inflammation can be controlled, therapeutic options to revert remodeling do not exist. Thus, there is a large and unmet need to understand the underlying molecular mechanisms to develop novel therapies. We previously identified a pivotal role for miR-142-3p in regulating airway smooth muscle (ASM) precursor cell proliferation during lung development by fine-tuning the Wingless/Integrase I (WNT) signaling. Thus, we here aimed to investigate the relevance of this interaction in asthma. We performed quantitative RT-PCR and immune staining in a murine model for ovalbumin-induced allergic airway inflammation and in bronchial biopsies from patients with asthma and isolated primary fibroblasts thereof. miR 142-3p was increased in hyperproliferative regions of lung in murine and human asthma, whereas this microRNA (miRNA) was excluded from regions with differentiated ASM cells. Increases in miR-142-3p were associated with a decrease of its known target Adenomatous polyposis coli. Furthermore, we observed a differential expression of miR-142-3p in bronchial biopsies from patients with early or late onset severe asthma, which coincided with a differential WNT signature. Our data suggest that miR-142-3p is involved in regulating the balance between proliferation and differentiation of ASM cells in asthma, possibly via controlling WNT signaling. Thus, this miRNA might be an interesting target to prevent ASM hyperproliferation in asthma. PMID- 29722561 TI - The role of noncoding RNAs in regulating epithelial responses in COPD. AB - Chronic obstructive pulmonary disease (COPD), one of the leading causes of death in the world, is a chronic inflammatory disease of the airways usually caused by long-term exposure to inhaled irritants. Airway epithelial cells (AECs) play a key role in initializing COPD and driving the exacerbation of this disease through the release of various cytokines. This AEC-derived cytokine response is tightly regulated possibly through the regulatory effects of noncoding RNAs (ncRNAs). Although the importance of ncRNAs in pulmonary diseases has been increasingly realized, little is known about the role of ncRNA in the regulation of inflammatory responses in COPD. This review outlines the features of AEC derived cytokine responses in COPD and how ncRNAs regulate these inflammatory responses. PMID- 29722563 TI - Damage-associated molecular patterns in resuscitated hemorrhagic shock are mitigated by peritoneal fluid administration. AB - Conventional resuscitation (CR) of hemorrhagic shock (HS), a significant cause of trauma mortality, is intravenous blood and fluids. CR restores central hemodynamics, but vital organ flow can drop, causing hypoperfusion, hypoxia, damage-associated molecular patterns (DAMPs), and remote organ dysfunction (i.e., lung). CR plus direct peritoneal resuscitation (DPR) prevents intestinal and hepatic hypoperfusion. We hypothesized that DPR prevents lung injury in HS/CR by altering DAMPs. Anesthetized male Sprague-Dawley rats were randomized to groups ( n = 8/group) in one of two sets: 1) sham (no HS, CR, or DPR), 2) HS/CR (HS = 40% mean arterial pressure (MAP) for 60 min, CR = shed blood + 2 volumes normal saline), or 3) HS/CR + DPR. The first set underwent whole lung blood flow by colorimetric microspheres. The second set underwent tissue collection for Luminex, ELISAs, and histopathology. Lipopolysaccharide (LPS) and DAMPs were measured in serum and/or lung, including cytokines, hyaluronic acid (HA), high mobility group box 1 (HMGB1), Toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 protein (MYD88), and TIR-domain-containing adapter-inducing interferon-beta (TRIF). Statistics were by ANOVA and Tukey Kramer test with a priori P < 0.05. HS/CR increased serum LPS, HA, HMGB1, and some cytokines [interleukin (IL)-1alpha, IL-1beta, IL-6, and interferon-gamma]. Lung TLR4 and MYD88 were increased but not TRIF compared with Shams. HS/CR + DPR decreased LPS, HA, cytokines, HMGB1, TLR4, and MYD88 levels but did not alter TRIF compared with HS/CR. The data suggest that gut-derived DAMPs can be modulated by adjunctive DPR to prevent activation of lung TLR-4-mediated processes. Also, DPR improved lung blood flow and reduced lung tissue injury. Adjunctive DPR in HS/CR potentially improves morbidity and mortality by downregulating the systemic DAMP response. PMID- 29722560 TI - Intrauterine growth restriction decreases NF-kappaB signaling in fetal pulmonary artery endothelial cells of fetal sheep. AB - Intrauterine growth restriction (IUGR) in premature newborns increases the risk for bronchopulmonary dysplasia, a chronic lung disease characterized by disrupted pulmonary angiogenesis and alveolarization. We previously showed that experimental IUGR impairs angiogenesis; however, mechanisms that impair pulmonary artery endothelial cell (PAEC) function are uncertain. The NF-kappaB pathway promotes vascular growth in the developing mouse lung, and we hypothesized that IUGR disrupts NF-kappaB-regulated proangiogenic targets in fetal PAEC. PAECs were isolated from the lungs of control fetal sheep and sheep with experimental IUGR from an established model of chronic placental insufficiency. Microarray analysis identified suppression of NF-kappaB signaling and significant alterations in extracellular matrix (ECM) pathways in IUGR PAEC, including decreases in collagen 4alpha1 and laminin alpha4, components of the basement membrane and putative NF kappaB targets. In comparison with controls, immunostaining of active NF-kappaB complexes, NF-kappaB-DNA binding, baseline expression of NF-kappaB subunits p65 and p50, and LPS-mediated inducible activation of NF-kappaB signaling were decreased in IUGR PAEC. Although pharmacological NF-kappaB inhibition did not affect angiogenic function in IUGR PAEC, angiogenic function of control PAEC was reduced to a similar degree as that observed in IUGR PAEC. These data identify reductions in endothelial NF-kappaB signaling as central to the disrupted angiogenesis observed in IUGR, likely by impairing both intrinsic PAEC angiogenic function and NF-kappaB-mediated regulation of ECM components necessary for vascular development. These data further suggest that strategies that preserve endothelial NF-kappaB activation may be useful in lung diseases marked by disrupted angiogenesis such as IUGR. PMID- 29722562 TI - NMDA receptor activation inhibits the antifibrotic effect of BM-MSCs on bleomycin induced pulmonary fibrosis. AB - Endogenous glutamate (Glu) release and N-methyl-d-aspartate (NMDA) receptor (NMDAR) activation are associated with lung injury in different animal models. However, the underlying mechanism is unclear. Bone marrow-derived mesenchymal stem cells (BM-MSCs), which show potential use for immunomodulation and tissue protection, play a protective role in pulmonary fibrosis (PF) process. Here, we found the increased Glu release from the BM cells of bleomycin (BLM)-induced PF mice in vivo. BLM stimulation also increased the extracellular Glu in BM-MSCs via the antiporter system xc- in vitro. The gene expression of each subunit of NMDAR was detected in BM-MSCs. NMDAR activation inhibited the proliferation, migration, and paracrine function of BM-MSCs in vitro. BM-MSCs were derived from male C57BL/6 mice, transfected with lentiviral vectors carrying the enhanced green fluorescence protein gene, pretreated with NMDA, and transplanted into the female recipient mice that were intratracheally injected with BLM to induce PF. Transplantation of NMDA-pretreated BM-MSCs significantly aggravated PF as compared with that in the normal BM-MSCs transplantation group. The sex determination gene Y chromosome and green fluorescence protein genes of BM-MSCs were detected to observe BM-MSCs homing in the fibrotic lungs. Moreover, NMDAR activation inhibited BM-MSC migration by downregulating the stromal cell-derived factor-1/C-X-C chemokine receptor type 4 signaling axis. NMDAR activation aggravated the transforming growth factor-beta1-induced extracellular matrix production in alveolar epithelial cells and fibroblasts through the paracrine effects of BM-MSCs. In summary, these findings suggested that NMDAR activation mediated Glu excitotoxicity induced by BLM in BM-MSCs abolished the therapeutic effects of normal BM-MSCs transplantation on BLM-induced PF. PMID- 29722565 TI - MMP-12 activates protease-activated receptor-1, upregulates placenta growth factor, and leads to pulmonary emphysema. AB - Because of the expansion of aging and smoking populations, chronic obstructive pulmonary disease (COPD) is predicted to be the third leading cause of death worldwide in 2030. Therefore, it is pertinent to develop effective therapy to improve management for COPD. Cigarette smoke-mediated protease-antiprotease imbalance is a major pathogenic mechanism for COPD and results in massive pulmonary infiltration of neutrophils and macrophages, releasing excessive neutrophil elastase (NE) and matrix metalloproteinases (MMPs). Our previous studies indicated that placenta growth factor (PGF) and PGF-triggered downstream signaling molecules mediate NE-induced lung epithelial cell apoptosis, which is a major pathogenic mechanism for pulmonary emphysema. However, the relationship between MMP-directed COPD and PGF remains elusive. We hypothesize that MMPs may upregulate PGF expression and be involved in MMP-mediated pathogenesis of COPD. In this study, we demonstrate that only MMP-12 can increase the expression of PGF by increasing early-growth response protein 1 (Egr-1) level through the activation of protease-activated receptor 1 (PAR-1). The PGF-mediated downstream signaling molecules drive caspase-3 and caspase-9-dependent apoptosis in bronchial epithelial cells. Both the upregulation of PGF by MMP-12 and PGF downstream signaling molecules with pulmonary apoptosis and emphysema were also demonstrated in animals. Given these findings, we suggest that both human COPD associated elastases, NE, and MMP-12, upregulate PGF expression and promote the progression of emphysema and COPD. PMID- 29722564 TI - Long-term culture and cloning of primary human bronchial basal cells that maintain multipotent differentiation capacity and CFTR channel function. AB - While primary cystic fibrosis (CF) and non-CF human bronchial epithelial basal cells (HBECs) accurately represent in vivo phenotypes, one barrier to their wider use has been a limited ability to clone and expand cells in sufficient numbers to produce rare genotypes using genome-editing tools. Recently, conditional reprogramming of cells (CRC) with a Rho-associated protein kinase (ROCK) inhibitor and culture on an irradiated fibroblast feeder layer resulted in extension of the life span of HBECs, but differentiation capacity and CF transmembrane conductance regulator (CFTR) function decreased as a function of passage. This report details modifications to the standard HBEC CRC protocol (Mod CRC), including the use of bronchial epithelial cell growth medium, instead of F medium, and 2% O2, instead of 21% O2, that extend HBEC life span while preserving multipotent differentiation capacity and CFTR function. Critically, Mod CRC conditions support clonal growth of primary HBECs from a single cell, and the resulting clonal HBEC population maintains multipotent differentiation capacity, including CFTR function, permitting gene editing of these cells. As a proof-of concept, CRISPR/Cas9 genome editing and cloning were used to introduce insertions/deletions in CFTR exon 11. Mod CRC conditions overcome many barriers to the expanded use of HBECs for basic research and drug screens. Importantly, Mod CRC conditions support the creation of isogenic cell lines in which CFTR is mutant or wild-type in the same genetic background with no history of CF to enable determination of the primary defects of mutant CFTR. PMID- 29722566 TI - Inhibition of Raf1 ameliorates bleomycin-induced pulmonary fibrosis through attenuation of TGF-beta1 signaling. AB - Idiopathic pulmonary fibrosis (IPF) is a fatal fibrotic lung disease associated with aberrant activation and differentiation of fibroblasts, leading to abnormal extracellular matrix production. Currently, it is still an untreatable disease (except for lung transplantation). Here, we demonstrate that the Raf1 inhibitor GW5074 ameliorates lung fibrosis in bleomycin-induced pulmonary fibrosis. Posttreatment with GW5074 reduced fibronectin (FN) expression, collagen deposition, and inflammatory cell infiltration in bleomycin-challenged mice, suggesting an antifibrotic property of GW5074. To determine the molecular mechanisms by which inhibition of Raf1 ameliorates lung fibrosis, we investigated the role of Raf1 in TGF-beta1 signaling in human lung fibroblasts. GW5074 or downregulation of Raf1 by siRNAs significantly attenuated TGF-beta1-induced smooth muscle actin, FN, and collagen I expression, whereas overexpression of Raf1 promoted the effects of TGF-beta1 in lung fibroblasts. Furthermore, we found that Raf1-promoted TGF-beta1 signaling was through the Raf1/ERK/Smad pathway and contributed to the cell proliferation and migration in human lung fibroblasts. This study provides preclinical and mechanistic evidence for development of Raf1 inhibitors as potential antifibrotic drugs for the treatment of IPF. PMID- 29722567 TI - Alveolar epithelial cell processing of nanoparticles activates autophagy and lysosomal exocytosis. AB - Using confocal microscopy, we quantitatively assessed uptake, processing, and egress of near-infrared (NIR)-labeled carboxylated polystyrene nanoparticles (PNP) in live alveolar epithelial cells (AEC) during interactions with primary rat AEC monolayers (RAECM). PNP fluorescence intensity (content) and colocalization with intracellular vesicles in a cell were determined over the entire cell volume via z stacking. Isotropic cuvette-based microfluorimetry was used to determine PNP concentration ([PNP]) from anisotropic measurements of PNP content assessed by confocal microscopy. Results showed that PNP uptake kinetics and steady-state intracellular content decreased as diameter increased from 20 to 200 nm. For 20-nm PNP, uptake rate and steady-state intracellular content increased with increased apical [PNP] but were unaffected by inhibition of endocytic pathways. Intracellular PNP increasingly colocalized with autophagosomes and/or lysosomes over time. PNP egress exhibited fast Ca2+ concentration-dependent release and a slower diffusion-like process. Inhibition of microtubule polymerization curtailed rapid PNP egress, resulting in elevated vesicular and intracellular PNP content. Interference with autophagosome formation led to slower PNP uptake and markedly decreased steady-state intracellular content. At steady state, cytosolic [PNP] was higher than apical [PNP], and vesicular [PNP] (~80% of intracellular PNP content) exceeded both cytosolic and intracellular [PNP]. These data are consistent with the following hypotheses: 1) autophagic processing of nanoparticles is essential for maintenance of AEC integrity; 2) altered autophagy and/or lysosomal exocytosis may lead to AEC injury; and 3) intracellular [PNP] in AEC can be regulated, suggesting strategies for enhancement of nanoparticle-driven AEC gene/drug delivery and/or amelioration of AEC nanoparticle-related cellular toxicity. PMID- 29722570 TI - Finite element models of the thigh-buttock complex for assessing static sitting discomfort and pressure sore risk: a literature review. AB - Being seated for long periods, while part of many leisure or occupational activities, can lead to discomfort, pain and sometimes health issues. The impact of prolonged sitting on the body has been widely studied in the literature, with a large number of human-body finite element models developed to simulate sitting and assess seat-induced discomfort or to investigate the biomechanical factors involved. Here, we review the finite element models developed to investigate sitting discomfort or risk of pressure sores. Our study examines finite element models from twenty-seven papers, seventeen dedicated to assessing seating discomfort and ten dedicated to investigating pressure ulcers caused by prolonged sitting. The models' mesh composition and material properties are found to differ widely. These models share a lack of validation and generally make little allowance for anthropometric diversity. PMID- 29722569 TI - Exacerbated liver injury of antithyroid drugs in endotoxin-treated mice. AB - Drug-induced liver injury is a major concern in clinical studies as well as in post-marketing surveillance. Previous evidence suggested that drug exposure during periods of inflammation could increase an individual's susceptibility to drug hepatoxicity. The antithyroid drugs, methimazole (MMI) and propylthiouracil (PTU) can cause adverse reactions in patients, with liver as a usual target. We tested the hypothesis that MMI and PTU could be rendered hepatotoxic in animals undergoing a modest inflammation. Mice were treated with a nonhepatotoxic dose of LPS (100 ug/kg, i.p) or its vehicle. Nonhepatotoxic doses of MMI (10, 25 and 50 mg/kg, oral) and PTU (10, 25 and 50 mg/kg, oral) were administered two hours after LPS treatment. It was found that liver injury was evident only in animals received both drug and LPS, as estimated by increases in serum alanine aminotransferase (ALT), lactate dehydrogenase (LDH), aspartate aminotransferase (AST), and TNF-alpha. An increase in liver myeloperoxidase (MPO) enzyme activity and tissue lipid peroxidation (LPO) in addition of liver glutathione (GSH) depletion were also detected in LPS and antithyroid drugs cotreated animals. Furthermore, histopathological changes including, endotheliitis, fatty changes, severe inflammatory cells infiltration (hepatitis) and sinusoidal congestion were detected in liver tissue. Methyl palmitate (2 g/kg, i.v, 44 hours before LPS), as a macrophage suppressor, significantly alleviated antithyroids hepatotoxicity in LPS-treated animals. The results indicate a synergistic liver injury from antithyroid drugs and bacterial lipopolysaccharide coexposure. PMID- 29722568 TI - Liver fat imaging-a clinical overview of ultrasound, CT, and MR imaging. AB - Hepatic steatosis is a frequently encountered imaging finding that may indicate chronic liver disease, the most common of which is non-alcoholic fatty liver disease. Non-alcoholic fatty liver disease is implicated in the development of systemic diseases and its progressive phenotype, non-alcoholic steatohepatitis, leads to increased liver-specific morbidity and mortality. With the rising obesity epidemic and advent of novel therapeutics aimed at altering metabolism, there is a growing need to quantify and monitor liver steatosis. Imaging methods for assessing steatosis range from simple and qualitative to complex and highly accurate metrics. Ultrasound may be appropriate in some clinical instances as a screening modality to identify the presence of abnormal liver morphology. However, it lacks sufficient specificity and sensitivity to constitute a diagnostic modality for instigating and monitoring therapy. Newer ultrasound techniques such as quantitative ultrasound show promise in turning qualitative assessment of steatosis on conventional ultrasound into quantitative measurements. Conventional unenhanced CT is capable of detecting and quantifying moderate to severe steatosis but is inaccurate at diagnosing mild steatosis and involves the use of radiation. Newer CT techniques, like dual energy CT, show potential in expanding the role of CT in quantifying steatosis. MRI proton density fat fraction is currently the most accurate and precise imaging biomarker to quantify liver steatosis. As such, proton-density fat fraction is the most appropriate noninvasive end point for steatosis reduction in clinical trials and therapy response assessment. PMID- 29722571 TI - 1D simulation of blood flow characteristics in the circle of Willis using THINkS. AB - One-dimensional (1D) simulation of the complete vascular network, so called THINkS (Total Human Intravascular Network Simulation) is developed to investigate changes of blood flow characteristics caused by the variation of CoW. THINkS contains 158 major veins, 85 major arteries, and 77 venous and 43 arterial junctions. THINkS is validated with available in vivo blood flow waveform data. The overall trends of flow rates in variations of the CoW, such as the missing anterior cerebral artery (missing-A1) or missing posterior cerebral artery (missing-P1), are confirmed by in vivo experimental data. It is demonstrated that the CoW has the ability to shunt blood flow to different areas in the brain. Flow rates in efferent arteries remain unaffected under the variation of CoW, while the flow rates in afferent vessels can be subject to substantial changes. The redistribution of blood flow can cause particular vessels to undergo extra flow rate and hemodynamic stresses. PMID- 29722572 TI - An innovative appendage invagination procedure to reduce thrombus formation - a numerical model. AB - Invagination is an innovative technique for closing the left atrial appendage (LAA) to reduce the risk of thrombi formation. The influence of LAA invagination on the flow fields in the atria was investigated based on a computational fluid dynamics. The simulation results demonstrated that the novel invagination process can eliminate low velocities (blood stasis) and low shear rate and thus decrease the risk of thrombus formation during atrial fibrillation. This innovative technique may enhance the clinical treatment of patients with atrial fibrillation by improving the atrial flow field while lowering the risk of creating emboli. PMID- 29722573 TI - Electrochemical immunoassay for tumor markers based on hydrogels. AB - INTRODUCTION: Hydrogel-based electrochemical immunoassays exhibit a large surface to-volume ratio, excellent biocompatibility, unique stimuli-responsive behavior, high permeability and hydrophilicity and, thus, have shown great potential in the sensitive and accurate detection of tumor markers. Electrochemical immunosensing techniques for tumor markers based on hydrogels have greatly progressed in recent years. Areas covered: In this review, the authors describe the recent advances of hydrogel-based electrochemical immunosensing interface of tumor markers based on the different functions of hydrogels including conductive, catalytic, redox, stimuli-responsive and antifouling hydrogels. Expert commentary: Hydrogels have been successfully employed in electrochemical immunoassay of tumor markers, which is accountable to their unique properties. For further exploitation of hydrogel based electrochemical biosensors, more variety of hydrogels need be fabricated with improved functionality. PMID- 29722574 TI - Secondary outcomes of the guided self-help behavioral activation and physical activity for depression trial. AB - BACKGROUND: This article presents secondary outcome variables from a randomized controlled trial evaluating the efficacy of two guided self-help interventions for the treatment of depression: behavioral activation (BA) and physical activity (PA). Both interventions resulted in significant reductions in depressive symptoms compared to the wait-list control group, however the mechanisms by which these interventions influenced depression were not presented. PURPOSE: The purpose of this paper was to compare changes in secondary outcome variables to gain insight into the mechanisms by which reactivation interventions reduce depressive symptoms. RESULTS: Mixed-model analysis of variances (ANOVAs) revealed significant increases in life satisfaction (Main effect: F(3, 91.71) = 4.63, p < 0.01) and self-efficacy (Main effect: F(3, 91.32) = 4.05, p < 0.01) as well as significant decreases in negative affect (Main effect: F(2, 75.88) = 5.24, p < 0.01) and loneliness (Main effect: F(2, 71.78) = 7.49, p < 0.01) in both interventions at pre-, mid-, post-intervention and follow-up. The group x time interactions were not significant, suggesting that the PA and BA interventions had comparable effects over time. CONCLUSION: These findings provide insight into the potential mechanisms underlying the effectiveness of guided self-help PA and BA interventions on depressive symptoms. PMID- 29722575 TI - Joint lavage followed by intra-articular injection of hyaluronic acid and/or corticosteroids in patients with severe hemophilic arthropathy of the knee: Is this intervention really effective? AB - INTRODUCTION: The aim of this review is to explore the scientific rationale and evidence for a potential benefit of joint lavage followed by intra-articular injection of hyaluronic acid and/or corticosteroids in patients with severe hemophilic arthropathy of the knee (SHAK). Areas covered: This article is a narrative review of the evidence for potential benefits of joint lavage followed by intra-articular injection of hyaluronic acid and corticosteroids in SHAK compared with osteoarthritis of the knee in non-hemophilia patients. Expert commentary: Although some reports on hemophilic arthropathy with a low-grade of evidence seem to indicate a benefit of joint lavage followed by intra-articular injection of hyaluronic acid and/or corticosteroids in patients with SHAK, the short-lived improvements afforded by hyaluronic acid, and the doubtful benefits of corticosteroids and joint lavage in hemophilia, do not warrant their use in hemophilic patients. The scientific rationale of these procedures is poor and they are not recommended. PMID- 29722576 TI - Is Bypassing the Stomach a Means to Optimize Sodium Bicarbonate Supplementation? A Case Study With a Postbariatric Surgery Individual. AB - Sodium bicarbonate (SB) is an ergogenic supplement shown to improve high intensity exercise via increased blood bicarbonate buffering. Substantial amounts of the ingested bicarbonate are neutralized in the stomach. Bariatric surgery results in a small gastric pouch which dramatically reduces exposure time of any ingested food in the stomach. The aim of this study was to examine the pharmacokinetics of orally ingested SB in a postgastric bypass individual to determine the magnitude of changes in blood bicarbonate and associated side effects. We hypothesized that SB supplementation in a gastric bypass model would result in greater blood bicarbonate increases and fewer side effects than in healthy individuals due to minimal bicarbonate losses in the stomach. One postbariatric male ingested 0.3 g/kg.body mass of SB on three occasions (SB1, SB2, and SB3) and 0.3 g/kg.body mass of placebo on a further occasion. Blood bicarbonate was determined before and every 10 min following supplement ingestion for 3 hr and then every 20 min for a further 1 hr. Side effects were reported using an adapted questionnaire at identical time points. Maximal increases in blood bicarbonate with SB were +20.0, +15.2, and +12.6 mM, resulting in maximal bicarbonate concentrations of 42.8, 39.3, and 36.2 mM. Area under the curve was SB1: 8,328 mM/min; SB2: 7,747 mM/min; SB3: 7,627 mM/min, and 6,436 mM/min for placebo. Side effects with SB were scarce. Maximal bicarbonate increases were well above those shown previously, with minimal side effects, indicative of minimal neutralization of bicarbonate in the stomach. The large increases in circulating bicarbonate and minimal side effects experienced by our postgastric surgery bypass patient are indicative that minimizing neutralization of bicarbonate in the stomach, as would occur with enteric coated capsules, may optimize SB supplementation and thus warrants investigation. PMID- 29722577 TI - Rehabilitation technology services and employment outcomes among consumers using division of rehabilitation services. AB - PURPOSE: The primary goal of the study was to evaluate how the use of rehabilitation technology impacted closure status for consumers receiving services in fiscal year (FY) 2014. MATERIALS AND METHODS: Rehabilitation Service Administration (RSA-911) Case Service Report FY 2014 archival dataset was obtained from the U.S. Department of Education (2014) and secondary analyses was performed for this study. RSA-911 archival data is updated on an annual basis and consists of all state-federal rehabilitation consumers who were served in the specific fiscal year. The dataset contains information related to each consumer's demographic information (e.g. age, gender, race) and other supplemental information (e.g. weekly earnings at closure, cause of disability, services provided). RESULTS AND CONCLUSIONS: A multiple logistic regression analysis was utilized and revealed that white consumers receiving rehabilitation technology (RT) services have significantly higher closure rate than consumers of other races, RT services differ by the employment status at application, RT services differ by the type of disability, educational level at application for people receiving RT services did predict closure status (i.e. exiting with an employment outcome), IEP status did not predict closure status, weekly earnings at application did predict closure status and the interaction effect between IEP and RT services is statistically significant. The odds ratio (ORs) were presented at the 95% confidence interval (CI). Vocational rehabilitation counselors needs training to correctly identify appropriate RT services for consumers, so that the likelihood of exiting with an employment outcome is obtained. Implications for Rehabilitation RT services significantly improved their chances of successful employment compared to those who did not receive RT services. Education at closure would also have some significant impact on employment outcomes. Training in Assistive Technology (AT) for Vocational Rehabilitation counselors will assist in the proper identification of AT requirements, which may lead to a higher likelihood of consumers exiting with an employment outcome. PMID- 29722578 TI - A Review of Prevention, Diagnosis, and Treatment of Relative Energy Deficiency in Sport in Artistic (Synchronized) Swimming. AB - The syndrome of relative energy deficiency in sport (RED-S) is a clinical entity characterized by low energy availability, which can negatively affect the health and performance of both male and female athletes. The underlying mechanism of RED S is an inadequacy of dietary energy to support optimal health and performance. This syndrome refers to impaired physiological function, including metabolic rate, menstrual function, bone health, immunity, protein synthesis, and cardiovascular health, with psychological consequences that can either precede (through restrictive dietary habits) or result from RED-S. The term RED-S extends beyond the condition termed the "Female Athlete Triad." Formerly known as synchronized swimming, artistic swimming is an Olympic sport requiring a high level of fitness as well as technical skill and artistry. The risk of RED-S is high in artistic swimming as it is an aesthetic, judged sport with an emphasis on a lean physique. RED-S is of significant concern in the sport of artistic swimming because of the potential negative effects on physical and mental health as well as consequences on athletic performance. This paper reviews health and performance consequences associated with low energy availability resulting in RED S in artistic swimming. Medical and nutritional considerations specific to artistic swimming are reviewed, and methods to help detect and manage RED-S are discussed. Prevention and management of RED-S in this athlete population should be a priority for coaches, and the sport medicine professionals working with artistic swimming athletes should utilize the RED-S CAT, a Clinical Assessment Tool for screening and managing RED-S. PMID- 29722579 TI - University staff experiences of students with mental health problems and their perceptions of staff training needs. AB - BACKGROUND: University students experience high levels of mental health problems; however, very few seek professional help. Teaching staff within the university are well placed to assist students to seek support. AIMS: To investigate university teaching staff experiences of, and training needs around, assisting students with mental health problems. METHOD: A total of 224 teaching staff at the Australian National University completed an anonymous online survey (16.4% response rate from n ~ 1370). Data on mental health training needs, and experiences of assisting students with mental health problems were described using tabulation. Qualitative data were analysed using thematic analysis. RESULTS: Most teaching staff (70.1-82.2%) reported at least moderate confidence in their ability to provide emotional support for students. However, many staff (60.0%) felt under-equipped overall to deal with student mental health problems; almost half (49.6%) reported they did not have access to formal training. Specific actions described in assisting students included referrals, offering support, or consulting others for advice. CONCLUSION: Given the high rates of students who approach staff about mental health problems, there is a critical need to provide and promote both formal mental health response training and explicit guidelines for staff on when, how, and where to refer students for help. PMID- 29722580 TI - Reliability of the Spanish version of the wheelchair skills test 4.2 for manual wheelchair users with spinal cord injury. AB - STUDY DESIGN: Cross-sectional. OBJECTIVES: The majority of people with a spinal cord injury (SCI) are dependent on wheelchair for their mobility. Approximately, 36% of wheelchair users reported that obstacles such as curbs, uneven terrain, flooring surfaces and thresholds were barriers to mobility. Several studies have shown that assessment and training of wheelchair skills leads to improvements in those skills. The purpose of our study was to translate the Wheelchair Skill Test (4.2) and its report form into Spanish and then determine the inter-rater reliability of the WST 4.2 for manual wheelchairs operated by their users. SETTING: Rehabilitation Unit, FLENI Institute, Buenos Aires, Argentina. METHODS: The translation was performed by a physical therapist with advanced English language skills and specialized in the treatment of SCI subjects. We administrated and video-recorded the WST 4.2 manual Spanish version in 11 SCI subjects. Two physical therapists received specific training for administering the test and scoring the record. The reliability of the total percentage WST score were statistically quantified by intraclass correlation coefficient (ICC). RESULTS: ICC values for Interrater were 0.998 (p < .0001). 17 out of the 32 skills had a 100 percentage of agreement. Percentage of agreement in the three skills that presented less rating agreement was 73%, 81 % and 82 %, respectively. CONCLUSION: The results show that the Spanish version of WST 4.2 is a reliable assessment tool to evaluate the skills capacity of spinal cord manual wheelchair users. Implications for rehabilitation Wheelchair users require a proficient management of various wheelchair skills to achieve maximum independence in daily life. Determining which wheelchair skills should be addressed during the rehabilitation process is of great importance for their correct training. The WST 4.2 is an appropriate assessment tool to determine the functional capacity of wheelchair users. Making available the WST 4.2 in the Spanish language and demonstrating its reliability in this language allows its use in the Spanish speaking world. A reliable wheelchair skills test is needed in the Spanish language. PMID- 29722583 TI - Molecular and Hematological Characterization of Two Novel delta-Globin Gene Mutations Found in Chinese Individuals. AB - We identified two novel delta-globin gene mutations in two families during routine thalassemia screening. One missense mutation at codon 73 on the delta globin gene [delta73(E17)Asp->Val, HBD: c.221A>T] which results in a Hb A2 variant homologous to the beta-globin gene variant called Hb Mobile [beta73(E17)Asp->Val, HBB: c.221A>T] and we have named this variant Hb A2-Henan. The other is a nonsense mutation [delta7(A4)Glu->Stop, HBD: c.22G>T] which gives rise to a stop codon (TAG) at codon 7, resulting in delta0-thalassemia (delta0 thal). The Hb A2 in one individual with homozygous HBD: c.22G>T was absent. PMID- 29722582 TI - Synthesis, antimicrobial, anti-biofilm evaluation, and molecular modelling study of new chalcone linked amines derivatives. AB - A series of amide chalcones conjugated with different secondary amines were synthesised and characterised by different spectroscopic techniques 1H NMR, 13C NMR, and ESI-MS. They were screened for in vitro antibacterial activity. Compounds 36, 37, 38, 42, and 44 are the most active among the synthesised series exhibiting MIC value of 2.0-10.0 ug/ml against different bacterial strains. Compound 36 was equipotent to the standard drug Ampicillin displaying MBC value of 2.0 ug/ml against the bacterial strain Staphylococcus aureus. The products were screened for anti-biofilm activity. Compounds 36, 37, and 38 exhibited promising anti-biofilm activity with IC50 value ranges from 2.4 to 8.6 ug. Molecular modelling was performed suggesting parameters of signalling anti biofilm mechanism. AspB327 HisB340 (arene-arene interaction) and IleB328 amino acid residues seemed of higher importance to inhibit c-di-GMP. Hydrophobicity may be crucial for activity. ADME calculations suggested that compounds 36, 37, and 38 could be used as good orally absorbed anti-biofilm agents. PMID- 29722581 TI - Antibacterial activity of 3-methylbenzo[d]thiazol-methylquinolinium derivatives and study of their action mechanism. AB - The increasing incidence of multidrug resistant bacterial infection renders an urgent need for the development of new antibiotics. To develop small molecules disturbing FtsZ activity has been recognized as promising approach to search for antibacterial of high potency systematically. Herein, a series of novel quinolinium derivatives were synthesized and their antibacterial activities were investigated. The compounds show strong antibacterial activities against different bacteria strains including MRSA, VRE and NDM-1 Escherichia coli. Among these derivatives, a compound bearing a 4-fluorophenyl group (A2) exhibited a superior antibacterial activity and its MICs to the drug-resistant strains are found lower than those of methicillin and vancomycin. The biological results suggest that these quinolinium derivatives can disrupt the GTPase activity and dynamic assembly of FtsZ, and thus inhibit bacterial cell division and then cause bacterial cell death. These compounds deserve further evaluation for the development of new antibacterial agents targeting FtsZ. PMID- 29722584 TI - No Difference Between the Effects of Supplementing With Soy Protein Versus Animal Protein on Gains in Muscle Mass and Strength in Response to Resistance Exercise. AB - Much attention has been given to determining the influence of total protein intake and protein source on gains in lean body mass (LBM) and strength in response to resistance exercise training (RET). Acute studies indicate that whey protein, likely related to its higher leucine content, stimulates muscle protein synthesis to a greater extent than proteins such as soy and casein. Less clear is the extent to which the type of protein supplemented impacts strength and LBM in long-term studies (>=6 weeks). Therefore, a meta-analysis was conducted to compare the effect of supplementation with soy protein to animal protein supplementation on strength and LBM in response to RET. Nine studies involving 266 participants suitable for inclusion in the meta-analysis were identified. Five studies compared whey with soy protein, and four studies compared soy protein with other proteins (beef, milk, or dairy protein). Meta-analysis showed that supplementing RET with whey or soy protein resulted in significant increases in strength but found no difference between groups (bench press: chi2 = 0.02, p = .90; squat: chi2 = 0.22, p = .64). There was no significant effect of whey or soy alone (n = 5) on LBM change and no differences between groups (chi2 = 0.00, p = .96). Strength and LBM both increased significantly in the "other protein" and the soy groups (n = 9), but there were no between-group differences (bench: chi2 = 0.02, p = .88; squat: chi2 = 0.78, p = .38; and LBM: chi2 = 0.06, p = .80). The results of this meta-analysis indicate that soy protein supplementation produces similar gains in strength and LBM in response to RET as whey protein. PMID- 29722586 TI - Australian Football Athletes Lack Awareness of Current Sport Nutrition Guidelines. AB - Sports nutrition is an evolving field, but there is a lack of data on Australian athletes' knowledge of current sports nutrition guidelines. Additionally, several tools used to assess nutrition knowledge (NK) have not undergone adequate validation. The purpose of this study was to assess and compare the sports NK of elite and nonelite Australian football (AF) athletes using a newly validated questionnaire-The Nutrition for Sport Knowledge Questionnaire. Elite AF players (n = 46) were recruited directly from their club dietitian and nonelite AF players (n = 53) were invited to participate via e-mail from their club president or secretary. The mean NK score of elite and nonelite AF players was 46 +/- 16% and 51 +/- 11%, respectively (p = .041). In both groups, knowledge of macronutrients, weight management, and alcohol was better than knowledge of supplements, micronutrients, and sports nutrition. Nonelite athletes achieved statistically significantly higher scores on the questionnaire subsections testing weight management (elite: 48 +/- 18; nonelite: 57 +/- 19, p = .019), micronutrients (elite: 39 +/- 19; nonelite: 50 +/- 16, p = .004), and alcohol (elite: 52 +/- 13; nonelite: 71 +/- 17, p = .002). While overall NK of Australian athletes was poor, scores varied greatly among individuals (range: 10-70%) and across the six subsections (topics) being assessed. Professionals working with athletes should undertake an assessment of the athletes' NK so that they can provide targeted education programs. PMID- 29722587 TI - The preclinical discovery and development of cariprazine for the treatment of schizophrenia. AB - INTRODUCTION: Cariprazine is approved in the United States and Europe for the treatment of manic or mixed episodes associated with bipolar I disorder and for the treatment of schizophrenia in adult patients. It is typically administered orally once a day (a dose range 1.5 - 6 mg/day), does require titration, and may be given with or without food. It has a half-life of 2 - 4 days with an active metabolite that has a terminal half-life of 2 - 3 weeks. Areas covered: This review article focuses on the preclinical discovery of cariprazine providing details regarding its pharmacological, behavioral, and neurochemical mechanisms and its contribution to clinical therapeutic benefits. This article is based on the available literature with respect to the preclinical and clinical findings and product labels of cariprazine. Expert opinion: Cariprazine shows highest affinity toward D3 receptors, followed by D2, 5-HT2B, and 5-HT1A receptors. It also shows moderate affinity toward sigma1, 5-HT2A, and histamine H1 receptors. Long-term administration of cariprazine altered the abundance of dopamine, serotonin, and glutamate receptor subtypes in different brain regions. All these mechanisms of cariprazine may contribute toward its unique preclinical profile and its clinically observed benefits in the treatment of schizophrenia, bipolar mania, and possibly other psychiatric disorders. PMID- 29722585 TI - Drug delivery systems based on biocompatible imino-chitosan hydrogels for local anticancer therapy. AB - A series of drug delivery systems were prepared by chitosan hydrogelation with citral in the presence of an antineoplastic drug: 5-fluorouracil. The dynamic covalent chemistry of the imine linkage allowed the obtaining of supramolecular tridimensional architectures in which the drug has been homogenously dispersed. Fourier-transform infrared spectroscopy (FTIR), wide-angle X-ray diffraction (WXRD) and polarized light microscopy (POM) measurements were used in order to follow the hydrogelation and drug encapsulation processes. The ability of the prepared systems to release the drug has been investigated by UV-Vis spectroscopy using a calibration curve and by fitting the results with different mathematic models. To mimic the behavior of the hydrogel matrix in bio-environmental conditions in view of applications, their enzymatic degradability was monitored in the presence of lysozyme. The in vivo side effects of the systems, in terms of their influence on the blood elements, biochemical and immune parameters were monitored on white Swiss mice by intraperitoneal administration of the injectable obtained hydrogels. All the characteristics of the obtained systems, such as micro-porous morphology, uniform drug encapsulation, enzymatic degradability, lack of side effects, other than the one of the drug itself, along with their ability to release the drug in a sustained manner proved that these material meet the requirements for the development of drug delivery systems, making them suitable for being applied in intraperitoneal chemotherapy. PMID- 29722588 TI - The interactions between non-motor symptoms of Parkinson's disease. PMID- 29722589 TI - Evidence-based pediatric asthma interventions and outcome measures in a healthy homes program: An integrative review. AB - OBJECTIVE: Asthma disproportionately impacts and has poorer outcomes in low income, minority, and inner-city children. The home environment has a profound impact on a child's asthma. Home-based asthma visits have the potential to positively impact a child's asthma, especially in targeted populations. The purpose of this integrative review is 1.) to explore the effectiveness of home based education and environmental measures and 2.) to explore specific indicators and tools to measure pediatric asthma control and program effectiveness. DATA SOURCES: Medline, CINHAL, and Ovid databases were searched from 2010 to 2017 utilizing the keywords healthy homes AND asthma and home based interventions AND asthma. STUDY SELECTIONS: A total of 71 articles were retrieved of which 27 articles met the inclusion criteria of English language, human subjects, and the inclusion of pediatric populations. Three additional articles were hand-searched from previous references. In total, 30 articles were reviewed. A quality appraisal was conducted utilizing standardized appraisal tools. RESULTS: Home based asthma education and environmental interventions have proven to be effective. The programs reviewed varied in types of interventions, intensity and duration, the type of provider, length of follow-up, and outcome measures. Successful programs were patient-centered, included a home assessment and individualized education and interventions, and were collaborative. Multiple outcome indicators such as health care utilization, asthma control, missed days of school or productivity, asthma symptoms, and verification of environmental remediation have been utilized. CONCLUSION: Home-based asthma programs can be beneficial to children with poorly controlled asthma and have the potential to be cost-effective. PMID- 29722590 TI - Correcting Vitamin D Insufficiency Improves Some But Not All Aspects of Physical Performance During Winter Training in Taekwondo Athletes. AB - We investigated the effects of vitamin D3 supplementation on physical performance during winter training in vitamin D insufficient taekwondo athletes. Thirty-five collegiate male and female taekwondo athletes, aged 19-22 years with low serum 25(OH)D concentration (28.8 +/- 1.10 nmol/L), were randomly assigned to a vitamin D group (n = 20) or a placebo group (n = 15). Subjects received either a vitamin D3 capsule (5,000 IU/day) or a placebo during 4 weeks of winter training. Blood samples were collected for analyzing serum 25(OH)D concentration. Physical performance tests included Wingate anaerobic test, isokinetic muscle strength and endurance, a countermovement jump test, sit-ups, agility test, and 20-m pacer. Serum 25(OH)D concentrations increased significantly in the vitamin D group (96.0 +/- 3.77 nmol/L) after 4 weeks of supplementation, but no changes were found in the placebo group (F = 242.44, p = .000). There were significant interaction effects for anaerobic peak power (F = 7.49, p = .010) and isokinetic knee extension at 180 deg/s (F = 6.08, p = .019). Changes in serum 25(OH)D concentration were positively associated with changes in peak power and isokinetic knee extension at 180 deg/s. However, no significant interaction effects were observed in other performance variables. This study suggests that 4 weeks of vitamin D supplementation elevates serum 25(OH)D concentration to sufficient levels. Correcting vitamin D insufficiency improves some but not all aspects of performance. Thus, efficacy of vitamin D supplementation to enhance performance remains unclear. PMID- 29722591 TI - Using the Rasch analysis for the psychometric validation of the Irregular Word Reading Test (TeLPI): A Portuguese test for the assessment of premorbid intelligence. AB - OBJECTIVE: The present study aims to analyze the psychometric characteristics of the TeLPI (Irregular Words Reading Test), a Portuguese premorbid intelligence test, using the Rasch model for dichotomous items. RESULTS: The results reveal an overall adequacy and a good fit of values regarding both items and persons. A high variability of cognitive performance level and a good quality of the measurements were also found. The TeLPI has proved to be a unidimensional measure with reduced DIF effects. CONCLUSIONS: The present findings contribute to overcome an important gap in the psychometric validity of this instrument and provide good evidence of the overall psychometric validity of TeLPI results. PMID- 29722592 TI - Age-Related Changes in Achilles Tendon Stiffness and Impact on Functional Activities: A Systematic Review and Meta-Analysis. AB - Achilles tendon stiffness determines calf muscle functioning during functional activities. However, contrasting evidence was found in studies comparing Achilles tendon stiffness in older and younger adults. Therefore, this systematic review compares Achilles tendon stiffness and elastic modulus in older and younger adults and reviews functional implications. Studies revealed by systematic bibliographic searches were included if healthy older adults were investigated, and if Achilles tendon stiffness was measured using ultrasound and dynamometry. Meta-analyses were performed to compare Achilles tendon stiffness and elastic modulus in older and younger adults. Achilles tendon stiffness (weighted standardized mean difference = 1.40, 95% confidence intervals [0.42-2.38]) and elastic modulus (weighted standardized mean difference = 1.74, 95% confidence intervals [0.99-2.49]) were decreased in older compared with younger adults. Decreased Achilles tendon stiffness was related to walking performance and balance. Possibly, decreased Achilles tendon stiffness is caused by altered elastic modulus in older adults. Training interventions increasing Achilles tendon stiffness could improve functional capacity. PMID- 29722593 TI - A Life Course Examination of Women's Team Sport Participation in Late Adulthood. AB - This study contributes to the fields of aging and physical activity by applying the key principles of the life course perspective to investigate women's team sport participation experience in late adulthood. Through focus groups, data were collected from six competitive softball teams of women (N = 64) ranging from 55 to 79 years old. Data were audio recorded, transcribed verbatim, and analyzed for themes related to the life course principles of historical context and place, social embeddedness, agency, as well as trajectories and timing. A key study finding was that the women experienced cultural lag and age-related barriers to resources when playing competitive softball in late adulthood. In addition, the network of shared relationships occupied by these women had both positive and negative influences on their participation in competitive sports. Study findings can help inform services and programs at the local community level aimed at enhancing women's physical activity and health in late adulthood. PMID- 29722594 TI - Stereotactic body radiotherapy for second primary lung cancer and intra parenchymal lung metastasis in patients previously treated with surgery: evaluation of indications and predictors of decreased respiratory function. AB - BACKGROUND: The adaptation criteria for administration of stereotactic body radiotherapy (SBRT) to patients with lung cancer who previously underwent surgery and subsequently developed a second primary lung cancer (SPLC) or intra parenchymal lung metastasis (IPLM) are controversial, unlike the criteria for repeat surgery. We aimed to evaluate the feasibility of SBRT for these patients. Factors associated with decreased respiratory function were also evaluated. MATERIAL AND METHODS: Sixty-nine patients with 89 lesions who underwent SBRT between 2008 and 2017 were analyzed. Of these, 29 were diagnosed with SPLC while the remaining 40 had IPLM. The distribution of histological types was as follows: squamous cell carcinoma (n = 13 lesions); adenocarcinoma (n = 25); non-small cell carcinoma (n = 1); unknown histological type (n = 49). The prescribed doses to the planning target volume (PTV) were 50 Gy in five fractions for 85 lesions and 60 Gy in 10 fractions for four lesions at PTV mean. RESULTS: Over a median follow up period of 55 months, the 4-year overall survival and local control rates were 50.3% and 87.6%, respectively. Six patients experienced grade 2 radiation pneumonitis and one experienced grade 3. Two patients experienced grade 5 pulmonary fibrosis. Decreased respiratory function was observed in 10 patients (15.1%). On multivariate analysis, the presence of pulmonary disease before SBRT was the only statistically significant factor associated with decreased respiratory function. CONCLUSIONS: SBRT is safe and feasible in patients with SPLC or IPLM previously treated surgically. Pre-existing pulmonary disease was a predictive factor for decreased respiratory function. PMID- 29722595 TI - How do we measure the epigenome(s)? PMID- 29722596 TI - Cultural health literacy: the experiences of Maori in palliative care. AB - : Health literacy is a concept that is frequently applied to the patient's ability to find and comprehend health information. However, recent literature has included the skill of the health professional and the accessibility of health resources as important factors in the level of health literacy achieved by individuals and populations. In 2014 a qualitative study undertaken in Aotearoa New Zealand, investigated the context of health literacy for Maori in a palliative care setting (Maori are the indigenous people of Aotearoa New Zealand). The study included the experiences of patients, whanau (families), and health professionals. METHOD: Individual semi-structured interviews were held with 21 patients, whanau and six key informants: a medical specialist, a service leader involved in developing culturally specific responses to patients, two Maori service managers, and two Maori health team leaders. Focus groups were held with a total of 54 health professionals providing palliative care services. DATA ANALYSIS: A thematic analysis was undertaken using a general inductive approach. The trustworthiness and reliability of the analysis was supported by sharing analysis of the transcripts among the research team. Member checking or respondent validation was used in seeking confirmation of the interim findings at five hui (meetings) with the research communities involved. FINDINGS: This study found that the shock and grief that attends a life-limiting illness made hearing and processing health information very difficult for patients and whanau. Further, 'hard conversations' about moving from active treatment to palliative care were often avoided by health professionals, leaving patients and whanau distressed and confused about their choices and prognosis. Finally, poor cultural health literacy on the part of organisations has likely impacted on late access to or avoidance of palliative care for Maori. PMID- 29722597 TI - Positive predictive value of acute and chronic pancreatitis diagnoses in the Danish National Patient Registry: A validation study. AB - AIMS: To examine the validity of the diagnoses of acute and chronic pancreatitis registered in the Danish National Patient Registry. METHODS: We identified all patients in the Danish National Patient Registry admitted to two Danish hospitals with acute or chronic pancreatitis from 1996 to 2013. From this population, we randomly sampled 100 patients with acute pancreatitis and 100 patients with chronic pancreatitis. For each cohort, we computed the positive predictive values and associated 95% confidence intervals (CIs) for the discharge diagnosis of acute or chronic pancreatitis using medical records as the gold standard. RESULTS: We identified 2617 patients with acute pancreatitis and 1284 patients with chronic pancreatitis discharged from either of the two hospitals during the study period. Of these, 776 (19.9%) had a diagnosis of both acute and chronic pancreatitis and are thus present in both cohorts. From the 200 sampled patients, a total of 138 (69.0%) medical records were available for review. The positive predictive value for a diagnosis of acute pancreatitis in the Danish National Patient Registry was 97.3% (95% CI 90.5-99.2%) and for chronic pancreatitis 83.1% (95% CI 72.2-90.3%). CONCLUSIONS: The validity of diagnoses of acute and chronic pancreatitis registered in the Danish National Patient Registry since 1996 is generally high. PMID- 29722598 TI - Spontaneous regression of tumor-stage cutaneous T-cell lymphoma in a multiple sclerosis patient after discontinuing fingolimod. PMID- 29722599 TI - Champions are racers, not pacers: an analysis of qualification patterns of Olympic and IAAF World Championship middle distance runners. AB - The aim of this study was to analyse qualification patterns in middle distance running and identify whether athletes adopt theoretically optimal tactics, or whether the will to win overrides these. The performances of 295 men and 258 women finalists in the Olympic and IAAF World Championship 800 m and 1500 m events from 1999 to 2017 were analysed across all three rounds of competition. Finishing position, time and ranking amongst all competitors were found for each athlete. Position in the final was correlated with finishing position in the heats and semi-finals (all P < 0.001), but not with finishing times in those rounds. Of the 57 champions, 40 won both their heat and semi-final, even though a lower automatic qualification position would have been sufficient, and only 18 achieved a season's best time in the final. The will to win amongst the eventual champions (and other medallists) suggests predominantly ego oriented behaviour that is encouraged by a performance climate, and which did not appear to differ between men and women. Coaches and athletes are recommended to note that championship-specific physiological and psychological factors are important to develop in training and prior competition to improve both short- and long-term championship strategies. PMID- 29722600 TI - Improving collaboration between primary care and mental health services. AB - OBJECTIVE: Previous guidelines and planning documents have identified the key role primary care providers play in delivering mental health care, including the recommendation from the WHO that meeting the mental health needs of the population in many low and middle income countries will only be achieved through greater integration of mental health services within general medical settings. This position paper aims to build upon this work and present a global framework for enhancing mental health care delivered within primary care. METHODS: This paper synthesizes previous guidelines, empirical data from the literature and experiences of the authors in varied clinical settings to identify core principles and the key elements of successful collaboration, and organizes these into practical guidelines that can be adapted to any setting. RESULTS: The paper proposes a three-step approach. The first is mental health services that any primary care provider can deliver with or without the presence of a mental health professional. Second is practical ways that effective collaboration can enhance this care. The third looks at wider system changes required to support these new roles and how better collaboration can lead to new responses to respond to challenges facing all mental health systems. CONCLUSIONS: This simple framework can be applied in any jurisdiction or country to enhance the detection, treatment, and prevention of mental health problems, reinforcing the role of the primary care provider in delivering care and showing how collaborative care can lead to better outcomes for people with mental health and addiction problems. PMID- 29722601 TI - Asymetrie de pouvoir dans les partenariats de recherche en sante mondiale : etude qualitative aupres de chercheurs en Cote d'Ivoire. AB - : Resume : Contexte : L'asymetrie de pouvoir dans les partenariats de recherche en sante mondiale constitue un enjeu de justice et d'equite pour les institutions de recherche, les chercheurs et les communautes, en particulier dans les pays en developpement. Pour les chercheurs, l'asymetrie de pouvoir peut constituer un obstacle pour une recherche efficiente et equitable et ils sont a risque d'etre en situation de vulnerabilite. Objectifs : Ces enjeux sont largement discutes dans la litterature mais ce phenomene reste encore etudie au plan theorique et peu de donnees empiriques sont disponibles, particulierement dans les pays en developpement. Cette etude a donc pour objectifs d'identifier les facteurs et les mecanismes de l'asymetrie de pouvoir en recherche en sante mondiale dans la perspective de chercheurs dans un pays du sud. Methodologie : Une etude qualitative a ete menee aupres de 19 chercheurs dans le domaine de la sante en Cote d'Ivoire. Tous les participants poursuivaient une carriere universitaire d'enseignement et recherche, dont 17 cliniciens en Centre Hospitalier Universitaire et 2 chercheurs non cliniciens. Des entrevues semi-dirigees ont ete realisees pour evaluer leur perception sur les facteurs qui influencent l'asymetrie de pouvoir et les mecanismes par lesquels ils operent. Resultats : Deux themes principaux emergent de l'analyse des donnees : les defis du financement et la complexite des relations interpersonnelles dans les partenariats. DISCUSSION: Cette etude montre que la pression sur l'acces aux ressources contribue a deteriorer les conditions dans lesquelles les partenariats sont mis en oeuvre. Par ailleurs, l'environnement institutionnel de la recherche montre des liens de subordination qui font peser des risques sur l'autonomie des jeunes chercheurs et l'integrite de leurs travaux. A cet egard nous recommandons une analyse approfondie de l'environnement dans lequel ces partenariats sont mis en oeuvre notamment sur les dimensions de reddition de comptes, d'imputabilite et d'integrite professionnelle. PMID- 29722602 TI - Low-level laser therapy and interferential current in patients with knee osteoarthritis: a randomized controlled trial protocol. AB - The aim of this study is to investigate the effects of low-level laser therapy and interferential current (IFC) on pain intensity, central sensitization, muscle strength and functional capacity in patients with knee osteoarthritis. Participants will be patients aged between 50 and 80 years, with knee osteoarthritis, pain intensity ranging from 3 to 8 points (0-10 scale), Lequesne Algofunctional Index ranging from 5 to 15 points, and Kellgren & Lawrence grade >=2. A total of 168 patients will be randomly allocated into four groups as follows: active IFC + laser sham (G1), IFC sham + active laser (G2), active IFC + laser (G3) and IFC + laser sham (G4). Evaluators will be blinded to group allocation. Primary outcomes will be pain at rest and during movement measured with the visual analog pain scale. Clinical Trials Registry (NCT02898025. Registered on 20 April 2016). PMID- 29722603 TI - A Keynesian (demand reduction) approach to the opioid epidemic. PMID- 29722604 TI - Kilocalorie Expenditure and All-Cause Mortality in Older Male Veterans and Nonveterans. AB - The objective of this study was to determine the effect of self-reported leisure time physical activity, converted to kilocalorie expenditure and expressed as average daily expenditure, on all-cause mortality among older males 65 years of age and older in the University of Alabama at Birmingham (UAB) Study of Aging (SOA). Mean age of participants was 75.4 years. Multivariable Cox proportional hazard models evaluated the predictors of overall survival. Kilocalorie expenditure (p = .01), Black race (p = .02), young age (p < .00), fewer depressive symptoms (p = .00), and absence of cognitive impairment (p < .00) were significant independent predictors of higher rates of survival. Low body mass index was a significant independent predictor of death (p = .03). Veteran status did not improve survival. Further study about kilocalorie expenditure and mortality could lead to reductions in premature mortality in community-dwelling older men in the Deep South. PMID- 29722605 TI - A case-control study analyzing mannitol dosing for prevention of cisplatin induced acute nephrotoxicity. AB - Background Mannitol is an osmotic diuretic given routinely as part of cisplatin regimens to prevent nephrotoxicity, but there are limited data on the ideal dosage. At our center, three different doses of mannitol are used: 12, 20, and 40 g per cycle for cisplatin doses of >=50 mg/m2. The primary objective was to determine if variations in mannitol dosing significantly influence the incidence of cisplatin-induced acute nephrotoxicity. Methods A case-control study was performed. Electronic records of 1462 consecutive outpatients who received cisplatin at >= 50 mg/m2 per cycle between January 2010 and December 2014 were reviewed. Patients experiencing nephrotoxicity of any grade within 30 days of last cisplatin dose, as defined by NCI CTCAE 4.0, were matched to a minimum of two and maximum of five controls based on the following criteria: age +/- 5 years, baseline estimated glomerular filtration rate +/- 10 ml/min/1.73 m2, cisplatin dose per cycle, and presence of diabetes. Conditional logistic regression was used to identify baseline predictors of cisplatin-induced acute nephrotoxicity. Results Of the 1245 included patients, 237 had nephrotoxicity and 1008 were matched controls. Median baseline estimated glomerular filtration rate for cases and controls were 83 and 80 ml/min/1.73 m2, respectively. A total of 3.8% of cases experienced >= grade 3 nephrotoxicity. Univariable analysis showed that diabetes, lymphoma, low baseline estimated glomerular filtration rate, and low baseline magnesium level were significantly associated with nephrotoxicity, whereas mannitol dosing did not show any association (odds ratio 1.08; p = 0.29). In multivariable analysis, diabetes and lymphoma retained statistical significance, but baseline estimated glomerular filtration rate and baseline magnesium level showed nonsignificant associations with nephrotoxicity. Conclusions Cisplatin-induced acute nephrotoxicity remains common in patients with good baseline renal function despite preventive measures. Diabetes and lymphoma are predictors of nephrotoxicity, whereas mannitol dosing has no significant influence, suggesting that doses may be standardized across cisplatin regimens. PMID- 29722606 TI - Effect of virtual reality headset for pediatric fear and pain distraction during immunization. AB - AIM: Fear of needles is a well-known phobia among children and adults. This study presents the rationale, feasibility and results of a pilot study applying a virtual reality (VR) headset as a fear reduction and pain distraction during immunizations. PATIENTS & METHODS: 17 subjects and 17 parents rated their fear and pain level pre- and postimmunization using Wong-Baker pain scale and McMurtry children's fear scale. Immunization was provided, while subject was wearing a VR headset. RESULTS: Ratings of anticipated versus actual fear and pain due to immunizations improved following use of the VR headset in 94.1% of pediatric subjects. CONCLUSION: The use of a VR headset was well received and reduced overall fear and pain in children receiving immunizations. PMID- 29722607 TI - Feedback Control-Based Navigation of a Flying Insect-Machine Hybrid Robot. AB - This study reports the first ever demonstration of the aero navigation of a free flying insect based on feedback control. Instead of imitating the complicated kinetics and mechanisms of insect locomotion, a live insect can be directly transformed into a soft robot by embedding it with artificial devices. Since many insects can perform acrobatics aerially, thereby exhibiting far greater flexibility than current man-made flyers, correctly commanding the internal structures of an insect to perform based on the instructions would be a breakthrough. Herein, beetles (Mecynorrhina torquata) were chosen as the flying platform, and an inertial measurement unit-implemented electronic backpack was designed and manufactured to remotely command the beetles. To achieve horizontal flight control, multiple flight muscles of the beetles, that is, the basalar and third axillary muscles were stimulated to control the flight directions. However, the beetles were found to gradually adapt to the electrical stimulation, and the flight corrections were elicited by generating compensatory flight forces during a long-lasting stimulation (>300 ms), which were revealed by the decrease in induced lateral force. Based on this finding, a proportional derivative feedback controller was designed to navigate the flying beetles based on the predetermined path using frequency-dependent electrical pulses. To avoid a continuous stimulation, we proposed a stimulation protocol which separated two stimulations with a 50-ms rest. Compared to long stimulations (>300 ms), a 150-ms stimulation with 200-ms update interval was more efficient in correcting the flight direction of the beetles. PMID- 29722608 TI - Lysergic acid diethylamide and psilocybin for the management of patients with persistent pain: a potential role? AB - Recently, there has been interest in lysergic acid diethylamide (LSD) and psilocybin for depression, anxiety and fear of death in terminal illness. The aim of this review is to discuss the potential use of LSD and psilocybin for patients with persistent pain. LSD and psilocybin are 5-hydroxytryptamine receptor agonists and may interact with nociceptive and antinociceptive processing. Tentative evidence from a systematic review suggests that LSD (7 studies, 323 participants) and psilocybin (3 studies, 92 participants) may be beneficial for depression and anxiety associated with distress in life-threatening diseases. LSD and psilocybin are generally safe if administered by a healthcare professional, although further investigations are needed to assess their utility for patients with persistent pain, especially associated with terminal illness. PMID- 29722609 TI - "I didn't have anything to decide, I wanted to help my kids"-An interview-based study of consent procedures for sampling human biological material for genetic research in rural Pakistan. AB - BACKGROUND: Individual, comprehensive, and written informed consent is broadly considered an ethical obligation in research involving the sampling of human material. In developing countries, however, local conditions, such as widespread illiteracy, low levels of education, and hierarchical social structures, complicate compliance with these standards. As a result, researchers may modify the consent process to secure participation. To evaluate the ethical status of such modified consent strategies it is necessary to assess the extent to which local practices accord with the values underlying informed consent. METHODS: Over a 2-week period in April 2014 we conducted semistructured interviews with researchers from a genetic research institute in rural Pakistan and families who had given blood samples for their research. Interviews with researchers focused on the institute's requirements for consent, and the researchers' strategies for and experiences with obtaining consent in the field. Interviews with donors focused on their motivation for donating samples, their experience of consent and donation, and what factors were central in their decisions to give consent. RESULTS: Researchers often reported modifications to consent procedures suited to the local context, standardly employing oral and elder consent, and tailoring information to the social education level of donor families. Central themes in donors' accounts of their decision to consent were the hope of getting something out of their participation and their remarkably high levels of trust in the researchers. Several donor accounts indicated a degree of confusion about participation and diagnosis, resulting in misconceived expectations of therapeutic benefits. CONCLUSIONS: We argue that while building and maintaining trusting relationships in research is important-not least in developing countries strategies that serve this endeavor should be supplemented with efforts to ensure proper provision and understanding of relevant information, specifically about the nature of research and measures for individual consent and opt-out. PMID- 29722610 TI - Cinnamon Consumption Improves Clinical Symptoms and Inflammatory Markers in Women With Rheumatoid Arthritis. AB - OBJECTIVE: This study evaluated the effect of cinnamon on disease activity, serum levels of some inflammatory markers, and cardiovascular risk factors in women with rheumatoid arthritis (RA). METHODS: In this randomized double-blind clinical trial, 36 women with RA were randomly divided to 2 groups, receiving 4 capsules of either 500 mg cinnamon powder or placebo daily for 8 weeks. Fasting blood sugar (FBS), lipid profile, liver enzymes, serum levels of C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-alpha), erythrocyte sedimentation rate (ESR), blood pressure, and clinical symptoms were determined at baseline and end of the week 8. RESULTS: At the end of the study, there was a significant decrease of serum levels of CRP (p < 0.001) and TNF-alpha (p < 0.001) in the cinnamon group as compared to the placebo group. Diastolic blood pressure was also significantly lower in the intervention group compared with the control group (p = 0.017). Compared with placebo, cinnamon intake significantly reduced the Disease Activity Score (DAS-28) (p < 0.001), Visual Analogue Scale (VAS) (p < 0.001), and tender (TJC) (p < 0.001) and swollen joints (SJC) (p < 0.001) counts. No significant changes were observed for FBS, lipid profile, liver enzymes, or ESR. CONCLUSION: Cinnamon supplementation can be a safe and potential adjunct treatment to improve inflammation and clinical symptoms in patients with RA. PMID- 29722611 TI - The Race Has Begun! But How to Learn How to Race and Pace? PMID- 29722612 TI - Human errors and occupational injuries of older female workers in residential healthcare facilities for the elderly. AB - This study aimed to describe the characteristics of occupational injuries of female workers in residential healthcare facilities for the elderly, and to analyze human errors as causes of accidents. From the national industrial accident compensation data, 506 female injuries were analyzed by age and occupation. The results showed that medical service worker was the most prevalent (54.1%), followed by social welfare worker (20.4%). Among injuries, 55.7% had <1 year of work experience and 37.9% were aged >=60 years. Slips/falls were the most common type of accident (42.7%), and the proportion injured by slips/falls increases with age. Among human errors, action errors were the primary reasons, followed by perception errors and cognition errors. In addition, the ratios of injuries by perception errors and action errors increase with age. The findings of this study suggest that there is a need to design workplaces that accommodate the characteristics of older female workers. PMID- 29722613 TI - A comparison between the clinical significance and growth mixture modelling early change methods at predicting negative outcomes. AB - OBJECTIVE: Routine outcome monitoring benefits treatment by identifying potential no change and deterioration. The present study compared two methods of identifying early change and their ability to predict negative outcomes on self report symptom and wellbeing measures. METHOD: 1467 voluntary day patients participated in a 10-day group Cognitive Behaviour Therapy (CBT) program and completed the symptom and wellbeing measures daily. Early change, as defined by (a) the clinical significance method and (b) longitudinal modelling, was compared on each measure. RESULTS: Early change, as defined by the simpler clinical significance method, was superior at predicting negative outcomes than longitudinal modelling. The longitudinal modelling method failed to detect a group of deteriorated patients, and agreement between the early change methods and the final unchanged outcome was higher for the clinical significance method. CONCLUSIONS: Therapists could use the clinical significance early change method during treatment to alert them of patients at risk for negative outcomes, which in turn could allow therapists to prevent those negative outcomes from occurring. PMID- 29722614 TI - Editorial. PMID- 29722615 TI - Experimental investigation of nitric oxide removal from flue gas using hexamminecobalt(II) solution scrubbing in a pilot-scale facility. AB - An experimental investigation of operational parameters, including liquid/gas ratio (L/G), inlet nitric oxide (NO) concentration, reaction temperature, and pH value of absorbing agent, on NO removal efficiency with hexamminecobalt(II) solution scrubbing was conducted on a pilot-scale facility to search optimal operation conditions. The experimental results show that NO removal efficiency increased with the pH value of hexamminecobalt solution, while the improving rate dropped gradually. When the reaction temperature increased, the NO removal efficiency increased first and then decreased. At the same time, NO removal efficiency increased with the increasing of L/G and hexamminecobalt concentration, while the removal efficiency did not change much at low NO concentration. The pH of 10.4 and L/G of 16 L/m3 were close to the optimal operation conditions, and the scrubbing temperature fell within a reasonable operation temperature. The experimental results can be used as a reference for the design and operation of scaled-up industrial devices. PMID- 29722617 TI - Cheap labor: myosin fiber type expression and enzyme activity in the forelimb musculature of sloths (Pilosa: Xenarthra). AB - Sloths are canopy-dwelling inhabitants of American neotropical rainforests that exhibit suspensory behaviors. These abilities require both strength and muscular endurance to hang for extended periods of time; however, the skeletal muscle mass of sloths is reduced, thus requiring modifications to muscle architecture and leverage for large joint torque. We hypothesize that intrinsic muscle properties are also modified for fatigue resistance and predict a heterogeneous expression of slow/fast myosin heavy chain (MHC) fibers that utilize oxidative metabolic pathways for economic force production. MHC fiber type distribution and energy metabolism in the forelimb muscles of three-toed ( Bradypus variegatus, n = 5) and two-toed ( Choloepus hoffmanni, n = 4) sloths were evaluated using SDS-PAGE, immunohistochemistry, and enzyme activity assays. The results partially support our hypothesis by a primary expression of the slow MHC-1 isoform as well as moderate expression of fast MHC-2A fibers, whereas few hybrid MHC-1/2A fibers were found in both species. MHC-1 fibers were larger in cross-sectional area (CSA) than MHC-2A fibers and comprised the greatest percentage of CSA in each muscle sampled. Enzyme assays showed elevated activity for the anaerobic enzymes creatine kinase and lactate dehydrogenase compared with low activity for aerobic markers citrate synthase and 3-hydroxyacetyl CoA dehydrogenase. These findings suggest that sloth forelimb muscles may rely heavily on rapid ATP resynthesis pathways, and lactate accumulation may be beneficial. The intrinsic properties observed match well with suspensory requirements, and these modifications may have further evolved in unison with low metabolism and slow movement patterns as means to systemically conserve energy. NEW & NOTEWORTHY Myosin heavy chain (MHC) fiber type and fiber metabolic properties were evaluated to understand the ability of sloths to remain suspended for extended periods without muscle fatigue. Broad distributions of large, slow MHC-1 fibers as well as small, fast MHC-2A fibers are expressed in sloth forelimbs, but muscle metabolism is generally not correlated with myosin fiber type or body size. Sloth muscles rely on rapid, anaerobic pathways to resist fatigue and sustain force production. PMID- 29722618 TI - Noninvasive in-ear monitoring of intracranial pressure during microgravity in parabolic flights. AB - Among possible causes of visual impairment or headache experienced by astronauts in microgravity or postflight and that hamper their performance, elevated intracranial pressure (ICP) has been invoked but never measured for lack of noninvasive methods. The goal of this work was to test two noninvasive methods of ICP monitoring using in-ear detectors of ICP-dependent auditory responses, acoustic and electric, in acute microgravity afforded by parabolic flights. The devices detecting these responses were handheld tablets routinely used in otolaryngology for hearing diagnosis, which were customized for ICP extraction and serviceable by unskilled operators. These methods had been previously validated against invasive ICP measurements in neurosurgery patients. The two methods concurred in their estimation of ICP changes with microgravity, i.e., 11.0 +/- 7.7 mmHg for the acoustic method ( n = 7 subjects with valid results out of 30, auditory responses being masked by excessive in-flight noise in 23 subjects) and 11.3 +/- 10.6 mmHg for the electric method ( n = 10 subjects with valid results out of 10 tested despite the in-flight noise). These results agree with recent publications using invasive access to cerebrospinal fluid in parabolic flights and suggest that acute microgravity has a moderate average effect on ICP, similar to body tilt from upright to supine, yet with some subjects undergoing large effects whereas others seem immune. The electric in-ear method would be suitable for ICP monitoring in circumstances and with subjects such that invasive measurements are excluded. NEW & NOTEWORTHY In-ear detectors of intracranial pressure-dependent auditory responses allow intracranial pressure to be monitored noninvasively during acute microgravity. The average pressure increase during 20-s long sessions in microgravity is 11 mmHg, comparable with an effect of body tilt. However, intersubject variability is large, with subjects who repeatedly experience from nothing to twice the average effect. A systematic in-flight use would allow the relationship between space adaptation syndrome and ICP to be established or dismissed. PMID- 29722619 TI - Whole body vibration training increases physical measures and quality of life without altering inflammatory-oxidative biomarkers in patients with moderate COPD. AB - Whole body vibration training (WBVT) has been identified as an alternative intervention to improve exercise capacity and quality of life of patients with chronic obstructive pulmonary disease (COPD). However, the effect of WBVT on inflammatory-oxidative biomarkers remains unknown. The aim of this trial was to investigate the effects of WBVT on quality of life and physical and inflammatory oxidative parameters in patients with COPD. Twenty patients were equally divided into 1) an intervention group (IG) that performed the WBVT, and 2) a control group (CG) that did not receive any intervention. Intervention consisted in performing static squatting on a vibrating platform, in six series of 30 s, 3 days/wk, for 12 wk. Patients were evaluated for plasma levels of IL-6, IL-8, IFN gamma, soluble receptors of TNF-alpha; white cell count; plasma levels of oxidant and antioxidant markers; 6-min walking distance (6MWD); peak oxygen uptake (Vo2peak); handgrip strength; quality of life; timed 5-chair sit-to-stand (5STS); and timed get-up and go test (TUG). After WBVT, patients from IG showed a significant increase in the 6MWD, Vo2peak, and handgrip strength ( P < 0.05). Furthermore, patients from the IG reached minimal clinically important difference regarding quality of life. No significant differences were found in 5STS, TUG, inflammatory-oxidative biomarkers, and white cell count in the IG. The CG did not show significant improvement in all assessments ( P > 0.05). Taken together, our results demonstrated that the WBVT induced clinically significant benefits regarding exercise capacity, muscle strength, and quality of life in patients with COPD that were not related to inflammatory-oxidative biomarker changes. NEW & NOTEWORTHY Whole body vibration training is a new option for nonpharmacological treatment of chronic obstructive pulmonary disease (COPD). This study showed the potential of this training to improve exercise capacity, quality of life, and muscle strength in patients with COPD. Furthermore, to our knowledge this was the first study showing that vibration exercise does not modify the plasma levels of inflammatory-oxidative biomarkers, suggesting that the beneficial effects on physical measures and quality of life are independent of changes in biomarkers. PMID- 29722621 TI - Microvascular permeability of skeletal muscle after eccentric contraction-induced muscle injury: in vivo imaging using two-photon laser scanning microscopy. AB - Via modulation of endothelial integrity and vascular permeability in response to damage, skeletal muscle microvessels play a crucial permissive role in tissue leukocyte invasion. However, direct visual evidence of altered microvascular permeability of skeletal muscle has not been technically feasible, impairing mechanistic understanding of these responses. Two-photon laser scanning microscopy (TPLSM) allows three-dimensional in vivo imaging of skeletal muscle microcirculation. We hypothesized that the regulation of microvascular permeability in vivo is temporally related to acute inflammatory and regenerative processes following muscle injury. To test our hypothesis, tibialis anterior muscles of anesthetized male Wistar rats were subjected to eccentric contractions (ECCs) via electrical stimulation. The skeletal muscle microcirculation was imaged by an intravenously infused fluorescent dye (rhodamine B isothiocyanate dextran) to assess microvascular permeability via TPLSM 1, 3, and 7 days after ECC. Immunohistochemistry on serial muscle sections was performed to determine the proportion of VEGF-A-positive muscle fibers in the damaged muscle. Compared with control rats, the volumetrically determined interstitial leakage of fluorescent dye (5.1 +/- 1.4, 5.3 +/- 1.2 vs. 0.51 +/- 0.14 MUm3 * 106; P < 0.05, days 1 and 3, respectively, vs. control) and percentage of VEGF-A-positive fibers in the damaged muscle (10 +/- 0.4%, 22 +/- 1.1% vs. 0%; days 1 and 3, respectively, vs. control) were significantly higher on days 1 and 3 after ECC. The interstitial leakage volume returned to control by day 7. These results suggest that microvascular hyperpermeability assessed by in vivo TPLSM imaging is associated with ECC-induced muscle damage and increased VEGF expression. NEW & NOTEWORTHY This investigation employed a novel in vivo imaging technique for skeletal muscle microcirculation using two-photon laser scanning microscopy that enabled microvascular permeability to be assessed by four-dimensional image analysis. By combining in vivo imaging and histological analysis, we found the temporal profile of microvascular hyperpermeability to be related to that of eccentric contraction-induced skeletal muscle injury and pronounced novel myocyte VEGF expression. PMID- 29722622 TI - Blood flow occlusion-related O2 extraction "reserve" is present in different muscles of the quadriceps but greater in deeper regions after ramp-incremental test. AB - It was recently demonstrated that an O2 extraction reserve, as assessed by the near-infrared spectroscopy (NIRS)-derived deoxygenation signal ([HHb]), exists in the superficial region of vastus lateralis (VL) muscle during an occlusion performed at the end of a ramp-incremental test. However, it is unknown whether this reserve is present and/or different in magnitude in other portions and depths of the quadriceps muscles. We tested the hypothesis that an O2 extraction reserve would exist in other regions of this muscle but is greater in deep compared with more superficial portions. Superficial (VL-s) and deep VL (VL-d) as well as superficial rectus femoris (RF-s) were monitored by a combination of low- and high-power time-resolved (TRS) NIRS. During the occlusion immediately post ramp-incremental test there was a significant overshoot in the [HHb] signal ( P < 0.05). However, the magnitude of this increase was greater in VL-d (93.2 +/- 42.9%) compared with VL-s (55.0 +/- 19.6%) and RF-s (47.8 +/- 14.0%) ( P < 0.05). The present study demonstrated that an O2 extraction reserve exists in different pools of active muscle fibers of the quadriceps at the end of a ramp exercise to exhaustion. The greater magnitude in the reserve observed in the deeper portion of VL, however, suggests that this portion of muscle may present a greater surplus of oxygenated blood, which is likely due to a greater population of slow twitch fibers. These findings add to the notion that the plateau in the [HHb] signal toward the end of a ramp-incremental exercise does not indicate the upper limit of O2 extraction. NEW & NOTEWORTHY Different portions of the quadriceps muscles exhibited an untapped O2 extraction reserve during a blood flow occlusion performed at the end of a ramp-incremental exercise. In the deeper portion of the vastus lateralis muscle, this reserve was greater compared with superficial vastus lateralis and rectus femoris. These data suggest that the O2 extraction reserve may be dependent on the vascular and/or oxidative capacities of the muscles. PMID- 29722620 TI - Elevated extracellular potassium prior to muscle contraction reduces onset and steady-state exercise hyperemia in humans. AB - The increase in interstitial potassium (K+) during muscle contractions is thought to be a vasodilatory signal that contributes to exercise hyperemia. To determine the role of extracellular K+ in exercise hyperemia, we perfused skeletal muscle with K+ before contractions, such that the effect of any endogenously-released K+ would be minimized. We tested the hypothesis that local, intra-arterial infusion of potassium chloride (KCl) at rest would impair vasodilation in response to subsequent rhythmic handgrip exercise in humans. In 11 young adults, we determined forearm blood flow (FBF) (Doppler ultrasound) and forearm vascular conductance (FVC) (FBF/mean arterial pressure) during 4 min of rhythmic handgrip exercise at 10% of maximal voluntary contraction during 1) control conditions, 2) infusion of KCl before the initiation of exercise, and 3) infusion of sodium nitroprusside (SNP) as a control vasodilator. Infusion of KCl or SNP elevated resting FVC similarly before the onset of exercise (control: 39 +/- 6 vs. KCl: 81 +/- 12 and SNP: 82 +/- 13 ml.min-1.100 mmHg-1; both P < 0.05 vs. control). Infusion of KCl at rest diminished the hyperemic (DeltaFBF) and vasodilatory (DeltaFVC) response to subsequent exercise by 22 +/- 5% and 30 +/- 5%, respectively (both P < 0.05 vs. control), whereas SNP did not affect the change in FBF ( P = 0.74 vs. control) or FVC ( P = 0.61 vs. control) from rest to steady state exercise. These findings implicate the K+ ion as an essential vasodilator substance contributing to exercise hyperemia in humans. NEW & NOTEWORTHY Our findings support a significant and obligatory role for potassium signaling in the local vasodilatory and hyperemic response to exercise in humans. PMID- 29722624 TI - Cross talk between androgen and Wnt signaling potentially contributes to age related skeletal muscle atrophy in rats. AB - We sought to determine whether age-related gastrocnemius muscle mass loss was associated with parallel decrements in androgen receptor (AR) or select Wnt signaling markers. To test this hypothesis, serum-free and total testosterone (TEST) and gastrocnemius AR and Wnt signaling markers were analyzed in male Fischer 344 rats that were 3, 6, 12, 18, and 24 mo (mo) old ( n = 9 per group). Free and total TEST was greatest in 6 mo rats, and AR protein and Wnt5 protein levels linearly declined with aging. There were associations between Wnt5 protein levels and relative gastrocnemius mass ( r = 0.395, P = 0.007) as well as AR and Wnt5 protein levels (r = 0.670, P < 0.001). We next tested the hypothesis that Wnt5 affects muscle fiber size by treating C2C12-derived myotubes with lower (75 ng/ml) and higher (150 ng/ml) concentrations of recombinant Wnt5a protein. Both treatments increased myotube size ( P < 0.05) suggesting this ligand may affect muscle fiber size in vivo. We next tested if Wnt5a protein levels were androgen modulated by examining 10-mo-old male Fischer 344 rats ( n = 10-11 per group) that were orchiectomized and treated with testosterone-enanthate (TEST-E); trenbolone enanthate (TREN), a nonaromatizable synthetic testosterone analogue; or a vehicle (ORX only) for 4 wk. Interestingly, TEST-E and TREN treatments increased Wnt5a protein in the androgen-sensitive levator ani/bulbocavernosus muscle compared with ORX only ( P < 0.05). To summarize, aromatizable and nonaromatizable androgens increase Wnt5a protein expression in skeletal muscle, age-related decrements in muscle AR may contribute Wnt5a protein decrements, and our in vitro data imply this mechanism may contribute to age-related muscle loss. NEW & NOTEWORTHY Results from this study demonstrate androgen and Wnt5 protein expression decrease with aging, and this may be a mechanism involved with age related muscle loss. PMID- 29722623 TI - Force properties of skinned cardiac muscle following increasing volumes of aerobic exercise in rats. AB - The positive effects of chronic endurance exercise training on health and performance have been well documented. These positive effects have been evaluated primarily at the structural level, and work has begun to evaluate mechanical adaptations of the myocardium. However, it remains poorly understood how the volume of exercise training affects cardiac adaptation. To gain some understanding, we subjected 3-mo-old Sprague-Dawley rats ( n = 23) to treadmill running for 11 wk at one of three exercise volumes (moderate, high, and extra high). Following training, hearts were excised and mechanical testing was completed on skinned trabecular fiber bundles. Performance on a maximal fitness test was dose dependent on training volume, where greater levels of training led to greater performance. No differences were observed between animals from any group for maximal active stress and passive stress at a sarcomere length of 2.2 um. Heart mass and passive stress at sarcomere lengths beyond 2.4 um increased in a dose-dependent manner for animals in the control and moderate- and high duration groups. However, hearts from animals in the extra high-duration group presented with inhibited responses for heart mass and passive stress, despite performing greatest on a graded treadmill fitness test. These results suggest that heart mass and passive stress adapt in a dose-dependent manner, until exercise becomes excessive and adaptation is inhibited. Our findings are in agreement with the beneficial role exercise has in cardiac adaptation. However, excessive exercise comes with risks of maladaptation, which must be weighed against the desire to increase performance. NEW & NOTEWORTHY For the first time, we present findings on cardiac trabecular muscle passive stiffness and show the effect of excessive exercise on the heart. We demonstrated that heart mass increases with exercise until a maximum, after which greater exercise volume results in inhibited adaptation. At paraphysiological lengths, passive stiffness increases with exercise but to a lesser degree with excessive training. Despite greater performance on graded exercise tests, animals in the highest trained group exhibited possible maladaptation. PMID- 29722625 TI - Microvascularization is not a limiting factor for exercise in adults with cerebral palsy. AB - Muscle contractures are a common complication in patients with central nervous system (CNS) lesions which limit range of movement and cause joint deformities. Furthermore, it has previously been shown that muscles with contractures have a reduced number of capillaries, indicating decreased tissue vascularization. The aim of the present study was to investigate the microvascular volume (MV) at rest and after acute exercise in the muscle tissue of individuals with cerebral palsy (CP) and healthy control individuals. Contrast-enhanced ultrasound (CEUS) was used before and after 30 min of walking or running on a treadmill in 10 healthy control participants and 10 individuals with CP to detect MV of their skeletal muscle tissue. A significant increase in the MV was observed after exercise both in the adult CP group (21-53 yr) and in the control group (21-52 yr) (1.8 +/- 0.8 DeltadB to 3.1 +/- 0.9 DeltadB or 42.9% and 1.5 +/- 0.6 DeltadB to 2.5 +/- 0.9 DeltadB or 39.0%, respectively). Furthermore, a difference in the resting MV was observed between the most severe cases of CP [gross motor function classification scale (GMFCS) 3 and 4] (2.3 +/- 0.5 DeltadB) and the less severe cases (GMFCS 1 and 2) (1.5 +/- 0.2 DeltadB). When the CP group was walking (3.4 km/h), the lactate levels, Borg score, and heart rate matched the level of controls when they were running (9.8 km/h). In conclusion, individuals with CP become exhausted at much lower exercise intensities than healthy individuals. This is not explained by impaired microvascularization, since the MV of the individuals with CP respond normally to increased O2 demand during acute exercise. NEW & NOTEWORTHY Cerebral palsy (CP) patients were less physically active compared with typically developed individuals. This may affect the microvascularization. We observed that the CP group became exhausted at much lower exercise intensities compared with healthy individuals. However, impaired microvascularization was not the reason for the decreased physical activity as the CP group responded normally to increased O2 demand during acute exercise. These results indicate that walking may be recommended as an intervention to train and maintain skeletal muscle tissue in individuals with CP. PMID- 29722626 TI - Abundance of ClC-1 chloride channel in human skeletal muscle: fiber type specific differences and effect of training. AB - Cl- channel protein 1 (ClC-1) may be important for excitability and contractility in skeletal muscle, but ClC-1 abundance has not been examined in human muscle. The aim of the present study was to examine ClC-1 abundance in human skeletal muscle, including fiber type specific differences and the effect of exercise training. A commercially available antibody was tested with positive and negative control tissue, and it recognized specifically ClC-1 in the range from 100 to 150 kDa. Abundance of ClC-1 was 38% higher ( P < 0.01) in fast twitch Type IIa muscle fibers than in slow twitch Type I. Muscle ClC-1 abundance did not change with 4 wk of training consisting of 30 min cycling at 85% of maximal heart rate (HRmax) and 3 * 30-s all out sprints or during a 7-wk training period with 10-12 * 30 s uphill cycling and 4-5 * ~4 min cycling at 90%-95% of HRmax. ClC-1 abundance correlated negatively ( P < 0.01) with maximal oxygen consumption ( r = -0.552) and incremental exercise performance ( r = -0.546). In addition, trained cyclists had lower ( P < 0.01) ClC-1 abundance than lesser trained individuals. The present observations indicate that a low abundance of muscle ClC-1 may be beneficial for exercise performance, but the role of abundance and regulation of ClC-1 in skeletal muscle of humans with respect to exercise performance and trainability need to be elucidated. NEW & NOTEWORTHY Abundance of the Cl- channel protein 1 (ClC-1) chloride channel may be important for excitability and contractility in human skeletal muscle and may therefore have implications for fatigue development. In this study, we confirmed ClC-1 specificity for a commercially available antibody, and this study is first to our knowledge to determine ClC-1 protein abundance in human muscle by Western blotting. We observed that abundance of ClC-1 was higher in fast compared with slow twitch fibers and lower in trained individuals than in recreationally active. PMID- 29722627 TI - Effect of dietary nitrate supplementation on conduit artery blood flow, muscle oxygenation, and metabolic rate during handgrip exercise. AB - Dietary nitrate supplementation has positive effects on mitochondrial and muscle contractile efficiency during large muscle mass exercise in humans and on skeletal muscle blood flow (Q) in rats. However, concurrent measurement of these effects has not been performed in humans. Therefore, we assessed the influence of nitrate supplementation on Q and muscle oxygenation characteristics during moderate- (40 %peak) and severe-intensity(85% peak) handgrip exercise in a randomized, double-blind, crossover design. Nine healthy men (age: 25 +/- 2 yr) completed four constant-power exercise tests (2/intensity) randomly assigned to condition [nitrate-rich (nitrate) or nitrate-poor (placebo) beetroot supplementation] and intensity (40 or 85% peak). Resting mean arterial pressure was lower after nitrate compared with placebo (84 +/- 4 vs. 89 +/- 4 mmHg, P < 0.01). All subjects were able to sustain 10 min of exercise at 40% peak in both conditions. Nitrate had no effect on exercise tolerance during 85% peak (nitrate: 358 +/- 29; placebo: 341 +/- 34 s; P = 0.3). Brachial artery Q was not different after nitrate at rest or any time during exercise. Deoxygenated [hemoglobin + myoglobin] was not different for 40% peak ( P > 0.05) but was elevated throughout 85% peak ( P < 0.05) after nitrate. The metabolic cost (Vo2) was not different at the end of exercise; however, the Vo2 primary amplitude at the onset of exercise was elevated after nitrate for the 85% peak work rate (96 +/- 20 vs. 72 +/- 12 ml/min, P < 0.05) and had a faster response. These findings suggest that an acute dose of nitrate reduces resting blood pressure and speeds Vo2 kinetics in young adults but does not augment Q or reduce steady-state Vo2 during small muscle mass handgrip exercise. NEW & NOTEWORTHY We show that acute dietary nitrate supplementation via beetroot juice increases the amplitude and speed of local muscle Vo2 on kinetics parameters during severe- but not moderate-intensity handgrip exercise. These changes were found in the absence of an increased blood flow response, suggesting that the increased Vo2 was attained via improvements in fractional O2 extraction and/or spatial distribution of blood flow within the exercising muscle. PMID- 29722628 TI - The imagined order. PMID- 29722630 TI - An industry update: the latest developments in Therapeutic delivery. AB - The present industry update covers the period of 1 January-31 January 2018, with information sourced from company press releases, regulatory and patent agencies as well as scientific literature. Several public offerings (Gecko, Insmed), licensing (Foresee) and commercialization agreements (Alnylam, Collegium Pharmaceutical) as well as patent filings (Elute) continue to prove the sustained investments in the drug delivery market. In increasing numbers, more effective ways to deliver the active ingredient to the right location and the right dose through devices (Boehringer Ingelheim's Respimat, Medtronics' SynchroMedII) or improved compound properties through formulation (Aquestive Therapeutics' PharmFilm, Noven Pharmaceuticals' transdermal patch) are reaching the market. Furthering biologics and gene delivery (Avacta, Bracco) proves that novel drug delivery technologies are successfully addressing more challenging drug formats. PMID- 29722629 TI - Cognitive function, disease burden and the structural connectome in systemic lupus erythematosus. AB - Objective To investigate brain structural connectivity in relation to cognitive abilities and systemic damage in systemic lupus erythematosus (SLE). Methods Structural and diffusion MRI data were acquired from 47 patients with SLE. Brains were segmented into 85 cortical and subcortical regions and combined with whole brain tractography to generate structural connectomes using graph theory. Global cognitive abilities were assessed using a composite variable g, derived from the first principal component of three common clinical screening tests of neurological function. SLE damage ( LD) was measured using a composite of a validated SLE damage score and disease duration. Relationships between network connectivity metrics, cognitive ability and systemic damage were investigated. Hub nodes were identified. Multiple linear regression, adjusting for covariates, was employed to model the outcomes g and LD as a function of network metrics. Results The network measures of density (standardised beta = 0.266, p = 0.025) and strength (standardised beta = 0.317, p = 0.022) were independently related to cognitive abilities. Strength (standardised beta = -0.330, p = 0.048), mean shortest path length (standardised beta = 0.401, p = 0.020), global efficiency (standardised beta = -0.355, p = 0.041) and clustering coefficient (standardised beta = -0.378, p = 0.030) were independently related to systemic damage. Network metrics were not related to current disease activity. Conclusion Better cognitive abilities and more SLE damage are related to brain topological network properties in this sample of SLE patients, even those without neuropsychiatric involvement and after correcting for important covariates. These data show that connectomics might be useful for understanding and monitoring cognitive function and white matter damage in SLE. PMID- 29722631 TI - Nano-carriers for targeted delivery and biomedical imaging enhancement. AB - Theranostic approaches using nanotechnology have been a hot research area for the past decade. All nano drug delivery techniques and architectures have some limitations, as do diagnostic nano-approaches. Thus, combining nano drug delivery strategies with diagnostic techniques using nanoparticles for improving imaging modalities has been the key to fill up those gaps. In the past decade, lots of approaches have been made with different combinations of biomaterials fabricated/synthesized to nanostructures with modified surface functionalization to improve their overall theranostic properties. This article summarizes recent research works based on the biomaterials used for fabricating these nanostructures. Their combinations with other biomaterials have been demonstrated with their overall advantages and limitations. PMID- 29722632 TI - Track analysis of the passage of rhodamine-labeled liposomes across porcine jejunal mucus in a microchannel device. AB - AIM: To investigate how surface charge and hydrophilicity affect the mucopermeation of liposomes across intestinal mucus. METHODOLOGY: Rhodamine labeled liposomes (~120-130 nm) with different surface charges were investigated for their capacity to flux across fresh porcine jejunal mucus in a microchannel device. Fluorescent microscopy and tracking analysis were used to measure liposome movement, while fluorescence lifetime imaging microscopy was utilized to determine mucus pH. RESULTS: Mucopermeation was dependent on hydrophilicity and surface charge - anionic liposomes permeated more than cationic. The most cationic liposomal prototype agglomerated mucus. Presence of Na+, K+ and Mg2+ increased both speed and straightness of the pathways for all prototypes. Cationic but not anionic liposomes caused acidification (pH 2.5). CONCLUSION: Acidification caused by cationic liposomes explains their ability to interfere with mucus stability. Surface charge of liposomes strongly influences mucopermeation capability. PMID- 29722633 TI - A novel transdermal drug-delivery patch for treating local muscular pain. PMID- 29722634 TI - Reverse-engineered silk hydrogels for cell and drug delivery. AB - Silk is an important biopolymer for (bio)medical applications because of its unique and highly versatile structure and its robust clinical track record in human medicine. Silk can be processed into many material formats, including physically and chemically cross-linked hydrogels that have almost limitless applications ranging from tissue engineering to biomedical imaging and sensing. This concise review provides a detailed background of silk hydrogels, including silk structure-function relationships, biocompatibility and biodegradation, and it explores recent developments in silk hydrogel utilization, with specific reference to drug and cell delivery. We address common pitfalls and misconceptions while identifying emerging opportunities, including 3D printing. PMID- 29722635 TI - Recent and future advances in anticancer drug delivery: an interview with Khaled Greish. AB - Khaled Greish speaks to Hannah Makin, Commissioning Editor: Khaled Greish is Associate Professor of Molecular Medicine, and head of the Nano-research unit, at Princes Al-Jawhara Center, Arabian Gulf University, Kingdom of Bahrain. His previous appointments included Senior lecturer of Pharmacology at the University of Otago, New Zealand, and Assistant Professor of Pharmaceutical Chemistry at University of Utah (UT, USA). He has published >70 peer reviewed papers, and ten book chapters in the field of targeted anticancer drug delivery. Controlled Release Society (CRS) awarded him the CRS Postdoctoral Achievement Award in 2008 and in 2010; he was elected as member of the CRS College of Fellows. In recognition of his research, University of Otago awarded him "Early Career Awards for Distinction in Research" in 2014. His research focuses on nanomedicine, tumor vascular biology and anticancer drug discovery/development. PMID- 29722637 TI - Psychometric Properties of Eight-Item Physical Activity Enjoyment Scale in a Chinese Population. AB - This study examined the psychometric properties of the eight-item Physical Activity Enjoyment Scale (PACES) in Hong Kong older adults. Study 1 assessed the scale's factor validity and test-retest reliability, whereas Study 2 examined its convergent validity in Hong Kong older adults. A total of 168 (Study 1) older adults completed the PACES twice over a 2-week interval, and 57 (Study 2) older adults completed both the eight-item PACES and a measure of quality of life. The results of both studies showed that the eight-item PACES had a high degree of internal consistency. Both the composite reliability and average variance extracted from Study 1 were high, suggesting that as a set, the eight items of the PACES reliably measured the construct. The observed test-retest reliability was satisfactory over a 2-week interval. This eight-item PACES is an expedited and reliable instrument for assessing physical activity enjoyment in Chinese older adults. PMID- 29722636 TI - Recent advances in nanomedicine for sepsis treatment. AB - Sepsis and septic shock are life-threating conditions, which form a continuum of the body's response to overwhelming infection. The current treatment consists of fluid and metabolic resuscitation, hemodynamic and end-organ support, and timely initiation of antibiotics. However, these measures may be ineffective and the sepsis-related mortality toll remains substantial; therefore, an urgent need exists for new therapies. Recently, several nanoparticle (NP) systems have shown excellent protective effects against sepsis in preclinical models, suggesting a potential utility in the management of sepsis and septic shock. These NPs serve as antibacterial agents, provide platforms to immobilize endotoxin adsorbents, interact with inflammatory cells to restore homeostasis and detect biomarkers of sepsis for timely diagnosis. This review discusses the recent developments in NP based approaches for the treatment of sepsis. PMID- 29722638 TI - Health assessment of self-employed in the food service industry. AB - Objectives This study's objective was to assess the morbidity of self-employed workers in the food service industry, an industry with a large amount of occupational health risks. Methods A cross-sectional study, consisting of 437 participants, was conducted between 2011 and 2013 in Champagne-Ardenne, France. The health questionnaire included an interview, a clinical examination, and medical investigations. Results The study population consisted of 146 self employed workers (not working for an employer) and 291 employees (working with employment contracts for an employer). Logistic regression analysis revealed that self-employed workers had a higher morbidity than employees, after adjusting for age (OR: 3.45; 95% CI: 1.28 to 9.25). Main adverse health conditions were joint pain (71.2% self-employed vs. 38.1% employees, p < 0.001), ear disorders (54.1% self-employed vs. 33.7%, employees, p < 0.001), and cardiovascular diseases (47.3% self-employed vs. 21% employees, p < 0.001). Conclusions The study highlights the need for occupational health services for self-employed workers in France so that they may benefit from prevention of occupational risks and health surveillance. Results were presented to the self-employed healthcare insurance fund in order to establish an occupational health risks prevention system. PMID- 29722639 TI - Efficacy of rituximab in refractory RRMS. AB - OBJECTIVE: To investigate the efficacy of rituximab as rescue therapy in patients with relapsing-remitting multiple sclerosis (RRMS) and persistent disease activity confirmed by magnetic resonance imaging (MRI) despite immunosuppressive disease-modifying therapy (DMT). METHODS: In this observational nationwide retrospective multicenter study, we first identified 351 off-label rituximab treated patients through a cohort of 15,984 RRMS patients. In this group, we identified patients with disease activity prior to rituximab confirmed by MRI (one or more new T2 lesion and/or gadolinium-enhancing lesion) despite immunosuppressive DMT (fingolimod, natalizumab, or mitoxantrone) with a follow-up after rituximab initiation longer than 6 months. Outcome data were collected from the French Observatory of Multiple Sclerosis (OFSEP) register and medical charts. RESULTS: A total of 50 patients were identified. Median rituximab treatment duration was 1.1 (0.5-6.4) year. Mean annualized relapse rate significantly decreased from 0.8 during last immunosuppressive DMT to 0.18 after rituximab ( p < 0.0001). While 72% of patients showed gadolinium-enhancing lesions on the last MRI performed during last immunosuppressive DMT, 8% of them showed gadolinium enhancing lesions on the first MRI performed 6.1 (range 1.4-18.4) months after rituximab ( p < 0.0001). CONCLUSION: This study provides level IV evidence that rituximab reduces clinical and MRI disease activity in patients with active RRMS despite immunosuppressive DMT. PMID- 29722641 TI - Editorial: In Silico Methodologies Applied to Drug Discovery. PMID- 29722640 TI - Extracorporeal shockwave therapy for intermittent claudication: Medium-term outcomes from a double-blind randomised placebo-controlled pilot trial. AB - : Objectives Peripheral arterial disease most commonly presents as intermittent claudication (IC). Early evidence has suggested that extracorporeal shockwave therapy is efficacious in the short term for the management of intermittent claudication. The objective of this pilot trial was to evaluate the medium-term efficacy of this treatment. Methods This double-blind randomised placebo controlled pilot trial randomised patients with unilateral intermittent claudication in a 1:1 fashion to receive extracorporeal shockwave therapy or a sham treatment for three sessions per week over three weeks. Primary outcomes were maximum walking distance and intermittent claudication distance using a fixed-load treadmill test. Secondary outcomes included pre- and post-exertional ankle-brachial pressure indices, safety and quality of life assessed using generic (SF36, EQ-5D-3L) and disease-specific (vascular quality of life) measures. All outcome measures were assessed at 12 months post-treatment. Results Thirty participants were included in the study (extracorporeal shockwave therapy, n = 15; sham, n = 15), with 26 followed up and analysed at 12 months (extracorporeal shockwave therapy, n = 13; sham, n = 13). Intragroup analysis demonstrated significant improvements in maximum walking distance, intermittent claudication distance and post-exertional ankle-brachial pressure indices ( p < 0.05) in the active treatment group, with no improvements in pre-exertional ankle brachial pressure indices. Significant improvements in quality of life were observed in 3 out of 19 domains assessed in the active group. A re-intervention rate of 26.7% was seen in both groups. Conclusions These findings suggest that extracorporeal shockwave therapy is effective in improving walking distances at 12 months. Although this study provides important pilot data, a larger study is needed to corroborate these findings and to investigate the actions of this treatment. ISRCTN: NCT02652078. PMID- 29722642 TI - Editorial: Computational Methods for Drug Aid Design. PMID- 29722643 TI - A focus on paediatric obstructive sleep apnoea. PMID- 29722644 TI - Oceanisphaera avium sp. nov., isolated from the gut of the cinereous vulture, Aegypius monachus. AB - A Gram-stain-negative, aerobic, catalase- and oxidase-positive, rod-shaped, flagellated bacterial strain, designated AMac2203T, was isolated from the gut of the cinereous vulture, Aegypiusmonachus, collected from the Seoul Grand Park Zoo, Republic of Korea. Strain AMac2203T grew optimally at 15-25 degrees C, pH 7-8 and in the presence of 3-5 % (w/v) NaCl. Phylogenetic analysis revealed 97.4-97.9 % and 96.9-97.3 % sequence similarities of the 16S rRNA genes to its counterparts in Oceanisphaera profunda SM1222T and Oceanisphaera ostreae T-w6T, respectively. The predominant fatty acids (>10 %) of strain AMac2203T were summed feature 3 (C16 : 0omega7c and/or C16 : 1omega6c, 33.6 %), summed feature 8 (C18 : 1omega7c, 24.5 %) and C16 : 0 (19.9 %). The primary isoprenoid quinone was ubiquinone-8. Polar lipids included phosphatidylethanolamine, phosphatidylglycerol, diphosphatidylglycerol, an unidentified amino lipid and an unidentified lipid. Based on complete genome sequencing of strain AMac2203T and the closest related type strain, O. profunda, the OrthoANI value is 77.5 %, which is below the 95 % cut-off for species demarcation. The genomic DNA G+C content of strain AMac2203T is 47.1 mol%. Thus, strain AMac2203T represents a novel species candidate of the genus Oceanisphaera. We propose the name Oceanisphaeraavium sp. nov., with strain AMac2203T (=KCTC 62118T=JCM 32207T) as the type strain. PMID- 29722645 TI - Paracoccus fontiphilus sp. nov., isolated from a freshwater spring. AB - Strain MVW-1T, isolated from a freshwater spring in Taiwan, was characterized by using a polyphasic taxonomy approach. Phylogenetic analyses based on 16S rRNA gene sequences indicated that strain MVW-1T belongs to the genus Paracoccus and has the highest levels of sequence similarity to Paracoccus caeni MJ17T (97.6 %), Paracoccus sediminis CMB17T (97.4 %), Paracoccus angustae E6T (97.3 %) and Paracoccus acridae SCU-M53T (97.1 %). Cells were Gram-stain-negative, aerobic, poly-beta-hydroxybutyrate-accumulating, non-motile, rod-shaped and formed light orange-coloured colonies. Optimal growth occurred at 20-25 degrees C, pH 6-7, and in the presence of 0-3 % NaCl. The major fatty acid of strain MVW-1T was C18 : 1omega7c. The polar lipid profile consisted of phosphatidylglycerol, phosphatidylethanolamine, phosphatidylcholine, diphosphatidylglycerol, an unidentified glycolipid, an unidentified aminolipid and three unidentified phospholipids. The predominant polyamines were spermidine, putrescine and cadaverine. The only isoprenoid quinone was Q-10. The genomic DNA G+C content of strain MVW-1T was 63.4 mol%. Strain MVW-1T exhibited less than 35 % DNA-DNA relatedness to P. caeni MJ17T, P. angustae E6T, P. sediminis CMB17T and P. acridae SCU-M53T. On the basis of phenotypic and genotypic properties and phylogenetic inference, strain MVW-1T should be classified in a novel species of the genus Paracoccus, for which the name Paracoccus fontiphilus sp. nov. is proposed. The type strain is MVW-1T (=BCRC 80974T=LMG 29554T=KCTC 52239T). PMID- 29722646 TI - Two novel noroviruses and a novel norovirus genogroup in California sea lions. AB - In this study, two novel noroviruses (NoVs) were discovered from faecal samples from California sea lions from an oceanarium in Hong Kong, and named California sea lion NoV 1 (Csl/NoV1) and California sea lion NoV 2 (Csl/NoV2). Whole-genome sequencing showed that the genome organization and amino acid motifs of both Csl/NoV1 and Csl/NoV2 were typical of those of other NoVs in their open reading frames (ORFs). Csl/NoV1 possessed only 52.6-52.8 % amino acid identity in VP1 to the closest matches in genogroup GII. Therefore, Csl/NoV1 should constitute a novel genogroup of NoV. Shifting of the phylogenetic position of Csl/NoV1 in the RdRp, VP1 and VP2 trees was observed, which may have been due to recombination events and/or biased mutations. Csl/NoV2 possessed 55.4-56.2 % amino acid identity in VP1 to its closest relatives in genogroup GVI, which means that it represents a new genotype in genogroup GVI. Further studies will reveal what diseases these NoVs can cause in marine mammals. PMID- 29722650 TI - Locally Advanced Lung Cancer: Is It Time to Take Cardiac Protection Seriously in Radiation Planning? PMID- 29722651 TI - Relapsing Prostate Cancer: Castrate or Cure? PMID- 29722652 TI - Live to SABR Another Day? PMID- 29722649 TI - Network oscillation rules imposed by species-specific electrical coupling. AB - Electrical junctions are widespread within the mammalian CNS. Yet, their role in organizing neuronal ensemble activity remains incompletely understood. Here, in a functionally well-characterized system - neuroendocrine tuberoinfundibular dopamine (TIDA) neurons - we demonstrate a striking species difference in network behavior: rat TIDA cells discharge in highly stereotyped, robust, synchronized slow oscillations, whereas mouse oscillations are faster, flexible and show substantial cell-to-cell variability. We show that these distinct operational modes are explained by the presence of strong TIDA-TIDA gap junction coupling in the rat, and its complete absence in the mouse. Both species, however, encompass a similar heterogeneous range of intrinsic resonance frequencies, suggesting similar network building blocks. We demonstrate that gap junctions select and impose the slow network rhythm. These data identify a role for electrical junctions in determining oscillation frequency and show how related species can rely on distinct network strategies to accomplish adaptive control of hormone release. PMID- 29722648 TI - Distinct 'safe zones' at the nuclear envelope ensure robust replication of heterochromatic chromosome regions. AB - Chromosome replication and transcription occur within a complex nuclear milieu whose functional subdomains are beginning to be mapped out. Here we delineate distinct domains of the fission yeast nuclear envelope (NE), focusing on regions enriched for the inner NE protein, Bqt4, or the lamin interacting domain protein, Lem2. Bqt4 is relatively mobile around the NE and acts in two capacities. First, Bqt4 tethers chromosome termini and the mat locus to the NE specifically while these regions are replicating. This positioning is required for accurate heterochromatin replication. Second, Bqt4 mobilizes a subset of Lem2 molecules around the NE to promote pericentric heterochromatin maintenance. Opposing Bqt4 dependent Lem2 mobility are factors that stabilize Lem2 beneath the centrosome, where Lem2 plays a crucial role in kinetochore maintenance. Our data prompt a model in which Bqt4-rich nuclear subdomains are 'safe zones' in which collisions between transcription and replication are averted and heterochromatin is reassembled faithfully. PMID- 29722653 TI - Androgen Deprivation Fortified. PMID- 29722654 TI - Apply an Oligometastatic Paradigm for Nodal Recurrence. PMID- 29722655 TI - The Role of Radiation Therapy in Patients With Relapsed or Refractory Hodgkin Lymphoma: Guidelines From the International Lymphoma Radiation Oncology Group. AB - Relapsed and refractory Hodgkin lymphoma (HL) challenges clinicians to devise treatment strategies that are effective and safe. This problem is particularly prominent in an era when de-escalation trials are designed to minimize therapeutic toxicities in both early- and advanced-stage disease. Radiation therapy is the single most effective treatment modality for HL, and its integration into salvage regimens, or its independent use in select patients, must be understood to maximize our success in treating these patients. The complexity of treating relapsed or refractory HL derives from the spectrum of primary treatment approaches currently in use that creates heterogeneity in both treatment exposure and the potential toxicities of salvage therapy. Patients can have relapsed or refractory disease after limited or aggressive primary therapy (with or without radiation therapy), at early or delayed time points, with limited or extensive disease volumes, and with varying degrees of residual morbidity from primary therapy. Their response to salvage systemic therapy can be partial or complete, and the use of consolidative stem cell transplantation is variably applied. New biologics and immunotherapeutic approaches have broadened but also complicated salvage treatment approaches. Through all of this, radiation therapy remains an integral component of treatment for many patients, but it must be used effectively and judiciously. The purpose of this review is to describe the different treatment scenarios and provide guidance for radiation dose, volume, and timing in patients with relapsed or refractory HL. PMID- 29722656 TI - Patterns of Involved-Field Radiation Therapy Protocol Deviations in Pediatric Versus Adolescent and Young Adults With Hodgkin Lymphoma: A Report From the Children's Oncology Group AHOD0031. AB - PURPOSE: The presented protocol for pediatric intermediate-risk Hodgkin lymphoma evaluated the use of a dose-intensive chemotherapy regimen (ABVE-PC [doxorubicin, bleomycin, vincristine, etoposide, cyclophosphamide, prednisone]) with response based therapy augmentation (addition of DECA [dexamethasone, etoposide, cisplatin, cytarabine]) or therapy reduction (elimination of radiation). METHODS AND MATERIALS: A central review of the radiation therapy data for quality assurance was performed, and the association between radiation protocol deviation (RPD) and relapse was assessed in the pediatric group (age <15 years) and adolescent and young adult (AYA) group (age >=15-21 years). Involved-field radiation therapy (IFRT) planning was reviewed before the start of treatment and at treatment completion. The records were reviewed through the Quality Assurance Review Center's central review to identify RPD, classified according to dose deviation (DD), volume deviation (VD), undertreatment (UT), and overtreatment (OT). DDs and VDs were further classified as major or minor. RESULTS: Of the 1712 patients enrolled, 1155 received IFRT, of whom, 216 (18.7%) had RPDs. The DD and VD patterns were similar between the pediatric and AYA groups. Minor VDs were most common. UT RPDs accounted for 69% in the pediatric group and 75% in the AYA group. Of the 35 patients with relapse and a RPD, 29 had an undertreatment RPD. Among the patients who received IFRT, a significant difference was found in the cumulative incidence rates of relapse between the pediatric and AYA groups (P = .03); however, no significant difference was found between patients with and without RPD (P = .2). CONCLUSIONS: Most RPDs were minor and consisted of UT in the AYA and pediatric populations both. No difference was observed in RPDs between the pediatric and AYA patients. Thus, in a well-defined and standardized protocol, the RPD distributions for AYA patients will be similar to those for pediatric population. However, the increased cumulative incidence of relapse in the AYA patients who had received IFRT compared with the pediatric population requires further exploration, given the potential differences in clinical outcomes in the AYA population. PMID- 29722657 TI - Patterns of Failure in Patients With Double Hit or Double Expressor Lymphomas: Implications for Radiation Therapy. AB - PURPOSE: Lymphomas with MYC and either BLC2 or BCL6 rearrangements or MYC and BCL 2 protein overexpression, classified as double-hit (DHL) or double-expressor (DEL) lymphomas, respectively, are associated with poorer response to standard immunochemotherapy. Optimal therapy is not clear, and little information exists on the contribution of consolidative radiation therapy in these patients. This study describes the patterns of failure of DHL/DEL in relation to initial sites of disease and indications for radiation therapy in unselected diffuse large B cell lymphoma (DLBCL). METHODS AND MATERIALS: A retrospective single-institution study of all patients with diagnoses of non-Hodgkin lymphoma between 2011 and 2015 was performed. DHL status was determined by fluorescence in-situ hybridization, and DEL status was determined by immunohistochemistry. Progression free survival (PFS) was calculated from the end of chemotherapy using the Kaplan Meier method. Cox modeling was used for multivariable analysis. RESULTS: Screening of 275 DLBCL patients yielded a 53-patient cohort, including 32 patients with DHL, 10 with DEL, 9 with a triple rearrangement, and 2 triple expressors. Of the 26 patients whose disease progressed, 15 had primary refractory disease. The remaining 11 failures were relapses after complete response to initial chemotherapy. Of those failures, 6 (55%) occurred at initially involved site(s), and 4 (36%) were isolated initial site relapses. Consolidative radiation therapy was associated significantly with improved PFS on multivariable analysis (hazard ratio 0.17, 95% confidence interval 0.02-0.94, P = .04). CONCLUSIONS: DHL/DEL are associated with high relapse rates, which preferentially occur at initially involved sites. Among patients achieving complete response to chemotherapy, consolidative radiation therapy was associated with improved PFS. This provides a rationale for the continued role of radiation therapy in the treatment of DHL and DEL and requires validation in a larger cohort. PMID- 29722658 TI - Management of Borderline Resectable Pancreatic Cancer. AB - With the rapid development of imaging modalities and surgical techniques, the clinical entity representing tumors that are intermediate between resectable and unresectable pancreatic adenocarcinoma has been identified has been termed "borderline resectable" (BR). These tumors are generally amenable for resection but portend an increased risk for positive margins after surgery and commonly necessitate vascular resection and reconstruction. Although there is a lack of consensus regarding the appropriate definition of what constitutes a BR pancreatic tumor, it has been demonstrated that this intermediate category carries a particular prognosis that is in between resectable and unresectable disease. In order to downstage the tumor and increase the probability of clear surgical margins, neoadjuvant therapy is being increasingly utilized and studied. There is a lack of high-level evidence to establish the optimal treatment regimen for BR tumors. When resection with negative margins is achieved after neoadjuvant therapy, the prognosis for BR tumors approaches and even exceeds that for resectable disease. This review presents the current definitions, different treatment approaches, and the clinical outcomes of BR pancreatic cancer. PMID- 29722659 TI - Tolerability of ADXS11-001 Lm-LLO Listeria-Based Immunotherapy With Mitomycin, Fluorouracil, and Radiation for Anal Cancer. AB - PURPOSE: To obtain safety and preliminary efficacy data of the combination of ADXS11-001, live attenuated Listeria monocytogenes bacterium, with mitomycin, 5 fluorouracil (5-FU), and intensity modulated radiation therapy in locally advanced anal cancer. PATIENTS AND METHODS: Eligibility included patients with previously untreated, nonmetastatic anal cancer with a primary tumor >4 cm or node-positive disease. Patients received 2 cycles of mitomycin and 5-FU concurrent with 54.0 Gy intensity modulated radiation therapy. One intravenous dose of ADXS11-001 (1 * 109 colony-forming units) was administered before chemoradiation; 3 additional monthly doses were given after chemoradiation. RESULTS: Ten patients were treated, including 1 with N2 and 4 with N3 disease. Two patients had grade 3 acute toxicities after the initial dose of ADXS11-001, including chills/rigors (n = 2), back pain (n = 1), and hyponatremia (n = 1). All ADXS11-001 toxicities occurred within 24 hours of administration. There was no apparent increase in chemoradiation toxicities or myelosuppression. One patient had a grade 5 cardiopulmonary event shortly after beginning 5-FU treatment. All 9 assessable patients had complete clinical responses by sigmoidoscopy. Eight of 9 patients (89%) are progression-free at a median follow-up of 42 months. CONCLUSIONS: Preliminary data show that ADXS11-001 can be safely administered with standard chemoradiation for anal cancer. Further studies of listeria-based immunotherapy with radiation are warranted. PMID- 29722660 TI - The Efficacy and Safety of Conventional and Hypofractionated High-Dose Radiation Therapy for Prostate Cancer in an Elderly Population: A Subgroup Analysis of the CHHiP Trial. AB - PURPOSE: Outcome data on radiation therapy for prostate cancer in an elderly population are sparse. The CHHiP (Conventional or Hypofractionated High Dose Intensity Modulated Radiotherapy in Prostate Cancer) trial provides a large, prospectively collected, contemporary dataset in which to explore outcomes by age. METHODS AND MATERIALS: CHHiP participants received 3 to 6 months of androgen deprivation therapy and were randomly assigned (1:1:1) to receive 74 Gy in 37 fractions (conventional fractionation), 60 Gy in 20 fractions, or 57 Gy in 19 fractions. Toxicity was assessed using clinician-reported outcome (CRO) and patient-reported outcome questionnaires. Participants were categorized as aged < 75 years or >= 75 years. Outcomes were compared by age group. RESULTS: Of 3216 patients, 491 (15%) were aged >= 75 years. There was no difference in biochemical or clinical failure rates between the groups aged < 75 years and >= 75 years for any of the fractionation schedules. In the group aged >= 75 years, biochemical or clinical failure-free rates favored hypofractionation, and at 5 years, they were 84.7% for 74 Gy, 91% for 60 Gy, and 87.7% for 57 Gy. The incidence of CRO (grade 3) acute bowel toxicity was 2% in both age groups. The incidence of grade 3 acute bladder toxicity was 8% in patients aged < 75 years and 7% in those aged >= 75 years. The 5-year cumulative incidence of CRO grade >= 2 late bowel side effects was similar in both age groups. However, in the group aged >= 75 years, there was a suggestion of a higher cumulative incidence of bowel bother (small or greater) with 60 Gy compared with 74 Gy and 57 Gy. Patient-reported bladder bother was slightly higher in the group aged >= 75 years than the group aged < 75 years, and there was a suggestion of a lower cumulative incidence of bladder bother with 57 Gy compared with 74 Gy and 60 Gy in patients aged >= 75 years, which was not evident in those aged < 75 years. CONCLUSIONS: Hypofractionated radiation therapy appears to be well tolerated and effective in men aged >= 75 years. The 57-Gy schedule has potential advantages in that it may moderate long-term side effects without compromising treatment efficacy in this group. PMID- 29722662 TI - A Retrospective Long-term Follow-up Study of Stereotactic Body Radiation Therapy for Non-Small Cell Lung Cancer From a Single Institution: Incidence of Late Local Recurrence. AB - PURPOSE: To assess the local recurrence (LR) rate and timing after stereotactic body radiation therapy (SBRT) for non-small cell lung cancer using long-term follow-up data from a single institution. METHODS AND MATERIALS: Patients with primary or recurrent non-small cell lung cancer with or without pathologic verification, with tumors <3 cm, treated with SBRT (isocenter prescription of 48 Gy in 4 fractions) between April 1998 and August 2014, and with >6 months' follow up were eligible. The LR rate was calculated by the cumulative incidence function, accounting for death as a competing risk. Univariate and multivariate analyses were performed to identify prognostic factors for LR. RESULTS: A total of 216 patients and 230 tumors were analyzed. The median follow-up time of tumors without LR was 3.9 years, and the crude number of LR cases was 49 (21%). The actuarial rate of LR was 19% (95% confidence interval, 14%-25%) at 5 years. The number of LR cases in each period was 10 in year 1, 17 in year 2, 9 in year 3, 3 in year 4, 3 in year 5, and 7 after 5 years. Among 73 tumors with >5 years' follow-up, we observed 7 late LRs. The tumor histology of these late LRs was adenocarcinoma in 3, squamous cell carcinoma in 2, and unknown in 2 (1 of the unknown cases was confirmed as adenocarcinoma following salvage surgery). The median time to LR was 2.1 years (interquartile range, 1.5-4.2 years) for adenocarcinoma compared with 1.3 years (interquartile range, 1.0-2.3 years) for squamous cell carcinoma. Multivariate analysis revealed that larger tumor size, squamous cell histology compared with adenocarcinoma, and use of abdominal compression for respiratory motion management were independent negative prognostic factors for LR. CONCLUSIONS: Long-term follow-up data demonstrated that late LR was not uncommon and that careful follow-up after SBRT is needed, especially in patients with adenocarcinoma. PMID- 29722663 TI - ...of Radiation Oncology, Biology, and Physics. PMID- 29722664 TI - In Regard to Wortel et al. PMID- 29722661 TI - Phase 2 Study of Bortezomib Combined With Temozolomide and Regional Radiation Therapy for Upfront Treatment of Patients With Newly Diagnosed Glioblastoma Multiforme: Safety and Efficacy Assessment. AB - PURPOSE: To assess the safety and efficacy of upfront treatment using bortezomib combined with standard radiation therapy (RT) and temozolomide (TMZ), followed by adjuvant bortezomib and TMZ for <=24 cycles, in patients with newly diagnosed glioblastoma multiforme (GBM). METHODS AND MATERIALS: Twenty-four patients with newly diagnosed GBM were enrolled. The patients received standard external beam regional RT with concurrent TMZ beginning 3 to 6 weeks after surgery, followed by adjuvant TMZ and bortezomib for <=24 cycles or until tumor progression. During RT, bortezomib was given at 1.3 mg/m2 on days 1, 4, 8, 11, 29, 32, 36, and 39. After RT, bortezomib was given at 1.3 mg/m2 on days 1, 4, 8, and 11 every 4 weeks. RESULTS: No unexpected adverse events occurred from the addition of bortezomib. The efficacy analysis showed a median progression-free survival (PFS) of 6.2 months (95% confidence interval [CI] 3.7-8.8), with promising PFS rates at >=18 months compared with historical norms (25.0% at 18 and 24 months; 16.7% at 30 months). In terms of overall survival (OS), the median OS was 19.1 months (95% CI 6.7-31.4), with improved OS rates at >=12 months (87.5% at 12, 50.0% at 24, 34.1% at 36-60 months) compared with the historical norms. The median PFS was 24.7 months (95% CI 8.5-41.0) in 10 MGMT methylated and 5.1 months (95% CI 3.9 6.2) in 13 unmethylated patients. The estimated median OS was 61 months (95% CI upper bound not reached) in the methylated and 16.4 months (95% CI 11.8-21.0) in the unmethylated patients. CONCLUSIONS: The addition of bortezomib to current standard radiochemotherapy in newly diagnosed GBM patients was tolerable. The PFS and OS rates appeared promising, with more benefit to MGMT methylated patients. Further clinical investigation is warranted in a larger cohort of patients. PMID- 29722665 TI - In Reply to Gungor et al. PMID- 29722666 TI - In Regard to Jang et al. PMID- 29722667 TI - In Reply to Hamstra. PMID- 29722668 TI - In Regard to Yang et al. PMID- 29722670 TI - In Reply to Ong et al. PMID- 29722669 TI - In Regard to Routman et al. PMID- 29722671 TI - In Reply to Garden. PMID- 29722672 TI - In Regard to Rana et al. PMID- 29722673 TI - In Regard to Cahlon et al. PMID- 29722674 TI - Radiation Oncology Crossword: Central Nervous System. PMID- 29722675 TI - Erratum to: Mahmood J, Connors CQ, Alexander AA, et al. Cavernous nerve injury by radiation therapy may potentiate erectile dysfunction in rats. Int J Radiat Oncol Biol Phys 2017;99:680-688. PMID- 29722676 TI - Erratum to: Routman DM, Funk RK, Tangsriwong K, et al. Relapse rates with surgery alone in human papillomavirus-related intermediate- and high-risk group oropharynx squamous cell cancer: A multi-institutional review. Int J Radiat Oncol Biol Phys 2017;99:938-946. PMID- 29722677 TI - Theoretical approach to embed nanocrystallites into a bulk crystalline matrix and the embedding influence on the electronic band structure and optical properties of the resulting heterostructures. AB - We develop an approach and present results of the combined molecular dynamics and density functional theory calculations of the structural and optical properties of the nanometer-sized crystallites embedded in a bulk crystalline matrix. The method is designed and implemented for both compatible and incompatible lattices of the nanocrystallite (NC) and the host matrix, when determining the NC optimal orientation relative to the matrix constitutes a challenging problem. We suggest and substantiate an expression for the cost function of the search algorithm, which is the energy per supercell generalized for varying number of atoms in the latter. The epitaxial relationships at the Si/NC interfaces and the optical properties are obtained and found to be in a reasonable agreement with experimental data. Dielectric functions show significant sensitivity to the NC's orientation relative to the matrix at energies below 0.5 eV. PMID- 29722678 TI - Clogging and transport of driven particles in asymmetric funnel arrays. AB - We numerically examine the flow and clogging of particles driven through asymmetric funnel arrays when the commensurability ratio of the number of particles per plaquette is varied. The particle-particle interactions are modeled with a soft repulsive potential that could represent vortex flow in type-II superconductors or driven charged colloids. The velocity-force curves for driving in the easy flow direction of the funnels exhibit a single depinning threshold; however, for driving in the hard flow direction, we find that there can be both negative mobility where the velocity decreases with increasing driving force as well as a reentrant pinning effect in which the particles flow at low drives but become pinned at intermediate drives. This reentrant pinning is associated with a transition from smooth 1D flow at low drives to a clogged state at higher drives that occurs when the particles cluster in a small number of plaquettes and block the flow. When the drive is further increased, particle rearrangements occur that cause the clog to break apart. We map out the regimes in which the pinned, flowing, and clogged states appear as a function of plaquette filling and drive. The clogged states remain robust at finite temperatures but develop intermittent bursts of flow in which a clog temporarily breaks apart but quickly reforms. PMID- 29722679 TI - Zitterbewegung in time-reversal Weyl semimetals. AB - We perform a systematic study of the Zitterbewegung effect of fermions, which are described by a Gaussian wave with broken spatial-inversion symmetry in a three dimensional low-energy Weyl semimetal. Our results show that the motion of fermions near the Weyl points is characterized by rectilinear motion and Zitterbewegung oscillation. The ZB oscillation is affected by the width of the Gaussian wave packet, the position of the Weyl node, and the chirality and anisotropy of the fermions. By introducing a one-dimensional cosine potential, the new generated massless fermions have lower Fermi velocities, which results in a robust relativistic oscillation. Modulating the height and periodicity of periodic potential demonstrates that the ZB effect of fermions in the different Brillouin zones exhibits quasi-periodic behavior. These results may provide an appropriate system for probing the Zitterbewegung effect experimentally. PMID- 29722680 TI - Decoupling of magnetism and electric transport in single-crystal (Sr1-x A x )2IrO4 (A = Ca or Ba). AB - We report a systematical structural, transport and magnetic study of Ca or Ba doped Sr2IrO4 single crystals. Isoelectronically substituting Ca2+ (up to 15%) or Ba2+ (up to 4%) ion for the Sr2+ ion provides no additional charge carriers but effectively changes the lattice parameters in Sr2IrO4. In particular, 15% Ca doping considerably reduces the c-axis and the unit cell by nearly 0.45% and 1.00%, respectively. These significant, anisotropic compressions in the lattice parameters conspicuously cause no change in the Neel temperature which remains at 240 K, but drastically reduces the electrical resistivity by up to five orders of magnitude or even precipitates a sharp insulator-to-metal transition at lower temperatures, i.e. the vanishing insulating state accompanies an unchanged Neel temperature in (Sr1-x A x )2IrO4. This observation brings to light an intriguing difference between chemical pressure and applied pressure, the latter of which does suppress the long-range magnetic order in Sr2IrO4. This difference reveals the importance of the Ir1-O2-Ir1 bond angle and homogenous volume compression in determining the magnetic ground state. All results, along with a comparison drawn with results of Tb and La doped Sr2IrO4, underscore that the magnetic transition plays a nonessential role in the formation of the charge gap in the spin-orbit tuned iridate. PMID- 29722681 TI - Glass transition memorized by the enthalpy-entropy compensation in the shear thinning of supercooled metallic liquids. AB - To unravel the true nature of glass transition, broader insights into glass forming have been gained by examining the stress-driven glassy systems, where strong shear thinning, i.e. a reduced viscosity under increasing shear rate, is encountered. It is argued that arbitrarily small stress-driven shear rates would 'melt' the glass and erase any memory of its thermal history. In this work, we report a glass transition memorized by the enthalpy-entropy compensation in strongly shear-thinned supercooled metallic liquids, which coincides with the thermal glass transition in both the transition temperature and the activation Gibbs free energy. Our findings provide distinctive insights into both glass forming and shear thinning, and enrich current knowledge on the ubiquitous enthalpy-entropy compensation empirical law in condensed matter physics. PMID- 29722682 TI - Removal of sewage phosphorus by adsorption and mineral precipitation, with recovery as a fertilizing soil amendment. AB - Clear sand adsorbs 15-35% total phosphorus (P) from septic tank effluent, but P is mobilized when low-P effluent is applied. Amorphous P compounds formed by alkali aluminate chemical addition may also be subject to leaching. Crystalline mineralization is the desired end effect that isolates P thoroughly from the water resource. Using new low-energy iron electrochemistry (EC-P process), dissolved ferrous iron reacts with sewage phosphate ions (PO4) and precipitates onto filtration medium as vivianite [Fe3(PO4)2.8H2O], as identified by scanning electron microscopy and X-ray diffraction and predicted from Eh-pH-aHPO42- phase relations. Removal rates of 90-99% in sand, soil and synthetic foam filters are obtained. The precipitation of vivianite demonstrates that P can be immobilized quickly and without intermediary adsorption phases, as with Fe-rich soils. Vitreous silicate material (VSM) or rockwool that traps and precipitates mineral P after EC-P treatment was investigated as a means of P reuse as a fertilizing soil amendment. Comparative soil leaching and growth studies using corn plants demonstrate that the VSM alone reduces P losses from soils, and that VSM which has received EC-P effluent is equivalent to or better than commercial superphosphate fertilizer. PMID- 29722683 TI - Improvement of sewage sludge dewaterability by bioleaching in a continuous plug flow bioreactor: optimization of process parameters. AB - A novel process for sewage sludge bioleaching by mixed Thiobacilli (Acidithiobacillus thiooxidans and Acidithiobacillus ferrooxidans) using a 12 stage, 180 L working volume continuous plug-flow bioreactor, is presented. The objective of the present study was to assess the impact of some parameters on the sludge dewaterability and to improve the sludge dewaterability by optimization of these parameters. The parameters examined were sludge moisture content, nutrients dosage, aeration rate, and the number of reactors. The order of the influence of these factors on sludge dewaterability was found to be sludge moisture content > nutrients dosage > aeration rate > number of reactors. The optimized conditions were: sludge moisture content, 98.0%, nutrients dosage, 9 g/L, aeration rate, 8 m3/h, and 10 reactors. Confirmation experiments conducted under optimum conditions demonstrate the sludge dewaterability to be remarkably improved. After 2 days of bioleaching, the moisture of bioleached sludge cake was reduced to below 60%. PMID- 29722684 TI - Application of forward osmosis membrane in nanofiltration mode to treat reverse osmosis concentrate from wastewater reclamation plants. AB - Reverse osmosis concentrate (ROC) from wastewater reclamation plants have high concentrations of organic and inorganic compounds, which have to be removed before its disposal. Forward osmosis (FO) and nanofiltration (NF) membranes were tested to treat the ROC for possible water reuse. This research investigated the combined and individual influence of organic and inorganic matter on the fouling of NF and FO membranes. The results revealed that the NF membrane removed most of the organic compounds and some inorganics. The study further highlighted that the FO membrane at NF mode removed the majority of the inorganic compounds and some organics from the ROC. A pretreatment of granulated activated carbon (GAC) adsorption removed 90% of the organic compounds from ROC. In addition, GAC adsorption and acid pretreatment of ROC improved the net water permeate flux by 17% when an FO membrane was used in the NF system. Acid treatment (by bringing the pH down to 5) helped to remove inorganic ions. Therefore, the resultant permeate can be recycled back to the RO water reclamation plant to improve its efficiency. PMID- 29722685 TI - Relationship between total dissolved solids and electrical conductivity in Marcellus hydraulic fracturing fluids. AB - The production of hydraulic fracturing fluids (HFFs) in natural gas extraction and their subsequent management results in waste streams highly variable in total dissolved solids (TDS). Because TDS measurement is time-consuming, it is often estimated from electrical conductivity (EC) assuming dissolved solids are predominantly ionic species of low enough concentration to yield a linear TDS-EC relationship: TDS (mg/L) = ke * EC (MUS/cm) where ke is a constant of proportionality. HHFs can have TDS levels from 20,000 to over 300,000 mg/L wherein ion-pair formation and non-ionized solutes invalidate a simple TDS-EC relationship. Therefore, the composition and TDS-EC relationship of several fluids from Marcellus gas wells in Pennsylvania were assessed. Below EC of 75,000 MUS/cm, TDS (mg/L) can be estimated with little error assuming ke = 0.7. For more concentrated HFFs, a curvilinear relationship (R2 = 0.99) is needed: TDS = 27,078e1.05 * 10-5*EC. For hypersaline HFFs, the use of an EC/TDS meter underestimates TDS by as much as 50%. A single linear relationship is unreliable as a predictor of brine strength and, in turn, potential water quality and soil impacts from accidental releases or the suitability of HFFs for industrial wastewater treatment. PMID- 29722686 TI - Use of the terrestrial weed Alternanthera ficoidea in treating greywater in soil less SHEFROL(r) bioreactors. AB - The ornamental plant Alternanthera ficoidea (also named A. tenella), which is common and widespread throughout the tropics and is being increasingly regarded as an invasive, problematic weed, has been explored as a bioagent in greywater treatment. In the recently developed SHEFROL(r) bioreactor, it was seen to treat greywater of varying strengths (250-1,300 mg/L chemical oxygen demand, COD) quickly and substantially to the extent of 75-77%. Biological oxygen demand (BOD), nitrogen, phosphorus, suspended solids, and heavy metals copper, nickel, manganese, and zinc were also removed to the extents of 83.5, 94.9, 33.1, 27.0, 44.8, 27.5, 38.2, and 43.2%, respectively. As all this was achieved in a single pot, single step, and in a simple reactor operation, at hydraulic retention times of a mere 6 h, it shows the process to be several times more efficient as well as potentially less expensive than the conventional treatment systems which utilize macrophytes in tanks or constructed wetlands. PMID- 29722687 TI - Bacterial community diversity in a full scale biofilter treating wastewater odor. AB - Constantly, the odors coming from sewage plants are considered a problem by the population. The purpose of this study was to evaluate the microbial community present in a full scale biofilter used for odor treatment. The filter was packed with peat. The main gas treated was hydrogen sulphide (H2S). The removal efficiency reached 99%, with an empty bed residence time of 30 seconds. Molecular analysis can enhance our understanding of the microbial communities in biofilters treating wastewater odor. The analysis made to characterize microbial community was High-throughput 16S rRNA sequencing analysis MiSeq(r) Illumina. The sampling, carried out in the year 2015, was seasonal (summer and winter) and spatial (depth and position in the biofilter). In this study, a total of 206,174 raw sequence reads for six samples were analyzed using Mothur software (v 1.33.3) based on MiSeq SOP protocol. After Mothur analysis, the results of the bacterial community were explored at the Phylum and Genus levels. In this study, the efficiency removal of hydrogen sulfide reached values greater than 99% during the monitoring, and the main bacterial genera found were Acidotermus, Telmatobacter, Methylovirgula and Bryobacter representing the bacterial community active in the transformation of H2S into a system with long operating time. PMID- 29722688 TI - Ranking media for multi-pollutant removal efficiency in bioretention. AB - Bioretention is an effective best management practice for urban stormwater. This study aims to provide guidance for selecting the best bioretention medium in terms of pollutant removal capacity. Fuzzy set theory was applied with the improved analytic hierarchy process (IAHP) for weight determination, thus forming the fuzzy synthetic evaluation model, to assess the comprehensive efficiencies of certain sand media. This work is the first to use this method to study bioretention. Results demonstrated that the fuzzy synthetic evaluation model was a rational choice for the selection of bioretention media. The studied media were ranked by pollutant removal capacity as follows: Media III > Media V > Media I > Media VI > Media II > Media VII > Media IV. Media I had the best comprehensive removal efficiency and infiltration rate in bioretention. Moreover, the removal rates for Cd2+, Zn2+ and Pb2+ were excellent (>80%), those for Cu2+ and NH+4-N fluctuated from 58.1% to 92.7% and 64.7% to 95.9%, respectively, and those for NO 3-N and TP of the seven media did not show distinct differences. PMID- 29722689 TI - Long-term operation of a novel electrically-enhanced biomass concentrator reactor for wastewater treatment. AB - Membrane biological reactors (MBRs) are a key technology in wastewater treatment nowadays. However, due to their high construction cost and energetic requirements, alternatives based on the same principle of biomass retention have been designed and operated. Amongst these, biomass concentrator reactors (BCRs), using a coarser filter medium instead of a membrane, have shown to be able to remove a wide range of contaminants from wastewater and groundwater. A new BCR derived technology enhanced with an electric field, called the electrically enhanced biomass concentrator reactor (E2BCR), was designed and tested for urban wastewater treatment at different organic loads for a period of 180 days. The electrically-enhanced reactor showed better chemical oxygen demand (COD) removal performances than a non-enhanced control reactor (92.4% and 83.6% respectively) thanks also to electrocoagulation effects, and a lower fouling tendency, and proved to be more energy efficient in comparison with the control reactor in terms of energy consumption per mass of COD removed. PMID- 29722690 TI - The novel PEI-modified biochars and their application for the efficient elimination of Cr(VI) from aqueous solutions. AB - In this study, the polyethyleneimine (PEI) was grafted onto the biochars from chestnut shells and nori via the cross-linking reaction. Scanning electron microscopy, transmission electron microscopy and Fourier transferred infrared spectroscopy analysis indicated that the PEI was successfully grafted on the surface of biochars. The PEI modified and pristine biochars were used as adsorbents to remove Cr(VI) from aqueous solutions as a function of pH, ionic strength, contact time and initial concentrations of Cr(VI) through batch technique. The strongly pH-dependent and ionic strength-independent of Cr(VI) sorption indicated that the sorption was mainly dominated by electrostatic interaction and inner-sphere surface complexation. The maximum sorption capacities of PEI modified chestnut shell and nori biochars were 141.42 and 222.84 mg/g, respectively, which were significantly higher than those of pristine biochars. The PEI grafted onto the biochars significantly enhanced Cr(VI) sorption capacity because PEI, which contains volumes of amine/imine groups, provided an excellent platform for Cr(VI) ions removal. In addition, the sorption desorption experimental results indicated that the PEI modified biochars possessed a stable and recyclable performance. All these results manifested that the PEI modified biochars could be applied as environmentally friendly and efficient adsorbents for the removal of Cr(VI) from wastewater. PMID- 29722691 TI - Activity corrections are required for accurate anaerobic digestion modelling. AB - The impact on the prediction of key process variables in anaerobic digestion (AD) when activity corrections are neglected (e.g. when ideal solution is assumed) is evaluated in this paper. The magnitude of deviations incurred in key variables was quantified using a generalised physicochemistry modelling framework that incorporates activity corrections. Deviations incurred on the intermediate and partial alkalinity ratio (a key control variable in AD) already reach values over 20% in typical AD scenarios at low ionic strengths. Deviations of moderate importance (~5%) in free ammonia, hydrogen sulfide inhibition, as well as in the biogas composition, were observed. Those errors become very large for components involving multiple deprotonations, such as inorganic phosphorus, and their magnitude (~40%) would impede proper precipitation modelling. A dynamic AD case simulation involving a series of overloads showed model underpredictions of the process acidification when activity corrections are neglected. This compromises control actions based on such models. Based on these results, a systematic incorporation of activity corrections in AD models is strongly recommended. This will prevent model overfitting to observations related to inaccurate physicochemistry modelling, at a marginal computational cost. Alternatives for these implementations are also discussed. PMID- 29722692 TI - Combining high-rate aerobic wastewater treatment with anaerobic digestion of waste activated sludge at a pulp and paper mill. AB - The activated sludge process within the pulp and paper industry is generally run to minimize the production of waste activated sludge (WAS), leading to high electricity costs from aeration and relatively large basin volumes. In this study, a pilot-scale activated sludge process was run to evaluate the concept of treating the wastewater at high rate with a low sludge age. Two 150 L containers were used, one for aeration and one for sedimentation and sludge return. The hydraulic retention time was decreased from 24 hours to 7 hours, and the sludge age was lowered from 12 days to 2-4 days. The methane potential of the WAS was evaluated using batch tests, as well as continuous anaerobic digestion (AD) in 4 L reactors in mesophilic and thermophilic conditions. Wastewater treatment capacity was increased almost four-fold at maintained degradation efficiency. The lower sludge age greatly improved the methane potential of the WAS in batch tests, reaching 170 NmL CH4/g VS at a sludge age of 2 days. In addition, the continuous AD showed a higher methane production at thermophilic conditions. Thus, the combination of high-rate wastewater treatment and AD of WAS is a promising option for the pulp and paper industry. PMID- 29722693 TI - Refitted inclined plate for improving suspended solids removal in standard storm water sumps. AB - Suspended solids (SS) in the storm-water makes up a significant source of total suspended solids in wet weather flow. With appropriate modification and maintenance, the standard sumps in the drainage system can remove SS from storm water runoff as a best management practice device. To increase the removal efficiency, especially in the condition of high flow rate, inclined plates, based on the shallow pool sedimentation theory, have been designed and refitted to the sump. Its performance under the different surface load and flow rate were evaluated through scale models. The results show that the preliminary design, Model A, had limited removal efficiency, and even played a negative role sometimes due to the concentrated flow in the axis. The optimizations through installing a non-uniform porous baffle (Model B) and adopting inverted V-shaped plates (Model C) were improved, and results show that removal efficiency rate can be increased by around 15-20%, even at high flow rates. Moreover, too many plates cannot improve the removal rate further, because they make the cross-section decline and lead to higher velocity between plates. PMID- 29722694 TI - Rapid surface water intervention performance comparison for urban planning. AB - Surface water flooding can be a significant source of damage and disruption in urban areas. The complexity of urban surfaces, the need for spatially disaggregated approaches and the multiplicity of interventions makes management challenging from a number of perspectives. This research responds to the challenge of selecting appropriate surface water management interventions by applying a fast assessment framework to generate evidence for comparing strategies at low resource cost during initial design. This is demonstrated by simulating flood dynamics and comparing damage costs in 144 flood scenarios. The main finding of this work is that a high-level quantitative assessment of large numbers of scenarios is capable of providing evidence to identify performance trends and consider resilience to extreme events at an early stage of planning. PMID- 29722695 TI - Behaviour of polysulfone ultrafiltration membrane for dyes removal. AB - Although ultrafiltration membranes have been used for the separation of macromolecules and colloids from solutions, this process has a limited application in the removal of dyes present in coloured discharges of textile industry, as these typically have much lower molecular weight than the molecular cut-off of the membranes (MWCO). In the present work, we have evaluated the behaviour of a polysulfone ultrafiltration membrane in the removal of different dyes from aqueous solutions (Congo red, methyl green and amaranth). Different variables (tangential flow rate, concentration of dye and pH of the feed) were studied to determine their influence on the separation processes (permeate flux and rejection coefficient). The results show that Congo red is easily removed with a GR60PP membrane (MWCO = 25 kDa), whereas methyl green and amaranth show rejection coefficient values of approximately 25.78% and 13.85%, respectively, at neutral pH. Also, an interesting effect is observed for the rejection coefficient for methyl green at different pH values. In addition, several treatments were performed to the membrane so as to modify its surface, trying to improve the values obtained for permeate flux and rejection rate. PMID- 29722696 TI - Bioremediation of steel plant wastewater and enhanced electricity generation in microbial desalination cell. AB - Microbial desalination cell (MDC) is a propitious technology towards water desalination by utilizing wastewater as an energy source. In this study, a multi chambered MDC was used to bioremediate steel plant wastewater using the same wastewater as a fuel for anodic bacteria. A pure culture of Pseudomonas putida MTCC 1194 was isolated and inoculated to remove toxic phenol. Three different inoculum conditions, namely P. putida (INC-A), a mixture of P. putida and activated sludge (INC-B), and activated sludge alone (INC-C) were employed in an anodic chamber to mainly compare the electricity generation and phenol degradation in MDCs. The study revealed the maximum phenol removal of 82 +/- 2.4%, total dissolved solids (TDS) removal of 68 +/- 1.5%, and power generation of 10.2 mW/m2 using INC-B. The synergistic interactions between microorganisms, can enhance the toxic phenol degradation and also electricity generation in MDC for onsite wastewater application. PMID- 29722697 TI - Heptachlor degradation characteristics of a novel strain and its application. AB - With heptachlor as the sole carbon source, an effective heptachlor-degrading microorganism (named strain H) was isolated from the sludge of heptachlor polluted sewage of a chemical plant, via enrichment, screening and purification. Strain H was identified as a facultative anaerobic Gram-negative bacterial strain belonging to genus Shigella based on the physiological-biochemical characteristics and the similarity analysis of its 16S rDNA gene sequence with the sequences logged in the Ribosomal Database Project and GenBank databases. When the optimal inoculation volume and the pH were 20% and 7.1-7.6, respectively, strain H was able to degrade heptachlor by more than 88.2% after130 h, with initial concentration of heptachlor being 300 MUg/L at 30 +/- 0.5 degrees C. It was also shown that strain H can grow on the degradation products of heptachlor such as 1-hydroxychlordene or heptachlor epoxide. Furthermore, additional carbon sources can accelerate the degradation rate of heptachlor because of co-metabolism. The degradation dynamics could be described by a first order reaction model. A real-world field experiment demonstrated that strain H was effective in practical applications of heptachlor biodegradation in contaminated soil. PMID- 29722698 TI - Build-up and characterisation of pollutants on urban impervious surfaces. AB - This paper presents the results of the investigation of pollutant build-up on impervious surfaces of a parking lot in Belgrade, Serbia during the summer months. Contaminant build-up was found to be greater on asphalt surfaces directly exposed to vehicular traffic than on concrete walkways. The difference in the amounts of accumulated pollutants between asphalt and concrete were significant: for total solids (TS), total suspended solids (TSS), chemical oxygen demand (COD), heavy metals and total phosphorus (TP) accumulations were two to three times higher, while only 30% higher for total nitrogen (TN) and anions. Build-up of most of the measured parameters was best described by power functions. The highest surface loads were found for solids, COD, iron and zinc. A strong correlation was found between turbidity, TS, TSS, COD, heavy metals and phosphorus, while conductivity, nitrates and nitrites were weakly correlated to other parameters. PMID- 29722699 TI - Microbiological aspects of thermophile pretreatment of activated sludge inhibiting electricity generation of microbial fuel cell. AB - Thermophile pretreatment of activated sludge greatly improves the biodegradability of sludge, but whether the pretreated products are suitable for the electricity generation of microbial fuel cells (MFCs) is still little known. In this study, municipal activated sludge pretreated by a thermophilic bacterium and heating, respectively, was separately fed into the MFCs. The performance of MFCs was examined and changes of anodic microbial communities were investigated with scanning electron microscopy and 16S rRNA gene high-throughput sequencing on the Illumina Miseq platform. The results showed that MFCs fed with heating pretreated sludge performed preferably and the power density reached 0.91-2.86 W/m3. MFC anodes were covered with considerable Geobacter spp. However, the bioaugmentation of sludge with the thermophile was not able to support a high potential output although the pretreatment significantly increased the soluble chemical oxygen demand. The maximum power density approached 0.20 W/m3 even when the anolyte was regularly changed. It was observed that amending pH did not improve the performance of MFC. Investigation on this anodic microbial community found that the relative abundance of Lactobacillus spp. exceeded 91%. Consequently, the thermophile-pretreated products stimulated the growth of non exoelectrogens and finally the niches of anodic biofilm were completely occupied by Lactobacillus spp. PMID- 29722700 TI - What can we learn from a 500-year event? Experiences from urban drainage in Austria. AB - Urban drainage systems are designed to capture the runoff for a certain return period of a design rainfall event. Typically, numerical models are used, which are calibrated by comparing model response and measured system performance. The applicability of such models to predict the system behaviour under extreme events is unclear, as usually then no data are available. This paper describes the analysis of an extreme rainfall event in the year 2016. The event is characterized by a very short duration and very high rainfall intensities. The maximum-recorded rainfall peak was 47.1 mm rainfall within 10 min, which corresponds to a return period of 500 years. The event caused local flooding on streets, interruptions of traffic and damages in buildings. In order to improve the flood resilience of the city, the event was analysed with an existing 1D hydrodynamic model of the sewer system. Model results were compared to water level measurements in the drainage system and citizen observations of surface flooding (gathered from social media and citizen reports). Although the hydrodynamic model could reproduce water level measurements in parts of the system, the plausibility check using descriptive data showed that the model failed to predict flooding in some areas. PMID- 29722701 TI - Predicting permeability of compacted clay filtrated with landfill leachate by k Nearest Neighbors modelling method. AB - It is important to protect the soil and groundwater from the pollution originating from leachate. Compacted clay soils is a favorable and economic method to protect groundwater and soil against contamination. In this study, compaction tests of leachate was done by using Modified Proctor method. The effects of microbial activity on the permeability of compacted clay soils were analyzed and the obtained data were applied to k-Nearest Neighbors (k-NN) method to predict the permeability of soils in landfill sites. k-NN method, which is a non-parametric distance-based machine learning method and widely used in classification and regression problems was applied to model the relationship between the microorganisms and the permeability. By using k-NN classification method, total heterotrophic bacteria and fungi microorganisms correctly classified the permeability variance as 78.59% and 77.31% success rate, respectively. Also, k-NN modelling was set on regression mode to predict permeability value and produced similar success rates in regression similarity with the actual value. Although, fecal coliforms and fecal streptococci microorganisms had neutral or negative contribution on analyses. For prediction accuracy and regression analysis, the k-NN method was considered for modeling the data. The results of the k-Nearest Neighbors method proved that it is a promising tool for predicting permeability of compacted clay by using microbial activity. PMID- 29722702 TI - You're Never Too Old. PMID- 29722704 TI - Pediatric Nasogastric Tubes in the Home: Recommendations for Practice. AB - One of the dilemmas facing home healthcare nurses is the placement of a nasogastric tube (NGT) in the home setting coupled with being assured and confident that the NGT tip is in the correct position, that is, the stomach. There are very limited data to address the issue of management of an NGT in the home care setting with even less guidance for the pediatric population. Therefore, home healthcare nurses must use agency policy and procedures coupled with their own education, knowledge, experience, and skills when performing this procedure. These may vary from agency to agency, thus providing inconsistencies in teaching and techniques. PMID- 29722705 TI - Maintaining Professional Nursing Boundaries in the Pediatric Home Care Setting. AB - Pediatric home care nurses often become a valuable part of the family unit, and this can blur the professional boundary between nurse and patient. Home care professionals must educate themselves as well as patients and family members about the integrity of their professional relationship, and prevent boundary crossing before it occurs. This article highlights four case studies that describe situations of boundary crossing that could have been managed differently. Strategies for maintaining professional boundaries with patients and their families are provided. PMID- 29722707 TI - Multiple Sclerosis: An Update for Home Healthcare Clinicians. AB - Multiple sclerosis (MS) is a chronic neurologic disease and the most common cause of nontraumatic disability in young adults in the United States. It strikes adults in the prime of life and can gradually diminish physical and mental function, affect relationships, employment, financial capacity, and independence. Neurologic symptoms fluctuate in a pattern of remissions and exacerbations for the majority of those with MS. A multidisciplinary treatment approach is essential. There are a wide number of medications that can be used. Treating the disease at an early stage within the first 5 years of clinical symptom onset is optimal. Home healthcare clinicians can use assessment tools to evaluate disease progression, teach the patient and family how to live with the disorder, and monitor the patient for medication side effects. PMID- 29722706 TI - Home Delivered Meals to Older Adults: A Critical Review of the Literature. AB - The United States is witnessing a growing aging population stemming in part from medical advancements allowing people to live decades longer than previous generations. Simultaneously, food insecurity among older adults has increased, and is projected to get worse as the Baby Boomer generation ages. This review focuses on an assistance program for older adults: home-delivered meals. Specifically, we focus on the effects of Meals on Wheels (MOW) on the physical and emotional well-being of older adults, and the wide variety of procedural and operational issues that various MOW programs around the country experience. Findings from the literature highlight the positive outcomes these programs have on their clients. Although there have been recent budget cut threats from the federal government, evidence suggests that more funding should be allocated so these programs can provide services to everyone in need, and even expand what they are able to offer to older adults. PMID- 29722709 TI - Reach for the Stars. AB - Star Ratings were implemented by the Centers for Medicare and Medicaid Services for home healthcare agencies with the first release of measures in 2015 and 2016. Hospital Compare also displays Star Ratings, and Hospice also will soon have the Hospice Information Set displayed on Hospice Compare. Star Ratings in home healthcare are determined by a specific methodology and are based on nine quality areas. One set of Stars designates the nine quality areas and a second set of Stars reflects consumer satisfaction. This article discusses quality of patient care Star Ratings but not those based on Consumer Assessment of Healthcare Provider and Systems outcomes. Few agencies reach above 3-Star Ratings; the majority fall within 3 and 3.5 with the national benchmark being 3.5. Agencies should strive for high Star Ratings as consumers, hospitals, and other referral sources may base their decisions on the number of stars received. PMID- 29722708 TI - Communicating With Older Adults. AB - As people age, physiological changes can occur causing deterioration of one or more of the senses, including hearing, vision, taste, and smell. The loss of sensory function can decrease the extent to which older adults can communicate, especially with their healthcare providers. The purpose of this article is to examine communication between older adults and healthcare providers, focusing on best practices and devices that can enhance and benefit their health and well being. One consideration is the use of digital technology, such as smart phones, electronic tablets, and computers, to help mitigate the effects of aging on communication. PMID- 29722710 TI - Individualizing Targets for Glycemic Control. PMID- 29722711 TI - Nutrition in Older Adults. PMID- 29722712 TI - The Otago Exercise Program: Perspectives of a Home Healthcare Physical Therapist. PMID- 29722713 TI - Healthcare Consumers Are Watching! PMID- 29722714 TI - Do We Have to Ban Healthcare to Prevent Healthcare Fraud? PMID- 29722715 TI - A Day in the Life of a Psychiatric Home Care Nurse. PMID- 29722716 TI - Important Insurance Terms All Home Healthcare Providers Should Know. PMID- 29722717 TI - Welcoming Millennials Home. PMID- 29722718 TI - In the Eye of the Storm. PMID- 29722719 TI - Pediatric Nasogastric Tubes in the Home: Recommendations for Practice. PMID- 29722720 TI - MRI Linac and How It May Potentially Lead to More Complete Response in Rectal Cancer. PMID- 29722721 TI - Kill the Sitz Bath and Save the Planet. PMID- 29722722 TI - Health Care in Guatemala. PMID- 29722723 TI - Locally Recurrent Rectal Cancer. PMID- 29722724 TI - Expert Commentary on Locally Recurrent Rectal Cancer. PMID- 29722725 TI - Antegrade Enema After Total Mesorectal Excision for Rectal Cancer: The Last Chance to Avoid Definitive Colostomy for Refractory Low Anterior Resection Syndrome and Fecal Incontinence. AB - BACKGROUND: Total mesorectal excision and preoperative radiotherapy in mid and low rectal cancer allow us to achieve very good oncological results. However, major and refractory low anterior resection syndrome and fecal incontinence alter the quality of life of patients with a long expected life span. OBJECTIVE: We assessed the functional results of patients treated by antegrade enema for refractory low anterior resection syndrome and fecal incontinence after total mesorectal excision. DESIGN: This is a prospective monocentric study from 2012 to 2016. PATIENTS: Patients who underwent percutaneous endoscopic cecostomy for refractory low anterior resection syndrome and fecal incontinence after total mesorectal excision were prospectively analyzed. MAIN OUTCOME MEASURES: We assessed the morbidity of the procedure and compared low anterior resection syndrome score, Wexner score, and Gastrointestinal Quality of Life Index before and after the use of antegrade enema. RESULTS: Of 25 patients treated by antegrade enema over the study period, 6 (24%) had a low anterior resection, 18 (72%) had a coloanal anastomosis, and 1 (4%) had a perineal colostomy. Postoperatively, the rate of local abscess was 8%, all treated by antibiotics. Low anterior resection syndrome score (33 vs 4, p < 0.001), Wexner score (16 vs 4, p <0.001), and Gastrointestinal Quality of Life Index (73 vs 104, p < 0.001) were all significantly improved after antegrade enema. The 2 main symptoms reported by patients were sweating (28%) and local pain (36%). At the end of the follow-up, 16% (n = 4) catheters were removed, and the rate of definitive colostomy was 12% (n = 3). LIMITATIONS: The main limitations of this study are the monocentric features and the sample size. CONCLUSION: Antegrade enema for major and refractory low anterior resection syndrome and fecal incontinence after total mesorectal excision appears to be a promising treatment to avoid definitive colostomy. See Video Abstract at http://links.lww.com/DCR/A608. PMID- 29722726 TI - Characteristics and Prognostic Factors of Bone Metastasis in Patients With Colorectal Cancer. AB - BACKGROUND: Because bone metastasis from colorectal cancer is rare, there are little available data regarding such cases. OBJECTIVE: The study aim was to identify the prognostic factors and characteristics associated with survival in colorectal cancer patients with bone metastasis. DESIGN: This was a retrospective study from a prospectively collected database. SETTINGS: The study took place in a multidisciplinary, high-volume tertiary cancer center in Japan. PATIENTS: Examined were records from 104 consecutive patients treated between 2004 and 2015 for bone metastasis from colorectal cancer. MAIN OUTCOME MEASURES: The primary outcome measure was overall survival. RESULTS: The spine was the most common site of bone metastasis from colorectal cancer. Right colon cancer correlated significantly with long bone metastasis (p = 0.046), whereas left colon cancer correlated significantly with spinal bone metastasis (p = 0.034). Liver metastasis was also significantly correlated with spinal bone metastasis (p = 0.036). The median interval between the primary therapy for colorectal cancer and the metachronous diagnosis of bone metastasis was 20.0 months (quartile 1 to quartile 3, 9.0-46.5 mo). The median survival time from diagnosis of bone metastasis from colorectal cancer was 5.0 months (95% CI, 4.0-9.0 mo), and the 1 year survival rate was 30.0% (95% CI, 21.1%-39.4%). Multivariate analysis revealed that >=2 extra-bone metastatic organs, hypercalcemia, and pathologic fractures were independent poor prognostic factors (p < 0.001, 0.001, and 0.033). The number of extra-bone metastatic organs correlated with prognosis. LIMITATIONS: This study was limited by its retrospective, nonrandomized design, as well as selection bias and performance at a single institute. CONCLUSIONS: The location of colorectal cancer correlates significantly with the site of bone metastasis; the prognosis of patients with bone metastasis from colorectal cancer is very poor, and the significant prognostic factors are number of extra-bone metastatic organs, hypercalcemia, and pathologic fractures. See Video Abstract at http://links.lww.com/DCR/A589. PMID- 29722727 TI - Grading of Total Mesorectal Excision Specimens: Assessment of Interrater Agreement. AB - BACKGROUND: Total mesorectal excision is the standard of care for patients with rectal cancer. Pathological evaluation of the quality of the total mesorectal excision specimen is an important prognostic factor that correlates with local recurrence, but is potentially subjective. OBJECTIVE: This study aimed to determine the degree of variation in grading, both between assessors and between fresh and formalin-fixed specimens. DESIGN: Raters included surgeons, pathologists, pathology residents, pathologists' assistants, and pathologists' assistant trainees. Specimens were assessed by up to 6 raters in the fresh state and by 2 raters postfixation. Four parameters were evaluated: mesorectal bulk, surface regularity, defects, and coning. Interrater agreement was measured using ordinal alpha-values. SETTING: The study was conducted at a single academic center. MAIN OUTCOME MEASURES: The primary outcome was agreement between individuals when grading total mesorectal excision specimens. RESULTS: A total of 37 total mesorectal excision specimens were assessed. Reliability between all raters for fresh specimens for mesorectal bulk, surface regularity, defects, coning, and overall grade were 0.85, 0.85, 0.92, 0.84, and 0.91. When compared with all raters, pathologists and residents had higher agreement and pathologists and surgeons had lower agreement. Ordinal alpha-values comparing pathologist and pathologist's assistant agreement for overall grade were similar pre- and postfixation (0.78 vs 0.80), but agreement for assessing defects decreased postfixation. Among pathologists' assistants, agreement was higher when grading specimens postfixation than when grading fresh specimens. LIMITATIONS: Assessment bias may have occurred because of the greater number of pathologists' assistants participating than the number of residents and pathologists. CONCLUSIONS: The results indicate good interrater agreement for the assessment of overall grade, with defects showing the best interrater agreement in fresh specimens. Although total mesorectal excision specimens may be consistently graded postfixation, the assessment of defects postfixation may be less reliable. This study highlights the need for additional knowledge-transfer activities to ensure consistency and accurate grading of total mesorectal excision specimens. See Video Abstract at http://links.lww.com/DCR/A497. PMID- 29722728 TI - An Optimal Orthotopic Mouse Model for Human Colorectal Cancer Primary Tumor Growth and Spontaneous Metastasis. AB - BACKGROUND: Colorectal cancer is a leading cause of cancer-related death. Small animal models allow for the study of different metastatic patterns, but an optimal model for metastatic colorectal cancer has not been established. OBJECTIVE: The purpose of this study was to determine which orthotopic model most accurately emulates the patterns of primary tumor growth and spontaneous liver and lung metastases seen in patients with colorectal cancer. DESIGN: Using luciferase-tagged HT-29 cells coinoculated with lymph node stromal analog HK cells, 3 tumor cell delivery models were compared: intrarectal injection, intracecal injection, and acid enema followed by cancer cell instillation. Tumor growth was monitored weekly by bioluminescent imaging, and mice were sacrificed based on primary tumor size or signs of systemic decline. Liver and lungs were evaluated for metastases via bioluminescent imaging and histology. SETTINGS: The study was conducted at a single university center. MAIN OUTCOME MEASURES: Primary tumor and metastasis bioluminescent imaging were measured. RESULTS: Intrarectal injection had the lowest mortality at 4.0% (1/25) compared with the intracecal group at 17.4% (4/23) and the acid enema followed by cancer cell instillation group at 15.0% (3/20).The primary tumors in intrarectal mice had the highest average bioluminescence (3.78 * 10 +/- 4.94 * 10 photons) compared with the mice in the intracecal (9.52 * 10 +/- 1.92 * 10 photons; p = 0.012) and acid enema followed by cancer cell instillation groups (6.23 * 10 +/- 1.23 * 10 photons; p = 0.0016). A total of 100% of intrarectal and intracecal mice but only 35% of mice in the acid enema followed by cancer cell instillation group had positive bioluminescent imaging before necropsy. Sixty percent of intrarectal mice had liver metastases, and 56% had lung metastases. In the intracecal group, 39% of mice had liver metastases, and 35% had lung metastases. Only 2 acid enema followed by cancer cell instillation mice developed metastases. LIMITATIONS: Tumor injections were performed by multiple investigators. Distant metastases were confirmed, but local lymph node status was not evaluated. CONCLUSIONS: Intrarectal injection is the safest, most reproducible, and successful orthotopic mouse model for human colorectal cancer primary tumor growth and spontaneous metastasis. PMID- 29722729 TI - Visceral Fat Is Associated With Mucosal Healing of Infliximab Treatment in Crohn's Disease. AB - BACKGROUND: Visceral fat is the pathogenesis of Crohn's disease and is associated with disease status. OBJECTIVE: This study aimed to evaluate the effect of the visceral fat on mucosal healing in patients with Crohn's disease after infliximab induction therapy DESIGN:: This was a retrospective study. SETTINGS: The study was conducted in a tertiary referral hospital. PATIENTS: Between 2011 and 2017, 97 patients with Crohn's disease with the presence of ulcers underwent infliximab therapy. MAIN OUTCOME MEASURES: We studied them retrospectively. Mucosal healing was the end point. Patients composed 2 groups: mucosal healing and no mucosal healing. Univariate, multivariate, and receiver operating characteristic curve analyses determined the predictive value of the visceral fat area. RESULTS: Univariate analysis showed a statistically significant difference in the smoking history between the groups. Mucosal healing rates after infliximab were lower among active smokers (p = 0.022). Healed patients had significantly less visceral fat area before therapy (47.76 +/- 4.94 vs 75.88 +/- 5.55; p = 0.000) and a lower mesenteric fat index (0.52 +/- 0.04 vs 0.89 +/- 0.07; p = 0.000). There was no significant difference in the subcutaneous fat area (87.39 +/- 5.01 vs 93.31 +/- 6.95; p = 0.500). Multivariate analysis showed that only visceral fat area (OR = 0.978 (95% CI, 0.964-0.992); p = 0.002) and smoking history (OR = 0.305 (95% CI, 0.089-0.996); p = 0.041) were independent factors for mucosal healing. Receiver operating characteristic curve analysis showed predictive cutoff values of 61.5 cm and 0.62 for visceral fat area and mesenteric fat index. LIMITATIONS: This was a retrospective study. CONCLUSIONS: There was an association between increased visceral fat area and attenuated mucosal healing after infliximab therapy in biologically naive patients with Crohn's disease, indicating a need for earlier increased infliximab doses among patients with increased visceral fat. See Video Abstract at http://links.lww.com/DCR/A590. PMID- 29722731 TI - Using Endoscopic Submucosal Dissection as a Routine Component of the Standard Treatment Strategy for Large and Complex Colorectal Lesions in a Western Tertiary Referral Unit. AB - BACKGROUND: Colorectal endoscopic submucosal dissection results in high rates of en bloc resection, few recurrences, and accurate diagnosis, and it is useful in lesions with significant fibrosis. However, endoscopic submucosal dissection has not been widely adopted by Western endoscopists and the published experience from Western centers is very limited. OBJECTIVES: This study aims to report the outcomes from a UK tertiary center using colorectal endoscopic submucosal dissection as part of a standard lesion specific treatment approach. DESIGN: This was a retrospective study. SETTING: The study was conducted in a tertiary referral unit for interventional endoscopy in the United Kingdom. PATIENTS: A total of 116 colorectal lesions were resected using endoscopic submucosal dissection or hybrid endoscopic submucosal dissection in 107 patients. MAIN OUTCOME MEASURES: Outcomes included complications, recurrence, requirement for surgery, en bloc and R0 resection. RESULTS: One hundred sixteen lesions (mean size 58.8mm) were resected using endoscopic submucosal dissection (n = 58) and hybrid endoscopic submucosal dissection (n = 58). Eighty-two (70.7%) had failed attempts at resection (n = 58) or extensive sampling before referral. Twelve contained invasive adenocarcinoma; endoscopic resection was curative in 6. Only 2 of 6 patients with noncurative endoscopic resection agreed to surgery, and none had lymph node metastases. Six of 7 perforations were successfully treated with endoscopic clips. Where endoscopic submucosal dissection was used alone, en bloc resection was achieved in 93% and R0 resection was achieved in 91%. Two patients experienced recurrence; both were managed with endoscopic resection. LIMITATIONS: This was a retrospective study. Procedures were planned as endoscopic submucosal dissection, but some may have been converted to hybrid endoscopic submucosal dissection and not recorded. CONCLUSION: Colorectal endoscopic submucosal dissection can be used in a Western center as part of a standard lesion-specific approach to deliver effective organ-conserving treatment to patients with large challenging lesions. Lesion assessment in Western practice should be improved to reduce the incidence of prior heavy manipulation and to guide appropriate referral. See Video Abstract at http://links.lww.com/DCR/A601. PMID- 29722730 TI - Virtual Reality Exploration and Planning for Precision Colorectal Surgery. AB - BACKGROUND: Medical software can build a digital clone of the patient with 3 dimensional reconstruction of Digital Imaging and Communication in Medicine images. The virtual clone can be manipulated (rotations, zooms, etc), and the various organs can be selectively displayed or hidden to facilitate a virtual reality preoperative surgical exploration and planning. OBJECTIVE: We present preliminary cases showing the potential interest of virtual reality in colorectal surgery for both cases of diverticular disease and colonic neoplasms. DESIGN: This was a single-center feasibility study. SETTINGS: The study was conducted at a tertiary care institution. PATIENTS: Two patients underwent a laparoscopic left hemicolectomy for diverticular disease, and 1 patient underwent a laparoscopic right hemicolectomy for cancer. The 3-dimensional virtual models were obtained from preoperative CT scans. The virtual model was used to perform preoperative exploration and planning. Intraoperatively, one of the surgeons was manipulating the virtual reality model, using the touch screen of a tablet, which was interactively displayed to the surgical team. MAIN OUTCOME MEASURES: The main outcome was evaluation of the precision of virtual reality in colorectal surgery planning and exploration. RESULTS: In 1 patient undergoing laparoscopic left hemicolectomy, an abnormal origin of the left colic artery beginning as an extremely short common trunk from the inferior mesenteric artery was clearly seen in the virtual reality model. This finding was missed by the radiologist on CT scan. The precise identification of this vascular variant granted a safe and adequate surgery. In the remaining cases, the virtual reality model helped to precisely estimate the vascular anatomy, providing key landmarks for a safer dissection. LIMITATIONS: A larger sample size would be necessary to definitively assess the efficacy of virtual reality in colorectal surgery. CONCLUSIONS: Virtual reality can provide an enhanced understanding of crucial anatomical details, both preoperatively and intraoperatively, which could contribute to improve safety in colorectal surgery. PMID- 29722732 TI - Procedure for Prolapse and Hemorrhoids Complication Solutions: Repair of a Completely Closed Off Rectum. PMID- 29722733 TI - Oral Antibiotics as Adjunct to Systemic Antibiotics and Mechanical Bowel Preparation for Prevention of Surgical Site Infections in Colorectal Surgery. Do We Really Need More Trials? PMID- 29722734 TI - Endoscopic Pilonidal Sinus: How Far Have We Come? PMID- 29722735 TI - The Authors Reply. PMID- 29722737 TI - Role of Immune Checkpoint Inhibitors in Small Cell Lung Cancer. AB - BACKGROUND: Small cell lung cancer (SCLC) accounts for approximately 13% of all lung cancer diagnoses each year. SCLC is characterized by a rapid doubling time, early metastatic spread, and an unfavorable prognosis overall. AREAS OF UNCERTAINTY: Most patients with SCLC will respond to initial treatment; however, the majority will experience a disease recurrence and response to second-line therapies is poor. Immune checkpoint inhibitors may be an option given the success in other diseases. DATA SOURCES: A literature search was conducted using Medline (1946-July week 1, 2017) and Embase (1996-2017 week 28) with the search terms small cell lung cancer combined with nivolumab or ipilimumab or pembrolizumab or atezolizumab or tremelimumab or durvalumab. Five clinical trials, including extended follow-up for 2, that evaluated immune checkpoint inhibitors in limited stage or extensive stage SCLC were included. RESULTS: In 2 phase 2 trials, ipilimumab was added to upfront chemotherapy. In both trials, an improvement in progression-free survival was seen. Toxicity, when combined with a platinum and etoposide, was significant. In a confirmatory phase 3 trial, ipilimumab did not prolong overall survival when added to first-line chemotherapy. Overall, response rates were similar between the placebo and ipilimumab groups. A phase 1/2 trial evaluated nivolumab alone or in combination with ipilimumab in recurrent SCLC. Results revealed that nivolumab monotherapy and the combination of nivolumab and ipilimumab were relatively safe and had antitumor activity. Pembrolizumab has been evaluated in a multicohort, phase 1b trial. Preliminary data showed a durable response in the second-line setting. CONCLUSION: Given the lack of overall survival data and significant toxicity associated with the combination of ipilimumab with first-line chemotherapy, this treatment is not a reasonable option at this time. Nivolumab alone or in combination with ipilimumab is a valid option for recurrent SCLC. PMID- 29722738 TI - Analysis of Risk Factors in Patients With Peripheral Vertigo or Central Vertigo. AB - INTRODUCTION: This study was aimed to determine risk factors for central vertigo (CV) in patients with isolated vertigo accompanied by hearing loss or not. PATIENTS AND METHODS: Patients with CV or peripheral vertigo (PV) who were admitted to our hospital between January 2014 and July 2016 were retrospectively reviewed. All patients underwent thorough physical examination with detailed medical histories recorded, including smoking, hypertension, diabetes, cardiovascular disease, and stroke history. Logistic regression estimated odds ratio (OR) of the risk factors. RESULTS: Eighty-seven patients were enrolled into the study, including 41 cases of CV and 46 cases of PV. There was significant difference in sex, age above 60, hypertension, diabetes, smoking, and stroke history between the 2 groups. The patients without any risk factors did not have CV. The risk for CV in the patients with >=3 risk factors was greater (OR, 11.43; 95% confidence interval, 3.27-39.93; P<0.001) than the patients with 1 risk factor. The risk for CV in the patients with 2 risk factors was similar (OR, 0.833; 95% confidence interval, 0.17-4.28; P=0.825) to the patients with 1 risk factor. CONCLUSION: The patients with isolated vertigo (accompanied by hearing loss or not) and 3 or more risk factors are at higher risk for CV. They should have a comprehensive neurological examination and be closely followed up. PMID- 29722739 TI - Stroke Severity Affects Timing: Time From Stroke Code Activation to Initial Imaging is Longer in Patients With Milder Strokes. AB - Optimizing the time it takes to get a potential stroke patient to imaging is essential in a rapid stroke response. At our hospital, door-to-imaging time is comprised of 2 time periods: the time before a stroke is recognized, followed by the period after the stroke code is called during which the stroke team assesses and brings the patient to the computed tomography scanner. To control for delays due to triage, we isolated the time period after a potential stroke has been recognized, as few studies have examined the biases of stroke code responders. This "code-to-imaging time" (CIT) encompassed the time from stroke code activation to initial imaging, and we hypothesized that perception of stroke severity would affect how quickly stroke code responders act. In consecutively admitted ischemic stroke patients at The Mount Sinai Hospital emergency department, we tested associations between National Institutes of Health Stroke Scale scores (NIHSS), continuously and at different cutoffs, and CIT using spline regression, t tests for univariate analysis, and multivariable linear regression adjusting for age, sex, and race/ethnicity. In our study population, mean CIT was 26 minutes, and mean presentation NIHSS was 8. In univariate and multivariate analyses comparing CIT between mild and severe strokes, stroke scale scores <4 were associated with longer response times. Milder strokes are associated with a longer CIT with a threshold effect at a NIHSS of 4. PMID- 29722740 TI - Rheumatoid Meningitis: A Case Review. AB - INTRODUCTION: Rheumatoid meningitis (RM) is a rare complication of rheumatoid arthritis (RA) and has a high mortality rate. It can present as a first diagnosis of RA, in long-standing disease, or in active or well-controlled disease. Neurological manifestations vary widely. CASE REPORT: A patient with a 30-year history of RA, well controlled with methotrexate therapy, presented with new onset seizures. Magnetic resonance imaging showed leptomeningeal and pachymeningeal enhancement. A de novo workup resulted in diagnosis of RM. CONCLUSIONS: Cerebrospinal fluid findings for RM are nonspecific, typically lymphocytic pleocytosis; however, they can be neutrophilic, as in this case. Magnetic resonance imaging findings consist of leptomeningeal and pachymeningeal enhancement but can also involve the parenchyma. The diagnosis is typically confirmed with meningeal biopsy. Treatment involves high-dose corticosteroids or immunomodulatory therapy, or both. Long-term follow-up with radiologic surveillance typically ranges from improvement to resolution. PMID- 29722741 TI - Neuroinvasive Listeriosis: Could Petechial Hemorrhages be a Diagnostic Clue? AB - INTRODUCTION: Listeria monocytogenes-related central nervous system infections may involve the cerebral parenchyma. Meningitis and meningoencephalitis are the most commonly seen forms and mainly affect immunocompromised patients; however, a less frequent form, rhombencephalitis, can occur in otherwise healthy people. Early treatment with appropriate antibiotic therapy is crucial for this otherwise fatal disorder. However, it is not always possible to rapidly establish the diagnosis because of varying presentations and discrepancies in diagnostic tests. CASE REPORT: Herein we report 3 cases of listerial infections involving the central nervous system parenchyma, with versatile diagnostic challenges and related possible solutions and radiologic hints to overcome similar issues in the future. CONCLUSIONS: We point out the importance of nonconventional magnetic resonance imaging techniques in the diagnosis, as we detected petechial hemorrhages in the brain parenchyma in all cases, which can be a diagnostic clue. PMID- 29722742 TI - Neuromyelitis Optica and Herpes Simplex Virus 2: A Viral Trigger for Aquaporin-4 Autoimmunity? AB - The clinical and radiographic spectrum of Neuromyelitis optica spectrum disorder has broadened following the description of the aquaporin-4 antibody. The initial triggering event and reason for disease quiescence between relapses is unclear. We present a case of myeloradiculitis associated with aquaporin-4 antibody and concomitant herpes simplex virus 2 infection. PMID- 29722743 TI - Ongoing Photosensitivity in An Elderly Patient With Jeavons Sydrome. AB - INTRODUCTION: Photosensitivity, which is a main feature of Jeavons syndrome, can be seen in other types of idiopathic or genetic epilepsies with focal or generalized seizures and tends to disappear spontaneously usually in the second decade. Although it responds well to antiepileptic treatment, especially to valproic acid, it may continue into adulthood in rare cases. CASE REPORT: We describe a 63-year-old male patient with eyelid myoclonia with absences, generalized tonic-clonic seizures, and severe photosensitivity accompanied by eyelid myoclonia. Seizures were treated with antiepileptic treatment, whereas photosensitivity still continued on electroencephalogram without clinical findings. CONCLUSION: Our elderly patient with Jeavons syndrome with ongoing remarkable photosensitivity demonstrated that it may continue to older ages, although it is uncommon. PMID- 29722744 TI - The Mayo Clinic Experience With the Neurological Complications of the CTLA-4 Inhibitor Ipilimumab. AB - Neurological complications are an increasingly recognized complication of the use of the immune checkpoint inhibitors in the treatment of solid tumors. Ipilimumab is a monoclonal antibody against cytotoxic T-lymphocyte antigen-4, an immune checkpoint inhibitor that suppresses T-cell effector function. The clinical spectrum of ipilimumab-associated neurological complications and optimum treatment approach is not established. We describe our institution's experience with ipilimumab and illustrate 2 cases of presumed autoimmune neurological phenomenon resulting from its use. PMID- 29722745 TI - Vertebral Artery Occlusion Causing Facial Colliculus and Opalski Stroke Syndromes Simultaneously. AB - Brainstem stroke syndromes refer to a group of vascular disorders that occur secondary to occlusion of small perforating arteries of the posterior circulation. Although such syndromes result in a characteristic clinical picture, they are challenging to localize. In practice, such syndromes are rarely seen in their pure form, and the clinical consequences of a given vascular lesion are probably less predictable than for arteries in the anterior circulation. If 2 or more brainstem strokes happen simultaneously, localization becomes much harder. In this article, we present a case with 2 embolic strokes that occurred simultaneously because of left vertebral artery occlusion. The first in the right facial colliculus causing right sixth and seventh cranial nerves' palsy. The second happened in the left lateral medulla extending below the pyramidal decussation causing a classic left lateral medullary syndrome with ipsilateral hemiparesis, which constitutes a left Opalski stroke syndrome. To our knowledge, this is the first reported case of these 2 brainstem stroke syndromes happening simultaneously. PMID- 29722746 TI - Spot Sign in Acute Intracerebral Hemorrhage in Magnetic Resonance Imaging: A Case Report and Review of the Literature. AB - INTRODUCTION: Intracranial hemorrhage (ICH) is associated with significant mortality and morbidity. Current treatment paradigms focus on correcting hypertension and coagulopathy to prevent hematoma expansion. Magnetic resonance imaging (MRI) is becoming more common in the hyperactive phase of ICH management. The finding of contrast extravasation (ie, spot sign) on MRI may be a marker of active bleeding. We present a case of MRI spot sign and review of the literature. CASE REPORT: We present a patient on oral coumadin for history of deep venous thrombosis and pulmonary embolus who presented with a right basal ganglia hemorrhage. She had a computed tomography angiography showing contrast extravasation and also had a hyperacute MRI showing similar contrast extravasation. Follow-up imaging showed hematoma enlargement. DISCUSSION: We present here a case of corroboration of the computed tomography angiography spot sign with the MRI spot sign. The prognostic value of the MRI spot sign is unclear. Future studies should evaluate the prognostic value of the hyperacute MRI in ICH management. PMID- 29722748 TI - Context for Practice: Excellence in Prevention. PMID- 29722747 TI - Is Adjunctive Progesterone Effective in Reducing Seizure Frequency in Patients With Intractable Catamenial Epilepsy? A Critically Appraised Topic. AB - BACKGROUND: Catamenial epilepsy refers to cyclic seizure exacerbation in relation to the menstrual cycle. Three distinct patterns have been described: C1 perimenstrual, C2-periovulatory, and C3-inadequate luteal. There is experimental and clinical evidence that gonadal steroid hormones affect neuronal excitability with estrogens being mainly proconvulsant and progesterone anticonvulsant. If reproductive steroids have a role in seizure occurrence, they may also have a role in treatment. OBJECTIVE: The objective of this study was to critically assess current evidence regarding the efficacy of progesterone as adjunctive therapy in women with intractable catamenial epilepsy. METHODS: The objective was addressed through the development of a structured critically appraised topic. This included a clinical scenario with a clinical question, literature search strategy, critical appraisal, results, evidence summary, commentary, and bottom line conclusions. Participants included consultant and resident neurologists, medical librarian, and content experts in the fields of epilepsy and gynecology. RESULTS: A randomized, placebo-controlled clinical trial was selected for critical appraisal. This trial compared the efficacy of adjunctive cyclic natural progesterone therapy versus placebo for seizures in women with intractable partial epilepsy, stratified by catamenial and noncatamenial status. There was no significant difference in proportions of responders between progesterone and placebo in the catamenial and noncatamenial strata. Prespecified secondary analysis showed that the level of perimenstrual seizure exacerbation is a significant predictor of the responder rate for progesterone therapy. CONCLUSIONS: Cyclic natural progesterone is not superior to placebo in reducing seizure frequency in women with intractable partial epilepsy. Posthoc findings suggest that progesterone may benefit a subset of women with perimenstrually exacerbated seizures. PMID- 29722749 TI - The Impact of Pediatric Pressure Injury Prevention Bundle on Pediatric Pressure Injury Rates: A Secondary Analysis. AB - PURPOSE: The primary aim of this study was to explore the relationship between a pediatric pressure injury prevention bundle (PPIPB) implemented by pediatric hospitals across the nation and pressure injury (PI) rates over a 6-year period. A secondary aim of this study was to identify whether any one risk factor addressed in the PPIPB had a greater effect on PI occurrences than any other factor. DESIGN: Nonexperimental, retrospective correlation analysis of secondary data. SUBJECTS AND SETTING: Analysis of data from 99 pediatric hospitals participating in the national initiative Solutions for Patient Safety (SPS). METHODS: Data were extracted from the SPS, an initiative designed to reduce PI rates in pediatric hospitals. We analyzed data related to nursing interventions implemented to ameliorate 5 factors associated with PI development. They were presence of medical devices, moisture, immobility, skin integrity, and absence of pressure redistribution with some support surfaces. Paired t test and correlation analysis were used to determine the relationship between the use of a PPIPB and PI incidence per 1000 patient-days. RESULTS: Findings indicated a 57% reduction in PI incidence when the PPIPB was used. A significant inverse relationship between the PPIPB and PI incidence was found. None of the 5 risk factors addressed by the PPIPB had a stronger correlation with PI occurrences than any other factor. CONCLUSIONS: Study findings strongly suggest the use of a PPIPB decreases PI incidence in pediatric hospitals and should be considered when implementing a PI prevention program. PMID- 29722750 TI - A Survey of Canadian Occupational Therapy Practices to Prevent Pressure Injuries Among Wheelchair Users via Weight Shifting. AB - PURPOSE: The purpose of this study was to describe occupational therapy weight shifting practices and explore recommended strategies for patients, healthcare staff, and family/caregivers across healthcare settings. DESIGN: Cross-sectional survey. SUBJECTS AND SETTING: Respondents included 97 currently practicing occupational therapists working in 5 main practice settings (ie, acute care, inpatient rehabilitation, outpatient rehabilitation, home and community care, and residential) from 9 out of 10 Canadian provinces. METHODS: We created a 25-item questionnaire that included forced choice and open-ended queries. Items queried demographic information, weight-shifting techniques taught to patients, frequency and duration of weight shifting recommended, educational approaches used to teach weight shifting, and resources used to guide decision making. Participants were recruited via professional organizations and health authorities across Canada. Participants were excluded if they were not currently working with manual or power wheelchair users. Descriptive statistics were used to analyze quantitative data, and content analysis was used for qualitative data (responses to open-ended queries). RESULTS: The most frequently recommended weight-shifting techniques were tilt (83.3%-92.8%), leaning to one side (47.9%-87.5%), and forward leaning (46.9%-83.3%). Study findings revealed a wide range of recommendations regarding frequency (every 10 minutes or less to >2 to 3 hours) and duration (<=30 seconds to as long as tolerated) of weight shifting. Weight-shifting interventions were most commonly guided by clinical experience (81.7%), practice guidelines (62.4%), and expertise of other team members (54.8%). CONCLUSIONS: Results from this study highlight the need for further research to inform weight-shifting techniques and to build a more comprehensive understanding of weight-shifting education practices. PMID- 29722751 TI - Incontinence-Associated Dermatitis and Intertriginous Dermatitis as Nurse Sensitive Quality Indicators: A Delphi Study. AB - PURPOSE: This purpose of this study was to determine whether consensus exists concerning the need to collect epidemiologic data about 2 forms of moisture associated skin damage, incontinence-associated dermatitis (IAD) and intertriginous dermatitis (ITD), and whether these data should be part of data routinely collected as part of the National Database of Nursing Quality Indicators (NDNQI). DESIGN: Modified Delphi technique. SAMPLE AND SETTING: Questionnaires were sent via e-mail to 50 identified experts, with an initial response of 17. Thirteen clinical experts responded to the second round and 11 responded to a third round. METHODS: Items on the questionnaires were investigator-developed. Consensus was defined as 80% or more agreement. Three rounds of questionnaires were employed to attempt consensus. Descriptive statistics were performed using mean and standard deviation for continuous data and frequencies and percentages for categorical data. Qualitative data were analyzed question by question by the primary researcher using content analysis. RESULTS: Consensus was achieved indicating that individual facilities should regularly collect data about IAD prevalence or incidence. Consensus was not reached about the need to regularly collect data about ITD prevalence or incidence. Panelists also failed to reach consensus that IAD or ITD prevalence or incidence should be incorporated into the NDNQI indicators. CONCLUSION: Panelists did not reach consensus that IAD or ITD epidemiologic data should be incorporated on the NDNQI. Additional research is needed, particularly in the area of ITD, before benchmarks can be established regarding these data as nurse-sensitive indicators of quality care. PMID- 29722753 TI - Knowledge and Attitudes of Nurses Toward Pressure Injury Prevention: A Cross Sectional Multisite Study. AB - PURPOSE: The purpose of the study was to examine the knowledge and attitudes of nurses on pressure injury prevention and determine if there was a relationship between knowledge, attitude, and years of experience following an unexplained increase in reported hospital-acquired pressure injuries across 1 health district in Sydney, Australia. DESIGN: Multisite cross-sectional study. SUBJECTS AND SETTING: Registered and enrolled nurses working in acute, medical, and rehabilitation units in 4 hospitals and 5 community health centers across a local health district. METHODS: Using a modified version of the Pressure Ulcer Knowledge Test and the Staff Attitude Scale, nurses were invited to complete the survey online or on paper. RESULTS: A total of 3123 surveys were distributed and 998 were returned yielding a response rate of 32%. Approximately one-third of nurse respondents who participated in the survey had been practicing for 5 to 10 years. Almost 80% of participants scored 33/47 or more (70% or more correct) on the knowledge survey; the mean score was 35.21. The mean score for the attitudes test was 44.43 +/- 4.77, out of 55 (80.7%), indicating a positive attitude toward pressure injury prevention. There was a significant positive correlation between nurses' years of experience and attitudes, but there was no correlation between years of experience and knowledge. Knowledge and attitudes were also significantly positively correlated. CONCLUSIONS: Nurses had sound knowledge and held positive attitudes toward pressure injury prevention. Positive attitudes were associated with greater time spent in the workforce. Additional research is required to examine relationships between knowledge of and attitude toward pressure injury prevention and clinical practice. Further research is also needed to determine if improving knowledge and attitudes results in a sustained reduction of hospital-acquired pressure injuries. PMID- 29722752 TI - Pressure Injuries Among Hospitalized Patients With Cancer: Prevalence and Use of Preventive Interventions. AB - PURPOSE: The purpose of this study was to measure the prevalence of pressure injuries (PIs) in hospitalized patients with cancer. DESIGN: Multicenter, cross sectional prevalence survey. SUBJECTS AND SETTING: The sample comprised 110 adults with cancer; their mean age was 50.65 years (SD: 17.32); and more than half were females (n = 60, 54.5%). The study setting was 5 hospitals in Jordan. METHODS: A prevalence survey was conducted using methods recommended by the European Pressure Ulcer Advisory Panel. Data collection included skin assessment, PI risk, and preventive measures. RESULTS: The prevalence of PIs was 15.5% (n = 17); it was 7.3% (n = 8) when grade/category I PIs were excluded. Heel PIs were the most frequent (n = 11; 64.7%) and most PIs were grade I (n = 9; 52.9%). Only 26.9% of at-risk patients received appropriate preventive interventions. CONCLUSIONS: Study findings support the need to prioritize PI prevention in patients with cancer. Additional research is needed to add to the knowledge base regarding PIs within vulnerable groups such as individuals with cancer. PMID- 29722754 TI - Assessment, Selection, Use, and Evaluation of Body-Worn Absorbent Products for Adults With Incontinence: A WOCN Society Consensus Conference. AB - The Wound, Ostomy and Continence Nurses (WOCN) Society charged a task force with creating recommendations for assessment, selection, use, and evaluation of body worn absorbent products. The 3-member task force, assisted by a moderator with knowledge of this area of care, completed a scoping literature review to identify recommendations supported by adequate research to qualify as evidence-based, and area of care where evidence needed to guide care was missing. Based on findings of this scoping review, the Society then convened a panel of experts to develop consensus statements guiding assessment, use, and evaluation of the effect of body-worn absorbent products for adults with urinary and/or fecal incontinence. These consensus-based statements underwent a second round of content validation using a modified Delphi technique using a different panel of clinicians with expertise in this area of care. This article reports on the scoping review and subsequent evidence-based statements, along with generation and validation of consensus-based statements that will be used to create an algorithm to aid clinical decision making. PMID- 29722756 TI - The Use of Immersion Therapy Mattress With Low Air Loss in Patients With Myocutaneous Flaps. AB - BACKGROUND: In our hospital, air-fluidized therapy beds were used for all patients undergoing surgery for the creation of myocutaneous flaps. These beds were associated with staff injuries and patients reported dissatisfaction. The WOC nurses were asked to find an alternative support surface for postmyocutaneous flap patients. CASES: We report findings from 5 patients placed on a low air loss immersion mattress after myocutaneous flap surgery. On week 2, per our hospital's clinical pathway, all were transferred to our critical access hospitals with the immersion therapy mattress. Upon discharge, all flap incisions were approximated and closed. CONCLUSION: Our experiences with these 5 cases suggest that a support surface combining immersion and low air loss feature is a viable alternative to an air-fluidized bed for postoperative management of patient undergoing myocutaneous flap surgery for the management of full-thickness pressure injuries. PMID- 29722758 TI - Advanced Practice Ostomy Care. PMID- 29722757 TI - Nurses Specialized in Wound, Ostomy & Continence Canada (NSWOCC): A Name Change to Strategically Position the Canadian Association for Enterostomal Therapy (CAET). PMID- 29722759 TI - Cost-effectiveness of a Ceramide-Infused Skin Barrier Versus a Standard Barrier: Findings From a Long-Term Cost-effectiveness Analysis: Erratum. PMID- 29722761 TI - Biological Therapies in Orthopedic Sports Medicine. PMID- 29722762 TI - PRP as an Adjunct to Rotator Cuff Tendon Repair. AB - Arthroscopic rotator cuff repair is a commonly performed repair. Technical developments provide surgeons the tools to create biomechanically robust repairs. How can the biological response mirror the strong and stable surgery? Platelet rich plasma (PRP) is a supraphysiological platelet concentration which may positively augment rotator cuff healing. Not all PRPs are the same. High leukocyte levels and thrombin activation may be detrimental to tendon healing. Thrombin activation triggers an immediate release of growth factors and may actually inhibit some parts of the healing response. Clear differences exist between liquid PRP (products released within hours after activation) and solid fibrin PRP which slowly releases factors over days. The heterogenicity data and grouping liquid and solid PRP together make systematic reviews confusing. Solid PRP fibrin constructs are often associated with increased tendon healing. PRP fibrin matrix offers the greatest promise for improving clinical success after rotator cuff tendon repair. PMID- 29722763 TI - Cell Therapies in Tendon, Ligament, and Musculoskeletal System Repair. AB - In the last few decades, several techniques have been used to optimize tendon, ligament, and musculoskeletal healing. The evidence in favor of these techniques is still not proven, and level I studies are lacking. We performed an analysis of the therapeutic strategies and tissue engineering projects recently published in this field. Here, we try to give an insight into the current status of cell therapies and the latest techniques of bioengineering applied to the field of orthopedic surgery. The future areas for research in the management of musculoskeletal injuries are outlined. There are emerging technologies developing into substantial clinical treatment options that need to be critically evaluated. Mechanical stimulation of the constructs reproduces a more propitious environment for effective healing. PMID- 29722764 TI - Platelet-rich Plasma and Mesenchymal Stem Cells: Exciting, But ... are we there Yet? AB - Joint conditions incapacitate free movement driving to a sedentary lifestyle, a major risk factor for chronic diseases. Regenerative procedures, involving the use of mesenchymal stem/stromal cells along with platelet-rich plasma (PRP), can help patients with these conditions. We describe the main characteristics of cellular products (bone marrow concentrate, stromal vascular fraction of adipose tissue, and mesenchymal stem/stromal cells derived from these tissues), and the potential benefits of combination with PRP in 3 scenarios: PRP lysates used during laboratory cell expansion; PRP to prime cellular products or the host tissue before cell implantation; PRP used as a vehicle for cell transplantation and to provide trophic signals. Clinical studies exploring the benefits of combination products are limited to case series and few controlled studies, involving either arthroscopy or percutaneous injections. Combination products are making their way to clinics but further experimental and clinical research is needed to establish protocols and indications. PMID- 29722765 TI - Making Them Commit: Strategies to Influence Phenotypic Differentiation in Mesenchymal Stem Cells. AB - Tendon injuries, bone defects, and cartilage defects are complex clinical conditions leading to pain and dysfunctions. Tendon, bone, and cartilage are highly specialized and organized tissues, and the self-healing may be limited by their histologic features, or impaired by the local conditions. Furthermore, the resultant tissue often shows inferior properties compared with native tissue, leading to high rates of reruptures and revision surgeries. A growing field of research has explored tendon, bone, and cartilage regeneration using mesenchymal stem cells (MSCs), because of their multipotency, and because they are relatively easy to harvest. Great expectations arose from the use of MSCs in regenerative medicine in the last decade, although both the potential and the drawbacks of this method remain under reflection. This is a narrative review of the literature about different strategies to differentiate MSCs into tenocytes, osteoblasts, and chondrocytes. Challenges and limitations on the use of MSCs in vivo and in clinical practice are also discussed. PMID- 29722766 TI - Microcapsule Technology for Controlled Growth Factor Release in Musculoskeletal Tissue Engineering. AB - Tissue engineering strategies have relied on engineered 3-dimensional (3D) scaffolds to provide architectural templates that can mimic the native cell environment. Among the several technologies proposed for the fabrication of 3D scaffold, that can be attractive for stem cell cultivation and differentiation, moulding or bioplotting of hydrogels allow the stratification of layers loaded with cells and with specific additives to obtain a predefined microstructural organization. Particularly with bioplotting technology, living cells, named bio ink, and additives, such as biopolymer microdevices/nanodevices for the controlled delivery of growth factors or biosignals, can be organized spatially into a predesigned 3D pattern by automated fabrication with computer-aided digital files. The technologies for biopolymer microcarrier/nanocarrier fabrication can be strategic to provide a controlled spatiotemporal delivery of specific biosignals within a microenvironment that can better or faster address the stem cells loaded within it. In this review, some examples of growth factor controlled delivery by biopolymer microdevices/nanodevices embedded within 3D hydrogel scaffolds will be described, to achieve a bioengineered 3D interactive microenvironment for stem cell differentiation. Conventional and recently proposed technologies for biopolymer microcapsule fabrication for controlled delivery over several days will also be illustrated and critically discussed. PMID- 29722767 TI - Amniotic Epithelial Stem Cells: Salient Features and Possible Therapeutic Role. AB - This is a study of amniotic epithelial cells, which form the innermost layer of the amniotic membrane. These cells can be easily isolated and display peculiar and unique properties, such as plasticity and differentiation potential toward the 3 germinal layers, that may aid regeneration and/or repair of damaged or diseased tissues and organs. A robust literature based on in vitro, experimental, and clinical studies in large animals demonstrates that these cells can enhance the regeneration of tendons, bone, and articular cartilage. On the basis of these considerations, allotransplantation of human amniotic epithelial cells could be proposed for clinical trials in human orthopedic conditions. PMID- 29722768 TI - ACL Allograft: Advantages and When to Use. AB - It is commonly recommended to reconstruct a torn anterior cruciate ligament in active patients; however, there is no consensus concerning the tissue source to use for the reconstruction. Bone-patellar tendon-bone and hamstring (semitendinosis +/- gracilis) autografts are most commonly used, with allografts being another option. Each tissue has its pros and cons, with allografts often cited as having higher failure rates. However, review of the literature comparing autografts and allografts have showed similar outcomes in age-matched adult populations. Some authors have had particular concern with using allografts in patients under 25 years of age, with several studies showing significantly higher failure rates with allografts versus autografts. More recent literature has shown than allografts can successfully be used in this younger age group with proper graft processing and compliance with a slower rehabilitation protocol. PMID- 29722770 TI - Complications of Tibial Tuberosity Osteotomy: Erratum. PMID- 29722769 TI - Alternatives to Biologics in Management of Knee Osteoarthritis: A Systematic Review. AB - BACKGROUND: Knee osteoarthritis (KOA) is a common condition encountered by physicians. KOA is addressed by a wide array of modalities including a number of nonbiological treatments. METHODS: PubMed, ISI Web of Science, and SPORTDiscus were searched for level 1 to 4 studies published from inception to August 2017. RESULTS: A total of 18 studies were evaluated and results demonstrated moderate supporting evidence for prolotherapy and limited evidence for botulinum toxin type A, sodium bicarbonate and calcium gluconate, and low-molecular weight fraction of 5% human serum albumin. Evidence for local anesthetic agents was conflicting. CONCLUSION: There is moderate supportive evidence for the effectiveness of prolotherapy in improving pain and function in both, short-term and long-term. Limited supporting evidence found for botulinum toxin type A, sodium bicarbonate and calcium gluconate, and low-molecular weight fraction of 5% human serum albumin in improving pain and function. There is conflicting evidence for the use of local anesthetic agents in patients with KOA. PMID- 29722771 TI - Effects of early diagnosis of the wrist over-use syndrome on the treatment. AB - Aim To demonstrate the effects of early diagnosis of overuse syndrome in the wrist on healing, pain intensity and quick recovery to daily work and sport activities. Methods This clinical retrospective study included 60 patients of both sexes aged from 22 to 44 years, with pain in the wrist and clinical signs of creeping tenosynovitis. Patients were divided into two groups: the first group - persons doing sports activity, and the second group - patients who did not deal with sports activities. Results Females in 31 (51.7%) cases compared to males with 29 (48.3%) were slightly more represented in the total sample. Patients with injuries due to sports activities had previously reported to the physician and the diagnosis was set at an average of 3.1+/-0.9 days after the first symptoms (the range of 2-5 days), compared to the patients of the second group whose diagnosis was set at an average of 4.7+/-1.1 days after the first symptoms (p<0.05). Conclusion Patients involved in sports activities were more motivated for faster recovery, they had earlier doctor's examination with rapid reduction of subjective symptoms during intensive physical therapy. PMID- 29722772 TI - Hydroelectric power plant on a paper strip. AB - We exploit the combinatorial advantage of electrokinetics and tortuosity of a cellulose-based paper network on laboratory grade filter paper for the development of a simple, inexpensive, yet extremely robust (shows constant performance for 12 days) 'paper-and-pencil'-based device for energy harvesting applications. We successfully achieve harvesting of a maximum output power of ~640 pW in a single channel, while the same is significantly improved (by ~100 times) with the use of a multichannel microfluidic array (maximum of up to 20 channels). Furthermore, we also provide theoretical insights into the observed phenomenon and show that the experimentally predicted trends agree well with our theoretical calculations. Thus, we envisage that such ultra-low cost devices may turn out to be extremely useful in energizing analytical microdevices in resource limited settings, for instance, in extreme point of care diagnostic applications. PMID- 29722773 TI - Concomitant desalting and concentration of neuropeptides on a donut-shaped surface pattern for MALDI mass spectrometry. AB - We demonstrate that a donut-shaped surface pattern consisting of a central hydrophobic region and a surrounding hydrophilic region simultaneously concentrates and desalts a solution of neuropeptides with a high salt content. Our approach greatly simplifies the sample preparation process for MALDI mass spectrometry. PMID- 29722774 TI - Modulation of plant chemistry by beneficial root microbiota. AB - Covering: 1981-2017Plants are colonized by an astounding number of microorganisms that can reach cell densities much greater than the number of plant cells. Various plant-associated microorganisms can have profound beneficial effects on plant growth, development, physiology and tolerance to (a)biotic stress. In return, plants release metabolites into their direct surroundings, thereby feeding the microbial community and influencing their composition, gene expression and the production of secondary metabolites. Similarly, microbes living on and in plant tissue may induce known and yet unknown biosynthetic pathways in plants leading to diverse alterations in the plant metabolome. Here, we provide an overview of the impact of beneficial microbiota on plant chemistry, with an emphasis on bacteria living on or inside root tissues. We will also provide new perspectives on deciphering the yet untapped potential of microbe mediated alteration of plant chemistry as an alternative platform to discover new pathways, genes and enzymes involved the biosynthesis of high value natural plant products. PMID- 29722775 TI - Alkene-alkyl interconversion: an experimental and computational study of the olefin insertion and beta-hydride elimination processes. AB - The preparation and characterization of various alkyl, allyl or alkene Rh(iii) and Ir(iii) complexes as well as studies on the intramolecular reactions leading to transformation of one into another are reported. The silyl-hydrido-Rh(iii) complex {Rh(H)[SiMe(o-C6H4SMe)2](PPh3)}[BArF4], with a vacant coordination site, reacts with 1,5-cyclooctadiene (cod) leading to olefin insertion into the Rh-H bond and rearrangement to yield the 16e cyclooctenyl-Rh(iii) complex {Rh(eta3 cyclooctenyl)[SiMe(o-C6H4SMe)2]}[BArF4] (1). This compound can be also synthesized by reaction of the 18e chloride precursor {Rh(eta3 cyclooctenyl)[SiMe(o-C6H4SMe)2]Cl} with NaBArF4. The reaction of the thioether silane SiMeH(o-C6H4SMe)2 with [Rh(nbd)Cl]2 (nbd = norbornadiene) leads to {Rh(sigma-ntyl)[SiMe(o-C6H4SMe)2]Cl} (ntyl = nortricyclyl) (2). The abstraction of chloride from this neutral 16e ntyl-Rh(iii) complex with NaBArF4 results in the unusual isomerization of sigma-nortricyclyl into sigma,pi-norbornenyl forming the 16e and cationic {Rh(sigma,pi-nbyl)[SiMe(o-C6H4SMe)2][BArF4] (nbyl = norbornenyl)} compound 3. Coordinatively saturated {Ir(eta3-cyclooctenyl)[SiMe(o C6H4SMe)2]Cl} (4) has been synthesized by the reaction of [Ir(cod)Cl]2 with SiMeH(o-C6H4SMe)2. The reaction of 4 with NaBArF4 led to the formation of the unsaturated and cationic Ir(iii) compound {Ir(eta3-cyclooctenyl)[SiMe(o C6H4SMe)2]}[BArF4] (5). Compound 5 shows low stability in solution and undergoes successive beta-hydride elimination and olefin insertion steps, which were elucidated by DFT calculations, to form 18e {Ir(H)[SiMe(o-C6H4SMe)2](eta4 cod)}[BArF4] (6). PMID- 29722776 TI - A general formulation of the quasiclassical trajectory method for reduced dimensionality reaction dynamics calculations. AB - Dimension reduction by freezing the unimportant coordinates is widely used in intramolecular and reaction dynamics calculations when the solution of the accurate full-dimensional nuclear Schrodinger equation is not feasible. In this paper we report on a novel form of the exact classical internal-coordinate Hamiltonian for full and reduced-dimensional vibrational motion of polyatomic molecules with the purpose of using it in quasiclassical trajectory (QCT) calculations. The derivation is based on the internal to body-fixed frame transformation, as in the t-vector formalism, however it does not require the introduction of rotational variables to allow cancellation of non-physical rotations within the body-fixed frame. The formulas needed for QCT calculations: normal mode analysis and state sampling as well as for following the dynamics and normal-mode quantum number assignment at instantaneous states are presented. The procedure is demonstrated on the CH4, CD4, CH3D and CHD3 isotopologs of methane using three reduced-dimensional models, which were previously used in quantum reactive scattering studies of the CH4 + X -> CH3 + HX type reactions. The reduced-dimensional QCT methodology formulated this way combined with full dimensional QCT calculations makes possible the classical validation of reduced dimensional models that are used in the quantum mechanical description of the nuclear dynamics in reactive systems [A. Vikar et al., J. Phys. Chem. A, 2016, 120, 5083-5093]. PMID- 29722777 TI - Keggin-type polyoxometalate nanosheets: synthesis and characterization via scanning transmission electron microscopy. AB - Polyoxometalate nanosheets were synthesized at the gas/liquid interface of an aqueous solution of Keggin-type silicotungstic acid, cesium chloride, and n octylamine. The structure of the nanosheets was elucidated via aberration corrected scanning transmission electron microscopy at the atomic and molecular levels. PMID- 29722778 TI - Constructing a ZnIn2S4 nanoparticle/MoS2-RGO nanosheet 0D/2D heterojunction for significantly enhanced visible-light photocatalytic H2 production. AB - A zero-dimensional (0D)/two-dimensional (2D) heterojunction has an excellent advantage of boosting the photo-generated carrier separation and obtaining enhanced photocatalytic activities. Here, a ZnIn2S4 nanoparticle/MoS2-RGO nanosheet 0D/2D heterojunction was prepared by a rapid and low temperature hydrothermal method. TEM characterization results reveal that ZnIn2S4 nanoparticles are uniformly dispersed on the surface of MoS2-RGO nanosheets, which can provide abundant active sites and shorten the charge-migration distance, while the MoS2-RGO nanosheet acts as a support to avoid the aggregation of 0D ZnIn2S4 nanoparticles and also serves as a low-cost cocatalyst for effective hydrogen evolution. Through optimizing the MoS2-RGO composition and content, the highest hydrogen evolution rate of 425.1 MUmol g-1 h-1 was obtained over the ZnIn2S4/MoS2-RGO 0D/2D heterojunction photocatalyst under visible light irradiation (lambda > 420 nm), which is about 34.6 times higher than that of pure ZnIn2S4. Efficient charge separation can be attributed to the significantly enhanced photocatalytic performance, which originates from the favorable properties of the ZnIn2S4/MoS2-RGO 0D/2D heterojunction. This study provides an effective method to improve the photocatalytic performance of the ZnIn2S4 photocatalyst based on the 0D/2D heterojunction. PMID- 29722779 TI - Electronic effect of substituents on anilines favors 1,4-addition to trans-beta nitrostyrenes: access to N-substituted 3-arylindoles and 3-arylindoles. AB - A simple and an efficient method for the regioselective synthesis of N alkyl/aryl/H 3-arylindole derivatives from N-substituted anilines and trans-beta nitrostyrenes has been described using 10 mol% of bismuth(iii) triflate as a catalyst in acetonitrile at 80 degrees C. The present protocol profits from the formation of new C-C and C-N bonds, broad substrate scope and moderate to good yields. PMID- 29722780 TI - Mesoporous silica nanoparticles induced hepatotoxicity via NLRP3 inflammasome activation and caspase-1-dependent pyroptosis. AB - Increased biomedical applications of mesoporous silica nanoparticles (MSNs) raise considerable attention concerning their toxicological effects; the toxicities of MSNs are still undefined and the underlying mechanisms are unknown. We conducted this study to determine the hepatotoxicity of continuous administration of MSNs and the potential mechanisms. MSNs caused cytotoxicity in hepatic L02 cells in a dose- and time-dependent manner. Then, MSNs were shown to elicit NOD-like receptor protein 3 (NLRP3) inflammasome activation in hepatocytes, leading to caspase-1-dependent pyroptosis, a novel manner of cell death. In vivo MSN administration triggered hepatotoxicity as indicated by increased histological injury, serum alanine aminotransferase and serum aspartate aminotransferase. Notably, NLRP3 inflammasome and pyroptosis were also activated during the treatment. Meanwhile, in NLRP3 knockout mice and caspase-1 knockout mice, MSN induced liver inflammation and hepatotoxicity could be abolished. Furthermore, experiments indicated that MSNs induced mitochondrial reactive oxygen species (ROS) generation, and the ROS scavenger could attenuate the MSN-activated NLRP3 inflammasomes and pyroptosis in the liver. Collectively, these data suggested that MSNs triggered liver inflammation and hepatocyte pyroptosis through NLRP3 inflammasome activation, which was caused by MSN-induced ROS generation. Our study provided novel insights into the hepatotoxicity of MSNs and the underlying mechanisms, and facilitated the potential approach to increase the biosafety of MSNs. PMID- 29722781 TI - Correction: Reactions of metallodrugs with proteins: selective binding of phosphane-based platinum(ii) dichlorides to horse heart cytochrome c probed by ESI MS coupled to enzymatic cleavage. AB - Correction for 'Reactions of metallodrugs with proteins: selective binding of phosphane-based platinum(ii) dichlorides to horse heart cytochrome c probed by ESI MS coupled to enzymatic cleavage' by Carolin Mugge et al., Metallomics, 2011, 3, 987-990. PMID- 29722782 TI - Chemo-enzymatic synthesis of (E)-2,3-diaryl-5-styryl-trans-2,3-dihydrobenzofuran based scaffolds and their in vitro and in silico evaluation as a novel sub-family of potential allosteric modulators of the 90 kDa heat shock protein (Hsp90). AB - Herein we propose a facile, versatile and selective chemo-enzymatic synthesis of substituted (E)-2,3-diaryl-5-styryl-trans-2,3-dihydrobenzofurans based on the exploitation of the laccase-mediated oxidative (homo)coupling of (E)-4 styrylphenols. Thanks to this novel synthetic strategy, a library of benzofuran based potential allosteric activators of the Heat shock protein 90 (Hsp90) was easily prepared. Moreover, considering their structural analogies to previously reported allosteric modulators, the sixteen new compounds synthesized in this work were tested in vitro for their potential stimulatory action on the ATPase activity of the molecular chaperone Hsp90. Combining experimental and computational results, we propose a mechanism of action for these compounds, and expand the structure-activity relationship (SAR) information available for benzofuran-based Hsp90 activators. PMID- 29722783 TI - Belamchinenin A, an unprecedented tricyclic-fused triterpenoid with cytotoxicity from Belamcanda chinensis. AB - Belamchinenin A (1), an unprecedented 6/5/6-fused tricyclic triterpenoid with a novel carbon skeleton, has been isolated from the rhizomes of Belamcanda chinensis. Compound 1 features a half-caged tricyclic nucleus with a flexible geranyl side chain. Its structure was determined by the interpretation of spectroscopic data. The absolute configuration of tricyclic nucleus system of 1 was unequivocally assigned by ECD calculation. Geometries optimization indicated that the tricyclic nucleus system is rigid. Compound 1 showed cytotoxic activities against five cells with IC50 values from 2.29 to 4.47 MUM. PMID- 29722784 TI - Persistent homology analysis of ion aggregations and hydrogen-bonding networks. AB - Despite the great advancement of experimental tools and theoretical models, a quantitative characterization of the microscopic structures of ion aggregates and their associated water hydrogen-bonding networks still remains a challenging problem. In this paper, a newly-invented mathematical method called persistent homology is introduced, for the first time, to quantitatively analyze the intrinsic topological properties of ion aggregation systems and hydrogen-bonding networks. The two most distinguishable properties of persistent homology analysis of assembly systems are as follows. First, it does not require a predefined bond length to construct the ion or hydrogen-bonding network. Persistent homology results are determined by the morphological structure of the data only. Second, it can directly measure the size of circles or holes in ion aggregates and hydrogen-bonding networks. To validate our model, we consider two well-studied systems, i.e., NaCl and KSCN solutions, generated from molecular dynamics simulations. They are believed to represent two morphological types of aggregation, i.e., local clusters and extended ion networks. It has been found that the two aggregation types have distinguishable topological features and can be characterized by our topological model very well. Further, we construct two types of networks, i.e., O-networks and H2O-networks, for analyzing the topological properties of hydrogen-bonding networks. It is found that for both models, KSCN systems demonstrate much more dramatic variations in their local circle structures with a concentration increase. A consistent increase of large sized local circle structures is observed and the sizes of these circles become more and more diverse. In contrast, NaCl systems show no obvious increase of large-sized circles. Instead a consistent decline of the average size of the circle structures is observed and the sizes of these circles become more and more uniform with a concentration increase. As far as we know, these unique intrinsic topological features in ion aggregation systems have never been pointed out before. More importantly, our models can be directly used to quantitatively analyze the intrinsic topological invariants, including circles, loops, holes, and cavities, of any network-like structures, such as nanomaterials, colloidal systems, biomolecular assemblies, among others. These topological invariants cannot be described by traditional graph and network models. PMID- 29722785 TI - Improved enzyme annotation with EC-specific cutoffs using DETECT v2. AB - Summary: We present DETECT v2-an enzyme annotation tool which considers the effect of sequence diversity when assigning enzymatic function [as an Enzyme Commission (EC) number] to a protein sequence. In addition to capturing more enzyme classes than the previous version, we now provide EC-specific cutoffs that greatly increase precision and recall of assignments and show its performance in the context of pathways. Availability and implementation: https://github.com/ParkinsonLab/DETECT-v2. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29722786 TI - polymapR-linkage analysis and genetic map construction from F1 populations of outcrossing polyploids. AB - Motivation: Polyploid species carry more than two copies of each chromosome, a condition found in many of the world's most important crops. Genetic mapping in polyploids is more complex than in diploid species, resulting in a lack of available software tools. These are needed if we are to realize all the opportunities offered by modern genotyping platforms for genetic research and breeding in polyploid crops. Results: polymapR is an R package for genetic linkage analysis and integrated genetic map construction from bi-parental populations of outcrossing autopolyploids. It can currently analyse triploid, tetraploid and hexaploid marker datasets and is applicable to various crops including potato, leek, alfalfa, blueberry, chrysanthemum, sweet potato or kiwifruit. It can detect, estimate and correct for preferential chromosome pairing, and has been tested on high-density marker datasets from potato, rose and chrysanthemum, generating high-density integrated linkage maps in all of these crops. Availability and implementation: polymapR is freely available under the general public license from the Comprehensive R Archive Network (CRAN) at http://cran.r-project.org/package=polymapR. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29722787 TI - Divergent adaptation in thyroid cancers. PMID- 29722789 TI - The importance of jointly analyzing treatment administration and toxicity associated with targeted therapies: a case study of regorafenib in soft tissue sarcoma patients. AB - Background: Different methods have been proposed to analyze adverse events (AEs) associated with targeted therapies. While these AEs lead to dose adjustments for many patients, conventional reporting methods do not take drug administration into consideration. This paper underlines the importance of jointly reporting AEs and drug administration using prevalence, and proposes a complementary approach to reporting. Patients and methods: The prevalence method estimates the probability of progression-free patients being in a particular health state (state 1: AEs with full dose; state 2: AEs with reduced dose; state 3: no AEs with reduced dose) at different time points. To take into account the impact of dose adjustments on efficacy, the weighted prevalence method can be used by assigning utility weights to the different health states. The benefit of these methods was illustrated using data from a phase II trial of regorafenib. Results: Only 4.6% of progression-free patients developed mucositis/stomatitis (grade >=2) at 3 months. The prevalence of patients not experiencing this AE but whose dose was reduced or treatment interrupted was 58.1%. The weighted prevalence of the regorafenib toxicity profile and dose reduction was higher in the control arm. Conclusion: This case study confirms the importance of jointly analyzing AEs and drug administration. The weighted prevalence approach is an average score that incorporates the dimension of drug administration into AE assessment. This can be helpful for regulatory agencies as well as for clinicians to evaluate the benefit risk ratio of therapies in their treatment choice. Clinical trial: NCT01900743. PMID- 29722788 TI - Renal Protective Effects of N-Acetyl-Seryl-Aspartyl-Lysyl-Proline (Ac-SDKP) in Obese Rats on a High-Salt Diet. AB - BACKGROUND: Obesity is a public health problem, associated with salt sensitive hypertension, kidney inflammation, and fibrosis. N-acetyl-seryl-aspartyl-lysyl proline (Ac-SDKP) is a tetra peptide with anti-inflammatory and anti-fibrotic properties. However, its effect on preventing kidney damage in obesity is unknown. We hypothesized that Zucker obese (ZO) rats on a high-salt (HS) diet develop renal damage, inflammation, fibrosis, and this is prevented with Ac-SDKP treatment. METHODS: Zucker lean (ZL) and ZO rats (8 weeks old) were treated with Ac-SDKP (1.6 mg/kg/day) while maintained on either a normal-salt (NS; 0.4%) or HS (4%) diet for 8 weeks. Systolic blood pressure (SBP), albuminuria, renal inflammation, and fibrosis were evaluated. RESULTS: HS diet increased macrophage infiltration in the kidneys of both ZL and ZO rats but was significantly higher in ZO rats receiving the HS diet (ZL + NS, 13.9 +/- 1.3 vs. ZL + HS, 19.14 +/- 1.5 and ZO + NS, 25.5 +/- 1.4 vs. ZO + HS, 87.8 +/- 10.8 cells/mm2; P < 0.05). Ac SDKP prevented macrophage infiltration in ZO rats (ZO + HS + Ac-SDKP, 32.18 +/- 2.4 cells/mm2; P < 0.05). Similarly, glomerulosclerosis, cortical, and medullary interstitial fibrosis were increased in ZO rats fed the HS diet, and Ac-SDKP attenuated these alterations (P < 0.05). SBP was increased in ZO rats fed the HS diet (ZO + NS, 121.3 +/- 8.9 vs. ZO + HS, 164 +/- 6.9 mm Hg; P < 0.05), and it was significantly decreased with Ac-SDKP treatment (ZO + HS + Ac-SDKP, 144.05 +/- 14.1 mm Hg; P = 0.004). Albuminuria was higher in ZO rats than in ZL rats; however, neither HS nor Ac-SDKP treatment affected it. CONCLUSIONS: Ac-SDKP treatment in ZO rats fed a HS diet prevented renal damage by reducing inflammation, fibrosis, and SBP. PMID- 29722790 TI - Utility of Adipocyte Fractions in Fat Grafting in an Athymic Rat Model. AB - Background: Multiple processing and handling methods of autologous fat yield to variations in graft retention and viability, which results in unpredictable clinical outcomes. Objectives: This study aims to understand the skin effects of fat graft preparations that contain a varying ratio of free-lipid and stem-cell bearing stromal vascular fractions (SVF). Methods: Lipoaspirates from consenting patients were processed into emulsified fat and then SVF and adipocyte fractions (free-lipid). SVF enriched with 0%, 5%, and 15% free-lipid were grafted along the dorsum of athymic rats. The xenografts were collected 45 days after grafting and then prepped for immunostaining. Results: Xenografts resulted in viable tissue mass under the panniculus carnosus of rats as confirmed with human specific markers. A low percentage of human cells was also detected in the lower reticular dermis. Although grafts with SVF formed adipocytes of normal architecture, grafts formed with free-lipid alone resulted in large lipid vacuoles in varying sizes. Among graft preparations, SVF with 10% free-lipid resulted in much-developed adipocyte architecture with collagen and elastin. Compared with SVF alone grafts, SVF with free-lipid had higher CD44 expression, suggesting a localized immune response of adipocytes. Conclusions: Current studies suggest that SVF enriched with approximately 10% free-lipid provides the best conditions for fat graft differentiation into viable fat tissue formation as well as collagen and elastin production to provide mechanical support for overlaying skin in an athymic rat model. Additionally, application of this therapeutic modality in a simple clinical setting may offer a practical way to concentrate SVF with free-lipid in a small volume for the improvement of clinical defects. Level of Evidence 5: PMID- 29722792 TI - AlphaMate: a program for optimizing selection, maintenance of diversity and mate allocation in breeding programs. AB - Summary: AlphaMate is a flexible program that optimizes selection, maintenance of genetic diversity and mate allocation in breeding programs. It can be used in animal and cross- and self-pollinating plant populations. These populations can be subject to selective breeding or conservation management. The problem is formulated as a multi-objective optimization of a valid mating plan that is solved with an evolutionary algorithm. A valid mating plan is defined by a combination of mating constraints (the number of matings, the maximal number of parents, the minimal/equal/maximal number of contributions per parent, or allowance for selfing) that are gender specific or generic. The optimization can maximize genetic gain, minimize group coancestry, minimize inbreeding of individual matings, or maximize genetic gain for a given increase in group coancestry or inbreeding. Users provide a list of candidate individuals with associated gender and selection criteria information (if applicable) and coancestry matrix. Selection criteria and coancestry matrix can be based on pedigree or genome-wide markers. Additional individual or mating specific information can be included to enrich optimization objectives. An example of rapid recurrent genomic selection in wheat demonstrates how AlphaMate can double the efficiency of converting genetic diversity into genetic gain compared to truncation selection. Another example demonstrates the use of genome editing to expand the gain-diversity frontier. Availability and implementation: Executable versions of AlphaMate for Windows, Mac and Linux platforms are available at http://www.AlphaGenes.roslin.ed.ac.uk/AlphaMate. PMID- 29722791 TI - Phase III safety study of intravenous NEPA: a novel fixed antiemetic combination of fosnetupitant and palonosetron in patients receiving highly emetogenic chemotherapy. AB - Background: NEPA, an oral fixed combination of the NK1RA netupitant (300 mg) and clinically/pharmacologically distinct 5-HT3RA palonosetron (PALO, 0.50 mg), is the first fixed antiemetic combination to have been approved. A single oral NEPA capsule plus dexamethasone (DEX) given before anthracycline-cyclophosphamide (AC) and non-AC highly emetogenic chemotherapy (HEC) showed superior prevention of chemotherapy-induced nausea and vomiting (CINV) over PALO plus DEX for 5 days postchemotherapy. The safety of NEPA was well-established in the phase II/III clinical program in 1169 NEPA-treated patients. An intravenous (i.v.) formulation of the NEPA combination (fosnetupitant 235 mg plus PALO 0.25 mg) has been developed. Patients and methods: This randomized, multinational, double-blind, stratified (by sex and country) phase III study (NCT02517021) in chemotherapy naive patients with solid tumors assessed the safety of a single dose of i.v. NEPA infused over 30 min before initial and repeated cycles of HEC. Patients received either i.v. NEPA or oral NEPA, both with oral DEX on days 1-4. Safety was assessed primarily by treatment-emergent adverse events (AEs) and electrocardiograms. Results: A total of 404 patients completed 1312 cycles. The incidence and type of treatment-emergent AEs were similar for both treatment groups with the majority of AEs as mild/moderate in intensity. There was no increased incidence of AEs in subsequent cycles in either group. The incidence of treatment-related AEs was similar and relatively low in both groups (12.8% i.v. NEPA and 11.4% oral NEPA during the entire study), with constipation being the most common (6.4% i.v. NEPA, 6.0% oral NEPA). No serious treatment-related AEs occurred in either group. No infusion site or anaphylactic reactions related to i.v. NEPA occurred. No clinically relevant changes in QTc and no cardiac safety concerns were observed. Conclusions: Intravenous NEPA was well-tolerated with a similar safety profile to oral NEPA in patients with various solid tumors receiving HEC. PMID- 29722793 TI - Autism-associated 16p11.2 microdeletion impairs prefrontal functional connectivity in mouse and human. AB - Human genetic studies are rapidly identifying variants that increase risk for neurodevelopmental disorders. However, it remains unclear how specific mutations impact brain function and contribute to neuropsychiatric risk. Chromosome 16p11.2 deletion is one of the most common copy number variations in autism and related neurodevelopmental disorders. Using resting state functional MRI data from the Simons Variation in Individuals Project (VIP) database, we show that 16p11.2 deletion carriers exhibit impaired prefrontal connectivity, resulting in weaker long-range functional coupling with temporal-parietal regions. These functional changes are associated with socio-cognitive impairments. We also document that a mouse with the same genetic deficiency exhibits similarly diminished prefrontal connectivity, together with thalamo-prefrontal miswiring and reduced long-range functional synchronization. These results reveal a mechanistic link between specific genetic risk for neurodevelopmental disorders and long-range functional coupling, and suggest that deletion in 16p11.2 may lead to impaired socio cognitive function via dysregulation of prefrontal connectivity. PMID- 29722795 TI - Preferential Representation of Past Outcome Information and Future Choice Behavior by Putative Inhibitory Interneurons Rather Than Putative Pyramidal Neurons in the Primate Dorsal Anterior Cingulate Cortex. AB - The dorsal anterior cingulate cortex (dACC) plays crucial roles in monitoring the outcome of a choice and adjusting a subsequent choice behavior based on the outcome information. In the present study, we investigated how different types of dACC neurons, that is, putative pyramidal neurons and putative inhibitory interneurons, contribute to these processes. We analyzed single-unit database obtained from the dACC in monkeys performing a reversal learning task. The monkey was required to adjust choice behavior from past outcome experiences. Depending on their action potential waveforms, the recorded neurons were classified into putative pyramidal neurons and putative inhibitory interneurons. We found that these neurons do not equally contribute to outcome monitoring and behavioral adjustment. Although both neuron types evenly responded to the current outcome, a larger proportion of putative inhibitory interneurons than putative pyramidal neurons stored the information about the past outcome. The putative inhibitory interneurons further represented choice-related signals more frequently, such as whether the monkey would shift the last choice to an alternative at the next choice opportunity. Our findings suggest that putative inhibitory interneurons, which are thought not to project to brain areas outside the dACC, preferentially transmit signals that would adjust choice behavior based on past outcome experiences. PMID- 29722794 TI - DNA methylation of the cancer-related genes F2RL3 and AHRR is associated with occupational exposure to polycyclic aromatic hydrocarbons. AB - Some polycyclic aromatic hydrocarbons (PAH) are known carcinogens and workplace PAH exposure may increase the risk of cancer. Monitoring early cancer-related changes can indicate whether the exposure is carcinogenic. Here, we enrolled 151 chimney sweeps, 152 controls and 19 creosote-exposed male workers from Sweden. We measured urinary PAH metabolites using LC/MS/MS, the cancer-related markers telomere length (TL) and mitochondrial DNA copy number (mtDNAcn) using qPCR, and DNA methylation of lung cancer-related genes F2RL3 and AHRR using pyrosequencing. The median 1-hydroxypyrene (PAH metabolite) concentrations were highest in creosote-exposed workers (8.0 MUg/g creatinine) followed by chimney sweeps (0.34 MUg/g creatinine) and controls (0.05 MUg/g creatinine). TL and mtDNAcn did not differ between study groups. Chimney sweeps and creosote-exposed workers had significantly lower methylation of AHRR CpG site cg05575921 (88.1 and 84.9%, respectively) than controls (90%). Creosote-exposed workers (73.3%), but not chimney sweeps (76.6%) had lower methylation of F2RL3 cg03636183 than controls (76.7%). Linear regression analyses showed that chimney sweeps had lower AHRR cg05575921 methylation (B = -2.04; P < 0.057, adjusted for smoking and age) and lower average AHRR methylation (B = -2.05; P < 0.035), and non-smoking chimney sweeps had lower average F2RL3 methylation (B = -0.81; P < 0.042, adjusted for age) compared with controls. These cancer-related markers were not associated with urinary concentrations of PAH metabolites. In conclusion, although we found no associations with PAH metabolites in urine (short-term exposure), our results suggest dose-response relationship between PAH exposure and DNA hypomethylation of lung cancer-related loci. These findings indicate that further protective measures should be taken to reduce PAH exposure. PMID- 29722796 TI - A randomized multicentre trial to compare revascularization with optimal medical therapy for the treatment of chronic total coronary occlusions. AB - Aims: The clinical value of percutaneous coronary intervention (PCI) for chronic coronary total occlusions (CTOs) is not established by randomized trials. This study should compare the benefit of PCI vs. optimal medical therapy (OMT) on the health status in patients with at least one CTO. Method and results: Three hundred and ninety-six patients were enrolled in a prospective randomized, multicentre, open-label, and controlled clinical trial to compare the treatment by PCI with OMT with a 2:1 randomization ratio. The primary endpoint was the change in health status assessed by the Seattle angina questionnaire (SAQ) between baseline and 12 months follow-up. Fifty-two percent of patients have multi-vessel disease in whom all significant non-occlusive lesions were treated before randomization. An intention-to-treat analysis was performed including 13.4% failed procedures in the PCI group and 7.3% cross-overs in the OMT group. At 12 months, a greater improvement of SAQ subscales was observed with PCI as compared with OMT for angina frequency [5.23, 95% confidence interval (CI) 1.75; 8.71; P = 0.003], and quality of life (6.62, 95% CI 1.78-11.46; P = 0.007), reaching the prespecified significance level of 0.01 for the primary endpoint. Physical limitation (P = 0.02) was also improved in the PCI group. Complete freedom from angina was more frequent with PCI 71.6% than OMT 57.8% (P = 0.008). There was no periprocedural death or myocardial infarction. At 12 months, major adverse cardiac events were comparable between the two groups. Conclusion: Percutaneous coronary intervention leads to a significant improvement of the health status in patients with stable angina and a CTO as compared with OMT alone. Trial registration: NCT01760083. PMID- 29722799 TI - About That Sex-Related Stiffening. PMID- 29722797 TI - Action Observation Areas Represent Intentions From Subtle Kinematic Features. AB - Mirror neurons have been proposed to underlie humans' ability to understand others' actions and intentions. Despite 2 decades of research, however, the exact computational and neuronal mechanisms implied in this ability remain unclear. In the current study, we investigated whether, in the absence of contextual cues, regions considered to be part of the human mirror neuron system represent intention from movement kinematics. A total of 21 participants observed reach-to grasp movements, performed with either the intention to drink or to pour while undergoing functional magnetic resonance imaging. Multivoxel pattern analysis revealed successful decoding of intentions from distributed patterns of activity in a network of structures comprising the inferior parietal lobule, the superior parietal lobule, the inferior frontal gyrus, and the middle frontal gyrus. Consistent with the proposal that parietal regions play a key role in intention understanding, classifier weights were higher in the inferior parietal region. These results provide the first demonstration that putative mirror neuron regions represent subtle differences in movement kinematics to read the intention of an observed motor act. PMID- 29722798 TI - Stochastic processes govern bacterial communities from the blood of pikas and from their arthropod vectors. AB - Vector-borne microbes influence pathogen transmission and blood microbiomes, thereby affecting the emergence of infectious diseases. Thus, understanding the relationship between host and vector microbiomes is of importance. In this study, we investigated the bacterial community composition, diversity and assembly of the flea (Rhadinopsylla dahurica vicina), torsalo (Hypoderma curzonial), and the blood and gut of their shared pika host, Ochotona curzoniae. Bartonella, Sphingomonas and Bradyrhizobium were enriched in blood, while Wolbachia and Fusobacterium were more abundant in fleas and torsaloes. Most of potential pathogenic microbes (belonging to Fusobacterium, Rickettsia, Kingella, Porphyromonas, Bartonella and Mycoplasma) were present in the blood of pikas and their vectors. Blood communities were more similar to those from fleas than other sample types and were independent of host factors or geographical sites. Notably, blood microbes originate mainly from fleas rather than gut or torsaloes. Interestingly, the community assembly of blood, fleas or torsaloes was primarily governed by stochastic processes, while the gut microbiome was determined by deterministic processes. Ecological drift plays a dominant role in the assembly of blood and flea microbiomes. These results reflect the difficulty for predicting and regulating the microbial ecology of fleas for the prevention of potential microbiome-associated diseases. PMID- 29722801 TI - Cardioprotection research must leave its comfort zone. PMID- 29722800 TI - Effects of orthodontic treatment and different fluoride regimens on numbers of cariogenic bacteria and caries risk: a randomized controlled trial. AB - Background: Caries is an undesirable side-effect of treatment with fixed orthodontic appliances. Therefore, it is crucial to understand how orthodontic treatment and different fluoride regimens affect caries risk and individual risk factors. Objective: To evaluate the effects of orthodontic treatment and different fluoride regimens on caries risk and caries risk factors, including cariogenic bacteria. Trial design: Three-armed, parallel group, randomized, controlled trial. Methods: Patients referred to the Specialist Clinic of Orthodontics, Molndal Hospital, Sweden, were distributed randomly into the following groups: group I (Control group), 1450 ppm fluoride (F) toothpaste; group II, 1450 ppm F toothpaste plus 0.2 per cent sodium fluoride (NaF) mouth rinse; and group III, 5000 ppm F toothpaste. The inclusion criteria were: age 12 20 years; and bimaxillary treatment with fixed appliances. The primary outcome variables were: caries risk; and the numbers of cariogenic bacteria. Radiographs were taken before treatment to determine the caries status. Data were collected before treatment and after 1 year with a fixed appliance. The variables were compiled into a Cariogram to assess the caries risk. Comparisons were made over time within and between the groups. The generation of randomization sequence was performed in blocks of 30. Blinding was employed during the data analysis and the caries registration. Recruitment: The clinical study duration was from October 2010 to December 2012. Results: Overall, 270 patients were randomized, of which 15 were excluded from the study. Therefore, 255 patients were included in the analyses. The caries risk increased significantly during orthodontic treatment in group I (P < 0.0001), whereas groups II and III had unchanged caries risks. All the groups showed statistically significant increases in the numbers of cariogenic bacteria. Harms: No harms were reported during the trial. Conclusions: To avoid an increased risk of caries during orthodontic treatment, everyday use of high-fluoride toothpaste (5000 ppm F) or mouth rinse (0.2% NaF) in combination with ordinary toothpaste is recommended. Registration: The trial was not registered. PMID- 29722802 TI - Corrigendum. PMID- 29722803 TI - Self-consistency test reveals systematic bias in programs for prediction change of stability upon mutation. AB - Motivation: Computational prediction of the effect of mutations on protein stability is used by researchers in many fields. The utility of the prediction methods is affected by their accuracy and bias. Bias, a systematic shift of the predicted change of stability, has been noted as an issue for several methods, but has not been investigated systematically. Presence of the bias may lead to misleading results especially when exploring the effects of combination of different mutations. Results: Here we use a protocol to measure the bias as a function of the number of introduced mutations. It is based on a self-consistency test of the reciprocity the effect of a mutation. An advantage of the used approach is that it relies solely on crystal structures without experimentally measured stability values. We applied the protocol to four popular algorithms predicting change of protein stability upon mutation, FoldX, Eris, Rosetta and I Mutant, and found an inherent bias. For one program, FoldX, we manage to substantially reduce the bias using additional relaxation by Modeller. Authors using algorithms for predicting effects of mutations should be aware of the bias described here. Availability and implementation: All calculations were implemented by in-house PERL scripts. Supplementary information: Supplementary data are available at Bioinformatics online. Note: The article 10.1093/bioinformatics/bty348, published alongside this paper, also addresses the problem of biases in protein stability change predictions. PMID- 29722804 TI - Hippocampal Radial Glial Subtypes and Their Neurogenic Potential in Human Fetuses and Healthy and Alzheimer's Disease Adults. AB - Neuropathological conditions might affect adult granulogenesis in the adult human dentate gyrus. However, radial glial cells (RGCs) have not been well characterized during human development and aging. We have previously described progenitor and neuronal layer establishment in the hippocampal pyramidal layer and dentate gyrus from embryonic life until mid-gestation. Here, we describe RGC subtypes in the hippocampus from 13 gestational weeks (GW) to mid-gestation and characterize their evolution and the dynamics of neurogenesis from mid-gestation to adulthood in normal and Alzheimer's disease (AD) subjects. In the pyramidal ventricular zone (VZ), RGC density declined with neurogenesis from mid-gestation until the perinatal period. In the dentate area, morphologic and antigenic differences among RGCs were observed from early ages of development to adulthood. Density and proliferative capacity of dentate RGCs as well as neurogenesis were strongly reduced during childhood until 5 years, few DCX+ cells are seen in adults. The dentate gyrus of both control and AD individuals showed Nestin+ and/or GFAPdelta+ cells displaying different morphologies. In conclusion, pools of morphologically, antigenically, and topographically diverse neural progenitor cells are present in the human hippocampus from early developmental stages until adulthood, including in AD patients, while their neurogenic potential seems negligible in the adult. PMID- 29722806 TI - Redox-gradient driven electron transport in a mixed community anodic biofilm. AB - Here, we describe the long-distance (multi-cell-length) extracellular electron transport (LD-EET) that occurs in an anode-grown mixed community biofilm (MCB) enriched from river sediment that contains 3%-45% Geobacter spp. High signal-to noise temperature-dependent electrochemical gating measurements (EGM) using interdigitated microelectrode arrays reveal a peak-shaped electrical conductivity vs. potential dependency, indicating MCB acts as a redox conductor, similar to pure culture anode-grown Geobacter sulfurreducens biofilms (GSB). EGM also reveal that the maximum sustained rate of LD-EET in MCB is comparable to GSB, and the same whether under acetate-oxidizing or acetate-free conditions. Voltammetry indicated that MCB possesses 3- to 5-fold less electrode-accessible redox cofactors than GSB, suggesting that MCB may be more efficiently organized than GSB for LD-EET or that a small portion of electrode accessible redox cofactors of GSB are involved in LD-EET. The activation energy for LD-EET (0.11 +/- 0.01 eV) was comparable to GSB, consistent with the possible role of c-type cytochromes as LD-EET cofactors, detected in abundance by confocal resonance Raman microscopy. Taken together, the results demonstrate LD-EET for a mixed community anode-grown microbial biofilm that is remarkably similar to GSB even though it contains many different types of microorganisms and appears to utilize far fewer EET redox cofactors. PMID- 29722807 TI - The UEA sRNA Workbench (version 4.4): a comprehensive suite of tools for analyzing miRNAs and sRNAs. AB - Motivation: RNA interference, a highly conserved regulatory mechanism, is mediated via small RNAs (sRNA). Recent technical advances enabled the analysis of larger, complex datasets and the investigation of microRNAs and the less known small interfering RNAs. However, the size and intricacy of current data requires a comprehensive set of tools, able to discriminate the patterns from the low level, noise-like, variation; numerous and varied suggestions from the community represent an invaluable source of ideas for future tools, the ability of the community to contribute to this software is essential. Results: We present a new version of the UEA sRNA Workbench, reconfigured to allow an easy insertion of new tools/workflows. In its released form, it comprises of a suite of tools in a user friendly environment, with enhanced capabilities for a comprehensive processing of sRNA-seq data e.g. tools for an accurate prediction of sRNA loci (CoLIde) and miRNA loci (miRCat2), as well as workflows to guide the users through common steps such as quality checking of the input data, normalization of abundances or detection of differential expression represent the first step in sRNA-seq analyses. Availability and implementation: The UEA sRNA Workbench is available at: http://srna-workbench.cmp.uea.ac.uk. The source code is available at: https://github.com/sRNAworkbenchuea/UEA_sRNA_Workbench. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29722805 TI - Network-Based Asymmetry of the Human Auditory System. AB - Converging evidence from activation, connectivity, and stimulation studies suggests that auditory brain networks are lateralized. Here we show that these findings can be at least partly explained by the asymmetric network embedding of the primary auditory cortices. Using diffusion-weighted imaging in 3 independent datasets, we investigate the propensity for left and right auditory cortex to communicate with other brain areas by quantifying the centrality of the auditory network across a spectrum of communication mechanisms, from shortest path communication to diffusive spreading. Across all datasets, we find that the right auditory cortex is better integrated in the connectome, facilitating more efficient communication with other areas, with much of the asymmetry driven by differences in communication pathways to the opposite hemisphere. Critically, the primacy of the right auditory cortex emerges only when communication is conceptualized as a diffusive process, taking advantage of more than just the topologically shortest paths in the network. Altogether, these results highlight how the network configuration and embedding of a particular region may contribute to its functional lateralization. PMID- 29722808 TI - Knoto-ID: a tool to study the entanglement of open protein chains using the concept of knotoids. AB - Summary: The backbone of most proteins forms an open curve. To study their entanglement, a common strategy consists in searching for the presence of knots in their backbones using topological invariants. However, this approach requires to close the curve into a loop, which alters the geometry of curve. Knoto-ID allows evaluating the entanglement of open curves without the need to close them, using the recent concept of knotoids which is a generalization of the classical knot theory to open curves. Knoto-ID can analyse the global topology of the full chain as well as the local topology by exhaustively studying all subchains or only determining the knotted core. Knoto-ID permits to localize topologically non trivial protein folds that are not detected by informatics tools detecting knotted protein folds. Availability and implementation: Knoto-ID is written in C++ and includes R (www.R-project.org) scripts to generate plots of projections maps, fingerprint matrices and disk matrices. Knoto-ID is distributed under the GNU General Public License (GPL), version 2 or any later version and is available at https://github.com/sib-swiss/Knoto-ID. A binary distribution for Mac OS X, Linux and Windows with detailed user guide and examples can be obtained from https://www.vital-it.ch/software/Knoto-ID. PMID- 29722809 TI - Repeatability and reproducibility of measurements obtained by dual-energy X-ray absorptiometry on pig carcasses. AB - The precision of a dual-energy X-ray absorptiometry (DXA) device in terms of repeatability and reproducibility was evaluated on nine left half-carcasses from pigs with large variability in body weight and fat content. Repeatability was assessed by scanning each carcass 10 times sequentially in the same position. Reproducibility was assessed by scanning each carcass in 10 different positions. Images were analyzed with DXA software using a custom region of interest (ROI) and the standard head, trunk, arm, and leg ROI. Predicted values from the DEXA for bone mineral content (BMC), bone area, bone mineral density (BMD), total weight, soft-tissue weight, fat-tissue weight, and lean-tissue weight were considered. Repeatability was associated with the variance between measurements on the same carcass in the same position (repeatability conditions). An average variance value was obtained with all the carcasses combined, and the SD was calculated as the square root of this combined variance. The CV was the ratio between the SD of the measurements and its average value. Reproducibility was calculated for each carcass as the difference between the variance obtained under the reproducibility conditions and that obtained under the repeatability conditions. The effects of the ROI and conditions were evaluated by ANOVA and Tukey's test. Means of BMC, bone area, BMD, fat tissue, and lean tissue differed among the ROI (P < 0.05) in both the repeatability and reproducibility conditions. The CV of DXA measurements under repeatability condition obtained in the head, arm, and leg ROI was lesser than 1%. Only the repeatability errors of fat tissue differed (P < 0.05) among the ROI, with the lowest precision found for the trunk ROI. The reproducibility errors of BMC, bone area, fat tissue, and lean tissue differed (P < 0.05) among the ROI. The custom ROI had reproducibility errors greater than 2% for fat tissue and greater than 3.5% for BMC and bone area. In addition, the trunk ROI had the highest reproducibility errors for fat tissue (20.7%) and lean tissue (6.2%) when compared to the other ROI. In conclusion, repeatability and reproducibility results obtained for most of the studied ROI indicate that DXA is a valuable tool for carcass evaluation. From a methodological viewpoint and considering the variations observed in this study, the ROI should be chosen based on the item to be evaluated or on the conditions in which the DXA measurements are to be taken. PMID- 29722812 TI - Antibiotics in IBD: Still a Role in the Biological Era? AB - Despite compelling evidence pointing to a critical role of gut microflora in inflammatory bowel disease (IBD) pathogenesis, the role of antibiotics in clinical practice remains limited, largely due to heterogeneous trials with often conflicting evidence. In this review, we revisit previous randomized controlled trials and high-quality uncontrolled studies in an effort to better elucidate the role of antibiotics in contemporary treatment algorithms. The most established role of antibiotics is in perianal Crohn's disease (CD), utilizing ciprofloxacin with or without metronidazole often as an adjunct to biological therapy. Evidence also points to a likely modest role of various antibiotic classes in mild to moderate luminal CD, including ciprofloxacin, metronidazole, azithromycin, and rifaximin. The benefit of metronidazole in preventing postoperative recurrence in CD is well reported; however, the long-term benefit of this intervention remains uncertain. The use of antibiotics in ulcerative colitis (UC) is even more controversial, but studies using broad-spectrum oral antibiotic cocktails have reported a possible role in acute severe colitis and chronic persistent UC. Similarly, the role of oral vancomycin and gentamicin in very early-onset IBD has interesting preliminary results. Adverse events of antibiotics, the resulting alterations in the microbiome with its associated unknown long-term sequela, and the emergence of antibiotic-resistant strains must be carefully balanced. Therefore, although antibiotics may be underused in the treatment of IBD, their integration into clinical practice must be approached judiciously and individually. PMID- 29722811 TI - Obesity following ART initiation is common and influenced by both traditional and HIV-/ART-specific risk factors. AB - Background: Obesity rates are increasing among HIV-infected individuals, but risk factors for obesity development on ART remain unclear. Objectives: In a cohort of HIV-infected adults in Rio de Janeiro, Brazil, we aimed to determine obesity rates before and after ART initiation and to analyse risk factors for obesity on ART. Methods: We retrospectively analysed data from individuals initiating ART between 2000 and 2015. BMI was calculated at baseline (time of ART initiation). Participants who were non-obese at baseline and had >=90 days of ART exposure were followed until the development of obesity or the end of follow-up. Obesity incidence rates were estimated using Poisson regression models and risk factors were assessed using Cox regression models. Results: Of participants analysed at baseline (n = 1794), 61.3% were male, 48.3% were white and 7.9% were obese. Among participants followed longitudinally (n = 1567), 66.2% primarily used an NNRTI, 32.9% a PI and 0.9% an integrase strand transfer inhibitor (INSTI); 18.3% developed obesity and obesity incidence was 37.4 per 1000 person-years. In multivariable analysis, the greatest risk factor for developing obesity was the use of an INSTI as the primary ART core drug (adjusted HR 7.12, P < 0.0001); other risk factors included younger age, female sex, higher baseline BMI, lower baseline CD4+ T lymphocyte count, higher baseline HIV-1 RNA, hypertension and diabetes mellitus. Conclusions: Obesity following ART initiation is frequent among HIV-infected adults. Key risk factors include female sex, HIV disease severity and INSTI use. Further research regarding the association between INSTIs and the development of obesity is needed. PMID- 29722810 TI - Genome-Wide Detection of Genes Under Positive Selection in Worldwide Populations of the Barley Scald Pathogen. AB - Coevolution between hosts and pathogens generates strong selection pressures to maintain resistance and infectivity, respectively. Genomes of plant pathogens often encode major effect loci for the ability to successfully infect specific host genotypes. Hence, spatial heterogeneity in host genotypes coupled with abiotic factors could lead to locally adapted pathogen populations. However, the genetic basis of local adaptation is poorly understood. Rhynchosporium commune, the pathogen causing barley scald disease, interacts at least partially in a gene for-gene manner with its host. We analyzed global field populations of 125 R. commune isolates to identify candidate genes for local adaptation. Whole genome sequencing data showed that the pathogen is subdivided into three genetic clusters associated with distinct geographic and climatic regions. Using haplotype-based selection scans applied independently to each genetic cluster, we found strong evidence for selective sweeps throughout the genome. Comparisons of loci under selection among clusters revealed little overlap, suggesting that ecological differences associated with each cluster led to variable selection regimes. The strongest signals of selection were found predominantly in the two clusters composed of isolates from Central Europe and Ethiopia. The strongest selective sweep regions encoded protein functions related to biotic and abiotic stress responses. Selective sweep regions were enriched in genes encoding functions in cellular localization, protein transport activity, and DNA damage responses. In contrast to the prevailing view that a small number of gene-for gene interactions govern plant pathogen evolution, our analyses suggest that the evolutionary trajectory is largely determined by spatially heterogeneous biotic and abiotic selection pressures. PMID- 29722813 TI - IMPUTOR: Phylogenetically Aware Software for Imputation of Errors in Next Generation Sequencing. AB - We introduce IMPUTOR, software for phylogenetically aware imputation of missing haploid nonrecombining genomic data. Targeted for next-generation sequencing data, IMPUTOR uses the principle of parsimony to impute data marked as missing due to low coverage. Along with efficiently imputing missing variant genotypes, IMPUTOR is capable of reliably and accurately correcting many nonmissing sites that represent spurious sequencing errors. Tests on simulated data show that IMPUTOR is capable of detecting many induced mutations without making erroneous imputations/corrections, with as many as 95% of missing sites imputed and 81% of errors corrected under optimal conditions. We tested IMPUTOR with human Y chromosomes from pairs of close relatives and demonstrate IMPUTOR's efficacy in imputing missing and correcting erroneous calls. PMID- 29722816 TI - Higher Cord Blood Levels of Fatty Acids in Pregnant Women With Type 1 Diabetes Mellitus. AB - Context: Type 1 diabetes mellitus (T1DM) is associated with a disturbance of carbohydrate and lipid metabolism. Objective: To determine whether T1DM alters maternal and neonatal fatty acid (FA) levels. Design: Observational study. Setting: Academic hospital. Patients: Sixty pregnant women (30 women with T1DM with good glycemic control and 30 healthy women) were included in the study. Maternal blood, umbilical vein, and artery blood samples were collected immediately upon delivery. Following lipid extraction, the FA profiles of the total FA pool of maternal serum and umbilical vein and artery serum were determined by gas chromatography. Results: Total FA concentration in maternal serum did not differ between the study groups; it was significantly higher in umbilical vein serum of the T1DM group compared with that in the control group [median (interquartile range)]: T1DM 2126.2 (1446.4 to 3181.3) and control 1073.8 (657.5 to 2226.0; P < 0.001), and in umbilical artery vein serum: T1DM 1805.7 (1393.1 to 2125.0) and control 990.0 (643.3 to 1668.0; P < 0.001). Composition of FAs in umbilical vein serum showed significantly higher concentrations of saturated, monounsaturated, and polyunsaturated FAs (SFAs, MUFAs, and PUFAs, respectively) in the T1DM group than compared with those in the control group (P = 0.001). Furthermore, cord blood levels of leptin (P < 0.001), C-peptide (P < 0.001), and insulin resistance (P = 0.015) were higher in the T1DM group compared with controls. Conclusion: The neonates born to mothers with T1DM had higher concentrations of total FAs, SFAs and MUFAs, as well as PUFAs, compared with control newborns. PMID- 29722818 TI - Validation of a Risk Index Model for Predicting Eastern Equine Encephalitis Virus Transmission to Horses in Florida. AB - Eastern Equine Encephalitis Virus (EEEV) is the most pathogenic arbovirus endemic to the United States. EEEV primarily infects birds but can be fatal to humans, horses, and some other mammals. Although EEEV transmission occurs in the Northeastern, Southeastern, and Midwestern United States, the largest number of horse and human cases have been reported in Florida, the only state where transmission occurs year round. Currently, a GIS-based risk index (RI) model is used to map EEE transmission risk to horses in Florida. This study validates that RI model using a 5-yr dataset of horse cases in Florida. RI values were similar between summer (N = 152, x- = 0.59) and winter (N = 25, x- = 0.66) cases, suggesting the model is effective for mapping risk during both transmission seasons. These risk values were larger and remained similar when a 100-m buffer was applied to the case locations to account for modest spatial errors in case reporting (summer x- = 0.73, winter x- = 0.77). In both comparisons, RI values for summer and winter cases were higher than expected at random in the Panhandle, North, and Central regions of the state, although the analysis was inconclusive in the South, where only two cases were observed. This suggests the RI map could be used to target EEEV surveillance, prevention, and control efforts in both transmission seasons in Florida. PMID- 29722815 TI - A missense allele of KARRIKIN-INSENSITIVE2 impairs ligand-binding and downstream signaling in Arabidopsis thaliana. AB - A smoke-derived compound, karrikin (KAR), and an endogenous but as yet unidentified KARRIKIN INSENSITIVE2 (KAI2) ligand (KL) have been identified as chemical cues in higher plants that impact on multiple aspects of growth and development. Genetic screening of light-signaling mutants in Arabidopsis thaliana has identified a mutant designated as ply2 (pleiotropic long hypocotyl2) that has pleiotropic light-response defects. In this study, we used positional cloning to identify the molecular lesion of ply2 as a missense mutation of KAI2/HYPOSENSITIVE TO LIGHT, which causes a single amino acid substitution, Ala219Val. Physiological analysis and genetic epistasis analysis with the KL signaling components MORE AXILLARY GROWTH2 (MAX2) and SUPPRESSOR OF MAX2 1 suggested that the pleiotropic phenotypes of the ply2 mutant can be ascribed to a defect in KL-signaling. Molecular and biochemical analyses revealed that the mutant KAI2ply2 protein is impaired in its ligand-binding activity. In support of this conclusion, X-ray crystallography studies suggested that the KAI2ply2 mutation not only results in a narrowed entrance gate for the ligand but also alters the structural flexibility of the helical lid domains. We discuss the structural implications of the Ala219 residue with regard to ligand-specific binding and signaling of KAI2, together with potential functions of KL-signaling in the context of the light-regulatory network in Arabidopsis thaliana. PMID- 29722814 TI - Whole-genome de novo sequencing reveals unique genes that contributed to the adaptive evolution of the Mikado pheasant. AB - Background: The Mikado pheasant (Syrmaticus mikado) is a nearly endangered species indigenous to high-altitude regions of Taiwan. This pheasant provides an opportunity to investigate evolutionary processes following geographic isolation. Currently, the genetic background and adaptive evolution of the Mikado pheasant remain unclear. Results: We present the draft genome of the Mikado pheasant, which consists of 1.04 Gb of DNA and 15,972 annotated protein-coding genes. The Mikado pheasant displays expansion and positive selection of genes related to features that contribute to its adaptive evolution, such as energy metabolism, oxygen transport, hemoglobin binding, radiation response, immune response, and DNA repair. To investigate the molecular evolution of the major histocompatibility complex (MHC) across several avian species, 39 putative genes spanning 227 kb on a contiguous region were annotated and manually curated. The MHC loci of the pheasant revealed a high level of synteny, several rapidly evolving genes, and inverse regions compared to the same loci in the chicken. The complete mitochondrial genome was also sequenced, assembled, and compared against four long-tailed pheasants. The results from molecular clock analysis suggest that ancestors of the Mikado pheasant migrated from the north to Taiwan about 3.47 million years ago. Conclusions: This study provides a valuable genomic resource for the Mikado pheasant, insights into its adaptation to high altitude, and the evolutionary history of the genus Syrmaticus, which could potentially be useful for future studies that investigate molecular evolution, genomics, ecology, and immunogenetics. PMID- 29722819 TI - Nonequilibrium Neutral Theory for Hitchhikers. AB - Selective sweep is a phenomenon of reduced variation at presumably neutrally evolving sites (hitchhikers) in the genome that is caused by the spread of a selected allele at a linked focal site, and is widely used to test for action of positive selection. Nonetheless, selective sweep may also provide an unprecedented opportunity for studying nonequilibrium properties of the neutral variation itself. We have demonstrated this possibility in relation to ancient selective sweep for modern human-specific changes and ongoing selective sweep for local population-specific changes. PMID- 29722817 TI - Molecular Characterization of Respiratory Syncytial Virus in Children With Repeated Infections With Subgroup B in the Philippines. AB - Background: Human respiratory syncytial virus (RSV) is the leading cause of severe acute respiratory infection in infants and young children, which is characterized by repeated infections. However, the role of amino acid substitutions in repeated infections remains unclear. Hence, this study aimed to elucidate the genetic characteristics of RSV in children with repeated infections using molecular analyses of F and G genes. Methods: We conducted a cohort study of children younger than 5 years in the Philippines. We collected nasopharyngeal swabs from children with acute respiratory symptoms and compared F and G sequences between initial and subsequent RSV infections. Results: We examined 1802 children from May 2014 to January 2016 and collected 3471 samples. Repeated infections were observed in 25 children, including 4 with homologous RSV-B reinfections. Viruses from the 4 pairs of homologous reinfections had amino acid substitutions in the G protein mostly at O-glycosylation sites, whereas changes in the F protein were identified at antigenic sites V (L173S) and theta (Q209K), considered essential epitopes for the prefusion conformation of the F protein. Conclusions: Amino acid substitutions in G and F proteins of RSV-B might have led to antigenic changes, potentially contributing to homologous reinfections observed in this study. PMID- 29722820 TI - Leishmania (Viannia) guyanensis in tegumentary leishmaniasis. AB - Leishmania (Viannia) guyanensis is a causal agent of American tegumentary leishmaniasis (ATL). This protozoan has been poorly investigated; however, it can cause different clinical forms of ATL, ranging from a single cutaneous lesion to severe lesions that can lead to destruction of the nasopharyngeal mucosa. L. (V.) guyanensis and the disease caused by this species can present unique aspects revealing the need to better characterize this parasite species to improve our knowledge of the immunopathological mechanisms and treatment options for ATL. The mechanisms by which some patients develop a more severe form of ATL remain unclear. It is known that the host immune profile and parasite factors may influence the clinical manifestations of the disease. Besides intrinsic parasite factors, Leishmaniavirus RNA 1 (LRV1) infecting L. guyanensis can contribute to ATL immunopathogenesis. In this review, general aspects of L. guyanensis infection in humans and mouse models are presented. PMID- 29722823 TI - Immunogenicity and Immunological Memory Induced by the 13-Valent Pneumococcal Conjugate Followed by the 23-Valent Polysaccharide Vaccine in HIV-Infected Adults. AB - Background: Vaccine-induced memory B-cell (MBC) subsets have distinct roles in the establishment of protective immunity; MBCs expressing nonswitched immunoglobulin M (IgM+ MBCs) replenish the MBC pool, whereas MBCs expressing isotype-switched immunoglobulin (sIg+ MBCs) differentiate into plasma cells upon antigen reencounter. We investigated immunogenicity and MBCs induced by combined 13-valent pneumococcal conjugate vaccine (PCV13) and 23-valent pneumococcal polysaccharide vaccine (PPV23) in human immunodeficiency virus (HIV)-infected adults. Methods: Forty HIV-seropositive adults receiving ART with undetectable viral loads were enrolled. Seventeen had a CD4+ T-cell count of >=400 cells/MUL (group A), and 23 had a CD4+ T-cell count of 200-399 cells/MUL (group B). All adults received PCV13 and, 1 year later, PPV23. Levels of IgM+ MBCs (defined as polysaccharide [PS]-specific CD19+CD10-CD27+CD21++IgM+ MBCs) and sIg+ MBCs (defined as PS-specific CD19+CD10-CD27+CD21++IgM- MBCs) and antibodies against PS14 and PS3 were measured prior and 1 month after each vaccination. Results: Immunization caused a significant increase in PS antibodies, compared with levels at baseline (P < .001). Group B achieved significantly lower titers than group A (P < .05 for both PS14 and PS3). After receipt of PCV13, levels of IgM+ MBCs were unchanged, whereas levels of sIg+ MBCs increased significantly (P < .05 for PS14 and P < .001 for PS3). In contrast, following PPV23 receipt, levels of IgM+ MBCs were significantly reduced, and levels of sIg+ MBCs remained stable. A positive correlation was observed between baseline IgM+ and sIg+ MBC counts 1 month after PCV13 receipt but not after PPV23 receipt. Conclusions: PPV23 receipt 12 months after PCV13 receipt improved PCV13 immunogenicity. The reduction in the IgM+ MBC count observed after PPV23 receipt suggests that PPV23 has a depleting effect on PCV13-associated immunological memory. Clinical Trials Registration: NCT03041051. PMID- 29722822 TI - Mycobacterial extracellular vesicles and host pathogen interactions. AB - Mycobacteria, like other bacteria, archaea and eukaryotic cells, naturally release extracellular vesicles (EVs) to interact with their environment. EVs produced by pathogenic bacteria are involved in many activities including cell cell communication, immunomodulation, virulence and cell survival. Although EVs released by thick cell wall microorganisms like mycobacteria were recognized only recently, studies of Mycobacterium tuberculosis EVs already point to their important roles in host pathogen interactions, opening exciting new areas of investigation. This minireview will summarize the current understanding of mycobacterial EV biology and roles in pathogenesis and will discuss their potential therapeutic applications. PMID- 29722821 TI - Mannose-capped lipoarabinomannan in Mycobacterium tuberculosis pathogenesis. AB - Mannose-capped lipoarabinomannan (ManLAM), present in all members of the Mycobacterium tuberculosis complex and in other pathogenic Mycobacterium spp, is a high molecular mass amphipathic lipoglycan with a defined critical role in mycobacterial survival during infection. In particular, ManLAM is well characterized for its importance in providing M. tuberculosis a safe portal of entry to phagocytes, regulating the intracellular trafficking network, as well as immune responses of infected host cells. These ManLAM immunological characteristics are thought to be linked to the subtle but unique and well defined structural characteristics of this molecule, including but not limited to the degree of acylation, the length of the D-mannan and D-arabinan cores, the length of the mannose caps, as well as the presence of other acidic constituents such as succinates, lactates and/or malates, and also the presence of 5 methylthioxylosyl. The impact of all these structural features on ManLAM spatial conformation and biological functions during M. tuberculosis infection is still uncertain. In this review, we dissect the relationship between ManLAM structure and biological function addressing how this relationship determines M. tuberculosis interactions with host cells, and how it aids this exceptional pathogen during the course of infection. PMID- 29722825 TI - Feasibility of split-course stereotactic ablative radiotherapy for oligometastases. AB - Background: There is growing interest in the use of stereotactic ablative radiotherapy (SABR) for oligometastases. However, extreme caution should be exercised in treating tumors closely located to organs at risk (OARs) with SABR. To reduce complications, we have applied split-course SABR to oligometastases closely located to OARs or to those being retreated with radiotherapy. Methods: We retrospectively reviewed the records of patients with oligometastases who were treated with planned split-course SABR between January 2012 and December 2016. Results: A total of 23 patients with 29 oligometastatic lesions were enrolled. The primary diagnoses were bone and soft tissue cancers in 13 lesions, liver cancers in 12 lesions, and colorectal cancers in four lesions. The median tumor volume was 78 cm3 (range, 4-1781 cm3). The lesions were treated with 1-3 fractions in the first stage of SABR (first SABR), and one or two fractions in the second stage of SABR (second SABR). The time interval between the two stages was about 4 weeks. A partial response was noted in 16 lesions (55%) after the first SABR, and practical reductions in the doses to OARs were observed in the second SABR compared with the first SABR. The 1-, 2- and 3-year local control rates were 92%, 65% and 43%, respectively. No Grade 4 or 5 toxicities were observed during or after treatment. Conclusion: Split-course SABR appeared to be feasible for the treatment of oligometastases closely located to OARs. PMID- 29722824 TI - Glutathione modulates the expression of heat shock proteins via the transcription factors BZIP10 and MYB21 in Arabidopsis. AB - The contribution of glutathione (GSH) in combating environmental stress in plants has long been known. Previous reports have pointed to the involvement of GSH in inducing various heat shock proteins (HSPs), but the molecular mechanism is yet to be explored. Here, we investigate how GSH induces the expression of important HSP genes in Arabidopsis. Expression of HSP genes BiP3, HSP70B, and HSP90.1 was positively regulated by GSH, and a promoter activation assay suggested a role for GSH in their induction. Lower expression of BiP3 and HSP70B in the GSH-fed Atmyb21 mutant and of HSP90.1 in the GSH-fed Atbzip10 mutant, in comparison with GSH-fed Col-0, revealed a role for GSH in activating their promoters through the transcription factors MYB21 and BZIP10. Co-transfection of transcription factor mutant protoplasts with transcription factor constructs and HSP promoters confirmed the results. Comparative proteomics also revealed proteins whose expression was controlled by MYB21 and BZIP10 in response to GSH feeding. A co immunoprecipitation assay demonstrated a role for GSH in modulating the level of interaction of glutathione-S-transferase with HSP70. Collectively, our results demonstrate a role for GSH in activating the promoters of BiP3 and HSP70B via MYB21 and of HSP90.1 via BZIP10. PMID- 29722828 TI - ROS and redox balance as multifaceted players of cross-tolerance: epigenetic and retrograde control of gene expression. AB - Retrograde pathways occurring between chloroplasts, mitochondria, and the nucleus involve oxidative and antioxidative signals that, working in a synergistic or antagonistic mode, control the expression of specific patterns of genes following stress perception. Increasing evidence also underlines the relevance of mitochondrion-chloroplast-nucleus crosstalk in modulating the whole cellular redox metabolism by a controlled and integrated flux of information. Plants can maintain the acquired tolerance by a stress memory, also operating at the transgenerational level, via epigenetic and miRNA-based mechanisms controlling gene expression. Data discussed in this review strengthen the idea that ROS, redox signals, and shifts in cellular redox balance permeate the signalling network leading to cross-tolerance. The identification of specific ROS/antioxidative signatures leading a plant to different fates under stress is pivotal for identifying strategies to monitor and increase plant fitness in a changing environment. This review provides an update of the plant redox signalling network implicated in stress responses, in particular in cross tolerance acquisition. The interplay between reactive oxygen species (ROS), ROS derived signals, and antioxidative pathways is also discussed in terms of plant acclimation to stress in the short and long term. PMID- 29722829 TI - Fecal Calprotectin as a Selection Tool for Small Bowel Capsule Endoscopy in Suspected Crohn's Disease. AB - Background: Small bowel capsule endoscopy (SBCE) is a firstline examination in patients with suspected Crohn's disease (CD) after negative ileocolonoscopy. Fecal calprotectin (FC) is a noninvasive marker of intestinal inflammation. The aim of this study was to evaluate the predictive value of FC in inflammatory activity detected by SBCE in patients with suspected CD. Methods: This is a retrospective study including patients who underwent SBCE for suspected CD between March 2015 and October 2016. FC was measured within 1 week of SBCE. Inflammatory activity at SBCE was considered significant when the Lewis score (LS) was >=135. FC correlation with LS was assessed using the Spearman correlation. The diagnostic accuracy of FC for significant inflammatory activity at SBCE was calculated by the area under the receiver operating characteristic curve (AUC). Results: Seventy-five patients were included: 52 females (69.3%), with a mean age of 37 years. SBCE detected significant inflammatory activity (LS >= 135) in 42 patients (56%), and FC was positively correlated to LS (rank correlation = 0.56; P < 0.001). The AUC of FC was 0.854 for significant inflammatory activity (LS >= 135). For values of FC >=100 ug/g, an LS >=135 was found in 33 of 37 patients (89.2%, P < 0.001), corresponding to a sensitivity, specificity, positive predictive value, and negative predictive value of 78.6%, 87.9%, 89.2%, and 76.3%, respectively. Conclusions: FC has shown a good ability to predict significant inflammatory activity in SBCE in patients with suspected CD. Thus, FC proved to be a useful tool to select patients with suspected CD for SBCE. PMID- 29722826 TI - Gene Presence-Absence Polymorphism in Castrating Anther-Smut Fungi: Recent Gene Gains and Phylogeographic Structure. AB - Gene presence-absence polymorphisms segregating within species are a significant source of genetic variation but have been little investigated to date in natural populations. In plant pathogens, the gain or loss of genes encoding proteins interacting directly with the host, such as secreted proteins, probably plays an important role in coevolution and local adaptation. We investigated gene presence absence polymorphism in populations of two closely related species of castrating anther-smut fungi, Microbotryum lychnidis-dioicae (MvSl) and M. silenes-dioicae (MvSd), from across Europe, on the basis of Illumina genome sequencing data and high-quality genome references. We observed presence-absence polymorphism for 186 autosomal genes (2% of all genes) in MvSl, and only 51 autosomal genes in MvSd. Distinct genes displayed presence-absence polymorphism in the two species. Genes displaying presence-absence polymorphism were frequently located in subtelomeric and centromeric regions and close to repetitive elements, and comparison with outgroups indicated that most were present in a single species, being recently acquired through duplications in multiple-gene families. Gene presence-absence polymorphism in MvSl showed a phylogeographic structure corresponding to clusters detected based on SNPs. In addition, gene absence alleles were rare within species and skewed toward low-frequency variants. These findings are consistent with a deleterious or neutral effect for most gene presence-absence polymorphism. Some of the observed gene loss and gain events may however be adaptive, as suggested by the putative functions of the corresponding encoded proteins (e.g., secreted proteins) or their localization within previously identified selective sweeps. The adaptive roles in plant and anther-smut fungi interactions of candidate genes however need to be experimentally tested in future studies. PMID- 29722827 TI - A broadly conserved NERD genetically interacts with the exocyst to affect root growth and cell expansion. AB - The exocyst, a conserved, octameric protein complex, helps mediate secretion at the plasma membrane, facilitating specific developmental processes that include control of root meristem size, cell elongation, and tip growth. A genetic screen for second-site enhancers in Arabidopsis identified NEW ENHANCER of ROOT DWARFISM1 (NERD1) as an exocyst interactor. Mutations in NERD1 combined with weak exocyst mutations in SEC8 and EXO70A1 result in a synergistic reduction in root growth. Alone, nerd1 alleles modestly reduce primary root growth, both by shortening the root meristem and by reducing cell elongation, but also result in a slight increase in root hair length, bulging, and rupture. NERD1 was identified molecularly as At3g51050, which encodes a transmembrane protein of unknown function that is broadly conserved throughout the Archaeplastida. A functional NERD1-GFP fusion localizes to the Golgi, in a pattern distinct from the plasma membrane-localized exocyst, arguing against a direct NERD1-exocyst interaction. Structural modeling suggests the majority of the protein is positioned in the lumen, in a beta-propeller-like structure that has some similarity to proteins that bind polysaccharides. We suggest that NERD1 interacts with the exocyst indirectly, possibly affecting polysaccharides destined for the cell wall, and influencing cell wall characteristics in a developmentally distinct manner. PMID- 29722830 TI - Linear relationships between shoot magnesium and calcium concentrations among angiosperm species are associated with cell wall chemistry. AB - Background: Linear relationships are commonly observed between shoot magnesium ([Mg]shoot) and shoot calcium ([Ca]shoot) concentrations among angiosperm species growing in the same environment. Scope and Conclusions: This article argues that, in plants that do not exhibit 'luxury' accumulation of Mg or Ca, (1) distinct stoichiometric relationships between [Mg]shoot and [Ca]shoot are exhibited by at least three groups of angiosperm species, namely commelinid monocots, eudicots excluding Caryophyllales, and Caryophyllales species; (2) these relationships are determined by cell wall chemistry and the Mg/Ca mass quotients in their cell walls; (3) differences between species in [Mg]shoot and [Ca]shoot within each group are associated with differences in the cation exchange capacity (CEC) of the cell walls of different species; and (4) Caryophyllales constitutively accumulate more Mg in their vacuoles than other angiosperm species when grown without a supra-sufficient Mg supply. PMID- 29722832 TI - Rising Incidence of Intestinal Infections in Inflammatory Bowel Disease: A Nationwide Analysis. AB - Background: Intestinal infections are common in patients with inflammatory bowel disease (IBD) and may mimic IBD flares. In this study, we estimate the changing incidence of intestinal infections among IBD hospitalizations and assess the impact of intestinal infections on key hospitalization metrics. Methods: The National Inpatient Sample (NIS) was analyzed for hospitalizations from IBD between 1998 and 2014. Intestinal infections were identified using ICD-9-CM codes, and incidence for each infection was calculated for Crohn's disease (CD) and ulcerative colitis (UC). Linear and logistic regression analyses were used to assess the effects of intestinal infections on hospitalization duration, charges, and mortality. Results: There were 4,030,620 hospitalizations for IBD between 1998 and 2014. The annual incidence of intestinal infections rose from 26.2 to 70.6 infections per 1000 IBD hospitalizations (Ptrend < 0.01). A main driver of this rising incidence was Clostridium difficile infections, which increased from 7.8 to 32.1 per 1000 CD hospitalizations and from 23.0 to 84.7 per 1000 UC hospitalizations (Ptrend < 0.01). The incidence of other intestinal infections increased from 10.2 to 15.3 per 1000 CD hospitalizations and 16.5 to 25.3 per 1000 UC hospitalizations. Intestinal infections and particularly C. difficile infections were associated with longer hospitalizations, greater hospital charges, and greater all-cause mortality. Conclusions: The incidence of intestinal infections among hospitalized IBD patients has increased over the past 15 years, primarily driven by C. difficile infections. Intestinal infections are associated with length of stay, hospital charges, and all-cause mortality. More aggressive measures for prevention of C. difficile infections are needed. 10.1093/ibd/izy086_video1izy086.video15779257979001. PMID- 29722833 TI - An 18-mo randomized, double-blind, placebo-controlled trial of DHA-rich fish oil to prevent age-related cognitive decline in cognitively normal older adults. AB - Background: Fish oil trials in cognitively healthy older adults have yielded inconsistent results. Supplementation may differentially affect the domains that underpin cognitive performance, and effects may differ across sex or genotype. Objective: The aim of this study was to test whether docosahexaenoic acid (DHA) rich fish oil slows 18-mo cognitive decline in cognitively healthy elders. Design: In a double-blind, randomized, placebo-controlled, parallel-group trial, cognitively healthy Australian community-dwelling adults (aged 65-90 y) consumed either 1720 mg DHA and 600 mg eicosapentaenoic acid or low-polyphenolic olive oil daily, as capsules, for 18 mo. Groups were allocated by permuted-block randomization and stratified by age. Cognitive assessment was conducted at baseline and then every 6 mo. Primary analyses tested the difference between groups in the rate of 18-mo cognitive change via latent growth curve models on any of the following: reasoning, working memory, short-term memory, retrieval fluency, and cognitive speed-related constructs. Treatment interactions with sex and APOE-epsilon4 were tested. Secondary outcomes were self-reported changes in well-being and everyday functioning, blood pressure, biomarkers of n-3 (omega-3) long-chain polyunsaturated fatty acids (LC PUFAs), lipids, glucose metabolism, inflammation, oxidative stress, DNA damage, and Mini-Mental State Examination. Results: A total of 403 people were randomly assigned. Data from those who completed baseline were analyzed (n = 390; intervention n = 194, control n = 196). Daily supplementation with 2.3 g DHA-rich fish oil for 18 mo did not maintain or improve cognitive performance. A small negative main effect was found on psychomotor speed (intervention = -0.02, 95% CI: -0.04 to 0.00; d = 0.24, P = 0.03). Treatment effects differed according to sex on retrieval fluency and some speed-based domains, including psychomotor speed, and according to APOE-epsilon4 carrier status on reaction time and reasoning. For secondary outcomes, treatment was associated with increased perceived cognitive mistakes (d = 0.24; P = 0.003), increased oxidative stress, and expected changes in fatty acid metabolism. Conclusions: Findings do not support supplementing older adults with fish oil to prevent cognitive decline. Treatment interactions with sex and APOE-epsilon4 carrier status warrant further investigation. This trial was registered at the Australia and New Zealand Clinical Trials Register (ANZCTR) as ACTRN12607000278437. PMID- 29722831 TI - The Neutral Theory in Light of Natural Selection. AB - In this perspective, we evaluate the explanatory power of the neutral theory of molecular evolution, 50 years after its introduction by Kimura. We argue that the neutral theory was supported by unreliable theoretical and empirical evidence from the beginning, and that in light of modern, genome-scale data, we can firmly reject its universality. The ubiquity of adaptive variation both within and between species means that a more comprehensive theory of molecular evolution must be sought. PMID- 29722834 TI - Effects of caloric and noncaloric sweeteners on antroduodenal motility, gastrointestinal hormone secretion and appetite-related sensations in healthy subjects. AB - Background: Activation of gastrointestinal (GI) sweet taste receptors by caloric sweeteners triggers secretion of anorexigenic and inhibition of orexigenic GI hormones to regulate food intake. The effect of noncaloric sweeteners on these mechanisms is controversial. We have recently shown that motilin-induced gastric phase III contractions signal hunger feelings, thereby identifying GI motility, and its regulatory hormone motilin, as novel players in food intake regulation. Objective: The objective of the present study was to determine the effect of caloric and noncaloric sweeteners on GI motility, GI hormone secretion, and hunger in humans. Design: The study was a randomized, double-blind, crossover trial. Twelve healthy volunteers underwent 4 gastroduodenal manometry recordings in which the occurrence of phase III contractions was followed by the intragastric (i.g.) administration of 250 mL tap water or equisweet caloric (1) 50 g glucose and 2) 25 g fructose) and noncaloric sweeteners [220 mg acesulfame-K (ace-K)] dissolved in 250 mL tap water. Measurement continued until >=1 subsequent phase III. Blood samples were collected for the measurement of GI hormones. Visual analog scales were used to rate hunger and satiety feelings. Response curves were analyzed using (generalized) linear mixed models. Results: We found: 1) an inhibitory effect of the 2 caloric sweeteners on antral motility (P < 0.01), but no effect after ace-K, 2) an inhibitory effect of the 2 caloric sweeteners on motilin secretion (P < 0.01), but no effect after ace-K, 3) an early increase in cholecystokinin (CCK) secretion after the 2 caloric sweeteners (P < 0.01), but no effect after ace-K, and 4) an initial stronger decrease in hunger feelings and stronger increase in satiety after ace-K (P < 0.05), followed by a steeper return of hunger and decrease of satiety after ace-K (P < 0.05). Conclusions: Our results demonstrate, for the first time to our knowledge, that the caloric sweeteners glucose and fructose, but not the noncaloric sweetener ace K, inhibit motilin secretion and antral motility while increasing CCK secretion. This trial was registered at clinicaltrials.gov as NCT02891525. PMID- 29722835 TI - Catheter-related bloodstream infections in patients with intestinal failure receiving home parenteral support: risks related to a catheter-salvage strategy. AB - Background: In intestinal failure (IF) patients receiving home parenteral support (HPS), catheter-related bloodstream infections (CRBSIs) frequently result in replacement of their tunneled central venous catheters (CVCs), which may lead to future loss of central venous access. Objective: This observational study investigated the consequences of a catheter-salvage strategy related to CRBSIs. Design: All CRBSIs from 2002 to 2016 in the Copenhagen IF and microbiological databases were retrospectively analyzed. Catheter salvage was defined by successful antimicrobial therapy with a retained CVC at discharge. Re-occurrences of CRBSIs with the same microbial species and identical antibiogram were defined as a relapse (<30 d) or as a recurrent (30-100 d) infection. Cox regression analyses incorporated a frailty factor to account for recurrent events and overrepresentation by some patients. Cumulative incidence curves are presented with a competing risk model. Results: There were 2006 tunneled CVCs inserted in 715 adult HPS patients covering 2014.3 CVC years, with a CRBSI incidence rate of 1.83/1000 (n = 1350) and a mortality rate of 0.007/1000 CVC days (n = 5). The mean +/- SD salvage rate was 55.3% +/- 5.5%, varying according to infection type [monoinfections (62.9% +/- 4.4%) and polyinfections (58.6% +/- 17.3%)] and causative microorganism [coagulase-negative Staphylococci (CoNS) (68.1% +/- 9.4%), Staphylococcus aureus (42.6% +/- 17.5%), and Enterobacteriaceae (54.3% +/- 16.7%)]. The overall risk of CRBSI relapse was 7.5%, and the risk of CRBSI recurrence was 7.3%. The HR for a subsequent CRBSI was 14% lower in a replaced than in a retained CVC (95% CI: 0.74, 0.99). The HR for a new CRBSI after catheter salvage was 36% higher after polyinfections than after monoinfections (95% CI: 1.03, 1.79). Enterobacteriaceae entailed an increased risk of CRBSI recurrence compared with CoNS (2.26; 95% CI; 1.08, 4.75) and S. aureus (4.45; 95% CI: 1.28, 15.5). Conclusions: High catheter-salvage rates related to CRBSIs were achievable and safe in HPS patients within a broad range of microorganisms but contributed to an increased risk of CRBSI relapse or recurrence. PMID- 29722836 TI - Adverse effects on thyroid of Chinese children exposed to long-term iodine excess: optimal and safe Tolerable Upper Intake Levels of iodine for 7- to 14-y old children. AB - Background: The adverse effects of iodine excess on the thyroid in children are not well understood, and the Tolerable Upper Intake Level for iodine in children is unclear. Objective: The aims of this study were to assess the effects of chronic long-term iodine excess on thyroid function in children and to explore the safe Tolerable Upper Intake Level of iodine in Chinese children. Design: A multistage cross-sectional study was conducted in 2224 children from areas with adequate to excessive iodine content in drinking water. Repeated samples of 24-h urine and spot urine samples were collected to estimate habitual daily iodine intakes of children. The thyroid volume in children was measured and blood samples were collected to determine thyroid function. Results: The habitual iodine intake of children was 298 MUg/d (range: 186-437 MUg/d). The total goiter rate was 9.7%, 232 (11.2%) children had hyperthyrotropinemia, and 232 (11.2%) children had thyroglobulin (Tg) concentrations >40 MUg/L. The prevalence of hyperthyrotropinemia was >10% in children at iodine intakes of 200-300 MUg/d. Tg concentrations increased with increased iodine intake (beta = 0.5; 95% CI: 0.4, 0.6), and the prevalence of Tg >40 MUg/L was >3% in all iodine-intake groups. Multivariate logistic regression analysis indicated that the risk of total goiter significantly increased at iodine intakes >=250-299 MUg/d in 7- to 10-y-old children (OR: 8.8; 95% CI: 2.3, 34.0) and at iodine intakes >=300-399 MUg/d in 11 to 14-y-old children (OR: 5.2; 95% CI: 1.5, 18.3). However, there were no consistent differences in the risk of hyperthyrotropinemia and Tg >40 MUg/L in children between different iodine-intake groups. Conclusions: Thyroid volume and goiter appear to be more sensitive indicators of thyroid stress than thyrotropin and Tg in children with long-term excess iodine intakes. We recommend 250 and 300 MUg/d as safe Tolerable Upper Intake Levels of iodine for children aged 7-10 y and 11-14 y, respectively. This trial was registered at www.clinicaltrials.gov as NCT02915536. PMID- 29722837 TI - Early nutrition and signs of metabolic syndrome at 6 y of age in children born very preterm. AB - Background: In term-born infants, the risk of developing metabolic syndrome (MetS) has been shown to be associated with formula feeding and early rapid growth. Breastfeeding, however, seems to be associated with a lower risk of MetS among term-born infants. Objective: The possible association between type of early nutrition, early growth, and possible influence on different metabolic outcomes at 6 y of age was investigated in very-preterm-born children. Design: This study is a 6-y follow-up of 281 very-preterm-born infants with a gestational age of <=32 wk. Infants breastfed at discharge from the hospital were randomly assigned to receive unfortified or fortified mother's milk, whereas those who were not breastfed received a preterm formula. The intervention lasted until 4 mo of corrected age. At 6 y of age, height, weight, and body mass index were measured and a dual-energy X-ray absorptiometry scan and blood sampling were performed. Results: In total, 239 children participated in the follow-up. No differences were found between the 2 breastfed groups. Formula-fed children were more often predisposed to obesity and from families with a lower social status than were children who were breastfed only. Early rapid growth (crossing of weight percentiles with >1 SD in either direction) was seen in 53% of the children from 34 wk of postmenstrual age and until 2 mo of corrected age and was significantly correlated with several metabolic outcomes at 6 y of age. Conclusions: Children fed a preterm formula postdischarge more often showed early rapid growth than did breastfed children, and early rapid growth was correlated with early signs of MetS at 6 y of age. However, all of the values were within normal ranges. This trial was registered at as NCT02078687. PMID- 29722838 TI - Vitamin A and D intake in pregnancy, infant supplementation, and asthma development: the Norwegian Mother and Child Cohort. AB - Background: Western diets may provide excess vitamin A, which is potentially toxic and could adversely affect respiratory health and counteract benefits from vitamin D. Objective: The aim of this study was to examine child asthma at age 7 y in relation to maternal intake of vitamins A and D during pregnancy, infant supplementation with these vitamins, and their potential interaction. Design: We studied 61,676 school-age children (born during 2002-2007) from the Norwegian Mother and Child Cohort with data on maternal total (food and supplement) nutrient intake in pregnancy (food-frequency questionnaire validated against biomarkers) and infant supplement use at age 6 mo (n = 54,142 children). Linkage with the Norwegian Prescription Database enabled near-complete follow-up (end of second quarter in 2015) for dispensed medications to classify asthma. We used log binomial regression to calculate adjusted RRs (aRRs) for asthma with 95% CIs. Results: Asthma increased according to maternal intake of total vitamin A [retinol activity equivalents (RAEs)] in the highest (>=2031 RAEs/d) compared with the lowest (<=779 RAEs/d) quintile (aRR: 1.21; 95% CI: 1.05, 1.40) and decreased for total vitamin D in the highest (>=13.6 ug/d) compared with the lowest (<=3.5 ug/d) quintile (aRR: 0.81; 95% CI: 0.67, 0.97) during pregnancy. No association was observed for maternal intake in the highest quintiles of both nutrients (aRR: 0.99; 95% CI: 0.83, 1.18) and infant supplementation with vitamin D or cod liver oil. Conclusions: Excess vitamin A (>=2.5 times the recommended intake) during pregnancy was associated with increased risk, whereas vitamin D intake close to recommendations was associated with a reduced risk of asthma in school-age children. No association for high intakes of both nutrients suggests antagonistic effects of vitamins A and D. This trial was registered at http://www.clinicaltrials.gov as NCT03197233. PMID- 29722839 TI - Glycemic response and the glycemic index of foods: more remains to be seen on the second-meal effect of proteins. PMID- 29722840 TI - Reply to Brighenti F et al. PMID- 29722842 TI - A dynamic model for predicting growth in zinc-deficient stunted infants given supplemental zinc. AB - Background: Zinc deficiency limits infant growth and increases susceptibility to infections, which further compromises growth. Zinc supplementation improves the growth of zinc-deficient stunted infants, but the amount, frequency, and duration of zinc supplementation required to restore growth in an individual child is unknown. A dynamic model of zinc metabolism that predicts changes in weight and length of zinc-deficient, stunted infants with dietary zinc would be useful to define effective zinc supplementation regimens. Objective: The aims of this study were to develop a dynamic model for zinc metabolism in stunted, zinc-deficient infants and to use that model to predict the growth response when those infants are given zinc supplements. Design: A model of zinc metabolism was developed using data on zinc kinetics, tissue zinc, and growth requirements for healthy 9 mo-old infants. The kinetic model was converted to a dynamic model by replacing the rate constants for zinc absorption and excretion with functions for these processes that change with zinc intake. Predictions of the dynamic model, parameterized for zinc-deficient, stunted infants, were compared with the results of 5 published zinc intervention trials. The model was then used to predict the results for zinc supplementation regimes that varied in the amount, frequency, and duration of zinc dosing. Results: Model predictions agreed with published changes in plasma zinc after zinc supplementation. Predictions of weight and length agreed with 2 studies, but overpredicted values from a third study in which other nutrient deficiencies may have been growth limiting; the model predicted that zinc absorption was impaired in that study. Conclusions: The model suggests that frequent, smaller doses (5-10 mg Zn/d) are more effective for increasing growth in stunted, zinc-deficient 9-mo-old infants than are larger, less-frequent doses. The dose amount affects the duration of dosing necessary to restore and maintain plasma zinc concentration and growth. PMID- 29722841 TI - A meat- or dairy-based complementary diet leads to distinct growth patterns in formula-fed infants: a randomized controlled trial. AB - Background: Protein intake from cow milk-based infant formula has been associated with rapid weight gain and increased adiposity, but the effect of protein from complementary foods has not been prospectively evaluated, and the effect of protein from sources other than formula during complementary feeding is not clear. Objective: The aim of this study was to directly compare the effect of protein from 2 common complementary food sources, meat and dairy, on infant growth and weight trajectory. Design: Healthy term, formula-fed infants were recruited from the metro Denver area, matched by sex and race/ethnicity and randomly assigned to a meat or a dairy complementary food group from 5 to 12 mo of age. Total protein intake during this 7-mo intervention was ~3 g ? kg-1 ? d-1 for both groups. Intakes of infant formula, cereal, fruit, and vegetables were ad libitum. Caregivers also completed 3-d diet records at 5, 10, and 12 mo of age. Anthropometric measures were obtained during monthly home visits, and blood samples were collected at 5 and 12 mo of age. Results: Sixty-four infants completed the intervention (meat: n = 32; dairy: n = 32). The average total protein intake (mean +/- SD) increased from 2.01 +/- 0.06 g ? kg-1 ? d-1 at 5 mo to 3.35 +/-0.12 g ? kg-1 ? d-1 at 12 mo and did not differ between groups. Over time, weight and weight-for-age z score increased by 0.48 +/- 0.07. However, there was a significant group-by-time interaction for both length-for-age z score (LAZ) and weight-for-length z score (WLZ). Post hoc analysis showed that LAZ increased in the meat group (+0.33 +/- 0.09; P = 0.001 over time) and decreased in the dairy group (-0.30 +/- 0.10; P = 0.0002 over time); WLZ significantly increased in the dairy group (0.76 +/- 0.21; P = 0.000002 over time) compared with the meat group (0.30 +/- 0.17; P = 0.55 over time). Insulin-like growth factor I and insulin-like growth factor-binding protein 3 both increased over time without group differences. Conclusions: Protein source may have an important role in regulating growth. In these formula-fed older infants, meat- and dairy based complementary foods led to distinct growth patterns, especially for length. This trial was registered at www.clinicaltrials.gov as NCT02142647. PMID- 29722843 TI - Diet quality among US-born and foreign-born non-Hispanic blacks: NHANES 2003-2012 data. AB - Background: Non-Hispanic blacks in the United States are less likely to not meet national dietary recommendations than non-Hispanic whites; however, most studies do not consider nativity of US blacks. Objective: With the use of the Alternative Healthy Eating Index-2010 (AHEI-2010) and the Dietary Approach to Stop Hypertension (DASH) scores, this cross-sectional study compared diet quality between US-born (n = 3,911) and foreign-born (n = 408) non-Hispanic black adults aged 22-79 y, based on pooled nationally representative data (NHANES 2003-2012) as well as by length of US residency. Design: The association between nativity and diet quality was determined by using multivariable-adjusted linear regression for the continuous total diet quality scores and their components or multinomial (polytomous) logistic regression for categorical tertiles (low, medium, or high) of the total scores and their components. Results: Foreign-born blacks had significantly higher AHEI-2010 (beta: 9.3; 95% CI: 7.5, 11.0) and DASH (beta: 3.1; 95% CI: 2.5, 3.8) scores compared with US-born blacks and more favorable intakes for many of the score components. Among foreign-born blacks, diet quality did not significantly differ by length of residency. Foreign-born blacks were more likely to be in the high than in the low tertile for vegetables [excluding starchy vegetables; relative risk ratio (RRR): 1.68; 95% CI: 1.24, 2.29], fruit [excluding and including fruit juice-RRR: 2.42 (95% CI: 1.69, 3.47) and RRR: 2.95 (95% CI: 1.90, 4.59), respectively], percentage of whole grains (RRR: 2.39; 95% CI: 1.64, 3.49), and omega-3 (omega-3) fatty acids (RRR: 2.03; 95% CI: 1.38, 2.97). Conclusions: Foreign-born blacks have better diet quality than their US born counterparts. In nutrition research and public health efforts, considering the place of birth among US blacks may improve the accuracy of characterizing dietary intakes and facilitate the development of targeted nutrition interventions to reduce diet-related diseases in the diverse black population in the United States. PMID- 29722844 TI - Joint effects of fatty acid desaturase 1 polymorphisms and dietary polyunsaturated fatty acid intake on circulating fatty acid proportions. AB - Background: Polyunsaturated fatty acids (PUFAs) are associated with a lower risk of multiple diseases. Fatty acid desaturase 1 gene (FADS1) polymorphisms and dietary PUFA intake are both established determinants of circulating PUFA proportions. Objective: We explored the joint effects of FADS1 polymorphisms and dietary PUFA intake on circulating PUFA proportions. Design: We studied 2288 participants from a nested case-control study of coronary artery disease among participants who provided blood samples in the Nurses' Health Study and the Health Professionals Follow-Up Study. Dietary PUFA intake was obtained from semiquantitative food-frequency questionnaires. FADS1 rs174546 was genotyped by using the Affymetrix 6.0 platform, and circulating PUFA proportions were measured with gas-liquid chromatography. Linear regression models were used to examine the associations between rs174546 and circulating proportions of each fatty acid. Gene-diet interactions were tested by including a cross-product term of dietary intake of each PUFA by rs174546 genotype in the linear regression models. Results: After adjustment for sex and ancestry, each copy of the C allele of rs174546 was associated with higher circulating proportions of arachidonic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) and lower proportions of linoleic acid and alpha-linolenic acid. The magnitude of positive association between higher consumption of dietary EPA or DHA and circulating proportions of EPA increased with each copy of the rs174546_T allele (P-interaction = 0.01 and 0.007, respectively). Each 1-SD increment in EPA intake was associated with an average 3.7% increase in circulating EPA proportions among participants with the rs174546_CC genotype and an average 7.8% increase among participants with the TT genotype. Conclusions: Carriers of the T allele at FADS1 rs174546 may need higher doses of dietary EPA and DHA to achieve the same circulating proportions of EPA as carriers of the C allele. The implications of these findings on disease risk and dietary guidelines require further study. PMID- 29722845 TI - Mediterranean diet and risk of frailty syndrome among women with type 2 diabetes. AB - Background: Previous research indicates that patients with type 2 diabetes are at higher risk of becoming frail. Emerging evidence also indicates that the Mediterranean diet may prevent frailty in the older population. Objective: The aim of this study was to assess whether a Mediterranean-style diet pattern was associated with lower risk of frailty among older women with diabetes. Design: This was a prospective cohort study in 8970 women aged >=60 y with type 2 diabetes from the Nurses' Health Study. Adherence to the alternate Mediterranean diet (aMED) score was first measured in 1990 and repeated every 4 y until 2010. Frailty occurrence was ascertained up to 2012 and was defined as having >=3 of the following 5 criteria from the fatigue, resistance, aerobic, illnesses, loss of weight (FRAIL) scale: Fatigue, low Resistance, low Aerobic capacity, having >=5 Illnesses, and weight Loss of >=5%. Those with frailty at baseline were excluded. Results: During follow-up, we identified 569 incident cases of frailty. After adjustment for lifestyle factors and medication use, the HR (95% CI) of frailty was 1 for the lowest quartile of the aMED score, 0.88 (0.71, 1.10) for the second quartile, 0.69 (0.53, 0.88) for the third quartile, and 0.54 (0.42, 0.71) for the highest quartile (P-trend < 0.001). A 2-point (~1 SD) increase in the aMED score was associated with a 28% (95% CI: 19%, 36%) reduced risk of frailty. The largest reduction in the risk was observed for a higher consumption of vegetables and fruit, as well as for alcohol intake. Conclusions: A Mediterranean-style diet pattern was associated with reduced risk of frailty syndrome in older women with type 2 diabetes. PMID- 29722846 TI - High-dose vitamin D3 in the treatment of severe acute malnutrition: a multicenter double-blind randomized controlled trial. AB - Background: Vitamin D deficiency is common in children with severe acute malnutrition, in whom it is associated with severe wasting. Ready-to-use therapeutic food (the standard treatment) contains modest amounts of vitamin D that do not reliably correct deficiency. Objective: The aim of this study was to determine whether high-dose oral vitamin D3 enhances weight gain and development in children with uncomplicated severe acute malnutrition. Design: We conducted a randomized placebo-controlled trial of high-dose vitamin D3 supplementation in children aged 6-58 mo with uncomplicated severe acute malnutrition in Pakistan. Participants were randomly assigned to receive 2 oral doses of 200,000 IU vitamin D3 or placebo at 2 and 4 wk after starting ready-to-use therapeutic food. The primary outcome was the proportion of participants gaining >15% of baseline weight at 8 wk after starting ready-to-use therapeutic food (the end of the study). Secondary outcomes were mean weight-for-height or -length z score and the proportion of participants with delayed development at the end of the study (assessed with the Denver Development Screening Tool II), adjusted for baseline values. Results: Of the 194 randomly assigned children who started the study, 185 completed the follow-up and were included in the analysis (93 assigned to intervention, 92 to control). High-dose vitamin D3 did not influence the proportion of children gaining >15% of baseline weight at the end of the study (RR: 1.04; 95% CI: 0.94,1.15, P = 0.47), but it did increase the weight-for height or -length z score (adjusted mean difference: 1.07; 95% CI: 0.49,1.65, P < 0.001) and reduce the proportion of participants with delayed global development [adjusted RR (aRR): 0.49; 95% CI: 0.31, 0.77, P = 0.002], delayed gross motor development (aRR: 0.29; 95% CI: 0.13, 0.64, P = 0.002), delayed fine motor development (aRR: 0.59; 95% CI: 0.38, 0.91, P = 0.018), and delayed language development (aRR: 0.57; 95% CI: 0.34, 0.96, P = 0.036). Conclusions: High-dose vitamin D3 improved the mean weight-for-height or -length z score and developmental indexes in children receiving standard therapy for uncomplicated severe acute malnutrition in Pakistan. This trial was registered at clinicaltrials.gov as NCT03170479. PMID- 29722848 TI - Response to: Fried potato consumption is associated with elevated mortality: an 8 y longitudinal cohort study. PMID- 29722847 TI - Dietary acid load and bone turnover during long-duration spaceflight and bed rest. AB - Background: Bed rest studies document that a lower dietary acid load is associated with lower bone resorption. Objective: We tested the effect of dietary acid load on bone metabolism during spaceflight. Design: Controlled 4-d diets with a high or low animal protein-to-potassium (APro:K) ratio (High and Low diets, respectively) were given to 17 astronauts before and during spaceflight. Each astronaut had 1 High and 1 Low diet session before flight and 2 High and 2 Low sessions during flight, in addition to a 4-d session around flight day 30 (FD30), when crew members were to consume their typical in-flight intake. At the end of each session, blood and urine samples were collected. Calcium, total protein, energy, and sodium were maintained in each crew member's preflight and in-flight controlled diets. Results: Relative to preflight values, N-telopeptide (NTX) and urinary calcium were higher during flight, and bone-specific alkaline phosphatase (BSAP) was higher toward the end of flight. The High and Low diets did not affect NTX, BSAP, or urinary calcium. Dietary sulfur and age were significantly associated with changes in NTX. Dietary sodium and flight day were significantly associated with urinary calcium during flight. The net endogenous acid production (NEAP) estimated from the typical dietary intake at FD30 was associated with loss of bone mineral content in the lumbar spine after the mission. The results were compared with data from a 70-d bed rest study, in which control (but not exercising) subjects' APro:K was associated with higher NTX during bed rest. Conclusions: Long-term lowering of NEAP by increasing vegetable and fruit intake may protect against changes in loss of bone mineral content during spaceflight when adequate calcium is consumed, particularly if resistive exercise is not being performed. This trial was registered at clinicaltrials.gov as NCT01713634. PMID- 29722849 TI - An evidence-based approach to globally assess the covariate-dependent effect of the MTHFR single nucleotide polymorphism rs1801133 on blood homocysteine: a systematic review and meta-analysis. AB - Background: The single nucleotide polymorphism of the gene 5,10 methylenetetrahydrofolate reductase (MTHFR) C677T (or rs1801133) is the most established genetic factor that increases plasma total homocysteine (tHcy) and consequently results in hyperhomocysteinemia. Yet, given the limited penetrance of this genetic variant, it is necessary to individually predict the risk of hyperhomocysteinemia for an rs1801133 carrier. Objective: We hypothesized that variability in this genetic risk is largely due to the presence of factors (covariates) that serve as effect modifiers, confounders, or both, such as folic acid (FA) intake, and aimed to assess this risk in the complex context of these covariates. Design: We systematically extracted from published studies the data on tHcy, rs1801133, and any previously reported rs1801133 covariates. The resulting metadata set was first used to analyze the covariates' modifying effect by meta-regression and other statistical means. Subsequently, we controlled for this modifying effect by genotype-stratifying tHcy data and analyzed the variability in the risk resulting from the confounding of covariates. Results: The data set contains data on 36 rs1801133 covariates that were collected from 114,799 participants and 256 qualified studies, among which 6 covariates (sex, age, race, FA intake, smoking, and alcohol consumption) are the most frequently informed and therefore included for statistical analysis. The effect of rs1801133 on tHcy exhibits significant variability that can be attributed to effect modification as well as confounding by these covariates. Via statistical modeling, we predicted the covariate-dependent risk of tHcy elevation and hyperhomocysteinemia in a systematic manner. Conclusions: We showed an evidence based approach that globally assesses the covariate-dependent effect of rs1801133 on tHcy. The results should assist clinicians in interpreting the rs1801133 data from genetic testing for their patients. Such information is also important for the public, who increasingly receive genetic data from commercial services without interpretation of its clinical relevance. This study was registered at Research Registry with the registration number reviewregistry328. PMID- 29722850 TI - Reply to KA Beals and to C Parks. PMID- 29722851 TI - Calcium, magnesium, and whole-milk intakes and high-aggressive prostate cancer in the North Carolina-Louisiana Prostate Cancer Project (PCaP). AB - Background: Calcium and dairy product intakes have been positively associated with prostate cancer risk. An imbalance in concentrations of calcium and magnesium has been associated with multiple chronic diseases, although few studies have examined the relation with prostate cancer aggressiveness. Objective: The goal of this study was to examine the association between dietary intakes of calcium and magnesium, the calcium-to-magnesium ratio (Ca:Mg), and dairy products and prostate cancer aggressiveness. Design: Dietary intake was assessed with the use of an interviewer-administered modified National Cancer Institute Diet History Questionnaire in 996 African American and 1064 European American men with a recent histologically confirmed diagnosis of prostate cancer from the North Carolina-Louisiana Prostate Cancer Project (PCaP). High-aggressive disease was defined as Gleason sum >=8, or prostate-specific antigen (PSA) >20 ng/mL, or Gleason score >=7 and clinical stage T3-T4. The comparison group was all other prostate cancer cases. Logistic regression was used to determine the adjusted ORs and 95% CIs for high-aggressive prostate cancer by tertile of diet and supplement exposures. Results: There was a positive association across tertiles of dietary Ca:Mg intake, with odds of high-aggressive prostate cancer in the upper tertiles as follows-OR for tertile 2 compared with tertile 1: 1.38 (95% CI: 1.01, 1.88); OR for tertile 3 compared with tertile 1: 1.46 (95% CI: 1.06, 2.02). When stratified by race, the positive association was more pronounced in African American men (OR for tertile 3 compared with tertile 2: 1.62; 95% CI: 1.04, 2.53). Men who reported the highest daily consumption of whole-fat milk had a 74% increased odds of high-aggressive prostate cancer compared with non-whole fat milk drinkers, which was attenuated after adjustment for potential mediating factors, such as saturated fat and Ca:Mg intake. Conclusions: Among both African American and European American men diagnosed with prostate cancer, a higher Ca:Mg and whole-milk intake were associated with higher odds of high-aggressive prostate cancer. This study was registered at www.clinicaltrials.gov as NCT03289130. PMID- 29722853 TI - Another strategy to help counter the effects of low gravity? PMID- 29722852 TI - Evidence of acculturation's impact on dietary quality among non-Hispanic blacks. PMID- 29722854 TI - Comparison of robotic magnetic navigation-guided and manual catheter ablation of ventricular arrhythmias arising from the papillary muscles. AB - Aims: Due to the complex anatomy of the left ventricular (LV) and right ventricular (RV) papillary muscles (PMs), PM ventricular arrhythmias (VAs) can be challenging to target with ablation. We sought to compare the outcomes of robotic magnetic navigation-guided (RMN) ablation and manual ablation of VAs arising from the LV and RV PMs. Methods and results: We evaluated 35 consecutive patients (mean age 65 +/- 12 years, 69% male) who underwent catheter ablation of 38 VAs originating from the LV and RV PMs as confirmed by intracardiac echocardiography. Catheter ablation was initially performed using RMN-guidance in 24 (69%) patients and manual guidance in 11 (31%) patients. Demographic and procedural data were recorded and compared between the two groups. The VA sites of origin were mapped to 20 (53%) anterolateral LV PMs, 14 (37%) posteromedial LV PMs, and 4 (11%) RV PMs Acute successful ablation was achieved for 20 (74%) VAs using RMN-guided ablation and 8 (73%) VAs using manual ablation (P = 1.000). Fluoroscopy times were significantly lower among patients undergoing RMN ablation compared to patients undergoing manual ablation [median 7.3, interquartile range (IQR) 3.9-18 vs. 24 (16-44) min; P = 0.005]. Retrograde transaortic approach was used in 1 (4%) RMN patients and 5 (46%) manual patients (P = 0.005). No procedural complications were seen in study patients. Conclusion: Use of an RMN-guided approach to target PM VAs results in comparable success rates seen with manual ablation but with lower fluoroscopy times and decreased use of transaortic retrograde access. PMID- 29722855 TI - Clinical research: remote magnetic navigation vs. manually controlled catheter ablation of right ventricular outflow tract arrhythmias: a retrospective study. AB - Aims: Remote magnetic navigation (RMN) is an alternative to manual catheter control (MCC) radiofrequency ablation of right ventricular outflow tract (RVOT) arrhythmias. The data to support RMN approach is limited. We aimed to investigate the clinical and procedural outcomes in a cohort of patients undergoing RVOT premature ventricular complex/ventricular tachycardia (PVCs/VT) ablation procedures using RMN vs. MCC. Methods and results: Data was collected from two centres. Eighty-nine consecutive RVOT PVCs/VT ablation procedures were performed in 75 patients; RMN: 42 procedures and MCC: 47 procedures. CARTOXPTM or CARTO3 (Biosense Webster) was used for endocardial mapping in 19/42 (45%) in RMN group and 28/47 (60%) in MCC group; EnSiteTM NavXTM (St. Jude Medical) was used in the rest of the cohort. Stereotaxis platform (Stereotaxis Inc., St. Louis, MO, USA) was used for RMN approach. Procedural time was 113 +/- 53 min in the RMN group and 115 +/- 69 min in MCC (P = 0.90). Total fluoroscopic time was 10.9 +/- 5.8 vs. 20.5 +/- 13.8 (P < 0.05) and total ablation energy application time 7.0 +/- 4.7 vs 11.9 +/- 16 (P = 0.67) accordingly. There were two complications in RMN group and five in MCC (P = 0.43). Acute procedural success rate was 80% in RMN vs. 74% in MCC group (P = 0.46). After a median follow-up of 25 months (interquartile range 13-34), the success rate remained 55% in the RMN group and 53% in MCC (P = 0.96). Conclusion: Right ventricular outflow tract arrhythmia ablations were performed using half of fluoroscopic times with Stereotaxis platform RMN compared to manual approach. Acute and chronic success rates as well as complication rates were not significantly different. PMID- 29722856 TI - Long-term clinical outcomes of magnetically navigated rotor ablation as an adjunct to conventional pulmonary vein isolation. AB - Aims: The objective of this study is to evaluate the outcomes of magnetically guided ablation of atrial fibrillation (AF) rotors in conjunction with magnetically guided pulmonary vein isolation (PVI) in a large consecutive series of patients. Methods and results: A total of 110 consecutive patients with drug refractory AF underwent rotor ablation followed by conventional PVI and ablation of other spontaneous arrhythmias, all of which were performed with remote magnetic navigation (RMN). The patients were followed to assess the recurrence of atrial arrhythmia. Patients had a mean age of 62.5 +/- 9.9 years, 64.5% had persistent AF, and 36.4% had a prior failed PVI. All patients had mapped rotors (3.9 +/- 1.5 per patient), with right atrial (RA) rotors in 77.3% (85/110) of patients. After a mean follow-up of 17.6 +/- 9.5 months, 90.9% (100/110) were in stable sinus rhythm including patients on previously ineffective antiarrhythmic drugs (AADs). 69.1% (76/110) were in stable sinus rhythm without any AADs. Outcome did not differ between patients with persistent or paroxysmal AF (69.2% vs. 69.0%; P = 0.75), failed prior ablation or those undergoing an initial ablation (77.5% vs. 64.3%; P = 0.193), or patients with and without intra procedural AF termination (67.3% vs. 70.5%; P = 0.723). Conclusion: Ablation of rotors in combination with PVI using RMN was associated with a high success rate in this large cohort of consecutive patients. Significant proportion of patients exhibited RA rotors, which was associated with persistent AF, obstructive sleep apnoea, and obesity. PMID- 29722857 TI - Procedural and long-term outcome after catheter ablation of idiopathic outflow tract ventricular arrhythmias: comparing manual, contact force, and magnetic navigated ablation. AB - Aims: Currently, comparative data on procedural and long-term clinical outcome of outflow tract (OT) idiopathic ventricular arrhythmia (IVA) ablation with manual (MAN), contact force (CF), and magnetic navigation system (MNS) ablation are lacking. The aim of this study was to compare the procedural and long-term clinical outcome of MAN, CF, and MNS ablation of OT IVAs. Methods and results: Seventy-three patients (31 MAN, 17 CF, and 25 MNS patients; consecutive per group) with OT IVA, who underwent catheter ablation in our centre were analysed. Procedural success rates (success at the end of the procedure), procedural data and long-term follow-up data were compared. Baseline patient demographics were comparable. Procedural success rates were similar (MAN 81%, 71% CF, and MNS 92%; P = 0.20). Median fluoroscopy time was shorter in the MNS group: MAN 29 (16-38), CF 37 (21-46), and MNS 13 (10-20) min (P = 0.002 for MNS vs. CF and MAN). The overall complication rate was: MAN 10%, CF 0%, and MNS 0% (P = 0.12). Median follow-up was: MAN 2184 (1672-2802), CF 1721 (1404-1913), and MNS 3031 (2524 3286) days (P <0.001). Recurrences occurred in MAN 46%, CF 50%, and MNS 46% (P = 0.97). Repeat procedures were performed in MAN 20%, CF 40%, and MNS 33% (P = 0.32). Conclusion: Procedural and long-term clinical outcome of OT IVA ablation are equal for MAN, CF, and MNS. MNS has a favourable procedural safety profile due to the shorter fluoroscopy time compared with MAN and CF. PMID- 29722858 TI - Catheter ablation of incisional atrial tachycardia using remote magnetic navigation in patients after heart surgery: comparison between acquired and congenital heart disease. AB - Aims: The objectives of this study were to assess the acute and long-term outcomes of catheter ablation in incisional atrial tachycardia (IAT) using remote magnetic navigation (RMN) in patients after heart surgery. Methods and results: A total of 46 patients with IAT after heart surgery who underwent catheter ablation using RMN were included. Of these patients, 22 patients had acquired heart disease (AHD) and the remaining 24 patients had various types of congenital heart disease (CHD). In these 46 patients, 57 re-entry circuits were found in 56 procedures. The re-entry circuits were mainly distributed in right atrium (RA). Acute success of first ablation reached in 42 of 46 (91%) patients. Mean procedure duration was 115 +/- 39 min, ablation duration was 678 (920.5) s, X-ray time was 4 (4.8) min, and X-ray dose was 3 (6.0) gy cm2. After a mean follow-up of 28 +/- 19 months, 39 of 46 (85%) patients were free from IAT. No major complications were observed. There were no significant differences in procedure durations (AHD 113 +/- 40 min vs. CHD 119 +/- 38 min), ablation durations [AHD 643 (1027) s vs. CHD 712 (929) s], X-ray time [AHD 4 (4.5) min vs. CHD 4 (5.0) min], circuits in RA (AHD 85% vs. CHD 86%), acute success rates (AHD 91% vs. CHD 92%), and long-term success rates (AHD 86% vs. CHD 83%) between the two groups (P > 0.05). Conclusion: Catheter ablation of IAT in patients after heart surgery using RMN is safe and effective. No significant differences related to success rates and procedure characteristics were found between patients with AHD and CHD. PMID- 29722859 TI - Contact force with magnetic-guided catheter ablation. AB - Aims: Achieving adequate catheter tip-tissue contact is essential for delivering robust radiofrequency (RF) ablation lesions. We measured the contact force generated by a remote magnetic-guided catheter navigation system. Methods and results: A plexiglass model with an integrated scale was fashioned to mimic transvenous and retrograde access to sites in the right atrium and right and left ventricles. An 8 Fr RF ablation catheter was steered by remote magnetic guidance at fields of 0.08 and 0.10 T, with and without a long sheath positioned at the entrance of the chamber. Ten contact force readings were taken at each setting, with the scale recalibrated prior to each measurement. Generalized estimating equations were used to compare contact force measurements while adjusting for the non-independent data structure. A total of 240 contact force measurements were taken. Without a long sheath, contact forces with magnetic fields of 0.10 T (n = 60) and 0.08 T (n = 60) were similar (6.1 +/- 1.4 g vs. 6.0 +/- 1.3 g, P = 0.089). Contact forces were not significantly different with simulated transvenous (n = 80) and retrograde aortic (n = 40) approaches (6.2 +/- 1.4 g vs. 5.7 +/- 1.2 g, P = 0.132). The contact force increased substantially with a long sheath (P < 0.001) and was significantly higher with 0.10 T (n = 60) vs. 0.08 T (n = 60) fields (20.4 +/- 0.6 g vs. 18.0 +/- 0.5 g, P < 0.001). Conclusion: Magnetic fields of 0.08 and 0.10 T provide stable catheter contact forces, as reflected by the small variability between measurements. The average contact force is approximately 6 g without a sheath and increases to 20 g with a long sheath positioned at the entrance of the chamber of interest. PMID- 29722860 TI - Oesophageal injury following magnetically guided single-catheter ablation for atrial fibrillation: insights from the MAGNA-AF registry. AB - Aims: Oesophagogastroduodenoscopy (OGD) after catheter ablation (CA) of atrial fibrillation (AF) revealed a high rate of procedure related oesophageal lesions. We hypothesized that magnetically guided CA with careful radiofrequency energy titration at the posterior left atrial (LA) wall limits the incidence of oesophageal tissue damage. Methods and results: As a part of the prospective "Remote MAGNetic catheter Ablation for Atrial Fibrillation" (MAGNA-AF) registry, 251 out of 266 consecutive patients underwent OGD after magnetically guided single-CA for AF. All detected pathologies were analysed. Simultaneous pacing and ablation from the tip of the magnetically guided catheter was found to be a safe and feasible method for energy titration. Post-interventional OGD documented midoesophageal tissue damage in four (1.6%) patients. Although a thermal origin of these injuries must be discussed, none of them was located at the anterior oesophageal wall. Risk factors for midoesophageal lesions were female gender and concomitant acetylsalicylic acid (ASA) treatment. Mechanical lesions in 16 patients were attributed to periprocedural transoesophageal echocardiography (TOE). There was no atrio-oesophageal fistula (AOF). Five hundred and one incidental pathologies were found endoscopically, most frequent axial oesophageal herniation (71%), oesophagitis (22%), and gastritis (57%). Conclusion: Magnetically guided CA for AF with careful energy titration at the posterior LA wall and no oesophageal temperature monitoring is not associated with an increased incidence of oesophageal thermal injury. The routine use of periprocedural TOE may cause a low rate of mechanical oesophageal lesions but reliably prevents major complications like transient ischaemic attack, stroke, or cardiac tamponade. An observed high prevalence of upper digestive system inflammation (63%) may further support the recommendation for a routine post interventional treatment with a proton-pump-inhibitor. PMID- 29722861 TI - Early and long-term outcomes after manual and remote magnetic navigation-guided catheter ablation for ventricular tachycardia. AB - Aims: Remote magnetic navigation (RMN) is a safe and effective means of performing ventricular tachycardia (VT) ablation. It may have advantages over manual catheter ablation due to ease of manoeuvrability and catheter stability. We sought to compare the safety and efficacy of RMN vs. manual VT ablation. Methods and results: Retrospective study of procedural outcomes of 139 consecutive VT ablation procedures (69 RMN, 70 manual ablation) in 113 patients between 2009 and 2015 was performed. Remote magnetic navigation was associated with overall higher acute procedural success (80% vs. 60%, P = 0.01), with a trend to fewer major complications (3% vs. 9% P = 0.09). Seventy-nine patients were followed up for a median of 17.0 [interquartile range (IQR) 3.0-41.0] months for the RMN group and 15.5 (IQR 6.5-30.0) months for manual ablation group. In the ischaemic cardiomyopathy subgroup, RMN was associated with longer survival from the composite endpoint of VT recurrence leading to defibrillator shock, re hospitalization or repeat catheter ablation and all-cause mortality; single procedure adjusted hazard ratio (HR) 0.240 (95% CI 0.070-0.821) P = 0.023, multi procedure HR 0.170 (95% CI 0.046-0.632) P = 0.002. In patients with implanted defibrillators, multi-procedure VT-free survival was superior with RMN, HR 0.199 (95% CI 0.060-0.657) P = 0.003. Conclusion: Remote magnetic navigation may improve clinical outcomes after catheter ablation of VT in patients with ischaemic cardiomyopathy. Further prospective clinical studies are required to confirm these findings. PMID- 29722862 TI - Honeybees Prefer to Steer on a Smooth Wall With Tetrapod Gaits. AB - Insects are well equipped in walking on complex three-dimensional terrain, allowing them to overcome obstacles or catch prey. However, the gait transition for insects steering on a wall remains unexplored. Here, we find that honeybees adopted a tetrapod gait to change direction when climbing a wall. On the contrary to the common tripod gait, honeybees propel their body forward by synchronously stepping with both middle legs and then both front legs. This process ensures the angle of the central axis of the honeybee to be consistent with the crawling direction. Interestingly, when running in an alternating tripod gait, the central axis of honeybee sways around the center of mass under alternating tripod gait to maintain stability. Experimental results show that tripod, tetrapod, and random gaits result in the amazing consensus harmony on the climbing speed and gait stability, whether climbing on a smooth wall or walking on smooth ground. PMID- 29722863 TI - Uptake of Supplemental Nutrition Assistance Program Benefits by Participants in a Home Visiting Program. AB - In 2015, over 15 percent of U.S. households with children were food insecure at some point during the year. The largest program created to address food insecurity in the United States is the Supplemental Nutritional Assistance Program (SNAP). However, research has suggested that safety net programs such as SNAP may be underutilized by eligible families. This secondary data analysis examined receipt of SNAP benefits among 2,249 SNAP-eligible participants in a South Carolina home visiting program. Benefit status was obtained at program enrollment and six months post-enrollment. Results showed that 15.6 percent of home visiting program participants without SNAP benefits at program enrollment were receiving benefits by six months post-enrollment. Unmarried caregivers were least likely to obtain SNAP benefits. Programs such as home visiting can be important to ensuring that eligible families receive federal assistance promoting food security, and targeted efforts to overcome barriers to SNAP enrollment continue to be important. PMID- 29722864 TI - Participatory Investigation of the Great East Japan Disaster: PhotoVoice from Women Affected by the Calamity. AB - Disasters exacerbate predisaster inequities and intensify the vulnerability of women and other marginalized and disempowered groups. Thus, disaster policies and responses should incorporate the experiences and perspectives of those who are marginalized. The authors sought to conduct a participatory research project to help develop more inclusive, gender-informed disaster responses and policies in Japan. In June 2011, following three months of planning and preparation, they initiated a participatory examination of the impact of the Great East Japan Disaster using PhotoVoice methodology. Engaging the very women affected by the calamity, the authors first implemented the project in three localities in the hardest-hit areas of northern Japan-the prefectures of Fukushima, Miyagi, and Iwate. The authors have since expanded the project to other locations, and the project is ongoing. Focused on the planning, implementation, and outcomes of the initial phase, this article examines the role and potential of participatory action research using the PhotoVoice methodology in the aftermath of a major disaster. PMID- 29722865 TI - Predicting RNA-protein binding sites and motifs through combining local and global deep convolutional neural networks. AB - Motivation: RNA-binding proteins (RBPs) take over 5-10% of the eukaryotic proteome and play key roles in many biological processes, e.g. gene regulation. Experimental detection of RBP binding sites is still time-intensive and high costly. Instead, computational prediction of the RBP binding sites using patterns learned from existing annotation knowledge is a fast approach. From the biological point of view, the local structure context derived from local sequences will be recognized by specific RBPs. However, in computational modeling using deep learning, to our best knowledge, only global representations of entire RNA sequences are employed. So far, the local sequence information is ignored in the deep model construction process. Results: In this study, we present a computational method iDeepE to predict RNA-protein binding sites from RNA sequences by combining global and local convolutional neural networks (CNNs). For the global CNN, we pad the RNA sequences into the same length. For the local CNN, we split a RNA sequence into multiple overlapping fixed-length subsequences, where each subsequence is a signal channel of the whole sequence. Next, we train deep CNNs for multiple subsequences and the padded sequences to learn high-level features, respectively. Finally, the outputs from local and global CNNs are combined to improve the prediction. iDeepE demonstrates a better performance over state-of-the-art methods on two large-scale datasets derived from CLIP-seq. We also find that the local CNN runs 1.8 times faster than the global CNN with comparable performance when using GPUs. Our results show that iDeepE has captured experimentally verified binding motifs. Availability and implementation: https://github.com/xypan1232/iDeepE. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29722867 TI - Evaluating the quality of the processes of care and clinical outcomes of premature newborns admitted to neonatal intensive care units in Mexico. AB - Objectives: To develop quality of care (QoC) indicators, evaluate the quality of the processes of care (QPC) and clinical outcomes, and analyze the association between the QPC and severe clinical outcomes of preterm newborns admitted to neonatal intensive care units (NICUs). Design: Mixed methods approach: (1) development of QoC indicators via modified RAND/UCLA method; (2) cross-sectional study of QoC evaluation and (3) multiple logistic regression analysis to ascertain the association between the QPC and severe clinical outcomes. Setting: Two NICUs belonged to the Mexican Institute of Social Security in Mexico City. Participants: About 489 preterm neonates (<37 weeks of gestation) without severe congenital anomalies. Main Outcome Measure(s): The QoC indicators; >=60% of recommended QPC and severe clinical outcomes. Results: The QoC included 10 QPC indicators across four domains: respiratory, nutrition and metabolism, infectious diseases, and screening, and five outcome indicators. The lower QPC indicators were for the nutrition and metabolism domain (17.8% started enteral feeding with human milk, and 20.7% received sodium bicarbonate appropriately). The higher QPC indicator was for the screening domain (97.6% of neonates <30 weeks gestation underwent early (<=14 days) transfontanelar ultrasound). The mean recommended QPC that neonates received was 47.5%. Only 26.6% of neonates received >=60% of recommended QPC. About 60.7% of neonates developed severe clinical outcomes including mortality and healthcare-related major morbidity. Receiving >=60% of recommended QPC was associated with a decrease of nearly half of odds of severe clinical outcomes. Conclusion: The evaluation of the QoC in NICUs is essential to address modifiable gaps in quality. PMID- 29722866 TI - In vitro reconstitution and analysis of eukaryotic RNase P RNPs. AB - RNase P is a ubiquitous site-specific endoribonuclease primarily responsible for the maturation of tRNA. Throughout the three domains of life, the canonical form of RNase P is a ribonucleoprotein (RNP) built around a catalytic RNA. The core RNA is well conserved from bacteria to eukaryotes, whereas the protein parts vary significantly. The most complex and the least understood form of RNase P is found in eukaryotes, where multiple essential proteins playing largely unknown roles constitute the bulk of the enzyme. Eukaryotic RNase P was considered intractable to in vitro reconstitution, mostly due to insolubility of its protein components, which hindered its studies. We have developed a robust approach to the in vitro reconstitution of Saccharomyces cerevisiae RNase P RNPs and used it to analyze the interplay and roles of RNase P components. The results eliminate the major obstacle to biochemical and structural studies of eukaryotic RNase P, identify components required for the activation of the catalytic RNA, reveal roles of proteins in the enzyme stability, localize proteins on RNase P RNA, and demonstrate the interdependence of the binding of RNase P protein modules to the core RNA. PMID- 29722869 TI - Screwworm (Diptera: Calliphoridae) in the United States: Response to and Elimination of the 2016-2017 Outbreak in Florida. AB - Eradicating screwworm, Cochliomyia hominivorax (Coquerel), from continental North American via the sterile insect technique has provided huge economic benefit to livestock producers by eliminating screwworm myiasis. After confirmatory identification of fly samples from infested deer by the USDA National Veterinary Services Laboratory on September 30, 2016, an alert was issued that screwworm myiasis was discovered in the Florida Keys. Personnel from USDA Animal and Plant Health Inspection Service, Agricultural Research Service, the State of Florida, U.S. Fish and Wildlife Service and local officials responded to the outbreak focus on Big Pine Key. After witnessing infested Key deer (Odocoileus virginianus clavium Barboyr & Allen), screwworm adult sampling was initiated at 0930 h on October 5, 2016 using nets to collect flies arriving at putrid liver, with the first female collected within 1 h. Larval samples were collected from infested animals for DNA analyses and to develop a "Florida outbreak" colony to test mating compatibility with the mass-produced strain used for sterile fly releases. Ground release chambers for sterile screwworm releases were placed in favorable habitats based on satellite image analyses. Sterile pupae were first placed in the chambers on October 11, 2016. Further liver trapping showed that 13 Keys were infested. One case, presumably through animal movement, occurred near Homestead on the Florida mainland. Ultimately there were 35 sterile fly release stations, including 4 located around Homestead, but no further cases were identified. About 188 million sterile flies were released until successful eradication was declared on March 23, 2017. Containing the outbreak prevented economic losses to livestock producers and other wildlife on the mainland and kept eradication costs to a minimum. PMID- 29722868 TI - Long term outcome of patients suffering from cancer and Takotsubo syndrome or myocardial infarction. AB - Background: The pathophysiology of takotsubo syndrome (TTS) is unclear so far. There is strong association of the occurrence of TTS and malignant diseases. An association between malignant diseases and myocardial infarction (MI) was found recently and ascribed to common molecular and lifestyle mechanisms. Aim: To compare the outcome of patients with MI or TTS and malignant diseases in a matched cohort. Methods: Patients with TTS or with MI (n = 138 per group) were matched for age and sex and assessed retrospectively and prospectively. Occurrence of malignant diseases and clinical outcome was followed up over 4 years. Results: At the time of the index event, 8 (5.8%) MI patients and 17 (12.3%) TTS patients were already diagnosed with cancer. During follow up, the rate of patients who developed cancer was significantly higher in the TTS group than in the MI group (log rank P = 0.01). Mortality was higher in the TTS group, but also in the subgroup of TTS patients with cancer (log rank P < 0.05). In the multivariate analysis, male gender, renal impairment and the history of cancer was associated with an increased risk for death. Conclusions: Patients with TTS have more often malignant diseases than patients with MI. Cancer patients with TTS have a worse clinical outcome. The underlying mechanism is unclear yet, but the results point at TTS being the syndrome of an extracardiac disease rather than a disease of cardiac origin. Longer and closer follow up of patients with TTS and further studies addressing the mechanism of TTS are needed. PMID- 29722870 TI - Patscanui: an intuitive web interface for searching patterns in DNA and protein data. AB - Patterns in biological sequences frequently signify interesting features in the underlying molecule. Many tools exist to search for well-known patterns. Less support is available for exploratory analysis, where no well-defined patterns are known yet. PatScanUI (https://patscan.secondarymetabolites.org/) provides a highly interactive web interface to the powerful generic pattern search tool PatScan. The complex PatScan-patterns are created in a drag-and-drop aware interface allowing researchers to do rapid prototyping of the often complicated patterns useful to identifying features of interest. PMID- 29722871 TI - Gap in Basic Needs Products and One Project's Attempt to Help. PMID- 29722873 TI - Using a Macro Social Work Strategy to Improve Outreach in Parkinson's Disease Research. PMID- 29722872 TI - ComM is a hexameric helicase that promotes branch migration during natural transformation in diverse Gram-negative species. AB - Acquisition of foreign DNA by natural transformation is an important mechanism of adaptation and evolution in diverse microbial species. Here, we characterize the mechanism of ComM, a broadly conserved AAA+ protein previously implicated in homologous recombination of transforming DNA (tDNA) in naturally competent Gram negative bacterial species. In vivo, we found that ComM was required for efficient comigration of linked genetic markers in Vibrio cholerae and Acinetobacter baylyi, which is consistent with a role in branch migration. Also, ComM was particularly important for integration of tDNA with increased sequence heterology, suggesting that its activity promotes the acquisition of novel DNA sequences. In vitro, we showed that purified ComM binds ssDNA, oligomerizes into a hexameric ring, and has bidirectional helicase and branch migration activity. Based on these data, we propose a model for tDNA integration during natural transformation. This study provides mechanistic insight into the enigmatic steps involved in tDNA integration and uncovers the function of a protein required for this conserved mechanism of horizontal gene transfer. PMID- 29722875 TI - Hepatic, Metabolic, and Toxicity Evaluation of Repeated Oral Administration of SnS2 Nanoflowers in Mice. AB - Tin sulfide (SnS2) nanoflowers (NFs) with highly photocatalytic activity for wastewater treatment may lead to potential health hazards via oral routes of human exposure. No studies have reported the hepatic effects of SnS2 NFs on the metabolic function and hepatotoxicity. In this study, we examined the hepatic effects of the oral administration of SnS2 NFs (250-1000 mg/kg) to ICR mice for 14 days, with the particle size ranging from 50 to 200 nm. Serum and liver tissue samples were assayed using biochemical analysis, liver histopathology and metabolic gene expression. The different sizes of SnS2 NFs (250 mg/kg dose), such as 50, 80, and 200 nm, did not induce any adverse hepatic effect related to biochemical parameters or histopathology in the treated mice compared with controls. The oral administration of 50-nm SnS2 NFs at doses of 250, 500, and 1000 mg/kg for 14 days produced dose-dependent hepatotoxicity and inflammatory responses in treated mice. Furthermore, the expression of metabolic genes in the liver tissues was altered, supporting the SnS2 NF-related hepatotoxic phenotype. The oral administration of SnS2 NFs also produced abnormal microstructures in the livers of the treated mice. Taken together, these data indicate that the increased risk of hepatotoxicity in SnS2 NF-treated mice was independent of the particle size but was dependent on their dose. The no-observed-adverse effect level was <250 mg/kg for the 50-nm SnS2 NFs. Our study provides an experimental basis for the safe application of SnS2 NFs. PMID- 29722874 TI - RSAT 2018: regulatory sequence analysis tools 20th anniversary. AB - RSAT (Regulatory Sequence Analysis Tools) is a suite of modular tools for the detection and the analysis of cis-regulatory elements in genome sequences. Its main applications are (i) motif discovery, including from genome-wide datasets like ChIP-seq/ATAC-seq, (ii) motif scanning, (iii) motif analysis (quality assessment, comparisons and clustering), (iv) analysis of regulatory variations, (v) comparative genomics. Six public servers jointly support 10 000 genomes from all kingdoms. Six novel or refactored programs have been added since the 2015 NAR Web Software Issue, including updated programs to analyse regulatory variants (retrieve-variation-seq, variation-scan, convert-variations), along with tools to extract sequences from a list of coordinates (retrieve-seq-bed), to select motifs from motif collections (retrieve-matrix), and to extract orthologs based on Ensembl Compara (get-orthologs-compara). Three use cases illustrate the integration of new and refactored tools to the suite. This Anniversary update gives a 20-year perspective on the software suite. RSAT is well-documented and available through Web sites, SOAP/WSDL (Simple Object Access Protocol/Web Services Description Language) web services, virtual machines and stand-alone programs at http://www.rsat.eu/. PMID- 29722876 TI - Necklace: combining reference and assembled transcriptomes for more comprehensive RNA-Seq analysis. AB - Background: RNA sequencing (RNA-seq) analyses can benefit from performing a genome-guided and de novo assembly, in particular for species where the reference genome or the annotation is incomplete. However, tools for integrating an assembled transcriptome with reference annotation are lacking. Findings: Necklace is a software pipeline that runs genome-guided and de novo assembly and combines the resulting transcriptomes with reference genome annotations. Necklace constructs a compact but comprehensive superTranscriptome out of the assembled and reference data. Reads are subsequently aligned and counted in preparation for differential expression testing. Conclusions: Necklace allows a comprehensive transcriptome to be built from a combination of assembled and annotated transcripts, which results in a more comprehensive transcriptome for the majority of organisms. In addition RNA-seq data are mapped back to this newly created superTranscript reference to enable differential expression testing with standard methods. PMID- 29722877 TI - Rituximab for induction and maintenance therapy of granulomatosis with polyangiitis: a single-centre cohort study on 114 patients. AB - Objectives: To assess efficacy and safety of rituximab (RTX) induction and maintenance therapy for granulomatosis with polyangiitis (GPA) in a single-centre cohort study. Methods: All patients with active GPA, not enrolled in trials, who received ?1 RTX infusion(s) for induction were included. At remission, protocolized maintenance RTX infusions were given every 6 months for 18 months. Kaplan-Meier curves were used to estimate survival rates. Univariable analyses identified factors associated with remission failure and relapse, and Cox models retained independent predictors of relapse. Results: One hundred and fourteen adults with relapsing (65%), refractory/grumbling (22%) or new-onset (13%) GPA received RTX for induction; 100 were given ?1 RTX maintenance infusion(s) and 90 received 500 mg every 6 months. Median daily prednisone induction dose was 30 mg; 76% of patients were still receiving a median daily prednisone dose of 5 mg at 2 years. Median follow-up was 3.6 years. Respective 2-year relapse-free survival and RTX retention rates were 85 and 78%. Serious infection and serious adverse event rates were 4.9 and 8.1 per 100 patient-years, respectively. Refractory/grumbling vs new-onset and/or relapsing GPA (P < 0.01 for each individually; P < 0.001 vs the latter two taken together), pachymeningitis (P < 0.05), pure granulomatous disease (P < 0.05) or estimated glomerular filtration rate ?60 ml/min (P < 0.01) were associated with remission failure. Multivariate analyses retained refractory/grumbling GPA (P = 0.05), subglottic stenosis (P < 0.005), ENT involvement (P = 0.01) and skin involvement (P < 0.0005) as independent predictors of relapse. Conclusion: RTX induction and low-dose preemptive maintenance can effectively and safely induce sustained remission in GPA in a real-life setting. PMID- 29722879 TI - Lung cavity accompanied by hemoptysis: lymphoepithelioma-like carcinoma. PMID- 29722878 TI - Global DNA methylation synergistically regulates the nuclear and mitochondrial genomes in glioblastoma cells. AB - Replication of mitochondrial DNA is strictly regulated during differentiation and development allowing each cell type to acquire its required mtDNA copy number to meet its specific needs for energy. Undifferentiated cells establish the mtDNA set point, which provides low numbers of mtDNA copy but sufficient template for replication once cells commit to specific lineages. However, cancer cells, such as those from the human glioblastoma multiforme cell line, HSR-GBM1, cannot complete differentiation as they fail to enforce the mtDNA set point and are trapped in a 'pseudo-differentiated' state. Global DNA methylation is likely to be a major contributing factor, as DNA demethylation treatments promote differentiation of HSR-GBM1 cells. To determine the relationship between DNA methylation and mtDNA copy number in cancer cells, we applied whole genome MeDIP Seq and RNA-Seq to HSR-GBM1 cells and following their treatment with the DNA demethylation agents 5-azacytidine and vitamin C. We identified key methylated regions modulated by the DNA demethylation agents that also induced synchronous changes to mtDNA copy number and nuclear gene expression. Our findings highlight the control exerted by DNA methylation on the expression of key genes, the regulation of mtDNA copy number and establishment of the mtDNA set point, which collectively contribute to tumorigenesis. PMID- 29722881 TI - Changes in nocturnal sleep and daytime nap durations predict all-cause mortality among older adults: the Panel on Health and Ageing of Singaporean Elderly. AB - Study Objectives: To determine the effects of changes in nocturnal sleep and daytime nap durations on all-cause mortality among older adults. Methods: Two thousand four-hundred forty-eight community-dwelling older Singaporeans (>=60 years) reported their nocturnal sleep and daytime nap durations at baseline (2009) and the 2-year follow-up. At each phase, they were grouped into the recommended (7-8 hours), short (<=6 hours), and long (>=9 hours) sleep duration categories, and the none (0 hour), short (<=1 hour), and long (>1 hour) nap duration categories. Cox regression analysis was conducted to quantify the associations of changes in sleep and nap durations over 2 years with all-cause mortality risk in the subsequent 4 years (till end of 2015). Multivariable fractional polynomial regression, which treated sleep and nap durations as continuous variables was conducted as a supplementary analysis. Results: Relative to individuals who had the recommended sleep durations at both baseline and follow-up, the risks of all-cause mortality were higher among older adults who reported considerable changes in sleep duration (from short to long sleep and vice versa, hazard ratio [HR] = 2.14-2.56). Furthermore, compared to those who did not nap at both time points, significantly higher mortality risks were found in individuals who showed any increase in nap duration (HR = 1.86-2.16), or reduced their nap from long to short duration (HR = 1.86). Supplementary analysis revealed similar findings. Conclusions: In addition to the change in nocturnal sleep duration, change in daytime nap duration can also predict risks of all cause mortality among older adults. It is crucial to track older adults' sleep and nap durations longitudinally. PMID- 29722880 TI - Extensive Differential Splicing Underlies Phenotypically Plastic Aphid Morphs. AB - Phenotypic plasticity results in a diversity of phenotypes from a single genotype in response to environmental cues. To understand the molecular basis of phenotypic plasticity, studies have focused on differential gene expression levels between environmentally determined phenotypes. The extent of alternative splicing differences among environmentally determined phenotypes has largely been understudied. Here, we study alternative splicing differences among plastically produced morphs of the pea aphid using RNA-sequence data. Pea aphids express two separate polyphenisms (plasticity with discrete phenotypes): a wing polyphenism consisting of winged and wingless females and a reproduction polyphenism consisting of asexual and sexual females. We find that pea aphids alternatively splice 34% of their genes, a high percentage for invertebrates. We also find that there is extensive use of differential spliced events between genetically identical, polyphenic females. These differentially spliced events are enriched for exon skipping and mutually exclusive exon events that maintain the open reading frame, suggesting that polyphenic morphs use alternative splicing to produce phenotype-biased proteins. Many genes that are differentially spliced between polyphenic morphs have putative functions associated with their respective phenotypes. We find that the majority of differentially spliced genes is not differentially expressed genes. Our results provide a rich candidate gene list for future functional studies that would not have been previously considered based solely on gene expression studies, such as ensconsin in the reproductive polyphenism, and CAKI in the wing polyphenism. Overall, this study suggests an important role for alternative splicing in the expression of environmentally determined phenotypes. PMID- 29722883 TI - Assessing Deep and Shallow Learning Methods for Quantitative Prediction of Acute Chemical Toxicity. AB - Animal-based methods for assessing chemical toxicity are struggling to meet testing demands. In silico approaches, including machine-learning methods, are promising alternatives. Recently, deep neural networks (DNNs) were evaluated and reported to outperform other machine-learning methods for quantitative structure activity relationship modeling of molecular properties. However, most of the reported performance evaluations relied on global performance metrics, such as the root mean squared error (RMSE) between the predicted and experimental values of all samples, without considering the impact of sample distribution across the activity spectrum. Here, we carried out an in-depth analysis of DNN performance for quantitative prediction of acute chemical toxicity using several datasets. We found that the overall performance of DNN models on datasets of up to 30 000 compounds was similar to that of random forest (RF) models, as measured by the RMSE and correlation coefficients between the predicted and experimental results. However, our detailed analyses demonstrated that global performance metrics are inappropriate for datasets with a highly uneven sample distribution, because they show a strong bias for the most populous compounds along the toxicity spectrum. For highly toxic compounds, DNN and RF models trained on all samples performed much worse than the global performance metrics indicated. Surprisingly, our variable nearest neighbor method, which utilizes only structurally similar compounds to make predictions, performed reasonably well, suggesting that information of close near neighbors in the training sets is a key determinant of acute toxicity predictions. PMID- 29722885 TI - Are some e-cigarette users "blowing smoke?": Assessing the Accuracy of Self Reported Smoking Abstinence in Exclusive e-cigarette Users. PMID- 29722882 TI - Modeling one thousand intron length distributions with fitild. AB - Motivation: Intron length distribution (ILD) is a specific feature of a genome that exhibits extensive species-specific variation. Whereas ILD contributes to up to 30% of the total information content for intron recognition in some species, rendering it an important component of computational gene prediction, very few studies have been conducted to quantitatively characterize ILDs of various species. Results: We developed a set of computer programs (fitild, compild, etc.) to build statistical models of ILDs and compare them with one another. Each ILD of more than 1000 genomes was fitted with fitild to a statistical model consisting of one, two, or three components of Frechet distributions. Several measures of distances between ILDs were calculated by compild. A theoretical model was presented to better understand the origin of the observed shape of an ILD. Availability and implementation: The C++ source codes are available at https://github.com/ogotoh/fitild.git/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29722884 TI - De Novo Mutations Resolve Disease Transmission Pathways in Clonal Malaria. AB - Detecting de novo mutations in viral and bacterial pathogens enables researchers to reconstruct detailed networks of disease transmission and is a key technique in genomic epidemiology. However, these techniques have not yet been applied to the malaria parasite, Plasmodium falciparum, in which a larger genome, slower generation times, and a complex life cycle make them difficult to implement. Here, we demonstrate the viability of de novo mutation studies in P. falciparum for the first time. Using a combination of sequencing, library preparation, and genotyping methods that have been optimized for accuracy in low-complexity genomic regions, we have detected de novo mutations that distinguish nominally identical parasites from clonal lineages. Despite its slower evolutionary rate compared with bacterial or viral species, de novo mutation can be detected in P. falciparum across timescales of just 1-2 years and evolutionary rates in low complexity regions of the genome can be up to twice that detected in the rest of the genome. The increased mutation rate allows the identification of separate clade expansions that cannot be found using previous genomic epidemiology approaches and could be a crucial tool for mapping residual transmission patterns in disease elimination campaigns and reintroduction scenarios. PMID- 29722886 TI - Usefulness of routine computed tomography in the evaluation of penetrating war injuries to the chest. AB - OBJECTIVES: This review was conducted to compare the contributions of chest X-ray (CXR) and computed tomography (CT) towards detecting intrathoracic damage in patients with penetrating war injuries to the chest and to determine whether identification of additional injuries by chest CT will have an impact on the choice of therapeutic interventions and clinical outcomes. METHODS: We reviewed records of 449 patients (374 men, mean age 29.3 +/- 14.8 years) who were admitted to our hospital with penetrating war injuries to the chest over a 7-year period. Collected data included mechanisms of injury, associated injuries, results of CXRs and chest CTs, methods of management, in-hospital stays, complications and mortalities. RESULTS: Immediate screening CXRs were obtained in all patients not requiring emergent thoracotomies, of which 91.4% showed positive signs of injury. Chest CTs were performed at the discretion of the physicians in 49.4% of patients, and CXR-positive findings were confirmed in all cases, while revealing additional injuries in 11% of patients. Chest CT findings led to additional closed chest drainage in 5.6% of patients but had no impact on treatment strategy in 94.4% of scanned patients. Follow-up CXRs showed new positive findings in 22 patients, leading to additional closed chest drainage in 3 patients and delayed open thoracotomies in 7 other patients. CONCLUSIONS: CXRs continue as the primary diagnostic modality in the assessment of patients with penetrating war injuries to the chest. Chest CTs can be omitted in most patients, thus reducing CT imaging case-load substantially, while most clinically significant chest injuries remain sufficiently recognized. PMID- 29722887 TI - MEGA X: Molecular Evolutionary Genetics Analysis across Computing Platforms. AB - The Molecular Evolutionary Genetics Analysis (Mega) software implements many analytical methods and tools for phylogenomics and phylomedicine. Here, we report a transformation of Mega to enable cross-platform use on Microsoft Windows and Linux operating systems. Mega X does not require virtualization or emulation software and provides a uniform user experience across platforms. Mega X has additionally been upgraded to use multiple computing cores for many molecular evolutionary analyses. Mega X is available in two interfaces (graphical and command line) and can be downloaded from www.megasoftware.net free of charge. PMID- 29722889 TI - Double-arterial cannulation: a strategy for whole body perfusion during aortic arch reconstruction. AB - OBJECTIVES: Double-arterial cannulation enables cerebral perfusion and lower body perfusion during aortic arch reconstruction. The aim of this study was to analyse and report our experience of using this cannulation and perfusion technique on paediatric patients. METHODS: A retrospective single-centre study was carried out on 407 consecutive paediatric patients who underwent an aortic arch reconstruction under double-arterial cannulation between 2003 and 2015. The median age of the patients at surgery was 8 (range 2-5570) days, and body weight was 3.3 (range 1.8-60) kg. All operations were performed through standard median sternotomy. One arterial cannula was inserted into the innominate artery and the second one into the supradiaphragmatic descending aorta. Primary end points were 30-day mortality, acute renal failure requiring dialysis and time until lactate level decreased to <=2 mmol/l postoperatively. RESULTS: We found an in-hospital mortality of 8.6%. Lethal incident was not associated with the cannulation method, and 1 intraoperative lesion of the descending aorta could be repaired immediately. The median lactate level of the patients on arrival at the intensive care unit was 3.5 mmol/l [quartile (Q)1: 2.3-Q3: 4.7] and creatinine was 0.48 mg/100 ml (Q1: 0.40-Q3: 0.58). The longest duration until the lactate level decreased to <= 2 mmol/l was found in the group of 264 univentricular patients (median 11 h, Q1: 6-Q3: 24). Seven (1.7%) patients of the whole cohort required peritoneal dialysis postoperatively. CONCLUSIONS: Double-arterial cannulation is a simple and safe method for perfusing the brain and the lower parts of the body during aortic arch reconstruction. Perioperative survival and freedom from procedure-related complications in this demanding patient population are encouraging. PMID- 29722888 TI - Applying graph theory to protein structures: an Atlas of coiled coils. AB - Motivation: To understand protein structure, folding and function fully and to design proteins de novo reliably, we must learn from natural protein structures that have been characterized experimentally. The number of protein structures available is large and growing exponentially, which makes this task challenging. Indeed, computational resources are becoming increasingly important for classifying and analyzing this resource. Here, we use tools from graph theory to define an Atlas classification scheme for automatically categorizing certain protein substructures. Results: Focusing on the alpha-helical coiled coils, which are ubiquitous protein-structure and protein-protein interaction motifs, we present a suite of computational resources designed for analyzing these assemblies. iSOCKET enables interactive analysis of side-chain packing within proteins to identify coiled coils automatically and with considerable user control. Applying a graph theory-based Atlas classification scheme to structures identified by iSOCKET gives the Atlas of Coiled Coils, a fully automated, updated overview of extant coiled coils. The utility of this approach is illustrated with the first formal classification of an emerging subclass of coiled coils called alpha-helical barrels. Furthermore, in the Atlas, the known coiled-coil universe is presented alongside a partial enumeration of the 'dark matter' of coiled-coil structures; i.e. those coiled-coil architectures that are theoretically possible but have not been observed to date, and thus present defined targets for protein design. Availability and implementation: iSOCKET is available as part of the open source GitHub repository associated with this work (https://github.com/woolfson group/isocket). This repository also contains all the data generated when classifying the protein graphs. The Atlas of Coiled Coils is available at: http://coiledcoils.chm.bris.ac.uk/atlas/app. PMID- 29722891 TI - Management of Crohn's Disease and Complications in Patients With Ostomies. AB - Fecal diversion with ostomy construction can be a temporary or definitive surgical measure for the treatment of refractory inflammatory bowel disease (IBD). However, the fecal diversion surgery is associated with various stoma, peristomal complications, and recurrence or occurrence of de novo small bowel Crohn's disease (CD). Stoma complications often need enterostomal therapy or surgical revision. Peristomal cutaneous lesions, such as pyoderma gangrenosum, usually require immunomodulator or biological therapy. Routine monitoring for occurrence or recurrence of CD with endoscopy or imaging should be performed, and prophylaxis with mesalamines, antibiotics, immunomodulators, or anti-TNFalpha or anti-integrin agents is needed for patients at risk. Those agents, along with corticosteroids, may also be used for the treatment of CD of the neo-small intestine, particularly inflammatory and fistulizing phenotypes. Endoscopic balloon dilation or endoscopic stricturotomy via stoma is safe and feasible to treat short (<4-5 cm), straight strictures in the neo-small intestine. Medically or endoscopically refractory fibrostenotic disease usually requires surgical intervention, with bowel-sparing stricturoplasty being the surgical treatment of choice. PMID- 29722892 TI - Inter-rater agreement for visual discrimination of phasic and tonic electromyographic activity in sleep. AB - Study Objectives: The objective of this study was to determine the confidence of expert raters in discriminating phasic and tonic electromyographic (EMG) activity. We undertook this study because we suspected that even expert scorers may disagree on whether a given EMG segment contained phasic activity, tonic activity, or both. Methods: Six individuals holding either Fellowship status in the American Academy of Sleep Medicine or Board Certification in Sleep Medicine with at least 5 years experience in interpreting polysomnography visually examined 60 segments containing EMG activity. Raters determined their relative confidence that each segment contained phasic and tonic activity by noting whether they were highly certain or somewhat certain that the segment contained such activity or somewhat certain or highly certain that each segment did not contain such activity. Every segment was rated by every rater twice, once for phasic and once for tonic activity. Results: Substantial differences among raters existed in certainty regarding presence/absence of both phasic and tonic activity, although raters agreed on segments far above chance. Consensus was higher on certainty regarding presence of phasic, relative to tonic, activity. Conclusions: These findings indicate the limitations of visual analyses for discriminating abnormal muscle activity during sleep. Conversely, when expert judgments are combined with digitized measurements of EMG activity in sleep (e.g. REM atonia index), some allowance must be made for the unique contribution of visual analyses to such judgments, most notably for short duration EMG signals. These results may have relevance for polysomnographic interpretation in suspected synucleinopathies. PMID- 29722890 TI - The association between obstructive sleep apnea and metabolic abnormalities in women with polycystic ovary syndrome: a systematic review and meta-analysis. AB - Study Objectives: In this systematic review and meta-analysis, we aimed to examine the relationship between obstructive sleep apnea (OSA) and metabolic abnormalities in women with polycystic ovary syndrome (PCOS). Methods: Electronic databases (Medline, Embase, Cinahl, PsycInfo, Scopus, Web of Science, Opengrey, and CENTRAL), conference abstracts, and reference lists of relevant articles were searched. No restriction was applied for language or publication status. Results: Six studies involving 252 participants were included. Women with PCOS and OSA had significantly higher body mass index (mean difference [MD]: 6.01 kg/m2, 95% confidence intervals [CI]: 4.69-7.33), waist circumference (MD: 10.93 cm, 95% CI: 8.03-13.83), insulin resistance, systolic and diastolic blood pressure, and worse lipids' profile and impaired glucose regulation compared with women with PCOS without OSA. Most studies did not adjust for weight in their between-groups analysis. Total and free testosterone levels were not significantly different between the two groups. The majority of studies were found to be at high risk of selection bias, did not account for important confounders, were conducted in one country (United States), and used different methodologies to assess testosterone levels (preventing a meta-analysis for this specific outcome). Conclusions: OSA is associated with obesity and worse metabolic profiles in women with PCOS. However, whether the effects of OSA are independent of obesity remain unclear. As OSA is a treatable condition, research focused on the independent effects of OSA on key clinical outcomes in women with PCOS, including fertility, psychological health, type 2 diabetes, and cardiovascular risk, is lacking and needed. PROSPERO registration number: CRD42016048587. PMID- 29722893 TI - Response to chronic sleep restriction, extension, and subsequent total sleep deprivation in humans: adaptation or preserved sleep homeostasis? AB - Sleep is regulated by a homeostatic process which in the two-process model of human sleep regulation is represented by electroencephalogram slow-wave activity (SWA). Many studies of acute manipulation of wake duration have confirmed the precise homeostatic regulation of SWA in rodents and humans. However, some chronic sleep restriction studies in rodents show that the sleep homeostatic response, as indexed by SWA, is absent or diminishes suggesting adaptation occurs. Here, we investigate the response to 7 days of sleep restriction (6 hr time in bed) and extension (10 hr time in bed) as well as the response to subsequent total sleep deprivation in 35 healthy participants in a cross-over design. The homeostatic response was quantified by analyzing sleep structure and SWA measures. Sleep restriction resulted primarily in a reduction of rapid eye movement (REM) sleep. SWA and accumulated SWA (slow-wave energy, SWE) were not much affected by sleep extension/restriction. The SWA responses did not diminish significantly in the course of the intervention and did not deviate significantly from the predictions of the two-process model. The response to total sleep deprivation consisted of an increase in SWA and rise rate of SWA and SWE and did not differ between the two conditions. The data show that changes in sleep duration within an ecologically relevant range have a marked effect on REM sleep and that SWA responds in accordance with predictions based on a saturating exponential increase during wake and an exponential decline in sleep of homeostatic sleep pressure during both chronic sleep restriction and extension. PMID- 29722896 TI - Cerebrospinal fluid findings in reversible cerebral vasoconstriction syndrome: a way to differentiate from cerebral vasculitis? AB - Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by an acute onset of severe headache and multi-focal segmental vasoconstriction of cerebral arteries resolving within 12 weeks. Diagnostic criteria include normal or near normal findings in cerebrospinal fluid (CSF) analysis, especially leucocyte levels < 10/mm3. Distinguishing RCVS from primary angiitis of the central nervous system (PACNS) is essential to avoid unnecessary and sometimes unfavourable immunosuppressive treatment. We reviewed retrospectively the clinical and diagnostic data of 10 RCVS patients who presented in our neurological department from 1 January 2013 to February 2017. The main purpose was to verify whether CSF leucocyte counts < 10/mm3 serve to discriminate RCVS from PACNS. Five of six patients who underwent lumbar puncture presented with CSF leucocyte levels >= 10/mm3. Two patients had a history of misinterpretation of CSF pleocytosis as cerebral vasculitis and of immunosuppressive treatment. A complete restitution of cerebral vasoconstriction was evident in all. No patient had further cerebral strokes or bleedings without immunosuppressive treatment over more than 12 weeks. Despite the established diagnostic criteria, RCVS can manifest with CSF leucocyte levels > 10/mm3. Careful anamnesis and the response of 'vasculitis-like angiography' to nimodipine given as a test during angiography and as oral medication are key to differentiate RCVS from cerebral vasculitis. PMID- 29722895 TI - Interactions between lipids and proteins are critical for organization of plasma membrane-ordered domains in tobacco BY-2 cells. AB - The laterally heterogeneous plant plasma membrane (PM) is organized into finely controlled specialized areas that include membrane-ordered domains. Recently, the spatial distribution of such domains within the PM has been identified as playing a key role in cell responses to environmental challenges. To examine membrane order at a local level, BY-2 tobacco suspension cell PMs were labelled with an environment-sensitive probe (di-4-ANEPPDHQ). Four experimental models were compared to identify mechanisms and cell components involved in short-term (1 h) maintenance of the ordered domain organization in steady-state cell PMs: modulation of the cytoskeleton or the cell wall integrity of tobacco BY-2 cells; and formation of giant vesicles using either a lipid mixture of tobacco BY-2 cell PMs or the original lipid and protein combinations of the tobacco BY-2 cell PM. Whilst inhibiting phosphorylation or disrupting either the cytoskeleton or the cell wall had no observable effects, we found that lipids and proteins significantly modified both the abundance and spatial distribution of ordered domains. This indicates the involvement of intrinsic membrane components in the local physical state of the plant PM. Our findings support a major role for the 'lipid raft' model, defined as the sterol-dependent ordered assemblies of specific lipids and proteins in plant PM organization. PMID- 29722897 TI - Mucopolysaccharidosis VI and effects on growth of the apical bases: a case report. AB - OBJECTIVE: Mucopolysaccharidosis (MPS) VI is a rare disorder caused by an autosomal recessive mutation in the short arm of chromosome 5 (5q12-13) leading to an N-acetylgalactosamine-sulfatase lysosomal enzyme deficiency and numerous systemic clinical changes. The oral and maxillofacial complex may exhibit tooth eruption anomalies, macroglossia, gingival hypertrophy, mouth breathing, increased lower facial height, open bite, retrognathia, and progressive TMJ arthrosis. This report describes craniofacial growth changes in two MPS VI patients, sisters and daughters of outbred parents, who were longitudinally monitored from 11 to 15 years of age. STUDY DESIGN: Skull lateral teleradiography and cephalometric tracings were performed. The measurements were assessed in the anteroposterior and vertical directions based on protocols by McNamara and Usp/Unicamp and compared to the normal reported ranges. RESULTS: A similar skeletal class III malocclusion was observed in both patients. The jaw was retruded, the anterior skull base decreased, and the mandibular body was normal or larger than normal. The vertical growth direction differed between the patients; one was hyperdivergent, while the other was hypodivergent. CONCLUSIONS: By understanding the craniofacial growth changes in MPS VI patients, new treatment options may be developed for affected patients. PMID- 29722899 TI - Comment on Greenhalgh et al. 2018. PMID- 29722898 TI - LW106, a novel indoleamine 2,3-dioxygenase 1 inhibitor, suppresses tumour progression by limiting stroma-immune crosstalk and cancer stem cell enrichment in tumour micro-environment. AB - BACKGROUND AND PURPOSE: Indoleamine 2,3-dioxygenase 1 (IDO1) is emerging as an important new therapeutic target for treatment of malignant tumours characterized by dysregulated tryptophan metabolism. However, the antitumour efficacy of existing small-molecule inhibitors of IDO1 is still unsatisfactory and the underlying mechanism remains largely undefined. Hence, we discovered a novel potent small-molecule inhibitor of IDO1, LW106, and studied its antitumour effects and the underlying mechanisms in two tumour models. EXPERIMENTAL APPROACH: C57BL6 mice, athymic nude mice or Ido1-/- mice were inoculated with IDO1-expressing and -nonexpressing tumour cells and treated with vehicle, epacadostat or increasing doses of LW106. Xenografted tumours, plasma, spleens and other vital organs were harvested and subjected to kynurenine/tryptophan measurement and flow cytometric, histological and immunohistochemical analyses. KEY RESULTS: LW106 dose-dependently inhibited the outgrowth of xenografted tumours that were inoculated in C57BL6 mice but not nude mice or Ido1-/- mice, showing a stronger antitumour efficacy than epacadostat, an existing IDO1 inhibitor. LW106 substantially elevated intratumoural infiltration of proliferative Teff cells, while reducing recruitment of proliferative Treg cells and non-haematopoietic stromal cells such as endothelial cells and cancer associated fibroblasts. LW106 treatment resulted in a reduced subpopulation of cancer stem cells (CSCs) in xenografted tumours in which fewer proliferative/invasive tumour cells and more apoptotic tumour cells were observed. CONCLUSIONS AND IMPLICATIONS: LW106 inhibits tumour outgrowth by limiting stroma-immune crosstalk and CSC enrichment in the tumour micro environment. LW106 has potential as a immunotherapeutic agent for use in combination with immune checkpoint inhibitors and (or) chemotherapeutic drugs for cancer treatment. PMID- 29722900 TI - Response to Faggion. PMID- 29722901 TI - Organellar phylogenomics inform systematics in the green algal family Hydrodictyaceae (Chlorophyceae) and provide clues to the complex evolutionary history of plastid genomes in the green algal tree of life. AB - PREMISE OF THE STUDY: Phylogenomic analyses across the green algae are resolving relationships at the class, order, and family levels and highlighting dynamic patterns of evolution in organellar genomes. Here we present a within-family phylogenomic study to resolve genera and species relationships in the family Hydrodictyaceae (Chlorophyceae), for which poor resolution in previous phylogenetic studies, along with divergent morphological traits, have precluded taxonomic revisions. METHODS: Complete plastome sequences and mitochondrial protein-coding gene sequences were acquired from representatives of the Hydrodictyaceae using next-generation sequencing methods. Plastomes were characterized, and gene order and content were compared with plastomes spanning the Sphaeropleales. Single-gene and concatenated-gene phylogenetic analyses of plastid and mitochondrial genes were performed. KEY RESULTS: The Hydrodictyaceae contain the largest sphaeroplealean plastomes thus far fully sequenced. Conservation of plastome gene order within Hydrodictyaceae is striking compared with more dynamic patterns revealed across Sphaeropleales. Phylogenetic analyses resolve Hydrodictyon sister to a monophyletic Pediastrum, though the morphologically distinct P. angulosum and P. duplex continue to be polyphyletic. Analyses of plastid data supported the neochloridacean genus Chlorotetraedron as sister to Hydrodictyaceae, while conflicting signal was found in the mitochondrial data. CONCLUSIONS: A phylogenomic approach resolved within-family relationships not obtainable with previous phylogenetic analyses. Denser taxon sampling across Sphaeropleales is necessary to capture patterns in plastome evolution, and further taxa and studies are needed to fully resolve the sister lineage to Hydrodictyaceae and polyphyly of Pediastrum angulosum and P. duplex. PMID- 29722902 TI - Tolerance to high-internalizing delta opioid receptor agonist is critically mediated by arrestin 2. AB - BACKGROUND AND PURPOSE: Opioid delta receptor agonists are potent antihyperalgesics in chronic pain models, but tolerance develops after prolonged use. Previous evidence indicates that distinct forms of tolerance occur depending on the internalization properties of delta receptor agonists. As arrestins are important in receptor internalization, we investigated the role of arrestin 2 (beta-arrestin 1) in mediating the development of tolerance induced by high- and low-internalizing delta receptor agonists. EXPERIMENTAL APPROACH: We evaluated the effect of two delta receptor agonists with similar analgesic potencies, but either high-(SNC80) or low-(ARM390) internalization properties in wild-type (WT) and arrestin 2 knockout (KO) mice. We compared tolerance to the antihyperalgesic effects of these compounds in a model of inflammatory pain. We also examined tolerance to the convulsant effect of SNC80. Furthermore, effect of chronic treatment with SNC80 on delta agonist-stimulated [35 S]-GTPgammaS binding was determined in WT and KO mice. KEY RESULTS: Arrestin 2 KO resulted in increased drug potency, duration of action and decreased acute tolerance to the antihyperalgesic effects of SNC80. In contrast, ARM390 produced similar effects in both WT and KO animals. Following chronic treatment, we found a marked decrease in the extent of tolerance to SNC80-induced antihyperalgesia and convulsions in arrestin 2 KO mice. Accordingly, delta receptors remained functionally coupled to G proteins in arrestin 2 KO mice chronically treated with SNC80. CONCLUSIONS AND IMPLICATIONS: Overall, these results suggest that delta receptor agonists interact with arrestins in a ligand-specific manner, and tolerance to high- but not low-internalizing agonists are preferentially regulated by arrestin 2. PMID- 29722903 TI - Advanced maxillofacial imaging for temporomandibular disorder in special needs patients. AB - Temporomandibular disorder (TMD) is prevalent in special needs patients. Clinical examination of the temporomandibular joint (TMJ) complex and imaging in this patient population can be challenging due to patient disposition and cooperation. We report a case of a 29-year-old male with neurologic and behavioral special needs who required advanced maxillofacial imaging for a suspected TMD under general anesthesia, which has not been reported previously. This article intends to serve as a resource for health care providers who may encounter similar clinical situations. PMID- 29722905 TI - Influence of biological factors on hematological and serum biochemistry values in captive Adelie, Chinstrap, Gentoo, and Macaroni penguins in Pingtung, Taiwan. AB - Hematology and serum biochemistry reference values are essential for health evaluation and disease diagnosis in penguins. However, there are currently no published physiological values for captive Adelie (Pygoscelis adeliae) and Chinstrap penguins (P. antarcticus), nor for wild or captive Macaroni penguins (Eudyptes chrysolophus). The present study is the first investigation regarding hematology and serum biochemistry reference values for captive Adelie, Gentoo (P. papua), Chinstrap, and Macaroni penguins in Asia. Fixed effect models for repeated measure were applied to determine the influence of penguin species, age, gender, and age-gender interaction on each blood parameter. Hematology and serum biochemical data from 122 apparently healthy penguins (24 Adelie, 38 Chinstrap, 46 Gentoo, and 14 Macaroni) were collected between 2009 and 2014. The effects of penguin species were observed for most blood parameters, except total bilirubin, creatine kinase (CK), creatinine, and potassium ion (K+ ). Values of mean corpuscular volume, mean corpuscular hemoglobin (MCH), heterophil, ratio of heterophils to lymphocytes (H/L), alanine aminotransferase (ALT), and chloride ion (Cl- ) had significant positive correlation with age, while significant negative correlation with age was observed in total red blood cells (RBCs), lymphocytes, thrombocytes, alkaline phosphatase (ALP), CK, lactate dehydrogenase (LDH), and plasma iron. Compared to male penguins, females had lower mean corpuscular hemoglobin concentration (MCHC) and blood urea nitrogen (BUN) but higher calcium ion (Ca2+ ) values. As for age-gender interaction, significant positive correlation was shown in MCHC and K+ , and the reverse was true in H/L ratio. PMID- 29722907 TI - Use of somatic cell banks in the conservation of wild felids. AB - The conservation of biological resources is an interesting strategy for the maintenance of biodiversity, especially for wild felids who are constantly threatened with extinction. For this purpose, cryopreservation techniques have been used for the long-term storage of gametes, embryos, gonadal tissues, and somatic cells and tissues. The establishment of these banks has been suggested as a practical approach to the preservation of species and, when done in tandem with assisted reproductive techniques, could provide the means for reproducing endangered species. Somatic cell banks have been shown remarkable for the conservation of genetic material of felids; by merely obtaining skin samples, it is possible to sample a large group of individuals without being limited by factors such as gender or age. Thus, techniques for somatic tissue recovery, cryopreservation, and in vitro culture of different wild felids have been developed, resulting in a viable method for the conservation of species. One of the most notable conservation programs for wild felines using somatic samples was the one carried out for the Iberian lynx, the most endangered feline in the world. Other wild felids have also been studied in other continents, such as the jaguar in South America. This review aims to present the technical progress achieved in the conservation of somatic cells and tissues in different wild felids, as well address the progress that has been achieved in a few species. PMID- 29722906 TI - Manikin study showed that counting inflation breaths out loud improved the speed of resuming chest compressions during two-person paediatric cardiopulmonary resuscitation. AB - AIM: We investigated whether counting inflation breaths out loud during cardiopulmonary resuscitation (CPR) led to an earlier resumption of chest compressions. METHODS: In this randomised controlled manikin simulation study, conducted from February 2015 to April 2015, 32 fourth-year Korean medical students, equally divided into study and control groups, performed 10 cycles of 15:2 CPR while administering inflation breaths using a bag mask. The first study participant counted the number of inflation breaths out loud, and the second study participant was told to perform chest compressions as soon as they heard their colleague say two. The control group did not count out loud. The groups were blinded to the study outcomes and put in separate rooms. RESULTS: The median chest compression interruption time was shorter in the study group than the control group (40 vs 46 seconds, p < 0.01, r = 0.70), and the median chest compression fraction (CCF) was higher (68 vs 62%, p < 0.01, r = 0.71). Other quality outcomes related chest compressions and ventilation did not differ between the groups. CONCLUSION: Counting the number of inflation breaths out loud was a simple method that improved the speed of resuming chest compressions and increased CCFs in 15:2 CPR. PMID- 29722908 TI - Multiple Hydrogen-Bond Activation in Asymmetric Bronsted Acid Catalysis. AB - An efficient protocol for the asymmetric synthesis of chiral tetrahydroquinolines bearing multiple stereogenic centers by means of asymmetric Bronsted acid catalysis was developed. A chiral 1,1'-spirobiindane-7,7'-diol (SPINOL)-based N triflylphosphoramide (NTPA) proved to be an effective Bronsted acid catalyst for the in situ generation of aza-ortho-quinone methides (aza-o-QMs) and their subsequent cycloaddition reaction with unactivated alkenes to provide the products with excellent diastereo- and enantioselectivities. In addition, DFT calculations provided insight into the activation mode and nature of the interactions between the N-triflylphosphoramide catalyst and the generated aza-o QMs. PMID- 29722904 TI - Renal complications of lipodystrophy: A closer look at the natural history of kidney disease. AB - OBJECTIVES: Lipodystrophy syndromes are a group of heterogeneous disorders characterized by adipose tissue loss. Proteinuria is a remarkable finding in previous reports. STUDY DESIGN: In this multicentre study, prospective follow-up data were collected from 103 subjects with non-HIV-associated lipodystrophy registered in the Turkish Lipodystrophy Study Group database to study renal complications in treatment naive patients with lipodystrophy. METHODS: Main outcome measures included ascertainment of chronic kidney disease (CKD) by studying the level of proteinuria and the estimated glomerular filtration rate (eGFR). Kidney volume was measured. Percutaneous renal biopsies were performed in 9 patients. RESULTS: Seventeen of 37 patients with generalized and 29 of 66 patients with partial lipodystrophy had CKD characterized by proteinuria, of those 12 progressed to renal failure subsequently. The onset of renal complications was significantly earlier in patients with generalized lipodystrophy. Patients with CKD were older and more insulin resistant and had worse metabolic control. Increased kidney volume was associated with poor metabolic control and suppressed leptin levels. Renal biopsies revealed thickening of glomerular basal membranes, mesangial matrix abnormalities, podocyte injury, focal segmental sclerosis, ischaemic changes and tubular abnormalities at various levels. Lipid vacuoles were visualized in electron microscopy images. CONCLUSIONS: CKD is conspicuously frequent in patients with lipodystrophy which has an early onset. Renal involvement appears multifactorial. While poorly controlled diabetes caused by severe insulin resistance may drive the disease in some cases, inherent underlying genetic defects may also lead to cell autonomous mechanisms contributory to the pathogenesis of kidney disease. PMID- 29722910 TI - Glycemic Management in the Bariatric Surgery Population: A Review of the Literature. AB - Obesity is a worldwide epidemic often complicated by multiple comorbidities, including type 2 diabetes mellitus (T2DM). Bariatric surgery is an increasingly common and effective weight-loss strategy for obese patients that may result in resolution of metabolic-related disease states, such as T2DM. Although bariatric surgery has many positive outcomes for patients, dietary and pathophysiologic changes can create difficult-to-control blood glucose, especially in the immediate perioperative setting. Depending on oral antidiabetic agent and insulin needs preoperatively, many patients require cessation of oral agents and reduction or cessation of insulin. Unfortunately, despite available perioperative bariatric surgery guidelines, no specific recommendations for perioperative oral antidiabetic agent or insulin management exist. The purpose of this article is to review the current body of evidence for blood glucose management in the setting of bariatric surgery. An English-language PubMed and MEDLINE search was conducted from 1964 through March 2018 using the following search terms alone and in various combinations: bariatric surgery, gastric banding, laparoscopic sleeve gastrectomy (LSG), Roux-en-Y gastric bypass (RYGB), glucose management, insulin, and oral antidiabetic agent. Five articles were identified evaluating insulin management in the perioperative bariatric surgery setting, which were separated into two categories: immediate perioperative insulin management and long-term postoperative insulin management. Overall, various blood glucose management insulin protocols were evaluated. All studies included some type of insulin reduction in the perioperative setting. No studies identified specifically evaluated down-titration or discontinuation of oral antidiabetic agents. Given the lack of specific guideline recommendations, limitations of standardized insulin protocols, and inconsistency of outcomes studied, perioperative insulin at reduced doses compared to previous maintenance doses coupled with frequent blood glucose monitoring is reasonable. An opportunity exists for successful protocols to be addressed in future, larger studies. PMID- 29722909 TI - Atypical Antipsychotic Exposure May Not Differentiate Metabolic Phenotypes of Patients with Schizophrenia. AB - STUDY OBJECTIVE: Patients with schizophrenia are known to have higher rates of metabolic disease than the general population. Contributing factors likely include lifestyle and atypical antipsychotic (AAP) use, but the underlying mechanisms are unknown. The objective of this study was to identify metabolomic variability in adult patients with schizophrenia who were taking AAPs and grouped by fasting insulin concentration, our surrogate marker for metabolic risk. DESIGN: Metabolomics analysis PARTICIPANTS: Ninety-four adult patients with schizophrenia who were taking an AAP for at least 6 months, with no changes in their antipsychotic regimen for the previous 8 weeks, and who did not require treatment with insulin, participated in the study. Twenty age- and sex-matched nonobese (10 subjects) and obese (10 subjects) controls without cardiovascular disease or mental health diagnoses were used to match the body mass index (BMI) range of the patients with schizophrenia to account for metabolite concentration differences attributable to BMI. MEASUREMENTS AND MAIN RESULTS: Existing serum samples were used to identify aqueous metabolites (to differentiate fasting insulin concentration quartiles) and fatty acids with quantitative nuclear magnetic resonance and gas chromatography methods, respectively. To exclude metabolites from our pathway mapping analysis that were due to variability in weight, we also subjected serum samples from the nonobese and obese controls to the same analyses. Patients with schizophrenia had a median age of 47.0 years (interquartile range 41.0-52.0 years). Using a false discovery rate threshold of less than 25%, 10 metabolites, not attributable to weight, differentiated insulin concentration quartiles in patients with schizophrenia and identified variability in one-carbon metabolism between groups. Patients with higher fasting insulin concentrations (quartiles 3 and 4) also trended toward higher levels of saturated fatty acids compared with patients with lower fasting insulin concentrations (quartiles 1 and 2). CONCLUSION: Our results illustrate the utility of metabolomics to identify pathways underlying variable fasting insulin concentration in patients with schizophrenia. Importantly, no significant difference in AAP exposure was observed among groups, suggesting that current antipsychotic use may not be a primary factor that differentiates middle-aged adult patients with schizophrenia by fasting insulin concentration. PMID- 29722911 TI - Behavioral responses of three lemur species to different food enrichment devices. AB - Environmental enrichment is a tool used to promote the welfare and well-being of captive animals by encouraging the display of species-specific behaviors and reducing the stress or boredom induced by captive environments. Lemurs are highly endangered, yet few studies have analyzed the behavioral impacts of enrichment on captive populations. We studied the impacts of two novel enrichment devices on three lemur species (ring-tailed lemurs [Lemur catta], red-ruffed lemurs [Varecia rubra], and Coquerel's sifaka [Propithecus coquereli]) to determine both the overall and species-specific impacts of enrichment on lemur behavior. We recorded lemur behavior using the continuous sampling method to obtain behavior duration and analyzed our results using ANOVA Repeated Measures. Results showed enrichment effectiveness differed for each species and that different enrichment devices had varying impacts on lemur behavior across all species. We attributed the differences in species-specific responses to the unique locomotor patterns and methods of diet acquisition of each species, and the variances in behavioral responses across all species to the characteristics of each device. Our study highlights the importance of species-specific enrichment and encourages further research in this field in order to maximize the positive effects of enrichment, which in turn has the potential to affect the overall well-being of captive populations. PMID- 29722912 TI - Region-specific deletions of the glutamate transporter GLT1 differentially affect nerve injury-induced neuropathic pain in mice. AB - Glutamate is a major excitatory neurotransmitter and plays an important role in neuropathic pain, which is frequently caused by nerve damage. According to recent studies, nerve injury induces changes in glutamatergic transmission in the spinal cord and several supraspinal regions, including the periaqueductal gray (PAG). Among glutamate signaling components, accumulating evidence suggests that the glial glutamate transporter GLT1 plays a critical role in neuropathic pain. Indeed, GLT1 expression is reduced in the spinal cord but increased in the PAG after nerve injury, suggesting that the role of GLT1 in neuropathic pain may vary according to the brain region. In this study, we generated PAG-specific and spinal cord-specific GLT1 knockout mice. Nerve injury-induced neuropathic pain was enhanced in spinal cord-specific GLT1 knockout mice but alleviated in PAG specific GLT1 knockout mice. Thus, nerve injury may enhance glutamatergic neurotransmission from primary sensory neurons to the post-synaptic dorsal horn following downregulation of GLT1 in the spinal cord and result in inadequate descending pain inhibition caused by GLT1 upregulation in the PAG, resulting in neuropathic pain. In addition, ceftriaxone upregulated GLT1 expression in the spinal cord, but not the PAG, of control mice and attenuated tactile hypersensitivity in nerve-injured control mice but not in nerve-injured spinal cord-specific GLT1 knockout mice. Based on these results, the anti-neuropathic pain effect of ceftriaxone is mediated by the upregulation of GLT1 expression in the spinal cord. Thus, selective upregulation of spinal GLT1 and/or downregulation of GLT1 in the PAG represents a potentially novel strategy for the treatment of neuropathic pain. PMID- 29722915 TI - The global regulator of pathogenesis PnCon7 positively regulates Tox3 effector gene expression through direct interaction in the wheat pathogen Parastagonospora nodorum. AB - To investigate effector gene regulation in the wheat pathogenic fungus Parastagonospora nodorum, the promoter and expression of Tox3 was characterised through a series of complementary approaches. Promoter deletion and DNase I footprinting experiments identified a 25 bp region in the Tox3 promoter as being required for transcription. Subsequent yeast one-hybrid analysis using the DNA sequence as bait identified that interacting partner as the C2H2 zinc finger transcription factor PnCon7, a putative master regulator of pathogenesis. Silencing of PnCon7 resulted in the down-regulation of Tox3 demonstrating that the transcription factor has a positive regulatory role on gene expression. Analysis of Tox3 expression in the PnCon7 silenced strains revealed a strong correlation with PnCon7 transcript levels, supportive of a direct regulatory role. Subsequent pathogenicity assays using PnCon7-silenced isolates revealed that the transcription factor was required for Tox3-mediated disease. The expression of two other necrotrophic effectors (ToxA and Tox1) was also affected but in a non-dose dependent manner suggesting that the regulatory role of PnCon7 on these genes was indirect. Collectively, these data have advanced our fundamental understanding of the Con7 master regulator of pathogenesis by demonstrating its positive regulatory role on the Tox3 effector in P. nodorum through direct interaction. PMID- 29722914 TI - Dissecting the conformational determinants of chitosan and chitlac oligomers. AB - Chitosan and its highly hydrophilic 1-deoxy-lactit-1-yl derivative (Chitlac) are polysaccharides with increasing biomedical applications. Aimed to unravel their conformational properties we have performed a series of molecular dynamics simulations of Chitosan/Chitlac decamers, exploring different degrees of substitution (DS) of lactitol side chains. At low DS, two conformational regions with different populations are visited, while for DS >= 20% the oligomers remain mostly linear and only one main region of the glycosidic angles is sampled. These conformers are (locally) characterized by extended helical "propensities". Helical conformations 32 and 21, by far the most abundant, only develop in the main region. The accessible conformational space is clearly enlarged at high ionic strength, evidencing also a new region accessible to the glycosidic angles, with short and frequent interchange between regions. Simulations of neutral decamers share these features, pointing to a central role of electrostatic repulsion between charged moieties. These interactions seem to determine the conformational behavior of the chitosan backbone, with no evident influence of H bond interactions. Finally, it is also shown that increasing temperature only slightly enlarges the available conformational space, but certainly without signs of a temperature-induced conformational transition. PMID- 29722913 TI - The TSC1-mTOR-PLK axis regulates the homeostatic switch from Schwann cell proliferation to myelination in a stage-specific manner. AB - Proper peripheral myelination depends upon the balance between Schwann cell proliferation and differentiation programs. The serine/threonine kinase mTOR integrates various environmental cues to serve as a central regulator of cell growth, metabolism, and function. We report here that tuberous sclerosis complex 1 (TSC1), a negative regulator of mTOR activity, establishes a stage-dependent program for Schwann cell lineage progression and myelination by controlling cell proliferation and myelin homeostasis. Tsc1 ablation in Schwann cell progenitors in mice resulted in activation of mTOR signaling, and caused over-proliferation of Schwann cells and blocked their differentiation, leading to hypomyelination. Transcriptome profiling analysis revealed that mTOR activation in Tsc1 mutants resulted in upregulation of a polo-like kinase (PLK)-dependent pathway and cell cycle regulators. Attenuation of mTOR or pharmacological inhibition of polo-like kinases partially rescued hypomyelination caused by Tsc1 loss in the developing peripheral nerves. In contrast, deletion of Tsc1 in mature Schwann cells led to redundant and overgrown myelin sheaths in adult mice. Together, our findings indicate stage-specific functions for the TSC1-mTOR-PLK signaling axis in controlling the transition from proliferation to differentiation and myelin homeostasis during Schwann cell development. PMID- 29722916 TI - A Robust, Self-Healable, and Shape Memory Supramolecular Hydrogel by Multiple Hydrogen Bonding Interactions. AB - A versatile double-network (DN) hydrogel with two noncovalent crosslinked networks is synthesized by multiple hydrogen bonding (H-bonding) interactions. The DN hydrogels are synthesized via a heating-cooling photopolymerization process by adding all reactants of agar, N-acryloyl glycinamide (NAGA) and N benzylacrylamide (NBAA) monomers, UV initiators to a single water pot. Poly(N acryloyl glycinamide-co-N-benzyl acrylamide) (P(NAGA-co-NBAA)) with a triple amide in one side group is synthesized via UV-light polymerization between NAGA and NBAA, forming a strong intermolecular H-bonding network. Meanwhile, the intramolecular H-bonding network is formed between P(NAGA-co-NBAA) and agars. The sol-gel phase transition of agars at 86 degrees C generates the molecular entanglement network. Such a double network enables the hydrogel high self healing efficiency (about 95%), good shape memory ability, and high mechanical strength (1.1 MPa). Additionally, the DN hydrogel is completely crosslinked by multiple hydrogen bonds (H-bonds) and the physical crosslinking of agar without extra potential toxic chemical crosslinker. The DN hydrogels find extensive applications in the biomedical materials due to their excellent biocompatibility. PMID- 29722917 TI - PATHOGENIC VARIANTS IN THE ABCC6 GENE ARE ASSOCIATED WITH AN INCREASED RISK FOR ISCHEMIC STROKE. AB - Ischemic stroke causes a high mortality and morbidity worldwide. It results from a complex interplay of incompletely known environmental and genetic risk factors. We investigated the ABCC6 gene as a candidate risk factor for ischemic stroke because of the increased ischemic stroke incidence in the autosomal recessive disorder pseudoxanthoma elasticum, caused by biallelic pathogenic ABCC6 variants, the higher cardiovascular risk in heterozygous carriers and the established role of ABCC6 dysfunction in myocardial ischemia. We established segregation of a known pathogenic ABCC6 variant (p.(Arg1314Gln)) in 11/19 family members of an ischemic stroke patient in a large multigenerational family suffering from ischemic stroke and/or cardiovascular disease at a relatively young age. In an independent case-control study in 424 ischemic stroke patients and 250 healthy controls, pathogenic ABCC6 variants were 4.9 times more frequent (p = 0.036; 95% confidence interval 1.11-21.33) in the ischemic stroke patient cohort. To study cellular consequences of ABCC6 deficiency in the brain, immunostaining of brain sections in Abcc6-deficient mice and wildtype controls were performed. An upregulation of Bmp4 and Eng and a downregulation of Alk2 was identified in Abcc6 /- mice, suggesting an increase in apoptosis and angiogenesis. As both of these processes are induced in ischemia, we propose that a pro-ischemic state may explain the higher risk to suffer from ischemic stroke in patients carrying a pathogenic ABCC6 variant, as this may lower the threshold to develop acute ischemic events in these patients. In conclusion, this study identified heterozygous ABCC6 variants as a risk factor for ischemic stroke. Further, dysregulation of Bmp (Bmp4, Alk2) and Tgfbeta (Eng) signaling in the brain of Abcc6-/- mice could lead to a pro-ischemic state, lowering the threshold to develop acute ischemic events. These data demonstrate the importance of a molecular analysis of the ABCC6 gene in patients diagnosed with cryptogenic ischemic stroke. This article is protected by copyright. All rights reserved. PMID- 29722918 TI - Functionalization of Bambusurils by a Thiol-Ene Click Reaction and a Facile Method for the Preparation of Anion-Free Bambus[6]urils. AB - Sulfide-functionalized bambus[4]urils ((RS)8 BU[4]) and bambus[6]urils ((RS)12 BU[6]) were synthesized through thiol-ene click coupling reactions (TEC) of allylbambus[n]urils. Thiosugars were grafted to BU[4] and BU[6]. Synthesis of BU[6] derivatives always requires the use of a template anion (iodide, chloride, or bromide), which is enclosed in the cavity of BU[6]. We show that this anion influences the reactivity of bambus[6]urils. An encapsulated iodide makes allyl functions of allyl12 BU[6] less reactive towards TEC and hydrogenation reactions in comparison to the corresponding chloride or bromide inclusion complexes. This is critical for the chemical reactivity of BU[6] and even more to determine their anion-binding properties. We report a new, facile and fast method using AgSbF6 to prepare anion-free BU[6]. NMR spectroscopic methods were used to estimate association constants of these new empty BU[6] with different anions. Quantum chemical calculations were employed to rationalize the observed results. These new functionalized bambusuril scaffolds in alternate conformations could find applications as multivalent binders. PMID- 29722919 TI - Computer-assisted cognitive behavioural therapy: The experiences of adults who have an intellectual disability and anxiety or depression. AB - BACKGROUND: Despite its evidence base in the general population, computerized cognitive behavioural therapy (cCBT) has not yet been adapted for use with people with intellectual disability. This study aimed to explore the experiences of adults with an intellectual disability who played a cCBT program. METHOD: Twenty four adults (with a mild or moderate intellectual disability and clinically significant anxiety or depression) who were in the treatment arm of a pilot randomized controlled trial evaluating the cCBT program were individually interviewed. Thematic analysis was used to analyse and report themes within the data. RESULTS: Participants found playing the program to be an enjoyable and novel experience and that it was challenging and helpful. It allowed them to develop and reflect on relationships and increased their awareness of thoughts, feelings and behaviours. CONCLUSIONS: Combining technology with CBT is an effective way to reduce barriers to accessing mental health interventions and technology for this population. PMID- 29722921 TI - Beta-2 transferrin is detectable for 14 days whether refrigerated or stored at room temperature. AB - BACKGROUND: The effect of time and temperature on beta-2 transferrin stability in cerebrospinal fluid (CSF) is not well established. After collecting nasal CSF for testing, beta-2 transferrin has been found to be stable and detectable for 1 week, whether being refrigerated or stored at room temperature. The purpose of this study was to determine if beta-2 transferrin remained detectable longer than 1 week and whether refrigeration improved its detectability. METHODS: In patients undergoing therapeutic CSF diversion, 2-mL CSF samples were collected from 18 patients. The samples were divided and stored either at room temperature, or at 4 degrees C, and tested for beta-2 transferrin at 7 and 14 days. CSF was collected from external ventricular drains (EVDs) (n = 15), lumbar drains (n = 2), and subdural drains (n = 1). RESULTS: Of the 18 CSF samples originally testing positive for beta-2 transferrin, none turned negative at 7 or 14 days, in both the refrigerated and room temperature groups (95% confidence interval [CI], 0% to 18.5%). CONCLUSION: Beta-2 transferrin remained detectable for 14 days in all CSF samples, regardless of being stored at 4 degrees C or room temperature. PMID- 29722920 TI - Prognostic relevance and performance characteristics of serum IGFBP-2 and PAPP-A in women with breast cancer: a long-term Danish cohort study. AB - Measurement of circulating insulin-like growth factors (IGFs), in particular IGF binding protein (IGFBP)-2, at the time of diagnosis, is independently prognostic in many cancers, but its clinical performance against other routinely determined prognosticators has not been examined. We measured IGF-I, IGF-II, pro-IGF-II, IGF bioactivity, IGFBP-2, -3, and pregnancy-associated plasma protein A (PAPP-A), an IGFBP regulator, in baseline samples of 301 women with breast cancer treated on four protocols (Odense, Denmark: 1993-1998). We evaluated performance characteristics (expressed as area under the curve, AUC) using Cox regression models to derive hazard ratios (HR) with 95% confidence intervals (CIs) for 10 year recurrence-free survival (RFS) and overall survival (OS), and compared those against the clinically used Nottingham Prognostic Index (NPI). We measured the same biomarkers in 531 noncancer individuals to assess multidimensional relationships (MDR), and evaluated additional prognostic models using survival artificial neural network (SANN) and survival support vector machines (SSVM), as these enhance capture of MDRs. For RFS, increasing concentrations of circulating IGFBP-2 and PAPP-A were independently prognostic [HRbiomarker doubling : 1.474 (95% CIs: 1.160, 1.875, P = 0.002) and 1.952 (95% CIs: 1.364, 2.792, P < 0.001), respectively]. The AUCRFS for NPI was 0.626 (Cox model), improving to 0.694 (P = 0.012) with the addition of IGFBP-2 plus PAPP-A. Derived AUCRFS using SANN and SSVM did not perform superiorly. Similar patterns were observed for OS. These findings illustrate an important principle in biomarker qualification-measured circulating biomarkers may demonstrate independent prognostication, but this does not necessarily translate into substantial improvement in clinical performance. PMID- 29722922 TI - Predictive value of SNOT-22 on additional opiate prescriptions after endoscopic sinus surgery. AB - BACKGROUND: Endoscopic sinus surgery (ESS) is generally well tolerated, yet a subset of patients require an additional opiate prescription in the postoperative period. The purpose of this study was to quantify differences in both preoperative and immediate postoperative 22-item Sino-Nasal Outcome Test (SNOT 22) scores between patients with a single prescription and those requiring additional opiate prescriptions (AOPs). METHODS: Patients undergoing ESS between November 2016 and August 2017 were reviewed retrospectively. The Medical and Controlled Substance Utilization Review and Evaluation System (CURES) records were reviewed; patients requiring AOP within 60 days after surgery were identified. The primary and secondary outcomes of interest were the association of baseline and first postoperative visit SNOT-22 total and domain scores with AOP. RESULTS: A total of 121 patients were reviewed, 22 (18.2%) required AOP. Baseline SNOT-22 scores were higher in aggregate (58.7 +/- 16.0 vs 46.1 +/- 22.5) and ear/facial domain (11.4 +/- 4.8 vs 8.5 +/- 5.4) in the AOP group (p < 0.01). AOP patients also demonstrated higher scores across all SNOT-22 domains (p < 0.001) at the immediate preoperative visit. There was no difference in the absolute improvement between groups (15.5 +/- 18.30 vs 12.3 +/- 23.9, p = 0.54). AOP patients experienced less relative improvement (20.2% vs 34.8%, p < 0.05) and smaller mean effect size (0.57 vs 0.70, p < 0.001) after ESS. CONCLUSION: Patients reporting increased ear and facial symptoms at baseline have an increased risk of additional opiate prescription after surgery; preoperative SNOT 22 scores may provide utility in identifying these patients. Subjects in both cohorts report symptomatic improvement after ESS; however, relative, not absolute, improvement in SNOT-22 scores is more predictive of AOP. PMID- 29722923 TI - Enriched Environment and Effects on Neuropathic Pain: Experimental Findings and Mechanisms. AB - Neuropathic pain inflicts tremendous biopsychosocial suffering for patients worldwide. However, safe and effective treatment of neuropathic pain is a prominent unmet clinical need. Environmental enrichment (EE) is an emerging cost effective nonpharmacological approach to alleviate neuropathic pain and complement rehabilitation care. We present here a review of preclinical studies in ascertaining the efficacy of EE for neuropathic pain. Their proposed mechanisms, including the suppression of ascending nociceptive signaling to the brain, enhancement of the descending inhibitory system, and neuroprotection of the peripheral and central nervous systems, may collectively reduce pain perception and improve somatic and emotional functioning in neuropathic pain. The current evidence offers critical insights for future preclinical research and the translational application of EE in clinical pain management. PMID- 29722924 TI - Structural Basis of Outstanding Multivalent Effects in Jack Bean alpha Mannosidase Inhibition. AB - Multivalent design of glycosidase inhibitors is a promising strategy for the treatment of diseases involving enzymatic hydrolysis of glycosidic bonds in carbohydrates. An essential prerequisite for successful applications is the atomic-level understanding of how outstanding binding enhancement occurs with multivalent inhibitors. Herein we report the first high-resolution crystal structures of the Jack bean alpha-mannosidase (JBalpha-man) in apo and inhibited states. The three-dimensional structure of JBalpha-man in complex with the multimeric cyclopeptoid-based inhibitor displaying the largest binding enhancements reported so far provides decisive insight into the molecular mechanisms underlying multivalent effects in glycosidase inhibition. PMID- 29722925 TI - Molecular Dynamics, Phase Transition and Frequency-Tuned Dielectric Switch of an Ionic Co-Crystal. AB - Dielectric switches that can be converted between high and low dielectric states by thermal stimuli have attracted much interest owing to their many potential applications. Currently one main drawback for practical application lies in the non-tunability of their switch temperatures (TS ). We report here an ionic co crystal (Me3 NH)4 [Ni(NCS)6 ] that contains a multiply rotatable Me3 NH+ ion and a solely rotatable one due to a more spacious supramolecular cage for the former one. This compound undergoes an isostructural order-disorder phase transition and it can function as a frequency-tuned dielectric switch with highly adjustable TS , which is further revealed by the variable-temperature structure analyses and molecular dynamics simulations. In addition, the distinct arrangements and molecular dynamics of two coexisting Me3 NH+ ions confined in different lattice spaces as well as the notable offset effect on the promoting/hindering of dipolar reorientation after dielectric transition provide a rarely observed but fairly good model for understanding and modulating the dipole motion in crystalline environment. PMID- 29722927 TI - NF-kappaB signaling mechanisms in HTLV-1-induced adult T-cell leukemia/lymphoma. AB - The human T-cell leukemia virus type 1 (HTLV-1) is a complex deltaretrovirus linked to adult T-cell leukemia/lymphoma (ATLL), a fatal CD4 + malignancy in 3 5% of infected individuals. The HTLV-1 Tax regulatory protein plays indispensable roles in regulating viral gene expression and activating cellular signaling pathways that drive the proliferation and clonal expansion of T cells bearing HTLV-1 proviral integrations. Tax is a potent activator of NF-kappaB, a key signaling pathway that is essential for the survival and proliferation of HTLV-1 infected T cells. However, constitutive NF-kappaB activation by Tax also triggers a senescence response, suggesting the possibility that only T cells capable of overcoming NF-kappaB-induced senescence can selectively undergo clonal expansion after HTLV-1 infection. Tax expression is often silenced in the majority of ATLL due to genetic alterations in the tax gene or DNA hypermethylation of the 5'-LTR. Despite the loss of Tax, NF-kappaB activation remains persistently activated in ATLL due to somatic mutations in genes in the T/B-cell receptor (T/BCR) and NF kappaB signaling pathways. In this review, we focus on the key events driving Tax dependent and -independent mechanisms of NF-kappaB activation during the multistep process leading to ATLL. PMID- 29722928 TI - Letter from Australia. PMID- 29722926 TI - A Minimal Functional Complex of Cytochrome P450 and FBD of Cytochrome P450 Reductase in Nanodiscs. AB - Structural interactions that enable electron transfer to cytochrome-P450 (CYP450) from its redox partner CYP450-reductase (CPR) are a vital prerequisite for its catalytic mechanism. The first structural model for the membrane-bound functional complex to reveal interactions between the full-length CYP450 and a minimal domain of CPR is now reported. The results suggest that anchorage of the proteins in a lipid bilayer is a minimal requirement for CYP450 catalytic function. Akin to cytochrome-b5 (cyt-b5 ), Arg 125 on the C-helix of CYP450s is found to be important for effective electron transfer, thus supporting the competitive behavior of redox partners for CYP450s. A general approach is presented to study protein-protein interactions combining the use of nanodiscs with NMR spectroscopy and SAXS. Linking structural details to the mechanism will help unravel the xenobiotic metabolism of diverse microsomal CYP450s in their native environment and facilitate the design of new drug entities. PMID- 29722929 TI - Metal-Free Acetylene Coupling by the (C6 F5 )2 B-X 1,2-Halogenoboration Reaction. AB - (C6 F5 )2 B-halides were conveniently prepared by treatment of (C6 F5 )2 BH with tritylchloride or -bromide, respectively. With cyclopropylacetylene, (C6 F5 )2 BBr underwent sequential cis-1,2-halogenoboration followed by 1,2-carboboration to give the 4-bromo-2,4-dicyclopropylbutadienyl-B(C6 F5 )2 product. It reacted further with additional cyclopropylacetylene to give the linear triene and tetraene products in a metal-free alkyne oligomerization reaction. The pyridine adduct of the initial diene product was characterized by X-ray diffraction. (C6 F5 )2 BCl reacted analogously. Similar (C6 F5 )2 BX induced oligomerization reactions were carried out with two conjugated enynes. PMID- 29722930 TI - Septins regulate the equatorial dynamics of the separation initiation network kinase Sid2p and glucan synthases to ensure proper cytokinesis. AB - Septins generally function as scaffolds and as cortical barriers to restrict the diffusion of membrane proteins. In the fission yeast Schizosaccharomyces pombe, septins form a ring structure at the septum after spindle breakdown during the constriction of the contractile actomyosin ring (CAR) and serve as a scaffold to recruit glucanases to mediate ultimate daughter cell separation. Despite this, it remains unclear if septins play any significant roles before the cell separation during cytokinesis. Employing live cell microscopy, we carefully examined SIN (Septation Initiation Network) signaling and glucan synthases, two key factors ensuring proper function of the CAR. In the absence of the core septin component Spn1p, the formation of a compact CAR is advanced and the CAR constriction rate is slightly but significantly decreased. Moreover, the SIN kinase Sid2p and the glucan synthases Bgs1p and Ags1p form an equatorial ring quite prematurely, but their maintenance at the equatorial region is diminished spn1Delta cells. These findings suggest that septins act as key players in an accurate establishment and the maintenance of CAR by orchestrating the equatorial dynamics of Sid2p and glucan synthases. Hence, this work demonstrates that, in addition to their function during ultimate cell septation, septins have important roles in regulating earlier cytokinetic events, including CAR assembly and constriction, SIN signaling, and the cortical dynamics of the glucan synthases. PMID- 29722933 TI - May 2018. PMID- 29722934 TI - Advances in Multi-Scale Pores and Channels Systems. PMID- 29722931 TI - PEP06 polypeptide 30 exerts antitumour effect in colorectal carcinoma via inhibiting epithelial-mesenchymal transition. AB - BACKGROUND AND PURPOSE: PEP06, a polypeptide modified from endostatin, was investigated for its antitumour effects on colorectal cancer (CRC) and the possible mechanisms of this antitumour activity were examined in in vitro and in vivo models. EXPERIMENTAL APPROACH: After PEP06 treatment, cell proliferation and migration assays were performed in CRC cells. Epithelial-mesenchymal transition (EMT) progression was determined by Western blotting, immunofluorescent staining and immunohistochemistry in vitro and in a residual xenograft model. MiRNAs regulated by PEP06 were identified by miRNA microarray and verified by in situ hybridization and quantitative real-time PCR. The interactions between PEP06 and integrin alphavbeta3 were determined with Biacore SA biochips. The cellular function of miR-146b-5p was validated by gain-of-function and loss-of-function approaches. A mouse model of lung metastasis was used to determine the effect of PEP06 on metastatic growth. KEY RESULTS: PEP06 did not affect cell viability but reduced migration and EMT in SW620 and HCT116 cells. PEP06 significantly repressed the expression of miR-146b-5p in these two cell lines through binding to integrin alphavbeta3. MiR-146b-5p was shown to increase EMT by targeting Smad4, and the miR-146b-5p-Smad4 cascade regulated EMT in CRC. PEP06 also suppressed CRC pulmonary metastasis, increased survival of mice and hampered residual tumour growth by inhibiting EMT through down-regulating miR-146b-5p. CONCLUSIONS AND IMPLICATIONS: PEP06 is a polypeptide that inhibits the growth and metastasis of colon cancer through its RGD motif binding to integrin alphavbeta3, thereby down-regulating miR-146b-5p to inhibit EMT in vitro and in vivo. It might have potential as a therapeutic for CRC. PMID- 29722932 TI - Rapid on-site evaluation facilitated the diagnosis of a rare case of Talaromyces marneffei infection. PMID- 29722935 TI - Are Mixed Symptoms a Red Flag for Conversion of Postpartum Depression to Bipolar Disorder? PMID- 29722936 TI - Antibiotics for PANDAS? Limited Evidence: Review and Putative Mechanisms of Action. AB - Objective: Antibiotics have been used extensively by clinicians to treat patients with PANDAS or PANS (pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections and pediatric acute-onset neuropsychiatric syndrome, respectively). This review examines the best-quality evidence supporting the practice-based use of antibiotics in these psychiatric conditions. Data Sources: PubMed was searched for English-language articles published between January 1994 and July 2017 using the search terms [PANDAS OR PANS OR new-onset pediatric OCD] AND [antibiotics OR macrolides OR beta-lactams]. Study Selection: Randomized clinical trials, observational studies, and case reports concerning antibiotic use in PANDAS/PANS were reviewed. Four publications were included in the quantitative synthesis. Data Extraction: The evidence was rated using the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) method. Results: Although the single studies conveyed no statistically significant results, there is some evidence for efficacy of antibiotic therapy in reducing neuropsychiatric symptoms in the PANDAS/PANS population. Conclusions: Whereas the use of eradicating antibiotic therapy during active infections in PANDAS/PANS is well established, there is still a need for studies that improve the quality of evidence supporting use of antibiotics in this population independent of ongoing infections. Studies that compare antibiotics with other therapies, as well as studies that assess safety and efficacy of long-term use of antibiotic therapy in PANDAS/PANS, are still lacking. However, the available research supports evidence of a subgroup in the pediatric OCD population that is sensitive to antibiotic treatment and immunomodulatory therapy, independent of ongoing infectious conditions. Thus, more studies are warranted in the overall OCD spectrum. PMID- 29722937 TI - A Novel Methodology to Validate the Accuracy of Extraoral Dental Scanners and Digital Articulation Systems. AB - PURPOSE: The aim of the current study is to develop a novel method to investigate the accuracy of 3D scanners and digital articulation systems. MATERIALS AND METHODS: An upper and a lower poured stone model were created by taking impression of fully dentate male (fifty years old) participant. Titanium spheres were added to the models to allow for an easily recognisable geometric shape for measurement after scanning and digital articulation. Measurements were obtained using a Coordinate Measuring Machine to record volumetric error, articulation error and clinical effect error. Three scanners were compared, including the Imetric 3D iScan d104i, Shining 3D AutoScan-DS100 and 3Shape D800, as well as their respective digital articulation software packages. Stoneglass Industries PDC digital articulation system was also applied to the Imetric scans for comparison with the CMM measurements. RESULTS: All the scans displayed low volumetric error (p?0.05), indicating that the scanners themselves had a minor contribution to the articulation and clinical effect errors. The PDC digital articulation system was found to deliver the lowest average errors, with good repeatability of results. CONCLUSION: The new measuring technique in the current study was able to assess the scanning and articulation accuracy of the four systems investigated. The PDC digital articulation system using Imetric scans was recommended as it displayed the lowest articulation error and clinical effect error with good repeatability. The low errors from the PDC system may have been due to its use of a 3D axis for alignment rather than the use of a best fit. PMID- 29722938 TI - [Diagnosis and treatment of ejaculatory duct obstruction: Current status and advances]. AB - Ejaculatory duct obstruction (EDO) is one of the obstructive factors for 1-5% of all cases of male infertility and it is, however, surgically correctable. Congenital developmental abnormality is a most common cause of EDO. The clinical manifestations of EDO are varied, typically with the decline of four semen parameters. Transrectal ultrasonography is an important imaging method for the diagnosis of EDO and guidance in its surgery. MRI provides high-resolution images of the reproductive system as evidence. Transurethral resection of the ejaculatory duct (TURED) is a classical operation, the application of transurethral seminal vesiculoscopy has become a new trend of minimally invasive surgery in the treatment of EDO, and the latest flexible vesiculovasoscopy (FVV) or vasoscopy techniques may further improve the diagnosis and treatment of EDO. PMID- 29722939 TI - [Effects of obesity on global genome DNA methylation and gene imprinting in mouse spermatozoa]. AB - Objective: To investigate the influence of high fat diet-induced obesity (HFDIO) on the differentially methylated region (DMR) of the imprinted gene and global genome methylation of sperm DNA. METHODS: We performed bisulfite sequencing on the DMR of the imprinted gene and global genome methylation of sperm DNA in the mouse model of HFDIO. RESULTS: No statistically significant differences were found between the HFDIO model and normal control mice in MEG3-IG (93.73 vs 97.26%, P = 0.252), H19 (98.00 vs 97.83%, P = 0.920), IGF2 (97.34 vs 96.25%, P =0.166), IGF2R (1.43 vs 1.11%, P = 0.695), PEG3 (0.19 vs 0.38%, P = 0.537), MEST (0.23 vs 0.68%, P = 0.315), NNAT (0.31 vs 0.00%, P = 0.134), or SNRPN (1.88 vs 3.13%, P = 0.628). A total of 8 942 DMRs were detected across the sperm genome (P <0.05). Gene functional enrichment analysis indicated that the enriched terms with the largest numbers of genes were the metabolic process (n = 1 482), RNA synthesis (n = 779), and transcription (n = 767). CONCLUSIONS: The methylation level underwent no significant change in the DMRs of the imprinted genes from the mice with HFDIO, but the CG methylation of the genes involved in the metabolic process, RNA synthesis and transcription were significantly altered. PMID- 29722940 TI - [H2O2 alters metabolism in TM4 Sertoli cells in the mouse]. AB - Objective: To explore the mechanisms of oxidative stress-induced damage to TM4 Sertoli cells in the mouse using metabolomics techniques based on gas chromatography-mass spectrometry (GC-MS). METHODS: We established the model of oxidative stress-induced damage to mouse TM4 Sertoli cells by treatment with H2O2. Then, we detected the survival rate and apoptosis rate of the TM4 cells by MTT and flow cytometry respectively, measured the concentration of ROS in the TM4 cells with the DCFH-DA fluorescent probe, and determined the levels of endogenous metabolites in the TM4 cells by GC-MS after H2O2 intervention. RESULTS: After 2 hours of treatment with H2O2 at 600 MUmol/L, the survival rate of the TM4 cells was reduced to about 50%, and the total apoptosis rates in the low- (100 MUmol/L), medium- (300 MUmol/L), and high-dose (600 MUmol/L) groups were (19.45 +/- 0.53), (20.12 +/- 0.58), and (37.13 +/- 0.35)%, respectively, increased in a dose-dependent manner as compared with (10.28 +/- 0.35)% in the blank control (P <0.05). The ROS level was significantly higher in the medium- and high-dose groups than in the control ([1.27 +/- 0.10] vs [1.00 +/- 0.08]%, P <0.05; [2.07 +/- 0.09] vs [1.00 +/- 0.08]%, P <0.01). Compared with the blank control group, the high-dose H2O2 group showed evident changes in the levels of amino acid and carbohydrates in the TM4 cells, more significantly in the levels of valine, norvaline, leucine, glutamic acid, arabinose, fructose, and 5-serotonin cholesterol (VIP >1, P <0.05). CONCLUSIONS: Oxidative stress-induced damage and apoptosis of TM4 Sertoli cells are closely associated with the metabolism of amino acid, glucose, and energy in the cells. PMID- 29722941 TI - [Culture of rat corpus cavernosal endothelial cells using modified immunomagnetic beads and cloning]. AB - Objective: To search for the methods of isolating, purifying and culturing corpus cavernosal endothelial cells (CCECs) from SD rats, observe their growth characteristics, and providing seed cells for the study of erectile dysfunction (ED). METHODS: The corpus cavernosal tissue from the SD rat was digested with 0.1% elastase, followed by purification of CCECs with immunomagnetic beads. After further amplification, monoclonal CCECs were sorted out with the cloning cylinder and their morphological and proliferative characteristics were observed. The von Willebrand factor (VWF) in the CCECs was identified by immunofluorescence staining, the CD31 molecule detected by immumohistochemistry, the purity of the CCECs determined by flow cytometry, and the proliferation of the cells measured with CCK-8 and growth curves. RESULTS: After 7 days of purification and culture, the CCECs were fused into a monolayer under the inverted phase-contrast microscope, arranged like flagstones. The growth curves showed that the CCECs were in latency with a low growth rate at 1-2 days, in the logarithmic growth phase with a rapid rate at 3-4 days, and into the platform phase around the 6th day. VWF was positively expressed in the CCECs with much green fluorescence, and so was CD31 with a large number of brownish particles. The positive rate of the CCECs which were labelled with the VWF purified with magnetic beads combined with cloning cylinders was up to (91.9+/-3.75)%. CONCLUSIONS: High-purity rat CCECs can be cultured successfully using immunomagnetic beads combined with cloning cylinders, with stable proliferation and passage in the endothelial cell medium. PMID- 29722942 TI - [Role of TGF-beta1 in Sertoli cells and tight junction]. AB - Objective: To explore the role of TGF-beta1 in the proliferation and apoptosis of Sertoli cells and its effect on the expressions of tight junction-related proteins and genes in rats. METHODS: Rat Sertoli cells were isolated in vitro, primarily cultured, and divided into groups A (blank control), B (TGF-beta1 receptor blocker), C (TGF-beta1), and D (TGF-beta1 + receptor blocker). The proliferation and apoptosis of the cells were detected by CCK-8 and flow cytometry, respectively. After establishment of the dual-chamber model for the primary culture of Sertoli cells, the trans-epithelia electrical resistance (TER) value was measured and the relative expressions of Occludin, ZO-1 and Claudin II determined by RT-PCR and Western blot. RESULTS: The OD value of the proliferation of the Sertoli cells was markedly higher in group C than in groups A and D (0.79 +/- 0.04 vs 0.66 +/- 0.05 and 0.68 +/- 0.02, P<0.05), with statistically significant differences among the four groups (F = 5.05, P <0.05). However, no remarkable difference with found among the four groups in the apoptosis rate of the cells (F = 1.13, P >0.05). The TER value was dramatically decreased in group C as compared with groups A and D ([176.37 +/- 16.61] vs [281.42 +/- 9.83] and [254.37 +/- 13.55] /cm2, P<0.01), with statistically significant differences among the four groups (F = 38.99, P<0.01). There were no remarkable differences among the four groups in the mRNA expressions of ZO-1 and Claudin II (F = 0.49 and 0.93, P>0.05) or their protein expressions (F = 0.28 and 1.31, P>0.05). Both the mRNA and protein expressions of Occludin were markedly lower in group C than in A and D (P<0.01 and P<0.05), with statistically significant differences among the four groups (F = 6.86 and 6.87, P<0.01). CONCLUSIONS: TGF-beta1 can promote the proliferation of Sertoli cells in rats and act on the tight junction of the cells by regulating the expression of Occludin. PMID- 29722943 TI - [Testosterone Undecanoate Pills improves insulin resistance in type-2 diabetes men with hypogonadism]. AB - Objective: To evaluate the effects of Testosterone Undecanoate Pills (TUP) on insulin resistance (IR) in type-2 diabetes men with hypogonadism. METHODS: We randomly divided 82 type-2 diabetes patients with hypogonadism into a treatment (n = 42) and a control group (n = 40), both maintaining their glucose- and lipid reducing therapies, while the former treated orally with TUP in addition. After 6 months of medication, we compared the body mass index (BMI), waist circumference (WC), blood glucose level, HbA1c, lipid profile, IR index obtained by homeostatic model assessment (HOMA-IR), insulin sensitivity index (ISI), sex hormone levels, and sexual function scores between the two groups of patients. RESULTS: Compared with the baseline, the patients in the treatment group showed significant decreases after medication in BMI ([26.71 +/- 2.39] vs [25.15 +/- 2.28] kg/m2, P <0.05), WC ([89.96 +/- 9.13] vs [85.03 +/- 9.58] cm, P <0.05), HbA1C ([7.73 +/- 1.31] vs [7.01 +/- 1.25] %, P <0.05), and triglyeride ([1.97 +/- 0.83] vs [1.41 +/- 0.69] mmol/L, P <0.05), a markedly elevated level of total testosterone ([7.16 +/- 2.21] vs [14.22 +/- 2.63] nmol/L, P <0.05), and remarkable improvement in HOMA-IR (3.76 +/- 1.18 vs 2.55 +/- 1.03, P <0.05), ISI (96 +/- 51 vs 138 +/- 53, P <0.05) and total scores of the Aging Males' Symptoms (P <0.05). But no significant changes were observed in the scores of the International Index of Erectile Function (IIEF) after treatment (13.28 +/- 6.38 vs 14.95 +/- 6.08, P >0.05). CONCLUSIONS: TUP can significantly improve insulin resistance in type-2 diabetes men with hypogonadism. PMID- 29722944 TI - [Effects of different medications with tadalafil on erectile dysfunction in males with primary sexual failure]. AB - Objective: To evaluate the effects of three different medications with tadalafil on erectile dysfunction (ED) in young men with primary sexual failure. METHODS: This study included 76 male ED patients aged 21-35 years who had primary sexual failure but normal nocturnal penile tumescence and rigidity and failed to respond to psychotherapy. We randomly assigned them to receive oral tadalafil once daily, on demand, or once-daily + on-demand. After 2-3 months of treatment, we evaluated the effects based on the scores of the patients in the five domains of the International Index of Erectile Function (IIEF-5). RESULTS: After medication, all the patients showed significantly increased scores in the four domains of IIEF-5, namely, erectile function, orgasmic function, intercourse satisfaction, and overall satisfaction. The on-demand group achieved even higher scores in erectile and orgasmic functions but a lower score in sexual desire than the once-daily group. However, the patients in the once-daily + on-demand group exhibited more significant improvement than those in the other two in all the five domains. CONCLUSIONS: Once-daily + on-demand medication with tadalafil can significantly enhance the therapeutic effect on psychogenic ED in young men with primary sexual failure. PMID- 29722945 TI - [Traversing the vertical pedicle flap for the treatment of severely buried penis in children]. AB - Objective: To assess the effect of traversing the vertical pedicle flap (TVPF) for the treatment of severely buried penis in children. METHODS: Totally 43 children with severely buried penis underwentTVPF (n = 21)or modifiedShiraki surgery (control, n = 22) in our hospitalfrom February to December 2014. Wecompared the operation time, intra-operation blood loss, foreskin swelling time, and parents' satisfaction with penile appearance between the two groups. RESULTS: No statistically significant differences were observed between the TVPFand control groups in the operation time ([45.0 +/-6.8] vs [42.0 +/-5.3] min, P>0.05) or intra-operation blood loss([5.0 +/-1.2] vs [6.0 +/-0.8] ml, P>0.05). The average foreskin swelling time was markedly shorter in the TVPFgroup than in the control ([9.0 +/-2.3] vs [15.0 +/-4.8] d, P<0.05)and the parents' satisfaction with penile appearancewas higher in the former than in the latter (95.23vs31.81 %, P<0.05). The elastic bandages were removedfor all the patientsat 3 days postoperatively, and 3 to 6-month follow-up revealed no penile retraction or relapse. CONCLUSIONS: The method of traversing the vertical pedicle flap is a feasible surgical option for the treatment of severely buried penis in children, which can make a rational use of the foreskin,remove the tight ring, and achieve a satisfactory appearance of the penis. PMID- 29722946 TI - [Correlation of serum anti-Mullerian hormone with semen parameters]. AB - Objective: To investigate the relationship between the serum anti-Mullerian hormone (AMH) level and semen parameters. METHODS: We collected the data about 726 outpatients at the Male Infertility Clinic of Jinling Hospital from September 2015 to November 2016, including 72 with non-obstructive azoospermia, 123 with oligospermia, and 531 with normal sperm concentration. We obtained the semen volume, total sperm count, sperm concentration, sperm motility, the percentages of progressively motile sperm (PMS) and morphologically normal sperm (MNS), and the levels of serum AMH, inhibin B (INH-B), total testosterone (TT) and follicle stimulating hormone (FSH) of the patients, analyzed the correlation of the serum AMH level with the other parameters, and compared the AMH level among different groups. RESULTS: The serum AMH level was found to be correlated positively with the total sperm count (r = 0.227, P <0.001), sperm concentration (r = 0.215, P <0.001), sperm motility (r = 0.111, P = 0.003), the percentage of PMS (r = 0.120, P = 0.001), and the levels of INH-B (r = 0.399, P <0.001) and TT (r = 0.184, P = 0.002), negatively with the FSH level (r = -0.283, P <0.001), but insignificantly with age, time of abstinence, semen volume, and the percentage of MNS (P >0.05). There was a statistically significant difference in the serum AMH level among the patients with non-obstructive azoospermia, oligozoospermia, and normal sperm concentration ([6.33 +/- 4.26] vs [8.26 +/- 3.98] vs [9.8 +/- 5.19] ng/ml, P <0.001). CONCLUSIONS: Serum AMH is a biomarker reflecting the function of Sertoli cells and its level is significantly correlated with sperm concentration and motility, suggesting that AMH may be involved in spermatogenesis and sperm maturation. PMID- 29722947 TI - [Benefits of nursing care service in the assisted reproduction clinic to self cycle-management and self-efficiency of infertility patients]. AB - Objective: To investigate the benefits of nursing care service in the assisted reproduction clinic to self-cycle-management and self-efficiency of the outpatients with infertility. METHODS: We randomly divided 600 females preliminarily diagnosed with infertility into a control and an experimental group, 288 in the former and 285 in the latter group excluding those whose husbands had azoospermia. For the women patients of the experimental group, we conducted nursing care intervention concerning related knowledge, skills, diet, excise, medication, and psychology, by one-to-one consultation, individualized or group communication, establishing files, telephone follow-up, and wechat guidance. After 3 months of intervention, we compared the compliance of medical visits, effectiveness of cycle management, sense of self-efficiency, satisfaction, and anxiety score between the two groups of patients. RESULTS: In comparison with the controls, the patients of the experimental group showed significantly better knowledge about assisted reproduction and higher effectiveness of self-cycle-management, self-efficiency, and satisfaction (P <0.05), but a markedly lower degree of anxiety (P <0.05). CONCLUSIONS: Nursing care service in the assisted reproduction clinic can improve the compliance of medical visits, effectiveness of self-cycle-management, self-efficiency, and satisfaction and reduce the anxiety of the patients. PMID- 29722948 TI - [Transperitoneal versus extraperitoneal robot-assisted radical prostatectomy for localized prostate cancer]. AB - Objective: To compare the clinical effects of transperitoneal (Tp) versus extraperitoneal (Ep) robot-assisted radical prostatectomy (RARP) in the treatment of localized prostate cancer. METHODS: We searched PubMed, EMBASE, Web of Science, EBSCO, Cochrane Library, Wanfang, CNKI, and CBM for the articles comparing the clinical effect Tp-RARP with that of Ep-RARP in the treatment of localized prostate cancer published from January 2000 to November 2016. All the articles must meet the inclusion criteria, that is, dealing with at least one of the following aspects: operation time, intraoperative blood loss, postoperative catheterization time, length of bed confinement, perioperative complications, positive surgical margins, bowel-related complications, postoperative anastomotic leakage, and postoperative urinary continence. We subjected the data obtained to statistical analysis using the RevMan5.3 software. RESULTS: Two randomized controlled trials and six case-control studies were included in this meta analysis, involving 451 cases of Tp-RARP and 676 cases of Ep-RARP. Compared with Tp-RARP, Ep-RARP showed significantly shorter operation time (WMD = 21.39, 95% CI: 7.54-35.24, P = 0.002), shorter length of bed confinement (WMD = 0.85, 95% CI: 0.61-1.09, P <0.001), and lower rate of bowel-related complications (RR = 9.74, 95% CI: 3.26-29.07, P <0.001). However, no statistically significant differences were found between the two strategies in intraoperative blood loss (WMD = -8.12, 95% CI: -27.86-11.63, P = 0.42), postoperative catheterization time (WMD = 0.17, 95% CI: -0.55-0.21, P = 0.38), or the rates of perioperative complications (RR = 1.34, 95% CI: -0.97-1.87, P = 0.08), positive surgical margins (RR = 1.24, 95% CI: 0.95-1.61, P = 0.12), anastomotic leakage (RR = 0.98, 95% CI: 0.46-2.10, P = 0.95), urinary continence at 3 months (RR = 0.96, 95% CI: 0.91-1.00, P = 0.05) and urinary continence at 6 months (RR = 1.00, 95% CI: 0.97 1.02, P = 0.82). CONCLUSIONS: Ep-RARP has the advantages of shorter operation time, shorter length of bed confinement and lower rate of bowel-related complications over Tp-RARP, and therefore may be a better option for the treatment of localized prostate cancer. However, more multi-centered randomized controlled clinical trials are needed for further evaluation of these two approaches. PMID- 29722949 TI - [Factors influencing the postoperative resolution of varicocele-associated scrotal pain]. AB - Objective: To investigate the factors influencing the postoperative resolution of varicocele-associated scrotal pain. METHODS: Using the keywords "varicocele", "testicular pain", "scrotal pain", "painful varicocele", "ligation", and "varicocelectomy", we searched the PubMed, Embase, Cochrane Collaboration's Database, CNKI, Wanfang, and VIP Database up to October 2016 for the studies relating to surgical treatment of varicocele-associated scrotal pain. We assessed the quality of the cohort studies included using the Newcastle-Ottawa Scale and that of the randomized controlled trials included with the Cochrane Collaboration's tool. We conducted a meta-analysis using the RevMan software. RESULTS: Finally 14 studies were included in this meta-analysis, of which, 2 involved the history of disease, 8 involved the nature of pain, 2 involved the intensity of pain, 9 involved the grade of varicocele, 3 involved the side of varicocele, 9 involved surgical approaches, 3 involved surgical techniques, and 4 involved postoperative recurrence. The pain resolution rate was significantly higher after subinguinal ligation than after high or inguinal ligation (RR = 0.82, 95% CI: 0.76-0.89, P <0.01; RR = 0.92, 95% CI: 0.86-0.99, P = 0.02), and so was it after microsurgery than after laparoscopic varicocelectomy (RR = 0.77, 95% CI: 0.60-0.99, P = 0.04). CONCLUSIONS: Subinguinal varicocelectomy and microsurgery are more effective options than laparoscopic and high or trans inguinal ligation of the spermatic vein for resolution of varicocele-associated scrotal pain, while the history of disease, the nature and intensity of pain, the grade and side of varicocele, or postoperative recurrence cannot be regarded as the influencing factors. PMID- 29722950 TI - [Adipose-derived stem cells for the treatment of penile erectile dysfunction: An update]. AB - Adipose-derived stem cells (ADSCs) are pluripotent stem cells isolated from the adipose tissue and have the potential for self-renewal and multi-directional differentiation into neurogenic cells, smooth muscle cells, endothelial cells, and so on. Erectile dysfunction (ED) is a common male sexual dysfunction that has a negative impact on the lives of the patients and their partners. Current treatments of ED include surgery and medication, with oral 5-phosphodiesterase inhibitors as the first-line drugs. However, a small number of the patients are not sensitive to these therapies and cannot be improved or cured pathologically. So far, animal experiments and preclinical trials have confirmed the safety and efficacy of ADSCs, which act on ED though paracrine mechanisms. This review summarizes the advances in the recent 5 years in the studies of ADSCs for the treatment of ED. PMID- 29722951 TI - [Epigenetics of male infertility: An update]. AB - Epigenetic factors play an important role in male infertility though about 60% 65% of the disease is idiopathic and its underlying causes are not yet clear. Many studies have indicated that epigenetic modifications, including DNA methylation, histone tail modifications, chromatin remodeling, and non-coding RNAs, may be involved in idiopathic male infertility. Abnormal methylation is associated with decreased sperm quality and fertility. It is known that 1 881 miRNAs are related to male fertility and such non-coding RNAs as piRNA, IncRNA, and circRNA play a regulating role in male reproduction. This review focuses on the value of epigenetics in the etiology and pathogenesis of male infertility, aiming to provide some evidence for the establishment of some strategies for the treatment and prediction of the disease. PMID- 29722952 TI - A nursing student's reflective account of decision-making in a school nursing setting. AB - Reflection is integral to professional revalidation and enhancing nursing practice; it is an art and a science to be learned. Learning the art of reflection begins as a student in clinical placement settings. Drawing on a reflective model, this article presents an account of one second-year children's nursing student's experiences in a community-based placement with a school nursing team. A school nurse appointment was reflected on where advice was offered to a 13-year-old student with sleep difficulties, low affect and lethargy, which included avoiding caffeinated drinks, reducing use of a laptop and mobile phone before going to sleep, and establishing a regular bedtime routine. Providing nursing care to this young person enabled the nursing student to improve their decision-making skills, become more self-aware, increase their confidence when communicating with a patient and reinforce the importance of applying theory to practice. PMID- 29722953 TI - Can trophectoderm morphology act as a predictor for euploidy? AB - OBJECTIVE: Euploid embryo transfers yield better implantation rates. In Brazil, morphological evaluation is performed to select the best embryos, since genetic analysis is still an expensive procedure. This study aimed to evaluate whether there is an association between trophectoderm morphology and ploidy status. METHODS: The study included 113 blastocysts formed in D5/D6 from 58 in vitro fertilization cycles held from January/2016 to May/2017. All patients with indication for PGD/PGS were included in the study. The mean age of the female patients was 37.04+/-5.65years. Biopsied blastocysts were categorized for morphology. Cells were sent for genetic analysis using the CGH array, SNP array or NGS techniques. Statistical analysis was performed using the chi square test, and statistical significance was assigned to differences with p<=0.05. RESULTS: Chromosome analysis revealed that 44 (38.9%) blastocysts were euploid. Blastocysts with trophectoderm grades A, B, and C had euploidy rates of 71.43%, 60% and 19.67%, respectively (p<=0.05). CONCLUSION: Although the best trophectoderm morphology grades had higher euploidy rates, this indicator alone is not enough to warrant embryo genetic viability. PMID- 29722954 TI - Ecofriendly Fruit Switches: Graphene Oxide-Based Wrapper for Programmed Fruit Preservative Delivery To Extend Shelf Life. AB - According to Food and Agriculture Organization 2015 report, post-harvest agricultural loss accounts for 20-50% annually; on the other hand, reports about preservatives toxicity are also increasing. Hence, preservative release with response to fruit requirement is desired. In this study, acid synthesized in the overripe fruits was envisaged to cleave acid labile hydrazone to release preservative salicylaldehyde from graphene oxide (GO). To maximize loading and to overcome the challenge of GO reduction by hydrazine, two-step activation with ethylenediamine and 4-nitrophenyl chloroformate respectively, are followed. The final composite shows efficient preservative release with the stimuli of the overripe fruit juice and improves the fruit shelf life. The composite shows less toxicity as compared to the free preservative along with the additional scope to reuse. The composite was vacuum-filtered through a 0.4 MUm filter paper, to prepare a robust wrapper for the fruit storage. PMID- 29722955 TI - Increased Iron Deposition on Brain Quantitative Susceptibility Mapping Correlates with Decreased Cognitive Function in Alzheimer's Disease. AB - The excessive accumulation of iron in deep gray structures is an important pathological characteristic in patients with Alzheimer's disease (AD). Quantitative susceptibility mapping (QSM) is more specific than other imaging based iron measurement modalities and allows noninvasive assessment of tissue magnetic susceptibility, which has been shown to correlate well with brain iron levels. This study aimed to investigate the correlations between the magnetic susceptibility values of deep gray matter nuclei and the cognitive functions assessed by mini-mental state examination (MMSE) and Montreal cognitive assessment (MoCA) in patients with mild and moderate AD. Thirty subjects with mild and moderate AD and 30 age- and sex-matched healthy controls were scanned with a 3.0 T magnetic resonance imaging (MRI) scanner. The magnetic susceptibilities of the regions of interest (ROIs), including caudate nucleus (Cd), putamen (Pt), globus pallidus (Gp), thalamus (Th), red nucleus (Rn), substantia nigra (Sn), and dentate nucleus (Dn), were quantified by QSM. We found that the susceptibility values of the bilateral Cd and Pt were significantly higher in AD patients than the controls ( P < 0.05). In contrast, bilateral Rn had significantly lower susceptibility values in AD than the controls. Regardless of gender and age, the increase of magnetic susceptibility in the left Cd was significantly correlated with the decrease of MMSE scores and MoCA scores ( P < 0.05). Our study indicated that magnetic susceptibility value of left Cd could be potentially used as a biomarker of disease severity in mild and moderate AD. PMID- 29722956 TI - Electrical Mapping of Silver Nanowire Networks: A Versatile Tool for Imaging Network Homogeneity and Degradation Dynamics during Failure. AB - Electrical stability and homogeneity of silver nanowire (AgNW) networks are critical assets for increasing their robustness and reliability when integrated as transparent electrodes in devices. Our ability to distinguish defects, inhomogeneities, or inactive areas at the scale of the entire network is therefore a critical issue. We propose one-probe electrical mapping (1P-mapping) as a specific simple tool to study the electrical distribution in these discrete structures. 1P-mapping has allowed us to show that the tortuosity of the voltage equipotential lines of AgNW networks under bias decreases with increasing network density, leading to a better electrical homogeneity. The impact of the network fabrication technique on the electrical homogeneity of the resulting electrode has also been investigated. Then, by combining 1P-mapping with electrical resistance measurements and IR thermography, we propose a comprehensive analysis of the evolution of the electrical distribution in AgNW networks when subjected to increasing voltage stresses. We show that AgNW networks experience three distinctive stages: optimization, degradation, and breakdown. We also demonstrate that the failure dynamics of AgNW networks at high voltages occurs through a highly correlated and spatially localized mechanism. In particular the in situ formation of cracks could be clearly visualized. It consists of two steps: creation of a crack followed by propagation nearly parallel to the equipotential lines. Finally, we show that current can dynamically redistribute during failure, by following partially damaged secondary pathways through the crack. PMID- 29722957 TI - Tuning the Ionomer Distribution in the Fuel Cell Catalyst Layer with Scaling the Ionomer Aggregate Size in Dispersion. AB - With the demands for better performance of polymer electrolyte membrane fuel cells, studies on controlling the distribution of ionomers have recently gained interest. Here, we present a tunable ionomer distribution in the catalyst layer (CL) with dipropylene glycol (DPG) and water mixtures as the ionomer dispersion medium. Dynamic light scattering and molecular dynamics simulation demonstrate that, by increasing the DPG content in the dispersion, the size of the ionomer aggregates in the dispersion is exponentially reduced because of the higher affinity of DPG for Nafion ionomers. The ionomer distribution of the resulting CLs dictates the dimensional feature of the ionomer dispersion. Although the ionomer distribution becomes more uniform with increasing the DPG content, an optimal power performance is obtained at a DPG content of 50 wt % regardless of feed humidity because of balanced proton and mass transports. As a guide for tuning the ionomer distribution, we suggest that the ionomer aggregates in the dispersion with a size close to that of the Pt/C aggregates form a highly connected ionomer network and maintain a porosity in the catalyst/ionomer aggregate, resulting in high power performance. PMID- 29722958 TI - High-Throughput Measurement of Lipid Turnover Rates Using Partial Metabolic Heavy Water Labeling. AB - Novel analytical platforms for high-throughput determination of lipid turnover in vivo have been developed based on partial metabolic 2H2O labeling. The performance on lipid kinetics measurement of our methods was validated in three different liquid chromatography-mass spectrometry (LC-MS) setups: MS-only, untargeted MS/MS, and targeted MS/MS. The MS-only scheme consisted of multiple LC MS runs for quantification of lipid mass isotopomers and an extra LC-MS/MS run for lipid identification. The untargeted MS/MS format utilized multiple data dependent LC-MS/MS runs for both quantification of lipid mass isotopomers and lipid identification. An in-house software was also developed to streamline the data processing from peak area quantification of mass isotopomers to exponential curve fitting for extracting the turnover rate constant. With HeLa cells cultured in 5% 2H2O media for 48 h, we could deduce the species-level turnover rates of 108 and 94 lipids in the MS-only and untargeted MS/MS schemes, respectively, which covers 13 different subclasses and spans 3 orders of magnitude. Furthermore, the targeted MS/MS setup, which performs scheduled LC-MS/MS experiments for some targeted lipids, enabled differential measurement between the turnover rates of the head and tail groups of lipid. The reproducibility of our lipid kinetics measurement was also demonstrated with lipids that commonly detected in both positive and negative ion modes or in two different adduct forms. PMID- 29722959 TI - Heavy Atom Effect of Bromine Significantly Enhances Exciton Utilization of Delayed Fluorescence Luminogens. AB - Raising triplet exciton utilization of pure organic luminescent materials is of significant importance for efficiency advancement of organic light-emitting diodes (OLEDs). Herein, by introducing bromine atom(s) onto a typical molecule (bis(carbazol-9-yl)-4,5-dicyanobenzene) with thermally activated delayed fluorescence, we demonstrate that the heavy atom effect of bromine can increase spin-orbit coupling and promote the reverse intersystem crossing, which endow the molecules with more distinct delayed fluorescence. In consequence, the triplet exciton utilization is improved greatly with the increase of bromine atoms, affording apparently advanced external quantum efficiencies of OLEDs. Utilizing the enhancement effect of bromine atoms on delayed fluorescence should be a simple and promising design concept for efficient organic luminogens with high exciton utilization. PMID- 29722960 TI - Natural Triterpenoid-Tailored Phosphate: In Situ Reduction of Heavy Metals Spontaneously to Generate Electrochemical Hybrid Gels. AB - In this work, we reported a biocompatible nature product-based soft material which could convert heavy metals to nanoparticles (NPs) in situ spontaneously in a simple step. We have designed and synthesized a natural triterpenoid-tailored phosphate (methyl glycyrrhetate phosphate (MGP)), and this amphiphilic MGP could form the stable hydrogel and extract gold salt from water, followed by spontaneous in situ AuNP formation without external reductants. Notably, the AuNPs were mainly localized on nanofibers instead of gel cavities, and the resulting MGP-AuNPs hybrid gel exhibited attractive electrocatalytic and conductive properties. In addition, as an efficient leaching extraction agent, MGP hydrogel showed higher affinity toward heavy metals over other common metals on account of the high reduction potential of heavy metals. Our work not only provides a novel yet simple way in generating electrochemical hybrid gels by in situ reduction of heavy metals spontaneously but also expands the application of nature product-based functional materials. PMID- 29722961 TI - Assembly of Hollow Carbon Nanospheres on Graphene Nanosheets and Creation of Iron Nitrogen-Doped Porous Carbon for Oxygen Reduction. AB - Triblock copolymer micelles coated with melamine-formaldehyde resin were self assembled into closely packed two-dimensional (2D) arrangements on the surface of graphene oxide sheets. Carbonizing these structures created a 2D architecture composed of reduced graphene oxide (rGO) sandwiched between two monolayers of sub 40 nm diameter hollow nitrogen-doped carbon nanospheres (N-HCNS). Electrochemical tests showed that these hybrid structures had better performance for oxygen reduction compared to physically mixed rGO and N-HCNS that were not chemically bonded together. Further impregnation of the sandwich structures with iron (Fe) species followed by carbonization yielded Fe1.6-N-HCNS/rGO-900 with a high specific surface area (968.3 m2 g-1), a high nitrogen doping (6.5 at%), and uniformly distributed Fe dopant (1.6 wt %). X-ray absorption fine structure analyses showed that most of the Fe in the nitrogen-doped carbon framework is composed of single Fe atoms each coordinated to four N atoms. The best Fe1.6-N HCNS/rGO-900 catalyst performed better in electrocatalytic oxygen reduction than 20 wt % Pt/C catalyst in alkaline medium, with a more positive half-wave potential of 0.872 V and the same limiting current density. Bottom-up soft patterning of regular carbon arrays on free-standing 2D surfaces should enable conductive carbon supports that boost the performance of electrocatalytic active sites. PMID- 29722962 TI - Inhibition of 14-3-3/Tau by Hybrid Small-Molecule Peptides Operating via Two Different Binding Modes. AB - Current molecular hypotheses have not yet delivered marketable treatments for Alzheimer's disease (AD), arguably due to a lack of understanding of AD biology and an overreliance on conventional drug modalities. Protein-protein interactions (PPIs) are emerging drug targets, which show promise for the treatment of, e.g., cancer, but are still underexploited for treating neurodegenerative diseases. 14 3-3 binding to phosphorylated Tau is a promising PPI drug target based on its reported destabilizing effect on microtubules, leading to enhanced neurofibrillary tangle formation as a potential cause of AD-related neurodegeneration. Inhibition of 14-3-3/Tau may therefore be neuroprotective. Previously, we reported the structure-guided development of modified peptide inhibitors of 14-3-3/Tau. Here, we report further efforts to optimize the binding mode and activity of our modified Tau peptides through a combination of chemical synthesis, biochemical assays, and X-ray crystallography. Most notably, we were able to characterize two different high-affinity binding modes, both of which inhibited 14-3-3-binding to full-length PKA-phosphorylated Tau protein in vitro as measured by NMR spectroscopy. Our findings, besides producing useful tool inhibitor compounds for studying 14-3-3/Tau, have enhanced our understanding of the molecular parameters for inhibiting 14-3-3/Tau, which are important milestones toward the establishment of our 14-3-3 PPI hypothesis. PMID- 29722964 TI - Expanding the Scope of Cross-Link Identifications by Incorporating Collisional Activated Dissociation and Ultraviolet Photodissociation Methods. AB - With the advent of new cross-linking chemistries, analytical technologies, and search algorithms, cross-linking has become an increasingly popular strategy for evaluating tertiary and quaternary structures of proteins. Collisional activated dissociation remains the primary MS/MS method for identifications of peptide cross-links in high throughput workflows. Ultraviolet photodissociation (UVPD) at 193 nm has emerged as an alternative ion activation method well-suited for characterization of peptides and has been found in some cases to identify different peptides or provide distinctive sequence information than obtained by collisional activation methods. Complementary high energy collision dissociation (HCD) and UVPD were used in the present study to characterize protein cross linking for bovine serum albumin, hemoglobin, and E. coli ribosome. Cross-links identified by HCD and UVPD using bis(sulfosuccinimidyl)suberate (BS3), a homobifunctional amine-to-amine cross-linker, and 4-(4,6-dimethoxy-1,3,5-triazin 2-yl)-4-methylmorpholinium chloride (DMTMM), a heterofunctional amine-to carboxylic acid cross-linker, were evaluated in the present study. While more unique BS3 cross-links were identified by HCD, UVPD, and HCD provided a complementary panel of DMTMM cross-links which extended the degree of structural insight obtained for the proteins. PMID- 29722963 TI - Detection of Cyclooxygenase-2-Derived Oxygenation Products of the Endogenous Cannabinoid 2-Arachidonoylglycerol in Mouse Brain. AB - Cyclooxygenase-2 (COX-2) catalyzes the formation of prostaglandins, which are involved in immune regulation, vascular function, and synaptic signaling. COX-2 also inactivates the endogenous cannabinoid (eCB) 2-arachidonoylglycerol (2-AG) via oxygenation of its arachidonic acid backbone to form a variety of prostaglandin glyceryl esters (PG-Gs). Although this oxygenation reaction is readily observed in vitro and in intact cells, detection of COX-2-derived 2-AG oxygenation products has not been previously reported in neuronal tissue. Here we show that 2-AG is metabolized in the brain of transgenic COX-2-overexpressing mice and mice treated with lipopolysaccharide to form multiple species of PG-Gs that are detectable only when monoacylglycerol lipase is concomitantly blocked. Formation of these PG-Gs is prevented by acute pharmacological inhibition of COX 2. These data provide evidence that neuronal COX-2 is capable of oxygenating 2-AG to form a variety PG-Gs in vivo and support further investigation of the physiological functions of PG-Gs. PMID- 29722965 TI - Database for CO2 Separation Performances of MOFs Based on Computational Materials Screening. AB - Metal-organic frameworks (MOFs) are potential adsorbents for CO2 capture. Because thousands of MOFs exist, computational studies become very useful in identifying the top performing materials for target applications in a time-effective manner. In this study, molecular simulations were performed to screen the MOF database to identify the best materials for CO2 separation from flue gas (CO2/N2) and landfill gas (CO2/CH4) under realistic operating conditions. We validated the accuracy of our computational approach by comparing the simulation results for the CO2 uptakes, CO2/N2 and CO2/CH4 selectivities of various types of MOFs with the available experimental data. Binary CO2/N2 and CO2/CH4 mixture adsorption data were then calculated for the entire MOF database. These data were then used to predict selectivity, working capacity, regenerability, and separation potential of MOFs. The top performing MOF adsorbents that can separate CO2/N2 and CO2/CH4 with high performance were identified. Molecular simulations for the adsorption of a ternary CO2/N2/CH4 mixture were performed for these top materials to provide a more realistic performance assessment of MOF adsorbents. The structure-performance analysis showed that MOFs with Delta Qst0 > 30 kJ/mol, 3.8 A < pore-limiting diameter < 5 A, 5 A < largest cavity diameter < 7.5 A, 0.5 < phi < 0.75, surface area < 1000 m2/g, and rho > 1 g/cm3 are the best candidates for selective separation of CO2 from flue gas and landfill gas. This information will be very useful to design novel MOFs exhibiting high CO2 separation potentials. Finally, an online, freely accessible database https://cosmoserc.ku.edu.tr was established, for the first time in the literature, which reports all of the computed adsorbent metrics of 3816 MOFs for CO2/N2, CO2/CH4, and CO2/N2/CH4 separations in addition to various structural properties of MOFs. PMID- 29722966 TI - Sodium Hyaluronate/Chitosan Composite Microneedles as a Single-Dose Intradermal Immunization System. AB - Enhancing the immune response to vaccines and minimizing the need for repeated inoculations remain a challenge in clinical vaccination. This study developed a composite microneedle (MN), composed of a sodium hyaluronate (HA) tip and a chitosan base, for biphasic antigen release and evaluated the potential of using this MN formulation as an intradermal delivery system for single-dose vaccination. Upon skin insertion, the dissolvable HA tip dissolved within the skin for rapid release of the encapsulated antigens, thus priming the immune system, while the biodegradable chitosan base remained in the dermis for prolonged antigen release for 4 weeks, thus further boosting the stimulated immunity. Our results showed that a single immunization with the HA/chitosan MN containing ovalbumin (OVA) (100 MUg * 1) stimulated both T helper type 1 (Th1) and Th2 immune responses in rats and induced considerably higher and more durable antibody responses than a traditional two-dose (100 MUg OVA * 2) or double-dose (200 MUg OVA * 1) subcutaneous vaccination. Thus, the proposed MN exerts strong adjuvanticity to greatly augment the antigen's immunogenicity. Moreover, given its unique rapid and sustained release properties, the HA/chitosan MN formulation has the potential to replace the conventional prime-boost regimen to serve as an effective single-dose vaccine formulation. PMID- 29722968 TI - Bimetallic Uranyl Organic Frameworks Supported by Transition-Metal-Ion-Based Metalloligand Motifs: Synthesis, Structure Diversity, and Luminescence Properties. AB - A bifunctional ligand, 2,2'-bipyridine-4,4'-dicarboxylic acid (H2bpdc), has been used in the investigation of constructing bimetallic uranyl organic frameworks (UOFs). Seven novel uranyl-transition metal bimetallic coordination polymers, [(UO2)Zn(bpdc)2] n (1), [Cd(UO2)(bpdc)2(H2O)2.2H2O] n (2), [Cu(UO2)(bpdc)(SO4)(H2O)3.2H2O] n (3), [CuCl(UO2)(bpdc)(Hbpdc)(H2O)2.H2O] n (4), [Cu(UO2)(bpdc)2(H2O)] n (5), [Co2(UO2)3(bpdc)6] n (6), and [Co3(UO2)4(bpdc)8(Hbpdc)(H2O)2] n (7), have been successfully constructed through the assembly of various transition-metal salts, uranyl ions, and H2bpdc ligands under hydrothermal conditions. UOFs 1, 5, 6, and 7 adopt three-dimensional (3D) frameworks with different architectures; UOFs 2 and 3 exhibit two-dimensional (2D) wavelike and stairlike layers, respectively, while UOF 4 is a one dimensional (1D) chain assembly. These UOFs include a wide range of dimensionalities (1D-3D), interpenetrated frameworks, and cation-cation interaction species, suggesting that anion-dependent structure regulation based on the metalloligand [M(bpdc) m] n- motifs, the coordination modes of the metal centers and bpdc2- ligands, along with the reaction temperature, has a remarkable influence on the formation of bimetallic UOFs, which could be a representative system for the structural modulation of UOFs with various dimensionalities and structures. Furthermore, the thermal stability and luminescent properties of compounds 1, 3, and 6 are also investigated. PMID- 29722967 TI - Influences of Air, Oxygen, Nitrogen, and Carbon Dioxide Nanobubbles on Seed Germination and Plant Growth. AB - Nanobubbles (NBs) hold promise in green and sustainable engineering applications in diverse fields (e.g., water/wastewater treatment, food processing, medical applications, and agriculture). This study investigated the effects of four types of NBs on seed germination and plant growth. Air, oxygen, nitrogen, and carbon dioxide NBs were generated and dispersed in tap water. Different plants, including lettuce, carrot, fava bean, and tomato, were used in germination and growth tests. The seeds in water-containing NBs exhibited 6-25% higher germination rates. Especially, nitrogen NBs exhibited considerable effects in the seed germination, whereas air and carbon dioxide NBs did not significantly promote germination. The growth of stem length and diameter, leave number, and leave width were promoted by NBs (except air). Furthermore, the promotion effect was primarily ascribed to the generation of exogenous reactive oxygen species by NBs and higher efficiency of nutrient fixation or utilization. PMID- 29722969 TI - Endo- and Exocyclic Coordination of a 20-Membered N2O2S2-Macrocycle and Cascade Complexation of a 40-Membered N4O4S4-Macrocycle. AB - A 20-membered N2O2S2-macrocycle (L1) and a 40-membered N4O4S4-macrocycle (L2) were employed as a [1:1] and a [2:2] cyclization product, respectively, for the preparation of diverse types of supramolecular complexes including a cascade complex. Six complexes (1-6) of the smaller macrocycle L1 including discrete to continuous forms, mono- to heteronuclear, and endo- to exo- and endo/exocoordination were prepared and their coordination modes were discussed systemically. First, the reaction of L1 with CuI in the presence of trifluoroacetic acid afforded an exocyclic 1-D coordination polymer {[(MU4 Cu4I4)(HL1)2](CF3COO)2} n (1). Meanwhile, the reaction of L1 with Cu(ClO4)2.6H2O afforded a typical endocyclic mononuclear complex [CuII(L1)](ClO4)2.H2O (2). In the reactions of L1 with CdX2 (X = Br and I), isostructural sandwich-type complexes [Cd(L1)2Br2] (3) and [Cd(L1)2I2] (4) were isolated. The treatment of L1 with Hg(ClO4)2 also afforded a sandwich-type complex [Hg(L1)2](ClO4)2 (5). One pot reaction of L1 with a mixture of HgI2 and CdI2 afforded a dumbbell-type heteronuclear complex {[Cd(L1)]2(MU-Hg2I6)}[Hg2I6] (6), in which the Cd(II) ion occupies the macrocyclic cavity. Further, such two endocyclic Cd(II) complex units are bridged by a square-type (MU-Hg2I6)2- cluster remaining another same cluster separately. The comparative NMR data exhibited a higher affinity of Cd(II) over Hg(II) toward L1, in the parallel to the situation occurred in the solid state. Meanwhile, complexations of the extra-large macrocycle L2 is more challenging to afford some interesting dimercury(II) coordination products including a cascade complex. In solution, the dimercury(II) perchlorato complex of L2 as a metalloligand shows a preferential binding of dabco (1,4 diazabicyclo[2,2,2]octane), but its dimercury(II) iodo complex has a much smaller affinity for dabco. In order to explain these results, the solid dimercury(II) complexes with different anions [Hg2(L2)X4] (7: X = I, 8: X = ClO4) were prepared and characterized. Further, the dimercury(II) perchlorato complex 8 reacts with dabco to forms a cascade complex [Hg2(L2)(MU-dabco)(ClO4)2](ClO4)2.2DMF.2ether (9), exhibiting its formation being metal-driven and coordinated anion-regulated. The observed cascade complexation both in solution and solid states is an example of the adaptive guest binding. PMID- 29722970 TI - Matching Protein Interfaces for Improved Medium-Chain Fatty Acid Production. AB - Medium-chain fatty acids (MCFAs) are key intermediates in the synthesis of medium chain chemicals including alpha-olefins and dicarboxylic acids. In bacteria, microbial production of MCFAs is limited by the activity and product profile of fatty acyl-ACP thioesterases. Here, we engineer a heterologous bacterial medium chain fatty acyl-ACP thioesterase for improved MCFA production in Escherichia coli. Electrostatically matching the interface between the heterologous medium chain Acinetobacter baylyi fatty acyl-ACP thioesterase (AbTE) and the endogenous E. coli fatty acid ACP ( E. coli AcpP) by replacing small nonpolar amino acids on the AbTE surface for positively charged ones increased secreted MCFA titers more than 3-fold. Nuclear magnetic resonance titration of E. coli 15N-octanoyl-AcpP with a single AbTE point mutant and the best double mutant showed a progressive and significant increase in the number of interactions when compared to AbTE wildtype. The best AbTE mutant produced 131 mg/L of MCFAs, with MCFAs being 80% of all secreted fatty acid chain lengths after 72 h. To enable the future screening of larger numbers of AbTE variants to further improve MCFA titers, we show that a previously developed G-protein coupled receptor (GPCR)-based MCFA sensor differentially detects MCFAs secreted by E. coli expressing different AbTE variants. This work demonstrates that engineering the interface of heterologous enzymes to better couple with endogenous host proteins is a useful strategy to increase the titers of microbially produced chemicals. Further, this work shows that GPCR-based sensors are producer microbe agnostic and can detect chemicals directly in the producer microbe supernatant, setting the stage for the sensor guided engineering of MCFA producing microbes. PMID- 29722971 TI - Site-Specific Conjugation of Polymers to Proteins. AB - Conjugation of polymer to protein has been widely employed in therapeutics, medicine, biotechnology, and enzymatic catalysis. The synergistic effect benefits both counterparts and potentially overcomes their inherent limitations. This article reviews the strategies for the site-specific synthesis of well-defined protein-polymer conjugates, aiming to provide a toolbox for the community. First, it is essential to set a definite reactive site on the protein because the position of the reaction site can directly influence the reaction activity and the bioactivity of the protein after modification. The origins of the specific functional groups on protein include the utilization of the unique natural amino acid, mutagenesis to introduce a sole reactive amino acid, chemical modification, noncanonical amino acid incorporation, and enzyme-mediated introduction of functional groups. Second, the main conjugation methods, i.e., "grafting to" and "grafting from" methods, are summarized and compared with each other. In the "grafting to" method, a comprehensive investigation on the reactions used to attach an end functional polymer chain to a protein is conducted according to the position of the target site and its nature. In the "grafting from" method, a comparison between the commonly used controlled polymerization, i.e., atom transfer radical polymerization (ATRP) and reversible addition-fragmentation transfer (RAFT), is surveyed. Further, a special case where a noncovalent bond is adopted to link the protein and polymer together is investigated due to its high specificity and reversibility, typically biotin-(strept)avidin-based interactions and metal-mediated conjugation. Finally, applications of protein-polymer conjugates in drug delivery, biomedicine, biosensor, and the disease-related protein self-assembly are illustrated. This precise review on the conjugation of polymer chain to protein to form well-defined protein-polymer conjugates summarizes the representative strategies and may provide useful cues in the areas of biotechnology, therapeutic drugs, and biomedicine. PMID- 29722972 TI - Capillary HILIC-MS: A New Tool for Sensitive Top-Down Proteomics. AB - Recent progress in top-down proteomics has driven the demand for chromatographic methods compatible with mass spectrometry (MS) that can separate intact proteins. Hydrophilic interaction liquid chromatography (HILIC) has recently shown good potential for the characterization of glycoforms of intact proteins. In the present study, we demonstrate that HILIC can separate a wide range of proteins exhibiting orthogonal selectivity with respect to reversed-phase LC (RPLC). However, the application of HILIC to the analysis of low abundance proteins (e.g., in proteomics analysis) is hampered by low volume loadability, hindering down-scaling of the method to column diameters below 2.1 mm. Moreover, HILIC-MS sensitivity is decreased due to ion suppression from the trifluoroacetic acid (TFA) often used as the ion-pair agent to improve the selectivity and efficiency in the analysis of glycoproteins. Here, we introduce a capillary-based HILIC-MS method that overcomes these problems. Our method uses RPLC trap-columns to load and inject the sample, circumventing issues of protein solubility and volume loadability in capillary columns (200 MUm ID). The low flow rates and use of a dopant gas in the electrospray interface improve protein-ionization efficiencies and reduce suppression by TFA. Overall, this allows the separation and detection of small protein quantities (down to 5 ng injected on column) as indicated by the analysis of a mixture of model proteins. The potential of the new capillary HILIC MS is demonstrated by the analysis of a complex cell lysate. PMID- 29722973 TI - Calixarene-Based {Ni18} Coordination Wheel: Highly Efficient Electrocatalyst for the Glucose Oxidation and Template for the Homogenous Cluster Fabrication. AB - Catalyst plays a very important role in the exploration of new energy. To obtain a highly efficient electrocatalyst for the glucose oxidation and tiny metal nanocluster catalysts, a calixarene-based {Ni18} coordination wheel with sulfur atoms on the cavity surface was designed, synthesized, and used as the porous template. Contributing from the active sites of nickel cations, the as synthesized coordination wheels can efficiently catalyze the electrochemical oxidation of glucose with the onset and peak potentials of 0.3 and 0.46 V in alkaline medium, and the catalysis does not depend on the atmosphere (N2, air, or O2), which indicates that the coordination wheel will be a promising electrocatalyst candidate for the compartmentless glucose-air fuel cell. Meanwhile, benefiting from its confined cavity and inner sulfur surface, such a coordination wheel can serve as a general template for the fabrication and encapsulation of tiny metal nanoclusters of Au, Pd, Ir, Ru, Rh, Pt, and AuPd. In electrochemical examinations, the bimetallic AuPd clusters confined in the coordination wheel show higher current density than commercial Pt/C toward hydrogen evolution reaction (HER). The present study shows that the designed coordination wheel can be used as not only a type of novel catalyst itself but also a class of templates for metal cluster catalysts. PMID- 29722975 TI - Local Optoelectronic Characterization of Solvent-Annealed, Lead-Free, Bismuth Based Perovskite Films. AB - Traditional organolead-halide perovskite-based devices have shown rapid improvements in their power conversion efficiency in less than a decade, yet challenges remain for improving stability and film uniformity, as well as the elimination of lead to address toxicity issues. We fabricated lead-free methylammonium bismuth iodide (MBI) perovskite films and studied the effect of solvent annealing with dimethylformamide (DMF) on both (1) the crystallinity and structure of the films with X-ray diffraction and scanning electron microscopy and (2) the local optoelectronic properties of the films as measured via (photo)conductive atomic force microscopy. We found that solvent annealing leads to improved crystallinity and increased grain size in the MBI films as compared to the thermally annealed films. Furthermore, solvent-annealed MBI films show significantly increased electrical conductivity in the out-of-plane direction. Photoconductivity in both solvent-annealed and thermally annealed MBI films was increased in the grain interiors versus the grain boundaries. It was observed that DMF-induced solvent annealing impacts charge transport through the film, which can be a unique design parameter for optimizing local optoelectronic properties. By studying how solvent annealing affects the MBI film structure and changes the ways in which charges are transported through the film, we have developed a better understanding of how local optoelectronic properties are affected by DMF annealing. PMID- 29722976 TI - GMars-T Enabling Multimodal Subdiffraction Structural and Functional Fluorescence Imaging in Live Cells. AB - Fluorescent probes with multimodal and multilevel imaging capabilities are highly valuable as imaging with such probes not only can obtain new layers of information but also enable cross-validation of results under different experimental conditions. In recent years, the development of genetically encoded reversibly photoswitchable fluorescent proteins (RSFPs) has greatly promoted the application of various kinds of live-cell nanoscopy approaches, including reversible saturable optical fluorescence transitions (RESOLFT) and stochastic optical fluctuation imaging (SOFI). However, these two classes of live-cell nanoscopy approaches require different optical characteristics of specific RSFPs. In this work, we developed GMars-T, a monomeric bright green RSFP which can satisfy both RESOLFT and photochromic SOFI (pcSOFI) imaging in live cells. We further generated biosensor based on bimolecular fluorescence complementation (BiFC) of GMars-T which offers high specificity and sensitivity in detecting and visualizing various protein-protein interactions (PPIs) in different subcellular compartments under physiological conditions (e.g., 37 degrees C) in live mammalian cells. Thus, the newly developed GMars-T can serve as both structural imaging probe with multimodal super-resolution imaging capability and functional imaging probe for reporting PPIs with high specificity and sensitivity based on its derived biosensor. PMID- 29722974 TI - Versatile Histochemical Approach to Detection of Hydrogen Peroxide in Cells and Tissues Based on Puromycin Staining. AB - Hydrogen peroxide (H2O2) is a central reactive oxygen species (ROS) that contributes to diseases from obesity to cancer to neurodegeneration but is also emerging as an important signaling molecule. We now report a versatile histochemical approach for detection of H2O2 that can be employed across a broad range of cell and tissue specimens in both healthy and disease states. We have developed a first-generation H2O2-responsive analogue named Peroxymycin-1, which is based on the classic cell-staining molecule puromycin and enables covalent staining of biological samples and retains its signal after fixation. H2O2 mediated boronate cleavage uncages the puromycin aminonucleoside, which leaves a permanent and dose-dependent mark on treated biological specimens that can be detected with high sensitivity and precision through a standard immunofluorescence assay. Peroxymycin-1 is selective and sensitive enough to image both exogenous and endogenous changes in cellular H2O2 levels and can be exploited to profile resting H2O2 levels across a panel of cell lines to distinguish metastatic, invasive cancer cells from less invasive cancer and nontumorigenic counterparts, based on correlations with ROS status. Moreover, we establish that Peroxymycin-1 is an effective histochemical probe for in vivo H2O2 analysis, as shown through identification of aberrant elevations in H2O2 levels in liver tissues in a murine model of nonalcoholic fatty liver disease, thus demonstrating the potential of this approach for studying disease states and progression associated with H2O2. This work provides design principles that should enable development of a broader range of histochemical probes for biological use that operate via activity-based sensing. PMID- 29722978 TI - Domain-Invariant Partial-Least-Squares Regression. AB - Multivariate calibration models often fail to extrapolate beyond the calibration samples because of changes associated with the instrumental response, environmental condition, or sample matrix. Most of the current methods used to adapt a source calibration model to a target domain exclusively apply to calibration transfer between similar analytical devices, while generic methods for calibration-model adaptation are largely missing. To fill this gap, we here introduce domain-invariant partial-least-squares (di-PLS) regression, which extends ordinary PLS by a domain regularizer in order to align the source and target distributions in the latent-variable space. We show that a domain invariant weight vector can be derived in closed form, which allows the integration of (partially) labeled data from the source and target domains as well as entirely unlabeled data from the latter. We test our approach on a simulated data set where the aim is to desensitize a source calibration model to an unknown interfering agent in the target domain (i.e., unsupervised model adaptation). In addition, we demonstrate unsupervised, semisupervised, and supervised model adaptation by di-PLS on two real-world near-infrared (NIR) spectroscopic data sets. PMID- 29722977 TI - Phosphonomethyl Oligonucleotides as Backbone-Modified Artificial Genetic Polymers. AB - Although several synthetic or xenobiotic nucleic acids (XNAs) have been shown to be viable genetic materials in vitro, major hurdles remain for their in vivo applications, particularly orthogonality. The availability of XNAs that do not interact with natural nucleic acids and are not affected by natural DNA processing enzymes, as well as specialized XNA processing enzymes that do not interact with natural nucleic acids, is essential. Here, we report 3'-2' phosphonomethyl-threosyl nucleic acid (tPhoNA) as a novel XNA genetic material and a prime candidate for in vivo XNA applications. We established routes for the chemical synthesis of phosphonate nucleic acids and phosphorylated monomeric building blocks, and we demonstrated that DNA duplexes were destabilized upon replacement with tPhoNA. We engineered a novel tPhoNA synthetase enzyme and, with a previously reported XNA reverse transcriptase, demonstrated that tPhoNA is a viable genetic material (with an aggregate error rate of approximately 17 * 10-3 per base) compatible with the isolation of functional XNAs. In vivo experiments to test tPhoNA orthogonality showed that the E. coli cellular machinery had only very limited potential to access genetic information in tPhoNA. Our work is the first report of a synthetic genetic material modified in both sugar and phosphate backbone moieties and represents a significant advance in biorthogonality toward the introduction of XNA systems in vivo. PMID- 29722980 TI - Multilevel Molecular Modeling Approach for a Rational Design of Ionic Current Sensors for Nanofluidics. AB - The complexity displayed by nanofluidic-based systems involves electronic and dynamic aspects occurring across different size and time scales. To properly model such kind of system, we introduced a top-down multilevel approach, combining molecular dynamics simulations (MD) with first-principles electronic transport calculations. The potential of this technique was demonstrated by investigating how the water and ionic flow through a (6,6) carbon nanotube (CNT) influences its electronic transport properties. We showed that the confinement on the CNT favors the partially hydrated Na, Cl, and Li ions to exchange charge with the nanotube. This leads to a change in the electronic transmittance, allowing for the distinguishing of cations from anions. Such an ionic trace may handle an indirect measurement of the ionic current that is recorded as a sensing output. With this case study, we are able to show the potential of this top-down multilevel approach, to be applied on the design of novel nanofluidic devices. PMID- 29722979 TI - RPtag as an Orally Bioavailable, Hyperstable Epitope Tag and Generalizable Protein Binding Scaffold. AB - Antibodies are the most prolific biologics in research and clinical environments because of their ability to bind targets with high affinity and specificity. However, antibodies also carry liabilities. A significant portion of the life science reproducibility crisis is driven by inconsistent performance of research grade antibodies, and clinical antibodies are often unstable and require costly cold-chain management to reach their destinations in active form. In biotechnology, antibodies are also limited by difficulty integrating them in many recombinant systems due to their size and structural complexity. A switch to small, stable, sequence-verified binding scaffolds may overcome these barriers. Here we present such a scaffold, RPtag, based on a ribose-binding protein (RBP) from extremophile Caldanaerobacter subterraneus. RPtag binds an optimized peptide with pM affinity, is stable to extreme temperature, pH, and protease treatment, readily refolds after denaturation, is effective in common laboratory applications, was rationally engineered to bind bioactive PDGF-beta, and was formulated as a gut-stable orally bioavailable preparation. PMID- 29722981 TI - Highly Stable [C60AuC60]+/- Dumbbells. AB - Ionic complexes between gold and C60 have been observed for the first time. Cations and anions of the type [Au(C60)2]+/- are shown to have particular stability. Calculations suggest that these ions adopt a C60-Au-C60 sandwich-like (dumbbell) structure, which is reminiscent of [XAuX]+/- ions previously observed for much smaller ligands. The [Au(C60)2]+/- ions can be regarded as Au(I) complexes, regardless of whether the net charge is positive or negative, but in both cases, the charge transfer between the Au and C60 is incomplete, most likely because of a covalent contribution to the Au-C60 binding. The C60-Au-C60 dumbbell structure represents a new architecture in fullerene chemistry that might be replicable in synthetic nanostructures. PMID- 29722982 TI - Copper-Catalyzed Oxidative Cyclization/1,2-Amino Migration Cascade Reaction. AB - A novel and efficient copper-catalyzed tandem oxidative cyclization/1,2-amino migration of readily available enamino esters for the synthesis of substituted pyrroles has been developed. In this reaction, one C-N bond was cleaved, and two new C-N bonds and one C(sp2)-C(sp2) bond were constructed in one pot. This catalytic system has the obvious advantages of mild reaction conditions and the use of oxygen as the oxidant. The reaction tolerates a wide range of functional groups and is a reliable method for the straightforward synthesis of valuable aminomethyl-substituted pyrroles in good yields. PMID- 29722983 TI - N-Heterocyclic Carbene-Catalyzed Michael-Michael-Lactonization Cascade for the Enantioselective Synthesis of Tricyclic delta-Lactones. AB - Enantioselective synthesis of tricyclic delta-lactones with three contiguous stereocenters has been demonstrated by the N-heterocyclic carbene (NHC)-catalyzed functionalization of benzylic C(sp3)-H bonds. The NHC-catalyzed reaction of enals with dinitrotoluene derivatives under oxidative conditions proceeds via the chiral alpha,beta-unsaturated acylazoliums and produces the delta-lactones in good yields and excellent diastereoselectivity and enantioselectivity. This mild and atom-economic cascade reaction takes place in a Michael/Michael/lactonization sequence and tolerates a broad range of functional groups. PMID- 29722984 TI - Dimerization and Conformational Exchanges of the Receiver Domain of Response Regulator PhoB from Escherichia coli. AB - PhoB is a response regulator of PhoR/PhoB two-component system from Escherichia coli that is involved in the environmental phosphate regulation. It has been reported that the N-terminal receiver domain (PhoBN) forms a dimer using the alpha1-alpha5 face in the apo state and a dimer using the alpha4-beta5-alpha5 face in the active state investigated by X-ray crystallography. However, it is not clear whether the conformational switch of the dimer is dependent on phosphorylation. Here, we report the NMR studies of PhoBN in solution in its apo form. We observed that the secondary structural fragments of apo PhoBN characterized by NMR are almost the same as those determined by crystallography, but the NMR spectrum of PhoBN shows inhomogeneous amide signals. Concentration dilution experiments and backbone relaxation parameters showed that PhoBN exists in equilibrium between monomer and dimer states. Using paramagnetic relaxation enhancement experiments, we demonstrated that the dimer of apo PhoBN forms several transient dimer interfaces in solution. This finding suggested that, in addition to the monomer-to-dimer exchange, the inactive conformation of PhoBN has different domain arrangements, which are independent of phosphorylation. It provides an experimental data for the conformational selection mechanism of the phosphorylation of PhoBN. PMID- 29722985 TI - Short-Range Electron Transfer in Reduced Flavodoxin: Ultrafast Nonequilibrium Dynamics Coupled with Protein Fluctuations. AB - Short-range electron transfer (ET) in proteins is an ultrafast process on the similar time scales as local protein-solvent fluctuation, and thus the two dynamics are coupled. Here we use semiquinone flavodoxin and systematically characterized the photoinduced redox cycle with 11 mutations of different aromatic electron donors (tryptophan and tyrosine) and local residues to change redox properties. We observed the forward and backward ET dynamics in a few picoseconds, strongly following a stretched behavior resulting from a coupling between local environment relaxations and these ET processes. We further observed the hot vibrational-state formation through charge recombination and the subsequent cooling dynamics also in a few picoseconds. Combined with the ET studies in oxidized flavodoxin, these results coherently reveal the evolution of the ET dynamics from single to stretched exponential behaviors and thus elucidate critical time scales for the coupling. The observed hot vibration-state formation is robust and should be considered in all photoinduced back ET processes in flavoproteins. PMID- 29722986 TI - Surface Plasmon Enhanced Strong Exciton-Photon Coupling in Hybrid Inorganic Organic Perovskite Nanowires. AB - Manipulating strong light-matter interaction in semiconductor microcavities is crucial for developing high-performance exciton polariton devices with great potential in next-generation all-solid state quantum technologies. In this work, we report surface plasmon enhanced strong exciton-photon interaction in CH3NH3PbBr3 perovskite nanowires. Characteristic anticrossing behaviors, indicating a Rabi splitting energy up to ~564 meV, are observed near exciton resonance in hybrid perovskite nanowire/SiO2/Ag cavity at room temperature. The exciton-photon coupling strength is enhanced by ~35% on average, which is mainly attributed to surface plasmon induced localized excitation field redistribution. Further, systematic studies on SiO2 thickness and nanowire dimension dependence of exciton-photon interaction are presented. These results provide new avenues to achieve extremely high coupling strengths and push forward the development of electrically pumped and ultralow threshold small lasers. PMID- 29722988 TI - Direct Catalytic Asymmetric 1,6-Conjugate Addition of Amides to p-Quinone Methides. AB - Amide pronucleophiles were successfully incorporated into a 1,6-conjugate addition reaction manifold using p-quinone methides ( p-QMs) as electrophiles. Four different types of functionalities were tolerated as alpha-substituents of the amides, allowing for expeditious access to a range of enantiomerically enriched diarylmethine products. The 7-azaindoline unit is critically important for in situ catalytic enolization of the amide pronucleophile, engaging in 1,6 conjugate addition to p-QMs with readily available catalyst components. PMID- 29722987 TI - Interaction of Myelin Basic Protein with Myelin-like Lipid Monolayers at Air Water Interface. AB - Interaction of myelin basic protein (MBP) and the cytoplasmic leaflets of the oligodendrocyte membrane is essential for the formation and compaction of the myelin sheath of the central nervous system and is altered aberrantly and implicated in the pathogenesis of neurodegenerative diseases like multiple sclerosis. To gain more detailed insights into this interaction, the adsorption of MBP to model lipid monolayers of similar composition to the myelin of the central nervous system was studied at the air-water interface with monolayer adsorption experiments. Measuring the surface pressure and the related maximum insertion pressure of MBP for different myelin-like lipid monolayers provided information about the specific role of each of the single lipids in the myelin. Depending on the ratio of negatively charged lipids to uncharged lipids and the distance between charges, the adsorption process was found to be determined by two counteracting effects: (i) protein incorporation, resulting in an increasing surface pressure and (ii) lipid condensation due to electrostatic interaction between the positively charged protein and negatively charged lipids, resulting in a decreasing surface pressure. Although electrostatic interactions led to high insertion pressures, the associated lipid condensation lowered the fluidity of the myelin-like monolayer. PMID- 29722989 TI - Lattice Dynamics and Thermal Conductivity in Cu2Zn1- xCo xSnSe4. AB - The quaternary compound Cu2ZnSnSe4 (CZTSe), as a typical candidate for both solar cells and thermoelectrics, is of great interest for energy harvesting applications. Materials with a high thermoelectric efficiency have a relatively low thermal conductivity, which is closely related to their chemical bonding and lattice dynamics. Therefore, it is essential to investigate the lattice dynamics of materials to further improve their thermoelectric efficiency. Here we report a lattice dynamic study in a cobalt-substituted CZTSe system using temperature dependent X-ray absorption fine structure spectroscopy (TXAFS). The lattice contribution to the thermal conductivity is dominant, and its reduction is mainly ascribed to the increment of point defects after cobalt substitution. Furthermore, a lattice dynamic study shows that the Einstein temperature of atomic pairs is reduced after cobalt substitution, revealing that increasing local structure disorder and weakened bonding for each of the atomic pairs are achieved, which gives us a new perspective for understanding the behavior of lattice thermal conductivity. PMID- 29722991 TI - Pd(II)-Catalyzed Cyclization-Oxidation of Urea-Tethered Alkylidenecyclopropanes. AB - A Pd(OAc)2-catalyzed intramolecular oxidative cyclization of urea-tethered alkylidenecyclopropanes with urea as a nitrogen source through a Pd(II)/Pd(IV) catalytic cycle has been presented, giving the corresponding cyclobuta[ b]indoline derivatives in moderate to good yields with a broad substrate scope. The reaction proceeds through a ring expansion of alkylidenecyclopropane along with the nucleophilic attack of nitrogen atom onto the in situ generated palladium carbenoid species as well as an oxidation process. PMID- 29722990 TI - [2.2.2]- to [3.2.1]-Bicycle Skeletal Rearrangement Approach to the Gibberellin Family of Natural Products. AB - Synthetic studies toward the gibberellin family of natural products are reported. An oxidative dearomatization/Diels-Alder cascade assembles the carbon skeleton as a [2.2.2]-bicycle, which is then transformed to the [3.2.1]-bicyclic gibberellin core via a novel Lewis acid catalyzed rearrangement. Strategic synthetic handles allow for late-stage modification of the gibberellin skeleton and provides efficient access to this important family of natural compounds. PMID- 29722992 TI - A [4 + 3] Annulation Reaction of aza- o-Quinone Methides with Arylcarbohydrazonoyl Chlorides for Synthesis of 2,3-Dihydro-1 H-benzo[ e][1,2,4]triazepines. AB - An unprecedented [4 + 3] annulation reaction of aza- ortho-quinone methides with arylcarbohydrazonoyl chlorides has been achieved under mild conditions. The annulation underwent a sequential conjugate addition/intramolecular annulation/rearrangement, providing a useful method for the synthesis of biologically interesting 2,3-dihydro-1 H-benzo[ e][1,2,4]triazepine. PMID- 29722993 TI - Developing an Anticancer Copper(II) Multitarget Pro-Drug Based on the His146 Residue in the IB Subdomain of Modified Human Serum Albumin. AB - Designing a multitarget anticancer drug with improved delivery and therapeutic efficiency in vivo presents a great challenge. Thus, we proposed to design an anticancer multitarget metal pro-drug derived from thiosemicarbazone based on the His146 residue in the IB subdomain of palmitic acid (PA)-modified human serum albumin (HSA-PA). The structure-activity relationship of six Cu(II) compounds with 6-methyl-2-formylpyridine-4N-substituted thiosemicarbazones were investigated, and then the multitarget capability of 4b was confirmed in cancer cell DNA and proteins. The structure of the HSA-PA-4b complex (HSA-PA-4b) revealed that 4b is bound to the IB subdomain of modified HSA, and that His146 replaces the nitrate ligand in 4b, coordinating with Cu2+, whereas PA is complexed with the IIA subdomain by its carboxyl forming hydrogen bonds with Lys199 and His242. In vivo data showed that 4b and the HSA-PA-4b complex inhibit lung tumor growth, and the targeting ability and therapeutic efficacy of the PA modified HSA complex was stronger than 4b alone. PMID- 29722994 TI - Role of Transmembrane Potential and Defects on the Permeabilization of Lipid Bilayers by Alamethicin, an Ion-Channel-Forming Peptide. AB - The insertion and ion-conducting channel properties of alamethicin reconstituted into a 1,2-di- O-phytanyl- sn-glycero-3-phosphocholine bilayer floating on the surface of a gold (111) electrode modified with a 1-thio-beta-d-glucose (beta-Tg) self-assembled monolayer were investigated using a combination of electrochemical impedance spectroscopy (EIS) and polarization modulation infrared reflection absorption spectroscopy (PM-IRRAS). The hydrophilic beta-Tg monolayer separated the bilayer from the gold substrate and created a water-rich spacer region, which better represents natural cell membranes. The EIS measurements acquired information about the membrane resistivity (a measure of membrane porosity), and the PM-IRRAS experiments provided insight into the conformation and orientation of the membrane constituents as a function of the transmembrane potential. The results showed that the presence of alamethicin had a small effect on the conformation and orientation of phospholipid molecules within the bilayer for all studied potentials. In contrast, the alamethicin peptides assumed a surface state, where the helical axes adopted a large tilt angle with respect to the surface normal, at small transmembrane potentials, and inserted into the bilayer at sufficiently negative transmembrane potentials forming pores, which behaved as barrel-stave ion channels for ionic transport across the membrane. The results indicated that insertion of alamethincin peptides into the bilayer was driven by the dipole-field interactions and that the transitions between the inserted and surface states were electrochemically reversible. Additionally, the EIS measurements performed on phospholipid bilayers without alamethicin also showed that the application of negative transmembrane potentials introduces defects into the bilayer. The membrane resistances measured in both the absence and presence of alamethicin show similar dependencies on the electrode potential, suggesting that the insertion of the peptide may also be assisted by the electroporation of the membrane. The findings in this study provide new insights into the mechanism of alamethicin insertion into phospholipid bilayers. PMID- 29722995 TI - From theoretical to empirical: Considering reflections of psychopathy across the thin blue line. AB - The majority of psychopathy research has focused on negative outcomes in criminal populations. However, psychopathy encompasses a variety of traits, and recent research suggests that certain features of psychopathy, such as a fearless temperament, may be related to psychological resiliency, "successful" functioning, and even heroic behavior (Hall & Benning, 2006; Lykken, 1995). Despite anecdotal discussion, little is known about the possible "successful" or adaptive reflections of psychopathic personality traits in ostensible heroes. This study expands on the knowledge of "successful" psychopathy by considering police recruits; we examined the degree to which these aspiring first responders share traits with psychopathic individuals. When compared with a student sample and the community and offender samples in the Psychopathic Personality Inventory Revised manual (Lilienfeld & Widows, 2005), the police recruits reported higher Fearless Dominance and Coldheartedness scores and lower Self-Centered Impulsivity scores. Fearless dominance traits were positively correlated with narcissism, and self-centered impulsivity traits were positively associated with covert narcissism. These findings suggest that although our police recruit sample is not classically psychopathic, the dominance and coldheartedness associated with psychopathy may be common among those beginning a police career. Further, our results imply that certain features of psychopathy may be reflected across the thin blue line in those on the verge of entering their police careers. (PsycINFO Database Record PMID- 29722996 TI - Validity of the Multidimensional Schizotypy Scale: Associations with schizotypal traits and normal personality. AB - The present study provided the first examination of the construct validity of the Multidimensional Schizotypy Scale (MSS) and the first assessment of its psychometric properties outside of its derivation samples. The MSS contains 77 items that assess positive, negative, and disorganized schizotypy. A large multisite sample of 1,430 participants completed the MSS and measures of schizotypal personality traits and the five-factor model of personality. The MSS subscales had good-to-excellent internal consistency reliability that showed no shrinkage relative to the MSS derivation samples. The psychometric properties and intercorrelations of the MSS subscales were closely consistent with the derivation findings. The MSS Positive Schizotypy subscale had a strong association with cognitive-perceptual schizotypal traits (large effect), positive associations with personality traits of neuroticism and openness to experience, and negative associations with agreeableness. The MSS Negative Schizotypy subscale had a strong association with interpersonal schizotypal traits (medium effect) and negative associations with personality traits of extraversion, openness, and agreeableness. The MSS Disorganized Schizotypy subscale had a strong association with disorganized schizotypal traits (medium effect), a positive association with neuroticism, and a negative association with conscientiousness. The findings were consistent with the a priori predictions and support the construct validity of the MSS. (PsycINFO Database Record PMID- 29722997 TI - Provider and consumer perspectives of community mental health services: Implications for consumer-driven care. AB - Public mental health services in the community are broad and continue to expand to address the multiple issues faced by those with serious mental illnesses. However, few studies examine and contrast how helpful consumers and providers find the spectrum of services. The present study examines the services at community mental health service clinics (CMHCs) from the perspectives of providers and consumers. There were 351 consumers and 147 providers from 15 CMHCs who rated and ranked the helpfulness of 24 types of common services. All of the agencies were participating in a Practice-Based Research Network (PBRN). Social support was the highest rated service by both types of respondents, and the creation of a welcoming environment was the highest ranked service by both. There were also areas of disagreement. Consumers identified traditional mental health services (individual therapy and medication services) as being most helpful to them whereas providers selected longer-term services that promote self-reliance (e.g., securing housing, and promoting self-sufficiency) as the most helpful. Understanding how consumers and providers perceive the range of CMHC services provided in usual care is important to develop new targets for intervention. A welcoming milieu and providing social support appear important to both, but significant differences exist between these groups regarding other aspects of services. This holds implications for the design and implementation of consumer driven services. (PsycINFO Database Record PMID- 29722998 TI - Honor among thieves: The interaction of team and member deviance on trust in the team. AB - In this article, we examine member trust in deviant teams. We contend that a member's trust in his or her deviant team depends on the member's own deviant actions; although all members will judge the actions of their deviant teams as rational evidence that they should not be trusted, deviant members, but not honest members, can hold on to trust in their teams because of a sense of connection to the team. We tested our predictions in a field study of 562 members across 111 teams and 24 organizations as well as in an experiment of 178 participants in deviant and non-deviant teams. Both studies show that honest members experience a greater decline in trust as team deviance goes up. Moreover, our experiment finds that deviant members have as much trust in their deviant teams as honest members do in honest teams, but only in teams with coordinated rather than independent acts of deviance, in which deviant members engage in a variety of ongoing dynamics foundational to a sense of connection and affective based trust. (PsycINFO Database Record PMID- 29722999 TI - Cleansing my abuse: A reparative response model of perpetrating abusive supervisor behavior. AB - Research on abusive supervision has predominantly focused on the consequences for victims while overlooking how leaders respond to their own abusive behavior. Drawing from the literature on moral cleansing, we posit that supervisors who engage in abusive behavior may paradoxically engage in more constructive leadership behaviors subsequently as a result of feeling guilty and perceiving loss of moral credits. Results from two experience sampling studies show that, within leaders on a daily basis, perpetrating abusive supervisor behavior led to an increase in experienced guilt and perceived loss of moral credits, which in turn motivated leaders to engage in more constructive person-oriented (consideration) and task-oriented (initiating structure) leadership behaviors. In addition, leader moral attentiveness and moral courage strengthen these indirect effects by amplifying leaders' awareness of their immoral behavior and their willingness and determination to make reparations for such behavior. Our research contributes to the theoretical understanding of leaders' responses toward their own abusive supervisor behavior and provides insights into how and when destructive leadership behaviors may, paradoxically, trigger more constructive behaviors. (PsycINFO Database Record PMID- 29723000 TI - Changing abilities vs. changing tasks: Examining validity degradation with test scores and college performance criteria both assessed longitudinally. AB - We explore potential explanations for validity degradation using a unique predictive validation data set containing up to four consecutive years of high school students' cognitive test scores and four complete years of those students' college grades. This data set permits analyses that disentangle the effects of predictor-score age and timing of criterion measurements on validity degradation. We investigate the extent to which validity degradation is explained by criterion dynamism versus the limited shelf-life of ability scores. We also explore whether validity degradation is attributable to fluctuations in criterion variability over time and/or GPA contamination from individual differences in course-taking patterns. Analyses of multiyear predictor data suggest that changes to the determinants of performance over time have much stronger effects on validity degradation than does the shelf-life of cognitive test scores. The age of predictor scores had only a modest relationship with criterion-related validity when the criterion measurement occasion was held constant. Practical implications and recommendations for future research are discussed. (PsycINFO Database Record PMID- 29723002 TI - Sex through a sacred lens: Longitudinal effects of sanctification of marital sexuality. AB - Research attending to the role of religion and spirituality in enhancing sexuality in marriage is virtually absent. In response to this scarcity, this longitudinal study examined the sanctification of marital sexuality among newly married, heterosexual individuals (N = 67; married 4-18 months at Time 1). Greater sanctification of marital sexuality early in the marriage predicted more frequent sexual intercourse, sexual satisfaction, and marital satisfaction 1 year later for individual respondents, after controlling for initial levels of the dependent variable as well as age, frequencies of religious service attendance and prayer, and biblical conservatism. Greater sanctification continued to longitudinally predict greater sexual frequency and sexual satisfaction after also controlling for initial marital satisfaction. Participants with higher initial levels of sanctification of marital sexuality, relative to those with lower levels, experienced smaller declines in sexual satisfaction across 1 year. Findings add to empirical evidence that greater sanctification of close relationships facilitates relational well-being. (PsycINFO Database Record PMID- 29723001 TI - Mindfulness on-the-go: Effects of a mindfulness meditation app on work stress and well-being. AB - We investigated whether a mindfulness meditation program delivered via a smartphone application could improve psychological well-being, reduce job strain, and reduce ambulatory blood pressure during the workday. Participants were 238 healthy employees from two large United Kingdom companies that were randomized to a mindfulness meditation practice app or a wait-list control condition. The app offered 45 prerecorded 10- to 20-min guided audio meditations. Participants were asked to complete one meditation per day. Psychosocial measures and blood pressure throughout one working day were measured at baseline and eight weeks later; a follow-up survey was also emailed to participants 16 weeks after the intervention start. Usage data showed that during the 8-week intervention period, participants randomized to the intervention completed an average of 17 meditation sessions (range 0-45 sessions). The intervention group reported significant improvement in well-being, distress, job strain, and perceptions of workplace social support compared to the control group. In addition, the intervention group had a marginally significant decrease in self-measured workday systolic blood pressure from pre- to post-intervention. Sustained positive effects in the intervention group were found for well-being and job strain at the 16-week follow up assessment. This trial suggests that short guided mindfulness meditations delivered via smartphone and practiced multiple times per week can improve outcomes related to work stress and well-being, with potentially lasting effects. (PsycINFO Database Record PMID- 29723003 TI - Temporality of couple conflict and relationship perceptions. AB - Using 5 waves of longitudinal survey data gathered from 3,405 couples, the present study investigates the temporal associations between self-reported couple conflict (frequency and each partner's constructive and withdrawing behaviors) and relationship perceptions (satisfaction and perceived instability). Autoregressive cross-lagged model results revealed couple conflict consistently predicted future relationship perceptions: More frequent conflict and withdrawing behaviors and fewer constructive behaviors foretold reduced satisfaction and conflict frequency and withdrawal heightened perceived instability. Relationship perceptions also shaped future conflict, but in surprising ways: Perceptions of instability were linked with less frequent conflict, and male partner instability predicted fewer withdrawing behaviors for female partners. Higher satisfaction from male partners also predicted more frequent and less constructive conflict behavior in the future. These findings illustrate complex bidirectional linkages between relationship perceptions and couple conflict behaviors in the development of couple relations. (PsycINFO Database Record PMID- 29723005 TI - A new coefficient of interrater agreement: The challenge of highly unequal category proportions. AB - We derive a general structure that encompasses important coefficients of interrater agreement such as the S-coefficient, Cohen's kappa, Scott's pi, Fleiss' kappa, Krippendorff's alpha, and Gwet's AC1. We show that these coefficients share the same set of assumptions about rater behavior; they only differ in how the unobserved category proportions are estimated. We incorporate Bayesian estimates of the category proportions and propose a new agreement coefficient with uniform prior beliefs. To correct for guessing in the process of item classification, the new coefficient emphasizes equal category probabilities if the observed frequencies are unstable due to a small sample, and the frequencies increasingly shape the coefficient as they become more stable. The proposed coefficient coincides with the S-coefficient for the hypothetical case of zero items; it converges to Scott's pi, Fleiss' kappa, and Krippendorff's alpha as the number of items increases. We use simulation to show that the proposed coefficient is as good as extant coefficients if the category proportions are equal and that it performs better if the category proportions are substantially unequal. (PsycINFO Database Record PMID- 29723004 TI - Reduced mortality rates among caregivers: Does family caregiving provide a stress buffering effect? AB - Multiple studies have confirmed a seemingly paradoxical finding that family caregivers have lower mortality rates than comparable samples of noncaregivers. Caregivers are often also found to report more symptoms of depression and higher stress levels, but psychological distress and mortality are rarely examined in the same study. This study tests a possible mechanism for the mortality effect by applying a theoretical model that posits psychological and physiological stress buffering benefits from prosocial helping behaviors. Participants in the population-based REasons for Geographic and Racial Differences in Stroke (REGARDS) study included 3,580 family caregivers who were individually matched to 3,580 noncaregivers on 15 demographic, health history, and health behavior variables using a propensity score matching algorithm. Baseline measures of depressive symptoms and perceived stress levels were also collected. The results indicated that caregivers reported significantly more depressive symptoms and higher perceived stress levels than propensity-matched noncaregivers (ps < .0001). However, consistent with our previous analysis (Roth et al., 2013), an analysis of 7-year survival rates showed that caregivers had a 16.5% lower mortality rate than noncaregivers (hazard ratio = 0.835, 95% CI = 0.719, 0.970). Significant caregiving*psychological distress interaction effects supported the stress-buffering hypothesis. Both depressive symptoms and perceived stress scores were significant predictors of mortality for the matched noncaregivers (ps < .0001), but not for the caregivers (ps > .49). Family caregiving appears to be similar to other prosocial helping behaviors in that it provides stress-buffering adaptations that ameliorate the impact of stress on major health outcomes such as mortality. (PsycINFO Database Record PMID- 29723006 TI - Object-based target templates guide attention during visual search. AB - During visual search, attention is believed to be controlled in a strictly feature-based fashion, without any guidance by object-based target representations. To challenge this received view, we measured electrophysiological markers of attentional selection (N2pc component) and working memory (sustained posterior contralateral negativity; SPCN) in search tasks where two possible targets were defined by feature conjunctions (e.g., blue circles and green squares). Critically, some search displays also contained nontargets with two target features (incorrect conjunction objects, e.g., blue squares). Because feature-based guidance cannot distinguish these objects from targets, any selective bias for targets will reflect object-based attentional control. In Experiment 1, where search displays always contained only one object with target-matching features, targets and incorrect conjunction objects elicited identical N2pc and SPCN components, demonstrating that attentional guidance was entirely feature-based. In Experiment 2, where targets and incorrect conjunction objects could appear in the same display, clear evidence for object-based attentional control was found. The target N2pc became larger than the N2pc to incorrect conjunction objects from 250 ms poststimulus, and only targets elicited SPCN components. This demonstrates that after an initial feature-based guidance phase, object-based templates are activated when they are required to distinguish target and nontarget objects. These templates modulate visual processing and control access to working memory, and their activation may coincide with the start of feature integration processes. Results also suggest that while multiple feature templates can be activated concurrently, only a single object-based target template can guide attention at any given time. (PsycINFO Database Record PMID- 29723007 TI - A recursive Bayesian updating model of haptic stiffness perception. AB - Stiffness of many materials follows Hooke's Law, but the mechanism underlying the haptic perception of stiffness is not as simple as it seems in the physical definition. The present experiments support a model by which stiffness perception is adaptively updated during dynamic interaction. Participants actively explored virtual springs and estimated their stiffness relative to a reference. The stimuli were simulations of linear springs or nonlinear springs created by modulating a linear counterpart with low-amplitude, half-cycle (Experiment 1) or full-cycle (Experiment 2) sinusoidal force. Experiment 1 showed that subjective stiffness increased (decreased) as a linear spring was positively (negatively) modulated by a half-sinewave force. In Experiment 2, an opposite pattern was observed for full-sinewave modulations. Modeling showed that the results were best described by an adaptive process that sequentially and recursively updated an estimate of stiffness using the force and displacement information sampled over trajectory and time. (PsycINFO Database Record PMID- 29723009 TI - Operators who readily acquire patterns and cues, risk being miscued in routinized settings. AB - The detection of critical cues is a hallmark of expert performance, and in high risk settings, it can prevent serious incidents. A sensitivity to cues and a proclivity to rapidly acquire patterns during routinized tasks, however, can miscue performance when these patterns change. In the present study, 75 university students undertook an assessment of cue utilization and engaged in a 24-min rail control simulation. The rail control task involved monitoring with periodic interventions to reroute trains, according to a train-track matching rule. A hidden pattern in the sequencing of trains presented an opportunity to predict train movements and reduce the workload. This pattern was programmed to abruptly change 3 times during the rail task. Based on the response latency performance of participants and their detection of the rail task pattern (verbal descriptions), the results suggested that individuals who are sensitive to cues and who also detect patterns of dynamic stimuli (following limited exposure) experience a relatively greater risk of misapplying rules or misdiagnosing situations in routinized environments when stimuli change. Following a temporary decline in performance, however, if there are continued pattern changes, the performance of these individuals will remain unaffected. The implications are discussed for training and system design. (PsycINFO Database Record PMID- 29723010 TI - When pretesting fails to enhance learning concepts from reading texts. AB - Prior research suggests that people can learn more from reading a text when they attempt to answer pretest questions first. Specifically, pretests on factual information explicitly stated in a text increases the likelihood that participants can answer identical questions after reading than if they had not answered pretest questions. Yet, a central goal of education is to develop deep conceptual understanding. The present experiments investigated whether conceptual pretests facilitate learning concepts from reading texts. In Experiment 1, participants were given factual or conceptual pretest questions; a control group was not given a pretest. Participants then read a passage and took a final test consisting of both factual and conceptual questions. Some of the final test questions were repeated from the pretest and some were new. Although factual pretesting improved learning for identical factual questions, conceptual pretesting did not enhance conceptual learning. Conceptual pretest errors were significantly more likely to be repeated on the final test than factual pretest errors. Providing correct answers (Experiment 2) or correct/incorrect feedback (Experiment 3) following pretest questions enhanced performance on repeated conceptual test items, although these benefits likely reflect memorization and not conceptual understanding. Thus, pretesting appears to provide little benefit for learning conceptual information. (PsycINFO Database Record PMID- 29723008 TI - To compute lightness, illumination is not estimated, it is held constant. AB - The light reaching the eye from a surface does not indicate the black-gray-white shade of a surface (called lightness) because the effects of illumination level are confounded with the reflectance of the surface. Rotating a gray paper relative to a light source alters its luminance (intensity of light reaching the eye) but the lightness of the paper remains relatively constant. Recent publications have argued, as had Helmholtz (1866/1924), that the visual system unconsciously estimates the direction and intensity of the light source. We report experiments in which this theory was pitted against an alternative theory according to which illumination level and surface reflectance are disentangled by comparing only those surfaces that are equally illuminated, in other words, by holding illumination level constant. A 3-dimensional scene was created within which the rotation of a target surface would be expected to become darker gray according to the lighting estimation theory, but lighter gray according to the equi-illumination comparison theory, with results clearly favoring the latter. In a further experiment cues held to indicate light source direction (cast shadows, attached shadows, and glossy highlights) were completely eliminated and yet this had no effect on the results. (PsycINFO Database Record PMID- 29723011 TI - Association of belief in the "firewater myth" with strategies to avoid alcohol consequences among American Indian and Alaska Native college students who drink. AB - Belief in an American Indian/Alaska Native (AI/AN) specific biological vulnerability (BV) to alcohol problems (aka the "firewater myth") is associated with worse alcohol outcomes among AI/AN college students who drink, despite also being associated with greater attempts to reduce drinking. The current study examined how belief in a BV may have affected how 157 AI/AN college students who drink (a) attempted to moderate their alcohol use and avoid alcohol-related problems using abstinence-based and harm reduction strategies, and (b) attitudes toward these strategies as a means of addressing alcohol problems. Contrary to our hypotheses, belief in a BV was not found to be associated with use of harm reduction strategies or with how effective students believed these strategies to be. However, greater belief in a BV was associated with lower self-efficacy for the use of harm reduction strategies among more frequent heavy episodic drinkers. This is concerning, as the use of harm reduction strategies was associated with less frequent heavy episodic drinking in this sample. In contrast, belief in a BV was positively associated with the use of abstinence-based strategies and with how effective these strategies were perceived to be. However, for individuals with average or greater belief in a BV, abstinence-based strategies were associated with greater alcohol consequences. The results suggest that for AI/AN students who drink, belief in a BV may be influencing the strategies used to moderate alcohol use and avoid alcohol-related harm, as well as attitudes toward these strategies, in ways that do not appear helpful. (PsycINFO Database Record PMID- 29723012 TI - Rating motivational interviewing fidelity from thin slices. AB - Monitoring fidelity to psychosocial treatments is critical to dissemination, process and outcome research, and internal validity in efficacy trials. However, the costs required to behavior code fidelity to treatments like motivational interviewing (MI) over many therapists and sessions quickly become intractable. Coding less of a session accelerates the process, but it is not clear how much of a session must be evaluated to capture the fidelity of the entire session. The present study used a "thin slice" (Ambady & Rosenthal, 1992) paradigm to explore the degree to which variously sized thin slices of MI fidelity related to fidelity ratings for a full session. We randomly selected contiguous and noncontiguous segments of MI sessions at each whole percent of sessions (i.e., a slice consisting of 1% of session utterances, another at 2%, etc.). We then computed MI fidelity scores from these segments and calculated agreement with fidelity ratings obtained from the full session. We compared thin slice agreement with full sessions against interrater agreement and found that approximately a third of a session (9 min, 26 seconds in our sample) had sufficient agreement to approach interrater levels. These results provide a reference for researchers and clinicians to make efficient and informed use of their behavior coding resources. In addition, our results add to the behavior slicing literature, indicating that small therapist behavior samples adequately describe overall session behavior. (PsycINFO Database Record PMID- 29723013 TI - Implementing cognitive behavioral therapy for psychosis: An international survey of clinicians' attitudes and obstacles. AB - OBJECTIVE: This study aimed to better understand the implementation of cognitive behavioral therapy for psychosis (CBTp) by exploring the impact of clinicians' attitudes toward CBTp within the Theory of Planned Behavior framework (i.e., by considering attitudes, behaviors, intention, and social norms) as well as perceived obstacles and response to proposed solutions. METHOD: One hundred forty two clinicians from 2 sites in Canada and 1 site in Australia answered an online survey involving both Likert scales and open-ended questions. The role of attitudes, social norms, and behavioral control (i.e., freedom to decide or act) on intention of offering CBTp delivering CBTp were analyzed using linear and logistic regressions. Sites were compared using analysis of variance. Reponses to perceived obstacles were thematically analyzed. RESULTS: Results were similar across settings. Entered together in the model, attitudes, social norms, and behavioral control were significant in predicting the intention of offering CBTp, F(3, 125) = 38.49, p < .001, with 49% of the variance explained, although behavioral control did not significantly contribute to the model. CBTp training (odds ratio = 0.23, confidence interval = 0.06-0.58) and social norms (odds ratio = 0.79, confidence interval = 0.68-0.93) significantly predicted CBTp delivery. Six themes that emerged regarding perceived obstacles are provided. Training, supervision, and local support were the most frequently endorsed solutions. Brief or modular CBTp and group or online delivery were also positively endorsed. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Clinicians' individual and collective attitudes should be targeted by more and better training to increase their delivery of CBTp. Given organizational barriers, CBTp-informed interventions warrant further investigation. (PsycINFO Database Record PMID- 29723014 TI - Psychosocial approaches to improving the military-to-civilian transition process. AB - This special issue of Psychological Services provides a glimpse of some of the most recent work in the arena of psychosocial interventions for military service members who are reintegrating into civilian society and becoming veterans. The psychological effects that can occur as members go through the military-to civilian transition as they leave the military have been extensively recorded and treated. While psychosocial interventions have been utilized throughout history, we are seeing a new interest and recent renaissance in their use. These psychosocial interventions will help our veterans reintegrate into civilian society not just by focusing on reducing the symptoms from their visible and invisible wounds but by taking a more holistic and integrative perspective that works to improve the veterans' functioning in their surrounding social environments through community reengagement, treatment of the individual and their social environment, and functional improvement. The articles in this special issue illustrate how clinicians and researchers are validating new techniques to improve functioning among those learning to change careers as warriors in their new civilian occupations. (PsycINFO Database Record PMID- 29723015 TI - Using peer support groups to enhance community integration of veterans in transition. AB - Peer support groups, also known as "self-help groups," provide a unique tool for helping veterans working through the military-to-civilian transition to achieve higher levels of social support and community integration. The number and variety of community-based peer support groups has grown to the point that there are now more visits to these groups each year than to mental health professionals. The focus of these groups on the provision of social support, the number and variety of groups, the lack of cost, and their availability in the community make them a natural transition tool for building community-based social support. A growing literature suggests that these groups are associated with measurable improvements in social support, clinical symptoms, self-efficacy and coping. For clinical populations, the combination of peer support groups and clinical care results in better outcomes than either alone. Given this evidence, we suggest clinical services use active referral strategies to help veterans engage in peer support groups as a means of improving community reintegration and clinical outcomes. Finally, suggestions for identifying appropriate peer support groups and assisting with active referrals are provided. (PsycINFO Database Record PMID- 29723016 TI - Family-focused interventions and resources for veterans and their families. AB - Accelerated by the decreasing military presence in Iraq and Afghanistan, many military members are currently transitioning out of active duty into civilian life. Many of these new veterans have recently experienced combat deployment(s), and some are struggling with the aftermath of combat exposure, separation from family, and reintegration stressors. These challenges often follow these military families as they enter the civilian world, a time with its own major life changes vocationally, socially, and interpersonally. Although numerous resources have been developed to assist service members during their transition to the civilian world, relatively fewer exist for partners, children, and broader family systems. Family psychoeducation is a nonpathologizing, strengths-focused model of care that has documented benefits in the arena of mental illness. This article describes some manualized family psychoeducational programs and online and phone based resources that may be useful to veteran families during this time of change. The programs and resources described herein are all available for free, primarily online. Because of a wide variety of barriers and limitations for family based care in the Veterans Affairs health care system, veteran families are and will continue to seek mental health care in public sector settings. Community providers can enhance their military culture competence by familiarizing themselves with these resources and drawing upon them in working with transitioning military families. (PsycINFO Database Record PMID- 29723017 TI - It's not just showing up: How social identification with a veterans service organization relates to benefit-finding and social isolation among veterans. AB - Social identity theory suggests that the degree to which people identity with an organizational group can have multiple beneficial outcomes. This research focuses on how membership in and engagement with a Veterans Service Organization (VSO) relate to veterans' social isolation and perceptions that military service was beneficial to society, ultimately leading to improved veterans' health. Data from an online survey of 444 military veterans show that physical attendance and the degree to which veterans identify identification with the VSO play different roles in improving veterans' lives. Not only is VSO attendance linked to reduced social isolation but social isolation is further reduced when members both attend and feel strong social identification with the VSO. The degree to which veterans identify with the VSO is also directly linked to greater perceptions of benefit finding from military service, even for those who do not physically partake in the VSO's activities. Lesser isolation and greater benefit-finding are related to lower levels of posttraumatic stress symptomology. The results suggest that VSOs may be integrated into new approaches to assist veterans' transition from military into civilian life. (PsycINFO Database Record PMID- 29723018 TI - Coming home from prison: Adapting military resilience training to enhance successful community reintegration for justice-involved Iraq-Afghanistan veterans. AB - We propose a veteran-centric justice model of resilience training developed by the military for assisting service members coming home from war and modify it to assist Iraq/Afghanistan veterans coming home from prison. Incarceration has been identified as a stress aftereffect of the prolonged Iraq and Afghanistan combat deployments. Notably, the rate of Iraq and Afghanistan-era incarcerated veterans increased from 4% to 13% between 2004 and 2012 for all incarcerated veterans. Successful reentry to the community from prison incarceration is difficult, with rearrest and reincarceration a frequent occurrence. Moreover, combat stress conditions may weaken the justice-involved Iraq/Afghanistan's veteran's ability to face challenges posed by the return home from prison. As in the war zone, the return home from prison may be idealized with unrealistic expectations and/or goals, thus setting up the returning veteran for disappointment, anger, deepening of alienation and disconnection from larger civilian society, and the risk of return to maladaptive mechanisms for coping. Resilience training can be provided in psychoeducational venues prior to prison release and with follow-up postrelease. Resilience building offers promise as an intervention to enhance the justice-involved veteran's successful community reentry. (PsycINFO Database Record PMID- 29723019 TI - Actuarial prediction of psychotherapy retention among Iraq-Afghanistan veterans with posttraumatic stress disorder. AB - The present study aimed to identify predictors of treatment retention in a sample of Operation Enduring Freedom/Operation Iraqi Freedom/Operation New Dawn (OEF/OIF/OND) veterans with posttraumatic stress disorder (PTSD) who were referred for PTSD-focused treatment through completion of a Veterans Affairs (VA) specialty clinic introductory information session. A total of 124 returning veterans (89% male, 53% Caucasian, 40% African American, 2% Latino; average age = 37 years) participated in an introductory session intended to facilitate informed decision making about treatment selection for PTSD. To evaluate patient, therapist, and system characteristics that were associated with risk of prematurely dropping out of psychotherapy for PTSD, we used recursive partitioning or "classification tree" methods commonly used to derive actuarial models of risk for high or low scores on a particular outcome when the set of independent or predictor variables is large. Findings revealed interactions among predictors involving access to care, readiness for change, histories of traumatic brain injury, and previous PTSD treatment. Results from the exploratory recursive model indicated that participation in therapy was highest when veterans entered psychotherapy within 68 days of the information session, believed that they needed help, and had a history of traumatic brain injury, while participation was lowest when entry into treatment exceeded 68 days and belief in needing help was low. Effects associated with partitions in the recursive model were substantial, with Cohen's d statistics ranging from .60 to 1.75. Results of the present effectiveness study implicate the importance of access to care as well as motivation for treatment in the returning cohort of OEF/OIF/OND veterans seeking help for PTSD. (PsycINFO Database Record PMID- 29723020 TI - Effects of social support and resilient coping on violent behavior in military veterans. AB - Violence toward others has been identified as a serious postdeployment adjustment problem in a subset of Iraq- and Afghanistan-era veterans. In the current study, we examined the intricate links between posttraumatic stress disorder (PTSD), commonly cited psychosocial risk and protective factors, and violent behavior using a national randomly selected longitudinal sample of Iraq- and Afghanistan era United States veterans. A total of 1,090 veterans from the 50 United States and all United States military branches completed 2 waves of self-report survey data collection 1 year apart (retention rate = 79%). History of severe violent behavior at Wave 1 was the most substantial predictor of subsequent violence. In bivariate analyses, high correlations were observed among risk and protective factors, and between risk and protective factors and severe violence at both time points. In multivariate analyses, baseline violence (OR = 12.43, p < .001), baseline alcohol misuse (OR = 1.06, p < .05), increases in PTSD symptoms between Waves 1 and 2 (OR = 1.01, p < .05), and decreases in social support between Waves 1 and 2 (OR = .83, p < .05) were associated with increased risk for violence at Wave 2. Our findings suggest that rather than focusing specifically on PTSD symptoms, alcohol use, resilience, or social support in isolation, it may be more useful to consider how these risk and protective factors work in combination to convey how military personnel and veterans are managing the transition from wartime military service to civilian life, and at what point it might be most effective to intervene. (PsycINFO Database Record PMID- 29723022 TI - A supported education service pilot for returning veterans with posttraumatic stress disorder. AB - A randomized controlled pilot of supported education services was conducted with 33 Operation Enduring Freedom, Operation Iraqi Freedom, and Operation New Dawn (OEF, OIF, OND, respectively) veterans with posttraumatic stress disorder (PTSD) who had higher education goals. Veteran peers delivered supported education services to an intervention group; for the control group, peers provided "matched attention" of generalized support without supporting educational goals. The intervention was based on a manualized veteran-centric program of supported education using principles of supported employment for individuals living with mental illness and components of civilian models of supported education. The attrition rate was high, with 30% lost to services between the baseline screening and the first peer session, although this drop-out rate is comparable to other rehabilitation studies. Despite a small sample and a matched attention control that could have diluted possible effects, significant positive differences were found, with the intervention group spending greater amounts of time on educational activities than did the control group. Effect sizes for the impact of the intervention were large between Time 1 and Time 2, and moderately large between Time 2 and Time 3. PTSD-symptom severity and recovery attitudes did not predict the impact of the supported education intervention. Implementation of the veteran supported education program using veteran peers appears feasible, although assertive outreach may be necessary to recruit and engage veterans with PTSD. Findings suggest that supported education services can have a measurable effect on time spent attaining an educational goal. Future studies will need to be longitudinal, as well as attend to the attrition issue and capture the impact on other education outcomes, such as successful program completion. (PsycINFO Database Record PMID- 29723021 TI - Promising practices in vocational services for the community reintegration of returning veterans: The individual placement and support model and beyond. AB - Supporting returning veterans' job-seeking, hiring, and retention issues has become an essential goal for effective community reintegration. Given both the particular strengths and challenges associated with veterans transitioning from military to civilian life, multiple models for supported employment have become integrated into Veterans Affairs health care facilities across the nation. In this article, we review the state of vocational rehabilitation for veterans, with a particular focus on individual placement and support-supported employment (IPS SE), the current vocational services model that is considered the gold standard of vocational rehabilitation. Various modifications to the IPS-SE model are presented, including additions such as cognitive rehabilitation, contingency management, motivational interviewing, supported self-employment, and transitional work. Finally, recommendations are made about future directions and strategies to expand access to IPS-SE-based programs and to effectively meet the needs of returning veterans for employment in jobs of their choice. (PsycINFO Database Record PMID- 29723023 TI - An evaluation of mobile applications designed to assist service members and veterans transitioning to civilian life. AB - Mobile technologies may be able to provide service members and veterans with the knowledge necessary to transition to civilian life successfully in a cost effective and accessible manner. Although a number of transition applications (apps) currently exist in the marketplace, to our knowledge, none of them has been evaluated for quality or effectiveness. For this study, 6 experts used the Mobile App Rating Scale (MARS; Stoyanov et al., 2015) to evaluate the quality of 16 transition apps. The majority of these apps focused on providing service members with resource lists, employment assistance, or assistance with disability applications. Only 2 apps had been downloaded more than 10,000 times on GooglePlay, with the majority being downloaded between 100 and 1,000 times. Only 1 app received an above-average overall quality rating, and half received below average overall quality ratings. Based on these findings, the authors recommend that researchers and developers create more high-quality apps by focusing on education and health-care transition issues, as well as work to better disseminate their products. (PsycINFO Database Record PMID- 29723024 TI - Development and validation of a measure of PTSD-related psychosocial functional impairment: The Inventory of Psychosocial Functioning. AB - This study describes the three-phase development and validation of the Inventory of Psychosocial Functioning (IPF), an 80-item, self-report measure of posttraumatic stress disorder (PTSD)-related psychosocial functional impairment. In Phase I, we conducted 12 focus groups with male and female veterans (n = 53) to identify and operationalize the domains of psychosocial impairment associated with PTSD. This information was used to develop the IPF. We subsequently evaluated the psychometric properties of the newly developed inventory in Phases II (n = 276) and III (n = 368) using two independent samples of veterans. We found that the overall IPF score demonstrated stronger correlations with measures of mental health-related impairment (all rs > |.39|; all ps < .05) and weaker correlations with measures of physical health-related impairment (all rs < |.29|; all ps < .05). Overall IPF scores were most strongly associated with PTSD and other disorders associated with the anxious-misery factor of the three-factor model of psychiatric comorbidity (all rs > .56; all ps < .05) and less strongly associated with disorders associated with the fear factor (all rs < .48; all ps < .05) and the externalizing factor (r = .16; p < .05). The IPF demonstrated strong test-retest reliability (r = .77; p < .05). Our results suggest that the IPF is a valid and reliable measure of PTSD-related psychosocial functional impairment. (PsycINFO Database Record PMID- 29723026 TI - Crisis-counselor perceptions of job training, stress, and satisfaction during disaster recovery. AB - OBJECTIVE: The United States Crisis Counseling Assistance and Training Program (CCP; authorized by the Robert T. Stafford Disaster Relief and Emergency Assistance Act, 1974/2013) aims to provide disaster-recovery support to communities following natural or human-caused disasters through outreach. Job satisfaction among the crisis counselors the CCP employs may affect the delivery of outreach services to survivors and their communities. The present study was conducted to gain insight into CCP crisis counselors' experiences with job training and work-related stress as predictors of job satisfaction. METHOD: Data was collected from 47 CCP service-provider agencies, including 532 completed service-provider feedback surveys to examine the usefulness of the CCP training they had received, the support and supervision provided by program management, the workload and its duration, resources provided, and the stress experienced. Quantitative and qualitative data were examined, and a multiple linear regression was calculated to predict job satisfaction based on training usefulness, job stress, gender, age, race, full- or part-time status, highest level of education achieved, and supervisory position. RESULTS: The overall regression equation was significant, F(8, 341) = 8.428, p < .000. The regression coefficients indicated that the higher the job training was rated as useful (p < .001), the lower the job stress (p < .01), and the older the age of the respondents (p < .05), the greater the level of job satisfaction. CONCLUSION: Findings suggest that proper training and management of stress among crisis counselors are necessary for influencing levels of staff job satisfaction. Where self-care and stress management were not adequately emphasized, more stress was reported. (PsycINFO Database Record PMID- 29723025 TI - Gender differences in associations between DSM-5 posttraumatic stress disorder symptom clusters and functional impairment in war veterans. AB - Understanding the links between posttraumatic stress disorder (PTSD) symptoms and functional impairment is essential for assisting veterans in transitioning to civilian life. Moreover, there may be differences between men and women in the relationships between PTSD symptoms and functional impairment. However, no prior studies have examined the links between functional impairment and the revised symptom clusters as defined in the Diagnostic and Statistical Manual of Mental Disorders, 5th ed. (DSM-5; American Psychiatric Association, 2013) or whether the associations between PTSD symptom clusters and functional impairment differ by gender. We examined the associations between the DSM-5 PTSD symptom clusters and functional impairment in 252 trauma-exposed Iraq and Afghanistan war veterans (79 females). Regression analyses included demographic factors and exposure to both combat and military sexual trauma as covariates. In the total sample, both the intrusions cluster (beta = .18, p = .045) and the negative alterations in cognition and mood cluster (beta = .45, p < .001) were associated with global functional impairment. Among male veterans, global functional impairment was associated only with negative alterations in cognition and mood (beta = .52, p < .001). However, by contrast, among female veterans, only marked alterations in arousal and reactivity were associated with global functional impairment (beta = .35, p = .027). These findings suggest that there may be important gender differences with respect to the relationship between PTSD symptoms and functional impairment. (PsycINFO Database Record PMID- 29723027 TI - Sex differences in PTSD symptoms: A differential item functioning approach. AB - OBJECTIVE: Evidence has suggested there are sex differences in posttraumatic stress disorder (PTSD) symptom expression; however, few studies have assessed whether these differences are due to measurement invariance. This study aimed to examine sex differences in PTSD symptoms based on the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5) using differential item functioning (DIF). METHOD: Confirmatory factor analysis was conducted on the DSM-5 model of PTSD, followed by a multiple indicators multiple causes (MIMIC) model to examine possible DIF using the PTSD Checklist for DSM-5. Data were analyzed from a Malaysian adolescent sample (n = 481) of which 61.7% were female, with a mean age of 17.03 years. RESULTS: The results indicated the presence of DIF for 2 of 20 PTSD criteria. Females scored significantly higher on emotional cue reactivity (B4), and males reported significantly higher rates of reckless or self destructive behavior (E2) while statistically controlling for the latent variables in the model. However, the magnitude of these item-level differences was small. CONCLUSION: These findings indicate that despite the presence of DIF for 2 DSM-5 symptoms, this does not provide firm support for nonequivalence across sex. (PsycINFO Database Record PMID- 29723028 TI - Children's behavioral health needs and satisfaction and commitment of foster and adoptive parents: Do trauma-informed services make a difference? AB - OBJECTIVE: Caring for children in foster or adoptive care with behavioral health needs can severely stress parents, contributing to adverse outcomes for children and families. Trauma-informed services from the child welfare and mental health sectors may help prevent poor outcomes by helping children and parents identify and understand trauma and its impact on children's behavioral health and receive effective treatment. To help understand the role of trauma-informed services for the child welfare population, we examined whether trauma-informed child welfare and mental health services moderated the relationship between children's behavioral health needs and parent satisfaction and commitment. METHOD: The researchers analyzed data from a cross-sectional statewide survey of foster and adoptive parents (n = 512 respondents, 42% of 1,206 contacted) from one state. RESULTS: Foster (but not adoptive) parent ratings of trauma-informed mental health services significantly moderated the relationship between children's behavioral health needs and foster and adoptive parent satisfaction and commitment. As ratings of trauma-informed mental health services increased, the association between child behavioral health needs and parent satisfaction and commitment became nonsignificant, suggesting a buffering effect. Trauma-informed child welfare services did not moderate the relationship for foster or adoptive parents. CONCLUSIONS: Leaders and policymakers are urged to promote trauma informed mental health services for children involved with child welfare to potentially buffer foster parents against lower parenting satisfaction and commitment. More research is needed to replicate and expand on these findings and to examine the effectiveness of trauma-informed services on other relevant child and family outcomes. (PsycINFO Database Record PMID- 29723029 TI - Youth victimization profiles and change in mental health symptoms over one year. AB - OBJECTIVE: To understand how youth PTSD symptoms and externalizing problems emerge and change over time for youth with different profiles of victimization, including polyvictimization. METHOD: We conducted a latent class analysis (LCA) to identify empirically derived victimization profiles in a sample of 2,776 youth who participated in an evaluation study. We then conducted growth curve analyses to determine whether these victimization profiles predicted change in the course of PTSD symptoms and externalizing problems over a 1-year time period for youth engaged in a variety of community-based services. RESULTS: The LCA revealed three profiles: a low victimization profile defined by relatively low endorsement of victimization across types; a witnessing profile defined by particularly high endorsement of witnessing violence; and a polyvictimization profile defined by high endorsement of multiple types of victimization. We found that overall, despite differing initial levels of PTSD symptoms and externalizing problems, all three groups' symptoms improved over the year, but the polyvictimization class generally showed the steepest decreases, particularly in caregiver-reported PTSD symptoms. CONCLUSION: Polyvictimized youth participating in community-based services are at increased risk for developing PTSD and externalizing problems, but symptoms appear to decrease to levels similar to other victimized youth after one year. (PsycINFO Database Record PMID- 29723030 TI - Trauma characteristics and posttraumatic growth: The mediating role of avoidance coping, intrusive thoughts, and social support. AB - OBJECTIVE: Previous research suggests trauma characteristics can impact on posttraumatic growth (PTG). The current study considers whether previously identified predictors of PTG may produce different outcomes dependent on the characteristics of the trauma experienced. METHOD: Active coping, avoidant coping, emotional coping, intrusive thoughts, social support, and spirituality were examined as potential mediators of relationships between trauma characteristics (interpersonal trauma, number of trauma types, and childhood trauma) and PTG. The responses of 268 adults exposed to multiple and wide-ranging stressors were used to generate three multiple mediation models. RESULTS: Intrusive thoughts and social support exerted small but significant indirect effects in all three multiple mediation models. Avoidant coping mediated associations between the number of trauma types and PTG, and the relationship between childhood trauma to PTG. CONCLUSION: Relationships between trauma characteristics and PTG appear to be explained through the presence of avoidant coping strategies, intrusive thoughts, and the individual's social environment, which could be the focus of intervention efforts to promote positive change. (PsycINFO Database Record PMID- 29723031 TI - Interpersonal relationship quality mediates the association between military related posttraumatic stress and academic dysfunction among student veterans. AB - OBJECTIVE: Large numbers of United States service members and veterans are enrolling in colleges and universities. Many are experiencing posttraumatic stress symptoms secondary to their military service, and these symptoms are associated with academic dysfunction. However, little is known about the mechanism(s) through which posttraumatic stress increases risk for academic difficulties. The goal of the current study was to evaluate perceived interpersonal relationship quality as a mediator of this association. METHOD: The current study investigated the indirect effect of posttraumatic stress on academic dysfunction through three indices of perceived interpersonal relationship quality (i.e., family distress, family support, and social network support) in a clinical sample of 2,120 student service members and veterans. Participants were further divided into four groups based on relationship status and gender (i.e., partnered women, nonpartnered women, partnered men, and nonpartnered men), and moderation by group was examined. RESULTS: For all four groups, there were significant indirect effects of posttraumatic stress on academic dysfunction through greater family distress and lower social network support. Further, the overall indirect effect of posttraumatic stress on academic dysfunction was stronger for partnered women compared with the three other groups and was attributable to the stronger path from family distress to academic dysfunction for partnered women. CONCLUSIONS: Poor perceived relationship quality may be a modifiable risk factor for academic dysfunction among student service members and veterans experiencing military-related posttraumatic stress. Partnered women may be especially well-suited to interventions that enhance the interpersonal context of posttraumatic stress as a way to optimize academic outcomes. (PsycINFO Database Record PMID- 29723032 TI - "I knew it was wrong the moment I got the order": A narrative thematic analysis of moral injury in combat veterans. AB - OBJECTIVE: Moral injury is a nascent construct intended to capture reactions to events that violate deeply held beliefs and moral values. Although a model of moral injury has been proposed, many of the theoretical propositions of this model have yet to be systematically studied. METHOD: We conducted semistructured interviews with eight veterans who reported experiencing morally injurious events during war zone deployments. RESULTS: Using narrative thematic analysis, five main themes and associated subthemes emerged from the data. The main themes capture the timing of the event, contextual factors that affected the decision making process during the morally injurious event, reactions to the moral injurious event, search for purpose and meaning, and opening up. CONCLUSION: The findings from the present study supported an existing model of moral injury, while extending it in several important ways. Preliminary clinical recommendations and directions for future research are discussed based on the study findings. These include directly exploring the context surrounding the morally injurious event, examining the veterans' moral appraisals, and helping them assume appropriate responsibility for their actions to reduce excessive self blame. (PsycINFO Database Record PMID- 29723033 TI - Adolescent clinical populations and associations between trauma and behavioral and emotional problems. AB - OBJECTIVE: Trauma exposure is common during childhood and adolescence and is associated with youth emotional and behavioral problems. The present study adds to the current literature on trauma exposure among adolescent clinical populations by examining the association between trauma exposure and adolescent self-report of emotional and behavioral problems broadly, including internalizing and externalizing symptoms, in addition to the trauma-specific symptoms of posttraumatic stress disorder (PTSD). METHOD: This study included 94 female (64%) and male (36%) adolescents, ages 13-19, representing 4 clinical populations: those seeking inpatient psychiatry, outpatient psychiatry, residential substance abuse, and outpatient medical services. Adolescents self-reported trauma history and internalizing, externalizing, and PTSD symptoms. RESULTS: Most adolescents reported experiencing at least 1 traumatic event (83%; M = 2.28, SD = 1.83). Multiple regression analyses controlling for age, race/ethnicity, gender, and treatment setting indicated a greater number of types of trauma are associated with externalizing symptoms (beta = .31, p < .01) and PTSD symptoms (beta = .35, p < .01). CONCLUSION: Trauma is a common experience among adolescents, particularly those presenting for behavioral health services, making trauma informed care essential in these service delivery settings. Treatment that addresses adolescent risk behaviors and prevents recurrent trauma may be particularly important given the negative impact of multiple traumatic events on developing adolescents. (PsycINFO Database Record PMID- 29723034 TI - Large Critical Shoulder Angle Has Higher Risk of Tendon Retear After Arthroscopic Rotator Cuff Repair. AB - BACKGROUND: The critical shoulder angle (CSA) is the angle created between the superior and inferior bone margins of the glenoid and the most lateral border of the acromion. A few studies recently investigated the relation between CSA and functional outcomes after rotator cuff repair. However, there is a lack of research investigating the effect of CSA on postoperative tendon integrity after rotator cuff repair. PURPOSE: To assess the effects of the CSA on postoperative tendon integrity after rotator cuff repair. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: All patients who underwent rotator cuff repair for full thickness supraspinatus tears by 1 senior surgeon between January 2010 and January 2014 were included in this study. All patients had standardized anteroposterior shoulder radiographs the day before surgery. CSA and acromial index (AI) were measured. AI was derived by measuring the distance from the glenoid plane to the lateral border of the acromion and dividing it by the distance from the glenoid plane to the lateral aspect of the humeral head. Functional scores-including American Shoulder and Elbow Surgeons shoulder evaluation form, modified University of California at Los Angeles score, Constant Murley score, and visual analog scale for pain-were used to evaluate shoulder function at a minimum follow-up of 2 years. Meanwhile, magnetic resonance imaging examinations were performed to evaluate rotator cuff integrity according to the Sugaya method and the signal/noise quotient (SNQ) of the rotator cuff tendon. RESULTS: A total of 90 patients were included in this study: 42 patients with a single-row repair and 48 with a double-row repair. There was a significant positive correlation between CSA or AI and tendon SNQ. On the basis of CSA, the patients were divided into 2 groups: large CSA (>38 degrees ) and control (CSA <=38 degrees ). At final follow-up, the large CSA group and the control CSA group demonstrated no significant differences in American Shoulder and Elbow Surgeons, University of California at Los Angeles, Constant, and visual analog scale scores. Postoperative magnetic resonance imaging revealed that the large CSA group had 9 cases of retear, with a significantly higher retear rate than the control group (15% vs 0%, P = .03). Furthermore, the tendon SNQ of the large CSA group was significantly greater than that of the control group. CONCLUSION: CSA did not appear to influence postoperative functional outcomes, while those in the large CSA group had poor tendon integrity after rotator cuff repair. These findings indicate that a large CSA is associated with an increased risk of rotator cuff tendon retear after repair. PMID- 29723035 TI - Targeting IL-8 in Cystic Fibrosis: Enough but Not Too Much. PMID- 29723036 TI - Patellar Redislocation Rates and Clinical Outcomes After Medial Patellofemoral Ligament Reconstruction: Suture Anchor Versus Double Transpatellar Tunnel Fixation. AB - BACKGROUND: Few studies to date have compared clinical outcomes in patients who have undergone medial patellofemoral ligament (MPFL) reconstruction using the suture anchor and double transpatellar tunnel fixation methods. This meta analysis therefore compared the clinical results, including the patellar redislocation rate and improvement in functional scores, of suture anchor and double transpatellar tunnel fixation. HYPOTHESIS: The recurrence rate and improvement in functional outcomes after surgery would be similar using the suture anchor and double transpatellar tunnel fixation methods. STUDY DESIGN: Meta-analysis. METHODS: Studies evaluating MPFL reconstruction using either the suture anchor or double transpatellar tunnel technique for patellar site fixation were included if they reported the patellar redislocation rate after surgery and/or validated patient-reported outcomes such as the Kujala and Lysholm scores. RESULTS: Twenty-one studies were included in this meta-analysis. The mean patellar redislocation rates were similar using the suture anchor (3.2% [95% CI, 1.6%-6.2%]) and double transpatellar tunnel (3.4% [95% CI, 2.1%-5.4%]) techniques ( P = .879). The mean improvement in the Kujala score from before to after MPFL reconstruction was greater using the suture anchor (37.2 [95% CI, 31.1-43.4]) method than the double transpatellar tunnel method (28.7 [95% CI, 21.2-36.1]) ( P = .018). However, the mean improvement in the Lysholm score did not differ significantly using the 2 techniques. CONCLUSION: The patellar redislocation rate did not differ significantly in patients who underwent MPFL reconstruction using the suture anchor and double transpatellar tunnel fixation methods. The suture anchor fixation method, however, resulted in a greater degree of improvement in patient-reported outcomes. PMID- 29723037 TI - Celecoxib treatment improves muscle function in mdx mice and increases utrophin A expression. AB - Duchenne muscular dystrophy (DMD) is a genetic and progressive neuromuscular disorder caused by mutations and deletions in the dystrophin gene. Although there is currently no cure, one promising treatment for DMD is aimed at increasing endogenous levels of utrophin A to compensate functionally for the lack of dystrophin. Recent studies from our laboratory revealed that heparin treatment of mdx mice activates p38 MAPK, leading to an upregulation of utrophin A expression and improvements in the dystrophic phenotype. Based on these findings, we sought to determine the effects of other potent p38 activators, including the cyclooxygenase (COX)-2 inhibitor celecoxib. In this study, we treated 6-wk-old mdx mice for 4 wk with celecoxib. Immunofluorescence analysis of celecoxib treated mdx muscles revealed a fiber type switch from a fast to a slower phenotype along with beneficial effects on muscle fiber integrity. In agreement, celecoxib-treated mdx mice showed improved muscle strength. Celecoxib treatment also induced increases in utrophin A expression ranging from ~1.5- to 2-fold in tibialis anterior diaphragm and heart muscles. Overall, these results highlight that activation of p38 in muscles can indeed lead to an attenuation of the dystrophic phenotype and reveal the potential role of celecoxib as a novel therapeutic agent for the treatment of DMD.-Peladeau, C., Adam, N. J., Jasmin, B. J. Celecoxib treatment improves muscle function in mdx mice and increases utrophin A expression. PMID- 29723038 TI - The Gut-Lung Axis and Pulmonary Responses to Ozone. PMID- 29723039 TI - Transcriptome profiling to identify key mediators of granulosa cell proliferation upon FSH stimulation in the goose (Anser cygnoides). AB - 1. The low reproductive performance of geese has seriously hampered the development of the industry. Reproductive performance, particularly the egg laying rate mainly depends on the development of the follicle. Previous studies have shown that follicle-stimulating hormone (FSH) plays an important role in the process of follicular development, but the exact underlying mechanism remains unclear. 2. This study showed that FSH stimulated granulosa cell proliferation in a dose-dependent manner. The effect of FSH treatment on granulosa cell proliferation was greatest at a dose of 100 mIU/ml FSH for 24 h. 3. Secondly, the effect of different concentrations of FSH on goose granulosa cell proliferation was investigated, and de novo transcriptome assembly and gene expression analysis performed using short-read sequencing technology (Illumina). High-throughput sequencing results yielded 62.61 M reads and 7.8 G base pairs from granulosa cells treated with 100 mIU/ml FSH. These reads were assembled into 65,757 unigenes (mean length: 705 bp) with an N50 of 903 bp. A total of 110 upregulated and 510 downregulated differentially expressed genes (DEGs) were identified by RNA-seq. 4. Functional analysis by gene ontology (GO) and KEGG pathway annotation indicated that hormone biosynthesis (GO:0042446), positive regulation of hormone secretion (GO:0046887), steroid biosynthesis, oxidative phosphorylation and carbon metabolism pathways were involved in FSH-mediated proliferation of goose granulosa cells. 5. After screening, a group of key responsive genes including superoxide dismutase 1, fatty acyl-CoA reductase 1, transforming growth factor beta receptor-associated protein 1 and follistatin were tested by real-time reverse transcription PCR to confirm differential expression in granulosa cells stimulated by FSH. 6. FSH-stimulated goose granulosa cells and DEG profiling data provided comprehensive gene expression information at the transcriptional level that could promote better understanding of the molecular mechanisms underlying follicle development in response to FSH stimulation. PMID- 29723041 TI - Transcriptional factor Pdx1 is involved in age-related GIP hypersecretion in mice. AB - Fat accumulation with aging is a serious problem; glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) is an incretin that plays an important role in fat accumulation. GIP receptor knockout mice show reduced fat mass and improved insulin sensitivity associated with aging. Therefore, GIP is involved in fat accumulation and insulin resistance with aging. However, age-related changes of GIP secretion remain unclear. The present study aimed to elucidate age-related changes of GIP secretion and enteroendocrine K cells using GIP reporter [GIP-green fluorescent protein (GFP) knock-in heterozygous (GIPgfp/+)] mice. Aged 1-yr-old GIPgfp/+ mice exhibited a phenotype of fat accumulation, insulin resistance, and GIP hypersecretion compared with young (3-4 mo old) GIPgfp/+ mice. In aged mice, K-cell number in the small intestine and the mRNA expression levels of GIP and transcriptional factor pancreatic and duodenal homeobox-1 (Pdx1) in K cells were increased. K-cell number, GIP mRNA expression and content in small intestine, and GIP secretion were decreased after posteriori suppression of Pdx1 using intestine-specific gene transfer. Thus, Pdx1 positively regulates GIP mRNA and K-cell number in small intestine. Increased Pdx1 expression might be involved in GIP hypersecretion with aging. NEW & NOTEWORTHY Age-related changes of glucose-dependent insulinotropic polypeptide/gastric inhibitory polypeptide (GIP) secretion and K cells were investigated. We found that K-cell number and GIP and pancreatic and duodenal homeobox-1 (Pdx1) expression in K cells were increased in aged mice, which showed greater GIP secretion compared with young mice. In addition, we have succeeded in posteriori suppression of Pdx1 in small intestine using the method of intestine specific gene transfer, and showed that K-cell number, GIP expression, and GIP secretion were decreased in the Pdx1-knockdown intestine. PMID- 29723042 TI - Extracting DNA from FFPE Tissue Biospecimens Using User-Friendly Automated Technology: Is There an Impact on Yield or Quality? AB - DNA extracted from formalin-fixed, paraffin-embedded (FFPE) tissue blocks is amenable to analytical techniques, including sequencing. DNA extraction protocols are typically long and complex, often involving an overnight proteinase K digest. Automated platforms that shorten and simplify the process are therefore an attractive proposition for users wanting a faster turn-around or to process large numbers of biospecimens. It is, however, unclear whether automated extraction systems return poorer DNA yields or quality than manual extractions performed by experienced technicians. We extracted DNA from 42 FFPE clinical tissue biospecimens using the QiaCube (Qiagen) and ExScale (ExScale Biospecimen Solutions) automated platforms, comparing DNA yields and integrities with those from manual extractions. The QIAamp DNA FFPE Spin Column Kit was used for manual and QiaCube DNA extractions and the ExScale extractions were performed using two of the manufacturer's magnetic bead kits: one extracting DNA only and the other simultaneously extracting DNA and RNA. In all automated extraction methods, DNA yields and integrities (assayed using DNA Integrity Numbers from a 4200 TapeStation and the qPCR-based Illumina FFPE QC Assay) were poorer than in the manual method, with the QiaCube system performing better than the ExScale system. However, ExScale was fastest, offered the highest reproducibility when extracting DNA only, and required the least intervention or technician experience. Thus, the extraction methods have different strengths and weaknesses, would appeal to different users with different requirements, and therefore, we cannot recommend one method over another. PMID- 29723040 TI - Role of the blood coagulation cascade in hepatic fibrosis. AB - Liver is the primary source of numerous proteins that are critical for normal function of the blood coagulation cascade. Because of this, diseases of the liver, particularly when affiliated with severe complications like cirrhosis, are associated with abnormalities of blood clotting. Although conventional interpretation has inferred cirrhosis as a disorder of uniform bleeding risk, it is now increasingly appreciated as a disease wherein the coagulation cascade is precariously rebalanced. Moreover, prothrombotic risk factors are also associated with a more rapid progression of fibrosis in humans, suggesting that coagulation proteases participate in disease pathogenesis. Indeed, strong evidence drawn from experimental animal studies indicates that components of the coagulation cascade, particularly coagulation factor Xa and thrombin, drive profibrogenic events, leading to hepatic fibrosis. Here, we concisely review the evidence supporting a pathologic role for coagulation in the development of liver fibrosis and the potential mechanisms involved. Further, we highlight how studies in experimental animals may shed light on emerging clinical evidence, suggesting that beneficial effects of anticoagulation could extend beyond preventing thrombotic complications to include reducing pathologies like fibrosis. PMID- 29723043 TI - SPDEFending the Lung through Mucin Expression. PMID- 29723044 TI - Are Results of Arthroscopic Labral Repair Durable in Dysplasia at Midterm Follow up? A 2-Center Matched Cohort Analysis. AB - BACKGROUND: Studies assessing dysplasia's effect on hip arthroscopy are often limited to the short term and unable to account for demographic factors that may vary between dysplastic and nondysplastic populations. PURPOSE: To determine the midterm failure rate and patient-reported outcomes of arthroscopic labral repair in the setting of dysplasia and make subsequent failure and outcome comparisons with a rigorously matched nondysplastic control group. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Primary arthroscopic labral repair cases at 2 centers from 2008 to 2011 were reviewed. Patients with lateral center edge angle (LCEA) <25 degrees were matched to nondysplastic controls by age, sex, laterality, body mass index (BMI), Tonnis grade, and capsular repair per a 1:2 matching algorithm. Groups were compared with a visual analog scale (VAS) for pain, modified Harris Hip Score (mHHS), and Hip Outcome Score-Sports Specific Subscale (HOS-SSS) to determine predictors of outcome and failure. RESULTS: Forty eight patients with dysplasia (mean LCEA, 21.6 degrees ; range, 13.0 degrees 24.9 degrees ; n = 25 with capsular repair) were matched to 96 controls (mean LCEA, 32.1 degrees ; range, 25 degrees -52 degrees ; n = 50 with capsular repair) and followed for a mean of 5.7 years (range, 5.0-7.7 years). Patients achieved mean VAS improvements of 3.3 points, mHHS of 19.5, and HOS-SSS of 29.0 points ( P < .01) with no significant differences between the dysplasia and control populations ( P > .05). Five-year failure-free survival was 83.3% for patients with dysplasia and 78.1% for controls ( P = .53). No survival or outcomes difference was observed between patients with dysplasia who did or did not have capsular repair ( P >= .45) or when comparing LCEA <20 degrees and LCEA 20 degrees to 25 degrees ( P >= .60). BMI <=30 was associated with increased revision surgery risk ( P < .01). Age >35 years ( P < .05) and Tonnis grade 0 radiographs ( P < .01) predicted failure to reach minimal clinically important differences. CONCLUSION: With careful selection and modern techniques, patients with dysplasia can benefit significantly and durably from arthroscopic labral repair. The dysplastic cohort had outcomes and failure rates similar to those of rigorously matched controls at midterm follow-up. Subanalyses comparing LCEA <20 degrees and LCEA 20 degrees to 25 degrees are presented for completeness; however, this study was not designed to detect differences in dysplastic subpopulations. BMI <=30 was associated with increased revision risk. Age >35 years and Tonnis grade 0 radiographs predicted failure to achieve minimal clinically important differences. PMID- 29723045 TI - Salmonella Detection and Counting on Pig Carcasses and Cutting Lines in Italian Slaughterhouses. AB - During 2014-2015, 300 pig carcasses before chilling and 85 food contact surfaces (FCSs) at cutting lines were tested for Salmonella in three slaughterhouses (namely A, B, and C) of northern Italy. In slaughterhouses A and B, four carcass sites of 100 cm2 each (from both the exterior and interior side) were swabbed with a single sponge. In abattoir C, four 100 cm2 sites of the exterior and the interior sides were swabbed with two independent sponges. The population average prevalence of Salmonella-positive carcasses (which takes into account the structure of the study design, with multiple samples collected in a single day) in slaughterhouses A and B was 12.3%, while in slaughterhouse C it was 11.2%. Presence of Salmonella on exterior and interior sides of carcasses showed a low level of concordance (only 3/12 of the contaminated carcasses were positive on both sides). No significant difference was found for FCSs contamination in the three slaughterhouses, with a population average prevalence of Salmonella positive FCSs of 19.9%. In addition, we found that the clustering due to the day of sampling account for more than 36% and 60% of the overall prevalence variation on carcasses and FCSs, respectively. Eight serovars were identified, with Salmonella Derby as the most common type. The counting of Salmonella on carcasses showed large variability. It was low (<0.0075 most probable number [MPN]/cm2) in 46.6% of the carcasses and as high as 2.7 MPN/cm2 in 4.7%. Specifically, we found that counts on carcasses fit with "heavy tailed" distributions (lognormal and Weibull with a small shape parameter), suggesting not negligible probability of episodes of high Salmonella contamination. The mean values of contamination obtained with the two distributions ranged from 0.235 to 0.435 MPN/cm2. PMID- 29723046 TI - Metal resistant rhizobia and ultrastructure of Anthyllis vulneraria nodules from zinc and lead contaminated tailing in Poland. AB - This present paper studies the response of Anthyllis vulneraria-Rhizobium symbiosis to heavy metal stress. The symbiotic rhizobium bacteria isolated from root nodules of A. vulneraria from zinc and lead wastes were examined in this project. Light microscopy (LM) and transmission electron microscopy (TEM) were used to analyze the nodule anatomy and ultrastructure and conduct a comparison with nonmetal-treated nodules. 16S ribosomal DNA sequence analysis of bacteria isolated from metal-treated nodules revealed the presence of Rhizobium metallidurans and Bradyrhizobium sp. In regard to heavy metal resistance/tolerance, a similar tolerance to Pb was shown by both strains, and a high tolerance to Zn and a lower tolerance to Cd and Cu by R. metallidurans, whereas a high tolerance to Cd and Cu and a lower tolerance to Zn by Bradyrhizobium were found. The nodules of Anthyllis from metal-polluted tailing sites were identified as the typical determinate type of nodules. Observed under TEM microscopy changes in nodules ultrastructure like: (1) wall thickening; (2) infection thread reduction; (3) vacuole shrinkage; (4) synthesis of phenolics in vacuoles; (5) various differentiation of bacteroids and (6) simultaneous symbiosis with arbuscular mycorrhiza fungi could be considered as a form of the A.vulneraria-Rhizobium symbiosis adaptation to metal stress. PMID- 29723047 TI - Statistical optimization of the phytoremediation of arsenic by Ludwigia octovalvis- in a pilot reed bed using response surface methodology (RSM) versus an artificial neural network (ANN). AB - In this study, the removal of arsenic (As) by plant, Ludwigia octovalvis, in a pilot reed bed was optimized. A Box-Behnken design was employed including a comparative analysis of both Response Surface Methodology (RSM) and an Artificial Neural Network (ANN) for the prediction of maximum arsenic removal. The predicted optimum condition using the desirability function of both models was 39 mg kg-1 for the arsenic concentration in soil, an elapsed time of 42 days (the sampling day) and an aeration rate of 0.22 L/min, with the predicted values of arsenic removal by RSM and ANN being 72.6% and 71.4%, respectively. The validation of the predicted optimum point showed an actual arsenic removal of 70.6%. This was achieved with the deviation between the validation value and the predicted values being within 3.49% (RSM) and 1.87% (ANN). The performance evaluation of the RSM and ANN models showed that ANN performs better than RSM with a higher R2 (0.97) close to 1.0 and very small Average Absolute Deviation (AAD) (0.02) and Root Mean Square Error (RMSE) (0.004) values close to zero. Both models were appropriate for the optimization of arsenic removal with ANN demonstrating significantly higher predictive and fitting ability than RSM. PMID- 29723048 TI - Enhanced degradation of phenol in floating treatment wetlands by plant-bacterial synergism. AB - Phenol is a commonly found organic pollutant in industrial wastewaters. Its ecotoxicological significance is well known and, therefore, the compound is often required to be removed prior to discharge. In this study, plant-bacterial synergism was established in floating treatment wetlands (FTWs) in an attempt to maximize the removal of phenol from contaminated water. A common wetland plant, Typha domingensis, was vegetated on a floating mat and augmented with three phenol-degrading bacterial strains, Acinetobacter lwofii ACRH76, Bacillus cereus LORH97, and Pseudomonas sp. LCRH90, to develop FTWs for the remediation of water contaminated with phenol. All of the strains are known to have phenol-reducing properties, and grow well in FTWs. Results showed that T. domingensis was able to remove a small amount of phenol from the contaminated water; however, bacterial augmentation enhanced the removal potential significantly, i.e., 0.146 g/m2/day vs. 0.166 g/m2/day, respectively. Plant biomass also increased in the presence of bacterial consortia; and inoculated bacteria displayed successful colonization/survival in the rhizosphere, root interior and shoot interior of the plant. Similarly, highest reduction in chemical oxygen demand (COD), biochemical oxygen demand (BOD5), and total organic carbon (TOC) was achieved by the combined application of plants and bacteria. The study demonstrates that the plant bacterial synergism in a FTW may be a more effective approach for the remediation of phenol-contaminated water. PMID- 29723049 TI - Improving the growth of Ni-hyperaccumulating plants in serpentine quarry tailings. AB - Phytomining techniques based on metal-hyperaccumulating plants can be implemented in serpentine quarry wastes for Ni recovery. However, strategies must be developed to overcome the unfavourable plant growth conditions that these substrates present and to optimize Ni yields. In this study, the Ni hyperaccumulators Alyssum serpyllifolium, Alyssum inflatum, and Alyssum bracteatum were evaluated for their Ni phytoextraction efficiency from quarry tailings. Effects of two organic amendments, composted municipal sewage sludge and cow manure, on plant growth and physiological status and Ni removal were determined. Organic amendments were incorporated at two addition rates (5% and 20% w/w). The best-performing hyperaccumulators were A. inflatum and A. serpyllifolium. Organic amendments improved plant biomass production, photosynthetic efficiency and nutrition, but reduced shoot Ni concentrations. However, the stimulation in biomass resulted in significantly enhanced Ni yields. The most promising results were found using low addition rates and after manure incorporation. PMID- 29723050 TI - Enhancement of toxic Cr (VI), Fe, and other heavy metals phytoremediation by the synergistic combination of native Bacillus cereus strain and Vetiveria zizanioides L. AB - Bioremediation of Cr (VI), Fe, and other heavy metals (HMs) through plant microbes interaction is one of the efficient strategies due to its high efficiency, low cost, and ecofriendly nature. The aim of the study was to isolate, characterize, and assess the potential of rhizospheric bacteria to enhance growth and metal accumulation by the chromium hyperaccumulator Vetiveria zizanoides. The bacterial strain isolated from mine tailings was identified to be Bacillus cereus (T1B3) strain exhibited plant growth-promoting traits including, 1-aminocyclopropane-1-carboxylate deaminase, indole acetic acid, and siderophores production, nitrogen fixation, and P solubilization. Removal capacity (mg L-1) of T1B3 strain was 82% for Cr+6 (100), 92% for Fe (100), 67% for Mn(50), 36% for Zn (50), 31% for Cd (30), 25% for Cu (30), and 43% for Ni (50) during the active growth cycle in HM-amended, extract medium. Results indicate that inoculating the native V. zizanioides with T1B3 strain improves its phytoremediation efficiency of HMs. The mineralogical characteristics of chromite ore tailings and soil were also confirmed by X-ray diffraction, Fourier Transform Infrared, scanning electron microscope-energy dispersive spectroscopy analysis. PMID- 29723051 TI - Phytoremediation removal rates of benzene, toluene, and chlorobenzene. AB - Phytoremediation is a sustainable remedial approach, although performance efficacy is rarely reported. In this study, we assessed a phytoremediation plot treating benzene, toluene, and chlorobenzene. A comparison of the calculated phytoremediation removal rate with estimates of onsite contaminant mass was used to forecast cleanup periods. The investigation demonstrated that substantial microbial degradation was occurring in the subsurface. Estimates of transpiration indicated that the trees planted were removing approximately 240,000 L of water per year. This large quantity of water removal implies substantial removal of contaminant due to large amounts of contaminants in the groundwater; however, these contaminants extensively sorb to the soil, resulting in large quantities of contaminant mass in the subsurface. The total estimate of subsurface contaminant mass was also complicated by the presence of non-aqueous phase liquids (NAPL), additional contaminant masses that were difficult to quantify. These uncertainties of initial contaminant mass at the site result in large uncertainty in the cleanup period, although mean estimates are on the order of decades. Collectively, the model indicates contaminant removal rates on the order of 10-2 100 kg/tree/year. The benefit of the phytoremediation system is relatively sustainable cleanup over the long periods necessary due to the presence of NAPL. PMID- 29723052 TI - Successful phytoremediation of crude-oil contaminated soil at an oil exploration and production company by plants-bacterial synergism. AB - Phytoremediation is a promising approach for the cleanup of soil contaminated with petroleum hydrocarbons. This study aimed to develop plant-bacterial synergism for the successful remediation of crude oil-contaminated soil. A consortia of three endophytic bacteria was augmented to two grasses, Leptochloa fusca and Brachiaria mutica, grown in oil-contaminated soil (46.8 g oil kg-1 soil) in the vicinity of an oil exploration and production company. Endophytes augmentation improved plant growth, crude oil degradation, and soil health. Maximum oil degradation (80%) was achieved with B. mutica plants augmented with the endophytes and it was significantly (P < 0.05) higher than the use of plants or bacteria individually. Moreover, endophytes showed more persistence, the abundance and expression of alkB gene in the rhizosphere as well as in the endosphere of the tested plants than in unvegetated soil. A positive relationship (r = 0.70) observed between gene expression and crude oil reduction indicates that catabolic gene expression is important for hydrocarbon mineralization. This investigation showed that the use of endophytes with appropriate plant is an effective strategy for the cleanup of oil-contaminated soil under field conditions. PMID- 29723053 TI - Grafting of watermelon (Citrullus lanatus cv. Mahbubi) onto different squash rootstocks as a means to minimize cadmium toxicity. AB - To test the possibility that using appropriate rootstocks could improve the tolerance of watermelon to cadmium (Cd) toxicity, a greenhouse experiment was conducted to determine growth and antioxidant activities of watermelons, either nongrafted or grafted onto summer squash and winter squash. We provided nutrient solutions having four levels (0, 50, 100, and 200 MUM) of cadmium to treat the plants. Shoot and root biomass reduction were significantly lower in summer squash rootstock-grafted watermelon than winter squash rootstock-grafted and nongrafted watermelons. Cadmium induced a smaller decrease in leaf area index in grafted watermelons compared with nongrafted plants. The Cd- related reductions in chlorophyll content and efficiency of photosynthesis were more severe in nongrafted watermelons compared with dose grafted onto summer squash. Cd accumulation in shoot at the highest dose (200 uM) of CdCl2 was significantly lower (19.76 mg/kg) in summer squash rootstock-grafted watermelon compared with winter squash rootstock-grafted (37.58 mg/kg) and nongrafted watermelon (72.12 mg/kg). H2O2, MDA production and electrolyte leakage of summer squash rootstock grafted watermelon showed less increase, which was associated with a significant increase in the activities of antioxidant. The improved crop performance of grafted watermelons was attributed to their strong capacity to inhibit Cd accumulation in the aerial parts. PMID- 29723054 TI - Coupling of bioaugmentation and phytoremediation to improve PCBs removal from a transformer oil-contaminated soil. AB - This study was carried out to assess the dissipation of 17 selected polychlorinated biphenyl (PCBi) congeners in a transformer oil-contaminated soil using bioaugmentation with 2 PCB-degrading bacterial strains, i.e., Pseudomonas spp. S5 and Alcaligenes faecalis, assisted or not by the maize (Zea mays L.) plantation. After 5 and 10 weeks of treatment, the remaining concentrations of the target PCBi congeners in the soil were extracted and measured using GC-MS. Results showed that the bacterial augmentation treatments with Pseudomonas spp. S5 and A. faecalis led to 21.4% and 20.4% reduction in the total concentration of the target PCBs (SigmaPCBi), respectively, compared to non-bioaugmented unplanted control soil. The SigmaPCBi decreased by 35.8% in the non-bioaugmented planted soil compared with the control. The greatest degradation of the PCB congeners was observed over a 10-week period in the soil inoculated with Pseudomonas spp. S5 and cultivated with maize. Under this treatment, the SigmaPCBi decreased from 357 to 119 ng g-1 (66.7% lower) and from 1091 to 520 ng g-1 (52.3% lower). Overall, the results suggested that the combined application of phytoremediation and bioaugmentation was an effective technique to remove PCBs and remediate transformer oil-contaminated soils. PMID- 29723055 TI - Cadmium tolerance and phytoremediation potential of acacia (Acacia nilotica L.) under salinity stress. AB - In this study, we explored the effect of salinity on cadmium (Cd) tolerance and phytoremediation potential of Acacia nilotica. Two-month-old uniform plants of A. nilotica were grown in pots contaminated with various levels of Cd (0, 5, 10, and 15 mg kg-1), NaCl (0%, 0.5%, 1.0% (hereafter referred as salinity), and all possible combinations of Cd + salinity for a period of six months. Results showed that shoot and root growth, biomass, tissue water content and chlorophyll (chl a, chl b, and total chl a+b) contents decreased more in response to salinity and combination of Cd + salinity compared to Cd alone. Shoot and root K concentrations significantly decreased with increasing soil Cd levels, whereas Na and Cl concentrations were not affected significantly. Shoot and root Cd concentrations, bioconcentration factor (BCF) and translocation factor (TF) increased with increasing soil Cd and Cd + salinity levels. At low level of salinity (0.5%), shoot and root Cd uptake enhanced, while it decreased at high level of salinity (1.0%). Due to Cd tolerance, high shoot biomass and shoot Cd uptake, this tree species has some potential for phytoremediation of Cd from the metal contaminated saline and nonsaline soils. PMID- 29723056 TI - Reclassification of Acute Respiratory Distress Syndrome: A Secondary Analysis of the ARDS Network Trials. PMID- 29723057 TI - Myocardial Infarction and Ischemic Stroke after Exacerbations of Chronic Obstructive Pulmonary Disease. AB - RATIONALE: Previous studies have suggested that acute exacerbations of chronic obstructive pulmonary disease (COPD) may be associated with increased risk of myocardial infarction and ischemic stroke. OBJECTIVES: We aimed to quantify the increased risks of myocardial infarction and ischemic stroke risk associated with both moderate and severe acute exacerbation, and to investigate factors that may modify these risks. METHODS: We performed a self-controlled case series to investigate the rates of myocardial infarction and ischemic stroke after acute exacerbation compared with stable time, within individuals. The participants were 5,696 adults with COPD with a first myocardial infarction (n = 2,850) or ischemic stroke (n = 3,010) and at least one acute exacerbation from the UK Clinical Practice Research Datalink with linked Hospital Episodes Statistics data. RESULTS: The risks of both myocardial infarction and ischemic stroke were increased in the 91 days after an acute exacerbation. The risks were greater after a severe exacerbation (incidence rate ratio [IRR], 2.58; 95% confidence interval [CI], 2.26-2.95 for myocardial infarction; and IRR, 1.97; 95% CI, 1.66 2.33 for ischemic stroke) than after a moderate exacerbation (IRR, 1.58; 95% CI, 1.46-1.71 for myocardial infarction; and IRR, 1.45; 95% CI, 1.33-1.57 for ischemic stroke). The relative risks of myocardial infarction and ischemic stroke associated with acute exacerbation were lower among those with more frequent exacerbations (IRR, 1.42; 95% CI, 1.24-1.62 vs. IRR, 1.69; 95% CI, 1.50-1.91 for myocardial infarction; and IRR, 1.30; 95% CI, 1.15-1.48 vs. IRR, 1.68; 95% CI, 1.50-1.89 for ischemic stroke). Higher GOLD stage was associated with a lower rate of myocardial infarction (IRR, 1.98; 95% CI, 1.61-2.05 vs. IRR, 1.69; 95% CI, 1.45-1.98) but not for ischemic stroke. Aspirin use at baseline was associated with a lower risk of ischemic stroke (IRR, 1.28; 95% CI, 1.10-1.50 vs. IRR, 1.63; 95% CI, 1.47-1.80) but not with myocardial infarction. CONCLUSIONS: Acute exacerbations of COPD are associated with an increased risk of myocardial infarction and ischemic stroke within 28 days of their onset. Several patient characteristics were identified that are associated with these events. PMID- 29723058 TI - Contact frequency and cognitive health among older adults in Israel. AB - OBJECTIVES: The current study set out to examine the links between contact frequency with one's social network and cognitive health in later life. It assessed both direct and indirect pathways and the possible role of ethnicity in the effect of the social network on cognitive function. METHOD: We used data from adults aged 50 and above, which was collected in Israel as part of the Survey of Ageing, Retirement and Health (SHARE). A moderated mediation analysis was conducted to test the direct and indirect associations between contact frequency and cognitive function, as well as the moderation of these associations by population group. Three population groups were examined - veteran-Jews, Arabs and immigrants from the former Soviet Union. RESULTS: Contact frequency with the close social milieu was found to be directly positively related to cognitive function. The association was also mediated by depressive symptoms, such that frequent contacts were linked to cognitive health via reduced depressive symptoms. This indirect link differed, however, among the three population groups. CONCLUSION: Contact frequency is important for cognitive health in the second half of life, and it operates both directly and by decreasing depressive symptoms. However, these links are not found among all ethnic groups and may, therefore, depend on the culture and social norms of each group and the meaning attributed to social ties. PMID- 29723060 TI - A Milestone: Therapeutic Innovation & Regulatory Science Has Been Accepted for Inclusion in MEDLINE. PMID- 29723059 TI - Improving Expanded Access in the United States: The Role of the Institutional Review Board. AB - BACKGROUND: The FDA allows patients with a serious or immediately life threatening illness to use investigational medical products outside of clinical trials through its "expanded access" program. In response to criticism that the process to apply for expanded access is too onerous, numerous changes have been made over the last few years. These have been largely focused on the FDA and the pharmaceutical industry, while institutional review boards (IRBs)-which must approve expanded access protocols, except in emergencies when there is not time to do so-have remained relatively unstudied. We conducted a pilot study to review a sample of publicly available IRB policies from the United States to investigate how these entities handle expanded access. METHODS: We performed an online search to find publicly available policies for IRBs operating in the United States, utilizing a convenience sampling strategy, selecting the first 100 eligible policies we identified. RESULTS: Of the 95 policies reviewed, the majority (92.6%, n = 88) contained language referencing nonemergency expanded access and/or expanded access for emergency requests for a single patient. Of these 88 policies, 11.4% (n = 19) did not explicitly specify detailed procedures for handling nonemergency single-patient expanded access requests. Of the 88 policies that mentioned expanded access in nonemergency situations, 11.5% did not explicitly specify whether full IRB review was required, as was the rule at that time. There was considerable variation in other aspects of these policies, including charging patients for use of investigational products and the use of data from expanded access. CONCLUSIONS: Based on the findings of our pilot, IRB policies on expanded access vary considerably. It is often difficult to find, interpret, and understand IRB policies on expanded access. Further research is needed to determine if and to what extent this negatively impacts patient access to investigational products outside of clinical trials. PMID- 29723061 TI - Keeping a Focus on Research Ethics. PMID- 29723062 TI - Resolvin E1 attenuates injury-induced vascular neointimal formation by inhibition of inflammatory responses and vascular smooth muscle cell migration. AB - Mechanical insults, such as stent implantation, can induce endothelial injury, vascular inflammation, and ultimately lead to vascular neointimal hyperplasia. Resolvin E1 (RvE1), derived from the omega3 fatty acid eicosapentaenoic acid, can facilitate the resolution of inflammation in many settings. We therefore aimed to determine if there was a role for RvE1 in preventing neointimal formation after arterial injury and to understand the underlying mechanisms. Vascular inflammation and neointimal hyperplasia were induced by wire injury in the femoral arteries of mice. Administration of exogenous RvE1 and endogenously generated RvE1 via dietary supplementation with eicosapentaenoic acid and aspirin markedly reduced vascular neointima formation in this model. Mechanistically, RvE1 was found to inhibit vascular neutrophil infiltration, promote macrophage polarization toward an M2-like phenotype, suppress T-cell trafficking by reducing RANTES secretion from vascular smooth muscle cells, and inhibit vascular smooth muscle cell migration. In summary, RvE1 demonstrated a protective role against vascular inflammation and remodeling in response to mechanical injury, suggesting that it may serve as an adjuvant therapeutic agent for percutaneous coronary interventions, such as stent implantation.-Liu, G., Gong, Y., Zhang, R., Piao, L., Li, X., Liu, Q., Yan, S., Shen, Y., Guo, S., Zhu, M., Yin, H., Funk, C. D., Zhang, J., Yu, Y. Resolvin E1 attenuates injury-induced vascular neointimal formation by inhibition of inflammatory responses and vascular smooth muscle cell migration. PMID- 29723063 TI - Placenta-specific 1 regulates oocyte meiosis and fertilization through furin. AB - Placenta-specific 1 (Plac1) has been found to be essential for placentation, and abnormal Plac1 expression and distribution is highly correlated with preeclampsia and implantation failure; however, its function in mammalian oocytes has not been elucidated. Here, we report that Plac1 was more prominent in mouse oocytes and enriched at the membrane region throughout meiosis. On the one hand, Plac1 knockdown severely disrupted microvillus organization; however, on the other hand, Plac1 significantly decreased oocyte maturation and increased aneuploidy, consequently disrupting normal fertilization. On the basis of immunoprecipitate matrix-assisted laser desorption/ionization, we established a working model, then verified and suggested that, at the germinal vesicle stage, Plac1 enriches the membrane to activate furin, and active furin subsequently activates IGF-1 receptor to maintain regular microvillus organization. Upon meiosis onset, active furin/IGF-1 receptor relocates into the cytoplasm to activate (phosphorylate) Akt to promote meiosis. In summary, our finding suggests that Plac1, a protein that is crucial for placentation, is also essential for oocyte meiosis and fertilization.-Shi, L.-Y., Ma, Y., Zhu, G.-Y., Liu, J.-W., Zhou, C.-X., Chen, L. J., Wang, Y., Li, R.-C., Yang, Z.-X., Zhang, D. Placenta-specific 1 regulates oocyte meiosis and fertilization through furin. PMID- 29723065 TI - Why We Need a Formal Systematic Approach to Validating Psychological Tests: The Case of the Rorschach Comprehensive System. AB - This article documents and discusses the importance of using a formal systematic approach to validating psychological tests. To illustrate, results are presented from a systematic review of the validity findings cited in the Rorschach Comprehensive System (CS; Exner, 2003) test manual, originally conducted during the manuscript review process for Mihura, Meyer, Dumitrascu, and Bombel's (2013) CS meta-analyses. Our review documents (a) the degree to which the CS test manual reports validity findings for each test variable, (b) whether these findings are publicly accessible or unpublished studies coordinated by the test developer, and (c) the presence and nature of data discrepancies between the CS test manual and the cited source. Implications are discussed for the CS in particular, the Rorschach more generally, and psychological tests more broadly. Notably, a history of intensive scrutiny of the Rorschach has resulted in more stringent standards applied to it, even though its scales have more published and supportive construct validity meta-analyses than any other psychological test. Calls are made for (a) a mechanism to correct data errors in the scientific literature, (b) guidelines for test developers' key unpublished studies, and PMID- 29723064 TI - Cell free hemoglobin in the fetoplacental circulation: a novel cause of fetal growth restriction? AB - Cell free hemoglobin impairs vascular function and blood flow in adult cardiovascular disease. In this study, we investigated the hypothesis that free fetal hemoglobin (fHbF) compromises vascular integrity and function in the fetoplacental circulation, contributing to the increased vascular resistance associated with fetal growth restriction (FGR). Women with normal and FGR pregnancies were recruited and their placentas collected freshly postpartum. FGR fetal capillaries showed evidence of erythrocyte vascular packing and extravasation. Fetal cord blood fHbF levels were higher in FGR than in normal pregnancies ( P < 0.05) and the elevation of fHbF in relation to heme oxygenase-1 suggests a failure of expected catabolic compensation, which occurs in adults. During ex vivo placental perfusion, pathophysiological fHbF concentrations significantly increased fetal-side microcirculatory resistance ( P < 0.05). fHbF sequestered NO in acute and chronic exposure models ( P < 0.001), and fHbF-primed placental endothelial cells developed a proinflammatory phenotype, demonstrated by activation of NF-kappaB pathway, generation of IL-1alpha and TNF-alpha (both P < 0.05), uncontrolled angiogenesis, and disruption of endothelial cell flow alignment. Elevated fHbF contributes to increased fetoplacental vascular resistance and impaired endothelial protection. This unrecognized mechanism for fetal compromise offers a novel insight into FGR as well as a potential explanation for associated poor fetal outcomes such as fetal demise and stillbirth.-Brook, A., Hoaksey, A., Gurung, R., Yoong, E. E. C., Sneyd, R., Baynes, G. C., Bischof, H., Jones, S., Higgins, L. E., Jones, C., Greenwood, S. L., Jones, R. L., Gram, M., Lang, I., Desoye, G., Myers, J., Schneider, H., Hansson, S. R., Crocker, I. P., Brownbill, P. Cell free hemoglobin in the fetoplacental circulation: a novel cause of fetal growth restriction? PMID- 29723066 TI - The effectiveness of web-based patient education and action and coping plans as an adjunct to patient treatment in physiotherapy: A randomized controlled trial. AB - OBJECTIVE: The study investigated: (1) the effect of combining web-based patient education (WBPE) with action and coping plans on patients' adherence to physiotherapy and their subsequent functional outcomes; and (2) the participants' satisfaction with the WBPE program. METHODS: One hundred and eight participants enrolled in this 8-week two group randomized controlled trial. They were allocated to either the WBPE planning group or the attention-control group. The WBPE group made action and coping plans and were familiarized with their web based program. The attention control group was given access to a web-based neutral information program about shoulder injuries and physiotherapy rehabilitation. Throughout the 8-week study physiotherapists measured the participants' clinic-based adherence and participants recorded their home-based adherence using a self-report diary. Functional outcomes for all participants were measured at the beginning and end of the study. Participants provided feedback about their respective websites. RESULTS: The intervention group had a significantly higher clinic based adherence than the control group (p < 0.04). Both groups had a significant improvement in shoulder function but there was no significant difference between them. Participants in the intervention group were highly satisfied with the WBPE program. The preferred delivery of physiotherapy by 87% of the intervention group was a combination of face-to-face appointments and WBPE. Control participants indicated that they would have appreciated information about shoulder exercises and the shoulder complex in their program. DISCUSSION: The WBPE program was an effective adjunct to physiotherapy in terms of patient satisfaction and clinic-based treatment adherence. PMID- 29723067 TI - Incremental Validity of the Durand Adaptive Psychopathic Traits Questionnaire Above Self-Report Psychopathy Measures in Community Samples. AB - Although highly debated, the notion of the existence of an adaptive side to psychopathy is supported by some researchers. Currently, 2 instruments assessing psychopathic traits include an adaptive component, which might not cover the full spectrum of adaptive psychopathic traits. The Durand Adaptive Psychopathic Traits Questionnaire (DAPTQ; Durand, 2017 ) is a 41-item self-reported instrument assessing adaptive traits known to correlate with the psychopathic personality. In this study, I investigated in 2 samples (N = 263 and N = 262) the incremental validity of the DAPTQ over the Psychopathic Personality Inventory-Short Form (PPI SF) and the Triarchic Psychopathy Measure (TriPM) using multiple criterion measures. Results showed that the DAPTQ significantly increased the predictive validity over the PPI-SF on 5 factors of the HEXACO. Additionally, the DAPTQ provided incremental validity over both the PPI-SF and the TriPM on measures of communication adaptability, perceived stress, and trait anxiety. Overall, these results support the validity of the DAPTQ in community samples. Directions for future studies to further validate the DAPTQ are discussed. PMID- 29723069 TI - Prosodic and segmental aspects of nonword repetition in 4- to 6-year-old children who are deaf and hard of hearing compared to controls with normal hearing. AB - Children who are deaf or hard of hearing (DHH) are at an increased risk of speech and language deficits. Nonword repetition (NWR) is a potential predictor of problems with phonology, grammar and lexicon in DHH children. The aim of the present study was to examine repetition of prosodic features and segments in nonwords by DHH children compared to children with normal hearing (NH) and to relate NWR performance to measures of language ability and background variables. In this cross-sectional study, 14 Swedish-speaking children with mild-profound sensorineural hearing loss, aged 4-6 years, and 29 age-matched controls with NH and typical language development participated. The DHH children used cochlear implants (CI), hearing aids or a combination of both. The assessment materials included a prosodically controlled NWR task, as well as tests of phonological production, expressive grammar and receptive vocabulary. The DHH children performed below the children with NH on the repetition of tonal word accents, stress patterns, vowels and consonants, with consonants being hardest, and tonal word accents easiest, to repeat. NWR performance was also correlated with language ability, and to hearing level, in the DHH children. Both prosodic and segmental features of nonwords are problematic for Swedish-speaking DHH children compared to children with NH, but performance on tonal word accent repetition is comparably high. NWR may have potential as a clinically useful tool for identification of children who are in need of speech and language intervention. PMID- 29723070 TI - Examining the Interpersonal Nature of Criterion A of the DSM-5 Section III Alternative Model for Personality Disorders Using Bootstrapped Confidence Intervals for the Interpersonal Circumplex. AB - Criterion A of the alternative model of personality disorders (AMPD) involves the assessment of impairments in self and self in relation to other functioning and can be assessed using the Level of Personality Functioning Scale (LPFS). This study uses responses to a self-report version of the LPFS (AMPD-CAS) from 248 college students to examine the interpersonal implications of AMPD personality impairments using the interpersonal circumplex (IPC) as a nomological net. Results suggest that AMPD-CAS self-impairments are related to problems of low communion and interpersonal distress and do not appear to tap expected interpersonal problems of low agency. Additionally, AMPD-CAS identity is specifically associated with sensitivity to control, suggesting that individuals with diffuse identity find it aversive and intrusive when others take the lead. AMPD-CAS self in relation to other impairments are related to being too argumentative and suspicious of others, having difficulty connecting and caring for others, and finding others' affection and reliance aversive. Both self and self in relation to other AMPD-CAS impairments are related to interpersonal distress and misanthropy, suggesting they tap pathological aspects of personality functioning. These findings represent a first step toward fully examining the interpersonal nature of Criterion A impairments and provides preliminary evidence for the construct validity of AMPD-CAS scores. PMID- 29723068 TI - Advances in the discovery of cathepsin K inhibitors on bone resorption. AB - Cathepsin K (Cat K), highly expressed in osteoclasts, is a cysteine protease member of the cathepsin lysosomal protease family and has been of increasing interest as a target of medicinal chemistry efforts for its role in bone matrix degradation. Inhibition of the Cat K enzyme reduces bone resorption and thus, has rendered the enzyme as an attractive target for anti-resorptive osteoporosis therapy. Over the past decades, considerable efforts have been made to design and develop highly potent, excellently selective and orally applicable Cat K inhibitors. These inhibitors are derived from synthetic compounds or natural products, some of which have passed preclinical studies and are presently in clinical trials at different stages of advancement. In this review, we briefly summarised the historic development of Cat K inhibitors and discussed the relationship between structures of inhibitors and active sites in Cat K for the purpose of guiding future development of inhibitors. PMID- 29723071 TI - High Expression of PLOD1 Drives Tumorigenesis and Affects Clinical Outcome in Gastrointestinal Carcinoma. AB - BACKGROUND: PLOD1 (procollagen-lysine, 2-oxoglutarate 5-dioxygenase 1) is important for extracellular matrix formation and is involved in various diseases, including cancer; however, its role in gastrointestinal cancer is unclear. In this study, the expression of PLOD1 in gastrointestinal carcinoma and its relationships with patient survival were examined. MATERIALS AND METHODS: Sample expression profiles were downloaded from the Gene Expression Omnibus database and methylation data were obtained from the Cancer Genome Atlas. Correlations between PLOD1 expression and clinicopathological features were analyzed by chi-square tests. Patient survival was evaluated by a Kaplan-Meier analysis. RESULTS: PLOD1 expression was upregulated in gastric cancer and colorectal cancer compared with that in normal tissues. High PLOD1 levels indicated a poor prognosis. The high methylation group had a significantly lower level of PLOD1 expression. CONCLUSION: These results indicated that PLOD1 is highly expressed in gastrointestinal carcinoma and is a potential prognostic marker and therapeutic target. The data also indicate that hypomethylation contributes to PLOD1 upregulation in gastric and colon cancers. PMID- 29723072 TI - 5-year-old child with late discovered traumatic patellar tendon rupture-a case report. PMID- 29723073 TI - A longitudinal assessment of change in marijuana use with other substance use problems. AB - BACKGROUND: Despite increasing marijuana use rates over the past decade, the longitudinal association between marijuana use and other substance use problems among adults is unclear. OBJECTIVES: To examine associations of self-reported changes in marijuana use and marijuana use frequency with self-reported other substance use problems over a 12-month period. METHODS: Two waves (W1 and W2) of the Population Assessment of Tobacco and Health Study provided data. The study sample (N = 26,204, female = 13,261; male = 12,943, aged 18+) included W1-W2 never marijuana users, W1-W2 ex-users (used prior to 12 months of W1), and those who either quit, initiated, resumed, or continued marijuana use between W1 and W2. We used multinomial and binary logistic regression analyses. RESULTS: The past-year marijuana use rate was 12.4% at W2. A quarter of W1 users quit using marijuana in the 12 months preceding their W2 interview, and one-third of all the W2 users were new/resumed users since W1. Compared to W1-W2 ex-users, W2 quitters were more likely to report alcohol use problems and tobacco addiction at W2. Compared to quitters, continued users were more likely to report alcohol use problems (RRR = 1.62, 95% CI = 1.27-2.07) and tobacco addiction (RRR = 1.37, 95% CI = 1.11-1.69). New users (RRR = 2.05, 95% CI = 1.12-3.74), resumed users (RRR = 2.69, 95% CI = 1.55-4.70), and continued users (RRR = 3.40, 95% CI = 2.08-5.55) reported more drug use problems. Compared to less frequent marijuana users, frequent users had greater odds of reporting alcohol use problems (RRR = 1.44, 95% CI = 1.21-1.72) and drug use problems (OR = 1.63, 95% CI = 1.19-2.23). CONCLUSIONS: Given increased prevalence of marijuana use, polysubstance use problems among marijuana users should be assessed. PMID- 29723074 TI - The Impacts of Sexual Arousal and Its Suppression on Executive Functioning. AB - Suppression of certain types of reflexive emotional responses is thought to temporarily deplete executive functions (EF), as evidenced by poorer performance on measures of EF, but does not deplete other, lower-order cognitive processes. This study examined whether similar decrements in performance on EF tests would occur following suppression of sexual arousal. A sample of 44 male college students underwent baseline cognitive assessment (EF and lower-order cognitive processes), followed by experimental manipulation consisting of exposure to sexually explicit audiovisual stimuli. Sexual arousal was monitored using penile plethysmography. In this study, 21 participants were assigned to a suppression condition and were instructed to suppress sexual arousal during the video, while 23 were assigned to an arousal condition and were instructed to allow themselves to become aroused. Following experimental manipulation, cognition was reassessed. Unexpectedly, results showed EF decrements in the arousal group but not in the suppression group. As expected, only EF was affected by experimental manipulation, with no group differences in lower-order cognitive processes. Thus, the findings suggest that sexual arousal is associated with temporary decrements in EF performance, at least among young, primarily White, male college students. The results contribute to understanding why sexually charged situations are sometimes associated with poor decisions or unsafe/reckless sexual practices. PMID- 29723075 TI - Orlistat as a FASN inhibitor and multitargeted agent for cancer therapy. AB - INTRODUCTION: Cancer cells have increased glycolysis and glutaminolysis. Their third feature is increased de novo lipogenesis. As such, fatty acid (FA) synthesis enzymes are over-expressed in cancer and their depletion causes antitumor effects. As fatty acid synthase (FASN) plays a pivotal role in this process, it is an attractive target for cancer therapy. Areas covered: This is a review of the lipogenic phenotype of cancer and how this phenomenon can be exploited for cancer therapy using inhibitors of FASN, with particular emphasis on orlistat as a repurposing drug. Expert opinion: Disease stabilization only has been observed with a highly selective FASN inhibitor used as a single agent in clinical trials. It is too early to say whether the absence of tumor responses other than stabilization results because even full inhibition of FASN is not enough to elicit antitumor responses. The FASN inhibitor orlistat is a 'dirty' drug with target-off actions upon at least seven targets with a proven role in tumor biology. The development of orlistat formulations suited for its intravenous administration is a step ahead to shed light on the concept that drug promiscuity can or not be a virtue. PMID- 29723076 TI - Feasibility of Bystander Administration of Public-Access Naloxone for Opioid Overdose. AB - OBJECTIVE: Pre-stationing naloxone, a competitive antagonist that can reverse the effects of opioid overdose, in public spaces may expedite antidote delivery. Our study aimed to determine the feasibility of bystander-assisted overdose treatment using pre-stationed naloxone. METHODS: Convenience sample of bystanders in Cambridge, Massachusetts in April 2017. Subjects assisted a simulated patient described as unconscious. Subjects interacted with simulated EMS dispatch to locate a nearby box, unlock it, and administer naloxone. RESULTS: Fifty participants completed the simulation. Median time from simulated ambulance dispatch to naloxone administration was 189 seconds, and from arrival at patient side to administration 61 seconds. All but one participant (98.0%) correctly administered naloxone. Subjects' comfort with administration and willingness to provide medical care increased from before to after the trial. Comfort in administering naloxone varied significantly with level of previous training prior to, but not following, study participation. CONCLUSIONS: Bystanders are willing and able to access pre-stationed naloxone and administer it to a simulated patient in a public space. Public access naloxone stations may be a useful tool to reduce time to naloxone administration, particularly in areas where opioid overdoses are clustered. PMID- 29723077 TI - Severe acute respiratory infection surveillance in Montenegro, 2014-2017. AB - AIM: The study aim was to analyze the epidemiology and clinical characteristics of severe acute respiratory infection (SARI) cases and to compare demographic and clinical characteristics as well as outcomes of influenza-positive SARI cases to those of influenza-negative SARI cases in Montenegro. METHODS: SARI surveillance was established in 2014 in nine healthcare institutions. Retrospective analysis of case-based surveillance data pertaining to all reported SARI cases during three seasons was conducted. RESULTS: Among the 90 identified SARI cases, 64 (71%) were influenza positive. Death outcome was reported in 25 (28%) of all registered SARI cases. Cardiovascular disease was more prevalent among the patients in the influenza-positive SARI group (36% vs. 12%, p = .021), as was concurrence of two or more chronic medical conditions (57% vs. 30%, p = .042). These patients were also more likely to be immunocompromised (16% vs. 0%, p = .057) and have viral pneumonia (14.4% vs. 20.3%, p = .017), compared to those in the influenza-negative SARI group. Younger age, presence of cardiovascular disease and being immunocompromised were patient characteristics independently associated with SARI related to influenza. CONCLUSION: Continued and extended monitoring of SARI is necessary in order to fully assess the burden of flu disease, define risk groups and establish better control measures. PMID- 29723078 TI - Evaluation of the losartan solubility in the biowaiver context by shake-flask method and intrinsic dissolution. AB - This study aimed at evaluating the shake-flask use as a universal method to evaluate drug solubility in a biowaiver context as proposed by FDA, EMA and ANVISA. The solubility of losartan was determined in three buffers using the shake-flask method, intrinsic dissolution (ID) and Quantum Chemistry. Moreover, the evaluation of a losartan dissolution profile from coated tablets was conducted. The losartan low solubility in pH 1.2 and high solubility in pH 6.8 were observed using the shake-flask method. However, the solubility results using ID demonstrated its high solubility in pH 1.2 and 6.8. It was not possible to find conclusive results regarding the solubility of the drug in pH 4.5. The studies conducted by Quantum Chemistry provide molecular and electronic data that helped understand the losartan solvation in different pH values. Our experimental results defined that losartan can be classified as a low-solubility drug. In addition, this work shows that shake-flask cannot be a universal method of solubility studies in biowaiver context. Individual analysis will be necessary. The intrinsic dissolution should be considered as a complementary method. PMID- 29723079 TI - A New Measure of Life Satisfaction: The Riverside Life Satisfaction Scale. AB - The Satisfaction With Life Scale (Diener, Emmons, Larsen, & Griffin, 1985) has been the dominant measure of life satisfaction since its creation more than 30 years ago. We sought to develop an improved measure that includes indirect indicators of life satisfaction (e.g., wishing to change one's life) to increase the bandwidth of the measure and account for acquiescence bias. In 3 studies, we developed a 6-item measure of life satisfaction, the Riverside Life Satisfaction Scale, and obtained reliability and validity evidence. Importantly, the Riverside Life Satisfaction Scale retained the high internal consistency, test-retest stability, and unidimensionality of the Satisfaction With Life Scale. In addition, the Riverside Life Satisfaction Scale correlated with other well-being measures, Big Five personality traits, values, and demographic information in expected ways. Although the Riverside Life Satisfaction Scale correlated highly with the Satisfaction With Life Scale, we believe it improves the Satisfaction With Life Scale by appropriately increasing construct breadth and reducing the potential for bias. PMID- 29723080 TI - Basic Body Awareness Therapy in patients suffering from fibromyalgia: A randomized clinical trial. AB - INTRODUCTION: The aim of this study is to assess whether Basic Body Awareness Therapy (BBAT) improves musculoskeletal pain, movement quality, psychological function, and quality of life. METHODS: The effects of BBAT in addition to treatment as usual (TAU) were studied in a randomized controlled trial. Forty-one patients were randomly assigned to a control group (n = 21) and an intervention group (n = 20). Both groups received TAU including pharmacological therapy. The intervention group took part in 10 BBAT sessions. Outcome variables were measured regarding pain, movement quality, psychological function, and quality of life. Outcome measures were assessed before intervention, in posttest, and in follow ups at 12 and 24 weeks. RESULTS: The BBAT group showed significant improvement in 'pain' at posttest (p = 0.037) and in 'movement quality' from baseline to 24 weeks (p = 0.000). Intragroup analysis showed significant improvements in the SF 36 body pain subscale at 12 and 24 weeks (p = 0.001, p = 0.014), Hospital Anxiety Depression scale in anxiety subscale at 12 weeks (p = 0.019), State-Trait Anxiety Inventory anxiety questionnaire at 12 and 24 weeks (p = 0.012, p = 0.002), and STAI state at 12 and 24 weeks (p = 0.042, p = 0.004). CONCLUSION: This study showed that BBAT might be an effective intervention in patients suffering from fibromyalgia in relation to pain, movement quality, and anxiety. PMID- 29723082 TI - Microbial Analysis of Donor Corneoscleral Rims and Storage Media. AB - PURPOSE: We aim to investigate bacterial and fungal cultures of hypothermic donor corneal storage media (Optisol-GS) and donor rims. METHODS: All corneal transplants performed from January 1, 2015 to June 30, 2016 by a single surgeon at a single facility were retrospectively reviewed. Aerobic, anaerobic, and fungal cultures were routinely obtained from all donor rims and cornea storage media. Culture results and clinical courses were recorded. RESULTS: Eighty-four corneal transplants were performed. Five of 84 grafts (5.95%) had positive bacteria donor rim cultures. Fungal donor rim cultures were positive in 5/84 grafts (5.95%) of which two grew Candida spp. Storage media bacterial cultures were positive in 2/84 (2.4%) cultures. Storage media fungal cultures were positive in 1/84 (1.2%) cultures. No patients developed any evidence of clinical infection. CONCLUSIONS: Given the increasing rates of postkeratoplasty fungal infections, the identification of positive fungal cultures from donor rims and storage media warrants further evaluation of adding antifungals to storage media. PMID- 29723081 TI - A cost-effectiveness analysis of revaccination and catch-up strategies with the 23-valent pneumococcal polysaccharide vaccine (PPV23) in older adults in Japan. AB - OBJECTIVE: In Japan, the National Immunization Program (NIP) includes PPV23 as the primary vaccination for adults and catch-up cohorts. The Japanese Association for Infectious Diseases recommends revaccination for older adults who received primary vaccination >=5 years earlier. The cost-effectiveness of adding revaccination and/or continuing catch-up vaccination in the NIP was evaluated from the public payer perspective in Japan. METHODS: The Markov model included five health states: no pneumococcal disease, invasive pneumococcal diseases (IPD), non-bacteremic pneumococcal pneumonia (NBPP), post-meningitis sequelae, and death. Cohorts of adults aged 65-95 were followed until age 100 or death: 2014 cohort (aged 65-95, vaccinated: 2014); 2019 cohort (aged 65: 2019); and 2019 catch-up cohort (aged 70-100: 2019, unvaccinated: 2014). Strategies included: (1) vaccinate 2014 and 2019 cohorts; (2) vaccinate 2014 and 2019 cohorts and revaccinate both; (3) strategy 1 and vaccinate 2019 catch-up cohort; (4) strategy 2 and vaccinate 2019 catch-up cohort; and (5) strategy 4 and revaccinate 2019 catch-up cohort. Parameters were retrieved from global and Japanese sources, costs and QALYs discounted at 2%, and incremental cost-effectiveness ratios (ICERs) estimated. RESULTS: Strategy 1 had the highest number of IPD and NBPP cases, and strategy 5 the lowest. Strategies 3-5 dominated strategy 1 and strategy 2 was cost-effective compared to strategy 1 (ICER: Y1,622,153 per QALY gained). At a willingness-to-pay threshold of Y5 million per QALY gained, strategy 2 was cost-effective and strategies 3-5 were cost-saving compared to strategy 1. CONCLUSIONS: Strategies including revaccination, catch-up, or both were cost-effective or cost-saving in comparison to no revaccination and no catch up. Results can inform future vaccine policies and programs in Japan. PMID- 29723083 TI - A review of the Alcohol Use Disorders Identification Test (AUDIT), AUDIT-C, and USAUDIT for screening in the United States: Past issues and future directions. AB - BACKGROUND: The US Preventive Services Task Force recommends that clinicians screen all adults for alcohol misuse and provide brief counseling to those engaged in risky or hazardous drinking. The World Health Organization's (WHO's) Alcohol Use Disorders Identification Test (AUDIT) is the most widely tested instrument for screening in primary health care. OBJECTIVES: This paper describes the structural and functional features of the AUDIT and methodological problems with the validation of the alcohol consumption questions (AUDIT-C). The content, scoring, and rationale for a new version of the AUDIT (called the USAUDIT), adapted to US standard drink size and hazardous drinking guidelines, is presented. METHOD: Narrative review focusing on the consumption elements of the AUDIT. Four studies of the AUDIT-C are reviewed and evaluated. RESULTS: The AUDIT has been used extensively in many countries without making the changes in the first three consumption questions recommended in the AUDIT User's Manual. As a consequence, the original WHO version is not compatible with US guidelines and AUDIT scores are not comparable with those obtained in countries that have different drink sizes, consumption units, and safe drinking limits. Clinical and Scientific Significance. The USAUDIT has adapted the WHO AUDIT to a 14 g standard drink, and US low-risk drinking guidelines. These changes provide greater accuracy in measuring alcohol consumption than the AUDIT-C. PMID- 29723085 TI - Correlates of Immune Response in Trichinella spiralis Infection. AB - Trichinella spiralis infection induces Trichinella-specific IgG antibody and high level of blood eosinophil. However, the kinetics induced by different parasite burdens during infectious periods remains unclear. In this study, rats were infected with 100, 1000, or 3000 larvae of T. spiralis (100 TS, 1000 TS, or 3000 TS). Correlates of eosinophils, antibody responses, and Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) with worm burdens were evaluated at 1 week, 2 weeks, 1 month, and 2 months postinfection. Heavy infections (1000 TS and 3000 TS) showed significantly higher levels of eosinophil, IgG, and IgG1 antibody responses at 2 weeks postinfection compared to light infection (100 TS). The highest RANTES mRNA expression was also found in the heavy infection group (3000 TS). The results indicate, at early stage of infection (week 2), heavy infection induced higher levels of IgG, IgG1, eosinophil, and RANTES responses. However, at late stage of infection (month 2), there were no correlates of immunity with parasite burdens. Higher levels of IgG and IgG1 antibody responses are critical in heavy T. spiralis infection. These results provide important information in evaluating immune responses by T. spiralis infective stage during the T. spiralis infection. PMID- 29723084 TI - Patient Navigation Preferences for Adolescent and Young Adult Cancer Services by Distance to Treatment Location. AB - PURPOSE: To describe how distance to treatment location influences patient navigation preferences for adolescent and young adult (AYA) cancer patients and survivors. METHODS: This study is part of a statewide needs assessment to inform the development of an AYA cancer patient and survivor navigation program. Participants were recruited from outpatient oncology clinics in Utah. Eligible participants had been diagnosed with cancer between ages 15-39 and had completed at least 1 month of treatment. Participants completed a semi-structured interview on preferences for patient navigation. Summary statistics of demographic and cancer characteristics were generated. Thematic content analysis was used to describe navigation preferences among participants classified as distance (>=20 miles) and local (<20 miles), to explain differences in their needs based on distance from their treatment center. RESULTS: The top three patient navigation needs were general information, financial, and emotional support. More local patients were interested in patient navigation services (95.2%) compared to distance participants (77.8%). Fewer local (38.1%) than distance participants (61.1%) reported challenges getting to appointments, and distance patients needed specific financial support to support their travel (e.g., fuel, lodging). Both local and distance patients desired to connect with a navigator in person before using another form of communication and wanted to connect with a patient navigator at the time of initial diagnosis. CONCLUSION: Distance from treatment center is an important patient navigation consideration for AYA cancer patients and survivors. After initially connecting with AYAs in person, patient navigators can provide resources remotely to help reduce travel burden. PMID- 29723086 TI - A Portable Microscale Cell Culture System with Indirect Temperature Control. AB - A physiologically relevant environment is essential for successful long-term cell culturing in vitro. Precise control of temperature, one of the most crucial environmental parameters in cell cultures, increases the fidelity and repeatability of the experiments. Unfortunately, direct temperature measurement can interfere with the cultures or prevent imaging of the cells. Furthermore, the assessment of dynamic temperature variations in the cell culture area is challenging with the methods traditionally used for measuring temperature in cell culture systems. To overcome these challenges, we integrated a microscale cell culture environment together with live-cell imaging and a precise local temperature control that is based on an indirect measurement. The control method uses a remote temperature measurement and a mathematical model for estimating temperature at the desired area. The system maintained the temperature at 37+/ 0.3 degrees C for more than 4 days. We also showed that the system precisely controls the culture temperature during temperature transients and compensates for the disturbance when changing the cell cultivation medium, and presented the portability of the heating system. Finally, we demonstrated a successful long term culturing of human induced stem cell-derived beating cardiomyocytes, and analyzed their beating rates at different temperatures. PMID- 29723087 TI - Characterization of Extractable Species from Polypropylene Microplates. AB - The use of microplates (for bioassays, immunoassays, and general research) that are manufactured from plastic materials has proved problematic due to issues with accuracy, repeatability, and specificity of the results generated. The cause of these issues has been identified as leachables present in the plastic materials. This article presents an extractables study performed with available microplates manufactured with plastic. Common microplates from five different vendors were obtained, including plates from SiO2 Medical Products (SIO) containing a plasma treatment designed to produce an ultra-low protein-binding surface. The microplates were solvent extracted, and the resulting extracts were analyzed for organic extractables. The extractables profiles were examined and compared among the five different plate types. Detected extractables were identified in each of the extracts, and the potential effect on protein binding is discussed. PMID- 29723089 TI - Inconclusive Analysis of the Connection Between Secondary Hematologic Malignancies and Radioiodine Treatment. PMID- 29723090 TI - Risk of Hematologic Malignancies After Radioiodine Treatment of Well Differentiated Thyroid Cancer. PMID- 29723091 TI - Well-Founded Recommendations for Radioactive Iodine Treatment of Differentiated Thyroid Cancer Require Balanced Study of Benefits and Harms. PMID- 29723088 TI - Molecular alterations associated with chronic exposure to cigarette smoke and chewing tobacco in normal oral keratinocytes. AB - Tobacco usage is a known risk factor associated with development of oral cancer. It is mainly consumed in two different forms (smoking and chewing) that vary in their composition and methods of intake. Despite being the leading cause of oral cancer, molecular alterations induced by tobacco are poorly understood. We therefore sought to investigate the adverse effects of cigarette smoke/chewing tobacco exposure in oral keratinocytes (OKF6/TERT1). OKF6/TERT1 cells acquired oncogenic phenotype after treating with cigarette smoke/chewing tobacco for a period of 8 months. We employed whole exome sequencing (WES) and quantitative proteomics to investigate the molecular alterations in oral keratinocytes chronically exposed to smoke/ chewing tobacco. Exome sequencing revealed distinct mutational spectrum and copy number alterations in smoke/ chewing tobacco treated cells. We also observed differences in proteomic alterations. Proteins downstream of MAPK1 and EGFR were dysregulated in smoke and chewing tobacco exposed cells, respectively. This study can serve as a reference for fundamental damages on oral cells as a consequence of exposure to different forms of tobacco. PMID- 29723092 TI - Radioiodine and Its Relationship to Hematologic Malignancy: The Confounding Role of Supraphysiologic Thyroxine. PMID- 29723093 TI - Selective Focus on Rare Hematologic Malignancies Misleads Risk-Benefit Assessment of Radioiodine Therapy of Thyroid Cancer. PMID- 29723094 TI - Power of Absolute Values to Avoid Data Misinterpretations: The Case of Radioiodine-Induced Leukemia and Myelodysplasia. PMID- 29723095 TI - Questionable Relevance of Leukemia Risk After Radioiodine Ablation of Thyroid Cancer. PMID- 29723096 TI - Reply to A. Piccardo et al, E. Hindie et al, M.C. Kreissl et al, M. Doss, J. Buscombe, R. Fisher, M. Sollini et al, M. Lichtenstein, and M. Tulchinsky et al. PMID- 29723097 TI - Risk of Hematologic Malignancies After Radioactive Iodine Treatment of Thyroid Cancer: An Unjustified Warning. PMID- 29723098 TI - Concerns About the Risk of Myeloid Malignancies After Radioiodine Therapy in Thyroid Cancer. PMID- 29723099 TI - Exploring Healthy Eating and Exercise Behaviors Among Low-Income Breastfeeding Mothers. AB - BACKGROUND: Postpartum weight retention is often a significant contributor to overweight and obesity. Lactation is typically not sufficient for mothers to return to pre-pregnancy weight. Modifiable health behaviors (e.g., healthy eating and exercise) are important for postpartum weight loss; however, engagement among mothers, especially those who are resource-limited, is low. A deeper understanding of low-income breastfeeding mothers' healthy-eating and exercise experience, a population that may have unique motivators for health-behavior change, may facilitate creation of effective intervention strategies for these women. Research Aim: To describe the healthy-eating and exercise experiences of low-income postpartum women who choose to breastfeed. METHODS: Focus group discussions were conducted with low-income mothers (N = 21) who breastfed and had a child who was 3 years old or younger. Transcript analysis employed integrated grounded analysis using both a priori codes informed by the theory of planned behavior and grounded codes. RESULTS: Three major themes were identified from five focus groups: (a) Mothers were unable to focus on their own diet and exercise due to preoccupation with infant needs and more perceived barriers than facilitators; (b) mothers became motivated to eat healthfully if it benefited the infant; and (c) mothers did not seek out information on maternal nutrition or exercise but used the Internet for infant-health information and health professionals for breastfeeding information. CONCLUSION: Low-income breastfeeding mothers may be more receptive to nutrition education or interventions that focus on the mother-infant dyad rather than solely on maternal health. PMID- 29723100 TI - RESISTANCE TO DELTAMETHRIN IN PRAIRIE DOG ( CYNOMYS LUDOVICIANUS) FLEAS IN THE FIELD AND IN THE LABORATORY. AB - Sylvatic plague poses a substantial risk to black-tailed prairie dogs ( Cynomys ludovicianus) and their obligate predator, the black-footed ferret ( Mustela nigripes). The effects of plague on prairie dogs and ferrets are mitigated using a deltamethrin pulicide dust that reduces the spread of plague by killing fleas, the vector for the plague bacterium. In portions of Conata Basin, Buffalo Gap National Grassland, and Badlands National Park, South Dakota, US, 0.05% deltamethrin has been infused into prairie dog burrows on an annual basis since 2005. We aimed to determine if fleas ( Oropsylla hirsuta) in portions of the Conata Basin and Badlands National Park have evolved resistance to deltamethrin. We assessed flea prevalence, obtained by combing prairie dogs for fleas, as an indirect measure of resistance. Dusting was ineffective in two colonies treated with deltamethrin for >8 yr; flea prevalence rebounded within 1 mo of dusting. We used a bioassay that exposed fleas to deltamethrin to directly evaluate resistance. Fleas from colonies with >8 yr of exposure to deltamethrin exhibited survival rates that were 15% to 83% higher than fleas from sites that had never been dusted. All fleas were paralyzed or dead after 55 min. After removal from deltamethrin, 30% of fleas from the dusted colonies recovered, compared with 1% of fleas from the not-dusted sites. Thus, deltamethrin paralyzed fleas from colonies with long-term exposure to deltamethrin, but a substantial number of those fleas was resistant and recovered. Flea collections from live-trapped prairie dogs in Thunder Basin National Grassland, Wyoming, US, suggest that, in some cases, fleas might begin to develop a moderate level of resistance to deltamethrin after 5-6 yr of annual treatments. Restoration of black-footed ferrets and prairie dogs will rely on an adaptive, integrative approach to plague management, for instance involving the use of vaccines and rotating applications of insecticidal products with different active ingredients. PMID- 29723101 TI - Breast cancer in an 18-year-old female: A fatal case report and literature review. AB - Breast cancer (BC) is the most frequent malignancy in both pre- and postmenopausal women. However, it is exceedingly rare in very young patients, and especially in adolescents. Herein, we report a case of an 18-year-old female diagnosed with invasive BC. The proband had been found to be negative for BC in close family members. A common BC genetic screening test for the Polish population did not detect any known founder mutations in the BRCA1 gene. Further evaluation identified a p.Ile157Thr (I157T) mutation in the CHEK2 gene, a p.Ala1991Val (A1991V) variant of unknown significance in the BRCA2 gene, p.Lys751Gln (K751Q) variant in the XPD (ERCC2) gene, and a homozygous p.Glu1008Ter (E1008*) mutation in the NOD2 gene. No other mutation had been found by next generation sequencing in major BC high-risk susceptibility genes BRCA1, BRCA2, as well as 92 other genes. To date, all these found alterations have been considered as low to moderate risk factors in the general population and moderate risk factors in younger women (<35 years of age). There are no previous articles relating low and moderate risk gene mutations to very young onset (below 20 years) BC with a fatal outcome. In our patient, a possible cumulative or synergistic risk effect for these 4 alterations, and a mutation in the NOD2 gene in particular, of which both presumably healthy parents were found to be carriers, is suggested. PMID- 29723103 TI - A Liberation Health Approach to Examining Challenges and Facilitators of Peer-to Peer Human Milk Sharing. AB - BACKGROUND: Human milk sharing between peers is a common and growing practice. Although human milk has been unequivocally established as the ideal food source for infants, much stigma surrounds the practice of human milk sharing. Furthermore, there is little research examining peer-to-peer human milk sharing. Research Aim: We used the liberation health social work model to examine the experiences of mothers who have received donated human milk from a peer. Research questions were as follows: (a) What challenges do recipient mothers experience in peer-to-peer human milk sharing? (b) What supports do recipient mothers identify in peer-to-peer human milk sharing? METHODS: Researchers conducted in-depth interviews with mothers ( N = 20) in the United States and Canada who were recipients of peer-to-peer human milk sharing. Researchers independently reviewed transcripts and completed open, axial, and selective coding. The authors discussed conflicts in theme identification until agreement was reached. RESULTS: Challenges to peer-to-peer human milk sharing were (a) substantial effort required to secure human milk; (b) institutional barriers; (c) milk bank specific barriers; and (d) lack of societal awareness and acceptance of human milk sharing. Facilitators included (a) informed decision making and transparency and (b) support from healthcare professionals. CONCLUSION: Despite risks and barriers, participants continued to pursue peer-to-peer human milk sharing. Informed by a liberation health framework, healthcare professionals-rather than universally discouraging human milk sharing between peers-should facilitate open dialogue with parents about the pros and cons of this practice and about screening recommendations to promote safety and mitigate risk. PMID- 29723104 TI - Turning cancer's metabolic plasticity into fragility- an evolving paradigm. AB - In an elegant report, Corbet et al 1 recently demonstrated the much needed insight to exploit cancer's metabolic reprogramming for potential therapeutic intervention. In brief, the findings underscore the principle that abrogation of mitochondrial pyruvate metabolism upregulates glycolysis, and sensitizes cancer cells to radiation. Distinctive from the conventional approach of inhibition/ down-regulation of glycolysis, this emerging paradigm of forced-upregulation of glycolysis (i.e., a "hyperglycolytic" phenotype) concomitant with a reduced mitochondrial capacity turns the metabolic plasticity into vulnerability that may have implications in therapeutic targeting. Nevertheless, this commendable report 1 also provokes scientific curiosity and future directions of research on the opportunities and challenges of such forced upregulation of glycolysis in cancer. PMID- 29723102 TI - Cardioprotection by Cocoa Polyphenols and omega-3 Fatty Acids: A Disease Prevention Perspective on Aging-Associated Cardiovascular Risk. AB - Cardiovascular disease (CVD) remains the leading cause of death today. Many of the biochemical alterations associated with the pathophysiology of CVD can be modified by adequate intakes of bioactive nutrients through a correct diet or supplementation. Recently, there has been growing public and clinical interest in cocoa polyphenols (CPs) and omega-3 (omega-3) fatty acids. A plethora of nutritional intervention trials and experimental studies demonstrates that consumption of these bioactive food compounds is beneficial to promote cardiovascular health. The purpose of this review is to summarize the major cardioprotective effects of CPs and omega-3 fatty acids, providing a scientific rationale for incorporating the combination of these molecules as a nutritional intervention in the prevention of CVD. Although several studies have shown the individual cardioprotective nature of these compounds, a combination treatment with CPs and omega-3 fatty acids may be a promising approach to enhance the preventive value of these molecules and reduce cardiovascular risk factors associated with aging. Therefore, this article also reviews some of the key studies on the interaction between CPs and the metabolism of omega-3 fatty acids. PMID- 29723105 TI - Probiotics drive gut microbiome triggering emotional brain signatures. AB - Experimental manipulation of the gut microbiome was found to modify emotional and cognitive behavior, neurotransmitter expression and brain function in rodents, but corresponding human data remain scarce. The present double-blind, placebo controlled randomised study aimed at investigating the effects of 4 weeks' probiotic administration on behavior, brain function and gut microbial composition in healthy volunteers. Forty-five healthy participants divided equally into three groups (probiotic, placebo and no intervention) underwent functional MRI (emotional decision-making and emotional recognition memory tasks). In addition, stool samples were collected to investigate the gut microbial composition. Probiotic administration for 4 weeks was associated with changes in brain activation patterns in response to emotional memory and emotional decision-making tasks, which were also accompanied by subtle shifts in gut microbiome profile. Microbiome composition mirrored self-reported behavioral measures and memory performance. This is the first study reporting a distinct influence of probiotic administration at behavioral, neural, and microbiome levels at the same time in healthy volunteers. The findings provide a basis for future investigations into the role of the gut microbiota and potential therapeutic application of probiotics. PMID- 29723106 TI - Therapeutic Effect of Acupoint Catgut Embedding in Abdominally Obese Women: A Randomized, Double-Blind, Placebo-Controlled Study. AB - INTRODUCTION: Acupuncture and electroacupuncture have been proved to be beneficial in weight control among obese women. Acupoint catgut embedding treatment, a derivative type of acupuncture, is considered to be more effective than acupuncture and electroacupuncture in reducing weight. This study is to investigate the therapeutic effects and safety of acupoint stimulation by catgut embedding in obese women. The influence of catgut embedding on obesity-related hormones was also examined. SUBJECT/METHODS: In this randomized, double-blind trial, ninety obese women with body mass index (BMI) >=27 kg/m2 and waist circumference (WC) >=80 cm were randomized to catgut embedding group A (n = 45) and sham catgut embedding group B (n = 45) for 6-week treatment with frequency 1 time/week. Body weight (BW), BMI, and WC were measured at the beginning and after 6 weeks along with biochemical data, obesity-related hormones and quality of life. RESULTS: After 6-week treatment, BW reduction in catgut embedding group A was greater than sham catgut embedding group B (-1.65 kg vs. -0.38 kg, p < 0.001). Greater WC reduction was also noted in group A compared to group B (4.84 cm vs. 1.68 cm, p = 0.04). The trend of triglyceride and glycohemoglobin also revealed decline after catgut embedding treatment. Leptin to adiponectin ratio was shown to decrease significantly (3.0 +/- 4.8 to 1.9 +/- 1.6, p = 0.043) following the catgut embedding treatment. No serious adverse events were reported during the treatment course. CONCLUSIONS: Under complete antiseptic condition, catgut embedding is a safe and effective adjunct treatment in reducing weight and WC in obese women, which is likely through improving leptin resistance in obese women. PMID- 29723107 TI - Lactobacillus gasseri PA-3 utilizes the purines GMP and guanosine and decreases their absorption in rats. AB - Excessive intake of purine-rich foods elevates serum uric acid levels, making it a risk factor for hyperuricemia. We hypothesized that lactic acid bacteria ingested with food might utilize purines and contribute to their decreased absorption in the intestines, thereby preventing hyperuricemia. We previously reported that Lactobacillus gasseri PA-3 (PA-3) incorporates adenosine/inosine and related purines and that oral ingestion of PA-3 reduced the absorption of these purines in rats. However, it is unclear whether PA-3 also decreases the absorption of other purines, such as guanosine 5'-monophosphate (GMP) and guanosine. This study investigated whether PA-3 incorporates GMP and guanosine and reduces their absorption in rats. PA-3 incorporated both purines, with 14C GMP uptake being greater than that of 14C-guanosine. Radioactivity in rat blood was significantly lower 30, 45, and 60 minutes after administration of 14C-GMP plus PA-3 than after administration of 14C-GMP alone and was significantly lower 15 minutes after administration of 14C-guanosine plus PA-3 than after administration of 14C-guanosine alone. PA-3 incorporates GMP and guanosine in vitro. Oral administration of PA-3 with GMP and guanosine reduces the intestinal absorption of these purines in vivo. These findings, together with those of previous studies, indicate that PA-3 reduces the absorption of major purines contained in foods. PA-3 may also attenuate the excessive absorption of dietary purines in humans, protecting these individuals against hyperuricemia. PMID- 29723110 TI - Polyamidoamine (PAMAM) dendrimers as potential release modulators and oral bioavailability enhancers of vardenafil hydrochloride. AB - Vardenafil hydrochloride (VAR) is an erectile dysfunction treating drug. VAR has a short elimination half-life (4-5 h) and suffers low oral bioavailability (15%). This work aimed to explore the dual potential of VAR-dendrimer complexes as drug release modulators and oral bioavailability enhancers. VAR-dendrimer complexes were prepared by solvent evaporation technique using four dendrimer generations (G4.5, G5, G5.5 and G6) at three concentrations (190 nM, 380 nM and 950 nM). The systems were evaluated for intermolecular interactions, particle size, zeta potential, drug entrapment efficiency percentages (EE%) and drug released percentages after 2 h (Q2h) and 24 h (Q24h). The results were statistically analyzed, and the system showing the highest desirability was selected for further pharmacokinetic studies in rabbits, in comparison to Levitra(r) tablets. The highest desirability (0.82) was achieved with D10 system comprising VAR (10 mg) and G6 (190 nM). It possessed small particle size (113.85 nm), low PDI (0.19), positive zeta potential (+21.53), high EE% (75.24%), promising Q2 h (41.45%) and Q24 h (74.05%). Compared to Levitra(r) tablets, the significantly (p < 0.01) delayed Tmax, prolonged MRT(0-infinity) and higher relative bioavailability (3.7-fold) could clarify the dual potential of D10 as a sustained release system capable of enhancing VAR oral bioavailability. PMID- 29723111 TI - Elucidation of the TMab-6 Monoclonal Antibody Epitope Against Telomerase Reverse Transcriptase. AB - Telomerase reverse transcriptase (TERT) and mutations of the TERT promoter are significant in the pathogenesis of 1p/19q-codeleted oligodendrogliomas and isocitrate dehydrogenase gene wild-type glioblastomas, as well as melanomas and squamous cell carcinomas. We previously developed an antihuman TERT monoclonal antibody (mAb), TMab-6, which is applicable in immunohistochemistry for human tissues. However, the binding epitope of TMab-6 against TERT is yet to be elucidated. In this study, enzyme-linked immunosorbent assay and immunohistochemistry were utilized for investigating the epitope of TMab-6. The findings revealed that the critical epitope of TMab-6 is the TERT sequence PSTSRPPRPWD; Thr310 and Ser311 of TERT are especially significant amino acids for TMab-6 recognition. PMID- 29723109 TI - Impact of a Six-Year Project to Enhance the Awareness of Community-Based Palliative Care on the Place of Death. AB - OBJECT: To examine the clinical outcomes of a project to enhance the awareness of community-based palliative care (awareness-enhancing project), focusing on home death and care rates in communities. METHODS: A single-center study on community based intervention was conducted. The awareness-enhancing project, consisting of three intervention approaches (outreach, palliative care education for community based medical professionals, and information-sharing tool use), was executed, and changes in the home death rate in the community were examined. RESULTS: The home death rate markedly exceeded the national mean from 2010. In 2012-2013, it was as high as 19.9%, greater than the previous 5.9% (p = 0.001). Through multivariate analysis, the participation of home care physicians and visiting nurses in a palliative care education program, and patients' Palliative Prognostic Index values were identified as factors significantly influencing the home death rate. CONCLUSION: The three intervention approaches time dependently increased the home death rate as a clinical outcome in the community, although they targeted limited areas. These approaches may aid in increasing the number of individuals who die in their homes. PMID- 29723112 TI - Effect of Green Coffee Consumption on Resting Energy Expenditure, Blood Pressure, and Body Temperature in Healthy Women: A Pilot Study. AB - OBJECTIVE: This study was conducted to determine the effects of green coffee consumption on resting energy expenditures (REEs), blood pressure, and body temperature of individuals. METHOD: The study was conducted with 24 women. The REE values of the individuals were measured with the COSMED Fitmate PRO. After the first REE measurements, individuals were given 1 cup of green coffee that was prepared to contain 6 mg caffeine per kg of lean body mass. After coffee consumption, REE measurements were made at 30, 60, 120, and 180 minutes. Blood pressure (mm Hg) and body temperature values ( degrees C) were measured simultaneously with REE measurement. RESULTS: There was a positive correlation between the caffeine amounts given with green coffee and 30-minute (p < 0.05), 60 minute (p = 0.06), and 120-minute (p < 0.05) REE (kcal/d) values. There was also a positive correlation between the total chlorogenic acid taken with green coffee and 30-minute (p < 0.05), 60-minute (p = 0.06), and 120-minute (p < 0.05) REE (kcal/d) values. The intracellular and extracellular fluid amounts liter(l) before and after consumption of green coffee by individuals were 18.7 +/- 1.57 versus 18.6 +/- 1.44 (p < 0.05) and 11.4 +/- 1.01 versus 11.2 +/- 0.97 (p < 0.05), respectively. The body temperature ( degrees C) changes observed in the individuals whose usual dietary caffeine intake was less than or equal to the 50th percentile after green coffee consumption were statistically significant (p < 0.05). Similarly, the diastolic blood pressure changes observed in the individuals whose usual dietary caffeine intake was less than or equal to the 50th percentile after green coffee consumption was almost statistically significant (p = 0.06). CONCLUSIONS: The results of this study showed that 6 mg caffeine/kg (lean body mass) intake among women changed body temperature and blood pressure values and liquid balance depending on the usual dietary coffee intake. In addition, chlorogenic acid is also correlated with REE values besides green coffee caffeine. Key teaching points * There are several findings, and chlorogenic acid may have antihypertensive effects. * There is a significant correlation between green coffee chlorogenic acid amount and REE. * Intracellular and extracellular liquid amounts decrease following green coffee consumption (215 280 mg caffeine), and these changes are observed in individuals whose usual dietary caffeine intake is relatively both low and high. * The body temperature values of individuals whose usual dietary caffeine intake was in the 50th percentile or greater (relatively high) increased after green coffee consumption. PMID- 29723108 TI - Animal models for studying tumor microenvironment (TME) and resistance to lymphocytic infiltration. AB - In cancer immunotherapy, cytotoxic T or NK cells need to engage cancer cells to initiate the killing. However, in clinical studies and in mouse models, some solid tumors are found with no lymphocytes. It is likely that these tumors will be resistant to all sorts of immunotherapies. Thus, restoring lymphocytic infiltration will be vital to the success of immunotherapies on solid tumors. In order to understand the complex interaction between cancer cells and stromal cells, we propose to establish animal models for studying the tumor microenvironment and to develop and test therapies to restore lymphocytic infiltration of tumors Without lymphocytes infiltrating tumors, all immunotherapies on solid tumors become ineffective. PMID- 29723113 TI - Draft Genome Resources for the Phytopathogenic Fungi Monilinia fructicola, M. fructigena, M. polystroma, and M. laxa, the Causal Agents of Brown Rot. AB - Fungi in the genus Monilinia cause brown rot disease of stone and pome fruits. Here, we report the draft genome assemblies of four important phytopathogenic species: M. fructicola, M. fructigena, M. polystroma, and M. laxa. The draft genome assemblies were 39 Mb (M. fructigena), 42 Mb (M. laxa), 43 Mb (M. fructicola), and 45 Mb (M. polystroma) with as few as 550 contigs (M. laxa). These are the first draft genome resources publicly available for M. laxa, M. fructigena, and M. polystroma. PMID- 29723114 TI - Evaluating the contributions of task expectancy in the testing and guessing benefits on recognition memory. AB - Recently, we have shown that two types of initial testing (recall of a list or guessing of critical items repeated over 12 study/test cycles) improved final recognition of related and unrelated word lists relative to restudy. These benefits were eliminated, however, when test instructions were manipulated within subjects and presented after study of each list, procedures designed to minimise expectancy of a specific type of upcoming test [Huff, Balota, & Hutchison, 2016. The costs and benefits of testing and guessing on recognition memory. Journal of Experimental Psychology: Learning, Memory, and Cognition, 42, 1559-1572. doi: 10.1037/xlm0000269 ], suggesting that testing and guessing effects may be influenced by encoding strategies specific for the type of upcoming task. We follow-up these experiments by examining test-expectancy processes in guessing and testing. Testing and guessing benefits over restudy were not found when test instructions were presented either after (Experiment 1) or before (Experiment 2) a single study/task cycle was completed, nor were benefits found when instructions were presented before study/task cycles and the task was repeated three times (Experiment 3). Testing and guessing benefits emerged only when instructions were presented before a study/task cycle and the task was repeated six times (Experiments 4A and 4B). These experiments demonstrate that initial testing and guessing can produce memory benefits in recognition, but only following substantial task repetitions which likely promote task-expectancy processes. PMID- 29723115 TI - Synthesis of novel 3'-azido-3'-deoxy-alpha-L-ribo configured nucleosides: A comparative study between chemical and chemo-enzymatic methodologies. AB - Syntheses of novel 3'-azido-3'-deoxy-2'-O,4'-C-methylene-alpha-L-ribofuranosyl nucleosides have been carried out from 3'-azido-3'-deoxy-4'-C-hydroxymethyl-beta D-xylofuranosyl nucleosides following both chemical and chemo-enzymatic methodologies. The precursor nucleoside in turn was synthesized from a common glycosyl donor 4-C-acetoxymethyl-1,2,5-tri-O-acetyl-3-azido-3-deoxy-alpha,beta-D xylofuranose, which was obtained by the acetolysis of 4-C-acetoxymethyl-5-O acetyl-3-azido-3-deoxy-1,2-O-isopropylidene-alpha-D-xylofuranose in 96% yield. It has been observed that a chemo-enzymatic pathway for the synthesis of targeted nucleosides is much more efficient than a chemical pathway, leading to the improvement in yield for the synthesis of 3'-azido-3'-deoxy-alpha-L-ribofuranosyl thymine and uracil from 49 to 89% and 55 to 93%, respectively. PMID- 29723116 TI - High inter-individual variability of serum xanthine oxidoreductase activity in IBD patients. AB - OBJECTIVES: Thiopurines play an essential role in the management of inflammatory bowel diseases (IBD, i.e. Crohn's disease and ulcerative colitis). Over the past decade, several strategies to optimize treatment with thiopurines have been evaluated, including co-administration of allopurinol, a xanthine-oxidoreductase (XO) inhibitor, to low-dose thiopurine therapy. We aimed to assess the inter individual variability of XO-activity between IBD-patients. METHODS: We assessed XO activity in serum of IBD-patients of two medical centers in The Netherlands using the Amplex(r) Red Xanthine/Xanthine Oxidase Assay Kit, which measures the superoxide formation in a coupled reaction to the red-fluorescent oxidation product, resofurine. RESULTS: We observed a high inter-individual variability of XO-activity in 119 patients, with a median activity of 16 uU/ml/hour (range 1-85 uU/ml/hour). The XO-activity was influenced by gender (male 19.5 vs. female 14.0 uU/ml/hour, p < 0.01), patient's age (Pearson's correlation r = 0.21, p = 0.02) and duration of IBD (r = 0.23, p = 0.01). The XO activity was not affected by the type of IBD, smoking status, body mass index or (type of) thiopurine use (p > 0.05). CONCLUSIONS: There is a high inter-individual variability of XO-activity in IBD-patients; XO-activity is positively associated with male gender and patient's age. PMID- 29723117 TI - Hereditary xanthinuria is not so rare disorder of purine metabolism. AB - Hereditary xanthinuria (type I) is caused by an inherited deficiency of the xanthine oxidorectase (XDH/XO), and is characterized by very low concentration of uric acid in blood and urine and high concentration of urinary xanthine, leading to urolithiasis. Type II results from a combined deficiency of XDH/XO and aldehyde oxidase. Patients present with hematuria, renal colic, urolithiasis or even acute renal failure. Clinical symptoms are the same for both types. In a third type, clinically distinct, sulfite oxidase activity is missing as well as XDH/XO and aldehyde oxidase. The prevalence is not known, but about 150 cases have been described so far. Hypouricemia is sometimes overlooked, that's why we have set up the diagnostic flowchart. This consists of a) evaluation of uric acid concentrations in serum and urine with exclusion of primary renal hypouricemia, b) estimation of urinary xanthine, c) allopurinol loading test, which enables to distinguish type I and II; and finally assay of xanthine oxidoreductase activity in plasma with molecular genetic analysis. Following this diagnostic procedure we were able to find first patients with hereditary xanthinuria in our Czech population. We have detected nine cases, which is one of the largest group worldwide. Four patients were asymptomatic. All had profound hypouricemia, which was the first sign and led to referral to our department. Urinary concentrations of xanthine were in the range of 170-598 mmol/mol creatinine (normal < 30 mmol/mol creatinine). Hereditary xanthinuria is still unrecognized disorder and subjects with unexplained hypouricemia need detailed purine metabolic investigation. PMID- 29723118 TI - Protective Effects of Interferon-tau Against Lipopolysaccharide-Induced Embryo Implantation Failure in Pregnant Mice. AB - Interferon-tau (IFN-tau), a novel type I interferon, is produced by trophoblast cells in ruminants. Previous studies have confirmed that IFN-tau could induce immunological tolerance in humans and other species. However, there are few reports on whether IFN-tau has a protective effect on embryo implantation failure caused by excessive inflammation at the maternal-fetal interface. In our study, a mouse model of lipopolysaccharide (LPS)-induced implantation failure was successfully established, and we investigated the protective effects of IFN-tau. First, we showed that IFN-tau increased the number of implanted embryos in LPS treated pregnant mice. Subsequently, quantitative real-time polymerase chain reaction (qPCR) and ELISA results showed that several inflammatory cytokines [IL 1beta and tumor necrosis factor-alpha (TNF-alpha)] whose expression was upregulated by LPS were reversed by IFN-tau treatment. Furthermore, we performed Western blotting and found that IFN-tau restrained the LPS-induced phosphorylation of IkappaBalpha and NF-kappaB p65. Moreover, qPCR and immunohistochemistry analyses showed that IFN-tau decreased the LPS-induced expression of mouse major histocompatibility complex (MHC) class I genes (H-2K and H-2D) in LPS-treated pregnant mice. Taken together, these results suggest that IFN-tau has a protective effect in LPS-induced implantation failure by downregulating MHC class I genes expression and inhibiting the production of inflammatory cytokines. PMID- 29723119 TI - Novel dihydropyridine thioglycosides and their corresponding dehydrogenated forms as potent anti-hepatocellular carcinoma agents. AB - A novel method for preparation of a new class of dihydropyridine thioglycosides and their corresponding dehydrogenated forms, via reaction of piperidinium salts of dihydropyridinethiones with 2,3,4,6-tetra-O-acetyl-alpha-D-gluco- and galactopyranosyl bromides has been studied. The evaluation of antiproliferative activity against HepG-2 cell lines (liver carcinoma cell lines) of the dihydropyridine thioglycosides and pyridine thioglycosides revealed that many of the thioglycosides have interesting antitumor activities specifically 5c, 5g, 5l, 5o, 5p, 7a, 7i, 7p, 8b, 8f, 8s, and 8v. PMID- 29723121 TI - Seroprevalence and Genetic Characterization of Toxoplasma gondii In Naturally Infected Synanthropic Rodents In Yunnan Province, Southwestern China. AB - Rodents play an important role in the transmission of Toxoplasma gondii; however, little is known about the seroprevalence and genetic diversity of T. gondii infection in rodents in Yunnan Province, China. In this study, we examined the seroprevalence and genetically characterized T. gondii infection in naturally infected rodents in Yunnan Province between March and July 2016. In total, 261 serum samples were collected from rodents in the Jingha district, Xishuangbanna Dai Autonomous Prefecture, Yunnan Province, and examined for T. gondii antibodies by modified agglutination test (MAT) at a 1:20 cut-off, with titers of 1:20 in 24 samples, 1:40 in 10, 1:80 in 10, and 1:160 in 4. Thirty-two of 261 (12.26%) serum samples were positive for T. gondii by MAT. In total, 751 rodent brain samples were examined by semi-nested PCR; 46 (6.13%) were positive for the T. gondii B1 gene, 2 of which showed complete genotyping results for all 11 polymorphic loci (SAG1, SAG2, alt.SAG2, SAG3, BTUB, GRA6, L358, PK1, C22-8, C29-2, and Apico). The 2 samples were characterized to represent ToxoDB#137 ( http://toxodb.org/toxo/ ). These findings enriched the epidemiological and genetic diversity of T. gondii in China and have implications for the better prevention and control of T. gondii infection in humans and animals. PMID- 29723120 TI - Transabdominal Versus Subcuticular Sutures to Secure a Laparoscopic Gastrostomy. AB - PURPOSE: Traditional methods for securing a laparoscopic gastrostomy (LG) involve the placement of two monofilament transabdominal (TA) sutures to be removed after a short interval of 5 days. A modified technique employing an absorbable suture tunneled subcutaneously has been adopted by many surgeons. The aim of this study was to compare wound complications between these techniques. METHODS: A retrospective review of patients who underwent LG placement between 2010 and 2016 was conducted, dividing patients into two cohorts by securing stitch type, TA and subcutaneous (SC), and evaluating for complications. RESULTS: A total of 740 children underwent laparoscopic gastrostomy tube (GT) placement, of whom 554 (75%) patients had a TA stitch and the remaining 186 (25%) had a SC stitch. Demographic data were comparable in both groups. The most common wound complication was granulation tissue (22%), dislodgement (19%), external drainage (16%), cellulitis (10%), erosion (3%), and abscess formation (2%). Seven patients required operative revision for dislodgement; TA patients comprised the majority of these patients. Operative times were significantly longer in the SC group (22 minutes versus 28 minutes, P < .05). Rates of granulation, erosion, external and internal leakage, and dislodgement were equivalent between cohorts. There were higher rates of cellulitis (7.3% versus 19%, P < .05) and abscess (0.8% versus 7.6%, P < .05) noted in the SC group. Time to external leakage was significantly earlier in the SC group (P < .05); however, all other complications occurred at comparable times following initial operation. Persistent gastrocutaneous fistula requiring surgical closure occurred at equal rates with no difference in times to closure from GT discontinuation in both groups. CONCLUSION: While both techniques are feasible, there was a significant increase in infectious complications and operative times observed in the SC stitch patients, suggesting this may not be the optimal securing method. PMID- 29723123 TI - Re-imagining the role of the physiotherapist when managing people with long-term conditions. AB - The rising prevalence of long-term conditions (LTCs) is placing increasing pressures on healthcare systems. With the future prospect that more individuals will experience multiple comorbidities, LTCs are becoming a growing concern. This article aims to discuss the challenges faced by and the opportunities afforded to physiotherapists when caring for people with LTCs. It highlights the complexity of managing people with LTCs and the demands faced by physiotherapists when working within a transitioning healthcare service that necessitates cost effective yet, sustainable care. It considers ways that interventions can be optimized to not only support individuals with LTCs to improve their quality of life, but live an existence that has meaning and purpose. It also explores health promotion strategies that could be influential in changing the future healthcare landscape, by helping to prevent the occurrence of LTCs. The wider intention is to facilitate discussion of the future role of the physiotherapy profession in LTC management, in the hope that a shared vision can be created that is inspiring and transformative. A vision that imagines a physiotherapy service that is resilient to change and contemporary in approach, which continues to evolve to support the changing needs of people with LTCs. PMID- 29723122 TI - Antimicrobial Resistance Profiles of Enterohemorrhagic and Enteropathogenic Escherichia coli of Serotypes O157:H7, O26:H11, O103:H2, O111:H8, O145:H28 Compared to Escherichia coli Isolated from the Same Adult Cattle. AB - The aim of this study was to compare the antimicrobial resistance profiles of top five enterohemorrhagic Escherichia coli (EHEC) and enteropathogenic E. coli (EPEC) to E. coli isolated from the fecal flora of the same adult cattle. Previous prevalence studies had led to the isolation by immunomagnetic separation (IMS) of 39 EHEC and 80 EPEC. Seven EHEC were resistant (17.9%), and six were multidrug resistant (MDR) (15.4%). None of the top five EHEC was resistant to azithromycin. Nine EPEC O26:H11 (11.3%) were resistant. They were all resistant to tetracycline, and four were MDR (5.0%). An E. coli strain was isolated from the feces (without preselection by IMS) of 97 bovine carriers of top 5 strains. All these strains were susceptible to antibiotics. Comparative analyses did not reveal any differences between the cytotoxic activities of resistant EHEC and their susceptible counterparts or in the production of attachment and effacement lesions. These results highlighted the higher percentage of resistance of EHEC and EPEC strains compared to other E. coli. They also showed that resistance traits did not have any impact on the expression of virulence phenotypes in EHEC strains. PMID- 29723124 TI - Use of a modified treatment-based classification system for subgrouping patients with low back pain: Agreement between telerehabilitation and face-to-face assessments. AB - OBJECTIVE: To examine the agreement between telerehabilitation and face-to-face assessments of patients with acute and subacute low back pain (LBP) using a modified treatment-based classification (TBC) system. A secondary aim was to evaluate patient satisfaction with the telerehabilitation assessment. METHODS: Patients with LBP of less than 90 days' duration underwent both telerehabilitation and face-to-face assessments. After physical examination, patients were classified into one of three intervention groups (mobilization/manipulation, specific exercise, and stabilization). The assessment order and clinicians were randomized, and the clinicians were blinded to each other's classification decision. RESULTS: Forty-seven patients participated (mean [SD] age, 48.6 [15.0] years; 70% female). The overall rate of percentage agreement was 68.1% (kappa = 0.52; 95% confidence interval, 0.32-0.72). There was no difference in classification distributions between assessments (chi2 = 2.14, p = 0.54). The percentage agreement was 48.9%-59.6% for the modified TBC algorithm variables except for straight leg raise greater than 91 degrees , which was markedly lower at 35.1%. This was the only variable that was significantly different between the telerehabilitation and face-to-face scenarios. The overall satisfaction with the telerehabilitation assessment was good. CONCLUSIONS: The results suggest that a telerehabilitation assessment using the modified TBC system may be able to direct treatment of patients with acute and subacute LBP. However, challenges still remain in applying this approach to clinical practice. PMID- 29723125 TI - Copper(II)nitrate catalyzed regioselective protection of primary alcohols with 4,4'-dimethoxytrityl and 2,7-dimethyl-9-phenyl xanthen-9-yl groups in nucleosides and carbohydrates. AB - Regioselective protection of primary hydroxyl group in nucleoside and carbohydrate analogs was accomplished using dimethoxytrityl alcohol (DMTr-OH) or dimethylpixyl alcohol (DMPx-OH) in presence of copper(II)nitrate as a Lewis acid catalyst. Excellent selectivity was observed for the protection of primary hydroxyl group over secondary while glycosidic bond remain unaffected. Utility of this methodology was further exemplified via DMTr- and DMPx-protection of alipahtic acyclic and cyclic diols. PMID- 29723126 TI - Quality of life of older adults with cancer in Korea. AB - This study examines the quality of life (QoL) of older adults with cancer (N = 176), by comparing them with age- and gender-matched groups without cancer (N = 176), and investigates factors associated with their QoL. The results of Medical Outcome Study Short Form-36 (MOS SF-36) showed that the study group had significantly lower scores than the noncancer group on all eight scales and on the Physical Component Summary and the Mental Component Summary. Comparison with gender and age groups revealed some differences. Optimism and social support were positively related to QoL while comorbidity, cancer-related concerns, and financial worries were inversely related. PMID- 29723127 TI - Ethics and sexual health: Exploration of the ethical code of conduct for physiotherapists concerning sexual health in clinical practice. AB - Physiotherapists have an important role in sexual health, but there are specific ethical considerations regarding sexuality and the practice of physiotherapy which require serious consideration. This article aims to illustrate how the professional ethical code of physiotherapy can serve as a tool for ethical clinical reasoning regarding sexual health in clinical physiotherapy practice. We analyse the ethical codes for physical therapy, in relation to a definition of sexual health and the declaration of sexual rights. The analysis outlines several ethical considerations crucial in dealing with sexual health, while also acknowledging the critical role of cultural context in any ethical analysis. We conclude that physiotherapists need to practise ethical reasoning and that the ethical code of physiotherapy can act as a point of departure for reflection on thought-provoking ethical dilemmas to improve the practice of physiotherapy and support clients' overall health. PMID- 29723128 TI - Factors Influencing Family Surrogates' Intention with Regard to Do-Not Resuscitate Directive for Patients with Dementia. AB - OBJECTIVE: To investigate the prevalence of family surrogates' do-not-resuscitate (DNR) intention for patients with dementia (PwD), and factors influencing family surrogates' decisions. METHODS: This is a descriptive and cross-sectional study. Patients with dementia and their family surrogates from Dementia Outpatient Clinic of a teaching hospital in southern Taiwan were included. Data were collected using chart review and questionnaire survey. Influential factors were analyzed using multiple logistic regression. RESULTS: One hundred and forty of the 223 participants (62.8%) have intention to sign DNR consents for their dementia relatives. Factors influencing the intention were: (1) Comorbid with musculoskeletal diseases or diabetes (p < .05); (2) psychological symptoms of repetitive wording and behavior (p < .05); (3) spouse (p < .05) and lineal relatives (p < .01); (4) previous discussion between families and patient about DNR directive (p = .001); (5) believers of Taiwan folk belief (Buddhism or Taoism) (p < .05). CONCLUSIONS: Advanced dementia patients cannot express intention about their end-of-life care and depend on family surrogates to decide for them. Our study showed that spouse and direct relatives, comorbidities of musculoskeletal disease or diabetes, psychological symptoms of repetitive wording and behavior, previous discussion about patients' intention, and believers of Taiwan folk belief are all positive influencing factors for surrogates to consent DNR directive for patients. Our findings are important in promoting DNR directive for PwD. CLINICAL IMPLICATIONS: Our results may help to promote DNR decisions for dementia patients, especially in Chinese populations. PMID- 29723129 TI - Self-Compassion, Coping Strategies, and Caregiver Burden in Caregivers of People with Dementia. AB - OBJECTIVE: Caring for someone with dementia can have negative consequences for caregivers, a phenomenon known as caregiver burden. Coping strategies influence the impact of caregiving-related stress. Specifically, using emotion-focused strategies has been associated with lower levels of burden, whereas dysfunctional strategies have been related to increased burden. The concept of self-compassion has been linked to both positive outcomes and the coping strategies that are most advantageous to caregivers. However, as yet, no research has studied self compassion in caregivers. Therefore, the aim of this study was to explore the relationship between self-compassion, coping strategies and caregiver burden in dementia caregivers. METHOD: Cross-sectional survey data was collected from 73 informal caregivers of people with dementia recruited from post-diagnostic support services and caregiver support groups. RESULTS: Self-compassion was found to be negatively related to caregiver burden and dysfunctional coping strategies and positively related to emotion-focused coping strategies. Dysfunctional strategies mediated the relationship between self-compassion and caregiver burden, whereas emotion-focused strategies did not. CONCLUSION: Caregivers with higher levels of self-compassion report lower levels of burden and this is at least partly due to the use of less dysfunctional coping strategies. CLINICAL IMPLICATIONS: Interventions that develop self-compassion could represent a useful intervention for struggling caregivers. PMID- 29723131 TI - Insulin acts as a repressive factor to inhibit the ability of PAR2 to induce islet cell transdifferentiation. AB - Recently, we showed that pancreatitis in the context of profound beta-cell deficiency was sufficient to induce islet cell transdifferentiation. In some circumstances, this effect was sufficient to result in recovery from severe diabetes. More recently, we showed that the molecular mechanism by which pancreatitis induced beta-cell neogenesis by transdifferentiation was activation of an atypical GPCR called Protease-Activated Receptor 2 (PAR2). However, the ability of PAR2 to induce transdifferentiation occurred only in the setting of profound beta-cell deficiency, implying the existence of a repressive factor from those cells. Here we show that the repressor from beta-cells is insulin. Treatment of primary islets with a PAR2 agonist (2fLI) in combination with inhibitors of insulin secretion and signaling was sufficient to induce insulin and PAX4 gene expression. Moreover, in primary human islets, this treatment also led to the induction of bihormonal islet cells coexpressing glucagon and insulin, a hallmark of islet cell transdifferentiation. Mechanistically, insulin inhibited the positive effect of a PAR2 agonist on insulin gene expression and also led to an increase in PAX4, which plays an important role in islet cell transdifferentiation. The studies presented here demonstrate that insulin represses transdifferentiation of alpha- to beta-cells induced by activation of PAR2. This provides a mechanistic explanation for the observation that alpha- to beta-cell transdifferentiation occurs only in the setting of severe beta-cell ablation. The mechanistic understanding of islet cell transdifferentiation and the ability to modulate that process using available pharmacological reagents represents an important step along the path towards harnessing this novel mechanism of beta-cell neogenesis as a therapy for diabetes. PMID- 29723130 TI - Trefoil factor 3 in perinatal pancreas is increased by gestational low protein diet and associated with accelerated beta-cell maturation. AB - The endocrine pancreas expands markedly in the first postnatal days and the insulin producing beta-cells initiate a functional maturation preceded by a morphological change of the islets of Langerhans. Trefoil factor 3 (TFF3) is a secreted peptide expressed in intestinal epithelia, where it promotes migration, but its role in the pancreas is not characterized. The aim of this study was to examine the expression and function of TFF3 in perinatal rat pancreas, ex vivo cultured fetal rat pancreas and in the rat beta-cell line INS-1E. Control or gestational low-protein diet perinatal rat pancreas was harvested at embryonic day 20 (E20), day of birth (P0) and postnatal day 2 (P2). TFF3 mRNA was upregulated 4.5-fold at P0 vs. E20 and downregulated again at P2. In protein undernourished pups induction of TFF3 at P0 was further increased to 9.7-fold and was increased at P2. TFF3 caused tyrosine phosphorylation of EGFR in INS-1E beta cells, and purified recombinant TFF3 increased both attachment and spreading of INS-1E beta-cells. In ex vivo cultures of collagenase digested fetal rat pancreas, a model of perinatal beta-cell maturation, TFF3 increased cellular spreading as well as insulin mRNA levels. TFF3 also increased the expression of Pref1/Dlk1 that shares similarities in expression and regulation with TFF3. These results suggest that TFF3 may promote adhesion and spreading of cells to accelerate beta-cell maturation. This study indicates a functional role for TFF3 in pancreatic beta-cell maturation in the perinatal period, which is altered by low protein diet during gestation. PMID- 29723133 TI - Antipyrimidine effects of five different pyrimidine de novo synthesis inhibitors in three head and neck cancer cell lines. AB - The pyrimidine de novo nucleotide synthesis consists of 6 sequential steps. Various inhibitors against these enzymes have been developed and evaluated in the clinic for their potential anticancer activity: acivicin inhibits carbamoyl phosphate-synthase-II, N-(phosphonacetyl)-L- aspartate (PALA) inhibits aspartate transcarbamylase, Brequinar sodium and dichloroallyl-lawsone (DCL) inhibit dihydroorotate-dehydrogenase, and pyrazofurin (PF) inhibits orotate phosphoribosyltransferase. We compared their growth inhibition against 3 cell lines from head-and-neck-cancer (HEP-2, UMSCC-14B and UMSCC-14C) and related the sensitivity to their effects on nucleotide pools. In all cell lines Brequinar and PF were the most active compounds with IC50 (50% growth inhibition) values between 0.06-0.37 uM, Acivicin was as potent (IC50s 0.26-1 uM), but DCL was 20-31 fold less active. PALA was most inactive (24-128 uM). At equitoxic concentrations, all pure antipyrimidine de novo inhibitors depleted UTP and CTP after 24 hr exposure, which was most pronounced for Brequinar (between 6-10% of UTP left, and 12-36% CTP), followed by DCL and PF, which were almost similar (6 16% UTP and 12-27% CTP), while PALA was the least active compound (10-70% UTP and 13-68% CTP). Acivicin is a multi-target inhibitor of more glutamine requiring enzymes (including GMP synthetase) and no decrease of UTP was found, but a pronounced decrease in GTP (31-72% left). In conclusion, these 5 inhibitors of the pyrimidine de novo nucleotide synthesis varied considerably in their efficacy and effect on pyrimidine nucleotide pools. Inhibitors of DHO-DH were most effective suggesting a primary role of this enzyme in controlling pyrimidine nucleotide pools. PMID- 29723132 TI - Endoscopic Cauterization with Pneumatic Distension for Piriform Fossa Sinus Tracts. AB - INTRODUCTION: Piriform fossa sinus tracts (PFSTs) are a cause of recurrent neck infections in the pediatric population. Conventional management required open resection, but over the last years minimally invasive approaches have been reported in an attempt to endoscopically obliterate the PFST, using different methods such as electrocautery, laser, trichloroacetic acid, or silver nitrate. MATERIALS AND METHODS: We undertook a retrospective review of the medical records of 12 children (aged 4 months to 14 years) with PFSTs treated with endoscopic sclerosis with diathermy (ESD) between 2010 and 2016 at a tertiary care children's hospital. We also present a technical modification of ESD, using continuous infusion of airflow through the gastroscopy, to distend the piriform sinus and facilitate its recognition. PFST obliteration was performed using diathermy through a guide wire. RESULTS: Clinical presentation of the 12 affected children included neck tumor (7 [58%]), neck abscesses (4 [33%]), and thyroiditis (5 [41%]). All lesions occurred on the left side. All patients underwent both ultrasonography and barium esophagography (the latter being positive only in 50%). Two patients were treated with ESD after the open approach had failed. There was no procedure-related morbidity. One patient had a recurrence (positive barium swallow without symptoms). The success rate of this procedure in our series was 91% with one attempt and 100% with two attempts. CONCLUSION: In our experience, treatment of PFST with ESD is a reproducible, noninvasive, and an effective option. ESD could be considered a primary approach and also for revision after open surgery has failed in these patients. PMID- 29723134 TI - Introduction to a special grouping of papers from the 2016 A&WMA Specialty Conference on Atmospheric Optics: Aerosols, Visibility, and the Radiative Balance. PMID- 29723135 TI - Exploring the self-compassion of health-care social workers: How do they fare? AB - Indubitably, the challenges facing health-care social workers are becoming increasingly complex. Whilst these problematic professional circumstances compound the need for self-compassion among health-care social workers, few studies, if any, have explicitly examined self-compassion among this practitioner group. This cross-sectional study explored self-compassion among a sample of practitioners (N = 138) in one southeastern state. Results indicate that health care social workers in this sample engage in self-compassion only moderately. Further, occupational and demographic/life characteristics (e.g., age, years practicing social work, average hours worked per week, health status, and relationship status, among others) are able to predict self-compassion scores. After a terse review of relevant literature, this paper will explicate findings from this study, discuss relevant points derived from said findings, and identify salient implication for health-care social work praxis. PMID- 29723136 TI - The History of Aerobics (50 Years and Still Counting). AB - Looking back over the 50 years since Aerobics was published, I could never have expected for there to have been a major change in physicians' attitudes toward the value of exercise in the practice of medicine. In my lifetime, I never thought I would see a stress test be considered a mandatory component of a complete examination, inactivity classified as importantly as high blood pressure and high cholesterol, and cigarette smoking considered a coronary risk factor. I have tried in this Research Quarterly for Exercise and Sport (RQES) Lecture presentation to document how this slow but gradual transition took place due to my work and the work of many of my colleagues in this field, along with the important work of The Cooper Institute. In June 1970, I chartered the institute 6 months before I saw my first patient at the Cooper Clinic, but now with the Cooper Center Longitudinal Study being the largest database in the world comparing measured levels of fitness, instead of relying only on questionnaires and correlating fitness and health in our more than 700 published peer-review articles, we have proven and can safely say that "exercise is medicine." In greater detail, I want this lecture to present what we and others have done in this scientific endeavor, and even the harshest critics are now saying that "these results are too impressive to be ignored." PMID- 29723138 TI - Visual Interactive Map Matching. AB - Map matching is the process of assigning observed geographic positions of vehicles and their trajectories to the actual road links in a road network. In this paper, we present Visual Interactive Map Matching, a visual analytics approach to fine-tune the data preprocessing and matching process. It is based on ST-matching, a state-of-the-art and easy-to-understand map matching algorithm. Parameters of the preprocessing step and algorithm can be optimized with immediate visual feedback. Visualizations show current matching issues and performance metrics on a map and in diagrams. Manual and computer-supported editing of the road network model leads to a refined alignment of trajectories and roads. We demonstrate our approach with large-scale taxi trajectory data. We show that optimizing the matching on a subsample results in considerably improved matching quality, also when later scaled to the full dataset. An optimized matching ensures data faithfulness and prevents misinterpretation when the matched data might be investigated in follow-up analysis. PMID- 29723139 TI - Predominance Tag Maps. AB - A predominance map expresses the predominant data category for each geographical entity and colors are used to differentiate a small number of data categories. In tag maps, many data categories are present in the form of different tags, but related tag map approaches do not account for predominance, as tags are either displaced from their respective geographical locations or visual clutter occurs. We propose predominance tag maps, a layout algorithm that accounts for predominance for arbitrary aggregation granularities. The algorithm is able to utilize the font sizes of the tags as visual variable and it is further configurable to implement aggregation strategies beyond visualizing predominance. We introduce various measures to evaluate numerically the qualitative aspects of tag maps regarding local predominance, global features, and layout stability and we comparatively analyze our method to the tag map approach by Thom et al. [1] on the basis of real world data sets. PMID- 29723140 TI - GANViz: A Visual Analytics Approach to Understand the Adversarial Game. AB - Generative models bear promising implications to learn data representations in an unsupervised fashion with deep learning. Generative Adversarial Nets (GAN) is one of the most popular frameworks in this arena. Despite the promising results from different types of GANs, in-depth understanding on the adversarial training process of the models remains a challenge to domain experts. The complexity and the potential long-time training process of the models make it hard to evaluate, interpret, and optimize them. In this work, guided by practical needs from domain experts, we design and develop a visual analytics system, GANViz, aiming to help experts understand the adversarial process of GANs in-depth. Specifically, GANViz evaluates the model performance of two subnetworks of GANs, provides evidence and interpretations of the models' performance, and empowers comparative analysis with the evidence. Through our case studies with two real-world datasets, we demonstrate that GANViz can provide useful insight into helping domain experts understand, interpret, evaluate, and potentially improve GAN models. PMID- 29723137 TI - Linking time-series of single-molecule experiments with molecular dynamics simulations by machine learning. AB - Single-molecule experiments and molecular dynamics (MD) simulations are indispensable tools for investigating protein conformational dynamics. The former provide time-series data, such as donor-acceptor distances, whereas the latter give atomistic information, although this information is often biased by model parameters. Here, we devise a machine-learning method to combine the complementary information from the two approaches and construct a consistent model of conformational dynamics. It is applied to the folding dynamics of the formin-binding protein WW domain. MD simulations over 400 MUs led to an initial Markov state model (MSM), which was then "refined" using single-molecule Forster resonance energy transfer (FRET) data through hidden Markov modeling. The refined or data-assimilated MSM reproduces the FRET data and features hairpin one in the transition-state ensemble, consistent with mutation experiments. The folding pathway in the data-assimilated MSM suggests interplay between hydrophobic contacts and turn formation. Our method provides a general framework for investigating conformational transitions in other proteins. PMID- 29723141 TI - MeetingVis: Visual Narratives to Assist in Recalling Meeting Context and Content. AB - In team-based workplaces, reviewing and reflecting on the content from a previously held meeting can lead to better planning and preparation. However, ineffective meeting summaries can impair this process, especially when participants have difficulty remembering what was said and what its context was. To assist with this process, we introduce MeetingVis, a visual narrative-based approach to meeting summarization. MeetingVis is composed of two primary components: (1) a data pipeline that processes the spoken audio from a group discussion, and (2) a visual-based interface that efficiently displays the summarized content. To design MeetingVis, we create a taxonomy of relevant meeting data points, identifying salient elements to promote recall and reflection. These are mapped to an augmented storyline visualization, which combines the display of participant activities, topic evolutions, and task assignments. For evaluation, we conduct a qualitative user study with five groups. Feedback from the study indicates that MeetingVis effectively triggers the recall of subtle details from prior meetings: all study participants were able to remember new details, points, and tasks compared to an unaided, memory only baseline. This visual-based approaches can also potentially enhance the productivity of both individuals and the whole team. PMID- 29723143 TI - [The role of exosomal tetraspanins and proteases in tumor progression]. AB - Major (CD9, CD63, CD81) and others (CD82, CD151, Tspan8) tetraspanins are widely represented in exosomes, where they interact with various proteins and form functional tetraspanin complexes. Tetraspanin complexes include proteases. Tetraspanin-associated exosomal proteases (ADAM proteases, MMPs, EMMPRIN) play an important role in the processes of cell motility, migration, invasion and formation of metastases. Also, a significant contribution to tumor progression is made by proteases that are not associated with tetraspanins. They destabilize intercellular contacts, promote migration and invasion of tumor cells, participate in the regulation of the expression IGF-I, VEGF and transcription factors activation/deactivation. The role of other proteases of exosomes in the processes of tumor progression is being clarified. PMID- 29723142 TI - Use of a Novel Foam Dressing With Negative Pressure Wound Therapy and Instillation: Recommendations and Clinical Experience. AB - A new reticulated open-cell foam dressing with through holes (ROCF-CC) has been introduced to assist with wound cleansing by removing thick wound exudate and infectious materials during neg- ative pressure wound therapy with instillation. Due to the limited published evidence supporting use of ROCF-CC dressings with negative pressure wound therapy with instillation and dwell time (NPWTi-d), clinicians have been relying on practical application experience to gain pro ciency with the dressing and NPWTi-d. To help provide general guidelines for safe and e cient use of ROCF-CC dressings with NPWTi-d, a multidisciplinary expert panel of clinicians was convened from September 28 to 29, 2017. Principal aims of the meeting were to develop recommendations based on panel members' experience and lim- ited published results for use of ROCF-CC dressings, appropriate wound and patient characteristics for use, application settings, and clinical techniques to optimize outcomes. An algorithm to guide use of ROCF-CC dressings with NPWTi-d was also created. Panelists recommended the following goals for using ROCF-CC dressings: cleanse wounds when areas of slough or nonviable tissue remain on the wound surface, remove thick exudate, remove infectious materials, promote granulation tissue formation, and help provide a bridge to a de ned endpoint. Negative pressure wound therapy with instillation and dwell time with ROCF-CC dressings may be an appropriate adjunct therapy for wound cleansing, especially in cases when sharp excisional debridement is not available or appropriate. All panel members agreed that controlled clinical and scienti c studies of NPWTi-d with ROCF-CC are needed to further elucidate best practices and e ectiveness in various wound types. PMID- 29723144 TI - [Ubiquitin-independent protein degradation in proteasomes]. AB - Proteasomes are large supramolecular protein complexes present in all prokaryotic and eukaryotic cells, where they perform targeted degradation of intracellular proteins. Until recently, it was generally accepted that prior proteolytic degradation in proteasomes the proteins had to be targeted by ubiquitination: the ATP-dependent addition of (typically four sequential) residues of the low molecular ubiquitin protein, involving the ubiquitin-activating enzyme, ubiquitin conjugating enzyme and ubiquitin ligase. The cytoplasm and nucleoplasm proteins labeled in this way are then digested in 26S proteasomes. However, in recent years it has become increasingly clear that using this route the cell eliminates only a part of unwanted proteins. Many proteins can be cleaved by the 20S proteasome in an ATP-independent manner and without previous ubiquitination. Ubiquitin-independent protein degradation in proteasomes is a relatively new area of studies of the role of the ubiquitin-proteasome system. However, recent data obtained in this direction already correct existing concepts about proteasomal degradation of proteins and its regulation. Ubiquitin-independent proteasome degradation needs the main structural precondition in proteins: the presence of unstructured regions in the amino acid sequences that provide interaction with the proteasome. Taking into consideration that in humans almost half of all genes encode proteins that contain a certain proportion of intrinsically disordered regions, it appears that the list of proteins undergoing ubiquitin-independent degradation will demonstrate further increase. Since 26S of proteasomes account for only 30% of the total proteasome content in mammalian cells, most of the proteasomes exist in the form of 20S complexes. The latter suggests that ubiquitin-independent proteolysis performed by the 20S proteasome is a natural process of removing damaged proteins from the cell and maintaining a constant level of intrinsically disordered proteins. In this case, the functional overload of proteasomes in aging and/or other types of pathological processes, if it is not accompanied by triggering more radical mechanisms for the elimination of damaged proteins, organelles and whole cells, has the most serious consequences for the whole organism. PMID- 29723145 TI - [Methods for determining of cytochrome P450 isozymes functional activity]. AB - The review is dedicated to modern methods and technologies for determining of cytochrome P450 isozymes functional activity, such as absorbance and fluorescent spectroscopy, electron paramagnetic resonance (EPR), nuclear magnetic resonance (NMR), Raman, Mossbauer, and X-ray spectroscopy, surface plasmon resonance (SPR), atomic force microscopy (AFM). Methods of molecular genetic analysis were reviewed from personalized medicine point of view. The use of chromate-mass spectrometric methods for cytochrome P450-dependent catalytic reactions' products was discussed. The review covers modern electrochemical systems based on cytochrome P450 isozymes for their catalytic activity analysis, their use in practice and further development perspectives for experimental pharmacology, biotechnology and translational medicine. PMID- 29723146 TI - [The analysis of participation of individual proteins in the protein interactome formation]. AB - It becomes increasingly clear that most proteins of living systems exist as components of various protein complexes rather than individual molecules. The use of various proteomic techniques significantly extended our knowledge not only about functioning of individual complexes but also formed a basis for systemic analysis of protein-protein interactions. In this study gel-filtration chromatography accompanied by mass-spectrometry was used for the interactome analysis of human liver proteins. In six fractions (with average molecular masses of 45 kDa, 60 kDa, 85 kDa, 150 kDa, 250 kDa, and 440 kDa) 797 proteins were identified. In dependence of their distribution profiles in the fractions, these proteins could be subdivided into four groups: (1) single monomeric proteins that are not involved in formation of stable protein complexes; (2) proteins existing as homodimers or heterodimers with comparable partners; (3) proteins that are partially exist as monomers and partially as components of protein complexes; (4) proteins that do not exist in the monomolecular state, but also exist within protein complexes containing three or more subunits. Application of this approach to known isatin-binding proteins resulted in identification of proteins involved in formation of the homo- and heterodimers and mixed protein complexes. PMID- 29723147 TI - [Enzymatic and bactericidal activity of monomeric and dimeric forms of myeloperoxidase]. AB - This study was carried out to compare the enzymatic and bactericidal activity of mature, dimeric myeloperoxidase (MPO) and its monomeric form. Dimeric MPO was isolated from HL-60 cells. Hemi-MPO obtained from dimeric MPO by reductive cleavage of a disulfide bond between protomeric subunits was used as the monomeric form. Both peroxidase and halogenating (chlorinating) activities of MPO were assayed, each of them by two methods. Bactericidal activity of the MPO/N2O2/Cl- system was tested using the Escherichia coli laboratory strain DH5a. No difference in the enzymatic and bactericidal activity between dimeric MPO and hemi-MPO was found. Both forms of the enzyme also did not differ in the resistance to HOCl, the main product of MPO. HOCl caused a dose-dependent decrease in peroxidase and chlorinating activity, and the pattern of this decrease was identical for dimeric MPO and hemi-MPO. At equal heme concentration, a somewhat higher bactericidal effect was observed for the hemi-MPO/N2O2/Cl- system compared with the dimeric MPO/N2O2/Cl- system. However, this is most likely not related to some specific property of hemi-MPO and can be accounted for by the higher probability of contacting between bacterial surface and hemi-MPO molecules due to their two-fold greater number relative to that of dimeric MPO molecules at the same heme concentration. By using Western-blotting with antibodies to MPO, we showed, for the first time, that the dimeric molecule of MPO could be cleaved into two monomeric subunits by HOCl, most probably due to oxidation of the disulfide bond between these subunits. This finding suggests that appearance in blood of MPO corresponding in mass to its monomer may result from the damage of dimeric MPO by reactive halogen species, especially upon their overproduction underlying oxidative/halogenative stress in inflammatory diseases. PMID- 29723148 TI - [The influence of acizolum to bioelements content in rat's blood plasma, parenchimal organs and brain]. AB - Zinc content in blood plasma and brain tissue of rats was studied by analytic mass-spectrometry with inductively coupled plasma. In control (saline-treated animal) zinc content in plasma was 3.6+/-1.4 mg/ml, in the liver - 12.5+/-2.5 mg/mg, in the spleen - 10.9+/-4.1 mg/mg, in the brain - 8.7+/-3.0 mg/mg. After a single intraperitoneal injection of zinc donator acizolum (24 mg/kg) zinc content decreased in all examined tissues, especially in brain. After a course of sequential acizolum injections (seven administrations during two weeks) essential elevation of zinc content in blood plasma and tissues investigated was detected. The maximal increase zinc concentration in blood plasma and liver was detected in 15 h after the last acizolum injections. Selen, calcium, copper and iron contents demonstrated a more complex behaviour. The obtained data suggest that prolonged acizolum administration has a significant impact on the bioelements content, and this should be taken into consideration when this zinc donator is used as a drug. PMID- 29723149 TI - [Evaluation of the cardioprotective effect of ubiquinol on the model of reperfusion injury of rat myocardium]. AB - The cardioprotective effect of ubiquinol on the model of myocardium reperfusion injury in rats was investigated. The study was carried out using mature males of outbred rats. Myocardial ischemia-reperfusion injury was performed after 30 minute ligation of the left coronary artery followed by reperfusion. The main criteria for assessing the development of pathology included the results of electrocardiography, biochemical analysis of blood plasma, histological and histochemical study of the myocardium. Development of the reperfusion damage of the myocardium caused specific changes in non-treated animals. The best therapeutic effect on biochemical indices was provided by a drug with the known cardioprotective activity - Mexidola and the tested object ubiquinol at doses of 2-6 mg/kg. Evaluation of the results of electrocardiography allowed to confirm the development of ischemic myocardial damage in all groups. The results of histochemical and histological examination of the myocardium suggest a high cardioprotective activity of ubiquinol at a dose of 3 mg/kg and a potential cardioprotective effect of ubiquinol in doses closest to the therapeutic doses of 2 and 6 mg/kg. Ubiquinol is a dose 9 mg/kg showed signs of prooxidant activity, manifested in the form of aggravation of reperfusion injury of the myocardium. The most effective in the conditions of experimental pathology is 1% solution of ubiquinol, at a dose of 3 mg/kg, whose cardioprotective effect is comparable or higher than that for the reference drug Mexidola at the therapeutic dose. In doses that are greater than therapeutic ubiquinol is able to act as a pro oxidant. PMID- 29723150 TI - [Apolipoprotein A-I stimulates secretion of insulin and matrix metalloproteinases by islets of Langerhans]. AB - The development of type 2 diabetes mellitus (DM2) is accompanied by disturbances in lipid metabolism. These include the increase in serum levels of atherogenic fractions of very low-density (VLDL) and low-density lipoproteins (LDL), total cholesterol, triglycerides and apo B. In contrast, the level of antiatherogenic high density lipoproteins (HDL) and the content of apolipoprotein A-I (apoA-I) decreased. To study the effect of the observed metabolic changes on insulin secretion in vitro, we used the islets of Langerhans isolated from the rat pancreas. It has been found that incubation of the islets in the presence of serum of the obese patients and patients with decompensated DM2 leads to a decrease in insulin secretion by 2.4 and 5.0 times, respectively. On the contrary, the addition of HDL to the incubation medium increased the insulin secretion by 3.4 times. A similar effect was observed in the presence of apoA-I, the main protein component of HDL. In the presence of apoA-I, the extracellular activity of matrix metalloproteinases (MMPs) demonstrated a 10-fold increase. The addition of LDL and VLDL to the islets did not change the secretion of insulin and activity of MMP. Our results testify to the important role of HDL and apoA-I in regulation of the insulin secretion by b-cells and the activity of MMPs in the islets of Langerhans. PMID- 29723151 TI - [The effect of antipsychotic drug on monoamine receptors in peripheral blood mononuclear cells: affinity linked mechanism]. AB - Schizophrenia is one of the most serious and common mental disorders, which is characterized by high levels of pathogenic heterogeneity as well as neuroimmune abnormalities, which require treatment with antipsychotic drugs. Monoamines are one of the key neurotransmitters which play an important role in neuroimmune interactions of the human organism. We suggest that the quantity of the monoamine receptors on mononuclear cells of the peripheral blood (PBMCs) can be associated with the cytokine profile of patients. With this quantity being a key component of the mental status correction mechanism in antipsychotic therapy. In this study we measured cytokine levels (IL-6, IL-1b and TGF-b) in blood serum, the protein expression status of the serotonin receptor 5HTR2A and the dopamine receptors D1 (DRD1), DRD2, DRD3 in PBMCs of drug-naive, first episode schizophrenia patients before and after the treatment with olanzapine and haloperidol. This study has shown for the first time that the antipsychotic therapy leads to a decrease in protein levels of monoamine receptors in PBMCs associated with the affinity of the drug used. Blood cytokine levels were significantly higher in serum from studied patients as compared with the reference values. The antipsychotic-linked change of the TGF-b production caused by the therapy is probably associated with the reduction of various monoamine receptors. The relationship between the psychopathological status and the protein level of 5THR2A suggests that the amount of 5HTR2A may serve as a potential biomarker for the personalized appointment of the antipsychotic therapy. PMID- 29723152 TI - [The role of single nucleotide polymorphisms in GIPR gene in the changes of secretion in hormones and adipokines in patients with obesity with type 2 diabetes]. AB - The relationship between the rs2302382, rs8111428 and Glu354Gln (rs1800437) polymorphisms in GIPR (glucosedependent insulinotropic polypeptide receptor) gene and plasma levels of mediators involved in the regulation of carbohydrate metabolism in obese patients with type 2 diabetes (before and after a test breakfast) was investigated. The contribution of polymorphic variants of rs2302382, rs8111428 in GIPR gene in the predisposition to type 2 diabetes in individuals belonging to the Slavic population of Russia was found. Polymorphisms rs2302382 and rs8111428 in the GIPR gene were characterized by the nonequilibrium cohesion. The decrease in the level of expression of the GIPR gene in adipose tissue of the small intestine mesentery in the carriers of the CC genotype rs2302382 and AA rs8111428 was associated with the increase in the plasma leptin level, whereas during normal expression, the plasma content of insulin, and GIP (in persons with the genotype of the polymorphism rs2302382 and AG polymorphism rs8111428), resistin and ghrelin (in individuals with the genotype of the polymorphism rs2302382) increased. We propose the stimulating effect of GIP on the secretion of resistin, leptin and ghrelin, with an increase in insulin production in obese patients with type 2 diabetes. PMID- 29723153 TI - Recent initiatives in harmonization of hemostasis practice. PMID- 29723154 TI - An aqueous extract of the Anogeissus leiocarpus bark (AEAL) induces the endothelium-dependent relaxation of porcine coronary artery rings involving predominantly nitric oxide. AB - BACKGROUND: Anogeissus leiocarpus is a Sahel tree traditionally used by the residents of Burkina Faso for its antihypertensive properties. In this study, experiments were conducted to evaluate whether an aqueous extract of the Anogeissus leiocarpus (AEAL) trunk bark induces a vasorelaxant effect on porcine coronary artery rings and to investigate the underlying mechanism. METHODS: AEAL induced relaxations were assessed using porcine coronary artery rings suspended in organ chambers. The phosphorylation levels of Src, Akt and endothelial nitric oxide synthase (eNOS) were assessed in a primary endothelial cell culture by Western blot. The reactive oxygen species (ROS) formation was assessed using dihydroethidine. RESULTS: In porcine coronary artery rings, AEAL at 0.1-300 MUg/mL induced endothelium-dependent relaxations, which were inhibited in the presence of inhibitors of nitric oxide (NO) and the endothelium-derived hyperpolarization pathways. Moreover, the AEAL-induced NO-mediated relaxations were significantly reduced by the inhibitors of Src and PI3-kinase as well as by the membrane-permeant ROS scavengers. In cultured porcine coronary artery endothelial cells, treatment with AEAL is associated with an intracellular generation of ROS. Moreover, the AEAL induced the phosphorylations of Akt (Ser473), eNOS (Ser1177) and a transient phosphorylation of Src (Ser17) in a time dependent manner. CONCLUSIONS: These findings indicate that AEAL is a potent inducer of endothelium-dependent NO-mediated relaxations in porcine coronary arteries through the redox-sensitive Src/PI3-kinase/Akt pathway-dependent activation of eNOS. PMID- 29723155 TI - A pilot study exploring the impact of cardiac medications on ciliary beat frequency: possible implications for clinical management. PMID- 29723156 TI - Circulating soluble RAGE and cell surface RAGE on peripheral blood mononuclear cells in healthy children. AB - BACKGROUND: The receptor for advanced glycation end products (RAGE) has a critical role in the pathogenesis of inflammation. In healthy children, its basal expression on the peripheral blood mononuclear cell (PBMC) and the basal circulating soluble RAGE (sRAGE) levels are unknown. The aim of this study was to describe both. METHODS: This is a monocentric, observational and descriptive study of samples obtained from healthy children. The RAGE expression on PBMC was analyzed using flow cytometry. The sRAGE values were determined with a specific sandwich enzyme-linked immunosorbent assay (ELISA) kit, later the relation between cellular RAGE and sRAGE was described. RESULTS: Forty-three children were included. The median sRAGE level was 849.0+/-579.0 pg/mL. The RAGE mean fluorescence intensity (MFI) was 1382+/-506 in monocytes and 792+/-506 in lymphocytes. There were no differences between genders. A negative correlation was found between sRAGE and RAGE MFI in lymphocytes (r=-0.3; p=0.04). CONCLUSIONS: We describe for the first time the RAGE surface levels on PBMC in children. It showed a negative correlation with sRAGE. The sRAGE circulating level is lower than the sRAGE level described in adult population or non-healthy children. Our findings should be confirmed in order to apply them as reference values for future investigations. PMID- 29723157 TI - Testosterone and dihydrotestosterone reduce platelet activation and reactivity in older men and women. AB - The cardiovascular effects of testosterone and dihydrotestosterone are generally attributed to their modulatory action on lipid and glucose metabolism. However, no ex vivo studies suggest that circulating androgen levels influence the activation and reactivity of blood platelets - one of the main components of the haemostasis system directly involved in atherosclerosis. The levels of testosterone, dihydrotestosterone and oestradiol in plasma from men and women aged from 60 to 65 years were measured by LC-MS; the aim was to identify any potential relationships between sex steroid levels and the markers of platelet activation (surface membrane expression of GPII/IIIa complex and P-selectin) and platelet reactivity in response to arachidonate, collagen or ADP, monitored with whole blood aggregometry and flow cytometry. The results of the ex vivo part of the study indicate that the concentrations of testosterone and its reduced form, dihydrotestosterone are significantly negatively associated with platelet activation and reactivity. These observations were confirmed in an in vitro model: testosterone and dihydrotestosterone significantly inhibited platelet aggregation triggered by arachidonate or collagen. Our findings indicate that testosterone and dihydrotestosterone are significant haemostatic steroids with inhibitory action on blood platelets in older people. PMID- 29723159 TI - Electrical property of macroscopic graphene composite fibers prepared by chemical vapor deposition. AB - Graphene fibers are promising candidates in portable and wearable electronics due to their tiny volume, flexibility and wearability. Here, we successfully synthesized macroscopic graphene composite fibers via a two-step process, i.e. first electrospinning and then chemical vapor deposition (CVD). Briefly, the well dispersed PAN nanofibers were sprayed onto the copper surface in an electrified thin liquid jet by electrospinning. Subsequently, CVD growth process induced the formation of graphene films using a PAN-solid source of carbon and a copper catalyst. Finally, crumpled and macroscopic graphene composite fibers were obtained from carbon nanofiber/graphene composite webs by self-assembly process in the deionized water. Temperature-dependent conduct behavior reveals that electron transport of the graphene composite fibers belongs to hopping mechanism and the typical electrical conductivity reaches 4.59 * 103 S m-1. These results demonstrated that the graphene composite fibers are promising for the next generation flexible and wearable electronics. PMID- 29723158 TI - CircRNAs in the tree shrew (Tupaia belangeri) brain during postnatal development and aging. AB - Circular RNAs (circRNAs) are a novel type of non-coding RNA expressed across different species and tissues. At present, little is known about the expression and function of circRNAs in the tree shrew brain. In this study, we used RNA-seq to identify 35,007 circRNAs in hippocampus and cerebellum samples from infant (aged 47-52 days), young (aged 15-18 months), and old (aged 78-86 months) tree shrews. We observed no significant changes in the total circRNA expression profiles in different brain regions over time. However, circRNA tended to be downregulated in the cerebellum over time. Real-time RT-PCR analysis verified the presence of circRNAs. KEGG analysis indicated the occurrence of ubiquitin mediated proteolysis, the MAPK signaling pathway, phosphatidylinositol signaling system, long-term depression, the rap1 signaling pathway, and long-term potentiation in both brain regions. We also observed that 29,087 (83.1%) tree shrew circRNAs shared homology with human circRNAs. The competing endogenous RNA networks suggested novel_circRNA_007362 potential functions as a 24-miRNAs sponge to regulate UBE4B expression. Thus, we obtained comprehensive circRNA expression profiles in the tree shrew brain during postnatal development and aging, which might help to elucidate the functions of circRNAs during brain aging and in age related diseases. PMID- 29723160 TI - One step hydrothermal synthesis of 3D CoS2@MoS2-NG for high performance supercapacitors. AB - A three-dimensional (3D) MoS2 coated CoS2-nitrogen doped graphene (NG) (CoS2@MoS2 NG) hybrid has been synthesized by a one step hydrothermal method as supercapacitor (SC) electrode material for the first time. Such a composite consists of NG embedded with stacked CoS2@MoS2 sheets. With a 3D skeleton, it prevents the agglomeration of CoS2@MoS2 nanoparticles, resulting in sound conductivity, rich porous structures and a large surface area. The results indicate that CoS2@MoS2-NG has higher specific capacitance (198 F g-1 at 1 A g 1), better rate performance (with about 56.57% from 1 to 16 A g-1) and an improved cycle stability (with about 96.97% after 1000 cycles). It is an ideal candidate for SC electrode materials. PMID- 29723162 TI - HIV-1 replicates and persists in vaginal epithelial dendritic cells. AB - HIV-1 acquisition occurs most commonly after sexual contact. To establish infection, HIV-1 must infect cells that support high-level replication, namely CD4+ T cells, which are absent from the outermost genital epithelium. Dendritic cells (DCs), present in mucosal epithelia, potentially facilitate HIV-1 acquisition. We show that vaginal epithelial DCs, termed CD1a+ VEDCs, are unlike other blood- and tissue-derived DCs because they express langerin but not DC SIGN, and unlike skin-based langerin+ DC subset Langerhans cells (LCs), they do not harbor Birbeck granules. Individuals primarily acquire HIV-1 that utilizes the CCR5 receptor (termed either R5 or R5X4) during heterosexual transmission, and the mechanism for the block against variants that only use the CXCR4 receptor (classified as X4) remains unclear. We show that X4 as compared with R5 HIV-1 shows limited to no replication in CD1a+ VEDCs. This differential replication occurs after fusion, suggesting that receptor usage influences postentry steps in the virus life cycle. Furthermore, CD1a+ VEDCs isolated from HIV-1-infected virologically suppressed women harbor HIV-1 DNA. Thus, CD1a+ VEDCs are potentially infected early during heterosexual transmission and also retain virus during treatment. Understanding the interplay between HIV-1 and CD1a+ VEDCs is important for future prevention and cure strategies. PMID- 29723161 TI - Metreleptin-mediated improvements in insulin sensitivity are independent of food intake in humans with lipodystrophy. AB - BACKGROUND: Recombinant leptin (metreleptin) ameliorates hyperphagia and metabolic abnormalities in leptin-deficient humans with lipodystrophy. We aimed to determine whether metreleptin improves glucose and lipid metabolism in humans when food intake is held constant. METHODS: Patients with lipodystrophy were hospitalized for 19 days, with food intake held constant by a controlled diet in an inpatient metabolic ward. In a nonrandomized, crossover design, patients previously treated with metreleptin (n = 8) were continued on metreleptin for 5 days and then taken off metreleptin for the next 14 days (withdrawal cohort). This order was reversed in metreleptin-naive patients (n = 14), who were reevaluated after 6 months of metreleptin treatment on an ad libitum diet (initiation cohort). Outcome measurements included insulin sensitivity by hyperinsulinemic-euglycemic clamp, fasting glucose and triglyceride levels, lipolysis measured using isotopic tracers, and liver fat by magnetic resonance spectroscopy. RESULTS: With food intake constant, peripheral insulin sensitivity decreased by 41% after stopping metreleptin for 14 days (withdrawal cohort) and increased by 32% after treatment with metreleptin for 14 days (initiation cohort). In the initiation cohort only, metreleptin decreased fasting glucose by 11% and triglycerides by 41% and increased hepatic insulin sensitivity. Liver fat decreased from 21.8% to 18.7%. In the initiation cohort, changes in lipolysis were not independent of food intake, but after 6 months of metreleptin treatment on an ad libitum diet, lipolysis decreased by 30% (palmitate turnover) to 35% (glycerol turnover). CONCLUSION: Using lipodystrophy as a human model of leptin deficiency and replacement, we show that metreleptin improves insulin sensitivity and decreases hepatic and circulating triglycerides and that these improvements are independent of its effects on food intake. TRIAL REGISTRATION: ClinicalTrials.gov NCT01778556FUNDING. This research was supported by the intramural research program of the NIDDK. PMID- 29723164 TI - Diabetes in a Hepatitis C and HIV-Coinfected Patient Treated With the Ledipasvir and Sofosbuvir Regimen. PMID- 29723163 TI - A fibrin biofilm covers blood clots and protects from microbial invasion. AB - Hemostasis requires conversion of fibrinogen to fibrin fibers that generate a characteristic network, interact with blood cells, and initiate tissue repair. The fibrin network is porous and highly permeable, but the spatial arrangement of the external clot face is unknown. Here we show that fibrin transitioned to the blood-air interface through Langmuir film formation, producing a protective film confining clots in human and mouse models. We demonstrated that only fibrin is required for formation of the film, and that it occurred in vitro and in vivo. The fibrin film connected to the underlying clot network through tethering fibers. It was digested by plasmin, and formation of the film was prevented with surfactants. Functionally, the film retained blood cells and protected against penetration by bacterial pathogens in a murine model of dermal infection. Our data show a remarkable aspect of blood clotting in which fibrin forms a protective film covering the external surface of the clot, defending the organism against microbial invasion. PMID- 29723165 TI - Interleukin-22 (IL-22) Regulates Apoptosis of Paclitaxel-Resistant Non-Small Cell Lung Cancer Cells Through C-Jun N-Terminal Kinase Signaling Pathway. AB - BACKGROUND Reducing drug resistance in tumor cells has become an important issue for cancer treatment. The purpose of this study was to investigate whether IL-22 was involved in lung cancer cell resistance to paclitaxel (PTX), and to explore the underlying molecular mechanism. MATERIAL AND METHODS Non-small cell lung cancer (NSCLC) cell line A549 and the drug resistant cell line A549/PTX were used in the present study. The inhibitory rate of PTX on A549 and A549/PTX cell proliferation was determined by MTT assay and the half-maximal inhibitory concentration (IC50) value was calculated. The expression level of IL-22 was detected using Western blot and qRT-PCR. To elucidate the mechanism by which IL 22 is involved in PTX resistance, a stable IL-22-silenced A549/PTX cell line was generated by using IL-22-siRNA. Cell apoptosis was analyzed by flow cytometry, and the c-Jun N-terminal kinase (JNK) signal pathway was determined using Western blot analysis. RESULTS We found that IL-22 expression level was markedly higher in A549/PTX cells than in A549 cells, and IL-22 gene knockdown significantly enhanced the cell proliferation inhibition rate of PTX to A549/PTX cells and decreased the IC50 value of PTX to A549/PTX cells, indicating IL-22 was involved in cell PTX resistance. Our findings also suggest that IL-22 knockdown notably increased PTX induced apoptosis in A549/PTX cells. Moreover, the results showed that p-JNK and Caspase 3 expression were significantly increased in IL-22 knockdown A549/PTX cells, while Bcl-2 expression was significantly decreased. CONCLUSIONS IL-22 is involved in A549 cell resistance to PTX through regulating cell apoptosis via the JNK signaling pathway. PMID- 29723167 TI - Notes from the Field: Increase in Hepatitis A Virus Infections - Marshall Islands, 2016-2017. PMID- 29723169 TI - QuickStats: Percentage Distribution* of Long-Term Care Staffing? Hours,S by Staff Member Type and Sector - United States, 2016. PMID- 29723166 TI - Vital Signs: Trends in Reported Vectorborne Disease Cases - United States and Territories, 2004-2016. AB - INTRODUCTION: Vectorborne diseases are major causes of death and illness worldwide. In the United States, the most common vectorborne pathogens are transmitted by ticks or mosquitoes, including those causing Lyme disease; Rocky Mountain spotted fever; and West Nile, dengue, and Zika virus diseases. This report examines trends in occurrence of nationally reportable vectorborne diseases during 2004-2016. METHODS: Data reported to the National Notifiable Diseases Surveillance System for 16 notifiable vectorborne diseases during 2004 2016 were analyzed; findings were tabulated by disease, vector type, location, and year. RESULTS: A total 642,602 cases were reported. The number of annual reports of tickborne bacterial and protozoan diseases more than doubled during this period, from >22,000 in 2004 to >48,000 in 2016. Lyme disease accounted for 82% of all tickborne disease reports during 2004-2016. The occurrence of mosquitoborne diseases was marked by virus epidemics. Transmission in Puerto Rico, the U.S. Virgin Islands, and American Samoa accounted for most reports of dengue, chikungunya, and Zika virus diseases; West Nile virus was endemic, and periodically epidemic, in the continental United States. CONCLUSIONS AND IMPLICATIONS FOR PUBLIC HEALTH PRACTICE: Vectorborne diseases are a large and growing public health problem in the United States, characterized by geographic specificity and frequent pathogen emergence and introduction. Differences in distribution and transmission dynamics of tickborne and mosquitoborne diseases are often rooted in biologic differences of the vectors. To effectively reduce transmission and respond to outbreaks will require major national improvement of surveillance, diagnostics, reporting, and vector control, as well as new tools, including vaccines. PMID- 29723170 TI - Notes from the Field: Salmonella Oranienburg Infection Linked to Consumption of Rattlesnake Pills - Kansas and Texas, 2017. PMID- 29723168 TI - Malaria Surveillance - United States, 2015. AB - PROBLEM/CONDITION: Malaria in humans is caused by intraerythrocytic protozoa of the genus Plasmodium. These parasites are transmitted by the bite of an infective female Anopheles species mosquito. The majority of malaria infections in the United States occur among persons who have traveled to regions with ongoing malaria transmission. However, malaria is occasionally acquired by persons who have not traveled out of the country through exposure to infected blood products, congenital transmission, laboratory exposure, or local mosquitoborne transmission. Malaria surveillance in the United States is conducted to provide information on its occurrence (e.g., temporal, geographic, and demographic), guide prevention and treatment recommendations for travelers and patients, and facilitate transmission control measures if locally acquired cases are identified. PERIOD COVERED: This report summarizes confirmed malaria cases in persons with onset of illness in 2015 and summarizes trends in previous years. DESCRIPTION OF SYSTEM: Malaria cases diagnosed by blood film microscopy, polymerase chain reaction, or rapid diagnostic tests are reported to local and state health departments by health care providers or laboratory staff members. Case investigations are conducted by local and state health departments, and reports are transmitted to CDC through the National Malaria Surveillance System (NMSS), the National Notifiable Diseases Surveillance System (NNDSS), or direct CDC consultations. CDC reference laboratories provide diagnostic assistance and conduct antimalarial drug resistance marker testing on blood samples submitted by health care providers or local or state health departments. This report summarizes data from the integration of all NMSS and NNDSS cases, CDC reference laboratory reports, and CDC clinical consultations. RESULTS: CDC received reports of 1,517 confirmed malaria cases, including one congenital case, with an onset of symptoms in 2015 among persons who received their diagnoses in the United States. Although the number of malaria cases diagnosed in the United States has been increasing since the mid-1970s, the number of cases decreased by 208 from 2014 to 2015. Among the regions of acquisition (Africa, West Africa, Asia, Central America, the Caribbean, South America, Oceania, and the Middle East), the only region with significantly fewer imported cases in 2015 compared with 2014 was West Africa (781 versus 969). Plasmodium falciparum, P. vivax, P. ovale, and P. malariae were identified in 67.4%, 11.7%, 4.1%, and 3.1% of cases, respectively. Less than 1% of patients were infected by two species. The infecting species was unreported or undetermined in 12.9% of cases. CDC provided diagnostic assistance for 13.1% of patients with confirmed cases and tested 15.0% of P. falciparum specimens for antimalarial resistance markers. Of the U.S. resident patients who reported purpose of travel, 68.4% were visiting friends or relatives. A lower proportion of U.S. residents with malaria reported taking any chemoprophylaxis in 2015 (26.5%) compared with 2014 (32.5%), and adherence was poor in this group. Among the U.S residents for whom information on chemoprophylaxis use and travel region were known, 95.3% of patients with malaria did not adhere to or did not take a CDC-recommended chemoprophylaxis regimen. Among women with malaria, 32 were pregnant, and none had adhered to chemoprophylaxis. A total of 23 malaria cases occurred among U.S. military personnel in 2015. Three cases of malaria were imported from the approximately 3,000 military personnel deployed to an Ebola affected country; two of these were not P. falciparum species, and one species was unspecified. Among all reported cases in 2015, 17.1% were classified as severe illnesses and 11 persons died, compared with an average of 6.1 deaths per year during 2000-2014. In 2015, CDC received 153 P. falciparum-positive samples for surveillance of antimalarial resistance markers (although certain loci were untestable for some samples); genetic polymorphisms associated with resistance to pyrimethamine were identified in 132 (86.3%), to sulfadoxine in 112 (73.7%), to chloroquine in 48 (31.4%), to mefloquine in six (4.3%), and to artemisinin in one (<1%), and no sample had resistance to atovaquone. Completion of data elements on the malaria case report form decreased from 2014 to 2015 and remains low, with 24.2% of case report forms missing at least one key element (species, travel history, and resident status). INTERPRETATION: The decrease in malaria cases from 2014 to 2015 is associated with a decrease in imported cases from West Africa. This finding might be related to altered or curtailed travel to Ebola-affected countries in in this region. Despite progress in reducing malaria worldwide, the disease remains endemic in many regions, and the use of appropriate prevention measures by travelers is still inadequate. PUBLIC HEALTH ACTIONS: The best way to prevent malaria is to take chemoprophylaxis medication during travel to a country where malaria is endemic. As demonstrated by the U.S. military during the Ebola response, use of chemoprophylaxis and other protection measures is possible in stressful environments, and this can prevent malaria, especially P. falciparum, even in high transmission areas. Detailed recommendations for preventing malaria are available to the general public at the CDC website (https://www.cdc.gov/malaria/travelers/drugs.html). Malaria infections can be fatal if not diagnosed and treated promptly with antimalarial medications appropriate for the patient's age and medical history, the likely country of malaria acquisition, and previous use of antimalarial chemoprophylaxis. Health care providers should consult the CDC Guidelines for Treatment of Malaria in the United States and contact the CDC's Malaria Hotline for case management advice when needed. Malaria treatment recommendations are available online (https://www.cdc.gov/malaria/diagnosis_treatment) and from the Malaria Hotline (770-488-7788 or toll-free at 855-856-4713). Persons submitting malaria case reports (care providers, laboratories, and state and local public health officials) should provide complete information because incomplete reporting compromises case investigations and efforts to prevent infections and examine trends in malaria cases. Compliance with recommended malaria prevention strategies is low among U.S. travelers visiting friends and relatives. Evidence based prevention strategies that effectively target travelers who are visiting friends and relatives need to be developed and implemented to reduce the numbers of imported malaria cases in the United States. Molecular surveillance of antimalarial drug resistance markers (https://www.cdc.gov/malaria/features/ars.html) has enabled CDC to track, guide treatment, and manage drug resistance in malaria parasites both domestically and internationally. More samples are needed to improve the completeness of antimalarial drug resistance marker analysis; therefore, CDC requests that blood specimens be submitted for all cases diagnosed in the United States. PMID- 29723171 TI - Progress Toward Measles Elimination - Western Pacific Region, 2013-2017. AB - In 2005, the Regional Committee for the World Health Organization (WHO) Western Pacific Region (WPR)* established a goal for measles elimination? by 2012 (1). To achieve this goal, the 37 WPR countries and areas implemented the recommended strategies in the WPR Plan of Action for Measles Elimination (2) and the Field Guidelines for Measles Elimination (3). The strategies include 1) achieving and maintaining >=95% coverage with 2 doses of measles-containing vaccine (MCV) through routine immunization services and supplementary immunization activities (SIAs), when required; 2) conducting high-quality case-based measles surveillance, including timely and accurate testing of specimens to confirm or discard suspected cases and detect measles virus for genotyping and molecular analysis; and 3) establishing and maintaining measles outbreak preparedness to ensure rapid response and appropriate case management. This report updates the previous report (4) and describes progress toward measles elimination in WPR during 2013-2017. During 2013-2016, estimated regional coverage with the first MCV dose (MCV1) decreased from 97% to 96%, and coverage with the routine second MCV dose (MCV2) increased from 91% to 93%. Eighteen (50%) countries achieved >=95% MCV1 coverage in 2016. Seven (39%) of 18 nationwide SIAs during 2013-2017 reported achieving >=95% administrative coverage. After a record low of 5.9 cases per million population in 2012, measles incidence increased during 2013-2016 to a high of 68.9 in 2014, because of outbreaks in the Philippines and Vietnam, as well as increased incidence in China, and then declined to 5.2 in 2017. To achieve measles elimination in WPR, additional measures are needed to strengthen immunization programs to achieve high population immunity, maintain high-quality surveillance for rapid case detection and confirmation, and ensure outbreak preparedness and prompt response to contain outbreaks. PMID- 29723173 TI - Live kidney donation: managing the "tyranny of the gift". PMID- 29723174 TI - "It's hard to ask": examining the factors influencing decision-making among end stage renal disease patients considering approaching family and friends for a kidney. AB - AIM: People needing kidney transplants in New Zealand can receive organs from deceased donors or from a living kidney donor. This project explored issues surrounding donor recruitment, examining the lived experience of end-stage renal disease (ESRD) patients in order to facilitate improved donor recruitment for ESRD patients. METHOD: A qualitative study comprising interviews of ESRD patients in Hawke's Bay, focusing on the factors surrounding approaching family and friends for a kidney. Purposeful sampling and thematic analysis of data was utilised. RESULTS: Fifteen participants were interviewed (Five female; mean age 49.8yrs). Most stated it was hard to ask for a kidney; almost half had never approached anyone. For many, approaching potential donors was a barrier. Many Maori had limited recruitment opportunities due to comorbidities within extended whanau, making the decision of who to approach difficult. Other barriers included concern for donor health, poor health literacy and poor self-efficacy. CONCLUSION: Recipients desired more support to facilitate approaching donors, with cultural differences observed between Maori and non-Maori in recruitment expectations. Tailored support could be enabled with development of a screening tool to assess willingness and motivation to accept donation, cultural needs, self-efficacy, communication skills and health literacy. Psychosocial support could help address barriers such as reciprocity concerns. PMID- 29723175 TI - Early onset dementia in New Zealand Pacific boxers: a case series. AB - AIM: To describe the biopsychosocial characteristics of a series of Pacific men living in South Auckland with a history of boxing presenting with early onset dementia. We discuss the history of boxing in Pacific people and the possibility of increased risk of early onset dementia in New Zealand Pacific men compared to their European counterparts. METHOD: We reviewed the files of Pacific men with a history of amateur or professional boxing who presented to our memory and older adult mental health services with early onset dementia over a 45-month period. We gathered relevant information to construct a biopsychosocial paradigm as possible explanation of this phenomenon. RESULTS: We identified a series of eight New Zealand Pacific men with early onset dementia and with a history of boxing. Alcohol was a contributing factor in seven of the eight cases, and vascular risk factors in five. CONCLUSION: Historical, cultural and socio-economic factors underpin the attraction of some Pacific men to boxing as a sport. Given that New Zealand Pacific peoples may have an earlier onset of dementia than their European counterparts, further research is required to establish whether boxing is a contributory factor. Sports physicians should advise young New Zealand Pacific boxers about the long-term risks associated with their sport. PMID- 29723172 TI - Health Care Provider Counseling for Weight Loss Among Adults with Arthritis and Overweight or Obesity - United States, 2002-2014. AB - In the United States, 54.4 million adults report having doctor-diagnosed arthritis (1). Among adults with arthritis, 32.7% and 38.1% also have overweight and obesity, respectively (1), with obesity being more prevalent among persons with arthritis than among those who do not have arthritis (2). Furthermore, severe joint pain among adults with arthritis in 2014 was reported by 23.5% of adults with overweight and 31.7% of adults with obesity (3). The American College of Rheumatology recommends weight loss for adults with hip or knee osteoarthritis and overweight or obesity,* which can improve function and mobility while reducing pain and disability (4,5). The Healthy People 2020 target for health care provider (hereafter provider) counseling for weight loss among persons with arthritis and overweight or obesity is 45.3%.? Adults with overweight or obesity who receive weight-loss counseling from a provider are approximately four times more likely to attempt to lose weight than are those who do not receive counseling (6). To estimate changes in the prevalence of provider counseling for weight loss reported by adults with arthritis and overweight or obesity, CDC analyzed National Health Interview Survey (NHIS) data.S Overall, age-standardized estimates of provider counseling for weight loss increased by 10.4 percentage points from 2002 (35.1%; 95% confidence interval [CI] = 33.0-37.3) to 2014 (45.5%; 95% CI = 42.9-48.1) (p<0.001). Providing comprehensive behavioral counseling (including nutrition, physical activity, and self-management education) and encouraging evidence-based weight-loss program participation can result in enhanced health benefits for this population. PMID- 29723176 TI - The Dunedin Dementia Risk Awareness Project: a convenience sample of general practitioners. AB - AIMS: Recent recommendations of US and UK governmental and academic agencies suggest that up to 35% of dementia cases are preventable. We aimed to appraise general practitioners' (GPs) awareness of risk and protective factors associated with dementia and their intentions to act within the context of the Health Beliefs Model. METHODS: We canvassed degree of dementia awareness, using the modified Lifestyle for Brain Health (LIBRA) scale among a convenience sample of local GPs. RESULTS: Thirty-five GPs, mean age 56.7 + 6.8 years (range: 43-72) participated. There were 19 women and 16 men, all New Zealand European. Genetics was the most commonly cited risk for dementia and exercise the most commonly cited protective factor. More than 80% of participants correctly identified 8/12 LIBRA factors. Factors not identified were: renal dysfunction, obesity, Mediterranean diet and high cognitive activity. The majority of participants felt they were at risk of suffering from dementia, that lifestyle changes will help reduce their risk and wished to start these changes soon. CONCLUSIONS: GPs are knowledgeable about dementia risk and protective factors. They reported optimism in their ability to modify their own risk factors through lifestyle interventions. This places GPs in a unique position to help disseminate this knowledge to their clients. PMID- 29723178 TI - Off label or on trend: a review of the use of quetiapine in New Zealand. PMID- 29723177 TI - Co-prescribing of contraindicated and use-with-caution drugs in a national cohort of new users of simvastatin: how well are prescribing guidelines followed? AB - AIM: To describe the use of contraindicated and use-with-caution medicines among new users of simvastatin. METHODS: We used information from Ministry of Health national datasets to establish a cohort of all patients aged >18 years who initiated simvastatin use between January 2006 and December 2013 (n=349,371). We estimated the cumulative incidences of the first dispensing of contraindicated and use-with-caution medicines during simvastatin use, and explored factors associated with co-prescription, using Kaplan-Meir and Cox regression methods, respectively. RESULTS: Eleven percent and 16% of patients were dispensed a contraindicated and use-with-caution medicine, respectively, during the first two years of simvastatin use; by seven years, the figures were 17% and 26%. Thirty six percent of patients were co-prescribed a contraindicated medicine on >1 occasion; the corresponding proportion for use-with-caution medicines was 84%. For a substantial proportion of those co-prescribed a use-with-caution medicine, the concomitant daily dose of simvastatin exceeded the maximum dose recommended at the time of prescribing. In the majority of cases, the prescriber of simvastatin and the contraindicated or use-with-caution medicine were the same. Co-prescribing of contraindicated medicines varied by sex, age, ethnicity and comorbidity. CONCLUSIONS: The prescription of contraindicated and use-with caution drugs to patients taking simvastatin is not uncommon in New Zealand. PMID- 29723179 TI - Outcomes following therapeutic lymphadenectomy for Stage III malignant melanoma in a single unit. AB - BACKGROUND: Malignant melanoma is the fourth most common cancer in New Zealand. Surgery is the only treatment modality that can achieve high cure rates for regional disease, but is associated with high complication rates. Our study documents the morbidity associated with regional lymphadenectomy; audits nodal harvest numbers and considers nodal harvest targets. METHODS: We retrospectively reviewed regional lymphadenectomies for Stage III melanoma at a single tertiary centre from 2004 to 2014. Data was collected on patient demographics, site of operation, number of lymph nodes recovered, all complications within six months of surgery, loco-regional recurrence, distal progression and five-year survival. We also used key performance indicators (KPI) to assess the quality of dissection. RESULTS: A total of 219 lymphadenectomies were carried out. Forty three percent of all patients experienced at least one complication. This was markedly higher for those undergoing a groin dissection. Recurrence, progression and survival rates did not vary between nodal basins. There was a mean of 31.6, 17.6 and 10.9 nodes recovered from neck, axillary and groin dissection groups respectively. Our KPIs were achieved in 80%, 86.6% and 90% of cases and resulted in a significant improvement in recurrence and progression rates. CONCLUSION: Lymphadenectomy has a high risk of post-operative complications, especially for groin dissections. Quality of lymphadenectomy can be assessed by monitoring nodal harvest numbers, and achieving nodal harvest targets provides significant prognostic information. We support the development of national tumour standards, including key performance indicators, for management of Stage III melanoma. PMID- 29723180 TI - Confidence in the safety of standard childhood vaccinations among New Zealand health professionals. AB - AIMS: To investigate the level of confidence in the safety of standard childhood vaccinations among health professionals in New Zealand. METHOD: Data from the 2013/14 New Zealand Attitudes and Values Study (NZAVS) was used to investigate the level of agreement that "it is safe to vaccinate children following the standard New Zealand immunisation schedule" among different classes of health professionals (N=1,032). RESULTS: Most health professionals showed higher levels of vaccine confidence, with 96.7% of those describing their occupation as GP or simply 'doctor' (GPs/doctor) and 90.7% of pharmacists expressing strong vaccine confidence. However, there were important disparities between some other classes of health professionals, with only 65.1% of midwives and 13.6% of practitioners of alternative medicine expressing high vaccine confidence. CONCLUSION: As health professionals are a highly trusted source of vaccine information, communicating the consensus of belief among GPs/doctors that vaccines are safe may help provide reassurance for parents who ask about vaccine safety. However, the lower level of vaccine confidence among midwives is a matter of concern that may have negative influence on parental perceptions of vaccinations. PMID- 29723181 TI - Eikenella corrodens retroperitoneal necrotising fasciitis post-endoscopic retrograde cholangio-pancreatography. PMID- 29723182 TI - Enteric duplication cyst as a cause for small bowel obstruction in adulthood. AB - We report a case of a patient presenting with small bowel obstruction secondary to an enteric ileal duplication cyst. Although common in infancy, they are rarely seen in adults. Radiologically they may be difficult to distinguish from a Meckel diverticulum and often the diagnosis is made retrospectively. Optimal management of the asymptomatic adult is unclear. PMID- 29723183 TI - A case of skeletal fluorosis? PMID- 29723184 TI - Considering the issue of euthanasia. PMID- 29723185 TI - A New Zealand osteoarthritis model of care in South Canterbury, New Zealand. PMID- 29723186 TI - Active photosynthetic inhibition mediated by MPK3/MPK6 is critical to effector triggered immunity. AB - Extensive research revealed tremendous details about how plants sense pathogen effectors during effector-triggered immunity (ETI). However, less is known about downstream signaling events. In this report, we demonstrate that prolonged activation of MPK3 and MPK6, two Arabidopsis pathogen-responsive mitogen activated protein kinases (MPKs), is essential to ETI mediated by both coiled coil-nucleotide binding site-leucine rich repeats (CNLs) and toll/interleukin-1 receptor nucleotide binding site-leucine rich repeats (TNLs) types of R proteins. MPK3/MPK6 activation rapidly alters the expression of photosynthesis-related genes and inhibits photosynthesis, which promotes the accumulation of superoxide ([Formula: see text]) and hydrogen peroxide (H2O2), two major reactive oxygen species (ROS), in chloroplasts under light. In the chemical-genetically rescued mpk3 mpk6 double mutants, ETI-induced photosynthetic inhibition and chloroplastic ROS accumulation are compromised, which correlates with delayed hypersensitive response (HR) cell death and compromised resistance. Furthermore, protection of chloroplasts by expressing a plastid-targeted cyanobacterial flavodoxin (pFLD) delays photosynthetic inhibition and compromises ETI. Collectively, this study highlights a critical role of MPK3/MPK6 in manipulating plant photosynthetic activities to promote ROS accumulation in chloroplasts and HR cell death, which contributes to the robustness of ETI. Furthermore, the dual functionality of MPK3/MPK6 cascade in promoting defense and inhibiting photosynthesis potentially allow it to orchestrate the trade-off between plant growth and defense in plant immunity. PMID- 29723187 TI - Ebolaviruses: New roles for old proteins. AB - In 2014, the world witnessed the largest Ebolavirus outbreak in recorded history. The subsequent humanitarian effort spurred extensive research, significantly enhancing our understanding of ebolavirus replication and pathogenicity. The main functions of each ebolavirus protein have been studied extensively since the discovery of the virus in 1976; however, the recent expansion of ebolavirus research has led to the discovery of new protein functions. These newly discovered roles are revealing new mechanisms of virus replication and pathogenicity, whilst enhancing our understanding of the broad functions of each ebolavirus viral protein (VP). Many of these new functions appear to be unrelated to the protein's primary function during virus replication. Such new functions range from bystander T-lymphocyte death caused by VP40-secreted exosomes to new roles for VP24 in viral particle formation. This review highlights the newly discovered roles of ebolavirus proteins in order to provide a more encompassing view of ebolavirus replication and pathogenicity. PMID- 29723188 TI - beachmat: A Bioconductor C++ API for accessing high-throughput biological data from a variety of R matrix types. AB - Biological experiments involving genomics or other high-throughput assays typically yield a data matrix that can be explored and analyzed using the R programming language with packages from the Bioconductor project. Improvements in the throughput of these assays have resulted in an explosion of data even from routine experiments, which poses a challenge to the existing computational infrastructure for statistical data analysis. For example, single-cell RNA sequencing (scRNA-seq) experiments frequently generate large matrices containing expression values for each gene in each cell, requiring sparse or file-backed representations for memory-efficient manipulation in R. These alternative representations are not easily compatible with high-performance C++ code used for computationally intensive tasks in existing R/Bioconductor packages. Here, we describe a C++ interface named beachmat, which enables agnostic data access from various matrix representations. This allows package developers to write efficient C++ code that is interoperable with dense, sparse and file-backed matrices, amongst others. We evaluated the performance of beachmat for accessing data from each matrix representation using both simulated and real scRNA-seq data, and defined a clear memory/speed trade-off to motivate the choice of an appropriate representation. We also demonstrate how beachmat can be incorporated into the code of other packages to drive analyses of a very large scRNA-seq data set. PMID- 29723189 TI - Prevalence and risk factors of Rift Valley fever in humans and animals from Kabale district in Southwestern Uganda, 2016. AB - BACKGROUND: Rift Valley fever (RVF) is a zoonotic disease caused by Rift Valley fever virus (RVFV) found in Africa and the Middle East. Outbreaks can cause extensive morbidity and mortality in humans and livestock. Following the diagnosis of two acute human RVF cases in Kabale district, Uganda, we conducted a serosurvey to estimate RVFV seroprevalence in humans and livestock and to identify associated risk factors. METHODS: Humans and animals at abattoirs and villages in Kabale district were sampled. Persons were interviewed about RVFV exposure risk factors. Human blood was tested for anti-RVFV IgM and IgG, and animal blood for anti-RVFV IgG. PRINCIPAL FINDINGS: 655 human and 1051 animal blood samples were collected. Anti-RVFV IgG was detected in 78 (12%) human samples; 3 human samples (0.5%) had detectable IgM only, and 7 (1%) had both IgM and IgG. Of the 10 IgM-positive persons, 2 samples were positive for RVFV by PCR, confirming recent infection. Odds of RVFV seropositivity were greater in participants who were butchers (odds ratio [OR] 5.1; 95% confidence interval [95% CI]: 1.7-15.1) and those who reported handling raw meat (OR 3.4; 95% CI 1.2-9.8). No persons under age 20 were RVFV seropositive. The overall animal seropositivity was 13%, with 27% of cattle, 7% of goats, and 4% of sheep seropositive. In a multivariate logistic regression, cattle species (OR 9.1; 95% CI 4.1-20.5), adult age (OR 3.0; 95% CI 1.6-5.6), and female sex (OR 2.1; 95%CI 1.0-4.3) were significantly associated with animal seropositivity. Individual human seropositivity was significantly associated with animal seropositivity by subcounty after adjusting for sex, age, and occupation (p < 0.05). CONCLUSIONS: Although no RVF cases had been detected in Uganda from 1968 to March 2016, our study suggests that RVFV has been circulating undetected in both humans and animals living in and around Kabale district. RVFV seropositivity in humans was associated with occupation, suggesting that the primary mode of RVFV transmission to humans in Kabale district could be through contact with animal blood or body fluids. PMID- 29723191 TI - Role of duplicate genes in determining the tissue-selectivity of hereditary diseases. AB - A longstanding puzzle in human genetics is what limits the clinical manifestation of hundreds of hereditary diseases to certain tissues, while their causal genes are expressed throughout the human body. A general conception is that tissue selective disease phenotypes emerge when masking factors operate in unaffected tissues, but are specifically absent or insufficient in disease-manifesting tissues. Although this conception has critical impact on the understanding of disease manifestation, it was never challenged in a systematic manner across a variety of hereditary diseases and affected tissues. Here, we address this gap in our understanding via rigorous analysis of the susceptibility of over 30 tissues to 112 tissue-selective hereditary diseases. We focused on the roles of paralogs of causal genes, which are presumably capable of compensating for their aberration. We show for the first time at large-scale via quantitative analysis of omics datasets that, preferentially in the disease-manifesting tissues, paralogs are under-expressed relative to causal genes in more than half of the diseases. This was observed for several susceptible tissues and for causal genes with varying number of paralogs, suggesting that imbalanced expression of paralogs increases tissue susceptibility. While for many diseases this imbalance stemmed from up-regulation of the causal gene in the disease-manifesting tissue relative to other tissues, it was often combined with down-regulation of its paralog. Notably in roughly 20% of the cases, this imbalance stemmed only from significant down-regulation of the paralog. Thus, dosage relationships between paralogs appear as important, yet currently under-appreciated, modifiers of disease manifestation. PMID- 29723190 TI - Gene regulatory network architecture in different developmental contexts influences the genetic basis of morphological evolution. AB - Convergent phenotypic evolution is often caused by recurrent changes at particular nodes in the underlying gene regulatory networks (GRNs). The genes at such evolutionary 'hotspots' are thought to maximally affect the phenotype with minimal pleiotropic consequences. This has led to the suggestion that if a GRN is understood in sufficient detail, the path of evolution may be predictable. The repeated evolutionary loss of larval trichomes among Drosophila species is caused by the loss of shavenbaby (svb) expression. svb is also required for development of leg trichomes, but the evolutionary gain of trichomes in the 'naked valley' on T2 femurs in Drosophila melanogaster is caused by reduced microRNA-92a (miR-92a) expression rather than changes in svb. We compared the expression and function of components between the larval and leg trichome GRNs to investigate why the genetic basis of trichome pattern evolution differs in these developmental contexts. We found key differences between the two networks in both the genes employed, and in the regulation and function of common genes. These differences in the GRNs reveal why mutations in svb are unlikely to contribute to leg trichome evolution and how instead miR-92a represents the key evolutionary switch in this context. Our work shows that variability in GRNs across different developmental contexts, as well as whether a morphological feature is lost versus gained, influence the nodes at which a GRN evolves to cause morphological change. Therefore, our findings have important implications for understanding the pathways and predictability of evolution. PMID- 29723192 TI - The ARE-binding protein Tristetraprolin (TTP) is a novel target and mediator of calcineurin tumor suppressing function in the skin. AB - An increased incidence of skin inflammatory diseases is frequently observed in organtransplanted patients being treated with calcineurin inhibitor-based immunosuppressive agents. The mechanism of increased skin inflammation in this context has however not yet been clarified. Here we report an increased inflammation following inhibition of calcineurin signaling seen in both chemically induced mouse skin tumors and in tumors grafted from H-rasV12 expressing primary human keratinocytes (HKCs). Following UVB or TPA treatment, we specifically found that deletion of the calcineurin gene in mouse keratinocytes (MKCs) resulted in increased inflammation, and this was accompanied by the enhanced production of pro-inflammatory cytokines, such as TNFalpha, IL-8 and CXCL1. Furthermore, expression of the RNA-binding protein, tristetraprolin (TTP) was down-regulated in response to calcineurin inhibition, wherein TTP was shown to negatively regulate the production of pro-inflammatory cytokines in keratinocytes. The induction of TTP following TPA or UVB treatment was attenuated by calcineurin inhibition in keratinocytes, and correspondingly, disruption of calcineurin signaling down-regulated the amounts of TTP in both clinical and H rasV12-transformed keratinocyte tumor models. Our results further demonstrated that calcineurin positively controls the stabilization of TTP in keratinocytes through a proteasome-dependent mechanism. Reducing the expression of TTP functionally promoted tumor growth of H-rasV12 expressing HKCs, while stabilizing TTP expression counteracted the tumor-promoting effects of calcineurin inhibition. Collectively these results suggest that calcineurin signaling, acting through TTP protein level stabilization, suppresses keratinocyte tumors by downregulating skin inflammation. PMID- 29723193 TI - (S)WASH-D for Worms: A pilot study investigating the differential impact of school- versus community-based integrated control programs for soil-transmitted helminths. AB - BACKGROUND: Soil-transmitted helminths (STH) infect nearly 1.5 billion individuals globally, and contribute to poor physical and cognitive development in children. STH control programs typically consist of regular delivery of anthelminthic drugs, targeting school-aged children. Expanding STH control programs community-wide may improve STH control among school-aged children, and combining deworming with improvements to water, sanitation and hygiene (WASH) may further reduce transmission. The (S)WASH-D for Worms pilot study aims to compare the differential impact of integrated WASH and deworming programs when implemented at primary schools only versus when additionally implemented community-wide. METHODOLOGY/PRINCIPAL FINDINGS: A two-arm, non-randomized cluster intervention study was conducted. Six communities were identified by partner WASH agencies and enrolled in the study. All communities received a school-based WASH and deworming program, while three additionally received a community-based WASH and deworming program. STH infections were measured in school-aged children at baseline and six months after deworming. Over 90% of eligible children were recruited for the study, of whom 92.3% provided stool samples at baseline and 88.9% at follow-up. The school WASH intervention improved school sanitation, while the community WASH intervention reduced open defecation from 50.4% (95% CI 41.8-59.0) to 23.5% (95% CI 16.7-32.0). There was a trend towards reduced odds of N. americanus infection among children who received the community-wide intervention (OR 0.42, 95% CI 0.07-2.36, p = 0.32). CONCLUSIONS: This pilot study provides proof of principle for testing the hypothesis that community-wide STH control programs have a greater impact on STH infections among children than school-based programs, and supports the rationale for conducting a full-scale cluster randomized controlled trial. High recruitment and participation rates and successful implementation of school WASH programs demonstrate study feasibility and acceptability. However, eliminating open defecation remains a challenge; ongoing work is required to develop community sanitation programs that achieve high and sustainable latrine coverage. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR) ACTRN12615001012561. PMID- 29723196 TI - All science should inform policy and regulation. AB - In the context of a recent proposal to exclude research from consideration at the Environmental Protection Agency, John Ioannidis points out that "perceived perfection is not a characteristic of science, but of dogma" and envisions how governments can promote a standard of openness in science. PMID- 29723195 TI - Human local adaptation of the TRPM8 cold receptor along a latitudinal cline. AB - Ambient temperature is a critical environmental factor for all living organisms. It was likely an important selective force as modern humans recently colonized temperate and cold Eurasian environments. Nevertheless, as of yet we have limited evidence of local adaptation to ambient temperature in populations from those environments. To shed light on this question, we exploit the fact that humans are a cosmopolitan species that inhabit territories under a wide range of temperatures. Focusing on cold perception-which is central to thermoregulation and survival in cold environments-we show evidence of recent local adaptation on TRPM8. This gene encodes for a cation channel that is, to date, the only temperature receptor known to mediate an endogenous response to moderate cold. The upstream variant rs10166942 shows extreme population differentiation, with frequencies that range from 5% in Nigeria to 88% in Finland (placing this SNP in the 0.02% tail of the FST empirical distribution). When all populations are jointly analyzed, allele frequencies correlate with latitude and temperature beyond what can be explained by shared ancestry and population substructure. Using a Bayesian approach, we infer that the allele originated and evolved neutrally in Africa, while positive selection raised its frequency to different degrees in Eurasian populations, resulting in allele frequencies that follow a latitudinal cline. We infer strong positive selection, in agreement with ancient DNA showing high frequency of the allele in Europe 3,000 to 8,000 years ago. rs10166942 is important phenotypically because its ancestral allele is protective of migraine. This debilitating disorder varies in prevalence across human populations, with highest prevalence in individuals of European descent-precisely the population with the highest frequency of rs10166942 derived allele. We thus hypothesize that local adaptation on previously neutral standing variation may have contributed to the genetic differences that exist in the prevalence of migraine among human populations today. PMID- 29723197 TI - Morphological changes of plasma membrane and protein assembly during clathrin mediated endocytosis. AB - Clathrin-mediated endocytosis (CME) proceeds through a series of morphological changes of the plasma membrane induced by a number of protein components. Although the spatiotemporal assembly of these proteins has been elucidated by fluorescence-based techniques, the protein-induced morphological changes of the plasma membrane have not been fully clarified in living cells. Here, we visualize membrane morphology together with protein localizations during CME by utilizing high-speed atomic force microscopy (HS-AFM) combined with a confocal laser scanning unit. The plasma membrane starts to invaginate approximately 30 s after clathrin starts to assemble, and the aperture diameter increases as clathrin accumulates. Actin rapidly accumulates around the pit and induces a small membrane swelling, which, within 30 s, rapidly covers the pit irreversibly. Inhibition of actin turnover abolishes the swelling and induces a reversible open close motion of the pit, indicating that actin dynamics are necessary for efficient and irreversible pit closure at the end of CME. PMID- 29723194 TI - A direct link between MITF, innate immunity, and hair graying. AB - Melanocyte stem cells (McSCs) and mouse models of hair graying serve as useful systems to uncover mechanisms involved in stem cell self-renewal and the maintenance of regenerating tissues. Interested in assessing genetic variants that influence McSC maintenance, we found previously that heterozygosity for the melanogenesis associated transcription factor, Mitf, exacerbates McSC differentiation and hair graying in mice that are predisposed for this phenotype. Based on transcriptome and molecular analyses of Mitfmi-vga9/+ mice, we report a novel role for MITF in the regulation of systemic innate immune gene expression. We also demonstrate that the viral mimic poly(I:C) is sufficient to expose genetic susceptibility to hair graying. These observations point to a critical suppressor of innate immunity, the consequences of innate immune dysregulation on pigmentation, both of which may have implications in the autoimmune, depigmenting disease, vitiligo. PMID- 29723198 TI - Telesonography in emergency medicine: A systematic review. AB - Ultrasound is an efficacious, versatile and affordable imaging technique in emergencies, but has limited utility without expert interpretation. Telesonography, in which experts may remotely support the use of ultrasound through a telecommunications link, may broaden access to ultrasound and improve patient outcomes, particularly in remote settings. This review assesses the literature regarding telesonography in emergency medicine, focussing on evidence of feasibility, diagnostic accuracy and clinical utility. A systematic search was performed for articles published from 1946 to February 2017 using the Cochrane, Medline, EMBASE, and CINAHL databases. Further searches utilising Scopus, Google Scholar, and citation lists were conducted. 4388 titles were identified and screened against inclusion criteria which resulted in the inclusion of 28 papers. These included feasibility, diagnostic accuracy and clinical pilot studies. Study design, methodology and quality were heterogeneous. There was good evidence of feasibility from multiple studies. Where sufficient bandwidth and high quality components were used, diagnostic accuracy was slightly reduced by image transmission. There was evidence of clinical utility in remote hospitals and low resource settings, although reliability was infrequently reported. Further exploratory research is required to determine minimum requirements for image quality, bandwidth, frame rate and to assess diagnostic accuracy. Clinical trials in remote settings are justifiable. Telecommunication options will depend on local requirements; no one system conveys universal advantages. The methodological quality of research in this field must improve: studies should be designed to minimise bias, and must include details of their methods to allow replication. Analysis of cost effectiveness and sustainability should be provided. PMID- 29723199 TI - Isothiocyanate from Moringa oleifera seeds mitigates hydrogen peroxide-induced cytotoxicity and preserved morphological features of human neuronal cells. AB - Reactive oxygen species are well known for induction of oxidative stress conditions through oxidation of vital biomarkers leading to cellular death via apoptosis and other process, thereby causing devastative effects on the host organs. This effect is believed to be linked with pathological alterations seen in several neurodegenerative disease conditions. Many phytochemical compounds proved to have robust antioxidant activities that deterred cells against cytotoxic stress environment, thus protect apoptotic cell death. In view of that we studied the potential of glucomoringin-isothiocyanate (GMG-ITC) or moringin to mitigate the process that lead to neurodegeneration in various ways. Neuroprotective effect of GMG-ITC was performed on retinoic acid (RA) induced differentiated neuroblastoma cells (SHSY5Y) via cell viability assay, flow cytometry analysis and fluorescence microscopy by means of acridine orange and propidium iodide double staining, to evaluate the anti-apoptotic activity and morphology conservation ability of the compound. Additionally, neurite surface integrity and ultrastructural analysis were carried out by means of scanning and transmission electron microscopy to assess the orientation of surface and internal features of the treated neuronal cells. GMG-ITC pre-treated neuron cells showed significant resistance to H2O2-induced apoptotic cell death, revealing high level of protection by the compound. Increase of intracellular oxidative stress induced by H2O2 was mitigated by GMG-ITC. Thus, pre-treatment with the compound conferred significant protection to cytoskeleton and cytoplasmic inclusion coupled with conservation of surface morphological features and general integrity of neuronal cells. Therefore, the collective findings in the presence study indicated the potentials of GMG-ITC to protect the integrity of neuron cells against induced oxidative-stress related cytotoxic processes, the hallmark of neurodegenerative diseases. PMID- 29723201 TI - Performance on the APACHE II, SAPS II, SOFA and the OHCA score of post-cardiac arrest patients treated with therapeutic hypothermia. AB - OBJECTIVE: This study assessed the ability of the Acute Physiologic and Chronic Health Evaluation (APACHE) II score, Simplified Acute Physiology Score (SAPS) II, Sequential Organ Failure Assessment (SOFA) score, and out-of-hospital cardiac arrest (OHCA) score to predict the outcome of OHCA patients who underwent therapeutic hypothermia (TH). METHODS: This study included OHCA patients treated with TH between January 2010 and December 2013. The APACHE II score, SAPS II, and SOFA score were calculated at the time of admission and 24 h and 48 h after intensive care unit admission. The OHCA score was calculated at the time of admission. The area under the curve (AUC) of the receiver operating characteristic curve and logistic regression analysis were used to evaluate outcome predictability. RESULTS: Data from a total of 173 patients were included in the analysis. The APACHE II score at 0 h and 48 h, SAPS II at 48 h, and OHCA score had moderate discrimination for mortality (AUC: 0.715, 0.750, 0.720, 0.740). For neurologic outcomes, the APACHE II score at 0 h and 48 h, SAPS II at 0 h and 48 h, and OHCA score showed moderate discrimination (AUC: 0.752, 0.738, 0.771, 0.771, 0.764). The APACHE II score, SAPS II and SOFA score at various time points, in addition to the OHCA score, were independent predictors of mortality and a poor neurologic outcome. CONCLUSIONS: The APACHE II score, SAPS II, SOFA score, and OHCA score have different capabilities in discriminating and estimating hospital mortality and neurologic outcomes. The OHCA score, APACHE II score and SAPS II at time zero and 48 h offer moderate predictive accuracy. Other scores at 0 h and 48 h, except for the SOFA score, are independently associated with 30-day mortality and poor cerebral performance. PMID- 29723200 TI - Longitudinal motor performance development in early adolescence and its relationship to adult success: An 8-year prospective study of highly talented soccer players. AB - Several talent identification and development (TID) programs in soccer have implemented diagnostics to measure players' motor performance. Yet, there is a lack of research investigating the relationship between motor development in adolescence and future, adult performance. This longitudinal study analyzed the three-year development of highly talented young soccer players' speed abilities and technical skills and examined the relevance of this development to their adult success. The current research sample consisted of N = 1,134 players born between 1993 and 1995 who were selected for the German Soccer Association's TID program and participated in nationwide motor diagnostics (sprinting, agility, dribbling, ball control, shooting) four times between the Under 12 (U12) and Under 15 (U15) age class. Relative age (RA) was assessed for all players, and a total motor score was calculated based on performances in the individual tests. In order to investigate players' future success, participants were divided into two groups according to their adult performance level (APL) in the 2014/2015 season: Elite (1st-5th German division; N = 145, 12.8%) and non-elite players (lower divisions; N = 989, 87.2%). Using multilevel regression analyses each motor performance was predicted by Time, Time2 (level-1 predictors), APL, and RA (level-2 covariates) with simultaneous consideration for interaction effects between the respective variables. Time and Time2 were significant predictors for each test performance. A predictive value for RA was confirmed for sprinting and the total motor score. A significant relationship between APL and the motor score as well as between APL and agility, dribbling, ball control, and shooting emerged. Interaction effects distinctly failed to reach significance. The study found a non-linear improvement in players' performance for all considered motor performance factors over a three-year period from early to middle adolescence. While their predictive value for future success was confirmed by a significant relationship between APL and most of the considered factors, there was no significant interaction between APL and Time. These findings indicate that future elite players had already been better at the beginning of the TID program and maintained this high level throughout their promotion from U12 to U15. PMID- 29723202 TI - Genomic evolution of Staphylococcus aureus isolates colonizing the nares and progressing to bacteremia. AB - BACKGROUND: Nasal colonization by Staphylococcus aureus is a key risk factor for bacteremia. The objective of this study is to identify genomic modifications occurring in nasal carriage strains of S. aureus as they progress to bacteremia in a cohort of hospitalized patients. METHODS: Eight patients with S. aureus bacteremia were identified. Genomic sequences of the bloodstream isolates were compared with 57 nasal isolates collected longitudinally prior to the occurrence of bacteremia, which covered a timespan of up to 326 days before bacteremia. RESULTS: Within each subject, nasal colonizing strains were closely related to bacteremia strains. Within a subject, the number of single nucleotide polymorphisms (SNPs) observed between time points was greater than within a single time point. Co-colonization and strain replacement were observed in one case. In all cases colonization progressed to bacteremia without addition of new virulence genes. In one case, a mutation in the accessory gene regulator gene caused abrogation of agr function. CONCLUSION: S. aureus evolves in the human nares at a variable rate. Progression of S. aureus nasal colonization to nosocomial infection is seldom associated with acquisition of new virulence determinants. Mutation in the agr gene with abrogation of function was associated with progression to bacteremia in one case. PMID- 29723203 TI - Tobacco use in Nigerian youth: A systematic review. AB - BACKGROUND: Tobacco use is the most important preventable cause of premature death and major risk factor for non-communicable diseases. Due to strict tobacco legislation in the western hemisphere, many African nations like Nigeria have shifted from being a tobacco-producing nation to a tobacco-consuming one. The purpose of this study was to systematically review existing literature on tobacco use among Nigerian adolescents and young people and identify the prevalence, distribution and factors influencing of tobacco smoking. These data are necessary to formulate and adapt control measures aimed at tobacco cessation among young people, and preventing long-term smoking behaviors. METHODS: Three databases (African Journals Online, PsychInfo, PubMed) were searched for peer-reviewed publications, published between January 2000 and March 2017. Additional searches were completed on Google Scholar, and other documents and reports of the Nigerian government and the Global Youth Tobacco Survey were consulted. Using the PRISMA guidelines to evaluate studies, we included studies that reported prevalence of tobacco use in adolescents or youths, aged 10 to 24, and excluded evaluations of tobacco-related medical conditions. RESULTS: A total of 30 studies with a total population of 26,709 were reviewed. Prevalence rates of tobacco smoking ranged from 0.2% to 32.5%. Among the gender-specific studies, the prevalence of smoking among females ranged between 2.2% to 10% while that of males ranged from 1% to 32.5%. Gender distribution among these studies was mixed (80.0%), males only (13.3%) and females only (6.7%). Smoking prevalence was higher among males than females. The most common risk factors for tobacco use included peer influence, family conditions, psychosocial factors and male gender. Additional risk factors included concomitant substance abuse, media advertisements and increasing age. CONCLUSIONS: Tobacco smoking poses a huge burden to Nigerian youths and various determinants were highlighted in this review. It is imperative that all stakeholders engage in concerted efforts to target both in-school and out-of school youths in tobacco control strategies. PMID- 29723204 TI - Stopping at a red light: Recruitment of inhibitory control by environmental cues. AB - Environmental cues can influence basic perceptual and attentional processes especially in an emotional context. In the current study, we aimed to investigate the effect of a non-emotional common environmental cue-a traffic light-on a higher cognitive operation-inhibition. In two experiments, we administered a novel version of the stop-signal task, in which the go task was to determine the color of a traffic light. In order to investigate the influence of each of the cues on inhibitory processes, separate tracking procedures (one for each cue) were applied simultaneously to the stop-signal delay. In Experiment 1, we found that reaction time in no-stop-signal trials was faster when a green traffic light was present, whereas stop-signal reaction time was longer when a red traffic light was present. In Experiment 2, neutral control cues were used in addition to a red and green light. The results indicate that the differences between red and green stem from an association between the color red and stop processes (rather than from the green-go association). These results strengthen previous findings showing the effect of environmental cues on attentional processes and go beyond them by showing that the effect is not restricted to emotional cues. Most importantly, the current study results suggest that environmental cues can also influence complex cognitive operations such as inhibitory control. These results might have specific implications for our understanding of the processes that underlie specific psychiatric disorders characterized by inhibitory deficit. PMID- 29723206 TI - Carbon innumeracy. AB - Individuals must have a quantitative understanding of the carbon footprint tied to their everyday decisions to make efficient sustainable decisions. We report research of the innumeracy of individuals as it relates to their carbon footprint. In three studies that varied in terms of scale and sample, respondents estimate the quantity of CO2 released when combusting a gallon of gasoline in comparison to several well-known metrics including food calories and travel distance. Consistently, respondents estimated the quantity of CO2 from gasoline compared to other metrics with significantly less accuracy while exhibiting a tendency to underestimate CO2. Such relative absence of carbon numeracy of even a basic consumption habit may limit the effectiveness of environmental policies and campaigns aimed at changing individual behavior. We discuss several caveats as well as opportunities for policy design that could aid the improvement of people's quantitative understanding of their carbon footprint. PMID- 29723208 TI - An R package for simulating growth and organic wastage in aquaculture farms in response to environmental conditions and husbandry practices. AB - A new R software package, RAC, is presented. RAC allows to simulate the rearing cycle of 4 species, finfish and shellfish, highly important in terms of production in the Mediterranean Sea. The package works both at the scale of the individual and of the farmed population. Mathematical models included in RAC were all validated in previous works, and account for growth and metabolism, based on input data characterizing the forcing functions-water temperature, and food quality/quantity. The package provides a demo dataset of forcings for each species, as well as a typical set of husbandry parameters for Mediterranean conditions. The present work illustrates RAC main features, and its current capabilities/limitations. Three test cases are presented as a proof of concept of RAC applicability, and to demonstrate its potential for integrating different open products nowadays provided by remote sensing and operational oceanography. PMID- 29723207 TI - Benefit, risk and cost of new oral anticoagulants and warfarin in atrial fibrillation; A multicriteria decision analysis. AB - INTRODUCTION: Warfarin and new oral anticoagulants are effective in reducing stroke in atrial fibrillation; however, the benefits and risks rates in clinical trials show heterogeneity for each anticoagulant, and is unknown the cost influence on a model considering most of the treatment consequences. We designed a benefit-risk and cost assessment of oral anticoagulants. DESIGN: We followed the roadmap proposed by IMI-PROTECT and the considerations of emerged good practice to perform Multi-Criteria Decision Analysis (MCDA). The roadmap defines the following steps: (1) planning, (2) evidence gathering and data preparation, (3) analyses, (4) explorations, and (5) conclusions. We defined two reference points (0-100) to allocate numerical values for scores and weights, and used an analogue numeric scale to assess physicians' preferences. As benefits of the anticoagulant therapy, we included reductions in stroke and all-cause mortality; intracranial haemorrhage, gastrointestinal haemorrhage, minor bleeding and myocardial infarction were considered risks. We also made an estimation of the annual drug cost per person. MAIN RESULTS: The scores were: Apixaban 33, Dabigatran 25, warfarin 18 and Rivaroxaban 14 this score reveals the most preferred up to the less preferred option, considering the benefit-risk ratio and drug costs altogether. The relative model weights were: 51.1% for risks, 40.4% for benefits and 8.5% for cost. The sensitivity analysis confirms the model robustness. CONCLUSIONS: From this analysis, apixaban should be considered as the preferred anticoagulant option -due to a better benefit-risk balance and a minor cost influence- followed by dabigatran, warfarin and rivaroxaban. PMID- 29723205 TI - Dietary yeast-derived mannan oligosaccharides have immune-modulatory properties but do not improve high fat diet-induced obesity and glucose intolerance. AB - The indigestible mannan oligosaccharides (MOS) derived from the outer cell wall of yeast Saccharomyces cerevisiae have shown potential to reduce inflammation. Since inflammation is one of the underlying mechanisms involved in the development of obesity-associated metabolic dysfunctions, we aimed to determine the effect of dietary supplementation with MOS on inflammation and metabolic homeostasis in lean and diet-induced obese mice. Male C57BL/6 mice were fed either a low fat diet (LFD) or a high fat diet (HFD) with, respectively, 10% or 45% energy derived from lard fat, with or without 1% MOS for 17 weeks. Body weight and composition were measured throughout the study. After 12 weeks of intervention, whole-body glucose tolerance was assessed and in week 17 immune cell composition was determined in mesenteric white adipose tissue (mWAT) and liver by flow cytometry and RT-qPCR. In LFD-fed mice, MOS supplementation induced a significant increase in the abundance of macrophages and eosinophils in mWAT. A similar trend was observed in hepatic macrophages. Although HFD feeding induced a classical shift from the anti-inflammatory M2-like macrophages towards the pro inflammatory M1-like macrophages in both mWAT and liver from control mice, MOS supplementation had no effect on this obesity-driven immune response. Finally, MOS supplementation did not improve whole-body glucose homeostasis in both lean and obese mice.Altogether, our data showed that MOS had extra-intestinal immune modulatory properties in mWAT and liver. However these effects were not substantial enough to significantly ameliorate HFD-induced glucose intolerance or inflammation. PMID- 29723211 TI - Using an integral projection model to assess the effect of temperature on the growth of gilthead seabream Sparus aurata. AB - Accurate information on the growth rates of fish is crucial for fisheries stock assessment and management. Empirical life history parameters (von Bertalanffy growth) are widely fitted to cross-sectional size-at-age data sampled from fish populations. This method often assumes that environmental factors affecting growth remain constant over time. The current study utilized longitudinal life history information contained in otoliths from 412 juveniles and adults of gilthead seabream, Sparus aurata, a commercially important species fished and farmed throughout the Mediterranean. Historical annual growth rates over 11 consecutive years (2002-2012) in the Gulf of Lions (NW Mediterranean) were reconstructed to investigate the effect of temperature variations on the annual growth of this fish. S. aurata growth was modelled linearly as the relationship between otolith size at year t against otolith size at the previous year t-1. The effect of temperature on growth was modelled with linear mixed effects models and a simplified linear model to be implemented in a cohort Integral Projection Model (cIPM). The cIPM was used to project S. aurata growth, year to year, under different temperature scenarios. Our results determined current increasing summer temperatures to have a negative effect on S. aurata annual growth in the Gulf of Lions. They suggest that global warming already has and will further have a significant impact on S. aurata size-at-age, with important implications for age structured stock assessments and reference points used in fisheries. PMID- 29723209 TI - Cognitive dysfunction improves in systemic lupus erythematosus: Results of a 10 years prospective study. AB - OBJECTIVE: Cognitive impairment (CI) has been described in 3-80% of Systemic lupus erythematosus (SLE) patients but only short-term studies evaluated its over time changes, suggesting that CI is usually a stable finding. We aimed at evaluating the changes of SLE-related CI in a 10-years prospective single center cohort study. METHODS: We evaluated 43 patients (M/F 5/38; mean age = 45.7+/-10.1 years; mean disease duration = 230.8+/-74.3 months) at baseline (T0) and after 10 years (T1). A test battery designed to detect fronto-subcortical dysfunction across five domains (memory, attention, abstract reasoning, executive and visuospatial function) was administered. A global cognitive dysfunction score (GCD) was obtained and associated with clinical and laboratory features. RESULTS: Prevalence of CI was 20.9% at T0 and 13.9% at T1 (P = NS). This impairment was prevalently mild at T0 (55.5%) and mild or moderate at T1 (36.3% for both degrees). After 10 years, CI improved in 50% of patients, while 10% worsened. Impaired memory (P = 0.02), executive functions (P = 0.02) and abstract reasoning (P = 0.03) were associated with dyslipidemia at T0. Worsening of visuospatial functions was significantly associated with dyslipidemia and Lupus Anticoagulant (P = 0.04 for both parameters). Finally, GCD significantly correlated with chronic damage measured by SLICC/damage index at T0 (r = 0.3; P = 0.04) and T1 (r = 0.3; P = 0.03). CONCLUSIONS: For the first time, we assessed CI changes over 10 years in SLE. CI improved in the majority of the patients. Furthermore, we observed an improvement of the overall cognitive functions. These results could suggest that an appropriate management of the disease during the follow-up could be able to control SLE-related CI. PMID- 29723212 TI - From arterial stiffness to kidney graft microvasculature: Mortality and graft survival within a cohort of 220 kidney transplant recipients. AB - BACKGROUND: Aortic stiffness assessed by carotid-femoral pulse wave velocity (CF PWV) is a predictor of mortality in several populations. However, little is known in kidney transplant recipients. Our objectives were to evaluate the ability of CF-PWV measured 3 months following transplantation to predict mortality, graft loss and its potential links to measured Glomerular Filtration Rate (mGFR) or kidney graft microvasculature parameters. METHODS: The study is based on a monocentric retrospective cohort including 220 adult kidney graft recipients evaluated three months after transplantation. CF-PWV measures, clinical, laboratory and histological data performed at 3 (M3) and 12 months (M12) following transplantation were retrospectively collected. The two primary endpoints were all-cause mortality and occurrence of end stage renal disease (ESRD) defined by initiation of dialysis. RESULTS: After a median follow up of 5.5 years [1.9; 8.8], death and graft loss occurred in 10 and 12 patients respectively. M3 CF-PWV was an independent mortality risk factor (HR = 1.29 [1.03; 1.61]; p = 0.03), despite no aortic stiffness variation during the first year of transplantation. Of notice, M3 CF-PWV was not associated with M12 mGFR or ESRD outcome. Graft microcirculation assessed by Banff vascular fibrous intimal thickening score (cv) worsened between M3 and M12 (p = 0.01), but no link was found with CF-PWV, mGFR or ESRD outcome. Surprisingly, acute rejections at M3 were associated after adjustment with mortality (p = 0.03) but not ESRD. CONCLUSION: Aortic stiffness measured 3 months after kidney transplantation is a strong predictor of mortality with no obvious influence on kidney graft microvasculature or graft loss. PMID- 29723210 TI - Predictive modelling of a novel anti-adhesion therapy to combat bacterial colonisation of burn wounds. AB - As the development of new classes of antibiotics slows, bacterial resistance to existing antibiotics is becoming an increasing problem. A potential solution is to develop treatment strategies with an alternative mode of action. We consider one such strategy: anti-adhesion therapy. Whereas antibiotics act directly upon bacteria, either killing them or inhibiting their growth, anti-adhesion therapy impedes the binding of bacteria to host cells. This prevents bacteria from deploying their arsenal of virulence mechanisms, while simultaneously rendering them more susceptible to natural and artificial clearance. In this paper, we consider a particular form of anti-adhesion therapy, involving biomimetic multivalent adhesion molecule 7 coupled polystyrene microbeads, which competitively inhibit the binding of bacteria to host cells. We develop a mathematical model, formulated as a system of ordinary differential equations, to describe inhibitor treatment of a Pseudomonas aeruginosa burn wound infection in the rat. Benchmarking our model against in vivo data from an ongoing experimental programme, we use the model to explain bacteria population dynamics and to predict the efficacy of a range of treatment strategies, with the aim of improving treatment outcome. The model consists of two physical compartments: the host cells and the exudate. It is found that, when effective in reducing the bacterial burden, inhibitor treatment operates both by preventing bacteria from binding to the host cells and by reducing the flux of daughter cells from the host cells into the exudate. Our model predicts that inhibitor treatment cannot eliminate the bacterial burden when used in isolation; however, when combined with regular or continuous debridement of the exudate, elimination is theoretically possible. Lastly, we present ways to improve therapeutic efficacy, as predicted by our mathematical model. PMID- 29723213 TI - ResearchMaps.org for integrating and planning research. AB - To plan experiments, a biologist needs to evaluate a growing set of empirical findings and hypothetical assertions from diverse fields that use increasingly complex techniques. To address this problem, we operationalized principles (e.g., convergence and consistency) that biologists use to test causal relations and evaluate experimental evidence. With the framework we derived, we then created a free, open-source web application that allows biologists to create research maps, graph-based representations of empirical evidence and hypothetical assertions found in research articles, reviews, and other sources. With our ResearchMaps web application, biologists can systematically reason through the research that is most important to them, as well as evaluate and plan experiments with a breadth and precision that are unlikely without such a tool. PMID- 29723214 TI - Micro/nano hierarchical structured titanium treated by NH4OH/H2O2 for enhancing cell response. AB - In this paper, two kinds of titanium surfaces with novel micro/nano hierarchical structures, namely Etched (E) surface and Sandblast and etched (SE) surface, were successfully fabricated by NH4OH and H2O2 mixture. And their cellular responses of MG63 were investigated compared with Sandblast and acid-etching (SLA) surface. Scanning electron microscope (SEM), Surface profiler, X-ray photoelectron spectroscopy (XPS), and Contact angle instrument were employed to assess the surface morphologies, roughness, chemistry and wettability respectively. Hierarchical structures with micro holes of 10-30 MUm in diameter and nano pits of tens of nanometers in diameter formed on both E and SE surfaces. The size of micro holes is very close to osteoblast cell, which makes them wonderful beds for osteoblast. Moreover, these two kinds of surfaces possess similar roughness and superior hydrophilicity to SLA. Reactive oxygen species were detected on E and SE surface, and thus considerable antimicrobial performance and well fixation can be speculated on them. The cell experiments also demonstrated a boost in cell attachment, and that proliferation and osteogenic differentiation were achieved on them, especially on SE surface. The results indicate that the treatment of pure titanium with H2O2/NH4OH is an effective technique to improve the initial stability of implants and enhance the osseointegration, which may be a promising surface treatment to titanium implant. PMID- 29723215 TI - Core signaling pathways in ovarian cancer stem cell revealed by integrative analysis of multi-marker genomics data. AB - Tumor recurrence occurs in more than 70% of ovarian cancer patients, and the majority eventually becomes refractory to treatments. Ovarian Cancer Stem Cells (OCSCs) are believed to be responsible for the tumor relapse and drug resistance. Therefore, eliminating ovarian CSCs is important to improve the prognosis of ovarian cancer patients. However, there is a lack of effective drugs to eliminate OCSCs because the core signaling pathways regulating OCSCs remain unclear. Also it is often hard for biologists to identify a few testable targets and infer driver signaling pathways regulating CSCs from a large number of differentially expression genes in an unbiased manner. In this study, we propose a straightforward and integrative analysis to identify potential core signaling pathways of OCSCs by integrating transcriptome data of OCSCs isolated based on two distinctive markers, ALDH and side population, with regulatory network (Transcription Factor (TF) and Target Interactome) and signaling pathways. We first identify the common activated TFs in two OCSC populations integrating the gene expression and TF-target Interactome; and then uncover up-stream signaling cascades regulating the activated TFs. In specific, 22 activated TFs are identified. Through literature search validation, 15 of them have been reported in association with cancer stem cells. Additionally, 10 TFs are found in the KEGG signaling pathways, and their up-stream signaling cascades are extracted, which also provide potential treatment targets. Moreover, 40 FDA approved drugs are identified to target on the up-stream signaling cascades, and 15 of them have been reported in literatures in cancer stem cell treatment. In conclusion, the proposed approach can uncover the activated up-stream signaling, activated TFs and up-regulated target genes that constitute the potential core signaling pathways of ovarian CSC. Also drugs and drug combinations targeting on the core signaling pathways might be able to eliminate OCSCs. The proposed approach can also be applied for identifying potential activated signaling pathways of other types of cancers. PMID- 29723217 TI - Fitting item response unfolding models to Likert-scale data using mirt in R. AB - While a large family of unfolding models for Likert-scale response data have been developed for decades, very few applications of these models have been witnessed in practice. There may be several reasons why these have not appeared more widely in published research, however one obvious limitation appears to be the absence of suitable software for model estimation. In this article, the authors demonstrate how the mirt package can be adopted to estimate parameters from various unidimensional and multidimensional unfolding models. To concretely demonstrate the concepts and recommendations, a tutorial and examples of R syntax are provided for practical guidelines. Finally, the performance of mirt is evaluated via parameter-recovery simulation studies to demonstrate its potential effectiveness. The authors argue that, armed with the mirt package, applying unfolding models to Likert-scale data is now not only possible but can be estimated to real-datasets with little difficulty. PMID- 29723218 TI - Associations between retinal arteriolar and venular calibre with the prevalence of impaired fasting glucose and diabetes mellitus: A cross-sectional study. AB - BACKGROUND: This study aims to explore retinal vessel calibre in individuals at risk of coronary artery disease (CAD), diagnosed with impaired fasting glucose (IFG) or diabetes mellitus (DM), and whether indices of CAD extent and severity modifies these associations with DM. METHODS: A cross-sectional study was undertaken of 1680 patients presenting to Westmead Hospital (Sydney, Australia) for evaluation of potential CAD. Baseline digital retinal photographs, cardiovascular risk factor measurements, fasting blood tests and self-reported diabetes by patient questionnaire was recorded. Extent and severity of CAD was assessed using Extent and Gensini scores from angiography findings, respectively. Multivariate analysis including age and hypertension was undertaken to assess the association between retinal vessel calibre and IFG or DM. RESULTS: A total of 748 patients were included; 96 (12.8%) and 189 (25.3%), respectively, had IFG or DM (together termed 'hyperglycaemia'). No consistent association between hyperglycaemia and retinal arteriolar calibre was apparent. Wider retinal venular calibre (second and third tertile) carried a significantly higher odds of DM in men only (multivariable-adjusted OR 2.447, p = 0.005; and OR 2.76, p = 0.002; respectively). No equivalent association was apparent in women. This association was marginally significant (p = 0.08) in patients with CAD Extent scores below the median (i.e. less diffuse CAD). Retinal vessel calibre was not associated with impaired fasting glucose. CONCLUSIONS: This study reports a significant association between retinal venular widening and diabetes mellitus in men. This association was marginally stronger among participants with less diffuse CAD. PMID- 29723216 TI - c-Src kinase is involved in the tyrosine phosphorylation and activity of SLC11A1 in differentiating macrophages. AB - Studies have demonstrated that the solute carrier family 11 member 1 (SLC11A1) is heavily glycosylated and phosphorylated in macrophages. However, the mechanisms of SLC11A1 phosphorylation, and the effects of phosphorylation on SLC11A1 activity remain largely unknown. Here, the tyrosine phosphorylation of SLC11A1 is observed in SLC11A1-expressing U937 cells when differentiated into macrophages by phorbol myristate acetate (PMA). The phosphorylation of SLC11A1 is almost completely blocked by treatment with PP2, a selective inhibitor of Src family kinases. Furthermore, we found that SLC11A1 is a direct substrate for active c Src kinase and siRNA-mediated knockdown of cellular Src (c-Src) expression results in a significant decrease in tyrosine phosphorylation. We found that PMA induces the interaction of SLC11A1 with c-Src kinase. We demonstrated that SLC11A1 is phosphorylated by Src family kinases at tyrosine 15 and this type of phosphorylation is required for SLC11A1-mediated modulation of NF-kappaB activation and nitric oxide (NO) production induced by LPS. Our results demonstrate important roles for c-Src tyrosine kinase in phosphorylation and activation of SLC11A1 in macrophages. PMID- 29723219 TI - Dynamics of phosphorus and bacterial phoX genes during the decomposition of Microcystis blooms in a mesocosm. AB - Cyanobacterial blooms are a worldwide environmental problem and frequently occur in eutrophic lakes. Organophosphorus mineralization regulated by microbial alkaline phosphatase provides available nutrients for bloom regeneration. To uncover the dynamics of bacterial alkaline phosphatase activity and microbial backgrounds in relation to organophosphorus mineralization during the decomposition process of cyanobacterial blooms, the response of alkaline phosphatase PhoX-producing bacteria were explored using a 23-day mesocosm experiment with three varying densities of Microcystis biomass from eutrophic Lake Taihu. Our study found large amounts of soluble reactive phosphorus and dissolved organophosphorus were released into the lake water during the decomposition process. Bacterial alkaline phosphatase activity showed the peak values during days 5~7 in groups with different chlorophyll-a densities, and then all decreased dramatically to their initial experimental levels during the last stage of decomposition. Bacterial phoX abundances in the three experimental groups increased significantly along with the decomposition process, positively related to the dissolved organic carbon and organophosphorus released by the Microcystis blooms. The genotypes similar to the phoX genes of Alphaproteobacteria were dominant in all groups, whereas the genotypes most similar to the phoX genes of Betaproteobacteria and Cyanobacteria were also abundant in the low density (~15 MUg L-1 chlorophyll-a) group. At the end of the decomposition process, the number of genotypes most similar to the phoX of Betaproteobacteria and Cyanobacteria increased in the medium (~150 MUg L-1 chlorophyll-a) and high (~1500 MUg L-1 chlorophyll-a) density groups. The released organophosphorus and increased bacterial phoX abundance after decomposition of Microcystis aggregates could potentially provide sufficient nutrients and biological conditions for algal proliferation and are probably related to the regeneration of Microcystis blooms in eutrophic lakes. PMID- 29723221 TI - Impact of silencing hepatic SREBP-1 on insulin signaling. AB - Sterol Regulatory Element Binding Protein-1 (SREBP-1) is a conserved transcription factor of the basic helix-loop-helix leucine zipper family (bHLH Zip) that plays a central role in regulating expression of genes of carbohydrate and fatty acid metabolism in the liver. SREBP-1 activity is essential for the control of insulin-induced anabolic processes during the fed state. In addition, SREBP-1 regulates expression of key molecules in the insulin signaling pathway, including insulin receptor substrate 2 (IRS2) and a subunit of the phosphatidylinositol 3-kinase (PI3K) complex, PIK3R3, suggesting that feedback mechanisms exist between SREBP-1 and this pathway. Nevertheless, the overall contribution of SREBP-1 activity to maintain insulin signal transduction is unknown. Furthermore, Akt is a known activator of mTORC1, a sensor of energy availability that plays a fundamental role in metabolism, cellular growth and survival. We have silenced SREBP-1 and explored the impact on insulin signaling and mTOR in mice under fed, fasted and refed conditions. No alterations in circulating levels of insulin were observed. The studies revealed that depletion of SREBP-1 had no impact on IRS1Y612, AktS473, and downstream effectors GSK3alphaS21 and FoxO1S256 during the fed state. Nevertheless, reduced levels of these molecules were observed under fasting conditions. These effects were not associated with changes in phosphorylation of mTOR. Overall, our data indicate that the contribution of SREBP-1 to maintain insulin signal transduction in liver is modest. PMID- 29723222 TI - Lipidomic profiling reveals free fatty acid alterations in plasma from patients with atrial fibrillation. AB - Atrial fibrillation (AF) is the most common cardiac arrhythmia, and its incidence is increasing worldwide. One method used to restore sinus rhythm is direct current cardioversion (DCCV). Despite the high success rate of DCCV, AF typically recurs within the first 2 weeks. However, our understanding of the pathophysiology of AF recurrence, incidence, and progression are highly limited. Lipidomic profiling was applied to identify altered lipids in plasma from patients with AF using ultra-performance liquid chromatography/quadrupole time-of flight mass spectrometry coupled with multivariate statistical analysis. Partial least-squares discriminant analysis revealed a clear separation between AF patients and healthy controls. The levels of several lipid species, including fatty acids and phospholipids, were different between AF patients and healthy controls, indicating that oxidative stress and inflammation are associated with the pathogenesis of AF. Similar patterns were also detected between recurrent and non-recurrent AF patients. These results suggest that the elevated saturated fatty acid and reduced polyunsaturated fatty acid levels in AF patients may be associated with enhanced inflammation and that free fatty acid levels may play a crucial role in the development and progression of AF. PMID- 29723220 TI - Disease activity, autoantibodies, and inflammatory molecules in serum and cerebrospinal fluid of patients with Systemic Lupus Erythematosus and Cognitive Dysfunction. AB - OBJECTIVE: To determine if cognitive dysfunction in patients with systemic lupus erythematosus (SLE) derives from an inflammatory process with continuing disease activity, and increased levels of autoantibodies and inflammatory molecules in serum and cerebrospinal fluid (CSF). METHODS: 100 randomly selected patients participating in an inception SLE cohort were studied. At entry into the cohort, a standardized medical history and extensive laboratory tests profile, including autoantibodies were completed. Follow-up occurred every 3-6 months with assessment of lupus characteristics, comorbidities, and treatment. After a mean follow-up of six-years, cross-sectional evaluation of cognitive function was done with standardized tests, and in a subset of patients an extended profile of autoantibodies, cytokines and chemokines was measured in serum and CSF. RESULTS: At enrollment into the cohort, patients were 26.4+/-8.2 years of age and lupus duration 5.3+/-3.7 months. Moderate/severe cognitive dysfunction was diagnosed in 16 patients; in comparison to patients with normal cognitive function, they had lower education 9 vs. 12 years (P = 0.006), higher body mass index 26.7 vs. 24.3 (P = 0.03), positive IgG anticardiolipin antibodies 50% vs 18% (P = 0.009), and a higher median number of concomitant NPSLE syndromes 3 vs. 1, (P = 0.04). The prevalence of cardiovascular-risk factors, other auto-antibodies, lupus activity, treatment, and incidence of critical events did not differ. In serum and CSF, the levels of autoantibodies, cytokines and chemokine were similar, only CCL2 was elevated in CSF [886.1 (374.9-1439.7) vs. 515.8 (3.2-1958.2) pg/mL, P = 0.04]. CONCLUSION: Scant evidence of inflammation in SLE patients with cognitive dysfunction was observed. Only a higher prevalence of IgG anticardiolipin antibodies in serum and increased levels of CCL2 in CSF were detected. PMID- 29723224 TI - Effects of anthracycline, cyclophosphamide and taxane chemotherapy on QTc measurements in patients with breast cancer. AB - AIM: Acute and subacute cardiotoxicity are characterized by prolongation of the corrected QT interval (QTc) and other measures derived from the QTc interval, such as QTc dispersion (QTdc) and transmural dispersion of repolarization (DTpTe). Although anthracyclines prolong the QTc interval, it is unclear whether breast cancer patients who undergo the ACT chemotherapy regimen of anthracycline (doxorubicin: A), cyclophosphamide (C) and taxane (T) may present with QTc, QTdc and DTpTe prolongation. METHODS: Twenty-three consecutive patients with breast cancer were followed prospectively during ACT chemotherapy and were analyzed according to their QT measurements. QTc, QTdc and DTpTe measurements were determined by a 12-lead electrocardiogram (EKG) prior to chemotherapy (baseline), immediately after the first phase of anthracycline and cyclophosphamide (AC) treatment, and immediately after T treatment. Serum troponin and B-type natriuretic peptide (BNP) levels were also measured. RESULTS: Compared to baseline values, the QTc interval was significantly prolonged after the AC phase (439.7 +/- 33.2 ms vs. 472.5 +/- 36.3 ms, p = 0.001) and after T treatment (439.7 +/- 33.2 ms vs. 467.9 +/- 42.6 ms, p < 0.001). Troponin levels were elevated after the AC phase (23.0 pg/mL [min-max: 6.0-85.0] vs. 6.0 pg/mL [min-max: 6.0 22.0], p < 0.001) and after T treatment (25.0 pg/mL [min-max: 6.0-80.0] vs. 6.0 pg/mL [min-max: 6.0-22.0], p < 0.001) compared to baseline values. CONCLUSION: In this prospective study of patients with non-metastatic breast cancer who underwent ACT chemotherapy, significant QTc prolongation and an elevation in serum troponin levels were observed. PMID- 29723223 TI - Characterization of postural control impairment in women with fibromyalgia. AB - The main goal of this cross-sectional study was to detect whether women with fibromyalgia syndrome (FMS) have altered postural control and to study the sensory contribution to postural control. We also explored the possibility that self-induced anxiety and lower limb strength may be related to postural control. For this purpose, 129 women within an age range of 40 to 70 years were enrolled. Eighty of the enrolled women had FMS. Postural control variables, such as Ellipse, Root mean square (RMS) and Sample entropy (SampEn), in both directions (i.e. mediolateral and anteroposterior), were calculated under five different conditions. A force plate was used to register the center of pressure shifts. Furthermore, isometric lower limb strength was recorded with a portable dynamometer and normalized by lean body mass. The results showed that women with FMS have impaired postural control compared with healthy people, as they presented a significant increase in Ellipse and RMS values (p<0.05) and a significant decrease in SampEn in both directions (p<0.05). Postural control also worsens with the gradual alteration of sensory inputs in this population (p<0.05). Performing a stressor dual task only impacts Ellipse in women with FMS (p>0.05). There were no significant correlations between postural control and lower limb strength (p>0.05). Therefore, women with FMS have impaired postural control that is worse when sensory inputs are altered but is not correlated with their lower limb strength. PMID- 29723225 TI - Survival outcomes in patients with large (>=7cm) clear cell renal cell carcinomas treated with nephron-sparing surgery versus radical nephrectomy: Results of a multicenter cohort with long-term follow-up. AB - BACKGROUND: Does the dogma of nephron sparing surgery (NSS) still stand for large renal masses? Available studies dealing with that issue are considerably biased often mixing imperative with elective indications for NSS and also including less malignant variants or even benign renal tumors. Here, we analyzed the oncological long-term outcomes of patients undergoing elective NSS or radical tumor nephrectomy (RN) for non-endophytic, large (>=7cm) clear cell renal carcinoma (ccRCC). METHODS: Prospectively acquired, clinical databases from two academic high-volume centers were screened for patients from 1980 to 2010. The query was strictly limited to patients with elective indications. Surgical complications were retrospectively assessed and classified using the Clavien-Dindo classification system (CDS). Overall survival (OS) and cancer specific survival (CSS) were analyzed using the Kaplan-Meier-method and the log-rank test. RESULTS: Out of in total 8664 patients in the databases, 123 patients were identified (elective NSS (n = 18) or elective RN (n = 105)) for >=7cm ccRCC. The median follow-up over all was 102 months (range 3-367 months). Compared to the RN group, the NSS group had a significantly longer median OS (p = 0.014) and median CSS (p = 0.04). CONCLUSIONS: In large renal masses, NSS can be performed safely with acceptable complication rates. In terms of long-term OS and CSS, NSS was at least not inferior to RN. Our findings suggest that NSS should also be performed in patients presenting with renal tumors >=7cm whenever technically feasible. Limitations include its retrospective nature and the limited availability of data concerning long-term development of renal function in the two groups. PMID- 29723226 TI - Prevalence of clinically apparent hypertrophic cardiomyopathy in Germany-An analysis of over 5 million patients. AB - BACKGROUND: Hypertrophic cardiomyopathy (HCM) is the most common inherited heart disease. Reported prevalence rates vary substantially between 1:500 (0.2%) and 1:3,000 (0.03%), which may be attributed to different study designs and population characteristics. Prevalence data for Germany is not available. Consequently, this study aimed (1) to quantify age- and gender-specific clinically diagnosed HCM prevalence in Germany based on the analysis of health care claims data of > 5 million insurants in 2015, and (2) to analyze temporal prevalence trends from 2011 to 2015. METHODS: Data were extracted from the InGef (Insitute for Applied Health Research) database, which is an anonymized healthcare claims database with longitudinal data from patients insured in one of approximately 70 German social health insurances (SHIs). Patients were classified as HCM prevalent, if they had at least one verified ambulatory or one hospital main- or secondary discharge diagnosis of HCM (I42.1 or I42.2). RESULTS: In 2015, HCM was prevalent in 4,000 out of 5,490,810 patients (0.07%; 1:1,372). HCM prevalence increased gradually with age from 7.4/100,000 persons (95% CI 5.2 10.1) in 0-9 years old to 298.7/100,000 persons (95% CI 276.4-322.4) in patients > 80 years. In all age categories, men had a numerically higher prevalence than women with significant differences in patients > 30 years. There was a gradual annual prevalence increase from 75.8 (95% CI 75.2-76.4) in 2011 to 84.2 (95% CI 83.5-84.8) in 2015 per 100,000 persons. CONCLUSIONS: Overall, prevalence of clinically diagnosed HCM in Germany is lower than in systematic population studies based on echocardiographic diagnosis. Prevalence increased with advancing age and showed a constant yearly rise. Those observations may improve our understanding of the burden of this genetic heart disease on the health care system in Germany, increase the diagnostic awareness among clinicians and shape future screening and management strategies. PMID- 29723228 TI - Divergent antioxidant capacity of human islet cell subsets: A potential cause of beta-cell vulnerability in diabetes and islet transplantation. AB - BACKGROUND: Type 1 and Type 2 diabetes mellitus (T1DM and T2DM) are caused by beta(beta)-cell loss and functional impairment. Identification of mechanisms of beta-cell death and therapeutic interventions to enhance beta-cell survival are essential for prevention and treatment of diabetes. Oxidative stress is a common feature of both T1DM and T2DM; elevated biomarkers of oxidative stress are detected in blood, urine and tissues including pancreas of patients with DM. Islet transplantation is a promising treatment for diabetes. However, exposure to stress (chemical and mechanical) and ischemia-reperfusion during isolation and transplantation causes islet loss by generation of reactive oxygen species (ROS). Human intracellular antioxidant enzymes and related molecules are essential defenses against ROS. Antioxidant enzyme levels including superoxide dismutase (SOD), catalase, and glutathione peroxidase (GPX) have been shown to be low in islet cells. However, little is known about the expression and function of antioxidant enzymes within islet cell subsets. We evaluated the expression of the key antioxidant enzymes in beta- and alpha(alpha)-cell and accessed effects of oxidative stress, islet isolation and transplantation on beta/alpha-cell ratio and viability in human islets. METHODS: Human pancreata from T1DM, T2DM and non diabetic deceased donors were obtained and analyzed by confocal microscopy. Isolated islets were (I) transplanted in the renal sub-capsular space of streptozotocin-induced diabetic nude mice (in vivo bioassay), or (II) exposed to oxidative (H2O2) and nitrosative (NO donor) stress for 24 hrs in vitro. The ratio, % viability and death of beta- and alpha-cells, and DNA damage (8OHdG) were measured. RESULTS AND CONCLUSIONS: Catalase and GPX expression was much lower in beta- than alpha-cells. The beta/alpha-cell ratio fells significantly following islet isolation and transplantation. Exposure to oxidative stress caused a significantly lower survival and viability, with higher DNA damage in beta- than alpha-cells. These findings identified the weakness of beta-cell antioxidant capacity as a main cause of vulnerability to oxidative stress. Potential strategies to enhance beta-cell antioxidant capacity might be effective in prevention/treatment of diabetes. PMID- 29723229 TI - Effects of an acute bout of dynamic stretching on biomechanical properties of the gastrocnemius muscle determined by shear wave elastography. AB - AIMS: The aim of this study was to examine the acute effects of dynamic stretching (DS) exercise on passive ankle range of motion (RoM), resting localized muscle stiffness, as measured by shear wave speed (SWS) of medial gastrocnemius muscle, fascicle strain, and thickness. METHODS/RESULTS: Twenty three participants performed a DS protocol. Before and after stretching, SWS was measured in the belly of the resting medial gastrocnemius muscle (MGM) using shear wave elastography. DS produced small improvements in maximum dorsiflexion (+1.5 degrees +/-1.5; mean difference +/-90% confidence limits) and maximum plantarflexion (+2.3 degrees +/-1.8), a small decrease in fascicle strain (-2.6% +/-4.4) and a small increase in SWS at neutral resting angle (+11.4% +/-1.5). There was also a small increase in muscle thickness (+4.1mm +/-2.0). CONCLUSIONS: Through the use of elastography, this is the first study to suggest that DS increases muscle stiffness, decreases fascicle strain and increases muscle thickness as a result of improved RoM. These results can be beneficial to coaches, exercise and clinical scientists when choosing DS as a muscle conditioning or rehabilitation intervention. PMID- 29723227 TI - Performance and comparability of laboratory methods for measuring ferritin concentrations in human serum or plasma: A systematic review and meta-analysis. AB - BACKGROUND: Different laboratory methods are used to quantify ferritin concentrations as a marker of iron status. A systematic review was undertaken to assess the accuracy and comparability of the most used methods for ferritin detection. METHODS AND FINDINGS: National and regional databases were searched for prospective, retrospective, sectional, longitudinal and case-control studies containing the characteristics and performance of at least one method for serum/plasma ferritin determinations in humans published to date. The analysis included the comparison between at least 2 methods detailing: sensitivity, precision, accuracy, predictive values, inter-methods adjustment, and use of international reference materials. Pooled method performance was analyzed for each method and across methods. OUTCOMES: Search strategy identified 11893 records. After de-duplication and screening 252 studies were assessed, including 187 studies in the qualitative analysis and 148 in the meta-analysis. The most used methods included radiometric, nonradiometric and agglutination assays. The overall within-run imprecision for the most reported ferritin methods was 6.2+/ 3.4% (CI 5.69-6.70%; n = 171), between-run imprecision 8.9+/-8.7% (CI 7.44 10.35%; n = 136), and recovery rate 95.6% (CI 91.5-99.7%; n = 94). The pooled regression coefficient was 0.985 among all methods analyzed, and 0.984 when comparing nonradiometric and radiometric methods, without statistical differences in ferritin concentration ranging from 2.3 to 1454 MUMUg/L. CONCLUSION: The laboratory methods most used to determine ferritin concentrations have comparable accuracy and performance. Registered in PROSPERO CRD42016036222. PMID- 29723231 TI - Long-term effect of statins on the risk of new-onset osteoporosis: A nationwide population-based cohort study. AB - BACKGROUND: Several observational cohort and meta-analytical studies in humans have shown that statin users have a lower risk of fractures or greater bone mineral densities (BMD) than nonusers. However, some studies including randomized clinical trials have the opposite results, particularly in Asian populations. OBJECTIVE: This study investigates the impacts of statins on new-onset osteoporosis in Taiwan. METHODS: In a nationwide retrospective population-based cohort study, 45,342 subjects aged between 50-90 years having received statin therapy (statin-users) since January 1 2001, and observed through December 31 2013 were selected from the National Health Insurance Research Database of Taiwan. Likewise, 115,594 patients had no statin therapy (statin-non-users) were included as controls in this study. Multivariable Cox proportional hazards analysis for drug exposures was employed to evaluate the association between statin treatment and new-onset of osteoporosis risk. We also used the long-rank test to evaluate the difference of probability of osteoporosis-free survival. RESULTS: During the 13-year follow-up period, 16,146 of all enrolled subjects (10.03%) developed osteoporosis, including 3097 statin-users (6.83%) and 13,049 statin-non-users (11.29%). Overall, statin therapy reduced the risk of new-onset osteoporosis by 48% (adjusted hazard ratio [HR] 0.52; 95% CI 0.50 to 0.54). A dose-response relationship between statin treatment and the risk of new-onset osteoporosis was observed. The adjusted hazard ratios for new-onset osteoporosis were 0.84 (95% CI, 0.78 to 0.90), 0.56 (95% CI, 0.52 to 0.60) and 0.23 (95% CI, 0.21 to 0.25) when cumulative defined daily doses (cDDDs) ranged from 28 to 90, 91 to 365, and more than 365, respectively, relative to nonusers. Otherwise, high potency statins (rosuvastatin and atorvastatin) and moderate-potency statin (simvastatin) seemed to have a potential protective effect for osteoporosis. CONCLUSIONS: In this population-based cohort study, we found that statin use is associated with a decreased risk of osteoporosis in both genders. The osteoprotective effect of statins seemed to be more prominent with a dependency on the cumulative dosage and statin intensity. PMID- 29723230 TI - Consumption of antibiotics in Chinese public general tertiary hospitals (2011 2014): Trends, pattern changes and regional differences. AB - BACKGROUND: China has a high rate of antibiotic use. The Chinese Ministry of Health (MOH) established the Center for Antibacterial Surveillance (CAS) to monitor the use of antibacterial agents in hospitals in 2005. The purpose of this study was to identify trends, pattern changes and regional differences in antibiotic consumption in 151 public general tertiary hospitals across China from 2011-2014. MATERIALS AND METHODS: Valid data for antibiotic use were collected quarterly, and the antibiotic consumption data were expressed as the defined daily dose (DDD) per 100 inpatient days (ID). We compared the patterns of antibiotic use in different classes and geographical clusters. RESULTS: Total antibiotic use significantly decreased (P = 0.018) from 75.86 DDD/100 ID in 2011 to 47.03 DDD/100 ID in 2014. The total consumption of flomoxef sodium and cefminox increased from 1.31 DDD/100 BD in 2011 to 8.6 DDD/100 BD in 2014. Cephalosporins were the most frequently used antibiotics in all regions. Third generation cephalosporins accounted for more than 45% of the cephalosporins used. Carbapenem use substantially increased (P = 0.043). Penicillin combinations with inhibitors accounted for 50% of the penicillin used, and prescribed meropenem accounted for most of the carbapenems used in all regions in 2014. The subclasses in each antibiotic group were used differently between the seven regions, and the total hospital antibiotic use in 2014 differed significantly by region (P = 0.014). CONCLUSION: Although the volume and intensity of total antibiotic use decreased, the antibiotic use patterns were not optimal, and broad-spectrum antibiotics were still the main classes. The aggregate data obtained during the study period reveal similar antibiotic consumption patterns in different regions. These findings provide useful information for improving the rational use of antibiotics. More detailed data on antibiotics linked to inpatient diseases need to be collected in future studies. PMID- 29723232 TI - Ant Lion Optimization algorithm for kidney exchanges. AB - The kidney exchange programs bring new insights in the field of organ transplantation. They make the previously not allowed surgery of incompatible patient-donor pairs easier to be performed on a large scale. Mathematically, the kidney exchange is an optimization problem for the number of possible exchanges among the incompatible pairs in a given pool. Also, the optimization modeling should consider the expected quality-adjusted life of transplant candidates and the shortage of computational and operational hospital resources. In this article, we introduce a bio-inspired stochastic-based Ant Lion Optimization, ALO, algorithm to the kidney exchange space to maximize the number of feasible cycles and chains among the pool pairs. Ant Lion Optimizer-based program achieves comparable kidney exchange results to the deterministic-based approaches like integer programming. Also, ALO outperforms other stochastic-based methods such as Genetic Algorithm in terms of the efficient usage of computational resources and the quantity of resulting exchanges. Ant Lion Optimization algorithm can be adopted easily for on-line exchanges and the integration of weights for hard-to match patients, which will improve the future decisions of kidney exchange programs. A reference implementation for ALO algorithm for kidney exchanges is written in MATLAB and is GPL licensed. It is available as free open-source software from: https://github.com/SaraEl Metwally/ALO_algorithm_for_Kidney_Exchanges. PMID- 29723234 TI - Protecting the child while preserving the relationship: Using baby's relational withdrawal to gauge the effect of parental visitation. AB - The impact of children's interactions with parents in the context of out-of-home placements is receiving much-needed cross-disciplinary attention. However, the paucity of instruments that can reliably represent young children's experiences of such interactions precludes a nuanced evaluation of their impact on wellbeing and development. In response to this empirical gap, the present study investigates children's relational withdrawal as a clinically salient, easily observable and conceptually valid measure of infants' and toddlers' responses to parents. Relational withdrawal, challenging behaviors and salivary cortisol were assessed before, during and after parental visits. Conceptually, the findings suggest that observations of relational withdrawal correlate meaningfully with measure of neurobiological reactivity. Clinically, three profiles of cross variable responses in children appeared, distinguishing between groups that experience increased, decreased or unchanged levels of stress in response to parental visits. Taken together, the findings lend empirical support to systematic observations of relational withdrawal to bolster evaluations of young children's experience of parental visitation during out-of-home placements. PMID- 29723233 TI - Enhanced hypocrellin production of Shiraia sp. SUPER-H168 by overexpression of alpha-amylase gene. AB - Relative expression levels of twenty-four amylase genes in Shiraia sp. SUPER-H168 were investigated by real-time quantitative PCR when various carbohydrates, including glucose, sucrose, maltose, amylose, amylopectin and corn flour, were used as carbon source. Genes, including an alpha-glucosidase gene Amy33 (2997 bp), an alpha-amylase gene Amy365-1 (1749 bp) and a glycogen debranching enzyme gene Amy130 (2487 bp), were overexpressed, and four overexpression transformants were constructed, respectively. When Amy365-1 and Amy130 were co-overexpressed, relative expression levels of seven hypocrellin biosynthesis genes and four related genes in central carbon catabolism were all increased. Expression of Amy33 was also increased along with increase of Amy365-1 and Amy130. Under liquid state fermentation, biomasses and hypocrellin productions were both gradually increased in four overexpression strains than those of wild type strain. Under SSF, hypocrellin production of Amy365-1 and Amy130 co-expression strain reached 71.85 mg/gds, which was 2.83 fold than that of wild type strain, and residual sugar was decreased from 35.47% to 16.68%. These results can provide a practical approach for other secondary metabolites by filamentous fungi under SSF when raw starch material is used as carbon source. PMID- 29723236 TI - Health management and pattern analysis of daily living activities of people with dementia using in-home sensors and machine learning techniques. AB - The number of people diagnosed with dementia is expected to rise in the coming years. Given that there is currently no definite cure for dementia and the cost of care for this condition soars dramatically, slowing the decline and maintaining independent living are important goals for supporting people with dementia. This paper discusses a study that is called Technology Integrated Health Management (TIHM). TIHM is a technology assisted monitoring system that uses Internet of Things (IoT) enabled solutions for continuous monitoring of people with dementia in their own homes. We have developed machine learning algorithms to analyse the correlation between environmental data collected by IoT technologies in TIHM in order to monitor and facilitate the physical well-being of people with dementia. The algorithms are developed with different temporal granularity to process the data for long-term and short-term analysis. We extract higher-level activity patterns which are then used to detect any change in patients' routines. We have also developed a hierarchical information fusion approach for detecting agitation, irritability and aggression. We have conducted evaluations using sensory data collected from homes of people with dementia. The proposed techniques are able to recognise agitation and unusual patterns with an accuracy of up to 80%. PMID- 29723235 TI - Effects of Anma therapy (Japanese massage) on health-related quality of life in gynecologic cancer survivors: A randomized controlled trial. AB - OBJECTIVES: Anma therapy (Japanese massage therapy, AMT) significantly reduces the severity of physical complaints in survivors of gynecologic cancer. However, whether this reduction of severity is accompanied by improvement in health related quality of life is unknown. METHODS: Forty survivors of gynecologic cancer were randomly allocated to either an AMT group that received one 40-min AMT session per week for 8 weeks or a no-AMT group. We prospectively measured quality of life by using the Japanese version of the European Organization for Research and Treatment of Cancer QLQ-C30 version 3.0 (EORTC QLQ-C30) at baseline and at 8-week follow-up. The QLQ-C30 response rate was 100%. Hospital Anxiety Depression Scale (HADS), Profile of Mood States (POMS), and Measure of Adjustment to Cancer were also prespecified and prospectively evaluated. RESULTS: The QLQ C30 Global Health Status and Quality of Life showed significant improvement at 8 weeks (P = 0.042) in the AMT group compared with the no-AMT group, and the estimated mean difference reached a minimal clinically important difference of 10 points (10.4 points, 95% CI = 1.2 to 19.6). Scores on fatigue and insomnia showed significant improvement in the AMT group compared with the no-AMT group (P = 0.047 and 0.003, respectively). There were no significant between-group improvements in HADS anxiety and depression scales; however, POMS-assessed anger hostility showed significant improvement in the AMT group compared with the no AMT group (p = 0.028). CONCLUSIONS: AMT improved health-related quality of life in gynecologic cancer survivors. AMT can be of potential benefit for applications in oncology. PMID- 29723237 TI - Association of maternal nutrition with transient neonatal hyperinsulinism. AB - OBJECTIVE: The objective was to determine whether maternal nutritional factors are associated with transient neonatal hyperinsulinism (HI). DESIGN AND SETTING: Case control study in 4 French tertiary Obstetrics and Neonatology Departments between 2008 and 2015. METHODS: Sixty-seven mothers of neonates diagnosed with transient hyperinsulinism and 113 mothers of controls were included. The screening for hyperinsulinemic hypoglycemia in neonates was performed because of clinical symptoms suggestive of hypoglycemia or in the presence of conventional risk factors (small-for-gestational-age, prematurity, anoxo-ischemia, hypothermia, macrosomia, gestational diabetes). Hyperinsulinemic hypoglycemia was confirmed in the HI neonates and ruled out in the controls. This allowed for comparing maternal nutrition in cases and controls in a context of similar risk factors. One to 2 mothers of control neonates were included per case, and a food frequency questionnaire was addressed to the mothers between day 5 and day 10 after the birth of their newborn. RESULTS: Crude odds ratio showed that maternal weight gain, abnormal fetal rate, C-section, gender, consumption of fresh cooked vegetables, fresh fruits and fruit juices, low fat diary products, light fat products, and daily bread were significantly associated with hyperinsulinism. Maternal body mass index, hypertension, gestational diabetes, birth weight percentile, gestational age and 5-minute Apgar score were not related to HI. In a multiple backward logistic regression model, consumption of fresh cooked vegetable >=1/day (OR = 0.33 [0.14-0.77]) and light-fat products >=1/week (OR = 0.24 [0.08-0.71]) was protective against hyperinsulinism, whereas gestational weight gain >20 kg (OR = 9.5 [2.0-45.5]) and between 15-20 kg (OR = 4.0 [1.2 14.0]), abnormal fetal heart rate (OR = 4.4 [1.6-12.0]), and C-section (OR = 3.4 [1.3-8.9]) were risk factors. CONCLUSIONS: A diet rich in fresh cooked vegetable and reduced in fat, together with the avoidance of a high gestational weight gain may be protective against transient neonatal hyperinsulinism. PMID- 29723238 TI - Interruption of onchocerciasis transmission in Bioko Island: Accelerating the movement from control to elimination in Equatorial Guinea. AB - BACKGROUND: Onchocerciasis, also known as river blindness, is a parasitic disease. More than 99 percent of all cases occur in Africa. Bioko Island (Equatorial Guinea) is the only island endemic for onchocerciasis in the world. Since 2005, when vector Simulium yahense was eliminated, there have not been any reported cases of infection. This study aimed to demonstrate that updated WHO criteria for stopping mass drug administration (MDA) have been met. METHODOLOGY/PRINCIPAL FINDINGS: A cross-sectional study was conducted from September 2016 to January 2017. Participants were 5- to 9-year-old school children. Onchocerciasis/lymphatic Filariasis (LF, only in endemic districts) rapid diagnostic tests (RDTs) were performed. Blood spots were collected from RDT positive children and 10 percent of the RDT negatives to determine Ov16 and Wb123 IgG4 antibodies through enzyme-linked immunosorbent assay (ELISA). Skin snips were collected from RDT positives. Filarial detection was performed by PCR in positives and indeterminate sera. Black fly collection was carried out in traditional breeding sites. A total of 7,052 children, ranging from 5 to 9 years of age, were included in the study. Four children (0.06%) were Ov16 IgG4 RDT positives, but negative by ELISA Ov16, while 6 RDT negative children tested positive by ELISA. A total of 1,230 children from the Riaba and Baney districts were tested for LF. One child was Wb123 RDT positive (0.08%), but ELISA negative, while 3 RDT negative children were positive by Wb123 ELISA. All positive samples were negative by PCR for onchocerciasis and LF (in blood spot and skin snip). All fly collections and larval prospections in the traditional catching and prospection sites were negative. CONCLUSIONS/SIGNIFICANCE: WHO criteria have been met, therefore MDA in Bioko Island can be stopped. Three years of post-treatment surveillance should be implemented to identify any new occurrences of exposure or infection. PMID- 29723240 TI - Racism and health in New Zealand: Prevalence over time and associations between recent experience of racism and health and wellbeing measures using national survey data. AB - OBJECTIVES: Racism is an important health determinant that contributes to ethnic health inequities. This study sought to describe New Zealand adults' reported recent experiences of racism over a 10 year period. It also sought to examine the association between recent experience of racism and a range of negative health and wellbeing measures. METHODS: The study utilised previously collected data from multiple cross-sectional national surveys (New Zealand Health Surveys 2002/03, 2006/07, 2011/12; and General Social Surveys 2008, 2010, 2012) to provide prevalence estimates of reported experience of racism (in the last 12 months) by major ethnic groupings in New Zealand. Meta-analytical techniques were used to provide improved estimates of the association between recent experience of racism and negative health from multivariable models, for the total cohorts and stratified by ethnicity. RESULTS: Reported recent experience of racism was highest among Asian participants followed by Maori and Pacific peoples, with Europeans reporting the lowest experience of racism. Among Asian participants, reported experience of racism was higher for those born overseas compared to those born in New Zealand. Recent experience of racism appeared to be declining for most groups over the time period examined. Experience of racism in the last 12 months was consistently associated with negative measures of health and wellbeing (SF-12 physical and mental health component scores, self-rated health, overall life satisfaction). While exposure to racism was more common in the non European ethnic groups, the impact of recent exposure to racism on health was similar across ethnic groups, with the exception of SF-12 physical health. CONCLUSIONS: The higher experience of racism among non-European groups remains an issue in New Zealand and its potential effects on health may contribute to ethnic health inequities. Ongoing focus and monitoring of racism as a determinant of health is required to inform and improve interventions. PMID- 29723239 TI - Analysis of the microRNA signature in left atrium from patients with valvular heart disease reveals their implications in atrial fibrillation. AB - BACKGROUND: Among the potential factors which may contribute to the development and perpetuation of atrial fibrillation, dysregulation of miRNAs has been suggested. Thus in this study, we have quantified the basal expressions of 662 mature human miRNAs in left atrium (LA) from patients undergoing cardiac surgery for valve repair, suffering or not from atrial fibrillation (AF) by using TaqMan(r) Low Density arrays (v2.0). RESULTS: Among the 299 miRNAs expressed in all patients, 42 miRNAs had altered basal expressions in patients with AF. Binding-site predictions with Targetscan (conserved sites among species) indicated that the up- and down-regulated miRNAs controlled respectively 3,310 and 5,868 genes. To identify the most relevant cellular functions under the control of the altered miRNAs, we focused on the 100 most targeted genes of each list and identified 5 functional protein-protein networks among these genes. Up regulated networks were involved in synchronisation of circadian rythmicity and in the control of the AKT/PKC signaling pathway (i.e., proliferation/adhesion). Down-regulated networks were the IGF-1 pathway and TGF-beta signaling pathway and a network involved in RNA-mediated gene silencing, suggesting for the first time that alteration of miRNAs in AF would also perturbate the whole miRNA machinery. Then we crossed the list of miRNA predicted genes, and the list of mRNAs altered in similar patients suffering from AF and we found that respectively 44.5% and 55% of the up- and down-regulated mRNA are predicted to be conserved targets of the altered miRNAs (at least one binding site in 3'-UTR). As they were involved in the same biological processes mentioned above, these data demonstrated that a great part of the transcriptional defects previously published in LA from AF patients are likely due to defects at the post-transcriptional level and involved the miRNAs. CONCLUSIONS: Our stringent analysis permitted us to identify highly targeted protein-protein networks under the control of miRNAs in LA and, among them, to highlight those specifically affected in AF patients with altered miRNA signature. Further studies are now required to determine whether alterations of miRNA levels in AF pathology are causal or represent an adaptation to prevent cardiac electrical and structural remodeling. PMID- 29723241 TI - Intra-operative cerebrospinal fluid sampling versus post-operative lumbar puncture for detection of leptomeningeal disease in malignant paediatric brain tumours. AB - INTRODUCTION: Leptomeningeal disease is a feared sequelae of malignant paediatric brain tumours. Current methods for its detection is the combined use of cranio spinal MRI, and CSF cytology from a post-operative lumbar puncture. In this study, the authors hypothesize that CSF taken at the start of surgery, either from an external ventricular drain or neuroendoscope will have equal sensitivity for positive tumour cells, in comparison to lumbar puncture. Secondary hypotheses include positive correlation between CSF cytology and MRI findings of LMD. From a clinical perspective, the key aim of the study was for affected paediatric patients to avoid an additional procedure of a lumbar puncture, often performed under anaesthesia after neurosurgical intervention. METHODS: This is single institution, retrospective study of paediatric patients diagnosed with malignant brain tumours. Its main aim was to compare cytological data from CSF collected at the time of surgery versus data from an interval lumbar puncture. In addition, MRI imaging of the same cohort of patients was examined for leptomeningeal disease and corroborated against CSF tumour cytology findings. RESULTS: Thirty patients are recruited for this study. Data analysis demonstrates a statistically significant association between our intra-operative CSF and LP sampling. Furthermore, our results also show for significant correlation between evidence of leptomeningeal disease on MRI findings versus intra-operative CSF positivity for tumour cells. CONCLUSION: Although this is a retrospective study with a limited population, our data concurs with potential to avoid an additional procedure for the paediatric patient diagnosed with a malignant brain tumour. PMID- 29723243 TI - It's the deceiver, not the receiver: No individual differences when detecting deception in a foreign and a native language. AB - Individual differences in lie detection remain poorly understood. Bond and DePaulo's meta-analysis examined judges (receivers) who were ascertaining lies from truths and senders (deceiver) who told these lies and truths. Bond and DePaulo found that the accuracy of detecting deception depended more on the characteristics of senders rather than the judges' ability to detect lies/truths. However, for many studies in this meta-analysis, judges could hear and understand senders. This made language comprehension a potential confound. This paper presents the results of two studies. Extending previous work, in Study 1, we removed language comprehension as a potential confound by having English-speakers (N = 126, mean age = 19.86) judge the veracity of German speakers (n = 12) in a lie detection task. The twelve lie-detection stimuli included emotional and non emotional content, and were presented in three modalities-audio only, video only, and audio and video together. The intelligence (General, Auditory, Emotional) and personality (Dark Triads and Big 6) of participants was also assessed. In Study 2, a native German-speaking sample (N = 117, mean age = 29.10) were also tested on a similar lie detection task to provide a control condition. Despite significantly extending research design and the selection of constructs employed to capture individual differences, both studies replicated Bond and DePaulo's findings. The results of Study1 indicated that removing language comprehension did not amplify individual differences in judge's ability to ascertain lies from truths. Study 2 replicated these results confirming a lack of individual differences in judge's ability to detect lies. The results of both studies suggest that Sender (deceiver) characteristics exerted a stronger influence on the outcomes of lie detection than the judge's attributes. PMID- 29723242 TI - Adaptation and validation of a short French version of the Drive for Muscularity Scale in male athletes (DMS-FR). AB - The purpose of this paper was to adapt and examine the psychometric properties of a French-language Drive for Muscularity Scale (DMS). First, a preliminary version of the scale, based on both the English-language version of the DMS and the literature on the drive for muscularity, was developed following a committee validation process. Second, the factor structure of the DMS-FR was investigated with principal component analysis (PCA) in a sample of 114 male athletes (Mage = 23.35; SDage = 4.93), leading to a nine-item scale (Study 1). Third, in Study 2, the internal factor structure, temporal stability, and concurrent validity were examined through a series of structural hypothetical modelisation in a sample of 129 male athletes (Mage = 27.03; SDage = 7.81). The results indicated that the scale has good psychometric properties. Specifically, the PCA, and the series of structural hypothetical modelisation, suggested two theoretical factors (i.e., Muscularity Body Dissatisfaction and Muscularity Behaviors), and more, with a bi factor model in a SEM. The results also indicated sufficient concurrent validity with the Male Body Dissatisfaction Scale (MBDS) and adequate internal consistency (Cronbach's alphas were .87 for the Muscularity Body Dissatisfaction subscale, and .88 for the Muscularity Behaviors subscale). The findings overall suggest good reliability and construct validity for this French version of the DMS (DMS FR), which will be useful for future research and clinical practice in French speaking countries. PMID- 29723244 TI - The "social brain" is highly sensitive to the mere presence of social information: An automated meta-analysis and an independent study. AB - How the human brain processes social information is an increasingly researched topic in psychology and neuroscience, advancing our understanding of basic human cognition and psychopathologies. Neuroimaging studies typically seek to isolate one specific aspect of social cognition when trying to map its neural substrates. It is unclear if brain activation elicited by different social cognitive processes and task instructions are also spontaneously elicited by general social information. In this study, we investigated whether these brain regions are evoked by the mere presence of social information using an automated meta analysis and confirmatory data from an independent study of simple appraisal of social vs. non-social images. Results of 1,000 published fMRI studies containing the keyword of "social" were subject to an automated meta-analysis (http://neurosynth.org). To confirm that significant brain regions in the meta analysis were driven by a social effect, these brain regions were used as regions of interest (ROIs) to extract and compare BOLD fMRI signals of social vs. non social conditions in the independent study. The NeuroSynth results indicated that the dorsal and ventral medial prefrontal cortex, posterior cingulate cortex, bilateral amygdala, bilateral occipito-temporal junction, right fusiform gyrus, bilateral temporal pole, and right inferior frontal gyrus are commonly engaged in studies with a prominent social element. The social-non-social contrast in the independent study showed a strong resemblance to the NeuroSynth map. ROI analyses revealed that a social effect was credible in 9 out of the 11 NeuroSynth regions in the independent dataset. The findings support the conclusion that the "social brain" is highly sensitive to the mere presence of social information. PMID- 29723245 TI - Sarcopenia and myosteatosis are accompanied by distinct biological profiles in patients with pancreatic and periampullary adenocarcinomas. AB - INTRODUCTION: Pancreatic and periampullary adenocarcinomas are associated with abnormal body composition visible on CT scans, including low muscle mass (sarcopenia) and low muscle radiodensity due to fat infiltration in muscle (myosteatosis). The biological and clinical correlates to these features are poorly understood. METHODS: Clinical characteristics and outcomes were studied in 123 patients who underwent pancreaticoduodenectomy for pancreatic or non pancreatic periampullary adenocarcinoma and who had available preoperative CT scans. In a subgroup of patients with pancreatic cancer (n = 29), rectus abdominus muscle mRNA expression was determined by cDNA microarray and in another subgroup (n = 29) 1H-NMR spectroscopy and gas chromatography-mass spectrometry were used to characterize the serum metabolome. RESULTS: Muscle mass and radiodensity were not significantly correlated. Distinct groups were identified: sarcopenia (40.7%), myosteatosis (25.2%), both (11.4%). Fat distribution differed in these groups; sarcopenia associated with lower subcutaneous adipose tissue (P<0.0001) and myosteatosis associated with greater visceral adipose tissue (P<0.0001). Sarcopenia, myosteatosis and their combined presence associated with shorter survival, Log Rank P = 0.005, P = 0.06, and P = 0.002, respectively. In muscle, transcriptomic analysis suggested increased inflammation and decreased growth in sarcopenia and disrupted oxidative phosphorylation and lipid accumulation in myosteatosis. In the circulating metabolome, metabolites consistent with muscle catabolism associated with sarcopenia. Metabolites consistent with disordered carbohydrate metabolism were identified in both sarcopenia and myosteatosis. DISCUSSION: Muscle phenotypes differ clinically and biologically. Because these muscle phenotypes are linked to poor survival, it will be imperative to delineate their pathophysiologic mechanisms, including whether they are driven by variable tumor biology or host response. PMID- 29723246 TI - Early changes in rpS6 phosphorylation and BH3 profiling predict response to chemotherapy in AML cells. AB - Blasts from different patients with acute myeloid leukemia (AML) vary in the agent(s) to which they are most responsive. With a myriad of novel agents to evaluate, there is a lack of predictive biomarkers to precisely assign targeted therapies to individual patients. Primary AML cells often survive poorly in vitro, thus confounding conventional cytotoxicity assays. The purpose of this work was to assess the potential of two same-day functional predictive assays in AML cell lines to predict long-term response to chemotherapy. (i) Ribosomal protein S6 (rpS6) is a downstream substrate of PI3K/akt/mTOR/ kinase and MAPK kinase pathways and its dephosphorylation is also triggered by DNA double strand breaks. Phospho-rpS6 is reliably measurable by flow cytometry and thus has the potential to function as a biomarker of responsiveness to several therapeutic agents. (ii) A cell's propensity for apoptosis can be interrogated via a functional assay termed "Dynamic BH3 Profiling" in which mitochondrial outer membrane permeabilization in drug-treated cells can be driven by pro-apoptotic BH3 domain peptides such as PUMA-BH3. The extent to which a particular cell is primed for apoptosis by the drug can be determined by measuring the amount of cytochrome C released on addition of BH3 peptide. We demonstrate that phospho rpS6 expression and PUMA-BH3 peptide-induced cytochrome C release after 4 hours both predict long term chemoresponsiveness to tyrosine kinase inhibitors and DNA double strand break inducers in AML cell lines. We also describe changes in expression levels of the prosurvival BCL-2 family member Mcl-1 and the pro apoptotic protein BIM after short term drug culture. PMID- 29723247 TI - Fc engineering of anti-Nectin-2 antibody improved thrombocytopenic adverse event in monkey. AB - Nectin-2 is a transmembrane glycoprotein which is involved in the process of Ca2+ independent cell-cell adhesion. In our previous study, we have demonstrated that Nectin-2 is over-expressed in breast and ovarian cancer tissues by using gene expression analysis and immunohistochemistry. Furthermore, we discovered multiple anti-Nectin-2 fully human monoclonal antibodies which inhibited tumor growth in in vivo subcutaneous xenograft models with antibody-dependent cellular cytotoxicity (ADCC) as the principal mechanism of action. In this report, we assessed the toxicity of Y-443, a fully human IgG1/kappa anti-Nectin-2 monoclonal antibody exhibiting strong in vitro ADCC and in vivo anti-tumor activity in cynomolgus monkeys (Macaca fascicularis (Cynos)). Unexpectedly, upon administration, Y-443 induced strong thrombocytopenia through Nectin-2 expressed on Cyno platelets, presumably followed by phagocytosis in the mononuclear phagocytic system. To mitigate the adverse safety profile, we mutated the Fc region of Y-443 to reduce the Fc binding activity to Fcgamma receptor I, which is the primary receptor for phagocytosis on macrophages. Moreover, we further engineered the Fc through defucosylation to maintain ADCC activity. The resultant Fc engineered antibody, termed Y-634, demonstrated diminished thrombocytopenia in Cyno toxicological studies and maintained anti-tumor activity in a mouse xenograft model. These findings suggest that Y-634 may have a therapeutic potential for the treatment of Nectin-2 positive cancers, and moreover, Fc engineering is a potential mitigation strategy to ameliorate safety liabilities in antibody induced thrombocytopenia while maintaining antibody potency. PMID- 29723248 TI - Activation of M1 macrophages in sepsis-induced acute kidney injury in response to heparin-binding protein. AB - BACKGROUND: In the early stage of sepsis, M1 macrophages result in the production of inflammatory mediators and AKI. Heparin-binding protein (HBP) have been shown to play important roles in sepsis-induced AKI. In this study, we investigate the association of HBP with M1 macrophages in sepsis-induced AKI. METHODS: Male C57BL6 mice were subjected to cecal ligation and puncture (CLP) or sham surgery. Biochemical and histological renal damage was assessed. Macrophage infiltration was assessed by immunohistochemistry. RT-PCR was used to investigate the expression of heparin-binding protein (HBP), the inducible nitric oxide synthase (iNOS) and arginase 1 (Arg-1) mRNAs. Western blots were performed to assay the tissue levels of HBP, tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6). RESULTS: High levels of HBP were obviously detected 24 h after sepsis induced AKI. Heparin inhibited HBP expression during sepsis-induced AKI. The suppression of HBP expression by heparin injection after the establishment of sepsis-induced AKI resulted in a reduction in renal injury severity accompanied with a significant repression of M1 macrophage activation and expression of TNF alpha and IL-6. CONCLUSIONS: HBP plays an important role in the initial inflammatory reaction associated with sepsis-induced AKI, presumably by activating M1 macrophages and suppressing TNF-alpha and IL-6 secretion. PMID- 29723249 TI - Potentially inappropriate prescribing in Ethiopian geriatric patients hospitalized with cardiovascular disorders using START/STOPP criteria. AB - BACKGROUND: There was a paucity of data on the magnitude of potentially inappropriate prescriptions (PIPs) among Ethiopian elderly cardiovascular patients. OBJECTIVE: The aim of this study was to assess PIPs and associated factors in the elderly population with cardiovascular disorders using the START/STOPP screening criteria. METHODS: A hospital-based cross-sectional study was conducted at medical wards of a teaching hospital in Ethiopia from 1 December 2016-30 May 2017. Included patients were hospitalized elderly patients aged 65 years or older with cardiovascular disorders; their medications were evaluated using the START/STOPP screening criteria from admission to discharge. Multivariable logistic regression was applied to identify factors associated with inappropriate medications. One Way Analysis Of Variance (ANOVA) was carried out to test significant differences on the number of PIPs per individual diagnosis. RESULTS: Two hundred thirty-nine patients were included in the analysis. More than a third of the patients were diagnosed with heart failure, 88 (36.82%). A total of 221 PIPs were identified in 147 patients, resulting in PIP prevalence of 61.5% in the elderly population. Of the total number of PIPs, occurrence of one, two and three PIPs accounted for 83 (56.4%), 52(35.4%), and 12(8.2%) respectively. One way ANOVA test showed significant differences on the mean number of PIPs per individual diagnosis (f = 5.718, p<0.001). Angiotensin Converting Enzyme Inhibitors (ACEIs) were the most common inappropriately prescribed medications, 32(14.5%). Hospital stay, AOR: 1.086 (1.016-1.160), number of medications at discharge, AOR: 1.924 (1.217-3.041) and the presence of co-morbidities, AOR: 3.127 (1.706-5.733) increased the likelihood of PIP. CONCLUSION: Approximately, two-thirds of elderly cardiovascular patients encountered potentially inappropriate prescriptions. ACEIs were the most commonly mis-prescribed medications. Longer hospital stay, presence of comorbidities and prescription of large number of medications at discharge have been correlated with the occurrence of inappropriate medication. It is essential to evaluate patients' medications during hospital stay using the STOPP and START tool to reduce PIPs. PMID- 29723250 TI - Inhibition of the H3K4 methyltransferase SET7/9 ameliorates peritoneal fibrosis. AB - Transforming growth factor-beta1 (TGF-beta1) is a major mediator of peritoneal fibrosis and reportedly affects expression of the H3K4 methyltransferase, SET7/9. SET7/9-induced H3K4 mono-methylation (H3K4me1) critically activates transcription of fibrosis-related genes. In this study, we examined the effect of SET7/9 inhibition on peritoneal fibrosis in mice and in human peritoneal mesothelial cells (HPMCs). We also examined SET7/9 expression in nonadherent cells isolated from the effluent of peritoneal dialysis (PD) patients. Murine peritoneal fibrosis was induced by intraperitoneal injection of methylglyoxal (MGO) into male C57/BL6 mice over 21 days. Sinefungin, a SET7/9 inhibitor, was administered subcutaneously just before MGO injection (10 mg/kg). SET7/9 expression was elevated in both MGO-injected mice and nonadherent cells isolated from the effluent of PD patients. SET7/9 expression was positively correlated with dialysate/plasma ratio of creatinine in PD patients. Sinefungin was shown immunohistochemically to suppress expression of mesenchymal cells and collagen deposition, accompanied by decreased H3K4me1 levels. Peritoneal equilibration tests showed that sinefungin attenuated the urea nitrogen transport rate from plasma and the glucose absorption rate from the dialysate. In vitro, sinefungin suppressed TGF-beta1-induced expression of fibrotic markers and inhibited H3K4me1. These findings suggest that inhibiting the H3K4 methyltransferase SET7/9 ameliorates peritoneal fibrosis. PMID- 29723252 TI - Test-retest reliability of knee extensor rate of velocity and power development in older adults using the isotonic mode on a Biodex System 3 dynamometer. AB - Isotonic testing and measures of rapid power production are emerging as functionally relevant test methods for detection of muscle aging. Our objective was to assess reliability of rapid velocity and power measures in older adults using the isotonic mode of an isokinetic dynamometer. Sixty-three participants (aged 65 to 82 years) underwent a test-retest protocol with one week time interval. Isotonic knee extension tests were performed at four different loads: 0%, 25%, 50% and 75% of maximal isometric strength. Peak velocity (pV) and power (pP) were determined as the highest values of the velocity and power curve. Rate of velocity (RVD) and power development (RPD) were calculated as the linear slopes of the velocity- and power-time curve. Relative and absolute measures of test-retest reliability were analyzed using intraclass correlation coefficients (ICC), standard error of measurement (SEM) and Bland-Altman analyses. Overall, reliability was high for pV, pP, RVD and RPD at 0%, 25% and 50% load (ICC: .85 - .98, SEM: 3% - 10%). A trend for increased reliability at lower loads seemed apparent. The tests at 75% load led to range of motion failure and should be avoided. In addition, results demonstrated that caution is advised when interpreting early phase results (first 50ms). To conclude, our results support the use of the isotonic mode of an isokinetic dynamometer for testing rapid power and velocity characteristics in older adults, which is of high clinical relevance given that these muscle characteristics are emerging as the primary outcomes for preventive and rehabilitative interventions in aging research. PMID- 29723251 TI - Spatiotemporal assessment of spontaneous metastasis formation using multimodal in vivo imaging in HER2+ and triple negative metastatic breast cancer xenograft models in mice. AB - BACKGROUND: Preclinical breast cancer models recapitulating the clinical course of metastatic disease are crucial for drug development. Highly metastatic cell lines forming spontaneous metastasis following orthotopic implantation were previously developed and characterized regarding their biological and histological characteristics. This study aimed to non-invasively and longitudinally characterize the spatiotemporal pattern of metastasis formation and progression in the MDA-MB-231-derived triple negative LM2-4 and HER2+ LM2 4H2N cell lines, using bioluminescence imaging (BLI), contrast enhanced computed tomography (CT), fluorescence imaging, and 2-deoxy-2-[fluorine-18]fluoro-D glucose positron emission tomography ([18F]FDG-PET). MATERIAL AND METHODS: LM2-4, LM2-4H2N, and MDA-MB-231 tumors were established in the right inguinal mammary fat pad (MFP) of female SCID mice and resected 14-16 days later. Metastasis formation was monitored using BLI. Metabolic activity of primary and metastatic lesions in mice bearing LM2-4 or LM2-4H2N was assessed by [18F]FDG-PET. Metastatic burden at study endpoint was assessed by CT and fluorescence imaging following intravenous dual-modality liposome agent administration. RESULTS: Comparable temporal metastasis patterns were observed using BLI for the highly metastatic cell lines LM2-4 and LM2-4H2N, while metastasis formed about 10 days later for MDA-MB-231. 21 days post primary tumor resection, metastases were detected in 86% of LM2-4, 69% of LM2-4H2N, and 60% of MDA-MB-231 inoculated mice, predominantly in the axillary region, contralateral MFP, and liver/lung. LM2-4 and LM2-4H2N tumors displayed high metabolism based on [18F]FDG-PET uptake. Lung metastases were detected as the [18F]FDG-PET uptake increased significantly between pre- and post-metastasis scan. Using a liposomal dual-modality agent, CT and fluorescence confirmed BLI detected lesions and identified additional metastatic nodules in the intraperitoneal cavity and lung. CONCLUSIONS: The combination of complementary anatomical and functional imaging techniques can provide high sensitivity characterization of metastatic disease spread, progression and overall disease burden. The described models and imaging toolset can be implemented as an effective means for quantitative treatment response evaluation in metastatic breast cancer. PMID- 29723253 TI - Why some women fail to give birth at health facilities: A comparative study between Ethiopia and Nigeria. AB - BACKGROUND: Obstetric complications and maternal deaths can be prevented through safe delivery process. Facility based delivery significantly reduces maternal mortality by increasing women's access to skilled personnel attendance. However, in sub-Saharan Africa, most deliveries take place without skilled attendants and outside health facilities. Utilization of facility-based delivery is affected by socio-cultural norms and several other factors including cost, long distance, accessibility and availability of quality services. This study examined country level variations of the self-reported causes of not choosing to deliver at a health facility. METHODS: Cross-sectional data on 37,086 community dwelling women aged between 15-49 years were collected from DHS surveys in Ethiopia (n = 13,053) and Nigeria (n = 24,033). Outcome variables were the self-reported causes of not delivering at health facilities which were regressed against selected sociodemographic and community level determinants. In total eight items complaints were identified for non-use of facility delivery: 1) Cost too much 2) Facility not open, 3) Too far/no transport, 4) don't trust facility/poor service, 5) No female provider, 6) Husband/family didn't allow, 7) Not necessary, 8) Not customary. Multivariable regression methods were used for measuring the associations. RESULTS: In both countries a large proportion of the women mentioned facility delivery as not necessary, 54.9% (52.3-57.9) in Nigeria and 45.4% (42.0-47.5) in Ethiopia. Significant urban-rural variations were observed in the prevalence of the self-reported causes of non-utilisation. Women in the rural areas are more likely to report delivering at health facility as not customary/not necessary and healthy facility too far/no transport. However, urban women were more likely to complain that husband/family did not allow and that the costs were too high. CONCLUSION: Women in the rural were more likely to regard facility delivery as unnecessary and complain about transportation and financial difficulties. In order to achieving the maternal mortality related targets, addressing regional disparities in accessing maternal healthcare services should be regarded as a priority of health promotion programs in Nigeria and Ethiopia. PMID- 29723255 TI - Why we sometimes punish the innocent: The role of group entitativity in collective punishment. AB - Because punishments are expected to give offenders what they deserve proportionally to the severity of their offenses, the punishment of an entire group because of the misdeed of a few of its members is generally considered as unfair. Group entitativity might increase support for such collective punishment, because members of highly entitative groups are perceived as more similar and interchangeable. We designed three experiments comparing support for third-party collective punishment of low versus high entitative groups. As comparison base rate, we included conditions in which participants punish an individual wrongdoer (Experiments 1 & 2). Results show that although support for individual punishment is higher than support for collective punishment, this difference was reduced (Experiment 1) or absent (Experiment 2) when the group was highly entitative. Experiment 3 replicated the increasing effect of group entitativity on support for collective punishment. We conclude that group entitativity increases the likelihood of an entire group being treated as a single unit, facilitating collective punishment when a few group members commit an offense. PMID- 29723254 TI - Carbon stocks of three secondary coniferous forests along an altitudinal gradient on Loess Plateau in inland China. AB - Natural forests in inland China are generally distributed in montane area and secondary due to a semi-arid climate and past anthropogenic disturbances. However, quantification of carbon (C) stock in these forests and the role of altitude in determining C storage and its partition among ecosystem components are unclear. We sampled 54 stands of three secondary coniferous forests (Larix principis-rupprechtii (LP) forest, Picea meyerii (PM) forest and Pinus tabulaeformis (PT) forest) on Loess Plateau in an altitudinal range of 1200-2700m a.s.l. C stocks of tree layer, shrub layer, herb layer, coarse wood debris, forest floor and soil were estimated. We found these forests had relatively high total C stocks. Driven by both higher vegetation and soil C stocks, total C stocks of LP and PM forests in the high altitudinal range were 375.0 and 368.4 t C ha-1 respectively, significantly higher than that of PT forest in the low altitudinal range (230.2 t C ha-1). In addition, understory shrubs accounted for about 20% of total biomass in PT forest. The proportions of vegetation to total C stock were similar among in the three forests (below 45%), so were the proportions of soil C stock (over 54%). Necromass C stocks were also similar among these forests, but their proportions to total C stock were significantly lower in LP and PM forests (1.4% and 1.6%) than in PT forest (3.0%). Across forest types, vegetation biomass and soil C stock simultaneously increased with increasing altitude, causing fairly unchanged C partitioning among ecosystem components along the altitudinal gradient. Soil C stock also increased with altitude in LP and PT forests. Forest floor necromass decreased with increasing altitude across the three forests. Our results suggest the important role of the altitudinal gradient in C sequestration and floor necromass of these three forests in terms of alleviated water conditions and in soil C storage of LP and PM forests in terms of temperature change. PMID- 29723256 TI - Renal protective effect of antiplatelet therapy in antiphospholipid antibody positive lupus nephritis patients without antiphospholipid syndrome. AB - OBJECTIVE: We sought to evaluate the effect of antiplatelet therapy in addition to conventional immunosuppressive therapy for lupus nephritis (LN) patients positive for antiphospholipid antibodies (aPL) without definite antiphospholipid syndrome (APS). METHODS: Patients with biopsy-proven LN class III or IV were retrospectively evaluated. We selected patients positive for anticardiolipin antibody (aCL) or lupus anticoagulant (LA) who did not meet the criteria for a diagnosis of APS. The patients were divided into two subgroups according to whether antiplatelet therapy was received. The cumulative complete renal response (CR) rate, relapse-free rate, and change in estimated glomerular filtration rate (eGFR) over 3 years after induction therapy were calculated. RESULTS: We identified 17 patients who received antiplatelet therapy and 21 who did not. Baseline clinicopathological characteristics and immunosuppressive therapy did not show a significant difference between the two groups except for a higher incidence of LN class IV in the treatment group (p = 0.03). There was no difference in cumulative CR rate, relapse-free rate, or eGFR change between these subgroups. However, when data on LA-positive patients were assessed, an improvement in eGFR was found (p = 0.04) in patients receiving antiplatelet treatment. CONCLUSION: Addition of anti-platelet therapy was associated with an improvement of eGFR in LA-positive patients with LN class III or IV. PMID- 29723258 TI - Causal interpretation of correlational studies - Analysis of medical news on the website of the official journal for German physicians. AB - BACKGROUND: Media frequently draws inappropriate causal statements from observational studies. We analyzed the reporting of study results in the Medical News section of the German medical journal Deutsches Arzteblatt (DA). METHODS: Study design: Retrospective quantitative content analysis of randomly selected news reports and related original journal articles and press releases. A medical news report was selected if headlines comprised at least two linked variables. Two raters independently categorized the headline and text of each news report, conclusions of the abstract and full text of the related journal article, and the press release. The assessment instrument comprised five categories from 'neutral' to 'unconditionally causal'. Outcome measures: degree of matching between 1) news headlines and conclusions of the journal article, 2) headlines and text of news reports, 3) text and conclusions, and 4) headlines and press releases. We analyzed whether news headlines rated as unconditionally causal based on randomized controlled trials (RCTs). RESULTS: One-thousand eighty-seven medical news reports were published between April 2015 and May 2016. The final random sample comprised 176 news reports and 100 related press releases. Degree of matching: 1) 45% (79/176) for news headlines and journal article conclusions, 2) 55% (97/176) for headlines and text, 3) 53% (93/176) for text and conclusions, and 4) 41% (41/100) for headlines and press releases. Exaggerations were found in 45% (80/176) of the headlines compared to the conclusions of the related journal article. Sixty-five of 137 unconditionally causal statements of the news headlines were phrased more weakly in the subsequent news text body. Only 52 of 137 headlines (38%) categorized as unconditionally causal reported RCTs. CONCLUSION: Reporting of medical news in the DA medical journal is misleading. Most headlines that imply causal associations were not based on RCTs. Medical journalists should follow standards of reporting scientific study results. PMID- 29723257 TI - Pharmacological characterization of potent and selective NaV1.7 inhibitors engineered from Chilobrachys jingzhao tarantula venom peptide JzTx-V. AB - Identification of voltage-gated sodium channel NaV1.7 inhibitors for chronic pain therapeutic development is an area of vigorous pursuit. In an effort to identify more potent leads compared to our previously reported GpTx-1 peptide series, electrophysiology screening of fractionated tarantula venom discovered the NaV1.7 inhibitory peptide JzTx-V from the Chinese earth tiger tarantula Chilobrachys jingzhao. The parent peptide displayed nominal selectivity over the skeletal muscle NaV1.4 channel. Attribute-based positional scan analoging identified a key Ile28Glu mutation that improved NaV1.4 selectivity over 100-fold, and further optimization yielded the potent and selective peptide leads AM-8145 and AM-0422. NMR analyses revealed that the Ile28Glu substitution changed peptide conformation, pointing to a structural rationale for the selectivity gains. AM 8145 and AM-0422 as well as GpTx-1 and HwTx-IV competed for ProTx-II binding in HEK293 cells expressing human NaV1.7, suggesting that these NaV1.7 inhibitory peptides interact with a similar binding site. AM-8145 potently blocked native tetrodotoxin-sensitive (TTX-S) channels in mouse dorsal root ganglia (DRG) neurons, exhibited 30- to 120-fold selectivity over other human TTX-S channels and exhibited over 1,000-fold selectivity over other human tetrodotoxin-resistant (TTX-R) channels. Leveraging NaV1.7-NaV1.5 chimeras containing various voltage sensor and pore regions, AM-8145 mapped to the second voltage-sensor domain of NaV1.7. AM-0422, but not the inactive peptide analog AM-8374, dose-dependently blocked capsaicin-induced DRG neuron action potential firing using a multi electrode array readout and mechanically-induced C-fiber spiking in a saphenous skin-nerve preparation. Collectively, AM-8145 and AM-0422 represent potent, new engineered NaV1.7 inhibitory peptides derived from the JzTx-V scaffold with improved NaV selectivity and biological activity in blocking action potential firing in both DRG neurons and C-fibers. PMID- 29723259 TI - Generation and characterization of monoclonal antibodies against the N-terminus of alpha-2-antiplasmin. AB - Around 70% of circulating alpha-2-antiplasmin (alpha2AP), the main natural plasmin inhibitor, is N-terminally cleaved between residues Pro12 and Asn13 by antiplasmin-cleaving enzyme. This converts native Met-alpha2AP into the more potent fibrinolysis inhibitor Asn-alpha2AP. The Arg6Trp (R6W) polymorphism affects the N-terminal cleavage rate of Met-alpha2AP in a purified system, with ~8-fold faster conversion of Met(R6)-alpha2AP than Met(W6)-alpha2AP. To date, assays to determine N-terminally intact Met-alpha2AP in plasma have been limited to an ELISA that only measures Met(R6)-alpha2AP. The aim of this study was to generate and characterize monoclonal antibodies (mAbs) against Met(R6)-alpha2AP, Met(W6)-alpha2AP and all alpha2AP forms (total-alpha2AP) in order to develop specific Met(R6)-alpha2AP and Met(W6)-alpha2AP ELISAs. Recombinant Met(R6) alpha2AP, Met(W6)-alpha2AP and Asn-alpha2AP were expressed in Drosophila S2 cells. Using hybridoma technology, a panel of 25 mAbs was generated against a mixture of recombinant Met(R6)-alpha2AP and Met(W6)-alpha2AP. All mAbs were evaluated for their specific reactivity using the three recombinant alpha2APs in one-site non-competitive ELISAs. Three mAbs were selected to develop sandwich type ELISAs. MA-AP37E2 and MA-AP34C4 were selected for their specific reactivity against Met(R6)-alpha2AP and Met(W6)-alpha2AP, respectively, and used for coating. MA-AP15D7 was selected for its reactivity against total-alpha2AP and used for detection. With the novel ELISAs we determined Met(R6)-alpha2AP and Met(W6)-alpha2AP levels in plasma samples and we showed that Met(R6)-alpha2AP was converted faster into Asn-alpha2AP than Met(W6)-alpha2AP in a plasma milieu. In conclusion, we developed two specific ELISAs for Met(R6)-alpha2AP and Met(W6) alpha2AP, respectively, in plasma. This will enable us to determine N-terminal heterogeneity of alpha2AP in plasma samples. PMID- 29723260 TI - Younger vampire bats (Desmodus rotundus) are more likely than adults to explore novel objects. AB - The effects of age on neophobia and exploration are best described in birds and primates, and broader comparisons require reports from other taxa. Here we present data showing age-dependent exploration in a long-lived social species, the common vampire bat (Desmodus rotundus). A previous study found that vampire bats regurgitated food to partners trapped in a cage. Interestingly, while only a few adult bats visited the trapped bat, in every trial all or most of the eight young males in the colony would visit the trapped bat without feeding it. To test whether this behavioral difference resulted from age class differences in exploration, we compared responses of the bats to a trapped conspecific versus an inanimate novel object. Some adults and young showed interest in trapped conspecifics, but only the young males explored the novel objects. Additional novel object tests in a second captive colony showed that higher rates of novel object exploration were shown by young of both sexes. Our results corroborate past findings from other mammals and birds that age predicts exploration. If age dependent exploration is indeed adaptive, then the role of age as a predictor of exploration tendency should depend on species-specific life history traits. Finally, because younger vampire bats also appear to have higher exposure to pathogens such as rabies virus, there may be implications for pathogen transmission if younger and more exploratory vampire bats are more likely to feed on novel hosts. PMID- 29723261 TI - Microvolt T-wave alternans and autonomic nervous system parameters can be helpful in the identification of low-arrhythmic risk patients with ischemic left ventricular systolic dysfunction. AB - INTRODUCTION: The role of implantable cardioverter-defibrillator (ICD) placement in the primary prevention of sudden cardiac death (SCD) in all consecutive patients with left ventricular ejection fraction (LVEF) <= 35% is still a matter of hot debate due to the fact that the population of these patients is highly heterogeneous in terms of the SCD risk. Nevertheless, reduced LVEF is still the only established criterion during qualification of patients for ICD implantation in the primary prevention of SCD, therefore identification of persons with particularly high risk among patients with LVEF <=35% is currently of lesser importance. More important seems to be the selection of individuals with relatively low risk of SCD in whom ICD implantation can be safely postponed. The aim of the study was to determine whether well-known, non-invasive parameters, such as microvolt T-wave alternans (MTWA), baroreflex sensitivity (BRS) and short term heart rate variability (HRV), can be helpful in the identification of low arrhythmic risk patients with ischemic left ventricular systolic dysfunction. METHODS: In 141 patients with coronary artery disease and LVEF <= 35%, MTWA testing, as well as BRS and short-term HRV parameters, were analysed. During 34 +/- 13 months of follow-up 37 patients had arrhythmic episode (EVENT): SCD, non fatal sustained ventricular arrhythmia (ventricular tachycardia [VT] or ventricular fibrillation [VF]), or adequate high-voltage ICD intervention (shock) due to a rapid ventricular arrhythmia >=200/min. LVEF, non-negative MTWA (MTWA_non-neg), BRS and low frequency power in normalized units (LFnu) turned out to be associated with the incidence of EVENT in univariate Cox analysis. The cut off values for BRS and LFnu that most accurately distinguished between patients with and without EVENT were 3 ms/mmHg and 23, respectively. The only variable that provided 100% negative predictive value (NPV) for EVENT was negative MTWA result (MTWA_neg), but solely for initial 12 months of the follow-up; the NPVs for other potential predictors of the EVENT were lower. The cut-off values for BRS and LFnu that provide 100% NPV for EVENT during 12 and 24 months were higher: 6.0 ms/mmHg and 73 respectively, but the gain in the NPV occurred at an expense of the number of identified patients. However, the number of identified non-risk patients turned out to be higher when the predictive model included MTWA_neg and the lower cut-off values for ANS parameters: 100% NPV for 12 and 24 months of follow-up was obtained for combination MTWA_neg and BRS >= 3 ms/mmHg, for combination MTWA_neg and LFnu >= 23 100% NPV was obtained for 12 months. CONCLUSION: Well-known, non-invasive parameters, such as MTWA, BRS and short-term HRV indices may be helpful in the identification of individuals with a relatively low risk of malignant ventricular arrhythmias among patients with ischemic left ventricular systolic dysfunction; in such persons, implantation of ICD could be safely postponed. PMID- 29723262 TI - Using the Person-Based Approach to optimise a digital intervention for the management of hypertension. AB - BACKGROUND: For behaviour-change interventions to be successful they must be acceptable to users and overcome barriers to behaviour change. The Person-Based Approach can help to optimise interventions to maximise acceptability and engagement. This article presents a novel, efficient and systematic method that can be used as part of the Person-Based Approach to rapidly analyse data from development studies to inform intervention modifications. We describe how we used this approach to optimise a digital intervention for patients with hypertension (HOME BP), which aims to implement medication and lifestyle changes to optimise blood pressure control. METHODS: In study 1, hypertensive patients (N = 12) each participated in three think-aloud interviews, providing feedback on a prototype of HOME BP. In study 2 patients (N = 11) used HOME BP for three weeks and were then interviewed about their experiences. Studies 1 and 2 were used to identify detailed changes to the intervention content and potential barriers to engagement with HOME BP. In study 3 (N = 7) we interviewed hypertensive patients who were not interested in using an intervention like HOME BP to identify potential barriers to uptake, which informed modifications to our recruitment materials. Analysis in all three studies involved detailed tabulation of patient data and comparison to our modification criteria. RESULTS: Studies 1 and 2 indicated that the HOME BP procedures were generally viewed as acceptable and feasible, but also highlighted concerns about monitoring blood pressure correctly at home and making medication changes remotely. Patients in study 3 had additional concerns about the safety and security of the intervention. Modifications improved the acceptability of the intervention and recruitment materials. CONCLUSIONS: This paper provides a detailed illustration of how to use the Person-Based Approach to refine a digital intervention for hypertension. The novel, efficient approach to analysis and criteria for deciding when to implement intervention modifications described here may be useful to others developing interventions. PMID- 29723263 TI - Borrelia burgdorferi adhere to blood vessels in the dura mater and are associated with increased meningeal T cells during murine disseminated borreliosis. AB - Borrelia burgdorferi, the causative agent of Lyme disease, is a vector-borne bacterial infection that is transmitted through the bite of an infected tick. If not treated with antibiotics during the early stages of infection, disseminated infection can spread to the central nervous system (CNS). In non-human primates (NHPs) it has been demonstrated that the leptomeninges are among the tissues colonized by B. burgdorferi spirochetes. Although the NHP model parallels aspects of human borreliosis, a small rodent model would be ideal to study the trafficking of spirochetes and immune cells into the CNS. Here we show that during early and late disseminated infection, B. burgdorferi infects the meninges of intradermally infected mice, and is associated with concurrent increases in meningeal T cells. We found that the dura mater was consistently culture positive for spirochetes in transcardially perfused mice, independent of the strain of B. burgdorferi used. Within the dura mater, spirochetes were preferentially located in vascular regions, but were also present in perivascular, and extravascular regions, as late as 75 days post-infection. At the same end-point, we observed significant increases in the number of CD3+ T cells within the pia and dura mater, as compared to controls. Flow cytometric analysis of leukocytes isolated from the dura mater revealed that CD3+ cell populations were comprised of both CD4 and CD8 T cells. Overall, our data demonstrate that similarly to infection in peripheral tissues, spirochetes adhere to the dura mater during disseminated infection, and are associated with increases in the number of meningeal T cells. Collectively, our results demonstrate that there are aspects of B. burgdorferi meningeal infection that can be modelled in laboratory mice, suggesting that mice may be useful for elucidating mechanisms of meningeal pathogenesis by B. burgdorferi. PMID- 29723264 TI - Dexmedetomidine inhibits inflammatory reaction in the hippocampus of septic rats by suppressing NF-kappaB pathway. AB - Dexmedetomidine (DEX) is known to provide neuroprotective effect in the central nervous system. However, the detailed mechanism remains far more elusive. This study was designed to investigate the relevant mechanisms of DEX's neuroprotective effect. Sprague-Dawley (SD) rats were injected with dexmedetomidine and/or Lipopolysaccharide (LPS) intraperitoneally, and inflammatory cytokines in serum and in the hippocampus were measured by enzyme linked immunosorbent assay (ELISA). NF-kappaB in the brain tissue extracts was analyzed with western-blot. Then, we investigated whether NF-kappaB inhibitor prevents the elevation of inflammatory cytokines in rats injected with LPS. Our results indicated that compared with the control group, the rats exposed to LPS showed significant cognitive dysfunction. When compared to controls, the levels of TNF-alpha and IL-6 in the serum and hippocampus homogenate were increased in rats treated with LPS. DEX pretreatment inhibited the rats' TNF-alpha, IL-6 and NF-kappaB levels induced by LPS. In response to LPS, PDTC pretreatment restrains the production of proinflammatory cytokines (TNF-alpha and IL-6). Rats treated with PDTC and DEX alongside LPS exhibited less TNF-alpha and IL-6 than the LPS treated group. In combination, PDTC and DEX showed addictive effects. Our data suggest that DEX exerts a neuroprotective effect through NF-kappaB in part after LPS-induced cognitive dysfunction. PMID- 29723265 TI - Molecular structures of cdc2-like kinases in complex with a new inhibitor chemotype. AB - Cdc2-like kinases (CLKs) represent a family of serine-threonine kinases involved in the regulation of splicing by phosphorylation of SR-proteins and other splicing factors. Although compounds acting against CLKs have been described, only a few show selectivity against dual-specificity tyrosine phosphorylation regulated-kinases (DYRKs). We here report a novel CLK inhibitor family based on a 6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one core scaffold. Within the series, 3-(3 chlorophenyl)-6,7-dihydropyrrolo[3,4-g]indol-8(1H)-one (KuWal151) was identified as inhibitor of CLK1, CLK2 and CLK4 with a high selectivity margin towards DYRK kinases. The compound displayed a potent antiproliferative activity in an array of cultured cancer cell lines. The X-ray structure analyses of three members of the new compound class co-crystallized with CLK proteins corroborated a molecular binding mode predicted by docking studies. PMID- 29723266 TI - Recognition of early stage thigmotaxis in Morris water maze test with convolutional neural network. AB - The Morris water maze test (MWM) is a useful tool to evaluate rodents' spatial learning and memory, but the outcome is susceptible to various experimental conditions. Thigmotaxis is a commonly observed behavioral pattern which is thought to be related to anxiety or fear. This behavior is associated with prolonged escape latency, but the impact of its frequency in the early stage on the final outcome is not clearly understood. We analyzed swim path trajectories in male C57BL/6 mice with or without bilateral common carotid artery stenosis (BCAS) treatment. There was no significant difference in the frequencies of particular types of trajectories according to ischemic brain surgery. The mouse groups with thigmotaxis showed significantly prolonged escape latency and lower cognitive score on day 5 compared to those without thigmotaxis. As the next step, we made a convolutional neural network (CNN) model to recognize the swim path trajectories. Our model could distinguish thigmotaxis from other trajectories with 96% accuracy and specificity as high as 0.98. These results suggest that thigmotaxis in the early training stage is a predictive factor for impaired performance in MWM, and machine learning can detect such behavior easily and automatically. PMID- 29723267 TI - The maximum evaporative potential of constant wear immersion suits influences the risk of excessive heat strain for helicopter aircrew. AB - The heat exchange properties of aircrew clothing including a Constant Wear Immersion Suit (CWIS), and the environmental conditions in which heat strain would impair operational performance, were investigated. The maximum evaporative potential (im/clo) of six clothing ensembles (three with a flight suit (FLY) and three with a CWIS) of varying undergarment layers were measured with a heated sweating manikin. Biophysical modelling estimated the environmental conditions in which body core temperature would elevate above 38.0 degrees C during routine flight. The im/clo was reduced with additional undergarment layers, and was more restricted in CWIS compared to FLY ensembles. A significant linear relationship (r2 = 0.98, P<0.001) was observed between im/clo and the highest wet-bulb globe temperature in which the flight scenario could be completed without body core temperature exceeding 38.0 degrees C. These findings provide a valuable tool for clothing manufacturers and mission planners for the development and selection of CWIS's for aircrew. PMID- 29723268 TI - An optimized electroporation approach for efficient CRISPR/Cas9 genome editing in murine zygotes. AB - Electroporation of zygotes represents a rapid alternative to the elaborate pronuclear injection procedure for CRISPR/Cas9-mediated genome editing in mice. However, current protocols for electroporation either require the investment in specialized electroporators or corrosive pre-treatment of zygotes which compromises embryo viability. Here, we describe an easily adaptable approach for the introduction of specific mutations in C57BL/6 mice by electroporation of intact zygotes using a common electroporator with synthetic CRISPR/Cas9 components and minimal technical requirement. Direct comparison to conventional pronuclear injection demonstrates significantly reduced physical damage and thus improved embryo development with successful genome editing in up to 100% of living offspring. Hence, our novel approach for Easy Electroporation of Zygotes (EEZy) allows highly efficient generation of CRISPR/Cas9 transgenic mice while reducing the numbers of animals required. PMID- 29723270 TI - Creating an arsenal of Adeno-associated virus (AAV) gene delivery stealth vehicles. AB - The Adeno-associated virus (AAV) gene delivery system is ushering in a new and exciting era in the United States; following the first approved gene therapy (Glybera) in Europe, the FDA has approved a second therapy, Luxturna [1]. However, challenges to this system remain. In viral gene therapy, the surface of the capsid is an important determinant of tissue tropism, impacts gene transfer efficiency, and is targeted by the human immune system. Preexisting immunity is a significant challenge to this approach, and the ability to visualize areas of antibody binding ("footprints") can inform efforts to improve the efficacy of viral vectors. Atomic resolution, smaller proteins, and asymmetric structures are the goals to attain in cryo-electron microscopy and image reconstruction (cryo EM) as of late. The versatility of the technique and the ability to vitrify a wide range of heterogeneous molecules in solution allow structural biologists to characterize a variety of protein-DNA and protein-protein interactions at lower resolution. Cryo-EM has served as an important means to study key surface areas of the AAV gene delivery vehicle-specifically, those involved with binding neutralizing antibodies (NAbs) [2-4]. This method offers a unique opportunity for visualizing antibody binding "hotspots" on the surface of these and other viral vectors. When combined with mutagenesis, one can eliminate these hotspots to create viral vectors with the ability to avoid preexisting host immune recognition during gene delivery and genetic defect correction in disease treatment. Here, we discuss the use of structure-guided site-directed mutagenesis and directed evolution to create "stealth" AAV vectors with modified surface amino acid sequences that allow NAb avoidance while maintaining natural capsid functions or gaining desired novel tropisms. PMID- 29723271 TI - When do we care about political neutrality? The hypocritical nature of reaction to political bias. AB - Claims and accusations of political bias are common in many countries. The essence of such claims is a denunciation of alleged violations of political neutrality in the context of media coverage, legal and bureaucratic decisions, academic teaching etc. Yet the acts and messages that give rise to such claims are also embedded within a context of intergroup competition. Thus, in evaluating the seriousness of, and the need for taking a corrective action in reaction to a purported politically biased act people may consider both the alleged normative violation and the political implications of the act/message for the evaluator's ingroup. The question thus arises whether partisans react similarly to ingroup aiding and ingroup-harming actions or messages which they perceive as politically biased. In three separate studies, conducted in two countries, we show that political considerations strongly affect partisans' reactions to actions and messages that they perceive as politically biased. Namely, ingroup-harming biased messages/acts are considered more serious and are more likely to warrant corrective action in comparison to ingroup-aiding biased messages/acts. We conclude by discussing the implications of these findings for the implementations of measures intended for correcting and preventing biases, and for the nature of conflict and competition between rival political groups. PMID- 29723269 TI - 17beta-Estradiol and/or estrogen receptor alpha signaling blocks protein phosphatase 1 mediated ISO induced cardiac hypertrophy. AB - Earlier studies have shown that estrogen possess protective function against the development of pathological cardiac hypertrophy. However, the molecular mechanisms of estrogens (E2) protective effect are poorly understood. Additionally, abnormal activation of beta-adrenergic signaling have been implicated in the development of pathological cardiac remodeling. However, the role of serine/threonine protein phosphatase 1 (PP1) in pathological cardiac remodeling under the influence of beta-adrenergic signaling have been sparsely investigated. In this study, we assessed the downstream effects of abnormal activation of PP1 upon isoproterenol (ISO) induced pathological cardiac changes. We found that pre-treatment of 17beta-estradiol (E2), tet-on estrogen receptor alpha, or both significantly inhibited ISO-induced increase in cell size, hypertrophy marker gene expression and cytosolic calcium accumulation in H9c2 cells. Additionally, treatment with estrogen receptor inhibitor (ICI) reversed those effects, implicating role of E2 in inhibiting pathological cardiac remodeling. However, specific inhibition of ERalpha using melatonin, reduced ISO induced PP1c expression and enhanced the level of ser-16 phosphorylated phospholamban (PLB), responsible for regulation of sarcoplasmic reticulum Ca2+ ATPase (SERCA) activity. Furthermore, hypertrophic effect caused by overexpression of PP1calpha was reduced by treatment with specific inhibitor of ERalpha. Collectively, we found that estrogen and estrogen receptor-alpha have protective effect against pathological cardiac changes by suppressing PP1 expression and its downstream signaling pathway, which further needs to be elucidated. PMID- 29723272 TI - CT scan exposure in Spanish children and young adults by socioeconomic status: Cross-sectional analysis of cohort data. AB - Recent publications reported that children in disadvantaged areas undergo more CT scanning than others. The present study is aimed to assess the potential differences in CT imaging by socioeconomic status (SES) in Spanish young scanned subjects and if such differences vary with different indicators or different time point SES measurements. The associations between CT scanning and SES, and between the CT scan rate per patient and SES were investigated in the Spanish EPI-CT subcohort. Various SES indicators were studied to determine whether particular SES dimensions were more closely related to the probability of undergoing one or multiple CTs. Comparisons were made with indices based on 2001 and 2011 censuses. We found evidence of socio-economic variation among young people, mainly related to autonomous communities of residence. A slightly higher rate of scans per patient of multiple body parts in the less affluent categories was observed, possibly reflecting a higher rate of accidents and violence in these groups. The number of CT scans per patient was higher both in the most affluent and the most deprived categories and somewhat lower in the intermediate groups. This relation varied with the SES indicator used, with lower CT scans per patients in categories of high unemployment and temporary work, but not depending on categories of unskilled work or illiteracy. The relationship between these indicators and number of CTs in 2011 was different than that seen with the 2001 census, with the number of CTs increasing with higher unemployment. Overall we observed some differences in the SES distribution of scanned patients by Autonomous Community in Spain. There was, however, no major differences in the frequency of CT scans per patient by SES overall, based on the 2001 census. The use of different indicators and of SES data collected at different time points led to different relations between SES and frequency of CT scans, outlining the difficulty of adequately capturing the social and economic dimensions which may affect health and health service utilisation. PMID- 29723273 TI - Distinct roles for REV-ERBalpha and REV-ERBbeta in oxidative capacity and mitochondrial biogenesis in skeletal muscle. AB - The nuclear receptors REV-ERBalpha and REV-ERBbeta have been demonstrated to be core members of the circadian clock and participate in the regulation of a diverse set of metabolic functions. Due to their overlapping tissue expression patterns and gene expression profiles, REV-ERBbeta is thought to be redundant to REV-ERBalpha. Recent work has highlighted REV-ERBalpha's role in the regulation of skeletal muscle oxidative capacity and mitochondrial biogenesis. Considering the similarity between the REV-ERBs and the hypothesized overlap in function, we sought to determine whether REV-ERBbeta-deficiency presented with a similar skeletal muscle phenotype as REV-ERBalpha-deficiency. Ectopic overexpression in C2C12 cells demonstrated that REV-ERBbeta drives mitochondrial biogenesis and the expression of genes involved in fatty acid oxidation. Intriguingly, knock down of REV-ERBbeta in C2C12 cultures also resulted in mitochondrial biogenesis and increased expression of genes involved in fatty acid beta-oxidation. To determine whether these effects occurred in vivo, we examined REV-ERBbeta-deficient mice and observed a similar increase in expression of genes involved in mitochondrial biogenesis and fatty acid beta-oxidation. Consistent with these results, REV ERBbeta-deficient mice exhibited an altered metabolic phenotype compared to wild type littermate controls when measured by indirect calorimetry. This likely compensated for the increased food consumption that occurred, possibly aiding in the maintenance of their weight over time. Since feeding behaviors are a direct circadian output, this study suggests that REV-ERBbeta may have more subtle effects on circadian behaviors than originally identified. Furthermore, these data implicate REV-ERBbeta in the control of skeletal muscle metabolism and energy expenditure and suggest that development of REV-ERBalpha versus REV ERBbeta selective ligands may have therapeutic utility in the treatment of metabolic syndrome. PMID- 29723274 TI - Rapid chemical de-N-glycosylation and derivatization for liquid chromatography of immunoglobulin N-linked glycans. AB - Glycan analysis may result in exploitation of glycan biomarkers and evaluation of heterogeneity of glycosylation of biopharmaceuticals. For N-linked glycan analysis, we investigated alkaline hydrolysis of the asparagine glycosyl carboxamide of glycoproteins as a deglycosylation reaction. By adding hydroxylamine into alkaline de-N-glycosylation, we suppressed the degradation of released glycans and obtained a mixture of oximes, free glycans, and glycosylamines. The reaction was completed within 1 h, and the mixture containing oximes was easily tagged with 2-aminobenzamide by reductive amination. Here, we demonstrated N-linked glycan analysis using this method for a monoclonal antibody, and examined whether this method could liberate glycans without degradation from apo-transferrin containing NeuAc and NeuGc and horseradish peroxidase containing Fuc alpha1-3 GlcNAc at the reducing end. Furthermore, we compared glycan recoveries between conventional enzymatic glycan release and this method. Increasing the reaction temperature and reaction duration led to degradation, whereas decreasing these parameters resulted in lower release. Considering this balance, we proposed to carry out the reaction at 80 degrees C for 1 h for asialo glycoproteins from mammals and at 50 degrees C for 1 h for sialoglycoproteins. PMID- 29723275 TI - Droplet-based microfluidic analysis and screening of single plant cells. AB - Droplet-based microfluidics has been used to facilitate high-throughput analysis of individual prokaryote and mammalian cells. However, there is a scarcity of similar workflows applicable to rapid phenotyping of plant systems where phenotyping analyses typically are time-consuming and low-throughput. We report on-chip encapsulation and analysis of protoplasts isolated from the emergent plant model Marchantia polymorpha at processing rates of >100,000 cells per hour. We use our microfluidic system to quantify the stochastic properties of a heat inducible promoter across a population of transgenic protoplasts to demonstrate its potential for assessing gene expression activity in response to environmental conditions. We further demonstrate on-chip sorting of droplets containing YFP expressing protoplasts from wild type cells using dielectrophoresis force. This work opens the door to droplet-based microfluidic analysis of plant cells for applications ranging from high-throughput characterisation of DNA parts to single cell genomics to selection of rare plant phenotypes. PMID- 29723276 TI - ENTPRISE-X: Predicting disease-associated frameshift and nonsense mutations. AB - To exploit the plethora of information provided by Next Generation Sequencing, the identification of the genetic mutations responsible for disease in general or cancer in particular, among the thousands of neutral germline or somatic variations is a crucial task. Genome-wide association studies for the detection of disease-associated genes or cancer drivers can only identify common variations or driver genes in a cohort of patients. Thus, they cannot discover unique disease-associated mutations or cancer driver genes on a personal basis. Moreover, even when there are such common variations, their significance is unknown. Here, we extend the machine learning based approach ENTPRISE developed for predicting the disease association of missense mutations to frameshift and nonsense mutations. The new approach, ENTPRISE-X, is shown to outperform the state-of-the-art methods VEST-indel and DDIG-in for predicting the disease association of germline frameshift mutations in terms of balanced measure Matthew's correlation coefficient, MCC, with a MCC of 0.586 for ENTPRISE-X, versus 0.412 by VEST-indel and 0.321 by DDIG-in, respectively. Large scale testing on the ExAC dataset shows ENTPRISE-X has a much lower fraction of 16% of variations classified as disease causing, as compared to VEST-indel's 26% and DDIG-in's 65% of predictions as being disease-associated. A web server for ENTPRISE-X is freely available for academic users at http://cssb2.biology.gatech.edu/entprise-x. PMID- 29723277 TI - The mediating role of risk perception in the association between industry-related air pollution and health. AB - BACKGROUND: Heavy industry emits many potentially hazardous pollutants into the air which can affect health. Awareness about the potential health impacts of air pollution from industry can influence people's risk perception. This in turn can affect (self-reported) symptoms. Our aims were to investigate the associations of air pollution from heavy industry with health symptoms and to evaluate whether these associations are mediated by people's risk perception about local industry. METHODS: A cross-sectional questionnaire study was conducted among children (2-18 years) and adults (19 years and above) living in the direct vicinity of an area with heavy industry. A dispersion model was used to characterize individual-level exposures to air pollution emitted from the industry in the area. Associations between PM2.5 and NOX with presence of chronic diseases (adults) and respiratory symptoms (adults and children) were investigated by logistic regression analysis. Risk perception was indirectly measured by worries about local industry (0-10 scale). Mediation analyses were performed to investigate the role of mediation by these worries. RESULTS: The response was 54% (2,627/4,877). In adults exposure to modelled PM2.5 from industry (per MUg/m3) was related with reported high blood pressure (OR 1.56, 95% CI 1.13-2.15) and exposure to modelled NOX (per MUg/m3) was inversely related with cardiovascular diseases (OR 0.91, 95% CI 0.84-0.98). In children higher PM2.5 and NOX concentrations (per MUg/m3) were related with wheezing (OR 2.00, 95% CI 1.24-3.24 and OR 1.13, 95% CI 1.06-1.21 respectively) and dry cough (OR 2.33, 95% CI 1.55-3.52 and OR 1.16, 95% CI 1.10-1.22 respectively). Parental worry about local industry was an important mediator in exposure-health relations in children (indirect effect between 19-28%). CONCLUSION: Exposure from industry was associated with self-reported reported high blood pressure among adults and respiratory symptoms among their children. Risk perception was found to mediate these associations for children. PMID- 29723278 TI - Does pathogen plasticity facilitate host shifts? PMID- 29723279 TI - Water and soil loss from landslide deposits as a function of gravel content in the Wenchuan earthquake area, China, revealed by artificial rainfall simulations. AB - A large number of landslides were triggered by the Mw7.9 Wenchuan earthquake which occurred on 12th May 2008. Landslides impacted extensive areas along the Mingjiang River and its tributaries. In the landslide deposits, soil and gravel fragments generally co-exist and their proportions may influence the hydrological and erosion processes on the steep slopes of the deposit surface. Understanding the effects of the mixtures of soil and gravels in landslide deposits on erosion processes is relevant for ecological reconstruction and water and soil conservation in Wenchuan earthquake area. Based on field surveys, indoor artificial rainfall simulation experiments with three rainfall intensities (1.0, 1.5 and 2.0 mm.min-1) and three proportions of gravel (50%, 66.7% and 80%) were conducted to measure how the proportion of gravel affected soil erosion and sediment yield in landslide sediments and deposits. Where the proportion of gravel was 80%, no surface runoff was produced during the 90 minute experiment under all rainfall intensities. For the 66.7% proportion, no runoff was generated at the lowest rainfall intensity (1.0 mm.min-1). As a result of these interactions, the average sediment yield ranked as 50> 66.6> 80% with different proportions of gravel. In addition, there was a positive correlation between runoff generation and sediment yield, and the sediment yield lagging the runoff generation. Together, the results demonstrate an important role of gravel in moderating the mobilization of landslide sediment produced by large earthquakes, and could lay the foundation for erosion models which provide scientific guidance for the control of landslide sediment in the Wenchuan earthquake zone, China. PMID- 29723280 TI - Prevalence of stunting and its associated factors among children 6-59 months of age in Libo-Kemekem district, Northwest Ethiopia; A community based cross sectional study. AB - BACKGROUND: Children in developing countries are highly vulnerable to impaired physical growth because of poor dietary intake, lack of appropriate care, and repeated infections. This study aimed at assessing the prevalence of stunting and associated factors among children 6-59 months of age in Libo-kemekem district, northwest Ethiopia. METHODS: A community based cross sectional study was conducted in Libo-Kemekem from October 15 to December 15, 2015. The multistage sampling technique was employed to select 1,320 children aged 6-59months. Data were collected by trained community health extension workers under regular supervision. Data were entered into EPI-Info version 3.5.1, and height for age was converted to Z-score with ENA-SMART software. Data were then exported to SPSS version 20 for descriptive and binary logistic regression analysees. The significance of associations was determined at p<0.05. RESULTS: Out of 1287 children included in the analysis, 49.4% (95% CI: 46.7%-52.3%) were found to be stunted. In the multivariate analysis, increased child age [AOR = 6.31, 95%CI: (3.65, 10.91)], family size of six and above [AOR = 1.77, 95%CI: (1.35, 2.32)] were positively associated with stunting, while, fathers with secondary school education [AOR = 0.50, 95%CI: (0.30, 0.81)], farmers as household heads [AOR = 0.56, 95%CI: (0.38, 0.84)] and self-employed parents as household head [AOR = 0.45, 95% CI: (0.28, 0.72)] were found to be preventive factors. CONCLUSION: The prevalence of stunting was high in the study area. We found that stunting was significantly correlated with child age, occupational status of household head, family size, and fathers' education. Therefore, intervention focusing on supporting housewives, family planning, and education on child feeding and nutrition should be implemented. PMID- 29723281 TI - Immunity to LuloHya and Lundep, the salivary spreading factors from Lutzomyia longipalpis, protects against Leishmania major infection. AB - Salivary components from disease vectors help arthropods to acquire blood and have been shown to enhance pathogen transmission in different model systems. Here we show that two salivary enzymes from Lutzomyia longipalpis have a synergist effect that facilitates a more efficient blood meal intake and diffusion of other sialome components. We have previously shown that Lundep, a highly active endonuclease, enhances parasite infection and prevent blood clotting by inhibiting the intrinsic pathway of coagulation. To investigate the physiological role of a salivary hyaluronidase in blood feeding we cloned and expressed a recombinant hyaluronidase from Lu. longipalpis. Recombinant hyaluronidase (LuloHya) was expressed in mammalian cells and biochemically characterized in vitro. Our study showed that expression of neutrophil CXC chemokines and colony stimulating factors were upregulated in HMVEC cells after incubation with LuloHya and Lundep. These results were confirmed by the acute hemorrhage, edema and inflammation in a dermal necrosis (dermonecrotic) assay involving a massive infiltration of leukocytes, especially neutrophils, in mice co-injected with hemorrhagic factor and these two salivary proteins. Moreover, flow cytometry results showed that LuloHya and Lundep promote neutrophil recruitment to the bite site that may serve as a vehicle for establishment of Leishmania infection. A vaccination experiment demonstrated that LuloHya and Lundep confer protective immunity against cutaneous leishmaniasis using the Lu. longipalpis-Leishmania major combination as a model. Animals (C57BL/6) immunized with LuloHya or Lundep showed minimal skin damage while lesions in control animals remained ulcerated. This protective immunity was abrogated when B-cell-deficient mice were used indicating that antibodies against both proteins play a significant role for disease protection. Rabbit-raised anti-LuloHya antibodies completely abrogated hyaluronidase activity in vitro. Moreover, in vivo experiments demonstrated that blocking LuloHya with specific antibodies interferes with sand fly blood feeding. This work highlights the relevance of vector salivary components in blood feeding and parasite transmission and further suggests the inclusion of these salivary proteins as components for an anti-Leishmania vaccine. PMID- 29723282 TI - Chemical composition, in vitro antitumor and pro-oxidant activities of Glandora rosmarinifolia (Boraginaceae) essential oil. AB - The biological properties of essential oils have been demonstrated in the treatment of several diseases and to enhance the bioavailability of other drugs. In natural habitats the essential oils compounds may play important roles in the protection of the plants as antibacterials, antivirals, antifungals, insecticides and also against herbivores by reducing their appetite for such plants or by repelling undesirable others. We analyzed by gas-chromatography mass spectrometry the chemical composition of the essential oil of aerial parts of Glandora rosmarinifolia (Ten.) D.C. Thomas obtained by hydrodistillation and verified some biological activities on a panel of hepatocellular carcinoma cell lines (HA22T/VGH, HepG2, Hep3B) and triple negative breast cancer cell lines (SUM 149, MDA-MB-231). In the essential oil we detected 35 compounds. The results of the biological assays indicate that essential oil of G. rosmarinifolia induces cell growth inhibition at concentration-dependent way in all cell line models. This oil does not seem to possess antioxidant activity, while the cytotoxicity of G. rosmarinifolia essential oil appeared to involve, at least in part, a pro-oxidant mechanism. Our results show for the first time the antitumoral and pro-oxidant activities of G. rosmarinifolia essential oil and suggest that it may represent a resource of pharmacologically active compounds. PMID- 29723284 TI - Correction: Exploring the reproducibility of functional connectivity alterations in Parkinson's disease. AB - [This corrects the article DOI: 10.1371/journal.pone.0188196.]. PMID- 29723283 TI - Tilapia-waste flour as a natural nutritional replacer for bread: A consumer perspective. AB - Six bread formulations with different levels of tilapia-waste flour (BTF0%, BTF2.5%, BTF5%, BTF10%, BTF15%, and BTF20%) were analyzed for nutritional composition and sensory characterization. Tilapia-waste flour (TF) increased (P < 0.05) the lipid, protein and ash contents, and decreased (P < 0.05) the levels of carbohydrates and total dietary fiber. BTF0%, BTF2.5% and BTF5% received the highest (P < 0.05) scores for acceptance and preference. Despite this apparent consumer preference for low or no levels, TF can be added to bread at levels below 12.17% (P < 0.05) without triggering consumer rejection. TF changed (P < 0.05) the sensory characterization of bread because of a disagreeable flavor, aroma, and texture; however, airy appearance, sticky in the teeth and cream color did not influence the overall liking. TF at 5% enhanced the nutritional value while maintaining acceptable sensory scores for bread, constituting a potential strategy to satisfy consumer and industry requirements. PMID- 29723286 TI - Is the relationship between parental abuse and mobile phone dependency (MPD) contingent across neighborhood characteristics? A multilevel analysis of Korean Children and Youth Panel Survey. AB - Research indicates that mobile phone dependency (MPD) is associated with various behavioral and internalizing problems. While a significant amount of findings points to its negative outcomes, there is a dearth of evidence concerning the determinants of MPD. This study focuses on this critical, yet understudied, subject by analyzing the associations between abusive parenting style, neighborhood characteristics, and MPD among youths in South Korea, a country with one of the highest mobile broadband penetration rates in the world. Based on the secondary analysis of two waves of Korean Children and Youth Panel Survey (KCYPS), a government-funded multiyear study, we investigate individual- and contextual-level factors underlying MPD. Findings show that, net of a host of time-lagged controls (including baseline dependency from the previous year), abusive parenting style significantly increases adolescent MPD. After adjusting for individual level characteristics, however, no contextual-level effect is found, i.e., residing in a neighborhood with a relatively higher proportion of parental abuse is not related to greater MPD. Finally, two cross-level interaction effects are observed. First, the association between parental abuse and MPD is weaker in a neighborhood context with better educated inhabitants (more college graduates). Second, it is reinforced in demographically "aged" communities with more elderly residents. PMID- 29723285 TI - Vasostatin-1: A novel circulating biomarker for ileal and pancreatic neuroendocrine neoplasms. AB - BACKGROUND: Chromogranin A (CgA) is a plasma biomarker widely used in the follow up of patients with neuroendocrine neoplasms (NENs). However, its accuracy as a tumor biomarker is relatively low because plasma CgA can increase also in patients with other diseases or in subjects treated with proton-pump inhibitors (PPIs), a class of widely-used drugs. METHODS: In the attempt to identify a more reliable biomarker for NENs, we investigated, by ELISA, the circulating levels of full-length CgA (CgA1-439) and of various CgA-derived fragments in 17 patients with ileal or pancreatic NENs, 10 healthy controls, and 21 healthy volunteers before and after treatment with PPIs. RESULTS: Patients with ileal or pancreatic NENs showed increased plasma levels of total-CgA and CgA1-76 fragment (vasostatin 1, VS-1) compared to controls [median (25th-75th-percentiles); total-CgA: 1.85 nM (1.01-4.28) vs 0.75 nM (0.52-0.89), p = 0.004; VS-1: 2.76 nM (1.09-7.10) vs 0.29 nM (0.26-0.32), p<0.001, respectively], but not of CgA1-439 or CgA1-373 fragment. VS-1 positively correlated with total-CgA (r = 0.65, p<0.001). The Receiver Operating Characteristic area under the curve was 0.9935 for VS-1 and 0.8824 for total-CgA (p = 0.067). Treatment of patients with somatostatin analogues decreased both total-CgA and VS-1. In contrast, administration of PPIs increased the plasma levels of total-CgA, but not of VS-1. CONCLUSION: These findings suggest that plasma VS-1 is a novel biomarker for ileal and pancreatic NENs. Considering that VS-1 is a well-defined fragment not induced by proton-pump inhibitors, this polypeptide might represent a biomarker for NENs diagnosis and follow-up more accurate and easier to standardize than CgA. PMID- 29723288 TI - Food hygiene and safety measures among food handlers in street food shops and food establishments of Dessie town, Ethiopia: A community-based cross-sectional study. AB - INTRODUCTION: In sub-Saharan Africa foodborne disease and foodborne disease outbreaks are frequently ascribed to poor personal hygiene of street food vendors and food handlers in food establishments. Evidence on the level of food hygiene practices and food safety measures among food handlers is required for proper planning and implementation of targeted interventions. In this study, we aimed to determine the level of food hygiene and safety measures among street food vendors and food handlers in food establishments of Dessie Town, Ethiopia. METHOD: A community-based cross-sectional study was performed in Dessie town, Ethiopia from December 2013 to June 2014. Data were collected using a pre-tested structured questionnaire and an observational checklist by a trained data collector among 116 food handlers from 116 food establishments and 19 food handlers from 19 street food vendors. Multivariable logistic regression analysis with 95% confidence interval (CI) was used to identify the factors significantly associated with good level of food hygiene and safety practices. RESULT: Almost three-quarter (72%; 84/116) of food handlers in food establishments had a good level of food hygiene and safety practices compared to nearly half (53%; 10/19) of street food vendors. However, this difference was not statistically significant. Average monthly income of >$21 US (adjusted odds ratio [AOR] = 3.2; 95%CI: 1.3-7.7), availability of service training (AOR = 6.7; 95%CI: 1.8-25), wearing a gown during food handling (AOR = 19; 95%CI: 6.8-51) and medical checkup (AOR = 5.2; 95%CI: 2.1-13) were significantly associated with good levels of food hygiene and safety measures. CONCLUSION: Comprehensive health education and promotion programs through continuous training on food hygiene and safety, with promotion of wearing gown during food handling, regular medical checkups of food handlers and programs that enhance the monthly income of food handlers are promising strategies for promoting proper food handling practices in Dessie town, Ethiopia. PMID- 29723287 TI - A streamlined method for transposon mutagenesis of Rickettsia parkeri yields numerous mutations that impact infection. AB - The rickettsiae are obligate intracellular alphaproteobacteria that exhibit a complex infectious life cycle in both arthropod and mammalian hosts. As obligate intracellular bacteria, rickettsiae are highly adapted to living inside a variety of host cells, including vascular endothelial cells during mammalian infection. Although it is assumed that the rickettsiae produce numerous virulence factors that usurp or disrupt various host cell pathways, they have been challenging to genetically manipulate to identify the key bacterial factors that contribute to infection. Motivated to overcome this challenge, we sought to expand the repertoire of available rickettsial loss-of-function mutants, using an improved mariner-based transposon mutagenesis scheme. Here, we present the isolation of over 100 transposon mutants in the spotted fever group species Rickettsia parkeri. Transposon insertions disrupted genes whose products are implicated in a variety of pathways, including bacterial replication and metabolism, the type IV secretion system, factors with previously established roles in host cell interactions and pathogenesis, or are of unknown function. Given the need to identify critical virulence factors, forward genetic screens such as this will provide an excellent platform to more directly investigate rickettsial biology and pathogenesis. PMID- 29723289 TI - Monoamines differentially modulate neuropeptide release from distinct sites within a single neuron pair. AB - Monoamines and neuropeptides often modulate the same behavior, but monoaminergic peptidergic crosstalk remains poorly understood. In Caenorhabditis elegans, the adrenergic-like ligands, tyramine (TA) and octopamine (OA) require distinct subsets of neuropeptides in the two ASI sensory neurons to inhibit nociception. TA selectively increases the release of ASI neuropeptides encoded by nlp-14 or nlp-18 from either synaptic/perisynaptic regions of ASI axons or the ASI soma, respectively, and OA selectively increases the release of ASI neuropeptides encoded by nlp-9 asymmetrically, from only the synaptic/perisynaptic region of the right ASI axon. The predicted amino acid preprosequences of genes encoding either TA- or OA-dependent neuropeptides differed markedly. However, these distinct preprosequences were not sufficient to confer monoamine-specificity and additional N-terminal peptide-encoding sequence was required. Collectively, our results demonstrate that TA and OA specifically and differentially modulate the release of distinct subsets of neuropeptides from different subcellular sites within the ASIs, highlighting the complexity of monoaminergic/peptidergic modulation, even in animals with a relatively simple nervous system. PMID- 29723290 TI - Detection of Clavibacter michiganensis subsp. michiganensis in viable but nonculturable state from tomato seed using improved qPCR. AB - Clavibacter michiganensis subsp. michiganensis (Cmm) is a seed-borne pathogen that causes bacterial canker disease of tomato. Cmm is typically detected in tomato seeds using quantitative real-time polymerase chain reaction (qPCR) combined with culture-based isolation. The viable but nonculturable (VBNC) state of Cmm may result in the underestimation or false negative detection of the pathogen. In the present study, propidium monoazide (PMA) and its improved structure PMAxx were used to pretreat Cmm prior to DNA extraction, followed by qPCR. Both PMA and PMAxx could bind to the chromosomal DNA of dead bacterial cells and therefore block DNA amplification by PCR. This effect, however, does not occur in living bacterial cells, as the chemicals cannot penetrate through the undamaged cell membrane. Both viable and dead Cmm cells were treated with PMA and PMAxx at various concentrations. With this treatment, the range of the cell population was determined for effective detection. PMAxx showed a better discrimination effect than PMA on the viable and dead cells of Cmm and was therefore used throughout the present study. VBNC cells of Cmm (108 CFU mL-1) was induced by 50 MUM copper sulfate, which was detected at different sampling times up to a month by using both PMAxx-qPCR and flow cytometry assays. The optimal PMAxx concentration was 20 MUM for detecting membrane-intact Cmm cells. High specificity and sensitivity were obtained at Cmm concentrations ranging from 103 to 107 CFU mL-1. The accurate and robust results of PMAxx-qPCR were confirmed by flow cytometry method to detect viable Cmm cells. Furthermore, the PMAxx-qPCR assay was successfully used in detecting VBNC Cmm cells in tomato seeds with as few as 10 seeds per set. PMID- 29723291 TI - Prion protein protects mice from lethal infection with influenza A viruses. AB - The cellular prion protein, designated PrPC, is a membrane glycoprotein expressed abundantly in brains and to a lesser extent in other tissues. Conformational conversion of PrPC into the amyloidogenic isoform is a key pathogenic event in prion diseases. However, the physiological functions of PrPC remain largely unknown, particularly in non-neuronal tissues. Here, we show that PrPC is expressed in lung epithelial cells, including alveolar type 1 and 2 cells and bronchiolar Clara cells. Compared with wild-type (WT) mice, PrPC-null mice (Prnp0/0) were highly susceptible to influenza A viruses (IAVs), with higher mortality. Infected Prnp0/0 lungs were severely injured, with higher inflammation and higher apoptosis of epithelial cells, and contained higher reactive oxygen species (ROS) than control WT lungs. Treatment with a ROS scavenger or an inhibitor of xanthine oxidase (XO), a major ROS-generating enzyme in IAV-infected lungs, rescued Prnp0/0 mice from the lethal infection with IAV. Moreover, Prnp0/0 mice transgenic for PrP with a deletion of the Cu-binding octapeptide repeat (OR) region, Tg(PrPDeltaOR)/Prnp0/0 mice, were also highly susceptible to IAV infection. These results indicate that PrPC has a protective role against lethal infection with IAVs through the Cu-binding OR region by reducing ROS in infected lungs. Cu content and the activity of anti-oxidant enzyme Cu/Zn-dependent superoxide dismutase, SOD1, were lower in Prnp0/0 and Tg(PrPDeltaOR)/Prnp0/0 lungs than in WT lungs. It is thus conceivable that PrPC functions to maintain Cu content and regulate SOD1 through the OR region in lungs, thereby reducing ROS in IAV-infected lungs and eventually protecting them from lethal infection with IAVs. Our current results highlight the role of PrPC in protection against IAV infection, and suggest that PrPC might be a novel target molecule for anti influenza therapeutics. PMID- 29723292 TI - Caenorhabditis elegans susceptibility to Daldinia cf. concentrica bioactive volatiles is coupled with expression activation of the stress-response transcription factor daf-16, a part of distinct nematicidal action. AB - The bionematicidal effect of a synthetic volatile mixture (SVM) of four volatile organic compounds (VOCs) emitted by the endophytic fungus Daldinia cf. concentrica against the devastating plant-parasitic root-knot nematode Meloidogyne javanica has been recently demonstrated in both in vitro and greenhouse experiments. However, the mode of action governing the observed irreversible paralysis of J2 larvae upon exposure to SVM is unknown. To unravel the mechanism underlying the anthelmintic and nematicidal activities, we used the tractable model worm Caenorhabditis elegans. C. elegans was also susceptible to both the fungal VOCs and SVM. Among compounds comprising SVM, 3-methyl-1-butanol, (+/-)-2-methyl-1-butanol, and 4-heptanone showed significant nematicidal activity toward L1, L4 and young adult stages. Egg hatching was only negatively affected by 4-heptanone. To determine the mechanism underlying this activity, we examined the response of C. elegans mutants for glutamate-gated chloride channel and acetylcholine transporter, targets of the nematicidal drugs ivermectin and aldicarb, respectively, to 4-heptanone and SVM. These aldicarb- and ivermectin resistant mutants retained susceptibility upon exposure to 4-heptanone and SVM. Next, we used C. elegans TJ356 strain zIs356 (daf-16::GFP+rol-6), LD1 ldIs7 [skn 1B/C::GFP + pRF4(rol-6(su1006))], LD1171 ldIs3 [gcs-1p::gfp; rol-6(su1006))], CL2166 dvIs19 (gst-4p::GFP) and CF1553 muIs84 (sod-3p::GFP+rol-6), which have mutations in genes regulating multiple stress responses. Following exposure of L4 larvae to 4-heptanone or SVM, there was clear nuclear translocation of DAF 16::GFP, and SKN-1::GFP indicating that their susceptibility involves DAF-16 and SKN1 regulation. Application of 4-heptanone, but not SVM, induced increased expression of, gcs-1::GFP and gst-4::GFP compared to controls. In contrast, application of 4-heptanone or SVM to the sod-3::GFP line elicited a significant decline in overall fluorescence intensity compared to controls, indicating SOD-3 downregulation and therefore overall reduction in cellular redox machinery. Our data indicate that the mode of action of SVM and 4-heptanone from D. cf. concentrica differs from that of currently available nematicides, potentially offering new solutions for nematode management. PMID- 29723293 TI - Elevated androstenedione in young adult but not early adolescent prenatally androgenized female rats. AB - BACKGROUND: Elevated testosterone (T) is routinely reported as a marker of hyperandrogenemia in rodent models for polycystic ovary syndrome (PCOS). In women with PCOS, elevated serum androstenedione (A4) is associated with more severe phenotypes, including a positive correlation with serum T, DHEAS, free androgen index (FAI), LH, and LH/FSH ratio. Furthermore, A4, along with calculated free T and FAI, was identified as one of the best predictors of PCOS in adult women of all ages (18 to > 50 y). OBJECTIVE: The objective of this study was to investigate serum A4 levels in early adolescent and young adult prenatally androgenized (PNA) female rats, a model for PCOS. METHODS: Pregnant rats were injected with 5 mg T daily during gestational days 16-19 (PNA rats, experimental group) or an equal volume of vehicle (control group). Female offspring of both groups had tail vein blood drawn for serum analysis at 8 and 16 weeks of age. ELISAs were used to quantify serum A4 and T levels. RESULTS: Serum A4 and T were elevated in 16-week-old PNA rats compared to controls. There was no significant difference in either hormone at 8 weeks of age. CONCLUSIONS: The PNA rats demonstrated elevated serum A4 and T in young adulthood, as has been observed in women with PCOS, further validating this as a model for PCOS and underscoring the importance of serum A4 elevation as a parameter inherent to PCOS and a rodent model for the disorder. Significant A4 elevation develops between early adolescence and early adulthood in this PNA rat model. PMID- 29723295 TI - Dependence of credit spread and macro-conditions based on an alterable structure model. AB - The fat-tail financial data and cyclical financial market makes it difficult for the fixed structure model based on Gaussian distribution to characterize the dynamics of corporate bonds spreads. Using a flexible structure model based on generalized error distribution, this paper focuses on the impact of macro-level factors on the spreads of corporate bonds in China. It is found that in China's corporate bonds market, macroeconomic conditions have obvious structural transformational effects on bonds spreads, and their structural features remain stable with the downgrade of bonds ratings. The impact of macroeconomic conditions on spreads is significant for different structures, and the differences between the structures increase as ratings decline. For different structures, the persistent characteristics of bonds spreads are obviously stronger than those of recursive ones, which suggest an obvious speculation in bonds market. It is also found that the structure switching of bonds with different ratings is not synchronous, which indicates the shift of investment between different grades of bonds. PMID- 29723294 TI - Probing the role of PPARgamma in the regulation of late-onset Alzheimer's disease associated genes. AB - Peroxisome proliferator-activated receptor-gamma (PPARgamma), is a transcription factor that governs pathways, such as lipid metabolism and immune response, that have been implicated in the etiology of LOAD. Previously, we established HepG2 derived cell-lines with stable knockdown of PPARgamma gene, and showed an increase in mRNA levels of genes mapped in the APOE linkage disequilibrium (LD) region on chromosome 19q13.32, with the greatest effect observed for APOE-mRNA. Here, we extended the analysis using our PPARgamma knockdown model system and investigated the broader effect on expression changes of genes implicated in LOAD via genome wide association studies (GWAS). We applied the nCounter gene expression assay (NanoString) using a panel of twenty-four LOAD-associated genes inferred by proximity to the top significantly associated SNPs. Two independent PPARgamma knockdown cell-lines showed changes in mRNA levels of a total of seven genes compared to a control HepG2 cell-line; six of which, ABCA7, APOE, CASS4, CELF1, PTK2B, and ZCWPW1, were upregulated and one, DSG2, was downregulated upon PPARgamma knockdown. Our results propose that PPARgamma may act as a master regulator of the transcription of several genes involved in LOAD pathogenesis. Our study provided the premise for further analyses including a larger set of genes positioned within a wider range of linkage disequilibrium (LD) regions tagged by all LOAD significantly associated SNPs. PMID- 29723296 TI - Longevity of outstanding sporting achievers: Mind versus muscle. AB - BACKGROUND: While there is strong evidence showing the survival advantage of elite athletes, much less is known about those engaged in mind sports such as chess. This study aimed to examine the overall as well as regional survival of International Chess Grandmasters (GMs) with a reference to the general population, and compare relative survival (RS) of GMs with that of Olympic medallists (OMs). METHODS: Information on 1,208 GMs and 15,157 OMs, respectively, from 28 countries were extracted from the publicly available data sources. The Kaplan-Meier method was used to estimate the survival rates of the GMs. A Cox proportional hazards model was used to adjust the survival for region, year at risk, age at risk and sex, and to estimate the life expectancy of the GMs. The RS rate was computed by matching each GM or OM by year at risk, age at risk and sex to the life table of the country the individual represented. RESULTS: The survival rates of GMs at 30 and 60 years since GM title achievement were 87% and 15%, respectively. The life expectancy of GMs at the age of 30 years (which is near the average age when they attained a GM title) was 53.6 ([95% CI]: 47.7 58.5) years, which is significantly greater than the overall weighted mean life expectancy of 45.9 years for the general population. Compared to Eastern Europe, GMs in North America (HR [95% CI]: 0.51 [0.29-0.88]) and Western Europe (HR [95% CI]: 0.53 [0.34-0.83]) had a longer lifespan. The RS analysis showed that both GMs and OMs had a significant survival advantage over the general population, and there was no statistically significant difference in the RS of GMs (RS [95% CI]: 1.14 [1.08-1.20]) compared to OMs: (RS [95% CI]: 1.09 [1.07-1.11]) at 30 years. CONCLUSION: Elite chess players live longer than the general population and have a similar survival advantage to elite competitors in physical sports. PMID- 29723297 TI - Immigration, citizenship, and the mental health of adolescents. AB - PURPOSE: To examine the reported mental health outcomes of adolescent foreign born non-citizens and adolescent foreign-born U.S. citizens compared to adolescent U.S.-born citizens. METHODS: Using the Strengths and Difficulties Questionnaire in the National Health Interview Survey, we compared mental health status of U.S.-born adolescent citizens to foreign-born citizens and non-citizens in the years 2010-2015, and examined how differences in emotional difficulty changed based on time spent in the U.S. RESULTS: Results suggest that non-citizen adolescents experience better mental health outcomes than U.S.-born citizens. However, the mental health status of foreign-born citizens is indistinguishable from that of the U.S.-born, after accounting for basic socio-demographic characteristics. The prevalence of emotional difficulty experienced by immigrant adolescents increased with a family's duration in the U.S. CONCLUSION: Our findings are consistent with a broader health advantage for the foreign-born, but we present new evidence that the mental health advantage of foreign-born adolescents exists only for non-citizens. PMID- 29723299 TI - Retraction: Novel Approach to Activity Evaluation for Release-Active Forms of Anti-Interferon-Gamma Antibodies Based on Enzyme-Linked Immunoassay. PMID- 29723300 TI - Increased resistance to sudden noise by audio stimulation during early ontogeny in German shepherd puppies. AB - The period of early ontogeny constitutes a time when the physical immaturity of an organism is highly susceptible to external stimuli. Thus, early development plays a major role in shaping later adult behavior. The aim of the study was to check whether stimulating puppies at this early stage in life with sound would improve their responsiveness towards unfamiliar noises during the selection process of the police behavioral test for puppies. The cohort comprised 37 puppies from the litters of three mothers. At the commencement of the experiment the dogs were aged 16 days, rising to the age of 32 days at its close. The mothers and litters of the treatment group were either exposed to radio broadcasts, (see below; three litters totaling 19 puppies), while the control group was not exposed to any radio programs (eight litters totaling 18 puppies). All three mothers had previously experienced both auditory circumstances, as described herein. Ordinary radio broadcasts were played to the puppies in the treatment group three times a day for 20 minute periods, always during feeding time. The cohort was subjected to the so-called Puppy Test, i.e. analysis of the potential of each animal, once the dogs had reached the age of 7 weeks. Such tests included exposure to a sudden noise caused by a shovel (100 dB), noise when alone in a room, and response to loud distracting stimuli (the latter two at 70 dB). Said tasks were rated by the same analyst on a scale of 0-5 points; the better the response of the dog, the higher the score given. The differences between the treatment and control groups were analyzed via Mixed Models (PROC MIXED) in SAS. The animals comprising the treatment group responded with a higher score to the sudden noise caused by the shovel than the control dogs (P<0.01). Interestingly, gender was seen to affect response, with the males scoring more than the females (P<0.1). In conclusion, the results suggested that audio stimulation early in life improved the response of the dogs to intense sudden noise, as caused by the shovel. Therefore, acoustic stimulation during the very early period of life has the potential to raise the necessary skills of dogs for military and police purposes, or civilian life. PMID- 29723298 TI - Oral administration of short chain fatty acids could attenuate fat deposition of pigs. AB - Short chain fatty acids (SCFAs) are the main products of indigestible carbohydrates that are fermented by microbiota in the hindgut. This study was designed to investigate the effects of oral SCFAs administration on the lipid metabolism of weaned pigs. A total of 21 barrows were randomly allocated into three groups, including control group (orally infused with 200 mL physiological saline per day), low dose SCFAs group (orally infused with 200 mL SCFAs containing acetic acid 20.04 mM, propionic acid 7.71 mM and butyric acid 4.89 mM per day), and high dose SCFAs group (orally infused with 200 mL SCFAs containing acetic acid 40.08 mM, propionic acid 15.42 mM and butyric acid 9.78 mM per day). The results showed that the average daily feed intake of SCFAs groups were lower than that of control group (P<0.05). Oral administration of SCFAs decreased the concentrations of triglyceride (TG), total cholesterol (TC), high density lipoprotein-cholesterol and insulin (P<0.05), and increased the leptin concentration in serum (P<0.05). The total fat, as well as TC and TG levels in liver, was decreased by oral SCFAs administration (P<0.05). In addition, SCFAs down-regulated the mRNA expressions of fatty acid synthase (FAS) and sterol regulatory element binding protein 1c (P<0.05), and enhanced the mRNA expression of carnitine palmitoyltransferase-1alpha (CPT-1alpha) in liver (P<0.05). SCFAs also decreased FAS, acetyl-CoA carboxylase (ACC) and peroxisome proliferator activated receptor sigma mRNA expressions in longissimus dorsi (P<0.05). And in abdominal fat, SCFAs reduced FAS and ACC mRNA expressions (P<0.05), and increased CPT-1alpha mRNA expression (P<0.05). These results suggested that oral administration of SCFAs could attenuate fat deposition in weaned pigs via reducing lipogenesis and enhancing lipolysis of different tissues. PMID- 29723301 TI - Genome-wide analysis of the NAC transcription factor family and their expression during the development and ripening of the Fragaria * ananassa fruits. AB - NAC proteins are a family of transcription factors which have a variety of important regulatory roles in plants. They present a very well conserved group of NAC subdomains in the N-terminal region and a highly variable domain at the C terminus. Currently, knowledge concerning NAC family in the strawberry plant remains very limited. In this work, we analyzed the NAC family of Fragaria vesca, and a total of 112 NAC proteins were identified after we curated the annotations from the version 4.0.a1 genome. They were placed into the ligation groups (pseudo chromosomes) and described its physicochemical and genetic features. A microarray transcriptomic analysis showed six of them expressed during the development and ripening of the Fragaria x ananassa fruit. Their expression patterns were studied in fruit (receptacle and achenes) in different stages of development and in vegetative tissues. Also, the expression level under different hormonal treatments (auxins, ABA) and drought stress was investigated. In addition, they were clustered with other NAC transcription factor with known function related to growth and development, senescence, fruit ripening, stress response, and secondary cell wall and vascular development. Our results indicate that these six strawberry NAC proteins could play different important regulatory roles in the process of development and ripening of the fruit, providing the basis for further functional studies and the selection for NAC candidates suitable for biotechnological applications. PMID- 29723302 TI - Preserved SCN4B expression is an independent indicator of favorable recurrence free survival in classical papillary thyroid cancer. AB - Voltage-gated sodium channel beta subunits (encoded by SCN1B to SCN4B genes) have been demonstrated as important multifunctional signaling molecules modulating cellular processes such as cell adhesion and cell migration. In this study, we aimed to explore the expression profiles of SCN4B in papillary thyroid cancer (PTC) and its prognostic value in terms of recurrence-free survival (RFS) in classical PTC. In addition, we also examined the potential effect of DNA methylation on its expression. A retrospective study was performed by using data from available large databases, including the Gene Expression Omnibus (GEO) datasets and the Cancer Genome Atlas (TCGA)-Thyroid Cancer (THCA). Results showed that SCN4B is downregulated at both RNA and protein level in PTC compared with normal thyroid tissues. Preserved SCN4B expression was an independent indicator of favorable RFS in patients with classical PTC, no matter as categorical variables (HR: 0.243, 95%CI: 0.107-0.551, p = 0.001) or as a continuous variable (HR: 0.684, 95%CI: 0.520-0.899, p = 0.007). The methylation status of one CpG site (Chr11: 118,022,316-318) in SCN4B DNA had a moderately negative correlation with SCN4B expression in all PTC cases (Pearson's r = -0.48) and in classical PTC cases (Pearson's r = -0.41). In comparison, SCN4B DNA copy number alterations (CNAs) were not frequent and might not influence its mRNA expression. In addition, no somatic mutation was found in SCN4B DNA. Based on these findings, we infer that preserved SCN4B expression might independently predict favorable RFS in classical PTC. Its expression might be suppressed by DNA hypermethylation, but is less likely to be influenced by DNA CNAs/mutations. PMID- 29723303 TI - Factors associated with the presentation of erosive esophagitis symptoms in health checkup subjects: A prospective, multicenter cohort study. AB - BACKGROUND: We aimed to clarify the factors associated with the presentation of erosive esophagitis (EE) symptoms in subjects undergoing health checkups. METHODS: We utilized baseline data from 7,552 subjects who underwent upper endoscopy for health screening in a prospective, multicenter cohort study. The subjects were asked to complete a questionnaire detailing their upper abdominal symptoms and lifestyle. Based on the heartburn and/or acid regurgitation frequency, the EE subjects were stratified into the following three groups: (1) at least one day a week (symptomatic EE [sEE]), (2) less than one day a week (mild symptomatic EE [msEE]), and (3) never (asymptomatic EE [aEE]). Postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS) were defined according to the Rome III criteria. RESULTS: Of the 1,262 (16.7%) subjects (male 83.8%, mean age 52.6 years) with EE, the proportions of sEE, msEE and aEE were 15.0%, 37.2% and 47.9%, respectively. The sEE group showed significant associations with overlapping EPS (OR: 58.4, 95% CI: 25.2-160.0), overlapping PDS (OR: 9.96, 95% CI: 3.91-26.8), severe hiatal hernia (OR: 2.43, 95% CI: 1.43-4.05), experiencing high levels of stress (OR: 2.20, 95% CI: 1.43-3.40), atrophic gastritis (OR: 1.57, 95% CI: 1.03-2.36) and Los Angeles (LA) grade B or worse (OR: 1.72, 95% CI: 1.12-2.60) in the multivariate analysis. CONCLUSIONS: Approximately one-sixth of EE subjects were symptomatic. A multifactorial etiology, including factors unrelated to gastric acid secretion, was associated with the symptom presentation of EE subjects. PMID- 29723304 TI - Associations between structure and function are different in healthy and glaucomatous eyes. AB - PURPOSE: To assess if there are differences in the structure-function associations between healthy and glaucomatous eyes. METHODS: Structure-function associations were assessed in healthy and glaucomatous eyes in three datasets, globally and in the six sectors of the optic nerve head. Structural parameters included rim area (RA) and retinal nerve fiber layer thickness (RNFLT). Functional parameters included unweighted mean of sensitivity thresholds (MS) and unweighted mean of total deviation values (MD), assessed with standard automated perimetry, short-wavelength automated perimetry, frequency-doubling technology perimetry, or contrast sensitivity perimetry. All structural and functional parameters were expressed as percent of mean normal. SF associations were assessed with correlation analyses (Pearson, Spearman and Kendall). We also assessed the SF associations with linear regression analyses: the generalized estimating equation (GEE) was used to adjust for inter-eye correlations and ordinary least squares (OLS) linear models were used when these adjustments were not necessary. We applied Bonferroni corrections to adjust for the impact of multiple comparisons. RESULTS: Overall, none of the Pearson correlations tested in healthy eyes were significant (correlations ranged from -0.17 to 0.37), whereas 77% of the correlations tested in glaucomatous eyes were significant (correlations ranged from 0.01 to 0.79). Similarly, none of the slopes obtained with GEE and OLS were significant in healthy eyes (slopes ranged from -0.30 to 0.87), whereas 82% of the slopes obtained in glaucomatous eyes were significant (slopes ranged from 0.02 to 1.38). CONCLUSIONS: Significant associations between structure and function were consistently observed in glaucomatous eyes, but not in healthy eyes. These differences in association should be considered in the design of structure-function models for progression. PMID- 29723306 TI - Impact of consumer power on consumers' reactions to corporate transgression. AB - We addressed how individuals' power influences their judgments regarding corporate transgressions. Based on the Situated Focus Theory of Power, which theorizes that powerful people respond more in accordance to circumstantial factors, we tested the interaction of power and the type of corporate discourse offered by the accused company. Across two studies (overall N = 216), we experimentally primed power (Study 1) and manipulated participants' sense of direct control over the company (Study 2). We consistently found an interaction effect of power and corporate discourse on people's negative attitudes toward the company-particularly on the unwillingness to use the company's products. Particularly, high-power individuals were prone to strongly vary their attitudes based on the mitigative/non-mitigative nature of the discourse, while those low in power were unsusceptible to the type of discourse. The results suggest how the potential rise of consumer power in society may critically influence the consumer corporate relationships following corporate transgressions. PMID- 29723305 TI - ESCRT machinery components are required for Orthobunyavirus particle production in Golgi compartments. AB - Peribunyaviridae is a large family of RNA viruses with several members that cause mild to severe diseases in humans and livestock. Despite their importance in public heath very little is known about the host cell factors hijacked by these viruses to support assembly and cell egress. Here we show that assembly of Oropouche virus, a member of the genus Orthobunyavirus that causes a frequent arboviral infection in South America countries, involves budding of virus particles toward the lumen of Golgi cisternae. As viral replication progresses, these Golgi subcompartments become enlarged and physically separated from Golgi stacks, forming Oropouche viral factory (Vfs) units. At the ultrastructural level, these virally modified Golgi cisternae acquire an MVB appearance, and while they lack typical early and late endosome markers, they become enriched in endosomal complex required for transport (ESCRT) proteins that are involved in MVB biogenesis. Further microscopy and viral replication analysis showed that functional ESCRT machinery is required for efficient Vf morphogenesis and production of infectious OROV particles. Taken together, our results indicate that OROV attracts ESCRT machinery components to Golgi cisternae to mediate membrane remodeling events required for viral assembly and budding at these compartments. This represents an unprecedented mechanism of how viruses hijack host cell components for coordinated morphogenesis. PMID- 29723308 TI - Correction: Cross-species multiple environmental stress responses: An integrated approach to identify candidate genes for multiple stress tolerance in sorghum (Sorghum bicolor (L.) Moench) and related model species. AB - [This corrects the article DOI: 10.1371/journal.pone.0192678.]. PMID- 29723309 TI - Correction: Comparative study of impaction and sedimentation in an aerosol chamber using defined fungal spore and bacterial concentrations. AB - [This corrects the article DOI: 10.1371/journal.pone.0187039.]. PMID- 29723307 TI - Contributions from the silent majority dominate dengue virus transmission. AB - Despite estimates that, each year, as many as 300 million dengue virus (DENV) infections result in either no perceptible symptoms (asymptomatic) or symptoms that are sufficiently mild to go undetected by surveillance systems (inapparent), it has been assumed that these infections contribute little to onward transmission. However, recent blood-feeding experiments with Aedes aegypti mosquitoes showed that people with asymptomatic and pre-symptomatic DENV infections are capable of infecting mosquitoes. To place those findings into context, we used models of within-host viral dynamics and human demographic projections to (1) quantify the net infectiousness of individuals across the spectrum of DENV infection severity and (2) estimate the fraction of transmission attributable to people with different severities of disease. Our results indicate that net infectiousness of people with asymptomatic infections is 80% (median) that of people with apparent or inapparent symptomatic infections (95% credible interval (CI): 0-146%). Due to their numerical prominence in the infectious reservoir, clinically inapparent infections in total could account for 84% (CI: 82-86%) of DENV transmission. Of infections that ultimately result in any level of symptoms, we estimate that 24% (95% CI: 0-79%) of onward transmission results from mosquitoes biting individuals during the pre-symptomatic phase of their infection. Only 1% (95% CI: 0.8-1.1%) of DENV transmission is attributable to people with clinically detected infections after they have developed symptoms. These findings emphasize the need to (1) reorient current practices for outbreak response to adoption of pre-emptive strategies that account for contributions of undetected infections and (2) apply methodologies that account for undetected infections in surveillance programs, when assessing intervention impact, and when modeling mosquito-borne virus transmission. PMID- 29723310 TI - The Effects of Sleeping With or Without Prostheses on Sleep Quality, Sleep Bruxism, and Signs of Obstructive Sleep Apnea Syndrome: A Pilot Study. AB - PURPOSE: To evaluate the effects of sleeping with or without a maxillary mucosa supported complete denture (CD) in edentulous patients wearing a mandibular fixed implant-supported CD on sleep quality, sleep bruxism (SB) activity, and signs of obstructive sleep apnea syndrome (OSAS). MATERIALS AND METHODS: A total of 18 female patients with maxillary mucosa-supported CDs opposing mandibular fixed implant-supported CDs were selected and tested for sleep quality, SB activity, and signs of OSAS during one night while wearing the maxillary CD and another night without wearing it, with a washout period of 7 days in between. The validated Brazilian Portuguese versions of the Pittsburgh Sleep Quality Index (PSQI-BR), Sleep Assessment Questionnaire (SAQ), and Epworth Sleepiness Scale (ESSBR) were used to assess subjective sleep quality. Diagnosis of OSAS followed the American Academy of Sleep Medicine (AASM) guidelines and was confirmed with an objective and validated type 3 portable cardiorespiratory monitor (ApneaLink Plus v.9.00) by measuring the respiratory disturbance index (RDI). SB activity was assessed with a subjective self-report questionnaire and an objective and validated portable electromyographic device (BiteStrip). RESULTS: The objective measurements of SB activity and the RDI showed significant reduction (ie, improvement) when patients did not wear the maxillary CD. The subjective measurements of sleep quality and self-reports of SB activity showed no significant differences between wearing and not wearing a maxillary CD. CONCLUSION: The present results have shown that not wearing a maxillary CD at night is preferable as far as SB and OSAS are concerned, but larger-scale studies are still needed. PMID- 29723311 TI - Oromandibular Dystonia-Related Temporomandibular Joint Osteoarthritis: A Case History Report. AB - Dystonia affecting the perioral and pharyngeal regions is called oromandibular dystonia (OMD). OMD can affect the jaw muscles and may cause trismus, mouth closing disturbance, tooth wear/loss, and damage to the oral soft tissues and temporomandibular joint (TMJ). This case history reports a case of jaw-closing OMD accompanied by trismus-related TMJ osteoarthritis (OA). In the present case history, treatment for OMD was started as soon as the diagnosis of jaw-closing OMD was established, and dental treatment intervention for preventing its development or progression was considered at the same time. PMID- 29723312 TI - Adhesive Failure of Lava Ultimate and Lithium Disilicate Crowns Bonded to Zirconia Abutments: A Prospective Within-Patient Comparison. AB - PURPOSE: To demonstrate the influence of restorative material on the success of clinical bonding to zirconia. MATERIALS AND METHODS: A total of 50 participants with a single implant received screw-retained restorations; ie, Lava Ultimate (LU) crowns extraorally bonded to zirconia abutments. After 1 year, lithium disilicate (LDS) was used as an alternative restorative material. These restorations were also followed for 1 year. RESULTS: Forty LU restorations (80%) debonded within 1 year of clinical service, whereas no bonding failures occurred with LDS restorations. CONCLUSION: The choice of restorative material for single crowns luted to zirconia implant abutments strongly influences the incidence of bonding failures. PMID- 29723313 TI - A Five-Year Retrospective Assay of Implant Treatments and Complications in Private Practice: Restorative Treatment Profiles of Long-Span, Implant-Supported Fixed and Removable Dental Prostheses. AB - PURPOSE: To describe the restorative treatment profiles of long-span (> three units), implant-supported dental prostheses (LIDPs) prescribed in 27 private practices in the state of Victoria, Australia, during the period from January 1, 2005, to December 31, 2009. The restorative treatment profiles of these prostheses refer to the framework/veneering materials, number of prosthetic units/supporting implants, location in the oral cavity, retention methods, and cantilever designs. LIDPs refer to implant-supported prostheses of fixed or removable design; namely, fixed partial dentures (IFPDs), fixed complete dentures (IFCDs), removable partial dentures (IRPDs), and complete overdentures (IODs). MATERIALS AND METHODS: Private dental practitioners providing implant treatment in Victoria, Australia, were invited to enroll in this study, which was conducted through a dental practice-based research network (the eviDent Foundation). The enrolled practitioners' clinical records of the implant treatments provided during the specified period were accessed for data collection. Descriptive statistics, cross-tabulations, and linear mixed models were conducted for data analyses. RESULTS: During the study period, 627 LIDPs were prescribed to 556 patients by 18 general dentists and 5 prosthodontists. LIDPs were more common in the maxilla than in the mandible except in the case of IODs. Of the fixed prostheses, 60% replaced missing teeth in more than one sextant, 33% in the anterior sextant, and 7% in the posterior sextant. The average number of prosthetic units per implant was higher in mandibular compared to maxillary IFPDs/IFCDs (2.5 vs 1.9, respectively, P < .001). Cantilever pontic(s) were present in 68% of IFCDs (more often in the mandible than in the maxilla) compared to 28% of IFPDs (use of cantilever pontics was about the same in the maxilla and mandible). Screw retention was the most commonly reported retention method in IFPDs/IFCDs (95%). Locator attachment was used for the majority of IRPDs/IODs (83%). CONCLUSION: The clinicians enrolled in this study preferred fixed over removable LIDPs for partially dentate and maxillary edentulous cases. For mandibular edentulous patients, IODs were prescribed more often than IFCDs. A retrievable retention design was favored for IFPDs/IFCDs. IFPDs were predominantly metal-ceramic, and metal-acrylic designs were more popular for IFCDs. PMID- 29723315 TI - Technical Report: Crown Fabrication Without an Impression. AB - Prosthetic treatment for elderly patients is a challenge that addresses both patient- and technology-mediated dental concerns. This report describes the fabrication of a cobalt-chromium crown without an impression using a digitized and scanned temporary crown to provide excellent integration. PMID- 29723314 TI - Factors Associated with Sleep Quality in Maxillectomy Patients. AB - PURPOSE: To investigate factors affecting sleep quality in maxillectomy patients after prosthetic rehabilitation and to determine the association between defect status and sleep quality. MATERIALS AND METHODS: A total of 57 patients participated in this study. Sleep quality, general health, and oral health related quality of life (OHRQoL) were evaluated. RESULTS: Of the total sample, 89% had poor sleep quality. Early morning awakening and daytime sleepiness were the most common complaints. CONCLUSION: Defect status and the extent of neck dissection could affect sleep quality in these patients. Improvement of OHRQoL in patients with dentomaxillary prostheses may help improve sleep. PMID- 29723316 TI - Geometric Evaluation of the Effect of Prosthetic Rehabilitation on Facial Asymmetry in Patients with Unilateral Maxillectomy. AB - PURPOSE: This study aimed (1) to geometrically evaluate areas of facial asymmetry in patients with two different types of maxillectomy defect compared to a control group, (2) to geometrically evaluate the effect of an obturator prosthesis on facial asymmetry, and (3) to investigate the correlation between three dimensional (3D) deviation values and number of missing teeth. MATERIALS AND METHODS: Facial data from 13 normal control participants and 26 participants with two types of maxillectomy defect (groups 1 and 2) were acquired with a noncontact 3D digitizer. Facial asymmetry was evaluated by superimposing a facial scan onto its mirror scan using 3D evaluation software. Facial scans with and without obturator prostheses were also superimposed to evaluate the obturator effect. The correlation between 3D deviation values and number of missing teeth was also evaluated. Statistical analyses were performed. RESULTS: Facial asymmetry was significantly different between the control group and each maxillectomy defect group (group 1: P < .0001 and P = .020 without and with obturator, respectively; group 2: P < .0001 for both conditions). There were no significant differences in asymmetry between groups 1 and 2 either without or with obturator (P = .457 and P = .980, respectively). There was a significant difference in the obturator effect between groups 1 and 2 (P = .038). 3D deviation values were positively correlated with number of missing teeth in group 1 (r = 0.594, P = .032), but not in group 2. CONCLUSION: A noncontact 3D digitizer and 3D deviation assessment were effective for analyzing facial data of maxillectomy patients. Obturators were effective for improving facial deformities in these patients. PMID- 29723317 TI - Accuracy of Milled Titanium Frameworks Constructed with Direct Scanning and Splinted Impression Techniques. AB - PURPOSE: To compare vertical microgaps of milled titanium implant frameworks constructed using (1) direct model scanning (DMS) and (2) splinted impression (SIM) techniques. MATERIALS AND METHODS: Three BioHorizon external hex implants were embedded in an epoxy resin model, and convenience samples of four identical frameworks in the DMS group and five in the SIM group were constructed. Implant framework interfaces were scanned with a microcomputed tomography (CT) scanner, and the vertical microgap measured with one-screw and two-screw tests using CT analyzer (CTAn) software. RESULTS: The mean maximum vertical microgap measured using the one-screw test was 13.25 MUm in the DMS group and 72.40 MUm in the SIM group (P < .0001). The mean maximum vertical microgap measured using the two screw test was 10.5 MUm in the DMS group and 36.2 MUm in the SIM group (P = .0002). CONCLUSION: The milled titanium frameworks produced from direct scanning of implants had a smaller vertical microgap than frameworks produced from splinted impressions and master models. PMID- 29723318 TI - Do Type 1 Diabetes Mellitus and Color-Vision Deficiencies Influence Shade Matching Ability? AB - PURPOSE: To evaluate the effect of color-vision deficiencies and type 1 diabetes mellitus (DM) on visual shade-matching ability. MATERIALS AND METHODS: Four groups of participants were investigated: a control group (n = 68); a group with protanomalia (n = 10); a group with deuteranomalia (n = 19); and a group with type 1 DM (n = 13). Color vision was evaluated monocularly using the Ishihara test, Farnsworth-Munsell 100 hue (FM100H) test, Hardy Rand Rittler (HRR) test, and with an HMC Anomaloskop MR (Rayleigh and Moreland tests). The final exam was on a Toothguide Training Box (TTB) and consisted of 15 lightness-chroma-hue tasks. The color difference (DeltaE*ab) and the shade-matching score (SigmaDeltaE*ab) were computed, and the correct lightness (L*), chroma (C*), and hue (h*) selections were counted. The means and standard deviations for the SigmaDeltaE*ab, DeltaE*ab, L*, C*, h*, Ishihara, HRR, FM100H, and Rayleigh and Moreland tests were calculated. One-way analysis of variance (ANOVA) and post hoc Bonferroni test were used for statistical analyses and a comparison of means (alpha = .05). The data analyses were performed using SPSS 22.0 for Windows (IBM). RESULTS: The control group selected the shade tab on the TTB significantly better (SigmaDeltaE*ab = 31.57 +/- 13.50) than the group with protanomalia (SigmaDeltaE*ab = 55.50 +/- 12.36; P < .0001) and the group with deuteranomalia (SigmaDeltaE*ab = 59.18 +/- 16.35; P < .0001), but not significantly better than the group with type 1 DM (SigmaDeltaE*ab = 39.43 +/- 11.46; P = .368). The group with type 1 DM selected the shade tab on the TTB significantly better than the group with protanomalia (P = .038) and the group with deuteranomalia (P < .0001). CONCLUSION: Participants with color-vision deficiencies are less accurate at shade matching than the control group and the group with type 1 DM. PMID- 29723319 TI - Prosthetic Tooth Replacement in a German Population Over the Course of 11 Years: Results of the Study of Health in Pomerania. AB - PURPOSE: To evaluate changes in distribution of teeth and in prosthodontic tooth replacement during an 11-year period in an adult population. MATERIALS AND METHODS: Information on prosthetic status was collected from 4,288 participants aged 20 to 81 years at baseline in the Study of Health in Pomerania (SHIP-0) and from 2,244 participants aged 30 to 92 years who reappeared in the 11-year follow up (SHIP-2). The tooth distribution per arch was classified into one of the six following classes: class 0 (edentulous), class 1 (one to three remaining teeth), class 2 (extended tooth-bounded space or extreme shortened dental arch), class 3 (small anterior space), class 4 (small posterior space with one or more missing premolars), or class 5 (functional dentition). RESULTS: Longitudinally, the most pronounced change in class was the transition from class 1 to class 0 (maxilla: 54.5%, mandible: 58.3%). The percent change from other higher classes to lower classes ranged between 10% and 40%. In the same age groups of 40 to 79 years, the number of edentate arches was cut in half, with a corresponding increase in functional dentitions. The proportion of unrestored arches decreased in all classes. Double crown-retained partial removable dental prostheses (PRDPs) showed the highest increase (a 15% to 20% increase) at the expense of acrylic PRDPs in classes 1 and 2. In small spaces, the proportion of fixed dental prostheses (FDPs) also increased by 15% to 20%. Seven participants of SHIP-0 (0.16%) and 56 participants of SHIP-2 (2.5%) had dental implants. CONCLUSION: Similar age groups showed improvement in oral conditions. The proportion of higher-end restorations (FDPs and double crown-retained PRDPs), including the frequency of dental implants, increased. PMID- 29723320 TI - The Effect of Too Much Caring: A Preliminary Study. AB - PURPOSE: To determine the presence of burnout and psychiatric morbidity among prosthodontic residents and prosthodontists working in a maxillofacial prosthetic clinic and to compare these outcomes between those treating cancer patients and those not treating cancer patients. MATERIALS AND METHODS: Two questionnaires were used: the Maslach Burnout Inventory (MBI) and the General Health Questionnaire (GHQ-12). MBI assesses the three components of burnout (emotional exhaustion, depersonalization, and personal accomplishment), and the GHQ-12 screens for nonpsychotic psychiatric morbidity. Six residents and four specialists involved in managing head and neck cancer patients were referred to as cancer clinicians to distinguish them from the specialists not involved in managing cancer patients (noncancer clinicians), who served as controls for other stressors within this work environment. RESULTS: Twelve (86%) questionnaires were returned. There were no statistically significant (P = .89) differences between the cancer and noncancer clinicians from the GHQ-12 results; however, the cancer clinicians showed increased levels of exhaustion and depersonalization. These differences were not statistically significant (P = .36 and P = .41, respectively), but the effect sizes (Cohen's d) were moderate. For personal accomplishment both groups scored in the moderate burnout range, with the noncancer clinicians scoring higher. CONCLUSION: There is no doubt that the clinicians participating in this preliminary study were under some stress, and a moderate effect size indicated that cancer clinicians experience this to a greater extent. PMID- 29723321 TI - Strategic Use of Microscrews for Enhancing the Accuracy of Computer-Guided Implant Surgery in Fully Edentulous Arches: A Case History Report. AB - Implant guide systems can be classified by their supporting structure as tooth-, mucosa-, or bone-supported. Mucosa-supported guides for fully edentulous arches show lower accuracy in implant placement because of errors in image registration and guide positioning. This article introduces the application of a novel microscrew system for computer-aided implant surgery. This technique can markedly improve the accuracy of computer-guided implant surgery in fully edentulous arches by eliminating errors from image fusion and guide positioning. PMID- 29723322 TI - In Vitro Fatigue and Fracture Testing of Implant-Supported Anterior Ceramic Crowns. AB - PURPOSE: To evaluate the fatigue and fracture resistance of anterior implant supported and tooth-supported crowns made of different monolithic ceramics. MATERIALS AND METHODS: Anterior crowns were fabricated of lithium disilicate or one of two zirconia ceramics and were tested as tooth-supported (reference) or as implant-supported crowns with chairside or labside (screw channel) procedures. After thermocycling and mechanical loading (TCML), crowns were loaded to fracture. RESULTS: All crowns survived TCML. Implant-supported crowns (chairside and labside) showed higher fracture values than tooth-supported crowns. Fracture resistance was comparable or higher for zirconia than for lithium disilicate crowns. CONCLUSION: Implant-supported ceramic crowns may withstand clinical anterior loading forces. PMID- 29723323 TI - Repair Success of Two Innovative Hybrid Materials as a Function of Different Surface Treatments. AB - PURPOSE: To evaluate surface treatments for chipping in order to avoid bonding problems between hybrid materials and composite resin and to determine the optimal surface treatment method during intraoral repair of restorations to achieve clinical success. MATERIALS AND METHODS: A total of 96 samples were prepared from computer-aided design/computer-assisted manufactured (CAD/CAM) blocks: 48 polymer-infiltrated ceramic (PIC) and 48 resin nano-ceramic (RNC). Prior to application of the surface treatments, the two test groups were each divided into four subgroups: control group; hydrofluoric acid group; hydrofluoric acid with silane group; and air-abraded with silica-coated aluminum oxide (Al2O3) sand with silane group. Each subgroup contained 12 samples. A shear bond strength (SBS) test was performed after artificial aging (5,000 cycles, 5 degrees C to 55 degrees C). RESULTS: For both types of ceramic used, all subgroups showed significantly higher SBS values than the control groups (P < .05). The highest SBS values for both types of ceramic were observed in the air-abraded with silica coated Al2O3 particles group. CONCLUSION: Each of the surface treatment methods increased the SBS, with the most effective method being air abrasion with silica coated Al2O3. PMID- 29723324 TI - Relationship Between Quality of Complete Dentures and User Satisfaction at 1 and 5 Years Postinsertion. AB - AIMS: To evaluate the effects of complete denture (CD) quality and user satisfaction on the use of CDs provided by primary care services at 1 and 5 years postinsertion. MATERIALS AND METHODS: A random sample of 233 individuals were evaluated regarding the use of maxillary and/or mandibular CDs at 1 and 5 years after insertion; at both time points, denture quality, integrity, and user satisfaction were measured. The covariates included age, gender, marital status, years of education, family income, past use of CD, time since maxillary teeth loss, mandibular ridge height, and frequency of return visits to the dentist after receiving the prostheses. The effect of the variables on the use of CDs throughout the period was estimated using logistic regression models with random effects in the intercept. RESULTS: Overall, 64.9% and 64.1% of the participants were using their CD at 1 and 5 years, respectively. Of those who used the pair of prostheses at 5 years, 86.3% reported using them in the first evaluation. Use of CDs at 1 year was greater among users with some degree of education, higher satisfaction, and those whose CD had adequate stability and free functional space. Use of CDs at 5 years was greater in satisfied users and those with a stable CD. CONCLUSION: Denture quality and user satisfaction were associated with the use of CDs after 1 and 5 years. CD use was greater in individuals who had used it for 1 year, indicating greater abandonment in the first year than in other periods. PMID- 29723325 TI - Maintenance of the Maxillomandibular Position with Digital Workflow in Oral Rehabilitation: A Technical Note. AB - Prosthodontic oral rehabilitation procedures are time consuming and require efforts to maintain the confirmed maxillomandibular relationship. Several occlusal registrations and impressions are needed, and cross-mounting is performed to transfer the diagnostic wax-up to master working casts. The introduction of a digital workflow protocol reduces steps in the required process, and occlusal registrations with less deformation are used. The outcome is a maintained maxillomandibular position that is accurately and conveniently transferred. PMID- 29723326 TI - Survival Rates of Lithium Disilicate Single Restorations: A Retrospective Study. AB - PURPOSE: To assess the clinical performance of lithium disilicate single restorations on natural teeth. MATERIALS AND METHODS: All patients who received lithium disilicate single restorations between 2009 and 2013 at the dental clinic of the University of Ferrara were recalled for clinical evaluation. A total of 43 partial and total restorations in 17 patients were evaluated from a minimum of 36 months follow-up to a maximum of 81 months follow-up, with a mean follow-up of 51 months. RESULTS: The cumulative survival rate was 97.7%, and the cumulative success rate was 94.2%. CONCLUSION: Lithium disilicate can be successfully used for single-tooth restorations. PMID- 29723327 TI - Implant-Assisted Removable Partial Denture Prostheses: A Critical Review of Selected Literature. AB - PURPOSE: A critical review of selected relevant publications assessed clinical efficacy and effectiveness of implant-assisted removable partial dentures (IARPDs) with implant survival and failure rates, biologic and technical complications, and maintenance and patient satisfaction after rehabilitation as outcomes. MATERIALS AND METHODS: Screening of three databases (Medline [PubMed], Embase [OVID], and the Cochrane Library [CENTRAL]) and a manual search of related articles were performed. Reports on outcomes from human studies conducted between 1 January 1980 and 31 May 2016 were considered. A quality assessment of the identified full-text articles was performed to assess risk of bias and to evaluate heterogeneity. RESULTS: Only nine studies were included, and all nine demonstrated high risk of bias. The mean observation period ranged from 1 to 10 years, and only four studies included at least one control group. The studies reported implant survival rates of 91.7% to 100%, abutment tooth survival rates of 79.2% to 100%, and prosthesis survival rates of 90% to 100%. Approximal peri implant crestal bone level changes (DeltaCBL) ranged from -0.17 to -2.2 mm. IARPDs were associated with a higher frequency of technical complications and maintenance interventions than biologic complications. Only two question-based studies assessed patient satisfaction before and after treatment, and both reported marked improvement. A meta-analysis was not possible because of substantial heterogeneity in study design. CONCLUSION: Limited availability of robust publications related to the selected review topic precluded significant conclusions. Nonetheless, the preliminary assessment suggests that IARPDs are a simple and cost-effective approach to providing symmetric prosthesis support and stability, plus improved patient satisfaction. PMID- 29723330 TI - Erratum: Association between executive and food functions in the acute phase after stroke. PMID- 29723328 TI - Paroxysmal Atrial Fibrillation in Females: Understanding gender diferences. AB - BACKGROUND: The catheter ablation of atrial fibrillation (AF) is performed less frequently in women. In addition, there is divergent information in the literature regarding the effectiveness and safety for the ablative procedure to females. OBJECTIVES: The objective of this study was to compare the clinical characteristics and outcomes in men and women undergoing paroxysmal atrial fibrillation (PAF) ablation. METHODS: Cohort study of patients undergoing first ever PAF catheter ablation procedure refractory to antiarrhythmic drugs. The information was taken from patients' records by means of a digital collection instrument and indexed to an online database (Syscardio(r)). Clinical characteristics and procedures were compared between each gender (M x F), adopting a level of statistical significance of 5%. The primary endpoint associated with efficacy was freedom from atrial arrhythmia over the follow-up time. RESULTS: 225 patients were included in the study, 64 (29%) women and 161 (71%) men. Women presented more symptoms due to AF according to the CCS-SAF score (1.8 +/- 0.8M x 2.3 +/- 0.8F p = 0.02) and higher CHADS2 score compared to men (0.9 +/- 0.8M x 1.2 +/- 1F). Post-ablation recurrence occurred in 20% of the patients, with no difference based on gender (21% M x 20% F p = 0.52). The rate of complications was less than 3% for both groups (p = 0.98). CONCLUSION: Women undergoing the first-ever PAF catheter ablation procedure present similar complication rate and clinical outcome compared to men. These findings suggest that the current underutilization of AF catheter ablation in women may represent a discrepancy in care. PMID- 29723331 TI - Sociodemographic inequalities in leisure-time physical activity and active commuting to school in Brazilian adolescents: National School Health Survey (PeNSE 2009, 2012, and 2015). AB - The objective of this study was to identify inequalities in leisure-time physical activity and active commuting to school in Brazilian adolescents, as well as trends according to gender, type of school, maternal schooling, and geographic region, from 2009 to 2015. This was a descriptive study based on data from the Brazilian National School Health Survey (PeNSE) in 2009, 2012, and 2015. Students were defined as active in their leisure time when they practiced at least 60 minutes of physical activity a day on five or more of the seven days prior to the interview. Active commuting to school was defined as walking or biking to school on the week prior to the interview. The outcomes were stratified by gender, type of school, maternal schooling, and geographic region. Inequalities were assessed by differences and ratios between the estimates, as well as summary inequality indices. The 2009, 2012, and 2015 surveys included 61,301, 61,145, and 51,192 schoolchildren, respectively. Prevalence of leisure-time physical activity was 13.8% in 2009, 15.9% in 2012, and 14.7% in 2015; the rates for active commuting to school were 70.6%, 61.7%, and 66.7%, respectively. Boys showed 10 percentage points higher prevalence of leisure-time physical activity and 5 points higher active commuting to school than girls. Children of mothers with more schooling showed a mean of 10 percentage points higher prevalence of leisure-time physical activity than children of mothers with the lowest schooling and some 30 percentage points lower in relation to active commuting to school. The observed inequalities remained constant over the course of the period. The study identified socioeconomic and gender inequalities that remained constant throughout the period and which were specific to each domain of physical activity. PMID- 29723329 TI - Atherosclerotic Plaque in Patients with Zero Calcium Score at Coronary Computed Tomography Angiography. AB - BACKGROUND: In view of the high mortality for cardiovascular diseases, it has become necessary to stratify the main risk factors and to choose the correct diagnostic modality. Studies have demonstrated that a zero calcium score (CS) is characteristic of a low risk for cardiovascular events. However, the prevalence of individuals with coronary atherosclerotic plaques and zero CS is conflicting in the specialized literature. OBJECTIVE: To evaluate the frequency of patients with coronary atherosclerotic plaques, their degree of obstruction and associated factors in patients with zero CS and indication for coronary computed tomography angiography (CCTA). METHODS: This is a cross-sectional, prospective study with 367 volunteers with zero CS at CCTA in four diagnostic imaging centers in the period from 2011 to 2016. A significance level of 5% and 95% confidence interval were adopted. RESULTS: The frequency of atherosclerotic plaque in the coronary arteries in 367 patients with zero CS was 9.3% (34 individuals). In this subgroup, mean age was 52 +/- 10 years, 18 (52.9%) were women and 16 (47%) had significant coronary obstructions (> 50%), with involvement of two or more segments in 4 (25%) patients. The frequency of non-obese individuals (90.6% vs 73.9%, p = 0.037) and alcohol drinkers (55.9% vs 34.8%, p = 0.015) was significantly higher in patients with atherosclerotic plaques, with an odds ratio of 3.4 for each of this variable. CONCLUSIONS: The frequency of atherosclerotic plaque with zero CS was relatively high, indicating that the absence of calcification does not exclude the presence of plaques, many of which obstructive, especially in non-obese subjects and alcohol drinkers. PMID- 29723332 TI - Vocal risk in preachers: talkativeness, vocal loudness, and knowledge about vocal health and hygiene. AB - Purpose The objective of this study was to investigate the knowledge of preachers about aspects of vocal health and hygiene and evaluate talkativeness and vocal loudness self-perceived during labor and extra-labor situations aiming to understand the possibility of vocal risk in these professionals. Methods Fifty male preachers aged 22 to 73 years were evaluated. They responded to two self assessment questionnaires on vocal health and hygiene and talkativeness and vocal loudness. The results were submitted to statistical analysis. Results The preachers presented satisfactory scores in the Vocal Health and Hygiene Questionnaire; however, their scores in the Scale of Vocal Loudness and Talkativeness were lower in the labor situation compared with the extra-labor situations. The variables length of professional experience as a preacher and extra-labor talkativeness and vocal loudness were also associated with knowledge about vocal health and hygiene. Conclusion Preachers show good knowledge about vocal health and hygiene but are at high risk of vocal disorders due to excessive use of talkativeness and vocal loudness in the work environment. PMID- 29723333 TI - Influence of ethanol on dentin roughness, surface free energy, and interaction between AH Plus and root dentin. AB - This study aimed to evaluate the influence of different ethanol concentrations on dentin roughness, surface free energy, and contact angle between AH Plus and the root canal dentin. One hundred human maxillary anterior teeth were split longitudinally and 200 dentin specimens were polished to make the surface flatter and smoother. An acrylic bar was positioned between two dentin specimens and impression material was added to create a block, simulating an instrumented root canal space. Specimens were removed from the mold and cleaned in an ultrasonic bath for 10 min. Thereafter, dentin specimens were divided into four groups (n = 50) according to the drying methods used: a) wet: vacuum only, b) paper points: vacuum + absorbent paper points, c) 70% alcohol: 70% alcohol (1 min) + vacuum + absorbent paper points, and d) 100% alcohol: 100% alcohol (1 min) + vacuum + absorbent paper points. A rugosimeter and a goniometer were used to verify the roughness (Ra) and to measure the surface free energy and the contact angle between the AH Plus sealer and the root canal dentin. ANOVA and Tukey tests (alpha = 0.05) were used for statistical analysis. The 70% and 100% ethanol groups showed significantly decreased roughness as well as increased surface free energy in the root canal dentin when compared to the wet and paper point groups. In addition, ethanol significantly reduced the contact angle between the AH Plus sealer and the root canal dentin. Ethanol solutions (70% and 100%) provide better wettability of AH Plus sealer on dentin surfaces. PMID- 29723334 TI - A multicenter study of oral health behavior among adult subjects from three South American cities. AB - The aims of this study were to describe the self-reported oral hygiene habits, dental visit frequency, and gingival bleeding perception in adult populations from three South American cities, and also to assess the association of these variables with sociodemographic data and with the clinical presence of plaque and gingival inflammation. Five-hundred and fifty adult subjects from each city (Porto Alegre, Brazil; Tucuman, Argentina; Santiago, Chile) received full mouth examinations to determine visible plaque and gingival index. A structured questionnaire on demographics, habits, attitudes and knowledge of oral health was also administered. The data were analyzed according to dental visit frequency, toothbrushing frequency, interproximal tooth cleaning frequency, subjects' perception of gum bleeding, and proportion of subject sites with VP and bleeding sites. Analysis of the association among the variables was performed using either a chi-square test or Fischer's exact test. Toothbrushing twice a day or more was reported by 84.2% of the subjects, but only 17.7% reported daily interdental cleaning, and 60.2% reported visiting a dental clinic only in an emergency. Only 2.97% had no bleeding sites, whereas 33.7% had 50% or more bleeding sites. Regular interdental self-cleaning and a dental visit every 3-6 months was associated with less plaque and less gingival bleeding. More than 12 years of education was associated with healthier habits, less bleeding and plaque scores. In conclusion, the oral health behavior of South American adult subjects from these cities is below the international recommendations, especially in relation to interdental cleaning and regular dental visits. PMID- 29723335 TI - Effect of grinding and aging on subcritical crack growth of a Y-TZP ceramic. AB - This study aimed to investigate slow crack growth (SCG) behavior of a zirconia ceramic after grinding and simulated aging with low-temperature degradation (LTD). Complementary analysis of hardness, surface topography, crystalline phase transformation, and roughness were also measured. Disc-shaped specimens (15 mm O * 1.2 mm thick, n = 42) of a full-contour Y-TZP ceramic (Zirlux FC, Amherst) were manufactured according to ISO:6872-2008, and then divided into: Ctrl - as sintered condition; Ctrl LTD - as-sintered after aging in autoclave (134 degrees C, 2 bar, 20 h); G - ground with coarse diamond bur (grit size 181 MUm); G LTD - ground and aged. The SCG parameters were measured by a dynamic biaxial flexural test, which determines the tensile stress versus stress rate under four different rates: 100, 10, 1 and 0.1 MPa/s. LTD led to m-phase content increase, as well as grinding (m-phase content: Ctrl - 0%; G - 12.3%; G LTD - 59.9%; Ctrl LTD - 81%). Surface topography and roughness analyses showed that grinding created an irregular surface (increased roughness) and aging did not promote any relevant surface change. There was no statistical difference on surface hardness among different conditions. The control group presented the lowest strength values in all tested rates. Regarding SCG, ground conditions were less susceptible to SCG, delaying its occurrence. Aging (LTD) caused an increase in SCG susceptibility for the as-sintered condition (i.e. G < G LTD < Ctrl < Ctrl LTD). PMID- 29723336 TI - Cross-cultural adaptation of the Brazilian version of the Dentine Hypersensitivity Experience Questionnaire (DHEQ-15). AB - The dentine hypersensitivity (DH) is able to impair the oral health related quality of life (OHRQoL). However, there isn't any specific validated questionnaire to be used in Brazil. The objective was to adapt and to validate the English version of the Dentine Hypersensitivity Experience Questionnaire (DHEQ-15) for use in Brazil. DHEQ-15 was cross-culturally adapted into the Brazilian-Portuguese language and then validated in a cross-sectional study with 100 participants recruited at a University clinic. Study sample comprised 2 groups: 100 individuals with DH, and 100 individuals without. The instrument was self-administered twice 7 to 10 days apart. The participants answered a global rating of oral health. The psychometric properties of the Brazilian version of DHEQ-15 were verified through internal consistency (Cronbach's alpha) and test retest reliability (intraclass correlation coefficient - ICC), convergent (Spearman correlation) and discriminant (Mann-Whitney test) validity. The significance threshold was set at p<0.05. Sample comprised 69 men and 131 women, of mean age 30.4y. The Brazilian DHEQ-15 demonstrated very good internal consistency (alpha = 0.945). Test-retest reliability revealed excellent reproducibility (ICC = 0.959, p < 0.001). There was statistically significant correlation between the scores obtained on all DHEQ-15 domains and the global rating of oral health (p<0.001). Participants with DH scored significantly higher than those without DH (p<0.001). This study provides evidence supporting the cross-cultural validity of the Brazilian version of DHEQ-15 for use in Brazil. PMID- 29723337 TI - Medication-related osteonecrosis of the jaw, osteoradionecrosis, and osteomyelitis: A comparative histopathological study. AB - It is largely known that some oral diseases can be diagnosed based upon their clinical manifestation combined with the patient's medical history and generally not depending on examination. This is the case of some bone diseases such as osteoradionecrosis of the jaw (ORNJ), osteomyelitis of the jaw (OMJ), and medication-related osteonecrosis of the jaw (MRONJ). The present study aimed to analyze the histopathological features of these specific bone diseases in order to evaluate similarities and differences. Forty-four bone specimens resected from each bone disease (22 cases of ORNJ, 6 cases of OMJ, and 16 cases of MRONJ) were analyzed by two experienced oral pathologists without prior knowledge of the diagnosis, considering bone tissue condition, inflammation, vascularization, and the presence of microorganisms. In addition, the examiners formulated a diagnostic hypothesis for each specimen. Many histopathological similarities were found among the diseases, especially considering the presence of necrotic bone, inflammation, and microorganisms. Statistically significant differences were detected in empty bone lacunae, which was decreased in ORN (p = 0.042), and considering neutrophil count, which was low in the MRONJ group (p <= 0.001). The Kappa coefficient was calculated and agreement was detected based on the histopathological parameters, but not for diagnostic suggestion (p=0.23). In conclusion, histopathological aspects of ORNJ, OMJ, and MRONJ do not permit a conclusive diagnosis, emphasizing the necessity of a detailed clinical report. PMID- 29723338 TI - A systematic review and meta-analysis of the survival rate of implants placed in previously failed sites. AB - The aim of this study was to conduct a systematic review and meta-analysis to assess the clinical outcomes of dental implants placed in previously early and late implant failed sites. An electronic literature search was conducted in several databases for articles published up to February 2018. Human clinical trials that received at least one implant in a previously failed site were included. Hence, the PICO question that was aimed to be addressed was: Do patients undergoing implant replacement (second and third attempts) in previous failed sites have survival rates similar to implants placed at first attempts? A random effects model was used to calculate survival weighted means and corresponding 95% Confidence Intervals (CI) among studies. Eleven studies of low to moderate methodological quality were included in this review. Implants placed in sites with history of one and two implant failures had a weighted survival rate (SR) of 88.7% (95%CI 81.7-93.3) and 67.1% (95%CI 51.1-79.9), respectively. Implants placed in sites with a previous early failure revealed a weighted SR of 91.8% (95%CI 85.1-95.6). First implants presented higher SR than implants placed in sites with one or two previous implant failures. In contrast, implants placed in sites with one and two implant failures had similar SR. Within its limitations, this review suggests that replacement implants have moderate SR. Larger prospective studies with well-defined criteria for early and late implant failure are necessary to confirm and expand on these results. PMID- 29723339 TI - Comparing osteogenic effects between concentrated growth factors and the acellular dermal matrix. AB - Concentrated growth factor (CGF) is an autogenuous product that contains highly concentrated number of platelets and can be derived from venous blood by selective centrifugation. It has been speculated that local growth factors in human platelets (insulinlike growth factor, IGF; transforming growth factor, TGF b; platelet derived growth factor, PDGF) would enhance healing of grafts and also counteract resorption. The osteogensis effect of CGF and acellular dermal matrix (ADM) for alveolar cleft defects was evaluated in this study. Twenty alveolar cleft patients were divided randomly into two groups. One group underwent guided bone regeneration (GBR) using acellular dermal matrix film combined with alveolar bone grafting using iliac crest bone grafts (GBR group), while the other group underwent alveolar bone grafting combined with CGF (CGF group). Cone beam computed tomography (CBCT) images were obtained at 1 week and 6 months following the procedure. Using Mimics 17.0 software, the bone resorption rate and bone density improvement rate were calculated and compared between the two groups. Although not significant between ADM and CGF in bone resorption rate, the bone density improvement in cases with CGF(61.62 +/- 4.728%) was much better than in cases with ADM (27.05 +/- 5.607%) (p = 0.0002). Thus, CGF could be recommended to patients with alveolar cleft as a better choice. PMID- 29723340 TI - Stroke risk among patients with chronic obstructive pulmonary disease: A systematic review and meta-analysis. AB - Increased stroke risk among chronic obstructive pulmonary disease patients has not yet been established. In this study, we conducted a systematic review and meta-analysis to assess stroke risk among chronic obstructive pulmonary disease patients. PubMed, EMBASE, and the Cochrane Library were systematically searched from database inception until December 31, 2016 to identify longitudinal observational studies that investigated the association between chronic obstructive pulmonary disease and stroke. Stroke risk was quantified by overall and subgroup analyses, and a pooled hazard ratio was calculated. Study quality was evaluated using the Newcastle-Ottawa Scale. Publication bias was assessed using Begg's rank correlation test. Eight studies met the inclusion criteria. In a random-effects model, significantly increased stroke risk was observed among chronic obstructive pulmonary disease patients (hazard ratio, 1.30; 95% confidence interval, 1.18-1.43). In subgroup analyses stratified by stroke subtype, study quality, and adjustment by socioeconomic status, the association between increased stroke risk and chronic obstructive pulmonary disease patients was robust. Statistically significant publication bias was not detected. In summary, chronic obstructive pulmonary disease was found to be associated with increased stroke risk. Additional prospective studies are required to elucidate the mechanisms underlying the increase in stroke risk and identify effective preventive interventions. PMID- 29723341 TI - Impact of discharge medication counseling in the cardiology unit of a tertiary hospital in Brazil: A randomized controlled trial. AB - OBJECTIVES: This study aimed to evaluate the impact of pharmacist-provided discharge counseling on mortality rate, hospital readmissions, emergency department visits, and medication adherence at 30 days post discharge. METHODS: This randomized controlled trial was approved by the local ethics committee and included patients aged 18 years or older admitted to the cardiology ward of a Brazilian tertiary hospital. The intervention group received a pharmacist-led medication counseling session at discharge and a telephone follow-up three and 15 days after discharge. The outcomes included the number of deaths, hospital readmissions, emergency department visits, and medication adherence. All outcomes were evaluated during a pharmacist-led ambulatory consultation performed 30 days after discharge. RESULTS: Of 133 patients, 104 were included in the analysis (51 and 53 in the intervention and control groups, respectively). The intervention group had a lower overall readmission rate, number of emergency department visits, and mortality rate, but the differences were not statistically significant (p>0.05). However, the intervention group had a significantly lower readmission rate related to heart disease (0% vs. 11.3%, p=0.027), despite the small sample size. Furthermore, medication counseling contributed significantly to improved medication adherence according to three different tools (p<0.05). CONCLUSIONS: Pharmacist-provided discharge medication counseling resulted in better medication adherence scores and a lower incidence of cardiovascular associated hospital readmissions, thus representing a useful service for cardiology patients. PMID- 29723343 TI - Early psychiatric morbidity in a Brazilian sample of acute ischemic stroke patients. AB - OBJECTIVE: Stroke is a major public health problem worldwide, and its neuropsychiatric sequelae are frequent and disabling. Furthermore, there is evidence that these sequelae impair recovery. Brazil has the highest stroke rates in Latin America, but data on the frequency of neuropsychiatric disorders in these patients are scarce. This study aimed to identify mental disorders among in hospital patients with acute ischemic stroke. METHODS: The Mini International Neuropsychiatric Interview-Plus (MINI-Plus) was applied to 60 patients during the first week of hospitalization. RESULTS: Psychiatric disorders were diagnosed in 55% of the patients. A wide range of neuropsychiatric disorders have been identified, mainly mood and anxiety disorders. Specifically, we identified major depression (26.7%), alcohol abuse or dependence (11.7%), specific phobia (8.3%), generalized anxiety disorder (6.7%), psychosis (5.0%), social phobia (3.3%), adjustment disorder (3.3%) and panic disorder (1.7%). CONCLUSION: Psychiatric comorbidity should be evaluated as part of the rehabilitation of stroke patients and should be carefully examined by physicians. PMID- 29723342 TI - Brazilian Guidelines for Hereditary Angioedema Management - 2017 Update Part 1: Definition, Classification and Diagnosis. AB - Hereditary angioedema is an autosomal dominant disease characterized by recurrent angioedema attacks with the involvement of multiple organs. The disease is unknown to many health professionals and is therefore underdiagnosed. Patients who are not adequately diagnosed and treated have an estimated mortality rate ranging from 25% to 40% due to asphyxiation by laryngeal angioedema. Intestinal angioedema is another important and incapacitating presentation that may be the main or only manifestation during an attack. In this article, a group of experts from the "Associacao Brasileira de Alergia e Imunologia (ASBAI)" and the "Grupo de Estudos Brasileiro em Angioedema Hereditario (GEBRAEH)" has updated the Brazilian guidelines for the diagnosis and treatment of hereditary angioedema. PMID- 29723344 TI - En bloc vertebrectomy for the treatment of spinal lesions. Five years of experience in a single institution: a case series. AB - OBJECTIVES: The objective of this study is to describe the experience of a Brazilian public university hospital regarding the treatment of metastatic or benign spine lesions with en bloc vertebrectomy of the thoracic and lumbar spines. METHODS: This study was a retrospective case series and included all medical records of patients with benign aggressive, primary malignant, or metastatic spine lesions who underwent en bloc vertebrectomy from 2010 to 2015. RESULTS: A total of 17 patients were included in the analysis. Most of them (71%) were indicated for surgery based on an oncologic resection for localized disease cure. Overall, 10 of the 17 patients (59%) underwent vertebrectomy via an isolated posterior approach using the technique described by Roy-Camille et al. and Tomita et al., while 7 patients (41%) underwent double approach surgeries. Of the 17 patients who underwent the en bloc resection, 8 are still alive and in the outpatient follow-up (47%), and almost all patients with metastatic lesions (8/9) died. The average survival time following the surgical procedure was 23.8 months. Considering the cases of metastatic lesions and the cases of localized disease (malignant or benign aggressive disease) separately, we observed an average survival time of 15 months and 47.6 months respectively. CONCLUSION: This study demonstrates and reinforces the reproducibility of the en bloc vertebrectomy technique described by Tomita et al. PMID- 29723347 TI - Type II and III Selective Fetal Growth Restriction: Perinatal Outcomes of Expectant Management and Laser Ablation of Placental Vessels. AB - OBJECTIVES: To describe the perinatal outcomes of type II and III selective fetal growth restriction (sFGR) in monochorionic-diamniotic (MCDA) twin pregnancies treated with expectant management or laser ablation of placental vessels (LAPV). METHODS: Retrospective analysis of cases of sFGR that received expectant management (type II, n=6; type III, n=22) or LAPV (type II, n=30; type III, n=9). The main outcomes were gestational age at delivery and survival rate. RESULTS: The smaller fetus presented an absent/reversed "a" wave in the ductus venosus (arAWDV) in all LAPV cases, while none of the expectant management cases presented arAWDV. The median gestational age at delivery was within the 32nd week for expectant management (type II and III) and for type II LAPV, and the 30th week for type III LAPV. The rate of at least one twin alive at hospital discharge was 83.3% and 90.9% for expectant management type II and III, respectively, and 90% and 77.8% for LAPV type II and III, respectively. CONCLUSION: LAPV in type II and III sFGR twins with arAWDV in the smaller fetus seems to yield outcomes similar to those of less severe cases that received expectant management. PMID- 29723348 TI - Vitiligo patients show significant up-regulation of aryl hydrocarbon receptor transcription factor. AB - IL-22 has been implicated in the pathogenesis of vitiligo. However, the role of aryl hydrocarbon receptor transcription factor that acts as a master regulator of IL-22-producing Th22 cells is not fully understood. The goal of this study was to investigate the expression pattern of aryl hydrocarbon receptor in peripheral blood mononuclear cells of patients with vitiligo and in normal controls. Transcript levels were determined by a reverse transcription quantitative real time polymerase chain reaction. Aryl hydrocarbon receptor mRNA expression was drastically increased in patients with vitiligo compared to healthy controls (P = 0.000). Th22 cells may contribute to abnormal immune responses underlying vitiligo. PMID- 29723349 TI - Ultrasonographic findings in primary umbilical endometriosis. AB - Primary cutaneous endometriosis is a rare condition. It appears without a prior history of surgical procedure and the umbilicus is the most frequently involved area. Primary umbilical endometriosis, or Villar's nodule, usually presents as a painful nodule. Its differential diagnosis may be challenging. Although histopathological assessment represents the gold standard for diagnosis, cutaneous ultrasonography may be useful in guiding the surgical treatment. Ultrasonographic features of cutaneous endometriosis have not yet been fully explored in the literature. Hence, we report peculiar ultrasonographic findings of primary umbilical endometriosis. PMID- 29723345 TI - Low estrogen doses normalize testosterone and estradiol levels to the female range in transgender women. AB - OBJECTIVE: The ideal dosage of cross-sex hormones remains unknown. The aim of this study was to evaluate the luteinizing hormone, follicle-stimulating hormone, testosterone, estradiol and prolactin levels after low-dose estrogen therapy with or without cyproterone acetate in transgender women. METHODS: The serum hormone and biochemical profiles of 51 transgender women were evaluated before gonadectomy. Hormone therapy consisted of conjugated equine estrogen alone or combined with cyproterone acetate. The daily dose of conjugated equine estrogen was 0.625 mg in 41 subjects and 1.25 mg in 10 subjects, and the daily dose of cyproterone acetate was 50 mg in 42 subjects and 100 mg in one subject. RESULTS: Estrogen-only therapy reduced the testosterone, luteinizing hormone and follicle stimulating hormone levels from 731.5 to 18 ng/dL, 6.3 to 1.1 U/L and 9.6 to 1.5 U/L, respectively. Estrogen plus cyproterone acetate reduced the testosterone, luteinizing hormone and follicle-stimulating hormone levels from 750 to 21 ng/dL, 6.8 to 0.6 U/L and 10 to 1.0 U/L, respectively. The serum levels of luteinizing hormone, follicle-stimulating hormone, testosterone, estradiol and prolactin in the patients treated with estrogen alone and estrogen plus cyproterone acetate were not significantly different. The group receiving estrogen plus cyproterone acetate had significantly higher levels of gamma-glutamyltransferase than the group receiving estrogen alone. No significant differences in the other biochemical parameters were evident between the patients receiving estrogen alone and estrogen plus cyproterone acetate. CONCLUSION: In our sample of transgender women, lower estrogen doses than those usually prescribed for these subjects were able to adjust the testosterone and estradiol levels to the physiological female range, thus avoiding high estrogen doses and their multiple associated side effects. PMID- 29723346 TI - Post-Traumatic Stress Disorder and severe maternal morbidity: is there an association? AB - OBJECTIVE: To evaluate the occurrence of Post-Traumatic Stress Disorder among women experiencing a severe maternal morbidity event and associated factors in comparison with those without maternal morbidity. METHODS: In a retrospective cohort study, 803 women with or without severe maternal morbidity were evaluated at 6 months to 5 years postpartum for the presence of Post-Traumatic Stress Disorder. Interviews were conducted by telephone and electronic data was stored. Data analysis was carried out by using chi2, Fisher's Exact test, and logistic regression analysis. RESULTS: There was no significant change in the prevalence of Post-Traumatic Stress Disorder related to a previous severe maternal morbidity experience. There were also no differences in diagnostic criteria for severe maternal morbidity (hypertensive syndromes, hemorrhage, surgical intervention or intensive care unit admission required, among other management criteria). Low parity (2.5-fold risk) and increasing age were factors associated with Post Traumatic Stress Disorder. CONCLUSIONS: A severe maternal morbidity episode is not associated with Post-Traumatic Stress Disorder symptoms within five years of the severe maternal morbidity event and birth. However, a more advanced maternal age and primiparity increased the risk of Post-Traumatic Stress Disorder. This does not imply that women who had experienced a severe maternal morbidity event did not suffer or need differentiated care. PMID- 29723350 TI - Clinical and pathological features of myeloid leukemia cutis. AB - BACKGROUND: Myeloid leukemia cutis is the terminology used for cutaneous manifestations of myeloid leukemia. OBJECTIVE: The purpose of this study was to study the clinical, histopathological and immunohistochemical features of myeloid leukemia cutis. METHODS: This was a retrospective study of clinical and pathological features of 10 patients with myeloid leukemia cutis. RESULTS: One patient developed skin lesions before the onset of leukemia, seven patients developed skin infiltration within 4-72 months after the onset of leukemia, and two patients developed skin lesions and systemic leukemia simultaneously. Of these patients, five presented with generalized papules or nodules, and five with localized masses. The biopsy of skin lesions showed a large number of tumor cells within the dermis and subcutaneous fat layer. Immunohistochemical analysis showed strong reactivity to myeloperoxidase (MPO), CD15, CD43 and CD45 (LCA) in most cases. NPM1 (nucleophosmin I) and FLT3-ITD (Fms-like tyrosine kinase 3-internal tandem duplication) mutations were identified in one case. Five patients with acute myelogenous leukemia and one patient with chronic myelomonocytic leukemia died within two months to one year after the onset of skin lesions. STUDY LIMITATIONS: This was a retrospective and small sample study. CONCLUSIONS: In patients with myelogenous leukemia, skin infiltration usually occurs after, but occasionally before, the appearance of hemogram and myelogram abnormalities, and the presence of skin infiltration is often associated with a poor prognosis and short survival time. myeloid leukemia cutis often presents as generalized or localized nodules or masses with characteristic pathological and histochemical findings. PMID- 29723351 TI - Coexistence of chronic cutaneous lupus erythematosus and frontal fibrosing alopecia. AB - Lupus erythemathosus is a chronic, relapsing disease with acute, subacute, and chronic lesions. Effluvium telogen occurs in the setting of systemic activity of the disease, and cicatricial alopecia results from discoid lesionsin on the scalp. Other types of alopecia, like alopecia areata, may rarely be found in lupus. Frontal fibrosing alopecia is characterized by frontotemporal hairline recession and eybrow loss. Histophatologically, it cannot be differentiated from lichen planopilaris.It is controversial whether frontal fibrosing alopecia is a subtype of lichen planopilaris.. A pacient with chronic lichenoid lupus erythematosus is described with clinical, histophatological and dermoscopic features of frontal fibrosing alopecia.We have not been able to find in the literature cases of frontal fibrosing alopecia as a clinical manifestation of lupus. PMID- 29723353 TI - Multiple dermatomyofibromas. AB - This study describes a case of a 19-year-old patient with seven asymptomatic lesions on the chest, measuring between 0.5 to 1cm in diameter, with no history of trauma in the region. The immunohistochemical evaluation was positive for vimentin and smooth muscle actin, determining Dermatomyofibroma as definitive diagnosis. Dermatomyofibroma is a benign skin tumor, with a myofibroblastic origin, prevalent in young women. It usually presents as a single lesion, with very few reports of multiple lesions. PMID- 29723352 TI - Urticaria and angioedema as possible reactions of omalizumab. PMID- 29723355 TI - Diphencyprone as a therapeutic option in cutaneous metastasis of melanoma. A single-institution experience. AB - Diphencyprone has been reported as a local immunotherapy for cutaneous melanoma metastases. We aim to report cases of melanoma patients treated with diphencyprone in a single Brazilian institution and highlight their outcomes. Since 2012, we have treated 16 melanoma patients with cutaneous metastases with topical diphencyprone. To date, we have had 37.5% of complete response, 25% of partial responses, and 31.25% patients without any response. Treatment was well tolerated and local toxicity was easily controlled. We believe topical diphencyprone is a feasible treatment that can be another option for treating melanoma patients, especially in cases of in-transit or extensive disease. PMID- 29723354 TI - Blocking or enhancing effects of some basic emollients in UVA penetration. AB - BACKGROUND: Topical agents used in combination with phototherapy or photochemotherapy may have both blocking or enhancing effects in ultraviolet rays. OBJECTIVE: In this in vivo study, the effects of topical petrolatum, basis cream, glycerine, and olive oil on the transmission of ultraviolet A radiation were investigated. METHODS: A test was performed to determine the minimal phototoxic dose on 29 volunteers with only psoralen plus ultraviolet A (PUVA) and then the same test was repeated with white petrolatum, basis cream, glycerine, olive oil, and sunscreen (0.3cc/25cm2). The effects of each agent on the minimal phototoxic dose were determined after 72 h. RESULTS: When compared to pure PUVA, there was a statistically significant increase in the mean minimal phototoxic dose values by the application of white petrolatum (P = 0.011), but there was no significant increase or decrease in the mean minimal phototoxic dose values after the application of basis cream (P = 0.326), glycerine (P = 0.611) or olive oil (P = 0.799). STUDY LIMITATIONS: Low number of patients Conclusion: The application of white petrolatum, which has a blocking effect, and also of basis cream immediately before PUVA therapy should not be recommended. Although we specify that glycerine and maybe olive oil can be used before photochemotherapy, there is a need for further research in larger series. PMID- 29723356 TI - Intralesional betamethasone as a therapeutic option for alopecia areata. PMID- 29723357 TI - Cutaneous leiomyosarcoma on the face. AB - Leiomyosarcoma is a rare skin tumor, most common in white men in the fifth to eighth decades of life. Primary tumors are classified in dermal or subcutaneous, that differ by clinical and prognostic features. They may appear on any site of the body, but are rare on the face. A 54-year-old female was admitted with a 5cm exophytic nodular lesion of 8 months duration on the right cheek, site of previous chronic radiodermatitis. Histopathology revealed spindle-shaped cell neoplasia, positive for smooth muscle actin on immunohistochemistry. Cutaneous leiomyosarcomas on the face are rare and may occur in previously irradiated areas. Immunohistochemistry is mandatory for an accurate diagnosis. Its similarity with other tumors may complicate the diagnosis, with delay expansion of the tumor. PMID- 29723358 TI - Atypical Gianotti-Crosti syndrome. AB - We report the case of a male 22-month-old child, with atypical presentation of Gianotti-Crosti syndrome after infection with Epstein-Barr virus. PMID- 29723359 TI - Lingual melanotic macule - the first case report in an adult patient. PMID- 29723360 TI - Metastatic pleomorphic dermal sarcoma: an uncommon skin tumour. PMID- 29723362 TI - Sclerodermiform basal cell carcinoma: how much can we rely on dermatoscopy to differentiate from non-aggressive basal cell carcinomas? Analysis of 1256 cases. AB - BACKGROUND: The behaviour of each basal cell carcinoma is known to be different according to the histological growth pattern. Among these aggressive lesions, sclerodermiform basal cell carcinomas are the most common type. This is a challenging-to-treat lesion due to its deep tissue invasion, rapid growth, risk of metastasis and overall poor prognosis if not diagnosed in early stages. OBJECTIVE: To investigate if sclerodermiform basal cell carcinomas are diagnosed later compared to non-sclerodermiform basal cell carcinoma Method: All lesions excised from 2000 to 2010 were included. A pathologist classified the lesions in two cohorts: one with specimens of non-aggressive basal cell carcinoma (superficial, nodular and pigmented), and other with sclerodermiform basal cell carcinoma. For each lesion, we collected patient's information from digital medical records regarding: gender, age when first attending the clinic and the tumor location. RESULTS: 1256 lesions were included, out of which 296 (23.6%) corresponded to sclerodermiform basal cell carcinoma, whereas 960 (76.4%) were non-aggressive subtypes of basal cell carcinoma. The age of diagnosis was: 72.78+/-12.31 years for sclerodermiform basal cell and 69.26+/-13.87 years for non-aggressive basal cell carcinoma (P<.0001). Sclerodermiform basal cell carcinomas are diagnosed on average 3.52 years later than non-aggressive basal cell carcinomas. Sclerodermiform basal cell carcinomas were diagnosed 3.40 years and 2.34 years later than non-aggressive basal cell carcinomas in younger and older patients respectively (P=.002 and P=.03, respectively). STUDY LIMITATIONS: retrospective design. CONCLUSION: The diagnostic accuracy and primary clinic conjecture of sclerodermiform basal cell carcinomas is quite low compared to other forms of basal cell carcinoma such as nodular, superficial and pigmented. The dermoscopic vascular patterns, which is the basis for the diagnosis of non melanocytic nonpigmented skin tumors, may not be particularly useful in identifying sclerodermiform basal cell carcinomas in early stages. As a distinct entity, sclerodermiform basal cell carcinomas show a lack of early diagnosis compared to less-aggressive subtypes of BCC, and thus, more accurate diagnostic tools apart from dermatoscopy are required to reach the goal of early-stage diagnosis of sclerodermiform basal cell carcinomas. PMID- 29723361 TI - The association between psoriasis and health-related quality of life, work productivity, and healthcare resource use in Brazil. AB - BACKGROUND: Psoriasis is a chronic, immune mediated inflammatory condition that affects a significant amount of the global population. Yet geographic variability in the consequences of psoriasis warrants region-level analyses. OBJECTIVE: The current study contributes to the psoriasis outcomes literature by offering a comprehensive assessment of the humanistic and economic burden in Brazil. METHODS: The 2012 Brazil National Health and Wellness Survey (N=12,000) was used to assess health-related quality of life (Short Form-12, version 2), work productivity, and healthcare resource use associated with experiencing psoriasis vs. no psoriasis, along with varying levels of psoriasis severity. RESULTS: A total of 210 respondents reported diagnosis of psoriasis (N=157, 42, and 11 reporting mild, moderate, and severe psoriasis, respectively). Compared with controls, respondents with psoriasis reported diminished mental component summary scores and health utilities, as well as increased presenteeism, activity impairment, and physician visits over the past six months, adjusting for covariates. Among those with psoriasis, physical health decreased as psoriasis severity increased. Although work productivity and healthcare resource utilization did not differ with psoriasis severity, the high rates of productivity loss (e.g. 45.5% presenteeism in the severe psoriasis group) suggest an economic burden. STUDY LIMITATIONS: Cost analyses were not performed, and cross-sectional patient-reported data limit causal conclusions and may reflect reporting biases. CONCLUSIONS: Nevertheless, these results suggest a significant burden to patients with psoriasis across both humanistic and economic outcomes. The association between psoriasis and mental health aspects and health utilities were particularly strong and exceeded what would be considered clinically meaningful. PMID- 29723364 TI - Most frequent dermatoses at a vulvar pathology outpatient clinic. AB - The vulva corresponds to the external female genitalia. Special features of this region favor a wide range of diseases, whose knowledge allows for better clinical management, impacting on the quality of life. This is a cross-sectional and descriptive study carried out at a vulvar pathology outpatient clinic, between May and December/ 2015. Data obtained from a standard form included demographic parameters, habits, and vulvar dermatosis and allowed to identify the epidemiological profile of patients with vulvar dermatosis treated in this outpatient clinic and to determine the most prevalent dermatoses. Our results, partially concordant with the literature, provide original data that should stimulate further studies. PMID- 29723363 TI - Macrophage migration inhibitory factor as an incriminating agent in vitiligo. AB - BACKGROUND: Vitiligo is an autoimmune skin disorder in which the loss of melanocytes is mainly attributed to defective autoimmune mechanisms and, lately, there has been more emphasis on autoinflammatory mediators. Among these is the macrophage migration inhibitory factor, which is involved in many autoimmune skin diseases. However, little is known about the contribution of this factor to vitiligo vulgaris. OBJECTIVE: To determine the hypothesized role of migration inhibitory factor in vitiligo via estimation of serum migration inhibitory factor levels and migration inhibitory factor mRNA concentrations in patients with vitiligo compared with healthy controls. We also aimed to assess whether there is a relationship between the values of serum migration inhibitory factor and/or migration inhibitory factor mRNA with disease duration, clinical type and severity in vitiligo patients. METHODS: Evaluation of migration inhibitory factor serum level and migration inhibitory factor mRNA expression by ELISA and real time PCR, respectively, were performed for 50 patients with different degrees of vitiligo severity and compared to 15 age- and gender-matched healthy volunteers as controls. RESULTS: There was a highly significant increase in serum migration inhibitory factor and migration inhibitory factor mRNA levels in vitiligo cases when compared to controls (p<0.001). There was a significant positive correlation between both serum migration inhibitory factor and migration inhibitory factor mRNA concentrations in vitiligo patients, and each of them with duration and severity of vitiligo. In addition, patients with generalized vitiligo have significantly elevated serum migration inhibitory factor and mRNA levels than control subjects. STUDY LIMITATIONS: Small number of investigated subjects. CONCLUSIONS: Migration inhibitory factor may have an active role in the development of vitiligo, and it may also be a useful index of disease severity. Consequently, migration inhibitory factor may be a new treatment target for vitiligo patients. PMID- 29723365 TI - Lymphoepithelioma-like carcinoma of the skin. AB - Primary cutaneous lymphoepithelioma-like carcinoma is a rare disease with low metastatic potential. Its morphologic and pathological features are similar to those of nasopharyngeal lymphoepithelial carcinoma. We report the case of a 60 year-old man with an infrapalpebral pearly papule, measuring 0.6 cm in diameter. The lesion was excised with a clinical hypothesis of basal cell carcinoma or squamous cell carcinoma. Histopathological analysis revealed a malignant neoplasm with syncytial arrangement of cells with vesicular nuclei, associated with dense lymphocytic infiltrate. Immunohistochemistry revealed cytokeratin-positive cells (AE1/AE3) and p63 protein, indicating epithelial histogenesis and squamous differentiation. A negative Epstein-Barr virus test result was achieved by immunohistochemistry. Primary lymphoepithelioma-like carcinoma of the skin is a differential diagnosis of lesions with prominent inflammatory infiltrates. PMID- 29723366 TI - Metabolic syndrome, C-reactive protein and cardiovascular risk in psoriasis patients: a cross-sectional study. AB - BACKGROUND: Psoriasis has been associated with co-morbidities and elevated cardiovascular risk. OBJECTIVES: To analyze the relationships among metabolic syndrome, cardiovascular risk, C-reactive protein, gender, and Psoriasis severity. METHODS: In this cross-sectional study, plaque Psoriasis patients (n=90), distributed equally in gender, were analyzed according to: Psoriasis Area and Severity Index, cardiovascular risk determined by the Framingham risk score and global risk assessment, C-reactive protein and metabolic syndrome criteria (NCEPT-ATP III). RESULTS: Metabolic syndrome frequency was 43.3% overall, without significance between genders (P=0.14); but women had higher risk for obesity (OR 2.56, 95%CI 1.02-6.41; P=0.04) and systemic arterial hypertension (OR 3.29, 95%CI 1.39-7.81; P=0.006). The increase in the Psoriasis Area and Severity Index also increased the risk for metabolic syndrome (OR 1.060, 95%CI 1.006-1.117; P=0.03). Absolute 10-year cardiovascular risk was higher in males (P=0.002), but after global risk assessment, 51.1% patients, 52.2% women, were re-classified as high intermediate cardiovascular risk; without significance between genders (P=0.83). C-reactive protein level was elevated nearly six-fold overall, higher in metabolic syndrome (P=0.05), systemic arterial hypertension (P=0.004), and high intermediate 10-year cardiovascular risk patients (P<0.001); positively correlated to: Framingham risk score (P<0.001; r=0.60), absolute 10-year cardiovascular risk (P<0.001; r=0.58), and age (P=0.001; r=0.35); but not to Psoriasis Area and Severity Index (P=0.14; r=0.16); increased the 10-year cardiovascular risk (R2=33.6; P<0.001), MetS risk (OR 1.17, 95%CI 0.99-1.37; P=0.05) and with age (P=0.001). HDL-cholesterol level was higher in normal C reactive protein patients (t=1.98; P=0.05). STUDY LIMITATIONS: Restricted sample, hospital-based and representative of a single center and no specification of psoriatic arthritis. CONCLUSIONS: Psoriasis, metabolic syndrome, systemic arterial hypertension and age share the increase in C-reactive protein, which could implicate in additional burden for increasing the cardiovascular risk and be an alert for effective interventions. PMID- 29723368 TI - Atypical crusted scabies in a patient with chronic liver disease caused by hepatitis B and D viruses. AB - Crusted scabies is a less common variant of scabies that is highly contagious, difficult to treat and involves infestation by Sarcoptes scabiei var. hominis. The classical clinical presentation includes crusted, scaly and generally non pruritic lesions usually located on the head, neck, palmar, plantar and periungual region. It was first described in Norway in 1848 in patients with leprosy who presented with crusted lesions. In this study, we report the case of a patient with crusted scabies with florid clinical manifestations and chronic liver disease due to hepatitis B and delta virus infection. PMID- 29723367 TI - Innate immunity and effector and regulatory mechanisms involved in allergic contact dermatitis. AB - Skin's innate immunity is the initial activator of immune response mechanisms, influencing the development of adaptive immunity. Some contact allergens are detected by Toll-like receptors (TLRs) and inflammasome NLR3. Keratinocytes participate in innate immunity and, in addition to functioning as an anatomical barrier, secrete cytokines, such as TNF, IL-1beta, and IL-18, contributing to the development of Allergic Contact Dermatitis. Dendritic cells recognize and process antigenic peptides into T cells. Neutrophils cause pro-inflammatory reactions, mast cells induce migration/maturation of skin DCs, the natural killer cells have natural cytotoxic capacity, the gammadelta T cells favor contact with hapten during the sensitization phase, and the innate lymphoid cells act in the early stages by secreting cytokines, as well as act in inflammation and tissue homeostasis. The antigen-specific inflammation is mediated by T cells, and each subtype of T cells (Th1/Tc1, Th2/Tc2, and Th17/Tc17) activates resident skin cells, thus contributing to inflammation. Skin's regulatory T cells have a strong ability to inhibit the proliferation of hapten-specific T cells, acting at the end of the Allergic Contact Dermatitis response and in the control of systemic immune responses. In this review, we report how cutaneous innate immunity is the first line of defense and focus its role in the activation of the adaptive immune response, with effector response induction and its regulation. PMID- 29723369 TI - Atypical aquagenic keratoderma treated with oxybutynin chloride. PMID- 29723370 TI - Dermoscopy of inflammatory breast cancer. AB - Inflammatory breast cancer is an aggressive and infiltrative malignancy that is often misdiagnosed as an infection because of its symptoms and signs of inflammation, delaying proper diagnosis and treatment. We report a case of inflammatory breast cancer showing correlation between dermoscopic and histopathological diagnoses. We highlight the utility of dermoscopy for skin biopsy site selection. PMID- 29723371 TI - Effectiveness of the retreatment of patients with multibacillary leprosy and episodes of erythema nodosum leprosum and/or persistent neuritis: a single-center experience. AB - BACKGROUND: Erythema nodosum leprosum may appear before, during or after treatment of leprosy and is one of the main factors for nerve damage in patients. When it occurs or continues to occur after treatment, it may indicate disease recurrence and a new treatment may be instituted again. OBJECTIVE: To evaluate the retreatment of patients with multibacillary leprosy who underwent standard treatment with multidrug therapy, but developed or continued to present reactions of erythema nodosum leprosum and/or neuritis 3-5 years after its end. METHOD: For this objective, a new treatment was performed in 29 patients with multibacillary leprosy who maintained episodes of erythema nodosum and/or neuritis 3-5 years after conventional treatment. RESULTS: In general, we observed that 27 (93.10%) had no more new episodes after a follow up period of eight months to five years. In five of these patients the reason for the retreatment was the occurrence of difficult-to-control neuritis, and that has ceased to occur in all of them. STUDY LIMITATIONS: Small number of patients.. CONCLUSION: In the cases observed, retreatment was an effective measure to prevent the occurrence of erythema nodosum leprosum and/or persistent neuritis. PMID- 29723372 TI - Suppression of wheal and flare in histamine test by the main H1 antihistamines commercialized in Brazil. AB - BACKGROUND: Several dermatoses are mediated by histamine, such as urticaria, angioedema, and papular urticaria. There are no Brazilian studies comparing the potency of antihistamines. OBJECTIVES: To evaluate the tolerability and efficacy of the main commercial brand and generic H1 antihistamines, regarding the suppression of the wheal and flare to the histamine test. METHODS: A quasi experimental, open study with 10 healthy adults submitted to the histamine test on the ventral aspect of the forearms. After 20 minutes, wheal and flares were measured. The tests were performed after two hours of intake of dexchlorpheniramine, hydroxyzine, levocetirizine, fexofenadine, cetirizine, loratadine, ebastine, desloratadine, epinastine and rupatadine, as well as generics of loratadine, cetirizine and fexofenadine. RESULTS: All antihistamines presented a reduction in the wheal compared to the control (p <0.02), as well as in the flare, except for rupatadine (p = 0.70). In the internal comparison, cetirizine, fexofenadine, epinastine, levocetirizine, dexchlorpheniramine and hydroxyzine were the most potent, with no difference between them (p > 0.1). As for halo, cetirizine, epinastine, hydroxyzine and fexofenadine were the most potent, with no difference between them (p > 0.1). The most common adverse effect was drowsiness, which was more prevalent among first-generation drugs (p < 0.01). Generic loratadine, fexofenadine and cetirizine halos were higher than their controls (p <0.03).. STUDY LIMITATIONS: A single-center study evaluating only aspects related to histamine. CONCLUSIONS: Brazilian commercial antihistamines presented different profiles of inhibition of wheal and flares in the histamine test, as well as adverse effects. Generic loratadine, fexofenadine and cetirizine presented larger flares than brand drugs. PMID- 29723374 TI - Case for diagnosis. Multinucleated cell angiohistiocytoma. AB - Multinucleate cell angiohistiocytoma is a rare idiopathic benign fibrohistiocytic and vascular proliferation usually presenting as multiple asymptomatic papules, red to violaceous in colour, primarily located on the extremities of middle-aged females. This entity is probably underdiagnosed due to the lack of recognition by clinicians and pathologists. We describe a patient with a multinucleate cell angiohistiocytoma of the face, a less frequent localization, in order to increase awareness of this entity and elucidate its clinical, histopathological, and immunohistochemistry features. PMID- 29723373 TI - Skin manifestations of tick bites in humans. AB - Ticks are blood-sucking arthropods that attach to human skin through oral devices causing diverse initial cutaneous manifestations, and may also transmit serious infectious diseases. In certain situations, the Health Teams (and especially dermatologists) may face difficulties in identifying the lesions and associating them to the parasites. To assist them in clinical diagnosis, we suggest a classification of the skin manifestations in primary lesions, which occur by the attachment the tick to the host (for toxicity and the anticoagulant substances in the saliva and/or marked inflammation by the penetration and permanence of the mouthparts) and secondary lesions that are manifestations of infections caused by rickettsia, bacteria, protozoa and fungi inoculated by the ticks. PMID- 29723375 TI - Diphenciprone as a therapeutic alternative to exuberant periungual warts. PMID- 29723376 TI - Acute prurigo simplex in humans caused by pigeon lice. AB - Pigeon lice are insects that feed on feathers of these birds; their life cycle includes egg, nymph and adult and they may cause dermatoses in humans. Four persons of the same family, living in an urban area, presented with widespread intensely pruritic erythematous papules. A great number of lice were seen in their house, which moved from a nest of pigeons located on the condenser of the air-conditioning to the dormitory of one of the patients. Even in urban environments, dermatitis caused by parasites of birds is a possibility in cases of acute prurigo simplex. Pigeon lice are possible etiological agents of this kind of skin eruption, although they are often neglected, even by dermatologists. PMID- 29723377 TI - Gnathostomiasis: an emerging infectious disease relevant to all dermatologists. AB - Gnathostomiasis is a parasitic infection caused by the third larval stage of nematodes of the genus Gnathostoma. The disease is endemic in some countries around the world. In the American continent, the majority of cases is concentrated in Mexico, Ecuador, and Peru. However, due to increasing traveling either at the intercontinental or intracontinental level, the disease is seen each time more frequently in tourists. Furthermore, countries, such as Brazil, that have never been considered endemic are reporting autochthonous cases. The disease usually presents as a deep-seated or slightly superficial migratory nodule in patients with history of eating raw fish, in the form of ceviche, sushi, or sashimi. Along with the clinical presentation, diagnostic criteria include either blood or tissue eosinophilia. In most instances, these criteria are enough for the attending physician to institute therapy. Chances of finding the parasite are low, unless the biopsy is taken from a very specific area that develops after antiparasitic treatment is started. The potential of other organ involvement with more serious consequences should always be kept in mind. PMID- 29723378 TI - Oral mucosa lesions as atypical manifestation of adult-onset Still's disease. AB - Adult-onset Still's disease is a systemic inflammatory disorder of unknown etiology, characterized by skin rash, spiking fever, arthralgias or arthritis, and leukocytosis. The typical skin rash is evanescent, salmon-pink, nonpruritic and maculopapular, predominantly on the extremities. It is considered one of the major Yamaguchi's criteria in adult-onset Still's disease. However, atypical skin lesions are also described. Here, a 61-year-old woman with sore throat, spiking fever, polyarthritis and evanescent salmon-pink nonpruritic maculopapular skin rash on the extremities was diagnosed with adult-onset Still's disease. In addition, atypical brown macules on oral mucosa, localized on the inner lips and tongue were also observed. Biopsy revealed a neutrophilic infiltrate. Despite treatment and improvement of the adult-onset Still's disease, the atypical oral mucosal lesions persisted. PMID- 29723379 TI - Oxidative stress in patients with endemic pemphigus foliaceus and healthy subjects with anti-desmoglein 1 antibodies. AB - BACKGROUND: Previous studies have shown oxidative stress in pemphigus vulgaris and pemphigus foliaceus, nevertheless, it remains unknown whether a similar response is characteristic of endemic pemphigus foliaceus in Peru. OBJECTIVES: To determine the oxidative stress response in endemic pemphigus foliaceus patients and subjects with positive for anti-desmoglein1 antibodies (anti-dsg1) from endemic areas of Peru. SUBJECTS AND METHODS: This is a cross-sectional study. The study population included 21 patients with Endemic Pemphigus foliaceus and 12 healthy subjects with anti-dsg1 antibodies from the Peruvian Amazon (Ucayali), as well as 30 healthy control subjects. Malondialdehyde, an indicator of lipid peroxidation by free radicals, was measured in serum. RESULTS: We collected 21 cases of endemic pemphigus foliaceus, 15 of them with active chronic disease and 6 in clinical remission. Serum malondialdehyde values in patients with chronic active evolution and healthy subjects with anti-dsg1 antibodies were statistically higher than those of healthy controls (p<0.001). There was no significant difference between serum values of localized and generalized clinical forms. STUDY LIMITATIONS: The main limitation of this present study is the small number of patients with endemic pemphigus and healthy subjects positive for desmoglein 1 antibodies. CONCLUSIONS: The increased serum levels of malondialdehyde in patients with chronic active endemic pemphigus foliaceus and healthy subjects from endemic areas with anti-dsg1 antibodies may suggest a contribution of systemic lipid peroxidation in the pathogenesis of endemic pemphigus foliaceus. PMID- 29723380 TI - Lobomycosis: a therapeutic challenge. AB - Lobomycosis or lacaziosis is a chronic granulomatous fungal infection caused by Lacazia loboi. Most cases are restricted to tropical regions. Transmission is believed to occur through traumatic inoculation in the skin, mainly in exposed areas. It is characterized by keloid-like nodules. There are only a few hundred cases reported. The differential diagnoses include many skin conditions, and treatment is difficult. The reported case, initially diagnosed as keloid, proved to be refractory to surgical treatment alone. It was subsequently approached with extensive surgery, cryotherapy every three months and a combination of itraconazole and clofazimine for two years. No signs of clinical and histopathological activity were detected during follow-up. PMID- 29723382 TI - What does the 4th edition of the World Health Organization Classification of Head and Neck Tumors (2017) bring new about mucosal melanomas? AB - The recently published 4th Edition of the World Health Organization Classification of Head and Neck Tumors addresses the most relevant and updated aspects of tumor biology, including clinical presentation, histopathology, immunohistochemistry, and prognosis of head and neck tumors. The objective of the present study is to compare these updates to the 3rd edition of that book with regard to mucosal melanomas and to highlight the potential factors that differ those tumors from cutaneous melanomas. We observed progress in the understanding of oral and sinonasal mucosal melanomas, which also present themselves, in the molecular scope, differently form cutaneous melanomas. PMID- 29723383 TI - An unusual variant of atrophic dermatofibrosarcoma protuberans. AB - Dermatofibrosarcoma protuberans is an uncommon neoplasm that is most often seen in young adults. The most common clinical presentation is the protruding form; however, other subtypes are known, such as the atrophic. In 2012 there were only 33 reports of this variant in the literature. Many cases of Dermatofibrosarcoma protuberans in children are only discovered in adulthood because they were not diagnosed early. Due the high morbidity, we raise the need for attention from the dermatologist to recognize uncommon neoplasms in the clinical practice. We report a case of a 15-year-old patient diagnosed with atrophic Dermatofibrosarcoma protuberans on the back. PMID- 29723381 TI - The tendency towards the development of psychosexual disorders in androgenetic alopecia according to the different stages of hair loss: a cross-sectional study. AB - BACKGROUND: Androgenetic alopecia is a common dermatological condition affecting both genders. OBJECTIVE: To evaluate the tendency towards development of psychosexual disorders according to the clinical stages of androgenetic alopecia. METHODS: A cross-sectional study was conducted including 353 patients of both sexes on different clinical stages of hair loss, and the patients were enquired about self-perception, self-esteem, sexual experiences, anxiety and depression states. Hair loss was classified by standardized hair loss scales, and psychological effects were assessed with questionnaires. Results were compared to p<0.05. RESULTS: Negative effects on each psychological parameter of androgenetic alopecia in females were higher than in males. While overall comparisons according to hair loss stages for each parameter were significant in males, only sexual experiences, anxiety and depression values were significant in females. Sexual experiences and depression values were higher in Ludwig 3 than in 1&2, while anxiety was higher in Ludwig 3 than 1. Self-perception values in Norwood 2&2A were higher than 3A, 3V, 4 and 4A, while self-esteem values in 2A were higher than 3&4. Sexual experiences values in 2&2A were lower than 3, 3A, 3V, 4 and 4A, while 3&3A were lower than 4&4A. Depression was lower in 2A than 3, 3A, and 3V, and lower in 2A than 4A. Anxiety was lower in 2A than in 4&4A. STUDY LIMITATIONS: Relatively small number of patients, who were from a single center. CONCLUSIONS: In the management of androgenetic alopecia, it should be considered that patients may need psychological support according to the clinical stages, because of increased tendency to develop psychosexual disorders. PMID- 29723384 TI - Prevalence of smoking, alcohol consumption and metabolic syndrome in patients with psoriasis. AB - BACKGROUND: Coexistence of obesity, hypertension, insulin resistance and dyslipidemia is defined as metabolic syndrome (MBS), which is among the important risk indicators for cardiovascular diseases, diabetes and stroke. Smoking and alcohol consumption are the other factors which lead to an increase in the risk of cardiovascular disease. OBJECTIVE: To investigate the prevalence of metabolic syndrome, smoking and alcohol consumption in psoriasis patients and the relationship between disease severity and these factors. METHODS: This cross sectional study enrolled 563 patients with chronic plaque-type psoriasis, all of which completed a questionnaire and underwent a complete physical examination. Data about MBS components, psoriasis severity/duration, smoking and alcohol consumption, and cardiovascular diseases were recorded. RESULTS: A total of 563 patients with ages ranging from 18 to 78 years were evaluated. Metabolic syndrome was found in 12.6% of the patients [central obesity (38.7%), hypertension (14.3%), dyslipidemia (18.6%), diabetes (9.2%)], while 50.3% had smoking, and 3.3% had alcohol consumption. Patients with metabolic syndrome were older and more likely to have a longer disease duration than those without metabolic syndrome (p<0.05 for each). The prevalence of metabolic syndrome was higher in women than in men. Psoriasis was more severe in patients with central obesity, diabetes and smoking than in those without (p<0.05 for each). STUDY LIMITATIONS: Retrospective design. CONCLUSIONS: Our results indicate that MBS is a risk factor for psoriasis patients with advanced age. The relationship between disease severity and obesity, diabetes, and smoking in psoriasis patients indicates that the patients should be informed about the potential metabolic risks and receive therapies for behavioral changes besides anti-psoriatic treatment in order to minimize these risks. PMID- 29723386 TI - Factors associated with diarrhea in children under five years old in the state of Pernambuco, according to surveys conducted in 1997 and 2006. AB - OBJECTIVE Describe and compare variations of the factors associated with the prevalence of diarrhea in children under five years old in the state of Pernambuco. METHODS We used the databases of two population-based surveys from the years 1997 and 2006, with 2,078 and 1,650 children, respectively, evaluated in 18 municipalities of Pernambuco (Metropolitan Region of Recife, urban and rural interior). The variables, allocated at hierarchical levels, were analyzed using prevalence and Poisson regression ratios. RESULTS Only four variables were independently associated and were included in the final hierarchical model: geographical area, number of people per room, maternal age and the age of the child. In 1997: urban interior = 1.33 (95%CI 1.06-1.66), rural interior = 1.22 (95%CI 0.97-1.53) and in 2006: urban interior = 1.87 (95%CI 1.31-2.66), rural interior = 2.07 (95%CI 1.50-2.85); number of persons per room (1997): 1 to less than 2 = 1.29 (95%CI 0.98-1.68), two or more = 1.47 (95%CI 1.11-1.95) and in 2006: 1 to less than 2 = 0.86 (95%CI 0.68-1.09), two or more = 1.29 (95%CI 0.94 1.75); maternal age (1997): 10 to 19 years = 1.48 (95%CI 1.05-2.08), 20 to 24 years = 1.23 (95%CI 0.94-1.60), 25 to 34 years = 1.01 (95%CI 0.78-1.30) and in 2006: 10 to 19 years old = 1.70 (95%CI 1.08-2.66), 20 to 24 years old = 1.64 (95%CI 1.16-2.32), 25 to 34 years = 1.20 (95%CI 0.89-1.62); and age of the child (1997): 0-11 months = 1.57 (95%CI 1.27-1.94), 12-23 months = 1.73 (95%CI 1.41 2.12) and in 2006: 0-11 months = 1.04 (95%CI 0.76-1.41), 12-23 months = 1.77 (95%CI 1.41-2.23). CONCLUSIONS There was a great variability of the conditioners of diarrhea in children between the two periods analyzed. At the public policy level, despite changes in terms of people, time sequences, and geographic spaces, diarrhea remains on an important scale in the ranking of government power. PMID- 29723385 TI - Prepregnancy body mass index, gestational weight gain, and birth weight in the BRISA cohort. AB - OBJECTIVE To analyze the effects of maternal pre-pregnancy body mass index and weight gain during pregnancy on the baby's birth weight. METHODS We conducted a cross-sectional study with 5,024 mothers and their newborns using a Brazilian birth cohort study. In the proposed model, estimated by structural equation modeling, we tested socioeconomic status, age, marital status, pre-pregnancy body mass index, smoking habit and alcohol consumption during pregnancy, hypertension and gestational diabetes, gestational weight gain, and type of delivery as determinants of the baby's birth weight. RESULTS For a gain of 4 kg/m2 (1 Standard Deviation [SD]) in pre-pregnancy body mass index, there was a 0.126 SD increase in birth weight, corresponding to 68 grams (p < 0.001). A 6 kg increase (1 SD) in gestational weight gain represented a 0.280 SD increase in newborn weight, correponding to 151.2 grams (p < 0.001). The positive effect of pre pregnancy body mass index on birth weight was direct (standardized coefficient [SC] = 0.202; p < 0.001), but the negative indirect effect was small (SC = 0.076, p < 0.001) and partially mediated by the lower weight gain during pregnancy (SC = -0.070, p < 0.001). The positive effect of weight gain during pregnany on birth weight was predominantly direct (SC = 0.269, p < 0.001), with a small indirect effect of cesarean delivery (SC = 0.011; p < 0.001). Women with a higher pre-pregnancy body mass index gained less weight during pregnancy (p < 0.001). CONCLUSIONS The effect of gestational weight gain on the increase in birth weight was greater than that of pre-pregnancy body mass index. PMID- 29723387 TI - Are there differences in the quality of the diet of working and stay-at-home women? AB - OBJECTIVE To verify whether there is an association between the quality of the diet and the inclusion of women in the labor market and whether the education level would modify this association. We have analyzed the differences according to education level and evaluated whether the insertion or not in the market modifies the association between the quality of the diet and education level. METHODS This is a cross-sectional population-based study that has used data from the Campinas Health Survey (2008 ISACamp). We have evaluated the diet of 464 women, aged 18 to 64 years, using the Brazilian Healthy Eating Index - Revised. We have estimated the means of the total score and index components using simple and multiple linear regression. RESULTS We have observed no difference in the quality of diet of working and stay-at-home women. The analysis stratified by education level showed a lower intake of fruits among stay-at-home women in the segment of lower education level, in relation to working women. Among all women, a lower education level was associated with lower overall quality of the diet, higher intake of sodium, and lower intake of fruits, vegetables, whole grains, milk, and saturated fat. On the other hand, the inclusion in the labor market changed the effect of the education level on the quality of the diet. In the stay at-home stratum, a low education level was associated with poorer quality of the diet and lower consumption of fruits, dark green and orange vegetables, and whole grains. Among the working women, a low education level was associated with higher intake of sodium and lower intake of vegetables, whole grains, and milk and dairy products. CONCLUSIONS The results show inequities in the profile of food in relation to education level and inclusion in the labor market, which shows the relevance of public policies that increase the access to education and provide guidance on a healthy diet. PMID- 29723388 TI - Burnout in the staff of a chronic care hospital. AB - OBJECTIVE To estimate the prevalence of Burnout in a medium or long-stay hospital, to monitor its evolution and to highlight the importance of cut-off points used to avoid distortions in the interpretation of the results. METHODS Two cross-sectional studies (2013-2016) were carried out, applying the Spanish version of the Maslach Burnout Inventory to the staff of a chronic care hospital (n = 323). Result variables were: Burnout prevalence and a high degree of affectation of the subscales and predictor variables: sociodemographic characteristics and factors that trigger and modulate the syndrome. The association between variables was quantified using odds ratio. RESULTS The participation rate went from 31.5% to 39.3%. The professionals presented a mean level of Burnout in both moments, observing a lower degree of affectation of the depersonalization subscales and personal accomplishment in the 2016 cut-off. The average score of the subscales in 2016 was 21.5 for emotional fatigue, 4.7 for depersonalization and 41.7 for personal fulfillment, compared to the values of emotional fatigue = 21.6, depersonalization = 6.9 and personal fulfillment = 36.3 obtained in 2013. The emotional fatigue score was slightly higher than the mean value of the national studies (19.9), while the rest of the values were similar to the mean values of the studies considered. The prevalence of Burnout and the interpretation of the results varied significantly according to the cut-off points considered. In both studies, sociodemographic variables showed little significance, while social support and interpersonal relationships were associated with the degree of burnout among professionals. CONCLUSIONS Our prevalence of Burnout was similar to that of other studies consulted, although the emotional component is more marked in our environment. The interpretation of the results varied significantly according to the cut-off points applied, due to the cross-cultural differences. PMID- 29723389 TI - Factors associated with preventable infant death: a multiple logistic regression. AB - OBJECTIVE To identify and analyze factors associated with preventable child deaths. METHODS This analytical cross-sectional study had preventable child mortality as dependent variable. From a population of 34,284 live births, we have selected a systematic sample of 4,402 children who did not die compared to 272 children who died from preventable causes during the period studied. The independent variables were analyzed in four hierarchical blocks: sociodemographic factors, the characteristics of the mother, prenatal and delivery care, and health conditions of the patient and neonatal care. We performed a descriptive statistical analysis and estimated multiple hierarchical logistic regression models. RESULTS Approximatelly 35.3% of the deaths could have been prevented with the early diagnosis and treatment of diseases during pregnancy and 26.8% of them could have been prevented with better care conditions for pregnant women. CONCLUSIONS The following characteristics of the mother are determinant for the higher mortality of children before the first year of life: living in neighborhoods with an average family income lower than four minimum wages, being aged <= 19 years, having one or more alive children, having a child with low APGAR level at the fifth minute of life, and having a child with low birth weight. PMID- 29723390 TI - Green spaces and mortality due to cardiovascular diseases in the city of Rio de Janeiro. AB - OBJECTIVE Investigate the association between exposure to green spaces and mortality from ischemic heart and cerebrovascular diseases, and the role of socioeconomic status in this relationship, in the city of Rio de Janeiro, Brazil. METHODS Ecological study, with the census tracts as unit of analysis. This study used data from deaths due to ischemic heart and cerebrovascular diseases among residents aged over 30 years, from 2010 to 2012. Exposure to green was estimated using the Normalized Difference Vegetation Index based on satellite images. The associations between exposure to green spaces and mortality rates due to ischemic heart and cerebrovascular diseases, standardized by gender and age, were analyzed using conditional autoregressive models, adjusted for the density of light and heavy traffic routes, pollution proxy, and by the socioeconomic situation, measured by the Social Development Index. Analyzes stratified by socioeconomic levels were also carried out, given by the tertiles of the Social Development Index. RESULTS Among the greener sectors, with a Normalized Difference Vegetation Index above the third quartile, the reduction in mortality due to ischemic heart disease was 6.7% (95%CI 3.5-9.8) and cerebrovascular was 4.7% (95%CI 1.2-8.0). In the stratified analysis, the protective effect of green spaces on ischemic heart disease mortality was observed among the greenest sectors of all strata, and it was higher for those with a lower socioeconomic level (8.6%, 95%CI 1.8-15.0). In the case of mortality due to cerebrovascular diseases, the protective effect was verified only for the greenest sectors of the lowest socioeconomic level (9.6%, 95%CI 2.3-16.5). CONCLUSIONS Mortality rates for ischemic heart and cerebrovascular diseases are inversely associated with exposure to green spaces when controlling socioeconomic status and air pollution. The protective effect of green spaces is greater among the tracts of lower socioeconomic level. PMID- 29723391 TI - In vivo transposon tagging in the nonheterocystous nitrogen-fixing cyanobacterium Leptolyngbya boryana. AB - Nitrogenase is an oxygen-vulnerable metalloenzyme that catalyzes nitrogen fixation. It largely remains unknown how nitrogenase coexists with oxygenic photosynthesis in nonheterocystous cyanobacteria, since there have been no appropriate model cyanobacteria so far. Here, we demonstrate in vivo transposon tagging in the nonheterocystous cyanobacterium Leptolyngbya boryana as a forward genetics approach. By conjugative transfer, a mini-Tn5-derived vector, pKUT-Tn5 Sm/Sp, was transferred from Escherichia coli to L. boryana cells. Of 1839 streptomycin-resistant colonies, we isolated three mutants showing aberrant diazotrophic growth. Genome resequencing identified the insertion sites of the transposon in the mutants. This in vivo transposon tagging mutagenesis of L. boryana provides a promising system to investigate molecular mechanisms to resolve the Oxygen Paradox between nitrogen fixation and oxygenic photosynthesis in cyanobacteria. PMID- 29723392 TI - High-frequency autonomic modulation: a new model for analysis of autonomic cardiac control. AB - BACKGROUND AND PURPOSE: Increase in high-frequency beat-to-beat heart rate oscillations by torsadogenic hERG blockers appears to be associated with signs of parasympathetic and sympathetic co-activation which cannot be assessed directly using classic methods of heart rate variability analysis. The present work aimed to find a translational model that would allow this particular state of the autonomic control of heart rate to be assessed. EXPERIMENTAL APPROACH: High frequency heart rate and heart period oscillations were analysed within discrete 10 s intervals in a cohort of 200 healthy human subjects. Results were compared to data collected in non-human primates and beagle dogs during pharmacological challenges and torsadogenic hERG blockers exposure, in 127 genotyped LQT1 patients on/off beta-blocker treatment and in subgroups of smoking and non smoking subjects. KEY RESULTS: Three states of autonomic modulation, S1 (parasympathetic predominance) to S3 (reciprocal parasympathetic withdrawal/sympathetic activation), were differentiated to build a new model of heart rate variability referred to as high-frequency autonomic modulation. The S2 state corresponded to a specific state during which both parasympathetic and sympathetic systems were coexisting or co-activated. S2 oscillations were proportionally increased by torsadogenic hERG-blocking drugs, whereas smoking caused an increase in S3 oscillations. CONCLUSIONS AND IMPLICATIONS: The combined analysis of the magnitude of high-frequency heart rate and high-frequency heart period oscillations allows a refined assessment of heart rate autonomic modulation applicable to long-term ECG recordings and offers new approaches to assessment of the risk of sudden death both in terms of underlying mechanisms and sensitivity. PMID- 29723393 TI - Phase 2 trial of bortezomib in combination with rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with bortezomib, rituximab, methotrexate, and cytarabine for untreated mantle cell lymphoma. AB - BACKGROUND: Although the outcomes of patients with mantle cell lymphoma (MCL) have improved, there is still no cure. Bortezomib has a 33% response rate in relapsed/refractory MCL and has shown additive and/or synergistic effects in preclinical trials with known effective agents. METHODS: This is a report of a prospective phase 2 trial of bortezomib added to rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (BzR hyperCVAD)/rituximab, high-dose methotrexate, and high-dose cytarabine (BzR-MA) for 95 patients with newly diagnosed MCL. RESULTS: The overall and complete response rates were 100% and 82%, respectively. Hematologic toxicity was high but expected and did not lead to an increased incidence of neutropenic fever or dose reductions in comparison with a similar reported regimen without bortezomib. After a median follow-up of 44 months, the median overall survival had not been reached, and the time to treatment failure (TTF) was 55 months, which is not different from that of historical controls. CONCLUSIONS: BzR-hyperCVAD/BzR-MA at the dose and schedule studied produced high rates of response and a TTF similar to that of historical reports without bortezomib. Cancer 2018;124:2561-9. (c) 2018 American Cancer Society. PMID- 29723394 TI - Discontinuation of long-acting reversible contraception versus short-term hormonal methods in urban Ghana: A pilot longitudinal study. PMID- 29723395 TI - The scale for body image concerns during pregnancy: Development and validation. AB - PURPOSE: This study aimed to develop a scale that measures body image concerns during pregnancy. DESIGN AND METHODS: The study administered draft of the scale for validity and reliability analysis to 320 pregnant women who visited the maternity polyclinic of a public hospital in eastern Turkey between February and May 2016. FINDINGS: The Cronbach's alpha reliability coefficient of the entire scale was 0.88. Factor analysis determined that the 23 items that explained 58.578% of total variance were in four of the factors. PRACTICE IMPLICATIONS: The scale for body image concerns during pregnancy was a valid and reliable scale. PMID- 29723396 TI - Risk factors for locoregional disease recurrence after breast-conserving therapy in patients with breast cancer treated with neoadjuvant chemotherapy: An international collaboration and individual patient meta-analysis. AB - BACKGROUND: Several studies have reported a high risk of local disease recurrence (LR) and locoregional disease recurrence (LRR) in patients with breast cancer after neoadjuvant chemotherapy (NCT) and breast-conserving therapy (BCT). The objective of the current study was to identify potential risk factors for LR and LRR after NCT and BCT. METHODS: Individual patient data sets from 9 studies were pooled. The outcomes of interest were the occurrence of LR and/or LRR. A 1-stage meta-analytic approach was used. Cox proportional hazards regression models were applied to identify factors that were predictive of LR and LRR, respectively. RESULTS: A total of 9 studies (4125 patients) provided their data sets. The 10 year LR rate was 6.5%, whereas the 10-year LRR rate was 10.3%. Four factors were found to be associated with a higher risk of LR: 1) estrogen receptor-negative disease; 2) cN + disease; 3) a lack of pathologic complete response in axilla (pN0); and 4) pN2 to pN3 disease. The predictive score for LR determined 3 risk groups: a low-risk, intermediate-risk, and high-risk group with 10-year LR rates of 4.0%, 7.9%, and 20.4%, respectively. Two additional factors were found to be associated with an increased risk of LRR: cT3 to cT4 disease and a lack of pathologic complete response in the breast. The predictive score for LRR determined 3 risk groups; a low-risk, intermediate-risk, and high-risk group with 10-year LRR rates of 3.2%, 10.1%, and 24.1%, respectively. CONCLUSIONS: BCT after NCT appears to be an oncologically safe procedure for a large percentage of patients with breast cancer. Two easy-to-use clinical scores were developed that can help clinicians to identify patients at higher risk of LR and LRR after NCT and BCT and individualize the postoperative treatment plan and follow-up. Cancer 2018;124:2923-30. (c) 2018 American Cancer Society. PMID- 29723397 TI - Early results of lower dose dasatinib (50 mg daily) as frontline therapy for newly diagnosed chronic-phase chronic myeloid leukemia. AB - BACKGROUND: Dasatinib is a potent BCR-ABL1 and Src family tyrosine kinase inhibitor. It is approved at a dose of 100 mg orally daily for the treatment of chronic myeloid leukemia in chronic phase (CML-CP). This dose schedule is associated with myelosuppression and pleural effusions. Anecdotal data suggest that lower doses may be as effective and less toxic. The aim of this study was to assess the efficacy and safety of a lower dose of dasatinib (50 mg daily) in patients with newly diagnosed CML-CP. METHODS: Seventy-five patients with newly diagnosed CML-CP received dasatinib 50 mg daily. The eligibility and response criteria were standards used in previous protocols. RESULTS: At a median follow up of 9 months, 60 patients were evaluable for a response at 3 months. The rates of patients achieving BCR-ABL1 transcript levels <= 10% and <= 1% at 3 months by the International Standard were 93% and 72%, respectively. The rates of complete cytogenetic response by conventional cytogenetics or fluorescence in situ hybridization at 6 and 12 months were 86% and 88%, respectively. At 12 months, 79%, 71%, and 46% of the patients had achieved a major molecular response, a molecular response with a 4.0-log reduction, and a molecular response with a 4.5 log reduction, respectively. Nine patients had a dose interruption for <=14 days. Only 1 patient developed a pleural effusion requiring a dose reduction to 20 mg. All patients remained alive and with no transformation so far. CONCLUSION: Dasatinib 50 mg daily is active and well tolerated in patients with newly diagnosed CML-CP. It should be further explored as a new potential standard-of care option for chronic myeloid leukemia. Cancer 2018;124:2740-2747. (c) 2018 American Cancer Society. PMID- 29723398 TI - Trends in incidence and 5-year mortality in men with newly diagnosed, metastatic prostate cancer-A population-based analysis of 2 national cohorts. AB - BACKGROUND: Early detection has increased prostate cancer (PCa) incidence. Randomized trials have demonstrated that early detection reduces the incidence of de novo metastatic PCa. Concurrently, life-prolonging treatments have been introduced for patients with advanced PCa. On a populations-based level, the authors analyzed whether early detection and improved treatments changed the incidence and 5-year mortality of men with de novo metastatic PCa. METHODS: Men diagnosed with PCa during the periods 1980 to 2011 and 1995 to 2011 were identified in the US Surveillance, Epidemiology, and End Results (SEER) program and the Danish Prostate Cancer Registry (DaPCaR), respectively, and stratified according to period of diagnosis. Age-standardized incidence rates were calculated. Five-year mortality rates for de novo metastatic PCa were analyzed using competing risk analysis. RESULTS: Totals of 426,266 and 47,024 men were identified in SEER and DaPCaR, respectively. Of these, 29,555 and 6874 had de novo metastatic PCa. The incidence of de novo metastatic PCa decreased (from 12.0 to 4.4 per 100,000 men) in the SEER cohort (1980-2011), whereas it increased (from 6.7 to 9.9 per 100,000 men) in the DaPCaR cohort (1995-2011). Five-year PCa mortality in the SEER cohort was stable for men diagnosed with de novo metastatic PCa from 1980 to 1994 and increased slightly in the latest periods studied (P < .0001), whereas it decreased by 16.6% (P < .0001) in the DaPCaR cohort. CONCLUSIONS: Despite earlier detection, de novo metastatic PCa remains associated with a high risk of 5-year disease-specific mortality. The reduced 5-year PCa mortality in the Danish cohort is largely explained by lead-time. Early detection strategies do indeed decrease the incidence of de novo metastatic PCa, as observed in the SEER cohort. This achievement, however, must be weighed against the unsolved issue of overdetection and overtreatment of indolent PCa. Cancer 2018;124:2931-8. (c) 2018 American Cancer Society. PMID- 29723399 TI - Outcomes of microvascular flap reconstruction of the head and neck in patients receiving systemic immunosuppressive therapy for organ transplantation. AB - BACKGROUND: For organ transplant recipients, cancer secondary to immunosuppressive therapy threatens long-term survival. The associated multiple comorbidities make major free flap reconstruction following cancer surgery a complicated event. This study evaluates the outcomes of free flap reconstruction in this population. METHODS: A retrospective chart review of all head and neck free flap cases in patients with a history of organ transplantation receiving systemic immunosuppressive therapy between 2005 and 2017 at a single-institution was conducted. RESULTS: Of 57 organ transplant patients, 25 patients (28 flaps) were included. Flaps used included the anterolateral thigh (n = 17), radial forearm (n = 4), latissimus dorsi (n = 3), fibula (n = 2), lateral arm (n = 1), and thoracodorsal artery perforator (n = 1) flaps. The most common organ transplant was kidney, then lung, liver, and heart. Mean inpatient stay was 8.2 days (range, 4-28). Complications occurred in 15 patients, with no total or partial flap losses. CONCLUSION: Major head and neck free flap reconstructive surgery can be performed safely in organ transplant patients receiving immunosuppressive therapy. Meticulous multidisciplinary care is required to achieve consistently successful outcomes. PMID- 29723400 TI - Meta-regression analysis to evaluate relationships between maternal blood levels of placentation biomarkers and low delivery weight. AB - BACKGROUND: Caution is required for women at increased risk of low neonatal delivery weight. OBJECTIVE: To evaluate relationships between maternal placentation biomarkers and the odds of low delivery weight. SEARCH STRATEGY: Databases including PubMed/MEDLINE were searched up to May 2017 using keywords involving biomarker names and "low birthweight." SELECTION CRITERIA: English language studies providing true- and false-positive, and true- and false-negative results of low delivery weight classified by maternal blood levels of placentation biomarkers (in units of multiple of the mean [MoM]) were included. DATA COLLECTION AND ANALYSIS: Coefficients representing changes in log odds ratio for low delivery weight per 1 MoM increase in maternal blood placentation biomarkers, and those adjusted for race, sampling period, and/or study quality were calculated. MAIN RESULTS: Adjusted coefficients representing changes in log odds ratio for low delivery weight per 1 MoM increase in maternal blood levels of alpha-fetoprotein (AFP) and beta-human chorionic gonadotropin (beta-hCG) were significantly greater than 0 (both P<0.001), whereas that for pregnancy associated plasma protein A (PAPP-A) was significantly less than 0 (P=0.028). Adjusted models explained the higher proportion of between-study variance better than non-adjusted models. CONCLUSIONS: Elevated AFP and beta-hCG, and reduced PAPP-A in maternal blood were positively associated with odds of low delivery weight. PMID- 29723401 TI - Sparse data and use of logistic regression. PMID- 29723402 TI - Response: The risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptic drugs: Comment on data sparsity. PMID- 29723403 TI - Photosensitivity as an early marker of epileptic and developmental encephalopathies. PMID- 29723404 TI - The risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptic drugs: Comment on data sparsity. PMID- 29723405 TI - Cystic bone tumors of the foot and ankle. AB - Bone tumors are relatively rare in the foot and ankle region. Many of them present as cystic lesions on plain films. Due to the relative rarity of these lesions and the complex anatomy of the foot and ankle region, identification of such lesions is often delayed or they get misdiagnosed and mismanaged. This review discusses the most common cystic tumors of the foot and ankle including their radiographic features and principles of management. PMID- 29723406 TI - LOgistic File for Robson Classification (LOFIROC) as a practical solution for worldwide practical implementation of the Robson classification. PMID- 29723409 TI - Prostate cancer screening: And the pendulum swings. PMID- 29723407 TI - Rationale and emerging strategies for immune checkpoint blockade in soft tissue sarcoma. AB - Soft tissue sarcomas (STS) are heterogeneous, mesenchymal malignancies with variable biologic behavior. The primary management for localized STS is surgical resection, which may be combined with neoadjuvant or adjuvant radiation therapy to increase the probability of achieving local control. Many patients with large, high-grade STS develop metastatic disease. Several clinical trials of immune checkpoint blockade for STS have produced promising responses in patients with metastatic disease. In this review, recent and ongoing clinical trials of immune checkpoint inhibition for STS are discussed. The authors explain the rationale for immune checkpoint inhibition and radiation therapy and highlight new studies testing this combination in the neoadjuvant setting for patients with high-risk STS. In addition, they describe novel combinations of immunotherapy with targeted therapies and chemotherapies being tested in the metastatic setting and discuss how these combinations have the potential to be integrated into adjuvant therapy in the future. PMID- 29723411 TI - The clinical behavior of well differentiated liposarcoma can be extremely variable: A retrospective cohort study at a major sarcoma center. AB - BACKGROUND: The pathogenesis of well differentiated liposarcoma (WDLPS) is poorly understood and pathologic characterization is often challenging. Descriptive terms (such as sclerosing, myxoid, inflammatory, spindle cell) are frequently encountered in the pathology reports and are of unknown clinical significance. METHODS: Sixty-two patients with primary retroperitoneal WDLPS resected at our institution were identified (1996-2011). Pathology reports of surgical resection specimens were retrospectively reviewed and descriptive qualifiers to the WDLPS diagnosis noted. RESULTS: Descriptive qualifiers were associated with 36 (58%) cases. WDLPS with pathologic qualifiers were more likely to be larger (median size 32 vs 25.5 cm, P = 0.01) and multifocal (36.1 vs 7.7%, P = 0.01) at diagnosis, require concomitant organ resection at surgery (50 vs 23.1%, P = 0.03), and have higher incidence of local recurrence (83.3 vs 38.5%, P < 0.01). WDLPS with pathologic qualifiers showed significantly shorter local recurrence free survival (LRFS) and trend towards shorter distant recurrence-free survival and overall survival. Use of pathologic qualifiers with a WDLPS diagnosis independently predicted risk of worse LRFS. CONCLUSIONS: Retroperitoneal WDLPS tumors characterized by pathologic descriptive qualifiers appear to behave more aggressively than their more typical counterparts. Further investigation is warranted to more consistently characterize and define the pathologic features commonly seen in WDLPS as these may impact patient outcomes. PMID- 29723412 TI - Single-incision laparoscopic abdominal cerclage placement: A retrospective study of single-port and robotic single-port versus multiport laparoscopy. PMID- 29723410 TI - The association between preoperative serum interleukin-6 levels and postoperative prognosis in patients with T2 gallbladder cancer. AB - BACKGROUND: Interleukin-6 (IL-6) is closely associated with tumor progression. Whether it can predict postoperative prognosis of patients with T2 gallbladder cancer (GBC) remains controversial. METHODS: We retrospectively collected the medical records of 125 patients with T2 GBC. Then, we analyzed the association between preoperative serum IL-6 levels and postoperative survival by multivariate Cox analyses and Kaplan-Meier curves in exploratory subgroups. RESULTS: Predictive effects of serum IL-6 levels on overall survival were similar across most of the evaluated subgroups, except in different tumor location subgroups. The independent odds ratio (OR) of serum IL-6 levels was 2.57 (95%CI 1.73-3.82) in the hepatic side subgroup, while it was 1.15 (95%CI 0.68-1.93) in the peritoneal side subgroup (P = 0.014 for interaction). When we categorized serum IL-6 levels by median value (4.2 pg/mL), the 5-year survival rate of patients with high serum IL-6 levels was significantly higher in the hepatic side subgroup (58.5% vs 14.8%, P < 0.001), but no such difference was found in the peritoneal side subgroup (62.2% vs 67.6%, P = 0.722). CONCLUSIONS: Preoperative serum IL-6 is significantly associated with prognostic implications in patients with hepatic side T2 GBC, not in those with peritoneal side tumors. PMID- 29723413 TI - Reply to "Poorly differentiated clusters in colorectal liver metastases: Prognostic significance in synchronous and metachronous metastases". PMID- 29723408 TI - A novel cross-species inhibitor to study the function of CatSper Ca2+ channels in sperm. AB - BACKGROUND AND PURPOSE: Sperm from many species share the sperm-specific Ca2+ channel CatSper that controls the intracellular Ca2+ concentration and, thereby, the swimming behaviour. A growing body of evidence suggests that the mechanisms controlling the activity of CatSper and its role during fertilization differ among species. A lack of suitable pharmacological tools has hampered the elucidation of the function of CatSper. Known inhibitors of CatSper exhibit considerable side effects and also inhibit Slo3, the principal K+ channel of mammalian sperm. The compound RU1968 was reported to suppress Ca2+ signaling in human sperm by an unknown mechanism. Here, we examined the action of RU1968 on CatSper in sperm from humans, mice, and sea urchins. EXPERIMENTAL APPROACH: We resynthesized RU1968 and studied its action on sperm from humans, mice, and the sea urchin Arbacia punctulata by Ca2+ fluorimetry, single-cell Ca2+ imaging, electrophysiology, opto-chemistry, and motility analysis. KEY RESULTS: RU1968 inhibited CatSper in sperm from invertebrates and mammals. The compound lacked toxic side effects in human sperm, did not affect mouse Slo3, and inhibited human Slo3 with about 15-fold lower potency than CatSper. Moreover, in human sperm, RU1968 mimicked CatSper dysfunction and suppressed motility responses evoked by progesterone, an oviductal steroid known to activate CatSper. Finally, RU1968 abolished CatSper-mediated chemotactic navigation in sea urchin sperm. CONCLUSION AND IMPLICATIONS: We propose RU1968 as a novel tool to elucidate the function of CatSper channels in sperm across species. PMID- 29723414 TI - Fast reactivation of photosynthesis in arctic phytoplankton during the polar night1. AB - Arctic microalgae experience long periods of continuous darkness during the polar night, when they are unable to photosynthesize. Despite numerous studies on overwintering strategies, such as utilization of stored energy products, formation of resting stages, reduction of metabolic rates and heterotrophic lifestyles, there have been few attempts to assess the in situ physiological state and restoration of the photosynthetic apparatus upon re-illumination. In this study, we found diverse and active marine phytoplankton communities during the polar night at 78 degrees N. Furthermore, we observed rapid changes (<=20 min) in the efficiency of photosynthetic electron transport upon re-illumination. High photosynthetic capacity and net primary production were established after 24 h of re-illumination. Our results suggest that some Arctic autotrophs maintain fully functional photosystem II and downstream electron acceptors during the polar night even though the low in situ net primary production levels measured in January prove that light was not sufficient to support any measurable primary production. Due to low temperatures resulting in low respiratory rates as well as the absence of photodamage during the polar night, maintenance of basic photosynthetic machinery may actually pose relatively low metabolic costs for algal cells. This could allow Arctic microalgae to endure the polar night without the formation of dormant stages, enabling them to recover and take advantage of light immediately upon the suns return during the winter-spring transition. PMID- 29723416 TI - The evolution of dasatinib dosage over the years and its relevance to other anticancer medications. PMID- 29723417 TI - Discontinuation of tyrosine kinase inhibitors in chronic myeloid leukemia: Recommendations for clinical practice from the French Chronic Myeloid Leukemia Study Group. AB - BACKGROUND: The ultimate goal of chronic myeloid leukemia management in the tyrosine kinase inhibitor (TKI) era for patients who obtain deep molecular responses is maintaining a durable off-treatment response after treatment discontinuation; this situation is called treatment-free remission (TFR). Knowledge accumulated during the last 10 years justifies moving TFR strategies from research to clinical practice. METHODS: Twenty experts from the French Chronic Myeloid Leukemia Study Group (France Intergroupe des Leucemies Myeloides Chroniques), including 17 hematologists, 2 molecular biologists, and 1 cytogeneticist, critically reviewed published data with the goal of developing evidence-based recommendations for TKI discontinuation in clinical practice. RESULTS: Clinically relevant questions were addressed, including the selection of candidate patients (with known prognostic factors for outcomes taken into account), detailed monitoring procedures during the treatment-free phase, a definition of relapse requiring therapy resumption, and monitoring after treatment reintroduction. CONCLUSIONS: This work presents consensus statements with the aim of guiding physicians and biologists by means of pragmatic recommendations for safe TKI discontinuation in daily practice. Cancer 2018;124:2956-63. (c) 2018 American Cancer Society. PMID- 29723418 TI - Multiple Doses of Rifabutin Reduce Exposure of Doravirine in Healthy Subjects. AB - Doravirine is a nonnucleoside reverse transcriptase inhibitor in clinical development for the treatment of human immunodeficiency virus-1 infection in combination with other antiretroviral therapies. The cytochrome P450 (CYP)3A dependent metabolism of doravirine makes it susceptible to interactions with modulators of this pathway, including the antituberculosis treatment rifampin. Rifabutin, an alternative antibiotic used to treat tuberculosis, may have a lower magnitude effect on CYP3A. The aim of this trial was to determine the effect of steady-state rifabutin on doravirine single-dose pharmacokinetics and tolerability. In this open-label, 2-period, fixed-sequence, drug-drug interaction study, healthy subjects received a single dose of doravirine 100 mg alone and coadministered on day 14 of once-daily administration of rifabutin 300 mg for 16 days. Plasma samples were taken to determine doravirine pharmacokinetics, and safety was monitored throughout. Dose adjustment of doravirine in the presence of coadministered rifabutin was explored through nonparametric superposition analysis. Rifabutin reduced doravirine area under the concentration-time curve from time zero to infinite and plasma drug concentration 24 hours postdose with geometric mean ratios ([rifabutin+doravirine]/[doravirine alone]) (90%CIs) of 0.50 (0.45-0.55) and 0.32 (0.28-0.35), respectively. Doravirine apparent clearance increased from 5.9 L/h without rifabutin to 12.2 L/h when coadministered. Doravirine pharmacokinetics with and without coadministered rifabutin were not equivalent. Nonparametric superposition analysis projected that administration of doravirine 100 mg twice daily with rifabutin will restore steady-state trough concentration values to efficacious levels associated with doravirine 100 mg once daily in the absence of CYP3A inducers. Doravirine may be coadministered with rifabutin when the doravirine dose frequency is increased from 100 mg once daily to 100 mg twice daily. PMID- 29723415 TI - The tale of two talins - two isoforms to fine-tune integrin signalling. AB - Talins are cytoplasmic adapter proteins essential for integrin-mediated cell adhesion to the extracellular matrix. Talins control the activation state of integrins, link integrins to cytoskeletal actin, recruit numerous signalling molecules that mediate integrin signalling and coordinate recruitment of microtubules to adhesion sites via interaction with KANK (kidney ankyrin repeat containing) proteins. Vertebrates have two talin genes, TLN1 and TLN2. Although talin1 and talin2 share 76% protein sequence identity (88% similarity), they are not functionally redundant, and the differences between the two isoforms are not fully understood. In this Review, we focus on the similarities and differences between the two talins in terms of structure, biochemistry and function, which hint at subtle differences in fine-tuning adhesion signalling. PMID- 29723420 TI - Simultaneous Determination of 13 Anticoagulant Rodenticidesin Human Blood by Liquid Chromatography-Tandem Mass Spectrometry and its Application in Three Poisoning Cases. AB - Anticoagulant rodenticides are widely used for rodent control around the world. A rapid and sensitive method was developed and validated for the simultaneous determination of 13 anticoagulant rodenticides (coumafuryl, pindone, valone, warfarin, coumatetralyl, coumachlor, diphacinone, dicumarol, chlorophacinone, bromadiolone, difenacoum, flocoumafen, and brodifacoum) in human blood by liquid chromatography-tandem mass spectrometry. After liquid-liquid extraction, the anticoagulant rodenticides were separated on an Eclipse Plus C18 column. Linearities were observed for each analyte in blood ranging from 0.5 to 50 ng/mL, with correlation coefficients over 0.99. The limits of detection ranged from 0.01 to 0.2 ng/mL, and the limits of quantification were 0.5 ng/mL for all analytes. The intraday and interday precisions were <15%, and accuracies ranged from 80.3% to 111.0%. This validated method with high sensitivity has been applied in three anticoagulant rodenticide poisoning cases and has been used successfully in monitoring blood concentrations for months. PMID- 29723419 TI - Vein resection during pancreaticoduodenectomy for pancreatic adenocarcinoma: Patency rates and outcomes associated with thrombosis. AB - BACKGROUND AND OBJECTIVES: Venous patency rates after pancreaticoduodenectomy (PD) with portal vein (PV) resection are not well established, and the oncologic impact of portal vein thrombosis (PVT) is unknown. The primary aim of this study was to determine rates and predictors of PVT after PD with PV resection for pancreatic adenocarcinoma (PDAC). METHODS: A retrospective cohort study was performed on PDAC patients treated with preoperative therapy and PD with PV resection at a high-volume institution (2008-15). Primary outcomes were early and late PVT (<= or >90 days of surgery). Secondary outcomes included major complications and OS. RESULTS: Patients undergoing vein resection (N = 120) included 41.7% (N = 50) primary repair or patch venoplasty, 29.2% (N = 35) primary anastomosis, and 29.2% (N = 35) interposition graft. Thirty-four (28.3%) patients developed PVT (early 7.5% [N = 9]; late 20.8% [N = 25]). Late PVT was often detected concurrently with local recurrence (76.0%; N = 19). There was no association of PVT with vascular resection extent or complications (P > 0.05). On multivariable analysis, PVT was associated with worse OS (HR 2.2 [95% CI 1.34 3.5], P < 0.001). CONCLUSIONS: Overall postoperative patency rates following PV resection PDAC were high. PVT is associated with worse OS, which appears less likely related to technical issues, but rather representative of disease biology. PMID- 29723422 TI - Poorly differentiated clusters in colorectal liver metastases: Prognostic significance in synchronous and metachronous metastases. PMID- 29723423 TI - Is bad intent negligible? Linking victim justice sensitivity, hostile attribution bias, and aggression. AB - The hostile attribution bias (HAB) is a well-established risk factor for aggression. It is considered part of the suspicious mindset that may cause highly victim-justice sensitive individuals to behave uncooperatively. Thus, links of victim justice sensitivity (JS) with negative behavior, such as aggression, may be better explained by HAB. The present study tested this hypothesis in N = 279 German adolescents who rated their JS, HAB, and physical, relational, verbal, reactive, and proactive aggression. Victim JS predicted physical, relational, verbal, reactive, and proactive aggression when HAB was controlled. HAB only predicted physical and proactive aggression. There were no moderator effects. Injustice seems an important reason for aggression irrespective of whether or not it is intentionally caused, particularly among those high in victim JS. Thus, victim JS should be considered as a potential important risk factor for aggression and receive more attention by research on aggression and preventive efforts. PMID- 29723424 TI - Core Entrustable Professional Activities in Clinical Pharmacology for Entering Residency: Value of Interprofessional Health-Care Teams in Medication Prescribing and Medication Error Prevention. AB - In recent years, health care has been increasingly delivered by interprofessional teams in the inpatient, outpatient, and transition-of-care arenas. For many reasons, effective communication between patient-centered care teams and patients is critically important in order to optimize care, ensure patient safety, and prevent medical and medication misadventures. In rapid-paced, high-stress medical environments, it is especially important to carefully evaluate the causes of all misadventures in a manner that avoids assigning blame and identifies the root causes and, through team activity, leads to development of remedies that reduce the likelihood of future misadventures. Using a series of illustrative cases, this paper seeks to bring attention to these issues and provide insights regarding some tools developed to assist in improving patient safety and effective team communication. PMID- 29723421 TI - Oral rehabilitation of the cancer patient: A formidable challenge. AB - Rehabilitation of oral functions following surgery on the jaws is a goal that is often difficult to achieve. Removable dentures supported by remaining teeth or gum are often unstable and seldom satisfactory. On the other hand, endosseous (dental) implants offer a mechanism to provide stability to the dentures. This review, discusses factors related to the tumor, patient, treatment, and physicians which impact upon the feasibility and success of dental implants in patients with oral cancer. PMID- 29723425 TI - Non-Covalent Interactions of a Neuroprotective Peptide Revealed by Photodissociative Cross-Linking in the Gas Phase. AB - The small neuroprotective peptide Cys-Ala-Gln-Lys (CAQK) was selectively tagged with a diazirine group and its photochemical cross-linking was studied with model target peptides. Experimental results in combination with Born-Oppenheimer molecular dynamics revealed the structural preferences for binding to the amino acid residues in the target peptides. Effects of the target peptide sequence and N- and C-terminal modifications are discussed. PMID- 29723426 TI - CYP2C19 or CYP3A5 Genotyping Does Not Predict Clinical Response to Clopidogrel. AB - Along with aspirin, clopidogrel has been a widely used antiplatelet therapeutic regimen. Although generally well tolerated, its efficacy varies among individuals, with the main hypothesis that its bioavailability relies on its bioconversion to the active compound, which, in turn, depends on the genetic background and/or interactions with other drugs. To determine which factors influenced response in our patients, 368 patients receiving combined antiaggregation therapy with aspirin and clopidogrel were followed for 1 year to record 30 novel cardiovascular acute events. This clinical relapse was considered a surrogate end point to measure therapeutic response under the influence of the CYP2C19*2, *3, and *17 and CYP3A5*3 alleles, as well as the effects of concomitant medication and the presence of known cardiovascular risk factors and comorbidity. We show that either single CYP2C19 or CYP3A5 genotyping or combined were not useful to predict clinical efficacy in this cohort. Rather than genetic testing, we have found that clinical observations such as suffering type 2 diabetes mellitus requiring insulin, having several vessels affected, and concurrent medication with calcium channel blockers, regardless of CYP3A5 genotype or drug class were, in that order, the strongest independent predictors of disease relapse. PMID- 29723427 TI - A Robust Approach to Risk Assessment Based on Species Sensitivity Distributions. AB - The guidelines for setting environmental quality standards are increasingly based on probabilistic risk assessment due to a growing general awareness of the need for probabilistic procedures. One of the commonly used tools in probabilistic risk assessment is the species sensitivity distribution (SSD), which represents the proportion of species affected belonging to a biological assemblage as a function of exposure to a specific toxicant. Our focus is on the inverse use of the SSD curve with the aim of estimating the concentration, HCp, of a toxic compound that is hazardous to p% of the biological community under study. Toward this end, we propose the use of robust statistical methods in order to take into account the presence of outliers or apparent skew in the data, which may occur without any ecological basis. A robust approach exploits the full neighborhood of a parametric model, enabling the analyst to account for the typical real-world deviations from ideal models. We examine two classic HCp estimation approaches and consider robust versions of these estimators. In addition, we also use data transformations in conjunction with robust estimation methods in case of heteroscedasticity. Different scenarios using real data sets as well as simulated data are presented in order to illustrate and compare the proposed approaches. These scenarios illustrate that the use of robust estimation methods enhances HCp estimation. PMID- 29723428 TI - Dulcie Coleman: A pioneer of cytology in the UK and Europe. PMID- 29723429 TI - Ruthenium(II)-Catalyzed Dearomatized C-H Activation and Annulation Reaction of Vinylnaphthols with Alkynes: Access to Spiro-Pentacyclic Naphthalenones. AB - The ruthenium(II)-catalyzed annulation of vinylnaphthols and alkynes is described. The reaction proceeds through C-H activation, dearomatization, and alkyne insertion. This reaction affords spiro-pentacyclic naphthalenones that have biological significance in good yields. PMID- 29723430 TI - Relationships of Changes in Pharmacokinetic Parameters of Substrate Drugs in Drug Drug Interactions on Metabolizing Enzymes and Transporters. AB - A general objective of drug-drug interaction (DDI) studies is to determine whether potential interactions of new molecular entities with concomitantly administered other drugs exist and, if DDIs occur, whether dosage adjustments are required. A typical end point for DDI evaluations is the ratio of area under the plasma concentration-time curve (AUC) of substrate drugs (AUCR), whereas the ratios of maximal plasma concentration (Cmax ) and terminal half-life (t1/2 ) are also important to understand DDI mechanisms (Cmax R and t1/2 R, respectively). Because changes in substrate AUC by precipitant drugs ultimately result from alterations of Cmax and t1/2 , AUCR can be considered a hybrid parameter of Cmax R and t1/2 R, for example, AUCR ~ Cmax R * t1/2 R. The primary objective of this study was to investigate the relationships between AUCR, Cmax R, and t1/2 R in physiologically based pharmacokinetic model-predicted and clinically observed DDI results. First, the model-predicted results showed the excellent proportional relationship between AUCR and (Cmax R * t1/2 R) in DDI results of virtual substrates having a wide range of oral bioavailability with coadministration of ketoconazole, ritonavir, and rifampin. Second, the reasonable proportional relationships were also observed in the clinically observed DDI results of midazolam and statins (atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, and simvastatin) with various inhibitors and inducers. Finally, these results suggest that utilization of the proportional relationship between AUCR and (Cmax R * t1/2 R) can provide an additional framework to further interpret DDI results reasonably and clearly. Furthermore, the proportional relationship can be purposely used to assess study design and pharmacokinetic analyses in DDI studies. PMID- 29723431 TI - Measures of Drug Prescribing at Care Transitions in an Internal Medicine Unit. AB - Care transitions represent a common source of drug errors and confusions. The purpose of our prospective observational study was to assess the prevalence of medication discrepancies at care transitions, along with potentially inappropriate medications and potential drug-drug interactions, in an internal medicine unit of an Italian hospital. Adverse drug reactions that occurred in the 30-day period after the discharge from the hospital were included. A related samples McNemar test was performed for evaluating the effects of hospitalization on the above-mentioned measures of drug prescribing. Medication discrepancies were frequent both on admission (93.4% [95%CI 0.8749, 0.9713]) and at discharge (78.7% [95%CI 0.7035, 0.8558]), with a significant difference between transition times (-14.7% [95%CI -21.82%, -7.69%]; P < .001)]. A high potentially inappropriate medication use prevalence was revealed without differences between care transitions. Potential drug-drug interactions were more frequent at admission to the hospital, with a significant difference of 8.2% in the distribution of patients with potential drug-drug interactions between care transitions. None of the adverse drug reactions recorded on follow-up was related to unintentional discrepancies, and the prevalence rate of patients with potentially inappropriate medication-related adverse drug reactions ranged between 4.9% and 6.9%, and the prevalence rate of patients with drug-drug interaction-related adverse drug reactions was 4.1% of patients. This study is important to raise awareness of the potential dangers medication discrepancies, potentially inappropriate medications, and potential drug-drug interactions could have on older adults. Clinicians and clinical pharmacologists must collaborate to improve patient care and minimize drug-related clinical outcomes. PMID- 29723432 TI - Intercepting a Transient Phosphino-Arsinidene. AB - A phosphino-arsinidene derived from a diazaphospholidine scaffold (Ar**NCH2 )2 PAs (where Ar**=2,6-bis[(4-tert-butylphenyl)methyl]-4-methylphenyl) was generated in situ and trapped with a range of reagents. Metathesis reactions between (Ar**NCH2 )2 PCl and either [Na(18-crown-6)][AsCO] or [Na(dioxane)x ][AsCO] are believed to afford an arsaketene, (Ar**NCH2 )2 PAsCO, which readily loses carbon monoxide under ambient conditions. The resulting transient arsinidene was shown to undergo cycloaddition reactions with excess AsCO- , but can be stabilised in the presence of Lewis bases. It displays contrasting reactivity from a previously reported phosphino-phosphinidene. With isonitriles, rearrangements occur, however with PPh3 a phosphine-stabilised arsinidene could be isolated and used for subsequent reactivity studies. This species was found to be a suitable starting material for a transition metal complex of the phosphino-arsinidene, in which the P-As moiety coordinates side-on to the metal centre. PMID- 29723433 TI - Standardized extract of wild apple fruit in alkyl-polyglucoside-based cosmetic cream - estimation of stability, safety, antioxidant activity and efficiency. AB - OBJECTIVE: The aim of this study was in vitro and in vivo characterization of cosmetic cream with 6% of wild apple fruit water extract, containing 3.5% of alpha-hydroxyacids-AHAs and polyphenolic compounds, stabilized by biodegradable alkyl-polyglucoside emulsifiers. METHODS: In vitro characterization of cream included organoleptic and physico-chemical (pH values and electrical conductivity) analysis, antioxidant activity-AA estimation (using DPPH test) during 180 days of storage at 22+/-2 degrees C and determination of cosmetic active substances content-AHAs (using HPLC analysis). In vivo estimation of skin irritation potential after creams application under occlusion during 24h was investigated employing the biophysical methods on 12 healthy volunteers; hydration efficiency, transepidermal water loss-TEWL, skin pH, erythema-EI and melanin index-MI on 10 healthy volunteers after 28 days of cream application and bleaching efficiency on 10 healthy volunteers after 7 days of cream application after artificially induced skin hyperpigmentation. RESULTS: Investigated cosmetic cream was pale beige color, odorless, semi-solid consistency and homogeneous, with pH values of 6.53+/-0.14, electrical conductivity above 50 MUS/cm and AA of 24.96%RSC after preparation and these characteristics were stable during investigated period. In vivo measurements revealed absence of skin irritation after cream application under occlusion, which was part of it's safety profile. Increase of skin hydration after 14 days of cream application was 17.28+/-12.23 and after 28 days 21.19+/-7.59. In addition, in performed experiment TEWL and skin pH values during cream application remained unchanged. Cream application after artificial hyperpigmentation induced decrease of MI (?MI after 7 days was 45.30+/-18.55) CONCLUSION: Formulated cosmetic cream with 6% of standardized wild apple fruit water extract and stabilized by biodegradable alkyl-polyglucoside emulsifiers demonstrated good stability, acceptable level of in vitro antioxidant activity, absence of skin irritation after cream application under occlusion and positive effects of cream on human skin after application (hydrating and bleaching effects). All mentioned properties make the cream suitable for possible usage as cosmetic product for preventing the skin damages caused by oxidative stress, for moisturizing the dry skin and bleaching of skin hyperpigmentation. This article is protected by copyright. All rights reserved. PMID- 29723435 TI - Impact on clinical follow-up of the Milan System for salivary gland cytology: A comparison with a traditional diagnostic classification. AB - INTRODUCTION: No universally accepted classification exists for salivary gland FNA. The proposed Milan System for Reporting Salivary Gland Cytopathology (MSRSGC) offers a uniform classification with management recommendations. We compared FNA diagnoses from a prior study with specific diagnoses with corresponding MSRSGC diagnoses. METHODS: One-hundred and sixty-four cases from a prior cytological study with histological follow-up were re-reviewed by one of the authors and assigned to one of the MSRSGC categories. The original and MSRSCG diagnoses were compared, as were follow-up recommendations. RESULTS: The MSRSGC system classified 29 specimens as non-diagnostic (seven histologically shown to be benign salivary gland, two non-mucinous cysts, 14 sialadenitis, one pleomorphic adenoma, one haemangioma, one lymphoma, one adenoid cystic carcinoma, one squamous carcinoma and one benign lymphoid proliferation). The original study diagnosed these lesions as: seven benign cysts, 15 benign salivary gland tissue, one benign neoplasm and two insufficient for diagnosis. In seven cases, MSRSGC disagreed with original diagnoses and surgical resection showed lesions where optimal follow-up was more consistent with original cytological diagnosis. In 10 cases with disagreement, the MSRSGC was associated with a more appropriate follow up based on the surgical diagnosis. Malignancy risks for the Milan categories were: non-diagnostic (12%), non-neoplastic (5%), atypia of undetermined significance (19%), neoplasm, benign (5%), neoplasm (40%), suspicious for malignancy (60%) and malignant (93%). CONCLUSION: MSRSGC was comparable with the original reported diagnoses in the majority of cases. Both systems had high accuracy for distinguishing benign from malignant lesions and both were associated with appropriate follow-up in most cases. PMID- 29723436 TI - Insights from Computations on the Mechanism of Reduction by Ascorbic Acid of PtIV Prodrugs with Asplatin and Its Chlorido and Bromido Analogues as Model Systems. AB - The elucidation of the mechanism by which the reduction of coordinatively saturated PtIV prodrugs occurs, leading to the release of the two axial ligands, is of foremost importance, being the key step for the activation of these anticancer compounds, and addressing their synthetic strategies. A systematic DFT computational analysis of the reduction process by small biomolecules, which is supposed to occur by inner- or outer-sphere electron-transfer mechanisms, has been undertaken using the recently synthesised Asplatin PtIV complex, c,c,t [PtCl2 (NH3 )2 (OH)(aspirin)], as model system and l-ascorbic acid as reducing agent. Further calculations have been carried out on Asplatin analogues that should be obtained replacing the OH- ligand with Cl- and Br- . The most accredited inner-sphere mechanistic suggestions have been explored and a recently proposed computational methodology has been applied to estimate the corresponding standard redox potentials, which cannot be directly obtained from voltammetric experiments due to the irreversibility of the platinum(IV)-to-platinum(II) reduction process. PMID- 29723437 TI - Heterodimeric O-methyltransferases involved in the biosynthesis of noscapine in opium poppy. AB - Noscapine biosynthesis in opium poppy involves three characterized O methyltransferases (OMTs) and a fourth responsible for the 4'-methoxyl on the phthalide isoquinoline scaffold. The first three enzymes are homodimers, whereas the latter is a heterodimer encoded by two linked genes (OMT2 and OMT3). Neither OMT2 nor OMT3 form stable homodimers, but yield a substrate-specific heterodimer when their genes are co-expressed in Escherichia coli. The only substrate, 4'-O desmethyl-3-O-acetylpapaveroxine, is a seco-berbine pathway intermediate that undergoes ester hydrolysis subsequent to 4'-O-methylation leading to the formation of narcotine hemiacetal. In the absence of 4'-O-methylation, a parallel pathway yields narcotoline hemiacetal. Dehydrogenation produces noscapine and narcotoline from the corresponding hemiacetals. Phthalide isoquinoline intermediates with a 4'-hydroxyl (i.e. narcotoline and narcotoline hemiacetal), or the corresponding 1-hydroxyl on protoberberine intermediates, were not accepted. Norcoclaurine 6OMT, which shares 81% amino acid sequence identity with OMT3, also formed a functionally similar heterodimer with OMT2. Suppression of OMT2 transcript levels in opium poppy increased narcotoline accumulation, whereas reduced OMT3 transcript abundance caused no detectable change in the alkaloid phenotype. Opium poppy chemotype Marianne accumulates high levels of narcotoline and showed no detectable OMT2:OMT3 activity. Compared with the active subunit from the Bea's Choice chemotype, Marianne OMT2 exhibited a single S122Y mutation in the dimerization domain that precluded heterodimer formation based on homology models. Both subunits contributed to the formation of the substrate-binding domain, although site-directed mutagenesis revealed OMT2 as the active subunit. The occurrence of physiologically relevant OMT heterodimers increases the catalytic diversity of enzymes derived from a smaller number of gene products. PMID- 29723434 TI - PrgB promotes aggregation, biofilm formation, and conjugation through DNA binding and compaction. AB - Gram-positive bacteria deploy type IV secretion systems (T4SSs) to facilitate horizontal gene transfer. The T4SSs of Gram-positive bacteria rely on surface adhesins as opposed to conjugative pili to facilitate mating. Enterococcus faecalis PrgB is a surface adhesin that promotes mating pair formation and robust biofilm development in an extracellular DNA (eDNA) dependent manner. Here, we report the structure of the adhesin domain of PrgB. The adhesin domain binds and compacts DNA in vitro. In vivo PrgB deleted of its adhesin domain does not support cellular aggregation, biofilm development and conjugative DNA transfer. PrgB also binds lipoteichoic acid (LTA), which competes with DNA binding. We propose that PrgB binding and compaction of eDNA facilitates cell aggregation and plays an important role in establishment of early biofilms in mono- or polyspecies settings. Within these biofilms, PrgB mediates formation and stabilization of direct cell-cell contacts through alternative binding of cell bound LTA, which in turn promotes establishment of productive mating junctions and efficient intra- or inter-species T4SS-mediated gene transfer. PMID- 29723438 TI - Chronic periodontitis is associated with erectile dysfunction. A case-control study in european population. AB - AIM: To determine the association between chronic periodontitis and erectile dysfunction adjusting for biochemical markers and other comorbidities. METHODS: A case-control study was conducted on 158 male patients; 80 cases with erectile dysfunction according to the International Index of Erectile Function and 78 controls. Sociodemographic data were gathered, and a periodontal examination was performed. Testosterone, lipid profile, C-reactive protein and glycaemic parameters were assessed. All variables were compared between groups, and multivariate logistic regression analyses were performed. RESULTS: 74% of the cases were diagnosed with chronic periodontitis. Number of sites with pocket probing depth 4-6 mm (p = 0.05) and number of sites with clinical attachment loss >3 mm (p < 0.01) were higher in the cases. Triglycerides (p < 0.01), C-reactive protein (p = 0.02) and glycosylated haemoglobin (p = 0.04) were also higher in the cases. Logistic regression showed that patients with chronic periodontitis were more likely to have erectile dysfunction (OR=2.17; 95% CI (1.06-4.43); p = 0.03) independently of other confounders. CONCLUSION: Patients with erectile dysfunction showed worse periodontal condition. Chronic periodontitis seems to play a key role as a risk factor in the pathogenesis of erectile dysfunction independently of other morbidities. PMID- 29723439 TI - Liquid chromatography/electrospray ionization tandem mass spectrometry study of repaglinide and its forced degradation products. AB - RATIONALE: Stress stability studies of drugs have been recognized as an essential part of the drug development process. These studies are used to investigate the intrinsic stability of the drugs and for the development of a selective stability indicating assay method (SIAM). Stress testing is also useful for the formulation and packaging development, shelf-life determination and designing of manufacturing processes. As per regulatory guidelines, stress degradation studies and structural characterization should be carried out to establish degradation pathways of the drug, which is essential from both the efficacy and safety point of view. As the stress stability studies of repaglinide have not been reported in the literature, the present study has been undertaken. METHODS: Repaglinide (RP), an oral anti-diabetic drug, was subjected to hydrolysis (acidic, alkaline and neutral), oxidation, photolysis and thermal stress conditions as per International Conference on Harmonization (ICH) guidelines Q1A (R2). The chromatographic separation of the drug and its degradation products (DPs) was achieved on an Agilent XDB C-18 column using the gradient elution method with a mobile phase consisting of 20 mM ammonium acetate and acetonitrile at flow rate of 1.0 mL min-1 . The DPs were characterized using liquid chromatography/electrospray ionization tandem mass spectrometry (LC/ESI-MS/MS) in combination with accurate mass measurements. RESULTS: The drug degraded under hydrolytic and oxidative stress, while it was stable under thermal and photolytic stress conditions. In total, six DPs were formed and the LC/MS method described here can resolve all DPs from the parent as well as from each other under various stress conditions. To elucidate the structures of DPs, fragmentation of the [M + H]+ ions of RP and its DPs was studied by using LC/ESI-MS/MS combined with accurate mass measurements. CONCLUSIONS: The forced degradation of RP carried out as per ICH guidelines results in the formation of six degradation products which have been characterized using LC/MS/MS in combination with accurate mass measurements. PMID- 29723440 TI - Antimicrobial activity in culturable gut microbial communities of springtails. AB - AIMS: The rise of antibiotic resistance pushes the pharmaceutical industry to continually search for substances with new structures and novel mechanisms of action. Many environmental niches are still to be explored as sources of antimicrobials. In this paper, we assess the antimicrobial potential of gut microbes of springtails, soil invertebrates which live in a microbe-dominated environment and are known to be tolerant to entomopathogenic micro-organisms. METHODS AND RESULTS: Bacteria isolated from the guts of five springtail species were tested for inhibitory activity against different microbial pathogens. We identified 46 unique isolates belonging to 17 genera and 15 families. Thirty-five of these isolates (76%) showed inhibitory activity, and 18 inhibited both bacterial and fungal pathogens. One isolate was active against all the pathogens tested. CONCLUSIONS: We demonstrated a range of antimicrobial activities in bacteria isolated from the guts of springtails, indicative of complex interactions within the gut community, possibly relating to nutrition or defence against pathogens. SIGNIFICANCE AND IMPACT OF THE STUDY: Our results suggest that a large proportion of cultivatable microbes associated with Collembola have a potential for antimicrobial production. We propose that soil invertebrates and their associated microbes are interesting targets for drug discovery. PMID- 29723441 TI - Pharmacokinetic and Pharmacodynamic Correlations From 2 Studies Evaluating Abuse Potential of Hydrocodone Extended-Release Tablets. AB - Pharmacokinetic (PK)/pharmacodynamic (PD) correlations were explored in 2 human abuse potential studies of orally and intranasally administered hydrocodone extended-release (ER) 45 mg in healthy, nondependent opioid users. In a crossover study design, subjects received intact hydrocodone ER, finely milled hydrocodone ER, and hydrocodone powder in solution in the oral study and finely milled hydrocodone ER, hydrocodone powder, and finely milled Zohydro(r) ER in the intranasal study. Spearman rho2 and Pearson r2 values were calculated for PD (maximum effect [Emax ] for "at the moment" Drug Liking, Overall Drug Liking, and Take Drug Again visual analog scales [VAS]) vs PK (partial area under the concentration-time curve [AUC], maximum drug concentration [Cmax ], time to Cmax [Tmax ], and abuse quotient [PK AQ; Cmax /Tmax ]) for all treatments. In the oral study, correlations were strongest between Emax of "at the moment" Drug Liking and PK parameters (Cmax [rho2 = 0.4446], PK AQ [rho2 = 0.5179], Tmax [rho2 = 0.5093], and early systemic exposure [rho2 = 0.4782]). For Overall Drug Liking and Take Drug Again VAS, rho2 values for correlations with PK parameters ranged from 0.2620 to 0.3637. In the intranasal study, no clear correlations between PK and PD parameters were apparent. PMID- 29723443 TI - Does Dapagliflozin Affect Energy Intake and Appetite? A Randomized, Controlled Exploratory Study in Healthy Subjects. AB - The primary aims of this study were to assess the effects of dapagliflozin versus placebo on energy intake and appetite ratings in healthy individuals. This was a randomized, single-blind, placebo-controlled, 2-period crossover study. In each period, healthy individuals received either dapagliflozin or placebo for 2 weeks. On assessment days, participants were asked to consume a standard preload breakfast. Appetite ratings were measured with 100-mm visual analog scales immediately before and during the 4.25-hour period after breakfast. Energy intake was measured at an ad libitum lunch. Energy intake and appetite responses were assessed at the end of each 2-week treatment period by mixed-design analysis of variance. Eighteen individuals completed all assessments (44% female; mean age, 22.8 years; 44% Caucasian; mean BMI, 25.2 kg/m2 ). There was no difference in energy intake on dapagliflozin compared to placebo (mean difference, -19.8 kcal; P = .516). Mean differences in prebreakfast desire for salty foods (11.3 mm, P = .094) and postbreakfast desire for sweet foods (8.1 mm, P = .054) trended higher with dapagliflozin relative to placebo. Our data do not support an effect of dapagliflozin on energy intake or appetite measures in young, healthy subjects. Although not statistically significant, the size of the mean differences in prebreakfast desire for salty foods and postbreakfast desire for sweet foods on dapagliflozin were larger than placebo and reflect the drug's natriuretic and glucuretic effects. These findings should be further evaluated in patients with type 2 diabetes. PMID- 29723442 TI - Total Synthesis and Biological Investigation of (-)-Artemisinin: The Antimalarial Activity of Artemisinin Is not Stereospecific. AB - Here, we describe an efficient and diversity-oriented entry to both (-) artemisinin (1) and its natural antipode (+)-artemisinin, starting from commercially and readily available S-(+)- and R-(-)-citronellene, respectively. Subsequently, we answered the still open question regarding the specificity of artemisinins action. By using a drug-sensitive Plasmodium falciparum NF54 strain, we showed that the antimalarial activity of artemisinin is not stereospecific. Our straightforward and biomimetic approach to this natural endoperoxide enables the synthesis of artemisinin derivatives that are not accessible through applying current methods and may help to address the problem of emerging resistance of Plasmodium falciparum towards artemisinin. PMID- 29723444 TI - Boronic Acids as Bioorthogonal Probes for Site-Selective Labeling of Proteins. AB - Over the past two decades, bioorthogonal chemistry has become a preferred tool to achieve site-selective modifications of proteins. However, there are only a handful of commonly applied bioorthogonal reactions and they display some limitations, such as slow rates, use of unstable or cytotoxic reagents, and side reactions. Hence, there is significant interest in expanding the bioorthogonal chemistry toolbox. In this regard, boronic acids have recently been introduced in bioorthogonal chemistry and are exploited in three different strategies: 1) boronic ester formation between a boronic acid and a 1,2-cis diol; 2) iminoboronate formation between 2-acetyl/formyl-arylboronic acids and hydrazine/hydroxylamine/semicarbazide derivatives; 3) use of boronic acids as transient groups in a Suzuki-Miyaura cross-coupling or other reactions that leave the boronyl group off the conjugation product. In this Review, we summarize progress made in the use of boronic acids in bioorthogonal chemistry to enable site-selective labeling of proteins and compare these methods with the most commonly utilized bioorthogonal reactions. PMID- 29723445 TI - Basal level of autophagy and MAP1LC3B-II as potential biomarkers for DHA-induced cytotoxicity in colorectal cancer cells. AB - : The omega-3 fatty acid docosahexaenoic acid (DHA) is known as an anticancer agent. Colorectal cancer (CRC) cells exhibit different sensitivity toward DHA, but the mechanisms involved are still unclear. Gene expression profiling of 10 CRC cell lines demonstrated a correlation between the level of DHA sensitivity and different biological stress responses, such as endoplasmic reticulum (ER) stress, oxidative stress, and autophagy. The basal level of autophagy and MAP1LC3B-II protein correlated with DHA sensitivity in the cell lines studied. DHA induced oxidative stress, ER stress, and autophagy in DHA-sensitive DLD-1 cells, while the less sensitive LS411N cells were affected to a much lesser extent. Co-treatment with DHA and the autophagy inducer rapamycin reduced DHA sensitivity in DLD-1 and HCT-8 cells, while co-treatment with DHA and the autophagy inhibitors chloroquine and 3-methyladenine increased the DHA sensitivity in LS411N and LS513 cells. Differentially expressed genes correlating with DHA sensitivity and the level of autophagy demonstrated an overlap in biological pathways involved. Results indicate the basal level of autophagy and MAP1LC3B-II protein as potential biomarkers for DHA sensitivity in CRC cells. DATABASES: Protocol and data for gene expression experiments have been submitted to ArrayExpress with accession number E-MTAB-5750. PMID- 29723446 TI - Total Synthesis of (+)- and (+/-)-Hosieine A. AB - Described herein is a concise total synthesis of the highly potent nicotinic acetylcholine receptor ligand hosieine A in racemic and enantioenriched forms. The synthesis requires only seven steps and features a telescoped reaction sequence initiated by a gold-catalyzed Rautenstrauch reaction. PMID- 29723447 TI - A cautionary TALE: how plant breeding may have favoured expanded TALE repertoires in Xanthomonas. PMID- 29723448 TI - [Disease-syndrome combination in integrated traditional Chinese and Western medicine in andrology: Confusions and countermeasures in studies]. AB - Researches on the mechanisms underlying the therapeutic effects of the disease syndrome combination approach in integrated traditional Chinese and Western medicine are becoming a hot spot in andrology, but many recent studies of this kind have failed to explain the connotation of integrated traditional Chinese and Western medicine in andrology. Related existing problems include repeated researches into the same indexes of action mechanisms of different therapeutic principles of traditional Chinese medicine (TCM), Chinese herbal compound and special prescriptions, studies focusing on individual diseases but ignoring symptoms, immature syndrome models for studies of mechanisms, and too much attention to uncertain or immature target mechanisms. The stress should be placed on the action mechanisms of Chinese herbal compound and special prescriptions on male diseases and, what is more important, on the clarification of the essential principles of differentiation and treatment of TCM syndromes. In the recent years, proteomics, genomics, transcriptomics and metabolomics have shed some light upon researches into the mechanisms underlying the therapeutic effects of the disease-syndrome combination approach in integrated traditional Chinese and Western medicine in andrology. An insight into the TCM syndrome, a macroscopic inductive analysis, and a comprehension of such microcosmic aspects as the gene, protein, metabolism and metagenome may contribute to some breakthroughs and new ideas in the studies of disease-syndrome combination in integrated traditional Chinese and Western medicine in andrology. PMID- 29723450 TI - [Downregulation of PTTG1 expression inhibits the proliferation and invasiveness and promotes the apoptosis of human prostate cancer LNCaP-AI cells]. AB - Objective: To investigate the effects of down-regulation of PTTG1 expression on the proliferation, invasiveness and apoptosis of androgen-independent human prostate cancer LNCaP-AI cells and their sensitivity to androgen antagonists. METHODS: Human prostate cancer LNCaP-AI cells were transfected with siRNA targeting the PTTG1 gene using the Lipofectamine 2000 transfection reagent. The proliferation, invasiveness and apoptosis of the cells were detected by MTT, Transwell assay and flow cytometry, respectively. The protein expressions of PTTG1, p-Akt, and p-ERK were determined by Western blot and the mRNA expression of PTTG1 measured by agarose gel electrophoresis. RESULTS: The siRNA expression vector markedly down-regulated the expression of PTTG1, which effectively suppressed the proliferation of the LNCaP-AI cells, with the inhibition rates of (19.47 +/- 2.12), (24.01 +/- 2.13) and (48.02 +/- 2.22)% at 24, 48 and 72 hours, respectively, after transfection, with statistically significant differences among the three groups (P <0.05). The number of the cells passing through the polycarbonate film was remarkably decreased at 24, 48 and 72 hours (74.67 +/- 9.85, 56.44 +/- 8.66 and 37.33 +/- 6.14) as compared with the baseline (111.11 +/ 13.47) (P <0.01), while the apoptosis rate of the cells was significantly increased at 24, 48 and 72 hours (18.32 +/- 0.94), (19.94 +/- 1.30) and (21.73 +/ 1.88)% in comparison with the baseline ([2.17 +/- 0.49]%), (P <0.05). PTTG1 siRNA combined with androgen antagonist flumatide exhibited even more significant effects in inhibiting the proliferation and promoting the apoptosis of the LNCaP AI cells than either used alone, and in a flumatide dose-dependent manner. The inhibition and apoptosis rates of the LNCaP-AI cells treated with 50 nmol/L flumatide were (27.13 +/- 3.52) and (3.94 +/- 0.48)%, and those treated with siRNA + 50 nmol/L flumatide were (67.51 +/- 5.13) and (19.93 +/- 1.72)%, respectively, both with statistically significant differences between the two groups (P <0.05). The inhibition and apoptosis rates of the cells treated with 100 nmol/L flumatide were (43.72 +/- 3.90) and (5.33 +/- 0.66)%, and those treated with siRNA + 100 nmol/L flumatide were (73.19 +/- 4.78) and (23.43 +/- 1.76)%, respectively, both with statistically significant differences between the two groups (P <0.05). CONCLUSIONS: The siRNA expression vector can down-regulate the expression of PTTG1, which can inhibit the proliferation and invasiveness of LNCaP-AI cells, promote their apoptosis, and increase their sensibility to androgen antagonists. Suppressing the expression of PTTG1 may enhance the effect of androgen-deprivation therapy on advanced prostate cancer. PMID- 29723449 TI - [Impacts of DES on the expressions of related genes in the gubernaculums testis of newborn mice]. AB - Objective: To investigate the influence of diethylstilbestrol (DES) on the mRNA expressions of the androgen receptor (AR), estrogen receptor alpha (ERalpha), proliferating cell nuclear antigen (PCNA), and actin alpha 1 (ACTalpha1) in the gubernaculums testis of newborn mice and explore their action mechanisms. METHODS: A total of 140 male Kunming mice were randomly divided into a blank control, a dimethyl sulfoxide (DMSO) control, and 5 experimental groups to be treated subcutaneously with normal saline, DMSO, and DES at 0.02, 0.1, 0.5, 10 and 50 MUg per kg of the body weight per day, respectively, at gestation days 9 17. On the first day after birth, the animals were sacrificed and the gubernaculums testis collected for detection of the mRNA expressions of AR, ERalpha, PCNA and ACTalpha1 by RT-PCR. RESULTS: Compared with the DMSO control, the experimental groups, particularly the DES 10 and 50 MUg groups, showed significant increases in the mRNA expression of ERalpha (RE2 = 0.825, P <0.05), but remarkable decreases in those of AR, PCNA and ACTalpha1 (RA2 = 0.713, RP2 = 0.946, RT2 = 0.960, P <0.01), all in a dose-dependent manner. CONCLUSIONS: The AR, ERalpha, PCNA, and ACTalpha1 mRNA are expressed in the gubernaculum testis of normal newborn mice, and their expression levels may be influenced by intervention with different concentrations of DES during the gestation. Exogenous estrogens may affect the proliferation and contraction of gubernaculum testis cells and consequently the normal development of the testis or even the whole male reproductive system by influencing the metabolism of ER and/or AR. PMID- 29723451 TI - [Risks of diabetes mellitus and impaired glucose tolerance induced by intermittent versus continuous androgen-deprivation therapy for advanced prostate cancer]. AB - Objective: To investigate the correlation of intermittent androgen-deprivation therapy (IADT) and continuous androgen-deprivation therapy (CADT) for advanced prostate cancer (PCa) with the risks of secondary diabetes mellitus (DM) and impaired glucose tolerance (IGT). METHODS: We conducted a retrospective case control study of the advanced PCa patients treated by IADT or CADT in our hospital from January 2013 to December 2015. Based on the levels fasting blood glucose and 2-hour postprandial blood glucose, results of oral glucose tolerance test, and clinical symptoms of the patients, we statistically analyzed the IADT- or CADT-related risk factors for DM and IGT and the relationship of the body mass index (BMI), hypertension, smoking, and alcohol consumption with secondary DM and IGT. RESULTS: IADT was given to 53 (46.5%) of the patients, aged (69.1 +/- 4.3) years, and CADT to 61 (53.5%), aged (70.2 +/- 5.7) years. No statistically significant differences were observed in clinical characteristics between the two groups of patients (P > 0.05). BMI, blood pressure, smoking and drinking exhibited no significant influence on the development of DM or IGT either in the IADT (P > 0.05) or the CADT group. The incidence of IGT was significantly lower in the IADT than in the CADT group (P = 0.03), but that of DM showed no statistically significant difference between the two groups (P = 0.64). CONCLUSIONS: Compared with CADT, IADT has a lower risk of IGT and a higher safety in the treatment of advanced prostate cancer. PMID- 29723453 TI - [Erectile dysfunction and psychological status in infertile males]. AB - Objective: To investigate the relationship of erectile dysfunction (ED) with psychological factors in male patients with infertility. METHODS: We conducted a questionnaire investigation among 252 male patients with infertility, which involved the general condition, results of semen routine examination, sexual life, and scores in IIEF-5, self-reported 9-item patient health questionnaire (PHQ-9) and 7-item generalized anxiety disorder scale (GAD-7). We analyzed the prevalence of ED, depression, and anxiety and their correlations among the patients in comparison with 100 fertile male controls. RESULTS: In 245 of the infertility patients, the most common symptoms of depression and anxiety were "feeling tired or no vitality" and "easily getting worried or impatient", 20.4% of them with depression disorder and 42.9% with anxiety disorder. The PHQ-9 and GAD-7 scores were significantly higher in the infertile males than in the normal fertile controls (P <0.05), and so was the incidence of ED (28.6% vs 12.4%, P <0.05), while the IIEF-5 scores were markedly lower in the former than in the latter group (P <0.01), and so were sex frequency and sexual satisfaction (P <0.05). The PHQ-9 and GAD-7 scores were remarkably higher in the infertility patients with ED than in those without (P <0.01). Logistic regression analysis showed that the level of libido and results of semen routine examination were the risk factors for depression disorder, while age, education level, disease course and experience of assisted reproduction were those for anxiety disorder. CONCLUSIONS: Male infertility patients have a poorer mental health and a higher incidence of ED than normal fertile men, and there is some interaction between psychological status and ED prevalence. PMID- 29723452 TI - [Circulating miR-152 helps early prediction of postoperative biochemical recurrence of prostate cancer]. AB - Objective: To investigate the value of circulating miR-152 in the early prediction of postoperative biochemical recurrence of prostate cancer. METHODS: Sixty-six cases of prostate cancer were included in this study, 35 with and 31 without biochemical recurrence within two years postoperatively, and another 31 healthy individuals were enrolled as normal controls. The relative expression levels of circulating miR-152 in the serum of the subjects were detected by qRT PCR, its value in the early diagnosis of postoperative biochemical recurrence of prostate cancer was assessed by ROC curve analysis, and the correlation of its expression level with the clinicopathological parameters of the patients were analyzed. RESULTS: The expression of circulating miR-152 was significantly lower in the serum of the prostate cancer patients than in the normal controls (t = 5.212, P = 0.001), and so was it in the patients with than in those without postoperative biochemical recurrence (t = -5.727, P = 0.001). The ROC curve for the value of miR-152 in the early prediction of postoperative biochemical recurrence of prostate cancer showed the area under the curve (AUC) to be 0.906 (95% CI: 0.809-0.964), with a sensitivity of 91.4% and a specificity of 80.6%. The expression level of miR-152 was correlated with the Gleason score, clinical stage of prostate cancer, biochemical recurrence, and bone metastasis (P <0.05), decreasing with increased Gleason scores and elevated clinical stage of the malignancy. No correlation, however, was found between the miR-152 expression and the patients' age or preoperative PSA level (P >0.05). CONCLUSIONS: The expression level of circulating miR-152 is significantly reduced in prostate cancer patients with biochemical recurrence after prostatectomy and could be a biomarker in the early prediction of postoperative biochemical recurrence of the malignancy. PMID- 29723454 TI - [Aripiprazole for drug-induced sexual dysfunction in schizophrenic males]. AB - Objective: To investigate the clinical effects of aripiprazole on sexual dysfunction induced by amisulpride or risperidone in male patients with schizophrenia. METHODS: This study included 75 male patients with drug-induced secondary sexual dysfunction after treated with amisulpride or risperidone for first-episode schizophrenia between October 2014 and October 2016. We substituted aripiprazole for amisulpride or risperidone, gradually increased the dose from 10 to 30 mg/d within 2 weeks, and maintained 30 mg/d from the 3rd week. At 4 and 8 weeks after medication, we evaluated the sexual function of the patients, measured the levels of serum prolactin (PRL) and testosterone (T), obtained the scores of the Positive and Negative Symptoms Scale (PANSS), recorded adverse reactions, and compared the parameters with those before aripiprazole administration. RESULTS: Compared with pre-aripiprazole administration, the patients showed significant increases after 4 weeks of medication in the sexual function score (24.3 +/- 2.1 vs 32.6 +/- 3.6, P <0.05) and T level ([13.3 +/- 2.7] vs [17.4+/-3.0] mmol/L, P <0.05) but a decreased level of PRL ([38.5 +/- 10.5] vs [27.9 +/- 8.2] ng/ml, P <0.05). At 8 weeks, the sexual function score and serum PRL were both restored to the baseline levels at admission, and the erectile function score, ejaculation score, total score, and serum T level even exceeded the baseline, though with no statistically significant differences (P >0.05). In comparison with pre-aripiprazole administration, the PANSS score was significantly decreased at 4 weeks after medication (62.1 +/- 4.9 vs 57.2 +/- 5.5, P <0.05) and even lower at 8 weeks (51.2 +/- 5.2) (P <0.05). The incidence rates of medication-related excitation, dizziness, insomnia, and loss of appetite were 6.7%, 5.3%, 4.0% and 1.3% respectively, and no other serious adverse reactions were observed. CONCLUSIONS: Aripiprazole is effective for the treatment of drug-induced sexual dysfunction in schizophrenic men by continuously alleviating their positive and negative symptoms and meanwhile improving their sexual function and restoring their sexual hormone levels. PMID- 29723455 TI - [Impacts of different procedures of testicular sperm retrieval on testicular function and antisperm antibodies in azoospermia patients]. AB - Objective: To investigate the influence of different procedures of testicular sperm retrieval on the levels of serum inhibin B (INHB), antisperm antibodies (AsAb), follicle-stimulating hormone (FSH), and testosterone (T) in patients with azoospermia. METHODS: We randomly assigned 210 azoospermia patients to receive testicular sperm extraction (TESE, n = 50), testicular sperm aspiration (TESA, n = 56), testicular fine needle aspiration (TEFNA, n = 64), or microscopic TESE (micro-TESE, n = 40). We measured the levels of serum INHB, FSH, and T and the positive rate of AsAb before and at 1 and 3 months after surgery. RESULTS: Compared with the baseline, the levels of serum FSH at 1 and 3 months after surgery showed no statistically significant differences in the TESE ([8.51 +/- 4.34] vs [8.76 +/- 3.07] and [7.24 +/- 3.32] IU/L, P >0.05), TESA ([7.70 +/- 2.72] vs [7.90 +/- 4.57] and [8.04 +/- 3.65] IU/L, P >0.05), TEFNA ([6.04 +/- 3.17] vs [6.08 +/- 2.70] and [6.10 +/- 3.32] IU/L, P >0.05), or micro-TESE group ([6.59 +/- 2.74] vs [6.89 +/- 1.78] and [6.75 +/- 2.57] IU/L, P >0.05); the positive rate of AsAb (IgM) was significantly increased at 1 month in the TESE (0.00 vs 14.00%, P <0.05) and micro-TESE groups (2.50% vs 15.00%, P <0.05), while the serum T level markedly decreased in the two groups ([16.52 +/- 6.25] vs [9.25 +/- 5.76] nmol/L and [14.16 +/- 5.45] vs [8.23 +/- 4.12] nmol/L, P <0.05); the levels of serum INHB were remarkably reduced at 1 and 3 months in the TESE ([70.56 +/- 23.17] vs [42.63 +/- 15.34] and [44.05 +/- 18.47] pg/ml, P <0.05), TESA ([68.71 +/- 14.74] vs [40.55 +/- 20.51] and [42.11 +/- 19.34] pg/ml, P <0.05), TEFNA ([76.81 +/- 27.04] vs [46.31 +/- 19.28] and [48.32 +/- 20.54] pg/ml, P <0.05), and micro-TESE groups ([74.74 +/- 28.35] vs [45.27 +/- 18.83] and [47.64 +/- 28.34] pg/ml, P <0.05), but with no statistically significant differences among the four groups (P >0.05). CONCLUSIONS: Different procedures of testicular sperm retrieval have different impacts on the testicular function and AsAb in patients with azoospermia. PMID- 29723456 TI - [Contrast-enhanced ultrasonography in the diagnosis of venous erectile dysfunction]. AB - Objective: To investigate the effect and safety of contrast-enhanced ultrasonography (CEUS) in the diagnosis of venous erectile dysfunction (VED). METHODS: From June 2015 to March 2016, 43 ED patients underwent corpus cavernography, of whom 23 were diagnosed with and the other 20 without corpus cavernosal venous leakage (CCVL). All the patients received intracorporal injection of a vasoactive drug and CEUS. RESULTS: Of the 23 patients with CCVL, 21 were confirmed by CEUS, including 12 cases of double venous leakage, 2 cases of single venous leakage, 5 cases of crural venous leakage, and 2 cases of the mixed type, while the other 2 showed no CCVL on CEUS. Of the 20 patients with CCVL, 2 presented CCVL on CEUS. CONCLUSIONS: CEUS has the advantages of accuracy, safety, and less invasiveness in the diagnosis of VED. PMID- 29723457 TI - [One-puncture one-needle TRUS-guided prostate biopsy for prevention of postoperative infections]. AB - Objective: To explore the feasibility and effectiveness of "one-puncture one needle" transrectal ultrasound (TRUS)-guided prostate biopsy in the prevention of postoperative infections. METHODS: We retrospectively analyzed the clinical data about "one-puncture one-needle" (the observation group) and "one-person one needle" (the control group) TRUS-guided prostate biopsy performed in the Second People's Hospital of Guangdong Province from January 2005 to December 2015, and compared the incidence rates of puncture-related infection between the two strategies. By "one-puncture one-needle", one needle was used for one biopsy puncture, while by "one-person one-needle", one needle was used for all biopsy punctures in one patient and the needle was sterilized with iodophor after each puncture. RESULTS: Totally, 120 patients received 6+1-core or 12+1-core "one person one-needle" and 466 underwent 12+1-core "one-puncture one-needle" TRUS guided prostate biopsy. There were no statistically significant differences between the two groups of patients in age, the prostate volume, the serum PSA level, or the detection rate of prostate cancer (P >0.05). Compared with the control group, the observation group showed remarkably lower incidence rates of puncture-related urinary tract infection (7.5% vs 0.9%, P <0.05), fever (5.0% vs 1.1%, P <0.05), bacteriuria (2.5% vs 0.2%, P <0.05), and total infections (16.7% vs 2.6%, P<0.05) postoperatively. Two cases of bacteremia or sepsis were found in each of the groups, with no significant difference between the two. CONCLUSIONS: "One-puncture one-needle" TRUS-guided prostate biopsy can effectively prevent puncture-related infections. PMID- 29723458 TI - [Topical application of clobetasol propionate cream in the treatment of phimosis in prepubertal children: A report of 237cases]. AB - Objective: To investigate the clinical effect of 0.02% clobetasol propionate cream (CPC) on phimosis in prepubertal children. METHODS: We retrospectively analyzed the clinical data about 237 prepubertal children with phimosis present at the Outpatient Department from June 2012 to December 2015. The patients were aged 2-14 (mean 8.6) years, all treated by topical application of 0.02% CPC to the narrowed opening and adhered part of the foreskin twice a day, in the morning and evening respectively. At the time of CPC application, the foreskin was slightly retracted. We evaluated the therapeutic effect every week from the end of the first week of treatment. RESULTS: Totally, 233 of the patients completed the 8-week treatment, of whom 181 (77.68%) showed full retraction of the foreskin, 28 (12.01%) experienced improvement (disappearance of the phimotic ring), and 24 (10.30%) failed to respond, with a total effectiveness rate of 89.70%. No significant local or systemic adverse reactions were observed during the treatment. CONCLUSIONS: Topical application of 0.02% Clobetasol Propionate Cream is a safe, effective, painless, and inexpensive option for the treatment of phimosis in prepubertal chilodren. PMID- 29723459 TI - [Clinicopathological features of primary seminal vesicle adenocarcinoma: A report of 4 cases and review of the literature]. AB - Objective: To investigate the clinicopathological characteristics, diagnosis, and treatment of primary seminal vesicle adenocarcinoma (SVAC). METHODS: We analyzed the clinical data and clinicopathological characteristics of 4 cases of primary SVAC treated in the Department of Urology of the Second Hospital of Tianjin Medical University and reviewed relevant literature. RESULTS: All the 4 patients were treated by open radical resection of the seminal vesicle and prostate and pathologically diagnosed with SVAC. Preoperative prostatic biopsy had shown 1 of the cases to be negative, while preoperative CT and transrectal ultrasound had revealed a huge pelvic cystic neoplasm in another patient. Immunohistochemistry manifested that the 4 cases were all negative for prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), and cytokeratin 20 (CK20), but positive for cancer antigen 125 (CA125) and CK7. All the patients recovered smoothly after surgery and experienced no recurrence or metastasis during 154, 41, 20, and 12 months of follow-up. CONCLUSIONS: Primary seminal vesicle carcinoma is extremely rare and presents in an advanced stage. Immunohistochemistry plays a valuable role in its differential diagnosis. Various combinations of radical surgery, radiotherapy, androgen-deprivation therapy, and chemotherapy are recommended for the treatment of the disease. PMID- 29723461 TI - [Related immunologic mechanisms of chronic prostatitis: Advances in studies]. AB - Chronic prostatitis is a common male disease with a high incidence rate and a serious impact on the patients' quality of life. The pathogenesis of chronic prostatitis remains unclear though it is considered to be possibly related to infection, inflammation, and abnormal pelvic nerve muscle activity. Recently, a growing number of studies have reported immune imbalance and changes of inflammatory cytokines in patients with chronic prostatitis as well as a close correlation of abnormal immune response with the occurrence of diseases, pelvic pain symptoms, mental symptoms, hyperalgesia, and so on. This review summarizes the latest advances in the studies of immunologic mechanisms of chronic prostatitis. PMID- 29723460 TI - [Qilan Capsules plus androgen-deprivation therapy for Qi-deficiency blood-stasis type of prostate cancer after castration]. AB - Objective: To observe the synergistic effect of Qilan Capsules in the treatment of the patient with Qi-deficiency blood-stasis type of prostate cancer receiving androgen-deprivation therapy after castration. METHODS: This randomized controlled double-blind study included 246 cases of Qi-deficiency blood-stasis type of prostate cancer after castration, which were randomly divided into an experiment and a control group of equal number to be treated with Qilan Capsules + androgen-deprivation and placebo + androgen-deprivation, respectively. After 6 months of treatment, we compared the International Prostate Symptoms Scores (IPSS), TCM Symptoms Scores (TCMSS), maximal urine flow rate (Qmax), and the level of serum prostate-specific antigen (PSA) between the two groups of patients. RESULTS: Statistically significant differences were observed between the experiment and control groups in the syndrome classification-based efficacy (87.7% vs 67.9%, P <0.05) and total effectiveness rate (86.0% vs 71.6%, P <0.05). Compared with the baseline, the experiment group showed remarkable improvement after treatment in TCMSS (17.1+/-5.1 vs 8.3+/-4.0, P <0.05), IPSS (17.7+/-7.5 vs 11.4+/-4.6, P <0.05), and Qmax ([10.9+/-4.3] ml/s vs [14.7+/-3.7] ml/s, P <0.05), and so did the control group (16.8+/-5.2 vs 11.5+/-5.2, 17.8+/-6.7 vs 14.6+/-5.8, and [11.0+/-4.3] ml/s vs [12.0+/-4.1] ml/s, P <0.05). The above three parameters were even more markedly improved in the former than in the latter group (P <0.05). However, there was no statistically significant difference between the two groups in the improvement of the PSA level after treatment (P >0.05). CONCLUSIONS: Qilan Capsules can significantly enhance the effect of androgen deprivation therapy in the treatment of Qi-deficiency blood-stasis type of prostate cancer after castration though cannot obviously improve the PSA level. PMID- 29723462 TI - [Prevention and treatment of erectile dysfunction after prostatectomy: An update]. AB - Prostate cancer has the highest incidence among malignant tumors of the urinary system in China. Radical prostatectomy (RP) is the most effective treatment for localized prostate cancer with a good long-term prognosis. Erectile dysfunction (ED) is a common complication after RP, which seriously affects the patient's quality of life. With the rising incidence and early diagnosis of prostate cancer, the proportion of young cases of RP is increasing, and so is the importance of the treatment of post-RP ED. The restoration of erectile function after RP is closely related to the timing of penile rehabilitation as well as to pre- and intra-operative measures such as surgical strategies and methods. Common options for the treatment of post-RP ED include oral medication of phosphodiesterase type 5 inhibitors, application of vasoactive substances in the urethra or corpus cavernosum, use of vacuum erection devices, and implantation of penile prosthesis. Stem cell therapy, nerve transplantation, low-intensity extracorporeal shockwave therapy, and erythropoietin have shown great potential in penile rehabilitation after RP. At present, the stress is placed on the remission of symptoms in the treatment of ED. Stem cell therapy may reverse the cause of disease or cure ED by reversing its pathophysiological changes. A series of clinical trials of stem cell therapy are underway and have preliminarily confirmed the safety of stem cell therapy and proved that it can improve erectile function in patients with post-RP ED. This review focuses on the progress in the prevention and treatment of ED after RP. PMID- 29723463 TI - [Gene regulation of prostaglandin synthase and prostate diseases]. AB - Prostaglandin synthase (PGS) can catalyze the production of various types of prostaglandins and regulate the expression levels of related substances. The regulation mechanisms of the PGS gene are closely related with the occurrence and development of prostate diseases. However, few studies are reported on the regulation mechanisms of PGS in prostatic diseases, such as benign prostatic hyperplasia (BPH) and prostate cancer (PCa), or on the relationship between PGS gene regulation and prostate diseases. This review aims to analyze their correlation and provide some ideas for the prevention and control of BPH and PCa by intervention of the prostaglandin synthase regulatory pathway. PMID- 29723464 TI - Mimicking Pathogenic Invasion with the Complexes of Au22(SG)18-Engineered Assemblies and Folic Acid. AB - Biological systems provide the richest spectrum of sophisticated design for materials engineering. We herein provide a paradigm of Au22(SG)18-engineered (SG, glutathione thiolate) and hydrogen bonds engaged assemblies for mimicking capsid protein self-assembly. The water-evaporation-induced self-assembly method allows discrete ultrasmall gold nanoclusters (GNCs) to be self-assembled into super-GNCs assemblies (SGNCs) ranging from nano-, meso- to microscale in water-dimethyl sulfoxide binary solvents in a template-free manner. After removing free and hydration layer water molecules, the formation of SGNCs is engaged by the collective cohesion of hydrogen bonds between glutathione ligands of gradually approaching GNCs. Then, a series of tightly orchestrated cellular events induced by the complexes of Au22(SG)18-engineered assemblies and folic acid are demonstrated to mimic the invasion of eukaryotic cells by pathogens. First, the activation of macropinocytosis mimics the macropinocytic entry used by the pathogens to invade host cells. Then the cytoplasmic vacuolization is a mimicry of vacuolating effects induced by the oligomeric vacuolating toxins secreted by some bacteria. Lastly, the escaping from macropinosomes into cytosol is in a vacuolating toxin's strategy. The findings demonstrate the capabilities of artificial pathogens to emulate the structures and functions of natural pathogens. PMID- 29723465 TI - A Versatile Strategy for Characterization and Imaging of Drip Flow Microbial Biofilms. AB - The inherent architectural and chemical complexities of microbial biofilms mask our understanding of how these communities form, survive, propagate, and influence their surrounding environment. Here we describe a simple and versatile workflow for the cultivation and characterization of model flow-cell-based microbial ecosystems. A customized low-shear drip flow reactor was designed and employed to cultivate single and coculture flow-cell biofilms at the air-liquid interface of several metal surfaces. Pseudomonas putida F1 and Shewanella oneidensis MR-1 were selected as model organisms for this study. The utility and versatility of this platform was demonstrated via the application of several chemical and morphological imaging techniques-including matrix-assisted laser desorption/ionization mass spectrometry imaging, secondary ion mass spectrometry imaging, and scanning electron microscopy-and through the examination of model systems grown on iron substrates of varying compositions. Implementation of these techniques in combination with tandem mass spectrometry and a two-step imaging principal component analysis strategy resulted in the identification and characterization of 23 lipids and 3 oligosaccharides in P. putida F1 biofilms, the discovery of interaction-specific analytes, and the observation of several variations in cell and substrate morphology present during microbially influenced corrosion. The presented workflow is well-suited for examination of both single and multispecies drip flow biofilms and offers a platform for fundamental inquiries into biofilm formation, microbe-microbe interactions, and microbially influenced corrosion. PMID- 29723466 TI - Toward a Charged Homo[2]catenane Employing Diazaperopyrenium Homophilic Recognition. AB - An octacationic diazaperopyrenium (DAPP2+)-based homo[2]catenane (DAPPHC8+), wherein no fewer than eight positive charges are associated within a mechanically interlocked molecule, has been produced in 30% yield under ambient conditions as a result of favorable homophilic interactions, reflecting a delicate balance between strong pi-pi interactions and the destabilizing penalty arising from Coulombic repulsions between DAPP2+ units. This DAPPHC8+ catenane is composed of two identical mechanically interlocked tetracationic cyclophanes, namely DAPPBox4+, each of which contains one DAPP2+ unit and one extended viologen (ExBIPY2+) unit, linked together by two p-xylylene bridges. The solid-state structure of the homo[2]catenane demonstrates how homophilic interactions play an important role in the formation of DAPPHC8+, in which the mean ring planes of the two DAPPBox4+ cyclophanes are oriented at about 60 degrees with respect to each other, with a centroid-to-centroid separation of 3.7 A between the mean planes of the outer ExBIPY2+ and inner DAPP2+ units, and 3.6 A between the mean planes of the two inner DAPP2+ units. We show that irradiation of the DAPPHC8+ catenane at 330 nm in acetonitrile solution results in simultaneous energy and electron transfer. The latter occurs from the inner DAPP2+ dimer to the outer ExBIPY2+ unit, leading to the generation of a temporary charge-separated state within a rigid and robust homo[2]catenane. Compared to DAPPBox4+, both forward- and back electron transfer in DAPPHC8+ occur with faster rates, owing to the closer proximity between the electron donor and acceptor in the homo[2]catenane than in the separated cyclophane. PMID- 29723467 TI - Facile Preparation of Ag-Coated Superhydrophobic/Superoleophilic Mesh for Efficient Oil/Water Separation with Excellent Corrosion Resistance. AB - We present the facile preparation of a superhydrophobic-oleophilic stainless steel mesh with excellent oil/water separation efficiency and resistance to corrosion through hydrofluoric (HF) acid etching, Ag nanoparticle coating, and stearic acid modification, to construct a superhydrophobic micro/nanohierarchical structure. The surface of the treated mesh exhibits superhydrophobicity, with a water contact angle of 152 degrees , and superoleophilicity, with an oil contact angle of 0 degrees . The effects of variation in the HF etching time and Ag nanoparticle coating on surface wettability were explored. The treated mesh demonstrated a very high separation efficiency, as high as 98% for the optimal preparation, on a series of oil/water mixtures. The durability of the treated mesh was tested by repeated separation of kerosene/water mixtures, with the separation efficiency remaining higher than 97% after 40 cycles. In addition, the mesh exhibited an excellent chemical resistance to both acidic and alkaline conditions, with good wearing in hot water. The improved superhydrophobic oleophilic mesh represents a feasible and realistic oil/water separation methodology even under harsh conditions, and it could have wide application in industrial processes. PMID- 29723468 TI - DART-MS: A New Analytical Technique for Forensic Paint Analysis. AB - Automotive paint evidence is one of the most significant forms of evidence obtained in automotive-related incidents. Therefore, the analysis of automotive paint evidence is imperative in forensic casework. Most analytical schemes for automotive paint characterization involve optical microscopy, followed by infrared spectroscopy and pyrolysis-gas chromatography mass spectrometry ( py GCMS) if required. The main drawback with py-GCMS, aside from its destructive nature, is that this technique is relatively time intensive in comparison to other techniques. Direct analysis in real-time-time-of-flight mass spectrometry (DART-TOFMS) may provide an alternative to py-GCMS, as the rapidity of analysis and minimal sample preparation affords a significant advantage. In this study, automotive clear coats from four vehicles were characterized by DART-TOFMS and a standard py-GCMS protocol. Principal component analysis was utilized to interpret the resultant data and suggested the two techniques provided analogous sample discrimination. Moreover, in some instances DART-TOFMS was able to identify components not observed by py-GCMS and vice versa, which indicates that the two techniques may provide complementary information. Additionally, a thermal desorption/pyrolysis DART-TOFMS methodology was also evaluated to characterize the intact paint chips from the vehicles to ascertain if the linear temperature gradient provided additional discriminatory information. All the paint samples were able to be discriminated based on the distinctive thermal desorption plots afforded from this technique, which may also be utilized for sample discrimination. On the basis of the results, DART-TOFMS may provide an additional tool to the forensic paint examiner. PMID- 29723469 TI - Automated Removal of Phospholipids from Membrane Proteins for H/D Exchange Mass Spectrometry Workflows. AB - Membrane proteins are currently the most common targets for pharmaceuticals. However, characterization of their structural dynamics by hydrogen/deuterium exchange mass spectrometry (HDX-MS) is sparse due to insufficient automated methods to handle full-length membrane proteins in lipid bilayers. Additionally, membrane lipids used to mimic the membrane environment and to solubilize membrane proteins can impair chromatography performance and cause ion suppression in the mass spectrometer. The workflow discussed herein advances HDX-MS capabilities and other MS applications for membrane proteins by providing a fully automated method for HDX-MS analysis based on a phospholipid removal scheme compatible with robotic handling. Phospholipids were depleted from protein samples by the addition of zirconium oxide beads, which were subsequently removed by inline filtration using syringeless nanofilters. To demonstrate this method, single-pass transmembrane protein FcgammaRIIa (CD32a) expressed into liposomes was used. Successful depletion of phospholipids ensured optimal liquid-chromatography-mass spectrometry performance, and measurement of peptides from the transmembrane domain of FcgammaRIIa indicated phospholipids associated with this region were either not present or did not shield the transmembrane domain from digestion by pepsin. Furthermore, amino acid sequence coverage provided by this method was suitable to enable future measurement of structural dynamics of ectodomain, transmembrane domain, and endodomain of FcgammaRIIa. Moreover, this method is the first to enable fully automated HDX-MS on full-length transmembrane proteins in lipid bilayers, a notable advancement to facilitate understanding of membrane proteins, development of pharmaceuticals, and characterization for regulatory agencies. PMID- 29723470 TI - Rapid Production of Internally Structured Colloids by Flash Nanoprecipitation of Block Copolymer Blends. AB - Colloids with internally structured geometries have shown great promise in applications ranging from biosensors to optics to drug delivery, where the internal particle structure is paramount to performance. The growing demand for such nanomaterials necessitates the development of a scalable processing platform for their production. Flash nanoprecipitation (FNP), a rapid and inherently scalable colloid precipitation technology, is used to prepare internally structured colloids from blends of block copolymers and homopolymers. As revealed by a combination of experiments and simulations, colloids prepared from different molecular weight diblock copolymers adopt either an ordered lamellar morphology consisting of concentric shells or a disordered lamellar morphology when chain dynamics are sufficiently slow to prevent defect annealing during solvent exchange. Blends of homopolymer and block copolymer in the feed stream generate more complex internally structured colloids, such as those with hierarchically structured Janus and patchy morphologies, due to additional phase separation and kinetic trapping effects. The ability of the FNP process to generate such a wide range of morphologies using a simple and scalable setup provides a pathway to manufacturing internally structured colloids on an industrial scale. PMID- 29723471 TI - Effects of Dielectric Inhomogeneity and Electrostatic Correlation on the Solvation Energy of Ions in Liquids. AB - Electrolytes often involve the spatially varying dielectric response of liquids and electrostatic correlation. Nevertheless, the complexity of their synergistic effects complicates our understanding of ion solvation and often limits theoretical approaches. Thus, we develop a Ginzburg-Landau-like (GL) theory that simultaneously considers these two features. We derive the modified Born solvation energy of ions, which accounts for the effect of saturated dipoles near the ions on the solvation energy, which is in good agreement with experimental data for different ionic charges and even for some selected liquid mixtures. Moreover, we consider the phase diagram of a mixture of polyelectrolyte and uncharged polymer and that of a mixture of ionic liquid and uncharged polymer. The GL theory encompasses the results of the previous mean-field theories, accounting for fluctuations of the electrostatic potentials and hence serves as a simple alternative approach to dielectrically inhomogeneous media. PMID- 29723472 TI - Process-Tracing Study on the Postassembly Modification of Highly Stable Zirconium Metal-Organic Cages. AB - Metal-organic cages (MOCs) are discrete molecular assemblies formed by coordination bonds between metal nodes and organic ligands. The application of MOCs has been greatly limited due to their poor stability, especially in aqueous solutions. In this work, we thoroughly investigate the stability of several Zr MOCs and reveal their excellent stability in aqueous solutions with acidic, neutral, and weak basic conditions. In addition, we present for the first time a process-tracing study on the postassembly modification of one MOC, ZrT-1-NH2, highlighting the excellent stability and versatility of Zr-MOCs as a new type of molecular platform for various applications. PMID- 29723473 TI - Thio-Linked UDP-Peptide Conjugates as O-GlcNAc Transferase Inhibitors. AB - O-GlcNAc transferase (OGT) is an essential glycosyltransferase that installs the O-GlcNAc post-translational modification on the nucleocytoplasmic proteome. We report the development of S-linked UDP-peptide conjugates as potent bisubstrate OGT inhibitors. These compounds were assembled in a modular fashion by photoinitiated thiol-ene conjugation of allyl-UDP and optimal acceptor peptides in which the acceptor serine was replaced with cysteine. The conjugate VTPVC(S propyl-UDP)TA ( Ki = 1.3 MUM) inhibits the OGT activity in HeLa cell lysates. Linear fusions of this conjugate with cell penetrating peptides were explored as prototypes of cell-penetrant OGT inhibitors. A crystal structure of human OGT with the inhibitor revealed mimicry of the interactions seen in the pseudo Michaelis complex. Furthermore, a fluorophore-tagged derivative of the inhibitor works as a high affinity probe in a fluorescence polarimetry hOGT assay. PMID- 29723474 TI - Pore-Size-Tuned Graphene Oxide Frameworks as Ion-Selective and Protective Layers on Hydrocarbon Membranes for Vanadium Redox-Flow Batteries. AB - The laminated structure of graphene oxide (GO) membranes provides exceptional ion separation properties due to the regular interlayer spacing ( d) between laminate layers. However, a larger effective pore size of the laminate immersed in water (~11.1 A) than the hydrated diameter of vanadium ions (>6.0 A) prevents its use in vanadium redox-flow batteries (VRFB). In this work, we report an ion-selective graphene oxide framework (GOF) with a d tuned by cross-linking the GO nanosheets. Its effective pore size (~5.9 A) excludes vanadium ions by size but allows proton conduction. The GOF membrane is employed as a protective layer to address the poor chemical stability of sulfonated poly(arylene ether sulfone) (SPAES) membranes against VO2+ in VRFB. By effectively blocking vanadium ions, the GOF/SPAES membrane exhibits vanadium-ion permeability 4.2 times lower and a durability 5 times longer than that of the pristine SPAES membrane. Moreover, the VRFB with the GOF/SPAES membrane achieves an energy efficiency of 89% at 80 mA cm 2 and a capacity retention of 88% even after 400 cycles, far exceeding results for Nafion 115 and demonstrating its practical applicability for VRFB. PMID- 29723475 TI - Tuning Molecular Interactions for Highly Reproducible and Efficient Formamidinium Perovskite Solar Cells via Adduct Approach. AB - The Lewis acid-base adduct approach has been widely used to form uniform perovskite films, which has provided a methodological base for the development of high-performance perovskite solar cells. However, its incompatibility with formamidinium (FA)-based perovskites has impeded further enhancement of photovoltaic performance and stability. Here, we report an efficient and reproducible method to fabricate highly uniform FAPbI3 films via the adduct approach. Replacement of the typical Lewis base dimethyl sulfoxide (DMSO) with N methyl-2-pyrrolidone (NMP) enabled the formation of a stable intermediate adduct phase, which can be converted into a uniform and pinhole-free FAPbI3 film. Infrared and computational analyses revealed a stronger interaction between NMP with the FA cation than DMSO, which facilitates the formation of a stable FAI.PbI2.NMP adduct. On the basis of the molecular interactions with different Lewis bases, we proposed criteria for selecting the Lewis bases. Owed to the high film quality, perovskite solar cells with the highest PCE over 20% (stabilized PCE of 19.34%) and average PCE of 18.83 +/- 0.73% were demonstrated. PMID- 29723476 TI - Synthesis of Cyclic Megamolecules. AB - This paper describes the synthesis of giant cyclic molecules having diameters of 10-20 nm. The molecules are prepared through the reactions of a fusion protein building block with small molecule linkers that are terminated in irreversible inhibitors of enzyme domains present in the fusion. This building block has N terminal cutinase and C-terminal SnapTag domains that react irreversibly with p nitrophenyl phosphonate (pNPP) and benzylguanine (BG) groups, respectively. We use a bis-BG and a BG-pNPP linker to join these fusion proteins into linear structures that can then react with a bis-pNPP linker that joins the ends into a cyclic product. The last step can occur intramolecularly, to give the macrocycle, or intermolecularly with another equivalent of linker, to give a linear product. Because these are coupled first- and second-order processes, an analysis of product yields from reactions performed at a range of linker concentrations gives rate constants for cyclization. We determined these to be 9.7 * 10-3 s-1, 2.3 * 10-3 s-1, and 8.1 * 10-4 s-1 for the dimer, tetramer, and hexamer, respectively. This work demonstrates an efficient route to cyclic macromolecules having nanoscale dimensions and provides new scaffolds that can be generated using the megamolecule approach. PMID- 29723477 TI - Formation of Catalytically Active Binuclear Center of Glycerophosphodiesterase: A Molecular Dynamics Study. AB - Glycerophosphodiesterase (GpdQ) is a binuclear metallophosphatase that catalyzes the hydrolytic cleavage of mono-, di-, and triphosphoester bonds of a wide range of critical molecules. Upon substrate binding, this enzyme undergoes a complex transformation from an inactive mononuclear form (Em, where the metal resides in the alpha site) to an active binuclear center (Eb-S, with metals bound to both the alpha and beta sites) through a mononuclear, substrate-bound intermediate state (Em-S). In this study, all-atom molecular dynamics simulations have been employed to investigate structures and dynamical transformations in this process using eight different variants, i.e., five wild-type and three mutant forms of the enzyme. Additionally, the effects of an actual substrate, bis-( para nitrophenyl) phosphate (b pNPP), a metal-bridging nucleophilic hydroxyl, and specific first and second coordination shell residues have been investigated. The initial binding of the substrate to Em enhances the metal binding affinity of the alpha site and prepares the beta site for coordination of the second metal ion. These results are in agreement with stopped-flow fluorescence and calorimetry data. In Eb-S, the computed increase in the substrate and metal (both alpha and beta) binding energies is also in line with the experimental data. However, removal of the substrate from this complex is found to cause substantial reduction in binding energies of both alpha and beta metals. The role of the substrate in the creation and stabilization of the active site predicted in this study is supported by the kinetic measurements using both stopped-flow and nuclear magnetic resonance techniques. Importantly, residue Asn80, a ligand of the metal in the beta site, exhibits coordination flexibility by acting as a gate in the formation of Eb-S, in good agreement with mutagenesis and spectroscopic data. PMID- 29723478 TI - Adsorption Mechanisms of Nucleobases on the Hydrated Au(111) Surface. AB - The solution environment is of fundamental importance in the adsorption of molecules on surfaces, a process that is strongly affected by the capability of the adsorbate to disrupt the hydration layer above the surface. Here we disclose how the presence of interface water influences the adsorption mechanism of DNA nucleobases on a gold surface. By means of metadynamics simulations, we describe the distinctive features of a complex free-energy landscape for each base, which manifests activation barriers for the adsorption process. We characterize the different pathways that allow each nucleobase to overcome the barriers and be adsorbed on the surface, discussing how they influence the kinetics of adsorption of single-stranded DNA oligomers with homogeneous sequences. Our findings offer a rationale as to why experimental data on the adsorption of single-stranded homo oligonucleotides do not straightforwardly follow the thermodynamics affinity rank. PMID- 29723479 TI - Strategies in Context: How Perceptions of Romantic Partner Support for Weight Loss Vary by the Relational Context. AB - Because romantic partners can be a strong influence on individuals' weight loss efforts and progress, the current study assessed the relational context of weight loss-dynamics within the relationship that pertain to weight loss. Three relational characteristics were examined: whether the weight loss was a team effort, how much partners had opposing approaches to weight loss, and individuals' difficulty in balancing their weight loss goals within their relationship goals. Findings showed that the relational characteristics were associated with both the perceived frequency and effectiveness of partner strategies (i.e., instrumental influence, encouragement, and coercion). Team effort was associated with perceiving all three strategies as more frequent and effective; opposing approaches were negatively associated with encouragement but positively associated with coercion for both frequency and effectiveness; and balance struggle was positively associated with coercion frequency and effectiveness. Additionally, a cluster analysis of the three relational characteristics yielded four relational climates: synchronized (high team effort, low relational strains), contentious cooperatives (moderate in all three relational characteristics), autonomous (low in all relational characteristics), and lone battlers (low team effort, high relational strains). The groups varied in the strategies they perceived as effective. All of these findings emerged beyond the variance explained by general relationship satisfaction. Overall, these results better explicate relationship characteristics that can be incorporated into a larger, ecological model on health behavior change. PMID- 29723480 TI - Response to: 'Letter to the Editor: "Management of multidrug-resistant Pseudomonas aeruginosa in the Intensive Care Unit: state of the art"'. PMID- 29723481 TI - The potential for machine learning algorithms to improve and reduce the cost of 3 dimensional printing for surgical planning. AB - INTRODUCTION: 3D-printed anatomical models play an important role in medical and research settings. The recent successes of 3D anatomical models in healthcare have led many institutions to adopt the technology. However, there remain several issues that must be addressed before it can become more wide-spread. Of importance are the problems of cost and time of manufacturing. Machine learning (ML) could be utilized to solve these issues by streamlining the 3D modeling process through rapid medical image segmentation and improved patient selection and image acquisition. The current challenges, potential solutions, and future directions for ML and 3D anatomical modeling in healthcare are discussed. Areas covered: This review covers research articles in the field of machine learning as related to 3D anatomical modeling. Topics discussed include automated image segmentation, cost reduction, and related time constraints. Expert commentary: ML based segmentation of medical images could potentially improve the process of 3D anatomical modeling. However, until more research is done to validate these technologies in clinical practice, their impact on patient outcomes will remain unknown. We have the necessary computational tools to tackle the problems discussed. The difficulty now lies in our ability to collect sufficient data. PMID- 29723482 TI - Factors Affecting Breastfeeding Outcomes at Six Months in Preterm Infants. AB - BACKGROUND: Preterm mother-infant dyads often face many obstacles to breastfeeding. Preterm infants are at highest risk for low rates of exclusive breastfeeding. Research Aim: To determine the prevalence of breastfeeding at 6 months among preterm infants and to identify factors that influenced mothers' breastfeeding practices. METHODS: A longitudinal observational study was conducted in a metropolitan hospital in Beijing, China. Mothers ( N = 270) and their preterm infants ( N = 280) were included in the study. Characteristics of preterm mothers and their perceptions of breastfeeding self-efficacy, knowledge, social support, and postpartum depression symptoms were measured at the discharge of neonatal intensive care. Breastfeeding data were collected by phone interview at 6 months corrected age. RESULTS: At discharge, mothers of very preterm infants perceived a lower level of breastfeeding self-efficacy (measured with the Breastfeeding Self-Efficacy Scale-Short Form) and had a higher level of depression symptoms (measured with the Edinburgh Postnatal Depression Scale [EPDS]) than mothers of moderate and late preterm infants ( p < .05-.01). Nearly half of all mothers had an elevated EPDS score, considered to be symptomatic of postpartum depression. At 6 months, only 22.5% of all infants were exclusively breastfeeding. Factors associated with exclusive breastfeeding, including younger maternal age, previous breastfeeding experience, shorter mother-infant separation time during intensive care, older infant gestational age, and a higher level of breastfeeding self-efficacy, significantly predicted exclusive breastfeeding practice ( p < .05-.001). CONCLUSION: The prevalence of breastfeeding at 6 months for preterm infants in this sample was low. Strategies to improve breastfeeding duration for preterm infants are needed, including support and education of mothers while in the hospital. PMID- 29723483 TI - Breastfeeding Intention Compared With Breastfeeding Postpartum Among Women Receiving Medication-Assisted Treatment. AB - BACKGROUND: Women taking methadone or buprenorphine are encouraged to breastfeed if stable without polysubstance use. Research Aim: We aimed to determine the difference between stated intention to breastfeed prenatally in women taking methadone or buprenorphine compared with breastfeeding at discharge and 2 months postpartum. Secondary outcomes were determining whether breastfeeding was more common in women taking buprenorphine, in women without hepatitis C infection, and in women without a history of heroin use, and whether breastfeeding reduced the need for pharmacological treatment of neonatal opioid withdrawal syndrome. METHODS: This was a retrospective cohort study of 228 women enrolled in a perinatal substance abuse treatment program. Electronic medical records were reviewed to abstract data on mother-infant dyads. Chi-square tests were used to analyze our outcomes. RESULTS: Women taking buprenorphine had a higher prevalence of breastfeeding compared with women taking methadone (83% [ n = 100] vs. 71% [ n = 76]; chi2 = 4.35, p = .03), despite no difference in their prenatal intention to breastfeed (87% vs. 81%; chi2 = 1.28, p = .25). Only 31% ( n = 38) of women taking buprenorphine and 19.6% ( n = 21) of women taking methadone exclusively breastfed at discharge (chi2 = 5.43, p = .06). Exclusively breastfed infants required less pharmacological treatment for neonatal opioid withdrawal syndrome compared with formula-fed infants (15.8% [ n = 21] vs. 47.4% [ n = 38]; chi2 = 19.72, p < .05). CONCLUSION: Despite most women reporting a high prenatal intention to breastfeed, exclusive breastfeeding at hospital discharge postpartum was low. Breastfeeding was associated with a decreased likelihood of pharmacological treatment for neonatal opioid withdrawal syndrome. PMID- 29723484 TI - Investigational drugs for alcohol use disorders: a review of preclinical data. AB - INTRODUCTION: Alcohol use disorders (AUDs) are one of the leading causes of preventable death in the developed world. In the U.S., only three FDA-approved pharmacotherapies for AUDs currently exist, but at a population level they display poor efficacy, low compliance rates, and adverse side effects. Therefore, identifying novel neurobiological targets for pharmacological treatment of AUDs is of urgent concern. Areas covered: We discuss recent preclinical data on investigational drugs that have been assessed for their therapeutic potential in AUDs. We focus on three neurobiological domains underlying AUDs: neuropeptide systems, neuroinflammatory/neuroimmune mediators, and epigenetic modifications. We iterate the therapeutic potential of ghrelin receptor antagonists, oxytocin, neurokinin 1 receptor antagonists, and glucagon-like peptide-1 receptor agonists. In the context of neuroinflammatory/neuroimmune modulators, we draw attention to P2X4 receptor positive allosteric modulators and phosphodiesterase inhibitors. Finally, we highlight the prospects of histone deacetylase inhibitors and DNA methyltransferases that modulate the dysregulated epigenetic landscape in alcohol dependence. Expert opinion: We propose that several of the compounds discussed may be suitable to be repurposed for AUD treatment. We allude to the possibility of combined pharmacotherapy for AUDs and anticipate the efforts that must be enacted to advance the field of personalised medicine for the treatment of this devastating condition. PMID- 29723486 TI - Doppler ultrasound can be used to monitor umbilical arterial blood flow in lightly sedated pigs at multiple gestational ages. AB - Doppler ultrasound was performed under moderate sedation (ketamine and azaperone) for 30min to monitor umbilical arterial (UA) blood flow in one uterine horn of Large White*Landrace gilts (n=23) at Gestational Days (GD) 30, 45, 60 and 90. Gilts were scanned before they were killed to examine relationships between litter size, sex ratio and five UA parameters (peak systolic velocity (PSV), end diastolic velocity (EDV), A/B (PSV to EDV) ratio, fetal heart rate (FHR) and resistance index (RI)). In gilts in which scans were obtained from all fetuses in the scanned horn, relationships between UA parameters, and fetal weight and sex were examined. A subset of gilts were sedated, scanned and recovered (SSR) earlier in gestation (GD30 or GD45) to assess the effects of sedation on later fetal development by comparison with control litters (no previous sedation). Temporal changes were observed in all UA parameters (P<=0.001). At GD60 and GD90, FHR decreased with increasing duration of sedation (P<=0.001). Sex ratio and fetal weight affected UA blood flow, whereas litter size and fetal sex did not. SSR at GD30 and GD45 was associated with decreased fetal weight at GD60 (P<=0.001) and GD90 (P=0.06) respectively, compared with controls. These results suggest maternal sedation during gestation affects fetal development, which should be investigated further. Measuring UA blood flow in growth-restricted porcine fetuses throughout gestation may be feasible. PMID- 29723485 TI - Late or Lack of Vaccination Linked to Importation of Yellow Fever from Angola to China. AB - During March and April 2016, 11 yellow fever cases were identified in China. We report epidemic and viral information for 10 of these patients, 6 of whom had been vaccinated before travel. Phylogenetic analyses suggest these viruses nested within the diversity of strains endemic to Angola, where an outbreak began in 2015. PMID- 29723487 TI - Clinical investigation and characterization of vertebrobasilar dolichoectasia and vertebral artery dominance. AB - In clinical practice, the vertebral arteries of a patient are often found to be not equal in size and the basilar artery may not be situated in the center. Our observational study showed that vertebral dominance and basilar bending are common, and their occurrence is related to advanced age and hypertension. The right vertebral dominance tends to coincide with left basilar bending, and, vice versa, the left vertebral dominance tends to coincide with right basilar bending. The left vertebral dominance is more common than the right dominance. Vertebral dominance and basilar bending are risk factors for brainstem infarction and transient ischemic attack (TIA) and their early detection can prompt measures to be taken to prevent the onset of brain infarction and TIA. PMID- 29723488 TI - Grifola frondosa polysaccharide: a review of antitumor and other biological activity studies in China. AB - Grifola frondosa, a species of Basidiomycotina, is an edible medicinal mushroom with a large fruiting body characterized by overlapping caps. The beta-glucan is the major biologically active component in G. frondosa polysaccharide (GFP) or D fraction, which has been studied extensively for nearly 30 years. GFP was approved as an adjunctive therapeutic drug in China for treating cancers in 2010. In this article, based on the search results of Chinese VIP, CNKI, and Wanfang databases, 105 independent animal studies were summarized. The chemical structure, the antitumor, immunomodulatory, anti-diabetic, anti-hyperlipidemia, and antiviral activities and molecular mechanisms of GFP are reviewed and discussed. PMID- 29723489 TI - Scaffolding protein RanBPM and its interactions in diverse signaling pathways in health and disease. AB - Ran-binding protein in the microtubule-organizing center (RanBPM) is an evolutionarily conserved, nucleocytoplasmic scaffolding protein involved in various cellular processes and several signal transduction pathways. RanBPM has a crucial role in mediating disease pathology by interacting with diverse proteins to regulate their functions. Previously, we compiled diverse cellular functions of RanBPM. Since then the functions of RanBPM have increased exponentially. In this article, we have updated the functions of RanBPM through its manifold interactions that have been investigated to date, according to their roles in protein stability, transcriptional activity, cellular development, neurobiology, and the cell cycle. Our review provides a complete guide on RanBPM interactors, the physiological role of RanBPM in cellular functions, and potential applications in disease therapeutics. PMID- 29723490 TI - Controlled release of gene therapy constructs from solid scaffolds for therapeutic applications in orthopedics. AB - Injuries occurring in orthopedic tissues do not completely heal if left untreated due to their imperfect self abilities for spontaneous repair. As most of the current clinical treatments often fail to fully restore the damaged tissues, there is a critical need to develop potent alternatives to activate the processes of repair in sites of orthopedic lesions. In this regard, combining gene therapy approaches with tissue engineering procedures to generate therapeutic gene vector guided delivery systems, especially those based on mechanically stable solid scaffolds, is an attractive strategy to provide off-the-shelf compounds for the convenient spatiotemporal expression of candidate agents in orthopedic tissue defects. The goal of this review is to report the most advanced technologies using such scaffolds as tools for the controlled delivery of gene transfer vectors to improve orthopedic tissue repair. PMID- 29723491 TI - QSOX1, a novel actor of cardiac protection upon acute stress in mice. AB - QSOX1, a sulfhydryl oxidase, was shown to be upregulated in the heart upon acute heart failure (AHF). The aim of the study was to unravel QSOX1 roles during AHF. We generated and characterized mice with QSOX1 gene deletion. The QSOX1-/- mice were viable but adult male exhibited a silent dilated cardiomyopathy. The QSOX1-/ hearts were characterized by low protein SERCA2a levels associated with a calcium homeostasis alteration, high levels of the endoplasmic reticulum (ER) chaperone proteins Grp78/Bip, and of the ER apoptosis sensor CHOP, indicating a chronic unfolded protein response (UPR). Importantly the QSOX1invalidation led to overexpression of two ER oxidases, ERO1-alpha and PRDX4. Acute stress was induced by isoproterenol injection (ISO, 300 mg/kg/12 h) for 2 days. In both groups, the PERK UPR pathway was transiently activated 6 h after the first ISO injection as indicated by eIF2 phosphorylation. By day-3 after the onset of stress, both WT and QSOX1-/- mice exhibited AHF profile but while high cardiac QSOX1 level was induced in WT hearts, ERO1-alpha and PRDX4 levels drop down in QSOX1-/-. At that time, QSOX1-/- hearts exhibited an enhanced inflammation (CD68+ cells and Galectin-3 expression) and oxidative stress (DHE staining and oxyblot) when compared to WT ones. In conclusion, the lack of QSOX1 promotes the upregulation of two ER oxidases ERO1alpha and PRDX4 that likely rescues oxidative protein folding in the hearts. However, signs of chronic ER stress remained present and were associated with a dilated cardiomyopathy. The superimposition of acute stress allowed us to propose that QSOX1 participate to the early response to cardiac stress but not to immediate UPR response. Taken altogether, the data indicated that QSOX1 is required 1) for a proper protein folding in the endo/sarcoplasmic reticulum (ER/SR) and 2) for resolution and protective response during acute stress. PMID- 29723492 TI - Microbial Host Interactions and Impaired Wound Healing in Mice and Humans: Defining a Role for BD14 and NOD2. AB - Chronic wounds cause significant patient morbidity and mortality. A key factor in their etiology is microbial infection, yet skin host-microbiota interactions during wound repair remain poorly understood. Microbiome profiles of noninfected human chronic wounds are associated with subsequent healing outcome. Furthermore, poor clinical healing outcome was associated with increased local expression of the pattern recognition receptor NOD2. To investigate NOD2 function in the context of cutaneous healing, we treated mice with the NOD2 ligand muramyl dipeptide and analyzed wound repair parameters and expression of antimicrobial peptides. Muramyl dipeptide treatment of littermate controls significantly delayed wound repair associated with reduced re-epithelialization, heightened inflammation, and up-regulation of murine beta-defensins 1, 3, and particularly 14. We postulated that although murine beta-defensin 14 might affect local skin microbial communities, it may further affect other healing parameters. Indeed, exogenously administered murine beta-defensin 14 directly delayed mouse primary keratinocyte scratch wound closure in vitro. To further explore the role of murine beta-defensin 14 in wound repair, we used Defb14-/- mice and showed they had a global delay in healing in vivo, associated with alterations in wound microbiota. Taken together, these studies suggest a key role for NOD2-mediated regulation of local skin microbiota, which in turn affects chronic wound etiology. PMID- 29723493 TI - Validation of housekeeping genes for quantitative mRNA expression analysis in OsHV-1 infected ark clam, Scapharca broughtonii. AB - Ostreid herpesvirus-1 (OsHV-1) presents interspecies transmission among bivalves. Recently, events of mass mortalities of ark clams (Scapharca broughtonii) infected with OsHV-1 have been recorded. To accurately assess the gene responding patterns of ark clams post OsHV-1 infection, constant stable housekeeping genes (HKGs) are needed as internal control to normalize raw mRNA expression data. In this study, ten candidate HKGs were selected, including 18S rRNA (18S), beta actin (ACT), Glyceraldehyde 3-phosphate dehydrogenase (GAPDH), NADH dehydrogenase subunit (NADH), Elongation factor-1a (EF-1a), Elongation factor-1beta (EF-1beta), Elongation factor-1gamma (EF-1gamma), Ribosomal protein L7 (RL7), Ribosomal protein L15 (RL15) and Ribosomal protein S18 (S18). The expression levels of ten candidate HKGs were analyzed by real-time PCR under given experimental conditions, including various tissues, OsHV-1 challenge, temperature stress and OsHV-1 challenge at different temperature. Their expression stability values were further calculated using two different statistical models (geNorm and NormFinder). The results showed that different tissues presented distinct best pair genes combinations for gene expression analysis under OsHV-1 challenge. RL15 was comparatively more stable than other HKGs under various experimental conditions, while commonly used 18s and ACT seemed to be more greatly influenced by most given experimental conditions in ark clams. This study emphasized the necessity of prior validation of HKGs and would facilitate future gene expression analysis in ark clams or other shellfishes. PMID- 29723494 TI - Systematic characterization of Bacillus Genetic Stock Center Bacillus thuringiensis strains using Multi-Locus Sequence Typing. AB - The goal of this work was to perform a systematic characterization of Bacillus thuringiensis (Bt) strains from the Bacillus Genetic Stock Center (BGSC) collection using Multi-Locus Sequence Typing (MLST). Different genetic markers of 158 Bacillus thuringiensis (Bt) strains from 73 different serovars stored in the BGSC, that represented 92% of the different Bt serovars of the BGSC were analyzed, the 8% that were not analyzed were not available. In addition, we analyzed 72 Bt strains from 18 serovars available at the pubMLST bcereus database, and Bt strains G03, HBF18 and Bt185, with no H serovars provided by our laboratory. We performed a systematic MLST analysis using seven housekeeping genes (glpF, gmK, ilvD, pta, pur, pycA and tpi) and analyzed correlation of the results of this analysis with strain serovars. The 233 Bt strains analyzed were assigned to 119 STs from which 19 STs were new. Genetic relationships were established by phylogenetic analysis and showed that STs could be grouped in two major Clusters containing 21 sub-groups. We found that a significant number of STs (101 in total) correlated with specific serovars, such as ST13 that corresponded to nine Bt isolates from B. thuringiensis serovar kenyae. However, other serovars showed high genetic variability and correlated with multiple STs; for example, B. thuringiensis serovar morrisoni correlated with 11 different STs. In addition, we found that 16 different STs correlated with multiple serovars (2 4 different serovars); for example, ST12 correlated with B. thuringiensis serovar alesti, dakota, palmanyolensis and sotto/dendrolimus. These data indicated that only partial correspondence between MLST and serotyping can be established. PMID- 29723495 TI - New Molecular Insights into the Excitation-Transcription Coupling. AB - Neuronal activity-induced gene transcription is an important cellular mechanism for long-term plasticity. In this issue of Neuron, Tyssowski et al. (2018) provide new genome-wide features of the activity-transcription coupling mechanism that have deepened our molecular understanding of activity pattern-dependent synaptic plasticity. PMID- 29723496 TI - Opening a "Wide" Window onto Taste Signal Transmission. AB - Taste bud cells for sweet, umami, and bitter transmit sensory signals without a synapse. A study by Ma et al. (2018) finds a key ATP-permeable pore-forming subunit required for rapid neurotransmission from the tongue to secondary taste neurons. PMID- 29723497 TI - Dopamine Is Differentially Encoded by D2 Receptors in Striatal Subregions. AB - Striatal dopamine signaling is differentially regulated along the dorso-ventral axis, but how these differences are encoded by dopamine receptors is unknown. In this issue of Neuron, Marcott et al. (2018) show that dopamine activates D2 receptors in regionally distinct ways and dissect the underlying mechanisms behind striatal D2 heterogeneity. PMID- 29723498 TI - I Can't Watch: A Genetic and Circuit-Level Investigation of Observational Fear Learning. AB - In this issue of Neuron, Keum et al. (2018) identify a Nrxn3 variant that produces an enhancement of observational fear learning. Results suggest that Nrxn3 loss of function, specifically within somatostatin-positive interneurons of the anterior cingulate cortex, is responsible. PMID- 29723499 TI - Visions for the Future of Neuroscience. AB - Neuroscience is a broad discipline that embraces technology at multiple scales to understand the brain and to develop potential therapies. Scientists share their perspectives on the evolution of neuroscience research and what excites them about the future prospects for the field. PMID- 29723500 TI - Calcium Channels, Synaptic Plasticity, and Neuropsychiatric Disease. AB - Voltage-gated calcium channels couple depolarization of the cell-surface membrane to entry of calcium, which triggers secretion, contraction, neurotransmission, gene expression, and other physiological responses. They are encoded by ten genes, which generate three voltage-gated calcium channel subfamilies: CaV1; CaV2; and CaV3. At synapses, CaV2 channels form large signaling complexes in the presynaptic nerve terminal, which are responsible for the calcium entry that triggers neurotransmitter release and short-term presynaptic plasticity. CaV1 channels form signaling complexes in postsynaptic dendrites and dendritic spines, where their calcium entry induces long-term potentiation. These calcium channels are the targets of mutations and polymorphisms that alter their function and/or regulation and cause neuropsychiatric diseases, including migraine headache, cerebellar ataxia, autism, schizophrenia, bipolar disorder, and depression. This article reviews the molecular properties of calcium channels, considers their multiple roles in synaptic plasticity, and discusses their potential involvement in this wide range of neuropsychiatric diseases. PMID- 29723502 TI - Heterophilic Type II Cadherins Are Required for High-Magnitude Synaptic Potentiation in the Hippocampus. PMID- 29723503 TI - Activation of Striatal Neurons Causes a Perceptual Decision Bias during Visual Change Detection in Mice. PMID- 29723504 TI - Gamma Oscillation Dysfunction in mPFC Leads to Social Deficits in Neuroligin 3 R451C Knockin Mice. PMID- 29723501 TI - Peripheral and Central Mechanisms of Itch. AB - Itch is a unique sensory experience that is encoded by genetically distinguishable neurons both in the peripheral nervous system (PNS) and central nervous system (CNS) to elicit a characteristic behavioral response (scratching). Itch interacts with the other sensory modalities at multiple locations, from its initiation in a particular dermatome to its transmission to the brain where it is finally perceived. In this review, we summarize the current understanding of the molecular and neural mechanisms of itch by starting in the periphery, where itch is initiated, and discussing the circuits involved in itch processing in the CNS. PMID- 29723505 TI - Phenotypic changes and DNA methylation status in cryopreserved seeds of rye (Secale cereale L.). AB - Conserving genetic diversity is a major priority of the National Laboratory for Genetic Resources Preservation (NLGRP), operated by the U.S. Department of Agriculture, Agricultural Research Service. There are two long-term preservation methods employed in the NLGRP: storage in a -18 degrees C freezer (conventional storage) and storage in liquid nitrogen vapor phase at -135 to -180 degrees C (cryopreservation). To test the phenotypic and epigenetic effects of long-term cryopreservation of orthodox seeds, we evaluated 40 cereal rye accessions (20 spring habit and 20 winter habit) stored for 25 years under both conventional storage and cryogenic conditions. In laboratory evaluations of winter habit rye, seeds from cryopreserved samples had significantly higher normal germination percentage (P < 0.05) and lower abnormal germination percentage (P < 0.05) than those stored under conventional conditions. Cryopreserved spring habit rye also had higher normal germination percentage (P < 0.01) than conventionally stored samples. In addition, winter rye seedlings from cryopreserved seeds had longer roots and smaller root diameter (P < 0.05) than seedlings from conventionally stored seeds. In field evaluations conducted in Fort Collins, Colorado in 2014 15, spikes of plants grown from conventionally stored seeds of the winter accessions were slightly longer than those from cryopreserved seeds (P = 0.045). To detect DNA methylation changes, a methylation-sensitive amplified fragment length polymorphism (metAFLP) technique was applied to two accessions. After false discovery rate adjustment, no differences in methylation were detected between storage treatments on an individual locus basis. Our study indicated that cryopreservation slowed seed deterioration as evidenced by higher germination rates compared to conventional storage, had only minimal effects on other phenotypic traits, and had no significant effects on DNA methylation status. PMID- 29723508 TI - Inhibition of PP2A by hesperetin may contribute to Akt and ERK1/2 activation status in cortical neurons. AB - Flavonoids and their metabolites are well reported to modulate the activation/phosphorylation of various cellular kinases, such as ERK1/2 and JNK, although the mechanism by which they do so is unclear. In this study, we investigated the impact of flavanones on the activation of PI3K/Akt and ERK1/2 and determine whether this is mediated, in part, by the inhibition of phosphatases. Primary cortical neurons were exposed to physiological concentrations of hesperetin and the phosphorylation status of the kinases PI3K/Akt and ERK1/2 and the phosphatases PP2A and PTEN were assessed by immunoblotting after 30 min. Exposure to 100-300 nM hesperetin led to significant increases in the phosphorylation of ERK1/2 and Akt and significant decreases in PP2A levels and enzyme activity. Using in silico docking, hesperetin was found to fit into the active site of PP2A interacting within the hydrophobic cage of the catalytic unit. These data suggest a potential mechanism by which flavanones may lead to increased activation of ERK1/2 and Akt, commonly observed in cell models. Their interaction with and inhibition of cellular phosphatases counteract normal physiological regulation of signaling pathway activation thus facilitating and/or maintaining the activation status of ERK1/2 and Akt, important regulators of brain functions. PMID- 29723507 TI - Endoscopic Screening in Asian Countries Is Associated With Reduced Gastric Cancer Mortality: A Meta-analysis and Systematic Review. AB - BACKGROUND & AIMS: It is not clear how endoscopic screening for gastric cancer affects incidence or mortality. We performed a systematic review and meta analysis to evaluate the relationship between endoscopic screening for gastric cancer and mortality and incidence. METHODS: We conducted a systematic search of PubMed and EMBASE for published cohort and case-control studies of adults without gastric cancer who underwent endoscopic screening at least once that included a comparator and reported outcomes of mortality or incidence through March 8, 2018. Two investigators independently reviewed the included studies and extracted relevant data. The effect estimate of interest was the relative risk (RR). We used a random effects model to combine RRs and 95% confidence intervals (Cis). RESULTS: Our final analysis included 6 cohort studies and 4 nested case-control studies comprising 342,013 individuals, all from Asia. The combined result (RR, 0.60; 95% CI, 0.49-0.73) indicated that endoscopic screening was associated with a 40% RR reduction in gastric cancer mortality. We did not observe an association between endoscopic screening and incidence (RR, 1.14; 95% CI, 0.93-1.40). Subgroup analysis showed significant reductions in gastric cancer mortality after endoscopic screening compared with no screening (RR, 0.58; 95% CI, 0.48-0.70) or radiographic screening (RR, 0.33; 95% CI, 0.12-0.91). However, endoscopic screening did not significantly reduce mortality compared with expected deaths (RR, 0.67; 95% CI, 0.38-1.16). CONCLUSIONS: In a systematic review and meta analysis, we found that endoscopic screening may reduce the risk of death from gastric cancer and not affect incidence in Asian countries. Population-based prospective cohort studies are warranted to confirm our findings. PMID- 29723506 TI - Fasting Blood Glucose Levels Provide Estimate of Duration and Progression of Pancreatic Cancer Before Diagnosis. AB - BACKGROUND & AIMS: It is unclear how long pancreatic ductal adenocarcinomas (PDACs) are present before diagnosis. Patients with PDAC usually develop hyperglycemia and diabetes before the tumor is identified. If early invasive PDACs are associated with hyperglycemia, the duration of hyperglycemia should associate with the time that they have had the tumor. METHODS: We collected data on patients with PDACs from medical databases in Olmsted County, Minnesota, from 2000 through 2015 and from the Mayo Clinic's tumor registry from January 1, 1976, through January 1, 2017. We compared glycemic profiles of patients with PDAC (cases) compared with patients without cancer, matched for age and sex (controls). We analyzed temporal fasting blood glucose (FBG) profiles collected for 60 months before patients received a PDAC diagnosis (index date) (n = 219) (cohort A), FBG profiles of patients with resected PDAC (n = 526) stratified by tumor volume and grade (cohort B), and temporal FBG profiles of patients with resected PDACs from whom long-term FBG data were available (n = 103) (cohort C). The primary outcome was to estimate duration of presence of invasive PDAC before its diagnosis based on hyperglycemia, defined as significantly higher (P < .05) FBG levels in cases compared with controls. RESULTS: In cohort A, the mean FBG did not differ significantly between cases and controls 36 months before the index date. Hyperglycemia was first noted 36 to 30 months before PDAC diagnosis in all cases, those with or without diabetes at baseline and those with or without resection at diagnosis. FBG level increased until diagnosis of PDAC. In cohort B, the mean FBG did not differ significantly in controls vs cases with PDACs below 1.0 mL. The smallest tumor volume associated with hyperglycemia was 1.1 to 2.0 mL; FBG level increased with tumor volume. FBG varied with tumor grade: well- or moderately differentiated tumors (5.8 mL) produced the same FBG levels as smaller, poorly differentiated tumors (1.5 mL) (P < .001). In cohort C, the duration of prediagnostic hyperglycemia for cases with large-, medium-, or small-volume PDACs was 36 to 24, 24 to 12, and 12 to 0 months, respectively. PDAC resection resolved hyperglycemia, regardless of tumor location. CONCLUSIONS: In a case-control study of patients with PDAC from 2 databases, we associated FBG level with time to PDAC diagnosis and tumor volume and grade. Patients are hyperglycemic for a mean period of 36 to 30 months before PDAC diagnosis; this information might be incorporated into strategies for early detection. PMID- 29723509 TI - Long non-coding RNA UCA1 upregulation promotes the migration of hypoxia-resistant gastric cancer cells through the miR-7-5p/EGFR axis. AB - A variety of solid tumors are surrounded by a hypoxic microenvironment, which is known to be associated with high metastatic capability and resistance to various clinical therapies, contributing to a poor survival rate for cancer patients. Although the majority of previous studies on tumor-associated hypoxia have focused on acute hypoxia, chronic hypoxia more closely mimics the actual hypoxic microenvironment of a tumor. In this study, two novel hypoxia-resistant gastric cancer (HRGC) cell lines which could grow normally in 2% oxygen were established. The long non-coding RNA UCA1 was upregulated in HRGC cells, which promoted their migration. Bioinformatics analysis and a luciferase reporter assay showed that miR-7-5p could bind to specific sites of UCA1 to regulate the target EGFR through competitive endogenous RNA function. UCA1 directly interacted with miR-7-5p and decreased the binding of miR-7-5p to the EGFR 3'-untranslated region, which suppressed the degradation of EGFR mRNA by miR-7-5p. Therefore, long-term hypoxia induced UCA1 to promote cell migration by enhancing the expression of EGFR. This study thus reveals a new mechanism by which a hypoxic microenvironment promotes tumor metastasis, and highlights UCA1 as a potential biomarker for predicting the metastasis of gastric cancer to guide clinical treatment. PMID- 29723510 TI - Infection of mosquitoes from in vitro cultivated Plasmodium knowlesi H strain. AB - In vitro studies of sexual blood stages of the most fatal malaria species, Plasmodium falciparum, have revealed key processes by which gametocytes develop and transmit infection from humans to anopheline mosquitoes. However, most malaria cases outside sub-Saharan Africa are caused by other Plasmodium spp., frequently Plasmodium vivax and Plasmodium knowlesi, a zoonotic parasite of macaque monkeys. Gametocytes of P. vivax and P. knowlesi exhibit distinct morphology, faster development, and a shorter life span compared with gametocytes of P. falciparum, reflecting the evolutionary separation and biological differences of these species. Unlike P. falciparum, P. vivax cannot be cultivated in vitro, necessitating access to infected primates for laboratory studies. In contrast, P. knowlesi asexual stages have been successfully adapted to cultures in macaque and human red blood cells, but these stages have not been reported to produce gametocytes infective to mosquitoes. Here, we show that gametocyte production and sporadic, low-level mosquito infectivity of a P. knowlesi strain was not improved by application of a "crash" method commonly used to induce gametocytes in P. falciparum cultures. However, Percoll-gradient purified schizonts from this strain yielded highly synchronised populations that, in three of six experiments, produced infections at an average rate of 0.97-9.1 oocysts in Anopheles dirus mosquitoes. Oocyst counts were most abundant in mosquitoes that were fed from the synchronised cultures 36 h after schizont purification. Gametocytes in these cultures occurred at low prevalence and were difficult to observe. Transcription from orthologs of P. falciparum gametocyte-specific markers did not correlate with infectivity of the P. knowlesi parasites to mosquitoes. The ability to infect mosquitoes from in vitro-cultivated P. knowlesi will support research on the unique features of this emerging pathogen and facilitate comparative studies of transmission by the different human malarias. PMID- 29723511 TI - Oxidative stress markers and thrombomodulin plasma levels in women with early and late severe preeclampsia. AB - BACKGROUND: Preeclampsia (PE) is a pregnancy disease associated with oxidative stress and endothelial dysfunction. It can be classified according to the severity and onset-time of clinical symptoms (early PE:<34 weeks, late PE:>=34 weeks). METHODS: We evaluated markers of oxidative stress (thiobarbituric acid reactive substances-TBARs and 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide)-MTT) and endothelial lesion (thrombomodulin-TM) in early (N = 24) and late severe PE(N = 22) and normotensive pregnant women(N = 26). RESULTS: MTT levels were higher in early sPE than in normotensive pregnancy (P = 0.03). No difference was found comparing late sPE versus normotensive pregnancy, and early sPE versus late sPE. TM levels were higher in early sPE comparing to late sPE women (P = 0.05), but no difference was found between early or late sPE versus normotensive groups. TBARs levels did not differ significantly among the three groups. These data suggest that endothelial lesion and the antioxidant status are more pronounced in early sPE. Moreover, lipid peroxidation might be an early event in PE, stimulating a compensatory antioxidant defense later in pregnancy. CONCLUSIONS: Longitudinal studies involving pregnant women with risk factors for PE development and including other methods for oxidative stress and endothelial lesion determination should be conducted in order to better evaluate the role of these processes in PE pathogenesis. PMID- 29723513 TI - Cardiac Cath Labs: Their Origins and Their Future. AB - More than 1 million diagnostic cardiac catheterizations (excluding percutaneous coronary intervention-only procedures) are performed each year in the nearly 2,000 cardiac catheterization laboratories in the United States.1. PMID- 29723512 TI - A phase III study evaluating the efficacy and safety of remimazolam (CNS 7056) compared with placebo and midazolam in patients undergoing colonoscopy. AB - BACKGROUND AND AIMS: Remimazolam is an ultrashort-acting benzodiazepine. METHODS: We performed a randomized double-blind comparison of remimazolam to placebo for outpatient colonoscopy. This study design was a requirement of the U.S. Food and Drug Administration. An additional group was randomized to open-label midazolam administered according to its package insert instructions (the randomization ratio for remimazolam:placebo:midazolam was 30:6:10). Study medications were administered under the supervision of the endoscopist, without any involvement of an anesthesia specialist. Patients were given 50 to 75 MUg of fentanyl before receiving study medications. Patients who failed to achieve adequate sedation in any arm were rescued with midazolam dosed at the investigator's discretion. The primary endpoint was a composite that required 3 criteria be met: completion of the colonoscopy, no need for rescue medication, and <=5 doses of remimazolam or placebo in any 15-minute interval (<=3 doses of midazolam in any 12-minute interval in the open-label midazolam arm). RESULTS: There were 461 randomized patients in 12 U.S. sites. The primary endpoint was met for remimazolam, placebo, and midazolam in 91.3%, 1.7%, and 25.2% of patients, respectively (P < .0001 for remimazolam vs placebo). Patients administered remimazolam received less fentanyl, had faster recovery of neuropsychiatric function, were ready for discharge earlier, and felt back to normal sooner than patients with both placebo and midazolam. Hypotension was less frequent with remimazolam, and hypoxia occurred in 1% of patients with remimazolam or midazolam. There were no treatment emergent serious adverse events. CONCLUSION: Remimazolam can be administered safely under the supervision of endoscopists for outpatient colonoscopy, and it allows faster recovery of neuropsychiatric function compared with placebo (midazolam rescue) and midazolam. (Clinical trial registration number: NCT02290873.). PMID- 29723514 TI - The Evolutional History of Electromagnetic Navigation Bronchoscopy: State of the Art. AB - Electromagnetic navigation bronchoscopy (ENB) has come a long way from the early roots of electromagnetic theory. Current ENB devices have the potential to change the way lung cancer is detected and treated. This paper provides an overview of the history, current state, and future of ENB. PMID- 29723516 TI - Regularized Atrial Fibrillation. PMID- 29723515 TI - Lipid tempering simulation of model biological membranes on parallel platforms. AB - In this report we have tested a parallel implementation for the simulation of lipid bilayers at the atomistic level, based on a generalized ensemble protocol where only the torsional degrees of freedom of the alkyl chains of the lipids are heated. The results in terms of configurational sampling enhancement have been compared with a conventional simulation produced with a widespread molecular dynamics code. Results show that the proposed thermodynamic-based multiple trajectories parallel protocol for membrane simulations allows for an efficient use of CPU resources with respect to the conventional single trajectory, providing accurate results for area and volume per lipid, membrane thickness, undulation spectra and boosting significantly diffusion and mixing in lipid bilayers due to the sampling enhancement of gauche/trans ratios of the alkyl chain dihedral angles. PMID- 29723517 TI - Inhibitory effect of alpha-terpinyl acetate on cytochrome P450 2B6 enzymatic activity. AB - Human cytochrome P450 2B6 is an important hepatic enzyme for the metabolism of xenobiotics and clinical drugs. Recently, more attention has been paid to P450 2B6 because of the increasing number of drugs it metabolizes. It has been known to interact with terpenes, the major constituents of the essential oils used for various medicinal purposes. In this study, the effect of monoterpenes on P450 2B6 catalytic activity was investigated. Recombinant P450 2B6 was expressed in Escherichia coli and purified using Ni-affinity chromatography. The purified P450 2B6 enzyme displayed bupropion hydroxylation activity in gas-mass spectrometry (GC-MS) analysis with a kcat of 0.5 min-1 and a Km of 47 MUM. Many terpenes displayed the type I binding spectra to purified P450 2B6 enzyme and alpha terpinyl acetate showed strong binding affinity with a Kd value of 5.4 MUM. In GC MS analysis, P450 2B6 converted alpha-terpinyl acetate to a putative oxidative product. The bupropion hydroxylation activity of P450 2B6 was inhibited by alpha terpinyl acetate and its IC50 value was 10.4 MUM alpha-Terpinyl acetate was determined to be a competitive inhibitor of P450 2B6 with a Ki value of 7.6 MUM. The molecular docking model of the binding site of the P450 2B6 complex with alpha-terpinyl acetate was constructed. It showed the tight binding of alpha terpinyl acetate in the active site of P450 2B6, which suggests that it could be a competitive substrate for P450 2B6. PMID- 29723518 TI - How cardiolipin peroxidation alters the properties of the inner mitochondrial membrane? AB - Cardiolipins have multiple vital functions within biological cell membranes, most notably in the energy metabolism associated with the inner mitochondrial membrane. Considering their essential role, peroxidation of cardiolipins may plausibly have significant effects, as peroxidation is known to alter the functionality of lipid molecules. We used atomistic molecular dynamics simulations to study how peroxidation of cardiolipin affects the properties of the inner mitochondrial membrane. To this end, we explored what happens when varying fractions of fatty acid chains of cardiolipin are replaced by its four different oxidized products in systems modeling the inner mitochondrial membrane. We found that the oxidation of cardiolipin leads to a conformational change both in the backbone/head group and in chain regions of oxidized cardiolipin molecules. The oxidized groups were observed to shift closer to the membrane water interface region, where they formed hydrogen bonds with several other groups. Additionally, the conformational change turned out to decrease bilayer thickness, and to increase the area per lipid chain, though these changes were minor. The acyl chain conformational order of unoxidized lipids exposed to interactions with oxidized cardiolipins was increased in carbons 3-5 and decreased in carbons 13-17 due to the structural reorganization of the cardiolipin molecules. Overall, the results bring up that the conformation of cardiolipin is altered upon oxidation, suggesting that its oxidation may interfere its interactions with mitochondrial proteins and thereby affect cardiolipin-dependent cellular processes such as electron and proton transport. PMID- 29723519 TI - Bio-electrochemical microelectrode arrays for glutamate and electrophysiology detection in hippocampus of temporal lobe epileptic rats. AB - Temporal Lobe Epilepsy (TLE) is a chronic neurological disorder, characterized by sudden, repeated and transient central nervous system dysfunction. For better understanding of TLE, bio-nanomodified microelectrode arrays (MEA) are designed, for the achievement of high-quality simultaneous detection of glutamate signals (Glu) and multi-channel electrophysiological signals including action potentials (spikes) and local field potentials (LFPs). The MEA was fabricated by Micro Electro-Mechanical System fabrication technology and all recording sites were modified with platinum black nano-particles, the average impedance decreased by nearly 90 times. Additionally, glutamate oxidase was also modified for the detection of Glu. The average sensitivity of the electrode in Glu solution was 1.999 +/- 0.032 * 10-2pA/MUM.MUm2(n = 3) and linearity was R = 0.9986, with a good selectivity of 97.82% for glutamate and effective blocking of other interferents. In the in-vivo experiments, the MEA was subjected in hippocampus to electrophysiology and Glu concentration detection. During seizures, the fire rate of spikes increases, and the interspike interval is concentrated within 30 ms. The amplitude of LFPs increases by 3 times and the power increases. The Glu level (4.22 MUM, n = 4) was obviously higher than normal rats (2.24 MUM, n = 4). The MEA probe provides an advanced tool for the detection of dual-mode signals in the research of neurological diseases. PMID- 29723520 TI - Electrocatalytic artificial carbonylation assay for observation of human serum albumin inter-individual properties. AB - Human serum albumin (HSA) is a multifunctional protein with ligand binding, transporting and buffering properties. Posttranslational modifications and ligand binding processes are closely related to albumin final functional status. In the last few decades, HSA has been characterized using a broad spectrum of methods, but quantitative data on the HSA's modifications among individuals have not been reported. The investigations presented here are based on the non-denaturing electrocatalytic screening of HSA samples isolated from the blood serum of healthy subjects. The electrocatalytic responses of the native protein (Rnat) varied depending on its modifications among individuals, which enable us to express the inter-individual variability. Consequently, the native HSA samples were subjected to ex vivo carbonylation with 50 mM methylglyoxal for 36 h. The differences between Rnat and the responses of artificially carbonylated protein (Rmod) corresponded with inter-individual binding capacity variations (DeltaR = Rnat-Rmod). The coefficients of variation for the Rnat and DeltaR values of purified HSA samples were estimated to be 8.5 and 23.2%, respectively. A sensitive non-denaturing electrocatalytic assay was utilized to provide new data about albumin inter-individual variations and evaluate its oxidative modifications and binding capacity, which could be used for further studies targeting not only on HSA but also other clinically important proteins. PMID- 29723522 TI - Transcriptomic profiling of trigeminal nucleus caudalis and spinal cord dorsal horn. AB - The pain sensation system is highly conserved among species, thus animal models have been used to investigate relevant tissues. The focus for head-specific pain has been on the primary nociceptive neurons in the trigeminal pathway, i.e. trigeminal ganglia. The secondary nociceptive neurons of the trigeminal pathway, trigeminal nucleus caudalis (TNC), have not been assessed. We expect different gene expression profiles compared to the homologous spinal cord dorsal horn (SDH), as several signalling substances provoke head-specific pain but not peripheral pain. We aim to provide expression profiles of TNC and SDH, tissues highly relevant for pain- and migraine-studies. We extracted RNA from laser capture microdissected laminae I-V from TNC and SDH from six Wistar rats for RNA Sequencing. We showed the expression profiles of genes involved in neural signal transmission and found that among all G protein-coupled receptors Gabbr1 was highest expressed in both tissues. Among the migraine-associated genes we showed that Cacna1a, where non-synonyms mutations can cause familial hemiplegic migraine, was highly expressed with a slightly lower expression in TNC than in SDH. To show the genetic differences between the two homologous systems we performed a differential expression analysis, revealing 1696 genes higher and 1895 genes lower expressed genes in TNC than in SDH, of which many were neuronal related. The high number of differentially expressed genes shows the large genetic difference between the trigeminal and spinothalamic system. Our results contribute to the characterization of nociceptive pathways, which may help us understanding why several signalling molecules cause headache and no peripheral pain. PMID- 29723521 TI - MicroRNA-124 and microRNA-146a both attenuate persistent neuropathic pain induced by morphine in male rats. AB - We have recently reported that a short course of morphine, starting 10 days after sciatic chronic constriction injury (CCI), prolonged the duration of mechanical allodynia for months after morphine ceased. Maintenance of this morphine-induced persistent sensitization was dependent on microglial reactivity and Toll-like receptor 4 signaling. Given that microRNAs (miRNAs) such as miR-124 and miR-146a possess the ability to modulate such signaling, we directly compared their function in this model. We found that both miRNAs reversed established allodynia in our model of morphine-induced persistent sensitization. The efficacy of miR 124 and miR-146a were comparable, and in both cases allodynia returned within hours to days of miRNA dosing conclusion. Our findings demonstrate that miRNAs targeting Toll-like receptor signaling are effective in reversing neuropathic pain, which underscores the clinical potential of these non-coding RNAs. PMID- 29723524 TI - Synchronous firing patterns of induced pluripotent stem cell-derived cortical neurons depend on the network structure consisting of excitatory and inhibitory neurons. AB - The balance between glutamate-mediated excitation and GABA-mediated inhibition is critical to cortical functioning. However, the contribution of network structure consisting of the both neurons to cortical functioning has not been elucidated. We aimed to evaluate the relationship between the network structure and functional activity patterns in vitro. We used mouse induced pluripotent stem cells (iPSCs) to construct three types of neuronal populations; excitatory-rich (Exc), inhibitory-rich (Inh), and control (Cont). Then, we analyzed the activity patterns of these neuronal populations using microelectrode arrays (MEAs). Inhibitory synaptic densities differed between the three types of iPSC-derived neuronal populations, and the neurons showed spontaneously synchronized bursting activity with functional maturation for one month. Moreover, different firing patterns were observed between the three populations; Exc demonstrated the highest firing rates, including frequent, long, and dominant bursts. In contrast, Inh demonstrated the lowest firing rates and the least dominant bursts. Synchronized bursts were enhanced by disinhibition via GABAA receptor blockade. The present study, using iPSC-derived neurons and MEAs, for the first time show that synchronized bursting of cortical networks in vitro depends on the network structure consisting of excitatory and inhibitory neurons. PMID- 29723523 TI - The physiological and pathological biophysics of phase separation and gelation of RNA binding proteins in amyotrophic lateral sclerosis and fronto-temporal lobar degeneration. AB - Many RNA binding proteins, including FUS, contain moderately repetitive, low complexity, intrinsically disordered domains. These sequence motifs have recently been found to underpin reversible liquid: liquid phase separation and gelation of these proteins, permitting them to reversibly transition from a monodispersed state to liquid droplet- or hydrogel-like states. This function allows the proteins to serve as scaffolds for the formation of reversible membraneless intracellular organelles such as nucleoli, stress granules and neuronal transport granules. Using FUS as an example, this review examines the biophysics of this physiological process, and reports on how mutations and changes in post translational state alter phase behaviour, and lead to neurodegenerative diseases such as amyotrophic lateral sclerosis and frontotemporal lobar degeneration. PMID- 29723525 TI - ALK is required for NLRP3 inflammasome activation in macrophages. AB - The NLRP3 inflammasome is a key mediator of host immune responses through the induction of pyroptosis and the release of cytokines. Although the pathologic role of inflammasome in infection and sterile inflammation is well known, the mechanism and regulation of NLRP3 inflammasome activation remains obscure. Here, we report that anaplastic lymphoma kinase (ALK) is a novel regulator of NLRP3 inflammasome activation in macrophages. Pharmacologic or genetic inhibition of ALK through targeted drugs (ceritinib and lorlatinib) or RNAi blocked extracellular ATP-induced NLRP3 inflammasome activation in macrophages. Mechanically, ALK-mediated NF-kappaB activation was required for the priming step of NLRP3 upregulation, whereas ALK-mediated lipid peroxidation contributed to the sensing step of NLRP3-NEK7 complex formation. These studies indicate that inhibition of ALK could be utilized to treat NLRP3-related inflammatory diseases. PMID- 29723526 TI - AFP2 as the novel regulator breaks high-temperature-induced seeds secondary dormancy through ABI5 and SOM in Arabidopsis thaliana. AB - Imbibed seeds monitor environmental and endogenous signals to break dormancy and initiate growth under appropriate conditions. In Arabidopsis thaliana, high temperature (HT) induces secondary seed dormancy, but the underlying mechanism remains unclear. In this study, we found that the abi5-1 mutant was insensitive to high temperature, whereas plants overexpressing ABI5 displayed sensitivity. We then identified ABA-insensitive five-binding protein 2 (AFP2), which interacts with ABI5 and is involved in HT-induced secondary seed dormancy. Under HT stress, the loss-of-function afp2 mutant showed lower seeds germination frequency, reversely, AFP2 overexpressing lines (OE-AFP2) showed high germination frequency. Similar to the abi5 mutant, the crossed OE-AFP2 abi5 or afp2 abi5 lines showed high germination under HT, suggesting that ABI5 is epistatic to AFP2. SOM is reported to negatively regulate seeds germination by altering GA/ABA metabolism, here we found that AFP2 and ABI5 altered SOM transcription. Specifically, overexpressing AFP2 suppressed SOM transcription, resulting in high expression of GA biosynthesis-related genes and low expression of ABA biosynthesis-related genes, ultimately promoting seed germination under HT. Thus, our data demonstrate that AFP2 is a novel regulator to control HT-induced secondary seed dormancy through ABI5 and SOM. PMID- 29723527 TI - Inhibitory effect of fasiglifam on hepatitis B virus infections through suppression of the sodium taurocholate cotransporting polypeptide. AB - Fasiglifam is a selective partial agonist of G-protein-coupled receptor 40 (GPR40), which was developed for the treatment of type 2 diabetes mellitus. However, the clinical development of fasiglifam was voluntarily terminated during phase III clinical trials due to adverse liver effects. Fasiglifam showed an inhibitory effect on sodium taurocholate cotransporting polypeptide (NTCP) in human and rat hepatocytes. Recently, NTCP was reported to be a functional receptor for human hepatitis B virus (HBV) infections. Therefore, in this study, we hypothesised that fasiglifam would be a good candidate for a novel HBV entry inhibitor, and its effects were evaluated by using NTCP-overexpressing HepG2 cells, human hepatocyte cell lines and human hepatocytes (PXB cells) obtained from PXB mice. Pre-treatment with fasiglifam at a concentration of 30 MUM prior to HBV infection significantly suppressed supernatant HBV DNA levels after HBV infection in NTCP-overexpressing HepG2 cells, human hepatocyte cell lines and PXB cells. Fasiglifam did not suppress supernatant HBV DNA levels up to 50 MUM in HepG2.2.15.7 cells, which are stably transfected with a complete HBV genome without HBV infection. These results indicated that fasiglifam only affect on HBV infection via NTCP inhibition. For HBV treatment of fasiglifam, further investigation including additional non clinical research in addition to the evaluation of safety and efficacy in humans would be needed in the future study. PMID- 29723528 TI - Resveratrol induces dynamic changes to the microglia transcriptome, inhibiting inflammatory pathways and protecting against microglia-mediated photoreceptor apoptosis. AB - Microglia activation is central to the pathophysiology of retinal degenerative disorders. Resveratrol, a naturally occurring non-flavonoid phenolic compound present in red wine has potent anti-inflammatory and immunomodulatory properties. However, molecular mechanisms by which resveratrol influences microglial inflammatory pathways and housekeeping functions remain unclear. Here, we first studied the immuno-modulatory effects of resveratrol on BV-2 microglial cells at the transcriptome level using DNA-microarrays and selected qRT-PCR analyses. We then analyzed resveratrol effects on microglia morphology, phagocytosis and migration and estimated their neurotoxicity on 661 W photoreceptors by quantification of caspase 3/7 levels. We found that resveratrol effectively blocked gene expression of a broad spectrum of lipopolysaccharide (LPS)-induced pro-inflammatory molecules, including cytokines and complement proteins. These transcriptomic changes were accompanied by potent inhibition of LPS-induced nitric oxide secretion and reduced microglia-mediated apoptosis of 661 W photoreceptor cultures. Our findings highlight novel targets involved in the anti inflammatory and neuroprotective action of resveratrol against neuroinflammatory responses. PMID- 29723529 TI - Suppression of Elp2 prevents renal fibrosis and inflammation induced by unilateral ureter obstruction (UUO) via inactivating Stat3-regulated TGF-beta1 and NF-kappaB pathways. AB - Renal fibrosis and inflammation are common underlying processes of progressive kidney diseases. Elongator protein 2 (Elp2), identical to signal transducer and activator of transcription-3 (STAT-3)-interacting protein-1 (Stip1), is a component of the Elongator complex that regulates RNA polymerase II. Elp2 regulates STAT-3 activation to control various cellular processes. The mechanisms of Elp2 prevention in renal interstitial fibrosis and inflammation remain unknown. In the study, Elp2 transgenic knockout (KO) and wild type (WT) mice were employed to investigate the effects of Elp2 on renal fibrosis and inflammation development after unilateral ureter obstruction (UUO) surgery. The results indicted that Elp2 was significantly expressed in renal tissues of WT/UUO mice. Elp2-KO mice exhibited attenuated histological changes of kidney, as well as collagen and fibrosis accumulation. Lower expressions of transforming growth factor (TGF)-beta1, alpha-smooth muscle actin (alpha-SMA), fibronectin, vimentin, and phospho-Smad2/3 were observed in kidney of Elp2-KO mice than that of WT mice after UUO. Elp2-KO mice showed less inflammation, as evidenced by the decrease of circulating or renal pro-inflammatory cytokines, as well as the reduction of phospho-nuclear factor (NF)-kappaB. Additionally, Elp2-KO apparently led to a decrease in phospho-STAT3 in kidney of UUO mice. In vitro, we found that TGF beta1- and LPS-induced fibrosis and inflammation were abrogated by Elp2 knockdown, which were intriguingly abolished by activating STAT3 phosphorylation using its activator of colivelin (Col). Together, our findings supplied that Elp2 might be a potential therapeutic target to prevent the progression of renal fibrosis and inflammation. PMID- 29723530 TI - Abeta1-40 mediated aggregation of proteins and metabolites unveils the relevance of amyloid cross-seeding in amyloidogenesis. AB - The multicomponent nature of neuronal plaques in Alzheimer's disease signifies the possible recruitment of non-Abeta candidates during the amyloid growth of Abeta peptides. Here, we show that amyloid fibrils of Abeta1-40 peptide can effectively initiate amyloid formation in different globular proteins and metabolites, converting native structures into beta-sheet rich assemblies. Structural and biophysical properties of the resultant protein fibrils display amyloid like characteristic features. Viable contacts between Abeta peptide's cross-beta architecture and the native structure of proteins, mediated through H bonds and hydrophobic interactions seem crucial for the onset of amyloid cross seeding. Results reveal the inherent cross-seeding potential of Abeta amyloids to initiate amyloid formation process in proteins and metabolites and revelation of such a property may further our mechanistic understanding of amyloid pathologies. PMID- 29723531 TI - Transplant Outcomes for Congenital Heart Disease Patients Bridged With a Ventricular Assist Device. AB - BACKGROUND: Ventricular assist device (VAD) use as a bridge to transplant (BTT) for children with end-stage heart failure and congenital heart disease (CHD), although challenging, has increased, but its effect on posttransplant outcome is unknown. This study describes posttransplant outcomes of CHD patients BTT with a VAD. METHODS: All heart transplant recipients identified in United Network of Organ Sharing database from 2006 to 2015 (n = 21,865) were divided into four groups by those with (+) and without (-) a diagnosis of CHD and with (+) and without (-) VAD support at transplant: +CHD/+VAD, +CHD/-VAD, +VAD/-CHD, and -VAD/ CHD. Posttransplant survival of +CHD/+VAD was compared with +CHD/-VAD, -CHD/+VAD, and -CHD/-VAD in addition to pretransplant characteristics comparison between +CHD/+VAD and +CHD/-VAD. RESULTS: Of 1,871 patients (8.6%) with CHD, 1,348 (72%) were younger than 18 years old, and 143 (7.6%) were BTT with a VAD (+CHD/+VAD). At transplant, +CHD/+VAD compared with +CHD/-VAD were more likely to have worse functional status (<50%: 60% vs 46%, p = 0.004), infections (29% vs 14%, p < 0.001), to be sensitized (47% vs 30%, p < 0.001) and on ventilator support (20% vs 13%, p = 0.029) and dialysis (13% vs 2.5%, p < 0.001). Overall, 1-year (84% vs 87%) and 5-year (72% vs 75%) survival was similar for +CHD/+VAD and +CHD/-VAD (p = 0.694). Survival was also similar when +CHD/+VAD were compared with -CHD/+VAD (n = 7,363; p = 0.529) and -CHD/-VAD (n = 12,613; p = 0.097). CONCLUSIONS: Although more ill pretransplant, CHD patients BTT with a VAD have similar posttransplant survival compared with CHD patients without a VAD and with other non-CHD heart transplant patients. VAD support may mitigate certain risk factors for poor posttransplant outcomes in the challenging CHD cohort. PMID- 29723532 TI - The Persistent Problem of Local/Regional Failure After Surgical Intervention for Early-Stage Lung Cancer. AB - BACKGROUND: The goal of the present study was to estimate the rate of local/regional failure (LRF) after definitive surgical intervention for early stage non-small cell lung cancer (NSCLC), without postoperative radiotherapy, in the era of contemporary imaging and minimally invasive surgical techniques. METHODS: Medical records of patients with early-stage NSCLC (pathologic T1-4, N0 1) who underwent lobectomy, sleeve lobectomy, bilobectomy, or pneumonectomy, with or without adjuvant chemotherapy, between 2007 and 2015, were retrospectively reviewed. LRF was defined as recurrence at the ipsilateral lung, bronchial stump, mediastinum, chest wall, or supraclavicular region. The Kaplan-Meier method was used to estimate time to LRF, with patients censored at death, and log-rank tests were used for comparisons. A two-sided p value of less than 0.05 was considered significant. RESULTS: Included were 217 patients (median age, 65 years). Preoperative staging with positron emission tomography/computed tomography was performed in 89% of patients, mediastinoscopy was performed in 42%, and video assisted thoracoscopic surgery was performed in 51%. At a median follow-up of 36 months (range, 1 to 120 months), the 5-year estimated LRF was 26% (95% confidence interval, 20% to 35%). LRF rates were not significantly different in those with and without staging positron emission tomography/computed tomography (hazard ratio, 1.52; p = 0.43) and those with video-assisted thoracoscopic surgery versus open thoracotomy (hazard ratio, 1.00; p = 0.99). CONCLUSIONS: Despite contemporary staging procedures and surgical techniques for early-stage NSCLC, LRF occurs in approximately 1 of 4 patients. The observed rates of LRF are similar to those reported more than a decade ago, suggesting that local/regional control remains a persistent problem. The use of additional local treatments, such as radiotherapy, should be reevaluated to further improve outcomes. PMID- 29723533 TI - Early Degeneration Caused by Cusp Tear of First-Generation Trifecta Bioprosthesis. AB - The Trifecta aortic valve has excellent hemodynamic performance as result of an expansive valve design with a bovine pericardial sheet externally mounted on a titanium stent. We report 2 cases of early Trifecta valve degeneration, both caused by partial rupture of one of the leaflet cusps 3 and 4 years post-implant. Post discharge, both patients had routinely performed echocardiography check-ups, without signs of valve failure. Transesophageal echocardiography performed during emergency hospital readmission due to severe dyspnea revealed transvalvular aortic regurgitation without signs of endocarditis. Urgent redo-surgery was successful in both cases, replacing the Trifecta prosthesis with a different bovine bioprosthesis. PMID- 29723534 TI - Neurologic Injury Predicts Plaintiff Award in Federal Cardiac Surgery Trials. AB - BACKGROUND: Cardiothoracic surgery is one of the more highly litigated medical specialties. The incidence and outcomes of federal cases related to cardiac surgery have not been previously explored. METHODS: A legal research service was queried for cardiac surgery-related terms. Citations and related documents were reviewed for relevance and case details. Inclusion criteria were federal district court cases involving cardiac operations. Exclusion criteria were rulings on solely procedural matters. Associations were explored using the Fisher exact test. RESULTS: Of 354 unique citations from 1956 to 2017, 19.2% (n = 68) met criteria. The highest number of cases (25% [n = 17]) were litigated in the Third Circuit. Operations involved coronary artery bypass grafting in 33.8% (n = 23), valves in 32.4% (n = 22), and congenital operations in 19.1% (n = 13). Litigation was prompted by media reporting in 10.3% (n = 7) and involved neurologic injury in 17.6% (n = 12), death in 33.8% (n = 23), and informed consent issues in 29.4% (n = 20). Findings were summary judgment for the defendant in 45.6% (n = 31), partial summary judgment in 17.6% (n = 12), dismissal in 27.9% (n = 19), and ruling for the plaintiff in 7.4% (n = 5). Of the rulings for the plaintiffs, damages had a median dollar amount of $591,300 (interquartile range, $214,2673.50 to $5,807,687.00]. In Fisher's exact test analysis, neurologic injury was significantly associated with ruling for the plaintiff (p < 0.01); death, surgeon defendant, surgical decision-making/conduct, and adult cardiac case type were not associated. CONCLUSIONS: Federal cardiac malpractice court cases are rare. Rulings in favor of the plaintiff, although also rare, are associated with neurologic injury. A comprehensive picture of cardiac surgery-related litigation will require advances in data abstraction techniques and codification. PMID- 29723535 TI - Effect of tributyltin chloride (TBT-Cl) exposure on expression of HSP90beta1 in the river pufferfish (Takifugu obscurus): Evidences for its immunologic function involving in exploring process. AB - HSP90beta1 (known as glyco-protein 96, GP96) is a vital endoplasmic reticulum (ER) depended chaperonin among the HSPs (heat shock proteins) family. Furthermore, it always processes and presents antigen of the tumor and keeps balance for the intracellular environment. In the present study, we explored the effect of tributyltin chloride (TBT-Cl) exposure on HSP90beta1 expression in river pufferfish, Takifugu obscurus. The full length of To-HSP90beta1 was gained with 2775 bp in length, with an ORF (open reading frame) encoding an 803 aa polypeptide. A phylogenetic tree was constructed and showed the close relationship to other fish species. The HSP90beta1 mRNA transcript was expressed in all tissues investigated with higher level in the gill and liver. After the acute and chronic exposure of TBT-Cl, the To-HSP90beta1 mRNA transcript significantly was up-regulated in gills. Moreover, the histology study indicated the different injury degree of TBT-Cl in liver and gill. Immunohistochemistry (IHC) staining results implied the cytoplasm reorganization after TBT-Cl stress and the function of immunoregulation for To-HSP90beta1 to TBT-Cl exposure. All the results indicated that HSP90beta1 may be involved in the resistance to the invasion of TBT-Cl for keeping autoimmune homeostasis. PMID- 29723536 TI - 4-((5-(Tert-butyl)-3-chloro-2-hydroxybenzyl) amino)-2-hydroxybenzoic acid protects against oxygen-glucose deprivation/reperfusion injury. AB - AIMS: Oxidative stress is one of the most important pathological mechanisms which could aggravate ischemic stroke injury. In order to seek for better treatment therapies to alleviate stroke injury, novel chemicals have been synthetized. In the present study, a new compound 4-((5-(tert-butyl)-3-chloro-2-hydroxybenzyl) amino)-2- hydroxybenzoic acid, named LX009, was used to determine whether it could reduce the oxidative stress caused by oxygen-glucose deprivation (OGD)/reperfusion (RP) and exert neuroprotective effect both in mouse Neuro 2A (N2A) neuroblastoma cells and mouse primary cortical neurons. MAIN METHODS: OGD/RP was performed as an in vitro model to mimic the pathologic process of ischemic stroke. We explored the anti-apoptosis effect of LX009 through CCK8 assay, calcein acetoxymethylester/propidium iodide (calcein-AM/PI) staining, Annexin V-fluorescein isothiocyanate (FITC)/propidium iodide (PI) apoptosis kit, caspase-3 activity assay. Besides, the anti-oxidative stress effect of the drug was determined by intracellular reactive oxygen species (ROS) detection, nitrite analysis, measurement of mitochondrial membrane potential (MMP), intracellular catalase (CAT) and Mn-superoxide dismutase (Mn-SOD) activity. KEY FINDINGS: Our results indicated that LX009 could alleviate OGD/RP-induced cell apoptosis. Furthermore, OGD/RP induced oxidative stress could be reserved by LX009, including measurements of intracellular ROS production, MMP, CAT and Mn-SOD activity. Mechanistically, the phosphorylation level of Akt, as well as the expression of nuclear factor-E2-related factor 2 (Nrf2) and heme oxygenase-1 (HO 1) were elevated after LX009 treatment. SIGNIFICANCE: Our present study indicated that LX009 might have the potential to be an anti-oxidative stress agent in the future. PMID- 29723538 TI - ATR-FTIR Characterization of Janus Nanoparticles. Part I: Implementation of Spectroscopic Descriptors. AB - The present work deals with original bicompartmental lipid Janus nanoparticles (JNPs), which are characterized by the presence of an oily compartment associated with an aqueous compartment delimited by a phospholipid-based bilayer. The size of JNP varies between 150 and 300 nm. As JNP are promising candidates for cutaneous application, the purpose of this study was to implement reliable infrared descriptors over time of JNP, to follow the physical stability of JNP in open air and over time. Therefore, a comparative study with the nanoemulsion and the physical mixture formulations was conducted by attenuated total reflection by FTIR spectroscopy. We defined herein spectroscopic descriptor reflecting the integrity of the JNP. Principal component analysis and orthogonal partial least square-discriminant analysis were used to validate the relevant descriptor and permitted to extract relevant and useful information from the spectral data. Dynamic light scattering measurements were also carried and gave supporting data for our conclusion on the fate of JNP over time. PMID- 29723537 TI - RING finger protein 10 prevents neointimal hyperplasia by promoting apoptosis in vitro and in vivo. AB - AIMS: Vascular restenosis and neointimal hyperplasia are enhanced in metabolic syndrome (MetS). Vascular smooth muscle cell (VSMC) proliferation is a key step during restenosis and is suppressed by RING finger protein 10 (RNF10). However, the effect of RNF10 on neointimal hyperplasia is unknown. In the present study, we explored whether RNF10 over-expression prevents neointimal hyperplasia in a MetS rat model and in cultured VSMCs exposed to high glucose. MAIN METHODS: An adenovirus encoding RNF10 (Ad-RNF10) or control green fluorescent protein (Ad GFP) was delivered to balloon-injured carotid arteries in MetS rats and cultured rat VSMCs exposed to high glucose. Neointimal hyperplasia was measured, and the apoptosis index in the neointima was evaluated. The protein levels of RNF10, caspase-3, Bcl-2 and Bax in the injured vessels and VSMCs were determined. KEY FINDINGS: Ad-RNF10 prevented the development of neointimal hyperplasia in balloon injured vessels. Furthermore, an increase in the apoptosis index and cleaved caspase-3 protein expression and a decrease in Bcl-2 expression were detected in the injured vessels after Ad-RNF10 treatment. Meanwhile, increased caspase-3 protein expression and decreased Bcl-2 expression were detected in VSMCs treated with Ad-RNF10. SIGNIFICANCE: RNF10 over-expression strongly suppresses neointimal hyperplasia via increased apoptosis, constituting a promising new therapeutic target for vascular restenosis. PMID- 29723539 TI - Differential effect of COMT gene methylation on the prefrontal connectivity in subjects with depression versus healthy subjects. AB - Expression of the catechol-O-methyl transferase (COMT) gene mainly determines prefrontal dopaminergic availability. Deficient prefrontal dopaminergic activity leads to loss of interest, energy, and motivation, which are core symptoms of depression. Given the role of stress-environmental interactions in major depressive disorder (MDD), we investigated the impact of COMT gene methylation status on prefrontal connectivity. We measured COMT gene methylation and polymorphisms (Val158Met) at the rs4468 locus in peripheral blood samples of healthy controls (n = 90) and patients with MDD (n = 90). We used diffusion tensor imaging to calculate the fractional anisotropy (FA) and radial diffusivity (RD) of the white matter tracts related to prefrontal cortex. Finally, we examined the effects of COMT gene methylation on the white matter connectivity in patients with MDD. The FA and RD values in the prefrontal white matter tracts of patients with MDD were positively and negatively associated with COMT gene methylation, respectively. In the control group, on the other hand, the association between white matter connectivity and COMT gene methylation showed opposite pattern to those of MDD. COMT gene methylation has a substantial effect on the prefrontal connectivity in patients with MDD. Moreover, COMT gene methylation and prefrontal connectivity showed opposite relationships in patients and controls. Thus, stress-related alterations in dopaminergic neurotransmission have a differential effect on white matter connectivity according to the microenvironment in the brain. PMID- 29723540 TI - TNFalpha-dependent anhedonia and upregulation of hippocampal serotonin transporter activity in a mouse model of collagen-induced arthritis. AB - The serotonin transporter (SERT) facilitates high affinity reuptake of 5-HT from the extracellular fluid and dysregulation of transporter function has been implicated in a range of mood disorders including depression. Recent studies have linked immune system activation to depression as well as to altered serotonin transporter activity. Advancing previous studies, which have mainly focussed on acute effects of immune system activation, in this study we used collagen-induced arthritis (CIA) in mice as a model of chronic inflammatory disease, to investigate the effect of prolonged inflammation on brain SERT function and behaviour. We found that 5-6 weeks after immunisation, CIA mice display anhedonia, a core depression-like behaviour. Behavioural symptoms are temporally correlated with a region-specific upregulation of SERT activity in the hippocampus, which occurs at a post-translational level and is independent of SERT trafficking. Kinetic analysis of 5-HT uptake revealed that the elevation of transporter activity is due to an increase in 5-HT transport capacity (Vmax) with no change in apparent Km values, suggesting that different regulatory mechanisms govern SERT modulation under chronic versus acute inflammatory conditions. Protein expression of tumour necrosis factor receptor 1 (TNFR1) was specifically upregulated in the hippocampus of CIA mice, indicating altered TNFalpha signalling. Anti-TNFalpha treatment using etanercept not only diminished joint inflammation, but also prevented the development of anhedonia and the upregulation of SERT activity in the hippocampus, suggesting a key role for TNFalpha signalling in brain function regulation in this disease model. Our study provides novel insight into molecular mechanisms underlying mood symptoms in chronic inflammatory diseases, with particular relevance to rheumatoid arthritis. PMID- 29723541 TI - Predator-prey-subsidy population dynamics on stepping-stone domains with dispersal delays. AB - We examine the role of the travel time of a predator along a spatial network on predator-prey population interactions, where the predator is able to partially or fully sustain itself on a resource subsidy. The impact of access to food resources on the stability and behaviour of the predator-prey-subsidy system is investigated, with a primary focus on how incorporating travel time changes the dynamics. The population interactions are modelled by a system of delay differential equations, where travel time is incorporated as discrete delay in the network diffusion term in order to model time taken to migrate between spatial regions. The model is motivated by the Arctic ecosystem, where the Arctic fox consumes both hunted lemming and scavenged seal carcass. The fox travels out on sea ice, in addition to quadrennially migrating over substantial distances. We model the spatial predator-prey-subsidy dynamics through a "stepping-stone" approach. We find that a temporal delay alone does not push species into extinction, but rather may stabilize or destabilize coexistence equilibria. We are able to show that delay can stabilize quasi-periodic or chaotic dynamics, and conclude that the incorporation of dispersal delay has a regularizing effect on dynamics, suggesting that dispersal delay can be proposed as a solution to the paradox of enrichment. PMID- 29723542 TI - Effects of fibroblast growth factors and the transcription factor, early growth response 1, on bovine theca cells. AB - The theca cell layer of the ovarian follicle secretes growth factors that impact the function of granulosa cells. One such factor is fibroblast growth factor 18 (FGF18) that causes apoptosis of granulosa cells, however it is not known if FGF18 induces apoptosis also in theca cells. Addition of recombinant FGF18 to bovine theca cells in vitro inhibited steroidogenesis but, in contrast to previous data in granulosa cells, decreased the incidence of apoptosis. FGF18 activated typical FGF signaling pathways in theca cells, which was not previously observed in granulosa cells. The transcription factor Early Growth Response-1 (EGR1) was a target of FGF18 action; overexpression and knock-down experiments demonstrated that EGR1 is a major upstream component of FGF signaling in theca cells and that it directs cell fate toward proliferation. These data suggest that FGF18 is mitogenic for theca cells while being pro-apoptotic in granulosa cells. PMID- 29723543 TI - The transcription factor SMAD4 and miR-10b contribute to E2 release and cell apoptosis in ovarian granulosa cells by targeting CYP19A1. AB - The cytochrome P450 family 19 subfamily A member 1 (CYP19A1) gene, encodes aromatase, a key enzyme in estradiol (E2) synthesis, and is down-regulated during porcine follicular atresia. However, its role in and the mechanism of transcriptional repression in follicular atresia is largely unknown. In the present study, we show that the CYP19A1 gene stimulates E2 release and inhibits cell apoptosis in porcine granulosa cells (GCs). SMAD4, an anti-apoptotic moderator, was identified as a transcription factor of the porcine CYP19A1 gene and enhanced the expression and function of CYP19A1 in porcine GCs through direct binding to a SMAD4-binding element (SBE) within the promoter region of CYP19A1 gene. Moreover, we found that miR-10b, a pro-apoptotic factor, directly interacted with 3'-UTR of the porcine CYP19A1 mRNA, inhibiting its expression and function in porcine GCs. Collectively, we demonstrated that CYP19A1 is an inhibitor of follicular atresia and is regulated by both SMAD4 and miR-10b. These findings provide further insight into the mechanisms of CYP19A1 in steroid hormone synthesis and GC apoptosis and provide molecular targets for exploring methods of treatment for steroid-dependent reproductive disorders. PMID- 29723544 TI - Alternative dimerization interfaces in the glucocorticoid receptor-alpha ligand binding domain. AB - BACKGROUND: Nuclear hormone receptors (NRs) constitute a large family of multi domain ligand-activated transcription factors. Dimerization is essential for their regulation, and both DNA binding domain (DBD) and ligand binding domain (LBD) are implicated in dimerization. Intriguingly, the glucocorticoid receptor alpha (GRalpha) presents a DBD dimeric architecture similar to that of the homologous estrogen receptor-alpha (ERalpha), but an atypical dimeric architecture for the LBD. The physiological relevance of the proposed GRalpha LBD dimer is a subject of debate. METHODS: We analyzed all GRalpha LBD homodimers observed in crystals using an energetic analysis based on the PISA and on the MM/PBSA methods and a sequence conservation analysis, using the ERalpha LBD dimer as a reference point. RESULTS: Several dimeric assemblies were observed for GRalpha LBD. The assembly generally taken to be physiologically relevant showed weak binding free energy and no significant residue conservation at the contact interface, while an alternative homodimer mediated by both helix 9 and C-terminal residues showed significant binding free energy and residue conservation. However, none of the GRalpha LBD assemblies found in crystals are as stable or conserved as the canonical ERalpha LBD dimer. GRalpha C-terminal sequence (F domain) forms a steric obstacle to the canonical dimer assembly in all available structures. CONCLUSIONS: Our analysis calls for a re-examination of the currently accepted GRalpha homodimer structure and experimental investigations of the alternative architectures. GENERAL SIGNIFICANCE: This work questions the validity of the currently accepted architecture. This has implications for interpreting physiological data and for therapeutic design pertaining to glucocorticoid research. PMID- 29723545 TI - Reversible inactivation of yeast mitochondrial phenylalanyl-tRNA synthetase under oxidative stress. AB - BACKGROUND: Under oxidative stress cytoplasmic aminoacyl-tRNA synthetase (aaRSs) substrate specificity can be compromised, leading to tRNA mischarging and mistranslation of the proteome. Whether similar processes occur in mitochondria, which are major cellular sources of reactive oxygen species (ROS), is unknown. However, relaxed substrate specificity in yeast mitochondrial phenylalanyl-tRNA synthetase (ScmitPheRS) has been reported to increase tRNA mischarging and blocks mitochondrial biogenesis. METHODS: Non-reducing denaturing PAGE, cysteine reactivity studies, MALDI-TOF mass spectrometry, enzyme assay, western blot, growth assay, circular dichroism, dynamic light scattering and fluorescence spectroscopy were used to study the effect of oxidative stress on ScmitPheRS activity. RESULTS: ScmitPheRS is reversibly inactivated under oxidative stress. The targets for oxidative inactivation are two conserved cysteine residues resulting in reversible intra-molecular disulfide bridge formation. Replacement of either conserved cysteine residue increased viability during growth under oxidative stress. CONCLUSION: Formation of intra-molecular disulfide bridge under oxidative stress hinders the tRNAPhe binding of the enzyme, thus inactivating ScmitPheRS reversibly. GENERAL SIGNIFICANCE: The ScmitPheRS activity is compromised under oxidative stress due to formation of intra-molecular disulfide bridge. The sensitivity of ScmitPheRS to oxidation may provide a protective mechanism against error-prone translation under oxidative stress. PMID- 29723546 TI - Alginate-perlite encapsulated Pseudomonas putida A (ATCC 12633) cells: Preparation, characterization and potential use as plant inoculants. AB - Microbial immobilization can be used to prepare encapsulated inoculants. Here, we characterize and describe the preparation of Ca-alginate-perlite microbeads loaded with cells of plant growth-promoting Pseudomonas putida A (ATCC 12633), for their future application as agricultural inoculants. The microbeads were prepared by dropwise addition of a CaCl2-paraffin emulsion mixture to an emulsion containing alginate 2% (w/v), perlite 0.1-0.4% (w/v) and bacterial suspension in 0.9% NaCl (1010 CFU/mL). For all perlite concentrations used, microbead size was 90-120 MUm, the trapped population was 108 CFU/g microbeads and the increase in mechanical stability was proportional to perlite concentration. Microbeads containing 0.4% (w/v) perlite were able to release bacteria into the medium after 30 days of incubation. When we evaluated how P. putida A (ATCC 12633) entrapped in Ca-alginate-perlite (0.4% (w/v)) microbeads colonized the Arabidopsis thaliana rhizosphere, an increase in colonization over time was detected (from an initial 2.1 * 104 to 9.2 * 105 CFU/g soil after 21 days). With this treatment, growth promotion of A. thaliana occurred with an increase in the amount of proteins, and in root and leaf biomass. It was concluded that the microbeads could be applied as possible inoculants, since they provide protection and a controlled release of microorganisms into the rhizosphere. PMID- 29723547 TI - Hyperglycemia elicits anxiety-like behaviors in zebrafish: Protective role of dietary diphenyl diselenide. AB - Diabetes mellitus (DM) is a chronic metabolic disease that may comorbid with various psychiatric disorders, such as anxiety and depression. The search for effective therapeutics to alleviate hyperglycemia and complications resulting from DM is continuous. Here we investigate the effects of diphenyl diselenide (DD), an organoselenium compound with several pharmacological properties, in a zebrafish model of hyperglycemia. Fish were fed for 74 days with a diet containing 3 mg/Kg DD, a concentration chosen after experiments based in a dose response curve (DD 1, 2 and 3 mg/Kg) that did not cause overt toxicity (mortality, weight loss and neurobehavioral deficits). In the last 14 days of the experimental period, fish were concomitantly exposed to a glucose solution (111 mM). Afterwards, blood glucose levels, brain selenium (Se) content, and behavioral analysis aiming to assess anxiety-like behaviors and locomotor/exploratory activities were performed. In the novel tank diving test, glucose decreased vertical exploration and fish spent less time in the lit area when tested in the light-dark test, suggesting increased anxiety-like behavior. Moreover, DD decreased blood glucose levels in hyperglycemic fish as well as prevented the development of anxiety-related symptoms. DD diet alone did not change glycemia and behavioral parameters, but increased Se levels in the brain without affecting the cellular viability. Collectively, our findings highlight the growing utility of this zebrafish hyperglycemia model as a valuable strategy for further research in DM field and neuroprotective approaches. PMID- 29723548 TI - Sealing or infiltrating proximal carious lesions. AB - OBJECTIVES: Micro-invasive treatment (sealing, infiltration) seems more efficacious to arrest early (non-cavitated) proximal carious lesions than non invasive treatment (NI). Uncertainty remains as to the efficacy of sealing versus infiltration and the robustness of the evidence. We aimed to review and synthesize this evidence using pairwise and network meta-analysis (NMA) and to perform trial sequential analysis (TSA). SOURCES: Searching three electronic databases (Medline, Embase, Cochrane Central) was complemented by hand searches and cross-referencing. STUDY SELECTION: Randomized controlled trials comparing micro-invasive strategies against each other, NI or placebo for managing proximal carious lesions were included. The primary outcome was radiographically assessed lesion progression. Pairwise and Bayesian network meta-analyses as well as TSA were used for synthesis. DATA: Thirteen split-mouth studies (486 participants, mean age 15 years) were included. Mean follow-up was 25 months (min/max 12/36 months). Firm evidence on the superior efficacy of sealing/infiltration over NI (OR; 95% CI: 0.25; 0.18-0.32) was reached. Firm evidence was also reached on the superior efficacy of sealing (OR; 95% CI: 0.29; 0.18-0.46, 7 studies) and infiltration (OR; 95% CI: 0.22; 0.15-0.33, 7 studies) over NI. One study compared infiltration versus sealing and found no significant difference (0.70; 0.34 1.47). Based on Bayesian NMA, infiltration was ranked first in 80% of the simulations (sealing 20%, NI 0%). The surface-under-the-cumulative-ranking (SUCRA) values were 0.90 for infiltration, 0.60 for sealing and 0.00 for NI. We did not detect significant inconsistency (p = 0.89, node-split). CONCLUSIONS: Sealing or infiltration are likely to be more efficacious for arresting early (non-cavitated) proximal lesions than NI. CLINICAL SIGNIFICANCE: Practitioners should strive to perform micro-invasive treatment instead of NI for early proximal lesions. The decision between sealing or infiltration should be guided by practical concerns beyond efficacy. PMID- 29723550 TI - Scorpion toxins to unravel the conundrum of ion channel structure and functioning. AB - The consequences of scorpion stings on the affected victims, including humans, have been known since ancient times. The effects of the venom, first on neurotransmission and thereafter on many physiological processes at the organism, tissue, cellular or molecular levels, have been the subject of intense research. It is, therefore, not surprising that a large number of toxins acting on a variety of ion channels have been isolated and described to date. Many of these toxins show high specificities and affinities towards their natural targets. Along with their own biochemical and biophysical characterization, scorpion toxins have been used as invaluable tools for studies regarding the structure and function of ion channels. They have also become important leads in drug development aiming at diagnosing, targeting or direct treatment of channelopathies caused by the improper function of those channels they recognize, as well as other anomalous physiological conditions, including autoimmune diseases and cancer. The main families of scorpion toxins are reviewed here, among which are those specific for Na+, K+ and ryanodine-sensitive Ca2+ channels. The focus is placed on the historical events that led to their discovery and their use in the identification and characterization of the structure and function of ion channels. Their potential use in medicine is also presented. PMID- 29723549 TI - Genomic structure and molecular characterization of Toll-like receptors 1 and 2 from golden pompano Trachinotus ovatus (Linnaeus, 1758) and their expression response to three types of pathogen-associated molecular patterns. AB - Toll-like receptors (TLRs) play an essential role in the immune response. Here two Toll-like receptors from golden pompano (Trachinotus ovatus), ToTLR1 and ToTLR2, were characterized, the full-length cDNAs were 3126 bp and 7430 bp, and the deduced proteins consisted of 801 and 825 amino acids, respectively. ToTLR1 and ToTLR2 both contained the typical TLR domain architecture including signal peptide, leucine rich repeat (LRR), C-terminal LRR domain at the extracellular region and Toll/interleukin (IL)-1 receptor (TIR) domain in the cytoplasmic region. ToTLR1 only had one intron and two exons, but ToTLR2 consisted of twelve introns and thirteen exons. The promoters of ToTLR1 and ToTLR2 contained several putative transcription factor binding sites. Phylogenetic analysis showed that ToTLR1 and ToTLR2 were clustered into the clade of TLR1 and TLR2, respectively. Tissues distribution analysis indicated that both genes were ubiquitously expressed in all examined tissues, with higher expression levels observed in blood, head-kidney and spleen. After injection with poly inosinic:cytidylic [poly(I:C)], flagellin and lipopolysaccharides (LPS), ToTLR1 and ToTLR2 mRNAs were significantly up-regulated in the immune related tissues, indicating the possible the role of ToTLR1 and ToTLR2 in defense against pathogenic microbes. Further research should be carried out to identify ligands of fish TLR1 and TLR2 in order to understand the function of these receptors. PMID- 29723551 TI - Evaluation of airborne asbestos exposure from routine handling of asbestos containing wire gauze pads in the research laboratory. AB - Three independently conducted asbestos exposure evaluations were conducted using wire gauze pads similar to standard practice in the laboratory setting. All testing occurred in a controlled atmosphere inside an enclosed chamber simulating a laboratory setting. Separate teams consisting of a laboratory technician, or technician and assistant simulated common tasks involving wire gauze pads, including heating and direct wire gauze manipulation. Area and personal air samples were collected and evaluated for asbestos consistent with the National Institute of Occupational Safety Health method 7400 and 7402, and the Asbestos Hazard Emergency Response Act (AHERA) method. Bulk gauze pad samples were analyzed by Polarized Light Microscopy and Transmission Electron Microscopy to determine asbestos content. Among air samples, chrysotile asbestos was the only fiber found in the first and third experiments, and tremolite asbestos for the second experiment. None of the air samples contained asbestos in concentrations above the current permissible regulatory levels promulgated by OSHA. These findings indicate that the level of asbestos exposure when working with wire gauze pads in the laboratory setting is much lower than levels associated with asbestosis or asbestos-related lung cancer and mesothelioma. PMID- 29723552 TI - PI3K/Akt/GSK3beta induced CREB activation ameliorates arsenic mediated alterations in NMDA receptors and associated signaling in rat hippocampus: Neuroprotective role of curcumin. AB - Protective efficacy of curcumin in arsenic induced NMDA receptor dysfunctions and PI3K/Akt/ GSK3beta signalling in hippocampus has been investigated in vivo and in vitro. Exposure to sodium arsenite (in vivo - 20 mg/kg, body weight p.o. for 28 days; in vitro - 10 MUM for 24 h) and curcumin (in vivo - 100 mg/kg body weight p.o. for 28 days; in vitro - 20 MUM for 24 h) was carried out alone or simultaneously. Treatment with curcumin ameliorated sodium arsenite induced alterations in the levels of NMDA receptors, its receptor subunits and synaptic proteins - pCaMKIIalpha, PSD-95 and SynGAP both in vivo and in vitro. Decreased levels of BDNF, pAkt, pERK1/2, pGSK3beta and pCREB on sodium arsenite exposure were also protected by curcumin. Curcumin was found to decrease sodium arsenite induced changes in hippocampus by modulating PI3K/Akt/GSK3beta neuronal survival pathway, known to regulate various cellular events. Treatment of hippocampal cultures with pharmacological inhibitors for ERK1/2, GSK3beta and Akt individually inhibited levels of CREB and proteins associated with PI3K/Akt/GSK3beta pathway. Simultaneous treatment with curcumin was found to improve sodium arsenite induced learning and memory deficits in rats assessed by water maze and Y-maze. The results provide evidence that curcumin exercises its neuroprotective effect involving PI3K/Akt pathway which may affect NMDA receptors and downstream signalling through TrKbeta and BDNF in arsenic induced cognitive deficits in hippocampus. PMID- 29723553 TI - A strategic tension for hospitals moving upstream: Cede control but maintain accountability. AB - Health systems are focusing attention on the role that social determinants of health (SDOH) can and should play in health care delivery. This is especially true among accountable care organizations (ACOs) and Medicaid ACOs in particular. In crafting SDOH strategies, senior leadership teams may face an organizational tension in aiming to cede control over dollars, data and patient experience to community-based organizations (CBOs) while also maintaining financial accountability for health outcomes. We review the history of neighborhood health centers (NHCs) in order to foreshadow the types of critiques ACOs are likely to face in working with CBOs. We conclude by suggesting a several strategies by which ACOs may be lessen accountability concerns, including raising the issue with regulators, using low-risk dollars to fund joint-work, working through an intermediary, providing technical assistance and viewing the relationship as a partnership rather than contract. PMID- 29723555 TI - Assessing cross-modal target transition effects with a visual-auditory oddball. AB - Prior research has shown contextual manipulations involving temporal and sequence related factors significantly moderate attention-related responses, as indexed by the P3b event-related-potential, towards infrequent (i.e., deviant) target oddball stimuli. However, significantly less research has looked at the influence of cross-modal switching on P3b responding, with the impact of target-to-target cross-modal transitions being virtually unstudied. To address this gap, this study recorded high-density (256 electrodes) EEG data from twenty-five participants as they completed a cross-modal visual-auditory oddball task. This task was comprised of unimodal visual (70% Nontargets: 30% Deviant-targets) and auditory (70% Nontargets: 30% Deviant-targets) oddballs presented in fixed alternating order (i.e., visual-auditory-visual-auditory, etc.) with participants being tasked with detecting deviant-targets in both modalities. Differences in the P3b response towards deviant-targets as a function of preceding deviant target's presentation modality was analyzed using temporal-spatial PCA decomposition. In line with predictions, the results indicate that the ERP response to auditory deviant-targets preceded by visual deviant-targets exhibits an elevated P3b, relative to the processing of auditory deviant-targets preceded by auditory deviant-targets. However, the processing of visual deviant-targets preceded by auditory deviant-targets exhibited a reduced P3b response, relative to the P3b response towards visual deviant-targets preceded by visual deviant targets. These findings provide the first demonstration of temporally and perceptually decoupled target-to-target cross-modal transitions moderating P3b responses on the oddball paradigm, generally providing support for the context updating interpretation of the P3b response. PMID- 29723554 TI - Decreased resting-state BOLD regional homogeneity and the intrinsic functional connectivity within dorsal striatum is associated with greater impulsivity in food-related decision-making and BMI change at 6-month follow up. AB - Increasing animal models as well as brain imaging studies among human suggest an association between substance-related impulsivity in decision-making and decreased function of dorsal striatum. However, the resting-state intrinsic functional organization of dorsal striatum underlying food-choice impulsivity remains unknown. To address this issue, we used resting-state functional MRI (rs fMRI) to measure brain activity among adult females. Subjects underwent the food rating task, during which they rated each food item according to their subjective perception of its taste (from Dislike it very much to Like it very much), its long term effect on health (from very unhealthy to very healthy) and decision strength to eat it (from Strong no to Strong yes). Behaviorally, impulsivity in food-choice was indexed by the decision strength of the palatable high-calorie food rather than of the low-caloric food. Results on rs-fMRI showed that greater impulsivity in food-related decision-making was inversely correlated with spontaneous regional homogeneity in the dorsal striatum (dorsal caudate), as well as the resting-state functional connectivity (rs-FC) between the dorsal caudate seed and the rostral putamen. Furthermore, the caudate-putamen rs-FC inversely predicted BMI change at six-month follow-up. These findings may suggest the insensitivity to reward signals in dorsal caudate in decision-making coupled with an imbalance between goal-directed behaviors (modulated by dorsal caudate) and habitual actions (modulated by putamen) underlying impulsivity and future weight gain. In sum, these findings extend our understanding on the neural basis of food related impulsivity, and provide evidence for the dorsal striatum as one of the landmarks in over eating and weight change. PMID- 29723556 TI - Use of Neodymium magnetic discs as pressure earrings for ear lobe keloid post excision. PMID- 29723557 TI - 2-to-Z flap for reconstruction of adjacent skin defects. PMID- 29723558 TI - Split Ear Lobe Repair with Piercing Preservation and Optimal Ear Lobe Aesthetics. PMID- 29723559 TI - Effect of petrolatum coating on fast-absorbing gut suture. PMID- 29723560 TI - Associations Between Catecholaminergic and Serotonergic Genes and Persistent Breast Pain Phenotypes After Breast Cancer Surgery. AB - : Genetic variations in the catecholaminergic and serotonergic pathways may contribute to the development and severity of persistent breast pain. However, investigations of these associations are limited. The purpose of this study was to evaluate for associations between breast pain phenotypes and single nucleotide polymorphisms among 15 genes involved in catecholaminergic and serotonergic neurotransmission. Women rated the presence and intensity of breast pain monthly for 6 months after breast cancer surgery. Distinct latent classes of patients were identified using growth mixture modeling. Logistic regression analyses identified significant differences between genotype or haplotype frequencies and the breast pain classes (ie, no breast pain [n = 96] vs mild breast pain [n = 141], moderate breast pain [n = 46], and severe breast pain [n = 27]). Polymorphisms in 5 genes were associated with membership in the mild pain class: ** beta-2-adrenergic receptor (ADRB2) rs2400707, beta adrenergic receptor kinase 2 (ADRBK2) HapA04, 5-hydroxytryptamine receptor 3A (HTR3A) rs10160548, solute like carrier (SLC) family 6 member 2-noradrenaline transporter (SLC6A2) rs1566652, and tryptophan hydroxylase 2 (TPH2) rs11179000. Polymorphisms in 3 genes were associated with membership in the moderate pain class: 5 hydroxytryptamine receptor 2A (HTR2A) rs2296972, SLC6A2 rs17841327, and SLC6A3 rs403636. Polymorphisms in 3 genes were associated with membership in the severe pain class: COMT HPS haplotype, SLC family 6 member 2-noradrenaline transporter (SLC6A2) HapD01, and SLC family 6 member 3-noradrenaline transporter (SLC6A3) rs464049. The identification of these associations suggest possible underlying mechanisms that play a role in the development and severity of persistent breast pain. PERSPECTIVE: Findings from this study of women with breast cancer suggest that a number of catecholaminergic and serotonergic mechanisms may play a role in the development and severity of persistent breast pain phenotypes after surgery. PMID- 29723561 TI - Monoterpene indole alkaloids from Rhazya stricta. AB - Twenty-seven monoterpene indole alkaloids (MIAs) including three new ones were isolated from the plant of Rhazya stricta. Their structures were elucidated by analyses of HRMS and NMR data. Secopleiocarpamine A (1) represents a novel 2,3 seco pleiocarpamine type MIA possessing a cyano group. A possible biosynthetic pathway for 1 was postulated. All compounds were evaluated for their inhibitory activities against six Candida strains, and the results showed that 2, 5, 12, 21, 23, and 27 exhibited moderate inhibitory activities with MIC values ranging from 3.125 to 50 MUg/mL. PMID- 29723562 TI - Nematicidal amide alkaloids from the seeds of Clausena lansium. AB - Five new amide alkaloids (1-3, 5-6) were isolated from the seeds of Clausena lansium together with one new natural product (4) and four known analogues (7 10). The structures of the new amide alkaloids were elucidated based on a comprehensive spectroscopic data analysis including 1D and 2D NMR as well as HRESIMS, and by comparison with the literature. The bioactivity results showed that compound 8 expressed potent nematicidal activity against Panagrellus redivevus, with IC50 value of 0.12 mM, while compounds 3 and 5 presented moderate nematicidal activity with IC50 values of 2.75 and 3.93 mM, respectively (abamectin as the positive control with IC50 value of 1.05 mM). PMID- 29723563 TI - New alkylresorcinols from the fruits of Embelia ribes. AB - Nine new alkylresorcinols, designated as embelialkylresorcinols A-I (1-9), along with five known compounds (10-14) were isolated from the fruits of Embelia ribes. Their structures were elucidated by extensive spectroscopic analysis (1D, 2D NMR and HRESIMS), optical rotation data and modified Mosher method. Notably, embelialkylresorcinols A-H (1-8), possessing double aromatic rings linked with an aliphatic chain, are reported from the genus of Embelia (Myrsinaceae) for the first time. Most of the isolated compounds were evaluated for cytotoxic activity, and the results indicated that compounds 3, 5, 6 and 8 displayed moderate cytotoxicity against three human cancer cell lines (Hep3B, A549 and HCC1806) with IC50 values ranging from 23.06 to 41.49 MUM. PMID- 29723564 TI - Oleanane-type glycosides from the roots of Weigela florida "rumba" and evaluation of their antibody recognition. AB - Three triterpene glycosides were isolated from the roots of Weigela florida "rumba" (Bunge) A. DC.: two previously undescribed 3-O-beta-d-xylopyranosyl-(1 >2)-[beta-d-xylopyranosyl-(1->4)]-beta-d-xylopyranosyl-(1->4)-beta-d xylopyranosyl-(1->3)-alpha-L-rhamnopyranosyl-(1->2)-alpha-l arabinopyranosyloleanolic acid (1) and 3-O-beta-d-xylopyranosyl-(1->2)-[beta-d glucopyranosyl-(1->4)]-beta-d-xylopyranosyl-(1->4)-beta-d-xylopyranosyl-(1->3) alpha-l-rhamnopyranosyl-(1->2)-alpha-L-arabinopyranosyloleanolic acid (2), and one isolated for the first time from a natural source 3-O-beta-d-xylopyranosyl-(1 >3)-alpha-l-rhamnopyranosyl-(1->2)-alpha-l-arabinopyranosyloleanolic acid (3). Their structures were elucidated mainly by 2D NMR spectroscopic analysis (COSY, TOCSY, NOESY, HSQC, HMBC) and mass spectrometry. Compounds 2 and 3 were further evaluated as antigens in enzyme-linked immunosorbent assay (ELISA) to recognize IgM antibodies in multiple sclerosis (MS) patients' sera. PMID- 29723565 TI - Using Social Network Analysis to Investigate Positive EOL Communication. AB - CONTEXT: End-of-life (EOL) communication is a complex process involving the whole family and multiple care providers. Applications of analysis techniques that account for communication beyond the patient and patient/provider will improve clinical understanding of EOL communication. OBJECTIVES: The objectives of the study were to introduce the use of social network analysis to EOL communication data and to provide an example of applying social network analysis to home hospice interactions. METHODS: We provide a description of social network analysis to model communication patterns during home hospice nursing visits. We describe three social network attributes (i.e., magnitude, directionality, and reciprocity) in the expression of positive emotion among hospice nurses, family caregivers, and hospice cancer patients. Differences in communication structure by primary family caregiver across gender and time were also examined. RESULTS: Magnitude (frequency) in the expression of positive emotion occurred most often between nurses and caregivers or between nurses and patients. Female caregivers directed more positive emotion to nurses, and nurses directed more positive emotion to other family caregivers when the primary family caregiver was male. Reciprocity (mutuality) in positive emotion declined toward day of death but increased on day of actual patient death. There was a variation in reciprocity by the type of positive emotion expressed. CONCLUSION: Our example demonstrates that social network analysis can be used to better understand the process of EOL communication. Social network analysis can be expanded to other areas of EOL research, such as EOL decision making and health care teamwork. PMID- 29723566 TI - Triptolide-induced mitochondrial damage dysregulates fatty acid metabolism in mouse sertoli cells. AB - Triptolide is a major active ingredient of tripterygium glycosides, used for the therapy of immune and inflammatory diseases. However, its clinical applications are limited by severe male fertility toxicity associated with decreased sperm count, mobility and testicular injures. In this study, we determined that triptoide-induced mitochondrial dysfunction triggered reduction of lactate and dysregulation of fatty acid metabolism in mouse Sertoli cells. First, triptolide induced mitochondrial damage through the suppressing of proliferator-activated receptor coactivator-1 alpha (PGC-1alpha) activity and protein. Second, mitochondrial damage decreased lactate production and dysregulated fatty acid metabolism. Finally, mitochondrial dysfunction was initiated by the inhibition of sirtuin 1 (SIRT1) with the regulation of AMP-activated protein kinase (AMPK) in Sertoli cells after triptolide treatment. Meanwhile, triptolide induced mitochondrial fatty acid oxidation dysregulation by increasing AMPK phosphorylation. Taken together, we provide evidence that the mechanism of triptolide-induced testicular toxicity under mitochondrial injury may involve a metabolic change. PMID- 29723567 TI - Novel Observations of Female Genital Anatomy in Classic Bladder Exstrophy Using 3 Dimensional Magnetic Resonance Imaging Reconstruction. AB - PURPOSE: Understanding the distinct female anatomy in classic bladder exstrophy is crucial for optimal reconstructive and functional outcomes. We present novel quantitative anatomical data in females with classic bladder exstrophy before primary closure. MATERIALS AND METHODS: 3-Dimensional reconstruction was performed in patients undergoing pelvic magnetic resonance imaging, and pelvic anatomy was characterized, including measurements of the vagina, cervix and erectile bodies. RESULTS: We examined magnetic resonance imaging of 5 females (mean age 5.5 months) with classic bladder exstrophy and 4 age matched controls (mean age 5.8 months). Mean distance between the anal verge and vaginal introitus was greater in patients with classic bladder exstrophy (2.43 cm) than in controls (1.62 cm). Mean total vaginal length in patients with classic bladder exstrophy was half that of controls (1.64 cm vs 3.39 cm). All 4 controls had posterior facing cervical ora, while 4 of 5 females with exstrophy had anterior facing cervical ora located in the anterior vaginal wall. Lateral deviation of the cervical ora was also seen in all 5 patients with classic bladder exstrophy but in only 1 control. Clitoral body length was comparable in both groups (26.2 mm and 28.0 mm). However, the anterior cavernosa-to-posterior (pelvic rami associated) cavernosa ratio was much greater in patients with classic bladder exstrophy (6.4) compared to controls (2.5). CONCLUSIONS: This study uncovers the uniquely novel finding that contrary to their male counterparts, females with classic bladder exstrophy have the majority of the clitoral body anterior to the pelvic attachment. This discovery has surgical and embryological implications. PMID- 29723569 TI - Pain is Independent of Stone Burden and Predicts Surgical Intervention in Patients with Ureteral Stones. AB - PURPOSE: Patients with obstructing ureteral stones typically experience sudden onset, severe pain. We examined the use of the NIH (National Institutes of Health) PROMIS(r) (Patient-Reported Outcome Measurement Information System) pain instruments in patients with acute ureteral stones. MATERIALS AND METHODS: PROMIS pain measures were obtained from a complete cohort of patients who presented to a subspecialty kidney stone clinic after emergency department discharge. Patients were followed longitudinally through the course of care. Raw scores were translated into population normed T-scores with a T-score of 50 indicating the mean pain population in the United States. Objective and patient centered factors were evaluated with reference to T-score thresholds for pain intensity with 60 equal to 1 SD above the mean and pain interference with 70 equal to 2 SD. RESULTS: Multivariable logistic regression in 650 patients demonstrated an absent association between pain scores and stone size or location. Pain scores were associated with patient age, gender and emergency department pain scores (p <0.05). Initial stone surgery was predicted by a stone size less than 4 mm (OR 0.14, 95% CI 0.07-0.3), greater than 6 mm (OR 19.1, 95% CI 0.22-39.58), proximal location (OR 1.75, 95% CI 1.34-2.3) and pain intensity greater than 60 (OR 7.03, 95% CI 3.63-13.6) but not pain interference (p <0.001). Failed attempted stone passage was less likely for stones less than 4 mm (OR 0.26, 95% CI 0.14-0.48, p <0.001) and more likely for proximal stones (OR 1.61, 95% CI 1.21-2.14, p <0.01) and pain intensity greater than 60 (OR 2.74, 95% CI 1.23-6.07, p <0.05). CONCLUSIONS: PROMIS pain scores are independent of stone size and location. Attention to emergency department discharge symptom control offers the potential to improve patient care. PROMIS pain intensity is an independent predictor of surgical intervention in patients with ureteral stones 1 cm or less. PMID- 29723568 TI - Family History is Underestimated in Children with Isolated Hypospadias: A French Multicenter Report of 88 Families. AB - PURPOSE: While familial forms of complex disorders/differences of sex development have been widely reported, data regarding isolated hypospadias are sparse and a family history is thought to be less frequent. We aimed to determine the frequency of hypospadias in families of boys with hypospadias, to establish whether these familial forms exhibit a particular phenotype and to evaluate the prevalence of genetic defects of the main candidate genes. MATERIALS AND METHODS: A total of 395 boys with hypospadias were prospectively screened for a family history with a standardized questionnaire, extensive clinical description, family tree and sequencing of AR, SF1, SRD5A2 and MAMLD1. RESULTS: Family history of hypospadias was more frequent than expected (88 patients, 22.3%). In 17 instances (19.3%) familial hypospadias cases were multiple. Familial hypospadias was related to the paternal side in 59.1% of cases, consisting of the father himself (30.7%) as well as paternal uncles and cousins. Premature birth, assisted reproductive techniques, other congenital abnormalities and growth retardation were not more frequent in familial hypospadias than in sporadic cases. The severity of phenotype was similar in both groups. The results of genetic analysis combined with previous data on androgen receptor sequencing revealed that familial cases more frequently tend to demonstrate genetic defects than sporadic cases (5.68% vs 1.63%, p = 0.048). CONCLUSIONS: Familial forms of hypospadias are far more frequent than previously reported. Even minor and isolated forms justify a full clinical investigation of the family history. Detecting these hereditary forms may help to determine the underlying genetic defects, and may improve followup and counseling of these patients. PMID- 29723570 TI - Investigation of trimethoprim/sulfamethoxazole resistance in an emerging sequence type 5 methicillin-resistant Staphylococcus aureus clone reveals discrepant resistance reporting. PMID- 29723571 TI - Pharmacokinetics of colistin in a 8-year-old child with acute bone infection. PMID- 29723572 TI - Iteratively improving Hi-C experiments one step at a time. AB - The 3D organization of eukaryotic chromosomes affects key processes such as gene expression, DNA replication, cell division, and response to DNA damage. The genome-wide chromosome conformation capture (Hi-C) approach can characterize the landscape of 3D genome organization by measuring interaction frequencies between all genomic regions. Hi-C protocol improvements and rapid advances in DNA sequencing power have made Hi-C useful to study diverse biological systems, not only to elucidate the role of 3D genome structure in proper cellular function, but also to characterize genomic rearrangements, assemble new genomes, and consider chromatin interactions as potential biomarkers for diseases. Yet, the Hi C protocol is still complex and subject to variations at numerous steps that can affect the resulting data. Thus, there is still a need for better understanding and control of factors that contribute to Hi-C experiment success and data quality. Here, we evaluate recently proposed Hi-C protocol modifications as well as often overlooked variables in sample preparation and examine their effects on Hi-C data quality. We examine artifacts that can occur during Hi-C library preparation, including microhomology-based artificial template copying and chimera formation that can add noise to the downstream data. Exploring the mechanisms underlying Hi-C artifacts pinpoints steps that should be further optimized in the future. To improve the utility of Hi-C in characterizing the 3D genome of specialized populations of cells or small samples of primary tissue, we identify steps prone to DNA loss which should be considered to adapt Hi-C to lower cell numbers. PMID- 29723573 TI - Morphological, histological and molecular characterization of three Myxobolus species (Cnidaria: Myxosporea) from silver carp Hypophthalmichthys molitrix Valenciennes and bighead carp Hypophthalmichthys nobilis Richardson in China. AB - Three Myxobolus species were obtained from silver carp Hypophthalmichthys molitrix Valenciennes and bighead carp Hypophthalmichthys nobilis Richardson in China. In the present study, we supplemented their taxonomic characteristics by the morphological, histological and molecular methods. Myxobolus kiuchowensis Chen in Chen et Ma, 1998 formed small ellipsoidal plasmodia in the intestinal wall of bighead carp. Its spores appeared asymmetrical obovate in frontal view and fusiform in lateral view. Tiny mamillary protrusion in the anterior of some spores was observed. Two pyriform polar capsules were unequal. Histologically, M. kiuchowensis infected the tunica muscularis of host intestine. Myxobolus abitus Li et Nie, 1973 formed sausage-like plasmodia in the gills of silver carp. Its spores appeared oblate in frontal view and fusiform in lateral view. Two pyriform polar capsules were unequal and an obvious inter-capsule appendix was observed. Histological examination revealed that M. abitus developed in the interlamellar epithelium of host gills. Myxobolus pavlovskii (Akhmerov, 1954) Landsberg et Lom, 1991 formed sausage-like plasmodia both in the gills of silver carp and bighead carp. Spores of M. pavlovskii were proximate oval in frontal view and fusiform in lateral view. Two pyriform polar capsules were unequal. The BLAST search indicated the SSU rDNA sequences of M. kiuchowensis and M. abitus were not identical to any sequence, however, the SSU rDNA sequences of M. pavlovskii were identical to that of M. pavlovskii recorded previously. Phylogenetic analysis showed that the present three species robustly clustered together in Cyprinid group and Asia group. PMID- 29723574 TI - Influences of Hunger, Satiety and Oral Glucose on Functional Brain Connectivity: A Multimethod Resting-State fMRI Study. AB - A major regulatory task of the organism is to keep brain functions relatively constant in spite of metabolic changes (e.g., hunger vs. satiety) or availability of energy (e.g., glucose administration). Resting-state functional magnetic resonance imaging (rs-fMRI) can reveal resulting changes in brain function but previous studies have focused mostly on the hypothalamus. Therefore, we took a whole-brain approach and examined 24 healthy normal-weight men once after 36 h of fasting and once in a satiated state (six meals over the course of 36 h). At the end of each treatment, rs-fMRI was recorded before and after the oral administration of 75 g of glucose. We calculated local connectivity (regional homogeneity [ReHo]), global connectivity (degree of centrality [DC]), and amplitude (fractional amplitude of low-frequency fluctuation [fALFF]) maps from the rs-fMRI data. We found that glucose administration reduced all measures selectively in the left supplementary motor area and increased ReHo and fALFF in the right middle and superior frontal gyri. For fALFF, we observed a significant interaction between metabolic states and glucose in the left thalamus. This interaction was driven by a fALFF increase after glucose treatment in the hunger relative to the satiety condition. Our results indicate that fALFF analysis is the most sensitive measure to detect effects of metabolic states on resting-state brain activity. Moreover, we show that multimethod rs-fMRI provides an unbiased approach to identify spontaneous brain activity associated with changes in homeostasis and caloric intake. PMID- 29723575 TI - Retrieval of Inhibitory Avoidance Memory Induces Differential Transcription of arc in Striatum, Hippocampus, and Amygdala. AB - Similar to the hippocampus and amygdala, the dorsal striatum is involved in memory retrieval of inhibitory avoidance, a task commonly used to study memory processes. It has been reported that memory retrieval of fear conditioning regulates gene expression of arc and zif268 in the amygdala and the hippocampus, and it is surprising that only limited effort has been made to study the molecular events caused by retrieval in the striatum. To further explore the involvement of immediate early genes in retrieval, we used real-time PCR to analyze arc and zif268 transcription in dorsal striatum, dorsal hippocampus, and amygdala at different time intervals after retrieval of step-through inhibitory avoidance memory. We found that arc expression in the striatum increased 30 min after retrieval while no changes were observed in zif268 in this region. Expression of arc and zif268 also increased in the dorsal hippocampus but the changes were attributed to context re-exposure. Control procedures indicated that in the amygdala, arc and zif268 expression was not dependent on retrieval. Our data indicate that memory retrieval of inhibitory avoidance induces arc gene expression in the dorsal striatum, caused, very likely, by the instrumental component of the task. Striatal arc expression after retrieval may induce structural and functional changes in the neurons involved in this process. PMID- 29723576 TI - Beta and Gamma Oscillations in Prefrontal Cortex During NMDA Hypofunction: An In Vitro Model of Schizophrenia Features. AB - NMDA receptor (NMDAr) hypofunction has been widely used as a schizophrenia model. Decreased activation of NMDAr is associated with a disrupted excitation/inhibition balance in the prefrontal cortex and with alterations in gamma synchronization. Our aim was to investigate whether this phenomenon could be reproduced in the spontaneous oscillatory activity generated by the local prefrontal network in vitro and, if so, to explore the effects of antipsychotics on the resulting activity. Extracellular recordings were obtained from prefrontal cortex slices bathed in in vivo-like ACSF solution. Slow (<1 Hz) oscillations consisting of interspersed Up (active) and Down (silent) states spontaneously emerged. Fast-frequency oscillations (15-90 Hz) occurred during Up states. We explored the effects of the NMDAr antagonist MK-801 on the spontaneously generated activity. Bath-applied MK-801 induced a dose-dependent decrease in Up state duration and in the frequency of Up states. However, the beta/gamma power during Up states significantly increased; this increase was in turn prevented by the antipsychotic drug clozapine. The increased beta/gamma power with NMDAr blockade implies that NMDAr activation in physiological conditions prevents hypersynchronization in this frequency range. High-frequency hypersynchronization following NMDAr blockade occurring in cortical slices suggests that-at least part of-the underlying mechanisms of this schizophrenia feature persist in the local cortical circuit, even in the absence of long-range cortical or subcortical inputs. The observed action of clozapine decreasing hypersynchronization in the local circuit may be one of the mechanisms of action of clozapine in preventing schizophrenia symptoms derived from NMDA hypofunction. PMID- 29723577 TI - AMPA Receptor-Dependent Glutamatergic Signaling is Present in the Carotid Chemoreceptor. AB - Exposure to both sustained and intermittent hypoxia for as little as a day produces sustained augmentation of carotid chemoreceptor sensitivity; however, the molecular basis for this chemoreflex plasticity remains uncertain. We previously reported that NMDA receptor-dependent glutamatergic signaling in rat carotid body played a role in altered hypoxic sensitivity after exposure to cyclic intermittent hypoxia (CIH). Here we found that mRNAs of multiple AMPA and Kainate glutamate receptors were expressed in rat carotid body. The AMPA receptor subunit GluR1 showed intense immunoreactivity in the carotid body, co-localizing with tyrosine hydroxylase in type I cells. Treatment of rat carotid body-derived primary cells with AMPA activated ERK1/2 in a time-dependent manner. Exposing Sprague-Dawley rats to CIH for 8 h/day for 3 weeks significantly enhanced the expression level of GluA1 mRNA as well as GluR1 protein in the carotid body. In addition, our results showed that multiple of vesicular glutamate transporters (VGLUTs) and excitatory amino acid transporters (EAATs) were expressed in the rat carotid body, indicating that glutamate might be as a neurotransmitter stored, released and uptake in the carotid body. Finally, we found that mRNAs of GluA1, GluA2 and GluA3 as well as PSD-95-like membrane-associated granulate kinase family members, PSD-95, PSD-93, and SAP97, were expressed in human carotid body. Our data suggest AMPA receptor-dependent glutamatergic signaling is present in the carotid body and might be involved in the carotid chemoreceptor response to hypoxia. PMID- 29723578 TI - Conventional Epidural vs Transversus Abdominis Plane Block with Liposomal Bupivacaine: A Randomized Trial in Colorectal Surgery. AB - BACKGROUND: Colorectal surgery is a focus of enhanced recovery protocols (ERP). The use of transversus abdominis plane (TAP) block for abdominal surgery has demonstrated effectiveness in ERP, however, no direct comparison of epidural vs TAP for nonanalgesic clinical factors has been published to date. The primary aim of this study was to compare epidural with TAP for length of stay in colorectal surgery. STUDY DESIGN: Patients undergoing open and laparoscopic colorectal surgery were prospectively randomized into epidural (n = 39) or TAP (n = 44) groups preoperatively. Anesthesiologists performed blocks in the preoperative area. A standardized ERP and discharge protocol were initiated on patients. Five patients unable to complete the ERP due to unrelated postoperative complications or technical factors were excluded from analysis. RESULTS: The study arms were statistically similar for demographic factors, operations, and intraoperative measures. Time to first flatus was equivalent in both groups (postoperative day 1.7 vs 1.9; p = 0.39). Length of stay was shorter with TAP (postoperative day 3.3 vs 2.8; p = 0.023). Postoperative nausea and vomiting rates were higher with TAP (14% vs 33%; p = 0.057). Urinary retention occurred with higher frequency with epidural (30% vs 15%; p = 0.11). CONCLUSIONS: Transversus abdominis plane block was associated with a 0.5-day reduction in length of stay in a standardized ERP compared with epidural. Early indication favors TAP in patients with a history of postoperative urinary retention, as a trend of urinary retention was associated with epidural. Transversus abdominis plane block offers an effective alternative to epidural in colorectal surgery, regardless of operative approach. PMID- 29723579 TI - Perineal Closure after Abdominoperineal Resection Using a Pedicled Deep Inferior Epigastric Perforator Flap: A Safe Alternative to Rectus Abdominis Myocutaneous Flap. PMID- 29723580 TI - The pupillary light responses of animals; a review of their distribution, dynamics, mechanisms and functions. AB - The timecourse and extent of changes in pupil area in response to light are reviewed in all classes of vertebrate and cephalopods. Although the speed and extent of these responses vary, most species, except the majority of teleost fish, show extensive changes in pupil area related to light exposure. The neuromuscular pathways underlying light-evoked pupil constriction are described and found to be relatively conserved, although the precise autonomic mechanisms differ somewhat between species. In mammals, illumination of only one eye is known to cause constriction in the unilluminated pupil. Such consensual responses occur widely in other animals too, and their function and relation to decussation of the visual pathway is considered. Intrinsic photosensitivity of the iris muscles has long been known in amphibia, but is in fact widespread in other animals. The functions of changes in pupil area are considered. In the majority of species, changes in pupil area serve to balance the conflicting demands of high spatial acuity and increased sensitivity in different light levels. In the few teleosts in which pupil movements occur they do not serve a visual function but play a role in camouflaging the eye of bottom-dwelling species. The occurrence and functions of the light-independent changes in pupil size displayed by many animals are also considered. Finally, the significance of the variations in pupil shape, ranging from circular to various orientations of slits, ovals, and other shapes, is discussed. PMID- 29723581 TI - The nitric oxide-guanylate cyclase pathway and glaucoma. AB - Glaucoma is a prevalent optic neuropathy characterized by the progressive dysfunction and loss of retinal ganglion cells (RGCs) and their optic nerve axons, which leads to irreversible visual field loss. Multiple risk factors for the disease have been identified, but elevated intraocular pressure (IOP) remains the primary risk factor amenable to treatment. Reducing IOP however does not always prevent glaucomatous neurodegeneration, and many patients progress with the disease despite having IOP in the normal range. There is increasing evidence that nitric oxide (NO) is a direct regulator of IOP and that dysfunction of the NO-Guanylate Cyclase (GC) pathway is associated with glaucoma incidence. NO has shown promise as a novel therapeutic with targeted effects that: 1) lower IOP; 2) increase ocular blood flow; and 3) confer neuroprotection. The various effects of NO in the eye appear to be mediated through the activation of the GC- guanosine 3:5'-cyclic monophosphate (cGMP) pathway and its effect on downstream targets, such as protein kinases and Ca2+ channels. Although NO-donor compounds are promising as therapeutics for IOP regulation, they may not be ideal to harness the neuroprotective potential of NO signaling. Here we review evidence that supports direct targeting of GC as a novel pleiotrophic treatment for the disease, without the need for direct NO application. The identification and targeting of other factors that contribute to glaucoma would be beneficial to patients, particularly those that do not respond well to IOP-dependent interventions. PMID- 29723582 TI - Mesenteric organ lymphatics and inflammatory bowel disease. AB - Inflammatory bowel disease (IBD) is a complex gastrointestinal disorder and its etiology is unclear yet. Current theory in IBD is focused on genetics, immunity and intestinal microbes. Emerging clinical evidence and experimental results suggest that morphologic abnormalities and dysfunction of mesenteric lymphatics may have potential roles in the pathogenesis and disease course of IBD. In this review, we summarize the findings of specific investigations of the lymphatics and explore its role in IBD. PMID- 29723583 TI - Psychometric development of the Upper Limb Lymphedema Quality of Life Questionnaire demonstrated the patient-reported outcome measure to be a robust measure for breast cancer-related lymphedema. AB - OBJECTIVES: To develop and undertake initial validation of a patient-reported outcome measure to assess health-related quality of life in patients with breast cancer-related upper limb lymphedema (ULL). STUDY DESIGN AND SETTING: We developed and validated the Upper Limb Lymphedema Quality of Life (ULLQoL) scale in two stages: devising the items and pretesting with patients and clinicians; longitudinal validation to test its psychometric properties-underlying dimensions, internal consistency, test-retest reliability, construct validity, and responsiveness. Patients with ULL were recruited from two outpatient clinics. RESULTS: We derived the ULLQoL scale from a pool of 98 items generated by patients. After further consultation, we produced the draft ULLQoL scale. For validation, 103 patients with ULL completed the draft scale and two generic health measures: SF-36 and ED-5D-3L. Psychometric analysis identified two components, physical and emotional well-being, with good internal consistency and test-retest reliability. Significant correlations with SF-36, EQ-5D-3L, and percentage excess limb volume confirmed construct validity. The ULLQoL scale showed good responsiveness to change reported by lymphedema patients and moderate to large effect sizes. CONCLUSION: The 14-item ULLQoL scale is a robust ULL specific measure that is feasible and valid to use in both the clinical and research settings. PMID- 29723584 TI - Preclinical safety evaluation of the ethanolic extract from guavira fruits (Campomanesia pubescens (D.C.) O. BERG) in experimental models of acute and short term toxicity in rats. AB - Campomanesia pubescens is a fruit plant widely distributed in South America and used by the population for medicinal and nutritional purposes, with important economic and cultural value. This study evaluated the toxic potential of the ethanolic extract from C. pubescens (EEFCP) fruits through acute and short-term toxicity tests. For the acute toxicity test, female rats received a single oral dose of 2000 mg/kg body weight of EEFCP and were observed for 14 days. In the short-term toxicity test, male and female rats received repeated oral doses of 125, 250, 500 or 1000 mg/kg of EEFCP, being treated and observed for 28 days, and after the treatment period, a satellite and satellite control group remained under observation for another 14 days. No mortality, clinical and organ weight alterations were observed, indicating that LD50 is greater than 2000 mg/kg body weight. In addition, the doses tested did not produce significant changes in the behavioral, physiological, hematological or histopathological parameters of animals. These results demonstrate the low acute and short-term toxicity of EEFCP in rats. The data obtained are of great relevance since they provide important information about a plant species of great economic, nutritional and ethnopharmacological value. PMID- 29723585 TI - Platycodon grandiflorum-derived saponin enhances exercise function, skeletal muscle protein synthesis, and mitochondrial function. AB - Lower physical performance is an important risk factor in hypokinetic-related chronic disease, metabolic syndrome, and muscle atrophy. Our previous research demonstrated that Platycodon grandiflorum-derived saponin (PS) protects against eccentric exercise-induced muscle damage and mitochondrial function-related peroxisomal acyl-coenzme A oxidase (ACOX-1) and carnitine palmitoyltransferase (CPT-1) in high-fat diet-induced non-alcoholic steatohepatitis, and it inhibits osteoclast differentiation. However, the effects of PS on physical performance remain unknown. Therefore, we investigated whether PS enhances physical activity and skeletal muscle function. Supplementation with PS (2 mg/kg for 4 weeks) increased grip strength, wheel running repetition, and time to exhaustion in treadmill and swimming exercises. Marked increases in the synthesis of skeletal muscle proteins and muscle stem cell-related paired-box 7 (PAX7) were observed, and a decrease in the negative regulator myostatin was associated with enhanced muscle regeneration. Furthermore, PS induced expression of mitochondrial function proteins, including OXPHOS-III and -IV, in vivo and in vitro. These results suggest that PS enhances exercise function by ameliorating skeletal muscle protein synthesis and mitochondrial function. PMID- 29723586 TI - Consumption and exposure assessment to toothpaste in French families. AB - The aim of the study was to assess the consumption and the exposure to toothpaste in French families leaving the consumers free to use their own product at home according to their habits. Consumption data were collected on 104 families. 206 adults (103 women and 103 men) and 195 children aged 2-17 participated in the study. Differences in toothpaste consumption depending on gender and on age were highlighted. As an example, frequency data were higher in adult women (2.0 day-1 on average) than in adult men (1.8 day-1 on average); amount per use data were higher in adult men (1.2 g on average) than in adult women (0.9 g on average). The frequency of use and the amount of toothpaste used per application increased with age. The exposure to toothpaste decreased with age. Children aged 2-6 were the most exposed to toothpaste with a P95 value equal to 8.2 mg/kg bw/day. Adult's P95 exposure value was equal to 2.8 mg/kg bw/day. Exposure values were in the same order of magnitude for both genders in children and in adults. These new data will be useful for safety assessors, especially children data which remain scarce. PMID- 29723589 TI - 46-XY Denys-Drash Syndrome. Is There a Role for Nephron-sparing Modalities in Management of Renal Masses? A Report of 2 Cases. AB - Denys-Drash syndrome (DDS) is a combination of genital and urinary anomalies that are mostly associated with renal and gonadal malignancies. We report 2 patients who presented with genital ambiguity and were diagnosed as 46-XY DDS. Both patients had renal masses during follow-up and underwent partial nephrectomy aiming to have transplant at older age. PMID- 29723587 TI - Duplex Ultrasound-guided Direct Percutaneous Management of Pseudoaneurysm of Branch of Segmental Renal Artery: Technique and Its Outcome. AB - OBJECTIVE: To describe the role of duplex ultrasound imaging (DUI) in prompt diagnosis of pseudoaneurysm (PSA) of a branch of the segmental renal artery (b SRA) and to evaluate outcomes of DUI directed percutaneous embolization. MATERIALS AND METHODS: Forty-five patients were referred to us for the management of intractable renal hematuria. A total of 20 cases (44.44%) had developed PSA after nephrolithotomy, 12 cases (12.66%) had developed PSA after guided renal biopsies, 6 cases (13.33%) had developed PSA following road side trauma, and 2 cases (4.44%) of the tuberous sclerosis complex had developed PSA. Three cases (6.66%) of arteriovenous and 2 cases (4.44%) of arteriocalyceal fistulae had been excluded from the study. DUI-guided direct percutaneous management (DPM) was done as a 4-step process. First is the identification of PSA sac in the neck and offending b-SRA. Second is the puncture of PSA sac with 18 g puncture needle under DUI. Subsequently, manual injection of temporary embolic agent was done followed by N-butyl cyanoacrylate glue. Thrombosis of the PSA sac was confirmed by absent flow on DUI. RESULTS: Forty cases of b-SRA were managed successfully in a single session and followed up by clinical findings, DUI, and computed tomography angiography. There was no need for the second session of DPM, transarterial embolization, or surgery in this cohort. Twelve cases (30%) had developed a mild fever and were managed conservatively. All 40 cases had no evidence of renal hematuria after follow-up of 3 months. CONCLUSION: DUI-guided DPM is a safe, feasible, cost-effective, and nephron-sparing promising alternative to TAE or surgery for management of PSA of b-SRA. PMID- 29723588 TI - Separating the Wheat From the Chaff: An Evaluation of Readability, Quality, and Accuracy of Online Health Information for Treatment of Peyronie Disease. AB - OBJECTIVE: To characterize available information about Peyronie disease online and evaluate its readability, quality, accuracy, and respective associations with HONcode certification and website category. METHODS: The search term "Peyronie disease" was queried on 3 major search engines (Google, Bing, and Yahoo) and the first 50 search results on each search engine were assessed. All websites were categorized as institutional or reference, commercial, charitable, personal or patient support, or alternative medicine, and cross-referenced with the Health on the Net (HON) Foundation. Websites that met the inclusion criteria were analyzed for readability using 3 validated algorithms, for quality using the DISCERN instrument, and for accuracy by a fellowship-trained urologist. RESULTS: On average, online health information about treatment of Peyronie disease is written at or above the 11th grade level, exceeding the current reading guidelines of 6th 8th grade. The mean total DISCERN score for all website categories was 50.44 (standard deviation [SD] 11.94), the upper range of "fair" quality. The mean accuracy score of all online Peyronie treatment information was 2.76 (SD 1.23), corresponding to only 25%-50% accurate information. Both institutional or reference and HONcode-certified websites were of "good" quality (53.44, SD 11.64 and 60.86, SD 8.74, respectively). Institutional or reference websites were 50% 75% accurate (3.13, SD 1.20). CONCLUSION: Most of the online Peyronie disease treatment information is of mediocre quality and accuracy. The information from institutional or reference websites is of better quality and accuracy, and the information from HONcode-certified websites is of better quality. The mean readability of all websites exceeds the reading ability of most US adults by several grade levels. PMID- 29723590 TI - Unclassifiable CD20-negative Testicular Diffuse Large B-cell Lymphoma. AB - CD20-negative diffuse large B-cell lymphoma (DLBCL) is a very uncommon neoplasm, and very rare unclassifiable cases that did not meet the criteria for well established subtypes of CD20-negative DLBCLs have been reported. CD20-negative DLBCLs often present an aggressive clinical course with important chemoresistance and poor prognosis. Here, we report a case of CD20-negative DLBCL presented as a testicular mass. To the best of our knowledge, this is one of the first reported cases of testicular unclassifiable CD20-negative DLBCL. PMID- 29723591 TI - Do Women Work Less Than Men in Urology: Data From the American Urological Association Census. AB - OBJECTIVE: To further explore the issue of work parity between male and female urologists in the context of demographics, practice characteristics, subspecialty affiliation, and planned retirement. MATERIALS AND METHODS: We analyzed data from the 2014 American Urological Association census, which is a specialty wide survey distributed to the entire urology community in the United States. A total of 2204 census samples were weighted to represent 11,703 urologists who practiced in the United States in 2014. We compared clinical and nonclinical hours worked by gender after adjusting for age, practice setting, fellowship type, and whether or not the urologist performed inpatient operations. RESULTS: Of the 11,703 practicing urologists in the United States, female urologists make up approximately 7.7% of the workforce (n ~ 897). Female practicing urologists were younger (66.4%, <45 years old), had shorter training intervals, and a younger planned retirement age than their male counterparts (63 years vs 68.5 years, P <.001). More women were fellowship-trained in a urologic subspecialty (54.9% vs 34.9%, P <.001) and more were in academic practices (33.2% vs 21.9%, P = .03). After adjusting for age, practice type, subspecialty, and inpatient operations performed, there was no difference in hours worked between women and men (beta coefficient -2.8, 95% confidence interval -6.4 to 0.7, P = .12). CONCLUSION: Gender does not appear to drive the number of hours urologists work per week. There is work hour parity between women and men practicing urologists in both clinical and nonclinical hours. Women are proportionately more likely to pursue fellowship training and hold academic positions. PMID- 29723592 TI - Randomized controlled trial investigating the experimental effects of reduced habitual physical activity on cardiometabolic profile. AB - OBJECTIVE: Previous work suggests that reduced habitual physical activity is unfavorably associated with cardiometabolic health. Fewer lifestyle-based, experimental studies on this topic have been conducted. Thus, the purpose of this study was to experimentally reduce habitual physical activity over a one-week period to evaluate its potential effects on cardiometabolic profile. METHODS: Young physically active adults (Mage = 21 yrs) were randomized into a Reduced Activity Group (N = 19) or a Control Group (N = 20). The Reduced Activity group engaged in baseline week of normal activity, then reduced their activity for one week (from approximately 9000 steps/day to approximately 6000 steps/day), followed by resumption of habitual activity for a week. The Control Group maintained their normal active lifestyle for two-weeks. At all time points, the following cardiometabolic parameters were assessed: systolic blood pressure, diastolic blood pressure, mean arterial blood pressure, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), atherogenic index of plasma (AIP), TC/HDL-C, LDL C/HDL-C, TG/HDL-C, non-HDL-C, and glucose. RESULTS: The Reduced Activity Group, compared to the Control Group, had an unfavorable change in TG/HDL-C (FInteraction = 4.995, P = 0.03, eta2p = 0.14). No other biomarkers were altered CONCLUSION: A one-week period of reduced activity among a young adult, active population, increased TG/HDL-C levels, with no changes observed in any of the other evaluated cardiometabolic parameters. Thus, a temporary lapse in habitual physical activity does not considerably change cardiometabolic outcomes in young, healthy physically active adults. PMID- 29723593 TI - Sex-dependent impact of different degrees of maternal separation experience on OFT behavioral performances after adult chronic unpredictable mild stress exposure in rats. AB - Early-life social-environmental factors are important for normal development, and different degrees of early-life stress experience have different impacts on adult behaviors and stress responsiveness. The aim of present study was to investigate the long-term effects of different degrees of maternal separation (MS) on male and female rats and subsequent responsiveness to chronic unpredictable mild stress (CUMS) exposure in adults. Sprague-Dawley (SD) newborn pups were exposed to either 15 min/day of MS (MS15), 360 min/day of MS (MS360) or no separation (NS) during postnatal day (PND)4-PND10. At PND56, behavioral tasks, including sucrose preference test (SPT), forced swimming test (FST) and open field test (OFT), were used to explore depressive and anxiety-like behaviors. Then the rats received a series of CUMS for 28 days, behavioral tasks were recorded after CUMS. Prior to CUMS, the behavioral performances in male and female rats were consistent, MS360 led to increased immobile time in FST and decreased activity in OFT, while MS15 rats exhibited behavioral performances similar to NS group. After CUMS, sexual dimorphism was observed in the OFT behavioral responses to adult stress re-exposure, but no differences in FST were observed. CUMS male rats with MS360 experiences showed the worst behavioral performances in OFT compared to those of the other male rats groups, while CUMS female rats without MS experience showed the worst behavioral performances in OFT compared to those of the other female rats groups. Both CUMS male and female rats with MS15 experiences showed better trend in OFT performances than those of CUMS rats with MS360 experience and without MS experiences. These results suggest that brief MS experiences increase the OFT behavioral resilience of rats to adult stress re-exposure, and prolonged MS promotes OFT behavioral resilience of female rats to adult stress re exposure, while increases vulnerability of male rats to adult stress re-exposure. PMID- 29723594 TI - A single exercise bout augments adenovirus-specific T-cell mobilization and function. AB - Adoptive transfer of virus-specific T-cells (VSTs) effectively treats viral infections following allogeneic hematopoietic stem cell transplantation (alloHSCT), but logistical difficulties have limited widespread availability of VSTs as a post-transplant therapeutic. A single exercise bout mobilizes VSTs specific for latent herpesviruses (i.e. CMV and EBV) to peripheral blood and augments their ex vivo expansion. We investigated whether exercise exerts similar effects on T-cells specific for a NON-latent virus such as adenovirus, which is a major contributor to infection-related morbidity and mortality after alloHSCT. Thirty minutes of cycling exercise increased circulating adenovirus-specific T cells 2.0-fold and augmented their ex vivo expansion by ~33% compared to rest without altering antigen and MHC-specific autologous target cell killing capabilities. We conclude that exercise is a simple and economical adjuvant to boost the isolation and manufacture of therapeutic VSTs specific to latent and non-latent viruses from healthy donors. PMID- 29723595 TI - Cost-Effectiveness Benefits of a Disease Management Program:The REMADHE Trial Results. AB - BACKGROUND: Published studies have generated mixed, controversial results regarding the cost-effectiveness of heart failure disease management programs (HF DMPs). This study assessed the cost-effectiveness of an HF-DMP in ambulatory patients compared with usual care (UC). METHODS: In the prospective randomized REMADHE trial, we evaluated incremental costs per quality-adjusted life-year (QALY) and life-year (LY) gained as effectiveness ratios (ICERs) over a study period of 2.47 +/- 1.75 years. RESULTS: The REMADHE HF-DMP was more effective and less costly than UC in terms of both QALYs and LYs (95% and 55% chance of dominance, respectively). Average saving was US$7345 (2.5%-97.5% bootstrapped confidence interval -16,573 to +921). The chance of DMP being cost-effective at a willingness to pay US$10,000 per QALY or LY was 99% and 96%, respectively. Cost effectiveness of HF-DMP was highest in subgroups with left ventricular ejection fraction <35%, age >50 years, male sex, New York Heart Association (NYHA) functional class >=III, and ischemic etiology. The chance of DMP being cost effective at a willingness to pay US$10,000 per QALY was >=90% in all subgroups apart from NYHA functional class I-II, where it was 70%. Even when the intervention costs increased by 500% or when excluding outliers in costs, DMP had a high chance of being cost-effective (87%-99%). CONCLUSIONS: The HF-DMP of the REMADHE trial, which encompasses long-term repeated education alongside telephone monitoring, has a high probability of being cost-effective in ambulatory patients with HF. PMID- 29723597 TI - Hybrid Ear Cubes for local controlled dexamethasone delivery to the inner ear. AB - A new type of miniaturized implants for local controlled drug delivery to the inner ear is proposed: Hybrid Ear Cubes. They are composed of two main parts: (i) a cylinder, which is placed into a tiny hole (<0.4 mm) drilled into (or close to) the oval (or round) window, and (ii) a cuboid, which is placed into the middle ear. The drug is released at a pre-programmed rate into the perilymph: (i) via the cylindrical part of the implant, which is in direct contact with this liquid, and (ii) via diffusion from the cuboid through the oval/round window. Importantly, the cylindrical part assures a reliable fixation of the drug delivery system at the site of administration. Furthermore, the cuboid provides a relatively "large" drug reservoir, without expulsing perilymph from the cochlea. The required surgery is minimized compared to the placement of an intracochlear implant. In contrast to previously proposed Ear Cubes, which are mono-block systems, Hybrid Ear Cubes consist of two halves, which can: (i) be loaded with different drugs, (ii) be loaded with the same drug at different concentrations, and/or (iii) be based on two different matrix formers. This offers a substantially increased formulation flexibility. Different types of silicone based Hybrid Ear Cubes were prepared, loaded with 10% dexamethasone in one half and 0-60% dexamethasone in the other half. Importantly, tiny drug crystals were homogeneously distributed throughout the respective implant halves. The observed drug release rates were very low (e.g., <0.5% after 2 months), which can be attributed to the type of drug and silicone as well as to the very small surface area exposed to the release medium. Importantly, no noteworthy implant swelling was observed. PMID- 29723596 TI - Combination of urea-crosslinked hyaluronic acid and sodium ascorbyl phosphate for the treatment of inflammatory lung diseases: An in vitro study. AB - This in vitro study evaluated, for the first time, the safety and the biological activity of a novel urea-crosslinked hyaluronic acid component and sodium ascorbyl phosphate (HA-CL - SAP), singularly and/or in combination, intended for the treatment of inflammatory lung diseases. The aim was to understand if the combination HA-CL - SAP had an enhanced activity with respect to the combination native hyaluronic acid (HA) - SAP and the single SAP, HA and HA-CL components. Sample solutions displayed pH, osmolality and viscosity values suitable for lung delivery and showed to be not toxic on epithelial Calu-3 cells at the concentrations used in this study. The HA-CL - SAP displayed the most significant reduction in interleukin-6 (IL-6) and reactive oxygen species (ROS) levels, due to the combined action of HA-CL and SAP. Moreover, this combination showed improved cellular healing (wound closure) with respect to HA - SAP, SAP and HA, although at a lower rate than HA-CL alone. These preliminary results showed that the combination HA-CL - SAP could be suitable to reduce inflammation and oxidative stress in lung disorders like acute respiratory distress syndrome, asthma, emphysema and chronic obstructive pulmonary disease, where inflammation is prominent. PMID- 29723598 TI - The contribution of facial dynamics to subtle expression recognition in typical viewers and developmental visual agnosia. AB - Facial expressions are inherently dynamic cues that develop and change over time, unfolding their affective signal. Although facial dynamics are assumed important for emotion recognition, testing often involves intense and stereotypical expressions and little is known about the role of temporal information in the recognition of subtle, non-stereotypical expressions. In Experiment 1 we demonstrate that facial dynamics are critical for recognizing subtle and non stereotypical facial expressions, but not for recognizing intense and stereotypical displays of emotion. In Experiment 2 we further examined whether the facilitative effect of motion can lead to improved emotion recognition in LG, an individual with developmental visual agnosia and prosopagnosia, who has poor emotion recognition when tested with static facial expressions. LG's emotion recognition improved when subtle, non-stereotypical faces were dynamic rather than static. However, compared to controls, his relative gain from temporal information was diminished. Furthermore, LG's eye-tracking data demonstrated atypical visual scanning of the dynamic faces, consisting of longer fixations and lower fixation rates for the dynamic-subtle facial expressions, comparing to the dynamic-intense facial expressions. We suggest that deciphering subtle dynamic expressions strongly relies on integrating broad facial regions across time, rather than focusing on local emotional cues, skills which are impaired in developmental visual agnosia. PMID- 29723599 TI - Adaptive control and the avoidance of cognitive control demands across development. AB - Young adults adaptively coordinate their behavior to avoid demands placed on cognitive control. We investigated how this adaptive coordination develops by having 6-7- and 11-12-year-olds and young adults complete a demand selection task, in which participants could select between two tasks that varied in cognitive control demands via differences in rule switch frequency. Adults and older children exhibited significant preference for selecting the less demanding task, as well as a metacognitive signal guiding adaptive demand avoidance behavior across a variety of behavioral and self-report assessments. In contrast, despite evidence of differential demands on cognitive control, younger children did not coordinate their task selections to avoid higher demand. Together, these findings suggest that sensitivity and adaptive responses to control demands emerge with development and are consistent with gradual development of lateral prefrontal cortex, dorsal anterior cingulate cortex, and their functional connectivity, which support effort avoidance in adults. PMID- 29723600 TI - Cognitive training with action-related verbs induces neural plasticity in the action representation system as assessed by gray matter brain morphometry. AB - Embodied cognition theories of semantic memory still face the need for multiple sources of converging evidence in support of the involvement of sensory-motor systems in action-related knowledge. Previous studies showed that training manual actions improves semantic processing of verbs referring to the trained actions. The present work aimed to provide complementary evidence by measuring the brain plasticity effects of a cognitive training requiring sustained lexical-semantic processing of action-related verbs. We included two groups of participants, namely the Proximal Group (PG) and the Distal Group (DG), which underwent a 3 week training with verbs referring to actions involving the proximal and the distal upper limb musculature, respectively. Before and after training, we measured gray matter voxel brain morphometry based on T1 structural magnetic resonance imaging. By means of this 2 (Group: PG, DG) * 2 (Time: pre-, post training) factorial design, we tested whether sustained cognitive experience with specific action-related verbs induces congruent brain plasticity modifications in target regions of interest pertaining to the action representation system. We found significant post- versus pre-training gray matter volume increases, specifically for PG in the left dorsal precentral gyrus, and for DG in the right cerebellar lobule VIIa. These preliminary results suggest that a cognitive training can induce structural plasticity modifications in brain regions specifically coding for the distal and proximal motor actions the trained verbs refer to. PMID- 29723601 TI - Clinical utility of EZH1 mutations in the diagnosis of follicular-patterned thyroid tumors. AB - Follicular-patterned tumors of the thyroid gland are characterized by a predominantly follicular growth pattern. They frequently harbor RAS mutations, not BRAF mutations. Technological advances in molecular testing have discovered novel RAS-type mutations. However, clinical significance of these mutations remains unknown. We investigated the prevalence and clinical impact of mutations of BRAF, NRAS, HRAS, KRAS, EZH1, EIF1AX, and TERT genes by Sanger sequencing in a series of 201 follicular-patterned thyroid tumors including follicular adenoma (n = 40), Hurthle cell adenoma (n = 54), noninvasive follicular thyroid neoplasms with papillary-like nuclear features (n = 50), follicular thyroid carcinoma (n = 40), Hurthle cell carcinoma (n = 10), and poorly differentiated thyroid carcinoma arising in a well-differentiated follicular neoplasm (n = 7), and 120 classic papillary carcinoma. Two hotspots of EZH1 mutations were only found in RAS negative follicular-patterned tumors. EZH1 mutations were detected in 3% of follicular adenoma and in 20% of Hurthle cell adenoma, and one minimally invasive Hurthle cell carcinoma. Thyroid tumors with EZH1 mutations reported in the literature were benign in most cases. Otherwise, they were minimally invasive or noninvasive cancer. EIF1AX mutation was found in one follicular adenoma. We confirmed the presence of RAS mutations and BRAF K601E mutation in benign, borderline, and malignant follicular-patterned tumors. No BRAF V600E was found in all follicular-patterned tumors. This study also confirmed the occurrence of TERT promoter mutations in high-risk thyroid cancers. These genetic markers can be used for the diagnostic purpose and risk stratification of thyroid nodules. PMID- 29723602 TI - Non-small cell lung cancers with isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations. AB - Isocitrate dehydrogenases 1 and 2 (IDH1/2) are important metabolic enzymes that convert isocitrate to alpha-ketoglutarate. IDH1/2 mutations are associated with the development of multiple malignancies. In this study, we examine the prevalence and features of non-small cell lung cancers (NSCLC) with IDH1/2 mutations. From May 2013 to March 2017, 800 lung cancer samples were successfully sequenced for somatic mutations on the Ion Torrent PGM with the 50-gene AmpliSeq Cancer Hotspot Panel v2 on the Ion Torrent PGM (318 chip). Variants were identified using the Ion Torrent Variant Caller Plugin and reference genome hg19. Golden Helix's SVS software was used for variant annotation and prediction of significance. Nine samples (1.1%) from 8 patients harbored an IDH1 (3 p.R132C and 2 p.R132L) or IDH2 mutation (p.R140W, p.R172S, and p.R172T). All patients' tumors had adenocarcinoma histology, and all patients had a smoking history. Eighty eight percent of patients' tumors had a coexisting KRAS mutation and 6 of 8 were diagnosed at greater than 70 years of age. Five patients presented with stage IV disease and 3 with stage I. After comparison to a cohort of KRAS-mutated NSCLC with a history of smoking, IDH-mutated cases were significantly older but presented with similar rates of advanced-stage disease and sex distribution. Additional studies are needed to understand the role of IDH1/2 mutations in the development of NSCLC, but such patients who have poor prognostic indicators (KRAS mutation and advanced stage at presentation) may benefit from IDH1/2-directed therapies. PMID- 29723603 TI - Histology of colorectal adenocarcinoma with double somatic mismatch-repair mutations is indistinguishable from those caused by Lynch syndrome. AB - Lynch syndrome (LS) is the most common form of hereditary colon cancer. Germline mutations in the mismatch-repair (MMR) genes MLH1, MSH2 (EPCAM), MSH6, and PMS2, followed by a second hit to the remaining allele, lead to cancer development. Universal tumor screening for LS is routinely performed on colon cancer, and screening has identified patients with unexplained MMR deficiency that lack MLH1 methylation and a germline mutation. Tumor sequencing has since identified double somatic (DS) mutations in the MMR gene corresponding with the absent protein in 69% of these patients. We assessed whether histomorphology could distinguish patients with DS mutations from those with LS. Colorectal cancer patients with DS mutations were identified from population-based cohorts from Iceland (2000-2009); Columbus, Ohio (1999-2005); and the state of Ohio (2013-2016). Next-generation sequencing was performed on tumors with unexplained MMR deficiency. Patients with LS from Ohio cohorts were the comparison group. The histologic features associated with MMR deficiency (tumor-infiltrating lymphocytes, Crohn-like reaction, histologic subtype, necrosis) were evaluated. We identified 43 tumors with DS mutations and 48 from patients with LS. There was no significant difference in histologic features between tumors in LS patients and tumors with DS mutations. Because histology of tumors with DS mutations is indistinguishable from those caused by LS, tumor sequencing for evaluation of DS mutations should be considered to help clarify sporadic versus hereditary causes of unexplained MMR deficiency. PMID- 29723604 TI - Frozen section evaluation via dynamic real-time nonrobotic telepathology system in a university cancer center by resident/faculty cooperation team. AB - Frozen section telepathology interpretation experience has been largely limited to practices with locations significantly distant from one another with sporadic need for frozen section diagnosis. In 2010, we established a real-time nonrobotic telepathology system in a very active cancer center for daily frozen section service. Herein, we evaluate its accuracy compared to direct microscopic interpretation performed in the main hospital by the same faculty and its cost efficiency over a 1-year period. From 643 (1,416 parts) cases requiring intraoperative consultation, 333 cases (690 parts) were examined by telepathology and 310 cases (726 parts) by direct microscopy. Corresponding discrepancy rates were 2.6% (18 cases: 6 [0.9%] sampling and 12 [1.7%] diagnostic errors) and 3.2% (23 cases: 8 [1.1%] sampling and 15 [2.1%] diagnostic errors), P = .63. The sensitivity and specificity of intraoperative frozen diagnosis were 0.92 and 0.99, respectively, in telepathology and 0.90 and 0.99, respectively, in direct microscopy. There was no correlation of error incidence with postgraduate year level of residents involved in the telepathology service. Cost analysis indicated that the time saved by telepathology was $19,691.00 over 1 year of the study period, whereas the capital cost for establishing the system was $8,924.00. Thus, real-time nonrobotic telepathology is a reliable and easy-to-use tool for frozen section evaluation in busy clinical settings, especially when frozen section service involves more than one hospital, and it is cost-efficient when travel is a component of the service. PMID- 29723605 TI - Crosstalk between presynaptic trafficking and autophagy in Parkinson's disease. AB - Parkinson's disease (PD) is a debilitating neurodegenerative disorder that profoundly affects one's motor functions. The disease is characterized pathologically by denervation of dopaminergic (DAergic) nigrostriatal terminal and degeneration of DAergic neurons in the substantia nigra par compacta (SNpc); however, the precise molecular mechanism underlying disease pathogenesis remains poorly understood. Animal studies in both toxin-induced and genetic PD models suggest that presynaptic impairments may underlie the early stage of DA depletion and neurodegeneration (reviewed in Schirinzi, T., et al. 2016). Supporting this notion, human genetic studies and genomic analysis have identified an increasing number of PD risk variants that are associated with synaptic vesicle (SV) trafficking, regulation of synaptic function and autophagy/lysosomal system (Chang, D., et al. 2017, reviewed in Trinh, J. & Farrer, M. 2013; Singleton, A.B., et al. 2013). Although the precise mechanism for autophagy regulation in neurons is currently unclear, many studies demonstrate that autophagosomes form at the presynaptic terminal (Maday, S. & Holzbaur, E.L. 2014; Vanhauwaert, R., et al. 2017; reviewed in Yue, Z. 2007). Growing evidence has revealed overlapping genes involved in both SV recycling and autophagy, suggesting that the two membrane trafficking processes are inter-connected. Here we will review emergent evidence linking SV endocytic genes and autophagy genes at the presynaptic terminal. We will discuss their potential relevance to PD pathogenesis. PMID- 29723606 TI - Salidroside mediated stabilization of Bcl -xL prevents mitophagy in CA3 hippocampal neurons during hypoxia. AB - Chronic hypoxic stress results in deposition of lipofuscin granules in the CA3 region of hippocampal neurons which contributes to neurodegeneration and accelerated neuronal aging. Oxidative stress and mitophagy during hypoxia are crucial to cause aggregation of these lipofuscin granules in hypoxic neurons. Salidroside, a glucoside derivative of beta-Tyrosol, has been reported to protect hypoxic neurons through maintenance of mitochondrial activity. The present study is aimed at investigating the potential of Salidroside in preventing mitophagy during chronic hypoxia and identification of the molecular targets and underlying signaling mechanisms. In-silico analysis for interaction of salidroside with Bcl xL was carried out using VLife MDS software. The prophylactic efficacy of Salidroside for amelioration of global hypoxia induced neuronal aging was studied in adult male Sprague-Dawley rats exposed to hypobaric hypoxia simulating an altitude of 7600 m for 21 days. Salidroside was supplemented at a daily dose of 25 mg kg-1b.w. p.o. during hypoxic exposure. Ultra-structural and immune histological studies were conducted to study lipofuscin aggregation and mitophagy. In-silico findings on salidroside mediated stabilization of Bcl-xL were validated by investigating its effect on downstream signaling molecules involved in mitophagy. Administration of Salidroside reduced deposition of lipofuscin in hypoxic CA3 hippocampal neurons and prevented mitophagy. Salidroside stabilizes Bcl-xL in hypoxic neurons resulting in inhibition of PGAM5 phosphatase activity and maintenance of FUNDC1 in phosphorylated state. Salidroside mediated inhibition of pFUNDC1 dephosphorylation prevents FUNDC1-LC3 II interaction which is crucial for mitophagy. The present study demonstrates potential of Salidroside in preventing lipofuscin deposition during chronic hypoxic stress. PMID- 29723607 TI - Predicting neurologically intact survival after in-hospital cardiac arrest external validation of the Good Outcome Following Attempted Resuscitation score. AB - BACKGROUND: A do-not-attempt-resuscitation order is issued when it is against the wishes of the patient that cardiopulmonary resuscitation is performed, or when the chance of good quality survival is minimal. Therefore it is essential for physicians to make an objective prearrest prediction of the outcome after an in hospital cardiac arrest (IHCA). Our aim was external validation of the Good Outcome Following Attempted Resuscitation (GO-FAR) score in a population based setting. METHODS: The study was based on a retrospective cohort of adult IHCAs in Stockholm County 2013-2014 identified through the Swedish Cardiopulmonary Resuscitation Registry. This registry provided patient and event characteristics and neurological outcome at discharge. Neurologically intact survival is defined as Cerebral Performance Category score (CPC) 1 at discharge. Data for the GO-FAR variables was obtained from manual review of electronic patient records. Model performance was evaluated by measure of discrimination with the area under the receiver operating curve (AUROC) and calibration with assessment of the calibration plot. RESULTS: The cohort included 717 patients with neurologically intact survival at discharge of 22%. In complete case analysis (523 cases) AUROC was 0.82 (95% CI 0.78-0.86) indicating good discrimination. The calibration plot showed that the GO-FAR score systematically underestimates the probability of neurologically intact survival. CONCLUSION: The GO-FAR score has satisfactory discrimination, but assessment of the calibration shows that neurologically intact survival is systematically underestimated. Therefore, only with caution should it without model update be taken into clinical practice in settings similar to ours. PMID- 29723608 TI - Osborn waves following out-of-hospital cardiac arrest-Effect of level of temperature management and risk of arrhythmia and death. AB - BACKGROUND: The Osborn or J-wave, an upright deflection of the J-point on the electrocardiogram (ECG), is often observed during severe hypothermia. A possible relation between Osborn waves (OW) and increased risk of ventricular arrhythmia has been reported. We sought to determine whether the level of targeted temperature management (TTM) following out-of-hospital cardiac arrest (OHCA) affects the prevalence of OW and to assess the associations between OW and risk of ventricular arrhythmia and death. METHODS AND RESULTS: The present study is part of the TTM-trial ECG-substudy (including OHCA-patients randomized to TTM at 33 degrees C vs. 36 degrees C from 24 of 36 sites). Serial 12-lead ECGs from 680 (94%) patients were analysed and stratified by OW at predefined time-points (0, 4, 28, 36, 72-h after admission). On admission, the overall prevalence of OW was 16%, increasing to 32% at target temperature, with higher prevalence in the 33 degrees C-group (40% vs. 23%, p < 0.0001). No difference in prevalence was found between the 33 degrees C- and 36 degrees C-groups on admission (18% vs. 14%, p = .11) or after rewarming (13% vs. 10%, p = .44). OW were not associated with increased risk of ventricular arrhythmia (Odds ratio = 0.78 (0.51-1.20), p = .26), but associated with significantly lower 180-day mortality as compared to no OW (38% vs. 52%, plog-rank = 0.001) in univariable analyses only. CONCLUSION: OW are frequent during TTM, particularly in patients treated with 33 degrees C. OW are not associated with increased risk of ventricular arrhythmia, and may be considered a benign physiological phenomenon, associated with lower mortality in univariable analyses. PMID- 29723609 TI - Advanced vs. Basic Life Support in the Treatment of Out-of-Hospital Cardiopulmonary Arrest in the Resuscitation Outcomes Consortium. AB - BACKGROUND: Prior observational studies suggest no additional benefit from advanced life support (ALS) when compared with providing basic life support (BLS) for patients with out-of-hospital cardiac arrest (OHCA). We compared the association of ALS care with OHCA outcomes using prospective clinical data from the Resuscitation Outcomes Consortium (ROC). METHODS: Included were consecutive adults OHCA treated by participating emergency medical services (EMS) agencies between June 1, 2011, and June 30, 2015. We defined BLS as receipt of cardiopulmonary resuscitation (CPR) and/or automated defibrillation and ALS as receipt of an advanced airway, manual defibrillation, or intravenous drug therapy. We compared outcomes among patients receiving: 1) BLS-only; 2) BLS + late ALS; 3) BLS + early ALS; and 4) ALS-first care. Using multivariable logistic regression, we evaluated the associations between level of care and return of spontaneous circulation (ROSC), survival to hospital discharge, and survival with good functional status, adjusting for age, sex, witnessed arrest, bystander CPR, shockable initial rhythm, public location, EMS response time, CPR quality, and ROC site. RESULTS: Among 35,065 patients with OHCA, characteristics were median age 68 years (IQR 56-80), male 63.9%, witnessed arrest 43.8%, bystander CPR 50.6%, and shockable initial rhythm 24.2%. Care delivered was: 4.0% BLS-only, 31.5% BLS + late ALS, 17.2% BLS + early ALS, and 47.3% ALS-first. ALS care with or without initial BLS care was independently associated with increased adjusted ROSC and survival to hospital discharge unless delivered greater than 6 min after BLS arrival (BLS + late ALS). Regardless of when it was delivered, ALS care was not associated with significantly greater functional outcome. CONCLUSION: ALS care was associated with survival to hospital discharge when provided initially or within six minutes of BLS arrival. ALS care, with or without initial BLS care, was associated with increased ROSC, however it was not associated with functional outcome. PMID- 29723611 TI - Effective treatment of the primary tumor and lymph node metastasis by polymeric micelles with variable particle sizes. AB - Nanoparticles (NPs) offer new solutions for the diagnosis and treatment of tumors. However, the anti-tumor effect has not been greatly improved. Tumors are easily spread through the lymphatic system while the traditional NPs (~100 nm) can hardly reach lymph nodes for the treatment of metastasis. In addition, the NPs with fixed particle size cannot achieve efficient "penetration" and long-term "retention" simultaneously. Herein, we established "transformable" micelles modified with azide/alkyne groups for click chemical reaction. Not surprisingly, the small micelles (~25 nm) could effectively target lymph nodes, limiting the growth of the metastases associated with their size-regulated abilities to extravasate from the vasculature. Tumor lymph node metastasis dropped by 66.7%. After reaching primary tumors, cycloaddition reaction occurred between groups on micelles, resulting in the formation of aggregates. The strategy resulted in improved retention of the micelles in 4 T1 cells both in vitro and in vivo owing to the decreasing of nanoparticle exocytosis and minimizing the backflow to the bloodstream. Enhanced cytotoxicity on 4 T1 cells and improved antitumor efficacy were also observed. S-PTX (+) exhibited 76.23% tumor suppression, and tumor mass at the end of the treatment also showed the best tumor inhibitory effect. In conclusion, this drug delivery system provides a strategy for effective treatment of the primary tumor and lymphatic metastasis. PMID- 29723612 TI - Ignoring the modeling approaches: Towards the shadowy paths in nanomedicine. AB - Limited efficiency of the conventional therapeutic options against a variety of diseases has provoked nanotech-based research efforts to develop advanced materials and devices for targeted delivery of theranostics which may provide imminent breakthroughs in medicine. However, nonspecific distribution or inappropriate tissue penetration of nanoparticles, complexity of drug delivery process, insufficient drug accumulation, loss of targeting ability, occurrence of the unexpected phenomena, safety concerns, and data reliability have remained challenging. Indeed, translation of nanotechnology-based products to the clinical applications necessitates the rigorous consideration of the challenging issues associated with currently available nanoformulations. Computational models and simulations which enable to design the nanoparticles with optimized properties along with method validation, provide fundamental knowledge about the complex interaction of nanomaterials with environmental or biological systems, and predict the pharmacological profile of nanomaterials, should constitute a key part of the innovative drug delivery research leading to the maximal efficacy and minimal safety concerns. This review highlights the importance of computational modeling in the development of efficient nanotherapeutic delivery systems. PMID- 29723610 TI - Repurposing rosiglitazone, a PPAR-gamma agonist and oral antidiabetic, as an inhaled formulation, for the treatment of PAH. AB - Peroxisome-proliferator-activated-receptor-gamma (PPAR-gamma) is implicated, in some capacity, in the pathogenesis of pulmonary arterial hypertension (PAH). Rosiglitazone, an oral antidiabetic and PPAR-gamma agonist, has the potential to dilate pulmonary arteries and to attenuate arterial remodeling in PAH. Here, we sought to test the hypothesis that rosiglitazone can be repurposed as inhaled formulation for the treatment of PAH. We have tested this conjecture by preparing and optimizing poly(lactic-co-glycolic) acid (PLGA) based particles of rosiglitazone, assessing the drug particles for pulmonary absorption, investigating the efficacy of the plain versus particulate drug formulation in improving the respiratory hemodynamics in PAH animals, and finally studying the effect of the drug in regulating the molecular markers associated with PAH pathogenesis. The optimized particles were slightly porous and spherical, and released 87.9% +/- 6.7% of the drug in 24 h. The elimination half-life of the drug formulated in PLGA particles was 2.5-fold greater than that of the plain drug administered via the same route at the same dose. The optimized formulation, given via the pulmonary route, produced pulmonary selective vasodilation in PAH animals, but oral rosiglitazone had no effect in pulmonary hemodynamics. Rosiglitazone ameliorates the pathogenesis of PAH by balancing the molecular regulators involved in the vasoconstriction and vasodilation of human pulmonary arterial smooth muscle cells. All in all, data generated using intact animal and cellular models point to the conclusion that PLGA particles of an antidiabetic drug can be used for the treatment of a different disease, PAH. PMID- 29723613 TI - CD44 targeting biocompatible and biodegradable hyaluronic acid cross-linked zein nanogels for curcumin delivery to cancer cells: In vitro and in vivo evaluation. AB - In this study, we developed novel hyaluronic acid cross-linked zein nanogels (HA Zein NGs) to deliver the potential anticancer agent curcumin (CRC), a naturally occurring phytochemical drug in cancer cells. In vitro studies showed that they are highly compatible with the tested cell lines. They showed CD44 specific uptake in CT26 cell line more than by the CD44 receptor pre-inhibited CT26 cells. The CRC encapsulated HA-Zein NGs (HA-Zein-CRC NGs) found to exert a specific toxicity against CT26 sparing healthy normal fibroblast cells in vitro. The apoptotic effects were further confirmed with flow cytometry showing that the HA Zein-CRC NGs exhibited high anticancer activity against the CT26 cells. The in vivo bio-distribution with a CT26 tumor model showed their high tumor accumulation thereby improved antitumor efficacy with a low dosage of CRC, compared to the previous reports. Thus, the preclinical studies clearly showed that these novel HA-Zein NGs would be highly beneficial in encapsulating hydrophobic drugs with improved pharmacokinetics thereby enhancing the therapeutic outcomes. PMID- 29723614 TI - The effect of jet speed on large volume jet injection. AB - Jet injection presents a promising alternative to needle and syringe injection for transdermal drug delivery. The controllability of recently-developed jet injection devices now allows jet speed to be modulated during delivery, and has enabled efficient and accurate delivery of volumes up to 0.3 mL. However, recent attempts to inject larger volumes of up to 1 mL using the same methods have highlighted the different requirements for successful delivery at these larger volumes. This study aims to establish the jet speed requirements for delivery of 1 mL of liquid using a controllable, voice coil driven injection device. Additionally, the effectiveness of a two-phase jet speed profile is explored (where jet speed is deliberately decreased toward the end of the injection) and compared to the constant jet speed case. A controllable jet injection device was developed to deliver volumes of 1 mL of liquid at jet speeds >140 m/s. This device was used to deliver a series of injections into post-mortem porcine tissue in single and two-phase jet speed profiles. Single-phase injections were performed over the range 80 m/s to 140 m/s. Consistent delivery success (>80% of the liquid delivered) was observed at a jet speed of 130 m/s or greater. Consistent penetration into the muscle layer coincided with delivery success. Two phase injections of 1 mL were performed with a first phase volume of 0.15 mL, delivered at 140 m/s, while the injection of the remainder of fluid was delivered at a second phase speed that was varied over the range 60 m/s to 120 m/s. Ten two phase injections were performed with a second phase speed of 100 m/s producing a mean delivery volume of 0.8 mL +/- 0.2 mL, while the single-phase injections at 100 m/s achieved a mean delivery volume of 0.4 mL +/- 0.3 mL. These results demonstrate that a reduced jet speed can be used in the later stages of a 1 mL injection to achieve delivery success at a reduced energy cost. We found that a jet speed approaching 100 m/s was required following initial penetration to successfully deliver 1 mL, whereas speeds as low as 50 m/s have been used for volumes of <0.3 mL. These findings provide valuable insight into the effect of injection volume and speed on delivery success; this information is particularly useful for devices that have the ability to vary jet speed during drug delivery. PMID- 29723615 TI - Streptavidin-mirror DNA tetrahedron hybrid as a platform for intracellular and tumor delivery of enzymes. AB - Despite the extremely high substrate specificity and catalytically amplified activity of enzymes, the lack of efficient cellular internalization limits their application as therapeutics. To overcome this limitation and to harness enzymes as practical biologics for targeting intracellular functions, we developed the streptavidin-mirror DNA tetrahedron hybrid as a platform for intracellular delivery of various enzymes. The hybrid consists of streptavidin, which provides a stoichiometrically controlled loading site for the enzyme cargo and an L-DNA (mirror DNA) tetrahedron, which provides the intracellular delivery potential. Due to the cell-penetrating ability of the mirror DNA tetrahedron of this hybrid, enzymes loaded on streptavidin can be efficiently delivered into the cells, intracellularly expressing their activity. In addition, we demonstrate tumor delivery of enzymes in an animal model by utilizing the potential of the hybrid to accumulate in tumors. Strikingly, the hybrid is able to transfer the apoptotic enzyme specifically into tumor cells, leading to strong suppression of tumor growth without causing significant damage to other tissues. These results suggest that the hybrid may allow anti-proliferative enzymes and proteins to be utilized as anticancer drugs. PMID- 29723616 TI - Image-guided thermosensitive liposomes for focused ultrasound drug delivery: Using NIRF-labelled lipids and topotecan to visualise the effects of hyperthermia in tumours. AB - Image guided drug delivery using imageable thermosensitive liposomes (iTSLs) and high intensity focused ultrasound (FUS or HIFU) has attracted interest as a novel and non-invasive route to targeted delivery of anti-cancer therapeutics. FUS induced hyperthermia is used as an externally applied "trigger" for the release of a drug cargo from within thermosensitive drug carriers. It is suggested that sub-ablative hyperthermia significantly modifies the permeability of tumour vasculature and enhances nanoparticle uptake. Here we describe the preparation and use of magnetic resonance imaging (MRI) and near infrared fluorescence (NIRF) labelled thermosensitive liposomes for imaging and tracking of biodistribution and drug release in a murine cancer model. We prepared iTSLs to encapsulate topotecan (Hycamtin(r)), a chemotherapeutic agent which when released in tumours can be monitored by an increase in its intrinsic drug fluorescence. FUS was applied using feedback via subcutaneously placed fine-wire thermocouples to maintain and monitor hyperthermic temperatures. iTSL accumulation was detected within tumours using NIRF imaging immediately after liposome administration. Mild FUS-induced hyperthermia (3 min at 42 degrees C, 30 min post i.v. administration) greatly enhanced iTSLs uptake. A co-localised enhancement of topotecan fluorescence emission was also observed immediately after application of FUS indicating rapid triggered drug release. The phenomena of increased iTSL accumulation and concomitant topotecan release appeared to be amplified by a second mild hyperthermia treatment applied one hour after the first. MRI in vivo also confirmed enhanced iTSLs uptake due to the FUS treatments. Our imaging results indicate the effects of hyperthermia on the uptake of carriers and drug. FUS-induced hyperthermia combined with real time imaging could be used as a tool for tumour targeted drug delivery. PMID- 29723617 TI - CD14+ monocytes contribute to inflammation in chronic nonbacterial osteomyelitis (CNO) through increased NLRP3 inflammasome expression. AB - The pathophysiology of chronic nonbacterial osteomyelitis (CNO) remains incompletely understood. Increased NLRP3 inflammasome activation and IL-1beta release in monocytes from CNO patients was suggested to contribute to bone inflammation. Here, we dissect immune cell infiltrates and demonstrate the involvement of monocytes across disease stages. Differences in cell density and immune cell composition may help to discriminate between BOM and CNO. However, differences are subtle and infiltrates vary in CNO. In contrast to other cells involved, monocytes are a stable element during all stages of CNO, which makes them a promising candidate in the search for "drivers" of inflammation. Furthermore, we link increased expression of inflammasome components NLRP3 and ASC in monocytes with site-specific DNA hypomethylation around the corresponding genes NLRP3 and PYCARD. Our observations deliver further evidence for the involvement of pro-inflammatory monocytes in the pathophysiology of CNO. Cellular and molecular alterations may serve as disease biomarkers and/or therapeutic targets. PMID- 29723618 TI - Adiponectin gene polymorphisms and obesity increase the susceptibility to arsenic related renal cell carcinoma. AB - Our recent study found that high urinary total arsenic levels were associated with renal cell carcinoma (RCC). Recent studies demonstrated that low circulating adiponectin was related to RCC. The aim of the present study was to explore the relationship between adiponectin gene (ADIPOQ) polymorphisms and RCC and investigate whether individuals with an ADIPOQ risk genotype, obesity, and high urinary total arsenic levels have a modified odds ratio (OR) of RCC. A total of 389 RCC patients and 389 age- and sex-matched controls were recruited between November 2006 and December 2012 in Taiwan. Image-guided biopsy or surgical resection of renal tumors was performed to pathologically verify RCC. Genomic DNA was used to examine the genotypes of the ADIPOQ rs182052, ADIPOQ rs2241766, ADIPOQ rs1501299, and ADIPOQ rs1063539 SNPs by PCR-RFLP. HPLC-HG-AAS was used to measure the concentrations of urinary arsenic species. Participants with the ADIPOQ rs182052 G/A+A/A genotype had a significantly higher OR of RCC compared with those with the ADIPOQ rs182052 G/G genotype. The OR (95% confidence interval [CI]) was 1.70 (1.23-2.36). The OR of RCC for the combined effect of high urinary total arsenic levels and obesity, which was dose-dependent, in individuals with the ADIPOQ rs182052 G/A+A/A genotype was 9.33 (3.85-22.62). The present study found significant combined effects of obesity and the ADIPOQ rs182052 G/A+A/A genotype on the arsenic-related risk of RCC in a population with low arsenic exposure. Arsenic exposure, obesity, and the ADIPOQ rs182052 polymorphism could be predictors of a higher OR of RCC. PMID- 29723619 TI - Carboxymethyl Assam Bora rice starch coated SPIONs: Synthesis, characterization and in vitro localization in a micro capillary for simulating a targeted drug delivery system. AB - Carboxymethyl Assam Bora rice starch coated superparamagnetic iron oxide nanoparticles (CM-ABRS SPIONs) were chemically synthesized by co-precipitation method and particle size reduction was controlled by high energy homogenization process. Effects of various process variables (polymer concentration, homogenization speed and cycles) were optimized on the basis of average particle size (Z-average) and polydispersity index (PDI) of CM-ABRS SPIONs. The optimized CM-ABRS SPIONs were characterized for their particle size, surface morphology, electrokinetic potential, chemical interactions, crystallinity, magnetic properties, and targeting potential in presence of external magnetic field. In vitro localization of CM-ABRS SPIONs in a suspension of FITC (Fluorescein isothiocyanate) labeled RBCs (Red blood cells; hematocrit value; 45% (v/v)) was conducted inside a square glass capillary (500 * 500 MUm2 cross section) in the presence of an externally applied magnetic field (Ms = 150 mT), simulating the case of magnetic drug targeting (MDT) approach. The aggregation dynamics of CM ABRS SPIONs inside a micro capillary was observed with respect to time (t = 0 to 600 s), which shows proportionality to time of exposure to the externally applied magnetic field. This in vitro study acts as an important platform for design and optimization of active targeted drug delivery system. PMID- 29723621 TI - Novel bionanocomposite materials used for packaging skimmed milk acid coagulated cheese (Karish). AB - Bionanocomposites have attracted a tremendous level of consideration as alternatives for a broad group of commercial materials based on petroleum-derived compounds and used for coating cheese. Sustainable, economical and environmentally compatible materials based on chitosan (CS), poly vinyl alcohol (PVA), glycerol (Gy) and titanium dioxide nanoparticles (TiO2-NPs) were prepared. Moreover, the prepared bionanocomposites (CS/PVA/Gy/TiO2-NPs) were characterized using XRD, SEM, TEM, WVTR and mechanical strength. The developed CS/PVA/Gy/TiO2 NPs bionanocomposites exhibited homogeneous, compact morphological features and enhanced mechanical and barrier properties. Also, the prepared bionanocomposite exhibited variable inhibitory effects against several pathogenic bacteria and fungi. Karish was made and coated with the prepared bionanocomposite containing 1, 2 and 3% TiO2-NPs, and cold stored. Changes in the weight losses, cheese composition, microbiological quality, textural parameters, and sensory properties were followed during storage for 25 days. Coated Karish cheese retained acceptable quality until the end of the storage period, while uncoated developed surface fungi growth and deteriorated quality after 15 days. Karish cheese coated with the bionanocomposite containing 3% TiO2-NPs ranked the highest acceptability at the end of storage period. PMID- 29723620 TI - Structural characterization of a pectin-type polysaccharide from Curcuma kwangsiensis and its effects on reversing MDSC-mediated T cell suppression. AB - Myeloid-derived suppressor cells (MDSCs) accumulate in tumor-bearing hosts and play a major role in tumor-induced immunosuppression. The potent modulatory effects of polysaccharides on the innate and adaptive immune system stimulate antitumor responses. In this study, a polysaccharide with an apparent molecular weight of 14.0 kD was isolated from Curcuma kwangsiensis and designated as CKAP 2. The polysaccharide was characterized through high-performance gel permeation chromatography, chemical derivative analyses, GC-MS, FT-IR, and NMR. Results revealed that CKAP-2 is a highly methyl-esterified pectin-type polysaccharide. It is predominantly composed of a homogalacturonan region and small amounts of type I rhamonogalacturonan regions. Its degree of methyl-esterification is approximately 62.4%. The effect of CKAP-2 on MDSC-medicated immunosuppression was primarily tested. CKAP-2 recovered the MSC2-supressed proliferation of CD4+ and CD8+ T-cells. This finding suggested that CKAP-2 can reverse MDSC-mediated T-cell suppression and that CKAP-2 can be potentially applied in antitumor therapy. PMID- 29723622 TI - Purification and characterization of a novel GH1 beta-glucosidase from Jeotgalibacillus malaysiensis. AB - Beta-glucosidase (BGL) is an important industrial enzyme for food, waste and biofuel processing. Jeotgalibacillus is an understudied halophilic genus, and no beta-glucosidase from this genus has been reported. A novel beta-glucosidase gene (1344 bp) from J. malaysiensis DSM 28777T was cloned and expressed in E. coli. The recombinant protein, referred to as BglD5, consists of a total 447 amino acids. BglD5 purified using a Ni-NTA column has an apparent molecular mass of 52 kDa. It achieved the highest activity at pH 7 and 65 degrees C. The activity and stability were increased when CaCl2 was supplemented to the enzyme. The enzyme efficiently hydrolyzed salicin and (1 -> 4)-beta-glycosidic linkages such as in cellobiose, cellotriose, cellotetraose, cellopentose, and cellohexanose. Similar to many BGLs, BglD5 was not active towards polysaccharides such as Avicel, carboxymethyl cellulose, Sigmacell cellulose 101, alpha-cellulose and xylan. When BglD5 blended with Cellic(r) Ctec2, the total sugars saccharified from oil palm empty fruit bunches (OPEFB) was enhanced by 4.5%. Based on sequence signatures and tree analyses, BglD5 belongs to the Glycoside Hydrolase family 1. This enzyme is a novel beta-glucosidase attributable to its relatively low sequence similarity with currently known beta-glucosidases, where the closest characterized enzyme is the DT-Bgl from Anoxybacillus sp. DT3-1. PMID- 29723623 TI - Chitosan coated PLGA nanoparticles amplify the ocular hypotensive effect of forskolin: Statistical design, characterization and in vivo studies. AB - PURPOSE: Enhancing the ocular hypotensive effect of forskolin (FK) by means of biodegradable chitosan (CS) coated poly lactic-co-glycolic acid (PLGA) nanoparticles (NP's). METHODS: One step emulsion-sonication process was employed for the formulation of CS-PLGA NP's with optimization being carried out by employing a four factor four level Box Behnken Design. The physical and spectral characterization, drug release, permeation, confocal and ocular tolerance studies (ex-vivo &in vivo) were performed. The corneal retention was assessed by gamma scintigraphic analysis and dexamethasone induced glaucamotous rabbit's intraocular pressure (IOP) was measured by means of Schiotz tonometer. RESULTS AND DISCUSSION: Particle size of optimized CS-PLGA NP's was found as 201.56 +/- 10.92 nm with a good PDI and positive zeta potential value. Entrapment efficiency and drug loading were found to be 72.32 +/- 1.12% and 28.39 +/- 1.67% respectively. Spectral characterization confirmed the purity and encapsulation of the drug within polymeric system. Sustained drug release and enhanced permeation profile was observed with maximum depth penetration. Ocular tolerance studies explicated its safe use. Scintigraphy studies indicated longer retention of CS PLGA NP's while increased effectiveness after single instillation in reducing the intraocular pressure was observed. CONCLUSION: CS-PLGA-NP's could be successfully formulated and are an excellent vehicle for FK in ocular delivery. PMID- 29723624 TI - Localization of MIF-II on mammalian spermatozoa: A study revealing its structure, function and motility inhibitory pathway. AB - Motility of spermatozoa is a crucial factor for determining semen quality. Here we report motility inhibitory factor (MIF-II) from goat epididymal plasma, revealing its structure, function, localization and motility inhibitory pathway. Structural characterization with MALDI revealed novelty of this protein while circular dichroism data confirmed its alpha helical nature. Higher dilutions of MIF-II antibody increased cauda sperm motility and induced immature/immotile caput sperm motility as tested microscopically. Higher number of sperm cells and lower dilutions of antibody induced agglutination in cauda sperm showing surface localization. Indirect immuno-fluorescence showed MIF-II localization throughout the caput sperm surface which relocated more towards acrosomal region with maturation. ELISA assay revealed gradual increase and decrease in concentration of MIF-II in epididymal plasma and plasma membrane respectively from caput to cauda. Signaling cascade that leads to sperm motility inhibition elevates nitric oxide levels through cAMP dependent pathway. MIF-II treatment doesn't alter sperm surface morphology. Expression pattern of MIF-II during epididymal maturation goes hand-in-hand with gaining motility potential as well as dormancy of spermatozoa before ejaculation. Both MIF-II and its antibody inhibit fertilization in-vitro thus expected to open new gateway for future male infertility and contraceptive development research. PMID- 29723625 TI - Thermodynamic and kinetic studies on pectinase extracted from Aspergillus aculeatus: Free and immobilized enzyme entrapped in alginate beads. AB - The kinetics and thermodynamics of Aspergillus aculeatus pectinase, either free or immobilized in alginate beads, were investigated. Pectinase immobilization ensured an enzyme immobilization yield of 59.71%. The irreversible denaturation of pectinase in both preparations was evaluated at temperatures ranging from 30 to 60 degrees C. When temperature was raised, the first-order thermal denaturation constant increased from 0.0011 to 0.0231 min-1 for the free enzyme and from 0.0017 to 0.0700 min-1 for the immobilized one, respectively. The results of residual activity tests enabled us to estimate, for denaturation of both free and immobilized pectinase, the activation energy (E*d = 85.1 and 101.6 kJ.mol-1), enthalpy (82.59 <= DeltaH*d <= 82.34 kJ.mol-1 and 99.11 <= DeltaH*d <= 98.86 kJ.mol-1), entropy (-63.26 <= DeltaS*d <= -63.85 J.mol-1.K-1 and -5.50 <= DeltaS*d <= -5.23 J.mol-1.K-1) and Gibbs free energy (101.8 <= DeltaG*d <= 104.7 kJ.mol-1 and 100.6 <= DeltaG*d <= 102.0 kJ.mol-1). The integral activity of a continuous system using the free and immobilized enzyme was also predicted, whose results indicated a satisfactory enzyme long-term thermostability in both preparations at temperatures commonly used to clarify juice. These results suggest that both free and immobilized pectinase from A. aculeatus may be profitably exploited in future food industrial applications, with special concern to the immobilized enzyme because of its reusability. PMID- 29723626 TI - Doxorubicin hydrochloride - Loaded electrospun chitosan/cobalt ferrite/titanium oxide nanofibers for hyperthermic tumor cell treatment and controlled drug release. AB - In the present study, the potential of doxorubicin hydrochloride (DOX)-loaded electrospun chitosan/cobalt ferrite/titanium oxide nanofibers was studied to investigate the simultaneous effect of hyperthermia and chemotherapy against melanoma cancer B16F10 cell lines. The cobalt ferrite nanoparticles were synthesized via microwave heating method. The titanium oxide nanoparticles were mixed with cobalt ferrite to control the temperature rise. The synthesized nanoparticles and nanofibers were characterized using X-ray diffraction (XRD), field emission scanning electron microscopy (FESEM), and vibrating sample magnetometer (VSM) analysis. The DOX loading efficiency and in vitro drug release of DOX from nanofibers were investigated at both physiological and acidic conditions by an alternating of magnetic field and without magnetic field effect. The fastest release of DOX from prepared magnetic nanofibers was observed at acidic pH by alternating of magnetic field. The antitumor activity of synthesized nanofibers was also investigated on the melanoma cancer B16F10 cell lines. The obtained results revealed that the DOX loaded-electrospun chitosan/cobalt ferrite/titanium oxide nanofibers can be used for localized cancer therapy. PMID- 29723627 TI - Production of high molecular weight poly(3-hydroxybutyrate-co-4-hydroxybutyrate) copolymer by Cupriavidus malaysiensis USMAA1020 utilising substrate with longer carbon chain. AB - Long carbon chain alkanediols are used in the production of poly(3 hydroxybutyrate-co-4-hydroxybutyrate) [P(3HB-co-4HB)], however these substrates possess high toxicity towards bacterial cells. This study demonstrated the effective utilisation of a long carbon chain alkanediol, namely 1,8-octanediol, to enhance the yield and production of a copolymer with a high molecular weight of over 1000 kDa, which is desirable for novel applications in medical and biopharmaceuticals. The increased PHA content (47-61 wt%) and concentration (1.7 4.5 g/L) was achieved by additional feeding of a combination of C4 substrates at C/N 10, with 1,8-octanediol + gamma-butyrolactone producing P(3HB-co-22 mol% 4HB) with a high molecular weight (1060 kDa) and elongation at break of 970%. The DO stat feeding strategy of C/N 10 has shown an increment of PHA concentration for both carbon combination, 0.45-4.27 g/L and 0.32-3.36 g/L for 1,8-octanediol + sodium 4-hydroxybutyrate (4HB-Na) and 1,8-octanediol + gamma-butyrolactone, but with a slight reduction on molecular weight and mechanical strength. Nonetheless, further study revealed that a nitrogen-absence feeding strategy could retain the high molecular weight and elongation at break of the copolymer, and simultaneously improving the overall P(3HB-co-4HB) production. PMID- 29723628 TI - Tear inflammatory mediators and protein in eyes of post allogenic hematopoeitic stem cell transplant patients. AB - AIM: To analyze tear cytokines levels and their correlation to ocular surface parameters in allogenic hematopoietic stem cell transplants (allo-HSCT) patients. METHODS: Prospective longitudinal study of allo-HSCT patients and controls for ocular surface evaluation (OSDI, TBUT, Schirmer's test, staining scores), tear biochemical analysis for protein, cytokines [IL-10, IL-12, IL-2, IL-4, IL-6, IL 17, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, VEGF], MMPs [MMP 2, 9, 7, 13, 10 and chemokine (IL-8)], & VEGF on three consecutive follow up visits (at three monthly interval) was done. RESULTS: Of 24 post allo-HSCT patients (19 males, 5 females) & 12 controls (mean age 34.3 + 5.8 years) enrolled, 20 patients [mean age 33.4 + 7.77 years; mean time of recruitment of 5.2 + 2.12 months following alloHSCT] who completed three consecutive follow up visits were included for analysis. Ocular GVHD (oGVHD) was seen in 8 patients (33.3%). Tears biochemical analysis showed elevated levels of interferon gamma, IL 6, IL 8, IL 10, IL 12AP70, IL 17A, MMP 9 and VEGF in oGVHD eyes as compared to non-oGVHD & control eyes. Non-oGVHD eyes showed elevated tear MMP 7 and MMP 9 as compared to healthy controls. Tear protein levels were significantly decreased in oGVHD eyes and were equivocal in nonGVHD and control eyes. TBUT and ocular staining scores to correlate best with tear interleukins and MMPs. CONCLUSION: Evaluation of levels of tear VEGF, total protein & MMP 9 can be of significance in identifying oGVHD in post alloHSCT patients. PMID- 29723630 TI - Quantitative market survey of non-woody plants sold at Kariakoo Market in Dar es Salaam, Tanzania. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In Tanzania, traditional medicine plays a significant role in health care and local economies based on the harvesting, trade and sale of medicinal plant products. The majority of this plant material is said to originate from wild sources, and both traditional healers and vendors are concerned about the increasing scarcity of certain species. AIM OF THE STUDY: A market survey of non-powdered, non-woody medicinal plants was conducted at Kariakoo Market in Dar es Salaam, the major hub for medicinal plant trade in Tanzania, to assess sustainability of traded herbal medicine. MATERIALS AND METHODS: For this study, fresh and dried herbs, seeds and fruits were collected and interviews were conducted to obtain information on vernacular names, preparation methods, monthly sales, uses and prices. Bundles of herbal medicine offered for sale were weighed and counted to calculate the value and volumes of daily stock at the market. RESULTS: A total of 71 medicinal plant products belonging to 62-67 different species from at least 41 different plant families were identified. We identified 45 plant products to species level, 20 products to genus level and four to family level. Plant species most encountered at the market were Suregada zanzibariensis, Myrothamnus flabellifolia and Sclerocarya birrea. The major use categories reported by the vendors were ritual purposes, digestive disorders and women's health. Annual sales are estimated to be in excess of 30 t and close to 200,000 USD, and trade in herbal medicine at Kariakoo Market provides subsistence income to many local vendors. CONCLUSIONS: A large diversity of wild-harvested plant species is traded as medicinal products in Tanzania, including species listed on CITES Appendices. Identifying and monitoring temporal changes in availability per season and from year to year will reveal which species are most affected by this trade, and help relevant authorities in Tanzania to find alternative sources of income for dependent stakeholders and initiate targeted efforts to protect threatened plant species. PMID- 29723629 TI - Oil from the fruits of Pterodon emarginatus Vog.: A traditional anti inflammatory. Study combining in vivo and in silico. AB - ETHNOBOTANICAL RELEVANCE: The oil obtained from the fruits of Pterodon emarginatus Vog. (OPe) is used orally and topically, in traditional medicine for some purposes, such as acute and chronic inflammatory states as rheumatoid arthritis. MATERIALS AND METHODS: In this work, the anti-inflammatory activity of the OPe was demonstrated based on several animal models and presented an in silico study based on the 6alpha,7beta-dihydroxy-vouacapan-17beta-oic acid (DHVA) majority compound of the OPe to evaluate the interaction this compound, with cyclooxygenase-2 (COX-2) in 4COX (Mus musculus) and 5KIR (Homo sapiens) and molecular dynamics simulation. RESULTS: The OPe (498 mg/kg, p.o) significantly inhibited (p < 0.05, Student t-test) the primary and secondary reactions of arthritis by Freund's Complete Adjuvant (FCA) and in dermatitis induced by croton oil in mice, OPe inhibited peak of edema. In vascular permeability test in rats, the treatment with OPe was able to block the response to PGE2, serotonin, and bradykinin (p < 0.05, Student t-test). In the writhing test in mice, the OPe at doses of 498 and 980 mg/kg (p.o) produced inhibition of 73% and 92%, respectively, and was not significantly effective in the hot plate test. In the evaluation of the potency in relation to gastric injury (gastric ulcer induced by stress) and combined assay in the assessment of anti-inflammatory potency and gastric damage, it was observed that indomethacin (10 mg/kg, p.o.) inhibited carrageenan edema by 51% and produced a higher number of gastric lesions when compared to the group treated with OPe, where only areas of hyperemia were observed, without the occurrence of ulcerative lesion, and which inhibited the edema by 47%. In the in silico study, it was found that the DHVA is capable of binding to two organisms (4COX - Mus musculus and 5KIR - Homo sapiens), however, with higher binding affinity to the organism Homo sapiens. CONCLUSIONS: As expected, all tested ligands were capable of forming hydrogen interactions with residues at their respective binding sites, but the DHVA ligand was capable of creating slightly more hydrogen bonds when docked to either 4COX or 5KIR than the other tested ligands, thus demonstrating the participation of this compound in the anti-inflammatory and antialgic responses observed in the in vivo assays as a COX-2 inhibitor. Therefore, the results obtained support the traditional use of OPe for inflammatory and gastric problems. PMID- 29723631 TI - Paraptosis in human glioblastoma cell line induced by curcumin. AB - Curcumin is a polyphenol compound extracted from Curcuma longa plant, is a molecule with pleiotropic effects that suppresses transformation, proliferation and metastasis of malignant tumors. Curcumin can cause different kinds of cell death depending of its concentration on the exposed cell type. Here we show that exposure of the glioblastoma cell line A172 to curcumin at 50 MUM, the IC50, causes morphological change characteristic of paraptosis cell-death. Vesicles derived from the endoplasmic reticulum (ER) and low membrane potential of the mitochondria were constantly found in the exposed cells. Furthermore, changes in expression of the ER Stress Response (ERSR) genes IRE1 and ATF6, and the microRNAs (miRNAs) miR-27a, miR-222, miR-449 was observed after exposure to curcumin. AKT-Insulin and p53-BCL2 networks were predicted being modulated by the affected miRNAs. Furthermore, AKT protein levels reduction was confirmed. Our data, strongly suggest that curcumin exerts its cell-death properties by affecting the integrity of the reticulum, leading to paraptosis in the glioblastoma cells. These data unveils the versatility of curcumin to control cancer progression. PMID- 29723632 TI - Phenotypic markers of oral keratinocytes seeded on two distinct 3D oral mucosa models. AB - This study validates the use of a full-thickness oral mucosa model for in vitro studies with a collagen type I matrix, by comparison of this model with two other 3D oral mucosa models: human-sourced and porcine acellular dermal matrices (AlloDerm(r)/Strattice(r), respectively). For the collagen matrix model, gingival fibroblasts were seeded either onto the dermal side of the AlloDerm(r) and Strattice(r) matrices or within the collagen matrices in complete culture medium (DMEM). For all scaffolds, DMEM was replaced every 24 h up to 72 h. For the full thickness oral mucosa models, 72 h after fibroblast seeding, oral keratinocytes were seeded on the epidermal sides of AlloDerm(r) and Strattice(r) matrices or collagen matrices. All matrices and models were subjected to histological analysis, complementing phenotypic characterization by evaluation of glucose consumption, cell proliferation, gene expression and synthesis of growth factors. A higher fibroblast ratio was observed for the collagen matrix, in which the distribution of gingival fibroblasts was also more homogeneous. Metabolism, proliferation, and gene expression and synthesis of VEGF of these cells were also increased for the collagen matrix. All matrices provided a suitable substrate for oral keratinocytes adhesion, proliferation, and phenotypic expression; however, higher proliferation, stratification, and differentiation were noted when oral keratinocytes were seeded on the dermal matrices. PMID- 29723633 TI - Associations between the chemokine biomarker CCL2 and knee osteoarthritis outcomes: the Johnston County Osteoarthritis Project. AB - OBJECTIVE: Our study analyzes the association between chemokine-ligand-2 (CCL2) serum concentrations at baseline and knee radiographic osteoarthritis (OA) (knee rOA), knee-rOA progression, individual radiographic features and knee symptomatic OA at 5-year follow-up. DESIGN: OA outcomes were analyzed in a community-based cohort including a baseline enrollment and a 5-year follow-up. Baseline CCL2 serum concentrations were assessed by multiplex assay and associated with presence or progression of individual radiographic features at 5-year follow-up. Separate multiple logistic regression models were used to examine adjusted associations between baseline CCL2 and each of the knee OA variables at follow up. CCL2 at baseline was modeled as an explanatory variable, whereas each of the knee OA variables at follow-up served as the response variables. Models were adjusted for age, BMI, race, and sex. Trend tests were conducted to assess any linear effect on outcomes across CCL2 tertiles. RESULTS: Participants (n = 168) had a median age of 57-years and median BMI of 29 kg/m2. About 63% of all participants were women, and 58% Caucasian (42% African American). In adjusted logistic models, continuous log-CCL2 was significantly associated with knee-rOA. For each unit increase in log CCL2, the odds of having knee-rOA at follow-up was increased by 72%. CCL2 tertiles showed significant linear associations with presence and progression of knee-rOA and medial joint space narrowing (JSN), but not with presence or progression of osteophytes, bone sclerosis, knee symptoms, or symptomatic knee-rOA. CONCLUSIONS: Serum CCL2 may help to elucidate some mechanisms of joint destruction and identify individuals with higher odds of structural knee changes. PMID- 29723634 TI - Total knee replacement and non-surgical treatment of knee osteoarthritis: 2-year outcome from two parallel randomized controlled trials. AB - OBJECTIVES: To compare 2-year outcomes of total knee replacement (TKR) followed by non-surgical treatment to that of non-surgical treatment alone and outcomes of the same non-surgical treatment to that of written advice. DESIGN: In two randomized trials, 200 (mean age 66) adults with moderate to severe knee osteoarthritis (OA), 100 eligible for TKR and 100 not eligible for TKR, were randomized to TKR followed by non-surgical treatment, non-surgical treatment alone, or written advice. Non-surgical treatment consisted of 12 weeks of supervised exercise, education, dietary advice, use of insoles, and pain medication. The primary outcome was the mean score of the Knee Injury and Osteoarthritis Outcome Score (KOOS) subscales, covering pain, symptoms, activities of daily living (ADL), and quality of life (QOL). RESULTS: Patients randomized to TKR had greater improvements than patients randomized to non surgical treatment alone (difference of 18.3 points (95% CI; 11.3 to 25.3)), who in turn improved more than patients randomized to written advice (difference of 7.0 points (95% CI; 0.4 to 13.5)). Among patients eligible for TKR, 16 (32%) from the non-surgical group underwent TKR during 2 years and among those initially ineligible, seven patients (14%) from the non-surgical group and ten (20%) from the written advice group underwent TKR. CONCLUSIONS: TKR followed by non-surgical treatment is more effective on pain and function than non-surgical treatment alone, which in turn is more effective than written advice. Two out of three patients with moderate to severe knee OA eligible for TKR delayed surgery for at least 2 years following non-surgical treatment. TRIAL REGISTRATION: ClinicalTrials.gov numbers NCT01410409 and NCT01535001. PMID- 29723636 TI - Mechanical loading of intervertebral disc modulates microglia proliferation, activation, and chemotaxis. AB - OBJECTIVE: The aim of the study is to assess the effects of the neuroinflammatory microenvironment of a mechanically-induced degenerating intervertebral disc (IVD) on neuroinflammatory like cells such as microglia, in order to comprehend the role of microglial cells in degenerative disc disease. METHODS: Bovine caudal IVDs were kept in culture in an ex vivo bioreactor under high frequency loading and limited nutrition or in free swelling conditions as control samples. Conditioned media (CM) were collected, analysed for cytokine and neurotrophin content and applied to microglial cells for neuroinflammatory activation assessment. RESULTS: Degenerative conditioned medium (D-CM) induced a higher production of interleukin (IL)-8, nerve growth factor (NGF), interferon (IFN) gamma, IL-17 from IVD cells than unloaded control conditioned medium (U-CM). Upon 48 h of co-incubation with microglia, D-CM stimulated microglia proliferation, activation, with increased expression of ionized calcium binding adaptor molecule 1 (IBA1) and CD68, and chemotaxis. Moreover, an increment of nitrite production was observed. Interestingly, D-CM caused an upregulation of IL-1beta, IL-6, tumour necrosis factor alpha (TNFalpha), inducible NO synthase (iNOS), IBA1, and vascular endothelial growth factor (VEGF) genes in microglia. Similar results were obtained when microglia were treated with the combination of the measured cytokines. CONCLUSIONS: Our findings show that in IVD degenerative microenvironment, IL-8, NGF, IFN-gamma, IL-17 drive activation of microglia in the spinal cord and increase upregulation of neuroinflammatory markers. This, in turn, enhances the inflammatory milieu within IVD tissues and in the peridiscal space, aggravating the cascade of degenerative events. This study provides evidence for an important role of microglia in maintaining IVD neuroinflammatory microenvironment and probably inducing low back pain. PMID- 29723635 TI - Subchondral bone circulation in osteoarthritis of the human knee. AB - OBJECTIVE: The hypothesis of this study is that human subchondral bone exhibits abnormal patterns of perfusion in osteoarthritis (OA) that can be characterized by kinetic parameters of blood flow using dynamic contrast enhanced (DCE) MRI. DESIGN: Fifteen subjects with advanced OA of the knee and seven control subjects without OA were studied at 1.5 T with DCE-MRI. Region of interest (ROIs) analysis of pharmacokinetic perfusion parameters were used to examine initial uptake and washout of the contrast agent in the lateral tibial plateau. RESULTS: Arterial and venous perfusion kinetics were abnormal in subchondral OA bone compared to those of normal controls. Time-intensity curves (TIC) exhibited delayed contrast clearance in OA knees compared to normal. Quantitatively, changes were observed in the kinetic parameters, kep, Akep, and kel. The mean kep and Akep were reduced in OA, compared to normal bone, indicating a reduction of arterial inflow and delayed signal enhancement. The kel in OA bone was lower than in normal bone, the negative kel indicating a reduction in venous outflow. The area under the TIC (AUC60) indicated greater residual contrast in OA bone. CONCLUSIONS: DCE-MRI can quantitatively assess subchondral bone perfusion kinetics in human OA and identify heterogeneous regions of perfusion deficits. The results are consistent with venous stasis in OA, reflecting venous outflow obstruction, and can affect intraosseous pressure, reduce arterial inflow, reduce oxygen content, and may contribute to altered cell signaling in, and the pathophysiology of, OA. PMID- 29723637 TI - Multidimensional co-segmentation of longitudinal brain MRI ensembles in the presence of a neurodegenerative process. AB - MRI Segmentation of a pathological brain poses a significant challenge, as the available anatomical priors that provide top-down information to aid segmentation are inadequate in the presence of abnormalities. This problem is further complicated for longitudinal data capturing impaired brain development or neurodegenerative conditions, since the dynamic of brain atrophies has to be considered as well. For these cases, the absence of compatible annotated training examples renders the commonly used multi-atlas or machine-learning approaches impractical. We present a novel segmentation approach that accounts for the lack of labeled data via multi-region multi-subject co-segmentation (MMCoSeg) of longitudinal MRI sequences. The underlying, unknown anatomy is learned throughout an iterative process, in which the segmentation of a region is supported both by the segmentation of the neighboring regions, which share common boundaries, and by the segmentation of corresponding regions, in the other jointly segmented images. A 4D multi-region atlas that models the spatio-temporal deformations and can be adapted to different subjects undergoing similar degeneration processes is reconstructed concurrently. An inducible mouse model of p25 accumulation (the CK p25 mouse) that displays key pathological hallmarks of Alzheimer disease (AD) is used as a gold-standard to test the proposed algorithm by providing a conditional control of rapid neurodegeneration. Applying the MMCoSeg to a cohort of CK-p25 mice and littermate controls yields promising segmentation results that demonstrate high compatibility with expertise manual annotations. An extensive comparative analysis with respect to current well-established, atlas-based segmentation methods highlights the advantage of the proposed approach, which provides accurate segmentation of longitudinal brain MRIs in pathological conditions, where only very few annotated examples are available. PMID- 29723638 TI - Magnetic stimulation selectively affects pre-stimulus EEG microstates. AB - Different electrophysiological (EEG) correlates may provide specific important assessment of the period that anticipates an imperative stimulus. Previous study of our group showed that a local (i.e. parietal) anticipatory EEG marker (i.e. the event related de-synchronization of the alpha rhythms; ERD) is selectively affected when transcranial magnetic stimulation (TMS) is delivered over crucial nodes belonging to well-known human networks involved in different cognitive domains. Here, we investigated whether such distinction is also present in the whole brain activity as seen through the pre-stimulus microstate's topography, representing a global and reference-free measure of the neural activity. First, when subjects received a pseudo-stimulation (sham), we found two distinct pre stimulus topographies during perceptual or memory task, respectively. Second, we reported that, during the visuo-spatial attention task, stimulation of left intraparietal sulcus (IPS), but not left angular gyrus (AG), significantly modifies the topography observed in the Sham condition. Conversely, stimulation of AG, but not IPS, changes the topography observed in the Sham condition during a semantic memory task. These findings provide the first causal evidence for the task and region specificity of the pre-stimulus EEG microstates, thus proposing this EEG index as of particular interest for the assessment of the period that precedes a predictable event. PMID- 29723639 TI - Spatial analysis and high resolution mapping of the human whole-brain transcriptome for integrative analysis in neuroimaging. AB - The quantification of big pools of diverse molecules provides important insights on brain function, but is often restricted to a limited number of observations, which impairs integration with other modalities. To resolve this issue, a method allowing for the prediction of mRNA expression in the entire brain based on microarray data provided in the Allen Human Brain Atlas was developed. Microarray data of 3702 samples from 6 brain donors was registered to MNI and cortical surface space using FreeSurfer. For each of 18,686 genes, spatial dependence of transcription was assessed using variogram modelling. Variogram models were employed in Gaussian process regression to calculate best linear unbiased predictions for gene expression at all locations represented in well-established imaging atlases for cortex, subcortical structures and cerebellum. For validation, predicted whole-brain transcription of the HTR1A gene was correlated with [carbonyl-11C]WAY-100635 positron emission tomography data collected from 30 healthy subjects. Prediction results showed minimal bias ranging within +/-0.016 (cortical surface), +/-0.12 (subcortical regions) and +/-0.14 (cerebellum) in units of log2 expression intensity for all genes. Across genes, the correlation of predicted and observed mRNA expression in leave-one-out cross-validation correlated with the strength of spatial dependence (cortical surface: r = 0.91, subcortical regions: r = 0.85, cerebellum: r = 0.84). 816 out of 18,686 genes exhibited a high spatial dependence accounting for more than 50% of variance in the difference of gene expression on the cortical surface. In subcortical regions and cerebellum, different sets of genes were implicated by high spatially structured variability. For the serotonin 1A receptor, correlation between PET binding potentials and predicted comprehensive mRNA expression was markedly higher (Spearman rho = 0.72 for cortical surface, rho = 0.84 for subcortical regions) than correlation of PET and discrete samples only (rho = 0.55 and rho = 0.63, respectively). Prediction of mRNA expression in the entire human brain allows for intuitive visualization of gene transcription and seamless integration in multimodal analysis without bias arising from non-uniform distribution of available samples. Extension of this methodology promises to facilitate translation of omics research and enable investigation of human brain function at a systems level. PMID- 29723640 TI - Dual-radiotracer translational SPECT neuroimaging. Comparison of three methods for the simultaneous brain imaging of D2/3 and 5-HT2A receptors. AB - PURPOSE: SPECT imaging with two radiotracers at the same time is feasible if two different radioisotopes are employed, given their distinct energy emission spectra. In the case of 123I and 125I, dual SPECT imaging is not straightforward: 123I emits photons at a principal energy emission spectrum of 143.1-179.9 keV. However, it also emits at a secondary energy spectrum (15-45 keV) that overlaps with the one of 125I and the resulting cross-talk of emissions impedes the accurate quantification of 125I. In this paper, we describe three different methods for the correction of this cross-talk and the simultaneous in vivo [123I]IBZM and [125I]R91150 imaging of D2/3 and 5-HT2A receptors in the rat brain. METHODS: Three methods were evaluated for the correction of the effect of cross-talk in a series of simultaneous, [123I]IBZM and [125I]R91150 in vivo and phantom SPECT scans. Method 1 employs a dual-energy window (DEW) approach, in which the cross-talk on 125I is considered a stable fraction of the energy emitted from 123I at the principal emission spectrum. The coefficient describing the relationship between the emission of 123I at the principal and the secondary spectrum was estimated from a series of single-radiotracer [123I]IBZM SPECT studies. In Method 2, spectral factor analysis (FA) is applied to separate the radioactivity from 123I and 125I on the basis of their distinct emission patterns across the energy spectrum. Method 3 uses a modified simplified reference tissue model (SRTMC) to describe the kinetics of [125I]R91150. It includes the coefficient describing the cross-talk on 125I from 123I in the model parameters. The results of the correction of cross-talk on [125I]R91150 binding potential (BPND) with each of the three methods, using cerebellum as the reference region, were validated against the results of a series of single-radiotracer [123I]R91150 SPECT studies. In addition, the DEW approach (Method 1), considered to be the most straightforward to apply of the three, was further applied in a dual radiotracer SPECT study of the relationship between D2/3 and 5-HT2A receptor binding in the striatum, both at the voxel and at the regional level. RESULTS: Average regional BPND values of [125I]R91150, estimated on the cross-talk corrected dual-radiotracer SPECT studies provided satisfactory correlations with the BPND values for [123I]R91150 from single-radiotracer studies: r = 0.92, p < 0.001 for Method 1, r = 0.92, p < 0.001 for Method 2, r = 0.92, p < 0.001, for Method 3. The coefficient describing the ratio of the 123I-emitted radioactivity at the 125I-emission spectrum to the radioactivity that it emits at its principal emission spectrum was 0.34 in vivo. Dual-radiotracer in vivo SPECT studies corrected with Method 1 demonstrated a positive correlation between D2/3 and 5 HT2A receptor binding in the rat nucleus accumbens at the voxel level. At the VOI level, a positive correlation was confirmed in the same region (r = 0.78, p < 0.01). CONCLUSION: Dual-radiotracer SPECT imaging using 123I and 125I-labeled radiotracers is feasible if the cross-talk of 123I on the 125I emission spectrum is properly corrected. The most straightforward approach is Method 1, in which a fraction (34%) of the radioactivity emitted from 123I at its principal energy spectrum is subtracted from the measured radioactivity at the spectrum of 125I. With this method, a positive correlation between the binding of [123I]IBZM and [125I]R91150 was demonstrated in the rat nucleus accumbens. This result highlights the interest of dual-radiotracer SPECT imaging to study multiple neurotransmitter systems at the same time and under the same biological conditions. PMID- 29723641 TI - Contributions of dopaminergic and non-dopaminergic neurons to VTA-stimulation induced neurovascular responses in brain reward circuits. AB - Mapping the activity of the human mesolimbic dopamine system by BOLD-fMRI is a tempting approach to non-invasively study the action of the brain reward system during different experimental conditions. However, the contribution of dopamine release to the BOLD signal is disputed. To assign the actual contribution of dopaminergic and non-dopaminergic VTA neurons to the formation of BOLD responses in target regions of the mesolimbic system, we used two optogenetic approaches in rats. We either activated VTA dopaminergic neurons selectively, or dopaminergic and mainly glutamatergic projecting neurons together. We further used electrical stimulation to non-selectively activate neurons in the VTA. All three stimulation conditions effectively activated the mesolimbic dopaminergic system and triggered dopamine releases into the NAcc as measured by in vivo fast-scan cyclic voltammetry. Furthermore, both optogenetic stimulation paradigms led to indistinguishable self-stimulation behavior. In contrast to these similarities, however, the BOLD response pattern differed greatly between groups. In general, BOLD responses were weaker and sparser with increasing stimulation specificity for dopaminergic neurons. In addition, repetitive stimulation of the VTA caused a progressive decoupling of dopamine release and BOLD signal strength, and dopamine receptor antagonists were unable to block the BOLD signal elicited by VTA stimulation. To exclude that the sedation during fMRI is the cause of minimal mesolimbic BOLD in response to specific dopaminergic stimulation, we repeated our experiments using CBF SPECT in awake animals. Again, we found activations only for less-specific stimulation. Based on these results we conclude that canonical BOLD responses in the reward system represent mainly the activity of non dopaminergic neurons. Thus, the minor effects of projecting dopaminergic neurons are concealed by non-dopaminergic activity, a finding which highlights the importance of a careful interpretation of reward-related human fMRI data. PMID- 29723642 TI - Predictors of Overnight Admission after Minimally Invasive Hysterectomy in the Expert Setting. AB - OBJECTIVE: To identify predictors of Same Day Discharge (SDD) overnight admission after laparoscopic and robot-assisted hysterectomy to improve preoperative counseling and patient optimization. DESIGN: A Single-center retrospective cohort study. (Canadian Task Force classification III). SETTING: Academic university hospital. PATIENTS: Patients undergoing straight-stick laparoscopic and robot assisted hysterectomy by fellowship-trained minimally invasive gynecologic surgeons for benign indications INTERVENTIONS: Straight-stick laparoscopic and robot-assisted hysterectomy. Same Day Discharge (SDD) after surgery. MAIN OUTCOME MEASURES: SDD vs. overnight stay. All preoperative, intraoperative, variables were collected for analysis as predictors. RESULTS: Data from 396 consecutive minimally invasive hysterectomy procedures was collected for analysis. Three hundred and twelve patients (79%) were discharged the same day, 84 (21%) were admitted for at least one night. Data from the two groups were compared. Overnight stay compared to SDD was associated with older age (47.3 vs. 43.4 years, P< 0.001), lower preoperation hematocrit (35.8% vs. 37.3%, P= 0.035), history of prior laparotomy (31% vs. 14.1%, P=0.003), prolonged operative time (190.5 vs. 115.2 min, P<0.001), estimated blood loss (244.6 vs. 104.1 mL P<0.001), lysis of adhesion (27.4% vs. 13.5%), and intraoperative organ injury (17% vs. 3%, P=0.005). Logistic regression analysis, adjusting for all included variables as confounders, showed that hematocrit increments of 5%, was protective against any overnight stay, OR 0.622 (p=0.015), 30 minutes increase in operative time increased the odds of an overnight stay by 1.6 (P<0.001). History of a laparotomy remained a significant predictive factor for an overnight stay, OR 3.2 (p=0.006). Later surgery end time, by increments of 60 minutes, increased the odds of an overnight stay by 1.2 (p<0.01). CONCLUSION: Perioperative factors such as age, hematocrit, surgery time, and surgical history as well as intraoperative factors such as prolonged operative time are predictive of overnight hospital stay. PMID- 29723643 TI - Transvaginal Natural Orifice Transluminal Endoscopic Surgery for Female-to-Male Transgender Men. AB - STUDY OBJECTIVE: Previous studies suggest female-to-male transgender men tend to choose less invasive procedures, but the superior route of hysterectomy for them remains undetermined. DESIGN: A retrospective study (Canadian Task Force Classification II-3). SETTING: An academic tertiary hospital. PATIENTS: Fifty-six female-to-male transsexuals received total vaginal hysterectomy (VH) with bilateral salpingo-oophorectomy (BSO) between April 2008 and August 2016 at Taipei Veterans General Hospital, Taipei, Taiwan. INTERVENTIONS: The patients underwent natural orifice transluminal endoscopic surgery (NOTES) (n = 14) or the conventional approach (n = 42). MEASUREMENTS AND MAIN RESULTS: Medical charts and surgical records were reviewed retrospectively. The general characteristics of the patients were similar in both groups. There were no statistically significant differences in operative time, estimated blood loss, intraoperative and immediate postoperative complications, or length of hospital stay between the 2 groups. However, postoperative pain was significantly reduced in the NOTES group compared with the conventional group as evidenced by lower mean scores on the visual analog scale (4.9 +/- 3.0 vs 7.1 +/- 1.4 at 2 hours, p = .008; 1.5 +/- 1.2 vs 3.0 +/- 1.7 at 48 hours, p = .001; and 1.7 +/- 1.0 vs 2.7 +/- 1.1 at 72 hours, p < .001) and a lower mean accumulated dose of postoperative analgesics (38.9 +/- 49.2 mg vs 88.8 +/- 82.3 mg meperidine hydrochloride, p = .037). Analysis of variance with repeated measures with a Greenhouse-Geisser correction also showed that the mean scores for wound pain were statistically lower in the NOTES group (p < .001). There was no significant difference in the complication rate between the NOTES and conventional groups (7% vs 12%, p = .618). There were no severe complications, including infection episodes or internal bleeding events, within the NOTES group. CONCLUSION: NOTES VH with BSO in female-to-male transgender men significantly decreases postoperative pain and analgesic use. NOTES in female-to male sex reassignment surgery provides a novel choice for transgender men, with equivalent safety compared with VH. PMID- 29723644 TI - Transversus Abdominis Plane Block for Post Hysterectomy Pain: A Systematic Review and Meta-Analysis. AB - The objective of this study was to address the efficacy of transversus abdominis plane (TAP) blocks in pain management among women who undergo elective hysterectomy for benign pathology in both open and minimally invasive surgeries. We performed a systematic review by searching for bibliographic citations from Medline, Embase, and Cochrane Library. MeSH headings for TAP blocks and hysterectomy were combined and restricted to the English language. We included randomized controlled trials comparing TAP blocks with placebo or no block in patients who underwent elective hysterectomy. Pain was measured using a visual analog scale (VAS) on a scale of 0 to 100. We calculated pooled mean differences in VAS and total morphine consumption at 2 and 24 hours by performing a random effects meta-analysis. Fourteen studies met the inclusion criteria, comprising 855 participants. At 2 hours mean VAS scores for patients who underwent TAP blocks were significantly lower after both total abdominal hysterectomy (TAH) (mean difference, -14.97; 95% confidence interval [CI], -20.35 to -9.59) and total laparoscopic hysterectomy (TLH; mean difference, -18.16; 95% CI, -34.78 to 1.53) compared with placebo or no block. Pain scores at 24 hours for patients who underwent TAP blocks were significantly lower after both TAH (-10.09; 95% CI, 17.35 to -2.83) and TLH (-9.12; 95% CI, -18.12 to -.13) compared with placebo or no block. Mean difference in morphine consumption was -9.53 mg (95% CI, -15.43 to -3.63) for TAH and -3.15 mg (95% CI, -8.41 to 2.12) for TLH. In conclusion, TAP blocks provide significant postoperative early and delayed pain control compared with placebo or no block among women who undergo hysterectomy. There was reduced morphine consumption among patients who underwent TAH but not TLH. (Registration: International Prospective Register of Systematic Reviews ID: CRD42016036791.). PMID- 29723645 TI - A Novel Treatment for Cervical and Cesarean Section Scar Pregnancies by Transvaginal Injection of Absolute Ethanol to Trophoblasts: Efficacy in 19 Cases. AB - STUDY OBJECTIVE: To evaluate the efficacy of a nonsurgical treatment for cervical pregnancy (CP) and cesarean section scar pregnancy (CSP). DESIGN: Retrospective clinical study (Canadian Task Force classification III). SETTING: Private assisted reproductive technology practice. PATIENTS: Nineteen women with CP (n = 16) or CSP (n = 3), including 6 patients with positive fetal heartbeat. INTERVENTION: Transvaginal local injection of absolute ethanol (AE) into the hyperechoic ring (lacunar space) around the gestational sac under ultrasound guidance. MEASUREMENTS AND MAIN RESULTS: Serum beta-human chorionic gonadotropin (beta-hCG) was measured at frequent intervals, and ultrasound and/or magnetic resonance imaging was used to observe the gestational sac. In 9 patients, the serum beta-hCG level was effectively reduced with a single AE injection at 2 hours. In the remaining 10 patients, the level decreased but then increased in 4 and slowly decreased in the other 6; all of these 10 patients required 2 to 5 repeat AE injections. In all patients, serum beta-hCG level was reduced by 50% within 3 days and decreased to <10% of the initial level within 14 days. In 18 patients (95%), the level was decreased to 1.0 mIU/mL within 40 days. Seven patients were treated on an outpatient basis. Twelve patients received no anesthesia. Five patients subsequently became pregnant, and each had a live birth. There was no recurrent CP or CSP. The procedure was successful in all 19 patients. CONCLUSION: This procedure is an effective treatment for CP or CSP that could be used in place of conventional surgical interventions and medical treatment using MTX. PMID- 29723646 TI - Hiya: A new genus segregated from Hypolepis in the fern family Dennstaedtiaceae, based on phylogenetic evidence and character evolution. AB - The relationship of Hypolepis brooksiae, H. nigrescens, and H. scabristipes to the remainder of Hypolepis (Dennstaedtiaceae) has been questioned by previous authors based on their unique combination of morphological characters and different base chromosome number. Using four chloroplast genes including rbcL, atpA, rpL6, and rps4-trnS intergenic spacer (IGS) from 32 samples, representing 24 species of Dennstaedtiaceae, we recovered a clade comprising H. brooksiae and H. nigrescens, distinct from the remaining species of Hypolepis. This clade is resolved as sister to the clade comprising Blotiella, Paesia and Histiopteris. We reconstructed ancestral states of 16 morphological characters and found that this clade is distinguished by indeterminate, scandent leaves exhibiting rhythmic growth, provided with recurved black-tipped prickles, and stipule-like pinnules that protect the emerging crosier and pinnae departures, rachis-costa architecture where the adaxial sulcus is confluent with the next lower order, and a base chromosome number of x = 29. In light of this molecular and morphological evidence, we describe a new genus, Hiya, and provide nomenclatural combinations to accommodate the three known species segregated from Hypolepis: Hiya brooksiae, Hiya nigrescens, and Hiya scabristipes. PMID- 29723647 TI - Origins of East Asian Campanuloideae (Campanulaceae) diversity. AB - The Campanulaceae comprises approximately 2300 species that are distributed among five major lineages: Campanuloideae, Cyphioideae, Cyphocarpoideae, Lobelioideae, and Nemacladoideae. Of these, the Campanuloideae, a primarily Old World clade, has the largest diversity in East Asia. In this study, we reconstruct the phylogeny of East Asian Campanuloideae based on one nuclear gene (i.e., PPR70) and five plastid markers (i.e., atpB, matK, petD, rbcL, and trnL-trnF). We then use this phylogenetic framework to reconstruct the biogeographical history of the genus. Our molecular dataset includes 376 of the 1045 currently recognized species in the Campanuloideae. Of the 376 sampled species, 116 are from East Asia, representing ca. 60% of the East Asian Campanuloideae. Our PPR dataset included sequences for 156 accessions, representing 54 species, while our plastid dataset included sequences for 305 accessions, representing 354 species. Phylogenetic analyses recovered three large clades containing East Asian taxa: Campanulinae, Platycodinae, and Wahlenberginae. The historical assembly of Campanuloideae diversity in East Asia appears to have resulted from numerous, independent movements from Africa, Europe/W. Asia, and North America. Africa was inferred as the ancestral range for the Campanuloideae. Movement of the largest East Asian clade (Platycodinae) occurred at approximately 53.1 Ma (46.6-58.73 95% HPD) from Africa, with much of the current diversity found in East Asia having resulted from in situ diversification. Thirteen additional movements into East Asia, primarily from Europe/Western Asia, occurred subsequently. One dispersal event from western North America was also inferred. In contrast, only six movements out of East Asia were found. Our results suggest that East Asia has acted primarily as a sink for Campanuloideae diversity, with Europe, Western Asia, and Africa representing major source areas. PMID- 29723648 TI - Molecular phylogeny of Banjo catfishes (Ostaryophisi: Siluriformes: Aspredinidae): A continental radiation in South American freshwaters. AB - The family Aspredinidae is a moderately diverse and broadly distributed group of freshwater fishes endemic to South America. Commonly known as Banjo Catfishes, Aspredinidae currently includes 44 valid species divided among 13 genera. The first species-comprehensive hypothesis on phylogenetic relationships among aspredinids is presented. The phylogeny is based on DNA sequence data for five gene fragments (mitochondrial 16S and COI; nuclear RAG1, MYH6 and SH3PX3) from 114 individuals representing 31 species in 12 aspredinid genera. Analyses of molecular data support the monophyly of most genera (Bunocephalus excepted) and several higher-level relationships previously proposed by morphological studies. Based on the molecular phylogeny, a new suprageneric classification for Aspredinidae is proposed with the new monotypic subfamily Pseudobunocephalinae as the sister taxon to all other aspredinids. PMID- 29723650 TI - Calcaneus range of motion underestimated by markers on running shoe heel. AB - BACKGROUND: The measurement of rearfoot kinematics by placing reflective markers on the shoe heel assumes its motion is identical to the foot's motion. Studies have compared foot and shoe kinematics during running but with conflicting results. The primary purpose of this study was to compare shoe and calcaneus three-dimensional range of motion during running. A secondary purpose was to determine the effect of a less rigid heel counter on tibia motion. RESEARCH QUESTION: Do markers placed on the shoe heel accurately represent calcaneus kinematics during running? METHODS: Three-dimensional coordinate data were collected on 14 subjects (M/F: 9/5) who ran on an instrumented treadmill at 3.35 m/s under four conditions: modified/intact neutral shoes, and modified/intact support shoes. Shoes were modified by placing holes through the heel to allow for shoe heel and calcaneus coordinate data to be collected simultaneously via reflective markers on the shoe and on the skin of the heel within the shoe. Calcaneus, shoe heel, and tibia ROM were calculated from 0 to 50% stance phase and compared across shoe conditions. RESULTS: Calcaneal frontal plane ROM was significantly greater than neutral and support shoe heel ROM (p < 0.001). Calcaneus ROM was also significantly greater than shoe heel ROM in the transverse (p < 0.001) and sagittal (p < 0.001) planes. No change in tibial transverse plane ROM was observed (p = 0.346) across shoe heel conditions. SIGNIFICANCE: Shoe markers significantly underestimated calcaneus ROM across all planes of motion. These findings suggest calcaneus kinematics cannot be accurately measured with markers placed solely on the shoe heel. Additionally, the required modifications to the shoe's heel had no effect on tibia ROM in the transverse plane. PMID- 29723649 TI - Differential associations between dual-task walking abilities and usual gait patterns in healthy older adults-Results from the Baltimore Longitudinal Study of Aging. AB - BACKGROUND: It is well established that facing a cognitive challenge while carrying out a motor task interferes with the motor task performance, and in general the ability of handling a dual-task declines progressively with aging. However, the reasons for this decline have not been fully elucidated. Understanding the association between usual-walking gait patterns and dual-task walking performance may provide new insights into the mechanisms that lead to gait deterioration in normal aging and its link to motor and cognitive function. RESEARCH QUESTION: Our aim was to assess usual gait parameters in kinematics and kinetics to understand how these parameters are related with a specific task in dual-task walking. METHODS: We hypothesized that difficulty in dual-task walking would be associated with gait deteriorations as reflected in range of motion and mechanical work expenditure. We tested this hypothesis by quantifying the gait of 383 participants in the Baltimore Longitudinal Study of Aging (68% of whom successfully completed the dual-task walk, 21% failed the motor task, and 11% failed the cognitive task). RESULTS: Compared to successful performers, participants who failed the single motor task had slower gait speed, shorter stride length, higher cadence, and lower range of motion in the knee and ankle joints (p < 0.05, for all), while the participants who failed the cognitive task while walking had longer double support time (p = 0.003), and greater knee absorptive mechanical work (p = 0. 001) and lower ankle generative mechanical work (p < 0. 001). SIGNIFICANCE: These results suggest that dual-task walking may be useful for monitoring subtle and diverse gait deteriorations in aging and possibly for designing interventions for maintaining and regaining proper gait patterns in older adults. PMID- 29723651 TI - Quadrupedal rodent gait compensations in a low dose monoiodoacetate model of osteoarthritis. AB - BACKGROUND: Rodent gait analysis provides robust, quantitative results for preclinical musculoskeletal and neurological models. In prior work, surgical models of osteoarthritis have been found to result in a hind limb shuffle stepping gait compensation, while a high dose monoiodoacetate (MIA, 3 mg) model resulted in a hind limb antalgic gait. However, it is unknown whether the antalgic gait caused by MIA is associated with severity of degeneration from the high dosage or the whole-joint degeneration associated with glycolysis inhibition. RESEARCH QUESTION: This study evaluates rodent gait changes resulting from a low dose, 1 mg unilateral intra-articular injection of MIA compared to saline injected and naive rats. METHODS: Spatiotemporal and dynamic gait parameters were collected from a total of 42 male Lewis rats spread across 3 time points: 1, 2, and 4 weeks post-injection. To provide a detailed analysis of this low dose MIA model, gait analysis was used to uniquely quantify both fore and hind limb gait parameters. RESULTS: Our data indicate that 1 mg of MIA caused relatively minor degeneration and a shuffle-step gait compensation, similar to the compensation observed in prior surgical models. SIGNIFICANCE: These data from a 1 mg MIA model show a different gait compensation compared to a previously studied 3 mg model. This 1 mg MIA model resulted in gait compensations more similar to a previously studied surgical model of osteoarthritis. Additionally, this study provides detailed 4 limb analysis of rodent gait that includes spatiotemporal and dynamic data from the same gait trial. These data highlight the importance of measuring dynamic data in combination with spatiotemporal data, since compensatory gait patterns may not be captured by spatial, temporal, or dynamic characterizations alone. PMID- 29723652 TI - Kinetic differences between level walking and ramp descent in individuals with unilateral transfemoral amputation using a prosthetic knee without a stance control mechanism. AB - BACKGROUND: Individuals with transfemoral amputation (TFA) have difficulty in descending ramps. Although individuals with TFA who descend ramps are speculated to have greater biomechanical demands, this has not been quantified. RESEARCH QUESTION: How do individuals with TFA wearing a prosthetic knee without a stance control mechanism adapt their gait biomechanics to a slightly declined surface? METHODS: We retrospectively analyzed data of level walking and ramp descent (5 degrees decline) from six subjects with TFA who used a prosthesis without a stance control mechanism. Ground reaction force and joint moment, power, and kinematics were derived from three-dimensional motion capture, combined with force measurement. Kinematic and kinetic variables were compared during level walking and ramp descent using the paired tests. RESULTS: Compared with level walking, ramp descent increased the maximum contralateral vertical ground reaction force by 16% of the body weight, on average (standard deviation: 20%). Ramp descent tended to induce smaller concentric hip power during late swing and greater hip eccentric power on the prosthetic-side during late stance. Greater biomechanical demands during ramp descent were indicated by increased maximum medial ground reaction force on both sides, and eccentric joint power of the contralateral ankle during stance. SIGNIFICANCE: For individuals with TFA using a prosthetic knee without a stance control mechanism, descending a ramp can increase loading on the contralateral limb during the loading response; slower walking may alleviate the effect. Ramp descent can change prosthetic-side hip muscles' control of the swinging prosthetic limb, eccentric work on the contralateral ankle plantarflexors during stance, and mediolateral balance. All of these factors should be taken into consideration when individuals with TFA learn to descend a ramp. PMID- 29723654 TI - CTCF knockout reveals an essential role for this protein during the zebrafish development. AB - Chromatin regulation and organization are essential processes that regulate gene activity. The CCCTC-binding factor (CTCF) is a protein with different and important molecular functions related with chromatin dynamics. It is conserved since invertebrates to vertebrates, posing it as a factor with an important role in the physiology. In this work, we aimed to understand the distribution and functional relevance of CTCF during the embryonic development of the zebrafish (Danio rerio). We generated a zebrafish specific anti-Ctcf antibody, and found this protein to be ubiquitous, through different stages and tissues. We used the CRISPR-Cas9 system to induce molecular alterations in the locus. This resulted in early lethality. We delayed the lethality performing knockdown morpholino experiments, and found an aberrant embryo morphology involving malformations in structures through all the length of the embryo. These phenotypes were rescued with human CTCF mRNA injections, showing the specificity of the morpholinos and a partial functional conservation between the fish and the human proteins. Lastly, we found that the pro-apoptotic genes p53 and bbc3/PUMA are deregulated in the ctcf morpholino-injected embryos. In conclusion, CTCF is a ubiquitous factor during the zebrafish development, which regulates the correct formation of different structures of the embryo, and its deregulation impacts on essential cell survival genes. Overall, this work provides a basis to look for the particular functions of CTCF in the different developing tissues and organs of the zebrafish. PMID- 29723653 TI - A Persian-version of the stuttering severity instrument-version four (SSI-4): How the new additions to SSI-4 complement its stuttering severity score? AB - PURPOSE: The fourth version of the Stuttering Severity Instrument (SSI-4) has been available since 2009. It has some modifications and new features which make it more appropriate at least for clinical practice, although further documentation is needed. The objective of the current research was to translate SSI-4 into Persian language and to discuss its relative and absolute reliability as well as its criterion validity for Persian adults who stutter (PWS). We also aimed to study how the new subjective self-reports of the SSI-4 complement the stuttering severity score obtained from the SSI-3 or the SSI-4. METHOD: The cross cultural guideline recommended by the International Quality of Life Assessment project was used to translate the SSI-4 into Persian language. Thirty five PWS from ages 17 to 42 were recruited and 10 speech and language pathologists assessed their stuttering severity using either the SSI-4 or stuttering severity ratings (SR) to test validity and reliability of the Persian translated version. RESULTS: A very high inter-judge relative reliability along with a poor absolute inter-judge reliability was found for the SSI-4 scores. The results were more promising for the intra-judge absolute reliability. Test-retest reliability of the complementary questions to the SSI-4 was also found acceptable. However, no strong relationship was found between the SSI-4 scores and its complementary questions. CONCLUSION: The Persian version of the SSI-4 can be used reliably by trained SLPs for research and clinical purposes, but not to document small changes in stuttering severity. We argue that the response of participants to the complementary self-report questions should also be considered in calculating their stuttering severity score. PMID- 29723655 TI - Effects of aging and insulin resistant states on protein anabolic responses in older adults. AB - Insulin is the principal postprandial anabolic hormone and resistance to its action could contribute to sarcopenia. We developed different types of hyperinsulinemic clamp protocols to measure simultaneously glucose and protein metabolism in insulin resistant states (older adults, obesity, diabetes, etc.). To define effects of healthy aging in response to insulin, we employed the hyperinsulinemic, euglycemic and isoaminoacidemic (HYPER-1) clamp. The net whole body anabolic (protein balance) response to hyperinsulinemia was lower in the elderly vs young (p = 0.007) and was highly correlated with the clamp glucose rate of disposal (r = 0.671, p < 0.001), indicating insulin resistance of protein metabolism concurrent with that of glucose. Differences in insulin resistance due to aging were observed predominantly in men, with older ones exhibiting significant lower anabolism compared with young ones. As most of the anabolism occurs during feeding, we studied the fed-state metabolic responses with aging using the hyperinsulinemic, hyperglycemic and hyperaminoacidemic clamp, including muscle biopsies. Older women showed comparable whole-body protein anabolic responses and stimulation of mixed-muscle protein synthesis by feeding to the young. The responses of skeletal muscle insulin signaling through the Akt-mTORC1 pathway were also unaltered, and therefore consistent with muscle protein synthesis results. Given that type 2 diabetes infers insulin resistance of protein metabolism with aging, we studied 10 healthy, 8 obese, and 8 obese type 2 diabetic elderly women using the HYPER-1 clamp. When compared to the group of young lean women to define the effects of obesity and diabetes with aging, whole body change in net protein balance with hyperinsulinemia was similarly blunted in obese and diabetic older women. However, only elderly obese women with diabetes had lower net balance than lean older women. We conclude that with usual aging, the blunted whole-body anabolic response in elderly subjects is mediated by the failure of insulin to stimulate protein synthesis to the same extent as in the young, especially in men. This blunted response can be overcome at the whole-body and muscle levels during an intravenous fed state supplying a generous amount of protein, in active healthy elderly women. Obese elderly women with and without type 2 diabetes have insulin resistance of protein anabolism at the whole-body level, but this resistance is worsened with diabetes when glucose metabolism is further impaired. More investigation is needed to determine the exact role of insulin in promoting anabolism with aging. The findings from our group are relevant for the field of sarcopenia research as they provide a rationale to offer low cost nutritional interventions for overcoming this detrimental condition associated with aging and diabetes. PMID- 29723656 TI - White matter microstructure alterations correlate with terminally differentiated CD8+ effector T cell depletion in the peripheral blood in mania: Combined DTI and immunological investigation in the different phases of bipolar disorder. AB - BACKGROUND: White matter (WM) microstructural abnormalities and, independently, signs of immunological activation were consistently demonstrated in bipolar disorder (BD). However, the relationship between WM and immunological alterations as well as their occurrence in the various phases of BD remain unclear. METHOD: In 60 type I BD patients - 20 in manic, 20 in depressive, 20 in euthymic phases - and 20 controls we investigated: (i) diffusion tensor imaging (DTI)-derived fractional anisotropy (FA), radial diffusivity (RD) and axial diffusivity (AD) using a tract-based spatial statistics (TBSS) approach; (ii) circulating T cell subpopulations frequencies, as well as plasma levels of different cytokines; (iii) potential relationships between WM and immunological data. RESULTS: We found: (i) a significant widespread combined FA-RD alteration mainly in mania, with involvement of the body of corpus callosum (BCC) and superior corona radiata (SCR); (ii) significant increase in CD4+ T cells as well as significant decrease in CD8+ T cells and their subpopulations effector memory (CD8+ CD28-CD45RA-), terminal effector memory (CD8+ CD28-CD45RA+) and CD8+ IFNgamma+ in mania; (iii) a significant relationship between WM and immunological alterations in the whole cohort, and a significant correlation of FA-RD abnormalities in the BCC and SCR with reduced frequencies of CD8+ terminal effector memory and CD8+ IFNgamma+ T cells in mania only. CONCLUSIONS: Our data show a combined occurrence of WM and immunological alterations in mania. WM abnormalities highly correlated with reduction in circulating CD8+ T cell subpopulations that are terminally differentiated effector cells prone to tissue migration, suggesting that these T cells could play a role in WM alteration in BD. PMID- 29723657 TI - The use of reconstruction plates to treat benign mandibular pathological lesions: A retrospective clinical study. AB - INTRODUCTION: The purpose of this retrospective clinical study was to evaluate the indications for and the utility of reconstruction plates in the management of benign mandibular pathological lesions. The complications associated with plate use were also assessed. PATIENTS AND METHODS: The clinical and radiological data of 23 patients (16 males, 7 females) with large, benign mandibular pathologies were evaluated. During operations, reconstruction plates were used to prevent mandibular fracture or to allow for bone reconstruction after segmental or disarticulation resection. The mean follow-up time was 11.2months. RESULTS: Condylar sag was observed in one patient who had undergone disarticulation resection. A reconstruction plate was removed from one patient because of pain. A plate became exposed in one patient who had undergone a disarticulation resection. Two patients reported slight paraesthesia. Screw-loosening was observed in one patient who had received a non-locking plate. CONCLUSION: Reconstruction plates can be safely used to manage benign mandibular lesions. Preoperative bending of the plates on individualised models is useful for reducing the time required for plate adaptation during operation. Locking reconstruction plates are preferable for preventing screw-loosening. All complications can be managed with careful follow up. PMID- 29723658 TI - Common risk factors of dry socket (alveolitis osteitis) following dental extraction: A brief narrative review. AB - Dry socket is a common complication of dental extraction, especially extraction of third molars. Knowledge of the frequent risk factors of alveolitis osteitis is useful in determining high-risk patients, treatment planning, and preparing the patients mentally. The aim of this narrative review was to summarize the common risk factors of dry socket. Unlike surgery difficulty, surgeon's experience, oral contraception use, and oral hygiene which showed stronger evidence, the influences of age, gender, and smoking were rather inconclusive. The case of female or oral contraceptive effect might relate mainly to estrogen levels (when it comes to dry socket) which can differ considerably from case to case. Many risk factors might be actually a combination of various independent variables, which should be targeted instead, in more comprehensive designs. PMID- 29723659 TI - Impact of green tea intake on clinical improvement in chronic periodontitis: A randomized clinical trial. AB - PURPOSE: To investigate the effects of daily consuming of green tea on clinical criteria in Periodontitis. METHODS: Thirty patients with chronic periodontitis were randomly divided into control and experimental groups after scaling and root planning (SRP). Experimental group consumed green tea herbal for 6 weeks and the control group received no intervention. Clinical indices were measured before and 6 weeks after the intervention, and compared for each groups by non-parametric Wilcoxon test and between two groups by Man-Witheny test. Significance level of the test was considered at 95%. RESULTS: The results showed that probing depth (PD) and bleeding index (BI) reduced significantly in both groups before and after SRP, this reduction in the intervention group was higher than the control group (P=0.003 and 0.031, respectively). On the other hand, reducing the amount of plaque index (PI) despite being significant in each group, was not significant between the two groups (P=0.135). CONCLUSIONS: According to the results of this study, daily consumption of green tea herbal can have a positive impact on the treatment of periodontal diseases and can be applied as a supplement for improving the effects of phase I periodontal therapy. PMID- 29723660 TI - MiR-373 exacerbates renal injury and fibrosis via NF kappaB/MatrixMetalloproteinase-9 signaling by targeting Sirtuin1. AB - BACKGROUND: Renal fibrosis is a final common pathway of chronic kidney disease. SIRT1, a NAD+-dependent protein deacetylase, deacetylates the p65 of NF-kappaB and shows protective effects in kidney disorders. miR-373 directly targets the 3'UTR of SIRT1. However, roles of miR-373 in renal fibrosis are unclear. METHODS: TGF-beta1, a critical regulator of fibrosis, was used to stimulate human kidney-2 cells to establish cell model for renal fibrosis. Unilateral ureteral obstruction (UUO) was performed as an in vivo model. RESULTS: TGF-beta1 induced the level of miR-373, reduced level of SIRT1, and promoted p65 acetylation and MMP-9 expression. These effects were reversed by the miR-373 inhibitor. In the animal model, UUO caused a consistent pattern as demonstrated in vitro. CONCLUSION: These results indicated an undesired effect of miR-373 in the regulation of renal injury and fibrosis by targeting SIRT1-mediated NF-kappaB/MMP-9 signaling, which might provide a potential therapeutic strategy for renal fibrosis. PMID- 29723661 TI - PML nuclear bodies: from architecture to function. AB - PML nuclear bodies are nucleated by the PML protein, which polymerizes into spherical shells where it concentrates many unrelated partner proteins. Emerging data has connected PML bodies to post-translational control, notably conjugation by SUMOs. High concentrations of SUMO-bound proteins were proposed to condense into liquid-like droplets and such phase transition may occur within NBs. Many stress pathways modulate NB formation and recent findings have directly implicated PML in oxidative stress response in vivo. PML may also undergo SUMO dependent ubiquitination/degradation. We highlight recent advances linking PML to partner degradation and other adaptative post-translational modifications in the context of chromatin remodeling, telomere biology, senescence or viral infections. PMID- 29723662 TI - Critical evaluation on proper antithrombotic treatment in different groups of patients undergoing vascular surgery. AB - Antithrombotic treatment including anticoagulants and antiplatelets has evolved during the last decades, and several recommendations have been included in the latest guidelines regarding the proper management of patients undergoing vascular surgery. However, there are significant differences compared to older recommendations, and indications vary among patients with peripheral artery disease, carotid disease, and abdominal aortic aneurysm. In this mini review, we critically evaluate all these data to produce useful conclusions for everyday clinical practice. PMID- 29723663 TI - Hemolytic reactions in the hemolymph of bivalve Sinonovacula constricta show complement-like activity. AB - The complement-like hemolysis method was used to determine the total complement like activity of the plasma of Sinonovacula constricta. In this study, the effects of both physical and chemical conditions on complement hemolysis of S. constricta were measured. Physical conditions included proportion (S. constricta plasma: 2% rabbit red blood cells), temperature, time, and incubation, while the chemical factors consisted of Lipopolysaccharide (LPS), Flagellin (FLA), Zymosan, Peptidoglycan (PGN), Phenylmethanesulfonyl fluoride (PMSF), Methylamine, and Poly (I: C). The results showed that LPS, flagellin, Zymosan and PGN could activate complement-like activity of S. constricta plasma and cause hemolysis. PMSF and methylamine inhibited complement-like activity, resulting in the disappearance of hemolysis. Poly (I: C) had no effect on plasma complement-like activity. When the reaction temperature was less than 50 degrees C, hemolytic activity would increase following an increase in temperature. The ratio of plasma to rabbit blood cells had a great impact on the rate of hemolysis. Additionally, incubation with low speed oscillation could improve the hemolysis rate. It is indicated that the hemolytic reactions in the hemolymph of bivalve S. constricta show complement like activity. The results contribute to further research on immune function of complement in bivalve. PMID- 29723664 TI - Nucleotide-binding oligomerization domain-containing protein 1 (NOD1) in Asian seabass, Lates calcarifer: Cloning, ontogeny and expression analysis following bacterial infection or ligand stimulation. AB - NOD1 (Nucleotide-binding oligomerization domain-containing protein 1) is one of the most prominent intracellular Nod-like receptors (NLRs), responsible for detecting different microbial components and products arising from tissue injury. Here, we have identified and cloned NOD1 transcript in the Asian seabass, Lates calcarifer (AsNOD1), which consists of 3749 nucleotides and encodes for a predicted putative protein of 900 AA. The AsNOD1 possesses the typical structure of NLR family, consisting of N-terminal CARD domain, centrally located NACHT domain and C-terminal LRRs. The AsNOD1 showed ubiquitous tissue expression in 11 different tissues of healthy animals tested with high levels of expression in hindgut and gill. From the ontogenetic expression profile of AsNOD1, it is quite evident that this gene might follow a maternally-transferred trend in euryhaline teleosts, as it is highly abundant in embryonic developmental stages. The constitutive immunomodulation of AsNOD1 in terms of expression level was clearly evident in the different tissues of Asian seabass-injected either with Vibrio alginolyticus or poly I:C. However, injection with Staphylococcus aureus did not elicit similar immunomodulation except for the up-regulation noticed at few time points in some tissues. SISK-cell line induced with different ligands such as poly I:C, LPS and PGN also showed up-regulation of AsNOD1 in certain time-points in vitro. Based on the results obtained in the present study, it can be inferred that the AsNOD1 might play an immunoregulatory role upon exposure to different bacterial as well as viral PAMPs and also might be an important component of innate immune element during embryonic and larval development in the euryhaline teleost Asian seabass. PMID- 29723665 TI - The proinflammatory effects of macrophage-derived NADPH oxidase function in autoimmune diabetes. AB - Type 1 diabetes (T1D) is an autoimmune disease culminating in the destruction of insulin-producing pancreatic beta-cells. While ultimately a T cell-mediated disease, macrophages play an indispensable role in disease initiation and progression. Infiltrating macrophages generate an inflammatory environment by releasing NADPH oxidase-derived superoxide and proinflammatory cytokines. The synthesis of reactive oxygen species (ROS) is acknowledged as putative factors contributing to autoimmunity and beta-cell damage in T1D. In addition to direct lysis, free radicals collectively participate in beta-cell destruction by providing a redox-dependent third signal necessary for islet-reactive CD4 and CD8 T cell maturation and by inducing oxidative post-translational modifications of beta-cell epitopes to further exacerbate autoimmune responses. This review will provide an overview of macrophage function and a synergistic cross-talk with redox biology that contributes to autoimmune dysregulation in T1D. PMID- 29723666 TI - Metal exposure and oxidative stress markers in pregnant Navajo Birth Cohort Study participants. AB - Contamination of soil and water by waste from abandoned uranium mines has led to chronic exposures to metal mixtures in Native American communities. Our previous work demonstrated that community exposures to mine waste increase the likelihood of developing cardiovascular disease, as well as the likelihood of developing multiple chronic diseases including diabetes, hypertension and kidney disease. Exposure to various environmental metals is associated with elevated oxidative stress, which is considered a contributor to these and other chronic disease states. The purpose of the current research was to assess potential associations between exposure to uranium and arsenic and evidence for increased oxidative stress as measured by urinary F2 -isoprostanes in pregnant women enrolled in the Navajo Birth Cohort Study. The current study also included an analysis of zinc as a potential mediator of oxidative stress in the study population. Urinary arsenic and uranium, serum zinc and urinary F2 -isoprostanes were measured for each study participant at enrollment. Study participants were pregnant women with median age of 26.8; 18.9% were enrolled in the 1st trimester, 44.7% were enrolled in the 2nd trimester, and 36.4% were enrolled in the 3rd trimester. Median urinary metal levels were 5.5 and 0.016 ug/g creatinine for arsenic and uranium, respectively. Multivariable regression analysis indicated a significant association between arsenic exposure and the lipid peroxidation product 8-iso-prostaglandin F2alpha, controlling for zinc and trimester. No associations were detected with uranium despite evidence that levels were in the Navajo Birth Cohort samples were 2.3 times the median reported for women in the National Health and Nutrition Examination Survey (2011-12). Zinc was not found to have any causal mediation of the effects of the other metals on oxidative stress. The current work is consistent with other studies that have detected an association between arsenic and elevated oxidative stress. In contrast to arsenic, uranium did not appear to increase oxidative stress response in this study population. These findings are relevant to assessing the potential human impact of chronic exposure to mixed metal waste from abandoned uranium mines. PMID- 29723667 TI - The missing piece in the puzzle: Prediction of aggregation via the protein protein interaction parameter A*2. AB - The tendency of protein pharmaceuticals to form aggregates is a major challenge during formulation development, as aggregation affects quality and safety of the product. In particular, the formation of large native-like particles in the context of liquid-air interfacial stress is a well-known but not fully understood problem. Focusing on the two most fundamental criteria of protein formulation affecting protein-protein interaction, the impact of pH and ionic strength on the interaction parameter A*2 and its link to aggregation upon mechanical stress was investigated. A*2 of two monoclonal antibodies (mABs) and a polyclonal IgG was determined using dynamic light scattering and was correlated to the number of particles formed upon shaking in vials analyzed by visual inspection, turbidity analysis, light obscuration and micro-flow imaging. A good correlation between aggregation induced by interfacial stress and formulation pH was given. It could be shown that A*2 was highest for mAB1 and lowest for IgG, what was in good accordance with the number of particles formed. Shaking of IgG resulted in overall higher numbers of particles compared to the two mABs. A*2 decreased and particle numbers increased with increasing pH. Different to pH, ionic strength only slightly affected A*2. Nevertheless, at high ionic (100 mM) strength the samples exhibited more pronounced particle formation, particularly of large particles >25 um, which was most pronounced at high pH. Protein solutions were identified to form continuous films with an inhomogeneous protein distribution at the liquid-air interface. These areas of agglomerated, native-like protein material can be transferred into the bulk solution by compression-decompression of the interface. Whether or not those clusters lead to the appearance of large protein aggregates or fall apart depends on the attractive or repulsive forces between protein molecules. Thus, protein aggregation due to interfacial stress is correlated with the protein-protein interactions as determined by A*2. This enables to differentiate different antibodies according to their propensity to form particles upon mechanical stress and to identify optimum formulation conditions. PMID- 29723668 TI - Why do proteases mess up with antigen presentation by re-shuffling antigen sequences? AB - The sequence of a large number of MHC-presented epitopes is not present as such in the original antigen because it has been re-shuffled by the proteasome or other proteases. Why do proteases throw a spanner in the works of our model of antigen tagging and immune recognition? We describe in this review what we know about the immunological relevance of post-translationally spliced epitopes and why proteases seem to have a second (dark) personality, which is keen to create new peptide bonds. PMID- 29723669 TI - Cerebellar contribution to locomotor behavior: A neurodevelopmental perspective. AB - The developmental trajectory of the formation of cerebellar circuitry has significant implications for locomotor plasticity and adaptive learning at later stages. While there is a wealth of knowledge on the development of locomotor behavior in human infants, children, and adolescents, pre-clinical animal models have fallen behind on the study of the emergence of behavioral motifs in locomotor function across postnatal development. Since cerebellar development is protracted, it is subject to higher risk of genetic or environmental disruption, potentially leading to abnormal behavioral development. This highlights the need for more sophisticated and specific functional analyses of adaptive cerebellar behavior within the context of whole-body locomotion across the entire span of postnatal development. Here we review evidence on cerebellar contribution to adaptive locomotor behavior, highlighting methodologies employed to quantify and categorize behavior at different developmental stages, with the ultimate goal of following the course of early behavioral alterations in neurodevelopmental disorders. Since experimental paradigms used to study cerebellar behavior are lacking in both specificity and applicability to locomotor contexts, we highlight the use of the Erasmus Ladder - an advanced, computerized, fully automated system to quantify adaptive cerebellar learning in conjunction with locomotor function. Finally, we emphasize the need to develop objective, quantitative, behavioral tasks which can track changes in developmental trajectories rather than endpoint measurement at the adult stage of behavior. PMID- 29723670 TI - Circuit mechanisms of hippocampal reactivation during sleep. AB - The hippocampus is important for memory and learning, being a brain site where initial memories are formed and where sharp wave - ripples (SWR) are found, which are responsible for mapping recent memories to long-term storage during sleep related memory replay. While this conceptual schema is well established, specific intrinsic and network-level mechanisms driving spatio-temporal patterns of hippocampal activity during sleep, and specifically controlling off-line memory reactivation are unknown. In this study, we discuss a model of hippocampal CA1 CA3 network generating spontaneous characteristic SWR activity. Our study predicts the properties of CA3 input which are necessary for successful CA1 ripple generation and the role of synaptic interactions and intrinsic excitability in spike sequence replay during SWRs. Specifically, we found that excitatory synaptic connections promote reactivation in both CA3 and CA1, but the different dynamics of sharp waves in CA3 and ripples in CA1 result in a differential role for synaptic inhibition in modulating replay: promoting spike sequence specificity in CA3 but not in CA1 areas. Finally, we describe how awake learning of spatial trajectories leads to synaptic changes sufficient to drive hippocampal cells' reactivation during sleep, as required for sleep-related memory consolidation. PMID- 29723671 TI - Non-accidental properties, metric invariance, and encoding by neurons in a model of ventral stream visual object recognition, VisNet. AB - When objects transform into different views, some properties are maintained, such as whether the edges are convex or concave, and these non-accidental properties are likely to be important in view-invariant object recognition. The metric properties, such as the degree of curvature, may change with different views, and are less likely to be useful in object recognition. It is shown that in a model of invariant visual object recognition in the ventral visual stream, VisNet, non accidental properties are encoded much more than metric properties by neurons. Moreover, it is shown how with the temporal trace rule training in VisNet, non accidental properties of objects become encoded by neurons, and how metric properties are treated invariantly. We also show how VisNet can generalize between different objects if they have the same non-accidental property, because the metric properties are likely to overlap. VisNet is a 4-layer unsupervised model of visual object recognition trained by competitive learning that utilizes a temporal trace learning rule to implement the learning of invariance using views that occur close together in time. A second crucial property of this model of object recognition is, when neurons in the level corresponding to the inferior temporal visual cortex respond selectively to objects, whether neurons in the intermediate layers can respond to combinations of features that may be parts of two or more objects. In an investigation using the four sides of a square presented in every possible combination, it was shown that even though different layer 4 neurons are tuned to encode each feature or feature combination orthogonally, neurons in the intermediate layers can respond to features or feature combinations present is several objects. This property is an important part of the way in which high capacity can be achieved in the four-layer ventral visual cortical pathway. These findings concerning non-accidental properties and the use of neurons in intermediate layers of the hierarchy help to emphasise fundamental underlying principles of the computations that may be implemented in the ventral cortical visual stream used in object recognition. PMID- 29723672 TI - Tranexamic acid versus aminocaproic acid for blood management after total knee and total hip arthroplasty: A systematic review and meta-analysis. AB - OBJECTIVE: To compare the efficacy and safety of tranexamic acid and aminocaproic acid for reducing blood loss and transfusion requirements after total knee and total hip arthroplasty. METHODS: We conduct electronic searches of Medline (1966 2017.11), PubMed (1966-2017.11), Embase (1980-2017.11), ScienceDirect (1985 2017.11) and the Cochrane Library (1900-2017.11). The primary outcomes, including total blood loss, hemoglobin decline and transfusion requirements. Secondary outcomes include length of hospital stay and postoperative complications such as the incidence of deep vein thrombosis and pulmonary embolism. Each outcome is combined and calculated using the statistical software STATA 12.0. Fixed/random effect model is adopted based on the heterogeneity tested by I2 statistic. RESULTS: A total of 1714 patients are analyzed across three randomized controlled trials (RCTs) and one non-RCT. The present meta-analysis reveals that TXA is associated with a significantly reduction of total blood loss and postoperative hemoglobin drop compared with EACA. No significant differences are identified in terms of transfusion rates, length of hospital stay, and the incidence of postoperative complications. CONCLUSION: Although total blood loss and postoperative hemoglobin drop are significant greater in EACA groups, there is no significant difference between TXA and EACA groups in terms of transfusion rates. Based on the current evidence available, higher quality RCTs are still required for further research. PMID- 29723673 TI - Risk factors of central lymph node metastasis in papillary thyroid carcinoma: A retrospective cohort study. AB - OBJECTIVE: The aim of this study was to explore the risk factors that were associated with central lymph node metastases (CLNM) in papillary thyroid carcinoma (PTC) patients. METHODS: A total of 180 patients with PTC who underwent surgery in our hospital between January 2014 and December 2016 were identified retrospectively. The relationship between clinicopathological factors and CLNM were analyzed by univariate and multivariate logistic regression. RESULTS: The incidence of CLNM was 67.8% (122/180) in PTC patients. Univariate analysis showed that multifocality (p = 0.002), HT (p < 0.001) and LVI (p < 0.001) were significant associated with CLNM. No significant associations were found between factors and CLNM, including age, gender, tumor size and ETE. Multivariate logistic regression analysis showed that multifocality (p = 0.011), HT (p < 0.001) and LVI (p < 0.001) were independent predictors of CLNM in PTC patients. CONCLUSIONS: Our study identified several independent risk factors predicting CLNM in PTC patients, such as multifocality, HT and LVI. The CLNM is very common in PTC patients, and routine prophylactic central neck dissection (PCND) may recommended in PTC patients with those risk factors of CLNM. PMID- 29723674 TI - The surgical challenges of salvage living donor liver transplantation for Hepatocellular carcinoma; The cumulative experience of 100 cases - A retrospective cohort study and a propensity score analysis. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is increasingly managed by liver resection first then salvage liver transplantation in case of recurrence within accepted criteria. Many reports compared the safety of the salvage against the primary surgery in the setting of deceased donation but the difference in case of living donation is not sufficiently defined. Salvage living donor liver transplantation (SLDLT) is believed to be a more challenging surgery than primary living donor liver transplantation (PLDLT) due to operative field adhesions, in addition to the inherent difficulties particularly short vasculobiliary stumps. In this report, we compared both pathways from a surgical perspective in a homogenous LDLT-only cohort. MATERIALS AND METHODS: Over 15 years, 448 LDLTs for HCC were performed in a single liver transplant institution in Taiwan, including PLDLT (n = 348) and SLDLT (n = 100). A retrospective comparative review of the surgical outcomes of both pathways using a propensity score matching model (1-1, 100 pairs) was performed with adjustment for age, Child score and MELD score. The surgical outcome and survival were compared across 2 time eras. RESULTS: The operative data showed that SLDLT surgery encountered more extensive adhesions (57% vs. 0%, p < 0.001), longer operative duration (650 vs. 618 min, p=0.04), and was followed by more incidence of re-exploration (16% vs. 5%, p=0.01), than the PLDLT surgery. There was no significant difference regarding the incidence of in hospital mortality, vascular and biliary complications, or overall survival (OS). The 1-year OS of SLDLT was inferior to PLDLT in the first 50 cases (90% vs. 98%, p=0.03), then the same OS was found in the 2nd 50 cases (96% vs. 96%, p=0.9). CONCLUSIONS: The SLDLT surgery is a demanding lengthy procedure with extensive adhesions and possibility of frequent re-explorations. Significant case load and high centre volume are important factors for safe practice of SLDLT and better cumulative OS. PMID- 29723675 TI - Retroperitoneal laparoscopic nephron sparing surgery for large renal angiomyolipoma: Our technique and experience. A case series of 41 patients. AB - OBJECTIVES: To introduce a 'kidney priority' strategy in treating large renal angiomyolipoma (RAML) with retroperitoneal laparoscopic nephron sparing surgery (RLNSS). PATIENTS AND METHODS: From 2010 to 2017, 41 patients with large RAML underwent RLNSS. Distinguished from the standard practice, the kidney was preferentially mobilized and separated from the RAML. Subsequently, it was reconstructed. Finally, the RAML was resected from the perinephric fat. The perioperative variables, surgical technique and complications were reviewed. Patients were followed up with ultrasonography and computed tomography. RESULTS: RLNSS was successfully performed in 35 patients with four conversions to open surgery and two conversions to nephrectomy, respectively. Eight patients required an intraoperative blood transfusion. Seven patients experienced postoperative complications, including one wound infection, one urinary tract infection, one pneumonia, one urinary fistula and three hemorrhage. The median operation time was 167min (range, 95-285min), the median warm ischemia time was 21 min (range, 0 40 min), and the median estimated blood loss was 200 ml (range, 30-2500 ml). The median postoperative stay was 6.5 days (range, 3-11 days). Angiomyolipoma was confirmed pathologically in all patients. Median serum creatine increased after surgery, from 0.7 mg/dl (range, 0.4-1.1 mg/dl) preoperatively to 0.8 mg/dL (range, 0.5-1.4 mg/dl) postoperatively (P = 0.016). No patient required dialysis, and no recurrence was observed after a median follow-up of 35 months (range, 3-85 months). CONCLUSIONS: RLNSS is a safe, feasible, effective and minimally invasive procedure to manage large RAML in selected patients. PMID- 29723676 TI - Towards optimal intraoperative conditions in esophageal surgery: A review of literature for the prevention of esophageal anastomotic leakage. AB - BACKGROUND: Esophageal anastomotic leakage (EAL) is a severe complication following gastric and esophageal surgery for cancer. Several non-modifiable, patient or surgery related risk factors for EAL have been identified, however, the contribution of modifiable intraoperative parameters remains undetermined. This review provides an overview of current literature on potentially modifiable intraoperative risk factors for EAL. MATERIALS AND METHODS: The PubMed, EMBASE and Cochrane databases were searched by two researchers independently. Clinical studies published in English between 1970 and January 2017 that evaluated the effect of intraoperative parameters on the development of EAL were included. Levels of evidence as defined by the Centre of Evidence Based Medicine (CEBM) were assigned to the studies. RESULTS: A total of 25 articles were included in the final analysis. These articles show evidence that anemia, increased amount of blood loss, low pH and high pCO2 values, prolonged duration of procedure and lack of surgical experience independently increase the risk of EAL. Supplemental oxygen therapy, epidural analgesia and selective digestive decontamination seem to have a beneficial effect. Potential risk factors include blood pressure, requirement of blood products, vasopressor use and glucocorticoid administration, however the results are ambiguous. CONCLUSION: Apart from fixed surgical and patient related factors, several intraoperative factors that can be modified in clinical practice can influence the risk of developing EAL. More prospective, observational studies are necessary focusing on modifiable intraoperative parameters to assess more evidence and to elucidate optimal values of these factors. PMID- 29723677 TI - A meta-analysis of long-term survival outcomes between surgical resection and radiofrequency ablation in patients with single hepatocellular carcinoma <= 2 cm (BCLC very early stage). AB - INTRODUCTION: The optimal management choice in consideration of long-term overall survival (OS) and disease-free survival (DFS) for patients with BLCL very early stage is a matter of debate. AIM: A systematic review and meta-analysis was conducted to evaluate the efficacy of liver resection (RES) and radiofrequency ablation (RFA) for single HCC 2 cm or less. MATERIAL AND METHOD: The primary sources of the reviewed studies through December 2017, without restriction on the languages or regions, were Pubmed and Embase. The hazard ratio (HR) was used as a summary statistic for long-term outcomes. RESULTS: A total of 5 studies qualified for inclusion in this quantified meta-analysis with a total of 729 HCC patients of BCLC very early stage. Only postoperative 1-year OS was comparable in both RES and RFA groups. As for long-term outcomes of 3-year and 5-year OSs, RES was significantly better than RFA, the HRs were 0.64 (95%CI: 0.41, 1.00; P = 0.05) and 0.63 (95%CI: 0.42, 0.95; P = 0.03) respectively. In terms of postoperative DFS, reduced tumor recurrence was observed in RES, and all the short- and long terms outcomes were favored RES. DISCUSSION: RES offers better long-term oncologic outcomes compared with RFA in current clinical evidences. PMID- 29723678 TI - Role of bowel suspension technique to prevent early intestinal obstruction after radical cystectomy with ileal orthotopic neobladder: A retrospective cohort study. AB - OBJECTIVE: We investigate the impact of the bowel suspension technique (BST) on paralytic ileus and early intestinal obstruction (<=60days) after radical cystectomy (RC) with ileal orthotopic neobladder (IONB). METHODS: We retrospectively reviewed 310 patients who underwent RC with IONB for bladder cancer between 2001 and 2017. After forming the Studer IONB, ileal continuity was restored by side-to-side stapled anastomosis. Then, we suspended stapled anastomotic portion of bowel on the posterior peritoneum not to fall into the pelvic cavity. The clinicopathologic characteristics of patients were examined and the onset of paralytic ileus and early intestinal obstruction were identified. Logistic regression analysis was used to identify predictors associated with paralytic ileus and early intestinal obstruction. RESULTS: Of the 310 total patients, paralytic ileus and early intestinal obstruction were identified in 100 (32.3%) and 15 (4.8%), respectively. When patients were divided into two groups (BST [-] vs. BST [+]), the rates of paralytic ileus were not significantly different (64/205[31.2%] vs. 36/105[34.3%], P = 0.585). However, early intestinal obstruction that required surgical treatment was significantly decreased (14/205[6.8%] vs. 1/105[1.0%], P = 0.024). On multivariate analysis, older age was commonly associated with paralytic ileus and early intestinal obstruction (P = 0.008 and P = 0.016). BST was inversely associated with early intestinal obstruction (95% CI: 0.01-0.85, P = 0.034), but not related to paralytic ileus. CONCLUSION: BST significantly reduced early intestinal obstruction without increasing paralytic ileus after RC with IONB. BST could be used as useful technique to reduce severe bowel complications. PMID- 29723679 TI - Neural correlates of active controlled retrieval development: An exploratory ERP study. AB - Working memory is composed of different processes and encompasses not only the temporary storage of information but also its manipulation in order to perform complex cognitive activities. During childhood, one of these manipulation processes, namely active controlled retrieval, improves significantly between the age of 6 to 10, suggesting that the neuronal network supporting this function undergoes substantial maturational changes. The present study examined the neural activity of 14 healthy children and 14 adults while performing an active controlled retrieval task. Results showed differences in brain activity according to active controlled retrieval in a 300-500 ms window corresponding to the retrieval period. Active controlled retrieval was associated with a P3b-like potential in parietal sites for both children and adults. In fronto-central sites, children demonstrated a "N400 like" potential associated with active retrieval processing. These results are discussed in terms of maturational development. PMID- 29723680 TI - Selective impairments in components of affective prosody in neurologically impaired individuals. AB - The intent and feelings of the speaker are often conveyed less by what they say than by how they say it, in terms of the affective prosody - modulations in pitch, loudness, rate, and rhythm of the speech to convey emotion. Here we propose a cognitive architecture of the perceptual, cognitive, and motor processes underlying recognition and generation of affective prosody. We developed the architecture on the basis of the computational demands of the task, and obtained evidence for various components by identifying neurologically impaired patients with relatively specific deficits in one component. We report analysis of performance across tasks of recognizing and producing affective prosody by four patients (three with right hemisphere stroke and one with frontotemporal dementia). Their distinct patterns of performance across tasks and quality of their abnormal performance provides preliminary evidence that some of the components of the proposed architecture can be selectively impaired by focal brain damage. PMID- 29723681 TI - Action affordances and visuo-spatial complexity in motor imagery: An fMRI study. AB - Imagining a complex action requires not only motor-related processing but also visuo-spatial imagery. In the current study, we examined visuo-spatial complexity and action affordances in motor imagery (MI). Using functional magnetic resonance imaging, we investigated the neural activity in MI of reach-to-grasp movements of the right hand in five conditions. Thirty participants were scanned while imagining grasping an everyday object, grasping a geometrical shape, grasping next to an everyday object, grasping next to a geometrical shape, and grasping at nothing (no object involved). We found that MI of grasping next to an object recruited the visuo-spatial cognition network including posterior parietal and premotor regions more strongly than MI of grasping an object. This indicates that grasping next to an object requires additional processing resources rendering MI more complex. MI of a grasping movement involving a familiar everyday object compared to a geometrical shape yielded stronger activation in motor-related regions, including the bilateral supplementary motor area. This activation might be due to inhibitory processes preventing motor execution of motor scripts evoked by everyday objects (action affordances). Our results indicate that visuo-spatial cognition plays a significant role in MI. PMID- 29723683 TI - Beyond the length and look of repolarization: Defining the non-QTc electrocardiographic profiles of patients with congenital long QT syndrome. AB - BACKGROUND: Little is known about the spectrum and prevalence of ECG features beyond the length and morphology of repolarization in patients with congenital long QT syndrome (LQTS). OBJECTIVE: The purpose of this study was to characterize the full ECG phenotype of LQTS patients and evaluate differences by age and LQTS genotype. METHODS: Retrospective review of 943 patients with LQTS (57% female; median age 25 years; interquartile range 9-34 years) was performed. Comprehensive analysis of their initial evaluation ECG was performed using definitions outlined in professional guidelines. RESULTS: Bradycardia was common (n = 320 [34%]), regardless of beta-blocker use. Left-axis deviation (n = 33 [3.5%]) and bundle branch block (n = 5 [0.5%]) were uncommon. T-wave inversion (TWI) involving leads V1 and V3 was more common in LQTS type 2 compared to LQTS type 1 or type 3 (odds ratio [OR] for V1: 2.67, 95% confidence interval [CI] 1.8-3.9; OR for V3: 1.76, 95% CI 1.2-2.6), whereas TWI in leads III and aVF was most common in LQTS type 3 (OR for III: 2.38, 95% CI 1.4-4.2; OR for aVF: 3.14, 95% CI 1.6-6.4). Notched T waves were most apparent at younger ages (48% in patients age 4-10 compared to 12% in patients age >40: P <.0001). CONCLUSION: Beyond the QT interval and bradycardia, ECG abnormalities are uncommon in LQTS patients, and patients almost never have concomitant bundle branch block. Notably, 19% of LQTS patients overall and 27% of LQTS type 2 patients exhibit anterior TWI that would satisfy a diagnostic criterion for arrhythmogenic right ventricular cardiomyopathy, thus creating the potential for diagnostic miscues. PMID- 29723682 TI - Intra-host sequence variability in human papillomavirus. AB - Human papillomaviruses (HPVs) co-evolve slowly with the human host and each HPV genotype displays epithelial tropisms. We assessed the evolution of intra HPV genotype variants within samples, and their association to anogenital site, cervical cytology and HIV status. Variability in the L1 gene of 35 HPV genotypes was characterized phylogenetically using maximum likelihood, and portrayed by phenotype. Up to a thousand unique variants were identified within individual samples. In-depth analyses of the most prevalent genotypes, HPV16, HPV18 and HPV52, revealed that the high diversity was dominated by a few abundant variants. This suggests high intra-host mutation rates. Clades of HPV16, HPV18 and HPV52 were associated to anatomical site and HIV co-infection. Particularly, we observed that one HPV16 clade was specific to vaginal cells and one HPV52 clade was specific to anal cells. One major HPV52 clade, present in several samples, was strongly associated with cervical neoplasia. Overall, our data suggest that tissue tropism and HIV immunosuppression are strong shapers of HPV evolution. PMID- 29723685 TI - Mitochondria-targeted quinones suppress the generation of reactive oxygen species, programmed cell death and senescence in plants. AB - This work focuses on the effect of mitochondria-targeted quinones (SkQs) on plants. SkQs with antioxidant properties are accumulated in the mitochondria of pea cells and suppress the generation of reactive oxygen species. At nanomolar concentrations, SkQs prevented the death of pea leaf epidermal or guard cells caused by chitosan, bacterial lipopolysaccharide or KCN. The protective effect of SkQs was removed by a protonophoric uncoupler. SkQs at micromolar concentrations inhibited the O2 evolution by illuminated chloroplasts and stimulated the respiration of mitochondria. SkQs slowed down the senescence and the death of Arabidopsis thaliana leaves and improved the wheat crop structure. PMID- 29723684 TI - The Role of Exportin-5 in MicroRNA Biogenesis and Cancer. AB - MicroRNAs (miRNAs) are conserved small non-coding RNAs that play an important role in the regulation of gene expression and participate in a variety of biological processes. The biogenesis of miRNAs is tightly controlled at multiple steps, such as transcription of miRNA genes, processing by Drosha and Dicer, and transportation of precursor miRNAs (pre-miRNAs) from the nucleus to the cytoplasm by exportin-5 (XPO5). Given the critical role of nuclear export of pre-miRNAs in miRNA biogenesis, any alterations of XPO5, resulting from either genetic mutation, epigenetic change, abnormal expression level or posttranslational modification, could affect miRNA expression and thus have profound effects on tumorigenesis. Importantly, XPO5 phosphorylation by ERK kinase and its cis/trans isomerization by the prolyl isomerase Pin1 impair XPO5's nucleo-to-cytoplasmic transport ability of pre-miRNAs, leading to downregulation of mature miRNAs in hepatocellular carcinoma. In this review, we focus on how XPO5 transports pre miRNAs in the cells and summarize the dysregulation of XPO5 in human tumors. PMID- 29723686 TI - Minority stress, perceived burdensomeness, and depressive symptoms among sexual minority youth. AB - Although studies have shown links between minority stress and mental health (e.g., Meyer, 2003), there is little research explaining this association. Research has suggested that adequate coping skills might protect youth from the negative impact of stress (Compas et al., 2017). Thus, we aimed to examine: 1) whether associations between minority stress and depressive symptoms occurred through mechanisms of perceived burdensomeness and thwarted belongingness, and 2) whether these associations were dependent on level of problem-solving coping (moderated mediation). Using an online survey of 267 sexual minority youth from the Netherlands (16-22 years; 28.8% male), the results show an indirect relationship of sexual orientation victimization and internalized homophobia with depressive symptoms occurring through perceived burdensomeness; for both males and females. Problem-solving coping skills did not significantly moderate the aforementioned indirect relationships. These results have implications for prevention and intervention work that currently focuses on social isolation rather than perceived burdensomeness. PMID- 29723688 TI - BRAF Mutant Lung Cancer: Programmed Death Ligand 1 Expression, Tumor Mutational Burden, Microsatellite Instability Status, and Response to Immune Check-Point Inhibitors. AB - INTRODUCTION: The efficacy of immune checkpoint inhibitors (ICPi) in BRAF mutant NSCLC is unknown. METHODS: Multi-institutional retrospective chart review identified 39 patients with BRAF mutant NSCLC. The patients were divided into two groups: V600E (group A, n = 21) and non-V600E (group B, n = 18). Programmed death ligand 1 (PD-L1) expression, tumor mutational burden (TMB) and microsatellite instability status were assessed in 29 (74%), 11 (28%), and 12 (31%) patients, respectively. Objective response rate, progression-free survival (PFS) with ICPi, and overall survival were analyzed. RESULTS: High (>=50%), intermediate (1-49%), and no (<1%) PD-L1 expression was observed in 8 of 19 (42%), 6 of 19 (32%), 5 of 19 (26%), and 5 of 10 (50%), 1 of 10 (10%), and 4 of 10 (40%) cases in groups A and B, respectively. Two tumors in group A showed high TMB (25%); none were microsatellite instability status-high. Twenty-two patients (group A, n = 12; group B, n = 10) received ICPi. Objective response rate with ICPi was 25% and 33% in groups A and B, respectively (p = 1.0). Median PFS with ICPi was 3.7 months (95% confidence interval [CI]: 1.6-6.6), and 4.1 months (95% CI: 0.1-19.6) in groups A and B, respectively (log-rank test = 0.81, p = 0.37). Neither BRAF mutation type nor PD-L1 expression affected the response probability/PFS. Median overall survival was not reached (95% CI: 13-NR) and comprised 21.1 months (95% CI: 1.8-NR) for patients who were and were not exposed to ICPi, respectively (log rank test = 5.58, p = 0.018). CONCLUSIONS: BRAF mutant NSCLC is associated with high level of PD-L1 expression, low/intermediate TMB and microsatellite-stable status. ICPi have favorable activity both in BRAF V600E and BRAF non-V600E mutant NSCLC. PMID- 29723687 TI - New Insights on Diagnostic Reproducibility of Biphasic Mesotheliomas: A Multi Institutional Evaluation by the International Mesothelioma Panel From the MESOPATH Reference Center. AB - INTRODUCTION: The 2015 WHO classification of tumors categorized malignant mesothelioma into epithelioid, biphasic (BMM), and sarcomatoid (SMM) for prognostic relevance and treatment decisions. The survival of BMM is suspected to correlate with the amount of the sarcomatoid component. The criteria for a sarcomatoid component and the interobserver variability between pathologists for identifying this component are not well described. In ambiguous cases, a "transitional" (TMM) subtype has been proposed but was not accepted as a specific subtype in the 2015 WHO classification. The aims of this study were to evaluate the interobserver agreement in the diagnosis of BMM, to determine the nature and the significance of TMM subtype, and to relate the percentage of sarcomatoid component with survival. The value of staining for BRCA-1-associated protein (BAP1) and CDKN2A(p16) fluorescence in situ hybridization (FISH) were also assessed with respect to each of the tumoral components. METHODS: The study was conducted by the International Mesothelioma Panel supported by the French National Cancer Institute, the network of rare cancer (EURACAN) and in collaboration with the International Association for the Study of Lung Cancer (IASLC). The patient cases include a random group of 42 surgical biopsy samples diagnosed as BMM with evaluation of SMM component by the French Panel of MESOPATH experts was selected from the total series of 971 BMM cases collected from 1998 to 2016. Fourteen international pathologists with expertise in mesothelioma reviewed digitally scanned slides (hematoxylin and eosin - stained and pan cytokeratin) without knowledge of prior diagnosis or outcome. Cases with at least 7 of 14 pathologists recognizing TMM features were selected as a TMM group. Demographic, clinical, histopathologic, treatment, and follow-up data were retrieved from the MESOBANK database. BAP1 (clone C-4) loss and CDKN2A(p16) homozygous deletion (HD) were assessed by immunohistochemistry (IHC) and FISH, respectively. Kappa statistics were applied for interobserver agreement and multivariate analysis with Cox regression adjusted for age and gender was performed for survival analysis. RESULTS: The 14 panelists recorded a total of 544 diagnoses. The interobserver correlation was moderate (weighted Kappa = 0.45). Of the cases originally classified as BMM by MESOPATH, the reviewers agreed in 71% of cases (385 of 544 opinions), with cases classified as pure epithelioid in 17% (93 of 544), and pure sarcomatoid in 12% (66 of 544 opinions). Diagnosis of BMM was made on morphology or IHC alone in 23% of the cases and with additional assessment of IHC in 77% (402 of 544). The median overall survival (OS) of the 42 BMM cases was 8 months. The OS for BMM was significantly different from SMM and epithelioid malignant mesothelioma (p < 0.0001). In BMM, a sarcomatoid component of less than 80% correlated with a better survival (p = 0.02). There was a significant difference in survival between BMM with TMM showing a median survival at 6 months compared to 12 months for those without TMM (p < 0.0001). BAP1 loss was observed in 50% (21 of 42) of the total cases and in both components in 26%. We also compared the TMM group to that of more aggressive patterns of epithelioid subtypes of mesothelioma (solid and pleomorphic of our large MESOPATH cohort). The curve of transitional type was persistently close to the OS curve of the sarcomatoid component. The group of sarcomatoid, transitional, and pleomorphic mesothelioma were very close to each other. We then considered the contribution of BAP1 immunostaining and loss of CDKN2A(p16) by FISH. BAP1 loss was observed in 50% (21 of 41) of the total cases and in both component in 27% of the cases (11 of 41). There was no significant difference in BAP1 loss between the TMM and non-TMM groups. HD CDKN2A(p16) was detected in 74% of the total cases with no significant difference between the TMM and non-TMM groups. In multivariate analysis, TMM morphology was an indicator of poor prognosis with a hazard ratio = 3.2; 95% confidence interval: 1.6 - 8.0; and p = 0.003 even when compared to the presence of HD CDKN2A(p16) on sarcomatoid component (hazard ratio = 4.5; 95% confidence interval: 1.2 - 16.3, p = 0.02). CONCLUSIONS: The interobserver concordance among the international mesothelioma and French mesothelioma panel suggests clinical utility for an updated definition of biphasic mesothelioma that allows better stratification of patients into risk groups for treatment decisions, systemic anticancer therapy, or selection for surgery or palliation. We also have shown the usefulness of FISH detection of CDKN2A(p16) HD compared to BAP1 loss on the spindle cell component for the separation in ambiguous cases between benign florid stromal reaction from true sarcomatoid component of biphasic mesothelioma. Taken together our results further validate the concept of transitional pattern as a poor prognostic indicator. PMID- 29723690 TI - Abdominal Wall Pseudohernia and Colonic Pseudo-obstruction as Complications of Herpes Zoster. PMID- 29723689 TI - Development and Validation of a Test to Identify Drugs That Cause Idiosyncratic Drug-Induced Liver Injury. AB - BACKGROUND & AIMS: Idiosyncratic drug-induced liver injury (iDILI) is one of the most challenging diagnoses in hepatology. It is frequently impossible to identify the agent that has caused iDILI in patients who take multiple medicines. We developed an in vitro method to identify drugs that cause liver injury in patients, based on drug toxicity to monocyte-derived hepatocyte-like (MH) cells from patient blood samples. We then collected data on patients who were re exposed to drugs found to be toxic in the MH test to validate test performance. METHODS: We performed a prospective study of patients referred to the University Hospital in Munich, Germany, with acute liver injury believed to be caused by medications (300 patients were enrolled in the study and we present data from 40 patients with iDILI and re-exposure to implicated drugs). We collected data from patients on medical history, laboratory test and imaging results, findings from biopsy analyses, and medications taken. Blood samples were collected from all patients and MH cells were isolated and cultured for 10 days. MH cells were then incubated with drugs to which each patient had been exposed, and toxicity was measured based on release of lactate dehydrogenase. Agents found to be toxic to MH cells were considered as candidates for the cause of liver injury. Patients were followed up for up to 6 months after liver injury and data on drug re exposures and subsequent liver damage within the following 3 to 24 months were associated with findings from MH tests. RESULTS: Our test identified 10 drugs that were toxic to MH cells from 13 patients (amoxicillin/clavulanate to cells from 2 patients; diclofenac to cells from 2 patients; methylprednisolone to cells from 2 patients; and atorvastatin, metamizole, pembrolizumab, piperacillin/tazobactam, moxifloxacin, duloxetine, or sertraline each to cells from 1 patient). Thirteen patients had a recurrence of liver injury after inadvertent re-exposure to a single drug, and the MH test correctly identified 12 of the 13 drugs that caused these liver re-injury events. All 86 drugs that were not toxic to MH cells in our assay were safely resumed by patients and were not associated with liver re-injury in 27 patients. Therefore, the MH test identifies drugs that cause liver injury with 92.3% sensitivity and 100% specificity (1 false-negative and 12 true-positive results). CONCLUSIONS: We developed a test to identify drugs that cause liver injury in patients based on their toxicity to MH cells isolated from patients with DILI. We validated results from the assay and found it to identify drugs that cause DILI with 92.3% sensitivity and 100% specificity. The MH cell test could be a tool to identify causes of iDILI, even in patients taking multiple medications. ClinicalTrials.gov no: NCT 02353455. PMID- 29723691 TI - Telehealth-Based Evaluation Identifies Patients Who Are Not Candidates for Liver Transplantation. AB - The burden of chronic liver disease has increased exponentially, driving more patients toward orthotopic liver transplant (OLT) evaluation.1 Because of limited access to transplant centers, patients often travel long distances to be evaluated for OLT.2 Liver transplantation in the VA system is offered at 6 Veterans Affairs transplant centers (VATCs) across the United States, including Richmond. To increase access to specialty care, the VA introduced the Specialty Care Access Network-Extension of Community Healthcare Outcomes (SCAN-ECHO) program,3,4 which was designed to transfer subspecialty knowledge to primary care physicians. In 2011, the Richmond VA introduced SCAN-ECHO for gastroenterology/hepatology providers to facilitate case-based distance learning combined with real-time consultation in hepatology, and the opportunity for an initial triage without completing a formal transplant evaluation. We studied the role of SCAN-ECHO in triaging OLT evaluations and the utility of this health care delivery in the field of transplantation. PMID- 29723693 TI - In-silico approach to investigate death domains associated with nano-particle mediated cellular responses. AB - The current research is based on computational study of the Death Domain (DD) superfamily of proteins involved in the cytoplasmic inflammasome complexes associated with apoptosis and inflammation in response to the nanoparticle treatment. The PYD domains of the DD superfamily proteins, NALP3 and ASC, were chosen for investigation as they are found to be primarily involved in the regulation of innate immunity and are associated with apoptosis and inflammation. The in-vitro studies of these proteins have proven to be a challenge as the proteins have a tendency to aggregate under laboratory conditions. The interactions between PYD-PYD domains of NALP3 & ASC proteins as well as PYD-PYD domains of NALP3 and ASC2 proteins were studied using the computational tools. In our study, the protein structures were taken from Protein Data Bank, and molecular dynamics simulation was performed using NAMD software followed by molecular docking studies using HADDOCK. The generated protein models were validated using PROCHECK and then the protein-protein interactions were analyzed using the molecular visualization tool CHIMERA. We noticed that the affinity between PYD of NALP3-ASC complex is better when compared to the NALP3-ASC2 complex based on their binding energies and docking scores. In the case of NALP3 ASC complex, seven key amino acids of ASC-PYD protein interface interact with four key amino acids of NALP3-PYD protein interface. However, in the case of NALP3-ASC2 complex, six key amino acids of ASC-PYD protein interact with four key amino acids of NALP3-PYD protein. Although, there is not much difference in the number of interacting amino acid residues between the two protein complexes, we understand that the NALP3-ASC exhibits better binding interaction and stability than the NALP3-ASC2 protein complex because the number of hydrogen bonding between them is more when compared to the latter. The hydrogen bonds between the interacting amino acids of the NALP3-ASC protein interface are 12, whereas it is 6 in the case of NALP3-ASC2 protein interaction. The protein-protein interaction seems to be dominated by the energetically significant hydrogen bonding followed by the electrostatic interaction in the NALP3-ASC protein interface, whereas both hydrogen bonding and the interaction between charged residues appears to play a significant role at the NALP3-ASC2 protein interfaces. PMID- 29723695 TI - Patient cost-sharing, socioeconomic status, and children's health care utilization. AB - This paper estimates the effect of cost-sharing on the demand for children's and adolescents' use of medical care. We use a large population-wide registry dataset including detailed information on contacts with the health care system as well as family income. Two different estimation strategies are used: regression discontinuity design exploiting age thresholds above which fees are charged, and difference-in-differences models exploiting policy changes. We also estimate combined regression discontinuity difference-in-differences models that take into account discontinuities around age thresholds caused by factors other than cost sharing. We find that when care is free of charge, individuals increase their number of doctor visits by 5-10%. Effects are similar in middle childhood and adolescence, and are driven by those from low-income families. The differences across income groups cannot be explained by other factors that correlate with income, such as maternal education. PMID- 29723694 TI - X-ray shielding performance of the EPVC composites with micro- or nanoparticles of WO3, PbO or Bi2O3. AB - Attenuation characteristics (mass attenuation coefficient, HVL and the 0.5-mm Pb equivalent thickness) of EPVC composites with micro- or nanoparticles of WO3, PbO, or Bi2O3 with respect to diagnostics X-rays (40-100 kVp) were studied. The composites with nanoparticles outperform the similar composites with microparticles in some respects. Among the composites with nanoparticles, the Bi2O3- and PbO-containing composites perform similarly. Thus, Bi2O3 can be used as a suitable alternative to PbO in shielding designs. PMID- 29723696 TI - Can natural gas save lives? Evidence from the deployment of a fuel delivery system in a developing country. AB - There has been a widespread displacement of coal by natural gas as space heating and cooking technology in Turkey in the last two decades, triggered by the deployment of natural gas networks. We examine the impact of this development on mortality among adults and the elderly by exploiting the variation in the timing of the deployment and the intensity of expansion of gas networks across provinces using data from 2001 to 2016. The results indicate that the expansion of natural gas has caused significant reductions in mortality among both adults and the elderly. These findings are supported by our auxiliary analysis, which demonstrates that the expansion of natural gas networks might have led to a significant improvement in air quality. Furthermore, we show that the mortality gains are primarily driven by reductions in cardio-respiratory deaths, which are more likely to be due to conditions caused or exacerbated by air pollution. PMID- 29723692 TI - A Learning Collaborative Approach Increases Specificity of Diagnosis of Acute Liver Failure in Pediatric Patients. AB - BACKGROUND & AIMS: Many pediatric patients with acute liver failure (PALF) do not receive a specific diagnosis (such as herpes simplex virus or Wilson disease or fatty acid oxidation defects)-they are left with an indeterminate diagnosis and are more likely to undergo liver transplantation, which is contraindicated for some disorders. Strategies to facilitate complete diagnostic testing should increase identification of specific liver diseases and might reduce liver transplantation. We investigated whether performing recommended age-specific diagnostic tests (AS-DTs) at the time of hospital admission reduces the percentage PALFs with an indeterminate diagnosis. METHODS: We performed a multinational observational cohort study of 658 PALF participants in the United States and Canada, enrolled at 10 medical centers, during 3 study phases from December 1999 through December 2014. A learning collaborative approach was used to implement AS-DT using an electronic medical record admission order set at hospital admission in phase 3 of the study. Data from 10 study sites participating in all 3 phases were compared before (phases 1 and 2) and after (phase 3) diagnostic test recommendations were inserted into electronic medical record order sets. RESULTS: The percentage of subjects with an indeterminate diagnosis decreased significantly between phases 1-2 (48.0%) and phase 3 (to 30.8%) (P = .0003). The 21-day cumulative incidence rates for liver transplantation were significantly different among phase 1 (34.6%), phase 2 (31.9%), and phase 3 (20.2%) (P = .030). The 21-day cumulative incidence rates for death did not differ significantly among phase 1 (17.9%), phase 2 (11.9%), and phase 3 (11.3%) (P = .20). CONCLUSIONS: In a multinational study of children with acute liver failure, we found that incorporating diagnostic test recommendations into electronic medical record order sets accessed at time of admission reduced the percentage with an indeterminate diagnosis that may have reduced liver transplants without increasing mortality. Widespread use of this approach could significantly enhance care of acute liver failure in children. PMID- 29723697 TI - An exploratory radiomics analysis on digital breast tomosynthesis in women with mammographically negative dense breasts. AB - PURPOSE: To compare Digital Breast Tomosynthesis (DBT) for cancers and normal screens in women with dense breasts and negative mammography using a Radiomics approach. MATERIALS AND METHODS: A substudy (N = 40) of the 'Adjunct Screening With Tomosynthesis or Ultrasound in Women With Mammography-Negative Dense Breasts (ASTOUND)' trial was done based on 20 women who had DBT-detected, histology proven, breast cancer and 20 controls matched for age and density. Using a Radiomics approach normal and pathological breast parenchyma were evaluated, and correlations among Radiomics features and clinical and prognostic parameters were investigated. RESULTS: The median age of the patients was 50 years (range 39-70 years). After Radiomics feature number reduction, 3 of 6 (50%) selected features differed between controls and cancers (Skewness (0.002); Entropy (p.004); 90percentile (p.006)). Three Radiomics features (Energy, Entropy and Dissimilarity) significantly correlated to tumor size (r = -0.15,r = 0.49,r = 0.51), but not with prognostic factors. Entropy correlated with Estrogen Receptor status (r = -0,46; p.004). CONCLUSION: Radiomics features in patients with dense breasts and negative mammography appear to differ between cancerous and normal breast tissue, with evidence of correlation with tumor size and estrogen receptors. This new information warrants further evaluation in larger studies and could contribute to improved understanding of breast cancer through imaging, and may support tailored screening and treatments. PMID- 29723699 TI - Measurement of pharmacokinetics and tissue distribution of three bioactive constituents from Zanthoxylum armatum DC in rat plasma and tissues through UFLC MS/MS. AB - The compounds of N-Methylanhydrotetrahydroberberrubine A, dictamnine and eudesmin were the primary bioactive components in the roots of Zanthoxylum armatum DC (Z. armatum). To clarify the pharmacokinetics and distribution of these three compounds, an ultra-fast liquid chromatography-tandem mass spectrometry (UFLC MS/MS) was employed to determine the contents of these three compounds in rat plasma and seven tissues. The separation was achieved on a Kinetex XB-C18 100A column (2.1 * 50 mm, 2.6 MUm, Phenomenex). The optimized mobile phase system was set with 0.10/00 formic acid aqueous solution (A) and acetonitrile (containing 0.10/00 formic acid) (B) with a programmed elution of 0.00 to 0.50 min, 2% B; 0.51-4.00 min, 30%-60% B; and 4.01-5.00 min, 2% B. All analytes were measured with optimized multiple reaction monitoring (MRM) in the positive ion ESI mode. Berberine hydrochloride was selected as the internal standard (IS). The MS/MS transitions of N-Methylanhydrotetrahydroberberrubine A, dictamnine, eudesmin and IS were 339.9135.1, 200.1 -> 129.1, 387.4 -> 369.0 and 337.1 -> 321.1, respectively. The lower limits quantification (LLOQ) of the three analytes was 0.5-20 ng/ml. The linear ranges were 0.5-400 ng/ml for N Methylanhydrotetrahydroberberrubine A and dictamnine and 20-4000 ng/ml for eudesmin. The present analysis showed that the two alkaloids were quickly absorbed, with Tmax in 0.167-0.292 h, and eudesmin was absorbed in 2.5 h. Moreover, all compounds were found at high concentrations in the gastrointestinal track. These results are helpful for further investigation of the clinical application of Z. armatum. PMID- 29723698 TI - ERK5/KLF2 activation is involved in the reducing effects of puerarin on monocyte adhesion to endothelial cells and atherosclerotic lesion in apolipoprotein E deficient mice. AB - Puerarin has properties of anti-oxidation and anti-inflammation, which has been demonstrated protective effects in atherosclerosis and other cardiovascular diseases. However, the detail molecular mechanism still remains unclear. Here, we determined whether the atheroprotective effect of puerarin was by reducing monocyte adhesion and explored the underlying mechanism. The results showed that puerarin dose- and time-dependently reduced oxLDL-induced monocyte THP-1 adhesion to HUVECs and the expression of adhesion-related genes such as VCAM-1, ICAM-1, MCP-1 and IL-8 in HUVECs. Puerarin activated ERK5 phosphorylation and up regulated expressions of downstream KLF2 and its targeted genes endothelial nitric oxide synthase and thrombomodulin. However, the protective effects were reversed by ERK5/KLF2 pathway inhibitor XDM8-92, BIX02189 or KLF2 siRNA suggesting the pathway involved in the function. The ex vivo assay, in which THP 1 adhesion to endothelium isolated from apoE-/- mice received various treatments further confirmed the results from HUVECs. Finally, we found that the atherosclerotic lesions in both cross sections at aortic root and whole aorta were significantly reduced in high fat-diet (HFD) mice with puerarin treatment compared with the HFD-only mice, but were increased respectively by 76% and 71% in XMD8-92 group, and 82% and 73% in BIX02189 group. Altogether, the data revealed that puerarin inhibited the monocyte adhesion in vitro and in vivo and thus reduced atherosclerotic lesions in apoE-/- mice; the protective effects were mediated by activation of ERK5/KLF2 signaling pathway. Our findings advance the understanding of puerarin function in atherosclerosis and point out a way to prevent the disease. PMID- 29723700 TI - Typologies of intimate partner violence-maternal parenting and children's externalizing problems: The moderating effect of the exposure to other forms of family violence. AB - Typologies of IPV and parenting practices in mothers who experienced police reported IPV remain surprisingly unexplored, in addition to how those typologies are linked with children's externalizing problems. Using data from 162 Portuguese mother-child dyads with a police or child protection services referral of IPV, this study aimed to: (a) identify IPV-parenting typologies; (b) test the associations between typologies and children's externalizing problems, and (c) examine the moderating effect of children's exposure to other forms of family violence in those associations. Using a person-centered approach, two IPV parenting typologies were found: a spillover typology, with high levels of physical, psychological, and sexual violence and high levels of harsh and inconsistent parenting practices; and a compartmentalized typology, with high levels of physical, psychological, and sexual violence and lower ineffective parenting practices. Results also showed that externalizing symptoms (reported by mothers and teachers) were significantly lower in children of mothers in the compartmentalized typology compared to those in the spillover typology. Children's direct exposure to other forms of family violence moderated this association. Findings suggested that children with a high exposure to other forms of family violence showed the highest levels of externalizing problems when their mothers were classified into the spillover typology, and they exhibited the lowest levels of externalizing problems when their mothers were classified in the compartmentalized typology. PMID- 29723701 TI - Ritualistic child sexual abuse in post-conflict Eastern DRC: Factors associated with the phenomenon and implications for social work. AB - Ritualistic child sexual abuse (RCSA) is a critical and under-recognised form of child maltreatment prevailing in developing countries. In the Democratic Republic of Congo (DRC), children from specific communities suffer complex forms of RCSA perpetrated with extreme brutality by various individuals and groups of conspirators. Although the DRC has achieved significant milestones towards combatting war-related sexual abuse of women and children, disturbing forms of RCSA, notably child kidnapping, rape, child defilement for fetish and superstitious beliefs, child sexual exploitation, and cult-based child marriage persist and affect many victims. This study examines the factors associated with the resurgence of RCSA in post-conflict eastern DRC. The article also discusses the implications of such forms of abuse for social work practice and education in a post-war context. PMID- 29723702 TI - Dynamic shear-lag model for understanding the role of matrix in energy dissipation in fiber-reinforced composites. AB - : Lightweight and high impact performance composite design is a big challenge for scientists and engineers. Inspired from well-known biological materials, e.g., the bones, spider silk, and claws of mantis shrimp, artificial composites have been synthesized for engineering applications. Presently, the design of ballistic resistant composites mainly emphasizes the utilization of light and high-strength fibers, whereas the contribution from matrix materials receives less attention. However, recent ballistic experiments on fiber-reinforced composites challenge our common sense. The use of matrix with "low-grade" properties enhances effectively the impact performance. In this study, we establish a dynamic shear lag model to explore the energy dissipation through viscous matrix materials in fiber-reinforced composites and the associations of energy dissipation characteristics with the properties and geometries of constituents. The model suggests that an enhancement in energy dissipation before the material integrity is lost can be achieved by tuning the shear modulus and viscosity of a matrix. Furthermore, our model implies that an appropriately designed staggered microstructure, adopted by many natural composites, can repeatedly activate the energy dissipation process and thus improve dramatically the impact performance. This model demonstrates the role of matrix in energy dissipation, and stimulates new advanced material design concepts for ballistic applications. STATEMENT OF SIGNIFICANCE: Biological composites found in nature often possess exceptional mechanical properties that man-made materials haven't be able to achieve. For example, it is predicted that a pencil thick spider silk thread can stop a flying Boeing airplane. Here, by proposing a dynamic shear-lag model, we investigate the relationships between the impact performance of a composite with the dimensions and properties of its constituents. Our analysis suggests that the impact performance of fiber-reinforced composites could improve surprisingly with "low grade" matrix materials, and discontinuities (often regarded as "defects") may play an important role in energy dissipation. Counter-intuitive as it may seem, our work helps understanding the secrets of the outstanding dynamic properties of some biological materials, and inspire novel ideas for man-made composites. PMID- 29723703 TI - 3D multicellular model of shock wave-cell interaction. AB - : Understanding the interaction between shock waves and tissue is critical for advancing the use of shock waves for medical applications, such as cancer therapy. This work aims to study shock wave-cell interaction in a more realistic environment, relevant to in vitro and in vivo studies, by using 3D computational models of healthy and cancerous cells. The results indicate that for a single cell embedded in an extracellular environment, the cellular geometry does not influence significantly the membrane strain but does influence the von Mises stress. On the contrary, the presence of neighbouring cells has a strong effect on the cell response, by increasing fourfold both quantities. The membrane strain response of a cell converges with more than three neighbouring cell layers, indicating that a cluster of four layers of cells is sufficient to model the membrane strain in a large domain of tissue. However, a full 3D tissue model is needed if the stress evaluation is of main interest. A tumour mimicking multicellular spheroid model is also proposed to study mutual interaction between healthy and cancer cells and shows that cancer cells can be specifically targeted in an early stage tumour-mimicking environment. STATEMENT OF SIGNIFICANCE: This work presents 3D computational models of shock-wave/cell interaction in a biophysically realistic environment using real cell morphology in tissue mimicking phantoms and multicellular spheroids. Results show that cell morphology does not strongly influence the membrane strain but influences the von Mises stress. While the presence of neighbouring cells significantly increases the cell response, four cell layers are enough to capture the membrane strain change in tissue. However, a full tissue model is necessary if accurate stress analysis is needed. The work also shows that cancer cells can be specifically targeted in early stage tumour mimicking environment. This work is a step towards realistic modelling of shock-wave/cell interactions in tissues and provides insight on the use of 3D models for different scenarios. PMID- 29723704 TI - Curvature-dependent effects of nanotopography on classical immune complement activation. AB - : The aim of this study was to investigate how the size of nanosized surface features affect classical immune complement activation through adsorption of IgG and the following binding of C1q. By using model surfaces with immobilized SiO2 nanoparticles of different sizes (8, 32 and 68 nm in diameter), three different curvatures with the same chemistry was systematically studied and analyzed using the acoustic sensing technique; Quartz Crystal Microbalance with Dissipation Monitoring (QCM-D). Circular Dichroism (CD) was employed to study any changes in the secondary structure of IgG using a methodology with stacked functionalized substrates. Our results show that the amount of IgG adsorption increased slightly with nanoparticle size, but also showed a strong size/curvature-dependent effect on the following C1q binding, with the highest binding to IgG adsorbed on the largest nanoparticles and a smooth control surface, indicating that classical immune complement activation possibly increase with decreasing curvature. We conclude that the difference in C1q binding was not due to changes in the secondary structure of IgG, suggesting that geometrical arrangement of adsorbed IgG is the determining factor. STATEMENT OF SIGNIFICANCE: We have shown that small changes at the topographical nanoscale can give large effects on the initiation of the classical immune complement cascade, an important immunological reaction that take place when a foreign material is inserted in the body. By developing a methodology using silicon dioxide nanoparticles with three different sizes, to systematically study their impact on the secondary structure and binding of human immunoglobulin G (IgG) to the initiator protein C1q of the classical complement cascade, we have shown that the initiation of the classical immune complement is hampered by the sharp curvature of the smaller nanoparticles. We conclude that this is not mediated by changes in the secondary structure of the adsorbed proteins, but rather an effect of curvature-induced spatial mismatch. The results provide a possible mechanistic explanation on how nanotopography may effect protein adsorption and protein cascade events. PMID- 29723705 TI - Nanoparticle-in-microparticle oral drug delivery system of a clinically relevant darunavir/ritonavir antiretroviral combination. AB - : Nanonizationhas been extensively investigated to increase theoral bioavailability of hydrophobicdrugsin general andantiretrovirals(ARVs)used inthe therapy of the human immunodeficiency virus (HIV) infection in particular. Weanticipatedthatin the caseofprotease inhibitors, a family of pH-dependent ARVsthatdisplay high aqueous solubility undertheacidconditionsof thestomach andextremely low solubilityunder the neutral ones ofthe small intestine, this strategy might failowing to an uncontrolled dissolution-re-precipitation process that will take place along the gastrointestinal tract.To tackle thisbiopharmaceutical challenge, in this work, wedesigned, produced and fully characterized a novelNanoparticle-in-MicroparticleDelivery System(NiMDS)comprised of pure nanoparticlesofthefirst-line protease inhibitor darunavir(DRV) and itsboosting agentritonavir (RIT) encapsulated within film-coated microparticles.For this, a clinically relevant combination of pure DRV and RIT nanoparticles wassynthesized by a sequential nanoprecipitation/solvent diffusion and evaporation method employing sodium alginateas viscosity stabilizer. Then, pure nanoparticles were encapsulated within calcium alginate/chitosanmicroparticlesthat were film-coated with a series ofpoly(methacrylate) copolymers with differential solubility in the gastrointestinal tract. This coating ensured full stability under gastric-like pH and sustained drug release under intestinal one. PharmacokineticstudiesconductedinalbinoSpragueDawleyratsshowed that DRV/RIT loadedNiMDSs containing 17% w/w drug loading based on dry weight significantlyincreasedthe oral bioavailabilityof DRVby 2.3-foldwith respect to both theunprocessedandthenanonized DRV/RIT combinations that showed statistically similar performance. Moreover, they highlighted the limited advantage of only drugnanonizationto improve the oral pharmacokinetics of protease inhibitors and the potential of our novel delivery approach to improve the oral pharmacokinetics of nanonized poorly water-soluble drugs displaying pH-dependent solubility. STATEMENT OF SIGNIFICANCE: Protease inhibitors (PIs) are gold-standard drugs in many ARV cocktails. Darunavir (DRV) is the latest approved PI and it is included in the 20th WHO Model List of Essential Medicines. PIs poorly-water soluble at intestinal pH and more soluble under gastric conditions. Drug nanonization represents one of the most common nanotechnology strategies to increase dissolution rate of hydrophobic drugs and thus, their oral bioavailability. For instance, pure drug nanosuspensions became the most clinically relevant nanoformulation. However, according to the physicochemical properties of PIs, nanonization does not appear as a very beneficial strategy due to the fast dissolution rate anticipated under the acid conditions of the stomach and their uncontrolled recrystallization and precipitation in the small intestine that might result in the formation of particles of unpredictable size and structure (e.g., crystallinity and polymorphism) and consequently, unknown dissolution rate and bioavailability. In this work, we developed a sequential nanoprecipitation method for the production of pure nanoparticles of DRV and its boosting agent ritonavir in a clinically relevant 8:1 wt ratio using alginate as viscosity stabilizer and used this nanosuspension to produce a novel kind of nanoparticle in-microparticle delivery system that was fully characterized and the pharmacokinetics assessed in rats. The most significant points of the current manuscript are. PMID- 29723706 TI - Sausage fermentation and starter cultures in the era of molecular biology methods. AB - Fermented sausages have a long tradition originating from Europe and they constitute a significant part of the Mediterranean diet. This kind of products has a specific microbiota that is typical of the region or area where they are produced. Therefore, in order to protect the traditional aspect of these products, it is essential to understand the microbial ecology during fermentation by studying the dynamic changes that occur and to select autochthonous starter cultures that can be used in the production. In this paper we summarize the state of the art concerning the selection and use of starter cultures and ecology aspects of naturally fermented sausages. We pay particular attention to the application of bacteriocinogenic strains as they could provide an additional tool in the prevention of foodborne pathogens as well as enhancing the competitiveness of the starter organisms. Microbial ecology of fermented sausages has been determined by traditional microbiological methods, but the introduction in food microbiology of new molecular techniques complements the studies carried out so far and allows scientists to overcome the limitations of traditional methods. Next Generation Sequencing (NGS) techniques represent a change in the way microbiologists address ecology and diversity in foods. Indeed the application of metataxonomics and metagenomics will permit a detailed understanding of microbial ecology. A thorough knowledge of the mechanisms behind the biological processes will enhance meat fermentation control and modulation to obtain products with desired organoleptic properties. PMID- 29723707 TI - Cross-regulation between Notch signaling pathway and miRNA machinery in cancer. AB - Despite their simple structure, the Notch family of receptors regulates a wide spectrum of key cellular processes including development, tissue patterning, cell fate determination, proliferation, differentiation and, cell death. On the other hand, accumulating date pinpointed the role of non-coding microRNAs, namely miRNAs in cancer initiation/progression via regulating the expression of multiple oncogenes and tumor suppressor genes, as such the Notch signaling. It is now documented that these two partners are in one or in the opposite directions and rule together the cancer fate. Here, we review the current knowledge relevant to this tricky interplay between different miRNAs and components of Notch signaling pathway. Further, we discuss the implication of this crosstalk in cancer progression/regression in the context of cancer stem cells, tumor angiogenesis, metastasis and emergence of multi-drug resistance. Understanding the molecular cues and mechanisms that occur at the interface of miRNA and Notch signaling would open new avenues for development of novel and effective strategies for cancer therapy. PMID- 29723708 TI - Broad spectrum detection of DNA damage by Repair Assisted Damage Detection (RADD). AB - Environmental exposures, reactive by-products of cellular metabolism, and spontaneous deamination events result in a spectrum of DNA adducts that if un repaired threaten genomic integrity by inducing mutations, increasing instability, and contributing to the initiation and progression of cancer. Assessment of DNA adducts in cells and tissues is critical for genotoxic and carcinogenic evaluation of chemical exposure and may provide insight into the etiology of cancer. Numerous methods to characterize the formation of DNA adducts and their retention for risk assessment have been developed. However, there are still significant drawbacks to the implementation and wide-spread use of these methods, because they often require a substantial amount of biological sample, highly specialized expertise and equipment, and depending on technique, may be limited to the detection and quantification of only a handful of DNA adducts at a time. There is a pressing need for high throughput, easy to implement assays that can assess a broad spectrum of DNA lesions, allowing for faster evaluation of chemical exposures and assessment of the retention of adducts in biological samples. Here, we describe a new methodology, Repair Assisted Damage Detection (RADD), which utilizes a DNA damage processing repair enzyme cocktail to detect and modify sites of DNA damage for a subsequent gap filling reaction that labels the DNA damage sites. This ability to detect and label a broad spectrum of DNA lesions within cells, offers a novel and easy to use tool for assessing levels of DNA damage in cells that have been exposed to environmental agents or have natural variations in DNA repair capacity. PMID- 29723709 TI - Aiding the search: Examining individual differences in multiply-constrained problem solving. AB - Understanding and resolving complex problems is of vital importance in daily life. Problems can be defined by the limitations they place on the problem solver. Multiply-constrained problems are traditionally examined with the compound remote associates task (CRAT). Performance on the CRAT is partially dependent on an individual's working memory capacity (WMC). These findings suggest that executive processes are critical for problem solving and that there are reliable individual differences in multiply-constrained problem solving abilities. The goals of the current study are to replicate and further elucidate the relation between WMC and CRAT performance. To achieve these goals, we manipulated preexposure to CRAT solutions and measured WMC with complex-span tasks. In Experiment 1, we report evidence that preexposure to CRAT solutions improved problem solving accuracy, WMC was correlated with problem solving accuracy, and that WMC did not moderate the effect of preexposure on problem solving accuracy. In Experiment 2, we preexposed participants to correct and incorrect solutions. We replicated Experiment 1 and found that WMC moderates the effect of exposure to CRAT solutions such that high WMC participants benefit more from preexposure to correct solutions than low WMC (although low WMC participants have preexposure benefits as well). Broadly, these results are consistent with theories of working memory and problem solving that suggest a mediating role of attention control processes. PMID- 29723710 TI - On a 'failed' attempt to manipulate visual metacognition with transcranial magnetic stimulation to prefrontal cortex. AB - Rounis, Maniscalco, Rothwell, Passingham, and Lau (2010) reported that stimulation of prefrontal cortex impairs visual metacognition. Bor, Schwartzman, Barrett, and Seth (2017) attempted to replicate this result, but adopted an experimental design that reduced their chanceof obtaining positive findings. Despite that, their results appeared initially consistent with those of Rounis et al., but they subsequently claimed it was necessary to discard ~30% of their subjects, after which they reported a null result. Using computer simulations, we found that, contrary to their supposed purpose, excluding subjects by Bor et al.'s criteria does not reduce false positive rates. Including both their positive and negative result in a Bayesian framework, we show the correct interpretation is that PFC stimulation likely impaired visual metacognition, exactly contradicting Bor et al.'s claims. That lesion and inactivation studies demonstrate similar positive effects further suggests that Bor et al.'s reported negative finding isn't evidence against the role of prefrontal cortex in metacognition. PMID- 29723711 TI - Implicit sequence learning of chunking and abstract structures. AB - The current study investigated whether people can simultaneously acquire knowledge about concrete chunks and abstract structures in implicit sequence learning; and whether the degree of abstraction determines the conscious status of the acquired knowledge. We adopted three types of stimuli in a serial reaction time task in three experiments. The RT results indicated that people could simultaneously acquire knowledge about concrete chunks and abstract structures of the temporal sequence. Generation performance revealed that ability to control was mainly based on abstract structures rather than concrete chunks. Moreover, ability to control was not generally accompanied with awareness of knowing or knowledge, as measured by confidence ratings and attribution tests, confirming that people could control the use of unconscious knowledge of abstract structures. The results present a challenge to computational models and theories of implicit learning. PMID- 29723712 TI - The presence of your absence: A conditioning theory of grief. AB - I present a conditioning theory of grief. From conditioning research on appetitive disorders (e.g., addiction and binge eating), I borrow the concept cue elicited craving. More precisely, the theory postulates that, throughout a life together, a variety of cues become associated with the presence of the loved one and that because of this these cues can trigger craving and (an action tendency for) searching for the deceased. Starting from this perspective, I additionally invoke extinction phenomena to explain the possible persistence of grief. Arguably, the theory has good heuristic value, because it allows to explain a variety of grief symptoms and to bring together existing knowledge in a unifying learning framework. In addition, the theory has good predictive value, because it opens the door to considering new research and treatment directions. PMID- 29723713 TI - Multiple fear-related stimuli enhance physiological arousal during extinction and reduce physiological arousal to novel stimuli and the threat conditioned stimulus. PMID- 29723714 TI - Monitoring of toxicity of As(V) solutions by AMPHITOX test without and with treatment with zerovalent iron nanoparticles. AB - Changes in toxicity of As(V) solutions from acute to chronic exposure have been evaluated by the AMPHITOX test. This test employs Rhinella arenarum, a widely distributed toad in Argentine areas. LOEC values were 6.37 and 1.88 mg L-1 for embryos and larvae, respectively, and serious sublethal effects have been observed. Toxicity of As(V) solutions has been also evaluated after treatment with zerovalent iron nanoparticles (nZVI). After 60 min of treatment with nZVI, As(V) removal was 77%, and neither lethal nor sublethal effects were observed. However, nZVI had to be eliminated before the bioassay because they caused adverse effects in both embryos and larvae. This work highlights the high sensitivity of R. arenarum to As(V), the relevance to assess toxicity on different periods of the lifecycle, and the need to expand exposure to As(V) to chronic times. The utility of the test for monitoring toxicity changes in As(V) solutions after nZVI treatment has been also shown. PMID- 29723715 TI - Expression of genes related to metal metabolism in the freshwater fish Hyphessobrycon luetkenii living in a historically contaminated area associated with copper mining. AB - Copper (Cu) mining in Minas do Camaqua-Brazil, released significant amounts of metals into the Joao Dias creek, where Hyphessobrycon luetkenii inhabit. Because the involvement of Cu in biological processes its concentration and availability is regulated by molecules as the metal regulatory transcription factor (MTF-1), metallothionein (MT) and transporters (ATP7A and CTR1). These genes were whole sequenced and their expression (GE) evaluated in gills, liver and intestine. Were collected fish in non-contaminated and contaminated (Cu 3.4-fold higher) sites of the creek (CC and PP) and respectively translocated (CP and PC) for 96 h. The GE of the non-translocated groups evidenced that MT, MTF-1 and CTR1 have organ specific differences between both communities. Additionally the translocation allowed to identify organ specific changes associated with the activation/inactivation of protective mechanisms. These findings indicate that MTF-1, MT and CTR-1 GE play an important role in the tolerance of H. luetkenii to Cu contamination. PMID- 29723716 TI - A practical strategy for the accurate measurement of residual dipolar couplings in strongly aligned small molecules. AB - Accurate measurement of residual dipolar couplings (RDCs) requires an appropriate degree of alignment in order to optimize data quality. An overly weak alignment yields very small anisotropic data that are susceptible to measurement errors, whereas an overly strong alignment introduces extensive anisotropic effects that severely degrade spectral quality. The ideal alignment amplitude also depends on the specific pulse sequence used for the coupling measurement. In this work, we introduce a practical strategy for the accurate measurement of one-bond 13C-1H RDCs up to a range of ca. -300 to +300 Hz, corresponding to an alignment that is an order of magnitude stronger than typically employed for small molecule structural elucidation. This strong alignment was generated in the mesophase of the commercially available poly-gamma-(benzyl-L-glutamate) polymer. The total coupling was measured by the simple and well-studied heteronuclear two dimensional J-resolved experiment, which performs well in the presence of strong anisotropic effects. In order to unequivocally determine the sign of the total coupling and resolve ambiguities in assigning total couplings in the CH2 group, coupling measurements were conducted at an isotropic condition plus two anisotropic conditions of different alignment amplitudes. Most RDCs could be readily extracted from these measurements whereas more complicated spectral effects resulting from strong homonuclear coupling could be interpreted either theoretically or by simulation. Importantly, measurement of these very large RDCs actually offers significantly improved data quality and utility for the structure determination of small organic molecules. PMID- 29723717 TI - Lipopolysaccharides and peptidoglycans modulating the interaction of Au naparticles with cell membranes models at the air-water interface. AB - Understanding the interactions between nanoparticles and biological surfaces is of great importance for many areas of nanomedicine and calls for detailed studies at the molecular level using simplified models of cellular membranes. In this paper, water-dispersed polyvinylpyrrolidonestabilized gold nanoparticles (AuNPs) were incorporated in floating monolayers of selected lipids at the air-water interface as cell membrane models. Surface pressure-area isotherms showed the condensation of glycoside-free lipid monolayers, suggesting their adsorption on the nanoparticle surface through the hydrophilic head groups. On the other hand, monolayers containing glycoside derivatives expanded upon AuNPs incorporation, pointing that the supramolecular structure formed should facilitate the incorporation of these nanoparticles in cellular membranes. These findings can be therefore correlated with the possible toxicity, microbicide and antitumorigenic effects of these nanoparticles in lipidic surfaces of erythrocyte and microbial membranes. PMID- 29723718 TI - Synthesis and semisynthesis of selenopeptides and selenoproteins. AB - The versatile chemistry of the genetically encoded amino acid selenocysteine (Sec) is employed in Nature to expand the reactivity of enzymes. In addition to, its role in biology, Sec is used in protein engineering to modify folding, stability, and reactivity of proteins, to introduce conjugations and to facilitate reactions. However, due to limitations related to Sec's insertion mechanism in Nature, much of the production of Sec containing peptides and proteins relies on synthesis and semisynthesis. Here, we review recent advances that have enabled the assembly of complicated selenoproteins, including novel uses of protecting groups for solid phase peptide synthesis, rapid selenoester driven chemical ligations and versatile expressed protein ligations. PMID- 29723719 TI - Procalcitonin and C - reactive protein as peripheral inflammatory markers in antipsychotic drug-free schizophrenia patients. AB - Inflammation is considered to be relevant in pathophysiology of schizophrenia. Existing literature indicates that controlling inflammation may be helpful in patient management. Procalcitonin (PCT) is an established marker of inflammation which has not been well studied in context with schizophrenia. The study recruited 34 schizophrenia patients free of antipsychotic treatment and 24 healthy controls without any signs of inflammation. Plasma C reactive protein was quantified using a high sensitivity turbidimetric assay. Plasma PCT levels was estimated by sandwich ELISA. The study ruled out autoimmune antibodies by ANA and RF tests which exclude confounding factors contributing to inflammation. The data shows a subgroup of patients 17/34 (50%) have either elevated PCT or CRP levels. This study is the first to report PCT values in antipsychotic drug-free patients with schizophrenia. PMID- 29723720 TI - Serum uric acid levels in first episode mania, effect on clinical presentation and treatment response: Data from a case control study. AB - Bipolar disorder (BD) patients have increased serum Uric Acid (UA) levels as compared to their healthy counterparts. They also demonstrate higher impulsivity while symptomatic, as well as when in remission. Impulsivity adds a risk of self harming behavior to BD, and studies show that it increases with UA levels. Given this complex relationship, the current project aimed at comparing UA levels in first-episode mania patients with matched controls, and analyzes its relationship with impulsivity, symptom severity and disease prognosis. Thirty-one first episode mania patients were assessed on BIS-11 and YMRS, serum uric acid levels were measured, and compared to matched controls. A follow up YMRS was rated after one month to evaluate the effects of treatment. We found significantly higher levels of UA in patients, which showed positive correlation with impulsivity and a negative correlation with symptom improvement at 1 month. The results of the study support a purinergic system dysfunction hypothesis in first-episode mania, and suggest its influence on impulsivity in this patient group. Further, the mentioned dysfunction appears to have a negative impact on treatment outcomes in such cases. PMID- 29723721 TI - The effectiveness of a cognitive training program in people with mild cognitive impairment: A study in urban community. AB - OBJECTIVE: To assess the effectiveness of a cognitive training program on global cognition among people with mild cognitive impairment. METHODS: In this experimental study, using purposive sampling, 60 participants age 50 years and over who complained of subjective memory impairment were screened in their communities by public health volunteers with the Abbreviated Mental Test. Those with dementia were excluded as well as those with depression, which were screened out by the Thai Geriatric Depression Scale (TGDS-15). Mild cognitive impairment was diagnosed and confirmed by the Montreal Cognitive Assessment (MoCA) and joint agreement between a psychiatrist and a neurologist. The participants were alternately assigned to receive a cognitive training program (intervention group) while the other half received their normal usual therapy (control group). The program involved training of 4 aspects of cognition through 6 sessions; 2 sessions per month for 3 months. The MoCA and TGDS-15 scales were given at baseline and again at week 13, and at months 6 and 9. Independent t-tests were used to compare changes in global cognition among the two groups. RESULTS: MoCA scores at 9 months were significantly higher than at baseline in both groups. However, the mean difference in intervention group was significantly higher than control group. TGDS-15 scores at 6 months was significantly lower than at baseline among the intervention group but not the control group. CONCLUSION: This cognitive training program helped to improve global cognition and reduce depressive symptoms. PMID- 29723723 TI - Enzymes in removal of pharmaceuticals from wastewater: A critical review of challenges, applications and screening methods for their selection. AB - At present, the removal of trace organic chemicals such as pharmaceuticals in wastewater treatment plants is often incomplete resulting in a continuous discharge into the aqueous environment. To overcome this issue, bioremediation approaches gained significant importance in recent times, since they might have a lower carbon footprint than chemical or physical treatment methods. In this context, enzyme-based technologies represent a promising alternative since they are able to specifically target certain chemicals. For this purpose, versatile monitoring of enzymatic reactions is of great importance in order to understand underlying transformation mechanisms and estimate the suitability of various enzymes exhibiting different specificities for bioremediation purposes. This study provides a comprehensive review, summarizing research on enzymatic transformation of pharmaceuticals in water treatment applications using traditional and state-of-the-art enzyme screening approaches with a special focus on mass spectrometry (MS)-based and high-throughput tools. MS-based enzyme screening represents an approach that allows a comprehensive mechanistic understanding of enzymatic reactions and, in particular, the identification of transformation products. A critical discussion of these approaches for implementation in wastewater treatment processes is also presented. So far, there are still major gaps between laboratory- and field-scale research that need to be overcome in order to assess the viability for real applications. PMID- 29723722 TI - Paradoxical reaction to benzodiazepines in elderly - Case series. PMID- 29723724 TI - High-dose acute exposure of paraquat induces injuries of swim bladder, gastrointestinal tract and liver via neutrophil-mediated ROS in zebrafish and their relevance for human health risk assessment. AB - The exact toxicological mechanisms of paraquat (PQ) poisoning are not entirely clear, especially on the high-level acute exposure. To assess the health risk of PQ, especially to suicidal individuals, accidental ingestion eaters, occupational groups, and special multitude, firstly we explored the acute toxic effect and the possible mechanisms of high-level exposure of PQ using zebrafish. The mainly target organs of PQ were swim bladder which is the homolog of the mammalian lung, followed by gastrointestinal tract and liver. Morphological malformations which were further defined by histopathologic examination include smaller size, fibrosis and inflammatory cell invasion for swim bladder; irregularly arranged or dissolved epithelial folds, loss of villous architecture, and ecclasis of mucosal cells in a smaller lumen for gastrointestinal tract; as well as smaller size, degeneration, fibrous proliferation, atrophy for liver. In addition, PQ enhanced leukocyte recruitment (neutrophil migrated first, followed by macrophage) into swim bladder and induced ROS which can be scavenged by glutathione. Moreover, qRT PCR results showed that PQ increased the expression level of genes involved in the inflammatory response, such as L-1beta, IL-6, IL-8, TNF-alpha, TNF-beta, IFN 1, TGF-beta, and NF-kB. For the first time, our results demonstrated that acute exposure of PQ induced pulmonary toxicity which was followed by gastrointestinal and hepatic toxicity via neutrophil-mediated ROS in zebrafish. In summary, these findings generated here will contribute to our better understanding of characteristics of PQ acute poisoning and can provide valuable information on better PQ poisoning treatments, occupational disease prevention, and providing theoretical foundation for risk management measures. PMID- 29723725 TI - Evaluating effects of prenatal exposure to phthalates on neonatal birth weight: Structural equation model approaches. AB - BACKGROUND: A large body of evidence has shown that phthalate exposure can lower birth weight in animals and human beings. However, there are only limited data on whether phthalates could affect birth weight directly or indirectly through gestational age and pregnancy syndrome. OBJECTIVES: To evaluate the effects of prenatal exposure to phthalates on birth weight in neonates and the mediation effects of gestational age and pregnancy syndrome on the association between phthalate exposure and birth weight. METHODS: In this study, 181 mother-newborn pairs were recruited from Wenzhou city. Maternal urine samples were collected during the third trimester and measured for phthalate metabolites by ESI-MS/MS. Structural equation models (SEMs) were used to evaluate effects of phthalate on birth weight controlling for maternal education, monthly income, nutritional supplements, infant gender, and maternal weight gain per week. The potential mediated effects of phthalate exposure through gestational age and pregnancy syndrome on birth weight were also calculated by structural equation modeling. RESULTS: After adjusting for potential confounders, urinary mono-phthalate levels (including MMP, MBP, MEHP, MEOHP, and MEHHP) were negatively associated with birth weight. A ten-fold increase in the concentration of MEOHP and MEHHP would be directly associated with lower birth weights (reduced to 124 g and 107 g, respectively). However, MBP had mediated effects on birth weight through gestational age, which was associated with an 85-g reduction in birth weight for every ten-fold increase in exposure. Both direct and mediated effects on birth weight were found in MMP and MEHP. The indirect effects of MMP and MEHP were mediated through gestational age and pregnancy syndrome. Thus, prenatal MMP and MEHP exposures were associated with decrease in birth weight. CONCLUSIONS: A negative association exists between prenatal phthalate exposure and birth weight in Chinese neonates. In addition to direct pathway, phthalate exposures could affect birth weight through the mediated effects of gestational age and pregnancy syndrome. PMID- 29723726 TI - The Quest for Predicting Sustained Shunt Response in Normal-Pressure Hydrocephalus: An Analysis of the Callosal Angle's Utility. AB - BACKGROUND: Diagnosing normal-pressure hydrocephalus (NPH) and selecting patients who will experience a sustained benefit from fluid diversion surgery remains challenging. This study seeks to evaluate the association between the callosal angle (CA) and the long-term postoperative response to ventriculoperitoneal shunt surgery in a different subgroup population than previously studied to assess its generalizability. METHODS: We studied 72 patients with idiopathic NPH who underwent ventriculoperitoneal shunt surgery and had at least 18 months of follow up between 2000 and 2016. We recorded their pre- and postoperative symptoms according to the NPH Eide scale and their comorbidities with the Kiefer index. Their CA, as well as Evans' Index, ventricular height, and transependymal signal were measured. Multivariable statistical models were used to determine which factors were associated with postoperative improvement while we controlled for the presence of the NPH triad. RESULTS: Fifty-nine patients (82%) demonstrated a successful response to surgery at their first postoperative follow-up. However, this declined to 54 patients (75%) at 1 year and 45 (62.5%) patients at their last follow-up. When we controlled for the presence of the triad of symptoms, the CA significantly predicted a good, sustained response to surgery; for every degree decrease in the CA, a patient is 4% more likely to experience benefit from surgery. CONCLUSIONS: The CA is a useful preoperative prognostic tool for predicting which patients will experience a sustained benefit from surgery. Further studies are required to clarify this disease in the context of old age, comorbidity, and possible concomitant neurodegenerative diseases. PMID- 29723727 TI - Increased cytotoxic potential of infrequent triterpenoid saponins of Cephalaria taurica obtained through alkaline hydrolysis. AB - Phytochemical investigations of the aerial parts of the plant Cephalaria taurica Szabo. (Caprifoliaceae) have resulted in the isolation of nine oleanane-type triterpenoid saponins, of which two still remain undescribed. The structures of tauricosides A and B were characterized based on NMR analysis, HRESIMS spectrometry, and chemical evaluations. The saponins tauricosides A and B have been rarely reported in the literature due to the presence of eight sugar moieties, and this is also the first report of saponins containing eight sugar moieties in the Caprifoliaceae family. The cytotoxic activities of tauricosides A and B, their undescribed prosapogenins, aglycone hederagenin, and n-butanol extract of C. taurica against the cancerous cells A-549, HeLa, PANC-1, and SH SY5Y and the noncancerous HEK-293 cells were evaluated by the MTT method. Although tauricosides A and B and the crude n-butanol extract did not exhibit any activity at the tested concentrations on all the tested cells, after alkaline hydrolysis, the cytotoxic activity potential of the compounds was obviously improved. The most active compound, obtained after the alkaline hydrolysis of tauricoside B, showed a significant inhibitory effect, which was higher than that of the standard, commercially available drug doxorubicin, on the cancerous A-549, HeLa, PANC-1, and SH-SY5Y cells with IC50 values of 9.04, 8.75, 6.87, and 4.32 MUM, respectively. In addition, prosapogenin, obtained after the alkaline hydrolysis of tauricoside A, exhibited considerable cytotoxic activity on the cancerous A-549, HeLa, PANC-1, and SH-SY5Y cells, with IC50 values of 13.19, 10.32, 11.91, and 7.49 MUM, respectively. In conclusion, the alkaline hydrolysis of the saponins (tauricosides A and B) obviously improved their cytotoxic activity potential. PMID- 29723730 TI - Target-oriented photofunctional nanoparticles (TOPFNs) for selective photodynamic inactivation of Methicillin-resistant Staphylococcus aureus (MRSA). AB - To inactivate methicillin-resistant Staphylococcus aureus (MRSA) with minimum damage to host cells and tissue, target-oriented photofunctional nanoparticles (TOPFNs) were fabricated and characterized. MRSA is a predominant infective pathogen even in hospital and non-hospital environments due to its ability to develop high levels of resistance to several classes of antibiotics through various pathways. To solve this major problem, photodynamic inactivation (PDI) method applies to treat antibiotic-resistant bacteria. PDI involves the photosensitizer (PS) and light with a specific wavelength to be able to apply for a non-invasive therapeutic procedure to treat pathogenic bacteria by inducing apoptosis or necrosis of microorganisms. However, most current PDI researches have suffered from the instability of PDI agents in the biological environment due to the lack of selectivity and low solubility of PDI agents, which leads to the low PDI efficiency. In this study, the TOPFNs were fabricated by an esterification reaction to introduce hematoporphyrin (HP) and MRSA antibody to the surface of Fe3O4 nanoparticles. The TOPFNs were designed as dispersible PDI agent in biological condition, which was effectively used for selectively capturing and killing of MRSA. The capture efficiency TOPFNs was compared with PFNs as a negative control. The results showed that the capture efficiency of TOPFNs and PFNs was 95.55% and 6.43% in MRSA and L-929 cell mixed condition, respectively. And TOPFNs have a selective killing ability for MRSA with minimum damage to L-929 cells. Furthermore, PDI effect of TOPFNs was evaluated on the mice in vivo condition in order to check the possibility of practical medical application. PMID- 29723728 TI - Fluency Bank: A new resource for fluency research and practice. PMID- 29723729 TI - Cortical associates of emotional reactivity and regulation in childhood stuttering. AB - PURPOSE: This study sought to determine the cortical associates of emotional reactivity and emotion regulation (as indexed by the amplitude of evoked response potentials [ERP]) in young children who do and do not stutter during passive viewing of pleasant, unpleasant and neutral pictures. METHOD: Participants were 17 young children who stutter and 22 young children who do not stutter (between 4 years 0 months to 6 years 11 months). The dependent measures were (1) mean amplitude of late positive potential (LPP, an ERP sensitive to emotional stimuli) during passive (i.e., no response required) picture viewing and directed reappraisal tasks and (2) emotional reactivity and regulation related scores on caregiver reports of young children's temperament (Children's Behavior Questionnaire, CBQ). RESULTS: Young CWS, when compared to CWNS, exhibited significantly greater LPP amplitudes when viewing unpleasant pictures, but no significant between-group difference when viewing pleasant pictures and during the emotion regulation condition. There were, however, for CWS, but not CWNS, significant correlations between temperament-related measures of emotion and cortical measures of emotional reactivity and regulation. CONCLUSIONS: Findings provide further empirical support for the notion that emotional processes are associated with childhood stuttering, and that CWS's inherent temperamental proclivities need to be taken into account when empirically studying or theorizing about this association. PMID- 29723732 TI - LGI1 tumor tissue expression and serum autoantibodies in patients with primary malignant glioma. AB - OBJECTIVES: The Leucine-rich glioma inactivated 1 (LGI1) protein is thought to be implicated in malignant progression of glioma tumors, and mutations in the encoding gene, LGI1, cause autosomal dominant lateral temporal epilepsy, a genetic focal epilepsy syndrome. The aim of this study was to investigate the possible involvement of LGI1 in high-grade glioma-associated epilepsy by analyzing its expression in tumor specimens of patients with and without epilepsy and by searching for LGI1 autoantibodies in the sera these patients. PATIENTS AND METHODS: We examined tumor tissue samples from 24 patients with high-grade gliomas (12 with and 12 without epilepsy) by immunoblot and detected variable amounts of LGI1 in tumor tissues from 9/24 (37%) patients. RESULTS: LGI1 was detected in 7/12 (58%) patients with epilepsy and in 2/12 (16%) patients without epilepsy (p = 0.0894; Fisher's exact test). Moreover, testing blood sera of five patients for antibodies against LGI1 revealed LGI1 autoantibodies in two patients, both suffering from epilepsy and expressing LGI1 in tumor tissue. CONCLUSION: Our findings suggest that there may be a preferential expression of LGI1 in high-grade glioma tumors of patients with epilepsy. We also unveil the presence of serum LGI1 autoantibodies in some patients with high-grade gliomas, where they might play an epileptogenic role. PMID- 29723731 TI - Isatin based macrocyclic Schiff base ligands as novel candidates for antimicrobial and antioxidant drug design: In vitro DNA binding and biological studies. AB - In the present work, five macrocyclic compounds, C18H12N2O4 (1), C38H24N8O6 (1a), C38H24N8O4S2 (1b), C40H32N8O4 (2a) and C48H32N8O4 (2b) have been synthesized and thoroughly characterized by elemental analysis, FT-IR, 1D & 2D NMR and electron spray ionization mass spectral analysis. The DNA binding ability of these compounds were investigated in vitro by UV-Visible, fluorescence, circular dichroism (CD) spectroscopy and viscosity measurements. The results indicate that these compounds possess strong DNA binding affinity via intercalation, while the order of binding strength followed the trend 2b (1.52 +/- 0.06 * 105 M-1) > 2a (1.12 +/- 0.11 * 105 M-1) > 1b (1.05 +/- 0.04 * 105 M-1) > 1a (0.97 +/- 0.14 * 104 M-1) > 1 (0.75 +/- 0.21 * 104 M-1). The radical scavenging potencies of the compounds were explored by employing DPPH, OH and NO assays, in which 1a exhibited highest inhibitory effect on the radicals (IC50 = 23.59 MUM (DPPH), 26.14 MUM (OH), 28.41 MUM (NO)). The in vitro antibacterial studies showed that these compounds have the potential to arrest the growth of bacteria, among which, 1a was found to be vulnerable against the bacterial stains. In addition, in silico molecular docking stimulations were also performed to position these compounds into the active sites of bacterial membrane proteins. The results of in vitro and in silico investigations reveal that the compounds apprehend the bacterial growth significantly. The data obtained from this piece of work would be helpful to design antibacterial drugs incorporating isatin based macrocyclic frameworks. PMID- 29723733 TI - Positive clinical effects of gamma knife capsulotomy in a patient with deep brain stimulation-refractory Tourette Syndrome and Obsessive Compulsive Disorder. AB - We report the first case of a patient with severe, intractable Tourette Syndrome with comorbid Obsessive Compulsive disorder, who recovered from both disorders with gamma-knife (GK) stereotactic radiosurgery following deep brain stimulation (DBS). This case highlights the possible role of the internal capsule within the neural circuitries underlying both TS and OCD, and suggests that in cases of treatment-refractory TS and comorbid OCD, bilateral anterior capsulotomy using stereotactic radiosurgery may be a viable treatment option. PMID- 29723734 TI - Characteristics of single-vehicle crashes with e-bikes in Switzerland. AB - In Switzerland, the usage and accident numbers of e-bikes have strongly increased in recent years. According to official statistics, single-vehicle accidents constitute an important crash type. Up to date, very little is known about the mechanisms and causes of these crashes. To gain more insight, a survey was conducted among 3658 e-cyclists in 2016. The crash risk and injury severity were analysed using logistic regression models. 638 (17%) e-cyclists had experienced a single-vehicle accident in road traffic since the beginning of their e-bike use. Risk factors were high riding exposure, male sex, and using the e-bike mainly for the purpose of getting to work or school. There was no effect of age on the crash risk. Skidding, falling while crossing a threshold, getting into or skidding on a tram/railway track and evasive actions were the most important accident mechanisms. The crash causes mentioned most often were a slippery road surface, riding too fast for the situation and inability to keep the balance. Women, elderly people, riders of e-bikes with a pedal support up to 45 km/h and e cyclists who considered themselves to be less fit in comparison to people of the same age had an increased risk of injury. This study confirms the high relevance of single-vehicle crashes with e-bikes. Measures to prevent this type of accident could include the sensitisation of e-cyclists regarding the most common accident mechanisms and causes, a regular maintenance of bicycle pathways, improvements regarding tram and railway tracks and technological advancements of e-bikes. PMID- 29723737 TI - Compartmentalisation of RAC1 signalling. AB - RAC1 signalling has been implicated in a variety of dynamic cell biological processes that are orchestrated through regulated localisation and activation of RAC1. As a small GTPase, RAC1 switches between active and inactive states at various subcellular locations that include the plasma membrane, nucleus and mitochondria. Once activated, RAC1 interacts with a range of effectors that then mediate various biological functions. RAC1 is regulated by a large number of proteins that can promote its recruitment, activation, deactivation, or stability. RAC1 and its regulators are subject to various post-translational modifications that further fine tune RAC1 localisation, levels and activity. Developments in technologies have enabled the accurate detection of activated RAC1 during processes such as cell migration, invasion and DNA damage. Here, we highlight recent advances in our understanding of RAC1 regulation and function at specific subcellular sites. PMID- 29723735 TI - Driver distraction by smartphone use (WhatsApp) in different age groups. AB - This paper investigates the effect that texting with WhatsApp, one of the most common applications for instant messaging, exerts on driving performance. Because distracted driving also affects older drivers, who can have seriously compromised vision, we also analysed the associations between visual-function parameters and driving performance. A total of 75 drivers, experienced in sending WhatsApp messages (>=10WhatsApp messages/week), participated in this study and were divided into four age categories. Visual-function tests included contrast sensitivity with and without glare, retinal straylight and objective assessment of optical quality. Simulated driving performance was assessed under a baseline driving condition (without distraction) as well as a texting condition (WhatsApp messages) while driving. The participants used their own mobile phone. Lastly, objective results of driving performance were compared with subjective self report data from the Driver Behaviour Questionnaire (DBQ). The analysis indicated that functional changes occurring with age, such as a lower contrast sensitivity and greater retinal straylight, were correlated with a higher number of collisions, longer distances driven outside the lane, and greater standard deviation of lateral position (SDLP). The results showed a significant main effect of age for the driving-performance parameters. Also, compared to the baseline, texting WhatsApp messages while driving worsens driving performance for all age groups, most notably among older participants. Thus, the older drivers' SDLP was ~14% higher than that for the baseline average of all the other drivers and rose to 29% under distraction, reflecting the impact of secondary tasks. The negative effect of the use of the smartphone during driving was also reflected in the number of collisions, with a greater risk of accidents in all the groups of drivers (by 8.3% for young adults, 25.0% for adults, 80.5% for middle-aged adults, and 134.5% for older drivers). Lastly, participants' subjective responses indicated that younger drivers (18-24 years) had a higher risk of deliberately violating safe driving practices (p < 0.05). The present study demonstrates that texting WhatsApp messages while driving significantly impairs the ability to drive safely, with older drivers being the group most adversely affected. It would be recommendable to include other nonstandard vision tests, which have shown associations with driving performance, in the examination for driver licensing. This would help raise the awareness of older drivers concerning their visual limitations, permitting them to adopt compensatory measures to improve their driving safety. Nevertheless, it is also necessary to raise awareness among the younger drivers of the risks involved in behaviour behind the wheel. PMID- 29723739 TI - A combined computational and experimental study on selective flucloxacillin hydroxylation by cytochrome P450 BM3 variants. AB - The 5'-hydroxymethyl metabolite of the penicillin based antibiotic flucloxacillin (FLX) is considered to be involved in bile duct damage occurring in a small number of patients. Because 5'-hydroxymethyl FLX is difficult to obtain by organic synthesis, biosynthesis using highly active and regioselective biocatalysts would be an alternative approach. By screening an in-house library of Cytochrome P450 (CYP) BM3 mutants, mutant M11 L437E was identified as a regioselective enzyme with relatively high activity in production of 5' hydroxymethyl FLX as was confirmed by mass spectrometry and NMR. In contrast, incubation of M11 L437E and other mutants with oxacillin (OX, which differs from FLX by a lack of aromatic halogens) resulted in formation of two metabolites. In addition to 5'-hydroxymethyl OX we identified a product resulting from aromatic hydroxylation. In silico studies of both FLX and OX with three CYP BM3 mutants revealed substrate binding poses allowing for 5'-methyl hydroxylation, as well as binding poses with the aromatic moiety in the vicinity of the heme iron for which the corresponding product of aromatic hydroxylation was not observed for FLX. Supported by the (differences in) experimentally determined ratios of product formation for OX hydroxylation by M11 and its L437A variant and M11 L437E, Molecular Dynamics simulations suggest that the preference of mutant M11 L437E to bind FLX in its catalytically active pose over the other binding orientation contributes to its biocatalytic activity, highlighting the benefit of studying effects of active-site mutations on possible alternative enzyme-substrate binding poses in protein engineering. PMID- 29723738 TI - Soil metabarcoding identifies season indicators and differentiators of pig and Agrostis/Festuca spp. decomposition. AB - To gain a better understanding of how environmental microbiota respond to cadaver decomposition, a forensic ecogenomic study was made with soil only control and 4g each of Sus scrofa domesticus and plant litter (Agrostis/Festuca spp.) buried individually in a sandy clay loam (80g) in sealed but perforated triplicate microcosms. The next-generation sequencing (Illumina Miseq) of the soil bacteria (16S rRNA gene) clade revealed seasonal taxomonic shifts at genus-level for the pig and plant litter microcosms compared to the non-burial controls. In particular, numerical abundances of Sphingobacterium (5.9%) and Pedobacter (24.1%) for the pig microcosms, and Rhodanobacter (18.1%) and Shinella (4.6%) for the plant litter microcosms, identified bacterial genera that could be tracked to establish a (seasonal) subsurface postmortem microbial clock. Also, family-level resolution revealed members that were unique to the control, grass and pig soils after 365 days. PMID- 29723736 TI - Balancing forces in migration. AB - The integrated molecular interactions of proteins can create active biological networks whose material properties and actions can impact a variety of physiological processes. Chief among these is the ability to generate and respond to physical forces. The cytoskeleton plays a key role in this behavior, characterized by active self-reorganization to control a cell's shape and mediate its physical interactions. This review discusses our current understanding of how the material properties of the cytoskeleton and its physical interactions with the extracellular environment impact cell migration. PMID- 29723740 TI - Conserved cysteine residues are necessary for nickel-induced allosteric regulation of the metalloregulatory protein YqjI (NfeR) in E. coli. AB - Transition metal homeostasis is necessary to sustain life. First row transition metals act as cofactors within the cell, performing vital functions ranging from DNA repair to respiration. However, intracellular metal concentrations exceeding physiological requirements may be toxic. In E. coli, the YqjH flavoprotein is thought to play a role in iron homeostasis. YqjH is transcriptionally regulated by the ferric uptake regulator and a newly discovered regulator encoded by yqjI. The apo-form of YqjI is a transcriptional repressor of both the yqjH and yqjI genes. YqjI repressor function is disrupted upon binding of nickel. The YqjI N terminus is homologous to nickel-binding proteins, implicating this region as a nickel-binding domain. Based on function, yqjI and yqjH should be renamed Ni responsive Fe-uptake regulator (nfeR) and Ni-responsive Fe-uptake flavoprotein (nfeF), respectively. X-ray Absorption Spectroscopy was employed to characterize the nickel binding site(s) within YqjI. Putative nickel binding ligands were targeted by site-directed mutagenesis and resulting variants were analyzed in vivo for repressor function. Isothermal titration calorimetry and competitive binding assays were used to further quantify nickel interactions with wild-type YqjI and its mutant derivatives. Results indicate plasticity in the nickel binding domain of YqjI. Residues C42 and C43 were found to be required for in vivo response of YqjI to nickel stress, though these residues are not required for in vitro nickel binding. We propose that YqjI may contain a vicinal disulfide bond between C42 and C43 that is important for nickel-responsive allosteric interactions between YqjI domains. PMID- 29723741 TI - Synthetic nicotinic/isonicotinic thiosemicarbazides: In vitro urease inhibitory activities and molecular docking studies. AB - Nicotinic and isonicotinic thiosemicarbazide or hydrazine carbothioamides 3-27 were synthesized and the structures of synthetic compounds were elucidated by various spectroscopic techniques such as EI-MS, 1H-, and 13C NMR. Synthetic derivatives were evaluated for their urease inhibitory activity which revealed that except few all derivatives demonstrated excellent inhibition in the range of IC50 values of 1.21-51.42 MUM as compared to the standard thiourea (IC50 = 21.25 +/- 0.13 MUM). Among the twenty-five synthetic derivatives nineteen 1-5, 7, 8, 10, 12, 14-18, 20-22, 24-27 were found to be more active showing IC50 values between 1.13 and 19.74 MUM showing superior activity than the standard. Limited structure-activity relationship demonstrated that the positions of substituent as well as position of nitrogen in pyridine ring are very important for inhibitory activity of this class of compound. To verify these interpretations, in silico study was also performed. A good correlation was obtained between the biological evaluation of active compounds and docking study. PMID- 29723742 TI - New AChE inhibitors from microbial transformation of trachyloban-19-oic acid by Syncephalastrum racemosum. AB - Trachyloban-19-oic acid (1) is a diterpene very abundant in nature and its structural modification can furnish new bioactive compounds. Biotransformation of 1 by fungus Syncephalastrum racemosum provided three derivatives, two hydroxylated products (2-3) and one product of rearrangement (4). Products 3 and 4 have never been reported so far, to the best of our knowledge. Structure of 3 was formed after oxidation and rearrangement of compound 2. Compounds 1-4 were evaluated for inhibition of acetylcholinesterase, enzyme linked to the symptomatic control of Alzheimer's disease. All the compounds presented inhibitory activity higher than starting material 1, and product 3 presented IC50 = 0.06 MUM, which is about six times higher than activity found for galanthamine (IC50 = 0.38 MUM), the positive control used in this assay. PMID- 29723743 TI - Spiropyrrolidine/spiroindolizino[6,7-b]indole heterocyclic hybrids: Stereoselective synthesis, cholinesterase inhibitory activity and their molecular docking study. AB - A regio and stereo- selective synthesis of hitherto unexplored hybrid heterocyclic system comprising spiropyrrolidine, indolizino[6,7-b]indole units in good to excellent yields, has been developed via three component 1,3-dipolar cycloaddition and concomitant trifluoroacetic acid catalyzed Pictet-Spengler cyclization with paraformaldehyde. The newly synthesized compounds were evaluated for their in vitro acetylcholinesterase (AChE) and butylcholinesterase (BChE) enzyme inhibitory activities. Most of the synthesized compounds showed good inhibitory activity, among them, compounds 4d and 4g displayed highest potency against AChE (IC50 1.88 and 1.98 MUM), and BChE (IC50 18.32 and 10.21 MUM) enzyme, respectively than the standard drug, galanthamine. Molecular modeling simulation was investigated for the most active compounds 4d and 4g on AChE and BChE enzymes to disclose the binding and orientation of these molecules into active site of respective receptors. PMID- 29723744 TI - Identification of novel indole based heterocycles as selective estrogen receptor modulator. AB - In the present study, we have designed and synthesized indole derivatives by coalescing the indole nucleus with chromene carbonitrile and dihydropyridine nucleus. Two compounds 5c and 6d were selected from series I and II after sequential combinatorial library generation, docking, absorption, distribution, metabolism and excretion (ADME) filtering, anti-proliferative activity, cytotoxicity, and ER-alpha competitor assay kit by utilizing estrogen receptor alpha (ER-alpha) dominant T47D BC cells line and PBMCs (Peripheral Blood Mononuclear Cells). Cell imaging experiment suggested that both the compounds successfully cross cellular biomembrane and accumulate in nuclear, cytoplasmic and plasma membrane region. Semiquantitative RT-PCR and Western blotting experiments further supported that both compounds reduced the expression of mRNA and receptor protein of ER-alpha, thereby preventing downstream transactivation and signaling pathway in T47D cells line. Current findings imply that 5c and 6d represent novel ER-alpha antagonists and may be used in the development of chemotherapy for the management of BC. PMID- 29723745 TI - A singular stochastic control model for sustainable population management of the fish-eating waterfowl Phalacrocorax carbo. AB - Using a tractable singular stochastic control model, this study seeks a sustainable population management policy for the fish-eating waterfowl Phalacrocorax carbo (Great Cormorant), a major predator of riverine fish in Japan. The bird population dynamics around a habitat lake are described by a stochastic differential equation with a singular control variable representing human interventions to suppress the predation. The optimal population management policy maximizes a performance index that covers the cost of countermeasures, the loss of riverine fish, and the ecosystem services provided by the bird. The dynamic programming principle obtains an exactly-solvable variational inequality that governs a sustainable, threshold-type optimal management policy. In this policy, countermeasures are taken when the population reaches a certain level. The model is applied to management of P. carbo population around Lake Biwa, Japan, where predation of riverine fish is the most severe in the country. The current management policy around the lake is analyzed and verified in the context of the proposed model, focusing on the population-control threshold and the average population reduction per unit time. PMID- 29723746 TI - Opportunities for adaptive online collaboration to enhance rural land management. AB - Cross-property cooperation has the potential to enhance the effectiveness of environmental management actions that cut across property boundaries. Online tools can facilitate this and overcome barriers to landholder engagement in collaborative management. However, collaborative online tools need to be designed and tailored to users' needs and values, and landholder participation in the development process is critical to ensuring uptake and long-term use. This article presents a case study from the Central Tablelands region of New South Wales, Australia, where landholders have been involved in participatory development of a new online collaboration tool. The case study results highlight the significance of issues such as internet access, privacy, technical proficiency and differing stakeholder objectives. A landholder survey identified mapping and the uploading of monitoring data as important functions for the online tool, but these were not rated as highly as functions relating to data security, sharing settings and key term searches. Consequently, we recommend that a future online collaboration tool for the region is not framed specifically as a mapping or citizen science tool, but rather as an adaptive collaboration and communication tool that can incorporate a variety of data types and formats and be modified over time in line with changing landholder needs. PMID- 29723747 TI - Histological investigations on thymus of male rats prenatally exposed to bisphenol A. AB - Bisphenol A is called as a endocrine-distrupting chemical because of the its steroid-like activity and it used in the construction of plastic containing materials. It is indicated that bisphenol A can pass the human serum, urine, follicular fluid, placenta and umblical cord as a result of the use of substances containing this agent. In this study, we aimed to investigate the effects of bisphenol A on the development of the thymus, a primary lymphoid organ which plays an important role in the specific immunity. The adult pregnant female rats were administered orally with bisphenol A (for 21 days) and postnatal thymus samples were obtained on day 21, 45 and 90 and were performed for histochemical and immunohistochemical staining for CD3, CD4, CD8 and CD79a and TUNEL assay for the apoptotic cells. Evaluation of all groups, CD3, CD4, CD8 and CD79a stainings were decreased in the experimental groups compared with control group. The apoptotic cells were determined in the all groups on day 90 as a result of the thymus involution. It is noted that there was not any histological and morphological damages in the rats prenatally exposed the bisphenol A. The effect of the bisphenol A is unknown in the future, but there is no problem in the adult rats. PMID- 29723748 TI - Electrochemical stripping of cotton fabrics dyed with Reactive Black 5 in water and wastewater. AB - Cotton fabrics dyed with Reactive Black 5 (RB5) was electrochemically stripped using Ti/TiO2-RuO2-IrO2 anode in water, pyridine and phenol solution. The results showed that RB5 dye could be easily stripped from the surface of cotton fabrics through the cleavage of chromophoric group (NN) under the attack of hydroxyl radicals (OH) and active chlorines generated in situ. Efficient stripping performance could be obtained in water and pyridine solution, whilst the stripping percent was not obviously affected by pyridine concentration and layers of dyed cotton fabrics. Whereas, phenol existing in water slowed the stripping rate due to the competition between the stripping of RB5 dye and the degradation of phenol. In the case of multi-layer dyed cotton fabrics, the stripping performance of the inner layer is superior to that of the outer layer owing to that the cotton fabrics hinder the diffusion of active chlorines and OH. The FTIR analysis of stripped cotton fabrics showed that the effect of electrochemical process and the existence of pollutant in water on the stripped cotton fabrics could be negligible. Electrochemical oxidation could also successfully strip various dyes from waste cotton fabrics in the investigated stripping solutions. Therefore, electrochemical oxidation provides an environmentally friendly alternative for color stripping of dyed cotton fabrics. The removal of dye from cotton fabrics and the degradation of pollutant in water could occur simultaneously, implying that wastewater containing chloride ions may replace the fresh water as stripping solution. PMID- 29723749 TI - Photocatalytic removal of organic phosphate esters by TiO2: Effect of inorganic ions and humic acid. AB - In this study, the TiO2-mediated photocatalytic removal of organic phosphate esters (OPEs) under UV irradiation was investigated. In addition, the effects of selected inorganic ions and humic acid (HA) were examined. TCEP, TCPP, and TDCPP hardly undergo degradation via photolysis, and TiO2-mediated photocatalysis was confirmed to be effective for removing OPEs present in a water matrix. Inorganic ions (e.g., PO43-, SO42-, Cl-, and NO3-) and HA inhibited the degradation of OPEs. Among these selected ions, PO43- exhibited the strongest inhibition ability, followed by SO42- and then Cl- and NO3-, and the inhibition effect increased with the ion concentration. The inhibition effect was caused by two main reasons: (1) Inorganic ions or HA served as .OH scavengers and competed with OPEs for .OH. (2) On account of the adsorption of inorganic ions and HA on TiO2, the available surface-active sites for OPEs decreased, followed by their oxidation with surface-bound .OH. The .OH concentrations were measured by electron spin resonance and the probe method, and it was positively correlated to the degradation rate of OPEs. This study emphasized the importance of inorganic species and HA on the photocatalytic degradation of OPEs and clarified the inhibition mechanism for the degradation of OPEs by the inorganic species or HA. PMID- 29723751 TI - New insights for risks of chlorophenols (CPs) exposure: Inhibition of UDP glucuronosyltransferases (UGTs). AB - Chlorophenols (CPs) are important pollutants extensively utilized in industry, agriculture and forestry. The present study aims to determine the inhibition of CPs on the activity of the important phase II drug-metabolizing enzymes (DMEs) UDP-glucuronosyltransferases (UGTs). 100 MUM of fourteen CPs were used for preliminary screening using in vitro incubation. Furthermore, half inhibition concentration (IC50) and inhibition kinetics were determined for CPs with significant inhibition towards UGT isoforms. In silico docking was used to explain the inhibition difference among CPs. Multiple UGT isoforms were inhibited by CPs. In silico docking showed that higher free binding energy due to hydrophobic interactions of 2.4-Dichlorophenol (2.4-DCP) or 4-Chloro-3 methylphenol (4C3MP) with UGT1A9 contributed to stronger inhibition potential of 2.4-Dichlorophenol (2.4-DCP) or 4-Chloro-3-methylphenol (4C3MP) towards UGT1A9 than 4-CP. Pentachlorophenol (PCP) was chosen as the representative CPs to determine the IC50 value towards UGT1A6, UGT1A9 and UGT2B7. IC50 was calculated to be 0.33 MUM, 0.24 MUM and 31.35 MUM for the inhibition of PCP towards UGT1A6, UGT1A9 and UGT2B7. PCP was demonstrated to show competitive inhibition towards UGT1A6, UGT1A9 and UGT2B7, and the inhibition kinetic parameters (Ki) was calculated to be 0.18 MUM, 0.01 MUM and 5.37 MUM for the inhibition of PCP towards UGT1A6, UGT1A9 and UGT2B7. All these information will be beneficial for elucidating the risk of CPs exposure from a new perspective. PMID- 29723750 TI - Occurrence state of co-existing arsenate and nickel ions at the ferrihydrite water interface: Mechanisms of surface complexation and surface precipitation via ATR-IR spectroscopy. AB - Arsenic and nickel are common contaminants that usually co-exist in many contaminated natural and mining environments. More research on the interaction of these two contaminants is needed such as their coordination structure and occurrence state at mineral-water interfaces. In this study, we investigated the structure of surface complexes and surface precipitates formed by co-existing As(V) and Ni(II) ions at the ferrihydrite-water interface by varying the order of adsorption processes, pH, aging time and Ni(II) concentration using attenuated total reflection-Fourier transform infrared spectroscopy (ATR-FTIR). ATR-FTIR analysis revealed the presence of complexed AsONi bonds which produced ternary surface complexes. These ternary AsONi surface complexes formed through a layer by layer alternative coordination on top of the binary AsOFe surface site complexes of ferrihydrite. Such multilayer surface complexes formed as initial surface precipitates which were found to refine their surface structure from amorphous to crystalline phases and were a function of incubation time, coverage of multilayer surface complexes, Ni(II) concentration and pH. Our results presented here can well explain the formation process of surface precipitates on the molecular scale and are of use to forecast the fate and mobility of commonly As(V) and Ni(II) species at the ferrihydrite-water interface commonly found in natural or mine tailings water-soil environments. PMID- 29723754 TI - Children inhibit global information when the forest is dense and local information when the forest is sparse. AB - Visual environments are composed of global shapes and local details that compete for attentional resources. In adults, the global level is processed more rapidly than the local level, and global information must be inhibited in order to process local information when the local information and global information are in conflict. Compared with adults, children present less of a bias toward global visual information and appear to be more sensitive to the density of local elements that constitute the global level. The current study aimed, for the first time, to investigate the key role of inhibition during global/local processing in children. By including two different conditions of global saliency during a negative priming procedure, the results showed that when the global level was salient (dense hierarchical figures), 7-year-old children and adults needed to inhibit the global level to process the local information. However, when the global level was less salient (sparse hierarchical figures), only children needed to inhibit the local level to process the global information. These results confirm a weaker global bias and the greater impact of saliency in children than in adults. Moreover, the results indicate that, regardless of age, inhibition of the most salient hierarchical level is systematically required to select the less salient but more relevant level. These findings have important implications for future research in this area. PMID- 29723753 TI - Teachers' rankings of children's executive functions: Validating a methodology for school-based data collection. AB - We developed a novel, vignette-based ranking procedure to simultaneously collect teacher-reported executive function (EF) data for all students in a classroom. This ranking measure is an improvement over existing Likert-type rating scales because it can be completed more quickly and with comparatively little effort by teachers. Data for this validation study were drawn from a large, school-based study of third, fourth, and fifth graders (N = 813 from 33 classrooms in eight schools) in which ranking data and direct assessments of EF were collected. Using a subsample of students for whom teachers' ratings of EF and school records data were also collected (N = 311), we demonstrated that teachers' rankings of EF showed high convergent validity with teachers' ratings of EF and that both teacher-reported measures showed similar convergent validity with direct assessments of EF and similar predictive validity with respect to students' scores on standardized English/language arts and math achievement tests. Using data from the larger sample (N = 813), we conducted a simulation study demonstrating that the impact of missing data on the association between the rankings and the direct assessments of EF is minimal. Based on these results, the ranking procedure is a methodological innovation that enables the collection of relatively high-quality teacher-reported EF data for all students in a classroom quickly and with minimal burden on teachers. This vignette-based assessment method could be adapted to other domains of non-academic skills. We discuss varied uses of the ranking method for researchers and practitioners. PMID- 29723752 TI - Prenatal lead, cadmium and mercury exposure and associations with motor skills at age 7 years in a UK observational birth cohort. AB - BACKGROUND: Lead and mercury are freely transferred across the placenta, while cadmium tends to accumulate in the placenta. Each contributes to adverse neurological outcomes for the child. Although prenatal heavy metal exposure has been linked with an array of neurodevelopmental outcomes in childhood, its association with the development of motor skills in children has not been robustly studied. AIMS/OBJECTIVE: The aim of the present study was to investigate the association between prenatal exposure to lead, cadmium and mercury, measured as maternal blood concentrations during pregnancy, and motor skills, measured as subtests of the Movement Assessment Battery for Children (Movement ABC) at age 7 years in a large sample of mother-child pairs enrolled in a UK observational birth cohort study (Avon Longitudinal Study of Parents and Children, ALSPAC). METHODS: Whole blood samples from pregnant women enrolled in ALSPAC were analysed for lead, cadmium and mercury. In a complete case analysis (n = 1558), associations between prenatal blood concentrations and child motor skills assessed by Movement ABC subtests of manual dexterity, ball skills and balance at 7 years were examined in adjusted regression models. Associations with probable developmental coordination disorder (DCD) were also investigated. RESULTS: The mean prenatal blood levels were: lead 3.66 +/- 1.55 MUg/dl; cadmium 0.45 +/- 0.54 MUg/l; mercury 2.23 +/- 1.14 MUg/l. There was no evidence for any adverse associations of prenatal lead, cadmium or mercury exposure with motor skills measured at age 7 years with Movement ABC subtests in adjusted regression models. Further, there were no associations with probable DCD. CONCLUSIONS: There was no evidence to support a role of prenatal exposure to heavy metals at these levels on motor skills in the child at age 7 years measured using the Movement ABC. Early identification of symptoms of motor skills impairment is important, however, to enable investigation, assessment and treatment. PMID- 29723755 TI - Engineered hybrid spider silk particles as delivery system for peptide vaccines. AB - The generation of strong T-cell immunity is one of the main challenges for the development of successful vaccines against cancer and major infectious diseases. Here we have engineered spider silk particles as delivery system for a peptide based vaccination that leads to effective priming of cytotoxic T-cells. The recombinant spider silk protein eADF4(C16) was fused to the antigenic peptide from ovalbumin, either without linker or with a cathepsin cleavable peptide linker. Particles prepared from the hybrid proteins were taken up by dendritic cells, which are essential for T-cell priming, and successfully activated cytotoxic T-cells, without signs of immunotoxicity or unspecific immunostimulatory activity. Upon subcutaneous injection in mice, the particles were taken up by dendritic cells and accumulated in the lymph nodes, where immune responses are generated. Particles from hybrid proteins containing a cathepsin cleavable linker induced a strong antigen-specific proliferation of cytotoxic T cells in vivo, even in the absence of a vaccine adjuvant. We thus demonstrate the efficacy of a new vaccine strategy using a protein-based all-in-one vaccination system, where spider silk particles serve as carriers with an incorporated peptide antigen. Our study further suggests that engineered spider silk-based vaccines are extremely stable, easy to manufacture, and readily customizable. PMID- 29723756 TI - Histone deacetylase inhibitor treated cell sheet from mouse tendon stem/progenitor cells promotes tendon repair. AB - Tendon stem/progenitor cells (TSPCs) have been identified as a rare population in tendons. In vitro propagation is indispensable to obtain sufficient quantities of TSPCs for therapies. However, culture-expanded TSPCs are prone to lose their phenotype, resulting in an inferior repaired capability. And little is known about the underlying mechanism. Here, we found that altered gene expression was associated with increased histone deacetylase (HDAC) activity and expression of HDAC subtypes. Therefore, we exposed ScxGFP mice-derived TSPCs to HDAC inhibitor (HDACi) trichostatin A (TSA) or valproic acid (VPA), and observed significant expansion of ScxGFP+ cells without altering phenotypic properties. TSA upregulated Scx expression by inhibiting HDAC1 and -3, and increasing the H3K27Ac level of Tgfb1 and -2 genome region. Additionally, cell sheets formed from TSA pretreated mTSPCs retained the ability to accelerate tendon repair in vivo. Thus, our results uncovered an unrecognized role of HDACi in phenotypic and functional mTSPCs expansion to enhance their therapeutic potential. PMID- 29723757 TI - Dual-triggered oxygen self-supply black phosphorus nanosystem for enhanced photodynamic therapy. AB - Nonspecific distribution of photosensitizer and the intrinsic hypoxic condition in the tumor microenvironment are two key factors limiting the efficacy of O2 dependent photodynamic therapy (PDT). Herein, a dual-triggered oxygen self supported nanosystem using black phosphorus nanosheet (BPNS) as both photosensitizer and nanocarrier was developed to enhance PDT for tumors within hypoxic microenvironment. The BPNS platform was functionalized with folate and a blocker DNA duplex of 5'-Cy5-aptamer-heme/3'-heme labeled oligonucleotides. The resulting heme dimer could passivate its peroxidase activity. After specific recognition of aptamer-target, the quenched fluorescence is "turned" on by cellular adenosine triphosphate. The passivated nanosystem then activates the catalytic function towards excessive intracellular H2O2 to generate O2 essential to sustain BPNS-mediated PDT, leading to 8.7-fold and 7.5-fold increase of PDT efficacy in treating the hypoxic cell and tumor, respectively. Therefore, the dual-triggered oxygen self-supply nanosystem not only exerts tumor microenvironment-associated stimulus for enhanced PDT but also surmounts hypoxia associated therapy resistance. PMID- 29723758 TI - Optimization of lipid-assisted nanoparticle for disturbing neutrophils-related inflammation. AB - Inflammation is closely related to the development of many diseases and is commonly characterized by abnormal infiltration of immune cells, especially neutrophils. The current therapeutics of inflammatory diseases give little attention to direct modulation of these diseases with respect to immune cells. Nanoparticles are applied for efficient drug delivery into the disease-related immune cells, but their performance is significantly affected by their surface properties. In this study, to optimize the properties of nanoparticles for modulating neutrophils-related inflammation, we prepared a library of poly(ethylene glycol)-b-poly(lactide-co-glycolide) (PEG-b-PLGA)-based cationic lipid-assisted nanoparticles (CLANs) with different surface PEG density and surface charge. Optimized CLANs for neutrophils targeting were screened in high fat diet (HFD)-induced type 2 diabetes (T2D) mice. Then, a CRISPR-Cas9 plasmid expressing a guide RNA (gRNA) targeting neutrophil elastase (NE) was encapsulated into the optimized CLAN and denoted as CLANpCas9/gNE. After intravenous injection, CLANpCas9/gNE successfully disrupted the NE gene of neutrophils and mitigated the insulin resistance of T2D mice via reducing the inflammation in epididymal white adipose tissue (eWAT) and in the liver. This strategy provides an example of abating the inflammatory microenvironment by directly modulating immune cells with nanoparticles carrying genome editing tools. PMID- 29723760 TI - High-performance microbial fuel cell anodes obtained from sewage sludge mixed with fly ash. AB - Microbial fuel cells (MFCs) are promising for converting biomass energy into electricity, and have attracted much research interest. However, few inexpensive high-performance anode materials for MFCs exist. In this study, MFC anodes composed of sewage sludge and different contents of fly ash (0%, 20%, 40%, 60%, and 80%) are fabricated via a one-step carbonization method. The maximum current density of 25.5 A m-2 is achieved using the electrode with 20% fly ash, which is 37.5% higher than that of the electrode without fly ash. The improved anode performance is attributed to its good hydrophilicity, which is indicated by its water contact angle of less than 60 degrees , facile adsorption of exoelectrogens, low electron transfer resistance, and good biocompatibility. In addition, the mechanical strength of the electrode with 20% fly ash is approximately 18 times that of the electrode without fly ash. This study reveals a promising method to fabricate high-performance MFC anodes and sheds light on the future development of MFCs using abundant municipal solid waste products. PMID- 29723759 TI - Hierarchically-structured SiO2-Ag@TiO2 hollow spheres with excellent photocatalytic activity and recyclability. AB - A new protocol for constructing sandwich-like SiO2-Ag@TiO2 hollow spheres (SAT) is introduced, in which SiO2 acts as an efficient support for the Ag nanoparticles (Ag NPs) immobilization, while TiO2 maintains its hierarchical structure and prevents the aggregation of Ag NPs during the photocatalytic reaction. As a photocatalytic agent, the inner and outer surfaces of TiO2 can be fully occupied by pollutants molecules because of its unique structure, which faster boosts the photo-generated electrons to transfer the substrates, leading to an enhanced photocatalytic performance. Compared with Ag NPs deposited on the surface of SiO2@TiO2 (STA), the as-synthesized SAT exhibits a markedly enhanced visible-light and UV light activity than STA for degrading tetracycline and traditional dyes. The excellent photocatalytic performances are ascribed to the enhanced transport paths of photo-generated electrons, reduced recombination probability of e-/h+ pairs, and decreased threat of oxidation and corrosion. Especially, the SAT still maintains its photocatalytic efficiency after five consecutive runs even though the sample is recovered under visible-light irradiation, far beyond the reusability of STA under the same conditions. Therefore, the outstanding photocatalytic activity and excellent recyclability make SAT more potential to purify aquatic contaminants and to meet the demands of future environmental issues. PMID- 29723761 TI - Stage-dependent effects of chlorpyrifos on medaka (Oryzias latipes) swimming behavior using a miniaturized swim flume. AB - By considering chlorpyrifos (CPF), an organophosphorus pesticide with known mechanisms of action that affect neurobehavioral development, we assessed the validity and sensitivity of a miniaturized swim flume by investigating the effects of the insecticide on swimming behavior in medaka (Oryzias latipes) fish growing stages. Medaka in three developmental periods, namely 0, 20 and 40 day old post-hatch (i.e. time points 0, 20 and 40, respectively), were exposed to CPF (12.5, 25, 50 and 100 MUg/L) for 48 h under semi-static conditions. The CPF half lives during exposures were evaluated and the swimming patterns in a flume section (arena) were presented on two-dimensional gradient maps of forced movement of fish against water current. A comparative numerical analysis of fish residence times between each time point control and the corresponding CPF groups was performed by dividing arenas into 15 proportional areas. The time point 0 control group gradient map showed a noticeably different swim pattern from those of the >=12.5 MUg CPF/L groups, which was statistically supported by the differences for residence times seen in >=12 corresponding areas. The control group gradient maps for time points 20 and 40 differed from those of the respective >=12.5 MUg CPF/L groups. The comparative analysis of the residence times in the corresponding 15 areas revealed differences in >=5 areas for time point 20 and in >=3 areas for time point 40. The integrative analysis of the gradient maps and the numerical statistics revealed stage-specific effects and a concentration-response relationship between CPF and alterations on forced medaka swimming despite the dissipation of CPF from the water column. These results indicate the validity of the miniaturized swim flume toward a more environmentally realistic scenario for the evaluation of neurodevelopmental and behavioral toxicity in small fish models. PMID- 29723763 TI - Behavioral activation therapy during transcranial magnetic stimulation for major depressive disorder. AB - BACKGROUND: Behavioral Activation (BA) Therapy and Transcranial Magnetic Stimulation (TMS) have each been shown to be effective in the treatment of adult outpatients with major depressive disorder (MDD). Combining both treatments may produce synergistic antidepressant outcomes. METHODS: We developed a new protocol for incorporating a simplified version of BA during a standard 6-week course of TMS and it was pilot tested in 11 consecutively treated outpatients with treatment resistant depression (TRD). BA was delivered in a 5-10 min interval daily prior to the start of TMS. Engagement in BA was measured by tracking the setting and attainment of between session "goals" during the course of TMS treatment. The Inventory of Depressive Symptoms (IDS-SR), the 9-item Patient Health Questionnaire (PHQ-9), and the Snaith-Hamilton Pleasure Scale (SHAPS) were used to measure overall symptom improvement. RESULTS: Patients who underwent a combined BA + TMS protocol demonstrated an average goal completion rate of 77% along with overall symptom improvement as demonstrated by an average decrease of 47%, 55%, and 39% in IDS-SR, PHQ-9, and SHAPS scores respectively. BA was easily incorporated into the daily routine of administering TMS procedures. LIMITATIONS: There is inadequate power in this current investigation to compare treatment efficacy of BA + TMS to TMS alone. CONCLUSION: Incorporation of a modified version of BA therapy into a standard acute course of TMS therapy is feasible, well tolerated, and holds potential for augmenting the efficacy of TMS treatment for patients with TRD. PMID- 29723764 TI - Emotional rigidity negatively impacts remission from anxiety and recovery of well being. AB - OBJECTIVES: Emotional rigidity is described in clinical literature as a significant barrier to recovery; however, few there are few empirical measures of the construct. The current study had two aims: Study 1 aimed to identify latent factors that may bear on the construct of emotional rigidity while Study 2 assessed the potential impact of the latent factor(s) on anxiety remission rates and well-being. METHOD: This study utilized data from 2472 adult inpatients (1176 females and 1296 males) with severe psychopathology. Study 1 utilized exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) to identify latent factors of emotional rigidity. Study 2 utilized hierarchical logistic regression analyses to assess the relationships among emotional rigidity factors and anxiety remission and well-being recovery at discharge. RESULTS: Study 1 yielded a two factor solution identified in EFA was confirmed with CFA. Factor 1 consisted of neuroticism, experiential avoidance, non-acceptance of emotions, impaired goal directed behavior, impulse control difficulties and limited access to emotion regulation strategies when experiencing negative emotions. Factor 2 consisted of lack of emotional awareness and lack of emotional clarity when experiencing negative emotions. Results of Study 2 indicated higher scores on Factor 1 was associated with lower remission rates from anxiety and poorer well-being upon discharge. Factor 2 was not predictive of outcome. CONCLUSIONS: Emotional rigidity appears to be a latent construct that negatively impacts remission rates from anxiety. Limitations of the present study include its retrospective design, and inefficient methods of assessing emotional rigidity. PMID- 29723765 TI - Exploring the use of telephone helpline pertaining to older adult suicide prevention: A Hong Kong experience. AB - BACKGROUND: Older adults usually have a higher suicide rate than the general population. There are helpline services provided to older adults but limited studies have examined the suicidal risks among the users, and how those services could be used as a platform to engage older adults in suicide prevention. METHODS: In regard to elderly suicide prevention, this study explored the potential usefulness and relevance of a telephone helpline service in Hong Kong, which had 106,583 users during 2012-2015. An estimation on the suicide rates of the users was made and compared with the general older adult population in Hong Kong. The users' suicide risks and their associated factors were assessed by survival analyses and an estimation system on the users' suicide mortality likelihood was also tested. RESULTS: The suicide rates of both male and female users were more than two times higher than the general older adult population in Hong Kong. The users' risks of suicides were greater at the early period of using the service; men, living alone, and having a history of mental illnesses were also associated with increased risks. Based on the identified factors, an estimation system was developed with a sensitivity of 0.73 and specificity of 0.54. LIMITATIONS: A secondary data analysis. CONCLUSIONS: By identifying a suicide risk profile and distinct telephone calling pattern among the users, early detection and a warning system should be implemented to allow timely intervention to reduce the number of older adult suicides in the community. PMID- 29723762 TI - Characterization of igf1 and igf2 genes during maraena whitefish (Coregonus maraena) ontogeny and the effect of temperature on embryogenesis and igf expression. AB - The insulin-like growth factors IGF-1 and IGF-2 play important roles in the growth, development, and metabolism of teleost fish. We isolated cDNA sequences of igf1, and igf2 genes from maraena whitefish. We quantified the mRNA and protein expressions of IGFs in different tissues of marketable juvenile maraena whitefish. Moreover, we analyzed the gene expression profiles during maraena whitefish development from unfertilized egg to fingerling and examined the effect of incubation temperature on igf1, and igf2 gene expression during embryonic and early larval development. Transcripts encoding IGF-1 or IGF-2 were detected in all tested tissues, with the greatest abundance in the liver. We measured higher igf2 than igf1 copy numbers in all tissues and at all developmental stages examined, even at advanced juvenile stages. Using the Western blot technique, we demonstrated that several isoforms of IGF-1 are expressed in the liver and gills but not in muscle tissue, indicating tissue-specific protein expression of IGF-1. We observed an accelerated embryonic development with increasing temperature, resulting in shortened hatching periods. Out of the three tested temperatures, we observed the highest hatching rate, larval hatching size, and larval growth at 6 degrees C. At 9 degrees C, hatching rate, larval hatching size and larval growth were reduced compared to the values we observed at 4 degrees C and 6 degrees C, since incubation temperature might have exceeded the optimum. To our knowledge, our data show for the first time that both igf1 and igf2 expression were upregulated due to elevated incubation temperature within embryonic development of fish. Further, we found significantly higher igf expression for the best developing larvae (6 degrees C group) at specific life stages of maraena whitefish. PMID- 29723766 TI - Timing and risk of mood disorders requiring psychotropics in long-term survivors of adult cancers: A nationwide cohort study. AB - BACKGROUND: The increasing number of long-term cancer survivors over the past few decades poses the challenge of mental health care needs. However, little is known about risks of mood disorders in long-term cancer survivors. METHODS: Long-term survivors (>=5 years) of adult cancers (LSAC) (n = 190,748) newly diagnosed between January 1, 2000 and December 31, 2007 were matched with one control. The primary outcome was diagnosis of mood disorders requiring psychotropics. Cumulative incidences and sub-hazard ratios (SHR) were calculated and multivariate analyses were conducted after accounting for mortality. RESULTS: The mood disorder risk was significantly higher in the LSAC cohort than in the control cohort (adjusted SHR = 1.16, 95% confidence interval [CI] = 1.13-1.18, P < 0.001). Patients with certain cancer types were at increased risk, particularly in the first 2 years after diagnosis. However, patients with head and neck cancers or esophageal cancers had a higher risk after the 5-year follow-up period. Multivariate analysis indicated that being female, aged 40-59 years, with more than two primary cancers, receiving two or more treatment modalities, having CCI scores higher than 3, a higher urbanization level, and lower monthly income were independently associated with an increased risk of mood disorders. LIMITATIONS: Some potential confounders such as lifestyle factors were not available in the study. CONCLUSION: These findings call for increased mental health awareness not only in the early years after the cancer diagnosis, but also during long-term follow-up for certain cancer subtypes. PMID- 29723767 TI - Tibolone improves depression in women through the menopause transition: A double blind randomized controlled trial of adjunctive tibolone. AB - BACKGROUND: Many women with no past psychiatric history experience severe mood symptoms for the first time in their life during the menopausal transition, with debilitating long-term consequences. Women with a history of depression can experience a relapse or worsening of symptoms during the menopause transition. Traditional antidepressants, SSRIs or SNRIs, are commonly prescribed as the first line response. However, such treatment has shown only small improvements with side effects. Hormone therapies directly targeting the perimenopausal fluctuations in reproductive hormonal systems such as tibolone, have significant potential to treat perimenopausal depression. Our study investigated the use of adjunctive tibolone, selective tissue estrogenic activity regulator, to treat de novo or relapsing depression occurring during the menopause transition period. METHODS: Women who were going through the menopause transition with depressive symptoms were invited to participate in a double-blind, 12 week randomized control trial with two arms: tibolone (2.5 mg oral/day) or oral placebo (NCT01470092). Forty-four women met inclusion/exclusion criteria; 22 were randomized to tibolone and 22 were randomized to oral placebo. Symptoms were measured with the 'Montgomery- Asberg depression rating scale' (MADRS) as the primary outcome measure. Latent growth curve analysis was used to assess the MADRS scores change over time. RESULTS: Participants in the tibolone group demonstrated a significant improvement in depression scores, as compared to the placebo group, without any significant side effects. LIMITATIONS: This trial only monitored tibolone's effects over 12 weeks. Future research should be conducted over an extended timeframe and explore whether the benefits of tibolone extend to other symptoms of perimenopausal depression. CONCLUSIONS: The use of hormone therapies such as tibolone provide exciting innovations for the treatment of depression during the menopause transition. PMID- 29723768 TI - Physical activity in pregnancy and postpartum depressive symptoms in a multiethnic cohort. AB - INTRODUCTION: There is strong evidence that postpartum depression is associated with adverse health effects in the mother and infant. Few studies have explored associations between physical activity in pregnancy and postpartum depression. We aimed to investigate whether physical activity during pregnancy was inversely associated with postpartum depressive symptoms, PPDS in a multiethnic sample. METHOD: Population-based, prospective cohort of 643 pregnant women (58% ethnic minorities) attending primary antenatal care from early pregnancy to postpartum in Oslo between 2008 and 2010. Data on demographics and health outcomes were collected during standardized interviews. PPDS was defined by a sum score >=10 from the Edinburgh Postnatal Depression Scale (EPDS), 3 months after birth. Physical activity was recorded with Sense WearTM Pro3 Armband (SWA) in gestational week 28 and defined as moderate-to-vigorous intensity physical activity (MVPA) accumulated in bouts >=10 min. RESULTS: Women who accumulated >=150 MVPA minutes/week had significantly lower risk (OR = 0.2, 95% CI: 0.06 0.90), for PPDS compared to those who did not accumulate any minutes/week of MVPA, adjusted for ethnic minority background, depressive symptoms in the index pregnancy and self-reported pelvic girdle syndrome. The results for MVPA persisted in the sub-sample of ethnic minority women. LIMITATIONS: Numbers of cases with PPDS were limited. The SWA does not measure water activities. Due to missing data for SWA we used multiple imputations. CONCLUSION: Women meeting the physical activity recommendation (>150 MVPA min/week) during pregnancy have a lower risk of PPDS compared to women who are not active during pregnancy. PMID- 29723769 TI - Gender differences in psychiatric and medical comorbidity with post-traumatic stress disorder. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) is associated with significant personal and societal burden. The present study examines the gender-specific differences in this burden in terms of the co-occurrence of psychiatric disorders and medical conditions with PTSD in the general population of France. METHODS: The study is based on a cross-sectional general population survey of 21,879 adults. Trained interviewers used a computer-assisted telephone interviewing system to administer the Composite International Diagnostic Interview-Short Form to screen for psychiatric disorders and medical conditions in the previous 12 months. RESULTS: One third of those with moderately severe PTSD (35.3%) and half of those with severe PTSD (54.2%) suffered from comorbid depression. The prevalence of anxiety disorders and substance use disorders was also greater among severe cases of PTSD. Chronic back or neck problems, frequent or severe headaches, arthritis or rheumatism and hypertension were highly prevalent among adults with PTSD. Adjusting for gender, age, education, employment and marital status, moderately severe and severe PTSD diagnoses were associated with significantly greater odds of comorbid psychiatric disorders and medical conditions. With few exceptions, the pattern of gender differences in psychiatric and medical morbidity among those with moderate or severe PTSD were similar to differences observed among those without PTSD. CONCLUSIONS: The findings highlight the burden of co-occurring psychiatric and medical conditions among PTSD sufferers in France and suggest the need for careful consideration of comorbidity in the assessment and service planning for PTSD. PMID- 29723770 TI - Genomic organization and adaptive evolution of IGHC genes in marine mammals. AB - Immunoglobulins are important elements of the adaptive immune system that bind to an immense variety of microbial antigens to neutralize infectivity and specify effector functions. In the present study, the immunoglobulin heavy chain constant region (IGHC) genes from marine mammals were identified and compared with those of their terrestrial relatives to explore their genomic organization and evolutionary characteristics. The genomic organization of marine mammal IGHC genes was shown to be conservative with other eutherian mammals. Stronger signals of positive selection on IGHC were revealed in terrestrial mammals than that in marine mammals with the branch-site model, displaying different selective pressure, which might suggest their divergent adaptations to contrasted environments. PMID- 29723771 TI - We cooperated so... now what? Infants expect cooperative partners to share resources. AB - Research has demonstrated that an understanding of and engagement in cooperative activities emerges early in life. However, little is known about the expectations infants hold about the consequences of cooperative action. We demonstrate that 14 month-old infants expect that cooperative partners will share the recently attained cooperative goal instead of keeping it for themselves. Interestingly, this prediction does not hold if infants saw the two individuals work towards individual goals. These findings contribute to the growing body of literature suggesting that infants possess at least a basic understanding of cooperation well before their second birthday. PMID- 29723772 TI - Construction of conducting polymer/cytochrome C/thylakoid membrane based photo bioelectrochemical fuel cells generating high photocurrent via photosynthesis. AB - In this study, a photo-bioelectrochemical fuel cell was constructed for photocurrent generation by illuminating the electrodes within an aqueous solution. In this purpose, gold electrode was coated with poly 4-(4H-Dithieno [3,2-b:2',3'-d]pyrol-4-yl) aniline, P(DTP-Ph-NH2) conductive polymer film by using electrochemical polymerization. Then, P(DTP-Ph-NH2) conductive polymer film coated surface was electrochemically modified with cytochrome C which covalently linked onto the surface via bis-aniline functionality of the polymer film and formed crosslinked-structure. The thylakoid membrane was attached on the surface of this electrode by using bissulfosaxinimidyl suberate (BS3) and used as photo anode in photo-bioelectrochemical fuel cell. The photo-cathode of the photo bioelectrochemical fuel cell fabrication was followed by the modification of conductive polymer poly[5-(4H-dithieno [3,2-b:2',3'-d]pyrol-4-yl) naphtalene-1 amine] film coating, glutaraldehyde activation, and bilirubin oxidase enzyme immobilization. During the photosynthesis occurring in thylakoid membrane under the light, water was oxidized and separated; while oxygen was released in anode side, the cathode side was reduced the oxygen gas into the water via a bio electro-catalytic method. The cytochrome C was used for binding of thylakoid membrane to the electrode surface and play an important role for transferring of electrons released as a result of photosynthesis. PMID- 29723773 TI - Different ketogenesis strategies lead to disparate seizure outcomes. AB - BACKGROUND: Despite the introduction of new medicines to treat epilepsy over the last 50 years, the number of patients with poorly-controlled seizures remains unchanged. Metabolism-based therapies are an underutilized treatment option for this population. We hypothesized that two different means of systemic ketosis, the ketogenic diet and intermittent fasting, would differ in their acute seizure test profiles and mitochondrial respiration. METHODS: Male NIH Swiss mice (aged 3 4 weeks) were fed for 12-13 days using one of four diet regimens: ketogenic diet (KD), control diet matched to KD for protein content and micronutrients (CD), or CD with intermittent fasting (24 h feed/24 h fast) (CD-IF), tested post-feed or post-fast. Mice were subject to the 6 Hz threshold test or, in separate cohorts, after injection of kainic acid in doses based on their weight (Cohort I) or a uniform dose regardless of weight (Cohort II). Mitochondrial respiration was tested in brain tissue isolated from similarly-fed seizure-naive mice. RESULTS: KD mice were protected against 6 Hz-induced seizures but had more severe seizure scores in the kainic acid test (Cohorts I & II), the opposite of CD-IF mice. No differences were noted in mitochondrial respiration between diet regimens. INTERPRETATION: KD and CD-IF do not share identical antiseizure mechanisms. These differences were not explained by differences in mitochondrial respiration. Nevertheless, both KD and CD-IF regimens protected against different types of seizures, suggesting that mechanisms underlying CD-IF seizure protection should be explored further. PMID- 29723774 TI - The linguistic transparency of first language calendar terms affects calendar calculations in a second language. AB - Calendar calculations - e.g., calculating the nth month after a certain month - are an important component of temporal cognition, and can vary cross linguistically. English speakers rely on a verbal list representation-processing system. Chinese speakers - whose calendar terms are numerically transparent - rely on a more efficient numerical system. Does knowing a numerically transparent calendar lexicon facilitate calendar calculations in an opaque second language? Late Chinese-English bilinguals and English native speakers performed a Month and a Weekday Calculation Task in English. Directionality (forward/backward) and boundary-crossing (within/across the year/week boundary) were manipulated. English speakers relied on verbal list processing, and were slower in backward than forward calculations. In spite of the English calendar system's opaqueness, bilinguals relied on numerical processing, were slower in across- than within boundary trials, and under some conditions had faster RTs than the native speakers. Results have implications for research on temporal cognition, linguistic relativity and bilingual cognition. PMID- 29723775 TI - Alterations in anterior cingulate cortex myoinositol and aggression in veterans with suicidal behavior: A proton magnetic resonance spectroscopy study. AB - Studies investigating the neurochemical changes that correspond with suicidal behavior (SB) have not yielded conclusive results. Suicide correlates such as aggression have been used to explore risk factors for SB. Yet the neurobiological basis for the association between aggression and SB is unclear. Aggression and SB are both prevalent in veterans relative to civilian populations. The current study evaluated the relationship between brain chemistry in the anterior (ACC) and the posterior cingulate cortex (POC), as well as the relationship between aggression and SB in a veteran population using proton magnetic resonance spectroscopy (1H-MRS). Single-voxel MRS data at 3 Tesla (T) were acquired from the ACC and POC voxels using a 2-dimensional J-resolved point spectroscopy sequence and quantified using the ProFit algorithm. Participants also completed a structured diagnostic interview and a clinical battery. Our results showed that the myoinositol (mI)/H2O ratio in the ACC and POC was significantly higher in veterans who reported SB when compared to veterans who did not. The two groups did not differ significantly with regard to other metabolites. Second, verbal aggression and SB measures positively correlated with mI/H2O in the ACC. Finally, verbal aggression mediated the relationship between mI/H2O in the ACC and SB. PMID- 29723776 TI - Association between schizophrenia polygenic risk and neural correlates of emotion perception. AB - The neural correlates of emotion perception have been shown to be significantly altered in schizophrenia (SCZ) patients as well as their healthy relatives, possibly reflecting genetic susceptibility to the disease. The aim of the study was to investigate the association between SCZ polygenic risk and brain activity whilst testing perception of multisensory, dynamic emotional stimuli. We created SCZ polygenic risk scores (PRS) for a sample of twenty-eight healthy individuals. The PRS was based on data from the Psychiatric Genomics Consortium and was used as a regressor score in the neuroimaging analysis. The results of a multivariate brain-behaviour analysis show that higher SCZ PRS are related to increased activity in brain regions critical for emotion during the perception of threatening (angry) emotions. These results suggest that individuals with higher SCZ PRS over-activate the neural correlates underlying emotion during perception of threat, perhaps due to an increased experience of fear or neural inefficiency in emotion-regulation areas. Moreover, over-recruitment of emotion regulation regions might function as a compensation to maintain normal emotion regulation during threat perception. If replicated in larger studies, these findings may have important implications for understanding the neurophysiological biomarkers relevant in SCZ. PMID- 29723777 TI - Circulating macrophage migration inhibitory factor (MIF) in patients with heart failure. AB - BACKGROUND: Heart failure (HF) is characterized by impaired systolic ejection capacity and/or diastolic filling of the heart, leading to a multisystem disorder. Remote organ failure, systemic inflammation or pulmonary hypertension (PH) are hallmarks of the pathophysiological changes in HF. The Macrophage migration inhibitory factor (MIF) is a pro-inflammatory cytokine that is involved in a variety of cardiovascular and inflammatory diseases. Circulating MIF levels and their potential role as a disease marker in the different subgroups of HF have not been investigated yet. We here aimed to unravel a potential role of MIF in HF. METHODS AND RESULTS: MIF plasma levels were assessed in 249 consecutive patients with HF. MIF was detectable in all investigated subjects and showed no difference with regard to the nature of HF (preserved or reduced ejection fraction). Spearman correlation revealed an association with inflammatory biomarkers (white blood cell count r = 0.18, p = 0.005; c-reactive protein r = 0.20, p = 0.003). MIF was associated with higher pulmonary artery systolic pressure (PASP) as assessed by echocardiography (r = 0.23, p < 0.001). Log transformed PASP was also independently associated with MIF in a multivariable linear regression model (p = 0.02). Follow-up (FU) data after 180 days revealed that patients with increased MIF values (in ng/ml) were more likely to reach the endpoint all-cause mortality (HR 1.01, 95% CI 1.004-1.02, p = 0.005, per unit change). CONCLUSION: MIF is detectable in the circulation of patients with HF and might be associated with clinical endpoints in HF, markers of inflammation and PH. These promising results should stimulate further research to elucidate the role of MIF in the multisystem disorder of HF. PMID- 29723778 TI - Does motor expertise facilitate amplitude differentiation of lower limb-movements in an asymmetrical bipedal coordination task? AB - The motor system's natural tendency is to move the limbs over equal amplitudes, for example in walking. However, in many situations in which people must perform complex movements, a certain degree of amplitude differentiation of the limbs is required. Visual and haptic feedback have recently been shown to facilitate such independence of limb movements. However, it is unknown whether motor expertise moderates the extent to which individuals are able to differentiate the amplitudes of their limb-movements while being supported with visual and haptic feedback. To answer this question 14 pre-professional dancers were compared to 14 non-dancers on simultaneously generating a small displacement with one foot, and a larger one with the other foot, in four different feedback conditions. In two conditions, haptic guidance was offered, either in a passive or active mode. In the other two conditions, veridical and enhanced visual feedback were provided. Surprisingly, no group differences were found regarding the degree to which the visual or haptic feedback assisted the generation of the different target amplitudes of the feet (mean amplitude difference between the feet). The correlation between the displacements of the feet and the standard deviation of the continuous relative phase between the feet, reflecting the degree of independence of the feet movements, also failed to show between-group differences. Sample entropy measures, indicating the predictability of the foot movements, did show a group difference. In the haptically-assisted conditions, the dancers demonstrated more predictable coordination patterns than the non dancers as reflected by lower sample entropy values whereas the reverse was true in the visual-feedback conditions. The results demonstrate that motor expertise does not moderate the extent to which haptic tracking facilitates the differentiation of the amplitudes of the lower limb movements in an asymmetrical bipedal coordination task. PMID- 29723779 TI - What's fair? How children assign reward to members of teams with differing causal structures. AB - How do children reward individual members of a team that has just won or lost a game? We know that from pre-school age, children consider agents' performance when allocating reward. Here we assess whether children can go further and appreciate performance in context: The same pattern of performance can contribute to a team outcome in different ways, depending on the underlying rule framework. Two experiments, with three age groups (4/5-year-olds, 6/7-year-olds, and adults), varied performance of team members, with the same performance patterns considered under three different game rules for winning or losing. These three rules created distinct underlying causal structures (additive, conjunctive, disjunctive), for how individual performance affected the overall team outcome. Even the youngest children differentiated between different game rules in their reward allocations. Rather than only rewarding individual performance, or whether the team won/lost, children were sensitive to the team structure and how players' performance contributed to the win/loss under each of the three game rules. Not only do young children consider it fair to allocate resources based on merit, but they are also sensitive to the causal structure of the situation which dictates how individual contributions combine to determine the team outcome. PMID- 29723780 TI - Understanding the enrolled nurse to registered nurse journey through a model adapted from Schlossberg's transition theory. AB - BACKGROUND: Substantial numbers of Enrolled Nurses (ENs) enrol in higher education programs to undergo the transition to Registered Nurse (RN) with the experience described as containing numerous challenges. OBJECTIVES: This paper reports on a synthesis of the literature that explores the experiences of ENs undertaking a program of study to convert to RN. Consequently, a model is developed to identify educational interventions and resources to enable a successful transition for these students. DESIGN: A narrative review was completed with thematic synthesis of the literature guided by Schlossberg's Transition Theory, and Thomas and Harden's framework for systematic analysis of qualitative studies. DATA SOURCES: CINAHL, Scopus, ProQuest Central and Health Collection were searched. REVIEW METHODS: The databases were searched for English language journal articles, theses and grey literature published from 1987 to 2016 from Australia, New Zealand, the United Kingdom, Canada and the USA. The key search words included truncations of: "enrolled nurse", 'licensed practical nurse', "transition", "conversion" and "experience". This resulted in the identification of 33 related articles for review. RESULTS: Themes and sub-themes developed from the literature synthesis were integrated into an 'EN to RN Transition model.' The four stages of the model reflect the experiences of the ENs as they overcame the various challenges they encountered during their transition to RN. The model was used to develop recommendations that may improve their transition experience and decrease attrition. CONCLUSION: This paper reports on a synthesis of the literature, and presents a four stage model, that reflects the experiences of ENs in their transition to RN. Recognising the elements within each stage can assist educators develop strategies and provide educational resources to enhance the EN journey. PMID- 29723781 TI - Emotional abilities and HbA1c levels in patients with type 1 diabetes. AB - In recent years a growing body of research is focused on the relationships between emotions and health. When it comes to diabetes, findings suggest that distress might play a key role in the acquisition and maintenance of health habits associated with diabetic management. This report describes two studies examining the roles of emotional abilities in diabetic management from two different conceptual points of view using two culturally different samples. In study 1, we examined the relationship between emotional intelligence and HbA1c levels in a sample of eighty-five patients with type 1 diabetes mellitus (DM1) in Israel. In study 2, we examined the relationship between specific emotional regulation strategies and HbA1c in sixty-seven adolescents with DM1, while examining the mediating role of distress in this association. The results showed a negative association between emotional intelligence and HbA1c levels, even after controlling for potential intervening factors. We found that the relationship between difficulties in emotion regulation and HbA1c seemed to be mediated by diabetes-related distress. These findings may aid in the design of psychological models for future research as well as interventions aimed at improving emotional abilities in people with DM1. PMID- 29723782 TI - A grounded theory of successful aging among select incarcerated older Filipino women. AB - BACKGROUND: Across the literature, impairment and disability among the older people have been associated with a decline in meeting their special needs. Failure in meeting such needs may cause deterioration of function and threaten successful aging. Accordingly, successful aging studies were carried out among males, in health care institutions, and in communities. In spite of these, the process by which successful aging is experienced by incarcerated older women remains to be a blank spot in research. AIM: This study purports to describe the process by which incarcerated older Filipino women experience successful aging. METHODS: Strauss and Corbin's grounded theory design was employed. Semistructured interviews were conducted among 15 purposively selected incarcerated older Filipino from a Philippine penal institution exclusive for women. Further, data gathered was reduced to field text and was analyzed through open, axial and selective coding. Finally, truthfulness and trustworthiness of the findings were established through member checking. FINDINGS: The study generated "The Road to Success Model". Interestingly, five phases relative to successful aging emerged, namely: Struggling, Remotivating, Reforming, Reintegrating and Sustaining. These phases describe how select incarcerated older Filipino women undergo transformation towards successful aging. Similar to a road, each phase is considered a station where one must pass through in order to get to the destination. CONCLUSION: Findings of the study serve as an impetus for structural and procedural changes in prison, with a view to providing an environment conducive to successful aging and appropriate recognition to the older prisoner's efforts to achieve successful aging. PMID- 29723783 TI - No evidence of association between native tissue vault suspension and risk of pelvic pain or sexual dysfunction. AB - OBJECTIVE: Hysterectomy is suspected of increasing risk of subsequent pelvic organ prolapse (POP). In attempt to prevent this, several suspension methods during hysterectomy on benign indication are used as a prophylactic procedure. However, possible complications to the use of prophylactic vaginal vault suspension to prevent POP are not fully investigated. We aimed to elucidate prophylactic vaginal vault suspension as a possible cause for pelvic pain and sexual dysfunction. STUDY DESIGN: We included all women registered with a total hysterectomy on benign indication and registered with a suspension method or specifically no suspension in the nationwide Danish Hysterectomy and Hysteroscopy Database (DHHD) between 10 May 2012 and 4 September 2013 (N = 3999). A postal questionnaire on pelvic pain and sexual dysfunction was sent to women 25.8 (range 23.8-28.4) months after hysterectomy. Questions were selected from a previous study as well as from the Pelvic Organ Prolapse/Urinary Incontinence Sexual Questionnaire (PISQ-12). We used independent samples t-tests and chi2-tests for univariate analyses. In multivariable analyses, we used log-binomial - and linear regression models adjusted for risk factors of pelvic pain and sexual dysfunction, respectively. RESULTS: The response rate was 60.3% (N = 2412). Of the respondents, 88.8% (N = 2143) were registered with a suspension method and 11.2% (N = 269) were registered with specifically no suspension. Overall, pelvic pain of any kind was reported in 24.3% (N = 576) of the respondents. In adjusted log-binomial regression, suspension did not increase risk of pelvic pain compared to no suspension (RR 0.92; 95% CI 0.75 to 1.14; p-value 0.45). In adjusted linear regression, suspension was significantly associated with less degree of sexual dysfunction (regression coefficient -0.92; 95% CI -1.70 to -0.14; p-value 0.02). CONCLUSIONS: In women undergoing prophylactic vaginal vault suspension during hysterectomy, we found less sexual dysfunction and no evidence of increased risk of pelvic pain compared to women with no vaginal vault suspension. PMID- 29723784 TI - Detection of HTLV-1 proviral DNA in BM mononuclear cells and cultured mesenchymal stromal cells isolated from patients with HTLV-1 infection. AB - The bone marrow (BM) biology during HTLV-1 infection is obscure. In this study, we investigated BM mononuclear cells and mesenchymal stromal cells (MSC) from HTLV-1 asymptomatic and symptomatic individuals. An infiltration of CD4+ T-cell lymphocytes in the BM of HTLV-1-infected individuals was observed when compared to healthy controls. The provirus detection in the BM CD4+ T cells confirmed the presence of integrated HTLV DNA. In regard to MSC, we observed that the number of fibroblast progenitor cells was lower in HTLV-1 infected individuals than in healthy controls. Isolated HTLV-1 infected BM-MSC demonstrated surface expression markers and in vitro differentiation potential similar to uninfected individuals. The presence of HTLV-1 proviral DNA in the BM-MSC of HTLV-1-infected patients was demonstrated but no p19 antigen was detected in supernatant from cultured MSC. We suppose that HTLV-1 infects human MSC probably by cell-to-cell contact from the infected CD4+ T-lymphocytes infiltrated into the bone marrow. PMID- 29723787 TI - Synthesis of docosapentaenoic acid-enriched diacylglycerols by enzymatic glycerolysis of Schizochytrium sp. oil. AB - Utilization of algae oil and glycerol for preparation of value-added products is vital for sustainable development of related industries. In this study, we aimed to prepare highly pure diacylglycerols (DAG) rich in docosapentaenoic acid (DPA). First, content of DPA in form of triacylglycerols (TAG) increased from 16.4% to 28.1% after low-temperature crystallization of Schizochytrium sp. oil at -80 degrees C for 6 h. Subsequently, DPA-enriched DAG was prepared by the enzymatic glycerolysis of the enriched oil. Under the optimum conditions, there was 48.4% DAG produced in the crude mixture. To remove polar impurities from the crude product, a novel two-step purification was developed and the final product consisted of 75.1% DAG and 24.9% TAG with a low peroxide value. The current method for the synthesis of DAG rich DPA is effective and relatively mild and the successful preparation of value-added product will reduce production costs for algae and biodiesel industries. PMID- 29723785 TI - Synthesis and biological activity of novel tert-butyl and tert-pentylphenoxyalkyl piperazine derivatives as histamine H3R ligands. AB - As a continuation of our search for novel histamine H3 receptor ligands, a series of twenty four new tert-butyl and tert-pentyl phenoxyalkylamine derivatives (2 25) was synthesized. Compounds with three to four carbon atoms alkyl chain spacer were evaluated for their binding properties at human histamine H3 receptor (hH3R). The highest affinities were observed for 4-pyridyl derivatives 4, 10, 16 and 22 (Ki = 16.0-120 nM). As it has been shown in docking studies, those specific heteroaromatic 4-N piperazine substituents might interact with one of the key receptor interacting amino acids. Moreover, the most promising compounds exhibited anticonvulsant activity in the maximal electroshock-induced seizure (MES) model in mice. Furthermore, the blood-brain barrier penetration, the functional H3R antagonist potency as well as the pro-cognitive properties in the passive avoidance test were demonstrated for compound 10. In order to estimate drug-likeness of compound 10,in silico and experimental evaluation of metabolic stability in human liver microsomes was performed. In addition, paying attention to the results obtained within this study, the 4-pyridyl-piperazino moiety has been established as a new bioisosteric piperidine replacement in H3R ligands. PMID- 29723788 TI - Quantifying the sensitivity of feedstock properties and process conditions on hydrochar yield, carbon content, and energy content. AB - Hydrothermal carbonization (HTC) is a wet, low temperature thermal conversion process that continues to gain attention for the generation of hydrochar. The importance of specific process conditions and feedstock properties on hydrochar characteristics is not well understood. To evaluate this, linear and non-linear models were developed to describe hydrochar characteristics based on data collected from HTC-related literature. A Sobol analysis was subsequently conducted to identify parameters that most influence hydrochar characteristics. Results from this analysis indicate that for each investigated hydrochar property, the model fit and predictive capability associated with the random forest models is superior to both the linear and regression tree models. Based on results from the Sobol analysis, the feedstock properties and process conditions most influential on hydrochar yield, carbon content, and energy content were identified. In addition, a variational process parameter sensitivity analysis was conducted to determine how feedstock property importance changes with process conditions. PMID- 29723786 TI - Design, synthesis and biological activities of 2,3-dihydroquinazolin-4(1H)-one derivatives as TRPM2 inhibitors. AB - Transient receptor potential melastatin 2 (TRPM2), a Ca2+-permeable cationic channel, plays critical roles in insulin release, cytokine production, body temperature regulation and cell death as a reactive oxygen species (ROS) and temperature sensor. However, few TRPM2 inhibitors have been reported, especially TRP-subtype selective inhibitors, which hampers the investigation and validation of TRPM2 as a drug target. To discover novel TRPM2 inhibitors, 3D similarity based virtual screening method was employed, by which 2,3-dihydroquinazolin-4(1H) one derivative H1 was identified as a TRPM2 inhibitor. A series of novel 2,3 dihydroquinazolin-4(1H)-one derivatives were subsequently synthesized and characterized. Their inhibitory activities against the TRPM2 channel were evaluated by calcium imaging and electrophysiology approaches. Some of the compounds exhibited significant inhibitory activity, especially D9 which showed an IC50 of 3.7 MUM against TRPM2 and did not affect the TRPM8 channel. The summarized structure-activity relationship (SAR) provides valuable insights for further development of specific TRPM2 targeted inhibitors. PMID- 29723789 TI - Next set of orders: Best practices for academia to ensure student success and military/veteran focus. PMID- 29723790 TI - What women value in the midwifery continuity of care model: A systematic review with meta-synthesis. AB - INTRODUCTION: There are a number of qualitative studies indicating women are more satisfied with a continuity model of midwifery care however, their experiences have not been understood to gain an overall picture of what it is they value, appreciate and want in such a model. A metasynthesis was undertaken in order to examine the current qualitative literature to gain a deeper understanding of the woman's perspective as a consumer of maternity care in a continuity model. AIM: To identify and synthesise research findings presenting childbearing women's perspectives on continuity of midwifery care. METHODS: A search using key words was undertaken using the following databases: CINAHL, Cochrane Library, Ovid, Medline, Nursing Reference Centre and Joanna Briggs Institute. Papers were included if they were published since 2006, in English and included qualitative data from the woman's perspective. The selection process followed was the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Quality appraisal was conducted by all authors using the Critical Appraisal Skills Programme (CASP) tool as a screening tool. This allowed for each paper to be appraised to determine risk of bias. FINDINGS: Thirteen quality appraised papers published between 2006 and 2016 were found which included qualitative data and were related to the woman's experience in a continuity model. Six papers were from Australia, three in the United Kingdom, two in New Zealand and one in the United States of America and Denmark. Themes identified included an overarching concept of the relationship which was underpinned by themes of personalised care, trust and empowerment. CONCLUSIONS: The midwife-woman relationship is the vehicle through which personalised care, trust and empowerment are achieved in the continuity of midwifery model of care. PMID- 29723791 TI - 3D mossy structures of zinc filaments: A facile strategy for superamphiphobic surface design. AB - The superamphiphobic surfaces with extreme repellency to liquids are very attractive in many fields, but their fabrication processes are always low effective and expensive. So it is still a challenge to create the superamphiphobic surfaces by simple, time saving and universal method. In this work, the mossy zinc (Zn) filaments, a promising re-entrant structure, was rapidly constructed on various metal surfaces by electrochemical deposition approach. After modification by 1H,1H,2H,2H- perfluorodecyltrichlorosilane (PFDTCS), the Zn@PFDTCS coating exhibited superamphiphobicity in air. The correlation between the morphology of Zn filaments and electrochemical deposition parameters has been studied. The superamphiphobic surface with contact angle higher than 154 degrees , sliding angle lower than 5 degrees and adhesive force lower than 0.043 mN to water and hexadecane was obtained, when the current density was 1.78 A .dm-2, the mass fraction of zinc was 0.71 wt% and the deposition time was 40 min. Furthermore, the Zn@PFDTCS 2D-meshes were used to collect oil droplets under water and cut water droplet in oil due to their superoleophilicity under water and superhydrophobicity under oil. We anticipated that the simple and rapid method guides the design of perfect artificial superamphiphobic surfaces in practical application. PMID- 29723793 TI - Synthesis of Cu0.5Mg1.5Mn0.5Al0.5Ox mixed oxide from layered double hydroxide precursor as highly efficient catalyst for low-temperature selective catalytic reduction of NOx with NH3. AB - We report a novel NH3-SCR catalyst Cu0.5Mg1.5Mn0.5Al0.5Ox synthesized from layered double hydroxides with superior activity in a wide temperature range and improved SO2 and H2O resistance comparing to conventional doped Mn/gamma-Al2O3. This catalyst results in a high NOx removal efficiency of 87.0-96.6% in the low temperature range of 100-250 degrees C, much better than Mn/gamma-Al2O3 (35.0 67.2%). Besides, it exhibits significant resistance to SO2 and H2O due to the existence of Cu and Mg. The promoting effects of Cu and Mg are thoroughly investigated using various physico-chemical techniques. The superior NH3-SCR activity of Cu0.5Mg1.5Mn0.5Al0.5Ox catalyst can be associated with its high specific surface area, high reducibility of MnO2 and CuO species, abundance of acid sites, and the well dispersion of MnO2 and CuO species. The interactions between SO2 and NH3, and the degradation mechanism caused by SO2 were investigated using in-situ DRIFT analysis. PMID- 29723792 TI - Friction and adhesion control between adsorbed layers of polyelectrolyte brush grafted nanoparticles via pH-triggered bridging interactions. AB - HYPOTHESIS: Adsorption of polyelectrolyte brush-grafted nanoparticles (BGNPs) produces a heterogeneous interface with sub-monolayer surface coverage resulting from lateral electrostatic repulsions that limit packing. As a result, the interaction forces between opposing BGNP layers include an adhesive cross-surface BGNP-substrate bridging force that depends on the interparticle spacing, particle size, and strength of electrostatic interactions. We hypothesize that BGNPs with pH-responsive, annealed polyelectrolyte brushes can undergo controlled changes in surface area coverage through post-adsorption swelling or de-swelling into non equilibrium layer conformations and that such changes in surface coverage can switch off or switch on particle intercalation, bridging attractions, and enhanced energy dissipation upon sliding. This work aims to characterize the nature of surface forces in heterogeneous BGNP adsorbed layers and to utilize pH sensitive bridging forces as a mechanism to tune friction and adhesion. EXPERIMENTS: Colloidal probe atomic force microscopy (CP-AFM) is used to measure normal and lateral forces between negatively charged silica surfaces with adsorbed pH-responsive cationic BGNPs. The BGNPs are poly(2-dimethylaminoethyl methacrylate) brush-grafted silica nanoparticles. Adhesion force and friction analysis is complemented by simultaneous quartz-crystal microbalance and ellipsometry measurements under conditions that render the particles strongly charged and swollen (acidic) or weakly charged and de-swollen (basic). FINDINGS: Adsorbed BGNPs can be swollen or de-swollen via pH rinses, enabling direct control of surface coverage and bridging interactions. Transitions from adhesive bridging contacts with high friction to non-adhesive contacts with low friction forces occur when adsorbed BGNP layers are switched from a de-swollen/weakly charged state to a swollen/highly charged state. The ability to controllably shift the character of normal and lateral forces via coverage-mediated bridging interactions is a unique feature of adsorbed nanoparticulate brush constructs and highlights their potential to condition surfaces with additional functionality compared to dense, planar homopolymer brushes. PMID- 29723794 TI - Self-assembly of fluorinated gradient copolymer in three-dimensional co-flow focusing microfluidic. AB - HYPOTHESIS: The microfluidic technology can drive molecules to organize into aggregates with nano-structures, and gives a possibility to control aggregate morphologies by adjusting hydrodynamic parameters of microfluidics. COMSOL Multiphysics is a useful software to simulate the mixing situation of solutions in microfluidic. Here, experiments and simulation are combined to study the self assembly of gradient copolymers in the microfluidic device. EXPERIMENTS: Fluorinated gradient copolymers self-assembled in a three-dimensional co-flow focusing microfluidic device (3D CFMD). Hydrodynamic parameters of 3D CFMD were adjusted to control morphologies and the sizes of copolymer aggregates. A simulation software, COMSOL Multiphysics, was used to simulate the mixing and diffusion of outer phase stream and inner phase stream to explore the mixing kinetics of two streams in the microchannels. FINDINGS: 3D CFMD offered a novel platform for the continuous and controllable self-assembly of fluorinated gradient copolymer. Various morphologies of copolymer aggregates were obtained in 3D CFMD, but just spherical micelles were formed by a traditional solvent inducing method. The flow velocity, initial water content of outer-phase stream, and the copolymer concentration of inner-phase stream had great effects on the morphology and size of copolymer aggregates. The simulation results made us a better understanding on the microfluidic self-assembly. PMID- 29723795 TI - Inducing and erasing of defect state in polymerized microgel colloidal crystals via external stimuli. AB - It remains a big challenge to introduce artificial extrinsic defects into colloidal crystals, which is critical for them to function as photonic crystals. The introduction of smart defects capable of responding to external stimuli is even harder. Here poly(N-isopropylacrylamide) (PNIPAM) microgel colloidal crystals doped with poly(N-isopropylacrylamide-co-acrylic acid) (P(NIPAM-AAc)) microgel were obtained by self-assembly of the two microgels with the same size. The crystalline structure was then stabilized in situ by photo-initiated polymerization of the vinyl groups on surface of the PNIPAM microgel. Defect state can be facilely induced and then erased reversibly by changing pH or temperature, taking advantage of the different response of the two microgels to external stimuli. The defect state can be induced and erased repeatedly. In addition, the response of the doped crystals is fast because of their inherent porous structure. PMID- 29723796 TI - Substrate-independent superliquiphobic coatings for water, oil, and surfactant repellency: An overview. AB - Superliquiphobic surfaces that exhibit self-cleaning, antifouling, finger touch resistance, and low drag properties with high transparency are of interest in industrial applications including optical devices, solar panels, and self cleaning windows. In this paper, an overview of coatings using a simple and scalable fabrication technique are presented that exhibit superoleophobic/philic properties, wear resistance, finger touch resistance, and transparency. The coating comprises hydrophobic SiO2 nanoparticles with a binder of methylphenyl silicone resin. After ultraviolet-ozone treatment to the coating, an additional coating of fluorosilane or fluorosurfactant modifies the coated surface for superoleophobicity or superoleophilicity, respectively. Data for these coatings are presented showing substrate independency, the ability to repel surfactant containing liquids such as shampoo and laundry detergent, oil-water separation, and the ability to survive up to 80 degrees C environments. The coatings were designed to have re-entrant geometry desirable for superoleophobicity with liquids with very low surface tension as well as surfactants. PMID- 29723797 TI - Psychometric evaluation of the Epilepsy-related Fears in Parents Questionnaire. AB - OBJECTIVE: The aim of the article was to examine the psychometric properties of the Epilepsy-related Fears in Parents Questionnaire (EFPQ). METHOD: Internal consistency, factor structure, and construct validity were analyzed based on data from 291 parents participating in the baseline assessment of a quasi-experimental study on the efficacy of the FAMOSES (modulares Schulungsprogramm Epilepsie fur Familien) parents' program. The control group of this study was used to calculate the test-retest reliability, while the responsiveness of the questionnaire was evaluated by comparing matched groups of FAMOSES participants and control parents. RESULTS: An exploratory factor analysis revealed two factors of epilepsy related fears, "Fears about short-term consequences of the child's epilepsy" (8 items) and "Fears about the future development of the child and the child's epilepsy" (9 items). Both showed good reliability (Cronbach's alpha=.89 and .91, resp.; test-retest reliability: ICC=.77 and .80, resp.), and construct validity was confirmed by correlations with epilepsy-related variables and psychosocial outcomes, e.g., with the Impact on Family Scale (r=.48 and .61, resp.). The FAMOSES parents' program significantly reduced epilepsy-related fears (p<.05 for both subscales). CONCLUSION: The EFPQ proved to be a reliable, valid, and responsive instrument for the assessment of parental fears about their child's epilepsy and can be recommended for use in future studies. PMID- 29723798 TI - Maximal voluntary isometric contraction tests for normalizing electromyographic data from different regions of supraspinatus and infraspinatus muscles: Identifying reliable combinations. AB - This study aimed to identify optimal sets of maximal voluntary isometric contractions (MVICs) for normalizing EMG data from anterior and posterior regions of the supraspinatus, and superior, middle and inferior regions of the infraspinatus. 31 right-handed young healthy individuals (15 males, 16 females) participated. EMG activity was obtained from two regions of supraspinatus and three regions of infraspinatus muscles via fine wire electrodes. Participants performed 15 MVIC tests against manual resistance. The EMG data were normalized to the maximum values. Optimal sets of MVIC combinations, defined as those which elicited >90% MVIC activation in the muscles of interest in >80% and >90% of the population, were obtained. EMG data from the inferior region of infraspinatus were removed from analysis due to technical problem. No single test achieved maximal activation of both regions of either the supraspinatus or infraspinatus. Instead, a combination of 6-8 MVICs were required to reach >90% MVIC activation in both parts of those muscles. In all regions of the rotator cuff muscles, the optimal combination was obtained with 8-10 MVICs. The proposed combinations can reduce inter-participant variability in generating maximal activation from different regions of the supraspinatus and infraspinatus muscles. PMID- 29723799 TI - Neuromuscular variability and spatial accuracy in children and older adults. AB - Our ability to control movements is influenced by the developmental status of the neuromuscular system. Consequently, movement control improves from childhood to early adulthood but gradually declines thereafter. However, no study has compared movement accuracy between children and older adults. The purpose of this study was to compare endpoint accuracy during a fast goal-directed movement task in children and older adults. Ten pre-adolescent children (9.7 +/- 0.67 yrs) and 19 older adults (71.95 +/- 6.99 yrs) attempted to accurately match a peak displacement of the foot to a target (9 degrees in 180 ms) with a dorsiflexion movement. We recorded electromyographic activity from the tibialis anterior (agonist) and soleus (antagonist) muscles. We quantified position error (i.e. spatial accuracy) as well as the coordination, magnitude, and variability of the antagonistic muscles. Children exhibited greater position error than older adults (36.4 +/- 13.4% vs. 27.0 +/- 9.8%). This age-related difference in spatial accuracy, was related to a more variable activation of the agonist muscle (R2: 0.358; P < 0.01). These results suggest that an immature neuromuscular system, compared to an aged one, affects the generation and refinement of the motor plan which increases the variability in the neural drive to the muscle and reduces spatial accuracy in children. PMID- 29723800 TI - Familial alcohol supply, adolescent drinking and early alcohol onset in 45 low and middle income countries. AB - AIMS: This study estimated the extent of familial alcohol supply in 45 low and middle income countries (LMIC), and examined the country-level effects of familial alcohol supply on adolescents' alcohol use. METHOD: We used data from 45 LMICs that participated in the Global School-Based Student Health Survey (GSHS) between 2003 and 2013 (n = 139,840). The weighted prevalence of familial alcohol supply in each country was estimated. Multilevel binary and ordinal logistic regression analyses were used to examine the country-level effect of familial alcohol supply on early onset of alcohol use (first alcohol before 12), past 30 day alcohol use, lifetime drunkenness and alcohol-related social problems. RESULTS: There were large variations between LMICs in the prevalence of familial alcohol supply and pattern of adolescent alcohol use. The prevalence of familial supply ranged from 0.1% in Tajikistan to 23.8% in St Lucia. It was estimated that a one percentage change in prevalence of familial alcohol supply was associated with 10%, 12% and 12% change in the odds of lifetime drunkenness (OR = 1.10, 95% CI = [1.04, 1.16]), early onset of alcohol use (OR = 1.12, 95% CI = [1.07, 1.08]) and more frequent drinking in the past month (OR = 1.12, 95% CI = [1.04, 1.20]). CONCLUSION: There were large variations in the prevalence of familial alcohol supply and adolescent alcohol use among LMICs. Adolescents in countries with higher prevalence of familial alcohol supply were more likely to start using alcohol at an earlier age, to have used alcohol in the past 30 days and experience intoxication. PMID- 29723801 TI - Role of smoking intention in tobacco use reduction: A mediation analysis of an effective classroom-based prevention/cessation intervention for adolescents. AB - INTRODUCTION: Although some school-based tobacco cessation and prevention programs have been proven to be effective, there remains a lack of understanding of how these programs succeed. METHODS: This longitudinal study aimed to test smoking intention as a mediator of Project EX's intervention efficacy to reduce tobacco use. Using a computerized random number generator, six high schools located in the Mediterranean coast were randomly selected to participate in the program condition (Spanish version of Project EX) or the waiting-list control group with baseline, immediate-posttest, and 12-month follow-up assessments. At baseline, 685 adolescents aged 14-20 years (mean age: 14.87; SD = 0.92; 47.4% were females) were evaluated using self-administered tests of tobacco, and smoking intention. A biomarker of smoke inhalation, a measurement of exhaled carbon monoxide (ECM), was used. Mediation analyses were conducted using the PROCESS v2.12 macro for Windows. RESULTS: Project EX had a significant effect on smoking intention. Indirect effects indicated that Project EX reduced the ECM level, and number of cigarettes used. CONCLUSIONS: This is the first Spanish study that explored intention as a mediator of the long-term efficacy of Project EX to reduce tobacco use in adolescents. Results suggested that interventions that reduce consumption intention at short-term are more likely to be successful in decreasing tobacco use in the long-term. PMID- 29723802 TI - Integrating smoking cessation care into routine service delivery in a medically supervised injecting facility: An acceptability study. AB - BACKGROUND: Among people who inject drugs (PWIDs) the prevalence of tobacco smoking exceeds 80%; making smoking cessation intervention a priority for this population. This study aims to examine staff and client perspectives from a supervised injecting facility regarding: i) whether an organizational change intervention increased rates of smoking cessation care delivery (pre- to post intervention); and ii) acceptability of the intervention. METHODS: A pre-and-post intervention pilot study in a supervised injecting facility was conducted in Sydney, Australia between July 2014-December 2015. The intervention employed an organizational change approach and included six components. Cross-sectional samples of staff (pre n = 27, post n = 22) and clients (pre n = 202, post n = 202) completed online surveys pre and post intervention. RESULTS: From pre to post-intervention staff reported smoking cessation practices significantly increased for the provision of verbal advice (30% to 82%; p < 0.001), offer of free or subsidized nicotine replacement therapy (30% to 91%; p < 0.001), referral to a general practitioner (19% to 64%; p = 0.001), and follow-up to check on quit smoking progress (18.5% to 64%; p = 0.001). Significantly more clients reported receiving all smoking cessation strategies post-intervention. Over 85% of staff agreed that it was acceptable to address client smoking as part of usual care and 95% of clients agreed that it was acceptable to be asked by staff about their tobacco smoking. CONCLUSIONS: Increasing the provision of smoking cessation care using an organizational change approach is both feasible for staff and acceptable to staff and clients of supervised injecting facilities. PMID- 29723803 TI - Electronic cigarette liquid and device parameters and aerosol characteristics: A survey of regular users. AB - INTRODUCTION: Electronic cigarettes are widely variable devices, typically with user definable liquid and device parameters. Yet, little is known about how regular users manipulate these parameters. There is also limited understanding of what factors drive electronic cigarette use and liquid purchasing, and whether two common ingredients, propylene glycol and vegetable glycerin, alter the subjective effects of these devices. METHODS: During the spring of 2016 522 adults, who reported daily use of electronic cigarettes containing nicotine, completed a survey on electronic cigarettes. Survey questions included an electronic cigarette dependence questionnaire, questions on tobacco and electronic cigarette use, and device and liquid preferences. RESULTS: Fifty-nine percent of respondents reported using another tobacco product, which was positively associated with level of nicotine dependence. On average, devices were set to 28.3 (SD = 24.2) watts. Ability to change device voltage, and level of resistance typically used, was significantly associated with level of nicotine dependence. Amount of liquid consumed, nicotine concentration, and milligrams of nicotine used per week, were positively associated with nicotine dependence. Participants rated 'good taste' as the most important consideration when using and purchasing liquids, and propylene glycol is associated with undesirable effects and vegetable glycerin with desirable effects. CONCLUSIONS: These data indicate that electronic cigarette users utilize a wide range device parameter settings and liquid variables, and that individuals with greater nicotine dependence favor voltage control devices, and lower resistance heating elements. Taste is a key factor for electronic cigarette selection, and concentrations of propylene glycol and vegetable glycerin may have a significant impact on the reinforcing effects of liquids. PMID- 29723805 TI - Severe microbiologically influenced corrosion of S32654 super austenitic stainless steel by acid producing bacterium Acidithiobacillus caldus SM-1. AB - Microbiologically influenced corrosion (MIC) of S32654 (654SMO) super austenitic stainless steel (SASS) by acid producing bacterium (APB), Acidithiobacillus caldus SM-1, a strain of sulfur-oxidizing bacteria (SOB) used in biohydrometallurgy field, was investigated using electrochemical measurements and surface characterizations during a 14-day immersion test. The results indicated that S32654 SASS was susceptible to MIC by APB, and A. caldus SM-1 was capable of producing an aggressive acidic environment underneath the biofilm, resulting in the dissolution of the passive film and severe pitting attacks against S32654 SASS, which is commonly regarded as a corrosion resistant material. PMID- 29723804 TI - Differential UV-vis absorbance can characterize the reaction of organic matter with ClO2. AB - UV-vis differential spectroscopy was applied to characterize and quantify the spectral changes after ClO2 oxidation of ten humic substances, seven aromatic model compounds and four surface waters. The differential spectra of ten humic substances after ClO2 oxidation all exhibited a peak near 230 nm and a broad absorbance band with a maximum at around 316 nm. The differential spectra after ClO2 oxidation were distinguished from the one after chlorination, which was indicative of their different oxidation mechanisms. The differential spectra after ClO2 treatment were well fitted by seven Gaussian bands with maxima at about 200, 225, 240, 276, 316, 385 and 457 nm. Differential absorbance at 316 nm and 400 nm (denoted as DA316 and DA400, respectively) were found to best quantify the degradation of organic matters during ClO2 oxidation with negligible interferences from water matrixes. Oxidation of substituted functional groups on aromatic structures, rather than destruction of aromatic rings, was more responsible for chlorite formation. Spectral parameters-DA316 and DA400 showed strong correlations with ClO2 consumption and chlorite formation during ClO2 oxidation of humic substances and surface water samples. The results demonstrate that DA316 and DA400 can serve as promising indicators of chlorite formation and ClO2 consumption, which provide a practical approach for online water quality monitoring during ClO2 water purification. PMID- 29723806 TI - Bioelectrical coupling in multicellular domains regulated by gap junctions: A conceptual approach. AB - We review the basic concepts involved in bioelectrically-coupled multicellular domains, focusing on the role of membrane potentials (Vmem). In the first model, single-cell Vmem is modulated by two generic polarizing and depolarizing ion channels, while intercellular coupling is implemented via voltage-gated gap junctions. Biochemical and bioelectrical signals are integrated via a feedback loop between Vmem and the transcription and translation of a protein forming an ion channel. The effective rate constants depend on the single-cell Vmem because these potentials modulate the local concentrations of signaling molecules and ions. This electrochemically-based idealization of the complex biophysical problem suggests that the spatio-temporal map of single-cell potentials can influence downstream patterning processes by means of the voltage-gated gap junction interconnectivity, much as in the case of electronic devices where the control of electric potentials and currents allows the local modulation of the circuitry to achieve full functionality. An alternative theoretical approach, the BioElectrical Tissue Simulation Engine (BETSE), is also presented. The BETSE modeling environment utilizes finite volume techniques to simulate bioelectric states from the perspective of ion concentrations and fluxes. This model has been successfully applied to make predictions and explain experimental observations in a variety of embryonic, regenerative, and oncogenic contexts. PMID- 29723807 TI - The molecular selectivity of UNC3866 inhibitor for Polycomb CBX7 protein from molecular dynamics simulation. AB - Polycomb CBX proteins regulate gene expression by targeting Polycomb repressive complex 1 (PRC1) to sites of H3K27me3 via their chromodomains, which plays a key role in the development of numerous cancers. UNC3866, is a recently reported peptide-based inhibitor of the methyllysine (Kme) reading function of CBX chromodomains (CBX2, 4 and 6-8). The previous experiments showed that UNC3866 bound the chromodomains of CBX7 strongly, with ~20-fold selectivity over other CBX chromodomains. However, the potential mechanism of UNC3866 preferentially binding to CBX7 is still unknown. In this study, we performed two pairs of microsecond molecular dynamic simulations (CBX2 (-UNC3866)) and (CBX7 (-UNC3866)) to study the inhibition and isoform-selective mechanism of UNC3866 to CBX7. The conformational analysis of apo- and holo- CBX2 and CBX7 indicated that the aromatic cage of CBX7 protein was more prone to be induced by UNC3866 relative to CBX2 protein. The results of predicted binding free energy suggested the binding affinity of UNC3866 with CBX7 was stronger than that with CBX2, because of the lower binding free energy of the former. Furthermore, the energetic origin of UNC3866 selective for CBX7 protein mainly came from the higher van der Waals contributions. The binding mode analysis showed that Asn47 of CBX2 formed a hydrogen bond with the OH group of C-terminal cap of UNC3866, inducing the conformational changes of diethyllysine of UNC3866 that is obviously different from that in CBX7. Additionally, His39 in CBX2 chromodomain interrupted the structured aromatic cage, partly explaining the reason for UNC3866 preferring for binding to CBX7. The proposal of this selective mechanism could be helpful for the rational design of novel selective inhibitors of the Polycomb CBX protein. PMID- 29723808 TI - Determine effect of pressure heating on carbohydrate related molecular structures in association with carbohydrate metabolic profiles of cool-climate chickpeas using Globar spectroscopy. AB - Grain has been heat-processed to alter rumen degradation characteristics and improve nutrient availabilities for ruminants. However, limited study was found on internal structure changes induced by processing on a molecular basis. The objectives of this study were to use advanced vibrational molecular spectroscopy to: (1) determine the processing induced carbohydrate (CHO) structure changes on a molecular basis, (2) investigate the effect of pressure heating on changes of CHO chemical profiles, CHO subfractions in cool-climate CDC Chickpea varieties, and (3) to reveal the association between carbohydrates related molecular spectra with carbohydrate metabolic profiles. The cool-climate CDC chickpea varieties with multisource were pressure heated in an autoclave at 120 degrees C for 60 min; and FTIR vibrational spectroscopy was used to detect the molecular spectra. Molecular spectroscopic results showed that compared to raw chickpea varieties, autoclave heating induced changes in both total CHO (region and baseline ca. 1186 946 cm-1) and structural CHO (STCHO, region and baseline ca. 1482-1186 cm-1), except for cellulosic compounds (CELC, region and baseline ca. 1374-1212 cm-1). The CHO chemical profile and rumen degradation results showed that autoclave heating decreased rumen degradable, undegradable and intestinal digestible sugar (CA4) content, but increased available fiber (CB3) content, without affecting available energy of chickpeas. The changes of CHO molecular spectra in chickpea varieties were strongly correlated with CHO chemical profiles, CHO subfractions, and CHO rumen degradation characteristics. Moreover, the regression analysis showed that STCHO peak 1 height could be used to predict sugar content, its rumen degradability and digestibility of chickpeas. Our results suggest that autoclave heating markedly changes sugar and fiber degradation characteristics. The carbohydrate molecular spectral profiles are associated with carbohydrate metabolic profiles in raw and pressure heated cool-climate chickpeas. PMID- 29723809 TI - Global sensitivity analysis of hepatic venous pressure gradient (HVPG) measurement with a stochastic computational model of the hepatic circulation. AB - Hepatic venous pressure gradient (HVPG) is a widely employed surrogate of portal pressure gradient (PPG) in the diagnosis of portal hypertension (PHT). However, little is known about how HVPG measurement is affected by the complex vascular changes associated with PHT. In this study, we employed a computational method to quantitatively evaluate the sensitivity of HVPG measurement to various vascular factors involved in the development of sinusoidal PHT, aiming to provide a theoretical reference to guide the clinical application of HVPG measurement. The method consisted of developing a lumped-parameter model of the hepatic circulation to simulate HVPG measurement, stochastic parameter sampling used to represent a wide range of pathological conditions, and global sensitivity analysis performed to identify factors that dominate the accuracy of HVPG measurement. The major findings included 1) presinusoidal portal vascular resistance (Rpxs) and splanchnic vascular resistance (Rspl) were the major factors determining the relative difference (EHVPG) between HVPG and PPG; 2) hepatic arteriolar resistance and portosystemic collateral resistance had little influence on EHVPG although they relate closely to the severity of PHT; and 3) postsinusoidal vascular resistance (Rpts) only mildly affected EHVPG, despite its marked influence on HVPG and PPG. Moreover, stochastic simulations calibrated to HVPG/PPG data measured in a patient cohort revealed that misdiagnosis of clinically significant PHT with HVPG was more likely to occur in the presence of high Rspl combined with low Rpxs and Rpts. These findings suggest that understanding patient-specific vascular conditions can help to improve the application or interpretation of HVPG measurement. PMID- 29723811 TI - Increased mortality among people with schizophrenia and other non-affective psychotic disorders in the community: A systematic review and meta-analysis. AB - INTRODUCTION: There is increasing evidence of excess mortality in schizophrenia but less information on other non-affective psychoses. We therefore generated standardised mortality ratios (SMRs) for community-dwelling people with schizophrenia and other non-affective psychoses, relative to the general population, and examined changes to the SMR over time. METHODS: We conducted a systematic review in which Pubmed, CINAHL, EMBASE, Google Scholar and PsycINFO were searched for publications that reported SMRs for all-cause mortality among community-dwelling people with schizophrenia and psychotic disorders. Meta analyses of SMRs were conducted, pooled across genders and then separately by gender. Sub-group analyses were conducted for diagnostic group, global region, decade and risk of study bias. RESULTS: We were able to include 34 studies covering 1,724,906 participants. The gender pooled SMR for schizophrenia and psychotic disorders was 3.08 (95%CI 2.88-3.31). Schizophrenia and broader psychotic disorders had similar SMRs. Stratification by decade of observation suggests that the difference in SMR is not declining and may possibly be widening. Analyses showed high levels of heterogeneity. CONCLUSIONS: The appearance of a static or widening mortality gap over time between people with schizophrenia and psychotic disorders and the general population is of concern. However, whether it is an increase over time is unclear, as there are insufficient studies to confirm this. PMID- 29723810 TI - Long Noncoding RNAs AC009014.3 and Newly Discovered XPLAID Differentiate Aggressive and Indolent Prostate Cancers. AB - INTRODUCTION: The molecular mechanisms underlying aggressive versus indolent disease are not fully understood. Recent research has implicated a class of molecules known as long noncoding RNAs (lncRNAs) in tumorigenesis and progression of cancer. Our objective was to discover lncRNAs that differentiate aggressive and indolent prostate cancers. METHODS: We analyzed paired tumor and normal tissues from six aggressive Gleason score (GS) 8-10 and six indolent GS 6 prostate cancers. Extracted RNA was split for poly(A)+ and ribosomal RNA depletion library preparations, followed byRNA sequencing (RNA-Seq) using an Illumina HiSeq 2000. We developed an RNA-Seq data analysis pipeline to discover and quantify these molecules. Candidate lncRNAs were validated using RT-qPCR on 87 tumor tissue samples: 28 (GS 6), 28 (GS 3+4), 6 (GS 4+3), and 25 (GS 8-10). Statistical correlations between lncRNAs and clinicopathologic variables were tested using ANOVA. RESULTS: The 43 differentially expressed (DE) lncRNAs between aggressive and indolent prostate cancers included 12 annotated and 31 novel lncRNAs. The top six DE lncRNAs were selected based on large, consistent fold changes in the RNA-Seq results. Three of these candidates passed RT-qPCR validation, including AC009014.3 (P < .001 in tumor tissue) and a newly discovered X-linked lncRNA named XPLAID (P = .049 in tumor tissue and P = .048 in normal tissue). XPLAID and AC009014.3 show promise as prognostic biomarkers. CONCLUSIONS: We discovered several dozen lncRNAs that distinguish aggressive and indolent prostate cancers, of which four were validated using RT-qPCR. The investigation into their biology is ongoing. PMID- 29723812 TI - Novel C-type lectin from razor clam Sinonovacula constricta agglutinates bacteria and erythrocytes in a Ca2+-dependent manner. AB - Among its other physiological roles, C-type lectins functioned as pattern recognition receptors (PRR) in innate immunity received much attention. In the present study, a novel C-type lectin was identified and characterized from the invertebrate razor clam Sinonovacula constrict and designated as ScCTL. The complete cDNA sequence of ScCTL was 828 bp in length and coded a secreted polypeptide of 158 amino acids with a typical CRD domain. Multiple sequence alignments combined with phylogenetic analysis both collectively confirmed that ScCTL was a novel member belong to lectin family. Spatial expression distribution analysis revealed that ScCTL was extensively expressed in all of the examined tissues, and the highest expression was detected in the hepatopancreas. After 1 * 107 CFU/mL Vibrio parahaemolyticus challenge by immersion infection, the ScCTL transcript in hepatopancreas and gill were markedly upregulated and arrived the maximum levels at 24 or 12 h after challenge, respectively. Recombinant ScCTL could agglutinate not only all tested bacteria but sheep and mouse erythrocyte in the presence of Ca2+. All of our studies suggested that ScCTL performed important roles in protecting cells from pathogenic infection in S. constrict. PMID- 29723813 TI - Synthesis of geopolymer-supported zeolites via robust one-step method and their adsorption potential. AB - The present study proposes a robust one-step hydrothermal treatment method for synthesis of high strength geopolymer-supported zeolites utilizing industrial by products (fly ash and blast furnace slag), which can be potentially used as bulk type solid adsorbents. The results revealed that the geopolymer-supported zeolites, possessing distinct strengths, zeolite phases (Na-P1, Na-chabazite, and analcime) and pore features depending on the mix design and synthesis conditions, can be easily synthesized employing the proposed one-step method. The geopolymer supported zeolites exhibited the characteristics of mesoporous materials which are typically desired for commercial adsorbents. The maximum adsorption capacity for Pb2+ was found to be about 37.9 mg/g which is relatively higher than the other bulk-type adsorbents reported for Pb2+ to date. Since industrial by products are used for synthesis of these materials, it will help in reducing the environmental hazards associated with the permanent disposal of such by-products, with an added advantage that these bulk-type solid adsorbents can be easily retrieved after use unlike granular adsorbents. PMID- 29723815 TI - Characterization of Acinetobacter baumannii from water and sludge line of secondary wastewater treatment plant. AB - The elimination of potentially pathogenic bacteria in wastewater treatment plants (WWTPs) attracts much attention in public health. Reports on the occurrence of the emerging hospital pathogen Acinetobacter baumannii in wastewaters do not include a continuous monitoring at all WWTP stages. The objective of this study was to characterize A. baumannii recovered from the water and sludge line of the secondary WWTP in Zagreb, Croatia over the period of one year. Recovery of A. baumannii was performed using CHROMagar Acinetobacter plates. Antimicrobial susceptibility testing was performed with broth microdilution and results interpreted using EUCAST breakpoints for clinical isolates of A. baumannii. Molecular characterization was performed by WGS and cgMLST. The secondary WWTP treating the urban wastewater is constantly receiving viable A. baumannii along with genes encoding carbapenem resistance, and emitting them via effluent into the environment. Furthermore, A. baumannii from influent are incorporated into activated sludge flocs in aeration basin. A. baumannii can survive the technological process of anaerobic mesophilic sludge digestion, and is finally destroyed in alkaline lime-treated stabilized sludge. The majority (102/119) of A. baumannii isolates were carbapenem-resistant, while antibiotic-susceptible isolates (17/119) were rarely recovered from all WWTP stages. Carbapenem resistant isolates belonged to international clonal lineage IC2 carrying OXA-23 and IC1 carrying OXA-72, while the susceptible isolates belonged to IC5 or were unclustered. Increased resistance to antibiotics, together with the appearance of carbapenem- and even pandrug-resistant isolates in effluent as compared to influent wastewater, suggests the need of additional disinfection of effluent prior to its discharge into the natural recipient. PMID- 29723814 TI - Effect of UVA/LED/TiO2 photocatalysis treated sulfamethoxazole and trimethoprim containing wastewater on antibiotic resistance development in sequencing batch reactors. AB - Controlling of antibiotics is the crucial step for preventing antibiotic resistance genes (ARGs) dissemination; UV photocatalysis has been identified as a promising pre-treatment technology for antibiotics removal. However, information about the effects of intermediates present in the treated antibiotics wastewater on the downstream biological treatment processes or ARGs development is very limited. In the present study, continuous UVA/LED/TiO2 photocatalysis removed more than 90% of 100 ppb sulfamethoxazole (SMX)/trimethoprim (TMP), the treated wastewater was fed into SBR systems for over one year monitoring. Residual SMX/TMP (2-3 ppb) and intermediates present in the treated wastewater did not adversely affect SBR performance in terms of TOC and TN removal. SMX and TMP resistance genes (sulI, sulII, sulIII, dfrII, dfrV and dfr13) were also quantified in SBRs microbial consortia. Results suggested that continuous feeding of treated SMX/TMP containing wastewaters did not trigger any ARGs promotion during the one year operation. By stopping the input of 100 ppb SMX/TMP, abundance of sulII and dfrV genes were reduced by 83% and 100%, respectively. sulI gene was identified as the most persistence ARG, and controlling of 100 ppb SMX input did not achieve significant removal of sulI gene. A significant correlation between sulI gene and class 1 integrons was found at the level of p = 1.4E-10 (r = 0.94), and sulII gene positively correlated with the plasmid transfer efficiency (r = 2.442E-10, r = 0.87). Continuous input of 100 ppb SMX enhanced plasmid transfer efficiency in the SBR system, resulting in sulII gene abundance increasing more than 40 times. PMID- 29723816 TI - Semi-passive in-situ pilot scale bioreactor successfully removed sulfate and metals from mine impacted water under subarctic climatic conditions. AB - Mine drainage contaminated with metals is a major environmental threat since it is a source of water pollution with devastating effects on aquatic ecosystems. Conventional active treatment technologies are prohibitively expensive and so there is increasing demand to develop reliable, cost-effective and sustainable passive or semi-passive treatment. These are promising alternatives since they leverage the metabolism of microorganisms native to the disturbed site at in situ or close to in situ conditions. Since this is a biological approach, it is not clear if semi-passive treatment would be effective in remote locations with extremely cold weather such as at mines in the subarctic. In this study we tested the hypothesis that sulfate-reducing bacteria, which are microorganisms that promote metal precipitation, exist in subarctic mine environments and their activity can be stimulated by adding a readily available carbon source. An experiment was setup at a closed mine in the Yukon Territory, Canada, where leaching of Zn and Cd occurs. To test if semi-passive treatment could precipitate these metals and prevent further leaching from waste rock, molasses as a carbon source was added to anaerobic bioreactors mimicking the belowground in-situ conditions. Microbial community analysis confirmed that sulfate-reducing bacteria became enriched in the bioreactors upon addition of molasses. The population composition remained fairly stable over the 14 month operating period despite temperature shifts from 17 to 5 degrees C. Sulfate reduction functionality was confirmed by quantification of the gene for dissimilatory sulfite reductase. Metals were removed from underground mine drainage fed into the bioreactors with Zn removal efficiency varying between 20.9% in winter and 89.3% in summer, and Cd removal efficiency between 39% in winter and 90.5% in summer. This study demonstrated that stimulation of native SRB in MIW was possible and that in situ semi-passive treatment can be effective in removing metals despite the cold climate. PMID- 29723817 TI - Extracellular matrix-coated polyethersulfone-TPGS hollow fiber membranes showing improved biocompatibility and uremic toxins removal for bioartificial kidney application. AB - In this study, L-3, 4-dihydroxyphenylalanine and human collagen type IV were coated over the outer surface of the custom-made hollow fiber membranes (HFMs) with the objective of simultaneously improving biocompatibility leading to proliferation of human embryonic kidney cells-293 (HEK-293) and improving separation of uremic toxins, thereby making them suitable for bioartificial kidney application. Physicochemical characterization showed the development of coated HFMs, resulting in low hemolysis (0.25 +/- 0.10%), low SC5b-9 marker level (7.95 +/- 1.50 ng/mL), prolonged blood coagulation time, and minimal platelet adhesion, which indicated their improved human blood compatibility. Scanning electron microscopy and confocal laser scanning microscopy showed significantly improved attachment and proliferation of HEK-293 cells on the outer surface of the coated HFMs, which was supported by the results of glucose consumption and MTT cell proliferation assay. The solute rejection profile of these coated HFMs was compared favorably with that of the commercial dialyzer membranes. These coated HFMs showed a remarkable 1.6-3.2 fold improvement in reduction ratio of uremic toxins as compared to standard dialyzer membranes. These results clearly demonstrated that these extracellular matrix-coated HFMs can be a potential biocompatible substrate for the attachment and proliferation of HEK-293 cells and removal of uremic toxins from the simulated blood, which may find future application for bioartificial renal assist device. PMID- 29723819 TI - Optimizing liposomes for delivery of Bowman-Birk protease inhibitors - Platforms for multiple biomedical applications. AB - One of the major challenges in the administration of therapeutic proteins involves delivery limitations. Liposomes are well-known drug delivery systems (DDS) that have been used to overcome this drawback; nevertheless, low protein entrapment efficiency (EE) still limits their wide biomedical application on a commercial scale. In the present work, different methods for protein entrapment into liposomes were tested in order to obtain tailored DDS platforms for multiple biomedical applications. The protein used as model was the Black-eyed pea Trypsin and Chymotrypsin Inhibitor (BTCI), a member of the Bowman-Birk protease inhibitor family (BBIs), which has been largely explored for its potential application in many biomedical therapies. We optimized reverse-phase evaporation (REV) and freeze/thaw (F/T) entrapment methods, using a cationic lipid matrix to entrap expressive amounts of BTCI (~100 MUM) in stable liposomes without affecting its protease inhibition activity. The influence of various parameters (e.g. entrapment method, liposome composition, buffer type) on particle size, charge, polydispersity, and EE of liposomes was investigated to provide an insight on how to control such parameters in view of obtaining a high entrapment yield. In addition, BTCI liposome platforms obtained herein showed to be versatile vesicles, allowing surface modification with moieties/polymers of interest (e.g. PEG, transferrin). The aforementioned results are relevant to focusing on the entrapment of other promising BBIs or protein agents sharing similar structural features. These findings encourage future studies to investigate the advantages of using the liposome platforms presented herein to broaden the use of this type of DDS for BBI biomedical applications. PMID- 29723820 TI - Adsorption of formamide over pristine and Al-doped boron nitride nanosheets: A dispersion-corrected DFT study. AB - Using the dispersion-corrected DFT calculations, different adsorption modes of formamide molecule are studied over the pristine and Al-doped boron nitride nanosheets (BNNS). It is found that the interaction between the Al atom and its neighboring N atoms in the Al-doped BNNS is very strong, which would hinder the dispersion and clustering of the Al atoms over the BNNS surface. Unlike the pristine nanosheet, the electronic properties of Al-doped BNNS are very sensitive to the formamide adsorption. The adsorption energies of formamide over the Al doped sheet are in the range of -0.93 to -1.85 eV, which indicates the quite strong interaction of this molecule with the surface. Moreover, the dehydrogenation of formamide over the Al-doped BNNS is examined. According to our results, the N-H bond scission of formamide is more energetically favorable than the C-H one. PMID- 29723821 TI - Capping of marine sediments with valuable industrial by-products: Evaluation of inorganic pollutants immobilization. AB - In-situ capping of polluted sediment is considered as an inexpensive and effective treatment technology to immobilize contaminants in a short time. In this remediation technique sediments are capped by placing a layer of sand, clean sediment or other materials over sediments in order to mitigate risk. In this study, low cost industrial by products (bauxaline, steel slag, and mixture of the two products) were applied as capping agents. A bench scale laboratory experiment in aquariums was performed to evaluate their effects on Cd, Zn, As, and Cr mobility from an artificially contaminated marine sediment. Without capping, all the contaminants are constantly released with various kinetic depending of mineral oxidation or dissolution or leaching. Nevertheless, release did not exceed 31% of the initial amount of pollutant. Capping sediment with steel slag, bauxaline and their mixture totally captured Cd, Zn, and As. In the case of Cr, only steel slag actively blocked its release. A kinetic model was developed to model As and Cr release, with and without capping. The release times for Cr and As from the sediment were close to 6 days. In the presence of capping agents, the capture time for Cr was found to be 57 days for steel slag, and 7 days for bauxaline. Despite a high capture time, steel slag was the best capping agent since bauxaline matrix was a source of Cr and rapidly released it (release time = 1 day). The results indicated that steel slag and its mixture additive can be used as potential capping materials for the remediation of contaminated sites due to their significant entrapping of Cd, Zn, As, and Cr. PMID- 29723818 TI - Therapeutic efficacy of rebamipide-loaded PLGA nanoparticles coated with chitosan in a mouse model for oral mucositis induced by cancer chemotherapy. AB - Oral mucositis is one of the most common side effects induced by cancer therapy, and the prevention or rapid treatment of the symptoms of oral mucositis can improve patients' quality of life and reduce the need for treatment interruption. In this study, poly(dl-lactide-co-glycolide) (PLGA) nanoparticles coated with chitosan hydroxypropyltrimonium chloride was used as a carrier of rebamipide, and its usefulness was evaluated using a mouse model for oral mucositis. The surface properties and particle size of this nanoparticle were considered to be advantageous for the treatment of oral mucositis. Positively charged nanoparticles with an average particle diameter of 97.0 +/- 36.7 nm were prepared. From the results of the mucin adsorption study using a periodic acid/Schiff colorimetric method, it was confirmed that the mucin adsorptive capacity of chitosan-coated nanoparticles was 2.3 times higher than that of bare nanoparticles. This result was consistent with the results of the oral retention study of chitosan-coated nanoparticles using an in vivo optical imaging system. Therapeutic efficacy of the nanoparticles on oral mucositis was evaluated using a mouse model for oral mucositis induced by cancer chemotherapy. The chitosan coated nanoparticles administration group significantly decreased the ulcer area at day 9, 11, and 13 compared with the non-treated control group. Moreover, this group significantly shortened the treatment period by 3.6 days compared to the bare nanoparticles administration group. Therefore, it was suggested that rebamipide-loaded PLGA nanoparticles coated with chitosan hydroxypropyltrimonium chloride were beneficial for the treatment of oral mucositis induced by cancer chemotherapy. PMID- 29723822 TI - Effects of brine contamination from energy development on wetland macroinvertebrate community structure in the Prairie Pothole Region. AB - Wetlands in the Prairie Pothole Region (PPR) of North America support macroinvertebrate communities that are integral to local food webs and important to breeding waterfowl. Macroinvertebrates in PPR wetlands are primarily generalists and well adapted to within and among year changes in water permanence and salinity. The Williston Basin, a major source of U.S. energy production, underlies the southwest portion of the PPR. Development of oil and gas results in the coproduction of large volumes of highly saline, sodium chloride dominated water (brine) and the introduction of brine can alter wetland salinity. To assess potential effects of brine contamination on macroinvertebrate communities, 155 PPR wetlands spanning a range of hydroperiods and salinities were sampled between 2014 and 2016. Brine contamination was documented in 34 wetlands with contaminated wetlands having significantly higher chloride concentrations, specific conductance and percent dominant taxa, and significantly lower taxonomic richness, Shannon diversity, and Pielou evenness scores compared to uncontaminated wetlands. Non-metric multidimensional scaling found significant correlations between several water quality parameters and macroinvertebrate communities. Chloride concentration and specific conductance, which can be elevated in naturally saline wetlands, but are also associated with brine contamination, had the strongest correlations. Five wetland groups were identified from cluster analysis with many of the highly contaminated wetlands located in a single cluster. Low or moderately contaminated wetlands were distributed among the remaining clusters and had macroinvertebrate communities similar to uncontaminated wetlands. While aggregate changes in macroinvertebrate community structure were observed with brine contamination, systematic changes were not evident, likely due to the strong and potentially confounding influence of hydroperiod and natural salinity. Therefore, despite the observed negative response of macroinvertebrate communities to brine contamination, macroinvertebrate community structure alone is likely not the most sensitive indicator of brine contamination in PPR wetlands. PMID- 29723823 TI - Acute sensitivity of three Cladoceran species to different types of microplastics in combination with thermal stress. AB - Microplastics (<5 mm, MP) are ubiquitously distributed in the environment, causing increasing concern regarding their potential toxicity to organisms. To date, most research has focussed on the impacts of MPs on marine and estuarine organisms, with fewer studies focussing on the effects of microplastics on freshwater ecosystems, especially under different environmental conditions. In the present study, the sensitivity of two temperate Cladoceran species, Daphnia magna and Daphnia pulex, and a smaller tropical species Ceriodaphnia dubia, to primary microplastics (PMP) and secondary (weathered) microplastics (SMP) was assessed. A prolonged acute toxicity assay (up to 72 or 96 h) was performed at 18 degrees , 22 degrees , and 26 degrees C, to determine the influence of temperature as an additional stressor and survival data were analysed using toxicokinetic-toxicodynamic (TK-TD) model. Acute sensitivity of D. magna and D. pulex to both PMP and SMP increased sharply with temperature, whereas that of C. dubia remained relatively stable across temperatures. C. dubia was the most sensitive species at 18 degrees C, followed by D. pulex and D. magna, which were of comparable sensitivity. However, this ranking was reversed at 26 degrees C as could be seen from the No Effect Concentration (NEC) estimates of the TK-TD model. In addition, SMP and PMP had a similar effect on D. magna and D. pulex, but PMP was more toxic to C. dubia. Effects on survival were strongly time dependent and became substantially more severe after the standard 48 h test period. Our results indicate that sensitivity to microplastics may differ between species for different types of microplastics, and could be drastically influenced by temperature albeit at high exposure concentrations. PMID- 29723824 TI - Analysis of WRKY transcription factors and characterization of two Botrytis cinerea-responsive LrWRKY genes from Lilium regale. AB - A major constraint in producing lilies is gray mold caused by Botrytis elliptica and B. cinerea. WRKY transcription factors play important roles in plant immune responses. However, limited information is available about the WRKY gene family in lily plants. In this study, 23 LrWRKY genes with complete WRKY domains were identified from the Botrytis-resistant species Lilium regale. The putative WRKY genes were divided into seven subgroups (Group I, IIa-e, and III) according to their structural features. Sequence alignment revealed that LrWRKY proteins have a highly conserved WRKYGQK domain and a variant, the WRKYGKK domain, and these proteins generally contained similar motif compositions throughout the same subgroup. Functional annotation predicted they might be involved in biological processes related to abiotic and biotic stresses. A qRT-PCR analysis confirmed that expression of six LrWRKY genes in L. regale or the susceptible Asian hybrid 'Yale' was induced by B. cinerea infection. Among these genes, LrWRKY4, LrWRKY8 and LrWRKY10 were expressed at a higher level in L. regale than 'Yale', while the expression of LrWRKY6 and LrWRKY12 was lower in L. regale. Furthermore, LrWRKY4 and LrWRKY12 genes, which also respond to salicylic acid (SA) and methyl jasmonate (MeJA) treatments, were isolated from L. regale. Subcellular localization analysis determined that they were targeted to the nucleus. Constitutive expression of LrWRKY4 and LrWRKY12 in Arabidopsis resulted in plants that were more resistant to B. cinerea than wild-type plants. This resistance was coupled with the transcriptional changes of SA and JA-responsive genes. Overall, our study provides valuable information about the structural and functional characterization of LrWRKY genes that will not only deepen our understanding of the molecular mechanisms underlying the defense of lily against B. cinerea but also offer potential targets for cultivar improvement via biotechnology. PMID- 29723825 TI - Rice tolerance to suboptimal low temperatures relies on the maintenance of the photosynthetic capacity. AB - The purpose of this research was to identify differences between two contrasting rice cultivars in their response to suboptimal low temperatures stress. A transcriptomic analysis of the seedlings was performed and results were complemented with biochemical and physiological analyses. The microarray analysis showed downregulation of many genes related with PSII and particularly with the oxygen evolving complex in the sensitive cultivar IR50. Complementary studies indicated that the PSII performance, the degree of oxygen evolving complex coupling with the PSII core and net photosynthetic rate diminished in this cultivar in response to the stress. However, the tolerant cultivar Koshihikari was able to maintain its energy equilibrium by sustaining the photosynthetic capacity. The increase of oleic acid in Koshihikari could be related with membrane remodelling of the chloroplasts and hence contribute to tolerance. Overall, these results work as a ground for future analyses that look forward to characterize possible mechanisms to tolerate this stress. PMID- 29723826 TI - Genome-wide transcriptomic analysis of BR-deficient Micro-Tom reveals correlations between drought stress tolerance and brassinosteroid signaling in tomato. AB - Brassinosteroids (BRs) are plant steroid hormones that play crucial roles in a range of growth and developmental processes. Although BR signal transduction and biosynthetic pathways have been well characterized in model plants, their biological roles in an important crop, tomato (Solanum lycopersicum), remain unknown. Here, cultivated tomato (WT) and a BR synthesis mutant, Micro-Tom (MT), were compared using physiological and transcriptomic approaches. The cultivated tomato showed higher tolerance to drought and osmotic stresses than the MT tomato. However, BR-defective phenotypes of MT, including plant growth and stomatal closure defects, were completely recovered by application of exogenous BR or complementation with a SlDWARF gene. Using genome-wide transcriptome analysis, 619 significantly differentially expressed genes (DEGs) were identified between WT and MT plants. Several DEGs were linked to known signaling networks, including those related to biotic/abiotic stress responses, lignification, cell wall development, and hormone responses. Consistent with the higher susceptibility of MT to drought stress, several gene sets involved in responses to drought and osmotic stress were differentially regulated between the WT and MT tomato plants. Our data suggest that BR signaling pathways are involved in mediating the response to abiotic stress via fine-tuning of abiotic stress related gene networks in tomato plants. PMID- 29723827 TI - Socioeconomic status and alcohol use in low- and lower-middle income countries: A systematic review. AB - BACKGROUND: Harmful use of alcohol is a major cause of global morbidity and mortality. The role of alcohol as a driver of the unfolding non-communicable disease crisis has led to high-profile calls for better epidemiological data. Despite causing a disproportionate amount of harm in low-income groups, there is a critical dearth of evidence on the intra-national socioeconomic patterning of alcohol use in low- and lower-middle income countries (LLMICs). This review aims to fill the gap, providing evidence on the association between socioeconomic status (SES) and alcohol use in these low-income settings. METHODS: We conducted a comprehensive literature search for primary research published between January 1, 1990 and June 30, 2015 using 13 electronic databases, including Embase and Medline. We also hand-searched references and reviewed 'gray literature' - studies that have not been published in peer-reviewed journals. We included studies from LLMICs presenting data on multiple measures of socioeconomic status and alcohol use. No age or language restrictions were applied. Due to high heterogeneity, we used a narrative approach for data synthesis. FINDINGS: After reviewing 4242 records and 247 full-text articles, 23 studies met our inclusion criteria, reporting data on 861,295 individuals aged >10 years from 10 countries. Alcohol use was found to be more prevalent in lower socioeconomic groups in the majority of Southeast Asian studies. The association was mixed for African studies, although these tended to have smaller sample sizes and weaker methods. Studies that measured multiple domains of SES found good agreement between different indicators. Definitions of alcohol use and abuse varied widely between studies, as did socioeconomic groupings. CONCLUSIONS: The lack of consistency between studies and the abject lack of data from the majority of LLMICs present a major barrier to policymakers tasked with reducing alcohol-related harm in these settings. Adherence to standardized definitions, the publication of WHO survey data on alcohol and SES, and enhanced surveillance is needed to build an accurate picture of the socioeconomic patterning of alcohol use in developing countries. PMID- 29723829 TI - Quality of life at the retirement transition: Life course pathways in an early 'baby boom' birth cohort. AB - Promoting quality of life (QoL) in later life is an important policy goal. However, studies using prospective data to explore the mechanisms by which earlier events influence QoL in older age are lacking. This study is the first to use prospective data to investigate pathways by which a range of measures of life course socioeconomic status contribute to later-life QoL. The study uses data from the Newcastle Thousand Families Study cohort (N = 1142), an early 'baby boom' birth cohort born in 1947 in Newcastle upon Tyne, an industrial city in north-east England. Using prospective survey data collected between birth and later adulthood (N = 393), a path analysis investigated the effects and relative contributions of a range of life-course socioeconomic factors to QoL at age 62-64 measured using the CASP-19 scale. Strong positive effects on later-life QoL were found for advantaged occupational status in mid-life and better self-reported health, employment and mortgage-freedom in later adulthood. Significant positive indirect effects on QoL were found from social class at birth and achieved education level, mediated through later-life socioeconomic advantage. Experiencing no adverse events by age five had a large total positive effect on QoL at age 62-64, comprising a direct effect and indirect effects, mediated through education, mid-life social class and later-life self-reported health. Results support a pathway model with the effects of factors in earlier life acting via later-life factors, and an accumulation model with earlier-life factors having large total, cumulative effects on later-life QoL. The presence of a direct effect of adverse childhood events by age five on QoL suggests a 'critical period' and indicates that policies across the life-course are needed to promote later-life QoL, with policies directed towards older adults perhaps too late to 'undo the damage' of earlier adverse events. PMID- 29723828 TI - Structural neural predictors of Farsi-English bilingualism. AB - The neurobiology of bilingualism is hotly debated. The present study examines whether normalized cortical measurements can be used to reliably classify monolinguals versus bilinguals in a structural MRI dataset of Farsi-English bilinguals and English monolinguals. A decision tree classifier classified bilinguals with an average correct classification rate of 85%, and monolinguals with a rate of 71.4%. The most relevant regions for classification were the right supramarginal gyrus, left inferior temporal gyrus and left inferior frontal gyrus. Larger studies with carefully matched monolingual and bilingual samples are needed to confirm that features of these regions can reliably categorize monolingual and bilingual brains. Nonetheless, the present findings suggest that a single structural MRI scan, analyzed with measures readily available using default procedures in a free open-access software (Freesurfer), can be used to reliably predict an individual's language experience using a decision tree classifier, and that Farsi-English bilingualism implicates regions identified in previous group-level studies of bilingualism in other languages. PMID- 29723830 TI - Quantum chemical calculations to determine partitioning coefficients for HgCl2 on iron-oxide aerosols. AB - Gas-to-particle phase partitioning controls the pathways for oxidized mercury deposition from the atmosphere to the Earth's surface. The propensity of oxidized mercury species to transition between these two phases is described by the partitioning coefficient (Kp). Experimental measurements of Kp values for HgCl2 in the presence of atmospheric aerosols are difficult and time-consuming. Quantum chemical calculations, therefore, offer a promising opportunity to efficiently estimate partitioning coefficients for HgCl2 on relevant aerosols. In this study, density functional theory (DFT) calculations are used to predict Kp values for HgCl2 on relevant iron-oxide surfaces. The model is first verified using a NaCl(100) surface, showing good agreement between the calculated (2.8) and experimental (29-43) dimensionless partitioning coefficients at room temperature. Then, the methodology is applied to six atmospherically relevant terminations of alpha-Fe2O3(0001): OH-Fe-R, (OH)3-Fe-R, (OH)3-R, O-Fe-R, Fe-O3-R, and O3-R (where R denotes bulk ordering). The OH-Fe-R termination is predicted to be the most stable under typical atmospheric conditions, and on this surface termination, a dimensionless HgCl2Kp value of 5.2 * 103 at 295 K indicates a strong preference for the particle phase. This work demonstrates DFT as a promising approach to obtain partitioning coefficients, which can lead to improved models for the transport of mercury, as well as for other atmospheric pollutant species, through and between the anthroposphere and troposphere. PMID- 29723831 TI - Technetium and iodine aqueous species immobilization and transformations in the presence of strong reductants and calcite-forming solutions: Remedial action implications. AB - At the Hanford Site in southeastern Washington, discharge of radionuclide laden liquid wastes resulted in vadose zone contamination, providing a continuous source of these contaminants to groundwater. The presence of multiple contaminants (i.e., 99Tc and 129I) increases the complexity of finding viable remediation technologies to sequester contaminants in situ and protect groundwater. Although previous studies have shown the efficiency of zero valent iron (ZVI) and sulfur modified iron (SMI) in reducing mobile Tc(VII) to immobile Tc(IV) and iodate incorporation into calcite, the coupled effects from simultaneously using these remedial technologies have not been previously studied. In this first-of-a-kind laboratory study, we used reductants (ZVI or SMI) and calcite-forming solutions to simultaneously remove aqueous Tc(VII) and iodate via reduction and incorporation, respectively. The results confirmed that Tc(VII) was rapidly removed from the aqueous phase via reduction to Tc(IV). Most of the aqueous iodate was transformed to iodide faster than incorporation into calcite occurred, and therefore the I remained in the aqueous phase. These results suggested that this remedial pathway is not efficient in immobilizing iodate when reductants are present. Other experiments suggested that iodate removal via calcite precipitation should occur prior to adding reductants for Tc(VII) removal. When microbes were included in the tests, there was no negative impact on the microbial population but changes in the makeup of the microbial community were observed. These microbial community changes may have an impact on remediation efforts in the long-term that could not be seen in a short-term study. The results underscore the importance of identifying interactions between natural attenuation pathways and remediation technologies that only target individual contaminants. PMID- 29723834 TI - Metalimnetic oxygen minima alter the vertical profiles of carbon dioxide and methane in a managed freshwater reservoir. AB - Metalimnetic oxygen minimum zones (MOMs) commonly develop during the summer stratified period in freshwater reservoirs because of both natural processes and water quality management. While several previous studies have examined the causes of MOMs, much less is known about their effects, especially on reservoir biogeochemistry. MOMs create distinct redox gradients in the water column which may alter the magnitude and vertical distribution of dissolved methane (CH4) and carbon dioxide (CO2). The vertical distribution and diffusive efflux of CH4 and CO2 was monitored for two consecutive open-water seasons in a eutrophic reservoir that develops MOMs as a result of the operation of water quality engineering systems. During both summers, elevated concentrations of CH4 accumulated within the anoxic MOM, reaching a maximum of 120 MUM, and elevated concentrations of CO2 accumulated in the oxic hypolimnion, reaching a maximum of 780 MUM. Interestingly, the largest observed diffusive CH4 effluxes occurred before fall turnover in both years, while peak diffusive CO2 effluxes occurred both before and during turnover. Our data indicate that MOMs can substantially change the vertical distribution of CH4 and CO2 in the water column in reservoirs, resulting in the accumulation of CH4 in the metalimnion (vs. at the sediments) and CO2 in the hypolimnion. PMID- 29723833 TI - Assessing changes in the value of ecosystem services in response to land-use/land cover dynamics in Nigeria. AB - Increasing human activities worldwide have significantly altered the natural ecosystems and consequently, the services they provide. This is no exception in Nigeria, where land-use/land-cover has undergone a series of dramatic changes over the years mainly due to the ever-growing large population. However, estimating the impact of such changes on a wide range of ecosystem services is seldom attempted. Thus, on the basis of GlobeLand30 land-cover maps for 2000 and 2010 and using the value transfer methodology, we evaluated changes in the value of ecosystem services in response to land-use/land-cover dynamics in Nigeria. The results showed that over the 10-year period, cultivated land sprawl over the forests and savannahs was predominant, and occurred mainly in the northern region of the country. During this period, we calculated an increase in the total ecosystem services value (ESV) in Nigeria from 665.93 billion (2007 US$) in 2000 to 667.44 billion (2007 US$) in 2010, 97.38% of which was contributed by cultivated land. The value of provisioning services increased while regulation, support, recreation and culture services decreased, amongst which, water regulation (-11.01%), gas regulation (-7.13%), cultural (-4.84%) and climate regulation (-4.3%) ecosystem functions are estimated as the most impacted. The increase in the total ESV in Nigeria associated with the huge increase in ecosystem services due to cultivated land expansion may make land-use changes (i.e. the ever-increasing agricultural expansion in Nigeria) appear economically profitable. However, continuous loss of services such as climate and water regulation that are largely provided by the natural ecosystems can result in huge economic losses that may exceed the apparent gains from cultivated land development. Therefore, we advocate that the conservation of the natural ecosystem should be a priority in future land-use management in Nigeria, a country highly vulnerable to climate change and incessantly impacted by natural disasters such as flooding. PMID- 29723835 TI - Abiotic and biotic factors modulate plant biomass and root/shoot (R/S) ratios in grassland on the Loess Plateau, China. AB - Plant biomass and the root/shoot ratio (R/S) are key parameters for estimating terrestrial ecosystem carbon (C) stocks. However, how environmental driving factors (abiotic and biotic factors) modulate plant biomass and R/S has not been well investigated on the Loess Plateau. Here, we tested the impacts of abiotic and biotic driving factors on plant biomass and R/S and whether they are in accordance with optimal partitioning theory in natural grassland in this region. The results showed that above-ground biomass (AGB) and below-ground biomass (BGB) were 63.96 g.m-2 and 311.18 g.m-2, respectively, and that R/S ranged from 0.13 to 0.46, with high spatial heterogeneity. There was a strong positive linear relationship between AGB and BGB (p < 0.05) in accordance with optimal partitioning theory. A principal component analysis (PCA) indicated that the topographic properties (Slope position, Slope gradient and Altitude) were negatively correlated with the soil physical properties (Ec,Electric conductivity; BD, Bulk density; ST, Soil temperature; and SM, Soil moisture) and positively correlated with the soil chemical properties (SOC, Soil organic carbon; TN, Total nitrogen; SMBC, Soil microbial biomass carbon and SMBN, Soil microbial biomass nitrogen), while soil total phosphorus (TP) was not correlated with the soil physical properties (p > 0.05). Structural equation modeling (SEM) suggested that R/S is indirectly driven by plant properties (Height, Density, Coverage), which are determined by soil and topographic properties. However, only 5% of R/S was explained by the soil physical properties and topographic properties, suggesting that these factors had no significant effect on R/S. The data do, however, provide information for quantifying C stocks in natural grassland on the Loess Plateau. Further, ecologists should focus on mechanistic and fresh approaches to understanding the abiotic and biotic factors influencing plant biomass and R/S. PMID- 29723836 TI - Occurrence, distribution and risk assessment of organophosphate esters in surface water and sediment from a shallow freshwater Lake, China. AB - Organophosphate esters (OPEs) are ubiquitous in the environment and pose a potential threat to ecosystem and human health. This study investigated the concentrations, distributions and risk of 12 OPEs in surface water and sediment from Luoma Lake, Fangting River and Yi River. Solid-phase extraction (SPE) method were used to extract OPEs from water samples, ultrasonic process and SPE method were used to extract OPEs from sediment samples, and the extracts were finally analyzed using the HPLC-MS/MS. The results revealed that the median and maximum concentrations of SigmaOPEs were 73.9 and 1066 ng/L in surface water, and were 28.7 and 35.9 ng/g in sediment, respectively. Tris(2-chloroethyl) phosphate (TCEP) and trimethyl phosphate (TMP) were the most abundant OPEs in the surface water with median concentrations of 24.3 and 16.4 ng/L in Luoma Lake, respectively. Triethyl phosphate (TEP) was the most abundant OPE in the sediment with a median concentrations of 28.9 ng/g. However, tricresyl phosphate (TCrP) and ethylhexyl diphenyl phosphate (EHDPP) predominantly contributed to the ecological risk with respective median risk quotients 0.07 and 0.01 for surface water in Luoma Lake. TEP and TCrP were the most significant contributors to the ecological risk with respective median risk quotients of 6.4 * 10-4 and 5.6 * 10 4 for sediment. It was also found that inflowing Fangting River could be the major pollution source to Luoma Lake. The no-cancer and carcinogenic risks of OPEs were lower than the theoretical threshold of risk. The study found that the ecological and human health risks due to the exposure to OPEs were currently acceptable. In other words, the Luoma Lake was relatively safer to use as a drinking water source in urban areas in the context of OPEs pollution. PMID- 29723837 TI - Effects of diethylene glycol dibenzoate and Bisphenol A on the lipid metabolism of Danio rerio. AB - Endocrine disrupting chemicals (EDCs) are known to disrupt normal metabolism and can influence the incidence of obesity in animals and humans. EDCs can exert adverse effects at low concentrations, often in a non-monotonic dose-related fashion. Among EDCs, Bisphenol A (BPA) is extensively used in the production of polycarbonate plastic, and is among the most abundant contaminants in the world. Diethylene glycol dibenzoate (DGB), an approved alternative to phthalates in the production of plastic and latex products, however, is less abundant and its effects are almost completely unknown. The aim of this study is to provide information on the hepatic effects of BPA and DGB on lipid metabolism, and investigate possible links between these contaminants and the increased incidence of obesity. In the present study, we exposed zebrafish to three different BPA doses (5; 10; 20 MUg/L) and five different doses of DGB (0.01; 0.1; 1; 10; 100 MUg/L) for a period of 21 days, and investigated transcript levels for genes involved in lipid metabolism as well as measuring liver content of phosphates, lipids and proteins. The results demonstrate disruptive effects of BPA and DGB on lipid metabolism in a non-monotonic dose-related fashion. The lowest dose of BPA increased the storage of triglycerides and promoted fatty acid synthesis, while the highest concentration promoted de novo lipogenesis and cholesterologenesis. Exposure to DGB was also found to affect lipid metabolism leading to increased lipid production and mobilization in a non-monotonic dose-related fashion. Analysis of BPA and DGB by FT-IR revealed that exposure to both compounds lead to changes in the biochemical composition of liver. The findings provide a support for the hypothesis that BPA and DGB may be among the environmental contaminants with obesogenic property. PMID- 29723838 TI - Alterations in oxidative responses and post-translational modification caused by p,p'-DDE in Mus spretus testes reveal Cys oxidation status in proteins related to cell-redox homeostasis and male fertility. AB - The major derivate of DDT, 1,1-dichloro-2,2-bis (p-chlorophenyl) ethylene (p,p' DDE), is a persistent pollutant previously associated with oxidative stress. Additionally, p,p'-DDE has been linked to several metabolic alterations related to sexual function in rodents. In this study, we analysed the effects of a non lethal p,p'-DDE dose to Mus spretus mice in testes, focusing on oxidative damage to biomolecules, defence mechanisms against oxidative stress and post translational protein modifications. No increase in lipid or DNA oxidation was observed, although antioxidative enzymatic defences and redox status of glutathione were altered in several ways. Global protein carbonylation and phosphorylation were significantly reduced in testes from p,p'-DDE-exposed mice; however, the total redox state of Cys thiols did not exhibit a defined pattern. We analysed the reversible redox state of specific Cys residues in detail with differential isotopic labelling and a shotgun labelling-based MS/MS proteomic approach for identification and quantification of altered peptides. Our results show that Cys residues are significantly affected by p,p'-DDE in several proteins related to oxidative stress and/or male fertility, particularly those participating in fertilization, sperm capacitation and blood coagulation. These molecular changes could explain the sexual abnormalities previously described in p,p'-DDE exposed organisms. PMID- 29723839 TI - SAR interferometry monitoring of subsidence in a detritic basin related to water depletion in the underlying confined carbonate aquifer (Torremolinos, southern Spain). AB - This research underlines the need to improve water management policies for areas linked to confined karstic aquifers subjected to intensive exploitation, and to develop additional efforts towards monitoring their subsidence evolution. We analyze subsidence related to intensive use of groundwater in a confined karstic aquifer, through the use of the InSAR technique, by the southern coast of Spain (Costa del Sol). Carbonates are overlain by an unconfined detritic aquifer with interlayered high transmissivity rocks, in connection with the Mediterranean Sea, where the water level is rather stable. Despite this, an accumulated deformation in the line-of-sight (LOS) direction greater than -100 mm was observed by means of the ERS-1/2 (1992-2000) and Envisat (2003-2009) satellite SAR sensors. During this period, the Costa del Sol experienced a major population increase due to the expansion of the tourism industry, with the consequent increase in groundwater exploitation. The maximum LOS displacement rates recorded during both time spans are respectively -6 mm/yr and -11 mm/yr, respectively. During the entire period, there was an accumulated descent of the confined water level of 140 m, and several fluctuations of more than 80 m correlating with the subsidence trend observed for the whole area. Main sedimentary depocenters (up to 800 m), revealed by gravity prospecting, partly coincide with areas of subsidence maxima; yet ground deformation is also influenced by other factors, the main ones being the fine-grained facies distribution and rapid urbanization due to high touristic pressure. PMID- 29723840 TI - Polycyclic aromatic hydrocarbons in surface waters and riverine sediments of the Hooghly and Brahmaputra Rivers in the Eastern and Northeastern India. AB - Sixteen priority polycyclic aromatic hydrocarbons (PAHs) regulated by the United States Environmental Protection Agency (USEPA) were analyzed in surface waters and riverine sediments of Brahmaputra and Hooghly Rivers, along urban-suburban rural transects. ?16 PAHs concentrations were higher in Hooghly riverine sediment (HRS) (Avg, 445 ng g-1) than Brahmaputra riverine sediment (BRS) (Avg, 169 ng g 1) dominated by 4-ring PAHs. In contrast, PAHs concentrations in surface water of Brahmaputra River (BRW) (Avg, 4.04 MUg L-1) were comparable with Hooghly River (HRW) (Avg, 4.8 MUg L-1), with dominance by 3-ring PAHs. Toxic PAHs (BaA, Chr, BbF, BkF, BaP, InP and DBA) were dominant in sub-urban transect of HRS (Avg, 387 ng g-1) and BRS (Avg, 14 ng g-1). Diagnostic ratios, principal component analysis (PCA) and ring wise composition suggested combustion as the main PAHs source in these riverine belts. In BRS, higher PAHs in suburban and rural transects were attributed to incomplete combustion of fossil fuel and biomass burning. In HRS, >85% of high molecular weight PAHs were found in the industrial areas of the suburban transect possibly associated with the discharge of industrial effluents. Harbor and port activities were other major contributors of HMW-PAHs in Hooghly riverine system. Carcinogenic potency estimated in terms of toxic equivalent (TEQ) was several folds higher in HRS (Avg, 106 ng TEQ g-1) compared with BRS (Avg, 2.5 ng TEQ g-1). Mostly low molecular weight PAHs are likely posing a risk to fishes in both the rivers. Risk on edible fish species may be a matter of concern considering the regular consumption of fishes in this region. PMID- 29723841 TI - Klebsiella pneumoniae as a key trafficker of drug resistance genes from environmental to clinically important bacteria. AB - Klebsiella pneumoniae is an opportunistic bacterial pathogen known for its high frequency and diversity of antimicrobial resistance (AMR) genes. In addition to being a significant clinical problem in its own right, K. pneumoniae is the species within which several new AMR genes were first discovered before spreading to other pathogens (e.g. carbapenem-resistance genes KPC, OXA-48 and NDM-1). Whilst K. pneumoniae's contribution to the overall AMR crisis is impossible to quantify, current evidence suggests it has a wider ecological distribution, significantly more varied DNA composition, greater AMR gene diversity and a higher plasmid burden than other Gram negative opportunists. Hence we propose it plays a key role in disseminating AMR genes from environmental microbes to clinically important pathogens. PMID- 29723842 TI - A Robust Method for Ultrasound Beamforming in the Presence of Off-Axis Clutter and Sound Speed Variation. AB - Previously, we introduced a model-based beamforming algorithm to suppress ultrasound imaging artifacts caused by clutter sources, such as reverberation and off-axis scattering. We refer to this method as aperture domain model image reconstruction (ADMIRE). In this study, we evaluated the algorithm's limitations and ability to suppress off-axis energy using Field II-based simulations, experimental phantoms and in vivo data acquired by a Verasonics ultrasound system with a curvilinear transducer (C5-2). We compared image quality derived from a standard delay-and-sum (DAS) beamformer, DAS with coherence factor (CF) weighting, ADMIRE and ADMIRE plus CF weighting. Simulations, phantoms and in vivo scan results demonstrate that ADMIRE substantially suppresses off-axis energy, while preserving the spatial resolution of standard DAS beamforming. We also observed that ADMIRE with CF weighting further improves some aspects of image quality. We identified limitations of ADMIRE when suppressing off-axis clutter in the presence of strong scattering, and we suggest a solution. Finally, because ADMIRE is a model-based beamformer, we used simulated phantoms to test the performance of ADMIRE under model-mismatch caused by gross sound speed deviation. The impact of sound speed errors largely mimics DAS beamforming, but ADMIRE never does worse than DAS itself in resolution or contrast. As expected the CF weighting used as a post processing technique provides a boost in contrast but decreases CNR and speckle SNR. The results indicate that ADMIRE is robust in terms of model-mismatch caused by sound speed variation, especially when the actual sound speed is slower than the assumed sound speed. As an example, the image contrast obtained using DAS, DAS + CF, ADMIRE and ADMIRE + CF in the presence of -5% gross sound speed error are 24.9 +/- 0.71 dB, 39.1 +/- 1.2 dB, 43.2 +/- 2.3 dB and 52.5 +/- 2.9 dB, respectively. PMID- 29723843 TI - Defining research & development process targets through retro-techno-economic analysis: The sugarcane biorefinery case. AB - A new approach is reported for techno-economic analysis of lignocellulosic ethanol production. With this methodology, general targets for key process variables can be draw, a valuable feedback for Research & Development teams. An integrated first- and second-generation ethanol from sugarcane biorefinery is presented as a case study for the methodology, with the biomass pretreated by liquid hot water, followed by enzymatic hydrolysis of the cellulose fraction. The hemicellulose fraction may be either fermented or biodigested. The methodology was able to identify the main variables that affect the process global economic performance: enzyme load in the cellulose hydrolysis reactor, cellulose-to glucose, and xylose-to-ethanol yields. Windows of feasible operation are the graphical output of the methodology, outlining regions to be further explored experimentally. One example of quantitative result is that the maximum feasible enzyme load was 11.3 FPU/gcellulose when xylose is fermented to ethanol and 7.7 FPU/gcellulose when xylose is biodigested. PMID- 29723844 TI - Effect of combining adsorption-stripping treatment with acidification on the growth of Chlorella vulgaris and nutrient removal from swine wastewater. AB - After swine wastewater (SW) was treated with adsorption-stripping stage, the concentration of NH4+-N and Total phosphorus (TP) in SW significantly decreased from 598.04, 42.95 to 338.02, 8.36 mg L-1, respectively. The concentration of heavy metals, especially Zn2+ (96.78%), decreased by the ion exchange of artificial zeolite (AZ). The acidification of SW could significantly improve the nutrient utilization efficiency and promote the growth rate of C. vulgaris due to the hydrolysis of macromolecular substances into smaller molecules usable for algae. By combining adsorption (Part I), stripping (Part II) and cultivation (Part III), the highest removal rates of NH4+-N, TP, chemical oxygen demand (COD) and total organic carbon (TOC) from SW were 80.50, 96.90, 72.91, and 84.17%, respectively, and the OD680 value was 1.129 (1.48 times of control) at pH 6.0. The combined system (Part I-III) can significantly enhance the removal efficiency of nutrient and biomass production by acidification. PMID- 29723845 TI - Influence of sulfur dioxide-ethanol-water pretreatment on the physicochemical properties and enzymatic digestibility of bamboo residues. AB - SO2-ethanol-water (SEW) is a promising pretreatment for improving enzymatic digestibility of biomass through simultaneously removing hemicellulose and lignin. In this work, SEW pretreatment was performed at different cooking times (10 min-60 min) and different SO2 concentrations (0.5%-2%) to produce pretreated bamboo residues for enzymatic hydrolysis. Meanwhile, physicochemical features of the residual cellulose and lignin were analyzed to better understand how SEW improves enzymatic digestibility. Under optimized SEW pretreatment condition (1% SO2 concentration, 150 degrees C, 60 min), 81.7% of xylan and 80.3% of lignin were solubilized, along with 89.1% of cellulose preserved in pretreated solid. A good enzymatic digestibility (80.4%) was achieved at optimum SEW condition. Several compelling correlations (R2 > 0.7) were observable between enzymatic digestibility and physicochemical features, demonstrating the importance of SEW pretreatment abilities of hemicellulose and lignin removal, reducing cellulose's degree of polymerization, and improving the amount of sulfonyl groups imparted to the original lignin structure. PMID- 29723846 TI - Diagnostic Value of Nineteen Different Imaging Methods for Patients with Breast Cancer: a Network Meta-Analysis. AB - BACKGROUND/AIMS: We performed a network meta-analysis (NMA) to investigate and compare the diagnostic value of 19 different imaging methods used for breast cancer (BC). METHODS: Cochrane Library, PubMed and EMBASE were searched to collect the relevant literature from the inception of the study until November 2016. A combination of direct and indirect comparisons was performed using an NMA to evaluate the combined odd ratios (OR) and draw the surface under the cumulative ranking curves (SUCRA) of the diagnostic value of different imaging methods for BC. RESULTS: A total of 39 eligible diagnostic tests regarding 19 imaging methods (mammography [MG], breast-specific gamma imaging [BSGI], color Doppler sonography [CD], contrast-enhanced magnetic resonance imaging [CE-MRI], digital breast tomosynthesis [DBT], fluorodeoxyglucose positron-emission tomography/computed tomography [FDG PET/CT], fluorodeoxyglucose positron-emission tomography [FDG-PET], full field digital mammography [FFDM], handheld breast ultrasound [HHUS], magnetic resonance imaging [MRI], automated breast volume scanner [ABUS], magnetic resonance mammography [MRM], scintimammography [SMM], single photon emission computed tomography scintimammography [SPECT SMM], ultrasound elastography [UE], ultrasonography [US], mammography + ultrasonography [MG + US], mammography + scintimammography [MG + SMM], and ultrasound elastography + ultrasonography [UE + US]) were included in the study. According to this network meta-analysis, in comparison to the MG method, the CE-MRI, MRI, MRM, MG + SMM and UE + US methods exhibited relatively higher sensitivity, and the specificity of the FDG PET/CT method was higher, while the BSGI and MRI methods exhibited higher accuracy. CONCLUSION: The results from this NMA indicate that the diagnostic value of the BSGI, MG + SMM, MRI and CE-MRI methods for BC were relatively higher in terms of sensitivity, specificity and accuracy. PMID- 29723847 TI - Epigallocatechin-3-Gallate Regulates Anti-Inflammatory Action Through 67-kDa Laminin Receptor-Mediated Tollip Signaling Induction in Lipopolysaccharide Stimulated Human Intestinal Epithelial Cells. AB - BACKGROUND/AIMS: Inflammatory bowel disease (IBD) is a condition that involves chronic inflammation in all or part of the digestive tract. Often painful and debilitating, IBD can lead to life-threatening complications and increase the risk for colon cancer. In this study, we investigated the epigallocatechin-3 gallate (EGCG) mediated anti-inflammation response in lipopolysaccharide (LPS) stimulated human colorectal cells through the negative regulator of Toll-like receptor (TLR) signaling. METHODS: human intestinal epithelial cells (HT-29) were used in all experiments. Cell cytotoxicity and nitric oxide (NO) were evaluated by WST-1 and the Griess reagent. Western blot analysis and ELISA were used to determine inflammatory mediators and 67-kDa laminin receptor (67LR)-mediated Tollip signaling pathways. RESULTS: Treatment of EGCG and LPS did not affect the cytotoxicity in HT-29 cells. LPS treatment dose-dependently increased the pro inflammatory cytokine, such as interleukin (IL)-8, whereas EGCG significantly reduced the LPS-stimulated IL-8 production. Additionally, EGCG treatment markedly increased the Toll-interacting protein (Tollip) expression, which negatively regulates the TLR signaling in a dose and time-dependent manner. In particular, in the result from an RNA interference-mediated assay, our finding showed that silencing of Tollip resulted in abrogation of the inhibitory action of EGCG on LPS-induced production of pro-inflammatory mediators (inducible nitric oxide synthase-mediated NO/COX2, and IL-8) and activation of MAPKs and NF-kappaB signaling pathways. Interestingly, we also found that Tollip expression induced by EGCG could be modulated through 67LR expressed on the surface of HT-29 cells. CONCLUSIONS: Our novel finding indicates that 67LR and Tollip signaling activated by EGCG treatment is essential for inhibition of inflammation in human intestinal epithelial cells. PMID- 29723848 TI - Risk Factors and Outcomes of Delirium in Older Patients Admitted to Postacute Care with and without Dementia. AB - BACKGROUND: Delirium research is poorly studied in postacute care, a growing setting due to aging populations, as well as in dementia, a critical risk factor for delirium and particularly prevalent in postacute care. We investigated risk factors for delirium and its outcomes in older adults with and without dementia admitted to a subacute care unit (SCU) after exacerbated chronic conditions. METHODS: This is a prospective cohort study including patients >=65 years old admitted to an SCU for 12 months. We collected demographics, comprehensive geriatric assessments, and presence of dementia and delirium at admission. Outcomes included discharge to previous living situation, mortality, and functional evolution. Due to the high prevalence of dementia, a subgroup analysis was performed to investigate specific risk factors for delirium and related outcomes. RESULTS: Of 909 patients (mean age [+/-SD] 85.8 +/- 6.7; 60% women, 47.5% with dementia), 352 (38.7%) developed delirium. The main risk factor for delirium was dementia (HR [95% CI] 5.2 [3.5-7.7]); age, functional status, and urinary tract infections were also independently associated with delirium. In dementia patients, only age (HR [95% CI] 1.0 [1.004-1.1]) and being male (HR [95% CI] 1.7 [1.04-2.6]) were associated with delirium. Delirium was associated with greater mortality (10.8 vs. 3.9%; p < 0.001) and greater functional decline in the entire sample (-12.3 vs. -6.4 Barthel index points; p < 0.001). In the dementia subgroup, patients with delirium experienced greater functional loss (p = 0.013) and less functional recovery (p = 0.025). CONCLUSIONS: In older patients admitted to postacute care, dementia is the main risk factor for delirium, and delirium carries worse clinical and functional outcomes. In patients with dementia, delirium is also relevant, since it entails a functional loss at admission and lower functional recovery. PMID- 29723849 TI - The Mechanism of Action of Zingerone in the Pacemaker Potentials of Interstitial Cells of Cajal Isolated from Murine Small Intestine. AB - BACKGROUND/AIMS: Zingerone, a major component found in ginger root, is clinically effective for the treatment of various diseases. Interstitial cells of Cajal (ICCs) are the pacemaker cells responsible for slow waves in the gastrointestinal (GI) tract. We investigated the effects of zingerone on the pacemaker potentials of ICCs to assess its mechanisms of action and its potential as a treatment for GI tract motility disorder. METHODS: We isolated ICCs from small intestines, and the whole-cell patch-clamp configuration was used to record the pacemaker potentials in cultured ICCs. RESULTS: Under the current clamping mode, zingerone inhibited pacemaker potentials of ICCs concentration-dependently. These effects were blocked not by capsazepine, a transient receptor potential vanilloid 1 (TRPV1) channel blocker, but by glibenclamide, a specific ATP-sensitive K+ channel blocker. Pretreatment with SQ-22536 (an adenylate cyclase inhibitor), LY294002 (a phosphoinositide 3-kinase inhibitor), and calphostin C (a protein kinase C (PKC) inhibitor) did not block the effects of zingerone on the pacemaker potentials relative to treatment with zingerone alone. However, zingerone-induced pacemaker potential inhibition was blocked by 1H-[1,2,4] oxadiazolo [4,3-a] quinoxalin-1-one (ODQ; a guanylate cyclase inhibitor), KT5823 (a protein kinase G (PKG) inhibitor), and L-NAME (a non-selective nitric oxide synthase (NOS) inhibitor). In addition, zingerone stimulated cyclic guanosine monophosphate (cGMP) production in ICCs. Finally, pretreatment with PD98059 (a p42/44 mitogen activated protein kinase (MAPK) inhibitor), SB203580 (a p38 MAPK inhibitor), and SP600125 (c-Jun N-terminal kinases (JNK)-specific inhibitor) blocked the zingerone-induced pacemaker potential inhibition. CONCLUSION: These results suggest that zingerone concentration-dependently inhibits pacemaker potentials of ICCs via NO/cGMP-dependent ATP-sensitive K+ channels through MAPK-dependent pathways. Taken together, this study shows that zingerone may have the potential for development as a GI regulation agent. PMID- 29723850 TI - The Favored Mechanism for Coping with Acute Cold Stress: Upregulation of miR-210 in Rats. AB - BACKGROUND/AIMS: The main aim of this study was to determine the mechanisms by which rno-miR-210-3p affects changes in gene expression, metabolism, apoptosis and proliferation of cells under acute cold stress (ACS) conditions. METHODS: The treatment group (n=6, weight 340+/-20 g) was exposed to ACS (temperature 4+/-0.5 degrees C, relative humidity 45+/-0.5%) and the control group (n=6, weight 340+/ 20 g) to normal temperature (NT) (temperature 24+/-0.5 degrees C, relative humidity 45+/-0.5%). Rat liver samples were collected for qRT-PCR and western blot analyses to detect relative expression of rno-miR-210-3p, ISCU, Rap1b, ATP1b1, GPD1, E2F3, RAD52, PSMB6 and GPD2. For cell experiments, 100 pmol/dish rno-miR-210-3p mimic and 150 pmol/dish rno-miR-210-3p inhibitor were used. Mitochondrial glucose flux and glycolysis were measured using the XFe24 Extracellular Flux Analyzer. Cells were collected for apoptosis analysis 24 h after transfection and proliferation was quantified using the WST-1 Cell Proliferation and Cytotoxicity Assay Kit (Beyotime, Shanghai, China), according to the manufacturer's instructions. RESULTS: In the rat experiment, expression of rno-miR-210-3p under ACS was increased sharply while ISCU, E2F3, RAD52, and PSMB6 levels declined, along with protein expression of ISCU and PSMB6. In cell experiments, ISCU, Rap1b, ATP1b1, GPD1, E2F3, RAD52, PSMB6 and GPD2 genes were downregulated while ISCU and PSMB6 protein expression decreased with upregulation of rno-miR-210-3p. Conversely, in response to decreased rno-miR-210-3p expression, ISCU, E2F3, RAD52, PSMB6 and GPD2 genes were upregulated, in addition to ISCU and PSMB6 proteins. Upregulation of miR-210 inhibited cell proliferation and induced cell death whereas its downregulation promoted cell proliferation. Upregulation or downregulation of miR-210 promoted glycolysis and mitochondrial respiration of BRL cells. However, downregulation of miR-210 caused acid production in cells. CONCLUSION: Expression of rno-miR-210-3p is significantly increased under ACS. Upregulation of rno-miR-210-3p inhibits the expression of ISCU, Rap1b, ATP1b1, GPD1, E2F3, RAD52, PSMB6 and GPD2 genes, promotes glycolysis of liver and enhances the mitochondrial respiratory capacity of cells, but may also cause cell death. Our findings collectively indicate that regulation of rno miR-210-3p is a preferential mechanism of choice used by the body to cope with ACS. PMID- 29723851 TI - Transplantation of Telocytes Attenuates Unilateral Ureter Obstruction-Induced Renal Fibrosis in Rats. AB - BACKGROUND/AIMS: Previous studies imply that telocytes may have a protective effect on fibrosis in various organs, including the liver, colon, and heart. The effect of telocytes on renal fibrosis remains unknown. Herein, this study was designed to investigate the effect of telocytes on renal fibrosis and the potential mechanisms involved. METHODS: In a unilateral ureteral obstruction (UUO)-induced renal fibrosis model, telocytes were injected via the tail vein every other day for 10 days. The degree of renal damage and fibrosis was determined using histological assessment. The expression of collagen I, fibronectin, epithelial-mesenchymal transition markers, and Smad2/3 phosphorylation was examined by western blot analyses. Real-time PCR and enzyme linked immunosorbent assay were performed in vivo to detect the levels of transforming growth factor (TGF)-beta1 and various growth factors. RESULTS: Telocytes attenuated renal fibrosis, as evidenced by reduced interstitial collagen accumulation, decreased expression of fibronectin and collagen I, upregulation of E-cadherin, and downregulation of alpha-smooth muscle actin. Furthermore, telocytes decreased serum TGF-beta1 levels, suppressed Smad2/3 phosphorylation, and increased the expression of hepatocyte growth factor (HGF) in rat kidney tissue following UUO. Blockage of HGF counteracted the protective effect of telocytes on UUO-treated kidneys. Through the detection of HGF mRNA levels in vitro, we found that telocytes had no effect on HGF expression compared with renal fibroblasts. CONCLUSION: Telocytes attenuated UUO-induced renal fibrosis in rats, likely through enhancing the expression of HGF in an indirect manner. PMID- 29723852 TI - Flexural Strength of Glass Carbomer Cement and Conventional Glass Ionomer Cement Stored in Different Storage Media over Time. AB - OBJECTIVES: Glass ionomer cement (GIC) is routinely placed as a restorative material in dentistry. However, due to its poor physical properties, its use is limited to cases where the level of stress on restoration is minimal. Improved formulations of GIC have been developed to overcome these drawbacks. The purpose of this study was to evaluate flexural strength of a conventional GIC (Fuji IX) against a newly developed glass carbomer cement (GCP). MATERIALS AND METHODS: For Fuji IX and GCP, a total of 80 blocks were prepared and divided into 16 groups (n = 5). These groups were further categorized according to the storage medium (artificial saliva and Vaseline) and time intervals (24 h and 1, 2, and 4 weeks). A 3-point bending test was carried out, and statistical analysis was done using ANOVA and Tukey post hoc tests. RESULTS: Fuji IX showed a mean flexural strength of 25.14 +/- 13.02 versus 24.27 +/- 12.57 MPa for GCP. There was no significant statistical difference between both materials when compared under storage media. Both materials showed the highest value for flexural strength at 2 weeks of storage and lowest at 4 weeks. CONCLUSION: The storage media do not affect the flexural strength of the specimens with reference to time. Time is the unique factor with relative influence on mean resistance to fracture. Further testing is required to evaluate the true potential of the newly developed GCP. PMID- 29723853 TI - Data, Technology, and Public Health. PMID- 29723854 TI - Diagnostic Accuracy of Lateral Decubitus Chest Radiography before Pleural Maneuvers for the Management of Pleurisies in the Era of Chest Ultrasound. AB - BACKGROUND: Chest ultrasound (CUS) is the gold standard to detect pleural adhesions before pleural maneuvers. However, the CUS technique is not available in all countries where the assessment is only based on clinical examination and chest radiography. OBJECTIVE: To assess the value of lateral decubitus chest radiography (LDCR) to detect pleural adhesions. METHODS: Consecutive patients with pleural effusions undergoing LCDR followed by medical thoracoscopy the day after were identified from an institutional database. The diagnostic sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy for LDCR were calculated. RESULTS: Eighty-six patients were included in the study. The sensitivity, specificity, PPV, and NPV of LDCR for the presence of adhesions taking into account the shape of the horizontal level were 71.2% (56.7-82.5), 44.1% (27.6-61.9), 66.1% (52.1-77.8), and 50% (31.7-68.3), respectively. The accuracy to predict pleural adhesions for the sign "incomplete horizontal level" was 60.5 (49.3-70.7). The accuracy to predict pleural adhesions in case of irregular aspect of the horizontal level was 53.5 (42.5-64.2). CONCLUSIONS: The accuracy of LDCR for the detection of pleural adhesions is low in patients with pleural effusion and LDCR is not sufficient before pleural maneuvers. This has to be taken into account in countries with a high prevalence of pleural tuberculosis which usually lead to loculated pleural effusions. CUS has to be urgently included in dedicated educational programs in these areas in order to decrease the complications related to unexpected pleural adhesions and achieve better planning for the management of pleural effusions. PMID- 29723855 TI - Dioleoylphosphoethanolamine Retains Cell Surface GLUT4 by Inhibiting PKCalpha Driven Internalization. AB - BACKGROUND/AIMS: Phosphatidylethanolamine, a component of the plasma membrane, regulates diverse cellular processes. The present study investigated the role of 1,2-dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) in the trafficking of the glucose transporter GLUT4 and the glucose homeostasis. METHODS: Monitoring of GLUT4 trafficking, GLUT4 internalization assay, and glucose uptake assay were carried out using differentiated 3T3-L1-GLUT4myc adipocytes. Akt1/2 and PKC isozymes were knocked-down by transfecting each siRNA. Cell-free PKC assay and in situ PKCalpha assay with a FRET probe were carried out. Oral glucose tolerance test (OGTT) was performed using BKS.Cg-+Lepdb/+Lebdb/Jcl mice, an animal model of type 2 diabetes mellitus (DM). RESULTS: DOPE increased cell surface localization of the glucose transporter GLUT4 in differentiated 3T3-L1-GLUT4myc adipocytes, regardless of Akt activation. Likewise, PKCalpha deficiency increased cell surface localization of GLUT4, that occludes the effect of DOPE. DOPE clearly suppressed phorbol 12-myristate 13-acetate-induced PKCalpha activation in the cell-free and in situ PKC assay. DOPE and PKCalpha deficiency cancelled endocytic internalization of GLUT4 localized on the plasma membrane after insulin stimulation. DOPE significantly enhanced glucose uptake into cells. A similar effect was obtained by knocking-down PKCalpha, that occludes the effect of DOPE. In OGTT, oral administration with DOPE effectively restricted an increase in the blood glucose levels after glucose loading in type 2 DM model mice. CONCLUSION: The results of the present study show that DOPE retains cell surface GLUT4 by suppressing PKCalpha-driven endocytic internalization of GLUT4, to enhance glucose uptake into cells and restrict an increase in the blood glucose levels after glucose loading in type 2 DM. PMID- 29723856 TI - Are Antidepressants Harmful in the "General Population"? PMID- 29723857 TI - Resveratrol Modulates Apoptosis and Autophagy Induced by High Glucose and Palmitate in Cardiac Cells. AB - BACKGROUND/AIMS: Diabetic cardiomyopathy is associated with increased apoptosis and suppressed autophagy in cardiac cells. The polyphenol resveratrol has shown beneficial effects in various cardiovascular diseases. This study investigated if resveratrol protected cardiac cells by modulating apoptosis and autophagy in the context of diabetes. METHODS: H9c2 cardiac myoblast cells were exposed to high glucose combined with palmitate. Autophagy was evaluated by estimating LC3-II/I ratio, P62 protein levels, and LC3 fluorescent puncta. Apoptosis was assessed by using terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL), flow cytometry, and analysis of the protein expression of apoptotic markers (cleavage of caspase-3 and PARP). RESULTS: High glucose and palmitate suppressed autophagic activity and exacerbated apoptotic cell death in cardiac myoblast cells. Resveratrol restored autophagy and attenuated apoptosis in cells upon diabetic stimuli. Moreover, resveratrol activated AMPK and JNK1, thereby suppressing mTOR and its downstream effectors p70S6K1 and 4EBP1, as well as disrupting the Beclin1 Bcl-2 complex. CONCLUSION: Resveratrol protects cardiac cells by regulating the switch between autophagy and apoptotic machinery under diabetic conditions, which is attributed by AMPK-mediated phosphorylation of mTORC1/p70S6K1/4EBP1 and JNK mediated dissociation of Beclin1-Bcl-2. Our study suggests that autophagy may be an important target for resveratrol in the treatment of diabetic cardiomyopathy. PMID- 29723858 TI - Unhealthy Stem Cells: When Health Conditions Upset Stem Cell Properties. AB - The stem cell field has grown very rapidly during the last decade, offering the promise of innovative therapies to treat disease. Different stem cell populations have been isolated from various human adult tissues, mainly from bone marrow and adipose tissue, but many other body tissues harbor a stem cell population. Adult tissue stem cells are invariably found in discrete microenvironments termed niches, where they play key roles in tissue homeostasis by enabling lifelong optimization of organ form and function. Some diseases are known to strike at the stem cell population, through alterations in their specific microenvironments, making them non-viable. Furthermore, it has been shown that a transformed stem cell population could prompt the development of certain cancers. This review focuses on the potential negative aspects of a range of diseases on the activity of stem cells and how their potential use in cell therapies may be affected. PMID- 29723859 TI - Upregulation of NOX2 and NOX4 Mediated by TGF-beta Signaling Pathway Exacerbates Cerebral Ischemia/Reperfusion Oxidative Stress Injury. AB - BACKGROUND/AIMS: Ischemic stroke is still one of the leading debilitating diseases with high morbidity and mortality. NADPH oxidase (NOX)-derived reactive oxygen species (ROS) play an important role in cerebral ischemia/reperfusion (I/R) injury. However, the mechanism underlying the regulation of ROS generation is still not fully elucidated. This study aims to explore the role of transforming growth beta (TGF-beta) signals in ROS generation. METHODS: Sprague Dawley rats were subjected to I/R injury, and PC-12 cells were challenged by hypoxia/reoxygenation (H/R) and/or treated with activin receptor-like kinase (ALK5) inhibitor Sb505124 or siRNA against ALK5. Brain damage was evaluated using neurological scoring, triphenyl tetrazolium chloride staining, hematoxylin and eosin staining, infarct volume measurement, TUNEL staining, and caspase-3 activity measurement. Expression of TGF-beta and oxidative stress-related genes was analyzed by real-time polymerase chain reaction and Western blot; NOX activity and ROS level were measured using spectrophotometry and fluorescence microscopy, respectively. RESULTS: I/R contributed to severe brain damage (impaired neurological function, brain infarction, tissue edema, apoptosis), TGF beta signaling activation (upregulation of ALK5, phosphorylation of SMAD2/3) and oxidative stress (upregulation of NOX2/4, rapid release of ROS [oxidative burst]). However, Sb505124 significantly reversed these alterations and protected rats against I/R injury. As in the animal results, H/R also contributed to TGF beta signaling activation and oxidative stress. Likewise, the inhibition of ALK5 or ALK5 knockdown significantly reversed these alterations in PC-12 cells. Other than ALK5 knockdown, ALK5 inhibition had no effect on the expression of ALK5 in PC-12 cells. CONCLUSIONS: Our studies demonstrated that TGF-beta signaling activation is involved in the regulation of NOX2/NOX4 expression and exacerbates cerebral I/R injury. PMID- 29723860 TI - Animal Models of Proliferative Vitreoretinopathy and Their Use in Pharmaceutical Investigations. AB - Animal models are indispensable for pharmaceutical investigations. However, investigators often have difficulty choosing the appropriate modal for their research. To provide a comprehensive and convenient source of information about animal models of proliferative vitreoretinopathy (PVR), the current review sorted and analyzed representative animal models for pharmacotherapy of PVR since 1976. PMID- 29723861 TI - Better Renal Resistive Index Profile in Subjects with Beta Thalassemia Minor. AB - OBJECTIVE: Beta thalassaemia minor is a common genetic disorder without any characteristic symptoms except mild anemia. It is found to be associated with some cardiovascular risk factors such as insulin resistance and diabetes mellitus. The renal resistive index (RRI) is a measure of renal arterial resistance to blood flow. The aim of this study was to evaluate the RRI in subjects with beta thalassemia minor (BTM). SUBJECTS AND METHODS: A total of 253 subjects were included in this cross-sectional study. The study group consisted of 148 subjects with BTM and the control group consisted of 105 healthy subjects. BTM was diagnosed by a complete blood count and hemoglobin electrophoresis. Blood pressure measurement and biochemical tests were performed. The RRI of all subjects was measured using renal Doppler ultrasonography. RESULTS: Subjects with BTM had lower renal resistive indices compared to healthy subjects (0.58 +/- 0.04 vs. 0.60 +/- 0.06, p = 0.0016). Additionally, the RRI levels of subjects with BTM were correlated with systolic blood pressure (p = 0.017, r = 0.194). CONCLUSION: In this study, lower RRI were found in subjects with BTM. This may be associated with a decreased vascular resistance and blood viscosity in these subjects. PMID- 29723862 TI - High Amount of Organic Matter during Caries Formation Reduces Remineralization and Resin Infiltration of Enamel Caries. AB - The amount of organic material in the cariogenic environment correlates with the amount of organic material incorporated in carious enamel. The incorporated organic material may be expected to reduce the pore volumes available for remineralization and resin infiltration, but these expected outcomes have not yet been quantified. We tested the effect of the amount of organic content in the cariogenic agent on remineralization and the resin-occluded pore volume in artificial subsurface enamel caries. An acid gel (organic-rich; G1) and an aqueous solution (organic-poor; G2) were used to induce subsurface lesions in human enamel. Undemineralized histological sections were prepared, microradiographed, and then submitted to resin infiltration in vitro. The enamel component volumes (mineral, organic, remineralizable [total water volume], loosely and firmly bound water volumes, and resin-occluded volume) were measured (by microradiography and polarizing microscopy) at histological sites (n = 38, G1; n = 34, G2). The main outcomes were the differences between the experimental and the predicted volumes (Deltaremineralizable and Deltaresin-occluded volumes). Resin infiltration was confirmed by confocal scanning laser microscopy. Compared to G2, G1 presented more incorporated organic volume and lower Deltaremineralizable volume (p = 0.003; Hedges g = 0.66; power = 0.87), a lower increase in loosely bound water volume (p = 0.0013; Hedges g = 0.74; power = 0.93), a lower remineralization volume in the surface layer (p = 0.017; Hedges g = 0.68; power = 0.8), and a lower Deltaresin-occluded volume (p = 0.0015; Hedges g = 0.73; power = 0.92). In conclusion, the higher amount of organic matter in the cariogenic gel negatively affected remineralization and the resin-occluded volume in subsurface lesions. PMID- 29723864 TI - Enrichment of Female Germline Stem Cells from Mouse Ovaries Using the Differential Adhesion Method. AB - BACKGROUND/AIMS: The isolation and establishment of female germline stem cells (FGSCs) is controversial because of questions regarding the reliability and stability of the isolation method using antibody targeting mouse vasa homologue (MVH), and the molecular mechanism of FGSCs self-renewal remains unclear. Thus, there needs to be a simple and reliable method for sorting FGSCs to study them. METHODS: We applied the differential adhesion method to enrich FGSCs (DA-FGSCs) from mouse ovaries. Through four rounds of purification and 7-9 subsequent passages, DA-FGSC lines were established. In addition, we assessed the role of the phosphoinositide-3 kinase (PI3K)-AKT pathway in regulating FGSC self-renewal. RESULTS: The obtained DA-FGSCs spontaneously differentiated into oocyte-like cells in vitro and formed functional eggs in vivo that were fertilized and produced healthy offspring. AKT was rapidly phosphorylated when the proliferation rate of FGSCs increased after 10 passages, and the addition of a chemical PI3K inhibitor prevented FGSCs self-renewal. Furthermore, over-expression of AKT induced proliferation and differentiation of FGSCs, c-Myc, Oct-4 and Gdf-9 levels were increased. CONCLUSIONS: The differential adhesion method provides a more feasible approach and is an easier procedure to establish FGSC lines than traditional methods. The AKT pathway plays an important role in regulation of the proliferation and maintenance of FGSCs. These findings could help promote stem cell studies and provide a better understanding of causes of ovarian infertility, thereby providing potential treatments for infertility. PMID- 29723865 TI - Impact of Caries Severity/Activity and Psychological Aspects of Caregivers on Oral Health-Related Quality of Life among 5-Year-Old Children. AB - The aim of the present study was to evaluate the influence of the severity/activity of dental caries as well as sense of coherence (SOC) and locus of control (LOC) on oral health-related quality of life (OHRQoL) among 5-year-old children. A cross-sectional study was conducted involving 769 children at schools in a city in northeast Brazil. Parents/caregivers answered validated questionnaires addressing SOC and LOC. The children and parents/caregivers answered their respective modules of the Brazilian version of the Scale of Oral Health Outcomes for 5-year-old children (SOHO-5). Data were also collected on sociodemographic characteristics, visits to the dentist, and the occurrence of toothache. Clinical examinations were performed by 2 trained examiners. A directed acyclic graph was used to select covariates for statistical adjustment, and logistic regression for complex samples was used to test associations between the dependent and independent variables (alpha = 5%). For parents/caregivers, the variables associated with a negative impact on OHRQoL were the occurrence of toothache (odds ratio, OR: 10.53; 95% confidence interval, CI: 6.34-17.51; p < 0.001) and a low SOC (OR: 2.17; 95% CI: 1.37-3.43; p = 0.001). According to the children's perceptions, the following variables were associated with a negative impact on OHRQoL: toothache (OR: 3.58; 95% CI: 2.30-5.55; p < 0.001), caries activity (OR: 1.97; 95% CI: 1.07-3.62; p = 0.028), and traumatic dental injury (OR: 1.71; 95% CI: 1.15-2.53; p = 0.007). Among parents/caregivers, a low SOC led to poorer OHRQoL. For the children, however, neither psychological aspect affected OHRQoL. In the perception of both the parents/caregivers and children, toothache was the oral condition that exerted a negative impact on OHRQoL. PMID- 29723863 TI - Epicardial Fat Thickness in Patients with Autosomal Dominant Polycystic Kidney Disease. AB - INTRODUCTION: Autosomal dominant polycystic kidney disease (ADPKD) is associated with early organ damage such as left ventricular hypertrophy and higher cardiovascular risk when compared to essential hypertension (EH). Epicardial adipose tissue (EAT) is a new cardiovascular risk factor, but its role and correlation with left ventricular mass (LVM) in ADPKD is unknown. AIMS: we sought to investigate whether EAT is higher and related to LVM indexed by body surface area (LVMi) in hypertensive patients with ADPKD compared to those with EH. METHODS: We performed ultrasound measurement of EAT thickness, LVM, LVMi, and left atrium size (left atrial volume indexed for body surface, LAVI) in 41 consecutive hypertensive patients with ADPKD, compared to 89 EH patients. RESULTS: EAT was significantly higher in the ADPKD group in comparison to EH subjects (9.2 +/- 2.9 mm vs. 7.8 +/- 1.6 mm, p < 0.001), and significantly correlated with LVM, LVMi, and LAVI in the ADPKD group (r = 0.56, p = 0.005; r = 0.424, p = 0.022; and r = 0.48, p = < 0.001, respectively). Comparing EAT against body mass index, systolic blood pressure, and age, we found that EAT was the strongest predictor of LVMi (beta = 0.42, p = 0.007). CONCLUSION: Our data showed that EAT was higher in ADPKD patients than in EH subjects and independently correlated with LVMi. EAT measurement can be a useful marker for the cardiovascular risk stratification in ADPKD. PMID- 29723866 TI - Prognostic Factors Associated with Postprogression Survival in Advanced Hepatocellular Carcinoma Patients Treated with Sorafenib Not Eligible for Second Line Regorafenib Treatment. AB - OBJECTIVES: The aim of this study was to investigate the prognostic factors associated with postprogression survival (PPS) in advanced hepatocellular carcinoma (HCC) patients treated with sorafenib, who were not eligible for second line treatment with regorafenib. METHODS: A total of 103 patients with radiological confirmation of progressive disease (PD) were enrolled. RESULTS: The median PPS (n = 67) was 6.1 months. Significant and independent prognostic factors at initial radiological PD associated with good PPS were an Eastern Cooperative Oncology Group Performance Status (ECOG-PS) score of 0, the absence of macrovascular invasion (MVI), and time to progression (TTP) >=4 months. Upon scoring these three variables as good PPS factors, the median PPS in the good PPS score of 3 or 2 group (n = 38) was significantly longer than that in the good PPS score of 1 or 0 group (n = 29) (16.6 vs. 2.9 months; p < 0.0001, respectively). CONCLUSIONS: An ECOG-PS score of 0, the absence of MVI, and TTP >=4 months at first radiological confirmation of PD may be useful for predicting good PPS in patients with advanced HCC who do not meet the eligibility criteria for the RESORCE trial. PMID- 29723867 TI - Preoperative Diagnosis of Neoplastic or Malignant Hurthle Cell Lesions: A Chimera? AB - OBJECTIVE: We aimed to review all cytological specimens with Hurthle cells (HC) diagnosed in our institution, identify cytological features related to neoplastic (adenoma or carcinoma) and malignant histology, and discuss the role of clinicopathological findings and clinical management in these cases. STUDY DESIGN: We included 359 thyroid fine-needle aspiration cytology cases in our study. We reviewed the clinical and cytological features of surgical cases and correlated them with histological diagnosis. We also reviewed the literature on this issue. RESULTS: We found a significant association between neoplasia and highly cellular smears, the absence of colloid, the presence of microfollicles, large-cell dysplasia, prominent nucleoli or macronucleoli, coarse chromatin, nuclear grooves and inclusions, nuclear irregularity, and pleomorphism. The absence of colloid, high cellularity, > 25% of isolated HC, the presence of tridimensional groups, transgressing vessels, nuclear irregularity, prominent nucleoli or macronucleoli, coarse chromatin, hyperchromatism, pleomorphism, and diffuse large-cell dysplasia were features significantly associated with malignancy. CONCLUSIONS: No cytological feature alone can predict histological outcome, but all findings related to a neoplastic or malignant histology must be assessed. Individualized management protocols should be developed in each institution. PMID- 29723868 TI - Natural Hypoxia is Not a Limiting Factor in Evaluating the Novel Arylidene Derivative MLT-401 Against an In Vitro Colorectal Cancer Model. AB - BACKGROUND/AIMS: Cancer cells in vivo develop resistance to many anti-tumor drugs. One known factor to influence such drug resistance is hypoxia, which is an important component of the tumor microenvironment. Standard cancer lines mostly do not exhibit a cellular hypoxic microenvironment and there is a paucity of information on the efficacy of lead molecules in both cellular- and environment induced hypoxic conditions. Therefore, in the present study, we have evaluated the efficacy of the arylidene derivative MLT-401, a lead molecule showing activity against colorectal cancer model using the HCT 116 cell line and CCD-80-C control cells in normoxic and natural (marginal) hypoxic conditions, which is usually observed in high-altitude regions. METHODS: The efficacy of MLT-401 on HCT 116 and CCD-80-C cells were tested in both normoxia and marginal hypoxia conditions. MTT assay was used to evaluate cell proliferation, Annexin V binding assay for apoptotic cell quantification and PI staining for cell cycle were done by flow cytometry. Induction of pro-apoptotic marker BAX and anti-apoptotic Bcl-2 were assessed by western blot. Bcl-2/BAX ratio was calculated based on protein expression by western blotting and bands were quantified by Image J software. RESULTS: Analysis of cell proliferation showed an average 10-fold reduction in the inhibition of HCT 116 cells in hypoxic conditions with approximately 500 nM MLT-401, while there was no significant change noted in marginal hypoxic conditions. A proportionate increase in the number of apoptotic cells and large M4 fraction of 10.5% and 26.7% of HCT116 against 6.3% of control cells in cell cycle assessment with MLT-401 concentrations ranging from 250 to 500 nM respectively clearly demonstrated anti-cancer activity. A Bcl-2/BAX ratio of < 1 showed that the induction of apoptosis was the gross mechanism underlying the inhibition of HCT 116 cells by MLT-401. CONCLUSION: Collectively, these results show MLT-401 as an effective anti-colorectal cancer lead molecule irrespective of normoxia or natural hypoxia. PMID- 29723869 TI - Genetic Analysis of TREM2 Variants in Tunisian Patients with Alzheimer's Disease. AB - OBJECTIVE: Rare variants in the TREM2 gene have been reported to significantly increase the risk of Alzheimer's disease in Caucasian populations. Hitherto, this association was not studied in North African populations. In this work, we aimed to study the association between TREM2 exon 2 variants and the risk of late-onset Alzheimer's disease (LOAD) in a Tunisian population. SUBJECTS AND METHODS: We sequenced exon 2 of TREM2 in a Tunisian cohort of 172 LOAD patients and 158 control subjects. We used the Fisher exact test to compare the distribution of allelic frequencies between the two groups. RESULTS: We identified 4 previously reported nonsynonymous variants (p.Asp39Glu, p.Arg62His, p.Thr96Lys, and p.Val126Gly) and 1 novel synonymous variant (p.Gln109Gln), none of which was significantly associated with the risk of Alzheimer's disease. Moreover, the rare TREM2 variant (p.Arg47His), which was considered to be a risk factor for Alzheimer's disease in European descent populations, was not detected in our cohort. CONCLUSION: These findings do not support a major role for TREM2 in the pathogenesis of LOAD in the Tunisian population. PMID- 29723870 TI - Functional Disconnectivity during Inter-Task Resting State in Dementia with Lewy Bodies. AB - AIMS: Limited research has been done on the functional connectivity in visuoperceptual regions in dementia with Lewy bodies (DLB) patients. This study aimed to investigate the functional connectivity differences between a task condition and an inter-task resting state condition within a visuoperceptual paradigm, in DLB patients compared with Alzheimer disease (AD) patients and healthy elderly control subjects. METHODS: Twenty-six DLB, 29 AD, and 22 healthy subjects underwent a detailed clinical and neuropsychological examination along with a functional MRI during the different conditions of a visuoperceptual paradigm. Functional images were analyzed using group-level spatial independent component analysis and seed-based connectivity analyses. RESULTS: While the DLB patients scored well and did not differ from the control and AD groups in terms of functional activity and connectivity during the task conditions, they showed decreased functional connectivity in visuoperceptual regions during the resting state condition, along with a temporal impairment of the default-mode network activity. Functional connectivity disturbances were also found within two attentional-executive networks and between these networks and visuoperceptual regions. CONCLUSION: We found a specific functional profile in the switching between task and resting state conditions in DLB patients. This result could help better characterize functional impairments in DLB and their contribution to several core symptoms of this pathology such as visual hallucinations and cognitive fluctuations. PMID- 29723872 TI - Knee Osteoarthritis after Arthroscopic Partial Meniscectomy: Prevalence and Progression of Radiographic Changes after 5 to 12 Years Compared with Contralateral Knee. AB - The purpose of this study was to study the clinical and radiographic changes in the knee after arthroscopic partial meniscectomy (APM) at a long-term follow-up compared with the contralateral knee. We assessed 57 patients (38 males and 19 females) with pre- and postoperative weight-bearing radiography with a follow-up ranging from 5.1 to 12.1 years (mean: 8.1) to analyze prevalence and progression of knee osteoarthritis (OA) after APM. We stratified patients according to body mass index (BMI), type of lesion (degenerative vs. traumatic), and side of meniscectomy (medial, lateral, and medial plus lateral). Patients were evaluated both clinically with Knee Osteoarthritis Outcome Score (KOOS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score and radiographically with the Kellgren and Lawrence (K/L) score. Radiographic OA was defined as K/L grade 2 or worse. The prevalence of knee OA was 62.69% in the tibiofemoral compartment. The progression of knee OA was statistically significant, ranging from 17.2% preoperatively to 65.95% postoperatively (p = 0.001) in the medial compartment and from 17.64% preoperatively to 58.82% postoperatively (p = 0.0324) in the lateral compartment. The progression of knee OA in the patellofemoral compartment ranged from 5.26 to 42.10% (p = 0.001). The OA progression regarding BMI was higher into the obese group than the normal-weight group and greater in the degenerative group than the traumatic one. The mean KOOS was 72.01 and the mean WOMAC was 73.84. The Spearman's test showed a statistical significance between clinical and radiographic results. Patients in the obese, overweight, and degenerative tear group had a greater predisposition to OA in the tibiofemoral and patellofemoral compartments after meniscectomy. The level of evidence is III, retrospective study. PMID- 29723871 TI - CD38-cADPR-SERCA Signaling Axis Determines Skeletal Muscle Contractile Force in Response to beta-Adrenergic Stimulation. AB - BACKGROUND/AIMS: Cyclic ADP-ribose (cADPR) is a Ca2+ -mobilization messenger that acts on ryanodine-sensitive Ca2+ channels in the sarcoplasmic reticulum (SR) Ca2+ stores. Moreover, it has been proposed that cADPR serves an additional role in activating the sarcoendoplasmic reticulum Ca2+ -ATPase (SERCA) pump. The aim of this study was to determine the exact mechanism by which cADPR regulates SR Ca2+ stores in physiologically relevant systems. METHODS: We analyzed Ca2+ signals as well as the production of Ca2+ mobilizing messengers in the skeletal muscle cells of mice subjected to intensive exercise or in the SR fractions from skeletal muscle cells after beta-adrenergic receptor (beta-AR) stimulation. RESULTS: We show that cADPR enhances SERCA activity in skeletal muscle cells in response to beta-AR agonists, increasing SR Ca2+ uptake. We demonstrate that cADPR is generated by CD38, a cADPR-synthesizing enzyme, increasing muscle Ca2+ signals and contractile force during exercise. CD38 is upregulated by the cAMP response element-binding protein (CREB) transcription factor upon beta-AR stimuli and exercise. CD38 knockout (KO) mice show defects in their exercise and cADPR synthesis capabilities, lacking a beta-AR agonist-induced muscle contraction when compared to wild-type mice. The skeletal muscle of CD38 KO mice exhibits delayed cytosolic Ca2+ clearance and reduced SERCA activity upon exercise. CONCLUSION: These findings provide insight into the physiological adaptive mechanism by which the CD38- cADPR-SERCA signaling axis plays an essential role in muscle contraction under exercise, and define cADPR as an endogenous activator of SERCA in enhancing the SR Ca2+ load. PMID- 29723873 TI - Antibodies against HDL Components in Ischaemic Stroke and Coronary Artery Disease. AB - Quantitative and qualitative defects of high-density lipoprotein (HDL) are important in atherogenesis. In this study, we investigated whether antibodies against HDL components had additional value to conventional cardiovascular risk factors for the diagnosis of ischaemic stroke (IS) and coronary artery disease (CAD). Cross-sectional study was conducted on 53 patients with IS, 51 with CAD and 55 healthy controls, and in vitro studies to validate findings of the clinical study. We determined serum immunoglobulin G (IgG) antibodies against HDL (aHDL), apolipoproteins (aApoA-I, aApoA-II and aApoC-I) and paraoxonase-1 (aPON1) as well as PON1 activity (PON1a), total antioxidant capacity and biomarkers of endothelial activation (serum nitric oxide metabolites, 3-nitrotyrosine, VCAM-1 and ICAM-1); in vitro assays tested the capacity of IgG aHDL purified from high titer patients to inhibit PON1a and to reverse protective effect of HDL on endothelial cells. IgG aHDL, aApoA-I and aPON1 were higher in IS and CAD than controls (p < 0.001), predicted negatively PON1a and positively VCAM-1 and ICAM 1. By adding IgG aHDL and aApoA-I to a traditional cardiovascular risk factors model for IS and by adding IgG aHDL in a similar model for CAD, we obtained better discrimination of IS and CAD from healthy controls. IgG aHDL purified from IS and CAD inhibited PON1a by 38% (p < 0.01) and abrogated the protective effect of HDL on VCAM-1 expression by 126% compared with non-specific human IgG (p < 0.001). IgG against HDL components interfere with the antioxidant and anti inflammatory properties of HDL and may represent novel biomarkers for vascular disease that need to be investigated in prospective studies. PMID- 29723874 TI - Peri-operative Adverse Outcomes in Patients with Atrial Fibrillation Taking Warfarin or Edoxaban: Analysis of the ENGAGE AF-TIMI 48 Trial. AB - BACKGROUND: Peri-operative management of anticoagulated patients with atrial fibrillation (AF) is challenging. To gain information on the peri-operative management of edoxaban, we compared outcomes in patients on warfarin or edoxaban enrolled in ENGAGE AF-TIMI 48 who underwent a surgery or invasive procedure. METHODS: Data from patients undergoing their first surgery/procedure were analysed and results compared by anticoagulant (warfarin vs. higher- or lower dose edoxaban regimen [HDER and LDER, respectively]). Patients were classified by procedural management: anticoagulant interrupted (last dose 4-10 days pre procedure) or anticoagulant continued (last dose <= 3 days pre-procedure). Stroke/systemic embolism (SSE), major bleeding (MB), MB or clinically relevant non-MB (CRNMB) and death were assessed from 7 days pre- until 30 days post procedure. The chi-square test was used to compare outcomes across treatment groups. RESULTS: A total of 7,193 patients (34%) underwent surgery/procedure: 3,116 had anticoagulant interrupted, 4,077 had anticoagulant continued. Among patients on warfarin, HDER and LDER who had anticoagulant interrupted, rates of SSE were 0.6, 0.5 and 0.9% (p = 0.53), rates of MB were 1.0, 1.2 and 1.1% (p = 0.94) and rates of MB or CRNMB were 3.9, 4.2 and 3.6% (p = 0.78); among patients on warfarin, HDER and LDER who had anticoagulant continued, rates of SSE were 1.1, 0.7 and 0.9% (p = 0.51), rates of MB were 3.6, 2.6 and 2.4% (p = 0.13) and rates of MB or CRNMB were 8.5, 7.9 and 6.6% (p = 0.17). CONCLUSION: In patients requiring surgery/procedure in ENGAGE AF-TIMI 48, peri-operative rates of SSE, MB and death were not significantly different in patients who received edoxaban or warfarin. PMID- 29723875 TI - Dynamic Changes of CHA2DS2-VASc Score and the Risk of Ischaemic Stroke in Asian Patients with Atrial Fibrillation: A Nationwide Cohort Study. AB - BACKGROUND: Stroke risk in atrial fibrillation (AF) is often assessed at initial presentation, and risk stratification performed as a 'one off'. In validation studies of risk prediction, baseline values are often used to 'predict' events that occur many years later. Many clinical variables have 'dynamic' changes over time, as the patient is followed up. These dynamic changes in risk factors may increase the CHA2DS2-VASc score, stroke risk category and absolute ischaemic stroke rate. OBJECTIVE: This article evaluates the 'dynamic' changes of CHA2DS2 VASc variables and its effect on prediction of stroke risk. PATIENTS AND METHODS: From the Korea National Health Insurance Service database, a total of 167,262 oral anticoagulant-naive non-valvular AF patients aged >= 18 years old were enrolled between January 1, 2002, and December 31, 2005. These patients were followed up until December 31, 2015. RESULTS: At baseline, the proportions of subjects categorized as 'low', 'intermediate' or 'high risk' by CHA2DS2-VASc score were 15.4, 10.6 and 74.0%, respectively. Mean CHA2DS2-VASc score increased annually by 0.14, particularly due to age and hypertension. During follow-up of 10 years, 46.6% of 'low-risk' patients and 72.0% of 'intermediate risk' patients were re-classified to higher stroke risk categories. Among the original 'low risk' patients, annual ischaemic stroke rates were significantly higher in the re classified 'intermediate' (1.17 per 100 person-years, p < 0.001) or re-classified 'high-risk' groups (1.44 per 100 person-years, p = 0.048) than consistently 'low risk' group (0.29 per 100 person-years). The most recent CHA2DS2-VASc score and the score change with the longest follow-up had the best prediction for ischaemic stroke. CONCLUSION: In AF patients, stroke risk as assessed by the CHA2DS2-VASc score is dynamic and changes over time. Rates of ischaemic stroke increased when patients accumulated risk factors, and were re-classified into higher CHA2DS2 VASc score categories. Stroke risk assessment is needed at every patient contact, as accumulation of risk factors with increasing CHA2DS2-VASc score translates to greater stroke risks over time. PMID- 29723877 TI - Effect of Bipolar Radiofrequency Energy on Canine Stifle Joint Fluid Temperature. AB - OBJECTIVE: The aim of this study was to evaluate the effect of bipolar radiofrequency (RF) energy on canine stifle joint fluid temperature. MATERIALS AND METHODS: A standard stifle arthroscopy was performed on 15 canine large breed cadaveric stifle joints. A bipolar RF (VAPR III, 2.3-mm side effect electrode; Depuy Mitek, Raynham, Massachusetts, United States) unit was activated in the joint (1) with or without direct tissue contact, (2) with or without additional 18-gauge needle outflow and (3) for 15 and 30 seconds. The joint fluid temperature was monitored with two fibre optic intra-articular sensors. RESULTS: The stifle joint fluid temperature was significantly higher when there was no contact between the tissue and RF probe (mean: 58.6 degrees C with 95% confidence interval [CI]: 53.3-64.0 degrees C) compared with when tissue was contacted (mean: 29.0 degrees C with 95% CI: 26.3-31.6 degrees C). An 18-gauge egress needle had minimal effect on reducing joint fluid temperature. The temperature was higher during the 30-second application of RF energy than the 15-second group. CLINICAL SIGNIFICANCE: Bipolar RF energy without firm tissue contact rapidly and significantly increased joint fluid temperature beyond the level reported to damage chondrocytes (above 45 degrees C). Caution is required in the use of bipolar RF energy in the canine stifle joint. PMID- 29723878 TI - Biomechanical Comparison between Preloaded Position Screw and Lag Screw Fixations for Their Compressive Effects in a Porcine Rib Fracture Model. AB - OBJECTIVES: The aim of this study was to compare the compressive effect between preloaded position screws and lag screws in fracture fixation. METHODS: Pairs of semi-cylindrical bone fragments were created on a porcine rib model to simulate fractured bones. The compressive forces of fracture fixation generated by preloaded position screws (P group) and conventional lag screws (L group) were recorded by a film stress sensor. In the P group, a pair of Angus bone holding forceps was used to compress the interfragmentary interface until reaching the preloading force of 1.3 MPa. Similar preloading procedure was applied on lag screw fixations to explore its potential of additional compressive force. RESULTS: With 1.3 MPa preloading force and 0.2 Nm screw insertion torque force, the interfragmentary compressive force of P group was similar to that of L group. When the insertion torque force was increased to 0.4 Nm, all screws in the L group failed due to thread stripping. When screws in the P group were installed under 0.4 Nm torque and in the L group under 0.2 Nm torque, the P group generated significantly greater compressive force. With preloading device applied on lag screw installation, it did not further increase the interfragmentary compressive force. CLINICAL SIGNIFICANCE: Compared with lag screws, preloaded position screws tolerated greater torque in screw installation and provided greater interfragmentary compressive force. The study suggests the applicability of preloaded position screws in fracture fixation requiring interfragmentary compression. PMID- 29723879 TI - Anthropometric and Anthroposcopic Analysis of Periorbital Features in Malaysian Population: An Inter-racial Study. AB - In oculoplastic operations, knowledge of the dimensions of periorbital features based on age, gender, and race is essential for achieving better aesthetic result. This article seeks to determine the racial and gender differences of periorbital features among Malaysian Malay (MM), Malaysian Indian (MI), and Malaysian Chinese (MI) subjects. Evaluation of periorbital features was done on photographs of 200 MM, 200 MI, and 200 MC subjects, aged 18 to 26 years. The measured values were evaluated by an independent t-test. A significant difference was found between MM and MI in all measurements except interbrow distance in males, eyebrow thickness in females, and apex to lateral limbus distance in both sexes. Between MI and MC the difference was insignificant for interbrow distance in male groups, apex to lateral limbus distance in females, and palpebral fissure inclination and eyebrow apex angle in both sexes. Between MM and MC, significant differences were found for eyebrow thickness and medial canthus tilt in female group. Male groups showed significant difference for apex to lateral limbus and lateral canthus distance and eyebrow apex angle. Eyebrow height, palpebral fissure width, and intercanthal distance were significantly different in both sexes. Sexual dimorphism was found for all measurements in MI, but MM and MC showed insignificant difference for eyebrow apex angle. Four types of epicanthus were observed in MM and MC and three types in MI. Eyebrow apex between lateral limbus and lateral canthus was the most common position in all racial groups. Significant racial and gender differences exist for certain periorbital measurements. The knowledge of these differences is expected to influence the surgical outcome. PMID- 29723880 TI - Factors Known to Influence the Development of Necrotizing Enterocolitis to Modify Expression and Activity of Intestinal Alkaline Phosphatase in a Newborn Neonatal Rat Model. AB - INTRODUCTION: Prematurity, formula feeding, and early weaning strongly influence enterocyte differentiation. Intestinal alkaline phosphatase (IAP), an endogenous protein expressed in the intestines, is one enzyme that is affected by these factors. IAP supplementation decreases the severity of necrotizing enterocolitis (NEC) injury. We, therefore, hypothesized that prematurity predisposes this population to NEC due to IAP deficiency and investigated IAP expression and function in a neonatal rat model. MATERIALS AND METHODS: Pre- and full-term newborn Sprague-Dawley rat pups were sacrificed on consecutive days of life both after vaginal or cesarean birth and following either breast or formula feeding. RESULTS: Compared with controls, cesarean delivery and formula feeding are associated with lower levels of IAP. The formula-fed pups continued to have low baseline IAP activity. Neither prematurity nor formula feeding led to differences of intestinal injury. CONCLUSION: Prematurity and formula feeding are associated with inhibition of IAP expression and activity. Both may increase the risk of NEC and early enteral supplementation of IAP to newborns at risk of NEC may be of therapeutic benefit. PMID- 29723881 TI - Postburn Neck Contracture: Principles of Reconstruction and a Treatment Algorithm. AB - BACKGROUND: Various techniques have been developed for postburn neck reconstruction, but a treatment algorithm is needed. METHODS: We retrospectively reviewed all patients treated for postburn neck contracture at our institution between February 2008 and December 2015. Necks were divided into one anterior subunit and two lateral subunits marked by the sternocleidomastoid muscle. Deformities were categorized into three types according to their size and location. Type I deformities involve less than one subunit, type II deformities involve at least one subunit but less than two subunits, and type III deformities affect two or more subunits. Type II deformities were further divided into type IIa deformities, which mainly involve the anterior region, and type IIb deformities, which mainly involve the lateral region. RESULTS: Local random pattern flaps were constructed for type I deformities. Pedicled flaps from the anterior chest and supraclavicular areas were preferred for type IIa deformities, and pedicled flaps from the back were preferred for type IIb deformities. Pedicled flaps from other areas were the second choice for type II deformities, followed by free and prefabricated flaps. For type III deformities, bipedicled flaps were usually required. At a follow-up of at least 12 months, all patients showed near-normal neck function, and aesthetic features were significantly improved. CONCLUSION: The proposed classification and treatment algorithm for postburn neck reconstruction may help achieve satisfactory outcomes. PMID- 29723882 TI - Cumulative Experience in Lymphovenous Anastomosis for Lymphedema Treatment: The Learning Curve Effect on the Overall Outcome. AB - BACKGROUND: The lymphovenous anastomosis (LVA) has become one of the treatment options for lymphedema. However, it is regarded as a difficult surgery that many young microsurgeons are reluctant to try. This report investigates the learning curve in regard to symptom improvement. METHODS: This is a retrospective analysis performed in 33 consecutive lymphedema patients (38 extremities) who underwent only LVAs from August 2010 to February 2016. Surgical outcomes in regard to surgeon's experience were evaluated. The surgeons experience was divided into three groups: early group with less than 2 years, moderate with 2 to 4 years, and mature group with more than 4 years of experience. RESULTS: A total of 31 limbs (8/8 in upper extremity and 23/30 in lower extremity) showed improvement. When we compare volume change and recurrence of cellulitis with regard to surgeon's experience, there were no statistically significant differences. However, the mean time per LVA was significantly decreased as the experience increased over time (p = 0.017). CONCLUSION: LVA is an effective treatment option to reduce the volume in the affected limb and to improve symptoms involved. Regardless of the number and experience of the surgeons, cellulitis improves significantly after LVA. The experience of the surgeon does not significantly impact the positive outcome while proficiency increases with experience. PMID- 29723883 TI - Adipose-Derived Stem Cells Ameliorate Ischemia-Reperfusion Injury in a Rat Skin Free Flap Model. AB - BACKGROUND: Ischemia-reperfusion (I/R) injury is inevitable during free tissue transfers. When the period of ischemia exceeds the tissue tolerance, it causes necrosis and flap failure. The aim of this study was to investigate the effects of adipose-derived stem cells (ASCs) embedded in a collagen type I scaffold on the survival of free skin flaps to counteract I/R injury. METHODS: Left superficial caudal epigastric skin flaps (3 * 6 cm) were performed in 28 Wistar rats that were divided into four groups. The flaps elevated in the animals of the control group did not suffer any ischemic insult, and the vascular pedicle was not cut. All other flaps were subjected to 8 hours of ischemia prior to revascularization: I/R control group (8 hours of ischemia), I/R scaffold group (8 hours of ischemia + collagen type I scaffold), and I/R scaffold-ASCs group (8 hours of ischemia + collagen type I scaffold with rat ASCs embedded). Transit time ultrasound blood flow measurements were performed. After 7 days, the areas of flap survival were measured and tissues were stained with hematoxylin/eosin and Masson's trichrome stain for histological analysis. RESULTS: The mean percentage flap survival area was significantly higher in the ASCs-treated flaps (I/R scaffold-ASCs group) compared with the ischemic controls (I/R control group and I/R scaffold group). Higher vascular proliferation and lower severity of necrosis and inflammatory changes were seen histologically in the samples of the ASCs-treated group. No significant difference in blood flow was detected between groups. CONCLUSION: Subcutaneous administration of ASCs embedded on a collagen type I scaffold reduces tissue damage after I/R injury in microvascular free flaps. PMID- 29723884 TI - The S&T Lecture: An Introduction to the 9th Congress of WSRM. AB - Just what is the S&T lecture? In the beginning it appeared to be a dubious distinction, another task thrust upon me but different in that I had absolutely no idea what was wanted or would be appropriate. At the least, it seemed reasonable to recite a simple introductory story for what would be an extraordinary conclave. First, an appreciation was due to our dedicated leaders of World Society of Reconstructive Microsurgery (WSRM), who this year (2017) have put together the most extravagant meeting ever, intended to include not just the glamorous but the entire scope of rudimentary reconstructive microsurgery. We know we must acquire all this knowledge to succeed today and tomorrow, but also need not to overlook the struggles and sacrifices our predecessors had to overcome. Too often the past is forgotten, only to then inefficiently be repeated. Today then, this will be a short story, a story of our past that must never be cast aside. The WSRM here today is a great international forum where we can then mingle with all of our colleagues to help dictate the present, but also define the future role of all specialities here where the ultimate goal is to help those most in need. This S&T lecture will just be a history story, subject to your interpretation. Enjoy! PMID- 29723885 TI - [Early Diagnosis and Successful Medical Treatment of Acanthamoeba Keratitis]. PMID- 29723886 TI - [Nevus or Melanoma of the Iris? A Progressive Course Over at Least 43 Years]. PMID- 29723887 TI - [Lidline Tattoo Associated with Basal Cell Carcinoma of the Lid Margin - Coincidence or Association?] AB - A cystic lesion of the lid margin was excised suspecting basal cell carcinoma. On histology, black-turquoise pigment was seen in the dermis adjacent to the basal cell carcinoma. It was pronounced perivascular, intracellular in macrophages and fibroblasts, but also extracellular as free pigment in the tissue, compatible with an eyelid line tattoo. Typical tissue reactions to tattoo ink, meibomian gland dysfunction after lid margin tattoo, as well as inflammatory reactions in the retina and choroid associated with tattoos distant from the eye are discussed. The correlation of lid tumors and lid margin tattoos seems coincidental. PMID- 29723889 TI - Medical and Semi-surgical Treatments for Fuchs Endothelial Corneal Dystrophy. AB - Unraveling the genetic mechanisms of Fuchs endothelial corneal dystrophy has opened new possibilities for future targeted medical therapy of the disease. Until these possibilities mature, regenerative semi-surgical approaches by cell injection or cell sheet transfer could help expand the donor pool, and possibly enable autologous transplantation. Descemet membrane stripping alone and acellular Descemet membrane transfer are more immediate surgical approaches that could be temporary treatments in some patients, though there is a lack of understanding of the factors that predict success for these procedures. Regardless of approach, clinical trials will be necessary, and clinicians should therefore try to standardize their methods of assessing disease severity and the outcomes of intervention. PMID- 29723888 TI - [The Influence of the Type of Anaesthesia on the Frequency of Postoperative Haemorrhage Requiring Revision After Removal of the Silicone Oil Tamponade]. AB - In this retrospective data analysis, it was examined whether the mode of anesthesia influenced postoperative haemorrhage in patients with first time complete silicone oil removal in 2002, 2005, 2010, 2014 - 2016 in our clinic and if there was a change in frequency over time. Haemorrhage was defined as a postoperative haemorrhage within 2 weeks after the operation and which led to revision vitrectomy. In all, there were 939 operations and 9 cases of postoperative surgery requiring revision in the analysed years. Even though the number of patients with intubation anesthesia (355) was smaller than the number with local anesthesia (584), the majority of patients with postoperative haemorrhage had been given intubation anesthesia (6). This difference corresponds to a trend (p = 0.089) towards a lower rate of postoperative haemorrhage with local anesthesia, which could encourage the surgeon to perform silicone oil removal under local anaesthesia. Over the course of time, there was a decline in postoperative haemorrhage. In 2002, 2005 and 2010 there were 7 cases of postoperative haemorrhage, but only 2 in the years 2014 - 2016. Aside from the higher proportion of operations under local anaesthesia, the decline in the frequency of postoperative haemorrhage may be attributed to "smoother extubation", the emergence of trocar-guided surgical procedure and the use of anti-VEGF therapy - all leading to a change in the spectrum of illnesses treated by silicone oil instillation. PMID- 29723891 TI - Evaluating the Effects of an Evidence-Based Hemostasis and Thrombosis Treatment Algorithm on Medical Practitioner and Trainee Clinical Decision-Making. PMID- 29723890 TI - Predictive Scoring for Severity of Acute Pulmonary Embolism: Does Timing Matter? PMID- 29723892 TI - Treatment Regimens with Bypassing Agents in Patients with Hemophilia A and Inhibitors: A Survey from the Italian Association of Hemophilia Centers (AICE). AB - The development of neutralizing antibodies (inhibitors) against infused factor VIII currently represents the main complication of replacement therapy in patients with severe hemophilia A. Inhibitors, indeed, particularly high-titer inhibitors (>5 BU/mL), greatly complicate the management of bleeding, exposing patients to an increased morbidity and mortality risk, thus representing a significant burden for physicians of Hemophilia Treatment Centers (HTCs). Although bypassing agents (i.e., activated prothrombin complex concentrate [APCC] and recombinant activated factor VII [rFVIIa]) are available for the treatment and prevention of bleeding in inhibitor patients, their efficacy, safety, and cost-benefit outcomes are poorly known in the long term and should be further improved. In the frame of the update of recommendations for the management of inhibitor patients by the Italian Association of Hemophilia Centers (AICE), to collect more information on real-life therapeutic approaches with bypassing agents in this setting, a survey was conducted among the Directors of the Italian HTCs. From questionnaires returned by 55% of them, data on the use of rFVIIa and APCC in children, adolescent, and adult patients with hemophilia A and inhibitors were obtained and are summarized in this article, including information about the implementation of prophylaxis with both bypassing agents, the adopted regimens, and reasons for starting, adjusting, and interrupting such a therapeutic approach. PMID- 29723894 TI - Anxiety-Related Bleeding and Thrombosis. AB - Anxiety, a normal response to stressful situations, is characterized by increased levels of factor VIII, fibrinogen, and von Willebrand factor, and by enhanced platelet aggregability. One would expect acute anxiety to be a prothrombotic state, but since acute mental stress induces tissue plasminogen activator (tPA) release from endothelial and chromaffin cells, fibrinolysis counteracts procoagulant stimuli. It could be said that procoagulant changes accompanying the fight-or-flight response reduce the risk of bleeding in case of potential injuries, while activation of fibrinolysis counteracts activation of hemostasis to prevent intravascular thrombus formation before injuries occur. Acutely anxious patients are prone to bleeding or thrombosis when the balance between hypercoagulation and hyperfibrinolysis is disturbed. Acute anxiety not only increases the risk of bleeding in hemophilia or von Willebrand disease, but many reports have shown that anxiolytic interventions such as hypnosis are effective in controlling bleeding in hemostatic disorders. The pathogenesis of cardiovascular and thrombotic diseases in highly anxious patients is multifactorial. An important element is alpha-adrenergic vasoconstriction, which increases viscosity due to leakage of intravascular fluid into the interstitium, and also causes hypertension, favoring plaque rupture. Paradoxical as it may seem, over secretion of tPA may increase cardiovascular risk. This is because tPA degrades the extracellular matrix, causing vascular stiffness that increases cardiac workload, and thus oxygen requirements. Anxious patients with conditions associated with increased plasminogen activator inhibitor-1 levels, such as depression or postprandial hyperinsulinemia, are at high risk of thrombosis. Postprandial hyperinsulinemia may result from consumption of high-carbohydrate foods, considered anxiolytic, combined with a sedentary life, which is common among anxious individuals. Preliminary evidence suggests that high anxiety combined with either depression or a lifestyle that results in hyperinsulinemia has an important role in the pathogenesis of thrombotic events currently classified as unprovoked. PMID- 29723893 TI - Causes of Death in Patients with Venous Thromboembolism Anticoagulated with Direct Oral Anticoagulants: A Systematic Review and Meta-Analysis. AB - Death is more frequent than nonfatal recurrent venous thromboembolism (VTE) and major bleeding after acute VTE. The analysis of the causes of death is fundamental to explore new strategies to reduce mortality rates in these patients. The authors performed a meta-analysis to analyze mortality and independently adjudicated causes of death in anticoagulated patients due to VTE, and to evaluate potential differences between different anticoagulant schemes. They searched MEDLINE and CENTRAL, from January 1, 2000, to January 31, 2017, and performed additional searches in Web sites of regulatory agencies, clinical trial registers, and conference proceedings. Two investigators independently selected studies and extracted the data. Study quality was assessed with the Cochrane Collaboration's tool for assessing the risk of bias in randomized studies. Seven prospective randomized trials in 29,844 patients (22,025 patient-year follow-up) were included, comparing dabigatran, rivaroxaban, apixaban, and edoxaban with the standard anticoagulant treatment of VTE. A total of 718 patients died during the follow-up (3.4% per year; 95% confidence interval [CI]: 2.3-4.8). The most frequent causes of death were cancer (42%), followed by VTE (20%), infections (13%), hemorrhage (6%), heart disease (4%), and stroke (2%). There were no differences in the overall survival and causes of death according to the anticoagulant type. Concomitant active cancer during the study was significantly associated with death (odds ratio: 15.2; 95% CI: 9.2-25.1). Cancer is the leading cause of death in contemporary VTE trials. Interventions beyond anticoagulation, particularly in patients with active cancer, are needed. PMID- 29723895 TI - Anticancer Drug-Related Nonvalvular Atrial Fibrillation: Challenges in Management and Antithrombotic Strategies. AB - Cancer patients may experience nonvalvular atrial fibrillation (AF) as a manifestation of cardiotoxicity. AF may be a direct effect of a neoplasm or, more often, appear as a postsurgical complication, especially after thoracic surgery. AF may also develop as a consequence of anticancer therapy (chemotherapy or radiotherapy), a condition probably underestimated. Cancer patients with AF require a multidisciplinary approach involving oncologists/hematologists, cardiologists, and coagulation experts. An echocardiogram should be performed to detect possible abnormalities of left ventricular systolic and diastolic function, as well as left atrial dilation and the existence of valvular heart disease, to determine pretest probability of sinus rhythm restoration, and identify the best treatment. The choice of antiarrhythmic treatment in cancer patients may be difficult because scanty information is available on the interactions between anticancer agents and antiarrhythmic drugs. A careful evaluation of the antithrombotic strategy with the best efficacy/safety ratio is always needed. The use of vitamin K antagonists (VKAs) may be problematic because of the unpredictable therapeutic response and high bleeding risk in patients with active cancer who are undergoing chemotherapy and who may experience thrombocytopenia and changes in renal or hepatic function. Low molecular weight heparins (in particular for short and intermediate periods) and non-VKA oral anticoagulants (NOACs) should be preferred. However, the possible pharmacological interactions of NOACs with both anticancer and antiarrhythmic drugs should be considered. Based on all these considerations, antiarrhythmic and anticoagulant therapy for AF should be tailored individually for each patient. PMID- 29723897 TI - Relationship Between the Brain Natriuretic Peptide (BNP) Level and Prognosis of Diabetic Nephropathy with Microalbuminuria: A 7-Year Follow-Up Study. AB - The aim of the study was to examine the relationship between the brain natriuretic peptide (BNP) level and prognosis of diabetic nephropathy. The subjects were 100 Japanese outpatients with type 2 diabetes mellitus with microalbuminuria. Associations between metabolic parameters at baseline, including BNP, and prognosis of diabetic nephropathy (progression of diabetic nephropathy, cardiovascular events, and death) were examined for 7 years. In Cox proportional hazard analysis, HbA1c, albumin-creatinine ratio (ACR) and BNP were identified as significant factors for progression of diabetic nephropathy (p=0.033, p=0.037, and p=0.044, respectively), BNP was identified as significant factor for cardiovascular events (p=0.046), and estimated glomerular filtration rate (eGFR) and BNP were identified as significant factors for death (p=0.046 and p=0.048, respectively). In Kaplan-Meier analysis, risks of progression of diabetic nephropathy, cardiovascular events, and death were significantly different between patients with a low and a high BNP level (p=0.046, p=0.002, and p=0.025, respectively). ROC curve analysis gave cutoff values for BNP of 14.9 pg/ml for progression of diabetic nephropathy, 16.3 pg/ml for cardiovascular events, and 17.6 pg/ml for death (p=0.047, p=0.035, p=0.018, respectively). In conclusion, the BNP level is associated with prognosis in diabetic nephropathy. PMID- 29723896 TI - Mineralocorticoid Receptor Blockers and Aldosterone to Renin Ratio: A Randomized Controlled Trial and Observational Data. AB - Current guidelines recommend to withdraw mineralocorticoid receptor (MR) blocker treatment for at least 4 weeks when measuring the aldosterone to renin ratio (ARR) as a screening test for primary aldosteronism (PA). We aimed to evaluate the effect of MR blocker treatment on ARR and its components, plasma aldosterone concentration (PAC), and direct renin concentration (DRC). First, we performed a post-hoc analysis of the effect of eplerenone on parathyroid hormone levels in primary hyperparathyroidism (EPATH) study, a randomized controlled trial (RCT) in 110 patients with primary hyperparathyroidism (pHPT). Patients were 1:1 randomly assigned to receive either 25 mg eplerenone once daily (up-titration after 4 weeks to 50 mg/day) or placebo for 8 weeks. Second, we measured the ARR in 4 PA patients from the Graz Endocrine Causes of Hypertension Study (GECOH) before and after MR blocker treatment. Ninety-seven participants completed the EPATH trial, and the mean treatment effect (95% confidence interval) for log(e)ARR was 0.08 ( 0.32 to 0.48) ng/dl/MUU/ml (p=0.694). The treatment effect was 0.71 (0.47 to 0.96; p<0.001) ng/dl for log(e)PAC and 0.64 (0.19 to 1.10; p=0.006) MUU/ml for log(e)DRC, respectively. In the 4 PA patients, the ARR decreased from 11.24+/ 3.58 at baseline to 2.70+/-1.03 (p=0.013) ng/dl/MUU/ml after MR blocker treatment. In this study with limited sample size, MR blocker treatment did not significantly alter the ARR in pHPT patients but significantly reduced the ARR in PA patients. Diagnostic utility of ARR and its components for PA diagnostics under MR blocker treatment warrants further study. PMID- 29723898 TI - The Relationship Between Liver Enzymes and Insulin Resistance in Type 2 Diabetes Patients with Nonalcoholic Fatty Liver Disease. AB - Non-: alcoholic fatty liver disease (NAFLD) is prevalent worldwide, especially in patients with type 2 diabetes. Liver enzymes are the main warning signs of liver injury and insulin resistance (IR) is critical to NAFLD. This study was aimed to investigate the association between liver enzymes and insulin resistance in type 2 diabetes patients with NAFLD. Data from 212 diabetes patients with NAFLD were analyzed, including 118 males and 94 females who received care from 2014 to 2015. The patients were divided into three groups by severity (mild n=87, moderate n=89, severe n=36). All patients underwent standard clinical and laboratory examinations. Liver enzymes including alanine aminotransferase (ALT), aspartate aminotransferase (AST), and gamma-glutamyl transferase (GGT) were measured, serum fasting glucose and serum fasting insulin were obtained. IR was assessed using the homeostasis model assessment insulin resistance index (HOMA-IR). Age, sex, and BMI did not significantly differ in patients (p>0.05). Compared with normal levels, elevated ALT and AST were associated with a higher HOMA-IR (p=0.0035, p=0.0096, respectively). HOMA-IR did not significantly differ (p>0.05) between patients with normal and elevated GGT. HOMA-IR increased as the levels of liver enzymes increased, and each enzyme showed a significant association with HOMA-IR (p=0.0166, p<0.0001, and p <0.0001). HOMA-IR differs between normal and elevated ALT and AST. Liver enzymes are associated with HOMA-IR in type 2 diabetes patients with NAFLD. These findings can help evaluate the degree of IR and hepatocellular steatosis in patients and prevent the progression of type 2 diabetes and NAFLD in clinical practice. PMID- 29723899 TI - Dietary Inflammatory Index and its Association with the Risk of Cardiovascular Diseases, Metabolic Syndrome, and Mortality: A Systematic Review and Meta Analysis. AB - Findings from previous studies on the association between the Dietary Inflammatory Index (DII) and the risk of chronic diseases and mortality have been inconsistent. We aimed to summarize studies on the association of the DII and the risk for cardiovascular disease (CVD), metabolic syndrome (MetS), and mortality in a systematic review and meta-analysis. We performed a systematic search in PubMed/Medline, Web of Knowledge, and Scopus databases for relevant studies written in English and published until 31 December 2017. Studies that reported the relative risk (RR), odd ratio (OR) or hazard ratio (HR) for the most pro inflammatory versus the most anti-inflammatory diets were included. Finally, 17 studies [CVD (n=6), MetS (n=5), mortality (n=6)] were included for systematic review and meta-analysis. Findings indicated a trend toward a positive relationship between the DII and the risk for CVD (pooled RR: 1.35; 95% CI: 1.13, 1.60; I2: 28.6%, p=0.21), all-cause mortality (pooled HR: 1.21; 95% CI: 1.09, 1.35; I2: 72.6%, p=0.003), CVD mortality (pooled HR: 1.30, 95% CI: 1.07, 1.57; I2: 74.0%, p=0.009) and cancer mortality (pooled HR: 1.28; 95% CI: 1.07, 1.53; I2: 62.5%, p=0.03). However, no significant association was found between the DII and the risk for MetS (pooled RR: 1.01; 95% CI: 0.82, 1.24; I2: 32.6%, p=0.20). Although in the current meta-analysis the most pro-inflammatory diet versus the most anti-inflammatory diet was not associated with the risk of MetS, we observed a substantial association between the DII and the risk for CVD and all types of mortality. However, further cohort studies in different populations are needed to clarify this association. PMID- 29723900 TI - Severe Maternal Morbidity and Hospital Cost among Hospitalized Deliveries in the United States. AB - OBJECTIVE: The objective of this study was to estimate the contemporary national rate of severe maternal morbidity (SMM) and its associated hospital cost during delivery hospitalization. STUDY DESIGN: We conducted a retrospective study identifying all delivery hospitalizations in the United States between 2011 and 2012. We used data from the National (Nationwide) Inpatient sample of the Healthcare Cost and Utilization Project. The delivery hospitalizations with SMM were identified by having at least one of the 25 previously established list of diagnosis and procedure codes. Aggregate and mean hospital costs were estimated. A generalized linear regression model was used to examine the association between SMM and hospital costs. RESULTS: Of 7,438,946 delivery hospitalizations identified, the rate of SMM was 154 per 10,000 delivery hospitalizations. Without any SMM, the mean hospital cost was $4,300 and with any SMM, the mean hospital cost was $11,000. After adjustment, comparing to those without any SMM, the mean cost of delivery hospitalizations with any SMM was 2.1 (95% confidence interval: 2.1-2.2) times higher, and this ratio increases from 1.7-fold in those with only one SMM to 10.3-fold in those with five or more concurrent SMM. CONCLUSION: The hospital cost with any SMM was 2.1 times higher than those without any SMM. Our findings highlight the need to identify interventions and guide research efforts to mitigate the rate of SMM and its economic burden. PMID- 29723901 TI - Metoclopramide and Diphenhydramine: A Randomized Controlled Trial of a Treatment for Headache in Pregnancy when Acetaminophen Alone Is Ineffective (MAD Headache Study). AB - OBJECTIVE: We investigated whether metoclopramide administered with diphenhydramine (MAD) relieves headache in pregnant women when acetaminophen alone is ineffective, using codeine for comparison. STUDY DESIGN: Normotensive pregnant women in the second or third trimester were randomized to MAD intravenously (10 mg and 25 mg, respectively) or codeine orally (30 mg) for headache after 650 to 1,000 mg of acetaminophen failed to relieve their headaches. Headache severity (pain score 0-10) was noted at intervals over 24 hours. The primary outcome was reduction in pain score 6 hours after medication administration. A sample size calculation of 35 patients per group was based on estimated reduction in headache pain score by at least two points, with an alpha of 0.05 and a power of 80%. RESULTS: No difference was seen in the primary outcome. MAD pain scores were lower at 30 minutes (3 +/- 2.8 versus 5.8 +/- 2.3, p < 0.001), 1 hour (2.2 +/- 2.3 vs. 4.1 +/- 3; p < 0.01), and 12 hours (1.3 +/- 2.5 vs. 2.7 +/- 3; p < 0.05), but not at 6 hours. Time to perceived headache relief was shorter for MAD than for codeine (20.2 +/- 13.4 vs. 62.4 +/- 62.2 minutes; p < 0.001). More patients in the MAD group reported full headache relief within 24 hours (76.5 vs. 37.5%; p < 0.01). CONCLUSION: MAD effectively relieves headaches in pregnant women when acetaminophen fails. PMID- 29723902 TI - Factors Associated with Stillbirth Autopsy in Georgia and Utah, 2010-2014: The Importance of Delivery Location. AB - OBJECTIVE: This article determines whether demographic, delivery, and medical factors are associated with stillbirth autopsy performance in Georgia and Utah. STUDY DESIGN: This study used fetal death certificates from 2010 to 2014 to determine which factors are associated with stillbirth autopsy performance in Georgia and Utah. Analyses were conducted using logistic regression with a predicted margins approach. RESULTS: The stillbirth autopsy rate was low in both states: 11.9% in Georgia (N = 5,610) and 23.9% in Utah (N = 1,425). In Utah, the autopsy rate significantly declined during the study period (p = 0.01). Stillbirths delivered outside of large metropolitan areas were less likely to receive an autopsy (medium/small metropolitans: prevalence ratioGA [PR] = 0.57, 95% confidence interval [CI]: 0.48-0.68 and PRUT = 0.48, CI: 0.38-0.59; nonmetropolitans: PRGA = 0.57, CI: 0.43-0.75 and PRUT = 0.37, CI: 0.21-0.63). In Georgia, autopsies were less common among stillbirths of Hispanic (vs. white) women (PR = 0.57, CI: 0.41-0.79), at earlier (vs. later) gestational ages (PR = 0.59, CI: 0.51-0.69), and of multiple birth pregnancies (PR = 0.71, CI: 0.53 0.96). CONCLUSION: Despite strong evidence supporting the value of stillbirth autopsies, autopsy rates were low, especially outside metropolitan areas, where approximately half of stillbirths were delivered. PMID- 29723903 TI - Nonmedically Indicated Induction of Labor Compared with Expectant Management in Nulliparous Women Aged 35 Years or Older. AB - OBJECTIVE: This article compares maternal and neonatal outcomes in women aged >= 35 years who experienced nonmedically indicated induction of labor (NMII) versus expectant management. STUDY DESIGN: This was a retrospective cohort study of nulliparas aged >= 35 years with a singleton and cephalic presentation who delivered at term. Outcomes were compared between women who underwent NMII at 37, 38, 39, and 40 weeks' gestation and those with expectant management that week. Adjusted odds ratios (aORs) with 95% confidence intervals (95% CIs) were calculated, controlling for predefined covariates. RESULTS: Of 3,819 nulliparas aged >= 35 years, 1,409 (36.9%) women underwent NMII. Overall at 39 weeks' gestation or later, maternal and neonatal outcomes were similar or improved with NMII. At 37, 38, and 39 weeks' gestation, NMII compared with expectant management was associated with decreased odds of cesarean delivery at 37, 38, and 39 weeks' gestation. At 40 weeks' gestation, NMII compared with expectant management was associated with an increased odds of operative vaginal delivery and a decreased odds of neonatal intensive care unit (NICU) admission. CONCLUSION: In nulliparous women aged >= 35 years, NMII was associated with decreased odds of cesarean delivery at 37 to 39 weeks' gestation and decreased odds of NICU admission at 40 weeks' gestation compared with expectant management. PMID- 29723904 TI - [Psychosocial Aspects of Organ Transplantation]. PMID- 29723905 TI - [Psychologically/Psychosomatically Relevant Aspects in the German Medical Association's Guidelines for Transplant Medicine]. AB - Transplant medicine in Germany is regulated by mandatory guidelines of the German Medical Association, the transplant law passed in 1997 serving as the legal basis. In 2012 a comprehensive modification of the guideline procedure was initiated. Since then, all guidelines are subject to an elaborate revision process. The present contribution initially depicts relevant background information and explains the formal aspects of the guideline procedure. Subsequently, the psychologically/psychosomatically relevant contents of the guidelines for organ transplantation are presented. With regard to this matter, first of all the state of the guidelines prior to the current revisions is described. Afterwards, already adopted revisions as well as published drafts are explicated, followed by the authors' evaluation of the revisions and recommendations for further revisions to be pursued. In addition, recommendations on psychosocial aspects regarding the evaluation and follow-up in living organ donation are presented, which have been submitted in similar form to the German Medical Association for a currently drawn up guideline. PMID- 29723906 TI - [Psychosocial Evaluation of Transplant Patients - Recommendations for the Guidelines for Organ Transplantation]. AB - For the last few years, the German Medical Association's guidelines for transplant medicine have been subject to an extensive revision process. The present contribution presents recommendations regarding the psychosocial evaluation of patients prior to organ transplantation, which were developed by experts from the Psychology/Psychosomatics committee of the German Transplant Society with the aim to incorporate the recommendations into the guidelines. The main objective is to establish a mandatory psychosocial evaluation for all patients prior to their admission to the transplant waiting list. Contents, potential contraindications, and the procedure of the evaluation are described. Furthermore, the qualification deemed necessary for the examiners is addressed in detail. Finally, the future need for action is determined. PMID- 29723907 TI - [Patient's Experience with Living Donation: A Questionnaire-Based Survey of 144 Living Kidney Donors]. AB - Living organ donation becomes more and more important as the number of patients needing organ transplantation is increasing. The University Hospital of Erlangen initiated a survey of living kidney donors to improve the process of living donation. The survey aimed to assess the donor's needs and experiences during the process of living kidney donation. From 2003 to 2014 n=199 living kidney donations were registered at the University Hospital of Erlangen. A total of n=144 living kidney donors (65.3% females, mean age M=58.7 years) participated in the study. In general, the majority of the living kidney donors were satisfied with the process of donation. Almost all of them (98%) confirmed to donate again, if it was possible. A large part of the living kidney donors denied any negative physical or psychological consequences of the donation. However, around 25% reported still physical problems for example wound healing, pain or long-term hypertension. Furthermore, a lack of pre- and post-operative psychological care or a regular medical follow-up care was reported. Thus, clinical practice needs to be further developed to meet the patient's needs. PMID- 29723908 TI - [Impact of Emotion Regulation and Emotional Arousal on Quality of Life and Adherence of Couples after Kidney Transplantation]. AB - INTRODUCTION: Nonadherence to immunosuppressive medication increases the risk of graft failure. Maladaptive emotion regulation strategies (ERS) seem to be a risk factor for nonadherence, whereas for patients in relationships spousal support appears as a protective resource. Emotional arousal, objectively measured by the fundamental frequency (f0) during spousal supportive communication is associated with supportive behavior. MATERIALS & METHODS: This study examined the relationship between beliefs about immunosuppressive medication, quality of life, ERS, emotions and emotional arousal, assessed during social support interactions of both spouses of N=50 couples after kidney transplantation. RESULTS: Maladaptive ERS of the transplant recipient were associated with lower mental quality of life of the partner, marginally higher own negative affect and lower beliefs about medication. Maladaptive ERS of the partner showed negative correlations with own mental quality of life. Regarding f0, gender differences were found. Higher f0 of the male transplant recipient were associated with more maladaptive ERS of the female partner. Marginally significate correlations were found with lower own beliefs about medication. Higher f0 of the wife of the male transplant recipient showed correlations with lower own positive affect, more negative affect of the male patient and lower beliefs about medication. Higher f0 of female transplant recipients were associated with lower own maladaptive ERS and lower maladaptive ERS of the husband. DISCUSSION: The findings support the relevance of early interventions focusing on identifying and modifying maladaptive ERS for both the patient and partner. PMID- 29723909 TI - [Psychological Foundations of Pediatric Liver Transplantation]. AB - Liver transplantation (LTX) is an established therapy for pediatric patients with liver failure. In recent decades, survival rates have risen continuously. With increased life expectancy, there has been greater attention to children's and adolescents' quality of life following transplantation. This article provides an overview of the tasks of pediatric transplant psychology. We summarize the reviewed literature of research on health-related quality of life in pediatric liver transplant recipients. Furthermore, we present studies on fatigue, mental health, cognitive development and family strain. In adolescents and young adults, the risk of non-adherence is particularly high. Therefore, adherence and transition, i. e. transfer from pediatric to adult-centered transplant care, are discussed separately. Subsequently, studies on long-term survival after LTX are summarized. In conclusion, recommendations for clinical practice are given. PMID- 29723910 TI - SurePath(r) LBC improves the diagnostic accuracy of intrahepatic and hilar cholangiocarcinoma. AB - INTRODUCTION: The current study aimed to compare cytology using SurePath(r) (SP) LBC and biliary tissue histology (BTH) for the diagnosis of biliary disease. METHODS: Between January 2014 and December 2016, 57 patients underwent endoscopic retrograde cholangiopancreatography for the diagnosis of biliary disease. Biliary cytological samples were processed using SP-LBC and subsequently BTH was performed. A final diagnosis was confirmed by surgery (23 malignant cases) and clinical follow-up (34 benign and malignant cases): 18 extrahepatic cholangiocarcinoma; 17 intrahepatic/hilar cholangiocarcinoma (intra/H-CC); eight other malignant disease; and 14 benign biliary disease. The diagnoses made using SP-LBC and BTH were classified into four categories: (1) benign; (2) indeterminate; (3) suspicious for malignancy/malignant; and (4) inadequate. In addition, diagnostic accuracy was compared between SP-LBC and BTH. RESULTS: Although 23% (13/57) of BTH samples were classified as inadequate, all SP-LBC cases were classified as adequate. Among 43 malignant cases, 11 normal, four indeterminate and 28 suspicious for malignancy/malignant were found using SP-LBC (26%, 9% and 65%, respectively), in contrast to 10 inadequate, nine normal, 10 indeterminate and 14 suspicious for malignancy/malignant observed using BTH (23%, 21%, 23%, and 33%, respectively). The identification of malignant cells was strikingly different between SP-LBC and BTH. Furthermore, limited to intra/H-CC, accuracy was significantly higher using SP-LBC than using BTH (P < .001). CONCLUSIONS: SP-LBC of the biliary tract is a useful and reliable method for diagnosing biliary malignant disease and has an advantage over BTH for detecting malignant cells and accurately diagnosing intra/H-CC. PMID- 29723911 TI - Specialized properties of the triceps surae muscle-tendon unit in professional ballet dancers. AB - This study compared professional ballet dancers (n = 10) to nonstretching controls (n = 10) with the purpose of comparing muscle and tendon morphology, mechanical, neural, and functional properties of the triceps surae and their role for ankle joint flexibility. Torque-angle and torque-velocity data were obtained during passive and active conditions by use of isokinetic dynamometry, while tissue morphology and mechanical properties were evaluated by ultrasonography. Dancers displayed longer gastrocnemius medialis fascicles (55 +/- 5 vs 47 +/- 6 mm) and a longer (207 +/- 33 vs 167 +/- 10 mm) and more compliant (230 +/- 87 vs 364 +/- 106 N/mm) Achilles tendon compared to controls. Greater passive ankle dorsiflexion range of motion (40 +/- 7 vs 17 +/- 9 degrees ) was seen in dancers, resulting from greater fascicle strain and greater elongation of the muscle. Peak electromyographic (EMG) activity recorded during passive stretching was lower in dancers, and at common joint angles, dancers displayed lower EMG amplitude and lower passive joint stiffness. No differences between groups were seen in maximal isometric plantar flexor torque, isokinetic peak torque, angle of peak torque, or work. In conclusion, the greater ankle joint flexibility of professional dancers seems attributed to multiple differences in morphological and mechanical properties of muscle and tendinous tissues, and to factors related to neural activation. PMID- 29723912 TI - High prevalence and low spontaneous eradication rate of Helicobacter pylori infection among schoolchildren aged 7-12 years. AB - AIM: Helicobacter pylori infections mainly occur during childhood and may cause chronic diseases and persist for life unless they are treated. The aim of this study was to identify the prevalence and infection status of H. pylori infection among schoolchildren. METHODS: We conducted a cross-sectional study of 867 children (52% male) aged 7-12 years in a primary school in the Minhang District of Shanghai, China, in 2014, and a one-year follow-up study of 352 subjects. The 13C-urea breath test was used to identify the H. pylori infection at baseline and one year later. A parental questionnaire provided information regarding the children's socioeconomic status and household environment. RESULTS: The overall prevalence of the H. pylori infection was 24.1% (209/867), with a 95% confidence interval of 21.3% to 27.0%. The one-year follow-up study of 352 subjects found that 33.5% were positive for the infection at baseline and 66.5% were negative. We found that 27.1% of the positive cases recovered and 8.9% of the negative cases acquired the infection during the year. The spontaneous eradication rate was only 2.9% over the one-year period. CONCLUSION: The prevalence of the H. pylori infection among Chinese schoolchildren aged 7-12 was high and spontaneous eradication was low. PMID- 29723913 TI - Observational pre-post study showed that a quality improvement project reduced paediatric antibiotic prescribing rates in primary care. AB - AIM: This study assessed the effectiveness of a quality improvement project that aimed to promote more considered antibiotic prescribing in paediatric primary care. METHOD: This was an observational pre-post study that used patient-level prescribing data from the Emilia-Romagna region of Italy to monitor indicators from 2005 to 2016. Multilevel interventions and activities were started in 2007 and these included developing guidelines and updates, disseminating evidence, audits and feedback, public information campaigns, engaging health managers and performance incentives. The primary outcomes were total antibiotic prescription rates for children aged 0-13 years and the rates for specific drugs. RESULTS: The intervention was associated with a significant reduction in the antibiotic prescribing rate, from 1307 per 1000 children in 2005 to 881 prescriptions in 2016 (p for trend <0.001), and a significant increase in the ratio of amoxicillin to amoxicillin-clavulanic acid, from 0.6 to 1.1 (p for trend = 0.001). Prescriptions of other second-choice antibiotics also declined significantly. In contrast, antibiotic prescribing rates remained high in the rest of Italy. CONCLUSION: The intervention was effective in promoting a more considered use of antibiotic in paediatric primary care in an Italian region. Further studies are needed to confirm its effectiveness in other settings. PMID- 29723914 TI - Cumulative exposure to biological therapy and risk of cancer in patients with psoriasis: a meta-analysis of Psonet studies from Israel, Italy, Spain, the U.K. and Republic of Ireland. AB - BACKGROUND: Cancer risk following long-term exposure to systemic immunomodulatory therapies in patients with psoriasis is possible. OBJECTIVES: To assess a dose response relationship between cumulative length of exposure to biological therapy and risk of cancer. METHODS: Four national studies (a healthcare database from Israel, and prospective cohorts form Italy, Spain and the U.K. and Republic of Ireland) collaborating through Psonet (European Registry of Psoriasis) participated in these nested case-control studies, including nearly 60 000 person years of observation. 'Cases' were patients who developed an incident cancer. Patients with previous cancers and benign or in situ tumours were excluded. Four cancer-free controls were matched to each case on year of birth, sex, geographic area and registration year. Follow-up for controls was censored at the date of cancer diagnosis for the matched case. Conditional logistic regression was performed by each registry. Results were pooled using random-effects meta analysis. RESULTS: A total of 728 cases and 2671 controls were identified. After matching, differences between cases and controls were present for the Charlson Comorbidity Index in all three registries, and in the prevalence of previous exposure to psoralen-ultraviolet A and smoking (the British Association of Dermatologists Biologic Interventions Register only). The risk of first cancers was not significantly associated with cumulative exposure to biologics (adjusted odds ratio per year of exposure 1.02, 95% confidence interval 0.92-1.13). Results were similar if squamous and basal cell carcinomas were included in the outcome. CONCLUSIONS: Cumulative length of exposure to biological therapies in patients with psoriasis in real-world clinical practice does not appear to be linked to a higher risk of cancer after several years of use. PMID- 29723915 TI - Causes of reduced leaf-level photosynthesis during strong El Nino drought in a Central Amazon forest. AB - Sustained drought and concomitant high temperature may reduce photosynthesis and cause tree mortality. Possible causes of reduced photosynthesis include stomatal closure and biochemical inhibition, but their relative roles are unknown in Amazon trees during strong drought events. We assessed the effects of the recent (2015) strong El Nino drought on leaf-level photosynthesis of Central Amazon trees via these two mechanisms. Through four seasons of 2015, we measured leaf gas exchange, chlorophyll a fluorescence parameters, chlorophyll concentration, and nutrient content in leaves of 57 upper canopy and understory trees of a lowland terra firme forest on well-drained infertile oxisol. Photosynthesis decreased 28% in the upper canopy and 17% in understory trees during the extreme dry season of 2015, relative to other 2015 seasons and was also lower than the climatically normal dry season of the following non-El Nino year. Photosynthesis reduction under extreme drought and high temperature in the 2015 dry season was related only to stomatal closure in both upper canopy and understory trees, and not to chlorophyll a fluorescence parameters, chlorophyll, or leaf nutrient concentration. The distinction is important because stomatal closure is a transient regulatory response that can reverse when water becomes available, whereas the other responses reflect more permanent changes or damage to the photosynthetic apparatus. Photosynthesis decrease due to stomatal closure during the 2015 extreme dry season was followed 2 months later by an increase in photosynthesis as rains returned, indicating a margin of resilience to one-off extreme climatic events in Amazonian forests. PMID- 29723917 TI - Opiate-Free Pain Therapy Using Carbamazepine-Loaded Microparticles Provides Up to 2 Weeks of Pain Relief in a Neuropathic Pain Model. AB - INTRODUCTION: Opioids remain a mainstay in the treatment of acute and chronic pain, despite numerous and potentially dangerous side effects. There is a great unmet medical need for alternative treatments for patients suffering from pain that do not result in addiction or adverse side effects. Anticonvulsants have been shown to be effective in managing pain, though high systemic levels and subsequent side effects limit their widespread usage. Our goal was to determine if the incorporation of an anticonvulsant, carbamazepine, into a biodegradable microparticle for local sustained perineural release would be an efficacious analgesic following a peripheral injury. METHODS: Following induction of the chronic constriction injury model in Sprague-Dawley rats, mechanical allodynia testing was performed using von Frey filaments and thermal allodynia was evaluated using the Hargreaves method. Histology and blood work were performed to evaluate toxicity as well as to monitor drug and metabolite presence over time. RESULTS: A 2-fold increase in hindpaw withdrawal thresholds in animals receiving carbamazepine-loaded microparticles relative to controls was observed for up to 14 days after treatment. Drug and metabolite had a peak blood concentration of 54.7 ng/mL and dropped off exponentially to < 5 ng/mL over a few days. CONCLUSION: This formulation reduced systemic exposure to carbamazepine over 1,000-fold relative to traditional analgesic dosing regimens. This 2-component drug delivery system has been specifically engineered to release a controlled amount of carbamazepine over a 14-day period, providing significant pain relief with no toxicological or observable adverse events via behavioral or histochemical analysis. PMID- 29723916 TI - Genome-wide association analyses of plant growth traits during the stem elongation phase in wheat. AB - One of the primary objectives of wheat breeding was to increase grain yield. Floral abortion during the stem elongation phase (SEP) leads to a loss of more than 50% of the grain number potential. In this study, we quantified 75 plant growth-associated traits at seven stages during the SEP and mapped 15 696 single nucleotide polymorphism (SNP) markers in 210 accessions of wheat (Triticum aestivum). Our genomewide association study identified trait-associated SNPs that are shared among various stages of the SEP, as well as SNPs that are shared between plant growth traits and grain yield in the field. The genomic selection analysis shows variation among the prediction abilities of various traits and stages. Furthermore, we found that the allelic variants of Ppd-D1 (chromosome 2D) and Rht-D1 (chromosome 4D) loci affect some plant growth traits (e.g. leaf area and spike length). These results have identified a narrow time window within the SEP in which plant growth traits can be manipulated to alter grain yield. This suggests that there may be multiple ways to regulate plant growth during the SEP, to ultimately influence grain number in wheat. PMID- 29723919 TI - Beyond neutrality: disentangling the effects of species sorting and spurious correlations in community analysis. AB - The methods of direct gradient analysis and variation partitioning are the most widely used frameworks to evaluate the contributions of species sorting to metacommunity structure. In many cases, however, species are also driven by spatial processes that are independent of environmental heterogeneity (e.g., neutral dynamics). As such, spatial autocorrelation can occur independently in both species (due to limited dispersal) and the environmental data, leading to spurious correlations between species distributions and the spatialized (i.e., spatially autocorrelated) environment. In these cases, the method of variation partitioning may present high Type I error rates (i.e., reject the null hypothesis more often than the pre-established critical level) and inflated estimates regarding the environmental component that is used to estimate the importance of species sorting. In this paper, we (1) demonstrate that metacommunities driven by neutral dynamics (via limited dispersal) alone or in combination with species sorting leads to inflated estimates and Type I error rates when testing for the importance of species sorting; and (2) propose a general and flexible new variation partitioning procedure to adjust for spurious contributions due to spatial autocorrelation from the environmental fraction. We used simulated metacommunity data driven by pure neutral, pure species sorting, and mixed (i.e., neutral + species sorting dynamics) processes to evaluate the performances of our new methodological framework. We also demonstrate the utility of the proposed framework with an empirical plant dataset in which we show that half of the variation initially due to the environment by the standard variation partitioning framework was due to spurious correlations. PMID- 29723918 TI - Genotyping genome-edited mutations in plants using CRISPR ribonucleoprotein complexes. AB - Despite the great achievements in genome editing, accurately detecting mutations induced by sequence-specific nucleases is still a challenge in plants, especially in polyploidy plants. An efficient detection method is particularly vital when the mutation frequency is low or when a large population needs to be screened. Here, we applied purified CRISPR ribonucleoprotein complexes to cleave PCR products for genome-edited mutation detection in hexaploid wheat and diploid rice. We show that this mutation detection method is more sensitive than Sanger sequencing and more applicable than PCR/RE method without the requirement for restriction enzyme site. We also demonstrate that this detection method is especially useful for genome editing in wheat, because target sites are often surrounded by single nucleotide polymorphisms. Using this screening method, we were also able to detect foreign DNA-free tagw2 mutations induced by purified TALEN protein. Finally, we show that partial base editing mutations can also be detected using high-fidelity SpCas9 variants or FnCpf1. The PCR/RNP method is low cost and widely applicable for rapid detection of genome-edited mutation in plants. PMID- 29723920 TI - Association between hepatitis C infection and cerebro-cardiovascular disease: analysis of a national population-based survey in Egypt. AB - OBJECTIVES: To examine the association between hepatitis C virus (HCV) infection, cardiovascular risk factors and cerebro-cardiovascular (CCV) disease. METHODS: The source of data was the Egypt Health Issues Survey conducted in 2015. Participants were 11 256 individuals with complete HCV testing, age 25-59 years. Data on demographics, cardiovascular risk factors, CCV disease (myocardial infarction and/or cerebral stroke) and HCV infection were retrieved. Descriptive, bivariate, multivariable logistic regression and sensitivity analyses were performed to determine the independent association of past HCV exposure or chronic infection with diabetes, hypertension and CCV disease. RESULTS: 3.9% of participants were antibody positive/RNA negative and considered to have past HCV exposure; 7.9% had detectable HCV-RNA and were considered to have chronic infection. Participants with negative antibodies and no history of liver disease (n = 9928) were the control group. In addition to the previously known risk factors, multivariable analyses revealed that diabetes was independently associated with past HCV exposure (OR = 1.71, 95% CI: 1.27-2.32) and HCV chronic infection (OR = 1.56, 95% CI: 1.23-1.97), whereas CCV disease was independently associated with past exposure (OR = 2.69, 95% CI: 1.62-4.46) and not with chronic infection. No evidence of an association between hypertension and either HCV status was found. CONCLUSION: The association of both past HCV exposure and chronic infection with diabetes and that of past HCV exposure with CCV disease may suggest targeting HCV-positive reactors for preventive and curative programmes addressing extrahepatic complications. PMID- 29723921 TI - De novo belatacept in clinical vascularized composite allotransplantation. AB - Most immunosuppressive regimens used in clinical vascularized composite allotransplantation (VCA) have been calcineurin inhibitor (CNI)-based. As such, most recipients have experienced CNI-related side effects. Costimulation blockade, specifically CD28/B7 inhibition with belatacept, has emerged as a clinical replacement for CNI-based immunosuppression in kidney transplantation. We have previously shown that belatacept can be used as a centerpiece immunosuppressant for VCA in nonhuman primates, and subsequently reported successful conversion from a CNI-based regimen to a belatacept-based regimen after clinical hand transplantation. We now report on the case of a hand transplant recipient, whom we have successfully treated with a de novo belatacept based regimen, transitioned to a CNI-free regimen. This case demonstrates that belatacept can provide sufficient prophylaxis from rejection without chronic CNI associated side effects, a particularly important goal in nonlifesaving solid organ transplants such as VCA. PMID- 29723922 TI - Tumor-infiltrating neutrophils predict prognosis and adjuvant chemotherapeutic benefit in patients with biliary cancer. AB - Tumor-infiltrating neutrophils (TIN) carry out quite significant but opposite functions in different cancers, and their function in biliary cancer has not been fully characterized. To investigate the prognostic significance of TIN in biliary cancer, a training set (n = 118) and a validation set (n = 127) were involved in this study. TIN were evaluated by immunohistochemical staining of CD66b, and then defined as low (neutrophils <18/high-power field [HPF]) vs high (neutrophils >=18/HPF). Kaplan-Meier curve, Cox proportional hazards models and receiver operating characteristic curve were used to assess the prognostic significance. TIN was identified as an independent prognostic factor for overall survival in the training set (HR: 4.720; 95% CI: 2.623-8.493; P < .001) which was confirmed in the validation set (HR: 4.993; 95% CI: 2.626-9.492; P < .001). Notably, among patients with stage III and IV disease, those with low TIN could benefit from adjuvant chemotherapy, with a reduced risk of compromised survival compared with those with high TIN (HR: 0.294; 95% CI: 0.099-0.873; P = .047 in the training set; and HR: 0.100; 95% CI: 0.022-0.462; P = .006 in the validation set). In addition, TIN were negatively related to biological pathways as regulation of activated T-cell proliferation and lymphocyte-mediated immunity, and showed a negative correlation with CD8 + T cells (r = -.324, P < .001). Taken together, our results implicate TIN as an independent marker of prognosis and indicator of patients who would benefit from adjuvant chemotherapy in biliary cancer. PMID- 29723923 TI - A humidifier in the invasive mode during noninvasive respiratory support could increase condensation and thereby impair airway patency. AB - AIM: Humidifying noninvasively ventilated preterm infants is critical to prevent dehydration of respiratory mucosa, but over-humidification can result in impaired airway patency and lung mechanics. This neonatal bench study investigated the humidity delivered using invasive and noninvasive humidification modes during nasal continuous positive airway pressure. METHODS: The study was conducted at the neonatal intensive care unit of Emma Children's Hospital, the Netherlands, in March 2014. A mannequin was connected to a CareFusion Infant Flow SiPAP system, combined with a Fisher & Paykel MR850 humidifier and a Carefusion Infant Flow LP Generator. We measured the temperature, relative humidity and absolute humidity at the humidification chamber's expiratory port and at the patient's mask. RESULTS: The absolute humidity at the mask was 35-40 mg H2 O/L at 38-39 degrees C (relative humidity 74-80%) for the invasive mode of the humidifier and 23-27 mg H2 O/L at 34-35 degrees C (relative humidity 63-70%) for the noninvasive mode. The absolute humidities exceeded the recommended values for the invasive mode of the humidifier, but not the noninvasive mode, and could be associated with increased condensation. CONCLUSION: The absolute humidity delivered by the humidifier in invasive mode could be associated with increased condensation, which has been associated with airway impairment. PMID- 29723924 TI - Cellular immune responses to platelet factor 4 and heparin complexes in patients with heparin-induced thrombocytopenia. AB - : Essentials The immunogenesis of Heparin-induced thrombocytopenia (HIT) is not well understood. Immunization to platelet factor 4 (PF4)-heparin occurs early in life, before any heparin exposure. PF4 and PF4-heparin complexes induce the proliferation of CD14+ cells. Reduced levels of regulatory cytokines contribute to immune dysregulation in HIT. SUMMARY: Background Heparin-induced thrombocytopenia (HIT) is an adverse reaction to heparin characterized by thrombocytopenia and thrombotic complications. HIT is caused by pathogenic antibodies that bind to complexes of platelet factor 4 (PF4) and heparin, leading to platelet activation and inducing a hypercoagulable state. Previous studies have shown immunity to PF4-heparin complexes occurs early in life, even before heparin exposure; however, the immunogenesis of HIT is not well characterized. Objectives To investigate cellular proliferation in response to PF4-heparin complexes in patients with HIT. Patients/Methods Peripheral blood mononuclear cells (PBMCs) from healthy controls (n = 30), postoperative cardiac surgery patients who had undergone cardiopulmonary bypass (CPB) (n = 17) and patients with confirmed HIT (n = 41) were cultured with PF4 and PF4-heparin complexes. Cellular proliferation was assessed by [3 H]thymidine uptake and 5-ethynyl-2' deoxyuridine detection. Results and Conclusions PBMCs proliferated in the presence of PF4, and this was enhanced by the addition of heparin in all study groups. CPB and HIT patients showed significantly greater proliferative responses than healthy controls. PBMC proliferation was antigen-specific, depended on the presence of platelets, and only CD14+ cells were identified as proliferating cells. Culture supernatants were tested for the levels of regulatory cytokines, and both CPB and HIT patients produced significantly lower levels of interleukin 10 and transforming growth factor-beta1 than healthy controls. These findings further demonstrate cellular immune sensitization to PF4-heparin complexes occurs before heparin exposure, and suggests immune dysregulation can contribute to HIT. PMID- 29723925 TI - Neonatologists can impede or support parents' participation in decision-making during medical rounds in neonatal intensive care units. AB - AIM: We explored the dynamics of neonatologist-parent communication and decision making during medical rounds in a level three neonatal intensive care unit. METHODS: This was a qualitative study, with an ethnographic approach, that was conducted at Turku University Hospital, Finland, from 2013 to 2014. We recruited eight mothers and seven couples, their 11 singletons and four sets of twins and two neonatologists and observed and video recorded 15 medical rounds. The infants were born at 23 + 5 to 40 + 1 weeks, and the parents were aged 24-47. The neonatologists and parents were interviewed separately after the rounds. RESULTS: Four patterns of interaction emerged. The collaborative pattern was most consistent, with the ideal of shared decision-making, as the parents' preferences were genuinely and visibly integrated into the treatment decisions. In the neonatologist-led interactional pattern, the decision-making process was only somewhat inclusive of the parents' observations and preferences. The remaining two patterns, emergency and disconnected, were characterised by a paternalistic decision-making model where the parents' observations and preferences had minimal to no influence on the communication or decision-making. CONCLUSION: The neonatologists played a central role in facilitating parental participation and their interaction during medical rounds were characterised by the level of parent participation in decision-making. PMID- 29723926 TI - Variation in Cardiovascular Risk Related to Individual Antimuscarinic Drugs Used to Treat Overactive Bladder: A UK Cohort Study. AB - BACKGROUND: Blocking muscarinic receptors could have an effect on cardiac function, especially among elderly patients with overactive bladder (OAB). STUDY OBJECTIVE: To investigate the risk of cardiovascular (CV) events in users of antimuscarinic drugs to treat OAB. DESIGN, SETTING, AND PARTICIPANTS: Cohort study of new users of darifenacin, fesoterodine, oxybutynin, solifenacin, tolterodine, or trospium, 18 years or older, in the United Kingdom's Clinical Practice Research Datalink (CPRD), 2004-2012. OUTCOME MEASUREMENTS AND MAIN RESULTS: Using tolterodine as the reference, we estimated propensity-score stratified incidence rate ratios (IRRs) for acute myocardial infarction, stroke, CV mortality, major adverse cardiac events (MACE, a combined end point of the previous three), and all-cause death for individual antimuscarinic drugs. The study cohort included 119,912 new users of OAB drugs. The mean age at cohort entry was 62 years, 70% were female, and the mean follow-up was 3.3 years. The adjusted IRR for MACE and current use of oxybutynin compared with current use of tolterodine was 1.14 (95% confidence interval [CI] 1.01-1.30). In contrast, the IRR was 0.65 (CI 0.56-0.76) for current use of solifenacin compared with tolterodine. In this study, performed with health care data, the distribution of risk factors was relatively similar across users of different OAB drugs and, although our analyses controlled for a range of measured potential confounders, residual confounding cannot be ruled out. CONCLUSIONS: In an observational comparative study of users of medications to treat OAB conducted in routine clinical practice, the risk for CV side effects was increased in users of oxybutynin and decreased in users of solifenacin compared with users of tolterodine. PMID- 29723927 TI - Cardiovascular impact of intravenous caffeine in preterm infants. AB - AIM: To evaluate the acute effect of intravenous caffeine on heart rate and blood pressure variability in preterm infants. METHODS: We extracted and compared linear and nonlinear features of heart rate and blood pressure variability at two time points: prior to and in the two hours following a loading dose of 10 mg/kg caffeine base. RESULTS: We studied 31 preterm infants with arterial blood pressure data and 25 with electrocardiogram data, and compared extracted features prior to and following caffeine administration. We observed a reduction in both scaling exponents (alpha1 , alpha2 ) of mean arterial pressure from detrended fluctuation analysis and an increase in the ratio of short- (SD1) and long-term (SD2) variability from Poincare analysis (SD1/SD2). Heart rate variability analyses showed a reduction in alpha1 (mean (SD) of 0.92 (0.21) to 0.86 (0.21), p < 0.01), consistent with increased vagal tone. Following caffeine, beat-to-beat pulse pressure variability (SD) also increased (2.1 (0.64) to 2.5 (0.65) mmHg, p < 0.01). CONCLUSION: This study highlights potential elevation in autonomic nervous system responsiveness following caffeine administration reflected in both heart rate and blood pressure systems. The observed increase in pulse pressure variability may have implications for caffeine administration to infants with potentially impaired cerebral autoregulation. PMID- 29723928 TI - Effect of ABCB1 C3435T Polymorphism on Pharmacokinetics of Antipsychotics and Antidepressants. AB - P-glycoprotein, encoded by ABCB1, is an ATP-dependent drug efflux pump which exports substances outside the cell. Some studies described connections between C3435T polymorphism T allele and lower P-glycoprotein expression; therefore, homozygous T/T could show higher plasma levels. Our aim was to evaluate the effect of C3435T on pharmacokinetics of 4 antipsychotics (olanzapine, quetiapine, risperidone and aripiprazole) and 4 antidepressants (trazodone, sertraline, agomelatine and citalopram). The study included 473 healthy volunteers receiving a single oral dose of one of these drugs, genotyped by real-time PCR. Multivariate analysis was performed to adjust the effect of sex and genotype of the main cytochrome P450 enzymes. C3435T polymorphism had an effect on olanzapine pharmacokinetics, as T/T individuals showed lower clearance and volume of distribution. T/T individuals showed lower T1/2 of 9-OH-risperidone, but this difference disappeared after multivariate correction. T/T homozygous individuals showed lower dehydro-aripiprazole and trazodone area under the concentration-time curve, along with lower half-life and higher clearance of trazodone. C/T genotype was associated to higher citalopram maximum concentration. C3435T had no effect on quetiapine, sertraline or agomelatine pharmacokinetics. C3435T can affect the elimination of some drugs in different ways. Regarding risperidone, trazodone and dehydro-aripiprazole, we observed enhanced elimination while it was reduced in olanzapine and citalopram. However, in quetiapine, aripiprazole, sertraline and agomelatine, no changes were detected. These results suggest that P-glycoprotein polymorphisms could affect CNS drugs disposition, but the genetic factor that alters its activity is still unknown. This fact leads to consider the analysis of ABCB1 haplotypes instead of individual variants. PMID- 29723929 TI - Predicting shifting sustainability trade-offs in marine finfish aquaculture under climate change. AB - Defining sustainability goals is a crucial but difficult task because it often involves the quantification of multiple interrelated and sometimes conflicting components. This complexity may be exacerbated by climate change, which will increase environmental vulnerability in aquaculture and potentially compromise the ability to meet the needs of a growing human population. Here, we developed an approach to inform sustainable aquaculture by quantifying spatio-temporal shifts in critical trade-offs between environmental costs and benefits using the time to reach the commercial size as a possible proxy of economic implications of aquaculture under climate change. Our results indicate that optimizing aquaculture practices by minimizing impact (this study considers as impact a benthic carbon deposition >= 1 g C m-2 day-1 ) will become increasingly difficult under climate change. Moreover, an increasing temperature will produce a poleward shift in sustainability trade-offs. These findings suggest that future sustainable management strategies and plans will need to account for the effects of climate change across scales. Overall, our results highlight the importance of integrating environmental factors in order to sustainably manage critical natural resources under shifting climatic conditions. PMID- 29723930 TI - A new retrospective, multi-evidence veterinary drug screening method using drift tube ion mobility mass spectrometry. AB - RATIONALE: The retrospectivity (the ability to retrospect to a previously unknown compound in raw data) is very meaningful for food safety and risk assessment when facing new emerging drugs. Accurate mass and retention time based screening may lead false positive and false negative results so new retrospective, reliable platform is desirable. METHODS: Different concentration levels of standards with and without matrix were analyzed using ion mobility (IM)-quadrupole-time-of flight (Q-TOF) for collecting retrospective accurate mass, retention time, drift time and tandem MS evidence for identification in a single experiment. The isomer separation ability of IM and the four-dimensional (4D) feature abundance quantification abilities were evaluated for veterinary drugs for the first time. RESULTS: The sensitivity of the IM-Q-TOF workflow was obviously higher than that of the traditional database searching algorithm [find by formula (FbF) function] for Q-TOF. In addition, the IM-Q-TOF workflow contained most of the results from FbF and removed the false positive results. Some isomers were separated by IM and the 4D feature abundance quantitation removed interference with similar accurate mass and showed good linearity. CONCLUSION: A new retrospective, multi-evidence platform was built for veterinary drug screening in a single experiment. The sensitivity was significantly improved and the data can be used for quantification. The platform showed its potential to be used for food safety and risk assessment. PMID- 29723932 TI - Reserve design to optimize the long-term persistence of multiple species. AB - Protected areas form the cornerstone of global efforts to conserve biodiversity. Most current methods for designing reserve networks focus on maximizing the representation of species, but with no assurance that those species will persist in the protected landscapes into the future. We present a new strategy for reserve design that combines metapopulation theory with spatial conservation prioritization to estimate conservation solutions that minimize extinction risk across numerous species simultaneously. Our framework optimizes the spatial configuration of reserves to maximize metapopulation persistence for an entire assemblage of species by accounting for both species representation and landscape connectivity. As a case study, we design a reserve network for 114 terrestrial mammal species in Indonesian New Guinea. Our approach builds on Marxan, the flagship representation-based reserve design tool, improving estimated persistence (metapopulation capacity) by an average of 4.6-fold across species, without increasing the socioeconomic cost. We suggest that enhancing species persistence, rather than protecting arbitrary proportions of species' ranges, should be the ultimate objective of conservation planning. PMID- 29723931 TI - Photosensitizing antihypertensive drug use and risk of cutaneous squamous cell carcinoma. AB - BACKGROUND: Many antihypertensive drugs (ADs) are photosensitizing, heightening reactivity of the skin to sunlight. Photosensitizing ADs have been associated with lip cancer, but whether they impact the risk of cutaneous squamous cell carcinoma (cSCC) is unknown. OBJECTIVES: To examine the association between AD use and cSCC risk among a cohort of non-Hispanic white individuals with hypertension enrolled in a comprehensive integrated healthcare delivery system in northern California (n = 28 357). METHODS: Electronic pharmacy data were used to determine exposure to ADs, which were classified as photosensitizing, nonphotosensitizing or unknown, based on published literature. We identified patients who developed a cSCC during follow-up (n = 3010). We used Cox modelling to estimate adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs). Covariates included age, sex, smoking, comorbidities, history of cSCC and actinic keratosis, survey year, healthcare utilization, length of health plan membership and history of photosensitizing AD use. RESULTS: Compared with nonuse of ADs, risk of cSCC was increased with ever having used photosensitizing ADs (aHR = 1.17, 95% CI 1.07-1.28) and ever having used ADs of unknown photosensitizing potential (aHR = 1.11, 95% CI 1.02-1.20), whereas no association was seen with ever having used nonphotosensitizing ADs (aHR = 0.99; 95% CI 0.91-1.07). Additionally, there was a modest increased risk with an increased number of prescriptions for photosensitizing ADs (aHR = 1.12, 95% CI 1.02-1.24; aHR = 1.19, 95% CI 1.06-1.34; aHR = 1.41, 95% CI 1.20-1.67 for one to seven, eight to 15 and >= 16 fills, respectively). CONCLUSIONS: These findings provide moderate support for an increased cSCC risk among individuals treated with photosensitizing ADs. PMID- 29723933 TI - Handgrip and knee extension strength as predictors of cancer mortality: A systematic review and meta-analysis. AB - The specific role of different strength measures on mortality risk needs to be clarified to gain a better understanding of the clinical importance of different muscle groups, as well as to inform intervention protocols in relation to reducing early mortality. The aim of the systematic review and meta-analysis was to determine the relationship between muscular strength and risk of cancer mortality. Eligible cohort studies were those that examined the association between muscular strength, as assessed using validated tests, and cancer mortality in healthy youth and adults. The hazard ratio (HR) estimates obtained were pooled using random effects meta-analysis models. The outcome was cancer mortality assessed using the HR (Cox proportional hazards model). Eleven prospective studies with 1 309 413 participants were included, and 9787 cancer specific deaths were reported. Overall, greater handgrip (HR = 0.97, 95% CI, 0.92 1.02; P = .055; I2 = 18.9%) and knee extension strength (HR = 0.98, 95% CI, 0.95 1.00; P = .051; I2 = 60.6%) were barely significant associated with reduced risk of cancer mortality. Our study suggests that higher level of muscular strength is not statistically associated with lower risk of cancer mortality. PMID- 29723934 TI - Multifaceted Pharmacist-led Interventions in the Hospital Setting: A Systematic Review. AB - Clinical pharmacy services often comprise complex interventions. In this MiniReview, we conducted a systematic review aiming to evaluate the impact of multifaceted pharmacist-led interventions in a hospital setting. We searched MEDLINE, Embase, Cochrane Library and CINAHL for peer-reviewed articles published from 2006 to 1 March 2018. Controlled trials concerning hospitalized patients in any setting receiving patient-related multifaceted pharmacist-led interventions were considered. All types of outcome were accepted. Inclusion and data extraction were performed. Study characteristics were collected, and risk of bias assessment was conducted utilizing the Cochrane Risk of Bias tools. All stages were conducted by at least two independent reviewers. The review was registered in PROSPERO (CRD42017075808). A total of 11,896 publications were identified, and 28 publications were included. Of these, 17 were conducted in Europe. Six of the included publications were multi-centre studies, and 16 were randomized trials. Usual care was the comparator. Significant results on quality of medication use were reported as positive in eleven studies (n = 18; 61%) and negative in one (n = 18, 6%). Hospital visits were reduced significantly in seven studies (n = 16; 44%). Four studies (n = 12; 33%) reported a positive significant effect on either length of stay or time to revisit, and one study reported a negative effect (n = 12; 6%). All studies investigating mortality (n = 6), patient-reported outcome (n = 7) and cost-effectiveness (n = 1) showed no significant results. This MiniReview indicates that multifaceted pharmacist-led interventions in a hospital setting may improve the quality of medication use and reduce hospital visits and length of stay, while no effect was seen on mortality, patient-reported outcome and cost-effectiveness. PMID- 29723935 TI - A systematic review and Bayesian network meta-analysis of risk of intracranial hemorrhage with direct oral anticoagulants. AB - : Essentials Risk of intracranial hemorrhage (ICH) may differ between direct oral anticoagulants (DOACs). We compared the risk of ICH between DOACs using network meta-analysis. Dabigatran 110 mg and 150 mg were safer than rivaroxaban on Bayesian analysis. Dabigatran 110 mg ranked as the safest DOAC while rivaroxaban ranked last. SUMMARY: Background The comparative risk of intracranial hemorrhage (ICH) among direct oral anticoagulants (DOACs) (dabigatran, rivaroxaban, apixaban and edoxaban) remains unclear. Objective To determine the difference in risk of ICH between DOACs Methods Seventeen randomized controlled trials (RCTs) were selected using PubMed/MEDLINE, EMBASE and CENTRAL (Inception, 31 December 2017). Estimates were reported as odds ratio (OR) with 95% credible interval (CR.I) in Bayesian network meta-analysis (NMA), and OR with 95% confidence interval (CI) in traditional meta-analyses. Relative ranking probability of each group was generated based on surface under the cumulative ranking curve (SUCRA). Results In NMA of 116 618 patients from 17 RCTs (apixaban = 19 495 patients, rivaroxaban = 14 157 patients, dabigatran = 16 074 patients, edoxaban = 11 652 patients, and comparator = 55 315 patients), all DOACs were safer than warfarin for risk of ICH. Dabigatran 110 mg ranked as the safest drug (SUCRA, 0.85) and reduced the risk of ICH by 56% compared to rivaroxaban (OR, 0.44; 95% Cr.I, 0.22-0.82). Pairwise meta-analysis validated these findings, showing that DOACs were safer than warfarin (OR, 0.46; 95% CI, 0.35-0.59). Subgroup analysis showed that the benefit was present when DOACs were used in non-valvular atrial fibrillation (NVAF) (OR, 0.51; 95% CI, 0.38-0.68) or venous thromboembolism (VTE) (OR, 0.32; 95% CI, 0.18-0.58). Conclusion Dabigatran 110 mg may be the safest choice among any anticoagulant regarding risk of ICH. Both dabigatran 110 mg and 150 mg were safer than rivaroxaban. PMID- 29723936 TI - [Latex-papaya syndrome: an infrequent association]. AB - BACKGROUND: Latex-fruit syndrome (LFS) is characterized by allergy to latex and plants. Papain, chymopapain, caricaine and class I chitinases are papaya's most allergenic proteins. The similarity between latex hevein epitopes and papaya class I chitinases might explain the latex-papaya syndrome (LPS). OBJECTIVE: To describe the clinical characteristics of patients with LPS. METHODS: Cross sectional, observational, descriptive study where 11 patients diagnosed with latex allergy by skin prick test and clinically diagnosed with papaya-induced anaphylaxis were included. The results were analyzed with descriptive statistics. RESULTS: Out of 11 patients with LPS, 72.7% were females (7 to 46 years), all with a history of papaya-induced anaphylaxis, identified by medical history and medical notes plus latex-positive skin prick tests, with 63.3% exhibiting anaphylaxis in the skin prick tests. Risk factors included multiple surgeries, another allergic disease, and being employed in the field of health; 63.6% were allergic to to other foods, 45.4% to medications, 45.4% had allergic rhinitis and 27.3% had asthma. CONCLUSIONS: Hypersensitivity to papaya increases the risk of anaphylaxis in patients with latex allergy and, therefore, mortality. Clinical data is the main diagnostic tool. Education for the management of anaphylaxis with adrenaline self-administration is essential. PMID- 29723937 TI - [Latex allergy self-report in medical students: prevalence and associated factors]. AB - BACKGROUND: Prevalence of latex allergy in medical students is not known. OBJECTIVE: To determine the prevalence of self-reported latex allergy and associated factors in medical students. METHODS: Cross-sectional, analytical study of students with or without self-reported latex allergy. By means of a structured questionnaire, past personal and family history of allergic disease, time and frequency of exposure to latex gloves and symptoms after exposure to products or foods associated with latex allergy were inquired. Logistic regression models were carried out. RESULTS: Out of 854 subjects, 431 (50.5%) were females. Median age was 21 years. Overall prevalence of latex allergy was 4.3% (95% CI = 3.1 to 5.9). Associated risk factors were age (OR = 1.37; 95% CI = 1.05 to 1.79), personal history of atopic dermatitis (OR = 7.32; 95% CI = 3.14 to 17.08), use of gloves >= 15/week (OR = 2.59; 95% CI = 1.17 to 5.76), use of latex products (OR = 5.76; 95% CI = 2.15 to 15.49) and fruit allergy (OR = 3.24; 95% CI = 1.27 t o8.27). CONCLUSION: Four out of a hundred students reported latex allergy. Age, personal history of atopic dermatitis, higher frequency of exposure to latex gloves and history of fruit allergy were risk factors for self-report latex allergy. PMID- 29723938 TI - [Prevalence of sensitization and allergy to kiwi fruit (Actinidia deliciosa) in adults with allergic diseases]. AB - BACKGROUND: The kiwi fruit (Actinidia deliciosa) is a food that has been recognized for its allergenic capability for more than 30 years. In general, kiwi allergy is characterized by local discomfort, but systemic reactions such as rash, angioedema, rhinitis, conjunctivitis or anaphylaxis can be triggered. OBJECTIVE: To determine the prevalence of sensitization and allergy to kiwi in adults with allergic diseases. METHODS: By means of a cross-sectional, retrolective study, data corresponding to 370 patients aged >=16 years were analyzed. RESULTS: 226 patients had positive skin reaction against aeroallergens. The prevalence of food sensitization was 84/226 (37.2%; 95 % CI = 31.1 to 43.6). Overall, the prevalence of sensitization to kiwi fruit was 15/226 (6.6%; 95% CI = 3.9 to 10.7), and of kiwi allergy, 2/15 (13.3%; 95% CI = 2.5 to 39.1); one patient had symptoms consistent with oral allergy syndrome, and another, gastrointestinal and cutaneous manifestations. CONCLUSION: The prevalence of sensitization to kiwi fruit is not a rare event; in contrast, symptoms related to its consumption are uncommon. PMID- 29723939 TI - [Allergen extracts for immunotherapy in Latin America]. AB - BACKGROUND: The Latin American Society of Allergy, Asthma, and Immunology (SLAAI) presents a document about the use of immunotherapy (IT) in Latin America, where administration patterns, indications and contraindications, effects on health, adverse events and socioeconomic impact are reviewed. OBJECTIVE: To review publications analyzing the use of IT in Latin America. METHODS: A literature review was carried out in order to identify works addressing IT in Latin America. This review was focused on practical scientific information available on IT in the region, and a parallel comparison was made with practices observed in the United States and European countries. RESULTS: Of the 21 Latin American countries included, only 9 had original articles meeting the selection criteria; a total of 82 articles were selected, most of them from Brazil and Mexico. Most widely used allergenic extracts in Latin America tropical and subtropical regions were those of mites and pollen. CONCLUSION: Although it is true that there are huge challenges for the future of IT in Latin America, studies on subcutaneous IT and sublingual IT are increasing, but most of them are retrospective and some have design bias, and more prospective studies are therefore required, using internationally validated scales for clinical evaluation. PMID- 29723940 TI - [Intradermal immunotherapy with low-dose house dust mite allergens in patients with allergic rhinitis: A proof-of-concept study]. AB - BACKGROUND: High-dose aqueous subcutaneous immunotherapy is a validated and effective administration route for house dust mite and pollen allergens. OBJECTIVE: A proof-of-concept study using intradermal immunotherapy (IDIT) with low-dose house dust mite allergens (Dermatophagoides pteronyssinnus/Dermatophagoides farinae [Dp/Df] and Blomia tropicalis [Bt]) was carried out in children with allergic rhinitis symptomatic upon exposure to house dust. METHODS: Eight immunotherapy-naive patients with positive prick skin tests and specific serum IgE to a Dp/Df mixture and to Bt were weekly administered 0.05 mL of an IDIT consisting of a phenolyzed albumin-saline preparation containing low-dose dust mites (8.3 AU [5 ng] of Dp/Df and 2.5 DBU of Bt), for 3 months. Nasal (Total Nasal Symptom Score) and facial symptoms (Visual Analog Scale) were recorded 2 weeks prior to treatment and once weekly during its course. Serial dilutions skin prick tests (1/100-1/1.000.000) and serum allergen-specific IgG4 determinations were performed at baseline and at treatment conclusion. RESULTS: Values on the scales suggested clinical improvement. There was a significant decrease in serial dilutions skin prick tests' wheal diameters, as well as an increase in serum IgG4 values at treatment completion. IDIT was well tolerated. CONCLUSION: If the present results are confirmed by further studies, allergen specific immunotherapy wider use could be promoted. PMID- 29723941 TI - [Characterization of children younger than five years with suspected allergic diseases]. AB - BACKGROUND: Symptoms of allergic diseases are a common cause of consultation during childhood. OBJECTIVE: To describe the profile of a population of Colombian preschool children seen in an allergology department and assess possible risk factors. METHODS: Descriptive, cross-sectional study of patients younger than 5 years who were assessed for one year. A complete medical history was obtained and allergology workup was carried out with skin prick tests as appropriate for each case. Risk factors were assessed by means of multivariate analysis. RESULTS: A total of 674 patients were included, out of which 382 (52.7%) were males. Median age was 34 months. The reasons for consultation were cough or recurrent wheezing (54.3%), rhinitis (48.7%), and eczema (32.2%). Skin prick tests were performed with aeroallergens in 299 patients (48%) and with food in 170 (27%), with positivity being found in 114 (38%) and 16 (9.4%), respectively. Main sensitizers were dust mites and egg. A direct association was found between eczema and prematurity (OR = 0.496; 95 % CI = 0.289-0.823)], between recurrent cough/wheezing and family history of allergy (OR = 1.837; 95 % CI = 1,306-2,586), and between recurrent cough/wheezing and history of bronchiolitis (OR = 2.646; 95 % CI = 1.812-3.886). CONCLUSION: Respiratory symptoms represented the main cause of consultation. Dust mites were the most commonly identified allergens. Family history of allergy and bronchiolitis. PMID- 29723942 TI - [Antioxidant vitamins in asthma]. AB - Asthma is a condition of unknown etiology characterized by chronic airway inflammation. Cells that mediate the inflammatory response generate reactive oxygen species that, together with other respiratory tract naturally-occurring oxidant species, produce a rupture of the redox balance, generating oxidative stress. It has been proposed that oxidative stress can be reverted by supplemental or dietary intake of antioxidant vitamins such as vitamin A, C, D and E, and this way relieve, improve or protect people with asthma. In this research, observational and placebo-controlled trials with regard to the role of antioxidant vitamins in the course of asthma, published between 1979 and 2016, were reviewed. The search engines were Google and Google Scholar, whereas consulted databases were PubMed and The Cochrane Library. There were 75 articles relevant to the subject that were found and reviewed, and it was concluded that it is not clear if the intake of supplements of these vitamins has any beneficial clinical effect on asthma control. Further controlled, longer trials are needed to elucidate the role of these nutrients in the course of asthma. PMID- 29723943 TI - [Aspirin-exacerbated respiratory disease. Case-based review]. AB - Aspirin-exacerbated respiratory disease comprises a series of signs and symptoms mainly involving the upper and lower posterior airway after the consumption of cyclooxygenase enzyme inhibitors. Adverse reactions that occur are not considered to be an allergy and are common to all non-steroidal anti-inflammatory drugs, and cross-reactivity between these agents is therefore common. The description of 3 clinical cases serves to review key aspects of this condition, such as epidemiology, pathophysiology, clinical manifestations, diagnosis and management. Adequate diagnosis and education on the use or elimination of all different NSAIDs is essential, as well as availability of different analgesic options, verified with challenge tests. Aspirin-exacerbated respiratory disease management includes surgical procedures for nasal polyp control, pharmacological treatment for asthma control and desensitization with aspirin in selected individuals. PMID- 29723944 TI - [The importance of clinical case reports in research]. AB - Clinical case reports correspond to articles that have the lowest level of evidence within different research trials. However, not only are they common and significant in the medical field, but they have often been the basis the generation of research. The purpose of their publication can be scientific or educational. In general terms, the discovery of new diseases, the presentation of rare diseases, unusual forms of common diseases, the complications of a common treatment, or the effect (beneficial or adverse) of a treatment, among other things, are narrated in these documents. Clinical case reports continue to be one of the most important sources of knowledge. The advent of a standardized guideline for the creation of this type of reports allows homogenizing the form and content of the cases intended to be described in the near future and, furthermore, will enable authors to have a reference when preparing this type of publications. Case reports are valuable resources of new and unusual information that can encourage and serve to conduct future research studies with a higher level of evidence. PMID- 29723945 TI - [Are natural analgesic products safe in patients with allergy to non-steroidal anti-inflammatory drugs?] AB - BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAID)-induced hypersensitivity reactions can be clinically apparent with asthma, rhinosinusitis, anaphylaxis or rash. Although natural anti-inflammatory products can have similar components, they are not subjected to rigorous quality control standards. CASE REPORT: The case is presented of a 22-year-old female with NSAID allergy who attended with facial and laryngeal angioedema associated with pruritus in eyelids and pharynx. She developed these symptoms fifteen minutes after taking an over-the-counter (OTC) natural anti-inflammatory product. She received treatment with epinephrine, antihistamines and corticosteroids. CONCLUSION: Different natural anti inflammatory products are freely available both OTC and online. Some contain dangerous substances that can cause important, and even lethal. side effects. Allergologists, dermatologists and general practitioners should be able to recognize that the consumption of these products, which is widely spread, can cause angioedema. PMID- 29723946 TI - [Plantago psyllium-secondary anaphylaxis. Case report]. AB - BACKGROUND: Psyllium is a derivative of Plantago ovata ground seed and husk that is used as bulk-forming laxatives owing to its hydrocolloid properties. CASE REPORT: 43-year-old female nurse with previous diagnosis of drug allergy and allergic rhinitis who, after the preparation and administration of a laxative, developed rhinoconjunctivitis symptoms, urticarial syndrome, angioedema and bronchospasm, which led to conclude that she had an anaphylactic reaction. She was treated with adrenaline, corticosteroids and antihistamines. After symptom resolution, with in vivo tests by means of the skin prick technique and by in vitro assay (specific IgE), hypersensitivity to plantago psyllium was determined. DISCUSSION: Most cases of anaphylaxis have been reported with psyllium ingestion, since, through that route, antigenic burden is higher. It should be noted that, even when exposure in the described patient was only by inhalation, manifestations were life-threatening. PMID- 29723947 TI - [Identification of new mutations in TCIRG1 as a cause of infantile malignant osteopetrosis in two Mexican patients]. AB - BACKGROUND: Osteopetrosis is a heterogeneous group of diseases that are characterized by increased bone density due to abnormalities in osteoclast differentiation or function, which result in a lack of bone resorption. CASE REPORTS: Two patients with osteopetrosis onset since the first months of life, with facial dysmorphia, blindness, deafness, hepatosplenomegaly, hypotonia, neurodevelopmental retardation and bicytopenia. Bone radiographs showed osteosclerosis. They were assessed by different specialists prior to definitive diagnosis. Genetic analysis determined mutations in the TCIRG1 gene. Patient 1 had a homozygous mutation for p.Ile720Alafs*14 identified, which hasn't been previously reported. Patient 2 had a compound heterozygous mutation: the first one, p.Phe459Leufs*79, and the second one, p.Gly159Argfs*68, none of which has been previously reported as far as we know. CONCLUSION: The only therapeutic option for patients with osteopetrosis is hematopoietic stem cell transplantation (HSCT), which should be carried out in the course of the first 3 months of life, before neurological damage occurs. Although osteopetrosis diagnosis is relatively simple, it is delayed owing to the lack of clinical suspicion. PMID- 29723949 TI - The Outdated Thinking That Drove the Dis-Impaction of the Journal Impact Factor. PMID- 29723948 TI - Characterization of engineered nanoparticles in commercially available spray disinfectant products advertised to contain colloidal silver. AB - Given the potential for human exposure to silver nanoparticles from spray disinfectants and dietary supplements, we characterized the silver-containing nanoparticles in 22 commercial products that advertised the use of silver or colloidal silver as the active ingredient. Characterization parameters included: total silver, fractionated silver (particulate and dissolved), primary particle size distribution, hydrodynamic diameter, particle number, and plasmon resonance absorbance. A high degree of variability between claimed and measured values for total silver was observed. Only 7 of the products showed total silver concentrations within 20% of their nominally reported values. In addition, significant variations in the relative percentages of particulate vs. soluble silver were also measured in many of these products reporting to be colloidal. Primary silver particle size distributions by transmission electron microscopy (TEM) showed two populations of particles - smaller particles (<5nm) and larger particles between 20 and 40nm. Hydrodynamic diameter measurements using nanoparticle tracking analysis (NTA) correlated well with TEM analysis for the larger particles. Z-average (Z-Avg) values measured using dynamic light scattering (DLS); however, were typically larger than both NTA or TEM particle diameters. Plasmon resonance absorbance signatures (peak absorbance at around 400nm indicative of metallic silver nanoparticles) were only noted in 4 of the 9 yellow-brown colored suspensions. Although the total silver concentrations were variable among products, ranging from 0.54mg/L to 960mg/L, silver containing nanoparticles were identified in all of the product suspensions by TEM. PMID- 29723950 TI - Use of a Contralateral Nasoseptal Flap for Sino-Orbital Fistula Closure. AB - Sino-orbital fistulas can occur after orbital exenteration. Chronic nonhealing fistulas lead to bothersome symptoms including malodorous discharge, hypernasal speech, crusting, wound breakdown, or inability to wear an ocular prosthesis. Reconstruction can be difficult due to the complexity of the defects and the multitude of treatments patients often undergo for the management of the primary disease. Prior radiation, lack of available local tissue, or compromised blood supply are some of the issues that make successful fistula closure problematic. This report describes a method for autologous vascularized tissue coverage using a contralateral nasoseptal flap to successfully close a sino-orbital fistula. PMID- 29723951 TI - Pharmacological Cyclophilin Inhibitors Prevent Intoxication of Mammalian Cells with Bordetella pertussis Toxin. AB - The Bordetella pertussis toxin (PT) is one important virulence factor causing the severe childhood disease whooping cough which still accounted for approximately 63,000 deaths worldwide in children in 2013. PT consists of PTS1, the enzymatically active (A) subunit and a non-covalently linked pentameric binding/transport (B) subunit. After endocytosis, PT takes a retrograde route to the endoplasmic reticulum (ER), where PTS1 is released into the cytosol. In the cytosol, PTS1 ADP-ribosylates inhibitory alpha subunits of trimeric GTP-binding proteins (Giα) leading to increased cAMP levels and disturbed signalling. Here, we show that the cyclophilin (Cyp) isoforms CypA and Cyp40 directly interact with PTS1 in vitro and that Cyp inhibitors cyclosporine A (CsA) and its tailored non-immunosuppressive derivative VK112 both inhibit intoxication of CHO K1 cells with PT, as analysed in a morphology-based assay. Moreover, in cells treated with PT in the presence of CsA, the amount of ADP-ribosylated Giα was significantly reduced and less PTS1 was detected in the cytosol compared to cells treated with PT only. The results suggest that the uptake of PTS1 into the cytosol requires Cyps. Therefore, CsA/VK112 represent promising candidates for novel therapeutic strategies acting on the toxin level to prevent the severe, life-threatening symptoms caused by PT. PMID- 29723953 TI - Effect of DS Concentration on the PRO Performance Using a 5-Inch Scale Cellulose Triacetate-Based Hollow Fiber Membrane Module. AB - In this study, pressure-retarded osmosis (PRO) performance of a 5-inch scale cellulose triacetate (CTA)-based hollow fiber (HF) membrane module was evaluated under a wide range of operating conditions (0.0-6.0 MPa of applied pressure, 0.5 2.0 L/min feed solution (FS) inlet flow rate, 1.0-6.0 L/min DS inlet flow rate and 0.1-0.9 M draw solution (DS) concentration) by using a PRO/reverse osmosis (RO) hybrid system. The subsequent RO system for DS regeneration enabled the evaluation of the steady-stated module performance. In the case of pilot-scale module operation, since the DS dilution and the feed solution (FS) up concentration had occurred and was not negligible, unlike the lab-scale experiment, PRO performance strongly depended on operating conditions such as inlet flow rates of both the DS and FS concentration. To compare the module performance with different configurations, we proposed a converted parameter in which a difference of the packing density between the spiral wound (SW) and the HF module was fairly considered. In the case of HF configuration, because of high packing density, volumetric-based performance was higher than that of SW module, that is, the required number of the module would be less than that of SW module in a full-scale PRO plant. PMID- 29723954 TI - Endovascular Interventions for the Morbidly Adherent Placenta. AB - Morbidly adherent placentas are a spectrum of abnormalities ranging from placental invasion of the myometrium to invasion past the myometrium and muscular layers into adjacent structures. This entity is becoming more prevalent recently with increased number of cesarean deliveries. Given the high risk of morbidity and mortality, this was traditionally treated with pre-term planned cesarean hysterectomy. However, recently, uterine preservation techniques have been implemented for those women wishing to preserve future fertility or their uterus. Early identification is crucial as studies have shown better outcomes for women treated at tertiary care facilities by a dedicated multidisciplinary team. Interventional radiologists are frequently included in the care of these patients as there are several different endovascular techniques which can be implemented to decrease morbidity in these patients both in conjunction with cesarean hysterectomy and in the setting of uterine preservation. This article will review the spectrum of morbidly adherent placentas, imaging, as well as the surgical and endovascular interventions implemented in the care of these complex patients. PMID- 29723952 TI - Why is Skeletal Muscle Regeneration Impaired after Myonecrosis Induced by Viperid Snake Venoms? AB - Skeletal muscle regeneration after myonecrosis involves the activation, proliferation and fusion of myogenic cells, and a coordinated inflammatory response encompassing phagocytosis of necrotic cell debris, and the concerted synthesis of cytokines and growth factors. Myonecrosis often occurs in snakebite envenomings. In the case of venoms that cause myotoxicity without affecting the vasculature, such as those of many elapid snakes, regeneration proceeds successfully. In contrast, in envenomings by most viperid snakes, which affect the vasculature and extracellular matrix in addition to muscle fibers, regeneration is largely impaired and, therefore, the muscle mass is reduced and replaced by fibro-adipose tissue. This review discusses possible causes for such poor regenerative outcome including: (a) damage to muscle microvasculature, which causes tissue hypoxia and affects the inflammatory response and the timely removal of necrotic tissue; (b) damage to intramuscular nerves, which results in atrophy of regenerating fibers; (c) degradation of muscle cell basement membrane, compromising the spatial niche for proliferating myoblasts; (d) widespread degradation of the extracellular matrix; and (e) persistence of venom components in the damaged tissue, which may affect myogenic cells at critical points in the regenerative process. Understanding the causes of poor muscle regeneration may pave the way for the development of novel therapeutic interventions aimed at fostering the regenerative process in envenomed patients. PMID- 29723956 TI - Molecular Sex Identification in Dioecious Hippophae rhamnoides L. via RAPD and SCAR Markers. AB - The dioecious property of the sea buckthorn (Hippophae rhamnoides L.) prevents sex recognition via traditional observation at the juvenile stage, thus impeding breeding and economic cropping; A random amplified polymorphic DNA (RAPD) and a sequence characterized amplified region (SCAR) markers were used to identify the sexes. A total of 45 random decamer primers were used to screen genomic DNA pools of staminate and pistillate genotypes for genetic polymorphisms. One female sex linked marker was identified. D15 (5′-CATCCGTGCT-3′) amplified a particular band of 885 bp, which showed polymorphism among staminate and pistillate genotype plants. The SCAR marker Hrcx-15 was obtained by sequencing the fragment. The alleles of 140 pistillate genotypes were examined but not of the 140 staminate genotypes discerned via taxonomy. Staminate and pistillate genotypes of sea buckthorn plants can be distinguished, using Hrcx-15 as a genetic marker for sex identification and for expediting cultivation for commercial applications. PMID- 29723955 TI - The Methylome of Vertebrate Sex Chromosomes. AB - DNA methylation is a key epigenetic modification in vertebrate genomes known to be involved in the regulation of gene expression, X chromosome inactivation, genomic imprinting, chromatin structure, and control of transposable elements. DNA methylation is common to all eukaryote genomes, but we still lack a complete understanding of the variation in DNA methylation patterns on sex chromosomes and between the sexes in diverse species. To better understand sex chromosome DNA methylation patterns between different amniote vertebrates, we review literature that has analyzed the genome-wide distribution of DNA methylation in mammals and birds. In each system, we focus on DNA methylation patterns on the autosomes versus the sex chromosomes. PMID- 29723957 TI - Maternal Educational Attainment at Birth Promotes Future Self-Rated Health of White but Not Black Youth: A 15-Year Cohort of a National Sample. AB - BACKGROUND: Socioeconomic status (SES) is essential for maintaining health, and self-rated health (SRH) is not an exception to this rule. This study explored racial differences in the protective effects of maternal educational attainment at birth against poor SRH of the youth 15 years later. METHODS: Using data from the Fragile Families and Child Wellbeing Study (FFCWS), this 15-year longitudinal study followed 1934 youths from birth to age 15. This sample was composed of White (n = 497, 25.7%), and Black (n = 1437, 74.3%) youths. The independent variable was maternal educational attainment at birth. SRH at age 15 was the dependent variable. Family structure was the covariate. Race was the focal moderator. We ran logistic regression models in the pooled sample, as well as stratified models based on race. RESULTS: In the pooled sample, maternal educational attainment and family structure were not predictive of SRH for the youths at age 15. Race interacted with maternal educational attainment, indicating a stronger association between maternal educational attainment at birth on youth SRH for Whites compared to Blacks. In race stratified models, maternal educational attainment at birth was protective against poor SRH for White but not Black youths. CONCLUSION: White but not Black youths gain less SRH from their maternal educational attainment. Enhancing education attainment may not have identical effects across racial groups. The health status of Blacks may be less responsive to improvements in maternal educational attainment. Policies should go beyond investing in educational attainment by empowering Black families to better use the educational attainment that they gain. Policies and programs should reduce the costs of upward social mobility for minority families. PMID- 29723958 TI - The Vast Complexity of the Epigenetic Landscape during Neurodevelopment: An Open Frame to Understanding Brain Function. AB - Development is a well-defined stage-to-stage process that allows the coordination and maintenance of the structure and function of cells and their progenitors, in a complete organism embedded in an environment that, in turn, will shape cellular responses to external stimuli. Epigenetic mechanisms comprise a group of process that regulate genetic expression without changing the DNA sequence, and they contribute to the necessary plasticity of individuals to face a constantly changing medium. These mechanisms act in conjunction with genetic pools and their correct interactions will be crucial to zygote formation, embryo development, and brain tissue organization. In this work, we will summarize the main findings related to DNA methylation and histone modifications in embryonic stem cells and throughout early development phases. Furthermore, we will critically outline some key observations on how epigenetic mechanisms influence the rest of the developmental process and how long its footprint is extended from fecundation to adulthood.